PMID- 26600972 TI - Magnetic resonance imaging biomarkers of gastrointestinal motor function and fluid distribution. AB - Magnetic resonance imaging (MRI) is a well established technique that has revolutionized diagnostic radiology. Until recently, the impact that MRI has had in the assessment of gastrointestinal motor function and bowel fluid distribution in health and in disease has been more limited, despite the novel insights that MRI can provide along the entire gastrointestinal tract. MRI biomarkers include intestinal motility indices, small bowel water content and whole gut transit time. The present review discusses new developments and applications of MRI in the upper gastrointestinal tract, the small bowel and the colon reported in the literature in the last 5 years. PMID- 26600973 TI - Eosinophilic esophagitis: From pathophysiology to treatment. AB - Eosinophilic esophagitis (EoE) is a chronic immune disease, characterized by a dense eosinophilic infiltrate in the esophagus, leading to bolus impaction and reflux-like symptoms. Traditionally considered a pediatric disease, the number of adult patients with EoE is continuously increasing, with a relatively higher incidence in western countries. Dysphagia and food impaction represent the main symptoms complained by patients, but gastroesophageal reflux-like symptoms may also be present. Esophageal biopsies are mandatory for the diagnosis of EoE, though clinical manifestations and proton pump inhibitors responsiveness must be taken into consideration. The higher prevalence of EoE in patients suffering from atopic diseases suggests a common background with allergy, however both the etiology and pathophysiology are not completely understood. Elimination diets are considered the first-line therapy in children, but this approach appears less effective in adults patients, who often require steroids; despite medical treatments, EoE is complicated in some cases by esophageal stricture and stenosis, that require additional endoscopic treatments. This review summarizes the evidence on EoE pathophysiology and illustrates the safety and efficacy of the most recent medical and endoscopic treatments. PMID- 26600974 TI - Host-microbiome interaction in Crohn's disease: A familiar or familial issue? AB - An impaired interaction between the gut and the intestinal microbiome is likely to be the key element in the pathogenesis of Crohn's disease (CD). Family studies have provided invaluable information on CD pathogenesis and on its etiology. Relatives share the same genetic risk of developing the disease as affected subjects. Relatives also exhibit similar features relating to their host microbiome interaction, namely genetic variants in loci involved in detecting bacteria, a greater sero-reactivity to microbial components, and an impaired intestinal permeability. The burden of environmental factors such as cigarette smoking and dysbiosis also seems to be particularly relevant in these genetically predisposed subjects. Diet is emerging as an important factor and could account for the changing epidemiology of CD in recent years. Despite the pivotal role of genetics in the disease's pathogenesis (especially in familial CD), screening tests in healthy relatives cannot be recommended. PMID- 26600975 TI - Gastrointestinal dysbiosis and the use of fecal microbial transplantation in Clostridium difficile infection. AB - The impact of antibiotics on the human gut microbiota is a significant concern. Antibiotic-associated diarrhea has been on the rise for the past few decades with the increasing usage of antibiotics. Clostridium difficile infections (CDI) have become one of the most prominent types of infectious diarrheal disease, with dramatically increased incidence in both the hospital and community setting worldwide. Studies show that variability in the innate host response may in part impact upon CDI severity in patients. That being said, CDI is a disease that shows the most prominent links to alterations to the gut microbiota, in both cause and treatment. With recurrence rates still relatively high, it is important to explore alternative therapies to CDI. Fecal microbiota transplantation (FMT) and other types of bacteriotherapy have become exciting avenues of treatment for CDI. Recent clinical trials have generated excitement for the use of FMT as a therapeutic option for CDI; however, the exact components of the human gut microbiota needed for protection against CDI have remained elusive. Additional investigations on the effects of antibiotics on the human gut microbiota and subsequent CDI will help reduce the socioeconomic burden of CDI and potentially lead to new therapeutic modalities. PMID- 26600976 TI - Lymphoproliferative disorders in inflammatory bowel disease patients on immunosuppression: Lessons from other inflammatory disorders. AB - Immunosuppressive agents, such as thiopurines, methotrexate, and biologics, have revolutionized the treatment of inflammatory bowel disease (IBD). However, a number of case reports, case control studies and retrospective studies over the last decade have identified a concerning link between immunosuppression and lymphoproliferative disorders (LPDs), the oncological phenomenon whereby lymphocytes divide uncontrollably. These LPDs have been associated with Epstein Barr virus (EBV) infection in which the virus provides the impetus for malignant transformation while immunosuppression hampers the immune system's ability to detect and clear these malignant cells. As such, the use of immunosuppressive agents may come at the cost of increased risk of developing LPD. While little is known about the LPD risk in IBD, more is known about immunosuppression in the post-transplantation setting and the development of EBV associated post transplantation lymphoproliferative disorders (PTLD). In review of the PTLD literature, evidence is available to demonstrate that certain immune suppressants such as cyclosporine and T-lymphocyte modulators in particular are associated with an increased risk of PTLD development. As well, high doses of immunosuppressive agents and multiple immunosuppressive agent use are also linked to increased PTLD development. Here, we discuss these findings in context of IBD and what future studies can be taken to understand and reduce the risk of EBV associated LPD development from immunosuppression use in IBD. PMID- 26600977 TI - Current understanding of the neuropathophysiology of pain in chronic pancreatitis. AB - Chronic pancreatitis (CP) is a chronic inflammatory disease of the pancreas. The main symptom of patients with CP is chronic and severe abdominal pain. However, the pathophysiology of pain in CP remains obscure. Traditionally, researchers believed that the pain was caused by anatomical changes in pancreatic structure. However, treatment outcomes based on such beliefs are considered unsatisfactory. The emerging explanations of pain in CP are trending toward neurobiological theories. This article aims to review current evidence regarding the neuropathophysiology of pain in CP and its potential implications for the development of new treatments for pain in CP. PMID- 26600978 TI - Faecal calprotectin: Management in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is a chronic and relapsing disorder which leads to an inflammation of the gastrointestinal tract. A tailored therapy to achieve mucosal healing with the less adverse events has become a key issue in the management of IBD. In the past, the clinical remission was the most important factor to consider for adapting diagnostic procedures and therapeutic strategies. However, there is no a good correlation between symptoms and intestinal lesions, so currently the goals of treatment are to achieve not only the control of symptoms, but deep remission, which is related with a favourable prognosis. Thus, the determination of biological markers or biomarkers of intestinal inflammation play a crucial role. Many biomarkers have been extensively evaluated in IBD showing significant correlation with endoscopic lesions, risk of recurrence and response to treatment. One of the most important markers is faecal calprotectin (FC). Despite calprotectin limitations, this biomarker represents a reliable and noninvasive alternative to reduce the need for endoscopic procedures. FC has demonstrated its performance for regular monitoring of IBD patients, not only to the diagnosis for discriminating IBD from non-IBD diagnosis, but for assessing disease activity, relapse prediction and response to therapy. Although, FC provides better results than other biomarkers such as C-reactive protein and erythrocyte sedimentation rate, these surrogate markers of intestinal inflammation should not be used isolation but in combination with other clinical, endoscopic, radiological or/and histological parameters enabling a comprehensive assessment of IBD patients. PMID- 26600979 TI - Risk factors for osteoporosis in inflammatory bowel disease patients. AB - Inflammatory bowel disease (IBD) patients exhibit higher risk for bone loss than the general population. The chronic inflammation causes a reduction in bone mineral density (BMD), which leads to osteopenia and osteoporosis. This article reviewed each risk factor for osteoporosis in IBD patients. Inflammation is one of the factors that contribute to osteoporosis in IBD patients, and the main system that is involved in bone loss is likely RANK/RANKL/osteoprotegerin. Smoking is a risk factor for bone loss and fractures, and many mechanisms have been proposed to explain this loss. Body composition also interferes in bone metabolism and increasing muscle mass may positively affect BMD. IBD patients frequently use corticosteroids, which stimulates osteoclastogenesis. IBD patients are also associated with vitamin D deficiency, which contributes to bone loss. However, infliximab therapy is associated with improvements in bone metabolism, but it is not clear whether the effects are because of inflammation improvement or infliximab use. Ulcerative colitis patients with proctocolectomy and ileal pouches and Crohn's disease patients with ostomy are also at risk for bone loss, and these patients should be closely monitored. PMID- 26600980 TI - Promising biological therapies for ulcerative colitis: A review of the literature. AB - Ulcerative colitis (UC) is a chronic lifelong condition characterized by alternating flare-ups and remission. There is no single known unifying cause, and the pathogenesis is multifactorial, with genetics, environmental factors, microbiota, and the immune system all playing roles. Current treatment modalities for UC include 5-aminosalicylates, corticosteroids, immunosuppressants (including purine antimetabolites, cyclosporine, and tacrolimus), and surgery. Therapeutic goals for UC are evolving. Medical treatment aims to induce remission and prevent relapse of disease activity. Infliximab, an anti-tumor necrosis factor (TNF) alpha monoclonal antibody, is the first biological agent for the treatment of UC. Over the last decade, infliximab and adalimumab (anti-TNF-alpha agents) have been used for moderate to severe UC, and have been shown to be effective in inducing and maintaining remission. Recent studies have indicated that golimumab (another anti-TNF-alpha agent), tofacitinib (a Janus kinase inhibitor), and vedolizumab and etrolizumab (integrin antagonists), achieved good clinical remission and response rates in UC. Recently, golimumab and vedolizumab have been approved for UC by the United States Food and Drug Administration. Vedolizumab may be used as a first-line alternative to anti-TNF-alpha therapy in patients with an inadequate response to corticosteroids and/or immunosuppressants. Here, we provide updated information on various biological agents in the treatment of UC. PMID- 26600981 TI - Predictive factors at birth of the severity of gastroschisis. AB - AIM: To establish children born with gastroschisis (GS). METHODS: We performed a retrospective study covering the period from January 2000 to December 2007. The following variables were analyzed for each child: Weight, sex, apgar, perforations, atresia, volvulus, bowel lenght, subjective description of perivisceritis, duration of parenteral nutrition, first nasogastric milk feeding, total milk feeding, necrotizing enterocolitis, average period of hospitalization and mortality. For statistical analysis, descriptive data are reported as mean +/ standard deviation and median (range). The non parametric test of Mann-Whitney was used. The threshold for statistical significance was P < 0.05 (Two-Tailed). RESULTS: Sixty-eight cases of GS were studied. We found nine cases of perforations, eight of volvulus, 12 of atresia and 49 children with subjective description of perivisceritis (72%). The mortality rate was 12% (eight deaths). Average duration of total parenteral nutrition was 56.7 d (8-950; median: 22), with five cases of necrotizing enterocolitis. Average length of hospitalization for 60 of our patients was 54.7 d (2-370; median: 25.5). The presence of intestinal atresia was the only factor correlated with prolonged parenteral nutrition, delayed total oral milk feeding and longer hospitalization. CONCLUSION: In our study, intestinal atresia was our predictive factor of the severity of GS. PMID- 26600982 TI - Role of anti-stromal polypharmacy in increasing survival after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. AB - AIM: To investigate the survival impact of common pharmaceuticals, which target stromal interactions, following a pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. METHODS: Data was collected retrospectively for 164 patients who underwent a pancreaticoduodenectomy for pancreatic ductal adenocarcinoma (PDAC). Survival analysis was performed on patients receiving the following medications: angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARB), calcium channel blockers (CCB), aspirin, and statins. Statistical analysis included Kaplan-meier survival estimates and cox multivariate regression; the latter of which allowed for any differences in a range of prognostic indicators between groups. Medications showing a significant survival benefit were investigated in combination with other medications to evaluate synergistic effects. RESULTS: No survival benefit was observed with respect to ACEI/ARB (n = 41), aspirin or statins on individual drug analysis (n = 39). However, the entire CCB group (n = 26) showed a significant survival benefit on multivariate cox regression; hazard ratio (HR) of 0.475 (CI = 0.250-0.902, P = 0.023). Further analysis revealed that this was influenced by a group of patients who were taking aspirin in combination with CCB; median survival was significantly higher in the CCB + aspirin group (n = 15) compared with the group taking neither drug (n = 98); 1414 d vs 601 d (P = 0.029, log-rank test). Multivariate cox regression revealed neither aspirin nor CCB had a statistically significant impact on survival when given alone, however in combination the survival benefit was significant; HR = 0.332 (CI = 0.126-0.870, P = 0.025). None of the other medications showed a survival benefit in any combination. CONCLUSION: Aspirin + CCB in combination appears to increase survival in patients with PDAC, highlighting the potential clinical use of combination therapy to target stromal interactions in pancreatic cancer. PMID- 26600983 TI - Energetic etiologies of acute pancreatitis: A report of five cases. AB - There are several common causes of acute pancreatitis, principally excessive alcohol intake and gallstones, and there are many rare causes. However, cases of pancreatitis still occur in the absence of any recognizable factors, and these cases of idiopathic pancreatitis suggest the presence of unrecognized etiologies. Five cases of acute pancreatitis in four patients came to attention due to a strong temporal association with exposure to nerve stimulators and energy drinks. Given that these cases of pancreatitis were otherwise unexplained, and given that these exposures were not clearly known to be associated with pancreatitis, we performed a search for precedent cases and for mechanistic bases. No clear precedent cases were found in PubMed and only scant, weak precedent cases were found in public-health databases. However, there was a coherent body of intriguing literature in support of a mechanistic basis for these exposures playing a role in the etiology of pancreatitis. PMID- 26600984 TI - [Arteriovenous Malformations - checking and descriptive analysis of 52 AVMs treated for the 2000-2010 period]. AB - BACKGROUND: To describe our experience in treating AVMs based on age, sex, reasons for consultation and symptoms, localization and clinical diagnosis, size, types, relation with aneurysms, endovascular procedures used, postoperative results and complications. METHODS: We present 52 patients with AVMs, analysing Neurological Exam, Ct, Irm and Brain Arteriography. RESULTS: Average age: 37.71 years. Male patients 61.53% females 38.46%. Reasons for consultation Cephalea: 63.46%, hemorrhagic events: 59.61%, seizures 26.92%. AVM location: supratentorial: 92.85%, infratentorial: 7.15%. AVMs frequency: grade 2: 30.76%, grade 3: 30.76%. Of the total number 50%, presented associated aneurysms. 32.69% of them presented hemorrhagic events. Of the total of AVMs, 59.61% showed bleeding, 26.92% showed seizures and 13.46% showed neurological deficit. 30.76% of the patients received endovascular treatment 23.07% improved their clinical condition, 57.69% showed no changes, and 19.23% experienced deterioration during the postoperative period. There were 13.46%. Mortal cases. CONCLUSION: We agree with the authors that the group mostly affected is (20- 40 years). As regards sex distribution: male patients (61.53%) female ones (38.46%). AVM location was mostly supratentorial, but also that cephalea, hemorrhagic events and seizures were the most frequent symptoms and reasons for consultation. Hemorrhagic CVA, cephalea, epileptic seizures and neurological deficit represented the most common admission diagnoses. We believe that the subgroup of AVMs grade III, IV and V has unique features that requiring extreme care when making decisions. The mortal cases in the postoperative period coincided with those mentioned in the bibliography consulted. PMID- 26600985 TI - [Cervical aspergillosis with dissemination to the central nervous system: Case reports and review of the literature]. AB - BACKGROUND: Invasive aspergillosis (IA) of the central nervous system (CNS) is an uncommon condition that usually occurs in immunocompromised patients. This illness can manifest as meningitis, or as a micotic aneurism, stroke or abscess. The infection affects the CNS either primarily or, more often, secondarily via blood dissemination from a distant focus, and has a poor prognosis. We present a patient with IA primarily affecting the cervical bones, with later spread into the brain. CASE DESCRIPTION: A 25-year old male was receiving chemotherapy for acute lymphocytic leukemia when he developed pneumonitis secondary to methotrexate and was started on corticosteroids. He subsequently developed cervicalgia, prompting a needle biopsy of the fourth vertebrae, after which a diagnosis of osteomyelitis was made. Even though the biopsy culture was negative, empirical antibiotics were initiated. A parietal lobe lesion was treated surgically months later after the patient presented with three episodes of transient aphasia. After A. fumigatus grew in culture, the patient's antibiotic regimen was changed to treat the specific agent with a good response. CONCLUSION: IA must be considered a possibility whenever an immunocompromised patient presents with a new brain lesion. These lesions require surgical evacuation, a procedure that allows for diagnostic confirmation and enhances prognosis. Appropriate anti-fungal therapy must be started as soon as the diagnosis is confirmed. In addition, the patient's neurological exam must be repeated and images obtained periodically to monitor treatment and detect possible recurrences. PMID- 26600986 TI - [Microsurgical anatomy and approaches of mesial temporal cavernomas]. AB - OBJECTIVE: To describe the microsurgical anatomy and approaches to the mesial temporal region (MTR), in relation with cavernomas. METHODS: Five adult cadaveric heads, fixed in formol and injected with colored silicon were studied. Since January 2007 and June 2014, the author operated 7 patients with cavernomas located in the MTR. RESULTS: ANATOMY: The MTR was divided in 3 portions: Anterior, middle and posterior. PATIENTS: The author operated 7 patients with MTR cavernomas. Four cavernomas were located in the anterior portion, 2 were located in the middle portion, and 1 cavernoma was located in the posterior portion. The transsylvian-transinsular approach was used for the anterior portion of the MTR; the transtemporal approach (anterior temporal lobectomy) was used for the middle portion of the MTR; and the supracerebellar-transtentorial approach was used for the posterior portion of the MTR. CONCLUSION: The idea of divide the MTR in 3 portions help to select the correct approach. PMID- 26600988 TI - Biocompatible silk step-index optical waveguides. AB - Biocompatible optical waveguides were constructed entirely of silk fibroin. A silk film (n=1.54) was encapsulated within a silk hydrogel (n=1.34) to form a robust and biocompatible waveguide. Such waveguides were made using only biologically and environmentally friendly materials without the use of harsh solvents. Light was coupled into the silk waveguides by direct incorporation of a glass optical fiber. These waveguides are extremely flexible, and strong enough to survive handling and manipulation. Cutback measurements showed propagation losses of approximately 2 dB/cm. The silk waveguides were found to be capable of guiding light through biological tissue. PMID- 26600987 TI - Three-dimensional printed optical phantoms with customized absorption and scattering properties. AB - Three-dimensional (3D) printing offers the promise of fabricating optical phantoms with arbitrary geometry, but commercially available thermoplastics provide only a small range of physiologically relevant absorption (ua) and reduced scattering (us') values. Here we demonstrate customizable acrylonitrile butadiene styrene (ABS) filaments for dual extrusion 3D printing of tissue mimicking optical phantoms. ua and us' values were adjusted by incorporating nigrosin and titanium dioxide (TiO2) in the filament extrusion process. A wide range of physiologically relevant optical properties was demonstrated with an average repeatability within 11.5% for ua and 7.71% for us'. Additionally, a mouse-simulating phantom, which mimicked both the geometry and optical properties of a hairless mouse with an implanted xenograft tumor, was printed using dual extrusion methods. 3D printed tumor optical properties matched the live tumor with less than 3% error at a wavelength of 659 nm. 3D printing with user defined optical properties may provide a viable method for durable optically diffusive phantoms for instrument characterization and calibration. PMID- 26600989 TI - Design and performance of an ultra-flexible two-photon microscope for in vivo research. AB - We present a cost-effective in vivo two-photon microscope with a highly flexible frontend for in vivo research. Our design ensures fast and reproducible access to the area of interest, including rotation of imaging plane, and maximizes space for auxiliary experimental equipment in the vicinity of the animal. Mechanical flexibility is achieved with large motorized linear stages that move the objective in the X, Y, and Z directions up to 130 mm. 360 degrees rotation of the frontend (rotational freedom for one axis) is achieved with the combination of a motorized high precision bearing and gearing. Additionally, the modular design of the frontend, based on commercially available optomechanical parts, allows straightforward updates to future scanning technologies. The design exceeds the mobility of previous movable microscope designs while maintaining high optical performance. PMID- 26600991 TI - Analytical reconstructions of intensity modulated x-ray phase-contrast imaging of human scale phantoms. AB - This paper presents analytical approach to modeling of a full planar and volumetric acquisition system with image reconstructions originated from partial illumination x-ray phase-contrast imaging at a human scale using graphics processor units. The model is based on x-ray tracing and wave optics methods to develop a numerical framework for predicting the performance of a preclinical phase-contrast imaging system of a human-scaled phantom. In this study, experimental images of simple numerical phantoms and high resolution anthropomorphic phantoms of head and thorax based on non-uniform rational b spline shapes (NURBS) prove the correctness of the model. Presented results can be used to simulate the performance of partial illumination x-ray phase-contrast imaging system on various preclinical applications. PMID- 26600990 TI - Sensitivity analysis aimed at blood vessels detection using interstitial optical tomography during brain needle biopsy procedures. AB - A brain needle biopsy procedure is performed for suspected brain lesions in order to sample tissue that is subsequently analysed using standard histopathology techniques. A common complication resulting from this procedure is brain hemorrhaging from blood vessels clipped off during tissue extraction. Interstitial optical tomography (iOT) has recently been introduced by our group as a mean to assess the presence of blood vessels in the vicinity of the needle. The clinical need to improve safety requires the detection of blood vessels within 2 mm from the outer surface of the needle, since this distance is representative of the volume of tissue that is aspirated durirng tissue extraction. Here, a sensitivity analysis is presented to establish the intrinsic detection limits of iOT based on simulations and experiments using brain tissue phantoms. It is demonstrated that absorbers can be detected with diameters >300 MUm located up to >2 mm from the biopsy needle core for bulk optical properties consistent with brain tissue. PMID- 26600992 TI - Biomedical Optics Express feature issue introduction: optical trapping applications (OTA). AB - This feature issue of Biomedical Optics Express presents studies which were the focus of the fourth OTA Topical Meeting that was held on 12-15 April 2015 in Vancouver, Canada. PMID- 26600993 TI - Introduction to the novel techniques in microscopy feature issue. AB - The editors introduce the feature issue on "Novel Techniques in Microscopy," which was the topic of a symposium held on April 12-15, 2015, in Vancouver, BC. This symposium was part of the Optics in the Life Sciences Congress. PMID- 26600994 TI - Effect of recombinant interleukin-12 on murine skin regeneration and cell dynamics using in vivo multimodal microscopy. AB - Interleukin-12 (IL-12) is a pro-inflammatory cytokine known for its role in immunity, and previous studies have shown that IL-12 provides mitigation of radiation injury. In this study, we utilize a multimodal microscopy system equipped with second harmonic generation (SHG) and fluorescence lifetime imaging microscopy (FLIM) to examine the effect of IL-12 on collagen structure and cellular metabolic activity in vivo during skin wound healing. This preliminary study illustrates the highly dynamic and heterogeneous in vivo microenvironment of the wounded skin. In addition, results suggest that IL-12 triggers a significantly more rapid and greater cellular metabolic response in the wounded animals. These results can elucidate insights into the response mechanism of IL 12 in both wound healing and acute radiation syndrome. PMID- 26600995 TI - Assessment of the best flow model to characterize diffuse correlation spectroscopy data acquired directly on the brain. AB - Diffuse correlation spectroscopy (DCS) is a non-invasive optical technique capable of monitoring tissue perfusion. The normalized temporal intensity autocorrelation function generated by DCS is typically characterized by assuming that the movement of erythrocytes can be modeled as a Brownian diffusion-like process instead of by the expected random flow model. Recently, a hybrid model, referred to as the hydrodynamic diffusion model, was proposed, which combines the random and Brownian flow models. The purpose of this study was to investigate the best model to describe autocorrelation functions acquired directly on the brain in order to avoid confounding effects of extracerebral tissues. Data were acquired from 11 pigs during normocapnia and hypocapnia, and flow changes were verified by computed tomography perfusion (CTP). The hydrodynamic diffusion model was found to provide the best fit to the autocorrelation functions; however, no significant difference for relative flow changes measured by the Brownian and hydrodynamic diffusion models was observed. PMID- 26600996 TI - Robust motion tracking based on adaptive speckle decorrelation analysis of OCT signal. AB - Speckle decorrelation analysis of optical coherence tomography (OCT) signal has been used in motion tracking. In our previous study, we demonstrated that cross correlation coefficient (XCC) between Ascans had an explicit functional dependency on the magnitude of lateral displacement (deltax). In this study, we evaluated the sensitivity of speckle motion tracking using the derivative of function XCC(deltax) on variable deltax. We demonstrated the magnitude of the derivative can be maximized. In other words, the sensitivity of OCT speckle tracking can be optimized by using signals with appropriate amount of decorrelation for XCC calculation. Based on this finding, we developed an adaptive speckle decorrelation analysis strategy to achieve motion tracking with optimized sensitivity. Briefly, we used subsequently acquired Ascans and Ascans obtained with larger time intervals to obtain multiple values of XCC and chose the XCC value that maximized motion tracking sensitivity for displacement calculation. Instantaneous motion speed can be calculated by dividing the obtained displacement with time interval between Ascans involved in XCC calculation. We implemented the above-described algorithm in real-time using graphic processing unit (GPU) and demonstrated its effectiveness in reconstructing distortion-free OCT images using data obtained from a manually scanned OCT probe. The adaptive speckle tracking method was validated in manually scanned OCT imaging, on phantom as well as in vivo skin tissue. PMID- 26600997 TI - Rapid imaging of surgical breast excisions using direct temporal sampling two photon fluorescent lifetime imaging. AB - Two photon fluorescent lifetime imaging is a modality that enables depth sectioned, molecularly-specific imaging of cells and tissue using intrinsic contrast. However, clinical applications have not been well explored due to low imaging speed and limited field of view, which make evaluating large pathology samples extremely challenging. To address these limitations, we have developed direct temporal sampling two photon fluorescent lifetime imaging (DTS-FLIM), a method which enables a several order of magnitude increase in imaging speed by capturing an entire lifetime decay in a single fluorescent excitation. We use this greatly increased speed to perform a preliminary study using gigapixel-scale imaging of human breast pathology surgical specimens. PMID- 26600998 TI - Influence of a skin status on the light interaction with dermis. AB - We present experimental evidence that the parameters of green light remitted from a human tissue in-vivo strongly depend on skin contact status. In case when the skin is free of any contact, simultaneous recording of imaging photoplethysmogram (iPPG) and electrocardiogram revealed that contactless iPPG fails in correct estimates of the heart rate in almost half of the cases. Meanwhile, the number of successful correlations between ECG and iPPG is significantly increased when the skin is in contact with a glass plate. These observations are in line with the recently proposed model in which pulsatile arteries deform the connective-tissue components of the dermis thus resulting in temporal modulation of the capillary density interacting with slightly penetrating light. PMID- 26600999 TI - Reflectance confocal microscopy of red blood cells: simulation and experiment. AB - Measuring the morphology of red blood cells is important for clinical diagnosis, providing valuable indications on a patient's health. In this work, we have simulated the appearance of normal red blood cells under a reflectance confocal microscope and discovered unique relations between the morphological parameters and the resulting characteristic interference patterns of the cell. The simulation results showed good agreement with in vitro reflectance confocal images of red blood cells, acquired using spectrally encoded flow cytometry that imaged the cells in a linear flow without artificial staining. By matching the simulated patterns to confocal images of the cells, this method could be used for measuring cell morphology in three dimensions and for studying their physiology. PMID- 26601000 TI - Non-invasive manipulation of Drosophila behavior by two-photon excited red activatable channelrhodopsin. AB - Scattering and absorption limit light penetration through inhomogeneous tissue. To reduce scattering, biochemists have shifted the wavelengths of excitation light for optogenetic actuators and fluorescent proteins to the orange-red range, while physicists have developed multiphoton technologies for deep tissue stimulation. We have built a rapid multiphoton spectroscopic screening system of genetically encoded red-activatable channelrhodopsin (ReaChR), and considered specific behaviors in transgenic Drosophila melanogaster as readouts to optimize the laser parameters for two-photon optogenetic activation. A wavelength-tunable optical parametric amplifier was adopted as the major light source for widefield two-photon excitation (TPE) of ReaChR. Our assays suggest that the optimized TPE wavelength of ReaChR is 1250 nm. Exploiting its capacity for optogenetic manipulation to induce macroscopic behavioral change, we realized rapid spectroscopic screening of genetically encoded effectors or indicators in vivo, and used modulation of ReaChR in the fly as a successful demonstration of such a system. PMID- 26601001 TI - Compact multi-band fluorescent microscope with an electrically tunable lens for autofocusing. AB - Autofocusing is a routine technique in redressing focus drift that occurs in time lapse microscopic image acquisition. To date, most automatic microscopes are designed on the distance detection scheme to fulfill the autofocusing operation, which may suffer from the low contrast of the reflected signal due to the refractive index mismatch at the water/glass interface. To achieve high autofocusing speed with minimal motion artifacts, we developed a compact multi band fluorescent microscope with an electrically tunable lens (ETL) device for autofocusing. A modified searching algorithm based on equidistant scanning and curve fitting is proposed, which no longer requires a single-peak focus curve and then efficiently restrains the impact of external disturbance. This technique enables us to achieve an autofocusing time of down to 170 ms and the reproductivity of over 97%. The imaging head of the microscope has dimensions of 12 cm * 12 cm * 6 cm. This portable instrument can easily fit inside standard incubators for real-time imaging of living specimens. PMID- 26601002 TI - Reproducibility of optical coherence tomography airway imaging. AB - Optical coherence tomography (OCT) is a promising imaging technique to evaluate small airway remodeling. However, the short-term insertion-reinsertion reproducibility of OCT for evaluating the same bronchial pathway has yet to be established. We evaluated 74 OCT data sets from 38 current or former smokers twice within a single imaging session. Although the overall insertion-reinsertion airway wall thickness (WT) measurement coefficient of variation (CV) was moderate at 12%, much of the variability between repeat imaging was attributed to the observer; CV for repeated measurements of the same airway (intra-observer CV) was 9%. Therefore, reproducibility may be improved by introduction of automated analysis approaches suggesting that OCT has potential to be an in-vivo method for evaluating airway remodeling in future longitudinal and intervention studies. PMID- 26601003 TI - Remote monitoring of breathing dynamics using infrared thermography. AB - An atypical or irregular respiratory frequency is considered to be one of the earliest markers of physiological distress. In addition, monitoring of this vital parameter plays a major role in diagnosis of respiratory disorders, as well as in early detection of sudden infant death syndrome. Nevertheless, the current measurement modalities require attachment of sensors to the patient's body, leading to discomfort and stress. The current paper presents a new robust algorithm to remotely monitor breathing rate (BR) by using thermal imaging. This approach permits to detect and to track the region of interest (nose) as well as to estimate BR. In order to study the performance of the algorithm, and its robustness against motion and breathing disorders, three different thermal recordings of 11 healthy volunteers were acquired (sequence 1: normal breathing; sequence 2: normal breathing plus arbitrary head movements; and sequence 3: sequence of specific breathing patterns). Thoracic effort (piezoplethysmography) served as "gold standard" for validation of our results. An excellent agreement between estimated BR and ground truth was achieved. Whereas the mean correlation for sequence 1-3 were 0.968, 0.940 and 0.974, the mean absolute BR errors reached 0.33, 0.55 and 0.96 bpm (breaths per minute), respectively. In brief, this work demonstrates that infrared thermography is a promising, clinically relevant alternative for the currently available measuring modalities due to its performance and diverse remarkable advantages. PMID- 26601004 TI - Automatic neuron segmentation and neural network analysis method for phase contrast microscopy images. AB - Phase Contrast Microscopy (PCM) is an important tool for the long term study of living cells. Unlike fluorescence methods which suffer from photobleaching of fluorophore or dye molecules, PCM image contrast is generated by the natural variations in optical index of refraction. Unfortunately, the same physical principles which allow for these studies give rise to complex artifacts in the raw PCM imagery. Of particular interest in this paper are neuron images where these image imperfections manifest in very different ways for the two structures of specific interest: cell bodies (somas) and dendrites. To address these challenges, we introduce a novel parametric image model using the level set framework and an associated variational approach which simultaneously restores and segments this class of images. Using this technique as the basis for an automated image analysis pipeline, results for both the synthetic and real images validate and demonstrate the advantages of our approach. PMID- 26601005 TI - Columnar deformation of human red blood cell by highly localized fiber optic Bessel beam stretcher. AB - A single human red blood cell was optically stretched along two counter propagating fiber-optic Bessel-like beams in an integrated lab-on-a-chip structure. The beam enabled highly localized stretching of RBC, and it induced a nonlinear mechanical deformation to finally reach an irreversible columnar shape that has not been reported. We characterized and systematically quantified this optically induced mechanical deformation by the geometrical aspect ratio of stretched RBC and the irreversible stretching time. The proposed RBC mechanism can realize a versatile and compact opto-mechanical platform for optical diagnosis of biological substances in the single cell level. PMID- 26601006 TI - All-plastic, miniature, digital fluorescence microscope for three part white blood cell differential measurements at the point of care. AB - Three-part differential white blood cell counts are used for disease diagnosis and monitoring at the point-of-care. A low-cost, miniature achromatic microscope was fabricated for identification of lymphocytes, monocytes, and granulocytes in samples of whole blood stained with acridine orange. The microscope was manufactured using rapid prototyping techniques of diamond turning and 3D printing and is intended for use at the point-of-care in low-resource settings. The custom-designed microscope requires no manual adjustment between samples and was successfully able to classify three white blood cell types (lymphocytes, granulocytes, and monocytes) using samples of peripheral whole blood stained with acridine orange. PMID- 26601007 TI - SPIM-fluid: open source light-sheet based platform for high-throughput imaging. AB - Light sheet fluorescence microscopy has recently emerged as the technique of choice for obtaining high quality 3D images of whole organisms/embryos with low photodamage and fast acquisition rates. Here we present an open source unified implementation based on Arduino and Micromanager, which is capable of operating Light Sheet Microscopes for automatized 3D high-throughput imaging on three dimensional cell cultures and model organisms like zebrafish, oriented to massive drug screening. PMID- 26601008 TI - Method for in vitro assessment of straylight from intraocular lenses. AB - Ocular straylight has been measured by means of psychophysical methods over the years. This approach gives a functional parameter yielding a straight comparison with optically defined light scattering, and the point-spread-function. This is of particular importance when the effect of intraocular lenses (IOLs) on postoperative straylight is sought. An optical system for straylight measurements of IOLs was adapted to a commercial device (C-Quant, Oculus), which employs such psychophysical method. The proposed modifications were validated using light scattering filters and some sample IOLs. The measurements were performed by 3 observers to prove that results are independent from straylight of the eye. Other applications will be discussed. PMID- 26601009 TI - Fingerprint imaging from the inside of a finger with full-field optical coherence tomography. AB - Imaging below fingertip surface might be a useful alternative to the traditional fingerprint sensing since the internal finger features are more reliable than the external ones. One of the most promising subsurface imaging technique is optical coherence tomography (OCT), which, however, has to acquire 3-D data even when a single en face image is required. This makes OCT inherently slow for en face imaging and produce unnecessary large data sets. Here we demonstrate that full field optical coherence tomography (FF-OCT) can be used to produce en face images of sweat pores and internal fingerprints, which can be used for the identification purposes. PMID- 26601010 TI - Temporal integration property of stereopsis after higher-order aberration correction. AB - Based on a binocular adaptive optics visual simulator, we investigated the effect of higher-order aberration correction on the temporal integration property of stereopsis. Stereo threshold for line stimuli, viewed in 550nm monochromatic light, was measured as a function of exposure duration, with higher-order aberrations uncorrected, binocularly corrected or monocularly corrected. Under all optical conditions, stereo threshold decreased with increasing exposure duration until a steady-state threshold was reached. The critical duration was determined by a quadratic summation model and the high goodness of fit suggested this model was reasonable. For normal subjects, the slope for stereo threshold versus exposure duration was about -0.5 on logarithmic coordinates, and the critical duration was about 200 ms. Both the slope and the critical duration were independent of the optical condition of the eye, showing no significant effect of higher-order aberration correction on the temporal integration property of stereopsis. PMID- 26601011 TI - Label-free near-infrared reflectance microscopy as a complimentary tool for two photon fluorescence brain imaging. AB - In vivo two-photon imaging combined with targeted fluorescent indicators is currently extensively used for attaining critical insights into brain functionality and structural plasticity. Additional information might be gained from back-scattered photons from the near-infrared (NIR) laser without introducing any exogenous labelling. Here, we describe a complimentary and versatile approach that, by collecting the reflected NIR light, provides structural details on axons and blood vessels in the brain, both in fixed samples and in live animals under a cranial window. Indeed, by combining NIR reflectance and two-photon imaging of a slice of hippocampus from a Thy1-GFPm mouse, we show the presence of randomly oriented axons intermingled with sparsely fluorescent neuronal processes. The back-scattered photons guide the contextualization of the fluorescence structure within brain atlas thanks to the recognition of characteristic hippocampal structures. Interestingly, NIR reflectance microscopy allowed the label-free detection of axonal elongations over the superficial layers of mouse cortex under a cranial window in vivo. Finally, blood flow can be measured in live preparations, thus validating label free NIR reflectance as a tool for monitoring hemodynamic fluctuations. The prospective versatility of this label-free technique complimentary to two-photon fluorescence microscopy is demonstrated in a mouse model of photothrombotic stroke in which the axonal degeneration and blood flow remodeling can be investigated. PMID- 26601012 TI - Label-free assessment of replicative senescence in mesenchymal stem cells by Raman microspectroscopy. AB - Here, Raman microspectroscopy was employed to assess replicative senescence of mesenchymal stem cells (MSC). A regular spectral change related to the cell senescence was found in the ratio of two peaks at 1157 cm(-1) and 1174 cm(-1), which are assigned to C-C, C-N stretching vibrations in proteins and C-H bending vibrations in tyrosine and phenylalanine, respectively. With the cell aging, the ratio I1157 / I1174 exhibited a monotonic decline and showed small standard deviations, so that it can statistically distinguish between cells having slight changes in terms of aging. We propose that I1157 / I1174 can act as a characteristic spectral signature for label-free assessment of MSC senescence. PMID- 26601013 TI - Calculation of crystalline lens power using a modification of the Bennett method. AB - We present a method for measuring lens power from extended depth OCT biometry, corneal topography, and refraction using an improvement on the Bennett method. A reduced eye model was used to derive a formula for lens power in terms of ocular distances, corneal power, and objective spherical equivalent refraction. An error analysis shows that the formula predicts relaxed lens power with a theoretical accuracy of +/- 0.5 D for refractive error ranging from -10 D to + 10 D. The formula was used to calculate lens power in 16 eyes of 8 human subjects. Mean lens power was 24.3 D +/- 1.7 D. PMID- 26601014 TI - Handheld, rapidly switchable, anterior/posterior segment swept source optical coherence tomography probe. AB - We describe the first handheld, swept source optical coherence tomography (SSOCT) system capable of imaging both the anterior and posterior segments of the eye in rapid succession. A single 2D microelectromechanical systems (MEMS) scanner was utilized for both imaging modes, and the optical paths for each imaging mode were optimized for their respective application using a combination of commercial and custom optics. The system has a working distance of 26.1 mm and a measured axial resolution of 8 MUm (in air). In posterior segment mode, the design has a lateral resolution of 9 MUm, 7.4 mm imaging depth range (in air), 4.9 mm 6dB fall-off range (in air), and peak sensitivity of 103 dB over a 22 degrees field of view (FOV). In anterior segment mode, the design has a lateral resolution of 24 MUm, imaging depth range of 7.4 mm (in air), 6dB fall-off range of 4.5 mm (in air), depth-of-focus of 3.6 mm, and a peak sensitivity of 99 dB over a 17.5 mm FOV. In addition, the probe includes a wide-field iris imaging system to simplify alignment. A fold mirror assembly actuated by a bi-stable rotary solenoid was used to switch between anterior and posterior segment imaging modes, and a miniature motorized translation stage was used to adjust the objective lens position to correct for patient refraction between -12.6 and + 9.9 D. The entire probe weighs less than 630 g with a form factor of 20.3 x 9.5 x 8.8 cm. Healthy volunteers were imaged to illustrate imaging performance. PMID- 26601015 TI - Screening neonatal jaundice based on the sclera color of the eye using digital photography. AB - A new screening technique for neonatal jaundice is proposed exploiting the yellow discoloration in the sclera. It involves taking digital photographs of newborn infants' eyes (n = 110) and processing the pixel colour values of the sclera to predict the total serum bilirubin (TSB) levels. This technique has linear and rank correlation coefficients of 0.75 and 0.72 (both p<0.01) with the measured TSB. The mean difference ( +/- SD) is 0.00 +/- 41.60 umol/l. The receiver operating characteristic curve shows that this technique can identify subjects with TSB above 205 umol/l with sensitivity of 1.00 and specificity of 0.50, showing its potential as a screening device. PMID- 26601016 TI - Mitochondrial swelling and restorable fragmentation stimulated by femtosecond laser. AB - Mitochondria play a key role in all cellular physiology, processes, and behaviors. It is very difficult to precisely stimulate single mitochondria noninvasively in traditional biomedical research. In this study, we report that femtosecond laser can stimulate fragmentation or swelling of single mitochondria in human mesenchymal stem cells rather than physical disruption or ablation. In experiments, fragmented mitochondria can recover normal very soon but swelling ones cannot. At the same time, laser-induced generation of mitochondrial reactive oxygen species and opening of mitochondria permeability transition pores are involved in mitochondrial responses to photostimulation. Furthermore, the localized translocation of proapoptotic molecules are found in those stimulated mitochondria. Those results suggest femtosecond-laser photostimulation as a noninvasive and precise method for mitochondrial manipulation and related research. PMID- 26601017 TI - Minimally invasive microendoscopy system for in vivo functional imaging of deep nuclei in the mouse brain. AB - The ability to image neurons anywhere in the mammalian brain is a major goal of optical microscopy. Here we describe a minimally invasive microendoscopy system for studying the morphology and function of neurons at depth. Utilizing a guide cannula with an ultrathin wall, we demonstrated in vivo two-photon fluorescence imaging of deeply buried nuclei such as the striatum (2.5 mm depth), substantia nigra (4.4 mm depth) and lateral hypothalamus (5.0 mm depth) in mouse brain. We reported, for the first time, the observation of neuronal activity with subcellular resolution in the lateral hypothalamus and substantia nigra of head fixed awake mice. PMID- 26601018 TI - High-speed intravascular photoacoustic imaging at 1.7 MUm with a KTP-based OPO. AB - Lipid deposition inside the arterial wall is a hallmark of plaque vulnerability. Based on overtone absorption of C-H bonds, intravascular photoacoustic (IVPA) catheter is a promising technology for quantifying the amount of lipid and its spatial distribution inside the arterial wall. Thus far, the clinical translation of IVPA technology is limited by its slow imaging speed due to lack of a high pulse-energy high-repetition-rate laser source for lipid-specific first overtone excitation at 1.7 MUm. Here, we demonstrate a potassium titanyl phosphate (KTP) based optical parametric oscillator with output pulse energy up to 2 mJ at a wavelength of 1724 nm and with a repetition rate of 500 Hz. Using this laser and a ring-shape transducer, IVPA imaging at speed of 1 frame per sec was demonstrated. Performance of the IVPA imaging system's resolution, sensitivity, and specificity were characterized by carbon fiber and a lipid-mimicking phantom. The clinical utility of this technology was further evaluated ex vivo in an excised atherosclerotic human femoral artery with comparison to histology. PMID- 26601020 TI - Modular platform for low-light microscopy. AB - Cell imaging using low-light techniques such as bioluminescence, radioluminescence, and low-excitation fluorescence has received increased attention, particularly due to broad commercialization of highly sensitive detectors. However, the dim signals are still regarded as difficult to image using conventional microscopes, where the only low-light microscope in the market is primarily optimized for bioluminescence imaging. Here, we developed a novel modular microscope that is cost-effective and suitable for imaging different low light luminescence modes. Results show that this microscope system features excellent aberration correction capabilities and enhanced image resolution, where bioluminescence, radioluminescence and epifluorescence images were captured and compared with the commercial bioluminescence microscope. PMID- 26601019 TI - Fast and efficient image reconstruction for high density diffuse optical imaging of the human brain. AB - Real-time imaging of human brain has become an important technique within neuroimaging. In this study, a fast and efficient sensitivity map generation based on Finite Element Models (FEM) is developed which utilises a reduced sensitivitys matrix taking advantage of sparsity and parallelisation processes. Time and memory efficiency of these processes are evaluated and compared with conventional method showing that for a range of mesh densities from 50000 to 320000 nodes, the required memory is reduced over tenfold and computational time fourfold allowing for near real-time image recovery. PMID- 26601021 TI - Hollow core photonic crystal fiber for monitoring leukemia cells using surface enhanced Raman scattering (SERS). AB - The present paper demonstrates an antibody-free, robust, fast, and portable platform for detection of leukemia cells using Raman spectroscopy with a 785-nm laser diode coupled to a hollow core photonic crystal (HC-PCF) containing silver nanoparticles. Acute myeloid leukemia is one of the most common bone marrow cancers in children and youths. Clinical studies suggest that early diagnosis and remission evaluation of myoblasts in the bone marrow are pivotal for improving patient survival. However, the current protocols for leukemic cells detection involve the use of expensive antibodies and flow cytometers. Thus, we have developed a new technology for detection of leukemia cells up to 300 cells/ml using a compact fiber HC-PCF, which offers a novel alternative to existing clinical standards. Furthermore, we were also able to accurately distinguish live, apoptotic and necrotic leukemic cells. PMID- 26601022 TI - Dynamic heart rate estimation using principal component analysis. AB - In this paper, facial images from various video sequences are used to obtain a heart rate reading. In this study, a video camera is used to capture the facial images of eight subjects whose heart rates vary dynamically, between 81 and 153 BPM. Principal component analysis (PCA) is used to recover the blood volume pulses (BVP) which can be used for the heart rate estimation. An important consideration for accuracy of the dynamic heart rate estimation is to determine the shortest video duration that realizes it. This video duration is chosen when the six principal components (PC) are least correlated amongst them. When this is achieved, the first PC is used to obtain the heart rate. The results obtained from the proposed method are compared to the readings obtained from the Polar heart rate monitor. Experimental results show the proposed method is able to estimate the dynamic heart rate readings using less computational requirements when compared to the existing method. The mean absolute error and the standard deviation of the absolute errors between experimental readings and actual readings are 2.18 BPM and 1.71 BPM respectively. PMID- 26601023 TI - The Dissemination of Mass in the United States: Results and Implications of Recent BIPM Calibrations of US National Prototype Kilograms. AB - The National Institute of Standards and Technology (NIST) is responsible for the dissemination of the unit of mass within the United States of America through the national prototype kilogram K20 and its check standard K4. These platinum-iridium artifacts have been in use since 1889 and are periodically sent to the International Bureau of Weights and Measures (BIPM) for recalibration. The following is a brief description of the roles of the national prototype kilograms in the dissemination of mass in the United States of America, and the implications for NIST mass calibration customers of the most recent recalibrations of K20 and K4. PMID- 26601024 TI - Sensitivity Analysis of Fatigue Crack Growth Model for API Steels in Gaseous Hydrogen. AB - A model to predict fatigue crack growth of API pipeline steels in high pressure gaseous hydrogen has been developed and is presented elsewhere. The model currently has several parameters that must be calibrated for each pipeline steel of interest. This work provides a sensitivity analysis of the model parameters in order to provide (a) insight to the underlying mathematical and mechanistic aspects of the model, and (b) guidance for model calibration of other API steels. PMID- 26601025 TI - Are Bragg Peaks Gaussian? AB - It is common practice to assume that Bragg scattering peaks have Gaussian shape. The Gaussian shape function is used to perform most instrumental smearing corrections. Using Monte Carlo ray tracing simulation, the resolution of a realistic small-angle neutron scattering (SANS) instrument is generated reliably. Including a single-crystal sample with large d-spacing, Bragg peaks are produced. Bragg peaks contain contributions from the resolution function and from spread in the sample structure. Results show that Bragg peaks are Gaussian in the resolution-limited condition (with negligible sample spread) while this is not the case when spread in the sample structure is non-negligible. When sample spread contributes, the exponentially modified Gaussian function is a better account of the Bragg peak shape. This function is characterized by a non-zero third moment (skewness) which makes Bragg peaks asymmetric for broad neutron wavelength spreads. PMID- 26601026 TI - WWVB: A Half Century of Delivering Accurate Frequency and Time by Radio. AB - In commemoration of its 50th anniversary of broadcasting from Fort Collins, Colorado, this paper provides a history of the National Institute of Standards and Technology (NIST) radio station WWVB. The narrative describes the evolution of the station, from its origins as a source of standard frequency, to its current role as the source of time-of-day synchronization for many millions of radio controlled clocks. PMID- 26601027 TI - Concepts and Engineering Aspects of a Neutron Resonance Spin-Echo Spectrometer for the National Institute of Standards and Technology Center for Neutron Research. AB - Following a brief introduction, the Neutron Resonance Spin-Echo (NRSE) principle is discussed classically in Sec. 2. In Sec. 3, two idealized 4-coil NRSE spectrometers are discussed (one using single pi-flipper coil units and one using paired "bootstrap" coils); some idealized (exact pi-flip) expressions are given for the spin-echo signal and some theoretical limitations are discussed. A more quantum mechanical discussion of NRSE is presented in Sec. 4 and additional theory related to the spin-echo signal, including wavelength-dependence, is given is Sec. 5. Factors affecting the instrumental resolution are discussed in Sec. 6. In Sec. 7, a variety of engineering issues are assessed in the context of challenging performance goals for a NIST Center for Neutron Research (NCNR) NRSE spectrometer. In Sec. 8, some Monte Carlo simulations are presented that examine the combined influences of spectrometer imperfections on the NRSE signal. These are compared with analytical predictions developed in previous sections. In Sec. 9, possible alternatives for a NCNR NRSE spectrometer configuration are discussed together with a preliminary assessment of the spectrometer neutron guide requirements. A summary of some of the useful formulas is given in Appendix A. PMID- 26601028 TI - A Framework for Reproducible Latent Fingerprint Enhancements. AB - Photoshop processing of latent fingerprints is the preferred methodology among law enforcement forensic experts, but that appproach is not fully reproducible and may lead to questionable enhancements. Alternative, independent, fully reproducible enhancements, using IDL Histogram Equalization and IDL Adaptive Histogram Equalization, can produce better-defined ridge structures, along with considerable background information. Applying a systematic slow motion smoothing procedure to such IDL enhancements, based on the rapid FFT solution of a Levy stable fractional diffusion equation, can attenuate background detail while preserving ridge information. The resulting smoothed latent print enhancements are comparable to, but distinct from, forensic Photoshop images suitable for input into automated fingerprint identification systems, (AFIS). In addition, this progressive smoothing procedure can be reexamined by displaying the suite of progressively smoother IDL images. That suite can be stored, providing an audit trail that allows monitoring for possible loss of useful information, in transit to the user-selected optimal image. Such independent and fully reproducible enhancements provide a valuable frame of reference that may be helpful in informing, complementing, and possibly validating the forensic Photoshop methodology. PMID- 26601029 TI - Threshold Digraphs. AB - A digraph whose degree sequence has a unique vertex labeled realization is called threshold. In this paper we present several characterizations of threshold digraphs and their degree sequences, and show these characterizations to be equivalent. Using this result, we obtain a new, short proof of the Fulkerson-Chen theorem on degree sequences of general digraphs. PMID- 26601030 TI - Optical Passive Sensor Calibration for Satellite Remote Sensing and the Legacy of NOAA and NIST Cooperation. AB - This paper traces the cooperative efforts of scientists at the National Oceanic and Atmospheric Administration (NOAA) and the National Institute of Standards and Technology (NIST) to improve the calibration of operational satellite sensors for remote sensing of the Earth's land, atmosphere and oceans. It gives a chronological perspective of the NOAA satellite program and the interactions between the two agencies' scientists to address pre-launch calibration and issues of sensor performance on orbit. The drive to improve accuracy of measurements has had a new impetus in recent years because of the need for improved weather prediction and climate monitoring. The highlights of this cooperation and strategies to achieve SI-traceability and improve accuracy for optical satellite sensor data are summarized. PMID- 26601031 TI - Detection of Hazardous Liquids Using Microwaves. AB - We investigate the feasibility of using dielectric spectra to classify hazardous and nonhazardous liquids. The dielectric spectra of several liquids was obtained with a shielded-open coaxial fixture, and we present a new full-wave model for calculating the complex permittivity of liquids using this fixture. Using the measured complex permittivity for each liquid, we examine several classification methods for distinguishing between the hazardous and nonhazardous liquids and report on the error rates of each method. PMID- 26601032 TI - Translating Radiometric Requirements for Satellite Sensors to Match International Standards. AB - International scientific standards organizations created standards on evaluating uncertainty in the early 1990s. Although scientists from many fields use these standards, they are not consistently implemented in the remote sensing community, where traditional error analysis framework persists. For a satellite instrument under development, this can create confusion in showing whether requirements are met. We aim to create a methodology for translating requirements from the error analysis framework to the modern uncertainty approach using the product level requirements of the Advanced Baseline Imager (ABI) that will fly on the Geostationary Operational Environmental Satellite R-Series (GOES-R). In this paper we prescribe a method to combine several measurement performance requirements, written using a traditional error analysis framework, into a single specification using the propagation of uncertainties formula. By using this approach, scientists can communicate requirements in a consistent uncertainty framework leading to uniform interpretation throughout the development and operation of any satellite instrument. PMID- 26601033 TI - Post-Irradiation Study of the Alanine Dosimeter. AB - Post-irradiation stability of high-dose dosimeters has traditionally been an important measurement influence quantity. Though the exceptional stability of the alanine dosimeter response with time has rendered this factor a non-issue for routine work, the archival quality of the alanine dosimeter has not been characterized. Here the alanine pellet dosimeter response is measured up to seven years post-irradiation for a range of absorbed doses. This long-term study is accompanied by an examination of the environmental influence quantities (e.g., ambient light) on the relatively short-term (3-4 month) stability of both pellet and film commercial dosimeters. Both dosimeter types demonstrated exceptional stability in the short term and proved to be relatively insensitive to common influence quantities. The long-term data revealed a complex dose-dependent response trend. PMID- 26601034 TI - Retrospective Analysis of NIST Standard Reference Material 1450, Fibrous Glass Board, for Thermal Insulation Measurements. AB - Thermal conductivity data acquired previously for the establishment of Standard Reference Material (SRM) 1450, Fibrous Glass Board, as well as subsequent renewals 1450a, 1450b, 1450c, and 1450d, are re-analyzed collectively and as individual data sets. Additional data sets for proto-1450 material lots are also included in the analysis. The data cover 36 years of activity by the National Institute of Standards and Technology (NIST) in developing and providing thermal insulation SRMs, specifically high-density molded fibrous-glass board, to the public. Collectively, the data sets cover two nominal thicknesses of 13 mm and 25 mm, bulk densities from 60 kg.m(-3) to 180 kg.m(-3), and mean temperatures from 100 K to 340 K. The analysis repetitively fits six models to the individual data sets. The most general form of the nested set of multilinear models used is given in the following equation: [Formula: see text]where lambda(rho,T) is the predicted thermal conductivity (W.m(-1).K(-1)), rho is the bulk density (kg.m( 3)), T is the mean temperature (K) and ai (for i = 1, 2, ... 6) are the regression coefficients. The least squares fit results for each model across all data sets are analyzed using both graphical and analytic techniques. The prevailing generic model for the majority of data sets is the bilinear model in rho and T. [Formula: see text] One data set supports the inclusion of a cubic temperature term and two data sets with low-temperature data support the inclusion of an exponential term in T to improve the model predictions. Physical interpretations of the model function terms are described. Recommendations for future renewals of SRM 1450 are provided. An Addendum provides historical background on the origin of this SRM and the influence of the SRM on external measurement programs. PMID- 26601036 TI - Introduction to Special NIST Journal of Research Issue on Additive Manufacturing. PMID- 26601035 TI - A Review of NIST Primary Activity Standards for (18)F: 1982 to 2013. AB - The new NIST activity standardization for (18)F, described in 2014 in Applied Radiation and Isotopes (v. 85, p. 77), differs from results obtained between 1998 and 2008 by 4 %. The new results are considered to be very reliable; they are based on a battery of robust primary measurement techniques and bring the NIST standard into accord with other national metrology institutes. This paper reviews all ten (18)F activity standardizations performed at NIST from 1982 to 2013, with a focus on experimental variables that might account for discrepancies. We have identified many possible sources of measurement bias and eliminated most of them, but we have not adequately accounted for the 1998-2008 results. PMID- 26601037 TI - Mechanical Properties of Austenitic Stainless Steel Made by Additive Manufacturing. AB - Using uniaxial tensile and hardness testing, we evaluated the variability and anisotropy of the mechanical properties of an austenitic stainless steel, UNS S17400, manufactured by an additive process, selective laser melting. Like wrought materials, the mechanical properties depend on the orientation introduced by the processing. The recommended stress-relief heat treatment increases the tensile strength, reduces the yield strength, and decreases the extent of the discontinuous yielding. The mechanical properties, assessed by hardness, are very uniform across the build plate, but the stress-relief heat treatment introduced a small non-uniformity that had no correlation to position on the build plate. Analysis of the mechanical property behavior resulted in four conclusions. (1) The within-build and build-to-build tensile properties of the UNS S17400 stainless steel are less repeatable than mature engineering structural alloys, but similar to other structural alloys made by additive manufacturing. (2) The anisotropy of the mechanical properties of the UNS S17400 material of this study is larger than that of mature structural alloys, but is similar to other structural alloys made by additive manufacturing. (3) The tensile mechanical properties of the UNS S17400 material fabricated by selective laser melting are very different from those of wrought, heat-treated 17-4PH stainless steel. (4) The large discontinuous yielding strain in all tests resulted from the formation and propagation of Luders bands. PMID- 26601038 TI - Sustainability Characterization for Additive Manufacturing. AB - Additive manufacturing (AM) has the potential to create geometrically complex parts that require a high degree of customization, using less material and producing less waste. Recent studies have shown that AM can be an economically viable option for use by the industry, yet there are some inherent challenges associated with AM for wider acceptance. The lack of standards in AM impedes its use for parts production since industries primarily depend on established standards in processes and material selection to ensure the consistency and quality. Inability to compare AM performance against traditional manufacturing methods can be a barrier for implementing AM processes. AM process sustainability has become a driver due to growing environmental concerns for manufacturing. This has reinforced the importance to understand and characterize AM processes for sustainability. Process characterization for sustainability will help close the gaps for comparing AM performance to traditional manufacturing methods. Based on a literature review, this paper first examines the potential environmental impacts of AM. A methodology for sustainability characterization of AM is then proposed to serve as a resource for the community to benchmark AM processes for sustainability. Next, research perspectives are discussed along with relevant standardization efforts. PMID- 26601039 TI - An Additive Manufacturing Test Artifact. AB - A test artifact, intended for standardization, is proposed for the purpose of evaluating the performance of additive manufacturing (AM) systems. A thorough analysis of previously proposed AM test artifacts as well as experience with machining test artifacts have inspired the design of the proposed test artifact. This new artifact is designed to provide a characterization of the capabilities and limitations of an AM system, as well as to allow system improvement by linking specific errors measured in the test artifact to specific sources in the AM system. The proposed test artifact has been built in multiple materials using multiple AM technologies. The results of several of the builds are discussed, demonstrating how the measurement results can be used to characterize and improve a specific AM system. PMID- 26601040 TI - Characterization of Metal Powders Used for Additive Manufacturing. AB - Additive manufacturing (AM) techniques can produce complex, high-value metal parts, with potential applications as critical parts, such as those found in aerospace components. The production of AM parts with consistent and predictable properties requires input materials (e.g., metal powders) with known and repeatable characteristics, which in turn requires standardized measurement methods for powder properties. First, based on our previous work, we assess the applicability of current standardized methods for powder characterization for metal AM powders. Then we present the results of systematic studies carried out on two different powder materials used for additive manufacturing: stainless steel and cobalt-chrome. The characterization of these powders is important in NIST efforts to develop appropriate measurements and standards for additive materials and to document the property of powders used in a NIST-led additive manufacturing material round robin. An extensive array of characterization techniques was applied to these two powders, in both virgin and recycled states. The physical techniques included laser diffraction particle size analysis, X-ray computed tomography for size and shape analysis, and optical and scanning electron microscopy. Techniques sensitive to structure and chemistry, including X ray diffraction, energy dispersive analytical X-ray analysis using the X-rays generated during scanning electron microscopy, and X-Ray photoelectron spectroscopy were also employed. The results of these analyses show how virgin powder changes after being exposed to and recycled from one or more Direct Metal Laser Sintering (DMLS) additive manufacturing build cycles. In addition, these findings can give insight into the actual additive manufacturing process. PMID- 26601041 TI - Porosity Measurements and Analysis for Metal Additive Manufacturing Process Control. AB - Additive manufacturing techniques can produce complex, high-value metal parts, with potential applications as critical metal components such as those found in aerospace engines and as customized biomedical implants. Material porosity in these parts is undesirable for aerospace parts - since porosity could lead to premature failure - and desirable for some biomedical implants - since surface breaking pores allows for better integration with biological tissue. Changes in a part's porosity during an additive manufacturing build may also be an indication of an undesired change in the build process. Here, we present efforts to develop an ultrasonic sensor for monitoring changes in the porosity in metal parts during fabrication on a metal powder bed fusion system. The development of well characterized reference samples, measurements of the porosity of these samples with multiple techniques, and correlation of ultrasonic measurements with the degree of porosity are presented. A proposed sensor design, measurement strategy, and future experimental plans on a metal powder bed fusion system are also presented. PMID- 26601042 TI - Towards a Standard Mixed-Signal Parallel Processing Architecture for Miniature and Microrobotics. AB - The conventional analog-to-digital conversion (ADC) and digital signal processing (DSP) architecture has led to major advances in miniature and micro-systems technology over the past several decades. The outlook for these systems is significantly enhanced by advances in sensing, signal processing, communications and control, and the combination of these technologies enables autonomous robotics on the miniature to micro scales. In this article we look at trends in the combination of analog and digital (mixed-signal) processing, and consider a generalized sampling architecture. Employing a parallel analog basis expansion of the input signal, this scalable approach is adaptable and reconfigurable, and is suitable for a large variety of current and future applications in networking, perception, cognition, and control. PMID- 26601043 TI - The Metrology of a Rastered Spot of X Rays used in Security Screening. AB - In recent times, ionizing radiation has been used around the world to screen persons for non-medical purposes, namely to detect bulk explosives or other contraband hidden on the body including materials not registered by metal detectors. In contrast to conventional transmission or projection imaging, backscatter and forward-scatter systems employ a "flying spot" of x rays and large-area detectors. A small spot is rastered across an individual and the Compton scatter signal collected by these detectors is quickly integrated and assigned to a pixel value in an image corresponding to the transient location of the small flying spot. These systems have been controversial due in part to possible radiation health risks, and lack of independent and accurate measurements of radiation exposures to the subjects, bystanders, and operators of such systems. In this paper we will outline the techniques and instrumentation used at the National Institute of Standards and Technology (NIST) to accurately determine the incident air kerma from a swept beam of x rays. We discuss in detail the response of a large-area free-air ionization chamber under the unusual temporal and spatial radiation fields delivered by commercial scanning systems and report typical values for air kerma levels as well as estimates of air kerma rates. PMID- 26601044 TI - New National Air-Kerma Standard for Low-Energy Electronic Brachytherapy Sources. AB - The new primary standard for low-energy electronic brachytherapy sources for the United States is described. These miniature x-ray tubes are inserted in catheters for interstitial radiation therapy and operate at tube potentials of up to about 50 kV. The standard is based on the realization of the air kerma produced by the x-ray beam at a reference distance in air of 50 cm. PMID- 26601045 TI - Fired Cartridge Case Identification Using Optical Images and the Congruent Matching Cells (CMC) Method. AB - The Congruent Matching Cells (CMC) method for ballistics identification was invented at the National Institute of Standards and Technology (NIST). The CMC method is based on the correlation of pairs of small correlation cells instead of the correlation of entire images. Four identification parameters - T CCF, T theta, T x and T y are proposed for identifying correlated cell pairs originating from the same firearm. The correlation conclusion (matching or non-matching) is determined by whether the number of CMC is >= 6. This method has been previously validated using a set of 780 pair-wise 3D topography images. However, most ballistic images stored in current local and national databases are in an optical intensity (grayscale) format. As a result, the reliability of applying the CMC method on optical intensity images is an important issue. In this paper, optical intensity images of breech face impressions captured on the same set of 40 cartridge cases are correlated and analyzed for the validation test of CMC method using optical images. This includes correlations of 63 pairs of matching images and 717 pairs of non-matching images under top ring lighting. Tests of the method do not produce any false identification (false positive) or false exclusion (false negative) results, which support the CMC method and the proposed identification criterion, C = 6, for firearm breech face identifications using optical intensity images. PMID- 26601046 TI - A Low-Cost Time Transfer Receiver for Contributions to Coordinated Universal Time. AB - This paper describes a low-cost time transfer receiver that allows timing laboratories, including national metrology institutes and other designated institutions, to contribute data to the computation of Coordinated Universal Time (UTC). The time transfer receiver compares a laboratory's local realization of UTC, to signals broadcast by Global Positioning System (GPS) satellites. It stores the measurement results in a format compatible with international standards, and sends data via the Internet to the Bureau International des Poids et Mesures (BIPM) for inclusion in the UTC computation. In addition to being inexpensive, the receiver was designed to be easy to use, allowing recently established timing laboratories to begin contributing to UTC with a minimal investment in training. PMID- 26601047 TI - Optical Properties of CdSe/ZnS Nanocrystals. AB - Measurements are presented of the absorbance, fluorescence emission, fluorescence quantum yield, and fluorescence lifetime of CdSe/ZnS nanocrystals, also known as quantum dots (QDs). The study included three groups of nanocrystals whose surfaces were either passivated with organic molecules, modified further with carboxyl groups, or conjugated with CD14 mouse anti-human antibodies. The surface modifications had observable effects on the optical properties of the nanocrystals. The oscillator strength (OS) of the band edge transition was about 1.0 for the nanocrystals emitting at 565 nm, 605 nm, and 655 nm. The OS could not be determined for QDs with emission at 700 nm and 800 nm. The fluorescence lifetimes varied from 26 ns for nanocrystals emitting near 600 nm to 150 ns for nanocrystals emitting near 800 nm. The quantum yield ranged between 0.4 and 0.9 for the nanocrystals in this study. A brightness index (BI) was used to evaluate the suitability of the nanocrystal labels for flow cytometer measurements. Most QD labels are at least as bright as fluorescein for applications in flow cytometer assays with 488 nm excitation. For optimal brightness the QDs should be excited with 405 nm light. We observed a strong dependence of the QD absorbance at 250 nm on the surface modification of the QD. PMID- 26601048 TI - Measurement of Microsphere Concentration Using a Flow Cytometer with Volumetric Sample Delivery. AB - Microsphere concentrations are needed to assign equivalent reference fluorophores (ERF) units to microspheres used in quantitative flow cytometry. A flow cytometer with a syringe based sample delivery system was evaluated for the measurement of the concentration of microspheres contained in a vial of lyophilized microspheres certified by BD Biosciences to contain 50,600 microspheres. The concentration was measured by counting the number of microspheres contained in the volume delivered by the flow cytometer and dividing the number by the volume. The syringe volume was calibrated both in the delivery and draw modes, and the results of the volume calibration were summarized by two calibration lines. The delivered volume was obtained by dividing the number of recorded events by the concentration of microsphere count standard in the sample tube. The draw volume was obtained by weighting the sample tube before and after the draw. The slope of the draw volume calibration line was equal to 1.00 with an offset of -13 uL. The slope of the delivered volume calibration was 0.93 suggesting a systematic volume-dependent bias, which can be rationalized as an effect of suspension flow in capillaries. When the sample volume was set to values between 150 uL and 300 uL, both calibration curves gave similar results suggesting that a good estimate of the true delivered volume can be obtained by subtracting 13 uL from the delivered volume indicated by the syringe settings. The number of microspheres in the volume was obtained by passing the suspension contained in the volume through a laser beam and counting the number of events in which the signals from the scattering and fluorescence detectors exceeded threshold values. Measurements were performed with the lyophilized microspheres made by BD Biosciences and fluorescein microspheres (expired reference material RM 8640) in three buffers: a phosphate buffer saline (PBS), a buffer containing PBS and 0.05 % BSA (bovine serum albumin) by mass, and a buffer containing PBS and 0.05 % TWEEN 20 detergent solution (P1379 Sigma-Aldrich) by mass. It was found that the concentration of count standard was significantly higher in the PBS+BSA buffer relative to the value obtained in PBS buffer. Values for PBS+0.05 % TWEEN 20 buffer were intermediate. The effect of buffer on the measured microsphere concentration was reported previously. The suggested procedure for the measurement of the concentration of microspheres with the flow cytometer is to use PBS+0.05 % BSA buffer, accumulate data for a delivered volume of 150 uL to 300 uL, and reduce the indicated delivered volume by 13 uL when performing the concentration calculation. The procedure was tested on a mixture of lyophilized microspheres and RM 8640 microspheres. The resulting lyophilized microsphere concentration was consistent with the certified value. The RM 8640 concentration determined using the suggested procedure was consistent with the concentration value determined using the relative method with the lyophilized microspheres as the reference. The uncertainties, obtained from one standard deviation of repeated measurements, were about 4 %. PMID- 26601049 TI - The Use of Index-Matched Beads in Optical Particle Counters. AB - In this paper, we demonstrate the use of 2-pyridinemethanol (2P) aqueous solutions as a refractive index matching liquid. The high refractive index and low viscosity of 2P-water mixtures enables refractive index matching of beads that cannot be index matched with glycerol-water or sucrose-water solutions, such as silica beads that have the refractive index of bulk fused silica or of polymethylmethacrylate beads. Suspensions of beads in a nearly index-matching liquid are a useful tool to understand the response of particle counting instruments to particles of low optical contrast, such as aggregated protein particles. Data from flow imaging and light obscuration instruments are presented for bead diameters ranging from 6 um to 69 um, in a matrix liquid spanning the point of matched refractive index. PMID- 26601050 TI - Recovery of Background Structures in Nanoscale Helium Ion Microscope Imaging. AB - This paper discusses a two step enhancement technique applicable to noisy Helium Ion Microscope images in which background structures are not easily discernible due to a weak signal. The method is based on a preliminary adaptive histogram equalization, followed by 'slow motion' low-exponent Levy fractional diffusion smoothing. This combined approach is unexpectedly effective, resulting in a companion enhanced image in which background structures are rendered much more visible, and noise is significantly reduced, all with minimal loss of image sharpness. The method also provides useful enhancements of scanning charged particle microscopy images obtained by composing multiple drift-corrected 'fast scan' frames. The paper includes software routines, written in Interactive Data Language (IDL),(1) that can perform the above image processing tasks. PMID- 26601051 TI - The Second National Ballistics Imaging Comparison (NBIC-2). AB - In response to the guidelines issued by the American Society of Crime Laboratory Directors/Laboratory Accreditation Board (ASCLD/LAB-International) to establish traceability and quality assurance in U.S. crime laboratories, NIST and the ATF initiated a joint project, entitled the National Ballistics Imaging Comparison (NBIC). The NBIC project aims to establish a national traceability and quality system for ballistics identifications in crime laboratories utilizing ATF's National Integrated Ballistics Information Network (NIBIN). The original NBIC was completed in 2010. In the second NBIC, NIST Standard Reference Material (SRM) 2461 Cartridge Cases were used as reference standards, and 14 experts from 11 U.S. crime laboratories each performed 17 image acquisitions and correlations of the SRM cartridge cases over the course of about half a year. Resulting correlation scores were collected by NIST for statistical analyses, from which control charts and control limits were developed for the proposed quality system and for promoting future assessments and accreditations for firearm evidence in U.S. forensic laboratories in accordance with the ISO 17025 Standard. PMID- 26601052 TI - The Prognostic Role and Relationship between E2F1 and SV40 in Diffuse Large B Cell Lymphoma of Egyptian Patients. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphomas worldwide. The pathogenesis of lymphomas is not yet well understood. SV40 induces malignant transformation by the large T-antigen (L-TAG) and promotes transformation by binding and inactivating p53 and pRb. L-TAG can bind pRb promoting the activation of the E2F1 transcription factor, thus inducing the expression of genes required for the entry to the S phase and leading to cell transformation. This immunohistochemical study was conducted to assess the prognostic role and relationship of SV40 L-TAG and E2F1 in diffuse large B-cell lymphoma (DLBCL) of Egyptian patients. This retrospective study was conducted on 105 tissue specimens including 20 follicular hyperplasia and 85 DLBCL cases. SV40 L-TAG was identified in 3/85 (4%) of DLBCL. High Ki-67 labeling index (Ki-67 LI) and apoptotic count were associated with high E2F1 expression (p<0.001 for all). No significant association was reached between E2F1 and SV40. E2F1 expression proved to be the most and first independent prognostic factor on overall survival of DLBCL patients (HR = 5.79, 95% CI = 2.3-14.6, and p<0.001). Upregulation of E2F1 has been implicated in oncogenesis, prognosis, and prediction of therapeutic response but is not seemingly to have a relationship with the accused SV40. PMID- 26601053 TI - Weight and blood pressure reduction among participants engaged in a cancer awareness and prevention program. AB - OBJECTIVES: African-Americans consume a diet high in fat, salt and sugar; such dietary habits increase the risks of cancer and other chronic diseases. The objective of this study was to engage rural communities in a nutrition and physical activity behavior modification program to promote cancer awareness and risk reduction. METHODS: Focus group discussions were conducted to generate information for the development of a nutrition and physical activity program. African Americans (N=62) from two rural counties (Bullock and Macon) in Alabama participated in a year-long intervention program in 2012 and 2013. Weight loss and blood pressure were evaluated to measure the impact of the intervention. RESULTS: Themes emerged for the focus group discussions were: nutrition, health, family, environment, and resource access. In Macon County participants lost weight irrespective of the exercise regimen, with those involved in floor exercise losing the most weight (-22.4 lbs, or-11.18 % change), while in Bullock county walking was most effective in weight loss (6.1 lbs or -3.40 % change) p<0.05. Systolic and diastolic pressure decreased from 5.3 to 10.5 mm Hg; -2.0 to -6.4 mmHg, respectively, for Bullock county, except for the walking group,). In Macon County, both systolic and diastolic pressure % change ranged from -8.94 to 12.66 and -5.34 to 12.66 mmHg respectively, irrespective of physical activity respectively. CONCLUSION: In this study, changes in weight lost and blood pressure were observed among individuals engaged in a nutrition education and physical activity program. PMID- 26601054 TI - Experience with targeted next generation sequencing for the care of lung cancer: insights into promises and limitations of genomic oncology in day-to-day practice. AB - INTRODUCTION: Tumor genotyping using single gene assays (SGAs) is standard practice in advanced non-small-cell lung cancer (NSCLC). We evaluated how the introduction of next generation sequencing (NGS) into day-to-day clinical practice altered therapeutic decision-making. METHODS: Clinicopathologic data, tumor genotype, and clinical decisions were retrospectively compiled over 6 months following introduction of NGS assay use at our institution in 82 patient tumor samples (7 by primary NGS, 22 by sequential SGAs followed by NGS, and 53 by SGAs). RESULTS: SGAs identified abnormalities in 34 samples, and all patients with advanced EGFR-mutated or ALK-rearranged tumors received approved tyrosine kinase inhibitors (TKIs) or were consented for clinical trials. NGS was more commonly requested for EGFR, ALK, and KRAS-negative tumors (p<0.0001). NGS was successful in 24/29 (82.7%) tumors. Of 17 adenocarcinomas (ACs), 11 (7 from patients with <=15 pack-years of smoking) had abnormalities in a known driver oncogene. This led to a change in decision-making in 8 patients, trial consideration in 6, and off-label TKI use in 2. Of 7 squamous cell (SC) carcinomas, 1 had a driver aberration (FGFR1); 6 had other genomic events (all with TP53 mutations). In no cases were clinical decisions altered (p=0.0538 when compared to ACs). CONCLUSIONS: Targeted NGS can identify a significant number of therapeutically-relevant driver events in lung ACs; particularly in never or light smokers. For SC lung cancers, NGS is less likely to alter current practice. Further research into the cost effectiveness and optimal use of NGS and improved provider training in genomic oncology are warranted. PMID- 26601055 TI - Conversion total hip arthroplasty: Primary or revision total hip arthroplasty. AB - Total hip arthroplasty (THA) is an increasingly common procedure among elderly individuals. Although conversion THA is currently bundled in a diagnosis related group (DRG) with primary THA, there is a lack of literature supporting this classification and it has yet to be identified whether conversion THA better resembles primary or revision THA. This editorial analyzed the intraoperative and postoperative factors and functional outcomes following conversion THA, primary THA, and revision THA to understand whether the characteristics of conversion THA resemble one procedure or the other, or are possibly somewhere in between. The analysis revealed that conversion THA requires more resources both intraoperatively and postoperatively than primary THA. Furthermore, patients undergoing conversion THA present with poorer functional outcomes in the long run. Patients undergoing conversion THA better resemble revision THA patients than primary THA patients. As such, patients undergoing conversion THA should not be likened to patients undergoing primary THA when determining risk stratification and reimbursement rates. Conversion THA procedures should be planned accordingly with proper anticipation of the greater needs both in the operating room, and for in-patient and follow-up care. We suggest that conversion THA be reclassified in the same DRG with revision THA as opposed to primary THA as a step towards better allocation of healthcare resources for conversion hip arthroplasties. PMID- 26601056 TI - Orthopedic cellular therapy: An overview with focus on clinical trials. AB - In this editorial, the authors tried to evaluate the present state of cellular therapy in orthopedic field. The topics the authors try to cover include not only the clinical trials but the various research areas as well. Both the target diseases for cellular therapy and the target cells were reviewed. New methods to activate the cells were interesting to review. Most advanced clinical trials were also included because several of them have advanced to phase III clinical trials. In the orthopedic field, there are many diseases with a definite treatment gap at this time. Because cellular therapies can regenerate damaged tissues, there is a possibility for cellular therapies to become disease modifying drugs. It is not clear whether cellular therapies will become the standard of care in any of the orthopedic disorders, however the amount of research being performed and the number of clinical trials that are on-going make the authors believe that cellular therapies will become important treatment modalities within several years. PMID- 26601057 TI - Effects of exercise on physical limitations and fatigue in rheumatic diseases. AB - Physical activity covers not just sports but also simple everyday movements such as housework, walking and playing. Regular exercise has a great importance in maintaining good health, indeed inactivity is a risk factor for different chronic diseases. Physical exercise can play a crucial role in the treatment of rheumatic diseases, optimizing both physical and mental health, enhancing energy, decreasing fatigue and improving sleep. An exercise program for patients with rheumatic diseases aims to preserve or restore a range of motion of the affected joints, to increase muscle strength and endurance, and to improve mood and decrease health risks associated with a sedentary lifestyle. In this editorial I describe the benefits of the exercise on physical limitations and fatigue in rheumatic diseases that seem to have a short and long-term effectiveness. A literature review was conducted on PubMed, Scopus and Google Scholar using appropriate keywords based on the present editorial. PMID- 26601058 TI - Treatment options for irreparable postero-superior cuff tears in young patients. AB - Rotator cuff tears (RCTs) occur more commonly with advanced age, with most rotator cuff abnormalities in patients less than 30 years old being painful tendinoses or partial-thickness RCTs. Irreparable postero-superior cuff tears has been reported as frequent as 7% to 10% in the general population, and the incidence of irreparable RCTs in young patients is still unknown. Several surgical procedures have been proposed for young patients with irreparable postero-superior RCTs, such as rotator cuff debridement, partial rotator cuff repair, biceps tenotomy/tenodesis, rotator cuff grafting, latissimus dorsi tendon transfer, and reverse shoulder arthroplasty. After being thoroughly investigated in open surgery, arthroscopic techniques for latissimus dorsi tendon transfer have been recently described. They have been shown to be an adequate option to open surgery for managing irreparable postero-superior RCTs refractory to conservative management. PMID- 26601059 TI - Surgical management of osteonecrosis of the femoral head in patients with sickle cell disease. AB - Sickle cell disease is a known risk factor for osteonecrosis of the hip. Necrosis within the femoral head may cause severe pain, functional limitations, and compromise quality of life in this patient population. Early stages of avascular necrosis of the hip may be managed surgically with core decompression with or without autologous bone grafting. Total hip arthroplasty is the mainstay of treatment of advanced stages of the disease in patients who have intractable pain and are medically fit to undergo the procedure. The management of hip pathology in sickle cell disease presents numerous medical and surgical challenges, and the careful perioperative management of patients is mandatory. Although there is an increased risk of medical and surgical complications in patients with sickle cell disease, total hip arthroplasty can provide substantial relief of pain and improvement of function in the appropriately selected patient. PMID- 26601060 TI - Collecting shoulder kinematics with electromagnetic tracking systems and digital inclinometers: A review. AB - The shoulder complex presents unique challenges for measuring motion as the scapula, unlike any other bony segment in the body, glides and rotates underneath layers of soft tissue and skin. The ability for clinicians and researchers to collect meaningful kinematic data is dependent on the reliability and validity of the instrumentation utilized. The aim of this study was to review the relevant literature pertaining to the reliability and validity of electromagnetic tracking systems (ETS) and digital inclinometers for assessing shoulder complex motion. Advances in technology have led to the development of biomechanical instrumentation, like ETS, that allow for the collection of three-dimensional kinematic data. The existing evidence has demonstrated that ETS are reliable and valid instruments for collecting static and dynamic kinematic data of the shoulder complex. Similarly, digital inclinometers have become increasingly popular among clinicians due to their cost effectiveness and practical use in the clinical setting. The existing evidence supports the use of digital inclinometers for the collection of shoulder complex kinematics as these instruments have been demonstrated to yield acceptable reliability and validity. While digital inclinometers pose a disadvantage to ETS regarding accuracy, precision, and are limited to two-dimensional and static measurements, this instrument provides clinically meaningful data that allow clinicians and researchers the ability to measure, monitor, and compare shoulder complex kinematics. PMID- 26601061 TI - Anterior knee pain following primary total knee arthroplasty. AB - Despite improvements in technique and technology for total knee arthroplasty (TKA), anterior knee pain impacts patient outcomes and satisfaction. Addressing the prosthetic and surgical technique related causes of pain after TKA, specifically as it relates to anterior knee pain, can aid surgeons in addressing these issues with their patients. Design features of the femoral and patellar components which have been reported as pain generators include: Improper femoral as well as patellar component sizing or designs that result in patellofemoral stuffing; a shortened trochlear groove distance from the flange to the intercondylar box; and then surgical technique related issues resulting in: Lateral patellar facet syndrome; overstuffed patella/flange combination; asymmetric patellar resurfacing, improper transverse plane component rotation resulting in patellar subluxation/tilt. Any design consideration that allows impingement of extensor mechanism anatomical elements has the possibility of impacting outcome by becoming a pain generator. As the number of TKA procedures continues to increase, it is increasingly critical to develop improved, evidence based prostheses that maximize function and patient satisfaction while minimizing pain and other complications. PMID- 26601062 TI - Minimally invasive knee arthroplasty: An overview. AB - Minimally invasive surgery (MIS) for arthroplasty of the knee began with surgery for unicondylar knee arthroplasty (UKA). Partial knee replacements were designed in the 1970s and were amenable to a more limited exposure. In the 1990s Repicci popularized the MIS for UKA. Surgeons began to apply his concepts to total knee arthroplasty. Four MIS surgical techniques were developed: quadriceps sparing, mini-mid vastus, mini-subvastus, and mini-medial parapatellar. The quadriceps sparing technique is the most limited one and is also the most difficult. However, it is the least invasive and allows rapid recovery. The mini-midvastus is the most common technique because it affords slightly better exposure and can be extended. The mini-subvastus technique entirely avoids incising the quadriceps extensor mechanism but is time consuming and difficult in the obese and in the muscular male patient. The mini-parapatellar technique is most familiar to surgeons and represents a good starting point for surgeons who are learning the techniques. The surgeries are easier with smaller instruments but can be performed with standard ones. The techniques are accurate and do lead to a more rapid recovery, with less pain, less blood loss, and greater motion if they are appropriately performed. PMID- 26601063 TI - Review on squeaking hips. AB - Squeaking is a well-recognized complication for hard-on-hard bearings. The nature of squeaking is not yet completely understood however it is considered a multifactorial phenomenon. Patient, implant, and surgical factors play a role in squeaking. It is believed that mechanisms damaging the fluid film lubrication in which these bearings function optimally have a critical role. Such mechanisms include edge loading, stripe wear, impingement, third body particles and ceramic fracture. The resonance of metallic parts can produce noise in the human audible range hence the implant metallurgic composition and design may play a role. Implant positioning can facilitate impingement and edge loading enhancing the occurrence of squeaking. The recent introduction of large heads (> 36 mm) 4(th) generation ceramic-on-ceramic bearing may accentuate the conditions facilitating noise formation; however the current literature is insufficient. Clinically, squeaking may manifest in extreme hip positions or during normal gait cycle however it is rarely associated with pain. Evaluations of patients with squeaking include clinical and radiographic assessments. Computer tomography is recommended as it can better reveal ceramic breakage and implant malposition. The treatments for most squeaking patients include reassurance and activity modification. However for some, noise can be a problem, requiring further surgical intervention. In the occurrence of ceramic fracture, implant failure, extreme components malposition, instability and impingement, surgery should be advised. This review will aim to discuss the current literature regarding squeaking. PMID- 26601064 TI - Novel computer-assisted method for revision arthroplasty of the knee. AB - AIM: To introduce the navigation system of software and instruments designed specifically for revision total knee arthroplasty (TKA). METHODS: We present an imageless navigation system for revision TKA, with optical point and tracker identification to assess kinematic and anatomical landmarks. The system automatically positions the cutting guides with a motorized cutting unit. The cutting unit is placed on the distal femur with a femoral clamp and acts as a rigid body and the base for all femoral cuts. The surgical technique for using the navigation system for revision TKA is based on the technique used in primary TKA. However, there are some important differences. The most notable are: (1) differences in estimation of the position of the primary implant relative to the bone and the mechanical axes; (2) the specific possibilities the revision navigation software offers in terms of optimal joint level positioning; and (3) the suggested "best fit" position, in which the clock position, stem position and offset, femoral component size, and mediolateral position of the femoral component are taken into account to find the optimal femoral component position. We assessed the surgical technique, and accompanying software procedural steps, of the system, identifying any advantages or disadvantages that they present. RESULTS: The system aims to visualize critical steps of the procedure and is intended as a tool to support the surgeon in surgical decision-making. Combining a computer-assisted cutting device with navigation makes it possible to carry out precise cuts without pinning. Furthermore, the femoral clamp provides a stable fixation mechanism for the motorized cutting unit. A stable clamp is paramount in the presence of periarticular bony defects. The system allows the position of the primary implant relative to the bone and mechanical axes to be estimated, at which point any malalignments can be corrected. It also offers an optimal joint level position for implantation, and suggests a "best fit" position, in which the clock position, stem position and offset, femoral component size, and mediolateral position of the femoral component are considered. The surgeon can therefore make decisions intraoperatively to maximise alignment and, hence, outcomes. Based on the intraoperative findings of joint stability, the surgeon can modify the preoperative plan and switch from a constrained condylar system to a hinged version, or vice versa. CONCLUSION: The system is flexible and easy to learn and allows improvements in workflow during TKA. PMID- 26601065 TI - Modified porous tantalum rod technique for the treatment of femoral head osteonecrosis. AB - AIM: To study a modified porous tantalum technique for the treatment of osteonecrosis of the femoral head. METHODS: The porous tantalum rod was combined with endoscopy, curettage, autologous bone grafting and use of bone marrow aspirates from iliac crest aspiration in 49 patients (58 hips) with a mean age of 38 years. The majority of the patients had idiopathic osteonecrosis, followed by corticosteroid-induced osteonecrosis. Thirty-eight hips were of Steinberg stage II disease and 20 hips were of stage III disease. Patients were followed for 5 years and were evaluated clinically with the Merle D'Aubigne and Postel score and radiologically. The primary outcome of the study was survival based on the conversion to total hip arthroplasty (THA). Secondary outcomes included deterioration of the osteonecrosis to a higher disease stage at 5 years compared to the preoperative period and identification of factors that were associated with survival. The Kaplan-Meier survival analysis was performed to evaluate the survivorship of the prosthesis, and the Fisher exact test was performed to test associations between various parameters with survival. RESULTS: No patient developed any serious intraoperative or postoperative complication including implant loosening or migration and donor site morbidity. During the 5-year follow up, 1 patient died, 7 patients had disease progression and 4 hips were converted to THA. The 5-year survival based on conversion to THA was 93.1% and the respective rate based on disease progression was 87.9%. Stage II disease was associated with statistically significant better survival rates compared to stage III disease (P = 0.04). The comparison between idiopathic and non-idiopathic osteonecrosis and between steroid-induced and non-steroid-induced osteonecrosis did not showed any statistically significant difference in survival rates. The clinical evaluation revealed statistically significantly improved Merle d'Aubigne scores at 12 mo postoperatively compared to the preoperative period (P < 0.001). The mean preoperative Merle d'Aubigne score was 13.0 (SD: 1.8). The respective score at 12 mo improved to 17.0 (SD: 2.0). The 12-mo mean score was retained at 5 years. CONCLUSION: The modified porous tantalum rod technique presented here showed encouraging outcomes. The survival rates based on conversion to THA are the lowest reported in the published literature. PMID- 26601066 TI - Operative vs non-operative management of displaced proximal humeral fractures in the elderly: A systematic review and meta-analysis of randomized controlled trials. AB - AIM: To perform a systematic review and meta-analysis comparing operative vs non operative treatment of displaced proximal humerus fractures in elderly patients. METHODS: A systematic literature search was performed using EMBASE and MEDLINE through the OVID interface, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL), Proquest, Web of Science, SAE digital library, and Transportation Research Board's TRID database. Searches of conference proceedings were also conducted. All available randomized controlled trials comparing operative vs non-operative management of displaced three- and four-part proximal humerus fractures in elderly patients were included. The primary outcomes measures included physical function, pain, health related quality of life, mortality, and the re-operation rate. RESULTS: Six randomized controlled trials (n = 287) were included. There was no statistically significant difference in function (MD = 1.72, 95%CI: -2.90-6.34, P = 0.47), as measured by the Constant score, between the operative and the non-operative treatment groups. There was no statistically significance difference in secondary outcomes of health related quality of life (standardized MD = 0.27, 95%CI: -0.05-0.59, P = 0.09), and mortality (relative risk 1.29, 95%CI: 0.50- 3.35, P = 0.60). Operative treatment had a statistically significant higher re-operation rate (relative risk 4.09, 95%CI: 1.50-11.15, P = 0.006), and statistically significant decreased pain (MD = 1.26, 95%CI: 0.02- 2.49, P = 0.05). CONCLUSION: There is moderate quality evidence to suggest that there is no difference in functional outcomes between the two treatments. Further high quality randomized controlled trials are required to determine if certain subgroup populations benefit from surgical management. PMID- 26601067 TI - "Push back" technique: A simple method to remove broken drill bit from the proximal femur. AB - Broken drill bits can be difficult to remove from the proximal femur and may necessitate additional surgical exploration or special instrumentation. We present a simple technique to remove a broken drill bit that does not require any special instrumentation and can be accomplished through the existing incision. This technique is useful for those cases where the length of the broken drill bit is greater than the diameter of the bone. PMID- 26601068 TI - Understanding the Healthy Thyroid State in 2015. AB - Thyroid hormones (TH) are of crucial importance for the physiological function of almost all organs. In cases of abnormal TH signaling, pathophysiological consequences may arise. The routine assessment of a healthy or diseased thyroid function state is currently based on the determination of serum concentrations of thyroid-stimulating hormone (TSH), and the TH T3 and T4. However, the definition of a 'normal' TSH range and similarly 'normal' T3 and T4 concentrations remains the subject of debate in different countries worldwide and has important implications on patient treatment in clinics. Not surprisingly, a significant number of patients whose thyroid function tests are biochemically determined to be within the normal range complain of impaired well-being. The reasons for this are so far not fully understood, but it has been recognized that thyroid function status needs to be 'individualized' and extended beyond simple TSH measurement. Thus, more precise and reliable parameters are required in order to optimally define the healthy thyroid status of an individual, and as a perspective to employ these in clinical routine. With the recent identification of new key players in TH action, a more accurate assessment of a patient's thyroid status may in the future become possible. Recently described distinct TH derivatives and metabolites, TH transporters, nongenomic TH effects (either through membrane bound or cytosolic signaling), and classical nuclear TH action allow for insights into molecular and cellular preconditions of a healthy thyroid state. This will be a prerequisite to improve management of thyroid dysfunction, and additionally to prevent and target TH-related nonthyroid disease. PMID- 26601069 TI - Evolutionary Conservation of 3-Iodothyronamine as an Agonist at the Trace Amine Associated Receptor 1. AB - OBJECTIVES: The trace amine-associated receptor 1 (Taar1) is a Gs protein-coupled receptor activated by trace amines, such as beta-phenylethylamine (beta-PEA) and 3-iodothyronamine (T1AM). T1AM is an endogenous biogenic amine and thyroid hormone derivative that exerts several biological functions. However, the physiological relevance of T1AM acting via Taar1 is still under discussion. Therefore, we studied the structural and functional evolution of Taar1 in vertebrates to provide evidence for a conserved Taar1-mediated T1AM function. STUDY DESIGN: We searched public sequence databases to retrieve Taar1 sequence information from vertebrates. We cloned and functionally characterized Taar1 from selected vertebrate species using cAMP assays to determine the evolutionary conservation of T1AM action at Taar1. RESULTS: We found intact open reading frames of Taar1 in more than 100 vertebrate species, including mammals, sauropsids and amphibians. Evolutionary conservation analyses of Taar1 protein sequences revealed a high variation in amino acid residues proposed to be involved in agonist binding, especially in rodent Taar1 orthologs. Functional characterization showed that T1AM, beta-PEA and p-tyramine (p-Tyr) act as agonists at all tested orthologs, but EC50 values of T1AM at rat Taar1 differed significantly when compared to all other tested vertebrate Taar1. CONCLUSIONS: The high structural conservation of Taar1 throughout vertebrate evolution highlights the physiological relevance of Taar1, but species-specific differences in T1AM potency at Taar1 orthologs suggest a specialization of rat Taar1 for T1AM recognition. In contrast, beta-PEA and p-Tyr potencies were rather conserved throughout all tested Taar1 orthologs. We provide evidence that the observed differences in potency are related to differences in constraint during Taar1 evolution. PMID- 26601070 TI - The Multitarget Ligand 3-Iodothyronamine Modulates beta-Adrenergic Receptor 2 Signaling. AB - BACKGROUND: 3-Iodothyronamine (3-T1AM), a signaling molecule with structural similarities to thyroid hormones, induces numerous physiological responses including reversible body temperature decline. One target of 3-T1AM is the trace amine-associated receptor 1 (TAAR1), which is a member of the rhodopsin-like family of G protein-coupled receptors (GPCRs). Interestingly, the effects of 3 T1AM remain detectable in TAAR1 knockout mice, suggesting further targets for 3 T1AM such as adrenergic receptors. Therefore, we evaluated whether beta adrenergic receptor 1 (ADRB1) and 2 (ADRB2) signaling is affected by 3-T1AM in HEK293 cells and in human conjunctival epithelial cells (IOBA-NHC), where these receptors are highly expressed endogenously. METHODS: A label-free EPIC system for prescreening the 3-T1AM-induced effects on ADRB1 and ADRB2 in transfected HEK293 cells was used. In addition, ADRB1 and ADRB2 activation was analyzed using a cyclic AMP assay and a MAPK reporter gene assay. Finally, fluorescence Ca(2+) imaging was utilized to delineate 3-T1AM-induced Ca(2+) signaling. RESULTS: 3 T1AM (10(-5)-10(-10)M) enhanced isoprenaline-induced ADRB2-mediated Gs signaling but not that of ADRB1-mediated signaling. MAPK signaling remained unaffected for both receptors. In IOBA-NHC cells, norepinephrine-induced Ca(2+) influxes were blocked by the nonselective ADRB blocker timolol (10 uM), indicating that ADRBs are most likely linked with Ca(2+) channels. Notably, timolol was also found to block 3-T1AM (10(-5)M)-induced Ca(2+) influx. CONCLUSIONS: The presented data support that 3-T1AM directly modulates beta-adrenergic receptor signaling. The relationship between 3-T1AM and beta-adrenergic signaling also reveals a potential therapeutic value for suppressing Ca(2+) channel-mediated inflammation processes, occurring in eye diseases such as conjunctivitis. PMID- 26601072 TI - Involvement of the L-Type Amino Acid Transporter Lat2 in the Transport of 3,3' Diiodothyronine across the Plasma Membrane. AB - Thyroid hormones are transported across cell membranes by transmembrane transporter proteins, for example by members of the monocarboxylate transporter (MCT) and the L-type amino acid transporter (LAT) families. LATs consist of a light chain (e.g. LAT2) and a heavy chain (CD98), which is essential for their cell surface expression and functionality. The specificity of Lat2 for thyroid hormones and their metabolites and its role in their transport was not fully clear. This fact motivated us to establish a cell system to elucidate the uptake of thyroid hormones and their metabolites by mouse Lat2. The coinjection of cRNA coding for Lat2 and CD98 into Xenopus laevis oocytes resulted in a markedly increased level of 3,3'-diiodo-L-thyronine (3,3'-T2) and to some extent also enhanced T3 transport. To gain insight into properties of thyroid hormones and their metabolites transported by Lat2, we inhibited 3,3'-T2 uptake by various iodothyronine derivatives. T1 and T2 derivatives as well as 2-aminobicyclo-[2, 2,1]-heptane-2-carboxylic acid strongly competed with 3,3'-T2 uptake. In addition, we performed T2 uptake measurements with the thyroid hormone-specific transporter MCT8. For both Lat2 and MCT8, Km values in a low micromolar range were calculated. We demonstrated that oocytes are a suitable system for thyroid hormone transport studies mediated by Lat2. Our data indicates that Lat2 compared to other thyroid hormone transporters prefers 3,3'-T2 as the substrate. Thus, Lat2 might contribute to the availability of thyroid hormone by importing and/or exporting 3,3'-T2, which is generated either by T3 inactivation or by rapid deiodinase 1-mediated rT3 degradation. PMID- 26601071 TI - Trace Amine-Associated Receptor 1 Localization at the Apical Plasma Membrane Domain of Fisher Rat Thyroid Epithelial Cells Is Confined to Cilia. AB - BACKGROUND: The trace amine-associated receptor 1 (Taar1) is one member of the Taar family of G-protein-coupled receptors (GPCR) accepting various biogenic amines as ligands. It has been proposed that Taar1 mediates rapid, membrane initiated effects of thyronamines, the endogenous decarboxylated and deiodinated relatives of the classical thyroid hormones T4 and T3. OBJECTIVES: Although the physiological actions of thyronamines in general and 3-iodothyronamine (T1AM) in particular are incompletely understood, studies published to date suggest that synthetic T1AM-activated Taar1 signaling antagonizes thyromimetic effects exerted by T3. However, the location of Taar1 is currently unknown. METHODS: To fill this gap in our knowledge we employed immunofluorescence microscopy and a polyclonal antibody to detect Taar1 protein expression in thyroid tissue from Fisher rats, wild-type and taar1-deficient mice, and in the polarized FRT cells. RESULTS: With this approach we found that Taar1 is expressed in the membranes of subcellular compartments of the secretory pathway and on the apical plasma membrane of FRT cells. Three-dimensional analyses further revealed Taar1 immunoreactivity in cilial extensions of postconfluent FRT cell cultures that had formed follicle like structures. CONCLUSIONS: The results suggest Taar1 transport along the secretory pathway and its accumulation in the primary cilium of thyrocytes. These findings are of significance considering the increasing interest in the role of cilia in harboring functional GPCR. We hypothesize that thyronamines can reach and activate Taar1 in thyroid follicular epithelia by acting from within the thyroid follicle lumen, their potential site of synthesis, as part of a nonclassical mechanism of thyroid autoregulation. PMID- 26601073 TI - Quantitative Analysis of Thyroid Hormone Metabolites in Cell Culture Samples Using LC-MS/MS. AB - A liquid-liquid extraction and liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS) method to determine iodothyronines and thyronamines (TAM) from cell culture media was developed. Thyroid hormones (TH) are metabolized by sequential deiodination to eventually yield thyronine (T0), but can also be decarboxylated, resulting in TAM. The method presented here for extraction of DMEM/F12 cell culture media is a fundamental procedure for a precise determination of 9 TH and 6 TAM from a single LC run. Analytes and internal standards (IS) were extracted from DMEM/F12 (w/o phenol red) by liquid liquid extraction using isopropanol-TBME (30:70 v/v). Measurement of TH and TAM was performed during a 10-min run time using (13)C6-T4, (13)C6-T3, (13)C6-rT3, (13)C6-3,3'T2 and (2)H4-T1AM as IS. Calibration curves covered 11 calibrators measured as triplicates each for the analysis of the 9 TH and 6 TAM metabolites, and the 5 IS were linear and reproducible in the range of 0.12-120 nM (R(2) 0.991 0.999) for all calibrators. The lower limit of quantification was 0.078-0.234 nM. Method validation and robustness were demonstrated by the analysis of precision, accuracy, process efficiency, matrix effects and recoveries, as well as intra- and interassay stability. These parameters were investigated for high, middle and low concentrations of quality controls of all 9 TH and 6 TAM metabolites. This validated, sensitive and interaction-free LC-MS/MS method allows rapid analysis and accurate determination of TH and TAM from DMEM/F12 (w/o phenol red) conditioned media and seems to be easily transferable and applied to commonly used buffers and cell culture media. PMID- 26601074 TI - The Effects of Thyroid Hormones on Gene Expression of Acyl-Coenzyme A Thioesterases in Adipose Tissue and Liver of Mice. AB - BACKGROUND: Thyroid hormones (TH) exert pleiotropic effects on glucose and lipid homeostasis. However, it is as yet unclear how TH regulate lipid storage and utilization in order to adapt to metabolic needs. Acyl-CoA thioesterases (ACOTs) have been proposed to play a regulatory role in the metabolism of fatty acids. OBJECTIVES: We investigated the interaction between thyroid dysfunction and Acot expression in adipose tissues and livers of thyrotoxic and hypothyroid mice. METHODS: Ten-week-old female C57BL/6NTac mice (n = 10/group) were made hyperthyroid by the application of L-thyroxine (2 ug/ml in drinking water) for 4 weeks. Hypothyroidism was induced in 10-week-old mice by feeding an iodine-free chow supplemented with 0.15% PTU for 4 weeks. We measured mRNA expression levels of Acot8, 11 and 13 in the liver and epididymal and inguinal white and brown adipose tissues (BAT). Furthermore, we investigated hepatic Acot gene expression in TRalpha- and TRbeta-deficient mice. RESULTS: We showed that the expression of Acot8, 11 and 13 is predominantly stimulated by a thyrotoxic state in the epididymal white adipose tissue. In contrast, hypothyroidism predominantly induces the expression of Acot8 in BAT in comparison with BAT of thyrotoxic and euthyroid mice (p < 0.01). However, no significant changes in Acot expression were observed in inguinal white adipose tissue. In liver, Acot gene expression is collectively elicited by a thyrotoxic state. CONCLUSIONS: These data suggest that ACOTs are targets of TH and are likely to influence 3,5,3'-triiodo-L-thyronine orchestrated mechanisms of lipid uptake, storage and utilization to adapt the regulation of metabolic demands. PMID- 26601075 TI - Sex-Dependent Claudin-1 Expression in the Liver of Euthyroid and Hypothyroid Mice. AB - BACKGROUND: In the liver the tight junction protein claudin-1 plays an important role in bile secretion by maintaining the paracellular barrier of bile canaliculi and the bile duct. A diminished bile excretion has been found in hypothyroid patients, and the prevalence of gallstones is increased in hypothyroidism. This association, however, only applies for men and is in contrast to the well established female preponderance of biliary disease in the general population. OBJECTIVES: We hypothesized that hypothyroidism could lead to altered claudin-1 expression in the liver, and that this effect may be sex specific. METHODS: We characterized claudin-1 expression and localization in livers of euthyroid and hypothyroid male and female C57BL/6NTac mice by real-time PCR, Western blot and immunofluorescence. RESULTS: Claudin-1 is expressed in canalicular regions and the bile ducts of the murine liver. Livers of female mice showed lower claudin-1 expression than male livers. In hypothyroid livers, female animals showed an elevated claudin-1 expression, whereas reduced claudin-1 expression was found in male animals compared to the euthyroid controls. CONCLUSION: We demonstrate a correlation between claudin-1 expression and hypothyroidism in the murine liver. Furthermore, a sex-dependent alteration of claudin-1 expression was found. PMID- 26601076 TI - Establishment of an Effective Radioiodide Thyroid Ablation Protocol in Mice. AB - Due to the high variance in available protocols on iodide-131 ((131)I) ablation in rodents, we set out to establish an effective method to generate a thyroid ablated mouse model that allows the application of the sodium iodide symporter (NIS) as a reporter gene without interference with thyroidal NIS. We tested a range of (131)I doses with and without prestimulation of thyroidal radioiodide uptake by a low-iodine diet and thyroid-stimulating hormone (TSH) application. Efficacy of induction of hypothyroidism was tested by measurement of serum T4 concentrations, pituitary TSHbeta and liver deiodinase type 1 (DIO1) mRNA expression, body weight analysis, and (99m)Tc-pertechnetate scintigraphy. While 200 uCi (7.4 MBq) (131)I alone was not sufficient to abolish thyroidal T4 production, 500 uCi (18.5 MBq) (131)I combined with 1 week of a low-iodine diet decreased serum concentrations below the detection limit. However, the high (131)I dose resulted in severe side effects. A combination of 1 week of a low iodine diet followed by injection of bovine TSH before the application of 150 uCi (5.5 MBq) (131)I decreased serum T4 concentrations below the detection limit and significantly increased pituitary TSHbeta concentrations. The systemic effects of induced hypothyroidism were shown by growth arrest and a decrease in liver DIO1 expression below the detection limit. (99m)Tc-pertechnetate scintigraphy revealed absence of thyroidal (99m)Tc-pertechnetate uptake in ablated mice. In summary, we report a revised protocol for radioiodide ablation of the thyroid gland in the mouse to generate an in vivo model that allows the study of thyroid hormone action using NIS as a reporter gene. PMID- 26601077 TI - Differences in Mouse Hepatic Thyroid Hormone Transporter Expression with Age and Hyperthyroidism. AB - BACKGROUND: Clinical features of thyroid dysfunction vary with age, and an oligosymptomatic presentation of hyperthyroidism is frequently observed in the elderly. This suggests age modulation of thyroid hormone (TH) action, which may occur, for example, by alterations in TH production, metabolism and/or TH action in target organs. OBJECTIVES: In this paper, we address possible changes in TH transporter expression in liver tissues as a mechanism of age-dependent variation in TH action. METHODS: Chronic hyperthyroidism was induced in 4- and 20-month-old C57BL6/NTac male mice (n = 8-10) by intraperitoneal injections of 1 ug/g body weight L-thyroxine (T4) every 48 h over 7 weeks. Control animals were injected with PBS. Total RNA was isolated from liver samples for analysis of the TH transporter and TH-responsive gene expression. TH concentrations were determined in mice sera. RESULTS: Baseline serum free T4 (fT4) concentrations were significantly higher in euthyroid young compared to old mice. T4 treatment increased total T4, fT4 and free triiodothyronine to comparable concentrations in young and old mice. In the euthyroid state, TH transporter expression was significantly higher in old than in young mice, except for Mct8 and Oatp1a1 expression levels. Hyperthyroidism resulted in upregulation of Mct10, Lat1 and Lat2 in liver tissue, while Oatp1a1, Oatp1b2 and Oatp1a4 expression was downregulated. This effect was preserved in old animals. CONCLUSION: Here, we show age-dependent differences in TH transporter mRNA expression in the euthyroid and hyperthyroid state of mice focusing on the liver as a classical TH target organ. PMID- 26601078 TI - High T3, Low T4 Serum Levels in Mct8 Deficiency Are Not Caused by Increased Hepatic Conversion through Type I Deiodinase. AB - BACKGROUND: The Allan-Herndon-Dudley syndrome is a severe psychomotor retardation accompanied by specific changes in circulating thyroid hormone levels (high T3, low T4). These are caused by mutations in the thyroid hormone transmembrane transport protein monocarboxylate transporter 8 (MCT8). OBJECTIVE: To test the hypothesis that circulating low T4 and high T3 levels are caused by enhanced conversion of T4 via increased activity of hepatic type I deiodinase (Dio1). METHODS: We crossed mice deficient in Mct8 with mice lacking Dio1 activity in hepatocytes. Translation of the selenoenzyme Dio1 was abrogated by hepatocyte specific inactivation of selenoprotein biosynthesis. RESULTS: Inactivation of Dio1 activity in the livers of global Mct8-deficient mice does not restore normal circulating thyroid hormone levels. CONCLUSIONS: Our data suggest that although hepatic Dio1 activity is increased in Mct8-deficient mice, it does not cause the observed abnormal circulating thyroid hormone levels. Since global inactivation of Dio1 in Mct8-deficient mice does normalize circulating thyroid hormone levels, the underlying mechanism and relevant tissues involved remain to be elucidated. PMID- 26601079 TI - Urine Metabolomics by (1)H-NMR Spectroscopy Indicates Associations between Serum 3,5-T2 Concentrations and Intermediary Metabolism in Euthyroid Humans. AB - CONTEXT: 3,5-Diiodo-L-thyronine (3,5-T2) is a thyroid hormone metabolite which exhibited versatile effects in rodent models, including the prevention of insulin resistance or hepatic steatosis typically forced by a high-fat diet. With respect to euthyroid humans, we recently observed a putative link between serum 3,5-T2 and glucose but not lipid metabolism. OBJECTIVE: The aim of the present study was to widely screen the urine metabolome for associations with serum 3,5-T2 concentrations in healthy individuals. STUDY DESIGN AND METHODS: Urine metabolites of 715 euthyroid participants of the population-based Study of Health in Pomerania (SHIP-TREND) were analyzed by (1)H-NMR spectroscopy. Multinomial logistic and multivariate linear regression models were used to detect associations between urine metabolites and serum 3,5-T2 concentrations. RESULTS: Serum 3,5-T2 concentrations were positively associated with urinary levels of trigonelline, pyroglutamate, acetone and hippurate. In detail, the odds for intermediate or suppressed serum 3,5-T2 concentrations doubled owing to a 1 standard deviation (SD) decrease in urine trigonelline levels, or increased by 29 50% in relation to a 1-SD decrease in urine pyroglutamate, acetone and hippurate levels. CONCLUSION: Our findings in humans confirmed the metabolic effects of circulating 3,5-T2 on glucose and lipid metabolism, oxidative stress and enhanced drug metabolism as postulated before based on interventional pharmacological studies in rodents. Of note, 3,5-T2 exhibited a unique urinary metabolic profile distinct from previously published results for the classical thyroid hormones. PMID- 26601080 TI - Serum Thyrotropin Concentrations Are Not Associated with the Ankle-Brachial Index: Results from Three Population-Based Studies. AB - BACKGROUND: There is only limited data on the potential association between thyroid dysfunction and peripheral arterial disease (PAD). OBJECTIVE: The aim of our study was to investigate the potential association of thyroid function, as defined by serum concentrations of the clinically used primary thyroid function marker thyrotropin [i.e. thyroid-stimulating hormone (TSH)] and 3,5 diiodothyronine (3,5-T2), with the ankle-brachial index (ABI) as a marker of PAD. METHODS: We used data from 5,818 individuals from three cross-sectional population-based studies conducted in Northeast (SHIP-2 and SHIP-TREND) and Central Germany (CARLA). Measurement of serum TSH concentrations was conducted in one central laboratory for all three studies. In a randomly selected subpopulation of 750 individuals of SHIP-TREND, serum 3,5-T2 concentrations were measured with a recently developed immunoassay. ABI was measured either by a hand held Doppler ultrasound using the Huntleigh Dopplex D900 or palpatorily by the OMRON HEM-705CP device. RESULTS: Serum TSH concentrations were not significantly associated with ABI values in any of the three studies. Likewise, groups of individuals with a TSH <0.3 mIU/l or with a TSH >=3.0 mIU/l had no significantly different ABI values in comparison with individuals with a TSH in the reference range. Analyses regarding TSH within the reference range or serum 3,5-T2 concentrations did not reveal consistent significant associations with the ABI. No sex-specific associations were detected. CONCLUSIONS: The results of our study do not substantiate evidence for an association between thyroid function and PAD, but further studies are needed to investigate the associations of overt forms of thyroid dysfunction with PAD. PMID- 26601081 TI - Two Novel Mutations in the Serpina7 Gene Are Associated with Complete Deficiency of Thyroxine-Binding Globulin. AB - BACKGROUND: Thyroxine-binding globulin (TBG) is the main transport protein for T4 in blood. Until now, 22 mutations leading to complete TBG deficiency (TBG-CD) have been reported. OBJECTIVE: We report two mutations associated with TBG-CD found in patients from Andrews, S.C., USA (TBG-CD-Andrews), and Berlin, Germany (TBG-CD-Berlin). METHODS: Automated chemiluminescence immunoassays were used for the determination of TSH, free and total T4 and T3 (fT4, TT4, TT3) and TBG. Direct DNA sequencing was used to identify the TBG mutations in the propositi. RESULTS: TBG-CD-Andrews was found in a 1-month-old boy who was euthyroid with normal TSH and fT4, but reduced TT4, indicating TBG deficiency. TBG was not detectable, confirming TBG-CD. No mutation in the coding region and the promoter of the TBG gene was found, but a single nucleotide substitution in intron 1 disrupts the donor splice site of exon 0 (IVS1+2T>C). Another mutation was found in an 11-year-old boy. He was also euthyroid with normal fT4 and TSH. However, TT4 and TT3 were low, suggesting TBG-CD. Sequencing revealed a 79-nucleotide deletion, ranging from intron 3 into exon 3. CONCLUSION: We report two novel mutations of the TBG gene associated with TBG-CD. Whereas most TBG-CDs are caused by small deletions, in TBG-CD-Andrews the disruption of a donor splice site was detected, whilst in TBG-CD-Berlin the largest deletion in the Serpina7 gene to date was found. PMID- 26601082 TI - Effect of Experimental Thyrotoxicosis on Brain Gray Matter: A Voxel-Based Morphometry Study. AB - BACKGROUND: Hyper-as well hypothyroidism have an effect on behavior and brain function. Moreover, during development thyroid hormones influence brain structure. OBJECTIVES: This study aimed to demonstrate an effect of experimentally induced hyperthyroidism on brain gray matter in healthy adult humans. METHODS: High-resolution 3D T1-weighted images were acquired in 29 healthy young subjects prior to as well as after receiving 250 ug of T4 per day for 8 weeks. Voxel-based morphometry analysis was performed using Statistical Parametric Mapping 8 (SPM8). RESULTS: Laboratory testing confirmed the induction of hyperthyroidism. In the hyperthyroid condition, gray matter volumes were increased in the right posterior cerebellum (lobule VI) and decreased in the bilateral visual cortex and anterior cerebellum (lobules I-IV) compared to the euthyroid condition. CONCLUSIONS: Our study provides evidence that short periods of hyperthyroidism induce distinct alterations in brain structures of cerebellar regions that have been associated with sensorimotor functions as well as working memory in the literature. PMID- 26601083 TI - Effect of Experimental Thyrotoxicosis onto Blood Coagulation: A Proteomics Study. AB - BACKGROUND: Hyperthyroidism is known to induce a hypercoagulable state. It stimulates plasma levels of procoagulative factors and reduces fibrinolytic activity. So far most of the data have been derived from patients with endogenous hyperthyroidism with a wide variability in the underlying pathogenesis and severity of the disease. OBJECTIVES: In this study we experimentally induced thyrotoxicosis in healthy volunteers to explore the effects of thyroxine excess on the plasma proteome. Using a shotgun proteomics approach, the abundance of plasma proteins was monitored before, during and after thyrotoxicosis. METHODS: Sixteen healthy male subjects were sampled at baseline, 4 and 8 weeks under 250 ug/day thyroxine p.o., as well as 4 and 8 weeks after stopping the application. Plasma proteins were analyzed after depletion of 6 high-abundance proteins (MARS6) by LC-ESI-MS/MS mass spectrometry. Mass spectrometric raw data were processed using a label-free, intensity-based workflow. Subsequently, the linear dependence between protein abundances and fT4 levels were calculated using a Pearson correlation. RESULTS: All subjects developed biochemical thyrotoxicosis, and this effect was reversed within the first 4 weeks of follow-up. None of the volunteers noticed any subjective symptoms. Levels of 10 proteins involved in the coagulation cascade specifically correlated with fT4, supporting an influence of thyroid hormone levels on blood coagulation even at nonpathological levels. CONCLUSIONS: The results suggest that experimental thyrotoxicosis exerts selective and specific thyroxine-induced effects on coagulation markers. Our study design allows assessment of thyroid hormone effects on plasma protein levels without secondary effects of other diseases or therapies. PMID- 26601084 TI - The effects of tamoxifen on spatial and nonspatial learning and memory impairments induced by scopolamine and the brain tissues oxidative damage in ovariectomized rats. AB - BACKGROUND: Modulatory effects of tamoxifen (TAM) on the central nervous system have been reported. The effects of TAM on spatial and nonspatial learning and memory impairments induced by scopolamine and the brain tissues oxidative damage was investigated. MATERIALS AND METHODS: The ovariectomized (OVX) rats were divided and treated: (1) Control (saline), (2) scopolamine (Sco; 2 mg/kg, 30 min before behavioral tests), (3-5) Sco-TAM 1, Sco-TAM 3 and Sco-TAM 10. TAM (1, 3 or 10 mg/kg; i.p.) was daily administered for 6 weeks. RESULTS: In Morris water maze (MWM), both the latency and traveled distance in the Sco-group were higher than control (P < 0.001) while, in the Sco-TAM 10 group it was lower than Sco-group (P < 0.05). In passive avoidance test, the latency to enter the dark compartment was higher than control (P < 0.05 - P < 0.01). Pretreatment by all three doses of TAM prolonged the latency to enter the dark compartment compared to Sco-group (P < 0.05 - P < 0.001). The brain tissues malondialdehyde (MDA) concentration was increased while, superoxide dismutase activity (SOD) decreased in the Sco-group compared to control (P < 0.05 - P < 0.01). Pretreatment by TAM lowered the concentration of MDA while, increased SOD compared to Sco-group (P < 0.05 - P < 0.001). CONCLUSIONS: It is suggested that TAM prevents spatial and nonspatial learning and memory impairments induced by scopolamine in OVX rats. The possible mechanism(s) might at least in part be due to protection against the brain tissues oxidative damage. PMID- 26601085 TI - Comparing right ventricular function and pulmonary artery pressure before and shortly after hemodialysis in patients with end-stage renal disease. AB - BACKGROUND: Early screening and diagnosis of right ventricular (RV) dysfunction and pulmonary artery hypertension is vital in patients with end-stage renal disease (ESRD) because of its relation to patients' survival. The present study is aimed to address and compare RV function parameters and pulmonary artery pressure (PAP) before and shortly after hemodialysis in patients with ESRD. MATERIALS AND METHODS: This quasi-experimental study performed at Alzahra Hospital in Isfahan in 2014, 40 consecutive patients with ESRD that referred to hemodialysis ward were assessed by M-mode echocardiography and tissue Doppler imaging before and 30 min after completing hemodialysis to assess RV function parameters and PAP. RESULTS: Following hemodialysis, mean body weight, both systolic, and diastolic blood pressures (BPs) and also mean systolic PAP significantly decreased, while tricuspid annulus plane systolic excursion (TAPSE), RV fractional area change (RVFAC) significantly increased 30 min after hemodialysis compared with before this procedure. However, systolic myocardial remained unchanged. Changes in body weight after dialysis was adversely associated with patients' age and duration of dialysis. Moreover, change in PAP was positively associated with the level of serum creatinine. CONCLUSION: Early reduction in body weight and BP, as well as improvement in RV function, and PAP is predictable shortly after starting hemodialysis in patients with ESRD. We found that RVFAC and TAPSE values were dependent on preload, but RV S' velocity was load independent. Change in body weight is predicted more in older patients and those who undergoing prolonged hemodialysis. Change in PAP is strongly affected by the severity of renal failure, but RV function may not be influenced by age or duration of dialysis. PMID- 26601086 TI - Comparison the results of two different vestibular system surgery in patients with persistent Meniere's disease. AB - BACKGROUND: Incidence rates of Meniere's disease vary considerably from 157/100,000 in the United Kingdom to 15/100,000 in the United States. Furthermore, in Iran prevalence of Meniere's disease is high, whereas we have not a reliable statistical study on it. A wide range of treatments are used for the treatment of the condition with no consensus on the most effective intervention. The aim of the present study, which involved 37 patients treated because of severe vertigo due to persistent Meniere's disease from 1996 to 2011, was to compare the effectiveness of two surgical methods cochleosacculotomy and endolymphatic sac decompression on vertigo and tinnitus. MATERIALS AND METHODS: In a cross-sectional study, we compared two surgical approaches in patients with Meniere's disease who did not respond to usual medical treatment. Twenty-three patients underwent cochleosacculotomy surgery and 14 patients endolymphatic sac decompression surgery. We compared all the patients for resolving of vertigo, tinnitus. RESULTS: After surgery, in patients of both group vertigo was improved significantly (P < 0.0001), tinnitus was improved, but it was not significant (P > 0.05) and hearing level was worse than before (especially in patients who had undergone cochleosacculotomy) (P < 0.0001). CONCLUSION: Based on the data of the current study, cochleosacculotomy and endolymphatic sac decompression improved vertigo in patients with persistent Meniere's disease. PMID- 26601087 TI - Ultrasound-guided percutaneous central venous catheterization in infants: Learning curve and related complications. AB - BACKGROUND: This study was performed to evaluate the learning curve and related complications of ultrasound (US) guided central venous catheter (CVC) insertion in infants. MATERIALS AND METHODS: This study was performed in Imam Hosein Hospital of Isfahan from September 2014 to March 2015. Participants were infants consecutively candidate for CVC insertion. Three steps were designed to complement the learning. For each step of learning, 20 patients were considered and for every patient one CVC was inserted: (1) In the first step, venous puncture and guide wire passage was performed by an experienced radiologist and the surgeon was taught how to do it, then CVC was placed by the surgeon. (2) In the second step, venous puncture and guide-wire passage was performed by the surgeon under the supervision of the same radiologist, and then CVC was placed by the surgeon. (3) In the third step, US-guided CVC insertion was performed by the surgeon completely, and the radiologist came to the operating room only if it was necessary. In each of these steps, the time spent of the US probe on the skin until the guide wire passage into the vein was recorded for every patient. All perioperative complications were recorded. RESULTS: The mean point for the time spent of the US probe on the skin until the guide wire passage into the vein was 84.9 +/- 13.6, 119.1 +/- 15.2, and 90.3 +/- 11.2 s in the step 1, 2 and 3, respectively (P = 0.04). There was no significant difference between the frequencies of complications among tree steps. CONCLUSION: US-guided percutaneous CVC insertion is a safe and reliable method which can be easily and rapidly learned. PMID- 26601088 TI - An investigation of the rate of cyclooxygenase-2 expression on the surface of adenomatous and colorectal adenocarcinoma polyps. AB - BACKGROUND: Colorectal cancer (CRC) (adenomatous, adenocarcinoma) is one of the major causes of mortality and morbidity in human societies. Considering the importance of cyclooxygenase-2 (COX-2) expression in the incidence of CRC, in this study, the rate of COX-2 gene expression on polyps and CRCs were addressed. MATERIALS AND METHODS: This is a cross-sectional descriptive analytic study carried out on the blocks of sampled tissue of adenomatous and colorectal adenocarcinoma polyps on 68 patients referred to Digestive Clinic in Isfahan Shariati Hospital in 2013. Patients were divided into two groups of polyps (n = 52) and cancer (n = 16). Given the presence of CRC or polyps by colonoscopy, samples were sent to the laboratory to measure the rate of COX-2 gene expression using immunohistochemistry. RESULTS: In polyp group, 41 individuals (78.8%) had two or <2 polyps, 24 cases (46.2%) had a tubular polyp, and about a third of all patients had a big polyp. The most frequency of the polyp site was related to sigmoid with 19 cases (36.54%), in cancer group, it was related to the rectum with 9 cases (56.25%) that there was no significant difference between two groups (P < 0.05). The overall prevalence of COX-2 expression was positive in 51 cases (75%) and negative in 17 cases (25%). COX-2 gene expression was separately observed in 38 individuals (73.10%) in the polyp group and in 13 cases (81.25%) in the cancer group, and no significant difference was found (P > 0.05). CONCLUSION: There is no relationship between COX-2 gene expression and the surface of adenomatous and colorectal adenocarcinoma polyps. PMID- 26601089 TI - In silico prediction of B- and T- cell epitope on Lassa virus proteins for peptide based subunit vaccine design. AB - BACKGROUND: Lassa fever is a severe, often-fatal and one of the most virulent disease in primates. However, the mechanism of escape of virus from the T-cell mediated immune response of the host cell is not explained in any studies yet. In our studies we had aimed to predict B- and T- cell epitope of Lassa virus protein, for impaling the futuristic approach of developing preventive measures against this disease, further we can also study its presumed viral- host mechanism. MATERIALS AND METHODS: Peptide based subunit vaccine was developed from all four protein against Lassa virus. We adopted sequence, 3D structure and fold level in silico analysis to predict B-cell and T-cell epitopes. The 3-D structure was determined for all protein by homology modeling and the modeled structure validated. RESULTS: One T-cell epitope from Glycoprotein (WDCIMTSYQ) and one from Nucleoprotein (WPYIASRTS) binds to maximum no of MHC class I and MHC class II alleles. They also specially bind to HLA alleles namely, A*0201, A*2705, DRB*0101 and DRB*0401. CONCLUSIONS: Taken together, the results indicate the Glycoprotein and nucleoprotein are most suitable vaccine candidates against Lassa virus. PMID- 26601091 TI - Effects of doxepin on brain-derived neurotrophic factor, tumor necrosis factor alpha, mitogen-activated protein kinase 14, and AKT1 genes expression in rat hippocampus. AB - BACKGROUND: It has been suggested that doxepin in addition to enhancement of noradrenaline and serotonin levels may have neuroprotective effects. Therefore, this study investigated the effect of doxepin on gene expression of brain-derived neurotrophic factor (BDNF), tumor necrosis factor alpha (TNF-alpha), mitogen activated protein kinase 14 (MAPK14), and serine-threonine protein kinase AKT1 in rat hippocampus. MATERIALS AND METHODS: Male rats were divided randomly into three groups: Control, doxepin 1 mg/kg, and doxepin 5 mg/kg. Rats received an i.p injection of doxepin for 21 days. Then the hippocampi were dissected for the measurement of the expression of BDNF, TNF-alpha, MAPK14, and AKT1 genes. RESULTS: Our results showed no significant effects of doxepin on gene expression of BDNF, TNF-alpha, MAPK14, and AKT1 genes in the hippocampus. CONCLUSIONS: These results did not show significant effects of doxepin on the genes that affect the neuronal survival in intact animals. However, more studies need to be done, especially in models associated with neuronal damage. PMID- 26601090 TI - The effects of L-arginine on spatial memory and synaptic plasticity impairments induced by lipopolysaccharide. AB - BACKGROUND: An important role of nitric oxide (NO) in neuroinflammation has been suggested. It is also suggested that NO has a critical role in learning and memory. Neuro-inflammation induced by lipopolysaccharide (LPS) has been reported that deteriorates learning and memory. The effect of L-arginine (LA) as a precursor of NO on LPS-induced spatial learning and memory and neuronal plasticity impairment was evaluated. MATERIALS AND METHODS: The animals were grouped into: (1) Control, (2) LPS, (3) LA-LPS, and (4) LA. The rats received intraperitoneally LPS (1 mg/kg) 2 h before experiments and LA (200 mg/kg) 30 min before LPS. The animals were examined in Morris water maze (MWM). Long-term potentiation (LTP) from CA1 area of the hippocampus was also assessed by 100 Hz stimulation in the ipsilateral Schaffer collateral pathway. RESULTS: In MWM, time latency and traveled path were higher in LPS group than the control group (P < 0.001) whereas in LA-LPS group they were shorter than LPS group (P < 0.001). The amplitude and slope of field excitatory postsynaptic potential (fEPSP) decreased in LPS group compared to control group (P < 0.05 and P < 0.01) whereas, there was not any significant difference in these parameters between LPS and LA-LPS groups. CONCLUSION: Administration of LPS impaired spatial memory and synaptic plasticity. Although LA ameliorated deleterious effects of LPS on learning of spatial tasks, it could not restore LPS-induced LTP impairment. PMID- 26601092 TI - Effect of self-care education on lifestyle modification, medication adherence and blood pressure in hypertensive adults: Randomized controlled clinical trial. AB - BACKGROUND: Self-care management has recently been suggested as an effective approach for secondary prevention of hypertension. This study was conducted to examine whether self-care behaviors could modulate blood pressure levels and also comparing the different training methods of self-care on patients' adherence and controlling hypertension. MATERIALS AND METHODS: This study was a prospective randomized controlled clinical trial, conducted on 180 hypertensive patients referring to four centers in Isfahan, Iran, between July and December 2013. Block randomization method were applied to divide eligible subjects into four equal groups, including group A in which the patients and their family were educated by cardiology resident about self-care behaviors through eight sessions, group B and group C were obtained self-care education through four pamphlets or eight short message services (SMS), respectively and group D were obtained only usual care of hypertension without any training about self-care management. RESULTS: Increasing vegetable intake and frequency of subject who took antihypertensive medication regularly and the reduction in the frequency of subjects who consumed high salt were significantly more in group A than the others (P = 0.001, P < 0.001 and P < 0.001, respectively). The systolic and diastolic blood pressure had significantly more reduction in the group A than the other groups (-8.18 +/- 18.3 and - 3.89 +/ 4.1; P < 0.001, respectively). CONCLUSIONS: The self-care management education integration into the usual care along with using SMS and other educational materials may improve the efficient and effective adherence strategies. PMID- 26601093 TI - Potential risk factors associated with stress urinary incontinence among Iranian women. AB - BACKGROUND: Stress urinary incontinence (SUI) is considered as one of the major hygienic problems among women. The main aim of the study is to assess the potential risk factors associated with SUI among Iranian women. MATERIALS AND METHODS: This study was conducted on 90 married women with history of SUI diagnosed by an urologist and were selected randomly. Their pelvic muscles contraction (PMC) and the history of the subjects were assessed for some of risk factors such as age, height, weight, body mass index (BMI), pregnancy history, miscarriage, type of delivery (normal vaginal delivery or cesarean section), number of offspring born healthy in addition to other risk factors such as chronic cough, constipation and hypothyroidism by use of POP Questionnaire. Data were analyzed using Pearson correlation coefficient and SPSS version 18 Software. RESULTS: There was a significant relation between SUI and height (P < 0.05, r = 0.45), vaginal delivery (NVD) (P < 0.05, r = 0.2), number of genitourinary surgery (P < 0.05, r = 0.42), hypothyroidism and constipation (P < 0.05). An inverse relatively strong significant relation was found between SUI and cesarean section (P < 0.05, r = -0.50) No significant relation was found between SUI and weight, BMI, age, chronic cough and miscarriage, and other study parameters. An inverse significant relation between PMC and weight (P < 0.05, r = -0.52), BMI (P < 0.05, r = -0.42) and number of genitourinary surgery (P < 0.05, r = -0.18). CONCLUSION: Cesarean section had a preventive effect on SUI versus normal vaginal delivery. The rate of SUI was higher in taller women or those suffering from hypothyroidism or constipation or who had genitourinary surgery. The women with high BMI had lower pelvic floor muscles strength. PMID- 26601094 TI - Ultrasound: A promising tool for contemporary airway management. AB - Airway evaluation and its management remains an ever emerging clinical science. Present airway management tools are static and do not provide dynamic airway management option. Visualized procedures like ultrasound (US) provide point of care real time dynamic views of the airway in perioperative, emergency and critical care settings. US can provide dynamic anatomical assessment which is not possible by clinical examination alone. US aids in detecting gastric contents and the nature of gastric contents (clear fluid, thick turbid or solid) as well. US can help in predicting endotracheal tube size by measuring subglottic diameter and diameter of left main stem bronchus. US was found to be a sensitive in detecting rotational malposition of LMA in children. Also, US is the fastest and highly sensitive tool to rule out a suspected intraoperative pneumothorax. In intensive care units, US helps torule out causes of inadequate ventilation, determine the tracheal width and distance from the skin to predict tracheotomy tube size and shape and assist with percutaneous dilatational tracheostomy. US can help in confirming the correct tracheal tube placement by dynamic visualisation of the endotracheal tube insertion, widening of vocal cords (children), and bilateral lung-sliding and diaphragmatic movement. Thus, ultrasonography has brought a paradigm shift in the practise of airway management. With increasing awareness, portability, accessibility and further sophistication in technology, it is likely to find a place in routine airway management. We are not far from the time when all of us will be carrying a pocket US machine like stethoscopes to corroborate our clinical findings at point of care. PMID- 26601095 TI - Physician disruptive behaviors: Five year progress report. AB - Disruptive behaviors in health care can have a significant adverse effect on staff interactions that can negatively impact staff satisfaction, staff performance, and patient outcomes of care. As referenced in a previously published article, the Obstetrics and Gynecology specialty is one of the service areas where these behaviors occur more frequently. Despite growing evidence of the ill effects of these types of behaviors many organizations are still having a difficult time in addressing these issues in an effective manner. Gaining a better understanding of the nature, causes, and impact of these behaviors is crucial to finding the right remedies for solution. Nobody intentionally starts the day planning to be disruptive, it's just that things get in the way. A combination of deep seated factors related to age and gender preferences, culture and ethnicity, life experiences, and other events that help shape values, attitudes and personalities, and more external factors related to training, environmental pressures, stress and burnout, and other personal issues all contribute to the mix. Given the complexities of today's health care environment, each person needs to recognize the importance of being held accountable for appropriate actions and behaviors that affect work relationships and care coordination that impact patient care. Early recognition, early intervention, and taking a pro-active supportive approach to improve individual behaviors will result in better relationships, less disruption, more satisfaction, and better outcomes of care. PMID- 26601096 TI - Cost-effectiveness in Clostridium difficile treatment decision-making. AB - AIM: To develop a framework for the clinical and health economic assessment for management of Clostridium difficile infection (CDI). METHODS: CDI has vast economic consequences emphasizing the need for innovative and cost effective solutions, which were aim of this study. A guidance model was developed for coverage decisions and guideline development in CDI. The model included pharmacotherapy with oral metronidazole or oral vancomycin, which is the mainstay for pharmacological treatment of CDI and is recommended by most treatment guidelines. RESULTS: A design for a patient-based cost-effectiveness model was developed, which can be used to estimate the cost-effectiveness of current and future treatment strategies in CDI. Patient-based outcomes were extrapolated to the population by including factors like, e.g., person-to-person transmission, isolation precautions and closing and cleaning wards of hospitals. CONCLUSION: The proposed framework for a population-based CDI model may be used for clinical and health economic assessments of CDI guidelines and coverage decisions for emerging treatments for CDI. PMID- 26601097 TI - Contrast induced neurotoxicity following coronary angiogram with Iohexol in an end stage renal disease patient. AB - Neurotoxicity is an infrequent adverse reaction to iodinated contrast agents. Contrast induced neurotoxicity following coronary angiogram is very rare. Renal disease is a risk factor for contrast induced neurotoxicity. We report a case of contrast induced neurotoxicity following coronary angiogram and intervention using Iohexol (Omnipaque 350) in an end stage renal disease patient on peritoneal dialysis who had prior exposure to iodinated contrast without any adverse reaction. Hemodialysis had to be initiated for rapid removal of the contrast agent with subsequent complete resolution of neurological deficits. This case highlights the need for interventionalists to be aware of an important adverse reaction to iodinated contrast agents, especially in individuals with renal dysfunction, and that neurotoxicity is a possibility even with prior uneventful exposures. The role and timing of hemodialysis in contrast induced neurotoxicity in patients with chronic kidney disease and in those without chronic kidney disease needs further deliberation. PMID- 26601098 TI - First description of cervical intradural thymoma metastasis. AB - Thymoma and thymic carcinoma are rare epithelial tumors, which originate from the thymus gland. According to the World Health Organization there are "organotypic" (types A, AB, B1, B2, and B3) and "non-organotypic" (thymic carcinomas) thymomas. Type B3 thymomas are aggressive tumors, which can metastasize. Due to the rarity of these lesions, only 7 cases of extradural metastasis are described in the literature. We report the first and unique case of a man with cervical intradural B3 thymoma metastasis. A 46-year-old man underwent thymoma surgical removal. The year after the procedure he was treated for a parietal pleura metastasis. In 2006 he underwent cervical-dorsal extradural metastasis removal and C5-Th1 stabilization. Seven years after he came to our observation complaining left cervicobrachialgia and a reduction of strength of the left arm. He underwent a cervical spine magnetic resonance imaging, which showed a new lesion at the C5-C7 level. The patient underwent a surgery for the intradural B3 thymoma metastasis. Neurological symptoms improved although the removal was subtotal. He went through postoperative radiation therapy with further mass reduction. Spinal metastases are extremely rare. To date, only 7 cases of spinal extradural metastasis have been described in the literature. This is the first case of spinal intradural metastasis. Early individuation of these tumors and surgical treatment improve neurological outcome in patients with spinal cord compression. A multimodal treatment including neoadjuvant chemotherapy, surgery and postoperative radiation therapy seems to improve survival in patients with metastatic thymoma. PMID- 26601099 TI - Laparoscopic splenectomy for a littoral cell angioma of the spleen: Case report. AB - A littoral cell angioma (LCA) is a primary vascular tumor of the spleen, that can have malignant potential and may present association with other malignancies. This is a case of LCA that was discovered incidentally in a 79-year-old woman who presented with a polycythemia at the time of consultation. The neoplasm was evaluated by ultrasound and computed tomography. The patient underwent a splenectomy that revealed LCA by pathological evaluation. The post-operative outcome was favorable with no complications or recurrent disease. This case presentation, clinical, radiographic, and pathological features of an uncommon splenic tumor can be studied in order to advance our knowledge in our understanding of LCA. PMID- 26601100 TI - Differential diagnosis of a vanishing brain space occupying lesion in a child. AB - We describe clinical, diagnostic features and follow up of a patient with a vanishing brain lesion. A 14-year-old child admitted to the department of Neurology at September 2009 with a history of subacute onset of fever, anorexia, vomiting, blurring of vision and right hemiparesis since one month. Magnetic resonance imaging (MRI) of the brain revealed presence of intra-axial large mass (25 mm * 19 mm) in the left temporal lobe and the brainstem which showed hypointense signal in T1W and hyperintense signals in T2W and fluid attenuated inversion recovery (FLAIR) images and homogenously enhanced with gadolinium (Gd). It was surrounded by vasogenic edema with mass effect. Intravenous antibiotics, mannitol (2 g/12 h per 2 d) and dexamethasone (8 mg/12 h) were given to relief manifestations of increased intracranial pressure. Whole craniospinal radiotherapy (brain = 4000 CGy/20 settings per 4 wk; Spinal = 2600/13 settings per 3 wk) was given based on the high suspicion of neoplastic lesion (lymphoma or glioma). Marked clinical improvement (up to complete recovery) occurred within 15 d. Tapering of the steroid dose was done over the next 4 mo. Follow up with MRI after 3 mo showed small lesion in the left antero-medial temporal region with hypointense signal in T1W and hyperintense signals in T2W and FLAIR images but did not enhance with Gd. At August 2012, the patient developed recurrent generalized epilepsy. His electroencephalography showed the presence of left temporal focus of epileptic activity. MRI showed the same lesion as described in the follow up. The diffusion weighted images were normal. The seizures frequency was decreased with carbamazepine therapy (300 mg/12 h). At October 2014, single voxel proton (1H) MR spectroscopy (MRS) showed reduced N-acetyl-aspartate (NAA)/creatine (Cr), choline (Cho)/Cr, NAA/Cho ratios consistent with absence of a neoplasm and highly suggested presence of gliosis. A solitary brain mass in a child poses a considerable diagnostic difficulty. MRS provided valuable diagnostic differentiation between tumor and pseudotumor lesions. PMID- 26601101 TI - Case of Fitz-Hugh-Curtis syndrome in male without presentation of sexually transmitted disease. AB - Fitz-Hugh-Curtis syndrome is a type of perihepatitis that causes liver capsular infection without infecting the hepatic parenchyma or pelvis. Fitz-Hugh-Curtis syndrome is known to occur commonly in women of childbearing age who do not use oral contraceptives and have sexual partners older than 25 years of age. However, the syndrome has been reported to occur rarely in males. The clinical symptoms are right upper quadrant pain and tenderness, and pleuritic right sided chest pain. The clinical presentation is similar in male and female. We experienced a case of Fitz-Hugh-Curtis syndrome in a 60-year-old man with the chief complaint of right upper quadrant abdominal pain. Despite a previous history of gonorrhea, we have also described our experiences of improved symptoms and recovery with allopathic medicines and have thereby reported the present case with a literature review. PMID- 26601102 TI - Lower gastrointestinal tract bleeding caused by dieulafoy-like lesion synchronous meckel diverticulum: A rare case report. AB - Meckel diverticulum is an embryonic remnant of the Gastrointestinal duct which causes symptoms < 5% in the 2% population. Painless bleeding and abdominal pain are the most often reported symptoms. Dieulafoy lesion/dieulafoy-like lesion often cause upper gastrointestinal (GI) tract bleeding, but massive lower gastrointestinal bleeding is rare. We reported a 19-year-old male presented massive lower GI tract bleeding caused by Meckel diverticulum synchronous dieulafoy-like lesion. PMID- 26601103 TI - Systematic Analysis and Prediction of In Situ Cross Talk of O-GlcNAcylation and Phosphorylation. AB - Reversible posttranslational modification (PTM) plays a very important role in biological process by changing properties of proteins. As many proteins are multiply modified by PTMs, cross talk of PTMs is becoming an intriguing topic and draws much attention. Currently, lots of evidences suggest that the PTMs work together to accomplish a specific biological function. However, both the general principles and underlying mechanism of PTM crosstalk are elusive. In this study, by using large-scale datasets we performed evolutionary conservation analysis, gene ontology enrichment, motif extraction of proteins with cross talk of O GlcNAcylation and phosphorylation cooccurring on the same residue. We found that proteins with in situ O-GlcNAc/Phos cross talk were significantly enriched in some specific gene ontology terms and no obvious evolutionary pressure was observed. Moreover, 3 functional motifs associated with O-GlcNAc/Phos sites were extracted. We further used sequence features and GO features to predict O GlcNAc/Phos cross talk sites based on phosphorylated sites and O-GlcNAcylated sites separately by the use of SVM model. The AUC of classifier based on phosphorylated sites is 0.896 and the other classifier based on GlcNAcylated sites is 0.843. Both classifiers achieved a relatively better performance compared with other existing methods. PMID- 26601104 TI - Effects of Fourteen-Day Bed Rest on Trunk Stabilizing Functions in Aging Adults. AB - Bed rest has been shown to have detrimental effects on structural and functional characteristics of the trunk muscles, possibly affecting trunk and spinal stability. This is especially important in populations such as aging adults with often altered trunk stabilizing functions. This study examined the effects of a fourteen-day bed rest on anticipatory postural adjustments and postural reflex responses of the abdominal wall and back muscles in sixteen adult men. Postural activation of trunk muscles was measured using voluntary quick arm movement and sudden arm loading paradigm. Measurements were conducted prior to the bed rest, immediately after, and fourteen days after the bed rest. Immediately after the bed rest, latencies of anticipatory postural adjustments showed significant shortening, especially for the obliquus internus and externus muscles. After a fourteen-day recuperation period, anticipatory postural adjustments reached a near to complete recovery. On the contrary, reactive response latencies increased from pre-bed-rest to both post-bed-rest measurement sessions. Results indicate an important effect of bed rest on stabilizing functions of the trunk muscles in elderly adults. Moreover, there proved to be a significant deterioration of postural reactive responses that outlasted the 14-day post-bed-rest rehabilitation. PMID- 26601105 TI - Assessment of Hip Fracture Risk Using Cross-Section Strain Energy Determined by QCT-Based Finite Element Modeling. AB - Accurate assessment of hip fracture risk is very important to prevent hip fracture and to monitor the effect of a treatment. A subject-specific QCT-based finite element model was constructed to assess hip fracture risk at the critical locations of femur during the single-leg stance and the sideways fall. The aim of this study was to improve the prediction of hip fracture risk by introducing a novel failure criterion to more accurately describe bone failure mechanism. Hip fracture risk index was defined using cross-section strain energy, which is able to integrate information of stresses, strains, and material properties affecting bone failure. It was found that the femoral neck and the intertrochanteric region have higher fracture risk than other parts of the femur, probably owing to the larger content of cancellous bone in these regions. The study results also suggested that women are more prone to hip fracture than men. The findings in this study have a good agreement with those clinical observations reported in the literature. The proposed hip fracture risk index based on strain energy has the potential of more accurate assessment of hip fracture risk. However, experimental validation should be conducted before its clinical applications. PMID- 26601106 TI - Bridging the Gap between Translational and Outcome Research in Cardiovascular Disease. PMID- 26601107 TI - Computational Approaches to Understanding the Role of Fibroblast-Myocyte Interactions in Cardiac Arrhythmogenesis. AB - The adult heart is composed of a dense network of cardiomyocytes surrounded by nonmyocytes, the most abundant of which are cardiac fibroblasts. Several cardiac diseases, such as myocardial infarction or dilated cardiomyopathy, are associated with an increased density of fibroblasts, that is, fibrosis. Fibroblasts play a significant role in the development of electrical and mechanical dysfunction of the heart; however the underlying mechanisms are only partially understood. One widely studied mechanism suggests that fibroblasts produce excess extracellular matrix, resulting in collagenous septa. These collagenous septa slow propagation, cause zig-zag conduction paths, and decouple cardiomyocytes resulting in a substrate for arrhythmia. Another emerging mechanism suggests that fibroblasts promote arrhythmogenesis through direct electrical interactions with cardiomyocytes via gap junctions. Due to the challenges of investigating fibroblast-myocyte coupling in native cardiac tissue, computational modeling and in vitro experiments have facilitated the investigation into the mechanisms underlying fibroblast-mediated changes in cardiomyocyte action potential morphology, conduction velocity, spontaneous excitability, and vulnerability to reentry. In this paper, we summarize the major findings of the existing computational studies investigating the implications of fibroblast-myocyte interactions in the normal and diseased heart. We then present investigations from our group into the potential role of voltage-dependent gap junctions in fibroblast-myocyte interactions. PMID- 26601109 TI - Comment on "HIV/AIDS Awareness among VCT Clients: A Cross-Sectional Study from Delhi, India". PMID- 26601110 TI - Varicocele Repair Improves Testicular Histology in Men with Nonobstructive Azoospermia. AB - OBJECTIVE: To determine the histopathological differences after varicocele repair in testicular tissue in males with nonobstructive azoospermia. METHODS: Between 2009 and 2014, 45 men with complete azoospermia and palpable varicocele, presenting with primary infertility of at least 1 year, undergoing varicocele repair at our institution were selected for the study. A standard systematic testicular 6-core Tru-Cut biopsy was performed during varicocele repair. Other biopsies were obtained from each testicle of all patients at the time of microscopic sperm extraction procedure. RESULTS: Nineteen patients were selected for the study. Testicular biopsy specimens were classified as Sertoli cell only on preoperative histopathological analysis in 14 patients. After varicocele repair, focal spermatogenesis (n = 3) and late maturation arrest (n = 2) were found in these patients. Average Johnsen score was significantly increased after varicocelectomy (P = 0.003). Motile sperm was found in one patient on postoperative semen analyses and in 10 more patients in the microscopic sperm extraction procedure. Preoperative high serum follicle stimulating hormone level and venous reflux were significantly and negatively correlated with the increase in average Johnsen score (P < 0.05). CONCLUSIONS: Our findings suggest significant improvement in testicular histology after varicocele repair. PMID- 26601111 TI - A High-Density SNP and SSR Consensus Map Reveals Segregation Distortion Regions in Wheat. AB - Segregation distortion is a widespread phenomenon in plant and animal genomes and significantly affects linkage map construction and identification of quantitative trait loci (QTLs). To study segregation distortion in wheat, a high-density consensus map was constructed using single nucleotide polymorphism (SNP) and simple sequence repeat (SSR) markers by merging two genetic maps developed from two recombinant-inbred line (RIL) populations, Ning7840 * Clark and Heyne * Lakin. Chromosome regions with obvious segregation distortion were identified in the map. A total of 3541 SNPs and 145 SSRs were mapped, and the map covered 3258.7 cM in genetic distance with an average interval of 0.88 cM. The number of markers that showed distorted segregation was 490 (18.5%) in the Ning7840 * Clark population and 225 (10.4%) in the Heyne * Lakin population. Most of the distorted markers (630) were mapped in the consensus map, which accounted for 17.1% of mapped markers. The majority of the distorted markers clustered in the segregation distortion regions (SDRs) on chromosomes 1B, 2A, 2B, 3A, 3B, 4B, 5A, 5B, 5D, 6B, 7A, and 7D. All of the markers in a given SDR skewed toward one of the parents, suggesting that gametophytic competition during zygote formation was most likely one of the causes for segregation distortion in the populations. PMID- 26601108 TI - Breast Cancer-Derived Extracellular Vesicles: Characterization and Contribution to the Metastatic Phenotype. AB - The study of extracellular vesicles (EVs) in cancer progression is a complex and rapidly evolving field. Whole categories of cellular interactions in cancer which were originally presumed to be due solely to soluble secreted molecules have now evolved to include membrane-enclosed extracellular vesicles (EVs), which include both exosomes and shed microvesicles (MVs), and can contain many of the same molecules as those secreted in soluble form but many different molecules as well. EVs released by cancer cells can transfer mRNA, miRNA, and proteins to different recipient cells within the tumor microenvironment, in both an autocrine and paracrine manner, causing a significant impact on signaling pathways, mRNA transcription, and protein expression. The transfer of EVs to target cells, in turn, supports cancer growth, immunosuppression, and metastasis formation. This review focuses exclusively on breast cancer EVs with an emphasis on breast cancer derived exosomes, keeping in mind that breast cancer-derived EVs share some common physical properties with EVs of other cancers. PMID- 26601112 TI - Study of the Structure, Oxygen-Transporting Functions, and Ionic Composition of Erythrocytes at Vascular Diseases. AB - The present paper explores the role of erythrocytes in the pathogenesis of vascular diseases. The state of erythrocytes, their ionic composition and structure, and properties of erythrocytes hemoglobin were studied by using laser interference microscopy, Raman scattering spectroscopy, and capillary electrophoresis. In patients suffering from vascular disorders we identified statistically significant changes in the shape of erythrocytes, their ionic composition, and redistribution of hemoglobin throughout cells. PMID- 26601113 TI - Application of Mathematical Modeling for Simulation and Analysis of Hypoplastic Left Heart Syndrome (HLHS) in Pre- and Postsurgery Conditions. AB - This paper is concerned with the mathematical modeling of a severe and common congenital defect called hypoplastic left heart syndrome (HLHS). Surgical approaches are utilized for palliating this heart condition; however, a brain white matter injury called periventricular leukomalacia (PVL) occurs with high prevalence at or around the time of surgery, the exact cause of which is not known presently. Our main goal in this paper is to study the hemodynamic conditions under which HLHS physiology may lead to the occurrence of PVL. A lumped parameter model of the HLHS circulation has been developed integrating diffusion modeling of oxygen and carbon dioxide concentrations in order to study hemodynamic variables such as pressure, flow, and blood gas concentration. Results presented include calculations of blood pressures and flow rates in different parts of the circulation. Simulations also show changes in the ratio of pulmonary to systemic blood flow rates when the sizes of the patent ductus arteriosus and atrial septal defect are varied. These changes lead to unbalanced blood circulations and, when combined with low oxygen and carbon dioxide concentrations in arteries, result in poor oxygen delivery to the brain. We stipulate that PVL occurs as a consequence. PMID- 26601114 TI - Cellular Immunity-Pathogen Interactions in Infectious Diseases. PMID- 26601115 TI - Cyclic AMP-Responsive Element Modulator alpha Polymorphisms Are Potential Genetic Risks for Systemic Lupus Erythematosus. AB - To investigate whether the cyclic AMP-responsive element modulator alpha (CREMalpha) polymorphisms are novel susceptibility factors for systemic lupus erythematosus (SLE), four tag SNPs, rs1057108, rs2295415, rs11592925, and rs1148247, were genotyped in 889 SLE cases and 825 healthy controls. Association analyses were performed on whole dataset or clinical/serologic subsets. Association statistics were calculated by age and sex adjusted logistic regression. The G allele frequencies of rs2295415 and rs1057108 were increased in SLE patients, compared with healthy controls (rs2295415: 21.2% versus 17.8%, OR 1.244, P = 0.019; rs1057108: 30.8% versus 27.7%, OR 1.165, P = 0.049). The haplotype constituted by the two risk alleles "G-G" from rs1057108 and rs2295415 displayed strong association with SLE susceptibility (OR 1.454, P = 0.00056). Following stratification by clinical/serologic features, a suggestive association was observed between rs2295415 and anti-Sm antibodies-positive SLE (OR 1.382, P = 0.044). Interestingly, a potential protective effect of rs2295415 was observed for SLE patients with renal disorder (OR 0.745, P = 0.032). Our data provide first evidence that CREMalpha SNPs rs2295415 and rs1057108 maybe novel genetic susceptibility factors for SLE. SNP rs2295415 appears to confer higher risk to develop anti-Sm antibodies-positive SLE and may play a protective role against lupus nephritis. PMID- 26601116 TI - Immunologic and MRI markers of the therapeutic effect of IFN-beta-1a in relapsing remitting MS. AB - OBJECTIVES: To assess potential roles of effector cells and immunologic markers in demyelinating CNS lesion formation, and their modulation by interferon beta-1a (IFN-beta-1a). METHODS: Twenty-three patients with relapsing-remitting multiple sclerosis (RRMS) received IFN-beta-1a for 6 months. Immunologic marker results were correlated with brain MRI lesion volumes, and volumes of normal-appearing brain tissue (NABT) with decreasing or increasing voxel-wise magnetization transfer ratio (VW-MTR), suggestive of demyelination and remyelination, respectively. RESULTS: Baseline expression of Th22 cell transcription factor aryl hydrocarbon receptor (AHR) and interleukin (IL)-17F, and percentages of IL-22 expressing CD4(+) and CD8(+) cells, were significantly higher in patients vs 15 healthy controls; IL-4 in CD4(+) cells was lower. Baseline percentage of IL-22 producing CD8(+) cells positively correlated with T2 lesion volumes, while percentage of IL-17A-producing CD8(+) cells positively correlated with T2 and T1 lesion volumes. IFN-beta-1a induced reductions in transcription factor AHR, T bet, and retinoic acid-related orphan nuclear hormone receptor C (RORc) gene expression, while it increased GATA3's expression in CD4(+) cells. Percentages of IL-22-, IL-17A-, and IL-17F-expressing T cells significantly decreased following treatment. Increased percentages of IL-10-expressing CD4(+) and CD8(+) cells correlated with greater NABT volume with increasing VW-MTR, while decreased percentage of IL-17F-expressing CD4(+) cells positively correlated with decreased NABT volume with decreasing VW-MTR. CONCLUSIONS: Findings indicate that IFN-beta 1a suppresses Th22 and Th17 cell responses, which were associated with decreased MRI-detectable demyelination. CLASSIFICATION OF EVIDENCE: This pilot study provides Class III evidence that reduced Th22 and Th17 responses are associated with decreased demyelination following IFN-beta-1a treatment in patients with RRMS. PMID- 26601117 TI - Pathologically confirmed autoimmune encephalitis in suspected Creutzfeldt-Jakob disease. AB - OBJECTIVE: To determine the clinical features and presence in CSF of antineuronal antibodies in patients with pathologically proven autoimmune encephalitis derived from a cohort of patients with suspected Creutzfeldt-Jakob disease (CJD). METHODS: The Dutch Surveillance Centre for Prion Diseases performed 384 autopsies on patients with suspected CJD over a 14-year period (1998-2011). Clinical information was collected from treating physicians. Antineuronal antibodies were tested in CSF obtained postmortem by immunohistochemistry on fresh frozen rat brain sections, by Luminex assay for the presence of well-characterized onconeural antibodies, and by cell-based assays for antibodies against NMDAR, GABABR1/2, GABAAR GLUR1/2, LGI1, Caspr2, and DPPX. RESULTS: In 203 patients, a diagnosis of definite CJD was made, while in 181 a variety of other conditions were diagnosed, mainly neurodegenerative. In 22 of these 181, the neuropathologist diagnosed autoimmune encephalitis. One patient was excluded because of lack of clinical information. Inflammatory infiltrates were predominantly perivascular and consisted mainly of T cells. The predominant locations were basal ganglia and thalamus (90%) and temporal lobes and hippocampus (81%). In 6 patients (29%), antineuronal antibodies were detected in postmortem CSF, directed against Hu, NMDAR, GABABR1/2, Caspr2, and an unidentified synaptic antigen in 2. The most frequent symptoms were dementia (90%), gait disturbance (86%), cerebellar signs (67%), and neuropsychiatric symptoms (67%). Immunopathologic and clinical findings did not differ between autoantibody-negative patients and patients with antineuronal antibodies. CONCLUSIONS: It is important to consider immune-mediated disorders in the differential diagnosis of rapidly progressive neurologic deficits. PMID- 26601118 TI - Glatiramer acetate treatment negatively regulates type I interferon signaling. AB - OBJECTIVE: Glatiramer acetate (GA; Copaxone), a disease-modifying therapy for multiple sclerosis (MS), promotes development of anti-inflammatory (M2, type II) monocytes that can direct differentiation of regulatory T cells. We investigated the innate immune signaling pathways that participate in GA-mediated M2 monocyte polarization. METHODS: Monocytes were isolated from myeloid differentiation primary response gene 88 (MyD88)-deficient, Toll-IL-1 receptor domain-containing adaptor inducing interferon (IFN)-beta (TRIF)-deficient, IFN-alpha/beta receptor subunit 1 (IFNAR1)-deficient, and wild-type (WT) mice and human peripheral blood. GA-treated monocytes were stimulated with Toll-like receptor ligands, then evaluated for activation of kinases and transcription factors involved in innate immunity, and secretion of proinflammatory cytokines. GA-treated mice were evaluated for cytokine secretion and susceptibility to experimental autoimmune encephalomyelitis. RESULTS: GA-mediated inhibition of proinflammatory cytokine production by monocytes occurred independently of MyD88 and nuclear factor kappaB, but was blocked by TRIF deficiency. Furthermore, GA did not provide clinical benefit in TRIF-deficient mice. GA inhibited activation of p38 mitogen activated protein kinase, an upstream regulator of activating transcription factor (ATF)-2, and c-Jun N-terminal kinase 1, which regulates IFN regulatory factor 3 (IRF3). Consequently, nuclear translocation of ATF-2 and IRF3, components of the IFN-beta enhanceosome, was impaired. Consistent with these observations, GA inhibited production of IFN-beta in vivo in WT mice, but did not modulate proinflammatory cytokine production by monocytes from IFNAR1-deficient mice. CONCLUSION: Our results demonstrate that GA inhibits the type I IFN pathway in M2 polarization of monocytes independently of MyD88, providing an important mechanism connecting innate and adaptive immune modulation in GA therapy and valuable insight regarding its potential use with other MS treatments. PMID- 26601120 TI - FPGA Implementation of Optimal 3D-Integer DCT Structure for Video Compression. AB - A novel optimal structure for implementing 3D-integer discrete cosine transform (DCT) is presented by analyzing various integer approximation methods. The integer set with reduced mean squared error (MSE) and high coding efficiency are considered for implementation in FPGA. The proposed method proves that the least resources are utilized for the integer set that has shorter bit values. Optimal 3D-integer DCT structure is determined by analyzing the MSE, power dissipation, coding efficiency, and hardware complexity of different integer sets. The experimental results reveal that direct method of computing the 3D-integer DCT using the integer set [10, 9, 6, 2, 3, 1, 1] performs better when compared to other integer sets in terms of resource utilization and power dissipation. PMID- 26601119 TI - Vasculitic neuropathy following exposure to minocycline. AB - OBJECTIVE: To report 3 patients with minocycline-induced autoimmunity resulting in peripheral nerve vasculitis. METHODS: We report 3 patients who, during minocycline treatment for acne vulgaris, developed subacute onset of pain and weakness caused by vasculitis in single and multiple mononeuropathy patterns. RESULTS: Each patient underwent either a nerve or muscle biopsy that confirmed vasculitis. One patient additionally developed systemic symptoms (including fever, fatigue, and night sweats) and another had a posterior circulation stroke. Symptoms developed with either early or prolonged use of minocycline. Despite withdrawal of minocycline, patients needed long-term immunotherapy to gain neurologic improvement. CONCLUSIONS: Our findings suggest that the typical neuropathy associated with minocycline use is painful single or multiple mononeuropathy due to peripheral nerve vasculitis, which may also be accompanied by presumed CNS vasculitis (presenting as stroke). PMID- 26601121 TI - Application of Artificial Intelligence for Bridge Deterioration Model. AB - The deterministic bridge deterioration model updating problem is well established in bridge management, while the traditional methods and approaches for this problem require manual intervention. An artificial-intelligence-based approach was presented to self-updated parameters of the bridge deterioration model in this paper. When new information and data are collected, a posterior distribution was constructed to describe the integrated result of historical information and the new gained information according to Bayesian theorem, which was used to update model parameters. This AI-based approach is applied to the case of updating parameters of bridge deterioration model, which is the data collected from bridges of 12 districts in Shanghai from 2004 to 2013, and the results showed that it is an accurate, effective, and satisfactory approach to deal with the problem of the parameter updating without manual intervention. PMID- 26601122 TI - Comparing Supervised Exercise Therapy to Invasive Measures in the Management of Symptomatic Peripheral Arterial Disease. AB - Peripheral arterial disease (PAD) is associated with considerable morbidity and mortality. Consensus rightly demands the incorporation of supervised exercise training (SET) into PAD treatment protocols. However, the exact role of SET particularly its relationship with intervention requires further clarification. While supervised exercise is undoubtedly an excellent tool in the conservative management of mild PAD its use in more advanced disease as an adjunct to open or endovascular intervention is not clearly defined. Indeed its use in isolation in this cohort is incompletely reported. The aim of this review is to clarify the exact role of SET in the management of symptomatic PAD and in particular to assess its role in comparison with or as an adjunct to invasive intervention. A systematic literature search revealed a total 11 randomised studies inclusive of 969 patients. All studies compared SET and intervention with monotherapy. Study results suggest that exercise is a complication-free treatment. Furthermore, it appears to offer significant improvements in patients walk distances with a combination of both SET and intervention offering a superior walking outcome to monotherapy in those requiring invasive measures. PMID- 26601123 TI - Steinach and Young, Discoverers of the Effects of Estrogen on Male Sexual Behavior and the "Male Brain". AB - In the 1930s, Eugen Steinach's group found that estradiol induces lordosis in castrated rats and reduces the threshold dose of testosterone that is necessary for the induction of ejaculation, and that estradiol-treated intact rats display lordosis as well as mounting and ejaculation. The bisexual, estrogen-sensitive male had been demonstrated. Another major, albeit contrasting, discovery was made in the 1950s, when William Young's group reported that male guinea pigs and prenatally testosterone-treated female guinea pigs are relatively insensitive to estrogen when tested for lordosis as adults. Reduced estrogen sensitivity was part of the new concept of organization of the neural tissues mediating the sexual behavior of females into tissues similar to those of males. The importance of neural organization by early androgen stimulation was realized immediately and led to the discovery of a variety of sex differences in the brains of adult animals. By contrast, the importance of the metabolism of testosterone into estrogen in the male was recognized only after a delay. While the finding that males are sensitive to estrogen was based on Bernhard Zondek's discovery in 1934 that testosterone is metabolized into estrogen in males, the finding that males are insensitive to estrogen was based on the hypothesis that testosterone-male sexual behavior is the typical relationship in the male. It is suggested that this difference in theoretical framework explains the discrepancies in some of the reported results. PMID- 26601125 TI - Systematic inequality and hierarchy in faculty hiring networks. AB - The faculty job market plays a fundamental role in shaping research priorities, educational outcomes, and career trajectories among scientists and institutions. However, a quantitative understanding of faculty hiring as a system is lacking. Using a simple technique to extract the institutional prestige ranking that best explains an observed faculty hiring network-who hires whose graduates as faculty we present and analyze comprehensive placement data on nearly 19,000 regular faculty in three disparate disciplines. Across disciplines, we find that faculty hiring follows a common and steeply hierarchical structure that reflects profound social inequality. Furthermore, doctoral prestige alone better predicts ultimate placement than a U.S. News & World Report rank, women generally place worse than men, and increased institutional prestige leads to increased faculty production, better faculty placement, and a more influential position within the discipline. These results advance our ability to quantify the influence of prestige in academia and shed new light on the academic system. PMID- 26601124 TI - Cell-Type Specific Channelopathies in the Prefrontal Cortex of the fmr1-/y Mouse Model of Fragile X Syndrome. AB - Fragile X syndrome (FXS) is caused by transcriptional silencing of the fmr1 gene resulting in the loss of fragile X mental retardation protein (FMRP) expression. FXS patients display several behavioral phenotypes associated with prefrontal cortex (PFC) dysfunction. Voltage-gated ion channels, some of which are regulated by FMRP, heavily influence PFC neuron function. Although there is evidence for brain region-specific alterations to the function a single type of ion channel in FXS, it is unclear whether subtypes of principal neurons within a brain region are affected uniformly. We tested for alterations to ion channels critical in regulating neural excitability in two subtypes of prefrontal L5 pyramidal neurons. Using somatic and dendritic patch-clamp recordings, we provide evidence that the functional expression of h-channels (Ih) is down-regulated, whereas A type K(+) channel function is up-regulated in pyramidal tract-projecting (PT) neurons in the fmr1-/y mouse PFC. This is the opposite pattern of results from published findings from hippocampus where Ih is up-regulated and A-type K(+) channel function is down-regulated. Additionally, we find that somatic Kv1 mediated current is down-regulated, resulting in increased excitability of fmr1 /y PT neurons. Importantly, these h- and K(+) channel differences do not extend to neighboring intratelencephalic-projecting neurons. Thus, the absence of FMRP has divergent effects on the function of individual types of ion channels not only between brain regions, but also variable effects across cell types within the same brain region. Given the importance of ion channels in regulating neural circuits, these results suggest cell-type-specific phenotypes for the disease. PMID- 26601126 TI - Gelatin-derived sustainable carbon-based functional materials for energy conversion and storage with controllability of structure and component. AB - Nonprecious carbon catalysts and electrodes are vital components in energy conversion and storage systems. Despite recent progress, controllable synthesis of carbon functional materials is still a great challenge. We report a novel strategy to prepare simultaneously Fe-N-C catalysts and Fe3O4/N-doped carbon hybrids based on the sol-gel chemistry of gelatin and iron with controllability of structure and component. The catalysts demonstrate higher catalytic activity and better durability for oxygen reduction than precious Pt/C catalysts. The active sites of FeN4/C (D1) and N-FeN2+2/C (D3) are identified by Mossbauer spectroscopy, and most of the Fe ions are converted into D1 or D3 species. The oxygen reduction reaction (ORR) activity correlates well with the surface area, porosity, and the content of active Fe-N x /C (D1 + D3) species. As an anode material for lithium storage, Fe3O4/carbon hybrids exhibit superior rate capability and excellent cycling performance. The synthetic approach and the proposed mechanism open new avenues for the development of sustainable carbon based functional materials. PMID- 26601127 TI - Addressing China's grand challenge of achieving food security while ensuring environmental sustainability. AB - China's increasingly urbanized and wealthy population is driving a growing and changing demand for food, which might not be met without significant increase in agricultural productivity and sustainable use of natural resources. Given the past relationship between lack of access to affordable food and political instability, food security has to be given a high priority on national political agendas in the context of globalization. The drive for increased food production has had a significant impact on the environment, and the deterioration in ecosystem quality due to historic and current levels of pollution will potentially compromise the food production system in China. We discuss the grand challenges of not only producing more food but also producing it sustainably and without environmental degradation. In addressing these challenges, food production should be considered as part of an environmental system (soil, air, water, and biodiversity) and not independent from it. It is imperative that new ways of meeting the demand for food are developed while safeguarding the natural resources upon which food production is based. We present a holistic approach to both science and policy to ensure future food security while embracing the ambition of achieving environmental sustainability in China. It is a unique opportunity for China to be a role model as a new global player, especially for other emerging economies. PMID- 26601128 TI - Refining lunar impact chronology through high spatial resolution (40)Ar/(39)Ar dating of impact melts. AB - Quantitative constraints on the ages of melt-forming impact events on the Moon are based primarily on isotope geochronology of returned samples. However, interpreting the results of such studies can often be difficult because the provenance region of any sample returned from the lunar surface may have experienced multiple impact events over the course of billions of years of bombardment. We illustrate this problem with new laser microprobe (40)Ar/(39)Ar data for two Apollo 17 impact melt breccias. Whereas one sample yields a straightforward result, indicating a single melt-forming event at ca. 3.83 Ga, data from the other sample document multiple impact melt-forming events between ca. 3.81 Ga and at least as young as ca. 3.27 Ga. Notably, published zircon U/Pb data indicate the existence of even older melt products in the same sample. The revelation of multiple impact events through (40)Ar/(39)Ar geochronology is likely not to have been possible using standard incremental heating methods alone, demonstrating the complementarity of the laser microprobe technique. Evidence for 3.83 Ga to 3.81 Ga melt components in these samples reinforces emerging interpretations that Apollo 17 impact breccia samples include a significant component of ejecta from the Imbrium basin impact. Collectively, our results underscore the need to quantitatively resolve the ages of different melt generations from multiple samples to improve our current understanding of the lunar impact record, and to establish the absolute ages of important impact structures encountered during future exploration missions in the inner Solar System. PMID- 26601129 TI - Settlement scaling and increasing returns in an ancient society. AB - A key property of modern cities is increasing returns to scale-the finding that many socioeconomic outputs increase more rapidly than their population size. Recent theoretical work proposes that this phenomenon is the result of general network effects typical of human social networks embedded in space and, thus, is not necessarily limited to modern settlements. We examine the extent to which increasing returns are apparent in archaeological settlement data from the pre Hispanic Basin of Mexico. We review previous work on the quantitative relationship between population size and average settled area in this society and then present a general analysis of their patterns of monument construction and house sizes. Estimated scaling parameter values and residual statistics support the hypothesis that increasing returns to scale characterized various forms of socioeconomic production available in the archaeological record and are found to be consistent with key expectations from settlement scaling theory. As a consequence, these results provide evidence that the essential processes that lead to increasing returns in contemporary cities may have characterized human settlements throughout history, and demonstrate that increasing returns do not require modern forms of political or economic organization. PMID- 26601130 TI - Membrane alternatives in worlds without oxygen: Creation of an azotosome. AB - The lipid bilayer membrane, which is the foundation of life on Earth, is not viable outside of biology based on liquid water. This fact has caused astronomers who seek conditions suitable for life to search for exoplanets within the "habitable zone," the narrow band in which liquid water can exist. However, can cell membranes be created and function at temperatures far below those at which water is a liquid? We take a step toward answering this question by proposing a new type of membrane, composed of small organic nitrogen compounds, that is capable of forming and functioning in liquid methane at cryogenic temperatures. Using molecular simulations, we demonstrate that these membranes in cryogenic solvent have an elasticity equal to that of lipid bilayers in water at room temperature. As a proof of concept, we also demonstrate that stable cryogenic membranes could arise from compounds observed in the atmosphere of Saturn's moon, Titan, known for the existence of seas of liquid methane on its surface. PMID- 26601131 TI - Unprecedented 21st century drought risk in the American Southwest and Central Plains. AB - In the Southwest and Central Plains of Western North America, climate change is expected to increase drought severity in the coming decades. These regions nevertheless experienced extended Medieval-era droughts that were more persistent than any historical event, providing crucial targets in the paleoclimate record for benchmarking the severity of future drought risks. We use an empirical drought reconstruction and three soil moisture metrics from 17 state-of-the-art general circulation models to show that these models project significantly drier conditions in the later half of the 21st century compared to the 20th century and earlier paleoclimatic intervals. This desiccation is consistent across most of the models and moisture balance variables, indicating a coherent and robust drying response to warming despite the diversity of models and metrics analyzed. Notably, future drought risk will likely exceed even the driest centuries of the Medieval Climate Anomaly (1100-1300 CE) in both moderate (RCP 4.5) and high (RCP 8.5) future emissions scenarios, leading to unprecedented drought conditions during the last millennium. PMID- 26601132 TI - N-doped carbon nanomaterials are durable catalysts for oxygen reduction reaction in acidic fuel cells. AB - The availability of low-cost, efficient, and durable catalysts for oxygen reduction reaction (ORR) is a prerequisite for commercialization of the fuel cell technology. Along with intensive research efforts of more than half a century in developing nonprecious metal catalysts (NPMCs) to replace the expensive and scarce platinum-based catalysts, a new class of carbon-based, low-cost, metal free ORR catalysts was demonstrated to show superior ORR performance to commercial platinum catalysts, particularly in alkaline electrolytes. However, their large-scale practical application in more popular acidic polymer electrolyte membrane (PEM) fuel cells remained elusive because they are often found to be less effective in acidic electrolytes, and no attempt has been made for a single PEM cell test. We demonstrated that rationally designed, metal-free, nitrogen-doped carbon nanotubes and their graphene composites exhibited significantly better long-term operational stabilities and comparable gravimetric power densities with respect to the best NPMC in acidic PEM cells. This work represents a major breakthrough in removing the bottlenecks to translate low cost, metal-free, carbon-based ORR catalysts to commercial reality, and opens avenues for clean energy generation from affordable and durable fuel cells. PMID- 26601133 TI - Identification of different oxygen species in oxide nanostructures with (17)O solid-state NMR spectroscopy. AB - Nanostructured oxides find multiple uses in a diverse range of applications including catalysis, energy storage, and environmental management, their higher surface areas, and, in some cases, electronic properties resulting in different physical properties from their bulk counterparts. Developing structure-property relations for these materials requires a determination of surface and subsurface structure. Although microscopy plays a critical role owing to the fact that the volumes sampled by such techniques may not be representative of the whole sample, complementary characterization methods are urgently required. We develop a simple nuclear magnetic resonance (NMR) strategy to detect the first few layers of a nanomaterial, demonstrating the approach with technologically relevant ceria nanoparticles. We show that the (17)O resonances arising from the first to third surface layer oxygen ions, hydroxyl sites, and oxygen species near vacancies can be distinguished from the oxygen ions in the bulk, with higher-frequency (17)O chemical shifts being observed for the lower coordinated surface sites. H2 (17)O can be used to selectively enrich surface sites, allowing only these particular active sites to be monitored in a chemical process. (17)O NMR spectra of thermally treated nanosized ceria clearly show how different oxygen species interconvert at elevated temperature. Density functional theory calculations confirm the assignments and reveal a strong dependence of chemical shift on the nature of the surface. These results open up new strategies for characterizing nanostructured oxides and their applications. PMID- 26601134 TI - Happy Birthday Science Advances! AB - Scientists are invited to join in our effort to publish significant, innovative original research that advances the frontiers of science. PMID- 26601135 TI - Origami-inspired active graphene-based paper for programmable instant self folding walking devices. AB - Origami-inspired active graphene-based paper with programmed gradients in vertical and lateral directions is developed to address many of the limitations of polymer active materials including slow response and violent operation methods. Specifically, we used function-designed graphene oxide as nanoscale building blocks to fabricate an all-graphene self-folding paper that has a single component gradient structure. A functional device composed of this graphene paper can (i) adopt predesigned shapes, (ii) walk, and (iii) turn a corner. These processes can be remote-controlled by gentle light or heating. We believe that this self-folding material holds potential for a wide range of applications such as sensing, artificial muscles, and robotics. PMID- 26601136 TI - Old World megadroughts and pluvials during the Common Era. AB - Climate model projections suggest widespread drying in the Mediterranean Basin and wetting in Fennoscandia in the coming decades largely as a consequence of greenhouse gas forcing of climate. To place these and other "Old World" climate projections into historical perspective based on more complete estimates of natural hydroclimatic variability, we have developed the "Old World Drought Atlas" (OWDA), a set of year-to-year maps of tree-ring reconstructed summer wetness and dryness over Europe and the Mediterranean Basin during the Common Era. The OWDA matches historical accounts of severe drought and wetness with a spatial completeness not previously available. In addition, megadroughts reconstructed over north-central Europe in the 11th and mid-15th centuries reinforce other evidence from North America and Asia that droughts were more severe, extensive, and prolonged over Northern Hemisphere land areas before the 20th century, with an inadequate understanding of their causes. The OWDA provides new data to determine the causes of Old World drought and wetness and attribute past climate variability to forced and/or internal variability. PMID- 26601137 TI - A new generation of alloyed/multimetal chalcogenide nanowires by chemical transformation. AB - One-dimensional metal chalcogenide nanostructures are important candidates for many technological applications such as photovoltaic and thermoelectric devices. However, the design and synthesis of one-dimensional metal chalcogenide nanostructured materials with controllable components and properties remain a challenge. We report a general chemical transformation process for the synthesis of more than 45 kinds of one-dimensional alloyed/hybrid metal chalcogenide nanostructures inherited from mother template Te x Se y @Se core-shell nanowires with tunable compositions. As many as nine types of monometal chalcogenide alloy nanowires (including AgSeTe, HgSeTe, CuSeTe, BiSeTe, PbSeTe, CdSeTe, SbSeTe, NiSeTe, and CoSeTe) can be synthesized. Alloyed and hybrid nanowires integrated with two or more alloyed metal chalcogenide phases can also be prepared. The compositions of all of these metal chalcogenide nanowires are tunable within a wide range. This protocol provides a new general route for the controllable synthesis of a new generation of one-dimensional metal chalcogenide nanostructures. PMID- 26601138 TI - Visualization of superparamagnetic dynamics in magnetic topological insulators. AB - Quantized Hall conductance is a generic feature of two-dimensional electronic systems with broken time reversal symmetry. In the quantum anomalous Hall state recently discovered in magnetic topological insulators, time reversal symmetry is believed to be broken by long-range ferromagnetic order, with quantized resistance observed even at zero external magnetic field. We use scanning nanoSQUID (nano-superconducting quantum interference device) magnetic imaging to provide a direct visualization of the dynamics of the quantum phase transition between the two anomalous Hall plateaus in a Cr-doped (Bi,Sb)2Te3 thin film. Contrary to naive expectations based on macroscopic magnetometry, our measurements reveal a superparamagnetic state formed by weakly interacting magnetic domains with a characteristic size of a few tens of nanometers. The magnetic phase transition occurs through random reversals of these local moments, which drive the electronic Hall plateau transition. Surprisingly, we find that the electronic system can, in turn, drive the dynamics of the magnetic system, revealing a subtle interplay between the two coupled quantum phase transitions. PMID- 26601139 TI - Uniform metal nanostructures with long-range order via three-step hierarchical self-assembly. AB - Large-scale nanopatterning is a major issue in nanoscience and nanotechnology, but conventional top-down approaches are challenging because of instrumentation and process complexity while often lacking the desired spatial resolution. We present a hierarchical bottom-up nanopatterning routine using exclusively self assembly processes: By combining crystal surface reconstruction, microphase separation of copolymers, and selective metal diffusion, we produce monodisperse metal nanostructures in highly regular arrays covering areas of square centimeters. In situ grazing incidence small-angle x-ray scattering during Fe nanostructure formation evidences an outstanding structural order in the self assembling system and hints at the possibility of sculpting nanostructures using external process parameters. Thus, we demonstrate that bottom-up nanopatterning is a competitive alternative to top-down routines, achieving comparable pattern regularity, feature size, and patterned areas with considerably reduced effort. Intriguing assets of the proposed fabrication approach include the option for in situ investigations during pattern formation, the possibility of customizing the nanostructure morphology, the capacity to pattern arbitrarily large areas with ultrahigh structure densities unachievable by top-down approaches, and the potential to address the nanostructures individually. Numerous applications of self-assembled nanostructure patterns can be envisioned, for example, in high density magnetic data storage, in functional nanostructured materials for photonics or catalysis, or in surface plasmon resonance-based sensing. PMID- 26601140 TI - Tuning bad metal and non-Fermi liquid behavior in a Mott material: Rare-earth nickelate thin films. AB - Resistances that exceed the Mott-Ioffe-Regel limit (known as bad metal behavior) and non-Fermi liquid behavior are ubiquitous features of the normal state of many strongly correlated materials. We establish the conditions that lead to bad metal and non-Fermi liquid phases in NdNiO3, which exhibits a prototype bandwidth controlled metal-insulator transition. We show that resistance saturation is determined by the magnitude of Ni eg orbital splitting, which can be tuned by strain in epitaxial films, causing the appearance of bad metal behavior under certain conditions. The results shed light on the nature of a crossover to a non Fermi liquid metal phase and provide a predictive criterion for Anderson localization. They elucidate a seemingly complex phase behavior as a function of film strain and confinement and provide guidelines for orbital engineering and novel devices. PMID- 26601141 TI - Neuropilin-1 and heparan sulfate proteoglycans cooperate in cellular uptake of nanoparticles functionalized by cationic cell-penetrating peptides. AB - Cell-penetrating peptides (CPPs) have been widely used to deliver nanomaterials and other types of macromolecules into mammalian cells for therapeutic and diagnostic use. Cationic CPPs that bind to heparan sulfate (HS) proteoglycans on the cell surface induce potent endocytosis; however, the role of other surface receptors in this process is unclear. We describe the convergence of an HS dependent pathway with the C-end rule (CendR) mechanism that enables peptide ligation with neuropilin-1 (NRP1), a cell surface receptor known to be involved in angiogenesis and vascular permeability. NRP1 binds peptides carrying a positive residue at the carboxyl terminus, a feature that is compatible with cationic CPPs, either intact or after proteolytic processing. We used CPP and CendR peptides, as well as HS- and NRP1-binding motifs from semaphorins, to explore the commonalities and differences of the HS and NRP1 pathways. We show that the CendR-NRP1 interaction determines the ability of CPPs to induce vascular permeability. We also show at the ultrastructural level, using a novel cell entry synchronization method, that both the HS and NRP1 pathways can initiate a macropinocytosis-like process and visualize these CPP-cargo complexes going through various endosomal compartments. Our results provide new insights into how CPPs exploit multiple surface receptor pathways for intracellular delivery. PMID- 26601142 TI - The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment. AB - The tumor microenvironment is profoundly immunosuppressive. We show that multiple tumor types create intratumoral immune suppression driven by a specialized form of regulatory T cell (Treg) activation dependent on the PTEN (phosphatase and tensin homolog) lipid phosphatase. PTEN acted to stabilize Tregs in tumors, preventing them from reprogramming into inflammatory effector cells. In mice with a Treg-specific deletion of PTEN, tumors grew slowly, were inflamed, and could not create an immunosuppressive tumor microenvironment. In normal mice, exposure to apoptotic tumor cells rapidly elicited PTEN-expressing Tregs, and PTEN deficient mice were unable to maintain tolerance to apoptotic cells. In wild-type mice with large established tumors, pharmacologic inhibition of PTEN after chemotherapy or immunotherapy profoundly reconfigured the tumor microenvironment, changing it from a suppressive to an inflammatory milieu, and tumors underwent rapid regression. Thus, the immunosuppressive milieu in tumors must be actively maintained, and tumors become susceptible to immune attack if the PTEN pathway in Tregs is disrupted. PMID- 26601144 TI - New precise dates for the ancient and sacred coral pyramidal tombs of Leluh (Kosrae, Micronesia). AB - Monumental tombs within ancient civilizations worldwide hold precious clues for deciphering the architectural skill, acumen, and industry of prehistoric cultures. Most tombs were constructed from abiotic materials-stone, soil, and/or clay, predominately-and were built to permanently inter royalty or high-status individuals. On the island of Kosrae in the central Pacific, monumental tombs were constructed with scleractinian coral and were confined to the prehistoric island capital of Leluh, where they served as temporary mortuary processing points. Like other prehistoric tombs, the Leluh tombs were dated by association from the remnants of the temporarily interred. We present new dates for three sacred tombs using high-precision U-Th dates from 24 corals collected directly from the structural materials. The results suggest that the tombs were built about 700 years ago during the 14th century, about three centuries earlier than previously reported. The new dates redefine the peak occupation of Leluh and place its ruling paramountcy at the leading edge of the developing trans-oceanic political hierarchies, as well as the social and economic systems that dominated the civilizations in this part of the world. PMID- 26601143 TI - Co-infections determine patterns of mortality in a population exposed to parasite infection. AB - Many individual hosts are infected with multiple parasite species, and this may increase or decrease the pathogenicity of the infections. This phenomenon is termed heterologous reactivity and is potentially an important determinant of both patterns of morbidity and mortality and of the impact of disease control measures at the population level. Using infections with Theileria parva (a tick borne protozoan, related to Plasmodium) in indigenous African cattle [where it causes East Coast fever (ECF)] as a model system, we obtain the first quantitative estimate of the effects of heterologous reactivity for any parasitic disease. In individual calves, concurrent co-infection with less pathogenic species of Theileria resulted in an 89% reduction in mortality associated with T. parva infection. Across our study population, this corresponds to a net reduction in mortality due to ECF of greater than 40%. Using a mathematical model, we demonstrate that this degree of heterologous protection provides a unifying explanation for apparently disparate epidemiological patterns: variable disease induced mortality rates, age-mortality profiles, weak correlations between the incidence of infection and disease (known as endemic stability), and poor efficacy of interventions that reduce exposure to multiple parasite species. These findings can be generalized to many other infectious diseases, including human malaria, and illustrate how co-infections can play a key role in determining population-level patterns of morbidity and mortality due to parasite infections. PMID- 26601145 TI - Observation of the simplest Criegee intermediate CH2OO in the gas-phase ozonolysis of ethylene. AB - Ozonolysis is one of the dominant oxidation pathways for tropospheric alkenes. Although numerous studies have confirmed a 1,3-cycloaddition mechanism that generates a Criegee intermediate (CI) with form R1R2COO, no small CIs have ever been directly observed in the ozonolysis of alkenes because of their high reactivity. We present the first experimental detection of CH2OO in the gas-phase ozonolysis of ethylene, using Fourier transform microwave spectroscopy and a modified pulsed nozzle, which combines high reactant concentrations with rapid sampling and sensitive detection. Nine other product species of the O3 + C2H4 reaction were also detected, including formaldehyde, formic acid, dioxirane, and ethylene ozonide. The presence of all these species can be attributed to the unimolecular and bimolecular reactions of CH2OO, and their abundances are in qualitative agreement with published mechanisms and rate constants. PMID- 26601146 TI - Natural and sexual selection act on different axes of variation in avian plumage color. AB - The bright colors of birds are often attributed to sexual selection on males, but in many species both sexes are colorful and it has been long debated whether sexual selection can also explain this variation. We show that most evolutionary transitions in color have been toward similar plumage in both sexes, and the color of both sexes (for example, bright or dull) was associated with indices of natural selection (for example, habitat type), whereas sexual differences in color were primarily associated with indices of sexual selection on males (for example, polygyny and large testes size). Debate about the evolution of bird coloration can be resolved by recognizing that both natural and sexual selection have been influential, but they have generally acted on two different axes: sexual selection on an axis of sexual differences and natural selection on both sexes for the type of color (for example, bright or dull). PMID- 26601147 TI - Pb pollution from leaded gasoline in South America in the context of a 2000-year metallurgical history. AB - Exploitation of the extensive polymetallic deposits of the Andean Altiplano in South America since precolonial times has caused substantial emissions of neurotoxic lead (Pb) into the atmosphere; however, its historical significance compared to recent Pb pollution from leaded gasoline is not yet resolved. We present a comprehensive Pb emission history for the last two millennia for South America, based on a continuous, high-resolution, ice core record from Illimani glacier. Illimani is the highest mountain of the eastern Bolivian Andes and is located at the northeastern margin of the Andean Altiplano. The ice core Pb deposition history revealed enhanced Pb enrichment factors (EFs) due to metallurgical processing for silver production during periods of the Tiwanaku/Wari culture (AD 450-950), the Inca empires (AD 1450-1532), colonial times (AD 1532-1900), and tin production at the beginning of the 20th century. After the 1960s, Pb EFs increased by a factor of 3 compared to the emission level from metal production, which we attribute to gasoline-related Pb emissions. Our results show that anthropogenic Pb pollution levels from road traffic in South America exceed those of any historical metallurgy in the last two millennia, even in regions with exceptional high local metallurgical activity. PMID- 26601148 TI - Near-infrared-driven decomposition of metal precursors yields amorphous electrocatalytic films. AB - Amorphous metal-based films lacking long-range atomic order have found utility in applications ranging from electronics applications to heterogeneous catalysis. Notwithstanding, there is a limited set of fabrication methods available for making amorphous films, particularly in the absence of a conducting substrate. We introduce herein a scalable preparative method for accessing oxidized and reduced phases of amorphous films that involves the efficient decomposition of molecular precursors, including simple metal salts, by exposure to near-infrared (NIR) radiation. The NIR-driven decomposition process provides sufficient localized heating to trigger the liberation of the ligand from solution-deposited precursors on substrates, but insufficient thermal energy to form crystalline phases. This method provides access to state-of-the-art electrocatalyst films, as demonstrated herein for the electrolysis of water, and extends the scope of usable substrates to include nonconducting and temperature-sensitive platforms. PMID- 26601149 TI - Vocal learning in a social mammal: Demonstrated by isolation and playback experiments in bats. AB - The evolution of human language is shrouded in mystery as it is unparalleled in the animal kingdom. Whereas vocal learning is crucial for the development of speech in humans, it seems rare among nonhuman animals. Songbirds often serve as a model for vocal learning, but the lack of a mammalian model hinders our quest for the origin of this capability. We report the influence of both isolation and playback experiments on the vocal development of a mammal, the Egyptian fruit bat. We continuously recorded pups from birth to adulthood and found that, when raised in a colony, pups acquired the adult repertoire, whereas when acoustically isolated, they exhibited underdeveloped vocalizations. Isolated pups that heard bat recordings exhibited a repertoire that replicated the playbacks they were exposed to. These findings demonstrate vocal learning in a social mammal, and suggest bats as a model for language acquisition. PMID- 26601150 TI - Silver(I) as a widely applicable, homogeneous catalyst for aerobic oxidation of aldehydes toward carboxylic acids in water-"silver mirror": From stoichiometric to catalytic. AB - The first example of a homogeneous silver(I)-catalyzed aerobic oxidation of aldehydes in water is reported. More than 50 examples of different aliphatic and aromatic aldehydes, including natural products, were tested, and all of them successfully underwent aerobic oxidation to give the corresponding carboxylic acids in extremely high yields. The reaction conditions are very mild and greener, requiring only a very low silver(I) catalyst loading, using atmospheric oxygen as the oxidant and water as the solvent, and allowing gram-scale oxidation with only 2 mg of our catalyst. Chromatography is completely unnecessary for purification in most cases. PMID- 26601151 TI - A general route to nanocrystal kebabs periodically assembled on stretched flexible polymer shish. AB - Assembling nanoparticles into one-dimensional (1D) nanostructures with precisely controlled size and shape renders the exploration of new properties and construction of 1D miniaturized devices possible. The physical properties of such nanostructures depend heavily on the size, chemical composition, and surface chemistry of nanoparticle constituents, as well as the close proximity of adjacent nanoparticles within the 1D nanostructure. Chemical synthesis provides an intriguing alternative means of creating 1D nanostructures composed of self assembled nanoparticles in terms of material diversity, size controllability, shape regularity, and low-cost production. However, this is an area where progress has been slower. We report an unconventional yet general strategy to craft an exciting variety of 1D nanonecklace-like nanostructures comprising uniform functional nanodiscs periodically assembled along a stretched flexible polymer chain by capitalizing on judiciously designed amphiphilic worm-like diblock copolymers as nanoreactors. These nanostructures can be regarded as organic-inorganic shish-kebabs, in which nanodisc kebabs are periodically situated on a stretched polymer shish. Simulations based on self-consistent field theory reveal that the formation of organic-inorganic shish-kebabs is guided by the self-assembled elongated star-like diblock copolymer constituents constrained on the highly stretched polymer chain. PMID- 26601152 TI - Structural patterns at all scales in a nonmetallic chiral Au133(SR)52 nanoparticle. AB - Structural ordering is widely present in molecules and materials. However, the organization of molecules on the curved surface of nanoparticles is still the least understood owing to the major limitations of the current surface characterization tools. By the merits of x-ray crystallography, we reveal the structural ordering at all scales in a super robust 133-gold atom nanoparticle protected by 52 thiolate ligands, which is manifested in self-assembled hierarchical patterns starting from the metal core to the interfacial -S-Au-S- ladder-like helical "stripes" and further to the "swirls" of carbon tails. These complex surface patterns have not been observed in the smaller nanoparticles. We further demonstrate that the Au133(SR)52 nanoparticle exhibits nonmetallic features in optical and electron dynamics measurements. Our work uncovers the elegant self-organization strategies in assembling a highly robust nanoparticle and provides a conceptual advance in scientific understanding of pattern structures. PMID- 26601153 TI - The search for signs of life on exoplanets at the interface of chemistry and planetary science. AB - The discovery of thousands of exoplanets in the last two decades that are so different from planets in our own solar system challenges many areas of traditional planetary science. However, ideas for how to detect signs of life in this melange of planetary possibilities have lagged, and only in the last few years has modeling how signs of life might appear on genuinely alien worlds begun in earnest. Recent results have shown that the exciting frontier for biosignature gas ideas is not in the study of biology itself, which is inevitably rooted in Earth's geochemical and evolutionary specifics, but in the interface of chemistry and planetary physics. PMID- 26601154 TI - Habitat fragmentation and its lasting impact on Earth's ecosystems. AB - We conducted an analysis of global forest cover to reveal that 70% of remaining forest is within 1 km of the forest's edge, subject to the degrading effects of fragmentation. A synthesis of fragmentation experiments spanning multiple biomes and scales, five continents, and 35 years demonstrates that habitat fragmentation reduces biodiversity by 13 to 75% and impairs key ecosystem functions by decreasing biomass and altering nutrient cycles. Effects are greatest in the smallest and most isolated fragments, and they magnify with the passage of time. These findings indicate an urgent need for conservation and restoration measures to improve landscape connectivity, which will reduce extinction rates and help maintain ecosystem services. PMID- 26601155 TI - Adding up the odds-Nitric oxide signaling underlies the decision to flee and post conflict depression of aggression. AB - Fighting is dangerous, which is why animals choose to flee once the costs outweigh the benefits, but the mechanisms underlying this decision-making process are unknown. By manipulating aggressive signaling and applying nitrergic drugs, we show that the evolutionarily conserved neuromodulator nitric oxide (NO), which has a suppressing effect on aggression in mammals, can play a decisive role. We found that crickets, which exhibit spectacular fighting behavior, flee once the sum of their opponent's aversive actions accrued during fighting exceeds a critical amount. This effect of aversive experience is mediated by the NO signaling pathway. Rather than suppressing aggressive motivation, NO increases susceptibility to aversive stimuli and with it the likelihood to flee. NO's effect is manifested in losers by prolonged avoidance behavior, characteristic for social defeat in numerous species. Intriguingly, fighting experience also induces, via NO, a brief susceptible period to aversive stimuli in winners just after victory. Our findings thus reveal a key role for NO in the mechanism underlying the decision to flee and post-conflict depression in aggressive behavior. PMID- 26601156 TI - Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model. AB - Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease affecting children. It is caused by mutations in the IGHMBP2 gene (11q13) and presently has no cure. Recently, adeno-associated virus serotype 9 (AAV9)-mediated gene therapy has been shown to rescue the phenotype of animal models of another lower motor neuron disorder, spinal muscular atrophy 5q, and a clinical trial with this strategy is ongoing. We report rescue of the disease phenotype in a SMARD1 mouse model after therapeutic delivery via systemic injection of an AAV9 construct encoding the wild-type IGHMBP2 to replace the defective gene. AAV9-IGHMBP2 administration restored protein levels and rescued motor function, neuromuscular physiology, and life span (450% increase), ameliorating pathological features in the central nervous system, muscles, and heart. To test this strategy in a human model, we transferred wild-type IGHMBP2 into human SMARD1-induced pluripotent stem cell derived motor neurons; these cells exhibited increased survival and axonal length in long-term culture. Our data support the translational potential of AAV mediated gene therapies for SMARD1, opening the door for AAV9-mediated therapy in human clinical trials. PMID- 26601157 TI - Quantum walks and wavepacket dynamics on a lattice with twisted photons. AB - The "quantum walk" has emerged recently as a paradigmatic process for the dynamic simulation of complex quantum systems, entanglement production and quantum computation. Hitherto, photonic implementations of quantum walks have mainly been based on multipath interferometric schemes in real space. We report the experimental realization of a discrete quantum walk taking place in the orbital angular momentum space of light, both for a single photon and for two simultaneous photons. In contrast to previous implementations, the whole process develops in a single light beam, with no need of interferometers; it requires optical resources scaling linearly with the number of steps; and it allows flexible control of input and output superposition states. Exploiting the latter property, we explored the system band structure in momentum space and the associated spin-orbit topological features by simulating the quantum dynamics of Gaussian wavepackets. Our demonstration introduces a novel versatile photonic platform for quantum simulations. PMID- 26601159 TI - By-product metals are technologically essential but have problematic supply. AB - The growth in technological innovation that has occurred over the past decades has, in part, been possible because an increasing number of metals of the periodic table are used to perform specialized functions. However, there have been increasing concerns regarding the reliability of supply of some of these metals. A main contributor to these concerns is the fact that many of these metals are recovered only as by-products from a limited number of geopolitically concentrated ore deposits, rendering their supplies unable to respond to rapid changes in demand. Companionality is the degree to which a metal is obtained largely or entirely as a by-product of one or more host metals from geologic ores. The dependence of companion metal availability on the production of the host metals introduces a new facet of supply risk to modern technology. We evaluated companionality for 62 different metals and metalloids, and show that 61% (38 of 62) have companionality greater than 50%. Eighteen of the 38-including such technologically essential elements as germanium, terbium, and dysprosium-are further characterized as having geopolitically concentrated production and extremely low rates of end-of-life recycling. It is this subset of companion metals-vital in current technologies such as electronics, solar energy, medical imaging, energy-efficient lighting, and other state-of-the-art products-that may be at the greatest risk of supply constraints in the coming decades. PMID- 26601158 TI - The supramammillary nucleus and the claustrum activate the cortex during REM sleep. AB - Evidence in humans suggests that limbic cortices are more active during rapid eye movement (REM or paradoxical) sleep than during waking, a phenomenon fitting with the presence of vivid dreaming during this state. In that context, it seemed essential to determine which populations of cortical neurons are activated during REM sleep. Our aim in the present study is to fill this gap by combining gene expression analysis, functional neuroanatomy, and neurochemical lesions in rats. We find in rats that, during REM sleep hypersomnia compared to control and REM sleep deprivation, the dentate gyrus, claustrum, cortical amygdaloid nucleus, and medial entorhinal and retrosplenial cortices are the only cortical structures containing neurons with an increased expression of Bdnf, FOS, and ARC, known markers of activation and/or synaptic plasticity. Further, the dentate gyrus is the only cortical structure containing more FOS-labeled neurons during REM sleep hypersomnia than during waking. Combining FOS staining, retrograde labeling, and neurochemical lesion, we then provide evidence that FOS overexpression occurring in the cortex during REM sleep hypersomnia is due to projections from the supramammillary nucleus and the claustrum. Our results strongly suggest that only a subset of cortical and hippocampal neurons are activated and display plasticity during REM sleep by means of ascending projections from the claustrum and the supramammillary nucleus. Our results pave the way for future studies to identify the function of REM sleep with regard to dreaming and emotional memory processing. PMID- 26601160 TI - Life and death of a single catalytic cracking particle. AB - Fluid catalytic cracking (FCC) particles account for 40 to 45% of worldwide gasoline production. The hierarchical complex particle pore structure allows access of long-chain feedstock molecules into active catalyst domains where they are cracked into smaller, more valuable hydrocarbon products (for example, gasoline). In this process, metal deposition and intrusion is a major cause for irreversible catalyst deactivation and shifts in product distribution. We used x ray nanotomography of industrial FCC particles at differing degrees of deactivation to quantify changes in single-particle macroporosity and pore connectivity, correlated to iron and nickel deposition. Our study reveals that these metals are incorporated almost exclusively in near-surface regions, severely limiting macropore accessibility as metal concentrations increase. Because macropore channels are "highways" of the pore network, blocking them prevents feedstock molecules from reaching the catalytically active domains. Consequently, metal deposition reduces conversion with time on stream because the internal pore volume, although itself unobstructed, becomes largely inaccessible. PMID- 26601161 TI - Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia. AB - Adult T cell leukemia (ATL) is an aggressive T cell malignancy caused by human T cell leukemia virus type 1 (HTLV-1) and has a poor prognosis. We analyzed the cytotoxic effects of various nucleoside analog reverse transcriptase inhibitors (NRTIs) for HIV-1 on ATL cells and found that abacavir potently and selectively kills ATL cells. Although NRTIs have minimal genotoxicities on host cells, the therapeutic concentration of abacavir induced numerous DNA double-strand breaks (DSBs) in the chromosomal DNA of ATL cells. DSBs persisted over time in ATL cells but not in other cell lines, suggesting impaired DNA repair. We found that the reduced expression of tyrosyl-DNA phosphodiesterase 1 (TDP1), a repair enzyme, is attributable to the cytotoxic effect of abacavir on ATL cells. We also showed that TDP1 removes abacavir from DNA ends in vitro. These results suggest a model in which ATL cells with reduced TDP1 expression are unable to excise abacavir incorporated into genomic DNA, leading to irreparable DSBs. On the basis of the above mechanism, we propose abacavir as a promising chemotherapeutic agent for ATL. PMID- 26601162 TI - Unraveling structures of protection ligands on gold nanoparticle Au68(SH)32. AB - New low-energy atomic structures of the thiolate-protected gold nanoparticle Au68(SH)32 are uncovered, where the atomic positions of the Au atoms are taken from the recent single-particle transmission electron microscopy measurement by Kornberg and co-workers, whereas the pattern of thiolate ligands on the gold core is attained on the basis of the generic formulation (or rule) of the "divide and protect" concept. Four distinct low-energy isomers, Iso1 to Iso4, whose structures all satisfy the generic formulation, are predicted. Density-functional theory optimization indicates that the four isomers are all lower in energy by 3 to 4 eV than the state-of-the-art low-energy isomer reported. Further analysis of the optimized structures of Au68(SH)32 shows that the structure of gold core in Iso1 to Iso4 is consistent with the experiment, whereas the positions of a few Au atoms at the surface of gold core are different. The computed optical absorption spectra of the four isomers are consistent with the measured spectrum. Computation of catalytic properties of Au68(SH)32 toward CO oxidation suggests that the magic number cluster can be a stand-alone nanoscale catalyst for future catalytic applications. PMID- 26601163 TI - PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors. AB - Inhibition of Dll4 (delta-like ligand 4)-Notch signaling-mediated tumor angiogenesis is an attractive approach in cancer therapy. However, inhibition of Dll4-Notch signaling has produced different effects in various tumors, and no biomarkers are available for predicting the anti-Dll4-Notch-associated antitumor activity. We show that human and mouse tumor cell-derived placental growth factor (PlGF) is a key determinant of the Dll4-Notch-induced vascular remodeling and tumor growth. In natural PlGF-expressing human tumors, inhibition of Dll4-Notch signaling markedly accelerated tumor growth by increasing blood perfusion in nonleaking tumor vasculatures. Conversely, in PlGF-negative tumors, Dll4 inhibition suppressed tumor growth by the formation of nonproductive and leaky vessels. Surprisingly, genetic inactivation of vascular endothelial growth factor receptor 1 (VEGFR1) completely abrogated the PlGF-modulated vascular remodeling and tumor growth, indicating a crucial role for VEGFR1-mediated signals in modulating Dll4-Notch functions. These findings provide mechanistic insights on PlGF-VEGFR1 signaling in the modulation of the Dll4-Notch pathway in angiogenesis and tumor growth, and have therapeutic implications of PlGF as a biomarker for predicting the antitumor benefits of Dll4 and Notch inhibitors. PMID- 26601164 TI - Experimental scattershot boson sampling. AB - Boson sampling is a computational task strongly believed to be hard for classical computers, but efficiently solvable by orchestrated bosonic interference in a specialized quantum computer. Current experimental schemes, however, are still insufficient for a convincing demonstration of the advantage of quantum over classical computation. A new variation of this task, scattershot boson sampling, leads to an exponential increase in speed of the quantum device, using a larger number of photon sources based on parametric down-conversion. This is achieved by having multiple heralded single photons being sent, shot by shot, into different random input ports of the interferometer. We report the first scattershot boson sampling experiments, where six different photon-pair sources are coupled to integrated photonic circuits. We use recently proposed statistical tools to analyze our experimental data, providing strong evidence that our photonic quantum simulator works as expected. This approach represents an important leap toward a convincing experimental demonstration of the quantum computational supremacy. PMID- 26601165 TI - Characteristic signatures of quantum criticality driven by geometrical frustration. AB - Geometrical frustration describes situations where interactions are incompatible with the lattice geometry and stabilizes exotic phases such as spin liquids. Whether geometrical frustration of magnetic interactions in metals can induce unconventional quantum critical points is an active area of research. We focus on the hexagonal heavy fermion metal CeRhSn, where the Kondo ions are located on distorted kagome planes stacked along the c axis. Low-temperature specific heat, thermal expansion, and magnetic Gruneisen parameter measurements prove a zero field quantum critical point. The linear thermal expansion, which measures the initial uniaxial pressure derivative of the entropy, displays a striking anisotropy. Critical and noncritical behaviors along and perpendicular to the kagome planes, respectively, prove that quantum criticality is driven be geometrical frustration. We also discovered a spin flop-type metamagnetic crossover. This excludes an itinerant scenario and suggests that quantum criticality is related to local moments in a spin liquid-like state. PMID- 26601166 TI - Electrically controlling single-spin qubits in a continuous microwave field. AB - Large-scale quantum computers must be built upon quantum bits that are both highly coherent and locally controllable. We demonstrate the quantum control of the electron and the nuclear spin of a single (31)P atom in silicon, using a continuous microwave magnetic field together with nanoscale electrostatic gates. The qubits are tuned into resonance with the microwave field by a local change in electric field, which induces a Stark shift of the qubit energies. This method, known as A-gate control, preserves the excellent coherence times and gate fidelities of isolated spins, and can be extended to arbitrarily many qubits without requiring multiple microwave sources. PMID- 26601167 TI - Crowdsourced earthquake early warning. AB - Earthquake early warning (EEW) can reduce harm to people and infrastructure from earthquakes and tsunamis, but it has not been implemented in most high earthquake risk regions because of prohibitive cost. Common consumer devices such as smartphones contain low-cost versions of the sensors used in EEW. Although less accurate than scientific-grade instruments, these sensors are globally ubiquitous. Through controlled tests of consumer devices, simulation of an M w (moment magnitude) 7 earthquake on California's Hayward fault, and real data from the M w 9 Tohoku-oki earthquake, we demonstrate that EEW could be achieved via crowdsourcing. PMID- 26601168 TI - Optimized unconventional superconductivity in a molecular Jahn-Teller metal. AB - Understanding the relationship between the superconducting, the neighboring insulating, and the normal metallic state above T c is a major challenge for all unconventional superconductors. The molecular A3C60 fulleride superconductors have a parent antiferromagnetic insulator in common with the atom-based cuprates, but here, the C60 (3-) electronic structure controls the geometry and spin state of the structural building unit via the on-molecule Jahn-Teller effect. We identify the Jahn-Teller metal as a fluctuating microscopically heterogeneous coexistence of both localized Jahn-Teller-active and itinerant electrons that connects the insulating and superconducting states of fullerides. The balance between these molecular and extended lattice features of the electrons at the Fermi level gives a dome-shaped variation of T c with interfulleride separation, demonstrating molecular electronic structure control of superconductivity. PMID- 26601169 TI - Growth of asteroids, planetary embryos, and Kuiper belt objects by chondrule accretion. AB - Chondrules are millimeter-sized spherules that dominate primitive meteorites (chondrites) originating from the asteroid belt. The incorporation of chondrules into asteroidal bodies must be an important step in planet formation, but the mechanism is not understood. We show that the main growth of asteroids can result from gas drag-assisted accretion of chondrules. The largest planetesimals of a population with a characteristic radius of 100 km undergo runaway accretion of chondrules within ~3 My, forming planetary embryos up to Mars's size along with smaller asteroids whose size distribution matches that of main belt asteroids. The aerodynamical accretion leads to size sorting of chondrules consistent with chondrites. Accretion of millimeter-sized chondrules and ice particles drives the growth of planetesimals beyond the ice line as well, but the growth time increases above the disc lifetime outside of 25 AU. The contribution of direct planetesimal accretion to the growth of both asteroids and Kuiper belt objects is minor. In contrast, planetesimal accretion and chondrule accretion play more equal roles in the formation of Moon-sized embryos in the terrestrial planet formation region. These embryos are isolated from each other and accrete planetesimals only at a low rate. However, the continued accretion of chondrules destabilizes the oligarchic configuration and leads to the formation of Mars sized embryos and terrestrial planets by a combination of direct chondrule accretion and giant impacts. PMID- 26601170 TI - Morphogenesis and mechanostabilization of complex natural and 3D printed shapes. AB - The natural selection and the evolutionary optimization of complex shapes in nature are closely related to their functions. Mechanostabilization of shape of biological structure via morphogenesis has several beautiful examples. With the help of simple mechanics-based modeling and experiments, we show an important causality between natural shape selection as evolutionary outcome and the mechanostabilization of seashells. The effect of biological growth on the mechanostabilization process is identified with examples of two natural shapes of seashells, one having a diametrically converging localization of stresses and the other having a helicoidally concentric localization of stresses. We demonstrate how the evolved shape enables predictable protection of soft body parts of the species. The effect of bioavailability of natural material is found to be a secondary factor compared to shape selectivity, where material microstructure only acts as a constraint to evolutionary optimization. This is confirmed by comparing the mechanostabilization behavior of three-dimensionally printed synthetic polymer structural shapes with that of natural seashells consisting of ceramic and protein. This study also highlights interesting possibilities in achieving a new design of structures made of ordinary materials which have bio inspired optimization objectives. PMID- 26601171 TI - Twentieth century turnover of Mexican endemic avifaunas: Landscape change versus climate drivers. AB - Numerous climate change effects on biodiversity have been anticipated and documented, including extinctions, range shifts, phenological shifts, and breakdown of interactions in ecological communities, yet the relative balance of different climate drivers and their relationships to other agents of global change (for example, land use and land-use change) remains relatively poorly understood. This study integrated historical and current biodiversity data on distributions of 115 Mexican endemic bird species to document areas of concentrated gains and losses of species in local communities, and then related those changes to climate and land-use drivers. Of all drivers examined, at this relatively coarse spatial resolution, only temperature change had significant impacts on avifaunal turnover; neither precipitation change nor human impact on landscapes had detectable effects. This study, conducted across species' geographic distributions, and covering all of Mexico, thanks to two large-scale biodiversity data sets, could discern relative importance of specific climatic drivers of biodiversity change. PMID- 26601172 TI - Collapse of the world's largest herbivores. AB - Large wild herbivores are crucial to ecosystems and human societies. We highlight the 74 largest terrestrial herbivore species on Earth (body mass >=100 kg), the threats they face, their important and often overlooked ecosystem effects, and the conservation efforts needed to save them and their predators from extinction. Large herbivores are generally facing dramatic population declines and range contractions, such that ~60% are threatened with extinction. Nearly all threatened species are in developing countries, where major threats include hunting, land-use change, and resource depression by livestock. Loss of large herbivores can have cascading effects on other species including large carnivores, scavengers, mesoherbivores, small mammals, and ecological processes involving vegetation, hydrology, nutrient cycling, and fire regimes. The rate of large herbivore decline suggests that ever-larger swaths of the world will soon lack many of the vital ecological services these animals provide, resulting in enormous ecological and social costs. PMID- 26601173 TI - Strontium isotopes delineate fine-scale natal origins and migration histories of Pacific salmon. AB - Highly migratory organisms present major challenges to conservation efforts. This is especially true for exploited anadromous fish species, which exhibit long range dispersals from natal sites, complex population structures, and extensive mixing of distinct populations during exploitation. By tracing the migratory histories of individual Chinook salmon caught in fisheries using strontium isotopes, we determined the relative production of natal habitats at fine spatial scales and different life histories. Although strontium isotopes have been widely used in provenance research, we present a new robust framework to simultaneously assess natal sources and migrations of individuals within fishery harvests through time. Our results pave the way for investigating how fine-scale habitat production and life histories of salmon respond to perturbations-providing crucial insights for conservation. PMID- 26601174 TI - Screening system for drug-induced arrhythmogenic risk combining a patch clamp and heart simulator. AB - To save time and cost for drug discovery, a paradigm shift in cardiotoxicity testing is required. We introduce a novel screening system for drug-induced arrhythmogenic risk that combines in vitro pharmacological assays and a multiscale heart simulator. For 12 drugs reported to have varying cardiotoxicity risks, dose-inhibition curves were determined for six ion channels using automated patch clamp systems. By manipulating the channel models implemented in a heart simulator consisting of more than 20 million myocyte models, we simulated a standard electrocardiogram (ECG) under various doses of drugs. When the drug concentrations were increased from therapeutic levels, each drug induced a concentration-dependent characteristic type of ventricular arrhythmia, whereas no arrhythmias were observed at any dose with drugs known to be safe. We have shown that our system combining in vitro and in silico technologies can predict drug induced arrhythmogenic risk reliably and efficiently. PMID- 26601175 TI - Artificial rheotaxis. AB - Motility is a basic feature of living microorganisms, and how it works is often determined by environmental cues. Recent efforts have focused on developing artificial systems that can mimic microorganisms, in particular their self propulsion. We report on the design and characterization of synthetic self propelled particles that migrate upstream, known as positive rheotaxis. This phenomenon results from a purely physical mechanism involving the interplay between the polarity of the particles and their alignment by a viscous torque. We show quantitative agreement between experimental data and a simple model of an overdamped Brownian pendulum. The model notably predicts the existence of a stagnation point in a diverging flow. We take advantage of this property to demonstrate that our active particles can sense and predictably organize in an imposed flow. Our colloidal system represents an important step toward the realization of biomimetic microsystems with the ability to sense and respond to environmental changes. PMID- 26601176 TI - Why resilience is unappealing to social science: Theoretical and empirical investigations of the scientific use of resilience. AB - Resilience is often promoted as a boundary concept to integrate the social and natural dimensions of sustainability. However, it is a troubled dialogue from which social scientists may feel detached. To explain this, we first scrutinize the meanings, attributes, and uses of resilience in ecology and elsewhere to construct a typology of definitions. Second, we analyze core concepts and principles in resilience theory that cause disciplinary tensions between the social and natural sciences (system ontology, system boundary, equilibria and thresholds, feedback mechanisms, self-organization, and function). Third, we provide empirical evidence of the asymmetry in the use of resilience theory in ecology and environmental sciences compared to five relevant social science disciplines. Fourth, we contrast the unification ambition in resilience theory with methodological pluralism. Throughout, we develop the argument that incommensurability and unification constrain the interdisciplinary dialogue, whereas pluralism drawing on core social scientific concepts would better facilitate integrated sustainability research. PMID- 26601177 TI - Critical flow and dissipation in a quasi-one-dimensional superfluid. AB - In one of the most celebrated examples of the theory of universal critical phenomena, the phase transition to the superfluid state of (4)He belongs to the same three-dimensional (3D) O(2) universality class as the onset of ferromagnetism in a lattice of classical spins with XY symmetry. Below the transition, the superfluid density rhos and superfluid velocity v s increase as a power law of temperature described by a universal critical exponent that is constrained to be identical by scale invariance. As the dimensionality is reduced toward 1D, it is expected that enhanced thermal and quantum fluctuations preclude long-range order, thereby inhibiting superfluidity. We have measured the flow rate of liquid helium and deduced its superfluid velocity in a capillary flow experiment occurring in single 30-nm-long nanopores with radii ranging down from 20 to 3 nm. As the pore size is reduced toward the 1D limit, we observe the following: (i) a suppression of the pressure dependence of the superfluid velocity; (ii) a temperature dependence of v s that surprisingly can be well fitted by a power law with a single exponent over a broad range of temperatures; and (iii) decreasing critical velocities as a function of decreasing radius for channel sizes below R ? 20 nm, in stark contrast with what is observed in micrometer-sized channels. We interpret these deviations from bulk behavior as signaling the crossover to a quasi-1D state, whereby the size of a critical topological defect is cut off by the channel radius. PMID- 26601178 TI - High-performance transistors for bioelectronics through tuning of channel thickness. AB - Despite recent interest in organic electrochemical transistors (OECTs), sparked by their straightforward fabrication and high performance, the fundamental mechanism behind their operation remains largely unexplored. OECTs use an electrolyte in direct contact with a polymer channel as part of their device structure. Hence, they offer facile integration with biological milieux and are currently used as amplifying transducers for bioelectronics. Ion exchange between electrolyte and channel is believed to take place in OECTs, although the extent of this process and its impact on device characteristics are still unknown. We show that the uptake of ions from an electrolyte into a film of poly(3,4 ethylenedioxythiophene) doped with polystyrene sulfonate ( PEDOT: PSS) leads to a purely volumetric capacitance of 39 F/cm(3). This results in a dependence of the transconductance on channel thickness, a new degree of freedom that we exploit to demonstrate high-quality recordings of human brain rhythms. Our results bring to the forefront a transistor class in which performance can be tuned independently of device footprint and provide guidelines for the design of materials that will lead to state-of-the-art transistor performance. PMID- 26601179 TI - Northwestern Pacific typhoon intensity controlled by changes in ocean temperatures. AB - Dominant climatic factors controlling the lifetime peak intensity of typhoons are determined from six decades of Pacific typhoon data. We find that upper ocean temperatures in the low-latitude northwestern Pacific (LLNWP) and sea surface temperatures in the central equatorial Pacific control the seasonal average lifetime peak intensity by setting the rate and duration of typhoon intensification, respectively. An anomalously strong LLNWP upper ocean warming has favored increased intensification rates and led to unprecedentedly high average typhoon intensity during the recent global warming hiatus period, despite a reduction in intensification duration tied to the central equatorial Pacific surface cooling. Continued LLNWP upper ocean warming as predicted under a moderate [that is, Representative Concentration Pathway (RCP) 4.5] climate change scenario is expected to further increase the average typhoon intensity by an additional 14% by 2100. PMID- 26601180 TI - Imaging atomic-scale effects of high-energy ion irradiation on superconductivity and vortex pinning in Fe(Se,Te). AB - Maximizing the sustainable supercurrent density, J C, is crucial to high-current applications of superconductivity. To achieve this, preventing dissipative motion of quantized vortices is key. Irradiation of superconductors with high-energy heavy ions can be used to create nanoscale defects that act as deep pinning potentials for vortices. This approach holds unique promise for high-current applications of iron-based superconductors because J C amplification persists to much higher radiation doses than in cuprate superconductors without significantly altering the superconducting critical temperature. However, for these compounds, virtually nothing is known about the atomic-scale interplay of the crystal damage from the high-energy ions, the superconducting order parameter, and the vortex pinning processes. We visualize the atomic-scale effects of irradiating FeSe x Te1-x with 249-MeV Au ions and find two distinct effects: compact nanometer-sized regions of crystal disruption or "columnar defects," plus a higher density of single atomic site "point" defects probably from secondary scattering. We directly show that the superconducting order is virtually annihilated within the former and suppressed by the latter. Simultaneous atomically resolved images of the columnar crystal defects, the superconductivity, and the vortex configurations then reveal how a mixed pinning landscape is created, with the strongest vortex pinning occurring at metallic core columnar defects and secondary pinning at clusters of point-like defects, followed by collective pinning at higher fields. PMID- 26601181 TI - Therapy using implanted organic bioelectronics. AB - Many drugs provide their therapeutic action only at specific sites in the body, but are administered in ways that cause the drug's spread throughout the organism. This can lead to serious side effects. Local delivery from an implanted device may avoid these issues, especially if the delivery rate can be tuned according to the need of the patient. We turned to electronically and ionically conducting polymers to design a device that could be implanted and used for local electrically controlled delivery of therapeutics. The conducting polymers in our device allow electronic pulses to be transduced into biological signals, in the form of ionic and molecular fluxes, which provide a way of interfacing biology with electronics. Devices based on conducting polymers and polyelectrolytes have been demonstrated in controlled substance delivery to neural tissue, biosensing, and neural recording and stimulation. While providing proof of principle of bioelectronic integration, such demonstrations have been performed in vitro or in anesthetized animals. Here, we demonstrate the efficacy of an implantable organic electronic delivery device for the treatment of neuropathic pain in an animal model. Devices were implanted onto the spinal cord of rats, and 2 days after implantation, local delivery of the inhibitory neurotransmitter gamma aminobutyric acid (GABA) was initiated. Highly localized delivery resulted in a significant decrease in pain response with low dosage and no observable side effects. This demonstration of organic bioelectronics-based therapy in awake animals illustrates a viable alternative to existing pain treatments, paving the way for future implantable bioelectronic therapeutics. PMID- 26601182 TI - Curious kinetic behavior in silica polymorphs solves seifertite puzzle in shocked meteorite. AB - The presence of seifertite, one of the high-pressure polymorphs of silica, in achondritic shocked meteorites has been problematic because this phase is thermodynamically stable at more than ~100 GPa, unrealistically high-pressure conditions for the shock events in the early solar system. We conducted in situ x ray diffraction measurements at high pressure and temperatures, and found that it metastably appears down to ~11 GPa owing to the clear difference in kinetics between the metastable seifertite and stable stishovite formations. The temperature-insensitive but time-sensitive kinetics for the formation of seifertite uniquely constrains that the critical shock duration and size of the impactor on differentiated parental bodies are at least ~0.01 s and ~50 to 100 m, respectively, from the presence of seifertite. PMID- 26601183 TI - Tailoring pathway modularity in the biosynthesis of erythromycin analogs heterologously engineered in E. coli. AB - Type I modular polyketide synthases are responsible for potent therapeutic compounds that include avermectin (antihelinthic), rapamycin (immunosuppressant), pikromycin (antibiotic), and erythromycin (antibiotic). However, compound access and biosynthetic manipulation are often complicated by properties of native production organisms, prompting an approach (termed heterologous biosynthesis) illustrated in this study through the reconstitution of the erythromycin pathway through Escherichia coli. Using this heterologous system, 16 tailoring pathways were introduced, systematically producing eight chiral pairs of deoxysugar substrates. Successful analog formation for each new pathway emphasizes the remarkable flexibility of downstream enzymes to accommodate molecular variation. Furthermore, analogs resulting from three of the pathways demonstrated bioactivity against an erythromycin-resistant Bacillus subtilis strain. The approach and results support a platform for continued molecular diversification of the tailoring components of this and other complex natural product pathways in a manner that mirrors the modular nature of the upstream megasynthases responsible for aglycone polyketide formation. PMID- 26601184 TI - Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline. AB - Multidrug-resistant tuberculosis (MDR-TB) is more prevalent today than at any other time in human history. Bedaquiline (BDQ), a novel Mycobacterium-specific adenosine triphosphate (ATP) synthase inhibitor, is the first drug in the last 40 years to be approved for the treatment of MDR-TB. This bactericidal compound targets the membrane-embedded rotor (c-ring) of the mycobacterial ATP synthase, a key metabolic enzyme required for ATP generation. We report the x-ray crystal structures of a mycobacterial c9 ring without and with BDQ bound at 1.55- and 1.7 A resolution, respectively. The structures and supporting functional assays reveal how BDQ specifically interacts with the rotor ring via numerous interactions and thereby completely covers the c-ring's ion-binding sites. This prevents the rotor ring from acting as an ion shuttle and stalls ATP synthase operation. The structures explain how diarylquinoline chemicals specifically inhibit the mycobacterial ATP synthase and thus enable structure-based drug design of next-generation ATP synthase inhibitors against Mycobacterium tuberculosis and other bacterial pathogens. PMID- 26601185 TI - Radially oriented mesoporous TiO2 microspheres with single-crystal-like anatase walls for high-efficiency optoelectronic devices. AB - Highly crystalline mesoporous materials with oriented configurations are in demand for high-performance energy conversion devices. We report a simple evaporation-driven oriented assembly method to synthesize three-dimensional open mesoporous TiO2 microspheres with a diameter of ~800 nm, well-controlled radially oriented hexagonal mesochannels, and crystalline anatase walls. The mesoporous TiO2 spheres have a large accessible surface area (112 m(2)/g), a large pore volume (0.164 cm(3)/g), and highly single-crystal-like anatase walls with dominant (101) exposed facets, making them ideal for conducting mesoscopic photoanode films. Dye-sensitized solar cells (DSSCs) based on the mesoporous TiO2 microspheres and commercial dye N719 have a photoelectric conversion efficiency of up to 12.1%. This evaporation-driven approach can create opportunities for tailoring the orientation of inorganic building blocks in the assembly of various mesoporous materials. PMID- 26601186 TI - Isotopically enhanced triple-quantum-dot qubit. AB - Like modern microprocessors today, future processors of quantum information may be implemented using all-electrical control of silicon-based devices. A semiconductor spin qubit may be controlled without the use of magnetic fields by using three electrons in three tunnel-coupled quantum dots. Triple dots have previously been implemented in GaAs, but this material suffers from intrinsic nuclear magnetic noise. Reduction of this noise is possible by fabricating devices using isotopically purified silicon. We demonstrate universal coherent control of a triple-quantum-dot qubit implemented in an isotopically enhanced Si/SiGe heterostructure. Composite pulses are used to implement spin-echo type sequences, and differential charge sensing enables single-shot state readout. These experiments demonstrate sufficient control with sufficiently low noise to enable the long pulse sequences required for exchange-only two-qubit logic and randomized benchmarking. PMID- 26601187 TI - Testosterone biases the amygdala toward social threat approach. AB - Testosterone enhances amygdala reactions to social threat, but it remains unclear whether this neuroendocrine mechanism is relevant for understanding its dominance enhancing properties; namely, whether testosterone biases the human amygdala toward threat approach. This pharmacological functional magnetic-resonance imaging study shows that testosterone administration increases amygdala responses in healthy women during threat approach and decreases it during threat avoidance. These findings support and extend motivational salience models by offering a neuroendocrine mechanism of motivation-specific amygdala tuning. PMID- 26601188 TI - Laser-assisted guiding of electric discharges around objects. AB - Electric breakdown in air occurs for electric fields exceeding 34 kV/cm and results in a large current surge that propagates along unpredictable trajectories. Guiding such currents across specific paths in a controllable manner could allow protection against lightning strikes and high-voltage capacitor discharges. Such capabilities can be used for delivering charge to specific targets, for electronic jamming, or for applications associated with electric welding and machining. We show that judiciously shaped laser radiation can be effectively used to manipulate the discharge along a complex path and to produce electric discharges that unfold along a predefined trajectory. Remarkably, such laser-induced arcing can even circumvent an object that completely occludes the line of sight. PMID- 26601189 TI - Biodiversity and distribution of polar freshwater DNA viruses. AB - Viruses constitute the most abundant biological entities and a large reservoir of genetic diversity on Earth. Despite the recent surge in their study, our knowledge on their actual biodiversity and distribution remains sparse. We report the first metagenomic analysis of Arctic freshwater viral DNA communities and a comparative analysis with other freshwater environments. Arctic viromes are dominated by unknown and single-stranded DNA viruses with no close relatives in the database. These unique viral DNA communities mostly relate to each other and present some minor genetic overlap with other environments studied, including an Arctic Ocean virome. Despite common environmental conditions in polar ecosystems, the Arctic and Antarctic DNA viromes differ at the fine-grain genetic level while sharing a similar taxonomic composition. The study uncovers some viral lineages with a bipolar distribution, suggesting a global dispersal capacity for viruses, and seemingly indicates that viruses do not follow the latitudinal diversity gradient known for macroorganisms. Our study sheds light into the global biogeography and connectivity of viral communities. PMID- 26601190 TI - Exploration of metastability and hidden phases in correlated electron crystals visualized by femtosecond optical doping and electron crystallography. AB - Characterizing and understanding the emergence of multiple macroscopically ordered electronic phases through subtle tuning of temperature, pressure, and chemical doping has been a long-standing central issue for complex materials research. We report the first comprehensive studies of optical doping-induced emergence of stable phases and metastable hidden phases visualized in situ by femtosecond electron crystallography. The electronic phase transitions are triggered by femtosecond infrared pulses, and a temperature-optical density phase diagram is constructed and substantiated with the dynamics of metastable states, highlighting the cooperation and competition through which the macroscopic quantum orders emerge. These results elucidate key pathways of femtosecond electronic switching phenomena and provide an important new avenue to comprehensively investigate optical doping-induced transition states and phase diagrams of complex materials with wide-ranging applications. PMID- 26601192 TI - Role of Toll-like receptors in diabetic renal lesions in a miniature pig model. AB - The mechanisms of diabetic renal injury remain unclear. Recent studies have shown that immunological and inflammatory elements play important roles in the initiation and development of diabetic nephropathy (DN). Toll-like receptors (TLRs) comprise a superfamily of innate immune system receptors. The roles and mechanisms of TLRs in the pathogenesis of diabetic renal lesions are mostly unknown. Compared with rodents, miniature pigs are more similar to humans with respect to metabolism, kidney structure, and immune system, and therefore represent an ideal large-animal model for DN mechanistic studies. A diabetes model was established by feeding miniature pigs with high-sugar and high-fat diets. Functional and pathological markers, expression and activation of endogenous TLR ligands [HSP70 (heat shock protein 70) and HMGB1], TLR1 to TLR11 and their downstream signaling pathway molecules (MyD88, IRAK-1, and IRF-3), nuclear factor kappaB (NF-kappaB) signaling pathway molecules (IKKbeta, IkappaBalpha, and NF-kappaBp65), inflammatory cytokines [IL-6 (interleukin-6), MIP-2, MCP-1, CCL5, and VCAM-1 (vascular cell adhesion molecule-1)], and infiltration of inflammatory cells were systematically evaluated. The expression of HSP70 was significantly increased in diabetic pig kidneys. The expression of MyD88-dependent TLR2, TLR4, TLR5, TLR7, TLR8, and TLR11 and their downstream signaling molecules MyD88 and phospho-IRAK-1 (activated IRAK-1), as well as that of MyD88-independent TLR3 and TLR4 and their downstream signaling molecule phospho-IRF-3 (activated IRF-3), was significantly up-regulated. The expression and activation of NF-kappaB pathway molecules phospho-IKKbeta, phospho IkappaBalpha, NF-kappaBp65, and phospho-NF-kappaBp65 were significantly increased. Levels of IL-6, MIP-2, MCP-1, CCL5, VCAM-1, and macrophage marker CD68 were significantly increased in diabetic pig kidneys. These results suggested that the metabolic inflammation activated by TLRs might play an important role in diabetic renal injuries. PMID- 26601191 TI - Planning tiger recovery: Understanding intraspecific variation for effective conservation. AB - Although significantly more money is spent on the conservation of tigers than on any other threatened species, today only 3200 to 3600 tigers roam the forests of Asia, occupying only 7% of their historical range. Despite the global significance of and interest in tiger conservation, global approaches to plan tiger recovery are partly impeded by the lack of a consensus on the number of tiger subspecies or management units, because a comprehensive analysis of tiger variation is lacking. We analyzed variation among all nine putative tiger subspecies, using extensive data sets of several traits [morphological (craniodental and pelage), ecological, molecular]. Our analyses revealed little variation and large overlaps in each trait among putative subspecies, and molecular data showed extremely low diversity because of a severe Late Pleistocene population decline. Our results support recognition of only two subspecies: the Sunda tiger, Panthera tigris sondaica, and the continental tiger, Panthera tigris tigris, which consists of two (northern and southern) management units. Conservation management programs, such as captive breeding, reintroduction initiatives, or trans-boundary projects, rely on a durable, consistent characterization of subspecies as taxonomic units, defined by robust multiple lines of scientific evidence rather than single traits or ad hoc descriptions of one or few specimens. Our multiple-trait data set supports a fundamental rethinking of the conventional tiger taxonomy paradigm, which will have profound implications for the management of in situ and ex situ tiger populations and boost conservation efforts by facilitating a pragmatic approach to tiger conservation management worldwide. PMID- 26601193 TI - Warm oceanographic anomalies and fishing pressure drive seabird nesting north. AB - Parallel studies of nesting colonies in Mexico and the United States show that Elegant Terns (Thalasseus elegans) have expanded from the Gulf of California Midriff Island Region into Southern California, but the expansion fluctuates from year to year. A strong inverse relationship between nesting pairs in three Southern California nesting areas [San Diego saltworks, Bolsa Chica Ecological Reserve, and Los Angeles Harbor (1991 to 2014)] and Isla Rasa in the Midriff (1980 to 2014) shows that terns migrate northward when confronting warm oceanographic anomalies (>1.0 degrees C), which may decrease fish availability and hamper nesting success. Migration pulses are triggered by sea surface temperature anomalies localized in the Midriff and, secondarily, by reductions in the sardine population as a result of intensive fishing. This behavior is new; before year 2000, the terns stayed in the Midriff even when oceanographic conditions were adverse. Our results show that terns are responding dynamically to rapidly changing oceanographic conditions and fish availability by migrating 600 km northwest in search of more productive waters. PMID- 26601194 TI - Staphylococcus aureus and the ecology of the nasal microbiome. AB - The human microbiome can play a key role in host susceptibility to pathogens, including in the nasal cavity, a site favored by Staphylococcus aureus. However, what determines our resident nasal microbiota-the host or the environment-and can interactions among nasal bacteria determine S. aureus colonization? Our study of 46 monozygotic and 43 dizygotic twin pairs revealed that nasal microbiota is an environmentally derived trait, but the host's sex and genetics significantly influence nasal bacterial density. Although specific taxa, including lactic acid bacteria, can determine S. aureus colonization, their negative interactions depend on thresholds of absolute abundance. These findings demonstrate that nasal microbiota is not fixed by host genetics and opens the possibility that nasal microbiota may be manipulated to prevent or eliminate S. aureus colonization. PMID- 26601195 TI - Accelerated modern human-induced species losses: Entering the sixth mass extinction. AB - The oft-repeated claim that Earth's biota is entering a sixth "mass extinction" depends on clearly demonstrating that current extinction rates are far above the "background" rates prevailing between the five previous mass extinctions. Earlier estimates of extinction rates have been criticized for using assumptions that might overestimate the severity of the extinction crisis. We assess, using extremely conservative assumptions, whether human activities are causing a mass extinction. First, we use a recent estimate of a background rate of 2 mammal extinctions per 10,000 species per 100 years (that is, 2 E/MSY), which is twice as high as widely used previous estimates. We then compare this rate with the current rate of mammal and vertebrate extinctions. The latter is conservatively low because listing a species as extinct requires meeting stringent criteria. Even under our assumptions, which would tend to minimize evidence of an incipient mass extinction, the average rate of vertebrate species loss over the last century is up to 100 times higher than the background rate. Under the 2 E/MSY background rate, the number of species that have gone extinct in the last century would have taken, depending on the vertebrate taxon, between 800 and 10,000 years to disappear. These estimates reveal an exceptionally rapid loss of biodiversity over the last few centuries, indicating that a sixth mass extinction is already under way. Averting a dramatic decay of biodiversity and the subsequent loss of ecosystem services is still possible through intensified conservation efforts, but that window of opportunity is rapidly closing. PMID- 26601196 TI - Unraveling the complexity of iron oxides at high pressure and temperature: Synthesis of Fe5O6. AB - The iron-oxygen system is the most important reference of rocks' redox state. Even as minor components, iron oxides can play a critical role in redox equilibria, which affect the speciation of the fluid phases chemical differentiation, melting, and physical properties. Until our recent finding of Fe4O5, iron oxides were assumed to comprise only the polymorphs of FeO, Fe3O4, and Fe2O3. Combining synthesis at high pressure and temperature with microdiffraction mapping, we have identified yet another distinct iron oxide, Fe5O6. The new compound, which has an orthorhombic structure, was obtained in the pressure range from 10 to 20 GPa upon laser heating mixtures of iron and hematite at ~2000 K, and is recoverable to ambient conditions. The high-pressure orthorhombic iron oxides Fe5O6, Fe4O5, and h-Fe3O4 display similar iron coordination geometries and structural arrangements, and indeed exhibit coherent systematic behavior of crystallographic parameters and compressibility. Fe5O6, along with FeO and Fe4O5, is a candidate key minor phase of planetary interiors; as such, it is of major petrological and geochemical importance. We are revealing an unforeseen complexity in the Fe-O system with four different compounds-FeO, Fe5O6, Fe4O5, and h-Fe3O4-in a narrow compositional range (0.75 < Fe/O < 1.0). New, finely spaced oxygen buffers at conditions of the Earth's mantle can be defined. PMID- 26601197 TI - Sacrificial amphiphiles: Eco-friendly chemical herders as oil spill mitigation chemicals. AB - Crude oil spills are a major threat to marine biota and the environment. When light crude oil spills on water, it forms a thin layer that is difficult to clean by any methods of oil spill response. Under these circumstances, a special type of amphiphile termed as "chemical herder" is sprayed onto the water surrounding the spilled oil. The amphiphile forms a monomolecular layer on the water surface, reducing the air-sea surface tension and causing the oil slick to retract into a thick mass that can be burnt in situ. The current best-known chemical herders are chemically stable and nonbiodegradable, and hence remain in the marine ecosystem for years. We architect an eco-friendly, sacrificial, and effective green herder derived from the plant-based small-molecule phytol, which is abundant in the marine environment, as an alternative to the current chemical herders. Phytol consists of a regularly branched chain of isoprene units that form the hydrophobe of the amphiphile; the chain is esterified to cationic groups to form the polar group. The ester linkage is proximal to an allyl bond in phytol, which facilitates the hydrolysis of the amphiphile after adsorption to the sea surface into the phytol hydrophobic tail, which along with the unhydrolyzed herder, remains on the surface to maintain herding action, and the cationic group, which dissolves into the water column. Eventual degradation of the phytol tail and dilution of the cation make these sacrificial amphiphiles eco-friendly. The herding behavior of phytol-based amphiphiles is evaluated as a function of time, temperature, and water salinity to examine their versatility under different conditions, ranging from ice-cold water to hot water. The green chemical herder retracted oil slicks by up to ~500, 700, and 2500% at 5 degrees , 20 degrees , and 35 degrees C, respectively, during the first 10 min of the experiment, which is on a par with the current best chemical herders in practice. PMID- 26601198 TI - Wear biomechanics in the slicing dentition of the giant horned dinosaur Triceratops. AB - Herbivorous reptiles rarely evolve occluding dentitions that allow for the mastication (chewing) of plant matter. Conversely, most herbivorous mammals have occluding teeth with complex tissue architectures that self-wear to complex morphologies for orally processing plants. Dinosaurs stand out among reptiles in that several lineages acquired the capacity to masticate. In particular, the horned ceratopsian dinosaurs, among the most successful Late Cretaceous dinosaurian lineages, evolved slicing dentitions for the exploitation of tough, bulky plant matter. We show how Triceratops, a 9-m-long ceratopsian, and its relatives evolved teeth that wore during feeding to create fullers (recessed central regions on cutting blades) on the chewing surfaces. This unique morphology served to reduce friction during feeding. It was achieved through the evolution of a complex suite of osseous dental tissues rivaling the complexity of mammalian dentitions. Tribological (wear) properties of the tissues are preserved in ~66-million-year-old teeth, allowing the creation of a sophisticated three dimensional biomechanical wear model that reveals how the complexes synergistically wore to create these implements. These findings, along with similar discoveries in hadrosaurids (duck-billed dinosaurs), suggest that tissue mediated changes in dental morphology may have played a major role in the remarkable ecological diversification of these clades and perhaps other dinosaurian clades capable of mastication. PMID- 26601199 TI - Membrane pore architecture of the CslF6 protein controls (1-3,1-4)-beta-glucan structure. AB - The cereal cell wall polysaccharide (1-3,1-4)-beta-glucan is a linear polymer of glucose containing both beta1-3 and beta1-4 bonds. The structure of (1-3,1-4) beta-glucan varies between different cereals and during plant growth and development, but little is known about how this is controlled. The cellulose synthase-like CslF6 protein is an integral membrane protein and a major component of the (1-3,1-4)-beta-glucan synthase. I show that a single amino acid within the predicted transmembrane pore domain of CslF6 controls (1-3,1-4)-beta-glucan structure. A new mechanism for the control of the polysaccharide structure is proposed where membrane pore architecture and the translocation of the growing polysaccharide across the membrane control how the acceptor glucan is coordinated at the active site and thus the proportion of beta1-3 and beta1-4 bonds within the polysaccharide. PMID- 26601200 TI - Oklahoma's recent earthquakes and saltwater disposal. AB - Over the past 5 years, parts of Oklahoma have experienced marked increases in the number of small- to moderate-sized earthquakes. In three study areas that encompass the vast majority of the recent seismicity, we show that the increases in seismicity follow 5- to 10-fold increases in the rates of saltwater disposal. Adjacent areas where there has been relatively little saltwater disposal have had comparatively few recent earthquakes. In the areas of seismic activity, the saltwater disposal principally comes from "produced" water, saline pore water that is coproduced with oil and then injected into deeper sedimentary formations. These formations appear to be in hydraulic communication with potentially active faults in crystalline basement, where nearly all the earthquakes are occurring. Although most of the recent earthquakes have posed little danger to the public, the possibility of triggering damaging earthquakes on potentially active basement faults cannot be discounted. PMID- 26601201 TI - Topological RPdBi half-Heusler semimetals: A new family of noncentrosymmetric magnetic superconductors. AB - We report superconductivity and magnetism in a new family of topological semimetals, the ternary half-Heusler compound RPdBi (R: rare earth). In this series, tuning of the rare earth f-electron component allows for simultaneous control of both lattice density via lanthanide contraction and the strength of magnetic interaction via de Gennes scaling, allowing for a unique tuning of the normal-state band inversion strength, superconducting pairing, and magnetically ordered ground states. Antiferromagnetism with ordering vector (1/2,1/2,1/2) occurs below a Neel temperature that scales with de Gennes factor dG, whereas a superconducting transition is simultaneously supressed with increasing dG. With superconductivity appearing in a system with noncentrosymmetric crystallographic symmetry, the possibility of spin-triplet Cooper pairing with nontrivial topology analogous to that predicted for the normal-state electronic structure provides a unique and rich opportunity to realize both predicted and new exotic excitations in topological materials. PMID- 26601202 TI - Isolation of bis(copper) key intermediates in Cu-catalyzed azide-alkyne "click reaction". AB - The copper-catalyzed 1,3-dipolar cycloaddition of an azide to a terminal alkyne (CuAAC) is one of the most popular chemical transformations, with applications ranging from material to life sciences. However, despite many mechanistic studies, direct observation of key components of the catalytic cycle is still missing. Initially, mononuclear species were thought to be the active catalysts, but later on, dinuclear complexes came to the front. We report the isolation of both a previously postulated pi,sigma-bis(copper) acetylide and a hitherto never mentioned bis(metallated) triazole complex. We also demonstrate that although mono- and bis-copper complexes promote the CuAAC reaction, the dinuclear species are involved in the kinetically favored pathway. PMID- 26601203 TI - Changes in coral reef communities across a natural gradient in seawater pH. AB - Ocean acidification threatens the survival of coral reef ecosystems worldwide. The negative effects of ocean acidification observed in many laboratory experiments have been seen in studies of naturally low-pH reefs, with little evidence to date for adaptation. Recently, we reported initial data suggesting that low-pH coral communities of the Palau Rock Islands appear healthy despite the extreme conditions in which they live. Here, we build on that observation with a comprehensive statistical analysis of benthic communities across Palau's natural acidification gradient. Our analysis revealed a shift in coral community composition but no impact of acidification on coral richness, coralline algae abundance, macroalgae cover, coral calcification, or skeletal density. However, coral bioerosion increased 11-fold as pH decreased from the barrier reefs to the Rock Island bays. Indeed, a comparison of the naturally low-pH coral reef systems studied so far revealed increased bioerosion to be the only consistent feature among them, as responses varied across other indices of ecosystem health. Our results imply that whereas community responses may vary, escalation of coral reef bioerosion and acceleration of a shift from net accreting to net eroding reef structures will likely be a global signature of ocean acidification. PMID- 26601205 TI - Quantum unidirectional rotation directly imaged with molecules. AB - A gas-phase molecular ensemble coherently excited to have an oriented rotational angular momentum has recently emerged as an appropriate microscopic system to illustrate quantum mechanical behavior directly linked to classical rotational motion, which has a definite direction. To realize an intuitive visualization of such a unidirectional molecular rotation, we report high-resolution direct imaging of direction-controlled rotational wave packets in nitrogen molecules. The rotational direction was regulated by a pair of time-delayed, polarization skewed laser pulses, introducing the dynamic chirality to the system. The subsequent spatiotemporal propagation was tracked by a newly developed Coulomb explosion imaging setup. From the observed molecular movie, time-dependent detailed nodal structures, instantaneous alignment, angular dispersion, and fractional revivals of the wave packet are fully characterized while the ensemble keeps rotating in one direction. The present approach, providing an accurate view on unidirectional rotation in quantum regime, will guide more sophisticated molecular manipulations by utilizing its capability in capturing highly structured spatiotemporal evolution of molecular wave packets. PMID- 26601204 TI - Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics. AB - Over the past 4 years, nearly 100 exome sequencing studies have revealed the high frequency of mutations in the genes encoding the subunits of ATP-dependent chromatin remodelers in human cancer. Most of these mutations are within the genes encoding subunits of the BAF (Brg/Brahma-associated factors) or mSWI/SNF complex, which is one of two dozen predicted ATP-dependent chromatin remodeling complexes in mammals. Considering BAF complexes as a single entity, the 15 subunits encoded by 29 genes are mutated in >20% of human cancer, across a broad range of tumor types. These observations demonstrate that there is little redundancy in the oncogenic function of BAF complexes with the other remodeling complexes, underscoring their unique roles. Several important conclusions emerge from these genomic data: specific subunits appear to be mutated in specific cancers, highlighting tissue-specific protective roles; mutations can function as tumor suppressors or oncogenes; mutations can be homozygous or, more commonly, heterozygous, implying their dosage-sensitive roles in an unknown yet fundamental process used to suppress the genesis of cancer. These new human genetic findings paired with biochemical studies are challenging old ideas on how chromatin remodeling complexes function, generating new hypotheses with respect to their normal and oncogenic mechanisms and highlighting potential avenues for therapeutic intervention in human cancer. PMID- 26601206 TI - Genome-environment associations in sorghum landraces predict adaptive traits. AB - Improving environmental adaptation in crops is essential for food security under global change, but phenotyping adaptive traits remains a major bottleneck. If associations between single-nucleotide polymorphism (SNP) alleles and environment of origin in crop landraces reflect adaptation, then these could be used to predict phenotypic variation for adaptive traits. We tested this proposition in the global food crop Sorghum bicolor, characterizing 1943 georeferenced landraces at 404,627 SNPs and quantifying allelic associations with bioclimatic and soil gradients. Environment explained a substantial portion of SNP variation, independent of geographical distance, and genic SNPs were enriched for environmental associations. Further, environment-associated SNPs predicted genotype-by-environment interactions under experimental drought stress and aluminum toxicity. Our results suggest that genomic signatures of environmental adaptation may be useful for crop improvement, enhancing germplasm identification and marker-assisted selection. Together, genome-environment associations and phenotypic analyses may reveal the basis of environmental adaptation. PMID- 26601207 TI - Structure of transcribed chromatin is a sensor of DNA damage. AB - Early detection and repair of damaged DNA is essential for cell functioning and survival. Although multiple cellular systems are involved in the repair of single strand DNA breaks (SSBs), it remains unknown how SSBs present in the nontemplate strand (NT-SSBs) of DNA organized in chromatin are detected. The effect of NT SSBs on transcription through chromatin by RNA polymerase II was studied. NT-SSBs localized in the promoter-proximal region of nucleosomal DNA and hidden in the nucleosome structure can induce a nearly quantitative arrest of RNA polymerase downstream of the break, whereas more promoter-distal SSBs moderately facilitate transcription. The location of the arrest sites on nucleosomal DNA suggests that formation of small intranucleosomal DNA loops causes the arrest. This mechanism likely involves relief of unconstrained DNA supercoiling accumulated during transcription through chromatin by NT-SSBs. These data suggest the existence of a novel chromatin-specific mechanism that allows the detection of NT-SSBs by the transcribing enzyme. PMID- 26601208 TI - Memcomputing NP-complete problems in polynomial time using polynomial resources and collective states. AB - Memcomputing is a novel non-Turing paradigm of computation that uses interacting memory cells (memprocessors for short) to store and process information on the same physical platform. It was recently proven mathematically that memcomputing machines have the same computational power of nondeterministic Turing machines. Therefore, they can solve NP-complete problems in polynomial time and, using the appropriate architecture, with resources that only grow polynomially with the input size. The reason for this computational power stems from properties inspired by the brain and shared by any universal memcomputing machine, in particular intrinsic parallelism and information overhead, namely, the capability of compressing information in the collective state of the memprocessor network. We show an experimental demonstration of an actual memcomputing architecture that solves the NP-complete version of the subset sum problem in only one step and is composed of a number of memprocessors that scales linearly with the size of the problem. We have fabricated this architecture using standard microelectronic technology so that it can be easily realized in any laboratory setting. Although the particular machine presented here is eventually limited by noise-and will thus require error-correcting codes to scale to an arbitrary number of memprocessors-it represents the first proof of concept of a machine capable of working with the collective state of interacting memory cells, unlike the present day single-state machines built using the von Neumann architecture. PMID- 26601209 TI - A vanished history of skeletonization in Cambrian comb jellies. AB - Ctenophores are traditionally regarded as "lower" metazoans, sharing with cnidarians a diploblastic grade of organization. Unlike cnidarians, where skeletonization (biomineralization and sclerotization) evolved repeatedly among ecologically important taxa (for example, scleractinians and octocorals), living ctenophores are characteristically soft-bodied animals. We report six sclerotized and armored ctenophores from the early Cambrian period. They have diagnostic ctenophore features (for example, an octamerous symmetry, oral-aboral axis, aboral sense organ, and octaradially arranged ctene rows). Unlike most modern counterparts, however, they lack tentacles, have a sclerotized framework, and have eight pairs of ctene rows. They are resolved as a monophyletic group (Scleroctenophora new class) within the ctenophores. This clade reveals a cryptic history and sheds new light on the early evolution of this basal animal phylum. Skeletonization also occurs in some other Cambrian animal groups whose extant members are exclusively soft-bodied, suggesting the ecological importance of skeletonization in the Cambrian explosion. PMID- 26601210 TI - High geothermal heat flux measured below the West Antarctic Ice Sheet. AB - The geothermal heat flux is a critical thermal boundary condition that influences the melting, flow, and mass balance of ice sheets, but measurements of this parameter are difficult to make in ice-covered regions. We report the first direct measurement of geothermal heat flux into the base of the West Antarctic Ice Sheet (WAIS), below Subglacial Lake Whillans, determined from the thermal gradient and the thermal conductivity of sediment under the lake. The heat flux at this site is 285 +/- 80 mW/m(2), significantly higher than the continental and regional averages estimated for this site using regional geophysical and glaciological models. Independent temperature measurements in the ice indicate an upward heat flux through the WAIS of 105 +/- 13 mW/m(2). The difference between these heat flux values could contribute to basal melting and/or be advected from Subglacial Lake Whillans by flowing water. The high geothermal heat flux may help to explain why ice streams and subglacial lakes are so abundant and dynamic in this region. PMID- 26601211 TI - Atomically thin layers of B-N-C-O with tunable composition. AB - In recent times, atomically thin alloys of boron, nitrogen, and carbon have generated significant excitement as a composition-tunable two-dimensional (2D) material that demonstrates rich physics as well as application potentials. The possibility of tunably incorporating oxygen, a group VI element, into the honeycomb sp(2)-type 2D-BNC lattice is an intriguing idea from both fundamental and applied perspectives. We present the first report on an atomically thin quaternary alloy of boron, nitrogen, carbon, and oxygen (2D-BNCO). Our experiments suggest, and density functional theory (DFT) calculations corroborate, stable configurations of a honeycomb 2D-BNCO lattice. We observe micrometer-scale 2D-BNCO domains within a graphene-rich 2D-BNC matrix, and are able to control the area coverage and relative composition of these domains by varying the oxygen content in the growth setup. Macroscopic samples comprising 2D BNCO domains in a graphene-rich 2D-BNC matrix show graphene-like gate-modulated electronic transport with mobility exceeding 500 cm(2) V(-1) s(-1), and Arrhenius like activated temperature dependence. Spin-polarized DFT calculations for nanoscale 2D-BNCO patches predict magnetic ground states originating from the B atoms closest to the O atoms and sizable (0.6 eV < E g < 0.8 eV) band gaps in their density of states. These results suggest that 2D-BNCO with novel electronic and magnetic properties have great potential for nanoelectronics and spintronic applications in an atomically thin platform. PMID- 26601212 TI - Hierarchical multiscale hyperporous block copolymer membranes via tunable dual phase separation. AB - The rational design and realization of revolutionary porous structures have been long-standing challenges in membrane science. We demonstrate a new class of amphiphilic polystyrene-block-poly(4-vinylpyridine) block copolymer (BCP)-based porous membranes featuring hierarchical multiscale hyperporous structures. The introduction of surface energy-modifying agents and the control of major phase separation parameters (such as nonsolvent polarity and solvent drying time) enable tunable dual-phase separation of BCPs, eventually leading to macro/nanoscale porous structures and chemical functionalities far beyond those accessible with conventional approaches. Application of this BCP membrane to a lithium-ion battery separator affords exceptional improvement in electrochemical performance. The dual-phase separation-driven macro/nanopore construction strategy, owing to its simplicity and tunability, is expected to be readily applicable to a rich variety of membrane fields including molecular separation, water purification, and energy-related devices. PMID- 26601213 TI - Rapid eye movement sleep promotes cortical plasticity in the developing brain. AB - Rapid eye movement sleep is maximal during early life, but its function in the developing brain is unknown. We investigated the role of rapid eye movement sleep in a canonical model of developmental plasticity in vivo (ocular dominance plasticity in the cat) induced by monocular deprivation. Preventing rapid eye movement sleep after monocular deprivation reduced ocular dominance plasticity and inhibited activation of a kinase critical for this plasticity (extracellular signal-regulated kinase). Chronic single-neuron recording in freely behaving cats further revealed that cortical activity during rapid eye movement sleep resembled activity present during monocular deprivation. This corresponded to times of maximal extracellular signal-regulated kinase activation. These findings indicate that rapid eye movement sleep promotes molecular and network adaptations that consolidate waking experience in the developing brain. PMID- 26601214 TI - Structural basis for recognition of diverse transcriptional repressors by the TOPLESS family of corepressors. AB - TOPLESS (TPL) and TOPLESS-related (TPR) proteins comprise a conserved family of plant transcriptional corepressors that are related to Tup1, Groucho, and TLE (transducin-like enhancer of split) corepressors in yeast, insects, and mammals. In plants, TPL/TPR corepressors regulate development, stress responses, and hormone signaling through interaction with small ethylene response factor associated amphiphilic repression (EAR) motifs found in diverse transcriptional repressors. How EAR motifs can interact with TPL/TPR proteins is unknown. We confirm the amino-terminal domain of the TPL family of corepressors, which we term TOPLESS domain (TPD), as the EAR motif-binding domain. To understand the structural basis of this interaction, we determined the crystal structures of the TPD of rice (Os) TPR2 in apo (apo protein) state and in complexes with the EAR motifs from Arabidopsis NINJA (novel interactor of JAZ), IAA1 (auxin-responsive protein 1), and IAA10, key transcriptional repressors involved in jasmonate and auxin signaling. The OsTPR2 TPD adopts a new fold of nine helices, followed by a zinc finger, which are arranged into a disc-like tetramer. The EAR motifs in the three different complexes adopt a similar extended conformation with the hydrophobic residues fitting into the same surface groove of each OsTPR2 monomer. Sequence alignments and structure-based mutagenesis indicate that this mode of corepressor binding is highly conserved in a large set of transcriptional repressors, thus providing a general mechanism for gene repression mediated by the TPL family of corepressors. PMID- 26601215 TI - Engineered binding to erythrocytes induces immunological tolerance to E. coli asparaginase. AB - Antigen-specific immune responses to protein drugs can hinder efficacy and compromise safety because of drug neutralization and secondary clinical complications. We report a tolerance induction strategy to prevent antigen specific humoral immune responses to therapeutic proteins. Our modular, biomolecular approach involves engineering tolerizing variants of proteins such that they bind erythrocytes in vivo upon injection, on the basis of the premise that aged erythrocytes and the payloads they carry are cleared tolerogenically, driving the deletion of antigen-specific T cells. We demonstrate that binding the clinical therapeutic enzyme Escherichia coli l-asparaginase to erythrocytes in situ antigen-specifically abrogates development of antibody titers by >1000-fold and extends the pharmacodynamic effect of the drug 10-fold in mice. Additionally, a single pretreatment dose of erythrocyte-binding asparaginase tolerized mice to multiple subsequent doses of the wild-type enzyme. This strategy for reducing antigen-specific humoral responses may enable more effective and safer treatment with therapeutic proteins and drug candidates that are hampered by immunogenicity. PMID- 26601216 TI - Natural aerosols explain seasonal and spatial patterns of Southern Ocean cloud albedo. AB - Atmospheric aerosols, suspended solid and liquid particles, act as nucleation sites for cloud drop formation, affecting clouds and cloud properties-ultimately influencing the cloud dynamics, lifetime, water path, and areal extent that determine the reflectivity (albedo) of clouds. The concentration N d of droplets in clouds that influences planetary albedo is sensitive to the availability of aerosol particles on which the droplets form. Natural aerosol concentrations affect not only cloud properties themselves but also modulate the sensitivity of clouds to changes in anthropogenic aerosols. It is shown that modeled natural aerosols, principally marine biogenic primary and secondary aerosol sources, explain more than half of the spatiotemporal variability in satellite-observed N d. Enhanced N d is spatially correlated with regions of high chlorophyll a, and the spatiotemporal variability in N d is found to be driven primarily by high concentrations of sulfate aerosol at lower Southern Ocean latitudes (35(o) to 45(o)S) and by organic matter in sea spray aerosol at higher latitudes (45(o) to 55(o)S). Biogenic sources are estimated to increase the summertime mean reflected solar radiation in excess of 10 W m(-2) over parts of the Southern Ocean, which is comparable to the annual mean increases expected from anthropogenic aerosols over heavily polluted regions of the Northern Hemisphere. PMID- 26601217 TI - Local variations of HER2 dimerization in breast cancer cells discovered by correlative fluorescence and liquid electron microscopy. AB - The formation of HER2 homodimers plays an important role in breast cancer aggressiveness and progression; however, little is known about its localization. We have studied the intra- and intercellular variation of HER2 at the single molecule level in intact SKBR3 breast cancer cells. Whole cells were visualized in hydrated state with correlative fluorescence microscopy and environmental scanning electron microscopy (ESEM). The locations of individual HER2 receptors were detected using an anti-HER2 affibody in combination with a quantum dot (QD), a fluorescent nanoparticle. Fluorescence microscopy revealed considerable differences of HER2 membrane expression between individual cells and between different membrane regions of the same cell (that is, membrane ruffles and flat areas). Subsequent ESEM of the corresponding cellular regions provided images of individually labeled HER2 receptors. The high spatial resolution of 3 nm and the close proximity between the QD and the receptor allowed quantifying the stoichiometry of HER2 complexes, distinguishing between monomers, dimers, and higher-order clusters. Downstream data analysis based on calculating the pair correlation function from receptor positions showed that cellular regions exhibiting membrane ruffles contained a substantial fraction of HER2 in homodimeric state. Larger-order clusters were also present. Membrane areas with homogeneous membrane topography, on the contrary, displayed HER2 in random distribution. Second, HER2 homodimers appeared to be absent from a small subpopulation of cells exhibiting a flat membrane topography, possibly resting cells. Local differences in homodimer presence may point toward functional differences with possible relevance for studying metastasis and drug response. PMID- 26601218 TI - Controlling the metal-to-insulator relaxation of the metastable hidden quantum state in 1T-TaS2. AB - Controllable switching between metastable macroscopic quantum states under nonequilibrium conditions induced either by light or with an external electric field is rapidly becoming of great fundamental interest. We investigate the relaxation properties of a "hidden" (H) charge density wave (CDW) state in thin single crystals of the layered dichalcogenide 1T-TaS2, which can be reached by either a single 35-fs optical laser pulse or an ~30-ps electrical pulse. From measurements of the temperature dependence of the resistivity under different excitation conditions, we find that the metallic H state relaxes to the insulating Mott ground state through a sequence of intermediate metastable states via discrete jumps over a "Devil's staircase." In between the discrete steps, an underlying glassy relaxation process is observed, which arises because of reciprocal-space commensurability frustration between the CDW and the underlying lattice. We show that the metastable state relaxation rate may be externally stabilized by substrate strain, thus opening the way to the design of nonvolatile ultrafast high-temperature memory devices based on switching between CDW states with large intrinsic differences in electrical resistance. PMID- 26601219 TI - The valence-fluctuating ground state of plutonium. AB - A central issue in material science is to obtain understanding of the electronic correlations that control complex materials. Such electronic correlations frequently arise because of the competition of localized and itinerant electronic degrees of freedom. Although the respective limits of well-localized or entirely itinerant ground states are well understood, the intermediate regime that controls the functional properties of complex materials continues to challenge theoretical understanding. We have used neutron spectroscopy to investigate plutonium, which is a prototypical material at the brink between bonding and nonbonding configurations. Our study reveals that the ground state of plutonium is governed by valence fluctuations, that is, a quantum mechanical superposition of localized and itinerant electronic configurations as recently predicted by dynamical mean field theory. Our results not only resolve the long-standing controversy between experiment and theory on plutonium's magnetism but also suggest an improved understanding of the effects of such electronic dichotomy in complex materials. PMID- 26601220 TI - Strong-coupling ansatz for the one-dimensional Fermi gas in a harmonic potential. AB - A major challenge in modern physics is to accurately describe strongly interacting quantum many-body systems. One-dimensional systems provide fundamental insights because they are often amenable to exact methods. However, no exact solution is known for the experimentally relevant case of external confinement. We propose a powerful ansatz for the one-dimensional Fermi gas in a harmonic potential near the limit of infinite short-range repulsion. For the case of a single impurity in a Fermi sea, we show that our ansatz is indistinguishable from numerically exact results in both the few- and many-body limits. We furthermore derive an effective Heisenberg spin-chain model corresponding to our ansatz, valid for any spin-mixture, within which we obtain the impurity eigenstates analytically. In particular, the classical Pascal's triangle emerges in the expression for the ground-state wave function. As well as providing an important benchmark for strongly correlated physics, our results are relevant for emerging quantum technologies, where a precise knowledge of one-dimensional quantum states is paramount. PMID- 26601221 TI - Ultrahigh-mobility graphene devices from chemical vapor deposition on reusable copper. AB - Graphene research has prospered impressively in the past few years, and promising applications such as high-frequency transistors, magnetic field sensors, and flexible optoelectronics are just waiting for a scalable and cost-efficient fabrication technology to produce high-mobility graphene. Although significant progress has been made in chemical vapor deposition (CVD) and epitaxial growth of graphene, the carrier mobility obtained with these techniques is still significantly lower than what is achieved using exfoliated graphene. We show that the quality of CVD-grown graphene depends critically on the used transfer process, and we report on an advanced transfer technique that allows both reusing the copper substrate of the CVD growth and making devices with mobilities as high as 350,000 cm(2) V(-1) s(-1), thus rivaling exfoliated graphene. PMID- 26601223 TI - Trading biodiversity for pest problems. AB - Recent shifts in agricultural practices have resulted in altered pesticide use patterns, land use intensification, and landscape simplification, all of which threaten biodiversity in and near farms. Pests are major challenges to food security, and responses to pests can represent unintended socioeconomic and environmental costs. Characteristics of the ecological community influence pest populations, but the nature of these interactions remains poorly understood within realistic community complexities and on operating farms. We examine how species diversity and the topology of linkages in species' abundances affect pest abundance on maize farms across the Northern Great Plains. Our results show that increased species diversity, community evenness, and linkage strength and network centrality within a biological network all correlate with significantly reduced pest populations. This supports the assertion that reduced biological complexity on farms is associated with increased pest populations and provides a further justification for diversification of agroecosystems to improve the profitability, safety, and sustainability of food production systems. Bioinventories as comprehensive as the one conducted here are conspicuously absent for most agroecosystems but provide an important baseline for community and ecosystem ecology and the effects of food production on local biodiversity and ecosystem function. Network analyses of abundance correlations of entire communities (rather than focal interactions, for example, trophic interactions) can reveal key network characteristics, especially the importance and nature of network centrality, which aid in understanding how these communities function. PMID- 26601222 TI - The rice immune receptor XA21 recognizes a tyrosine-sulfated protein from a Gram negative bacterium. AB - Surveillance of the extracellular environment by immune receptors is of central importance to eukaryotic survival. The rice receptor kinase XA21, which confers robust resistance to most strains of the Gram-negative bacterium Xanthomonas oryzae pv. oryzae (Xoo), is representative of a large class of cell surface immune receptors in plants and animals. We report the identification of a previously undescribed Xoo protein, called RaxX, which is required for activation of XA21-mediated immunity. Xoo strains that lack RaxX, or carry mutations in the single RaxX tyrosine residue (Y41), are able to evade XA21-mediated immunity. Y41 of RaxX is sulfated by the prokaryotic tyrosine sulfotransferase RaxST. Sulfated, but not nonsulfated, RaxX triggers hallmarks of the plant immune response in an XA21-dependent manner. A sulfated, 21-amino acid synthetic RaxX peptide (RaxX21 sY) is sufficient for this activity. Xoo field isolates that overcome XA21 mediated immunity encode an alternate raxX allele, suggesting that coevolutionary interactions between host and pathogen contribute to RaxX diversification. RaxX is highly conserved in many plant pathogenic Xanthomonas species. The new insights gained from the discovery and characterization of the sulfated protein, RaxX, can be applied to the development of resistant crop varieties and therapeutic reagents that have the potential to block microbial infection of both plants and animals. PMID- 26601224 TI - Extension of the generic amyloid hypothesis to nonproteinaceous metabolite assemblies. AB - The accumulation of amyloid fibrils is the hallmark of several major human diseases. Although the formation of these supramolecular entities has previously been associated with proteins and peptides, it was later demonstrated that even phenylalanine, a single amino acid, can form fibrils that have amyloid-like biophysical, biochemical, and cytotoxic properties. Moreover, the generation of antibodies against these assemblies in phenylketonuria patients and the correlating mice model suggested a pathological role for the assemblies. We determine that several other metabolites that accumulate in metabolic disorders form ordered amyloid-like ultrastructures, which induce apoptotic cell death, as observed for amyloid structures. The formation of amyloid-like assemblies by metabolites implies a general phenomenon of amyloid formation, not limited to proteins and peptides, and offers a new paradigm for metabolic diseases. PMID- 26601225 TI - Improving clustering by imposing network information. AB - Cluster analysis is one of the most popular data analysis tools in a wide range of applied disciplines. We propose and justify a computationally efficient and straightforward-to-implement way of imposing the available information from networks/graphs (a priori available in many application areas) on a broad family of clustering methods. The introduced approach is illustrated on the problem of a noninvasive unsupervised brain signal classification. This task is faced with several challenging difficulties such as nonstationary noisy signals and a small sample size, combined with a high-dimensional feature space and huge noise-to signal ratios. Applying this approach results in an exact unsupervised classification of very short signals, opening new possibilities for clustering methods in the area of a noninvasive brain-computer interface. PMID- 26601226 TI - Intrinsic coupling modes reveal the functional architecture of cortico-tectal networks. AB - In the absence of sensory stimulation or motor output, the brain exhibits complex spatiotemporal patterns of intrinsically generated neural activity. Analysis of ongoing brain dynamics has identified the prevailing modes of cortico-cortical interaction; however, little is known about how such patterns of intrinsically generated activity are correlated between cortical and subcortical brain areas. We investigate the correlation structure of ongoing cortical and superior colliculus (SC) activity across multiple spatial and temporal scales. Ongoing cortico-tectal interaction was characterized by correlated fluctuations in the amplitude of delta, spindle, low gamma, and high-frequency oscillations (>100 Hz). Of these identified coupling modes, topographical patterns of high-frequency coupling were the most consistent with patterns of anatomical connectivity, reflecting synchronized spiking within cortico-tectal networks. Cortico-tectal coupling at high frequencies was temporally parcellated by the phase of slow cortical oscillations and was strongest for SC-cortex channel pairs that displayed overlapping visual spatial receptive fields. Despite displaying a high degree of spatial specificity, cortico-tectal coupling in lower-frequency bands did not match patterns of cortex-to-SC anatomical connectivity. Collectively, our findings demonstrate that neural activity is spontaneously coupled between cortex and SC, with high- and low-frequency modes of coupling reflecting direct and indirect cortico-tectal interactions, respectively. PMID- 26601227 TI - Hierarchical Ni-Mo-S nanosheets on carbon fiber cloth: A flexible electrode for efficient hydrogen generation in neutral electrolyte. AB - A unique functional electrode made of hierarchal Ni-Mo-S nanosheets with abundant exposed edges anchored on conductive and flexible carbon fiber cloth, referred to as Ni-Mo-S/C, has been developed through a facile biomolecule-assisted hydrothermal method. The incorporation of Ni atoms in Mo-S plays a crucial role in tuning its intrinsic catalytic property by creating substantial defect sites as well as modifying the morphology of Ni-Mo-S network at atomic scale, resulting in an impressive enhancement in the catalytic activity. The Ni-Mo-S/C electrode exhibits a large cathodic current and a low onset potential for hydrogen evolution reaction in neutral electrolyte (pH ~7), for example, current density of 10 mA/cm(2) at a very small overpotential of 200 mV. Furthermore, the Ni-Mo S/C electrode has excellent electrocatalytic stability over an extended period, much better than those of MoS2/C and Pt plate electrodes. Scanning and transmission electron microscopy, Raman spectroscopy, x-ray diffraction, x-ray photoelectron spectroscopy, and x-ray absorption spectroscopy were used to understand the formation process and electrocatalytic properties of Ni-Mo-S/C. The intuitive comparison test was designed to reveal the superior gas-evolving profile of Ni-Mo-S/C over that of MoS2/C, and a laboratory-scale hydrogen generator was further assembled to demonstrate its potential application in practical appliances. PMID- 26601228 TI - "Newton's cradle" proton relay with amide-imidic acid tautomerization in inverting cellulase visualized by neutron crystallography. AB - Hydrolysis of carbohydrates is a major bioreaction in nature, catalyzed by glycoside hydrolases (GHs). We used neutron diffraction and high-resolution x-ray diffraction analyses to investigate the hydrogen bond network in inverting cellulase PcCel45A, which is an endoglucanase belonging to subfamily C of GH family 45, isolated from the basidiomycete Phanerochaete chrysosporium. Examination of the enzyme and enzyme-ligand structures indicates a key role of multiple tautomerizations of asparagine residues and peptide bonds, which are finally connected to the other catalytic residue via typical side-chain hydrogen bonds, in forming the "Newton's cradle"-like proton relay pathway of the catalytic cycle. Amide-imidic acid tautomerization of asparagine has not been taken into account in recent molecular dynamics simulations of not only cellulases but also general enzyme catalysis, and it may be necessary to reconsider our interpretation of many enzymatic reactions. PMID- 26601229 TI - Toxicology across scales: Cell population growth in vitro predicts reduced fish growth. AB - Environmental risk assessment of chemicals is essential but often relies on ethically controversial and expensive methods. We show that tests using cell cultures, combined with modeling of toxicological effects, can replace tests with juvenile fish. Hundreds of thousands of fish at this developmental stage are annually used to assess the influence of chemicals on growth. Juveniles are more sensitive than adult fish, and their growth can affect their chances to survive and reproduce. Thus, to reduce the number of fish used for such tests, we propose a method that can quantitatively predict chemical impact on fish growth based on in vitro data. Our model predicts reduced fish growth in two fish species in excellent agreement with measured in vivo data of two pesticides. This promising step toward alternatives to fish toxicity testing is simple, inexpensive, and fast and only requires in vitro data for model calibration. PMID- 26601230 TI - Structural basis of Lewis(b) antigen binding by the Helicobacter pylori adhesin BabA. AB - Helicobacter pylori is a leading cause of peptic ulceration and gastric cancer worldwide. To achieve colonization of the stomach, this Gram-negative bacterium adheres to Lewis(b) (Le(b)) antigens in the gastric mucosa using its outer membrane protein BabA. Structural information for BabA has been elusive, and thus, its molecular mechanism for recognizing Le(b) antigens remains unknown. We present the crystal structure of the extracellular domain of BabA, from H. pylori strain J99, in the absence and presence of Le(b) at 2.0- and 2.1-A resolutions, respectively. BabA is a predominantly alpha-helical molecule with a markedly kinked tertiary structure containing a single, shallow Le(b) binding site at its tip within a beta-strand motif. No conformational change occurs in BabA upon binding of Le(b), which is characterized by low affinity under acidic [K D (dissociation constant) of ~227 MUM] and neutral (K D of ~252 MUM) conditions. Binding is mediated by a network of hydrogen bonds between Le(b) Fuc1, GlcNAc3, Fuc4, and Gal5 residues and a total of eight BabA amino acids (C189, G191, N194, N206, D233, S234, S244, and T246) through both carbonyl backbone and side-chain interactions. The structural model was validated through the generation of two BabA variants containing N206A and combined D233A/S244A substitutions, which result in a reduction and complete loss of binding affinity to Le(b), respectively. Knowledge of the molecular basis of Le(b) recognition by BabA provides a platform for the development of therapeutics targeted at inhibiting H. pylori adherence to the gastric mucosa. PMID- 26601231 TI - Control of coupled oscillator networks with application to microgrid technologies. AB - The control of complex systems and network-coupled dynamical systems is a topic of vital theoretical importance in mathematics and physics with a wide range of applications in engineering and various other sciences. Motivated by recent research into smart grid technologies, we study the control of synchronization and consider the important case of networks of coupled phase oscillators with nonlinear interactions-a paradigmatic example that has guided our understanding of self-organization for decades. We develop a method for control based on identifying and stabilizing problematic oscillators, resulting in a stable spectrum of eigenvalues, and in turn a linearly stable synchronized state. The amount of control, that is, number of oscillators, required to stabilize the network is primarily dictated by the coupling strength, dynamical heterogeneity, and mean degree of the network, and depends little on the structural heterogeneity of the network itself. PMID- 26601232 TI - Why do animal eyes have pupils of different shapes? AB - There is a striking correlation between terrestrial species' pupil shape and ecological niche (that is, foraging mode and time of day they are active). Species with vertically elongated pupils are very likely to be ambush predators and active day and night. Species with horizontally elongated pupils are very likely to be prey and to have laterally placed eyes. Vertically elongated pupils create astigmatic depth of field such that images of vertical contours nearer or farther than the distance to which the eye is focused are sharp, whereas images of horizontal contours at different distances are blurred. This is advantageous for ambush predators to use stereopsis to estimate distances of vertical contours and defocus blur to estimate distances of horizontal contours. Horizontally elongated pupils create sharp images of horizontal contours ahead and behind, creating a horizontally panoramic view that facilitates detection of predators from various directions and forward locomotion across uneven terrain. PMID- 26601233 TI - Fractal circuit sensors enable rapid quantification of biomarkers for donor lung assessment for transplantation. AB - Biomarker profiling is being rapidly incorporated in many areas of modern medical practice to improve the precision of clinical decision-making. This potential improvement, however, has not been transferred to the practice of organ assessment and transplantation because previously developed gene-profiling techniques require an extended period of time to perform, making them unsuitable in the time-sensitive organ assessment process. We sought to develop a novel class of chip-based sensors that would enable rapid analysis of tissue levels of preimplantation mRNA markers that correlate with the development of primary graft dysfunction (PGD) in recipients after transplant. Using fractal circuit sensors (FraCS), three-dimensional metal structures with large surface areas, we were able to rapidly (<20 min) and reproducibly quantify small differences in the expression of interleukin-6 (IL-6), IL-10, and ATP11B mRNA in donor lung biopsies. A proof-of-concept study using 52 human donor lungs was performed to develop a model that was used to predict, with excellent sensitivity (74%) and specificity (91%), the incidence of PGD for a donor lung. Thus, the FraCS-based approach delivers a key predictive value test that could be applied to enhance transplant patient outcomes. This work provides an important step toward bringing rapid diagnostic mRNA profiling to clinical application in lung transplantation. PMID- 26601234 TI - Platform technology for scalable assembly of instantaneously functional mosaic tissues. AB - Engineering mature tissues requires a guided assembly of cells into organized three-dimensional (3D) structures with multiple cell types. Guidance is usually achieved by microtopographical scaffold cues or by cell-gel compaction. The assembly of individual units into functional 3D tissues is often time-consuming, relying on cell ingrowth and matrix remodeling, whereas disassembly requires an invasive method that includes either matrix dissolution or mechanical cutting. We invented Tissue-Velcro, a bio-scaffold with a microfabricated hook and loop system. The assembly of Tissue-Velcro preserved the guided cell alignment realized by the topographical features in the 2D scaffold mesh and allowed for the instant establishment of coculture conditions by spatially defined stacking of cardiac cell layers or through endothelial cell coating. The assembled cardiac 3D tissue constructs were immediately functional as measured by their ability to contract in response to electrical field stimulation. Facile, on-demand tissue disassembly was demonstrated while preserving the structure, physical integrity, and beating function of individual layers. PMID- 26601235 TI - Nanodiamonds: The intersection of nanotechnology, drug development, and personalized medicine. AB - The implementation of nanomedicine in cellular, preclinical, and clinical studies has led to exciting advances ranging from fundamental to translational, particularly in the field of cancer. Many of the current barriers in cancer treatment are being successfully addressed using nanotechnology-modified compounds. These barriers include drug resistance leading to suboptimal intratumoral retention, poor circulation times resulting in decreased efficacy, and off-target toxicity, among others. The first clinical nanomedicine advances to overcome these issues were based on monotherapy, where small-molecule and nucleic acid delivery demonstrated substantial improvements over unmodified drug administration. Recent preclinical studies have shown that combination nanotherapies, composed of either multiple classes of nanomaterials or a single nanoplatform functionalized with several therapeutic agents, can image and treat tumors with improved efficacy over single-compound delivery. Among the many promising nanomaterials that are being developed, nanodiamonds have received increasing attention because of the unique chemical-mechanical properties on their faceted surfaces. More recently, nanodiamond-based drug delivery has been included in the rational and systematic design of optimal therapeutic combinations using an implicitly de-risked drug development platform technology, termed Phenotypic Personalized Medicine-Drug Development (PPM-DD). The application of PPM-DD to rapidly identify globally optimized drug combinations successfully addressed a pervasive challenge confronting all aspects of drug development, both nano and non-nano. This review will examine various nanomaterials and the use of PPM-DD to optimize the efficacy and safety of current and future cancer treatment. How this platform can accelerate combinatorial nanomedicine and the broader pharmaceutical industry toward unprecedented clinical impact will also be discussed. PMID- 26601236 TI - Total structure determination of surface doping [Ag46Au24(SR)32](BPh4)2 nanocluster and its structure-related catalytic property. AB - The structure effect is widely present in the catalysis of alloy systems. However, the surface structure of this system is still ambiguous because of the limitations of the current surface characterization tools. We reported the x-ray crystallographic structure of the first and the largest AgAu alloy nanocluster with a doping shell formulated as [Ag46Au24(SR)32](BPh4)2. This nanocluster consists of an achiral bimetallic Ag2@Au18@Ag20 core protected by a chiral Ag24Au6(SR)32 shell. The catalysis experiments further revealed that the surface structure affects the selectivity of products significantly. This is the first case to find the structure effect in atomically precise alloy nanoclusters. Our work will benefit the basic understanding of bimetal distribution, as well as the structure-related catalytic property of alloy nanoclusters at the atomic level. PMID- 26601237 TI - Locomotor play drives motor skill acquisition at the expense of growth: A life history trade-off. AB - The developmental costs and benefits of early locomotor play are a puzzling topic in biology, psychology, and health sciences. Evolutionary theory predicts that energy-intensive behavior such as play can only evolve if there are considerable benefits. Prominent theories propose that locomotor play is (i) low cost, using surplus energy remaining after growth and maintenance, and (ii) beneficial because it trains motor skills. However, both theories are largely untested. Studying wild Assamese macaques, we combined behavioral observations of locomotor play and motor skill acquisition with quantitative measures of natural food availability and individual growth rates measured noninvasively via photogrammetry. Our results show that investments in locomotor play were indeed beneficial by accelerating motor skill acquisition but carried sizable costs in terms of reduced growth. Even under moderate natural energy restriction, investment in locomotor play accounted for up to 50% of variance in growth, which strongly contradicts the current theory that locomotor play only uses surplus energy remaining after growth and maintenance. Male immatures played more, acquired motor skills faster, and grew less than female immatures, leading to persisting size differences until the age of female maturity. Hence, depending on skill requirements, investment in play can take ontogenetic priority over physical development unconstrained by costs of play with consequences for life history, which strongly highlights the ontogenetic and evolutionary importance of play. PMID- 26601238 TI - CRISPR-Cas9 delivery to hard-to-transfect cells via membrane deformation. AB - The CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) nuclease system represents an efficient tool for genome editing and gene function analysis. It consists of two components: single-guide RNA (sgRNA) and the enzyme Cas9. Typical sgRNA and Cas9 intracellular delivery techniques are limited by their reliance on cell type and exogenous materials as well as their toxic effects on cells (for example, electroporation). We introduce and optimize a microfluidic membrane deformation method to deliver sgRNA and Cas9 into different cell types and achieve successful genome editing. This approach uses rapid cell mechanical deformation to generate transient membrane holes to enable delivery of biomaterials in the medium. We achieved high delivery efficiency of different macromolecules into different cell types, including hard to-transfect lymphoma cells and embryonic stem cells, while maintaining high cell viability. With the advantages of broad applicability across different cell types, particularly hard-to-transfect cells, and flexibility of application, this method could potentially enable new avenues of biomedical research and gene targeting therapy such as mutation correction of disease genes through combination of the CRISPR-Cas9-mediated knockin system. PMID- 26601239 TI - High-precision geochronology confirms voluminous magmatism before, during, and after Earth's most severe extinction. AB - The end-Permian mass extinction was the most severe in the Phanerozoic, extinguishing more than 90% of marine and 75% of terrestrial species in a maximum of 61 +/- 48 ky. Because of broad temporal coincidence between the biotic crisis and one of the most voluminous continental volcanic eruptions since the origin of animals, the Siberian Traps large igneous province (LIP), a causal connection has long been suggested. Magmatism is hypothesized to have caused rapid injection of massive amounts of greenhouse gases into the atmosphere, driving climate change and subsequent destabilization of the biosphere. Establishing a causal connection between magmatism and mass extinction is critically dependent on accurately and precisely knowing the relative timing of the two events and the flux of magma. New U/Pb dates on Siberian Traps LIP lava flows, sills, and explosively erupted rocks indicate that (i) about two-thirds of the total lava/pyroclastic volume was erupted over ~300 ky, before and concurrent with the end-Permian mass extinction; (ii) eruption of the balance of lavas continued for at least 500 ky after extinction cessation; and (iii) massive emplacement of sills into the shallow crust began concomitant with the mass extinction and continued for at least 500 ky into the early Triassic. This age model is consistent with Siberian Traps LIP magmatism as a trigger for the end-Permian mass extinction and suggests a role for magmatism in suppression of post-extinction biotic recovery. PMID- 26601240 TI - Abrupt recent trend changes in atmospheric nitrogen dioxide over the Middle East. AB - Nitrogen oxides, released from fossil fuel use and other combustion processes, affect air quality and climate. From the mid-1990s onward, nitrogen dioxide (NO2) has been monitored from space, and since 2004 with relatively high spatial resolution by the Ozone Monitoring Instrument. Strong upward NO2 trends have been observed over South and East Asia and the Middle East, in particular over major cities. We show, however, that a combination of air quality control and political factors, including economical crisis and armed conflict, has drastically altered the emission landscape of nitrogen oxides in the Middle East. Large changes, including trend reversals, have occurred since about 2010 that could not have been predicted and therefore are at odds with emission scenarios used in projections of air pollution and climate change in the early 21st century. PMID- 26601242 TI - Unified understanding of superconductivity and Mott transition in alkali-doped fullerides from first principles. AB - Alkali-doped fullerides A 3C60 (A = K, Rb, Cs) are surprising materials where conventional phonon-mediated superconductivity and unconventional Mott physics meet, leading to a remarkable phase diagram as a function of volume per C60 molecule. We address these materials with a state-of-the-art calculation, where we construct a realistic low-energy model from first principles without using a priori information other than the crystal structure and solve it with an accurate many-body theory. Remarkably, our scheme comprehensively reproduces the experimental phase diagram including the low-spin Mott-insulating phase next to the superconducting phase. More remarkably, the critical temperatures T c's calculated from first principles quantitatively reproduce the experimental values. The driving force behind the surprising phase diagram of A 3C60 is a subtle competition between Hund's coupling and Jahn-Teller phonons, which leads to an effectively inverted Hund's coupling. Our results establish that the fullerides are the first members of a novel class of molecular superconductors in which the multiorbital electronic correlations and phonons cooperate to reach high T c s-wave superconductivity. PMID- 26601241 TI - Carbon-based electrocatalysts for advanced energy conversion and storage. AB - Oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) play curial roles in electrochemical energy conversion and storage, including fuel cells and metal-air batteries. Having rich multidimensional nanoarchitectures [for example, zero-dimensional (0D) fullerenes, 1D carbon nanotubes, 2D graphene, and 3D graphite] with tunable electronic and surface characteristics, various carbon nanomaterials have been demonstrated to act as efficient metal-free electrocatalysts for ORR and OER in fuel cells and batteries. We present a critical review on the recent advances in carbon-based metal-free catalysts for fuel cells and metal-air batteries, and discuss the perspectives and challenges in this rapidly developing field of practical significance. PMID- 26601243 TI - The structure of DNA by direct imaging. AB - The structure of DNA was determined in 1953 by x-ray fiber diffraction. Several attempts have been made to obtain a direct image of DNA with alternative techniques. The direct image is intended to allow a quantitative evaluation of all relevant characteristic lengths present in a molecule. A direct image of DNA, which is different from diffraction in the reciprocal space, is difficult to obtain for two main reasons: the intrinsic very low contrast of the elements that form the molecule and the difficulty of preparing the sample while preserving its pristine shape and size. We show that through a preparation procedure compatible with the DNA physiological conditions, a direct image of a single suspended DNA molecule can be obtained. In the image, all relevant lengths of A-form DNA are measurable. A high-resolution transmission electron microscope that operates at 80 keV with an ultimate resolution of 1.5 A was used for this experiment. Direct imaging of a single molecule can be used as a method to address biological problems that require knowledge at the single-molecule level, given that the average information obtained by x-ray diffraction of crystals or fibers is not sufficient for detailed structure determination, or when crystals cannot be obtained from biological molecules or are not sufficient in understanding multiple protein configurations. PMID- 26601244 TI - A dietary phytochemical alters caste-associated gene expression in honey bees. AB - In the eusocial honey bee Apis mellifera, with reproductive queens and sterile workers, a female larva's developmental fate depends on its diet; nurse bees feed queen-destined larvae exclusively royal jelly, a glandular secretion, but worker destined larvae receive royal jelly for 3 days and subsequently jelly to which honey and beebread are added. RNA-Seq analysis demonstrated that p-coumaric acid, which is ubiquitous in honey and beebread, differentially regulates genes involved in caste determination. Rearing larvae in vitro on a royal jelly diet to which p-coumaric acid has been added produces adults with reduced ovary development. Thus, consuming royal jelly exclusively not only enriches the diet of queen-destined larvae but also may protect them from inhibitory effects of phytochemicals present in the honey and beebread fed to worker-destined larvae. PMID- 26601245 TI - Innovative qPCR using interfacial effects to enable low threshold cycle detection and inhibition relief. AB - Molecular diagnostics offers quick access to information but fails to operate at a speed required for clinical decision-making. Our novel methodology, droplet-on thermocouple silhouette real-time polymerase chain reaction (DOTS qPCR), uses interfacial effects for droplet actuation, inhibition relief, and amplification sensing. DOTS qPCR has sample-to-answer times as short as 3 min 30 s. In infective endocarditis diagnosis, DOTS qPCR demonstrates reproducibility, differentiation of antibiotic susceptibility, subpicogram limit of detection, and thermocycling speeds of up to 28 s/cycle in the presence of tissue contaminants. Langmuir and Gibbs adsorption isotherms are used to describe the decreasing interfacial tension upon amplification. Moreover, a log-linear relationship with low threshold cycles is presented for real-time quantification by imaging the droplet-on-thermocouple silhouette with a smartphone. DOTS qPCR resolves several limitations of commercially available real-time PCR systems, which rely on fluorescence detection, have substantially higher threshold cycles, and require expensive optical components and extensive sample preparation. Due to the advantages of low threshold cycle detection, we anticipate extending this technology to biological research applications such as single cell, single nucleus, and single DNA molecule analyses. Our work is the first demonstrated use of interfacial effects for sensing reaction progress, and it will enable point-of care molecular diagnosis of infections. PMID- 26601246 TI - Rationally designed graphene-nanotube 3D architectures with a seamless nodal junction for efficient energy conversion and storage. AB - One-dimensional (1D) carbon nanotubes (CNTs) and 2D single-atomic layer graphene have superior thermal, electrical, and mechanical properties. However, these nanomaterials exhibit poor out-of-plane properties due to the weak van der Waals interaction in the transverse direction between graphitic layers. Recent theoretical studies indicate that rationally designed 3D architectures could have desirable out-of-plane properties while maintaining in-plane properties by growing CNTs and graphene into 3D architectures with a seamless nodal junction. However, the experimental realization of seamlessly-bonded architectures remains a challenge. We developed a strategy of creating 3D graphene-CNT hollow fibers with radially aligned CNTs (RACNTs) seamlessly sheathed by a cylindrical graphene layer through a one-step chemical vapor deposition using an anodized aluminum wire template. By controlling the aluminum wire diameter and anodization time, the length of the RACNTs and diameter of the graphene hollow fiber can be tuned, enabling efficient energy conversion and storage. These fibers, with a controllable surface area, meso-/micropores, and superior electrical properties, are excellent electrode materials for all-solid-state wire-shaped supercapacitors with poly(vinyl alcohol)/H2SO4 as the electrolyte and binder, exhibiting a surface-specific capacitance of 89.4 mF/cm(2) and length-specific capacitance up to 23.9 mF/cm, - one to four times the corresponding record-high capacities reported for other fiber-like supercapacitors. Dye-sensitized solar cells, fabricated using the fiber as a counter electrode, showed a power conversion efficiency of 6.8% and outperformed their counterparts with an expensive Pt wire counter electrode by a factor of 2.5. These novel fiber-shaped graphene-RACNT energy conversion and storage devices are so flexible they can be woven into fabrics as power sources. PMID- 26601247 TI - Pt monolayer coating on complex network substrate with high catalytic activity for the hydrogen evolution reaction. AB - A deposition process has been developed to fabricate a complete-monolayer Pt coating on a large-surface-area three-dimensional (3D) Ni foam substrate using a buffer layer (Ag or Au) strategy. The quartz crystal microbalance, current density analysis, cyclic voltammetry integration, and X-ray photoelectron spectroscopy results show that the monolayer deposition process accomplishes full coverage on the substrate and the deposition can be controlled to a single atomic layer thickness. To our knowledge, this is the first report on a complete monolayer Pt coating on a 3D bulk substrate with complex fine structures; all prior literature reported on submonolayer or incomplete-monolayer coating. A thin underlayer of Ag or Au is found to be necessary to cover a very reactive Ni substrate to ensure complete-monolayer Pt coverage; otherwise, only an incomplete monolayer is formed. Moreover, the Pt monolayer is found to work as well as a thick Pt film for catalytic reactions. This development may pave a way to fabricating a high-activity Pt catalyst with minimal Pt usage. PMID- 26601248 TI - Direct quantification of energy intake in an apex marine predator suggests physiology is a key driver of migrations. AB - Pacific bluefin tuna (Thunnus orientalis) are highly migratory apex marine predators that inhabit a broad thermal niche. The energy needed for migration must be garnered by foraging, but measuring energy intake in the marine environment is challenging. We quantified the energy intake of Pacific bluefin tuna in the California Current using a laboratory-validated model, the first such measurement in a wild marine predator. Mean daily energy intake was highest off the coast of Baja California, Mexico in summer (mean +/- SD, 1034 +/- 669 kcal), followed by autumn when Pacific bluefin achieve their northernmost range in waters off northern California (944 +/- 579 kcal). Movements were not always consistent with maximizing energy intake: the Pacific bluefin move out of energy rich waters both in late summer and winter, coincident with rising and falling water temperatures, respectively. We hypothesize that temperature-related physiological constraints drive migration and that Pacific bluefin tuna optimize energy intake within a range of optimal aerobic performance. PMID- 26601249 TI - The shape of terrestrial abundance distributions. AB - Ecologists widely accept that the distribution of abundances in most communities is fairly flat but heavily dominated by a few species. The reason for this is that species abundances are thought to follow certain theoretical distributions that predict such a pattern. However, previous studies have focused on either a few theoretical distributions or a few empirical distributions. I illustrate abundance patterns in 1055 samples of trees, bats, small terrestrial mammals, birds, lizards, frogs, ants, dung beetles, butterflies, and odonates. Five existing theoretical distributions make inaccurate predictions about the frequencies of the most common species and of the average species, and most of them fit the overall patterns poorly, according to the maximum likelihood-related Kullback-Leibler divergence statistic. Instead, the data support a low-dominance distribution here called the "double geometric." Depending on the value of its two governing parameters, it may resemble either the geometric series distribution or the lognormal series distribution. However, unlike any other model, it assumes both that richness is finite and that species compete unequally for resources in a two-dimensional niche landscape, which implies that niche breadths are variable and that trait distributions are neither arrayed along a single dimension nor randomly associated. The hypothesis that niche space is multidimensional helps to explain how numerous species can coexist despite interacting strongly. PMID- 26601250 TI - Adaptive evolutionary paths from UV reception to sensing violet light by epistatic interactions. AB - Ultraviolet (UV) reception is useful for such basic behaviors as mate choice, foraging, predator avoidance, communication, and navigation, whereas violet reception improves visual resolution and subtle contrast detection. UV and violet reception are mediated by the short wavelength-sensitive (SWS1) pigments that absorb light maximally (lambdamax) at ~360 nm and ~395 to 440 nm, respectively. Because of strong nonadditive (epistatic) interactions among amino acid changes in the pigments, the adaptive evolutionary mechanisms of these phenotypes are not well understood. Evolution of the violet pigment of the African clawed frog (Xenopus laevis, lambdamax = 423 nm) from the UV pigment in the amphibian ancestor (lambdamax = 359 nm) can be fully explained by eight mutations in transmembrane (TM) I-III segments. We show that epistatic interactions involving the remaining TM IV-VII segments provided evolutionary potential for the frog pigment to gradually achieve its violet-light reception by tuning its color sensitivity in small steps. Mutants in these segments also impair pigments that would cause drastic spectral shifts and thus eliminate them from viable evolutionary pathways. The overall effects of epistatic interactions involving TM IV-VII segments have disappeared at the last evolutionary step and thus are not detectable by studying present-day pigments. Therefore, characterizing the genotype-phenotype relationship during each evolutionary step is the key to uncover the true nature of epistasis. PMID- 26601251 TI - Multinational teams and diseconomies of scale in collaborative research. AB - Collaborative research has become the mainstay in knowledge production across many domains of science and is widely promoted as a means of cultivating research quality, enhanced resource utilization, and high impact. An accurate appraisal of the value of collaborative research efforts is necessary to inform current funding and research policies. We reveal contemporary trends in collaborative research spanning multiple subject fields, with a particular focus on interactions between nations. We also examined citation outcomes of research teams and confirmed the accumulative benefits of having additional authors and unique countries involved. However, when per capita citation rates were analyzed to disambiguate the effects of authors and countries, decreasing returns in citations were noted with increasing authors among large research teams. In contrast, an increasing number of unique countries had a persistent additive citation effect. We also assessed the placement of foreign authors relative to the first author in paper bylines of biomedical research articles, which demonstrated a significant citation advantage of having an international presence in the second-to-last author position, possibly occupied by foreign primary co investigators. Our analyses highlight the evolution and functional impact of team dynamics in research and suggest empirical strategies to evaluate team science. PMID- 26601253 TI - Unraveling metamaterial properties in zigzag-base folded sheets. AB - Creating complex spatial objects from a flat sheet of material using origami folding techniques has attracted attention in science and engineering. In the present work, we use the geometric properties of partially folded zigzag strips to better describe the kinematics of known zigzag/herringbone-base folded sheet metamaterials such as Miura-ori. Inspired by the kinematics of a one-degree of freedom zigzag strip, we introduce a class of cellular folded mechanical metamaterials comprising different scales of zigzag strips. This class of patterns combines origami folding techniques with kirigami. Using analytical and numerical models, we study the key mechanical properties of the folded materials. We show that our class of patterns, by expanding on the design space of Miura ori, is appropriate for a wide range of applications from mechanical metamaterials to deployable structures at small and large scales. We further show that, depending on the geometry, these materials exhibit either negative or positive in-plane Poisson's ratios. By introducing a class of zigzag-base materials in the current study, we unify the concept of in-plane Poisson's ratio for similar materials in the literature and extend it to the class of zigzag-base folded sheet materials. PMID- 26601252 TI - Pim kinases modulate resistance to FLT3 tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia. AB - Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is frequently detected in acute myeloid leukemia (AML) patients and is associated with a dismal long-term prognosis. FLT3 tyrosine kinase inhibitors provide short-term disease control, but relapse invariably occurs within months. Pim protein kinases are oncogenic FLT3-ITD targets expressed in AML cells. We show that increased Pim kinase expression is found in relapse samples from AML patients treated with FLT3 inhibitors. Ectopic Pim-2 expression induces resistance to FLT3 inhibition in both FLT3-ITD-induced myeloproliferative neoplasm and AML models in mice. Strikingly, we found that Pim kinases govern FLT3-ITD signaling and that their pharmacological or genetic inhibition restores cell sensitivity to FLT3 inhibitors. Finally, dual inhibition of FLT3 and Pim kinases eradicates FLT3 ITD(+) cells including primary AML cells. Concomitant Pim and FLT3 inhibition represents a promising new avenue for AML therapy. PMID- 26601254 TI - Snakebites are associated with poverty, weather fluctuations, and El Nino. AB - Snakebites are environmental and occupational health hazards that mainly affect rural populations worldwide. The ectothermic nature of snakes raises the issue of how climate change's impact on snake ecology could influence the incidence of snakebites in humans in ways that echo the increased predation pressure of snakes on their prey. We thus ask whether snakebites reported in Costa Rica from 2005 to 2013 were associated with meteorological fluctuations. We emphasize El Nino Southern Oscillation (ENSO), a climatic phenomenon associated with cycles of other neglected tropical diseases (NTDs) in the region and elsewhere. We ask how spatial heterogeneity in snakebites and poverty are associated, given the importance of the latter for NTDs. We found that periodicity in snakebites reflects snake reproductive phenology and is associated with ENSO. Snakebites are more likely to occur at high temperatures and may be significantly reduced after the rainy season. Nevertheless, snakebites cluster in Costa Rican areas with the heaviest rainfall, increase with poverty indicators, and decrease with altitude. Altogether, our results suggest that snakebites might vary as a result of climate change. PMID- 26601255 TI - Polya's bees: A model of decentralized decision-making. AB - How do social systems make decisions with no single individual in control? We observe that a variety of natural systems, including colonies of ants and bees and perhaps even neurons in the human brain, make decentralized decisions using common processes involving information search with positive feedback and consensus choice through quorum sensing. We model this process with an urn scheme that runs until hitting a threshold, and we characterize an inherent tradeoff between the speed and the accuracy of a decision. The proposed common mechanism provides a robust and effective means by which a decentralized system can navigate the speed-accuracy tradeoff and make reasonably good, quick decisions in a variety of environments. Additionally, consensus choice exhibits systemic risk aversion even while individuals are idiosyncratically risk-neutral. This too is adaptive. The model illustrates how natural systems make decentralized decisions, illuminating a mechanism that engineers of social and artificial systems could imitate. PMID- 26601256 TI - Organic printed photonics: From microring lasers to integrated circuits. AB - A photonic integrated circuit (PIC) is the optical analogy of an electronic loop in which photons are signal carriers with high transport speed and parallel processing capability. Besides the most frequently demonstrated silicon-based circuits, PICs require a variety of materials for light generation, processing, modulation, and detection. With their diversity and flexibility, organic molecular materials provide an alternative platform for photonics; however, the versatile fabrication of organic integrated circuits with the desired photonic performance remains a big challenge. The rapid development of flexible electronics has shown that a solution printing technique has considerable potential for the large-scale fabrication and integration of microsized/nanosized devices. We propose the idea of soft photonics and demonstrate the function directed fabrication of high-quality organic photonic devices and circuits. We prepared size-tunable and reproducible polymer microring resonators on a wafer scale transparent and flexible chip using a solution printing technique. The printed optical resonator showed a quality (Q) factor higher than 4 * 10(5), which is comparable to that of silicon-based resonators. The high material compatibility of this printed photonic chip enabled us to realize low-threshold microlasers by doping organic functional molecules into a typical photonic device. On an identical chip, this construction strategy allowed us to design a complex assembly of one-dimensional waveguide and resonator components for light signal filtering and optical storage toward the large-scale on-chip integration of microscopic photonic units. Thus, we have developed a scheme for soft photonic integration that may motivate further studies on organic photonic materials and devices. PMID- 26601257 TI - Transcriptional regulation of APOBEC3 antiviral immunity through the CBF beta/RUNX axis. AB - A diverse set of innate immune mechanisms protects cells from viral infections. The APOBEC3 family of DNA cytosine deaminases is an integral part of these defenses. For instance, APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H would have the potential to destroy HIV-1 complementary DNA replication intermediates if not for neutralization by a proteasomal degradation mechanism directed by the viral protein Vif. At the core of this complex, Vif heterodimerizes with the transcription cofactor CBF-beta, which results in fewer transcription complexes between CBF-beta and its normal RUNX partners. Recent studies have shown that the Vif/CBF-beta interaction is specific to the primate lentiviruses HIV-1 and SIV (simian immunodeficiency virus), although related nonprimate lentiviruses still require a Vif-dependent mechanism for protection from host species' APOBEC3 enzymes. We provide a molecular explanation for this evolutionary conundrum by showing that CBF-beta is required for expression of the aforementioned HIV-1 restrictive APOBEC3 gene repertoire. Knockdown and knockout studies demonstrate that CBF-beta is required for APOBEC3 mRNA expression in the nonpermissive T cell line H9 and in primary CD4(+) T lymphocytes. Complementation experiments using CBF-beta separation-of-function alleles show that the interaction with RUNX transcription factors is required for APOBEC3 transcriptional regulation. Accordingly, the infectivity of Vif-deficient HIV-1 increases in cells lacking CBF-beta, demonstrating the importance of CBF-beta/RUNX-mediated transcription in establishing the APOBEC3 antiviral state. These findings demonstrate a major layer of APOBEC3 gene regulation in lymphocytes and suggest that primate lentiviruses evolved to hijack CBF-beta in order to simultaneously suppress this potent antiviral defense system at both transcriptional and posttranslational levels. PMID- 26601258 TI - Trait-mediated trophic cascade creates enemy-free space for nesting hummingbirds. AB - The indirect effects of predators on nonadjacent trophic levels, mediated through traits of intervening species, are collectively known as trait-mediated trophic cascades. Although birds are important predators in terrestrial ecosystems, clear examples of trait-mediated indirect effects involving bird predators have almost never been documented. Such indirect effects are important for structuring ecological communities and are likely to be negatively impacted by habitat fragmentation, climate change, and other factors that reduce abundance of top predators. We demonstrate that hummingbirds in Arizona realize increased breeding success when nesting in association with hawks. An enemy-free nesting space is created when jays, an important source of mortality for hummingbird nests, alter their foraging behavior in the presence of their hawk predators. PMID- 26601259 TI - An auditory feature detection circuit for sound pattern recognition. AB - From human language to birdsong and the chirps of insects, acoustic communication is based on amplitude and frequency modulation of sound signals. Whereas frequency processing starts at the level of the hearing organs, temporal features of the sound amplitude such as rhythms or pulse rates require processing by central auditory neurons. Besides several theoretical concepts, brain circuits that detect temporal features of a sound signal are poorly understood. We focused on acoustically communicating field crickets and show how five neurons in the brain of females form an auditory feature detector circuit for the pulse pattern of the male calling song. The processing is based on a coincidence detector mechanism that selectively responds when a direct neural response and an intrinsically delayed response to the sound pulses coincide. This circuit provides the basis for auditory mate recognition in field crickets and reveals a principal mechanism of sensory processing underlying the perception of temporal patterns. PMID- 26601260 TI - Unraveling the storage mechanism in organic carbonyl electrodes for sodium-ion batteries. AB - Organic carbonyl compounds represent a promising class of electrode materials for secondary batteries; however, the storage mechanism still remains unclear. We take Na2C6H2O4 as an example to unravel the mechanism. It consists of alternating Na-O octahedral inorganic layer and pi-stacked benzene organic layer in spatial separation, delivering a high reversible capacity and first coulombic efficiency. The experiment and calculation results reveal that the Na-O inorganic layer provides both Na(+) ion transport pathway and storage site, whereas the benzene organic layer provides electron transport pathway and redox center. Our contribution provides a brand-new insight in understanding the storage mechanism in inorganic-organic layered host and opens up a new exciting direction for designing new materials for secondary batteries. PMID- 26601261 TI - Early hominin auditory capacities. AB - Studies of sensory capacities in past life forms have offered new insights into their adaptations and lifeways. Audition is particularly amenable to study in fossils because it is strongly related to physical properties that can be approached through their skeletal structures. We have studied the anatomy of the outer and middle ear in the early hominin taxa Australopithecus africanus and Paranthropus robustus and estimated their auditory capacities. Compared with chimpanzees, the early hominin taxa are derived toward modern humans in their slightly shorter and wider external auditory canal, smaller tympanic membrane, and lower malleus/incus lever ratio, but they remain primitive in the small size of their stapes footplate. Compared with chimpanzees, both early hominin taxa show a heightened sensitivity to frequencies between 1.5 and 3.5 kHz and an occupied band of maximum sensitivity that is shifted toward slightly higher frequencies. The results have implications for sensory ecology and communication, and suggest that the early hominin auditory pattern may have facilitated an increased emphasis on short-range vocal communication in open habitats. PMID- 26601262 TI - Direct observation of an attosecond electron wave packet in a nitrogen molecule. AB - Capturing electron motion in a molecule is the basis of understanding or steering chemical reactions. Nonlinear Fourier transform spectroscopy using an attosecond pump/attosecond-probe technique is used to observe an attosecond electron wave packet in a nitrogen molecule in real time. The 500-as electronic motion between two bound electronic states in a nitrogen molecule is captured by measuring the fragment ions with the same kinetic energy generated in sequential two-photon dissociative ionization processes. The temporal evolution of electronic coherence originating from various electronic states is visualized via the fragment ions appearing after irradiation of the probe pulse. This observation of an attosecond molecular electron wave packet is a critical step in understanding coupled nuclear and electron motion in polyatomic and biological molecules to explore attochemistry. PMID- 26601263 TI - The energetic cost of vision and the evolution of eyeless Mexican cavefish. AB - One hypothesis for the reduction of vision in cave animals, such as the eyeless Mexican cavefish, is the high energetic cost of neural tissue and low food availability in subterranean habitats. However, data on relative brain and eye mass in this species or on any measure of the energetic cost of neural tissue are not available, making it difficult to evaluate the "expensive tissue hypothesis." We show that the eyes and optic tectum represent significant metabolic costs in the eyed phenotype. The cost of vision was calculated to be 15% of resting metabolism for a 1-g fish, decreasing to 5% in an 8.5-g fish as relative eye and brain size declined during growth. Our results demonstrate that the loss of the visual system in the cave phenotype substantially lowered the amount of energy expended on expensive neural tissue during diversification into subterranean rivers, in particular for juvenile fish. PMID- 26601264 TI - Detection of argon in the coma of comet 67P/Churyumov-Gerasimenko. AB - Comets have been considered to be representative of icy planetesimals that may have contributed a significant fraction of the volatile inventory of the terrestrial planets. For example, comets must have brought some water to Earth. However, the magnitude of their contribution is still debated. We report the detection of argon and its relation to the water abundance in the Jupiter family comet 67P/Churyumov-Gerasimenko by in situ measurement of the Rosetta Orbiter Spectrometer for Ion and Neutral Analysis (ROSINA) mass spectrometer aboard the Rosetta spacecraft. Despite the very low intensity of the signal, argon is clearly identified by the exact determination of the mass of the isotope (36)Ar and by the (36)Ar/(38)Ar ratio. Because of time variability and spatial heterogeneity of the coma, only a range of the relative abundance of argon to water can be given. Nevertheless, this range confirms that comets of the type 67P/Churyumov-Gerasimenko cannot be the major source of Earth's major volatiles. PMID- 26601265 TI - The chlorine isotope fingerprint of the lunar magma ocean. AB - The Moon contains chlorine that is isotopically unlike that of any other body yet studied in the Solar System, an observation that has been interpreted to support traditional models of the formation of a nominally hydrogen-free ("dry") Moon. We have analyzed abundances and isotopic compositions of Cl and H in lunar mare basalts, and find little evidence that anhydrous lava outgassing was important in generating chlorine isotope anomalies, because (37)Cl/(35)Cl ratios are not related to Cl abundance, H abundance, or D/H ratios in a manner consistent with the lava-outgassing hypothesis. Instead, (37)Cl/(35)Cl correlates positively with Cl abundance in apatite, as well as with whole-rock Th abundances and La/Lu ratios, suggesting that the high (37)Cl/(35)Cl in lunar basalts is inherited from urKREEP, the last dregs of the lunar magma ocean. These new data suggest that the high chlorine isotope ratios of lunar basalts result not from the degassing of their lavas but from degassing of the lunar magma ocean early in the Moon's history. Chlorine isotope variability is therefore an indicator of planetary magma ocean degassing, an important stage in the formation of terrestrial planets. PMID- 26601266 TI - Near-IR squaraine dye-loaded gated periodic mesoporous organosilica for photo oxidation of phenol in a continuous-flow device. AB - Periodic mesoporous organosilica (PMO) has been widely used for the fabrication of a variety of catalytically active materials. We report the preparation of novel photo-responsive PMO with azobenzene-gated pores. Upon activation, the azobenzene gate undergoes trans-cis isomerization, which allows an unsymmetrical near-infrared squaraine dye (Sq) to enter into the pores. The gate closure by cis trans isomerization of the azobenzene unit leads to the safe loading of the monomeric dye inside the pores. The dye-loaded and azobenzene-gated PMO (Sq azo@PMO) exhibits excellent generation of reactive oxygen species upon excitation at 664 nm, which can be effectively used for the oxidation of phenol into benzoquinone in aqueous solution. Furthermore, Sq-azo@PMO as the catalyst was placed inside a custom-built, continuous-flow device to carry out the photo oxidation of phenol to benzoquinone in the presence of 664-nm light. By using the device, about 23% production of benzoquinone with 100% selectivity was achieved. The current research presents a prototype of transforming heterogeneous catalysts toward practical use. PMID- 26601267 TI - Detection of single amino acid mutation in human breast cancer by disordered plasmonic self-similar chain. AB - Control of the architecture and electromagnetic behavior of nanostructures offers the possibility of designing and fabricating sensors that, owing to their intrinsic behavior, provide solutions to new problems in various fields. We show detection of peptides in multicomponent mixtures derived from human samples for early diagnosis of breast cancer. The architecture of sensors is based on a matrix array where pixels constitute a plasmonic device showing a strong electric field enhancement localized in an area of a few square nanometers. The method allows detection of single point mutations in peptides composing the BRCA1 protein. The sensitivity demonstrated falls in the picomolar (10(-12) M) range. The success of this approach is a result of accurate design and fabrication control. The residual roughness introduced by fabrication was taken into account in optical modeling and was a further contributing factor in plasmon localization, increasing the sensitivity and selectivity of the sensors. This methodology developed for breast cancer detection can be considered a general strategy that is applicable to various pathologies and other chemical analytical cases where complex mixtures have to be resolved in their constitutive components. PMID- 26601268 TI - Hierarchical spin-orbital polarization of a giant Rashba system. AB - The Rashba effect is one of the most striking manifestations of spin-orbit coupling in solids and provides a cornerstone for the burgeoning field of semiconductor spintronics. It is typically assumed to manifest as a momentum dependent splitting of a single initially spin-degenerate band into two branches with opposite spin polarization. Combining polarization-dependent and resonant angle-resolved photoemission measurements with density functional theory calculations, we show that the two "spin-split" branches of the model giant Rashba system BiTeI additionally develop disparate orbital textures, each of which is coupled to a distinct spin configuration. This necessitates a reinterpretation of spin splitting in Rashba-like systems and opens new possibilities for controlling spin polarization through the orbital sector. PMID- 26601269 TI - Cis-regulatory mechanisms governing stem and progenitor cell transitions. AB - Cis-element encyclopedias provide information on phenotypic diversity and disease mechanisms. Although cis-element polymorphisms and mutations are instructive, deciphering function remains challenging. Mutation of an intronic GATA motif (+9.5) in GATA2, encoding a master regulator of hematopoiesis, underlies an immunodeficiency associated with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Whereas an inversion relocalizes another GATA2 cis-element (-77) to the proto-oncogene EVI1, inducing EVI1 expression and AML, whether this reflects ectopic or physiological activity is unknown. We describe a mouse strain that decouples -77 function from proto-oncogene deregulation. The -77(-/-) mice exhibited a novel phenotypic constellation including late embryonic lethality and anemia. The -77 established a vital sector of the myeloid progenitor transcriptome, conferring multipotentiality. Unlike the +9.5(-/-) embryos, hematopoietic stem cell genesis was unaffected in -77(-/-) embryos. These results illustrate a paradigm in which cis-elements in a locus differentially control stem and progenitor cell transitions, and therefore the individual cis-element alterations cause unique and overlapping disease phenotypes. PMID- 26601270 TI - Nectar uptake in bats using a pumping-tongue mechanism. AB - Many insects use nectar as their principal diet and have mouthparts specialized in nectarivory, whereas most nectar-feeding vertebrates are opportunistic users of floral resources and only a few species show distinct morphological specializations. Specialized nectar-feeding bats extract nectar from flowers using elongated tongues that correspond to two vastly different morphologies: Most species have tongues with hair-like papillae, whereas one group has almost hairless tongues that show distinct lateral grooves. Recent molecular data indicate a convergent evolution of groove- and hair-tongued bat clades into the nectar-feeding niche. Using high-speed video recordings on experimental feeders, we show distinctly divergent nectar-feeding behavior in clades. Grooved tongues are held in contact with nectar for the entire duration of visit as nectar is pumped into the mouths of hovering bats, whereas hairy tongues are used in conventional sinusoidal lapping movements. Bats with grooved tongues use a specific fluid uptake mechanism not known from any other mammal. Nectar rises in semiopen lateral grooves, probably driven by a combination of tongue deformation and capillary action. Extraction efficiency declined for both tongue types with a similar slope toward deeper nectar levels. Our results highlight a novel drinking mechanism in mammals and raise further questions on fluid mechanics and ecological niche partitioning. PMID- 26601272 TI - Future extreme sea level seesaws in the tropical Pacific. AB - Global mean sea levels are projected to gradually rise in response to greenhouse warming. However, on shorter time scales, modes of natural climate variability in the Pacific, such as the El Nino-Southern Oscillation (ENSO), can affect regional sea level variability and extremes, with considerable impacts on coastal ecosystems and island nations. How these shorter-term sea level fluctuations will change in association with a projected increase in extreme El Nino and its atmospheric variability remains unknown. Using present-generation coupled climate models forced with increasing greenhouse gas concentrations and subtracting the effect of global mean sea level rise, we find that climate change will enhance El Nino-related sea level extremes, especially in the tropical southwestern Pacific, where very low sea level events, locally known as Taimasa, are projected to double in occurrence. Additionally, and throughout the tropical Pacific, prolonged interannual sea level inundations are also found to become more likely with greenhouse warming and increased frequency of extreme La Nina events, thus exacerbating the coastal impacts of the projected global mean sea level rise. PMID- 26601273 TI - Combustion of available fossil fuel resources sufficient to eliminate the Antarctic Ice Sheet. AB - The Antarctic Ice Sheet stores water equivalent to 58 m in global sea-level rise. We show in simulations using the Parallel Ice Sheet Model that burning the currently attainable fossil fuel resources is sufficient to eliminate the ice sheet. With cumulative fossil fuel emissions of 10,000 gigatonnes of carbon (GtC), Antarctica is projected to become almost ice-free with an average contribution to sea-level rise exceeding 3 m per century during the first millennium. Consistent with recent observations and simulations, the West Antarctic Ice Sheet becomes unstable with 600 to 800 GtC of additional carbon emissions. Beyond this additional carbon release, the destabilization of ice basins in both West and East Antarctica results in a threshold increase in global sea level. Unabated carbon emissions thus threaten the Antarctic Ice Sheet in its entirety with associated sea-level rise that far exceeds that of all other possible sources. PMID- 26601271 TI - A phylogenomic data-driven exploration of viral origins and evolution. AB - The origin of viruses remains mysterious because of their diverse and patchy molecular and functional makeup. Although numerous hypotheses have attempted to explain viral origins, none is backed by substantive data. We take full advantage of the wealth of available protein structural and functional data to explore the evolution of the proteomic makeup of thousands of cells and viruses. Despite the extremely reduced nature of viral proteomes, we established an ancient origin of the "viral supergroup" and the existence of widespread episodes of horizontal transfer of genetic information. Viruses harboring different replicon types and infecting distantly related hosts shared many metabolic and informational protein structural domains of ancient origin that were also widespread in cellular proteomes. Phylogenomic analysis uncovered a universal tree of life and revealed that modern viruses reduced from multiple ancient cells that harbored segmented RNA genomes and coexisted with the ancestors of modern cells. The model for the origin and evolution of viruses and cells is backed by strong genomic and structural evidence and can be reconciled with existing models of viral evolution if one considers viruses to have originated from ancient cells and not from modern counterparts. PMID- 26601274 TI - Writing in the granular gel medium. AB - Gels made from soft microscale particles smoothly transition between the fluid and solid states, making them an ideal medium in which to create macroscopic structures with microscopic precision. While tracing out spatial paths with an injection tip, the granular gel fluidizes at the point of injection and then rapidly solidifies, trapping injected material in place. This physical approach to creating three-dimensional (3D) structures negates the effects of surface tension, gravity, and particle diffusion, allowing a limitless breadth of materials to be written. With this method, we used silicones, hydrogels, colloids, and living cells to create complex large aspect ratio 3D objects, thin closed shells, and hierarchically branched tubular networks. We crosslinked polymeric materials and removed them from the granular gel, whereas uncrosslinked particulate systems were left supported within the medium for long times. This approach can be immediately used in diverse areas, contributing to tissue engineering, flexible electronics, particle engineering, smart materials, and encapsulation technologies. PMID- 26601275 TI - Boramino acid as a marker for amino acid transporters. AB - Amino acid transporters (AATs) are a series of integral channels for uphill cellular uptake of nutrients and neurotransmitters. Abnormal expression of AATs is often associated with cancer, addiction, and multiple mental diseases. Although methods to evaluate in vivo expression of AATs would be highly useful, efforts to develop them have been hampered by a lack of appropriate tracers. We describe a new class of AA mimics-boramino acids (BAAs)-that can serve as general imaging probes for AATs. The structure of a BAA is identical to that of the corresponding natural AA, except for an exotic replacement of the carboxylate with -BF3 (-). Cellular studies demonstrate strong AAT-mediated cell uptake, and animal studies show high tumor-specific accumulation, suggesting that BAAs hold great promise for the development of new imaging probes and smart AAT-targeting drugs. PMID- 26601276 TI - Individualistic sensitivities and exposure to climate change explain variation in species' distribution and abundance changes. AB - The responses of animals and plants to recent climate change vary greatly from species to species, but attempts to understand this variation have met with limited success. This has led to concerns that predictions of responses are inherently uncertain because of the complexity of interacting drivers and biotic interactions. However, we show for an exemplar group of 155 Lepidoptera species that about 60% of the variation among species in their abundance trends over the past four decades can be explained by species-specific exposure and sensitivity to climate change. Distribution changes were less well predicted, but nonetheless, up to 53% of the variation was explained. We found that species vary in their overall sensitivity to climate and respond to different components of the climate despite ostensibly experiencing the same climate changes. Hence, species have undergone different levels of population "forcing" (exposure), driving variation among species in their national-scale abundance and distribution trends. We conclude that variation in species' responses to recent climate change may be more predictable than previously recognized. PMID- 26601277 TI - Evidence for orbital order and its relation to superconductivity in FeSe0.4Te0.6. AB - The emergence of nematic electronic states accompanied by a structural phase transition is a recurring theme in many correlated electron materials, including the high-temperature copper oxide- and iron-based superconductors. We provide evidence for nematic electronic states in the iron-chalcogenide superconductor FeSe0.4Te0.6 from quasi-particle scattering detected in spectroscopic maps. The symmetry-breaking states persist above T c into the normal state. We interpret the scattering patterns by comparison with quasi-particle interference patterns obtained from a tight-binding model, accounting for orbital ordering. The relation to superconductivity and the influence on the coherence length are discussed. PMID- 26601278 TI - Drosophila Dicer-2 has an RNA interference-independent function that modulates Toll immune signaling. AB - Dicer-2 is the central player for small interfering RNA biogenesis in the Drosophila RNA interference (RNAi) pathway. Intriguingly, we found that Dicer-2 has an unconventional RNAi-independent function that positively modulates Toll immune signaling, which defends against Gram-positive bacteria, fungi, and some viruses, in both cells and adult flies. The loss of Dicer-2 expression makes fruit flies more susceptible to fungal infection. We further revealed that Dicer 2 posttranscriptionally modulates Toll signaling because Dicer-2 is required for the proper expression of Toll protein but not for Toll protein stability or Toll mRNA transcription. Moreover, Dicer-2 directly binds to the 3' untranslated region (3'UTR) of Toll mRNA via its PAZ (Piwi/Argonaute/Zwille) domain and is required for protein translation mediated by Toll 3'UTR. The loss of Toll 3'UTR binding activity makes Dicer-2 incapable of promoting Toll signaling. These data indicate that the interaction between Dicer-2 and Toll mRNA plays a pivotal role in Toll immune signaling. In addition, we found that Dicer-2 is also required for the Toll signaling induced by two different RNA viruses in Drosophila cells. Consequently, our findings uncover a novel RNAi-independent function of Dicer-2 in the posttranscriptional regulation of Toll protein expression and signaling, indicate an unexpected intersection of the RNAi pathway and the Toll pathway, and provide new insights into Toll immune signaling, Drosophila Dicer-2, and probably Dicer and Dicer-related proteins in other organisms. PMID- 26601279 TI - Below-ground plant-fungus network topology is not congruent with above-ground plant-animal network topology. AB - In nature, plants and their pollinating and/or seed-dispersing animals form complex interaction networks. The commonly observed pattern of links between specialists and generalists in these networks has been predicted to promote species coexistence. Plants also build highly species-rich mutualistic networks below ground with root-associated fungi, and the structure of these plant-fungus networks may also affect terrestrial community processes. By compiling high throughput DNA sequencing data sets of the symbiosis of plants and their root associated fungi from three localities along a latitudinal gradient, we uncovered the entire network architecture of these interactions under contrasting environmental conditions. Each network included more than 30 plant species and hundreds of mycorrhizal and endophytic fungi belonging to diverse phylogenetic groups. The results were consistent with the notion that processes shaping host plant specialization of fungal species generate a unique linkage pattern that strongly contrasts with the pattern of above-ground plant-partner networks. Specifically, plant-fungus networks lacked a "nested" architecture, which has been considered to promote species coexistence in plant-partner networks. Rather, the below-ground networks had a conspicuous "antinested" topology. Our findings lead to the working hypothesis that terrestrial plant community dynamics are likely determined by the balance between above-ground and below-ground webs of interspecific interactions. PMID- 26601280 TI - Response thresholds in bacterial chemotaxis. AB - Stimulation of Escherichia coli by exponential ramps of chemoattractants generates step changes in the concentration of the response regulator, CheY-P. Because flagellar motors are ultrasensitive, this should change the fraction of time that motors spin clockwise, the CWbias. However, early work failed to show changes in CWbias when ramps were shallow. This was explained by a model for motor remodeling that predicted plateaus in plots of CWbias versus [CheY-P]. We looked for these plateaus by examining distributions of CWbias in populations of cells with different mean [CheY-P]. We did not find such plateaus. Hence, we repeated the work on shallow ramps and found that motors did indeed respond. These responses were quantitatively described by combining motor remodeling with ultrasensitivity in a model that exhibited high sensitivities over a wide dynamic range. PMID- 26601281 TI - Dislocation-accommodated grain boundary sliding as the major deformation mechanism of olivine in the Earth's upper mantle. AB - Understanding the deformation mechanisms of olivine is important for addressing the dynamic processes in Earth's upper mantle. It has been thought that dislocation creep is the dominant mechanism because of extrapolated laboratory data on the plasticity of olivine at pressures below 0.5 GPa. However, we found that dislocation-accommodated grain boundary sliding (DisGBS), rather than dislocation creep, dominates the deformation of olivine under middle and deep upper mantle conditions. We used a deformation-DIA apparatus combined with synchrotron in situ x-ray observations to study the plasticity of olivine aggregates at pressures up to 6.7 GPa (that is, ~200-km depth) and at temperatures between 1273 and 1473 K, which is equivalent to the conditions in the middle region of the upper mantle. The creep strength of olivine deforming by DisGBS is apparently less sensitive to pressure because of the competing pressure hardening effect of the activation volume and pressure-softening effect of water fugacity. The estimated viscosity of olivine controlled by DisGBS is independent of depth and ranges from 10(19.6) to 10(20.7) Pa.s throughout the asthenospheric upper mantle with a representative water content (50 to 1000 parts per million H/Si), which is consistent with geophysical viscosity profiles. Because DisGBS is a grain size-sensitive creep mechanism, the evolution of the grain size of olivine is an important process controlling the dynamics of the upper mantle. PMID- 26601282 TI - Self-propelled particles that transport cargo through flowing blood and halt hemorrhage. AB - Delivering therapeutics deep into damaged tissue during bleeding is challenging because of the outward flow of blood. When coagulants cannot reach and clot blood at its source, uncontrolled bleeding can occur and increase surgical complications and fatalities. Self-propelling particles have been proposed as a strategy for transporting agents upstream through blood. Many nanoparticle and microparticle systems exhibiting autonomous or collective movement have been developed, but propulsion has not been used successfully in blood or used in vivo to transport therapeutics. We show that simple gas-generating microparticles consisting of carbonate and tranexamic acid traveled through aqueous solutions at velocities of up to 1.5 cm/s and delivered therapeutics millimeters into the vasculature of wounds. The particles transported themselves through a combination of lateral propulsion, buoyant rise, and convection. When loaded with active thrombin, these particles worked effectively as a hemostatic agent and halted severe hemorrhage in multiple animal models of intraoperative and traumatic bleeding. Many medical applications have been suggested for self-propelling particles, and the findings of this study show that the active self-fueled transport of particles can function in vivo to enhance drug delivery. PMID- 26601283 TI - Catenary optics for achromatic generation of perfect optical angular momentum. AB - The catenary is the curve that a free-hanging chain assumes under its own weight, and thought to be a "true mathematical and mechanical form" in architecture by Robert Hooke in the 1670s, with nevertheless no significant phenomena observed in optics. We show that the optical catenary can serve as a unique building block of metasurfaces to produce continuous and linear phase shift covering [0, 2pi], a mission that is extremely difficult if not impossible for state-of-the-art technology. Via catenary arrays, planar optical devices are designed and experimentally characterized to generate various kinds of beams carrying orbital angular momentum (OAM). These devices can operate in an ultra-broadband spectrum because the anisotropic modes associated with the spin-orbit interaction are almost independent of the incident light frequency. By combining the optical and topological characteristics, our approach would allow the complete control of photons within a single nanometric layer. PMID- 26601284 TI - A shortage of males causes female reproductive failure in yellow ground squirrels. AB - Sexual conflict theory suggests that female breeding success is strongly influenced by individual life history and environmental conditions and is much less affected by mate availability. Female mating failure due to a shortage of males remains poorly studied and understood. We present data on the effects of male availability on female breeding success in a wild colony of yellow ground squirrels (Spermophilus fulvus). A female's probability of breeding increased with the local density of males and was higher with higher male-biased operational sex ratio (OSR) but was independent of local female density, female age, and body condition, which are factors commonly assumed to influence female reproduction. The positive effect of male availability (as measured by OSR) on female breeding success was consistent across the years, and we conclude that male limitation contributes to female mating failure. This pattern, which is not commonly recorded in species with conventional sex roles, can be explained by a combination of sociodemographic and life history traits (sex differences in age of maturation, female-skewed adult sex ratio and seasonally varying OSR, solitary living at low population density, and low mobility of females combined with mate searching tactics of males) that are not confined to S. fulvus. Our findings indicate that the role of female mating failure (due to a shortage of males) in shaping mammalian life history may be underestimated. PMID- 26601285 TI - Co-potentiation of antigen recognition: A mechanism to boost weak T cell responses and provide immunotherapy in vivo. AB - Adaptive immunity is mediated by antigen receptors that can induce weak or strong immune responses depending on the nature of the antigen that is bound. In T lymphocytes, antigen recognition triggers signal transduction by clustering T cell receptor (TCR)/CD3 multiprotein complexes. In addition, it hypothesized that biophysical changes induced in TCR/CD3 that accompany receptor engagement may contribute to signal intensity. Nonclustering monovalent TCR/CD3 engagement is functionally inert despite the fact that it may induce changes in conformational arrangement or in the flexibility of receptor subunits. We report that the intrinsically inert monovalent engagement of TCR/CD3 can specifically enhance physiologic T cell responses to weak antigens in vitro and in vivo without stimulating antigen-unengaged T cells and without interrupting T cell responses to strong antigens, an effect that we term as "co-potentiation." We identified Mono-7D6-Fab, which biophysically altered TCR/CD3 when bound and functionally enhanced immune reactivity to several weak antigens in vitro, including a gp100 derived peptide associated with melanoma. In vivo, Mono-7D6-Fab induced T cell antigen-dependent therapeutic responses against melanoma lung metastases, an effect that synergized with other anti-melanoma immunotherapies to significantly improve outcome and survival. We conclude that Mono-7D6-Fab directly co potentiated TCR/CD3 engagement by weak antigens and that such concept can be translated into an immunotherapeutic design. The co-potentiation principle may be applicable to other receptors that could be regulated by otherwise inert compounds whose latent potency is only invoked in concert with specific physiologic ligands. PMID- 26601286 TI - Gold tetrahedra coil up: Kekule-like and double helical superstructures. AB - Magic-sized clusters, as the intermediate state between molecules and nanoparticles, exhibit critical transitions of structures and material properties. We report two unique structures of gold clusters solved by x-ray crystallography, including Au40 and Au52 protected by thiolates. The Au40 and Au52 clusters exhibit a high level of complexity, with the gold atoms in the cluster first segregated into four-atom tetrahedral units-which then coil up into a Kekule-like ring in the Au40 cluster and a DNA-like double helix in Au52. The solved structures imply a new "supermolecule" origin for revealing the stability of certain magic-sized gold clusters. The formation of supermolecular structures originates in the surface ligand bonding-induced stress and its propagation through the face-centered cubic (FCC) lattice. Moreover, the two structures reveal anisotropic growth of the FCC lattice in the cluster regime, which provides implications for the important roles of ligands at the atomic level. The rich structural information encoded in the Au40 and Au52 clusters provides atomic scale insight into some important issues in cluster, nanoscale, and surface sciences. PMID- 26601287 TI - Hazard potential of volcanic flank collapses raised by new megatsunami evidence. AB - Large-scale gravitational flank collapses of steep volcanic islands are hypothetically capable of triggering megatsunamis with highly catastrophic effects. Yet, evidence for the generation and impact of collapse-triggered megatsunamis and their high run-ups remains scarce or is highly controversial. Therefore, doubts remain on whether island flank failures truly generate enough volume flux to trigger giant tsunamis, leading to diverging opinions concerning the real hazard potential of such collapses. We show that one of the most prominent oceanic volcanoes on Earth-Fogo, in the Cape Verde Islands catastrophically collapsed and triggered a megatsunami with devastating effects ~73,000 years ago. Our deductions are based on the recent discovery and cosmogenic (3)He dating of tsunamigenic deposits found on nearby Santiago Island, which attest to the impact of this giant tsunami and document wave run-up heights exceeding 270 m. The evidence reported here implies that Fogo's flank failure involved at least one fast and voluminous event that led to a giant tsunami, in contrast to what has been suggested before. Our observations therefore further demonstrate that flank collapses may indeed catastrophically happen and are capable of triggering tsunamis of enormous height and energy, adding to their hazard potential. PMID- 26601288 TI - MED12 methylation by CARM1 sensitizes human breast cancer cells to chemotherapy drugs. AB - The RNA polymerase II mediator complex subunit 12 (MED12) is frequently mutated in human cancers, and loss of MED12 has been shown to induce drug resistance through activation of transforming growth factor-beta receptor (TGF-betaR) signaling. We identified MED12 as a substrate for coactivator-associated arginine methyltransferase 1 (CARM1). Not only are the expression levels of CARM1 and MED12 positively correlated, but their high expression also predicts better prognosis in human breast cancers after chemotherapy. MED12 was methylated at R1862 and R1912 by CARM1, and mutation of these sites in cell lines resulted in resistance to chemotherapy drugs. Furthermore, we showed that the methylation dependent drug response mechanism is distinct from activation of TGF-betaR signaling, because methylated MED12 potently suppresses p21/WAF1 transcription. Cells defective in MED12 methylation have up-regulated p21 protein, which correlates with poor prognosis in breast cancer patients treated with chemotherapy. Collectively, this study identifies MED12 methylation as a sensor for predicting response to commonly used chemotherapy drugs in human cancers. PMID- 26601289 TI - Cascading elastic perturbation in Japan due to the 2012 M w 8.6 Indian Ocean earthquake. AB - Since the discovery of extensive earthquake triggering occurring in response to the 1992 M w (moment magnitude) 7.3 Landers earthquake, it is now well established that seismic waves from earthquakes can trigger other earthquakes, tremor, slow slip, and pore pressure changes. Our contention is that earthquake triggering is one manifestation of a more widespread elastic disturbance that reveals information about Earth's stress state. Earth's stress state is central to our understanding of both natural and anthropogenic-induced crustal processes. We show that seismic waves from distant earthquakes may perturb stresses and frictional properties on faults and elastic moduli of the crust in cascading fashion. Transient dynamic stresses place crustal material into a metastable state during which the material recovers through a process termed slow dynamics. This observation of widespread, dynamically induced elastic perturbation, including systematic migration of offshore seismicity, strain transients, and velocity transients, presents a new characterization of Earth's elastic system that will advance our understanding of plate tectonics, seismicity, and seismic hazards. PMID- 26601290 TI - Blue whales (Balaenoptera musculus) optimize foraging efficiency by balancing oxygen use and energy gain as a function of prey density. AB - Terrestrial predators can modulate the energy used for prey capture to maximize efficiency, but diving animals face the conflicting metabolic demands of energy intake and the minimization of oxygen depletion during a breath hold. It is thought that diving predators optimize their foraging success when oxygen use and energy gain act as competing currencies, but this hypothesis has not been rigorously tested because it has been difficult to measure the quality of prey that is targeted by free-ranging animals. We used high-resolution multisensor digital tags attached to foraging blue whales (Balaenoptera musculus) with concurrent acoustic prey measurements to quantify foraging performance across depth and prey density gradients. We parameterized two competing physiological models to estimate energy gain and expenditure based on foraging decisions. Our analyses show that at low prey densities, blue whale feeding rates and energy intake were low to minimize oxygen use, but at higher prey densities feeding frequency increased to maximize energy intake. Contrary to previous paradigms, we demonstrate that blue whales are not indiscriminate grazers but instead switch foraging strategies in response to variation in prey density and depth to maximize energetic efficiency. PMID- 26601292 TI - Effects of ocean acidification on marine dissolved organic matter are not detectable over the succession of phytoplankton blooms. AB - Marine dissolved organic matter (DOM) is one of the largest active organic carbon reservoirs on Earth, and changes in its pool size or composition could have a major impact on the global carbon cycle. Ocean acidification is a potential driver for these changes because it influences marine primary production and heterotrophic respiration. We simulated ocean acidification as expected for a "business-as-usual" emission scenario in the year 2100 in an unprecedented long term mesocosm study. The large-scale experiments (50 m(3) each) covered a full seasonal cycle of marine production in a Swedish Fjord. Five mesocosms were artificially enriched in CO2 to the partial pressure expected in the year 2100 (900 MUatm), and five more served as controls (400 MUatm). We applied ultrahigh resolution mass spectrometry to monitor the succession of 7360 distinct DOM formulae over the course of the experiment. Plankton blooms had a clear effect on DOM concentration and molecular composition. This succession was reproducible across all 10 mesocosms, independent of CO2 treatment. In contrast to the temporal trend, there were no significant differences in DOM concentration and composition between present-day and year 2100 CO2 levels at any time point of the experiment. On the basis of our results, ocean acidification alone is unlikely to affect the seasonal accumulation of DOM in productive coastal environments. PMID- 26601291 TI - Contractility parameters of human beta-cardiac myosin with the hypertrophic cardiomyopathy mutation R403Q show loss of motor function. AB - Hypertrophic cardiomyopathy (HCM) is the most frequently occurring inherited cardiovascular disease. It is caused by mutations in genes encoding the force generating machinery of the cardiac sarcomere, including human beta-cardiac myosin. We present a detailed characterization of the most debated HCM-causing mutation in human beta-cardiac myosin, R403Q. Despite numerous studies, most performed with nonhuman or noncardiac myosin, there is no consensus about the mechanism of action of this mutation on the function of the enzyme. We use recombinant human beta-cardiac myosin and new methodologies to characterize in vitro contractility parameters of the R403Q myosin compared to wild type. We extend our studies beyond pure actin filaments to include the interaction of myosin with regulated actin filaments containing tropomyosin and troponin. We find that, with pure actin, the intrinsic force generated by R403Q is ~15% lower than that generated by wild type. The unloaded velocity is, however, ~10% higher for R403Q myosin, resulting in a load-dependent velocity curve that has the characteristics of lower contractility at higher external loads compared to wild type. With regulated actin filaments, there is no increase in the unloaded velocity and the contractility of the R403Q myosin is lower than that of wild type at all loads. Unlike that with pure actin, the actin-activated adenosine triphosphatase activity for R403Q myosin with Ca(2+)-regulated actin filaments is ~30% lower than that for wild type, predicting a lower unloaded duty ratio of the motor. Overall, the contractility parameters studied fit with a loss of human beta-cardiac myosin contractility as a result of the R403Q mutation. PMID- 26601293 TI - Pinning down the superfluid and measuring masses using pulsar glitches. AB - Pulsars are known for their superb timing precision, although glitches can interrupt the regular timing behavior when the stars are young. These glitches are thought to be caused by interactions between normal and superfluid matter in the crust of the star. However, glitching pulsars such as Vela have been shown to require a superfluid reservoir that greatly exceeds that available in the crust. We examine a model in which glitches tap the superfluid in the core. We test a variety of theoretical superfluid models against the most recent glitch data and find that only one model can successfully explain up to 45 years of observational data. We develop a new technique for combining radio and x-ray data to measure pulsar masses, thereby demonstrating how current and future telescopes can probe fundamental physics such as superfluidity near nuclear saturation. PMID- 26601294 TI - Dielectric capacitors with three-dimensional nanoscale interdigital electrodes for energy storage. AB - Dielectric capacitors are promising candidates for high-performance energy storage systems due to their high power density and increasing energy density. However, the traditional approach strategies to enhance the performance of dielectric capacitors cannot simultaneously achieve large capacitance and high breakdown voltage. We demonstrate that such limitations can be overcome by using a completely new three-dimensional (3D) nanoarchitectural electrode design. First, we fabricate a unique nanoporous anodic aluminum oxide (AAO) membrane with two sets of interdigitated and isolated straight nanopores opening toward opposite planar surfaces. By depositing carbon nanotubes in both sets of pores inside the AAO membrane, the new dielectric capacitor with 3D nanoscale interdigital electrodes is simply realized. In our new capacitors, the large specific surface area of AAO can provide large capacitance, whereas uniform pore walls and hemispheric barrier layers can enhance breakdown voltage. As a result, a high energy density of 2 Wh/kg, which is close to the value of a supercapacitor, can be achieved, showing promising potential in high-density electrical energy storage for various applications. PMID- 26601295 TI - Memristive phase switching in two-dimensional 1T-TaS2 crystals. AB - Scaling down materials to an atomic-layer level produces rich physical and chemical properties as exemplified in various two-dimensional (2D) crystals including graphene, transition metal dichalcogenides, and black phosphorus. This is caused by the dramatic modification of electronic band structures. In such reduced dimensions, the electron correlation effects are also expected to be significantly changed from bulk systems. However, there are few attempts to realize novel phenomena in correlated 2D crystals. We report memristive phase switching in nano-thick crystals of 1T-type tantalum disulfide (1T-TaS2), a first order phase transition system. The ordering kinetics of the phase transition were found to become extremely slow as the thickness is reduced, resulting in an emergence of metastable states. Furthermore, we realized unprecedented memristive switching to multistep nonvolatile states by applying an in-plane electric field. The reduction of thickness is essential to achieve such nonvolatile electrical switching behavior. The thinning-induced slow kinetics possibly make the various metastable states robust and consequently realize the nonvolatile memory operation. The present result indicates that a 2D crystal with correlated electrons is a novel nano-system to explore and functionalize multiple metastable states that are inaccessible in its bulk form. PMID- 26601296 TI - Hierarchical wrinkling in a confined permeable biogel. AB - Confined thin surfaces may wrinkle as a result of the growth of excess material. Elasticity or gravity usually sets the wavelength. We explore new selection mechanisms based on hydrodynamics. First, inspired by yoghurt-making processes, we use caseins (a family of milk proteins) as pH-responsive building blocks and the acidulent glucono-delta-lactone to design a porous biogel film immersed in a confined buoyancy-matched viscous medium. Under specific boundary conditions yet without any external stimulus, the biogel film spontaneously wrinkles in cascade. Second, using a combination of titration, rheology, light microscopy, and confocal microscopy, we demonstrate that, during continuous acidification, the gel first shrinks and then swells, inducing wrinkling. Third, taking into account both Darcy flow through the gel and Poiseuille flow in the surrounding solvent, we develop a model that correctly predicts the wrinkling wavelength. Our results should be universal for acid-induced protein gels because they are based on pH induced charge stabilization/destabilization and therefore could set a benchmark to gain fundamental insights into wrinkled biological tissues, to texture food, or to design surfaces for optical purposes. PMID- 26601297 TI - Wafer-scale growth of large arrays of perovskite microplate crystals for functional electronics and optoelectronics. AB - Methylammonium lead iodide perovskite has attracted intensive interest for its diverse optoelectronic applications. However, most studies to date have been limited to bulk thin films that are difficult to implement for integrated device arrays because of their incompatibility with typical lithography processes. We report the first patterned growth of regular arrays of perovskite microplate crystals for functional electronics and optoelectronics. We show that large arrays of lead iodide microplates can be grown from an aqueous solution through a seeded growth process and can be further intercalated with methylammonium iodide to produce perovskite crystals. Structural and optical characterizations demonstrate that the resulting materials display excellent crystalline quality and optical properties. We further show that perovskite crystals can be selectively grown on prepatterned electrode arrays to create independently addressable photodetector arrays and functional field effect transistors. The ability to grow perovskite microplates and to precisely place them at specific locations offers a new material platform for the fundamental investigation of the electronic and optical properties of perovskite materials and opens a pathway for integrated electronic and optoelectronic systems. PMID- 26601298 TI - Kinetics of small molecule interactions with membrane proteins in single cells measured with mechanical amplification. AB - Measuring small molecule interactions with membrane proteins in single cells is critical for understanding many cellular processes and for screening drugs. However, developing such a capability has been a difficult challenge. We show that molecular interactions with membrane proteins induce a mechanical deformation in the cellular membrane, and real-time monitoring of the deformation with subnanometer resolution allows quantitative analysis of small molecule membrane protein interaction kinetics in single cells. This new strategy provides mechanical amplification of small binding signals, making it possible to detect small molecule interactions with membrane proteins. This capability, together with spatial resolution, also allows the study of the heterogeneous nature of cells by analyzing the interaction kinetics variability between different cells and between different regions of a single cell. PMID- 26601299 TI - Optogenetic pacing in Drosophila melanogaster. AB - Electrical stimulation is currently the gold standard for cardiac pacing. However, it is invasive and nonspecific for cardiac tissues. We recently developed a noninvasive cardiac pacing technique using optogenetic tools, which are widely used in neuroscience. Optogenetic pacing of the heart provides high spatial and temporal precisions, is specific for cardiac tissues, avoids artifacts associated with electrical stimulation, and therefore promises to be a powerful tool in basic cardiac research. We demonstrated optogenetic control of heart rhythm in a well-established model organism, Drosophila melanogaster. We developed transgenic flies expressing a light-gated cation channel, channelrhodopsin-2 (ChR2), specifically in their hearts and demonstrated successful optogenetic pacing of ChR2-expressing Drosophila at different developmental stages, including the larva, pupa, and adult stages. A high-speed and ultrahigh-resolution optical coherence microscopy imaging system that is capable of providing images at a rate of 130 frames/s with axial and transverse resolutions of 1.5 and 3.9 MUm, respectively, was used to noninvasively monitor Drosophila cardiac function and its response to pacing stimulation. The development of a noninvasive integrated optical pacing and imaging system provides a novel platform for performing research studies in developmental cardiology. PMID- 26601300 TI - Persistent optical gating of a topological insulator. AB - The spin-polarized surface states of topological insulators (TIs) are attractive for applications in spintronics and quantum computing. A central challenge with these materials is to reliably tune the chemical potential of their electrons with respect to the Dirac point and the bulk bands. We demonstrate persistent, bidirectional optical control of the chemical potential of (Bi,Sb)2Te3 thin films grown on SrTiO3. By optically modulating a space-charge layer in the SrTiO3 substrates, we induce a persistent field effect in the TI films comparable to electrostatic gating techniques but without additional materials or processing. This enables us to optically pattern arbitrarily shaped p- and n-type regions in a TI, which we subsequently image with scanning photocurrent microscopy. The ability to optically write and erase mesoscopic electronic structures in a TI may aid in the investigation of the unique properties of the topological insulating phase. The gating effect also generalizes to other thin-film materials, suggesting that these phenomena could provide optical control of chemical potential in a wide range of ultrathin electronic systems. PMID- 26601301 TI - On the decadal scale correlation between African dust and Sahel rainfall: The role of Saharan heat low-forced winds. AB - A large body of work has shown that year-to-year variations in North African dust emission are inversely proportional to previous-year monsoon rainfall in the Sahel, implying that African dust emission is highly sensitive to vegetation changes in this narrow transitional zone. However, such a theory is not supported by field observations or modeling studies, as both suggest that interannual variability in dust is due to changes in wind speeds over the major emitting regions, which lie to the north of the Sahelian vegetated zone. We reconcile this contradiction showing that interannual variability in Sahelian rainfall and surface wind speeds over the Sahara are the result of changes in lower tropospheric air temperatures over the Saharan heat low (SHL). As the SHL warms, an anomalous tropospheric circulation develops that reduces wind speeds over the Sahara and displaces the monsoonal rainfall northward, thus simultaneously increasing Sahelian rainfall and reducing dust emission from the major dust "hotspots" in the Sahara. Our results shed light on why climate models are, to date, unable to reproduce observed historical variability in dust emission and transport from this region. PMID- 26601302 TI - Copper-catalyzed aerobic oxidative coupling: From ketone and diamine to pyrazine. AB - Copper-catalyzed aerobic oxidative C-H/N-H coupling between simple ketones and diamines was developed toward the synthesis of a variety of pyrazines. Various substituted ketones were compatible for this transformation. Preliminary mechanistic investigations indicated that radical species were involved. X-ray absorption fine structure experiments elucidated that the Cu(II) species 5 coordinated by two N atoms at a distance of 2.04 A and two O atoms at a shorter distance of 1.98 A was a reactive one for this aerobic oxidative coupling reaction. Density functional theory calculations suggested that the intramolecular coupling of cationic radicals was favorable in this transformation. PMID- 26601303 TI - Fingertip skin-inspired microstructured ferroelectric skins discriminate static/dynamic pressure and temperature stimuli. AB - In human fingertips, the fingerprint patterns and interlocked epidermal-dermal microridges play a critical role in amplifying and transferring tactile signals to various mechanoreceptors, enabling spatiotemporal perception of various static and dynamic tactile signals. Inspired by the structure and functions of the human fingertip, we fabricated fingerprint-like patterns and interlocked microstructures in ferroelectric films, which can enhance the piezoelectric, pyroelectric, and piezoresistive sensing of static and dynamic mechanothermal signals. Our flexible and microstructured ferroelectric skins can detect and discriminate between multiple spatiotemporal tactile stimuli including static and dynamic pressure, vibration, and temperature with high sensitivities. As proof-of concept demonstration, the sensors have been used for the simultaneous monitoring of pulse pressure and temperature of artery vessels, precise detection of acoustic sounds, and discrimination of various surface textures. Our microstructured ferroelectric skins may find applications in robotic skins, wearable sensors, and medical diagnostic devices. PMID- 26601304 TI - Mixing unmixables: Unexpected formation of Li-Cs alloys at low pressure. AB - Contrary to the empirical Miedema and Hume-Rothery rules and a recent theoretical prediction, we report experimental evidence on the formation of Li-Cs alloys at very low pressure (>0.1 GPa). We also succeeded in synthesizing a pure nonstoichiometric and ordered crystalline phase from an approximately equimolar mixture and resolved its structure using the maximum entropy method. The new alloy has a primitive cubic cell with the Li atom situated in the center and the Cs at the corners. This structure is stable to at least 10 GPa and has an anomalously high coefficient of thermal expansion at low pressure. Analysis of the valence charge density shows that electrons are donated from Cs to the Li "p" orbitals, resulting in a rare formal oxidation state of -1 for Li. The observation indicates the diversity in the bonding of the seeming simple group I Li element. PMID- 26601306 TI - Past and future rainfall in the Horn of Africa. AB - The recent decline in Horn of Africa rainfall during the March-May "long rains" season has fomented drought and famine, threatening food security in an already vulnerable region. Some attribute this decline to anthropogenic forcing, whereas others maintain that it is a feature of internal climate variability. We show that the rate of drying in the Horn of Africa during the 20th century is unusual in the context of the last 2000 years, is synchronous with recent global and regional warming, and therefore may have an anthropogenic component. In contrast to 20th century drying, climate models predict that the Horn of Africa will become wetter as global temperatures rise. The projected increase in rainfall mainly occurs during the September-November "short rains" season, in response to large-scale weakening of the Walker circulation. Most of the models overestimate short rains precipitation while underestimating long rains precipitation, causing the Walker circulation response to unrealistically dominate the annual mean. Our results highlight the need for accurate simulation of the seasonal cycle and an improved understanding of the dynamics of the long rains season to predict future rainfall in the Horn of Africa. PMID- 26601305 TI - Global prevalence and distribution of genes and microorganisms involved in mercury methylation. AB - Mercury (Hg) methylation produces the neurotoxic, highly bioaccumulative methylmercury (MeHg). The highly conserved nature of the recently identified Hg methylation genes hgcAB provides a foundation for broadly evaluating spatial and niche-specific patterns of microbial Hg methylation potential in nature. We queried hgcAB diversity and distribution in >3500 publicly available microbial metagenomes, encompassing a broad range of environments and generating a new global view of Hg methylation potential. The hgcAB genes were found in nearly all anaerobic (but not aerobic) environments, including oxygenated layers of the open ocean. Critically, hgcAB was effectively absent in ~1500 human and mammalian microbiomes, suggesting a low risk of endogenous MeHg production. New potential methylation habitats were identified, including invertebrate digestive tracts, thawing permafrost soils, coastal "dead zones," soils, sediments, and extreme environments, suggesting multiple routes for MeHg entry into food webs. Several new taxonomic groups capable of methylating Hg emerged, including lineages having no cultured representatives. Phylogenetic analysis points to an evolutionary relationship between hgcA and genes encoding corrinoid iron-sulfur proteins functioning in the ancient Wood-Ljungdahl carbon fixation pathway, suggesting that methanogenic Archaea may have been the first to perform these biotransformations. PMID- 26601307 TI - Accretion-induced variability links young stellar objects, white dwarfs, and black holes. AB - The central engines of disc-accreting stellar-mass black holes appear to be scaled down versions of the supermassive black holes that power active galactic nuclei. However, if the physics of accretion is universal, it should also be possible to extend this scaling to other types of accreting systems, irrespective of accretor mass, size, or type. We examine new observations, obtained with Kepler/K2 and ULTRACAM, regarding accreting white dwarfs and young stellar objects. Every object in the sample displays the same linear correlation between the brightness of the source and its amplitude of variability (rms-flux relation) and obeys the same quantitative scaling relation as stellar-mass black holes and active galactic nuclei. We also show that the most important parameter in this scaling relation is the physical size of the accreting object. This establishes the universality of accretion physics from proto-stars still in the star-forming process to the supermassive black holes at the centers of galaxies. PMID- 26601308 TI - Nearly free electrons in a 5d delafossite oxide metal. AB - Understanding the role of electron correlations in strong spin-orbit transition metal oxides is key to the realization of numerous exotic phases including spin orbit-assisted Mott insulators, correlated topological solids, and prospective new high-temperature superconductors. To date, most attention has been focused on the 5d iridium-based oxides. We instead consider the Pt-based delafossite oxide PtCoO2. Our transport measurements, performed on single-crystal samples etched to well-defined geometries using focused ion beam techniques, yield a room temperature resistivity of only 2.1 microhm.cm (MUOmega-cm), establishing PtCoO2 as the most conductive oxide known. From angle-resolved photoemission and density functional theory, we show that the underlying Fermi surface is a single cylinder of nearly hexagonal cross-section, with very weak dispersion along k z . Despite being predominantly composed of d-orbital character, the conduction band is remarkably steep, with an average effective mass of only 1.14m e. Moreover, the sharp spectral features observed in photoemission remain well defined with little additional broadening for more than 500 meV below E F, pointing to suppressed electron-electron scattering. Together, our findings establish PtCoO2 as a model nearly-free-electron system in a 5d delafossite transition-metal oxide. PMID- 26601309 TI - Epidermal devices for noninvasive, precise, and continuous mapping of macrovascular and microvascular blood flow. AB - Continuous monitoring of variations in blood flow is vital in assessing the status of microvascular and macrovascular beds for a wide range of clinical and research scenarios. Although a variety of techniques exist, most require complete immobilization of the subject, thereby limiting their utility to hospital or clinical settings. Those that can be rendered in wearable formats suffer from limited accuracy, motion artifacts, and other shortcomings that follow from an inability to achieve intimate, noninvasive mechanical linkage of sensors with the surface of the skin. We introduce an ultrathin, soft, skin-conforming sensor technology that offers advanced capabilities in continuous and precise blood flow mapping. Systematic work establishes a set of experimental procedures and theoretical models for quantitative measurements and guidelines in design and operation. Experimental studies on human subjects, including validation with measurements performed using state-of-the-art clinical techniques, demonstrate sensitive and accurate assessment of both macrovascular and microvascular flow under a range of physiological conditions. Refined operational modes eliminate long-term drifts and reduce power consumption, thereby providing steps toward the use of this technology for continuous monitoring during daily activities. PMID- 26601310 TI - A surface code quantum computer in silicon. AB - The exceptionally long quantum coherence times of phosphorus donor nuclear spin qubits in silicon, coupled with the proven scalability of silicon-based nano electronics, make them attractive candidates for large-scale quantum computing. However, the high threshold of topological quantum error correction can only be captured in a two-dimensional array of qubits operating synchronously and in parallel-posing formidable fabrication and control challenges. We present an architecture that addresses these problems through a novel shared-control paradigm that is particularly suited to the natural uniformity of the phosphorus donor nuclear spin qubit states and electronic confinement. The architecture comprises a two-dimensional lattice of donor qubits sandwiched between two vertically separated control layers forming a mutually perpendicular crisscross gate array. Shared-control lines facilitate loading/unloading of single electrons to specific donors, thereby activating multiple qubits in parallel across the array on which the required operations for surface code quantum error correction are carried out by global spin control. The complexities of independent qubit control, wave function engineering, and ad hoc quantum interconnects are explicitly avoided. With many of the basic elements of fabrication and control based on demonstrated techniques and with simulated quantum operation below the surface code error threshold, the architecture represents a new pathway for large scale quantum information processing in silicon and potentially in other qubit systems where uniformity can be exploited. PMID- 26601311 TI - Spectrometer-free vibrational imaging by retrieving stimulated Raman signal from highly scattered photons. AB - In vivo vibrational spectroscopic imaging is inhibited by relatively slow spectral acquisition on the second scale and low photon collection efficiency for a highly scattering system. Recently developed multiplex coherent anti-Stokes Raman scattering and stimulated Raman scattering techniques have improved the spectral acquisition time down to microsecond scale. These methods using a spectrometer setting are not suitable for turbid systems in which nearly all photons are scattered. We demonstrate vibrational imaging by spatial frequency multiplexing of incident photons and single photodiode detection of a stimulated Raman spectrum within 60 MUs. Compared to the spectrometer setting, our method improved the photon collection efficiency by two orders of magnitude for highly scattering specimens. We demonstrated in vivo imaging of vitamin E distribution on mouse skin and in situ imaging of human breast cancerous tissues. The reported work opens new opportunities for spectroscopic imaging in a surgical room and for development of deep-tissue Raman spectroscopy toward molecular level diagnosis. PMID- 26601312 TI - Three-dimensional printing of complex biological structures by freeform reversible embedding of suspended hydrogels. AB - We demonstrate the additive manufacturing of complex three-dimensional (3D) biological structures using soft protein and polysaccharide hydrogels that are challenging or impossible to create using traditional fabrication approaches. These structures are built by embedding the printed hydrogel within a secondary hydrogel that serves as a temporary, thermoreversible, and biocompatible support. This process, termed freeform reversible embedding of suspended hydrogels, enables 3D printing of hydrated materials with an elastic modulus <500 kPa including alginate, collagen, and fibrin. Computer-aided design models of 3D optical, computed tomography, and magnetic resonance imaging data were 3D printed at a resolution of ~200 MUm and at low cost by leveraging open-source hardware and software tools. Proof-of-concept structures based on femurs, branched coronary arteries, trabeculated embryonic hearts, and human brains were mechanically robust and recreated complex 3D internal and external anatomical architectures. PMID- 26601313 TI - Gold(III)-CO and gold(III)-CO2 complexes and their role in the water-gas shift reaction. AB - The water-gas shift (WGS) reaction is an important process for the generation of hydrogen. Heterogeneous gold catalysts exhibit good WGS activity, but the nature of the active site, the oxidation state, and competing reaction mechanisms are very much matters of debate. Homogeneous gold WGS systems that could shed light on the mechanism are conspicuous by their absence: gold(I)-CO is inactive and gold(III)-CO complexes were unknown. We report the synthesis of the first example of an isolable CO complex of Au(III). Its reactivity demonstrates fundamental differences between the CO adducts of the neighboring d (8) ions Pt(II) and Au(III): whereas Pt(II)-CO is stable to moisture, Au(III)-CO compounds are extremely susceptible to nucleophilic attack and show WGS reactivity at low temperature. The key to understanding these dramatic differences is the donation/back-donation ratio of the M-CO bond: gold-CO shows substantially less back-bonding than Pt-CO, irrespective of closely similar nu(CO) frequencies. Key WGS intermediates include the gold-CO2 complex [(C^N^C)Au]2(MU-CO2), which reductively eliminates CO2. The species identified here are in accord with Au(III) as active species and a carboxylate WGS mechanism. PMID- 26601314 TI - pNaKtide inhibits Na/K-ATPase reactive oxygen species amplification and attenuates adipogenesis. AB - Obesity has become a worldwide epidemic and is a major risk factor for metabolic syndrome. Oxidative stress is known to play a role in the generation and maintenance of an obesity phenotype in both isolated adipocytes and intact animals. Because we had identified that the Na/K-ATPase can amplify oxidant signaling, we speculated that a peptide designed to inhibit this pathway, pNaKtide, might ameliorate an obesity phenotype. To test this hypothesis, we first performed studies in isolated murine preadipocytes (3T3L1 cells) and found that pNaKtide attenuated oxidant stress and lipid accumulation in a dose dependent manner. Complementary experiments in C57Bl6 mice fed a high-fat diet corroborated our in vitro observations. Administration of pNaKtide in these mice reduced body weight gain, restored systemic redox and inflammatory milieu, and, crucially, improved insulin sensitivity. Thus, we propose that inhibition of Na/K ATPase amplification of oxidative stress may ultimately be a novel way to combat obesity, insulin resistance, and metabolic syndrome. PMID- 26601315 TI - Equilibrium shape of (4)He crystal under zero gravity below 200 mK. AB - Equilibrium crystal shape is the lowest energy crystal shape that is hardly realized in ordinary crystals because of their slow relaxation. (4)He quantum crystals in a superfluid have been expected as unique exceptions that grow extremely fast at very low temperatures. However, on the ground, gravity considerably deforms the crystals and conceals the equilibrium crystal shape, and thus, gravity-free environment is needed to observe the equilibrium shape of (4)He. We report the relaxation processes of macroscopic (4)He crystals in a superfluid below 200 mK under zero gravity using a parabolic flight of a jet plane. When gravity was removed from a gravity-flattened (4)He crystal, the crystal rapidly transformed into a shape with flat surfaces. Although the relaxation processes were highly dependent on the initial condition, the crystals relaxed to a nearly homothetic shape in the end, indicating that they were truly in an equilibrium shape minimizing the interfacial free energy. Thanks to the equilibrium shape, we were able to determine the Wulff's origin and the size of the c-facet together with the vicinal surface profile next to the c-facet. The c facet size was extremely small in the quantum crystals, and the facet-like flat surfaces were found to be the vicinal surfaces. At the same time, the interfacial free energy of the a-facet and s-facet was also obtained. PMID- 26601316 TI - A quantum annealing architecture with all-to-all connectivity from local interactions. AB - Quantum annealers are physical devices that aim at solving NP-complete optimization problems by exploiting quantum mechanics. The basic principle of quantum annealing is to encode the optimization problem in Ising interactions between quantum bits (qubits). A fundamental challenge in building a fully programmable quantum annealer is the competing requirements of full controllable all-to-all connectivity and the quasi-locality of the interactions between physical qubits. We present a scalable architecture with full connectivity, which can be implemented with local interactions only. The input of the optimization problem is encoded in local fields acting on an extended set of physical qubits. The output is-in the spirit of topological quantum memories-redundantly encoded in the physical qubits, resulting in an intrinsic fault tolerance. Our model can be understood as a lattice gauge theory, where long-range interactions are mediated by gauge constraints. The architecture can be realized on various platforms with local controllability, including superconducting qubits, NV centers, quantum dots, and atomic systems. PMID- 26601317 TI - Lunar impact basins revealed by Gravity Recovery and Interior Laboratory measurements. AB - Observations from the Gravity Recovery and Interior Laboratory (GRAIL) mission indicate a marked change in the gravitational signature of lunar impact structures at the morphological transition, with increasing diameter, from complex craters to peak-ring basins. At crater diameters larger than ~200 km, a central positive Bouguer anomaly is seen within the innermost peak ring, and an annular negative Bouguer anomaly extends outward from this ring to the outer topographic rim crest. These observations demonstrate that basin-forming impacts remove crustal materials from within the peak ring and thicken the crust between the peak ring and the outer rim crest. A correlation between the diameter of the central Bouguer gravity high and the outer topographic ring diameter for well preserved basins enables the identification and characterization of basins for which topographic signatures have been obscured by superposed cratering and volcanism. The GRAIL inventory of lunar basins improves upon earlier lists that differed in their totals by more than a factor of 2. The size-frequency distributions of basins on the nearside and farside hemispheres of the Moon differ substantially; the nearside hosts more basins larger than 350 km in diameter, whereas the farside has more smaller basins. Hemispherical differences in target properties, including temperature and porosity, are likely to have contributed to these different distributions. Better understanding of the factors that control basin size will help to constrain models of the original impactor population. PMID- 26601318 TI - Carbyne with finite length: The one-dimensional sp carbon. AB - Carbyne is the one-dimensional allotrope of carbon composed of sp-hybridized carbon atoms. Definitive evidence for carbyne has remained elusive despite its synthesis and preparation in the laboratory. Given the remarkable technological breakthroughs offered by other allotropes of carbon, including diamond, graphite, fullerenes, carbon nanotubes, and graphene, interest in carbyne and its unusual potential properties remains intense. We report the first synthesis of carbyne with finite length, which is clearly composed of alternating single bonds and triple bonds, using a novel process involving laser ablation in liquid. Spectroscopic analyses confirm that the product is the structure of sp hybridization with alternating carbon-carbon single bonds and triple bonds and capped by hydrogen. We observe purple-blue fluorescence emissions from the gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital of carbyne. Condensed-phase carbyne crystals have a hexagonal lattice and resemble the white crystalline powder produced by drying a carbyne solution. We also establish that the combination of gold and alcohol is crucial to carbyne formation because carbon-hydrogen bonds can be cleaved with the help of gold catalysts under the favorable thermodynamic environment provided by laser ablation in liquid and because the unique configuration of two carbon atoms in an alcohol molecule matches the elementary entity of carbyne. This laboratory synthesis of carbyne will enable the exploration of its properties and applications. PMID- 26601319 TI - Ethyl alcohol and sugar in comet C/2014 Q2 (Lovejoy). AB - The presence of numerous complex organic molecules (COMs; defined as those containing six or more atoms) around protostars shows that star formation is accompanied by an increase of molecular complexity. These COMs may be part of the material from which planetesimals and, ultimately, planets formed. Comets represent some of the oldest and most primitive material in the solar system, including ices, and are thus our best window into the volatile composition of the solar protoplanetary disk. Molecules identified to be present in cometary ices include water, simple hydrocarbons, oxygen, sulfur, and nitrogen-bearing species, as well as a few COMs, such as ethylene glycol and glycine. We report the detection of 21 molecules in comet C/2014 Q2 (Lovejoy), including the first identification of ethyl alcohol (ethanol, C2H5OH) and the simplest monosaccharide sugar glycolaldehyde (CH2OHCHO) in a comet. The abundances of ethanol and glycolaldehyde, respectively 5 and 0.8% relative to methanol (0.12 and 0.02% relative to water), are somewhat higher than the values measured in solar-type protostars. Overall, the high abundance of COMs in cometary ices supports the formation through grain-surface reactions in the solar system protoplanetary disk. PMID- 26601320 TI - Pharmacologic inhibition of JAK-STAT signaling promotes hair growth. AB - Several forms of hair loss in humans are characterized by the inability of hair follicles to enter the growth phase (anagen) of the hair cycle after being arrested in the resting phase (telogen). Current pharmacologic therapies have been largely unsuccessful in targeting pathways that can be selectively modulated to induce entry into anagen. We show that topical treatment of mouse and human skin with small-molecule inhibitors of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway results in rapid onset of anagen and subsequent hair growth. We show that JAK inhibition regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae. Our findings open new avenues for exploration of JAK-STAT inhibition for promotion of hair growth and highlight the role of this pathway in regulating the activation of hair follicle stem cells. PMID- 26601321 TI - Native proteins trap high-energy transit conformations. AB - During protein folding and as part of some conformational changes that regulate protein function, the polypeptide chain must traverse high-energy barriers that separate the commonly adopted low-energy conformations. How distortions in peptide geometry allow these barrier-crossing transitions is a fundamental open question. One such important transition involves the movement of a non-glycine residue between the left side of the Ramachandran plot (that is, phi < 0 degrees ) and the right side (that is, phi > 0 degrees ). We report that high-energy conformations with phi ~ 0 degrees , normally expected to occur only as fleeting transition states, are stably trapped in certain highly resolved native protein structures and that an analysis of these residues provides a detailed, experimentally derived map of the bond angle distortions taking place along the transition path. This unanticipated information lays to rest any uncertainty about whether such transitions are possible and how they occur, and in doing so lays a firm foundation for theoretical studies to better understand the transitions between basins that have been little studied but are integrally involved in protein folding and function. Also, the context of one such residue shows that even a designed highly stable protein can harbor substantial unfavorable interactions. PMID- 26601322 TI - Remote-controlled mice. PMID- 26601323 TI - Pollution of recreational beaches of Vlora Bay (Albania) assessed by microbiological tests. AB - A total of 5 sampling points along Vlora Bay beaches (Radhime, Plazhi i Ri, Akademia e Marines, Plazhi i Vjeter, Kabinat, Narte) were selected and monitored during the period of January 2014 to August 2014. Seawater samples were evaluated for faecal coliforms (FC) and faecal streptococci (FS). Akademia e Marines beach had the highest incidence of faecal indicators (FC and FS), 100% of samples respectively, followed by Plazhi i Ri (27.3% and 45.5%), mainly during summer. Whereas, Plazhi i Vjeter, Kabinat, Radhima and Narta beaches were in compliance with the Guidelines. High concentration of faecal indicators, at some of these beaches, especially during summer, emphasizes the necessity of periodical monitoring of these areas in order to prevent a health risk for bathers. PMID- 26601324 TI - Hydrophobic properties of Candida spp. under the influence of selected essential oils. AB - Processes of colonization of biotic and abiotic surfaces and biofilm formation depend inter alia on hydrophobic properties of Candida spp. The aim of this research was to determine the effect of tea tree, thyme and clove essential oils on hydrophobic properties of environmental and clinical Candida isolates. The relative cell surface hydrophobicity of strains tested was high, and ranged from 68.7% to 91.2%, with the highest value for a C. rugosa food-borne strain. The effectiveness of essential oils was diversified and depended on the type of essential oil, concentration and yeast strain. Statistically significant decrease of hydrophobicity indexes was observed after application of tea tree oil for C. krusei, clove oil for C. albicans reference strain, and all essential oils tested for C. rugosa. Only in the case of C. famata food-borne strain and C. albicans clinical isolate, solely used essential oils did not affect their hydrophobic properties. To determine the interactions of essential oils, their mixtures (1 MIC:1 MIC, 1 MIC:2 MIC and 2 MIC:1 MIC) were applied. Generally, essential oils used in combinations influenced yeast's hydrophobic properties much more than applied separately. The essential oils' mixtures reduced hydrophobicity of Candida yeasts in the range of 8.2 to 45.1%, depending on combination and strain. The interaction indexes of essential oils used in combinations predominantly indicate their additive effect. The application of tea tree, thyme and clove essential oils, especially in combinations, decreases hydrophobicity of the tested Candida isolates with implications of a probable advantageous limitation of their ability to colonize the food production industry environment. PMID- 26601325 TI - Health-promoting properties exhibited by Lactobacillus helveticus strains. AB - Many strains belonging to lactobacilli exert a variety of beneficial health effects in humans and some of the bacteria are regarded as probiotic microorganisms. Adherence and capabilities of colonization by Lactobacillus strains of the intestinal tract is a prerequisite for probiotic strains to exhibit desired functional properties. The analysis conducted here aimed at screening strains of Lactobacillus helveticus possessing a health-promoting potential. The molecular analysis performed, revealed the presence of a slpA gene encoding the surface S-layer protein SlpA (contributing to the immunostimulatory activity of L. helveticus M 92 probiotic strain) in all B734, DSM, T80, and T105 strains. The product of gene amplification was also identified in a Bifidobacterium animalis ssp. lactis BB12 probiotic strain. SDS-PAGE of a surface protein extract demonstrated the presence of a protein with a mass of about 50 kDa in all strains, which refers to the mass of the S-layer proteins. These results are confirmed by observations carried with transmission electron microscopy, where a clearly visible S-layer was registered in all the strains analyzed. The in vitro study results obtained indicate that the strongest adhesion capacity to epithelial cells (HT-29) was demonstrated by L. helveticus B734, while coaggregation with pathogens was highly diverse among the tested strains. The percentage degree of coaggregation was increasing with the incubation time. After 5 h of incubation, the strongest ability to coaggregate with Escherichia coli was expressed by T104. The T80 strain demonstrated a significant ability to co-aggregate with Staphylococcus aureus, while DSM with Bacillus subtilis. For B734, the highest values of co-aggregation coefficient was noted in samples with Salmonella. The capability of autoaggregation, antibiotic susceptibility, resistance to increasing salt concentrations, and strain survival in simulated small intestinal juice were also analyzed. PMID- 26601327 TI - Notice of Retraction. PMID- 26601326 TI - A quick Chan-Lam C-N and C-S cross coupling at room temperature in the presence of square pyramidal [Cu(DMAP)4I]I as a catalyst. AB - A rapid and efficient protocol for C-N and C-S cross coupling has been developed using a new square pyramidal copper complex, [Cu(DMAP)4I]I. The complex was successfully synthesized via a disproportionation reaction of CuI and DMAP in DMSO. The catalytic activity of the complex was found to be excellent for Chan Lam coupling reaction between aryl boronic acid and amine, amide, azide or thiol. The reaction could be carried out in the presence of only 2 mol% of the copper catalyst in methanol at room temperature within a short time. PMID- 26601328 TI - Findings of research misconduct. PMID- 26601329 TI - Findings of research misconduct. PMID- 26601330 TI - Osseous Resection Revisited: A Conservative Approach for Periodontal Therapy? PMID- 26601331 TI - Aromatic hydrocarbon degradation by Sphingomonas yanoikuyae B1. AB - Sphingomonas yanoikuyae B1 is able to grow on a wide variety of aromatic compounds including biphenyl, naphthalene,phenanthrene, toluene, m-, and p xylene. In addition, the initial enzymes for degradation of biphenyl have the ability to metabolize a wide variety of different polycyclic aromatic hydrocarbons. The catabolic pathways for the degradation of both the monocyclic and polycyclic aromatic hydrocarbons are intertwined, joining together at the level of (methyl)benzoate and catechol. Both upper branches of the catabolic pathways are induced when S. yanoikuyae B1 is grown on either class of compound. An analysis of the genes involved in the degradation of these aromatic compounds reveals that at least six operons are involved. The genes are not arranged in discrete pathway units but are combined in groups with genes for the degradation of both classes of compounds in the same operon.Genes for multiple dioxygenases are present perhaps explaining the ability of S. yanoikuyae B1 to grow on a wide variety of aromatic compounds. PMID- 26601332 TI - From the Editors. PMID- 26601333 TI - Implant Dentistry: Innovations, Improvements Creating an Ever-Advancing Landscape. PMID- 26601334 TI - "Painless Dentistry": Helping Patients Overcome Fear of the Dentist. PMID- 26601336 TI - Sir John and Lady Rita Cornforth: a distinguished chemical partnership. AB - This review describes the life of Sir John Cornforth AC CBE FRS, who was awarded the Nobel Prize for Chemistry in 1975. It covers his early life in Australia, his work in Oxford, the National Institute for Medical Research, the Milstead Laboratory of Chemical Enzymology and the University of Sussex, together with the contributions made by his wife, Lady Rita Cornforth. PMID- 26601337 TI - Sir John Cornforth AC CBE FRS: his synthetic work. AB - Sir John Cornforth work on the synthesis of cholesterolandpenicillamine, on the chemistry of oxazoles, the stereochemistry of the synthesis of alkenes, the synthesis of abscisic acid and of dibenzophospholes as mimics of enzyme action, is reviewed. PMID- 26601338 TI - Sir John Cornforth AC CBE FRS: his biosynthetic work. AB - Sir John Cornforth's work on the stereochemistry of enzyme reactions involved in the biosynthesis of squalene and cholesterol and in the formation and metabolism of a chiral methyl group in acetyl co-enzyme A, is reviewed. PMID- 26601339 TI - Applications of synthetic gene networks. AB - Synthetic gene networks have evolved from simple proof-of-concept circuits to complex therapy-oriented networks over the past 15 years. This advancement has greatly facilitated the expansion of the emerging field of synthetic biology. In this review, we highlight the main applications ofsynthetic gene networks in understanding biological design principles, developing biosensors for diagnosis, producing industrial and biomedical compounds, and treating human diseases. Finally, we outline current challenges and future prospects of synthetic gene networks for advancing practical applications. PMID- 26601341 TI - Principles and prospects of high-energy magnesium-ion batteries. AB - In the last decade or so, lithium batteries have gained important niche positions in the market for electrochemical storage systems. Their energy capacities per unit weight (or volume) are remarkably better than those of traditional batteries -yet they appear to be approaching their practical limit, and alternative cell systems are under active investigation. The potential advantages of replacing lithium by magnesium have long been recognised, but for years it was thought that materials limitations and technical problems would prevent them from being realised. However, a combination of commercial pressures and recent scientific breakthroughs has made it likely that magnesium batteries will soon be available for a wide range of applications; they are expected to be cheaper and safer than those based on lithium, with comparable performance. This article briefly reviews the current situation and looks at the general background, principles and cell components, outlining some of the technical problems and discussing some promising materials for magnesium-ion batteries. PMID- 26601340 TI - Between pathways and networks lies context: implications for precision medicine. AB - Precision medicine, broadly defined as considering individual variability in genes, environment, and lifestyle for each person in disease prevention and selection of suitable medical intervention, shows strong promise in the treatment of cancer Selecting therapies is complicated by multiple routes to gene dysregulation, which manifest in the individual patient within the many different types of genomic measurements. Additionally, multiple mutations exist in patients, aphenomenon known as oncogenic collaboration, which further complicates the selection of therapy. In this article, we discuss current approaches using biological pathways and networks to unify the many types of OMICs data. We argue that a contextual approach combining cancer pathways and networks could lead to a proper understanding of the biology of this significant disease. PMID- 26601343 TI - Muon tomography: looking inside dangerous places. PMID- 26601342 TI - Alexander Williamson and the modernisation of Japan. AB - One hundred and fifty years ago, five students were smuggled out of feudal Japan and came to London to learn Western technology, governance, and economics. They were put into the care of Alexander Williamson, who was Professor of Chemistry at University College London, and when they went back they, and the students who followed them, became the founders of the modern Japanese state. This is the British side of that remarkable story. Williamson's career and chemistry are briefly reviewed, followed by an account of the students' presence in Britain, and then the commemoration of the sesquicentenary of these events. PMID- 26601344 TI - THE HISTORY OF ADRENALIN. 1915. PMID- 26601345 TI - SOME EUGENIC ASPECTS OF WAR. 1915. PMID- 26601347 TI - [The Research of Spectral Dimension Reduction Method Based on Human Visual Characteristics]. AB - The traditional spectral dimension reduction methods are usually carried out by matching the reconstructed spectra to the original spectra mathematically, which will often result in reconstructed spectra of small spectral reconstruction errors but very poor colorimetric accuracy when compared with the original one. In order to minimize both the spectral and colorimetric errors more efficiently, we proposed three spectral dimension reduction methods by introducing the characteristics of human vision. The first method is VPCA, in which we apply spectral luminous efficiency function to the original spectra before reduction; The Second method (LMSPCA) uses a matrix derived from LMS cone sensitivity to weight the original spectra before reduction, and the matrix can be form by two methods, in which the L, M, S cones response offset is calculated by in two different ways: one is computed as the absolute value of each corresponding wave length offset, and the other is calculated as the square of each corresponding wave length offset. The third method is LMSPCAs, which is based on the second method LMSPCA by further applying PCA to the residual spectra. The result shows that the VPCA method produces the poorest perfomance. The two cones response weighted matrixes of LMSPCA method have similar performances by presenting better colorimetric accuracy and low spectral accuracy, while LMSPCAs method which compensates for the spectral loss of LMSPCA method can produce higher spectral and colorimetric reconstruction accuracy and color stability under different light source, and satisfies the requirements of spectral color reproduction. PMID- 26601348 TI - [Research of Identify Spatial Object Using Spectrum Analysis Technique]. AB - The high precision scattering spectrum of spatial fragment with the minimum brightness of 4.2 and the resolution of 0.5 nm has been observed using spectrum detection technology on the ground. The obvious differences for different types of objects are obtained by the normalizing and discrete rate analysis of the spectral data. Each of normalized multi-frame scattering spectral line shape for rocket debris is identical. However, that is different for lapsed satellites. The discrete rate of the single frame spectrum of normalized space debris for rocket debris ranges from 0.978% to 3.067%, and the difference of oscillation and average value is small. The discrete rate for lapsed satellites ranges from 3.118 4% to 19.472 7%, and the difference of oscillation and average value relatively large. The reason is that the composition of rocket debris is single, while that of the lapsed satellites is complex. Therefore, the spectrum detection technology on the ground can be used to the classification of the spatial fragment. PMID- 26601349 TI - [Simulation Study of Dynamic Color Modulation Based on Tunable Micro/Nano Structure Array]. AB - With the development of nanotechnology, it has been accessible to display colors by artificial micro/nano-structure, and then the study of structure coloring has become a hot subject, opening a new space for inkless printing. In this paper, a dynamic color modulation method based on tunable micro/nano-structure array is proposed. To tune colors on the same device, a periodic micro/nano-structure array is designed with functional material inside, which could alter the height difference between up and bottom surface precisely by applying an external voltage. It is modeled, and simulated by the Finite Difference Time Domain (FDTD) method in this work. In simulations, perpendicular incident linearly polarized light source is applied, and parameters of surface height difference and period are swept. Series reflective spectra of the devices are obtained, and their corresponding colors are calculated and marked on the CIE 1931 chromaticity diagram. Simulation results demonstrate that when the period is in the range of 100-300 nm, full-color modulation could be realized by varying the height of functional material film via applied voltage, and the peak intensities of reflective spectra are at about 60%, having high energy efficiency. This method is innovative and provides a theoretical basis for the dynamic color modulation micro/nano device, which is quite promising in fields like inkless printing and display technology. PMID- 26601350 TI - Evolution Characteristics of Electromagnetic Power Radiated in Lightning Discharge Processes. AB - Combining the spectra of could-to-ground lightning discharge processes obtained by a slit-less spectrograph with synchronous electric field information, the temperature, the conductivity, the current peak, electromagnetic power peak and the luminance of the discharge channel are calculated. The values are in a normal range reported by references. The correlation among cut-off time before a subsequent return stroke, the luminance and electromagnetic power peak of the channel is discussed. The change trends of the conductivity, the current peak and electromagnetic power peak are also investigated. The results show when cut-off time is long, neutralized charges will grow, the current will rise and electromagnetic power radiated from the channel will increase. When the conductivity and the peak of the electric field change increase simultaneously, the current in the channel will rise and electromagnetic power radiated from the channel will be greater. This work will provide some references for calculating optical and electromagnetic energy radiated by lightning discharge processes. PMID- 26601351 TI - [An Improved DDV Method to Retrieve AOT for HJ CCD Image in Typical Mountainous Areas]. AB - Domestic HJ CCD imaging applications in environment and disaster monitoring and prediction has great potential. But, HJ CCD image lack of Mid-Nir band can not directly retrieve Aerosol Optical Thickness (AOT) by the traditional Dark Dense Vegetation (DDV) method, and the mountain AOT changes in space-time dramatically affected by the mountain environment, which reduces the accuracy of atmospheric correction. Based on wide distribution of mountainous dark dense forest, the red band histogram threshold method was introduced to identify the mountainous DDV pixels. Subsequently, the AOT of DDV pixels were retrieved by lookup table constructed by 6S radiative transfer model with assumption of constant ratio between surface reflectance in red and blue bands, and then were interpolated to whole image. MODIS aerosol product and the retrieved AOT by the proposed algorithm had very good consistency in spatial distribution, and HJ CCD image was more suitable for the remote sensing monitoring of aerosol in mountain areas, which had higher spatial resolution. Their fitting curve of scatterplot was y = 0.828 6x-0.01 and R2 was 0.984 3 respectively. Which indicate the improved DDV method can effectively retrieve AOT, and its precision can satisfy the atmospheric correction and terrain radiation correction for Hj CCD image in mountainous areas. The improvement of traditional DDV method can effectively solve the insufficient information problem of the HJ CCD image which have only visible light and near infrared band, when solving radiative transfer equation. Meanwhile, the improved method fully considered the influence of mountainous terrain environment. It lays a solid foundation for the HJ CCD image atmospheric correction in the mountainous areas, and offers the possibility for its automated processing. In addition, the red band histogram threshold method was better than NDVI method to identify mountain DDV pixels. And, the lookup table and ratio between surface reflectance between red and blue bands were the important influence factor for AOT retrieval. These will be the important research directions to further improve algorithm and improve the retrieve accuracy. PMID- 26601352 TI - [Monitoring Water in Lubricating Oil with Min-Infrared LED]. AB - A method that could be used to quantify the water concentration in ship machinery lubricating oil based on Mid-infrared LED is discussed. A Mid-infrared LED with peak emission wavelength of 2 840 nm and FWHM of 400 nm is used as the light source, the emitting light is partly absorbed by the oil sample, the remaining is received by the infrared detector. The percentage of water is determined according to the absorbance. In the experiment, a optical configuration including the transmission, absorbing and receiving of infrared light is designed, calcium fluoride wafer is used as the window, a hard metal coil with circular section is selected as the washer to get the fixed thickness of oil film accurately, a photoelectric diode with detection wavelength of 2 500-4 800 nm and response time of 10-20 ns is used as the detector of light intensity. Matching with this, a system of signal preamplifier, microcontroller-based data acquisition, storage and communication is developed. Absorbance data of six oil samples with different water mass concentration: 0, 0.062 5%, 0.125%, 0.25%, 0.375% and 0.5% is acquired through experiment. Fitting the data by the method of least squares, a linear equation in terms of absorbance and water concentration is obtained, and the determination coefficient is 0.996. Finally, in order to test the accuracy of this measurement method, using oil sample with water concentration of 0.317 5% to validate the equation, measuring the absorbance by the experimental device, the water content is calculated through the linear equation, the results show that the relative error is 2.7% between the percentage calculated and the real sample, indicating that this method can accurately measure the water concentration in the oil. PMID- 26601353 TI - [Study on A White-Eye Pattern in Dielectric Barrier Discharge by Optical Emission Spectrum]. AB - The white-eye pattern was firstly observed and investigated in a dielectric barrier discharge system in the mixture of argon and air whose content can be varied whenever necessary, and the study shows that the white-eye cell is an interleaving of three different hexagonal sub-structures: the center spot, the halo, and the ambient spots. The white-eye pattern is observed at a lower applied voltage. In this experiment, the heat capacity of water is high so that the water in water electrode is good at absorbing heat. In the process of pattern discharging the gas gap didn't increase its temperature, and the discharging phenomenon of this pattern has not changed. The temperature of the water electrodes almost keeps unchanged during the whole experiment, which is advantageous for the long-term stable measurement. Pictures recorded by ordinary camera with long exposure time in the same argon content condition show that the center spot, the halo, and the ambient spots og the white-eye pattern have different brightness, which may prove that their plasma states are different. And, it is worth noting that there are obvious differences of brightness not only on the center spot, the halo, and the ambient spots at the same pressure but also at the different pressure, which shows that its plasma state also changed with the variation of the pressure. Given this, in this experiment plasma temperatures of the central spot, halo, and ambient spots in a white-eye pattern at different gas pressure were studied by using optical emission spectra. The molecular vibration temperature is investigated by the emission spectra of nitrogen band of second positive system ( C3Piu --> B3Pig ). The electron excitation temperature is researched by the relative intensity ratio method of spectral lines of Ar I 763. 51 nm (2P6 --> 1S5) and Ar I 772. 42 nm (2P2 --> 1S3). The electronic density is investigated by the broadening of spectral line 696.5 nm. Through the analysis of experimental results, it is found that the molecular vibration temperature, electron excitation temperature and electronic density of the central spot are lowest, and the plasma parameters of the ambient spots are second, while the plasma parameters of the halo are highest at the same condition. The molecular vibration temperature and the electron excitation temperature of the three different parts of the pattern (central spot, halo, and ambient spots) decrease with the pressure increasing from 40 to 60 kPa, but the electronic density increases. These results are of great important to the formation mechanism of the patterns in dielectric barrier discharge. PMID- 26601354 TI - [The Research of Oxygen Measurement by TDLAS Based on Levenberg-Marquardt Nonlinear Fitting]. AB - Oxygen concentration is an important monitoring parameter in industrial process. Wavelength modulation spectroscopy of tunable diode laser absorption spectroscopy (TDLAS) was used to measure concentration of oxygen gas in industrial process by online monitoring. In this paper, we use the characteristic absorption peak of Oxygen at 760 nm to measure the oxygen concentration. Because of the strong coherence of laser, the detection sensitivity of TDLAS is severely restricted by optical interference noise. Especially at low concentrations, there is larger error by extraction signal in the absorption peak waveform because of the background fluctuation caused by optical interference. In response to this situation, Levenberg-Marquardt nonlinear fitting algorithm was proposed, and the use of the absorption line-derivative form of Lorenz line to fit the second harmonic signal and to extract the peak amplitude. On the other hand, Levenberg Marquardt nonlinear fitting method needs a large amount of calculation. In order to develop the TDLAS analyzer can achieve real-time monitoring of the site, we use the C28 series of DSQ for data processing which support floating-point arithmetic, and the instrument achieve real-time monitoring capabilities in industrial process. Experimental results show that the algorithm can effectively extract the absorption peak characteristic value of the 2nd harmonic signal and overcome the background noise, The ratio of calculated by algorithm to actual oxygen concentration is nearly 1.01, the linear error of the concentration measurement is 1.18%. PMID- 26601355 TI - Radiation Parameters of Some Potential Bioactive Compounds. AB - In this study, we aimed to determine the radiation parameters of some potential bioactive compounds. 1-Aryl-3-dibenzylamino-propane-1-on hydrochloride type Mannich bases were synthesized via classical conventional heating method. Aryl part was changed as phenyl (C6H5), 4-methylphenyl (4-CH3C6H4), 4-fluorophenyl ( 4 FC6H4), 4-nitrophenyl (4-NO2C6H4), 4-chlorophenyl (4-ClC6H4), 4-bromophenyl (4 BrC6H4), and 2-thienyl (C4H3S-2-yl). Mass attenuation coefficient (MUm), effective atomic number (Z(eff)) and effective electron density (N(el)) of compounds were determined experimentally and theoretically for at 8.040, 8.910, 13.40, 14.96, 17.48, 19.61, 22.16, 24.94, 32.19, 36.38, 44.48, 50.38 and 59.54 keV photon energies by using an HPGe detector with a resolution of 182 eV at 5.9 keV. Radiation parameters of these compounds which can be anti-cancer drug candidate were given in the tables. The results show that phenyl ring behave like thiophene ring in terms of radiation absorption. It is thought that the results of study may drive allow the development of drug candidate new compounds in medical oncology. PMID- 26601356 TI - Natural Bond Orbital (NBO) Population Analysis, First Order Hyperpolarizabilities and Thermodynamic Properties of Cyclohexanone. AB - The molecular structure of cyclohexanone was calculated by the B3LYP density functional model with 6-31G(d, p) and 6-311++G(d,p) basis set by Gaussian program. The results from natural bond orbital (NBO) analysis have been analyzed in terms of the hybridization of atoms and the electronic structure of the title molecule. The electron density based local reactivity descriptors such as Fukui functions were calculated. The dipole moment (MU) and polarizability (a), anisotropy polarizability (Deltaalpha) and first order hyperpolarizability (beta(tot)) of the molecule have been reported. Thermodynamic properties of the title compound were calculated at different temperatures. PMID- 26601357 TI - [Applications of On-Line Near Infrared Spectroscopy Monitoring Technology in Polymer Processing]. AB - Due to the significant impact of processing on the performance of polymer products, it is crucial to develop in-line monitoring methods on processing. Based on the feedback data from in-line monitoring the processing parameters can be adjusted, which will contribute to the stability of production, thereby ensuring product quality, reducing energy waste and improving production efficiency. Near infrared spectroscopy (NIR), a low-cost, real-time and accurately quantitative analysis technology, has been widely used in many areas but still under study in polymer processing. The applications of in-line NIR monitoring technology in measuring the content of component, melt index, melt density and dispersion of filler of polymer during processing were reviewed. The existing problems about in-line NIR monitoring technology were pointed out, as well as the suggestions for the corresponding problems. The future trends of in line NIR monitoring technology were discussed. With the development of fiber optic spectrometer, computer science and chemometrics, it is foreseen that the in line NIR monitoring technology will make considerable progress in the stability of raw data, methods of pretreatment and modeling, the robustness and accuracy of model. Therefore, in-line NIR monitoring technology will be applied to more areas generating the great economic and environmental value. PMID- 26601358 TI - [Study on the Technology of the 4.4 MUm Mid-Infrared Laser Heterodyne Spectrum]. AB - In this paper, first time as our knowledge, we describe the development and performance evaluation of a 4.4 MUm external cavity quantum cascade laser based laser heterodyne radiometer. Laser heterodyne spectroscopy is a high sensitive laser spectroscopy technique which offers the potential to develop a compact ground or satellite based radiometer for Earth observation and astronomy. An external cavity quantum cascade laser operating at 4. 4 MUm, with output power up to 180 mW and narrow line width was used as a local oscillation. The external cavity quantum cascade laser offers wide spectral tuning range, it is tunable from 4.38 to 4.52 MUm with model hop free and can be used for simultaneous detections of CO2, CO and N2 O. A blackbody was used as a signal radiation source. Development and fundamental theory of Laser heterodyne spectroscopy was described. The performance of the developed Laser heterodyne radiometer was evaluated by measuring of CO2 spectral at different pressures. Analyses results showed that a signal-to-noise ratio of 86 was achieved which was less than the theoretical value of 287. The spectral resolution of the developed Laser heterodyne spectroscopy is about 0.007 8 cm(-1) which could meet the requirement of high resolution spectroscopy measurement in the case of Doppler linewidth. The experiment showed that middle Infrared laser heterodyne spectroscopy system had high signal-to-noise ratio and spectral resolution, and had broad application prospect in high precision measurement of atmospheric greenhouse gas concentration and vertical profile. PMID- 26601359 TI - [Attenuated Total Reflection Infrared Spectroscopy for Degradation Profile of High Density Polyethylene after Weathering Aging]. AB - High density polyethylene (HDPE) was widely used as rotational packaging case in the material reserve field. The chemical changes of HDPE, exposed to particular climatic conditions of tropic marine atmosphere for one year-long in Wanning Hainan, were elucidated by the attenuated total reflection infrared spectroscopy (ATR-FTIR). The structural changes were studied qualitatively, mainly from the polymeric chain breaking, branching and oxidation to distinguish the degradation profile. The variations of crystallinity & carbonyl index were also studied quantitatively according to the characteristic peaks intensity & area ratio. Finally, the relationships between structural changes and mechanical properties were investigated. The results showed that the polymeric chain breaking & branching play a leading role before 3 months in the aging progress. Then oxidation phenomena gradually takes place during 3-6 months. The chain branching & oxidation were predominant factors after 6 months. Nine months later, the oxidation was saturated gradually. Furthermore, the aging process is positively correlated to the temperature and irradiation. After 12 months aging, the carbonyl index increased by 112 times and crystallinity was 10% higher than before. The tensile/bending modulus deceased faster than tensile/bending strength of HDPE. The linear degree of tensile modulus and carbonyl index was 0.97. The degree of linearity of tensile strength and crystallinity calculated by feature bands (720-730 cm(-1)) was 0.96. It showed that the mechanical properties of HDPE can be speculated from the structural changes by ATR-FTIR. PMID- 26601360 TI - [The Study of Infrared Spectra of Acetophenone Molecule]. AB - By implying the density functional theory method, the geometry of acetophenone molecular is fully optimized at the B3LYP/6-311++G(d, p) level and the frequency is also calculated at the same level. The infrared spectrum and complete vibrational modes of acetophenone molecular are attained. Meanwhile, the infrared spectrum is obtained by experimental measurements. Through the comparison and analysis, it is found that the theoretical calculation results meet well with those of experiments. Finally, the vibrational modes of acetophenone molecule are assigned, and the strong vibration peaks in the experiment results belong to infrared characteristic peaks of acetophenone molecule. PMID- 26601361 TI - [Research on Analysis of Oil in Water Based on the Joint Optimization of Savitzky Golay Smoothing and IBPLS Models]. AB - Rapidly and accurately detection of the type and content of mineral oil in water pollution has important significance for the timely screening and control of pollution sources. The use of infrared spectral analysisi technology to detect mineral oil has advantanges of efficient, fast and pollution-free. Infrared spectrum technology is very for the detection of mineral oil in the water. In order to obtain a more reliable results, Fourier transforms attenuated total reflection infrared spectrometry (FITR-ATR) technology is used to get the spectral information of the mineral oil sample, and SPXY method is used to divide the sample set. The paper not only analyzed partial least squares (PLS) and iterative Bagging partial least squares (IBPLS) the two different methods to build regression model, also compared the difference of using the method of the combination of Savitzky-Golay (SG) smoothing and the method of a single iterative Bagging partial least squares (IBPLS) regression model. Based on the comparison of the predictive regression curve, we can get that the SG smooth has a better reflection on the results. And when the method of the combination of Savitzky Golay (SG) smoothing and the method of a single iterative Bagging partial least squares (IBPLS) is used to build the regression model, the gasoline model parameters RMSEP is 0.001 125 g x mL(-1), R is 0.992 5; diesel model parameters RMSEP is 0.001 384 g x mL(-1), R is 0.989 3. PMID- 26601362 TI - [Study on the Micro-FTIR Spectra of the Euhedral Faceted Polycrystalline Diamonds (EFPCDs) from Western Yangtze Craton and Its Geological Significance]. AB - The results of Micro-FTIR spectra analysis of the euhedral faceted polycrystalline diamonds (EFPCDs) from the Western Yangtze Craton show that the EFPCDs are mostly IaAB type, the concentration of nitrogen.varies greatly from 25. 70- 358.35 MUg x g(-1). Different nitrogen content distributes in different diamond grains or position in same sample. The C Center was not found in the samples and the conversion from A center to B center is incomplete, in the meanwhile, B% value concentrated in 40%. Thus, polycrystalline diamonds are not formed in the stage of nucleation but gathered together after formation of the individual diamond grains during the residence time in the mantle. And its formation environment is. more complex than the euhedral faceted polycrystalline diamonds from Mengyin kimberlite, the Eastern of North China Craton. The diamonds extremely possibly originated in the deep mantle from 160 to 180 km, reaching the depth of the core of the Yangtze Craton, at the same time it is close to the bottom of the lithosphere. The C-H bond of sp2 hybridization are conducive to the formation of platelets in diamonds. Meanwhile, its concentrations are generally higher than the C-H bond of sp3 hybridization in the samples. PMID- 26601363 TI - [Qualitative-Quantitative Analysis of Rice Bran Oil Adulteration Based on Laser Near Infrared Spectroscopy]. AB - The purpose of this study is mainly to have qualitative-quantitative analysis on the adulteration in rice bran oil by near-infrared spectroscopy analytical technology combined with chemo metrics methods. The author configured 189 adulterated oil samples according to the different mass ratios by selecting rice bran oil as base oil and choosing soybean oil, corn oil, colza oil, and waste oil of catering industry as adulterated oil. Then, the spectral data of samples was collected by using near-infrared spectrometer, and it was pre-processed through the following methods, including without processing, Multiplicative Scatter Correction(MSC), Orthogonal Signal Correction(OSC), Standard Normal Variate and Standard Normal Variate transformation DeTrending(SNV_DT). Furthermore, this article extracted characteristic wavelengths of the spectral datum from the pre processed date by Successive Projections Algorithm(SPA), established qualitatively classified calibration methods of adulterated oil through classification method of Support Vector Machine(SVM), optimized model parameters(C, g) by Mesh Search Algorithm and determined the optimal process condition. In extracting characteristic wavelengths of the spectral datum from pretreatment by Backward interval Partial Least Squares(BiPLS) and SPA, quantitatively classified calibration models of adulterated oil through Partial Least Squares(PLS) and Support Vector Machine Regression(SVR) was established respectively. In the end, the author optimized the combination of model parameters(C, g) by Mesh Search Algorithm and determined the optimal parameter model. According to the analysis, the accuracy of prediction set and calibration set for SVC model reached 95% and 100% respectively. Compared with the prediction of the adulteration oil content of rice bran oil which was established by the PLS model, the SVR model is the better one, although both of them could implement the content prediction. Furthermore, the correlation coefficient R is above 0.99 and the Root Mean Square Error (MSE) is below 5.55 x 10(-4). The results show that the near-infrared spectroscopy technology is effective in qualitative quantitative analysis on the adulteration of rice bran oil. And the method is applicable to analyze adulteration in other oils. PMID- 26601364 TI - [Quantification of Wood Flour and Polypropylene in Chinese Fir/Polypropylene Composites by FTIR]. AB - The ratio of wood and plastic in Wood Plastic Composites (WPCss) influences quality and price, but traditional thermochemical methods cannot rapidly and accurately quantify the ratio of wood/PP in WPCss. This paper was addressed to investigate the feasibility of quantifying the wood flour content and plastic content in WPCss by Fourier Transform Infrared (FTIR) spectroscopy. With Chinese fir, polypropylene (PP) and other additives as raw materials, 13 WPCs samples with different wood flour contents, ranging from 9.8% to 61.5%, were prepared by modifying wood flour, mixing materials and extrusion pelletizing. The samples were analyzed by FTIR with the KBr pellets technique. The absorption peaks of WPCss at 1059, 1 033 and 1 740 cm(-1) are considered as characteristic of Chinese fir, and the absorption peaks at 1 377, 2 839 and 841 cm(-1) are typical of PP by comparing the spectra of WPCss with that of Chinese fir, PP and other additives. The relationship between the wood flour content, PP content in WPCss and their characteristic IR peaks height ratio was established. The results show that there is a strong linear correlation between the wood flour content in WPCss and I1 059/l 1 377/I1 033, /I1377, R2 are 0.992 and 0.993 respectively; there is a high linear correlation between the PP content in WPCss and I1 377/I1 740, I2 839 /I1 740 R2 are 0.985 and 0.981, respectively. Quantitative methods of the wood flour content and PP content in WPCss by FTIR were developed, the predictive equations of the wood flour content in WPCss are y = 53.297x-9. 107 and y = 55.922x-10.238, the predictive equations of the PP content in WPCss are y = 6.828 5x+5.403 6 and y = 8.719 7x+3.295 8. The results of the accuracy test and precision test show that the method has strong repeatability and high accuracy. The average prediction relative deviations of the wood flour content and PP content in WPCss are about 5%. The prediction accuracy has been improved remarkably, compared to thermochemical methods. More importantly, FTIR is more easy-handing. This experiment may provide a simple, rapid and accurate method for quantification of wood flour and PP in Chinese fir/PP composites. PMID- 26601365 TI - [Traceability of Wine Varieties Using Near Infrared Spectroscopy Combined with Cyclic Voltammetry]. AB - To achieve the traceability of wine varieties, a method was proposed to fuse Near infrared (NIR) spectra and cyclic voltammograms (CV) which contain different information using D-S evidence theory. NIR spectra and CV curves of three different varieties of wines (cabernet sauvignon, merlot, cabernet gernischt) which come from seven different geographical origins were collected separately. The discriminant models were built using PLS-DA method. Based on this, D-S evidence theory was then applied to achieve the integration of the two kinds of discrimination results. After integrated by D-S evidence theory, the accuracy rate of cross-validation is 95.69% and validation set is 94.12% for wine variety identification. When only considering the wine that come from Yantai, the accuracy rate of cross-validation is 99.46% and validation set is 100%. All the traceability models after fusion achieved better results on classification than individual method. These results suggest that the proposed method combining electrochemical information with spectral information using the D-S evidence combination formula is benefit to the improvement of model discrimination effect, and is a promising tool for discriminating different kinds of wines. PMID- 26601366 TI - [The SERS Detection of Sudan I by Using AAO as Template to Prepare the Substrate]. AB - The large-scale controllable, ordered two-dimensional arrays of gold nanostructure with hot-spot were prepared together with chemical molecules were modified on the surface to concentrate Sudan I within the zone of the SERS effect, which lead to analytical detection of Sudan I in high resolution. The vapor of gold was deposed on anodic aluminum oxide(AAO) template by -200 nm thickness to replicate its nanochannels, and the negative structure i. e. large scale ordered gold nano-hemisphere array, was obtained after the removal of the template of AAO by NaOH solution. Au nano-hemisphere array was modified by 1 Dodecanethiol which can be self-assembled monolayer on the surface and concentrate Sudan I within the zone of the SERS detection, which can facilitate the measurement of Sudan I. Due to the order and regularity of Au nano-hemisphere array, the signal of Sudan I in the range of laser illumination is stable and uniform, and the quantitative analysis of Sudan I was realized. The SERS intensity of Sudan I is logistic proportional to the concentration in the range of 10(-7) to 5 x 10(-4) mol x L(-1). The corresponding correlation coefficient of the liner equation is 0.99, the recoveries of Sudan I are between 77% - 117%. The limit of detection for Sudan I is 4 x 10(-1) mol x L(-1), comparable to that of HPLC of Chinese national standard method. PMID- 26601367 TI - [DFT and Raman Scattering Studies of Benzimidazole]. AB - The Raman spectra of carbendazim, thiabendazole and benomyl were collected by laser Raman spectrometer. The molecules of the three pesticides were optimized and calculated by B3LYP hybrid functional and 6-31G(d, p) basis set. The results showed that the calculated value anastomosed preferably to measure value. Vibrational modes of pesticide molecules were assigned between 200 and 1 600 cm( 1) range, and found three characteristic peaks of benzimidazole about at 1 015, 1 265 and 1 595 cm(-1). The comparative analysis on the differences of normal Raman spectra, found different characteristic peaks in three pesticide molecules. The results can provide theoretical for analysis Raman spectra of benzimidazole pesticide. This work will promote the research of benzimidazole pesticide residue in food and agricultural products based on Raman spectra. PMID- 26601368 TI - [SERS Enhancement Factor Analysis and Experiment of Carbon Nanotube Arrays Coated by Ag Nanoparticles]. AB - To intuitive and accurate quantitatively analyze Raman enhancement of surface enhanced Raman scattering substrate structure, three-dimensional composite structure of silver nanoparticles modified vertically aligned carbon nanotube array is produced by magnetron sputtering and thermal annealing process; Relevant experiments using Rhodamine 6G (R6G) solution as the molecular probes are conducted to analyze surface enhanced Raman enhancement factor (EF), combining with confocal Raman microscopy systems. The result of scanning electron microscopy (SEM) shows that a large number of silver nanoparticles are attached onto the tips and sidewalls of the ordered carbon nanotubes array uniformly. EF of the sample which was produced 30 min annealing time and 450 degrees C annealing temperature evaluates to 2.2 x 10(3), and the reasons for the low EF are analyzed: on the one hand, thickness of silver film sputtered on vertically aligned carbon nanotube array is non-uniform, leading to distribution of silver nanoparticles is uneven after annealing, so that the value of sample roughness is too large, EF value is low; on the other hand, the excitation light source is not the advantage wavelength of silver nanoparticles in the experiments. PMID- 26601369 TI - [Quantitative Analysis of Dimethoate Pesticide Residues in Honey by Surface Enhanced Raman Spectroscopy]. AB - The feasibility of a combination method of surface-enhanced Raman spectroscopy (SERS) technology and linear regression algorithm was investigated for rapid quantitative analysis of pesticide residues in honey. The total of 30 samples was applied in the experiment with dimethoate pesticide residues range from 1 ppm to 10 ppm. The samples were divided into calibration set (20) and prediction set (10). The substrate of Klarite with an inverted pyramidal structure was adopted for improvement of the relative intensity of the majority of Raman shift peaks. The comparative analysis was carried out between SERS spectra of dimethoate pesticide residues in honey samples and conventional Raman spectra of dimethoate standard sample. And four characteristic Raman shift peaks at the wavenumbers of 867, 1 065, 1 317 and 1 453 cm(-1) were found, which were related with the vibrational information of dimethoate molecule. The relationship was developed by linear regression algorithm between the intensity of Raman shift and the concentration of dimethoate pesticide residues. The 10 new samples in the prediction set were applied to evaluate the performance of the models. By comparison, the optimal model was obtained with the characteristic Raman shift peak of 867 cm(-1). The higher correlation coefficient of prediction of 0.984 and lower root mean square error of prediction of 0.663 ppm were obtained. The detection limit of this method was 2 ppm, which was close to the maximum levels of pesticide residue detection limits. Experimental results showed that it was feasible to rapidly analyze quantitative of pesticide residues in honey with the combination method of SERS technology and linear regression algorithm. Compared with the conventional method coupled with the suitable pretreatment, the combination method of SERS technology and linear regression method could analyze the dimethoate pesticide residues in honey, and it also provided an optional method for rapid quantitative analysis pesticide residues in other agricultural products. PMID- 26601370 TI - [Determination of Gasoline Composition Based on Raman Spectroscopy]. AB - For the purpose of the rapid prediction of every composition in gasoline, the Raman spectra of the gasoline brand 93 and 97, a batch of one-one mixtures with aromatic, olefin, ben, methanol and ethanol with different ratios are measured, 410 mixture samples were measured totally in this research. The obtained Raman spectra were preprocessed by a series of processing, they were data smoothing, baseline deduction and spectral normalized, etc. After that 33 characteristic peaks were extracted to be the eigenvalues for the whole Raman spectra. According to the current national standard test method, the values of every composition were measured by the gas chromatography. By using the eigenvalues as inputs, and actual contents of aromatic, olefin, ben, methanol and ethanol got from gas chromatography as outputs, two mathematical models of multi-output least squares support vector regression and partial least squares combination with multiple regression analysis were established to predict the values of the above compositions of a sample, respectively. The predicting results were compared with the values calculated from the gas chromatography measurement results and the mixture proportions, the multi-output least squares support vector regression has a better effects, and the obtained root mean square error of prediction for aromatic, olefin, ben, methanol and ethanol are 0.27%, 0.27%, 0.22%, 0.17%, 0.14%; the correlation coefficients are 0.999 3, 0.998 5, 0.998 6, 0.992 3, 0.993 5, respectively. This model is also applied to the detection of the unknown sample, the root mean square error of the prediction for the results does not exceed 0.5%, which can achieve the measurement requirements in the industry. Results show that the Raman spectra analysis technology based on multi-output least squares support vector regression can be a precise, fast and convenient new method for gasoline composition detection, and can be applied to the quality control of the gasoline production process, transportation, storage of the gasoline. PMID- 26601371 TI - [Characterization of Time-Resolved Laser-Induced Fluorescence from Crude Oil Samples]. AB - To evaluate the feasibility of laser induced time-resolved fluorescence technique for in-situ detection of underwater suspended oil spill, extensive investigations have been carried out with different densities of crude oil samples from six different wells of Shengli Oilfield in this work. It was found that the fluorescence emission durations of these crude oil samples were almost the same, the Gate Pulse Delay of DDG (Digital Delay Generator) in the ICCD started at 52ns and ended at 82ns with a width (FWHM) of 10 ns. It appears that the peak location and lifetime of fluorescence for different crude oil samples varied with their densities, and those with similar densities shared a similar lifespan with the closer peak locations of fluorescence. It is also observed that the peak of fluorescence remained the same location before reaching the maximum intensity, subsequently shift to longer wavelength as fluorescence attenuated from maximum intensity with a red shift among 17-30 nm varied with samples. This demonstrated that the decay rate of fluorescent components in the crude oils was different, and energy transfer between these components might exist. It is hoped that those obtained results and characteristics could be the useful information for identification of suspended spilled-oil underwater. PMID- 26601373 TI - [Laser Induced Fluorescence Spectroscopic Analysis of Aromatics from One Ring to Four Rings]. AB - In order to distinguish small aromatics preferably, a Nd : YAG Laser was used to supply an excitation laser, which was adjusted to 0.085 J x cm(-2) at 266 nm. Benzene, toluene, naphthalene, phenanthrene, anthracene, pyrene and chrysene were used as the representative of different rings aromatics. The fluorescence emission spectra were researched for each aromatic hydrocarbon and mixtures by Laser induced fluorescence (LIF). Results showed that the rings number determined the fluorescence emission spectra, and the structure with same rings number did not affect the emission fluorescence spectrum ranges. This was due to the fact that the absorption efficiency difference at 266 nm resulted in that the fluorescence intensities of each aromatic hydrocarbon with same rings number were different and the fluorescence intensities difference were more apparently with aromatic ring number increasing. When the absorption efficiency was similar at 266 nm and the concentrations of each aromatic hydrocarbon were same, the fluorescence intensities were increased with aromatic ring number increasing. With aromatic ring number increasing, the fluorescence spectrum and emission peak wavelength were all red-shifted from ultraviolet to visible and the fluorescence spectrum range was also wider as the absorption efficiency was similar. The fluorescence emission spectra from one to four rings could be discriminated in the following wavelengths, 275 to 320 nm, 320 to 375 nm, 375 to 425 nm, 425 to 556 nm, respectively. It can be used for distinguish the type of the polycyclic aromatic hydrocarbons (PAHs) as it exists in single type. As PAHs are usually exist in a variety of different rings number at the same time, the results for each aromatic hydrocarbon may not apply to the aromatic hydrocarbon mixtures. For the aromatic hydrocarbon mixtures, results showed that the one- or two-ring PAHs in mixtures could not be detected by fluorescence as three- or four-ring PAHs existed in mixture. This was caused by radiation energy transfer mechanism, in which the ultraviolet light was lost in mixtures but the fluorescence intensities were increased with the one- or two-ring PAHs adding. When the mixture only contained three- and four-ring PAHs, the fluorescence emission spectrum showed the both characteristics of three- and four-ring PAHs fluorescence. When three- and four-ring PAHs existed in mixtures at the same time, the fluorescence emission spectra were related to each concentration, so the rings number could be discriminated to a certain extent. PMID- 26601372 TI - [Spectral Analysis of Dissolved Organic Matter of Tannery Wastewater in the Treatment Process]. AB - Tannery industry is one of the major traditional industries and important wastewater sources in China. The existing research mainly focus on the quality of inlet and outlet water, rather than the purification and transformation behavior of dissolved organic matter (DOM) in the treatment process of tannery wastewater. The UV spectra and fluorescence spectroscopy were used to detect the spectral characteristics of water samples in the treatment process, and it is analyzed that the formation process and the linear relationships between total fluorescence intensity and parameters. The results showed: the UV absorbance of DOM in wastewater increased firstly and then decreased with longer wavelength, and the wave peaks were found around the wavelength of 230 nr. The values of A253 /A203 and SUVA254 increased firstly and then decreased, indicating the complex reaction process related to free substituent and aromatic rings. The fluorescence peaks appeared at the regions of lambda(ex/em) = 320-350/440- 460 and lambda(ex/em) = 270-300/390-420, referred as visible humic-like and visible fulvic-like fluorescence, respectively. With the treatment process of tannery wastewater, the following fluorescence phenomenon were monitored, such as the blue-shift of humic-like fluorescence peak in the hydrolytic acidification tank, the appearance of tryptophan fluorescence peak in the second biochemical pond (lambda(ex/em) = 290/340), the weak fluorescence peak in the fourth biochemical pond (lambda(ex/em) = 350/520) and the stabilized fluorescence characteristics in the secondary sedimentation tank and water outlet. The achievements are helpful to investigate the degradation and formation behavior of water components, and significant for the fluorescence variation analysis in the treatment system. The removal rate of total fluorescence intensity of tannery wastewater fit better the removal rate of TOC with coefficient of r 0.835 5. The UV spectra and 3D-EEMs are effective to reveal the purification behavior and mechanism of tannery wastewater. PMID- 26601374 TI - [New Bipyridinium Salt: Synthesis and Application as a Fluorescence Enhancement Probe of Nitrate Ion]. AB - Anions are ubiquitously distributed not only in biological systems but also in environment. Accordingly, anion recognition and sensing have attracted increasing attention due to the important roles anion plays in biological, chemical and environmental fields. Among various anionic species, NO3- is a very important inorganic anions which has a great harm to the environment and human health. At present, methods for the determination of NO3- mainly contained electrochemical method, ion chromatography and ion selective electrode method. Although all methods have their own advantages, but also has the obvious deficiency. Such as, the reproducibility of electrochemical method is not good, and ion chromatography and ion selective electrode method usually require expensive apparatus and lengthy analytical time. As a contrast, fluorescence spectroscopy become a hot research topic in anion recognition and detection because of its high sensitivity and easy operation and other advantages in recent years. New bipyridinium salt L was designed and synthesized using pyrylium as a starting material. The molecular structure was determined by 1H NMR, 13C NMR, and high resolution mass spectrometry. The molecular recognition properties of L have been investigated through fluorescence titration experiments. The results indicate that L has sensitive and selective fluorescent response to NO3- among other different anions. Significant enhancements in the fluorescence intensity of L were observed when various concentrations of NO3- were added, while other competing anions have a quenching effect towards the initial fluorescence of solution. The fluorescence titration spectra shows that the bonding stoichiometry between receptor L and NO3 is 1 : 1 as a supramolecular complexes (1gK = 5 +/- 0.02). The chemosensing properties of L were evaluated through quantum chemical calculations and the variable temperature 1H NMR titration. These results suggested that L has strong binding affinity towards NO3- with high selectivity, which may be ascribed to the specific hydrogen bonding between the L and active H atom of the bipyrydinium salts. The interaction between L and NO3- made the complex more planar compared with L giving rise to enhanced fluorescence and specific selectivity towards NO3 . PMID- 26601375 TI - [Synthesis of YVO4 : Eu Fluorescent Nanomaterials and Their Applications in Development of Latent Fingerprints]. AB - YVO4 : Eu fluorescent nanomaterials with small size and strong fluorescent intensity were synthesized via a hydrothermal method by using polyethylenimine (PEI) as the modifier, and the reaction mechanism of this synthesis was also discussed. The as-synthesized nanomaterials were characterized through transmission electron microscopy (TEM), X-ray diffraction (XRD) measurements, Fourier transform infrared (FT-IR) spectroscopy and fluorescence spectroscopy (FS). The as-prepared fluorescent nanomaterials were well-dispersed and spherical in shape with an average diameter of about 30 nm, which were modified with a layer of PEI on surfaces. The fluorescent nanomaterials were of pure tetragonal YVO4 structure. They could emit strong red fluorescence under the 254 nm ultraviolet excitation. The YVO4 : Eu fluorescent dry powders were then used as a novel fluorescent label for the development of latent fingerprints on various smooth substrates. Furthermore, the sensitivity and the resistance to background interference in fingerprint development were investigated in detail. The results showed that, use of YVO4 : Eu fluorescent nanomaterials to develop latent fingerprints resulted in clearly defined friction ridge details of fingerprints and eliminated background interference under 254 nm ultraviolet light. Compared with the traditionally used fluorescent developing powders, our YVO4 : Eu fluorescent nanomaterials were a novel agent for latent fingerprint development with high sensitivity, high contrast, and low background interference. PMID- 26601376 TI - [Determination of the Sodium Methylparaben Content Based on Spectrum Fluorescence Spectral Technology and GA-BP Neural Network]. AB - Sodium methylparaben as one kind of preservatives is widely used in our life, but it will do harm to health if it is eaten too much. So there are strict rules on the dosage of sodium methylparaben in every country. The fluorescence spectral properties of sodium methylparaben in aqueous solution and orange juice solution are analyzed with FS920 fluorescence spectrometer. The research result shows that the fluorescence characteristic peak of sodium methylparaben solution is in lambda(ex)/lambda(em) = 380/5 10 nm, while sodium methylparaben orange juice solution has two fluorescence characteristic peaks which are in lambda(ex)/lambda(em) = 440/520 nm and 470/530 nm, and its best excitation wavelength is 440 nm. So it can be concluded from the result that there is a significant change between the characteristic peaks of sodium methylparaben in the two solution. Compared with the fluorescence characteristic peak of sodium methylparaben solution, thoses of sodium methylparaben orange juice solution are changed significantly, which are caused by the interference of orange juice fluorescence characteristics. In order to determine the content of sodium methylparaben in the fresh orange juice, a detection model of sodium methylparaben content in orange juice is built based on GA-BP neural network, according to the relationship between fluorescence intensity in lambda(ex) = 440 nm and the content of sodium methylparaben orange juice solution. When the accuracy of the mean square error in the process of network training reaches 10( 3), the correlation coefficient of network output and that of the expected is 0.996. At the same time, a better prediction result can be obtained that the average recovery of the forecast samples is 98.67% and the average relative standard deviation is 0.86%. When the concentration ranges from 0.02 to 1.0 g x L(-1), the results testify that detection method based on fluorescence spectroscopy and GA-BP neural network can accurately determine the content of sodium methylparaben in orange juice. This method has the features of novelty and simplicity and it is expected to be applied to the determination of sodium methylparaben in other kinds of drink. PMID- 26601377 TI - [The Implementation by PARAFAC Decompose Components Analysis in the Three Dimensional Fluorescence Spectroscopy Data]. AB - The paper systematically analyzes the implementation process of the parallel factor analysis (PARAFAC) method decompose matrix data. As example, The three dimensional fluorescence spectra of the water samples taken from the lake were analyzed by PARAFAC. According to the distribution of the core matrix elements, the core consistency, the degree of similarity between the model spectra and the original spectra, the physical meaning of the proposed decomposition components, the number of components was determined. Then the corresponding PARAFAC model was established. The components of the fluorescence material components dissolved in water samples can be decomposed by this PARAFAC model. PMID- 26601378 TI - [Application of SDS Micellar Solution in Fluorescence Spectral Measurement of Petroleum Pollutant]. AB - A new method of solubilizing, sensitizing and stabilizing petroleum substances by using sodium dodecyl sulfate (SDS) micellar solution as solvent was proposed. The variation relationship between fluorescence intensity of petroleum substances and SDS micellar solution concentration was studied, and the optimum concentration of SDS micelle solution as solvent was determined with 0.1 mol x L(-1). Gasoline, diesel and kerosene SDS micellar solution of different diluted concentration were measured using FLS920 fluorescence spectrometer and fluorescence excitation emission matrixes (EEMs) were obtained. After analyzing Rayleigh scattering, Raman scattering and instrument characteristics influence on measured spectrum, three-dimensional fluorescence spectra of three kinds of oil samples with excitation wavelength ranging from 250 to 400 nm and emission wavelength from 260 to 500 nm were established by spectral correction. The linear relationship between fluorescence intensity and concentration in certain concentration range was determined. By comparison with the spectra of gasoline, diesel, kerosene aqueous solution with the various concentrations under the same conditions and preparation method, the solubility and fluorescence intensity of petroleum pollutant in water was increased, and better stability was obtained. The measurement of petroleum substances without relying on some toxic solvent extraction was not only achieved, but its low solubility in water and difficult quantitative problems were solved. PMID- 26601379 TI - [Outlier Detection of Time Series Three-Dimensional Fluorescence Spectroscopy]. AB - The qualitative and quantitative analysis are often interfered by the outliers in time series three-dimensional fluorescence spectroscopy. In this work, an efficient outlier detection method is proposed by taking advantage of the characteristics in time dimension and the spectral dimension. Firstly, the wavelength points that are mostly the outliers are extracted by the variance in time dimension. Secondly, by the analysis of the existence styles of outliers and similarity score of any two samples, the cumulative similarity is introduced in spectral dimension. At last, fluorescence intensity at each wavelength of all samples is modified by the correction matrix in time dimension and the outlier detection is completed according the to cumulative similarity scores. The application of the correction matrix in time dimension not only improves the validity of the method but also reduces the computation by the choice of characteristics region in correction matrix. Numerical experiments show that the outliers can still be detected by the 50 percent of all points in spectral dimension. PMID- 26601380 TI - [Determination of Iodine and Iodate in Brine and Seafood Simultaneously by Ultraviolet Absorption Spectrometry]. AB - The iodide in samples was oxidized to iodate by bromine water, which could be removed by formic acid, and iodate could be transformed to I3- with excess of I- in phosphoric acid, the iodate in samples could be transformed directly to I3- with excess of I- in phosphoric acid. The I3- solution had strong absorption at 350 and 288 nm, and the absorbance had a linear relationship to the concentration of I3- in a certain range. Total content of iodide and iodate had been detected after samples were oxidized by bromine water and the content of iodate had been detected directly, and the content of iodide was obtained by difference of the two results. Based on this, the method had been established to detect iodide and iodate in brine and seafood simultaneously by ultraviolet absorption spectrometry. The volumes of bromine water, formic acid, phosphoric acid and potassium iodide had been optimized. The effect of illumination, temperature and time also had been discussed. The optional reagents condition for iodide was: 2 drops of 3% bromine water, 0.5 mL of 10% formic acid, 4 mL of 20% phosphoric acid and 1 mL of 100 g x L(-1 KI. The optional reagents condition for iodate was: 0. 2 mL of 20% phosphoric acid and 1 mL of 100 g x L(-1) KI. The absorbance were determined after reacting for 30 min at room temperature and natural light conditions. Under the optimized conditions, the concentration of iodide and iodate in the range of 0 - 1.2 and 0 -1.5 mg x L(-1) were well agreed with Lambert Beer law. The sample blank was detected for twelve times and the detection limit of iodide and iodate were 1.54 and 14.8 MUg x L(-1) respectively. The RSD of twelve times determination of 0.8 mg x L(-1) of iodide and iodate were 0.097% and 0.067%, respectively. The iodide and iodate in Zhabuye brine, Hong Feng underground brine, kelp, seaweed and sea cabbage had been detected, the recovery experiments also had been conducted at the same time, the recovery of iodide and iodate were between 80% - 120%. All the results met the requirement of analytical chemistry. PMID- 26601381 TI - [Study on Differential Optical Absorption Spectroscopy Data Processing Based on Chirp-Z Transformation]. AB - Differential optical absorption spectroscopy (DOAS) is a commonly used atmospheric pollution monitoring method. Denoising of monitoring spectral data will improve the inversion accuracy. Fourier transform filtering method is effectively capable of filtering out the noise in the spectral data. But the algorithm itself can introduce errors. In this paper, a chirp-z transform method is put forward. By means of the local thinning of Fourier transform spectrum, it can retain the denoising effect of Fourier transform and compensate the error of the algorithm, which will further improve the inversion accuracy. The paper study on the concentration retrieving of SO2 and NO2. The results show that simple division causes bigger error and is not very stable. Chirp-z transform is proved to be more accurate than Fourier transform. Results of the frequency spectrum analysis show that Fourier transform cannot solve the distortion and weakening problems of characteristic absorption spectrum. Chirp-z transform shows ability in fine refactoring of specific frequency spectrum. PMID- 26601382 TI - [The Research for Trace Ammonia Escape Monitoring System Based on Tunable Diode Laser Absorption Spectroscopy]. AB - In order to on-line measure the trace ammonia slip of the commercial power plant in the future, this research seeks to measure the trace ammonia by using tunable diode laser absorption spectroscopy under ambient temperature and pressure, and at different temperatures, and the measuring temperature is about 650 K in the power plant. In recent years lasers have become commercially available in the near-infrared where the transitions are much stronger, and ammonia's spectroscopy is pretty complicated and the overlapping lines are difficult to resolve. A group of ammonia transitions near 4 433.5 cm(-1) in the v2 +v3 combination band have been thoroughly selected for detecting lower concentration by analyzing its absorption characteristic and considering other absorption interference in combustion gases where H2O and CO2 mole fraction are very large. To illustrate the potential for NH3 concentration measurements, predictions for NH3, H2O and CO2 are simultaneously simulated, NH3 absorption lines near 4 433.5 cm(-1) wavelength meet weaker H2O absorption than the commercial NH3 lines, and there is almost no CO2 absorption, all the parameters are based on the HITRAN database, and an improved detection limit was obtained for interference-free NH3 monitoring, this 2.25 MUm band has line strengths several times larger than absorption lines in the 1.53 MUm band which was often used by NH3 sensors for emission monitoring and analyzing. The measurement system was developed with a new Herriott cell and a heated gas cell realizing fast absorption measurements of high resolution, and combined with direct absorption and wavelenguh modulation based on tunable diode laser absorption spectroscopy at different temperatures. The lorentzian line shape is dominant at ambient temperature and pressure, and the estimated detectivity is approximately 0.225 x 10(-6) (SNR = 1) for the directed absorption spectroscopy, assuming a noise-equivalent absorbance of 1 x 10(-4). The heated cell experiments with controlled the temperature were performed to validate the sensing strategy. Here the Wavelength Modulation Spectroscopy (WMS) strategy was usually used to measure lower gas concentration for high noise immunity to the non-absorption transmission losses. The great agreement 2f signal with the calibrated concentration is within the uncertainty at different temperatures by using simple digital signal processing such as multiple averages, wavelet analysis and so on. The denoise processing has a great advantage in application and implementation over other noise suppression techniques. The result provided a good basis for trace ammonia escape detection based on tunable diode laser absorption spectroscopy. PMID- 26601383 TI - [Research on the Tomato Metacaspase Protein Interactions with Ca2+ by Spectroscopy and Molecular Probe]. AB - Metacaspases are cysteine-dependent proteases found in protozoa, fungi and plants and are distantly related to metazoan caspases. Most of MCPs activation are the calcium dependent, but the mechanisms are still unknown. Based on the techniques of CD spectroscopy, fluorescence spectroscopy, and Terbium Stains-all probe, we selected three purified recombinant proteins from key residues mutated in tomato metacaspase (LeMCA1), including conserved catalytic site (C139A) mutant, N sequenced cleaved site (K223G) mutant and the predicted Ca2+ binding sites (D116A/D117A) mutant, to explore the interaction mechanism of LeMCA1 and Ca2+. CD spectroscopy and Stains-all probe results suggested that the intense binding does not exist between LeMCA1 and Ca2+ as well as Ca2+ has little effect on the secondary structure of LeMCA1. However, fluorescence spectroscopy and Tb3+ probe results showed that Ca(2+)-induced the changes occur in the tertiary structure of LeMCA1, which contributes to the activation of zymogen. In addition, predicted Ca2+ binding residues, Asp-116 and Asp117, are the key sites resporisible for the Ca2+ interaction with LeMCA1, and the loss of these two residues resulted in decreased interaction. Our data firstly provided insight on the mechanism of the interaction between Ca2+ and recombinant purified Solanaceae type II metacaspase by spectroscopy and molecular probe techniques. Combined the results we got before from sequence-alignment and sites-mutation, the key residues Asp-116 and Asp117 affect the Ca(2+)-induced the changes of LeMCA1 tertiary structure. Our data provided information for the further biochemical and crystal assays of LeMCA1. PMID- 26601384 TI - [Comparative Research on Estimating the Severity of Yellow Rust in Winter Wheat]. AB - In order to improve the accuracy of wheat yellow rust disease severity using remote sensing and to find the optimum inversion model of wheat diseases, the canopy reflectance and disease index (DI) of winter wheat under different severity stripe rust were acquired. The three models of PLS (Partial Least Square), BP neural network using seven hyperspectral vegetation indices which have significant relationship with the occurrence of disease and vegetation index (PRI) were adopted to build a feasible regression model for detecting the disease severity. The results showed that PLS performed much better. The inversion accuracy of PLS method is best than of the VI (PRI, Photochemical Reflectance Index) and BP neural network models. The coefficients of determination (R2) of three methods to estimate disease severity between predicted and measured values are 0.936, 0.918 and 0.767 respectively. Evaluation was made between the estimated DI and the measured DI, indicating that the model based on PLS is suitable for monitoring wheat disease. In addition, to explore the different contributions of diverse types of vegetation index to the models, the paper attempts to use NDVI, GNDVI and MSR which on behalf of vegetation greenness and NDWI and MSI that represents the moisture content to be input variables of PLS model. The results showed that, for the wheat yellow rust disease, changes in chlorophyll content is more sensitive to the disease severity than the changes in water content of the canopy. However, the accuracy of the two models are both lower than predicted when participating in all seven vegetation indices, namely using several species of vegetation indices tends to be more accurate than that using single category. It indicated that it has great potential for evaluating wheat disease severity by using hyper-spectral remote sensing. PMID- 26601385 TI - [The Study of the Spectral Model for Estimating Pigment Contents of Tobacco Leaves in Field]. AB - Fast and non-destructive measurements of tobacco leaf pigment contents by spectroscopy in situ in the field has great significance in production guidance for nutrient diagnosis and growth monitoring of tobacco in vegetative growth stage, and it is also very important for the quality evaluation of tobacco leaves in mature stage. The purpose of this study is to estimate the chlorophyll and carotenoid contents of tobacco leaves using tobacco leaf spectrum collected in the field. Reflectance spectrum of tobacco leaves in vegetative growth stage and mature stage were collected in situ in the field and the pigment contents of tobacco leaf samples were measured in this study, taking the tobacco leaf samples collected in each and both stages as modeling sets respectively, and using the methods of support vector machine (SVM) and spectral indice to establish the pigment content estimation models, and then compare the prediction performance of the models built by different methods. The study results indicated that the difference of estimation performance by each stage or mixed stages is not significant. For chlorophyll content, SVM and spectral indice modeling methods can both have a well estimation performance, while for carotenoid content, SVM modeling method has a better estimation performance than spectral indice. The coefficient of determination and the root mean square error of SVM model for estimating tobacco leaf chlorophyll content by each stage were 0.867 6 and 0.014 7, while the coefficient of determination and the root mean square error of SVM model for estimating tobacco leaf chlorophyll content by mixed stages were 0.898 6 and 0.012 3; The coefficient of determination and the root mean square error for estimating tobacco leaf carotenoid content by each stage were 0.861 4 and 0.002 5, while the coefficient of determination and the root mean square error of SVM model for estimating tobacco leaf carotenoid content by mixed stages were 0.839 9 and 0.002 5. The innovation point of this study is that on the basis of support vector machine and spectral indice, models established by each stage and mixed stages for estimating the pigment contents of tobacco leaf samples can provide scientific basis and technical support for quality control of tobacco leaf production in field and the ensurance of tobacco leaf recovery quality. PMID- 26601386 TI - [Preliminary Study on the Detection of Pork Tenderness by Three-Dimensional Diffuse Reflectance Spectroscopy]. AB - Tenderness is an important index to evaluate the pork's quality, in this paper a method called three-dimensional diffuse reflectance spectroscopy was proposed to detect pork tenderness. Because pork has a strong scattering impact on light, this method introduced more scattering information of pork samples into spectral analysis of tenderness. Using the special data acquisition system, three dimensional diffuse reflectance spectra of 64 pork samples were constructed by collecting the emergent light signals of different distances away from the light incident point. And n-way partial least squares (NPLS) regression was applied to establish the calibration model between the pork tenderness and three-dimensional diffuse reflectance spectra which were denoised by wavelet transform. The determination coefficient of model for the calibration set (R2(Cal)) is 0.883 1, and the root mean squared error of calibration (RMSEC) is 3.685 0N. The determination coefficient of model for the prediction set (R2(Pred)) is 0.874 7, and the root mean squared error of prediction (RMSEP) is 3.975 6N. The result indicates that the NPLS model of pork tenderness built by three-dimensional diffuse reflectance spectra has higher calibration accuracy and prediction stability than the traditional diffuse reflectance spectra. Three-dimensional diffuse reflectance spectroscopy can be expected to be a new method to quickly detect the tenderness and the other qualities of pork. PMID- 26601387 TI - [A Measurement Method for the Hepatic Functional Reserves Anti Oxygen Fluctuations]. AB - Hepatic functional reserves parameters are the key indictors to assess if the hepatic metabolic function is normal, they are also the important basis to a successful hepatectomy. Currently clinical hepatic functional reserves parameters are achieved through Indocyanine Green (ICG) concentration measurement in the method of pulse dye spectrophotometry, with the assumption that blood oxygen saturation is 100%, this hypothetical bias leads to an error in the calculated value of the hepatic functional reserves parameters. In order to solve this problem, hepatic functional reserves parameters measurement that resist fluctuation from blood is presented. The method is based on the modified Lambert Beer's law and realize the correction of ICG concentration measurement in the method of pulse dye spectrophotometry. While the ICG is injected into the patient's body by the cubital veins, using the data acquisition unit that developed by project team to collect 805 nm, 940 nm wavelengths of transmission signals and 730 nm, 805 nm and 890 nm wavelengths of reflected signals in the fingertip skin synchronously, and then upload 5 sets of data to the computer. Draw the ICG concentration curve according the collected data and blood oxygen saturation before injecting ICG to the human body and then calculate the characteristic parameters, according to the characteristic parameters calculate the hepatic reserves functional parameters. Taking the measurement of effective hepatic blood flow as an example, the relative error was obviously decreased when comparing this method and the pulse dye concentration method with the electromagnetic flowmeter (EMF) measurement which is the most accurate method to measure effective hepatic blood flow (EHBF) respectively. The results demonstrate that this method can improve the accuracy of hepatic reserves parameters, and it can also provide a more accurate detection method of hepatic functional reserves parameters for clinical application. PMID- 26601388 TI - Sophisticated Vegetation Classification Based on Feature Band Set Using Hyperspectral Image. AB - There are two major problems of sophisticated vegetation classification (SVC) using hyperspectral image. Classification results using only spectral information can hardly meet the application requirements with the needed vegetation type becoming more sophisticated. And applications of classification image are also limited due to salt and pepper noise. Therefore the SVC strategy based on construction and optimization of vegetation feature band set (FBS) is proposed. Besides spectral and texture features of original image, 30 spectral indices which are sensitive to biological parameters of vegetation are added into FBS in order to improve the separability between different kinds of vegetation. And to achieve the same goal a spectral-dimension optimization algorithm of FBS based on class-pair separability (CPS) is also proposed. A spatial-dimension optimization algorithm of FBS based on neighborhood pixels' spectral angle distance (NPSAD) is proposed so that detailed information can be kept during the image smoothing process. The results of SVC experiments based on airborne hyperspectral image show that the proposed method can significantly improve the accuracy of SVC so that some widespread application prospects like identification of crop species, monitoring of invasive species and precision agriculture are expectable. PMID- 26601389 TI - [Preparation and Photocatalytic Properties of Supported TiO2 Photocatalytic Material]. AB - Titanium dioxide (TiO2) supported on spherical alumina substrate was prepared by using sol-gel method combined with dip-coating process. The surface morphology and structure of the synthesized samples were characterized by scanning electron microscopy (SEM) and X-ray diffraction (XRD) pattern. The results show that the morphology of the supported TiO2 composite material was obviously different from that of the original support. It reveals a layer formed by anatase TiO2 nanoparticles of 10-20 nm was deposited on the alumina substrate. Energy dispersive X-ray spectroscopy (EDX) analyses on the spherical alumina substrate and the resulting TiO2 composite catalyst were performed to determine the TiO2 loading content in the samples. It indicates that the TiO2 loading content on alumina substrate could be effectively increased by increasing the times of dip coating alumina support in TiO2 sol. When dip-coating times increased to 5, the TiO2 loading content increased from 3.8 Wt. % to 15.7 Wt. %. In addition, the photocatalytic performances of the supported TiO2 materials prepared by different dip-coating times have been investigated by degrading methylene blue. It was found that the surface morphology of the supported TiO2 material was not only improved, but also the photocatalytic activity could be promoted significantly by increasing the dip-coating times. When the alumina substrate was dip-coated in TiO2 sol from 1 to 4 times, the degradation rate of methylene blue increased from 40% to 83.1%. However, after dip-coating the alumina support in TiO2 sol for 5 times, the degradation of methylene blue was only up to 85.6%. This indicates that the photocatalytic activity increased slowly when the TiO2 content in the supported catalyst was up to some extent. It is attributed to the continuous dip coating resulted in less opportunities and weak intensity of illumination for the TiO2 nano-particles that under lower layer. The photocatalytic activity was relatively stable after repeated use of the supported TiO2 material for 5 times. PMID- 26601390 TI - [A Composition Analysis Method of Mixed Pigments Based on Spectrum Expression and Independent Component Analysis]. AB - Reflectance spectrometry is a common method in composition analysis of mixed pigments. In this method, similarity is used to determine the type of basic pigments that constitute the mixed pigments. But its result may be inaccurate because it is easily influenced by a variety of basic pigments. In this study, a composition analysis method of mixed pigments based on spectrum expression and independent component analysis is proposed, and the composition of mixed pigments can be calculated accurately. First of all, the spectral information of mixed pigments is obtained with spectrometer, and is expressed as the discrete signal. After that, the spectral information of basic pigments is deduced with independent component analysis. Then, the types of basic pigments are determined by calculating the spectrum similarity between the basic pigments and known pigments. Finally, the ratios of basic pigments are obtained by solving the Kubelka-Munk equation system. In addition, the simulated spectrum data of Munsell color card is used to validate this method. The compositions of mixed pigments from three basic pigments are determined under the circumstance of normality and disturbance. And the compositions of mixture from several pigments within the set of eight basic pigments are deduced successfully. The curves of separated pigment spectrums are very similar to the curves of original pigment spectrums. The average similarity is 97.72%, and the maximum one can reach to 99.95%. The calculated ratios of basic pigments close to the original one. It can be seen that this method is suitable for composition analysis of mixed pigments. PMID- 26601391 TI - [Simulation of Atmospheric Nitrous Oxide Profiles Retrieval from AIRS Observations]. AB - Nitrous Oxide is a very important greenhouse gases and ozone-depleting substances. Due to the limited observations, there are still many uncertainties to quantitatively describe the role of nitrous oxide played in both cases. We can retrieve the methane and carbon dioxide gas using thermal infrared satellite data AIRS, but it is rarely for the nitrous oxide retrieval. Therefore, this paper retrieves nitrous oxide profiles from the AIRS data with an Optimal Estimate Method for the first time in China. The issue of the a priori and channels election is discussed. Comparison of the retrieved AIRS profiles with HIPPO profiles show the retrieved profiles are in good agreement with the smoothed HIPPO profiles, and a notable improvement in this algorithm than the eigen vector regression algorithm. For pressures between 300 and 900 hPa, we got the most accurate profiles and the relative error is only 0.1%, which is consistent with the jacobian peaks of the selected channels. PMID- 26601392 TI - [Experimental Methods and Result Analysis of a Variety of Spectral Reflectance Properties of the Thin Oil Film]. AB - In order to analysis the oil spill situation based on the obtained data in airborne aerial work, it's needed to get the spectral reflectance characteristics of the oil film of different oils and thickness as support and to select the appropriate operating band. An experiment is set up to measure the reflectance spectroscopy from ultraviolet to near-infrared for the film of five target samples, which means petrol, diesel, lubricating oil, kerosene and fossil, using spectral measurement device. The result is compared with the reflectance spectra of water in the same experimental environment, which shows that the spectral reflection characteristics of the oil film are related to the thickness and the type of the oil film. In case of the same thickness, the spectral reflectance curve of different types of film is far different, and for the same type of film, the spectral reflectance curve changes accordingly with the change of film thickness, therefore in terms of the single film, different film thickness can be distinguished by reflectance curves. It also shows that in terms of the same film thickness, the reflectance of diesel, kerosene, lubricants reaches peak around 380 nm wavelength, obviously different from the reflectance of water, and that the reflectance of crude oil is far less than that of water in more than 340 nm wavelength, and the obtained reflection spectrum can be used to distinguish between different types of oil film to some extent. The experiment covers main types of spilled oil, with data comprehensively covering commonly used detect spectral bands, and quantitative description of the spectral reflectance properties of film. It provides comprehensive theoretical and data support for the selection of airborne oil spill detection working band and the detection and analysis of water-surface oil spill. PMID- 26601393 TI - [A Method to Extract Content of Minerals Based on Measured Hyperspectral Data]. AB - To improve the accuracy of mineral content extraction by linear decomposition model, a method was established, which took rock spectra with wavelength from 350 to 2 500 nm as the data source, identified minerals based on spectral matching methods, applied Hapke model to transform spectral reflectance into single scattering albedo and resolved single scattering albedo to get mineral content. In this method, sectional noise filtering and regional mineral spectra library were added to improve the identifying accuracy. Based on the analysis on the fifth Baogutu rock body, compared with XRD results, accuracies of quartz, feldspar class and altered minerals identification were 75%, 100% and 92.2% separately. Accuracy of the content extraction of feldspar class, hornblende and altered minerals were 80.5%, 64%, 92.36% separately. This method added mineralogy symbiotic relationship into mineral identification to ensure the reliability, proposed the idea of sectional noise filtering to avoid the influence of filtering algorithm, applied the single scattering albedo to avoid the complex nonlinearly calculations to improve the accuracy theoretically. This method has a certain guiding significance for the work such as rapid analysis of alteration information. PMID- 26601394 TI - [Transferability of Hyperspectral Model for Estimating Soil Organic Matter Concerned with Soil Moisture]. AB - Hyperspectral remote sensing, known as the state-of-the-art technology in the field of remote sensing, can be used to retrieve physical and chemical properties of surface objects based on the interactions between electromagnetic waves and the objects. Soil organic matter (SOM) is one of the most important parameters used in the assessment of soil fertility. Quick estimation of SOM with hyperspectral remote sensing technique can provide essential soil data to support the development of precision agriculture. The presence of external parameters, however, may affect the modeling precision, and further handicap the transfer ability of existing model. With the aim to study the effects of soil moisture on the Vis/NIR estimation of soil organic matter, and the capacity of direct standardization(DS)algorithm in the calibration transfer, 95 soil samples collected in the Jianghan plain were rewetted and air-dried. Reflectance of these samples at 13 moisture levels was measured. Results show that the model calibrated using air-dried samples has the highest prediction accuracy. This model, however, was not suitable for SOM prediction of the rewetted samples. Prediction bias and RPD improved from -8.34-3.32 g x kg(-1) and 0.64-2.04 to 0 and 7.01, when DS algorithm was applied to the spectra of the rewetted samples. DS algorithm has been proven to be effective in removing the effects of soil moisture on the Vis/NIR estimation of SOM, ensuring a transferrable model for SOM prediction with soil samples at different moisture levels. PMID- 26601395 TI - [The Change Detection of High Spatial Resolution Remotely Sensed Imagery Based on OB-HMAD Algorithm and Spectral Features]. AB - The high spatial resolution remotely sensed imagery has abundant detailed information of earth surface, and the multi-temporal change detection for the high resolution remotely sensed imagery can realize the variations of geographical unit. In terms of the high spatial resolution remotely sensed imagery, the traditional remote sensing change detection algorithms have obvious defects. In this paper, learning from the object-based image analysis idea, we proposed a semi-automatic threshold selection algorithm named OB-HMAD (object based-hybrid-MAD), on the basis of object-based image analysis and multivariate alternative detection algorithm (MAD), which used the spectral features of remotely sensed imagery into the field of object-based change detection. Additionally, OB-HMAD algorithm has been compared with other the threshold segmentation algorithms by the change detection experiment. Firstly, we obtained the image object by the multi-solution segmentation algorithm. Secondly, we got the object-based difference image object using MAD and minimum noise fraction rotation (MNF) for improving the SNR of the image object. Then, the change objects or area are classified using histogram curvature analysis (HCA) method for the semi-automatic threshold selection, which determined the threshold by calculated the maximum value of curvature of the histogram, so the HCA algorithm has better automation than other threshold segmentation algorithms. Finally, the change detection results are validated using confusion matrix with the field sample data. Worldview-2 imagery of 2012 and 2013 in case study of Beijing were used to validate the proposed OB-HMAD algorithm. The experiment results indicated that OB-HMAD algorithm which integrated the multi-channel spectral information could be effectively used in multi-temporal high resolution remotely sensed imagery change detection, and it has basically solved the "salt and pepper" problem which always exists in the pixel-based change detection, and has mitigated the impact of building shadows and geometric registration error, and has improved the overall accuracy and kappa coefficient than other change detection algorithm, but it has more undetected error. By compared with the SNR of image object, we know that the MNF transformation could effectively improve to concentrate the change information. PMID- 26601396 TI - [Quantitative Analysis of Mn in Soil Samples Using LIBS]. AB - The trace element of Manganese element in the agricultural farm (Anhui Huaiyuan Nongkang) soil was quantitatively analyzed by Laser-induced breakdown spectroscopy. The line of 403.1 nm was selected as the analysis line of Mn. The matrix element of Fe in soil was chosen as the internal calibration element and the analysis line was 407.2 nm. Ten soil samples were used to construct calibration curves with traditional method and internal standard method, and four soil samples were selected as test samples. The experimental results showed that the fitting correlation coefficient (r) is 0.954 when using the traditional method, the maximum relative error of the measurement samples is 5.72%, and the detection limit of Mn in soil is 93 mg x kg(-1). While using the internal standard method to construct the calibration curve, the fitting correlation coefficient (r) is 0.983, the relative error of measurement samples is reduced to 4.1%, and the detection limit of Mn in soil is 71 mg x kg(-1). The result indicates that LIBS technique can be used to detect trace element Mn in soil. In a certain extent, the internal standard method can improve the accuracy of measurement. PMID- 26601397 TI - [Influence of C-Fe Lines Interference Correction on Laser-Induced Breakdown Spectroscopy Measurement of Unburned Carbon in Fly Ash]. AB - In coal-fired plants, Unburned carbon (UC) in fly ash is the major determinant of combustion efficiency in coal-fired boiler. The balance between unburned carbon and NO(x) emissions stresses the need for rapid and accurate methods for the measurement of unburned carbon. Laser-induced breakdown spectroscopy (LIBS) is employed to measure the unburned carbon content in fly ash. In this case, it is found that the C line interference with Fe line at about 248 nm. The interference leads to C could not be quantified independently from Fe. A correction approach for extracting C integrated intensity from the overlapping peak is proposed. The Fe 248.33 nm, Fe 254.60 nm and Fe 272.36 nm lines are used to correct the Fe 247.98 nm line which interference with C 247.86 nm, respectively. Then, the corrected C integrated intensity is compared with the uncorrected C integrated intensity for constructing calibration curves of unburned carbon, and also for the precision and accuracy of repeat measurements. The analysis results show that the regression coefficients of the calibration curves and the precision and accuracy of repeat measurements are improved by correcting C-Fe interference, especially for the fly ash samples with low level unburned carbon content. However, the choice of the Fe line need to avoid a over-correction for C line. Obviously, Fe 254.60 nm is the best PMID- 26601398 TI - [Application of ICP-MS and ICP-AES for Studying on Source Apportionment of PM2.5 during Haze Weather in Urban Beijing]. AB - To investigate the characteristics of chemical constitute and pollution sources of aerosol fine particulate matter during haze-fog day in Beijing in winter 2013. The samples of PM2.5 were collected in Beijing from January to February, 2013. The technique of ICP-MS and ICP-AES coupled with procedure of bathing-ultrasonic extraction was applied to determine the concentration of 40 elements in the aerosol samples to analyze the characteristics of elements distribution statistically. The absolute principal factor method was used to apportion the pollution sources of PM2.5 during the haze weather in Beijing city in winter 2013. The results showed that during the period of sampling, the volume concentration of Li, Mn, Pb, S etc. obeyed normal distribution approximately, and according to National Ambient Air Quality Standard issued by Ministry of Environmental Protection of the People's Republic of China, the geometric mean concentration of As was twice the annual limit of standard reference, while Pb of some aerosol samples beyond the annual limit of standard reference respectively. The mass fraction of Fe, Zn, Pb, Ti accounted for over 0.1%, while that of Mn, Cu, As, Se etc. 0.01%. These elements were primary inorganic pollutants, and especially the hazards and sources of As and Pb should be concerned. There were 6 main pollution sources were chosen by the factor analysis method, including industrial dust and human beings activities, biomass combustion and building dust, soil and sand dusts, fossil fuel, electronic waste and metal smelting, with the variance contribution rate of 40.3%, 27.0%, 9.1%, 4.9%, 4.8% and 4.6% respectively. ICP-MS and ICP-AES can be applied to analyzing multi-elements in PM2.5 accurately and quickly to facilitate source apportionment, and it indicated that the relevant pollution sources should be considered and the effect of regional transferring of haze pollution sources should be taken into account, and specific measures should be taken for control. PMID- 26601399 TI - [Metallic Elemental Analysis of Tibetan Herbal Medicines and Tibetan Medicine Preparations by Synchrotron Radiation X-Ray Fluorescence]. AB - To discuss the relationship between metallic element and disease through determine the elementals in Tibetan Herbal Medicines and Tibetan Medicine Preparations that have obvious effect on hepatobiliary diseases by Synchrotron Radiation X-ray Source, then to reveal the substance foundation of pharmacological action. The results show that all the Tibetan Herbal Medicines used in the experiment have the 9 kinds of metallic elements of potassium(K), calcium(Ca), titanium(Ti), vanadium(V), chromium(Cr), manganese(Mn), ferrum(Fe), zinc(Zn) and lead(Pb), the content of the elements are in the ppb or ppm level though the element constitute and the content have obvious difference. Tibetan Medicine Preparations have another 6 kinds of metallic elements of nickel(Ni), copper(Cu), rubidium(Rb), mercury(Hg), cobalt(Co), gallium(Ga) and 1 kind of nonmetallic elements of arsenic(As) when compare with Herbal Medicines, and the element constitute and the content also have obvious difference. Take advantage of SR-XRF, the test gets the basic data of elements of Tibetan Herbal Medicines and Preparations, supply the scientific support to discuss the interaction of pharmacological mechanism and the metallic elements, and find the suitability of the technique for the metallic elements detection in Tibetan Medicines. PMID- 26601400 TI - Fast Monitoring Soil Environmental Qualities of Heavy Metal by Portable X-Ray Fluorescence Spectrometer. AB - Portable X-ray fluorescence (PXRF) spectrometer as a new type of equipment for quick test has a prominent prospect, but there are also shortcomings of detection range and limition, therefore this paper studied the suitability of PXRF spectrometer in monitoring soil environmental qualities of heavy metals included Cr, Ni, Cu, Zn, Pb, Cd, As and Hg, the aim of this paper is to screen elements which can be detected by this kind of instrument and evaluate the accuracy of test results. The research method is to test heavy metals contaminated soil samples by PXRF spectrometer, evaluate the accuracy of test results of PXRF compared with inductively coupled plasma mass(ICP-MS), then establish linear regression relationship between analysis results of PXRF and ICP-MS method. The results show that, (1) When measuring the soil environmental quality, PXRF spectrometer is appropriate to measure the content of Pb, Zn, Cr and Cu, except Ni, Cd, As and Hg. (2) Compared with the test value of ICP-MS, the test value of Pb and Zn is lower, the test value of Cu is higher, the test value of Cr is too high, all the results of PXRF spectrometer should be linear corrected according to standard analysis method. In conclusion, PXRF spectrometer is suitable for monitoring environmental quality of soil which is polluted by heavy metal such as Pb, Zn, Cr and Cu, it is an analysis means with characteristics of simple and rapid, accurate and reliable. The innovation of this article is that reasonable avoiding the shortcomings of PXRF spectrometer as using the instrument to monitor soil environmental quality, at last improved the application value of test results. PMID- 26601401 TI - [Ultra-Fine Pressed Powder Pellet Sample Preparation XRF Determination of Multi Elements and Carbon Dioxide in Carbonate]. AB - The main analysis error of pressed powder pellet of carbonate comes from particle size effect and mineral effect. So in the article in order to eliminate the particle-size effect, the ultrafine pressed powder pellet sample preparation is used to the determination of multi-elements and carbon-dioxide in carbonate. To prepare the ultrafine powder the FRITSCH planetary Micro Mill machine and tungsten carbide media is utilized. To conquer the conglomeration during the process of grinding, the wet grinding is preferred. The surface morphology of the pellet is more smooth and neat, the Compton scatter effect is reduced with the decrease in particle size. The intensity of the spectral line is varied with the change of the particle size, generally the intensity of the spectral line is increased with the decrease in the particle size. But when the particle size of more than one component of the material is decreased, the intensity of the spectral line may increase for S, Si, Mg, or decrease for Ca, Al, Ti, K, which depend on the respective mass absorption coefficient . The change of the composition of the phase with milling is also researched. The incident depth of respective element is given from theoretical calculation. When the sample is grounded to the particle size of less than the penetration depth of all the analyte, the effect of the particle size on the intensity of the spectral line is much reduced. In the experiment, when grounded the sample to less than 8 MUm(d95), the particle-size effect is much eliminated, with the correction method of theoretical alpha coefficient and the empirical coefficient, 14 major, minor and trace element in the carbonate can be determined accurately. And the precision of the method is much improved with RSD < 2%, except Na2O. Carbon is ultra-light element, the fluorescence yield is low and the interference is serious. With the manual multi-layer crystal PX4, coarse collimator, empirical correction, X-ray spectrometer can be used to determine the carbon dioxide in the carbonate quantitatively. The intensity of the carbon is increase with the times of the measurement and the time delay even the pellet is stored in the dessicator. So employing the latest pressed powder pellet is suggested. PMID- 26601403 TI - [Development of a High Spectral Resolution UV Flat-Field Spectrograph]. AB - As an important optical splitting element, grating is used in many different spectrometers and spectrographs. Spherical varied-line-spacing grating (SVLSG) is easily combined with array detectors to get a wide wavelength range of spectrums in one time, because it can focus the spectrums in approximately a plane. Therefore, it's widely used in many spectral instruments. We usually only know the central groove density of a commercial grating and its mounting parameters, while its line spacing parameters are unknown. Moreover, the mounting parameters are optimized within the whole using wavelength range of the grating. However, in most circumstances only part of the wavelength range is used. Therefore, the mounting parameters are not optimized for the needed wavelength range. Under this condition, in this article we developed a method based on the focusing theory of the flat-field grating and the mounting parameters the manufacture provided to deduce the line spacing parameters of the grating. With these parameters, we can optimize the detector position according to the wavelength range we need and ray tracing can be done to test the optical system. In this article we developed a high spectral resolution ultraviolet spectrograph, covering a wavelength range of 230-280 nm. The grating used in this spectrograph has a central groove density of 1 200 lines x mm(-1) and a designed wavelength range of 170-500 nm. We deduced the line spacing parameters of the grating and optimized the detector mounting parameters. Hollow cathode lamps of different elements were used to calibrate the spectrograph and test the spectral resolution of it. Wavelength calibration of the spectrograph has been done with the parameter fitting method, and the calibration accuracy is better than 0.01 nm. Results show the spectral resolution of the spectral graph is about 0.08 nm at 280.20 nm. PMID- 26601402 TI - [Study on Provenance of Kraak Porcelains from "Nan'ao I" Shipwreck]. AB - The "Kraak Porcelain" was a kind of Blue and White Porcelain which exported from China to Europe in Ming and Qing period. The study of Kraak Porcelain is a focus issue in international field of porcelain research. In 2007, the discovery of "Nan'ao I" Shipwreck of Ming Dynasty and the porcelains loaded in it, provided precious materials for the research on Kraak Porcelain. In this paper, we explored the provenance of 10 Kraak Porcelain samples from Nan'ao I, using both traditional visual method and WDXRF. PMID- 26601404 TI - [Study on the Advanced Czerny-Turner Imaging Spectrometer with High Resolution in Broadband]. AB - This paper studies the Czerny-Turner optical structure which is used for the application in imaging spectrometers. To obtain the perfect astigmatism-corrected condition, the Czerny-Turner system has been analyzed and advanced. The basic structure of optical system is still as the traditional form which is composed by the spherical collimating mirror, the plane grating and the spherical focusing mirror. However, an off-the-shelf cylindrical lens is added after the focusing mirror to remove astigmatism differences between the tangential direction and the sagittaI direction. It makes the advanced optical system presents high resolution over the full bandwidth and decreases the cost. An example of the imaging spectrum system in the waveband of 380-760 nm has been designed to prove our theory. A system owns that NA equals to 0.05, and the modulation transfer functions (MTF) of all fields of view are more than 0.59 over the broadband under the required Nyquist frequency (20 lp x mm(-1)). It certificates that the optical system theory can be applied to the small scale imaging spectrometer with high resolution in spectral broadband. PMID- 26601405 TI - [Brain Organization of the Preparation for Visual Recognition in Preadolescent Children]. AB - The brain organization of the process of preparation for the perception of incomplete images fragmented to different extents. The functional connections of ventrolateral and dorsoventral cortical zones with other zones in 10-11-year-old and 11-12-year-old children were studied at three successive stages of the preparation for the perception of incomplete images. These data were compared with those obtained for adults. In order to reveal the effect of preparatory processes on the image recognition, we also analyzed the regional event-related potentials. In adults, the functional interaction between dorsolateral and ventrolateral prefrontal cortex and other cortical zones of the right hemisphere was found to be enhanced at the stage of waiting for not-yet-recognizable image, while in the left hemisphere the links became stronger shortly before the successful recognition of a stimulus. In children the stage-related changes in functional interactions are similar in both hemispheres, with peak of interaction activity.at the stage preceding the successful recognition. It was found that in 11-12-year-old children the ventrolateral cortex is involved in both preparatory stage and recognition processes to a smaller extent as compared with adults and 10-11-year-old children. At the same time, the group of 11-12-year-old children had more mature pattern of the dorsolateral cortex involvement, which provided more effective recognition of incomplete images in this group as compared with 10 11-year-old children. It is suggested that the features of the brain organization of visual recognition and preceding preparatory processes in 11-12-year-old children are caused by multidirectional effects of sex hormones on the functioning of different zones of the prefrontal cortex at early stages of sexual maturation. PMID- 26601406 TI - [Relationships between the Flexibility of Cognitive Performance and the Response of Alpha-Rhythm in the Go/NoGo Task]. AB - During the experiments, healthy subjects (n = 35) completed Go/NoGo task with a set towards the recognition of negative face expression; the visual stimuli were set in the middle of a 16-second-long interval between target (face) and triggering stimuli. The local changes in low-frequency alpha-oscillations in response to stimuli (desynchronization after a positive Go stimulus and synchronization after an inhibitory NoGo stimulus) take place in posterior frontal and anterior temporal lobes of the left hemisphere, i.e., in cortical areas directly involved in speech processes. In subjects with flexible set towards recognition, we observed synchronization of alpha-rhythm after inhibitory NoGo stimulus; in subjects with more stable set, this did not occur. Thus, we obtained new experimental data confirming that induced synchronization of alpha oscillations reflects the enhancement of descending inhibitory control of the prefrontal cortex. PMID- 26601407 TI - [The Influence of the Functioning of Brain Regulatory Systems onto the Voluntary Regulation of Cognitive Performance in Children. Report 2. Neuropsychological and Electrophysiological Assessment of Brain Regulatory Functions in Children Aged 10 12 with Learning Difficulties]. AB - A total number of 172 children aged 10-12 were electrophysiologically and neuropsychologically assessed in order to analyze the influence of the functioning of brain regulatory systems onto the voluntary regulation of cognitive performance during the preteen years. EEG patterns associated with the nonoptimal functioning of brain regulatory systems, particularly fronto-thalamic, limbic and fronto-striatal structures were significantly more often observed in children with learning and behavioral difficulties, as compared to the control group. Neuropsychological assessment showed that the nonoptimal functioning of different brain regulatory systems specifically affect the voluntary regulation of cognitive performance. Children with EEG patterns of fronto-thalamic nonoptimal functioning demonstrated poor voluntary regulation such as impulsiveness and difficulties in continuing the same algorithms. Children with EEG patterns of limbic nonoptimal functioning showed a less pronounced executive dysfunction manifested only in poor switching between program units within a task. Children with EEG patterns of fronto-striatal nonoptimal functioning struggled with such executive dysfunctions as motor and tactile perseverations and emotional-motivational deviations such as poor motivation and communicative skills. PMID- 26601408 TI - [The Ability to Successfully Perform Different Kinds of Cognitive Activity Is Reflected in the Topological Features of Intracortical Interactions (Sex Differences in Boys and Girls Aged 5-6 Years)]. AB - We studied the correlation of intellectual development according to The Wechsler Intelligence Scale for Children (WISC test) with the spatial organization of resting EEG in 52 children aged 5-6 years. It was found that the patterns of interregional interactions of different parts of the cortex which correspond with the best performance in the subtests in boys (n = 23) and girls (n = 29) have significant topological differences. In girls, successful subtest performance positively correlated to a greater extent with interhemispheric interactions; in boys--long longitudinal rostral-caudal interactions between various regions of the cortex. The results showed that there are important gender differences in the spatial organization of brain activity associated with the performance of different cognitive activities in preschool children. The successful performance of various subtests by boys required considerable variability in the organization of spatial patterns of interregional interactions; on the contrary, the spatial structure of these patterns in girls was relatively invariable. Obviously, for the successful performance of various cognitive activities at this age in boys, the cortex need to form highly specialized organization of intracortical interactions, while in girls the brain uses relatively similar reorganization of interactions. The data suggest that 5-6-year-old boys and girls use different cognitive strategies when performing the same subtests of the WISC test. PMID- 26601409 TI - [Transcranial Magnetic Stimulation in the Combined Treatment of Pharmacoresistant Depression: Dynamics of Clinical, Psychological and EEG Parameters]. AB - In order to investigate the mechanisms of the therapeutic effect of transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex in patients with depression, we studied the dynamics of clinical parameters, a number of cognitive functions, and the spectral structure of resting EEG in 20 patients with pharmacoresistant depression in the course of combined treatment including TMS. It was shown that short course (10 sessions) of TMS significantly enhanced and accelerated the effect of antidepressants. The course of TMS contributed not only to the reduction of depressive symptoms but also to the improvement of general condition and the recovery of some impaired cognitive functions. The therapeutic effect of TMS seems to be provided by the activation of not only the prefrontal cortex itself but also of some subcortical structures closely linked with it. Thus, TMS appears to be a promising non-drug method for the treatment of clinical conditions and for the correction of brain functional state in patients with depression, including the use in combined treatment of depressive disorders in cases of pharmacoresistance. PMID- 26601410 TI - [The Influence of Threatening Stimuli on the Component P200 in Patients with Paranoid Schizophrenia]. AB - We studied schizophrenic patients with the dominance of pseudohallucinations. As is well known, pseudohallucinations are the main syndrome of schizophrenia, the so-called first rank syndrome. Pseudohallucinations are defined as a disorder of sense (affective) perception. This disorder is mainly diagnosed from the clinical picture or by pathopsychologichal observations. We investigated the evoked potentials (EP) of brain after neutral and emotionally meaningful (threatening) visual stimuli in order to specify the neurophysiological disorders of affective perception in schizophrenic patients with severe paranoid-hallucinatory syndrome who did not receive neuroleptic therapy. The analysis of P200 component in healthy subjects showed an increase in the amplitude and shortening of the latency of this wave in response to thretaning stimuli, as compared to neutral stimuli. In the group of patients with schizophrenia, the analysis showed the same increase in the level of excitation in response to emotionally threatening stimuli. However, in schizophrenic patients there were also found certain areas where the amplitude and latency decreased or increased at the same time. The results show that patients with schizophrenia have the pathological effect of having parameters typical of the processes of both excitation and inhibition. PMID- 26601411 TI - [Age-Related Features of EEG Coherence in Children and Adolescents Living in the European North of Russia]. AB - The paper presents data on the formation of spatial synchronization of brain potentials in 91 children aged 7-18 years living in European North of Russia. We estimated coherence values for 19 derivations (pair 171) in five EEG frequency bands (delta, theta, alpha-1, alpha-2 and beta). We described age-related changes, gender differences and topical specific features of the formation of coherence in the left and right hemispheres, and in inter- and intrahemispheric synchronization. We carried out computer assessment of the differences in EEG coherence between three age groups of children in order to determine criteria for identification of children with retarded formation of spatial organization of local EEG processes. Age-related changes in the structure of EEG patterns observed in the study reflect the processes of morphofunctional brain development in children and adolescents at different stages of postnatal ontogenesis under severe conditions of northern climate. PMID- 26601412 TI - [The Effect of Audiovisual Stimulation on Psychological and Physiological Functions in Athletes]. AB - We studied the psychophysiological status (cognitive, psychoemotional and neurodynamic parameters), the power spectrum of EEG and heart rate variability of 18-23-year-old athletes, before and after a course of audiovisual stimulation (AVS) (experimental group) in comparison with sportsmen who did not receive AVS (control group). It was shown that a course of AVS (experimental group) has positive effect on psycho-emotional parameters (the levels of anxiety and neuroticism decreased; motivation to make progress and the level of hardiness increased), cognitive and neurodynamic parameters (the capacity of mechanical memory, the speed of attention switching and of a simple sensor-motor response increase; the range of fluctuation of reactions to a moving object is reduced). We also observed an increase in the power of alpha2 rhythm of EEG, the activity of parasympathetic nervous system and the influence of autonomic circuit of regulation in the experimental group; resting cardiac performance was more conservative as compared with the control group. We concluded that a course of AVS has positive effect on psychophysiological parameters and the mechanisms of autonomic heart regulation in athletes. PMID- 26601413 TI - [The Influence of Light Tactile Contact on the Maintenance of Vertical Posture under the Conditions of Destabilization of the Visual Environment]. AB - We studied the influence of a light contact of the index finger with a stationary surface of external environment on the maintenance of upright posture in healthy subjects "immersed" in unstable virtual visual environment. Under these conditions, the subjects saw the screen with a visual scene consisting of foreground and background. The foreground represented a window of a room with adjoining walls; and the background plan--an aqueduct with the adjacent terrain. The virtual visual environment was destabilized by setting inphase or antiphase links between the foreground and the oscillations of body. The analysis of the maintenance of upright posture was focused on the assessment of amplitude frequency characteristics of two elementary variables calculated from trajectories of the center of pressure of feet (CoP) in mediolateral and anteroposterior directions: trajectory of the vertical projection of the center of gravity (CG variable) and differences between the trajectories of CoP and CG (CoP-CG variable). Both in normal posture and in posture with fingertip contact, the root mean square (RMS) values of the spectra of both variables were lowest in motionless visual environment with antiphase link of the foreground with body oscillations; highest, with inphase link and with eyes closed. In cases with fingertip contact, the intencity of body oscillations in both directions were considerably lower; the influence of different visual conditions on RMS values of the spectra of both variables decreased. This effect was more significant for CG variable. The frequency of body ascillations decreased as well. We observed the effect of tactile contacst on the frequency of the spectra of both variables. The median frequencies of the spectra of CoP-CG variable calculated from body oscillations in anteroposterior and mediolateral directions increased under the conditions of a tactile contact. On the contrary, the median frequencies of the spectra of CG variable increased only in body ascillations in mediolateral direction. Our results showed that a light tactile contact (providing no mechanical support) significantly improves the maintenance of vertical posture, including under conditions of destabilization of the virtual visual environment. This improvement is provided by multidirectional and independent effects on the amplitude-frequency characteristics of elementary variables (CG and CoP-CG). PMID- 26601414 TI - [Determination of Aerobic-anaerobic Transition in Working Muscle Using EMG and Near Infrared-Spectroscopy Data]. AB - A method to evaluate aerobic-anaerobic transition (AAT) during exercise is suggested. The subjects performed two tests with incremental increase of load: bicycle exercise and one leg knee extensions. In both tests the relation of deoxygenated hemoglobin (HHb) to EMG-activity of m. vastus lateralis during test has characteristic peak corresponding to AAT. The statistically significant correlation (r = 0.78, p < 0.05) between the load corresponding to AAT and anaerobic threshold (blood [La] = 4 mmol) was found during bicycle test. The method is applicable to determination of AAT during exercise of small muscle group. PMID- 26601415 TI - [The Role of Insular Cortex in Autonomic Control]. AB - The purpose of this article is to review experimental data proving that the insular cortex is involved in the regulation of visceral systems: respiratory, cardiovascular and gastrointestinal systems. The paper deals with the data on the structure of the insular cortex, the pathways in brain by which visceral information ascend to the insular cortex, the results of neurophysiological experiments and clinical observations. The experimental evidence of viscerotopical organization of not only sensor, but also motor representation of visceral systems in the insular cortex is discussed. On the basis of these data the insular cortex is defined as sensorimotor visceral cortex. It is demonstrated that one of the mechanisms of influence of the insular cortex on the regulation of internal organs is the modulation of reflex reactions which take place at the bulbar level. PMID- 26601416 TI - [Physiological Laws of Ontogenesis and Their Possible Applications to the Theory of Sports Training]. AB - The article is an attempt of a theoretical analysis of the most important physiological laws of ontogenesis and their applicability to the process of adaptation to physical exercise as a result of sports training. The hypothesis of this analysis is that the basic physiological principles (laws) of the organism development can be used in the construction of sports training. Indeed, for the long-term adaptation are important principles of heterochrony and of periodization, while other systemic patterns that are typical for ontogenesis can not be observed in the process of adaptation to exercise or have some specific features of manifestation. PMID- 26601417 TI - Progress of pharmacogenomic research related to minerals and trace elements. AB - Pharmacogenomics explores the variations in both the benefits and the adverse effects of a drug among patients in a target population by analyzing genomic profiles of individual patients. Minerals and trace elements, which can be found in human tissues and maintain normal physiological functions, are also in the focus of pharmacogenomic research. Single-nucleotide polymorphisms (SNPs) affect the metabolism, disposition and efficacy of minerals and trace elements in humans, resulting in changes of body function. This review describes some of the recent progress in pharmacogenomic research related to minerals and trace elements. PMID- 26601418 TI - Application of the quantitative detection of a change in concentration of magnesium stearate in a feeder tube of tableting manufacture by real-time near infrared spectroscopy. AB - Process analytical technology is important for the analysis and control of manufacturing processes. Near-infrared spectroscopy is widely used in various process analytical technologies for the analysis of the chemical componentsof solid dosage forms. Lubrication is an important process carried out before a tablet is produced. In this process, the concentration of lubricant, such as magnesium stearate (StMg), might change for one of many reasons during powder transport, which would be a critical problem such as variation in tablet compressibility and dissolution failure of compressed tablets. Our group investigated the feasibility of the quantitative monitoring of a change in the concentration of StMg in the feeder tube of tableting equipment employing real time near-infrared spectroscopy. PMID- 26601419 TI - Acousto-optic tunable filter near-infrared spectroscopy for in-line monitoring liquid-liquid extraction of Gardenia jasminoides Ellis based on statistical analysis. AB - This study aimed to monitor liquid-liquid extraction of Gardenia jasminoides Ellis (Zhizi in Chinese) using in-line near-infrared spectroscopy. Shanzhiside (SZS), deacetyl asperulosidic acid methyl ester (DAAME), genipin-1-beta-D gentiobioside (GG), geniposide (GS), total acids (TA) and soluble solid content (SSC) were selected as quality control indicators, and measured by reference methods. Both partial least-squares regression (PLSR) and back propagation artificial neural networks (BP-ANN) were applied to create models to predict the content of above indicators. Paired-samples t-test and nonparametric test were used to compare differences in predictive values between two models of each indicator. Relative standard error of prediction (RSEP) and mean absolute percentage error (MAPE) were used to evaluate the predictive accuracy of the established models. The results showed that there was no significant difference in predicting DAAME, GS and TA between two models. However, PLSR model gave better accuracy in predicting GG and SZS than BP-ANN model. The BP-ANN model of SSC was better than PLSR model. This study shows that NIR spectroscopy can be used for rapid and accurate analysis of quality control indicators in the liquid liquid extraction of Zhizi. Simultaneously, this study can serve as technical support for the application of NIR spectroscopy in the industrial production process. PMID- 26601420 TI - The DNA methylation inhibitor 5-azacytidine decreases melanin synthesis by inhibiting CREB phosphorylation. AB - Here we examined the effects of a DNA methylation inhibitor, 5-azacytidine, on melanogenesis in Mel-Ab cells. We found that 5-azacytidine decreased the melanin content and tyrosinase activity in these cells in a dose-dependent manner; importantly, 5-azacytidine was not cytotoxic at the concentrations used in these experiments. On the other hand, 5-azacytidine did not affect tyrosinase activity in a cell-free system, indicating that 5-azacytidine is not a direct tyrosinase inhibitor. Instead, 5-azacytidine decreased the protein levels of microphthalmia associated transcription factor (MITF) and tyrosinase. Thus, we investigated the effects of 5-azacytidine on signal transduction pathways related to melanogenesis. However, 5-azacytidine did not have any effect on either Akt or glycogen synthase kinase 3beta (GSK3beta) phosphorylation. The phosphorylation of cAMP response element-binding protein (CREB) is well known to regulate MITF expression, thereby also regulating tyrosinase expression. We found that 5 azacytidine decreased the phosphorylation of CREB. Therefore, we propose that 5 azacytidine may decrease melanin synthesis by downregulating MITF and tyrosinase via CREB inactivation. PMID- 26601421 TI - Nicotinamide phosphoribosyltransferase inhibitor APO866 induces C6 glioblastoma cell death via autophagy. AB - APO866 is a potent inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), and inhibits nicotinamide adenine dinucleotide (NAD) synthesis. Our previous study showed that APO866 inhibits the proliferation of C6 glioblastoma cells, but failed to induce apoptosis. Since APO866 inhibits cellular metabolism and such metabolic stress is closely related with autophagy, thus we determined whether APO866 can induce autophagy in C6 glioblastoma cells and whether the autophagy induced by APO866 is pro-death or pro-survival. Using LC3 immunofluorescence imaging and transmission electron microscopy detection, we found that APO866 at 1 100 nM induced autophagy in C6 glioblastoma cells. APO866 at 1 nM mainly induced initial autophagic vacuoles. Whereas APO866 at 100 nM induced degrading autophagic vacuoles, as well as induced nuclei malformation and mitochondria swelling. In addition, APO866 concentration-dependently decreased the cell viability of C6 glioblastoma cells, and this effect was attenuated by autophagy inhibitors, including 3-methyladenine and LY294002. APO866 concentration dependently decreased intracellular NAD level. Interestingly, APO866 at 1 nM slightly decreased intracellular NAD level, but dramatically increased autophagy positive cells. The dramatical cell viability decreasing required the decreasing of intracellular NAD level to a very low threshold. Thus, our results indicated that APO866 induced pro-death autophagy in C6 glioblastoma cells by decreasing intracellular NAD, and low concentration of APO866 can be used as an autophagy inducer in autophagic-death sensitive glioblastoma. PMID- 26601422 TI - Aberrant frequency of IL-10-producing B cells and its association with the balance of Treg/Th17 in children with inflammatory bowel disease. AB - Regulatory B cells (Breg) are a distinct B cell subset, which contribute to the pathogenesis of autoimmune disorders. Interleukin-10 (IL-10) plays a pivotal function to Breg. It is well described in adults but little is known in a pediatric population. This study was to investigate the role of IL-10-producing B cell (B10) and its association with Treg and Th17 subsets in the children with inflammatory bowel diseases (IBD). Peripheral blood mononuclear cells from IBD children patients and controls were stimulated with PMA, ionomycin, and brefeldin A. The frequencies of CD19+IL-10+ B cells, CD3+CD4+IL-17+Th17 cells, and CD4+ CD25(hi)Foxp3+ Treg cells were analyzed by flow cytometry. The mRNA expression of Foxp3, IL-17a and RORgammat was detected by real-time quantitative PCR. The number of B10 cells was elevated in IBD children patients. There was a positive correlation between B10 cells and Tregs in IBD. The ratio of Treg/Th17 decreased in IBD, and it strongly correlated with B10 cells. The frequency of B10 cells is elevated in IBD and it correlates with both the Tregs counts and the Treg/Th17 ratio. B10 cells to regulate functional T cell subsets might be impaired in paediatric patients with IBD. PMID- 26601423 TI - 3'4'7-Trihydroxyflavone inhibits RANKL-induced osteoclast formation via NFATc1. AB - 3'4'7-Trihydroxyflavone is a flavonoid from ladino clover, alfalfa, and Albizzia julibrissin. In the present study, we found that 3'4'7-trihydroxyflavone markedly inhibited the receptor activator of nuclear factor kappa B ligand (RANKL) induced osteoclastic differentiation from mouse bone marrow derived macrophages (BMMs). 3'4'7-trihydroxyflavone also reduced the mRNA expression level of osteoclastic marker genes including calcitonin receptor (CTR), Cathepsin K1 v-ATPase V0 subunit d2 (ATP6v0d2), and dendritic cell-specific transmembrane protein (DC STAMP). In addition, 3'4'7-trihydroxyflavone decreased the bone resorption activity of osteoclasts on dentin slices. We found that 3'4'7-trihydroxyflavone inhibited RANKL-induced expression of nuclear factor of activated T cells c1 (NFATc1), a key transcription factor of osteoclast differentiation. Furthermore, 3'4'7-trihydroxyflavone attenuated RANKL-induced activation of p38 mitogen activated protein kinase (MAPK) and expression of B lymphocyte-induced maturation protein 1 (Blimp1), a repressor of negative regulators of NFATc1. Taken together, our data suggest that 3'4'7-trihydroxyflavone inhibits osteoclastogenesis via NFATc1. PMID- 26601424 TI - MicroRNA-184 acts as a potential diagnostic and prognostic marker in epithelial ovarian cancer and regulates cell proliferation, apoptosis and inflammation. AB - MicroRNA-184 (miR-184) is found to be significantly deregulated in human cancers associated with tumorigenesis and progression. In this study, we aimed to investigate the role and mechanism of miR-184 expression in epithelial ovarian cancer (EOC). Relative expression of miR-184 was measured by quantificational real-time polymerase chain reaction assay (qRT-PCR) in 80 EOC patients. Kaplan Meier curve and the log-rank test were conducted to detect the prognostic value of miR-184. Function assays including cell proliferation, apoptosis and inflammation were further explored in vitro. We found that miR-184 was down regulated in EOC tissues and cell lines compared with paired non-cancerous tissues and IOSE, respectively. Moreover, miR-184 was expressed at significantly lower levels in late-stage (III/IV) EOC tissues. Cox regression multivariate analysis indicated that miR-184 and FIGO stage were independent prognostic indicators for EOC patients. Patients with high miR-184 level achieved significantly a higher 5-year survival rate compared with low level group (P < 0.001). Functional assays showed that miR-184 over-expression could suppress EOC cell proliferation as well as inflammation and induce apoptosis in vitro. Altogether, our results suggest that miR-184 together with pathologic diagnosis is critical for prognosis determination in EOC patients and help select treatment strategy. PMID- 26601425 TI - Risk factors for developing infusion reaction after rituximab administration in patients with B-cell non-Hodgkin's lymphoma. AB - Rituximab (RTX), a monoclonal antibody against CD20, is known to cause fewer side effects than conventional anti-cancer drugs; however, infusion reaction (IR), which is specific to monoclonal antibody therapy, is frequently triggered by RTX. Therefore, we designed this study to identify risk factors based on clinical test values for developing IR after RTX administration. Eighty-nine patients with B cell non-Hodgkin's lymphoma who had received RTX for the first time between February 2010 and March 2013, at the Gifu Municipal Hospital were enrolled as subjects. Analysis of data was conducted for 87 patients, after excluding patients whose data were missing. Univariate analysis showed significant differences in the number of patients exhibiting a soluble interleukin-2 receptor (sLL-2R) level > 2,000 U/L and hemoglobin (Hb) < lower standard limit (LSL) between the IR and non-IR groups. Multivariate analysis showed significant differences with respect to slL-2R > 2,000 U/L [odds ratio (OR), 4.463; 95% confidence interval (Cl), 1.262-15.779; P = 0.020], Hb < LSL [OR, 3.568; 95% CI, 1.071-11.890; P = 0.038], and steroid administration [OR, 0.284; 95% Cl, 0.094 0.852; P = 0.025]. Our findings show that sIL-2R > 2,000 U/L, Hb < LSL, and a lack of steroid premedication are risk factors for developing IR following RTX treatment. PMID- 26601426 TI - Cysteine amide adduct formation from carboxylic acid drugs via UGT-mediated bioactivation in human liver microsomes. AB - Although chemical trapping has been widely used to evaluate cytochrome P450 mediated drug bioactivation, thus far, only a few in vitro-trapping studies have been performed on UDP-glucuronosyltransferase (UGT)-mediated drug bioactivation. In this study, we used cysteine (Cys) as trapping agent to gain new insights into the UGT-mediated bioactivation involving acyl glucuronides of carboxylic acid drugs. Diclofenac, ketoprofen and ibuprofen were incubated in human liver microsomes with UDPGA and Cys, followed by analysis using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS). The N-acyl-Cys amide adduct of diclofenac was characterized by mass analysis and was detectable even in photodiode array analysis. Our data indicated that the formation of such adducts reflects the reactivity of the corresponding acyl glucuronides. In addition, it was suggested that the adduct formation requires an N-terminal Cys moiety with both a free amine and a free thiol group, from the results using various cysteine derivatives. We propose that the S-acyl-Cys thioester adduct can form via transacylation of an acyl glucuronide and can then form to an N-acyl-Cys amide adduct through intramolecular S- to N-acyl rearrangement. This series of the reactions has important implications as a possible bioactivation mechanism for covalent binding of carboxylic acid drugs to macromolecules. PMID- 26601427 TI - The national pharmacopoeias of the Baltic States. AB - After Estonia, Latvia and Lithuania proclaimed their independence in 1918 and began to create their national health care systems, one of their stated priorities was the formulation and publication of national pharmacopoeias. In order to accomplish this, working groups as well as commissions composed of pharmacists, medical specialists and even linguists had to be formed. The process was long and difficult. New terminology in native languages had to be created. Sources for the monographs had to be chosen, researched, analyzed and compared. There were organizational and financial problems. Nevertheless, by the late 1930s, all three Baltic States published their national pharmacopoeias. Officially, they were not able to use them for long because during World War II all three were occupied and annexed by the Soviet Union. Pharmacists in those countries were obliged to use the Soviet pharmacopoeias, although unofficially, they also made good use of their national ones. Currently, the European Pharmacopoeia is in use in Estonia, Latvia and Lithuania. PMID- 26601428 TI - Healthy competition. PMID- 26601429 TI - Political Union. PMID- 26601430 TI - Rachael Maskell. PMID- 26601431 TI - Supporting families with a fussy eater. PMID- 26601432 TI - Reducing dog bites in children. PMID- 26601433 TI - The lived experience of homeless women: insights gained as a specialist practitioner. AB - ABSTRACT In this article, insights into the lived experience of homeless women arising from a PhD study on the specialist role of the SCPHN in homelessness are presented. A key narrative text of a rough sleeping pregnant woman is included. The reflexive narrative study, used an eclectic, philosophical framework which included reflective practice/guidance, narrative inquiry, and storytelling methodologies. Story texts uniquely illuminated complex knowledge about homelessness and homeless health care. Homeless women were found to be a heterogeneous group which included former health professionals. The women's stories were often shocking; they were frequently contextualised against a background of service exclusion, including GP services, learning disability services, mental health services, housing services and social services. The role of the specialist nurse (SCPHN) in engagement with homeless people is illuminated. A therapeutic model of 'Effective Engagement with Homeless People and Homeless Families' is presented to guide health professionals in holistic care. The author invites the reader to dialogue within their teams on how homeless people are included or excluded from SCPHN services. In this way, the term 'audiencing' rather than transferability of findings is used in a continuing dialogue with the reader to improve the health and wellbeing of homeless women. PMID- 26601434 TI - Students' and tutors perceptions of the use of reflection in post-registration nurse education. AB - The aim of this study was to explore post-registration nurse students' and tutors perceptions of the use of reflection in education. The benefits of reflection have been highlighted in a number of studies; however, there is a paucity of literature on students' perceptions of the use of reflection in post-registration nurse education. A qualitative approach was used to explore the six post registration nurse students' and three tutors perceptions of the use of reflection in education. Semi-structured interviews were used to access perceptions and the data was analysed. The findings of this study are discussed under the themes; benefits of reflection, barriers to reflection and suggestions for improvement of the use of reflection. Conclusions include recommendations for future research and practice. Recommendations include tutors providing sufficient time and regular support for reflective practice without the constraints of using set reflective models. These findings have implications for those involved in curriculum development for post-registration nurses' education and those seeking to develop reflective abilities in students. PMID- 26601435 TI - Early intervention for increased antenatal anxiety associated with foetal development risk. AB - Evidence is growing, documenting the adverse effect of prolonged heightened states of maternal anxiety on the developing foetus. Recent Government recommendations require a shift toward early identification and intervention for 'at risk' mothers. Following the successful development of the postnatal mental health and attachment care pathway in North Somerset in 2006, a new pilot was undertaken to create an antenatal pathway to embrace these recommendations. Midwives were given a tool to identify women with high levels of anxiety, a menu of suitable options for specialist referral, and basic Mental Health training. Current services and potential additions were assessed to inform future planning. The tool was found effective in highlighting 'at risk' women, and midwives recommended changes in implementation. Midwives reported increased confidence in addressing maternal anxiety following training and receipt of a clear pathway. A higher number of women requiring intervention were identified than anticipated, and a geographic inequity of service identified. A pilot extension will address these issues and develop formal handover to health visitors by linking the antenatal and postnatal pathways. PMID- 26601436 TI - Educating practice teachers and specialist practice mentors for their new role. PMID- 26601437 TI - African horse sickness. AB - African horse sickness (AHS) is a devastating disease of equids caused by an arthropod-borne virus belonging to the Reoviridae family, genus Orbivirus. It is considered a major health threat for horses in endemic areas in sub-Saharan Africa. African horse sickness virus (AHSV) repeatedly caused large epizootics in the Mediterranean region (North Africa and southern Europe in particular) as a result of trade in infected equids. The unexpected emergence of a closely related virus, the bluetongue virus, in northern Europe in 2006 has raised fears about AHSV introduction into Europe, and more specifically into AHSV-free regions that have reported the presence of AHSV vectors, e.g. Culicoides midges. North African and European countries should be prepared to face AHSV incursions in the future, especially since two AHSV serotypes (serotypes 2 and 7) have recently spread northwards to western (e.g. Senegal, Nigeria, Gambia) and eastern Africa (Ethiopia), where historically only serotype 9 had been isolated. The authors review key elements of AHS epidemiology, surveillance and prophylaxis. PMID- 26601438 TI - Bluetongue. AB - Summary Bluetongue (BT) is an arthropod-transmitted viral disease of non-African ungulates, principally sheep. The disease results from vascular injury analogous to that of human haemorrhagic viral fevers, with characteristic tissue infarction, haemorrhage, vascular leakage, oedema, and hypovolaemic shock. Importantly, BT is not zoonotic. Bluetongue virus (BTV) infection of ruminants and vector Culicoides midges is endemic throughout many tropical and temperate regions of the world; however, within this global range the virus exists within relatively discrete ecosystems (syn. episystems) where specific constellations of BTV serotypes are spread by different species of biting Culicoides midges. Recently discovered goat-associated BTVs, notably BTV serotype 25 (BTV-25) in central Europe, appear to have distinctive biological properties and an epidemiology that is not reliant on Culicoides midges as vectors for virus transmission. Bluetongue virus infection of ruminants is often subclinical, but outbreaks of severe disease occur regularly at the upper and lower limits of the virus's global range, where infection is distinctly seasonal. There have been recent regional alterations in the global distribution of BTV infection, particularly in Europe. It is proposed that climate change is responsible for these events through its impact on vector midges. However, the role of anthropogenic factors in mediating emergence of BTV into new areas remains poorly defined; for example, it is not clear to what extent anthropogenic factors were responsible for the recent translocation to northern and eastern Europe of live attenuated vaccine viruses and an especially virulent strain of BTV-8 with distinctive properties. Without thorough characterisation of all environmental and anthropogenic drivers of the recent emergence of BT in northern Europe and elsewhere, it is difficult to predict what the future holds in terms of global emergence of BTV infection. Accurate and convenient laboratory tests are available for the sensitive and specific serological and virological diagnosis of BTV infection and confirmation of BT in animals. Prevention and control strategies for BT are largely reactive in nature, and typically are reliant on vaccination of susceptible livestock and restrictions on animal trade and movement. PMID- 26601439 TI - Epizootic haemorrhagic disease. AB - Summary Epizootic haemorrhagic disease (EHD) is an arthropod-transmitted viral disease of certain wild ungulates, notably North American white-tailed deer and, more rarely, cattle. The disease in white-tailed deer results from vascular injury analogous to that caused by bluetongue virus (BTV), to which EHD virus (EHDV) is closely related. There are seven serotypes of EHDV recognised, and Ibaraki virus, which is the cause of sporadic disease outbreaks in cattle in Asia, is included in EHDV serotype 2. The global distribution and epidemiology of BTV and EHDV infections are also similar, as both viruses occur throughout temperate and tropical regions of the world where they are transmitted by biting Culicoides midges and infect a wide variety of domestic and wild ungulates. However, the global distribution and epidemiology of EHDV infection are less well characterised than they are for BTV. Whereas most natural and experimental EHDV infections (other than Ibaraki virus infection) of livestock are subclinical or asymptomatic, outbreaks of EHD have recently been reported among cattle in the Mediterranean Basin, Reunion Island, South Africa, and the United States. Accurate and convenient laboratory tests are increasingly available for the sensitive and specific serological and virological diagnosis of EHDV infection and confirmation of EHD in animals, but commercial vaccines are available only for prevention of Ibaraki disease and not for protection against other strains and serotypes of EHDV. PMID- 26601440 TI - Zoonotic and emerging orbivirus infections. AB - Many novel emerging orbiviruses have been isolated in the past 15 years. Important viruses include Peruvian horse sickness virus (PHSV) and Yunnan orbivirus (YUOV), pathogens of equids which were originally isolated almost simultaneously from 1997 to 1999 in the People's Republic of China, Australia and Peru. YUOV has also been isolated from cattle, sheep and a dog. The isolation of YUOVfrom a dog is not the first case of an orbivirus being isolated from a carnivore. Bluetongue virus and African horse sickness virus were earlier detected in carnivores which fed on contaminated meat. PHSV and YUOV both offer an opportunity to study the emergence of a single pathogen in geographically distant locations, although the original point of emergence is still unidentified. PHSV has been isolated from horses with neurological disease both in Australia and in Peru (where it is now endemic). Serological and molecular diagnostic assays have been developed for these viruses to assist in their identification and diagnosis. Other orbiviruses, such as Palyam virus and Equine encephalosis virus, have more recently been identified outside their geographical boundaries and may represent a threat to domesticated livestock and horses, respectively. The article also reviews four zoonotic orbivirus species (Corriparta virus, Changuinola virus, Kemerovo virus and Orungo virus) which have been identified in livestock and/or wildlife. PMID- 26601441 TI - Schmallenberg virus infection. AB - Since Schmallenberg virus, an orthobunyavirus of the Simbu serogroup, was identified near the German-Dutch border for the first time in late 2011 it has spread extremely quickly and caused a large epidemic in European livestock. The virus, which is transmitted by Culicoides biting midges, infects domestic and wild ruminants. Adult animals show only mild clinical symptoms or none at all, whereas an infection during a critical period of gestation can lead to abortion, stillbirth or the birth of severely malformed offspring. The impact of the disease is usually greater in sheep than in cattle. Vaccination could be an important aspect of disease control. PMID- 26601442 TI - Rift Valley fever. AB - Rift Valley fever (RVF) is a mosquito-borne zoonotic viral disease affecting domestic and wild ruminants, camels and humans. The causative agent of RVF, the RVF virus (RVFV), has the capacity to cause large and severe outbreaks in animal and human populations and to cross significant natural geographic barriers. Rift Valley fever is usually inapparent in non-pregnant adult animals, but pregnant animals and newborns can be severely affected; outbreaks are characterised by a sudden onset of abortions and high neonatal mortality. The majority of human infections are subclinical or associated with moderate to severe, non-fatal, febrile illness, but some patients may develop a haemorrhagic syndrome and/or ocular and neurological lesions. In both animals and humans, the primary site of RVFV replication and tissue pathology is the liver. Outbreaks of RVF are associated with persistent high rainfalls leading to massive flooding and the emergence of large numbers of competent mosquito vectors that transmit the virus to a wide range of susceptible vertebrate species. Outbreaks of RVF have devastating economic effects on countries for which animal trade constitutes the main source of national revenue. The propensity of the virus to spread into new territories and re-emerge in traditionally endemic regions, where it causes large outbreaks in human and animal populations, presents a formidable challenge for public and veterinary health authorities. The presence of competent mosquito vectors in RVF-free countries, the wide range of mammals susceptible to the virus, altering land use, the global changes in climate, and increased animal trade and travel are some of the factors which might contribute to international spread of RVF. PMID- 26601443 TI - Crimean-Congo haemorrhagic fever. AB - Crimean-Congo haemorrhagic fever (CCHF) is one of the most widespread arboviroses in the world. It is present in Africa, south-east Europe, the Middle East and Asia. It is caused by a nairovirus (Bunyaviridae family) transmitted by several species of ticks. The geographical distribution of the disease coincides with the distribution of Hyalomma ticks. While infected livestock do not show signs of illness, humans are severely affected, with a high mortality rate. The most common symptoms are high fever, dizziness, headache, vomiting and haemorrhages. Pathogenesis studies in interferon-receptor-deficient mice indicated that the interferon response is crucial in controlling virus propagation and in protecting against the disease. Detection of the virus in biological material is currently performed by reverse-transcription polymerase chain reaction. Enzyme-linked immunosorbent assay and indirect immunofluorescence are used to detect the presence of CCHF virus-specific antibodies. In the 1970s, a formalin-inactivated vaccine prepared from suckling mouse brain was used in Eastern Europe and the former Soviet Union, but its efficacy remains to be proven. Treatment of patients with ribavirin is recommended by the World Health Organization, but it should be administered as early as possible. Although important progress has been made over the last few decades, many questions about the pathogenesis and epidemiology of the disease are still to be addressed and there is a need to develop efficient vaccines and antivirals. PMID- 26601444 TI - Akabane virus infection. AB - Akabane virus is a Culicoides-borne orthobunyavirus that is teratogenic to the fetus of cattle and small ruminant species. Depending upon the stage of gestation atwhich infection occurs, and the length of gestation of the mammalian host, a range of congenital defects may be observed. The developing central nervous system is usually the most severely affected, with hydranencephaly and arthrogryposis most frequently observed. Less commonly, some strains of Akabane virus can cause encephalitis in the neonate or, rarely, adult cattle. Akabane viruses are known to be widespread in temperate and tropical regions of Australia, Southeast Asia, the Middle East and some African countries. Disease is infrequently observed in regions where this virus is endemic and the presence of the virus remains unrecognised in the absence of serological surveillance. In some Asian countries, vaccines are used to minimise the occurrence of disease. PMID- 26601445 TI - Lesser-known bunyavirus infections. AB - This paper reviews less well-known or less widely distributed viruses of the Bunyaviridae family that are nonetheless of significant veterinary and public health concern. These include: Cache Valley fever, Main Drain, Ingwavuma, Bhanja and Heartland viruses. A description of the agents, clinical signs of infection, epidemiology, and insect transmission is provided for each, and the authors discuss current diagnostic strategies plus the lack of control measures. PMID- 26601446 TI - West Nile virus. AB - This review covers the basic biology of the West Nile virus and the host-vector pathogen interactions that result in significant disease in wild birds, horses and humans. The review describes the basic properties of the virus, cellular infection and the pathogenesis of the disease, and the ecology of virus maintenance, amplification and transmission. Disease epidemiology and risk estimation strategies that are currently in use are also examined, and host immune responses and vaccination practices described. The principles of vector control, exposure control and long-term risks caused by climatic and habitat factors are also included. PMID- 26601447 TI - Japanese encephalitis. AB - Japanese encephalitis (JE) is an inflammation of the central nervous system in humans and animals, specifically horses and cattle. The disease, which can sometimes be fatal, is caused by the flavivirus Japanese encephalitis virus (JEV), of which there are five genotypes (genotypes 1, 2, 3, 4 and 5). The transmission cycle of the virus involves pigs and wild birds as virus amplifiers and mosquitoes as vectors for transferring the virus between amplifying hosts and to dead- end hosts, i.e. humans, horses and cattle. In horses and cattle the disease is usually asymptomatic, but when clinical signs do occur they include fever, decreased appetite, frothing at the mouth, rigidity of the legs and recumbency, and neurological signs, such as convulsive fits, circling, marked depression and disordered consciousness. In pigs, it can cause abortion and stillbirths. At present, the virus is detected in a wide area covering eastern and southern Asia, Indonesia, northern Australia, Papua New Guinea and Pakistan. JEV RNA has also been detected in Italy, first in dead birds in 1997 and 2000 and then in mosquitoes in 2010. Genotype shift, i.e. a change of genotype from genotype 3 to genotype 1, has occurred in some countries, namely Japan, South Korea, Chinese Taipei and Vietnam. Laboratory methods are available for confirming the causative agent of the disease. There are control measures to prevent or minimise infection and, among them, vaccination is one of the most important and one which should be adopted in endemic and epidemic areas. PMID- 26601448 TI - Tick-borne encephalitis. AB - Tick-borne encephalitis (TBE), a zoonotic arbovirosis caused by tick-borne encephalitis virus (TBEV), is an increasing public health concern. Infections result in neurological symptoms in humans and the virus has rapidly expanded to new geographical areas. Three subtypes are currently present in different parts of Europe and Asia. The virus is transmitted by ticks, mainly Ixodes spp., between small mammals such as rodents, which serve as virus amplifying hosts. Humans are infected sporadically, either by a tick bite or by ingestion of infected milk or milk products. Other mammals (e.g. ruminants) can also be infected, but most of the time do not show clinical signs. In contrast to rodents, other wild and domestic mammals probably play only a very small direct role in maintaining TBEV in an area, but they might play an important role as hosts in sustaining a large tick population. Therefore, the virus prevalence and the occurrence of TBE can be influenced by several environmental, genetic and behavioural factors associated with the virus, the vectors or the hosts, and understanding these factors is essential for implementation of effective control measures. This article reviews virus characteristics and the epidemiological and clinical aspects of TBEV infections and examines pathogenesis, diagnostic approaches and control measures. PMID- 26601449 TI - Dengue and other flavivirus infections. AB - Flaviviruses are responsible for yellow fever, Zika fever and dengue, all of which are major human diseases found in tropical regions of the globe. They are zoonoses with a transmission cycle that involves primates as reservoirs and mosquitoes of the genus Aedes as vectors. The recent upsurge of urban epidemics of yellow fever, Zika fever and dengue has involved human-to-human transmission with mosquitoes as the vector. This paper is primarily concerned with dengue, which has become the pre-eminent arbovirosis in terms of public health. PMID- 26601450 TI - Chikungunya. AB - Chikungunya is an acute viral disease characterised by fever and painful arthralgia. The arthritic symptoms associated with chikungunya can be debilitating and may persist for months or even years in some patients. Severe neurological complications such as encephalitis have also been reported during recent large outbreaks. The disease is caused by chikungunya virus (CHIKV), a mosquito-borne alphavirus from the Togaviridae family, which has recently emerged to become one of the most important exotic viral threats worldwide. Chikungunya is endemic throughout Africa, and over the past decade, it has also spread throughout the Indian Ocean, Asia, the South Pacific, southern Europe, the Caribbean and Central America. The rapid emergence of CHIKV has been linked to expansion of the mosquito vector species, Aedes aegypti and Ae. albopictus, throughout most tropical and subtropical regions of the world. Furthermore, mutations in some strains of CHIKV have been associated with increased transmissibility of the virus. The lack of a commercial vaccine and the failure of vector control strategies to limit the expansion of chikungunya have prompted the need for further options to prevent the spread of this disease. PMID- 26601451 TI - Alphaviral equine encephalomyelitis (Eastern, Western and Venezuelan). AB - Summary Alphaviral equine encephalomyelitis is a mosquito-borne infection that causes severe neurological disease and fatalities in horses and humans in the Americas. Consequently, the equine alphaviruses (Eastern, Western and Venezuelan) are of considerable concern worldwide and are notifiable to the World Organisation for Animal Health. In addition, these diseases are considered a potent potential biological weapon, emphasising the need to develop an effective vaccine. Alphaviral equine encephalomyelitis is caused by Eastern equine encephalomyelitis virus (EEEV), Western equine encephalomyelitis virus (WEEV) or Venezuelan equine encephalomyelitis virus (VEEV), which are related members of the Alphavirus genus in the Togaviridae family. Although related, the three viruses are genetically and antigenically distinct. The disease is characterised by fever, anorexia, depression and clinical signs of encephalomyelitis, and may be fatal in up to 90% of cases, for both humans and horses, particularly in the case of EEE. Surviving horses develop lifelong immunity but may have permanent neuropathology. The aim of this paper is to analyse the scientific information available on the evolution of EEE, WEE and VEE, and any potential vaccines. PMID- 26601452 TI - New insights into the role of ticks in African swine fever epidemiology. AB - African swine fever (ASF), one of the most important diseases of swine, is present in many African countries, as well as in eastern Europe, Russia and Sardinia. It is caused by a complex virus, ASF virus (ASFV), for which neither vaccine nor treatment is available. ASFV affects swine of all breeds and ages, and also replicates in soft ticks of the genus Ornithodoros, facilitating ASFV persistence and reocurrence of disease. Depending on the involvement of these ticks, and the presence or not of sylvatic asymptomatic animals, several epidemiological cycles have been identified. The disease persists in East and southern African countries in a sylvatic cycle between O. porcinus (of the O. moubata species complex) and common warthogs. In some countries a domestic pig tick cycle exists, whereas in other regions, notably West Africa, the role of soft ticks has not been demonstrated, and ASFV is transmitted between domestic pigs in the absence of tick vectors. Even in several East and Central African countries which have the sylvatic or domestic cycle, the majority of outbreaks are not associated with ticks or wild suids. In Europe, O. erraticus was detected and identified as a crucial vector for ASF maintenance in outdoor pig production on the Iberian Peninsula. However, in most parts of Europe, there is a lack of information about the distribution and role of Ornithodoros ticks in ASF persistence, particularly in eastern regions. This article reviews ASF epidemiology and its main characteristics, with a special focus on the distribution and role of soft ticks in ASF persistence in different settings. Information abouttick detection, control measures and future directions for research is also included. PMID- 26601453 TI - Equine infectious anaemia and mechanical transmission: man and the wee beasties. AB - There is no credible evidence that the lentivirus that causes equine infectious anaemia (EIA) replicates in invertebrates. The virus persistently infects its equid hosts and is often present in blood in significant quantities. Blood feeding arthropods thus have the potential to transfer the virus between hosts, especially if their feeding on the first host is interrupted and immediately continued on a second host. The general details and dynamics of mechanical transmission are included in this paper, as this agent presents an excellent model. Mechanical transmission can be effectively controlled if the dynamics and interactions of the host, virus and vector populations are understood. Efficient transmission is proportional to the amount of agent found in the source material, the environmental survival of the agent, the number of vector feedings, the number of interrupted feedings, vector refeeding, the proximity of infected and naive hosts, host population density, and the length of time during which vectors and hosts are in contact. Establishing firm quantitative risk estimates for EIA is impossible, mainly because the virus content in blood can change exponentially from day to day. The EIA virus can be transmitted by horse flies for at least 30 minutes after feeding on a horse with acute signs of EIA, butthe probability of a horse fly being interrupted and completing its blood feeding on a second host at a distance of 50 m is very low, and the separation of infected and uninfected equids by 200 m breaks transmission. The statements above assume that human interactions are absent or do not contribute to the risk of virus transmission; however, the risk from human interventions, such as the too-often-used procedure of administering > 200 ml of plasma to foals, can easily be more than 10(7) times greater than the risk posed by a single horse fly. Controlling EIA depends upon the identification of persistently infected equids by serological testing because other methods of identifying infective virus orviral genetic material are less accurate or impractical. PMID- 26601454 TI - Three-day fever. AB - Three-day fever is a viral disease caused by an Ephemerovirus of the family Rhabdoviridae, transmitted by arthropod vectors. It is common in tropical and sub tropical regions, where it affects mainly domestic cattle and buffaloes, especially in intensive dairy or fattening production systems. It is of economic importance because it reduces milk production and fertility and causes abortion. The disease is generally benign. It manifests in several susceptible subjects simultaneously, with a sudden episode of fever accompanied by muscle involvement with arthritis, stiffness of the limbs, and lameness, followed by rapid recovery. The presence of a serofibrinous exudate in the joints is indicative of the disease. Clinical diagnosis is often difficult in the absence of pathognomonic signs. Epidemiological factors (proliferation of arthropod vectors), associated with a short-lived fever and the presence of many immature neutrophils, point strongly to three-day fever. In the absence of any specific treatment, the symptoms are treated with antibiotics and anti-inflammatories. Medical prophylaxis currently uses live attenuated vaccines, pending the development of recombinant vaccines, which are giving promising results. PMID- 26601455 TI - Myxomatosis. AB - Myxomatosis, a major disease of European rabbits (Oryctolagus cuniculus), is enzootic on several continents. The disease is infectious, virulent and contagious. The pathogen is a virus of the family Poxviridae, genus Leporipoxvirus. In its classic form the disease is often fatal, characterised by severe immunosuppression and the appearance of skin pseudotumours (myxomas); it is conducive to effective mechanical transmission by many biting arthropods. Atypical clinical forms, referred to as amyxomatous, of variable severity and with an apparent preference for direct transmission, have recently emerged in Europe. Virus-host interactions have been particularly well studied since the voluntary introduction of the myxoma virus into Australia and Europe, revealing a remarkable process of co-evolution. Molecular analysis has recently demonstrated the extraordinary evolutionary capacity of the myxoma virus. PMID- 26601456 TI - Heartwater--Ehrlichia ruminantium infection. AB - Summary Heartwater is a notifiable disease that is listed by the World Organisation for Animal Health. It is caused by Ehrlichia ruminantium, an obligately intracellular Gram-negative bacterium in the order Rickettsiales and the family Anaplasmataceae. The disease is borne byticks in the genus Amblyomma and causes heartwater, or cowdriosis, in wild and domestic ruminants, primarily in Africa, but also in parts of the Caribbean. The disease was recognised in South Africa in the 19th Century and determined to be tick borne in 1900, while the organism was identified in 1925 and first cultured in vitro in 1985. This latter achievement boosted research into the disease at a time when biology was moving into the molecular genetic age. Over the last 20 years, there have been significant improvements in our understanding of E. ruminantium, yielding major advances in diagnosis, epidemiology, genetic characterisation, phylogeny, immunology, and vaccine development. The organism is genetically highly variable; this has important implications for future control measures, and is making it difficult to develop an effective vaccine for protection against tick challenge. Research is continuing into three different types of vaccine, inactivated, attenuated, and recombinant, and the current state of development of each is discussed. PMID- 26601457 TI - Lyme disease. AB - Lyme disease is among the most frequently diagnosed zoonotic tick-borne diseases worldwide. The number of human cases has been on the increase since the first recognition of its aetiological agent. Lyme disease is caused by spirochete bacteria belonging to the genus Borrelia, with B. burgdorferi sensu stricto (s.s.) found in the Americas, and B. afzelii and B. garinii, in addition to B. burgdorferi s.s., in Europe and Asia. Environmental factors, such as human encroachment onto habitats favourable to ticks and their hosts, reduced deforestation, increased human outdoor activities, and climatic factors favouring a wider distribution of tick vectors, have enhanced the impact of the disease on both humans and animals. Clinical manifestations in humans include, in the early phases, erythema migrans, followed several weeks later by neuro-borreliosis (meningo-radiculitis, meningitis or meningo-encephalitis), Lyme arthritis and/or Borrelia lymphocytoma. In dogs, acute signs include fever, general malaise, lameness, lymph node enlargement and polyarthritis, as well as neuro-borreliosis in the chronic form. Diagnosis is mainly serological in both humans and animals, based on either a two-tier approach (an immunoenzymatic test followed by a Western blot confirmatory test) in humans or C(6) peptide, only in dogs. Early treatment with antibiotics, such as doxycycline or amoxicillin, for three weeks usually reduces the risk of chronic disease. Tick control, including the use of tick repellents for both humans and animals, particularly dogs, is highly reliable in preventing transmission. Vaccines are not available to prevent human infection, whereas several vaccines are available to reduce transmission and the clinical manifestations of infection in dogs. PMID- 26601458 TI - The genus Anaplasma: new challenges after reclassification. AB - Summary The genus Anaplasmais one of four distinct genera in the family Anaplasmataceae, which are obligate intracellular pathogens vectored by ticks and found exclusively within parasitophorous vacuoles in the host cell cytoplasm. The 2001 reclassification of the order Rickettsiales expanded the genus Anaplasma, which previously contained pathogens that were host specific for ruminants (A. marginale, A. centrale and A. bovis), by adding A. phagocytophilum, a unification of three organisms previously classified as Ehrlichia (E. equi, E. phagocytophila and the unnamed agent of human granulocytic ehrlichiosis). Also included in the genus Anaplasma were A. bovis (formerly E. bovis), A. platys (formerly E. platys) and Aegyptianella pullorum. Despite the genomic relatedness of the regrouped organisms, many aspects of their biology are diverse, including their host specificity, host cell preferences, major surface proteins (MSPs) and tick vectors. This review focuses on the two most important pathogens: A. marginale, which causes bovine anaplasmosis, and A. phagocytophilum, the aetiologic agent of tick-borne fever in sheep and human granulocytic anaplasmosis, an emerging tick borne disease of humans. For both pathogens, strain diversity is much greater than previously recognised. While MSPs were found to be useful in phylogenetic studies and strain identification, highly conserved MSPs were found to affect the specificity of serologic tests. Comparison of these two important pathogens highlights the challenges and insight derived from reclassification and molecular analysis, both of which have implications for the development and evaluation of diagnosis and control strategies. PMID- 26601459 TI - Cattle trypanosomosis: the diversity of trypanosomes and implications for disease epidemiology and control. AB - Trypanosomosis is one of the most significant infectious threats to cattle in sub Saharan Africa, and one form has also spread to Asia and South America. The disease is caused by a complex of trypanosome species, and the species and strain of parasite can have a profound influence upon the epidemiology of the host parasite-vector relationships, the severity and course of infection, and, consequently, the implementation and development of control methods. This review will summarise our current knowledge of the relationship between trypanosome species/genotype and the phenotype of disease in cattle, and the implications that this has for ongoing efforts to develop diagnostics, drugs and vaccines for the control of cattle trypanosomosis. PMID- 26601460 TI - The aetiology, pathogenesis and control of theileriosis in domestic animals. AB - The Theileria genus includes a large number of species of tick-borne parasites that infect domestic animals and wildlife species, predominantly ruminants. These range from species, such as T. parva and T. annulata, which cause acute lymphoproliferative diseases in cattle resulting in high levels of mortality, to others that are non-pathogenic. In the last decade, several new pathogenic species of Theileria have been identified and pathogenic strains of other previously low-pathogenic species have emerged. Theileria parasites are characterised by developmental stages within leukocytes and erythrocytes. The capacity of the most pathogenic species to undergo extensive multiplication during intra-leukocyte development is central to their ability to cause disease. However, this is not the sole property responsible for disease, as illustrated by T. parva, which grows in a similar mannerin buffalo cells butdoes notcause disease inthisspecies. Because of the highly pathogenic nature of these parasites in livestock and the susceptibility of young animals to disease, control of the diseases is challenging. Control by chemotherapy and prevention of tick infestation has proved expensive and difficult to sustain. Vaccines using live parasites are available for T. parva and T. annulata and have been used with some success in the field. However, their widespread use has been hampered by practical constraints in production and distribution of the vaccines. Studies of the immune responses in immune cattle have helped to elucidate the protective immune responses and identified a number of parasite antigens that are currently being explored for development of alternative vaccines. PMID- 26601461 TI - Leishmaniosis (Leishmania infantum infection) in dogs. AB - The authors present an overview of canine leishmaniosis due to Leishmania infantum. This protozoan is transmitted by sandflies and the disease is frequently characterised by chronic evolution. Cutaneous and visceral clinical signs appear as the infection progresses. Lymph node enlargement, emaciation and skin lesions are the main signs observed in the classical forms of the disease. Control is difficult since infected dogs remain carriers for years and may relapse at any time. The mass screening of infected animals and their treatment or euthanasia represent the best way to reduce the prevalence of this disease in endemic regions. Further research is needed to improve the efficiency of the vaccines available to protect dogs against infection. This disease is zoonotic; in humans, clinical cases are reported mainly in elderly people, the young and those whose immune systems have been compromised. PMID- 26601462 TI - Babesiosis. AB - Babesiosis is the disease caused by infection of the erythrocytes of mammals by Babesia species, which are Apicomplexa protozoa belonging to the suborder Piroplasmidea and the family Babesiidae. They are different from the Theileriidae, which can also infect white blood cells and endothelial cells. Babesiosis is one of the most important tick-borne infectious diseases of domestic and wild mammals and still poses significant diagnostic and therapeutic challenges for veterinary practitioners around the world. It is an increasing problem worldwide because of the expansion of tick habitats and the increased mobility of animals, which promote the spread of parasites into new geographical areas. Babesia species can, exceptionally, infect humans, especially splenectomised or immunocompromised individuals. The majority of human cases involve B. microti, a parasite of rodents, but human infections may also be caused by B. divergens, which infects cattle, or by Babesia related to B. odocoilei, which infect cervids. The majority of new developments, in regard to taxonomy, epidemiology, pathogenesis and control, concern canine babesiosis, whereas piroplasmosis in horses or cattle retains the classical description, therefore the focus of this article will be on infection in dogs. PMID- 26601463 TI - Other vector-borne parasitic diseases: animal helminthiases, bovine besnoitiosis and malaria. AB - The parasitic diseases discussed elsewhere in this issue of the Scientific and Technical Review are not the only ones to make use of biological vectors (such as mosquitoes or ticks) or mechanical vectors (such as horse flies or Stomoxys flies). The authors discuss two major groups of vector-borne parasitic diseases: firstly, helminthiasis, along with animal filariasis and onchocerciasis, which are parasitic diseases that often take a heavytoll on artiodactylsthroughoutthe world; secondly, parasitic diseases caused by vector-borne protists, foremost of which is bovine besnoitiosis (or anasarca of cattle), which has recently spread through Europe by a dual mode of transmission (direct and by vector). Other protists, such as Plasmodium and Hepatozoon, are also described briefly. PMID- 26601464 TI - [CHANGES IN THE NUMBER OF REGENERATING MYELINATED FIBERS IN INJURED NERVE OF THE RAT AFTER ALLOTRANSPLANTATION OF THE DISSOCIATED CELLS OF THE EMBRYONIC CNS ANLAGES]. AB - The study was conducted on 6 female and 36 male adult Wistar rats to compare the effects of dissociated cells derived from different embryonic CNS anlages, on the growth of regenerating nerve fibers in the damaged nerve of the recipient. After the sciatic nerve was damaged by ligation, part of the animals received the injection into the proximal portion of the nerve with a suspension of the cells obtained by dissociation of the fragments of spinal cord or forebrain vesicle taken from rat embryos at Day 15 of development. The analysis of transverse semithin sections of the distal part of the nerves was performed 21 and 60 days after surgery. It was found that the number of regenerating myelinated nerve fibers was increased 60 days after the injection of dissociated embryonic spinal cord cells, but not the neocortical cells into the damaged nerve of the recipient. PMID- 26601465 TI - [ANGIOGENESIS IN THE TISSUES AFTER THE INJECTION OF STROMAL STEM CELLS OF BONE MARROW ORIGIN CLOSE TO THROMBOSED VEIN IN AN EXPERIMENT]. AB - The effects of the injection of autologous multipotent stromal stem cells of bone marrow origin (MSSCBM) (mesenchymal stem cells) with green fluorescent protein gene, additionally marked with DAPI nuclear stain, close to a thrombosed hindlimb vein, were studied by fluorescent microscopy in adult male Wag rats (n = 214). The control groups consisted of intact rats (n = 12), animals with venous thrombosis without the injection of MSSCBM (n = 71) and rats that received paravasal injection of MSSCBM, but without preliminary modeling of venous thrombosis (n = 72). It was found that MSSCBM participated in the development of granulation tissue at the site of surgical intervention performed during the modeling of thrombosis. The rapid development of granulation tissue at the site of surgical trauma may contribute to faster wound clearance from detritus, nonviable tissue and antigenic substances, early onset of tissue repair processes and rapid healing. Restoration of blood flow in the tissue region of a thrombosed vein began later than after the intravenous injection of MSSCBM. PMID- 26601466 TI - [PECULIARITIES OF THE CELLULAR COMPOSITION OF SPLENIC LYMPHOID TISSUE IN MICE AFTER LONG-TERM USE OF LIGHT WATER AND IRRADIATION]. AB - The changes of the cellular composition of splenic lymphoid tissue were studied 7, 15 and 30 days after irradiation with a dose of 50 rad, in BALB/c mice which received either distilled water or light (deuterium-depleted) water for a long time prior to and after irradiation. The irregular pattern of changes of splenic cellular composition was observed during the experiment. It was found that at day 7 after irradiation, the splenic structural zones in mice demonstrated a sharp decrease in the number of blast forms and mitotic cells, reflecting a lower level of lymphocytopoiesis, as well as an increased cellular destruction in mice consuming light water. By day 30 of the experiment, different responses of lymphoid structures were observed in the organ. In the periarteriolar lymphoid sheaths, the processes of cellular composition regeneration were more pronounced than in the germinal centers of lymphoid nodules, indicating the enhancement of body cell-mediated immunity and immunomodulating properties of light water in mice at later dates of post-irradiation period. PMID- 26601467 TI - [INTERSTITIAL CELLS OF CAJAL IN THE SMOOTH MUSCLE TISSUE OF THE GALLBLADDER AND BILE DUCTS]. AB - Interstitial cells of Cajal (ICC) in the gallbladder and in different parts of the biliary tract were identified in adult guinea pigs by means of immunocytochemical reactions to specific marker of these cells--C-kit receptor tyrosine kinase (CD117) and electron microscopic analysis. It was shown that C kit-positive cells were localized in the muscular component of the gallbladder wall and the various parts of the bile ducts. In the gallbladder wall their density was higher than in the bile ducts. ICC have numerous processes, and are characterized by the absence of the components of the contractile apparatus. They possess the capacity to form tight membrane contacts with smooth myocytes. PMID- 26601468 TI - [MORPHOLOGICAL PECULIARITIES OF THE LIVER IN COMMON VOLES INHABITING THE TERRITORY OF BORODINO COAL DEPOSITS AND RECULTIVATION AREAS]. AB - The aim of this work was to study the morphological changes of liver in common voles (Microtus arvalis Pallas) inhabiting the territories of brown coal deposition in Borodino coal opencast (Krasnoyarsk region) and on reclaimed dumps 10 and 20 years after its production. Trapping of the voles (10 animals in each group) living under natural conditions on each territory, was conducted for 30 days. Histological examination of the liver in all animals demonstrated degenerative changes and necrosis of hepatocytes, expressed to a various degree. Morphometric study has shown that the greatest changes in the structure of hepatic stroma and parenchyma took place in voles that lived in the dumps of coal, reclaimed 10 years before. It was found that in the animals of this group, the thickness of hepatocyte plates was increased 1.3 times, while the specific volume of necrotic hepatocytes was twice as much as this parameter in the animals that lived on intact territory. PMID- 26601469 TI - [MORPHOMETRIC CHARACTERISTICS OF THE ARTICULAR SURFACES OF THE TEMPOROMANDIBULAR JOINT IN DIFFERENT TYPES OF OCCLUSION IN ADULT PERSONS]. AB - Using 200 skull specimens of adult persons, morphometric characteristics of the articular surfaces of the temporomandibular joint were studied in different types of physiological and pathological occlusion. For systematization of the skulls studied by occlusion type, the classification of V. N. Trezubov was applied. It was found that the sizes of the head of the mandible, the mandibular fossa and articular tubercle in orthognathic occlusion and transient forms were practically the same. Maximum differences in these parameters (sagittal head diameter, anteroposterior size and depth of the mandibular fossa) was found between the groups of skulls with orthognatic and abnormal types of occlusion. It is shown that in the anomalous types of occlusion not only the morphological characteristics of the articular surfaces of the temporomandibular joint were changed, but mostly the intra-articular topography of the articulating joint surfaces. These changes can serve as the major. causes of development of dysfunction of the temporomandibular joint. PMID- 26601470 TI - [INDICATORS OF PUBERTY IN RURAL SCHOOLCHILDREN OF NIZHNIY NOVGOROD REGION]. AB - With the aim of developing standards and conducting comparative analysis of the level of puberty in rural schoolchildren of Nizhniy Novgorod region, with regard to the temporal and territorial factors, 2411 individuals of both sexes aged 11 17 years were examined. During medical examinations, that were conducted in 2011 2013, the development of secondary sexual characteristics was characterized. The results obtained were compared with those received in 1967-1968 surveys and in the studied of modern children and teenagers living in the city of Nizhniy Novgorod. It was found that the level of puberty in rural schoolchildren has grown statistically significantly over the past 45 years. The appearance of secondary sexual characteristics in boys was accelerated by 2-3 years. In girls, the shift of 1-2 years was observed, while the sequence of their development remained unchanged, and in boys it was accompanied by the delayed growth of the thyroid cartilage. Among rural and urban boys, the differences in the level of puberty was less pronounced than among the girls. By the rate of passage of puberty transformations, rural girls lag behind their urban peers for 1 year. Modern rural students of Nizhny Novgorod region are characterized by higher variability of the manifestation of secondary sexual characteristics and their expression than in other regions of the country, especially among boys. PMID- 26601471 TI - [EXPRESSION OF SEROTONIN TRANSPORT PROTEIN IN THE DORSAL RAPHE NUCLEUS IN THE EARLY POSTNATAL PERIOD IN RATS]. AB - In this work an expression of serotonin transport protein (5-HTT) was studied in the dorsal raphe nucleus (DRN)--in its dorsal, ventral and lateral subnuclei in Wistar rats (n = 15) during the early postnatal period. Histological methods and immunocytochemical staining demonstrating 5-HTT were used in the investigation. It was shown that at postnatal Day 5 major part of neurons of the subnuclei studied intensively expressed 5-HTT. However, by Day 10, the level of its expression decreased dramatically, but with age (by Day 20) the expression was increased once again. This was manifested by the augmentation of size of 5-HTT positive neuronal population, the increase in the density of plexus network of their processes. The detected changes of 5-HTT expression indicate the varying degrees of functional activity of serotonin in the DRN in the early postnatal period. PMID- 26601472 TI - [PECULIARITIES OF THE DISTRIBUTION OF ACETYLCHOLINESTERASE IN THE LATERAL POSTERIOR NUCLEUS OF THE THALAMUS OF THE CAT]. AB - Using the technique of histochemical detection of enzyme acetylcholinesterase (AChE), the existence of the loci with high enzyme activity in the lateral nucleus of the lateral posterior thalamic complex was demonstrated in 2-week-old kittens (n = 4) in contrast to the kittens aged 14 weeks (n = 4). These loci were located opposite similar loci in the medial nucleus of the lateral posterior thalamic complex. Possible link between identified AChE-positive loci and the organization of thalamo-cortical and cortico-thalamic projections is discussed. PMID- 26601473 TI - [INTRANUCLEAR IRON DISTRIBUTION IN THE PURKINJE CELLS OF HUMAN CEREBELLUM]. AB - The distribution of iron ions in the cerebellum of 15 human subjects aged 20-89 years was studied using highly-sensitive variant of Perls' histochemical technique. Increased iron content was found in the white matter and in Purkinje cells. In 10 out of 15 cases examined iron was detected in the nuclei of Purkinje cells, while in some cases iron was found in the nucleolus. PMID- 26601474 TI - [VISUALIZATION OF THREE-DIMENSIONAL RELIEF STRUCTURES OF SEROUS MEMBRANES WITH A LIGHT MICROSCOPE]. AB - Methods for three-dimensional visualization of histological film preparations were developed using traditional flat-field microscopes. Preliminarily, the structures examined acquired the light reflecting ability by the reduction of silver nitrate impregnating them. Microscopy of preparations is carried out in reflected incident tenebrous illumination. The methods of processing of preparations for the study of cell surface relief, limiting membrane of the mesothelium and subsurface collagen fibers. Preparations are stored and examined in the wet state. PMID- 26601475 TI - [THE METHODOLOGICAL BASIS FOR THE PLASTINATION OF BODY SAWCUTS]. AB - The article describes the technique for making transparent lamellar human body slices using the method of plastination with epoxy resin. Different factors influencing the velocity of dehydration and impregnation of body slices were examined, the dependence of transparency of plastinated slices on the refraction coefficient of the epoxy composition was established. Physical and chemical methods for viscosity correction and optical refraction of epoxy resin composition were suggested. It was shown that plastinated slices with the thickness from 3 to 5 mm had the best demonstration characteristics. The technique suggested can be used for producing educational plastinated specimens for topographic anatomy and for clinical anatomical studies. PMID- 26601476 TI - [PRECHORDAL AND MYOEPICARDIAL PLATES: TERMINOLOGICAL ASPECTS, THE PROBLEMS OF DEFINITION]. AB - Most accurately, the prechordal plate (PCP) can be defined as the zone of close contact of cells of endodermal epithelium and mesenchyme in the region between the oropharyngeal membrane and the notochord. This structure is involved in the induction of the anterior parts of the brain and, in particular, the pituitary gland, as well as in the formation of some of eye muscles and bones of the skull base (chordal chondrocranium). Further studies are needed to clarify PCP involvement in the development of pharynx, esophagus, and their derivatives, as well as to determine the source and the mechanisms of development of PCP mesenchymal cells. The term "prechordal plate" should not be confused with the Spemann's organizer, head organizer, oropharyngeal membrane, mesendoderm, head process and the prechordal mesoderm, which is common in the scientific literature. The term "myoepicardial plate" falsely indicates the common origin of myocardium and epicardium, thus its usage should be avoided. PMID- 26601477 TI - [THE BASOLATERAL NUCLEUS IN THE SYSTEM OF REPRODUCTIVE CENTERS OF THE AMYGDALA]. AB - In this review contains the systematized data available in modern literature, which characterize the basolateral nucleus of the amygdala as one of the sexual dimorphism zones (SDZ) and its relationship with other reproductive centers of the amygdala. The basolateral nucleus, as the structure of the phylogenetically new part of the amygdala--receives the major amount of the pheromone and olfactory information through phylogenetically old--corticomedial division of the amygdala. Integrating it with the sensory signals of different modality, coming from the thalamus and cortical formations, the basolateral nucleus, together with the SDZ of corticomedial division, participates in the organization of sexual behavior and regulation of gonadotropin secretion. Sexual dimorphism of the basolateral nucleus, which is involved in the functional system of emotion formation and memory mechanisms, determines sex-dependent features of their behavioral manifestations, especially in stress reactions. PMID- 26601478 TI - [Experience in teaching the discipline "Histology, Embryology, Cytology - Histology of the Oral Cavity"]. PMID- 26601479 TI - [The contribution of academician K.A. Zufarov to the development of morphological science (to 90th anniversary of birth)]. PMID- 26601481 TI - [Morphological sciences as the theoretical basis of clinical ophthalmology]. PMID- 26601480 TI - [The work of the Russian morphologist abroad]. PMID- 26601482 TI - [In memory of Mikhail Romanovich SAPIN]. PMID- 26601483 TI - [In memory of Pavel Aleksandrovich MOTAVKIN]. PMID- 26601484 TI - [Genotypic Diversity of Wolbachia pipientis in Native and Invasive Harmonia axyridis Pall., 1773 (Coleoptera, Coccinellidae) Populations]. AB - The distribution and variability of reproductive symbiotic Wolbachia pipientis bacteria were studied in seven native and six invasive H. axyridis populations. Wolbachia-infected individuals were found in two invasive and two native populations. We demonstrated for the first time an infection of invasive H. axyridis populations with Wolbachia. Two new molecular forms of Wolbachia were detected by a system of multilocus typing. The supergroup A Wolbachia was found for the first time in H. axyridis. The detected genotypic diversity of Wolbachia indicates repeated and independent infection events in the evolutionary past of H. axyridis. PMID- 26601485 TI - [The Effect of Introduction of the Heterologous Gene Encoding the N-acyl homoserine Lactonase (aiiA) on the Properties of Burkholderia cenocepacia 370]. AB - To study the role of Quorum Sensing (QS) regulation in the control of the cellular processes of Burkholderia cenocepacia 370, plasmid pME6863 was transferred into its cells. The plasmid contains a heterologous gene encoding for AiiA N-acyl-homoserine lactonase, which degrades the signaling molecules of the QS system of N-acyl-homoserine lactones (AHL). An absence or reduction of AHL in the culture was revealed with the biosensors Chromobacterium violaceum CV026 and Agrobacterium tumifaciens NT1/pZLR4, respectively. The presence of the aiiA gene, which was cloned from Bacillus sp. A24 in the cells of B. cenocepacia 370, resulted in a lack of hemolytic activity, which reduced the extracellular proteolytic activity and decreased the cells' ability to migration in swarms on the surface of the agar medium. The introduction of the aiiA gene did not affect lipase activity, fatty acids synthesis, HCN synthesis, or biofilm formation. Hydrogen peroxide was shown to stimulate biofilm formation by B. cenocepacia 370 in concentrations that inhibited or weakly suppressed bacterial growth. The introduction of the aiiA gene into the cells did not eliminate this effect but it did reduce it. PMID- 26601486 TI - [Study of Chloroplast DNA Polymorphism in the Sunflower (Helianthus L.)]. AB - The polymorphism of microsatellite loci of chloroplast genome in six Helianthus species and 46 lines of cultivated sunflower H. annuus (17 CMS lines and 29 Rf lines) were studied. The differences between species are confined to four SSR loci. Within cultivated forms of the sunflower H. annuus, the polymorphism is absent. A comparative analysis was performed on sequences of the cpDNA inbred line 3629, line 398941 of the wild sunflower, and the American line HA383 H. annuus. As a result, 52 polymorphic loci represented by 27 SSR and 25 SNP were found; they can be used for genotyping of H. annuus samples, including cultural varieties: twelve polymorphic positions, of which eight are SSR and four are SNP. PMID- 26601487 TI - [Creation of Blast Disease-Resistant Rice Sorts with Modern DNA-Markers]. AB - Based on modern technologies of molecular DNA-markers, blast disease-resistance genes (Pi-ta, Pi-b, Pi-1, Pi-2, and Pi-33) were introgressed and pyramided into domestic rice varieties to give them long-term disease resistance. For that purpose, this case study uses SSR-markers closely linked to these genes, as well as intragenic markers of genes Pi-ta and Pi-b. Multiplex PCR systems were created for simultaneous identification of two resistance genes in the hybrid progeny for the following combinations: Pi-1 + Pi-2, Pi-ta + Pi-b, Pi-ta + Pi-33. PMID- 26601488 TI - [Genetic Differentiation of the Three Species of Genus Astragalus L. of Section Cenantrum Bunge (Fabaceae)]. AB - Genetic differentiation based on allozyme data was detected between species of the genus Astragalus L., section Cenantrum Bunge (Fabaceae): A.frigidus (L.) A. Gray s.l., A. mongholicus Bunge s. l, and A. sericeocanus Gontsch, which is endemic to the Northeast coast of Lake Baikal. The results of allozyme analysis confirm the natural division of the section into subsections based on morphological features. Differences between A. frigidus (subsection Elliptica Gontsch.) and A. mongholicus and A. sericeocanus (subsection Semilunaria Gontsch.) were observed. These differences were caused by the presence of species specific alleles and the allele frequencies of the primary alleles, DN = 1.24. The genetic distance obtained for A. mongholicus and A. sericeocanus (0.10) corresponds to the status of closely related species of one subsection. Between populations of A. frigidus and between populations of A. mongholicus from the central part of areal, DN = 0.02 and 0.03 respectively. This genetic distance corresponds to the interpopulation level and was determined by the allele frequencies. The peripheral population of A. mongholicus is separated (DN = 0.36), which is probably due to the long isolation and the "founder effect." PMID- 26601489 TI - [The Use of Specific DNA Markers for the Identification of Alleles of the FAD3 Genes in Rape (Brassica napus L.)]. AB - A search was conducted for the alleles responsible for the quality of food-grade rapeseed oil in a collection of 21 samples of spring and winter oilseed rape of Belarusian and Russian breeding. We also developed A- and C-gene-specific DNA markers to assess the genomic polymorphisms of rape for FAD3 genes and selected plants with a low content of linolenic acid for use in the selection process. The development of a method for identifying FAD3 alleles, which control the level of linolenic acid in rapeseed oil, as well as of the design for new dCAPS markers, enabled the identification of plants homozygous for individual FAD3A and/or FAD3C genes in the F2-generation. These plants are currently involved in the selection process of new varieties with a reduced content of linolenic acid in rapeseed oil. PMID- 26601490 TI - ANALYSIS OF GENOMIC DNA METHYLATION AND GENE EXPRESSION IN CHINESE CABBAGE (Brassica rapa L. ssp. pekinensis) AFTER CONTINUOUS SEEDLING BREEDING. AB - Vernalization plays a key role in the bolting and flowering of Chinese cabbage (Brassica rapa L. ssp. pekinensis). Plants can switch from vegetative to reproductive growth and then bolt and flower under low temperature induction. The economic benefits of Chinese cabbage will decline significantly when the bolting happens before the vegetative body fully grows due to a lack of the edible value. It was found that continuous seedling breeding reduced the heading of Chinese cabbage and led to bolt and flower more easily. In the present study, two inbred lines, termed A161 and A105, were used as experiment materials. These two lines were subjected to vernalization and formed four types: seeds-seedling breeding once, seedling breeding twice, seedling breeding thrice and normal type. Differences in plant phenotype were compared. DNA methylation analysis was performed based on MSAP method. The differential fragments were cloned and analyzed by qPCR. Results showed that plants after seedling breeding thrice had a loosen heading leaves, elongated center axis and were easier to bolt and flower. It is suggested that continuous seedling breeding had a weaker winterness. It was observed that genome methylation level decreased with increasing generation. Four differential genes were identified, short for BraAPC1, BraEMP3, BraUBC26, and BraAL5. Fluorescent qPCR analysis showed that expression of four genes varied at different reproduction modes and different vernalization time. It is indicated that these genes might be involve in the development and regulation of bolting and flowering of plants. Herein, the molecular mechanism that continuous seedling breeding caused weaker winterness was analyzed preliminarily. It plays an important guiding significance for Chinese cabbage breeding. PMID- 26601491 TI - [Topological Conflicts in Phylogenetic Analysis of Different Regions of the Sable (Martes zibellina L.) Mitochondrial Genome]. AB - Phylogenetic analysis of different regions of the mitochondrial genome of the sable showed the presence of several topologies of phylogenetic trees, but the most statistically significant topology is A-BC, which was obtained as a result of the analysis of the mitochondrial genome as a whole, as well as of the individual CO1, ND4, and ND5 genes. Analysis of the intergroup divergence of the mtDNA haplotypes (Dxy) indicated that the maximum Dxy values between A and BC groups were accompanied by minimum differences between B and C groups only for six genes showing the A-BC topology (12S rRNA; CO1, CO2, ND4, ND5, and CYTB). It is assumed that the topological conflicts observed in the analysis of individual sable mtDNA genes are associated with the uneven distribution of mutations along the mitochondrial genome and the mitochondrial tree. This may be due to random causes, as well as the nonuniform effect of selection. PMID- 26601492 TI - [Cytogenetic Analysis of the Species Composition and Inversion Structure of Populations of Malarial Mosquitoes in the Astrakhan Region]. AB - A cytogenetic analysis of Anopheles mosquitoes in the Astrakhan region was carried out. Three species of Anopheles were identified. An. messeae lives everywhere and prevails in all of the areas of research, An. hyrcanus is found in the southwest of the region, and An. maculipennis in the northern part of the region. The populations of An. messeae show a high level of inversion polymorphism for the sex chromosome and the third autosome. A clear clinal trend of an increase in chromosomal rearrangements XL1, 3R1, and 3L1 and a decrease in the frequency of evolutionary source alternatives was revealed in laraval hemipopulations of the species from south to north. PMID- 26601493 TI - MARKER ASSISTED EVALUATION OF MORPHOLOGICAL AND GENETIC ATTRIBUTES OF SUB POPULATIONS OF NILI-RAVI BUFFALO: A VULNERABLE DAIRY TYPE RIVERINE BREED OF INDIA. AB - In the present study, we report the distribution of true to type and atypical Nili-Ravi buffalo, a vulnerable dairy type riverine breed of North India and its underlying genetic structure. Out of total investigated buffaloes 73.5% had bilateral wall eyes while 5.4% had unilateral wall eyes and 21.1% had no wall eyes. 41.15% of Nili-Ravi buffaloes maintained in the breeding farm were having typical true to the type characteristics (both eyes walled, white markings in forehead, muzzle/chin, all the four legs and tail) while only 28.5% of Nili-Ravi buffaloes were true to the type under field conditions. Genotypic data were generated in four groups of Nili-Ravi buffalo (FMTNR--Typical Nili-Ravi from farm; FMANR--Atypical Nili-Ravi from farm; FDTNR--Typical Nili-Ravi from field; FDANR--Atypical Nili-Ravi from field) at 16 microsatellite loci. Comparative genetic analysis of various groups of Nili-Ravi buffaloes with Murrah revealed significant between group differences with an estimated global F(ST) of 0.063. Pair-wise F(ST) values ranged from 0.003 (between FDTNR and FDANR) to 0.112 (between FMTNR and FDTNR). Phylogenetic analysis and multi-dimensional scaling revealed clustering of FDTNR and FDANR together while FMTNR and FMANR clustered separately with Murrah in between farm and field Nili-Ravi buffaloes. Based on the results, the paper also proposes three pronged strategy for conservation and sustainable genetic improvement of Nili-Ravi buffalo in India. PMID- 26601494 TI - [Ethnic Marriage Assortativeness and Intensity of Metisation of Karachays]. AB - On the basis of 11,280 marriage records of four regions of Karachay-Cherkessia (Karachaevsky, Malokarachaevsky, Ust-Dzhegutinsky, Prikubansky, 193.2 thousand people in total) for 1990-2000, the intensity of Karachay cross-breeding was determined, amounting to 11.7%. Comparison of the intensity of Karachay cross breeding with that for some other ethnoses is carried out. The ethnic assortativness H is approximately one. The population is characterized a preference for monoethnic marriages. The endogamy index in the studied regions varies from 0.29 to 0.53; after the exclusion from the analysis of repatriates, it increases to 0.34-0.63. The values of local inbreeding in an interval are 0.0001-0.0004, and no differences in terms of isolation by distance are revealed among the regions (0.01). The average square migration is 40-60 km. PMID- 26601495 TI - [Characteristic of the Genetic Variability of Four Polymorphic Variants (rs2069705, rs17880053, rs11126176, and rs804271) in Representative Samples of Indigenous and Alien Populations of Siberia]. AB - The variability of potentially important functional polymorphic variants rs2069705 (5'UTR of the IFNG gene), rs17880053 (near 5'UTR of the IFNGR2), rs11126176 (LOC100287361 pseudogene), and rs804271 (near 5'UTR of the NEIL2 gene) was characterized in representatives of four ethnic groups living in the Siberian region. These ethnic groups included three indigenous Mongoloid ethnic groups (Yakuts, the residents of the Republic of Sakha (Yakutia), Tuvinians from the Republic of Tuva, and Buryats from the Republic Buryatia) and the alien Russian population. All of the examined variants were polymorphic. The frequency of the rs2069705 allele C in Russians was 0.5833, while it was in a range from 0.7842 to 0.8967 in representatives of the indigenous populations. The frequency of rs17880053 deletion was 0.8073 in Russians and from 0.4474 to 0.5521 in the indigenous ethnic groups. The frequency of the rs11126176 allele A was equal to 0.5398 in Russians but was recorded with lower frequencies in indigenous ethnic groups (from 0.2722 to 0.4551). The frequency of the rs804271 allele Gwas 0.5215 in Russians and from 0.2527 to 0.4022 indigenous ethnic groups. With respect to the genotype structure, the alien Russian population was considerably distanced from indigenous Mongoloid populations. Specifically, the genetic distance was 0.0742 between Russians and Yakuts, 0.1365 between Russians and Tuvinians, and 0.1433 between Russians and Buryats. Among the Mongoloid indigenous ethnic groups of Siberia, Tuvinians and Yakuts were the most distant from each other (0.0262). The genetic distance was equal to 0.0151 between Yakuts and Buryats and 0.0127 between Buryats and Tuvinians. PMID- 26601496 TI - [Accounting for Expected Linkage in Biometric Analysis of Quantitative Traits]. AB - The problem of accounting for a genetic estimation of expected linkage in the disposition of random loci was solved for the additive-dominant model. The Comstock-Robinson estimations for the sum of squares of dominant effects, the sum of squares of additive effects, and the average degree of dominance were modified. Also, the Wright's estimation for the number of loci controlling the variation of a quantitative trait was modified and its application sphere was extended. Formulas that should eliminate linkage, on average, were derived for these estimations. Nonbiased estimations were applied to the analysis of maize data. Our result showed that the most likely cause of heterosis is dominance rather than overdominance and that the main part of the heterotic effect is provided by dozens of genes. PMID- 26601497 TI - [Analysis of Eight Polymorphic Alu Elements in the Teleuts Population]. AB - Allele frequencies and genetic diversity in the population of Teleuts were assessed by the Alu repeat polymorphism at eight autosomal loci (ACE, APOA1, PLAT, F13, PV92, A25, CD4, Dl). For comparison, the study included previously obtained data on the Alu polymorphism in 19 indigenous populations of Siberia. On the dendrogram of genetic distances, the Teleut population is located in the cluster of Siberian ethnic groups, which are similar in origin, geography, and cultural traditions. PMID- 26601498 TI - [A Role of the Wnt Signaling in the Regulation of Brain Function]. AB - The review describes the Writ signaling pathway participation in the embryonic development, such as cell specification, migration and polarity. Recent studies have shown that the Wnt pathway plays one of the key roles in the processes of synaptic plasticity and memory formation. In this review there are evidences of the Wnt cascade involvement in the modulation of synaptic efficacy at both pre- and postsynaptic levels. Here we analyze the role of Wnt ligands in synaptic plasticity and behavior. Finally, we describe that components of Wnt pathways are involved in the development of major neurological and psychiatric disorders, including a neuroprotective role of Wnt proteins in the pathogenesis of Alzheimer's disease. PMID- 26601499 TI - [Latencies of Sensory and Cognitive Components of Event Related Potentials during Perception of Verbal Stimuli in the Norm and Schizophrenic Patients]. AB - The aim of this work is the study of early and later indices of brain informational processing during the passive reading of concrete words in healthy subjects and schizophrenic patients using the ERP method. Comparative analysis of components P100, N170, P200 and P300 in implicit situation showed that in schizophrenic patients the latency of early components P100 and N170 is shorter while the latency of later components P200 and P300--is longer than in healthy subjects. It could be supposed that the patients have deficit of the early automatic sensory processing of the stimuli revealing through the shortening of their recognition time and this results in the decrease of completeness and preciseness of sensory analysis. In the study there were also revealed negative correlations between the latencies of P100 and P200 components (P200 being a "recognition potential") in healthy subjects confirming the hy pothesis that longer sensory processing of verbal stimuli leads to the shortness of the time for its recognition. For schizophrenic patients the relation between the duration of sensory and cognitive ERP components is disturbed. They have positive correlations between the latencies of early and late components possibly on account of the nonspecific contribution both in early and late components while in normal subjects the early components are more specific than the late ones. PMID- 26601500 TI - [Influence Additional Cognitive Tasks on EEG Beta Rhythm Parameters during Forming and Testing Set to Perception of the Facial Expression]. AB - The research of changes of a beta rhythm parameters on condition of working memory loading by extension of a interstimuli interval between the target and triggering stimuli to 16 sec is investigated on 70 healthy adults in two series of experiments with set to a facial expression. In the second series at the middle of this interval for strengthening of the load was entered the additional cognitive task in the form of conditioning stimuli like Go/NoGo--circles of blue or green color. Data analysis of the research was carried out by means of continuous wavelet-transformation on the basis of "mather" complex Morlet-wavelet in the range of 1-35 Hz. Beta rhythm power was characterized by the mean level, maxima of wavelet-transformation coefficient (WLC) and latent periods of maxima. Introduction of additional cognitive task to pause between the target and triggering stimuli led to essential increase in absolute values of the mean level of beta rhythm WLC and relative sizes of maxima of beta rhythm WLC. In the series of experiments without conditioning stimulus subjects with large number of mistakes (from 6 to 40), i.e. rigid set, in comparison with subjects with small number of mistakes (to 5), i.e. plastic set, at the forming stage were characterized by higher values of the mean level of beta rhythm WLC. Introduction of the conditioning stimuli led to smoothing of intergroup distinctions throughout the experiment. PMID- 26601501 TI - [P100 and N170 Components of ERPs in Abstinent Cannabinoid Users during the Modified Stroop Task]. AB - In the current work we conducted the comparative analysis of P100 and N170 components of ERPs in abstinent cannabinoid users and in healthy controls during the modified Stroop task. The latency of P100 and N170 components was shorter in the temporal, parietal and occipital areas in abstinent cannabinoid users in comparison with the control subjects. The cannabinoid group showed the decrease of P100 amplitude in the right temporal and parietal areas and the decrease of N170 amplitude in the left temporal and parietal areas. There were no differences in the behavioral indices between these two groups. Thus, cannabinoids influence upon the mechanisms of early selection and these alterations of brain activity are stable and long-term. PMID- 26601502 TI - [Identification of Spatial Coding Schemes by Errors Distribuition of Human Memory]. AB - The error distributions of sensory screen touches at kinesthetically memorization and reproduction of visual stimuli containing Muller-Lyer illusion and neutral stimuli were investigated. One group of right-handers begins the task with the right hand and continues with the left one, while the other group--vice versa. It was shown that the errors are distributed either exponentially (with the maximal amount of small errors) either with the maxima at the 2nd bin. The number of errors distributions decaying exponentially is higher for the group beginning the task with the right hand. The errors distributions of touches on the upper segment by the right hand decay exponentially faster than other distributions. Comparison of these data with the simulation results supports the hypothesis of specific for the right and left hemisphere positional and vector coding schemes at human memory. PMID- 26601503 TI - [Dynamics of Brain Activity during Voluntary Movement: fMRI Study]. AB - The use of event-related fMRI makes it possible to investigate spatio-temporal dynamics of cortical and subcortical human brain structures activity during voluntary movement performance in response to presentation of relevant verbal stimuli. The results of the study showed that voluntary movement was associated with higher contralateral brain activation in a number of areas: primary motor and somatosensory cortex, premotor cortex, supplementary motor area and insula with adjacent regions. Ipsilateral activation of the cerebellum also was observed. It should be emphasized that contralateral strio-pallidal complex and ventral thalamus showed significant response to motor tasks. Similarly, the dynamics of cortex and deep brain structures activation involving in the phasic and tonic components of voluntary movement was uncovered. We showed, in particular, the noticeable difference in brain activation between the right and left hand movement performance. The obtained results enable to enhance understanding of the role of deep brain structures in voluntary movement organization in human and motor control system as a whole. PMID- 26601504 TI - [Single and Network Neuron Activity of Subthalamic Nucleus at Impulsive and Delayed (Self-Control) Reactions in Choice Behavior]. AB - During our experiments on cats was investigated the subthalamic neuron activity at different types of behavior in case of reinforcement choice depending on its value and availability. In chronic experiences the multiunit activity in subthalamic nucleus (STN) and orbitofrontal cortex (FC) has been recorded. Multiunit activity was analyzed over frequency and network properties of spikes. It was shown, that STN neurons reaction to different reinforcements and conditional stimulus at short- or long-delay reactions was represented by increasing or decreasing of frequency of single neurons. However the same STN neu rons responded with increasing of frequency of single neuron during expectation of mix-bread-meat and decreasing--during the meat expectation. It has been revealed, that the number of STN interneuron interactions was authentic more at impulsive behavior than at self-control choice of behavior. The number of interactions between FC and STN neurons within intervals of 0-30 Ms was authentic more at display impulsive than during self-control behavior. These results suppose that FC and STN neurons participate in integration of reinforcement estimation; and distinctions in a choice of behavior are defined by the local and distributed interneuron interactions of STN and FC. PMID- 26601505 TI - [Latencies of Repeated Responses to Single Pulse Stimulation of the Schaffer Collaterals Registered in Hippocampal Field CA1 in Rats During Sleep]. AB - It is assumed that hippocampal neurons which were activated via the neocortex by new stimulus during the wakefulness and after that maintain its transient memory trace must be reactivated during the sleep to consolidate corresponding permanent memory trace in the neocortex. So we investigated the possibility of reverberation of excitation in the neuronal circuits connecting the hippocampus and entorhinal cortex. In sleeping rats within proximal part of the field CA1 of dorsal hippocampus we recorded double and triple responses to single pulse stimulation of Schaffer collaterals with previously potentiated synapses. Analysis of latent periods of repeated responses permitted to assume that the wave of excitation that was initiated in the field CA1 and returned from the entorhinal cortex to the locus of registration in the CA1 directly via perforant path fibers or throw the field CA2, can evoke repeated discharge of neurons in the CA1 but not the same that were activated initially by stimulation of Schaffer collaterals. So the neuronal circuits connecting the hippocampus and entorhinal cortex don't maintain reactivation of "learned" neurons in following periods of sleep. PMID- 26601506 TI - [Influence of D1, D2 Receptor Blockade in Basolateral Amygdala on Behavior of Rats with High or Low Levels of Anxiety and Fear]. AB - The influence of bilateral D1 or D2 receptors antagonists infusions into the rat basolateral amygdala on anxiety, as well as the expression, extinction and re learning of conditioned fear was studied. Subjects were the male Wistar rats with high and low anxiety behavior in elevated plus maze, and also rats with low and high freezing responses during fear conditioning. The infusion of D1 receptor antagonist (SCH23390, 1 ug/0.5 uL in each side) reduced the expression of the conditioned fear to sound in rats with low freezing level, accelerated fear extinction and impaired re-learning in all animals. The injection of D2 receptor antagonist (raclopride, 1 ug/0.5 uL in each side) accelerated the extinction of conditioned fear to contextual cues in all rats and had a weak anxiolytic-like effect on behavior of high anxiety rats in elevated plus maze. These findings testify to the role of D1 receptors in the acquisition, expression and extinction of conditioned fear to stimuli, and D2 receptors in the occurrence of anxiety and fear to the contextual cues. There was discovered different sensitivity of animals with different levels of anxiety and fear to the infusion of dopamine receptors antagonists in the amygdala that suggested the inequality of dopaminergic transmission in the amygdala of animals with individual differences. PMID- 26601507 TI - [Alteration of Social Behaviors in Male Mice of CBA/Lac Strain under Agonistic Interactions]. AB - Ability of people to communicate with each other is a necessary component of social behavior and normal development of individuals living in community. A pronounced impairment in communication may be the result of autism which is characterized by impaired socialization, low communication and restricted and/or repetitive behaviors. It is hypothesized that genes or rare mutations play a key role in the development of autism. However a multifold increase of the cases with autistic spectrum symptoms over the last years cannot be attributed exclusively to genetic mutations or heredity. Environmental contribution to the development of autistic symptoms has to be considered. The paper aimed to analyze the social behaviors of CBA/Lac mice with repeated experience of aggression or social defeats in daily agonistic interactions with accent on searches of associations with autistic symptoms in comparison with previously studied C57BL/6J animals. It has been shown that male mice of both strains with alternative social behaviors demonstrated the changes in social behaviors; however the expression of some form of behaviors was different. The data obtained to assert that long-term hostile social environment lead to development of disturbances in social behaviors, accompanying by autistic-like symptoms. PMID- 26601508 TI - [Neurophilosophy]. AB - In the paper the role of philosophical approaches in analyses of the MRT data, neuropathologies is dis cussed. Importance of teleological approaches is stressed. PMID- 26601509 TI - [Determinism and Freedom of Choice in the Brain Functioning]. AB - The problem is considered whether the brain response is completely determined by the stimulus and the personal experience or in some cases the brain is free to choose its behavioral response to achieve the desired goal. The attempt is made to approach to this important philosophical problem basing on modern knowledge about the brain. The paper consists of four parts. In the first part the theoretical views about the free choice problem solving are considered, including views about the freedom of choice as a useful illusion, the hypothesis on appliance of quantum mechanics laws to the brain functioning and the theory of mentalism. In other tree parts consequently the more complicated brain functions such as choice reaction, thinking and creation are analyzed. The general conclusion is that the possibility of quite unpredictable, but sometimes very effective decisions increases when the brain functions are more and more complicated. This fact can be explained with two factors: increasing stochasticity of the brain processes and the role of top-down determinations from mental to neural levels, according to the theory of mentalism. PMID- 26601510 TI - [CLOSING OF INTERVENTRICULAR SEPTUM DEFECT IN ONE-STEP AND STEPWISE SURGICAL TREATMENT IN PATIENTS WITH PULMONARY ATRESIA AND AORTO-PULMONARY COLLATERALS]. AB - Pulmonary atresia with defect of interventricular septum and collateral pulmonary blood flow refers to complicated congenital malformation of the heart. Surgical treatment represents itself as very difficult task because of anatomical variability of this abnormality. The main problem of surgery is a definitive repair of the defect including correction of maldistributions of pulmonary arterial bed (unifocalization of pulmonary blood flow), reconstruction of outflow tract of the right ventricle and closing of interventricular septum defect. The performance of closing interventricular septum defect could be successful in patients with pulmonary atresia and collateral pulmonary blood flow in case of stepwise and one-step surgical treatment. The combination of maximal number of pulmonary segments and sufficient development of central pulmonary arteries facilitates to progress of assigned task. Patients with the level of pulmonary arterial index more than 170 mm/m2 and integrity of pulmonary arterial bed, centralization of pulmonary segments (minimum 15) could be considered as a candidate for definite repair of the defect. PMID- 26601511 TI - [INTRAOPERATIVE DETECTION OF SENTINEL LYMPH NODES USING INFRARED IMAGING SYSTEM IN LOCAL NON-SMALL CELL CARCINOMA OF LUNG]. AB - The article presents the results of the first domestic experience of intraoperative fluorescence mapping of sentinel lymph nodes in lung cancer. The research included 10 patients, who underwent surgery over the period of time from September 2013 to May 2014. After performing thoracotomy, the solution of indocyanine green (ICG) was injected using subpleural position above the tumor in 3-4 points. Fluorescence (ICG) image guided surgery was carried out by using infrared radiation (wave length 808 nm) on lung surface, root of lung, mediastinum in real time. Fluorescence lymph nodes were mapped. In case that metastatic lesions weren't revealed in sentinel lymph nodes, they weren't noted in other nodes. Method specificity consisted of 100%. Biopsy and histological study of sentinel lymph nodes mapped during fluorescence (ICG) image guided surgery could be useful for prevention of lymphodissection in patients with non small cell carcinoma of lung. PMID- 26601512 TI - [FEATURES OF LYMPHADENECTOMY PERFORMANCE IN PATIENTS WITH STOMACH CANCER IN RADICAL SURGERY IN CASE OF VARIANT STRUCTURE OF CELIAC TRUNK]. AB - The authors developed and described an algorithm and technical aspects of lymphadenectomy performance in radical surgery based on structural variations of visceral vessels in 91 patients with stomach cancer. Preoperative helical computer tomography in regimen of angiography was carried out on 91 patients. Variant anatomy of visceral vessels was detected in 31 patients and that required change of surgical technique in order to minimize intraoperative risks of great vessel damage and allowed perforrming lymphadenectomy successfully. PMID- 26601513 TI - [PREVENTIVE COLOSTOMY IN PLANNED TREATMENT OF PATIENTS WITH RECTAL CANCER]. AB - The article described an original method of forming preventive colostomy, which reduced the rate of incompetence of interintestinal anastomosis in sphinctersaving resection concerning rectal cancer. This also facilitated patient's rehabilitation in early postoperative period. PMID- 26601514 TI - [PREDICTION OF RISK FACTORS OF LATERAL LYMPH NODE METASTASIS IN RECTAL CANCER]. AB - Standard methods of diagnostics haven't got a proper sensitivity and specificity concerning assessment of regional nodal involvement in case of rectal cancer. Therefore it is necessary to look for new method of diagnostics, detect risk factors and unfavorable prognosis in relation to lateral lymph node metastasis. At the same time, there should be a differentiated approach to the choice of therapeutic management in rectal cancer. Investigation of variability of blood supply of the rectum could be an additional method of diagnostics in rectal cancer. PMID- 26601515 TI - [CHOICE OF PROSTHESIS IN AXILLOFEMORAL BYPASS IN PATIENTS WITH HIGH RISK AND MULTILEVEL LESIONS OF LOWER LIMB ARTERIES]. AB - An analysis of results of experimental research was made in 60 patients with critical ischemia of lower extremities due to bilaterally atherosclerotic lesions of aorto-iliac segment, which had a high operationally anaesthetic risk. Synthetic polytetrafluoethylene prosthesis or biological shunt from internal pectoral bull arteries were used as a shunt. Revasculization was performed through the system of arteria profunda femoris considering multilevel lesions of lower limb arteries. An application of biological prosthesis allowed decreasing the rate of early postoperative complications on 13,3% , late thromboses--on 30%, extending the medium term of shunt functioning in 1.8%, improving physical component of health on 12.8% and mental--on 9.1% during the immediate postoperative period. The experiments on rabbits were carried out. It was shown, that biological prosthesis had the greatest biological compatibility. PMID- 26601516 TI - [COMBINATION OF VESSEL EMBOLIZATION AND CRYOTHERAPY IN SURGICAL TREATMENT OF SOFT TISSUE SARCOMAS]. AB - The article analyzed the results of surgical treatment of 153 patients with soft tissue sarcomas. The surgery was complemented by preoperative embolization of vessels, which supplied the tumor, cryotherapy on the tumor and postoperative wound in 72 patients of main group. The control group consisted of 81 patients and there weren't any perioperative actions. It was shown, that more than 80% of soft tissue sarcomas had the main and mixed type of tumor blood supply. Partial and full reduction of blood flow could be obtained by embolization of the tumor in more than 50% patients. Combination of surgical and preoperative embolization of vessels and cryotherapy decreased the rate of local recurrence and increased the quantity of organosafe interventions. PMID- 26601517 TI - [SIGNIFICANCE OF DOPPLER-GRAPHIC RESEARCHES FOR DIAGNOSTICS OF PROSTATE CANCER]. AB - An analysis of the Doppler-graphic results was made in transrectal ultrasound in 98 patients. Prostate cancer was detected in 44 cases. Priority zones for bioptic injection were determined. There were high probabilities of adenocarcinoma detection. The index of systolic speed of blood flow is significant for diagnostics. PMID- 26601518 TI - [WAYS OF IMPROVEMENT OF LIFE QUALITY OF PATIENTS UNDERGOING THYROID SURGERY]. AB - The authors analyzed quality of life before and after thyroid surgery in 350 patients. The article suggested the ways of improving of surgical treatment by developing some technical details. Indications to operation and choice of the operation volume were specified by morphological diagnostics refinement. PMID- 26601519 TI - [COGNITIVE ABNORMALITIES IN POSTOPERATIVE PERIOD OF THYROID SURGERY]. AB - An evaluation of cognitive functions was presented in 90 patients undergoing thyroid surgery. An attention deterioration, shot-term memory impairment and degradation were revealed after operation. It was shown that reduction of manifestations of cognitive dysfunction and stabilization of the haemodynamics indices were allowed due to application of cytoflavin during operation and in early postoperative period. PMID- 26601521 TI - [FEATURES OF PREOPERATIVE PREPARATION OF PATIENTS WITH DIFFERENT FORMS OF CLINICAL COURSE OF PHEOCHROMOCYTOMA]. AB - A comparative analysis of subjective and objective criterion was made in order to evaluate efficacy of preoperative preparation in 101 patients with pheochromocytoma of different clinical course. It was shown the reasonability of monitoring usage of noninvasive method of assessment of systemic hemodynamics (bio-impedance reo-vasography and daily monitoring of arterial pressure) for evaluation of preoperative preparation adequacy. The need of differentiated approach and strategy of preoperative preparation were based on clinical course of pheochromocytoma. PMID- 26601520 TI - [SCREENING OF PRIMARY HYPERPARATHYROIDISM IN PATIENTS WITH UROLITHIASIS]. AB - The aim of research was to study the rate of hypercalcemia and primary hyperparathyroidism among patients with uroli- thiasis. The investigation included 645 patients with urolithiasis. Patients were divided into 2 groups: with normocalcemia and hypercalcemia. The rate of hypercalcemia consisted of 18,9% among patients with urolithiasis. This frequency was 10-20 times higher than in a similar rate of general population. There were no significant differences in age, sex, history of urolithiasis and stone localization between two groups. The data obtained showed an importance of screening of hypercalcemia in patients with urolithiasis regardless the severity of clinical course. PMID- 26601522 TI - [NEW METHOD OF PARTIAL NEPHRECTOMY WITH SELECTIVE PARENCHYMA CLAMPING]. AB - The authors suggested a new method of performance of open, laparoscopic and robot assisted partial nephrectomy using specially developed instruments for selective parenchyma clamping in order to improve the functional results of renal cell carcinoma treatment. The operation with clamping of renal vessels was carried out in 86 cases and clamping of renal parenchyma was used in 24 cases. It was shown, that the open, laparoscopic and robot-assisted partial nephrectomy could be safely performed in conditions of selective ischemia of the renal parenchyma without clamping of renal vessels. PMID- 26601523 TI - [TREATMENT OF NON-SMALL CELL CARCINOMA OF LUNG IN SENILE PATIENTS]. AB - A comparative analysis of surgical treatment of non-small cell carcinoma of lung was made in 64 patients of senile age and more young patients. It was stated, that preference should be given to the partial lung resections (lob- and segmentectomies). The authors recommended to avoid pneumoectomy and typical resection of the lung as non-radical operations accompanied by high rate of local recurrences. The comorbidity background of patients should be thoroughly investigated before planning of surgery. If necessary, a surgical treatment of accompanied vascular pathology should be fulfilled as the first stage before oncology surgery. PMID- 26601524 TI - [DIAGNOSTICS AND TREATMENT OF BOERHAAVE'S SYNDROME]. AB - The article presents the results of diagnostics and treatment of 12 patients with Boerhaave's syndrome (men--9, women-- 3). The age of the patients was 19-68 years old. The prescription of spontaneous rupture of the oesophagus was 7 h-2 days from moment of the rupture to hospital admission. General aspects of disease were noted in 10 patients, though only 5 patients were directed to the hospital with suspicion on Boerhaave's syndrome. Emergency surgeries were performed on all patients. At first the opening was carried out, than drainage of posterior lower mediastinum were performed by Savinykh-Rozanov method with wound closure of the oesophagus walls. The complications were noted in 2 patients (the first case pleural empyema, the second case-pulmonary embolism). Late complications, such as esophagostenosis in the place of wound closure were followed up in 3 patients in terms more than one month after operation. PMID- 26601525 TI - [CHANGE OF ANTICOAGULANT EFFECT OF RIVAROXABAN DURING A DAY]. AB - The article presents an assessment of anticoagulant effect of rivaroxaban in 35 patients with thromboembolic diseases. The results of expressed anticoagulant effect of rivaroxaban were obtained during a day (or more). The data of increase in sensitivity to thrombomodulin indicated about work enchancement of protein C system against the background of rivaroxaban therapy. PMID- 26601526 TI - [Dilated combined pneumoectomy with resection of the percava and grafting using synthetical prosthesis in patient with small cell carcinoma of ling of IV degree]. PMID- 26601527 TI - [Spontaneous rupture of true aneurysm of the splenic artery in pregnant women]. PMID- 26601528 TI - [What does it mean to be a good surgeon?]. PMID- 26601529 TI - [Scientific school departments of general surgeryof Military Medical Academy (to the 215th anniversary of the department)]. PMID- 26601530 TI - [Clinical-epidemiological value of systemic inflammation and sepsis]. PMID- 26601531 TI - [Operative technique in the lung transplantation, the trachea and the lung tracheal complex in clinical experiment]. PMID- 26601533 TI - [Endovideosurgery in diagnostics and treatment of postoperative peritonitis]. PMID- 26601532 TI - [Tissue-engineered vascular grafts]. PMID- 26601534 TI - [Development of methods of the end colostomy formation as a real way to the prevention of paracolostomal complications]. PMID- 26601535 TI - [Academician of Russian Academy of Sciences Vitaliy Alexandrovich Khil'ko (to 85th anniversary of his birthday)]. PMID- 26601536 TI - [Retrospective Cytogenetic Dose Evaluation. I. Chromosome Aberration Levels in Remote Periods after Acute External Exposure in Different Situations]. AB - Cytogenetic analysis of peripheral blood lymphocyte cultures of 22 persons was performed in remote terms after acute external gamma-, gamma-beta- or gamma neutron irradiation as a result of various accidents using the classical me- thod. The initial dose estimates were obtained using physical calculations, the method of measuring the EPR signal in tooth enamel, according to haematological and/or cytogenetic parameters. The purpose of this study was to obtain evidence about the state of the lymphocyte chromosome apparatus of people approxi- mately 17-50 years after an accidental radiation exposure. In general, elevated levels of chromosome aberra- tions were detected. An average correlation was observed between the atypical chromosome frequency and absorbed dose. It is proposed to use the obtained results in the future to explore the possibility of retrospective dose evaluation on the basis of a special computer program. PMID- 26601537 TI - [Pooled Analysis of RET/PTC Gene Rearrangement Rate in Sporadic and Radiogenic Thyroid Papillary Carcinoma]. AB - The database of publications on molecular epidemiology of RET/PTC rearrangements in sporadic and radiogenic thyroid papillary carcinoma has been formed (197 sources at the end of 2014; coverage of 100%). Based on this database a pooled analysis of data on the rates of RET/PTC1, RET/PTC3 and RET/PTC in total was conducted. Statistical approach involves a simple pooling, as well as calculations on the models of random and fixed effects. Since almost all the strata were characterized by heterogeneity, simple pooling and random effect models were adequate. Calculations using both models led to almost identical results. For rates of RET/PTC1, RET/PTC3 and RET/PTC in total with respect to formed carcinoma striations the following values (pooling, in %) were obtained: sporadic, total--13.2; 8.9; 21.2; sporadic, adults--13.3; 9.9; 21.1; sporadic, children--22.4; 17.5; 44.5; radiogenic, total--20.9; 20.3; 40.4; radiotherapy (exposure in childhood)--31.1; 11.8; 42.5; children affected after the Chernobyl accident--19.9; 23.6; 46.1; radiological incidents (exposure in adulthood)--19.9; 7.7; 18.4. Statistically proven is the reliability of differences of carcinoma indicators for children compared with adults (both sporadic and radiogenic tumors) and for radiogenic cancer compared with sporadic. The greatest increase in rate after irradiation was found for RET/PTC1, previously characterized in vitro as one of radiogenic types of RET/PTC. PMID- 26601538 TI - [Polymorphism of Glucose-6-phosphate Dehydrogenase in the Chronically Irradiated Scots Pine Populations]. AB - Polymorphism of glucose-6-phosphate dehydrogenase enzyme was studied in the Scots pine populations growing in the sites of Bryansk region which were radioactively contaminated as a result of the Chernobyl accident. It was revealed that the frequency of mutations in isozyme loci increased along with the level of a dose rate (7-130 mGy/year) in the sites under the study. Significant changes in the activity of this enzyme did not depend on the level of radiation exposure. PMID- 26601539 TI - [Slow Formation and Degradation of gammaH2AX Foci in Human Skin Fibroblasts Exposed to Low-Dose X-Ray Radiation]. AB - It was shown that the kinetics of changes of gammaH2AX foci number (marker of DNA double-strand breaks) in human skin fibroblasts after exposure to low doses of X ray radiation (20, 40 and 80 mGy) differs from that observed after exposure to medium-low doses (160 and 240 mGy). After exposure to 160 and 240 mGy the highest number of gammaH2AX foci was detected at 30 min after exposure (first experimental point) and further their decrease was observed. At the same time we observed a fast phase of repair (upto 4 h), in which there was a decrease of the foci amount to ~50-60% and a slow phase of repair (from 4 h to 24 h). After 24 h only ~3-5% of the foci amount observed at 30 min after irradiation was left. After exposure to low doses, the foci number did not decrease during 2 h and even 24 h after exposure their amount was ~25% from that observed at maximum points (1 h after irradiation at 40 and 80 mGy and 2 h after irradiation at 20 mGy). PMID- 26601540 TI - [Background Level of gammaH2AX Foci in Human Cells as a Factor of Individual Radiosensitivity]. AB - The paper analyzes the effects of spontaneous level of yH2AX and 53BP1 foci on a frequency of radiation-induced centromere-negative and centromere-positive micronuclei in peripheral blood lymphocytes of 54 healthy individuals after exposure to 2 Gy of ionizing radiation in vitro. An inverse correlation was found between the level of spontaneous yH2AX foci and the frequency of centromere negative micronuclei after irradiation. The corresponding correlations between the spontaneous level of protein 53BP1 foci and the frequency of centromere negative micronuclei were not statistically significant. In addition, cells of the individuals with a high frequency of radiation-induced micronuclei were also characterized by a low proliferative activity. It was suggested that DNA double strand break repair works less efficiently in cells of the individuals with low levels of spontaneous yH2AX foci, and a greater number of DNA double strand breaks after exposure to ionizing radiation remains unrepaired, thus leading to a cell cycle block and an increase of the frequency of centromere-negative micronuclei. PMID- 26601541 TI - [Activity of cAMP System in Sheep Lymphocytes and Platelets Exposed to External gamma-Radiation in vivo]. AB - The activity of the cyclic adenosine-3,5-monophosphate (cAMP) in lymphocytes and platelets of sheep has been studied for 15 days after animal exposure to total external gamma-radiation at a dose of 4 Gy (LD50/30). The basal and E1 stimulated activity of adenylate cyclase and phosphodiesterase activity were determined by the thinlayer chromatography technique, and the cAMP content was determined using RIA-kits with 125J. Modification was revealed in the cAMP system functioning in the cell populations studied from the first day following radiation exposure. In particular, the basal adenylate cyclase activity in lymphocytes increased 1.7-4.3 times at all study dates, and stimulated enzyme activity increased on days 1-7, 21-8.8-fold compared to the initial data. Platelets showed increase in the basal adenylate cyclase activity on days I and 7, 2.7 and 35 times, and stimulated activity at the same times--9 and 5.7 times, respectively. The adenylate cyclase stimulation coefficient in lymphocytes raised 1.8 and 2.3 times on days 1 and 5, respectively, on day 7 it corresponded to the initial data and on days 10-15 it dropped below the control. However in platelets, this parameter did not have significant differences from the initial data. The phosphodiesterase activity in lymphocytes increased 3-fold on day 3, 2.4-fold on day 7, and in platelets it practically remained at the control level. The cAMP content in lymphocytes dropped within the first 12 hours and on day 3, 2.71 and 2.38 times, respectively, whereas in platelets it decreased 3.08 times within 12 hours and increased 1.91 times on day.3. At other times the cAMP content in lymphocytes and platelets did not differ from the initial data. The results suggest that the identified modification of cAMP system activity in lymphocytes and platelets in various periods after exposure of animals is based on different mechanisms. In the early period, alteration in the enzyme activity of cAMP system and cAMP content is caused by radiation effects on cytoplasmic membrane of cells circulating in the peripheral blood of animals. In the later periods, the recorded variations in the cAMP system activity are defined by the prevalence in the blood of more resistant to radiation damage cell subpopulation with an enhanced activity of cAMP enzymes and cAMP concentration corresponding to unexposed animals. PMID- 26601542 TI - [Searching Radiation Countermeasures using the Model of Prolonged Irradiation of Mice with Low Dose Rate and Evaluation of Their Influence on Heat Shock Protein Genes Expression]. AB - Different radiomodificators (cytokine betaleukine, antioxidant phenoxan, antigipoksant limontar and nucleoside riboxin) were investigated on mice for evaluating their radiation protective capacity against prolonged (21 h) exposure at a dose of 12.6 Gy at a low dose rate of 10 mGy/min. Bone marrow cellularity and endogenic CFUs were used as evaluation criteria 9 days after exposure. Simultaneously, expression of the heat shock proteins of 25, 70 and 90 kDa in unexposed mice bone marrow was studied 2, 24 and 48 h after injections. Betaleukine only had a positive significant effect in both tests in the variants of 50 mcg/kg and 3 mcg/kg when administered 2 h and 22 h before exposure, correspondingly. Effects of betaleukine HSPs on expression were both stimulating and inhibiting, that was in contradiction with a constant positive effect in 5 experiments on exposed mice for each betaleukine variant. It argues against the vital role of HSPs in the betaleukine antiradiation effect. In 2 experiments with high temperatures betaleukine administered at a dose of 50 mcg/kg evoked a very high HSP-70 gene expression after 24 h, and mice exposed to irradiation at that time in a parallel experiment showed an increased radiation effect. It corresponds to the idea that HSPs serve a stress indicator. PMID- 26601543 TI - [Theoretical and Experimental Dosimetry in Evaluation of Biological Effects of Electromagnetic Field for Portable Radio Transmitters. Report 2. Homogeneous Human Head Phantom]. AB - Results of theoretical (numerical) and experimental electromagnetic field dosimetry for homogeneous human head phantoms are considered. The simulation and measurement results are shown. This paper presents the results of Specific Absorption Rate (SAR) evaluation in the "special anthropomorphic model" of human head, when a source of electromagnetic radio frequency field is placed in front of the face. The minimal difference is shown between measurements and simulation results in Head Simulating Liquid, which makes it possible to conduct further brain tissue simulations. The investigations show that the type of electromagnetic field source and phantom form play an important part for SAR distribution. PMID- 26601544 TI - [Research of UV-Induced Changes in the Structural and Functional Properties of Inulinases]. AB - UV-induced changes in the catalytic activity and radiuses of inulinases molecules from various producers (plants, fungy, yeast) are studied. It is established that specific enzymes activity and the sizes of inulinases molecules from Helianthus tuberosus and Kluyveromyces marxianus under the influence of UV-light in the ranges of doses 4530-6040 and 755-6040 J/m2, respectively, are subjected to changes more than structural and functional characteristics of inulinase fromAspergillus niger. It is probably connected with lower contents in it of aromatic amino acids such as tyrosine and phenylalanine. The most expressed loss of functional properties of inulinase from Helianthus tuberosus can be caused by the'existence of significantly more numbers of cysteine in plant fructan exohydrolases in relation to microbic enzymes. A scheme for the stages of response of inulinases of various origins on the influence of UV-light in a certain range of radiation doses is offered. PMID- 26601545 TI - [XII Regional Scientific Conference "Man-Made Systems and Environmental Risk"]. PMID- 26601546 TI - [On the 90th Birth Anniversary of Yuri Grigorievich Grigoriev]. PMID- 26601547 TI - [On the 75th Birth Anniversary of Igor Gudkov]. PMID- 26601548 TI - The generalists' perception of quality of life in head and neck cancer. AB - OBJECTIVE: Patients with head and neck cancer are willing to undergo aggressive treatments and accept alterations in quality of life to attain recovery or to prolong their life. It is unclear how physicians perceive alterations in quality of life. This study examined whether physicians considered changes in quality of life when selecting a treatment for head and neck cancer. METHODOLOGY: A large, Belgian, general practitioner population received a questionnaire in the mail requesting their opinions on quality of life for patients with cancer. They assessed the impacts of symptoms, treatments, and side effects. RESULTS: 506 responses were received and evaluated. A majority of physicians (85.7%) thought that quality of life must be considered when selecting a treatment, even when it represented lower chance of survival. Moreover, 82.4% felt that proposing no treatment was justified when treatment caused impaired quality of life. Most physicians thought that the quality of life was worse for patients with cancer in the head and neck than for patients with cancer in any other location. Moreover, most physicians thought that the patient (98.2%) and the family doctor (89%) should participate in selecting the treatment. The symptoms that ranked highest for impacting quality of life were pain and breathing quality, followed by feeding requirements, voice quality, and physical appearance. Radiotherapy was thought to offer the best quality of life. CONCLUSION: Physicians considered quality of life a very important factor in treating patients with head and neck cancer. This medical perception strongly influences the choice of treatment. PMID- 26601549 TI - Review: Facial endophenotypes in non-syndromic orofacial clefting. AB - Cleft lip and/or palate (CL/P) is one of the most frequent congenital malformations, with a frequency of 1 in 700 live births. Non-syndromic orofacial clefting is a multifactorial condition, with both a genetic and an environmental component. Although numerous studies have been published addressing the genetic etiology of CL/P, this factor remains incompletely understood. A promising approach to find candidate gene regions for CL/P is the investigation of endophenotypes, which are characteristics associated with a certain condition and that can be an expression of underlying susceptibility genes. This review focuses on the known facial endophenotypes in CL/P (such as distortion of the orbicularis oris muscle and facial features in non-affected relatives of patients with CL/P) and genes that could be associated with these characteristics. Possibilities for further endophenotype-related studies in the field of non-syndromic CL/P are discussed. PMID- 26601550 TI - Otosclerosis: Shift in bone conduction after stapedotomy. AB - OBJECTIVES: To analyze changes in bone conduction (BC) thresholds before and after stapedotomy in patients with clinical otosclerosis with a focus on the Carhart notch, which is defined as a significant loss of BC at a certain audiometric frequency. METHODOLOGY: Retrospective case review of pure tone audiometry (PTA) in 213 patients who underwent a stapedotomy at a tertiary referral center between 2004 and 2011. The patients were grouped by age and the frequency of the Carhart notch. The non-operated ear was also evaluated. RESULTS: The Carhart notch was present on pre-operative audiometry in 158 (74%) patients at 0.5 (n = 18, 8.45%), 1 (n = 25, 11.70%), or 2 kHz (n = 115, 54.0%). We measured a mean postoperative improvement in BC of 7.5, 8.4, and 8.8 dB HL. Pre operatively, 55 (25.8%) patients did not exhibit a typical notch configuration. The mean gain in BC, defined on PTA according to the AAO-HNS criteria (0.5, 1, 2 and 3, or 4 kHz), was 1.8 dB HL after stapedotomy. CONCLUSION: The Carhart notch was not solely related to the 2 kHz frequency. The greatest gain in BC after stapedotomy for otosclerosis occurred at the notch frequency. PMID- 26601551 TI - Olivocochlear efferent reflex strength in vestibular schwannoma patients. AB - PROBLEM/OBJECTIVE: The olivocochlear reflex strength can be measured using contralateral acoustic stimulation (CAS) of transient evoked otoacoustic emissions (TEAOEs). The efferent suppression (ES) thus reflects the functional intactness of the efferent auditory system. In patients with unilateral vestibular schwannoma (VS), the results of ES are unclear. METHODS: This cross sectional study evaluated click and noise intensity conditions for measuring ES using CAS of TEOAEs in nine patients with unilateral VS and in gender-, age- and ear side-matched control subjects. RESULTS: Two optimal click and noise intensity level combinations were identified. This pilot study compared the amount of ES between tumour and non-tumour ears versus control ears in patients with unilateral VS, but there were no statistically significant differences. CONCLUSION: Future studies should include a larger population of unilateral VS patients with different grades of hearing loss. PMID- 26601552 TI - Duration of benign paroxysmal positional vertigo as a predictor for therapy. AB - OBJECTIVE: To evaluate the prognostic significance of the duration of disease in patients with benign paroxysmal positional vertigo (BPPV). METHODS: We studied all patients with idiopathic BPPV of the posterior semicircular canal who were treated during 3 consecutive years, divided into 2 groups: those with recent disease onset (within 4 weeks) and those with more remote disease onset. Outcome of treatment by repositioning maneuver and rate of recurrence were compared. RESULTS: 110 patients had BPPV of recent onset and 121 of more remote onset (mean ages 51.3 and 58.2, respectively). Treatment outcomes were similar in both groups, but the rate of recurrence was higher in patients with BPPV of longer duration (21.5% versus 10%). CONCLUSION: Long duration of the disease does not affect the treatment outcome in patients with idiopathic BPPV, but is correlated with increased rate of recurrence. Older age of these patients is probably a contributing factor for recurrence. PMID- 26601553 TI - Sudden hearing loss and the risk of subsequent cerebral ischemic stroke. AB - OBJECTIVE: Very few studies have investigated the risk of ischemic stroke after an episode of sudden sensorineural hearing loss (SSNHL), and findings have been controversial. The aim of this study was to estimate the risk of ischemic stroke among SSNHL patients within the province of Ferrara and compare the findings with data available in the literature. METHODS: This was a cohort study using hospital discharge records. The observation period was from 1 January 2001 to 31 December 2012. The study cohort consists of all adult patients hospitalized with a principal diagnosis of SSNHL (n = 484) and all adult patients with a diagnosis of ischemic stroke (n = 9985) among the resident population of the province of Ferrara, Emilia-Romagna, Italy. We calculated the incidence of SSNHL and ischemic stroke, as well as the incidence of ischemic stroke within the group of patients who experienced SSNHL. RESULTS: During the period 2001-2012 in Ferrara, the average annual crude incidence of SSNHL was 11.4/100,000 (95% CI 10.4-12.4), while the average annual crude incidence of the first ischemic stroke was 235.3/100,000. During the mean observation time period of 6 years, the expected and observed cases of ischemic stroke among the 484 patients with SSNHL did not differ significantly (6.8 expected vs. 9 observed [95% Poisson Confidence Interval 4.11-17.08]). CONCLUSIONS: Our findings suggest that SSNHL does not significantly increase the risk of ischemic stroke. PMID- 26601554 TI - Do viral infections have a role in benign paroxysmal positional vertigo? AB - OBJECTIVES: To investigate the role of viral infection in benign paroxysmal positional vertigo (BPPV). METHODS: In this retrospective study, 483 patients with BPPV were included in the study group. The control group consisted of 461 healthy subjects. In both groups, serologic analysis of viral agents (HSV1, HSV2, Herpes zoster, EBV, CMV, adenovirus, influenza, and parainfluenza virus) was performed. RESULTS: With the exception of influenza and parainfluenza, all viral serology values were higher in the BBPV group than the control group. We also observed seasonal variation. The BPPV group exhibited elevated values for HSV1 and adenovirus in March and May, for Herpes zoster, adenovirus, and influenza in April, for HSV1 in June, and for HSV1 and CMV in September, compared to the control group. In October, the BPPV group showed increased values for all of the viruses studied, compared to the control group. CONCLUSION: BPPV is associated with positive viral serology, particularly during certain months of the year, mainly in spring and autumn. Viral infection might promote BPPV attacks due to the development of vestibulopathy or induce secondary BPPV via viral infection related neurolabyrinthitis. PMID- 26601555 TI - Middle ear pressure changes with sevoflurane and propofol-remifentanil. AB - The present study aimed to compare the effects of sevoflurane (a commonly used inhalation anesthetic) and intravenous propofol on middle ear pressure (MEP) and determine the more appropriate option for middle ear operations. Fifty-seven American Society of Anesthesiologists risk class I-II patients aged 18-65 years who were not scheduled for ear or tympanic membrane operations were included in the study. The patients were randomly divided into two groups using the sealed envelope method. Propofol (0.2-0.5 mg/kg; Group P) and sevoflurane (1-2%; Group S) were used to maintain anesthesia. Baseline tympanometry was conducted on both ears and recorded before anesthesia was induced. Four additional measurements were performed and recorded at 5, 10, 15, and 30 minutes after induction. All post-induction MEP values were significantly higher than baseline measurements in Group S (P < 0.05 for all); there were no differences between post-induction and baseline measurements in Group P. At 10, 15, and 30 min post-induction, MEP values were significantly higher in Group S than in Group P (P < 0.05). Sevoflurane increased MEP values significantly compared with propofol anesthesia. We conclude that propofol can be used more reliably than sevoflurane in middle ear operations. PMID- 26601556 TI - Chronic otitis media surgery in the only hearing ear. AB - OBJECTIVES: The present study aimed to investigate how quality of life was impacted in patients who underwent surgery for chronic otitis media in their only remaining hearing ear (OHE). Such surgical treatment is controversial, and avoided by many surgeons due to the high risk of hearing loss due to surgery. However, if the patient is left untreated, hearing may further deteriorate over time, decreasing the patient's quality of life to an undesirable level. METHOD: We performed a retrospective single-institution study of a prospectively collected database in a tertiary university hospital. Twenty-three patients with OHE who underwent surgical treatment were retrospectively analyzed. The patients' age, sex, treated ear, indications, and preoperative and postoperative hearing levels were recorded. The data were statistically analyzed. RESULTS: Of the 23 patients with OHE, 15 regularly attended follow-up for at least two years. In all cases, the tympanic membrane perforations were closed and the ear drum became dry. An air-bone gap gain of >= 20 dB was measured in five patients, >= 10 dB in seven, and two patients showed no significant change (4-10 dB). One patient showed minimal hearing deterioration of -2 dB. CONCLUSION: Patients with OHE can be treated surgically to improve hearing levels and quality of life. Modern surgical techniques and instruments--especially in experienced hands--may reduce the possible surgical risks. If hearing deteriorates due to surgery, it may be improved, for example, with cochlear implantation surgery. PMID- 26601557 TI - Transnasal endoscopic microfractured fat injection in glottic insufficiency. AB - OBJECTIVE: We evaluated a novel treatment for glottic insufficiency involving the injection of autologous material with direct glottic visualisation in an outpatient setting. METHODS: Three patients with vocal cord palsy underwent laryngoplasty under local anaesthesia using only a flexible endoscope with a working canal for Microfractured Fat Fibre-endoscopic Injection (MFFI). Adipose tissue was processed using the Lipogems device, which allows optimal purity, fluidity, and mesenchymal stem cell content in the resultant emulsion. RESULTS: According to the preliminary data, MFFI was well tolerated and no complications were observed. During the 12-month follow-up period, voice improvement was constant in all three patients, hinting at the stem cell-related regenerative potential of the procedure. CONCLUSIONS: MFFI was proven to be a useful and straightforward tool, combining all of the relevant advantages of other known treatments for glottic insufficiency, and is an efficacious and innovative treatment that can be performed on an outpatient basis using only autologous material. PMID- 26601558 TI - Hypoglossal paresis as the only complication of malignant otitis externa. AB - BACKGROUND: Ipsilateral hypoglossal nerve (XII) paresis has never been reported as the first and only complication of malignant otitis external (MOE). CASE REPORT: A 73-year-old diabetic male with persistent left temporomandibular joint ache and ear fullness was admitted with the diagnosis of MOE. He received intravenous ciprofloxacin for 14 days and then continued with oral administration (per os). After two months, he returned with otalgia, swallowing difficulty, and ipsilateral XII paresis. He was re-admitted, received intravenous ciprofloxacin for 6 weeks, and continued with per os ciprofloxacin for 6 months. A Ga67-scan 6 months after the first admission revealed no active infection. Two years after his last admission, the patient still has XII paresis. There is no other cranial nerve involvement and inflammatory markers continue to be normal. CONCLUSION: Doctors should consider MOE in the differential diagnosis when there is XII paresis, especially in diabetic and immunocompromised patients. PMID- 26601559 TI - Middle turbinate chondro-osseous respiratory epithelial adenomatoid hamartoma. AB - OBJECTIVE: Chondroosseous respiratory epithelial adenomatoid hamaroma (COREAH) is an extremely rare, developmental malformation. COREAH is characterized by a spectrum of chondro-osseous metaplasia that arise from the mesenchymal stroma, and it includes dilated submucosal glands lined with respiratory epithelium. This case report aimed to describe a COREAH that originated in the nasal cavity. CASE REPORT: A 68-year-old woman presented with unilateral nasal obstruction. Endonasal and radiological findings suggested a diagnosis of an unilateral inflammatory polyp. However, after excision of the mass with endoscopic guidance, a histological examination supported a final diagnosis of a nasal COREAH. CONCLUSION: To our knowledge, this was the first description of a COREAH that originated from the middle turbinate and presented as a choanal polyp. The role of the pathologist is essential for a correct diagnosis. PMID- 26601560 TI - An isolated intracranial mucocoele herniated from the frontal sinus. AB - Mucocoeles are chronic mucosa-lined retention cysts that occur due to sinus ostium obstruction and expand along the path of least resistance, most commonly involving the frontal sinus. A frontal mucocoele typically appears as a smooth and rounded expansile enlargement of a completely opacified frontal sinus, with or without thinning of the bony wall of the sinus. Here we report a rare case of isolated intracranial mucocoele that presented with posterior herniation to the anterior cranial fossa through a small bony defect on the posterior table of the frontal sinus. The findings upon imaging could easily be confused with intracranial abscess, potentially leading to craniotomy drainage. In the present case of mucocoele, the frontal intracranial lesion was completely resolved following endoscopic frontal sinusotomy. PMID- 26601562 TI - Experimental investigations on effects of frequency in ultrasonically-assisted end-milling of AISI 316L: A feasibility study. AB - The effects of frequency in ultrasonic vibration assisted milling (UVAM) with axial vibration of the cutter is investigated in this paper. A series of face mill experiment in dry conditions were conducted on AISI 316L, an alloy of widespread use in industry. The finished surfaces roughness were studied along with basic considerations on tool wear for both conventional milling and an array of frequencies for UVAM (20-40-60 kHz) in a wide range of cutting conditions. Surface residual stresses and cross-cut metallographic slides were used to investigate the hidden effects of UVAM. Experimental results showed competitive results for both surface roughness and residual stress in UVAM when compared with conventional milling especially in the low range of frequency with similar trend for tool wear. PMID- 26601561 TI - Specificity of the minimal clinically important difference of the quick Disabilities of the Arm Shoulder and Hand (QDASH) for distal upper extremity conditions. AB - Retrospective cohort design. The minimal clinically important difference (MCID) for the quick Disabilities of the Arm, Shoulder and Hand (QDASH) has been established using a pool of multiple conditions, and only exclusively for the shoulder. Understanding diagnoses-specific threshold change values can enhance the clinical decision-making process. Before and after QDASH scores for 406 participants with conditions of surgical distal radius fracture, non-surgical lateral epicondylitis, and surgical carpal tunnel release were obtained. The external anchor administered at each fourth visit was a 15-point global rating of change scale. The test-retest reliability of the QDASH was moderate for all diagnoses: intraclass correlation coefficient model 2, 1, for surgical distal radius = 0.71; non-surgical lateral epicondylitis = 0.69; and surgical carpal tunnel = 0.69. The minimum detectable change at the 90% confidence level was 25.28; 22.49; and 27.63 points respectively; and the MCID values were 25.8; 15.8 and 18.7, respectively. For these three distal upper extremity conditions, a QDASH MCID of 16-26 points could represent the estimate of change in score that is important to the patient and guide clinicians through the decision-making process. PMID- 26601563 TI - Acoustic scattering by a two-layer cylindrical tube immersed in a fluid medium: Existence of a pseudo wave. AB - The present paper studies the acoustic signal backscattered by an air-filled copper-solid polymer two-layer cylindrical tube immersed in water. The work is done from the calculation of the backscattered pressure, an inverse Fourier Transform, which allows us to obtain an impulse signal. Smoothed pseudo Wigner Ville and Concentrated spectrogram representations have been chosen to analyze the scattering phenomenon. For reduced frequencies ranging from 0.1 to 200, the resonance trajectories and time-frequency images have shown the presence of the guided waves. The bifurcation of the A0 wave into the A0(-) and the A0(+) waves has also been observed. The authors provide the phase and the group velocities of guided waves and investigate the differences between curves. The findings are then compared with those obtained for the copper and the solid polymer one-layer cylindrical tubes. Group velocity values have also been extracted from smoothed pseudo Wigner-Ville and Concentrated spectrogram time-frequency images. A good agreement with the theory has, therefore, been observed. The study of acoustic backscattering by a copper-solid polymer two-layer tube has revealed the interaction and the coupling of guided waves, specially the presence of a pseudo A1 wave; which is a very interesting, remarkable phenomenon. PMID- 26601564 TI - Matrix Infrared Spectroscopic and Quantum Chemical Investigations of the Group 5 Transition Metal Atom and CX4 Molecule (X = H, F, and Cl) Reaction Products. AB - Laser-ablated vanadium, niobium, and tantalum atoms were reacted with CH2X2, CHX3, and CX4 (X = F and Cl) molecules in condensing argon, and the products were investigated by matrix isolation infrared spectroscopy. The major reaction products are new CH2-MX2, CHX-MX2, HC-MX3, and XC-MX3 complexes. These reactive species were identified by comparing their matrix infrared spectra with frequencies, intensities, and isotopic shifts from density functional theory calculations. Product structures and energies from these calculations are also presented. Results from previously studied Group 4 and 6 metal reaction products are compared. Little change is found in the calculated metal-carbon bond lengths in the early first row CH2?MF2 methylidene sigma(2)pi(2) series; however, the methylidyne complexes HC{}MF3 show considerable increase in bond strength for the nominally sigma(2)pi(1)pi(1)(Ti), sigma(2)pi(2)pi(1)(V), and sigma(2)pi(2)pi(2)(Cr) carbon{}metal bonds left to right. The Group 5 HC{}MF3 complexes have only a plane of symmetry whereas the Group 4 and 6 analogues have 3-fold symmetry. PMID- 26601565 TI - Prognostic markers in lentigo maligna patients treated with imiquimod cream: A long-term follow-up study. AB - BACKGROUND: More data are needed to define factors that predict long-term success after imiquimod therapy for lentigo maligna (LM). OBJECTIVE: We sought to determine the demographic, clinical, and histologic prognostic markers of relapse free survival in patients with LM who were treated with imiquimod. METHODS: This was a single-arm, open-label, nonrandomized, prospective study. RESULTS: Eighty nine patients with histologically confirmed LM and a median follow-up time of 4.8 years after imiquimod treatment were included in our study. Sixteen patients (18%) relapsed. Statistically significant indicators of an increased risk of local recurrence included: the total number of melanocytes, the number of basal and suprabasal melanocytes and the number of pagetoid spreading melanocytes. LIMITATIONS: Our study was a single-center, nonrandomized study. CONCLUSION: An assessment of different melanocyte fractions in the diagnostic baseline biopsy specimen may help to predict the response of LM to imiquimod therapy. PMID- 26601566 TI - Frequency of residual melanoma in wide local excision (WLE) specimens after complete excisional biopsy. AB - OBJECTIVE: We sought to better understand the role of wide local excision (WLE) in the treatment of cutaneous melanoma by analyzing residual or locally metastatic disease in WLE specimens of melanomas initially diagnosed with a complete excisional biopsy. METHODS: This was a retrospective review of 807 consecutive WLEs of melanomas diagnosed after complete excisional biopsy. All specimens were reviewed by a single dermatopathologist. Risk of residual or locally metastatic disease was analyzed using univariate and multivariate logistic regression models. RESULTS: In the 807 WLE specimens, further melanoma was found in 34 cases (4.2%; 95% confidence interval [CI] 2.9-5.8). Residual primary melanoma was found in 33 of these. On univariate analysis, features associated with residual or locally metastatic disease were histologic subtype (odds ratio 3.0; 95% CI 1.3-7.1, P = .01) and tumor location (odds ratio 7.3; 95% CI 2.0-26.6, P < .01). On multivariate analysis, lentigo maligna was independently associated with melanoma remaining in WLE specimens (odds ratio 2.7; 95% CI 1.0-7.3, P = .04). CONCLUSION: Residual melanoma in WLE specimens after histologically assessed complete excisional biopsy is not uncommon. Patients with lentigo maligna subtype melanomas are most at risk. Our findings indicate that the procedure of WLE is most important therapeutically for its role in controlling the primary tumor, rather than in preventing local metastatic recurrence. PMID- 26601568 TI - Site-dependent biomechanical responses of chondrocytes in the rabbit knee joint. AB - Biomechanical responses of chondrocytes were determined in specific locations within the superficial zone of patellar, femoral groove, femoral condyle and tibial plateau cartilages obtained from female New Zealand White rabbits. A confocal laser scanning microscope combined with a custom indentation system was utilized for experimentation. Changes in cell volumes and dimensions (i.e. cell height, width and depth) due to loading, global, local axial and transverse strains were determined for each site. Tissue composition and structure was analysed at each indentation site with digital densitometry, polarized light microscopy and Fourier transform infrared imaging spectroscopy. Patellar cells underwent greater volume decreases (compared to femoral groove cells; p<0.05) primarily due to greater decreases in cell height (p<0.05), consistent with greater levels of both global and local axial strains (p<0.05). Lateral condyle cells underwent greater volume decreases (compared to lateral plateau cells; p<0.05) primarily due to greater decreases in cell height, consistent with greater levels of tissue strains (p<0.05). Medial condyle cells underwent smaller volume decreases (compared to medial plateau cells; p<0.05) primarily due to elevated cell expansions in the depth direction, which was consistent with greater levels of minor transverse strains (p<0.05). Site-dependent differences in collagen orientation angles agreed conceptually with the observed cell dimensional changes. Chondrocyte biomechanical responses were highly site dependent and corresponded primarily with the orientation of the collagen fibrils. The observed differences were thought to be due to the different biomechanical loading conditions at each site. PMID- 26601569 TI - Clinical Biochemistry 2015 year in review: Material not for the faint of heart. PMID- 26601567 TI - Biotin-dependent functions in adiposity: a study of monozygotic twin pairs. AB - BACKGROUND: Biotin acts as a coenzyme for carboxylases regulating lipid and amino acid metabolism. We investigated alterations of the biotin-dependent functions in obesity and the downstream effects of biotin restriction in adipocytes in vitro. SUBJECTS: Twenty-four monozygotic twin pairs discordant for body mass index (BMI). Mean within-pair difference (heavy-lean co-twin, Delta) of BMI was 6.0 kg m(-2) (range 3.1-15.2 kg m(-)(2)). METHODS: Adipose tissue (AT) DNA methylation, gene expression of AT and adipocytes, and leukocytes (real-time quantitative PCR), serum biotin, C-reactive protein (CRP) and triglycerides were measured in the twins. Human adipocytes were cultured in low and control biotin concentrations and analyzed for lipid droplet content, mitochondrial morphology and mitochondrial respiration. RESULTS: The gene expression levels of carboxylases, PCCB and MCCC1, were upregulated in the heavier co-twins' leukocytes. DeltaPCCB (r=0.91, P=0.0046) and DeltaMCCC1 (r=0.79, P=0.036) correlated with DeltaCRP within-pairs. Serum biotin levels were lower in the heavier (274 ng l(-1)) than in the lean co-twins (390 ng l(-1), P=0.034). DeltaBiotin correlated negatively with Deltatriglycerides (r=-0.56, P=0.045) within-pairs. In AT, HLCS and ACACB were hypermethylated and biotin cycle genes HLCS and BTD were downregulated (P<0.05). Biotin-dependent carboxylases were downregulated (ACACA, ACACB, PCCB, MCCC2 and PC; P<0.05) in both AT and adipocytes of the heavier co-twins. Adipocytes cultured in low biotin had decreased lipid accumulation, altered mitochondrial morphology and deficient mitochondrial respiration. CONCLUSIONS: Biotin-dependent functions are modified by adiposity independent of genetic effects, and correlate with inflammation and hypertriglyceridemia. Biotin restriction decreases lipid accumulation and respiration, and alters mitochondrial morphology in adipocytes. PMID- 26601570 TI - Lactase persistence versus lactose intolerance: Is there an intermediate phenotype? AB - BACKGROUND: According to the prevailing theory about the genetic background to lactose intolerance, there are three genotypes but only two adult physiological phenotypes: lactase persistence in individuals with the CT and TT genotypes and lactase non-persistence in individuals with the CC genotype. However, analysis of lactase activity from intestinal biopsies has revealed three distinct levels of activity, suggesting that an intermediate physiological phenotype may exist. AIM: To assess possible disparities between different genotypes with regard to biomarkers of lactase activity and physical symptoms during an oral lactose load test. METHODS: A retrospective study using an oral lactose load test (n=487). Concentrations of hydrogen in exhaled air and blood glucose were measured. Afterwards, subjects were asked to provide oral mucosa samples for genotyping and answer a questionnaire (participation rate 56%, n=274). RESULTS: Mean hydrogen levels in exhaled air at 120min were significantly higher in the CT genotype than in the TT genotype. There was no significant difference in blood glucose levels between the two groups. Reported symptoms, with the possible exception of abdominal pain, were equally prevalent in both groups. CONCLUSIONS: Subjects with the CT and TT genotypes, hitherto classified as lactase-persistent, differ in their physiological response to lactose intake, indicating differences in phenotype which could have clinical significance. PMID- 26601571 TI - Miniaturization: The future of laboratory medicine. PMID- 26601572 TI - [Comparison of the effectiveness and safety of polyethylene glycol with and without electrolytes in the treatment of chronic constipation]. AB - INTRODUCTION: To compare the effectiveness and safety of polyethylene glycol with and without electrolytes (EL) over a 12 week period in treatment of chronic constipation in paediatrics. MATERIAL AND METHODS: This was an observational, prospective, longitudinal, parallel group study, including 62 children with chronic constipation according to ROME III criteria and a history of faecal impaction. The children were divided into groups, one group of 30 received polyethylene glycol without EL (PEG) and 32 PEG with EL (PEG+EL) for at least 12 weeks. The main outcomes were the number of bowel movements at 6 and 12 weeks, and the presence of electrolyte disturbances at 6 weeks. RESULTS: The mean weekly stool frequencies were similar in both groups at 6 and 12 weeks, with 5.4 and 4.6 stools per week in the PEG+EL and PEG groups, respectively at 12 weeks. After 6 weeks of treatment, 83% (25 of 30) of the PEG group had at least one electrolyte disturbance compared with 56% (18 of 32) in the PEG+EL group (P=.02). Hyponatraemia was found in 15% (5 of 32) vs. 36% (11 of 30) of PEG+EL and PEG groups, respectively (P=.05). None of the laboratory abnormalities were clinically relevant. CONCLUSIONS: PEG formulations with or without EL have a quite similar effectiveness, safety and acceptability. PEG without EL produced more electrolyte abnormalities, but none of them were symptomatic. PMID- 26601573 TI - Marker Detection in Electron Tomography: A Comparative Study. AB - We conducted a comparative study of three widely used algorithms for the detection of fiducial markers in electron microscopy images. The algorithms were applied to four datasets from different sources. For the purpose of obtaining comparable results, we introduced figures of merit and implemented all three algorithms in a unified code base to exclude software-specific differences. The application of the algorithms revealed that none of the three algorithms is superior to the others in all cases. This leads to the conclusion that the choice of a marker detection algorithm highly depends on the properties of the dataset to be analyzed, even within the narrowed domain of electron tomography. PMID- 26601574 TI - Antithrombotic therapy following transcatheter aortic valve implantation: what challenge do we face? AB - The issue of stroke and bleeding events following transcatheter aortic valve implantation (TAVI) and its relation with antithrombotic regimens before, during and after the procedure is increasingly recognized as an important issue. While dedicated trials are ongoing, there is no clear evidence at present on the best antithrombotic regimen in the context of TAVI. In this article, we will go through the mechanisms involved in embolic and bleeding complications of TAVI, and we will discuss the key aspects of antithrombotic treatment in patients undergoing TAVI. PMID- 26601575 TI - A Scientist-Skeptic-Agnostic's View of the Church of Anesthetic Cardioprotection. PMID- 26601576 TI - Short communication: Camel milk ameliorates inflammatory responses and oxidative stress and downregulates mitogen-activated protein kinase signaling pathways in lipopolysaccharide-induced acute respiratory distress syndrome in rats. AB - Acute respiratory distress syndrome (ARDS) is a complex syndrome disorder with high mortality rate. Camel milk (CM) contains antiinflammatory and antioxidant properties and protects against numerous diseases. This study aimed to demonstrate the function of CM in lipopolysaccharide (LPS)-induced ARDS in rats. Camel milk reduced the lung wet:dry weight ratio and significantly reduced LPS induced increases in neutrophil infiltration, interstitial and intra-alveolar edema, thickness of the alveolar wall, and lung injury scores of lung tissues. It also had antiinflammatory and antioxidant effects on LPS-induced ARDS. After LPS stimulation, the levels of proinflammatory cytokines (tumor necrosis factor alpha, IL-10, and IL-1beta) in serum and oxidative stress markers (malondialdehyde, myeloperoxidase, and total antioxidant capacity) in lung tissue were notably attenuated by CM. Camel milk also downregulated mitogen-activated protein kinase signaling pathways. Given these results, CM is a potential complementary food for ARDS treatment. PMID- 26601577 TI - Divergent utilization patterns of grass fructan, inulin, and other nonfiber carbohydrates by ruminal microbes. AB - Fructans are an important nonfiber carbohydrate in cool season grasses. Their fermentation by ruminal microbes is not well described, though such information is needed to understand their nutritional value to ruminants. Our objective was to compare kinetics and product formation of orchardgrass fructan (phlein; PHL) to other nonfiber carbohydrates when fermented in vitro with mixed or pure culture ruminal microbes. Studies were carried out as randomized complete block designs. All rates given are first-order rate constants. With mixed ruminal microbes, rate of substrate disappearance tended to be greater for glucose (GLC) than for PHL and chicory fructan (inulin; INU), which tended to differ from each other (0.74, 0.62, and 0.33 h(-1), respectively). Disappearance of GLC had almost no lag time (0.04 h), whereas the fructans had lags of 1.4h. The maximum microbial N accumulation, a proxy for cell growth, tended to be 20% greater for PHL and INU than for GLC. The N accumulation rate for GLC (1.31h(-1)) was greater than for PHL (0.75 h(-1)) and INU (0.26 h(-1)), which also differed. More microbial glycogen (+57%) was accumulated from GLC than from PHL, though accumulation rates did not differ (1.95 and 1.44 h(-1), respectively); little glycogen accumulated from INU. Rates of organic acid formation were 0.80, 0.28, and 0.80 h(-1) for GLC, INU, and PHL, respectively, with PHL tending to be greater than INU. Lactic acid production was more than 7-fold greater for GLC than for the fructans. The ratio of microbial cell carbon to organic acid carbon tended to be greater for PHL (0.90) and INU (0.86) than for GLC (0.69), indicating a greater yield of cell mass per amount of substrate fermented with fructans. Reduced microbial yield for GLC may relate to the greater glycogen production that requires ATP, and lactate production that yields less ATP; together, these processes could have reduced ATP available for cell growth. Acetate molar proportion was less for GLC than for fructans, and less for PHL than for INU. In studies with pure cultures, all microbes evaluated showed differences in specific growth rate constants (MU) for GLC, fructose, sucrose, maltose, and PHL. Selenomonas ruminantium and Streptococcus bovis showed the highest MU for PHL (0.55 and 0.67 h(-1), respectively), which were 50 to 60% of the MU achieved for GLC. The 10 other species tested had MU between 0.01 and 0.11h(-1) with PHL. Ruminal microbes use PHL differently than they do GLC or INU. PMID- 26601578 TI - Bovine Staphylococcus aureus: Subtyping, evolution, and zoonotic transfer. AB - Staphylococcus aureus is globally one of the most important pathogens causing contagious mastitis in cattle. Previous studies using ribosomal spacer (RS)-PCR, however, demonstrated in Swiss cows that Staph. aureus isolated from bovine intramammary infections are genetically heterogeneous, with Staph. aureus genotype B (GTB) and GTC being the most prominent genotypes. Furthermore, Staph. aureus GTB was found to be contagious, whereas Staph. aureus GTC and all the remaining genotypes were involved in individual cow disease. In addition to RS PCR, other methods for subtyping Staph. aureus are known, including spa typing and multilocus sequence typing (MLST). They are based on sequencing the spa and various housekeeping genes, respectively. The aim of the present study was to compare the 3 analytic methods using 456 strains of Staph. aureus isolated from milk of bovine intramammary infections and bulk tanks obtained from 12 European countries. Furthermore, the phylogeny of animal Staph. aureus was inferred and the zoonotic transfer of Staph. aureus between cattle and humans was studied. The analyzed strains could be grouped into 6 genotypic clusters, with CLB, CLC, and CLR being the most prominent ones. Comparing the 3 subtyping methods, RS-PCR showed the highest resolution, followed by spa typing and MLST. We found associations among the methods but in many cases they were unsatisfactory except for CLB and CLC. Cluster CLB was positive for clonal complex (CC)8 in 99% of the cases and typically positive for t2953; it is the cattle-adapted form of CC8. Cluster CLC was always positive for tbl 2645 and typically positive for CC705. For CLR and the remaining subtypes, links among the 3 methods were generally poor. Bovine Staph. aureus is highly clonal and a few clones predominate. Animal Staph. aureus always evolve from human strains, such that every human strain may be the ancestor of a novel animal-adapted strain. The zoonotic transfer of IMI- and milk-associated strains of Staph. aureus between cattle and humans seems to be very limited and different hosts are not considered as a source for mutual, spontaneous infections. Spillover events, however, may happen. PMID- 26601579 TI - Altered plasma pharmacokinetics of ceftiofur hydrochloride in cows affected with severe clinical mastitis. AB - Mastitis is a frequent problem among dairy cows, reducing milk yield and increasing cull rates. Systemic therapy with the cephalosporin antimicrobial ceftiofur hydrochloride (CEF) may improve therapeutic outcomes, but the incidence of CEF violative residues has increased annually since 2011. One potential explanation is that disease status may alter the pharmacokinetics (PK) of CEF. To test this hypothesis, we compared the plasma PK of CEF in healthy cows with those with severe endotoxic mastitis. Eight cows with naturally occurring mastitis and 8 clinically healthy cows were treated with 2.2 mg of CEF per kilogram of body weight once daily for 5d via the intramuscular route. Blood was collected at 0, 0.33, 0.67, 1, 1.5, 2, 3, 4, 8, 16, and 24h after the first CEF administration and every 8h thereafter until 120 h after the final dose. Plasma samples were analyzed for CEF concentrations using liquid chromatography coupled with mass spectrometry. With the exception of time 0, CEF was detected at all time points. The disease group had a significantly higher plasma CEF concentration at t=3h after the first injection and a significantly lower plasma concentration from 40 to 152 h following the first injection, with the exception of the t=64 h time point. Data following the first injection (time 0-24 h) were fit to a single dose, noncompartmental PK model. This model indicated that the disease group had a shorter plasma half-life. A multidose, noncompartmental model was used to determine steady-state PK. Compared with control cows, the disease group had an initially higher peak concentration and a higher volume of distribution and drug clearance rates. The disease group also had a lower area under the curve per dosing interval, steady-state concentration maximum, and dose-adjusted peak steady-state concentration. All other PK parameters were not different between the 2 groups. Altered PK, as suggested by this trial, may contribute to an increased risk for the development of a violative residue in meat. Further research is needed to more completely characterize drug distribution in diseased cattle and to study the effect of coadministration of other drugs on drug distribution. PMID- 26601580 TI - Anti-colon cancer and antioxidant activities of bovine skim milk fermented by selected Lactobacillus helveticus strains. AB - Bioactive compounds released during milk fermentation by proteolytic cleavage of milk proteins have a role beyond their nutritional importance. This study assessed the proteolytic activity of Lactobacillus helveticus strains ASCC953, ASCC474, ASCC1188, and ASCC1315 and their ability to release bioactive compounds capable of exerting antioxidative and in vitro anticarcinogenic properties during incubation at 37 degrees C in reconstituted skim milk. The performance of these strains was not affected by the pH decline during fermentation. Soluble extracts of fermented milk by L. helveticus 474 showed the highest free radical (1,1 diphenyl-2-picrylhydrazyl) scavenging activity at 12 h of fermentation, followed by a significant reduction of this activity at 24 h compared with the other strains and control (untreated milk). Skim milk fermented by L. helveticus strains contained compounds with anti-colon cancer activity at varied levels during fermentation. The activity (19.03-50.98% growth inhibition) was greatest in the extract obtained after 12 h of fermentation, which markedly declined (5.4 9.94%) at the end of fermentation. Lactobacillus helveticus 1315 released compounds into the skim milk supernatant with a greater growth inhibition (50.98%) on colon cancer HT-29 cell line than the other strains. More importantly, these compounds had no significant inhibition effect on normal, primary colon cells T4056. Whereas these results suggest that milk fermented by L. helveticus strains may release bioactive compounds with important multifunctional properties, the characteristics and activities of these compounds appear highly strain- and fermentation time-dependent. PMID- 26601581 TI - Considering genetic characteristics in German Holstein breeding programs. AB - Recently, several research groups have demonstrated that several haplotypes may cause embryonic loss in the homozygous state. Up to now, carriers of genetic disorders were often excluded from mating, resulting in a decrease of genetic gain and a reduced number of sires available for the breeding program. Ongoing research is very likely to identify additional genetic defects causing embryonic loss and calf mortality by genotyping a large proportion of the female cattle population and sequencing key ancestors. Hence, a clear demand is present to develop a method combining selection against recessive defects (e.g., Holstein haplotypes HH1-HH5) with selection for economically beneficial traits (e.g., polled) for mating decisions. Our proposed method is a genetic index that accounts for the allele frequencies in the population and the economic value of the genetic characteristic without excluding carriers from breeding schemes. Fertility phenotypes from routine genetic evaluations were used to determine the economic value per embryo lost. Previous research has shown that embryo loss caused by HH1 and HH2 occurs later than the loss for HH3, HH4, and HH5. Therefore, an economic value of ? 97 was used against HH1 and HH2 and ? 70 against HH3, HH4, and HH5. For polled, ? 7 per polled calf was considered. Minor allele frequencies of the defects ranged between 0.8 and 3.3%. The polled allele has a frequency of 4.1% in the German Holstein population. A genomic breeding program was simulated to study the effect of changing the selection criteria from assortative mating based on breeding values to selecting the females using the genetic index. Selection for a genetic index on the female path is a useful method to control the allele frequencies by reducing undesirable alleles and simultaneously increasing economical beneficial characteristics maintaining most of the genetic gain in production and functional traits. Additionally, we applied the genetic index to real data and found a decrease of the genetic trend for the birth years 1990 to 2006. Since 2010 the genetic index has increased due to a strong increase in the polled frequency. However, further investigation is needed to better understand the biology to determine the correct time of embryo loss and the economic value of fertility disorders. PMID- 26601582 TI - Associations between the degree of early lactation inflammation and performance, metabolism, and immune function in dairy cows. AB - The objective of the current study was to determine associations between the severity of systemic inflammation during the early postpartum period and performance, energy metabolism, and immune function in dairy cows. Cows were assigned to categorical quartiles (Q; Q1=0.18-0.59, Q2=0.60-1.14, Q3=1.15-2.05, and Q4=2.06-2.50 g of haptoglobin/L) based on the highest plasma haptoglobin (Hp) concentration measured during wk 1 postpartum. Although cows were assigned to different categories of inflammation during the postpartum period, we detected a quadratic relationship of inflammation on prepartum dry matter intake (DMI) and body weight (BW) such that cows in Q2 had lower prepartum DMI and cows in Q2 and Q3 had lower prepartum BW compared with cows in the other quartiles. We also detected a quadratic association of inflammation with postpartum DMI and BW such that cows in Q2 and Q3 also had generally lower postpartum DMI and BW compared with cows in Q1. There was a tendency for a Q * time interaction for milk yield and Q * time interactions for 3.5% fat-corrected milk and energy-corrected milk yields; quadratic relationships suggested decreased milk yield for Q2 and Q3 cows. We also found Q * parity and Q * time interactions for plasma glucose and insulin concentrations, suggesting alterations with differing degrees of inflammation. There was also a Q * time interaction for plasma nonesterified fatty acids concentration. In addition, alterations in liver triglyceride and glycogen contents for cows with inflammation as well as alterations in [1 (14)C]propionate oxidation in vitro were observed. Although we observed limited effects of inflammation on neutrophil and monocyte phagocytosis at d 7 postpartum, inflammation appeared to alter neutrophil and monocyte oxidative burst. Overall, cows with any degree of elevated haptoglobin in the first week after calving had alterations in both pre- and postpartum intake and postpartum metabolism. PMID- 26601583 TI - Effects of fermentation with Lactobacillus rhamnosus GG on product quality and fatty acids of goat milk yogurt. AB - The effect of fermentation with Lactobacillus rhamnosus GG on the product quality of goat milk yogurt using traditional yogurt starter was studied through single factor experiments and orthogonal experiments. The optimum fermentation condition was evaluated by the titratable acidity of goat milk yogurt, water-retaining capability, sensory score, and texture properties; the fatty acids of the fermented goat milk were determined by a gas chromatograph. Results indicate that high product quality of goat milk yogurt can be obtained and the content of short chain and medium-chain fatty acids can be decreased significantly when amount of sugar added was 7%, inoculation amount was 3%, the ratio of 3 lactic acid bacteria--Lactobacillus delbrueckii ssp. bulgaricus, Streptococcus thermophilus, and L. rhamnosus GG--was 1:1:3, and fermentation temperature was 42 degrees C. PMID- 26601584 TI - Overexpression of SREBP1 (sterol regulatory element binding protein 1) promotes de novo fatty acid synthesis and triacylglycerol accumulation in goat mammary epithelial cells. AB - Sterol regulatory element binding protein 1 (SREBP1; gene name SREBF1) is known to be the master regulator of lipid homeostasis in mammals, including milk fat synthesis. The major role of SREBP1 in controlling milk fat synthesis has been demonstrated in bovine mammary epithelial cells. Except for a demonstrated role in controlling the expression of FASN, a regulatory role of SREBP1 on milk fat synthesis is very likely, but has not yet been demonstrated in goat mammary epithelial cells (GMEC). To explore the regulatory function of SREBP1 on de novo fatty acids and triacylglycerol synthesis in GMEC, we overexpressed the mature form of SREBP1 (active NH2-terminal fragment) in GMEC using a recombinant adenovirus vector (Ad-nSREBP1), with Ad-GFP (recombinant adenovirus of green fluorescent protein) as control, and infected the GMEC for 48 h. In infected cells, we assessed the expression of 20 genes related to milk fat synthesis using real time-quantitative PCR, the protein abundance of SREBP1 and FASN by Western blot, the production of triacylglycerol, and the fatty acid profile. Expression of SREBF1 was modest in mammary compared with the other tissues in dairy goats but its expression increased approximately 30-fold from pregnancy to lactation. The overexpression of the mature form of SREBP1 was confirmed by >200-fold higher expression of SREBF1 in Ad-nSREBP1 compared with Ad-GFP. We observed no changes in amount of the precursor form of SREBP1 protein but a >10-fold increase of the mature form of SREBP1 protein with Ad-nSREBP1. Compared with Ad-GFP cells (control), Ad-nSREBP1 cells had a significant increase in expression of genes related to long-chain fatty acid activation (ACSL1), transport (FABP3), desaturation (SCD1), de novo synthesis of fatty acids (ACSS2, ACLY, IDH1, ACACA, FASN, and ELOVL6), and transcriptional factors (NR1H3 and PPARG). We observed a >10-fold increase in expression of INSIG1 but SCAP was downregulated by Ad nSREBP1. Among genes related to milk fat synthesis and lipid droplet formation, only LPIN1 and DGAT1 were upregulated by Ad-nSREBP1. Compared with the Ad-GFP, the cellular triacylglycerol content was higher and the percentage of C16:0 and C18:1 increased, whereas that of C16:1, C18:0, and C18:2 decreased in Ad-nSREBP1 cells. Overall, the data provide strong support for a central role of SREBP1 in the regulation of milk fat synthesis in goat mammary cells. PMID- 26601586 TI - Ability of 3 tanniferous forage legumes to modify quality of milk and Gruyere type cheese. AB - Condensed tannins (CT) may affect ruminal biohydrogenation of dietary polyunsaturated fatty acids. A feeding experiment was conducted with 24 Holstein cows to evaluate whether diets containing CT from different forage legumes can increase polyunsaturated fatty acids, especially n-3 fatty acid content in milk and cheese, without affecting negatively their physicochemical and sensorial properties. Cows were assigned to 4 treatment groups (n=6) for 52 d, divided into 2 periods: a control period (CoP) and an experimental period (ExP). During the CoP, cows received a basal diet composed of hay, corn silage, ExtruLin (Trinova Handel & Marketing AG, Wangen, Switzerland), concentrate, and alfalfa (AF) in a ratio of 45:25:5:7:18. In the ExP, in 3 of the 4 groups AF was replaced by either sainfoin (SF; 19% CT in dry matter) or 1 of 2 cultivars of birdsfoot trefoil [Polom (BP), 3% CT; Bull (BB), 5% CT]. At the end of each period, milk was collected on 3 consecutive days and analyzed for milk gross composition and fatty acid profile and was processed to Gruyere-type cheese. A trained panel assessed the sensory quality of raw milk and cheese using discriminative and descriptive tests. This experimental design consisting of AF in both the CoP and ExP allowed us to quantify effects due to lactation stage and experimental diets. In both the CoP and ExP, dry matter intake and milk yield did not differ among treatment groups. From the CoP to the ExP, milk urea content was reduced by 23% with SF, remained unchanged with BP, and tended to increase with AF and BB. The odor of the raw BB milk was judged to be different from AF milk. With SF, switching from the CoP to the ExP resulted in a 17% increase of the 18:3n-3 proportion in milk and cheese lipids. In BP cheese, the increase was 3%, whereas it tended to decrease in BB cheese. Additionally, the 20:5n-3 and 22:5n-3 proportions tended to increase in SF cheese from the CoP to the ExP. Compared with the AF cheeses, cheeses from cows fed CT-containing legumes were judged harder and tended to be less adhesive to the palate. In addition, SF and BP cheeses had less rind. In conclusion, feeding SF compared with BB and BP increased the content of 18:3n-3 in the milk and the cheese without a negative effect on flavor of the cheese. Despite a similar CT content, the 2 birdsfoot trefoil cultivars had opposite effects on milk urea and 18:3n-3 deposition, suggesting that, besides the content, the chemical structure may have had an important effect on the CT efficacy. PMID- 26601585 TI - Body condition score and plane of nutrition prepartum affect adipose tissue transcriptome regulators of metabolism and inflammation in grazing dairy cows during the transition period. AB - Recent studies demonstrating a higher incidence of metabolic disorders after calving have challenged the management practice of increasing dietary energy density during the last ~3 wk prepartum. Despite our knowledge at the whole animal level, the tissue-level mechanisms that are altered in response to feeding management prepartum remain unclear. Our hypothesis was that prepartum body condition score (BCS), in combination with feeding management, plays a central role in the peripartum changes associated with energy balance and inflammatory state. Twenty-eight mid-lactation grazing dairy cows of mixed age and breed were randomly allocated to 1 of 4 treatment groups in a 2 * 2 factorial arrangement: 2 prepartum BCS categories (4.0 and 5.0, based on a 10-point scale; BCS4, BCS5) obtained via differential feeding management during late-lactation, and 2 levels of energy intake during the 3 wk preceding calving (75 and 125% of estimated requirements). Subcutaneous adipose tissue was harvested via biopsy at -1, 1, and 4 wk relative to parturition. Quantitative polymerase chain reaction was used to measure mRNA and microRNA (miRNA) expression of targets related to fatty acid metabolism (lipogenesis, lipolysis), adipokine synthesis, and inflammation. Both prepartum BCS and feeding management had a significant effect on mRNA and miRNA expression throughout the peripartum period. Overfed BCS5 cows had the greatest prepartum expression of fatty acid synthase (FASN) and an overall greater expression of leptin (LEP); BCS5 was also associated with greater overall adiponectin (ADIPOQ) and peroxisome proliferator-activated receptor gamma (PPARG), whereas overfeeding upregulated expression of proadipogenic miRNA. Higher postpartum expression of chemokine ligand 5 (CCL5) and the cytokines interleukin 6 (IL6) and tumor necrosis factor (TNF) was detected in overfed BCS5 cows. Feed-restricted BCS4 cows had the highest overall interleukin 1 (IL1B) expression. Prepartum feed restriction resulted in greater chemokine ligand 2 (CCL2) expression. Overall, changes in mRNA expression were consistent with the expression pattern of inflammation-related miRNA. These data shed light on molecular mechanisms underlying the effect of prepartum BCS and feeding management on metabolic and inflammatory status of adipose tissue during the peripartum period. Data support the use of a controlled feed restriction prepartum in optimally conditioned cows, as well as the use of a higher level of dietary energy in under-conditioned cows. PMID- 26601587 TI - Effects of replacing grass silage with forage pearl millet silage on milk yield, nutrient digestion, and ruminal fermentation of lactating dairy cows. AB - This study investigated the effects of dietary replacement of grass silage (GS) with forage millet silages that were harvested at 2 stages of maturity [i.e., vegetative stage and dough to ripe seed (mature) stage] on milk production, apparent total-tract digestibility, and ruminal fermentation characteristics of dairy cows. Fifteen lactating Holstein cows were used in a replicated 3 * 3 Latin square experiment and fed (ad libitum) a total mixed ration (60:40 forage:concentrate ratio). Dietary treatments included control (GS), vegetative millet silage (EM), and mature millet silage (MM) diets. Experimental silages comprised 24% of dietary dry matter (DM). Soybean meal and slow-release urea were added in millet diets to balance for crude protein (CP). Three additional ruminally fistulated cows were used to determine the effect of treatments on ruminal fermentation and total-tract nutrient utilization. Cows fed the GS diet consumed more DM (22.9 vs. 21.7 +/- 1.02 kg/d) and CP (3.3 vs. 3.1 +/- 0.19 kg/d), and similar starch (4.9 +/- 0.39 kg/d) and neutral detergent fiber (NDF; 8.0 +/- 0.27 kg/d) compared with cows fed the MM diet. Replacing the EM diet with the MM diet did not affect DM, NDF, or CP intakes. Cows fed the MM diet produced less milk (26.1 vs. 29.1 +/- 0.79 kg/d), energy-corrected milk (28.0 vs.30.5 +/- 0.92 kg/d), and 4% fat-corrected milk (26.5 vs. 28.3 +/- 0.92 kg/d) yields than cows fed the GS diet. However, cows fed diets with EM and GS produced similar yields of milk, energy-corrected milk, and 4% fat-corrected milk. Feed efficiency (milk yield:DM intake) was greater only for cows fed the GS diet than those fed the MM diet. Milk protein yield and concentration were greater among cows fed the GS diet compared with those fed the EM or MM diets. Milk fat and lactose concentrations were not influenced by diet. However, milk urea N was lower for cows fed the GS diet than for those fed the MM diet. Ruminal NH3-N was greater for cows fed the EM diet than for those fed the GS diet. Total-tract digestibility of DM (average = 66.1 +/- 3.3%), NDF (average = 55.1 +/- 2.4%), CP (average = 63.6 +/- 4.2%), and gross energy (average = 64.5 +/- 2.6%) were not influenced by experimental diets. We concluded that cows fed GS and EM diets had comparable performance, whereas milk yield was significantly reduced with the MM diet, likely because reduced intakes of DM and net energy for lactation. PMID- 26601588 TI - Response to dietary-induced energy restriction in dairy sheep divergently selected for resistance or susceptibility to mastitis. AB - Dairy ruminants experiencing a severe postpartum negative energy balance (NEB) are considered to be more susceptible to mastitis. Although the genetic variability of mastitis resistance is well established, the biological basis of the link between energy metabolism and resistance is mostly unknown. The aim of this study was to characterize the effect of NEB on metabolism and immune response according to the genetic background for mastitis resistance or susceptibility. Forty-eight ewes from high and low somatic cell score (SCS) genetic lines were allocated to 2 homogeneous subgroups 2 wk after lambing: one group (NEB) received an energy-restricted diet to cover 60% of their energy requirements, and the other group received a control (positive energy balance: PEB) diet. Both diets met the protein requirements. After 10 d on either the NEB or PEB diet, all ewes were injected with a Pam3CSK4/MDP solution in one half udder to induce an inflammatory response. The ewes were monitored for milk production, somatic cell count (SCC), body weight (BW), body condition score (BCS), and blood metabolites. Differential milk cell counts were determined by flow cytometry. Plasma concentrations of glucose, insulin, nonesterified fatty acids (NEFA), beta-hydroxybutyrate (BHB), and triiodothyronine were determined. Energy restriction resulted in an increased fat:protein ratio in milk and decreased milk yield, BW, and BCS. The NEB ewes had significantly higher NEFA and BHB and lower plasma glucose concentrations than PEB ewes, reflecting a mobilization of body reserves and ketone body synthesis. High-SCS ewes had a higher SCS than low-SCS throughout the experiment, except after the inflammatory challenge, which resulted in similar SCS in all 4 groups. A noteworthy interaction between genetic background and diet was evidenced on metabolic parameters and BW. Indeed, high-SCS ewes subjected to NEB showed greater decrease in BW and increased NEFA and BHB concentrations compared with low-SCS ewes. Thus, NEB in early lactation led to extensive mobilization of body reserves and intense ketone body synthesis in mastitis-susceptible sheep. These results reinforce the hypothesis of a genetic association between mastitis susceptibility and energy metabolism and open the way to further studies on the biological basis for this association. PMID- 26601589 TI - Short communication: Identification of iron-binding peptides from whey protein hydrolysates using iron (III)-immobilized metal ion affinity chromatography and reversed phase-HPLC-tandem mass spectrometry. AB - Peptides with iron-binding capacity obtained by hydrolysis of whey protein with Alcalase (Novozymes, Araucaria, PR, Brazil), pancreatin, and Flavourzyme (Novozymes) were identified. Hydrolysates were subjected to iron (III) immobilized metal ion affinity chromatography, and the bound peptides were sequenced by mass spectrometry. Regardless of the enzyme used, the domains f(42 59) and f(125-137) from beta-lactoglobulin enclosed most of identified peptides. This trend was less pronounced in the case of peptides derived from alpha lactalbumin, with sequences deriving from diverse regions. Iron-bound peptides exhibited common structural characteristics, such as an abundance of Asp, Glu, and Pro, as revealed by mass spectrometry and AA analysis. In conclusion, this characterization of iron-binding peptides helps clarify the relationship between peptide structure and iron-chelating activity and supports the promising role of whey protein hydrolysates as functional ingredients in iron supplementation treatments. PMID- 26601590 TI - Comparison of ruminal lipid metabolism in dairy cows and goats fed diets supplemented with starch, plant oil, or fish oil. AB - Direct comparison of cow and goat performance and milk fatty acid responses to diets known to induce milk fat depression (MFD) in the bovine reveals relevant species-by-diet interactions in ruminal lipid metabolism. Thus, this study was conducted to infer potential mechanisms responsible for differences in the rumen microbial biohydrogenation (BH) due to diet and ruminant species. To meet this objective, 12 cows and 15 goats were fed a basal diet (control), a similar diet supplemented with 2.2% fish oil (FO), or a diet containing 5.3% sunflower oil and additional starch (+38%; SOS) according to a 3 * 3 Latin square design with 25-d experimental periods. On the last day of each period, fatty acid composition (by gas chromatography) and bacterial community (by terminal-RFLP), as well as fermentation characteristics, were measured in rumen fluid samples. Results showed significant differences in the response of cows and goats to dietary treatments, although variations in some fermentation parameters (e.g., decreases in the acetate-to-propionate ratio due to FO or SOS) were similar in both species. Main alterations in ruminal BH pathways potentially responsible for MFD on the SOS diet (i.e., the shift from trans-11 to trans-10 18:1 and related increases in trans-10,cis-12 18:2) tended to be more pronounced in cows, which is consistent with an associated MFD only in this species. However, changes linked to FO-induced MFD (e.g., decreases in 18:0 and increases in total trans-18:1) were stronger in caprine rumen fluid, which may explain their unexpected susceptibility (although less marked than in bovine) to the negative effect of FO on milk fat content. Altogether, these results suggest that distinct ruminal mechanisms lead to each type of diet-induced MFD and confirm a pronounced interaction with species. With regard to microbiota, differences between cows and goats in the composition of the rumen bacterial community might be behind the disparity in the microorganisms affected by the experimental diets (e.g., Ruminococcaceae, Lachnospiraceae, and Succinivibrionaceae in the bovine, and Pseudobutryrivibrio, Clostridium cluster IV, Prevotella, and Veillonellaceae in the caprine), which hindered the assignation of bacterial populations to particular BH steps or pathways. Furthermore, most relevant variations in microbial groups corresponded to as yet uncultured bacteria and suggest that these microorganisms may play a predominant role in the ruminal lipid metabolism in both cows and goats. PMID- 26601591 TI - Short communication: Effects of oral flavonoid supplementation on the metabolic and antioxidative status of newborn dairy calves. AB - Scientific proof for flavonoids as a health tool in calf nutrition is inconsistent. We investigated the effects of the most abundant flavonoid, quercetin, and of a green tea extract (GTE) containing various catechins on the metabolic and antioxidative traits in dairy calves to clarify their potential health-promoting effects. Male newborn German Holstein calves (n=7 per group) received either no flavonoid (control group), 10mg of quercetin equivalents as quercetin aglycone or as rutin/kg of body weight (BW) per day, or 10mg/kg of BW per day of a GTE from d 2 to 26 of life. The supplements were provided with the morning and evening feeding. The calves were fed colostrum and milk replacer, and BW, feed intake, and health status were evaluated daily. Blood samples were collected from a jugular vein on d 1, 5, 12, 19, and 26 before the morning feeding to investigate the metabolic and antioxidative status of the calves. The growth performance and health status remained unchanged, but the GTE-fed calves had fewer loose feces than the controls. The plasma concentrations of quercetin changed over time and were higher in the rutin-fed group than in the control group, whereas the catechins were below the detection limit. The plasma Trolox equivalent antioxidative capacity and ferric reducing ability of plasma were measured as markers for plasma antioxidative capacity. The concentrations of Trolox equivalent antioxidative capacity increased, whereas ferric reducing ability of plasma decreased after the first day of life in all the groups. The oxidative stress markers in the plasma were measured as thiobarbituric acid reactive substances and F2-isoprostanes, but these did not indicate treatment or time effects. The plasma concentrations of total protein, albumin, urea, lactate, glucose, and nonesterified fatty acids and of insulin and cortisol varied over time, but no group differences were caused by the flavonoid supplementation. In summary, orally administered quercetin and catechins at the dosages used in the present study resulted in weak effects on health and no effects on the metabolic and antioxidative status of newborn dairy calves. PMID- 26601592 TI - Straw particle size in calf starters: Effects on digestive system development and rumen fermentation. AB - Two trials were conducted to determine effects of straw particle size in calf starter on rumen fermentation and development in calves. Holstein calves (n=17 in trial 1; n=25 in trial 2) were housed in individual pens; bedding (wood shavings) was covered with landscape fabric to completely avoid consumption of bedding. Milk replacer was fed at 12% of birth body weight per day and water offered free choice. Calves were randomly assigned to 4 treatments differing in geometric mean particle length (Xgm) of straw comprising 5% of starter dry matter. Straw was provided within the pellet at manufacture (PS; 0.82 mm Xgm) or mixed with the pellet at time of feeding at Xgm of 3.04 (SS), 7.10 (MS), or 12.7 (LS) mm. Calves (n=12; 3/treatment) in trial 1 were fitted with a rumen cannula by wk 2 of age. A fixed amount of starter that was adjusted with age and orts were fed through the cannula in cannulated calves. Calves were euthanized 6 wk after starter was offered (9 and 7 wk of age for trials 1 and 2, respectively). Rumen digesta pH linearly decreased with age, whereas volatile fatty acid concentration increased with age. Overall pH had a cubic trend with SS lower than that of PS and MS. Molar proportion of acetate decreased with age whereas propionate proportion increased. Overall molar proportions of volatile fatty acids were not affected by diet. Fecal Xgm was not different in spite of changes in diet particle size and rumen digesta of PS being greater than SS, MS, and LS at slaughter. Fecal pH and starch concentration were not affected by diet; however, pH decreased whereas starch content increased with age. Weight of stomach compartments, rumen papillae length and width, and rumen wall thickness did not differ between diets. Omasum weight as a percentage of body weight at harvest linearly decreased as straw particle size increased. Under the conditions of this study, modifying straw particle length in starter grain resulted in minimal rumen fermentation parameter changes and no changes in rumen development. Rumen pH and fermentation changes with age were likely effects of increasing starter intake. PMID- 26601593 TI - IDOL, inducible degrader of low-density lipoprotein receptor, serves as a potential therapeutic target for dyslipidemia. AB - Low-density lipoprotein cholesterol (LDL-C) is the hall marker for the atherosclerotic cardiovascular disease (ASCVD). It has been shown that over 70% of circulating LDL-C is metabolized through binding and activation of hepatic LDL receptor (LDLR). Genetic LDLR mutations cause hypercholesterolemia in the patients. Therefore, elevation of LDLR levels is beneficial for the treatment of dyslipidemia. LDLR expression is regulated by the SREBP2/PCSK9 pathways. Targeting SREBP2/PCSK9 pathways by statins and human monoclonal PCSK9 antibody has been shown to reduce the progression of ASVCD. Recent studies identified that inducible degrader of LDLR (IDOL) is a novel regulator of LDLR. IDOL is an E3 ubiquitin ligase regulated via liver X receptors (LXRs) binding to the upstream of translation start site of IDOL. IDOL modulates LDLR distribution through ubiquitination and degradation of LDLR in lysosomes. Genome-wide association studies (GWAS) have revealed that the nonsynonymous substitution rs9370867 of IDOL probably contributes to the variability of circulating LDL levels. Recently studies also demonstrated that IDOL influences PCSK9 expression in a LDLR/SREBP2 dependent manner. Based upon these novel findings, we hypothesize that IDOL and PCSK9 would have a synergistic effect on LDLR distribution. Specifically, loss of IDOL increases LDLR distribution in the hepatic cell, and subsequently reduces serum LDL-C levels in dyslipidemic patients. IDOL might be a potential therapeutic target for the treatment of ASCVD. PMID- 26601594 TI - Immunomodulator plasmid projected by systems biology as a candidate for the development of adjunctive therapy for respiratory syncytial virus infection. AB - An imbalance in Th1/Th2 cytokine immune response has been described to influence the pathogenesis of respiratory syncytial virus (RSV) acute bronchiolitis and the severity of infection. Th2-driven response has been well described under first RSV vaccine (formalin-inactivated RSV vaccine antigens) and replicated in some conditions for RSV-infected mice, in which a Th2-dependent lung eosinophilia increases illness severity, accompanied of tissue damage. Currently, several prototypes of RSV vaccine are being tested, but there is no vaccine available so far. The advance of bioinformatics can help to solve this issue. Systems biology approaches based on network topological analysis may help to identify new genes in order to direct Th1 immune response during RSV challenge. For this purpose, network centrality analyses from high-throughput experiments were performed in order to select major genes enrolled in each T-helper immune response. Thus, genes termed Hub (B) and bottlenecks (H), which control the flow of biological information (Th1 or Th2 immune response, in this case) within the network, would be identified. As these genes possess high potential to promote Th1 immune response, they could be cloned under regulation of specific promoters in a plasmid, which will be available as a gene-transfer adjunctive to vaccines. Th1 immune response potentiated by our strategy may contribute to accelerate Th1/Th2 shift from neonatal immune system, which might favor protective immunity against RSV infection and reduce lung damage. PMID- 26601595 TI - Analysis of the impact of limitation of medical treatment orders during unplanned transfers from sub-acute care to Emergency Departments. AB - BACKGROUND: The impact of limitation of medical treatment orders (LOMT) on patient outcomes following transfer from sub-acute care to the Emergency Department remains unclear. METHODS: Retrospective medical record review of 431 adult in-patients who required ambulance transfer following clinical deterioration during a sub-acute care admission during 2010. RESULTS: Common reasons for transfer were respiratory (18.9%) or neurological (19.0%) conditions; 35.7% (154/431) were transferred within one week of sub-acute care admission. LOMT orders were in place for 37.8% (n=163) patients who were older (p<0.001), with more comorbidities (p<0.005), specifically cardiac, renal and pulmonary disease than patients without LOMT. Patients with LOMT orders had more physiological abnormalities before transfer; tachypnoea (43.7% vs 28.6%), hypoxaemia (63.5% vs 48.4%) and severe hypoxaemia (27.6% vs 14.5%). There were no differences in rates of admission, cardiac arrest, Medical Emergency Team activation or ICU admission. For admitted patients, those with LOMT orders had significantly (p<=0.005) higher mortality: in-hospital (21.9% vs 11.3%); 30 days (23.9% vs 12.3%) and 60 days (28.2% vs 13.4%). CONCLUSIONS: Patients with LOMT had higher levels of comorbidity and were more acutely ill during their sub-acute care admission. Once transferred those with a LOMT had similar rates of cardiac arrest, MET activation and unplanned ICU admission, but higher mortality. PMID- 26601596 TI - Internet Services for Communicating With the General Practice: Barely Noticed and Used by Patients. AB - BACKGROUND: The Netherlands is one of the frontrunners of eHealth in Europe. Many general practices offer Internet services, which can be used by patients to communicate with their general practice. In promoting and implementing such services, it is important to gain insight into patients' actual use and intention toward using. OBJECTIVE: The objective of the study is to investigate the actual use and intention toward using Internet services to communicate with the general practice by the general practice population. The secondary objective is to study the factors and characteristics that influence their intention to use such services. METHODS: There were 1500 members of the Dutch Health Care Consumer Panel, age over 18 years, that were invited to participate in this cross sectional study. People who had contacted their general practitioner at least once in the past year were included. Participants were asked to fill out a questionnaire about the following services: Internet appointment planning, asking questions on the Internet, email reminders about appointments, Internet prescription refill requests, Internet access to medical data, and Internet video consultation. Participants indicated whether they had used these services in the past year, they would like to use them, and whether they thought their general practice had these services. For the first two services, participants rated items based on the unified theory of acceptance and use of technology complemented with additional constructs. These items were divided into six subscales: effort expectancy, performance expectancy, trust, attitude, facilitating conditions, and social influence. RESULTS: There were 546 participants that were included in the analyses out of 593 who met the inclusion criteria. The participants had a mean age of 53 years (SD 15.4), 43.6% (n=238) were male, and 66.8% (n=365) had at least one chronic illness. Actual use of the services varied between 0% (n=0, video consultation) and 10.4% (n=57, requesting prescription refill by Internet). The proportion of participants with a positive intention to use the service varied between 14.7% (n=80, video consultation) and 48.7% (n=266, Internet access to medical data). For each service, approximately half indicated that they did not know whether the service was available. Univariate logistic regression analyses revealed that all the constructs as well as age, level of education, and Internet usage had a significant association with intention toward using Internet appointment planning and asking questions by Internet. CONCLUSIONS: Internet communication services to contact the general practice are not yet frequently used by this population. Although a substantial number of persons have a positive intention toward using such services, not all people who receive primary care seem willing to use them. The lack of awareness of the availability and functionality of such services might play an important role. PMID- 26601597 TI - [Extrinsic and intrinsic factors associated with mycotoxigenic fungi populations of maize grains (Zea mays L.) stored in silobags in Argentina]. AB - In order to determine the behavior of mycotoxin-producing fungal populations linked with silobags stored corn grains with a moisture content greater at the recommended as safe, 270 samples taken in three times (beginning, 90 days, final) over a five month period of storage were evaluated. The fungal biota was quantified and identified and the contamination with fumonisin and aflatoxin was determined. Extrinsic factors (environment), intrinsic factors (grains) and technological factors (location of the grains in the profile of silobag) were taken into account to evaluate the presence and quantity of total and mycotoxigenic fungal populations. The pH of grains and O2 levels were significantly reduced after five months, while CO2 concentration increased in the same period. The total counts of mycobiota were significantly higher in grains located in the top layer of silobag. Mycotoxigenic species of Fusarium, Aspergillus, Penicillium and Eurotium were identified. The frequency of isolation of Fusarium verticillioides decreased at the end of storage and Aspergillus flavus was isolated only at the beginning of storage. The counts of the Penicillium spp. and Eurotium spp. were increased at the end of storage. Fumonisin contamination was found in all the samples (100%) with maximum levels of 5.707mg/kg whereas aflatoxin contaminated only 40% with maximum levels of 0.0008mg/kg. The environmental and substrate conditions generated during the storage limited the development of mycotoxigenic fungi and mycotoxin production. PMID- 26601598 TI - Butyrate suppresses murine mast cell proliferation and cytokine production through inhibiting histone deacetylase. AB - Beyond their nutritional impact to colonic epithelial cells, the intestinal microbiota metabolite butyrate has pleotropic effects to host cells and is known for its beneficial effects on intestinal homeostasis and metabolism. However, it remains unclear how it modulates mast cell function. Here, we demonstrate that butyrate profoundly inhibited proliferation of mouse mastocytoma P815 cells through inducing cell cycle arrest and apoptosis, as well as decreasing c-Kit activation. In addition, butyrate increased early- and late-stage apoptotic P815 cells. In murine bone marrow-derived mast cells (BMMC), butyrate-suppressed FcepsilonRI-dependent tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) release without affecting beta-Hexosaminidase, but that was associated with decreased mitogen-activated protein kinase extracellular signal-regulated kinase 1/2, p38 and c-Jun N-terminal kinases activation. Butyrate treatment substantially enhanced histone 3 acetylation in both P815 and BMMC and decreased FcepsilonRI-dependent mRNA expression of tnf-alpha and il-6 in BMMC, mimicking the effect of Trichostatin A, a known histone deacetylase inhibitor. Chromatin immunoprecipitation revealed that butyrate enhanced acetylation of the tnf-alpha and il-6 promoter regions but blocked RNA polymerase II binding to the promoters of tnf-alpha and il-6 genes, indicating suppressed transcription initiation. These phenotypes mimicked those of Trichostatin A treatment. In conclusion, butyrate inhibits cell proliferation and increases cell apoptosis in mastocytoma P815 cells and suppresses FcepsilonRI-dependent cytokine production in murine primary BMMC, which are likely mediated by HDAC inhibition. PMID- 26601599 TI - Effect of a cocoa-enriched diet on immune response and anaphylaxis in a food allergy model in Brown Norway rats. AB - Previous studies have demonstrated that cocoa intake decreased Th2 immune-related antibodies in rats. In consequence, we aimed to study in depth this cocoa action, particularly assessing its effect on a rat model of food allergy (FA) and also on an anaphylactic response. The involvement of the intestinal immune system was analyzed to allow the action mechanisms to be investigated. The role of cocoa flavonoids in the antiallergic properties of cocoa was also established. Brown Norway rats were fed either a reference diet or diets containing conventional cocoa (CC) or nonfermented cocoa (NFC). FA to ovalbumin (OVA) was induced and, later, an anaphylactic response was provoked. As expected, the synthesis of anti OVA IgE and other Th2-related antibodies was inhibited by CC diet. In addition, the release of mast cell protease II after anaphylaxis was partially prevented by CC, although other variables were not modified. The CC diet also attenuated the increase of some Th2-related cytokines released from mesenteric lymph node and spleen cells, and modulated the intestinal gene expression of molecules involved in allergic response. These results demonstrated the local and systemic influence of CC diet. The effects of the NFC diet were weaker than those of CC, suggesting that cocoa components other than flavonoids play a role in cocoa's action. In conclusion, by acting on intestinal and systemic immune functions, a cocoa enriched diet in rats exhibited a protective effect against FA and partially against anaphylaxis, making this a food of high interest to the fields of health and immunonutrition. PMID- 26601600 TI - On the nature of cross-disciplinary integration: A philosophical framework. AB - Meeting grand challenges requires responses that constructively combine multiple forms of expertise, both academic and non-academic; that is, it requires cross disciplinary integration. But just what is cross-disciplinary integration? In this paper, we supply a preliminary answer by reviewing prominent accounts of cross-disciplinary integration from two literatures that are rarely brought together: cross-disciplinarity and philosophy of biology. Reflecting on similarities and differences in these accounts, we develop a framework that integrates their insights-integration as a generic combination process the details of which are determined by the specific contexts in which particular integrations occur. One such context is cross-disciplinary research, which yields cross-disciplinary integration. We close by reflecting on the potential applicability of this framework to research efforts aimed at meeting grand challenges. PMID- 26601601 TI - Molecular characterization and risk factors for carbapenem-resistant Gram negative bacilli colonization in children: emergence of NDM-producing Acinetobacter baumannii in a newborn intensive care unit in Turkey. AB - BACKGROUND: Multidrug-resistant Gram-negative bacilli are responsible for more than 50% of healthcare-associated infections. Colonization dynamics, characteristics, and risk factor data for CR-GNB are scarce in children. AIM: To examine the molecular characteristics of, and risk factors for nosocomial colonization with, carbapenem-resistant Gram-negative bacilli (CR-GNB) in hospitalized paediatric patients in a tertiary university hospital's paediatric units in Turkey. METHODS: A prospective case-control study was performed at a university hospital in Istanbul, Turkey. FINDINGS: A total of 1840 rectal swab specimens were collected from all 762 hospitalized children between March 2013 and October 2013. Among them, 176 (23%) patients were colonized with CR-GNB. Of these, 72 (9%) patients were colonized with carbapenem-resistant Enterobacteriaceae, 138 (18%) with CR-non-fermenter Gram-negative bacilli (CR-NF) and 34 (4%) with both. The median CR-GNB colonization time was 10 days (range: 1 116). The median duration of rectal colonization with CR-GNB was 8 days (range: 1 160). NDM (31%) was the second most frequent carbapenemase identified in Acinetobacter baumannii isolates, and has not previously been detected in Turkey. All of the 17 patients colonized with NDM-producing A. baumannii were newborns in the neonatal intensive care unit. Independent risk factors for CR-GNB colonization were: age <1 year, nasogastric tube placement, presence of underlying chronic diseases, ampicillin usage, surgical intervention, and carbapenem use. CONCLUSION: This is the first description of NDM in A. baumannii in newborn units in Turkey. Carbapenem usage is a common independent risk factor for both CRE and CR-NF colonization, which underscores the importance of antibiotic stewardship programmes. PMID- 26601602 TI - An Android app for recording hand hygiene observation data. PMID- 26601603 TI - Reducing needlestick injuries through safety-engineered devices: results of a Japanese multi-centre study. AB - BACKGROUND: Quantitative information on the effectiveness of safety-engineered devices (SEDs) is needed to support decisions regarding their implementation. AIM: To elucidate the effects of SED use in winged steel needles, intravenous (IV) catheter stylets and suture needles on needlestick injury (NSI) incidence rates in Japan. METHODS: Japan EPINet survey data and device utilization data for conventional devices and SEDs were collected from 26 participating hospitals between 1 April 2009 and 31 March 2014. The NSI incidence rate for every 100,000 devices was calculated according to hospital, year and SED use for winged steel needles, IV catheter stylets and suture needles. Weighted means and 95% confidence intervals (CI) were used to calculate overall NSI incidence rates. FINDINGS: In total, there were 236 NSIs for winged steel needles, 152 NSIs for IV catheter stylets and 180 NSIs for suture needles. The weighted NSI incidence rates per 100,000 devices for SEDs and non-SEDs were as follows: winged steel needles, 2.10 (95% CI 1.66-2.54) and 14.95 (95% CI 2.46-27.43), respectively; IV catheter stylets, 0.95 (95% CI 0.60-1.29) and 6.39 (95% CI 3.56-9.23), respectively; and suture needles, 1.47 (95% CI -1.14-4.09) and 16.50 (95% CI 4.15 28.86), respectively. All devices showed a significant reduction in the NSI incidence rate with SED use (P < 0.001 for winged steel needles, P = 0.035 for IV catheter stylets and P = 0.044 for suture needles). CONCLUSION: SED use substantially reduces the incidence of NSIs, and is therefore recommended as a means to prevent occupational infections in healthcare workers and improve healthcare safety. PMID- 26601604 TI - Benefits of NICE accreditation for guidelines. PMID- 26601605 TI - A lesson learned from the MERS outbreak in South Korea in 2015. PMID- 26601606 TI - Silver-impregnated external-ventricular-drain-related cerebrospinal fluid infections: a meta-analysis. AB - BACKGROUND: Cerebrospinal fluid (CSF) infection is the primary complication associated with placement of an external ventricular drain (EVD). The use of silver-impregnated EVD catheters has become commonplace in many neurosurgical centres. AIM: To assess the effect of silver-impregnated EVD catheter usage on catheter-related CSF infections. METHODS: A meta-analysis was performed by systematically searching Medline, Embase and the Cochrane Library. All randomized controlled trials (RCTs) and non-RCTs comparing silver-impregnated and plain EVD catheters were identified and analysed. FINDINGS: Six non-RCTs were included. The crude infection rate was 10.8% for plain catheters and 8.9% for silver impregnated catheters [pooled odds ratio (OR) 0.71, 95% confidence interval (CI) 0.46-1.08; P = 0.11]. In a microbiological spectrum analysis, silver-impregnated catheters demonstrated a significantly lower rate of CSF infections caused by Gram-positive organisms (2.0% vs 6.7% in the silver-impregnated and plain catheter groups, respectively; pooled OR 0.27, 95% CI 0.11-0.63; P = 0.002). CONCLUSION: The antimicrobial effects of silver-impregnated EVD catheters may be selective, and may need to be evaluated further in a prospective, controlled manner. PMID- 26601607 TI - Probiotics and synbiotics for the prevention of postoperative infections following abdominal surgery: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Postoperative infections, particularly surgical site infections (SSIs), cause significant morbidity and mortality. Probiotics or synbiotics are a potential prevention strategy. AIM: To evaluate the efficacy of probiotics/synbiotics for reducing postoperative infection risk following abdominal surgery. METHODS: We searched AMED, Central, CINAHL, Embase, Medline, and grey literature for randomized controlled trials of elective abdominal surgery patients administered probiotics or synbiotics compared to placebo or standard care. Primary outcome was SSIs. Secondary outcomes were adverse events, respiratory tract infections (RTIs), urinary tract infections (UTIs), combined infections, length of hospital stay, and mortality. Using random-effects meta analyses, we estimated the relative risk (RR) or mean difference (MD) and 95% confidence interval (CI). Tests were performed for heterogeneity, subgroup and sensitivity analyses were conducted, and the overall evidence quality was graded. FINDINGS: We identified 20 trials (N = 1374 participants) reporting postoperative infections. Probiotics/synbiotics reduced SSIs (RR: 0.63; 95% CI: 0.41-0.98; N = 15 studies), UTIs (RR: 0.29; 95% CI: 0.15-0.57; N = 11), and combined infections (RR: 0.49; 95% CI: 0.35-0.70; N = 18). There was no difference between groups for adverse events (RR: 0.89; 95% CI: 0.61-1.30; N = 6), RTIs (RR: 0.60; 95% CI: 0.36 1.00; N = 14), length of stay (MD: -1.19; 95% CI: -2.94 to 0.56; N = 12), or mortality (RR: 1.20; 95% CI: 0.58-2.48; N = 15). CONCLUSION: Our review suggests that probiotics/synbiotics reduce SSIs and UTIs from abdominal surgeries compared to placebo or standard of care, without evidence of safety risk. Overall study quality was low, owing mostly to imprecision (few patients and events, or wide CIs); thus larger multi-centered trials are needed to further assess the certainty in this estimate. PMID- 26601608 TI - Antimicrobial surfaces to prevent healthcare-associated infections: a systematic review. AB - Contamination of the healthcare environment with pathogenic organisms contributes to the burden of healthcare-associated infection (HCAI). Antimicrobial surfaces are designed to reduce microbial contamination of healthcare surfaces. We aimed to determine whether antimicrobial surfaces prevent HCAI, transmission of antibiotic-resistant organisms (AROs), or microbial contamination, we conducted a systematic review of the use of antimicrobial surfaces in patient rooms. Outcomes included HCAI, ARO, and quantitative microbial contamination. Relevant databases were searched. Abstract review, full text review, and data abstraction were performed in duplicate. Risk of bias was assessed using the Cochrane Effective Practice and Organization Care (EPOC) Group risk of bias assessment tool and the strength of evidence determined using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Eleven studies assessed the effect of copper (N = 7), silver (N = 1), metal-alloy (N = 1), or organosilane-treated surfaces (N = 2) on microbial contamination. Copper surfaces demonstrated a median (range) reduction of microbial contamination of <1 log10 (<1 to 2 log10). Two studies addressed HCAI/ARO incidence. An RCT of copper surfaces in an ICU demonstrated 58% reduction in HCAI (P = 0.013) and 64% reduction in ARO transmission (P = 0.063) but was considered low-quality evidence due to improper randomization and incomplete blinding. An uncontrolled before-after study evaluating copper impregnated textiles in a long-term care ward demonstrated 24% reduction in HCAI but was considered very-low-quality evidence based on the study design. Copper surfaces used in clinical settings result in modest reductions in microbial contamination. One study of copper surfaces and one of copper textiles demonstrated reduction in HCAI, but both were at high risk of bias. PMID- 26601610 TI - Isolation of a novel chronic lymphocytic leukemic (CLL) cell line and development of an in vivo mouse model of CLL. AB - Leukemic cell lines have become important tools for studies of disease providing a monoclonal cell population that can be extensively expanded in vitro while preserving leukemic cellular characteristics. However, studies of chronic lymphocytic leukemia (CLL) have been impeded in part by the lack of continuous human cell lines. CLL cells have a high spontaneous apoptosis rate in vitro and exhibit minimal proliferation in xenograft models. Therefore, there is a need for development of primary CLL cell lines and we describe the isolation of such a line from the bone marrow of a CLL patient (17p deletion and TP53 mutation) which has been in long term culture for more than 12 months with continuous proliferation. The CLL cell line (termed MDA-BM5) which was generated in vitro with continuous co-culture on autologous stromal cells is CD19+CD5+ and shows an identical pattern of somatic hypermutation as determined in the patient's bone marrow (BM), confirming the origin of the cells from the original CLL clone. MDA BM5 cells were readily transplantable in NOD/SCID gamma null mice (NSG) with disease developing in the BM, liver and spleen. BM cells from quaternary serial transplantation in NSG mice demonstrated the presence of CD19+CD5+ cells with Ig restricted to lambda which is consistent with the original patient cells. These studies describe a new CLL cell line from a patient with del(17p) that provides a unique model for in vitro and in vivo studies. PMID- 26601609 TI - Increased cytotoxicity and streptolysin O activity in group G streptococcal strains causing invasive tissue infections. AB - Streptococcus dysgalactiae subsp. equisimilis (SDSE) has emerged as an important cause of severe skin and soft tissue infections, but little is known of the pathogenic mechanisms underlying tissue pathology. Patient samples and a collection of invasive and non-invasive group G SDSE strains (n = 69) were analyzed with respect to virulence factor expression and cytotoxic or inflammatory effects on human cells and 3D skin tissue models. SDSE strains efficiently infected the 3D-skin model and severe tissue pathology, inflammatory responses and altered production of host structural framework proteins associated with epithelial barrier integrity were evident already at 8 hours post-infection. Invasive strains were significantly more cytotoxic towards keratinocytes and expressed higher Streptokinase and Streptolysin O (SLO) activities, as compared to non-invasive strains. The opposite was true for Streptolysin S (SLS). Fractionation and proteomic analysis of the cytotoxic fractions implicated SLO as a factor likely contributing to the keratinocyte cytotoxicity and tissue pathology. Analyses of patient tissue biopsies revealed massive bacterial load, high expression of slo, as well as immune cell infiltration and pro-inflammatory markers. Our findings suggest the contribution of SLO to epithelial cytotoxicity and tissue pathology in SDSE tissue infections. PMID- 26601611 TI - Primary cardiac lymphoma in a patient with concomitant renal cancer. AB - Primary cardiac lymphoma is defined as non-Hodgkin lymphoma involving the heart and/or pericardium. It is a rare cancer that primarily affects the right heart and in particular the right atrium. By contrast, renal cell carcinoma is a relatively common cancer, which in rare circumstances can metastasize to the heart. It is now known that there is an association between non-Hodgkin lymphoma and renal cell carcinoma, although the underlying mechanisms are not fully understood. The authors present a case of primary cardiac non-Hodgkin lymphoma in a patient with concomitant renal cell carcinoma and explore the possible reasons for this association. PMID- 26601612 TI - Cognitive dysfunction and health-related quality of life among older Chinese. AB - We aimed to assess the association of cognitive dysfunction with health-related quality of life (HRQOL) among older adults in China. We analyzed community-based cross-sectional data of 5,557 Chinese individuals aged 60 years and above in the Weitang Geriatric Diseases Study. Cognitive dysfunction and HRQOL were assessed using the Abbreviated Mental Test (AMT) and the European Quality of Life-5 dimensions (EQ-5D), respectively. We estimated the impacts of cognitive dysfunction on the EQ-5D index and visual analogue scale (VAS) scores using linear regression models, and the association between cognitive dysfunction and self-reported EQ-5D health problems using logistic regression models. The EQ-5D index and VAS scores were significantly lower for individuals with cognitive dysfunction than their counterparts. After controlling for covariates, the differences in EQ-5D index and VAS scores between individuals with and without cognitive dysfunction were -0.016 (95% confidence interval [CI]: -0.024, -0.008), and -3.4 (95% CI: -4.5, -2.4), respectively. Cognitive dysfunction was associated with reporting of problems in pain/discomfort (odds ration [OR]: 1.37; 95% CI: 1.12, 1.69), and anxiety/depression (OR: 2.13; 95% CI: 1.41, 3.23). The negative impact on HRQOL increased with the severity of cognitive dysfunction. The results indicate cognitive dysfunction was associated with worse HRQOL in older adults. PMID- 26601614 TI - Excitation energy dependent Raman spectrum of MoSe2. AB - Raman investigation of MoSe2 was carried out with eight different excitation energies. Seven peaks, including E1g, A1g, E2g(1), and A2u(2) peaks are observed in the range of 100-400 cm(-1). The phonon modes are assigned by comparing the peak positions with theoretical calculations. The intensities of the peaks are enhanced at different excitation energies through resonance with different optical transitions. The A1g mode is enhanced at 1.58 and 3.82 eV, which are near the A exciton energy and the band-to-band transition between higher energy bands, respectively. The E2g(1) mode is strongly enhanced with respect to the A1g mode for the 2.71- and 2.81-eV excitations, which are close to the C exciton energy. The different enhancements of the A1g and E2g(1) modes are explained in terms of the symmetries of the exciton states and the exciton-phonon coupling. Other smaller peaks including E1g and A2u(2) are forbidden but appear due to the resonance effect near optical transition energies. PMID- 26601613 TI - In Patients With Cirrhosis, Driving Simulator Performance Is Associated With Real life Driving. AB - BACKGROUND & AIMS: Minimal hepatic encephalopathy (MHE) has been linked to higher real-life rates of automobile crashes and poor performance in driving simulation studies, but the link between driving simulator performance and real-life automobile crashes has not been clearly established. Furthermore, not all patients with MHE are unsafe drivers, but it is unclear how to distinguish them from unsafe drivers. We investigated the link between performance on driving simulators and real-life automobile accidents and traffic violations. We also aimed to identify features of unsafe drivers with cirrhosis and evaluated changes in simulated driving skills and MHE status after 1 year. METHODS: We performed a study of outpatients with cirrhosis (n = 205; median 55 years old; median model for end-stage liver disease score, 9.5; none with overt hepatic encephalopathy or alcohol or illicit drug use within previous 6 months) seen at the Virginia Commonwealth University and McGuire Veterans Administration Medical Center, from November 2008 through April 2014. All participants were given paper-pencil tests to diagnose MHE (98 had MHE; 48%), and 163 patients completed a standardized driving simulation. Data were collected on traffic violations and automobile accidents from the Virginia Department of Motor Vehicles and from participants' self-assessments when they entered the study, and from 73 participants 1 year later. Participants also completed a questionnaire about alcohol use and cessation patterns. The driving simulator measured crashes, run-time, road center and edge excursions, and illegal turns during navigation; before and after each driving simulation session, patients were asked to rate their overall driving skills. Drivers were classified as safe or unsafe based on crashes and violations reported on official driving records; simulation results were compared with real life driving records. Multivariable regression analyses of real-life crashes and violations was performed using data on demographics, cirrhosis details, MHE status, and alcohol cessation patterns, at baseline and at 1 year. RESULTS: Drivers categorized as unsafe had more crashes and made more illegal turns on the driving simulator than drivers categorized as safe; a higher proportion of subjects with MHE were categorized as unsafe drivers at baseline (16%) than subjects without MHE (7%; P = .02), and at 1-year follow-up (18% vs 0%; P = .02). Alcohol cessation within <1 year and illegal turns during simulator navigation tasks were associated with real-life automobile crashes and MHE in regression analysis; road edge excursions in the simulator were associated with real-life traffic violations. Personal assessment of driving skills improved after each simulation episode. CONCLUSIONS: In a study of 205 patients with cirrhosis, we associated results from driving simulation tests with real-life driving records and MHE. Traffic safety counseling should focus on patients with cirrhosis who recently quit consuming alcohol and perform poorly on driving simulation. PMID- 26601615 TI - Ciprofloxacin plus erythromycin or ambroxol ameliorates endotracheal tube associated Pseudomonas aeruginosa biofilms in a rat model. AB - BACKGROUND AND OBJECTIVE: Pseudomonas aeruginosa is a multi-drug resistant bacterium, with its biofilm-growing mucoid (alginate-producing) strains being particularly resistant. As atomized drug administration is a common practice in pediatric patients, we compared the effect of inhalational therapy with erythromycin plus ciprofloxacin, with that of ambroxol plus ciprofloxacin, against biofilm producing strains of P. aeruginosa. RESULTS: Both combined treatment regimens were associated with a significant reduction in bacterial counts in endotracheal (ET) tubes and lungs, as compared to that observed with ambroxol and erythromycin monotherapies (P<0.05). Ciprofloxacin plus ambroxol appeared to have a higher efficacy than ciprofloxacin plus erythromycin, both in lowering bacterial counts (P<0.05) and in disrupting the structural integrity of biofilm. Histopathological changes in the lungs were milder in the two combined treatment groups, as compared to that in groups treated with single drugs. CONCLUSION: Erythromycin or ambroxol in combination with ciprofloxacin could eliminate P. aeruginosa biofilms. When combined with ciprofloxacin, ambroxol outperformed erythromycin in eradicating P. aeruginosa biofilm. PMID- 26601617 TI - Nanostructured Photodetectors: From Ultraviolet to Terahertz. AB - Inspired by nanoscience and nanoengineering, numerous nanostructured materials developed by multidisciplinary approaches exhibit excellent photoelectronic properties ranging from ultraviolet to terahertz frequencies. As a new class of building block, nanoscale elements in terms of quantum dots, nanowires, and nanolayers can be used for fabricating photodetectors with high performance. Moreover, in conjunction with traditional photodetectors, they exhibit appealing performance for practical applications including high density of integration, high sensitivity, fast response, and multifunction. Therefore, with the perspective of photodetectors constructed by diverse low-dimensional nanostructured materials, recent advances in nanoscale photodetectors are discussed here; meanwhile, challenges and promising future directions in this research field are proposed. PMID- 26601616 TI - First pregnancies, live birth, and in vitro fertilization outcomes after transplantation of frozen-banked ovarian tissue with a human extracellular matrix scaffold using robot-assisted minimally invasive surgery. AB - BACKGROUND: Ovarian tissue cryopreservation is an experimental fertility preservation method and the transplantation techniques are still evolving. OBJECTIVE: We attempted to improve the technique with the utility of a human decellularized extracellular tissue matrix (ECTM) scaffold, robot-assisted minimally invasive surgery, and perioperative pharmacological support. STUDY DESIGN: We prospectively studied 2 subjects with hemophagocytic lymphohistiocytosis (patient A) and non-Hodgkin lymphoma (patient B) who underwent ovarian tissue cryopreservation at the age of 23 years, before receiving preconditioning chemotherapy for hematopoietic stem cell transplantation. Both experienced ovarian failure postchemotherapy and we transplanted ovarian cortical tissues to the contralateral menopausal ovary 7 and 12 years later, using a human ECTM scaffold and robotic assistance. The ECTM scaffold tissue compatibility was shown in preclinical studies. Patients also received estrogen supplementation and baby aspirin preoperatively to aid in the revascularization process. RESULTS: Ovarian follicle development was observed approximately 10 (patient A) and 8 (patient B) weeks after ovarian tissue transplantation. Following 8 and 7 cycles of in vitro fertilization, 9 and 10 day 3 embryos were cryopreserved (patients A and B, respectively). While the baseline follicle-stimulating hormone (range 3.6-15.4 mIU/mL) levels near normalized by 7 months and remained steady postovarian transplantation in patient A, patient B showed improved but elevated follicle-stimulating hormone levels throughout (range 21-31 mIU/mL). Highest follicle yield was achieved 14 (8 follicles; patient A) and 11 (6 follicles; patient B) months postintervention. Patient A experienced a chemical pregnancy after the third frozen embryo transfer attempt. She then conceived following her first fresh in vitro fertilization embryo transfer and the pregnancy is currently ongoing. Patient B conceived after the first frozen embryo transfer attempt and delivered a healthy girl at term. CONCLUSION: We report the first pregnancies after the minimally invasive transplantation of previously cryopreserved ovarian tissue with an ECTM scaffold. This approach seems to be associated with steady ovarian function after a follow up of up to 2 years. PMID- 26601618 TI - Serological cross-reactivity between Strongyloides venezuelensis and Syphacia muris in Wistar rats (Rattus norvegicus). AB - One of the problems frequently faced in laboratory facilities is the possibility of the natural parasitic infection of lab animals, which can interfere with biomedical research results. The present study aimed to evaluate cross-reactivity among serum samples from Wistar rats (Rattus norvegicus) naturally infected with Syphacia muris and experimentally infected with Strongyloides venezuelensis. Forty rats were divided into four groups of ten animals each. Parasite load was evaluated by quantifying the adult worms from both helminthes species recovered from the intestines and the S. venezuelensis eggs eliminated in feces. Serological cross-reactivity by parasite-specific IgG detection was tested via enzyme linked immunosorbent assay (ELISA), immunofluorescence antibody test (IFAT) and immunoblotting. The results demonstrated that the quantity of S. venezuelensis eliminated eggs and parthenogenetic females decreased significantly in cases of co-infection with S. muris. ELISA revealed 100% cross-reactivity of serum samples from both species against the opposing antigen. IgG cross reactivity was confirmed by IFAT using tissue sections of S. venezuelensis larvae and adult S. muris. Immunoblotting showed that IgG antibodies from the sera of animals infected with S. muris recognized eight antigenic bands from S. venezuelensis saline extract and that IgG antibodies from the sera of animals infected with S. venezuelensis recognized seven bands from S. muris saline extract. These results demonstrate the serological cross-reactivity between S. muris and S. venezuelensis in infected rats. PMID- 26601619 TI - Olive pomace valorization by Aspergillus species: lipase production using solid state fermentation. AB - BACKGROUND: Pollution by olive mill wastes is an important problem in the Mediterranean area and novel solutions for their proper management and valorization are needed. The aim of this work was to optimize a solid-state fermentation (SSF) process to produce lipase using olive pomace (OP) as the main source of nutrients by several Aspergillus spp. Optimized variables in two different designs were: ratio between olive pomace and wheat bran (OP:WB), NaNO3 , Czapek nutrients, fermentation time, moisture content (MC) and temperature. RESULTS: Results showed that the mixture OP:WB and MC were the most significant factors affecting lipase production for all fungi strains tested. With MC and temperature optimization, a 4.4-fold increase in A. ibericus lipase was achieved (90.5 +/- 1.5 U g(-1) ), using a mixture of OP and WB at 1:1 ratio, 0.02 g NaNO3 g(-1) dry substrate, absence of Czapek nutrients, 60% of MC and incubation at 30 degrees C for 7 days. For A. niger and A. tubingensis, highest lipase activity obtained was 56.6 +/- 5.4 and 7.6 +/- 0.6 U g(-1) , respectively. CONCLUSION: Aspergillus ibericus was found to be the most promising microorganism for lipase production using mixtures of OP and WB. (c) 2015 Society of Chemical Industry. PMID- 26601621 TI - Unilateral pulmonary edema in acute coronary syndrome: A sinister sign. PMID- 26601622 TI - ? PMID- 26601623 TI - Double jeopardy: sleep apnea, atrial fibrillation, and stroke. PMID- 26601624 TI - Cortical excitability in restless legs syndrome. PMID- 26601620 TI - The molecular basis for centromere identity and function. AB - The centromere is the region of the chromosome that directs its segregation in mitosis and meiosis. Although the functional importance of the centromere has been appreciated for more than 130 years, elucidating the molecular features and properties that enable centromeres to orchestrate chromosome segregation is an ongoing challenge. Most eukaryotic centromeres are defined epigenetically and require the presence of nucleosomes containing the histone H3 variant centromere protein A (CENP-A; also known as CENH3). Ongoing work is providing important molecular insights into the central requirements for centromere identity and propagation, and the mechanisms by which centromeres recruit kinetochores to connect to spindle microtubules. PMID- 26601625 TI - I sleep, because we sleep: a synthesis on the role of culture in sleep behavior research. AB - AIM: The aim of this study was to synthesize the literature on the cultural aspects of sleep and their relevance to behavioral sleep research. METHODS: A narrative synthesis of the existing literature on sleep was conducted with a focus on its biological, sociological, political, and anthropological aspects. This synthesis was guided by the PEN-3 cultural model, developed by the primary author. RESULTS: The findings highlight the cross-cultural contexts within which people sleep and the role of varied sleeping arrangements in influencing sleep behavior and perspectives. Furthermore, the contexts in which sleep occurs, coupled with the influence of the family, and the positive aspects of sleep helped illustrate why cultural aspects of sleep are vital for a broader understanding of sleep. DISCUSSION: The authors conclude by highlighting the need to integrate studies on the biological, sociological, and political aspects of sleep. Our examination of the literature strongly suggests that careful assessment of epidemiological and clinical sleep data should consider the cultural aspects of sleep as well as the context in which sleep occurs, the role of the family, and positive aspects of sleep. PMID- 26601626 TI - Clinical significance and validity of the subclassification for colorectal laterally spreading tumor granular type. AB - BACKGROUND AND AIM: Colorectal laterally spreading tumor granular type (LST-G) is generally divided into two subtypes based on morphology. Here, we retrospectively investigated the clinical significance of a concrete, objective LST-G subclassification. METHODS: This study examined 636 consecutive cases that were resected endoscopically or surgically. LST-G was subclassified as follows: Type 1, a lesion with homogenous uniform granules with uniform (<5 mm) nodules; Type 2, a lesion with granules and small nodules (>=5 mm, <10 mm); or Type 3, a lesion accompanied by large nodules (>=10 mm). For the validation study, 194 images were compiled from 97 cases investigated using conventional colonoscopy and chromoendoscopy with indigo carmine dye spraying. Images were distributed in a randomized order to students without prior endoscopy experience, less-experienced endoscopists (LEE group), and highly experienced endoscopists (HEE group). Diagnostic accuracy and interobserver agreement were then evaluated. RESULTS: There was no submucosal invasion in Type 1 lesions. The incidence of deep submucosal invasive carcinoma was higher for Type 3 lesions than for Type 2 lesions. Interobserver agreement was good in each group. Diagnostic accuracy was higher in the HEE group than in the student and LEE groups. Chromoendoscopy had a higher accuracy rate than conventional colonoscopy in the LEE and HEE groups (LEE, 0.74 vs 0.69, P < 0.05; HEE, 0.84 vs 0.78, P < 0.05). CONCLUSIONS: This subclassification of LST-G according to the diameters of granules and nodules was both useful for choosing therapeutic strategies in the clinical setting and universally applicable. PMID- 26601627 TI - The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment. AB - BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a leading cause of cancer related death worldwide. An increasing number of reports describe HCC in the setting of obesity and diabetes, two major risk factors for non-alcoholic fatty liver disease (NAFLD). The increasing incidence of these conditions and the emerging evidence of HCC in non-cirrhotic NAFLD prioritize a better understanding of NAFLD-related HCC epidemiology and pathogenesis in order to target screening policies and develop preventive-therapeutic strategies. In this review, we focus on the epidemiological impact of this condition, suggesting a possible link between HCC in cryptogenic cirrhosis and NAFLD. Furthermore, we analyse the suggested pathogenic mechanisms and the possible preventive-therapeutic strategies. PMID- 26601628 TI - Ultrasonic Mastering of Filter Flow and Antifouling of Renewable Resources. AB - Inadequate access to pure water and sanitation requires new cost-effective, ergonomic methods with less consumption of energy and chemicals, leaving the environment cleaner and sustainable. Among such methods, ultrasound is a unique means to control the physics and chemistry of complex fluids (wastewater) with excellent performance regarding mass transfer, cleaning, and disinfection. In membrane filtration processes, it overcomes diffusion limits and can accelerate the fluid flow towards the filter preventing antifouling. Here, we outline the current state of knowledge and technological design, with a focus on physicochemical strategies of ultrasound for water cleaning. We highlight important parameters of ultrasound for the delivery of a fluid flow from a technical perspective employing principles of physics and chemistry. By introducing various ultrasonic methods, involving bubbles or cavitation in combination with external fields, we show advancements in flow acceleration and mass transportation to the filter. In most cases we emphasize the main role of streaming and the impact of cavitation with a perspective to prevent and remove fouling deposits during the flow. We also elaborate on the deficiencies of present technologies and on problems to be solved to achieve a wide-spread application. PMID- 26601629 TI - Liver Transplant From Unexpected Donation After Circulatory Determination of Death Donors: A Challenge in Perioperative Management. AB - Unexpected donation after circulatory determination of death (uDCD) liver transplantation is a complex procedure, in particular when it comes to perioperative recipient management. However, very little has been published to date regarding intraoperative and immediate postoperative care in this setting. Herein, we compare perioperative events in uDCD liver recipients with those of a matched group of donation after brain death liver recipients. We demonstrate that the former group of recipients suffers significantly greater hemodynamic instability and derangements in coagulation following graft reperfusion. Based on our experience, we recommend a proactive recipient management strategy in uDCD liver transplantation that involves early use of vasopressor support; maintaining adequate intraoperative levels of red cells, platelets, and fibrinogen; and routinely administering tranexamic acid before graft reperfusion. PMID- 26601630 TI - Brain potentials indicate the effect of other observers' emotions on perceptions of facial attractiveness. AB - Perceptions of facial attractiveness are sensitive to emotional expression of the perceived face. However, little is known about whether the emotional expression on the face of another observer of the perceived face may have an effect on perceptions of facial attractiveness. The present study used event-related potential technique to examine social influence of the emotional expression on the face of another observer of the perceived face on perceptions of facial attractiveness. The experiment consisted of two phases. In the first phase, a neutral target face was paired with two images of individuals gazing at the target face with smiling, fearful or neutral expressions. In the second phase, participants were asked to judge the attractiveness of the target face. We found that a target face was more attractive when other observers positively gazing at the target face in contrast to the condition when other observers were negative. Additionally, the results of brain potentials showed that the visual positive component P3 with peak latency from 270 to 330 ms was larger after participants observed the target face paired with smiling individuals than the target face paired with neutral individuals. These findings suggested that facial attractiveness of an individual may be influenced by the emotional expression on the face of another observer of the perceived face. PMID- 26601631 TI - An In Vitro Comparison of the Primary Stability of 2 Tapered Fluted Femoral Stem Designs. AB - BACKGROUND: Proximal bony deficiencies present a biomechanical challenge to achieving primary stability in revision hip arthroplasty. Long tapered fluted stems have been engineered to span these defects but concerns of early subsidence are well documented. This work aimed primarily to investigate the issue of subsidence with this design using a cadaveric model. A secondary aim was to compare the stability of 2 versions of this design. METHODS: Seven pairs of cadaveric femora were obtained, dual emission x-ray absorpitometry scanned, with calibration radiographs taken for digital templating. Each bone was potted according to the ISO standard for fatigue testing and a Paprosky type 3 defect was simulated. The established cone-conical Restoration Modular (Stryker) system and a novel design with a chamfered tip and flute configuration (Redapt, Smith & Nephew) were examined. Movement at the stem-bone interface was measured using radiostereometric analysis and micromotion transducers. RESULTS: All restoration stems and 85% of the Redapt stems achieved stability by recognized criteria, micromotion < 150 MUm and migration less than 2 mm. A Fisher exact test comparing the proportion of stems which were stable or unstable was not significant, P = .055. Mean axial subsidence (SD) was 0.17 mm (0.32) and 0.1 mm (0.131) for the Restoration and Redapt stems respectively. CONCLUSION: This study has demonstrated minimal subsidence in the immediate post-operative period using tapered fluted stems. Both designs achieved excellent stability despite simulation of Paprosky type 3 bony defects in the cadaveric model. This geometry appears satisfactory for use in revision surgery in the presence of significant proximal bony deficiencies. PMID- 26601632 TI - Changes in Bone Density in Metal-Backed and All-Polyethylene Medial Unicompartmental Knee Arthroplasty. AB - BACKGROUND: Proximal tibial strain in medial unicompartmental knee arthroplasty (UKA) may alter bone mineral density and cause pain. The aims of this retrospective cohort study were to quantify and compare changes in proximal tibial bone mineral density in metal-backed and all-polyethylene medial UKAs, correlating these with outcome, particularly ongoing pain. METHODS: Radiographs of 173 metal-backed and 82 all-polyethylene UKAs were analyzed using digital radiograph densitometry at 0, 1, 2, and 5 years. The mean grayscale of 4 proximal tibial regions was measured and converted to a ratio: the GSRb (grayscale ratio b), where GSRb>1 represents relative medial sclerosis. RESULTS: In both implants, GSRb reduced significantly to 1 year and stabilized with no differences between implants. Subgroup analysis showed less improvement in Oxford Knee Score in patients whose GSRb increased by more than 10% at 1 year (40/255) compared with patients whose GSRb reduced by more than 10% at both 1 years (8.2 vs 15.8, P=.002) and 5 years (9.6 vs 15.8, P=.022). Patients with persistently painful UKAs (17/255) showed no reduction in GSRb at 1 year compared with a 20% reduction in those without pain (P=.05). CONCLUSIONS: Bone mineral density changes under medial UKAs are independent of metal backing. Medial sclerosis appears to be associated with ongoing pain. PMID- 26601633 TI - Is There an Inherent Risk to Damage the Popliteus Tendon by Femoral Component With Inbuilt External Rotation? A Pilot Study in Indian Knees. AB - INTRODUCTION: Femoral components with inbuilt rotation require thicker flexion resection of the lateral femoral condyle and could have a potential risk of damaging the popliteus tendon, especially in the smaller Asian knees. MATERIALS AND METHODS: We prospectively evaluated 10 patients with bilateral varus osteoarthritis knee to size the cuts and their location in relation to the popliteus tendon. Two different types of implant were used on either side; one side requires resection in 3 degrees external rotation (group A) and the other side requires a femoral component with inbuilt external rotation (group B). We observed the incidence of injury to the popliteus tendon and distance between flexion cut to its attachment over the lateral femoral condyle between both groups. RESULTS: We had popliteus tendon injury in 3 knees all from group B. Risk of damaging the popliteus tendon was found higher in group B, as the distance between flexion cut to popliteus tendon attachment was significantly low. CONCLUSION: Femoral component with inbuilt external rotation has more risk of injuring the popliteus tendon because flexion cut takes out more bone from the lateral femoral condyle. PMID- 26601634 TI - Midterm Outcomes Following Total Knee Arthroplasty in Lupus Patients. AB - BACKGROUND: An increasing number of patients with systemic lupus erythematosus (SLE) are undergoing total knee arthroplasty (TKA), but there are few studies detailing their outcomes. The purpose of this study was to evaluate TKA cohort of patients who had SLE compared with a matched cohort who did not have this disease by analyzing (1) implant survivorship, (2) functional outcomes, (3) complication rates, (4) health-related quality of life, and (5) patient-perceived activity level. METHODS: A retrospective review of all patients who underwent TKA and had an International Classification of Diseases, Ninth Revision, code diagnosis for SLE was performed at 3 high-volume institutions. A total of 31 patients (34 arthroplasties) were identified, and they were compared with a matched cohort (1:3) who did not have SLE and had undergone a primary TKA during this same time period. RESULTS: After a mean 6-year follow-up (range, 2-10 years), both cohorts had similar implant survivorship (91% vs 99%). In addition, each cohort had similar complication rates (odds ratio = 1.9, 0.99-13). Functional outcomes were similar as measured by Knee Society Scores objective (90 vs 91 points) and functional (89 vs 90 points). There were no differences in Short Form-36 physical (47 vs 49 points) or mental components (51 vs 53 points). University of California Los Angeles activity scores were similar as well (5.1 vs 5.9 points). CONCLUSIONS: Our study demonstrated comparable excellent clinical and patient reported outcomes of TKA in patients with or without SLE. Prospective studies are necessary to evaluate these outcomes at longer follow-up. PMID- 26601635 TI - Cost Analysis of Tranexamic Acid in Anemic Total Joint Arthroplasty Patients. AB - BACKGROUND: Preoperative anemia is present in 20% of total joint arthroplasty patients. Current preoperative treatment options, including iron supplementation (FE) and erythropoietin (EPO), are expensive. Tranexamic acid (TXA) has been adopted as an intraoperative adjunct to decrease blood loss. Our hypothesis is that TXA is a cost-effective treatment compared to FE and EPO in anemic patients. METHODS: In this study, a cost analysis was performed, comparing the material costs of TXA and packed red blood cells (PRBCs) to the theoretical administration and material costs of FE and EPO per standard preoperative anemia protocol. RESULTS: A total of 243 patients were included in the study. Of this group, 18.5% (45/243) had preoperative anemia. The rate of transfusion was 6.7% (3/45), and 5 units of PRBCs was transfused. The combined cost of TXA and PRBCs was $5317.08. Even assuming a best-case scenario with FE or EPO treatment without a postoperative PRBC requirement, the cost of treatment would range from 2 to 17 times more than treatment with TXA. An additional 50 units of PRBC (1.1 units per patient) would need to be transfused for the cost of TXA treatment to be equivalent to FE or EPO treatment. CONCLUSION: Tranexamic acid is significantly less expensive than FE or EPO as a treatment option for total joint arthroplasty patients presenting with preoperative anemia. It is a cost-effective adjunct for limiting transfusion rates in this patient population. We recommend that new preoperative anemia levels that necessitate preoperative intervention be established. PMID- 26601636 TI - Risk Factors Predict Increased Length of Stay and Readmission Rates in Revision Joint Arthroplasty. AB - BACKGROUND: This study aimed to identify risk factors for 30-day readmission and extended length of stay (LOS) in revision total knee (RKA) and hip (RHA) arthroplasty patients. METHODS: Patients who underwent RKA or RHA from 2011 to 2013 were identified in the National Surgical Quality Improvement Program database. Bivariate and multivariate analyses of risk factors for 30-day readmission and extended LOS (>75th percentile) were assessed using preoperative and intraoperative variables. RESULTS: A total of 4977 RKA and 5135 RHA patients were reviewed. The most common causes for revision were mechanical (52% RKA, 52% RHA), infection (13% RKA, 8% RHA), dislocation (6% RKA, 13% RHA), and fracture (1% RKA, 4% RHA). Rate of readmission for RKA patients (6.4%; 318 patients) was lower than for RHA patients (8.0%; 409 patients) (P = .002). Multivariate analysis identified severe adverse event before discharge, male sex, pulmonary disease, stroke, cardiac disease, and American Society of Anesthesiologists class 3 or 4 as significant predictors of readmission (all P <= .03). Surgical complications were the more common cause of readmission for both groups. Multivariate analysis of extended LOS identified infection or fracture etiology relative to mechanical loosening etiology, functional status, body mass index greater than 40 kg/m2, history of smoking, diabetes, cardiac disease, stroke, bleeding-causing disorders, wound class 3 or 4, and American Society of Anesthesiologists class 3 or 4 (all P <= .05) as independent predictors. CONCLUSION: Modifiable risk factors should be addressed prior to revision total joint arthroplasty to reduce 30-day readmissions and LOS. Future P4P revision arthroplasty models should incorporate procedural diagnosis as rates of readmission and extended LOS significantly differ across procedural etiologies. PMID- 26601637 TI - Twenty-Five- to Twenty-Seven-Year Results of a Cemented vs a Cementless Stem in the Same Patients Younger Than 50 Years of Age. AB - BACKGROUND: No study to our knowledge evaluated the long-term survivorship of the contemporary cemented vs cementless stems more than 25 years of follow-up in the same patients younger than 50 years of age. PURPOSE OF STUDY: The purpose of the study is to determine (1) validated outcome scores, (2) prevalence of polyethylene wear and osteolysis, and (3) survivorship of the cemented vs cementless femoral components in the same young patients at minimum follow-up of 25 years. METHODS: We report 171 patients (mean age, 47.7 years) at the time of the surgery who received simultaneous bilateral total hip arthroplasty with a cemented stem in one hip and a cementless stem in the other (26.1-year follow up). A cementless acetabular component was used in all hips. There were 125 men and 46 women. The mean age at the time of the arthroplasty was 47.7 +/- 10.7 years (range, 21-50 years). RESULTS: The average Harris hip scores were similar between the groups of cemented stem (mean, 91 points) and cementless stem (93 points). Survival rate of the acetabular component (79% vs 78%) and that of the femoral component (96% vs 95%) at 26.1 years were similar between the 2 groups. CONCLUSIONS: The long-term fixation of the acetabular metallic shell and cemented or cementless femoral stem was outstanding. Polyethylene wear and periacetabular osteolysis were contributing factors to reduce the long-term survival of the contemporary total hip arthroplasties with or without cement in young patients. New bearing surfaces such as ceramic on ceramic or ceramic on highly cross-linked polyethylene would improve wear of the bearing surfaces. PMID- 26601638 TI - Patellar Height Decreasing After Distal Femur Endoprosthesis Reconstruction Does Not Affect Functional Outcome. AB - INTRODUCTION: The patellar height can influence extensor mechanism and the knee function. Thus, during knee arthroplasty, the surgeon seeks to maintain the correct patellar height. However, it is more difficult to define and maintain the correct patella height in megaprosthesis reconstructions after tumor resections. The objective of this study was to evaluate patellar height after distal femur endoprosthesis reconstruction and its association to knee function. METHODS: This retrospective analysis included 108 patients who underwent distal femur resections and endoprosthesis reconstruction. The minimum follow-up was 1 year or until the patients underwent patellar resurfacing or endoprosthesis revision. Patellar height was calculated using Insall-Salvati ratio (ISR) and Insall Salvati patellar tendon insertion ratio (PTR) at 2 different times: postoperatively and at the final follow-up. The postoperative ratio was calculated using the best postoperative radiograph taken at least 1 month after the procedure. The final measures were based on the radiograph available at the last follow-up consultation. The ISR and PTR were associated to anterior knee pain (AKP), range of motion (ROM), and extension lag (EXL). RESULTS: The average follow-up was 4.5years. The mean postoperative ISR was 1.02, and the mean ISR at final follow-up was 0.95 (P<.0001). The mean postoperative PTR was 1.45, and the mean PTR at final follow-up was 1.40 (P=.016). There was no association between patellar height and AKP, ROM, and EXL. Patellar height decreases significantly after distal femur resections but does not affect AKP, ROM, and EXL. PMID- 26601639 TI - Novel echocardiographic indicator for potential cardioembolic stroke. AB - BACKGROUND AND PURPOSE: In many cardioembolic strokes (CSs), the specific embolic source is uncertain. Despite the high mortality of CS, not enough attention is paid to its potential source. Although atrial fibrillation (AF) is the most common source of embolism, more complex and dynamic multiplicities may influence CS. The aim of this study was to evaluate novel indicators of transthoracic echocardiography (TTE) that have additional value for detecting CS. METHODS: In total, 1878 patients with acute ischaemic stroke who had TTE during admission were identified. Of the patients with undetermined etiology, 93 patients with incomplete evaluations were excluded. Thereafter, two stroke neurologists reviewed all of the magnetic resonance images to assess cardioembolic lesion patterns. The patients were classified into two groups: potential cardioembolic stroke (PCS) and non-PCS. RESULTS: Amongst a total of 1601 patients, 518 (32.4%) had PCS. About half of the patients with PCS had AF. Patients with PCS were more likely to have larger left ventricular (LV) end-diastolic diameters, larger LV end-systolic diameters, larger left atrial sizes, increased E/A ratios and reduced LV ejection fractions. After adjusting for multiple clinical and TTE variables including AF, an E/A ratio >=1.5 had a significant predictive value for PCS (odds ratio 2.89, 95% confidence interval 1.57-5.31, P < 0.01). CONCLUSION: An E/A ratio >=1.5 is independently associated with PCS after adjusting for multiple covariates including AF and provides incremental prognostic information for detecting PCS. PMID- 26601640 TI - Combined zinc sulphate and NSAID-induced gastric ulcer perforation in Wilson disease: A case report. PMID- 26601641 TI - Click Chemistry Mediated Functionalization of Vertical Nanowires for Biological Applications. AB - Semiconductor nanowires (NWs) are gaining significant importance in various biological applications, such as biosensing and drug delivery. Efficient and controlled immobilization of biomolecules on the NW surface is crucial for many of these applications. Here, we present for the first time the use of the Cu(I) catalyzed alkyne-azide cycloaddition and its strain-promoted variant for the covalent functionalization of vertical NWs with peptides and proteins. The potential of the approach was demonstrated in two complementary applications of measuring enzyme activity and protein binding, which is of general interest for biological studies. The attachment of a peptide substrate provided NW arrays for the detection of protease activity. In addition, green fluorescent protein was immobilized in a site-specific manner and recognized by antibody binding to demonstrate the proof-of-concept for the use of covalently modified NWs for diagnostic purposes using minute amounts of material. PMID- 26601642 TI - National and state prevalence of smoke-free rules in homes with and without children and smokers: Two decades of progress. AB - OBJECTIVE: The home is the primary source of secondhand smoke (SHS) exposure for children. We assessed national and state progress in smoke-free home (SFH) rule adoption in homes with and without children and adult smokers. METHODS: Data came from the 1992-1993 and 2010-2011 Tobacco Use Supplements to the Current Population Survey, a U.S. national probability household survey. Households were defined as having a SFH rule if all household respondents aged >=18 indicated no one was allowed to smoke inside the home at any time. Households with children were those with occupants aged <18. Smokers were those who smoked >=100 lifetime cigarettes and now smoked "everyday" or "some days". RESULTS: From 1992-1993 to 2010-2011, SFH rule prevalence increased from 43.0% to 83.0% (p<.05). Among households with children, SFH rules increased overall (44.9% to 88.6%), in households without smokers (59.7% to 95.0%), and households with >=1 smokers (9.7% to 61.0%) (p<.05). Among households without children, SFH rules increased overall (40.8% to 81.1%), in households without smokers (53.4% to 90.1%), and households with >=1 smokers (6.3% to 40.9%) (p<.05). Prevalence increased in all states, irrespective of smoker or child occupancy (p<.05). In 2010-2011, among homes with smokers and children, SFH rule prevalence ranged from 36.5% (West Virginia) to 86.8% (California). CONCLUSIONS: Considerable progress has been made adopting SFH rules, but many U.S. children continue to be exposed to SHS because their homes are not smoke-free. Further efforts to promote adoption of SFH rules are essential to protect all children from this health risk. PMID- 26601644 TI - Dog walking among adolescents: Correlates and contribution to physical activity. AB - PURPOSE: To assess the association of dog walking with adolescents' moderate-to vigorous physical activity (MVPA) and body mass index (BMI), and identify correlates of dog walking. METHODS/DESIGN: Participants were 12-17year-olds (n=925) from the Baltimore, MD and Seattle, WA regions. Differences in accelerometer-assessed minutes/day of MVPA and self-reported BMI (percentile) were compared among adolescents (1) without a dog (n=441) and those with a dog who (2) did (>=1days/week, n=300) or (3) did not (n=184) walk it. Correlates of (1) dog walking (any vs. none) among adolescents with dogs (n=484), and (2) days/week of dog walking among dog walkers (n=300) were investigated. Potential correlates included: demographic, psychosocial, home environment, perceived neighborhood environment, and objective neighborhood environment factors. RESULTS: 52% of adolescents lived in a household with a dog, and 62% of those reported dog walking >=1day/week. Dog walkers had 4-5 more minutes/day of MVPA than non-dog-walkers and non-dog-owners. BMI was not associated with dog walking or ownership. Among households with dogs, adolescents who lived in objectively walkable neighborhoods were 12% more likely to walk their dog than those in less walkable neighborhoods. Among dog walkers, having a multi-family home, college educated parent, lower perceived traffic safety, higher street connectivity and less mixed use were related to more days/week of dog walking. CONCLUSIONS: Dog walkers had 7-8% more minutes/day of MVPA than non-dog walkers, and correlates of dog walking were found at multiple levels of influence. Results suggest multilevel interventions that include both environmental and psychosocial components to increase dog walking should be evaluated. PMID- 26601643 TI - Abdominal obesity as a mediator of the influence of physical activity on insulin resistance in Spanish adults. AB - OBJECTIVE: The aim of the study was to analyze the relationship between moderate to-vigorous physical activity (MVPA) and insulin resistance (IR) in Spanish adults and to examine whether this relationship is mediated by abdominal obesity (waist circumference - WC). METHODS: The cross-sectional study included 1162 healthy subjects belonging to the EVIDENT study (mean age 55.0+/-13.3years; 61.8% women) from six different Spanish provinces. Moderate-to-vigorous physical activity (MVPA) was measured objectively over 7days using Actigraph accelerometers, collecting data in 60-second epochs, and retaining respondents with >=4 valid days for the analysis. The homeostasis model of assessment (HOMA IR) was used to determine IR, and its individual components - fasting glucose and insulin - were determined using standard protocols. Linear regression models were fitted according to Baron and Kenny's procedures for mediation analysis. RESULTS: Fasting insulin and HOMA-IR levels were significantly worse in adults who spent fewer minutes in MVPA (first quartile<=30.1 and 22.7min/day in men and women, respectively) after adjusting for age, sex, smoking habits, drinking habits, accelerometer wear time, sedentary time, and Mediterranean diet adherence. However, when WC was added to the ANCOVA models as a covariate, the effects disappeared. Mediation analysis reported that WC acts as a full mediator in the relationship between MVPA and IR (HOMA-IR and fasting insulin). CONCLUSION: These findings show that WC plays a pivotal role in the relationship between MVPA and IR, and therefore highlights that decreasing abdominal obesity might be considered as an intermediate outcome for evaluating interventions aimed at preventing diabetes mellitus. PMID- 26601645 TI - Evaluation of StO2 tissue perfusion monitoring as a tool to predict the need for lifesaving interventions in trauma patients. AB - BACKGROUND: Hemorrhage remains the leading cause of mortality in preventable trauma deaths. Earlier recognition of hemorrhagic shock decreases the time to implementation of life-saving interventions improves patient survival. The presence of hemorrhagic shock is not always apparent using standard vital signs monitoring, a clinical state referred to as occult shock. METHODS: This prospective, observational study was performed at Memorial Hermann Hospital in Houston, TX. Prisoners, pregnant women, and patients with burn injuries greater than 20% total body surface area or bilateral upper extremity fractures were excluded. Hutchinson Technologies Spot Check StO2 device was used to measure StO2 values. RESULTS: StO2 values less than 75% were predictive of the need for blood product transfusions (P < .01) and the need for emergency surgeries. Nearly one third of patients who presented with a systolic blood pressure 120 mm Hg or more presented with StO2 less than 75% and had a median base deficit of 5 (3 to 6.5). CONCLUSIONS: Admission StO2 measurements less than 75% predict the need for blood products and emergent surgical procedures and may be used as an adjunct method for identifying shock. StO2 measurements can aid where laboratory values are unavailable. PMID- 26601646 TI - Regional recurrence in the era of sentinel lymph node biopsy. AB - BACKGROUND: The incidence of all-location regional recurrence after sentinel lymph node biopsy is not well documented. This study attempts to identify risk factors. METHODS: A prospectively maintained database was queried to identify patients with a regional recurrence of breast cancer after a first operation for invasive unilateral breast cancer. Patients with regional recurrence were compared with those alive and disease free at 5 years. RESULTS: Twenty-one of 1,060 patients (2%) experienced a regional recurrence. Most patients (95%) underwent sentinel lymph node biopsy as their axillary staging. Those with regional recurrences had larger tumors (P < .001), higher stage disease (P < .001), more estrogen receptor- and triple-negative breast cancers (P < .001), and more positive lymph nodes (P = .007). Mastectomy (P = .001) and receipt of neoadjuvant and/or chemotherapy (P < .001) were more common among those with regional recurrences. CONCLUSIONS: Regional recurrence of breast cancer occurs infrequently. Risk factors include high-risk cancers, higher stage at presentation, nodal involvement, and need for therapies reflecting higher risk biology. PMID- 26601647 TI - Surgical resident involvement differentially affects patient outcomes in laparoscopic and open colectomy for malignancy. AB - BACKGROUND: We evaluated effect of resident involvement on outcomes after laparoscopic and open colon resection for malignancy. METHODS: Patients undergoing colectomy were queried using the American College of Surgeons' National Surgical Quality Improvement Program. "Attending alone" and "Resident" cohorts were compared with primary end point of overall morbidity. RESULTS: Of 37,330 patients, residents were involved in 26,190 (70.2%) cases. Attending alone patients were older with higher vascular, cardiac, and pulmonary comorbidity. Univariate analysis demonstrated increased operative time (181.0 +/- 98.4 vs 138.7 +/- 77.0, P < .001), reoperation (5.7% vs 5.2%, P = .041), and readmission rates (11.9% vs 9.6%, P = .037) with resident involvement. Serious (16.0% vs 13.9%, P < .001), minor (17.5% vs 14.1%, P < .001), and overall morbidity (26.4% vs 22.5%, P < .001) were higher with resident participation. Mortality (2.0% vs 2.8%, P < .001) and failure to rescue (.8% vs 1.2%, P < .029) were lower with resident involvement. Resident involvement showed independent association with overall morbidity in both laparoscopic (odds ratio, 1.2; 95% confidence interval, 1.13 to 1.38, P < .001) and open cases (odds ratio 1.3, 95% confidence interval, 1.18 to 1.35, P < .001). CONCLUSIONS: Resident participation in colectomy for malignancy is associated with lower mortality at the expense of higher overall morbidity. PMID- 26601648 TI - Tissue inhibitor of metalloproteinase-2 inhibits burn-induced derangements and hyperpermeability in microvascular endothelial cells. AB - BACKGROUND: Burns induce microvascular hyperpermeability. We hypothesize that this occurs partly through an imbalance between matrix metalloproteinases (MMPs) and endogenous MMP inhibitors such as tissue inhibitors of metalloproteinases (TIMPs), and that such derangements can be attenuated with the use of TIMP-2. METHOD: Rats underwent either sham or burn: serum and tissue were collected. Western blot was used to examine MMP-9 and TIMP-2 levels and MMP activity was assayed from lung tissue. Rat lung microvascular endothelial cells were used to assess monolayer permeability and evaluate the adherens junction proteins beta catenin, vascular endothelial cadherin and filamentous actin after exposure to burn serum +/- TIMP-2. RESULTS: Lung tissue from burn animals showed increased MMP activity, decreased levels of TIMP-2, and no difference in levels of active MMP-9 in burn vs control groups. Burn serum increased monolayer permeability, damaged adherens junction proteins, and incited actin stress fiber formation; TIMP-2 attenuated these derangements. CONCLUSIONS: Burns may lower TIMP-2 levels and increase MMP activity and that TIMP-2 application in vitro may attenuate burn induced hyperpermeability and decreases damage to endothelial structural proteins. These links warrant further investigation. PMID- 26601649 TI - The nature, patterns, clinical outcomes, and financial impact of intraoperative adverse events in emergency surgery. AB - BACKGROUND: Little is known about intraoperative adverse events (iAEs) in emergency surgery (ES). We sought to describe iAEs in ES and to investigate their clinical and financial impact. METHODS: The 2007 to 2012 administrative and American College of Surgeons-National Surgical Quality Improvement Program databases at our tertiary academic center were: (1) linked, (2) queried for all ES procedures, and then (3) screened for iAEs using the ICD-9-CM-based Patient Safety Indicator "accidental puncture/laceration". Flagged cases were systematically reviewed to: (1) confirm or exclude the occurrence of iAEs (defined as inadvertent injuries during the operation) and (2) extract additional variables such as procedure type, approach, complexity (measured by relative value units), need for adhesiolysis, and extent of repair. Univariate and multivariate analyses were performed to assess the independent impact of iAEs on 30-day morbidity, mortality, and hospital charges. RESULTS: Of a total of 9,288 patients, 1,284 (13.8%) patients underwent ES, of which 23 had iAEs (1.8%); 18 of 23 (78.3%) of the iAEs involved the small bowel or spleen, 10 of 23 (43.5%) required suture repair, and 8 of 23 (34.8%) required tissue or organ resection. Compared with those without iAEs, patients with iAEs were older (median age 62 vs 50; P = .04); their procedures were more complex (total relative value unit 46.7, interquartile range [27.5 to 52.6] vs 14.5 [.5 to 30.2]; P < .001), longer in duration (>3 hours: 52% vs 8%; P < .001), and more often required adhesiolysis (39.1% vs 13.5% P = .001). Patients with iAEs had increased total charges ($31,080 vs $11,330, P < .001), direct charges ($20,030 vs $7,387, P < .001), and indirect charges ($11,460 vs $4,088, P < .001). On multivariable analyses, iAEs were independently associated with increased 30-day morbidity (odds ratio, 3.56 [CI, 1.10 to 11.54]; P = .03) and prolonged postoperative length of stay (LOS; LOS >7 days; odds ratio, 5.60 [1.54 to 20.35]; P = .01]. A trend toward increased mortality did not reach statistical significance. CONCLUSIONS: In ES, iAEs are independently associated with significantly higher postoperative morbidity and prolonged LOS. PMID- 26601650 TI - The effect of multidisciplinary teams for rectal cancer on delivery of care and patient outcome: has the use of multidisciplinary teams for rectal cancer affected the utilization of available resources, proportion of patients meeting the standard of care, and does this translate into changes in patient outcome? AB - BACKGROUND: We hypothesized that mandatory multidisciplinary team (MDT) participation improves process evaluation, outcomes, and technical aspects of surgery for rectal cancer in a stable practice of colorectal surgery. METHODS: A retrospective review of MDT data was conducted of all patients with colorectal cancer since 2010. Demographic, clinical stage, process evaluation, quality of surgery, and outcome data were collected. Total mesorectal excision and MDT required participation started 2013. RESULTS: One hundred thirty patients were included in this study: 47 patients in 2014; 41 patients in 2013; and 42 patients pre-MDT. Improvements were seen in 12 of the 14 preoperative process variables, 6 significantly. Improvement in the completeness of total mesorectal excision (0% to 76%) was significant. Local recurrence occurred in 10% of the pre-MDT group, and follow-up is ongoing in the MDT groups. CONCLUSIONS: MDT participation improves care of patients with rectal cancer. Preoperative clinical staging, multimodality treatment, pathologic staging, and technical aspects of surgery have improved. PMID- 26601652 TI - Profiling of Free Fatty Acids Using Stable Isotope Tagging Uncovers a Role for Saturated Fatty Acids in Neuroexocytosis. AB - The phospholipase-catalyzed release of free fatty acids (FFAs) from phospholipids is implicated in many critical biological processes such as neurotransmission, inflammation, and cancer. However, determining the individual change in FFAs generated during these processes has remained challenging due to the limitations of current methods, and has hampered our understanding of these key mediators. Here, we developed an "iTRAQ"-like method for profiling FFAs by stable isotope tagging (FFAST), based on the differential labeling of the carboxyl group and designed to resolve analytical variance, through a multiplexed assay in cells and subcellular fractions. With nanomolar sensitivity, this method revealed a spectrum of saturated FFAs elicited during stimulation of exocytosis that was identical in neurons and neurosecretory cells. Purified secretory vesicles also generated these FFAs when challenged with cytosol. Our multiplex method will be invaluable to assess the range of FFAs generated in other physiological and pathological settings. PMID- 26601651 TI - A "safe and effective" protocol for management of post-thyroidectomy hypocalcemia. AB - BACKGROUND: This study evaluates the outcomes of a protocol to manage hypocalcemia after thyroidectomy (TTX). METHODS: A review of prospectively collected data was performed in 130 patients who underwent TTX after the introduction of a specific protocol. These patients were compared with a control group of 195 patients who underwent TTX the year prior when routine calcium supplementation was utilized and no specific protocol was used. RESULTS: Of the 120 patients in whom the protocol was followed, 44 (37%) patients were classified as high risk, 15 (13%) intermediate risk, and 61 (51%) low risk. The protocol had a sensitivity of 85% and a negative predictive value of 92% for predicting subsequent hypocalcemia. With the implementation of the protocol, there was significant reduction in temporary hypocalcemia events (P = .008) and intravenous calcium drip (P = .49). Also, calcium supplementation was significantly lower in the protocol group (P <= .001). CONCLUSIONS: This hypocalcemia protocol identifies patients who do not require additional supplementation and additional monitoring. At the same time, it identifies those who will benefit from supplementation after TTX. PMID- 26601653 TI - Scalable Synthesis of Efficient Water Oxidation Catalysts: Insights into the Activity of Flame-Made Manganese Oxide Nanocrystals. AB - Chemical energy storage by water splitting is a promising solution for the utilization of renewable energy in numerous currently impracticable needs, such as transportation and high temperature processing. Here, the synthesis of efficient ultra-fine Mn3O4 water oxidation catalysts with tunable specific surface area is demonstrated by a scalable one-step flame-synthesis process. The water oxidation performance of these flame-made structures is compared with pure Mn2O3 and Mn5O8, obtained by post-calcination of as-prepared Mn3O4 (115 m(2) g( 1)), and commercial iso-structural polymorphs, probing the effect of the manganese oxidation state and synthetic route. The structural properties of the manganese oxide nanoparticles were investigated by XRD, FTIR, high-resolution TEM, and XPS. It is found that these flame-made nanostructures have substantially higher activity, reaching up to 350 % higher surface-specific turnover frequency (0.07 MUmolO2 m(-2) s(-1)) than commercial nanocrystals (0.02 MUmolO2 m(-2) s(-1)), and production of up to 0.33 mmolO2 molMn (-1) s(-1). Electrochemical characterization confirmed the high water oxidation activity of these catalysts with an initial current density of 10 mA cm(-2) achieved with overpotentials between 0.35 and 0.50 V in 1 m NaOH electrolyte. PMID- 26601655 TI - Correction to article New Zealand Emergency Medicine Network: A collaboration for acute care research in New Zealand. PMID- 26601654 TI - Enhanced polarization by the coherent heterophase interface between polar and non polar phases. AB - A piezoelectric composite containing the ferroelectric polar (Bi(Na0.8K0.2)0.5TiO3: f-BNKT) and the non-polar (0.94Bi(Na0.75K0.25)0.5TiO3 0.06BiAlO3: BNKT-BA) phases exhibits synergetic properties which combine the beneficial aspects of each phase, i.e., the high saturated polarization (Ps) of the polar phase and the low coercive field (Ec) of the non-polar phase. To understand the origin of such a fruitful outcome from this type of polar/non polar heterophase structure, comprehensive studies are conducted, including transmission electron microscopy (TEM) and finite element method (FEM) analyses. The TEM results show that the polar/non-polar composite has a core/shell structure in which the polar phase (core) is surrounded by a non-polar phase (shell). In situ electrical biasing TEM experiments visualize that the ferroelectric domains in the polar core are aligned even under an electric field of ~1 kV mm(-1), which is much lower than its intrinsic coercive field (~3 kV mm( 1)). From the FEM analyses, we can find that the enhanced polarization of the polar phase is promoted by an additional internal field at the phase boundary which originates from the preferential polarization of the relaxor-like non-polar phase. From the present study, we conclude that the coherent interface between polar and non-polar phases is a key factor for understanding the enhanced piezoelectric properties of the composite. PMID- 26601656 TI - Potentially Inappropriate Medication and Health Care Outcomes: An Instrumental Variable Approach. AB - OBJECTIVE: To examine the effects of potentially inappropriate medication (PIM) use on health care outcomes in elderly individuals using an instrumental variable (IV) approach. DATA SOURCES/STUDY SETTING: Representative claim data from the universal health insurance program in Taiwan from 2007 to 2010. STUDY DESIGN: We employed a panel study design to examine the relationship between PIM and hospitalization. We applied both the naive generalized estimating equation (GEE) model, which controlled for the observed patient and hospital characteristics, and the two-stage residual inclusion (2SRI) GEE model, which further accounted for the unobserved confounding factors. The PIM prescription rate of the physician most frequently visited by each patient was used as the IV. PRINCIPAL FINDINGS: The naive GEE models indicated that patient PIM use was associated with a higher likelihood of hospitalization (odds ratio [OR], 1.399; 95 percent confidence interval [CI], 1.363-1.435). Using the physician PIM prescribing rate as an IV, we identified a stronger significant association between PIM and hospitalization (OR, 1.990; 95 percent CI, 1.647-2.403). CONCLUSIONS: PIM use is associated with increased hospitalization in elderly individuals. Adjusting for unobserved confounders is needed to obtain unbiased estimates of the relationship between PIM and health care outcomes. PMID- 26601657 TI - Determination of Hemicellulose, Cellulose and Lignin in Moso Bamboo by Near Infrared Spectroscopy. AB - The contents of hemicellulose, cellulose and lignin are important for moso bamboo processing in biomass energy industry. The feasibility of using near infrared (NIR) spectroscopy for rapid determination of hemicellulose, cellulose and lignin was investigated in this study. Initially, the linear relationship between bamboo components and their NIR spectroscopy was established. Subsequently, successive projections algorithm (SPA) was used to detect characteristic wavelengths for establishing the convenient models. For hemicellulose, cellulose and lignin, 22, 22 and 20 characteristic wavelengths were obtained, respectively. Nonlinear determination models were subsequently built by an artificial neural network (ANN) and a least-squares support vector machine (LS-SVM) based on characteristic wavelengths. The LS-SVM models for predicting hemicellulose, cellulose and lignin all obtained excellent results with high determination coefficients of 0.921, 0.909 and 0.892 respectively. These results demonstrated that NIR spectroscopy combined with SPA-LS-SVM is a useful, nondestructive tool for the determinations of hemicellulose, cellulose and lignin in moso bamboo. PMID- 26601658 TI - Multigenerational autosomal dominant inheritance of 5p chromosomal deletions. AB - Deletion of the short arm of chromosome 5 (5p-) is associated with phenotypic features including a cat-like cry in infancy, dysmorphic facial features, microcephaly, and intellectual disability, and when encompassing a minimal critical region, may be defined as Cri-du-Chat syndrome (CdCS). Most 5p deletions are de novo in origin, and familial cases are often associated with translocation and inversion. Herein, we report three multigenerational families carrying 5p terminal deletions of different size transmitted in an autosomal dominant manner causing variable clinical findings. Terminal 5p deletions and the mode of inheritance were clinically characterized and molecularly analyzed by a combination of microarray and fluorescence in situ hybridization analyses. Shared phenotypic features documented in this cohort included neuropsychiatric findings, poor growth, and dysmorphic facial features. This study supports newly recognized effects of aberrant SEMA5A and CTNND2 dosage on severity of autistic and cognitive phenotypes. Comparative analysis of the breakpoints narrows the critical region for the cat-like cry down to an interval less than 1 Mb encompassing a candidate gene ICE1, which regulates small nuclear RNA transcription. This study also indicates that familial terminal 5p deletion is a rare presentation displaying intra- and inter-familial phenotypic variability, the latter of which may be attributed to size and gene content of the deletion. The observed intra-familial phenotypic heterogeneity suggests that additional modifying elements including genetic and environmental factors may have an impact on the clinical manifestations observed in 5p deletion carriers, and in time, further high resolution studies of 5p deletion breakpoints will continue to aid in defining genotype-phenotype correlations. PMID- 26601659 TI - The relationship between living environment, well-being and lifestyle behaviours in young women in Shiraz, Iran. AB - There has been increasing interest in understanding the influence of the living environment on individual and population health. While our understanding of the connection is growing, there has been limited published research focusing on socially and economically transitioning countries such as Iran or specific populations such as young women. This study explores the relationship between the physical and social living environment with well-being outcomes and lifestyle behaviours of young women in Shiraz, Iran, in 2013. Using a cluster convenience sampling technique, 391 young Iranian women with the mean age of 27.3 (SD: 4.8) participated in a cross-sectional survey (response rate 93%). A scale adapted from the British General Household Social Capital scale was used to assess living environment characteristics. The International Health and Behaviour survey, Satisfaction with Life Scale (SwL) and WHO Quality of Life questionnaire (WHOQOL BREF) were used to measure lifestyle behaviours and well-being. The findings showed a moderate level of satisfaction with participants' living environment, with a mean score of 38.5 (SD: 7.7; score range: 11-45). There were correlations between physical and social neighbourhood environment, lifestyle behaviours and well-being outcomes (P < 0.05). Multiple regression analysis showed that the characteristics of living environments were determinants of quality of life (QoL), including physical, psychological, social and environmental QoL, as well as SwL (P < 0.05). Perceptions of individuals about their living environment issues were associated with demographic variables including ethnicity, income, level of education and occupation status. The current study shows how characteristics of the physical and social living environments play a significant role in shaping well-being and lifestyle behaviours among young Iranian women. Hence, there is a need for more focused attention to the meaning, measurement and building of neighbourhood livability, including both physical and social aspects of neighbourhood, in order to support QoL and SwL among young Iranian women, and enhance their healthy lifestyle behaviours. PMID- 26601660 TI - Maquet and TTA technique combination for the treatment of cranial cruciate ligament rupture in dog. PMID- 26601662 TI - The skin and its blossoms--fertile soil for clinical science. PMID- 26601661 TI - Antifungal activity and mode of action of thymol and its synergism with nystatin against Candida species involved with infections in the oral cavity: an in vitro study. AB - BACKGROUND: Limitations of antifungal agents used in the treatment of oral candidiasis, as the development of resistant strains, are known by the scientific community. In this context, the aim of this study was to evaluate the antifungal activity of thymol against Candida albicans, Candida tropicalis and Candida krusei strains and to determine its mode of action and synergistic effect when combined with the synthetic antifungal nystatin. METHODS: The minimum inhibitory concentration (MIC) was determined using a microdilution technique, and the minimum fungicidal concentration (MFC) was determined via subculture sowing. The mode of action of thymol was established by verifying fungal growth in the presence of sorbitol or ergosterol. The fractional inhibitory concentration index (FIC) was determined using the checkerboard method. RESULTS: Thymol presented an antifungal effect, with MICs of 39 MUg/mL for C. albicans and C. krusei and 78 MUg/mL for C. tropicalis. The results of the antifungal test remained unchanged in the presence of sorbitol; however, the MIC value of thymol against C. albicans increased eight times (from 39.0 to 312.5 MUg/mL) in presence of exogenous ergosterol. The combination of thymol and nystatin reduced the MIC values of both products by 87.4%, generating an FIC index of 0.25. CONCLUSIONS: Thymol was found to have a fungicidal effect on Candida species and a synergistic effect when combined with nystatin. PMID- 26601663 TI - Anesthesia Issues in Central Nervous System Disorders. AB - Every year, millions of people affected by disorders of the central nervous system (CNS) undergo various diagnostic, therapeutic and surgical procedures requiring administration of anesthetic agents. Anesthetics exert their anesthetic, amnesic and analgesic effects by acting on multiple neuronal membrane proteins in the CNS. While some of the causal anesthetic targets have been identified, a large number of anesthetic targets remain unknown. The consequent longterm effect of anesthetic agents on expression of these various molecular targets has been implicated in mediating potentially long-lasting adverse effects. Recent work suggested that the effects of general anesthetics may not be entirely reversible, with animal studies demonstrating persistent changes in CNS protein expression post recovery from anesthesia. Age-associated or disease induced alterations in the CNS can profoundly alter multiple aspects of brain structure, biochemistry, and function. Such maladaptive changes in the brain can render it increasingly vulnerable to the effects of various anesthetics. The selection of appropriate anesthesia drugs and protocol is mandatory, especially in individuals with pre-existing CNS disorders, so as to maximize anesthesia efficiency, avoid occurrence of adverse events, and ensure patient safety. This review aims to summarize and consider the effects and potential risks of commonly used anesthetic agents in patients with compromised CNS function. We provide a comprehensive review of the established as well as the implicated effects of anesthetic agents on the elderly as well as on the pathology and progression of common neurological conditions. PMID- 26601665 TI - Erratum to: Unraveling the mechanisms of synapse formation and axon regeneration: the awesome power of C. elegans genetics. PMID- 26601664 TI - Inhibition of Early Biochemical Defects in Prodromal Huntington's Disease by Simultaneous Activation of Nrf2 and Elevation of Multiple Micronutrients. AB - Huntington's disease (HD) is a progressive fatal dominant hereditary neurodegenerative disease of the brain, which primarily affects the cortex and the striatum. The disorder is typified by an expansion of more than 35 repeats of the nucleotide triplet cytosine- adenine-guanosine (CAG) which codes for the amino acid glutamine in the huntingtin gene. Despite studies of several decades, there are no effective means to block or postpone the appearance of symptoms of HD. Analysis of these studies led us to propose that increased oxidative stress and chronic inflammation are earliest events in the pathogenesis of HD, and together with excessive glutamate release, participate in the progression of the disease. This review briefly describes evidence for the involvement of oxidative stress, chronic inflammation and glutamate in the pathogenesis of HD. It is proposed that attenuation of these biochemical abnormalities together, may delay the appearance of symptoms of HD. In order to achieve this goal, the simultaneous activation of the nuclear transcriptional factor-2/antioxidant response elements (Nrf2/ARE) pathway that would enhance the transcription of target genes coding for antioxidant enzymes and phase-2-detoxifying enzymes, and an elevation of the levels of antioxidant compounds by supplementation may be needed. Normal mechanisms of activation of Nrf2 requiring reactive oxygen species (ROS) may be impaired in HD, but certain antioxidant compounds can activate Nrf2 without ROS. Use of a combination of micronutrients that can activate the Nrf2/ARE pathway and enhance the levels of antioxidant compounds is suggested. PMID- 26601666 TI - A Sensitive and Selective Fluorescent Coumarin-Based Probe for Detection of Hypochlorite ion and its Application to Cellular Imaging. AB - Selective, sensitive fluorescent probes for ClO(-) are desirable due to the importance of ClO(-) in biological processes. Herein, a readily available turn off fluorescent probe for ClO(-) is reported, which displays highly selectivity and sensitivity over other common anions and reactive oxygen/nitrogen. Moreover, it is able to detect ClO(-) in Ramos cells via cellular imaging. PMID- 26601667 TI - The intrahepatic expression levels of bile acid transporters are inversely correlated with the histological progression of nonalcoholic fatty liver disease. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) presents as a spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). The latter is progressive, and its pathogenesis remains poorly understood. Recently, bile acid (BA) metabolism has become a therapeutic focus in NASH patients. The aim of the present study was to explore changes in bile acid metabolism in NAFLD patients in the context of disease progression. METHODS: We prospectively enrolled patients with clinically suspected NAFLD. Patients taking ursodeoxycholic acid were excluded. The intrahepatic expression levels of genes associated with BA metabolism were determined by quantitative PCR and immunohistochemistry. RESULTS: Seventy-eight patients (male:female = 49:29) histologically diagnosed with NAFLD were analyzed. The expression levels of farnesoid X receptor, liver receptor homolog 1, and small heterodimer partner, key proteins in BA synthesis, significantly decreased as the NAFLD activity score (NAS) increased in either males or females. The levels of cholesterol 7 alpha hydroxylase, the rate-limiting enzyme of BA synthesis, were not changed. Notably, the expression levels of a main export transporter, bile salt export pump (BSEP), significantly decreased as the NAS and the each NAS component increased in both genders. The decreases of BSEP levels were also observed by immunohistochemistry, particularly in areas with pronounced fatty changes in cases with high NAS. CONCLUSIONS: The expression levels of the BA export transporter BSEP were inversely correlated with NAS in NAFLD patients. Such down-regulation may cause excessive BA levels in hepatocytes, leading to cell injury. Our findings may afford new insights into the pathogenesis of NASH. PMID- 26601668 TI - [Device-based treatment of mixed hearing loss: An audiological comparison of current hearing systems]. AB - BACKGROUND: Various different hearing systems are available for device-supported hearing rehabilitation of patients with mixed hearing loss. Using the recently introduced objective comparison criterion "maximum output" (i.e., the maximum output level of a hearing device), the indications for different hearing devices can be compared. OBJECTIVE: This article reviews important terms such as gain, dynamic range, and maximum output level-all of which are relevant for the selection of a hearing device. The experimental part of this study compares all currently available hearing devices and determines the range of their indication with respect to the maximum bone-conduction hearing threshold. MATERIALS AND METHODS: The maximum frequency-specific output levels reported in the literature for the Baha Cordelle 2, the Sophono Alpha 2, and the Bonebridge (measured at the skull simulator), as well as those of the Codacs and the Soundbridge (in-vivo measurements) are compared to the maximum output levels given in the datasheets of the BP110 Power, the Baha Cordelle 2, the Bonebridge, the Codacs, the Ponto Pro Power, and the Sophono Alpha 2. Using appropriate correction factors, the maximum dynamic range and thus the maximum indication based on the bone conduction threshold was determined. RESULTS: In patients with mild sensorineural hearing loss, passive transcutaneous hearing or Bonebridge implants can achieve good audiological results. In the transition region to moderate hearing loss, percutaneous devices are applicable. Combined hearing loss with more pronounced sensorineural hearing loss is best treated with a Soundbridge or Codacs implant. In the latter case, the cochlear potential for speech recognition has to be explored and, where appropriate, cochlear implants considered as an alternative. PMID- 26601669 TI - Reversible myocardial perfusion abnormalities in nonischemic dilated cardiomyopathy. PMID- 26601671 TI - The central role of the Journal reaffirmed. PMID- 26601670 TI - Assessment of late anthracycline-induced cardiotoxicity by 123I-mIBG cardiac scintigraphy in patients treated during childhood and adolescence. AB - PURPOSE: The goal of this study was to evaluate late cardiotoxic effects of anthracyclines (ATC) by evaluating cardiac sympathetic activity in a cohort of asymptomatic patients previously treated with ATC for childhood cancers. METHODS: We studied 89 asymptomatic patients previously treated with ATC with a normal echocardiogram (49 men and 40 women) and a control group of 40 healthy individuals (26 men and 14 women). Both groups underwent planar myocardial 123I meta-iodobenzylguanidine scintigraphy (123I-mIBG). From these images, the early and late heart-to-mediastinum (H/M) ratio and washout rate (WR) were assessed. RESULTS: The mean survival at the time of the 123I-mIBG scintigraphy was 5.3 +/- 3.4 years. Patients treated with ATC had a lower but clinical normal left ventricular ejection fraction (LVEF) compared to controls (60.44 +/- 6.5 vs 64.1 +/- 6.0%, P < 0.01). Both the late H/M ratio and WR were not able to discriminate ATC treated patients from controls. The cumulative ATC dose was the only independent predictor of the LVEF, explaining approximately 12% of the variation in LVEF (P = 0.01). CONCLUSIONS: Although the pathophysiology behind ATC cardiotoxicity is most likely multifactorial, myocardial sympathetic activity is not associated with a reduction in LVEF 5-years after completion of chemotherapy. PMID- 26601672 TI - Predicting cardiac events using ventricular dyssynchrony in patients who received implantable cardioverter defibrillators: Are more treatment options required? PMID- 26601673 TI - How to gather information from talkative patients in a respectful and efficient manner: a qualitative study of GPs' communication strategies. AB - BACKGROUND: Gathering information from talkative patients presents a challenge to clinicians. Empirical evidence on how to effectively deal with this challenge is scant. OBJECTIVE: This study explores communication strategies and their underlying mechanisms that GPs consider effective when gathering information from talkative patients in order to inform the development of best practices. METHODS: We conducted a qualitative study with experienced GPs. We held individual stimulated-recall interviews (SRIs) with six GPs using their videotaped consultations as a stimulus. The transcripts that ensued were triangulated with data from three focus-group discussions (FGs). We performed a thematic network analysis during an iterative process of data collection and analysis. RESULTS: To deal with talkative patients during consultations, GPs first try to pinpoint the cause of patients' talkativeness before deciding on the approach to take. Moreover, they resort to the familiar communication strategies, however, in doing so adopt take a more directive attitude. To prevent such attitude from damaging the relationship, GPs take a stepped approach in which they try not to be overly directive, make the patient co-responsible for efficient time management and make use of empathic interrupting. CONCLUSIONS: In the absence of evidence, this description of GPs' communication strategies can guide clinicians, residents and students in gathering information from talkative patients in an efficient, yet empathic and respectful manner. When developing best practices, heed should be paid to the causes of patients' talkativeness and the tension between taking a directive approach and building a doctor-patient relationship. PMID- 26601674 TI - Tracheobronchial foreign bodies in cats: a retrospective study of 12 cases. AB - Objectives The aim of the study was to evaluate age, sex, breed, clinical signs, time between onset of signs and presentation, diagnostic procedures, method of extraction, location and nature of foreign bodies (FBs) in confirmed cases of tracheobronchial FBs in cats. We hypothesised that bronchoscopy was effective in extracting tracheobronchial FBs in cats. Methods A retrospective study was performed using clinical reports from three private practices in France between May 2009 and November 2014. Cats were included if an intraluminal tracheobronchial FB had been identified and extracted (either by bronchoscopy or surgery). Results Twelve cats (six male, six female) were included. Mean age was 3.75 +/- 2.5 years. Coughing was the main complaint and was present in 9/12 (75%) of the cats. Thoracic radiographs were obtained in 12/12 cats (100%) and a FB was suspected in 11/12 (92%). Bronchoscopy was performed in all of the cats and enabled FB extraction in 10/12 (83%) of them. In 2/12 cats (17%), an additional surgical approach was required. In 6/12 (50%) cats, FBs were located in the trachea, while in 6/12 (50%) cats FBs were in the bronchial tree, particularly in the right caudal bronchus (4/6; 66%). Seven of 12 (58%) FBs were vegetal in nature, 3/12 (25%) were mineral and 2/12 (17%) were undetermined. All the mineral FBs were extracted from the trachea, while the majority of the vegetal ones (5/7; 71%) were found in the bronchi. Conclusions and relevance Feline respiratory FBs can be found in the trachea and in the bronchial tree, particularly in the right caudal bronchus. Vegetal FBs tend to migrate through the bronchial tree, whereas mineral ones tend to lodge in the trachea. Bronchoscopy seems to be a highly effective procedure for the extraction of tracheobronchial FBs in cats. PMID- 26601675 TI - Pfizer and Allergan agree $160bn merger deal. PMID- 26601676 TI - Women's Endorsement of Models of Sexual Response: Correlates and Predictors. AB - Few studies have investigated endorsement of female sexual response models, and no single model has been accepted as a normative description of women's sexual response. The aim of the study was to establish how women from a population-based sample endorse current theoretical models of the female sexual response--the linear models and circular model (partial and composite Basson models)--as well as predictors of endorsement. Accordingly, 174 heterosexual women aged 18-55 years were included in a cross-sectional study: 74 women diagnosed with female sexual dysfunction (FSD) based on DSM-5 criteria and 100 non-dysfunctional women. The description of sexual response models was used to divide subjects into four subgroups: linear (Masters-Johnson and Kaplan models), circular (partial Basson model), mixed (linear and circular models in similar proportions, reflective of the composite Basson model), and a different model. Women were asked to choose which of the models best described their pattern of sexual response and how frequently they engaged in each model. Results showed that 28.7% of women endorsed the linear models, 19.5% the partial Basson model, 40.8% the composite Basson model, and 10.9% a different model. Women with FSD endorsed the partial Basson model and a different model more frequently than did non-dysfunctional controls. Individuals who were dissatisfied with a partner as a lover were more likely to endorse a different model. Based on the results, we concluded that the majority of women endorsed a mixed model combining the circular response with the possibility of an innate desire triggering a linear response. Further, relationship difficulties, not FSD, predicted model endorsement. PMID- 26601677 TI - CAN THE COURTS FORCE THE DOCTOR'S HAND? ST GEORGE'S HEALTHCARE NHS TRUST V P [2015] EWCOP 42. PMID- 26601678 TI - The Impact of an eHealth Portal on Health Care Professionals' Interaction with Patients: Qualitative Study. AB - BACKGROUND: People who undergo weight loss surgery require a comprehensive treatment program to achieve successful outcomes. eHealth solutions, such as secure online portals, create new opportunities for improved health care delivery and care, but depend on the organizational delivery systems and on the health care professionals providing it. So far, these have received limited attention and the overall adoption of eHealth solutions remains low. In this study, a secure eHealth portal was implemented in a bariatric surgery clinic and offered to their patients. During the study period of 6 months, 60 patients and 5 health care professionals had access. The portal included patient information, self management tools, and communication features for online dialog with peers and health care providers at the bariatric surgery clinic. OBJECTIVE: The aim of this study was to characterize and assess the impact of an eHealth portal on health care professionals' interaction with patients in bariatric surgery. METHODS: This qualitative case study involved a field study consisting of contextual interviews at the clinic involving observing and speaking with personnel in their actual work environment. Semi-structured in-depth interviews were conducted with health care professionals who interacted with patients through the portal. Analysis of the collected material was done inductively using thematic analysis. RESULTS: The analysis revealed two main dimensions of using an eHealth portal in bariatric surgery: the transparency it represents and the responsibility that follows by providing it. The professionals reported the eHealth portal as (1) a source of information, (2) a gateway to approach and facilitate the patients, (3) a medium for irrevocable postings, (4) a channel that exposes responsibility and competence, and (5) a tool in the clinic. CONCLUSIONS: By providing an eHealth portal to patients in a bariatric surgery program, health care professionals can observe patients' writings and revelations thereby capturing patient challenges and acting and implementing measures. Interacting with patients through the portal can prevent dropouts and deterioration of patients' health. However, professionals report on organizational challenges and personal constraints related to communicating with patients in writing online. Further development of guidelines and education of health care professionals about how to handle, prioritize, communicate, and facilitate patients online is required in addition to increased attention to the organizational infrastructures and incentives for enabling such solutions in health care. PMID- 26601679 TI - A horse's eye view: size and shape discrimination compared with other mammals. AB - Mammals have adapted to a variety of natural environments from underwater to aerial and these different adaptations have affected their specific perceptive and cognitive abilities. This study used a computer-controlled touchscreen system to examine the visual discrimination abilities of horses, particularly regarding size and shape, and compared the results with those from chimpanzee, human and dolphin studies. Horses were able to discriminate a difference of 14% in circle size but showed worse discrimination thresholds than chimpanzees and humans; these differences cannot be explained by visual acuity. Furthermore, the present findings indicate that all species use length cues rather than area cues to discriminate size. In terms of shape discrimination, horses exhibited perceptual similarities among shapes with curvatures, vertical/horizontal lines and diagonal lines, and the relative contributions of each feature to perceptual similarity in horses differed from those for chimpanzees, humans and dolphins. Horses pay more attention to local components than to global shapes. PMID- 26601680 TI - Refugia and the evolutionary epidemiology of drug resistance. AB - Drug resistance is a long-standing economic, veterinary and human health concern in human and animal populations. Efficacy of prophylactic drug treatments targeting a particular pathogen is often short-lived, as drug-resistant pathogens evolve and reach high frequency in a treated population. Methods to combat drug resistance are usually costly, including use of multiple drugs that are applied jointly or sequentially, or development of novel classes of drugs. Alternatively, there is growing interest in exploiting untreated host populations, refugia, for the management of drug resistance. Refugia do not experience selection for resistance, and serve as a reservoir for native, drug-susceptible pathogens. The force of infection from refugia may dilute the frequency of resistant pathogens in the treated population, potentially at an acceptable cost in terms of overall disease burden. We examine this concept using a simple mathematical model that captures the core mechanisms of transmission and selection common to many host pathogen systems. We identify the roles of selection and gene flow in determining the utility of refugia. PMID- 26601681 TI - Faces and fitness: attractive evolutionary relationship or ugly hypothesis? AB - In recent years, various studies have attempted to understand human evolution by examining relationships between athletic performance or physical fitness and facial attractiveness. Over a wide range of five homogeneous groups (n = 327), there is an approximate 3% shared variance between facial attractiveness and athletic performance or physical fitness (95% CI = 0.5-8%, p = 0.002). Further, studies relating human performance and attractiveness often have major methodological limitations that limit their generalizability. Thus, despite statistical significance, the association between facial attractiveness and human performance has questionable biological importance. Here, we present a critique of these studies and provide recommendations to improve the quality of future research in this realm. PMID- 26601682 TI - Kinematic diversity suggests expanded roles for fly halteres. AB - The halteres of flies are mechanosensory organs that provide information about body rotations during flight. We measured haltere movements in a range of fly taxa during free walking and tethered flight. We find a diversity of wing-haltere phase relationships in flight, with higher variability in more ancient families and less in more derived families. Diverse haltere movements were observed during free walking and were correlated with phylogeny. We predicted that haltere removal might decrease behavioural performance in those flies that move them during walking and provide evidence that this is the case. Our comparative approach reveals previously unknown diversity in haltere movements and opens the possibility of multiple functional roles for halteres in different fly behaviours. PMID- 26601683 TI - Ultrastructure of the Salivary Glands of the Stink Bug Predator Podisus distinctus. AB - Podisus distinctus (Hemiptera: Pentatomidae) is a zoophytophagous insect with significant potential for use as a biological control agent in agriculture and forestry because their nymphs and adults actively prey on diverse insect species. The saliva of this insect possesses active substances that cause paralysis and death of the prey. As the first step in identifying compounds of P. distinctus saliva, this study describes the ultrastructure of the salivary glands of this predator. The salivary system of P. distinctus possesses a pair of main salivary glands with a short anterior lobe, a long posterior lobe, and a pair of tubular accessory glands. The main salivary gland of P. distinctus has no associated muscles, suggesting that the saliva-release mechanism occurs with the help of certain thorax muscles. The main salivary gland epithelium has a single layer of cells (varying from cubical to columnar) with cytoplasm rich in rough endoplasmic reticulum, spherical granules of different sizes, a nucleus with a predominance of decondensed chromatin, and nucleolus. The apical cell region has a few short microvilli and the basal region has plasma membrane infoldings. The epithelium of the accessory salivary glands possesses a single-layered epithelium of cubic cells delimiting a narrow lumen. The apical cell region has a high density of microvilli and pleomorphic mitochondria, whereas the central cell region is rich in rough endoplasmic reticulum with a well-developed nucleus and decondensed chromatin. The basal cell region is characterized by the presence of several basal plasma membrane infoldings associated with mitochondria and numerous openings to the hemocoel forming large channels. The ultrastructural characteristics suggest that the main salivary glands and accessory salivary glands play a vital role in protein synthesis for saliva production and that the accessory glands are involved in transport of materials of the hemolymph. PMID- 26601684 TI - New p-terphenyls from the fruiting bodies of Pseudomerulius curtisii and their antioxidant activity. PMID- 26601685 TI - Curromycin A as a GRP78 downregulator and a new cyclic dipeptide from Streptomyces sp. PMID- 26601687 TI - Onshore industrial wind turbine locations for the United States up to March 2014. AB - Wind energy is a rapidly growing form of renewable energy in the United States. While summary information on the total amounts of installed capacity are available by state, a free, centralized, national, turbine-level, geospatial dataset useful for scientific research, land and resource management, and other uses did not exist. Available in multiple formats and in a web application, these public domain data provide industrial-scale onshore wind turbine locations in the United States up to March 2014, corresponding facility information, and turbine technical specifications. Wind turbine records have been collected and compiled from various public sources, digitized or position verified from aerial imagery, and quality assured and quality controlled. Technical specifications for turbines were assigned based on the wind turbine make and model as described in public literature. In some cases, turbines were not seen in imagery or turbine information did not exist or was difficult to obtain. Uncertainty associated with these is recorded in a confidence rating. PMID- 26601686 TI - Compatibility between mitochondrial and nuclear genomes correlates with the quantitative trait of lifespan in Caenorhabditis elegans. AB - Mutations in mitochondrial genome have epistatic effects on organisms depending on the nuclear background, but a role for the compatibility of mitochondrial nuclear genomes (mit-n) in the quantitative nature of a complex trait remains unexplored. We studied a panel of recombinant inbred advanced intercrossed lines (RIAILs) of C. elegans that were established from a cross between the N2 and HW strains. We determined the HW nuclear genome content and the mitochondrial type (HW or N2) of each RIAIL strain. We found that the degree of mit-n compatibility was correlated with the lifespans but not the foraging behaviors of RIAILs. Several known aging-associated QTLs individually showed no relationship with mitotypes but collectively a weak trend consistent with a role in mit-n compatibility. By association mapping, we identified 293 SNPs that showed linkage with lifespan and a relationship with mitotypes consistent with a role in mit-n compatibility. We further found an association between mit-n compatibility and several functional characteristics of mitochondria as well as the expressions of genes involved in the respiratory oxidation pathway. The results provide the first evidence implicating mit-n compatibility in the quantitative nature of a complex trait, and may be informative to certain evolutionary puzzles on hybrids. PMID- 26601688 TI - Identification of Synergistic, Clinically Achievable, Combination Therapies for Osteosarcoma. AB - Systemic therapy has improved osteosarcoma event-free and overall survival, but 30-50% of patients originally diagnosed will have progressive or recurrent disease, which is difficult to cure. Osteosarcoma has a complex karyotype, with loss of p53 in the vast majority of cases and an absence of recurrent, targetable pathways. In this study, we explored 54 agents that are clinically approved for other oncologic indications, agents in active clinical development, and others with promising preclinical data in osteosarcoma at clinically achievable concentrations in 5 osteosarcoma cell lines. We found significant single-agent activity of multiple agents and tested 10 drugs in all permutations of two-drug combinations to define synergistic combinations by Chou and Talalay analysis. We then evaluated order of addition to choose the combinations that may be best to translate to the clinic. We conclude that the repurposing of chemotherapeutics in osteosarcoma by using an in vitro system may define novel drug combinations with significant in vivo activity. In particular, combinations of proteasome inhibitors with histone deacetylase inhibitors and ixabepilone and MK1775 demonstrated excellent activity in our assays. PMID- 26601689 TI - Impact of Anemia and Dual Antiplatelet Therapy on Mortality in Patients Undergoing Percutaneous Coronary Intervention with Drug-Eluting Stents. AB - The objective was to assess the impact of baseline anemia on all-cause mortality and whether 12-month dual antiplatelet therapy (DAPT) affects 1-year mortality linked to anemia in patients after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). 4109 enrolled patients divided into three groups based on their pre-procedural hemoglobin (Hb) level: Hb < 100 mg/L represented moderate severe anemia; 100 mg/L <= Hb < 120 mg/L for women and 100 mg/L <= Hb < 130 mg/L for men represented mild anemia; Hb >= 20 mg/L for women and Hb >= 130 mg/L for men represented no anemia. DAPT medications were prescribed when patients were discharged. There were significant differences in 30-day and 1-year mortality between moderate-severe anemia and no anemia patients (HR 8.05, 95% CI 1.46 to 44.33, P = 0.017; HR 3.93, 95% CI 1.11 to 13.98, P = 0.034), and in long-term mortality between anemia and no anemia groups (HR 1.82, 95% CI 1.17 to 2.83, P = 0.008 for mild anemia; HR 3.19,95% CI 1.29 to 7.86, P = 0.012 for moderate-severe anemia). There was not significant interaction between 12-month DAPT and anemia on mortality in anemic patients (P for interaction > 0.05). Anemia shows association with increased all-cause mortality in patients undergoing PCI. Twelve month DAPT does not show synergy with anemia to increase the risk of all-cause 1 year mortality in anemic patients after PCI. PMID- 26601690 TI - Elucidating the Mechanism of Weissella-dependent Lifespan Extension in Caenorhabditis elegans. AB - The mechanism whereby lactic acid bacteria extend the lifespan of Caenorhabditis elegans has previously been elucidated. However, the role of Weissella species has yet not been studied. We show that Weissella koreensis and Weissella cibaria significantly (p < 0.05) extend the lifespan of C. elegans compared with Escherichia coli OP50 and induce the expression of several genes related to lifespan extension (daf-16, aak-2, jnk-1, sod-3 and hif-1). Oral administration of Weissella altered reactive oxygen species (ROS) production and lowered the accumulation of lipofuscin and increased locomotor activity (which translates to a delay in ageing). Moreover, Weissella-fed C. elegans had decreased body sizes, brood sizes, ATP levels and pharyngeal pumping rates compared with E. coli OP50 fed worms. Furthermore, mutations in sod-3, hif-1 or skn-1 did not alter lifespan extension compared with wild-type C. elegans. However, C. elegans failed to display lifespan extension in loss-of-function mutants of daf-16, aak-2 and jnk 1, which highlights the potential role of these genes in Weissella-induced longevity in C. elegans. Weissella species extend C. elegans lifespan by activating DAF-16 via the c-Jun N-terminal kinase (JNK) pathway, which is related to stress response, and the AMP-activated protein kinase (AMPK)-pathway that is activated by dietary restriction. PMID- 26601691 TI - Increasing maternal body mass index during pregnancy increases neonatal intensive care unit admission in near and full-term infants. AB - BACKGROUND: Obesity is becoming an increasingly commonplace health problem. Obesity during pregnancy is important because the condition adversely affects not only the mother, but also the developing fetus and the newborn. OBJECTIVE: The primary objective of this study was to evaluate the association between maternal body mass index (mBMI) at the time of delivery and neonatal intensive care unit (NICU) admission of offspring and to analyze the role of possible confounding variables that are often associated with obesity. Comorbidities, such as gestational diabetes mellitus (DM), hypertension (HT) and/or pre-eclampsia (PEC), are more common in more obese mothers, as is a higher association of obesity among non-Caucasian patients. METHODS: Using a retrospective cohort design, 1736 mothers and their singleton live-born at >=35 weeks' gestation were analyzed for mBMI, maternal conditions of DM, HT and/or PEC, and whether NICU care was required and the reason for NICU admission. RESULTS: NICU admission rate was significantly associated with maternal obesity. In comparing women with mBMI < 30 versus mBMI >= 30, OR was 1.39 (p = 0.045); OR increased to 1.76 (p = 0.006) in comparing patients with mBMI >= 35. mBMI was significantly associated with an increased rate of maternal DM, HT and PEC (p < 0.05 each); however, NICU admission rate was not correlated with DM, HT or PEC. The relationship between NICU admission and mBMI was significant in Caucasian mothers versus a borderline significance in African-American mothers (p = 0.035 versus p = 0.05). After controlling for neonatal hypoglycemia (NH) as the reason for admission to the NICU, no mBMI-NICU association persisted. The rate of infants with NH increased in higher mBMI groups, independent of maternal DM diagnosis. CONCLUSION: This study demonstrated a significant association between higher mBMI groups and NICU admissions independent of diagnosis of maternal comorbidities. However, accounting for NH eliminating this association suggests a pre-clinical diabetic pathology in obese women that affects newborn outcome. Despite increased percentage of nonwhite mothers in higher mBMI groups, African-American race does not seem to be a significant contributing factor in the increased rate of NICU admission in our population. PMID- 26601692 TI - The specificity of anti-carbamylated protein antibodies for rheumatoid arthritis in a setting of early arthritis. AB - INTRODUCTION: Anti-carbamylated protein (anti-CarP) antibodies have been described in rheumatoid arthritis (RA) and arthralgia patients at risk of developing RA. To what extent these autoantibodies are specific for RA is unknown. Therefore, we investigated the diagnostic performance of the presence of anti-CarP antibodies for RA in a setting of early arthritis. METHODS: Anti-CarP antibodies were detected using carbamylated fetal calf serum as substrate. Anti CCP2 antibodies were measured using enzyme-linked immunosorbent assay and immunoglobulin M (IgM) rheumatoid factor (RF) as part of routine care. Sera were derived from patients in the Leiden Early Arthritis Clinic cohort obtained at inclusion. Test characteristics were determined using the fulfillment of the 2010 RA criteria after 1 year as outcome. RESULTS: In total 2086 early arthritis patients were studied regarding the presence of anti-CarP antibodies. We observed that the sensitivity and specificity of the presence of anti-CarP antibodies for RA were 44 % and 89 %, respectively. As a reference, sensitivity and specificity of the presence of anti-CCP2 antibodies were 54 % and 96 %, respectively, and of IgM-RF 59 % and 91 %. Patients harboring anti-CarP antibodies not classified as RA were mainly diagnosed with undifferentiated arthritis and less frequently reactive arthritis and psoriatic arthritis. CONCLUSION: Anti-CarP antibodies are predominantly present in RA but can also be detected in other forms of arthritis. PMID- 26601693 TI - Identifying the competencies of doctors in China. AB - BACKGROUND: China adopted a Flexnerian model as its medical institutions developed over the recent past but the political, social, and economic environment has changed significantly since then. This has generated the need for educational reform, which in other countries, has largely been driven by competencies-oriented models such as those developed in Canada, and the United States. Our study sought to establish the competencies model, relevant to China, which will support educational reform efforts. METHODS: Data was collected using a cross-sectional survey of 1776 doctors from seven provinces in China. The surveys were translated and adapted from the Occupational Information Network General Work Activity questionnaire (O*NET-GWA) and Work Style questionnaire (O*NET-WS) developed under the auspices of the US Department of Labor. Exploratory factor analysis and confirmatory factor analysis ascertained the latent dimensions of the questionnaires, as well as the factor structures of the competencies model for the Chinese doctors. RESULTS: In exploratory factor analysis, the questionnaires were able to account for 64.25 % of total variance. All responses had high internal consistency and reliability. In confirmatory factor analysis, the loadings of six constructs were between 0.53 ~ 0.89 and were significant, Construct reliability (CR) were between 0.79 ~ 0.93 respectively. The results showed good convergent validity. The resultant models fit the data well (GFI was 0.92, RMSEA was 0.07) and the six-factor competencies framework for Chinese doctors emerged. CONCLUSIONS: The Chinese doctors' competencies framework includes six elements: (a) technical procedural skills; (b) diagnosis and management; (c) teamwork and administration; (d) communication; (e) professional behavior; and (f) professional values. These findings are relevant to China, consistent with its current situation, and similar to those developed in other countries. PMID- 26601695 TI - Reduction of All-Atom Protein Folding Dynamics to One-Dimensional Diffusion. AB - Theoretical models have often modeled protein folding dynamics as diffusion on a low-dimensional free energy surface, a remarkable simplification. However, the accuracy of such an approximation and the number of dimensions required were not clear. For all-atom folding simulations of ten small proteins in explicit solvent we show that the folding dynamics can indeed be accurately described as diffusion on just a single coordinate, the fraction of native contacts (Q). The diffusion models reproduce both folding rates, and finer details such as transition-path durations and diffusive propagators. The Q-averaged diffusion coefficients decrease with chain length, as anticipated from energy landscape theory. Although the Q-diffusion model does not capture transition-path durations for the protein NuG2, we show that this can be accomplished by designing an improved coordinate Qopt. Overall, one-dimensional diffusion on a suitable coordinate turns out to be a remarkably faithful model for the dynamics of the proteins considered. PMID- 26601696 TI - Serum thyroid-stimulating hormone and cognition in older people. AB - BACKGROUND: high TSH concentrations and cognitive decline are both very common among older people and could be linked. OBJECTIVE: to assess cognition in our cohort of 335 home-dwelling older people (75 years and older) and to cross sectionally relate the results to thyroid-stimulating hormone (TSH) concentrations. Our special focus was on the upper normal TSH range and subclinical hypothyroidism. METHODS: cognitive performance was evaluated using the Consortium to Establish a Registry for Alzheimer's disease neuropsychological battery (CERAD-nb). The Clinical Dementia Rating (CDR) scale was used to evaluate severity of cognitive disorder. The APOEepsilon4 genotype was also defined. Subjects were divided into quartiles based on the TSH concentrations, and results were compared between these groups. RESULTS: expected relations were observed between CERAD domains and both educational level and APOEepsilon4 genotype. Female sex significantly associated with better performance in Boston naming (OR = 0.48; 95% CI = 0.27-0.85). In the whole cohort, higher TSH concentrations tended to associate with better scores in most parts of the CERAD-nb tests, but differences were not statistically significant. However, subjects with the highest TSH concentration (90th TSH percentile, range 4.14-14.4 mU/l) had better CDR scores compared with subjects with the lowest TSH concentration (10th percentile, range 0.001-0.63 mIU/l; OR 0.10; 95% CI 0.014-0.76). CONCLUSIONS: our results do not support the notion that higher TSH concentrations, not even in the range of subclinical hypothyroidism, would adversely affect cognition among older people. PMID- 26601697 TI - Association of increasing age with receipt of specialist care and long-term mortality in patients with non-ST elevation myocardial infarction. AB - BACKGROUND: observational studies suggest that older patients are less likely to receive secondary prevention medicines following acute coronary syndrome (ACS). OBJECTIVES: to examine the association of increasing age with receipt of specialist care and influence of specialist care on long-term mortality in patients with non-ST elevation myocardial infarction (NSTEMI). DESIGN: a cohort study. SETTING: National ACS registry of England and Wales. SUBJECTS: a total of 85,183 patients admitted with NSTEMI between 2006 and 2010. METHODS: logistic regression analyses to assess receipt of secondary prevention medicines (ACE inhibitor, beta-blocker, statin, aspirin) by age group; multivariate Cox regression models to examine longitudinal effect of cardiologist care on all cause mortality by age group. RESULTS: mean age 72.0 years (SD 13.0 years), mean follow-up was 2.13 years. Older patients received less cardiologist care (70.2% of NSTEMI patients >=85 years compared with 94.7% of patients <65) years and had more co-morbidity. Cardiologists prescribed more secondary prevention in all age groups than generalists, but this was mostly explained away by co-morbidity (receipt of statin crude OR 1.51 (1.27,1.80), fully adjusted OR 1.11 (0.92,1.33) in patients >=85 years). Receiving cardiologist care compared with generalist care was associated with a decreased risk of death in all even after adjustment for co-morbidity, disease severity and secondary prevention; this benefit reduced incrementally with older age group (adjusted hazard ratio (HR) 0.58 (0.49,0.68) aged <65; 0.87 (0.82,0.92) aged >=85). CONCLUSION: older patients with NSTEMI were less likely to see a cardiologist, but reduced treatment by generalists was explained away by co-morbidity. Cardiologist care was associated with lower mortality in all age groups than a generalist, but this survival benefit was less pronounced in older patients. PMID- 26601698 TI - Electromagnetic field redistribution induced selective plasmon driven surface catalysis in metal nanowire-film systems. AB - For the novel interpretation of Raman spectrum from molecule at metal surface, the plasmon driven surface catalysis (PDSC) reactions have become an interesting topic in the research field of surface enhanced Raman scattering (SERS). In this work, the selective PDSC reactions of p,p'-dimercaptoazobenzene (DMAB) produced from para-aminothiophenol (PATP) or 4-nitrobenzenethiol (4NBT) were demonstrated in the Ag nanowires dimer-Au film systems. The different SERS spectra collected at individual part and adjacent part of the same nanowire-film system pointed out the importance of the electromagnetic field redistribution induced by image charge on film in this selective surface catalysis, which was confirmed by the simulated electromagnetic simulated electro- magnetic field distributions. Our result indicated this electromagnetic field redistribution induced selective surface catalysis was largely affected by the polarization and wavelength of incident light but slightly by the difference in diameters between two nanowires. Our work provides a further understanding of PDSC reaction in metal nanostructure and could be a deep support for the researches on surface catalysis and surface analysis. PMID- 26601699 TI - Dataset on coherent control of fields and induced currents in nonlinear multiphoton processes in a nanosphere. AB - We model a scheme for the coherent control of light waves and currents in metallic nanospheres which applies independently of the nonlinear multiphoton processes at the origin of waves and currents. Using exact mathematical formulae, we calculate numerically with a custom fortran code the effect of an external control field which enable us to change the radiation pattern and suppress radiative losses or to reduce absorption, enabling the particle to behave as a perfect scatterer or as a perfect absorber. Data are provided in tabular, comma delimited value format and illustrate narrow features in the response of the particles that result in high sensitivity to small variations in the local environment, including subwavelength spatial shifts. PMID- 26601700 TI - Photoinhibition of Phaeocystis globosa resulting from oxidative stress induced by a marine algicidal bacterium Bacillus sp. LP-10. AB - Harmful algal blooms caused by Phaeocystis globosa have resulted in staggering losses to coastal countries because of their world-wide distribution. Bacteria have been studied for years to control the blooms of harmful alga, however, the action mechanism of them against harmful algal cells is still not well defined. Here, a previously isolated algicidal bacterium Bacillus sp. LP-10 was used to elucidate the potential mechanism involved in the dysfunction of P. globosa algal cells at physiological and molecular levels. Our results showed Bacillus sp. LP 10 induced an obvious rise of reactive oxygen species (ROS), which was supposed to be major reason for algal cell death. Meanwhile, the results revealed a significant decrease of photosynthetic physiological indexes and apparent down regulated of photosynthesis-related genes (psbA and rbcS) and protein (PSII reaction center protein D1), after treated by Bacillus sp. LP-10 filtrates, suggesting photoinhibition occurred in the algal cells. Furthermore, our results indicated that light played important roles in the algal cell death. Our work demonstrated that the major lethal reason of P. globosa cells treated by the algicidal bacterium was the photoinhibition resulted from oxidative stress induced by Bacillus sp. LP-10. PMID- 26601701 TI - Normal Values of Left Ventricular Mass Index Assessed by Transthoracic Three Dimensional Echocardiography. AB - BACKGROUND: Pathologic left ventricular (LV) hypertrophy is closely coupled with adverse cardiovascular events. However, normal values of LV mass determined by three-dimensional echocardiography (3DE) have not been established in a large number of healthy subjects over a wide age range. The aims of this study were to (1) validate the accuracy of 3DE for LV mass measurements against cardiac magnetic resonance (CMR), (2) establish the normal range of LV mass index in healthy subjects, and (3) investigate the effects of age, gender, and ethnic diversity on LV mass index. METHODS: In protocol 1, both transthoracic 3DE and CMR were performed on the same day in 57 patients who underwent clinically indicated CMR examinations. In protocol 2, full-volume data sets were acquired with 3DE in 390 healthy subjects. The LV endocardial and epicardial borders were semiautomatically determined at end-diastole using three-dimensional echocardiographic software. LV mass was calculated as (LV epicardial volume--LV endocardial volume) * 1.05. RESULTS: Excellent correlation was observed between three-dimensional echocardiographic and CMR measurements of LV mass (r = 0.96). Bland-Altman analysis revealed bias of -4.8 g (-3.9% of the mean), with 95% limits of agreement of +/- 27.7 g. Normal values of LV mass indexed to body surface area were found to be 70 +/- 9 g/m(2) in men and 61 +/- 8 g/m(2) in women. Significant age and gender dependence, but no racial dependence, was observed for LV mass index. CONCLUSIONS: Three-dimensional echocardiography is an accurate method for measuring LV mass. Age and gender dependence, but no ethnic dependence, of LV mass index was observed in Japanese and American populations. The reported normal reference values of 3DE-determined LV mass index according to age and gender could potentially be useful for diagnosing LV hypertrophy with excellent accuracy. PMID- 26601702 TI - Normal Values and Differences in Ascending Aortic Diameter in a Healthy Population of Adults as Measured by the Pediatric versus Adult American Society of Echocardiography Guidelines. AB - BACKGROUND: There is a lack of uniformity across echocardiographic society guidelines as to how the diameter of the ascending aorta is to be measured. The aims of this study were to compare measurements done using the diastolic leading edge-to-leading edge and systolic inner edge-to-inner edge (SIE) techniques in a large cohort of healthy adult individuals and to report the normal values for adults using the SIE technique. METHODS: Aortic diameters obtained according to the two guideline recommendations at the aortic annuls, sinuses of Valsalva, sinotubular junction, and ascending aorta in 1,148 healthy adult volunteers were compared. Bland-Altman analysis, paired t tests, and intraclass correlation coefficients were evaluated at each segment. SIE values are reported as normative data, according to age, gender, and body surface area. RESULTS: The diastolic leading edge-to-leading edge convention yielded smaller diameters (compared with SIE) at the aortic annulus and ascending aorta and larger diameters at the sinus of Valsalva and sinotubular junction (P < .001 for all). There was excellent correlation between these techniques, with intraclass correlation coefficients of 0.88 to 0.96. Interobserver variability was minimal and similar for both techniques. Using the SIE technique, diameters were larger for men and increased with age and larger body surface area. CONCLUSIONS: Although there was a statistically significant difference in aortic diameter measures between the two conventions used, this difference was very small and correlations were excellent, suggesting that the difference has no clinical significance. The authors recommend that a standard convention be adopted within the American Society of Echocardiography and across all professional cardiovascular imaging societies for consistency and improved communication. PMID- 26601703 TI - Fluidic Grooves on Doped-Ice Surface as Size-Tunable Channels. AB - We propose a new principle for fabrication of size-tunable fluidic nano- and microchannels with a ubiquitous green material, water. Grooves filled with a solution are spontaneously formed on the surface of ice when an appropriate dopant is incorporated. Sucrose doping allows the development of grooves with lengths of 300 MUm along the boundaries of ice crystal grains. This paper focuses on controlling the size of the liquid-filled groove and reveals its applicability to size-selective differentiation of nano- and micromaterials. The width of this groove can be varied in a range of 200 nm to 4 MUm by adjusting the working temperature of the frozen platform. The channel dimension is reproducible as long as the same frozen condition is employed. We demonstrate the size-selective entrapment of particles as well as the state evaluation of DNA by controlling the physical interference of the ice wall with the electrophoretic migration of particles. PMID- 26601704 TI - Biofilm removal: Erroneous methodologies cause even more confusion? PMID- 26601705 TI - Investigation of a cluster of Clostridium difficile infections in a pediatric oncology setting. AB - BACKGROUND: We investigated an increase in Clostridium difficile infection (CDI) among pediatric oncology patients. METHODS: CDI cases were defined as first C difficile positive stool tests between December 1, 2010, and September 6, 2012, in pediatric oncology patients receiving inpatient or outpatient care at a single hospital. A case-control study was performed to identify CDI risk factors, infection prevention and antimicrobial prescribing practices were assessed, and environmental sampling was conducted. Available isolates were strain-typed by pulsed-field gel electrophoresis. RESULTS: An increase in hospital-onset CDI cases was observed from June-August 2012. Independent risk factors for CDI included hospitalization in the bone marrow transplant ward and exposure to computerized tomography scanning or cefepime in the prior 12 weeks. Cefepime use increased beginning in late 2011, reflecting a practice change for patients with neutropenic fever. There were 13 distinct strain types among 22 available isolates. Hospital-onset CDI rates decreased to near-baseline levels with enhanced infection prevention measures, including environmental cleaning and prolonged contact isolation. CONCLUSION: C difficile strain diversity associated with a cluster of CDI among pediatric oncology patients suggests a need for greater understanding of modes and sources of transmission and strategies to reduce patient susceptibility to CDI. Further research is needed on the risk of CDI with cefepime and its use as primary empirical treatment for neutropenic fever. PMID- 26601706 TI - Lessons learned from initial reporting of carbapenem-resistant Enterobacteriaceae in New York State hospitals, 2013-2014. AB - BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) are an urgent concern in health care in the United States because of high attributable mortality and versatile resistance mechanisms. CRE reporting was mandated in New York State (NYS) hospitals in July 2013. METHODS: Infection preventionists from the NYS Department of Health audited hospital-reported CRE data by comparing laboratory records with cases reported to the National Healthcare Safety Network (NHSN). Information regarding microbiology laboratory testing methodologies was obtained through a survey in October 2013. RESULTS: There were 1,151 CRE laboratory reports audited, with 13.6% determined not to have been reported to the NHSN when they should have been and 4.6% determined to be reported in error. There were a variety of errors, including lapses in surveillance and misinterpretation of the surveillance definition. CONCLUSION: Educational initiatives that include microbiology laboratory staff, improvements in the use of laboratory information systems to communicate with infection prevention, and updated NHSN definitions should improve the accuracy and consistency of CRE reporting in NYS. PMID- 26601707 TI - Mechanical food properties and dental topography differentiate three populations of Lemur catta in southwest Madagascar. AB - Determining the proximate causes of tooth wear remains a major focus of dental study. Here we compare the diets of three ring-tailed lemur (Lemur catta) populations and examine how different dietary components may contribute to patterns of wear-related tooth shape. Casts were made from dental impressions collected between 2003 and 2010 from lemurs in the gallery and spiny/mixed forests of the Beza Mahafaly Special Reserve (BMSR; Parcels 1 and 2) and the spiny/mixed forests of Tsimanampesotse National Park (TNP), Madagascar. Tooth shape variables (occlusal relief and slope, angularity) were analyzed using dental topographic analysis. Focal observations and food mechanical properties (FMPs: toughness, hardness, elastic modulus) were conducted and tested, respectively, during wet and dry seasons from 2008 to 2012. We found that FMPs correlate with patterns of dental topography in these three populations. Specifically, food toughness and elastic modulus correlate with the dental variables, but hardness does not. Average food toughness and elastic modulus, but not hardness, are highest in BMSR Parcel 2, followed by BMSR Parcel 1 and TNP. Occlusal relief and slope, which serve as proxies for tooth wear, show the greatest wear in Parcel 2 and the least in TNP. Angularity is also more pronounced in TNP. Further, dental topographic patterns correspond to reliance on Tamarindus indica (tamarind) fruit. Both BMSR populations consume tamarind at high frequencies in the dry season, but the fruits are rare at TNP and only occasionally consumed. Thus, high seasonal tamarind consumption and its mechanical values help explain the low dental relief and slope among BMSR lemurs. By investigating the ecology of a single widespread species across a variety of habitats, we have been able to link specific components of diet to patterns of dental topography in this species. This provides a context for interpreting wear related tooth shape changes more generally, illustrating that populations can develop different dental wear patterns resulting from a mix of intrinsic factors (thin enamel) and local conditions (food properties, frequency of consumption). PMID- 26601708 TI - Human immune system diversity and its implications in diseases. PMID- 26601710 TI - Online eluent-switching technique coupled anion-exchange liquid chromatography ion trap tandem mass spectrometry for analysis of non-steroidal anti-inflammatory drugs in pig serum. AB - A novel method for online extraction, pH-gradient separation, and analysis of nine non-steroidal anti-inflammatory drugs (NSAIDs) was developed by coupling online eluent-switching technique to single anion-exchange chromatographic column/ion trap mass spectrometer (MS) and used for monitoring NSAIDs residues in pig serum. A neutral eluent and a pH-gradient eluent were used for extraction and separation of NSAIDs, respectively. Each of nine NSAIDs has an MS precursor ion of either [M-H]- or [M-Na]-. The extracted ion chromatogram for a specific product ion of each NSAID was used for its quantitative analysis. The dynamic linear ranges of calibration curves were all 0-200 ng mL-1 (R2 > 0.9950). The analysis accuracies estimated by spiking standard concentrations at 20, 100, and 200 ng mL-1 were 80.5-99.9%. The corresponding intra-day and inter-day precisions (RSD%) were 2.5-14.5% and 2.9-15.2%, respectively. The limit of detection/limit of quantitation of NSAIDs were 1.3/4.3, 0.5/1.6, 0.2/0.5, 2.5/8.2, 1.5/4.9, 0.6/2.1, 0.6/2.0, 0.5/1.7, and 0.6/2.1 ng mL-1 for carprofen, diclofenac, flunixin, ibuprofen, ketoprofen, meclofenamic acid sodium, mefenamic acid, niflumic acid, and tolfenamic acid, respectively. After 1 h injection of a dose containing 2 mg kg-1 weight pig of flunixin and tolfenamic acid to the pigs, a residue amount of 3480 +/- 36 ng mL-1 and 431 +/- 13 ng mL-1, respectively, was reached for the incurred pig serum specimens and both residues were reduced to about 20 ng mL-1 at the time of 24 h. PMID- 26601709 TI - Effect of low-level mechanical vibration on osteogenesis and osseointegration of porous titanium implants in the repair of long bone defects. AB - Emerging evidence substantiates the potential of porous titanium alloy (pTi) as an ideal bone-graft substitute because of its excellent biocompatibility and structural properties. However, it remains a major clinical concern for promoting high-efficiency and high-quality osseointegration of pTi, which is beneficial for securing long-term implant stability. Accumulating evidence demonstrates the capacity of low-amplitude whole-body vibration (WBV) in preventing osteopenia, whereas the effects and mechanisms of WBV on osteogenesis and osseointegration of pTi remain unclear. Our present study shows that WBV enhanced cellular attachment and proliferation, and induced well-organized cytoskeleton of primary osteoblasts in pTi. WBV upregulated osteogenesis-associated gene and protein expression in primary osteoblasts, including OCN, Runx2, Wnt3a, Lrp6 and beta-catenin. In vivo findings demonstrate that 6-week and 12-week WBV stimulated osseointegration, bone ingrowth and bone formation rate of pTi in rabbit femoral bone defects via MUCT, histological and histomorphometric analyses. WBV induced higher ALP, OCN, Runx2, BMP2, Wnt3a, Lrp6 and beta-catenin, and lower Sost and RANKL/OPG gene expression in rabbit femora. Our findings demonstrate that WBV promotes osteogenesis and osseointegration of pTi via its anabolic effect and potential anti-catabolic activity, and imply the promising potential of WBV for enhancing the repair efficiency and quality of pTi in osseous defects. PMID- 26601712 TI - Fast gas chromatographic residue analysis in animal feed using split injection and atmospheric pressure chemical ionisation tandem mass spectrometry. AB - Significant speed improvement for instrumental runtime would make GC-MS much more attractive for determination of pesticides and contaminants and as complementary technique to LC-MS. This was the trigger to develop a fast method (time between injections less than 10 min) for the determination of pesticides and PCBs that are not (or less) amenable to LC-MS. A key factor in achieving shorter analysis time was the use of split injection (1:10) which allowed the use of a much higher initial GC oven temperature. A shorter column (15 m), higher temperature ramp, and higher carrier gas flow rate (6 mL/min) further contributed to analysis-time reduction. Chromatographic resolution was slightly compromised but still well fit for-purpose. Due to the high sensitivity of the technique used (GC-APCI-triple quadrupole MS/MS), quantification and identification were still possible down to the 10 MUg/kg level, which was demonstrated by successful validation of the method for complex feed matrices according to EU guidelines. Other advantages of the method included a better compatibility of acetonitrile extracts (e.g. QuEChERS) with GC, and a reduced transfer of co-extractants into the GC column and mass spectrometer. PMID- 26601711 TI - Simultaneous determination of trace benzotriazoles and benzothiazoles in water by large-volume injection/gas chromatography-mass spectrometry. AB - Benzotriazole (BTR) and benzothiazole (BTH) derivatives have been acknowledged as emerging pollutants due to their widespread contamination in the environment and their adverse effects on aquatic organisms. A rapid and reliable analytical method, based on solid phase extraction (SPE) and large-volume injection, derivatized with N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide (MTBSTFA), and analyzed by gas chromatography-mass spectrometry (GC-MS), was developed for the determination of six 1,2,3-benzotriazoles and six 1,3-benzothiazoles in aquatic matrices. It was demonstrated that MTBSTFA had a better overall performance compared with N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) and N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA). The method detection limits in tap water, river water and effluent samples were 0.050-1.3 ng L(-1), 0.057-1.8 ng L(-1) and 0.10-4.0 ng L(-1), respectively. Mean recoveries of the target analytes at different aquatic matrices, ranged from 43% to 131% with relative standard deviations (RSDs) below 17%. The method was successfully employed to river water and effluent sewage samples collected from a sewage treatment plant in Germany. Seven target compounds were detected with the maximum concentration up to 2.9 MUg L(-1) for 4-Me-BTR in the effluent sample. PMID- 26601713 TI - Naproxen-imprinted xerogels in the micro- and nanospherical formsby emulsion technique. AB - Naproxen-imprinted xerogels in the microspherical and nanospherical forms were prepared by W/O emulsion and microemulsion, respectively. The work evolved from a sol-gel mixture previously reported for bulk synthesis. It was relatively simple to convert the original sol-gel mixture to one amenable to emulsion technique. The microspheres thus produced presented mean diameter of 3.7 MUm, surface area ranging 220-340 m2/g, selectivity factor 4.3 (against ibuprofen) and imprinting factor 61. A superior capacity (9.4 MUmol/g) was found, when comparing with imprints obtained from similar pre-gelification mixtures. However, slow mass transfer kinetics was deduced from column efficiency results. Concerning the nanospherical format, which constituted the first example of the production of molecularly imprinted xerogels in that format by microemulsion technique, adapting the sol-gel mixture was troublesome. In the end, nanoparticles with diameter in the order of 10 nm were finally obtained, exhibiting good indications of an efficient molecular imprinting process. Future refinements are necessary to solve serious aggregation issues, before moving to more accurate characterization of the binding characteristics or to real applications of the nanospheres. PMID- 26601714 TI - Manipulating IL-2 and IL-2R in autoimmune diseases and transplantation. PMID- 26601716 TI - Molecular Dynamics Simulations of the Interaction between Water Molecules and Aggregates of Acetic or Propionic Acid Molecules. AB - Water adsorption around small acetic and propionic acid aggregates has been studied by means of molecular dynamics simulation in the temperature range of 100 265 K as a function of the water content. Calculations have shown that acetic and propionic acid molecules behave similarly and that both the temperature and the water content have a strong influence on the behavior of the corresponding systems. Two situations have been evidenced for the acid-water aggregates, corresponding either to water adsorption on large acid grains at very low temperatures or to the formation of droplets consisting of acid molecules adsorbed at the surface of water aggregates at higher temperatures and high water content. At low water content and high temperature, only a partial mixing between water and acid molecules has been observed. The results of the present simulations emphasize the need for further experimental and simulation works to achieve a better characterization of the effects of both temperature and humidity on the behavior of organic aerosols in the troposphere. PMID- 26601715 TI - Banff study of pathologic changes in lung allograft biopsy specimens with donor specific antibodies. AB - BACKGROUND: The diagnosis of antibody-mediated rejection (AMR) in the lung transplant is still an area under investigation. We performed a blinded multicenter study to determine if any statistically significant histologic findings in transbronchial biopsy specimens from lung transplant patients correlate with the presence of donor-specific antibodies (DSAs). METHODS: We asked 9 pathologists with experience in lung transplantation to evaluate 161 lung transplant biopsy specimens for various histologic parameters. The findings were correlated with antibody status positive for DSAs, positive for non-DSAs, and no antibodies (NABs) present. The significance of each histologic variable was reviewed. RESULTS: We found no statistically significant association with acute cellular rejection, airway inflammation, or bronchiolitis obliterans and the presence or absence of antibodies. However, biopsy specimens with DSAs had a statistically significant difference vs NABs in the setting of acute lung injury, with or without diffuse alveolar damage (p = 0.0008), in the presence of capillary neutrophilic inflammation (p = 0.0014), and in samples with endotheliitis (p = 0.0155). In samples with complement 4d staining, there was a trend but no statistically significant difference between specimens associated with DSAs and specimens with NABs. CONCLUSIONS: Capillary inflammation, acute lung injury, and endotheliitis significantly correlated with DSAs. The infrequently observed diffuse staining for complement 4d limits the usefulness of this stain. PMID- 26601717 TI - A novel function for the DEAD-box RNA helicase DDX-23 in primary microRNA processing in Caenorhabditis elegans. AB - Primary microRNAs (pri-miRNAs) are cleaved by the nuclear RNase III Drosha to produce hairpin-shaped precursor miRNAs (pre-miRNAs). In humans, this process is known to be facilitated by the DEAD-box helicases p68 (DDX5) and p72 (DDX17). In this study, we performed a candidate-based RNAi screen in C. elegans to identify DEAD/H-box proteins involved in miRNA biogenesis. In a let-7(mg279) sensitized genetic background, knockdown of a homolog of yeast splicing factor Prp28p, DDX 23, or a homolog of human helicases p68 and p72, DDX-17, enhanced let-7 loss-of function phenotypes, suggesting that these helicases play a role in let-7 processing and/or function. In both ddx-23(RNAi) and ddx-17(RNAi), levels of mature let-7 were decreased while pri-let-7 was found to accumulate, indicating that the helicases likely act at the level of pri-let-7 processing. DDX-23 and DDX-17 were also required for the biogenesis of other known heterochronic miRNAs, including lin-4 and the let-7 family members miR-48, miR-84 and miR-241. Their function was not confined to the heterochronic pathway, however, since they were both necessary for down-regulation of cog-1 by the spatial patterning miRNA, lsy 6. Here, we present a novel function for C. elegans DDX-23 in pri-miRNA processing, and also suggest a conserved role for DDX-17 in this process. PMID- 26601718 TI - An explorative cross-sectional study examining self-reported health and nutritional status of disadvantaged people using food banks in Germany. AB - BACKGROUND: Even in high-income countries some population groups depend on food banks to support their food intake. We aimed to explore and compare health and nutritional status of food bank clients (Tafel e.V.) in different cities in Germany. METHODS: In a cross-sectional study, self-reported health and nutritional status of food bank clients living in three cities (Berlin - capital, Ludwigsburg- affluent city, Fulda - small town) which differ in size, available income and poverty rate, were assessed and compared to survey variables of the low socioeconomic status population of national surveys (DEGS and GEDA). RESULTS: Across cities, food bank clients (N = 276, response rate of 21.5 %) did not differ in main socio-demographic characteristics (age, nationality, education, professional qualification, household income). Smoking, having at least one chronic illness, estimating their own health status as moderate to poor and low consumption of fruits and vegetables were common characteristics. Comparing selected variables with the low socioeconomic status population of DEGS and GEDA, differences were found for a higher prevalence of diabetes among food bank clients and a worse self-reported health status. Considerably lower fruit consumption and lower hypertension prevalence among female and lower overweight rates among male food bank clients were found. CONCLUSIONS: Although people using food banks vary in socio-demographic background, no differences for main demographics across the cities were found. In addition, the study suggests that for some health- and nutrition-related variables, national surveys in Germany might underestimate socioeconomic differences. PMID- 26601719 TI - Effects of exercise on neuromuscular junction components across age: systematic review of animal experimental studies. AB - BACKGROUND: During almost one-third of our life, maturation of the nervous system promotes strength and muscle mass increase. However, as age advances, the nervous system begins to suffer a slow and continue reduction of its functions. Neuromuscular junction (NMJ) is one of the structures of which change due to aging process. Physical training leads to significant adjustments in NMJs of young and aged animals. Nevertheless, studies that aimed to investigate this effect have, in many cases, methodological variables that may have some influence on the result. Thus, this study aimed to carry out a systematic review about the effects of exercise training on the NMJ compartments of young, adult and aged animals. RESULTS: We searched PubMed, Google Scholar, Science Direct, Scielo and Lilacs databases for animal experimental studies that studied exercise effects on the NMJs components across age. After inclusion and exclusion criteria, we included nine articles in systematic review and two for meta-analysis (young/adult NMJ). CONCLUSIONS: We identified that exercise training cause NMJ hypertrophy on young animals and NMJ compression on aged ones. However, many methodological issues such as age, skeletal muscle and fibers type, and type of exercise and training protocol might influence the results. Graphical abstract: Flow gram is actually to be show at results section as Fig 1. PMID- 26601721 TI - Influence of the Supramolecular Micro-Assembly of Multiple Emulsions on their Biopharmaceutical Features and In vivo Therapeutic Response. AB - The ability of some surfactants to self-assemble in a water/oil bi-phase environment thus forming supramolecular structure leading to the formation of w/o/w multiple emulsions was investigated. The w/o/w multiple emulsions obtained by self-assembling (one-step preparation method) were compared with those prepared following the traditional two-step procedure. Methyl-nicotinate was used as a hydrophilic model drug. The formation of the multiple emulsion structure was evidenced by optical microscopy, which showed a mean size of the inner oil droplets of 6 MUm and 10 MUm for one-step and two-step multiple emulsions, respectively. The in vitrobiopharmaceutical features of the various w/o/w multiple emulsion formulations were evaluated by means of viscosimetry studies, drug release and in vitro percutaneous permeation experiments through human stratum corneum and viable epidermis membranes. The self-assembled multiple emulsions allowed a more gradual percutaneous permeation (a zero-order permeation rate) than the two-step ones. The in vivotopical carrier properties of the two different multiple emulsions were evaluated on healthy human volunteers by using the spectrophotometry of reflectance, an in vivonon invasive method. These multiple emulsion systems were also compared with conventional emulsion formulations. Our findings demonstrated that the multiple emulsions obtained by self-assembling were able to provide a more sustained drug delivery into the skin and hence a longer therapeutic action than two-step multiple emulsions and conventional emulsion formulations. Finally, our findings showed that the supramolecular micro-assembly of multiple emulsions was able to influence not only the biopharmaceutical characteristics but also the potential in vivotherapeutic response. PMID- 26601720 TI - Genome-wide DNA methylation analyses in lung adenocarcinomas: Association with EGFR, KRAS and TP53 mutation status, gene expression and prognosis. AB - BACKGROUND: DNA methylation alterations are early events in tumorigenesis and important in the regulation of gene expression in cancer cells. Lung cancer patients have in general a poor prognosis, and a deeper insight into the epigenetic landscape in lung adenocarcinoma tumors and its prognostic implications is needed. RESULTS: We determined whole-genome DNA methylation profiles of 164 fresh frozen lung adenocarcinoma samples and 19 samples of matched normal lung tissue using the Illumina Infinium 450K array. A large number of differentially methylated CpGs in lung adenocarcinoma tissue were identified, and specific methylation profiles were observed in tumors with mutations in the EGFR-, KRAS- or TP53 genes and according to the patients' smoking status. The methylation levels were correlated with gene expression and both positive and negative correlations were seen. Methylation profiles of the tumor samples identified subtypes of tumors with distinct prognosis, including one subtype enriched for TP53 mutant tumors. A prognostic index based on the methylation levels of 33 CpGs was established, and was significantly associated with prognosis in the univariate analysis using an independent cohort of lung adenocarcinoma patients from The Cancer Genome Atlas project. CpGs in the HOX B and HOX C gene clusters were represented in the prognostic signature. CONCLUSIONS: Methylation differences mirror biologically important features in the etiology of lung adenocarcinomas and influence prognosis. PMID- 26601722 TI - Inulin Derivatives Obtained Via Enhanced Microwave Synthesis for Nucleic Acid Based Drug Delivery. AB - A new class of therapeutic agents with a high potential for the treatment of different socially relevant human diseases is represented by Nucleic Acid Based Drugs (NABD), including small interfering RNAs (siRNA), decoy oligodeoxynucleotides (decoy ODN) and antisense oligonucleotides (ASOs). Although NABD can be engineered to be specifically directed against virtually any target, their susceptibility to nuclease degradation and the difficulty of delivery into target tissues severely limit their use in clinical practice and require the development of an appropriate nanostructured delivery system. For delivery of NABD, Inulin (Inu), a natural, water soluble and biocompatible polysaccharide, was derivatized by Spermine (Spm), a flexible molecule with four amine groups that, having pKa values in the range between 8-11, is mainly in the protonated form at pH 7.4. The synthesis of related copolymers (Inu-Spm) was performed by a two step reaction, using a method termed Enhanced Microwave Synthesis (EMS) which has the advantage, compared to conventional microwave reaction, that high amount of energy can be applied to the reaction system, by administering microwave irradiation and simultaneously controlling the temperature in the reaction vessel with cooled air. The synthesized inulin derivatives were characterized by FT-IR spectra and (1)H-NMR. INU-Spm derivatives with a degree of derivatization of about 14 % mol/mol were obtained. These polycations were tested to evaluate their ability to form non covalent complexes with genetic material (polyplexes). Agarose gel retardation assays showed that the obtained copolymers are able to electrostatically interact with DNA duplex to form polyplexes at different c/p weight ratios. Moreover, light scattering studies, performed to analyze size and z-potential of polyplexes, evidenced that copolymers are able to interact with genetic material leading to the formation of nanoscaled systems. In addition, biocompatibility of polyplexes was demonstrated by performing cytotoxicity assays on a 16HBE cell line. Transfection studies, performed by using siRNA able to silence luciferase expression, demonstrate the efficiency of polyplexes to transfect the same cell line, with a reduction of luciferase expression to about 70%. These results encourage us to work with these copolymers to obtain an efficient and feasible inulin based NABD delivery system. PMID- 26601724 TI - Ultrasound findings in ocular trauma. AB - OBJECTIVE: To evaluate the frequencies of various eye and/or orbital disorders by ultrasound examination in patients with ocular trauma. MATERIALS AND METHODS: This prospective and descriptive study was conducted on 100 patients with ocular trauma treated in the Conde de Valenciana Institute from March to November 2014. Ultrasound examination was performed primarily using ultrasound B mode, with standardised A mode only used as correlation method. Age, gender, type of trauma, and various ultrasound findings were recorded. RESULTS: Ocular trauma was more frequent in men (83%) compared to women (17%). The left eye was affected in 55%, and right eye in 45%, with 55% being open traumas and 45% blunt traumas. Most cases were young patients with a mean age of 33.7 years, with the group between 41 to 50 years being the most affected. Among the most frequent injuries found was the vitreous haemorrhage (45%) and posterior hyaloid detachment (38%), followed by retinal detachment (32%), and choroidal detachment (18%). CONCLUSION: Ultrasound remains as the investigation method of choice in patients with ocular trauma, since it is a simple, cheap and non-invasive study, and can be very useful in providing diagnostic and prognostic information. This study demonstrated that trauma is more common in young men, with vitreous haemorrhage as the most common finding. PMID- 26601725 TI - The High Prevalence of Anxiety Disorders After Stroke. AB - OBJECTIVES: Previous studies indicate that post-stroke anxiety is common and persistent. We aimed to determine whether point prevalence of anxiety after stroke is higher than in the population at large, and whether the profile of anxiety symptoms is different. METHODS: This case-control study was conducted in Goteborg, Sweden, with stroke patients recruited from the Sahlgrenska University Hospital and a comparison group selected from local population health studies. We included 149 stroke survivors (assessed at 20 months post-stroke) and 745 participants from the general population matched for age and sex. A comprehensive psychiatric interview was conducted, with anxiety and depressive disorders diagnosed according to DSM-III-R criteria. RESULTS: Those in the stroke group were significantly more likely than those in the comparison group to have generalized anxiety disorder (GAD) (27% versus 8%), phobic disorder (24% versus 8%) and obsessive-compulsive disorder (9% versus 2%). Multivariate regression indicated that being in the stroke group, female sex, and having depression were all significant independent associates of having an anxiety disorder. In terms of symptom profile, stroke survivors with GAD were significantly more likely to report vegetative disturbance than those in the comparison group with GAD but less likely to have observable muscle tension or reduced sleep. CONCLUSIONS: Point prevalence of anxiety disorders is markedly higher after stroke than in the general population, and this cannot be attributed to higher rates of comorbid depression. PMID- 26601723 TI - Safety of Nanoparticles in Medicine. AB - Nanomedicine involves the use of nanoparticles for therapeutic and diagnostic purposes. During the past two decades, a growing number of nanomedicines have received regulatory approval and many more show promise for future clinical translation. In this context, it is important to evaluate the safety of nanoparticles in order to achieve biocompatibility and desired activity. However, it is unwarranted to make generalized statements regarding the safety of nanoparticles, since the field of nanomedicine comprises a multitude of different manufactured nanoparticles made from various materials. Indeed, several nanotherapeutics that are currently approved, such as Doxil and Abraxane, exhibit fewer side effects than their small molecule counterparts, while other nanoparticles (e.g. metallic and carbon-based particles) tend to display toxicity. However, the hazardous nature of certain nanomedicines could be exploited for the ablation of diseased tissue, if selective targeting can be achieved. This review discusses the mechanisms for molecular, cellular, organ, and immune system toxicity, which can be observed with a subset of nanoparticles. Strategies for improving the safety of nanoparticles by surface modification and pretreatment with immunomodulators are also discussed. Additionally, important considerations for nanoparticle safety assessment are reviewed. In regards to clinical application, stricter regulations for the approval of nanomedicines might not be required. Rather, safety evaluation assays should be adjusted to be more appropriate for engineered nanoparticles. PMID- 26601726 TI - Drug and Exercise Treatment of Alzheimer Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of Effects on Cognition in Randomized Controlled Trials. AB - OBJECTIVE: Demographic changes are increasing the pressure to improve therapeutic strategies against cognitive decline in Alzheimer disease (AD) and mild cognitive impairment (MCI). Besides drug treatment, physical activity seems to be a promising intervention target as epidemiological and clinical studies suggest beneficial effects of exercise training on cognition. Using comparable inclusion and exclusion criteria, we analyzed the efficacy of drug therapy (cholinesterase inhibitors, memantine, and Ginkgo biloba) and exercise interventions for improving cognition in AD and MCI populations. METHODS: We searched The Cochrane Library, EBSCO, OVID, Web of Science, and U.S Food and Drug Administration data from inception through October 30, 2013. Randomized controlled trials in which at least one treatment arm consisted of an exercise or a pharmacological intervention for AD or MCI patients, and which had either a non-exposed control condition or a control condition that received another intervention. Treatment discontinuation rates and Standardized Mean Change score using Raw score standardization (SMCR) of cognitive performance were calculated. RESULTS: Discontinuation rates varied substantially and ranged between 0% and 49% with a median of 18%. Significantly increased discontinuation rates were found for galantamine and rivastigmine as compared to placebo in AD studies. Drug treatments resulted in a small pooled effect on cognition (SMCR: 0.23, 95% CI: 0.20 to 0.25) in AD studies (N = 45, 18,434 patients) and no effect in any of the MCI studies (N = 5, 3,693 patients; SMCR: 0.03, 95% CI: 0.00 to 0.005). Exercise interventions had a moderate to strong pooled effect size (SMCR: 0.83, 95% CI: 0.59 to 1.07) in AD studies (N = 4, 119 patients), and a small effect size (SMCR: 0.20, 95% CI: 0.11 to 0.28) in MCI (N = 6, 443 patients). CONCLUSIONS: Drug treatments have a small but significant impact on cognitive functioning in AD and exercise has the potential to improve cognition in AD and MCI. Head-to-head trials with sufficient statistical power are necessary to directly compare efficacy, safety, and acceptability. Combining these two approaches might further increase the efficacy of each individual intervention. IDENTIFIER: PROSPERO (2013:CRD42013003910). PMID- 26601728 TI - The influence of a learning object with virtual simulation for dentistry: A randomized controlled trial. AB - OBJECTIVE: The study aimed to evaluate the influence of virtual learning object (VLO) in the theoretical knowledge and skill practice of undergraduate dentistry students as it relates to zinc phosphate cement (ZPC). METHODS: Only students enrolled in the dentistry course the course were included in the trial. Forty-six students received a live class regarding ZPC and were randomized by electronic sorting into the following 4 groups: VLO Immediate (GIVLOn=9), VLO longitudinal (GLVLOn=15) and two control groups without VLO (GICn=9 and GLCn=13). The immediate groups had access to VLO or a book for 20 min before the ability assessment, whereas the longitudinal groups had access to VLO or a book for 15 days. RESULTS: A pre- and posttest on theoretical knowledge and two laboratory skill tests, evaluated by blinded examiners, were performed regarding zinc phosphate cement manipulation in all groups. The students who used the VLO obtained better results in all the tests performed than the control students. The theoretical posttest showed a significant difference between the longitudinal groups, GLC (6.0 +/- 1.15) and GLVLO (7.33 +/- 1.43). The lower film thickness presented with a significant difference in the VLO groups: (GIC 25 +/- 9.3) and GIVLO (16.24 +/- 5.17); GLC (50 +/- 27.08) and GLVLO (22.5+/-9.65). The higher setting time occurred in the VLO groups, and the immediate group showed a significant difference (GIC 896 +/- 218.90) and GIVLO (1138.5 +/- 177.95). CONCLUSIONS: The ZPC manipulated by the students who used the VLO had better mechanical properties in the laboratory tests. Therefore, the groups that used the VLO had clinical handling skills superior to its controls and greater retention of knowledge after 15 days. PMID- 26601727 TI - Oral vaccine (OM-89) in the recurrent urinary tract infection prophylaxis: a realistic systematic review with meta-analysis. AB - OBJECTIVE: To evaluate the efficacy of Escherichia Coli extract (OM-89) in the prophylaxis of recurrent uncomplicated urinary tract infection (UTI) through a contemporary systematic review and meta-analysis. METHODS: Inclusion criteria were double-blind randomized trials using orally administrated OM-89, 6mg daily, during three months with a minimum of three months of monitoring. Outcomes were the frequency of bacteriuria in 3 and 6 months, dysuria in 6 months and UTI in 6 months. DATABASES: PubMed, MEDLINE, Cochrane Collaboration and their key references. After analysis by three independent reviewers, 15 double-blind randomized trials were identified, 10 papers excluded due to methods flaws and 5 used for data analysis due to double blinding and reporting drop-outs. RESULTS: Among 5 selected studies the date of publication ranged from 1985 to 2005, totalizing 396 patients in the OM-89 group and 392 in the control group. Overall, there were 61 dropouts in the control group and 76 in the OM-89 group. As a major limitation there was no appropriate description of their methodologies and none of the studies described conflict of interest or commitment to the pharmaceutical industry. All studies were multi-centric, except for two, which showed no clarity on allocation concealment. All studies show benefit in favor of vaccine. CONCLUSIONS: Current literature on prospective randomized controlled trials evaluating the use of oral OM-89 vaccine in the recurrent UTI prophylaxis is of low quality, limited to the first six months only and with variable definition of bacteriuria and UTI. Although all studies show benefit in favor of vaccine, no robust trial was identified, resulting in a high heterogeneity in the data analyzed. Also, publication bias could not be excluded and future higher quality studies are warranted adding intermediate (>12 months) and long-term follow-up. PMID- 26601730 TI - [Early complications and management of newborns during the first month of life]. AB - OBJECTIVE: To describe early complications and management of newborns during the first month of life. METHODS: This systematic evidence review is based on Pubmed search, Cochrane library and experts recommendations. RESULTS: There is no optimal time for maternity discharge for low risk newborn in regard of the literature. It depends more on the organisation of the post-discharge follow-up (professional consensus). Extreme hyperbilirubinemia expose to neonatal mortality and severe neurodevelopmental impairment for survivors (level of evidence: 1). Neonatal hyperbilirubinemia occurs in almost all newborns and may be benign if its progression is monitored (transcutaneous bilirubinometer, capillar or venous bilirubin level) at least 24hours after any early discharge (professional consensus). Asymptomatic newborns with high risks of neonatal sepsis have to be closely monitored during the first 48hours of life (professional consensus). Clinical assessment (heart murmure and femoral pulse) at least 24hours after any early discharge and at any clinical examination almost up to 1 month after birth is recommended to detect possible congenital heart disease (professional consensus). Serial clinical examination of the hips by a trained clinician in the periodic health examination of all infants until they are walking independently is recommended (professional consensus). Neonatal screening blood tests are recommended between 60 and 84hours of life in every newborns, can be advanced between 48 and 60hours if necessary but never before 48hours of life (professional consensus). Neonatal screening of deafness is recommended in every newborns and has to be assessed before maternity discharge (professional consensus). All these data have to be reported in the newborn personal medical file (professional consensus). CONCLUSION: Early discharge has to be prepared during the prenatal period in order to ensure care continuity at home and to avoid any severe neonatal outcome. PMID- 26601729 TI - Conjoined twins: scientific cinema and Pavlovian physiology. AB - Through the lens of a 1957 documentary film, "Neural and humoral factors in the regulation of bodily functions (research on conjoined twins)," produced by the USSR Academy of Medical Sciences, this essay traces the entwined histories of Soviet physiology, studies of conjoined twins and scientific cinema. It examines the role of Ivan Pavlov and his students, including Leonid Voskresenkii, Dmitrii Fursikov and Petr Anokhin, in the development of "scientific film" as a particular cinematographic genre in Soviet Russia and explores numerous puzzles hidden behind the film's striking visuals. PMID- 26601731 TI - Case study of an MBT plant producing SRF for cement kiln co-combustion, coupled with a bioreactor landfill for process residues. AB - The paper describes the performances of the energy recovery pathway from the residual waste based on the production of a Solid Recovered Fuel (SRF) to be exploited via co-combustion in a cement kiln. The SRF is produced in a single stream Mechanical-Biological Treatment plant, where bio-drying of the waste is followed by mechanical refining in order to fulfil the quality requirements by the cement kilns. Peculiar of this MBT is the fact that sorting residues are disposed in a nearby landfill, managed according to a bioreactor approach, where landfill gas is collected for electric energy recovery. A detailed mass and energy balance of the system is presented based on one year operational data, followed by its Life Cycle Assessment. Results show that the system is energetically and environmentally effective, with most of the impacts being more than compensated by the savings of materials and energy. Major role in determining such outcome is the displacement of petcoke in the cement kiln, both in terms of its fossil CO2 emissions and of its life cycle impacts, including the trans-oceanic transport. To check the robustness of the results, two sensitivity analyses are performed on the landfill gas collection efficiency and on the avoided electric energy mix. PMID- 26601733 TI - Misoprostol for induction of labor. AB - Labor-induction rates have increased considerably in the United States as well as around the world. With up to half of all induced labors requiring cervical ripening, prostaglandins have been utilized to increase induction success and achieve vaginal delivery. Misoprostol, a synthetic prostaglandin E1 analog has the ability to mimic the changes of spontaneous labor and has been used off label for over 30 years as a labor-induction agent. In the following article, cervical ripening and induction of labor with misoprostol will be discussed. The risks and benefits of misoprostol for ripening and induction and routes of administration will be reviewed, as well as future directions and new developments for its use. PMID- 26601732 TI - Infant Feeding Beliefs and Day-to-Day Feeding Practices of NICU Nurses. AB - The purpose is to examine the infant feeding beliefs and day-to-day feeding practices of NICU nurses with the goal of identifying ways to improve breastfeeding promotion. DESIGN AND METHODS: An ethnographic approach incorporated 14 months of participant observation and interviewing. General informants consisted of 114 purposively selected NICU nurses from a northeastern, level-IV NICU, pediatric hospital. From this group, 18 nurses served as key informants. There was an average of 13 interactions with each key informant and 3.5 with each general informant. Audio taped interviews and observational field notes were gathered for descriptions of beliefs and practices. Data were coded and analyzed for patterns and themes with the aid of NUD*IST. RESULTS: 1. The nurses identified health benefits of breastfeeding, but spoke in greater detail and with more emotion about day-to-day challenges of breastfeeding in the NICU. 2. Formula feeding evoked less emotion and most nurses viewed it as safe and convenient. 3. Despite infant feeding challenges in the NICU, nurses who had breastfeeding continuing education and/or some positive experiences with breastfeeding: identified evidence based breastfeeding benefits for mothers and babies; emphasized the health-based differences between breast milk and formula; and were more committed to working through difficulties with breastfeeding. CONCLUSIONS: Breastfeeding promotion interventions should include every NICU nurse and incorporate both evidence-based and affective components to overcome day-to-day feeding practice challenges. PRACTICE IMPLICATIONS: Breastfeeding promotion interventions must address conflicting and emotionally evocative infant feeding beliefs of NICU nurses. Effective interventions must be integrated within the realities of bedside feeding practices. PMID- 26601734 TI - Microplasma-assisted rapid synthesis of luminescent nitrogen-doped carbon dots and their application in pH sensing and uranium detection. AB - Developing a simple synthesis method and expanding the application of carbon dots have attracted increasing attention. In this report, we have developed a facile method to synthesize fluorescent carbon dots (CDs) with the assistance of atmospheric-pressure microplasma. The CDs could be produced within a few minutes with no need of high temperature, external energy input, and multistep procedures. The as-prepared CDs had a relatively uniform size of approximately 2.3 nm. The FTIR spectrum and the XPS analysis showed that carbonyl groups and amide groups exist on the surface of CDs. The CDs showed bright blue luminescence and high stability in high salt concentration and low pH without further modification. A pH-dependent PL behavior was observed and could be applied for pH sensing in the range of 3-14. Moreover, the CDs could be utilized as a reagent capable of detecting U(vi) with a low detection limit and high selectivity. PMID- 26601735 TI - An update on primary hepatic solitary fibrous tumor: An examination of the clinical and pathological features of four case studies and a literature review. AB - BACKGROUND: Primary hepatic solitary fibrous tumor is a rare neoplasm that originates in the submesothelial tissue of the liver and is frequently misdiagnosed because of its rarity and unfamiliar characteristics. AIM: To analyze, summarize and update the clinical and pathological features of primary hepatic solitary fibrous tumor. METHODS: We systematically extract the clinical data of 4 cases from the relevant medical records, analyze the macroscopic, histological and immunohistochemical features and review the 59 previously reported cases in the English literatures. RESULTS: The patients' mean age 50.75 years (range, 49-52 years), and the gender ratio was 1:1. The tumors ranged in size from 2.3 to 12.0cm (average diameter, 7.85cm). The tumors were composed of spindle cells with oval, fusiform or banded nuclei that were arranged in bundled, storiform or peculiar random patterns. Mitosis and hemangiopericytoma-like vessels were occasionally observed. Immunohistochemically, three cases were positive for Signal transduction and activator of transcription 6, cluster of differentiation 34, B-cell lymphoma-2 and vimentin but were negative for nervous, muscular and hepatocellular markers. Hepatic lobectomy was performed in all cases, and one patient received adjuvant chemotherapy simultaneously. One patient suffered two recurrences without metastasis, and the remaining patients experienced favorable outcomes. CONCLUSIONS: A consensus on the essential and definite diagnostic criteria for primary hepatic solitary fibrous tumor must be reached in a timely manner. Signal transduction and activator of transcription 6 is a highly sensitive and specific immunohistochemical marker for primary hepatic solitary fibrous tumor. PMID- 26601736 TI - [Spontaneous coronary artery dissection and ST-segment elevation myocardial infarction (STEMI)]. AB - Spontaneous coronary artery dissection (SCAD) is a poorly understood and under diagnosed entity of acute coronary syndrome, affecting predominantly young women. On coronary angiography, the diagnosis remains challenging, particularly in case of intramural hematoma without intimal rupture. Intracoronary imaging, especially by optical coherence tomography (OCT), provides an incremental value in terms of diagnosis and management. We report the case of a 49-year-old woman admitted for STEMI caused by an intramural hematoma. In the discussion part, we aim to review the epidemiology, physiopathology, diagnosis, management and long-term prognosis of SCAD. PMID- 26601737 TI - Pyronaridine-artesunate retreatment for malaria. PMID- 26601738 TI - Safety and efficacy of re-treatments with pyronaridine-artesunate in African patients with malaria: a substudy of the WANECAM randomised trial. AB - BACKGROUND: Sparse data on the safety of pyronaridine-artesunate after repeated treatment of malaria episodes restrict its clinical use. We therefore compared the safety of pyronaridine-artesunate after treatment of the first episode of malaria versus re-treatment in a substudy analysis. METHODS: This planned substudy analysis of the randomised, open-label West African Network for Clinical Trials of Antimalarial Drugs (WANECAM) phase 3b/4 trial was done at six health facilities in Mali, Burkina Faso, and Guinea in patients (aged >=6 months and bodyweight >=5 kg) with uncomplicated microscopically confirmed Plasmodium spp malaria (parasite density <200 000 per MUL blood) and fever or history of fever. The primary safety endpoint was incidence of hepatotoxicity: alanine aminotransferase of greater than five times the upper limit of normal (ULN) or Hy's criteria (alanine aminotransferase or aspartate aminotransferase greater than three times the ULN and total bilirubin more than twice the ULN) after treatment of the first episode of malaria and re-treatment (>=28 days after first treatment) with pyronaridine-artesunate. Pyronaridine-artesunate efficacy was compared with artemether-lumefantrine with the adequate clinical and parasitological response (ACPR) in an intention-to-treat analysis. WANECAM is registered with PACTR.org, number PACTR201105000286876. FINDINGS: Following first treatment, 13 (1%) of 996 patients had hepatotoxicity (including one [<1%] possible Hy's law case) versus two (1%) of 311 patients on re-treatment (neither a Hy's law case). No evidence was found that pyronaridine-artesunate re-treatment increased safety risk based on laboratory values, reported adverse event frequencies, or electrocardiograph findings. For all first treatment or re treatment episodes, pyronaridine-artesunate (n=673) day 28 crude ACPR was 92.7% (95% CI 91.0-94.3) versus 80.4% (77.8-83.0) for artemether-lumefantrine (n=671). After exclusion of patients with PCR-confirmed new infections, ACPR was similar on treatment and re-treatment and greater than 95% at day 28 and greater than 91% at day 42 in both treatment groups. INTERPRETATION: The findings that pyronaridine-artesunate safety and efficacy were similar on first malaria treatment versus re-treatment of subsequent episodes lend support for the wider access to pyronaridine-artesunate as an alternative artemisinin-based combination treatment for malaria in sub-Saharan Africa. FUNDING: European and Developing Countries Clinical Trial Partnership, Medicines for Malaria Venture (Geneva, Switzerland), UK Medical Research Council, Swedish International Development Cooperation Agency, German Ministry for Education and Research, University Claude Bernard (Lyon, France), Malaria Research and Training Centre (Bamako, Mali), Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), Institut de Recherche en Sciences de la Sante (Bobo-Dioulasso, Burkina Faso), and Centre National de Formation et de Recherche en Sante Rurale (Republic of Guinea). PMID- 26601740 TI - Identification of mutations in Korean patients with amyotrophic lateral sclerosis using multigene panel testing. AB - Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease involving motor neurons. Because a growing number of genes have been identified as the genetic etiology of ALS, simultaneous screening of mutations in multiple genes is likely to be more efficient than gene-by-gene testing. In this study, we performed a multigene panel testing by using targeted capture of 18 ALS related genes followed by next-generation sequencing. Using this technique, we tried to identify mutations in 4 index patients with familial ALS and 148 sporadic ALS in Korean population and identified 4 known mutations in SOD1, ALS2, MAPT, and SQSTM1 genes, respectively, and 28 variants of uncertain significance in 9 genes. Among the 28 variants of uncertain significance, 6 missense variants were found in highly conserved residues and were consistently predicted to be deleterious by in silico analyses. These results suggest that multigene panel testing is an effective approach for mutation screening in ALS-related genes. Moreover, the relatively low frequency of mutations in known ALS genes implies marked genetic heterogeneity at least in Korean patients with ALS. PMID- 26601741 TI - Venovenous Extracorporeal Membrane Oxygenation for Cardiorespiratory Failure due to Congenital Diaphragmatic Hernia and Ebstein's Anomaly. PMID- 26601739 TI - Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression. AB - Multiple genetic variants have been linked to risk of Parkinson disease (PD), but known mutations do not explain a large proportion of the total PD cases. Similarly, multiple loci have been associated with PD risk by genome-wide association studies (GWAS). The influence that genetic factors confer on phenotypic diversity remains unclear. Few studies have been performed to determine whether the GWAS loci are also associated with age at onset (AAO) or motor progression. We used 2 PD case-control data sets (Washington University and the Parkinson's Progression Markers Initiative) to determine whether polymorphisms located at the GWAS top hits (GBA, ACMSD/TMEM163, STK39, MCCC1/LAMP3, GAK/TMEM175, SNCA, and MAPT) show association with AAO or motor progression. We found associations between single nucleotide polymorphisms at the GBA and MAPT loci and PD AAO and progression. These findings reinforce the complex genetic basis of PD and suggest that distinct genes and variants explain the genetic architecture of PD risk, onset, and progression. PMID- 26601742 TI - A Novel Technique for Laparoscopically Treating Chronic Pelvic Pain due to Extended Length Ventriculoperitoneal Shunts. PMID- 26601743 TI - Traumatic Pancreaticoduodenectomy and Superior Mesenteric Vein Injury After Blunt Trauma in a Pediatric Patient. PMID- 26601744 TI - Recurrent Pyloric Stenosis: A Rare Entity. PMID- 26601745 TI - Congenital Jejunal Tubular Duplication in a Patient with a Congenital Thoracic Meningocele. PMID- 26601746 TI - An Unusual Case of Metastatic Basal Cell Carcinoma from the Upper Extremity. PMID- 26601747 TI - Mesocolic Hernia: The Achilles Heel of the Retrocolic Gastric Bypass. PMID- 26601748 TI - Multidisciplinary Approach to Management of Abdominal Aortic Aneurysms on Texas Mexico Border. PMID- 26601749 TI - Occult Injury in the Context of Selective Use of Computed Tomography (CT) in Pediatric Thoracic Trauma. PMID- 26601750 TI - Role of Community Program Graduates in the Surgical Workforce: Can Recruitment Efforts Be Focused to Fulfill Future Demands for General Surgeons? PMID- 26601751 TI - Perivascular Epithelioid Cell Tumor of the Liver. PMID- 26601752 TI - The development of multisensory body representation and awareness continues to 10 years of age: Evidence from the rubber hand illusion. AB - Recent research using the "rubber hand illusion" shows that the multisensory processes underlying body representations are markedly different in children of 4 to 9years and adults. In representing the position of their own hand in external space, children of this age rely more on the sight of the hand, and less on its proprioceptively felt position, than adults do. The current study investigated when during later childhood the balance between visual and proprioceptive inputs reaches an adult-like weighting. After inducing the rubber hand illusion in 10- to 13-year-olds, we asked participants to point, with eyes closed, to the perceived position of their hand. We found that pointing responses reached adult levels at 10 to 11years, showing that at this age children perceive hand location using an adult-like balance of sensory cues. We conclude that the multisensory foundations of the bodily self undergo a protracted period of development through early and mid-childhood, reaching an adult state by 10 to 11years. PMID- 26601754 TI - Acute respiratory distress syndrome after orthotopic liver transplantation. AB - PURPOSE: Acute respiratory distress syndrome (ARDS) is a devastating complication with substantial mortality. The aims of this study were to identify the incidence, preoperative and intraoperative risk factors, and impact of ARDS on outcomes in patients after orthotopic liver transplantation (OLT). MATERIALS AND METHODS: Adult OLT patients between January 2004 and October 2013 at our center were included. Postoperative ARDS was determined using the criteria proposed by the Berlin Definition. Multivariate logistic models were used to identify preoperative and intraoperative risk factors for ARDS. RESULTS: Of 1726 patients during the study period, 71 (4.1%) developed ARDS. In the preoperative model, encephalopathy (odds ratio [OR], 2.22; P = .022), preoperative requirement of intubation (OR, 2.06; P = .020), and total bilirubin (OR, 1.02; P = .003) were independent risk factors. In the intraoperative model, large pressor bolus was the sole risk factor for ARDS (OR, 2.69; P = .001). Postoperatively, patients with ARDS had a 2-fold increase in 1-year mortality, mechanical ventilation time, and length of hospital stay. CONCLUSIONS: Acute respiratory distress syndrome occurred at a rate of 4.1% following OLT in adult patients and was associated with preoperative encephalopathy, requirement of intubation, and total bilirubin and intraoperative large boluses of pressors. Acute respiratory distress syndrome was associated with increased mortality, longer ventilation time, and hospital stay. PMID- 26601755 TI - How to delineate obstructive sleep apnea and continuous positive airway pressure link in postoperative atrial fibrillation conundrum? PMID- 26601753 TI - Bacterial diversity is strongly associated with historical penguin activity in an Antarctic lake sediment profile. AB - Current penguin activity in Antarctica affects the geochemistry of sediments and their microbial communities; the effects of historical penguin activity are less well understood. Here, bacterial diversity in ornithogenic sediment was investigated using high-throughput pyrosequencing. The relative abundances of dominant phyla were controlled by the amount of historical penguin guano deposition. Significant positive correlations were found between both the bacterial richness and diversity, and the relative penguin number (p < 0.01); this indicated that historical penguin activity drove the vertical distribution of the bacterial communities. The lowest relative abundances of individual phyla corresponded to lowest number of penguin population at 1,800-2,300 yr BP during a drier and colder period; the opposite was observed during a moister and warmer climate (1,400-1,800 yr BP). This study shows that changes in the climate over millennia affected penguin populations and the outcomes of these changes affect the sediment bacterial community today. PMID- 26601756 TI - Role of RuO2(100) in surface oxidation and CO oxidation catalysis on Ru(0001). AB - We have studied the oxidation of the Ru(0001) surface by in situ microscopy during exposure to NO2, an efficient source of atomic oxygen, at elevated temperatures. In a previous investigation [Flege et al., Phys. Rev. B: Condens. Matter Mater. Phys., 2008, 78, 165407], at O coverages exceeding 1 monolayer, using the combination of intensity-voltage (I(V)) low-energy electron microscopy (LEEM) and multiple scattering calculations for the (00) beam in the very-low energy range (E<= 50 eV) we identified three surface components during the initial Ru oxidation: a (1 * 1)-O chemisorption phase, the RuO2(110) oxide phase, and a surface oxide structure characterized by a trilayer O-Ru-O stacking. Here, we use dark-field LEEM imaging and micro-illumination low-energy electron diffraction in the range of 100 to 400 eV to show that this trilayer phase is actually a RuO2(100)-(1 * 1) phase with possibly mixed O and Ru surface terminations. This identification rationalizes the thermodynamic stability of this phase at elevated temperatures and is consistent with the observation of catalytic activity of the phase in CO oxidation. PMID- 26601757 TI - Drugs at the campsite: Socio-spatial relations and drug use at music festivals. AB - BACKGROUND: Music festivals have received relatively little research attention despite being key sites for alcohol and drug use among young people internationally. Research into music festivals and the social contexts of drug use more generally, has tended to focus on social and cultural processes without sufficient regard for the mediating role of space and spatial processes. METHODS: Adopting a relational approach to space and the social, from Actor-Network Theory and human geography, I examine how socio-spatial relations are generated in campsites at multiple-day music festivals. The data are drawn from ethnographic observations at music festivals around Melbourne, Australia; interviews with 18 23 year olds; and participant-written diaries. RESULTS: Through the analysis, the campsite is revealed as a space in process, the making of which is bound up in how drug use unfolds. Campsite relations mediate the formation of drug knowledge and norms, informal harm reduction practices, access to and exchange of drugs, and rest and recovery following drug use. CONCLUSIONS: Greater attendance to socio-spatial relations affords new insights regarding how festival spaces and their social effects are generated, and how they give rise to particular drug use practices. These findings also point to how festival harm reduction strategies might be enhanced through the promotion of enabling socio-spatial relations. PMID- 26601758 TI - VenomKB, a new knowledge base for facilitating the validation of putative venom therapies. AB - Animal venoms have been used for therapeutic purposes since the dawn of recorded history. Only a small fraction, however, have been tested for pharmaceutical utility. Modern computational methods enable the systematic exploration of novel therapeutic uses for venom compounds. Unfortunately, there is currently no comprehensive resource describing the clinical effects of venoms to support this computational analysis. We present VenomKB, a new publicly accessible knowledge base and website that aims to act as a repository for emerging and putative venom therapies. Presently, it consists of three database tables: (1) Manually curated records of putative venom therapies supported by scientific literature, (2) automatically parsed MEDLINE articles describing compounds that may be venom derived, and their effects on the human body, and (3) automatically retrieved records from the new Semantic Medline resource that describe the effects of venom compounds on mammalian anatomy. Data from VenomKB may be selectively retrieved in a variety of popular data formats, are open-source, and will be continually updated as venom therapies become better understood. PMID- 26601759 TI - Chitosan oligosaccharides alleviate cognitive deficits in an amyloid-beta1-42 induced rat model of Alzheimer's disease. AB - AIM: The objective of the present study was two-fold: (i) to evaluate the modulating effects of chitosan oligosaccharides (COS) on cognitive deficits and (ii) to explore their underlying molecular mechanisms. METHODS: The Morris water maze and passive avoidance tests were used to determine the neuroprotective effects of COS on Abeta1-42-induced learning and memory impairments. Biochemical methods were then used to assess COS antioxidant activity in hippocampus, including effects on apoptosis (TUNEL assay) and changes in inflammatory mediators (immunohistochemistry). RESULTS: Orally administered COS at 200, 400, or 800 mg/kg doses were effective at reducing the learning and memory deficits in Abeta1-42-induced rats. These same doses were also able to ameliorate neuronal apoptosis. The neuroprotective effects of COS were closely associated with its ability to inhibit oxidative stress. This was shown with decreasing levels of malondialdehyde, 8-hydroxy-2'-deoxyguanosine and increasing levels of glutathione peroxidase and super oxide dismutase activities. COS were also shown to suppress the inflammatory response and decrease measures of inflammation via a decrease in the release of proinflammatory cytokines (e.g. interleukin-1beta and tumor necrosis factor-alpha). CONCLUSION: Taken together, our findings suggest that COS have beneficial effects on the cognitive impairments seen in an Abeta1-42-induced model of Alzheimer's disease via inhibiting oxidative stress and neuroinflammatory responses. PMID- 26601760 TI - The C-terminal alpha-helices of mammalian Hsc70 play a critical role in the stabilization of alpha-synuclein binding and inhibition of aggregation. AB - Protein misfolding, followed by aggregation and amyloid formation is an underlying pathological hallmark in a number of prevalent diseases, including Parkinson's (PD), Alzheimer's (AD) and Type 2 diabetes (T2D). In the case of PD, the aggregation of alpha-synuclein protein (alpha-syn) has been shown to be highly cytotoxic and to play a key role in the death of dopaminergic cells. Thus, inhibition of the aggregation process may be considered as an attractive avenue for therapeutic intervention. In this respect, molecular chaperones, known to promote proper folding of proteins, are able to inhibit protein aggregation thus preventing amyloid formation. In this work, the effect of the constitutively expressed chaperone Hsc70 and its various domains on alpha-syn aggregation have been investigated using different approaches. The results show that the C terminal domain alone (residues 386-646) is as efficient in inhibiting alpha-syn aggregation as the entire Hsc70 protein, by increasing the lag phase for alpha syn oligomeric nucleus formation, suggesting that the chaperone interacts with and stabilizes alpha-syn monomers and/or small aggregates. Deletion of the C terminal helices (residues 510-646), which are known to play the role of a lid locking target peptide ligands in the peptide-binding site of the chaperone, strongly reduced the efficiency of inhibition of alpha-syn aggregation indicating that these helices play an essential in stabilizing the interaction between Hsc70 and alpha-syn. Furthermore, the effects of Hsc70 and its structural domains on aggregation appear to correlate with those on cytotoxicity, by reducing the fraction of alpha-syn toxic species to various degrees. Together these results suggest a mechanism in which inhibition of synuclein aggregation is the result of monomeric synuclein binding to the chaperone as any monomeric target unfolded protein or peptide binding to the chaperone. PMID- 26601761 TI - Antioxidant property of water-soluble polysaccharides from Poria cocos Wolf using different extraction methods. AB - Poria cocos Wolf is a popular traditional medicinal plant that has invigorating activity. Water-soluble polysaccharides (PCPs) are its main active components. In this study, four different methods were used to extract PCPs, which include hot water extraction (PCP-H), ultrasonic-assisted extraction (PCP-U), enzyme-assisted extraction (PCP-E) and microwave-assisted extraction (PCP-M). Their chemical compositions and structure characterizations were compared. In vitro antioxidant activities were studied on the basis of DPPH radical, hydroxyl radical, reducing power and metal chelating ability. The results showed that PCPs were composed of mannose, glucose, galactose, and arabinose, and had typical IR spectra characteristics of polysaccharides. Compared with other PCPs, PCP-M had lower neutral sugar content, higher mannose content and higher uronic acid content. The molecular weight were determined as PCP-E=2 mA; n = 15, 60%) stimulation levels were analyzed. RESULTS: At 12 months, peak TWA levels were reduced by 29% from 71.0 +/- 4.6 to 50.5 +/- 1.8 MUV (P < .0001). The number of patients with severely abnormal TWA (>=60 MUV) was reduced by 76% from 17 to 4 (P < .0005), and the number of patients with nonsustained VT decreased by 73% from 11 to 3 (P < .025). HRT slope (P < .025), high frequency heart rate variability (HRV) (P = .05), and square root of the mean squared differences of successive normal-to-normal interval HRV (P = .013) increased. The mean heart rate derived from 24-hour Holter electrocardiograms decreased by 10% from 77 +/- 2 to 69 +/- 2 beats/min (P = .0002). HRT onset was unchanged. CONCLUSION: Chronic ART in patients with symptomatic heart failure improves cardiac electrical stability, as reflected by reduced TWA levels and heart rate, suppresses VT, and increases baroreceptor sensitivity. These observations deserve study in a larger population. PMID- 26601771 TI - Drowning is an apparent and unexpected recurrent cause of mass mortality of Common starlings (Sturnus vulgaris). AB - Drowning is infrequently reported as a cause of death of wild birds and such incidents typically involve individual, rather than multiple, birds. Over a 21 year period (1993 to 2013 inclusive), we investigated 12 incidents of mortality of multiple (2 - 80+) Common starlings (Sturnus vulgaris) in Great Britain that appeared to be due to drowning. More than ten birds were affected in ten of these reported incidents. These incidents always occurred during the spring and early summer months and usually involved juvenile birds. In all cases, circumstantial evidence and post-mortem examinations indicated drowning to be the most likely cause of death with no underlying disease found. A behavioural explanation seems likely, possibly related to the gregarious nature of this species combined with juvenile inexperience in identifying water hazards. A review of data from the ringed bird recovery scheme across Great Britain (1909-2013 inclusive) of both starlings and Common blackbirds (Turdus merula), also a common garden visitor, identified additional suspected drowning incidents, which were significantly more common in the former species, supporting a species predisposition to drowning. For each species there was a marked seasonal peak from April to August. Drowning should be included as a differential diagnosis when investigating incidents of multiple starling mortality, especially of juveniles. PMID- 26601772 TI - Role of sex hormones in hypercapnia-induced activation of the locus coeruleus in female and male rats. AB - The locus coeruleus (LC) has been suggested as a CO2 chemoreceptor site in mammals. Most of the studies involving the role of the LC in hypercapnic ventilatory responses have been performed in males. Since ovarian steroids modulate the activity of LC neurons and females have a different respiratory response to CO2 than males, we evaluated the activity of LC noradrenergic neurons during normocapnia and hypercapnia in female and male rats with distinct sex hormone levels. Ovariectomized (OVX), estradiol (E2)-treated ovariectomized (OVX+E2) and female rats on the diestrous day of the estrous cycle were evaluated. Concurrently, males were investigated as gonad-intact, orchidectomized (ORX), testosterone (T)-treated ORX (ORX+T), and E2-treated ORX (ORX+E2). Activation of LC neurons was determined by double-label immunohistochemistry to c Fos and tyrosine hydroxylase (TH). Hypercapnia induced by 7% CO2 increased the number of c-Fos/TH-immunoreactive (ir) neurons in the LC of all groups when compared to air exposure. Hypercapnia-induced c-Fos expression did not differ between diestrous females and intact male rats. In the OVX+E2 group, there was attenuation in the c-Fos expression during normocapnia compared with OVX rats, but CO2 responsiveness was not altered. Moreover, in ORX rats, neither T nor E2 treatments changed c-Fos expression in LC noradrenergic neurons. Thus, in female rats, E2 reduces activation of LC noradrenergic neurons, whereas in males, sex hormones do not influence the LC activity. PMID- 26601773 TI - Combined therapy with m-TOR-dependent and -independent autophagy inducers causes neurotoxicity in a mouse model of Machado-Joseph disease. AB - A major pathological hallmark in several neurodegenerative disorders, like polyglutamine disorders (polyQ), including Machado-Joseph disease (MJD), is the formation of protein aggregates. MJD is caused by a CAG repeat expansion in the ATXN3 gene, resulting in an abnormal protein, which is prone to misfolding and forms cytoplasmic and nuclear aggregates within neurons, ultimately inducing neurodegeneration. Treatment of proteinopathies with drugs that up-regulate autophagy has shown promising results in models of polyQ diseases. Temsirolimus (CCI-779) inhibits the mammalian target of rapamycin (m-TOR), while lithium chloride (LiCl) acts by inhibiting inositol monophosphatase, both being able to induce autophagy. We have previously shown that chronic treatment with LiCl (10.4 mg/kg) had limited effects in a transgenic MJD mouse model. Also, others have shown that CCI-779 had mild positive effects in a different mouse model of the disease. It has been suggested that the combination of mTOR-dependent and independent autophagy inducers could be a more effective therapeutic approach. To further explore this avenue toward therapy, we treated CMVMJD135 transgenic mice with a conjugation of CCI-779 and LiCl, both at concentrations known to induce autophagy and not to be toxic. Surprisingly, this combined treatment proved to be deleterious to both wild-type (wt) and transgenic animals, failing to rescue their neurological symptoms and actually exerting neurotoxic effects. These results highlight the possible dangers of manipulating autophagy in the nervous system and suggest that a better understanding of the potential disruption in the autophagy pathway in MJD is required before successful long-term autophagy modulating therapies can be developed. PMID- 26601774 TI - Urodynamic function during sleep-like brain states in urethane anesthetized rats. AB - The aim was to investigate urodynamic parameters and functional excitability of the periaqueductal gray matter (PAG) during changes in sleep-like brain states in urethane anesthetized rats. Simultaneous recordings of detrusor pressure, external urethral sphincter (EUS) electromyogram (EMG), cortical electroencephalogram (EEG), and single-unit activity in the PAG were made during repeated voiding induced by continuous infusion of saline into the bladder. The EEG cycled between synchronized, high-amplitude slow wave activity (SWA) and desynchronized low-amplitude fast activity similar to slow wave and 'activated' sleep-like brain states. During (SWA, 0.5-1.5 Hz synchronized oscillation of the EEG waveform) voiding became more irregular than in the 'activated' brain state (2-5 Hz low-amplitude desynchronized EEG waveform) and detrusor void pressure threshold, void volume threshold and the duration of bursting activity in the external urethral sphincter EMG were raised. The spontaneous firing rate of 23/52 neurons recorded within the caudal PAG and adjacent tegmentum was linked to the EEG state, with the majority of responsive cells (92%) firing more slowly during SWA. Almost a quarter of the cells recorded (12/52) showed phasic changes in firing rate that were linked to the occurrence of voids. Inhibition (n=6), excitation (n=4) or excitation/inhibition (n=2) was seen. The spontaneous firing rate of 83% of the micturition-responsive cells was sensitive to changes in EEG state. In nine of the 12 responsive cells (75%) the responses were reduced during SWA. We propose that during different sleep-like brain states changes in urodynamic properties occur which may be linked to changing excitability of the micturition circuitry in the periaqueductal gray. PMID- 26601775 TI - Is the interaction between fatty acids and tryptophan responsible for the efficacy of a ketogenic diet in epilepsy? The new hypothesis of action. AB - The effects of a ketogenic diet in controlling seizure activity have been proven in many studies, although its mechanism of action remains elusive in many regards. We hypothesize that the ketogenic diet may exert its antiepileptic effects by influencing tryptophan (TRP) metabolism. The aim of this study was to investigate the influence of octanoic and decanoic fatty acids (FAs), the main components in the MCT diet (medium-chain triglyceride diet, a subtype of the ketogenic diet), on the metabolism of TRP, the activity of the kynurenic pathway and the concentrations of monoamines and amino acids, including branched-chain amino acids (BCAA) and aromatic amino acids (AAA) in rats. The acute effects of FA on the sedation index and hippocampal electrical after-discharge threshold were also assessed. We observed that intragastric administration of FA increased the brain levels of TRP and the central and peripheral concentrations of kynurenic acid (KYNA), as well as caused significant changes in the brain and plasma concentrations of BCAA and AAA. We found that the administration of FA clearly increased the seizure threshold and induced sedation. Furthermore, we have demonstrated that blocking TRP passage into the brain abolished these effects of FA but had no similar effect on the formation of ketone bodies. Given that FAs are major components of a ketogenic diet, it is suggested that the anticonvulsant effects of a ketogenic diet may be at least partly dependent on changes in TRP metabolism. We also propose a more general hypothesis concerning the intracellular mechanism of the ketogenic diet. PMID- 26601776 TI - Increase of transcription factor EB (TFEB) and lysosomes in rat DRG neurons and their transportation to the central nerve terminal in dorsal horn after nerve injury. AB - In the spinal dorsal horn (DH), nerve injury activates microglia and induces neuropathic pain. Several studies clarified an involvement of adenosine triphosphate (ATP) in the microglial activation. However, the origin of ATP together with the release mechanism is unclear. Recent in vitro study revealed that an ATP marker, quinacrine, in lysosomes was released from neurite terminal of dorsal root ganglion (DRG) neurons to extracellular space via lysosomal exocytosis. Here, we demonstrate a possibility that the lysosomal ingredient including ATP released from DRG neurons by lysosomal-exocytosis is an additional source of the glial activation in DH after nerve injury. After rat L5 spinal nerve ligation (SNL), mRNA for transcription factor EB (TFEB), a transcription factor controlling lysosomal activation and exocytosis, was induced in the DRG. Simultaneously both lysosomal protein, LAMP1- and vesicular nuclear transporter (VNUT)-positive vesicles were increased in L5 DRG neurons and ipsilateral DH. The quinacrine staining in DH was increased and co-localized with LAMP1 immunoreactivity after nerve injury. In DH, LAMP1-positive vesicles were also co localized with a peripheral nerve marker, Isolectin B4 (IB4) lectin. Injection of the adenovirus encoding mCherry-LAMP1 into DRG showed that mCherry-positive lysosomes are transported to the central nerve terminal in DH. These findings suggest that activation of lysosome synthesis including ATP packaging in DRG, the central transportation of the lysosome, and subsequent its exocytosis from the central nerve terminal of DRG neurons in response to nerve injury could be a partial mechanism for activation of microglia in DH. This lysosome-mediated microglia activation mechanism may provide another clue to control nociception and pain. PMID- 26601777 TI - Nicotine-induced plasticity in the retinocollicular pathway: Evidence for involvement of amyloid precursor protein. AB - During early postnatal development retinocollicular projections undergo activity dependent synaptic refinement that results in the formation of precise topographical maps in the visual layers of the superior colliculus (SC). Amyloid Precursor Protein (APP) is a widely expressed transmembrane glycoprotein involved in the regulation of several aspects of neural development, such as neurite outgrowth, synapse formation and plasticity. Stimulation of cholinergic system has been found to alter the expression and processing of APP in different cell lines. Herein, we investigated the effect of nicotine on the development of retinocollicular pathway and on APP metabolism in the SC of pigmented rats. Animals were submitted to intracranial Elvax implants loaded with nicotine or phosphate-buffered saline (vehicle) at postnatal day (PND) 7. The ipsilateral retinocollicular pathway of control and experimental groups was anterogradely labeled either 1 or 3 weeks after surgery (PND 14 or PND 28). Local nicotine exposure produces a transitory sprouting of uncrossed retinal axons outside their main terminal zones. Nicotine also increases APP content and its soluble neurotrophic fragment sAPPalpha. Furthermore, nicotine treatment upregulates nicotinic acetylcholine receptor alpha7 and beta2 subunits. Taken together, these data indicate that nicotine disrupts the ordering and topographic mapping of axons in the retinocollicular pathway and facilitates APP processing through the nonamyloidogenic pathway, suggesting that sAPPalpha may act as a trophic agent that mediates nicotine-induced morphological plasticity. PMID- 26601778 TI - Counter-regulation of the AP-1 monomers pATF2 and Fos: Molecular readjustment of brainstem neurons in hearing and deaf adult rats after electrical intracochlear stimulation. AB - Expression of the immediate-early gene fos (also known as c-fos) and phosphorylation of the product of the early response gene atf2 (pATF2) in the adult auditory brainstem can be modulated by electrical intracochlear stimulation. The Fos and pATF2 proteins are competitive monomers of the heterodimeric activator protein-1 (AP-1) transcription factor that triggers the expression of genes related to neural plasticity. Our previous findings showed that the stimulation-induced spatio-temporal pattern of Fos expression in the adult auditory system depends on hearing experience. In this study, we aimed to identify a possible correlation of pATF2 and Fos expression. Adult normal hearing and neonatally deafened rats were unilaterally stimulated with a cochlear implant (CI) for 45 min, 73 min, or 2h. The numbers of Fos- and pATF2-positive neurons in the anteroventral cochlear nucleus (AVCN), the lateral superior olive (LSO), and the central inferior colliculus (CIC) were evaluated. Following stimulation, an increased Fos expression was demonstrated in all these regions in hearing and deaf rats. However, in neonatally deafened rats, significantly more Fos-positive neurons emerged that did not obey a tonotopic order. Independent of hearing experience, Fos expression correlated with a locally matching decrease of pATF2 expression in AVCN and LSO, but not in CIC. We suggest that these changes in gene expression result in a shift of AP-1 dimer composition from ATF2:Jun to Fos:Jun. This change in AP-1 constellation is expected to invoke different transcriptional cascades leading to distinct modes of tissue reorganization and plasticity responses in the mature central auditory system under stimulation. PMID- 26601779 TI - Malignant sublingual gland tumors: demographics, prognostic factors, and treatment outcomes. AB - OBJECTIVE: To determine the demographic characteristics, prognostic factors, and optimal treatment modalities of patients diagnosed with malignant primary tumors of the sublingual gland. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) registry contains 210 patients diagnosed with sublingual gland tumors in the SEER database. Kaplan-Meier and multivariate Cox regression analysis were performed on age, sex, race, histologic subtype, stage, and treatment modality. RESULTS: Kaplan-Meier analysis found an overall survival and disease-specific survival at 5 years of 69% and 83%, respectively. Multivariate analysis demonstrated that age, sex, stage, and surgery were predictors of overall survival, whereas stage was a predictor of disease-specific survival. CONCLUSIONS: Here we report, to our knowledge, the largest study to date investigating demographic characteristics, prognostic factors, and treatment modalities of patients diagnosed with primary malignant tumors of the sublingual gland. Increased age and stage correlated with decreased survival, whereas female gender and surgical therapy correlated with increased survival in the overall population. Radiation therapy for patients diagnosed with adenoid cystic carcinoma in the sublingual gland was correlated with increased survival. PMID- 26601780 TI - Levy Walk Navigation in Complex Networks: A Distinct Relation between Optimal Transport Exponent and Network Dimension. AB - We investigate, for the first time, navigation on networks with a Levy walk strategy such that the step probability scales as pij ~ dij(-alpha), where dij is the Manhattan distance between nodes i and j, and alpha is the transport exponent. We find that the optimal transport exponent alpha(opt) of such a diffusion process is determined by the fractal dimension df of the underlying network. Specially, we theoretically derive the relation alpha(opt) = df + 2 for synthetic networks and we demonstrate that this holds for a number of real-world networks. Interestingly, the relationship we derive is different from previous results for Kleinberg navigation without or with a cost constraint, where the optimal conditions are alpha = df and alpha = df + 1, respectively. Our results uncover another general mechanism for how network dimension can precisely govern the efficient diffusion behavior on diverse networks. PMID- 26601781 TI - Similarities and differences between patients fulfilling axial and peripheral ASAS criteria for spondyloarthritis: Results from the Esperanza Cohort. AB - OBJECTIVES: To describe and compare the characteristics of patients fulfilling the ASAS criteria for axial Spondyloarthritis (SpA) versus peripheral SpA . METHODS: Baseline dataset from the ESPeranza cohort was used. In this programme, patients were referred to rheumatologist in case of (1) age <45 years, (2) symptoms duration 3-24 months and (3) inflammatory back pain (IBP) or asymmetrical arthritis or spinal/joint pain plus >=1 SpA features. The programme was developed between April 2008 and June 2011. Data from 377 patients fulfilling the ASAS classification criteria for SpA were used. Descriptive analysis was employed to compare demographic and disease characteristics between patients with axial SpA versus peripheral SpA. RESULTS: Two hundred and ninety (77.2%) patients were classified as axial SpA (109 ankylosing spondylitis and 182 non-radiographic SpA) while 86 (22.8%) patients had peripheral SpA. Age, gender distribution and degree of disease activity were similar in both groups. Patients with axial SpA were referred after having symptoms for a longer period and had more frequently uveitis and positive HLA-B27. Patients with peripheral SpA had in a greater percentage more working disability and had more frequently enthesitis, psoriasis, dactylitis and inflammatory bowel disease (IBD). CONCLUSIONS: The ASAS classification criteria for SpA seem to classify patients within the same spectrum of disease beyond the predominant symptoms at onset. However, despite having similar degree of disease activity, time to be referred to rheumatologist is increased in axial SpA patients compared with peripheral SpA patients. PMID- 26601782 TI - Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia. AB - Hematopoietic insufficiency is the hallmark of acute myeloid leukemia (AML) and predisposes patients to life-threatening complications such as bleeding and infections. Addressing the contribution of mesenchymal stromal cells (MSC) to AML induced hematopoietic failure we show that MSC from AML patients (n=64) exhibit significant growth deficiency and impaired osteogenic differentiation capacity. This was molecularly reflected by a specific methylation signature affecting pathways involved in cell differentiation, proliferation and skeletal development. In addition, we found distinct alterations of hematopoiesis regulating factors such as Kit-ligand and Jagged1 accompanied by a significantly diminished ability to support CD34+ hematopoietic stem and progenitor cells in long-term culture-initiating cells (LTC-ICs) assays. This deficient osteogenic differentiation and insufficient stromal support was reversible and correlated with disease status as indicated by Osteocalcin serum levels and LTC-IC frequencies returning to normal values at remission. In line with this, cultivation of healthy MSC in conditioned medium from four AML cell lines resulted in decreased proliferation and osteogenic differentiation. Taken together, AML-derived MSC are molecularly and functionally altered and contribute to hematopoietic insufficiency. Inverse correlation with disease status and adoption of an AML-like phenotype after exposure to leukemic conditions suggests an instructive role of leukemic cells on bone marrow microenvironment. PMID- 26601783 TI - Interferon-alpha for the therapy of myeloproliferative neoplasms: targeting the malignant clone. AB - Interferon alpha (IFN-alpha) has been used for over 30 years to treat myeloproliferative neoplasms (MPNs). IFN-alpha was shown to induce clinical, hematological, molecular and histopathological responses in small clinical studies. Such combined efficacy has never been achieved with any other drug to date in such a significant proportion of patients. However, toxicity remains a limitation to its broader use despite the development of pegylated forms with better tolerance. Several on going phase 3 studies of peg- IFN-alpha versus hydroxyurea will help to define its exact place in MPN management. IFN-alpha efficacy is likely the consequence of a broad range of biological properties, including enhancement of immune response, direct effects on malignant cells and ability to cycle dormant malignant stem cells. However, comprehensive elucidation of its mechanism of action is still lacking. Sustained clinical, molecular and morphological responses after IFN-alpha discontinuation raised the hope that this drug could eradicate MPN. There is now consistent evidence showing that IFN-alpha is able to eliminate malignant clones harboring JAK2V617F or Calreticulin mutations. However, the molecular complexity of these diseases could hamper IFN alpha efficacy, as the presence of additional non-driver mutations, like in the TET2 gene, could be associated with resistance to IFN-alpha. Therefore, combined therapy with another targeted agent could be required to eradicate MPN, and the best IFN-alpha companion for achieving this challenge remains to be determined. PMID- 26601785 TI - Effect of conservation efforts and ecological variables on waterbird population sizes in wetlands of the Yangtze River. AB - Forage quality and availability, climatic factors, and a wetland's conservation status are expected to affect the densities of wetland birds. However, the conservation effectiveness is often poorly studied. Here, using twelve years' census data collected from 78 wetlands in the Yangtze River floodplain, we aimed to understand the effect of these variables on five Anatidae species, and evaluate the effectiveness of the conservation measures by comparing population trends of these species among wetlands that differ in conservations status. We showed that the slope angle of a wetland and the variation thereof best explain the differences in densities of four species. We also found that the population abundances of the Anatidae species generally declined in wetlands along the Yangtze River floodplain over time, with a steeper decline in wetlands with a lower protection status, indicating that current conservation policies might deliver benefits for wintering Anatidae species in China, as population sizes of the species were buffered to some extent against decline in numbers in wetlands with a higher level protection status. We recommend several protection measures to stop the decline of these Anatidae species in wetlands along the Yangtze River floodplain, which are of great importance for the East Asian-Australasian Flyway. PMID- 26601784 TI - The multifaceted functions of C/EBPalpha in normal and malignant haematopoiesis. AB - The process of blood formation, haematopoiesis, depends upon a small number of haematopoietic stem cells (HSCs) that reside in the bone marrow. Differentiation of HSCs is characterised by decreased expression of genes associated with self renewal accompanied by a stepwise activation of genes promoting differentiation. Lineage branching is further directed by groups of cooperating and counteracting genes forming complex networks of lineage-specific transcription factors. Imbalances in such networks can result in blockage of differentiation, lineage reprogramming and malignant transformation. CCAAT/enhancer-binding protein-alpha (C/EBPalpha) was originally identified 30 years ago as a transcription factor that binds both promoter and enhancer regions. Most of the early work focused on the role of C/EBPalpha in regulating transcriptional processes as well as on its functions in key differentiation processes during liver, adipogenic and haematopoietic development. Specifically, C/EBPalpha was shown to control differentiation by its ability to coordinate transcriptional output with cell cycle progression. Later, its role as an important tumour suppressor, mainly in acute myeloid leukaemia (AML), was recognised and has been the focus of intense studies by a number of investigators. More recent work has revisited the role of C/EBPalpha in normal haematopoiesis, especially its function in HSCs, and also started to provide more mechanistic insights into its role in normal and malignant haematopoiesis. In particular, the differential actions of C/EBPalpha isoforms, as well as its importance in chromatin remodelling and cellular reprogramming, are beginning to be elucidated. Finally, recent work has also shed light on the dichotomous function of C/EBPalpha in AML by demonstrating its ability to act as both a tumour suppressor and promoter. In the present review, we will summarise the current knowledge on the functions of C/EBPalpha during normal and malignant haematopoiesis with special emphasis on the recent work. PMID- 26601786 TI - The effects of distraction and reappraisal on children's parasympathetic regulation of sadness and fear. AB - Children commonly experience negative emotions like sadness and fear, and much recent empirical attention has been devoted to understanding the factors supporting and predicting effective emotion regulation. Respiratory sinus arrhythmia (RSA), a cardiac index of parasympathetic function, has emerged as a key physiological correlate of children's self-regulation. But little is known about how children's use of specific cognitive emotion regulation strategies corresponds to concurrent parasympathetic regulation (i.e., RSA reactivity while watching an emotion-eliciting video). The current study describes an experimental paradigm in which 101 5- and 6-year-olds were randomly assigned to one of three different emotion regulation conditions: Control, Distraction, or Reappraisal. All children watched a sad film and a scary film (order counterbalanced), and children in the Distraction and Reappraisal conditions received instructions to deploy the target strategy to manage sadness/fear while they watched. Consistent with predictions, children assigned to use either emotion regulation strategy showed greater RSA augmentation from baseline than children in the Control condition (all children showed an overall increase in RSA levels from baseline), suggesting enhanced parasympathetic calming when children used distraction or reappraisal to regulate sadness and fear. But this pattern was found only among children who viewed the sad film before the scary film. Among children who viewed the scary film first, reappraisal promoted marginally better parasympathetic regulation of fear (no condition differences emerged for parasympathetic regulation of sadness when the sad film was viewed second). Results are discussed in terms of their implications for our understanding of children's emotion regulation and affective physiology. PMID- 26601787 TI - Mood congruity and episodic memory in young children. AB - Although mood congruity effects on episodic memory have been reported extensively in adults, they have not been reported for children younger than 10 years. The current research investigated mood congruity effects in story recall using an embodied approach to mood induction involving a facial manipulation task with 3- and 4-year-old children. Participants held a chopstick or a popsicle stick in their mouths in a way to either produce or inhibit a smile while they listened to a story featuring happy events for a happy character and sad events for a sad character. Children's mood ratings before and after mood induction indicated that mood became more positive in the smile condition, with no change in the no smile condition. Children in the smile condition, but not in the no smile condition, remembered more about the happy character than the sad character in the story. These results extend mood congruity effects to 3- and 4-year olds, suggesting that at this age representations of emotion interact with basic memory processes. Moreover, the efficacy of reenactment of sensorimotor components of emotion in modifying mood is consistent with embodied representation of emotion during early childhood. PMID- 26601788 TI - Orthostatic hypotension and diabetes are dangerous companions. PMID- 26601789 TI - Is serum Klotho protective against atherosclerosis in patients with type 1 diabetes mellitus? AB - OBJECTIVE: Klotho deficiency is associated with several metabolic disorders. Two dimensional (2D) longitudinal strain (LS) of left ventricle (LV), carotid artery intima-media thickness (CIMT), flow-mediated dilation (FMD) of brachial artery and epicardial fat thickness (EFT) have been reported to be early predictors of atherosclerosis. We aimed to investigate the relationship between serum Klotho levels and these early predictors of atherosclerosis in patients with type 1 diabetes mellitus (DM). METHODS: The study included 45 type 1 diabetic patients and 35 controls. Serum Klotho levels were determined by ELISA method. The patient group was also divided into two subgroups according to serum Klotho levels: high (HK) and low Klotho (LK) groups. EFT, CIMT and FMD were measured according to appropriate recommendations. Speckle tracking analysis was performed using the Echopac software. RESULTS: The patient group had significantly lower serum Klotho (p=0.001), FMD (p<0.001) and LS of LV (p<0.001) values, but larger EFT (p<0.001) and CIMT (p<0.001) values than controls. LK subgroup had also significantly lower FMD (p<0.001) and LS of LV (p<0.001) but larger EFT (p=0.002) and CIMT (p<0.001) values than HK subgroup. CONCLUSION: Serum Klotho may have a protective effect against atherosclerosis and endothelial dysfunction in type 1 DM. PMID- 26601790 TI - Operando Analysis of NiFe and Fe Oxyhydroxide Electrocatalysts for Water Oxidation: Detection of Fe4+ by Mossbauer Spectroscopy. AB - Nickel-iron oxides/hydroxides are among the most active electrocatalysts for the oxygen evolution reaction. In an effort to gain insight into the role of Fe in these catalysts, we have performed operando Mossbauer spectroscopic studies of a 3:1 Ni:Fe layered hydroxide and a hydrous Fe oxide electrocatalyst. The catalysts were prepared by a hydrothermal precipitation method that enabled catalyst growth directly on carbon paper electrodes. Fe(4+) species were detected in the NiFe hydroxide catalyst during steady-state water oxidation, accounting for up to 21% of the total Fe. In contrast, no Fe(4+) was detected in the Fe oxide catalyst. The observed Fe(4+) species are not kinetically competent to serve as the active site in water oxidation; however, their presence has important implications for the role of Fe in NiFe oxide electrocatalysts. PMID- 26601791 TI - Distracted Practice: A Concept Analysis. AB - PROBLEM: Distracted practice is a growing concern for all healthcare professionals working in today's complex, technology-rich, acute care hospital environment. Distractions are a threat to patient safety, frequently cited as a contributing factor when reporting an adverse event. The number of new technologies introduced to the healthcare environment has significantly increased the number of distractions. Shrinking resources and the resultant time pressure placed on all practitioners has added to the list of human factors known to be contributing to potential errors. Delivering safe, quality care in this environment has now become a daily challenge for all members of the healthcare team. Distracted practice was found to have no consistent definition in the healthcare literature. METHOD: Walker and Avant's method of concept analysis was used to develop a preliminary definition and model of distracted practice. FINDINGS: This analysis includes a definition, characteristics, antecedents, and consequences of distracted practice. CONCLUSION: More research is needed to fully understand this critical human experience of distracted practice. With additional knowledge we will be able to raise awareness and create interventions to reduce its occurrence among members of the healthcare team. This will positively contribute to the team's efforts to keep all our patients safe while in the hospital. D'Esmond. PMID- 26601792 TI - Liquid-Metal Microdroplets Formed Dynamically with Electrical Control of Size and Rate. AB - Liquid metal co-injected with electrolyte through a microfluidic flow-focusing orifice forms droplets with diameters and production frequencies controlled in real time by voltage. Applying voltage to the liquid metal controls the interfacial tension via a combination of electrochemistry and electrocapillarity. This simple and effective method can instantaneously tune the size of the microdroplets, which has applications in composites, catalysts, and microsystems. PMID- 26601793 TI - Quality and safety control of tumor-shrinking decoction (TSD): A Chinese herbal preparation for the treatment of uterine fibroids. AB - Reproducible efficacy assessments of Chinese herbal medicines are largely based on well-established quality control procedures. This study presents a comprehensive quality control procedure for tumor-shrinking decoction (TSD), a 15 herb preparation under study as a potential therapy for uterine fibroids. Morphological, microscopic, and physicochemical authentications were first carried out on individual herbal medicines composing TSD. Contaminant tests on TSD for the presence of heavy metals and pesticide residues were performed by atomic absorption spectrophotometry and gas chromatography-mass spectrometry analysis. Furthermore, batch-to-batch quality monitoring of the decoction was investigated via ultra-performance liquid chromatography (UPLC) and high performance liquid chromatography (HPLC). An aqueous extract of the herbal medicines was prepared and formulated into TSD. The tested contaminants were within the maximum permitted levels of the Hong Kong government in proprietary Chinese medicines. UPLC and HPLC fingerprints for quality tracking on TSD were established. The decoction was quantitatively standardized by UPLC and HPLC, respectively, with five and three chemical compounds serving as references. Collectively, the procedure established in this study will not only serve as a fundamental basis for the investigation and development of TSD as a novel therapy for uterine fibroids, but also as a protocol for studying other polycomponent herbal preparations. PMID- 26601794 TI - Selectively Probing the Structures and Dynamics of beta-Peptide Aggregates Using the Amide-A Vibrational Marker. AB - The N-H stretching vibration in a beta-peptide model compound, N ethylpropionamide (NEPA), was characterized by one-dimensional infrared (1D IR) and two-dimensional (2D) IR experiments and ab initio anharmonic frequency computations. A narrowband pump-broadband probe 2D IR method was applied to selectively probe a subensemble of the N-H stretching vibrations from a mixture of different NEPA molecular aggregates that were formed via an intermolecular hydrogen bond. Vibrational lifetime and anharmonicity were found to be sensitive to the aggregation ensembles. In particular, diagonal anharmonicities were observed experimentally and confirmed computationally to be smaller for NEPA trimer than for dimer, which was explained by the presence of non-negligible off diagonal anharmonicities in coupled N-H stretching modes. PMID- 26601795 TI - Evolving systemic targeted therapy strategies in uveal melanoma and implications for ophthalmic management: a review. AB - Uveal melanoma (UM) is the most common primary ocular tumour in adults. Despite good local control of the primary tumour with current methods, survival after the development of metastasis has remained poor over the last 30 years. After cutaneous melanoma, UM is the most common type of melanoma, and an ongoing debate exists regarding whether these conditions should be considered separate entities, particularly in the context of targeted therapy, where many of the initial trials for patients with metatatic cutaneous melanoma excluded metastatic UM. This paper will review the recent and ongoing investigations designed to validate systemic targeted therapy and immunotherapy in patients with metastatic UM and suggests ways in which these developments may affect management of UM by ophthalmologists in the near future. PMID- 26601796 TI - Complications of Ultrasound-Guided Renal Transplant Biopsies. AB - Renal transplant biopsies to diagnose transplant pathology are routinely performed using ultrasound guidance. Few large studies have assessed the rate and risk factors of major biopsy complications. This study is a single-center 5-year retrospective cohort analysis of 2514 biopsies. Major complications occurred in 47 of 2514 patients (1.9%) and included hospitalization, transfusion of blood products, operative exploration and interventional radiology procedures. The complication rate among "cause" biopsies was significantly higher than in "protocol" biopsies (2.7% vs. 0.33%, p < 0.001). Complications presented on postbiopsy days 0-14, with the majority diagnosed on the same day as the biopsy and manifested by hematocrit drop, although the presence of such delayed presentation of complications occurring >24 h after the biopsy on days 2-14 is previously unreported. Specific patient characteristics associated with increased risk of a complication were increased age and blood urea nitrogen, decreased platelet count, history of prior renal transplant, deceased donor transplant type and use of anticoagulant medications but not aspirin. PMID- 26601797 TI - Liver injury from nonsteroidal anti-inflammatory drugs in the United States. AB - BACKGROUND & AIMS: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used and have been associated with hepatotoxicity. Studies of liver injury from NSAIDs have been retrospective and prospective data are lacking. The aim was to report the features and outcomes of the subjects with severe drug-induced liver injury from NSAIDS. METHODS: The U.S. Drug Induced Liver Injury Network is a prospective registry of idiosyncratic drug hepatotoxicity. All patients are evaluated in a standard fashion and followed up for at least 6 months. RESULTS: Of 1221 Drug Induced Liver Injury Network cases that were adjudicated, 30 cases were attributed to eight different NSAIDs. The mean age was 52 years old, 24 (80%) were women, and 21 (70%) were Caucasian. The mean latency was 67 days. Common signs and symptoms at presentation were nausea (73%), jaundice (67%) and dark urine (67%). Mean peak serum aspartate aminotransferase, alanine aminotransferase, total bilirubin and alkaline phosphatase were 898 U/L, 1060 U/L, 12.2 mg/dl and 326 U/L. The most common pattern of injury was hepatocellular (70%) and autoantibodies were detected in 33% of cases. Diclofenac, was the most frequently implicated NSAID (16/30 cases), and characterized by hepatocellular injury. Seventeen cases resulted in hospitalization or prolongation of hospitalization and one patient died from complications of Stevens-Johnson syndrome because of diclofenac. CONCLUSIONS: Hepatocellular injury is the most common pattern seen with NSAID hepatotoxicity, and diclofenac is the most frequently implicated agent. Given the number of NSAID alternatives, diclofenac should be reserved for patients who fail other NSAIDs and a high level of suspicion for hepatotoxicity should be maintained. PMID- 26601798 TI - Processed Lignin as a Byproduct of the Generation of 5-(Chloromethyl)furfural from Biomass: A Promising New Mesoporous Material. AB - The lignin by-product of the conversion of lignocellulosic biomass to 5 (chloromethyl)furfural (CMF) has been characterised by thermogravimetric analysis, N2 physisorption porosimetry, attenuated internal reflectance IR spectroscopy, elemental analysis and solid-state NMR spectroscopy. The lignin (LCMF) has a moderate level of mesoporosity before thermal treatment and a surface area of 63 m(2) g(-1) , which increases dramatically on pyrolysis at temperatures above 400 degrees C. An assessment of the functionality and textural properties of the material was achieved by analysing LCMF treated thermally over a range of pyrolysis temperatures. Samples were sulfonated to test their potential as heterogeneous acid catalysts in the esterification of levulinic acid. It was shown that unpyrolysed catalysts gave the highest ester yields of up to 93 %. To the best of our knowledge, this is the first example of mesoporous lignin with an appreciable surface area that is produced directly from a bio-refinery process and with further textural modification of the material demonstrated. PMID- 26601799 TI - The Green House Model of Nursing Home Care in Design and Implementation. AB - OBJECTIVE: To describe the Green House (GH) model of nursing home (NH) care, and examine how GH homes vary from the model, one another, and their founding (or legacy) NH. DATA SOURCES/STUDY SETTING: Data include primary quantitative and qualitative data and secondary quantitative data, derived from 12 GH/legacy NH organizations February 2012-September 2014. STUDY DESIGN: This mixed methods, cross-sectional study used structured interviews to obtain information about presence of, and variation in, GH-relevant structures and processes of care. Qualitative questions explored reasons for variation in model implementation. DATA COLLECTION/EXTRACTION METHODS: Interview data were analyzed using related sample tests, and qualitative data were iteratively analyzed using a directed content approach. PRINCIPAL FINDINGS: GH homes showed substantial variation in practices to support resident choice and decision making; neither GH nor legacy homes provided complete choice, and all GH homes excluded residents from some key decisions. GH homes were most consistent with the model and one another in elements to create a real home, such as private rooms and baths and open kitchens, and in staff-related elements, such as self-managed work teams and consistent, universal workers. CONCLUSIONS: Although variation in model implementation complicates evaluation, if expansion is to continue, it is essential to examine GH elements and their outcomes. PMID- 26601800 TI - A benzamide-dependent ftsZ mutant reveals residues crucial for Z-ring assembly. AB - In almost all bacteria, cell division is co-ordinated by the essential tubulin homologue FtsZ and represents an attractive but as yet unexploited target for new antibiotics. The benzamides, e.g. PC190723, are potent FtsZ inhibitors that have the potential to yield an important new class of antibiotic. However, the evolution of resistance poses a challenge to their development. Here we show that a collection of PC190723-resistant and -dependent strains of Staphylococcus aureus exhibit severe growth and morphological defects, questioning whether these ftsZ mutations would be clinically relevant. Importantly, we show that the most commonly isolated substitution remains sensitive to the simplest benzamide 3-MBA and likely works by occluding compound binding. Extending this analysis to Bacillus subtilis, we isolated a novel benzamide-dependent strain that divides using unusual helical division events. The ftsZ mutation responsible encodes the substitution of a highly conserved residue, which lies outside the benzamide binding site and forms part of an interface between the N- and C-terminal domains that we show is necessary for normal FtsZ function. Together with an intragenic suppressor mutation that mimics benzamide binding, the results provide genetic evidence that benzamides restrict conformational changes in FtsZ and also highlights their utility as tools to probe bacterial division. PMID- 26601801 TI - Clinical and mutation profile of multicentric osteolysis nodulosis and arthropathy. AB - Multicentric osteolysis nodulosis and arthropathy (MONA) is an infrequently described autosomal recessive skeletal dysplasia characterized by progressive osteolysis and arthropathy. Inactivating mutations in MMP2, encoding matrix metalloproteinase-2, are known to cause this disorder. Fifteen families with mutations in MMP2 have been reported in literature. In this study we screened thirteen individuals from eleven families for MMP2 mutations and identified eight mutations (five novel and three known variants). We characterize the clinical, radiographic and molecular findings in all individuals with molecularly proven MONA from the present cohort and previous reports, and provide a comprehensive review of the MMP2 related disorders. PMID- 26601802 TI - The muscle contraction mode determines lymphangiogenesis differentially in rat skeletal and cardiac muscles by modifying local lymphatic extracellular matrix microenvironments. AB - AIM: Lymphatic vessels are of special importance for tissue homeostasis, and increases of their density may foster tissue regeneration. Exercise could be a relevant tool to increase lymphatic vessel density (LVD); however, a significant lack of knowledge remains to understand lymphangiogenesis in skeletal muscles upon training. Interestingly, training-induced lymphangiogenesis has never been studied in the heart. We studied lymphangiogenesis and LVD upon chronic concentric and chronic eccentric muscle contractions in both rat skeletal (Mm. Edl and Sol) and cardiac muscles. METHODS/RESULTS: We found that LVD decreased in both skeletal muscles specifically upon eccentric training, while this contraction increased LVD in cardiac tissue. These observations were supported by opposing local remodelling of lymphatic vessel-specific extracellular matrix components in skeletal and cardiac muscles and protein levels of lymphatic markers (Lyve-1, Pdpn, Vegf-C/D). Confocal microscopy further revealed transformations of lymphatic vessels into vessels expressing both blood (Cav-1) and lymphatic (Vegfr-3) markers upon eccentric training specifically in skeletal muscles. In addition and phenotype supportive, we found increased inflammation (NF-kappaB/p65, Il-1beta, Ifn-gamma, Tnf-alpha and MPO(+) cells) in eccentrically stressed skeletal, but decreased levels in cardiac muscles. CONCLUSION: Our data provide novel mechanistic insights into lymphangiogenic processes in skeletal and cardiac muscles upon chronic muscle contraction modes and demonstrate that both tissues adapt in opposing manners specifically to eccentric training. These data are highly relevant for clinical applications, because eccentric training serves as a sufficient strategy to increase LVD and to decrease inflammation in cardiac tissue, for example in order to reduce tissue abortion in transplantation settings. PMID- 26601803 TI - Pharmacological exploration of the resting membrane potential reserve: Impact on atrial fibrillation. AB - The cardiac action potential arises and spreads throughout the myocardium as a consequence of highly organized spatial and temporal expression of ion channels conducting Na(+), Ca(2+) or K(+) currents. The cardiac Na(+) current is responsible for the initiation and progression of the action potential. Altered Na(+) current has been found implicated in a number of different arrhythmias, including atrial fibrillation. In the atrium, the resting membrane potential is more depolarized than in the ventricles, and as cardiac Na(+) channels undergo voltage-dependent inactivation close to this potential, minor changes in the membrane potential have a relatively large impact on the atrial Na(+) current. The atrial resting membrane potential is established following ionic currents through the inwardly rectifying K(+) currents IK1, IK,ACh and IK,Ca and to a lesser extent by other ion channels as well as by exchangers and pumps. This review will focus on the relative and regulated contribution of IK1, IK,ACh and IK,Ca, and on pharmacological modification of the channels underlying these currents in respect to the resting membrane potential, Na(+) channel availability and atrial electrophysiology in health and disease. PMID- 26601804 TI - Involvement of AMPK/SIRT1 pathway in anti-allodynic effect of troxerutin in CCI induced neuropathic pain. AB - Neuropathic pain was regarded as a main form of chronic pain condition that remains difficult to treat. Conventional pharmacotherapy for neuropathic pain responsed vary and side effects limited their compliance. These prompted us to find new alternatives. In this study, we investigated the effect of troxerutin on treatment of CCI-induced neuropathic pain. Results showed that troxerutin significantly reversed mechanical allodynia and thermal hyperalgesia. In L4-6 spinal cord, troxerutin reduced the expression of INF-gamma, IL-1beta, TNF-alpha, and activation of NF-kappaB(p65). Immunofluorescence results showed that troxerutin significantly inhibited microglia activation induced by CCI surgery. Further, troxerutin treatment significantly induced AMPK activation and inhibited CCI-induced SIRT1 decrease. However, AMPK inhibitor compound C and SIRT1 inhibitor EX527 inhibited analgesic effect of troxerutin in CCI mice. This demonstrated the involvement of AMPK/SIRT1 pathway in anti-allodynic effect of troxerutin in CCI mice. Troxerutin could be developed as a potential therapeutic agent for neuropathic pain. PMID- 26601805 TI - Spanish consensus for the management of patients with advanced radioactive iodine refractory differentiated thyroid cancer. AB - BACKGROUND: Approximately one third of the patients with differentiated thyroid cancer (DTC) who develop structurally-evident metastatic disease are refractory to radioactive iodine (RAI). Most deaths from thyroid cancer occur in these patients. The main objective of this consensus is to address the most controversial aspects of management of these patients. METHODS: On behalf of the Spanish Society of Endocrinology & Nutrition (SEEN) and the Spanish Group for Orphan and Infrequent Tumors (GETHI), the Spanish Task Force for Thyroid Cancer, consisting of endocrinologists and oncologists, reviewed the relevant literature and prepared a series of clinically relevant questions related to management of advanced RAI-refractory DTC. RESULTS: Ten clinically relevant questions were identified by the task force. In answering to these 10 questions, the task force included recommendations regarding the best definition of refractoriness; the best therapeutic options including watchful waiting, local therapies, and systemic therapy (e.g. kinase inhibitors), when sodium iodide symporter (NIS) restoration may be expected; and how recent advances in molecular biology have increased our understanding of the disease. CONCLUSIONS: In response to our appointment as a task force by the SEEN and GHETI, we developed a consensus to help in clinical management of patients with advanced RAI-refractory DTC. We think that this consensus will provide helpful and current recommendations that will help patients with this disorder to get optimal medical care. PMID- 26601806 TI - Anti-Staphylococcus aureus activity of methanol extracts of 12 plants used in Cameroonian folk medicine. AB - BACKGROUND: The emergence of bacterial infections including those associated with Staphylococcus aureus causes a benefit of interest to medicinal plants as an effective means of control. The present study was designed to investigate the activities of 12 selected Cameroonian medicinal plants against S. aureus isolates. METHODS: The plant extracts were prepared by maceration in methanol at laboratory temperature. Qualitative phytochemical analysis was performed by chemical reaction methods. The broth microdilution method was used to evaluate the activities of plant extracts against 11 S. aureus clinical isolates. RESULTS: Dacryodes edulis was found to have significant antibacterial activity on all the S. aureus isolates (MIC = 64-256 ug/ml). Occimum gratissimum revealed significant inhibitory activity on 9 of the 11 isolates while Commelina erecta and Spilanthes filicaulis revealed similar results on 6 of the 11 clinical isolates. CONCLUSION: The present findings showed that D. eduli, O. gratissimum, C. erecta and S. filicaulis possess interesting inhibitory properties against S. aureus species. These plants could therefore be good candidates to overcome infectious diseases associated with these microorganisms. PMID- 26601807 TI - Emerging roles and competencies of district and sub-district pharmacists: a case study from Cape Town. AB - BACKGROUND: District and sub-district pharmacist positions were created during health sector reform in South Africa. High prevalence of HIV/AIDS, tuberculosis and increasing chronic non-communicable diseases have drawn attention to their pivotal roles in improving accessibility and appropriate use of medicines at the primary level. This research describes new roles and related competencies of district and sub-district pharmacists in Cape Town. METHODS: Between 2008 and 2011, the author (HB) conducted participatory action research in Cape Town Metro District, an urban district in the Western Cape Province of South Africa, partnering with pharmacists and managers of the two government primary health care (PHC) providers. The two providers function independently delivering complementary PHC services across the entire geographic area, with one provider employing district pharmacists and the other sub-district pharmacists. After an initiation phase, the research evolved into a series of iterative cycles of action and reflection, each providing increasing understanding of district and sub-district pharmacists' roles and competencies. Data was generated through workshops, semi-structured interviews and focus groups with pharmacists and managers which were recorded and transcribed. Thematic analysis was carried out iteratively during the 4-year engagement and triangulated with document reviews and published literature. RESULTS: Five main roles for district and sub-district pharmacists were identified: district/sub-district management; planning, co ordination and monitoring of pharmaceuticals; information and advice; quality assurance and clinical governance; and research (district pharmacists)/dispensing at clinics (sub-district pharmacists). Although the roles looked similar, there were important differences, reflecting the differing governance and leadership models and services of each provider. Five competency clusters were identified: professional pharmacy practice; health system and public health; management; leadership; and personal, interpersonal and cognitive competencies. Whilst professional pharmacy competencies were important, generic management and leadership competencies were considered critical for pharmacists working in these positions. CONCLUSIONS: Similar roles and competencies for district and sub district pharmacists were identified in the two PHC providers in Cape Town, although contextual factors influenced precise specifications. These insights are important for pharmacists and managers from other districts and sub-districts in South Africa and inform health workforce planning and capacity development initiatives in countries with similar health systems. PMID- 26601808 TI - Anaplastic extramedullary cervical ependymoma with leptomeningeal metastasis. AB - We present a rare extramedullary ependymoma with diffuse spinal metastatic disease, and review the previous reports of extramedullary spinal ependymomas. Ependymomas are the most common intramedullary spinal cord tumor in adults. These tumors rarely present as extramedullary masses. We treated a 23-year-old man with a history of progressive neck, shoulder and arm pain, with sensory and motor symptoms in the C7 dermatome. MRI of the cervical spine demonstrated a ventral contrast-enhancing lesion with evidence of enhancement along the dura and spinal cord of the upper cervical spine, thoracic spine, and cauda equina. He underwent a tumor debulking procedure without complications. Following surgery, he received craniospinal radiation to treat the remaining tumor and diffuse leptomeningeal disease. The final pathology of the tumor revealed that is was a World Health Organization Grade III anaplastic ependymoma. At the 1 year follow-up, the patient had stable imaging and had returned to his preoperative functional status. Of the 19 reported patients with primary intradural, extramedullary spinal ependymomas, two had extradural components and seven had anaplastic grades. Only one tumor with an anaplastic grade resulted in metastatic disease, but without spinal recurrence. To our knowledge, this is the first report of an intradural, extramedullary spinal ependymoma with an anaplastic grade, presenting with concomitant diffuse, nodular leptomeningeal metastasis involving the upper cervical spine, thoracic spine, conus medullaris, and cauda equina. Similar to the treatment of intramedullary ependymomas with metastasis, this patient underwent an aggressive debulking procedure followed by radiation therapy to the entire neuroaxis. PMID- 26601809 TI - Primary spinal cord glioblastoma multiforme treated with temozolomide. AB - Since virtually no trials have evaluated the effectiveness of temozolomide (TMZ) in the treatment of spinal cord (SC) glioblastoma multiforme (GBM), we conducted a systematic review to evaluate its efficacy. Primary SC GBM is rare. Its management remains unclear, even though treatment guidelines have been established since 2005 for its cranial counterpart. We performed a medical subject heading search with the terms "glioblastoma" and "primary spinal cord neoplasms, intramedullary". We stratified the papers into two groups according to the use of TMZ, and analyzed survival rates using the Kaplan-Meier method with a two-sided log-rank scale. The TMZ subgroup contained nine articles and a total of 19 patients with primary SC GBM who were treated with adjuvant TMZ. The non-TMZ group consisted of 19 articles including 45 patients who underwent other treatment modalities. The TMZ subgroup had an overall survival of 16 months, compared to the non-TMZ group with a median overall survival of 10 months. The difference between these two groups was not statistically significant (p = 0.57). While this review did not demonstrate a statistically significant difference in long term survival between patients with SC GBM treated with TMZ versus those not treated with TMZ, a slightly longer survival time was seen in the TMZ group. The small number of patients is likely a contributing factor to the lack of statistical significance. Our analysis highlights the need for a multi institutional, prospective, controlled study to evaluate the use of TMZ in the treatment of SC GBM. PMID- 26601810 TI - Synthetic cannabinoids revealing adrenoleukodystrophy. AB - We report a 41-year-old man who presented with a first generalized tonic-clonic seizure after recent consumption of a synthetic cannabinoid. MRI showed extensive bilateral, mainly frontal, white matter lesions. Blood analysis for very long chain fatty acids was compatible with adrenoleukodystrophy, and a missense mutation in the ABCD1 gene confirmed the diagnosis. We hypothesize that cannabinoid use might have contributed to metabolic decompensation with subacute worsening of the underlying condition. PMID- 26601811 TI - Evolving management of low grade glioma: No consensus amongst treating clinicians. AB - Following the widely publicized presentation of the Radiation Therapy Oncology Group (RTOG) 9802 data, we sought to understand how these data had been translated to the management of low grade gliomas (LGG) by Australian neuro oncology clinicians. The de novo management of LGG is transitioning to include postoperative radiotherapy and chemotherapy after the RTOG 9802 study results demonstrated a survival benefit in this setting. In 2014, neurosurgeons, radiation oncologists and neuro-oncologists who were members of the Australian Cooperative Trials Group for Neuro-oncology (COGNO), as well as additional attendants of the COGNO annual scientific meeting, were surveyed. The survey presented six LGG clinical scenarios and asked respondents to select their preferred management strategy. Some additional questions included the respondents' approach to 1p/19q testing and chemotherapy preferences. The response rate was 30.2% (61/202), with the majority (77%) working in tertiary referral neuro-oncology centers. There was no consensus regarding the management approach for each scenario, with postsurgery observation alone remaining a popular strategy. Only 25% of respondents reported that their institution routinely tests for 1p/19q status in LGG, although 69% were of the opinion that all LGG patients should be tested. The majority (81%) preferred to use temozolomide rather than the procarbazine, lomustine, and vincristine combination as the first line chemotherapy for LGG, but only 44% would actually use it in this setting. Up front chemotherapy, prior to radiotherapy, would be considered by 52% of respondents for certain LGG patients. This survey assessed the management strategies for LGG since the updated RTOG 9802 data were presented. It demonstrates no consensus in the postoperative treatment approaches for LGG. PMID- 26601812 TI - Acutely unstable cervical spine injury with normal CT scan findings: MRI detects ligamentous injury. AB - MRI can detect ligamentous injury not detectable with CT scan. The authors present a trauma patient with normal CT imaging despite dislocation on standing radiograph. MRI detected disruption of the C5-C6 posterior ligamentous complex that requires surgery. PMID- 26601813 TI - Delays to the diagnosis of cervical dystonia. AB - The diagnosis of cervical dystonia (CD) is based on physical examination and is therefore reliant on clinician experience. Due to variability of presenting symptoms it may be misdiagnosed, thus delaying the provision of effective treatment. We sought to determine the average time taken to make a diagnosis of CD in our clinical cohort and explore contributing factors to diagnostic delay. Forty-nine patients with a diagnosis of CD attending a movement disorder specialist for treatment completed a questionnaire regarding symptoms and clinical interactions at onset and diagnosis. The mean time from symptom onset to diagnosis was 6.8 years (range 0-53 years). More than 50% of patients sought physical therapies initially, prior to consulting their general practitioner. Only 40% of patients sought medical advice within the first 6 months of symptom onset and only 10% were given an initial diagnosis of CD. The first referral from the general practitioner was to a specialist other than a neurologist in 31% of patients. Patients were seen by a mean of three doctors (range one to nine) before being given the correct diagnosis of CD. Delay to diagnosis of CD may in part be due to lack of awareness of the condition amongst health care professionals. Improved diagnostic skill appears likely to have had a substantial impact on the delivery of appropriate treatment in this population. PMID- 26601814 TI - Value of repeat CT scans in low back pain and radiculopathy. AB - We assessed the clinical value of repeat spine CT scan in 108 patients aged 18-60 years who underwent repeat lumbar spine CT scan for low back pain or radiculopathy from January 2008 to December 2010. Patients with a neoplasm or symptoms suggesting underlying disease were excluded from the study. Clinical data was retrospectively reviewed. Index examinations and repeat CT scan performed at a mean of 24.3 +/- 11.3 months later were compared by a senior musculoskeletal radiologist. Disc abnormalities (herniation, sequestration, bulge), spinal stenosis, disc space narrowing, and bony changes (osteophytes, fractures, other changes) were documented. Indications for CT scan were low back pain (60 patients, 55%), radiculopathy (46 patients, 43%), or nonspecific back pain (two patients, 2%). A total of 292 spine pathologies were identified in 98 patients (90.7%); in 10 patients (9.3%) no spine pathology was seen on index or repeat CT scan. At repeat CT scan, 269/292 pathologies were unchanged (92.1%); 10/292 improved (3.4%), 8/292 worsened (2.8%, disc herniation or spinal stenosis), and five new pathologies were identified. No substantial therapeutic change was required in patients with worsened or new pathology. Added diagnostic value from repeat CT scan performed within 2-3 years was rare in patients suffering chronic or recurrent low back pain or radiculopathy, suggesting that repeat CT scan should be considered only in patients with progressive neurologic deficits, new neurologic complaints, or signs implying serious underlying conditions. PMID- 26601815 TI - Proximal ventricular shunt malfunctions in children: Factors associated with failure. AB - Ventricular shunt failures and subsequent revisions are a significant source of patient morbidity. We conducted a review of pediatric patients undergoing placement or revision of ventricular shunts at our institution between January 2007 and December 2008. Patients were followed through to July 2014. Data collected included patient demographics, shunt history and indication for procedure, approach taken for shunt placement, and location of shunt tip in relation to the foramen of Monro. Univariate and multivariate analyses were conducted to identify factors associated with proximal failure. A total of 87 procedures were identified in 40 patients, consisting of 23 initial placements and 64 revisions. Thirty-nine proximal catheter malfunctions were identified. Indications for shunt placement included Chiari II malformation (33%) and intraventricular hemorrhage (33%). Mean follow-up period was 5.5 years. Median time to shunt failure was 1.57 years. In the multivariate model, younger age at placement was associated with decreased time to proximal failure (hazard ratio [HR]=0.80 per increasing year of age, 95% confidence interval [CI] 0.64-0.98). Both anterior approach (HR=0.39, 95% CI 0.23-0.67) and farther distance to foramen of Monro (HR=0.02 per increasing 10mm, 95% CI 0.00-0.22) were associated with increased time to proximal failure when the catheter tip was located within the contralateral lateral ventricle. Optimizing outcomes in patients with shunt dependent hydrocephalus continues to be a challenge. Despite unsatisfactory outcomes, particularly in the pediatric population, few conclusions can be drawn from studies assessing operative variables. PMID- 26601816 TI - Intraparenchymal infratentorial ependymoma. AB - Ependymomas are glial series tumours that can occur throughout the neural axis, usually in close proximity to the ventricles or central canal. While the fourth ventricle is a common location for ependymoma, we present a rare case of an entirely intraparenchymal infratentorial tumour, remote from the ventricular surface, and discuss the imaging characteristics that may suggest the diagnosis. The histological features, which remain identical despite the varied morphology of intraventricular versus intraparenchymal tumours, are also considered. PMID- 26601817 TI - Should we forget about rectosigmoidoscopy for the diagnosis of advanced colorectal neoplasia? PMID- 26601818 TI - Risk factors associated with prolonged postoperative ileus after elective colon resection. AB - BACKGROUND: There is a coordinated inhibition of motility of the colon after its surgical manipulation that contributes to the accumulation of fluids and gas, in turn characterized by nausea,vomiting, pain, abdominal distension, and constipation. Motility is recovered in the majority of patients within the first 72 hours. A delay in its resolution is known as prolonged postoperative ileus. AIMS: To study the preoperative, intraoperative, and postoperative risk factors for developing prolonged ileus in patients that underwent elective colon resection.Materials and methods: The association between 25 perioperative variables and the presentation of prolonged ileus was analyzed in 85 patients that underwent colon resection at Hospital Christus Muguerza Alta Especialidad within the time frame of 2011 and 2014. RESULTS: Postoperative ileus occurred in 22.3% of the patients. The statistically significant predictors of ileus were obesity (OR 1.119, P=.048) and admission to the intensive care unit (OR3.571, P=.050). The use of peridural anesthesia during the surgical act was found to be a protective factor (OR 0.363, P=.050). CONCLUSIONS: The presence of these risk factors can alert the physician to the need for a closer follow-up in patients at high risk for postoperative ileus, and the use of peridural anesthesiacan possibly lower the incidence of ileus. PMID- 26601819 TI - Toric Intraocular Lenses in the Correction of Astigmatism During Cataract Surgery: A Systematic Review and Meta-analysis. AB - TOPIC: We performed a systematic review and meta-analysis to evaluate the benefit and harms associated with implantation of toric intraocular lenses (IOLs) during cataract surgery. Outcomes were postoperative uncorrected distance visual acuity (UCDVA) and distance spectacle independence. Harms were evaluated as surgical complications and residual astigmatism. CLINICAL RELEVANCE: Postoperative astigmatism is an important cause of suboptimal UCDVA and need for distance spectacles. Toric IOLs may correct for preexisting corneal astigmatism at the time of surgery. METHODS: We performed a systematic literature search in the Embase, PubMed, and CENTRAL databases within the Cochrane Library. We included randomized clinical trials (RCTs) if they compared toric with non-toric IOL implantation (+/- relaxing incision) in patients with regular corneal astigmatism and age-related cataracts. We assessed the risk of bias using the Cochrane Risk of Bias tool. We assessed the quality of evidence across studies using the GRADE profiler software (available at: www.gradeworkinggroup.org). RESULTS: We included 13 RCTs with 707 eyes randomized to toric IOLs and 706 eyes randomized to non toric IOLs; 225 eyes had a relaxing incision. We found high-quality evidence that UCDVA was better in the toric IOL group (logarithm of the minimum angle of resolution [logMAR] mean difference, -0.07; 95% confidence interval [CI], -0.10 to -0.04) and provided greater spectacle independence (risk ratio [RR], 0.51; 95% CI, 0.36-0.71) and moderate quality evidence that toric IOL implantation was not associated with an increased risk of complications (RR, 1.73; 95% CI, 0.60-5.04). Residual astigmatism was lower in the toric IOL group than in the non-toric IOL plus relaxing incision group (mean difference, 0.37 diopter [D]; 95% CI, -0.55 to -0.19). CONCLUSIONS: We found that toric IOLs provided better UCDVA, greater spectacle independence, and lower amounts of residual astigmatism than non-toric IOLs even when relaxing incisions were used. PMID- 26601820 TI - Commercially available molecular tests for human papillomaviruses (HPV): 2015 update. AB - Commercial molecular tests for human papillomaviruses (HPV) are invaluable diagnostic tools in cervical carcinoma screening and management of women with cervical precancerous lesions as well as important research tools for epidemiological studies, vaccine development, and implementation and monitoring of vaccination programs. In this third inventory of commercial HPV tests, we identified 193 distinct commercial HPV tests and at least 127 test variants available on the market in 2015, which represents a 54% and 79% increase in the number of distinct HPV tests and variants, respectively, in comparison to our last inventory performed in 2012. Identified HPV tests were provisionally divided into eight main groups and several subgroups. Among the 193 commercial HPV tests, all but two target alpha-HPV types only. Although the number of commercial HPV tests with at least one published study in peer-reviewed literature has increased significantly in the last three years, several published performance evaluations are still not in line with agreed-upon standards in the HPV community. Manufacturers should invest greater effort into evaluating their products and publishing validation/evaluation results in peer-reviewed journals. To achieve this, more clinically oriented external quality-control panels and initiatives are required. For evaluating the analytical performance of the entire range of HPV tests currently on the market, more diverse and reliable external quality control programs based on international standards for all important HPV types are indispensable. The performance of a wider range of HPV tests must be promptly evaluated on a variety of alternative clinical specimens. In addition, more complete HPV assays containing validated sample-extraction protocols and appropriate internal controls are urgently needed. Provision of a broader range of automated systems allowing large-scale HPV testing as well as the development of reliable, rapid, and affordable molecular point-of-care tests are priorities for the further improvement of HPV tests. PMID- 26601821 TI - Impact of Resident Involvement in Surgery (IRIS-NSQIP): Looking at the Bigger Picture Based on the American College of Surgeons-NSQIP Database. AB - BACKGROUND: Surgical residency training aims to prepare the surgical resident to become an independent practitioner of surgery. Because surgical residency training remains the sole educational channel to prepare surgeons for independent practice, our study aimed to explore the effect of resident involvement in surgery across a broad spectrum of surgical specialties to answer questions patients, surgeons, and surgical residency program directors may have concerning the effect of having residents participate in performing surgical operations. STUDY DESIGN: This analysis used the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database to establish whether patients having operations involving residents were at a risk of postoperative mortality or morbidity similar to patients having operations performed by attending surgeons alone, across a wide array of surgical procedures. RESULTS: For operations in which residents were involved, the adjusted odds ratio (OR) for mortality was 0.93 (95% CI 0.90 to 0.97), as compared with the group of patients on whom attending surgeons operated alone without any level of resident involvement. For operations in which residents were involved, the adjusted OR for morbidity was 1.02 (95% CI 1.00 to 1.04), as compared with the group of patients on whom attending surgeons operated alone without any level of resident involvement. There was a slightly statistically significantly higher risk of cardiac and respiratory morbidities in the group with any level of resident involvement as compared with the "attending alone" group. CONCLUSIONS: Our study confirms that, across different surgical subspecialties, resident involvement in surgery is associated with comparable morbidity and lower mortality outcomes. This provides a reassuring answer to patients, attending surgeons, and surgical program directors. PMID- 26601822 TI - Enhancement of hypocotyl elongation by LOV KELCH PROTEIN2 production is mediated by auxin and phytochrome-interacting factors in Arabidopsis thaliana. AB - KEY MESSAGE: Auxin and two phytochrome-interacting factors, PHYTOCHROME INTERACTING FACTOR4 (PIF4) and PIF5, play crucial roles in the enhancement of hypocotyl elongation in transgenic Arabidopsis thaliana plants that overproduce LOV KELCH PROTEIN2 (LKP2). LOV KELCH PROTEIN2 (LKP2) is a positive regulator of hypocotyl elongation under white light in Arabidopsis thaliana. In this study, using microarray analysis, we compared the gene expression profiles of hypocotyls of wild-type Arabidopsis (Columbia accession), a transgenic line that produces green fluorescent protein (GFP), and two lines that produce GFP-tagged LKP2 (GFP LKP2). We found that, in GFP-LKP2 hypocotyls, 775 genes were up-regulated, including 36 auxin-responsive genes, such as 27 SMALL AUXIN UP RNA (SAUR) and 6 AUXIN/INDOLE-3-ACETIC ACID (AUX/IAA) genes, and 21 genes involved in responses to red or far-red light, including PHYTOCHROME-INTERACTING FACTOR4 (PIF4) and PIF5; and 725 genes were down-regulated, including 15 flavonoid biosynthesis genes. Hypocotyls of GFP-LKP2 seedlings, but not cotyledons or roots, contained a higher level of indole-3-acetic acid (IAA) than those of control seedlings. Auxin inhibitors reduced the enhancement of hypocotyl elongation in GFP-LKP2 seedlings by inhibiting the increase in cortical cell number and elongation of the epidermal and cortical cells. The enhancement of hypocotyl elongation was completely suppressed in progeny of the crosses between GFP-LKP2 lines and dominant gain-of-function auxin-resistant mutants (axr2-1 and axr3-1) or loss-of function mutants pif4, pif5, and pif4 pif5. Our results suggest that the enhancement of hypocotyl elongation in GFP-LKP2 seedlings is due to the elevated level of IAA and to the up-regulated expression of PIF4 and PIF5 in hypocotyls. PMID- 26601823 TI - Expression and functional analyses of a putative phenylcoumaran benzylic ether reductase in Arabidopsis thaliana. AB - KEY MESSAGE: A candidate gene for phenylcoumaran benzylic ether reductase in Arabidopsis thaliana encodes a peptide with predicted functional activity and plays a crucial role in secondary metabolism. Phenylcoumaran benzylic ether reductase (PCBER) is thought to be an enzyme crucial in the biosynthesis of 8-5' linked neolignans. Genes of the enzyme have been isolated and characterized in several plant species. In this study, we cloned cDNA and the 5'-untranslated region of one PCBER candidate gene (At4g39230, designated AtPCBER1) from Arabidopsis thaliana. At the amino acid level, AtPCBER1 shows high sequence identity (64-71 %) with PCBERs identified from other plant species. Expression analyses of AtPCBER1 by reverse transcriptase-polymerase chain reaction and histochemical analysis of transgenic plants harboring the 5'-untranslated region of AtPCBER1 linked with gus coding sequence indicate that expression is induced by wounding and is expressed in most tissues, including flower, stem, leaf, and root. Catalytic analysis of recombinant AtPCBER1 with neolignan and lignans in the presence of NADPH suggests that the protein can reduce not only the 8-5' linked neolignan, dehydrodiconiferyl alcohol, but also 8-8' linked lignans, pinoresinol, and lariciresinol, with lower activities. To investigate further, we performed metabolomic analyses of transgenic plants in which the target gene was up- or down-regulated. Our results indicate no significant effects of AtPCBER1 gene regulation on plant growth and development; however, levels of some secondary metabolites, including lignans, flavonoids, and glucosinolates, differ between wild-type and transgenic plants. Taken together, our findings indicate that AtPCBER1 encodes a polypeptide with PCBER activity and has a critical role in the biosynthesis of secondary metabolites in A. thaliana. PMID- 26601825 TI - Association between Smoking and the Progression of Computed Tomography Findings in Chronic Pancreatitis. AB - BACKGROUND/AIMS: Smoking and alcohol intake are two wellknown risk factors for chronic pancreatitis. However, there are few studies examining the association between smoking and changes in computed tomography (CT) findings in chronic pancreatitis. The authors evaluated associations between smoking, drinking and the progression of calcification on CT in chronic pancreatitis. METHODS: In this retrospective study, 59 patients with chronic pancreatitis who had undergone initial and follow-up CT between January 2002 and September 2010 were included. Progression of calcification among CT findings was compared according to the amount of alcohol intake and smoking. RESULTS: The median duration of followup was 51.6 months (range, 17.1 to 112.7 months). At initial CT findings, there was pancreatic calcification in 35 patients (59.3%). In the follow-up CT, progression of calcification was observed in 37 patients (62.7%). Progression of calcification was more common in smokers according to the multivariate analysis (odds ratio [OR], 9.987; p=0.006). The amount of smoking was a significant predictor for progression of calcification in the multivariate analysis (OR, 6.051 in less than 1 pack per day smokers; OR, 36.562 in more than 1 pack per day smokers; p=0.008). CONCLUSIONS: Continued smoking accelerates pancreatic calcification, and the amount of smoking is associated with the progression of calcification in chronic pancreatitis. PMID- 26601824 TI - Occludin controls HIV transcription in brain pericytes via regulation of SIRT-1 activation. AB - HIV invades the brain early after infection; however, its interactions with the cells of the blood-brain barrier (BBB) remain poorly understood. Our goal was to evaluate the role of occludin, one of the tight junction proteins that regulate BBB functions in HIV infection of BBB pericytes. We provide evidence that occludin levels largely control the metabolic responses of human pericytes to HIV. Occludin in BBB pericytes decreased by 10% during the first 48 h after HIV infection, correlating with increased nuclear translocation of the gene repressor C-terminal-binding protein (CtBP)-1 and NFkappaB-p65 activation. These changes were associated with decreased expression and activation of the class III histone deacetylase sirtuin (SIRT)-1. Occludin levels recovered 96 h after infection, restoring SIRT-1 and reducing HIV transcription to 20% of its highest values. We characterized occludin biochemically as a novel NADH oxidase that controls the expression and activation of SIRT-1. The inverse correlation between occludin and HIV transcription was then replicated in human primary macrophages and differentiated monocytic U937 cells, in which occludin silencing resulted in 75 and 250% increased viral transcription, respectively. Our work shows that occludin has previously unsuspected metabolic properties and is a target of HIV infection, opening the possibility of designing novel pharmacological approaches to control HIV transcription. PMID- 26601826 TI - Ascitic Fluid Calprotectin and Serum Procalcitonin as Accurate Diagnostic Markers for Spontaneous Bacterial Peritonitis. AB - BACKGROUND/AIMS: The diagnosis of spontaneous bacterial peritonitis (SBP) is based on a polymorphonuclear leukocytes (PMNs) exceeding 250/MUL in ascitic fluid. The aim of the study was to evaluate serum procalcitonin and ascitic fluid calprotectin as accurate diagnostic markers for detecting SBP. METHODS: Seventy nine patients with cirrhotic ascites were included. They were divided into a SBP group, including 52 patients, and a non-SBP group of 27 patients. Serum procalcitonin, ascitic calprotectin, and serum and ascitic levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL- 6) were measured using an enzyme-linked immunosorbent assay. RESULTS: Serum procalcitonin and ascitic calprotectin were significantly higher in SBP patients than in non-SBP patients. Significant increases in both serum and ascitic levels of TNF-alpha and IL-6 were observed in SBP patients versus non- SBP patients. At a cutoff value of 0.94 ng/mL, serum procalcitonin had 94.3% sensitivity and 91.8% specificity for detecting SBP. In addition, at a cutoff value of 445 ng/mL, ascitic calprotectin had 95.4% sensitivity and 85.2% specificity for detecting SBP. Both were positively correlated with ascitic fluid proteins, PMN count, TNF-alpha, and IL 6. CONCLUSIONS: According to our findings, determination of serum procalcitonin levels and ascitic calprotectin appears to provide satisfactory diagnostic markers for the diagnosis of SBP. PMID- 26601827 TI - The IL-1B Genetic Polymorphism Is Associated with Aspirin-Induced PepticUlcers in a Korean Ethnic Group. AB - BACKGROUND/AIMS: Single nucleotide polymorphisms (SNPs) are associated with aspirin-induced peptic ulcers. However, SNPs of specific genes vary among races, and data regarding SNPs in the Korean population are scarce. In this study, we aimed to investigate the relationships between SNPs of the COX-1, IL-1beta, IL 1RN, and TNF genes and aspirin-induced peptic ulcers, as pilot research in a Korean population. METHODS: Patients who had been taking low-dose aspirin (100 mg) for at least 4 weeks were prospectively enrolled. DNA was extracted from whole blood, and DNA sequencing was subsequently performed. RESULTS: A total of 48 patients were enrolled (23 peptic ulcer patients vs 25 nonulcer controls). Three exon SNPs (IL-1beta -581C/T [rs1143627], IL-1beta -1061C/ T [rs16944], and IL-1RN -1129 [rs4251961]) and one intron SNP (IL-1beta IVS2+242C/T) were significantly different between the two groups. On the multivariate analysis after adjustments for age and sex, the CC/CT genotypes of IL-1beta -581C/ T, and the CT/TT genotypes of IL-1beta -1061C/T were positively associated with aspirin induced peptic ulcers (odds ratio [OR], 4.6, 95% confidence interval [CI], 1.054 to 20.303, p=0.04; OR, 4.6, 95% CI, 1.054 to 20.303, p=0.04). CONCLUSIONS: The IL 1beta -581C/T and IL-1beta -1061C/T genotypes may be associated with low-dose aspirin-induced peptic ulcers in a Korean ethnic group. PMID- 26601830 TI - [The necessity of resilience]. PMID- 26601829 TI - The Performance of a Modified Glasgow Blatchford Score in Predicting Clinical Interventions in Patients with Acute Nonvariceal Upper Gastrointestinal Bleeding: A Vietnamese Prospective Multicenter Cohort Study. AB - BACKGROUND/AIMS: To compare the performance of a modified Glasgow Blatchford score (mGBS) to the Glasgow Blatchford score (GBS) and the pre-endoscopic Rockall score (RS) in predicting clinical interventions in Vietnamese patients with acute nonvariceal upper gastrointestinal bleeding (ANVUGIB). METHODS: A prospective multicenter cohort study was conducted in five tertiary hospitals from May 2013 to February 2014. The mGBS, GBS, and pre-endoscopic RS scores were prospectively calculated for all patients. The accuracy of mGBS was compared with that of GBS and preendoscopic RS using area under the receiver operating characteristic curve (AUC). Clinical interventions were defined as blood transfusions, endoscopic or radiological intervention, or surgery. RESULTS: There were 395 patients including 128 (32.4%) needing endoscopic treatment, 117 (29.6%) requiring blood transfusion and two (0.5%) needing surgery. In predicting the need for clinical intervention, the mGBS (AUC, 0.707) performed as well as the GBS (AUC, 0.708; p=0.87) and outperformed the pre-endoscopic RS (AUC, 0.594; p<0.001). However, none of these scores effectively excluded the need for endoscopic intervention at a threshold of 0. CONCLUSIONS: mGBS performed as well as GBS and better than pre-endoscopic RS for predicting clinical interventions in Vietnamese patients with ANVUGIB. (Gut Liver 2016;10375- 381). PMID- 26601828 TI - Low-Dose Pegylated Interferon alpha-2b Plus Ribavirin for Elderly and/or Cirrhotic Patients with Genotype 2 Hepatitis C Virus. AB - BACKGROUND/AIMS: This study aimed to predict sustained viral response (SVR) to low-dose pegylated interferon (PEG-IFN) plus ribavirin of elderly and/or cirrhotic patients with genotype 2 hepatitis C virus (HCV) using viral response within 2 weeks. METHODS: Low-dose PEG-IFN-alpha-2b plus ribavirin was administered to 50 elderly and/or cirrhotic patients with genotype 2 HCV for 24 weeks. The dynamics of HCV RNA and HCV core antigen levels within 2 weeks were measured. RESULTS: The patients' median age was 66 years. There were 21 male and 29 female patients. The median baseline HCV RNA level was 5.7 log IU/mL. Rapid viral response was achieved in 17 patients (34%), SVR in 28 (56%), and two (4%) discontinued treatment. Univariate analysis of factors contributing to SVR showed significant differences for sex, baseline virus level, and response within 4 weeks. When 40 fmol/L was set as the cutoff value for the core antigen level at 1 week, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for predicting SVR were 93%, 75%, 84%, 88%, and 85%, respectively. CONCLUSIONS: Low-dose PEG-IFN plus ribavirin was a safe and costeffective treatment for elderly and/or cirrhotic patients with genotype 2 HCV, and the viral response within 2 weeks was a useful predictor of SVR. PMID- 26601831 TI - Comparison of Pharmacological Potency and Safety of Glutamate Blocker IEM-1913 and Memantine. AB - Adamantane-containing glutamate blocker IEM-1913 (1-amino-4-(1-adamantane-amino) butane dihydrochloride) equals to memantine in antiparkinsonian potency, but surpasses it in anticonvulsive, antidepressant, and analgesic activities. Moreover, its use is less toxic and safer. IEM-1913 produces significant pharmacological effects at a wide concentration diapason (0.03-1.00 mg/kg), while memantine is effective within a narrow range only (15-20 mg/kg). High pharmacological efficacy and low toxicity of IEM-1913 can be explained by the fact that in contrast to monocationic selective NMDA antagonist memantine, the dicationic glutamate blocker IEM-1913 produces a combined block of cerebral NMDA and AMPA receptors. PMID- 26601832 TI - Recombinant N-Domain of Pregnancy-Specific Glycoprotein from E. coli Cells: Analysis of the Spectrum of Polyclonal Antibodies. AB - We studied antibody spectrum in antisera to IgG-like recombinant N-domain of pregnancyspecific glycoprotein-1 (rPSG-N) from E. coli cells. In three experimental series, the fraction of IgG antibodies from anti-rPSG-N sera was immobilized on 3 immunoadsorbents: by polymerization with glutaraldehyde, on glutaraldehyde activated biogel P-300, and on commercial CNBr-activated 4B sepharose. Retroplacental serum was incubated with immobilized antibodies to rPSG1-N, protein was eluted and tested in the precipitation test in standard test systems with PSG1, IgG, and human serum albumin. Three proteins were eluted from all 3 immunoadsorbents: PSG1, IgG, and human serum albumin, which demonstrated the spectrum of antibodies to 3 proteins present also in natural serum PSG1 complex. The proportions of PSG1 and IgG obtained in these experiments were similar to those in natural serum PSG1 complex, while the level of human serum albumin was significantly higher in natural PSG1 complex. Thus, we failed to obtain PSG1 monoprotein free from IgG and human serum albumin. Antigenic mosaicism of the polypeptide chain of IgG-like rPSG1-N relative to the antigenic polyvalence of the complex of three proteins present in bioactive preparation of natural serum PSG1 was discussed. PMID- 26601833 TI - Lymph Region in the Female Internal Reproductive Organs during the Early Postpartum Period after Normal Pregnancy. AB - The structural and functional changes in the lymph region of the female internal reproductive organs in rats were studied during the early postpartum period after normal pregnancy. The results indicated that the main role of the lymph region in pregnancy consisted in supporting sufficient lymph production and drainage in the hypertrophic uterus. PMID- 26601834 TI - Potential Contribution of Cytomegalovirus Infection to Prenatal and Early Neonatal Mortality of Monkeys in the Adler Breeding Center. AB - Scrapings from the cervical canals and uterine cavities of females with a history of miscarriages, pathological deliveries, and stillbirths were tested for the cytomegalovirus DNA. The incidence of the agent in the females with a history of gestosis and abnormal deliveries was significantly higher than in females without anamnesis of this kind. Parenchymatous organs of stillborn neonates and animals dead during the first month of life were studied. This analysis and studies of the umbilical cords and placentas showed generalized cytomegalovirus infection in 22% dead animals, which objectively proved intrauterine infection. PMID- 26601835 TI - Pathomorphological Analysis and Evaluation of Microcirculation in Polyps of the External Urethral Meatus in Women. AB - Combinations of various factors of polypogenesis determine the formation of a mixed structural phenotype of urethral polyps consisting of heterogeneous changes of the epithelium (hyperplasia, metaplasia, and erosions), inflammatory cell infiltration of the stroma, and dilatation of the venous plexus vessels. Urogenital infections are associated with the predominance of symptoms of inflammation, high serum levels of IL-1beta and TNF-alpha, more extensive areas of inflammatory infiltration and subepithelial microvascular bed, predominance of hyperemic form of microcirculatory disorders. The combination of hyperplastic reactions of the epithelial layer with neoangiogenesis and myofibroblast proliferation in the subepithelial zone confirms the key role of dysregeneratory hyperplasia in the mechanisms of polypogenesis. PMID- 26601836 TI - Reconsolidation of Reminder-Induced Amnesia: Role of NMDA and AMPA Glutamate Receptors. AB - We studied the role of glutamate receptors and reminder in the mechanisms of amnesia maintenance caused by disruption of conditioned food aversion reconsolidation with an antagonist of NMDA glutamate receptor in snails. At the early stage of amnesia (day 3 after induction), injection or NMDA of AMPA glutamate receptor antagonists prior to reminder (presentation of the conditioned food stimulus) led to memory recovery. Reminder alone or injection of antagonists without reminder or after reminder was ineffective. At the late stage of amnesia (day 10), antagonists/reminder had no effect on amnesia maintenance. It was hypothesized that reminder at the early stage of amnesia led to reactivation and reconsolidation of the molecular processes of amnesia including activation NMDA and AMPA glutamate receptors. Injection of antagonists of these receptors prior to reminder led to disruption of reactivation/reconsolidation of amnesia and recovery of the conditioned food aversion memory. PMID- 26601837 TI - Peculiar Effects of Selective Blockade of alpha2-Adrenoceptor Subtypes on Cardiac Chronotropy in Newborn Rats. AB - We studied the effects of selective blockade of various subtypes of alpha2 adrenoceptors on cardiac chronotropy in newborn rats. This period in rats is characterized by the absence of adrenergic regulation of heart function. Blockade of alpha2A/D- and alpha2B-adrenoceptors in 1-weekold rats provoked tachycardia. In contrast, blockade of alpha2C-adrenoceptors in newborn rats had no effect on heart rate. PMID- 26601838 TI - Redistribution of Proximal and Distal Reabsorption of Water and Ions in Rat Kidney After Treatment with Glucagon-Like Peptide-1 Mimetic. AB - Injection of a glucagon-like peptide-1 mimetic accelerated recovery of the initial status of water-salt balance in rats after water or saline load (2.5% NaCl). This effect is mediated by a decrease in proximal fluid reabsorption and change in ion and water transport in the distal part of renal tubules. We developed a new approach to calculation of additional fluid inflow from the proximal tubule to the distal tubule and distal sodium reabsorption under the influence of this mimetic in rats. The expected values corresponded to experimental results, which confirmed our hypothesis on the physiological mechanism for the involvement of the kidneys in the homeostatic effect of glucagon-like peptide-1 under variations in water-salt balance. PMID- 26601839 TI - Role of PI3K, ERK, and p38 Signaling Pathways in the Production of Humoral Erythropoiesis Regulators under Normal Conditions. AB - PI3- and MAP-kinase signaling pathways duplicate and interchange each other in production of agents that determine total erythropoietic activity under conditions of balanced erythropoiesis. The alternative p38-dependent MAP-kinase pathway is the major regulator of erythropoietic activity of adherent bone marrow cells. Blockade of PI3K and p38 signaling pathways stimulated production of erythropoietin by cells that do not produce it constitutively. PMID- 26601840 TI - Methylarginines in Mice with Experimental Atherosclerosis. AB - We studied the dynamics of indexes for the system of endogenous regulation of NO bioavailability. The content of NO synthase inhibitors (monomethylarginine and asymmetric dimethylarginine) in the blood of mice was measured after intraperitoneal injections of a nonionic surfactant poloxamer 407 for 2 and 14 weeks. The concentrations of both methylarginines in animals with atherosclerosis due to 14-week administration of poloxamer were much higher than in control specimens. The amount of arginine and symmetric dimethylarginine practically did not differ from the control. Poloxamer-induced model of atherosclerosis is characterized by increased content of NO synthase inhibitors. These changes contribute to the development of endothelial dysfunction and atherosclerosis. PMID- 26601841 TI - Pharmaceutical Composition for Improving Physical Working Capacity. AB - For development of a pharmaceutical composition improving physical performance, effects of various drugs and their combinations on forced swimming test performance were studied on laboratory rats. Maximum increase in animal performance was produced by a 3-component composition asparcam+mildronate+metaprote in proportion of 5.0, 10.7, and 14.3 mg/kg, respectively. No changes in blood serum biochemistry and morphological composition of the peripheral blood were detected after single intragastric administration of the composition. PMID- 26601842 TI - Reproductive Health and Peculiarities of Lipid Peroxidation-Antioxidant Defense System in Men of the Main Ethnic Groups of the Baikal Region. AB - Quality of sperm and some parameters of LPO reflecting primary and end stages of oxidation and levels of alpha-tocopherol and total antioxidant activity were studied in ejaculate samples from 130 men (mean age of 24 years) living in Ulan Ude, Buryatia Republic. All participants took a part in survey and were examined by an andrologist. The observed peculiarities of LPO and antioxidant defense in Russian men, such as decreased level of substrate supply for the processes of LPO and alpha-tocopherol, attest to specificity of metabolic processes and development of compensatory reactions of the organism under physiological conditions. LPO processes were more active in Buryat men, which can indicate exposure of cell membranes to toxic oxygen species. However, the observed in these patients significant increase in alpha-tocopherol concentration reflects adequate functioning of the adaptive and protective mechanisms of the body. PMID- 26601843 TI - Effects of Liposomal Compositions with Oxidized Dextrans on Functional Activity of U937 Macrophage-Like Cells In Vitro. AB - We studied the effects of liposomal pharmaceutical compositions with oxidized dextrans on functional activity of U937 monocyte/macrophage-like cells. Liposomes in the emulsion contained oxidized dextran with a molecular weights of 40 kDa or 70 kDa or isonicotinic acid hydrazide (INAH) conjugated with oxidized dextran (40 kDa). Cell viability was evaluated by MTT test; mitochondrial transmembrane potential and production of superoxide anion and H2O2 were studied by fluorescent methods. The studied compositions exhibited no cytotoxic effect and even improved cell viability and mitochondrial respiration. Liposomes with oxidized 40 kDa dextran, including those with INAH-conjugated dextran, inhibited production of superoxide anion, but increased H2O2 generation. PMID- 26601844 TI - Activity of Glutathione Antioxidant System and NADPH-Generating Enzymes in Rats with Experimental Rheumatoid Arthritis. AB - Induction of rheumatoid arthritis in rats was accompanied by an increase in diene conjugate content and glutathione reductase and glutathione peroxidase activities in muscles and blood serum. These changes can be related to mobilization of the glutathione reductase/glutathione peroxidase system coupled with intensification of free radical oxidation. In addition, activity of glucose-6 phosphodehydrogenase and NADP-dependent isocitrate dehydrogenase increased, which can be related to increased demand of NADPH for the glutathione reductase/glutathione peroxidase system. The content of reduced glutathione in muscles and blood serum decreased, probably, due to its utilization for ROS neutralization. Glutathione transferase activity decreased in rheumatoid arthritis, which can be related to shortness of reduced glutathione developing during oxidative stress. The observed shifts in parameters of free radical homeostasis in rheumatoid arthritis are probably associated with intensification of free radical oxidation. PMID- 26601845 TI - The Effect of Changes in Health Beliefs Among African-American and Rural White Church Congregants Enrolled in an Obesity Intervention: A Qualitative Evaluation. AB - Church interventions can reduce obesity disparities by empowering participants with knowledge and skills within an established community. The purpose of this study was to evaluate the Biomedical/Obesity Reduction Trial (BMORe) and investigate changes in health beliefs among obese adult participants. Ten pre /post-intervention focus groups applying the Health Belief Model conducted in two African-American churches in Tennessee (n = 20) and South Carolina (n = 20), and one rural Appalachian church in Kentucky (n = 21). Two independent coders using NVivo analyzed transcribed audio data and notes. Participants' health status of being overweight/obese and having comorbidities of diabetes and high blood pressure motivated enrollment in BMORe. Initially participants voiced low self efficacy in cooking healthy and reading food labels. BMORe made participants feel "empowered" after 12 weeks compared to initially feeling "out of control" with their weight. Participants reported improvements in emotional health, quality of life, and fewer medications. During post-intervention focus groups, participants reported increased self-efficacy through family support, sharing healthy eating strategies, and having accountability partners. Solidarity and common understanding among BMORe participants led focus group attendees to comment how their peers motivated them to stay in the program for 12 weeks. Long-term barriers include keeping the weight off by maintaining habits of exercise and healthy eating. Implementation of pre-/post-intervention focus groups is an innovative approach to evaluate an obesity intervention and track how changes in health beliefs facilitated behavior change. This novel approach shows promise for behavioral interventions that rely on participant engagement for sustained effectiveness. PMID- 26601846 TI - [Injuries of the acromioclavicular joint: Hook plate versus arthroscopy]. AB - Acute acromioclavicular (AC) joint injuries are common in clinical practice. The hook plate is a well-established conventional operative treatment option for high grade instability; however, arthroscopically-assisted flexible double button techniques are increasingly being used. Both procedures lead to good or excellent results. The advantages of the hook plate are the simple surgical technique and the possibility of an early functional aftercare. The minimally invasive one-step procedure with the possibility of identification and treatment of frequently concomitant glenohumeral pathologies is advantageous for the arthroscopic technique but mobilization is more restrictive. Available comparative studies have shown no significant clinical differences but a tendency towards better results with a higher degree of acceptance among patients for the arthroscopic and minimally invasive non-rigid double button procedures. PMID- 26601847 TI - [Geriatric trauma centers from the idea to implementation. What has been achieved?]. AB - The geriatric trauma working party, a subgroup of the German Society of Trauma Surgery (Deutsche Gesellschaft fur Unfallchirurgie, DGU), focuses on the challenges of geriatric fractures, which are steadily increasing due to demographic changes. Inherent comorbidities implicate perioperative complications leading to loss of mobility and endangered independence followed by an increased burden on the social services. An interdisciplinary approach is required. The geriatric trauma working party defined criteria for interdisciplinary treatment and comprehensive care as well as early rehabilitation in interdisciplinary geriatric fracture centers. By passing an independent audit process these centers can achieve certification as a geriatric trauma center DGU (AltersTraumaZentrum DGU). Certified centers can participate in a recently established geriatric fracture registry which includes an internationally consented data set. Audit and registry enable centers to acquire an international benchmark, ensure permanent improvement in quality and allow participation in health services research. PMID- 26601848 TI - [No improved survival rate in severely injured patients by prehospital intubation : A retrospective data analysis and matched-pair analysis]. AB - BACKGROUND: Training programs for the treatment of trauma patients generally recommend establishing a secure airway if the patient presents with a Glasgow coma scale (GCS) score of less than 9; however, the evidence for its effectiveness is rather sparse. This study analyzed the effect of preclinical intubation on mortality of patients with a GCS <9 in an emergency medical situation. METHODS: This retrospective analysis included patients who were primarily admitted to a German level 1 trauma center between 2002 and 2012 with an injury severity score (ISS) >= 16, a GCS < 9 and primary transport from the site of the accident. Data were collected from the trauma registry of the German Society for Trauma Surgery and from hospital records. A total of 455 patients were included and a matched-pair analysis of 62 patients was conducted. RESULTS: Both analytical methods showed no significant reduction in mortality rate after prehospital intubation. In the retrospective analysis intubated patients presented with a significantly lower systolic blood pressure on admission, received a higher amount of fluid volume at all phases of treatment and arrived at the hospital after a prolonged rescue time. In the matched-pair analysis, intubated patients also received a higher amount of fluid volume and showed better peripheral oxygen saturation on admission. No further differences between the groups could be found. CONCLUSION: It appears that preclinical intubation in trauma patients with a GCS < 9 does not result in a better outcome. The preclinical intubation resulted in a reduced systolic blood pressure on arrival at hospital, a prolonged preclinical rescue time and a greater amount of infused fluid volume. PMID- 26601849 TI - Emergence agitation in children: risk factors, prevention, and treatment. AB - Emergence agitation (EA) in children is a major postoperative issue that increases the risk of patient self-harm, places a burden on nursing staff, and reduces parent satisfaction with treatment. Risk factors for EA include age, preoperative anxiety, patient personality, pain, anesthesia method, and surgical procedure. Sevoflurane and desflurane are widely used anesthetics due to their low blood/gas partition coefficients, but they have recently been posited as a cause of EA in children. The perioperative administration of opioids, midazolam, ketamine, alpha-2 agonist sedatives, and nonsteroidal anti-inflammatory drugs has demonstrated efficacy in the prevention and treatment of EA. Maintenance of anesthesia using propofol has also been shown to prevent EA. In children, anesthesia methods that are unlikely to cause EA should be selected, with the prompt adminstration of appropriate treatment in cases of EA. PMID- 26601850 TI - Long term trends in prevalence of neural tube defects in Europe: population based study. AB - STUDY QUESTION: What are the long term trends in the total (live births, fetal deaths, and terminations of pregnancy for fetal anomaly) and live birth prevalence of neural tube defects (NTD) in Europe, where many countries have issued recommendations for folic acid supplementation but a policy for mandatory folic acid fortification of food does not exist? METHODS: This was a population based, observational study using data on 11,353 cases of NTD not associated with chromosomal anomalies, including 4162 cases of anencephaly and 5776 cases of spina bifida from 28 EUROCAT (European Surveillance of Congenital Anomalies) registries covering approximately 12.5 million births in 19 countries between 1991 and 2011. The main outcome measures were total and live birth prevalence of NTD, as well as anencephaly and spina bifida, with time trends analysed using random effects Poisson regression models to account for heterogeneities across registries and splines to model non-linear time trends. SUMMARY ANSWER AND LIMITATIONS: Overall, the pooled total prevalence of NTD during the study period was 9.1 per 10,000 births. Prevalence of NTD fluctuated slightly but without an obvious downward trend, with the final estimate of the pooled total prevalence of NTD in 2011 similar to that in 1991. Estimates from Poisson models that took registry heterogeneities into account showed an annual increase of 4% (prevalence ratio 1.04, 95% confidence interval 1.01 to 1.07) in 1995-99 and a decrease of 3% per year in 1999-2003 (0.97, 0.95 to 0.99), with stable rates thereafter. The trend patterns for anencephaly and spina bifida were similar, but neither anomaly decreased substantially over time. The live birth prevalence of NTD generally decreased, especially for anencephaly. Registration problems or other data artefacts cannot be excluded as a partial explanation of the observed trends (or lack thereof) in the prevalence of NTD. WHAT THIS STUDY ADDS: In the absence of mandatory fortification, the prevalence of NTD has not decreased in Europe despite longstanding recommendations aimed at promoting peri-conceptional folic acid supplementation and existence of voluntary folic acid fortification. FUNDING, COMPETING INTERESTS, DATA SHARING: The study was funded by the European Public Health Commission, EUROCAT Joint Action 2011-2013. HD and ML received support from the European Commission DG Sanco during the conduct of this study. No additional data available. PMID- 26601851 TI - The modulation of adiponectin by STAT5-activating hormones. AB - Adiponectin is a hormone secreted from adipocytes that plays an important role in insulin sensitivity and protects against metabolic syndrome. Growth hormone (GH) and prolactin (PRL) are potent STAT5 activators that regulate the expression of several genes in adipocytes. Studies have shown that the secretion of adiponectin from adipose tissue is decreased by treatment with PRL and GH. In this study, we demonstrate that 3T3-L1 adipocytes treated with GH or PRL exhibit a reduction in adiponectin protein levels. Furthermore, we identified three putative STAT5 binding sites in the murine adiponectin promoter and show that only one of these, located at -3,809, binds nuclear protein in a GH- or PRL-dependent manner. Mutation of the STAT5 binding site reduced PRL-dependent protein binding, and supershift analysis revealed that STAT5A and -5B, but not STAT1 and -3, bind to this site in response to PRL. Chromatin immunoprecipitation (IP) analysis demonstrated that only STAT5A, and not STAT1 and -3, bind to the murine adiponectin promoter in a GH-dependent manner in vivo. Adiponectin promoter/reporter constructs were responsive to GH, and chromatin IP analysis reveals that STAT5 binds the adiponectin promoter in vivo following GH stimulation. Overall, these data strongly suggest that STAT5 activators regulate adiponectin transcription through the binding of STAT5 to the -3,809 site that leads to decreased adiponectin expression and secretion. These mechanistic observations are highly consistent with studies in mice and humans that have high GH or PRL levels that are accompanied by lower circulating levels of adiponectin. PMID- 26601852 TI - An outbreak of high-level azithromycin resistant Neisseria gonorrhoeae in England. AB - OBJECTIVES: To investigate a potential outbreak of high-level azithromycin resistant (HL-AziR) gonococcal infections diagnosed in eight patients attending a sexual health clinic in Leeds, North England, between November 2014 and March 2015. METHODS: Eight cases of infection with gonococci exhibiting azithromycin minimum inhibitory concentrations (MICs) >=256 mg/L were identified from patients in Leeds as part of the routine service provided by the Sexually Transmitted Bacteria Reference Unit. All patient records were reviewed to collate epidemiological and clinical information including evaluation of patient management. Whole-genome sequencing (WGS) was performed on seven gonococcal isolates to determine Neisseria gonorrhoeae multiantigen sequence type (NG-MAST), WGS comparison and mutations in the 23S rRNA genes. RESULTS: All patients were heterosexual (five male, three female) from a range of ethnic backgrounds and from the Leeds area. Three patients were linked by partner notification. All patients were infected at genital sites and two women had pharyngeal infection also. Six patients received the recommended first-line therapy for uncomplicated gonorrhoea, one was treated for pelvic inflammatory disease and one received spectinomycin followed later by ciprofloxacin. Test of cure was achieved in seven patients and confirmed successful eradication. All seven isolates sequenced were identical by NG-MAST and WGS comparison, and contained an A2143G mutation in all four 23S rRNA alleles. CONCLUSIONS: Epidemiological and microbiological investigations confirm that an outbreak of a gonococcal strain showing HL-AziR is ongoing in the North of England. Every effort should be made to identify and curtail dissemination of this strain as it presents a significant threat to the current recommended front-line dual therapy. PMID- 26601853 TI - Real-time scattered light dark-field microscopic imaging of the dynamic degradation process of sodium dimethyldithiocarbamate. AB - Single nanoparticle analysis (SNA) technique with the aid of a dark-field microscopic imaging (iDFM) technique has attracted wide attention owing to its high sensitivity. Considering that the degradation of pesticides can bring about serious problems in food and the environment, and that the real-time monitoring of the dynamic degradation process of pesticides can help understand and define their degradation mechanisms, herein we real-time monitored the decomposition dynamics of sodium dimethyldithiocarbamate (NaDDC) under neutral and alkaline conditions by imaging single silver nanoparticles (AgNPs) under a dark-field microscope (DFM); the localized surface plasmon resonance (LSPR) scattering signals were measured at a single nanoparticle level. As a result, the chemical mechanism of the degradation of NaDDC under neutral and alkaline conditions was proposed, and the inhibition effects of metal ions including Zn(II) and Cu(II) were investigated in order to understand the decomposition process in different environments. It was found that Cu(II) forms the most stable complex with NaDDC with a stoichiometric ratio of 1 : 2, which greatly reduces the toxicity. PMID- 26601854 TI - [Pneumopericardium in a patient with tracheal rupture after multiple injuries from a traffic accident]. PMID- 26601855 TI - Epidemiology of severe sepsis: 2008-2012. AB - INTRODUCTION: Severe sepsis continues to be a significant burden on society. METHODS: Using the International Classification of Diseases, Ninth Revision, Clinical Modification codes, we analyzed the Healthcare Cost and Utilization Project National Inpatient Sample in order to estimate epidemiologic trends of severe sepsis from the years 2008 to 2012. The 2010 US Census, which included 308,745,538 individuals, was used to calculate incidence per 100,000 persons. RESULTS: There were a total of 6,067,789 discharges for severe sepsis. The annual incidence increased from 346/100,000 to 436/100,000 persons (P < .05). Individuals with 3 or greater organ system failures increased from 31.6% to 35.5% (P < .05), and they accounted for 57.2% to 66.7% of the total number of deaths. Overall mortality decreased from 22.2% to 17.3% (P < .05). Length of stay decreased from 9 to 7 days (P < .05). Those discharged to home with and without home-health increased (23%-27%; P < .05), but those discharged to skilled nursing facilities remained the same (35%). CONCLUSIONS: The incidence of severe sepsis continues to increase, whereas mortality decreases. However, one third of patients (those with >=3 organ system failures) account for two thirds of the total number of deaths. More people are discharged home, whereas stable numbers go to facilities. PMID- 26601856 TI - Reply to "How delineate OSA and CPAP link in postoperative atrial fibrillation conundrum?". PMID- 26601857 TI - Heterogeneity in Melanoma. AB - Melanoma is among the most aggressive and therapy-resistant human cancers. While great strides in therapy have generated enthusiasm, many challenges remain. Heterogeneity is the most pressing issue for all types of therapy. This chapter summarizes the clinical classification of melanoma, of which the research community now adds additional layers of classifications for better diagnosis and prediction of therapy response. As the search for new biomarkers increases, we expect that biomarker analyses will be essential for all clinical trials to better select patient populations for optimal therapy. While individualized therapy that is based on extensive biomarker analyses is an option, we expect in the future genetic and biologic biomarkers will allow grouping of melanomas in such a way that we can predict therapy outcome. At this time, tumor heterogeneity continues to be the major challenge leading inevitably to relapse. To address heterogeneity therapeutically, we need to develop complex therapies that eliminate the bulk of the tumor and, at the same time, the critical subpopulations. PMID- 26601858 TI - Melanoma Epidemiology and Prevention. AB - The epidemiology of melanoma is complex, and individual risk depends on sun exposure, host factors, and genetic factors, and in their interactions as well. Sun exposure can be classified as intermittent, chronic, or cumulative (overall) exposure, and each appears to have a different effect on type of melanoma. Other environmental factors, such as chemical exposures-either through occupation, atmosphere, or food-may increase risk for melanoma, and this area warrants further study. Host factors that are well known to be important are the numbers and types of nevi and the skin phenotype. Genetic factors are classified as high penetrant genes, moderate-risk genes, or low-risk genetic polymorphisms. Subtypes of tumors, such as BRAF-mutated tumors, have different risk factors as well as different therapies. Prevention of melanoma has been attempted using various strategies in specific subpopulations, but to date optimal interventions to reduce incidence have not emerged. PMID- 26601859 TI - Methods of Melanoma Detection. AB - Detection and removal of melanoma, before it has metastasized, dramatically improves prognosis and survival. The purpose of this chapter is to (1) summarize current methods of melanoma detection and (2) review state-of-the-art detection methods and technologies that have the potential to reduce melanoma mortality. Current strategies for the detection of melanoma range from population-based educational campaigns and screening to the use of algorithm-driven imaging technologies and performance of assays that identify markers of transformation. This chapter will begin by describing state-of-the-art methods for educating and increasing awareness of at-risk individuals and for performing comprehensive screening examinations. Standard and advanced photographic methods designed to improve reliability and reproducibility of the clinical examination will also be reviewed. Devices that magnify and/or enhance malignant features of individual melanocytic lesions (and algorithms that are available to interpret the results obtained from these devices) will be compared and contrasted. In vivo confocal microscopy and other cellular-level in vivo technologies will be compared to traditional tissue biopsy, and the role of a noninvasive "optical biopsy" in the clinical setting will be discussed. Finally, cellular and molecular methods that have been applied to the diagnosis of melanoma, such as comparative genomic hybridization (CGH), fluorescent in situ hybridization (FISH), and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), will be discussed. PMID- 26601860 TI - Melanoma: Clinical Presentations. AB - The malignant cell in melanoma is the melanocyte. Because melanocytes are located in the basal layer of the epidermis, melanoma is most commonly seen on the skin. However, melanoma can also arise on mucosal surfaces such as the oral cavity, the upper gastrointestinal mucosa, the genital mucosa, as well as the uveal tract of the eye and leptomeninges. Melanomas tend to be pigmented but can also present as pink or red lesions. They can mimic benign or other malignant skin lesions. This chapter presents the spectrum of typical and less typical presentations of melanoma, as well as patterns of spread. It is divided into (1) cutaneous lesions; (2) patterns of regional spread, (3) non-cutaneous lesions; and (4) distant metastases. PMID- 26601861 TI - Principles of Melanoma Staging. AB - Although now commonplace in contemporary cancer care, the systematic approach to classification of disease-specific cancers into a formalized staging system is a relatively modern concept. Overall, the goals of cancer staging are to characterize the status of cancer at a specific moment in time, risk stratify, facilitate prognostication, and inform clinical decision making. The revisions to the American Joint Committee on Cancer (AJCC) melanoma staging system over time reflect changes in our understanding of the biology of the disease. Since the 1st edition, where tumor thickness was defined anatomically by its relationship to the reticular or papillary dermis (Clark level) as well as tumor thickness (Breslow thickness), there have been significant strides in our use of clinicopathological variables to stratify low- versus high-risk patients. Management of the regional nodal basin has also changed dramatically over time, impacted by techniques such as lymphatic mapping and sentinel lymph node biopsy (SLNB) and changes in pathological evaluation of the regional lymph nodes. Additionally, stratification of distant metastases has evolved as survival outcomes have been shown to vary based upon anatomic site of metastases and serum lactate dehydrogenase levels. The variables in use in the current (7th edition) AJCC staging system are surrogate markers of biology with validated impact of survival outcomes. Going forward, it is likely that these and additional clinicopathological factors will be integrated with molecular and other correlates of melanoma tumor biology to further refine and personalize melanoma staging. PMID- 26601862 TI - Surgical Management of Melanoma. AB - The surgical management of melanoma has undergone considerable changes over the past several decades, as new strategies and treatments have become available. Surgeons play a pivotal role in all aspects of melanoma care: diagnostic, curative, and palliative. There is a high potential for cure in patients with early-stage melanoma and the selection of an appropriate operation is very important for this reason. Staging the nodal basin has become widespread since the adoption of sentinel lymph node biopsy (SLNB) for the management of melanoma. This operation provides the best prognostic information that is currently available for patients with melanoma. The surgeon plays a central role in the palliation of symptoms resulting from nodal disease and metastases, as melanoma has a propensity to spread to almost any site in the body. PMID- 26601863 TI - Adjuvant Therapy of Melanoma. AB - The incidence of melanoma is rapidly increasing, especially in younger female and older male patients. Recent fundamental advances in our knowledge of melanoma tumorigenesis have established roles for inhibitors of the MAPK pathway and regulatory immune checkpoints CTLA-4 and PD-1/PD-L1. However, the majority of patients continue to present with non-metastatic disease-typically managed with surgical resection and adjuvant therapy. High-dose IFN-alpha2b (HDI) is the main adjuvant therapeutic mainstay in high-risk disease following definitive resection. In this chapter, we review the evidence supporting the use of adjuvant HDI in high-risk melanoma. We also discuss some of the other treatment modalities that have been evaluated including vaccines, chemotherapy, and radiotherapy. PMID- 26601864 TI - Chemotherapy for Melanoma. AB - Prior to the recent therapeutic advances, chemotherapy was the mainstay of treatment options for advanced-stage melanoma. A number of studies have investigated various chemotherapy combinations in order to expand on the clinical responses achieved with single-agent dacarbazine, but these have not demonstrated an improvement in overall survival. Similar objective responses were observed with the combination of carboplatin and paclitaxel as were seen with single-agent dacarbazine. The combination of chemotherapy and immunotherapy, known as biochemo therapy, has shown high clinical responses; however, biochemo-therapy has not been shown to improve overall survival and resulted in increased toxicities. In contrast, palliation and long-term responses have been observed with localized treatment with isolated limb perfusion or infusion in limb-isolated disease. Although new, improved therapeutic options exist for first-line management of advanced-stage melanoma, chemotherapy may still be important in the palliative treatment of refractory, progressive, and relapsed melanoma. We review the various chemotherapy options available for use in the treatment and palliation of advanced-stage melanoma, discuss the important clinical trials supporting the treatment recommendations, and focus on the clinical circumstances in which treatment with chemotherapy is useful. PMID- 26601865 TI - Checkpoint Blockade for the Treatment of Advanced Melanoma. AB - Immunotherapy with immune checkpoint inhibition has been improving the outcomes of patients with many different types of malignancies. Immune checkpoint inhibition has been most extensively studied in patients with advanced melanoma and there are three FDA approved antibodies already widely used in clinical practice (ipilimumab, nivolumab, and pembrolizumab). In this chapter, we review the mechanistic basis behind the development of immune checkpoint blocking antibodies. We then discuss specifics regarding each agent, unique clinical considerations in treating patients with this approach, and future directions, including combination strategies. This chapter is focused on melanoma, but the principles related to this immunotherapy approach are applicable to patients with many types of malignancies. PMID- 26601866 TI - Targeted Therapy for Melanoma. AB - Vemurafenib and dabrafenib, two potent tyrosine kinase inhibitors (TKIs) of the BRAF(V600E) kinase, are highly effective in the treatment of a BRAF (V600) mutant metastatic melanoma. These are selective type I inhibitors (functional against the active conformation of the kinase) of the RAF kinases, which are key players in the mitogen-activated protein kinase (MAPK) pathway. BRAF (V600) mutations are present in approximately 7 % of all cancers, including high frequencies of mutations reported in 50 % of advanced melanomas and 100 % of hairy cell leukemias. As with most targeted therapies, resistance to BRAF inhibitors is an issue, and mechanisms of resistance are varied. Combining BRAF inhibitors with MEK inhibitors such as trametinib delays the development of resistance. Rationally combining targeted therapies to address the mechanism of resistance or combining BRAF inhibitors with other effective therapies such as immunotherapy may result in further improvement in outcomes for patients. PMID- 26601867 TI - Treatment of Melanoma CNS Metastases. AB - The discovery of the BRAFV600 mutation and the development of targeted therapies directed against this mutation as well as effective immunotherapies with durable benefits have revolutionized the treatment of patients with melanoma. Nonetheless, the frequent occurrence of brain metastases in patients with advanced melanoma represents a significant obstacle to long-term, high quality survival. The application of stereotactic radiation therapy has provided an opportunity to control brain metastases in the majority of patients with metastatic melanoma reducing the impact of these lesions on morbidity and mortality and enabling patients to receive and potentially benefit from these novel systemic treatments. Encouragingly, several of these novel new therapies have shown antitumor activity against CNS metastases that approach that seen against extracranial disease. As a consequence, several effective treatment options are now available for patients with melanoma brain metastases. With these tools in hand, it is anticipated that further investigation into the optimal sequence and/or combination of systemic therapies and local therapies along with multidisciplinary team practice will continue to improve the outcome of patients with this previously life-limiting disease complication. PMID- 26601868 TI - Treatment of Uveal Melanoma. AB - Uveal melanoma (UM) comprises approximately 5 % of all melanoma diagnoses in the USA each year. Approximately half of patients with UM eventually develop metastases, most commonly involving the liver. Historically, prognosis for these patients has been poor, with death occurring 6-12 months from the time of metastases. Multiple trials of cytotoxic treatments largely extrapolated from cutaneous melanoma have been ineffective in metastatic UM. Trials of regional hepatic-directed therapy have led to high response rates, but these have yet to be translated into a survival benefit. Recently, it was discovered that the majority of UMs harbor activating mutations in genes encoding one of two G-alpha protein subunits, GNAQ and GNA11. This knowledge has led to the rational development of clinical trials specifically for UM utilizing targeted inhibitors of the activated signaling pathways such as mitogen-activated protein kinase, Akt, and protein kinase C. A recent trial of the oral MEK inhibitor selumetinib was the first to show clinical benefit for any systemic therapy in a randomized fashion. This increasing understanding of the biology of UM offers hope that novel treatments will continue to benefit patients with metastatic disease. PMID- 26601869 TI - Mucosal Melanoma: Epidemiology, Biology and Treatment. AB - Mucosal melanoma is an exceedingly rare variant of cutaneous melanoma that, due to its rarity, is poorly described and infrequently studied. Primary sites of origin include the head and neck, anorectum and vulvovaginal regions. It is uniquely different from cutaneous melanoma with respect to epidemiology, etiology, pathogenesis and prognosis. The etiology and pathogenesis remain unclear. Unlike cutaneous melanoma, exposure to UV light is not an apparent risk factor. Furthermore, distinct molecular features including a lower incidence of BRAF oncogene mutations but a higher incidence of KIT oncogene mutations suggest divergent genetic etiologies. Mucosal melanomas generally present at a later stage, are more aggressive and carry a worse prognosis regardless of the stage at diagnosis. Establishing standardized treatment guidelines has been challenging due to the rarity of the disease. Early detection provides the best chance at survival but is often difficult due to anatomic location. Surgery remains the primary therapeutic intervention if complete resection is technically feasible given the anatomic location. Radiotherapy may be used to achieve local control when resection is not feasible, or adjuvantly to enhance locoregional control, but most studies have failed to demonstrate an improvement in overall survival. There are no consensus guidelines on the optimal systemic therapy, and regimens are often extrapolated from data based on therapies used to treat advanced cutaneous melanoma. Clinical trials, particularly utilizing newer targeted therapies and immunotherapies, are investigating novel treatment approaches. PMID- 26601870 TI - Acral Lentiginous Melanoma. AB - Acral lentiginous melanoma (ALM) is a rare subtype of melanoma mainly arising on the palms, soles, and nail beds. ALM is the most common subtype of melanoma found in patients of Asian or African descent and tends to more advanced at presentation due to delays in diagnosis. Surgical treatment is difficult owing to the complexity and functional importance of the hands and feet and reconstruction after resection is usually needed. The prognosis for patients with ALM depends on stage of disease and tends to be worse than with other subtypes of melanoma. Newer treatment modalities such as immunotherapies and targeted agents are being tested in patients with advanced ALM with some promising preliminary results. PMID- 26601871 TI - Pediatric Melanoma and Atypical Melanocytic Neoplasms. AB - Melanoma is uncommon in the pediatric age range, but is increasing in frequency and often presents with atypical features compared to the classic ABCDE criteria common to adult melanoma cases. Moreover, many melanocytic neoplasms in childhood pose diagnostic challenges to the pathologist, and sometimes cannot be unequivocally classified as benign nevi or melanoma. This chapter addresses the evaluation and management of pediatric patients with melanoma and atypical melanocytic neoplasms, including the roles of and unresolved questions surrounding sentinel lymph node biopsy, completion lymphadenectomy, adjuvant therapy, and treatment of advanced disease. PMID- 26601872 TI - Novel Treatments in Development for Melanoma. AB - The past several years can be considered a renaissance era in the treatment of metastatic melanoma. Following a 30-year stretch in which oncologists barely put a dent in a very grim overall survival (OS) rate for these patients, things have rapidly changed course with the recent approval of three new melanoma drugs by the FDA. Both oncogene-targeted therapy and immune checkpoint blockade approaches have shown remarkable efficacy in a subset of melanoma patients and have clearly been game-changers in terms of clinical impact. However, most patients still succumb to their disease, and thus, there remains an urgent need to improve upon current therapies. Fortunately, innovations in molecular medicine have led to many silent gains that have greatly increased our understanding of the nature of cancer biology as well as the complex interactions between tumors and the immune system. They have also allowed for the first time a detailed understanding of an individual patient's cancer at the genomic and proteomic level. This information is now starting to be employed at all stages of cancer treatment, including diagnosis, choice of drug therapy, treatment monitoring, and analysis of resistance mechanisms upon recurrence. This new era of personalized medicine will foreseeably lead to paradigm shifts in immunotherapeutic treatment approaches such as individualized cancer vaccines and adoptive transfer of genetically modified T cells. Advances in xenograft technology will also allow for the testing of drug combinations using in vivo models, a truly necessary development as the number of new drugs needing to be tested is predicted to skyrocket in the coming years. This chapter will provide an overview of recent technological developments in cancer research, and how they are expected to impact future diagnosis, monitoring, and development of novel treatments for metastatic melanoma. PMID- 26601873 TI - Potential costs of breast augmentation mammaplasty. AB - BACKGROUND: Augmentation mammaplasty is one of the most common surgical procedures performed by plastic surgeons. The aim of this study was to estimate the cost of the initial procedure and its subsequent complications, as well as project the cost of Food and Drug Administration (FDA)-recommended surveillance imaging. METHODS: The potential costs to the individual patient and society were calculated. Local plastic surgeons provided billing data for the initial primary silicone augmentation and reoperative procedures. Complication rates used for the cost analysis were obtained from the Allergen Core study on silicone implants. Imaging surveillance costs were considered in the estimations. RESULTS: The average baseline initial cost of silicone augmentation mammaplasty was calculated at $6335. The average total cost of primary breast augmentation over the first decade for an individual patient, including complications requiring reoperation and other ancillary costs, was calculated at $8226. Each decade thereafter cost an additional $1891. Costs may exceed $15,000 over an averaged lifetime, and the recommended implant surveillance could cost an additional $33,750. DISCUSSION: The potential cost of a breast augmentation, which includes the costs of complications and imaging, is significantly higher than the initial cost of the procedure. LEVEL OF EVIDENCE: Level III, economic and decision analysis study. PMID- 26601874 TI - The V-Y capsulotomy release for correcting capsular contracture. PMID- 26601875 TI - A novel noninvasive three-dimensional volumetric analysis for fat-graft survival in facial recontouring using the 3L and 3M technique. AB - BACKGROUND: Autologous fat grafting for volume augmentation in soft tissue has grown in popularity in the plastic surgery. AIM: The aim of this study is to provide a new three-dimensional (3D) modeling and analyzing technique for evaluating long-term outcomes of autologous fat graft. METHODS: A retrospective study was conducted using the medical records of 22 patients who underwent autologous fat grafting by using our "3L and 3M" technique. The average follow-up period was 12 months. Every patient received 3D scanning before and 3, 6, and 12 months after the operation. The 3D facial models were analyzed with corresponding analyzing software to quantify the volume discrepancy at different periods. The retention rate of fat was calculated by comparing both postoperative and preoperative images. RESULTS: In the objective evaluation, the average injected fat volume was 18 +/- 12.68 ml, while the average survival fat volume was 11.61 +/- 7.58 ml at 3 months, 9.05 +/- 5.59 ml at 6 months, and 7.97 +/- 4.57 ml at the last follow-up, respectively. Therefore, the amount of fat graft remaining in the recipient sites was 28.94-56.25% (average 44.53 +/- 6.32%) at 12 months after operation. CONCLUSION: In this study, we have demonstrated the ability to use the novel noninvasive 3D volumetric analysis for the survival of fat graft. We consider that the "3L and 3M" technique is an effective and long-lasting treatment of fat grafting for correcting congenital or acquired defects compared with the outcomes of fat grafting reported by other researchers. PMID- 26601876 TI - Pediatric lower extremity sarcoma reconstruction: A review of limb salvage procedures and outcomes. AB - BACKGROUND: In recent years, dramatic advances in the multidisciplinary treatment of pediatric sarcoma have resulted in significant improvement in the long-term survival of the patient. Thus, following tumor resection, significant effort has gone into limb salvage and improving functional outcomes. Plastic surgeons, in conjunction with orthopedic surgeons, are using techniques in microvascular free tissue transfer and rotational flap surgery to preserve limb length. This study presents a review of the current reconstructive strategies and the oncologic, surgical, and functional outcomes in this population. METHODS: Using the Pubmed and Cochrane Library databases, studies describing lower extremity plastic surgical reconstruction were identified following pediatric lower extremity sarcoma resection. This study included those studies which described reconstructive techniques, oncologic and functional outcomes, and surgical complications. RESULTS: A total of nine articles were identified, yielding 96 pediatric patients. The most common procedures performed were free fibular flaps (53 patients) followed by pedicled muscle flaps (31 patients). A total of 72 of 96 patients (75%) achieved independent ambulation, and an additional 19 patients (20%) ambulated with assistance. There were only three (3%) amputations. A total of 13 patients died from metastatic disease (14%). CONCLUSIONS: Plastic surgery procedures play an increasingly important role in pediatric lower extremity sarcoma reconstruction and functional limb salvage. Published series are limited in number and case volume; to date, no systematic review has been published. The existing data emphasize the role of microvascular free-fibula transfer as well as local muscle flap coverage in preserving limb length and function, with minimal risk of local recurrence and need for amputation. PMID- 26601877 TI - Clearing the field: A novel device to assist microsurgeons. PMID- 26601878 TI - Running barbed suture quilting reduces abdominal drainage in perforator-based breast reconstruction. AB - Prolonged abdominal drainage after perforator-based breast reconstruction is a common problem that can result in seroma formation, patient morbidity, and increased duration of hospital stay. Abdominal quilting with progressive tension sutures has been effective in reducing abdominal drainage in abdominoplasty patients prompting a change of practice in our unit. We studied consecutive unilateral mastectomy patients undergoing breast reconstruction with a deep inferior epigastric artery perforator (DIEP) flap. The initial 27 patients underwent breast reconstruction without any form of abdominal flap plication. The subsequent 26 patients underwent an identical DIEP flap raise procedure after which the abdominal flap was progressively tensioned using a running barbed suture quilting technique. All patients had closed suction drains inserted bilaterally until daily drain output was <40 ml in 2 consecutive days. Primary outcome measures were total volume of abdominal drainage and length of hospital stay. Independent statistical analyses were performed using Welch's t-test. There were no demographic differences between the two groups. A statistically significant decrease in the mean total abdominal drainage was found after quilting (238 ml vs. 528 ml; p = 0.0005). Patients in the quilting group also showed a reduction in mean duration of hospital stay. Quilting of the abdominal flap helps to reduce abdominal drainage not only in abdominoplasty patients but also in patients undergoing breast reconstruction with DIEP flap. PMID- 26601879 TI - Reply: "Composite orbital reconstruction using the vascularized segmentalized Osteo-Fascio-Cutaneous Fibula flap". PMID- 26601880 TI - Inverse association of HbA1c with faecal elastase 1 in people without diabetes. AB - BACKGROUND/OBJECTIVES: Faecal elastase 1 (FE1) was inversely correlated with diabetes duration and HbA1c in type 2 diabetes. The association of FE1 and HbA1c has not been investigated in people without diabetes. METHODS: Type 2 diabetes patients (oral antidiabetic drugs or insulin: n = 391; medically untreated: n = 145) and matched (age, sex, practice) people without diabetes (n = 529) from general practices in Cambridgeshire (UK) were included. FE1 measurements (MUg/g stool) were performed centrally (ScheBo-Tech Institute, Wettenberg, Germany). Linear regression models were fitted using FE1 as dependent variable and HbA1c, diabetes (no, untreated diabetes, treated diabetes) and interactions as independent variables. Potential confounders were sex, age, BMI, current alcohol consumption, smoking, triglycerides, and amylase. RESULTS: In univariate linear regression models, HbA1c was significantly inversely related to FE1 in controls (beta-coefficient: -108.74, p < 0.0001), whereas no significant associations were found for the diabetes groups. The inverse relationship of HbA1c with FE1 concentrations in people without diabetes persisted after adjusting for potential confounders in multivariate regression (beta-coefficient: -109.18, p < 0.0001). In people without diabetes, there were lower FE1 concentrations among those with increased diabetes risk (HbA1c 5.7%-6.4% [38.8-46.4 mmol/mol]: 395 +/- 204 MUg/g vs. HbA1c <= 5.6% [<=37.7 mmol/mol]: 476 +/- 219 MUg/g; p < 0.0001). The prevalence of FE1<100 MUg/g was significantly increased among persons with an HbA1c of 5.7%-6.4% (38.8-46.4 mmol/mol) compared with those with a normal HbA1c <= 5.6% (<=37.7 mmol/mol) (6.1% vs. 1.4%; p = 0.004). CONCLUSION/INTERPRETATION: The present study suggests that pancreatic exocrine dysfunction might be an early disturbance that develops in parallel with hyperglycemia. PMID- 26601881 TI - Pretreatment C-reactive protein level predicts outcome and patterns of failure after chemoradiotherapy for locally advanced pancreatic cancer. AB - OBJECTIVES: In this study we evaluated the predictive value of pretreatment C reactive protein (CRP) levels on patterns of failure and survival outcomes in patients with locally advanced pancreatic cancer (LAPC) who received chemoradiotherapy (CRT). METHODS: Data from 65 patients who underwent CRT for LAPC from July 2001 to May 2013 were retrospectively collected. Factors, including age, gender, Eastern Cooperative Oncology Group performance status (PS), histological confirmation, tumor size, tumor location, biliary drainage, stage, induction chemotherapy, CRP levels, neutrophil-to-lymphocyte ratio, platelet-lymphocyte ratio, albumin and carbohydrate antigen 19-9, were evaluated with regard to overall survival (OS) and patterns of failure using a Cox proportional hazards model. RESULTS: The 1-year OS and median follow-up for all of the patients were 63.9% and 15.2 months, respectively. The median survival time and 1-year OS were 18.0 months and 72.5%, respectively, in the patients with lower CRP levels (<=3.0 mg/L), whereas 11.0 months and 30.8%, respectively, in the patients with higher CRP levels (>3.0 mg/L). Thirty-seven patients had tumor recurrence after CRT. All of the patients with higher CRP levels developed distant metastases as a primary sign of treatment failure. In a multivariate analysis, higher CRP levels were significantly correlated with distant disease free survival (p = 0.004, HR = 4.50) and OS (p = 0.004, HR = 3.001). By contrast, local progression-free survival was not significantly different between the CRP subgroups. CONCLUSION: The CRP levels were a significant predictor of survival and distant disease control for the LAPC patients who received CRT. PMID- 26601883 TI - Editorial overview: Circuit plasticity and memory. PMID- 26601882 TI - Exploring the Effects on Lipid Bilayer Induced by Noble Gases via Molecular Dynamics Simulations. AB - Noble gases seem to have no significant effect on the anesthetic targets due to their simple, spherical shape. However, xenon has strong narcotic efficacy and can be used clinically, while other noble gases cannot. The mechanism remains unclear. Here, we performed molecular dynamics simulations on phospholipid bilayers with four kinds of noble gases to elucidate the difference of their effects on the membrane. Our results showed that the sequence of effects on membrane exerted by noble gases from weak to strong was Ne, Ar, Kr and Xe, the same order as their relative narcotic potencies as well as their lipid/water partition percentages. Compared with the other three kinds of noble gases, more xenon molecules were distributed between the lipid tails and headgroups, resulting in membrane's lateral expansion and lipid tail disorder. It may contribute to xenon's strong anesthetic potency. The results are well consistent with the membrane mediated mechanism of general anesthesia. PMID- 26601884 TI - X-ray crystallography, an essential tool for the determination of thermodynamic relationships between crystalline polymorphs. AB - After a short review of the controversies surrounding the discovery of crystalline polymorphism in relation to our present day understanding, the methods of how to solve the stability hierarchy of different polymorphs will be briefly discussed. They involve either theoretical calculations, or, more commonly, experimental methods based on classical thermodynamics. The experimental approach is mainly carried out using heat-exchange data associated to the transition of one form into another. It will be demonstrated that work related data associated to the phase transition should be taken into account and the role of X-ray crystallography therein will be discussed. X-ray crystallography has become increasingly precise and can nowadays provide specific volumes and their differences as a function of temperature, and also as a function of pressure, humidity, and time. PMID- 26601885 TI - The topological pressure-temperature phase diagram and crystal structures of the dimorphic system spiperone. AB - The topological pressure-temperature phase diagram for the dimorphism of spiperone, a potent neuroleptic drug, has been constructed using literature data and improved crystal structures obtained with new crystallographic data from single-crystal X-ray diffraction at various temperatures. It is inferred that form II, which is the more dense form and exhibits the lower melting temperature, becomes the more stable phase under pressure. Under ambient conditions, form I is more stable. PMID- 26601886 TI - A collection of Australian Drosophila datasets on climate adaptation and species distributions. AB - The Australian Drosophila Ecology and Evolution Resource (ADEER) collates Australian datasets on drosophilid flies, which are aimed at investigating questions around climate adaptation, species distribution limits and population genetics. Australian drosophilid species are diverse in climatic tolerance, geographic distribution and behaviour. Many species are restricted to the tropics, a few are temperate specialists, and some have broad distributions across climatic regions. Whereas some species show adaptability to climate changes through genetic and plastic changes, other species have limited adaptive capacity. This knowledge has been used to identify traits and genetic polymorphisms involved in climate change adaptation and build predictive models of responses to climate change. ADEER brings together 103 datasets from 39 studies published between 1982-2013 in a single online resource. All datasets can be downloaded freely in full, along with maps and other visualisations. These historical datasets are preserved for future studies, which will be especially useful for assessing climate-related changes over time. PMID- 26601888 TI - The effect of hydrostatic pressure on model membrane domain composition and lateral compressibility. AB - Phase separation in ternary model membranes is known to occur over a range of temperatures and compositions and can be induced by increasing hydrostatic pressure. We have used small angle X-ray scattering (SAXS) to study phase separation along pre-determined tie lines in dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC) and cholesterol (CHOL) mixtures. We can unequivocally distinguish the liquid ordered (Lo) and liquid disordered (Ld) phases in diffraction patterns from biphasic mixtures and compare their lateral compressibility. The variation of tie line endpoints with increasing hydrostatic pressure was determined, at atmospheric pressure and up to 100 MPa. We find an extension and shift of the tie lines towards the DOPC rich region of the phase diagram at increased pressure, this behaviour differs slightly from that reported for decreasing temperature. PMID- 26601887 TI - An Exploratory Analysis of Child Feeding Beliefs and Behaviors Included in Food Blogs Written by Mothers of Preschool-Aged Children. AB - OBJECTIVE: This study analyzed child feeding beliefs and behaviors, types of recipes, and their associations in blogs focused on child feeding. DESIGN: The authors selected 13 blogs using purposive snowball sampling, from which 158 blog posts were sampled and coded using directed qualitative content analysis. VARIABLES MEASURED: Child feeding beliefs and behaviors and types of recipes were coded using schemes developed from existing literature. ANALYSIS: Code frequencies were calculated. Chi-square tests for independence examined associations between child feeding and recipe codes. Bonferroni corrections were applied: P < .05/(n tests). RESULTS: Child feeding beliefs and behaviors were coded in 78% and 49% of posts, respectively. Beliefs about children's food preferences (48% of posts) and involving children in food preparation (27% of posts) were the most frequent codes. Recipes were included in 66% of posts. Most recipes were for mixed dishes (32% of recipes), followed by sweets and desserts (19% of recipes). Vegetable recipes were more likely in posts that included behavior encouraging balance and variety (chi2 [1, n = 104] = 18.54; P < .001). CONCLUSIONS AND IMPLICATIONS: Blog posts contained information that may influence readers' child feeding practices. Future research should explore how mothers use blogs to learn about child feeding. PMID- 26601889 TI - Geochemical and VOC-constraints on landfill gas age and attenuation characteristics: A case study from a waste disposal facility in Southern California. AB - In this study, a multi-tracer approach was applied to a complex, methane-impacted site in Southern California to (1) distinguish between natural gas and landfill gas (LFG)-derived methane impacts at site perimeter gas probes, (2) estimate the relative age of the LFG at these probes, and (3) document natural attenuation trends during a 3-year monitoring period. Relationships between methane and ethane values suggest that at the majority of probes, methane is from LFG and not from natural gas and that the relative contribution of LFG methane at these probes has increased over the monitoring period. To evaluate whether LFG is attenuating in the subsurface, the relative age of LFG was estimated by comparing readily degraded VOCs that are major constituents in LFG (toluene in this case) with those resistant to degradation (Freons). Time-series data trends are consistent with several probes being impacted by fresh LFG from recent releases that occurred after the update of the local LFG collection and control system (LFGCCS). Data further indicate some probes to be only affected by legacy LFG from a past release that occurred prior to the LFGCCS update and that, because of a lack of oxygen in the subsurface, had not been fully degraded. The outlined attenuation evaluation methodology is potentially applicable to other sites or even groundwater contaminants; however, the assessment is limited by the degree of homogeneity of the LFG source composition and non-LFG-derived toluene inputs to the analyzed samples. PMID- 26601890 TI - Effects of exogenous aerobic bacteria on methane production and biodegradation of municipal solid waste in bioreactors. AB - Landfill is the most common and efficient ways of municipal solid waste (MSW) disposal and the landfill biogas, mostly methane, is currently utilized to generate electricity and heat. The aim of this work is to study the effects and the role of exogenous aerobic bacteria mixture (EABM) on methane production and biodegradation of MSW in bioreactors. The results showed that the addition of EABM could effectively enhance hydrolysis and acidogenesis processes of MSW degradation, resulting in 63.95% reduction of volatile solid (VS), the highest methane production rate (89.83Lkg(-1) organic matter) ever recorded and a threefold increase in accumulative methane production (362.9L) than the control (127.1L). In addition, it is demonstrated that white-rot fungi (WRF) might further promote the methane production through highly decomposing lignin, but the lower pH value in leachate and longer acidogenesis duration may cause methane production reduced. The data demonstrated that methane production and biodegradation of MSW in bioreactors could be significantly enhanced by EABM via enhanced hydrolysis and acidogenesis processes, and the results are of great economic importance for the future design and management of landfill. PMID- 26601891 TI - Peripheral injection of pancreatic polypeptide enhances colonic transit without eliciting anxiety or altering colonic secretion in rats. AB - Pancreatic polypeptide (PP) is a negative regulator of energy homeostasis that suppresses food intake and lowers body weight. Similar to other gastrointestinal derived peptides, PP also modulates gastrointestinal motility and may be involved in the regulation of anxiety. Previous studies revealed that PP suppresses gastric emptying but increases colonic motility in mice. In our present study, we assessed the effect of PP on anxiety as well as colonic motility and secretory function. Intracerebroventricular and intravenous routes of PP were administered in conscious rats. Our results showed that intracerebroventricular administration of PP did not affect anxiety in the open field test. Intravenous injection of PP accelerated colonic transit, but did not significantly change fecal amount and fecal fluid composition. On the other hand, intracerebroventricular injection of PP did not alter colonic transit, fecal amount, or fluid composition. In conclusion, peripheral, but not central PP administration enhances colonic motility without eliciting anxiety or altering colonic secretion. PMID- 26601892 TI - Sequence analysis and minimal replicon determination of a new haloarchaeal plasmid pHF2 isolated from Haloferax sp. strain Q22. AB - A new cryptic plasmid, pHF2 (2520 bp), was isolated from Haloferax sp. strain Q22 (CGMCC 1.15317), a haloarchaeal strain living in a subterranean halite deposit. Sequence analysis revealed that it is the smallest plasmid in the genus Haloferax so far, and three syntropic open reading frames (ORF1, ORF2, and ORF3) were identified on the same strand. ORF1 encodes a putative replication initiation protein (Rep). Three typical motifs (I, II, and III) were presented in the Rep proteins of rolling-circle replicating (RCR) plasmids. The amino acid sequence of the Rep protein is very similar to that of another haloarchaeal plasmid pNB101 in Natronobacterium sp. AS-7091 (coverage 97%, identity 56%). The minimal replicon (~1000 bp) of pHF2 was determined through the construction of a series of truncated plasmids. Interestingly, we also found that the incomplete rep gene still can drive plasmid replication. This plasmid has provided another valuable extra-chromosomal genetic resource, and deepened our knowledge in DNA replication. PMID- 26601893 TI - Nanoparticle induced miscibility in LCST polymer blends: critically assessing the enthalpic and entropic effects. AB - The use of copolymer and polymer blends widened the possibility of creating materials with multilayered architectures. Hierarchical polymer systems with a wide array of micro and nanostructures are generated by thermally induced phase separation (TIPS) in partially miscible polymer blends. Various parameters like the interaction between the polymers, concentration, solvent/non-solvent ratio, and quenching temperature have to be optimized to obtain these micro/nanophase structures. Alternatively, the addition of nanoparticles is another strategy to design materials with desired hetero-phase structures. The dynamics of the polymer nanocomposite depends on the statistical ordering of polymers around the nanoparticle, which is dependent on the shape of the nanoparticle. The entropic loss due to deformation of polymer chains, like the repulsive interactions due to coiling and the attractive interactions in the case of swelling has been highlighted in this perspective article. The dissipative particle dynamics has been discussed and is correlated with the molecular dynamics simulation in the case of polymer blends. The Cahn-Hillard-Cook model on variedly shaped immobile fillers has shown difference in the propagation of the composition wave. The nanoparticle shape has a contributing effect on the polymer particle interaction, which can change the miscibility window in the case of these phase separating polymer blends. Quantitative information on the effect of spherical particles on the demixing temperature is well established and further modified to explain the percolation of rod shaped particles in the polymer blends. These models correlate well with the experimental observations in context to the dynamics induced by the nanoparticle in the demixing behavior of the polymer blend. The miscibility of the LCST polymer blend depends on the enthalpic factors like the specific interaction between the components, and the solubility product and the entropic losses occurring due to the formation of any favorable interactions. Hence, it is essential to assess the entropic and enthalpic interactions induced by the nanoparticles independently. The addition of nanoparticles creates heterogeneity in the polymer phase it is localized. This can be observed as an alteration in the relaxation behavior of the polymer. This changes the demixing behavior and the interaction parameter between the polymers. The compositional changes induced due to the incorporation of nanoparticles are also attributed as a reason for the altered demixing temperature. The particle shape anisotropy causes a direction dependent depletion, which changes the phase behavior of the blend. The polymer grafted nanoparticles with varying grafting density show tremendous variation in the miscibility of the blend. The stretching of the polymer chains grafted on the nanoparticles causes an entropy penalty in the polymer blend. A comparative study on the different shaped particles is not available up to date for understanding these aspects. Hence, we have juxtaposed the various computational studies on nanoparticle dynamics, the shape effect of NPs on homopolymers and also the cases of various polymer blends without nanoparticles to sketch a complete picture on the effect of various particles on the miscibility of LCST blends. PMID- 26601894 TI - Vertically Conductive Single-Crystal SiC-Based Bragg Reflector Grown on Si Wafer. AB - Single-crystal silicon carbide (SiC) thin-films on silicon (Si) were used for the fabrication and characterization of electrically conductive distributed Bragg reflectors (DBRs) on 100 mm Si wafers. The DBRs, each composed of 3 alternating layers of SiC and Al(Ga)N grown on Si substrates, show high wafer uniformity with a typical maximum reflectance of 54% in the blue spectrum and a stopband (at 80% maximum reflectance) as large as 100 nm. Furthermore, high vertical electrical conduction is also demonstrated resulting to a density of current exceeding 70 A/cm(2) above 1.5 V. Such SiC/III-N DBRs with high thermal and electrical conductivities could be used as pseudo-substrate to enhance the efficiency of SiC based and GaN-based optoelectronic devices on large Si wafers. PMID- 26601895 TI - High-Rate and Cycling-Stable Nickel-Rich Cathode Materials with Enhanced Li(+) Diffusion Pathway. AB - The nickel-rich LiNi0.7Co0.15Mn0.15O2 material was sintered by Li source with the Ni0.7Co0.15Mn0.15(OH)2 precursor, which was prepared via hydrothermal treatment after coprecipitation. The intensity ratio of I(110)/I(108) obtained from X-ray diffraction patterns and high-resolution transmission electronmicroscopy confirm that the particles have enhanced growth of (110), (100), and (010) surface planes, which supply superior inherent Li(+) deintercalation/intercalation. The electrochemical measurement shows that the LiNi0.7Co0.15Mn0.15O2 material has high cycling stability and rate capability, along with fast charge and discharge ability. Li(+) diffusion coefficient at the oxidation peaks obtained by cyclic voltammogram measurement is as large as 10(-11) (cm(2) s(-1)) orders of magnitude, implying that the nickel-rich material has high Li(+) diffusion capability. PMID- 26601896 TI - Overdiagnosis Detrimental, Resection Consequential, NLST Challengeable. PMID- 26601897 TI - What counts for dogs (Canis lupus familiaris) in a quantity discrimination task? AB - Numerous studies have reported that animals reliably discriminate quantities of more or less food. However, little attention has been given to the relative salience of numerosity compared to the total amount of food when animals are making their choices. Here we investigated this issue in dogs. Dogs were given choices between two quantities of food items in three different conditions. In the Congruent condition, the total amount of food co-varied with the number of food items; in the Incongruent condition the total amount was pitted against the numerosity; and in the Controlled condition the total amount between the sets was equal. Results show that dogs based their choice on the total amount of edible food rather than on the number of food items, suggesting that, in food choice tasks, amount counts more than number. The presence of the largest individual item in a set did not bias dogs' choices. A control test excluded the possibility that dogs based their choices on olfactory cues alone. PMID- 26601898 TI - Sphingosine-1-phosphate and estrogen signaling in breast cancer. AB - Breast cancer remains the most common malignant disease in women. The estrogen receptor-alpha (ERalpha) and its ligand 17beta-estradiol (E2) play important roles in breast cancer. E2 elicits cellular effects by binding to ERalpha in the cytosol followed by receptor dimerization and translocation to the nucleus where it regulates gene expression by binding to ERE response elements. However, it has become apparent that E2 also exerts rapid non-genomic effects through membrane associated receptors. There is emerging evidence that this induces formation of the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P). S1P in turn has been implicated in many processes important in breast cancer progression. One of the enzymes that produce S1P, sphingosine kinase 1 (SphK1), is upregulated in breast cancer and its expression has been correlated with poor prognosis. This review is focused on the role of the SphK/S1P axis in estrogen signaling and breast cancer progression and will discuss new therapeutic approaches targeting this axis for breast cancer treatment. PMID- 26601899 TI - Trait-related decision making impairment in obsessive-compulsive disorder: evidence from decision making under ambiguity but not decision making under risk. AB - This study aimed to investigate whether deficits in decision making were potential endophenotype markers for OCD considering different phases of the disease. Fifty-seven non-medicated OCD patients (nmOCD), 77 medicated OCD patients (mOCD), 48 remitted patients with OCD (rOCD) and 115 healthy controls were assessed with the Iowa Gambling Task (IGT), which measured decision making under ambiguity, and the Game of Dice Task (GDT), which measured decision making under risk. While the three patients groups showed impaired performance on the IGT compared with healthy controls, all patients showed intact performance on the GDT. Furthermore, the rOCD patients showed a preference for deck B, indicating that they showed more sensitivity to the frequency of loss than to the magnitude of loss, whereas the mOCD patients showed a preference for deck A, indicating that they had more sensitivity to the magnitude of loss than to the frequency of loss. These data suggested that OCD patients had trait-related impairments in decision making under ambiguity but not under risk, and that dissociation of decision making under ambiguity and under risk is an appropriate potential neurocognitive endophenotype for OCD. The subtle but meaningful differences in decision making performance between the OCD groups require further study. PMID- 26601900 TI - Recurrent thrombosis in antiphospholipid syndrome may be associated with cardiovascular risk factors and inflammatory response. AB - INTRODUCTION: Antiphospholipid syndrome (APS) is a pro-thrombotic autoimmune disease that affects different vascular beds, with potential risk for recurrence. Systemic lupus erythematosus (SLE), specific autoantibodies profile and atherogenic disorders have been described as risk factors for the occurrence of first thrombosis in patients with antiphospholipid antibodies (aPL). However, factors associated with recurrent thrombosis have not yet been completely elucidated in APS. The aim of this study was to evaluate the association of recurrent thrombosis with markers of inflammation, autoimmunity and the presence of atherogenic disorders in APS patients. MATERIALS AND METHODS: We performed a retrospective evaluation of a cohort of APS patients in order to determine if markers of inflammation, autoimmunity and cardiovascular risk were associated with recurrence of thrombosis. RESULTS: One hundred fifteen patients with APS were included, 60% had primary APS. History of recurrent thrombosis was positive in 38.3% of patients, and 40% of them were on oral anticoagulants at the time of recurrence. Independent risk factors associated with recurrent thrombosis were arterial hypertension (OR = 3.7, 95% CI = 1.6-8.5, P = 0.002) and monocytosis above 500 u/mm(3) (OR = 2.4, 95% CI = 1.2-5.3, P = 0.02). These factors were particularly relevant in cases of venous index event. CONCLUSION: The results suggest that arterial hypertension and monocyte counts may be independent factors for thrombosis recurrence in APS. Given the morbidity of recurrent cases, the results may support the evaluation of therapeutic measures to a rigid control of blood pressures and modulation of inflammatory response in APS, as additional prophylaxis against the recurrence of vascular events. PMID- 26601901 TI - The activation of Wnt signaling by a STAT6-dependent macrophage phenotype promotes mucosal repair in murine IBD. AB - The complete repair of the mucosa constitutes a key goal in inflammatory bowel disease (IBD) treatment. The Wnt signaling pathway mediates mucosal repair and M2 macrophages that coordinate efficient healing have been related to Wnt ligand expression. Signal transducer and activator of transcription 6 (STAT6) mediates M2 polarization in vitro and we hypothesize that a STAT6-dependent macrophage phenotype mediates mucosal repair in acute murine colitis by activating the Wnt signaling pathway. Our results reveal an impaired mucosal expression of M2 macrophage-associated genes and delayed wound healing in STAT6(-/-) mice treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS). These mice also exhibited decreased mucosal expression of Wnt2b, Wnt7b, and Wnt10a, diminished protein levels of nuclear beta-catenin that is mainly located in crypts adjacent to damage, and reduced mRNA expression of two Wnt/beta-catenin target molecules Lgr5 and c-Myc when compared with wild-type (WT) mice. Murine peritoneal macrophages treated with interleukin-4 (IL-4) and polarized toward an M2a phenotype overexpressed Wnt2b, Wnt7b, and Wnt10a in a STAT6-dependent manner. Administration of a Wnt agonist as well as transfer of properly polarized M2a macrophages to STAT6(-/-) mice activated the Wnt signaling pathway in the damaged mucosa and accelerated wound healing. Our results demonstrate that a STAT6 dependent macrophage phenotype promotes mucosal repair in TNBS-treated mice through activation of the Wnt signaling pathway. PMID- 26601903 TI - Competitive lithium solvation of linear and cyclic carbonates from quantum chemistry. AB - The composition of the lithium cation (Li(+)) solvation shell in mixed linear and cyclic carbonate-based electrolytes has been re-examined using Born-Oppenheimer molecular dynamics (BOMD) as a function of salt concentration and cluster calculations with ethylene carbonate:dimethyl carbonate (EC:DMC)-LiPF6 as a model system. A coordination preference for EC over DMC to a Li(+) was found at low salt concentrations, while a slightly higher preference for DMC over EC was found at high salt concentrations. Analysis of the relative binding energies of the (EC)n(DMC)m-Li(+) and (EC)n(DMC)m-LiPF6 solvates in the gas-phase and for an implicit solvent (as a function of the solvent dielectric constant) indicated that the DMC-containing Li(+) solvates were stabilized relative to (EC4)-Li(+) and (EC)3-LiPF6 by immersing them in the implicit solvent. Such stabilization was more pronounced in the implicit solvents with a high dielectric constant. Results from previous Raman and IR experiments were reanalyzed and reconciled by correcting them for changes of the Raman activities, IR intensities and band shifts for the solvents which occur upon Li(+) coordination. After these correction factors were applied to the results of BOMD simulations, the composition of the Li(+) solvation shell from the BOMD simulations was found to agree well with the solvation numbers extracted from Raman experiments. Finally, the mechanism of the Li(+) diffusion in the dilute (EC:DMC)LiPF6 mixed solvent electrolyte was studied using the BOMD simulations. PMID- 26601902 TI - Antigen sampling by intestinal M cells is the principal pathway initiating mucosal IgA production to commensal enteric bacteria. AB - Secretory IgA (SIgA) directed against gut resident bacteria enables the mammalian mucosal immune system to establish homeostasis with the commensal gut microbiota after weaning. Germinal centers (GCs) in Peyer's patches (PPs) are the principal inductive sites where naive B cells specific for bacterial antigens encounter their cognate antigens and receive T-cell help driving their differentiation into IgA-producing plasma cells. We investigated the role of antigen sampling by intestinal M cells in initiating the SIgA response to gut bacteria by developing mice in which receptor activator of nuclear factor-kappaB ligand (RANKL) dependent M-cell differentiation was abrogated by conditional deletion of Tnfrsf11a in the intestinal epithelium. Mice without intestinal M cells had profound delays in PP GC maturation and emergence of lamina propria IgA plasma cells, resulting in diminished levels of fecal SIgA that persisted into adulthood. We conclude that M-cell-mediated sampling of commensal bacteria is a required initial step for the efficient induction of intestinal SIgA. PMID- 26601905 TI - Neurotransmitters and Novelty: A Systematic Review. AB - Our brains are highly responsive to novelty. However, how novelty is processed in the brain, and what neurotransmitter systems play a role therein, remains elusive. Here, we systematically review studies on human participants that have looked at the neuromodulatory basis of novelty detection and processing. While theoretical models and studies on nonhuman animals have pointed to a role of the dopaminergic, cholinergic, noradrenergic and serotonergic systems, the human literature has focused almost exclusively on the first two. Dopamine was found to affect electrophysiological responses to novelty early in time after stimulus presentation, but evidence on its effects on later processing was found to be contradictory: While neuropharmacological studies mostly yielded null effects, gene studies did point to an important role for dopamine. Acetylcholine seems to dampen novelty signals in the medial temporal lobe, but boost them in frontal cortex. Findings on 5-HT (serotonin) were found to be mostly contradictory. Two large gaps were identified in the literature. First, few studies have looked at neuromodulatory influences on behavioral effects of novelty. Second, no study has looked at the involvement of the noradrenergic system in novelty processing. PMID- 26601904 TI - Ground state search, hysteretic behaviour, and reversal mechanism of skyrmionic textures in confined helimagnetic nanostructures. AB - Magnetic skyrmions have the potential to provide solutions for low-power, high density data storage and processing. One of the major challenges in developing skyrmion-based devices is the skyrmions' magnetic stability in confined helimagnetic nanostructures. Through a systematic study of equilibrium states, using a full three-dimensional micromagnetic model including demagnetisation effects, we demonstrate that skyrmionic textures are the lowest energy states in helimagnetic thin film nanostructures at zero external magnetic field and in absence of magnetocrystalline anisotropy. We also report the regions of metastability for non-ground state equilibrium configurations. We show that bistable skyrmionic textures undergo hysteretic behaviour between two energetically equivalent skyrmionic states with different core orientation, even in absence of both magnetocrystalline and demagnetisation-based shape anisotropies, suggesting the existence of Dzyaloshinskii-Moriya-based shape anisotropy. Finally, we show that the skyrmionic texture core reversal dynamics is facilitated by the Bloch point occurrence and propagation. PMID- 26601906 TI - The "Hair-Collar" Sign. PMID- 26601907 TI - Periorbital Ecchymosis. PMID- 26601908 TI - Emphysematous Pyelonephritis in a Child with Nephrolithiasis. PMID- 26601909 TI - The Impact of Emotional States on Cognitive Control Circuitry and Function. AB - Typically in the laboratory, cognitive and emotional processes are studied separately or as a stream of fleeting emotional stimuli embedded within a cognitive task. Yet in life, thoughts and actions often occur in more lasting emotional states of arousal. The current study examines the impact of emotions on actions using a novel behavioral paradigm and functional neuroimaging to assess cognitive control under sustained states of threat (anticipation of an aversive noise) and excitement (anticipation of winning money). Thirty-eight healthy adult participants were scanned while performing an emotional go/no-go task with positive (happy faces), negative (fearful faces), and neutral (calm faces) emotional cues, under threat or excitement. Cognitive control performance was enhanced during the excited state relative to a nonarousing control condition. This enhanced performance was paralleled by heightened activity of frontoparietal and frontostriatal circuitry. In contrast, under persistent threat, cognitive control was diminished when the valence of the emotional cue conflicted with the emotional state. Successful task performance in this conflicting emotional condition was associated with increased activity in the posterior cingulate cortex, a default mode network region implicated in complex processes such as processing emotions in the context of self and monitoring performance. This region showed positive coupling with frontoparietal circuitry implicated in cognitive control, providing support for a role of the posterior cingulate cortex in mobilizing cognitive resources to improve performance. These findings suggest that emotional states of arousal differentially modulate cognitive control and point to the potential utility of this paradigm for understanding effects of situational and pathological states of arousal on behavior. PMID- 26601910 TI - Learning Temporal Statistics for Sensory Predictions in Aging. AB - Predicting future events based on previous knowledge about the environment is critical for successful everyday interactions. Here, we ask which brain regions support our ability to predict the future based on implicit knowledge about the past in young and older age. Combining behavioral and fMRI measurements, we test whether training on structured temporal sequences improves the ability to predict upcoming sensory events; we then compare brain regions involved in learning predictive structures between young and older adults. Our behavioral results demonstrate that exposure to temporal sequences without feedback facilitates the ability of young and older adults to predict the orientation of an upcoming stimulus. Our fMRI results provide evidence for the involvement of corticostriatal regions in learning predictive structures in both young and older learners. In particular, we showed learning-dependent fMRI responses for structured sequences in frontoparietal regions and the striatum (putamen) for young adults. However, for older adults, learning-dependent activations were observed mainly in subcortical (putamen, thalamus) regions but were weaker in frontoparietal regions. Significant correlations of learning-dependent behavioral and fMRI changes in these regions suggest a strong link between brain activations and behavioral improvement rather than general overactivation. Thus, our findings suggest that predicting future events based on knowledge of temporal statistics engages brain regions involved in implicit learning in both young and older adults. PMID- 26601911 TI - Reward Sensitivity of ACC as an Intermediate Phenotype between DRD4-521T and Substance Misuse. AB - The development and expression of the midbrain dopamine system is determined in part by genetic factors that vary across individuals such that dopamine-related genes are partly responsible for addiction vulnerability. However, a complete account of how dopamine-related genes predispose individuals to drug addiction remains to be developed. Adopting an intermediate phenotype approach, we investigated whether reward-related electrophysiological activity of ACC-a cortical region said to utilize dopamine reward signals to learn the value of extended, context-specific sequences of goal-directed behaviors-mediates the influence of multiple dopamine-related functional polymorphisms over substance use. We used structural equation modeling to examine whether two related electrophysiological phenomena associated with the control and reinforcement learning functions of ACC-theta power and the reward positivity-mediated the relationship between the degree of substance misuse and genetic polymorphisms that regulate dopamine processing in frontal cortex. Substance use data were collected from 812 undergraduate students. One hundred ninety-six returned on a subsequent day to participate in an electrophysiological experiment and to provide saliva samples for DNA analysis. We found that these electrophysiological signals mediated a relationship between the DRD4-521T dopamine receptor genotype and substance misuse. Our results provide a theoretical framework that bridges the gap between genes and behavior in drug addiction and illustrate how future interventions might be individually tailored for specific genetic and neurocognitive profiles. PMID- 26601912 TI - Long-term outcomes of Murray Valley encephalitis cases in Western Australia: what have we learnt? AB - BACKGROUND: Murray Valley encephalitis virus (MVEV) is a mosquito-borne flavivirus that causes encephalitis in some cases of infection. It is endemic in Northern Australia and cases occasionally occur in South Eastern Australia. The long-term sequelae of MVEV infection have not previously been well described. AIM: To investigate the long-term sequelae of MVEV infection. METHODS: This was a descriptive case series of all clinical MVEV infections using data linkage and standard surveys. Hospital admissions, emergency department, psychiatric outpatients and mortality data were obtained. We attempted to follow-up all 53 cases of MVEV clinical infection that occurred in Western Australia from 1978 to 2011 inclusive. Two cases opted out of the study. RESULTS: We followed-up 39 surviving cases. Seven of the nine with paralysis or paresis were under 5 years and they fared worse than other patients, requiring lengthy hospitalisation (median duration 133 days). Two died due to complications of quadriplegia following a total of 691 days in hospital. Nine surviving patients, including two with non-encephalitic illness, required care for depression and other psychiatric conditions following MVEV infection. Two patients who were discharged with neurological sequelae had no further documented hospital occasions of service but reported ongoing challenges with cognitive dysfunction and inability to work. CONCLUSIONS: This is the first study of long-term outcomes of Murray Valley encephalitis that included cases with no obvious sequelae at discharge. In spite of the small numbers involved, the study demonstrated the significant medical and social burden due to MVEV in Australia. PMID- 26601913 TI - Effectiveness of Shared Decision-Making Training Program in People With Schizophrenia in South Korea. AB - PURPOSE: This study aimed to investigate the effects of shared decision-making (SDM) training program on self-esteem, problem-solving ability, and quality of life in people with schizophrenia. DESIGN AND METHODS: A quasi-experiment with a nonequivalent control group pre-posttest design was conducted. The self-esteem scale, the problem-solving ability scale, and the WHOQOL Scale were used. FINDINGS: The SDM training program was effective in improving their self-esteem, problem-solving ability, and quality of life in people with schizophrenia. PRACTICE IMPLICATIONS: The SDM training program can be used in various mental health fields such as hospitals, mental health centers, and rehabilitation facilities. PMID- 26601914 TI - Stretchable Figures of Merit in Deformable Electronics. AB - Stretchable electronic systems accommodate strain in various ways-from the intrinsic mechanical properties, through composite structures, by the formation of cracks, or with other mechanisms. This has produced some imprecision in the literature on what is meant by the term "stretchable." PMID- 26601916 TI - Long noncoding RNA linc-ITGB1 promotes cell migration and invasion in human breast cancer. AB - Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death in women globally. Its high morbidity and mortality, as well as its elevated tendency to metastasize to other organs, warrant the urgency to find new biomarkers for breast cancer diagnosis and treatment. The specific roles of long noncoding RNA linc-ITGB1 on cell proliferation and metastasis in breast cancer were explored in this study. The expression of linc-ITGB1 was significantly upregulated in both clinical breast cancer tissues and cultured breast cancer cell lines. The linc-ITGB1 knockdown with specific short hairpin RNA (shRNA) decreased cell proliferation and colony formation in vitro. Tumor growth in vivo was also inhibited by linc-ITGB1 depletion. In addition, linc ITGB1 depletion caused cell accumulation in the G0/G1 phase. Breast cancer cell lines with linc-ITGB1 depletion exhibited decreased migration and invasion abilities compared with the control cells. Furthermore, the linc-ITGB1 knockdown decreased the expression of mesenchymal markers N-cadherin and vimentin while increasing the expression of the epithelial marker E-cadherin. Key cell cycle regulators Cdc25C and Cyclin B1 were also decreased by the linc-ITGB1 knockdown. These data suggest that linc-ITGB1 promotes breast cancer progression by inducing cell cycle arrest and interrupting the epithelial-to-mesenchymal transition process. PMID- 26601915 TI - Glutamate Receptor Interacting Protein 1 Regulates CD4(+) CTLA-4 Expression and Transplant Rejection. AB - PDZ domains are common 80- to 90-amino-acid regions named after the first three proteins discovered to share these domains: postsynaptic density 95, discs large, and zonula occludens. PDZ domain-containing proteins typically interact with the C-terminus of membrane receptors. Glutamate receptor interacting protein 1 (GRIP1), a seven-PDZ domain protein scaffold, regulates glutamate receptor surface expression and trafficking in neurons. We have found that human and mouse T cells also express GRIP1. T cell-specific GRIP1(-/-) mice >11 weeks old had prolonged cardiac allograft survival. Compared with wild-type T cells, in vitro stimulated GRIP1(-/-) T cells had decreased expression of activation markers and increased apoptotic surface marker expression. Surface expression of the strong T cell inhibitory molecule cytotoxic T lymphocyte antigen-4 (CTLA-4) was increased on GRIP1(-/-) T cells from mice >11 weeks old. CTLA-4 increases with T cell stimulation and its surface expression on GRIP1(-/-) T cells remained high after stimulation was removed, indicating a possible internalization defect in GRIP1 deficient T cells. CTLA-4-blocking antibody treatment following heart transplantation led to complete rejection in T cell GRIP1(-/-) mice, indicating that increased CTLA-4 surface expression contributed to the extended graft survival. Our data indicate that GRIP1 regulates T cell activation by regulating CTLA-4 surface expression. PMID- 26601917 TI - Two transcripts of HMG-CoA reductase related with developmental regulation from Scylla paramamosain: Evidences from cDNA cloning and expression analysis. AB - 3-Hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases (HMGRs), which catalyze the conversion of HMG-CoA to mevalonate, may have an important role in the synthesis of methyl farnesoate (MF). In this study, we obtained two HMGR cDNA sequences termed Sp-HMGR1 (membrane-bound form) and Sp-HMGR2 (soluble form), which encode 967 and 654 amino acids, respectively. The two cDNAs possess entirely identical sequences except that Sp-HMGR1 is 1,382 bp, which encodes a sterol-sensed domain (SSD; a membrane-bound domain) and was first found in crustacean HMGR, larger than Sp-HMGR2. Thus, it was deduced that these cDNAs might be derived from a single genomic DNA sequence. Sp-HMGRs have the typical features of the HMGR class of proteins. However, residue 844 in Sp-HMGR1, which is usually occupied by a Ser residue in other species, has an unusual Ala substitution. This Ser is thought to be involved in enzyme activity regulation by reversible phosphorylation. A putative "PEST" sequence that, until now, has only been found in crustacean species was also identified in the C-terminus of both transcripts, and a sterol-sensing domain, which was first found in crustacean species, was identified in Sp-HMGR1; these findings suggest that Sp-HMGR might function in some special regulatory mechanism. Furthermore, the quantitative real time polymerase chain reaction results showed that the two transcripts have different expression patterns; Sp-HMGR2 was mainly expressed in the mandibular organ (MO) of adult crabs, whereas Sp-HMGR1 was mainly expressed in other tissues and fertilized eggs up until the fourth juvenile crab stage. The fluctuating gene expression seemed to suggest a relationship between Sp-HMGRs and the development of the crab, especially during the larval stage. Besides, the fluctuation of Sp HMGR1 in ovary, brain, and thoracic ganglia during the ovary development seemed to have some correlation with the nutrition accumulation of ovaries, whether the SSD domain evolved in this process deserve further investigation. Moreover, it remains unclear whether the significant variation in ovary, brain, and thoracic ganglia during ovary development suggests that other tissues in addition to the MO could synthesize MF. PMID- 26601919 TI - Human lactoferrin protects against Streptococcus mutans-induced caries in mice. AB - OBJECTIVES: The objective of this study is to evaluate the importance of human lactoferrin (hLF) in an experimental caries induced by Streptococcus mutans in a lactoferrin-knockout (LFKO(-/-)) mouse model compared with C576J/BL wild-type (WT) mice. MATERIALS AND METHODS: The WT and LFKO(-/-) mice were infected with S. mutans (1 * 10(8) cells) and/or sham infection. Furthermore, the effect of hLF administration was evaluated in LFKO(-/-) mice infected with S. mutans. Mice were assessed for colonization, salivary pH, and caries development. RESULTS: The results showed that the lactoferrin-knockout infected (LFKO(-/-) I) mice had significantly higher colonization with S. mutans (P = 0.02), lower salivary pH (P = 0.01), and more carious lesions (P = 0.01) when compared to wild-type infected (WTI) mice. In addition, the administration of hLF did not show any evidence of S. mutans colonization as well as carious lesions (P = 0.001) in LFKO(-/-) I mice when compared to untreated LFKO(-/-) I mice. CONCLUSION: These results show that endogenous LF protects against S. mutans-induced caries and that exogenous hLF can exert a protective effect against caries development. PMID- 26601918 TI - Phthalate exposure and semen quality in fertile US men. AB - Several experimental and observational studies have demonstrated the antiandrogenicity of several phthalates. However, there is limited evidence of an association between phthalate exposure in adult life and semen quality. The aim of this study was to examine phthalate exposure during adulthood in relation to semen quality in fertile US men. This multi-center cross-sectional study included 420 partners of pregnant women who attended a prenatal clinic in one of five US cities during 1999-2001. Nine phthalate metabolites [mono (2-ethylhexyl) phthalate (MEHP), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono (2-ethyl 5-oxohexyl) phthalate (MEOHP), and mono (2-ethyl-5-carboxypentyl) phthalate (MECPP)], as well as mono-n-butyl phthalate (MBP) and mono-isobutyl phthalate (MiBP), mono (three carboxypropyl) phthalate (MCPP), monobenzyl phthalate (MBzP), and monoethyl phthalate (MEP)] were measured in urine collected at the same time as the semen sample. We regressed natural log-transformed (ln) sperm concentration, ln(total sperm count), ln(total motile sperm count), percent motile spermatozoa, and percent spermatozoa with normal morphology on each of the nine natural log-transformed metabolite concentrations and on the molar-weighted sum of DEHP metabolites in separate models. We fit unadjusted models and models that adjusted for confounders determined a priori. In unadjusted models, ln(MiBP) was significantly and positively associated with motility and ln(MBzP) significantly negatively associated with ln(total sperm count). In adjusted linear models, urinary metabolite concentrations of DEHP, DBP, DEP, and DOP were not associated with any semen parameter. We found an inverse association between ln(MBzP) concentrations and sperm motility (beta = -1.47, 95% CI: -2.61, -0.33), adjusted for ln(creatinine concentration), geographic location, age, race, smoking status, stress, recent fever, time from sample collection and time to complete analysis. Several sensitivity analyses confirmed the robustness of these associations. This study and the available literature suggest that impacts of adult exposure to phthalates at environmental levels on classical sperm parameters are likely to be small. PMID- 26601920 TI - Oral health needs of athletes with intellectual disability in Eastern Europe: Poland, Romania and Slovenia. AB - OBJECTIVES: The aims of this study were to evaluate the oral condition and treatment needs of Special Olympics (SO) athletes from Poland, Romania and Slovenia. METHODS: A cross-sectional study was performed with data collected through standardised oral screening of athletes who participated in the annual SO events held in Poland, Romania and Slovenia, between 2011 and 2012. The data were compiled and transferred to an SPSS data file for analysis using descriptive statistics. RESULTS: A total of 3,545 athletes participated in the study. Among the main findings, the prevalence of untreated decay was 41% in Poland and 61% in Slovenia, whilst 70% of the Romanian athletes had signs of gingival disease and only 3.8% presented molar fissure sealants. In addition, 47% of Polish athletes were in need of urgent treatment. CONCLUSIONS: Analysis of the results obtained following screening showed comparable oral health needs of athletes with intellectual disability among countries. Exploration of the oral health systems of the countries revealed similar significant co-payments and lack of incentive for dentists to treat patients with special needs. The results from Romania, Poland and Slovenia demonstrated the need for a structured system in which a special population is a target for oral-health-related education programmes and system-included preventive, restorative and maintenance interventions. PMID- 26601921 TI - Proton observed phosphorus editing (POPE) for in vivo detection of phospholipid metabolites. AB - The purpose of this article was to compare the sensitivity of proton observed phosphorus editing (POPE) with direct (31) P MRS with Ernst angle excitation for (1) H-(31) P coupled metabolites at 7 T. POPE sequences were developed for detecting phosphocholine (PC), phosphoethanolamine (PE), glycerophosphocholine (GPC), and glycerophosphoethanolamine (GPE) on the (1) H channel, thereby using the enhanced sensitivity of the (1) H nuclei over (31) P detection. Five healthy volunteers were examined with POPE and (31) P-MRS. POPE editing showed a more than doubled sensitivity in an ideal phantom experiment as compared with direct (31) P MRS with Ernst angle excitation. In vivo, despite increased relaxation losses, significant gains in signal-to-noise ratio (SNR) of 30-40% were shown for PE and GPE + PC levels in the human brain. The SNR of GPC was lower in the POPE measurement compared with the (31) P-MRS measurement. Furthermore, selective narrowband editing on the (31) P channel showed the ability to separate the overlapping GPE and PE signals in the (1) H spectrum. POPE can be used for enhanced detection of (1) H-(31) P coupled metabolites in vivo. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26601922 TI - Terminal illness and the increased mortality risk of conventional antipsychotics in observational studies: a systematic review. AB - INTRODUCTION: Numerous large observational studies have shown an increased risk of mortality in elderly users of conventional antipsychotics. Health authorities have warned against use of these drugs. However, terminal illness is a potentially strong confounder of the observational findings. So, the objective of this study was to systematically assess whether terminal illness may have biased the observational association between conventional antipsychotics and risk of mortality in elderly patients. METHODS: Studies were searched in PubMed, CINAHL, Embase, the references of selected studies and articles referring to selected studies (Web of Science). Inclusion criteria were (i) observational studies that estimated (ii) the risk of all-cause mortality in (iii) new elderly users of (iv) conventional antipsychotics compared with atypical antipsychotics or no use. Two investigators assessed the characteristics of the exposure and reference groups, main results, measured confounders and methods used to adjust for unmeasured confounders. RESULTS: We identified 21 studies. All studies were based on administrative medical and pharmaceutical databases. Sicker and older patients received conventional antipsychotics more often than new antipsychotics. The risk of dying was especially high in the first month of use, and when haloperidol was administered per injection or in high doses. Terminal illness was not measured in any study. Instrumental variables that were used were also confounded by terminal illness. CONCLUSIONS: We conclude that terminal illness has not been adjusted for in observational studies that reported an increased risk of mortality risk in elderly users of conventional antipsychotics. As the validity of the evidence is questionable, so is the warning based on it. PMID- 26601923 TI - Complete and partial XYLT1 deletion in a patient with neonatal short limb skeletal dysplasia. AB - We report on a boy with a neonatal short limb skeletal dysplasia with serious medical complications, associated with one intragenic and one complete deletion of XYLT1. XYLT1 mutations have recently been reported as causative in recessive Desbuquois skeletal dysplasia (DBSD), but the skeletal features in our patient do not fit this diagnosis. It is possible that the phenotype of XYLT1 mutations extends to more aspecific types of short limb skeletal dysplasias and not to DBSD alone. PMID- 26601924 TI - Patient expectation of a voice clinic consultation: development of the ACaPELa questionnaire by assessment of four hundred and fifty-five patients. PMID- 26601925 TI - Chemical and colloidal aspects of collectorless flotation behavior of sulfide and non-sulfide minerals. AB - Flotation has been widely used for separation of valuable minerals from gangues based on their surface characterizations and differences in hydrophobicity on mineral surfaces. As hydrophobicity of minerals widely differs from each other, their separation by flotation will become easier. Collectors are chemical materials which are supposed to make selectively valuable minerals hydrophobic. In addition, there are some minerals which based on their surface and structural features are intrinsically hydrophobic. However, their hydrophobicities are not strong enough to be floatable in the flotation cell without collectors such as sulfide minerals, coal, stibnite, and so forth. To float these minerals in a flotation cell, their hydrophobicity should be increased in specific conditions. Various parameters including pH, Eh, size distribution, mill types, mineral types, ore characterization, and type of reaction in flotation cells affect the hydrophobicity of minerals. Surface analysis results show that when sulfide minerals experience specific flotation conditions, the reactions on the surface of these minerals increase the amount of sulfur on the surface. These phenomenons improve the hydrophobicity of these minerals due to strong hydrophobic feature of sulfurs. Collectorless flotation reduces chemical material consumption amount, increases flotation selectivity (grade increases), and affects the equipment quantities; however, it can also have negative effects. Some minerals with poor surface floatability can be increased by adding some ions to the flotation system. Depressing undesirable minerals in flotation is another application of collectorless flotation. PMID- 26601927 TI - Mentoring: Helping Others Do What They Can, as Well as They Can. PMID- 26601926 TI - Changes in parvalbumin immunoreactive retinal ganglion cells and amacrine cells after optic nerve injury. AB - Parvalbumin (PARV) is a Ca(2+)-binding protein that may offer resistance to cell death as it primarily functions to maintain Ca(2+) homeostasis. The purpose of this study was to investigate whether PARV expressing retinal ganglion cells (RGCs) would be more resistant to cell death than RGCs that do not express PARV. RGCs in Sprague-Dawley rats were retrogradely labeled with Fluorogold (FG). After 2-28 days following an optic nerve crush (ONC) injury immunohistochemistry was performed on the sections using antibodies against PARV and markers of RGCs. The proportion of retinal ganglion cell layer cells labeled with PARV colocalized with FG or Brn3a and labeled only with PARV (displaced amacrine cells; dACs) were analyzed. PARV staining intensity was measured in ACs, dACs, and RGCs. Double labeling studies revealed that 49% of RGCs and 22% of dACs expressed PARV. There was an immediate reduction in RGC PARV staining after ONC but the overall rate of cell death after 28 days was similar in PARV and non-PARV expressing RGCs. There was no change in PARV AC or dAC number or staining intensity. Although this study suggests that there is no selective survival of the subpopulation of RGCs that contain PARV, there is down-regulation of PARV expression by these RGCs. This suggests that down-regulation of PARV may contribute to RGC death due to a compromised Ca(2+) buffering capacity. Maintaining PARV expression after injury could be an important neuroprotective strategy to improve RGC survival after injury. PMID- 26601929 TI - Automated Patient-Specific Dose Registries, or Radiation Dose Index Monitoring Software: Why They Are a Very Good Idea! PMID- 26601928 TI - Pictorial Review of Complications of Uterine Anomalies. PMID- 26601930 TI - Response to Letter on Appropriateness. PMID- 26601931 TI - Inappropriate Underutilisation of Magnetic Resonance Imaging in British Columbia. PMID- 26601933 TI - LASER: Large genome ASsembly EvaluatoR. AB - BACKGROUND: Genome assembly is a fundamental problem with multiple applications. Current technological limitations do not allow assembling of entire genomes and many programs have been designed to produce longer and more reliable contigs. Assessing the quality of these assemblies and comparing those produced by different tools is essential in choosing the best ones. The QUAST program has become the current state-of-the-art in quality assessment of genome assemblies. The only drawback of QUAST is high time and memory usage for large genomes, e.g., over 4 days and 120 GB of RAM for a single human genome assembly. RESULTS: We introduce LASER, a new tool for assembly evaluation that improves greatly the speed and memory requirements of QUAST. For a human genome assembly, LASER is 5.6 times faster than QUAST while using only half the memory; one human genome assembly is evaluated in 17 hours instead of 4 days. The code of LASER is based on that of QUAST and therefore inherits all its features. CONCLUSIONS: Genome assembly evaluation is an essential step in assessing the quality of an assembly that is too often done improperly, in part due to significant resource consumption. With the introduction of LASER, proper evaluation can be performed efficiently. PMID- 26601932 TI - SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer. AB - Protein conjugation with Small ubiquitin-like modifier (SUMOylation) has critical roles during cell cycle progression. Many important cell cycle regulators, including many oncogenes and tumor suppressors, are functionally regulated via SUMOylation. The dynamic SUMOylation pattern observed throughout the cell cycle is ensured via distinct spatial and temporal regulation of the SUMO machinery. Additionally, SUMOylation cooperates with other post-translational modifications to mediate cell cycle progression. Deregulation of these SUMOylation and deSUMOylation enzymes causes severe defects in cell proliferation and genome stability. Different types of cancer were recently shown to be dependent on a functioning SUMOylation system, a finding that could be exploited in anticancer therapies. PMID- 26601934 TI - Evaluation of an implementation of methadone maintenance treatment in China. AB - BACKGROUND: Methadone maintenance treatment (MMT) reduces the harms of opioid use disorder and is being rapidly scaled-up in China. This study evaluated the real world implementation of MMT system in Wuhan, China. METHODS: Data extracted from electronic medical records collected in 2010 on 8811 patients were used to compute for each patient indices of the prescribed and consumed daily methadone doses, an adherence index, dose adjustments following missed doses, the rates of opiate positive urine tests, self-reported drug use, injection drug use (IDU), and the duration of MMT exposure. FINDINGS: The modal daily doses prescribed were 60 mg and above for 68.5% of patients. Adherence was variable: 51% of patients attended less than 60% and 26% attended 80-100% of their treatment days; and patients with long MMT exposure had significantly higher adherence rates than patients with short MMT exposure. The differences between doses dispensed immediately before and after the interruption in dosing days ranged from 0 to 7 mg, independently of the length of the interruption or the prescribed dosing level. The overall rate of opiate positive tests was 20%; 45% of patients had at least one opiate positive test; 29% reported past month drug use and 53% of them reported past month IDU. Adherence and MMT exposure duration correlated significantly with the proportion of opiate negative urine tests (r=0.355, p<0.001; r=0.351, p<0.001, respectively). Treatment for males and females was comparable. CONCLUSIONS: Provision of safe methadone dosing after absences and improving daily attendance are identified as priority improvement areas. PMID- 26601935 TI - Of Skin and Teeth: Identifying Key Differences in Asians. PMID- 26601936 TI - Knee-Deep in Spider Leg Evolution. PMID- 26601937 TI - Comparative Genomics Identifies Epidermal Proteins Associated with the Evolution of the Turtle Shell. AB - The evolution of reptiles, birds, and mammals was associated with the origin of unique integumentary structures. Studies on lizards, chicken, and humans have suggested that the evolution of major structural proteins of the outermost, cornified layers of the epidermis was driven by the diversification of a gene cluster called Epidermal Differentiation Complex (EDC). Turtles have evolved unique defense mechanisms that depend on mechanically resilient modifications of the epidermis. To investigate whether the evolution of the integument in these reptiles was associated with specific adaptations of the sequences and expression patterns of EDC-related genes, we utilized newly available genome sequences to determine the epidermal differentiation gene complement of turtles. The EDC of the western painted turtle (Chrysemys picta bellii) comprises more than 100 genes, including at least 48 genes that encode proteins referred to as beta keratins or corneous beta-proteins. Several EDC proteins have evolved cysteine/proline contents beyond 50% of total amino acid residues. Comparative genomics suggests that distinct subfamilies of EDC genes have been expanded and partly translocated to loci outside of the EDC in turtles. Gene expression analysis in the European pond turtle (Emys orbicularis) showed that EDC genes are differentially expressed in the skin of the various body sites and that a subset of beta-keratin genes within the EDC as well as those located outside of the EDC are expressed predominantly in the shell. Our findings give strong support to the hypothesis that the evolutionary innovation of the turtle shell involved specific molecular adaptations of epidermal differentiation. PMID- 26601938 TI - Half-sandwich rhodium(III) transfer hydrogenation catalysts: Reduction of NAD(+) and pyruvate, and antiproliferative activity. AB - Organometallic complexes have the potential to behave as catalytic drugs. We investigate here Rh(III) complexes of general formula [(Cp(x))Rh(N,N')(Cl)], where N,N' is ethylenediamine (en), 2,2'-bipyridine (bpy), 1,10-phenanthroline (phen) or N-(2-aminoethyl)-4-(trifluoromethyl)benzenesulfonamide (TfEn), and Cp(x) is pentamethylcyclopentadienyl (Cp*), 1-phenyl-2,3,4,5 tetramethylcyclopentadienyl (Cp(xPh)) or 1-biphenyl-2,3,4,5-tetramethyl cyclopentadienyl (Cp(xPhPh)). These complexes can reduce NAD(+) to NADH using formate as a hydride source under biologically-relevant conditions. The catalytic activity decreased in the order of N,N-chelated ligand bpy > phen > en with Cp* as the eta(5)-donor. The en complexes (1-3) became more active with extension to the Cp(X) ring, whereas the activity of the phen (7-9) and bpy (4-6) compounds decreased. [Cp*Rh(bpy)Cl](+) (4) showed the highest catalytic activity, with a TOF of 37.4+/-2h(-1). Fast hydrolysis of the chlorido complexes 1-10 was observed by (1)H NMR (<10min at 310K). The pKa* values for the aqua adducts were determined to be ca. 8-10. Complexes 1-9 also catalysed the reduction of pyruvate to lactate using formate as the hydride donor. The efficiency of the transfer hydrogenation reactions was highly dependent on the nature of the chelating ligand and the Cp(x) ring. Competition reactions between NAD(+) and pyruvate for reduction by formate catalysed by 4 showed a preference for reduction of NAD(+). The antiproliferative activity of complex 3 towards A2780 human ovarian cancer cells increased by up to 50% when administered in combination with non-toxic doses of formate, suggesting that transfer hydrogenation can induce reductive stress in cancer cells. PMID- 26601939 TI - The Conserved Phenylalanine in the Transmembrane Domain Enhances Heteromeric Interactions of Syndecans. AB - The transmembrane domain (TMD) of the syndecans, a family of transmembrane heparin sulfate proteoglycans, is involved in forming homo- and heterodimers and oligomers that transmit signaling events. Recently, we reported that the unique phenylalanine in TMD positively regulates intramolecular interactions of syndecan 2. Besides the unique phenylalanine, syndecan-2 contains a conserved phenylalanine (SDC2-Phe-169) that is present in all syndecan TMDs, but its function has not been determined. We therefore investigated the structural role of SDC2-Phe-169 in syndecan TMDs. Replacement of SDC2-Phe-169 by tyrosine (S2F169Y) did not affect SDS-resistant homodimer formation but significantly reduced SDS-resistant heterodimer formation between syndecan-2 and -4, suggesting that SDC2-Phe-169 is involved in the heterodimerization/oligomerization of syndecans. Similarly, in an in vitro binding assay, a syndecan-2 mutant (S2(F169Y)) showed a significantly reduced interaction with syndecan-4. FRET assays showed that heteromolecular interactions between syndecan-2 and -4 were reduced in HEK293T cells transfected with S2(F169Y) compared with syndecan-2. Moreover, S2(F169Y) reduced downstream reactions mediated by the heterodimerization of syndecan-2 and -4, including Rac activity, cell migration, membrane localization of PKCalpha, and focal adhesion formation. The conserved phenylalanine in syndecan-1 and -3 also showed heterodimeric interaction with syndecan-2 and -4. Taken together, these findings suggest that the conserved phenylalanine in the TMD of syndecans is crucial in regulating heteromeric interactions of syndecans. PMID- 26601940 TI - What Can the Kinetics of Amyloid Fibril Formation Tell about Off-pathway Aggregation? AB - Some of the most prevalent neurodegenerative diseases are characterized by the accumulation of amyloid fibrils in organs and tissues. Although the pathogenic role of these fibrils has not been completely established, increasing evidence suggests off-pathway aggregation as a source of toxic/detoxicating deposits that still remains to be targeted. The present work is a step toward the development of off-pathway modulators using the same amyloid-specific dyes as those conventionally employed to screen amyloid inhibitors. We identified a series of kinetic signatures revealing the quantitative importance of off-pathway aggregation relative to amyloid fibrillization; these include non-linear semilog plots of amyloid progress curves, highly variable end point signals, and half life coordinates weakly influenced by concentration. Molecules that attenuate/intensify the magnitude of these signals are considered promising off pathway inhibitors/promoters. An illustrative example shows that amyloid deposits of lysozyme are only the tip of an iceberg hiding a crowd of insoluble aggregates. Thoroughly validated using advanced microscopy techniques and complementary measurements of dynamic light scattering, CD, and soluble protein depletion, the new analytical tools are compatible with the high-throughput methods currently employed in drug discovery. PMID- 26601941 TI - Cold Temperature Induces the Reprogramming of Proteolytic Pathways in Yeast. AB - Despite much evidence of the involvement of the proteasome-ubiquitin signaling system in temperature stress response, the dynamics of the ubiquitylome during cold response has not yet been studied. Here, we have compared quantitative ubiquitylomes from a strain deficient in proteasome substrate recruitment and a reference strain during cold response. We have observed that a large group of proteins showing increased ubiquitylation in the proteasome mutant at low temperature is comprised by reverses suppressor of Ty-phenotype 5 (Rsp5) regulated plasma membrane proteins. Analysis of internalization and degradation of plasma membrane proteins at low temperature showed that the proteasome becomes determinant for this process, whereas, at 30 degrees C, the proteasome is dispensable. Moreover, our observations indicate that proteasomes have increased capacity to interact with lysine 63-polyubiquitylated proteins during low temperature in vivo. These unanticipated observations indicate that, during cold response, there is a proteolytic cellular reprogramming in which the proteasome acquires a role in the endocytic-vacuolar pathway. PMID- 26601943 TI - RNA Editing Modulates Human Hepatic Aryl Hydrocarbon Receptor Expression by Creating MicroRNA Recognition Sequence. AB - Adenosine to inosine (A-to-I) RNA editing is the most frequent type of post transcriptional nucleotide conversion in humans, and it is catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes. In this study we investigated the effect of RNA editing on human aryl hydrocarbon receptor (AhR) expression because the AhR transcript potentially forms double-stranded structures, which are targets of ADAR enzymes. In human hepatocellular carcinoma-derived Huh-7 cells, the ADAR1 knockdown reduced the RNA editing levels in the 3'-untranslated region (3'-UTR) of the AhR transcript and increased the AhR protein levels. The ADAR1 knockdown enhanced the ligand-mediated induction of CYP1A1, a gene downstream of AhR. We investigated the possibility that A-to-I RNA editing creates miRNA targeting sites in the AhR mRNA and found that the miR-378-dependent down-regulation of AhR was abolished by ADAR1 knockdown. These results indicated that the ADAR1-mediated down-regulation of AhR could be attributed to the creation of a miR-378 recognition site in the AhR 3'-UTR. The interindividual differences in the RNA editing levels within the AhR 3'-UTR in a panel of 32 human liver samples were relatively small, whereas the differences in ADAR1 expression were large (220 fold). In the human liver samples a significant inverse association was observed between the miR-378 and AhR protein levels, suggesting that the RNA-editing dependent down-regulation of AhR by miR-378 contributes to the variability in the constitutive hepatic expression of AhR. In conclusion, this study uncovered for the first time that A-to-I RNA editing modulates the potency of xenobiotic metabolism in the human liver. PMID- 26601942 TI - Design and Optimization of Anti-amyloid Domain Antibodies Specific for beta Amyloid and Islet Amyloid Polypeptide. AB - Antibodies with conformational specificity are important for detecting and interfering with polypeptide aggregation linked to several human disorders. We are developing a motif-grafting approach for designing lead antibody candidates specific for amyloid-forming polypeptides such as the Alzheimer peptide (Abeta). This approach involves grafting amyloidogenic peptide segments into the complementarity-determining regions (CDRs) of single-domain (VH) antibodies. Here we have investigated the impact of polar mutations inserted at the edges of a large hydrophobic Abeta42 peptide segment (Abeta residues 17-42) in CDR3 on the solubility and conformational specificity of the corresponding VH domains. We find that VH expression and solubility are strongly enhanced by introducing multiple negatively charged or asparagine residues at the edges of CDR3, whereas other polar mutations are less effective (glutamine and serine) or ineffective (threonine, lysine, and arginine). Moreover, Abeta VH domains with negatively charged CDR3 mutations show significant preference for recognizing Abeta fibrils relative to Abeta monomers, whereas the same VH domains with other polar CDR3 mutations recognize both Abeta conformers. We observe similar behavior for a VH domain grafted with a large hydrophobic peptide from islet amyloid polypeptide (residues 8-37) that contains negatively charged mutations at the edges of CDR3. These findings highlight the sensitivity of antibody binding and solubility to residues at the edges of CDRs, and provide guidelines for designing other grafted antibody fragments with hydrophobic binding loops. PMID- 26601944 TI - Oxysterol-binding Protein Activation at Endoplasmic Reticulum-Golgi Contact Sites Reorganizes Phosphatidylinositol 4-Phosphate Pools. AB - Oxysterol-binding protein (OSBP) exchanges cholesterol and phosphatidylinositol 4 phosphate (PI-4P) at contact sites between the endoplasmic reticulum (ER) and the trans-Golgi/trans-Golgi network. 25-Hydroxycholesterol (25OH) competitively inhibits this exchange reaction in vitro and causes the constitutive localization of OSBP at the ER/Golgi interface and PI-4P-dependent recruitment of ceramide transfer protein (CERT) for sphingomyelin synthesis. We used PI-4P probes and mass analysis to determine how OSBP controls the availability of PI-4P for this metabolic pathway. Treatment of fibroblasts or Chinese hamster ovary (CHO) cells with 25OH caused a 50-70% reduction in Golgi-associated immunoreactive PI-4P that correlated with Golgi localization of OSBP. In contrast, 25OH caused an OSBP dependent enrichment in Golgi PI-4P that was detected with a pleckstrin homology domain probe. The cellular mass of phosphatidylinositol monophosphates and Golgi PI-4P measured with an unbiased PI-4P probe (P4M) was unaffected by 25OH and OSBP silencing, indicating that OSBP shifts the distribution of PI-4P upon localization to ER-Golgi contact sites. The PI-4P and sterol binding activities of OSBP were both required for 25OH activation of sphingomyelin synthesis, suggesting that 25OH must be exchanged for PI-4P to be concentrated at contact sites. We propose a model wherein 25OH activation of OSBP promotes the binding and retention of PI-4P at ER-Golgi contact sites. This pool of PI-4P specifically recruits pleckstrin homology domain-containing proteins involved in lipid transfer and metabolism, such as CERT. PMID- 26601945 TI - Interleukin 1beta Regulation of the System xc- Substrate-specific Subunit, xCT, in Primary Mouse Astrocytes Involves the RNA-binding Protein HuR. AB - System xc(-) is a heteromeric amino acid cystine/glutamate antiporter that is constitutively expressed by cells of the CNS, where it functions in the maintenance of intracellular glutathione and extracellular glutamate levels. We recently determined that the cytokine, IL-1beta, increases the activity of system xc(-) in CNS astrocytes secondary to an up-regulation of its substrate-specific light chain, xCT, and that this occurs, in part, at the level of transcription. However, an in silico analysis of the murine xCT 3'-UTR identified numerous copies of adenine- and uridine-rich elements, raising the possibility that undefined trans-acting factors governing mRNA stability and translation may also contribute to xCT expression. Here we show that IL-1beta increases the level of mRNA encoding xCT in primary cultures of astrocytes isolated from mouse cortex in association with an increase in xCT mRNA half-life. Additionally, IL-1beta induces HuR translocation from the nucleus to the cytoplasm. RNA immunoprecipitation analysis reveals that HuR binds directly to the 3'-UTR of xCT in an IL-1beta-dependent manner. Knockdown of endogenous HuR protein abrogates the IL-1beta-mediated increase in xCT mRNA half-life, whereas overexpression of HuR in unstimulated primary mouse astrocytes doubles the half-life of constitutive xCT mRNA. This latter effect is accompanied by an increase in xCT protein levels, as well as a functional increase in system xc(-) activity. Altogether, these data support a critical role for HuR in mediating the IL-1beta induced stabilization of astrocyte xCT mRNA. PMID- 26601946 TI - The Tomato Nucleotide-binding Leucine-rich Repeat Immune Receptor I-2 Couples DNA binding to Nucleotide-binding Domain Nucleotide Exchange. AB - Plant nucleotide-binding leucine-rich repeat (NLR) proteins enable plants to recognize and respond to pathogen attack. Previously, we demonstrated that the Rx1 NLR of potato is able to bind and bend DNA in vitro. DNA binding in situ requires its genuine activation following pathogen perception. However, it is unknown whether other NLR proteins are also able to bind DNA. Nor is it known how DNA binding relates to the ATPase activity intrinsic to NLR switch function required to immune activation. Here we investigate these issues using a recombinant protein corresponding to the N-terminal coiled-coil and nucleotide binding domain regions of the I-2 NLR of tomato. Wild type I-2 protein bound nucleic acids with a preference of ssDNA ~ dsDNA > ssRNA, which is distinct from Rx1. I-2 induced bending and melting of DNA. Notably, ATP enhanced DNA binding relative to ADP in the wild type protein, the null P-loop mutant K207R, and the autoactive mutant S233F. DNA binding was found to activate the intrinsic ATPase activity of I-2. Because DNA binding by I-2 was decreased in the presence of ADP when compared with ATP, a cyclic mechanism emerges; activated ATP-associated I-2 binds to DNA, which enhances ATP hydrolysis, releasing ADP-bound I-2 from the DNA. Thus DNA binding is a general property of at least a subset of NLR proteins, and NLR activation is directly linked to its activity at DNA. PMID- 26601947 TI - Glucose Modulation Induces Lysosome Formation and Increases Lysosomotropic Drug Sequestration via the P-Glycoprotein Drug Transporter. AB - Pgp is functional on the plasma membrane and lysosomal membrane. Lysosomal-Pgp can pump substrates into the organelle, thereby trapping certain chemotherapeutics (e.g. doxorubicin; DOX). This mechanism serves as a "safe house" to protect cells against cytotoxic drugs. Interestingly, in contrast to DOX, lysosomal sequestration of the novel anti-tumor agent and P-glycoprotein (Pgp) substrate, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), induces lysosomal membrane permeabilization. This mechanism of lysosomal-Pgp utilization enhances cytotoxicity to multidrug-resistant cells. Consequently, Dp44mT has greater anti-tumor activity in drug-resistant relative to non-Pgp expressing tumors. Interestingly, stressors in the tumor microenvironment trigger endocytosis for cell signaling to assist cell survival. Hence, this investigation examined how glucose variation-induced stress regulated early endosome and lysosome formation via endocytosis of the plasma membrane. Furthermore, the impact of glucose variation-induced stress on resistance to DOX was compared with Dp44mT and its structurally related analogue, di-2-pyridylketone 4-cyclohexyl-4 methyl-3-thiosemicarbazone (DpC). These studies showed that glucose variation induced stress-stimulated formation of early endosomes and lysosomes. In fact, through the process of fluid-phase endocytosis, Pgp was redistributed from the plasma membrane to the lysosomal membrane via early endosome formation. This lysosomal-Pgp actively transported the Pgp substrate, DOX, into the lysosome where it became trapped as a result of protonation at pH 5. Due to increased lysosomal DOX trapping, Pgp-expressing cells became more resistant to DOX. In contrast, cytotoxicity of Dp44mT and DpC was potentiated due to more lysosomes containing functional Pgp under glucose-induced stress. These thiosemicarbazones increased lysosomal membrane permeabilization and cell death. This mechanism has critical implications for drug-targeting in multidrug-resistant tumors where a stressful micro-environment exists. PMID- 26601948 TI - The Vps27/Hrs/STAM (VHS) Domain of the Signal-transducing Adaptor Molecule (STAM) Directs Associated Molecule with the SH3 Domain of STAM (AMSH) Specificity to Longer Ubiquitin Chains and Dictates the Position of Cleavage. AB - The deubiquitinating enzyme associated molecule with the SH3 domain of STAM (AMSH) is crucial for the removal of ubiquitin molecules during receptor-mediated endocytosis and lysosomal receptor sorting. AMSH interacts with signal transducing adapter molecule (STAM) 1 or 2, which enhances the activity of AMSH through an unknown mechanism. This stimulation is dependent on the ubiquitin interacting motif of STAM. Here we investigate the specific mechanism of AMSH stimulation by STAM proteins and the role of the STAM Vps27/Hrs/STAM domain. We show that, in the presence of STAM, the length of the ubiquitin chains affects the apparent cleavage rate. Through measurement of the chain cleavage kinetics, we found that, although the kcat of Lys(63)-linked ubiquitin chain cleavage was comparable for di- and tri-ubiquitin, the Km value was lower for tri-ubiquitin. This increased affinity for longer chains was dependent on the Vps27/Hrs/STAM domain of STAM and required that the substrate ubiquitin chain contain homogenous Lys(63)-linkages. In addition, STAM directed AMSH cleavage toward the distal isopeptide bond in tri-ubiquitin chains. Finally, we generated a structural model of AMSH-STAM to show how the complex binds Lys(63)-linked ubiquitin chains and cleaves at the distal end. These data show how a deubiquitinating enzyme interacting protein dictates the efficiency and specificity of substrate cleavage. PMID- 26601950 TI - Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions. AB - Exosomes regulate cell behavior by binding to and delivering their cargo to target cells; however, the mechanisms mediating exosome-cell interactions are poorly understood. Heparan sulfates on target cell surfaces can act as receptors for exosome uptake, but the ligand for heparan sulfate on exosomes has not been identified. Using exosomes isolated from myeloma cell lines and from myeloma patients, we identify exosomal fibronectin as a key heparan sulfate-binding ligand and mediator of exosome-cell interactions. We discovered that heparan sulfate plays a dual role in exosome-cell interaction; heparan sulfate on exosomes captures fibronectin, and on target cells it acts as a receptor for fibronectin. Removal of heparan sulfate from the exosome surface releases fibronectin and dramatically inhibits exosome-target cell interaction. Antibody specific for the Hep-II heparin-binding domain of fibronectin blocks exosome interaction with tumor cells or with marrow stromal cells. Regarding exosome function, fibronectin-mediated binding of exosomes to myeloma cells activated p38 and pERK signaling and expression of downstream target genes DKK1 and MMP-9, two molecules that promote myeloma progression. Antibody against fibronectin inhibited the ability of myeloma-derived exosomes to stimulate endothelial cell invasion. Heparin or heparin mimetics including Roneparstat, a modified heparin in phase I trials in myeloma patients, significantly inhibited exosome-cell interactions. These studies provide the first evidence that fibronectin binding to heparan sulfate mediates exosome-cell interactions, revealing a fundamental mechanism important for exosome-mediated cross-talk within tumor microenvironments. Moreover, these results imply that therapeutic disruption of fibronectin-heparan sulfate interactions will negatively impact myeloma tumor growth and progression. PMID- 26601951 TI - The Crystal Structure of the Ubiquitin-like Domain of Ribosome Assembly Factor Ytm1 and Characterization of Its Interaction with the AAA-ATPase Midasin. AB - The synthesis of eukaryotic ribosomes is a complex, energetically demanding process requiring the aid of numerous non-ribosomal factors, such as the PeBoW complex. The mammalian PeBoW complex, composed of Pes1, Bop1, and WDR12, is essential for the processing of the 32S preribosomal RNA. Previous work in Saccharomyces cerevisiae has shown that release of the homologous proteins in this complex (Nop7, Erb1, and Ytm1, respectively) from preribosomal particles requires Rea1 (midasin or MDN1 in humans), a large dynein-like protein. Midasin contains a C-terminal metal ion-dependent adhesion site (MIDAS) domain that interacts with the N-terminal ubiquitin-like (UBL) domain of Ytm1/WDR12 as well as the UBL domain of Rsa4/Nle1 in a later step in the ribosome maturation pathway. Here we present the crystal structure of the UBL domain of the WDR12 homologue from S. cerevisiae at 1.7 A resolution and demonstrate that human midasin binds to WDR12 as well as Nle1 through their respective UBL domains. Midasin contains a well conserved extension region upstream of the MIDAS domain required for binding WDR12 and Nle1, and the interaction is dependent upon metal ion coordination because removal of the metal or mutation of residues that coordinate the metal ion diminishes the interaction. Mammalian WDR12 displays prominent nucleolar localization that is dependent upon active ribosomal RNA transcription. Based upon these results, we propose that release of the PeBoW complex and subsequent release of Nle1 by midasin is a well conserved step in the ribosome maturation pathway in both yeast and mammalian cells. PMID- 26601949 TI - 1alpha,25-Dihydroxyvitamin D3 Regulates Mitochondrial Oxygen Consumption and Dynamics in Human Skeletal Muscle Cells. AB - Muscle weakness and myopathy are observed in vitamin D deficiency and chronic renal failure, where concentrations of the active vitamin D3 metabolite, 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), are low. To evaluate the mechanism of action of 1alpha,25(OH)2D3 in skeletal muscle, we examined mitochondrial oxygen consumption, dynamics, and biogenesis and changes in expression of nuclear genes encoding mitochondrial proteins in human skeletal muscle cells following treatment with 1alpha,25(OH)2D3. The mitochondrial oxygen consumption rate (OCR) increased in 1alpha,25(OH)2D3-treated cells. Vitamin D3 metabolites lacking a 1alpha-hydroxyl group (vitamin D3, 25-hydroxyvitamin D3, and 24R,25-dihydroxyvitamin D3) decreased or failed to increase OCR. 1alpha Hydroxyvitamin D3 did not increase OCR. In 1alpha,25(OH)2D3-treated cells, mitochondrial volume and branching and expression of the pro-fusion protein OPA1 (optic atrophy 1) increased, whereas expression of the pro-fission proteins Fis1 (fission 1) and Drp1 (dynamin 1-like) decreased. Phosphorylated pyruvate dehydrogenase (PDH) (Ser-293) and PDH kinase 4 (PDK4) decreased in 1alpha,25(OH)2D3-treated cells. There was a trend to increased PDH activity in 1alpha,25(OH)2D3-treated cells (p = 0.09). 83 nuclear mRNAs encoding mitochondrial proteins were changed following 1alpha,25(OH)2D3 treatment; notably, PDK4 mRNA decreased, and PDP2 mRNA increased. MYC, MAPK13, and EPAS1 mRNAs, which encode proteins that regulate mitochondrial biogenesis, were increased following 1alpha,25(OH)2D3 treatment. Vitamin D receptor-dependent changes in the expression of 1947 mRNAs encoding proteins involved in muscle contraction, focal adhesion, integrin, JAK/STAT, MAPK, growth factor, and p53 signaling pathways were observed following 1alpha,25(OH)2D3 treatment. Five micro RNAs were induced or repressed by 1alpha,25(OH)2D3. 1alpha,25(OH)2D3 regulates mitochondrial function, dynamics, and enzyme function, which are likely to influence muscle strength. PMID- 26601952 TI - Nuclear Factor of Activated T Cells-dependent Down-regulation of the Transcription Factor Glioma-associated Protein 1 (GLI1) Underlies the Growth Inhibitory Properties of Arachidonic Acid. AB - Numerous reports have demonstrated a tumor inhibitory effect of polyunsaturated fatty acids (PUFAs). However, the molecular mechanisms modulating this phenomenon are in part poorly understood. Here, we provide evidence of a novel antitumoral mechanism of the PUFA arachidonic acid (AA). In vivo and in vitro experiments showed that AA treatment decreased tumor growth and metastasis and increased apoptosis. Molecular analysis of this effect showed significantly reduced expression of a subset of antiapoptotic proteins, including BCL2, BFL1/A1, and 4 1BB, in AA-treated cells. We demonstrated that down-regulation of the transcription factor glioma-associated protein 1 (GLI1) in AA-treated cells is the underlying mechanism controlling BCL2, BFL1/A1, and 4-1BB expression. Using luciferase reporters, chromatin immunoprecipitation, and expression studies, we found that GLI1 binds to the promoter of these antiapoptotic molecules and regulates their expression and promoter activity. We provide evidence that AA induced apoptosis and down-regulation of antiapoptotic genes can be inhibited by overexpressing GLI1 in AA-sensitive cells. Conversely, inhibition of GLI1 mimics AA treatments, leading to decreased tumor growth, cell viability, and expression of antiapoptotic molecules. Further characterization showed that AA represses GLI1 expression by stimulating nuclear translocation of NFATc1, which then binds the GLI1 promoter and represses its transcription. AA was shown to increase reactive oxygen species. Treatment with antioxidants impaired the AA-induced apoptosis and down-regulation of GLI1 and NFATc1 activation, indicating that NFATc1 activation and GLI1 repression require the generation of reactive oxygen species. Collectively, these results define a novel mechanism underlying AA antitumoral functions that may serve as a foundation for future PUFA-based therapeutic approaches. PMID- 26601953 TI - Amyloid Assemblies of Influenza A Virus PB1-F2 Protein Damage Membrane and Induce Cytotoxicity. AB - PB1-F2 is a small accessory protein encoded by an alternative open reading frame in PB1 segments of most influenza A virus. PB1-F2 is involved in virulence by inducing mitochondria-mediated immune cells apoptosis, increasing inflammation, and enhancing predisposition to secondary bacterial infections. Using biophysical approaches we characterized membrane disruptive activity of the full-length PB1 F2 (90 amino acids), its N-terminal domain (52 amino acids), expressed by currently circulating H1N1 viruses, and its C-terminal domain (38 amino acids). Both full-length and N-terminal domain of PB1-F2 are soluble at pH values <=6, whereas the C-terminal fragment was found soluble only at pH <= 3. All three peptides are intrinsically disordered. At pH >= 7, the C-terminal part of PB1-F2 spontaneously switches to amyloid oligomers, whereas full-length and the N terminal domain of PB1-F2 aggregate to amorphous structures. When incubated with anionic liposomes at pH 5, full-length and the C-terminal part of PB1-F2 assemble into amyloid structures and disrupt membrane at nanomolar concentrations. PB1-F2 and its C-terminal exhibit no significant antimicrobial activity. When added in the culture medium of mammalian cells, PB1-F2 amorphous aggregates show no cytotoxicity, whereas PB1-F2 pre-assembled into amyloid oligomers or fragmented nanoscaled fibrils was highly cytotoxic. Furthermore, the formation of PB1-F2 amyloid oligomers in infected cells was directly reflected by membrane disruption and cell death as observed in U937 and A549 cells. Altogether our results demonstrate that membrane-lytic activity of PB1-F2 is closely linked to supramolecular organization of the protein. PMID- 26601954 TI - Characterization of Microfibrillar-associated Protein 4 (MFAP4) as a Tropoelastin and Fibrillin-binding Protein Involved in Elastic Fiber Formation. AB - MFAP4 (microfibrillar-associated protein 4) is an extracellular glycoprotein found in elastic fibers without a clearly defined role in elastic fiber assembly. In the present study, we characterized molecular interactions between MFAP4 and elastic fiber components. We established that MFAP4 primarily assembles into trimeric and hexameric structures of homodimers. Binding analysis revealed that MFAP4 specifically binds tropoelastin and fibrillin-1 and -2, as well as the elastin cross-linking amino acid desmosine, and that it co-localizes with fibrillin-1-positive fibers in vivo. Site-directed mutagenesis disclosed residues Phe(241) and Ser(203) in MFAP4 as being crucial for type I collagen, elastin, and tropoelastin binding. Furthermore, we found that MFAP4 actively promotes tropoelastin self-assembly. In conclusion, our data identify MFAP4 as a new ligand of microfibrils and tropoelastin involved in proper elastic fiber organization. PMID- 26601955 TI - Hyaluronan Rafts on Airway Epithelial Cells. AB - Many cells, including murine airway epithelial cells, respond to a variety of inflammatory stimuli by synthesizing leukocyte-adhesive hyaluronan (HA) cables that remain attached to their cell surfaces. This study shows that air-liquid interface cultures of murine airway epithelial cells (AECs) also actively synthesize and release a majority of their HA onto their ciliated apical surfaces to form a heavy chain hyaluronan (HC-HA) matrix in the absence of inflammatory stimuli. These matrices do not resemble the rope-like HA cables but occur in distinct sheets or rafts that can capture and embed leukocytes from cell suspensions. The HC-HA modification involves the transfer of heavy chains from the inter-alpha-inhibitor (IalphaI) proteoglycan, which has two heavy chains (HC1 and HC2) on its chondroitin sulfate chain. The transesterification transfer of HCs from chondroitin sulfate to HA is mediated by tumor necrosis factor-induced gene 6 (TSG-6), which is up-regulated in inflammatory reactions. Because the AEC cultures do not have TSG-6 nor serum, the source of IalphaI, assays for HCs and TSG-6 were done. The results show that AECs synthesize TSG-6 and their own heavy chain donor (pre-IalphaI) with a single heavy chain 3 (HC3), which are also constitutively expressed by human renal proximal tubular epithelial cells. These leukocyte adhesive HC3-HA structures were also found in the bronchoalveolar lavage of naive mice and were observed on their apical ciliated surfaces. Thus, these leukocyte-adhesive HA rafts are now identified as HC3-HA complexes that could be part of a host defense mechanism filling some important gaps in our current understanding of murine airway epithelial biology and secretions. PMID- 26601956 TI - Glutathionylation of the Active Site Cysteines of Peroxiredoxin 2 and Recycling by Glutaredoxin. AB - Peroxiredoxin 2 (Prx2) is a thiol protein that functions as an antioxidant, regulator of cellular peroxide concentrations, and sensor of redox signals. Its redox cycle is widely accepted to involve oxidation by a peroxide and reduction by thioredoxin/thioredoxin reductase. Interactions of Prx2 with other thiols are not well characterized. Here we show that the active site Cys residues of Prx2 form stable mixed disulfides with glutathione (GSH). Glutathionylation was reversed by glutaredoxin 1 (Grx1), and GSH plus Grx1 was able to support the peroxidase activity of Prx2. Prx2 became glutathionylated when its disulfide was incubated with GSH and when the reduced protein was treated with H2O2 and GSH. The latter reaction occurred via the sulfenic acid, which reacted sufficiently rapidly (k = 500 m(-1) s(-1)) for physiological concentrations of GSH to inhibit Prx disulfide formation and protect against hyperoxidation to the sulfinic acid. Glutathionylated Prx2 was detected in erythrocytes from Grx1 knock-out mice after peroxide challenge. We conclude that Prx2 glutathionylation is a favorable reaction that can occur in cells under oxidative stress and may have a role in redox signaling. GSH/Grx1 provide an alternative mechanism to thioredoxin and thioredoxin reductase for Prx2 recycling. PMID- 26601957 TI - The Dual Regulatory Role of Amino Acids Leu480 and Gln481 of Prothrombin. AB - Prothrombin (FII) is activated to alpha-thrombin (IIa) by prothrombinase. Prothrombinase is composed of a catalytic subunit, factor Xa (fXa), and a regulatory subunit, factor Va (fVa), assembled on a membrane surface in the presence of divalent metal ions. We constructed, expressed, and purified several mutated recombinant FII (rFII) molecules within the previously determined fVa dependent binding site for fXa (amino acid region 473-487 of FII). rFII molecules bearing overlapping deletions within this significant region first established the minimal stretch of amino acids required for the fVa-dependent recognition exosite for fXa in prothrombinase within the amino acid sequence Ser(478) Val(479)-Leu(480)-Gln(481)-Val(482). Single, double, and triple point mutations within this stretch of rFII allowed for the identification of Leu(480) and Gln(481) as the two essential amino acids responsible for the enhanced activation of FII by prothrombinase. Unanticipated results demonstrated that although recombinant wild type alpha-thrombin and rIIa(S478A) were able to induce clotting and activate factor V and factor VIII with rates similar to the plasma-derived molecule, rIIa(SLQ->AAA) with mutations S478A/L480A/Q481A was deficient in clotting activity and unable to efficiently activate the pro-cofactors. This molecule was also impaired in protein C activation. Similar results were obtained with rIIa(DeltaSLQ) (where rIIa(DeltaSLQ) is recombinant human alpha-thrombin with amino acids Ser(478)/Leu(480)/Gln(481) deleted). These data provide new evidence demonstrating that amino acid sequence Leu(480)-Gln(481): 1) is crucial for proper recognition of the fVa-dependent site(s) for fXa within prothrombinase on FII, required for efficient initial cleavage of FII at Arg(320); and 2) is compulsory for appropriate tethering of fV, fVIII, and protein C required for their timely activation by IIa. PMID- 26601958 TI - Loss of the Ubiquitin-conjugating Enzyme UBE2W Results in Susceptibility to Early Postnatal Lethality and Defects in Skin, Immune, and Male Reproductive Systems. AB - UBE2W ubiquitinates N termini of proteins rather than internal lysine residues, showing a preference for substrates with intrinsically disordered N termini. The in vivo functions of this intriguing E2, however, remain unknown. We generated Ube2w germ line KO mice that proved to be susceptible to early postnatal lethality without obvious developmental abnormalities. Although the basis of early death is uncertain, several organ systems manifest changes in Ube2w KO mice. Newborn Ube2w KO mice often show altered epidermal maturation with reduced expression of differentiation markers. Mirroring higher UBE2W expression levels in testis and thymus, Ube2w KO mice showed a disproportionate decrease in weight of these two organs (~50%), suggesting a functional role for UBE2W in the immune and male reproductive systems. Indeed, Ube2w KO mice displayed sustained neutrophilia accompanied by increased G-CSF signaling and testicular vacuolation associated with decreased fertility. Proteomic analysis of a vulnerable organ, presymptomatic testis, showed a preferential accumulation of disordered proteins in the absence of UBE2W, consistent with the view that UBE2W preferentially targets disordered polypeptides. These mice further allowed us to establish that UBE2W is ubiquitously expressed as a single isoform localized to the cytoplasm and that the absence of UBE2W does not alter cell viability in response to various stressors. Our results establish that UBE2W is an important, albeit not essential, protein for early postnatal survival and normal functioning of multiple organ systems. PMID- 26601960 TI - Descending neural drives to ankle muscles during gait and their relationships with clinical functions in patients after stroke. AB - OBJECTIVE: The objective of this study was to investigate the descending neural drive to ankle muscles during gait in stroke patients using a coherence analysis of surface electromyographic (EMG) recordings and the relationships of the drive with clinical functions. METHODS: EMG recordings of the paired tibialis anterior (TA), medial and lateral gastrocnemius (MG and LG), and TA-LG muscles were used to calculate intramuscular, synergistic, and agonist-antagonist muscle coherence, respectively, in 11 stroke patients and 9 healthy controls. Paretic motor function, sensory function, spasticity, ankle muscle strength, and gait performance were evaluated. RESULTS: Paretic TA-TA and MG-LG beta band (15-30 Hz) coherences were significantly lower compared with the non-paretic side and controls. TA-LG beta band coherence was significantly higher on both sides compared with controls. Paretic TA-TA beta band coherence positively correlated with gait speed, and paretic TA-LG beta band coherence negatively correlated with paretic ankle plantar flexor muscle strength. CONCLUSIONS: The intramuscular and synergistic muscle neural drives were reduced during gait on the paretic side in stroke patients. The agonist-antagonist muscle neural drive was increased to compensate for paretic ankle muscle weakness. SIGNIFICANCE: Descending neural drive reorganization to agonist-antagonist muscles is important for patients with paretic ankle muscle weakness. PMID- 26601959 TI - From Single Variants to Protein Cascades: MULTISCALE MODELING OF SINGLE NUCLEOTIDE VARIANT SETS IN GENETIC DISORDERS. AB - Understanding the role of genetics in disease has become a central part of medical research. Non-synonymous single nucleotide variants (nsSNVs) in coding regions of human genes frequently lead to pathological phenotypes. Beyond single variations, the individual combination of nsSNVs may add to pathogenic processes. We developed a multiscale pipeline to systematically analyze the existence of quantitative effects of multiple nsSNVs and gene combinations in single individuals on pathogenicity. Based on this pipeline, we detected in a data set of 842 nsSNVs discovered in 76 genes related to cardiomyopathies, associated nsSNV combinations in seven genes present in at least 70% of all 639 patient samples, but not in a control cohort of healthy humans. Structural analyses of these revealed primarily an influence on the protein stability. For amino acid substitutions located at the protein surface, we generally observed a proximity to putative binding pockets. To computationally analyze cumulative effects and their impact, pathogenicity methods are currently being developed. Our approach supports this process, as shown on the example of a cardiac phenotype but can be likewise applied to other diseases such as cancer. PMID- 26601961 TI - Conotoxins: Structure, Therapeutic Potential and Pharmacological Applications. AB - Cone snails, also known as marine gastropods, from Conus genus produce in their venom a diverse range of small pharmacologically active structured peptides called conotoxins. The cone snail venoms are widely unexplored arsenal of toxins with therapeutic and pharmacological potential, making them a treasure trove of ligands and peptidic drug leads. Conotoxins are small disulfide bonded peptides, which act as remarkable selective inhibitors and modulators of ion channels (calcium, sodium, potassium), nicotinic acetylcholine receptors, noradrenaline transporters, N-methyl-D-aspartate receptors, and neurotensin receptors. They are highly potent and specific against several neuronal targets making them valuable as research tools, drug leads and even therapeutics. In this review, we discuss their gene superfamily classification, nomenclature, post-translational modification, structural framework, pharmacology and medical applications of the active conopeptides. We aim to give an overview of their structure and therapeutic potential. Understanding these aspects of conopeptides will help in designing more specific peptidic analogues. PMID- 26601963 TI - Psychopharmacology of Attention-Deficit Hyperactivity Disorder: Effects and Side Effects. AB - Attention-deficit hyperactivity disorder (ADHD) is a common psychiatric disorder in children which manifests with hyperactivity, impulsivity, and/or inattention. Several drugs are used in treatment of ADHD. Stimulants, atomoxetine, anti depressants, and bupropion are common medications used in the treatment of ADHD. Stimulants are widely used as the first line treatment in children with ADHD. Their mechanism of action is the release of dopamine and norepinephrine in central nervous system. Methylphenidate is the most common stimulant used for the treatment of ADHD. Methylphenidate significantly reduces ADHD symptoms in children both at home and school and improves their social skills. Methylphenidate is safe in healthy children and has shown to have no cardiac side effects in these patients. Other medications include: Atomoxetine, Amphetamines, Clonidine, Melatonin, and anti-depressants. Effects, side effects, and mechanism of action these drugs have been discussed in this paper. PMID- 26601964 TI - Efficacy and Safety of Evacetrapib for Modifying Plasma Lipids: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Evacetrapib, a new cholesteryl ester transfer protein inhibitor, is being investigated as a potential therapeutic option for reducing cardiovascular events through increasing high-density lipoprotein cholesterol (HDL-C) concentrations. How evacetrapib affects other lipid parameters is less certain. The present study aimed to estimate the effect of evacetrapib on plasma lipid concentrations and to assess its safety through a systematic review and meta analysis of randomized controlled trials. METHODS: SCOPUS, Medline, and Google Scholar were searched to identify randomized controlled trials investigating the impact of evacetrapib on blood lipid concentrations published before December 29, 2014. A random-effects model (using the DerSimonian-Laird method) and the generic inverse variance method were used to examine the effect of evacetrapib on plasma lipid concentrations. The safety of evacetrapib was assessed by comparing the pooled incidence of adverse events (total adverse events, adverse events leading to study discontinuation, elevations in hepatic and muscular enzymes and blood pressure) between treatment and placebo groups. Sensitivity analyses were conducted using the one study remove approach. Meta-regression was performed to evaluate the association between changes plasma lipid concentrations and administered doses of evacetrapib. RESULTS: Meta-analysis of 14 randomized treatment arms over a mean of 2 months suggested that evacetrapib significantly reduces low-density lipoprotein cholesterol (LDL-C) (weighted mean difference [WMD]: -21.11%, 95% confidence interval (CI): -24.89, -17.33, p<0.001) and elevated HDL-C (WMD: +86.00%, 95% CI: +67.63, +104.37, p<0.001) concentrations following treatment with evacetrapib. Evacetrapib had no significant effect on plasma triglycerides (WMD: -2.97%, 95% CI: -8.63, +2.69, p = 0.303) concentrations. The effects of evacetrapib on all three lipid indices (LDL-C, HDL C and triglycerides) did not differ between subsets of trials administering evacetrapib as monotherapy or as add-on to statin therapy. Meta-regression suggested a dose-dependent effect of evacetrapib on plasma LDL-C and HDL-C, but not triglycerides concentrations. Meta-analysis suggested equivalent rates of adverse events in subjects receiving evacetrapib and placebo. CONCLUSION: Results of this meta-analysis suggested that evacetrapib, either as monotherapy or in combination with a statin, reduces LDL-C and increases HDL-C levels but has no effect on triglyceride concentrations. Adverse events appeared to be similar in subjects receiving evacetrapib and placebo in short-term follow-ups. PMID- 26601962 TI - Neuroprotective Mechanisms Mediated by CDK5 Inhibition. AB - Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase belonging to the family of cyclin-dependent kinases. In addition to maintaining the neuronal architecture, CDK5 plays an important role in the regulation of synaptic plasticity, neurotransmitter release, neuron migration and neurite outgrowth. Although various reports have shown links between neurodegeneration and deregulation of cyclin-dependent kinases, the specific role of CDK5 inhibition in causing neuroprotection in cases of neuronal insult or in neurodegenerative diseases is not wellunderstood. This article discusses current evidence for the involvement of CDK5 deregulation in neurodegenerative disorders and neurodegeneration associated with stroke through various mechanisms. These include upregulation of cyclin D1 and overactivation of CDK5 mediated neuronal cell death pathways, aberrant hyperphosphorylation of human tau proteins and/or neurofilament proteins, formation of neurofibrillary lesions, excitotoxicity, cytoskeletal disruption, motor neuron death (due to abnormally high levels of CDK5/p25) and colchicine- induced apoptosis in cerebellar granule neurons. A better understanding of the role of CDK5 inhibition in neuroprotective mechanisms will help scientists and researchers to develop selective, safe and efficacious pharmacological inhibitors of CDK5 for therapeutic use against human neurodegenerative disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis and neuronal loss associated with stroke. PMID- 26601965 TI - Inflammatory Process in Alzheimer's and Parkinson's Diseases: Central Role of Cytokines. AB - Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most widespread neurological disorders (NDs) characterized by degeneration of cognitive and motor functions due to malfunction and loss of neurons in the central nervous system (CNS). Numerous evidences have established the role of neuroinflammation in the AD and PD pathology. The inflammatory components such as microglia, astrocytes, complement system and cytokines are linked to neuroinflammation in the CNS. More specifically, cytokines have been found to play a central role in the neuroinflammation of AD and PD. A number of studies have demonstrated abnormally elevated levels of inflammatory cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF) in AD and PD patients. Activated microglial cells have been shown to be involved in the secretion of pro-inflammatory cytokines such as IL-1, IL-6, TNF-alpha and transforming growth factor-beta, thereby contributing towards the progress of NDs. In addition, studies on AD pathogenesis have demonstrated that microglia produce beta-amyloid protein (Abeta), which by itself is pro-inflammatory and causes activation of several inflammatory components. Similarly, chronic inflammation caused by microglial cells is the fundamental process involved in the destruction of neurons associated with dopamine (DA)-production in the brain of PD patients. Hence, there is a need to explore the key inflammatory components in AD and PD pathogenesis in order to fully understand the root cause and establish a substantial link between these two disorders. Such knowledge will help in better management and treatment of AD and PD. PMID- 26601966 TI - Computer Aided Drug Design: Success and Limitations. AB - Over the last few decades, computer-aided drug design has emerged as a powerful technique playing a crucial role in the development of new drug molecules. Structure-based drug design and ligand-based drug design are two methods commonly used in computer-aided drug design. In this article, we discuss the theory behind both methods, as well as their successful applications and limitations. To accomplish this, we reviewed structure based and ligand based virtual screening processes. Molecular dynamics simulation, which has become one of the most influential tool for prediction of the conformation of small molecules and changes in their conformation within the biological target, has also been taken into account. Finally, we discuss the principles and concepts of molecular docking, pharmacophores and other methods used in computer-aided drug design. PMID- 26601967 TI - Current Updates on Therapeutic Advances in the Management of Cardiovascular Diseases. AB - Despite the significant advances in the medical research and treatment methods, the rate of mortality associated with cardiovascular disease (CVD) is continuously rising and it remains the leading cause of death worldwide. There are several treatment methods for CVD and associated complications that have been considered till now. The current treatment methods cannot produce rapid cure, but could prevent or reduce the progression of this devastating disease. In the current article, we have summarized the use of various pharmacological agents viz. HMG-CoA reductase inhibitors (statins), antihypertensive, thrombolytic and anticoagulation agents that are currently being used for the management of CVD which targets different biochemical or molecular events. Based on our article, more research in this field is advocated which will provide the rapid and effective treatment methods in order to avoid fatal complications associated with CVD. PMID- 26601968 TI - Polyphenols: Potential Future Arsenals in the Treatment of Diabetes. AB - Diabetes mellitus (DM) is one of the most common endocrine metabolic disorders. In addition to exercise and diet, oral anti-diabetic drugs have been used as a part of the management strategy worldwide. Unfortunately, none of the conventional anti-diabetic drugs are without side effects, and these drugs pose an economic burden. Therefore, the investigation of novel anti-diabetic regimens is a major challenge for researchers, in which nature has been the primary resource for the discovery of potential therapeutics. Many plants have been shown to act as anti-diabetic agents, in which the main active constituents are believed to be polyphenols. Natural products containing high polyphenol levels can control carbohydrate metabolism by various mechanisms, such as protecting and restoring beta-cell integrity, enhancing insulin releasing activity, and increasing cellular glucose uptake. Blackberries, red grapes, apricots, eggplant and popular drinks such as coffee, cocoa and green tea are all rich in polyphenols, which may dampen insulin resistance and be natural alternatives in the treatment of diabetes. Therefore, the aim of this review is to report on the available anti-diabetic polyphenols (medicinal plants, fruits and vegetables), their mechanisms in the various pathways of DM and their correlations with DM. Additionally, this review emphasizes the types of polyphenols that could be potential future resources in the treatment of DM via either novel regimens or as supplementary agents. PMID- 26601969 TI - Unique Medicinal Properties of Withania somnifera: Phytochemical Constituents and Protein Component. AB - Withania somnifera is an important medicinal herb that has been widely used for the treatment of different clinical conditions. The overall medicinal properties of Withania somnifera make it a viable therapeutic agent for addressing anxiety, cancer, microbial infection, immunomodulation, and neurodegenerative disorders. Biochemical constituents of Withania somnifera like withanolideA, withanolide D, withaferin A and withaniamides play an important role in its pharmacological properties. Proteins like Withania somnifera glycoprotein and withania lectin like-protein possess potent therapeutic properties like antimicrobial, anti-snake venom poison and antimicrobial. In this review, we have tried to present different pharmacological properties associated with different extract preparations, phytochemical constituents and protein component of Withania somnifera. Future insights in this direction have also been highlighted. PMID- 26601970 TI - Interleukin-6: A Critical Cytokine in Cancer Multidrug Resistance. AB - Multidrug resistance (MDR) is a phenomenon through which tumor cells develop resistance against the cytotoxic effects of various structurally and mechanistically unrelated chemotherapeutic agents. The most consistent feature in MDR is overexpression and/or overactivity of ATP-dependent drug efflux transporters. Other mechanisms such as overexpression of drug-detoxifying enzymes and alterations in pro-survival or pro-death signaling pathways are also responsible for MDR. Inflammatory mediators including interleukin-6 (IL-6) play important roles in various events during inflammation and are also involved in development and progression of several types of cancers. Mounting evidence has suggested a crosstalk between IL-6 and MDR in cancer, highlighting the role of IL 6 in chemotherapy response, and the potential opportunity to control MDR through modulation of IL-6 expression. Upregulation of IL-6 has been shown to promote MDR through activation of Janus kinases (JAK)/signal transducer and activator of transcription 3 (STAT3), phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt), and Ras-MAPK (mitogen-activated protein kinase) pathways. Activation of the aforementioned pathways changes the expression pattern of several genes involved in proliferation, survival and cell cycle regulation, thus facilitating MDR. Conversely, IL-6 inhibition using different strategies (antibodies, siRNA, and antisense transfection) has been shown to improve tumor responsiveness and mitigate MDR in different cancer cell lines. This review focuses on the in vitro, experimental and clinical findings on the role of IL-6 in MDR, and potential therapeutic opportunities arising from this role of IL-6. PMID- 26601972 TI - Advantages of radial volumetric breath-hold examination (VIBE) with k-space weighted image contrast reconstruction (KWIC) over Cartesian VIBE in liver imaging of volunteers simulating inadequate or no breath-holding ability. AB - OBJECTIVES: To investigate the superiority of radial volumetric breath-hold examination (r-VIBE) with k-space weighted image contrast reconstruction (KWIC) over Cartesian VIBE (c-VIBE) for reducing motion artefacts. METHODS: We acquired r-VIBE-KWIC and c-VIBE images in 10 healthy volunteers. Each acquisition lasted 24 seconds. The volunteers held their breath for decreasing lengths of time during the acquisitions, from 24 to 0 seconds (protocols A-E). Magnetic resonance images at the level of the right portal vein and confluence of hepatic veins were assessed by two readers using a five-point scale with a higher number indicating a better study. RESULTS: The mean scores for the complete r-VIBE-KWIC series (r VIBEfull) and first r-VIBE-KWIC series (r-VIBE1) were not significantly lower than those for c-VIBE in any protocols. The mean scores for c-VIBE were lower than those for r-VIBEfull and r-VIBE1 in protocols C and D. The mean score for c VIBE was lower than that for r-VIBEfull in protocol E. The mean score for the eighth r-VIBE-KWIC series (r-VIBE8) was lower than that for c-VIBE only in protocol B. CONCLUSION: r-VIBE-KWIC minimised artefacts relative to c-VIBE at any slice location. The r-VIBE-KWIC's sub-frame images during the breath-holding period were hardly affected by another failed breath-holding period. KEY POINTS: * A two-reader study revealed r-VIBE-KWIC's advantages over c-VIBE * The image quality of r-VIBE-KWIC's sub-frame images was maintained during breath holding * Full-frame r-VIBE-KWIC images minimized motion artefacts caused by breathing * A complete breath holding over half the acquisition time is recommended for c-VIBE * c-VIBE was susceptible to respiratory motion especially in the subphrenic region. PMID- 26601971 TI - Second-order Texture Measurements of (3)He Ventilation MRI: Proof-of-concept Evaluation of Asthma Bronchodilator Response. AB - RATIONALE AND OBJECTIVES: (3)He magnetic resonance imaging (MRI) can be used to quantify functional responses to asthma therapy and provocation. Ventilation imaging offers quantitative information beyond ventilation defects that have not yet been exploited. Therefore, our objective was to evaluate hyperpolarized (3)He MRI ventilation defect percent (VDP) and compare this and pulmonary function measurements to ventilation image texture features and their changes post bronchodilator administration in patients with asthma. MATERIALS AND METHODS: Volunteers with a diagnosis of asthma provided written informed consent to an ethics board-approved protocol and underwent pulmonary function tests and MRI before and after salbutamol inhalation. MR images were analyzed using VDP, and their texture was evaluated via gray-level run-length matrices. These texture classifiers were compared to VDP in responders to bronchodilation based on VDP (VDP responders) and forced expiratory volume in 1 s (FEV1) (FEV1 responders). RESULTS: In total, 47 patients with asthma (18 males 39 +/- 13 years, FEV1 = 79 +/- 21%) reported significantly improved FEV1, FEV1/forced vital capacity (FVC), residual volume (RV)/total lung capacity (TLC) (all P = .0001) and VDP (P = .01) post-salbutamol. Post-salbutamol, VDP responders and nonresponders to salbutamol were significantly different for coarse-texture features including long-run emphasis (LRE) and long-run, low gray-level emphasis (LRLGE, both P < .05) and for FEV1 responders to salbutamol, there was significantly different long-run, high gray-level emphasis (LRHGE, P = .04). There were significant relationships for VDP with LRE (R = .50, P = .0003), LRLGE (R = .34, P = .02), and LRHGE (R = .56, P = .0001). Receiver operating characteristic curves showed VDP with the strongest performance (AUC = .92), followed by coarse-texture classifier LRHGE (AUC = .83), FEV1 (AUC = .80), LRE (AUC = .66), FVC (AUC = .58), and LRLGE (AUC = .42). CONCLUSIONS: In patients with asthma, differences in ventilation patchiness post-salbutamol can be quantified using coarse-texture classifiers that are significantly different in bronchodilator responders. PMID- 26601973 TI - Microanatomy of the subcallosal artery: an in-vivo 7 T magnetic resonance angiography study. AB - OBJECTIVES: To investigate in-vivo microanatomy of the subcallosal artery branching from the anterior communicating artery (ACoA) using time-of-flight (TOF) magnetic resonance angiography (MRA) at 7 Tesla. METHODS: Seventy-five subjects, including 15 healthy volunteers and 60 patients, were included in this prospective study. Three raters characterized branches from ACoA in maximum intensity projections of TOF MRA at 7 Tesla acquired with 0.22 * 0.22 * 0.41 mm(3) resolution. Furthermore, course patterns and anatomical features of the subcallosal artery (maximum diameter, length, and branching angle from ACoA) were measured. RESULTS: Branches from the anterior communicating artery were visualized in 63 of 74 (85.1 %) subjects and were identified as the subcallosal artery (93.7 %) and the accessory anterior cerebral artery (6.3 %). The course of the subcallosal artery was classified into 3 groups; C-shaped (55.9 %), straight (16.9 %), and S-shaped (27.2 %). There was a significant difference between the branching angles of C-shaped and straight (p < 0.0001), between C-shaped and S shaped (p < 0.0001), as well as between straight and S-shaped (p = 0.0113) course patterns. CONCLUSIONS: High-resolution in-vivo 7 T TOF MRA can delineate the microanatomy of the subcallosal artery. Three main variants of course patterns and branching angles from ACoA could be identified. KEY POINTS: * In-vivo 7 Tesla TOF MRA can delineate the subcallosal artery microanatomy * Three distinct course patterns of the subcallosal artery were identified * Branching angles from ACoA significantly differed between subcallosal artery course patterns. PMID- 26601974 TI - Treatment resistant fungal keratitis caused by Colletotrichum gloeosporioides. AB - CASE REPORT: A 56 year old woman suffered corneal injury from a branch of an orange tree. Forty days later she suffered a severe ocular infection, positive to Colletotrichum gloeosporioides (C. gloeosporioides). The patient did not respond to traditional treatment or crosslinking, and had to be treated with keratoplasty, suffering intraoperative and postoperative complications. DISCUSSION: Ocular infections due to C. gloeosporioides can occasionally be refractory to traditional and new treatments, such as crosslinking. PMID- 26601975 TI - Evolutionary multiobjective design of a flexible caudal fin for robotic fish. AB - Robotic fish accomplish swimming by deforming their bodies or other fin-like appendages. As an emerging class of embedded computing system, robotic fish are anticipated to play an important role in environmental monitoring, inspection of underwater structures, tracking of hazardous wastes and oil spills, and the study of live fish behaviors. While integration of flexible materials (into the fins and/or body) holds the promise of improved swimming performance (in terms of both speed and maneuverability) for these robots, such components also introduce significant design challenges due to the complex material mechanics and hydrodynamic interactions. The problem is further exacerbated by the need for the robots to meet multiple objectives (e.g., both speed and energy efficiency). In this paper, we propose an evolutionary multiobjective optimization approach to the design and control of a robotic fish with a flexible caudal fin. Specifically, we use the NSGA-II algorithm to investigate morphological and control parameter values that optimize swimming speed and power usage. Several evolved fin designs are validated experimentally with a small robotic fish, where fins of different stiffness values and sizes are printed with a multi-material 3D printer. Experimental results confirm the effectiveness of the proposed design approach in balancing the two competing objectives. PMID- 26601976 TI - [Sciatic perineural catheters: an alternative analgesia for diabetic patients]. AB - INTRODUCTION: Patients with diabetes mellitus have chronic neuropathic pain. The aim of our study was to 1) evaluate the feasibility of providing analgesia with a long-term sciatic perineural catheter in a medical unit for diabetic patients and 2) evaluate its effectiveness. METHODS: A prospective, monocentric, non randomized study was conducted over two years. All diabetic patients with an ineffective optimal systemic treatment were included. Written consent was obtained. Popliteal-sciatic nerve catheters were inserted under ultrasound guidance; ropivacaine was started. The primary endpoint was pain at Day 2. Pain intensity was measured using a numeric rating scale (NRS). Secondary endpoints were patient's pain relief, the impact on quality of life, and morphine consumption, evaluated at Day 0, Day 2, at the time of catheter removal, and one month after catheter removal. RESULTS: Feasibility was evaluated over one year. Fifty-five perineural catheters were placed in 32 patients. The median duration of catheter placement across patients was 13 [4-23] days. No toxic or infectious complications were seen. Effectiveness was evaluated during the second year of the study. Seventeen catheters were placed in 12 patients; 83% of patients had a NRS score <=3 at Day 2. More than 70% of patients experienced pain relief while the catheter was in place and at one month after its removal. The impact on quality of life was negligible. Morphine consumption was less on Day 2, at the time of catheter removal and one month after removal. CONCLUSION: The use of sciatic perineural catheters as an alternative analgesia technique in a non surgical environment for diabetic patients with chronic pain was possible and effective. PMID- 26601977 TI - Post-traumatic giant occipital pseudomeningocele. PMID- 26601979 TI - Inframesocolic Superior Mesenteric Artery First Approach as an Introductory Procedure of Radical Antegrade Modular Pancreatosplenectomy for Carcinoma of the Pancreatic Body and Tail. AB - Superior mesenteric artery (SMA)-first approaches are operative tactics used to determine tumor resectability early during pancreatoduodenectomy. With locally advanced carcinoma of the pancreatic body and tail, early determination of SMA involvement also helps establish whether curative resection is feasible. During either radical antegrade modular pancreatosplenectomy (RAMPS) or classic left-to right distal pancreatectomy, dissection of the SMA is performed after transection of the pancreas or wide detachment of the distal pancreas and spleen. Herein, we describe an inframesocolic SMA-first approach as an introductory procedure when treating carcinoma of the pancreatic body and tail. This first approach procedure provides a reliable and safe introduction to RAMPS. PMID- 26601980 TI - Genetically-modified R-omega-transaminase: purification and self-assembly facilitating interaction with substrate droplets. AB - OBJECTIVES: An easy-to-operate method of using R-omega-transaminase has been developed by fusing it to an elastin-like polypeptide and forming a complex with D-amino acid oxidase. RESULTS: R-omega-Transaminase (R-omega-TA) was fused to an elastin-like polypeptide (ELP) through genetic engineering of the enzyme. The enzyme was purified through reversible phase transition. For the single-enzyme system, in the reaction media, ELP-R-omega-TA self-assembled and formed enzyme clusters of micrometer size, and the substrate, (R)-1-phenylethylamine, also formed droplets of micrometer size. Intimate contact of the enzyme clusters and the substrate droplets provided a microenvironment of high substrate concentration close to the enzyme, facilitating the diffusion of substrate molecules into the active sites. For the two-enzyme system, ELP-R-omega-TA and ELP-fusion D-amino acid oxidase assembled to form two-enzyme complexes, forming clusters with a size much larger size than that of single enzymes. The efficiency of the combined enzymes for producing the product was 99.6 %. CONCLUSIONS: The two-enzyme complexes significantly improved the catalytic efficiency. Potentially, the two enzymes forming complex clusters can facilitate the immobilization of the two enzymes together through non covalent methods by entrapping in porous supports. PMID- 26601981 TI - Molecular understandings on 'the never thirsty' and apomictic Cenchrus grass. AB - The genus Cenchrus comprises around 25 species of 'bristle clade' grasses. Cenchrus ciliaris (buffel grass) is a hardy, perennial range grass that survives in poor sandy soils and limiting soil moisture conditions and, due to the very same reasons, this grass is one of the most prevalent fodder grasses of the arid and semi-arid regions. Most of the germplasms of Cenchrus produce seeds asexually through the process of apomeiosis. Therefore, the lack of sufficient sexual lines has hindered the crop improvement efforts in Cenchrus being confined to simple selection methods. Many attempts have been initiated in buffel grass to investigate the various molecular aspects such as genomic signatures of different species and genotypes, molecular basis of abiotic stress tolerance and reproductive performance. Even though it is an important fodder crop, molecular investigations in Cenchrus lack focus and the molecular information available on this grass is scanty. Cenchrus is a very good gene source for abiotic stress tolerance and apomixis studies. Biotechnological interventions in Cenchrus can help in crop improvement in Cenchrus as well as other crops through transgenic technology or marker assisted selection. To date no consolidated review on biotechnological interventions in Cenchrus grass has been published. Therefore we provide a thorough and in depth review on molecular research in Cenchrus focusing on molecular signatures of evolution, tolerance to abiotic stress and apomictic reproductive mechanism. PMID- 26601982 TI - Revisiting the Healthy Migrant Paradox in Perinatal Health Outcomes Through a Scoping Review in a Recent Host Country. AB - Ample evidence shows that, in many developed countries, immigrants have similar or better perinatal health outcomes than natives despite facing socioeconomic disadvantages in the host country ("healthy migrant paradox" -HMP). This scoping review aims to: (1) summarize the literature on perinatal health among immigrants and natives in Spain and (2) examine whether there is evidence of the HMP in a context of recent migration. A total of 25 articles published between 1998 and 2014 were reviewed. Overall, we found evidence of the HMP in low birthweight and to a lesser extent in preterm, though the patterns vary by origin, but not in macrosomia and post-term. The results are consistent across settings, levels of adjustment, and birth year. Policies should be oriented towards identifying the modifiable risk factors leading to a higher risk of macrosomia and post-term among immigrants. PMID- 26601983 TI - [Evaluation a parenting skills pilot programme from a public health perspective]. AB - OBJECTIVE: To evaluate the process and the results of the pilot phase of the Parenting skills development programme for families (PSP), an evidence-based strategy to promote positive parenting skills in socio-educational and community settings. METHODS: Before-after quasi-experimental design without a control group for the evaluation of the pilot phase of the PSD carried out in Barcelona (Spain) between October 2011 and June 2013. Eleven groups were established with the participation of 128 parents and 28 professionals. The intervention consisted of 10 or 11 sessions. Information was collected through questionnaires for parents and in-depth individual or group interviews for professionals. Parenting skills were identified through a questionnaire with six dimensions. The situation before the intervention (T0) and immediately after (T1) was compared. RESULTS: In T1 the number of participants decreased to 83 (retention=64.8%). Participants showed a high level of satisfaction with different dimensions of the program. On a maximum score of 10, the satisfaction of professionals was 8.7. Several key aspects and areas for improvement were identified for the future of the intervention. The quantitative analysis revealed improvements in all parenting skills dimensions and these improvements were consistent with the results of the qualitative analysis. CONCLUSIONS: The results of the pilot phase of this program suggest that a universal intervention on parenting skills can improve wellbeing among parents. PMID- 26601984 TI - [Erratum to: Mental disorders in the general population. Study on the health of adults in Germany and the additional module mental health (DEGS1-MH)]. PMID- 26601986 TI - Percutaneous stabilization of a T9/10 fracture in a patient with ankylosing spondylitis. PMID- 26601985 TI - [Flexibilization of sectoral borders? For]. PMID- 26601987 TI - Expert's comment concerning Grand Rounds case entitled "The management of high grade spondylolisthesis and co-existent late-onset idiopathic scoliosis" (Abhishek Srivastava, Edward Bayley, Bronek M. Boszczyk). PMID- 26601988 TI - Wider political context underlying the NHS junior doctors' dispute. PMID- 26601989 TI - Premenstrual Syndrome and Subsequent Risk of Hypertension in a Prospective Study. AB - The prevalence of hypertension is increasing among younger women, and new strategies are needed to identify high-risk women who should be targets for early intervention. Several mechanisms underlying hypertension might also contribute to premenstrual syndrome (PMS), but whether women with PMS have a higher risk of subsequently developing hypertension has not been assessed. We prospectively evaluated this possibility in a substudy of the Nurses' Health Study II. Participants were 1,257 women with clinically significant PMS (1991-2005) and 2,463 age-matched comparison women with few menstrual symptoms. Participants were followed for incident hypertension until 2011. Over 6-20 years, hypertension was reported by 342 women with PMS and 541 women without. After adjustment for age, smoking, body mass index, and other risk factors for hypertension, women with PMS had a hazard ratio for hypertension of 1.4 (95% confidence interval: 1.2, 1.6) compared with women without PMS. Risk was highest for hypertension that occurred before 40 years of age (hazard ratio = 3.3; 95% confidence interval: 1.7, 6.5; P for interaction = 0.0002). The risk associated with PMS was not modified by use of oral contraceptives or antidepressants but was attenuated among women with high intakes of thiamine and riboflavin (P < 0.05). These results suggest that PMS might be associated with future development of hypertension and that this risk may be modifiable. PMID- 26601991 TI - [Drugs and anti-drug antibody levels in the management of patients with inflammatory bowel disease]. PMID- 26601990 TI - Plasma matrix metalloproteinase 9 as an early surrogate biomarker of advanced colorectal neoplasia. AB - INTRODUCTION: Matrix metalloproteinases (MMPs) are overexpressed at different stages of colorectal carcinogenesis and could serve as early surrogate biomarkers of colorectal neoplasia. OBJECTIVE: To assess the utility of plasma MMP2 and MMP9 levels in the detection of advanced colorectal neoplasia and their correlation with tissue levels. METHODS: We analysed blood and tissue samples from patients with non-advanced adenomas (n=25), advanced adenomas (n=25), colorectal cancer (n=25) and healthy controls (n=75). Plasma and tissue gelatinase levels were determined by Luminex XMAP technology and gelatin zymography. Receiver operating characteristic (ROC) curve analysis was used to calculate the optimum cut-off for the detection of advanced colorectal neoplasia. RESULTS: Plasma MMP2 levels were similar between groups whatever the type of lesion. Plasma MMP9 levels were significantly higher in patients with neoplastic lesions than in healthy controls (median 292.3ng/ml vs. 139.08ng/ml, P<0.001). MMP9 levels were also higher in colorectal cancer than in non-advanced adenomas (median 314.6ng/ml vs. 274.3ng/ml, P=0.03). There was a significant correlation between plasma and tissue levels of MMP9 (r=0.5, P<0.001). The plasma MMP9 cut-off range with the highest diagnostic accuracy was between 173ng/ml and 204ng/ml (AUC=0.80 [95% CI: 0.72-0.86], P<0.001; sensitivity, 80-86% and specificity, 57-67%). CONCLUSION: Plasma MMP9 could be a surrogate biomarker for the early detection of advanced colorectal neoplasia, although its diagnostic performance could be increased by combination with other biomarkers. PMID- 26601992 TI - Adherence to a predefined vaccination program in patients with inflammatory bowel disease. AB - INTRODUCTION: The application of vaccination programs in patients with inflammatory bowel disease (IBD) is heterogeneous and generally deficient. As a result, adherence in these patients to a predefined vaccination program has not been clearly established. The aim of this study was to estimate adherence to a predefined vaccination program among patients with IBD and to identify the factors that may predict poor adherence. METHODS: All patients diagnosed with IBD and followed-up between January and March 2012 were referred to the Department of Preventive Medicine for evaluation of their immune status (with serological testing for hepatitis A, B and C viruses, varicella-zoster virus, mumps, rubella and measles), followed by vaccination based on the test results obtained and on the patient's vaccination history. The percentage of adherence to the vaccination program was determined, along with the factors associated with low adherence. RESULTS: A total of 153 patients with IBD (ulcerative colitis in 50.3% and Crohn's disease in 49.7%) were included (45.1% men and 54.9% women; mean age 43.30+/-14.19 years, range 17-83). The vaccination program adherence rate was 84.3%. The factors associated with poor adherence were drugs related to IBD (patients not receiving immunosuppressants and/or biological agents showed lower adherence than those receiving these treatments; p=0.021), adherence to medical treatment (poor adherence to treatment was also associated with poor adherence to vaccination; p=0.016), and marital status (single, divorced or separated patients showed lower adherence than married individuals; p=0.015). CONCLUSION: Adherence to vaccination is acceptable among patients with IBD. However, specific actions, such as optimization of patient information on the disease and emphasis on the need for adequate vaccination, are to improve adherence. PMID- 26601993 TI - Selective photochemical synthesis of Ag nanoparticles on position-controlled ZnO nanorods for the enhancement of yellow-green light emission. AB - A novel technique for the selective photochemical synthesis of silver (Ag) nanoparticles (NPs) on ZnO nanorod arrays is established by combining ultraviolet assisted nanoimprint lithography (UV-NIL) for the definition of growth sites, hydrothermal reaction for the position-controlled growth of ZnO nanorods, and photochemical reduction for the decoration of Ag NPs on the ZnO nanorods. During photochemical reduction, the size distribution and loading of Ag NPs on ZnO nanorods can be tuned by varying the UV-irradiation time. The photochemical reduction is hypothesized to facilitate the adsorbed citrate ions on the surface of ZnO, allowing Ag ions to preferentially form Ag NPs on ZnO nanorods. The ratio of visible emission to ultraviolet (UV) emission for the Ag NP-decorated ZnO nanorod arrays, synthesized for 30 min, is 20.5 times that for the ZnO nanorod arrays without Ag NPs. The enhancement of the visible emission is believed to associate with the surface plasmon (SP) effect of Ag NPs. The Ag NP-decorated ZnO nanorod arrays show significant SP-induced enhancement of yellow-green light emission, which could be useful in optoelectronic applications. The technique developed here requires low processing temperatures (120 degrees C and lower) and no high-vacuum deposition tools, suitable for applications such as flexible electronics. PMID- 26601994 TI - In defense of clinical conferences in clinical nursing education. AB - Clinical conferencing has been a consistent feature of clinical education, but the current clinical education environment poses many challenges to its continuance. The paper raises concern regarding the current state of clinical conferencing as part of clinical practice education in nursing. This topic is of great concern, but has there is little direction for clinical educators. The paper reviews the literature on conferencing and recommends avenues for future research. PMID- 26601995 TI - Rhinitis and pregnancy: literature review. AB - INTRODUCTION: There is a controversy concerning the terminology and definition of rhinitis in pregnancy. Gestational rhinitis is a relatively common condition, which has drawn increasing interest in recent years due to a possible association with maternal obstructive sleep apnea syndrome (OSAS) and unfavorable fetal outcomes. OBJECTIVE: To review the current knowledge on gestational rhinitis, and to assess its evidence. METHODS: Structured literature search. RESULTS: Gestational rhinitis and rhinitis "during pregnancy" are somewhat similar conditions regarding their physiopathology and treatment, but differ regarding definition and prognosis. Hormonal changes have a presumed etiological role, but knowledge about the physiopathology of gestational rhinitis is still lacking. Management of rhinitis during pregnancy focuses on the minimal intervention required for symptom relief. CONCLUSION: As it has a great impact on maternal quality of life, both the otorhinolaryngologist and the obstetrician must be careful concerning the early diagnosis and treatment of gestational rhinitis, considering the safety of treatment measures and drugs and their current level of evidence. PMID- 26601996 TI - Audiologic evaluations of children with mucopolysaccharidosis. AB - INTRODUCTION: Mucopolysaccharidosis is a hereditary lysosomal storage disease, which develops due to a deficiency in the enzymes that play a role in the metabolism of glycosaminoglycans (GAG). The incidence of mucopolysaccharidosis is 1/25,000, with autosomal recessive inheritance (except for MPS II). Mucopolysaccharidosis occurs in seven different types, each with a different congenital deficiency of lysosomal enzymes. In mucopolysaccharidosis patients, even though progression of clinical findings is not prominent, the disease advances and causes death at early ages. Facial dysmorphism, growth retardation, mental retardation, and skeletal or joint dysplasia are the most frequently found symptoms in these patients. OBJECTIVE: The purpose of our study is to present the types of hearing loss types and tympanometric findings of patients with mucopolysaccharidosis referred to our clinic with suspicion of hearing loss. METHODS: After otorhinolaryngological examination, 9 patients with different types of mucopolysaccharidosis, underwent to immittance and audiometric evaluations, performed according to their physical and mental abilities, and ages, in order to determine their hearing thresholds. RESULTS: The audiometric findings of the 9 patients followed with mucopolysaccharidosis were reported separately for each case. CONCLUSION: Based on the high frequency of hearing loss in mucopolysaccharidosis patients, early and detailed audiological evaluations are highly desirable. Therefore, regular and systematic multidisciplinary evaluations are very important. PMID- 26601997 TI - The role of aspirin desensitization in patients with aspirin-exacerbated respiratory disease (AERD). AB - INTRODUCTION: Aspirin-exacerbated respiratory disease (AERD) consists of a classic tetrad: moderate/severe asthma, chronic rhinosinusitis, nasal polyps, and intolerance to aspirin or other nonsteroidal anti-inflammatory drugs. Clinical control with drugs, surgery, and desensitization are treatment options. OBJECTIVE: To evaluate the efficacy and tolerability of aspirin desensitization in patients with AERD. METHODS: Periodic symptom assessment and endoscopy in patients with AERD undergoing surgery who were desensitized. RESULTS: Seventeen patients were desensitized. Eight patients completed the desensitization and were followed for a minimum of a one-year period (mean 3.1 years). These patients showed improvement in all symptoms. Moreover, surgical reassessment was not indicated in any of these patients and there was a decrease in costs with medication and procedures. Eight patients did not complete desensitization, mainly due to procedure intolerance and uncontrolled asthma, whereas another patient was lost to follow-up. CONCLUSION: Aspirin desensitization, when tolerated, was effective in patients with AERD and with poor clinical/surgical response. PMID- 26601998 TI - Evaluation of the improvement of quality of life with Azithromycin in the treatment of eosinophilic nasal polyposis. AB - INTRODUCTION: The Sino-Nasal Outcome Test 22 (SNOT-22) is an important tool in assessing the quality of life (QoL) of patients with chronic rhinosinusitis with a validated version in Brazil. The eosinophilic nasal polyposis (ENP) represents most of the cases of nasal polyposis (85-90%) and belongs to the group of chronic rhinosinusitis. It is a chronic inflammatory disease that impacts the QoL of patients, not only causing localized symptoms, but also resulting in a general malaise. The standard treatments (corticosteroids and nasal endoscopic surgery) lead to partial control of symptoms, but relapses are frequent. Macrolide acting as an immunomodulator is a promising tool for more effective control of this disease. Studies are still lacking to assess the real impact on the QoL in patients treated with macrolides. OBJECTIVE: To evaluate the improvement of QL, evaluated using SNOT-22, in patients with PNSE treated with immunomodulatory dose azithromycin. METHODS: This is a paired experimental study in patients with ENP. Comparison of pre-treatment and post-treatment with azithromycin was performed. Patients completed the SNOT-22 questionnaire before the start of treatment and returned for evaluation after eight weeks of treatment. Azithromycin was prescribed at a dose of 500 mg, orally, three times a week, for 8 weeks. RESULTS: SNOT-22 score decreased 20.3 points on average. There was a significant decrease in the SNOT-22 (difference greater than 14 points) in 19 patients (57.6%). There was no significant difference in improvement in SNOT in subgroups with or without asthma/aspirin intolerance. CONCLUSION: Azithromycin resulted in significant improvement of QoL, assessed by SNOT-22, in the studied population. PMID- 26601999 TI - Electrochemotherapy as palliative treatment in patients with thyroid papillary carcinoma. AB - INTRODUCTION: Local progression of papillary thyroid carcinoma (PTC) after failure of standard therapies may cause pain, ulceration, and bleeding. As patients are fully aware of the tumor growth, they might suffer high grade anxiety. Electrochemotherapy (ECT) is a new local palliative treatment for skin metastases of malignant melanoma or other tumors, including squamous head e neck cancer patients. OBJECTIVE: To evaluate the impact of ECT in patients with local progression of PTC. METHODS: Four patients with local progression of PTC were treated with ECT based on Bleomycin, and evaluated according to tumor response, local pain and side effects. RESULTS: In all cases, some grade of tumor response was observed, lasting 6, 7, 12 and 8 months, respectively. Also, reduction of local pain and anxiety was registered in all patients. Tumor infiltrated skin necrosis was the only collateral effect of the treatment. ECT induced a tumor response in all PTC patients with improvement of symptoms. CONCLUSIONS: ECT may be an option for local palliative treatment in PTC patients with local tumor progression. PMID- 26602000 TI - Tinnitus and cell phones: the role of electromagnetic radiofrequency radiation. AB - INTRODUCTION: Tinnitus is a multifactorial condition and its prevalence has increased on the past decades. The worldwide progressive increase of the use of cell phones has exposed the peripheral auditory pathways to a higher dose of electromagnetic radiofrequency radiation (EMRFR). Some tinnitus patients report that the abusive use of mobiles, especially when repeated in the same ear, might worsen ipsilateral tinnitus. OBJECTIVE: The aim of this study was to evaluate the available evidence about the possible causal association between tinnitus and exposure to electromagnetic waves. METHODS: A literature review was performed searching for the following keywords: tinnitus, electromagnetic field, mobile phones, radio frequency, and electromagnetic hypersensitivity. We selected 165 articles that were considered clinically relevant in at least one of the subjects. RESULTS: EMRFR can penetrate exposed tissues and safety exposure levels have been established. These waves provoke proved thermogenic effects and potential biological and genotoxic effects. Some individuals are more sensitive to electromagnetic exposure (electrosensitivity), and thus, present earlier symptoms. There may be a common pathophysiology between this electrosensitivity and tinnitus. CONCLUSION: There are already reasonable evidences to suggest caution for using mobile phones to prevent auditory damage and the onset or worsening of tinnitus. PMID- 26602001 TI - Vocal individuality cues in the African penguin (Spheniscus demersus): a source filter theory approach. AB - The African penguin is a nesting seabird endemic to southern Africa. In penguins of the genus Spheniscus vocalisations are important for social recognition. However, it is not clear which acoustic features of calls can encode individual identity information. We recorded contact calls and ecstatic display songs of 12 adult birds from a captive colony. For each vocalisation, we measured 31 spectral and temporal acoustic parameters related to both source and filter components of calls. For each parameter, we calculated the Potential of Individual Coding (PIC). The acoustic parameters showing PIC >= 1.1 were used to perform a stepwise cross-validated discriminant function analysis (DFA). The DFA correctly classified 66.1% of the contact calls and 62.5% of display songs to the correct individual. The DFA also resulted in the further selection of 10 acoustic features for contact calls and 9 for display songs that were important for vocal individuality. Our results suggest that studying the anatomical constraints that influence nesting penguin vocalisations from a source-filter perspective, can lead to a much better understanding of the acoustic cues of individuality contained in their calls. This approach could be further extended to study and understand vocal communication in other bird species. PMID- 26602002 TI - Mitral Stenosis and Aortic Atresia--A Risk Factor for Mortality After the Modified Norwood Operation in Hypoplastic Left Heart Syndrome. AB - BACKGROUND: There are conflicting reports regarding the importance of mitral stenosis and aortic atresia as a risk factor for Norwood mortality. This study reviews outcomes of this anatomic subgroup at our institution and examines the utility of preoperative cardiac catheterization and its correlation with clinical outcomes and pathology findings. METHODS: This is a single-center, retrospective review of hypoplastic left heart syndrome patients who underwent modified Norwood operation between October 2005 and May 2013. RESULTS: Fourteen of 74 hypoplastic left heart syndrome patients (19%) had mitral stenosis and aortic atresia. Operative mortality for MS/AA was 29% versus 7% for all other hypoplastic left heart syndrome anatomic subgroups (p = 0.04). Although only 19% of the entire cohort, the mitral stenosis and aortic atresia subgroup constituted 50% of the total operative mortality and the only interstage deaths. Autopsies support myocardial ischemia as the mechanism of death. Although preoperative angiography defined the presence of ventriculo-coronary connections, it did not clearly risk stratify patients in regard to operative mortality. CONCLUSIONS: Mitral stenosis and aortic atresia is a risk factor for perioperative myocardial ischemia and mortality. Further exploration of myocardial reserve is warranted. PMID- 26602003 TI - Excellent Long-Term Outcomes of the Arterial Switch Operation in Patients With Intramural Coronary Arteries. AB - BACKGROUND: Intramural coronary arteries may complicate coronary artery transfer during the arterial switch operation. We sought to determine the long-term outcomes of 28 patients with intramural coronary arteries who underwent an arterial switch operation at a single institution. METHODS: All patients who had intramural coronary arteries and underwent an arterial switch operation were identified from the hospital database and retrospectively reviewed. RESULTS: From 1983 to 2009, 720 patients underwent an arterial switch operation at our institution. Twenty-eight (3.9%, 28 of 720) had intramural coronary arteries. Patients with intramural coronary arteries had transposition of the great arteries (96%, n = 27) or Taussig-Bing anomaly (4%, n = 1). There were no deaths. Follow-up was 100% complete. Mean follow-up was 16.3 years (median, 15.5 years; range, 5.6 to 26.9 years). No patient required reoperation or catheter reintervention on the coronary arteries. Freedom from reoperation was 93% at 10 years. No patient had more than mild aortic regurgitation at last follow-up. Nine (32%, 9 of 28) patients had coronary angiograms at median 16 months (range, 14 months to 17 years) after arterial switch operation. All patients were asymptomatic at the time of angiogram. One patient had mild stenosis of the circumflex coronary artery demonstrated on a routine coronary angiogram 14 months postoperatively. All 28 patients were asymptomatic and in New York Heart Association functional class I at last follow-up. CONCLUSIONS: Patients with intramural coronary arteries are not at increased risk of death or coronary reinterventions and have excellent late outcomes after the arterial switch operation. PMID- 26602004 TI - Intermediate-Term Outcome of 140 Consecutive Fontan Conversions With Arrhythmia Operations. AB - BACKGROUND: Atrial arrhythmias and progressive circulatory failure frequently develop in patients with a Fontan circulation. Improvement of flow dynamics and revision of the arrhythmia substrate may improve outcomes in selected patients. We sought to determine intermediate-term outcomes after Fontan conversion with arrhythmia operations and identify characteristics associated with decreased transplant-free survival. METHODS: The first 140 Fontan conversions with arrhythmia operations at a single institution were analyzed for predictors of cardiac death or transplant and incidence of arrhythmia recurrence. RESULTS: The median age at the Fontan conversion operation was 23.2 years (range, 2.6 to 47.3 years). Preoperative arrhythmias were present in 136 patients: right atrial tachycardia in 48 patients, left atrial tachycardia in 21, and atrial fibrillation in 67. Freedom from cardiac death or transplant was 90% at 5 years, 84% at 10 years, and 66% at 15 years. The median age at the last follow-up among survivors was 32 years (range, 15 to 61 years). By multivariable analysis, risk factors for cardiac death or heart transplantation were a right or indeterminate ventricular morphology, cardiopulmonary bypass time exceeding 240 minutes, ascites, protein-losing enteropathy, or a biatrial arrhythmia operation at the time of conversion. Freedom from recurrence of atrial tachycardia was 77% at 10 years. Among 67 patients with atrial fibrillation undergoing biatrial arrhythmia operations, none had recurrent atrial fibrillation. CONCLUSIONS: Freedom from cardiac death or transplant for patients undergoing Fontan conversion with an arrhythmia operation is 84% at 10 years. The effects of atrial arrhythmia operations are durable in most patients. These outcomes may serve as useful benchmarks for alternative management strategies. PMID- 26602005 TI - Decreasing the Preincision Time for Pulmonary Lobectomy: The Process of Lean and Value Stream Mapping. AB - BACKGROUND: Our objective was to evaluate our results after the implementation of lean (the elimination of wasteful parts of a process). METHODS: After meetings with our anesthesiologists, we standardized our "in the operating room-to-skin incision protocols" before pulmonary lobectomy. Patients were divided into consecutive cohorts of 300 lobectomy patients. Several protocols were slowly adopted and outcomes were evaluated. RESULTS: One surgeon performed 2,206 pulmonary lobectomies, of which 84% were for cancer. Protocols for lateral decubitus positioning changed over time. We eliminated axillary rolls, arm boards, and beanbags. Monitoring devices were slowly eliminated. Central catheters decreased from 75% to 0% of patients, epidurals from 84% to 3%, arterial catheters from 93% to 4%, and finally, Foley catheters were reduced from 99% to 11% (p <= 0.001 for all). A protocol for the insertion of double-lumen endotracheal tubes was established and times decreased (mean, 14 minutes to 1 minute; p = 0.001). After all changes were made, the time between operating room entry and incision decreased from a mean of 64 minutes to 37 minutes (p < 0.001). Outcomes improved, mortality decreased from 3.2% to 0.26% (p = 0.015), and major morbidity decreased from 15.2% to 5.3% (p = 0.042). CONCLUSIONS: Lean and value stream mapping can be safely applied to the clinical algorithms of high-risk patient care. We demonstrate that elimination of non-value-added steps can safely decrease preincision time without increasing patient risk in patients who undergo pulmonary lobectomy. Selected centers may be able to adopt some of these lean driven protocols. PMID- 26602006 TI - Mini Bypass and Proinflammatory Leukocyte Activation: A Randomized Controlled Trial. AB - BACKGROUND: Coronary artery bypass grafting (CABG) with conventional cardiopulmonary bypass (CPB) induces systemic inflammation. Miniaturized CPB may attenuate systemic inflammatory activation. The intracellular signaling pathways promoting inflammation in cardiac operations and the relative effects of CPB on these processes are uncertain. In this study, induction of reactive oxygen species (ROS) and activation of nuclear factor (NF)-kappaB, p38 mitogen-activated protein kinase (MAPK) within leukocytes, and leukocyte accumulation in cantharidin-induced blisters was compared in patients exposed to miniaturized CPB (mCPB) and those who underwent conventional CPB (cCPB). METHODS: Patients undergoing CABG were randomized to receive either cCPB (n = 13) or mCPB (n = 13). Blood samples were collected preoperatively and 5 times after initiating CPB (up to 5 hours) and analyzed by flow cytometry for intracellular markers of activation (ROS, p38-MAPK, and NF-kappaB phosphorylation). RESULTS: ROS in lymphocytes were elevated in cCPB compared with mCPB (p < 0.01), whereas ROS in granulocytes and monocytes were similar between groups. After initiation of CPB, p38-MAPK was higher in patients receiving cCPB compared with those receiving mCPB (p < 0.05). NF-kappaB phosphorylation in leukocyte subsets was similar in patients exposed to cCPB and those exposed to mCPB. Leukocyte accumulation in cantharidin-induced blisters, white cell counts, and serum C-reactive protein (CRP) was enhanced in response to cardiac operations, but no differences were observed between mCPB and cCPB groups. Postoperative serum creatinine levels were reduced in the mCPB group compared with the cCPB group (p < 0.05). CONCLUSIONS: Both p38-MAPK activation and ROS were attenuated with the use of mCPB compared with cCPB, providing a potential mechanism for reduced inflammation in association with CPB miniaturization. PMID- 26602007 TI - Surgical Therapy for Bilateral Multiple Primary Lung Cancer. AB - BACKGROUND: With the development of diagnostic techniques, the incidence of multiple pulmonary nodules has increased. The management of multiple primary lung cancer patients based on currently established criteria, however, remains controversial. METHODS: Patients who underwent curative operations for bilateral multiple primary lung cancer (BMPLC) based on the Martini-Melamed criterion between January 2001 and June 2014 were reviewed retrospectively. RESULTS: Bilateral lobectomies and lobectomies with contralateral sublobar resections were performed in 39 and 49 patients, respectively. Bilateral sublobar resections were performed in the remaining 13 cases. Overall survival at 3 and 5 years was 84.5% and 75.0%, respectively. The use of a limited resection procedure for the contralateral second nodule in cases with stage I BMPLC did not have a negative effect on the 5-year overall survival (p = 0.752). Postoperative pathologic diagnosis classified by the most advanced TNM stage appeared to present a good correlation with prognosis in patients with BMPLC. Cox multivariate analysis identified the most advanced TNM stage (p = 0.018) and the number of lesions (p = 0.001) as significant predictors of overall survival. CONCLUSIONS: The prognosis of patients after bilateral surgical treatment with curative intent for BMPLC was shown to be promising. The use of a limited resection procedure for the contralateral second nodule in cases with stage I BMPLC did not have a negative effect on the 5-year overall survival. Postoperative pathologic diagnosis classified by the most advanced TNM had a good correlation with prognosis in patients with BMPLC. PMID- 26602008 TI - Rapid Deployment of Aortic Bioprosthesis in Elderly Patients With Small Aortic Annulus. AB - BACKGROUND: Aortic valve replacement in elderly patients with a small aortic annulus remains challenging. Patient-prosthesis mismatch (PPM) should be prevented without impacting operative mortality. Hemodynamic benefits resulting from rapid-deployment aortic valve replacement with the Edwards Intuity bioprosthesis for this indication were evaluated. METHODS: Elective patients with severe aortic stenosis who required an Edwards Intuity bioprosthesis, size 19 mm and 21 mm, were prospectively included between July 2012 and July 2014. Transthoracic echocardiography was performed preoperatively and at 1-month follow up. RESULTS: Sixty-six consecutive patients (mean age, 78 +/- 6.4 years; 54.5% women) were included. The Intuity 19 mm was inserted in 29 patients, and the Intuity 21 mm was inserted in 37 patients. No deaths or aortic annulus ruptures occurred. Mean aortic cross-clamp time was 42.7 +/- 18.2 minutes. At the 1-month follow-up, mean New York Heart Association classification was 1.6 +/- 0.5 versus 2.2 +/- 0.8 (p < 0.001). The mean gradient decreased from 59 +/- 17.6 mm Hg to 13.7 +/- 4.4 mm Hg (p < 0.001). Mean indexed effective orifice area was 0.77 +/- 0.17 cm(2)/m(2) for the Intuity 19 mm and 1.01 +/- 0.32 cm(2)/m(2) for the Intuity 21 mm. Twenty-one patients (32%) had a moderate PPM (indexed effective orifice area < 0.85 cm(2)/m(2)), and 10 patients (15%) had a severe PPM (indexed effective orifice area < 0.65 cm(2)/m(2)). The mean gradient was 15.1 +/- 3.5 mm Hg and 16.9 +/- 4.9 mm Hg in the moderate PPM group and severe PPM group, respectively (p = 0.3). The left ventricular mass index dramatically decreased from 153.2 +/- 32.7 g/m(2) to 118.4 +/- 20.2 g/m(2) (p < 0.001), and only 1 patient (1.5%) had a periprosthetic regurgitation greater than 1. CONCLUSIONS: Regarding the low rate of severe PPM and the early regression of left ventricular mass, these preliminary studies indicate the potential benefit of the Intuity bioprosthesis in patients with a small aortic annulus. Midterm results should be evaluated. PMID- 26602009 TI - Mapping dominant annual land cover from 2009 to 2013 across Victoria, Australia using satellite imagery. AB - There is a demand for regularly updated, broad-scale, accurate land cover information in Victoria from multiple stakeholders. This paper documents the methods used to generate an annual dominant land cover (DLC) map for Victoria, Australia from 2009 to 2013. Vegetation phenology parameters derived from an annual time series of the Moderate Resolution Imaging Spectroradiometer Vegetation Indices 16-day 250 m (MOD13Q1) product were used to generate annual DLC maps, using a three-tiered hierarchical classification scheme. Classification accuracy at the broadest (primary) class level was over 91% for all years, while it ranged from 72 to 81% at the secondary class level. The most detailed class level (tertiary) had accuracy levels ranging from 61 to 68%. The approach used was able to accommodate variable climatic conditions, which had substantial impacts on vegetation growth patterns and agricultural production across the state between both regions and years. The production of an annual dataset with complete spatial coverage for Victoria provides a reliable base data set with an accuracy that is fit-for-purpose for many applications. PMID- 26602011 TI - Amount of Antenatal Care Days in a Context of Effective Regionalization of Very Preterm Deliveries. AB - OBJECTIVE: To evaluate the amount of antenatal care days in level III hospitals caused by regionalization of very preterm deliveries. STUDY DESIGN: We included all 171,997 pregnancies registered in Finland between January 1, 2004 and December 31, 2006. Data on deliveries from the Medical Birth Register were linked to the Hospital Discharge Register. Maternal zip codes were used to define whether a mother lived inside or outside a level III hospital region. Regionalization was defined as care in level III hospitals between gestational weeks 22 and 32 among mothers living outside level III hospital regions. Pregnancies were divided into 3 groups based on the gestational age at delivery: very preterm (<32 weeks), late preterm (32-36 weeks), and term (>=37 weeks). RESULTS: There were 12,354 antenatal care days in level III hospitals caused by regionalization, which amounts to a need for 12 antenatal maternal beds annually. In the very preterm pregnancies, the antenatal length of stay was comparable for mothers living inside or outside level III hospital regions (median 4 days, P = .81) but significantly longer for mothers living outside level III hospital regions in the late preterm (median 9 vs 7 days, P = .001) and term groups (median 3 vs 2 days, P < .0001). CONCLUSIONS: The costs of regionalization of very preterm deliveries were low, as measured by antenatal care days. Regionalization did not increase the antenatal length of stay in very preterm deliveries. PMID- 26602012 TI - [A para-aortic opacity]. PMID- 26602010 TI - Elevations of C14:1 and C14:2 Plasma Acylcarnitines in Fasted Children: A Diagnostic Dilemma. AB - OBJECTIVES: To test whether follow-up testing for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency uncovers a diagnosis in patients with elevations of C14:1 and C14:2 plasma acylcarnitines after a controlled fasting study performed for clinically suspected hypoglycemia and to compare the acylcarnitine profiles from fasted patients without VLCAD deficiency vs patients with known VLCAD deficiency to determine whether metabolite testing distinguishes these groups. STUDY DESIGN: We performed a retrospective chart review and identified 17 patients with elevated C14:1 and C14:2 plasma acylcarnitine levels after a controlled fast and with testing for VLCAD deficiency (ACADVL sequencing or fibroblast fatty acid oxidation studies). The follow-up testing in all patients was inconsistent with a diagnosis of VLCAD deficiency. We compared the plasma acylcarnitine profiles from these fasted patients vs patients with VLCAD deficiency. RESULTS: C14:1/C12:1 was significantly lower (P < .001) in fasted patients vs patients with VLCAD deficiency. Metabolomics analysis performed in 2 fasted patients and 1 patient with VLCAD deficiency demonstrated evidence for up regulated lipolysis and beta-oxidation in the fasted state. CONCLUSIONS: Elevations of plasma C14:1 and C14:2 acylcarnitines appear to be a physiologic result of lipolysis that occurs with fasting. Both metabolomics analysis and/or C14:1/C12:1 may distinguish C14:1 elevations from physiologic fasting-induced lipolysis vs VLCAD deficiency. PMID- 26602014 TI - Hormonal manipulation with toremifene in sporadic desmoid-type fibromatosis. AB - INTRODUCTION: Many patients affected by desmoid-type fibromatosis (DF) are treated with a course of hormonal therapy as front line. So far, tamoxifene has been the preferred choice. Toremifene is an anti-oestrogen agent, but possible further mechanisms of action in desmoids are related to its role in regulation of transforming growth factor-beta and beta-catenin pathways. MATERIAL AND METHODS: We retrospectively reviewed all patients treated with toremifene between 2005 and 2012 at a reference institution. Indication to toremifene was radiologically progressive disease and/or symptomatic deterioration. Progression-free survival (PFS), clinical benefit (CB) and safety profile were analysed. RESULTS: Forty four patients were treated with toremifene 180 mg daily, 20 for radiological progression, 16 for pain and 8 for both. In 28 patients, toremifene was offered as front-line therapy, while in 11 after tamoxifen failure. PFS was 89.6% at 2 years. According to Response Evaluation Criteria in Solid Tumours, partial response, stable disease and disease progression were observed in 25%, 65% and 10% of the patients, respectively. Symptomatic relief was obtained in 75% of patients. Median time to response was 4 months. Overall CB was 86%. Adverse events G>=2 according to National Cancer Institute Common Toxicity Criteria were recorded in ten patients. DISCUSSION: Present series provides evidence to make toremifene an option in patients with DF, even after failure on different hormonal agents. A prospective trial is ongoing to confirm these results. PMID- 26602013 TI - Analytical Validation and Application of a Targeted Next-Generation Sequencing Mutation-Detection Assay for Use in Treatment Assignment in the NCI-MPACT Trial. AB - Robust and analytically validated assays are essential for clinical studies. We outline an analytical validation study of a targeted next-generation sequencing mutation-detection assay used for patient selection in the National Cancer Institute Molecular Profiling-Based Assignment of Cancer Therapy (NCI-MPACT) trial (NCT01827384). Using DNA samples from normal or tumor cell lines and xenografts with known variants, we assessed the sensitivity, specificity, and reproducibility of the NCI-MPACT assay in five variant types: single-nucleotide variants (SNVs), SNVs at homopolymeric (HP) regions (>=3 identical bases), small insertions/deletions (indels), large indels (gap >=4 bp), and indels at HP regions. The assay achieved sensitivities of 100% for 64 SNVs, nine SNVs at HP regions, and 11 large indels, 83.33% for six indels, and 93.33% for 15 indels at HP regions. Zero false positives (100% specificity) were found in 380 actionable mutation loci in 96 runs of haplotype map cells. Reproducibility analysis showed 96.3% to 100% intraoperator and 98.1% to 100% interoperator mean concordance in detected variants and 100% reproducibility in treatment selection. To date, 38 tumors have been screened, 34 passed preanalytical quality control, and 18 had actionable mutations for treatment assignment. The NCI-MPACT assay is well suited for its intended investigational use and can serve as a template for developing next-generation sequencing assays for other cancer clinical trial applications. PMID- 26602015 TI - The effects of age on health-related quality of life in cancer populations: A pooled analysis of randomized controlled trials using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 involving 6024 cancer patients. AB - BACKGROUND: Cancer incidence increases exponentially with advancing age, cancer patients live longer than in the past, and many new treatments focus on stabilizing disease and HRQOL. The objective of this study is to examine how cancer affects patients' HRQOL and whether their HRQOL is age-dependent. METHODS: Data from 25 EORTC randomized controlled trials was pooled. EORTC QLQ-C30 mean scores for the cancer cohort and five general population cohorts were compared to assess the impact of cancer on patients' HRQOL. Within the cancer cohort, multiple linear regressions (two-sided level P-value = 0.05 adjusted for multiple testing.) were used to investigate the association between age and HRQOL, adjusted for gender, WHO performance status (PS), distant metastasis and stratified by cancer site. A difference of 10 points on the 0-100 scale was considered clinically important. RESULTS: Cancer patients generally have worse HRQOL compared to the general population, but the specific HRQOL domains impaired vary with age. When comparing the cancer versus the general population, young cancer patients had worse financial problems, social and role functioning, while the older cancer groups had more appetite loss. Within the cancer cohort, HRQOL was worse with increasing age for physical functioning and constipation, and better with increasing age for social functioning, insomnia and financial problems (all p < 0.05). CONCLUSION: HRQOL is impaired in cancer patients compared to the general population, but the impact on specific HRQOL domains varies by age. Within the cancer population, some HRQOL components improve with age while others deteriorate. Optimal care for older cancer patients should target HRQOL domains most relevant to this population. PMID- 26602016 TI - Human papillomavirus genotype and oropharynx cancer survival in the United States of America. AB - BACKGROUND: The presence of human papillomavirus (HPV) DNA in oropharyngeal squamous cell cancer (OPSCC) tissue appears to be a strong predictor of improved prognosis, but this observation has not been explored in a population-based sample with generalisable findings. METHODS: Follow-up data from a large sample of OPSCC patients identified through six population-based cancer registries in the United States of America (USA) were used to characterise the association of tumour HPV status with survival. RESULTS: HPV DNA was detected in tumour tissue from 71% (378 in 529) of the OPSCC patients. A total of 65% of patients with HPV16-associated tumours survived 5 years compared to 46% of patients with other HPV types and 28% of patients with HPV-negative tumours (p log-rank test <0.0001). The OPSCC patients with detectable HPV16 DNA had a 62% reduced hazard of death at 5 years, and patients with other HPV types had a 42% reduced hazard of death at 5 years compared to HPV-negative patients. Compared to non-Hispanic Whites, Blacks with OPSCC had a 2.6-fold greater risk of death at 5 years after adjustment for HPV status and other prognostic variables. Both surgery and radiation therapy were associated with a reduced 5-year risk of death, but no evidence was found for an interaction between HPV status and radiotherapy or surgery on survival time. CONCLUSIONS: Data from this US study suggest that HPV16 positive OPSCC patients survive longer than HPV-negative patients regardless of treatment, highlighting the prognostic importance of HPV status for this malignancy. Optimal treatment regimens for OPSCC could be tailored to each patient's HPV status and prognostic profile. PMID- 26602018 TI - Chaperoning epigenetics: FKBP51 decreases the activity of DNMT1 and mediates epigenetic effects of the antidepressant paroxetine. AB - Epigenetic processes, such as DNA methylation, and molecular chaperones, including FK506-binding protein 51 (FKBP51), are independently implicated in stress-related mental disorders and antidepressant drug action. FKBP51 associates with cyclin-dependent kinase 5 (CDK5), which is one of several kinases that phosphorylates and activates DNA methyltransferase 1 (DNMT1). We searched for a functional link between FKBP51 (encoded by FKBP5) and DNMT1 in cells from mice and humans, including those from depressed patients, and found that FKBP51 competed with its close homolog FKBP52 for association with CDK5. In human embryonic kidney (HEK) 293 cells, expression of FKBP51 displaced FKBP52 from CDK5, decreased the interaction of CDK5 with DNMT1, reduced the phosphorylation and enzymatic activity of DNMT1, and diminished global DNA methylation. In mouse embryonic fibroblasts and primary mouse astrocytes, FKBP51 mediated several effects of paroxetine, namely, decreased the protein-protein interactions of DNMT1 with CDK5 and FKBP52, reduced phosphorylation of DNMT1, and decreased the methylation and increased the expression of the gene encoding brain-derived neurotrophic factor (Bdnf). In human peripheral blood cells, FKBP5 expression inversely correlated with both global and BDNF methylation. Peripheral blood cells isolated from depressed patients that were then treated ex vivo with paroxetine revealed that the abundance of BDNF positively correlated and phosphorylated DNMT1 inversely correlated with that of FKBP51 in cells and with clinical treatment success in patients, supporting the relevance of this FKBP51 directed pathway that prevents epigenetic suppression of gene expression. PMID- 26602017 TI - Nomograms for predicting survival and recurrence in patients with adenoid cystic carcinoma. An international collaborative study. AB - BACKGROUND: Due to the rarity of adenoid cystic carcinoma (ACC), information on outcome is based upon small retrospective case series. The aim of our study was to create a large multiinstitutional international dataset of patients with ACC in order to design predictive nomograms for outcome. METHODS: ACC patients managed at 10 international centers were identified. Patient, tumor, and treatment characteristics were recorded and an international collaborative dataset created. Multivariable competing risk models were then built to predict the 10 year recurrence free probability (RFP), distant recurrence free probability (DRFP), overall survival (OS) and cancer specific mortality (CSM). All predictors of interest were added in the starting full models before selection, including age, gender, tumor site, clinical T stage, perineural invasion, margin status, pathologic N-status, and M-status. Stepdown method was used in model selection to choose predictive variables. An external dataset of 99 patients from 2 other institutions was used to validate the nomograms. FINDINGS: Of 438 ACC patients, 27.2% (119/438) died from ACC and 38.8% (170/438) died of other causes. Median follow-up was 56 months (range 1-306). The nomogram for OS had 7 variables (age, gender, clinical T stage, tumor site, margin status, pathologic N-status and M-status) with a concordance index (CI) of 0.71. The nomogram for CSM had the same variables, except margin status, with a concordance index (CI) of 0.70. The nomogram for RFP had 7 variables (age, gender, clinical T stage, tumor site, margin status, pathologic N status and perineural invasion) (CI 0.66). The nomogram for DRFP had 6 variables (gender, clinical T stage, tumor site, pathologic N-status, perineural invasion and margin status) (CI 0.64). Concordance index for the external validation set were 0.76, 0.72, 0.67 and 0.70 respectively. INTERPRETATION: Using an international collaborative database we have created the first nomograms which estimate outcome in individual patients with ACC. These predictive nomograms will facilitate patient counseling in terms of prognosis and subsequent clinical follow-up. They will also identify high risk patients who may benefit from clinical trials on new targeted therapies for patients with ACC. FUNDING: None. PMID- 26602019 TI - The subcellular localization and activity of cortactin is regulated by acetylation and interaction with Keap1. AB - Cortactin is an F-actin-binding protein that localizes to the cell cortex, where the actin remodeling that is required for cell migration occurs. We found that cortactin shuttled between the cytoplasm and the nucleus under basal conditions. We identified Kelch-like ECH-associated protein 1 (Keap1), a cytosolic protein that is involved in oxidant stress responses, as a binding partner of cortactin that promoted the cortical localization of cortactin and cell migration. The ability of cortactin to promote cell migration is regulated by various posttranslational modifications, including acetylation. We showed that the acetylated form of cortactin was mainly localized to the nucleus and that acetylation of cortactin decreased cell migration by inhibiting the binding of cortactin to Keap1. Our findings reveal that Keap1 regulates cell migration by affecting the subcellular localization and activity of cortactin independently of its role in oxidant stress responses. PMID- 26602020 TI - The early synthesis of p35 and activation of CDK5 in LPS-stimulated macrophages suppresses interleukin-10 production. AB - Interleukin-10 (IL-10) is an important anti-inflammatory cytokine that is produced primarily by macrophages. We investigated mechanisms by which the timing of IL-10 production was controlled in macrophages and found that cyclin-dependent kinase 5 (CDK5) activity was markedly increased in lipopolysaccharide (LPS) stimulated macrophages through the synthesis of the CDK5-binding partner and activator p35. Degradation of p35 released the inhibition on anti-inflammatory signaling mediated by CDK5-p35 complexes. The transiently active CDK5-p35 complexes limited the LPS-stimulated phosphorylation and activation of various mitogen-activated protein kinases (MAPKs), thereby preventing the premature production of SOCS3 (suppressor of cytokine signaling 3), an inhibitor of inflammatory responses in macrophages, and IL-10. Furthermore, we showed that dextran sodium sulfate failed to induce colitis in p35-deficient mice, which was associated with the enhanced production of IL-10 by macrophages. Together, our results suggest that CDK5 enhances the inflammatory function of macrophages by inhibiting the MAPK-dependent production of IL-10. PMID- 26602021 TI - Hope and hype surrounding circulating microRNA as potential next generation AML biomarkers. PMID- 26602022 TI - Have we been ignoring the elephant in the room? Seven arguments for considering the cerebellum as part of addiction circuitry. AB - Addiction involves alterations in multiple brain regions that are associated with functions such as memory, motivation and executive control. Indeed, it is now well accepted that addictive drugs produce long-lasting molecular and structural plasticity changes in corticostriatal-limbic loops. However, there are brain regions that might be relevant to addiction other than the prefrontal cortex, amygdala, hippocampus and basal ganglia. In addition to these circuits, a growing amount of data suggests the involvement of the cerebellum in many of the brain functions affected in addicts, though this region has been overlooked, traditionally, in the addiction field. Therefore, in the present review we provide seven arguments as to why we should consider the cerebellum in drug addiction. We present and discuss compelling evidence about the effects of drugs of abuse on cerebellar plasticity, the involvement of the cerebellum in drug induced cue-related memories, and several findings showing that the instrumental memory and executive functions also recruit the cerebellar circuitry. In addition, a hypothetical model of the cerebellum's role relative to other areas within corticostriatal-limbic networks is also provided. Our goal is not to review animal and human studies exhaustively but to support the inclusion of cerebellar alterations as a part of the physiopathology of addiction disorder. PMID- 26602023 TI - Cognitive impairment in amyotrophic lateral sclerosis, clues from the SOD1 mouse. AB - Amyotrophic lateral sclerosis (ALS) is now recognized as a multisystem disorder, in which the primary pathology is the degeneration of motor neurons, with cognitive and/or behavioral dysfunctions that constitutes the non-motor manifestations of ALS. The combination of clinical, neuroimaging, and neuropathological data, and detailed genetic studies suggest that ALS and frontotemporal dementia (FTD) might form part of a disease continuum, with pure ALS and pure FTD at the two extremes. Mutations in the superoxide dismutase 1 (SOD1) gene were the first genetic mutations linked to the insurgence of ALS. Since that discovery numerous animal models carrying SOD1 mutations have been created. Despite their limitations these animal models, particularly the mice, have broaden our knowledge on the system alterations occurring in the ALS spectrum of disorders. The present review aims at providing an overview of the data obtained with the SOD1 animal models first and foremost on the cortical and subcortical regions, the cortico-striatal and hippocampal synaptic plasticity, dendritic branching and glutamate receptors function. PMID- 26602024 TI - Polymorphisms near the IFNL3 Gene Associated with HCV RNA Spontaneous Clearance and Hepatocellular Carcinoma Risk. AB - The aims of this study were to investigate associations between single nucleotide polymorphisms (SNPs) near the genes IFNL2, IFNL3, and IFNL4 and spontaneous clearance of hepatitis C virus (HCV) and to evaluate variants for their risk of hepatocellular carcinoma (HCC) among subjects in whom spontaneous HCV RNA clearance did not occur. In the first study, 889 untreated anti-HCV-seropositive patients without HCC symptoms were followed from 1991 to 2005. The spontaneous HCV clearance rate was found to be 33.1%. The TT variant of rs8099917 near IFNL3 was associated with increased spontaneous HCV RNA clearance, with an adjusted odds ratio (95% CI) of 2.78 (1.43-5.39), as was the newly-identified TT/TT dinucleotide variant rs368234815 near IFNL4 (adjusted odds ratio 2.68, 95% CI: 1.42-5.05). In the second study, associations between SNPs and HCC risk were examined in 483 HCC cases with detectable HCV RNA and 516 controls. In participants with HCV genotype 1, unfavorable genotypes for HCV clearance near IFNL3 were associated with increased HCC risk, the adjusted odds ratio (95% CI) for rs12979860 and rs8099917 being 1.73 (1.00-2.99) and 1.84 (1.02-3.33), respectively. Host characteristics should be considered to identify high-risk patients to prioritize the use of new antiviral agents and intensive screening. PMID- 26602025 TI - Telelap ALF-X vs Standard Laparoscopy for the Treatment of Early-Stage Endometrial Cancer: A Single-Institution Retrospective Cohort Study. AB - STUDY OBJECTIVE: To compare the surgical and clinical outcomes of patients affected by early-stage endometrial cancer treated using the Telelap ALF-X platform versus conventional laparoscopic surgery. DESIGN: Single institution retrospective cohort study (Canadian Task Force classification II-2). SETTING: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome, Italy. PATIENTS: The study involved 89 patients affected by early-stage endometrial cancer who underwent elective surgical staging between October 2013 and September 2014. Among them, 43 (48.3%) underwent Telelap ALF-X staging (ALF-X group), and 46 (51.7%) underwent conventional laparoscopic staging (laparoscopic group). INTERVENTIONS: All selected patients underwent laparoscopic staging with radical hysterectomy (class A sec Querleu-Morrow), bilateral salpingo-oophorectomy, and pelvic lymphadenectomy if required. The 2 surgical groups were further divided into patients who did not require pelvic lymphadenectomy (subgroup 1) and those who underwent pelvic lymphadenectomy (subgroup 2). MEASUREMENTS AND MAIN RESULTS: In the ALF-X group, the median operative time was 128 minutes (range, 69-260 minutes) for subgroup 1 and 193 minutes (range, 129-290 minutes) for subgroup 2. In the laparoscopic group, the median operative time was 82 minutes (range, 25 180 minutes) in subgroup 1 and 104 minutes (range, 36-160 minutes) in subgroup 2. The difference in operative time between subgroups was statistically significant in both the ALF-X and laparoscopic groups (p = .000). In subgroup 1 of the ALF-X group, there was 1 conversion to standard laparoscopy (2.3%) and 2 conversions to laparotomy (4.7%) (p = .234). No conversions to laparotomy occurred in the laparoscopic group. Postoperative complications included 1 case of pelvic hematoma (2.3%) in subgroup 1 of the ALF-X group and 1 case of subocclusion and 1 case of pulmonary edema (4.3%) in subgroup 1 of the laparoscopic group. CONCLUSION: Based on operative outcomes and complication rates, our results suggest that the Telelap ALF-X approach is feasible and safe for endometrial cancer staging; however, further studies are needed to definitively assess the role of Telelap ALF-X early-stage endometrial cancer staging. PMID- 26602026 TI - Bifunctional Polymer Nanocomposites as Hole-Transport Layers for Efficient Light Harvesting: Application to Perovskite Solar Cells. AB - A new approach to largely enhancing light harvesting of solar cells by employing bifunctional polymer nanocomposites as hole-transport layers (HTLs) is proposed. To illustrate our working principle, CH3NH3PbI3-xClx perovskite solar cells are used as examples. Gold nanoparticles (Au-NPs) are added into a conjugated poly(3 hexylthiophene-2,5-diyl) (P3HT) matrix, resulting in a ~4-fold enhancement in the electrical conductivity and carrier mobility of the native P3HT film. The improved electrical properties are attributed to enhanced polymer chain ordering caused by Au-NPs. By integration of those P3HT:Au-NP films with an optimum loading concentration of 20% into perovskite solar cells as HTLs, this leads to a more than 25% enhancement in the power conversion efficiency (PCE) compared with that of the NP-free one. In addition to the modulated electrical properties of the HTL, the improved performance can also be attributed to the scattering effect from the incorporated Au-NPs, which effectively extends the optical pathway to amplify photon absorption of the photoactive layer. The design principle shown here can be generalized to other organic materials as well, which should be very useful for the further development of high-performance optoelectronic devices. PMID- 26602027 TI - Five-year biochemical recurrence-free and overall survival following high-dose rate brachytherapy with additional external beam or radical prostatectomy in patients with clinically localized prostate cancer. AB - INTRODUCTION: High-dose-rate brachytherapy (HDR-BT) with external-beam radiation therapy and radical prostatectomy (RP) are common treatment options for clinically localized prostate cancer. The aim was to describe risk factors for biochemical recurrence (BCR) and death, as well as BCR rates and overall survival (OS) rates in both treatment groups. PATIENTS AND METHODS: Overall, 5,619 patients with localized prostate cancer underwent either RP (n = 5,200) or HDR-BT (n = 419) between 1999 and 2009. Median follow-up time was 72.4 months. Kaplan Meier analyses and multivariable Cox regression analyses were performed for the overall cohort and for a propensity score-matched cohort to predict BCR and OS rates. Within the matched cohort, stratified analyses were repeated for HDR-BT alone (n = 206) and HDR-BT plus androgen deprivation therapy (ADT) (n = 213). Sensitivity analyses were performed to adjust for prostate-specific antigen rebound. RESULTS: The 5-year BCR-free survival rates were 82.1% vs. 80.3% (P<0.01) for RP and HDR-BT, respectively. Corresponding 5-year OS rates were 97.1% vs. 92.4% (P<0.01). In the propensity score-matched cohort, 5-year BCR-free survival rates were 80.3% vs. 77.1%; P = 0.06 and 5-year OS rates were 95.7% vs. 92.4%; P = 0.5. In multivariable models, the overall HDR-BT exerted no significant effect on BCR, and the same results were recorded in the matched cohort. In stratified analyses, HDR-BT alone vs. RP increased BCR risk (1.45; P<0.01); conversely, HDR-BT plus ADT vs. RP decreased BCR risk (hazard ratio = 0.66; P = 0.02). CONCLUSIONS: First, RP offers equivalent oncological control without the need for concurrent hormone therapy and its morbidity. Second, patients who have RP avoid ADT (2%) and the need for salvage and adjuvant external-beam radiation therapy is low at 11% and 3%, respectively. PMID- 26602028 TI - A novel homozygous LMNA mutation (p.Met540Ile) causes mandibuloacral dysplasia type A. AB - Mandibuloacral dysplasia with type A lipodystrophy (MADA) is a rare genetic disorder inherited in an autosomal recessive fashion characterized by hypoplasia of the mandible and clavicles, acroosteolysis and lipodystrophy due to mutations in the LMNA or ZMPSTE24 genes. In the current study, we have investigated a consanguineous family clinically diagnosed with mandibuloacral dysplasia type A having an affected child for the LMNA gene alteration(s). Mother is now 15weeks pregnant, seeking advice on the health of her fetus. Peripheral blood was obtained from all family members after informed consent was achieved. Genomic DNA was isolated. The sequence of the LMNA gene, including all exons and intron boundaries was analyzed by PCR and Sanger sequencing. Chorionic villus was collected from the placenta to reveal the condition of the fetus. Molecular analysis ascertained a homozygous mutation c.1620G>A (p.M540I) in the proband and heterozygous alteration in the family. Genomic DNA isolated from the CVS was amplified using specific primers for identified deleterious mutation and analyzed by Sanger sequencing. Two pathogenic mutations c.1620G>A and c.1698C>T were identified in the fetus. Genetic counseling as well as justified rapid and sensitive genetic testing can provide reassurance for the families to prevent the high burden of genetic disorders. We have also applied several online tools including PolyPhen2, MUpro, SIFT, PoPMuSiC, Project HOPE and Mutation Taster to predict the impact of p.Met540Ile substitution as a hotspot region within LMNA. All tools showed reduction in the stability of the protein structure. We conclude that p.M540I mutation may causes disease in the homozygous state. PMID- 26602029 TI - Integrative transcriptomics and proteomics analysis of longissimus dorsi muscles of Canadian double-muscled Large White pigs. AB - Canadian double-muscled Large White pigs are characterized by notable muscle mass, showing high daily gain and lean rate and good meat quality. In order to identify the major genes or proteins involved in muscle hyperplasia and hypertrophy, three pairs of full-sib pigs with extreme muscle mass difference from Canadian Large White were selected as experimental animals at 3 months age. The phenotypic differences of longissimus dorsi muscles (LD) were investigated with microarray and proteomics (2-DE, MALDI-TOF-MS), and results were verified by real-time PCR and western bolting respectively. The gene expressing profiling identified 57 and 260 and 147 differently expressed genes (DEGs) from the three pairs respectively with Bayesian statistics and significant analysis of microarrays (SAM) (p<0.05, q<0.05, fold>2). From the network of these DEGs, some major genes were displayed, such as EGF, PPARG, FN1, SERPINE1, MYC, JUN, involved in Wnt, MAPK and TGF-beta signal pathway respectively, which mainly participated in cell differentiation and proliferation. In parallel, proteomics analyses revealed 50 differently expressed protein (DEP) spots with mass spectrum, and 33 spots of them were found annotated, which took part in energy metabolism and the structure and contraction of muscle fiber. In brief, our integrated study provides a good foundation for the further study on the genetic mechanism of the double muscle traits in pigs. PMID- 26602030 TI - DMDD in DSM-5.1: Do we need to be more lenient? PMID- 26602031 TI - PHOTO QUIZ: Immunosuppressed Patient Presenting With Fever, Interstitial Pneumonia, and Brain Lesions. PMID- 26602034 TI - Obliquity pacing of the western Pacific Intertropical Convergence Zone over the past 282,000 years. AB - The Intertropical Convergence Zone (ITCZ) encompasses the heaviest rain belt on the Earth. Few direct long-term records, especially in the Pacific, limit our understanding of long-term natural variability for predicting future ITCZ migration. Here we present a tropical precipitation record from the Southern Hemisphere covering the past 282,000 years, inferred from a marine sedimentary sequence collected off the eastern coast of Papua New Guinea. Unlike the precession paradigm expressed in its East Asian counterpart, our record shows that the western Pacific ITCZ migration was influenced by combined precession and obliquity changes. The obliquity forcing could be primarily delivered by a cross hemispherical thermal/pressure contrast, resulting from the asymmetric continental configuration between Asia and Australia in a coupled East Asian Australian circulation system. Our finding suggests that the obliquity forcing may play a more important role in global hydroclimate cycles than previously thought. PMID- 26602035 TI - Utilization of Site-Specific Recombination in Biopharmaceutical Production. AB - Mammalian expression systems, due to their capacity in post-translational modification, are preferred systems for biopharmaceutical protein production. Several recombinant protein systems have been introduced to the market, most of which are under clinical development. In spite of significant improvements such as cell line engineering, introducing novel expression methods, gene silencing and process development, expression level is unpredictable and unstable because of the random location of integration in the genome. Site-specific recombination techniques are capable of producing stable and high producer clonal cells; therefore, they are gaining more importance in the biopharmaceutical production. Site-specific recombination methods increase the recombinant protein production by specifically inserting a vector at a locus with specific expression trait. The present review focused on the latest developments in site-specific recombination techniques, their specific features and comparisons. PMID- 26602036 TI - Body visual discontinuity affects feeling of ownership and skin conductance responses. AB - When we look at our hands we are immediately aware that they belong to us and we rarely doubt about the integrity, continuity and sense of ownership of our bodies. Here we explored whether the mere manipulation of the visual appearance of a virtual limb could influence the subjective feeling of ownership and the physiological responses (Skin Conductance Responses, SCRs) associated to a threatening stimulus approaching the virtual hand. Participants observed in first person perspective a virtual body having the right hand-forearm (i) connected by a normal wrist (Full-Limb) or a thin rigid wire connection (Wire) or (ii) disconnected because of a missing wrist (m-Wrist) or a missing wrist plus a plexiglass panel positioned between the hand and the forearm (Plexiglass). While the analysis of subjective ratings revealed that only the observation of natural full connected virtual limb elicited high levels of ownership, high amplitudes of SCRs were found also during observation of the non-natural, rigid wire connection condition. This result suggests that the conscious embodiment of an artificial limb requires a natural looking visual body appearance while implicit reactivity to threat may require physical body continuity, even non-naturally looking, that allows the implementation of protective reactions to threat. PMID- 26602037 TI - Postoperative timing of computed tomography scans for abscess in pediatric appendicitis. AB - BACKGROUND: One-quarter to one half of pediatric appendicitis patients present with ruptured appendicitis and about 3%-25% go on to form postoperative intra abdominal abscesses. The optimal timing of postoperative imaging for suspected abscess formation has been a subject of debate. METHODS: All patients who underwent appendectomy for complex appendicitis and were not discharged before postoperative day (POD) #5 from April 2012-October 2014 were identified. Patients were stratified into groups for comparison as follows: group 1 had postoperative computed tomography (CT) scans before POD#7 (n = 26) and group 2 did not (n = 169). Group 2 was further divided into those who were afebrile (group 2a, n = 106) or febrile (group 2b, n = 63) at POD#5. RESULTS: A total of 195 patients met criteria. Early use of CT scans resulted in more drainage procedures (group 1, 73.1% versus group 2b, 28.6%, P < 0.001) and a higher recurrent CT scan rate (38.5% versus 9.5%). The groups had equivalent lengths of stay (11.9 versus 9.8 d, P = 0.10) and readmission rates due to abscesses (19.2% group 1 versus 6.3%, group 2b, P = 0.12) with no septic events. In total, 130 of the 169 patients (76.9%) in group 2 had resolution of symptoms before discharge without intervention with readmission for abscess in only 5.9%. CONCLUSIONS: Waiting until POD#7 before scanning led to fewer drainage procedures and recurrent CT scans without increasing length of stay or readmission rates. Most complex appendicitis patients still admitted at POD#5 had resolution of symptoms without need for intervention. PMID- 26602038 TI - Effects of occlusion on mandibular morphology and architecture in rats. AB - BACKGROUND: A rodent occlusal hypofunction model has been widely established in jawbone-related studies. However, the effects of occlusal stimuli, with total elimination of molar contacts, and its rehabilitation on mandibular remodeling remain unclear. MATERIALS AND METHODS: Forty-eight 5-wk-old Sprague-Dawley male rats were used. Twenty-four experimental rats underwent occlusal hypofunction by insertion of a bite-raising appliance. Twenty-four rats received no treatment (control group). Two weeks later, half the experimental rats (occlusal hypofunction group) were killed; the appliance was removed from the remaining experimental rats (recovery group) for two additional weeks before killing. Control animals were killed biweekly. Body weight and masseter muscle weight were measured, and the mandibles were subjected to micro-computed tomography to evaluate the mandibular morphology and cortical bone characteristics. The expressions of osteoblast- and osteoclast-related genes were evaluated with quantitative polymerase chain reaction. RESULTS: No significant body weight differences were observed between the experimental and control rats. However, lighter masseter muscle, shorter mandibular incisor crown, mandibular body and ramus, and higher mandibular alveolar process and first molar fossae were observed in the occlusal hypofunction group. Moreover, the cortical bone characteristics associated with the expression of osteoblast- and osteoclast related genes were remarkably different in the central and posterior mandible in the occlusal hypofunction group. At the 2-wk recovery time point after occlusal stimuli, the altered parameters in the masseter and mandible returned to normal levels. CONCLUSIONS: Mandibular remodeling via bone turnover is region specific for altered occlusal stimuli. Normal occlusion is an important determinant of the mandibular morphology and architecture. PMID- 26602039 TI - Requested Education on Screening Mammography. PMID- 26602040 TI - Response to "Screening Mammography: Update and Review of Publications Since Our Report in the New England Journal of Medicine on the Magnitude of the Problem in the United States". PMID- 26602041 TI - [Can structured dialogue get the debate on the PEPP-system moving? - A ray of hope for psychiatric hospital treatment of children and adolescents?]. PMID- 26602042 TI - [Diagnoses and treatment of (unaccompanied) refugee minors - a major challenge for child and adolescent psychiatry in Germany]. PMID- 26602043 TI - [Professor Dr. Andrea Gerda Ludolph]. PMID- 26602044 TI - [Structural quality in inpatient and daycare child and adolescent psychiatry- indicators for planning future staff ratios for the era following the Psychiatry Personnel Act]. AB - The German Psychiatry Personnel Act, which went into effect in 1990, has led to a decrease in the number of child and adolescent psychiatry inpatient beds, to a decrease in the length of stay, and to an increase in inpatient psychotherapy. Today, this act is outdated~ for a number of reasons, such as changes in the morbidity of the population, the rising number of emergencies, and new professional standards such as documentation. In addition, new legal provisions and conventions (like the UN Convention on the Rights of the Child) necessitate a complete reevaluation. Child and adolescent psychiatry needs a normative act to enable the necessary implementation. Many different rationales are available to support the debate. PMID- 26602045 TI - [Nonnative guidelines for allocating human resources in child and adolescent psychiatry using average values under convergence conditions instead of price determination - analysis of the data of university hospitals in Germany concerning the costs of calculating day and minute values according to Psych-PV and PEPP-System]. AB - OBJECTIVE: Despite substantial opposition in the practical field, based on an amendment to the Hospital Financing Act (KHG). the so-called PEPP-System was introduced in child and adolescent psychiatry as a new calculation model. The 2 year moratorium, combined with the rescheduling of the repeal of the psychiatry personnel regulation (Psych-PV) and a convergence phase, provided the German Federal Ministry of Health with additional time to enter a structured dialogue with professional associations. Especially the perspective concerning the regulatory framework is presently unclear. METHOD: In light of this debate, this article provides calculations to illustrate the transformation of the previous personnel regulation into the PEPP-System by means of the data of S21 KHEntgG stemming from the 22 university hospitals of child and adolescent psychiatry and psychotherapy in Germany. In 2013 there was a total of 7,712 cases and 263,694 calculation days. In order to identify a necessary basic reimbursement value th1?t would guarantee a constant quality of patient care, the authors utilize outcomes, cost structures, calculation days, and minute values for individual professional groups according to both systems (Psych-PV and PEPP) based on data from 2013 and the InEK' s analysis of the calculation datasets. CONCLUSIONS: The authors propose a normative agreement on the basic reimbursement value between 270 and 285 EUR. This takes into account the concentration phenomenon and the expansion of services that has occurred since the introduction of the Psych-PV system. Such a normative agreement on structural quality could provide a verifiable framework for the allocation of human resources corresponding to the previous regulations of Psych-PV. PMID- 26602046 TI - [Expressed emotion, mother-child relationship, and ADHD symptoms in preschool- a study on the validity of the German Preschool Five Minute Speech Sample]. AB - An inadequate parent-child relationship with hostility, low warmth, and a lack of responsiveness/sensitivity on the part of the primary caregiver often accompanies a child's externalizing disorders and predicts a negative developmental course. The Preschool Five Minute Speech Sample (PFMSS) was developed to enable an economic assessment of components of an inadequate parent-child relationship. In this article we investigate aspects of the validity of the German version of the PFMSS. We analyze whether the PFMSS scales are associated with observed maternal sensitivity, symptoms of attention deficit-/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and maternal depressive symptoms. The sample consists of n = 114 families with 4- to 5-year-old children, whereof n = 65 (57 %) show heightened ADHD-symptoms. The families were recruited from local kindergardens. Maternal sensitivity was assessed by observing the mother-child interaction at home. ADHD, ODD, and maternal depressive ~symptoms were measured by clinical interviews and questionnaires. Most of the PFMSS scales showed the expected associations with maternal sensitivity, ADHD, and ODD symptoms of the child. The German PFMSS thus validly captures significant components of an inadequate mother-child relationship within the context of preschool externalizing behavior problems. PMID- 26602047 TI - [Living with achondroplasia- how do young persons with disproportional short stature rate their quality of life and which factors are associated with quality of life?]. AB - OBJECTIVE: Presently, little is known aqout the quality of life (QoL) as well as the strengths and difficulties of young people with achondroplasia. This study describes these patient-reported indicators and identifies possible correlates. METHOD: At the invitation of a patient organization, a total of 89 short-statured patients aged 8 to 28 years and their parents participated in this study. QoL was assessed cross-sectionally with both generic and disease-specific instruments and the Strengths and Difficulties Questionnaire (SDQ) as a brief behavioral screening. In addition to descriptive analyses, patient data were compared with a reference population. Hierarchical regression analyses reflecting sociodemographic, clinical, and psychological variables were conducted to identify correlates of QoL. RESULTS: QoL and the strengths and difficulties of young patients with achondroplasia did not differ substantially from a healthy norm sample. However, the participants reported more behavioral problems and limitations in their physical and social QoL compared to patients with another short stature diagnosis. Strengths and difficulties, height-related beliefs, and social support correlated significantly with QoL. Adding psychological variables to the regression model increased the proportion of variance explained in QoL. CONCLUSIONS: Young persons with achondroplasia did not differ in their QoL and strengths and difficulties from healthy controls. Characteristics such as height appear less important for the self-perceived QoL than are strengths and difficulties and protective psychosocia~factors. PMID- 26602048 TI - [Need for youth welfare services following child and adolescent psychiatry treatment- a descriptive analysis]. AB - OBJECTIVE: Cooperation between health and youth welfare services plays a prominent role in the psychosocial healthcare of children and adolescents with mental disorders. The need analysis presented here measured how many children and adolescents engaged youth welfare services before and after inpatient or daycare treatment. METHOD: The number of completed treatments from 36 Bavarian daycare and inpatient child and adolescent psychiatric clinics were recorded over a period of 6 months. Besides sociodemographic and diagnostic data, information was collected about indicated and subsequently realized measures of youth welfare following clinical and day care treatment. RESULTS: 33 %of the clinically treated children and adolescents participated in a youth-welfare measure after psychiatric treatment. In the run-up to clinical treatment, 38 % of the treated children and adolescents had engaged services of youth welfare. Half of the children and adolescents contacted both youth welfare services as well as child and adolescent psychiatric services. The residential setting of youth care is of major importance to the cooperative treatment. CONCLUSIONS: The provision of both youth welfare services and child and adolescent psychiatry treatment is usually not a matter of going from one system to another, but rather consists of different constellations of complex processes of mutual assistance. The goal is to carry out a structured survey of the common clientele and to develop a crossover system and common care structures in order to improve the overall cooperation. PMID- 26602052 TI - Regional challenges: evaluation of a hepatitis outreach programme using transient elastography (FibroScan) in Victoria. AB - BACKGROUND: Evaluation of an outreach programme using a mobile transient elastography (TE) device (FibroScan) to improve liver disease assessment in different clinical settings. AIMS: To evaluate a programme of liver fibrosis assessment by TE and to compare fibrosis scores between different sites and patient groups. METHODS: Prospective cohort study. TE was conducted at a tertiary hospital and during outreach clinics in three different settings: community clinics, clinics for people who use drugs (PWUD) and regional clinics in rural Victoria. All patients referred for TE at the participating locations were eligible during the study period. RESULTS: A total of 200 of 623 patients was assessed and evaluated during outreach sessions (regional 100; PWUD 18; community 82). While the majority of patients in community centres were infected with hepatitis B (68%), most patients in regional clinics and in PWUD settings had hepatitis C virus (HCV) (81 and 100%, respectively). Significantly more patients assessed at regional clinics and PWUD settings presented with severe fibrosis (F3 F4, F4): regional clinics 39%; PWUD 31%; tertiary 11%; community 7%, (P <0.001). Multivariable logistic regression analysis revealed that older age, alcohol consumption, male sex, increased alanine transferase levels, HCV infection and importantly, evaluation at regional sites were independently associated with severe fibrosis. CONCLUSIONS: A TE-based outreach programme allows for assessment of liver fibrosis in varied and regional populations. The finding that patients in regional settings and PWUD presented with more advanced fibrosis should prompt improvements in healthcare to improve access for these populations. PMID- 26602053 TI - Secondary Traumatization in Psychiatric Mental Health Nurses: Validation of Five Key Concepts. AB - PURPOSE: The purpose of this study was to validate five concepts central to secondary traumatization (ST) using narratives of psychiatric mental health advanced practice nurses. DESIGN AND METHODS: The study was designed as a directed content analysis of narrative notes (N-30). FINDINGS: Consistency was found between narrative notes and the concepts. This study revealed that exposure and vulnerability precede empathic engagement, reaction, and alteration/transformation. The bidirectional outcome of alteration/transformation suggested that conditions leading to ST could have a positive outcome. PRACTICE IMPLICATIONS: Failure to recognize symptoms of ST and provide reflective supervision may compromise the nurse's ability to maintain a work-life balance and provide quality patient care. PMID- 26602054 TI - Influence of Post-Mortem Sperm Recovery Method and Extender on Unstored and Refrigerated Rooster Sperm Variables. AB - Many post-mortem sperm collection techniques have been described for mammalian species, but their use in birds is scarce. This paper compares the efficacy of two post-mortem sperm retrieval techniques - the flushing and float-out methods - in the collection of rooster sperm, in conjunction with the use of two extenders, i.e., L&R-84 medium and Lake 7.1 medium. To determine whether the protective effects of these extenders against refrigeration are different for post-mortem and ejaculated sperm, pooled ejaculated samples (procured via the massage technique) were also diluted in the above extenders. Post-mortem and ejaculated sperm variables were assessed immediately at room temperature (0 h), and after refrigeration at 5 degrees C for 24 and 48 h. The flushing method retrieved more sperm than the float-out method (596.5 +/- 75.4 million sperm vs 341.0 +/- 87.6 million sperm; p < 0.05); indeed, the number retrieved by the former method was similar to that obtained by massage-induced ejaculation (630.3 +/- 78.2 million sperm). For sperm collected by all methods, the L&R-84 medium provided an advantage in terms of sperm motility variables at 0 h. In the refrigerated sperm samples, however, the Lake 7.1 medium was associated with higher percentages of viable sperm, and had a greater protective effect (p < 0.05) with respect to most motility variables. In conclusion, the flushing method is recommended for collecting sperm from dead birds. If this sperm needs to be refrigerated at 5 degrees C until analysis, Lake 7.1 medium is recommended as an extender. PMID- 26602055 TI - 2013 Banff Criteria for Chronic Active Antibody-Mediated Rejection: Assessment in a Real-Life Setting. AB - Significant changes in the criteria for chronic active antibody-mediated rejection (CAABMR) were made in the Banff 2013 classification. These modifications expanded the number of patients diagnosed with CAABMR, with undetermined clinical significance. We compared the 2007 and 2013 criteria for the composite end point of death-censored graft failure or doubling of serum creatinine in 123 patients meeting the criterion related to the morphologic evidence of chronic tissue injury. In all, 18% and 36% of the patients met the 2007 and 2013 criteria, respectively. For the criterion related to antibody interaction with endothelium, only 25% were positive based on the 2007 definition compared with 82% using the 2013 definition. Cox modeling revealed that a 2013 but not a 2007 diagnosis was associated with the composite end point (adjusted hazard ratio 2.5 [95% confidence interval (CI) 1.2-5.2] vs. 1.6 [95% CI 0.7-3.8], respectively). The 2013 criterion based on both the C4d score and the glomerulitis plus peritubular capillaritis score (g+ptc) was more strongly associated with the end point than the 2007 criterion based only on C4d; however, when dissected by component, only the C4d component was significant. The association with clinical outcomes improved with the 2013 criteria. This is related to the new C4d threshold but not to the g+ptc >=2 component. PMID- 26602056 TI - The rs5934505 single nucleotide polymorphism (SNP) is associated with low testosterone and late-onset hypogonadism, but the rs10822184 SNP is associated with overweight and obesity in a Chinese Han population: a case-control study. AB - Low testosterone is associated with late-onset hypogonadism (LOH) and obesity. Recently, studies have shown that four single nucleotide polymorphisms (SNPs), rs12150660, rs727428, rs5934505, and rs10822184, are associated with testosterone levels in populations of European descent. Therefore, we investigated whether the SNP loci are related to low testosterone, LOH, or obesity in a Chinese Han population. Ruling out co-morbidities, DNA was prepared from 409 men (aged 40-65 years) with low serum testosterone (defined as total testosterone <11.6 nmol/L) and 1 : 1 normal controls (matched age, body mass index (BMI), and the same living area) who were selected from 6898 males. According to the same standards, 310 men with LOH and 1 : 1 normal controls were selected from 6898 males. Excluding the cases with an unreliable sequencing result, genetic analyses were performed. The minor allele frequencies of the SNP loci rs12150660, rs727428, rs5934505, and rs10822184 were 0.1%, 44.6%, 18.7%, and 38.9%, respectively. rs5934505 was associated with the serum total testosterone and calculated free testosterone (CFT) levels (p = 0.045 and p = 0.021). rs5934505 (C>T) was associated with an increased risk of low total testosterone, low CFT, and LOH and adjusted for other factors, with an odds ratio (OR) of 2.01 (1.34-3.01), 2.14 (1.42-3.20), and 1.64 (1.04-2.58). rs10822184 was significantly correlated with weight and BMI (p = 0.035 and p = 0.027). rs10822184 (T>C) was associated with an increased risk of overweight and obesity. We adjusted for other factors, with odds ratios (ORs) of 1.94 (1.36-2.78) and 1.56 (1.00-2.43). In summary, our study provided convincing evidence that rs5934505 (C>T) was associated with the risk of low testosterone and LOH in Chinese populations. We were the first to find that rs10822184 (T>C) was significantly correlated with the risk of overweight and obesity in Chinese populations. However, further large and functional studies are warranted to confirm our findings. PMID- 26602057 TI - Primary Cardiac Angiosarcoma. PMID- 26602058 TI - Emerging biomarkers in psoriatic arthritis. AB - Psoriasis is an immune-mediated skin disease which affects 2-4% of the worldwide population. Approximately 20-30% of patients with psoriasis develop psoriatic arthritis (PsA), a frequently destructive and disabling condition. As skin manifestations precede joint symptoms in nearly all patients with PsA, identification of biomarkers for early prediction of joint damage is an important clinical need. Because not all patients with PsA respond to treatment in the same fashion, identification of biomarkers capable of predicting therapeutic response is also imperative. Here, we review existing literature and discuss current investigations to identify potential biomarkers for PsA disease activity, with particular emphasis on microRNAs as novel markers of interest. Serum (soluble) biomarkers, peripheral osteoclast precursor as cellular biomarkers, and genetic loci associated with skin and joint disease are also reviewed. PMID- 26602059 TI - World Workshop on Oral Medicine VI: a systematic review of medication-induced salivary gland dysfunction. AB - The aim of this paper was to perform a systematic review of the pathogenesis of medication-induced salivary gland dysfunction (MISGD). Review of the identified papers was based on the standards regarding the methodology for systematic reviews set forth by the World Workshop on Oral Medicine IV and the PRISMA statement. Eligible papers were assessed for both the degree and strength of relevance to the pathogenesis of MISGD as well as on the appropriateness of the study design and sample size. A total of 99 papers were retained for the final analysis. MISGD in human studies was generally reported as xerostomia (the sensation of oral dryness) without measurements of salivary secretion rate. Medications may act on the central nervous system (CNS) and/or at the neuroglandular junction on muscarinic, alpha-and beta-adrenergic receptors and certain peptidergic receptors. The types of medications that were most commonly implicated for inducing salivary gland dysfunction were those acting on the nervous, cardiovascular, genitourinary, musculoskeletal, respiratory, and alimentary systems. Although many medications may affect the salivary flow rate and composition, most of the studies considered only xerostomia. Thus, further human studies are necessary to improve our understanding of the association between MISGD and the underlying pathophysiology. PMID- 26602060 TI - Psychic reality and the nature of consciousness. AB - In this paper we make the case for a psychoanalytically informed reconsideration of the phenomena of consciousness. Classically, following Freud, who viewed consciousness as merely a reflection or perception of unconscious mental activity, psychoanalysts have tended to regard a focus on conscious experience as potentially reductionistic and at risk of overlooking the mind's deeper structures. We describe the case of Mr K, a patient who experienced disturbances of consciousness that forced us to consider the possibility that the capacity to experience ourselves as conscious, intentional agents in a coherent world of objects is not merely a modality of perception but rather a maturational and developmental achievement that to some degree depends on adequate experiences of caregiving and is vital in ensuring the possibility of human communication. As such, it is a capacity that is vulnerable to experiences of neglect and maltreatment. We suggest that as well as compromising the capacity to think about one's own and other people's feelings, such experiences may have the further adverse consequence of leading the individual to experience and risk becoming conscious of certain dangerously maladaptive, destructive states of mind which in normal development remain inaccessible to conscious experience. Phenomenologically, such states of mind are experienced as fragmentation and disturbances of consciousness. We discuss the clinical implications of these reflections and the limitations they place on psychoanalytic work in the context of their impact on the work with Mr K. PMID- 26602061 TI - Relationship between diffusion parameters derived from intravoxel incoherent motion MRI and perfusion measured by dynamic contrast-enhanced MRI of soft tissue tumors. AB - Our aim was to evaluate the link between diffusion parameters measured by intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) and the perfusion metrics obtained with dynamic contrast-enhanced (DCE) MRI in soft tissue tumors (STTs). Twenty-eight patients affected by histopathologically confirmed STT were included in a prospective study. All patients underwent both DCE MRI and IVIM DWI. The perfusion fraction f, diffusion coefficient D and perfusion-related diffusion coefficient D* were estimated using a bi-exponential function to fit the DWI data. DCE MRI was acquired with a temporal resolution of 3-5 s. Maps of the initial area under the gadolinium concentration curve (IAUGC), time to peak (TTP) and maximum slope of increase (MSI) were derived using commercial software. The relationships between the DCE MRI and IVIM DWI measurements were assessed by Spearman's test. To exclude false positive results under multiple testing, the false discovery rate (FDR) procedure was applied. The Mann-Whitney test was used to evaluate the differences between all variables in patients with non-myxoid and myxoid STT. No significant relationship was found between IVIM parameters and any DCE MRI parameters. Higher f and D*f values were found in non-myxoid tumors compared with myxoid tumors (p = 0.004 and p = 0.003, respectively). MSI was significantly higher in non-myxoid tumors than in myxoid tumors (p = 0.029). From the visual assessments of single clinical cases, both f and D*f maps were in satisfactory agreement with DCE maps in the extreme cases of an avascular mass and a highly vascularized mass, whereas, for tumors with slight vascularity or with a highly heterogeneous perfusion pattern, this association was not straightforward. Although IVIM DWI was demonstrated to be feasible in STT, our data did not support evident relationships between perfusion-related IVIM parameters and perfusion measured by DCE MRI. PMID- 26602062 TI - Clinical Pearls in Using Antiarrhythmic Drugs in the Outpatient Setting. AB - A role for oral antiarrhythmic drugs (AADs) remains in clinical practice for patients with atrial and ventricular arrhythmias in spite of advances in nonpharmacologic therapy. Pharmacists play a vital role in the appropriate use of AAD dosing, administration, adverse effects, interactions, and monitoring. Pharmacists who are involved in providing care to patients with cardiac arrhythmias must remain updated regarding the efficacy and safety of the most commonly used AADs. This review will address key issues for appropriate initiation and maintenance of commonly selected Vaughan-Williams Class Ic and III agents in the outpatient setting. PMID- 26602063 TI - Device-Related Thrombosis in Continuous-Flow Left Ventricular Assist Device Support. AB - Advanced heart failure therapy has been revolutionized with the advent of continuous-flow ventricular assist devices (CF-LVADs) which have improved both survival and quality of life. Despite this, support with CF-LVADs is frequently complicated, with 70% of recipients experiencing a major complication in the first year of durable support. The most concerning of these complications to emerge is device-related thrombosis, which is associated with increased morbidity and mortality. Pathophysiology and diagnosis are multifaceted and complex, with pump-specific and patient-specific factors to be considered. Incidence estimates are evolving with increases seen in the past 2 years compared with earlier implant data. Evidence for treatment is limited to case series and reports, which are subject to significant publication bias. Finally, appropriate primary and secondary prophylaxis is imprecise with multiple antiplatelet and antithrombotic strategies described. This review seeks to summarize the current literature surrounding the pathophysiology, diagnosis, and management of thrombosis in CF LVAD recipients. PMID- 26602064 TI - Nature and frequency of drug therapy alerts generated by clinical decision support in community pharmacy. AB - PURPOSE: The purpose of this study is to investigate the nature, frequency, and determinants of drug therapy alerts generated by a clinical decision support system (CDSS) in community pharmacy in order to propose CDSS improvement strategies. METHODS: This is a retrospective analysis of dispensed drugs and drug therapy alerts generated by a CDSS in community pharmacies. RESULTS: Data were extracted from the CDSS of 123 community pharmacies. After taking a 10% random sample of patients with a prescription in the period August 2013-July 2014, 1,672,169 dispensed prescriptions from 81,742 patients were included in the analysis. Of all processed prescriptions, 43% led to one or more drug safety alerts, most frequently drug-drug interaction alerts (15% of all prescriptions), drug-disease interaction alerts (14%), duplicate medication alerts (13%), and dosing alerts (7%). The majority of prescriptions with alerts (80%) were clustered in a minority of patients (16%). The therapeutic drug group of the prescribed drug was the most important determinant of alert generation. Prescriptions for antithrombotic agents accounted for 9.4% of all prescriptions with an alert, beta-blocking agents for 7.5% and angiotensin-converting-enzyme inhibitors for 6.1%. DISCUSSION AND CONCLUSION: The investigated CDSS in Dutch community pharmacy generated one or more drug therapy alerts in nearly half of the processed prescriptions. The majority of alerts were concentrated in a minority of therapeutic drug groups and patients. To decrease the alert burden, CDSS improvements should be directed at the prioritization and integration of drug therapy alerts for these therapeutic groups within patients. PMID- 26602065 TI - Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer. AB - Delayed wound healing is a major complication associated with diabetes and is a result of a complex interplay among diverse deregulated cellular parameters. Although several genes and pathways have been identified to be mediating impaired wound closure, the role of microRNAs (miRNAs) in these events is not very well understood. Here, we identify an altered miRNA signature in the prolonged inflammatory phase in a wound during diabetes, with increased infiltration of inflammatory cells in the basal layer of the epidermis. Nineteen miRNAs were downregulated in diabetic rat wounds (as compared with normal rat wound, d 7 postwounding) together with inhibited levels of the central miRNA biosynthesis enzyme, Dicer, suggesting that in wounds of diabetic rats, the decreased levels of Dicer are presumably responsible for miRNA downregulation. Compared with unwounded skin, Dicer levels were significantly upregulated 12 d postwounding in normal rats, and this result was notably absent in diabetic rats that showed impaired wound closure. In a wound-healing specific quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) array, 10 genes were significantly altered in the diabetic rat wound and included growth factors and collagens. Network analyses demonstrated significant interactions and correlations between the miRNA predicted targets (regulators) and the 10 wound healing specific genes, suggesting altered miRNAs might fine-tune the levels of these genes that determine wound closure. Dicer inhibition prevented HaCaT cell migration and affected wound closure. Altered levels of Dicer and miRNAs are critical during delayed wound closure and offer promising targets to address the issue of impaired wound healing. PMID- 26602066 TI - SOX9 p.Lys106Glu mutation causes acampomelic campomelic dysplasia: Prenatal and postnatal clinical findings. PMID- 26602068 TI - Transformational and abusive leadership practices: impacts on novice nurses, quality of care and intention to leave. AB - AIMS: To investigate the impact of nurse managers exercising transformational vs. abusive leadership practices with novice nurses. BACKGROUND: In a nursing shortage context, it is important to understand better the factors that potentially influence the retention of nurses in the early stages of their career. A large body of research has found that transformational leadership practices have a positive influence on employee functioning. However, very little research exists about the detrimental impact of abusive leadership practices, much less in a nursing context. DESIGN: A cross-sectional design where 541 nurses from the province of Quebec (Canada) were questioned in the fall of 2013. METHODS: A self-administered questionnaire was completed by nurses with less than five years of nursing experience. RESULTS: Results from three linear regression analysis indicated that transformational leadership practices potentially lead to high quality care and weak intention to quit the healthcare facilities. Conversely, abusive leadership practices potentially lead to poorer quality care and to strong intention to quit the healthcare facilities and the nursing profession. CONCLUSION: Paying close attention to the leadership practices of nurse managers could prove effective in improving patient care and increasing the retention of new nurses, which is helpful in resolving the nursing shortage. Our results specifically suggest not only that we promote supportive leadership practices (transformational leadership) but, most of all, that we spread the word that abusive leadership creates working conditions that could be detrimental to the practice of nursing at career start. PMID- 26602069 TI - The antecedents, forms and consequences of patient involvement: A narrative review of the literature. AB - OBJECTIVES: Despite the centrality of patient involvement in the policy and rhetoric of health care, the theoretical and empirical basis for patient involvement is lacking at the micro-level of practice. The purpose of this narrative review is to provide an overview and synthesize the current empirical research related to patient involvement at the micro-level of health care. DESIGN: Narrative review. DATA SOURCES: A database search was conducted (in PubMed, CINAHL, Academic Search Premier, EconLit and PsycINFO) for articles published between 1990 and April 2015 in the field of patient involvement in health care. Out of 4238 references, 214 articles were eligible for this review. REVIEW METHODS: We analyzed our sample using thematic analysis. RESULTS: The reviewed articles revealed nine themes for patient involvement, concerning enablers; empowerment, patient education, communication for involvement, staff training, service systems, types; decision making, delivery, development, and consequences of patient involvement. The themes were synthesized into a tentative model that described patient-involvement research. CONCLUSIONS: Our narrative review includes a wide variety of empirical studies on patient involvement in decision-making, delivery and development, and provides an integrative perspective suggesting that patient involvement should be viewed not only as isolated activities, but also as a result of educating and preparing patients, staff and systems. PMID- 26602070 TI - Myocardial Infarct Size in Patients on Long-Term Statin Therapy Undergoing Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction. AB - Statin pretreatment has been reported to have a cardioprotective effect in patients undergoing elective or urgent percutaneous coronary intervention (PCI). However, data on patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI are still controversial. We prospectively evaluated the effect of long-term statin therapy on infarct size (IS), myocardial salvage index (MSI), and microvascular obstruction (MVO) in consecutive patients with STEMI who underwent primary PCI. Two-hundred thirty patients with STEMI (mean age 61 +/- 11 years, 183 men) who underwent primary PCI were evaluated with cardiac magnetic resonance (CMR) imaging during hospitalization (median 4 days after primary PCI). In all patients, we measured peak troponin I level, whereas IS, MSI, and MVO were determined by CMR. Fifty patients (22%) were on long-term statin therapy and showed a significantly lower troponin I peak value compared to patients without previous statins (54 +/- 47 vs 88 +/- 106 ng/ml; p = 0.02). At CMR evaluation, IS related to the index event was significantly smaller (12.5 +/- 11.5 vs 18.5 +/- 18.5 g, p = 0.05), and MSI was higher (0.68 +/- 0.25 vs 0.52 +/- 0.30; p <0.01) in patients with previous statin therapy. MVO was also less frequent (10% vs 20%; p = 0.14) in this group. At multivariate analysis, previous statin therapy remained significantly associated with IS and MSI (p = 0.05 and 0.02, respectively). In conclusion, this study suggests that long-term statin therapy before primary PCI in patients with STEMI is associated with smaller IS and higher MSI. Future studies are warranted to confirm these findings and to investigate potential clinical implications. PMID- 26602071 TI - Comparison of Outcomes of Patients With ST-Segment Elevation Myocardial Infarction Treated by Primary Percutaneous Coronary Intervention Analyzed by Age Groups (<75, 75 to 85, and >85 Years); (Results from the Bremen STEMI Registry). AB - As old patients, who were treated by percutaneous coronary interventions (PCI) for ST-segment elevation myocardial infarction (STEMI), are regularly excluded or underrepresented in randomized trials, data on treatment and outcomes of this patient group at high risk have to be collected by registries. The study population of the German Bremen STEMI Registry was divided into the age groups G1: <75 years (n = 4,108, young), G2: 75 to 85 years (n = 1,032, old), and G3: >85 years (n = 216, very old) and was evaluated for clinical management and course. PCI failure (Thrombolysis In Myocardial Infarction flow 0 or 1 after PCI) was observed more often with increasing age. Patients >85 years without successful PCI had a very high inhospital mortality (40.0% without PCI success vs 18.1% with PCI success, p <0.05). Despite a reduced rate of periinterventional treatment with glycoprotein IIb/IIIa inhibitors in elderly patients of G2 and G3, inhospital bleedings (Thrombolysis In Myocardial Infarction/Bleeding Academic Research Consortium >=2) occurred more frequently in these patients (G1: 5.4% vs G2: 11.0% vs G3: 19.6%, p <0.0001). Mortality rates during inhospital and long term course increased with increasing age. In a multivariate analysis successful PCI was associated with improved outcomes in all age groups; even in very old patients successful PCI was associated with a significantly lower inhospital mortality rate (odds ratio 0.26, 95% confidence interval 0.08 to 0.81) and a trend toward a lower 1-year mortality. In conclusion, the present "real-world" data demonstrate an elevated rate of PCI failure, bleeding complications, and mortality in elderly patients treated by primary PCI for STEMI. However, a beneficial effect of successful PCI on mortality was observed in all age groups, even in very old patients, indicating the crucial role of revascularization therapy. PMID- 26602072 TI - Short-Term and Long-Term Outcomes After Polytetrafluoroethylene-Covered Stent Implantation for the Treatment of Coronary Perforation. AB - This study sought to evaluate the short-term and 3-year outcomes of polytetrafluoroethylene-covered stent (PCS) for patients with coronary perforation. Implantation of a PCS has improved the immediate clinical outcomes of patients with coronary perforation. However, there are few reports regarding long-term outcomes. We evaluated a total of 57 patients who were treated with PCS for coronary perforation from April 2004 to March 2015 at a single high-volume center in Japan. Landmark analysis was performed at 30 days to determine short term and long-term outcomes. Major adverse cardiac events (MACE) were defined as death, myocardial infarction, target vessel revascularization, and requirement for surgical repair. Of 285 patients who experienced coronary perforation, 57 patients (20%) were treated with PCS. The MACE rates were 28% at 30 days, 22% at 1 year, and 38% at 3 years. 30-day MACE was mainly driven by high rates of myocardial infarction (18%) and surgical repair (16%). The rates of target lesion revascularization were 8% and 12% at 1 and 3 years, respectively. Definite stent thrombosis was reported in 2 patients during the follow-up period. In conclusion, despite the relatively high incidence of MACE during early stage of follow-up, implantation of a PCS provides acceptable late clinical outcomes. PMID- 26602067 TI - Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09-related pneumonia: an individual participant data meta-analysis. AB - BACKGROUND: The impact of neuraminidase inhibitors (NAIs) on influenza-related pneumonia (IRP) is not established. Our objective was to investigate the association between NAI treatment and IRP incidence and outcomes in patients hospitalised with A(H1N1)pdm09 virus infection. METHODS: A worldwide meta analysis of individual participant data from 20 634 hospitalised patients with laboratory-confirmed A(H1N1)pdm09 (n = 20 021) or clinically diagnosed (n = 613) 'pandemic influenza'. The primary outcome was radiologically confirmed IRP. Odds ratios (OR) were estimated using generalised linear mixed modelling, adjusting for NAI treatment propensity, antibiotics and corticosteroids. RESULTS: Of 20 634 included participants, 5978 (29.0%) had IRP; conversely, 3349 (16.2%) had confirmed the absence of radiographic pneumonia (the comparator). Early NAI treatment (within 2 days of symptom onset) versus no NAI was not significantly associated with IRP [adj. OR 0.83 (95% CI 0.64-1.06; P = 0.136)]. Among the 5978 patients with IRP, early NAI treatment versus none did not impact on mortality [adj. OR = 0.72 (0.44-1.17; P = 0.180)] or likelihood of requiring ventilatory support [adj. OR = 1.17 (0.71-1.92; P = 0.537)], but early treatment versus later significantly reduced mortality [adj. OR = 0.70 (0.55-0.88; P = 0.003)] and likelihood of requiring ventilatory support [adj. OR = 0.68 (0.54-0.85; P = 0.001)]. CONCLUSIONS: Early NAI treatment of patients hospitalised with A(H1N1)pdm09 virus infection versus no treatment did not reduce the likelihood of IRP. However, in patients who developed IRP, early NAI treatment versus later reduced the likelihood of mortality and needing ventilatory support. PMID- 26602073 TI - Effect of Randomized Lipid Lowering With Simvastatin and Ezetimibe on Cataract Development (from the Simvastatin and Ezetimibe in Aortic Stenosis Study). AB - Recent American College of Cardiology/American Heart Association guidelines on statin initiation on the basis of total atherosclerotic cardiovascular disease risk argue that the preventive effect of statins on cardiovascular events outweigh the side effects, although this is controversial. Studies indicate a possible effect of statin therapy on reducing risk of lens opacities. However, the results are conflicting. The Simvastatin and Ezetimibe in Aortic Stenosis study (NCT00092677) enrolled 1,873 patients with asymptomatic aortic stenosis and no history of diabetes, coronary heart disease, or other serious co-morbidities were randomized (1:1) to double-blind 40 mg simvastatin plus 10 mg ezetimibe versus placebo. The primary end point in this substudy was incident cataract. Univariate and multivariate Cox models were used to analyze: (1) if the active treatment reduced the risk of the primary end point and (2) if time-varying low density lipoproteins (LDL) cholesterol lowering (annually assessed) was associated with less incident cataract per se. During an average follow-up of 4.3 years, 65 patients (3.5%) developed cataract. Mean age at baseline was 68 years and 39% were women. In Cox multivariate analysis adjusted for age, gender, prednisolone treatment, smoking, baseline LDL cholesterol and high sensitivity C reactive protein; simvastatin plus ezetimibe versus placebo was associated with 44% lower risk of cataract development (hazard ratio 0.56, 95% confidence interval 0.33 to 0.96, p = 0.034). In a parallel analysis substituting time varying LDL-cholesterol with randomized treatment, lower intreatment LDL cholesterol was in itself associated with lower risk of incident cataract (hazard ratio 0.78 per 1 mmol/ml lower total cholesterol, 95% confidence interval 0.64 to 0.93, p = 0.008). In conclusion, randomized treatment with simvastatin plus ezetimibe was associated with a 44% lower risk of incident cataract development. This effect should perhaps be considered in the risk-benefit ratio of statin treatment. PMID- 26602074 TI - Impact of Diabetes Mellitus and Hemoglobin A1C on Outcome After Transcatheter Aortic Valve Implantation. AB - Surgical aortic valve replacement (SAVR) is associated with an increased mortality risk in elderly or high-risk patients. Transcatheter aortic valve implantation (TAVI) is an alternative to surgery in patients with symptomatic severe aortic stenosis who are inoperable or at high operative risk. The impact of diabetes mellitus (DM) on patients referred to TAVI merits further investigation. The aim of our study was to evaluate the clinical characteristics and the impact of DM status on the updated Valve Academic Research Consortium 2 defined outcomes of TAVI and to stratify patient outcomes according to their initial glycated hemoglobin (HbA1c) levels. We enrolled and stratified patients who underwent TAVI at our institution according to DM status. A total of 586 patients were enrolled: 348 (59%) without DM and 238 (41%) with DM. There were no significant differences in 30-day mortality patients with diabetes compared to patients without diabetes (3.3% vs 2.9%, p = 0.974). Insulin-treated DM was not associated with adverse outcome in comparison to orally treated DM. To delineate the prognostic power of HbA1C in these patients, the cohort was divided into 3 groups according to HbA1C levels (<5.7%, 5.7% to 6.49%, and >=6.5%). Patients with HbA1C >=6.5% were at increased risk for mortality during follow-up (hazard ratio 2.571, 95% confidence interval 1.077 to 6.136, p = 0.033) compared to patients with HbA1C <5.7%. In conclusion, unlike SAVR, DM is not associated with an increased mortality risk after TAVI, nor is it associated with increased complications rates. A more poorly controlled disease, as manifested by elevated HbA1c levels, may be associated with increased mortality during long-term follow up. PMID- 26602075 TI - Impact of Preprocedural B-Type Natriuretic Peptide Levels on the Outcomes After Transcatheter Aortic Valve Implantation. AB - There are limited data on the effect of baseline B-type natriuretic peptide (BNP) on the outcome after transcatheter aortic valve implantation (TAVI). We investigated the influence of baseline BNP levels on the short-term and midterm clinical outcomes after TAVI. During a 3-year period, 780 patients with severe aortic stenosis underwent TAVI at our institute and had baseline BNP levels. We compared the high, mid, and low tertiles of BNP levels. TAVI end points, device success, and adverse events were considered according to the Valve Academic Research Consortium 2 definitions. Device success was significantly lower for patients with high BNP (98.1% vs 96.2% vs 91.9% for the low, mid, and high BNP tertiles, respectively; p = 0.003). All-cause mortality up to 30 days was 1.2% (3 of 260) versus 2.3% (6 of 260) versus 5% (13 of 260), respectively (p = 0.03). Six-month mortality rate was 4.1% (10 of 241) for the low BNP tertile, 5% (12 of 239) for the mid BNP tertile, and 17.1% (40 of 234) for the high BNP tertile (p <0.001). In the multivariate model, high tertile of baseline BNP was found to be significantly associated with all-cause mortality (hazard ratio 3.3, 95% confidence interval 1.64 to 6.48; p = 0.001). In conclusion, elevated BNP levels are associated with increased short-term and midterm mortality after TAVI. We recommend measurement of baseline BNP as part of risk stratification models for TAVI. PMID- 26602076 TI - Outcomes of Patients at Estimated Low, Intermediate, and High Risk Undergoing Transcatheter Aortic Valve Implantation for Aortic Stenosis. AB - Intermediate- or low-risk patients with severe aortic stenosis were excluded from earlier transcatheter aortic valve implantation (TAVI) clinical trials; however, they are already being treated by TAVI despite a lack of data regarding the safety and efficacy in these patients. We aimed to assess the safety and efficacy of TAVI in patients at intermediate or low risk. Patients undergoing TAVI during 2008 to 2014 were included into a shared database (n = 1,327). Procedural outcomes were adjudicated according to Valve Academic Research Consortium 2 definitions. Patients were stratified according to their Society of Thoracic Surgeons (STS) score into 3 groups: high (STS >=8, n = 223, 17%), intermediate (STS 4 to 8; n = 496, 38%), or low risk (STS <4; n = 576, 45%). Low-risk patients were significantly younger and more likely to be men compared to intermediate- and high-risk patients. Baseline characteristics differed significantly between the groups with a gradual increase in the rates of previous bypass surgery, stroke, peripheral vascular disease, renal failure, lung disease, and frailty scores, from low to high risk groups. Compared with intermediate- and high-risk patients, low-risk patients were more likely to undergo TAVI through the transfemoral route (81% vs 88% vs 95%, p <0.001) and under conscious sedation (69% vs 72% vs 81%, <0.001). There were no significant differences in the rates of procedural complications apart from acute kidney injury (19% vs 17% vs 13%, p = 0.03) and stroke rates (4.5% vs 2% vs 2.3%, p = 0.1). Short- and long-term mortality rates were significantly higher for intermediate- (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2 to 2.9) and high-risk patients (HR 4.1, 95% CI 2.7 to 6.4) than low-risk patients also after multivariate adjustment (HR 1.6, 95% CI 1 to 2.6 and HR 2.7, 95% CI 1.7 to 4.5, respectively; all p <0.05). In conclusion, TAVI for intermediate- and low-risk patients is safe and associated with improved outcome compared with high-risk patients. PMID- 26602077 TI - Seasonal Changes in Hospital Admissions for Pulmonary Embolism in Metropolitan Areas of Tokyo (from the Tokyo Cardiovascular Care Unit Network). AB - Although several studies have shown the relation between temperature/atmospheric pressure and pulmonary embolism (PE), their results are inconsistent. Furthermore, diurnal temperature range (DTR) and diurnal pressure range (DPR) were not fully evaluated for their associations with hospital admissions for PE. Study subjects comprised cases of 1,148 PE treated at institutions belonging to the Tokyo Cardiovascular Care Unit Network from January 2005 to December 2012. Patient data were combined with a variety of daily local climate parameters obtained from the Japan Meteorological Agency. Every 1 degrees C increase in the DTR at lag0 corresponded to an increased relative risk of hospital admission for PE (odds ratio [OR] 1.036, 95% confidence interval [CI] 1.003 to 1.070). In the cooler season (November to April), an increase of 1 hPa (barometric pressure) in the DPR at lag4 and lag5 was associated with an increased relative risk of hospital admission for PE (OR 1.042, 95% CI 1.007 to 1.077 and OR 0.952, 95% CI 0.914 to 0.992, respectively). An increase in the PE hospitalization rate was seen only in the cool season. Using a metropolitan database, we showed that DTR and DPR have different impacts on hospital admissions for PE. In conclusion, we found that an increase in the DTR increases the PE hospitalization rate, especially during the cooler season. The impact of DTR and DPR on PE incidence and related hospitalizations needs to be further evaluated. PMID- 26602078 TI - The 35-Year Perspective as to Prognosis and Management of Myocardial Infarction. PMID- 26602079 TI - Mir-302c mediates influenza A virus-induced IFNbeta expression by targeting NF kappaB inducing kinase. AB - Little is known about the role of microRNA during influenza A virus (IAV) infection. We observed that NIK 3'UTR luciferase activity was elevated during IAV infection. Further studies demonstrated that miR-302c reduced NIK expression, resulting in the reduction of IFNbeta mRNA expression. We found that miR-302c prevented the translocation of NF-kappaB from the cytosol to the nucleus. Furthermore, IAV infection downregulated miR-302c expression, leading to the activation of IFNbeta expression and the inhibition of viral replication. Compared to miR-302c, miR-520e cannot promote viral replication and production, although the two microRNAs target the same site of the NIK 3'UTR. Collectively, our work defines a novel signaling pathway implicated in the control of IFNbeta mRNA expression during IAV infection. PMID- 26602080 TI - MgcRacGAP inhibition stimulates JAK-dependent STAT3 activity. AB - Male germ cell Rac GTPase-activating protein (MgcRacGAP) is a core regulator of cytokinesis. Furthermore, it appears to be involved in human oncogenesis through cytokinesis-independent mechanisms and has been reported to be essential for nuclear translocation of signal transducer and activator of transcription (STAT) proteins, including the oncoprotein STAT3. Here we utilized MgcRacGAP inhibitor compound 1 (MINC1), a small molecule inhibitor of MgcRacGAP, to further investigate how MgcRacGAP regulates STAT3. Surprisingly, both MINC1 treatment and small interference RNA (siRNA)-mediated gene silencing of MgcRacGAP resulted in increased STAT3 phosphorylation and STAT3-driven transcriptional activity in our experimental systems. Finally, we demonstrated that MINC1-induced STAT3 activation likely is due to increased STAT3 phosphorylation caused by a Rac1-PAR3 IL6-IL6R-JAK2 mediated autocrine/paracrine mechanism. PMID- 26602081 TI - Leucine-rich repeat 2 of human Toll-like receptor 4 contains the binding site for inhibitory monoclonal antibodies. AB - Excessive activation of Toll-like receptor 4 (TLR4)/MD-2 by lipopolysaccharide (LPS) causes septic shock. We previously produced an inhibitory antibody, HT52, against LPS-induced human TLR4 activation independently of LPS binding of MD-2. Consistent with the hypothesis that HT52 recognizes the epitopes inherent to inhibitory antibodies, we generated an HT52-crossblockable antibody and revealed the relationship between its inhibitory activity and the anti-TLR4 antibody epitope. Leucine-rich repeat 2 was identified as an inhibitory epitope, and Phe(75), Ser(76) and Pro(79) as antigenic determinants. These findings provide a way to design therapeutic antibodies targeted to TLR4 that are distinct from LPS analog antagonists targeting MD-2. PMID- 26602082 TI - Global mapping of the regulatory interactions of histone residues. AB - Histone residues can serve as platforms for specific regulatory function. Here we constructed a map of regulatory associations between histone residues and a wide spectrum of chromatin regulation factors based on gene expression changes by histone point mutations in Saccharomyces cerevisiae. Detailed analyses of this map revealed novel associations. Regarding the modulation of H3K4 and K36 methylation by Set1, Set2, or Jhd2, we proposed a role for H4K91 acetylation in early Pol II elongation, and for H4K16 deacetylation in late elongation and crosstalk with H3K4 demethylation for gene silencing. The association of H3K56 with nucleosome positioning suggested that this lysine residue and its acetylation might contribute to nucleosome mobility for transcription activation. Further insights into chromatin regulation are expected from this approach. PMID- 26602083 TI - Binding and entry of Clostridium difficile toxin B is mediated by multiple domains. AB - Clostridium difficile is responsible for a number of serious gastrointestinal diseases caused primarily by two exotoxins, TcdA and TcdB. These toxins enter host cells by binding unique receptors, at least partially via their combined repetitive oligopeptides (CROPs) domains. Our study investigated structural determinants necessary for binding and entry of TcdB. Deletion analyses identified TcdB residues 1372-1493 as essential for cytotoxicity in three cell lines. Consistent with this observation, overlapping TcdB fragments (residues 1372-1848, 1372-1493 and 1493-1848) were able to independently bind cells. Our data provide new evidence supporting a more complex model of clostridial glucosylating toxin uptake than previously suggested. PMID- 26602084 TI - 1-Benzyl-2-methyl-3-indolylmethylene barbituric acid derivatives: Anti-cancer agents that target nucleophosmin 1 (NPM1). AB - In the present study, we have designed and synthesized a series of 1-benzyl-2 methyl-3-indolylmethylene barbituric acid analogs (7a-7h) and 1-benzyl-2-methyl-3 indolylmethylene thiobarbituric acid analogs (7 i-7 l) as nucleophosmin 1 (NPM1) inhibitors and have evaluated them for their anti-cancer activity against a panel of 60 different human cancer cell lines. Among these analogs 7 i, 7 j, and 7 k demonstrated potent growth inhibitory effects in various cancer cell types with GI50 values <2 MUM. Compound 7 k exhibited growth inhibitory effects on a sub panel of six leukemia cell lines with GI50 values in the range 0.22-0.35 MUM. Analog 7 i also exhibited GI50 values <0.35 MUM against three of the leukemia cell lines in the sub-panel. Analogs 7 i, 7 j, 7 k and 7 l were also evaluated against the mutant NPM1 expressing OCI-AML3 cell line and compounds 7 k and 7 l were found to cause dose-dependent apoptosis (AP50 = 1.75 MUM and 3.3 MUM, respectively). Compound 7k also exhibited potent growth inhibition against a wide variety of solid tumor cell lines: that is, A498 renal cancer (GI50 = 0.19 MUM), HOP-92 and NCI-H522 lung cancer (GI50 = 0.25 MUM), COLO 205 and HCT-116 colon cancer (GI50 = 0.20 and 0.26 MUM, respectively), CNS cancer SF-539 (GI50 = 0.22 MUM), melanoma MDA-MB-435 (GI50 = 0.22 MUM), and breast cancer HS 578T (GI50 = 0.22 MUM) cell lines. Molecular docking studies suggest that compounds 7 k and 7 l exert their anti-leukemic activity by binding to a pocket in the central channel of the NPM1 pentameric structure. These results indicate that the small molecule inhibitors 7 i, 7 j, 7 k, and 7 l could be potentially developed into anti-NPM1 drugs for the treatment of a variety of hematologic malignancies and solid tumors. PMID- 26602085 TI - Antisense peptide nucleic acid-peptide conjugates for functional analyses of genes in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is one of the most common and clinically important pathogens because of its resistance to a wide variety of antibiotics. A number of treatments of P. aeruginosa have been developed, but there is still no definitive one. Antisense drugs have a great potential to treat multidrug-resistant P. aeruginosa because this technology, in principle, can inhibit the expression of any essential genes. Nucleic Acid Ther.2012, 22, 323 reported that peptide nucleic acid (PNA) antisenses conjugated to the carrier peptide (RXR)4 and targeted to ftsZ and acpP (essential genes) had antibacterial activity in P. aeruginosa. However, growth inhibition was also found with peptide-PNA antisense conjugates of mismatched sequences (negative controls), and hence there remains a possibility for considerable enhancement of basal level activity due to the general toxicity. To assess the true potential of peptide-PNA conjugates, we measured sequence-dependent knockdown of the (RXR)4-PNA conjugates by using a scrambled sequence as a negative control. In addition, we evaluated (RXR)4-PNA antisenses against three other essential genes (lepB, lptD and mraY) and a non essential gene (PA1303), and confirmed that multiple sequences targeting only the essential genes showed antimicrobial activity in P. aeruginosa PAO1 cells. We also conducted a rescue experiment and confirmed that the antimicrobial activity of anti-mraY antisenses was an on-target effect, not due to general toxicity. These findings indicate that the (RXR)4-PNA antisense should be a useful tool for target validation of a specific gene and could be a therapeutic platform capable of targeting a variety of genes in P. aeruginosa. PMID- 26602086 TI - Assessing Alzheimer's disease patients' quality of life: Discrepancies between patient and caregiver perspectives. AB - INTRODUCTION: Quality of life (QOL) is an important dimension to consider in Alzheimer's disease (AD), but few large-scale studies have analyzed self and caregiver reports of patient QOL. METHODS: Patient QOL was evaluated in a cohort of 574 AD patients with the QOL-AD scale over 2 years. RESULTS: Caregiver reports of patient QOL were lower at baseline than self reports. Older patient age was associated with overestimation of QOL by caregivers, whereas neuropsychiatric inventory score and caregiver burden were associated with underestimation. Activities of daily living limitation, depressive symptoms, and caregiver burden were systematically associated with poorer QOL, whereas caregiver relationship and apathy were associated with poorer QOL only for self reports or caregiver reports, respectively. Cognitive function and professional care were not associated with QOL. Self-rated patient QOL did not change over time, whereas disease severity markers and caregiver-rated patient QOL declined. DISCUSSION: It is important to assess both self and caregiver ratings when assessing patient QOL. PMID- 26602087 TI - The excess mortality of patients with diabetes and concurrent psychiatric illness is markedly reduced by structured personal diabetes care: A 19-year follow up of the randomized controlled study Diabetes Care in General Practice (DCGP). AB - OBJECTIVE: To assess the effectiveness of an intervention in Type 2 diabetic patients with concurrent psychiatric illness (PI) and compare this with the effectiveness in patients without PI. METHOD: In the Diabetes Care in General Practice trial, 1381 patients newly diagnosed with Type 2 diabetes were randomized to 6 years of structured personal diabetes care or routine diabetes care (ClinicalTrials.gov NCT01074762). In this observational post-hoc analysis, the effectiveness of the intervention for diabetes in 179 patients with concurrent PI was analyzed. RESULTS: During the 19-year follow-up period, patients with PI in the structured personal care group experienced a lower risk for all-cause mortality [105.3 vs. 140.4 events per 1000 patient-years; hazard ratio (HR): 0.63, P=0.023, multivariably adjusted], diabetes-related death (66.0 vs. 95.1; HR: 0.57, P=0.015), any diabetes-related endpoint (169.5 vs. 417.5; HR: 0.47, P=0.0009) and myocardial infarction (54.1 vs. 104.4; HR: 0.48, P=0.013), compared to patients with PI in the routine care group. This translates into a number needed to treat over 10 years of three or lower for these outcomes. CONCLUSION: These findings suggest that in primary care, structured diabetes care allowing for individualization was highly effective among diabetic patients with co-occurring PI. PMID- 26602088 TI - Prospective cohort study comparing transient EUS guided elastography to EUS-FNA for the diagnosis of solid pancreatic mass lesions. AB - BACKGROUND: Semiquantitative EUS-elastography has been introduced to distinguish between malignant and benign pancreatic lesions. This study investigated whether semiquantitative EUS-guided transient real time elastography increases the diagnostic accuracy for solid pancreatic lesions compared to EUS-FNA. PATIENTS AND METHODS: This single centre prospective cohort study included all patients with solitary pancreatic lesions on EUS during one year. Patients underwent EUS FNA and semiquantitative EUS-elastography during the same session. EUS and elastography results were compared with final diagnosis which was made on the basis of tissue samples and long-term outcome. RESULTS: 91 patients were recruited of which 68 had pancreatic malignancy, 17 showed benign disease and 6 had cystic lesions and were excluded from further analysis. Strain ratios from malignant lesions were significantly higher (24.00; 8.01-43.94 95% CI vs 44.00; 32.42-55.00 95% CI) and ROC analysis indicated optimal cut-off of 24.82 with resulting sensitivity, specificity and accuracy of 77%, 65% and 73% respectively. B-mode EUS and EUS-FNA had an accuracy for the correct diagnosis of malignant lesions of 87% and 85%. When lowering the cut-off strain ratio for elastography to 10 the sensitivity rose to 96% with specificity of 43% and accuracy of 84%, resulting in the least accurate EUS-based method. This was confirmed by pairwise comparison. CONCLUSION: Semiquantitative EUS-elastography does not add substantial value to the EUS-based assessment of solid pancreatic lesions when compared to B-mode imaging. PMID- 26602089 TI - Middle East respiratory syndrome coronavirus shows poor replication but significant induction of antiviral responses in human monocyte-derived macrophages and dendritic cells. AB - In this study we assessed the ability of Middle East respiratory syndrome coronavirus (MERS-CoV) to replicate and induce innate immunity in human monocyte derived macrophages and dendritic cells (MDDCs), and compared it with severe acute respiratory syndrome coronavirus (SARS-CoV). Assessments of viral protein and RNA levels in infected cells showed that both viruses were impaired in their ability to replicate in these cells. Some induction of IFN-lambda1, CXCL10 and MxA mRNAs in both macrophages and MDDCs was seen in response to MERS-CoV infection, but almost no such induction was observed in response to SARS-CoV infection. ELISA and Western blot assays showed clear production of CXCL10 and MxA in MERS-CoV-infected macrophages and MDDCs. Our data suggest that SARS-CoV and MERS-CoV replicate poorly in human macrophages and MDDCs, but MERS-CoV is nonetheless capable of inducing a readily detectable host innate immune response. Our results highlight a clear difference between the viruses in activating host innate immune responses in macrophages and MDDCs, which may contribute to the pathogenesis of infection. PMID- 26602090 TI - Effective treatment of post-spinal fusion methicillin-resistant Staphylococcus aureus vertebral osteomyelitis with linezolid in a renal-transplant patient. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA)-caused pyogenic spondylitis is a serious complication associated with lumbar fusion surgery. Often, anti-MRSA drugs are not used properly or patients discontinue drug use because of side effects including renal failure. CASE PRESENTATION: We report a case at our hospital of a 54-year-old male renal-transplant patient who developed MRSA vertebral osteomyelitis after spinal fusion and was treated effectively with linezolid. After diagnosis of post-fusion surgery osteomyelitis, we conducted emergency flushing and debridement and began linezolid treatment (1200 mg/day, divided) immediately after the surgery. The level of C-reactive protein gradually decreased and became negative 4 weeks after the initiation of linezolid treatment. Serum creatinine level was approximately 1.3 mg/dL throughout the treatment period, indicating no deterioration in renal function. CONCLUSION: These results suggest that early flushing and debridement together with linezolid administration is an effective treatment for MRSA vertebral osteomyelitis in renal-transplant patients. PMID- 26602091 TI - Evidence of IL-17, IP-10, and IL-10 involvement in multiple-organ dysfunction and IL-17 pathway in acute renal failure associated to Plasmodium falciparum malaria. AB - BACKGROUND: Plasmodium falciparum malaria in India is characterized by high rates of severe disease, with multiple organ dysfunction (MOD)-mainly associated with acute renal failure (ARF)-and increased mortality. The objective of this study is to identify cytokine signatures differentiating severe malaria patients with MOD, cerebral malaria (CM), and cerebral malaria with MOD (CM-MOD) in India. We have previously shown that two cytokines clusters differentiated CM from mild malaria in Maharashtra. Hence, we also aimed to determine if these cytokines could discriminate malaria subphenotypes in Odisha. METHODS: P. falciparum malaria patients from the SCB Medical College Cuttack in the Odisha state in India were enrolled along with three sets of controls: healthy individuals, patients with sepsis and encephalitis (n = 222). We determined plasma concentrations of pro- and anti-inflammatory cytokines and chemokines for all individuals using a multiplex assay. We then used an ensemble of statistical analytical methods to ascertain whether particular sets of cytokines/chemokines were predictors of severity or signatures of a disease category. RESULTS: Of the 26 cytokines/chemokines tested, 19 increased significantly during malaria and clearly distinguished malaria patients from controls, as well as sepsis and encephalitis patients. High amounts of IL-17, IP-10, and IL-10 predicted MOD, decreased IL-17 and MIP-1alpha segregated CM-MOD from MOD, and increased IL-12p40 differentiated CM from CM-MOD. Most severe malaria patients with ARF exhibited high levels of IL-17. CONCLUSION: We report distinct differences in cytokine production correlating with malarial disease severity in Odisha and Maharashtra populations in India. We show that CM, CM-MOD and MOD are clearly distinct malaria-associated pathologies. High amounts of IL-17, IP-10, and IL-10 were predictors of MOD; decreased IL-17 and MIP-1alpha separated CM-MOD from MOD; and increased IL-12p40 differentiated CM from CM-MOD. Data also suggest that the IL 17 pathway may contribute to malaria pathogenesis via different regulatory mechanisms and may represent an interesting target to mitigate the pathological processes in malaria-associated ARF. PMID- 26602092 TI - Renal-cell carcinoma risk estimates based on participants in the prostate, lung, colorectal, and ovarian cancer screening trial and national lung screening trial. AB - PURPOSE: Current knowledge regarding risk of renal-cell carcinoma (RCC) is based on meta-analyses of case-control studies. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and National Lung Screening Trial (NLST) provide robust prospective databases with clinical information and rates of cancer development. PLCO and NLST were used to identify risk factors for RCC. METHODS: Data were extracted from PLCO and NLST to stratify risk of RCC by sex, race, age at inclusion, obesity, and smoking status. Incidence rates between groups were compared using the chi-square test. We excluded urothelial carcinomas. RESULTS: Overall, 701/154,118 and 190/53,242 RCCs were detected in PLCO and NLST, respectively. Incidence rates were higher in men (PLCO: 0.56 vs. 0.28/1000 person y, NLST: 0.73 vs. 0.35/1000 person y; both with P<0.0001). In the PLCO, male sex, age>60 years, obesity, and intensity of smoking were associated with higher risk of developing RCC. In the NLST, sex and morbid obesity increased the risk for RCC but age, ethnicity, and smoking intensity were not predictors. There was no effect of screening for other cancers on detection of RCC. High-grade (grades >=3) RCCs were diagnosed in 145 (20.7%) and 60 (31.6%) in the PLCO and NLST. In PLCO, age (60-64y), male sex, obesity, and current smokers with>50 pack years were at increased risk for high-grade RCC. In NLST, only male sex was an independent predictor of high-grade RCC. CONCLUSIONS: Age over 60 years, male sex, smoking intensity, and obesity affect the risk of RCC. Identification of a high-risk population may allow a pilot study of rational screening for RCC. PMID- 26602094 TI - A locust-inspired miniature jumping robot. AB - Unmanned ground vehicles are mostly wheeled, tracked, or legged. These locomotion mechanisms have a limited ability to traverse rough terrain and obstacles that are higher than the robot's center of mass. In order to improve the mobility of small robots it is necessary to expand the variety of their motion gaits. Jumping is one of nature's solutions to the challenge of mobility in difficult terrain. The desert locust is the model for the presented bio-inspired design of a jumping mechanism for a small mobile robot. The basic mechanism is similar to that of the semilunar process in the hind legs of the locust, and is based on the cocking of a torsional spring by wrapping a tendon-like wire around the shaft of a miniature motor. In this study we present the jumping mechanism design, and the manufacturing and performance analysis of two demonstrator prototypes. The most advanced jumping robot demonstrator is power autonomous, weighs 23 gr, and is capable of jumping to a height of 3.35 m, covering a distance of 1.37 m. PMID- 26602093 TI - Enthusiasm for homework and improvement of psychological distress in subthreshold depression during behavior therapy: secondary analysis of data from a randomized controlled trial. AB - BACKGROUND: Cognitive behavioral therapy (CBT) usually involves homework, the completion of which is a known predictor of a positive outcome. The aim of the present study was to examine the session-by-session relationships between enthusiasm to complete the homework and the improvement of psychological distress in depressed people through the course of therapy. METHODS: Working people with subthreshold depression were recruited to participate in the telephone CBT (tCBT) program with demonstrated effectiveness. Their enthusiasm for homework was enhanced with motivational interviewing techniques and was measured by asking two questions: "How strongly do you feel you want to do this homework?" and "How confident do you feel you can actually accomplish this homework?" at the end of each session. The outcome was the K6 score, which was administered at the start of each session. The K6 is an index of psychological distress including depression and anxiety. We used structural equation modeling (SEM) to elucidate the relationships between enthusiasm and the K6 scores from session to session. RESULTS: The best fitting model suggested that, throughout the course of behavior therapy (BT), enthusiasm to complete the homework was negatively correlated with the K6 scores for the subsequent session, while the K6 score measured at the beginning of the session did not influence the enthusiasm to complete the homeworks assigned for that session. CONCLUSIONS: Empirical data now support the practitioners of BT when they try to enhance their patient's enthusiasm for homework regardless of the participant's distress, which then would lead to a reduction in distress in the subsequent week. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00885014 . April 20, 2009. PMID- 26602095 TI - [Ocular graft-versus-host disease]. AB - Ocular graft-versus-host disease (GvHD) is predominantly an inflammatory ocular surface disorder after allogeneic hematopoietic stem cell transplantation (HSCT) with increasing incidence. It is not only associated with reduced quality of life because of dry eye syndromes but can also impair visual acuity and lead to blindness due to corneal complications. The GvHD is mostly associated with severe moisturizing disorder of the ocular surface, which is often resistant to therapy and accompanied by chronic inflammation. Corneal complications are an important problem in these patients. An individually adapted multimodal stage-related and interdisciplinary therapy in cooperation with hematologists and oncologists is therefore important for the treatment of patients with ocular GvHD. PMID- 26602096 TI - [Unusual course of disease due to extensive stenosis of the internal carotid artery with ocular ischemia by occlusion of the ophthalmic artery]. PMID- 26602097 TI - [Immunotherapy of uveal melanoma: vaccination against cancer. Multicenter adjuvant phase 3 vaccination study using dendritic cells laden with tumor RNA for large newly diagnosed uveal melanoma]. AB - Uveal melanomas are the most common malignant tumors of the eye. With modern molecular biological diagnostic methods, such as chromosome 3 typing and gene expression analysis, these tumors can be categorized into highly aggressive (monosomy 3, class II) and less aggressive forms. This molecular biological stratification is primarily important for determining the risk of these tumors as no therapy is currently available that is able to prevent or delay metastases. A randomized study of patients with a poor prognosis (monosomy 3) is currently being carried out in order to determine whether a cancer vaccine prepared from autologous (patient's own) dendritic cells and uveal melanoma RNA can prevent or delay progression and further metastases of this extremely aggressive form of cancer. Inclusion in the uveal melanoma study, which hopes to provide a potential therapeutic option for patients, is only possible if patients are referred to an institution that is able to manufacture and provide this vaccination before the patient is operated on or treated with radiation. Untreated tumor material is necessary for producing the vaccine on an individualized patient basis. PMID- 26602098 TI - [Severe alveolar haemorrhage related to a silicone embolism syndrome revealed by a chronic penis ulcer: A case report]. AB - INTRODUCTION: Silicone injections, in particular illegal injections, carried out in an aesthetic purpose, can cause serious complications, like silicone embolism syndrome. CASE REPORT: We present a 39-year-old man who presented with a severe acute respiratory distress syndrome related to an alveolar hemorrhage associated with a persistent penis ulcer and a genital lymphedema. It was the complications of silicone injections which revealed a severe personality disorder. Diagnosis of silicone embolism syndrome was made, a few years later, thanks to the histopathology study of a persistent penis ulcer with genital lymphedema. The outcome was favorable. CONCLUSION: A serious alveolar hemorrhage in a young patient should raise suspicion of silicone embolism syndrome, especially if there are cutaneous lesions compatible with injections. PMID- 26602099 TI - The Toxicology Investigators Consortium Case Registry--the 2014 Experience. AB - The Toxicology Investigators Consortium (ToxIC) Case Registry was established in 2010 by the American College of Medical Toxicology. The Registry includes all medical toxicology consultations performed at participating sites. The Registry was queried for all cases entered between January 1 and December 31, 2014. Specific data reviewed for analysis included demographics (age, gender, ethnicity), source of consultation, reasons for consultation, agents involved in toxicological exposures, signs, symptoms, clinical findings, fatalities, and treatment. In 2014, 9172 cases were entered in the Registry across 47 active member sites. Females accounted for 51.1 % of cases. The majority (65.1 %) of cases were adults between the ages of 19 and 65. Caucasians made up the largest identified ethnic group (48.9 %). Most Registry cases originated from the inpatient setting (93.5 %), with a large majority of these consultations coming from the emergency department or inpatient admission services. Intentional and unintentional pharmaceutical exposures continued to be the most frequent reasons for consultation, accounting for 61.7 % of cases. Among cases of intentional pharmaceutical exposure, 62.4 % were associated with a self-harm attempt. Non pharmaceutical exposures accounted for 14.1 % of Registry cases. Similar to the past years, non-opioid analgesics, sedative-hypnotics, and opioids were the most commonly encountered agents. Clinical signs or symptoms were noted in 81.9 % of cases. There were 89 recorded fatalities (0.97 %). Medical treatment (e.g., antidotes, antivenom, chelators, supportive care) was rendered in 62.3 % of cases. Patient demographics and exposure characteristics in 2014 Registry cases remain similar to prior years. The majority of consultations arose in the acute care setting (emergency department or inpatient) and involved exposures to pharmaceutical products. Among exposures, non-opioid analgesics, sedative/hypnotics, and opioids were the most frequently encountered. A majority of cases required some form of treatment, but fatalities were rare. PMID- 26602100 TI - Randomized controlled clinical trials and meta-analyses. PMID- 26602101 TI - Different outcomes of meta-analyses and data inconsistency: response to comments by Pfeifer. PMID- 26602102 TI - Connectivity Analysis and Feature Classification in Attention Deficit Hyperactivity Disorder Sub-Types: A Task Functional Magnetic Resonance Imaging Study. AB - Attention deficit hyperactivity disorder (ADHD) is a pervasive neuropsychiatric disorder. Patients with different ADHD subtypes show different behaviors under different stimuli and thus might require differential approaches to treatment. This study explores connectivity differences between ADHD subtypes and attempts to classify these subtypes based on neuroimaging features. A total of 34 patients (13 ADHD-IA and 21 ADHD-C subtypes) underwent functional magnetic resonance imaging (fMRI) with six task paradigms. Connectivity differences between ADHD subtypes were assessed for the whole brain in each task paradigm. Connectivity measures of the identified regions were used as features for the support vector machine classifier to distinguish between ADHD subtypes. The effectiveness of connectivity measures of the regions were tested by predicting ADHD-related Diagnostic and Statistical Manual of Mental Disorders (DSM) scores. Significant connectivity differences between ADHD subtypes were identified mainly in the frontal, cingulate, and parietal cortices and partially in the temporal, occipital cortices and cerebellum. Classifier accuracy for distinguishing between ADHD subtypes was 91.18 % for both gambling punishment and emotion task paradigms. Linear prediction under the two task paradigms showed significant correlation with DSM hyperactive/impulsive score. Our study identified important brain regions from connectivity analysis based on an fMRI paradigm using gambling punishment and emotion task paradigms. The regions and associated connectivity measures could serve as features to distinguish between ADHD subtypes. PMID- 26602103 TI - [Sociodemographic factors associated with adherence to the Mediterranean dietary pattern in elderly people]. AB - OBJECTIVE: To assess the level of adherence to the Mediterranean dietary pattern (DMedit) in people over 65 in rural and urban areas of the region of Hoya de Huesca (Spain) and investigate whether there are sociodemographic factors related to that adherence. MATERIAL AND METHODS: Exploratory cross-sectional study. Two questionnaires were used: one self-made for sociodemographic factors, and the PREDIMED validated questionnaire to assess the level of adherence to the DMedit. After prior informed consent, a total of 240 questionnaires were collected over a period of 2 consecutive weeks in March 2014. RESULTS: The mean age was 74+/-6.8 years, with an equal proportion of rural and urban areas and both sexes. Both populations showed a similar adherence pattern to Dmedit, with an average overall score of 9 on a scale of 0 to 14. Furthermore, the influence of sociodemographic factors was observed on the level of adherence to the Dmedit, such as purchasing power or presence of chronic diet-related diseases. CONCLUSIONS: The urban and rural population of the Hoya de Huesca seems to have a good adherence to the Dmedit, although some economic and health factors could modify it. PMID- 26602104 TI - Motherhood in the Context of Normative Discourse: Birth Stories of Mothers of Children with Down Syndrome. AB - Using birth stories as our object of inquiry, this article examines the ways in which normative discourses about gender, disability and Down syndrome construct the birth stories of three mothers of children with Down syndrome. Their stories are composed of the mothers' recollections of the first hours after birth as a time when their infants are separated from them and their postpartum needs are ignored. Together, their stories illustrate socio-cultural tropes that position Down syndrome as a dangerous form of the "other" and mothers who give birth to children with Down syndrome as implicated in transgressing cultural norms. PMID- 26602105 TI - A novel cost effective fabrication technique for highly preferential oriented TiO2 nanotubes. AB - Single crystal like TiO(2) nanotubes with preferential orientation along the [001] direction, parallel to the growth direction of nanotubes, that offer ease of charge transport much higher than reported so far, are fabricated using a cost effective two step technique. The success of this method to grow the nanotubes with the anomalous intense [001] preferential orientation is attributed to the zinc assisted minimization of the (001) surface energy. The single crystal like TiO(2) nanotubes show superior performance as supercapacitor electrodes compared to the normal polycrystalline titanium dioxide nanotubes. PMID- 26602106 TI - A pilot study to evaluate a device for the intravaginal culture of embryos. AB - The aim of this comparative randomized embryology trial was to determine if an intravaginal culture device (IVC) can provide acceptable embryo development compared with conventional IVF. Ten women between the ages of 27 and 37 years with an indication for IVF treatment were included in this study. After ovarian stimulation, oocytes were randomized to fertilization in the IVC device or using conventional IVF. Fertilization rates were higher in the IVF group compared with the IVC device (68.7% +/- 36 % versus 40.7% +/- 27%), respectively, whereas cleavage rates were similar (93% +/- 1.5% versus 97% +/- 6%) for both groups. A significantly lower number of embryos of suitable quality for transfer was obtained from the IVC device compared with conventional IVF (OR, 0.47; 95% CI, 0.26 to 0.87). The clinical pregnancy rate from transfer of IVC device embryos was 30%. Satisfaction questionnaires were also completed by all participants. Most women (70%) placed high importance on having had fertilization and embryo development occur while carrying the device. Overall, the IVC device produced reasonable pregnancy rates suggesting this technology may have a place under certain circumstances. Cost-benefit analysis, psychological factors and future studies must be considered. PMID- 26602108 TI - Identify sepsis in patients by using early warning scores, doctors are urged. PMID- 26602109 TI - DSM-V Changes for Autism Spectrum Disorder (ASD): Implications for Diagnosis, Management, and Care Coordination for Children With ASDs. AB - The purpose of this article is to highlight issues about diagnosis and management of autism spectrum disorders (ASDs) in all settings, along with care coordination for all children with ASDs. The article outlines differences between the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th edition, revised (DSM-IV-TR) and the newer version (DSM-V) for ASDs. These changes may limit the eligibility of some children for services in school, leading to poorer social/academic outcomes, lower rates of employment, and decreased assistance in eventual independent living. Primary care providers identified a lack of knowledge regarding ASDs before the DSM-V was published, describing difficulty in making ASD diagnoses, recognizing early symptoms of developmental concern, and managing care. Care coordination is part of the role of the advanced practice nurse, and lack of understanding of ASD changes in the DSM-V may diminish the ability of advanced practice nurses to screen for ASDs and make the appropriate referrals. PMID- 26602110 TI - The Moderating Role of Dysfunctional Parent-Child Relationships on the Association Between Outward Anger Expression and Physical Health in Youth From Low-Income Families. AB - OBJECTIVE: The purpose of this study is to examine the role of outward anger expression on physical health outcomes (number of illnesses in the past year, 2 year medical service utilization, and health-related quality of life) while also expanding on previous research by assessing the moderating effect of parent-child dysfunction. METHOD: An ethnically diverse sample of 125 children, ages 8 to 11 years, was recruited from a family medicine practice serving a low-income population. RESULTS: High levels of outward anger expression were related to a greater number of illnesses, greater medical service utilization, and lower health-related quality of life. Additionally, worse parent-child dysfunction exacerbated this relationship for a number of illnesses and medical service utilization. CONCLUSION: Results suggest that health care providers should consider the influence of environmental and familial factors on the physical health of children with anger. Recommendations for identifying at-risk youth and improving anger expression as well as parent-child relationships are provided. PMID- 26602111 TI - Mass Spectrometry in Clinical Laboratory: Applications in Biomolecular Analysis. AB - Mass spectrometry (MS) is a technique that can identify analytes on the basis of mass-to-charge (m/z) ratio. Although this technique has been used in research and specialized clinical laboratories for decades, however, in recent years, MS has been increasingly used in routine clinical laboratories. MS, especially when coupled to gas chromatography or liquid chromatography, provides very specific and often sensitive analysis of many analytes. Other advantages of MS include simultaneous analysis of multiple analytes (>100) and generally without need for specialized reagents. Commonly measured analytes by MS include drugs, hormones, and proteins. PMID- 26602112 TI - Quantification of Free Carnitine and Acylcarnitines in Plasma or Serum Using HPLC/MS/MS. AB - Acylcarnitines are formed by esterification between fatty acids CoA or organic acids CoA molecules and carnitine. In various fatty acids oxidation defects and organic acidurias, there is increased concentration of corresponding acylcarnitines. Abnormalities in specific acylcarnitines are used in the diagnosis of fatty acids oxidation defects and organic acidurias. Most commonly used method for the assay of acylcarnitines is HPLC-tandem mass spectrometry (HPLC/MS/MS). A HPLC/MS/MS method is described for the quantification of number of acylcarnitines. The method involves butylation of carnitine/acylcarnitines using acidified butanol, HPLC flow injection, and measurement of acylcarnitines using precursor ion scan and multiple reactions monitoring (MRM). PMID- 26602113 TI - Quantification of Arginine and Its Methylated Derivatives in Plasma by High Performance Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). AB - Arginine is the substrate for nitric oxide synthases (NOS), thus the production of nitric oxide (NO) is based on arginine availability. Arginine is methylated through the activity of protein arginine methyltransferases (PRMT1 and PRMT2), to form asymmetrical dimethylarginine (ADMA) and symmetrical dimethylarginine (SDMA). These compounds have gained interest in recent years due to their influence on NO production rates and association with cardiovascular and renal diseases. The accurate and precise measurement of arginine and its methylated derivatives is needed for research studies investigating their role(s) in NO bioavailability and development of disease. We describe a high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method for quantifying arginine, ADMA, and SDMA requiring only 50 MUL of plasma. The sample preparation involves addition of internal standards (ADMA-d7 for ADMA and SDMA, and (13)C6 arginine for arginine) prior to protein precipitation with LCMS grade acetonitrile. Samples are centrifuged and supernatant is dried under nitrogen gas at 50 degrees C. Samples are reconstituted with mobile phase (ammonium acetate formic acid-water). Arginine, ADMA, and SDMA are separated using an isocratic HPLC method on a 3 MUM silica analytical column. MS/MS detection is performed in the multiple-reaction monitoring (MRM) mode and the transitions monitored are m/z 203 to m/z 70 for ADMA and SDMA, m/z 210 to m/z 77 for ADMA-d7, m/z 175 to m/z 70 for arginine, and m/z 181 to m/z 74 for (13)C6-arginine. PMID- 26602114 TI - Quantitation of Albumin in Urine by Liquid Chromatography Tandem Mass Spectrometry. AB - Urinary excretion of human serum albumin (HSA), a 6.65 kDa monomeric protein, is a sensitive marker of renal damage associated with many diseases including diabetes mellitus. Albumin is synthesized by the liver and functions as a transport protein for fat-soluble hormones and drugs and for maintaining plasma colloid osmotic pressure and pH. Albumin is not filtered at the glomerulus and its presence in the urine at concentration above 30 mg/day is suggestive of glomerular damage. Early diagnosis of microalbuminuria (30-300 mg/24 h urine albumin excretion or 30-300 mg/g creatinine in random collections) has prognostic value for monitoring disease progression and early clinical management of diabetic nephropathy in prediabetic patients. Current methods for quantitation of urine albumin are based on immunoassays or size exclusion high-performance liquid chromatography coupled with UV detection (SEC-HPLC-UV). Studies have demonstrated discordance between the existing methods. It has been suggested that while immunoassays underestimate albumin in urine, SEC-HPLC-UV method overestimates albumin as it cannot separate co-eluting interferences. This chapter describes a liquid chromatography tandem mass spectrometry LC-MS/MS candidate reference method for albumin quantitation. PMID- 26602115 TI - Quantitation of Aldosterone in Serum or Plasma Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). AB - Accurate determination of serum and plasma aldosterone is essential for screening, diagnosis, and subtype classification of primary aldosteronism (PA). Its measurement is also used in the investigation of adrenal incidentaloma, adrenal carcinoma, Addison's disease, congenital adrenal hyperplasia, renal artery stenosis, and renal tubular channelopathies. We describe a simple and robust method for the accurate and precise measurement of aldosterone in serum or plasma using liquid chromatography and tandem mass spectrometry (LC-MS/MS). After addition of internal standard, aldosterone is extracted from serum samples using supported liquid extraction (SLE) with methyl-t-butyl ether (MtBE). The MtBE is evaporated to dryness and sample is reconstituted with mobile phase before injection onto the LC-MS/MS and quantitation using an 8-point calibration curve. The assay calibration range is approximately 50-6500 pmol/L (0.16-234 ng/dL) with total imprecision between 6.8 and 4.1 % for concentrations between about 50 and 1000 pmol/L respectively. PMID- 26602116 TI - Quantification of Five Clinically Important Amino Acids by HPLC-Triple TOFTM 5600 Based on Pre-column Double Derivatization Method. AB - Phenylalanine, tyrosine, glycine, cystine, and phosphoethanolamine are commonly measured amino acids in various physiological fluids to diagnose or follow-up various inborn errors of metabolism. The gold standard method for the amino acids quantitation has been ion exchange chromatography with ninhydrin post-column derivatization. However, this method is very laborious and time consuming. In recent years, liquid-chromatography mass spectrometry is being increasingly used for the assay of amino acids. Pre-column butyl derivatization with reverse phase chromatography has been widely used for mass spectrometry analysis of amino acids. Phosphoethanolamine is not butylated and cannot be measured by this method. Nevertheless, phosphoethanolamine can be dansyl-derivatized using dansyl chloride. We developed a double derivatization method by using butanol and dansyl chloride to derivatize carboxylic and amino groups separately, and then combining the derivatives to simultaneously measure these five amino acids using TOF-MS scan. Stable isotope-labeled internal standards were used. PMID- 26602117 TI - Sensitive, Simple, and Robust Nano-Liquid Chromatography-Mass Spectrometry Method for Amyloid Protein Subtyping. AB - Amyloidosis is a rare condition characterized by deposits of insoluble proteins in the form of beta-pleated sheets. These deposits interfere with the normal structure and function of varying tissues. Thirty-one amyloid proteins have been identified, and the correct identification is critical due to the varying treatments. Immunohistochemistry, the most routine method for identification of amyloid proteins, suffers from limitations. Mass spectrometry (MS)-based methods offer better sensitivity and specificity. We describe here a sensitive, simple, and robust MS-based method for the identification of amyloid proteins. Amyloid deposits are excised from formalin-fixed tissue by laser microdissection and is put through protein extraction followed by trypsin digestion. The resulting peptides are separated by nano-liquid chromatography and analyzed by high resolution Orbitrap mass spectrometry. The mass spectrometry data are then searched against a human protein database for identification and semi quantification. PMID- 26602118 TI - Quantitation of Ubiquinone (Coenzyme Q10) in Serum/Plasma Using Liquid Chromatography Electrospray Tandem Mass Spectrometry (ESI-LC-MS/MS). AB - Dietary ubiquinone (Coenzyme Q10) is considered an essential co-factor in the mitochondrial respiratory chain responsible for oxidative phosphorylation. This oil-soluble vitamin-like substance is mobile in cellular membranes and plays a unique role in the electron transport chain (ETC). Coenzyme Q10 (CoQ10) is present in most eukaryotic cells and functions as an electron carrier and an antioxidant. Although the exact role of Coenzyme Q10 is often debated; there is a growing interest in the measurement of CoQ10 concentrations particularly in the area of cardiovascular disease, malignancies, exercise physiology, Parkinson's disease, and patients undergoing statin drug therapies. We describe a simple method for the quantitative measurement of the ammonium adduct of Coenzyme Q10 using a high-pressure liquid chromatography combined with positive electrospray ionization tandem mass spectroscopy (ESI-LC-MS/MS) utilizing a 3 MUm PFP(2) 50 * 2.0 mm 100 A column. A stable isotopic deuterated internal standard, in the form of Coenzyme Q10-[D9], is added to the patient serum. The extraneous proteins are precipitated from the sample with ethanol and isolation of the targeted compound is facilitated by the addition of hexane to aide in the cleanup and recovery. Quantitation occurs via a 6-point calibration that is linear from 0.16 to 6.0 MUg with an observed error of 6.2 % across the analytical range. PMID- 26602119 TI - Quantitative Analysis of Salivary Cortisol Using LC-MS/MS. AB - Cortisol is one of the most important glucocorticoids and plays important roles in regulating human metabolism. Midnight salivary cortisol has been shown to correlate well with free cortisol concentration in serum and is one of the first tests recommended for the diagnosis of Cushing's syndrome.The procedure described here involves centrifugation of the saliva samples to remove solids and mucus strands before they are diluted with buffer and mixed with deuterated internal standard D4-cortisol. The samples are then subjected to reverse phase separation on a C18 column and analyzed by a tandem mass spectrometry method (LC-MS/MS). Quantification is achieved by comparing the responses of a given sample to the responses of the calibrators of known concentrations. The calibrators are prepared and analyzed along with the patient samples. Analytical specificity is ensured by using multiple reaction monitoring with fragment ions that are unique to cortisol and deuterated internal standard. PMID- 26602120 TI - Quantification of Dihydroxyacetone Phosphate (DHAP) in Human Red Blood Cells by HPLC-TripleTOF 5600TM Mass Spectrometer. AB - Triosephosphate isomerase (TPI) is a glycolytic enzyme which catalyzes the interconversion between glyceraldehyde-3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP). TPI deficiency results in accumulation of DHAP in human red blood cells and other tissues. The disease is characterized by congenital hemolytic anemia, and progressive neuromuscular dysfunction. The laboratory diagnosis is generally made by measurement of TPI activity in RBCs. Measurement of DHAP can be useful in further confirmation and follow-up of the disease. We developed HPLC/TOF-MS method for quantitation of DHAP in RBCs. The method involves simple protein precipitation, reverse phase C8 column chromatography, ion pairing with tributylamine, and long run time of 50 min to separate the two isomers (G3P and DHAP). PMID- 26602121 TI - Simultaneous Quantitation of Estradiol and Estrone in Serum Using Liquid Chromatography Mass Spectrometry. AB - Accurate measurement of the endogenous estrogens, estrone (E1) and estradiol (E2), is important in the clinical diagnosis and monitoring of multiple disorders. Typically, given the efficacy and low cost, radioimmunoassays (RIA) and enzyme-linked immunoassays (EIA) are used to quantify these hormones in biological samples. Unfortunately, at low levels these assays lack the necessary sensitivity and specificity for diagnosis of certain disorders in adult and pediatric endocrinology and oncology. In response to this need, we developed a fast and sensitive high performance liquid chromatography negative electrospray ionization tandem mass spectrometry (LC-MS/MS) method to measure serum estrone (E1) and estradiol (E2) without chemical derivatization. Samples are spiked with a stable isotopic carbon thirteen ((13)C) labeled internal standard and the estrogens are isolated by liquid-liquid extraction (LLE) with hexane:Methyl-tert butyl ether (MTBE) (9:1). Following centrifugation and dry down samples are reconstituted with deionized water, and separated on a C18 reverse phase column. The analytes are quantified using a six point calibration curve with a linearity of 2.6-625 pg/ml and with a variability of less than 8 % across analytical range. PMID- 26602122 TI - Direct Measurement of Free Estradiol in Human Serum and Plasma by Equilibrium Dialysis-Liquid Chromatography-Tandem Mass Spectrometry. AB - We describe a direct method of measurement of free estradiol using equilibrium dialysis followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Serum aliquots and internal standards are extracted by liquid-liquid extraction using methyl-tert-butyl ether (MTBE) followed by derivatization with dansyl chloride. An API 5500 mass spectrometer operated in positive electrospray mode is used for detection. PMID- 26602123 TI - Quantification of gamma-Aminobutyric Acid in Cerebrospinal Fluid Using Liquid Chromatography-Electrospray Tandem Mass Spectrometry. AB - We describe a simple stable isotope dilution method for accurate and precise measurement of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in human cerebrospinal fluid (CSF) as a clinical diagnostic test. Determination of GABA in CSF (50 MUL) was performed utilizing high performance liquid chromatography coupled with electrospray positive ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Analysis of free and total GABA requires two individual sample preparations and mass spectrometry analyses. Free GABA in CSF is determined by a 1:2 dilution with internal standard (GABA-D2) and injected directly onto the HPLC-ESI-MS/MS system. Determination of total GABA in CSF requires additional sample preparation in order to hydrolyze all the bound GABA in the sample to the free form. This requires hydrolyzing the sample by boiling in acidic conditions (hydrochloric acid) for 4 h. The sample is then further diluted 1:10 with a 90 % acetonitrile/0.1 % formic acid solution and injected into the HPLC-ESI-MS/MS system. Each assay is quantified using a five point standard curve and is linear from 6 nM to 1000 nM and 0.63 MUM to 80 MUM for free and total GABA, respectively. PMID- 26602124 TI - Quantitation of Insulin Analogues in Serum Using Immunoaffinity Extraction, Liquid Chromatography, and Tandem Mass Spectrometry. AB - Insulin analysis is used in combination with glucose, C-peptide, beta hydroxybutyrate, and proinsulin determination for the investigation of adult hypoglycemia. The most common cause is the administration of too much insulin or insulin secretagogue to a diabetic patient or inadequate caloric intake after administration of either. Occasionally there is a question as to whether hypoglycemia has been caused by an exogenous insulin-whether by accident, intent, or even malicious intent. While traditionally this was confirmed by a low or undetectable C-peptide in a hypoglycemic specimen, this finding is not entirely specific and would also be expected in the context of impaired counter-regulatory response, fatty acid oxidation defects, and liver failure-though beta hydroxybutyrate levels can lend diagnostic clarity. For this reason, insulin is often requested. However, popular automated chemiluminescent immunoassays for insulin have distinctly heterogeneous performance in detecting analogue synthetic insulins with cross-reactivities ranging from near 0 % to greater than 100 %. The ability to detect synthetic insulins is vendor-specific and varies between insulin products. Liquid Chromatography and Tandem Mass Spectrometry (LC-MS/MS) offers a means to circumvent these analytical issues and both quantify synthetic insulins and identify the specific type. We present an immunoaffinity extraction and LC-MS/MS method capable of independent identification and quantitation of native sequence insulins (endogenous, Insulin Regular, Insulin NPH), and analogues Glargine, Lispro, Detemir, and Aspart with an analytical sensitivity for endogenous insulin of between 1 and 2 MUU/mL in patient serum samples. PMID- 26602125 TI - Quantitation of Insulin-Like Growth Factor 1 in Serum by Liquid Chromatography High Resolution Accurate-Mass Mass Spectrometry. AB - Insulin-like growth factor 1 (IGF-1) is a 70 amino acid peptide hormone which acts as the principal mediator of the effects of growth hormone (GH). Due to a wide variability in circulating concentration of GH, IGF-1 quantitation is the first step in the diagnosis of GH excess or deficiency. Majority (>95 %) of IGF-1 circulates as a ternary complex along with its principle binding protein insulin like growth factor 1 binding protein 3 (IGFBP-3) and acid labile subunit. The assay design approach for IGF-1 quantitation has to include a step to dissociate IGF-1 from its ternary complex. Several commercial assays employ a buffer containing acidified ethanol to achieve this. Despite several modifications, commercially available immunoassays have been shown to have challenges with interference from IGFBP-3. Additionally, inter-method comparison between IGF-1 immunoassays has been shown to be suboptimal. Mass spectrometry has been utilized for quantitation of IGF-1. In this chapter a liquid chromatography high resolution accurate-mass mass spectrometry (LC-HRAMS) based method for IGF-1 quantitation has been described. PMID- 26602126 TI - Quantitation of Free Metanephrines in Plasma by Liquid Chromatography-Tandem Mass Spectrometry. AB - Plasma metanephrines are measured to aid in the diagnosis of pheochromocytomas. In patients with pheochromocytomas there is excessive production of catecholamines and metanephrines. Measurement of plasma free metanephrines is one of the first-line clinical tests that are used for the diagnosis and follow-up of pheochromocytoma. We describe here a liquid chromatography-tandem mass spectrometry method to measure free metanephrines in plasma. Free metanephrine and normetanephrine are extracted via solid-phase extraction. After extraction and evaporation, the reconstituted supernatant is analyzed by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The MS/MS is set to selective reaction monitoring mode (180.1 -> 148.1 m/z for metanephrine, 183.1 -> 168.1 for d3-metanephrine, 166.1 -> 134.1 m/z for normetanephrine, and 169.1 -> 137.2 m/z for d3-normetanephrine) with positive electrospray ionization. Quantitation is based on peak area ratio of the analyte to its respective deuterated internal standard. The assay is linear from 5.9 to 4090.0 pg/mL for metanephrine and 22.0 to 4386.7 pg/mL for normetanephrine with precision of <6 % over the ranges. PMID- 26602127 TI - Quantification of Metanephrine and Normetanephrine in Urine Using Liquid Chromatography-Tandem Mass Spectrometry. AB - Measuring urinary metanephrines aides in the diagnosis of pheochromocytomas catecholamine producing tumors. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) allows for greater sensitivity and simpler sample preparation as compared with other techniques. Here we describe a simple LC-MS/MS method for measuring metanephrines in urine. Each urine sample was treated with diphenylboronic acid to create boronate complexes, and then applied to a Bond Elut Plexa cartridge. After solid phase extraction, samples were concentrated and analyzed on an Atlantis T3 column with chromatographic run time totaling 8.5 min. MS/MS was set in positive electrospray ionization mode with multiple reaction monitoring for data collection. The assay was linear from 0.2 to 27.4 MUmol/L and 0.3 to 14.6 MUmol/L for metanephrine and normetanephrine, respectively. Intra assay and total precision at three concentration levels over 10 days were <5 % for metanephrine and <10 % for normetanephrine. PMID- 26602128 TI - High-Throughput Analysis of Methylmalonic Acid in Serum, Plasma, and Urine by LC MS/MS. Method for Analyzing Isomers Without Chromatographic Separation. AB - Measurement of methylmalonic acid (MMA) plays an important role in the diagnosis of vitamin B12 deficiency. Vitamin B12 is an essential cofactor for the enzymatic carbon rearrangement of methylmalonyl-CoA (MMA-CoA) to succinyl-CoA (SA-CoA), and the lack of vitamin B12 leads to elevated concentrations of MMA. Presence of succinic acid (SA) complicates the analysis because mass spectra of MMA and SA are indistinguishable, when analyzed in negative ion mode and the peaks are difficult to resolve chromatographically. We developed a method for the selective analysis of MMA that exploits the significant difference in fragmentation patterns of di-butyl derivatives of the isomers MMA and SA in a tandem mass spectrometer when analyzed in positive ion mode. Tandem mass spectra of di-butyl derivatives of MMA and SA are very distinct; this allows selective analysis of MMA in the presence of SA. The instrumental analysis is performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in positive ion mode, which is, in combination with selective extraction of acidic compounds, is highly selective for organic acids with multiple carboxyl groups (dicarboxylic, tricarboxylic, etc.). In this method organic acids with a single carboxyl group are virtually undetectable in the mass spectrometer; the only organic acid, other than MMA, that is detected by this method is its isomer, SA. Quantitative measurement of MMA in this method is performed using a deconvolution algorithm, which mathematically resolves the signal corresponding to MMA and does not require chromatographic resolution of the MMA and SA peaks. Because of its high selectivity, the method utilizes isocratic chromatographic separation; reconditioning and re-equilibration of the chromatographic column between injections is unnecessary. The above features of the method allow high-throughput analysis of MMA with analysis cycle time of 1 min. PMID- 26602129 TI - Quantitation of 5-Methyltetrahydrofolate in Cerebrospinal Fluid Using Liquid Chromatography-Electrospray Tandem Mass Spectrometry. AB - We describe a simple stable isotope dilution method for accurate and precise measurement of cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5-MTHF) as a clinical diagnostic test. 5-MTHF is the main biologically active form of folic acid and is involved in regulation of homocysteine and DNA synthesis. Measurement of 5-MTHF in CSF provides diagnostic information regarding diseases affecting folate metabolism within the central nervous system, in particular inborn errors of folate metabolism. Determination of 5-MTHF in CSF (50 MUL) was performed utilizing high performance liquid chromatography coupled with electrospray positive ionization tandem mass spectrometry (HPLC-ESI-MS/MS). 5-MTHF in CSF is determined by a 1:2 dilution with internal standard (5-MTHF-(13)C5) and injected directly onto the HPLC-ESI-MS/MS system. Each assay is quantified using a five point standard curve (25-400 nM) and has an analytical measurement range of 3 1000 nM. PMID- 26602130 TI - Quantitative Organic Acids in Urine by Two Dimensional Gas Chromatography-Time of Flight Mass Spectrometry (GCxGC-TOFMS). AB - Seventy-six organic acids in urine specimens are determined with quantitative two dimensional Gas Chromatography-Time of Flight Mass Spectrometry (GCxGC-TOFMS). The specimen is treated with urease to remove urea then derivatized to form pentafluorobenzyl oximes (PFBO) of oxoacids. The sample is then treated with ethyl alcohol to precipitate proteins and centrifuged. After drying the supernatant, the organic acids are derivatized to form volatile trimethylsilyl (TMS) derivatives for separation by capillary two dimensional Gas Chromatography (GCxGC) with temperature programming and modulation. Detection is by Time of Flight Mass Spectrometry (TOFMS) with identification of the organic acids by their mass spectra. Organic acids are quantitated by peak areas of reconstructed ion chromatograms with internal standards and calibration curves. Organic acids are quantified to determine abnormal patterns for the diagnosis of more than 100 inherited disorders of organic acid metabolism. Characteristic abnormal metabolites are quantified to monitor dietary and other modes of treatment for patients who are diagnosed with specific organic acid disorders. PMID- 26602131 TI - High Sensitivity Measurement of Pancreatic Polypeptide and Its Variant in Serum and Plasma by LC-MS/MS. AB - Aliquots of serum or plasma samples are combined with stable isotope labeled internal standard. Pancreatic polypeptide (PP) and its truncated variant PP3-36 are enriched by incubation with anti-PP antibody conjugated to magnetic beads. Peptides are eluted from beads in acidic buffer and the samples analyzed using liquid chromatography coupled with tandem mass spectrometry. Instrumental analysis of PP and PP3-36 is performed using electrospray ionization ESI in positive ion mode and multiple reaction monitoring (MRM) acquisition. PMID- 26602132 TI - Quantitation of Parathyroid Hormone in Serum or Plasma by Liquid Chromatography Tandem Mass Spectrometry. AB - Parathyroid hormone (PTH), an 84 amino acid peptide hormone, is an important regulator of calcium homeostasis. Quantitation of PTH in serum is useful for the diagnosis of primary hyperparathyroidism, hypoparathyroidism, and for monitoring osteodystrophy in patients with renal failure. The biological activity of PTH arises from binding of PTH (N terminus) to its target receptor (D'Amour et al., Kidney Int 68: 998-1007, 2005). Several C-terminal and N-terminal fragments circulate in normal subjects. Recent studies have demonstrated that accurate quantitation of PTH fragments may be of clinical value. In this chapter a mass spectrometry based method for quantitation of PTH(1-84) is described. This method involves immunoaffinity capture of PTH followed by trypsinization and quantitation of PTH-specific tryptic peptides by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The N-terminal tryptic peptide, PTH(1-13) as surrogate of 1-84 PTH, is used for quantitation. PMID- 26602133 TI - Determination of Phenylalanine and Tyrosine by High Performance Liquid Chromatography-Tandem Mass Spectrometry. AB - Hyperphenylalaninemia/phenylketonuria (PKU) is one of the most common inborn errors of amino acid metabolism affecting about 1:15,000 infants in the United States. PKU is an autosomal recessive disorder that if untreated results in mental retardation. The most common cause of PKU is deficiency of the enzyme phenylalanine hydroxylase that converts phenylalanine to tyrosine. Tyrosine deficiency results in impaired synthesis of catecholamines and thyroxine. Less commonly, it can result from defects in the synthesis or regeneration of tetrahydrobiopterin (BH4), an essential cofactor for the enzyme phenylalanine hydroxylase. Increased phenylalanine and decreased tyrosine in blood are used in the diagnosis and follow-up of patients with PKU. LC/MS/MS method is described for the quantification of phenylalanine and tyrosine. PMID- 26602134 TI - Urine Purine Metabolite Determination by UPLC-Tandem Mass Spectrometry. AB - Inborn errors of purine metabolism, either deficiencies of synthesis or catabolism pathways, lead to a wide spectrum of clinical presentations: urolithiasis (adenine phosphoribosyltransferase), primary immune deficiency (adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency), severe intellectual disability, and other neurological symptoms (Lesch-Nyhan disease, adenylosuccinase deficiency, and molybdenum cofactor deficiency). A rapid quantitative purine assay was developed using UPLC-MS/MS to determine purine nucleoside and base concentrations in urine. Taking advantages of ultra performance liquid chromatography, we achieved satisfactory analyte separation and recovery with a polar T3 column in a short run time with no requirement of time-consuming sample preparation or derivatization. This targeted assay is intended for diagnosis and management of purine diseases, newborn screening follow-up of SCID, and evaluation of autism spectrum disorders. PMID- 26602135 TI - Urine Pyrimidine Metabolite Determination by HPLC Tandem Mass Spectrometry. AB - Pyrimidine diseases result from deficiencies in pyrimidine de novo synthesis, degradation, and salvage pathways. Enzymatic deficiencies in pyrimidine catabolism lead to mitochondrial neurogastrointestinal encephalopathy (MNGIE), pyrimidinuria, dihydropyrimidinuria, ureidopropionic aciduria, and other disorders. While MNGIE presents with gastrointestinal dysmotility, cachexia, and leukoencephalopathy, pyrimidinuria and dihydropyrimidinuria may show symptoms of epilepsy, autism, mental retardation, and dysmorphic features. The application of HPLC-MS/MS facilitates rapid screening of pyrimidine metabolites. Here we describe an LCMS method for determination of uracil, thymine, thymidine, dihydrouracil, and dihydrothymine that are diagnostic biomarkers of MNGIE, pyrimidinuria, and dihydropyrimidinuria. PMID- 26602136 TI - Quantitation of Plasma Renin Activity in Plasma Using Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). AB - Accurate determination of plasma renin activity (PRA) is essential for the development and maintenance of an effective screening program for primary aldosteronism (PA). PRA measurement can also be useful in the investigation of renal artery stenosis, syndrome of mineralocorticoid excess, Addison's disease, congenital adrenal hyperplasia, Bartter and Gitelman syndromes, and for inherited defects in the renin angiotensin aldosterone system (RAAS). We describe a semi automated and simple method for the accurate and precise measurement of PRA from 500 MUL of plasma (250 MUL if blank subtraction is omitted, as discussed) using a liquid chromatography and tandem mass spectrometry (LC-MS/MS) method for angiotensin I (AngI) in 96-well format. After a 3 h AngI generation step at 37 degrees C in buffering conditions at pH 6, the reaction is quenched with 10 % formic acid containing AngI internal standard. Sample preparation then proceeds with offline solid phase extraction, two wash steps, and methanol elution followed by injection into the LC-MS/MS system. Quantitation is performed against a 7-point calibration linear curve prepared in buffer. The assay calibration range is 0.34-30.0 ng/mL which corresponds to PRA values of 0.11-10.0 ng/mL/h: much wider than was possible using traditional competitive antibody-based methods. Total precision in clinical production has been observed to be 5.8 to 5.0 % for Bio-Rad Hypertension Control materials having nominal PRA values ranging from 1.73 to 12.43 ng/mL/h. At AngI concentrations of 0.06 ng/L (corresponding to a PRA of 0.02 ng/mL/h), signal to noise ratios are 50:1 indicating that the limit of quantitation is well below the level required for clinical use. PMID- 26602137 TI - Quantitation of S-Adenosylmethionine and S-Adenosylhomocysteine in Plasma Using Liquid Chromatography-Electrospray Tandem Mass Spectrometry. AB - We describe a simple stable isotope dilution method for accurate determination of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) in plasma as a diagnostic test. SAM and SAH are key metabolic intermediates of methionine metabolism and the methylation cycle. Determination of SAM and SAH in plasma was performed by high performance liquid chromatography coupled with electrospray positive ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Calibrators (SAM and SAH) and internal standards ((2)H3-SAM and (2)H4-SAH) were included in each analytical run for calibration. Sample preparation involved combining 20 MUL sample with 180 MUL of internal standard solution consisting of heavy isotope labeled internal standards in mobile phase A and filtering by ultracentrifugation through a 10 kd MW cutoff membrane. Sample filtrate (3 MUL) was injected by a Shimadzu Nexera LC System interfaced with a 5500 QTRAP((r)) (AB Sciex). Chromatographic separation was achieved on a 250 mm * 2.0 mm EA:faast column from Phenomenex. Samples were eluted at a flow rate of 0.20 mL/min with a binary gradient with a total run time of 10 min. The source operated in positive ion mode at an ion spray voltage of +5000 V. SAM and SAH resolved by a gradient to 100 % methanol with retention times of 6.0 and 5.7 min, respectively. The observed m/z values of the fragment ions were m/z 399 -> 250 for SAM, m/z 385 -> 136 for SAH, m/z 402 -> 250 for (2)H3-SAM, m/z 203 -> 46. The calibration curve was linear over the ranges of 12.5-5000 nmol/L for SAM and SAH. PMID- 26602138 TI - A Simple, High-Throughput Method for Analysis of Ceramide, Glucosylceramide, and Ceramide Trihexoside in Dried Blood Spots by LC/MS/MS. AB - A unique monophasic extraction system coupled with LC/MS/MS to reduce matrix effects for sphingolipid analysis was developed. A solvent mixture of methanol, acetonitrile, and water was identified to simultaneously extract multiple sphingolipids with broad polarity range. To reduce matrix effects, the targeted sphingolipids were analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). The extraction solvent was used as an isocratic mobile phase in chromatographic separation to eliminate solvent exchange steps and enable high throughput multiple lipid assay. The assay is linear for ceramide from 0.6 to 9 MUg/mL with bias <15 %. The intra-assay coefficient of variation is less than 10 % for concentrations from 1.2 to 9 MUg/mL, and less than 25 % for concentrations below 1.2 MUg/mL. For glucosylceramide and ceramide trihexoside the linear range is 0.05-3 MUg/mL with biases <10 % and <20 %, respectively. The intra-assay coefficient of variation for these analytes is less than 10 % at concentrations from 0.4 to 3 MUg/mL, and less than 25 % for concentrations below 0.4 MUg/mL. PMID- 26602139 TI - Quantification of Dehydroepiandrosterone, 11-Deoxycortisol, 17 Hydroxyprogesterone, and Testosterone by Liquid Chromatography-Tandem Mass Spectrometry (LC/MS/MS). AB - Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders due to enzymatic defects in the biosynthetic pathway of cortisol and/or aldosterone. The analysis of cortisol, 17-hydroxyprogesterone (OHPG), dehydroepiandrosterone (DHEA), 11-deoxycortisol, and testosterone is generally performed in the diagnosis and/or follow-up of CAH. Cortisol is generally analyzed by immunoassays whereas other hormones are preferably assayed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). A multiple reaction monitoring, positive mode atmospheric pressure chemical ionization, LC/MS/MS method is described for the simultaneous quantification of 17 hydroxyprogesterone, DHEA, 11-deoxycortisol, and testosterone. Stable-isotope labeled internal standards are added to serum samples and steroids are extracted by liquid-liquid extraction using methyl tert-butyl ether. The extract is evaporated under stream of nitrogen and the residue is reconstituted in methanol and analyzed by LC/MS/MS. PMID- 26602140 TI - Urinary Succinylacetone Analysis by Gas Chromatography-Mass Spectrometry (GC-MS). AB - Succinylacetone (SA) is used for the diagnosis and monitoring of patients with tyrosinemia type I (Tyr I). SA is exclusively elevated in blood and urine of patients with Tyr I. As urinary SA concentration is much higher than blood, SA is usually tested in urine samples. Urinary SA quantitation by gas chromatography mass spectrometry (GC-MS) is described in this chapter. The urine sample in the amount of 1 MUmol creatinine is used for testing. 3,4,5,6,7-(13)C5 succinylacetone ((13)C5-SA) is used as an internal standard (IS). SA and (13)C5 SA are oximated and extracted from urine with organic solvents, and then derivatized to form trimethylsilane (TMS) derivatives. TMS derivatives of SA and (13)C5-SA are detected and quantified by GC-MS using selective ion monitoring (SIM). The assay is linear from 0.05 to 450 mmol/mol creatinine to cover the broad range of urinary SA concentrations. PMID- 26602141 TI - Quantification of 1,25-Dihydroxyvitamin D2 and D3 in Serum Using Liquid Chromatography-Tandem Mass Spectrometry. AB - 1,25-Dihydroxyvitamin D is the active form of vitamin D and plays a critical role in the maintenance of calcium and phosphorous metabolism of the human body. Measurement of 1,25-dihydroxyvitamin D in serum can aid in clinical diagnosis and/or management of renal disease, sarcoidosis, and rare inherited diseases. We present here an effective and accurate method for measuring 1,25-dihydroxyvitamin D3 and 1,25-dihydroxyvitamin D2 by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) after immunoaffinity extraction. The MS/MS is operated in multiple reaction mode with positive electrospray. Quantification is based on peak area ratios of the analytes to respective deuterated internal standards. This method offered a linear range from 4.0 to 160.0 pg/mL with analytical recovery of 89.9-115.5 % for both 1,25-dihydroxyvitamin D3 and 1,25 dihydroxyvitamin D2. PMID- 26602142 TI - High-Throughput Serum 25-Hydroxy Vitamin D Testing with Automated Sample Preparation. AB - Serum from bar-coded tubes, and then internal standard, are pipetted to 96-well plates with an 8-channel automated liquid handler (ALH). The first precipitation reagent (methanol:ZnSO4) is added and mixed with the 8-channel ALH. A second protein precipitating agent, 1 % formic acid in acetonitrile, is added and mixed with a 96-channel ALH. After a 4-min delay for larger precipitates to settle to the bottom of the plate, the upper 36 % of the precipitate/supernatant mix is transferred with the 96-channel ALH to a Sigma Hybrid SPE((r)) plate and vacuumed through for removal of phospholipids and precipitated proteins. The filtrate is collected in a second 96-well plate (collection plate) which is foil-sealed, placed in the autosampler (ALS), and injected into a multiplexed LC-MS/MS system running AB Sciex Cliquid((r)) and MPX((r)) software. Two Shimadzu LC stacks, with multiplex timing controlled by MPX((r)) software, inject alternately to one AB Sciex API-5000 MS/MS using positive atmospheric pressure chemical ionization (APCI) and a 1.87 min water/acetonitrile LC gradient with a 2.1 * 20 mm, 2.7 MUm, C18 fused core particle column (Sigma Ascentis Express). LC-MS/MS through put is ~44 samples/h/LC-MS/MS system with dual-LC channel multiplexing. Plate maps are transferred electronically from the ALH and reformatted into LC-MS/MS sample table format using the Data Innovations LLC (DI) Instrument Manager middleware application. Before collection plates are loaded into the ALS, the plate bar code is manually scanned to download the sample table from the DI middleware to the LC MS/MS. After acquisition-LC-MS/MS data is analyzed with AB Sciex Multiquant((r)) software using customized queries, and then results are transferred electronically via a DI interface to the LIS. 2500 samples/day can be extracted by two analysts using four ALHs in 4-6 h. LC-MS/MS analysis of those samples on three dual-channel LC multiplexed LC-MS/MS systems requires 19-21 h and data analysis can be done by two analysts in 4-6 h. PMID- 26602143 TI - Quantitation of 25-OH-Vitamin-D2 and 25-OH-Vitamin-D3 in Urine Using LC-MS/MS. AB - Patients with significant proteinuria represent a unique population with respect to vitamin D status due to the urinary losses of vitamin D-binding protein (DBP) to which >99 % of circulating 25-hydroxy vitamin D (25(OH)D) is bound. Low serum concentrations of 25(OH)D have been found in children and adults with nephrotic syndrome (NS). However, previously described assays developed to quantify the magnitude of urinary loss are technically challenging. This chapter describes a simple and sensitive method to quantify 25(OH)D2 and 25(OH)D3 in urine specimens in a single analytical LC-MS/MS analysis. This assay is more sensitive than previously described radioimmunoassays and offers the ability to quantitate both forms of 25-hydroxy vitamin D. The assay involves no chemical derivitization, has a linear measurement range of 20-1500 pg/mL and displays imprecision (CVs) below 7 % at various concentrations across the analytical measurement range. PMID- 26602144 TI - An unexpected negative influence of light intensity on hydrogen production by dark fermentative bacteria Clostridium beijerinckii. AB - The role of light intensity on biohydrogen production from glucose by Clostridium beijerinckii, Clostridium acetobutylicum, and Rhodobacter sphaeroides was studied to evaluate the performance and possible application in co-culture fermentation system. The applied source of light had spectrum similar to the solar radiation. The influence of light intensity on hydrogen production in dark process by C. acetobutylicum was negligible. In contrast, dark fermentation by C. beijerinckii bacteria showed a significant decrease (83%) in produced hydrogen at light intensity of 540W/m(2). Here, the redirection of metabolism from acetic and butyric acid formation towards lactic acid was observed. This not yet reported effect was probably caused by irradiation of these bacteria by light within UVA range, which is an important component of the solar radiation. The excessive illumination with light of intensity higher than 200W/m(2) resulted in decrease in hydrogen production with photofermentative bacteria as well. PMID- 26602145 TI - Advances in improving the performance of cellulase in ionic liquids for lignocellulose biorefinery. AB - Ionic liquids (ILs) have been considered as a class of promising solvents that can dissolve lignocellulosic biomass and then provide enzymatic hydrolyzable holocellulose. However, most of available cellulases are completely or partially inactivated in the presence of even low concentrations of ILs. To more fully exploit the benefits of ILs to lignocellulose biorefinery, it is critical to improve the compatibility between cellulase and ILs. Various attempts have been made to screen natural IL-tolerant cellulases from different microhabitats. Several physical and chemical methods for stabilizing cellulases in ILs were also developed. Moreover, recent advances in protein engineering have greatly facilitated the rational engineering of cellulases by site-directed mutagenesis for the IL stability. This review is aimed to provide the first detailed overview of the current advances in improving the performance of cellulase in non-natural IL environments. New ideas from the most representative progresses and technical challenges will be summarized and discussed. PMID- 26602146 TI - Effect of major histocompatibility complex haplotype matching by C4 and MICA genotyping on acute graft versus host disease in unrelated hematopoietic stem cell transplantation. AB - We explored whether matching of human leukocyte antigen (HLA) haplotypes between the recipient and donor of hematopoietic stem cell transplantation (HSCT) predicted by C4 and MICA typing is associated with the incidence of acute graft versus host disease (aGVHD). DNA preparations collected from a total of 81 recipient and donor pairs were used for PCR-based C4 subtyping and/or MICA sequence-based typing. Incidences of aGVHD were compared according to C4 and MICA matching. The six most common MICA alleles were MICA*008:01, *010:01, *002:01, *004, *009:01/049, and *012:01. Among the 59 unrelated pairs, HLA alleles were matched in 34 (57.6%). C4 subtypes were identical between the recipient and donor in 28 (82.4%) HLA-matched unrelated pairs, while MICA genotypes were matched in all HLA-matched unrelated pairs. In the 22 HLA-matched related pairs, all recipients showed identical C4 subtypes with their respective donors. In multivariate analysis, C4 mismatch was a significant risk factor associated with the development of aGVHD in unrelated HSCT (hazard ratio=3.24, P=0.006). PCR based C4 subtyping is a simple method for assessing the genetic identity of the HLA region between a recipient and unrelated donor. This test would be also useful for prediction of aGVHD in HSCT. PMID- 26602148 TI - Conservative treatment planning in veneer replacement. AB - This clinical report describes a conservative treatment in veneer replacement where diastemas, malalignment, and midline shift were the main modifying factors. When replacement veneers are indicated, the definitive results can only be accurately predicted after an esthetic reanalysis of the existing restorations. PMID- 26602147 TI - Genetic adaptations of the plateau zokor in high-elevation burrows. AB - The plateau zokor (Myospalax baileyi) spends its entire life underground in sealed burrows. Confronting limited oxygen and high carbon dioxide concentrations, and complete darkness, they epitomize a successful physiological adaptation. Here, we employ transcriptome sequencing to explore the genetic underpinnings of their adaptations to this unique habitat. Compared to Rattus norvegicus, genes belonging to GO categories related to energy metabolism (e.g. mitochondrion and fatty acid beta-oxidation) underwent accelerated evolution in the plateau zokor. Furthermore, the numbers of positively selected genes were significantly enriched in the gene categories involved in ATPase activity, blood vessel development and respiratory gaseous exchange, functional categories that are relevant to adaptation to high altitudes. Among the 787 genes with evidence of parallel evolution, and thus identified as candidate genes, several GO categories (e.g. response to hypoxia, oxygen homeostasis and erythrocyte homeostasis) are significantly enriched, are two genes, EPAS1 and AJUBA, involved in the response to hypoxia, where the parallel evolved sites are at positions that are highly conserved in sequence alignments from multiple species. Thus, accelerated evolution of GO categories, positive selection and parallel evolution at the molecular level provide evidences to parse the genetic adaptations of the plateau zokor for living in high-elevation burrows. PMID- 26602149 TI - Comparison of conventional and plant-extract disinfectant solutions on the hardness and color stability of a maxillofacial elastomer after artificial aging. AB - STATEMENT OF PROBLEM: Silicone elastomers undergo physical and chemical degradation with disinfecting solutions. Phytotherapy may be a suitable solution for disinfection. However, its effect on the properties of the silicone material is unknown. PURPOSE: The purpose of this in vitro study was to evaluate the effect of disinfection with conventional and plant-extract solutions and of artificial aging on the hardness and color stability of a facial silicone associated with pigments and an opacifier. MATERIAL AND METHODS: Four hundred specimens of silicone (MDX4-4210) were fabricated (5*6 mm). Two pigment shades and 1 dry opacifier were combined in the tested material, and 4 groups (n=10) were obtained: colorless (GI), colorless with opacifier (GII), medium pigment with opacifier (GIII), and black pigment with opacifier (GIV). Specimens were subjected to disinfection (30 days) using saline solution, water, and neutral soap (digital friction, 30 seconds), chlorhexidine 4%, Hydrastis canadensis, and Cymbopogon nardus extracts (immersion, 10 minutes). Shore A hardness (ASTM D2240) and color analyses were performed before and after disinfection. Specimens were then exposed to 1008 hours of artificial aging (ASTM 53) and subjected to final hardness and color readings. The results were analyzed with ANOVA and the Tukey significant difference test (alpha=.05). RESULTS: The opacifier increased the hardness (GII). For GII, the H. canadensis solution and the friction with water and soap promoted significantly reduced hardness; the friction also promoted a reduction in this property for GIV. The GIII was not affected after disinfection. A significant difference was found between the DeltaE values of the specimens disinfected with H. canadensis, C. nardus, and chlorhexidine, and specimens subjected to saline solution and neutral soap. CONCLUSION: The hardness of MDX4 4210 after the experimental procedure was considered clinically acceptable for facial prostheses. All groups showed clinically unacceptable color alterations regardless of the disinfecting solution. PMID- 26602150 TI - VLUIS, a land use data product for Victoria, Australia, covering 2006 to 2013. AB - Land Use Information is a key dataset required to enable an understanding of the changing nature of our landscapes and the associated influences on natural resources and regional communities. The Victorian Land Use Information System (VLUIS) data product has been created within the State Government of Victoria to support land use assessments. The project began in 2007 using stakeholder engagement to establish product requirements such as format, classification, frequency and spatial resolution. Its genesis is significantly different to traditional methods, incorporating data from a range of jurisdictions to develop land use information designed for regular on-going creation and consistency. Covering the entire landmass of Victoria, the dataset separately describes land tenure, land use and land cover. These variables are co-registered to a common spatial base (cadastral parcels) across the state for the period 2006 to 2013; biennially for land tenure and land use, and annually for land cover. Data is produced as a spatial GIS feature class. PMID- 26602151 TI - Task-shifting Using a Pain Management Protocol in an Emergency Care Service: Nurses' Perception through the Eye of the Rogers's Diffusion of Innovation Theory. AB - It has been shown that over 70% of patients waiting in emergency departments (EDs) do not receive analgesics, despite the fact that more than 78% complain of pain. A clinical innovation in the form of a pain management protocol that includes task-shifting has been implemented in the ED of a university hospital in Switzerland in order to improve pain-related outcomes in patients. This innovation involves a change in clinical practice for physicians and nurses. The aim of this study is to explore nurses' perceptions on how well this innovation is adopted. This descriptive correlational study took place in the ED of a Swiss university hospital; the hospital provides healthcare for the city, the canton, and adjoining cantons. A convenience sample of 37 ED nurses participated. They were asked to complete a questionnaire comprising 56 statements based on Rogers's "Diffusion of Innovation" theory. Nurses' opinions (on a 1-10 Likert scale) indicate that the new protocol benefits the ED (mean [M] = 7.4, standard deviation [SD] = 1.21), is compatible with nursing roles (M = 8.0, SD = 1.9), is not too complicated to apply (M = 2.7, SD = 1.7), provides observable positive effects in patients (M = 7.0, SD = 1.28), and is relatively easy to introduce into daily practice (M = 6.5, SD = 1.0). Further studies are now needed to examine patients' experiences of this innovation. PMID- 26602152 TI - Medial Patellofemoral Ligament Injuries in Children With First-Time Lateral Patellar Dislocations: A Magnetic Resonance Imaging and Arthroscopic Study. AB - BACKGROUND: A lateral patellar dislocation (LPD) is the most common knee injury in children with traumatic knee hemarthrosis. The medial patellofemoral ligament (MPFL), the important passive stabilizer against LPDs, is injured in more than 90% of cases. The MPFL injury pattern is most often defined in adults or in mixed age populations. The injury pattern in the skeletally immature patient may be different. PURPOSE: To describe MPFL injuries in the skeletally immature patient by magnetic resonance imaging (MRI), and to compare the results with the injury pattern found at arthroscopic surgery. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This was a prospective series of patients aged 9 to 14 years with acute, first-time traumatic LPDs in whom clinical examinations, radiographs, MRI, and arthroscopic surgery were performed within 2 weeks from the index injury. The MPFL injury was divided into 3 different groups according to the location: patellar site, femoral site, or multifocal. The MPFL injury site was confirmed on MRI by soft tissue edema. The length of the MPFL injury at the patellar site was measured at arthroscopic surgery, and those >=2 cm were defined as total ruptures. RESULTS: A total of 74 patients (40 girls and 34 boys; mean age, 13.1 years) were included; 73 patients (99%) had an MPFL injury according to MRI and arthroscopic surgery. The MRI scans showed an isolated MPFL injury at the patellar attachment site in 44 of 74 patients (60%), a multifocal injury in 26 patients (35%), an injury at the femoral site in 3 patients (4%), and no injury in 1 patient (1%). Arthroscopic surgery disclosed an isolated MPFL injury at the patellar site in 60 of 74 patients (81%) and a multifocal injury in 13 patients (18%); the MPFL injury at the patellar site was a total rupture in 49 patients (66%). Edema at the patellar attachment site on MRI was proven to be an MPFL rupture at the same site at arthroscopic surgery in 99% of the patients. A patellar-based injury, isolated or as part of a multifocal injury, was present on MRI in 95% (n = 70) of the patients, with a false-negative rate of 5% (n = 4) of patients compared with arthroscopic surgery. CONCLUSION: Skeletally immature children are more prone to sustaining an MPFL injury at the patellar attachment site. Arthroscopic surgery and MRI complement each other in the investigation of MPFL injuries. PMID- 26602153 TI - Ultrasonic Percutaneous Tenotomy for Recalcitrant Lateral Elbow Tendinopathy: Sustainability and Sonographic Progression at 3 Years. AB - BACKGROUND: A previously published study found positive outcomes for a novel technique for ultrasound-guided percutaneous ultrasonic tenotomy, showing good tolerability, safety, and early efficacy within an office setting. PURPOSE: In this follow-up study, all 20 members of the original cohort were contacted after 3 years to explore the sustainability of symptomatic relief, functional improvement, and sonographic soft tissue response for percutaneous ultrasonic tenotomy. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: All 20 subjects of the clinical trial that was performed from June to November 2011 were further assessed at 36 months after the procedure in terms of visual analog scale for pain, Disabilities of the Arm, Shoulder and Hand (DASH)-Compulsory/Work scores, need for adjunct procedures, and overall satisfaction. Importantly, all 20 were reassessed with ultrasound imaging at 36 months, and evidence of the common extensor tendon response was assessed in terms of tendon hypervascularity, tendon thickness, and the progress of the hypoechoic scar tissue. RESULTS: A 100% clinical follow-up was achieved, inclusive of ultrasonographic assessment. None of the subjects required further treatment procedures, and 100% expressed satisfaction. Previous improvements in visual analog scale (current median +/- SD, 0 +/- 0.9; range, 0-3) and DASH-Work scores (current median, 0 +/- 0) were sustained with conformity to a linear pattern on polynomial measures. There was further reduction in DASH-Compulsory scores to a median of 0 +/- 0.644 (range, 0 2) with a significant decrease on repeated measures (P = .008). Tendon hypervascularity was resolved in 94% of patients, and 100% had reduction in tendon thickness. Overall reduction in the hypoechoic scar tissue was observed in all subjects, with a 90% response achieved by 6 months. Between 6 and 36 months, further reduction in the scar was observed in around 60% of patients, with 20% of patients having complete resolution of the hypoechoic scar. CONCLUSION: Minimally invasive percutaneous ultrasonic tenotomy provided sustained pain relief and functional improvement for recalcitrant tennis elbow at 3-year follow-up. It is one of the few procedures to demonstrate positive sonographic evidence of tissue healing response and is an attractive alternative to surgical intervention for definitive treatment of recalcitrant elbow tendinopathy. PMID- 26602154 TI - Stress management: An ignored challenge in clinical nursing education. PMID- 26602155 TI - Caregiver perceptions about mental health services after child sexual abuse. AB - The objective of this study was to describe caregiver perceptions about mental health services (MHS) after child sexual abuse (CSA) and to explore factors that affected whether their children linked to services. We conducted semi-structured, in-person interviews with 22 non-offending caregivers of suspected CSA victims<13 years old seen at a child advocacy center in Philadelphia. Purposive sampling was used to recruit caregivers who had (n=12) and had not (n=10) linked their children to MHS. Guided by the Health Belief Model framework, interviews assessed perceptions about: CSA severity, the child's susceptibility for adverse outcomes, the benefits of MHS, and the facilitators and barriers to MHS. Interviews were audio-recorded, transcribed, coded, and analyzed using modified grounded theory. Recruitment ended when thematic saturation was reached. Caregivers expressed strong reactions to CSA and multiple concerns about adverse child outcomes. Most caregivers reported that MHS were generally necessary for children after CSA. Caregivers who had not linked to MHS, however, believed MHS were not necessary for their children, most commonly because they were not exhibiting behavioral symptoms. Caregivers described multiple access barriers to MHS, but caregivers who had not linked reported that they could have overcome these barriers if they believed MHS were necessary for their children. Caregivers who had not linked to services also expressed concerns about MHS being re-traumatizing and stigmatizing. Interventions to increase MHS linkage should focus on improving communication with caregivers about the specific benefits of MHS for their children and proactively addressing caregiver concerns about MHS. PMID- 26602156 TI - The immunoprotective activity of interleukin-33 in mouse model of cecal ligation and puncture-induced sepsis. AB - Lymphocyte apoptosis plays a pivotal role in sepsis-induced immunosuppression and is the primary cause of high mortality rates. Interleukin-33 is a member of the interleukin-1 family that is involved in the polarization of T cells toward a T helper 2-cell phenotype and may regulate apoptotic cell death. The objective of the present study was to assess the effects of interleukin-33 on T lymphocyte apoptosis in sepsis and determine the mechanisms involved. Sepsis was induced in C57BL/6 mice via a cecal ligation and puncture. Mice were infused with recombinant interleukin-33 protein at 1h and 6h after surgery. The mortality rates were evaluated over the subsequent 7 days. In a separate experiment, mice were sacrificed 24h after surgery. Bacterial burdens in the blood and peritoneal cavity were calculated to assess the bacterial clearance. Liver, lung and renal pathology were observed via transmission electron microscopy. The serum levels of interleukin-6, interleukin-10, interleukin-17, interferon-gamma and tumor necrosis factor-alpha were measured via enzyme-linked immunosorbent assays. The number of T and B lymphocytes, the percentage of apoptotic cells and the expression of Fas, Bcl-2, caspase-3, caspase-8 and caspase-9 in CD3(+) T lymphocytes were analyzed by flow cytometry. Interleukin-33 enhanced bacterial clearance, attenuated the severity of organ damage and improved the survival of septic mice. Interleukin-33 decreased the levels of interleukin-6, interleukin 10, interferon-gamma and tumor necrosis factor-alpha, and it increased the levels of interleukin-17. Interleukin-33 also inhibited the apoptosis of CD4(+) and CD8(+) T lymphocytes and CD19(+) B cells in the spleen. The number of CD3(+) T cells was higher and the expression of active caspase-3, caspase-8 and caspase-9 was lower in the interleukin-33 group compared to the CLP group. The expression of Fas was lower and the expression of Bcl-2 was higher in the interleukin-33 group than in the CLP group. Interleukin-33 prevented apoptosis of T lymphocytes and improved survival in a mouse model of sepsis. PMID- 26602157 TI - Manumycin A downregulates release of proinflammatory cytokines from TNF alpha stimulated human monocytes. AB - Macrolide antibiotics such as azithromycin or clarithromycin are known to have potent anti-inflammatory and immunomodulatory effects but these properties cannot be widely used due to a risk of bacterial resistance. We studied another polyketide antibiotic, structurally related manumycin A known as a streptomycete derived farnesyltransferase inhibitor with limited antibacterial effects, with respect to its potential regulation of mRNA expression of several genes associated with proinflammatory responses. Downregulation of mRNA for IL-6, TLR 8, IL-1 beta and IL-10 was found in THP-1 cells after 4h stimulation with TNF alpha in the presence of manumycin A and downregulated TLR-8 and EGR-1 genes were observed after 8h. Among the genes upregulated in response to manumycin were HMOX 1, TNFRSF10A, IL-1R1, TICAM2, NLRP12 after 4h and only IL-1R1 after 8h. Furthermore, manumycin A was found to inhibit IL-1beta, IL-6, and IL-8 production in TNF alpha stimulated THP-1 cells and peripheral blood monocytes in a dose dependent manner (0.25-1 MUM of manumycin A) without affecting cell viability. Cell viability of blood monocytes decreased by about 30% at manumycin A doses of 2-5 MUM. Manumycin A also inhibited IL-18 release from THP-1 cells, while in cultures of blood monocytes, this cytokine was not detectable. That manumycin A mediated downregulation of proinflammatory genes in human monocytes confirmed by a measurement of cytokine levels in culture supernatants, together with a very limited effect on cell viability, might suggest potential anti-inflammatory properties of this polyketide antibiotic. PMID- 26602158 TI - Pharmacogenetics of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in resource-limited settings: Influence on antiretroviral therapy response and concomitant anti-tubercular, antimalarial and contraceptive treatments. AB - The burden of human immunodeficiency virus (HIV) is mainly concentrated to resources-limited countries where the response to available antiretroviral therapy is often limited by the occurrence of toxicity or by the emergence of HIV drug resistance. Efavirenz and nevirapine are the antiretroviral drugs most prescribed in resources-limited countries as part of antiretroviral combination therapy. Their metabolism and conjugation are largely influenced by enzymatic genetic polymorphisms. The genetic variability of their metabolism could be associated to different metabolic phenotypes causing reduced patients' adherence because of toxicity or drug-drug interactions with concomitant therapies. The purpose of this review is to summarize published evidence on pharmacogenetic and pharmacokinetic aspects related to efavirenz and nevirapine, the influence of concomitant anti-tubercular, anti-malarial or contraceptive treatments, and the impact of human genetic variation and drug-drug interaction on the virologic and immunologic response to antiretroviral therapy in resources-limited countries. PMID- 26602159 TI - Human bocavirus in hospitalized children with acute gastroenteritis in Russia from 2010 to 2012. AB - Human bocavirus (HBoV) can cause respiratory diseases and is detectable in the stool samples of patients with gastroenteritis. To assess the prevalence of HBoV in children hospitalized with acute gastroenteritis in Novosibirsk, Russia, as well as its genetic diversity and the potential role in the etiology of gastroenteritis in this region, a total of 5502 stool samples from children hospitalized with gastroenteritis from 2010 to 2012, n=5250, and healthy children, n=252, were assayed for the presence of HBoV DNA by semi-nested PCR. The HBoV DNA was found in 1.2% of stool samples from children, with gastroenteritis varying from 0.5% in 2012 to 1.7% in 2011. The prevalence of HBoV in healthy children was 0.3%. HBoV strains were detected throughout the year with an increase in the fall-winter season. In 87% of cases, HBoV was detected in children before 1 year of age. All known HBoV genetic variants have been detected in Novosibirsk, although with different prevalences: HBoV2>HBoV1>HBoV4>HBoV3. At the beginning of 2011, HBoV2 replaced HBoV1 as the most prevalent variant. The median age of children with detected HBoV1 was 8.3months, and that with HBoV2 was 8.0 months. All HBoV-positive samples were assayed for the presence of the rotaviruses A and C, norovirus GII, astrovirus, enterovirus, adenovirus F, Salmonella spp., Campylobacter spp., Shigella spp., and EIEC. HBoV1 and HBoV2 as single agents were found in 45.8% and 60% samples, respectively, although this difference was not statistically significant. In the case of co-infections, HBoV was most frequently recorded with rotavirus A and norovirus GII. This study demonstrated that the detection rate of HBoV in stool samples from children with gastroenteritis was low, although both HBoV1 and HBoV2 could be found as the sole agents in children with gastroenteritis in Novosibirsk. PMID- 26602160 TI - Shearing of the CENP-A dimerization interface mediates plasticity in the octameric centromeric nucleosome. AB - The centromeric nucleosome is a key epigenetic determinant of centromere identity and function. Consequently, deciphering how CENP-A containing nucleosomes contribute structurally to centromere function is a fundamental question in chromosome biology. Here, we performed microsecond timescale all-atom molecular dynamics (MD) simulations of CENP-A and H3 nucleosomes, and report that the octameric CENP-A core particles and nucleosomes display different dynamics from their canonical H3-containing counterparts. The most significant motion observed is within key interactions at the heart of the CENP-A octameric core, wherein shearing of contacts within the CENP-A:CENP-A' dimerization interface results in a weaker four helix bundle, and an extrusion of 10-30 bp of DNA near the pseudo dyad. Coupled to other local and global fluctuations, the CENP-A nucleosome occupies a more rugged free energy landscape than the canonical H3 nucleosome. Taken together, our data suggest that CENP-A encodes enhanced distortability to the octameric nucleosome, which may allow for enhanced flexing of the histone core in vivo. PMID- 26602161 TI - Anemia in cardiac surgery: next target for mortality and morbidity improvement? AB - OBJECTIVE: To assess the effects of preoperative anemia on outcomes of cardiac surgery and to explore the trend in mortality over an 8-year period. METHODS: During the study period (2005-2012), all 1170 patients undergoing elective or urgent cardiac surgery and classed as anemic were included. A matched group of non-anemic 1170 patients was used as a control group. Postoperative outcomes were compared between the 2 groups. The association between preoperative anemia and postoperative outcomes was analyzed using a logistic regression model. RESULTS: Compared with patients without anemia, the need for airway support (15% vs. 12%, p = 0.05), renal replacement therapy (13% vs. 8%, p < 0.01) and the rate of in hospital surgical site infection (9% vs. 7%, p = 0.05) were higher in the anemic group. Anemia was associated with greater need for renal replacement therapy (odds ratio = 1.76, confidence interval: 1.21-2.37, p = 0.002) and prolonged (> 7 days) hospital stay (odds ratio = 1.21, confidence interval: 0.97-1.51, p = 0.08). The blood transfusion rate (54% vs. 33%, p < 0.01) and hospital mortality (5.6% vs. 3.5%, p = 0.02) were higher in the anemic group. Over the 8-year period, there was a significant improvement in mortality in the non-anemic group (from 6.5% to 1.6%) but less so in the anemic group (from 6.7% to 4.7%). CONCLUSION: Anemia impacts significantly on morbidity and mortality after cardiac surgery, with less improvement over time compared to patients without anemia. Preoperative correction of anemia, when feasible, could potentially help to improve cardiac surgery outcomes. PMID- 26602162 TI - Systematic Review and Meta-analysis of Factors Influencing Survival Following Abdominal Aortic Aneurysm Repair. AB - BACKGROUND: Predicting long-term survival following repair is essential to clinical decision making when offering abdominal aortic aneurysm (AAA) treatment. A systematic review and a meta-analysis of pre-operative non-modifiable prognostic risk factors influencing patient survival following elective open AAA repair (OAR) and endovascular aneurysm repair (EVAR) was performed. METHODS: MEDLINE, Embase and Cochrane electronic databases were searched to identify all relevant articles reporting risk factors influencing long-term survival (>=1 year) following OAR and EVAR, published up to April 2015. Studies with <100 patients and those involving primarily ruptured AAA, complex repairs (supra celiac/renal clamp), and high risk patients were excluded. Primary risk factors were increasing age, sex, American Society of Anaesthesiologist (ASA) score, and comorbidities such as ischaemic heart disease (IHD), cardiac failure, hypertension, chronic obstructive pulmonary disease (COPD), renal impairment, cerebrovascular disease, peripheral vascular disease (PVD), and diabetes. Estimated risks were expressed as hazard ratio (HR). RESULTS: A total of 5,749 study titles/abstracts were retrieved and 304 studies were thought to be relevant. The systematic review included 51 articles and the meta-analysis 45. End stage renal disease and COPD requiring supplementary oxygen had the worst long-term survival, HR 3.15 (95% CI 2.45-4.04) and HR 3.05 (95% CI 1.93-4.80) respectively. An increase in age was associated with HR of 1.05 (95% CI 1.04 1.06) for every one year increase and females had a worse survival than men HR 1.15 (95% CI 1.07-1.27). An increase in ASA score and the presence of IHD, cardiac failure, hypertension, COPD, renal impairment, cerebrovascular disease, PVD, and diabetes were also factors associated with poor long-term survival. CONCLUSION: The result of this meta-analysis summarises and quantifies unmodifiable risk factors that influence late survival following AAA repair from the best available published evidence. The presence of these factors might assist in clinical decision making during discussion with patients regarding repair. PMID- 26602163 TI - Application of quantitative computed tomography for assessment of trabecular bone mineral density, microarchitecture and mechanical property. AB - Osteoporosis is a common metabolic bone disease, causing increased skeletal fragility characterized by a low bone mass and trabecular microarchitectural deterioration. Assessment of the bone mineral density (BMD) is the primary determinant of skeletal fragility. Computed tomography (CT)-based trabecular microarchitectural and mechanical assessments are important methods to evaluate the skeletal strength. In this review, we focus the feasibility of QCT BMD measurement using a calibration phantom or phantomless. The application of QCT could extend the bone mineral density assessment to all patients who underwent a heart, lung, whole-body, and as well as all routine clinical implications of CT scan. PMID- 26602164 TI - Blood fibrocytes are recruited during acute exacerbations of chronic obstructive pulmonary disease through a CXCR4-dependent pathway. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by peribronchial fibrosis. The chronic course of COPD is worsened by recurrent acute exacerbations. OBJECTIVE: The aim of the study was to evaluate the recruitment of blood fibrocytes in patients with COPD during exacerbations and, subsequently, to identify potential mechanisms implicated in such recruitment. METHODS: Using flow cytometry, we quantified circulating fibrocytes and characterized their chemokine receptor expression in 54 patients with COPD examined during an acute exacerbation (V1) and 2 months afterward (V2) and in 40 control subjects. The role of the chemokines CXCL12 and CCL11 in fibrocyte migration was investigated by using a chemotaxis assay. Patients were followed for up to 3 years after V1. RESULTS: We demonstrated a significantly increased number of circulating fibrocytes at V1 compared with control subjects. The number of circulating fibrocytes decreased at V2. A high percentage of circulating fibrocytes during exacerbation was associated with increased risk of death. The percentage of fibrocytes at V2 was negatively correlated with FEV1, forced vital capacity, FEV1/forced vital capacity ratio, transfer lung capacity of carbon monoxide, and Pao2. Fibrocytes highly expressed CXCR4 and CCR3, the chemokine receptors for CXCL12 and CCL11, respectively. Fibrocytes collected from patients with COPD at V1 had increased chemotactic migration in response to CXCL12 but not to CCL11 compared with those from control subjects. Plerixafor, a CXCR4 antagonist, decreased fibrocyte migration to plasma from patients with exacerbating COPD. CONCLUSION: Blood fibrocytes are recruited during COPD exacerbations and related to mortality and low lung function. The CXCL12/CXCR4 axis is involved in such fibrocyte recruitment (Firebrob study; ClinicalTrials NCT01196832). PMID- 26602166 TI - Oxidative stress response in canine in vitro liver, kidney and intestinal models with seven potential dietary ingredients. AB - In vitro cell culture systems are a useful tool to rapidly assess the potential safety or toxicity of chemical constituents of food. Here, we investigated oxidative stress and organ-specific antioxidant responses by 7 potential dietary ingredients using canine in vitro culture of hepatocytes, proximal tubule cells (CPTC), bone marrow-derived mesenchymal stem cells (BMSC) and enterocyte-like cells (ELC). Cellular production of free radical species by denatonium benzoate (DB), epigallocatechin gallate (EPI), eucalyptol (EUC), green tea catechin extract (GTE) and sodium copper chlorophyllin (SCC), tetrahydroisohumulone (TRA) as well as xylitol (XYL) were continuously measured for reactive oxygen/nitrogen species (ROS/RNS) and superoxide (SO) for up to 24h. DB and TRA showed strong prooxidant activities in hepatocytes and to a lesser degree in ELC. DB was a weak prooxidant in BMSC. In contrast DB and TRA were antioxidants in CPTC. EPI was prooxidant in hepatocytes and BMSC but showed prooxidant and antioxidant activity in CPTC. SCC in hepatocytes (12.5mg/mL) and CPTC (0.78mg/mL) showed strong prooxidant and antioxidant activity in a concentration-dependent manner. GTE was effective antioxidant only in ELC. EUC and XYL did not induce ROS/RNS in all 4 cell types. SO production by EPI and TRA increased in hepatocytes but decreased by SCC in hepatocytes and ELC. These results suggest that organ-specific responses to oxidative stress by these potential prooxidant compounds may implicate a mechanism of their toxicities. PMID- 26602165 TI - Intrinsic functional defects of type 2 innate lymphoid cells impair innate allergic inflammation in promyelocytic leukemia zinc finger (PLZF)-deficient mice. AB - BACKGROUND: The transcription factor promyelocytic leukemia zinc finger (PLZF) is transiently expressed during development of type 2 innate lymphoid cells (ILC2s) but is not present at the mature stage. We hypothesized that PLZF-deficient ILC2s have functional defects in the innate allergic response and represent a tool for studying innate immunity in a mouse with a functional adaptive immune response. OBJECTIVE: We determined the consequences of PLZF deficiency on ILC2 function in response to innate and adaptive immune stimuli by using PLZF(-/-) mice and mixed wild-type:PLZF(-/-) bone marrow chimeras. METHODS: PLZF(-/-) mice, wild-type littermates, or mixed bone marrow chimeras were treated with the protease allergen papain or the cytokines IL-25 and IL-33 or infected with the helminth Nippostrongylus brasiliensis to induce innate type 2 allergic responses. Mice were sensitized with intraperitoneal ovalbumin-alum, followed by intranasal challenge with ovalbumin alone, to induce adaptive TH2 responses. Lungs were analyzed for immune cell subsets, and alveolar lavage fluid was analyzed for ILC2 derived cytokines. In addition, ILC2s were stimulated ex vivo for their capacity to release type 2 cytokines. RESULTS: PLZF-deficient lung ILC2s exhibit a cell intrinsic defect in the secretion of IL-5 and IL-13 in response to innate stimuli, resulting in defective recruitment of eosinophils and goblet cell hyperplasia. In contrast, the adaptive allergic inflammatory response to ovalbumin and alum was unimpaired. CONCLUSIONS: PLZF expression at the innate lymphoid cell precursor stage has a long-range effect on the functional properties of mature ILC2s and highlights the importance of these cells for innate allergic responses in otherwise immunocompetent mice. PMID- 26602167 TI - Synchrotron X-ray microscopy reveals early calcium and iron interaction with crocidolite fibers in the lung of exposed mice. AB - Human exposure to asbestos can cause a wide variety of lung diseases that are still a current major health concern, even if asbestos has been banned in many countries. It has been shown in many studies that asbestos fibers, ingested by alveolar macrophages, disrupt lung iron homeostasis by sequestering iron. Calcium can also be deposited on the fibers. The pathways along which iron and above all calcium interact with fibers are still unknown. Our aim was that of investigating if the iron accumulation induced by the inhaled asbestos fibers also involves calcium ions accumulation. Lung sections of asbestos-exposed mice were analyzed using an extremely sensitive procedure available at the synchrotron facilities, that provides morphological and chemical information based on X-ray fluorescence microspectroscopy (MU-XRF). In this study we show that (1) where conventional histochemical procedures revealed only weak deposits of iron and calcium, MU-XRF analysis is able to detect significant deposits of both iron and calcium on the inhaled asbestos fibers; (2) the extent of the deposition of these ions is proportionally directly related and (3) iron and calcium deposition on inhaled asbestos fibers is concomitant with the appearance of inflammatory and hyperplastic reactions. PMID- 26602168 TI - N-acetylcysteine amide, a promising antidote for acetaminophen toxicity. AB - Acetaminophen (N-acetyl-p-aminophenol, APAP) is one of the most widely used over the counter antipyretic and analgesic medications. It is safe at therapeutic doses, but its overdose can result in severe hepatotoxicity, a leading cause of drug-induced acute liver failure in the USA. Depletion of glutathione (GSH) is one of the initiating steps in APAP-induced hepatotoxicity; therefore, one strategy for restricting organ damage is to restore GSH levels by using GSH prodrugs. N-acetylcysteine (NAC), a GSH precursor, is the only currently approved antidote for an acetaminophen overdose. Unfortunately, fairly high doses and longer treatment times are required due to its poor bioavailability. In addition, oral and I.V. administration of NAC in a hospital setting are laborious and costly. Therefore, we studied the protective effects of N-acetylcysteine amide (NACA), a novel antioxidant with higher bioavailability, and compared it with NAC in APAP-induced hepatotoxicity in C57BL/6 mice. Our results showed that NACA is better than NAC at a low dose (106mg/kg) in preventing oxidative stress and protecting against APAP-induced damage. NACA significantly increased GSH levels and the GSH/GSSG ratio in the liver to 66.5% and 60.5% of the control, respectively; and it reduced the level of ALT by 30%. However, at the dose used, NAC was not effective in combating the oxidative stress induced by APAP. Thus, NACA appears to be better than NAC in reducing the oxidative stress induced by APAP. It would be of great value in the health care field to develop drugs like NACA as more effective and safer options for the prevention and therapeutic intervention in APAP-induced toxicity. PMID- 26602169 TI - The ability of the YAS and AR CALUX assays to detect the additive effects of anti androgenic fungicide mixtures. AB - Actual risk assessment only takes single pesticides into account, although about one third of the analyzed food samples in the European Union was contaminated with pesticide mixtures in 2013. A cumulative approach would group pesticides that share the same mechanism of toxicity. We evaluated the combination effects of low effect concentrations of binary and ternary mixtures of six anti androgenic fungicides (procymidone, vinclozolin, tebuconazole, propiconazole, fenarimol and prochloraz) antagonizing the human androgen receptor (hAR) in the Yeast-based Androgen Screen assay (YAS) as well as in the AR Chemical-Activated LUciferase gene eXpression (AR CALUX) assay by means of concentration addition and nonlinear regression. The mixture effects were essentially additive when the fungicides were applied as iso-effective low inhibitory concentration combinations, independently from the used assay and as shown by the excellent agreement between experimental and predicted data. Both assays were successfully applied to evaluate the additive effects of fungicide mixtures at low concentrations. Since pesticide residues occur in/on foodstuffs in the EU at rather low concentrations and hormonally active environmental contaminants may concomitantly be present, more complex mixtures of anti-androgenic chemicals, not only pesticides, should be tested in the future when wanting to apply a target organ-based risk assessment approach. PMID- 26602170 TI - Symmetry breaking in drop bouncing on curved surfaces. AB - The impact of liquid drops on solid surfaces is ubiquitous in nature, and of practical importance in many industrial processes. A drop hitting a flat surface retains a circular symmetry throughout the impact process. Here we show that a drop impinging on Echevaria leaves exhibits asymmetric bouncing dynamics with distinct spreading and retraction along two perpendicular directions. This is a direct consequence of the cylindrical leaves that have a convex/concave architecture of size comparable to the drop. Systematic experimental investigations on mimetic surfaces and lattice Boltzmann simulations reveal that this novel phenomenon results from an asymmetric momentum and mass distribution that allows for preferential fluid pumping around the drop rim. The asymmetry of the bouncing leads to ~40% reduction in contact time. PMID- 26602171 TI - Comparison of Antimicrobial Susceptibility of Campylobacter Strains Isolated from Food Samples and Patients with Diarrhea. AB - BACKGROUND: Campylobacter infections may lead to serious conditions, including septicemia or other invasive forms of the disease, which require rapid and accurate laboratory diagnosis and subsequently appropriate antimicrobial therapy. The aim of this study was to compare the species distribution and antimicrobial susceptibility pattern of Campylobacter spp. strains isolated from patients and food samples. METHODS: Biochemical identification was performed on 15 clinical and 30 food isolates of Campylobacter recovered onto Brucella agar containing 5% sheep blood. PCR was carried out to confirm the identity of Campylobacter spp. using primers for cadF, hipO, and asp genes of Campylobacter. To determine antibiotic sensitivity of isolates, Kirby-Bauer assay was carried out using 16 different antibiotic discs. RESULTS: PCR assay and biochemical tests confirmed all 45 isolates as Campylobacter: 20 (44.44%) as C. jujeni, 10 (22.22%) as C. coli, and 15 (33.34%) as other Campylobacter strains. The maximum resistance was observed to cefotaxime and imipenem (each 86.49%) and the maximum sensitivity to erythromycin (48.65%). CONCLUSION: C. jujeni is dominant among isolates from clinical and food samples. In addition, tetracycline remains the first-line therapeutic agent against Campylobacter infections in Iran. PMID- 26602172 TI - Lubrication Properties of Ammonium-Based Ionic Liquids Confined between Silica Surfaces Using Resonance Shear Measurements. AB - To evaluate the friction properties of new lubrication systems, two types of ammonium-based ionic liquids (ILs), N,N-diethyl-N-methyl-N-(2-methoxyethyl) ammonium tetrafluoroborate ([DEME][BF4]) and N,N-diethyl-N-methyl-N-(2 methoxyethyl) ammonium bis(trifluoromethanesulfonyl) imide ([DEME][TFSI]), were investigated by resonance shear measurements (RSM) and reciprocating type tribotests between silica (glass) surfaces. RSM revealed that an IL layer of ca. 2 nm in thickness was maintained between the silica surfaces under an applied load of 0.40 mN ~ 1.2 mN. The relative intensity of the RMS signal indicated that the friction of the system was lower for [DEME][BF4], 0.12, than that of [DEME][TFSI], 0.18. On the other hand, the friction coefficients MUk obtained from the tribotests of [DEME][BF4] were lower than that of [DEME][TFSI] for sliding velocities in the range of 5.0 * 10(-4) m s(-1) to 3.0 * 10(-2) m s(-1) under applied loads of 196-980 mN. The friction coefficients obtained by the tribotest are discussed with reference to the RSM results. PMID- 26602173 TI - A new animal model of placebo analgesia: involvement of the dopaminergic system in reward learning. AB - We suggest a new placebo analgesia animal model and investigated the role of the dopamine and opioid systems in placebo analgesia. Before and after the conditioning, we conducted a conditioned place preference (CPP) test to measure preferences for the cues (Rooms 1 and 2), and a hot plate test (HPT) to measure the pain responses to high level-pain after the cues. In addition, we quantified the expression of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and c-Fos in the anterior cingulate cortex (ACC) as a response to reward learning and pain response. We found an enhanced preference for the low level-pain paired cue and enhanced TH expression in the VTA of the Placebo and Placebo + Naloxone groups. Haloperidol, a dopamine antagonist, blocked these effects in the Placebo + Haloperidol group. An increased pain threshold to high-heat pain and reduced c Fos expression in the ACC were observed in the Placebo group only. Haloperidol blocked the place preference effect, and naloxone and haloperidol blocked the placebo analgesia. Cue preference is mediated by reward learning via the dopamine system, whereas the expression of placebo analgesia is mediated by the dopamine and opioid systems. PMID- 26602174 TI - Trace metal enrichment and organic matter sources in the surface sediments of Arabian Sea along southwest India (Kerala coast). AB - The geochemical distribution and enrichment of trace metals (Cd, Co, Cu, Fe, Mn, Ni, Pb and Zn) were determined in the surface sediments of Arabian Sea, along southwest India, Kerala coast. The results of geochemical indices indicated that surficial sediments of five transects are uncontaminated with respect to Mn, Zn and Cu, uncontaminated to moderately contaminated with Co and Ni, and moderately to strongly contaminated with Pb. The deposition of trace elements exhibited three different patterns i) Cd and Zn enhanced with settling biodetritus from the upwelled waters, ii) Pb, Co and Ni show higher enrichment, evidenced by the association through adsorption of iron-manganese nodules onto clay minerals and iii) Cu enrichment observed close to major urban sectors, initiated by the precipitation as Cu sulfides. Correlation, principal component analysis (PCA) and cluster analysis (CA) were used to confirm the origin information of metals and the nature of organic matter composition. PMID- 26602175 TI - Cost Sharing in Medicaid: Assumptions, Evidence, and Future Directions. AB - Several states have received waivers to expand Medicaid to poor adults under the Affordable Care Act using more cost sharing than the program traditionally allows. We synthesize literature on the effects of cost sharing, focusing on studies of low-income U.S. populations from 1995 to 2014. Literature suggests that cost sharing has a deterrent effect on initiation of treatments, and can reduce utilization of ongoing treatments. Furthermore, cost sharing may be difficult for low-income populations to understand, patients often lack sufficient information to choose medical treatment, and cost sharing may be difficult to balance within the budgets of poor adults. Gaps in the literature include evidence of long-term effects of cost sharing on health and financial well-being, evidence related to effectiveness of cost sharing combined with patient education, and evidence related to targeted programs that use financial incentives for wellness. Literature underscores the need for evaluation of the effects of cost sharing on health status and spending, particularly among the poorest adults. PMID- 26602176 TI - Mild cognitive impairment in Parkinson's disease: Diagnosis and progression to dementia. AB - INTRODUCTION: Mild cognitive impairment is common in nondemented Parkinson disease patients (PD-MCI) and is considered as a risk factor for dementia (PDD). Recently, the Movement Disorder Society (MDS) published guidelines for PD-MCI, although the studies available are still limited. The aim of this work was to characterize PD-MCI and its progression to dementia. Moreover, the study variables could be considered as predictors for the progression of cognitive impairment. METHOD: The study included 43 patients with idiopathic PD (mean age = 59.19 years, SD = 9.64) and 20 healthy and neurologically normal controls (mean age = 60.85 years, SD = 12.26). The criteria proposed by the MDS Task Force were applied for the PD-MCI diagnosis. Follow-up assessments were conducted within six to eight years after the diagnosis of PD-MCI. RESULTS: The results showed that 60.5% of the patients were diagnosed with PD-MCI when a comprehensive assessment was performed (MDS criteria Level 2), while 23.3% of the patients met MCI criteria when a brief assessment was used (MDS criteria Level 1). Multiple domain impairment was the most frequent impairment (96.2%). A total of 42.3% of PD-MCI patients had dementia in the follow-up study. Logistic regression showed that the Hoehn and Yahr stage and education significantly contributed to the prediction of PD-MCI. Moreover, the Hoehn and Yahr stage and memory domain significantly contributed to the prediction of dementia. CONCLUSIONS: The results of the study: (a) provide relevant data about the process of validation of the MDS PD-MCI criteria, (b) reinforce the hypothesis that PD-MCI is more frequent than previous studies showed without applying MDS criteria, and (c) confirm that PD-MCI is a risk factor for the onset of dementia. Finally, the study shows that neurological impairment, educational level and memory impairment were predictors for the progression of cognitive impairment. PMID- 26602177 TI - Home medicines reviews in Australian war veterans taking warfarin do not influence international normalised ratio control. AB - BACKGROUND: The clinical outcomes of warfarin are largely dependent on the international normalised ratio (INR) control achieved, and strategies to improve the time in therapeutic range (TTR) should be identified and widely implemented in practice. AIMS: To investigate the influence of pharmacist-led medication reviews on INR control and observe the quality of INR control in Australian veterans who take warfarin. METHODS: We undertook a retrospective cohort study using administrative claims data for Australian veterans and war-widows identified by the Department of Veterans' Affairs who were regularly dispensed warfarin and invited them to contact the research team. Pathology providers were subsequently contacted to provide INR results. RESULTS: INR data were available for 344 of 818 (42.1%) veterans who consented to participate in the study; 64.4% were male and the median age was 83 years. The overall TTR for the veteran cohort during the study period was 64.0%. There was no difference in the TTR in the 6 months following home medicines review (HMR) compared with the control group (63.0% vs 67.0%, P = 0.27), with the TTR in patients with INR data available in the 6 months prior to, and the 6 months following HMR, remaining high (67.9% vs 69.6% P = 0.63). Approximately, one-third of veterans in this study had a percentage TTR below 60%. CONCLUSIONS: INR was well-controlled in this elderly cohort, comparable to that achieved in recent randomised trials involving warfarin. Pharmacist-led medication reviews were not associated with a change in INR control. PMID- 26602178 TI - Cost-effectiveness of multiparametric magnetic resonance imaging and targeted biopsy in diagnosing prostate cancer. AB - INTRODUCTION: Transrectal ultrasound-guided biopsy (TRUSGB) is the recommended approach to diagnose prostate cancer (PCa). Overdiagnosis and sampling errors represent major limitations. Magnetic resonance imaging (MRI)-targeted biopsy (MRTB) detects higher proportion of significant PCa and reduces diagnosis of insignificant PCa. Costs prevent MRTB from becoming the new standard in PCa diagnosis. The present study aimed at assessing whether added costs of MRI outweigh benefits of MRTB in a cost-utility model. MATERIALS AND METHODS: A Markov model was developed to estimate quality-adjusted life-year gained (QALY) and costs for 2 strategies (the standard 12-core TRUSGB strategy and the MRTB strategy) over 5, 10, 15, and 20 years. MRI was used as triage test in biopsy naive men with clinical suspicion of PCa. The model takes into account probability of men harboring PCa, diagnostic accuracy of both procedures, and probability of being assigned to various treatment options. Direct medical costs based on health care system perspective were included. RESULTS: Following standard TRUSGB pathway, calculated cumulative effects at 5, 10, 15, and 20 years were 4.25, 7.17, 9.03, and 10.09 QALY, respectively. Cumulative effects in MRTB pathway were 4.29, 7.26, 9.17, and 10.26 QALY, correspondingly. Costs related to TRUSGB strategy were $8,027, $11,406, $14,883, and $17,587 at 5, 10, 15, and 20 years, respectively, as compared with $7,231, $10,450, $13,267, and $15,400 for the MRTB strategy. At 5, 10, 15, and 20 years, MRTB was the established dominant strategy. CONCLUSIONS: Incorporation of MRI and MRTB in PCa diagnosis and management represents a cost-effective measure at 5, 10, 15, and 20 years after initial diagnosis. PMID- 26602179 TI - Pharmacoepidemiological considerations in observed-to-expected analyses for vaccines. PMID- 26602180 TI - Irradiation of primary human gliomas triggers dynamic and aggressive survival responses involving microvesicle signaling. AB - Malignant gliomas are heterogeneous populations of dynamically interacting cells. Genomic and transcriptional changes define this cellular hierarchy and allow certain tumor cells to co-opt metabolic machinery and adopt gene expression profiles that promote cellular reprogramming. Resultant expansion of privileged subpopulations can then rapidly adapt to microenvironmental stress that ultimately influence tumor response to therapeutic intervention. In this study, primary gliomas were subjected to acute or chronic irradiation and analyzed for changes in survival parameters, oxidative stress, gene expression, and cell invasion before and after treatment with secreted microvesicles isolated from irradiated and nonirradiated glioma cells. We found that primary gliomas exposed to ionizing radiation undergo metabolic changes that increase oxidative stress, alter gene expression, and affect the contents of and response to cellular secreted microvesicles. Radiation-induced changes were exacerbated under chronic as compared to acute irradiation paradigms and promoted cellular reprogramming through enhanced expression of key transcription factors and regulators involved in differentiation and pluripotency (SOX2, POU3F2, SALL2, OLIG2, NANOG, POU5F1v1, MSI1). Irradiation also affected changes in paracrine signaling mediated by cellular secreted microvesicles that significantly altered target cell phenotype. Primary gliomas treated with microvesicles exhibited increased radioresistance and treatment with microvesicles from chronically irradiated gliomas promoted invasion via induction of increased matrix metalloproteinase II activity. Together, our data describe a complex radiation response of primary glioma cells involving metabolic and transcriptional changes that alter radiation sensitivity and induce invasive behavior. These important changes can contribute to tumor growth and recurrence, and confound interventions designed to forestall disease progression. Environ. Mol. Mutagen. 57:405-415, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26602181 TI - Advances, practice, and clinical perspectives in high-throughput sequencing. AB - Remarkable advances in high-throughput sequencing technologies have fundamentally changed our understanding of the genetic and epigenetic molecular bases underlying human health and diseases. As these technologies continue to revolutionize molecular biology leading to fresh perspectives, it is imperative to thoroughly consider the enormous excitement surrounding the technologies by highlighting the characteristics of platforms and their global trends as well as potential benefits and limitations. To date, with a variety of platforms, the technologies provide an impressive range of applications, including sequencing of whole genomes and transcriptomes, identifying of genome modifications, and profiling of protein interactions. Because these applications produce a flood of data, simultaneous development of bioinformatics tools is required to efficiently deal with the big data and to comprehensively analyze them. This review covers the major achievements and performances of the high-throughput sequencing and further summarizes the characteristics of their applications along with introducing applicable bioinformatics tools. Moreover, a step-by-step procedure for a practical transcriptome analysis is described employing an analytical pipeline. Clinical perspectives with special consideration to human oral health and diseases are also covered. PMID- 26602182 TI - Left ventricular outflow tract embolization and balloon assisted recapture of a SAPIEN XT prosthesis during transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement has emerged within the last decade as a proven alternative therapy in patients with severe aortic stenosis and prohibitive surgical risk. Despite rapidly evolving device technology and growing operator experience, peri-procedural complications are still relatively common. We present a case in which a SAPIEN XT prosthetic valve embolized into the left ventricular outflow tract. This was followed by balloon assisted recapture and subsequent successful implantation of the valve across the aortic annulus without significant hemodynamic compromise or surgical intervention. (c) 2015 Wiley Periodicals, Inc. PMID- 26602183 TI - Changes in Testicular Interstitial Connective Tissue of Hamsters (Mesocricetus auratus) During Ageing and After Exposure to Short Photoperiod. AB - The testicular interstitium of Syrian hamster (Mesocricetus auratus) was studied during ageing and in testicular regression after exposure to a short photoperiod, in relation to the interstitial cells and their connective tissue. This tissue was assessed histochemically using Masson's trichrome technique and the expression of Heat Shock Protein 47 (HSP-47) and collagen IV (alpha5) was assessed in Leydig cells. Finally, an ultrastructural analysis of some cells of the testicular interstitium was made. Leydig cells were positive for HSP-47 and collagen IV (alpha5). Ageing did not change the parameters studied while the short photoperiod altered the synthetic activity of Leydig cells. The positivity index of these cells for HSP-47 was significantly higher in the regressed testis, but was lower for collagen IV (alpha5). During ageing no change were observed. Ultrastructural Leydig cells showed a discontinuous basal lamina that did not change during ageing. The basal lamina was not identified in Leydig cells regressed by exposure to a short photoperiod. In conclusion; the intertubular connective tissue suffers little change with age. By contrast, in the testis regressed after exposure to a short photoperiod the studied parameters related to the intertubular connective tissue were altered. These changes are probably related with the low synthetic activity of regressed Leydig cell. PMID- 26602184 TI - Crystal Structure of the 3.8-MDa Respiratory Supermolecule Hemocyanin at 3.0 A Resolution. AB - Molluscan hemocyanin, a copper-containing oxygen transporter, is one of the largest known proteins. Although molluscan hemocyanins are currently applied as immunotherapeutic agents, their precise structure has not been determined because of their enormous size. Here, we have determined the first X-ray crystal structure of intact molluscan hemocyanin. The structure unveiled the architecture of the 3.8-MDa supermolecule composed of homologous functional units (FUs), wherein the dimers of FUs hierarchically associated to form the entire cylindrical decamer. Most of the specific inter-FU interactions were localized at narrow regions in the FU dimers, suggesting that rigid FU dimers formed by specific interactions assemble with flexibility. Furthermore, the roles of carbohydrates in assembly and allosteric effect, and conserved sulfur-containing residues in copper incorporation, were revealed. The precise structural information obtained in this study will accelerate our understanding of the molecular basis of hemocyanin and its future applications. PMID- 26602185 TI - Negative Regulation of Peptidyl-Prolyl Isomerase Activity by Interdomain Contact in Human Pin1. AB - Pin1 is a modular peptidyl-prolyl isomerase specific for phosphorylated Ser/Thr Pro (pS/T-P) motifs, typically within intrinsically disordered regions of signaling proteins. Pin1 consists of two flexibly linked domains: an N-terminal WW domain for substrate binding and a larger C-terminal peptidyl-prolyl isomerase (PPIase) domain. Previous studies showed that binding of phosphopeptide substrates to Pin1 could alter Pin1 interdomain contact, strengthening or weakening it depending on the substrate sequence. Thus, substrate-induced changes in interdomain contact may act as a trigger within the Pin1 mechanism. Here, we investigate this possibility via nuclear magnetic resonance studies of several Pin1 mutants. Our findings provide new mechanistic insights for those substrates that reduce interdomain contact. Specifically, the reduced interdomain contact can allosterically enhance PPIase activity relative to that when the contact is sustained. These findings suggest Pin1 interdomain contact can negatively regulate its activity. PMID- 26602186 TI - Ligand Binding Mechanism in Steroid Receptors: From Conserved Plasticity to Differential Evolutionary Constraints. AB - Steroid receptor drugs have been available for more than half a century, but details of the ligand binding mechanism have remained elusive. We solved X-ray structures of the glucocorticoid and mineralocorticoid receptors to identify a conserved plasticity at the helix 6-7 region that extends the ligand binding pocket toward the receptor surface. Since none of the endogenous ligands exploit this region, we hypothesized that it constitutes an integral part of the binding event. Extensive all-atom unbiased ligand exit and entrance simulations corroborate a ligand binding pathway that gives the observed structural plasticity a key functional role. Kinetic measurements reveal that the receptor residence time correlates with structural rearrangements observed in both structures and simulations. Ultimately, our findings reveal why nature has conserved the capacity to open up this region, and highlight how differences in the details of the ligand entry process result in differential evolutionary constraints across the steroid receptors. PMID- 26602188 TI - The Effect of Nursing Care Based on Comfort Theory on Women's Postpartum Comfort Levels After Caesarean Sections. AB - PURPOSE: The aim of this study was to determine the effect of nursing care based on comfort theory on women's postpartum comfort levels after C-sections. METHODS: A quasi-experimental design was used. The sample comprised 100 women who had C sections (50 experimental, 50 control). RESULTS: A total of 27 nursing diagnoses were determined. The physical (p = .000), psychospiritual (p = .249), and sociocultural (p = .001) subdimension mean scores on the Postpartum Comfort Scale were higher in the experimental group than they were in the control group. The mean total scores on the Postpartum Comfort Scale were 138.70 +/- 8.79 in the experimental group and 131.06 +/- 9.30 in the control group (p = .000). CONCLUSION: Nursing care based on comfort theory for women having C-sections met their comfort needs and increased their postpartum comfort levels. PRACTICE IMPLICATIONS: It is recommended that nursing care outcomes be compared using different nursing models. PMID- 26602187 TI - Structure of the Complex of Human Programmed Death 1, PD-1, and Its Ligand PD-L1. AB - Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has recently provided breakthrough progress in the treatment of melanoma, non-small cell lung cancer, and other types of cancer. Small-molecule drugs interfering with this pathway are highly awaited, but their development is hindered by insufficient structural information. This study reveals the molecular details of the human PD-1/PD-L1 interaction based on an X-ray structure of the complex. First, it is shown that the ligand binding to human PD-1 is associated with significant plasticity within the receptor. Second, a detailed molecular map of the interaction surface is provided, allowing definition of the regions within both interacting partners that may likely be targeted by small molecules. PMID- 26602189 TI - Crystal Structure and Biochemical Characterization of Tetrahydrodipicolinate N Succinyltransferase from Corynebacterium glutamicum. AB - Tetrahydrodipicolinate N-succinyltransferase (DapD) is an enzyme involved in the biosynthesis of l-lysine by converting tetrahydrodipicolinate into N-succinyl-l-2 amino-6-oxopimelate, using succinyl-CoA as a cofactor. We determined the crystal structure of DapD from Corynebacterium glutamicum (CgDapD). CgDapD functions as a trimer, and each monomer consists of three domains: an N-terminal helical domain (NTD), a left-handed beta-helix (LbetaH) domain, and a beta C-terminal domain (CTD). The mode of cofactor binding to CgDapD, elucidated by determining the structure in complex with succinyl-CoA, reveals that the position of the CTD changes slightly as the cofactor binds to the enzyme. The superposition of this structure with that of Mycobacterium tuberculosis shows differences in residues that make up cofactor-binding sites. Moreover, we determined the structure of CgDapD in complex with the substrate analogue 2-aminopimelate and revealed that the analogue was stabilized by conserved residues. The catalytic and substrate binding sites of CgDapD were confirmed by site-directed mutagenesis experiments. PMID- 26602190 TI - Inference in dynamic systems using B-splines and quasilinearized ODE penalties. AB - Nonlinear (systems of) ordinary differential equations (ODEs) are common tools in the analysis of complex one-dimensional dynamic systems. We propose a smoothing approach regularized by a quasilinearized ODE-based penalty. Within the quasilinearized spline-based framework, the estimation reduces to a conditionally linear problem for the optimization of the spline coefficients. Furthermore, standard ODE compliance parameter(s) selection criteria are applicable. We evaluate the performances of the proposed strategy through simulated and real data examples. Simulation studies suggest that the proposed procedure ensures more accurate estimates than standard nonlinear least squares approaches when the state (initial and/or boundary) conditions are not known. PMID- 26602191 TI - Enhancing Dissemination, Implementation, and Improvement Science in CTSAs through Regional Partnerships. AB - BACKGROUND AND IMPORTANCE: Challenges in healthcare policy and practice have stimulated interest in dissemination and implementation science. The Institute of Medicine Committee on the Clinical Translational Science Award (CTSA) program recommended expanding the CTSA program's investment and activity in this domain. Guidance is needed to facilitate successful growth of DII science infrastructure, activity and impacts. OBJECTIVES: Several CTSAs in Southern California collaborated to identify and respond to local challenges and opportunities to expand dissemination, implementation and improvement research by strengthening capacity and relationships between DII researchers and community, health system, and population health partners. MAIN OUTCOMES: Planning and outreach by the Southern California CTSAs increased awareness and interest in DII research and generated recommendations for growth. Recommendations include: increasing strong partnerships with healthcare and population health systems to guide policy research agendas and collaborative DII science; promoting multi-sector partnerships that involve researchers and delivery systems throughout DII processes; bringing together multiple disciplines; and addressing national and international barriers as well as opportunities in DII science. IMPLICATIONS: CTSAs through regional collaboration can increase their contributions to improved community health via skill-building, partnership development and enhanced outreach to local healthcare and public health agencies and delivery systems. PMID- 26602192 TI - When are victims unlikely to cooperate with the police? AB - Data from the National Incident-Based Reporting System (NIBRS) are used to examine the tendency for victims of physical assault, sexual assault, and robbery to refuse to cooperate with the police (N= 3,856,171). Analyses of physical assaults involving homosexual and heterosexual couples did not support the hypothesis that women attacked by their male partners are less likely to cooperate than victims of other assaults. Analyses of violent offenses more generally showed that victims of violence were more likely to refuse to cooperate if they knew the offender in any way than if the offender was a stranger. In the case of physical and sexual assault, these effects were mainly observed for minor incidents. Finally, victims of sexual assault were more likely to cooperate with the police than victims of physical assault. The findings suggest the importance of comparing the victim's reactions to intimate partner violence and sexual assault to their reactions to other offenses. PMID- 26602193 TI - Performance of the fixed pressure valve with antisiphon device SPHERA(r) in the treatment of normal pressure hydrocephalus and prevention of overdrainage. AB - Normal pressure hydrocephalus (NPH) is characterized by the triad of gait apraxia, dementia and urinary incontinence associated with ventriculomegaly and normal pressure of cerebrospinal fluid. Treatment is accomplished through the implantation of a ventricular shunt (VPS), however some complications are still frequent, like overdrainage due to siphon effect. This study analyses the performance of a valve with anti-siphon device (SPHERA(r)) in the treatment of patients with NPH and compares it with another group of patients with NPH who underwent the same procedure without anti-siphon mechanism (PS Medical(r) valve). 30 patients were consecutively enrolled in two groups with 15 patients each and followed clinically and radiologically for 1 year. Patients submitted to VPS with SPHERA(r) valve had the same clinical improvement as patients submitted to VPS with PS Medical(r). However, complications and symptomatology due to overdrainage were significantly lower in SPHERA(r) group, suggesting it as a safe tool to treat NPH. PMID- 26602194 TI - Juvenile Huntington disease in Argentina. AB - We analyzed demographic, clinical and genetic characteristics of juvenile Huntington disease (JHD) and it frequency in an Argentinean cohort. Age at onset was defined as the age at which behavioral, cognitive, psychiatric or motor abnormalities suggestive of JHD were first reported. Clinical and genetic data were similar to other international series, however, in this context we identified the highest JHD frequency reported so far (19.72%; 14/71). Age at onset of JHD is challenging and still under discussion. Our findings reinforce the hypothesis that clinical manifestations, other than the typical movement disorder, may anticipate age at onset of even many years. Analyses of JHD cohorts are required to explore it frequency in populations with different backgrounds to avoid an underestimation of this rare phenotype. Moreover, data from selected populations may open new pathways in therapeutic approaches and may explain new potential correlations between HD presentations and environmental or biological factors. PMID- 26602195 TI - Survival score scales of patients operated with spinal metastases: retrospective application in a Brazilian population. AB - Spinal cord epidural metastasis (SEM) is a common complication of systemic cancer. Predicting these patient's survival is a key factor to select the proper treatment modality, but the three most used score scales to predict their survival (Tokuhashi revised score, Tomita score and Bauer modified score) were designed in single institutions and their reliability to predict correctly the patient's survival were first tested only in those specific populations. This prognostication issue is addressed in this article, evaluating retrospectively the survival of 17 patients with SEM from a Brazilian general hospital with these score scales. Our results show that the actual survival of those patients were worse than the predicted of all three score scales, suggesting that differences between the different populations might have affected their reliability and alert that their usage as a major factor to select the most appropriate treatment have to be done with caution. PMID- 26602196 TI - Corneal confocal microscopy in a healthy Brazilian sample. AB - OBJECTIVE: This study aims to evaluate the characteristics of the corneal sub basal plexus by performing in vivo confocal microscopy of healthy Brazilians to provide reference values for the Brazilian population. METHOD: This study is an observational, cross-sectional, descriptive study comparing corneas from 55 healthy Brazilian individuals across the age span of 20-70 years. RESULTS: The average number of fibers was 5.35 +/- 1.36, fiber density was 33.4 +/- 8.5 fibers per field, and the mean number of Langerhans cells was 5.13 +/- 8.10. A correlation between the average number of fibers and age showed an inverse relationship between the number and density of fibers and age for women (p < 0.05). In the multivariate analysis, each annual increase of age showed an average increase of 1.017 (95%CI: 1.008 to 1.026) in the number of Langerhans cells, adjusting for sex and thickness. CONCLUSION: Compared to other samples, this Brazilian population showed a higher average number of fibers, though further studies with a larger sample should be performed. PMID- 26602197 TI - Transient ischemic attack caused by cerebral ergotism. PMID- 26602198 TI - Endovascular thrombectomy for the treatment of acute ischemic stroke. AB - Few patients benefit from the current standard treatment for acute ischemic stroke (AIS), encouraging the development of new treatments. OBJECTIVE: To systematically review the literature on the efficacy and/or safety of endovascular thrombectomy in AIS compared to standard treatment and to identify ongoing randomized controlled trials (RCTs). METHOD: Searches for RCTs were performed in Medline/Embase, and for ongoing trials: International Clinical Trial Registry Platform, Clinicaltrials.gov and ISRCTN registry (to June 15th, 2015). RESULTS: From the eight published RCTs, five showed the superiority of treatment that includes thrombectomy compared to standard care alone. From the 13 ongoing RCTs, 3 have been halted, one has not started, one has unknown status and eight will end between 2016 - 2020. CONCLUSION: Evidence favours a combination of the standard therapy with endovascular thrombectomy. The selection criteria however limit the number of people who can benefit. Further studies are needed to prove its cost-effectiveness. PMID- 26602199 TI - A new era of endovascular treatment for acute ischemic stroke: what are the implications for stroke care in Brazil? PMID- 26602200 TI - Ecological validity of the five digit test and the oral trails test. AB - Tests evaluating the attentional-executive system are widely used in clinical practice. However, proximity of an objective cognitive test with real-world situations (ecological validity) is not frequently investigated. The present study evaluate the association between measures of the Five Digit Test (FDT) and the Oral Trails Test (OTT) with self-reported cognitive failures in everyday life as measured by the Cognitive Failures Questionnaire (CFQ). Brazilian adults from 18-to-65 years old voluntarily performed the FDT and OTT tests and reported the frequency of cognitive failures in their everyday life through the CFQ. After controlling for the age effect, the measures of controlled attentional processes were associated with cognitive failures, yet the cognitive flexibility of both FDT and OTT accounted for by the majority of variance in most aspects of the CFQ factors. The FDT and the OTT measures were predictive of real-world problems such as cognitive failures in everyday activities/situations. PMID- 26602201 TI - Development of a new haptic perception instrument: a pilot study. AB - OBJECTIVE: Hand sensory tests do not consider distinct physiological receptors, nor detect normal range variations concerning developmental or pathological changes. We developed an instrument with a set of tests with timing and scoring for assessing haptic perception, which is the interaction between sensory and motor systems, in surfaces exploration, by moving hands. METHOD: Firstly, group meetings were set for test/manual conception and materials testing. The test/manual were submitted to 30 reviewers in 3 stages (10 reviewers on each stage). RESULTS: The Hand Haptic Perception Instrument (HHPI) evaluates hand sensorimotor performance on six domains: depression, elevation, texture, compressibility, weight (barognosis) and form perception. Each domain requires specific materials. Score ranges from 0 to 57, being 0 the worst rating. CONCLUSION: This methodological process allowed the development of six domains and instructions to assess haptic perception. This version of HHPI is a pilot model. Further studies will determine reliability and normality ranges. PMID- 26602202 TI - Late diagnosis of Fabry disease caused by a de novo mutation in a patient with end stage renal disease. AB - BACKGROUND: We present the case of a white 35-year-old male with a diagnosis of Fabry disease and negative family history. CASE PRESENTATION: At the age of 31, he underwent a renal biopsy with a diagnosis of hypertension-induced nephroangiosclerosis. At the age of 35, he was referred to our hospital and started dialysis: the unusual finding of left ventricular hypertrophy with a normal ejection fraction and of myocardial fibrosis at the cardiac magnetic resonance suggested a diagnosis of Fabry disease, although there was no apparent family history-so extensive tests were subsequently undertaken. The patient had low plasma levels of alpha-galactosidase A and the genetic analysis showed a single nucleotide point mutation in hemizygosis at nucleotide c.901 C>T in exon 6 of the GLA gene, confirming the diagnosis of Fabry disease. We extended the genetic analysis to all family members of the patient (mother, sister and brothers) and none of them had any alteration in the GLA gene, suggesting a de novo mutation in the patient. CONCLUSIONS: In a family, it is rare to find only one Fabry disease affected subject with a de novo mutation. These findings emphasize the importance of early diagnosis, genetic counseling and studying the genealogical tree of suspicious patients, even in absence of a typical family history. PMID- 26602204 TI - [The duodenal microbiota composition in children with active coeliac disease is influenced by the degree of enteropathy]. AB - OBJECTIVES: To establish whether the duodenal mucosa microbiota of children with active coeliac disease (CD) and healthy controls (HC) differ in composition and biodiversity. MATERIAL AND METHODS: Samples of duodenal biopsies in 11 CD patients were obtained at diagnosis, and in 6 HC who were investigated for functional intestinal disorders of non-CD origin. Total duodenal microbiota and the belonging to the genus Lactobacillus using PCR-denaturing gradient gel electrophoresis (DGGE) were analysed. The banding patterns obtained in the resulting gels were analysed to determine the differences between the microbiota of CD patients and HC (FPQuest 4.5) while environmental indexes (richness, diversity and habitability) were calculated with the Past version 2.17 program. RESULTS: The intestinal microbiota of patients with Marsh 3c lesion showed similarity of 98% and differs from other CD patients with other type of histologic lesion as Marsh3a, Marsh3b and Marsh2. The main differences were obtained in ecological indexes belonging to the genus Lactobacillus, with significant richness, diversity and habitability reduction in CD patients. In CD bands were categorized primarily with Streptococcus, Bacteroides and E.coli species. In HC the predominant bands were Bifidobacterium, Lactobacillus and Acinetobacter, though the Streptococcus and Bacteroides were lower. CONCLUSIONS: The celiac patients with major histological affectation presented a similar microbiota duodenal. The ecological indexes applied to the genus Lactobacillus were significantly reduced in CD. PMID- 26602203 TI - T1 at 1.5T and 3T compared with conventional T2* at 1.5T for cardiac siderosis. AB - BACKGROUND: Myocardial black blood (BB) T2* relaxometry at 1.5T provides robust, reproducible and calibrated non-invasive assessment of cardiac iron burden. In vitro data has shown that like T2*, novel native Modified Look-Locker Inversion recovery (MOLLI) T1 shortens with increasing tissue iron. The relative merits of T1 and T2* are largely unexplored. We compared the established 1.5T BB T2* technique against native T1 values at 1.5T and 3T in iron overload patients and in normal volunteers. METHODS: A total of 73 subjects (42 male) were recruited, comprising 20 healthy volunteers (controls) and 53 patients (thalassemia major 22, sickle cell disease 9, hereditary hemochromatosis 9, other iron overload conditions 13). Single mid-ventricular short axis slices were acquired for BB T2* at 1.5T and MOLLI T1 quantification at 1.5T and 3T. RESULTS: In healthy volunteers, median T1 was 1014 ms (full range 939-1059 ms) at 1.5T and modestly increased to 1165ms (full range 1056-1224 ms) at 3T. All patients with significant cardiac iron overload (1.5T T2* values <20 ms) had T1 values <939 ms at 1.5T, and <1056 ms at 3T. Associations between T2* and T1 were found to be moderate with y =377 . x(0.282) at 1.5T (R(2) = 0.717), and y =406 . x(0.294) at 3T (R(2) = 0.715). Measures of reproducibility of T1 appeared superior to T2*. CONCLUSIONS: T1 mapping at 1.5T and at 3T can identify individuals with significant iron loading as defined by the current gold standard T2* at 1.5T. However, there is significant scatter between results which may reflect measurement error, but it is also possible that T1 interacts with T2*, or is differentially sensitive to aspects of iron chemistry or other biology. Hurdles to clinical implementation of T1 include the lack of calibration against human myocardial iron concentration, no demonstrated relation to cardiac outcomes, and variation in absolute T1 values between scanners, which makes inter-centre comparisons difficult. The relative merits of T1 at 3T versus T2* at 3T require further consideration. PMID- 26602206 TI - The metaphorical, the metonymical and the psychotic aspects of obsessive symptomatology. AB - This paper is an attempt to suggest an integrative formulation of obsessive symptomatology, based on the integration of Lacanian and object-relations points of view. This formulation manifests a singular interaction between three aspects of obsessive symptomatology, which I call "the metaphorical aspect", "the metonymical aspect" and "the psychotic aspect", and which are intertwined with a varying degree of dominance. The singular interaction between them has crucial influence on the capacity for symbolization and reflection, and therefore has immense implications concerning analytical work. The theoretical formulation will be followed by a detailed analytical illustration. PMID- 26602205 TI - DeltaPK oncolytic activity includes modulation of the tumour cell milieu. AB - Oncolytic virotherapy is a unique cancer therapeutic that encompasses tumour cell lysis through both virus replication and programmed cell death (PCD) pathways. Nonetheless, clinical efficacy is relatively modest, likely related to the immunosuppressive tumour milieu. Our studies use the herpes simplex virus type 2 (HSV-2)-based oncolytic virus DeltaPK that has documented anti-tumour activity associated with virus replication, PCD and cancer stem cell lysis. They are designed to examine whether DeltaPK-mediated oncolysis includes the ability to reverse the immunosuppressive tumour microenvironment by altering the balance of cytokines directly secreted by the melanoma cells and to define its mechanism. Here, we show that melanoma cells secreted the immunosuppressive cytokine IL-10, and that secretion was inhibited by DeltaPK through virus replication and c-Jun N terminal kinase/c-Jun activation. DeltaPK-induced IL-10 inhibition upregulated surface expression of MHC class I chain-related protein A, the ligand for the activating NKG2D receptor expressed on NK- and cytotoxic T-cells. Concomitantly, DeltaPK also upregulated the secretion of inflammatory cytokines TNF-alpha, granulocyte macrophage colony-stimulating factor and IL-1beta through autophagy mediated activation of Toll-like receptor 2 pathways and pyroptosis, and it inhibited the expression of the negative immune checkpoint regulator cytotoxic T lymphocyte antigen 4. Pharmacologic inhibition of these processes significantly reduces the oncolytic activity of DeltaPK. PMID- 26602207 TI - Sensitivity of porcine epidemic diarrhea virus (PEDV) to pH and heat treatment in the presence or absence of porcine plasma. AB - Emergence of porcine epidemic diarrhea virus (PEDV) resulted in massive neonatal mortality in the North-American and Asian pork industry. Measures to prevent its geographical spread are of utmost importance to safeguard susceptible porcine populations. The major infection route is direct or indirect faecal-oral contact. Adequate biosafety measures should be in place at all levels of the swine production chain, including feed and feed ingredients. Present study aimed to investigate the sensitivity of PEDV to thermal inactivation at neutral and alkaline pH in presence or absence of porcine plasma. Cell culture medium and porcine plasma at different pH (7.2, 9.2, 10.2) and temperature conditions (4 degrees C, 40 degrees C, 44 degrees C, 48 degrees C) were inoculated to a final titer of 5.5 log10 TCID50 PEDV/ml, incubated for up to 120 min and the residual infectivity was determined by endpoint dilution assay. Irrespective of presence of plasma, PEDV was not sensitive to pH 7.2-10.2 at 4 degrees C. At moderate temperatures (>=40 degrees C), both alkaline pH and presence of plasma potentiated thermal inactivation. Inactivation of 8 log10 TCID50/ml plasma within 30 min (8D value<30 min) by moderate pH and temperature would denote potential industrial processing conditions that ensure safety towards PEDV while limiting denaturation of bioactive components. Virus-spiked plasma required heat treatment of 40 degrees C and alkalinization to pH 9.2 to achieve 8 log10 reduction within such time. At pH 10.2 and 48 degrees C, the 8D value was 4.6 min in plasma and 15.2 min in MEM. Here we propose heat-alkalinity-time (HAT) pasteurization as a highly efficient method to inactivate PEDV during industrial processing of porcine plasma. PMID- 26602208 TI - Development of an operative suspension system for the performance of MRI-OR guided laparoscopic anoplasty. AB - BACKGROUND: MRI-guided laparoscopic assisted anorectoplasty (MRI-LAARP), a new approach for surgical correction of high imperforate anus, does not bisect the sphincter complex as in the PSARP and is able to pull the neorectum through the entire sphincter complex unlike the LAARP. There is no available MRI-compatible device to position and transport patients during this procedure. We report on the design of such a device here. METHODS AND DEVICE: The device was constructed from 1.0" polyvinylchloride tubing and poly-methyl methacrylate (Plexiglass((r))) platform. The device has a stable, rigid base on which platform is secure. An adjustable and removable superstructure is secured to this base to suspend legs for lithotomy position. RESULTS: MRI-LAARP has been performed on 6 patients. The device has performed well and meets requirements set forth in development including construction with MRI-compatible materials, size fitting in the MRI bore, ability to hold patient in lithotomy position, ability to position and support MRI flex coils, and providing stability while transporting to a separate OR with needle in position. CONCLUSIONS: This device provides a stable structure to position and transport a patient with a needle in a tenuous position without dislodgement allowing this procedure, and potentially other procedures, to be done in hospitals without MROR capability. PMID- 26602209 TI - Hepatoblastoma in a male with MECP2 duplication syndrome. PMID- 26602210 TI - Corrigendum. PMID- 26602211 TI - Genome-wide linkage disequilibrium and genetic diversity in five populations of Australian domestic sheep. AB - BACKGROUND: Knowledge of the genetic structure and overall diversity of livestock species is important to maximise the potential of genome-wide association studies and genomic prediction. Commonly used measures such as linkage disequilibrium (LD), effective population size (N e ), heterozygosity, fixation index (F ST) and runs of homozygosity (ROH) are widely used and help to improve our knowledge about genetic diversity in animal populations. The development of high-density single nucleotide polymorphism (SNP) arrays and the subsequent genotyping of large numbers of animals have greatly increased the accuracy of these population based estimates. METHODS: In this study, we used the Illumina OvineSNP50 BeadChip array to estimate and compare LD (measured by r (2) and D'), N e , heterozygosity, F ST and ROH in five Australian sheep populations: three pure breeds, i.e., Merino (MER), Border Leicester (BL), Poll Dorset (PD) and two crossbred populations i.e. F1 crosses of Merino and Border Leicester (MxB) and MxB crossed to Poll Dorset (MxBxP). RESULTS: Compared to other livestock species, the sheep populations that were analysed in this study had low levels of LD and high levels of genetic diversity. The rate of LD decay was greater in Merino than in the other pure breeds. Over short distances (<10 kb), the levels of LD were higher in BL and PD than in MER. Similarly, BL and PD had comparatively smaller N e than MER. Observed heterozygosity in the pure breeds ranged from 0.3 in BL to 0.38 in MER. Genetic distances between breeds were modest compared to other livestock species (highest F ST = 0.063) but the genetic diversity within breeds was high. Based on ROH, two chromosomal regions showed evidence of strong recent selection. CONCLUSIONS: This study shows that there is a large range of genome diversity in Australian sheep breeds, especially in Merino sheep. The observed range of diversity will influence the design of genome-wide association studies and the results that can be obtained from them. This knowledge will also be useful to design reference populations for genomic prediction of breeding values in sheep. PMID- 26602212 TI - Chronic Pain, Chronic Opioid Addiction: a Complex Nexus. AB - Over the past two decades, there has been a significant increase in the prescribing of opioids, with associated increases in opioid addiction and overdose deaths. This article reviews the evidence for the effectiveness and risk of developing an opioid use disorder (OUD) in those patients treated with chronic opioid therapy (COT) for chronic non-cancer pain (CNCP). Rates of development of OUD range from 0-50 %, and aberrant drug related behaviors (ADRBs) are reported to be 20 %. Health care providers must properly assess, screen, and carefully monitor patients on COT utilizing evidence-based tools. PMID- 26602213 TI - Influence of the Resected Gastric Volume on the Weight Loss After Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: The relation between the resected gastric volume and the weight loss after laparoscopic sleeve gastrectomy appears conflicting in the literature. Both the residual and the resected volumes represent the total gastric volume, and if the weight loss is related to one of the two volumes, it should be related to the other. While some reports indicate that the weight loss is related to the resected gastric volume, others state that the weight loss is not related to the residual volume. The aim is to investigate the influence of the resected gastric volume on the weight loss after surgery. METHODS: The study included 287 consecutive patients. Gastrectomy was performed encroaching over a 38-Fr calibrating tube all the way to the angle of His. Filling volume of the resected stomach, with tap water, was measured. Patients were analyzed into group 1 with BMI <=50 kg/m(2) and group 2 >50 kg/m(2). RESULTS: Females represented 74 % of cases. Mean age was 32.9 +/- 9.5 years; preoperative BMI = 48.7 +/- 7.9 kg/m(2). The mean resected gastric volume was 1525 +/- 408 ml, and it was significantly lower in females compared to that in males (1443 +/- 311 vs 1824 +/- 502 ml, p < 0.001). Data were analyzed in two groups: group 1 with BMI <=5050 kg/m(2) and group 2 >50 kg/m(2). Both groups were similar in preoperative BMI (p = 0.399) and excess weight percent (EW%) (p = 0.33). Group 2 had a resected gastric volume (1663 +/- 424.7 ml) greater than that of group 1 (1440 +/- 347 ml; p < 0.001). The percentage of excess weight loss (EWL%) was 57.9 +/- 14.5 % at 6 months (62.7 +/- 13.5 % vs 48.34 +/- 11.29 %, p < 0.001), 77 +/- 19 % at 12 months (84 +/- 19.6 % vs 68 +/- 14.2 %, p = 0.001), 76.6 +/- 7.4 % at 18 months (79.7 +/- 4.8 vs 74.7 +/- 8.2 %, p = 0.5), and 75.8 +/- 11.5 % at 24 months (81.7 +/- 11.17 vs 70 +/- 11 %, p = 0.8) (group 1 vs group 2, respectively). At 12 months, 86 % patients achieved more than 50 % EWL% (100 % of group 1 vs 60 % of group 2). Preoperative BMI correlated with resected gastric volume (r = 0.239, p = 0.004). In multiple regression, the initial BMI was a predictor of EWL% at 6 and 12 months (r partial = -0.65, p < 0.0001) while the resected gastric volume was not. CONCLUSIONS: The resected gastric volume is related to the total gastric volume when the technique is standardized and the residual volume is calibrated using a consistent technique. It is not in itself a predictor of weight loss, but it is related to the initial BMI which predicts the weight loss. PMID- 26602214 TI - Response to Letter to the Editor: Systemic Adiponectin Values in Humans Require Standardized Units. PMID- 26602215 TI - The Use of Intraoperative Endoscopy May Decrease Postoperative Stenosis in Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is becoming one of the most common bariatric surgeries performed worldwide. Leak or stenosis following LSG can lead to major morbidity. We aim to evaluate whether the routine use of intraoperative endoscopy (IOE) can reduce these complications. METHODS: All cases of LSG between 2009 and 2015 were reviewed. In all cases, we place the 32 Fr endoscope once we are done with the greater curvature dissection. We perform an IOE at the end of surgery. If IOE shows stenosis, the over-sewing sutures are removed and the IOE is repeated. RESULTS: During the study period, 310 LSG were performed (97.4 % were primary LSG cases). The study population included 213 (68.7 %) females. The average age for our cohort was 34.9 years (range 25-63 years), the average BMI was BMI 45 kg/M2 (range 35-65 kg/M2), and the average weight was 120 kg (89-180 kg). The average length of stay was 2.2 days [1-7]. Our clinical leak rate was 0.3 % (1/310). Our leak rate in primary LSG was 0 % (0/302), and in revisional LSG was 12.5 % (1/8). All IOE leak tests were negative and the only patient with leak had negative radiographic studies as well. In contrast, IOE showed stenosis in 10 LSG cases (3.2 %), which resolved after removing over-sewing sutures. Our clinical stenosis after LSG was 0 %. CONCLUSION: Routine use of IOE in LSG has led to a change in the operative strategy and could be one of the reasons behind the acceptable leak and stenosis in this series of laparoscopic sleeve gastrectomy. PMID- 26602216 TI - Depression and Somatization Are Associated With Increased Postprandial Symptoms in Patients With Irritable Bowel Syndrome. AB - BACKGROUND & AIMS: Patients with irritable bowel syndrome (IBS) have increased postprandial symptom responses and more psychosocial morbidities than healthy individuals. However, the relationship between psychosocial status and postprandial symptom responses in patients with IBS is unclear. We investigated this relationship in a prospective study of patients with IBS. METHODS: A total of 193 IBS patients, diagnosed according to Rome II (n = 126) or Rome III (n = 67) criteria, consumed a standard breakfast (540 kcal: 36% fat, 15% proteins, 49% carbohydrates, and 8.9 g fiber). They completed visual analogue scales assessing the severity of 5 gastrointestinal symptoms (abdominal pain, bloating, nausea, gas, and fullness) before breakfast and every 30 minutes, up to 240 minutes after eating. All patients completed validated self-report questionnaires for their current levels of anxiety and depression; patients diagnosed based on Rome II criteria also completed a somatization questionnaire. The relationship between these variables and the course of gastrointestinal symptom scores over time was analyzed using linear mixed models, controlling for comorbid functional dyspepsia. RESULTS: We observed a main effect of anxiety levels on fullness and bloating (P < .04), and of depression levels on abdominal pain (P = .007), reflecting a general upward shift of the entire symptom curve. Depression-by-time interactions were seen for nausea and gas (P < .03). Somatization levels had a main effect on all 5 symptoms (P < .0001), independent of anxiety and depression. We observed somatization-by-time interaction effects for bloating (P = .005), and nausea (P = .02), and a nonsignificant trend was found for pain (P = .054), reflecting a steeper early postprandial increase in symptoms among subjects with higher levels of somatization. CONCLUSIONS: Based on a prospective study of patients with IBS, psychosocial morbidities are associated with increased levels of gastrointestinal symptoms in general. Depression and somatization levels are associated specifically with increased postprandial symptoms. PMID- 26602217 TI - End Points Must Be Clinically Meaningful for Drug Development in Nonalcoholic Fatty Liver Disease. PMID- 26602219 TI - Time to Replace Assessment of Liver Histology With MR-Based Imaging Tests to Assess Efficacy of Interventions for Nonalcoholic Fatty Liver Disease. PMID- 26602218 TI - Liver X Receptor Regulates Triglyceride Absorption Through Intestinal Down regulation of Scavenger Receptor Class B, Type 1. AB - BACKGROUND & AIMS: Reducing postprandial triglyceridemia may be a promising strategy to lower the risk of cardiovascular disorders associated with obesity and type 2 diabetes. In enterocytes, scavenger receptor class B, type 1 (SR-B1, encoded by SCARB1) mediates lipid-micelle sensing to promote assembly and secretion of chylomicrons. The nuclear receptor subfamily 1, group H, members 2 and 3 (also known as liver X receptors [LXRs]) regulate genes involved in cholesterol and fatty acid metabolism. We aimed to determine whether intestinal LXRs regulate triglyceride absorption. METHODS: C57BL/6J mice were either fed a cholesterol-enriched diet or given synthetic LXR agonists (GW3965 or T0901317). We measured the production of chylomicrons and localized SR-B1 by immunohistochemistry. Mechanisms of postprandial triglyceridemia and SR-B1 regulation were studied in Caco-2/TC7 cells incubated with LXR agonists. RESULTS: In mice and in the Caco-2/TC7 cell line, LXR agonists caused localization of intestinal SR-B1 from apical membranes to intracellular organelles and reduced chylomicron secretion. In Caco-2/TC7 cells, LXR agonists reduced SR-B1-dependent lipidic-micelle-induced Erk phosphorylation. LXR agonists also reduced intracellular trafficking of the apical apolipoprotein B pool toward secretory compartments. LXR reduced levels of SR-B1 in Caco-2/TC7 cells via a post transcriptional mechanism that involves microRNAs. CONCLUSION: In Caco-2/TC7 cells and mice, intestinal activation of LXR reduces the production of chylomicrons by a mechanism dependent on the apical localization of SR-B1. PMID- 26602220 TI - Where Do We Stand With Aspirin for the Prevention of Colorectal Cancer? The USPSTF Recommendations. PMID- 26602221 TI - ABH-Glycan Microarray Characterizes ABO Subtype Antibodies: Fine Specificity of Immune Tolerance After ABO-Incompatible Transplantation. AB - Organ transplantation from ABO blood group-incompatible (ABOi) donors requires accurate detection, effective removal and subsequent surveillance of antidonor antibodies. Because ABH antigen subtypes are expressed differently in various cells and organs, measurement of antibodies specific for the antigen subtypes in the graft is essential. Erythrocyte agglutination, the century-old assay used clinically, does not discriminate subtype-specific ABO antibodies and provides limited information on antibody isotypes. We designed and created an ABO-glycan microarray and demonstrated the precise assessment of both the presence and, importantly, the absence of donor-specific antibodies in an international study of pediatric heart transplant patients. Specific IgM, IgG, and IgA isotype antibodies to nonself ABH subtypes were detected in control participants and recipients of ABO-compatible transplants. Conversely, in children who received ABOi transplants, antibodies specific for A subtype II and/or B subtype II antigens-the only ABH antigen subtypes expressed in heart tissue-were absent, demonstrating the fine specificity of B cell tolerance to donor/graft blood group antigens. In contrast to the hemagglutination assay, the ABO-glycan microarray allows detailed characterization of donor-specific antibodies necessary for effective transplant management, representing a major step forward in precise ABO antibody detection. PMID- 26602222 TI - Benefit/risk for adjuvant breast cancer therapy with tamoxifen or aromatase inhibitor use by age, and race/ethnicity. AB - In early adjuvant breast cancer trial reports, aromatase inhibitors more effectively reduced breast recurrence with lower risk of thromboembolic events and endometrial cancer than tamoxifen, while aromatase inhibitors had higher fracture and cardiovascular disease risk. We used data from updated patient-level meta-analyses of adjuvant trials in analyses to summarize the benefits and risks of these agents in various clinical circumstances. Baseline incidence rates for health outcomes by age and race/ethnicity, absent aromatase inhibitor, or tamoxifen use were estimated from the Women's Health Initiative. Aromatase inhibitor and tamoxifen effects on distant recurrence were obtained from a meta analysis of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group (Big-1-98) clinical trials. Impact on other health outcomes were obtained from meta-analyses of randomized trials comparing aromatase inhibitor to tamoxifen use and from placebo-controlled chemoprevention trials. All health outcomes were given equal weight when modeling net benefit/risk for aromatase inhibitor compared to tamoxifen use by breast cancer recurrence risk, age (decade), race/ethnicity, hysterectomy (yes/no), and by prior myocardial infarction. Over a 10-year period, the benefit/risk index was more favorable for aromatase inhibitor than for tamoxifen as adjuvant breast cancer therapy in almost all circumstances regardless of patient age, race/ethnicity, breast cancer recurrence risk, or presence or absence of a uterus. Only in older women with prior myocardial infarction and low recurrence risk was an advantage for tamoxifen seen. Using a benefit/risk index for endocrine adjuvant breast cancer therapy in postmenopausal women, benefit was higher for aromatase inhibitor use in almost all circumstances. PMID- 26602223 TI - Design of a New Risk Score in Critical Limb Ischaemia: The ERICVA Model. AB - OBJECTIVES: It is difficult to establish which patients suffering from critical lower limb ischaemia will benefit from revascularization. Risk scores can provide objectivity in decision making. The aim was to design a new risk score (ERICVA) and compare its predictive power with the PREVENT III and Finnvasc scores. METHODS: An observational retrospective study of patients who underwent revascularization (open or endovascular) in Valladolid's University Hospital between 2005 and 2010 was designed. The sample was divided into two subgroups (development and validation subsamples). After univariate analysis followed by a multivariate Cox regression, a number of variables associated with death and/or major amputation were selected, creating a weighed score called ERICVA, and a simplified version of it. The area under the curve (AUC) of receiver operating characteristic (ROC) curve analysis was performed and the AUC of these two scores were additionally compared with the AUC of the PREVENT III and Finnvasc scales. RESULTS: Six hundred and seventy two cases with an average surveillance of 778 days were included in the study. Amputation free survival (AFS) was 84.8% at 30 days and 63.1% at 1 year. Variables associated with death and/or major amputation in the Cox regression were cerebrovascular disease, prior contralateral major amputation, diabetes mellitus, dialysis, chronic obstructive pulmonary disease, cancer, haematocrit less than 30%, neutrophil/lymphocyte ratio exceeding 5, absence of arterial Doppler signal at the ankle, emergency admission, and Rutherford stage 6; these variables were used for the ERICVA and simplified ERICVA score designs. Scores were applied to both subsamples; in the development sample the AUC of ERICVA and simplified ERICVA was significantly higher than the PREVENT III (p = .008 and p = .045) and Finnvasc (p < .0001 and p = .0013) scores; in the validation sample the AUC of ERICVA and simplified ERICVA were significantly higher than Finnvasc score (p = .0323 and p = .0017). CONCLUSIONS: The ERICVA model has a good predictive capacity for death and/or major amputation in the clinical setting, and is better than the PREVENT III and Finnvasc scores. PMID- 26602224 TI - The implication of pro-inflammatory cytokines in the impaired production of gonadal androgens by patients with pulmonary tuberculosis. AB - BACKGROUND: The chronic nature of tuberculosis and the protracted immuno inflammatory reactions are implied in a series of metabolic and immune-endocrine changes accompanying the disease. We explored components from the hypothalamous pituitary-gonadal axis and their relationship with cytokines involved in disease immunopathology, in male TB patients. METHODS: Plasma samples from 36 active untreated pulmonary TB male patients were used to determine TNF-alpha, IFN-gamma, TGF-beta, IL-6, cortisol, dehydroepiandrosterone, testosterone, progesterone, estradiol, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by ELISA. Healthy controls corresponded to 21 volunteers without contact with TB patients and similar age (40 +/- 16,8 years). Testicular histological samples from necropsies of patients dying from TB were immune-stained for IL-1beta, TNF alpha, IL-6 and IFN-gamma. The TM3 mouse Leydig cell line was incubated with recombinants TNF-alpha, IFN-gamma and TGF-beta, supernatants were collected and used to measure testosterone by ELISA. RESULTS: Patients showed decreased levels of testosterone in presence of high amounts of LH, together with augmented IFN gamma, IL-6 and TGF-beta levels. Testicular histological sections showed abundant presence of IL-1beta, TNF-alpha, IL-6 and IFN-gamma in interstitial macrophages, Sertoli cells and some spermatogonia. In vitro treatment of Leydig cells with these cytokines led to a remarkable reduction of testosterone production. PMID- 26602225 TI - Executive Function: Comparing Bilingual and Monolingual Iranian University Students. AB - The study aimed to examine whether Kurdish-Persian early Bilingual university students (EBL) and Persian Monolingual university students (ML) differ on tasks of executive function (EF). Thirty male EBL and 30 male ML students from Ferdowsi University of Mashhad completed a Persian Stroop Color-Word task (SCWT), Backward Digit Span Test (BDST), Raven Standard Progressive Matrices, and a demographic questionnaire. The results of an analysis of variance showed EBL students responded faster on the SCWT compared with ML students, suggesting an inhibition advantage for EBL students. Moreover, mean scores of BDST showed better performance of EBL students in working memory than ML students. These results provided evidence of advantaged EF among EBL and were consistent with the possibility that individuals who began speaking a second language (L2) earlier in childhood have greater advantages, due either to effects of acquiring an L2 earlier or to a longer duration of bilingual experience. PMID- 26602226 TI - How capping protein enhances actin filament growth and nucleation on biomimetic beads. AB - Capping protein (CP), which caps the growing ends of actin filaments, accelerates actin-based motility. Recent experiments on biomimetic beads have shown that CP also enhances the rate of actin filament nucleation. Proposed explanations for these phenomena include (i) the actin funneling hypothesis (AFH), in which the presence of CP increases the free-actin concentration, and (ii) the monomer gating model, in which CP binding to actin filament barbed ends makes more monomers available for filament nucleation. To establish how CP increases the rates of filament elongation and nucleation on biomimetic beads, we perform a quantitative modeling analysis of actin polymerization, using rate equations that include actin filament nucleation, polymerization and capping, as modified by monomer depletion near the surface of the bead. With one adjustable parameter, our simulation results match previously measured time courses of polymerized actin and filament number. The results support a version of the AFH where CP increases the local actin monomer concentration at the bead surface, but leaves the global free-actin concentration nearly constant. Because the rate of filament nucleation increases with the monomer concentration, the increased local monomer concentration enhances actin filament nucleation. We derive a closed-form formula for the characteristic CP concentration where the local free-actin concentration reaches half the bulk value, and find it to be comparable to the global Arp2/3 complex concentration. We also propose an experimental protocol for distinguishing branching nucleation of filaments from spontaneous nucleation. PMID- 26602227 TI - Right Atrial Calcified Ball Thrombus Mimicking a Myxoma. AB - An 80-year-old woman was admitted to our hospital because of congestive heart failure. Transthoracic echocardiography revealed severe aortic valve stenosis, and a mobile calcified mass was attached to the interatrial septum in the right atrium. We suspected that the mass was cardiac myxoma. We urgently performed aortic valve replacement and resection of the mass. The histological diagnosis of the mass was thrombus, and her post-operative course was uneventful. Although the mechanism of right atrial thrombus formation in our case was unclear, it is important to continue anticoagulation therapy after surgery to avoid recurrence. Furthermore, strict follow-up in this patient is needed. PMID- 26602228 TI - Percutaneous Coronary Intervention for Coronary Thrombo-embolism during Balloon Mitral Valvuloplasty in a Pregnant Woman. AB - Coronary embolism as a cause of acute myocardial infarction is considered rarer than it actually is because of the difficulties associated with its documentation. Equally rare is the event of a clot embolising to the coronary artery during balloon mitral valvuloplasty (BMV). We had a unique and a rare opportunity to encounter, recognise, document and successfully manage this rare complication during BMV in a pregnant woman. PMID- 26602229 TI - Personality disorders among Spanish prisoners starting hepatitis C treatment: Prevalence and associated factors. AB - The purpose of this study was to assess the prevalence of personality disorders (PDs) and their associated factors in prisoners who initiate chronic hepatitis C (CHC) treatment in 25 Spanish prisons. The Personality Diagnostic Questionnaire-4 was used to diagnose PDs according to DSM-IV criteria. Factors potentially associated with a PD diagnosis were evaluated by logistic regression analysis. Two hundred and fifty-five patients were initially assessed and 62 (24.3%) were excluded due to an incomplete or invalid self-report screening questionnaire. PD prevalence was 70.5%, with antisocial PD being the most prevalent (46.1%). In terms of PD clusters, the most prevalent was cluster-B (55.4%). PD diagnosis was associated with HCV genotypes 1, 2, or 3 (odds ratio [OR] 2.14, 95% confidence interval [CI] 1.02-4.49). Patients with a cluster-B PD were more likely to be infected with HCV genotypes 1, 2, or 3 (OR 2.37, 95% CI 1.08-5.23) and be HIV infected (OR 2.20, 95% CI 1.10-4.39), to report past-year injection drug use (OR 7.17, 95% CI 1.49-34.58), and to have stage 3 or 4 fibrosis (OR 2.16, 95% CI 1.06 4.49). The prevalence of PDs in Spanish prisoners who initiate CHC treatment is very high. PD management issues should be considered in treating CHC patients in prisons. PMID- 26602231 TI - Neurocognitive functioning as an intermediary variable between psychopathology and insight in schizophrenia. AB - Based on the neuropsychological deficit model of insight in schizophrenia, we constructed exploratory prediction models for insight, designating neurocognitive measures as the intermediary variables between psychopathology and insight into patients with schizophrenia. The models included the positive, negative, and autistic preoccupation symptoms as primary predictors, and activation symptoms as an intermediary variable for insight. Fifty-six Korean patients, in the acute stage of schizophrenia, completed the Positive and Negative Syndrome Scale, as well as a comprehensive neurocognitive battery of tests at the baseline, 8-weeks, and 1-year follow-ups. Among the neurocognitive measures, the Korean Wechsler Adult Intelligence Scale (K-WAIS) picture arrangement, Controlled Oral Word Association Test (COWAT) perseverative response, and the Continuous Performance Test (CPT) standard error of reaction time showed significant correlations with the symptoms and the insight. When these measures were fitted into the model as intermediaries between the symptoms and the insight, only the perseverative response was found to have a partial mediating effect - both cross-sectionally, and in the 8-week longitudinal change. Overall, the relationship between insight and neurocognitive functioning measures was found to be selective and weak. PMID- 26602230 TI - Adjuvant pioglitazone for unremitted depression: Clinical correlates of treatment response. AB - Previous studies suggest that insulin-sensitizing agents could play a significant role in the treatment of major depression, particularly depression in patients with documented insulin resistance or those who are resistant to standard psychopharmacological approaches. This study aimed to assess the effects on depressive symptoms with adjuvant treatment with the PPARgamma-agonist pioglitazone. Patients (N=37) with non-psychotic, non-remitting depression receiving standard psychiatric regimens for depression were randomized across an insulin sensitivity spectrum in a 12-week double blind, randomized controlled trial of pioglitazone or placebo. Improvement in depression was associated with improvement in glucose metabolism but only in patients with insulin resistance. An age effect was also shown in that response to pioglitazone was more beneficial in younger aged patients. Study findings suggest differential improvement in depression severity according to both glucose metabolic status and level of depression at baseline. A greater understanding of the reciprocal links between depression and IR may lead to a dramatic shift in the way in which depression is conceptualized and treated, with a greater focus on treating and/or preventing metabolic dysfunction. PMID- 26602232 TI - Development of male sterile Eruca sativa carrying a Raphanus sativus/Brassica oleracea cybrid cytoplasm. AB - KEY MESSAGE: Alloplasmic male sterile breeding lines of Eruca sativa were developed by intergeneric hybridization with CMS- Brassica oleracea, followed by recurrent backcrosses and determination of the breeding value. ABSTRACT: Male sterile breeding lines of rocket salad (Eruca sativa) were developed by intergeneric hybridization with cytoplasmic male sterile (CMS) cauliflower (Brassica oleracea) followed by recurrent backcrosses. Five amphidiploid F1 plants (2n = 2x = 20, CE), achieved by manual crosses and embryo rescue, showed an intermediate habit. The plants were completely male sterile and lacked seed set after pollination with the Eruca parent. Allotetraploid F1-hybrid plants (4n = 4x = 40, CCEE) obtained after colchicine treatment were backcrossed six times with pollen of the Eruca parent to select alloplasmic diploid E. sativa lines. The hybrid status and the nucleo-cytoplasmic constellation were continuously controlled by RAPD and Southern analysis during subsequent backcrosses. The ploidy level was investigated by flow cytometry and chromosome analysis. Premeiotic (sporophytic) and postmeiotic (pollen abortive) defects during the anther development were observed in the alloplasmic E. sativus plants in comparison to the CMS-cauliflower donor. No further incompatibilities were noticed between the CMS-inducing cybrid cytoplasm and the E. sativa nuclear genome. The final alloplasmic E. sativa lines were diploid with 2n = 2x = 22 chromosomes and revealed complete male sterility and restored female fertility. Plant vigor and yield potential of the CMS-E. sativa BC5 lines were comparable to the parental E. sativus line. In conclusion, the employed cybrid-cytoplasm has been proven as a vital source of CMS for E. sativa. The developed lines are directly applicable for hybrid breeding of rocket salad. PMID- 26602233 TI - TaXA21-A1 on chromosome 5AL is associated with resistance to multiple pests in wheat. AB - KEY MESSAGE: The wheat ortholog of the rice gene OsXA21 against bacterial leaf blight showed resistance to multiple pests in bread wheat but different interacting proteins. ABSTRACT: A quantitative trait locus QYr.osu-5A on the long arm of chromosome 5A in bread wheat (Triticum aestivum L., 2n = 6x = 42; AABBDD) was previously reported to confer consistent resistance in adult plants to predominant stripe rust races, but the gene causing the quantitative trait locus (QTL) is not known. Single-nucleotide polymorphism (SNP) markers were used to saturate the QTL region. Comparative and syntenic regions between wheat and rice (Oryza sativa) were applied to identify candidate genes for QYr.osu-5A. TaXA21 A1, which is referred to as a wheat ortholog of OsXA21-like gene on chromosome 9 in rice, was mapped under the peak of the QYr.osu-5A. TaXA21-A1 not only explained the phenotypic variation in reaction to different stripe rust races but also showed significant effects on resistance to powdery mildew and Hessian fly biotype BP. The natural allelic variation resulted in the alternations of four amino acids in deduced TaXA21-A1 proteins. The interacting proteins of TaXA21-A1 were different from those identified by OsXA21 on rice chromosome 11 against bacterial leaf blight. TaXA21-A1 confers unique resistance against multiple pests in wheat but might not have common protein interactors or thus overlapping functions with OsXA21 in rice. XA21 function has diverged during evolution of cereal crops. The molecular marker developed for TaXA21-A1 would accelerate its application of the candidate gene at the QYr.osu-5A locus in wheat breeding programs. PMID- 26602234 TI - Genome-wide linkage mapping of flour color-related traits and polyphenol oxidase activity in common wheat. AB - KEY MESSAGE: Fifty-six QTL for flour color-related traits and polyphenol oxidase activity were identified using a genome-wide linkage mapping of data from a RIL population derived from a Gaocheng 8901/Zhoumai 16 cross. ABSTRACT: Flour color related traits, including L*, a*, b*, yellow pigment content (YPC), and polyphenol oxidase (PPO) activity are important parameters influencing the quality of wheat end-use products. Mapping quantitative trait loci (QTL) for these traits and characterization of candidate genes are important for improving wheat quality. The aims of this study were to identify QTL for flour color related traits and PPO activity and to characterize candidate genes using a high density genetic linkage map in a common wheat recombinant inbred line (RIL) population derived from a cross between Gaocheng 8901 and Zhoumai 16. A linkage map was constructed by genotyping the RILs with the wheat 90 K iSelect array. Fifty-six QTL were mapped on 35 chromosome regions on homoeologous groups 1, 2, 5 and 7 chromosomes, and chromosomes 3B, 4A, 4B and 6B. Four QTL were for PPO activity, and the others were for flour color-related traits. Compared with previous studies, five QTL for a*, two for b*, one for L*, one for YPC and one for PPO activity were new. The new QTL on chromosome 2DL was involved in both a* and YPC, and another on chromosome 7DS affected both a* and L*. The scan for SNP sequences tightly linked to QTL for flour color-related traits against the wheat and/or related cereals genomes identified six candidate genes significantly related to these traits, and five of them were associated with the terpenoid backbone biosynthesis pathway. The high-density genetic linkage map of Gaocheng 8901/Zhoumai 16 represents a useful tool to identify QTL for important quality traits and candidate genes. PMID- 26602235 TI - Preoperative predictive factors for surgical and functional outcomes in chronic subdural hematoma. AB - BACKGROUND: Chronic subdural hematoma (CSDH) is a frequently encountered neurosurgical condition, especially in the elderly. We investigated predictive factors for surgical and functional outcomes after burr-hole drainage (BHD) surgery. METHODS: All patients with CSDH treated by BHD between January 2012 and December 2014 were included in this study. All patients were classified by symptom, clinical grade, time, location, hematoma density, midline shift, and other characteristics. Pre- and postoperative CT evaluation was performed at 0, 3, and 6 months. Clinical grades were classified as described in Markwalder et al. Surgical and clinical outcomes were evaluated with the brain expansion rate and modified Rankin Scale (mRS). Brain expansion rate was calculated as the ratio between post- and pre-operative hematoma thickness. Recurrence was defined as the occurrence of symptoms and hematoma on CT within 6 months. RESULTS: This study included 130 patients over 2 years. Among the variable parameters, young age (<75), iso-density of hematoma on CT, and short duration from symptom to surgery were correlated with good brain expansion. Patients with good brain expansion had fewer recurrences. In terms of mRS, young age, iso-density, and good clinical grade were correlated with good functional outcomes. CONCLUSIONS: Clinicians should be more aware of general conditions and medical problems, especially in elderly patients. Membranectomy should be considered in patients with a long duration of symptoms or hypo-dense hematomas to promote good brain expansion and good mRS scores. PMID- 26602236 TI - The effect of dopaminergic therapy on intraoperative microelectrode recordings for subthalamic deep brain stimulation under GA: can we operate on patients 'on medications'? AB - OBJECTIVES: Microelectrode recording (MER) plays an important role in target refinement in deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD). Traditionally, patients were operated on in the 'off medication' state to allow intraoperative assessment of the patient response to direct STN stimulation. The development of intraoperative microelectrode recording (MER) has facilitated the introduction of general anaesthesia (GA). However, the routine withdrawal of dopaminergic medications has remained as standard practice. This retrospective review examines the effect of continuing these medications on intraoperative MER for subthalamic DBS insertion under GA and discusses the clinical implication of this approach. METHODS: Retrospective review of PD patients who had bilateral STN DBS insertion was conducted. A cohort of seven patients (14 STN microelectrodes) between 2012 and 2013, who inadvertently underwent the procedure while 'on medication', was identified. This 'on-medication' group was compared to all other patients who underwent the same procedure between 2012 and 2013 and had their medications withdrawn preoperatively, the 'off-medication' group, n = 26 (52 STN DBS). The primary endpoint was defined as the number of microelectrode tracks required to obtain adequate STN recordings. A second endpoint was the length of MERs that was finally used to guide the DBS lead insertion. The Reduction of the levo-dopa equivalent daily dose (LEDD) was also examined as a surrogate marker for clinical outcome 12 months postoperatively for both groups. For the on-medication group further analysis of the clinical outcome was done relying on the change in the motor examination at 12 months following STN DBS using the following parameters (Hoehn and Yahr scale, the number of waking hours spent in the OFF state as well as the duration of dyskinesia during the ON periods). RESULTS: The on-medication group was statistically comparable in all baseline characteristics to the off medication group, including age at operation 57 +/- 9.9 years vs. 61.5 +/- 9.2 years, p = 0.34 (mean +/- SD); duration of disease (11.6 +/- 5 years vs. 11.3 +/- 4 years, p = 0.68); gender F:M ratio (1:6 vs. 9:17, p = 0.40). Both groups had similar PD medication regimes preoperatively expressed as levodopa equivalent daily dose (LEDD) 916 mg (558-1850) vs. 744 mg (525-3591), respectively, p = 0.77. In the on-medication group, all seven patients (14 STN electrodes) had satisfactory STN recording from a single brain track versus 15 out of 26 patients (57.7 %) in the off-medication group, p = 0.06. The length of MER was 4.5 mm (3.0 5.5) in the on-medication group compared to 3.5 mm (3.0-4.5) in the off medication group, p = 0.16. The percentage of reduction in LEDD postoperatively for the on-medication group was comparable to that in the off-medication group, 62 % versus 58 %, respectively, p > 0.05. All patients in the on-medication group had clinically significant improvement in their PD motor symptoms as assessed by the Hoehn and Yahr scale; the number of hours (of the waking day) spent in the OFF state dropped from 6.9 (+/-2.3) h to 0.9 (+/-1.6) h; the duration of dyskinesia during the ON state dropped from 64 % (+/-13 %) of the ON period to only 7 % (+/-12 %) at 12 months following STN DBS insertion. CONCLUSION: STN DBS insertion under GA can be performed without the need to withdraw dompaminergic treatment preoperatively. In this review the inadvertent continuation of medications did not affect the physiological localisation of the STN or the clinical effectiveness of the procedure. The continuation of dopamine therapy is likely to improve the perioperative experience for PD patients, avoid dopamine withdrawal complications and improve recovery. A prospective study is needed to verify the results of this review. PMID- 26602237 TI - Effects of preventive surgery for unruptured intracranial aneurysms on attention, executive function, learning and memory: a prospective cohort study. AB - BACKGROUND: We prospectively evaluated the effects of preventive surgery for unruptured intracranial aneurysms on attention, executive function, learning and memory. METHODS: Between March 2012 and June 2013, 56 patients were recruited for this study. Fifty-one patients met the inclusion criteria and were enrolled. Inclusion criteria were as follows: (1) age <=65 years and (2) planned microsurgery or endovascular surgery for unruptured intracranial aneurysm. Exclusion criteria were as follows: (1) preoperative intelligence quotient <80 (n = 3); (2) initial modified Rankin scale >=1 (n = 1); (3) loss to follow-up (n = 1). An auditory controlled continuous performance test (ACCPT), word-color test (WCT) and verbal learning test (VLT) were performed before and after (6 months) preventive surgery. RESULTS: ACCPT (attention), WCT (executive function) and VLT (learning and memory) scores did not change significantly between the pre- and postoperative evaluations. The ACCPT, WCT, total VLT scores (verbal learning) and delayed VLT scores (memory) did not differ significantly between patients undergoing microsurgery and those undergoing endovascular surgery. However, ACCPT, WCT and delayed VLT scores decreased postoperatively in patients with leukoaraiosis on preoperative FLAIR images (OR 9.899, p = 0.041; OR 11.421, p = 0.006; OR 2.952, p = 0.024, respectively). CONCLUSIONS: Preventive surgery for unruptured intracranial aneurysms did not affect attention, executive function, learning or memory. However, patients with leukoaraiosis on FLAIR images might be prone to deficits in attention, executive function and memory postoperatively, whereas learning might not be affected. PMID- 26602238 TI - Teaching nursing students about terminating professional relationships, boundaries, and social media. AB - Nurse educators should teach students about the nature of the nurse-patient relationship, which is a professional relationship and different from other relationships they have. In addition to teaching students how to establish relationships with their patients, nurse educators should also teach students about terminating relationships with patients. Without this professional guidance, nursing students may be tempted to use social media to maintain a relationship with patients. This may inadvertently lead to professional boundary violations, causing harm to patients and problems for nursing students or nurses. PMID- 26602239 TI - Development, implementation, and evaluation of a mental rehearsal strategy to improve clinical performance and reduce stress: A mixed methods study. AB - BACKGROUND: Mental rehearsal is a form of mental training that has been used by physicians and nurses to improve performance of clinical skills, and as a vital component of stress management training. To help novice nurses deal with often stressful clinical events that require the processing of information essential to patient management, a mental rehearsal strategy was developed and implemented in a Year 3 nursing simulation program. Inherent to mental rehearsal is imagery, which facilitates cognitive and affective modification, and reduction of extraneous cognitive load. As such, it was expected that the mental rehearsal strategy would improve students' performance and reduce stress in managing deteriorating patients. METHODS: The study used a mixed methods design. Eighteen Year 3 nursing students participated in the pre- and post-design study, which consisted of the development and implementation of a mental rehearsal strategy. The Rescuing A Patient In Deteriorating Situations (RAPIDS) tool was used to assess performance. Heart rates and systolic blood pressures were used to measure stress. The State-Trait Anxiety Inventory (STAI) was used as a psychological measure of stress/anxiety. Five participants were involved in a focus group discussion that evaluated the usefulness of the mental rehearsal strategy. RESULTS: There was a significant improvement in performance (P<0.05). However, post-test heart rate and systolic blood pressure were not significantly different from pre-test measures. A comparison of STAI results did not show significant differences between pre- and post-test state anxiety and pre- and post-test trait anxiety. Three themes emerged from the focus group interview: managing stress, using a mental framework, and integrating realistic simulations with the mental rehearsal strategy. CONCLUSION: The mental rehearsal strategy for deteriorating patient management can be valuable based on the findings on performance and based on the participants' feedback. Its role in reducing stress, however, needs further evaluation. PMID- 26602240 TI - Association of triage time Shock Index, Modified Shock Index, and Age Shock Index with mortality in Emergency Severity Index level 2 patients. AB - BACKGROUND: Shock Index (SI) is considered to be a predictor of mortality in many medical and trauma settings. Many studies have shown its superiority to conventional vital sign measurements in mortality prediction. OBJECTIVES: The objectives were to compare mortality and intensive care unit admission prediction of triage time SI, Modified SI (MSI), and Age SI with each other and with triage time blood pressure in Emergency Severity Index (ESI) level 2 patients. METHODS: A retrospective medical record review was performed in the internal medicine emergency department of a general hospital in Kerman, Iran. Triage time vital signs were used to calculate the indices. Multivarible regression analysis was used to create the final model. RESULTS: A total of 1285 patients triaged to ESI level 2 were enrolled in the study. In the multivariate analysis, SI, MSI, and Age SI were found to be the only variables independently associated with mortality, whereas none of them were associated with intensive care unit admission. Sensitivity, specificity, and area under curve in the receiver operating characteristic curve for the model including SI, MSI, and Age SI were 60.8%, 65.4%, and 0.675, respectively. Sensitivity, specificity, and area under curve did not change significantly by excluding SI, MSI, or Age SI from the final model. CONCLUSION: In nontrauma adult patients, triage time SI, MSI, and Age SI are superior to blood pressure for mortality prediction in ESI level 2. They can be used alone or in combination with similar results, but their low sensitivity and specificity make them usable only as an adjunct for this purpose. PMID- 26602241 TI - Is this the next step for CPR? PMID- 26602242 TI - Carboxyl-functionalized polyurethane nanoparticles with immunosuppressive properties as a new type of anti-inflammatory platform. AB - The interaction of nanoparticles (NPs) with the body immune system is critically important for their biomedical applications. Most NPs stimulate the immune response of macrophages. Here we show that synthetic polyurethane nanoparticles (PU NPs, diameter 34-64 nm) with rich surface COO(-) functional groups (zeta potential -70 to -50 mV) can suppress the immune response of macrophages. The specially-designed PU NPs reduce the gene expression levels of proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) for endotoxin-treated macrophages. The PU NPs increase the intracellular calcium of macrophages (4.5-6.5 fold) and activate autophagy. This is in contrast to the autophagy dysfunction generally observed upon NP exposure. These PU NPs may further decrease the nuclear factor kappaB-related inflammation via autophagy pathways. The immunosuppressive activities of PU NPs can prevent animal death by inhibiting the macrophage recruitment and proinflammatory responses, confirmed by an in vivo zebrafish model. Therefore, the novel biodegradable PU NPs demonstrate COO(-) dependent immunosuppressive properties without carrying any anti-inflammatory agents. This study suggests that NP surface chemistry may regulate the immune response, which provides a new paradigm for potential applications of NPs in anti-inflammation and immunomodulation. PMID- 26602243 TI - BMI and FFMI do not seem universally applicable in nutritional assessment and the usefulness of SGA and functional evaluation should not be overlooked. PMID- 26602244 TI - Very-low-fat diets may be associated with increased risk of metabolic syndrome in the adult population. AB - BACKGROUND & AIMS: Although fat intake has often been targeted to decrease the prevalence of metabolic syndrome; however decreasing dietary fat intake has not had this result. We studied the association between fat intake and the prevalence of metabolic syndrome in adults using KNHANES 2007-2013 data, a representative sample of the non-institutionalized civilian population. METHODS: This cross sectional study included 34,003 Korean adults aged >=19 years. Adjusted odds ratios (OR) for the components of metabolic syndrome were measured according to fat intake (<=15, 15-25, >=25% of daily energy intake) while controlling for covariates that affect metabolic syndrome using linear and logistic regression analysis while incorporating the sample weights for the complex sample design of the survey. RESULTS: Surprisingly, the prevalence of metabolic syndrome was significantly higher in the <=15% fat intake group (OR = 1.277), accompanied by lower daily energy intake compared to the reference group (>=25% fat intake). Higher daily fat intake was associated with significantly lower ORs for four components of metabolic syndrome, except diabetes mellitus, using continuous variable analysis, whereas only three serum components (serum HDL, serum triglyceride, and blood pressure) exhibited significantly higher ORs in the lowest tertile of dietary fat intake (<=15%) compared with the reference group (>=25% fat-intake tertile). Subjects in a low-fat intake group had about 6.0 g polyunsaturated fatty acid/day that did not meet the recommended intake. Consumption of grain groups was a significant predictor of low fat intake, whereas milk food groups were significant predictors of not having low fat intake. Subjects in the low-fat group (<=15%) had much lower daily energy intake, by 500 kcal, compared with subjects who consumed high-fat diets (>=25%). All nutrients except carbohydrates had significantly lower mean values in the low-fat intake group as compared to the high-fat-intake group. CONCLUSIONS: Low fat intake, <15%, was associated with a higher incidence of metabolic syndrome in the adult population, despite the daily energy intakes being lower by 500 kcal and the intakes with proper ratio (1:1.03:1.01) of saturate, monounsaturated and polyunsaturated fatty acid; this may be related to lower intake of various nutrients other than carbohydrates. PMID- 26602245 TI - Association between day of delivery and obstetric outcomes: observational study. AB - STUDY QUESTION: What is the association between day of delivery and measures of quality and safety of maternity services, particularly comparing weekend with weekday performance? METHODS: This observational study examined outcomes for maternal and neonatal records (1,332,835 deliveries and 1,349,599 births between 1 April 2010 and 31 March 2012) within the nationwide administrative dataset for English National Health Service hospitals by day of the week. Groups were defined by day of admission (for maternal indicators) or delivery (for neonatal indicators) rather than by day of complication. Logistic regression was used to adjust for case mix factors including gestational age, birth weight, and maternal age. Staffing factors were also investigated using multilevel models to evaluate the association between outcomes and level of consultant presence. The primary outcomes were perinatal mortality and-for both neonate and mother-infections, emergency readmissions, and injuries. STUDY ANSWER AND LIMITATIONS: Performance across four of the seven measures was significantly worse for women admitted, and babies born, at weekends. In particular, the perinatal mortality rate was 7.3 per 1000 babies delivered at weekends, 0.9 per 1000 higher than for weekdays (adjusted odds ratio 1.07, 95% confidence interval 1.02 to 1.13). No consistent association between outcomes and staffing was identified, although trusts that complied with recommended levels of consultant presence had a perineal tear rate of 3.0% compared with 3.3% for non-compliant services (adjusted odds ratio 1.21, 1.00 to 1.45). Limitations of the analysis include the method of categorising performance temporally, which was mitigated by using a midweek reference day (Tuesday). Further research is needed to investigate possible bias from unmeasured confounders and explore the nature of the causal relationship. WHAT THIS STUDY ADDS: This study provides an evaluation of the "weekend effect" in obstetric care, covering a range of outcomes. The results would suggest approximately 770 perinatal deaths and 470 maternal infections per year above what might be expected if performance was consistent across women admitted, and babies born, on different days of the week. FUNDING, COMPETING INTERESTS, DATA SHARING: The research was partially funded by Dr Foster Intelligence and the National Institute for Health Research (NIHR) Imperial Patient Safety Translational Research Centre in partnership with the Health Protection Research Unit (HPRU) in Healthcare Associated Infection and Antimicrobial Resistance at Imperial College London. WLP was supported by the National Audit Office. PMID- 26602246 TI - The Behavioral Neuroscience of Motivation: An Overview of Concepts, Measures, and Translational Applications. AB - Motivation, defined as the energizing of behavior in pursuit of a goal, is a fundamental element of our interaction with the world and with each other. All animals share motivation to obtain their basic needs, including food, water, sex and social interaction. Meeting these needs is a requirement for survival, but in all cases the goals must be met in appropriate quantities and at appropriate times. Therefore motivational drive must be modulated as a function of both internal states as well as external environmental conditions. The regulation of motivated behaviors is achieved by the coordinated action of molecules (peptides, hormones, neurotransmitters etc), acting within specific circuits that integrate multiple signals in order for complex decisions to be made. In the past few decades, there has been a great deal of research on the biology and psychology of motivation. This work includes the investigation of specific aspects of motived behavior using multiple levels of analyses, which allows for the identification of the underpinning neurobiological mechanisms that support relevant psychological processes. In this chapter we provide an overview to the volume "The Behavioural Neuroscience of Motivation". The volume includes succinct summaries of; The neurobiology of components of healthy motivational drive, neural measures and correlates of motivation in humans and other animals as well as information on disorders in which abnormal motivation plays a major role. Deficits in motivation occur in a number of psychiatric disorders, affecting a large population, and severe disturbance of motivation can be devastating. Therefore, we also include a section on the development of treatments for disorders of motivation. It is hoped that the collection of reviews in the volume will expose scientists to a breadth of ideas from several different subdisciplines, thereby inspiring new directions of research that may increase our understanding of motivational regulation and bring us closer to effective treatments for disorders of motivation. PMID- 26602247 TI - Social Odors: Alarm Pheromones and Social Buffering. AB - In this chapter, I describe 2 types of olfactory communication in rats, which appear to arouse anxiety and relief, respectively. In alarm pheromonal communication, rats release 4-methylpentanal and hexanal from their perianal region when they are stressed. These molecules activate the anxiety circuit, including the bed nucleus of the stria terminalis, when 4-methylpentanal and hexanal are simultaneously detected by the vomeronasal system and the main olfactory system, respectively. Consequently, recipient rats show a variety of anxiety responses, depending on the threatening stimuli. In appeasing olfactory communication, non-stressed rats release an appeasing olfactory signal, which is detected by the main olfactory system of other rats. When detected, this olfactory signal suppresses activation of the basolateral complex of the amygdala and, as a result, ameliorates stress responses elicited by an auditory conditioned stimulus during social buffering phenomenon. Because social buffering appears to be based on affinity and attachment to accompanying animals, the appeasing olfactory signal may arouse relief in rats. A definition of social buffering is also proposed as we still have no set definition for the term social buffering yet. PMID- 26602248 TI - Genetic Animal Models for Autism Spectrum Disorder. AB - Autism spectrum disorder (ASD) affects approximately 1 % of the human population and has a strong genetic component. Hence, the recent discovery of major "ASD genes" has subsequently resulted in the generation of several genetic animal models of ASD. Careful analysis of behavioral phenotypes and characterization of the underlying neurobiological mechanisms in these models should further help us to identify novel therapeutic targets and develop more effective strategies in the future to ameliorate or even reverse core symptoms and comorbidities of ASD. In this review, we will focus on the mutant mouse as animal model and outline how to characterize both behavioral and neurobiological phenotypes in this organism. We will further discuss a selection of major ASD mutant mouse lines. Our conclusions will finally address the current goals and perspectives in the field to obtain a more comprehensive and possibly also converging picture of ASD pathogenesis, which could be most useful for the desired bench-to-bedside strategy of translational medicine for this complex disorder. PMID- 26602249 TI - Models, Mechanisms and Moderators Dissociating Empathy and Theory of Mind. AB - Most instances of social interaction provide a wealth of information about the states of other people, be it sensations, feelings, thoughts, or convictions. How we represent these states has been a major question in social neuroscience, leading to the identification of two routes to understanding others: an affective route for the direct sharing of others' emotions (empathy) that involves, among others, anterior insula and middle anterior cingulate cortex and a cognitive route for representing and reasoning about others' states (Theory of Mind) that entails, among others, ventral temporoparietal junction and anterior and posterior midline regions. Additionally, research has revealed a number of situational and personal factors that shape the functioning of empathy and Theory of Mind. Concerning situational modulators, it has been shown, for instance, that ingroup membership enhances empathic responding and that Theory of Mind performance seems to be susceptible to stress. Personal modulators include psychopathological conditions, for which alterations in empathy and mentalizing have consistently been demonstrated; people on the autism spectrum, for instance, are impaired specifically in mentalizing, while spontaneous empathic responding seems selectively reduced in psychopathy. Given the multifaceted evidence for separability of the two routes, current research endeavors aiming at fostering interpersonal cooperation explore the differential malleability of affective and cognitive understanding of others. PMID- 26602250 TI - Assessment of pharmacokinetic compatibility of short acting CDRI candidate trioxane derivative, 99-411, with long acting prescription antimalarials, lumefantrine and piperaquine. AB - The pharmacokinetic compatibility of short-acting CDRI candidate antimalarial trioxane derivative, 99-411, was tested with long-acting prescription antimalarials, lumefantrine and piperaquine. LC-ESI-MS/MS methods were validated for simultaneous bioanalysis of lumefantrine and 99-411 and of piperaquine and 99 411 combinations. The interaction studies were performed in rats using these validated methods. The total systemic exposure of 99-411 increased when administered with either lumefantrine or piperaquine. However, co-administration of 99-411 significantly decreased the systemic exposure of piperaquine by half fold while it had no effect on the kinetics of lumefantrine. 99-411, thus, seemed to be a good alternative to artemisinin derivatives for combination treatment with lumefantrine. To explore the reason for increased plasma levels of 99-411, an in situ permeability study was performed by co-perfusing lumefantrine and 99 411. In presence of lumefantrine, the absorption of 99-411 was significantly increased by 1.37 times than when given alone. Lumefantrine did not affect the metabolism of 99-411 when tested in vitro in human liver microsomes. Additionally, ATPase assay suggest that 99-411 was a substrate of human P-gp, thus, indicating the probability of interaction at the absorption level in humans as well. PMID- 26602251 TI - Analysis of short and long-term results of horizontal meniscal tears in young adults. AB - INTRODUCTION: Symptomatic horizontal meniscal tears are rare but worrisome lesions in young adults. These are overuse injuries not amenable to the classic arthroscopic sutures. An open meniscal repair allows the meniscal lesion to be suture vertically, perpendicular to its in the vascularized zone. The purpose of this study was to evaluate the short and long-term clinical and radiological outcomes of the aforementioned surgical technique. MATERIAL AND METHOD: The first cohort consisted of 24 patients operated between 2009 and 2011 (6 women, 18 men; mean age 26years) having 11 lateral and 13 medial meniscal tears. The second cohort was of 10 patients operated between 2001 and 2002 (3 women, 7 men; mean age 24years) having 8 lateral and 2 medial meniscal tears. Patients were reviewed at the last follow-up using the IKDC, Lysholm and KOOS scores. Patients in the first cohort had an MRI, while those in the second cohort had X-rays. RESULTS: Eighteen patients in the first cohort were reviewed with a mean follow-up of 2 years (12-45 months) and 9 patients from the second cohort were reviewed after 10years (97-142 months). In the first cohort, one patient required secondary menisectomy. The mean Lysholm score was 90 and the subjective IKDC was 85. Every MRI examination found reduced extent and intensity of the hyperintense signal. In the second cohort, no patients required secondary meniscectomy. Two patients had joint space narrowing (less than 50%) on radiographs. The mean Lysholm score was 99 and the subjective IKDC was 91. CONCLUSION: Open repair of horizontal meniscal tears in young adults leads to good subjective and objective results in the short term, which are maintained in the long-term. LEVEL OF EVIDENCE: Level IV - retrospective study. PMID- 26602252 TI - Meniscal survival rate after anterior cruciate ligament reconstruction. AB - BACKGROUND: Meniscal suture provides well-documented benefits. Integrity of the cruciate ligaments of the knee is a prerequisite for meniscal healing. Nevertheless, reconstruction of the anterior cruciate ligament (ACL) does not consistently prevent recurrent tearing of a sutured meniscus. We evaluated meniscal survival rates, 5 and 10 years after meniscal suture concomitant with an ACL reconstruction. We compared the outcomes of these repaired menisci to those in which no menisci tears were detected during ACL reconstruction. METHODS: In this multi-centric retrospective study, we included two groups. One group consists of patients who underwent a meniscal repair. This group was further divided into two subgroups based on whether follow-up was 5 years (n=76) or 10 years (n=39). The control group included 120 patients with normal menisci observed during surgery. We studied meniscal survival rates in each group, and we analyzed risk factors associated with the recurrence of meniscal lesions. RESULTS: The 5-year meniscal survival rate was significantly higher in the control group than in the meniscal-repair group (95% vs. 80%, respectively; P=0.0029). The controls group also had a higher meniscal survival rate after 10 years, although the difference was not statistically significant (88% vs. 77%, P=0.07). A difference in knee laxity greater than 4mm was associated with a 5 fold increase in the risk of recurrent meniscal tears (P=0.0057). After 5 years, the risk of recurrence was higher for the medial than for the lateral meniscus, whereas after 10 years the difference was no longer statistically significant. DISCUSSION: Although insufficient healing after meniscal suturing contributes to the risk of further meniscal tears, new lesions can develop in menisci that were undamaged at the time of ACL reconstruction. The risk of a new meniscal lesion is strongly associated with inadequate control of antero-posterior and rotational laxity. Some apparently "new menisci lesions" seems to have been missed during ACL reconstruction. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 26602254 TI - The sutureless valve redux: Innovation or hype? PMID- 26602253 TI - The Vocal Tract Discomfort Scale: Validity and Reliability of the Persian Version in the Assessment of Patients With Muscle Tension Dysphonia. AB - OBJECTIVE: To cross-culturally adapt of Persian Vocal Tract Discomfort (VTDp) scale and evaluate its validity and reliability in the assessment of patients with muscle tension dysphonia (MTD). STUDY DESIGN: A cross-sectional and prospective cohort design was used to psychometrically test the VTDp. METHODS: The VTD scale was cross-culturally adapted into Persian language following standard forward-backward translations. The VTDp scale was administrated to 100 patients with MTD (54 men and 46 women; mean age: 38.05 +/- 10.02 years) and 50 healthy volunteers (26 men and 24 women; mean age: 36.50 +/- 12.27 years). Forty five patients with MTD completed the VTDp 7 days later for test-retest reliability. Patients also completed the Persian Voice Handicap Index (VHIp) to assess construct validity. RESULTS: The results of discriminative validity demonstrated that the VTDp was able to discriminate between patients with MTD and healthy participants. The internal consistency was confirmed with Cronbach alpha .77 and 0.73 for VTDp frequency and severity subscales, respectively. The test retest reliability was excellent with an intraclass correlation coefficient (ICCagreement) of 0.93 for the frequency subscale and 0.91 for the severity subscale. Construct validity of the VTDp was shown with significant correlations between the VTDp frequency and severity subscales and the VHIp total scores (0.36 and 0.37, respectively). The standard error of measurement and smallest detectable change values for VTDp frequency (2.11 and 5.85, respectively) and severity (2.25 and 6.23, respectively) were acceptable. The Bland-Altman analysis for assessing the agreement between test and retest measurements showed no systematic bias. CONCLUSION: The VTDp is a valid and reliable self-administered scale to measure patient's vocal tract sensations in Persian-speaking population. PMID- 26602255 TI - Hybridizing the hybrid procedure. PMID- 26602256 TI - Is complex concomitant surgery justified or does it simply support guard rails? PMID- 26602257 TI - Right ventricle-to-pulmonary artery conduits: Do we really have an option? PMID- 26602258 TI - Aggressive surgical repair for ascending intramural hematoma is still a great option. PMID- 26602259 TI - Living longer and breathing better: Should we do transcatheter aortic valve replacement in patients who have severe chronic lung disease? PMID- 26602260 TI - Using social media: A way for us to sit at the table. PMID- 26602261 TI - The good, the bad, and the ugly: Contemporary options for biventricular support. PMID- 26602262 TI - Mitral valve replacement with a transcatheter valve in the setting of severe mitral annular calcification. PMID- 26602263 TI - Damned if you do or damned if you don't: Should heart allocation policy change for patients receiving prolonged durable mechanical support? PMID- 26602264 TI - Minimally invasive aortic valve replacement with sutureless valve is the appropriate treatment option for high-risk patients and the "real alternative" to transcatheter aortic valve implantation. PMID- 26602265 TI - Attenuation of Histone Methyltransferase KRYPTONITE-mediated transcriptional gene silencing by Geminivirus. AB - Although histone H3K9 methylation has been intensively studied in animals and a model plant Arabidopsis thaliana, little is known about the evolution of the histone methyltransferase and its roles in plant biotic stress response. Here we identified a Nicotiana benthamiana homolog of H3K9 histone methyltransferase KRYPTONITE (NbKYP) and demonstrated its fundamental roles on methylation of plant and virus, beside of leading to the suppression of endogenous gene expression and virus replication. NbKYP and another gene encoding DNA methyltransferase CHROMOMETHYLTRANSFERASE 3 (NbCMT3-1) were further identified as the key components of maintenance of transcriptional gene silencing, a DNA methylation involved anti-virus machinery. All three types of DNA methylations (asymmetric CHH and symmetric CHG/CG) were severely affected in NbKYP-silenced plants, but only severe reduction of CHG methylation found in NbCMT3-1-silenced plants. Attesting to the importance of plant histone H3K9 methylation immunity to virus, the virulence of geminiviruses requires virus-encoded trans-activator AC2 which inhibits the expression of KYP via activation of an EAR-motif-containing transcription repressor RAV2 (RELATED TO ABI3 and VP1). The reduction of KYP was correlated with virulence of various similar geminiviruses. These findings provide a novel mechanism of how virus trans-activates a plant endogenous anti silencing machinery to gain high virulence. PMID- 26602267 TI - Interventions to increase the uptake of seasonal influenza vaccination among pregnant women: A systematic review. AB - BACKGROUND: Pregnant women and their infants under 6 months of age infected with influenza have a high risk of serious morbidity and mortality. Influenza vaccine during pregnancy offers 3-for-1 benefits to pregnant women, fetuses and newborn infants. Current vaccination uptake rates during pregnancy, however, are often lower than other high-risk groups and the general population. METHODS: We systematically reviewed evidence on the effectiveness of interventions to improve influenza vaccination coverage in pregnant women. Risk differences (RDs) were calculated from the included studies. RESULTS: Eleven studies were included in the review, of which four were randomized controlled trials (RCTs). Three cohort studies assessed provider-focused interventions while four RCTs and one cohort study evaluated pregnant women-focused interventions. Two cohort studies and a prospective intervention study assessed the effectiveness of bundled interventions. No study solely assessed the effectiveness of interventions to enhance access to influenza vaccination. One moderate quality RCT showed that an influenza pamphlet, with or without a verbalized benefit statement, improved the vaccination rate (RD=0.26; RD=0.39). The other reviewed RCTs showed discordant results, with RDs ranging from -0.15 to 0.03. Although all observational studies significantly improved vaccination rates (RDs ranged from 0.03 to 0.44), the quality of the evidence varied. CONCLUSIONS: There is a lack of effective interventions to increase the influenza vaccination rate in pregnant women. Based on the existing research, we recommend that clinicians provide influenza pamphlets to pregnant women with a verbalized statement about the benefits of influenza vaccine to newborns. Further high-quality RCTs are needed to develop successful maternal influenza vaccination programs. Increased clarity in reporting the content of interventions would help to improve the comparability and generalizability of the published studies. PMID- 26602266 TI - Association of serotype with respiratory presentations of pneumococcal infection, Ontario, Canada, 2003-2011. AB - BACKGROUND: Pneumococcal disease burden is difficult to quantify due to limited data regarding non-bacteremic disease. We assessed serotype-specific differences in pneumococcal disease presentations in adults in Toronto, Canada. METHODS: From 2003 to 2011, population-based surveillance for invasive pneumococcal disease was conducted and respiratory pneumococcal isolates collected in Metropolitan Toronto/Peel Region, Canada. Episodes of care were classified into disease categories. RESULTS: Of 3105 eligible cases of IPD, 2060 cases were bacteremic pneumonia, and 1045 bacteremia without pneumonia. Of 2751 eligible respiratory cases, 1542 (56.0%) were non-bacteremic pneumonia (NBPP), 467 (17.0%) were other acute respiratory infection (oARI), and 742 (27.0%) were isolates representing colonization. Serotypes 3 (11.3%), 19A (8.4%) and 22F (6.2%) were the most common; serotypes 1,5, and 8 were rare. Serotypes 4, 14, 7F, 9V, 12F, 14, 19A and 6C were over-represented in bacteremic disease, and serotypes 3, 6A, 11A, 19F, 23A, 23F, 35B, 35F were more common in NBPP. The proportion of cases due to PCV7 serotypes declined from 48.7% to 8.7% in bacteremic pneumonia, from 35.3% to 10.9% in NBPP, from 34.2% to 7.5% in oARI, and from 38.7% to 12.2% in colonizing isolates. In 2010-2011, PCV13 serotypes accounted for 62.6% of isolates associated with bacteremic pneumonia, 42.0% of bacteremia without pneumonia, 41.1% of NBPP, 25.7% of oARI, and 32.9% of colonizing isolates. CONCLUSIONS: Serotype distributions differ significantly in different presentations of pneumococcal disease. Herd protection due to PCV7 has changed serotype distribution, but PCV13 serotypes remain important in all categories of disease. PMID- 26602268 TI - Serotypes, antimicrobial susceptibility, and molecular epidemiology of invasive and non-invasive Streptococcus pneumoniae isolates in paediatric patients after the introduction of 13-valent conjugate vaccine in a nationwide surveillance study conducted in Japan in 2012-2014. AB - Pneumococcal infection in children is a major public health problem worldwide, including in Japan. The pneumococcal conjugate vaccine 7 (PCV7) was licensed for use in Japan in 2010 followed by PCV13 in 2013. This report includes the results of a nationwide surveillance of invasive pneumococcal disease (IPD) and non-IPD in paediatric patients from January 2012 to December 2014. We collected 343 isolates from 337 IPD patients and 286 isolates from 278 non-IPD patients. Of the IPD isolates, the most identified serotypes included 19A, 24F, and 15A. The prevalence of non-PCV13 serotype isolates increased significantly from 2012 to 2014 (51.6-71.4%, p=0.004). Serotypes 19A, 15A and 35B were highly non susceptible to penicillin, and the rates of non-susceptible isolates from IPD patients to penicillin and cefotaxime significantly declined during the study period (p=0.029 and p=0.013, respectively). The non-susceptible rate to meropenem increased, particularly for serotype 15A. The IPD isolates comprised clonal complex (CC) 3111 (93.8% was serotype 19A) followed by CC2572 (81.5% was serotype 24F) and CC63 (97.1% was serotype 15A). CC3111, CC63 and CC156 (33.3% was serotype 23A, 28.6% was serotype 6B, and 14.3% was serotype 19A) were highly non susceptible to penicillin. Of the non-IPD isolates, the most identified serotypes included 19A, 15A, and 3. In conclusion, the introduction of PCV7 and PCV13 resulted in increasing non-PCV13 serotypes and clones, including antimicrobial resistant serotypes 15A and CC63 (Sweden(15A)-25 clone). PMID- 26602269 TI - Carriage of Streptococcus pneumoniae in asymptomatic, community-dwelling elderly in the Netherlands. AB - Colonization of the upper respiratory tract by Streptococcus pneumoniae is considered prerequisite for pneumococcal disease. Despite high rates of pneumococcal disease in elderly, pneumococcal carriage rates are usually below 5% when detected by the conventional culture method. We assessed pneumococcal carriage in 330 asymptomatic community-dwelling elderly aged 65 years and older. While pneumococci were cultured from 25 (8%) individuals, 65 (20%) elderly were positive for the pneumococcus-specific lytA gene when tested by quantitative-PCR, increasing the overall number of carriers to 75 (22%). Significantly more oropharyngeal samples were pneumococci-positive (18% versus 10%, p<0.001) when tested by the molecular method as compared to nasopharyngeal samples. Our findings indicate that pneumococcal carriage in elderly is higher than previously reported with up to 1 in 5 asymptomatic community-dwelling elderly positive for pneumococcal carriage, when detected by qPCR. The detection of pneumococci by conventional culture alone, greatly underestimates S. pneumoniae colonization in elderly. PMID- 26602270 TI - [Adaptation and validation of a brief screening questionnaire of depressive disorders in patients with cancer: Q2i study]. AB - BACKGROUND: Depression is a sustainable state of deep sadness and abatement. It is frequently identified in patients with cancer and often undervalued by oncologists. The reduced PRIME-MD questionnaire is a questionnaire of 2 items validated in French. However, it has been neither translated nor validated in French. The objective of our study is to translate the PRIME-MD and validate it into French. METHOD: The PRIME-MD questionnaire was translated into French by using the recommendations of the EORTC and compared to the French gold standard questionnaire Mini-International Neuropsychiatric Interview (MINI). RESULTS: Two hundred and ninety-nine patients were included in our study. With a 98% filling rate, the Q2i questionnaire has been well accepted. The prevalence of depression in our population was measured at 7.4%. With a sensitivity of 89.47%, a specificity of 58.85%, found percentages are equal to those of the questionnaire in English. The negative predictive value was measured at 98.52%. CONCLUSION: This study demonstrates that the Q2i questionnaire is a quick and easy screening tool, requiring less than 2minutes to target patients likely to benefit from psychological support. PMID- 26602272 TI - Oligoamylose-entwined porphyrin: excited-state induced-fit for chirality induction. AB - An oligoamylose-strapped porphyrin displayed circularly polarized luminescence (CPL) in the S1 state despite being silent in circular dichroism (CD) in the ground state, suggesting chirality induction in the photoexcited porphyrin moiety from the oligoamylose-strap in the photoexcited state. PMID- 26602271 TI - Recurrence Patterns and Second Primary Lung Cancers After Stereotactic Body Radiation Therapy for Early-Stage Non-Small-Cell Lung Cancer: Implications for Surveillance. AB - BACKGROUND: Patients treated with stereotactic body radiation therapy (SBRT) for early-stage non-small-cell lung cancer (NSCLC) are subject to locoregional and distant recurrence, as well as the formation of second primary lung cancers (SPLCs). The optimal surveillance regimen for patients treated with SBRT for early-stage NSCLC remains unclear; we therefore investigated the posttreatment recurrence patterns and development of SPLCs. METHODS: Three hundred sixty-six patients with pathologically proven inoperable early-stage NSCLC treated with SBRT between 2006 and 2013 were assessed. Patients underwent a computed tomographic (CT) scan of the chest every 3 months during years 1 and 2, every 6 months during years 3 and 4, and annually thereafter. Competing risk analysis was used for all time-to-event analyses. RESULTS: With a median follow-up of 23 months, the 2-year cumulative incidence of local, nodal, and distant treatment failures were 12.2%, 16.1%, and 15.5%, respectively. In patients with disease progression after SBRT (n = 108), 84% (n = 91) of cases occurred within the first 2 years. Five percent (n = 19) of patients experienced SPLCs. The median time to development of an SPLC was 16.5 months (range, 6.5-71.1 months), with 33% (n = 6) of these patients experiencing SPLCs after 2 years. None of the never smokers, but 4% of former tobacco smokers and 15% of current tobacco smokers, experienced an SPLC (P = .005). CONCLUSION: Close monitoring with routine CT scans within the first 2 years after SBRT is effective in detecting early disease progression. In contrast, the risk for the development of an SPLC remains elevated beyond 2 years, particularly in former and current smokers. PMID- 26602274 TI - Bioactive minor components of the total salvianolic acids injection prepared from Salvia miltiorrhiza Bge. AB - The total salvianolic acids are main effective constituents of Salvia miltiorrhiza Bge., a traditional Chinese medicine used for thousands of years. The purpose of present study was to make clear the composition and bioactivities of the minor components of the total salvianolic acids injection. As a result, three new minor phenolic acids (1-3) together with six known compounds (4-9) were characterized from the total salvianolic acids injection. Their structures were elucidated by extensive analysis of the spectral data. The absolute configuration of compounds 1-3 were confirmed by their J7',8' observed in (1)H NMR spectra, absorption band at approximately 250-260nm in their CD spectra as well as chemical shifts of C-8" and C-8''' displayed in (13)C NMR spectra. Then DPPH free radical scavenging assay and NAD(P)H: quinine oxidoreductase 1 (NQO1) inducing activity test were employed to evaluate the antioxidant effect of new minor compounds 1 and 2. Compound 2 showed significant NQO1 inducing activity at 20MUM with IR value 2.6. Meanwhile, DPPH scavenging assay revealed that the inhibition rates of compounds 1 and 2 were 84.3% and 74.9% at 2mM, respectively. PMID- 26602273 TI - Synthesis and evaluation of N-(methylthiophenyl)picolinamide derivatives as PET radioligands for metabotropic glutamate receptor subtype 4. AB - In recent years, mGlu4 has received great research attention because of the potential benefits of mGlu4 activation in treating numerous brain disorders, such as Parkinson's disease (PD). A specific mGlu4 PET radioligand could be an important tool in understanding the role of mGlu4 in both healthy and disease conditions, and also for the development of new drugs. In this study, we synthesized four new N-(methylthiophenyl)picolinamide derivatives 11-14. Of these ligands, 11 and 14 showed high in vitro binding affinity for mGlu4 with IC50 values of 3.4nM and 3.1nM, respectively, and suitable physicochemical parameters. Compound 11 also showed enhanced metabolic stability and good selectivity to other mGluRs. [(11)C]11 and [(11)C]14 were radiolabeled using the [(11)C]methylation of the thiophenol precursors 20a and 20c with [(11)C]CH3I in 19.0% and 34.8% radiochemical yields (RCY), and their specific activities at the end of synthesis (EOS) were 496+/-138GBq/MUmol (n=6) and 463+/-263GBq/MUmol (n=4), respectively. The PET studies showed that [(11)C]11 accumulated fast into the brain and had higher uptake, slower washout and 25% better contrast than [(11)C]2, indicating improved imaging characteristics as PET radiotracer for mGlu4 compared to [(11)C]2. Therefore, [(11)C]11 will be a useful radioligand to investigate mGlu4 in different biological applications. PMID- 26602275 TI - A synthetic chalcone derivative, 2-hydroxy-3',5,5'-trimethoxychalcone (DK-139), suppresses the TNFalpha-induced invasive capability of MDA-MB-231 human breast cancer cells by inhibiting NF-kappaB-mediated GROalpha expression. AB - 2-Hydroxy-3',5,5'-trimenthoxyochalcone (DK-139) is a synthetic chalcone-derived compound. This study evaluated the biological activity of DK-139 on the inhibition of tumor metastasis. Growth-regulated oncogene-alpha (GROalpha) plays an important role in the progression of tumor development by stimulating angiogenesis and metastasis. In this study, DK-139 inhibited tumor necrosis factor alpha (TNFalpha)-induced GROalpha gene promoter activity by inhibiting of IkappaB kinase (IKK) in MDA-MB231 cells. In addition, DK-139 prevented the TNFalpha-induced cell migration, F-actin formation, and invasive capability of MDA-MB-231 cells. These findings suggest that DK-139 is a potential drug candidate for the inhibition of tumor cell locomotion and invasion via the suppression of NF-kappaB-mediated GROalpha expression. PMID- 26602276 TI - Synthesis of 5-[3-(2-aminopyrimidin-4-yl)aminopropyn-1-yl]uracil derivative that recognizes Ade-Thy base pairs in double-stranded DNA. AB - 5-[3-(2-Aminopyrimidin-4-yl)aminopropyn-1-yl]uracil (Ura(Pyr)) was designed as a new nucleobase to recognize Ade-Thy base pair in double-stranded DNA. We successfully synthesized the dexoynucleoside phosphoramidite having Ura(Pyr) and incorporated it into triplex forming oligonucleotides (TFOs). Melting temperature analysis revealed that introduction of Ura(Pyr) into TFOs could effectively stabilize their triplex structures without loss of base recognition capabilities. PMID- 26602277 TI - Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia. AB - Herein, we present the identification of a novel class of pyrazolopyrimidine phosphodiesterase 10A (PDE10A) inhibitors. Beginning with a lead molecule (1) identified through a fragment-based drug discovery (FBDD) effort, lead optimization was enabled by rational design, X-ray crystallography, metabolic and off-target profiling, and fragment scaffold-hopping. We highlight the discovery of PyP-1, a potent, highly selective, and orally bioavailable pyrazolopyrimidine inhibitor of PDE10A. PyP-1 exhibits sub-nanomolar potency (PDE10A Ki=0.23nM), excellent pharmacokinetic (PK) and physicochemical properties, and a clean off target profile. It displays dose-dependent efficacy in numerous pharmacodynamic (PD) assays that measure potential for anti-psychotic activity and cognitive improvement. PyP-1 also has a clean preclinical profile with respect to cataleptic potential in rats, prolactin secretion, and weight gain, common adverse events associated with currently marketed therapeutics. Further, PyP-1 displays in vivo preclinical target engagement as measured by PET enzyme occupancy in concert with [(11)C]MK-8193, a novel PDE10A PET tracer. PMID- 26602278 TI - Hit-to-lead optimization of phenylsulfonyl hydrazides for a potent suppressor of PGE2 production: Synthesis, biological activity, and molecular docking study. AB - Preliminary hit-to-lead optimization of a novel series of phenylsulfonyl hydrazide derivatives, which were derived from the high throughput screening hit compound 1 (IC50=5700nM against PGE2 production), for a potent suppressor of PGE2 production is described. Subsequent optimization led to the identification of the potent lead compound 8n with IC50 values of 4.5 and 6.9nM, respectively, against LPS-induced PGE2 production and NO production in RAW 264.7 macrophage cells. In addition, 8n was about 30- and >150-fold more potent against mPGES-1 enzyme in a cell-free assay (IC50=70nM) than MK-886 and hit compound 1, respectively. Molecular docking suggests that compound 8n could inhibit PGE2 production by blocking the PGH2 binding site of human mPGES-1 enzyme. PMID- 26602279 TI - Identification of novel protein tyrosine phosphatase sigma inhibitors promoting neurite extension. AB - Protein tyrosine phosphatase sigma (PTPsigma) is a potential target for the therapeutic treatment of neurological deficits associated with impaired neuronal recovery, as this protein is the receptor for chondroitin sulfate proteoglycan (CSPG), which is known to inhibit neuronal regeneration. Through a high throughput screening approach started from 6400 representative compounds in the Korea Chemical Bank chemical library, we identified 11 novel PTPsigma inhibitors that can be classified as flavonoid derivatives or analogs, with IC50 values ranging from 0.5 to 17.5MUM. Biochemical assays and structure-based active site docking simulation indicate that our inhibitors are accommodated at the catalytic active site of PTPsigma as surrogates for the phosphotyrosine group. Treatments of these compounds on PC-12 neuronal cells led to the recovery of neurite extension attenuated by CSPG treatment, demonstrating their potential as antineurodegenerative agents. PMID- 26602280 TI - Protein ligand-tethered synthetic calcium indicator for localization control and spatiotemporal calcium imaging in plant cells. AB - In plant biology, calcium ions are involved in a variety of intriguing biological phenomena as a secondary messenger. However, most conventional calcium indicators are not applicable for plant cells because of the difficulty with their localization control in plant cells. We here introduce a method to monitor spatiotemporal Ca(2+) dynamics in living plant cells based on linking the synthetic calcium indicator Calcium Green-1 to a natural product-based protein ligand. In a proof-of-concept study using cultured BY-2 cells overexpressing the target protein for the ligand, the ligand-tethered probe accumulated in the cytosol and nucleus, and enabled real-time monitoring of the cytosolic and nucleus Ca(2+) dynamics under the physiological condition. The present strategy using ligand-tethered fluorescent sensors may be successfully applied to reveal the spatiotemporal dynamics of calcium ions in living plant cells. PMID- 26602281 TI - Synthesis and biological evaluation of thiophene and benzo[b]thiophene analogs of combretastatin A-4 and isocombretastatin A-4: A comparison between the linkage positions of the 3,4,5-trimethoxystyrene unit. AB - Combretastatin A-4 and isocombretastatin A-4 derivatives having thiophenes or benzo[b]thiophenes instead of the B ring were prepared and evaluated for their in cellulo tubulin polymerization inhibition (TPI) and antiproliferative activities. The presence of the benzo[b]thiophene ring proved to have a crucial effect as most of the thiophene derivatives, except those having one methoxy group, were inactive to inhibit tubulin polymerization into microtubules. The influence of the attachment position was also studied: benzo[b]thiophenes having iso or cis 3,4,5-trimethoxystyrenes at position 2 were 12-30-fold more active than the 3 regioisomers for the TPI activity. Some of the novel designed compounds exhibited interesting anti-proliferative effects on two different cell lines. PMID- 26602282 TI - Review of the Persistence of Herpes Zoster Vaccine Efficacy in Clinical Trials. AB - PURPOSE: The live attenuated herpes zoster vaccine(*) was approved for the prevention of shingles in 2006. Initial Phase III clinical trials proved vaccine efficacy persisted during the study duration; however, assessment of long-term efficacy required additional studies. This article reviews efficacy data for the zoster vaccine that have been published since 2004. It focuses on studies assessing declining vaccine efficacy. METHODS: MEDLINE, EMBASE, CENTRAL, and CINAHL databases were searched for zoster vaccine efficacy trials. Randomized controlled trials published from 2004 to 2015 were included in the review. FINDINGS: Six studies were included in the review. The zoster vaccine reduced the risk of herpes zoster by 51.3% to 72.4% in 2 Phase III trials. Primary and other analyses showed the vaccine was effective at reducing the burden of illness (61.1%), postherpetic neuralgia (66.5%), disease interference on functional status (66.2%), and disease impact on health-related quality of life (55%) compared with placebo. Surveillance studies showed a decrease in vaccine efficacy for reducing the incidence of herpes zoster during follow-up years 3.3 to 7.8 (39.6% relative reduction) and 4.7 to 11.6 (21.1% relative reduction). IMPLICATIONS: Initial zoster vaccine efficacy is significant, but declines in post-vaccination years 3 to 11. This raises the question about the need for possible revaccination with the zoster vaccine. Clinicians should consider the declining efficacy when administering the zoster vaccine to patients. Future studies will need to address the impact of the varicella vaccine on the incidence of shingles and whether this impacts the efficacy of the zoster vaccine. PMID- 26602283 TI - Neurobiological changes by cytotoxic agents in mice. AB - Cognitive deficit is a frequently reported side-effect of adjuvant chemotherapy. A large number of animal studies has been performed to examine the neurobiological mechanisms underlying this phenomenon, however, definite conclusions from these studies are restricted due to differences in experimental set-up. We systematically investigated the effects of 6 cytotoxic agents on various neurobiological parameters. C57Bl/6J mice were treated with cyclophosphamide, docetaxel, doxorubicin, 5-fluorouracil, methotrexate, or topotecan. The animals were sacrificed 3 or 15 weeks after treatment and the effect on neurogenesis, blood vessel density, and neuroinflammation was analyzed using immunohistochemistry. None of the cytostatic agents tested affected neurogenesis (cell survival or cell proliferation). Blood vessel density was increased in the hippocampus and prefrontal cortex 3 weeks after treatment with docetaxel and doxorubicin compared with control animals. A decrease in the number of microglial cells was observed in the prefrontal cortex after treatment with cyclophosphamide, docetaxel, 5-FU, and topotecan compared with control mice. The observed decrease in microglia cells is indicative of inflammation that occurred after treatment. Overall, the magnitude of the effects was relatively modest. Therefore, we conducted a similar study with topotecan in Abcg2;Abcb1a/b knock out and wildtype FVB mice. Animals were sacrificed 3 weeks after treatment and no notable effect was seen in hippocampal cell differentiation (DCX), microglia activation, or blood vessel density. Perhaps the FVB strain is more resistant to the neurotoxic effects of topotecan which makes this not the correct model to study the mechanism of chemotherapy-induced cognitive impairment. PMID- 26602284 TI - Central immune alterations in passive strategy following chronic defeat stress. AB - The relationship between stress, mood disorders and immune disorders is known, but what remains to be resolved is why certain individuals are more susceptible than others to suffer different disorders, along with the biological mechanisms that underlie these differences. The objective of this study was to analyze the changes in the expression patterns of proinflammatory cytokines in the hypothalamus, hippocampus, amygdala and prefrontal cortex after chronic defeat, depending on the coping strategy used. The expression levels of alpha1b and alpha2a adrenergic receptors and cytokine-inducible nitric oxide synthase (iNOS) in the prefrontal cortex were also measured. The results indicated that subjects with a passive coping strategy showed high levels of interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) expression in several cerebral structures in resting conditions after 21 days of chronic stress and increases in these cytokine levels in the hippocampus following an additional stress. Low expression levels of tumour necrosis factor-alpha (TNF-alpha) in the prefrontal cortex in active subjects at rest and in passive subjects after an additional defeat were detected. The iNOS expression levels were lower in the prefrontal cortex of the active group at rest. With respect to adrenergic receptor expression, there were no changes as a function of stress, but there were changes as a function of coping strategy. These results indicate differences in the variables studied in terms of the coping strategy adopted, with passive subjects having a biological profile that could be considered more vulnerable to the development of stress related disorders. PMID- 26602285 TI - Perioperative considerations in adult mitochondrial disease: A case series and a review of 111 cases. AB - Mitochondrial disease has been uncommon conditions, still results in death during childhood in many cases. The ideal anesthetic pharmacological management strategy for adult patients with mitochondrial disease is currently unclear. In this study, we presented features of the anesthesia methods employed and the perioperative complications of patients in our institution and in previously published case reports. We report the use of general anesthesia 7 times in 6 adult patients with mitochondrial disease during 2004-2014. All cases were performed with maintained intravenous anesthesia. One case was reintubated on the day after surgery, but the cause of death was not directly related to anesthesia. One hundred and eleven general anesthesia cases in 97 adult patients with mitochondrial disease were described in 83 the literature. Although several severe perioperative complications and deaths have been reported, malignant hyperthermia had not been reported in adult cases, and metabolic disorder called propofol infusion syndrome had also not been reported in adult patients undergone total intravenous anesthesia. Perioperative complications of lactic acidosis were reported more in inhalation anesthesia than intravenous anesthesia. Therefore we recommended intravenous anesthesia rather than inhalation anesthesia for adult mitochondrial disease. PMID- 26602286 TI - New insights into UTSA-16. AB - Among the metal organic framework materials proposed for CO2 separation, UTSA-16 possesses the highest CO2 volumetric density explained on the basis of favourable interactions between CO2 and structural water molecules in the material, as revealed by neutron diffraction. In this study, UTSA-16 was synthesised and extensively characterised by XRD, TEM combined with EDX analysis and DR-UV-Vis, Raman and FTIR spectroscopies, as well as by TGA measurements. The synthesised material shows XRD patterns, surface area, CO2 capacity and isosteric heat coincident to the ones reported for UTSA-16 in the original papers but a higher thermal stability and a complete removal of water upon activation under mild conditions (363 K). On the basis of EDX and IR measurements, the formula of UTSA 16 used in the present study is proposed to be K2Co3(cit)2. Infrared spectroscopy clearly shows that UTSA-16 described in this work reversibly interacts with water vapor, CO and CO2. The interaction is attributed to K(+) species, which are present as counterions in the pores. At 1 bar and 298 K a fraction of K(+) sites adsorbs 2 CO2 molecules. PMID- 26602287 TI - High Performance Heteroatoms Quaternary-doped Carbon Catalysts Derived from Shewanella Bacteria for Oxygen Reduction. AB - A novel heteroatoms (N, P, S and Fe) quaternary-doped carbon (HQDC-X, X refers to the pyrolysis temperature) can be fabricated by directly pyrolyzing a gram negative bacteria, S. oneidensis MR-1 as precursors at 800 degrees C, 900 degrees C and 1000 degrees C under argon atmosphere. These HQDC-X catalysts maintain the cylindrical shape of bacteria after pyrolysis under high temperatures, while heteroatoms including N, P, S and Fe distribute homogeneously on the carbon frameworks. As a result, HQDC-X catalysts exhibit excellent electrocatalytic activity for ORR via a dominant four-electron oxygen reduction pathway in alkaline medium, which is comparable with that of commercial Pt/C. More importantly, HQDC-X catalysts show better tolerance for methanol crossover and CO poisoning effects, long-term durability than commercial Pt/C, which could be promising alternatives to costly Pt-based electrocatalysts for ORR. The method may provide a promising avenue to develop cheap ORR catalysts from inexpensive, scalable and biological recursors. PMID- 26602288 TI - Positive density-dependent reproduction regulated by local kinship and size in an understorey tropical tree. AB - BACKGROUND AND AIMS: Global pollinator declines and continued habitat fragmentation highlight the critical need to understand reproduction and gene flow across plant populations. Plant size, conspecific density and local kinship (i.e. neighbourhood genetic relatedness) have been proposed as important mechanisms influencing the reproductive success of flowering plants, but have rarely been simultaneously investigated. METHODS: We conducted this study on a continuous population of the understorey tree Miconia affinis in the Forest Dynamics Plot on Barro Colorado Island in central Panama. We used spatial, reproductive and population genetic data to investigate the effects of tree size, conspecific neighbourhood density and local kinship on maternal and paternal reproductive success. We used a Bayesian framework to simultaneously model the effects of our explanatory variables on the mean and variance of maternal viable seed set and siring success. KEY RESULTS: Our results reveal that large trees had lower proportions of viable seeds in their fruits but sired more seeds. We documented differential effects of neighbourhood density and local kinship on both maternal and paternal reproductive components. Trees in more dense neighbourhoods produced on average more viable seeds, although this positive density effect was influenced by variance-inflation with increasing local kinship. Neighbourhood density did not have significant effects on siring success. CONCLUSIONS: This study is one of the first to reveal an interaction among tree size, conspecific density and local kinship as critical factors differentially influencing maternal and paternal reproductive success. We show that both maternal and paternal reproductive success should be evaluated to determine the population-level and individual traits most essential for plant reproduction. In addition to conserving large trees, we suggest the inclusion of small trees and the conservation of dense patches with low kinship as potential strategies for strengthening the reproductive status of tropical trees. PMID- 26602289 TI - Pathologic role of dietary advanced glycation end products in cardiometabolic disorders, and therapeutic intervention. AB - Reactive derivatives from nonenzymatic glucose-protein condensation reactions, as well as lipids and nucleic acids exposed to reducing sugars, form a heterogeneous group of irreversible adducts called AGEs (advanced glycation end products). The glycation process begins with the conversion of reversible Schiff base adducts to more stable, covalently bound Amadori rearrangement products. Over the course of days to weeks, these Amadori products undergo further rearrangement and condensation reactions to form irreversibly cross-linked macroprotein derivatives known as AGEs. The formation and accumulation of AGEs have been known to progress in a physiological aging process and at an accelerated rate under hyperglycemic and oxidative stress conditions. There is growing evidence that AGEs play a pathologic role in numerous disorders. Indeed, glycation and/or cross-linking modification of circulating or organic matrix proteins by AGEs the senescence of moieties and deteriorate their physiological function and structural integrity in multiple organ systems. Moreover, AGEs elicit oxidative stress and inflammatory reactions through the interaction with the receptor for advanced glycation products in a variety of cells, thereby contributing to the development and progression of various aging- or diabetes-related disorders, such as cardiovascular disease, chronic kidney disease, insulin resistance, and Alzheimer's disease. Recently, diet has been recognized as a major environmental source of AGEs that could cause proinflammatory reactions and organ damage in vivo. Therefore, this review summarizes the pathophysiological role of dietary AGEs in health and disease, especially focusing on cardiometabolic disorders. We also discuss the potential utility in targeting exogenously derived AGEs for therapeutic intervention. PMID- 26602290 TI - Effect of bovine lactoferrin from iron-fortified formulas on diarrhea and respiratory tract infections of weaned infants in a randomized controlled trial. AB - OBJECTIVE: The aim of this study was to evaluate the effect of supplementation with bovine lactoferrin (bLf) from iron-fortified formulas on diarrhea and respiratory tract infections (RTIs) in weaned infants. METHODS: In this prospective, multicenter, controlled intervention study, 260 infants ages 4 to 6 mo who previously were exclusively breastfed but weaned were randomized into two groups: a lactoferrin-fortified formula milk group (fortified group, FG, containing lactoferrin 38 mg/100 g milk) and a no lactoferrin-fortified milk (control group, CG); breastfed infants were enrolled and served as a reference group (breastfed group, BG). The intervention duration was 3 mo. The morbidity of diarrhea and RTIs were collected during supplementation. RESULTS: The results of the study demonstrated evidence of a lower incidence rate of respiratory-related illnesses and fewer symptoms of running nose, cough, and wheezing for infants in the FG and BG groups compared with those in the CG (P < 0.05). Despite the undistinguished incidence rate of vomiting, nausea, and colic, the occurrences of diarrhea-related illnesses were significantly lower for children in the FG and BG than for those in CG (P < 0.05). CONCLUSION: The beneficial effects on infectious morbidity over 3 mo highlighted the potential of bLF supplementation for previously weaned infants; these findings may be applicable to other infants living in similar socioeconomic districts. PMID- 26602291 TI - Elucidating the guest-host interactions and complex formation of praziquantel and cyclodextrin derivatives by (13)C and (15)N solid-state NMR spectroscopy. AB - Praziquantel is the drug of choice to treat several parasitic infections including the neglected tropical disease schistosomiasis. Due to its low aqueous solubility, cyclodextrins have been tested as potential host candidates to prepare praziquantel inclusion complexes with improved solubility. For the first time, the interactions of praziquantel with beta-cyclodextrin and beta cyclodextrin derivatives (methyl-beta-cyclodextrin and hydroxypropyl-beta cyclodextrin) were investigated using high resolution solid-state NMR spectroscopy. The results of this work confirmed that solid-state NMR experiments provided structural characterization, demonstrating the formation of inclusion complexes most probably with PZQ adopting an anti conformation, also the most likely in amorphous raw PZQ. Further information on the interaction of praziquantel with methyl-beta-cyclodextrin was obtained from proton rotating frame relaxation time measurements, sensitive to kilohertz-regime motions but modulated by spin-diffusion. Evidences were presented in all cases for praziquantel complexation through the aromatic ring. In addition, 1:2 drug:carrier molar ratio appears to be the most probable and therefore suitable stoichiometry to improve pharmaceutical formulations of this antischistosomal drug. PMID- 26602292 TI - Melatonin/HPbetaCD complex: Microwave synthesis, integration with chitosan scaffolds and inhibitory effects on MG-63CELLS. AB - In this study, melatonin/2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) inclusion complex was prepared by using microwave irradiation in a very short time. Phase solubility studies indicated a linear increase in the solubility of melatonin with HPbetaCD demonstrating Higuchi's AL-type phase solubility profiles and the formation of 1:1 stoichiometric inclusion complexes. Also, the ability of inclusion complex formation was promoted at microwave conditions compared to room conditions. The structure of inclusion complex was determined by FTIR, DSC, XRD, (1)H NMR and (13)C NMR studies. Both of pure melatonin and melatonin/HPbetaCD inclusion complex were loaded into the chitosan scaffolds that were prepared by freeze-drying method and the effect of released melatonin on human osteosarcoma cells (MG-63) was investigated in vitro. Approximately 9mM melatonin concentration caused time dependent cell death by reducing the proportion of the cells in the G2/M phase rather than S phase. In conclusion, melatonin/HPbetaCD inclusion complex loaded chitosan scaffolds could be considered as an alternative system for the human osteosarcoma therapy. PMID- 26602293 TI - Skin delivery by block copolymer nanoparticles (block copolymer micelles). AB - Block copolymer nanoparticles often referred to as "block copolymer micelles" have been assessed as carriers for skin delivery of hydrophobic drugs. Such carriers are based on organic biocompatible and biodegradable materials loaded with hydrophobic drugs: poly(lactide)-block-poly(ethylene glycol) copolymer (PLA b-PEG) nanoparticles that have a solid hydrophobic core made of glassy poly(d,l lactide), and poly(caprolactone)-block-poly(ethylene glycol) copolymer (PCL-b PEG) nanoparticles having a liquid core of polycaprolactone. In vitro skin absorption of all-trans retinol showed a large accumulation of retinol in stratum corneum from both block copolymer nanoparticles, higher by a factor 20 than Polysorbate 80 surfactant micelles and by a factor 80 than oil solution. Additionally, skin absorption from PLA-b-PEG nanoparticles was higher by one order of magnitude than PCL-b-PEG, although their sizes (65nm) and external surface (water-swollen PEG layer) were identical as revealed by detailed structural characterizations. Fluorescence microscopy of histological skin sections provided a non-destructive picture of the storage of Nile Red inside stratum corneum, epidermis and dermis. Though particle cores had a different physical states (solid or liquid as measured by (1)H NMR), the ability of nanoparticles for solubilization of the drug assessed from their Hildebrand solubility parameters appeared the parameter of best relevance regarding skin absorption. PMID- 26602294 TI - Airway administration of a highly versatile peptide-based liposomal construct for local and distant antitumoral vaccination. AB - With the discovery of tumor-associated antigens such as ErbB2, vaccination is considered as a promising strategy to prevent the development of cancer or treat the existing disease. Among routes of immunization, the respiratory route provides the opportunity to develop non-invasive approach for vaccine delivery. In the current study, this administration route was used in order to investigate the potency of a highly versatile di-epitopic liposomal construct to exhibit local or distant antitumoral efficiency after prophylactic or therapeutic vaccination in mice. Well-characterized liposomes, containing the ErbB2 (p63-71) TCD8(+) and HA (p307-319) TCD4(+) peptide epitopes and the Pam2CAG adjuvant, were formulated and administered into the airway of naive BALB/c mice. The nanoparticle vaccine candidate induced local and specific systemic immune response, as measured by immune cell infiltration and chemokine and cytokine production in BALF or lung tissue, and by spleen T-cell activation ex vivo, respectively. This potent immune response resulted in an efficient antitumor activity against both lung and solid s.c. tumors. Interestingly, the antitumor efficacy was observed after both prophylactic and therapeutic vaccinations, which are the most judicious ones to fight cancer. Our data showed an undeniable interest of liposomal peptide-based vaccines in antitumor vaccination by the respiratory route, opening new perspectives for cancer treatment. PMID- 26602295 TI - Highly active and durable methanol oxidation electrocatalyst based on the synergy of platinum-nickel hydroxide-graphene. AB - Active and durable electrocatalysts for methanol oxidation reaction are of critical importance to the commercial viability of direct methanol fuel cell technology. Unfortunately, current methanol oxidation electrocatalysts fall far short of expectations and suffer from rapid activity degradation. Here we report platinum-nickel hydroxide-graphene ternary hybrids as a possible solution to this long-standing issue. The incorporation of highly defective nickel hydroxide nanostructures is believed to play the decisive role in promoting the dissociative adsorption of water molecules and subsequent oxidative removal of carbonaceous poison on neighbouring platinum sites. As a result, the ternary hybrids exhibit exceptional activity and durability towards efficient methanol oxidation reaction. Under periodic reactivations, the hybrids can endure at least 500,000 s with negligible activity loss, which is, to the best of our knowledge, two to three orders of magnitude longer than all available electrocatalysts. PMID- 26602297 TI - Design of an Intervention to Minimize Ingestion of Fecal Microbes by Young Children in Rural Zimbabwe. AB - We sought to develop a water, sanitation, and hygiene (WASH) intervention to minimize fecal-oral transmission among children aged 0-18 months in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial. We undertook 4 phases of formative research, comprising in-depth interviews, focus group discussions, behavior trials, and a combination of observations and microbiological sampling methods. The resulting WASH intervention comprises material inputs and behavior change communication to promote stool disposal, handwashing with soap, water treatment, protected exploratory play, and hygienic infant feeding. Nurture and disgust were found to be key motivators, and are used as emotional triggers. The concept of a safe play space for young children was particularly novel, and families were eager to implement this after learning about the risks of unprotected exploratory play. An iterative process of formative research was essential to create a sequenced and integrated longitudinal intervention for a SHINE household as it expects (during pregnancy) and then cares for a new child. PMID- 26602298 TI - The SHINE Trial Infant Feeding Intervention: Pilot Study of Effects on Maternal Learning and Infant Diet Quality in Rural Zimbabwe. AB - The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial is designed to measure the independent and combined effects of improved water, sanitation, and hygiene and improved infant feeding on child stunting and anemia in Zimbabwe. We developed and pilot-tested the infant feeding intervention delivered by 9 village health workers to 19 mothers of infants aged 7-12 months. Between September 2010 and January 2011, maternal knowledge was assessed using mixed methods, and infant nutrient intakes were assessed by 24-hour recall. We observed positive shifts in mothers' knowledge. At baseline, 63% of infants met their energy requirement and most did not receive enough folate, zinc, or calcium; none met their iron requirement. Postintervention, all infants received sufficient fat and vitamin A, and most consumed enough daily energy (79%), protein (95%), calcium (89%), zinc (89%), folate (68%), and iron (68%). The SHINE trial infant feeding intervention led to significant short-term improvements in maternal learning and infant nutrient intakes. PMID- 26602299 TI - Using Geographic Information Systems and Spatial Analysis Methods to Assess Household Water Access and Sanitation Coverage in the SHINE Trial. AB - Access to water and sanitation are important determinants of behavioral responses to hygiene and sanitation interventions. We estimated cluster-specific water access and sanitation coverage to inform a constrained randomization technique in the SHINE trial. Technicians and engineers inspected all public access water sources to ascertain seasonality, function, and geospatial coordinates. Households and water sources were mapped using open-source geospatial software. The distance from each household to the nearest perennial, functional, protected water source was calculated, and for each cluster, the median distance and the proportion of households within <500 m and >1500 m of such a water source. Cluster-specific sanitation coverage was ascertained using a random sample of 13 households per cluster. These parameters were included as covariates in randomization to optimize balance in water and sanitation access across treatment arms at the start of the trial. The observed high variability between clusters in both parameters suggests that constraining on these factors was needed to reduce risk of bias. PMID- 26602300 TI - Assessment of Environmental Enteric Dysfunction in the SHINE Trial: Methods and Challenges. AB - Environmental enteric dysfunction (EED) is a virtually ubiquitous, but poorly defined, disorder of the small intestine among people living in conditions of poverty, which begins early in infancy and persists. EED is characterized by altered gut structure and function, leading to reduced absorptive surface area and impaired intestinal barrier function. It is hypothesized that recurrent exposure to fecal pathogens and changes in the composition of the intestinal microbiota initiate this process, which leads to a self-perpetuating cycle of pathology. We view EED as a primary gut disorder that drives chronic systemic inflammation, leading to growth hormone resistance and impaired linear growth. There is currently no accepted case definition or gold-standard biomarker of EED, making field studies challenging. The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in Zimbabwe is evaluating the independent and combined effects of a package of infant feeding and/or water, sanitation, and hygiene interventions on stunting and anemia. SHINE therefore provides an opportunity to longitudinally evaluate EED in a well-characterized cohort of infants, using a panel of biomarkers along the hypothesized causal pathway. Our aims are to describe the evolution of EED during infancy, ascertain its contribution to stunting, and investigate the impact of the randomized interventions on the EED pathway. In this article, we describe current concepts of EED, challenges in defining the condition, and our approach to evaluating EED in the SHINE trial. PMID- 26602301 TI - The Potential Role of Mycotoxins as a Contributor to Stunting in the SHINE Trial. AB - Children in developing countries experience multiple exposures that are harmful to their growth and development. An emerging concern is frequent exposure to mycotoxins that contaminate a wide range of staple foods, including maize and groundnuts. Three mycotoxins are suspected to contribute to poor child health and development: aflatoxin, fumonisin, and deoxynivalenol. We summarize the evidence that mycotoxin exposure is associated with stunting, and propose that the causal pathway may be through environmental enteric dysfunction (EED) and disturbance of the insulin-like growth factor 1 (IGF-1) axis. The objectives of this substudy are to assess the relationship between agricultural and harvest practices and mycotoxin exposure; to evaluate associations between mycotoxin exposure and child stunting; and to investigate EED as a potential pathway linking mycotoxin exposure to child stunting, to inform potential areas for intervention. PMID- 26602303 TI - Assessing Maternal Capabilities in the SHINE Trial: Highlighting a Hidden Link in the Causal Pathway to Child Health. AB - A potential bottleneck for increasing the adoption of child health interventions has been limited attention to designing actions that are built on the essential role that caregivers play in determining their effectiveness. In the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial, we utilize the concept of maternal capabilities to examine participants' skills and attributes that affect their ability to provide appropriate care for their young child, fully engage with trial interventions, and influence the response to these interventions at the household level. We hypothesize that the impact of SHINE interventions on child stunting and anemia will be modified by these maternal capabilities. Drawing upon multiple theories, we identify and define critical maternal capabilities domains, and describe how they are measured in the trial. Description of maternal capabilities and their role as potential modifiers on impact will increase understanding of the impact of SHINE interventions, and the generalizability of our findings. PMID- 26602302 TI - Assessing the Intestinal Microbiota in the SHINE Trial. AB - Advances in DNA sequencing technology now allow us to explore the dynamics and functions of the microbes that inhabit the human body, the microbiota. Recent studies involving experimental animal models suggest a role of the gut microbiota in growth. However, the specific changes in the human gut microbiota that contribute to growth remain unclear, and studies investigating the gut microbiota as a determinant of environmental enteric dysfunction (EED) and child stunting are lacking. In this article, we review the evidence for a link between the developing infant gut microbiota, infant feeding, EED, and stunting, and discuss the potential causal pathways relating these variables. We outline the analytic approaches we will use to investigate these relationships, by capitalizing on the longitudinal design and randomized interventions of the Sanitation Hygiene Infant Nutrition Efficacy trial in Zimbabwe. PMID- 26602305 TI - Probing Intramolecular versus Intermolecular CO2 Adsorption on Amine-Grafted SBA 15. AB - A mesoporous silica SBA-15 is modified with an array of amine-containing organosilanes including (i) propylamine, SiCH2CH2CH2NH2 (MONO), (ii) propylethylenediamine, SiCH2CH2CH2NHCH2CH2NH2 (DI), (iii) propyldiethylenetriamine, SiCH2CH2CH2NHCH2CH2NHCH2CH2NH2 (TRI), and (iv) propyltriethylenetetramine, SiCH2CH2CH2NHCH2CH2N(CH2CH2NH2)2 (TREN) and the low loading silane adsorbents (~0.45 mmol silane/g) are evaluated for their CO2 adsorption properties, with a focus on gaining insight into the propensity for intramolecular vs intermolecular CO2 adsorption. Adsorption isotherms at low CO2 coverages are measured while simultaneously recording the heat evolved via a Tian Calvet calorimeter. The results are compared on a silane molecule efficiency basis (mol CO2 adsorbed/mol silane) to assess the potential for intramolecular CO2 adsorption, employing two amine groups in a single silane molecule. As the number of amines in the silane molecule increases (MONO < DI < TREN ~ TRI), the silane molecule efficiency is enhanced owing to the ability to intramolecularly capture CO2. Analysis of the CO2 uptake for samples with the surface silanols removed by capping demonstrates that cooperative uptake due to amine-CO2-silanol interactions is also possible over these adsorbents and is the primary mode of sorption for the MONO material at the studied low silane loading. As the propensity for intramolecular CO2 capture increases due to the presence of multiple amines in a single silane molecule (MONO < DI < TREN ~ TRI), the measured heat of adsorption also increases. This study of various amine containing silanes at low coverage is the first to provide significant, direct evidence for intramolecular CO2 capture in a single silane molecule. Furthermore, it provides evidence for the relative heats of adsorption for physisorption on a silanol laden surface (ca. 37 kJ/mol), a silanol-capped surface (ca. 25 kJ/mol), via amine-CO2-silanol interactions (ca. 46 kJ/mol), and via amine-CO2-amine interactions at low surface coverages (ca. 65 kJ/mol). PMID- 26602304 TI - Theory-Driven Process Evaluation of the SHINE Trial Using a Program Impact Pathway Approach. AB - Two reasons for the lack of success of programs or interventions are poor alignment of interventions with the causes of the problem targeted by the intervention, leading to poor efficacy (theory failure), and failure to implement interventions as designed (program failure). These failures are important for both public health programs and randomized trials. In the Sanitation Hygiene and Infant Nutrition Efficacy (SHINE) Trial, we utilize the program impact pathway (PIP) approach to track intervention implementation and behavior uptake. In this article, we present the SHINE PIP including definitions and measurements of key mediating domains, and discuss the implications of this approach for randomized trials. Operationally, the PIP can be used for monitoring and strengthening intervention delivery, facilitating course-correction at various stages of implementation. Analytically, the PIP can facilitate a richer understanding of the mediating and modifying determinants of intervention impact than would be possible from an intention-to-treat analysis alone. PMID- 26602306 TI - Cellular cooperation with shift updating and repulsion. AB - Population structure can facilitate evolution of cooperation. In a structured population, cooperators can form clusters which resist exploitation by defectors. Recently, it was observed that a shift update rule is an extremely strong amplifier of cooperation in a one dimensional spatial model. For the shift update rule, an individual is chosen for reproduction proportional to fecundity; the offspring is placed next to the parent; a random individual dies. Subsequently, the population is rearranged (shifted) until all individual cells are again evenly spaced out. For large population size and a one dimensional population structure, the shift update rule favors cooperation for any benefit-to-cost ratio greater than one. But every attempt to generalize shift updating to higher dimensions while maintaining its strong effect has failed. The reason is that in two dimensions the clusters are fragmented by the movements caused by rearranging the cells. Here we introduce the natural phenomenon of a repulsive force between cells of different types. After a birth and death event, the cells are being rearranged minimizing the overall energy expenditure. If the repulsive force is sufficiently high, shift becomes a strong promoter of cooperation in two dimensions. PMID- 26602307 TI - [Ethical challenges of the finding of covert awareness with neuroimaging in vegetative states]. PMID- 26602308 TI - [Cranial lytic lesions]. PMID- 26602309 TI - [Methamizole-induced agranulocytosis]. PMID- 26602310 TI - [Fournier's gangrene]. PMID- 26602311 TI - [Pulmonary hypertension in hemodialysis patients: Prevalence and associated factors]. AB - BACKGROUND AND OBJECTIVE: Pulmonary hypertension (PH) is a progressive disorder that can be caused by several underlying conditions or an intrinsic alteration of the pulmonary vasculature. Chronic increased pressure in the pulmonary vasculature leads to changes in the architecture of the vessels that can perpetuate PH and produce right ventricular dysfunction. These structural and functional alterations can decrease survival and quality of life of patients on hemodialysis; however, there is a lack of evidence about this problem in this population. The aim of this study is to establish the prevalence of PH in patients on hemodialysis and its association with specific factors related to this patient population. MATERIAL AND METHODS: We included 202 prevalent patients on hemodialysis for at least 6 months and who were clinically stable. We collected demographic data, routine laboratory parameters and data of 2D Doppler echocardiography. PH was defined as a systolic pulmonary artery pressure (SPAP) estimated by Doppler ultrasound above 35mmHg. Hydration status was assessed by determining the plasma concentration of N-terminal pro brain natriuretic peptide (Nt-proBNP). RESULTS: PH prevalence was 37.1% (75 patients). The average SPAP in the entire study population was 32+/-12mmHg and in the group with PH it was 45+/ 11mmHg. We found a direct and statistically significant correlation between the presence of PH and age (P=.001), time on renal replacement therapy (P=.04), the presence of systolic dysfunction (P=.007), diastolic dysfunction (P= 01), mitral valve disease (P=.01) and double mitral and aortic disease (P=.007). Volume overload was closely associated with PH, as demonstrated by the correlation between the SPAP and Nt-proBNP levels (P=.001). CONCLUSION: We conclude that prevalence of PH in hemodialysis patients is high. And one of the most important associated factors is volume overload. More studies are needed to establish the impact of PH on morbidity and mortality of patients and to assess whether a better volume control improves PH. PMID- 26602312 TI - [Dexamethasone-induced hiccup]. PMID- 26602313 TI - [Transdiscal fracture of the vertebrae following an accidental fall in a patient with ankylosing spondylitis]. PMID- 26602314 TI - [Vesicular eruption in a patient under antituberculosis treatment]. PMID- 26602315 TI - Influence of pulmonary factors on pulse oximeter saturation in preterm infants. AB - AIM: To describe how the stability of oxygen saturation measured by pulse oximetry (SpO2%) varies within and between infants with bronchopulmonary dysplasia (BPD). METHODS: Clinically stable infants with BPD had SpO2 measured at different inspired oxygen concentrations (FIO2 expressed as %). A computer model of gas exchange, that is, ventilation/perfusion ratio (VA/Q) and shunt, plotted the curve of SpO2 versus FIO2 best fitting these data. The slope of this curve is the change in SpO2 per % change in FIO2, hence SpO2 stability, calculated at each SpO2 from 85% to 95%. RESULTS: Data from 16 infants with BPD previously described were analysed. The dominant gas exchange impairment was low VA/Q (median 0.35, IQR, 0.16-0.4, normal 0.86). Median shunt was 1% (IQR, 0-10.5; normal <2%). Slope varied markedly between infants, but above 95% SpO2 was always <1.5. In infants with least severe BPD (VA/Q ~0.4, shunt <=2%) median slope at 85% SpO2 was 5.1 (IQR, 3.7-5.5). With more severe BPD (VA/Q <=0.3) slope was flatter throughout the SpO2 range. The highest FIO2 for 90% SpO2 was in infants with the lowest VA/Q values. CONCLUSIONS: In infants with BPD, there was large variation in the slope of the curve relating SpO2% to inspired oxygen fraction in the SpO2 range 85% 95%. Slopes were considerably steeper at lower than higher SpO2, especially in infants with least severe BPD, meaning that higher SpO2 target values are intrinsically much more stable. Steep slopes below 90% SpO2 may explain why some infants appear dependent on remarkably low oxygen flows. PMID- 26602316 TI - Discussing Serious News. AB - AIM: The ability to communicate serious news to patients and families in a caring and compassionate way is a critical skill for physicians. This study explores the impact of a novel communication skills workshop that included bereaved parents in role play on pediatric residents' confidence to communicate serious news. METHODS: Following the workshop, pediatric residents were surveyed to assess their perceived efficacy of the educational intervention. The survey included anchored response and open-ended questions to yield qualitative and quantitative results. RESULTS: After completing the workshop, residents' confidence in discussing goals, managing emotions, and expressing empathy all increased significantly. Residents reported that the inclusion of bereaved parents was beneficial since it made the experience more realistic. In addition, they believed their ability to communicate with patients and families had improved. CONCLUSIONS: Including bereaved parents in this communication skills workshop improved the residents' confidence in discussing serious topics and enhanced the reality of the experience. PMID- 26602296 TI - The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) Trial: Rationale, Design, and Methods. AB - Child stunting and anemia are intractable public health problems in developing countries and have profound short- and long-term consequences. The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial is motivated by the premise that environmental enteric dysfunction (EED) is a major underlying cause of both stunting and anemia, that chronic inflammation is the central characteristic of EED mediating these adverse effects, and that EED is primarily caused by high fecal ingestion due to living in conditions of poor water, sanitation, and hygiene (WASH). SHINE is a proof-of-concept, 2 * 2 factorial, cluster-randomized, community-based trial in 2 rural districts of Zimbabwe that will test the independent and combined effects of protecting babies from fecal ingestion (factor 1, operationalized through a WASH intervention) and optimizing nutritional adequacy of infant diet (factor 2, operationalized through an infant and young child feeding [IYCF] intervention) on length and hemoglobin at 18 months of age. Within SHINE we will measure 2 causal pathways. The program impact pathway comprises the series of processes and behaviors linking implementation of the interventions with the 2 child health primary outcomes; it will be modeled using measures of fidelity of intervention delivery and household uptake of promoted behaviors and practices. We will also measure a range of household and individual characteristics, social interactions, and maternal capabilities for childcare, which we hypothesize will explain heterogeneity along these pathways. The biomedical pathway comprises the infant biologic responses to the WASH and IYCF interventions that ultimately result in attained stature and hemoglobin concentration at 18 months of age; it will be elucidated by measuring biomarkers of intestinal structure and function (inflammation, regeneration, absorption, and permeability); microbial translocation; systemic inflammation; and hormonal determinants of growth and anemia among a subgroup of infants enrolled in an EED substudy. This article describes the rationale, design, and methods underlying the SHINE trial. CLINICAL TRIALS REGISTRATION: NCT01824940. PMID- 26602317 TI - Barriers of Palliative Care in Neonatal Intensive Care Units. AB - OBJECTIVE: Neonatal nurses face numerous barriers in providing end-of-life (EOL) care for neonates and their families. Addressing neonatal nurses' attitudes could provide insight into barriers that impede neonatal palliative care (NPC). This study thus conducted to examine neonatal nurses' attitude toward barriers in providing NPC in Southeast Iran. METHOD: In this cross-sectional study, a translated modified version of Neonatal Palliative Care Attitude Scale was used to examine attitudes of 70 nurses toward barriers of palliative care in 3 neonatal intensive care units in Southeast Iran. RESULTS: Findings indicated that overall 42.63% of nurses were strongly agreed or agreed with the proposed barriers in NPC. Among all categories, the highest and the lowest scores belonged to the categories of "insufficient resources" (3.42 +/- 0.65) and "inappropriate personal and social attitudes" (2.33 +/- 0.48), respectively. Neonatal nurses who had less education and study regarding NPC reported the presence of more barriers to NPC in the categories of "inappropriate organizational culture" and/or "inadequate nursing proficiency." Also, younger nurses had more positive attitudes toward the category of inappropriate organizational culture as being a barrier to provision of NPC (4.62). CONCLUSION: The findings suggest that developing a context-based instrument is required to represent the barrier more precisely. Neonatal palliative care can be improved by establishing a special environment to focus on infants' EOL care. This establishment requires standard palliative care guidelines and adequate NPC-trained nurses. PMID- 26602318 TI - A single blueberry (Vaccinium corymbosum) portion does not affect markers of antioxidant defence and oxidative stress in healthy volunteers following cigarette smoking. AB - We previously reported that a portion of blueberries reversed endothelial dysfunction induced by acute cigarette smoking. Since smoking-induced endothelial dysfunction is associated with a condition of oxidative stress, we evaluated whether the observed effect was mediated by modulation of markers of oxidative stress and antioxidant defence. Fourteen out of 16 male healthy smokers previously enrolled, participated in a three-armed randomized controlled study with the following experimental conditions: smoking treatment (one cigarette); blueberry treatment (300g of blueberries) + smoking (one cigarette); control treatment (300ml of water with sugar) + smoking (one cigarette). The cigarette was smoked 100min after blueberry/control/water consumption. Each treatment was separated by 1 week of washout period. Plasma vitamin (C, B12 and folate) and aminothiol concentrations, endogenous [formamidopyrimidine-DNA glycosylase (FPG) sensitive sites] and oxidatively induced DNA damage (resistance to H2O2-induced DNA damage) in peripheral blood mononuclear cells (PBMCs) were measured at baseline and 20, 60, 90, 120min and 24h after smoking. On the whole, analysis of variance did not show a significant effect of treatment on the modulation of markers of oxidative stress and antioxidant defence but revealed an effect of time for plasma concentrations of vitamin C (P = 0.003), B12 (P < 0.001), folate (P < 0.001), total cysteine (P = 0.007) and cysteine-glycine (P = 0.010) that increased following the three treatments after smoking. No significant effect of treatment was observed for the levels of FPG-sensitive sites (P > 0.05) and H2O2 induced DNA damage (P > 0.05) in PBMCs. In conclusion, the consumption of a single blueberry portion failed to modulate markers of oxidative stress and antioxidant defence investigated in our experimental conditions. Further studies are necessary to elucidate this finding and help clarifying the mechanisms of protection of blueberries against smoking-induced endothelial dysfunction. PMID- 26602320 TI - Commentary on 'Obliterating Endo-aneurysmorrhaphy with Stent Graft Preservation for Treatment of Type II Progressive Endoleak'. PMID- 26602319 TI - Medication adherence 1 month after hospital discharge in medical inpatients. AB - BACKGROUND: The rate of medication non-adherence has been consistently reported to be between 20 and 50%. The majority of available data comes from international studies, and we hypothesised that a similar rate of adherence may be observed in Australian patients. AIMS: To determine the rate of adherence to medications after discharge from acute general hospital admission and identify factors that may be associated with non-adherence. METHODS: A prospective cohort study of 68 patients, comparing admission and discharge medication regimens to self-reported regimens 30-40 days after discharge from hospital. Patients were followed up via telephone call and univariate and multivariate binary logistic regression used to determine patient factors associated with non-adherence. RESULTS: In all, 27 of 68 patients (39.7%) were non-adherent to one or more regular medications at follow up. Intentional and unintentional non-adherence contributed equally to non adherence. Using multivariate analysis, presence of a carer responsible for medications was associated with significantly lower non-adherence (odds ratio (OR) 0.20 (0.05-0.83), P = 0.027) when adjusted for age, co-morbidities, chemist blister pack and total number of discharge medications. CONCLUSIONS: Non adherence to prescription medications is suboptimal and consistent with previous overseas studies. Having a carer responsible for medications is associated with significantly lower rates of non-adherence. Understanding patients' preferences and involving them in their healthcare may reduce intentional non-adherence. PMID- 26602321 TI - Training to Perform Ankle-Brachial Index: Systematic Review and Perspectives to Improve Teaching and Learning. AB - OBJECTIVE: To conduct a systematic review focusing on the impact of training programs on ankle-brachial index (ABI) performance by medical students, doctors and primary care providers. Lower extremity peripheral artery disease (PAD) is a highly prevalent disease affecting ~202 million people worldwide. ABI is an essential component of medical education because of its ability to diagnose PAD, and as it is a powerful prognostic marker for overall and cardiovascular related mortality. METHODS: A systematic search was conducted (up to May 2015) using Medline, Embase, and Web of Science databases. RESULTS: Five studies have addressed the impact of a training program on ABI performance by either medical students, doctors or primary care providers. All were assigned a low GRADE system quality. The components of the training vary greatly either in substance (what was taught) or in form (duration of the training, and type of support which was used). No consistency was found in the outcome measures. CONCLUSION: According to this systematic review, only few studies, with a low quality rating, have addressed which training program should be performed to provide the best way of teaching how to perform ABI. Future high quality researches are required to define objectively the best training program to facilitate ABI teaching and learning. PMID- 26602323 TI - Commentary on 'Changes in Aortoiliac Anatomy after Elective Treatment of Infrarenal Abdominal Aortic Aneurysm with a Sac-anchoring Endoprosthesis'. PMID- 26602322 TI - Predictors of Stroke, Myocardial Infarction or Death within 30 Days of Carotid Artery Stenting: Results from the International Carotid Stenting Study. AB - OBJECTIVES: Stroke, myocardial infarction (MI), and death are complications of carotid artery stenting (CAS). The effect of baseline patient demographic factors, processes of care, and technical factors during CAS on the risk of stroke, MI, or death within 30 days of CAS in the International Carotid Stenting Study (ICSS) were investigated. METHODS: In ICSS, suitable patients with recently symptomatic carotid stenosis > 50% were randomly allocated to CAS or endarterectomy. Factors influencing the risk of stroke, MI, or death within 30 days of CAS were examined in a regression model for the 828 patients randomized to CAS in whom the procedure was initiated. RESULTS: Of the patients, 7.4% suffered stroke, MI, or death within 30 days of CAS. Independent predictors of risk were age (risk ratio [RR] 1.17 per 5 years of age, 95% CI 1.01-1.37), a right-sided procedure (RR 0.54, 95% CI 0.32-0.91), aspirin and clopidogrel in combination prior to CAS (compared with any other antiplatelet regimen, RR 0.59, 95% CI 0.36-0.98), smoking status, and the severity of index event. In patients in whom a stent was deployed, use of an open-cell stent conferred higher risk than use of a closed-cell stent (RR 1.92, 95% CI 1.11-3.33). Cerebral protection device (CPD) use did not modify the risk. CONCLUSIONS: Selection of patients for CAS should take into account symptoms, age, and side of the procedure. The results favour the use of closed-cell stents. CPDs in ICSS did not protect against stroke. PMID- 26602324 TI - The Effect of Medical Marijuana Laws on Body Weight. AB - This study is the first to examine the effects of medical marijuana laws (MMLs) on body weight, physical wellness, and exercise. Using data from the 1990 to 2012 Behavioral Risk Factor Surveillance System and a difference-in-difference approach, we find that the enforcement of MMLs is associated with a 2% to 6% decline in the probability of obesity. We find some evidence of age-specific heterogeneity in mechanisms. For older individuals, MML-induced increases in physical mobility may be a relatively important channel, while for younger individuals, a reduction in consumption of alcohol, a substitute for marijuana, appears more important. These findings are consistent with the hypothesis that MMLs may be more likely to induce marijuana use for health-related reasons among older individuals, and cause substitution toward lower-calorie recreational 'highs' among younger individuals. Our estimates suggest that MMLs induce a $58 to $115 per-person annual reduction in obesity-related medical costs. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26602325 TI - Is YouTube useful as a source of information for Sjogren's syndrome? AB - OBJECTIVES: To quantitatively and qualitatively assess the characteristics of YouTube videos dealing with Sjogren's syndrome. MATERIALS & METHODS: A comprehensive electronic search was performed for 'Sjogren's syndrome' in YouTube. After excluding duplicates, irrelevant videos, and non-English-language domains, 70 videos were included for analysis. Videos were classified as useful, misleading, or personal experience. The overall quality of videos was scored according to the Global Quality Scale (GQS). Useful videos were assessed for reliability and comprehensiveness based on two 5-point scales. Key points of the misleading videos were explored and patients' personal experiences were further investigated. RESULTS: Thirty-six videos (51.4%) were classified as useful, 6 (8.6%) as misleading, and 28 (40%) as patient's personal experience. Independent users tend to upload videos with personal experience, while university channels/professional organizations share useful videos with evidence-based information. Significant difference was observed in GQS among useful, misleading videos, and patient's experiences. The mean reliability, comprehensiveness, and GQS scores of useful videos were 2.5 (s.d.:1.2), 2.6 (s.d.:1.4), and 3.4 (s.d.:1.0), respectively, whereas only six videos (16.7%) were rated as complete vis-a-vis content. The most frequently misleading topics were etiology and treatment. CONCLUSIONS: Specialists should refer their patients to validated e information resources and actively participate in the development of video sharing platforms. PMID- 26602326 TI - PI3K is required for both basal and LPA-induced DNA synthesis in oral carcinoma cells. AB - BACKGROUND: The glycerophospholipid lysophosphatidic acid (LPA), which is present in most tissues and in high concentrations in saliva, may exert profound effects on oral cancer cells. We have investigated mitogenic signalling induced by LPA in the two oral carcinoma cell lines, D2 and E10, focusing on the role of EGFR transactivation and downstream pathways. METHODS: Two oral squamous carcinoma cell lines, D2 and E10, were analysed for effects of LPA on signalling pathways and induction of DNA synthesis. Pathway activation was investigated by examining phosphorylation of signalling proteins and by the use of specific pathway inhibitors. RESULTS: The D2 cells had higher levels of activated signalling proteins and higher DNA synthesis activity in the basal condition than E10 cells. EGF did not induce proliferation in D2 cells, whereas LPA induced proliferation in both cell lines, by mechanisms depending on EGFR transactivation. Release of EGFR ligands was involved in basal and LPA-induced proliferation in both D2 and E10 cells. The proliferation in D2 cells was dependent on the PI3K/Akt pathway, but not the MEK/ERK pathway. In E10 cells, the PI3K/Akt, MEK/ERK and p38 pathways were all involved in the proliferation. CONCLUSION: Transactivation of EGFR is required for LPA-induced DNA synthesis in D2 and E10 cells. Our results also show that although proliferation of oral carcinoma cells is regulated by several pathways, and differentially in E10 and D2 cells, the PI3K pathway has a crucial role in both cell lines. PMID- 26602327 TI - Titanium Dioxide-Grafted Copper Complexes: High-Performance Electrocatalysts for the Oxygen Reduction Reaction in Alkaline Media. AB - The sluggish kinetics of the oxygen reduction reaction (ORR) at the cathodes of fuel cells significantly hampers fuel cell performance. Therefore, the development of high-performance, non-precious-metal catalysts as alternatives to noble metal Pt-based ORR electrocatalysts is highly desirable for the large-scale commercialization of fuel cells. TiO2 -grafted copper complexes deposited on multiwalled carbon nanotubes (CNTs) form stable and efficient electrocatalysts for the ORR. The optimized catalyst composite CNTs@TiO2 -ZA-[Cu(phen${{^{{?rm NO}{_{2}}}}}$)(BTC)] shows surprisingly high selectivity for the 4 e(-) reduction of O2 to water (approximately 97 %) in alkaline solution with an onset potential of 0.988 V vs. RHE, and demonstrates superior stability and excellent tolerance for the methanol crossover effect in comparison to a commercial Pt/C catalyst. The copper complexes were grafted onto the surface of TiO2 through coordination of an imidazole-containing ligand, zoledronic acid (ZA), which binds to TiO2 through its bis-phosphoric acid anchoring group. Rational optimization of the copper catalyst's ORR performance was achieved by using an electron-deficient ligand, 5-nitro-1,10-phenanthroline (phen${{^{{?rm NO}{_{2}}}}}$), and bridging benzene-1,3,5-tricarboxylate (BTC). This facile approach to the assembly of copper catalysts on TiO2 with rationally tuned ORR activity will have significant implications for the development of high-performance, non-precious-metal ORR catalysts. PMID- 26602328 TI - Development of novel PET probes targeting phosphatidylinositol 3-kinase (PI3K) in tumors. AB - Phosphatidylinositol 3-kinase (PI3K) activity and protein expression levels are often increased in tumor regions. Since PI3K plays a crucial role in regulating cell growth and proliferation, inhibiting PI3K-dependent pathways could be a promising approach for cancer treatment. In clinical practice, however, evaluation of PI3K expression levels is limited to immunohistochemistry of patient samples, which requires invasive biopsies. Here we report the synthesis of three candidate compounds, FMTA-1, 2 and 3, and evaluate their capacity to detect PI3K expression levels with positron emission tomography (PET). Among the three candidates, FMTA-2 showed a lower IC50 value for PI3K. (18)F Radiolabeling of FMTA-2 to produce [(18)F]FMTA-2 was accomplished and its capacity for detecting PI3K expression levels was evaluated in vitro and in vivo. Cell uptake of [(18)F]FMTA-2 correlated well with cellular PI3K expression levels, and was suppressed by the ATP-competitive PI3K inhibitor ZSTK474. In an in vivo experiment using tumor-transplanted model mice, a higher signal-to-noise ratio (S/N) was seen with [(18)F]FMTA-2 in animals transplanted with DMS114 cells (expressing high PI3K levels) relative to DU145 cells (expressing low PI3K levels). However, in vivo pharmacokinetics of [(18)F]FMTA-2 was undesirable and the absolute amount of this compound that accumulated at the tumor region was low. To the best of our knowledge, this study represents the first trial of a PET tracer for detecting PI3K. Although further improvement of the probe is required prior to clinical application, these results should encourage future work. PMID- 26602329 TI - Synthesis and preliminary evaluation of an 18F-labeled oleic acid analog for PET imaging of fatty acid uptake and metabolism. AB - INTRODUCTION: Imaging fatty acid uptake and utilization has broad impact in investigating myocardial diseases, hepatic functions, tumor progression, and the metabolic state of adipose tissue. The SPECT tracer (123)I-15-(p-iodophenyl)-3 (R,S)-methylpentadecanoic acid (BMIPP) is a clinically used nuclear medicine tracer to image myocardial uptake of fatty acid. Although ((18)F-5) has been in clinical use for PET imaging of adipose tissue as well as the myocardium, here we developed a click oleate analog to compare to FTO, with the goal of improved stability to defluorination and suitability for imaging myocardial uptake and oxidation of fatty acids. METHODS: A rapid and convenient synthetic approach for a precursor to a (18)F-labeled oleate analog using click chemistry was developed and evaluated for PET imaging in fasted mice. RESULTS: The overall yield for the preparation of the labeling precursor of the clicked oleate analog was 12%. This precursor was efficiently radiolabeled with F-18 in 17% non-decay-corrected radiochemical yield. PET/CT imaging and biodistribution results show that this fatty acid analog had reasonable heart uptake (0.94+/-0.28 %ID/g at 0.5 h p.i.) and heart-to-muscle ratio (2.05+/-0.39 at 0.5h p.i.) and is a potential lead for developing new PET tracers to image fatty acid uptake and utilization using click chemistry methodologies. The synthetic route to FTO was optimized to three steps from known starting materials. CONCLUSION: While the uptake of the clicked oleic acid analog was sufficient for visualizing the myocardium in mice, the preliminary metabolism data suggest that only a fraction of the uptake was due to fatty acid beta-oxidation. Studies are under way to explore the uptake/oxidation mechanism and kinetics. PMID- 26602330 TI - Preliminary Evidence for the Usefulness of Standardized Nursing Terminologies in Different Fields of Application: A Literature Review. AB - PURPOSE: To examine the effects of using standardized terminologies in nursing. METHODS: A systematic literature research was conducted in June 2015 going back to January 2007. A modified narrative synthesis was used as the structure for the analysis. RESULTS: Twenty-three articles were included. Three themes were identified: enable evaluation of nursing-sensitive outcome indicators, enable calculation of resource consumption, and characterize nursing care. CONCLUSIONS: The studies included in the analysis described evidence for usefulness rather than effect. In all the studies, standardized nursing terminology was found to be essential for measuring, clarifying, and understanding nursing care. IMPLICATIONS FOR NURSING PRACTICE: The use of standardized terminologies could be advantageous. However, there are shortcomings in nursing documentation and the use of standardized nursing terminologies that obstruct evaluation of nursing care. PMID- 26602331 TI - Construction Morphology and the Parallel Architecture of Grammar. AB - This article presents a systematic exposition of how the basic ideas of Construction Grammar (CxG) (Goldberg, ) and the Parallel Architecture (PA) of grammar (Jackendoff, ) provide the framework for a proper account of morphological phenomena, in particular word formation. This framework is referred to as Construction Morphology (CxM). As to the implications of CxM for the architecture of grammar, the article provides evidence against a split between lexicon and grammar, in line with CxG. In addition, it shows that the PA approach makes it possible to be explicit about what happens on which level of the grammar, and thus to give an insightful account of interface phenomena. These interface phenomena appear to require that various types of information are accessible simultaneously, and it is argued that constructional schemas have the right format for expressing these mutual dependencies between different types of information. PMID- 26602333 TI - Record of insects in two fern species of the genus Microgramma (Polypodiaceae) in the Atlantic Rain Forest, Rio de Janeiro state, Brazil. PMID- 26602332 TI - Developing the Translational Research Workforce: A Pilot Study of Common Metrics for Evaluating the Clinical and Translational Award KL2 Program. AB - PURPOSE: This pilot study describes the career development programs (i.e., NIH KL2 awards) across five Clinical and Translational Science Award (CTSA) institutions within the University of California (UC) system, and examines the feasibility of a set of common metrics for evaluating early outcomes. METHODS: A survey of program administrators provided data related to the institutional environment within which each KL2 program was implemented. Application and progress report data yielded a combined data set that characterized KL2 awardees, their initial productivity, and early career outcomes. RESULTS: The pilot project demonstrated the feasibility of aggregating common metrics data across multiple institutions. The data indicated that KL2 awardees were an accomplished set of investigators, both before and after the award period, representing a wide variety of disciplines. Awardees that had completed their trainee period overwhelmingly remained active in translational research conducted within an academic setting. Early indications also suggest high rates of success with obtaining research funding subsequent to the KL2 award. CONCLUSION: This project offers a model for how to collect and analyze common metrics related to the education and training function of the CTSA Consortium. Next steps call for expanding participation to other CTSA sites outside of the University of California system. PMID- 26602334 TI - Catastrophic shifts in the aquatic primary production revealed by a small low flow section of tropical downstream after dredging. AB - Dredging is a catastrophic disturbance that directly affects key biological processes in aquatic ecosystems, especially in those small and shallow. In the tropics, metabolic responses could still be enhanced by the high temperatures and solar incidence. Here, we assessed changes in the aquatic primary production along a small section of low-flow tropical downstream (Imboassica Stream, Brazil) after dredging. Our results suggested that these ecosystems may show catastrophic shifts between net heterotrophy and autotrophy in waters based on three short term stages following the dredging: (I) a strongly heterotrophic net primary production -NPP- coupled to an intense respiration -R- likely supported by high resuspended organic sediments and nutrients from the bottom; (II) a strongly autotrophic NPP coupled to an intense gross primary production -GPP- favored by the high nutrient levels and low solar light attenuation from suspended solids or aquatic macrophytes; and (III) a NPP near to the equilibrium coupled to low GPP and R rates following, respectively, the shading by aquatic macrophytes and high particulate sedimentation. In conclusion, changes in aquatic primary production could be an important threshold for controlling drastic shifts in the organic matter cycling and the subsequent silting up of small tropical streams after dredging events. PMID- 26602335 TI - Trends and biases in global scientific literature about ecological niche models. AB - Recently, ecological niche models have been employed to investigate the potential geographical distribution of species. However, it is necessary to analyze the vast number of publications on this topic to understand the trends and biases of research using ecological niche models (ENMs). Therefore, this study aims to investigate trends in the scientific literature regarding studies on ENMs. For the quantitative analysis of the literature on ENMs, we performed a search in the Thomson ISI (Web of Science) database between 1991 and 2013. The search identified 3042 papers containing preselected keywords in either the title or abstract. The results showed that the number of papers has increased over the years (r=0.77, P<0.001), with a sharp increase in recent years, highlighting the widespread use of the ENMs. There was an increase in the diversity of journals that published papers about ENMs (r=0.97, P<0.001). The research was conducted in different countries, predominantly the United States of America (550 papers), and the most commonly used method was the Maximum Entropy method (312 papers). Regarding the taxonomic group, most research has been conducted on plants (402 papers, or 28.36% of the total). There was no relationship between the modeling method used and the taxonomic group studied (chi2=4.8, P=0.15). Finally, the wide availability of biological, environmental and computational resources has elicited the broad use of tools for ENMs. Despite the conceptual discussions of the ENMs, this method is currently the most effective way to evaluate the potential geographical distribution of species, and to predict the distribution under different environmental conditions (i.e., future or past scenarios). PMID- 26602336 TI - Enchytraeid abundance in Araucaria Mixed Forest determined by cold and hot wet extraction. AB - Enchytraeids are small oligochaetes found worldwide in soils with sufficient moisture and organic matter, but scarcely studied in the Southern hemisphere. This is the third study on enchytraeid abundance in Brazil using wet extraction and the first carried out in Araucaria Mixed Forest (subtropical region). The sampling and extraction were based on the standard method ISO 23611-3/2007 using an adapted split soil corer and wet extraction with and without heat to assess the abundance of enchytraeids in a forest fragment at Embrapa Forestry in Colombo, Parana State. The samplings were performed in 3 occasions between September 2011 and April 2012. The average numbers estimated by each method varied from appr. 2.000-12.000 (cold) and 5.000-12.000 ind./ m2 (hot), respectively, with a maximum of 44.000 ind./ m2 in one of the samples, the highest value reported so far in Brazil. The hot extraction was more advantageous, given the speed and preservation of the specimens in vivo, allowing taxonomic identification. Advantages and disadvantages of wet extractions compared to handsorting and formol methods are also discussed. Guaranidrilus, Hemienchytraeus, Enchytraeus, Fridericia and Achaeta were the genera identified in the samples. PMID- 26602337 TI - ITS-2 sequences-based identification of Trichogramma species in South America. AB - ITS2 (Internal transcribed spacer 2) sequences have been used in systematic studies and proved to be useful in providing a reliable identification of Trichogramma species. DNAr sequences ranged in size from 379 to 632 bp. In eleven T. pretiosum lines Wolbachia-induced parthenogenesis was found for the first time. These thelytokous lines were collected in Peru (9), Colombia (1) and USA (1). A dichotomous key for species identification was built based on the size of the ITS2 PCR product and restriction analysis using three endonucleases (EcoRI, MseI and MaeI). This molecular technique was successfully used to distinguish among seventeen native/introduced Trichogramma species collected in South America. PMID- 26602338 TI - First report of the microlepidopteran Caloreas cydrota (Meyrick, 1915) (Lepidoptera: Choreutidae) in Brazil. PMID- 26602339 TI - Taxonomical and biological notes on Sabethes (Peytonulus) fabricii Lane & Cerqueira (Diptera: Culicidae). AB - Morphological features that remained uncertain in previous identification keys and descriptions of Sabethes fabricii were evaluated based on species type material and two recently collected males. As a result, the following features of Sa. fabricii should be considered: proboscis with a white ventral spot beyond the middle and variably enlarged to the apex, possibly spatulate in males; setae over root of wing yellowish and may be occasionally brownish, mainly in their basal portion; and proctiger ending in four teeth. Additionally, the first record of bamboo as a natural breeding site for Sa. fabricii as well as the first register of this species in the state of Minas Gerais, Brazil are reported here. PMID- 26602341 TI - Interaction between resource identity and bacterial community composition regulates bacterial respiration in aquatic ecosystems. AB - Resource identity and composition structure bacterial community, which in turn determines the magnitude of bacterial processes and ecological services. However, the complex interaction between resource identity and bacterial community composition (BCC) has been poorly understood so far. Using aquatic microcosms, we tested whether and how resource identity interacts with BCC in regulating bacterial respiration and bacterial functional diversity. Different aquatic macrophyte leachates were used as different carbon resources while BCC was manipulated through successional changes of bacterial populations in batch cultures. We observed that the same BCC treatment respired differently on each carbon resource; these resources also supported different amounts of bacterial functional diversity. There was no clear linear pattern of bacterial respiration in relation to time succession of bacterial communities in all leachates, i.e. differences on bacterial respiration between different BCC were rather idiosyncratic. Resource identity regulated the magnitude of respiration of each BCC, e.g. Ultricularia foliosa leachate sustained the greatest bacterial functional diversity and lowest rates of bacterial respiration in all BCC. We conclude that both resource identity and the BCC interact affecting the pattern and the magnitude of bacterial respiration in aquatic ecosystems. PMID- 26602340 TI - Study on the Hymenoptera parasitoid associated with Lepidoptera larvae in reforestation and agrosilvopastoral systems at Fazenda Canchim (Embrapa Pecuaria Sudeste) Sao Carlos, SP, Brazil. AB - The aim of this study was to characterize the local fauna of Hymenoptera parasitoids associated with Lepidoptera larvae in areas of reforestation and agrosilvopastoral systems at Fazenda Canchim (Embrapa Pecuaria Sudeste, Sao Carlos, SP, Brazil). Lepidoptera larvae collected with entomological umbrella were kept in the laboratory until emergence of adults or their parasitoids. From those collected in the agrosilvopastoral system, emerged 267 specimens of hymenopteran parasitoids belonging to 16 genera: Braconidae, Agathidinae (Alabagrus), Braconinae (Bracon), Microgastrinae (Cotesia, Diolcogaster, Glyptapanteles, Pholetesor and Protapanteles), Orgilinae (Orgilus); Ichneumonidae, Campopleginae (Casinaria, Charops and Microcharops); Chalcididae, Chalcidinae (Brachymeria and Conura); Eulophidae, Entedoninae (Horismenus), Eulophinae (Elachertus and Euplectrus). From the Lepidoptera larvae collected in the reforestation, emerged 68 specimens of hymenopteran parasitoids, belonging to 8 genera: Chalcididae, Chalcidinae (Conura); Ichneumonidae, Pimplinae (Neotheronia), Campopleginae (Charops and Microcharops) and Braconidae, Microgastrinae (Apanteles, Diolcogaster, Distatrix, Glyptapanteles and Protapanteles). The results of this study suggest the occurrence of a wide variety of Hymenoptera parasitoids in the studied environments. PMID- 26602342 TI - Effect of land use on the composition, diversity and abundance of insects drifting in neotropical streams. AB - Streams may exhibit differences in community structure of invertebrate drift, which may be a reflex of variation in environmental factors, able to change in conditions of anthropogenic interventions. The aim of this study was to analyze the composition, diversity and abundance of insects drifting in two neotropical streams under different land use and to identify the environmental factors involved in determining such patterns. 54 taxa of aquatic insects were identified in urban and rural streams. The results indicated significant differences in species composition due to the replacement of specialist species by generalist species in the urban stream. Higher diversity of taxa was recorded in the rural stream, with high levels of dissolved oxygen and high water flow, which favored the occurrence of sensitive groups to environmental disturbances, such as Ephemeroptera, Plecoptera, Trichoptera and Coleoptera taxa, that living mainly in clean and well oxygenated waters. On the other hand, a higher density of insects drifting, especially Chironomidae, was observed in the urban stream, where high values of pH, electrical conductivity and nitrogen were observed. These larvae are able to explore a wide range of environmental conditions, owing to their great capacity for physiological adaptation. Despite observing the expected patterns, there were no significant differences between streams for the diversity and abundance of species. Thus, the species composition can be considered as the best predictor of impacts on the drifting insect community. PMID- 26602343 TI - First record of a breeding colony of black-necked stilt Himantopus mexicanus (Aves: Recurvirostridae) in northeastern Brazil. PMID- 26602344 TI - Seed rain generated by bats under Cerrado's pasture remnant trees in a Neotropical savanna. AB - In this study we described the seed rain generated by bats under four Cerrado's tree species common within pastures, Buchenavia tomentosa, Couepia grandiflora, Licania humilis and Qualea grandiflora. We analyzed the similarity among the four tree species in terms of seed rain composition, and compared the number of seeds and seed species deposited under them. Besides that, we assessed the relationship between seed rain intensity and the density of each tree species. Then, we randomly selected 10 mature trees of each species to sample seed rain. We recorded a total of 4892 bat dispersed seeds from 11 species. Also, we observed that along the year seed deposition varied substantially under all trees. At least two seed sub-communities could be distinguished according to tree species used by bats as feeding roost. One related to Couepia grandiflora and Licania humilis, and the other to Buchenavia tomentosa and Qualea grandiflora trees. The variability of seed rain composition in any particular tree and the range of actual seed fall into a particular species indicate patchiness in seed rain, and the overall results appear to be consistent in terms of a substantial and diverse seed rain generated by bats in a highly anthropized landscape. This is the first study concerning seed dispersal by bats in modified Brazilian Cerrado, one of the most endangered biomes in the world. In this respect, by preserving a dense and diverse collection of remnant trees within today's pastures may, potentially, contribute to a faster Cerrado recovery in extensive areas that can be reclaimed for restoration in the future. PMID- 26602345 TI - Paecilomyces niveus Stolk & Samson, 1971 (Ascomycota: Thermoascaceae) as a pathogen of Nasonovia ribisnigri (Mosley, 1841) (Hemiptera, Aphididae) in Brazil. AB - Nasonovia ribisnigri is a key pest of lettuce (Lactuca sativa L.) in Brazil that requires alternative control methods to synthetic pesticides. We report, for the first time, the occurrence of Paecilomyces niveus as an entomopathogen of the aphid Nasonovia ribisnigri in Pinhais, Parana, Brazil. Samples of mummified aphids were collected from lettuce crops. The fungus P. niveus (PaePR) was isolated from the insect bodies and identified by macro and micromorphology. The species was confirmed by sequencing Internal Transcribed Spacer (ITS) rDNA. We obtained a sequence of 528 bp (accession number HQ441751), which aligned with Byssochlamys nivea strains (100% identities). In a bioassay, 120 h after inoculation of N. ribisnigri with pathogenic P. niveus had an average mortality of 74%. The presence of P. niveus as a natural pathogen of N. ribisnigri in Brazil suggests that it may be possible to employ P. niveus to minimize the use of chemical insecticides. PMID- 26602346 TI - Mesembrinellinae (Diptera: Calliphoridae) to edge effects in the Tingua Biological Reserve, Rio de Janeiro, Brazil. AB - In this study we describe the diversity of Mesembrinelinae in a biological reserve in the city of Nova Iguacu, State of Rio de Janeiro. Traps containing sardines were distributed seasonally, at four sites: Site A (22 degrees 58.788' S, 43 degrees 43.459' W), in a forest edge, and sites B (22 degrees 58.523' S, 43 degrees 44.540' W), C (22 degrees 58.350' S, 43 degrees 44.678' W), and D (22 degrees 34.865' S, 43 degrees 27.063' W), located 1,000 m, 500 m, and 2,000 m respectively, inwards from the edge. A total of 2,150 individuals of Mesembrinellinae were collected, representing ten species. Laneela nigripes Guimaraes, 1977 was the most abundant species, followed by Mesembrinella bellardiana Aldrich, 1922, Eumesembrinella cyaneicincta (Surcouf, 1919) and Mesembrinella semihyalina Mello, 1967. These species were common and constant during the study period. Mesembrinella batesi Aldrich, 1922, Eumesembrinella quadrilineata (Fabricius, 1805) and Huascaromusca aeneiventris (Wiedmann, 1830) were the less abundant flies, being considered rare and accidental. Eumesembrinella besnoiti (Seguy, 1925) was rare and accessory. Eumesembrinella cyaneicincta, M. bellardiana, M. semihyalina and M. bicolor were mostly collected in site B, while L. nigripes was mostly collected in site C. The edge effect was not evident since the four sites showed similar populations. Site B showed a strong positive relationship between abundance and richness, in site C the correlation was positive and weak, and there was no correlation in A and D. The highest abundance of specimens was recorded during autumn and winter. These flies occurred from the edge up to 2,000 m inside the forest. PMID- 26602347 TI - Karyotypic variation of Glanidium ribeiroi Haseman, 1911 (Siluriformes, Auchenipteridae) along the Iguazu river basin. AB - The Iguazu river is a tributary of the left margin of the Parana river, isolated from this basin about 22 million years ago with the appearance of the Iguazu Falls. The Iguazu river is characterized by high endemism due to two factors: its rugged topography and the old isolation caused by formation of the Iguazu Falls. This study analyzed cytogenetically a population of Glanidium ribeiroi collected in a region at the final stretch of this basin, by Giemsa staining, C-banding, impregnation by silver nitrate, and FISH with probes of 5S rDNA, 18S rDNA, telomeric sequence [TTAGGG]n, and [GATA]n repeats. The diploid number was equal to 58 chromosomes. The heterochromatin was present in the terminal region of almost all chromosomes. The Ag-NORs were simple and presented interstitially on the short arm of the submetacentric pair 14, which was confirmed by FISH with 18S rDNA probe. The 5S rDNA-FISH marked only the submetacentric pair 16 on the long arm in interstitial position. The FISH with [TTAGGG]n probe presented all telomeres labeled as expected, with an absence of Interstitial Telomeric Sequence (ITS). The repetitive [GATA]n sequence was dispersed throughout the genome, with preferential location in the terminal region of all chromosomes. The data obtained are discussed herein with other species of Auchenipteridae, and other previously analyzed populations of G. ribeiroi from the Iguazu river, verifying differences among these populations, which should be mainly related to the rugged topography of this basin. PMID- 26602348 TI - Effects of season on ecological processes in extensive earthen tilapia ponds in Southeastern Brazil. AB - In Southeastern Brazil tilapia culture is conducted in extensive and semi intensive flow-through earthen ponds, being water availability and flow management different in the rainy and dry seasons. In this region lettuce wastes are a potential cheap input for tilapia culture. This study examined the ecological processes developing during the rainy and dry seasons in three extensive flow-through earthen tilapia ponds fertilized with lettuce wastes. Water quality, plankton and sediment parameters were sampled monthly during a year. Factor analysis was used to identify the ecological processes occurring within the ponds and to construct a conceptual graphic model of the pond ecosystem functioning during the rainy and dry seasons. Processes related to nitrogen cycling presented differences between both seasons while processes related to phosphorus cycling did not. Ecological differences among ponds were due to effects of wind protection by surrounding vegetation, organic loading entering, tilapia density and its grazing pressure on zooplankton. Differences in tilapia growth among ponds were related to stocking density and ecological process affecting tilapia food availability and intraspecific competition. Lettuce wastes addition into the ponds did not produce negative effects, thus this practice may be considered a disposal option and a low-cost input source for tilapia, at least at the amounts applied in this study. PMID- 26602350 TI - Bioimpedance as a tool for evaluating the body composition of suruvi (Steindachneridion scriptum). AB - Bioelectrical impedance analysis (BIA) is regarded as an important tool for evaluating the body composition of different animals in a rapid, non-destructive, and low-cost manner. A South American fish species, Steindachneridion scriptum, known as suruvi, was selected for study in this investigation. A protocol to produce fish with different body composition was used to allow BIA to adequately predict the body composition of suruvi. The fish were fed twice each day with two different diets; a low lipid diet (8.90%), and a high lipid diet (18.68%). These dietary differences allowed suruvi specimens with different body compositions to be produced. The BIA readings were determined using a Quantum X Bioelectrical Body Composition Analyzer. Two readings (dorsal and ventral) were obtained for each fish. After BIA readings were obtained, the proximate composition of the fish bodies for each individual was determined. All of the study data were used to establish correlation equations between proximate analyses and BIA values. Strong correlations were found for S. scriptum. The highest correlations were obtained for the following pairs of quantities, using BIA data from dorsal readings: moisture and resistance in series (R2 = 0.87); protein and resistance in series (R2 = 0.87); and ash and reactance in parallel (R2 = 0.82). We conclude that BIA is an effective method in determining the body composition of S. scriptum without sacrificing the fish. However, to expand the use of this new technology it is important to define strict BIA protocols to guarantee accurate estimates. PMID- 26602349 TI - Environmental influence on coprophagous Scarabaeidae (Insecta, Coleoptera) assemblages in the Pantanal of Mato Grosso. AB - Here we examine assemblage structure of coprophagous Scarabaeidae (dung beetles) in the Pantanal of the state of Mato Grosso with respect to flooding regimes, soil texture, leaf litter volume and tree dominance in native and exotic pastures. Samples were collected along 30 transects of 250 m in length in a 5*5 km grid (25 km2). Five pitfalls baited with human feces were placed in each transect. A total of 1692 individuals in 19 species were captured, the majority in the subfamily Scarabaeinae and Aphodiinae. Assemblages were influenced by the duration of flooding and leaf litter volume. None of the other habitat variables was correlated with species richness. Cultivated pastures with exotic grasses were unimportant for composition of the assemblages of beetles. These results indicate that duration of flooding is the most important regulating force in this community. PMID- 26602351 TI - Two common species dominate the species-rich Euglossine bee fauna of an Atlantic Rainforest remnant in Pernambuco, Brazil. AB - Nowadays, the northern part of the Atlantic Rainforest of Brazil is largely destroyed and forest remnants rarely exceed 100 ha. In a 118 ha forest fragment within a state nature reserve of Pernambuco (Reserva Ecologica Gurjau), we surveyed the orchid bee fauna (Apidae, Euglossini) using eight different scent baits to attract males. Once a month during one year, the bees were actively collected with entomological nets, from November 2002 to October 2003 by two collectors. We collected 2,908 orchid bee males belonging to 23 species, one of the highest richness values of the Northern Atlantic Rainforest. Bees of only two species, Euglossa carolina (50%) and Eulaema nigrita (25%), which occurred throughout the year, accounted for three quarter of the collected individuals. Both species are typical for open or disturbed areas. Rainforest remnants like those of Gurjau within the predominant sugar cane monocultures in the coastal plains of the northern Atlantic Rainforest play an important role in orchid bee conservation and maintenance of biodiversity. PMID- 26602352 TI - Abiotic variability among different aquatic systems of the central Amazon floodplain during drought and flood events. AB - This paper examines water properties from lakes, (depression lakes, sensu Junk et al., 2012), channels (scroll lakes with high connectivity, sensu Junk et al., 2012) and paleo-channels (scroll lakes with low connectivity-sensu Junk et al., 2012, locally called ressacas) located in Mamiraua Sustainable Development Reserve, in Central Amazon floodplain, Amazonas, Brazil. We analysed surface temperature, conductivity, pH, dissolved oxygen, turbidity, transparency, suspended inorganic and organic matter, chlorophyll-a, pheophytin, total nitrogen, total phosphorus, organic and inorganic carbon in 2009 high water phase, 2009 and 2010 low water phases. Multivariate statistical analyses of 24 aquatic systems (6 ressacas, 12 lakes and 6 channels, 142 samples) were applied to the variables in order to: 1) quantify differences among aquatic system types; 2) assess how those differences are affected in the different phases of the hydrological year. First, we analysed the entire set of variables to test for differences among phases of the hydrological year and types of aquatic systems using a PERMANOVA two-way crossed design. The results showed that the all measured limnological variables are distinct regarding both factors: types of aquatic systems and hydrological phases. In general, the magnitude and amplitude of all variables were higher in the low water phase than in the high water phase, except for water transparency in all aquatic system's types. PERMANOVA showed that the differences between aquatic system's types and hydrological phases of all variables were highly significant for both main factors (type and phase) and for the type x phase interaction. Limnological patterns of Amazon floodplain aquatic systems are highly dynamic, dependent on the surrounding environment, flood pulse, main river input and system type. These patterns show how undisturbed systems respond to natural variability in such a diverse environment, and how distinct are those aquatic systems, especially during the low water phase. Aquatic systems in Mamiraua floodplain represent limnological patterns of almost undisturbed areas and can be used as future reference for comparison with disturbed areas, such as those of the Lower Amazon, and as a baseline for studies on the effects of anthropogenic influences and climate change and on Amazon aquatic ecosystem. PMID- 26602353 TI - Phenology of two Ficus species in seasonal semi-deciduous forest in Southern Brazil. AB - We analyzed the phenology of Ficus adhatodifolia Schott ex Spreng. (23 fig tree) and F. eximia Schott (12 fig tree) for 74 months in a remnant of seasonal semi deciduous forest (23 degrees 27'S and 51 degrees 15'W), Southern Brazil and discussed their importance to frugivorous. Leaf drop, leaf flush, syconia production and dispersal were recorded. These phenophases occurred year-round, but seasonal peaks were recorded in both leaf phenophases for F. eximia and leaf flushing for F. adhatodifolia. Climatic variables analyzed were positively correlated with reproductive phenophases of F. adhatodifolia and negatively correlated with the vegetative phenophases of F. eximia. In despite of environmental seasonality, little seasonality in the phenology of two species was observed, especially in the reproductive phenology. Both species were important to frugivorous, but F. adhatodifolia can play a relevant role in the remnant. PMID- 26602354 TI - Habitat selection by owls in a seasonal semi-deciduous forest in southern Brazil. AB - This paper tested the hypothesis that the structural components of vegetation have impact over the distribution of owl species in a fragment of a semi deciduous seasonal forest. This paper also determined which vegetation variables contributed to the spatial distribution of owl species. It was developed in the Perobas Biological Reserve (PBR) between September and December 2011. To conduct the owl census, a playback technique was applied at hearing points distributed to cover different vegetation types in the study area. A total of 56 individual owls of six species were recorded: Tropical Screech-Owl (Megascops choliba), Black capped Screech-Owl (Megascops atricapilla), Tawny-browed Owl (Pulsatrix koeniswaldiana), Ferruginous Pygmy-Owl (Glaucidium brasilianum), Mottled Owl (Strix virgata) and Stygian Owl (Asio stygius). The results suggest that the variables of vegetation structure have impact on the occurrence of owls. The canopy height, the presence of hollow trees, fallen trees and glades are the most important structural components influencing owl distribution in the sampled area. PMID- 26602355 TI - Seed dispersal and predation of Buchenavia tomentosa Eichler (Combretaceae) in a Cerrado sensu stricto, midwest Brazil. AB - The ecology of seed dispersal is critical to understand the patterns of distribution and abundance of plant species. We investigated seed dispersal aspects associated with the high abundance of Buchenavia tomentosa in the Serra Azul State Park (PESA). We estimated fruit production and conducted fruit removal experiments. We carried out diurnal and nocturnal observations on frugivory as well as germination tests. Fruiting occurred in the dry season and totaled 1,365,015 +/- 762,670 fruits.ha-1. B. tomentosa fruits were utilized by eight animal species. The lowland tapir (Tapirus terrestris) was considered the main seed disperser. Leafcutter ants (Atta laevigata and Atta sexdens) participated in the seed cleaning and occasionally dispersed seeds. The beetle Amblycerus insuturatus, blue-and-yellow macaw (Ara ararauna) and red-and-green macaw (Ara chloropterus) were considered pre-dispersal seed predators. The seeds manually cleaned presented higher germination rate (100%) and speed index (4.2 seeds.d-1) than that of seeds with pulp. Germination of seeds found in tapirs'feces was 40%, while for the seeds without pulp it was 25%. The high abundance of B. tomentosa in the cerrado of PESA may be due to massive fruit production, low rates of seed predation, and efficient seed dispersal by tapirs, occurring before the rains which promote germination and recruitment of this species. PMID- 26602356 TI - Coleoptera associated with macrophytes of the genus Salvinia in four oxbow lakes in two river basins in southeast Brazil. AB - Macrophytes in oxbow lakes represent an important substrate for the Coleoptera. Two oxbow lakes the Rio Paranapanema were studied and the other two Rio Mogi Guacu, in the State de Sao Paulo, Brasil. In this study, there is greater similarity between the communities of Coleoptera of lakes greater connectivity with the main river channel or the difference in the species of Salvinia collected in the lakes studied interferes Coleoptera fauna that uses as substrate. A total of 9,222 specimens of Coleoptera were collected and identified in 10 families and 40 genera. The analysis MDS for abundance of Coleoptera showed the grouping of the oxbow lakes the Paranapanema River and a distancing the oxbow lakes the Mogi-Guacu. The PERMANOVA test did not reveal any difference in the fauna between the wet and dry periods. It was concluded that the connectivity between river and lake is not decisive for the richness and abundance of aquatic fauna of Coleoptera. Therefore, the richness and abundance of aquatic Coleoptera associated vary with the species of Salvinia used as substrate. PMID- 26602358 TI - Feeding resource partitioning between two understorey insectivorous birds in a fragment of Neotropical cloud forest. AB - The food habits and niche overlap based on diet composition and prey size of two species of understorey insectivorous birds were investigated in an area of montane rain forest in the state of Minas Gerais, southeastern Brazil. A total of 43 birds were captured: 33 individuals of Conopophaga lineata (Conopophagidae) with 13 recaptures, and 10 individuals of Myiothlypis leucoblephara (Parulidae) with 12 recaptures, from which were obtained respectively 33 and 10 fecal samples. Fragments of 16 groups of arthropods, plus insect eggs, were identified in these samples. Conopophaga lineata predominantly consumed Formicidae (32%) and Isoptera (23.6%). However, the index of alimentary importance (AI) of Isoptera (3.53) was lower than other groups such as Formicidae (AI = 61.88), Coleoptera (AI = 16.17), insect larvae (AI = 6.95) and Araneae (AI = 6.6). Myiothlypis leucoblephara predominantly consumed Formicidae (28.2%) and Coleoptera (24.4%), although Coleoptera and Hymenoptera non-Formicidae had the highest values of AI (38.71 and 22.98 respectively). Differences in the proportions of the types of arthropods consumed by birds were not enough to reveal their separation into feeding niches (overlap = 0.618, p observed <= expected = 0.934), whereas differences in the use of resources was mainly due to the size of the prey (p<0.001), where C lineata, the species with the highest body mass (p<0.001) consumed larger prey. It is plausible that prey size is an axis of niche dimension that allows the coexistence of these species. PMID- 26602357 TI - [RETRACTED ARTICLE] Derivation of new Brazilian lineages of human embryonic stem cells under physiological oxygen conditions. Braz J Biol. 2015 Nov 24. pii: S1519 69842015005105121. PMID- 26602359 TI - Geographic distribution of Gastrotheca fissipes (Boulenger, 1888) (Anura: Hemiphractidae) in the Brazilian Atlantic Forest. PMID- 26602360 TI - Raynaud's phenomenon in children. AB - Raynaud's Phenomenon is caused by spasm of the small arteries and arterioles of the fingers. It is triggered by various stimuli including exposure to cold or a stressful event. It may be symmetrical or wrap one end. The appearance of this entity in children is rare. We report the case of a 4 year old male consultation health center by episodes of coldness, pallor and pain in both feet. PMID- 26602361 TI - Acute pneumonitis in a patient with adult-onset disease after toclizumab treatment with good response to anakinra. AB - Pulmonary involvement in the form of acute pneumonitis in adult-onset Still's disease (AOSD) is an uncommon manifestation, with few cases reported in the literature. We report the case of a 61-year-old male with 3 years of AOSD evolution, treated with methotrexate (MTX) and half-dose corticosteroids, which debuted with symptoms of fever, dyspnea and dry cough after 3 weeks of receiving the first dose of tocilizumab (TCZ). In the follow-up study showed leukocytosis with left shift, elevated serum ferritin and C-reactive protein standard. The chest CT scan showed ground-glass pattern predominantly in central and upper lobes and the BAL shows an increase in the percentage of lymphocyte with normal subpopulations and negative cultures. MTX and TCM were suspended, prednisone was increased to 30mg/day and within a week Anakinra 100mg/day SC was iniciated, noting in a few days a progressive clinical, analytical and radiological improvement. PMID- 26602362 TI - Beating phantasies: Mourned and unmourned. AB - This paper intends to explore the organizing function and fate of sado masochistic phantasies in their fixed form, in the psychic life of patients who have suffered early traumas, due to environmental vicissitudes and maternal psychopathology. The theoretical starting point is provided by the Novicks' research into transitory and permanent beating phantasies in adult and child patients, their onset and their psychic function, based on an examination of Freud's paper 'A child is being beaten'. In this text Freud achieves an unprecedented syncretism, locating the phantasy at the intersection between the oedipal complex, which is a vertical structure organizing sexual and generational differences, and the fraternal dimension, which is horizontal and organizes the lateral relationship with that similar but different other who is the sibling. Reporting in some detail material from the analyses of two young women, whose clinical presentation and early traumas show some similarities, the author puts in the context of the analytic work the emerging of the sado-masochistic phantasies, emphasizing their use and function in the transference countertransference interplay. The beating phantasies shore up a precarious sense of self, threatened with psychic depletion and death, in identification with the absent mother of early infancy. An overly close relationship with a sibling, experienced as a narcissistic double, compounds the clinical picture, to establish the triangle formed by the parent(s) and two children which features in the beating phantasy. Finally, the author explores the contribution of ameliorating factors, such as alternative identificatory figures, constitutional endowment and capacity for sublimation, to account for the different fate of the fixed beating phantasies. PMID- 26602363 TI - Effect of a non-dieting lifestyle randomised control trial on psychological well being and weight management in morbidly obese pre-menopausal women. AB - OBJECTIVE: This study examined the effects of a non-dieting lifestyle intervention approach for morbidly obese women designed in the framework of the self-determination theory (SDT) and Health at Every Size on weight maintenance and psychological functioning. PARTICIPANTS AND DESIGN: Predominantly white (97%), morbidly obese (BMI >= 35 kg m(-2) with at least one co-morbid condition or a BMI >= 40 kg m(-2)) pre-menopausal women (N=62), aged between 24 and 55 years were initially randomly assigned to 12 weeks of lifestyle intervention (IIG) or delayed start control group (DSCG). The program consisted of 3 months intensive lifestyle intervention followed by 9 month maintenance phase. The DSCG group commenced the program after 3 months. RESULTS AND CONCLUSIONS: Initially, the IIG showed a significant decrease in body weight (baseline to end of the RCT phase) compared with a significant increase in the DSCG group. However, no significant changes in weight status were evident in either group at 12 months compared with baseline. The 3-month intensive intervention resulted in significantly improved psychological functioning in both groups, which were maintained at 12 months. The study provides additional support for a non-dieting, theory-based, lifestyle approach to weight management and psychological well being among morbidly obese females. PMID- 26602364 TI - Association between age, gender and multimorbidity level and receiving home health care: a population-based Swedish study. AB - BACKGROUND: Home health care is an important part of primary health care. How delivery of home health care is organised is probably important for sustainability of the healthcare system as a whole. More than 50 % of individuals over 65 years old have multimorbidity, which increases with higher age, also influencing the needs of home health care. Our aim was to study the proportion of the population above 65 years receiving home health care according to age, gender and multimorbidity level. METHODS: The study population comprised 32,130 people aged 65 or more, living in Blekinge County in southern Sweden. We analysed data from patient electronic medical records for patients receiving home health care delivered in patients' own homes by nurses, physiotherapists and occupational therapists. We used the Adjusted Clinical Groups Case-Mix System in order to group individuals according to diagnoses into six levels of multimorbidity. In order to analyse the differences between individuals receiving home health care and those who did not, we used Chi squared test. Logistic regression analysis was conducted in order to study how the dependent variable was influenced by the independent variables. RESULTS: A total of 7860 (28 %) of the studied population received home health care in 2011. Logistic regression analysis showed that men had 26 % lower odds of receiving home care compared to women (OR = 0.74, 95 % CI 0.69-0.78). There was also a substantial group (22 %) with low multimorbidity level among people receiving home health care. Adjusting for gender and age showed no differences in odds of receiving home health care for patients with lower levels of multimorbidity. However, for patients with higher levels of morbidity the odds increased dramatically for both genders. CONCLUSION: The question of to whom and to what extent home health care should be provided is an important challenge for policy makers. Our results show that there are differences in the use of home health care dependent on gender, age and multimorbidity level, but also that home health care is provided to individuals with low morbidity. Further studies could explain the factors influencing home health care use. PMID- 26602366 TI - Characterization of MDAPhi, a temperate filamentous bacteriophage of Neisseria meningitidis. AB - The mechanism by which Neisseria meningitidis becomes invasive is not well understood. Comparative genomics identified the presence of an 8 kb island in strains belonging to invasive clonal complexes. This island was designated MDA for meningococcal disease associated. MDA is highly conserved among meningococcal isolates and its analysis revealed a genomic organization similar to that of a filamentous prophage such as CTXPhi of Vibrio cholerae. Subsequent molecular investigations showed that the MDA island has indeed the characteristics of a filamentous prophage, which can enter into a productive cycle and is secreted using the type IV pilus (tfp) secretin PilQ. At least three genes of the prophage are necessary for the formation of the replicative cytoplasmic form (orf1, orf2 and orf9). Immunolabelling of the phage with antibodies against the major capsid protein, ORF4, confirmed that filamentous particles, about 1200 nm long, covered with ORF4 are present at the bacterial surface forming bundles in some places and interacting with pili. The MDA bacteriophage is able to infect different N. meningitidis strains, using the type IV pili as a receptor via an interaction with the adsorption protein ORF6. Altogether, these data demonstrate that the MDA island encodes a functional prophage able to produce infectious filamentous phage particles. PMID- 26602365 TI - Late prenatal immune activation causes hippocampal deficits in the absence of persistent inflammation across aging. AB - BACKGROUND: Prenatal exposure to infection and/or inflammation is increasingly recognized to play an important role in neurodevelopmental brain disorders. It has recently been postulated that prenatal immune activation, especially when occurring during late gestational stages, may also induce pathological brain aging via sustained effects on systemic and central inflammation. Here, we tested this hypothesis using an established mouse model of exposure to viral-like immune activation in late pregnancy. METHODS: Pregnant C57BL6/J mice on gestation day 17 were treated with the viral mimetic polyriboinosinic-polyribocytidilic acid (poly(I:C)) or control vehicle solution. The resulting offspring were first tested using cognitive and behavioral paradigms known to be sensitive to hippocampal damage, after which they were assigned to quantitative analyses of inflammatory cytokines, microglia density and morphology, astrocyte density, presynaptic markers, and neurotrophin expression in the hippocampus throughout aging (1, 5, and 22 months of age). RESULTS: Maternal poly(I:C) treatment led to a robust increase in inflammatory cytokine levels in late gestation but did not cause persistent systemic or hippocampal inflammation in the offspring. The late prenatal manipulation also failed to cause long-term changes in microglia density, morphology, or activation, and did not induce signs of astrogliosis in pubescent, adult, or aged offspring. Despite the lack of persistent inflammatory or glial anomalies, offspring of poly(I:C)-exposed mothers showed marked and partly age-dependent deficits in hippocampus-regulated cognitive functions as well as impaired hippocampal synaptophysin and brain-derived neurotrophic factor (BDNF) expression. CONCLUSIONS: Late prenatal exposure to viral-like immune activation in mice causes hippocampus-related cognitive and synaptic deficits in the absence of chronic inflammation across aging. These findings do not support the hypothesis that this form of prenatal immune activation may induce pathological brain aging via sustained effects on systemic and central inflammation. We further conclude that poly(I:C)-based prenatal immune activation models are reliable in their effectiveness to induce (hippocampal) neuropathology across aging, but they appear unsuited for studying the role of chronic systemic or central inflammation in brain aging. PMID- 26602367 TI - Deceased Donor Organs: What Can Be Done to Raise Donation Rates Using Evidence From Malaysia? AB - Organ donation rates have continued to fall seriously short of needs worldwide, with the lowest rates recorded among developing economies. This study seeks to analyze evidence from a developing economy to explore the usefulness of social psychological theory to solve the problem. The study deployed a large survey (n = 10 412) using a convenience sampling procedure targeted at increasing the number of Malaysians registered with the Ministry of Health, Malaysia who are willing to donate organs upon death. Structural equation modeling was deployed to estimate simultaneously the relative influence of cognitive and noncognitive variables on willingness to donate deceased organs. The cognitive factors of donation perception, socioeconomic status and financial incentives, and the noncognitive factors of demography and fear showed a high statistically significant (1%) relationship with willingness to donate organs after death. While financial incentives were significant, cash rewards showed the least impact. Donation perception showed the highest impact, which shows that the development of effective pedagogic programs with simultaneous improvements to the quality of services provided by medical personnel engaged in retrieving and transplanting deceased donor organs can help raise organ donation rates. PMID- 26602368 TI - Exclusive breast feeding in early infancy reduces the risk of inpatient admission for diarrhea and suspected pneumonia in rural Vietnam: a prospective cohort study. AB - BACKGROUND: Acute respiratory infections and diarrhea remain the leading causes of infant morbidity and mortality, with a high burden of both pneumonia and diarrhea in South-East Asia. The aim of the study was to determine antenatal and early infant predictive factors for severe morbidity episodes during the first 6 months of life in Ha Nam province, Vietnam. METHODS: A prospective cohort study of 1049 infants, born to women who had previously participated in a cluster randomized controlled trial of antenatal micronutrient supplementation in rural Vietnam, was undertaken between 28th September 2010 and 8th Jan 2012. Infants were followed until 6 months of age, and the outcome measure was inpatient admission for suspected pneumonia or diarrheal illness during the first 6 months of life. Risk factors were assessed using univariable logistic regression and multiple logistic regression. RESULTS: Of the 1049 infants seen at 6 months of age, 8.8 % required inpatient admission for suspected pneumonia and 4 % of infants required inpatient admission for diarrheal illness. One third of infants (32.8 %) were exclusively breast fed at 6 weeks of age. Exclusive breast feeding at 6 weeks of age significantly reduced the odds of inpatient admission for suspected pneumonia (Odds Ratio (OR) 0.39, 95 % Confidence Interval (CI) 0.20 to 0.75) and diarrheal illness (OR 0.37, 95 % CI 0.15 to 0.88). CONCLUSIONS: Exclusive breast feeding in early infancy reduces the risk of severe illness from diarrhea and suspected pneumonia. Public health programs to reduce the burden of inpatient admission from diarrheal and respiratory illness in rural Vietnam should address barriers to exclusive breast feeding. PMID- 26602369 TI - Trained immunity: a new avenue for tuberculosis vaccine development. AB - Adaptive immunity towards tuberculosis (TB) has been extensively studied for many years. In addition, in recent years the profound contribution of innate immunity to host defence against this disease has become evident. The discovery of pattern recognition receptors, which allow innate immunity to tailor its response to different infectious agents, has challenged the view that this arm of immunity is nonspecific. Evidence is now accumulating that innate immunity can remember a previous exposure to a microorganism and respond differently during a second exposure. Although the specificity and memory of innate immunity cannot compete with the highly sophisticated adaptive immune response, its contribution to host defence against infection and to vaccine-induced immunity should not be underestimated and needs to be explored. Here, we present the concept of trained immunity and discuss how this may contribute to new avenues for control of TB. PMID- 26602370 TI - [Not Available]. PMID- 26602371 TI - Possible recovery or unavoidable fall? A model to predict the one step balance recovery threshold and its stepping characteristics. AB - In order to prevent fall related injuries and their consequences, one needs to be able to predict the outcome of a given balance perturbation: a possible Balance Recovery (BR) or an unavoidable fall? Given that results from the existing experimental studies are difficult to compare and to generalize, we propose to address this question with a numerical tool. Built on existing concepts from the biomechanics and robotics literature, it includes the optimal use of BR reactions and particularly the possibility to perform a recovery step. It allows estimating 1) the possibility to recover a steady balance from a given initial state or perturbation using at most one recovery step; 2) the set of recovery steps leading to a BR. Using standard sets of parameters for young and elderly population, we assessed this model's predictions against experimental data from the literature in the anterior direction. Two classical representations of the human body (inverted pendulum (IP) vs. linear inverted pendulum (LIP)) were also compared. The results showed that the model correctly predicted the possibility to recover using a single protective step (1-Step BR threshold) and the characteristics (step length and time) of the protective step for both the young and the elderly. This tool has a real potential in the field of fall prevention to detect risky situation. It could also be used to get insights into the neuromuscular mechanisms involved in the BR process. PMID- 26602372 TI - A model experiment to understand the oral phase of swallowing of Newtonian liquids. AB - A model experiment to understand the oral phase of swallowing is presented and used to explain some of the mechanisms controlling the swallowing of Newtonian liquids. The extent to which the flow is slowed down by increasing the viscosity of the liquid or the volume is quantitatively studied. The effect of the force used to swallow and of the gap between the palate and the roller used to represent the contracted tongue are also quantified. The residual mass of liquid left after the model swallow rises strongly when increasing the gap and is independent of bolus volume and applied force. An excessively high viscosity results in higher residues, besides succeeding in slowing down the bolus flow. A realistic theory is developed and used to interpret the experimental observations, highlighting the existence of an initial transient regime, at constant acceleration, that can be followed by a steady viscous regime, at constant velocity. The effect of the liquid viscosity on the total oral transit time is lower when the constant acceleration regime dominates bolus flow. Our theory suggests also that tongue inertia is the cause of the higher pressure observed at the back of the tongue in previous studies. The approach presented in this study paves the way toward a mechanical model of human swallowing that would facilitate the design of novel, physically sound, dysphagia treatments and their preliminary screening before in vivo evaluations and clinical trials. PMID- 26602373 TI - Assessing surgical treatment outcome following superficial temporal artery to middle cerebral artery bypass based on computational haemodynamic analysis. AB - To estimate haemodynamic modification of Internal Carotid Artery (ICA) after bypass surgery using computational fluid dynamic (CFD) technology and thereby aid in our understanding of the influence of hemodynamic parameters on the outcomes of bypass operations. 18 patients who underwent superficial temporal artery to middle cerebral artery bypass and encephaloduromyosynangiosis (EDMS) surgery were included. Reconstructed three-dimensional vessel geometries from MRA were segmented to create computational domains for CFD simulations. All cases were classified as three groups according to the proportion of the MCA area of distribution supplied by revascularization: A, more than two thirds; B, between two-thirds and one-third; and C, less than one-third of the MCA distribution. Pre operative and follow-up haemodynamic parameters, especially volume flow rate and pressure drop index (PDI) in ICA were compared. For all cases, PDI and volume flow rate in the surgical-side ICA decreased significantly at follow-up (P<0.05). For the cases of group A, volume flow rate in surgical-side ICA decreased by average 24.2%, whilst for the cases of group B and C, flow rate reduced by 10.5% and 3.7%, respectively. An average PDI for cases in group A was -1.67mmHg, conversely average PDI values of group B and C were -0.53 and 0.82mmHg, respectively. The remodelling of ICA after bypass was associated with reduction in the volume flow rate and pressure drop. Good correlation with angiographic grading suggested that CFD might play a critical role as a quantitative haemodynamic technique for predicting treatment outcome during the follow-up of MMD patients. PMID- 26602374 TI - Identification of hyperelastic properties of passive thigh muscle under compression with an inverse method from a displacement field measurement. AB - The mechanical behavior of muscle tissue is an important field of investigation with different applications in medicine, car crash and sport, for example. Currently, few in vivo imaging techniques are able to characterize the mechanical properties of muscle. Thus, this study presents an in vivo method to identify a hyperelatic behavior from a displacement field measured with ultrasound and Digital Image Correlation (DIC) techniques. This identification approach was composed of 3 inter-dependent steps. The first step was to perform a 2D MRI acquisition of the thigh in order to obtain a manual segmentation of muscles (quadriceps, ischio, gracilis and sartorius) and fat tissue, and then develop a Finite Element model. In addition, a Neo-Hookean model was chosen to characterize the hyperelastic behavior (C10, D) in order to simulate a displacement field. Secondly, an experimental compression device was developed in order to measure the in vivo displacement fields in several areas of the thigh. Finally, an inverse method was performed to identify the C10 and D parameters of each soft tissue. The identification procedure was validated with a comparison with the literature. The relevance of this study was to identify the mechanical properties of each investigated soft tissues. PMID- 26602375 TI - Effects of noxious stimulation to the back or calf muscles on gait stability. AB - Gait stability is the ability to deal with small perturbations that naturally occur during walking. Changes in motor control caused by pain could affect this ability. This study investigated whether nociceptive stimulation (hypertonic saline injection) in a low back (LBP) or calf (CalfP) muscle affects gait stability. Sixteen participants walked on a treadmill at 0.94ms(-1) and 1.67ms( 1), while thorax kinematics were recorded using 3D-motion capture. From 110 strides, stability (local divergence exponent, LDE), stride-to-stride variability and root mean squares (RMS) of thorax linear velocities were calculated along the three movement axes. At 0.94ms(-1), independent of movement axes, gait stability was lower (higher LDE) and stride-to-stride variability was higher, during LBP and CalfP than no pain. This was more pronounced during CalfP, likely explained by the biomechanical function of calf muscles in gait, as supported by greater mediolateral RMS and stance time asymmetry than in LBP and no pain. At 1.67ms( 1), independent of movement axes, gait stability was greater and stride-to-stride variability was smaller with LBP than no pain and CalfP, whereas CalfP was not different from no pain. Opposite effects of LBP on gait stability between speeds suggests a more protective strategy at the faster speed. Although mediolateral RMS was greater and participants had more asymmetric stance times with CalfP than LBP and no pain, limited effect of CalfP at the faster speed could relate to greater kinematic constraints and smaller effects of calf muscle activity on propulsion at this speed. In conclusion, pain effects on gait stability depend on pain location and walking speed. PMID- 26602376 TI - IGF-I and IGF-II effects on local IGF system and signaling pathways in gilthead sea bream (Sparus aurata) cultured myocytes. AB - The insulin-like growth factors (IGFs) have a fundamental role in a vast range of functions acting through a tyrosine-kinase receptor (IGF-IR). IGFs in muscle can affect the expression of components of the local IGF system, myogenic regulatory factors (MRFs), proliferating (proliferating cell nuclear antigen, PCNA) or differentiating molecules (myosin heavy chain, MHC) and, lead to the activation of different signaling pathways. The response of all these genes to IGFs incubation at two different times in day 4 cultured myocytes of gilthead sea bream was analyzed. Both IGFs increased the expression of IGF-I and IGFBP-5, but showed different effects on the receptors, with IGF-I suppressing the expression of both isoforms (IGF-IRa and IGF-IRb) and IGF-II up-regulating only IGF-IRb. Moreover, the protein levels of PCNA and target of rapamycin (TOR) increased after IGF-II incubation, although a decline in Myf5 and a rise in MHC gene expression was caused by IGF-I. Taken together, these results provide evidence for the importance of IGFs on controlling muscle development and growth in gilthead sea bream and suggest that each IGF may be preferentially acting through a specific IGF-IR. Moreover, the data support the hypothesis that IGF-II has a more important role during proliferation, whereas IGF-I seems to be relevant for the differentiation phase of myogenesis. PMID- 26602377 TI - Effect of polybrominated diphenyl ether (BDE-209) on testicular steroidogenesis and spermatogenesis through altered thyroid status in adult mice. AB - Polybrominated diphenyl ethers (PBDEs), a class of brominated flame retardants (BFRs), have been widely used in many products to minimize the risk of fire, mainly by mixing in polymer products. BDE-209, a congener of PBDEs having structural similarity with thyroid hormones, acts as an endocrine disruptor by interfering with thyroid homeostasis. However, little is known about the effect of BDE-209 exposure on testicular steroidogenesis and spermatogenesis. This study was therefore conducted in adult mice to examine the effect of BDE-209 on testicular steroidogenesis and spermatogenesis in relation to thyroid status, and to explore possible mechanism(s) of its action. Adult Parkes strain male mice were orally gavaged with 750 and 950mg/kg BW of BDE-209 in corn oil for 35days. Significant reductions were noted in the levels of serum total T3, T4 and testosterone in mice treated with 950mg/kg BW of BDE-209 compared to controls; histologically, testes showed nonuniform degenerative changes in the seminiferous tubules as both affected and normal tubules were observed in the same section; further, number and viability of spermatozoa were also adversely affected in cauda epididymidis of these mice. Semiquantitative RT-PCR and western blot analyses also showed significant reductions in both testicular mRNA and protein levels of steroidogenic factor 1 (SF-1), steroidogenic acute regulatory (StAR) protein, cytochrome P450scc (CYP11A1), 3beta-hydroxysteroid dehydrogenase (3beta HSD) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) in 950mg dose treated mice compared to controls. Immunohistochemical and immunoblot analyses further revealed a marked decrease in proliferating cell nuclear antigen (PCNA) positive cells in testes of 950mg dose of BDE-209-treated mice. However, 750mg dose of BDE 209 had no effect on the above parameters. In conclusion, our results suggest that exposure of BDE-209 to adult mice causes reduction in serum levels of thyroid hormones and altered thyroid status may partly result into impairment of testicular steroidogenesis because of down-regulated expression of SF-1, thereby causing suppression of spermatogenesis. PMID- 26602378 TI - Relationship between prolactin, reproductive experience, and parental care in a biparental songbird, the zebra finch (Taeniopygia guttata). AB - Hormonal systems have long been thought to play an important role in stimulating the onset of parental behavior, a critical component of reproductive success in a variety of taxa. Elevations in the peptide hormone prolactin (PRL) have been repeatedly positively correlated with the onset and maintenance of parental care across vertebrate species. A causal role for PRL in parental care has been established in several mammalian species, but less evidence for a causal role of PRL and parental care exists in birds. The zebra finch, a socially monogamous, biparental songbird, is an exceptionally useful animal model to study parental care and other close social relationships. Both sexes share parental care equally, exhibit the same parental behaviors, and show a marked improvement in breeding success with experience. We hypothesize that PRL is critically involved in the expression of zebra finch parental care and predict that circulating PRL levels will increase with breeding experience. To begin testing this, we measured plasma PRL concentrations in 14 male-female zebra finch pairs (N=28) across two breeding cycles, using a repeated measures design. PRL was measured in the birds' first, reproductively inexperienced, breeding cycle beginning at courtship and extending through chick fledging. PRL was measured again during the birds' second, reproductively experienced, breeding cycle, beginning with egg laying until chick fledging. We found that plasma PRL is significantly elevated from non breeding concentrations during late incubation and early post-hatch care and that this elevation is greater in the reproductively experienced cycle compared to the inexperienced cycle. Findings of this study will be used to inform hypotheses and predictions for future experimental manipulations of PRL during parental care. PMID- 26602379 TI - Using an Integrated -Omics Approach to Identify Key Cellular Processes That Are Disturbed in the Kidney After Brain Death. AB - In an era where we are becoming more reliant on vulnerable kidneys for transplantation from older donors, there is an urgent need to understand how brain death leads to kidney dysfunction and, hence, how this can be prevented. Using a rodent model of hemorrhagic stroke and next-generation proteomic and metabolomic technologies, we aimed to delineate which key cellular processes are perturbed in the kidney after brain death. Pathway analysis of the proteomic signature of kidneys from brain-dead donors revealed large-scale changes in mitochondrial proteins that were associated with altered mitochondrial activity and morphological evidence of mitochondrial injury. We identified an increase in a number of glycolytic proteins and lactate production, suggesting a shift toward anaerobic metabolism. Higher amounts of succinate were found in the brain death group, in conjunction with increased markers of oxidative stress. We characterized the responsiveness of hypoxia inducible factors and found this correlated with post-brain death mean arterial pressures. Brain death leads to metabolic disturbances in the kidney and alterations in mitochondrial function and reactive oxygen species generation. This metabolic disturbance and alteration in mitochondrial function may lead to further cellular injury. Conditioning the brain-dead organ donor by altering metabolism could be a novel approach to ameliorate this brain death-induced kidney injury. PMID- 26602381 TI - Introduction to the Special Issue. PMID- 26602380 TI - Replicate exome-sequencing in a multiple-generation family: improved interpretation of next-generation sequencing data. AB - BACKGROUND: Whole-exome sequencing (WES) is rapidly evolving into a tool of choice for rapid, and inexpensive identification of molecular genetic lesions within targeted regions of the human genome. While biases in WES coverage of nucleotides in targeted regions are recognized, it is not well understood how repetition of WES improves the interpretation of sequencing results in a clinical diagnostic setting. METHOD: To address this, we compared independently generated exome-capture of six individuals from three-generations sequenced in triplicate. This generated between 48x-86x mean target depth of high-quality mapped bases (>Q20) for each technical replicate library. Cumulatively, we achieved 179 - 208x average target coverage for each individual in the pedigree. Using this experimental design, we evaluated stochastics in WES interpretation, genotyping sensitivity, and accuracy to detect de novo variants. RESULTS: In this study, we show that repetition of WES improved the interpretation of the capture target regions after aggregating the data (93.5 - 93.9 %). Compared to 81.2 - 89.6 % (50.2-55.4 Mb of 61.7 M) coverage of targeted bases at >=20x in the individual technical replicates, the aggregated data covered 93.5 - 93.9 % of targeted bases (57.7 - 58.0 of 61.7 M) at >=20x threshold, suggesting a 4.3 - 12.7 % improvement in coverage. Each individual's aggregate dataset recovered 3.4 - 6.4 million bases within variable targeted regions. We uncovered technical variability (2-5 %) inherent to WES technique. We also show improved interpretation in assessing clinically important regions that lack interpretation under current conditions, affecting 12-16 of the 56 genes recommended for secondary analysis by American College of Medical Genetics (ACMG). We demonstrate that comparing technical replicate WES datasets and their derived aggregate data can effectively address overall WES genotyping discrepancies. CONCLUSION: We describe a method to evaluate the reproducibility and stochastics in exome library preparation, and delineate the advantages of aggregating the data derived from technical replicates. The implications of this study are directly applicable to improved experimental design and provide an opportunity to rapidly, efficiently, and accurately arrive at reliable candidate nucleotide variants. PMID- 26602383 TI - PGC-1beta regulates HER2-overexpressing breast cancer cells proliferation by metabolic and redox pathways. AB - Breast cancer is a prevalent neoplastic disease among women worldwide which treatments still present several side effects and resistance. Considering that cancer cells present derangements in their energetic homeostasis, and that peroxisome proliferator-activated receptor- gamma coactivator 1 (PGC-1) is crucial for cellular metabolism and redox signaling, the main objective of this study was to investigate whether there is a relationship between PGC-1 expression, the proliferation of breast cancer cells and the mechanisms involved. We initially assessed PGC-1beta expression in complementary DNA (cDNA) from breast tumor of patients bearing luminal A, luminal B, and HER2-overexpressed and triple negative tumors. Our data showed that PGC-1beta expression is increased in patients bearing HER2-overexpressing tumors as compared to others subtypes. Using quantitative PCR and immunoblotting, we showed that breast cancer cells with HER2 amplification (SKBR-3) have greater expression of PGC-1beta as compared to a non tumorous breast cell (MCF-10A) and higher proliferation rate. PGC-1beta expression was knocked down with short interfering RNA in HER2-overexpressing cells, and cells decreased proliferation. In these PGC-1beta-inhibited cells, we found increased citrate synthase activity and no marked changes in mitochondrial respiration. Glycolytic pathway was decreased, characterized by lower intracellular lactate levels. In addition, after PGC-1beta knockdown, SKBR-3 cells showed increased reactive oxygen species production, no changes in antioxidant activity, and decreased expression of ERRalpha, a modulator of metabolism. In conclusion, we show an association of HER2-overexpression and PGC 1beta. PGC-1beta knockdown impairs HER2-overexpressing cells proliferation acting on ERRalpha signaling, metabolism, and redox balance. PMID- 26602385 TI - Outcome measures in trials: the systematic reviewer's point of view. PMID- 26602384 TI - Wnt/beta-catenin signaling inhibits FBXW7 expression by upregulation of microRNA 770 in hepatocellular carcinoma. AB - FBXW7 (F-box and WD repeat domain-containing 7) is the F-box protein component of a Skp1-Cul1-F-box protein-type (SCF-type) ubiquitin ligase. Previous studies have shown that FBXW7 serves as a tumor suppressor and is frequently downregulated in many types of human neoplasms. However, the molecular mechanisms for its downregulation remain poorly understood. Hyperactivation of Wnt/beta-catenin signaling pathway is viewed as crucial for tumorigenesis, including hepatocellular carcinoma (HCC). In the present study, we show that protein levels, but not message RNA, of FBXW7 were suppressed by Wnt3a treatment or transfection of a constitutively activated beta-catenin in HCC cells. Besides, microRNA-770 was identified as an important downstream target of Wnt/beta-catenin signaling, to inhibit FBXW7 expression through targeting its 3'-untranslated region. Thus, our results suggest a previously unknown Wnt/beta catenin-miR-770 FBXW7 molecular network in the HCC development. PMID- 26602386 TI - Outcome measures in health research: from assessing validity to outcome reporting. PMID- 26602382 TI - The role of TWIST1 in epithelial-mesenchymal transition and cancers. AB - TWIST1 is a basic helix-loop-helix (bHLH) transcription factor which plays essential and pivotal roles in multiple stages of embryonic development, and significantly contributes to tumor metastasis, even tumor initiation and primary tumor growth. It is well recognized that TWIST1 is overexpressed in a variety of tumors. Overexpression of TWIST1 induces epithelial-mesenchymal transition (EMT), a key process in the metastases formation of cancer. TWIST1 also promotes the formation of cancer stem cells and facilitates the process of tumorigenesis. Numerous studies have shown that targeting TWIST1 or TWIST1-related molecules significantly inhibits tumor growth, restricts tumor metastasis, reverses drug resistance, and thus improves the survival of cancer patients. Therefore, it is important to provide a better understanding of the context-dependent regulation of TWIST1 in each individual epithelial tumor, which might reveal new therapeutic targets in cancer treatment. PMID- 26602388 TI - Black esophagus: an uncommon cause of upper gastrointestinal bleeding. PMID- 26602387 TI - Nonalcoholic fatty liver disease as trigger of cardiovascular and metabolic complication in metabolic syndrome. PMID- 26602389 TI - Human embryonic stem cells. AB - The establishment of permanent human embryonic stem cell lines (hESCs) was first reported in 1998. Due to their pluripotent nature and ability to differentiate to all cell types in the body, they have been considered as a cell source for regenerative medicine. Since then, intensive studies have been carried out regarding factors regulating pluripotency and differentiation. hESCs are obtained from supernumerary human IVF (in vitro fertilization) embryos that cannot be used for the couple's infertility treatment. Today, we can establish and expand these cells in animal substance-free conditions, even from single cells biopsied from eight-cell stage embryos. There are satisfactory tests for the demonstration of genetic stability, absence of tumorigenic mutations, functionality, and safety of hESCs. Clinical trials are ongoing for age-related macular degeneration (AMD) and spinal cord injury (SCI). This review focuses on the present state of these techniques. PMID- 26602390 TI - [Liquid Biopsy in Multimodal Treatment of Esophageal Carcinoma]. AB - Predicting and monitoring the treatment response of patients with esophageal carcinoma are important. Molecular analyses of biopsy specimens are useful; however, the characteristics of the biopsy specimen are not similar to those of whole tumors, including metastatic tumors. Therefore, liquid biopsy using blood samples has been applied for the prediction of the tumor stage, sensitivity to radiotherapy, sensitivity to chemotherapy, and recurrent disease. Liquid biopsy is advantageous for monitoring the treatment response and as an objective diagnostic tool; it is cost effective. PMID- 26602391 TI - [Concept and Overview of JSMO Guidelines for the Treatment of Bone Metastasis]. AB - Many diagnostic and treatment modalities for bone metastasis are available. They include biomarker examination, imaging techniques, surgery, radiation therapy, chemotherapy, palliation, and rehabilitation, among others. Diagnosis of the disease and administration of these treatments require caregivers and other medical personnel including medical oncologists for primary tumors, radiologists, pathologists, orthopedists, radiotherapists, palliative care doctors, rehabilitation doctors, dentists, nurses, pharmacists, physical therapists, psychologists, and medical social workers. In multidisciplinary teamwork, knowledge of the potency of each intervention performed for the patients is important to improve treatment outcomes. Therefore, guidelines can contribute to better understanding and collaboration of one intervention with another. Guidelines should be based on medical evidences obtained from clinical studies that yield highly reliable results. Evidences for the treatment of bone metastasis are still lacking. Especially, the evidences for multi-modal treatment are rarely of described. In 2015, the Japanese Society for Medical Oncology released guidelines for the diagnosis and treatment of bone metastases. These guidelines aim to improve clinical procedures and treatment outcomes. In these guidelines, we described the current measures applicable for the treatment and care of patients with bone metastasis, the cost of which is covered by Japanese medical insurance. During the development of these guidelines, we recognized unsolved clinical questions in some parts of this field. Although the development of these guidelines is just a step toward improvement of treatment outcomes in patients with bone metastases, we hope that these guidelines are beneficial for such patients. PMID- 26602392 TI - [Pharmacological Treatment for Bone Metastasis]. AB - An objective of improvement of treatment outcomes of cancer is alleviation of bone metastasis that occurs in many types of cancers. Recently, the guidelines for the diagnosis and treatment of bone metastasis were published by the Japanese Society of Medical Oncology in cooperation with other groups. These guidelines are essentially evidence based for the pharmacological treatment of bone metastasis by using bone modifying agents (BMA). Cancer cells inhibit osteoblast formation and promote osteoclast proliferation. Many growth factors that are produced by the bone marrow promote osteoclast proliferation. Furthermore, many growth factors enhance the rate of cancer cell growth. These processes underlie bone metastasis. Evidence for the effectiveness of BMA for the treatment of lung cancer, breast cancer, prostate cancer, multiple myeloma, and other cancers is provided in each section of the guidelines. These guidelines also provide evidence for the suppression of skeletal related events (SRE) in lung, breast, and prostate cancers. With regard to multiple myeloma, the guidelines provide evidence for the improvement of overall survival in addition to that for suppression of SRE. Based on these evidences, the guidelines recommend aggressive treatment with BMA for bone metastasis in such cancers. PMID- 26602393 TI - [Palliative Radiotherapy for Bone Metastases]. AB - Bone metastasis is associated with many symptoms such as bone pain, pathological fracture, and spinal cord compression. Especially, pain secondary to bone metastases is a serious problem in many patients with metastatic cancer. Radiotherapy can provide remarkable pain relief, reduce the requirement for analgesic drugs, and prevent pathological fracture or spinal cord compression with few complications in most patients. Many randomized controlled trials have shown equivalent extent of pain relief between single-fraction and multiple fraction regimens. Reirradiation of painful bone metastases is effective for palliation of pain in non-responders or patients with recurrent pain after an initial satisfactory response to a previous radiation therapy. Systemic administration of radioisotopes is an important palliative care option for painful multifocal bone metastases detected on nuclear imaging; however, the application of this option depends on the histologic features of the tumor and distribution of the metastases. Metastatic spinal cord compression is the most frequent oncologic emergency and necessitates timely and appropriate treatment. External beam radiotherapy is commonly used for the treatment of metastatic spinal cord compression. Surgical decompression and stabilization should be considered for metastatic spinal cord compression or pathological fracture in select patients. Postoperative radiotherapy should be administered to patients who have undergone surgical intervention for bone metastases. For patients at a high risk for oncologic emergency, optimal prophylactic management is highly recommended. PMID- 26602394 TI - [Orthopedic Management of Skeletal Metastases]. AB - Recent advances in drug therapy for metastatic bone diseases are changing the indications for surgical treatments. Bone modifying agents, including bisphosphonates and denosumab, have reduced skeletal-related events. Meanwhile, novel anticancer drugs that have been developed, especially molecular-targeted drugs, can improve the prognoses of patients with bone metastases, thereby potentially increasing the number of patients who could receive benefits from surgeries for metastases. A multidisciplinary approach and the early involvement of surgeons are required for the application of adequate orthopedic treatments, including braces, rehabilitation, and surgeries for local tumor control, palliative fixation, and spinal decompression. PMID- 26602395 TI - [Associations between Clinical Factors and Acute Renal Failure Due to Cisplatin Combination Chemotherapy for Lung Cancer]. AB - In this study, we investigated the clinical factors associated with acute kidney injury (AKI) due to combination therapy with cisplatin (CDDP) for treating lung cancer. We classified cases according to the presence or absence of adequate hydration and magnesium(Mg)administered above the regulations of the registered regimen to evaluate the effect due to differences in hydration on AKI. We also investigated clinical factors before and after administration of CDDP in each case group, and examined their association with AKI. Seventy-four patients with lung cancer that were indicated for treatment with a CDDP combination regimen between December 2012 and April 2013 were studied. The patients whose conditions progressed to AKI of Bgrade 2 accounted for 0% (0/33) in the Mg administration group and 7.3%(3/41)in the Mg non-administration group. In particular, 2 cases of serious AKI (grade 4) were observed in the Mg non-administration without additional hydration group. When compared with other groups, a high antiemetic rate and favorable urine volume were observed in the Mg administration with additional hydration group. In the patients with AKI, many developed hyponatremia of Bgrade 3 within 1 week after administration of CDDP. Although Mg administration and ample hydration seem to be effective measures to deal with CDDP-caused AKI, comprehensive monitoring, including antiemesis therapy, after CDDP administration and correction of electrolytes is important. PMID- 26602396 TI - [The Safety of Super-Selective Intra-Arterial Infusion Chemotherapy for Induction with Docetaxel, Cisplatin, and 5-Fluorouracil for Oral Cancer]. AB - Adverse events and complications were retrospectively evaluated in 13 oral cancer patients receiving 3-drug, super-selective, intra-arterial infusion induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (GroupA ), and another 13 patients receiving systemic chemotherapy (GroupB ). As a systemic adverse event, neutropenia was significantly milder in GroupA than in GroupB (p=0.043). However, among local adverse events, the incidence rates of oral mucous membrane disorders were 69.2% (9 patients) in GroupA and 23.1% (3 patients)in GroupB, and therefore significantly higher in Group A(p=0.021). No significant difference was observed between the two groups considering the time of onset of oral mucous membrane disorders. Among complications, there were no cerebral infarctions, but facial palsy occurred in 1 patient. Thus, in a comparison between adverse events associated with super-selective intra-arterial infusion induction chemotherapy for oral cancer and systemic chemotherapy, the former showed milder neutropenia and a trend toward milder systemic adverse events. However, the incidence rate of oral mucositis as a local adverse event was significantly higher. For super selective intra-arterial infusion chemotherapy, it appears to be important to prevent oral mucositis and to control the risks of complications such as facial palsy and cerebral infarction. PMID- 26602397 TI - [Influence of the Site of Port Insertion on the Flow Velocity of 5-FU Continuous Intravenous Injection by Using a Compression-Type Portable Continuous Infuser for Colorectal Cancer Patients]. AB - For the continuous intravenous injection off luorouracil (5-FU) over 46 hours in a chemotherapeutic regimen for colorectal cancer, a compression-type portable continuous infuser is used. However, there is an error in the flow velocity. Errors in the dose or time of administration completion may influence the efficacy and safety of 5-FU. Therefore, it is necessary to reduce the error in the flow velocity. The type of diluent, air temperature, and concentration of 5 FU are reportedly factors influencing the flow velocity. However, no study has examined the influence of the site of port insertion. In this study, we investigated factors associated with the flow velocity of 5-FU continuously and intravenously injected by using an infuser in patients with colorectal cancer, among whom the site of port insertion differed. The results showed that the site of port insertion influenced the flow velocity during the continuous intravenous injection of 5-FU using an infuser. It is important to reduce the error in the flow velocity by considering the site of port insertion in addition to the concentration of 5-FU and the air temperature. PMID- 26602398 TI - [Risk Factors for Oxaliplatin-Induced Phlebitis and Venous Pain, and Evaluation of the Preventive Effect of Preheating with a Hot Compress for Administration of Oxaliplatin]. AB - Venous pain induced by oxaliplatin(L-OHP)is a clinical issue related to adherence to the Cape OX regimen. To prevent LOHP- induced venous pain, we provided nursing care to outpatients who were administered a preheated L -OHP diluted solution using a hot compress. We retrospectively evaluated the risk factors for colorectal cancer patients who had L -OHP induced phlebitis and venous pain. Furthermore, the preventive effect of nursing care was compared between inpatients and outpatients from January 2010 to March 2012. At the L-OHP administration site, any symptoms were defined as phlebitis, whereas pain was defined as venous pain. A total of 132 treatment courses among 31 patients were evaluated. Multivariate logistic regression analysis revealed that both phlebitis and venous pain were significantly more common in female patients (adjusted odds ratio, 2.357; 95%CI: 1.053-5.418; and adjusted odds ratio, 5.754; 95%CI: 2.119 18.567, respectively). The prevalence of phlebitis and venous pain did not differ between inpatients and outpatients (phlebitis, 61.3% vs 67.7%; venous pain, 29.0%vs 19.4%). These results suggest that administration of L-OHP via a central venous route should be considered in female patients. PMID- 26602399 TI - [A Retrospective Analysis of Eye Disorders Due to Oxaliplatin]. AB - In recent years, the incidence of eye disorders due to antineoplastic agents such as S-1 has increased. Eye disorders including visual field defect, visual field impairment, optic neuritis, and visual acuity reduction have been reported as serious adverse effects of oxaliplatin, an agent that is frequently used as a standard therapy for colorectal cancer. However, specific details about these conditions, such as the timing relative to oxaliplatin administration and frequencies at which they appear, remain to be clarified; therefore, we conducted a retrospective analysis of patients with eye disorders due to oxaliplatin in order to obtain evidence that would be useful in routine medical practice. Of the 55 patients who were treated with oxaliplatin in this analysis 10 (18.2%) presented with eye disorders, including blepharoptosis (5 patients, 9.1%), visual field impairment (2 patients, 3.6%), visual acuity reduction (2 patients, 3.6%), eye pain (1 patient, 1.8%), congestion (1 patient, 1.8%), watering eyes (1 patient, 1.8%), and blurred vision (1 patient, 1.8%). These symptoms appeared during the early period of treatment, such as after the first or the second dose. We found that all patients had mild symptoms (Grade 1 or 2), and most improved spontaneously. Thus, eye disorders due to oxaliplatin affect Japanese patients somewhat frequently, although the symptoms are reversible and are mild in most cases. Detailed studies that include data from a larger number of facilities should be conducted in the future. PMID- 26602400 TI - [Transcatheter Arterial Chemoembolization with Super absorbent Polymer Microspheres for a Large Lung Cystic Adenocarcinoma in the Left Pulmonary Cavity]. AB - A 57-year-old woman presented with lung adenocarcinoma and carcinomatous pleurisy in January 2013. The primary lesion had been treated with 60-Gy radiation therapy. She, however, showed a recurrence of the tumor in her pulmonary cavity. She received systemic chemotherapy for 1 year but did not show any improvement. She visited our clinic in March 2014. Her performance level was 3. Her hemoglobin level was 8.5 g/dL. The CT scan showed that the size of the cystic tumor was 200 * 144 * 143 mm. The tumor severely compressed her heart. We performed TACE using a spherical embolic agent. The microcatheter was guided through the left bronchial artery; left intercostal artery 9, 10, and 11; and the left inferior phrenic artery. The anticancer drugs selected were CDDP and 5-FU. The embolic material used was SAP-MS. After 3 therapy sessions, the CT scan showed shrinkage of the target lesion to 100 * 93 * 54 mm. Her hemoglobin level increased to 13.8 g/dL; furthermore, the severity of dyspnea decreased, and she showed a performance status of 0. TACE with SAP-MS was successfully performed for the large cystic tumor in the pulmonary cavity that metastasized from the lung cancer and was refractory to standard treatments. After the treatment, the tumor size decreased and the patient's symptoms alleviated. PMID- 26602401 TI - [A Case of Advanced Esophageal Cancer and Tongue Cancer Treated with Induction DCF Chemotherapy Followed by Radical Surgery]. AB - A man in his 60s was admitted for the treatment of advanced cervical esophageal cancer with metastasis to the lymph nodes and advanced tongue cancer with metastasis to the lymph nodes. Esophageal cancer was suspected to have invaded the trachea. The tongue cancer was located on the left side and had invaded beyond the median line of the tongue. Both cancers were pathologically diagnosed as squamous cell carcinomas. Therefore, it was determined that pharyngo-laryngo- esophagectomy and total glossectomy were required prior to the treatment. However, after 2 courses of docetaxel/cisplatin/ 5-FU combined induction chemotherapy, both cancers remarkably decreased; consequently, an esophagectomy to preserve laryngeal function and partial glossectomy could be performed simultaneously. The patient is well without recurrence 1 year post-surgery. PMID- 26602402 TI - [A Case of Severe Bradycardia Induced by Combination Chemotherapy with Cisplatin and 5-Fluorouracil]. AB - A 78-year-old man with Stage III esophageal cancer was referred to our hospital. Combination chemotherapy with cisplatin (CDDP) and 5-fluorouracil (5-FU) was initiated. The patient experienced bradycardia episodes after starting the cisplatin infusion on day 1; he was otherwise asymptomatic. Therefore, combination chemotherapy was continued. However, on day 4, his heart rate dropped to 22 beats/min, with no other symptoms; however, treatment was stopped. After treatment was stopped, the patient's heart rate improved gradually and returned to normal in a few days. Combination chemotherapy with CDDP and 5-FU is a useful treatment for esophageal cancer, but it may induce severe bradycardia. Therefore, we must perform infusion therapy with caution. PMID- 26602403 TI - [Cases of Three Patients with Gastric Cancer and Metastasis to the Skeletal Muscle]. AB - Metastasis to the skeletal muscle from gastric cancer is relatively rare. We report cases of 3 patients undergoing chemotherapy for gastric cancer with metastasis to the skeletal muscle. Case 1: A man in his 70s was diagnosed with advanced gastric cancer (cT4N3M1P0, stage IV), with metastasis to the lung, brain, lymph node, and iliopsoas muscle. Case 2: A man in his 60s was diagnosed with advanced gastric cancer (cT3N3M1P0, stage IV), with metastasis to the brain, lung, lymph node, and iliopsoas muscle. Case 3: A man in his 50s was diagnosed with advanced gastric cancer (cT4N3M1P0, stage IV), with metastasis to the urinary duct, lymph node, back muscle, and iliopsoas muscle. All 3 patients died within 7-8 months after the diagnosis due to progressive disease despite chemotherapy. The prognosis of these 3 patients was significantly poorer than that of patients in our hospital with metastasis not involving the skeletal muscle (p<0.01). Accordingly, metastasis to the skeletal muscle may be an adverse prognostic factor in gastric cancer. PMID- 26602404 TI - [Pneumocystis Pneumonia during Adjuvant Chemotherapy for Advanced Colon Cancer - A Case Report]. AB - We report a case of pneumocystis pneumonia (PCP) during adjuvant chemotherapy for advanced sigmoid colon cancer. A 70-year-old Japanese man was referred to our hospital after complaining of bloody stools. He was diagnosed with advanced sigmoid colon cancer, T2N2aM1b, Stage IV B. After 3 cycles of mFOLFOX6 plus panitumumab as first-line chemotherapy, he received FOLFIRI plus bevacizumab as second-line chemotherapy because of progressive disease. Aprepitant and steroids were administered as antiemetic agents for a short period during each chemotherapy session. During the 2 cycle of FOLFIRI plus bevacizumab, he developed a high fever without respiratory symptoms. Chest CT revealed ground glass opacities in both the lungs. We first treated him with antibiotics (PIPC/TAZ plus GRNX), suspecting bacterial pneumonia. However, based on the elevation of serum b -D-glucan (148 pg/mL), we diagnosed PCP and initiated SMX/TMP in addition to PIPC/TAZ. The inflammation promptly decreased, and follow up chest CT revealed the disappearance of the ground-glass opacities. If a patient develops a fever or respiratory symptoms during a course of chemotherapy, we should consider the possibility of PCP and perform careful examinations. PMID- 26602405 TI - [Long-Term Successful Management of Recurrent Rectal Cancer in the Predialysis State with FOLFIRI Chemotherapy]. AB - A 71-year-old man with predialysis terminal renal insufficiency experienced peritoneal dissemination 1.5 years after low anterior resection for advanced rectal cancer. He received FOLFIRI therapy (70% dose); he achieved partial response (PR) under computed tomography and stable disease (SD) was maintained over a long term. Although Grade 3 myelosuppression was occasionally noted, he was treated with FOLFIRI for 2 years without other severe complications and without requiring the initiation of hemodialysis. After the initiation of hemodialysis, FOLFIRI treatment was continued for 1 year until progressive disease (PD). He received mFOLFOX6 as second-line therapy for 6 months, followed by LV-5-FU and a molecular targeting agent. These treatments prolonged his survival for 1 year and 8 months. FOLFIRI can be administered as an effective first-line therapy even for patients with predialysis terminal renal impairment without major renal damage. FOLFOX and molecular targeting agents should be made available and prolonged survival can be expected for advanced colorectal cancer patients with terminal renal disease after the initiation of hemodialysis. PMID- 26602406 TI - [A Case of Complete Pathological Response in a Patient with Locally Advanced Sigmoid Colon Cancer after FOLFOX IRI Chemotherapy]. AB - A 61-year-old man with advanced sigmoid colon cancer was admitted to our hospital. Abdominal computed tomography (CT) revealed locally advanced sigmoid colon cancer, with suspected invasion of the bladder and small intestine. The clinical stage of the disease was T4b, N1, M0, and Stage III a, with wild-type KRAS expression. A transverse colostomy was performed because of the presence of a bowel obstruction. The patient received 4 courses of Leucovorin, 5 fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI). The size of the tumor and lymph nodes decreased noticeably after chemotherapy and laparoscopic high anterior resection with lymph node dissection. During this phase, the pathological stage of the disease was ypT0, N0, and Stage 0(no viable carcinoma cells, Grade 3). This result suggested that preoperative FOLFOXIRI chemotherapy is a useful regimen for the treatment of locally advanced colon cancer. PMID- 26602407 TI - [Para-Aortic Lymphadenectomy and Subsequent Chemotherapy after Resection of the Primary Lesion for Poorly Differentiated Adenocarcinoma of the Sigmoid Colon - A Case Report]. AB - The patient was a 68-year-old male who had bloody stools. A colonoscopy revealed a sigmoid colon stricture, and a histological examination confirmed the presence of a poorly differentiated adenocarcinoma.Computed tomography revealed the involvement of a para-aortic lymph nodes, without other metastatic lesions. The patient underwent a sigmoidectomy (with regional lymph node dissection) and a para-aortic lymph node biopsy to prove the histological conformation. Subsequently, he was provided with 6 courses of modified FOLFOX6(mFOLFOX6) chemotherapy, resulting in a marked decrease in para-aortic lymph node involvement. He subsequently underwent a para-aortic lymphadenectomy. The resected specimen was mostly composed of fibrous degenerative tissue; viable cancer cells were observed only in a 2-mm2 area. The patient was provided with 6 more courses of mFOLFOX6 chemotherapy, and has since been free of recurrence (for 6 years and 1 month after the second surgery). PMID- 26602408 TI - [A Long-Term Survival Case of Unresectable Hilar Bile Duct Cancer Treated with Gemcitabine]. AB - A 69-year-old woman was diagnosed with liver dysfunction on blood testing in a nearby clinic. Computed tomography revealed stenosis of the hilar bile duct. Accordingly, an endoscopic nasobiliary drainage tube was inserted in the left hepatic duct and she was referred to our hospital for diagnostic examinations and treatment. The endoscopic retrograde cholangiopancreatography findings revealed obstruction of the cystic duct and stenosis of the hilar bile duct due to inflammation of the cystic duct or inflammation of the clamping type by cholecystitis. Considering the possibility of malignant tumor, surgical operation was performed. Radical resection was considered impossible and we instead performed cholecystectomy and resection of a bile duct wall specimen for diagnosis. The pathological diagnosis was poorly differentiated tubular adenocarcinoma. The patient was treated with gemcitabine as systemic chemotherapy for unresectable hilar bile duct cancer. Currently, 78 months after the start of chemotherapy, the patient is alive and well, without tumor progression. PMID- 26602409 TI - [Unidentified Inflammatory Disease Induced by Azacitidine Therapy for Myelodysplastic Syndrome]. AB - We report a 73-year-old woman with myelodysplastic syndromes (MDS) of the refractory anemia with excess of blasts-1 subtype, which was diagnosed in April 2014 on the basis of cytopenia for two cell types. After completing 3cycles of azacitidine (AZA) therapy, the patient was admitted to our hospital based on an initial presentation of high fever. During hospitalization, the high fever and increasing inflammatory reaction persisted. We reevaluated the effect of MDS in this patient and concluded that the AZA administration was successful and the MDS was extremely stable. On medical examination and inspection, the patient had an unidentified inflammatory disease. First, we treated her with high-dose steroid pulse therapy. However, the effect of the treatment was transient. Furthermore, the effects of cyclosporin A and oral steroid therapy were poor; therefore, we initiated tocilizumab administration. Nevertheless, she died of multiorgan failure. An increasing serum IL- 6 level induced by the AZA therapy was later confirmed. Recent studies have reported the immunomodulatory effects stimulated by AZA therapy in MDS. This case is a valuable reminder that an unidentified inflammatory disease can be induced in the course of AZA therapy for MDS. PMID- 26602410 TI - The impact of allogeneic-hematopoietic stem cell transplantation on patients' and close relatives' quality of life and relationships. AB - PURPOSE: Although evidence suggests considerable disruption to families, the impact of allo-Hematopoietic Stem Cell Transplantation (HSCT) on patients' partners and close relatives has not been sufficiently explored. The present mixed-methods study aimed to enlighten allo-HSCT effects on patients' and close relatives' quality of life (QOL) and their relationships. METHODS: Patients who received allo-HSCT between 2007 and 2010 (N = 58) and their close relatives (parents, partners and/or adult children) were asked to respond to an anonymous questionnaire including socio-demographic data, Likert-scale of the impact of HSCT on sexual, couple, family, professional and social life, as well as on perceived support. QOL of patients and close relatives was evaluated (by the FACT BMT and by WHO-QOL-bref) as were the adjustments of the couples (patients/partners by the DAS). In-depth interviews were performed with patients and partners who consented to this proposition. RESULTS: Patients (N = 28) and close relatives (N = 48) reported fatigue, sleep and sexual problems, emotional distress and relationship difficulties. Patients were mainly concerned with " being a burden " to their close relatives. Close relatives' main concerns were changes in marital and family dynamics, disruptions in daily routine tasks and the responsibility for being the main provider of physical and emotional care. These difficulties increased after HSCT - notably when patients have to face the long-term consequences of the procedure. CONCLUSION: HSCT has a negative impact on patients' partners and other close relatives' QOL. Data on this topic is still scarce and this study might pave the way for future research in this field and notably guide psychosocial interventions. PMID- 26602412 TI - Editorial on the skin-themed issue. PMID- 26602411 TI - Evaluation for abdominal aortic aneurysms is justified in patients with thoracic aortic aneurysms. AB - Aortic aneurysms are a significant cause of mortality, and the presence of multiple aneurysms may affect treatment plans. The purpose of this study was to determine the frequency of abdominal aortic aneurysms (AAAs) in patients with thoracic aortic aneurysms (TAAs) and to establish whether patient specific factors, such as gender and comorbidities, influenced the frequency of AAAs, thereby indicating if and when abdominal aortic evaluation is justified. Electronic medical records were reviewed from 1000 patients with a computed tomography (CT) angiogram of the chest and abdomen and a clinical diagnosis of TAA from Cardiac Surgery clinic between 2008 and 2013. 538 patients with history of aortic intervention, dissection, rupture or trauma were excluded. The frequency of AAAs among the 462 remaining patients was established, and statistical analysis was used to elucidate differences in frequency based on age, gender, comorbidities, and TAA location. Overall, 104 of 462 (22.5 %) patients with a TAA also had an AAA. There were significant differences in the frequency of AAA based on TAA location, age, and comorbidities. The following comorbidities showed positive associations with AAA using logistic regression analysis: age >=65 (P < 0.0001; OR 30.1; CI 7.14-126.61), smoking history (P < 0.0001; OR 4.1; 2.35-7.30), and hypertension (P = 0.024; OR 2.1; CI 1.11-4.16). Aneurysms in the proximal/mid descending (P < 0.0001; OR 4.96; CI 2.32-10.61) and diaphragm level (P < 0.0001; OR 38.4; CI 14.71-100.15) of the aorta also showed a positive association with AAAs when adjusted for age and gender. AAA screening in patients with TAA is a reasonable, evidence-based option regardless of the TAA location, with the strongest support in patients >age 55, with systemic hypertension, a smoking history and/or a TAA in the descending thoracic aorta. PMID- 26602413 TI - Lymphocytic panniculitis: an algorithmic approach to lymphocytes in subcutaneous tissue. AB - The diagnosis of panniculitis is a relatively rare occurrence for many practising pathologists. The smaller subset of lymphocyte-predominant panniculitis is further complicated by the diagnostic consideration of T cell lymphoma involving the subcutaneous tissue, mimicking inflammatory causes of panniculitis. Accurate classification of the panniculitis is crucial to direct clinical management as treatment options may vary from non-medical therapy to immunosuppressive agents to aggressive chemotherapy. Many diseases show significant overlap in clinical and histological features, making the process of determining a specific diagnosis very challenging. However, with an adequate biopsy including skin and deep subcutaneous tissue, a collaborative effort between clinician and pathologist can often lead to a specific diagnosis. This review provides an algorithmic approach to the diagnosis of lymphocyte-predominant panniculitis, including entities of septal-predominant pattern panniculitis (erythema nodosum, deep necrobiosis lipoidica, morphea profunda and sclerosing panniculitis) and lobular-predominant pattern panniculitis (lupus erythematous panniculitis/lupus profundus, subcutaneous panniculitis-like T cell lymphoma, cutaneous gamma-delta T cell lymphoma, Borrelia infection and cold panniculitis). PMID- 26602414 TI - Differential diagnosis of heavily pigmented melanocytic lesions: challenges and diagnostic approach. AB - The differential diagnosis of heavily pigmented melanocytic neoplasms includes melanoma (especially animal type), melanosis of partially or completely regressed melanoma, blue naevus (BN), pigmented Spitzoid lesions, recurrent naevus, combined naevus, pigmented spindle cell naevus, epithelioid blue naevus of the Carney complex/pigmented epithelioid melanocytoma, deep penetrating naevus, hyperpigmented scar after surgery of melanoma in which there are also melanophages and hyperpigmentation due to the minocycline, a tattoo or a hyperpigmented scar. Pathologists face challenges when evaluating a pigmented lesion, especially in a small superficial biopsy, because it is difficult to access important histopathological features to differentiate benign versus malignant melanocytic lesions. The histological features that favour a diagnosis of melanoma include dimension (>6 mm), asymmetry, poor circumscription, irregular confluent nests, confluent lentiginous junctional melanocytic proliferation, lack of maturation with descent in the dermis, suprabasal pagetoid melanocytes, asymmetrical distribution of melanin pigment, cytological atypia, dermal mitotic figures, asymmetrical dermal lymphocytic infiltrate and necrosis. PMID- 26602415 TI - Tumours and inflammatory lesions of the anal canal and perianal skin revisited: an update and practical approach. AB - Tumours of the anal and perianal region are relatively rare, and clinically often interpreted as innocuous lesions, leading to frequent delays in diagnosis and adequate treatment. Although squamous cell neoplasia represents the most common entity encountered in this anatomically complex area, many conditions, both neoplastic and inflammatory, may occur. Adding to the challenge of correct diagnosis and patient management, recent years have seen major updates in the terminology of squamous cell neoplasia, created to reflect advances in our understanding of the role of human papilloma virus and unify previous terminologies used for different sites in the anogenital tract. However, squamous cell neoplasia in the anal canal and perianal region may differ in terms of histology, biological behaviour, staging and treatment. The aim of this review is to present an overview of neoplastic and non-neoplastic lesions that may be seen in this area, an update on important developments and terminology, potential pitfalls that may be encountered in routine pathology practice and a practical approach on how to resolve these issues. PMID- 26602416 TI - Challenges in the diagnosis of cutaneous adnexal tumours. AB - The diagnosis of cutaneous adnexal neoplasms, a heterogeneous group of entities, is often perceived by practising pathologists as challenging. A systematic approach to diagnosis is necessary for classification of these lesions, which establishes the tumour differentiation (follicular, sebaceous, sweat gland or apocrine) and evaluates histological features differentiating between benign and malignant entities. Consideration of clinical history is a necessary adjunct in evaluation of the adnexal neoplasm, as characteristic anatomical sites are described for many adnexal lesions. In some instances, immunohistochemical studies may also be employed to aid the diagnosis. The differential diagnosis between primary cutaneous adnexal neoplasms and cutaneous metastases from visceral tumours may also be difficult. Clinical, radiological, histological and immunohistochemical characteristics will be further discussed, considering that the correct diagnosis has a significant impact on the patient's management and prognosis. PMID- 26602417 TI - Primary cutaneous T-cell lymphomas: a review. AB - Primary cutaneous T-cell lymphomas (CTCLs) represent a number of extranodal lymphomas arising from a malignant population of lymphocytes in the skin, with the most common type being mycosis fungoides (MF) representing half of all primary CTCLs. Despite advances in immunohistochemistry and molecular methodology, significant diagnostic challenges remain due to phenotypic overlap of primary CTCLs with several inflammatory dermatoses, secondary lymphomas, among other conditions. Clinical features such as presentation and morphology, staging, histology, immunophenotype and molecular features must be considered in detail before a diagnosis is made in order to minimise false-positive, false-negative and indeterminate diagnoses. Herein, we review primary CTCLs, including epidemiological data, a brief summary of clinical presentations, immunophenotype, molecular signatures and differential diagnoses. PMID- 26602418 TI - The Effects of Hormonal Contraception on the Voice: History of Its Evolution in the Literature. AB - OBJECTIVES: Women of reproductive age commonly use hormonal contraceptives, the vocal effects of which have been studied. Otolaryngologists should be aware of this relationship to make recommendations on hormonal contraception as it relates to each patient's voice requirements. METHODS/DESIGN: A comprehensive literature review of PubMed was completed. The terms "contraception," "vocal folds," "vocal cords," and "voice" were searched in various combinations. Articles from 1971 to 2015 that addressed the effects of contraception on the vocal folds were included. RESULTS: In total, 24 articles were available for review. Historically, contraception was believed to affect the voice negatively. However, more recent studies using low-dose oral contraceptive pills (OCPs) show that they stabilize the voice. However, stabilization generally occurs only during sustained vowel production; connected speech appears unaffected. Therefore, singers may be the only population that experiences clinically increased vocal stability as a result of taking hormonal contraceptives. Only combined OCPs have been studied; other forms of hormonal contraception have not been evaluated for effects on the voice. Significant variability exists between studies in the physical attributes of patients and parameters tested. CONCLUSIONS: Hormonal contraception likely has no clinically perceptible effects on the speaking voice. Singers may experience increased vocal stability with low-dose, combined OCP use. Other available forms of contraception have not been studied. Greater consistency in methodology is needed in future research, and other forms of hormonal contraception require study. PMID- 26602419 TI - Clinical Usefulness of Ultrasonography-Guided Laryngeal Electromyography. AB - OBJECTIVES/HYPOTHESIS: To investigate the proper approach and technical method of ultrasonography-guided laryngeal electromyography (US-guided LEMG). STUDY DESIGN: This is a prospective study. METHODS: Twenty patients who underwent US-guided LEMG were enrolled. US-guided LEMG was cooperatively performed by one otolaryngologist, one neurologist, and one radiologist. The location of the needle electrode was confirmed with US after electrode insertion into the laryngeal intrinsic muscle. The US transducer was applied on the neck by a transverse/midline and transverse/oblique approach to identify the cricothyroid (CT), thyroarytenoid (TA) muscles, and the location of the needle electrode. RESULTS: CT muscles were easily identified on US in all 20 patients. TA muscles were identified in 17 patients (85%). The transverse/oblique approach was helpful to detect TA muscle in case of calcified thyroid cartilage or anatomic variation. CONCLUSIONS: US-guided LEMG, which enables the exact insertion of the needle electrode, improves the reliability of examination and is helpful in early detection and to prevent complications. PMID- 26602420 TI - Evaluation of Self-Perceived Changes in Gastrointestinal Symptoms During Ramadan Fasting. AB - Little is known regarding the effects of Ramadan fasting on common gastrointestinal symptoms. The aim of this study was to assess the alterations of these symptoms in a healthy Iranian adult population during Ramadan. In a cross sectional study, self-administered questionnaires were used to evaluate the alterations in seven groups of gastrointestinal symptoms (esophageal symptoms, dyspeptic symptoms, bloating and abdominal distension, constipation, diarrhea, abdominal pain, and nausea) after Ramadan. A total of 900 individuals participated in the study. Almost 87 % of participants reported to fast for at least 2 weeks during Ramadan. After adjusting for potential confounders, we found no relationship between alteration in frequency of gastrointestinal symptoms and Ramadan fasting, except for constipation which increased significantly after Ramadan fasting (odds ratio 1.99, 95 % confidence interval 1.05-3.80, P < 0.05). In addition, those who fasted for at least 2 weeks reported to experience severe or very severe constipation-related symptoms three times more in comparison with those who fasted for less than 2 weeks (P < 0.05). There was no relationship between severity of other gastrointestinal symptoms and Ramadan fasting. We found that Ramadan fasting does not increase frequency and severity of common gastrointestinal symptoms in the general population except for constipation that may be experienced more frequently and severely among those who fast for 2 weeks or more. PMID- 26602421 TI - Islam, Assisted Reproduction, and the Bioethical Aftermath. AB - Assisted reproductive technologies (ARTs), including in vitro fertilization to overcome infertility, are now widely available across the Middle East. Islamic fatwas emerging from the Sunni Islamic countries have permitted many ARTs, while prohibiting others. However, recent religious rulings emanating from Shia Muslim dominant Iran have created unique avenues for infertile Muslim couples to obtain donor gametes through third-party reproductive assistance. The opening of Iran to gamete donation has had major impacts in Shia-dominant Lebanon and has led to so called reproductive tourism of Sunni Muslim couples who are searching for donor gametes across national and international borders. This paper explores the "bioethical aftermath" of donor technologies in the Muslim Middle East. Other unexpected outcomes include new forms of sex selection and fetal "reduction." In general, assisted reproduction in the Muslim world has been a key site for understanding how emerging biomedical technologies are generating new Islamic bioethical discourses and local moral responses, as ARTs are used in novel and unexpected ways. PMID- 26602422 TI - Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes. AB - AIMS/HYPOTHESIS: It is thought that T cells play a major role in the immune mediated destruction of beta cells in type 1 diabetes, causing inflammation of the islets of Langerhans (insulitis). The significance of insulitis at the onset of type 1 diabetes is debated, and the role of the T cells poorly understood. METHODS: In the Diabetes Virus Detection (DiViD) study, pancreatic tissue from six living patients with recent-onset type 1 diabetes was collected. The insulitis was characterised quantitatively by counting CD3(+) T cells, and qualitatively by transcriptome analysis targeting 84 T and B lymphocyte genes of laser-captured microdissected islets. The findings were compared with gene expression in T cells collected from kidney biopsies from allografts with ongoing cellular rejection. Cytokine and chemokine release from isolated islets was characterised and compared with that from islets from non-diabetic organ donors. RESULTS: All six patients fulfilled the criteria for insulitis (5-58% of the insulin-containing islets in the six patients had >= 15 T cells/islet). Of all the islets, 36% contained insulin, with several resembling completely normal islets. The majority (61-83%) of T cells were found as peri-insulitis rather than within the islet parenchyma. The expression pattern of T cell genes was found to be markedly different in islets compared with the rejected kidneys. The islet infiltrating T cells showed only background levels of cytokine/chemokine release in vitro. CONCLUSIONS/INTERPRETATION: Insulitis and a significant reserve reservoir for insulin production were present in all six cases of recent-onset type 1 diabetes. Furthermore, the expression patterns and levels of cytokines argue for a different role of the T cells in type 1 diabetes when compared with allograft rejection. PMID- 26602423 TI - Influence of a fermented protein-fortified dairy product on serum insulin-like growth factor-I in women with anorexia nervosa: A randomized controlled trial. AB - BACKGROUND & AIMS: Patients with anorexia nervosa (AN) have low serum IGF-I levels that may contribute to a lower bone mineral mass. We investigated the effects of a fermented, protein-fortified, dairy product on serum IGF-I levels in patients with AN during an in-hospital refeeding program. METHODS: In this multicenter, randomized, double-blind, placebo-controlled, clinical trial conducted at 3 university hospitals and 3 private clinics in France and Switzerland, 62 women recently admitted with confirmed AN and with a baseline low serum IGF-I level were randomized to 2 daily isocaloric fresh cheese pots containing either 15 g/150 g or 3 g/150 g (controls) of protein for 4 weeks. The primary outcome was the change in IGF-I levels. RESULTS: In the primary intention to-treat analysis, mean serum IGF-I levels increased during the intervention phase from 22.9 +/- 1.5 to 28.6 +/- 1.3 nmol/L (means +/- SEM) (+20.2%) in the intervention group and from 20.2 +/- 1.2 to 25.7 +/- 1.5 nmol/L (+16.8%) in controls. In a preplanned analysis of covariance with repeated measures, the between-group difference was close to statistical significance (P = 0.071). In a post-hoc mixed-regression model analysis, the difference was statistically significant (4.9 nmol/l increase; P = 0.003), as was the change of the ratio IGF I/IGF-BP3 (P=0.004). There was no between-group difference in biochemical markers of bone turnover (osteocalcin, P1NP, CTX) or in serum parathyroid hormone level. Serum calcium levels slightly increased during the intervention phase in the higher protein group (P = 0.02). IGF-BP2 decreased significantly more in the intervention group during the follow up period at week 4 after supplements cessation (P = 0.019). CONCLUSIONS: Intake of a fermented, protein-fortified, isocaloric dairy product during 4 weeks may slightly increase serum IGF-I levels in women with AN, without significant changes in bone turnover markers. CLINICAL TRIAL REGISTRATION NUMBER: NCT01823822 (www.clinicaltrials.gov). PMID- 26602424 TI - Timing of Emergency Medicine Student Evaluation Does Not Affect Scoring. AB - BACKGROUND: Evaluation of medical students rotating through the emergency department (ED) is an important formative and summative assessment method. Intuitively, delaying evaluation should affect the reliability of this assessment method, however, the effect of evaluation timing on scoring is unknown. OBJECTIVE: A quality-improvement project evaluating the timing of end-of-shift ED evaluations at the University of Arizona was performed to determine whether delay in evaluation affected the score. METHODS: End-of-shift ED evaluations completed on behalf of fourth-year medical students from July 2012 to March 2013 were reviewed. Forty-seven students were evaluated 547 times by 46 residents and attendings. Evaluation scores were means of anchored Likert scales (1-5) for the domains of energy/interest, fund of knowledge, judgment/problem-solving ability, clinical skills, personal effectiveness, and systems-based practice. Date of shift, date of evaluation, and score were collected. Linear regression was performed to determine whether timing of the evaluation had an effect on evaluation score. RESULTS: Data were complete for 477 of 547 evaluations (87.2%). Mean evaluation score was 4.1 (range 2.3-5, standard deviation 0.62). Evaluations took a mean of 8.5 days (median 4 days, range 0-59 days, standard deviation 9.77 days) to complete. Delay in evaluation had no significant effect on score (p = 0.983). CONCLUSIONS: The evaluation score was not affected by timing of the evaluation. Variance in scores was similar for both immediate and delayed evaluations. Considerable amounts of time and energy are expended tracking down delayed evaluations. This activity does not impact a student's final grade. PMID- 26602425 TI - Lidocaine-Induced Cardiac Arrest in the Emergency Department: Effectiveness of Lipid Therapy. AB - BACKGROUND: Local anesthetics are commonly used in the emergency department (ED). Overdoses can lead to disastrous complications including cardiac toxicity and arrest. Recognition of local anesthetic systemic toxicity (LAST) is important; however, prevention is even more critical. Knowledge of proper lidocaine dosage can prevent LAST. LAST may be effectively treated with lipid emulsion therapy. Although the mechanism is not well understood, its use may have a profound impact on morbidity and mortality. CASE REPORT: Fifty milliliters of 2% lidocaine was infiltrated for local anesthesia in a 35-year-old woman during the incision and drainage of a labial abscess. Following the procedure, the patient complained of vomiting, with rapid progression to an altered mental state and seizure requiring endotracheal intubation for airway protection. Suspecting lidocaine toxicity, intralipids were ordered. While waiting for the intralipids, the patient decompensated and suffered pulseless electrical activity (PEA) cardiac arrest. A 100-mL bolus of 20% intralipids was administered 3 minutes into the resuscitation, after which return of spontaneous circulation occurred. The intralipid bolus was then followed by a continuous infusion of 0.25 mL/kg/minute, for an infusion dose of 930 mL. Despite a complicated hospital course, the patient was discharged home neurologically intact. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: We believe this patient's cardiovascular collapse was secondary to an iatrogenic overdose of lidocaine. This is one of the first cases to support the efficacy of intravenous lipids in the treatment of LAST in humans in the ED. PMID- 26602426 TI - Wandering Wire...Where?--A Heartrending Report. PMID- 26602427 TI - Splenic Infarction in Acute Infectious Mononucleosis. AB - BACKGROUND: The evaluation of a febrile patient with acute abdominal pain represents a frequent yet possibly challenging situation in the emergency department (ED). Splenic infarction is an uncommon complication of infectious mononucleosis, and may have a wide range of clinical presentations, from dramatic to more subtle. Its pathogenesis is still incompletely understood, yet it may be associated with the occurrence of transient prothrombotic factors. CASE REPORT: We report the case of a 14-year-old boy who presented with fever, sore throat, left upper quadrant abdominal pain, and splenomegaly, with no history of recent trauma. Laboratory tests revealed a markedly prolonged activated partial thromboplastin time and positive lupus anticoagulant. Abdominal ultrasonography showed several hypoechoic areas in the spleen consistent with multiple infarctions. Magnetic resonance imaging eventually confirmed the diagnosis. He was admitted for observation and supportive treatment, and was discharged in good condition after 7 days. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Spontaneous splenic infarction should be considered in the differential list of patients presenting with left upper quadrant abdominal pain and features of infectious mononucleosis; the diagnosis, however, may not be straightforward, as clinical presentation may also be subtle, and abdominal ultrasonography, which is often used as a first-line imaging modality in pediatric EDs, has low sensitivity in this scenario and may easily miss it. Furthermore, although treatment is mainly supportive, close observation for possible complications is necessary. PMID- 26602428 TI - Phylogenetic relationships of Iranian infectious hematopoietic necrosis virus of rainbow trout (Oncorhynchus mykiss) based on the glycoprotein gene. AB - Infectious hematopoietic necrosis virus (IHNV), a member of family Rhabdoviridae and genus Novirhabdoviridae, causes a highly lethal disease of salmon and trout. In Iran IHNV was first detected in 2001 on farms rearing rainbow trout (Oncorhynchus mykiss). To evaluate the genetic relationships of IHNV from northern and western Iran, the sequences of a 651-nt region of the glycoprotein gene were determined for two Iranian isolates. These sequences were analyzed to evaluate their genetic relatedness to worldwide isolates representing the five known genogroups of IHNV. Iranian isolates were most closely related to European isolates within the genogroup E rather than those of North American genogroups U, M and L, or the Asian genogroup J. It appears that Iranian IHNV was most likely introduced to Iran from a source in Europe by the movement of contaminated fish eggs. PMID- 26602429 TI - Gold-copper nanostars as photo-thermal agents: synthesis and advanced electron microscopy characterization. AB - Nanoalloys have emerged as multi-functional nanoparticles with applications in biomedicine and catalysis. This work reports the efficient production and the advanced transmission electron microscopy characterization of gold-copper pentagonal nanostars. The morphology of the branches is controlled by the adequate choice of the capping agent. When oleylamine is used rounded nanostars are produced, while pointed nanostars are obtained by using hexadecylamine. Both types of nanostars were proved to be thermally stable and could therefore be used as therapeutic agents in photo-thermal therapies as confirmed by the near infrared absorption spectra. PMID- 26602430 TI - Paris climate change talks: what doctors need to know. PMID- 26602432 TI - Laser jetting of femto-liter metal droplets for high resolution 3D printed structures. AB - Laser induced forward transfer (LIFT) is employed in a special, high accuracy jetting regime, by adequately matching the sub-nanosecond pulse duration to the metal donor layer thickness. Under such conditions, an effective solid nozzle is formed, providing stability and directionality to the femto-liter droplets which are printed from a large gap in excess of 400 MUm. We illustrate the wide applicability of this method by printing several 3D metal objects. First, very high aspect ratio (A/R > 20), micron scale, copper pillars in various configuration, upright and arbitrarily bent, then a micron scale 3D object composed of gold and copper. Such a digital printing method could serve the generation of complex, multi-material, micron-scale, 3D materials and novel structures. PMID- 26602431 TI - Changes in vascular extracellular matrix composition during decidual spiral arteriole remodeling in early human pregnancy. AB - Uterine spiral arteriole (SA) remodeling in early pregnancy involves a coordinated series of events including decidual immune cell recruitment, vascular cell disruption and loss, and colonization by placental-derived extravillous trophoblast (EVT). During this process, decidual SA are converted from narrow, muscular vessels into dilated channels lacking vasomotor control. We hypothesized that this extensive alteration in SA architecture must require significant reorganization and/or breakdown of the vascular extracellular matrix (ECM). First trimester decidua basalis (30 specimens) was immunostained to identify spiral arterioles undergoing trophoblast-independent and -dependent phases of remodeling. Serial sections were then immunostained for a panel of ECM markers, to examine changes in vascular ECM during the remodeling process. The initial stages of SA remodeling were characterized by loss of laminin, elastin, fibrillin, collagen types III, IV and VI from the basement membrane, vascular media and/or adventitia, and surrounding decidual stromal cells. Loss of ECM correlated with disruption and disorganization of vascular smooth muscle cells, and the majority of changes occurred prior to extensive colonization of the vessel wall by EVT. The final stages of SA remodeling, characterized by the arrival of EVT, were associated with the increased mural deposition of fibronectin and fibrinoid. This study provides the first detailed analysis of the spatial and temporal loss of ECM from the walls of remodeling decidual SA in early pregnancy. PMID- 26602433 TI - A new videokymography system for evaluation of the vibration pattern of entire vocal folds. AB - OBJECTIVE: To overcome the limitations of previous videokymography methods, we developed a new videokymography system for the evaluation of the whole mucosal wave of the entire vocal cord mucous membrane. METHODS: To confirm the usefulness of the new videokymography system, we performed videokymography to evaluate the mucosal wave of the vocal folds during modal and falsetto phonation in normal adult males. Additionally, we serially performed both laryngeal videostroboscopy and the new videokymography method in patients diagnosed with acute ulcerative laryngitis. RESULTS: Using the new videokymography system, the mucosal wave pattern of entire vocal folds was captured during the examination. The opening and closing durations could be differentiated, and the symmetry of amplitude and phase could be assessed. The shape of the medial and lateral peaks could be assessed. In patients with acute laryngitis, the new videokymography system showed an enhanced ability to evaluate the flexibility of the vocal folds. CONCLUSION: The new videokymography system enables recording of the whole mucosal wave pattern of entire vocal folds. Although further studies are required to confirm its clinical efficacy for the evaluation of vocal folds, the system can be applied to evaluate the static and dynamic status of vocal folds in patients with vocal cord diseases. PMID- 26602434 TI - An aberrant carotid artery in the temporal bone with fatal complication. AB - We report the case of an 84-year-old female presenting with an aberrant ICA with cerebral air embolization caused by Eustachian tube air inflation (ETAI). High pressure of air inflation developed because of an aberrant ICA blocking the tympanic orifice of the Eustachian tube, with release of the high-pressure air into the aberrant ICA. It must be kept in mind that complications may occur not only during transtympanic treatment, but also in any treatment, such as ETAI, in aberrant ICA cases. PMID- 26602435 TI - Clinicopathological features of melanotic neuroectodermal tumor of infancy: Report of two cases. AB - Melanotic neuroectodermal tumor of infancy (MNTI) is an extremely rare, pigmented neoplastic entity of neural crest origin. Histological and immunohistochemical profiles indicate the presence of two components, small rounded neuroblast-like cellular areas and areas with large melanin-containing cells which consist of combination of neural, melanocytic, and epithelial cell types. Here we present two interesting cases of infants with MNTI which have different clinicopathological features. The first case is a 3-month-old female with rapidly growing MNTI involving the lacrimal sac and inferior wall of the orbital cavity, treated with total maxillectomy without orbital exenteration followed by chemotherapy. The second case is a 7-month-old male with slow-growing maxillary MNTI treated with complete surgical excision. In the female patient, histological findings revealed a predominance of neuroblast-like cellular areas and a high Ki67 index indicating rapid cellular proliferation. In the male patient however, large melanin-containing cells were dominant in this slow-growing tumor. These findings support the presence of two different types of MNTI, rapid-growing and slow-growing types, determined by the component of neuroblast-like cellular areas. PMID- 26602436 TI - Aberrant Kif2a and Ki67 expression predicts poor survival in laryngeal squamous cell carcinoma. AB - OBJECTIVE: Previous studies have demonstrated that aberrant Kif2a expression is associated with tumor aggressiveness and poor prognosis in various human cancers. However, the clinicopathological significance of Kif2a in laryngeal squamous cell carcinoma (LSCC) is unknown. The aim of this study is to analyze the prognostic significance of Kif2a, alone and in combination with Ki67 protein expression, in LSCC patients. METHODS: We examined the expression status of Kif2a and Ki67 protein in 165 laryngeal tissues (137 primary tumors and 28 cases of matched normal surgical margins) by immunohistochemistry (IHC) analysis using tissue microarrays. RESULTS: We found that expression correlated with clinical parameters and overall survival (OS). Our results revealed that Kif2a and Ki67 protein expression was significantly higher in cancerous tissues compared to normal surgical margins. High Kif2a protein expression (Kif2a+) was significantly associated with tumor stage (P=0.026) and cervical lymph node metastasis (P=0.034). A significant correlation between Kif2a and Ki67 protein expression was observed (P=0.040). Multivariate analysis revealed that patients with Kif2a+ (hazard ratio [HR] 3.640, 95% confidence interval [CI] 1.253-10.570; P=0.018) and high Ki67 (Ki67+) expression (HR 3.086, 95%CI 1.016-9.371; P=0.047) had poor OS. CONCLUSION: We speculate that Kif2a and Ki67 can be used as prognostic markers for LSCC patients. PMID- 26602437 TI - Muscle structure and stiffness assessment after botulinum toxin type A injection. A systematic review. AB - BACKGROUND: Botulinum toxin type A manages spasticity disorders in neurological central diseases. Some studies have reported that it might induce muscle changes. METHODS: We present a literature review abiding by the PRISMA statement guidelines. The purpose was to explore the structural and passive biomechanical muscle properties after botulinum toxin type A injections in healthy and spastic limb muscles, on animals and humans, as well as methods for evaluating these properties. We searched the PubMed and Cochrane Library databases using the following keywords: "Botulinum toxin" AND ("muscle structure" OR "muscle atrophy") and, "Botulinum toxin" AND "muscle elasticity". RESULTS: From the 228 initially identified articles, 21 articles were included. Histological analyses were performed, especially on animals. A neurogenic atrophy systematically occurred. In humans, one year after a single injection, the histological recovery remained incomplete. Furthermore, 2D ultrasound analyses showed a reduction of the gastrocnemius thickness and pennation angle. MRI volumetric analysis evidenced muscular atrophy six months or one year after a single injection. Passive muscle stiffness depends on these structural changes. On the short term, the biomechanical analysis showed an elastic modulus increase in animals whereas no change was recorded in humans. On the short term, ultrasound elastography imaging showed a decreased elastic modulus. DISCUSSION: To date, few data are available, but all show a structural and mechanical muscle impact post injections, specifically muscle atrophy which can linger over time. Further studies are necessary to validate this element, and the possibility of change must be taken into account particularly with repeated injections. Thus, in clinical practice, 2D ultrasound and ultrasound elastography are two non-invasive techniques that will help physicians to develop an efficient long term monitoring. PMID- 26602438 TI - A Dutch Prediction Tool to Assess the Risk of Additional Axillary Non-Sentinel Lymph Node Involvement in Sentinel Node-Positive Breast Cancer Patients. AB - BACKGROUND: Multiple predictive systems have previously been developed to identify the sentinel lymph node (SLN)-positive patients at low risk of additional axillary non-SLN involvement and for whom completion axillary lymph node dissection (ALND) could be avoided. However, previous studies showed that these tools had poor performance in Dutch patients with breast cancer, probably owing to variations in pathology settings and differences in population characteristics. The aim of the present study was to develop a predictive tool for the risk of non-SLN involvement in a Dutch population with SLN-positive breast cancer. MATERIALS AND METHODS: The data from 513 patients with SLN positive breast cancer at 10 participating hospitals, who had undergone ALND from January 2007 to December 2008 were studied. The uni- and multivariable associations of predictors for non-SLN metastases were analyzed, and a predictive model was developed. The discriminatory ability of the model was measured by the area under the receiver operating characteristic curve (AUC) and the agreement between predicted probabilities and observed frequencies was visualized by a calibration plot. RESULTS: A predictive model was developed that included the 2 strongest predictors: the size of the SLN metastases in millimeters and the presence of a negative sentinel lymph node. The model showed good discriminative ability (AUC, 0.75) and good calibration over the complete range of predicted probabilities. CONCLUSION: We have developed a tool to predict additional non-SLN metastases in Dutch patients with SLN-positive breast cancer that is easy to use in daily clinical breast cancer practice. PMID- 26602439 TI - Three-dimensional hyperbranched PdCu nanostructures with high electrocatalytic activity. AB - In this study, three-dimensional (3D) PdCu alloyed nanostructures, consisting of one-dimensional (1D) branches, were successfully synthesized through a facile wet chemical method without using any seeds or organic solvent. The success of this approach relies on the use of hydrochloric acid (HCl) to control the reduction rate, and on the presence of bromide ions (Br(-)) to selectively adsorb on certain facets of the PdCu nucleus. The as-prepared 3D PdCu nanostructures exhibit a greatly enhanced catalytic activity toward formic acid oxidation, owing to a suitable electronic landscape resulting from the alloy structure and the unique morphology. PMID- 26602440 TI - Living on the edge: Vulnerability of coral-dependent fishes in the Gulf. AB - In the Gulf, multiple human impacts and recurrent bleaching events have resulted in serious declines of coral assemblages, particularly in near-shore areas. However, the degree to which the extinction risk of coral-dependent fishes is impacted by these coral declines has been uncertain. Using primary literature and expert knowledge, coral-dependent fishes of the Gulf were identified and species specific data on the regional distribution, population status, life history characteristics, and major threats were compiled to determine their likelihood of extinction under the IUCN Red List of Threatened Species' Categories and Criteria. Due to the limited area and degraded and fragmented nature of coral assemblages in the Gulf, all coral-dependent fishes (where data was sufficient to assess) were listed at elevated risk of extinction. Cross-boundary collaboration among Gulf States is necessary for effective management and protection of coral assemblages and their associated communities within this globally important region. PMID- 26602441 TI - A spatial-seasonal analysis of the oiling risk from shipping traffic to seabirds in the Aleutian Archipelago. AB - Some of the largest seabird concentrations in the northern hemisphere are intersected by major shipping routes in the Aleutian Archipelago. Risk is the product of the probability and the severity incidents in an area. We build a seasonally explicit model of seabird distribution and combine the densities of seabirds with an oil vulnerability index. We use shipping density, as a proxy for the probability of oil spills from shipping accident (or the intensity chronic oil pollution). We find high-risk (above-average seabird and vessel density) areas around Unimak Pass, south of the Alaska Peninsula, near Buldir Island, and north of Attu Island. Risk to seabirds is greater during summer than during winter, but the month of peak risk (May/July) varies depending on how data is analyzed. The area around Unimak Pass stands out for being at high-risk year round, whereas passes in the western Aleutians are at high risk mostly during summer. PMID- 26602442 TI - Long range Trp-Trp interaction initiates the folding pathway of a pro-angiogenic beta-hairpin peptide. AB - HPLW, a designed VEGF (Vascular Endothelium Growth Factor) receptor-binding peptide, assumes a well folded beta-hairpin conformation in water and is able to induce angiogenesis in vivo. In this study, we investigated at atomic resolution the thermal folding/unfolding pathway of HPLW by means of an original multi technique approach combining DSC, NMR, MD and mutagenesis analyses. In particular, careful NMR investigation of the single proton melting temperatures together with DSC analysis accurately delineate the peptide folding mechanism, which is corroborated by computational folding/unfolding simulations. The HPLW folding process consists of two main events, which are successive but do not superimpose. The first folding step initiates at 320 K upon the hydrophobic collapse of the Trp5 and Trp13 side-chains which stabilizes the concurrent beta turn formation, whose COi-HNi + 3 hydrogen bond (Asp10 -> Arg7) appears particularly stable. At 316 K, once the beta-turn is completely formed, the two beta-strands pair, very likely starting by Trp5 and Trp13, which thus play a key role also in the final step of the beta-hairpin folding. Overall, here we describe a multi-state hierarchical folding pathway of a highly structured beta hairpin, which can be classified as a broken-zipper mechanism. PMID- 26602443 TI - Comparison of in vivo cone-beam and multidetector computed tomographic scans by three-dimensional merging software. AB - In dentomaxillofacial radiology, cone-beam computed tomography (CT) is used to give fast and high-resolution 3-dimensional images of bone with a low dose of radiation. However, its use for quantitative measurement of bone density based on absolute values (Hounsfield units, HU) as in multidetector CT is still controversial. We know of no in vivo study of 3-dimensional merging software that will reliably match identical bone areas of cone-beam and multidetector CT datasets. We studied 19 multidetector, and 19 cone-beam, CT scans of the skull. The two datasets were fused, corresponding points were identified for measurement, and we compared mean density. We used linear regression to analyse the relation between the two different scanning methods, and studied a total of 4180 measurements. The mean time interval between scans was 5.2 (4.7) months. Mean R(2) over all measurements was 0.63 (range 0.22 - 0.79) with a mean internal consistency (Cronbach's alpha) of 0.86 (range 0.61 - 0.93). The strongest linearity, seen at the left mastoid, was R(2)=0.79 with high internal consistency (Cronbach's alpha 0.89), and the weakest was at the left zygomatic bone with R(2)=0.22 and Cronbach's alpha=0.61. Measurements of bone density based on cone beam and multidetector CT scans generated in vivo showed high and reproducible internal consistency but poor linearity. PMID- 26602444 TI - The Two Lives of Bacillus thuringiensis: Response to Ruan et al. and Loguercio and Argolo-Filho. PMID- 26602446 TI - Expression of non-acetylatable lysines 10 and 14 of histone H4 impairs transcription and replication in Trypanosoma cruzi. AB - The histone H4 from Trypanosomatids diverged from other eukaryotes in the N terminus, a region that undergoes post-translation modifications involved in the control of gene expression, DNA replication, and chromatin assembly. Nonetheless, the N-terminus of Trypanosoma cruzi histone H4 is mainly acetylated at lysine 4. The lysines 10 and 14 are also acetylated, although at less extent, increasing during the S-phase or after DNA damage, which suggests a regulatory function. Here, we investigated the roles of these acetylations by expressing non acetylated forms of histone H4 in T. cruzi. We found that histone H4 containing arginines at positions 10 or 14, to prevent acetylation were transported to the nucleus and inserted into the chromatin. However, their presence, even at low levels, interfered with DNA replication and transcription, causing a significant growth arrest of the cells. The absence of acetylation also increased the amount of soluble endogenous histones H3 and H4 and affected the interaction with Asf1, a histone chaperone. Therefore, acetylation of lysines 10 and 14 of the histone H4 in trypanosomes could be required for chromatin assembly and/or remodeling required for transcription and replication. PMID- 26602445 TI - [Profuse sarcoidosis associated with multiple cutaneous squamous cell carcinomas]. AB - BACKGROUND: The cutaneous signs of sarcoidosis are polymorphous and occasionally misleading. Herein, we report a rare case of profuse sarcoidosis involving various rare cutaneous signs specific to the disease associated with multiple cutaneous squamous cell carcinomas. PATIENTS AND METHODS: A seventy-three-year old man had been presenting dry ichthyosiform erythroderma for 2 years. The examination also revealed diffuse cutaneous atrophy with ulceration, superficial adenopathy and pseudotumoral hypodermic masses. Ophthalmological examination revealed conjunctival nodules. Biopsy samples for the various cutaneous lesions, salivary glands, conjunctival nodules, a hypodermic nodule and an adenopathy yielded similar images evocative of epithelioid granulomas and giant cells without caseous necrosis. Infectious causes were ruled out. Respiratory function tests showed a restrictive respiratory disorder. ACE levels were extremely high. Proteinuria was noted for 24-hour urine tests and renal punch biopsy showed an appearance of membrane-proliferative glomerulonephritis. Oral corticosteroids produced clinical and laboratory improvement. Furthermore, the patient was also presenting several invasive cutaneous squamous cell carcinomas in a setting of marked helioderma. DISCUSSION: Erythrodermic, ichthyosiform, atrophied, ulcerated and pseudotumoral forms of cutaneous sarcoidosis are very uncommon and their simultaneous appearance in the same patient is extremely rare. Further, the existence of numerous cutaneous carcinomas in this patient raises the question of an association between sarcoidosis and cancer, with fortuitous association appearing unlikely. PMID- 26602447 TI - Elucidation of a key position for acyltransfer activity in Candida parapsilosis lipase/acyltransferase (CpLIP2) and in Pseudozyma antarctica lipase A (CAL-A) by rational design. AB - Performing transesterifications in aqueous media is becoming a priority challenge in lipid biotechnology in order to develop more eco-friendly and efficient biocatalytic processes in systems containing both polar and apolar substrates. In this context, our group has explored for several years the high potential of the lipase/acyltransferase CpLIP2 from Candida parapsilosis and of several of its homologs, that catalyze efficiently acyltransfer reactions in lipid/water media with high water activity (aw>0.9). The discovery of a new member of this group, CduLAc from Candida dubliniensis, with a higher acyltransferase activity than CpLIP2, has provided a new insight on structure-function relationships in this group. Indeed, the comparison of sequences and 3D models, especially of CpLIP2 and CduLAc, with those of the phylogenetically related lipase A from Pseudozyma antarctica (CAL-A), allowed elucidating a key structural determinant of the acyltransferase activity: serine S369 in CpLIP2 and its equivalents E370 in CAL-A and A366 in CduLAc. Mutants obtained by rational design at this key position showed significant changes in acyltransfer activity. Whereas mutation S369E resulted in an increase in the hydrolytic activity of CpLIP2, S369A increased alcoholysis. More strikingly, the single E370A mutation in CAL-A drastically increased the acyltransferase activity of this enzyme, giving it the character of a lipase/acyltransferase. Indeed, this single mutation lowered the methanol concentration for which the initial rates of alcoholysis and hydrolysis are equal from 2M in CAL-A down to 0.3M in its mutant, while the exceptional stability of the parental enzyme toward alcohol and temperature was conserved. PMID- 26602449 TI - A Novel Dentin Push-out Bond Strength Model That Uses Micro-Computed Tomography. AB - INTRODUCTION: Current push-out experimental methods used in endodontic research should be improved. This study introduced a novel dentin push-out bond strength model that uses micro-computed tomography (MUCT). METHODS: Roots filled with gutta-percha cones and different resin-based sealers (n = 10) were sectioned transversely to obtain two 2-mm-thick slices per root third. The first slice was subjected to a push-out test by using a material testing stage fitted inside a MUCT scanner. The apparatus was scanned before and after the test to evaluate areas of filling material ruptures. The images provided by MUCT were also used to generate models for a 3-dimensional finite element analysis. Confocal laser scanning microscopy was used to assess failure modes after the test and to measure interfacial gaps in slices not subjected to push-out. Bond-strength and gap data were statistically analyzed (P < .05). RESULTS: Proper coefficients of variation (average less than 30%) were observed for all the experimental conditions. The finite element analysis helped explain the results of bond strength and root-filling ruptures. A significant, moderate, indirect correlation was observed between the bond strength and gaps. CONCLUSIONS: The micromechanical model with the MUCT images resulted in a consistent root-filling bond strength evaluation. PMID- 26602450 TI - Inflammatory Myofibroblastic Tumor Mimicking Apical Periodontitis. AB - Inflammatory myofibroblastic tumors (IMTs) are rare. IMTs of the head and neck occur in all age groups, from neonates to old age, with the highest incidence occurring in childhood and early adulthood. An IMT has been defined as a histologically distinctive lesion of uncertain behavior. This article describes an unusual case of IMT mimicking apical periodontitis in the mandible of a 42 year-old man. At first presentation, the patient showed spontaneous pain and percussion pain at teeth #28 to 30, which continued after initial endodontic treatment. Panoramic radiography revealed a radiolucent lesion at the site. Cone beam computed tomographic imaging showed osteolytic lesions, suggesting an aggressive neoplasm requiring incisional biopsy. Histopathological examination indicated an IMT. The lesion was removed en bloc under general anesthesia, and the patient manifested no clinical evidence of recurrence for 24 months. Lesions of nonendodontic origin should be included in the differential diagnosis of apical periodontitis. Every available diagnostic tool should be used to confirm the diagnosis. Cone-beam computed tomographic imaging is very helpful for differential diagnosis in IMTs mimicking apical periodontitis. PMID- 26602448 TI - Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, beta-lapachone. AB - Base excision repair (BER) is an essential pathway for pancreatic ductal adenocarcinoma (PDA) survival. Attempts to target this repair pathway have failed due to lack of tumor-selectivity and very limited efficacy. The NAD(P)H: Quinone Oxidoreductase 1 (NQO1) bioactivatable drug, beta-lapachone (ARQ761 in clinical form), can provide tumor-selective and enhanced synergy with BER inhibition. beta Lapachone undergoes NQO1-dependent futile redox cycling, generating massive intracellular hydrogen peroxide levels and oxidative DNA lesions that stimulate poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Rapid NAD(+)/ATP depletion and programmed necrosis results. To identify BER modulators essential for repair of beta-lapachone-induced DNA base damage, a focused synthetic lethal RNAi screen demonstrated that silencing the BER scaffolding protein, XRCC1, sensitized PDA cells. In contrast, depleting OGG1 N-glycosylase spared cells from beta-lap induced lethality and blunted PARP1 hyperactivation. Combining beta-lapachone with XRCC1 knockdown or methoxyamine (MeOX), an apyrimidinic/apurinic (AP) modifying agent, led to NQO1-dependent synergistic killing in PDA, NSCLC, breast and head and neck cancers. OGG1 knockdown, dicoumarol-treatment or NQO1- cancer cells were spared. MeOX + beta-lapachone exposure resulted in elevated DNA double strand breaks, PARP1 hyperactivation and TUNEL+ programmed necrosis. Combination treatment caused dramatic antitumor activity, enhanced PARP1-hyperactivation in tumor tissue, and improved survival of mice bearing MiaPaca2-derived xenografts, with 33% apparent cures. SIGNIFICANCE: Targeting base excision repair (BER) alone has limited therapeutic potential for pancreatic or other cancers due to a general lack of tumor-selectivity. Here, we present a treatment strategy that makes BER inhibition tumor-selective and NQO1-dependent for therapy of most solid neoplasms, particularly for pancreatic cancer. PMID- 26602451 TI - Effects of Novel 3-dimensional Antibiotic-containing Electrospun Scaffolds on Dentin Discoloration. AB - INTRODUCTION: Although intracanal application of the triple antibiotic paste (TAP) may offer advantages (eg, disinfection), this practice has been associated with significant drawbacks, including tooth discoloration. In this study, the color change of dentin was monitored during treatment with distinct TAP pastes and novel tubular-shaped 3-dimensional electrospun scaffolds containing minocycline (MINO) or doxycycline (DOX). METHODS: Two TAP pastes (TAPMINO [MINO, metronidazole, and ciprofloxacin] and TAPDOX [DOX, metronidazole, and ciprofloxacin]), 4 scaffold-based groups containing MINO or DOX at distinct concentrations, 1 antibiotic-free scaffold, and 1 untreated group (control) were investigated. Human canines were sectioned at the cementoenamel junction and tubular-shaped scaffolds or paste were placed into the root canals and sealed. Color measurements (CIEL(*)a(*)b(*) parameters) were performed at baseline and after 1, 3, 7, 14, 21, and 28 days. Color changes were expressed as DeltaE(*) values. In addition, scanning electron microscopy and energy-dispersive X-ray spectroscopy were also performed on the specimens after treatment. Data were analyzed using repeated measures analysis of variance (alpha = 0.05). RESULTS: All antibiotic-containing groups led to greater discoloration than the antibiotic free groups. A severe discoloration occurred after 1 day. At the end of the experiment, antibiotic-treated samples exhibited crusts/agglomerates over the dentin surface, which totally or partially obliterated the dentinal tubules. The presence of MINO resulted in a greater color change than DOX. CONCLUSIONS: Scaffolds containing MINO or DOX produced similar color change to dentin when compared with their respective TAP systems, although DOX-related discoloration was less pronounced. PMID- 26602452 TI - Assessment of echinocandin regimens by pharmacokinetic/pharmacodynamic analysis against Candida spp. in paediatric patients. AB - This study aimed to investigate the cumulative fraction of response of various echinocandin (caspofungin, micafungin and anidulafungin) dosing regimens against Candida spp. in paediatric patients with invasive fungal infections (IFIs). Monte Carlo simulations were performed using previously published pharmacokinetic parameters and pharmacodynamic data to evaluate the ability of each echinocandin regimen in terms of fAUC/MIC (free drug area under the concentration-time curve/minimum inhibition concentration ratio) targets of caspofungin, micafungin and anidulafungin. Pharmacodynamic targets were attained in paediatric patients by both caspofungin regimens as well as by a high micafungin dosing regimens against Candida albicans and Candida glabrata. However, the results for anidulafungin suggested that the dosing regimens recommended were not optimal for paediatric patients. In addition, the predicted efficacy of all of the echinocandins against Candida parapsilosis was low. This is the first study to assess caspofungin, micafungin and anidulafungin therapy using Monte Carlo simulation. These results rationalise and optimise the dosage regimens of caspofungin, micafungin and anidulafungin against C. albicans, C. glabrata and C. parapsilosis for paediatric patients with IFIs. PMID- 26602453 TI - Reduction of Biomechanical and Welding Fume Exposures in Stud Welding. AB - The welding of shear stud connectors to structural steel in construction requires a prolonged stooped posture that exposes ironworkers to biomechanical and welding fume hazards. In this study, biomechanical and welding fume exposures during stud welding using conventional methods were compared to exposures associated with use of a prototype system that allowed participants to weld from an upright position. The effect of base material (i.e. bare structural beam versus galvanized decking) on welding fume concentration (particle number and mass), particle size distribution, and particle composition was also explored. Thirty participants completed a series of stud welding simulations in a local apprenticeship training facility. Use of the upright system was associated with substantial reductions in trunk inclination and the activity levels of several muscle groups. Inhalable mass concentrations of welding fume (averaged over ~18 min) when using conventional methods were high (18.2 mg m(-3) for bare beam; 65.7 mg m(-3) for through deck), with estimated mass concentrations of iron (7.8 mg m(-3) for bare beam; 15.8 mg m(-3) for through deck), zinc (0.2 mg m(-3) for bare beam; 15.8 mg m(-3) for through deck), and manganese (0.9 mg m(-3) for bare beam; 1.5 mg m(-3) for through deck) often exceeding the American Conference of Governmental Industrial Hygienists Threshold Limit Values (TLVs). Number and mass concentrations were substantially reduced when using the upright system, although the total inhalable mass concentration remained above the TLV when welding through decking. The average diameters of the welding fume particles for both bare beam (31+/-17 nm) through deck conditions (34+/-34 nm) and the chemical composition of the particles indicated the presence of metallic nanoparticles. Stud welding exposes ironworkers to potentially high levels of biomechanical loading (primarily to the low back) and welding fume. The upright system used in this study improved exposure levels during stud welding simulations, but further development is needed before field deployment is possible. PMID- 26602454 TI - Anxiolytic and sedative activities of aqueous leaf extract of Dichrocephala integrifolia (Asteraceae) in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Dichrocephala integrifolia (Asteraceae) is commonly used in the folk medicine in Cameroon to treat various ailments including headaches, jaundice, filariasis, neuritis and children's night agitation. It is also known to have anxiolytic properties. Since there were no scientific data supporting the above claims, we therefore aimed to evaluate the anxiolytic and sedative effects of the aqueous leaf extract of D. integrifolia. MATERIALS AND METHODS: The extract used was obtained after maceration of leaves of D. integrifolia in water at room temperature. The anxiolytic effect was tested by the elevated plus-maze (EPM) and Open Field tests while the sedative effect was evaluated by the diazepam-induced sleep test. RESULTS: D. integrifolia significantly induced an increase in the percentage of entries into open arms and a decrease in percentage of entries into closed arms at the dose of 22 mg/kg BW. The extract also induced a decrease of rearing and head dipping at the doses of 22 and 40 mg/kg BW during the EPM test. In addition, D. integrifolia extract induced a significant increase of crossing and time spent at the center of the experimental set at the dose of 40 mg/kg BW during the open field test. Lastly, D. integrifolia caused a significant reduction of the latency to sleep and an increase of total sleep time at the doses of 22 and 40 mg/kg BW in the diazepam induced sleep test. CONCLUSION: The results obtained in this study suggest that the aqueous leaf extract of D. integrifolia is endowed with anxiolytic and sedative properties, which justify its traditional use. PMID- 26602456 TI - Experimental fault-tolerant universal quantum gates with solid-state spins under ambient conditions. AB - Quantum computation provides great speedup over its classical counterpart for certain problems. One of the key challenges for quantum computation is to realize precise control of the quantum system in the presence of noise. Control of the spin-qubits in solids with the accuracy required by fault-tolerant quantum computation under ambient conditions remains elusive. Here, we quantitatively characterize the source of noise during quantum gate operation and demonstrate strategies to suppress the effect of these. A universal set of logic gates in a nitrogen-vacancy centre in diamond are reported with an average single-qubit gate fidelity of 0.999952 and two-qubit gate fidelity of 0.992. These high control fidelities have been achieved at room temperature in naturally abundant (13)C diamond via composite pulses and an optimized control method. PMID- 26602455 TI - Effect of active sub-fraction of Ichnocarpus frutescens (L.) R.Br. in the management of obesity. AB - AIM OF THE STUDY: Ichnocarpus frutescens (L.) R.Br. (Apocynaceae) is used by the traditional healers in India to treat diabetes and hyperlipidemia.This work aims to study the antiobesity effect of the active sub-fraction obtained from the leaves of this plant using in vitro and in vivo models. METHODOLOGY: Active sub fraction (Sfr3) isolated by column chromatography was analyzed using Gas chromatography and mass spectrometry. Adipogenesis and apoptosis were detected by oil red O and Hoechst-33342 staining, respectively, in 3T3-L1 adipocytes. Expression of specific marker genes involved in lipid metabolism was detected by Reverse Transcriptase Polymerase Chain Reaction in 3T3-L1 adipocytes and adipose tissues of C57 BL/6J mice, fed with high fat diet (HFD) and treated with Sfr3 and fenofibrate for 45 days. RESULTS: The treatment with Sfr3 decreased lipid accumulation and caused apoptosis in adipocytes. In the HFD induced obese animals, serum and liver lipid levels were decreased and a significant decrease in body weight gain was observed dose dependently in 45 days treatment. Histopathological examination showed decrease in adipose mass and liver lipid accumulation. The effect of Sfr3 on the marker genes of adipocytes was significantly regulated at the treated doses both in vitro and in vivo. CONCLUSION: Sfr3 of Ichnocarpus frutescens is effective in the management of obesity through adipocyte apoptosis. PMID- 26602457 TI - Characterization of Two Distinct Amorphous Forms of Valsartan by Solid-State NMR. AB - Valsartan (VAL) is an antihypertensive drug marketed in an amorphous form. Amorphous materials can have different physicochemical properties depending on preparation method, thermal history, etc., but the nature of such materials is difficult to study by diffraction techniques. This study characterizes two different amorphous forms of valsartan (AR and AM) using solid-state NMR (SSNMR) as a primary investigation tool, supported by solution-state NMR, FT-IR, TMDSC, and dissolution tests. The two forms are found to be clearly distinct, with a significantly higher level of structural arrangement in the AR form, as observed in (13)C, (15)N, and (1)H SSNMR. (13)C and (15)N NMR indicates that the fully amorphous material (AM) contains an approximately equal ratio of cis-trans conformers about the amide bond, whereas the AR form exists mainly as one conformer, with minor conformational "defects". (1)H ultrafast MAS NMR shows significant differences in the hydrogen bonding involving the tetrazole and acid hydrogens between the two materials, while (15)N NMR shows that both forms exist as a 1,2,3,4-tetrazole tautomer. NMR relaxation times show subtle differences in local and bulk molecular mobility, which can be connected with the glass transition, the stability of the glassy material, and its response to aging. Counterintuitively the fully amorphous material is found to have a significantly lower dissolution rate than the apparently more ordered AR material. PMID- 26602458 TI - Design of Warped Stretch Transform. AB - Time stretch dispersive Fourier transform enables real-time spectroscopy at the repetition rate of million scans per second. High-speed real-time instruments ranging from analog-to-digital converters to cameras and single-shot rare phenomena capture equipment with record performance have been empowered by it. Its warped stretch variant, realized with nonlinear group delay dispersion, offers variable-rate spectral domain sampling, as well as the ability to engineer the time-bandwidth product of the signal's envelope to match that of the data acquisition systems. To be able to reconstruct the signal with low loss, the spectrotemporal distribution of the signal spectrum needs to be sparse. Here, for the first time, we show how to design the kernel of the transform and specifically, the nonlinear group delay profile dictated by the signal sparsity. Such a kernel leads to smart stretching with nonuniform spectral resolution, having direct utility in improvement of data acquisition rate, real-time data compression, and enhancement of ultrafast data capture accuracy. We also discuss the application of warped stretch transform in spectrotemporal analysis of continuous-time signals. PMID- 26602459 TI - Highlight-What You Eat: Bacterivorous Green Algae Raises Questions about the Evolution of Eating, Photosynthesis. PMID- 26602460 TI - Lessons for leaders. AB - Hundreds of the country's most senior nurses are convening in Birmingham this month for the chief nursing officer (CNO) for England's summit 2015. PMID- 26602461 TI - Awards for work with black and minority ethnic communities. AB - A NURSE who created a smartphone app to explain the healthcare system to foreign visitors, and another who designed one to help healthcare professionals working with victims of female genital mutilation (FGM), are among the winners of this year's Mary Seacole Leadership and Development Awards. PMID- 26602462 TI - Charity to develop community nurses' leadership skills. AB - THE QUEEN'S Nursing Institute aims to boost leadership opportunities for community nurses through two initiatives next year. PMID- 26602463 TI - Lord Carter's report to include guidance on safe staffing. AB - GUIDANCE ON safe staffing levels, including a new method for measuring nursing hours against patient need, will form a key part of a report on productivity in NHS hospitals. PMID- 26602465 TI - Trust boards should do more to tackle race discrimination. AB - THE AUTHOR of a landmark review on discrimination in the NHS said that the voices of staff from black and minority ethnic backgrounds are still not being heard by senior managers. PMID- 26602466 TI - Report describes how poor record keeping affects patient care. AB - NHS TRUSTS in England are taking action to improve after a parliamentary and health service ombudsman's report revealed examples of poor nursing care, including a low standard of record keeping. PMID- 26602467 TI - Nurse directors struggle to balance cuts in finance with ensuring service quality. AB - NURSE DIRECTORS are torn between being responsible for care quality and the demands of balancing budgets, research has highlighted. PMID- 26602468 TI - Buying into a greater product procurement role for nurses. AB - AT THE chief nursing officer (CNO) for England's summit this month, the RCN will publicise its campaign encouraging nurses to have more say in the choice of products, supplies and medicines they use on a daily basis. PMID- 26602469 TI - Providing health care from army camp to civvy street. AB - NOT MANY nurses have to learn to use a pistol and rifle, but Elizabeth Shillito did. It was part of training during her 22-year career as a nurse in the Royal Air Force (RAF), which has taken her all over the world, including to the war zones of Iraq, Kuwait and Afghanistan. PMID- 26602470 TI - Food and drink message has to work down from the top. AB - FRESH GUIDANCE aimed at reducing poor nutrition and hydration in patients places more responsibility on senior nurses and clinical commissioners to ensure that messages trickle down to staff at all levels. PMID- 26602471 TI - Dealing with disaster. AB - WE LIVE in a world in which war and conflict abound, natural disasters strike frequently and, because of our global connectivity, infectious disease is just an incubation period away. PMID- 26602473 TI - Susan Williams - International outlook. AB - SOME HEARTENING news came for nursing staff, NHS employers and the care sector across the UK in October. The home secretary finally saw sense and agreed to put nursing on the shortage occupation list. PMID- 26602475 TI - Daily Water Free. AB - A study at Nottingham City Hospital found dehydration affects cognitive function, which in turn can affect nurses' judgement and the safe care of patients. Researchers found that more than half of nurses were dehydrated at the end of their shifts, and short-term memory tests revealed significant impairment. PMID- 26602476 TI - Vantage point - A private matter. AB - IMAGINE THAT you have been struggling with depression and your doctor has referred you for cognitive behaviour therapy (CBT). Such treatment is provided on the NHS through the Improving Access to Psychological Therapies (IAPT) programme. But there is a catch; you have been placed on a three-month waiting list. PMID- 26602478 TI - Culture club. AB - WHEN THE parliamentary group on patient safety gathers this month for only its second meeting, it will have on the table the latest white paper on infections. PMID- 26602480 TI - Out for consultation. AB - Night-time safety To promote a diverse night-time economy throughout Wales, while providing safe, accessible and attractive city and town centres, the Welsh Government has published a framework for managing the night-time economy. The framework is intended to help local health boards, local authorities, night-time economy teams, community safety leads and other stakeholders; the aim is to develop and deliver local plans and strategies to address drug and alcohol related disorder, and antisocial behaviour, in towns and cities. The general goals are to protect people and communities by creating safe and healthy environments, tackling the availability of alcohol and drugs by enforcing licensing regulations, and confronting antisocial behaviour, crime and the fear of crime. Consultation on the framework is open until December 17 at www.tinyurl.com/qajhxp8. PMID- 26602485 TI - How one trust made its way out of special measures. AB - United Lincolnshire Hospitals NHS Trust (ULHT) was placed into special measures by the Care Quality Commission in 2013 after problems were identified with its governance, patient and medicines safety, management and complaints handling. The author was appointed acting chief nurse six months later and has helped to identify and implement a package of improvements at the trust. As a result, ULHT was taken out of special measures in March 2015. This article describes the changes that were introduced and the processes involved that made this happen. PMID- 26602486 TI - Interpersonal behaviour in relation to burnout. AB - Organisational and work-related challenges faced by midwives make them vulnerable to burnout, but individual factors, such as interpersonal behaviour, can also contribute. A study in eight hospitals in the Dutch-speaking part of Belgium investigated the prevalence of burnout among Flemish midwives, assessed their interpersonal behaviour, and explored the relationship between interpersonal behaviour, burnout, job satisfaction and intention to leave. This article describes the study and reports the findings. PMID- 26602487 TI - How mentors can influence the values, behaviours and attitudes of nursing staff through positive professional socialisation. AB - This article explores the concept and processes involved in professional socialisation and how mentors and nurse managers can help to foster positive aspects of this in their practice. Positive professional socialisation needs champions to instil fundamental professional values and behaviours in nursing staff, and managers need to support mentors to influence and lead the way in promoting standards of excellence in the nursing profession to assure public trust and confidence, and ultimately patient safety. The time out activities will ask you to consider and develop possible strategies to help support mentors and staff, and aim to encourage you to explore the potential benefits of positive professional socialisation for your team in delivering high quality patient care. PMID- 26602488 TI - We are the future. AB - Why did you choose to work in the NHS? As a teenager, I was unclear about my ambitions, and took a job as a theatre orderly after I deferred my degree. I found the environment fascinating, and the prospect of training to work in theatres felt extremely exciting. To care for a patient, who in many cases entrusts his or her life to a team, appeared to be the most rewarding career. PMID- 26602489 TI - Prescription opioid analgesics for pain management in Australia: 20 years of dispensing. AB - BACKGROUND: Opioid prescribing/dispensing data can inform policy surrounding regulation by informing trends and types of opioid prescribed and geographic variations. In Australia so far only partial data on dispensing have been published, and data for states/territories remain unknown. AIM: Using a range of measures, this study examines 20-year (1992-2011) trends in prescription opioid analgesics in Australia - both nationally and for individual jurisdictions. METHODS: Dispensing data were obtained from the Drug Utilisation Sub-Committee and the Pharmaceutical Benefits Scheme (PBS) websites. Trends in numbers of prescriptions and daily defined dose (DDD)/1000 people/day were examined over time and across states/territories. Seasonal variations in PBS/Repatriation Pharmaceutical Benefits Scheme (RPBS) items for nationwide dispensing were adjusted using a centred moving smoothing technique. RESULTS: In two decades, 165.32 million prescriptions for opioids were dispensed, with codeine and its derivatives the most prescribed formulation (50.1%) followed by tramadol (13.5%) and oxycodone derivatives (12.7%). In terms of DDD/1000 people/day, dispensing increased from 5.38 in 1992 to 14.46 in 2011. There are significant increasing trends for total, PBS/RPBS and under co-payment prescriptions (priced below patient co-payment). The DDD/1000 people/day for items dispensed through PBS/RPBS was highest in Tasmania. CONCLUSION: Prescription opioid dispensing increased substantially over the study period. With an ageing population, this trend is likely to continue in future. A growing concern about harms associated with opioid use warrants balanced control measures so that harms could be minimised without reducing effective pain treatment. Research examining utilisation in small geographic areas may help design spatially tailored interventions. A real time drug-monitoring programme may reduce undue prescribing and dispensing. PMID- 26602490 TI - Methacholine challenge testing is superior to the exercise challenge for detecting asthma in children. AB - BACKGROUND: Exercise-induced bronchoconstriction occurs in a large proportion of children with asthma. OBJECTIVE: To compare the predictive value of methacholine challenge testing (MCCT) and the exercise treadmill challenge (ETC) for detecting asthma in children with postexercise symptoms. METHODS: This was a prospective study of children 10 to 18 years old with postexercise symptoms. During asthma diagnosis, they underwent MCCT and ETC. There were 2 study visits. All subjects underwent ECT at visit 1 and MCCT 1 week later at visit 2. RESULTS: One hundred one children were included; 62.9% had a history of atopy, and asthma was confirmed in 43.6%. MCCT showed 90.9% sensitivity, 82.5% specificity, 80.0% positive predictive value, and 92.2% negative predictive value; the respective values for ECT were 77.3%, 68.4%, 65.4%, and 79.6%. Positive MCCT results showed significantly higher sensitivity and higher positive predicative value in the diagnosis of asthma in children with postexercise symptoms compared with a 10% decrease in forced expiratory volume in 1 second for ECT (P = 0.034). Conducting MCCT during asthma diagnosis confirmed asthma in an additional 24.3% of children with exercise-induced symptoms. With a cutoff level at 17% of forced expiratory volume in 1 second for ECT, the discrepancy was decreased and reasonable values for sensitivity, specificity, positive predictive value, and negative predictive value were attained (61.0%, 77.1%, 69.4%, and 69.8%, respectively). CONCLUSION: A large number of school children with asthma and postexercise symptoms could have positive MCCT and negative ECT findings. Untreated asthma in children with exercise-induced bronchoconstriction could cause them to be discharged from physical education classes. TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT01798823. PMID- 26602491 TI - Successful treatment of occupational delayed pressure urticaria and angioedema with omalizumab. PMID- 26602492 TI - Sharing bad news of a lung cancer diagnosis: understanding through communication privacy management theory. AB - BACKGROUND: The aim of this paper is to understand the process of information disclosure and privacy as patients share their news of lung cancer with significant others. METHODS: Twenty patients with lung cancer and 17 family members/friends accompanying them at diagnosis-giving completed either individual or dyad semi-structured interviews. Initial thematic analysis, then Petronio's Communication Privacy Management theory was used to inform interpretation. RESULTS: Patients described a sense of ownership of the news of their cancer and sought control of how, when and with whom it was shared. Family members expressed a need to follow the patients' rules in sharing this news, which limited their own support systems. Patients and family members had to live within the relational communication boundaries in order to maintain their trusting relationship and avoid potential disruptions. CONCLUSION: Patients as individuals are strongly interlinked with significant others, which impacts on their experience of disclosing private information. This shapes their psychological processes and outcomes impacting on their illness experience. This should be considered when developing interventions to support patients with sharing bad news. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26602494 TI - Polynuclear Silver(I) Triazole Complexes: Ion Conduction and Nanowire Formation in the Mesophase. AB - Examples of polynuclear metallomesogens are few. Herein,1,2,4-triazole ligands were used to prepare mono- and polynuclear silver(I) triazole metallomesogens. Besides showing an SmA phase in the mesophase, two interesting properties were observed. First, higher ion conductivity is always found for the polynuclear complexes than for the mononuclear complexes with the same anion, an observation contrary to the knowledge that migration of a monomeric cation should be faster than that of a polymeric cation. Second, thermolysis of the polynuclear silver(I) triazole complexes in the assembled mesophase yielded Ag nanowires, in an excellent demonstration of the assembled nature of the polynuclear silver(I) ions in the thermolysis process. PMID- 26602493 TI - The level of acceptance of spanish medical students of the transplantation of solid organs from animals: a stratified and multicentre study. AB - INTRODUCTION: Research into the transplantation of solid organs from animals (xenotransplantation) is generating interest and curiosity given that this could be a way of resolving the shortage in transplant organs. However, the fact is that currently xenotransplantation is far from becoming a clinical practice. OBJECTIVE: To analyse the attitude of medical students from Spanish universities towards the donation of organs from animals and to determine the factors affecting their attitudes. MATERIAL AND METHODS: TYPE OF STUDY: A sociological, interdisciplinary, observational and multicentre study in Spain. STUDY POPULATION: Students enrolled on the medical degree in Spain (n = 34 000). SAMPLE SIZE: A sample of 9598 students (a confidence level of 99% and precision of +/- 1%) stratified by geographical area and academic year. Instrument of measurement: A validated questionnaire of attitude towards organ xenotransplantation (PCID XenoTx RIOS) which was self-administered and completed anonymously. RESULTS: A completion rate of 95.7% (n = 9275) was obtained. If the results of xenotransplantation were as good as in human donation, 81% (n = 7491) would be in favour, 3% (n = 308) against and 16% (n = 1476) undecided. The following variables affected this attitude: sex (P < 0.001); academic year (P < 0.001); discussion of transplantation with one's family (P < 0.001) and friends (P < 0.001); the opinion of one's partner (P < 0.001); the respondent's attitude towards organ donation (P < 0.001); religion (P < 0.001); and participation in altruistic activities (P < 0.001). The following variables persisted in the multivariate analysis: (1) being a female (OR = 1.794; P < 0.001); (2) academic year (OR = 2.487; P < 0.001); (3) having spoken about the issue with one's family (OR = 1.200; P = 0.019); (4) the favourable opinion of one's partner (OR = 1.526; P = 0.028); (5) an attitude in favour of donation (OR = 2.087; P < 0.001); (6) being an atheist/agnostic, (OR = 2.5; P < 0.001); and (7) a belief that one's religion is in favour of transplantation (OR = 1.317; P = 0.005). CONCLUSIONS: Spanish medical students have a favourable attitude towards xenotransplantation. This willingness and interest could be a decisive platform for the development and strengthening of research, both for centres with a pre-clinical xenotransplantation programme and new healthcare centres. PMID- 26602495 TI - Bilateral ductal stenting in a neonate with right isolated pulmonary artery of ductal origin and differential pulmonary vascular resistances. AB - We report our experience with stenting a right ductus arteriosus in a neonate with ductal origin of the right pulmonary artery (PA), who subsequently developed severe pulmonary hypertension in the left PA requiring decompression of the right ventricle with stenting of the left ductus. (c) 2015 Wiley Periodicals, Inc. PMID- 26602496 TI - A multicentric association study between 39 genes and nonsyndromic cleft lip and palate in a Brazilian population. AB - PURPOSE: The aim of this study was to use the TaqMan OpenArray system to evaluate associations between 39 genes and the etiology of nonsyndromic cleft lip and palate (NSCLP) in a Brazilian population. MATERIAL AND METHODS: This case-control association study was designed with 80.11% statistical power according to logistic regression (GPOWER software). The case group had 182 patients with NSCLP enrolled in the Brazilian Database on Orofacial Clefts. The controls included 355 healthy individuals with no history of oral clefting in the past three generations. All samples were genotyped for 253 tag single nucleotide polymorphisms (tagSNPs) in 39 genes, including two that had recently been associated with this process. The association analysis was performed using logistic regression and stepwise regression. The results were corrected for multiple testing [Bonferroni correction and False Discovery Rate (FDR)]. RESULTS: Twenty-four SNPs in 16 genes were significantly associated with the etiology of NSCLP, including MSX1, SPRY1, MSX2, PRSS35, TFAP2A, SHH, VAX1, TBX10, WNT11, PAX9, BMP4, JAG2, AXIN2, DVL2, KIF7, and TCBE3. Stepwise regression analysis revealed that 11 genes contributed to 15.5% of the etiology of NSCLP in the sample. CONCLUSION: This is the first study to associate KIF7 and TCEB3 with the etiology of NSCLP. New technological approaches using the same design should help to identify further etiological susceptibility variants. PMID- 26602500 TI - Properties and Permeability of Hypericin and Brominated Hypericin in Lipid Membranes. AB - The promising photosensitizing properties of hypericin, a substituted phenanthroperylene quinone naturally found in Saint John's wort, has led to the proposal that it can be utilized in photodynamic therapy. Structurally modified derivatives are at the present time being investigated to generate a more effective hypericin photosensitizer. Neither the detailed mechanism behind the powerful action of hypericin, arising as a result of light excitation, nor the intracellular localization and transportation is still fully understood. In the present work, molecular dynamics simulations have been performed to study the properties and the permeability of hypericin and modifications thereof, substituted with one or four bromine atoms, in a dipalmitoylphosphatidylcholine lipid membrane. The molecules were found to accumulate in the most dense region of the lipids due to competing interactions with the hydrophobic lipid interior and the polar aqueous environment. This was confirmed by analyzing the radial distribution functions and by the density profiles of the system components. Calculated free energy profiles display large negative changes in free energy for the transport process of the molecules into the lipids, which also support this finding. Permeability coefficients show overall fastest diffusion in the membrane system for hypericin containing one bromine. PMID- 26602501 TI - Performance of Kinetic Energy Functionals for Interaction Energies in a Subsystem Formulation of Density Functional Theory. AB - We have tested the performance of a large set of kinetic energy density functionals of the local density approximation (LDA), the gradient expansion approximation (GEA), and the generalized gradient approximation (GGA) for the calculation of interaction energies within a subsystem approach to density functional theory. Our results have been obtained with a new implementation of interaction energies for frozen-density embedding into the Amsterdam Density Functional program. We present data for a representative sample of 39 intermolecular complexes and 15 transition metal coordination compounds with interaction energies spanning the range from -1 to -783 kcal/mol. This is the first time that kinetic energy functionals have been tested for such strong interaction energies as the ligand-metal bonds in the investigated coordination compounds. We confirm earlier work that GGA functionals offer an improvement over the LDA and are particularly well suited for weak interactions like hydrogen bonds. We do, however, not find a particular reason to prefer any of the GGA functionals over another. Functionals derived from the GEA in general perform worse for all of the weaker interactions and cannot be recommended. An unexpectedly good performance is found for the coordination compounds, in particular with the GEA-derived functionals. However, the presently available kinetic energy functionals cannot be applied in cases in which a density redistribution between the subsystems leads to strongly overlapping subsystem electron densities. PMID- 26602502 TI - Using Molecular Similarity to Develop Reliable Models of Chemical Reactions in Complex Environments. AB - The use of molecular similarity to develop reliable low-cost quantum mechanical models for use in quantum mechanical/molecular mechanical simulations of chemical reactions is explored, using the H + HF -> H2 + F collinear reaction as a test case. The approach first generates detailed quantum chemical data for the reaction center in geometries and electrostatic environments that span those expected to arise during the molecular dynamics simulations. For each geometry and environment, both high- and low-level ab initio calculations are performed. A model is then developed to predict the high-level results using only inputs generated from the low-level theory. The inputs used here are based on principal component analysis of the low-level distributed multipoles, and the model is a simple linear regression. The distributed multipoles are monopoles, dipoles, and quadrupoles at each atomic center, and they summarize the electronic distribution in a manner that is comparable across basis set. The error in the model is dominated by extrapolation from small to large basis sets, with extrapolation from uncorrelated to correlated methods contributing much less error. A single regression can be used to make predictions for a range of reaction-center geometries and environments. For the trial collinear reaction, separate regressions were developed for the transition region and the entrance and exit channels. These models can predict the results of CCSD(T)/cc-pVTZ computations from HF/3-21G distributed multipoles, with an average error for the reaction energy profile of 0.69 kcal/mol. PMID- 26602503 TI - Oxidation of the Benzyl Radical: Mechanism, Thermochemistry, and Kinetics for the Reactions of Benzyl Hydroperoxide. AB - Oxidation of the benzyl radical plays a key role in the autoignition, combustion, and atmospheric degradation of toluene and other alkylated aromatic hydrocarbons. Under relevant autoignition conditions of moderate temperature and high pressure, and in the atmosphere, benzyl reacts with O2 to form the benzylperoxy radical, and the further oxidation reactions of this radical are not yet fully characterized. In this contribution, we further develop the reaction chemistry, thermodynamics, and kinetics of benzyl radical oxidation, highlighting the important role of benzyl hydroperoxide and the benzoxyl (benzyloxyl) radical. The benzylperoxy + H reaction mechanism is studied using computational chemistry and statistical reaction rate theory. High-pressure limit rate constants in the barrierless benzylperoxy + H association are obtained from variational transition state theory calculations, with internal rotor contributions. The benzylperoxy + H reaction is seen to produce an activated benzyl hydroperoxide adduct that has 87 kcal mol(-1) excess energy over the ground state. We show that this activated adduct proceeds almost exclusively to the benzoxyl radical + OH across a wide range of temperature and pressure conditions. Minor reaction paths include benzyl + HO2, alpha-hydroxylbenzyl + OH, and benzaldehyde + H2O, each constituting around 1% of the total reaction rate at higher temperatures. Thermal decomposition of benzyl hydroperoxide, formed by hydrogen abstraction reactions in the benzylperoxy radical and at low temperatures in the benzylperoxy + H and benzyl + HO2 reactions, is also investigated. Decomposition to benzoxyl + OH is fast at temperatures of 900 K and above. The contribution of benzyl hydroperoxide chemistry to the ignition and oxidation of alkylated aromatics is discussed. Benzyl radical oxidation chemistry achieves the conversion of toluene to benzaldehyde, aiding autoignition via processes that either release large amounts of energy or form reactive free radicals through chain-branching. PMID- 26602504 TI - Martini Coarse-Grained Force Field: Extension to Carbohydrates. AB - We present an extension of the Martini coarse-grained force field to carbohydrates. The parametrization follows the same philosophy as was used previously for lipids and proteins, focusing on the reproduction of partitioning free energies of small compounds between polar and nonpolar phases. The carbohydrate building blocks considered are the monosaccharides glucose and fructose and the disaccharides sucrose, trehalose, maltose, cellobiose, nigerose, laminarabiose, kojibiose, and sophorose. Bonded parameters for these saccharides are optimized by comparison to conformations sampled with an atomistic force field, in particular with respect to the representation of the most populated rotameric state for the glycosidic bond. Application of the new coarse-grained carbohydrate model to the oligosaccharides amylose and Curdlan shows a preservation of the main structural properties with 3 orders of magnitude more efficient sampling than the atomistic counterpart. Finally, we investigate the cryo- and anhydro-protective effect of glucose and trehalose on a lipid bilayer and find a strong decrease of the melting temperature, in good agreement with both experimental findings and atomistic simulation studies. PMID- 26602505 TI - Versatile Object-Oriented Toolkit for Coarse-Graining Applications. AB - Coarse-graining is a systematic way of reducing the number of degrees of freedom representing a system of interest. Several coarse-graining techniques have so far been developed, such as iterative Boltzmann inversion, force-matching, and inverse Monte Carlo. However, there is no unified framework that implements these methods and that allows their direct comparison. We present a versatile object oriented toolkit for coarse-graining applications (VOTCA) that implements these techniques and that provides a flexible modular platform for the further development of coarse-graining techniques. All methods are illustrated and compared by coarse-graining the SPC/E water model, liquid methanol, liquid propane, and a single molecule of hexane. PMID- 26602506 TI - First Principles Studies of Fe-Containing Aluminosilicate and Aluminogermanate Nanotubes. AB - A theoretical study of the electronic effects of the inclusion of iron on aluminosilicates and aluminogermanates nanotubes with imogolite-like structure was carried out by unrestricted all-electron density functional theory calculations of periodic boundary models. The iron ion was incorporated to the imogolitic models by an isomorphic substitution of Al by Fe and by the adsorption of the Fe ion in the inner and outer nanotube structure in the octahedral hydrated configuration. Additionally, the effects of the Fe concentration in the interval 0.05 <= x <= 0.1 were analyzed. We observe a drastic reduction of the bandgap value from 4.6 to 2.6 eV and from 4.2 to 1.0 eV for the silicon and germanium respectively. Finally, in all the models there is a shift of the Fermi energy toward the gap region as a result of the inclusion of iron electronic states in the bandgap region. PMID- 26602507 TI - Mixed Resolution Modeling of Interactions in Condensed-Phase Systems. AB - A new mixed resolution method is developed for modeling molecular interactions that employs a distance-dependent coupling of atomistic and coarse-grained force fields. In the mixed resolution interaction (MRI) method, detailed atomistic structure is maintained over the whole system. However, the atomistic force field is used for close interparticle separations (called the atomistic zone), while at large separations the coarse-grained forces are "unfolded" into atomistic interactions in a way that reduces the cost of the simulation compared to standard long-range approximations or cutoff schemes. Several variations of the unfolding scheme are described. The method is applied to develop MRI models of bulk TIP3P water, based on one-site multiscale coarse-grained (MS-CG) water potentials located at the molecular centers of either mass or geometry. With a sufficiently large atomistic zone (>0.7 nm), the MRI models provide excellent simulations of the bulk water phase. MRI modeling is further illustrated for liquid methanol with both one- and two-site coarse graining. The MRI water models are then used to simulate aqueous solutions, where the solutes are treated at the atomistic level. It is shown that the MRI treatment significantly alters solute association dynamics if it relies on the MS-CG force fields obtained solely from the bulk phase. Possible modifications of the MRI procedure to improve the transferability of water potentials to heterogeneous systems are, therefore, discussed. The best result is obtained if water molecules within a preselected cutoff distance from the solute are described using only atomistic potentials. As a final example, the MRI method is applied to model a solvated phospholipid bilayer. PMID- 26602508 TI - Electrostatic Interactions in Dissipative Particle Dynamics: Toward a Mesoscale Modeling of the Polyelectrolyte Brushes. AB - We report mesoscopic simulations of bulk electrolytes and polyelectrolyte brushes using the dissipative particle dynamics (DPD) method. The calculation of the electrostatic interactions is carried out using both the Ewald summation method and the particle-particle particle-mesh technique with charges distributed over the particles. The local components of the pressure tensor are calculated using the Irving and Kirkwood, and the method of planes and mechanical equilibrium is demonstrated. The profiles of the normal component of the pressure tensor are shown to be similar for both the Ewald and particle-particle particle-mesh methods for a single polyelectrolyte brush. We show that the PPPM method with the MOP technique is the appropriate choice for simulations of this type. The mesoscale modeling of a strongly stretched polylectrolyte brush formed by strong charged polymer chains at a high grafting density shows that the polyelectrolyte follows the nonlinear osmotic regime, as expected from the calculation of the Gouy-Chapman length and the dimensionless Manning ratio. PMID- 26602509 TI - Coarse Point Charge Models For Proteins From Smoothed Molecular Electrostatic Potentials. AB - To generate coarse electrostatic models of proteins, we developed an original approach to hierarchically locate maxima and minima in smoothed molecular electrostatic potentials. A charge-fitting program was used to assign charges to the so-obtained reduced representations. Templates are defined to easily generate coarse point charge models for protein structures, in the particular cases of the Amber99 and Gromos43A1 force fields. Applications to four small peptides and to the ion channel KcsA are presented. Electrostatic potential values generated by the reduced models are compared with the corresponding values obtained using the original sets of atomic charges. PMID- 26602510 TI - Molecular Dynamics Simulations of BcZBP, A Deacetylase from Bacillus cereus: Active Site Loops Determine Substrate Accessibility and Specificity. AB - BcZBP is an LmbE-like, homohexameric, zinc-dependent deacetylase from the opportunistic pathogen Bacillus cereus with three, thus far uncharacterized, homologues in B. anthracis. Although its specific substrate is still unknown, the enzyme has been shown to preferentially deacetylate N-acetylglucosamine and diacetylchitobiose via an active site based on a zinc-binding motif of the type HXDDXnH. In the crystal structure, the active site is located at a deep and partially blocked cleft formed at the interface between monomers related by the molecular 3-fold axis, although the major, in structural terms, building block of the enzyme is not the trimer, but the intertwined dimer. Here, we report results from a 50 ns molecular dynamics simulation of BcZBP in explicit solvent with full electrostatics and show that (i) the view of the intertwined dimer as the major structural and functional building block of this class of hexameric enzymes is possibly an oversimplification of the rather complex dynamics observed in the simulation, (ii) the most mobile (with respect to their atomic fluctuations) parts of the structure coincide with three surface loops surrounding the active site, and (iii) these mobile loops define the active site's accessibility, and may be implicated in the determination of the enzyme's specificity. PMID- 26602511 TI - Solvent Effects on Donor-Acceptor Couplings in Peptides. A Combined QM and MD Study. AB - We present a combined Quantum Chemical/Molecular Dynamics study on electronic coupling between tryptophan-based donor and acceptor in oligopeptides of variable length. Molecular dynamics was performed on Trp-(Pro)n-Trp (n = 1 to 6) molecules in gas phase and aqueous solvent and the electronic coupling matrix element was computed for thermal hole transfer applying semiempirical INDO/S together with the generalized Mulliken-Hush approach. For comparison, we also computed coupling values of 40 000 snapshots applying ab initio Hartree-Fock, showing good agreement with the INDO/S results. We demonstrate that the coupling values strongly fluctuate throughout the molecular dynamic trajectory and the mechanism of electron transfer is affected by the presence of solvent through restriction of the conformational space. Gas-phase calculations show gated electron transfer dominated by direct through-space coupling due to strong conformational changes bringing donor and acceptor in close vicinity. Solvent calculations establish a nongated mechanism dominated by bridge-mediated coupling. In agreement with experimental data, our results point to a donor-acceptor distance of ~20 A as a possible point for transition from superexchange to hopping electron transfer mechanism. PMID- 26602513 TI - Efficient Diffuse Basis Sets: cc-pVxZ+ and maug-cc-pVxZ. PMID- 26602512 TI - Discrete Optimization of Electronic Hyperpolarizabilities in a Chemical Subspace. AB - We introduce a general optimization algorithm based on an interpolation of property values on a hypercube. Each vertex of the hypercube represents a molecule, while the interior of the interpolation represents a virtual superposition ("alchemical" mutation) of molecules. The resultant algorithm is similar to branch-and-bound/tree-search methods. We apply the algorithm to the optimization of the first electronic hyperpolarizability for several tolane libraries. The search includes structural and conformational information. Geometries were optimized using the AM1 Hamiltonian, and first hyperpolarizabilities were computed using the INDO/S method. Even for small libraries, a significant improvement of the hyperpolarizability, up to a factor of ca. 4, was achieved. The algorithm was validated for efficiency and reproduced known experimental results. The algorithm converges to a local optimum at a computational cost on the order of the logarithm of the library size, making large libraries accessible. For larger libraries, the improvement was accomplished by performing electronic structure calculations on less than 0.01% of the compounds in the larger libraries. Alternation of electron donating and accepting groups in the tolane scaffold was found to produce candidates with large hyperpolarizabilities consistently. PMID- 26602514 TI - Creating a Standardized Order Set for DKA Admissions to the PICU. PMID- 26602515 TI - Diabetes Quality of Care Before and After Implementation of a Resident Clinic Practice Partnership System. AB - Deficiencies in resident diabetes care quality may relate to continuity clinic design. This retrospective analysis compared diabetes care processes and outcomes within a traditional resident continuity clinic structure (2005) and after the implementation of a practice partnership system (PPS; 2009). Under PPS, patients were more likely to receive annual foot examinations (odds ratio [OR] = 11.6; 95% confidence interval [CI] = 7.2, 18.5), microalbumin screening (OR = 2.4; 95% CI = 1.6, 3.4), and aspirin use counseling (OR = 3.8; 95% CI = 2.5, 6.0) and were less likely to receive eye examinations (OR = 0.54; 95% CI = 0.36, 0.82). Hemoglobin A1c and lipid testing were similar between periods, and there was no difference in achievement of diabetes and blood pressure goals. Patients were less likely to achieve cholesterol goals under PPS (OR = 0.62; 95% CI = 0.39, 0.98). Resident practice partnerships may improve processes of diabetes care but may not affect intermediate outcomes. PMID- 26602516 TI - Team Science Approach to Developing Consensus on Research Good Practices for Practice-Based Research Networks: A Case Study. AB - Using peer learning strategies, seven experienced PBRNs working in collaborative teams articulated procedures for PBRN Research Good Practices (PRGPs). The PRGPs is a PBRN-specific resource to facilitate PBRN management and staff training, to promote adherence to study protocols, and to increase validity and generalizability of study findings. This paper describes the team science processes which culminated in the PRGPs. Skilled facilitators used team science strategies and methods from the Technology of Participation (ToP(r)), and the Consensus Workshop Method to support teams to codify diverse research expertise in practice-based research. The participatory nature of "sense-making" moved through identifiable stages. Lessons learned include (1) team input into the scope of the final outcome proved vital to project relevance; (2) PBRNs with diverse domains of research expertise contributed broad knowledge on each topic; and (3) ToP(r) structured facilitation techniques were critical for establishing trust and clarifying the "sense-making" process. PMID- 26602517 TI - The importance of superficial basal cell carcinoma in a retrospective study of 139 patients who underwent Mohs micrographic surgery in a Brazilian university hospital. AB - OBJECTIVE: Mohs micrographic surgery is a specialized surgical procedure used to treat skin cancer. The purpose of this study was to better understand the profile of the patients who underwent the procedure and to determine how histology might be related to complications and the number of stages required for complete removal. METHODS: The records of patients who underwent Mohs micrographic surgery from October 2008 to November 2013 at the Dermatology Division of the Hospital of the Campinas University were assessed. The variables included were gender, age, anatomical location, histology, number of stages required and complications. RESULTS: Contingency tables were used to compare the number of stages with the histological diagnosis. The analysis showed that patients with superficial basal cell carcinoma were 9.03 times more likely to require more than one stage. A comparison between complications and histological diagnosis showed that patients with superficial basal cell carcinoma were 6.5 times more likely to experience complications. CONCLUSION: Although superficial basal cell carcinoma is typically thought to represent a less-aggressive variant of these tumors, its propensity for demonstrating "skip areas" and clinically indistinct borders make it a challenge to treat. Its particular nature may result in the higher number of surgery stages required, which may, as a consequence, result in more complications, including recurrence. Recurrence likely occurs due to the inadequate excision of the tumors despite their clear margins. Further research on this subtype of basal cell carcinoma is needed to optimize treatments and decrease morbidity. PMID- 26602518 TI - Myocardial blood flow assessment with 82rubidium-PET imaging in patients with left bundle branch block. AB - OBJECTIVES: Perfusion abnormalities are frequently seen in Single Photon Emission Computed Tomography (SPECT) when a left bundle branch block is present. A few studies have shown decreased coronary flow reserve in the left anterior descending territory, regardless of the presence of coronary artery disease. OBJECTIVE: We sought to investigate rubidium-82 (82Rb) positron emission tomography imaging in the assessment of myocardial blood flow and coronary flow reserve in patients with left bundle branch block. METHODS: Thirty-eight patients with left bundle branch block (GI), median age 63.5 years, 22 (58%) female, 12 with coronary artery disease (>=70%; GI-A) and 26 with no evidence of significant coronary artery disease (GI-B), underwent rest-dipyridamole stress 82Rb-positron emission tomography with absolute quantitative flow measurements using Cedars Sinai software (mL/min/g). The relative myocardial perfusion and left ventricular ejection fraction were assessed in 17 segments. These parameters were compared with those obtained from 30 patients with normal 82Rb-positron emission tomography studies and without left bundle branch block (GII). RESULTS: Stress myocardial blood flow and coronary flow reserve were significantly lower in GI than in GII (p<0.05). The comparison of coronary flow reserve between GI-A and GI B showed that it was different from the global coronary flow reserve (p<0.05) and the stress flow was significantly lower in the anterior than in the septal wall for both groups. Perfusion abnormalities were more prevalent in GI-A (p=0.06) and the left ventricular ejection fraction was not different between GI-A and GI-B, whereas it was lower in GI than in GII (p<0.001). CONCLUSION: The data confirm that patients with left bundle branch block had decreased myocardial blood flow and coronary flow reserve and coronary flow reserve assessed by 82Rb-positron emission tomography imaging may be useful in identifying coronary artery disease in patients with left bundle branch block. PMID- 26602519 TI - Can mastalgia be another somatic symptom in fibromyalgia syndrome? AB - OBJECTIVE: The purposes of this study were to determine the coexistence of mastalgia and fibromyalgia, to investigate the effects of this combination on pain patterns, and to discuss the status of breast pain in the diagnostic algorithm of fibromyalgia syndrome. METHODS: Sixty-one female patients reporting breast pain during the last three months and 53 female patients diagnosed with fibromyalgia syndrome were enrolled in this study. The Breast Pain Questionnaire was administered to all participants in the mastalgia group and to those in the fibromyalgia syndrome group who had experienced mastalgia during the past three months. The patients in the fibromyalgia syndrome group were evaluated using the 2010 preliminary American College of Rheumatology classification criteria. All of the patients in the mastalgia group were evaluated for the diagnosis of fibromyalgia syndrome by a single physiatrist. The coexistence and pain patterns of mastalgia and fibromyalgia were assessed statistically. RESULTS: Approximately half of the patients with fibromyalgia syndrome (47.2%) reported having mastalgia at the time of admission and 37.7% of the patients with mastalgia met the diagnostic criteria for fibromyalgia syndrome. The patients with mastalgia in the fibromyalgia syndrome group had significantly higher total breast pain scores compared with the women in the mastalgia group. In addition, the patients with fibromyalgia syndrome in the mastalgia group had significantly higher Widespread Pain Index and Symptom Severity Scale scores than the patients with fibromyalgia syndrome. CONCLUSIONS: We suggest that mastalgia can be an aspect of the central sensitivity syndrome and can be added to the somatic symptoms of fibromyalgia. PMID- 26602520 TI - Serum from patients with ankylosing spondylitis can increase PPARD, fra-1, MMP7, OPG and RANKL expression in MG63 cells. AB - OBJECTIVES: To explore the effects of serum from patients with ankylosing spondylitis on the canonical Wnt/beta-catenin pathway and to assess whether the serum has an osteogenic effect in MG63 cells. METHODS: MG63 cells were cultured with serum from 45 ankylosing spondylitis patients, 30 healthy controls, or 45 rheumatoid arthritis patients. The relative PPARD, fra-1, MMP7, OPG and RANKL mRNA levels were measured using quantitative real-time polymerase chain reaction. Associations between gene expression and patient demographics and clinical assessments were then analyzed. RESULTS: MG63 cells treated with serum from ankylosing spondylitis patients had higher PPARD, fra-1, MMP7 and OPG gene expression than did cells treated with serum from controls or rheumatoid arthritis patients (all p<0.05). RANKL expression was higher in MG63 cells treated with serum from patients with ankylosing spondylitis or rheumatoid arthritis than in those treated with serum from controls (both p<0.05). The OPG/RANKL ratio was also higher in MG63 cells treated with serum from ankylosing spondylitis patients than in those treated with serum from controls (p<0.05). No associations were found between the expression of the five genes and the patient demographics and clinical assessments (all p>0.05). CONCLUSIONS: Serum from ankylosing spondylitis patients increases PPARD, fra-1, MMP7, OPG and RANKL expression and the OPG/RANKL ratio in MG63 cells; these effects may be due to the stimulatory effect of the serum on the Wnt pathway. PMID- 26602521 TI - Baropodometric analyses of patients before and after bariatric surgery. AB - OBJECTIVE: The aim of this study was to evaluate the vertical component of the ground reaction force, plantar pressure, contact area of the feet and double support time using static and dynamic (gait) baropodometry before and after bariatric surgery. METHODS: Sixteen individuals with a body mass index of between 35 and 55 were evaluated before and after bariatric surgery. Thirteen patients (81.3%) were female and three (18.8%) male and their average age was 46+/-10 (21 60) years. An FSCAN system (version 3848) was used for baropodometric analyses (1 km/h and 3 km/h). The peak plantar pressure and ground reaction force were measured for the rear foot and forefoot. The double-support time and foot contact area were measured during gait. RESULTS: There were reductions in the ground reaction force in the forefoot and rear foot and in the foot contact area in all evaluations and of the double-support time at 3 km/h, as well as a significant reduction in the body mass index at six months post-surgery. The peak pressure did not vary at 1 km/h and at 3 km/h, reductions in peak pressure were observed in the left and right rear feet and left forefoot. CONCLUSIONS: Weight loss after bariatric surgery resulted in decreases in the ground reaction force and contact area of the foot. Plantar pressure was decreased at 3 km/h, especially in the forefoot. There was an increase in rhythm because of a reduction in the double support time at 3 km/h. PMID- 26602522 TI - The prevalence of adenoviral conjunctivitis at the Clinical Hospital of the State University of Campinas, Brazil. AB - OBJECTIVES: Viral conjunctivitis is a common, highly contagious disease that is often caused by an adenovirus. The aim of this study was to evaluate the prevalence of adenoviral conjunctivitis by analyzing data from a prospective clinical study of 122 consecutively enrolled patients who were treated at the Clinical Hospital of the State University of Campinas (UNICAMP) after a clinical diagnosis of infectious conjunctivitis between November 2011 and June 2012. METHODS: Polymerase chain reaction was used to evaluate all cases of clinically diagnosed infectious conjunctivitis and based on the laboratory findings, the prevalence of adenoviral infections was determined. The incidence of subepithelial corneal infiltrates was also investigated. RESULTS: Of the 122 patients with acute infectious conjunctivitis included, 72 had positive polymerase chain reaction results for adenoviruses and 17 patients developed subepithelial corneal infiltrates (13.93%). CONCLUSIONS: The polymerase chain reaction revealed that the prevalence of adenoviral conjunctivitis was 59% in all patients who presented with a clinical diagnosis of infectious conjunctivitis from November 2011 to June 2012. The prevalence of adenoviral conjunctivitis in the study population was similar to its prevalence in other regions of the world. PMID- 26602524 TI - A systematic review and meta-analysis of gestational weight gain recommendations and related outcomes in Brazil. AB - Worldwide, different guidelines are used to assess the adequacy of gestational weight gain. This study identified the recommendations for gestational weight gain in Brazilian women. We also determined the proportion of women with adequate weight gain in accordance with these recommendations and the associated perinatal outcomes. A systematic review was performed. A computerized search was conducted utilizing the following databases: PubMed, MEDLINE, Web of Science, Embase, SciELO and Google Scholar. Observational studies of healthy, Brazilian, pregnant women were included. Studies were excluded if they did not provide pregestational weight and gestational weight gain or if they studied women with comorbid conditions. A meta-analysis was performed to evaluate the odds ratio of inadequate (insufficient or excessive) gestational weight gain. Seventeen studies were included in the systematic review and four studies were included in the meta analysis. The most widely used recommendations were from the Institute of Medicine. Excessive gestational weight gain was associated with fetal macrosomia and high rates of cesarean delivery. Overweight women had a higher risk of excessive gestational weight gain than eutrophic women (OR=2.80, 95%CI=2.22 3.53). There are no standardized recommendations concerning gestational weight gain based on Brazilian population-based data. Many Brazilian women are overweight or obese at the beginning of pregnancy. Overweight pregnant women have a higher risk of excessive gestational weight gain. Excessive gestational weight gain was associated with cesarean delivery and fetal macrosomia. PMID- 26602523 TI - Mechanisms of the antihypertensive effects of Nigella sativa oil in L-NAME induced hypertensive rats. AB - OBJECTIVES: This study was conducted to determine whether the blood pressure lowering effect of Nigella sativa might be mediated by its effects on nitric oxide, angiotensin-converting enzyme, heme oxygenase and oxidative stress markers. METHODS: Twenty-four adult male Sprague-Dawley rats were divided equally into 4 groups. One group served as the control (group 1), whereas the other three groups (groups 2-4) were administered L-NAME (25 mg/kg, intraperitoneally). Groups 3 and 4 were given oral nicardipine daily at a dose of 3 mg/kg and Nigella sativa oil at a dose of 2.5 mg/kg for 8 weeks, respectively, concomitantly with L NAME administration. RESULTS: Nigella sativa oil prevented the increase in systolic blood pressure in the L-NAME-treated rats. The blood pressure reduction was associated with a reduction in cardiac lipid peroxidation product, NADPH oxidase, angiotensin-converting enzyme activity and plasma nitric oxide, as well as with an increase in heme oxygenase-1 activity in the heart. The effects of Nigella sativa on blood pressure, lipid peroxidation product, nicotinamide adenine dinucleotide phosphate oxidase and angiotensin-converting enzyme were similar to those of nicardipine. In contrast, L-NAME had opposite effects on lipid peroxidation, angiotensin-converting enzyme and NO. CONCLUSION: The antihypertensive effect of Nigella sativa oil appears to be mediated by a reduction in cardiac oxidative stress and angiotensin-converting enzyme activity, an increase in cardiac heme oxygenase-1 activity and a prevention of plasma nitric oxide loss. Thus, Nigella sativa oil might be beneficial for controlling hypertension. PMID- 26602526 TI - ICN ensuring nurses influence global strategy for health human resources. PMID- 26602527 TI - Writing about nursing policy and health policy. PMID- 26602525 TI - Treatment of infertility in women with polycystic ovary syndrome: approach to clinical practice. AB - Polycystic ovary syndrome represents 80% of anovulatory infertility cases. Treatment initially includes preconception guidelines, such as lifestyle changes (weight loss), folic acid therapy to prevent the risk of fetal neural tube defects and halting the consumption of tobacco and alcohol. The first-line pharmacological treatment for inducing ovulation consists of a clomiphene citrate treatment for timed intercourse. The second-line pharmacological treatment includes the administration of exogenous gonadotropins or laparoscopic ovarian surgery (ovarian drilling). Ovulation induction using clomiphene citrate or gonadotropins is effective with cumulative live birth rates of approximately 70%. Ovarian drilling should be performed when laparoscopy is indicated; this procedure is typically effective in approximately 50% of cases. Finally, a high complexity reproduction treatment (in vitro fertilization or intracytoplasmic sperm injection) is the third-line treatment and is recommended when the previous interventions fail. This option is also the first choice in cases of bilateral tubal occlusion or semen alterations that impair the occurrence of natural pregnancy. Evidence for the routine use of metformin in infertility treatment of anovulatory women with polycystic ovary syndrome is not available. Aromatase inhibitors are promising and longer term studies are necessary to prove their safety. PMID- 26602528 TI - Strong nursing presence is vital to global health. PMID- 26602530 TI - Comparison of nurse practice environments in Denmark and the USA. AB - AIMS: The aims were to translate, validate and test the reliability of the Practice Environment Scale of the Nursing Work Index in a Danish context; and to compare Danish nurses' ratings of their nurse work environments with the highest rated work environments, USA magnet hospitals. BACKGROUND: Patient quality and safety are priorities for managers, administrators and policy makers worldwide. A supportive work environment is an important factor to improve quality and safety. The most used scale to measure the nurse work environment is Practice Environment Scale of the Nursing Work Index. There is no Danish translation of the scale or a comparison of nurse work environment between Denmark and other countries. METHODS: The translation and cultural adaption followed the steps recommended by the World Health Organization. Content validity was evaluated using cognitive interviewing in-person and through surveys. The reliability was tested using Cronbach's alpha. Finally, Practice Environment Scale of the Nursing Work Index ratings from 127 nurses were compared with results from Magnet and non-Magnet hospitals using t-tests. FINDINGS: The Danish translation of Practice Environment Scale of the Nursing Work Index had a high validity and reliability. Danish nurses rated their nurse work environment more favourable than nurses in non Magnet hospitals and at the same level as Magnet hospitals. Lowest Danish scores were found in the two hospital-level subscales in items related to staff nurses' involvement in discussions on daily problems, the visibility of the chief nursing officer and importance of up-to-date nursing documentation. CONCLUSION: Danish nurses report a supportive nurse work environment with overall scores at the same level as Magnet hospitals. Opportunities for improvement were identified in the subscales. IMPLICATIONS FOR NURSING AND HEALTH POLICY: A first step to improve patient quality and safety is addressing factors that influence quality and safety. Using the Danish Practice Environment Scale of the Nursing Work Index, interventions to improve specific areas can be planned, implemented and evaluated. Further, Practice Environment Scale of the Nursing Work Index is a nursing quality indicator that can be included in quality databases in Denmark. PMID- 26602531 TI - Nurses' pain assessment practices with critically ill adult patients. AB - OBJECTIVES: This study aimed to describe the perceived barriers, enablers and acute pain assessment practices of nurses caring for critically ill adult patients in a resource-limited setting. BACKGROUND: Acute pain is a common problem among critically ill adult patients, and nurses' play a central role in its control. Very few studies have examined nurses' acute pain assessment practices in resource-limited settings. METHODS: A descriptive and cross sectional design was used. A total of 170 nurses working in a Ugandan hospital were enrolled. Data were collected using a questionnaire measuring various aspects of pain assessment for critically ill adult patients. RESULTS: The majority of nurses had poor pain assessment practices. The most commonly performed pain assessment practices were documenting assessment findings, discussing pain assessment and management during nurse-to-nurse reports, and assessing for analgesics need before wound care. The main barriers to pain assessment were workload; lack of education and familiarity with assessment tools; poor documentation and communication of pain assessment priorities. The only reported enabler was physician's prescriptions for analgesia. Pain assessment practices were significantly associated with perceived workload and priority given to pain assessment. CONCLUSION: Pain assessment practices of nurses caring for critically ill adult patients in a resource-limited setting are affected by several barriers. IMPLICATION FOR NURSING AND HEALTH POLICY: Interventions to reduce barriers and enhance enablers of acute pain assessment are needed to improve pain management in critically ill adult patients. To be effective, the interventions have to be holistic and implemented by professional bodies and employers of nurses. PMID- 26602532 TI - International nurse visitor programme. PMID- 26602533 TI - Thermal tissue change induced by a microwave surgical instrument in a rat hepatectomy model. AB - BACKGROUND: Microwaves exhibit great potential in tissue heating, which causes effective coagulation. Using this energy, we have developed the microwave coagulation surgical instrument (MWCX) for clinical application. Here, we characterized the impact of MWCX on tissues including heating property, tissue change, and spread of thermal injury. METHODS: Hepatectomy was performed with MWCX using a rat model. The resections were completed using various energy levels and powers. Tissue temperature during radiation was recorded. Tissue change and lateral thermal injury (LTI) was assessed immediately, 7 days, 3 months, and 6 months after resection. RESULTS: All cutting and hemostasis procedures were successfully accomplished. Major histologic findings consisted of deformation or destruction of hepatocytes, tissue edema, and peripheral hemorrhage. At various energy levels, 200 to 1000 J, the tissue was heated up to approximately 80 degrees C to 140 degrees C causing 2.7- to 6.5-mm LTI on the 7th day. LTI was then decreased gradually in the following term. At certain energy levels, the application of neither 20 W nor 40 W induced significant difference in both heating and LTI. CONCLUSIONS: MWCX achieved effective tissue coagulation with relevant tissue injury, and it should be a good candidate for clinical application. PMID- 26602535 TI - Unplanned readmission after appendectomy. AB - BACKGROUND: Unplanned readmission of patients who undergo appendectomy is a relatively frequent occurrence. Our aim was to report the most common reasons and the predictors of unplanned readmission after appendectomy. METHODS: The National Surgical Quality Improvement Program database was used to examine the clinical data of patients undergoing emergent and/or urgent appendectomy during 2012 to 2013. Multivariate regression analysis was performed to identify the predictors of unplanned readmission. RESULTS: We evaluated a total of 46,960 patients who underwent appendectomy. Of these, 18.5% had perforated appendicitis. Overall, 1,755 (3.7%) of patients had an unplanned readmission. The most common reasons for readmission were intra-abdominal infection (27.3%), nonspecific abdominal pain (7.9%), and paralytic ileus (4.6%). Factors such as perforated appendicitis (adjusted odds ratio [AOR], 1.38; P < .01), preoperative sepsis (AOR, 1.30; P < .01), and dirty surgical wound (AOR, 1.91; P < .01) were associated with unplanned readmission. CONCLUSIONS: Overall, 3.7% of patients who underwent emergent appendectomy had an unplanned readmission. Intra-abdominal infections and nonspecific abdominal pain are the most common reasons for readmission. Unplanned readmissions are predominantly related to postoperative complications and severity of disease. PMID- 26602534 TI - Restrictive blood transfusion protocol in malignant upper gastrointestinal and pancreatic resections patients reduces blood transfusions with no increase in patient morbidity. AB - BACKGROUND: The purpose of this study was to determine the impact of a restrictive blood transfusion protocol on the number of transfusions performed and the related effect on patient morbidity. METHODS: A cohort study was performed using our prospective database with information from January 1, 2000, to June 1, 2013. The restrictive blood transfusion protocol was implemented in September 2011, so this date served as the separation point for the date of operation criteria. RESULTS: For the study, 415 patients undergoing operation for an abdominal malignancy were reviewed. After the restrictive blood transfusion protocol, the percentage of patients who received blood dropped from 35.6% to 28.3%. The percentage of patients who experienced perioperative complication was significantly higher in transfused patients compared with those who did not receive blood (P = .0001). There was no statistical significance observed between the 5 groups for the length of stay at the hospital after their procedure. CONCLUSIONS: The restrictive blood transfusion protocol resulted in a reduction of the percentage of patients transfused, and there was no evidence to suggest that it negatively affected the outcomes of patients in this group. PMID- 26602536 TI - Use of a Right Lateral Sector Graft in Living Donor Liver Transplantation Is Feasible, but Special Caution Is Needed With Respect to Liver Anatomy. AB - Right lateral sector (RLS) grafting has been introduced to enlarge the potential donor pool for living donor liver transplantation (LDLT); however, evidence of its feasibility is limited. Data from 437 LDLTs carried out between 2000 and 2013 were analyzed retrospectively. LDLTs using a right liver graft (n = 251) were compared with those using a RLS graft (RLSG; n = 28). No donor mortality occurred, and the major complication rates were similar between the two groups. Postoperative liver function preservation was better in the RLSG donors. Concerning the recipients, the mortality and overall survival rates were similar between the two groups. The complication rate for the recipients was higher when more than two arterial or biliary anastomoses were necessary. A systematic literature search identified four reports on LDLT using RLSGs. Among 66 LDLTs, including the present series, there were no cases of donor death, and the rates of major and minor complications in the donors were 6% and 29%, respectively. The major complication and overall mortality rates in the recipients were 29% and 6%, respectively. LDLT using an RLSG is feasible, with an acceptable survival rate among the recipients. PMID- 26602537 TI - Community health workers recruitment from within: an inner-city neighborhood driven framework. AB - BACKGROUND: Community health workers (CHWs) are frontline public health workers who are trusted members of and/or have an unusually close understanding of the community served (APHA 2009). Among other roles, they are effective in closing critical communication gap between healthcare providers and patients as they possess key abilities to overcome cultural barriers, minimize disparities, and maximize adherence to clinical directions. In previous descriptions of the selection of CHWs, the role of community is clearly emphasized, but residence in the community is not indicated. OBJECTIVE: We present an effective model of CHW selection by the community of members that reside in the community to be served. METHODS: We outlined and implemented necessary steps for recruiting CHWs from within their target neighborhood between years 2011 and 2013. The identified community was an "isolated" part of Newark, New Jersey comprised of approximately 3000 people residing in three publicly-funded housing developments. We utilized a community empowerment model and established a structure of self-governance in the community of interest. In all phases of identification and selection of CHWs, the Community Advisory Board (CAB) played a leading role. RESULTS: The process for the successful development of a CHW initiative in an urban setting begins with community/resident engagement and ends with employment of trained CHWs. The steps needed are: (1) community site identification; (2) resident engagement; (3) health needs assessment; (4) CHW identification and recruitment; and (5) training and employment of CHWs. Using an empowered community model, we successfully initiated CHW selection, training, and recruitment. Thirteen CHW candidates were selected and approved by the community. They entered a 10-week training program and ten CHWs completed the training. We employed these ten CHWs. CONCLUSIONS: These five steps emerged from a retrospective review of our CHW initiative. Residing in the community served has significant advantages and disadvantages. Community empowerment is critical in changing the health indices of marginalized communities. PMID- 26602538 TI - An exploration of grip force regulation with a low-impedance myoelectric prosthesis featuring referred haptic feedback. AB - BACKGROUND: Haptic display technologies are well suited to relay proprioceptive, force, and contact cues from a prosthetic terminal device back to the residual limb and thereby reduce reliance on visual feedback. The ease with which an amputee interprets these haptic cues, however, likely depends on whether their dynamic signal behavior corresponds to expected behaviors-behaviors consonant with a natural limb coupled to the environment. A highly geared motor in a terminal device along with the associated high back-drive impedance influences dynamic interactions with the environment, creating effects not encountered with a natural limb. Here we explore grasp and lift performance with a backdrivable (low backdrive impedance) terminal device placed under proportional myoelectric position control that features referred haptic feedback. METHODS: We fabricated a back-drivable terminal device that could be used by amputees and non-amputees alike and drove aperture (or grip force, when a stiff object was in its grasp) in proportion to a myoelectric signal drawn from a single muscle site in the forearm. In randomly ordered trials, we assessed the performance of N=10 participants (7 non-amputee, 3 amputee) attempting to grasp and lift an object using the terminal device under three feedback conditions (no feedback, vibrotactile feedback, and joint torque feedback), and two object weights that were indiscernible by vision. RESULTS: Both non-amputee and amputee participants scaled their grip force according to the object weight. Our results showed only minor differences in grip force, grip/load force coordination, and slip as a function of sensory feedback condition, though the grip force at the point of lift-off for the heavier object was significantly greater for amputee participants in the presence of joint torque feedback. An examination of grip/load force phase plots revealed that our amputee participants used larger safety margins and demonstrated less coordination than our non-amputee participants. CONCLUSIONS: Our results suggest that a backdrivable terminal device may hold advantages over non-backdrivable devices by allowing grip/load force coordination consistent with behaviors observed in the natural limb. Likewise, the inconclusive effect of referred haptic feedback on grasp and lift performance suggests the need for additional testing that includes adequate training for participants. PMID- 26602539 TI - Myositis-specific autoantibodies: an important tool to support diagnosis of myositis. AB - The idiopathic inflammatory myopathies are characterized by muscle weakness, skin disease and internal organ involvement. Autoimmunity is known to have a role in myositis pathogenesis, and myositis-specific autoantibodies, targeting important intracellular proteins, are regarded as key biomarkers aiding in the diagnosis of patients. In recent years, a number of novel myositis autoantibodies including anti-TIF1, anti-NXP2, anti-MDA5, anti-SAE, anti-HMGCR and anti-cN1A have been identified in both adult and juvenile patients. These autoantibodies correlate with distinct clinical manifestations and importantly are found in inclusion body, statin-induced, clinically amyopathic and juvenile groups of myositis patients, previously believed to be mainly autoantibody negative. In this review, we will describe the main myositis-specific and myositis-associated autoantibodies and their frequencies and clinical associations across different ages and ethnic groups. We will also discuss preliminary studies investigating correlations between specific myositis autoantibody titres and clinical markers of disease course, collectively demonstrating the utility of myositis autoantibodies as both diagnostic and prognostic markers of disease. PMID- 26602541 TI - Competitive adsorption equilibrium model with continuous temperature dependent parameters for naringenin enantiomers on Chiralpak AD column. AB - Determination of competitive adsorption equilibrium model with continuous temperature dependent parameters is important for the design and optimization of a chromatographic separation process operated under non-isothermal conditions. In this study, linear pulse experiments were first carried to determine the parameters of transport-dispersive model and their temperature dependences in the range of 283-313 K. Overloaded band profiles of naringenin enantiomers on a Chiralpak AD column were acquired under various temperatures. Three of them were first separately fitted using Langmuir, linear-Langmuir and bi-Langmuir isotherm models substituted into the transport-dispersive column model. The comparison showed that bi-Langmuir model captures more details of the experimental results. This model was then extended with three extra parameters accounting for adsorption heat effects and used to simultaneously fit the band profiles at three temperatures. PMID- 26602540 TI - Non-fatal self-poisoning in Sri Lanka: associated triggers and motivations. AB - BACKGROUND: Attempted or non-fatal self-poisoning is common in Sri Lanka. To date, most preventive strategies have focused on limitation of access to toxic pesticides, which has reduced the rates of fatal self-poisoning. However the ongoing phenomenon of non-fatal self-poisoning indicates the need for exploration of alternate preventive strategies. Self-poisoning in Sri Lanka has been described as impulsive, with little premeditation, but the motivations associated with this act have not been studied in depth. This research describes the triggers and motivations associated with non-fatal self-poisoning in Sri Lanka. It is anticipated that the findings would help guide future preventive strategies. METHODS: Two studies were carried out, at Teaching Hospital Peradeniya, Sri Lanka, each using a different methodology - Study 1 consisted of qualitative semi-structured interviews, and Study 2 was a cross sectional survey. Both studies were conducted among those who had recently attempted self poisoning, and explored associated triggers and motivations associated with the act of self-poisoning. There was no overlap between participants of the two studies. RESULTS: A total of 24 persons participated in the semi-structured interviews (Study 1), and 921 took part in the cross-sectional survey (Study 2). Interpersonal conflict was the most common trigger prior to the act of non-fatal self-poisoning. A mixture of motivations was associated with the act of self poisoning, including intent to die, to escape, and difficulty tolerating distress associated with interpersonal conflict. CONCLUSIONS: Development of interpersonal skills and interpersonal problem solving skills, particularly in adolescents and young people, emerges as a key primary preventive strategy. Further, there is value in exploring and helping people to develop more adaptive strategies to cope with emotional distress associated with interpersonal conflict. While distress tolerance and interpersonal skill training strategies used in the West may be considered, it is also important to adapt and develop strategies suited to the local cultural background. Further research is needed to develop and evaluate such strategies, and findings may have implications not only to Sri Lanka but also for other countries in South Asia. PMID- 26602542 TI - An approach to evaluate the information in chromatographic fingerprints: Application to the optimisation of the extraction and conservation conditions of medicinal herbs. AB - A new approach is reported for high-performance liquid chromatography to measure the level of information in fingerprints. For this purpose, the concept of peak prominence, which is the protruding part of each visible peak with regard to the valleys that delimit it, was used. The peaks in the fingerprints are ranked according to the areas of the peak prominences, and a threshold is established to discriminate between the significant peaks and those that are irreproducible. The approach was applied to evaluate the impact of several extraction conditions (solvent nature and composition, time and temperature of the treatment, amount of sample, and time and temperature of conservation of the extracts) on the number of significant peaks found in the fingerprints of a medicinal herb (a green tea sample), using Plackett-Burman designs. Acetonitrile, ethanol and methanol were used for the extraction, and a linear gradient for chromatographic analysis, where the acetonitrile content was increased from 5.0% to 42.5% (v/v) in 45 min. The maximal number of significant peaks in the fingerprints was obtained using a methanol-water mixture as extraction solvent, high ultrasonication time and high temperature. The reported approach can be generalised to other complex samples and situations. PMID- 26602543 TI - Analysis of the reaction products from micro-vial pyrolysis of the mixture glucose/proline and of a tobacco leaf extract:Search for Amadori intermediates. AB - Micro-vial pyrolysis (PyroVial) was used to study the production of compounds important for the aroma of heat-treated natural products such as tobacco. Firstly, a mixture of glucose and proline was pyrolyzed as model, as this sugar and amino acid are also abundant in tobacco leaf (Nicotiana tobacum L.). The pyrolysate was analyzed using headspace-GC-MS, liquid injection GC-MS and LC-MS. Next, micro-vial pyrolysis in combination with LC-MS was applied to tobacco leaf extract. Using MS deconvolution, molecular feature extraction and differential analysis it was possible to identify Amadori intermediates of the Maillard reaction in the tobacco leaf extract. The intermediate disappeared as was the case for 1-deoxy-1-prolino-beta-d-fructose or the concentration decreased in the pyrolysate compared to the original extract such as for the 1-deoxy-1-[2-(3 pyridyl)-1-pyrrolidinyl]-beta-d-fructose isomers indicating that Amadori intermediates are important precursors for aroma compound formation. PMID- 26602544 TI - Vitamin D intake of Dutch infants from the combination of (fortified) foods, infant formula, and dietary supplements. AB - PURPOSE: Due to changes in the Dutch fortification policy for vitamin D and the vitamin D supplementation advice for infants (10-MUg/d for 0-4 year olds), a partially virtual scenario study was conducted to evaluate the risk of excessive vitamin D intake assigning all infants to a 100 % adherence to the supplementation advice and considering the current fortification practice. METHODS: Food consumption data from the Nutrition Intake Study (2002; N = 941, 7 19 months) were combined with Dutch food composition data from 2011 to estimate vitamin D intake from (fortified) foods. For infants 0-6 months of age, the consumption volume infant formula was estimated from energy requirement and body weight. All subjects were assigned to take a daily 10 ug vitamin D supplement, according the Dutch supplementation advice for infants. Habitual vitamin D intake was estimated using the Statistical Program to Assess Dietary Exposure and compared with the tolerable upper intake levels (ULs) set by the European Food Safety Authority. RESULTS: The median habitual total vitamin D intake was 16-22 ug/day for infants aged 0-6 months (increasing with age) and 13-21 ug/day for infants aged 7-19 months (decreasing with age). About 4-12 % of infants aged 7-11 months exceeded the UL. At the 99th percentile, the intake was 2-4 ug above the UL, depending on age. Infants aged 0-6 and 12-19 months did not exceed the UL. CONCLUSIONS: In case of combined intake from infant formula, (fortified) foods, and supplements, vitamin D intakes above the UL are possible among some infants during a limited time period. PMID- 26602545 TI - The Mononuclear Phagocyte System in Organ Transplantation. AB - The mononuclear phagocyte system (MPS) comprises monocytes, macrophages and dendritic cells (DCs). Over the past few decades, classification of the cells of the MPS has generated considerable controversy. Recent studies into the origin, developmental requirements and function of MPS cells are beginning to solve this problem in an objective manner. Using high-resolution genetic analyses and fate mapping studies, three main mononuclear phagocyte lineages have been defined, namely, macrophage populations established during embryogenesis, monocyte-derived cells that develop during adult life and DCs. These subsets and their diverse subsets have specialized functions that are largely conserved between species, justifying the introduction of a new, universal scheme of nomenclature and providing the framework for therapeutic manipulation of immune responses in the clinic. In this review, we have commented on the implications of this novel MPS classification in solid organ transplantation. PMID- 26602546 TI - Genome-wide analysis of Fusarium graminearum field populations reveals hotspots of recombination. AB - BACKGROUND: Fusarium graminearum (Fg) is a ubiquitous pathogen of wheat, barley and maize causing Fusarium head blight. Large annual yield losses and contamination of foodstuffs with harmful mycotoxins make Fg one of the most studied plant pathogens. Analyses of natural field populations can lead to a better understanding of the evolutionary processes affecting this pathogen. Restriction site associated DNA sequencing (RADseq) was used to conduct population genomics analyses including 213 pathogen isolates from 13 German field populations of Fg. RESULTS: High genetic diversity was found within Fg field populations and low differentiation (FST = 0.003) was found among populations. Linkage disequilibrium (LD) decayed rapidly over a distance of 1000 bp. The low multilocus LD indicates that significant sexual recombination occurs in all populations. Several recombination hotspots were detected on each chromosome, but different chromosomes showed different levels of recombination. There was some evidence for selection hotspots. CONCLUSIONS: The population genomic structure of Fg is consistent with a high degree of sexual recombination that is not equally distributed across the chromosomes. The high gene flow found among these field populations should enable this pathogen to adapt rapidly to changes in its environment, including deployment of resistant cultivars, applications of fungicides and a warming climate. PMID- 26602547 TI - Sublobar Resection for Clinical Stage IA Non-small-cell Lung Cancer in the United States. AB - BACKGROUND: This study evaluated the use of lobectomy and sublobar resection for clinical stage IA non-small-cell lung cancer (NSCLC) in the National Cancer Data Base (NCDB). METHODS: The NCDB from 2003 to 2011 was analyzed to determine factors associated with the use of a sublobar resection versus a lobectomy for the treatment of clinical stage IA NSCLC. Overall survival was assessed using the Kaplan-Meier method and Cox proportional hazard modeling. RESULTS: Among 39,403 patients included for analysis, 29,736 (75.5%) received a lobectomy and 9667 (24.5%) received a sublobar resection: 84.7% wedge resection (n = 8192) and 15.3% segmental resection (n = 1475). Lymph node evaluation was not performed in 2788 (28.8%) of sublobar resection patients, and 7298 (75.5%) of sublobar resections were for tumors <= 2 cm. After multivariable logistic regression, older age, higher Charlson-Deyo comorbidity scores, smaller tumor size, and treatment at lower-volume institutions were associated with sublobar resection (all P < .001). Overall, lobectomy was associated with significantly improved 5-year survival compared to sublobar resection (66.2% vs. 51.2%; P < .001, adjusted hazard ratio 0.66; P < .001). However among sublobar resection patients, nodal sampling was associated with significantly better 5-year survival (58.2% vs. 46.4%; P < .001). CONCLUSION: Despite adjustment for patient and tumor related characteristics, a sublobar resection is associated with significantly reduced long-term survival compared to a formal surgical lobectomy among patients with NSCLC, even for stage 1A tumors. For patients who cannot tolerate lobectomy and who are treated with sublobar resection, lymph node evaluation is essential to help guide further treatment. PMID- 26602548 TI - The Multi-Modal Immune Pathogenesis of Atopic Eczema. AB - Atopic eczema (AE) is one of the most common inflammatory diseases, often constituting a lifelong burden for afflicted individuals. Recent findings have provided new insights into the pathogenesis of AE, revealing contributions of genetics, skin microbiota, and both innate and adaptive immunity in disease onset and progression. We review these findings here, assembling contributing factors conceptually into four modules that can interact in various ways to ultimately lead to epidermal barrier impairment, unchecked type 2 immunity, and chronic disease. We present this modular framework as a basis for understanding the varied presentations of AE, and in this context we propose a diagnostic and therapeutic algorithm aimed at the precise stratification of AE patients and the implementation of individualized medicine in AE standard of care. PMID- 26602549 TI - Immunotherapy in Peripheral Neuropathies. AB - Immunotherapy has been investigated in a small subset of peripheral neuropathies, including an acute one, Guillain-Barre syndrome, and 3 chronic forms: chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and neuropathy associated with IgM anti-myelin-associated glycoprotein. Several experimental studies and clinical data are strongly suggestive of an immune mediated pathogenesis. Either cell-mediated mechanisms or antibody responses to Schwann cell, compact myelin, or nodal antigens are considered to act together in an aberrant immune response to cause damage to peripheral nerves. Immunomodulatory treatments used in these neuropathies aim to act at various steps of this pathogenic process. However, there are many phenotypic variants and, consequently, there is a significant difference in the response to immunotherapy between these neuropathies, as well as a need to improve our knowledge and long-term management of chronic forms. PMID- 26602551 TI - Combined use of the Ilizarov method, concentrated bone marrow aspirate (cBMA), and platelet-rich plasma (PRP) to expedite healing of bimalleolar fractures. AB - Distal tibial and fibular fractures, particularly in patients with comorbidities, heal slowly and have a high incidence of postoperative nonunion and infection. Autologous concentrated bone marrow aspirate (cBMA) and platelet-rich plasma (PRP) increase osteogenic potential of demineralized bone matrix (DBM). The purpose of this case series was to evaluate the efficacy of cBMA, PRP, DBM in conjunction with the Ilizarov fixator as compared to DBM and the Ilizarov fixator alone in expediting fracture healing. Ten patients (mean age 52.9 years) were in the cBMA Group, and 10 patients (mean age 54 years) were in the Control Group. Comorbidities included diabetes, obesity, smoking, and renal disease. Radiographs showed a significant difference in the rate of complete healing in the cBMA Group at 16 +/- 1.6 weeks post-surgery as compared to 24 +/- 1.3 weeks in the Control Group (P < 0.001). No differences were observed between groups in infection rate or nonunions. We conclude that the Ilizarov fixator combined with DBM, cBMA, and PRP expedites fracture healing of the distal tibia and fibula in patients with significant comorbidities. PMID- 26602552 TI - The callus fracture sign: a radiological predictor of progression to hypertrophic non-union in diaphyseal tibial fractures. AB - We report a radiological sign which predicts progression to hypertrophic non union for fractures of the tibial diaphysis. Radiographs of 46 tibial fractures were reviewed independently by four orthopaedic trauma surgeons and two musculoskeletal radiologists. Patients were identified from a database of tibial fractures managed with Ilizarov frame fixation. There were 23 fractures that progressed to non-union requiring further surgery. The controls were 23 fractures that had united without need for further surgery at 1-year follow-up. Radiographs selected were the first images taken following frame removal. All radiographs were anonymised and randomized prior to review. Presence of the callus fracture sign was identified in 16 radiographs of the fractures that progressed to non union, and 7 of the united fracture group. Sensitivity is 69.6 %. Specificity is 91.4 %. Positive and negative predictive values are 88.9 and 75.0 %, respectively. These results compare favourably with computerised tomography for predicting non-union. Intra- and inter-observer reliability was good (kappa = 0.68), and moderate (kappa = 0.57), respectively. The callus fracture sign is a useful radiological predictor of progression to non-union and may represent insufficient mechanical stability at the fracture site. PMID- 26602550 TI - The 3 Rs of Stroke Biology: Radial, Relayed, and Regenerative. AB - Stroke not only causes initial cell death, but also a limited process of repair and recovery. As an overall biological process, stroke has been most often considered from the perspective of early phases of ischemia, how these inter relate and lead to expansion of the infarct. However, just as the biology of later stages of stroke becomes better understood, the clinical realities of stroke indicate that it is now more a chronic disease than an acute killer. As an overall biological process, it is now more important to understand how early cell death leads to the later, limited recovery so as develop an integrative view of acute to chronic stroke. This progression from death to repair involves sequential stages of primary cell death, secondary injury events, reactive tissue progenitor responses, and formation of new neuronal circuits. This progression is radial: from the tissue that suffers the infarct secondary injury signals, including free radicals and inflammatory cytokines, radiate out from the stroke core to trigger later regenerative events. Injury and repair processes occur not just in the local stroke site, but are also triggered in the connected networks of neurons that had existed in the stroke center: damage signals are relayed throughout a brain network. From these relayed, distributed damage signals, reactive astrocytosis, inflammatory processes, and the formation of new connections occur in distant brain areas. In short, emerging data in stroke cell death studies and the development of the field of stroke neural repair now indicate a continuum in time and in space of progressive events that can be considered as the 3 Rs of stroke biology: radial, relayed, and regenerative. PMID- 26602553 TI - Measurement of nasal and fractional exhaled nitric oxide in children with upper airway inflammatory disease: Preliminary results. AB - OBJECTIVES: To assess the clinical significance of nasal nitric oxide (nNO) and fractional exhaled nitric oxide (FeNO) concentrations in children with upper airway inflammatory disease. METHODS: Fifteen healthy children, 30 with allergic rhinitis (AR), 10 with non-allergic rhinitis (NAR), and 30 with sleep disordered breathing (SDB) were enrolled. The FeNO and nNO concentrations were measured non invasively using a NIOX MINO system. RESULTS: Both nNO and FeNO were significantly higher in children with AR than in healthy children (P=0.000 and P=0.000, respectively). Compared to healthy children, nNO was also significant higher in children with NAR (P=0.011) or SDB (P=0.027). In contrast, FeNO did not differ from controls in children with NAR or SDB. CONCLUSIONS: Our data suggest that nNO has potential value for diagnosing upper airway inflammation. Moreover, elevated FeNO distinguishes allergic from non-allergic rhinitis. PMID- 26602554 TI - Analysis of neonatal hearing screening program performed on an outpatient basis: Analysis of an outpatient hearing screening program. AB - OBJECTIVE: The aims of the present study were to analyze the coverage of an outpatient hearing screening program in a public hospital for healthy newborns, to describe the social and demographic profile of the mothers and to identify the prevalence of infants with severe or profound hearing losses. METHODS: The method was descriptive and retrospective. In 2002 and 2003, the newborn hearing screening program was initiated in the maternity ward. Due to many logistic problems, in 2004, we implemented screening on an outpatient basis. Thus, upon discharge from the hospital, the mothers received a printed schedule referring the baby to an outpatient clinic. A two-stage screening protocol was implemented. The screening results were presented from 2004 to 2013. RESULTS: The program was initiated on an outpatient basis in 2004. From 2004 to 2013, 14,882 infants were screened but the complete data for 14,205 cases were obtained. The adherence of the families was 32% in 2004 and increased to 85% in 2013. The mean age of the screened newborns was 48.66 days in 2005 and 24.53 days in 2013. The number of newborns who failed the test and were referred for diagnosis decreased from 12.3% in 2004 to 3% in 2013. The majority of the mothers were young, 69.77% of them aged up to 29 years old and 74.86% had completed basic education. Seventy infants showed hearing loss, totaling 0.49% or approximately 5 cases in 1000, with eight individuals diagnosed with severe or profound sensorineural hearing loss, totaling 0.06% or approximately six cases in 10,000. CONCLUSIONS: The newborn hearing screening program offered by a public hospital in Brazil, over the years, has increased the coverage from 32% to 85%, and so, can be performed on an outpatient basis as an alternative to overcome the operating limitations that might occur in hospital hearing screening. The mothers of the newborns were young and had complete basic education; the prevalence was similar to international studies as hearing loss is concerned. PMID- 26602555 TI - Transcanal CO2 laser-enabled ablation and resection (CLEAR) for intratympanic membrane congenital cholesteatoma. AB - OBJECTIVES: Cholesteatoma in the tympanic membrane is frequently regarded as congenital but there has been no case series review or comparison study with typical pediatric congenital cholesteatoma (CC). METHODS: All pediatric CC cases from 2009 to 2014 were collected, and a total of 10 cases of intratymapnic membrane CC (ICC) out of 429 CC cases were reviewed. They were compared with 14 cases of iatrogenic intratympanic membrane keratin after pediatric CC surgery (IIKC). RESULTS: ICC constituted 2.3% (10/429) of CCs, and the median age of operation was 24 months, 12 months earlier than that for CC. ICC failed to show male preference which is found in both CC and IIKC. As CC is commonly abutting the medial side of malleus, almost 90% of ICCs were found abutting the umbo of malleus. However, IIKC was usually located at the epithelial trauma site during the CC surgery without malleus abutment. Except in case of spontaneous resolution, the other cases of ICC and IIKC were treated by minimally invasive transcanal CO2 laser-enabled ablation and resection (CLEAR) alleviating any ossicle vibration trauma, incision or graft harvest. All patients retained normal hearing without complication and recurrence. CONCLUSION: ICC might be a rare variant of early detectable pediatric CC estimated from its location close to the ossicle and the surgical findings, but without sex preference. Although ICC shares morphologic similarity with IIKC, their locations of development are different, thereby suggesting different pathogenesis rather than epithelial injury. However, CLEAR surgery can be a good treatment option for intratympanic membrane lesions. PMID- 26602556 TI - The neutrophil to lymphocyte ratios of our pediatric patients with Bell's palsy. AB - BACKGROUND: Neutrophil to Lymphocyte Ratio (NLR) is considered to be a reliable indicator in etiological investigation and identification of the disease severity in inflammatory disorders. There are numerous observations or evidences suggesting that Bell's palsy is an inflammatory disorder. OBJECTIVES: Our aim was to investigate the presence of any clue which might suggest inflammatory etiology and also the presence of compliance between NLR elevation and inflammation severity in children. METHODS: Patients younger than 18 years with Bell's palsy and who had not another inflammatory disorder in addition to Bell's palsy were included. A total of 25 patients and 25 healthy individuals were taken. The patient group and the control group were compared in terms of NLR, neutrophil and lymphocytes. The relationship of NLR with pre-treatment House-Brackmann classification was evaluated. RESULTS: The mean age was 9.86+/-5.07 in the patient group and 9.14+/-5.94 in the control group. In all members of the patient group, oral prednisolone (1 mg/kg/d) was administered for 7 days. The post treatment House-Brackmann classification of all patients was determined as grade 1. The average neutrophil values were significantly higher in the patient group. In terms of average lymphocyte values, no statistically significant difference was found. The average NLR value was 1.78 (0.93-4.58) in the pediatric patient group and 1.1 (0.6-2.05) in the control group. NLR was significantly higher in the patient group. NLR and pre-treatment House-Brackmann classification showed no statistically significant correlation (r=0.173, p>0.05). When cut-off value was taken as 3 for NLR, no statistically significant difference was found between groups. CONCLUSIONS: High NLR values determined in pediatric patients with Bell's palsy support the inflammatory feature of this disease. NLR is recommended as a supportive parameter in the diagnosis of pediatric patients with Bell's palsy. PMID- 26602557 TI - Alteration of hepatic anti-oxidant systems by 4-nonylphenol, a metabolite of alkylphenol polyethoxylate detergents, in Far Eastern catfish Silurus asotus. AB - OBJECTIVES: This study aimed to estimate the effects of 4-nonylphenol (NP), a ubiquitously present surfactant in aquatic environments, on the anti-oxidant systems of the liver in the Far Eastern catfish Silurus asotus. METHODS: Changes in biochemical parameters involved in glutathione (GSH)-related and other anti oxidant systems were analyzed following 4 weeks of 4-NP administration (0.1 and 1.0 mg/kg diet) via a formulated diet to catfish. RESULTS: 4-NP exposure induced an elevation in hepatic lipid peroxide levels and an accompanying decrease in reduced state GSH after 2 weeks, suggesting pro-oxidant effects of the chemical in catfish. This oxidative stress was associated with an inhibition of the GSH utilizing enzyme glutathione peroxidase at the same time point. This inhibition was restored after 4 weeks. The activities of other anti-oxidant enzymes, i.e., glutathione reductase, superoxide dismutase and catalase were increased after 4 weeks. These enzyme increases occurred more strongly at the higher 4-NP concentration (1.0 mg/kg diet). CONCLUSIONS: 4-NP given to catfish at 0.1 to 1.0 mg/kg diet, concentrations relevant to environmental levels, depletes the endogenous anti-oxidant molecule GSH and temporarily inhibits GSH-related anti oxidant enzymes. Such declines in anti-oxidant capacity and elevated oxidative stress seem to be compensated eventually by subsequent activation of various anti oxidant enzyme systems. PMID- 26602558 TI - Screening of toxic potential of graphene family nanomaterials using in vitro and alternative in vivo toxicity testing systems. AB - OBJECTIVES: The widely promising applications of graphene nanomaterials raise considerable concerns regarding their environmental and human health risk assessment. The aim of the current study was to evaluate the toxicity profiling of graphene family nananomaterials (GFNs) in alternative in vitro and in vivo toxicity testing models. METHODS: The GFNs used in this study are graphene nanoplatelets ([GNPs]-pristine, carboxylate [COOH] and amide [NH2]) and graphene oxides (single layer [SLGO] and few layers [FLGO]). The human bronchial epithelial cells (Beas2B cells) as in vitro system and the nematode Caenorhabditis elegans as in vivo system were used to profile the toxicity response of GFNs. Cytotoxicity assays, colony formation assay for cellular toxicity and reproduction potentiality in C. elegans were used as end points to evaluate the GFNs' toxicity. RESULTS: In general, GNPs exhibited higher toxicity than GOs in Beas2B cells, and among the GNPs the order of toxicity was pristine>NH2>COOH. Although the order of toxicity of the GNPs was maintained in C. elegans reproductive toxicity, but GOs were found to be more toxic in the worms than GNPs. In both systems, SLGO exhibited profoundly greater dose dependency than FLGO. The possible reason of their differential toxicity lay in their distinctive physicochemical characteristics and agglomeration behavior in the exposure media. CONCLUSIONS: The present study revealed that the toxicity of GFNs is dependent on the graphene nanomaterial's physical forms, surface functionalizations, number of layers, dose, time of exposure and obviously, on the alternative model systems used for toxicity assessment. PMID- 26602559 TI - The effects of a newsletter on bedding control on house dust mite allergen concentrations in childcare centers in Korea. AB - OBJECTIVES: Bedding in childcare centers (CCCs) can hold house dust mite (HDM) allergens. This study examined whether HDM allergen levels can be reduced through the distribution of an educational newsletter on bedding control to parents of CCC children in Korea. METHODS: All 38 CCCs were measured for Der 1 (sum of Der f 1 and Der p 1) concentrations on classroom floors and bedding before the intervention. Educational newsletters on children's bedding control were sent to 21 CCCs by mail, and teachers were asked to distribute the newsletters to the parents of the children (intervention group). The remaining 17 CCCs were not sent newsletters (control group). The measurement of Der 1 concentrations in 38 CCCs was repeated after the intervention. Dust samples were collected with a vacuum cleaner and analyzed using enzyme-linked immunosorbent assay methods. RESULTS: The Der 1 concentrations on the bedding were significantly higher than those on the floors in 38 CCCs at baseline (p<0.05). Although changes of the Der 1 concentrations for the control group (n=17) were not significant, Der 1 concentrations for the intervention group (n=21) decreased significantly from 2077.9 ng/g dust to 963.5 ng/g dust on the floors and from 3683.9 ng/g dust to 610.4 ng/g dust on bedding (p<0.05). CONCLUSIONS: The distribution of educational newsletters on bedding control to parents may be an effective means of controlling HDMs in CCCs. PMID- 26602560 TI - Urinary concentration of 3-phenoxybenzoic acid in elementary students in South Korea. AB - OBJECTIVES: Pyrethroid pesticides are among the most commonly using insecticides in South Korean households and have been the subject of considerable interest among public health professionals for their potential health effects. The objective of this study is to examine the level of urinary 3-phenoxybenzoic acid (3-PBA) among elementary students in South Korea. METHODS: We conducted a cross sectional study to evaluate pyrethroid pesticide exposure levels by measuring the urinary metabolites of 3-PBA using a gas chromatography-mass spectrometry method in March 2011. Study participants were 70 Asan-area and Incheon-area elementary students. RESULTS: All respondents had values above the detection limit, and the geometric means of 3-PBA in all children were 1.85 MUg/L and 1.46 MUg/g creatinine. Children with the top 10% urinary levels of 3-PBA were more likely to be girls, under nine years of age, living in a rural area, and living in a residential type apartment. CONCLUSIONS: South Korean children have a higher concentration of urinary 3-PBA compared with those of other countries. Further research identifying exposure pathways and intervention efforts to reduce environmental pesticide use are needed in South Korea. PMID- 26602561 TI - Computation of geographic variables for air pollution prediction models in South Korea. AB - Recent cohort studies have relied on exposure prediction models to estimate individuallevel air pollution concentrations because individual air pollution measurements are not available for cohort locations. For such prediction models, geographic variables related to pollution sources are important inputs. We demonstrated the computation process of geographic variables mostly recorded in 2010 at regulatory air pollution monitoring sites in South Korea. On the basis of previous studies, we finalized a list of 313 geographic variables related to air pollution sources in eight categories including traffic, demographic characteristics, land use, transportation facilities, physical geography, emissions, vegetation, and altitude. We then obtained data from different sources such as the Statistics Geographic Information Service and Korean Transport Database. After integrating all available data to a single database by matching coordinate systems and converting non-spatial data to spatial data, we computed geographic variables at 294 regulatory monitoring sites in South Korea. The data integration and variable computation were performed by using ArcGIS version 10.2 (ESRI Inc., Redlands, CA, USA). For traffic, we computed the distances to the nearest roads and the sums of road lengths within different sizes of circular buffers. In addition, we calculated the numbers of residents, households, housing buildings, companies, and employees within the buffers. The percentages of areas for different types of land use compared to total areas were calculated within the buffers. For transportation facilities and physical geography, we computed the distances to the closest public transportation depots and the boundary lines. The vegetation index and altitude were estimated at a given location by using satellite data. The summary statistics of geographic variables in Seoul across monitoring sites showed different patterns between urban background and urban roadside sites. This study provided practical knowledge on the computation process of geographic variables in South Korea, which will improve air pollution prediction models and contribute to subsequent health analyses. PMID- 26602562 TI - Altered microRNome Profiling in Statin-Induced HepG2 Cells: A Pilot Study Identifying Potential new Biomarkers Involved in Lipid-Lowering Treatment. AB - PURPOSE: Statins are widely prescribed drugs to manage hypercholesterolemia. Despite they are considered effective lipid-lowering agents, significant inter individual variability has been reported in relation to drug response. Among the reasons explaining this variation, genetic factors are known to partially contribute. Nonetheless, poor evidence exists regarding epigenetic factors involved. METHODS: We investigated if atorvastatin can modulate the cholesterol related miR-33 family. Furthermore, we analyzed the microRNA expression profiles in HepG2 cells treated for 24 hours with atorvastatin or simvastatin using a microarray platform. RESULTS: Our results indicate that atorvastatin does not influence the expression of the miR-33 family. In addition, microarray examination revealed that atorvastatin modulated thirteen miRs, whilst simvastatin only affected two miRs. All significantly modulated miRs after simvastastin therapy were also modulated by atorvastatin. In addition, four novel miRs with previously unreported functions were identified as statin-modulated. CONCLUSION: We identified several novel miRs affected by statin treatment. Additional research is needed to determine the biological significance of differentially expressed miRs identified in statins-induced HepG2 cells. PMID- 26602563 TI - The Vitamin D Receptor Activator Maxacalcitol Provides Cardioprotective Effects in Diabetes Mellitus. AB - PURPOSE: Recent reports showed a significant association between vitamin D levels and cardiovascular disease events and mortality. In the current study, we investigated the effect of the vitamin D receptor activator maxacalcitol (OCT) on cardiac damage in a rat model of type 2 diabetes. METHODS: At 20 weeks of age, the rats were divided into three groups: vehicle-treated (DM), insulin-treated (INS) and OCT-treated (OCT). At 30 weeks, the rats were sacrificed and urinary and blood biochemical analyses and cardiac histological and immunohistochemical analyses were performed. To evaluate the effect of OCT on the renin-angiotensin system, we performed a further study using aliskiren (ALS). At 20 weeks, the diabetic rats were divided into two groups: the ALS-treated group (ALS) and the ALS plus OCT-treated group (ALS + OCT), and we evaluated the renin-angiotensin system (RAS) and cardiac lesions at 30 weeks. RESULTS: At 30 weeks, despite comparable blood pressure and renal function, heart volume, intracardiac oxidative stress by immunohistological analysis, cardiac and perivascular fibrosis and urinary excretion of 8-hydroxydeoxyguanosine and serum N-terminal pro-brain natriuretic peptide levels were significantly decreased in the OCT group compared to the DM group. mRNA expressions of dihydronicotinamide adenine dinucleotide phosphate (NADPH) p47 subunit and cardiac injury-related markers in the heart were also significantly decreased in the OCT group compared to the DM group. The cardioprotective effect of OCT was preserved even in the context of RAS inhibition. CONCLUSION: Our results suggest that OCT prevents the development of cardiac damage in DM, independent of RAS inhibition. PMID- 26602564 TI - Loneliness, Stress, and Social Support in Young Adulthood: Does the Source of Support Matter? AB - Social support protects individuals against adversity throughout the lifespan, and is especially salient during times of intense social change, such as during the transition to adulthood. Focusing on three relationship-specific sources of social support (family, friends, and romantic partners), the current study examined the stress-buffering function of social support against loneliness and whether the association between social support and loneliness with stress held constant would vary by its source. The role of gender in these associations was also considered. The sample consisted of 636 ethnically diverse college youth (age range 18-25; 80 % female). The results suggest that the stress-buffering role of social support against loneliness varies by its source. Only support from friends buffered the association between stress and loneliness. Further, when stress was held constant, the association between social support and loneliness differed by the sources, in that support from friends or romantic partners (but not from family) was negatively associated with loneliness. Regarding gender differences, the adverse impact of lower levels of familial or friends' support on loneliness was greater in females than in males. This research advances our understanding of social support among college-aged youth; implications of the findings and directions for future research are discussed. PMID- 26602565 TI - Accumulation of disadvantage over the life course and mortality. PMID- 26602566 TI - Identification of Chromium Resistant Bacteria from Dry Fly Ash Sample of Mejia MTPS Thermal Power Plant, West Bengal, India. AB - Eight chromium resistant bacteria were isolated from a dry fly ash sample of DVC MTPS thermal power plant located in Bankura, West Bengal, India. These isolates displayed different degrees of chromate reduction under aerobic conditions. According to 16S rDNA gene analysis, five of them were Staphylococcus, two were Bacillus and one was Micrococcus. The minimum inhibitory concentration towards chromium and the ability to reduce hexavalent chromium to trivalent chromium was highest in Staphylococcus haemolyticus strain HMR17. All the strains were resistant to multiple heavy metals (As, Cu, Cd, Co, Zn, Mn, Pb and Fe) and reduced toxic hexavalent chromium to relatively non toxic trivalent chromium even in the presence of these multiple heavy metals. All of them showed resistance to different antibiotics. In a soil microcosm study, S. haemolyticus strain HMR17 completely reduced 4 mM hexavalent chromium within 7 days of incubation. PMID- 26602567 TI - Influence of Breastfeeding Time on Levels of Organochlorine Pesticides in Human Milk of a Mexican Population. AB - This study was conducted with the objective of determining whether there is a depuration of organochlorine pesticides in breast milk according to breastfeeding time. In total, 171 samples from mothers that lived in the State of Guerrero, Mexico were analyzed. There was a weak negative relationship between pp'DDE (r = 0.216) and Sigma-DDT (r = -0.222) concentrations with the days of lactation. In a comparison analysis, a statistically significant decrease of pp'DDT and pp'DDE levels was observed, as well as the Sigma-DDT from the first to the fifth week of lactation. A reduction of 0.188 mg/kg lipid of pp'DDE and 0.181 mg/kg lipid of Sigma-DDT per week was obtained. HCB, beta-HCH and op'DDT concentrations were low and had no major fluctuations between subgroups. The low levels found and the observed reduction in time involve less exposure to the infant to these pollutants. Through this methodology changes in levels of certain organochlorine pesticides in various stages of human milk production may be shown. PMID- 26602568 TI - Gas chromatographic-mass spectrometric analysis of the tripeptide glutathione in the electron-capture negative-ion chemical ionization mode. AB - The dicarboxylic tripeptide glutathione (GSH) is the most abundant intracellular thiol. GSH analysis by liquid chromatography is routine. Yet, GSH analysis by gas chromatography is challenged due to thermal instability and lacking volatility. We report a high-yield laboratory method for the preparation of (2)H-labeled GSH dimethyl ester ((d3Me)2-GSH) for use as internal standard (IS) which was characterized by LC-MS/MS. For GC-MS analysis, the dimethyl esters of GSH and the IS were derivatized with pentafluoropropionic (PFP) anhydride. Electron-capture negative-ion chemical ionization of the (Me)2-(PFP)3-GSH provided high sensitivity. We encourage increasing use of GC-MS in the analysis of amino acids as their Me-PFP derivatives in the ECNICI mode. PMID- 26602569 TI - Non-neoplastic pancreatic lesions that may mimic malignancy. AB - The widespread use of abdominal ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) has resulted in an increased identification of asymptomatic pancreatic lesions. Preoperative diagnoses of pancreatic lesions can be difficult. Solid and cystic lesions and anatomic variants of normal can all mimic tumor clinically and radiologically. Newer imaging modalities have increased the likelihood of the accurate diagnosis of non-neoplastic pancreatic disease, however, despite the many advances; it still remains a challenge to differentiate rarer non-neoplastic entities and inflammatory masses from adenocarcinoma, preoperatively. Adding to the challenge is the fact that a variety of inflammatory, solid and cystic non-neoplastic lesions have significant clinical and radiological overlap with malignancies. About 5-10% of pancreatectomies performed with the primary clinical diagnosis of pancreatic carcinoma are later proved to be essentially non-neoplastic lesions. It is vital to include these non-neoplastic entities in the differential diagnosis while working up abnormal clinical and radiological pancreatic findings because it may drastically alter therapeutic options for the patients. The significance of recognizing these lesions preoperatively is to help to guide the clinical decision-making process and the avoidance of an unnecessary pancreatectomy. Examples of such entities include chronic pancreatitis, sarcoidosis, intrapancreatic accessory spleen (IPAS), lymphoid hyperplasia, lipomatous pseudohypertrophy (LPH), lymphangioma, lymphoepithelial cyst (LEC) and endometriosis. PMID- 26602570 TI - Capsaicin and Related Food Ingredients Reducing Body Fat Through the Activation of TRP and Brown Fat Thermogenesis. AB - Brown adipose tissue (BAT) is a site of sympathetically activated adaptive nonshivering thermogenesis, thereby being involved in the regulation of energy balance and body fatness. Recent radionuclide imaging studies have revealed the existence of metabolically active BAT in adult humans. Human BAT is activated by acute cold exposure and contributes to cold-induced increase in whole-body energy expenditure. The metabolic activity of BAT is lower in older and obese individuals. The inverse relationship between the BAT activity and body fatness suggests that BAT, because of its energy dissipating activity, is protective against body fat accumulation. In fact, repeated cold exposure recruits BAT in association with increased energy expenditure and decreased body fatness. The stimulatory effects of cold are mediated through the activation of transient receptor potential (TRP) channels, most of which are also chemesthetic receptors for various naturally occurring substances including herbal plants and food ingredients. Capsaicin and its analog capsinoids, representative agonists of TRPV1, mimic the effects of cold to decrease body fatness through the activation and recruitment of BAT. The well-known antiobesity effect of green tea catechins is also attributable to the activation of the sympathetic nerve and BAT system. Thus, BAT is a promising target for combating obesity and related metabolic disorders in humans. PMID- 26602571 TI - School-Based Interventions to Reduce Obesity Risk in Children in High- and Middle Income Countries. AB - School-based interventions are relatively new and were first introduced in the United States in the 1990s. Early programs were mainly education based with many of the findings now embedded in school policy in the form of a healthy eating curriculum. More recent school programs have taken education outside the classroom and attempted to engage parents as well as teachers. Environmental changes such as improving the quality of foods available at lunchtime and at other times during the school day are now common. Reviews of evaluations of school-based programs have demonstrated that they are effective and successfully improve dietary quality such as increasing fruit and vegetable intake and decreasing sweet and savory snacks and sweetened drinks; not just in school but over the whole day and particularly in younger school children. School-based interventions are also effective at reducing obesity if components to increase physical activity and reduce sedentary behaviors are also targeted but not if only dietary behaviors are tackled. Most of the high-quality evaluation studies using randomized controlled trials have been carried out in high-income countries as they are costly to run. However, middle-income countries have benefitted from the information available from these evaluation studies and many are now starting to fund and evaluate school-based programs themselves, resulting in unique problems such as concomitant under- and overnutrition being addressed. Action for the future demands more focus on populations most at risk of poor dietary quality and obesity in order to reduce inequalities in health and on adolescents who have not benefited as much as younger children from school-based interventions. This will involve innovative solutions within schools as well as targeting the food environment outside schools such as reducing the density of fast-food outlets and marketing of sweet and savory snacks and drinks. PMID- 26602572 TI - Digestion and Postprandial Metabolism in the Elderly. AB - The elderly are an increasing segment of the population. Despite the rapid gains in medical knowledge and treatments, older adults are more likely to experience chronic illnesses that decrease quality of life and accelerate mortality. Nutrition is a key modifiable lifestyle factor which greatly impacts chronic disease risk. Yet despite the importance of nutrition, relatively little is known of the impact of advancing age on the gastrointestinal function, the digestive responses, and the post-meal metabolic adaptations that occur in response to ingested food. Knowledge of the age-related differences in digestion and metabolism in the elderly is essential to the development of appropriate nutritional recommendations for the maintenance of optimal health and prevention of disease. PMID- 26602574 TI - Preface. PMID- 26602573 TI - Gotu Kola (Centella asiatica): Nutritional Properties and Plausible Health Benefits. AB - Centella asiatica L. (Gotu Kola) is a nutritionally important plant and a valued traditional medicine in South East Asia. In this review, the chemical composition, nutritional values, and health benefits of C. asiatica have been discussed in detail to emphasize its usage as traditional food and medicine. C. asiatica is one of the most commonly used green leafy vegetables (GLVs) in some countries including Sri Lanka due to its high amounts of medicinally important triterpenoids and beneficial carotenoids. It is consumed in the form of GLVs and in the preparation of juice, drink, and other food products. It is also known to contain vitamins B and C, proteins, important minerals, and some other phytonutrients such as flavonoids, volatile oils, tannins, and polyphenol. In vitro and in vivo studies have shown important health benefits like antidiabetic, wound-healing, antimicrobial, memory-enhancing, antioxidant, and neuroprotecting activities. However, detailed scientific approaches on clinical trials regarding health benefits and nutritional values of C. asiatica are limited, hindering the perception of its benefits, mechanisms, and toxicity in order to develop new drug prototypes. In vitro studies have shown that the method of processing C. asiatica has an impact on its nutritional values and health-related beneficial compounds. The composition of its compounds is influenced by different biotic and abiotic factors which need to be studied in detail to provide information to the public in order to maximize the usage of this valuable plant. PMID- 26602575 TI - Is there a weekend effect in obstetrics? PMID- 26602576 TI - Outcome of Decolonization Therapy in a Hospital in Southern Puerto Rico. AB - OBJECTIVE: Methicillin resistant Staphylococcus aureus (MRSA) is a resistant bacteria responsible for hard-to-treat infections. To understand the primary impact of this infection in healthcare settings, a retrospective study was performed at a hospital in southern Puerto Rico. Our objectives were to classify the types of MRSA infection, identify factors associated with the infection, and evaluate the outcome of decolonization therapy after its having been implemented at the hospital. METHODS: Medical records of cases encompassing October 2009 through October 2011 were reviewed. A total of 761 MRSA-positive patients were identified and their infections classified as community-acquired MRSA (CA-MRSA), hospital-acquired MRSA (HA-MRSA), or healthcare-associated community-onset MRSA (HACO-MRSA). Basic demographics, reason for hospitalization, medical history, and culture sites, along with other information, were obtained for each case. SPSS v17 was used for statistical analysis. Fisher's exact test was used to measure the statistical significance of the crude OR, using the patients with CA-MRSA as the comparison group. HA-MRSA cases were compared before and after the intervention, using Epidat v4.0 to calculate the cumulative incidence of HA-MRSA before and after the implementation of decolonization therapy at the hospital. RESULTS: In our study, 5.0% of the patients were found to be infected with HA MRSA, 72.8%, with CA-MRSA, and 22.2%, with HACO-MRSA. After the intervention, we found a decrease of 10.35% (p = 0.704) in HA-MRSA, of 2.6% (p = 0.791) in CA MRSA, and of 7.0% in HACO-MRSA (p = 0.650). CONCLUSION: Our findings suggest that CA-MRSA could be responsible for the majority of the infections caused by MRSA within the hospital at which the study took place. Decolonization of MRSA is a useful tool in helping to control the spread of infection, although future studies are needed to confirm our study's findings. PMID- 26602577 TI - A Comparison of Brunt's Criteria, the Non-Alcoholic Fatty Liver Disease Activity Score (NAS), and a Proposed NAS Scoring that Includes Fibrosis in Non-Alcoholic Fatty Liver Disease Staging. AB - OBJECTIVE: The aim of this study was to determine the prevalence of NASH in veterans with metabolic syndrome and compare histologic grading using the Brunt criteria, the NAFLD activity score (NAS), and a proposed NAS scoring system that has been modified to include fibrosis staging. METHODS: Veterans with metabolic syndrome, hepatic steatosis, and elevated ALT and AST levels and who underwent liver biopsies from 2004 through 2010 were included in this study. Biopsies were evaluated by a single hepatopathologist. Each biopsy was analyzed using the Brunt criteria, the NAS system, and the NAS system plus fibrosis staging. RESULTS: Sixty patients having a mean age of 50.4 (+/-12.8 years) were included in the study; 88.3% were men. Fifty percent met criteria according to the Brunt system. When biopsies were classified using the NAS system, only 30.0% (18/60) were found to have a score of 5 or more, while, when adding fibrosis staging, the number of patients with a score of 5 or more increased to 33 (55.0%). Upon evaluating the predictive ability of the NAS scoring system, we found that when including fibrosis staging we obtained a higher sensitivity (86.7% vs. 40.0%) and a lower specificity (76.7% vs. 80.0%). CONCLUSION: In our population of patients with metabolic syndrome about 50 to 55% had steatohepatitis. There were significant differences between the scoring systems. When our NAS plus fibrosis system was used, more patients were recognized and the sensitivity increased. Further validation studies are required to evaluate this proposed modified NAS scoring system. PMID- 26602578 TI - Demographic and High-Risk Behaviors associated with HPV and HPV Vaccine Awareness among Persons Aged 15-74 Years in Puerto Rico. AB - OBJECTIVE: Studies of human papillomavirus (HPV) awareness in Puerto Rico (PR) are limited and are of interest given low HPV vaccine uptake in this population. This cross-sectional study aimed to determine factors associated to HPV and HPV vaccine awareness among persons aged 15-74 years living in Puerto Rico. METHODS: We analysed data from a sub-sample of 1,476 men and women who participated in a 2008 population-based island-wide household survey and who completed an HPV module. Multivariate logistic regression models were used to examine factors associated with HPV and HPV vaccine awareness. RESULTS: Overall, 37.2% of participants had heard about HPV and 33.4% had heard of the vaccine. Multivariate logistic regression showed that women were more likely to have heard of HPV (OR adjusted: 4.54; 95% CI=3.45, 5.98) or of the HPV vaccine (OR adjusted: 6.15; 95% CI=4.50, 8.40) as compared to men. HPV awareness was also lower among older adults, persons with lower income and with lower educational attainment, those without children and smokers (p < 0.05). CONCLUSION: In 2008, two years after the introduction of the first HPV vaccine in PR and the US, public awareness about HPV infection and the HPV vaccine was lower in Hispanics in PR as compared to other populations. Identified high-risk populations should be targeted in preventive care strategies. Future efforts should increase HPV knowledge and vaccine use in this population in order to maximize the impact of vaccination programs. PMID- 26602579 TI - Job Satisfaction and Relocation Desire among Pediatric Dentists in Puerto Rico. AB - OBJECTIVE: To determine the levels of satisfaction, license status, and desire to relocate of pediatric dentists in Puerto Rico. METHODS: Pediatric dentists in Puerto Rico were surveyed via telephone interviews. Data were collected through a 34-item questionnaire that explored satisfaction as related to income, continuing education, professional goals, and participation in the Mi Salud program. Frequencies, chi-square analysis, and Fisher's exact 2-tailed t-test were utilized to determine the relationships between satisfaction and the demographics of the pediatric dentists. RESULTS: Sixty pediatric dentists participated in our survey-77% of the total number of pediatric dentists practicing in Puerto Rico. Overall, 65% of the participating pediatric dentists expressed dissatisfaction. Male pediatric dentists were more dissatisfied than their female colleagues were. Most pediatric dentists participating in Mi Salud expressed dissatisfaction. When asked about whether or not they had considered migrating to the mainland, those who were dissatisfied were more likely to have considered that idea than were those who were satisfied. Overall, 57% of the pediatric dentists comprising our sample had considered relocating to the continental United States. CONCLUSION: In general, the pediatric dentists who participated in our study expressed dissatisfaction in most areas except when asked about their ability to reach professional goals. Determining the levels of satisfaction of health care providers is important in the maintaining of an adequate workforce. As current levels of dissatisfaction are high, it is important to determine what variables are related to satisfaction so that corrective measures can be taken to ensure that retention rates improve, thereby maintaining an adequate pediatric dental workforce. PMID- 26602580 TI - Burnout and its related Demographic Factors among the Medical Staff working in Hospitals associated with Bushehr University of Medical Sciences. AB - OBJECTIVE: Burnout exerts a significant negative influence on job performance, especially in such difficult jobs as those to be found in the health care industry. This research aimed to evaluate the association between 3 dimensions of burnout and demographic factors among the medical staff working in all of the hospitals associated with Bushehr University of Medical Sciences, Iran. METHODS: The research detailed herein was a descriptive, analytical cross-sectional study which was conducted on 461 medical staff working in all of the hospitals associated with Bushehr University of Medical Sciences, Iran, from April 2011 to February 2012. The data were collected using a self-response method and include demographic information as well as the Maslach Burnout Inventory. In this study, samples were selected using a stratified random sampling method. The scoring of the burnout questionnaire ranged from 0 (never) to 6 (every day), with the levels of each of the 3 dimensions of burnout (as well as burnout itself) then being categorized as being low, moderate, or high. The data were analyzed using an independent t-test, a chi-square test, ANOVA, and Pearson's correlation coefficient, all in SPSS 18. RESULTS: Most people had experienced moderate levels of burnout (53.6%). With regard to the 3 domains of burnout, 46.4% of the participants had experienced moderate levels of emotional exhaustion, more than half (56.4%) had experienced low levels of depersonalization, and more than half (52.5%), high levels of a diminished sense of accomplishment. Burnout was shown to be statistically significantly associated with gender, place of residence, the condition of that residence, educational level, and being or not being local (p>0.05). CONCLUSION: The research findings showed that the rate of burnout was moderate among the medical staff working in hospitals associated with Bushehr University of Medical Sciences. Probably, burnout can be reduced in the hospitals' different staff members through better and suitable planning and through the organization of human resources. PMID- 26602581 TI - Dermatologists in the Emergency Department: A 6-Year Retrospective Analysis. AB - OBJECTIVE: There are few studies documenting dermatological consultations in the emergency setting. The aim of this study was to evaluate the nature, purpose, and diagnostic accuracy of emergency care physicians in all the dermatology consults evaluated by the Department of Dermatology of the University of Puerto Rico School of Medicine. METHODS: A retrospective analysis of all the consultation reports pertaining to patients evaluated at 4 emergency departments served from July 1, 2007, to June 30, 2013. The data collected from each consultation report consisted of the demographic information of the patient, the name of the consulting hospital, the initial diagnostic impression, the diagnostic impression of a dermatologist, and the procedures, if any, performed by that dermatologist. RESULTS: A total of 429 patients were evaluated (53% men, 47% women) from July 2007 through June 2013. The most common diagnosis was infectious process (37%), followed by eczema (14%) and drug-induced skin reactions (12%). Seventeen percent (17%) of the cases for which consultations were sought were considered true dermatological emergencies. Forty-six percent of cases resulted in no diagnostic impression from the consulting physician. Of the cases that did result in diagnoses, these diagnoses were later changed by a dermatologist in 34% of the cases. CONCLUSION: This study suggests that the role of the dermatologist in the emergency department is very important. In addition, better education in the management of common skin disorders and the identification of true dermatological emergencies should be stressed during medical school and in residency training programs of specialties such as emergency medicine and those that offer primary care. PMID- 26602582 TI - Epiploic Appendagitis, an Uncommon Cause of Abdominal Pain: A Case Series and Review of the Literature. AB - OBJECTIVE: Epiploic appendagitis (EA) is a rare entity caused by the inflammation of the appendix epiploica. It is a benign and self-limited condition presenting as acute onset abdominal pain. The inaccurate diagnosis of EA can lead to unnecessary hospitalization, antibiotic therapy, and surgery. Our aim is to describe the common clinical features of patients who were diagnosed with EA over a 2-year period at the San Juan Veterans Administration Hospital. METHODS: A retrospective descriptive review of the records of all patients diagnosed with EA from 2007 to 2009. The clinical data was obtained through record review. Diagnoses were confirmed by 2 radiologists reviewing imaging studies. RESULTS: Eight patients were included in the study. All were male with a mean age of 58 years. Seven patients were overweight as per body mass index (BMI) scale. All had localized focal, non-migratory abdominal pain, most (75%) in the left lower quadrant. Nausea (37.5%), anorexia (12.5%), constipation (12.5%), and diarrhea (25%) were documented as well. Only 2 patients demonstrated mild elevations in WBC, but none of the 8 had a fever. During the study period, all the patients' symptoms resolved without documented recurrence. CONCLUSION: In our small case series, overweight was a common finding, supporting the described association between EA and obesity. History and physical exam should prompt the clinician to consider EA in the differential diagnosis of acute abdominal pain, particularly in those who are obese and who have pain localized to the left lower quadrant. PMID- 26602583 TI - Restoration of Anterior Dental Erosion with a Combination of Veneers and Crowns: A 3-Year Case Report. AB - This report describes the conservative management of a 40-year-old female patient with smooth, eroded facial enamel affecting her maxillary anterior and some posterior teeth. Using conventional enamel bonding, pressed leucite-reinforced laminate veneers were used to restore the length, contour, and esthetics of the maxillary right canine, as well as of the right lateral and both central incisors; at the same time, it was necessary to restore the maxillary left lateral incisor, canine, and first premolar of the same quadrant with all-ceramic crowns of the same material. The patient has been followed for 3 years and demonstrates a good esthetic outcome with no shade discrepancy between the two types of restoration. Apparently, the tooth structure, though eroded, was able to provide an adequate bonding substrate for these adhesive restorations. PMID- 26602584 TI - Anaphylactoid Purpura Manifested after Acute Gastroenteritis with Severe Dehydration in an 8-Year-Old Male Child: A Case Report. AB - Anaphylactoid purpura, also known as Henoch-Schonleinpurpura (HSP), is an IgA mediated vasculitis that tends to be a benign disease of childhood. Up to 50% of cases are preceded by an upper tract respiratory infection caused by group-A beta hemolytic streptococcus and present with the common tetrad of abdominal pain, arthritis, purpuric rash, and renal involvement. The majority of patients recover completely. Here we document a rare case of anaphylactoid purpura which manifested with skin lesions in the form of palpable purpura following about of acute gastroenteritis with severe dehydration; it was treated with a short regimen of steroid therapy, which resulted in the complete remission of the disease. We conclude that prompt diagnosis and multidisciplinary intervention will lead to appropriate management-consisting of the installation of early short course steroid therapy and thus, prevent further complications and the recurrence of the disease. PMID- 26602585 TI - Multiple Skeletal Deformities in a Middle-Aged Man. AB - A 54-year-old man was seen in our endocrinology clinic with evidence of a limited range of motion in his left foot. He had a history of diabetes mellitus type 2 and atrial fibrillation. His family history included evidence of skeletal deformities in some of his relatives. This could imply the potential existence of a hereditary condition. It is worth noting that spontaneous mutations have been reported in some cases. A pertinent physical examination revealed a surgical scar on the patient's left knee, a hallux valgus deformity on his left foot with compromised joint function, and painless bony prominences on that same foot. The skeletal survey findings were consistent with multiple hereditary exostoses. Multiple osteochondromatosis (MO) is a rare genetic disorder associated with serious complications that may significantly affect the health related quality of life of anyone having the disorder. To prevent further complications, these patients require long-term follow-up with regular clinical and radiological examinations. PMID- 26602586 TI - Effect of platelet-rich plasma in alveolar distraction osteogenesis: a controlled clinical trial. AB - We have evaluated the effect of the use of platelet-rich plasma in alveolar distraction osteogenesis. Fourteen patients who were partly edentulous in the anterior premaxilla region were selected and randomised into two groups (n=7 in each group). Those in the experimental group were give platelet-rich plasma at the time of distraction, and the control group had only distraction. Selected cases had defects in the alveolar ridge of more than 3mm, and a minimal bone height of 7 mm from the alveolar ridge crest to important anatomical structures. The plaque index and gingival index were recorded on days 3, 7, 14, 21, 28, 45, 60, 75, 90, and 105 postoperatively. There was a strong negative correlation between the gingival index and augmentation of bone, and a strong positive correlation between the mean gingival index and loss of bone from the transported segment. The addition of platelet-rich plasma had a protective effect on the mucosa around the distractor, which decreased the potential for complications. PMID- 26602587 TI - Vaccinations in patients with hematological malignancies. AB - Patients with hematological malignancies are at risk for a number of infections that are potentially preventable by vaccinations such as pneumococcal infections and influenza. Treatment, especially with anti-B-cell antibodies and hematopoietic stem cell transplantation (HSCT), negatively impacts the response to vaccination for several months. It is therefore recommended that patients be vaccinated before initiating immunosuppressive therapy if possible. The risk of side-effects with inactivated vaccines is low, but care has to be taken with live vaccines, such as varicella-zoster virus vaccine, since severe and fatal complications have been reported. HSCT patients require repeated doses of most vaccines to achieve long-lasting immune responses. New therapeutic options for patients with hematological malignancies that are rapidly being introduced into clinical practice will require additional research regarding the efficacy of vaccinations. New vaccines are also in development that will require well designed studies to ascertain efficacy and safety. PMID- 26602588 TI - Electro-spray deposition of a mesoporous TiO2 charge collection layer: toward large scale and continuous production of high efficiency perovskite solar cells. AB - The spin-coating method, which is widely used for thin film device fabrication, is incapable of large-area deposition or being performed continuously. In perovskite hybrid solar cells using CH(3)NH(3)PbI(3) (MAPbI(3)), large-area deposition is essential for their potential use in mass production. Prior to replacing all the spin-coating process for fabrication of perovskite solar cells, herein, a mesoporous TiO(2) electron-collection layer is fabricated by using the electro-spray deposition (ESD) system. Moreover, impedance spectroscopy and transient photocurrent and photovoltage measurements reveal that the electro sprayed mesoscopic TiO(2) film facilitates charge collection from the perovskite. The series resistance of the perovskite solar cell is also reduced owing to the highly porous nature of, and the low density of point defects in, the film. An optimized power conversion efficiency of 15.11% is achieved under an illumination of 1 sun; this efficiency is higher than that (13.67%) of the perovskite solar cell with the conventional spin-coated TiO(2) films. Furthermore, the large-area coating capability of the ESD process is verified through the coating of uniform 10 * 10 cm(2) TiO(2) films. This study clearly shows that ESD constitutes therefore a viable alternative for the fabrication of high-throughput, large-area perovskite solar cells. PMID- 26602590 TI - Paradoxical Improvement of Schizophrenic Symptoms by a Dopaminergic Agonist: An Example of Personalized Psychiatry in a Copy Number Variation-Carrying Patient. PMID- 26602591 TI - "Eye of tiger sign" mimic in an adolescent boy with mitochondrial membrane protein associated neurodegeneration (MPAN). AB - Neurodegeneration with brain iron accumulation (NBIA) refers to an inherited heterogeneous group of disorders pathologically characterized by focal brain iron deposition. Clinical phenotype, imaging findings and genotype are variable among the different types of this disorder. In this case report, we describe the imaging finding of an adolescent boy with mitochondrial membrane protein associated neurodegeneration (MPAN), a subentity of NBIA. Magnetic resonance imaging of brain revealed hypointensity of globi pallidi with medial medullary lamina appearing as a hyperintense streak in T2 weighted images. Mild cerebellar atrophy in T2 weighted images and blooming of substantia nigra and globi pallidi in susceptibility weighted images were also observed. Imaging findings in patients with MPAN mimics the eye of tiger appearance in patients with pantothenate kinase associated neurodegeneration. Classical phenotype and eye of tiger sign mimic in imaging of patients with NBIA should raise the suspect for MPAN. Genetic studies helps in the confirmation of diagnosis of this neurodegenerative disorder. PMID- 26602589 TI - Reduced Sleep Spindles in Schizophrenia: A Treatable Endophenotype That Links Risk Genes to Impaired Cognition? AB - Although schizophrenia (SZ) is defined by waking phenomena, abnormal sleep is a common feature. In particular, there is accumulating evidence of a sleep spindle deficit. Sleep spindles, a defining thalamocortical oscillation of non-rapid eye movement stage 2 sleep, correlate with IQ and are thought to promote long-term potentiation and enhance memory consolidation. We review evidence that reduced spindle activity in SZ is an endophenotype that impairs sleep-dependent memory consolidation, contributes to symptoms, and is a novel treatment biomarker. Studies showing that spindles can be pharmacologically enhanced in SZ and that increasing spindles improves memory in healthy individuals suggest that treating spindle deficits in patients with SZ may improve cognition. Spindle activity is highly heritable, and recent large-scale genome-wide association studies have identified SZ risk genes that may contribute to spindle deficits and illuminate their mechanisms. For example, the SZ risk gene CACNA1I encodes a calcium channel that is abundantly expressed in the thalamic spindle generator and plays a critical role in spindle activity based on a mouse knockout. Future genetic studies of animals and humans can delineate the role of this and other genes in spindles. Such cross-disciplinary research, by forging empirical links in causal chains from risk genes to proteins and cellular functions to endophenotypes, cognitive impairments, symptoms, and diagnosis, has the potential to advance the mechanistic understanding, treatment, and prevention of SZ. This review highlights the importance of deficient sleep-dependent memory consolidation among the cognitive deficits of SZ and implicates reduced sleep spindles as a potentially treatable mechanism. PMID- 26602592 TI - Heavy metal removal from MSS fly ash by thermal and chlorination treatments. AB - The thermal behavior of heavy metals in the co-incineration of municipal solid waste-sludge incinerator fly ash (MSS fly ash) was studied using a laboratory scale tube furnace. The results indicate that without the addition of chlorinating agents, temperature was an important parameter and had significantly influenced on heavy metal removal, whereas the residence time had a weak effect. Between 900 and 1000 degrees C for 60 to 300 min, heavy metals reacted with chloride-inherent in the fly ash, and approximately 80 to 89% of Pb, 48% to 56% of Cd, 27% to 36% of Zn and 6% to 24% of Cu were removed. After the adding chlorinating agents, the evaporation rate of the heavy metals improved dramatically, where the evaporation rates of Cu and Zn were larger than that of Pb and Cd. As the amount of added chlorinating agents increased, the removal rate of heavy metals increased. However, the effect of the type of chlorinating agent on the chlorination of heavy metals differed considerably, where NaCl had the weakest effect on the removal rate of Cu, Cd and Zn. In terms of resource recovery and decontamination, MgCl2 and CaCl2 are the best choices due to their efficient removal of Zn. PMID- 26602593 TI - The application of multilevel modelling to account for the influence of walking speed in gait analysis. AB - Differences in gait performance can be explained by variations in walking speed, which is a major analytical problem. Some investigators have standardised speed during testing, but this can result in an unnatural control of gait characteristics. Other investigators have developed test procedures where participants walking at their self-selected slow, preferred and fast speeds, with computation of gait characteristics at a standardised speed. However, this analysis is dependent upon an overlap in the ranges of gait speed observed within and between participants, and this is difficult to achieve under self-selected conditions. In this report a statistical analysis procedure is introduced that utilises multilevel modelling to analyse data from walking tests at self-selected speeds, without requiring an overlap in the range of speeds observed or the routine use of data transformations. PMID- 26602594 TI - Extra-mucosal enucleation of a giant circular leiomyoma of the middle esophagus. PMID- 26602595 TI - Robot-assisted laparoscopic left lateral sectionectomy for benign and malignant liver tumors. PMID- 26602596 TI - Colorectal Cancer Initial Diagnosis: Screening Colonoscopy, Diagnostic Colonoscopy, or Emergent Surgery, and Tumor Stage and Size at Initial Presentation. AB - INTRODUCTION/BACKGROUND: Rates of colorectal cancer screening are improving but remain suboptimal. Limited information is available regarding how patients are diagnosed with colorectal cancer (for example, asymptomatic screened patients or diagnostic workup because of the presence of symptoms). The purpose of this investigation was to determine how patients were diagnosed with colorectal cancer (screening colonoscopy, diagnostic colonoscopy, or emergent surgery) and tumor stage and size at diagnosis. PATIENTS AND METHODS: Adults evaluated between 2011 and 2014 with a diagnosis of colorectal cancer were identified. Clinical notes, endoscopy reports, surgical reports, radiology reports, and pathology reports were reviewed. Sex, race, ethnicity, age at the time of initial diagnosis, method of diagnosis, presenting symptom(s), and primary tumor size and stage at diagnosis were recorded. Colorectal cancer screening history was also recorded. RESULTS: The study population was 54% male (265 of 492) with a mean age of 58.9 years (range, 25-93 years). Initial tissue diagnosis was established at the time of screening colonoscopy in 10.7%, diagnostic colonoscopy in 79.2%, and during emergent surgery in 7.1%. Cancers diagnosed at the time of screening colonoscopy were more likely to be stage 1 than cancers diagnosed at the time of diagnostic colonoscopy or emergent surgery (38.5%, 7.2%, and 0%, respectively). Median tumor size was 3.0 cm for the screening colonoscopy group, 4.6 cm for the diagnostic colonoscopy group, and 5.0 cm for the emergent surgery group. At least 31% of patients diagnosed at the time of screening colonoscopy, 19% of patients diagnosed at the time of diagnostic colonoscopy, and 26% of patients diagnosed at the time of emergent surgery had never undergone a screening colonoscopy. CONCLUSION: Nearly 90% of colorectal cancer patients were diagnosed after development of symptoms and had more advanced disease than asymptomatic screening patients. Colorectal cancer outcomes will be improved by improving rates of colorectal cancer screening. PMID- 26602598 TI - A Century of Hyperthyroidism at Mayo Clinic. PMID- 26602597 TI - GPRC6A mediates Alum-induced Nlrp3 inflammasome activation but limits Th2 type antibody responses. AB - Alum adjuvanticity is still an unknown mechanism despite the frequent use as vaccine adjuvant in humans. Here we show that Alum-induced inflammasome activation in vitro and in vivo is mediated by the G protein-coupled receptor GPRC6A. The Alum-induced humoral response in vivo was independent of the inflammasome because Nlrp3-/- and ASC-/- mice responded normally to Alum and blockade of IL-1 had no effect on antibody production. In contrast, Alum adjuvanticity was increased in GPRC6A-/- mice resulting in increased antibody responses and increased Th2 cytokine concentrations compared to wildtype mice. In vitro activation of GPRC6A-/- splenic B cells also induced increased IgG1 concentrations compared to wildtype B cells. For the first time, we show GPRC6A expression in B cells, contributing to the direct effects of Alum on those cells. B cell produced immunostimulatory IL-10 is elevated in GPRC6A-/- B cells in vitro and in vivo. Our results demonstrate a dual role of GPRC6A in Alum adjuvanticity. GPCR6A activation by Alum leads to the initiation of innate inflammatory responses whereas it is an important signal for the limitation of adaptive immune responses induced by Alum, partially explained by B cell IL-10. PMID- 26602599 TI - Prevalence of Preexisting Cardiovascular Disease in Patients With Different Types of Cancer: The Unmet Need for Onco-Cardiology. AB - Cancer and cardiovascular diseases (CVDs) share many of the same risk factors. Using a cloud-based health care database, we identified patients with malignancies that often require cardiotoxic treatments (leukemia/lymphoma and lung, breast, colon, renal, and head and neck cancers). We report the prevalence of CVDs (coronary artery disease, carotid artery disease, peripheral vascular disease, cerebrovascular disease, and heart failure) in those populations. Overall, CVD prevalences were 33% for hematologic, 43% for lung, 17% for breast, 26% for colon, 35% for renal, and 26% for head and neck cancers. Generally, patients with lung and hematologic malignancies had the highest prevalence of all types of CVDs. Of those with CVD, only half were referred to cardiologists and received guideline-directed medical therapy. The prevalence of CVDs is unexpectedly high and suboptimally managed in patients with cancer. There seems to be an opportunity for onco-cardiologists to fulfill this unmet need and help improve outcomes in patients with cancer and coexisting heart disease. PMID- 26602600 TI - Obstructive sleep apnea syndrome after hematopoietic stem cell transplantation in children with mucopolysaccharidosis type I. AB - BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is very common in mucopolysaccharidosis I (MPS I). Hematopoietic stem cell transplantation (HSCT) is the preferred treatment for patients with severe MPS I diagnosed early in life. The protective effect of HSCT on the development of long term OSAS is not known. METHODS: Overnight polysomnography (PSG) and biomarker data were analyzed during the annual follow-up in consecutive MPS I patients treated with HSCT. RESULTS: The data of 13 patients (6 boys) were analyzed. Median age at HSCT was 17 (range 14-19) months, median age at PSG was 9.0 (4.5-14.5) years, and median time elapsed since HSCT was 7.6 (2.4-13.2) years. A significant correlation was observed between time elapsed since HSCT and the apnea-hypopnea index (AHI, r(2)=0.493, p=+0.003) and the oxygen desaturation index (r(2)=0.424, p=+0.02). Patients older than 10 years of age had a higher mean AHI (25.8/h vs 1.4/h, p=0.0008), a lower mean pulse oximetry (94.7% vs 97.2%, p=0.01) and a higher mean hypopnea index (18.8 vs 0.71/h, p=0.016) as compared to those younger than 10 years of age. No correlation was observed between the AHI and the metabolic clearance, assessed by urine glycosaminoglycan (GAG) excretion and residual enzyme activity, although there was a positive trend for the urinary GAG/higher normal value for age ratio (p=0.09). CONCLUSION: HSCT does not offer long term protection against OSAS in MPS I with OSAS being documented in all patients after a time elapse since HSCT exceeding 10 years. The potential benefit of additional enzyme replacement therapy needs to be assessed. PMID- 26602601 TI - Metastatic saccrococcygeal chordoma. AB - We report a 46-year-old man who presented with a 2week history of worsening headaches and acute onset left sided hemiplegia. He had undergone a surgical resection of a sacral chordoma 13years prior, followed by adjuvant radiotherapy and chemotherapy. MRI revealed multiple enhancing lesions in the brain, and the two largest were resected. The histopathology was consistent with chordoma. Sacrococcygeal chordomas are locally invasive notochord-related sarcomas. They rarely metastasize to the brain, and only eight patients have been reported. While currently available adjuvant radiotherapy and systemic chemotherapeutic regimens can be implemented in the management of these rare patients, they have shown limited success. The newer strategies that are reported here have also been disappointing. PMID- 26602602 TI - A prospective, multi-center clinical and radiographic outcomes evaluation of ChronOS strip for lumbar spine fusion. AB - This prospective clinical study evaluated the use of a composite bone void filler (ChronOS Strip, DePuy Synthes, West Chester, PA, USA), combined with bone marrow aspirate plus local autologous bone, in a series of patients undergoing instrumented posterolateral spinal fusion with interbody support. Seventy-six patients were enrolled and treated per protocol at 13 clinical sites. At 24 months, 55/76 patients (72%) were evaluated, with 49/76 (65%) having sufficient data to determine the primary endpoint. The primary endpoint, posterolateral fusion success, was achieved in 48/54 (88.9%) patients at 12 months and in 45/49 (91.8%) patients at 24 months. At all follow-up time points, statistically significant improvements were observed when compared to baseline in back and leg pain and functional status as measured by visual analog scale, Oswestry Disability Index and 12-Item Short Form health surveys. This prospective multi center series provides evidence that the composite bone void filler, when applied posterolaterally with instrumentation, bone marrow aspirate and/or local autologous bone and concomitant interbody support, can be used to achieve a successful posterolateral fusion, resulting in improvements in clinical outcomes in patients with degenerative disc disease. PMID- 26602603 TI - Multiple myeloma presenting with unilateral abducens and trigeminal nerve palsies. AB - Petrous apex masses can manifest with neurologic symptoms due to their involvement of various structures, including cranial nerves (CN) V and VI. The differential diagnosis of petrous masses is broad and includes a variety of both non-neoplastic and neoplastic lesions. We report a rare case of multiple myeloma confined to the right petrous apex, presenting with ipsilateral abducens and trigeminal nerve palsies. A 63-year-old woman presented with a 6-8 week history of facial numbness and a 2 week history of diplopia, with examination showing right-sided facial hypoesthesia in the CN V1-V3 region and right-sided lateral rectus palsy. MRI of the brain showed a solitary 2.0 cm lesion confined to the right petrous apex involving the right cavernous internal carotid artery and Meckel's cave. A transnasal biopsy showed a proliferation of plasmacytoid cells, which showed diffuse immunoreactivity with antibodies to CD138 and kappa, consistent with a plasma cell dyscrasia. A bone scan subsequently revealed multiple lytic bone lesions involving the skull, left humerus, bilateral femurs and possibly the L4 vertebral body. Bone marrow biopsy and serum laboratory results confirmed the diagnosis of kappa-type multiple myeloma. Although rare, multiple myeloma may initially present with petrous involvement and associated cranial nerve deficits. PMID- 26602604 TI - Glial fibrillary acidic protein as a marker of astrocytic activation in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis. AB - Glial fibrillary acidic protein (GFAP) has been shown to be increased in the cerebrospinal fluid (CSF) of patients suffering from neurological diseases involving the activation of astrocytes, but has not been studied in amyotrophic lateral sclerosis (ALS) patients to our knowledge. CSF samples of patients with definite ALS and of those with other neurological diseases were evaluated for their GFAP concentrations. CSF-GFAP concentrations of patients with ALS were significantly elevated by 53% compared to patients with other neurologic diseases. GFAP might serve as a biomarker in ALS. Our findings support the concept that astrocytes play a role in ALS pathogenesis. PMID- 26602605 TI - Are we ready to estimate daily ochratoxin A intake based on urinary concentrations? PMID- 26602607 TI - Web Resources for Metagenomics Studies. AB - The development of next-generation sequencing (NGS) platforms spawned an enormous volume of data. This explosion in data has unearthed new scalability challenges for existing bioinformatics tools. The analysis of metagenomic sequences using bioinformatics pipelines is complicated by the substantial complexity of these data. In this article, we review several commonly-used online tools for metagenomics data analysis with respect to their quality and detail of analysis using simulated metagenomics data. There are at least a dozen such software tools presently available in the public domain. Among them, MGRAST, IMG/M, and METAVIR are the most well-known tools according to the number of citations by peer reviewed scientific media up to mid-2015. Here, we describe 12 online tools with respect to their web link, annotation pipelines, clustering methods, online user support, and availability of data storage. We have also done the rating for each tool to screen more potential and preferential tools and evaluated five best tools using synthetic metagenome. The article comprehensively deals with the contemporary problems and the prospects of metagenomics from a bioinformatics viewpoint. PMID- 26602606 TI - Age-related arterial telomere uncapping and senescence is greater in women compared with men. AB - Telomere uncapping increases with advancing age in human arteries and this telomere uncapping is associated with increased markers of senescence, independent of mean telomere length. However, whether there are sex specific differences in arterial telomere uncapping is unknown. We found that telomere uncapping (serine 139 phosphorylated histone gamma-H2A.X in telomeres) in arteries was ~2.5 fold greater in post-menopausal women (n=17, 63+/-2 years) compared with pre-menopausal women (n=11, 30+/-2 years, p=0.02), while there was only a trend towards greater telomere uncapping in older men (n=26, 66+/-2 years) compared with young men (n=11, 31+/-2, p=0.11). Senescence markers, p53 bound to the p21 gene promoter and p21 gene expression, were 3-4 fold greater in post menopausal compared with pre-menopausal women (p=0.01-0.02), but only 1.5-2 fold greater in older compared with young men (p=0.02-0.08). Blood glucose was related to telomere uncapping in women, while systolic blood pressure, pulse pressure and serum creatinine were related to telomere uncapping in men. Mean arterial telomere length decreased similarly in women and men with age (p<0.01). Thus, the age-related increase in arterial telomere uncapping and senescence is greater in women than men, despite similar age-related reductions in mean telomere length in both sexes. PMID- 26602608 TI - Nonlinear analysis of fetal heart rate dynamics in fetuses compromised by asymptomatic partial placental abruption. AB - INTRODUCTION: We analyzed fetal heart rate (FHR) parameters, dynamics, and outcomes in pregnancies with asymptomatic partial placental abruption (PPA) compared with those in normal pregnancies. METHODS: We examined nonstress test (NST) data acquired from 2003 to 2012 at our institution. Normal pregnancies (N = 170) and PPA cases (N = 17) were matched for gestational age, fetal sex, and mean FHR. NSTs were performed at 33-42 weeks of gestation. FHR parameters obtained from the NST and perinatal outcomes were analyzed using linear methods. Nonlinear indices, including approximate entropy (ApEn), sample entropy (SampEn), short term and long-term scaling exponents (alpha1 and alpha2), and correlation dimension (CD), were used to interpret FHR dynamics and system complexity. The area under a receiver operating characteristic curve (AUC) was used to evaluate the nonlinear indices. RESULTS: There were no significant differences in general characteristics and FHR parameters between the PPA and control groups. However, gestational age at delivery, birth weight, 5-min Apgar scores, ApEn, SampEn, and CD were significantly lower in the PPA group than in the control group (P < 0.05). The long-term scaling exponent (alpha2) and crossover index (alpha2/alpha1) of the PPA fetuses were significantly higher than those of the controls (P < 0.01). A multiple regression model showed better performance in predicting PPA (AUC, 0.92; sensitivity 82.35%; specificity, 94.12%). DISCUSSION: Nonlinear dynamic indices of FHR in asymptomatic PPA were qualitatively different from those in normal pregnancies, whereas the conventional FHR parameters were not significantly different. PMID- 26602610 TI - Deep grey matter MRI abnormalities and cognitive function in relapsing-remitting multiple sclerosis. AB - Although deep grey matter (GM) involvement in multiple sclerosis (MS) is well documented, in-vivo multi-parameter magnetic resonance imaging (MRI) studies and association with detailed cognitive measures are limited. We investigated volumetric, diffusion and perfusion metrics in thalamus, hippocampus, putamen, caudate nucleus and globus pallidum, and neuropsychological measures, spanning 4 cognitive domains, in 60 relapsing-remitting MS patients (RRMS) (mean disease duration of 5.1 years, median EDSS of 1.5) and 30 healthy controls. There was significantly reduced volume of thalamus, hippocampus and putamen in the RRMS patients, but no diffusion or perfusion changes in these structures. Decreased volume in these deep GM volumes in RRMS patients was associated with a modest reduction in cognitive performance, particularly information processing speed, consistent with a subtle disruption of distributed networks, that subserve cognition, in these patients. Future longitudinal studies are needed to elucidate the influence of deep GM changes on the evolution of cognitive deficits in MS. PMID- 26602609 TI - miRNA-target chimeras reveal miRNA 3'-end pairing as a major determinant of Argonaute target specificity. AB - microRNAs (miRNAs) act as sequence-specific guides for Argonaute (AGO) proteins, which mediate posttranscriptional silencing of target messenger RNAs. Despite their importance in many biological processes, rules governing AGO-miRNA targeting are only partially understood. Here we report a modified AGO HITS-CLIP strategy termed CLEAR (covalent ligation of endogenous Argonaute-bound RNAs) CLIP, which enriches miRNAs ligated to their endogenous mRNA targets. CLEAR-CLIP mapped ~130,000 endogenous miRNA-target interactions in mouse brain and ~40,000 in human hepatoma cells. Motif and structural analysis define expanded pairing rules for over 200 mammalian miRNAs. Most interactions combine seed-based pairing with distinct, miRNA-specific patterns of auxiliary pairing. At some regulatory sites, this specificity confers distinct silencing functions to miRNA family members with shared seed sequences but divergent 3'-ends. This work provides a means for explicit biochemical identification of miRNA sites in vivo, leading to the discovery that miRNA 3'-end pairing is a general determinant of AGO binding specificity. PMID- 26602611 TI - Altered resting-state functional connectivity in women with chronic fatigue syndrome. AB - The biological underpinnings of the psychological factors characterizing chronic fatigue syndrome (CFS) have not been extensively studied. Our aim was to evaluate alterations of resting-state functional connectivity in CFS patients. Participants comprised 18 women with CFS and 18 age-matched female healthy controls who were recruited from the local community. Structural and functional magnetic resonance images were acquired during a 6-min passive-viewing block scan. Posterior cingulate cortex seeded resting-state functional connectivity was evaluated, and correlation analyses of connectivity strength were performed. Graph theory analysis of 90 nodes of the brain was conducted to compare the global and local efficiency of connectivity networks in CFS patients with that in healthy controls. The posterior cingulate cortex in CFS patients showed increased resting-state functional connectivity with the dorsal and rostral anterior cingulate cortex. Connectivity strength of the posterior cingulate cortex to the dorsal anterior cingulate cortex significantly correlated with the Chalder Fatigue Scale score, while the Beck Depression Inventory (BDI) score was controlled. Connectivity strength to the rostral anterior cingulate cortex significantly correlated with the Chalder Fatigue Scale score. Global efficiency of the posterior cingulate cortex was significantly lower in CFS patients, while local efficiency showed no difference from findings in healthy controls. The findings suggest that CFS patients show inefficient increments in resting-state functional connectivity that are linked to the psychological factors observed in the syndrome. PMID- 26602612 TI - Synthesis of Functionalized 1H-Isochromene Derivatives via a Au-Catalyzed Domino Cycloisomerization/Reduction Approach. AB - A Au-catalyzed versatile and efficient access to 1H-isochromenes is reported. The efficiency of the [AuCl2(Pic)] complex (1-5 mol %) was demonstrated and allowed a domino cycloisomerization/reduction reaction process starting from a wide range of functionalized ortho-alkynylbenzaldehydes and one example of ortho alkynylpyridinylaldehyde. The smooth reaction conditions were amenable to aryl- and alkyl-substituted alkynyl derivatives, as well as functionalized halogen and ether moieties, leading to a chemo- and regioselective 6-endo-cyclization with good to excellent yields. PMID- 26602613 TI - Mesoporous magnetic secondary nanostructures as versatile adsorbent for efficient scavenging of heavy metals. AB - Porous magnetic secondary nanostructures exhibit high surface area because of the presence of plentiful interparticle spaces or pores. Mesoporous Fe3O4 secondary nanostructures (MFSNs) have been studied here as versatile adsorbent for heavy metal scavenging. The porosity combined with magnetic functionality of the secondary nanostructures has facilitated efficient heavy metal (As, Cu and Cd) remediation from water solution within a short period of contact time. It is because of the larger surface area of MFSNs due to the porous network in addition to primary nanostructures which provides abundant adsorption sites facilitating high adsorption of the heavy metal ions. The brilliance of adsorption property of MFSNs has been realized through comprehensive adsorption studies and detailed kinetics. Due to their larger dimension, MFSNs help in overcoming the Brownian motion which facilitates easy separation of the metal ion sorbed secondary nanostructures and also do not get drained out during filtration, thus providing pure water. PMID- 26602614 TI - Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines. PMID- 26602615 TI - Advances in the Understanding and Treatment of Male Urethritis. AB - Neisseria gonorrhoeae and Chlamydia trachomatis are well-documented urethral pathogens, and the literature supporting Mycoplasma genitalium as an etiology of urethritis is growing. Trichomonas vaginalis and viral pathogens (herpes simplex virus types 1 and 2 and adenovirus) can cause urethritis, particularly in specific subpopulations. New data are emerging regarding the potential role of bacterial vaginosis-associated bacteria in urethritis, although results are inconsistent regarding the pathogenic role of Ureaplasma urealyticum in men. Mycoplasma hominis and Ureaplasma parvum do not appear to be pathogens. Men with suspected urethritis should undergo evaluation to confirm urethral inflammation and etiologic cause. Although nucleic acid amplification testing would detect N. gonorrhoeae and C. trachomatis (or T. vaginalis if utilized), there is no US Food and Drug Administration-approved clinical test for M. genitalium available in the United States at this time. The varied etiologies of urethritis and lack of diagnostic options for some organisms present treatment challenges in the clinical setting. PMID- 26602616 TI - Epididymitis. AB - In April 2013, the Centers for Disease Control and Prevention (CDC) convened an advisory group to assist in development of the 2015 CDC sexually transmitted diseases (STDs) treatment guidelines. The advisory group examined recent abstracts and published literature addressing the diagnosis and management of sexually transmitted infections. This article summarizes the key questions, evidence, and recommendations for the diagnosis and management of epididymitis that were considered in preparation of the 2015 CDC STD treatment guidelines. PMID- 26602617 TI - Diagnosis and Management of Uncomplicated Chlamydia trachomatis Infections in Adolescents and Adults: Summary of Evidence Reviewed for the 2015 Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines. AB - In preparation for the 2015 Centers for Disease Control and Prevention (CDC) Sexually Transmitted Diseases (STD) Treatment Guidelines, the CDC convened an advisory group in 2013 to examine recent abstracts and published literature addressing the epidemiology, diagnosis, and management of STDs. This article summarizes the key questions, evidence, and recommendations for the diagnosis and management of uncomplicated Chlamydia trachomatis (CT) infection in adolescents and adults that were considered in development of the 2015 CDC STD Treatment Guidelines. The evidence reviewed primarily focused on CT infection risk factors in women, clinical significance of oropharyngeal CT detection, acceptability and performance of CT testing on self-collected specimens in men, performance of CT point-of-care tests, efficacy of recommended and investigational CT infection treatments, and timing of test of cure following CT infection treatment in pregnant women. PMID- 26602618 TI - Management of Gonorrhea in Adolescents and Adults in the United States. AB - Gonorrhea is the second most commonly reported notifiable disease in the United States and is associated with serious health sequelae, including pelvic inflammatory disease, infertility, and ectopic pregnancy. Treatment for gonorrhea has been complicated by antimicrobial resistance. Neisseria gonorrhoeae has developed resistance to each of the antimicrobials that were previously recommended as first-line treatment regimens, and current treatment options are severely limited. This article summarizes the key questions and data that were discussed at the Sexually Transmitted Diseases (STD) Treatment Guidelines Expert Consultation meeting in April 2013, and the rationale for the 2015 Centers for Disease Control and Prevention STD treatment guidelines for gonococcal infections in adolescents and adults. Key issues addressed include whether to change the dosage of ceftriaxone and azithromycin used in the recommended dual treatment regimen, whether to continue to list dual treatment with cefixime and azithromycin as an alternative treatment regimen, and management of gonococcal infections in persons with severe cephalosporin allergy or suspected treatment failure. PMID- 26602619 TI - Efficacy of Antimicrobial Therapy for Mycoplasma genitalium Infections. AB - Mycoplasma genitalium has been causally linked with nongonococcal urethritis in men and cervicitis, pelvic inflammatory disease, preterm birth, spontaneous abortion, and infertility in women, yet treatment has proven challenging. To inform treatment recommendations, we reviewed English-language studies describing antimicrobial susceptibility, resistance-associated mutations, and clinical efficacy of antibiotic therapy, identified via a systematic search of PubMed supplemented by expert referral. Minimum inhibitory concentrations (MICs) from some contemporary isolates exhibited high-level susceptibility to most macrolides and quinolones, and moderate susceptibility to most tetracyclines, whereas other contemporary isolates had high MICs to the same antibiotics. Randomized trials demonstrated poor efficacy of doxycycline and better, but declining, efficacy of single-dose azithromycin therapy. Treatment failures after extended doses of azithromycin similarly increased, and circulating macrolide resistance was present in high levels in several areas. Moxifloxacin remains the most effective therapy, but treatment failures and quinolone resistance are emerging. Surveillance of M. genitalium prevalence and antimicrobial resistance patterns is urgently needed. PMID- 26602620 TI - Management of Adult Syphilis: Key Questions to Inform the 2015 Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines. AB - A panel of experts generated 8 "key questions" in the management of adult syphilis. A systematic literature review was conducted and tables of evidence were constructed to answer these important questions. Penicillin is the drug of choice to treat syphilis. Doxycycline to treat early and late latent syphilis is an acceptable alternate option if penicillin cannot be used. There is no added benefit to enhanced antimicrobial therapy when treating human immunodeficiency virus-infected persons with syphilis. If a patient misses a dose of penicillin in a course of weekly therapy for late syphilis, clinical experience suggests that an interval of 10-14 days between doses might be acceptable before restarting the sequence of injections. Pharmacologic considerations suggest that an interval of 7-9 days between doses, if feasible, may be more optimal. Missed doses are not acceptable for pregnant women. A cerebrospinal fluid examination to diagnose neurosyphilis is recommended in persons diagnosed with tertiary syphilis (eg, cardiovascular syphilis or late benign syphilis), persons with neurological signs or symptoms consistent with neurosyphilis, and asymptomatic persons whose serological titers do not decline appropriately following recommended therapy and in whom reinfection is ruled out. Infection and reinfection rates, particularly among men who have sex with men, are high. Frequent serological screening of this population appears to be the most cost-efficient intervention. The Centers for Disease Control and Prevention continues to recommend the use of the traditional rapid plasma reagin-based screening algorithm. The positive predictive value for syphilis associated with an isolated unconfirmed reactive treponemal chemiluminescence assay or enzyme immunoassay is low if the epidemiological risk and clinical probability for syphilis are low. Among pregnant women with serodiscordant serologies (positive treponemal tests and a negative nontreponemal test), the risk of vertical transmission from mother to infant is low. Several important questions regarding the management of syphilis remain unanswered and should be a priority for future research. PMID- 26602622 TI - Human Papillomavirus and Genital Warts: A Review of the Evidence for the 2015 Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines. AB - To provide updates for the 2015 Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines on human papillomavirus (HPV) and anogenital warts (AGWs), a review of the literature was conducted in key topic areas: (1) epidemiology and burden of disease; (2) transmission and natural history; (3) diagnosis and management of AGWs; (4) occupational exposure of healthcare workers; (5) anal cancer screening among men who have sex with men (MSM); and (6) HPV vaccine recommendations. Most sexually active persons will have detectable HPV at least once in their lifetime; 14 million persons are infected annually, and 79 million persons have prevalent infection. HPV is transmitted frequently between partners; more frequent transmission has been reported from females to males than from males to females. A new formulation of imiquimod (3.75% cream) is recommended for AGW treatment. Appropriate infection control, including performing laser or electrocautery in ventilated rooms using standard precautions, is recommended to prevent possible transmission to healthcare workers who treat anogenital warts, oral warts, and anogenital intraepithelial neoplasias (eg, cervical intraepithelial neoplasia). Data are insufficient to recommend routine anal cancer screening with anal cytology in persons living with human immunodeficiency virus (HIV)/AIDS or HIV-negative MSM. An annual digital anorectal examination may be useful for early detection of anal cancer in these populations. HPV vaccine is recommended routinely for 11- or 12 year-olds, as well as for young men through age 21 years and young women through age 26 years who have not previously been vaccinated. HPV vaccine is also recommended for MSM, people living with HIV/AIDS, and immunocompromised persons through age 26 years. PMID- 26602623 TI - Sexual Assault and Sexually Transmitted Infections in Adults, Adolescents, and Children. AB - Survivors of sexual assault are at risk for acquiring sexually transmitted infections (STIs). We conducted literature reviews and invited experts to assist in updating the sexual assault section for the 2015 Centers for Disease Control and Prevention sexually transmitted diseases (STD) treatment guidelines. New recommendations for STI management among adult and adolescent sexual assault survivors include use of nucleic acid amplification tests (NAATs) for detection of Trichomonas vaginalis by vaginal swabs; NAATs for detection of Neisseria gonorrhoeae and Chlamydia trachomatis from pharyngeal and rectal specimens among patients with a history of exposure or suspected extragenital contact after sexual assault; empiric therapy for gonorrhea, chlamydia, and trichomoniasis based on updated treatment regimens; vaccinations for human papillomavirus (HPV) among previously unvaccinated patients aged 9-26 years; and consideration for human immunodeficiency virus (HIV) nonoccupational postexposure prophylaxis using an algorithm to assess the timing and characteristics of the exposure. For child sexual assault (CSA) survivors, recommendations include targeted diagnostic testing with increased use of NAATs when appropriate; routine follow-up visits within 6 months after the last known sexual abuse; and use of HPV vaccination in accordance with national immunization guidelines as a preventive measure in the post-sexual assault care setting. For CSA patients, NAATs are considered to be acceptable for identification of gonococcal and chlamydial infections from urine samples, but are not recommended for extragenital testing due to the potential detection of nongonococcal Neisseria species. Several research questions were identified regarding the prevalence, detection, and management of STI/HIV infections among adult, adolescent, and pediatric sexual assault survivors. PMID- 26602624 TI - Lymphogranuloma Venereum 2015: Clinical Presentation, Diagnosis, and Treatment. AB - Lymphogranuloma venereum (LGV) has emerged as an important cause of proctitis and proctocolitis in men who have sex with men; classical inguinal presentation is now increasingly uncommon. We report summary findings of an extensive literature review on LGV clinical presentation, diagnosis, and treatment that form the evidence base for the 2015 Centers for Disease Control and Prevention treatment guidelines for sexually transmitted diseases. Proctitis and proctocolitis are now the most commonly reported clinical manifestations of LGV, with symptoms resembling those of inflammatory bowel disease. Newer molecular tests to confirm LGV infection are sensitive and specific, but are generally restricted to research laboratory or public health settings. Doxycycline (100 mg twice daily for 21 days) remains the treatment of choice for LGV. Patients with rectal chlamydial infection and signs or symptoms of proctitis should be tested for LGV, or if confirmatory testing is not available, should be treated empirically with a recommended regimen to cover LGV infection. PMID- 26602621 TI - A Review of Evidence-Based Care of Symptomatic Trichomoniasis and Asymptomatic Trichomonas vaginalis Infections. AB - Trichomonas vaginalis is the most prevalent nonviral sexually transmitted infection, affecting an estimated 3.7 million women and men in the United States. Health disparities are prominent in the epidemiology of this infection, which affects 11% of women aged >=40 years and a disproportionately high percentage of black women. Particularly high prevalences have been identified among sexually transmitted disease (STD) clinic patients and incarcerated individuals. This article reviews and updates scientific evidence in key topic areas used for the development of the 2015 STD Treatment Guidelines published by the Centers for Disease Control and Prevention. Current evidence is presented regarding conditions associated with Trichomonas vaginalis infection, including human immunodeficiency virus (HIV) and pregnancy complications such as preterm birth. Nucleic acid amplification tests and point-of-care tests are newly available diagnostic methods that can be conducted on a variety of specimens, potentially allowing highly sensitive testing and screening of both women and men at risk for infection. Usually, trichomoniasis can be cured with single-dose therapy of an appropriate nitroimidazole antibiotic, but women who are also infected with HIV should receive therapy for 7 days. Antimicrobial resistance is an emerging concern. PMID- 26602625 TI - Outline of a bacterial filter-based assay to detect beta-lactamases. AB - We describe a new phenotypic test to detect beta-lactamases. This assay is based on diffusion of beta-lactam/beta-lactamase through a bacterial filter. Beta lactam hydrolysis on (the other side of) the filter leads to a change in antibiotic susceptibility, which can be measured by disc diffusion tests. We illustrate its ease of use to detect beta-lactamases of different classes. PMID- 26602626 TI - The Relationship Between Posttraumatic Stress Symptoms and Physical Health in a Survey of U.S. Veterans of the Iraq and Afghanistan Era. AB - BACKGROUND: Although a large body of literature has linked posttraumatic stress disorder (PTSD) with poor physical health among older veterans, less is known regarding the association between PTSD and health among relatively younger cohorts of veterans. OBJECTIVE: The current study examined the association between PTSD and self-reported health among a sample of veterans who served in the recent conflicts in Iraq and Afghanistan. METHOD: Veterans (N = 1030) who served in the wars in Iraq and Afghanistan completed measures of PTSD symptom severity and self-rated health between September 2009 and February 2010. Analyses examined the association between PTSD symptoms and health outcomes. RESULTS: In analyses adjusted for age, sex, race, and combat exposure, PTSD symptom severity was positively related to the number of health conditions and health symptoms reported (ps<0.001). Additionally, in analyses adjusted for age, sex, race, combat exposure, number of health conditions, and number of health symptoms, PTSD symptom severity was associated with an increased likelihood of rating one's health as poor or fair and an increased likelihood of reporting that one's physical health limits participation in activities (ps<0.001). CONCLUSION: These findings suggest that, consistent with previous research, PTSD symptom severity has a broad negative effect on physical health among veterans of the Iraq and Afghanistan era. Health promotion among veterans with PTSD may help attenuate risk of physical health consequences. PMID- 26602627 TI - Clozapine-Induced Myocarditis: Prevention and Considerations in Rechallenge. PMID- 26602628 TI - Importance of home study visit capacity in dementia studies. AB - INTRODUCTION: The importance of home research study visit capacity in Alzheimer's disease (AD) studies is unknown. METHODS: All evaluations are from the prospective Adult Changes in Thought study. Based on analyses of factors associated with volunteering for a new in-clinic initiative, we analyzed AD risk factors and the relevance of neuropathologic findings for dementia comparing all data including home visits, and in-clinic data only. We performed bootstrapping to determine whether differences were greater than expected by chance. RESULTS: Of the 1781 people enrolled during 1994-1996 with >=1 follow-up, 1369 (77%) had in-clinic data, covering 61% of follow-up time. In-clinic data resulted in excluding 76% of incident dementia and AD cases. AD risk factors and the relevance of neuropathologic findings for dementia were both different with in clinic data. DISCUSSION: Limiting data collection in AD studies to research clinics alone likely reduces power and also can lead to erroneous inferences. PMID- 26602631 TI - Nanomechanical characterization of nanostructured bainitic steel: Peak Force Microscopy and Nanoindentation with AFM. AB - The full understanding of the deformation mechanisms in nanostructured bainite requires the local characterization of its mechanical properties, which are expected to change from one phase, bainitic ferrite, to another, austenite. This study becomes a challenging process due to the bainitic nanostructured nature and high Young's modulus. In this work, we have carried out such study by means of the combination of AFM-based techniques, such as nanoindentation and Peak Force Quantitative Nanomechanical Mapping (PF-QNM) measurements. We have addressed critically the limits and advantages of these techniques and been able to measure some elastoplastic parameters of both phases. Specifically, we have analyzed by PF-QNM two nanostructured bainitic steels, with a finer and a coarser structure, and found that both phases have a similar Young's modulus. PMID- 26602629 TI - Influence of amyloid and APOE on cognitive performance in a late middle-aged cohort. AB - INTRODUCTION: Few studies have examined the effects of amyloid and apolipoprotein E (APOE) genotype on cognition among middle-aged individuals. METHODS: We included 464 cognitively normal, test-naive, participants with Pittsburgh compound B positron emission tomography amyloid imaging, mean age of 62.7 (range, 51-71 years), enrolled in the Mayo Clinic Study of Aging. Participants completed multiple cognitive assessments, including a standard neuropsychological battery and the CogState computerized battery, over 30 months of follow-up. Linear mixed models were used to examine the effects of amyloid and APOE genotype on baseline cognition and cognitive decline. RESULTS: Elevated amyloid was not associated with tests of episodic memory but did predict declines on tests of executive function. APOE genotype was not associated with cognition. Among APOE E4 noncarriers, higher amyloid was predictive of decline on tests of executive function and on one episodic memory test. DISCUSSION: Elevated amyloidosis and APOE genotype do not appear to exert a dramatic influence on cognition in middle age. PMID- 26602633 TI - Ab initio variational predictions for understanding highly congested spectra: rovibrational assignment of 108 new methane sub-bands in the icosad range (6280 7800 cm(-1)). AB - A detailed study of methane spectra in the highly congested icosad range of 6280 7800 cm(-1) has been performed using global variational calculations derived from accurate ab initio potential energy and dipole moment surfaces. About 13,000 (12)CH4 lines of the WKLMC line lists recorded at 80 and 296 K using very sensitive laser techniques (DAS, CRDS) have been rovibrationally assigned from first principles predictions. Overall, a total of 7436 upper energy levels were determined. Among the 20 bands and the 134 sub-levels contained in the icosad system, 20 and 108 have been identified for the first time, respectively. The assigned transitions represent 98% of the sum of the experimental intensity at 80 K. This work demonstrates for the first time how accurate first principles global calculations allow assigning complicated spectra of a molecule with more than 4 atoms. PMID- 26602630 TI - Benzodiazepine, psychotropic medication, and dementia: A population-based cohort study. AB - INTRODUCTION: Benzodiazepine use has been associated with increased risk of dementia. However, it remains unclear whether the risk relates to short or long half-life benzodiazepines and whether it extends to other psychotropic drugs. METHODS: Prospective cohort study among 8240 individuals >=65, interviewed on medication use. Incident dementia confirmed by an end point committee after a multistep procedure. RESULTS: During a mean of 8 years of follow-up, 830 incident dementia cases were observed. Users of benzodiazepines at baseline had a 10% increased risk of dementia (adjusted hazard ratio [HR], 1.10; 95% confidence interval, 0.90-1.34). However, long half-life (>20 hours) benzodiazepine users had a marked increased risk of dementia (HR = 1.62; 1.11-2.37) compared with short half-life users (HR = 1.05; 0.85-1.30). Users of psychotropics had an increased risk of dementia (HR = 1.47; 1.16-1.86). DISCUSSION: Results of this large, prospective study show increased risk of dementia for long half-life benzodiazepine and psychotropic use. PMID- 26602632 TI - Multistimuli-Regulated Photochemothermal Cancer Therapy Remotely Controlled via Fe5C2 Nanoparticles. AB - Stimuli-controlled drug delivery and release is of great significance in cancer therapy, making a stimuli-responsive drug carrier highly demanded. Herein, a multistimuli-controlled drug carrier was developed by coating bovine serum albumin on Fe5C2 nanoparticles (NPs). With a high loading of the anticancer drug doxorubicin, the nanoplatform provides a burst drug release when exposed to near infrared (NIR) light or acidic conditions. In vitro experiment demonstrated a NIR regulated cell inhibition that is ascribed from cellular uptake of the carrier and the combination of photothermal therapy and enhanced drug release. The carrier is also magnetic-field-responsive, which enables targeted drug delivery under the guidance of a magnetic field and monitors the theranostic effect by magnetic resonance imaging. In vivo synergistic effect demonstrates that the magnetic-driven accumulation of NPs can induce a complete tumor inhibition without appreciable side effects to the treated mice by NIR irradiation, due to the combined photochemotherapy. Our results highlight the great potential of Fe5C2 NPs as a remote-controlled platform for photochemothermal cancer therapy. PMID- 26602634 TI - We can be a global force for good health. PMID- 26602635 TI - Nurse's boots go on display as icon of the battle against Ebola. PMID- 26602636 TI - NHS staff urged to speak up about assault as acute care attacks rise. PMID- 26602637 TI - Tell the story of your achievements to support the RCN's fair pay campaign. PMID- 26602638 TI - Profession falls behind in pay rise comparison. PMID- 26602639 TI - Nurse of the year sets domestic abuse agenda. PMID- 26602640 TI - PHE seeks to boost numbers of 'antibiotic guardians' to 100,000. PMID- 26602643 TI - Graduates could face L 50,000 debts. PMID- 26602641 TI - Nurses can help prevent suicides. PMID- 26602644 TI - Scotland considers using Dutch-style home care. PMID- 26602645 TI - Welsh nurse rewarded for stroke service. PMID- 26602646 TI - Social media campaign exposes reliance on parents for skilled care. PMID- 26602647 TI - Under pressure--why the nurse director's job can feel so thankless. PMID- 26602653 TI - Smoking and pregnancy. PMID- 26602654 TI - An alliance for action on climate change. PMID- 26602655 TI - Get on your bike to boost sustainability. PMID- 26602656 TI - A strategy to put nurses in the driving seat. PMID- 26602668 TI - Yellow Alert app. PMID- 26602669 TI - Unsocial hours pay cuts have implications far into the future. PMID- 26602670 TI - Nursing services will suffer in short-sighted public health cut. PMID- 26602671 TI - Time for nurses to drop the victim mentality and realise our worth. PMID- 26602672 TI - The big unanswered questions surrounding revalidation. PMID- 26602675 TI - Study fund can help open eyes and minds to working abroad. PMID- 26602677 TI - How to examine an eye. PMID- 26602678 TI - Non-pharmacological approaches to alleviate distress in dementia care. AB - Distress is one of the most common clinical manifestations associated with dementia. Pharmacological intervention may be appropriate in managing distress in some people. However, best practice guidelines advocate non-pharmacological interventions as the preferred first-line treatment. The use of non pharmacological interventions encourages healthcare professionals to be more person-centred in their approach, while considering the causes of distress. This article provides healthcare professionals with an overview of some of the non pharmacological approaches that can assist in alleviating distress for people living with dementia including: reminiscence therapy, reality orientation, validation therapy, music therapy, horticultural therapy, doll therapy and pet therapy. It provides a summary of their use in clinical practice and links to the relevant literature. PMID- 26602679 TI - Managing a patient with COPD and comorbidities: a case study. AB - This case study provides a critical analysis of the management of a patient with long-term conditions in a community matron service. Particular attention is given to the effect of chronic obstructive pulmonary disease (COPD). The effect of COPD on health and wellbeing, quality of life and hospital admissions is examined, and outcomes are detailed that resulted from the implementation of evidence-based interventions and a case management approach. PMID- 26602680 TI - An overview of nuclear medicine imaging procedures. AB - Nuclear medicine imaging is not generally well understood by nurses who work outside this area. Consequently, nurses can find themselves unable to answer patients' questions about nuclear medicine imaging procedures or give them proper information before they attend for a test. This article aims to explain what is involved in some common diagnostic nuclear medicine imaging procedures so that nurses are able to discuss this with patients. It also addresses some common issues about radiation protection that nurses might encounter in their usual working routine. The article includes links to videos showing some typical nuclear medicine imaging procedures from a patient's point of view and links to an e-Learning for Healthcare online resource that provides detailed information for nurses. PMID- 26602681 TI - Rheumatoid arthritis. PMID- 26602682 TI - Try to keep a calm head. PMID- 26602685 TI - How to find a career path that suits you. PMID- 26602683 TI - Compassion takes commitment. PMID- 26602686 TI - Developmental progress and current status of the Animal QTLdb. AB - The Animal QTL Database (QTLdb; http://www.animalgenome.org/QTLdb) has undergone dramatic growth in recent years in terms of new data curated, data downloads and new functions and tools. We have focused our development efforts to cope with challenges arising from rapid growth of newly published data and end users' data demands, and to optimize data retrieval and analysis to facilitate users' research. Evidenced by the 27 releases in the past 11 years, the growth of the QTLdb has been phenomenal. Here we report our recent progress which is highlighted by addition of one new species, four new data types, four new user tools, a new API tool set, numerous new functions and capabilities added to the curator tool set, expansion of our data alliance partners and more than 20 other improvements. In this paper we present a summary of our progress to date and an outlook regarding future directions. PMID- 26602687 TI - Effects of cooperation between translating ribosome and RNA polymerase on termination efficiency of the Rho-independent terminator. AB - An experimental system was designed to measure in vivo termination efficiency (TE) of the Rho-independent terminator and position-function relations were quantified for the terminator tR2 in Escherichia coli The terminator function was almost completely repressed when tR2 was located several base pairs downstream from the gene, and TE gradually increased to maximum values with the increasing distance between the gene and terminator. This TE-distance relation reflected a stochastic coupling of the ribosome and RNA polymerase (RNAP). Terminators located in the first 100 bp of the coding region can function efficiently. However, functional repression was observed when the terminator was located in the latter part of the coding region, and the degree of repression was determined by transcriptional and translational dynamics. These results may help to elucidate mechanisms of Rho-independent termination and reveal genomic locations of terminators and functions of the sequence that precedes terminators. These observations may have important applications in synthetic biology. PMID- 26602688 TI - Systematic identification and correction of annotation errors in the genetic interaction map of Saccharomyces cerevisiae. AB - The yeast mutant collections are a fundamental tool in deciphering genomic organization and function. Over the last decade, they have been used for the systematic exploration of ~6 000 000 double gene mutants, identifying and cataloging genetic interactions among them. Here we studied the extent to which these data are prone to neighboring gene effects (NGEs), a phenomenon by which the deletion of a gene affects the expression of adjacent genes along the genome. Analyzing ~90,000 negative genetic interactions observed to date, we found that more than 10% of them are incorrectly annotated due to NGEs. We developed a novel algorithm, GINGER, to identify and correct erroneous interaction annotations. We validated the algorithm using a comparative analysis of interactions from Schizosaccharomyces pombe. We further showed that our predictions are significantly more concordant with diverse biological data compared to their mis annotated counterparts. Our work uncovered about 9500 new genetic interactions in yeast. PMID- 26602689 TI - Gbp2 interacts with THO/TREX through a novel type of RRM domain. AB - Metazoan SR and SR-like proteins are important regulatory factors in RNA splicing, export, translation and RNA decay. We determined the NMR structures and nucleic acid interaction modes of Gbp2 and Hrb1, two paralogous budding yeast proteins with similarities to mammalian SR proteins. Gbp2 RRM1 and RRM2 recognise preferentially RNAs containing the core motif GGUG. Sequence selectivity resides in a non-canonical interface in RRM2 that is highly related to the SRSF1 pseudoRRM. The atypical Gbp2/Hrb1 C-terminal RRM domains (RRM3) do not interact with RNA/DNA, likely because of their novel N-terminal extensions that block the canonical RNA binding interface. Instead, we discovered that RRM3 is crucial for interaction with the THO/TREX complex and identified key residues essential for this interaction. Moreover, Gbp2 interacts genetically with Tho2 as the double deletion shows a synthetic phenotype and preventing Gbp2 interaction with the THO/TREX complex partly supresses gene expression defect associated with inactivation of the latter complex. These findings provide structural and functional insights into the contribution of SR-like proteins in the post transcriptional control of gene expression. PMID- 26602690 TI - Aging Chart: a community resource for rapid exploratory pathway analysis of age related processes. AB - Aging research is a multi-disciplinary field encompassing knowledge from many areas of basic, applied and clinical research. Age-related processes occur on molecular, cellular, tissue, organ, system, organismal and even psychological levels, trigger the onset of multiple debilitating diseases and lead to a loss of function, and there is a need for a unified knowledge repository designed to track, analyze and visualize the cause and effect relationships and interactions between the many elements and processes on all levels. Aging Chart (http://agingchart.org/) is a new, community-curated collection of aging pathways and knowledge that provides a platform for rapid exploratory analysis. Building on an initial content base constructed by a team of experts from peer-reviewed literature, users can integrate new data into biological pathway diagrams for a visible, intuitive, top-down framework of aging processes that fosters knowledge building and collaboration. As the body of knowledge in aging research is rapidly increasing, an open visual encyclopedia of aging processes will be useful to both the new entrants and experts in the field. PMID- 26602691 TI - PSORTdb: expanding the bacteria and archaea protein subcellular localization database to better reflect diversity in cell envelope structures. AB - Protein subcellular localization (SCL) is important for understanding protein function, genome annotation, and has practical applications such as identification of potential vaccine components or diagnostic/drug targets. PSORTdb (http://db.psort.org) comprises manually curated SCLs for proteins which have been experimentally verified (ePSORTdb), as well as pre-computed SCL predictions for deduced proteomes from bacterial and archaeal complete genomes available from NCBI (cPSORTdb). We now report PSORTdb 3.0. It features improvements increasing user-friendliness, and further expands both ePSORTdb and cPSORTdb with a focus on improving protein SCL data in cases where it is most difficult-proteins associated with non-classical Gram-positive/Gram-negative/Gram variable cell envelopes. ePSORTdb data curation was expanded, including adding in additional cell envelope localizations, and incorporating markers for cPSORTdb to automatically computationally identify if new genomes to be analysed fall into certain atypical cell envelope categories (i.e. Deinococcus-Thermus, Thermotogae, Corynebacteriales/Corynebacterineae, including Mycobacteria). The number of predicted proteins in cPSORTdb has increased from 3,700,000 when PSORTdb 2.0 was released to over 13,000,000 currently. PSORTdb 3.0 will be of wider use to researchers studying a greater diversity of monoderm or diderm microbes, including medically, agriculturally and industrially important species that have non-classical outer membranes or other cell envelope features. PMID- 26602692 TI - AREsite2: an enhanced database for the comprehensive investigation of AU/GU/U rich elements. AB - AREsite2 represents an update for AREsite, an on-line resource for the investigation of AU-rich elements (ARE) in human and mouse mRNA 3'UTR sequences. The new updated and enhanced version allows detailed investigation of AU, GU and U-rich elements (ARE, GRE, URE) in the transcriptome of Homo sapiens, Mus musculus, Danio rerio, Caenorhabditis elegans and Drosophila melanogaster. It contains information on genomic location, genic context, RNA secondary structure context and conservation of annotated motifs. Improvements include annotation of motifs not only in 3'UTRs but in the whole gene body including introns, additional genomes, and locally stable secondary structures from genome wide scans. Furthermore, we include data from CLIP-Seq experiments in order to highlight motifs with validated protein interaction. Additionally, we provide a REST interface for experienced users to interact with the database in a semi automated manner. The database is publicly available at: http://rna.tbi.univie.ac.at/AREsite. PMID- 26602693 TI - TCGASpliceSeq a compendium of alternative mRNA splicing in cancer. AB - TCGA's RNASeq data represent one of the largest collections of cancer transcriptomes ever assembled. RNASeq technology, combined with computational tools like our SpliceSeq package, provides a comprehensive, detailed view of alternative mRNA splicing. Aberrant splicing patterns in cancers have been implicated in such processes as carcinogenesis, de-differentiation and metastasis. TCGA SpliceSeq (http://bioinformatics.mdanderson.org/TCGASpliceSeq) is a web-based resource that provides a quick, user-friendly, highly visual interface for exploring the alternative splicing patterns of TCGA tumors. Percent Spliced In (PSI) values for splice events on samples from 33 different tumor types, including available adjacent normal samples, have been loaded into TCGA SpliceSeq. Investigators can interrogate genes of interest, search for the genes that show the strongest variation between or among selected tumor types, or explore splicing pattern changes between tumor and adjacent normal samples. The interface presents intuitive graphical representations of splicing patterns, read counts and various statistical summaries, including percent spliced in. Splicing data can also be downloaded for inclusion in integrative analyses. TCGA SpliceSeq is freely available for academic, government or commercial use. PMID- 26602694 TI - APD3: the antimicrobial peptide database as a tool for research and education. AB - The antimicrobial peptide database (APD, http://aps.unmc.edu/AP/) is an original database initially online in 2003. The APD2 (2009 version) has been regularly updated and further expanded into the APD3. This database currently focuses on natural antimicrobial peptides (AMPs) with defined sequence and activity. It includes a total of 2619 AMPs with 261 bacteriocins from bacteria, 4 AMPs from archaea, 7 from protists, 13 from fungi, 321 from plants and 1972 animal host defense peptides. The APD3 contains 2169 antibacterial, 172 antiviral, 105 anti HIV, 959 antifungal, 80 antiparasitic and 185 anticancer peptides. Newly annotated are AMPs with antibiofilm, antimalarial, anti-protist, insecticidal, spermicidal, chemotactic, wound healing, antioxidant and protease inhibiting properties. We also describe other searchable annotations, including target pathogens, molecule-binding partners, post-translational modifications and animal models. Amino acid profiles or signatures of natural AMPs are important for peptide classification, prediction and design. Finally, we summarize various database applications in research and education. PMID- 26602695 TI - Cancer RNA-Seq Nexus: a database of phenotype-specific transcriptome profiling in cancer cells. AB - The genome-wide transcriptome profiling of cancerous and normal tissue samples can provide insights into the molecular mechanisms of cancer initiation and progression. RNA Sequencing (RNA-Seq) is a revolutionary tool that has been used extensively in cancer research. However, no existing RNA-Seq database provides all of the following features: (i) large-scale and comprehensive data archives and analyses, including coding-transcript profiling, long non-coding RNA (lncRNA) profiling and coexpression networks; (ii) phenotype-oriented data organization and searching and (iii) the visualization of expression profiles, differential expression and regulatory networks. We have constructed the first public database that meets these criteria, the Cancer RNA-Seq Nexus (CRN, http://syslab4.nchu.edu.tw/CRN). CRN has a user-friendly web interface designed to facilitate cancer research and personalized medicine. It is an open resource for intuitive data exploration, providing coding-transcript/lncRNA expression profiles to support researchers generating new hypotheses in cancer research and personalized medicine. PMID- 26602698 TI - Spotting and designing promiscuous ligands for drug discovery. AB - The promiscuous binding behavior of bioactive compounds forms a mechanistic basis for understanding polypharmacological drug action. We present the development and prospective application of a computational tool for identifying potential promiscuous drug-like ligands. In combination with computational target prediction methods, the approach provides a working concept for rationally designing such molecular structures. We could confirm the multi-target binding of a de novo generated compound in a proof-of-concept study relying on the new method. PMID- 26602696 TI - Signature motifs of GDP polyribonucleotidyltransferase, a non-segmented negative strand RNA viral mRNA capping enzyme, domain in the L protein are required for covalent enzyme-pRNA intermediate formation. AB - The unconventional mRNA capping enzyme (GDP polyribonucleotidyltransferase, PRNTase; block V) domain in RNA polymerase L proteins of non-segmented negative strand (NNS) RNA viruses (e.g. rabies, measles, Ebola) contains five collinear sequence elements, Rx(3)Wx(3-8)PhixGxzetax(P/A) (motif A; Phi, hydrophobic; zeta, hydrophilic), (Y/W)PhiGSxT (motif B), W (motif C), HR (motif D) and zetaxxPhix(F/Y)QxxPhi (motif E). We performed site-directed mutagenesis of the L protein of vesicular stomatitis virus (VSV, a prototypic NNS RNA virus) to examine participation of these motifs in mRNA capping. Similar to the catalytic residues in motif D, G1100 in motif A, T1157 in motif B, W1188 in motif C, and F1269 and Q1270 in motif E were found to be essential or important for the PRNTase activity in the step of the covalent L-pRNA intermediate formation, but not for the GTPase activity that generates GDP (pRNA acceptor). Cap defective mutations in these residues induced termination of mRNA synthesis at position +40 followed by aberrant stop-start transcription, and abolished virus gene expression in host cells. These results suggest that the conserved motifs constitute the active site of the PRNTase domain and the L-pRNA intermediate formation followed by the cap formation is essential for successful synthesis of full-length mRNAs. PMID- 26602697 TI - Genome-wide cooperation by HAT Gcn5, remodeler SWI/SNF, and chaperone Ydj1 in promoter nucleosome eviction and transcriptional activation. AB - Chaperones, nucleosome remodeling complexes, and histone acetyltransferases have been implicated in nucleosome disassembly at promoters of particular yeast genes, but whether these cofactors function ubiquitously, as well as the impact of nucleosome eviction on transcription genome-wide, is poorly understood. We used chromatin immunoprecipitation of histone H3 and RNA polymerase II (Pol II) in mutants lacking single or multiple cofactors to address these issues for about 200 genes belonging to the Gcn4 transcriptome, of which about 70 exhibit marked reductions in H3 promoter occupancy on induction by amino acid starvation. Examining four target genes in a panel of mutants indicated that SWI/SNF, Gcn5, the Hsp70 cochaperone Ydj1, and chromatin-associated factor Yta7 are required downstream from Gcn4 binding, whereas Asf1/Rtt109, Nap1, RSC, and H2AZ are dispensable for robust H3 eviction in otherwise wild-type cells. Using ChIP-seq to interrogate all 70 exemplar genes in single, double, and triple mutants implicated Gcn5, Snf2, and Ydj1 in H3 eviction at most, but not all, Gcn4 target promoters, with Gcn5 generally playing the greatest role and Ydj1 the least. Remarkably, these three cofactors cooperate similarly in H3 eviction at virtually all yeast promoters. Defective H3 eviction in cofactor mutants was coupled with reduced Pol II occupancies for the Gcn4 transcriptome and the most highly expressed uninduced genes, but the relative Pol II levels at most genes were unaffected or even elevated. These findings indicate that nucleosome eviction is crucial for robust transcription of highly expressed genes but that other steps in gene activation are more rate-limiting for most other yeast genes. PMID- 26602699 TI - Clinical observation on treatment of Tourette syndrome in Chinese children by clonidine adhesive patch. AB - OBJECTIVE: To evaluate the therapeutic effectiveness and safety of clonidine adhesive patch in treating Tourette syndrome (TS). METHODS: From July 2010 to July 2014,a total of 261 children, who met the Chinese Classification of Mental Disorders (third edition) diagnostic criteria for TS, aged 5-12 years, were referred to the department of Pediatrics, Shaanxi Provincial People's Hospital. The patients were divided randomly into a treatment group (clonidine adhesive patch, n = 128) and a control group (haloperidol, n = 116), 17cases dropped out. The clinical effectiveness was assessed by the Yale Global Tic Severity Scale (YGTSS) at the end of fourth week. The short-term effectiveness and adverse reaction to the treatment were assessed at the end of treatment. RESULTS: The YGTSS score in both groups decreased after 4 weeks of treatment, but the clonidine adhesive patch group showed a higher reduction in the overall tic symptom scores (40.05 +/- 3.44%) than that of the control group (17.88 +/- 4.40%; P < 0.05). In the clonidine adhesive patch group, the effectiveness was 81.3% (effective in 104 patients), while it was 66.4% in the control group (effective in 77 patients). The overall effectiveness rate showed no statistical significance between the two groups (p > 0.05). There were no severe adverse events in both groups, but mild side effects (decrease of blood pressure and dizziness) were observed in 3 patients in the clonidine adhesive patch group. 2 had mild cervical muscle tension and 4 had mild drowsiness and fatigue in the control group. CONCLUSION: In the treatment of TS in children and adolescents, the clonidine adhesive patch is superior to the standard treatment with haloperidol with a safer and better-tolerated profile. PMID- 26602700 TI - Case of an adult tubular sigmoid duplication with associated vascular and urological abnormality. PMID- 26602703 TI - Correction to Importance of Purity Evaluation and the Potential of Quantitative (1)H NMR as a Purity Assay. PMID- 26602701 TI - Longitudinal social cognitive influences on physical activity and sedentary time in Hispanic breast cancer survivors. AB - OBJECTIVE: This study evaluated the effect of two home-based exercise interventions (one culturally adapted and one standard) on changes in social cognitive theory (SCT) variables, physical activity (PA), and sedentary time (ST), and determined the association between changes in SCT variables and changes in PA and ST in Hispanic breast cancer survivors. METHOD: Project VIVA! was a 16 week randomized controlled pilot study to test the effectiveness and feasibility of a culturally adapted exercise intervention for Mexican American and Puerto Rican breast cancer survivors in Houston, Texas and San Juan, Puerto Rico, respectively. Women (N = 89) completed questionnaires on SCT variables, PA, and ST and were then randomized to a 16-week culturally adapted exercise program, a non-culturally adapted standard exercise intervention or a wait-list control group. Multiple regression models were used to determine associations between changes in SCT variables and changes in PA and ST. RESULTS: Participants were in their late 50s (58.5 +/- 9.2 years) and obese (31.0 +/- 6.5 kg/m2 ). Women reported doing roughly 34.5 min/day of PA and spending over 11 h/day in sedentary activities. Across groups, women reported significant increases in exercise self efficacy and moderate-intensity, vigorous-intensity, and total PA from baseline to follow-up (p < 0.05). Increased social support from family was associated with increases in vigorous-intensity PA. Increases in social modeling were associated with increases in moderate-intensity and total PA and with decreases in ST from baseline to follow-up (p < 0.05). CONCLUSIONS: Hispanic cancer survivors benefit from PA interventions that focus on increasing social support from family and friends and social modeling. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26602702 TI - Macrophage Exosomes Induce Placental Inflammatory Cytokines: A Novel Mode of Maternal-Placental Messaging. AB - During pregnancy, the placenta forms the interface between mother and fetus. Highly controlled regulation of trans-placental trafficking is therefore essential for the healthy development of the growing fetus. Extracellular vesicle mediated transfer of protein and nucleic acids from the human placenta into the maternal circulation is well documented; the possibility that this trafficking is bi-directional has not yet been explored but could affect placental function and impact on the fetus.We hypothesized that the ability of the placenta to respond to maternal inflammatory signals is mediated by the interaction of maternal immune cell exosomes with placental trophoblast. Utilizing the BeWo cell line and whole placental explants, we demonstrated that the human placenta internalizes macrophage-derived exosomes in a time- and dose-dependent manner. This uptake was via clathrin-dependent endocytosis. Furthermore, macrophage exosomes induced release of proinflammatory cytokines by the placenta. Taken together, our data demonstrates that exosomes are actively transported into the human placenta and that exosomes from activated immune cells modulate placental cytokine production. This represents a novel mechanism by which immune cells can signal to the placental unit, potentially facilitating responses to maternal inflammation and infection, and thereby preventing harm to the fetus. PMID- 26602705 TI - SCAI/SVM expert consensus statement on carotid stenting: Training and credentialing for carotid stenting. AB - Carotid artery stenting (CAS) has become an integral part of the therapeutic armamentarium offered by cardiovascular medicine programs for the prevention of stroke. The purpose of this expert consensus statement is to provide physician training and credentialing guidance to facilitate the safe and effective incorporation of CAS into clinical practice within these programs. Since publication of the 2005 Clinical Competence Statement on Carotid Stenting, there has been substantial device innovation, publication of numerous clinical trials and observational studies, accumulation of extensive real-world clinical experience and widespread participation in robust national quality improvement initiatives [5]. Collectively, these advances have led to substantial evolution in the selection of appropriate patients, as well as in the cognitive, technical and clinical skills required to perform safe and effective CAS. Herein, we summarize published guidelines, describe training pathways, outline elements of competency, offer strategies for tracking outcomes, specify facility, equipment and personnel requirements, and propose criteria for maintenance of CAS competency. PMID- 26602706 TI - Case of alopecia similar to alopecia areata multilocularis accompanied with neurofibromatosis type 1. PMID- 26602704 TI - The Synthesis, Characterization and Dehydrogenation of Sigma-Complexes of BN Cyclohexanes. AB - The coordination chemistry of the 1,2-BN-cyclohexanes 2,2-R2 -1,2-B,N-C4 H10 (R2 =HH, MeH, Me2 ) with Ir and Rh metal fragments has been studied. This led to the solution (NMR spectroscopy) and solid-state (X-ray diffraction) characterization of [Ir(PCy3 )2 (H)2 (eta(2) eta(2) -H2 BNR2 C4 H8 )][BAr(F) 4 ] (NR2 =NH2 , NMeH) and [Rh(iPr2 PCH2 CH2 CH2 PiPr2 )(eta(2) eta(2) -H2 BNR2 C4 H8 )][BAr(F) 4 ] (NR2 =NH2 , NMeH, NMe2 ). For NR2 =NH2 subsequent metal-promoted, dehydrocoupling shows the eventual formation of the cyclic tricyclic borazine [BNC4 H8 ]3 , via amino-borane and, tentatively characterized using DFT/GIAO chemical shift calculations, cycloborazane intermediates. For NR2 =NMeH the final product is the cyclic amino-borane HBNMeC4 H8 . The mechanism of dehydrogenation of 2,2-H,Me-1,2 B,N-C4 H10 using the {Rh(iPr2 PCH2 CH2 CH2 PiPr2 )}(+) catalyst has been probed. Catalytic experiments indicate the rapid formation of a dimeric species, [Rh2 (iPr2 PCH2 CH2 CH2 PiPr2 )2 H5 ][BAr(F) 4 ]. Using the initial rate method starting from this dimer, a first-order relationship to [amine-borane], but half order to [Rh] is established, which is suggested to be due to a rapid dimer monomer equilibrium operating. PMID- 26602707 TI - Adolescence and public health: the thin line between a protagonist approach and risk for youths. PMID- 26602708 TI - Perception of adolescents on healthy eating. AB - The objective in this article is to analyze how adolescents at a school in the interior of the State of Pernambuco, Brazil, perceive healthy eating. A descriptive and exploratory study was undertaken, based on the qualitative method. Forty adolescents between 10 and 14 years of age were investigated, using a semistructured interview. The interviews were analyzed using the software Alceste, which evidenced two thematic axes: Eating practices, divided in two classes (routine eating diary and Eating at weekends); and Education practices, consisting of four classes (Factors interfering in and facilitating the maintenance of healthy eating, Role of the school in the education process for healthy eating, Knowledge on healthy eating, The family and the promotion of healthy eating). Although the interviewed adolescents are familiar with healthy eating, they do not always put it in practice, due to the multiple factors that interfere in their preferred diet. The school and the family play a fundamental role in encouraging healthy eating. The school needs to accomplish eating education practices that encourage the consumption of locally produced foods. PMID- 26602709 TI - [Quality of the diet of 18-year-old adolescents belonging to the birth cohort of 1993 in Pelotas in the State of Rio Grande do Sul, Brazil]. AB - The scope of this article is to describe the quality of the diet of adolescents according to sociodemographic and behavioral factors. It involved a cross sectional study with 3,959 eighteen-year-old adolescents belonging to the birth cohort of 1993 in Pelotas in the State of Rio Grande do Sul, Brazil. Dietary intake was assessed using a semi quantitative Food Frequency Questionnaire with a recall period of 12 months. The diet quality was assessed using the Diet Quality Index Revised (DQI-R). This index ranges from 0 to 100 points and the higher the score, the better the diet quality. The overall DQI-R mean score was 62.4 points (DP). The lowest rates were observed for dark green and orange vegetables (3.0), total vegetables (3.4) and dairy products (3.6). Non-Caucasian adolescents (63.1), from families in which the heads of the household had less schooling (63.6) and belonging to the lowest quintile of the asset index (64.7) had higher average scores in the DQI-R. Lower averages were found among adolescents who smoked (58.5) and who consumed alcoholic beverages (56.0). This study showed that diet quality of the adolescents assessed deserve attention, especially with regard to the intake of vegetables, milk and dairy products. PMID- 26602710 TI - Nutritional status and body fat distribution in children and adolescentes with Cystic Fibrosis. AB - OBJECTIVE: assessing the nutritional status and body fat distribution in children and adolescents with cystic fibrosis. METHOD: Fifty-six (56) 8-18 year old patients were assessed for fat distribution by dual energy X-ray absorptiometry, for nutritional status by height/age, and for body mass index to age and dietary intake by 24-hour dietary recall. RESULTS: Approximately 50% of the sample showed adequate nutritional status. Most of it showed inadequate caloric and lipid intake. BMI/age was the nutritional indicator that best showed the increased percentage of trunk fat, android/gynecoidratio and trunk fat/total fat ratio. Patients with Pancreatic Insufficiency and eutrophic individuals showed higher median android/gynecoidratio. CONCLUSION: Increased abdominal adiposity was evidenced by DXA. The BMI did not identify decreased lean body mass. However, when body mass was high, it was significant for abdominal adiposity. The anthropometric assessment of patients with cystic fibrosis should be associated with body composition and body fat distribution to obtain an earlier malnutrition and cardiometabolic risk factor diagnosis. PMID- 26602711 TI - [Sociodemographic factors and body image among high school students]. AB - The scope of this article is to investigate associations between body image dissatisfaction and sociodemographic indicators among adolescents. Participants included 1126 high school students in the city of Santa Maria in the State of Rio Grande do Sul. Aspects regarding body image dissatisfaction and sociodemographic indicators were analyzed. Association analyses were performed using crude Poisson regression duly adjusted for sex and age. Boys were found to be dissatisfied due to slimness and girls due to excess weight. Adolescents where the parents had less schooling, as well as those from lower socioeconomic classes and with lower income were found to be more likely to have body image dissatisfaction due to slimness. However, those where the parents had completed higher education and those living in the downtown area were more likely to have body image dissatisfaction due to excess weight. Sociodemographic indicators are closely associated with body image dissatisfaction. Body image dissatisfaction due to slimness can be explained by the lower level of schooling of the parents, lower socioeconomic class and lower income. Dissatisfaction due to excess weight can be explained by the higher schooling of the parents and the fact of living in the downtown area. PMID- 26602712 TI - Perceived barriers to leisure-time physical activity and associated factors in adolescents. AB - The objective of this study was to identify the prevalence of perceived barriers to leisure-time physical activity in teenagers and to examine the possible association of these barriers with leisure-time physical inactivity. This cross sectional study was conducted in 2011 and a representative sample of 1,409 high school students from public schools in the city of Londrina/Parana was selected through multistage sampling. For data collection, the adolescents completed a questionnaire. The relationship between leisure-time physical inactivity (<300 minutes/week) and perceived barriers was analyzed by calculating the prevalence ratio (PR) in Poisson regression models. "Lack of friends company" was the most prevalent barrier for both girls (75.8%) and boys (58.7%). "Feel lazy" for girls (PR: 1.21; CI 95%: 1.08 to 1.36) and "prefer to do other things" for the boys (PR: 1.48; CI 95%: 1.01 to 2.15) were the barriers most strongly associated with leisure-time physical inactivity. For both genders, a strong dose-response relationship was observed between the number of perceived barriers and leisure time physical inactivity. The perception of barriers was associated with a higher prevalence of leisure-time physical inactivity in adolescents and should therefore be considered in actions for promoting physical activity in this population.The objective of this study was to identify the prevalence of perceived barriers to leisure-time physical activity in teenagers and to examine the possible association of these barriers with leisure-time physical inactivity. This cross-sectional study was conducted in 2011 and a representative sample of 1,409 high school students from public schools in the city of Londrina/Parana was selected through multistage sampling. For data collection, the adolescents completed a questionnaire. The relationship between leisure-time physical inactivity (<300 minutes/week) and perceived barriers was analyzed by calculating the prevalence ratio (PR) in Poisson regression models. "Lack of friends company" was the most prevalent barrier for both girls (75.8%) and boys (58.7%). "Feel lazy" for girls (PR: 1.21; CI 95%: 1.08 to 1.36) and "prefer to do other things" for the boys (PR: 1.48; CI 95%: 1.01 to 2.15) were the barriers most strongly associated with leisure-time physical inactivity. For both genders, a strong dose response relationship was observed between the number of perceived barriers and leisure-time physical inactivity. The perception of barriers was associated with a higher prevalence of leisure-time physical inactivity in adolescents and should therefore be considered in actions for promoting physical activity in this population. PMID- 26602713 TI - [Tooth decay and associated factors among adolescents in the north of the State of Minas Gerais, Brazil: a hierarchical analysis]. AB - This is a cross-sectional population-based study (n = 763) conducted in the north of the State of Minas Gerais, which aimed to investigate the prevalence of tooth decay among adolescents and to identify the potential determinants of same. Probability sampling by conglomerates in multiple stages was used. Trained and calibrated professionals performed the data collection by means of intraoral examination and interviews in the previously selected households. In the analysis of the determinant factor for the presence of tooth decay, hierarchical binary logistic regression models were used. The prevalence of tooth decay, decayed, missing and filled teeth were 71.3%, 36.5%, 55.6% and 16%, respectively. The following averages were observed: DMFT (3.4 teeth), number of decayed (0.8 teeth), restored (2.4 teeth) and missing (0.2 teeth). The incidence of tooth decay was higher among adolescents who stated they were black/indigenous/brown (OR = 1.76), lived in crowded households (OR = 2.4), did not regularly visit or had never been to a dentist (OR = 1.9), used public or philanthropic services (OR = 1,8), had smoking habits (OR = 4.1), consumed alcohol (OR = 1.8), perceived their oral health negatively (OR = 5.9 and OR = 1.9) and had toothac in the last six months (OR = 2.0). PMID- 26602714 TI - Oral health and quality of life: an epidemiological survey of adolescents from settlement in Pontal do Paranapanema/SP, Brazil. AB - This study aimed to verify oral health, treatment needs, dental service accessibility, and impact of oral health on quality of life (QL) of subjects from settlement in Pontal do Paranapanema/SP, Brazil. In this epidemiological survey, 180 10-to 19- years old adolescents enrolled in the school that attend this population in settlement underwent oral examination, to verify caries index (DMFT decayed, missing and filled teeth) and periodontal condition (CPI), and were interviewed using the World Health Organization Quality of Life (WHOQOL-Bref) and Oral Impact Daily Performance (OIDP) instruments to evaluate QL, and the Global School-Based Health Survey (GSHS) about dental service accessibility. DMFT average was 5.49 (+/- 3.33). Overall, 37.2% of participants showed periodontal problems, mainly CPI = 1 (77.7%). Treatment needs were mainly restorations. GSHS showed that the last dental consultation occurred > 1 year previously for 58.3% of participants at a public health center (78.9%). The average WHOQOL-Bref was 87.59 (+/- 15.23). Social relationships were related to dental caries and health service type. The average OIDP was 6.49 (+/- 9.15). The prevalence of caries was high and observed periodontal problems were reversible. The social relationships of adolescents from settlement were influenced by caries and health services type. PMID- 26602715 TI - [The relationship between gingival condition and socio-demographic factors of adolescents living in a Brazilian region]. AB - The scope of this study is to correlate the gingival condition and sociodemographic status of adolescents living in an economically disadvantaged Brazilian region. The survey was conducted with a random sample of 450 adolescents in 13 cities selected in the Jequitinhonha Valley (State of Minas Gerais). The gingival condition was evaluated using a calibrated examiner (Kappa >= 0.85). The oral exam was based on the Community Periodontal Index (CPI). The frequencies of individuals were calculated and sextants subsequently assessed using Multiple Correspondence Analysis (ANACOR) to reveal the relationship between CPI and sociodemographic characteristics. The results showed that: 16 (3.6%) were healthy; 235 (52.2%) had gingival bleeding; 36 (8%) had dental calculus and 163 (36.2%) had both bleeding and calculus. ANACOR identified two groups with similarities in relation to periodontal disease. Group one featured 19-year-olds with healthy CPI who work and have higher family income. Group two included 15- and 16-year-olds of both sexes with CPI and gingival bleeding in elementary school with lower family income, who declared themselves to be of mixed or Afro-descendant race. The presence of gingivitis was related to the socioeconomic and demographic characteristics of adolescents in the region. PMID- 26602716 TI - Bruxism and quality of life in schoolchildren aged 11 to 14. AB - The purpose of this study is to assess quality of life in relation to oral health in schoolchildren with sleep bruxism. It is a transversal observational study of 594 schoolchildren (aged 11-14) of the municipality of Teresina, in the Brazilian State of Piaui. Quality of life was assessed through the Brazilian version of the CPQ11-14 questionnaire, in the short form (ISF:16).The presence of sleep bruxism was assessed from reports by the people legally responsible for the children. The results were analyzed by: calculation of an Odds Ratio (OR) estimate of chances; descriptive analysis; a Pearson Chi-squared test; a Likelihood Ratio test; and multiple logistic regression. A statistically significant association was found between sleep bruxism and the total score on the CPQ11-14 (p < 0.001), and with the scores in two domains: functional limitation (p = 0.033);and social wellbeing (p= 0.020).No association was found between quality of life and the variables gender or age. The final regression model showed that the presence of sleep bruxism increases the chance of having a greater effect on quality of life (ORadj=1.82 (1.54 - 2.10), IC = 95%).It is concluded that sleep bruxism had a negative impact on the quality of life of the schoolchildren, principally in the two domains functional limitations and changes in social wellbeing. PMID- 26602717 TI - Violence and youth in a territory of the Metropolitan Area of Brasilia, Brazil: a socio-spatial approach. AB - Young people are impacted by the relations established in the context of multidimensional violence distributed in private and public spaces of urban areas. This article presents stories of violence suffered and committed by young individuals who live in Itapoa, part of the Metropolitan Area of Brasilia. This is a transversal and descriptive study, using a quantitative approach and a convenience sample of 190 young men and women aged 15 to 24 years. Forty-four questions previously validated were used as the data collection instrument. As for the experiences of violence, 51% reported having experienced some sort throughout life, and 24% in the last 12 months. Young people who have experienced some episode of violence throughout life also declared that the area or neighborhood where they live does not promote urban well-being for its residents (p <0.023); they expressed feelings compatible with depression (p = 001); and self-reported their health condition as bad (p = 000). The experiences of violence and youth vulnerabilities processes were discussed in the context of social injustice and limitations of human capabilities. PMID- 26602718 TI - Training for the challenges of sexual violence against children and adolescents in four Brazilian capitals. AB - This article analyzes the training offered to municipal public employees to confront sexual violence against children and adolescents in four Brazilian capitals. Based on a multiple case study, it focuses on the training programs offered in the 2010-2011 biennium by the municipal government for professionals and managers in the public health network. We analyzed 66 semi-structured interviews and written documents pertaining to the training actions. We observed an unequal investment among the capitals and a lack of specificity in the treatment of the themes. There is a considerable lack of institutional memory which complicates the analysis of professional training strategies. Healthcare was the field which trained their professionals the most, including the subject of notification in training content. We noted little investment in training oriented toward the prevention of violence and the promotion of protective relationships and links. We emphasized the inductive role of federal and state programs in the areas of Tourism and Education. Few initiatives included the participation of more than one public sector. We suggest the creation of a training plan about violence and the sexual rights of children and adolescents, and in particular about sexual violence. PMID- 26602719 TI - Cross-cultural adaptation of the Parcours Amoureux des Jeunes - PAJ inventory of Canadian origin to the Brazilian context. AB - Analyzing violent events in the amorous trajectory of young people mobilizes researchers worldwide. The scope of this study is to perform the cross-cultural adaptation and content validation of the Canadian Parcours Amoureux des Jeunes (PAJ) inventory in the Brazilian context. It is a methodological study with the following steps: (a) translation and back-translation; (b) committee of experts (10) for analysis of equivalence, clarity and matching percentages; (c) calculation of the Content Validity Index / CVI. This analysis generated Pilot version III (d) submitted to a pre-test group of 36 adolescents aged 14 to 24 of both sexes to obtain cultural, conceptual, semantic and idiomatic equivalence. The PAJ showed adequate content validity (CVI 0.97). In section 1 (sociodemographic aspects of youths and families inherent to the Canadian context), the questions were appropriate to the Brazilian context shown by the low value of the CVI. Cross-cultural adaptation and content validation processes showed that the PAJ had adequate clarity and equivalence properties. This step makes it viable to conduct psychometric analysis to assess the replicability and reliability of the instrument to be applied in the Brazilian context. PMID- 26602720 TI - [Binge drinking among 12-year-old adolescent schoolchildren and its association with sex, socioeconomic factors and alcohol consumption by best friends and family members]. AB - This is a cross-sectional study with a convenience sample of 101 twelve-year-old adolescents enrolled in public and private schools in the city of Diamantina in the State of Minas Gerais. The scope was to evaluate the prevalence of binge drinking among 12-year-old schoolchildren and its association with gender, socioeconomic status and alcohol consumption by family members and best friends. The participants completed a self-administered questionnaire entitled the Alcohol Use Disorders Identification Test (AUDIT-C) and the consumption of alcoholic beverages by friends and family. Parents/guardians answered the form on sociodemographic questions. Descriptive analyses and association tests were performed (p < 0.05). The prevalence of binge drinking was 24.8%. Alcoholic beverage consumption began at the age of 10 (16.8%), though sex was not associated with binge drinking by adolescents. However, attending a public school (0.005) and alcohol consumption by best friends (p < 000.1) were associated with binge drinking by adolescents in the bivariate analysis. The prevalence of binge drinking was high and was associated with low socioeconomic status and alcohol consumption by the best friend. No association between sex and alcohol consumption by the family members of adolescents was detected. PMID- 26602721 TI - Suicidal-related behaviors and quality of life according to gender in adolescent Mexican high school students. AB - The study of pre-suicidal behaviors is important not only because of their association with suicide but also because of their impact on quality of life (QOL). Given the scarcity of information regarding this relationship in adolescence, the objective of this study was to analyze the association between suicidal-related behavior and QOL according to gender in adolescent Mexican high school students. This cross-sectional study was conducted with participants between 14 and 18 years of age. A translated version of the Youth Risk Behavior Survey and the Spanish version of the Youth Quality of Life Research - Instrument version were used. Non-parametric tests were applied. Informed consent was obtained from parents and students, and ethical committee approval was sought. The developmental-transactional model of suicidal behavior in adolescents by Bridge et al. was used. Separate analyses were conducted for males and females to show the suicidal-related behaviors associated with QOL. The behavior of having felt sad or hopeless generally presented the greatest effect sizes. The regression models showed that some suicidal-related behaviors increase the probability of a lower QOL even after adjusting for covariates. PMID- 26602722 TI - The (non)space of the young man in health policies regarding drugs in Brazil: genealogical approaches. AB - The study seeks to problematize the negotiations and conditions of possibility for the inclusion or exclusion of young men in the process of health policy formulation regarding drugs in Brazil. Situated in the field of gender studies and proposing to discuss the relationship between masculinities and the use of drugs from an intersectional perspective, the framework considers that: the increased vulnerability of young males to problems with drug use and the difficulties in access and/or links to services also need to be understood in light of the literature about gender and health; and that the form in which debates about gender are manifested in health policies - whether in official documents, or in the understanding of persons linked to the elaboration and/or implementation of such policy- directly or indirectly influence the way in which these men are recognized by, access, and are accepted by the services of the Unified Health System (SUS). Drawing upon three episodic and semi-structured interviews with managers who participated in the elaboration of health policy about drugs at the municipal, state, and federal levels, and through the study of the documents cited during the interviews, we develop a genealogical text that seeks to retell the history of drug policy in Brazil, guided by the events emphasized by the interlocutors. PMID- 26602723 TI - An association between the internalization of body image, depressive symptoms and restrictive eating habits among young males. AB - The scope of this study was to analyze the relationship between the internalization of body image and depressive symptoms with restrictive eating habits among young males. Three hundred and eighty-three male adolescents, aged between twelve and seventeen, took part in this survey. The "Overall Internalization" and "Athletic Internalization" sub-scales taken from the Sociocultural Attitudes Towards Appearance Questionnaire-3 (SATAQ-3) were used to evaluate the internalization of body images. The Major Depression Inventory (MDI) was used to evaluate depressive symptoms. The "Diet" sub-scale from the Eating Attitudes Test (EAT-26) was used to evaluate restrictive eating habits. The logistic regression findings indicated 2.01 times greater chances of youngsters with a high level of overall internalization adopting restrictive eating habits (Wald = 6.16; p = 0.01) when compared with those with low levels. On the other hand, the regression model found no significant association between "Athletic Internalization" (Wald = 1.16; p = 0.23) and depressive symptoms (Wald = 0.81; p = 0.35) with eating restrictions. The findings made it possible to conclude that only overall internalization was related to eating restrictions among young males. PMID- 26602724 TI - Experiences reported by the workers of Psychosocial Care Center for Children and Adolescents in Sao Paulo City - Brazil. AB - The objective of this paper was to describe and analyze the context of trajectories of workers of Psychosocial Care Centers for Children and Adolescents (CAPSis) with the insertion, practice and motivation of workers in this fieldwork. Comparing the context of trajectories of employees according to the managerial nature: Social Health Organization (OSS) and city hall. Narratives interviews were conducted with 8 workers from 2 Psychosocial Care Centers for Children and Adolescents (one managed by the City and other by Social Health Organizations), Sao Paulo City, Brazil. The narratives interviews were transcribed and analyzed from Shutze method. The Theoretical Framework was built from different authors and Psychiatric Reform principles. There are important differences between workers of 2 Psychosocial Care Centers for Children and Adolescents regarding professional profile, motivations, type of training and meanings attributed to work. The current trend in the field goes in opposite direction to the proposals of the Psychiatric Reform, lack of opportunities for discussion and empowerment work team of labor, which should be offered by institutions, makes both groups of professionals feel lost and alone. PMID- 26602725 TI - Prevalence of headache in adolescents and association with use of computer and videogames. AB - The aim of this study was to determine the prevalence of headache in adolescents and its association with excessive use of electronic devices and games. The sample comprised 954 adolescents of both sexes (14 to 19 years) who answered a questionnaire about use of computers and electronic games, presence of headache and physical activity. The binary and multinomial logistic regression, with significance level of 5% was used for inferential analysis. The prevalence of headache was 80.6%. The excessive use of electronics devices proved to be a risk factor (OR = 1.21) for headache. Subjects aged between 14 and 16 years were less likely to report headache (OR = 0.64). Regarding classification, 17.9% of adolescents had tension-type headache, 19.3% had migraine and 43.4% other types of headache. The adolescents aged form 14 to 16 years had lower chance (OR <= 0.68) to report the tension-type headache and other types of headache. The excessive use of digital equipment, electronic games and attending the third year of high school proved to be risk factors for migraine-type development (OR >= 1.84). There was a high prevalence of headache in adolescents and high-time use of electronic devices. We observed an association between excessive use of electronic devices and the presence of headache, and this habit is considered a risk factor, especially for the development of migraine-type. PMID- 26602726 TI - Fatherhood in adolescence: prevalence and associated factors in a community sample of youngsters. AB - This article aims to assess the prevalence of fatherhood in adolescence (FA) and associated factors in a community sample of 14 to 35 year-old men. Cross sectional population-based study realized in the urban area of the city of Pelotas-RS, Brazil. The sample was selected by clusters, according to the city census. This sub-study only comprised sexually active men. Data were collected using a self-administered questionnaire in the participants' homes. The sample was composed for 934 men. The prevalence of fatherhood in adolescence was 8% (n = 75). We verified higher prevalence of FA among those that reported paternal absence (p < 0.001), those that had lived with stepfather (p = 0.044), and among those that had sexual debut before the age of 14 (p = 0.011). Paternal absence, have lived with a stepfather, and early sexual experience are associated factors to fatherhood in adolescence. PMID- 26602727 TI - Social skills: a factor of protection against eating disorders in adolescentes. AB - The purpose of this study is to provide a review of the literature on the relationship between eating disorders and social skills in adolescents. A search was made on the Medline, SciELO and Lilacs databases, for items combining the terms 'eating disorders', 'anorexia nervosa', 'bulimia nervosa' and 'food behavior', with the terms 'social psychology' and 'social isolation', and with the keywords 'social competence', 'social skill' and 'interpersonal relations'. The following were included: studies on adolescents; in Portuguese, English and Spanish; published in the years 2007 through 2012. The search resulted in 63 articles, and 50 were included in this review. The majority of the studies were made in Brazil and the United States. Of the total, 43 were original articles. The studies aimed to understand how emotional state could influence the establishment of eating disorders, interpersonal relationships and peer relationship. The articles also discussed the influence of the media and of society in this process. Based on the analysis of the studies, it was observed that the greater an adolescent's repertory of social skills, the greater his or her factor of protection against the development of eating disorders. PMID- 26602728 TI - Bullying during adolescence in Brazil: an overview. AB - Bullying has been the subject of worldwide study for over four decades and is widely reported by social media. Despite this, the issue is a relatively new area of research in Brazil. This study analyzes academic literature addressing bullying produced in Brazil focusing on aspects that characterize this issue as a subtype of violence: gender differences, factors associated with bullying, consequences, and possible intervention and prevention approaches. The guiding question of this study was: what have Brazilian researchers produced regarding bullying among adolescents? The results show that over half of the studies used quantitative approaches, principally cross-sectional methods and questionnaires, and focused on determining the prevalence of and factors associated with bullying. The findings showed a high prevalence of bullying among Brazilian adolescents, an association between risk behavior and bullying, serious consequences for the mental health of young people, lack of awareness and understanding among adolescents about bullying and its consequences, and a lack of strategies to manage this type of aggression. There is a need for intervention studies, prevention and restorative practices that involve the community and can be applied to everyday life at school. PMID- 26602729 TI - Violence against women: systematic review of the Brazilian scientific literature within the period from 2009 to 2013. AB - Violence against women is a worldwide issue, and the number of publications addressing it tends to increase, due to its magnitude. This article analyzes the scientific literature on the issue, within the period from 2009 to 2013. This is a systematic review of articles indexed in the Virtual Health Library (VHL). It included studies freely available online and published in Brazil, in full text, in Portuguese. It excluded articles without a scientific standard, those published abroad, and government information. The studies were assessed regarding methodological aspects and those related to violence, and data underwent statistical analysis in the softwares SPSS and Excel. Most of the 148 texts were qualitative, published in 2011, by up to 3 authors, and the victims were individuals mainly assessed through Content Analysis. The violence types identified were physical, sexual, and psychological, with overlapping forms related to mental and physical consequences. The findings converge with the current trend to address violence in a qualitative way, in order to provide an in depth analysis of the victims' experiences. It is expected that this study contributes to raising awareness as for the need to approach the issue, with a view to promote women's health. PMID- 26602730 TI - [Research trends in public policy: an assessmentof the National School Food Program (PNAE)]. AB - The scope of the article is to evaluate the research trends of the Brazilian School Food Program (PNAE), by analyzing the papers published in journals on the Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES) website in the period from 2008 to 2013. It involved bibliographical research by means of qualitative analysis to detect the most relevant issues addressed and discussed by the program. Ten scientific articles related to the area were selected after reading the abstracts and research topics of the articles and by a search for the following key words: public policy, family farming, school food. Studies related to the PNAE and its impacts were also considered, due to the connection with the activities carried out in Brazilian public policy. The paper presents the issues analyzed and discussed most on the subject during the period under consideration. The conclusion reached is that the main research trends are characterized by the study of strategies for food and nutrition safety, analyzing the composition and acceptance of foods offered to students by an analysis of production, better living conditions and local development of rural producers. PMID- 26602731 TI - Mais Medicos Program: an effective action to reduce health inequities in Brazil. AB - The Program More Doctors (Programa Mais Medicos) aims to decrease the shortage of physicians and reduce the regional health disparities and involves three main strategies: i) more places and new Medical Courses based on the revised Curriculum Guidelines; ii) investments in the (re)construction of Primary Healthcare Units; iii) provision of Brazilian and foreign medical doctors. Until July 2014, the Program made the provision of 14,462 physicians to 3,785 municipalities with vulnerable areas. Evidence indicates a 53% reduction in the number of municipalities with physicians' shortage; in the North, 91% of the municipalities with physicians' shortage have been provisioned, with almost five physicians per municipality, on average. The professionals' integration in the Family Health Teams has strengthened and expanded the capacity of intervention, particularly in the context of adopting a healthcare model that encompasses different demands of health promotion, prevention, diagnosis and treatment of diseases and disorders, to face the challenge of the double burden of disease. The population is affected by obesity and non-communicable chronic diseases, alongside with infection, parasitic diseases and malnutrition remaining. The people of cities, rural areas and forests want more doctors, health perspectives and more social justice. PMID- 26602732 TI - Giovanni Berlinguer: socialist, sanitarian, and humanist! AB - This article highlights important aspects of the biography of Giovanni Berlinguer that led him to become a prominent scientist and political activist. His works were marked by a strong socialist conviction and deep humanism. His contribution to health in Brazil ranged from a vast academic output in the field of public health to an active involvement in the Brazilian Health Movement. His later publications addressing everyday bioethics reveal the common thread that runs through his entire works: the use of science to demonstrate the social determinants of health; the fight against unjust inequality; the defense of life against exploitation; and the struggle to prevent the commoditization of life, the human body, and health care. PMID- 26602733 TI - Walking and health care expenditures among adult users of the Brazilian public healthcare system: retrospective cross-sectional study. AB - Physical inactivity is a major public health challenge due to its association with chronic diseases and the resulting economic impact on the public healthcare system. However, walking can help alleviate these problems. Aim To verify associations between walking during leisure-time, risk factors and health care expenditure among users of the Brazilian public health care system. Methods The sample consisted of 963 adults. Walking was evaluated using the Baecke questionnaire. The total expenditure per year was evaluated through the demand for health care services, verified in the medical records of each participant. Results Walking was reported as a physical activity during leisure-time by 64.4% of the participants. The group with the highest engagement in walking was younger and presented lower values for BMI, WC and expenditure on medication. Participants inserted in the category of higher involvement in walking were 41% less likely to be inserted into the group with higher total expenditure (OR = 0:59; 95% CI 0.39-0.89). Conclusion It was found that walking was the most frequent leisure-time physical activity reported by users of the Brazilian health care system and was associated with lower total and medication expenditure. PMID- 26602734 TI - [Between evidence and negligence: coverage and invisibilityof health topics in the Portuguese printed media]. AB - The scope of this study is to conduct an assessment of the media coverage and dissemination of health issues in Portugal in order to problematize the aspects of coverage and invisibility of health topics and establish the themes neglected in media coverage. To achieve this, the coverage on health issues in the Portuguese daily newspaper Publico was compared with the epidemiological context regarding health priorities and the perceptions of key players on media dissemination and the themes that are relevant to the Portuguese population. The results showed that the recurrent health-associated themes do not deal with diseases per se, but with the politics and economics of health and medication. The themes neglected in media coverage identified in the Portuguese context include: communicable diseases, such as hepatitis and tuberculosis; issues related to mental health and suicide; and ailments and social consequences associated with the economic crisis that has beset Portugal recently. From the standpoint of the people interviewed, other neglected diseases include hemochromatosis and other rare diseases. In tandem with this, the study highlights the well covered media themes that revolve around the lives and activities of celebrities, which are exhaustively aired in the communication media in the country. PMID- 26602735 TI - Work Process in Primary Health Care: action research with Community Health Workers. AB - The aim of this article was to describe and analyze the work of community health workers (CHW). The main objective of study was to analyze the development process of primary health care practices related to drug consumption. The study is based on the Marxist theoretical orientation and the action research methodology, which resulted in the performance of 15 emancipatory workshops. The category work process spawned the content analysis. It exposed the social abandonment of the environment in which the CHWs work is performed. The latter had an essential impact on the identification of the causes of drug-related problems. These findings made it possible to criticize the reiterative, stressful actions that are being undertaken there. Such an act resulted in raising of the awareness and creating the means for political action. The CHWs motivated themselves to recognize the object of the work process in primary health care, which they found to be the disease or addiction in the case of drug users. They have criticized this categorization as well as discussed the social division of work and the work itself whilst recognizing themselves as mere instruments in the work process. The latter has inspired the CHW to become subjects, or co-producers of transformations of social needs. PMID- 26602736 TI - Fatherhood and parenting as health issues facing the rearrangements of gender. AB - In this theoretical essay we aim to discuss paternity as a health issue in the context of contemporary gender roles by considering two lines of argument: (a) paternity, parenting and rearrangements of gender roles; and (b) paternity and parenting as a mutual relationship based on care. In our discussion, we highlight the inclusion of men in the health system from the point of view of paternity. At present this appears to be operating in an instrumental manner, with the mother infant dyad still a major concern and men not being viewed as individuals with rights to health. Thus, we seek to question the system itself, in relation to its perceptions of the current state of paternity, by taking into consideration recent discussions about gender and sexuality as well as and new family arrangements that may challenge beliefs about the roles of families, fathers and mothers, which have impacts on care. Among other aspects, we conclude that we need to reinvent ourselves because we were not raised under the aegis of diversity and we were also not trained as professionals with a basis in the current problematic divisions that exist between father/mother and sex/gender, among many other previous certainties, all of which does not always help us to promote actions in the area of health. PMID- 26602737 TI - [Bioequivalence of dermatological topical medicines:the Brazilian scenario and the challenges for health surveillance]. AB - The comparative evaluation required for the registration of generic topical medicines in Brazil is conducted by means of a pharmaceutical equivalence study, which merely assesses the physical/chemical and microbiological parameters of the formulations. At the international level, clinical or pharmacodynamic studies are now being required to prove the efficacy and safety of semisolid topical generic formulations. This work presents a comparison of the different requirements for the registration of topical formulations, taking into consideration the various regulatory authorities, and presents a survey of topical medicines registered in Brazil prior to 2013. The survey revealed that in comparison with the USA there were many more copies of these formulations registered in Brazil. This fact, together with the large number of studies in the literature showing the lack of bioequivalence of topical medication, is clear proof of the major importance of the need to realign Brazilian legislation with respect to the technical requirements for the registration of generic and similar medication for dermatological topical application in Brazil. PMID- 26602739 TI - Establishing a community-wide DNA barcode library as a new tool for arctic research. AB - DNA sequences offer powerful tools for describing the members and interactions of natural communities. In this study, we establish the to-date most comprehensive library of DNA barcodes for a terrestrial site, including all known macroscopic animals and vascular plants of an intensively studied area of the High Arctic, the Zackenberg Valley in Northeast Greenland. To demonstrate its utility, we apply the library to identify nearly 20 000 arthropod individuals from two Malaise traps, each operated for two summers. Drawing on this material, we estimate the coverage of previous morphology-based species inventories, derive a snapshot of faunal turnover in space and time and describe the abundance and phenology of species in the rapidly changing arctic environment. Overall, 403 terrestrial animal and 160 vascular plant species were recorded by morphology based techniques. DNA barcodes (CO1) offered high resolution in discriminating among the local animal taxa, with 92% of morphologically distinguishable taxa assigned to unique Barcode Index Numbers (BINs) and 93% to monophyletic clusters. For vascular plants, resolution was lower, with 54% of species forming monophyletic clusters based on barcode regions rbcLa and ITS2. Malaise catches revealed 122 BINs not detected by previous sampling and DNA barcoding. The insect community was dominated by a few highly abundant taxa. Even closely related taxa differed in phenology, emphasizing the need for species-level resolution when describing ongoing shifts in arctic communities and ecosystems. The DNA barcode library now established for Zackenberg offers new scope for such explorations, and for the detailed dissection of interspecific interactions throughout the community. PMID- 26602741 TI - Long-term donor-site morbidity after vascularized free fibula flap harvesting: Clinical and gait analysis. AB - The aim of this study was to determine the clinical morbidity and changes in gait temporal spatial parameters after harvesting of a vascularized free fibula flap. This study included 11 patients (mean age: 52 +/- 17 years) and 11 healthy controls (mean age: 50 +/- 14 years). The patients were assessed between 5 and 104 months post surgery. The study consisted of a subjective functional evaluation with two validated clinical scores (Kitaoka Score and Point Evaluation System (PES) score), clinical and neurological examination of the legs, and evaluation of gait temporal spatial parameters while walking at a comfortable speed. The mean functional Kitaoka score was 78/100, and the mean PES score of 12.18 was considered average. At the time of the review, five patients had sensory disorders, two had toe deformities, and eight had pain at the donor site. The gait analysis showed that the patient's comfortable walking speed was significantly lower in comparison to that of the controls, and that stride length and cadence were reduced. In addition, most of the gait-specific parameters were significantly different. The donor leg displayed greater variability during walking. To reduce the risk of falling, this study revealed that the patients' gait pattern had changed as they took a more cautious approach during walking. Early rehabilitation is expected to help improve and/or restore the physical abilities of patients after harvesting of the vascularized free fibula flap. PMID- 26602740 TI - Pre-clinical heterotopic intrathoracic heart xenotransplantation: a possibly useful clinical technique. AB - BACKGROUND: As a step towards clinical cardiac xenotransplantation, our experimental heterotopic intrathoracic xenotransplantation model offers a beating and ejecting donor heart while retaining the recipient's native organ as a backup in case of graft failure. Clinically applicable immunosuppressive regimens (IS) were investigated first, then treatments known to be effective in hypersensitized patients or those with recalcitrant rejection reactions. METHODS: Consecutive experiments were carried out between 2009 and 2013. Twenty-one genetically modified pigs (GGTA1-knockout/hCD46/+/- thrombomodulin, in one case HLA-E instead) were used as donors. In all experiments, two cycles of immunoabsorption reduced preformed antibodies. Recipient baboons were divided into two groups according to IS regimen: In group one (n = 10), pre-treatment started either one (anti-CD20) or four weeks (anti-CD20 plus the proteasome inhibitor bortezomib) prior to transplantation. The extended conventional (as for allotransplantation) immunosuppressive maintenance regimen included anti-thymocyte globuline, tacrolimus, mycophenolate mofetil, methylprednisolone and weekly anti-CD20. In group two (n = 11), myeloablative pre-treatment as in multiple myeloma patients (long and short regimens) was added to extended conventional IS; postoperative total thoracic and abdominal lymphoid irradiation (TLI; single dose of 600 cGY) was used to further reduce antibody-producing cells. RESULTS: In the perioperative course, the surgical technique was safely applied: 19 baboons were weaned off extracorporeal circulation and 17 extubated. Nine animals were lost in the early postoperative course due to causes unrelated to surgical technique or IS regimen. Excluding these early failures, median graft survival times of group 1 and 2 were 18.5 (12-50) days and 16 (7-35) days. Necropsy examination of group 1 donor organs revealed hypertrophy of the left ventricular wall in the six longer-lasting grafts; myocardial histology confirmed pre-clinical suspicion of humoral rejection, which was not inhibited by the extended conventional IS including intensified treatments, and signs of thrombotic microangiopathy. Grafts of group 2 presented with only mild-to-moderate features of humoral rejection and thrombotic microangiopathy, except in one case of delayed rejection on day 17. The other experiments in this group were terminated because of untreatable pulmonary oedema, recurring ventricular fibrillation, Aspergillus sepsis, as well as a combination of a large donor organ and late toxic side effects due to TLI. CONCLUSIONS: Longer-term results were difficult to achieve in this model due to the IS regimens used. However, we conclude that heterotopic intrathoracic heart transplantation may be an option for clinical xenotransplantation. PMID- 26602742 TI - Influence of sleep-onset time on the development of 18-month-old infants: Japan Children's cohort study. AB - OBJECTIVE: We report here the influence of sleep patterns on the development of infants in Japan. A total of 479 infants were registered in two different Japanese cities. Direct neurological observations were performed by licensed pediatric neurologists. METHOD: We designed a prospective cohort study and identified the sleep factors of children showing atypical development. The Kinder Infant Developmental Scale (KIDS) was used to evaluate the infant developmental quotient (DQ); we also applied a neurobehavioral screening battery. Neurobehavioral observations in 18-month-old infants were designed to check all developmental categories within the three areas of motor function, language, and social function. Based on the observations, each infant was classified as having "atypical development" or "typical development". RESULT: We found that later sleep onset time (>22:00 h), and longer naps during the day each had significant positive correlations with atypical development patterns in 18-month-old infants. For each hour the infant sleep-onset time extended past 22:00 h, the infants showed worse neurodevelopmental outcomes, at an odds ratio increase of 2.944. CONCLUSION: Although our results may be confounded by sleep problems resulting from pre-existing developmental disabilities, we can safely conclude that appropriate sleeping habits are important for healthy development in 18-month-old infants. PMID- 26602744 TI - [Biphasic reaction to dobutamine stress echocardiography as a predictor of coronary artery spasm: Apropos of 3 cases]. AB - Dobutamine-related coronary spasm is a possible complication of dobutamine stress echocardiography potentially explaining a part of some erroneously labeled "false positive tests". Presently, there are no established echographic predictors of coronary spasm. We report 3 clinical cases in which dobutamine-induced spasm was strongly suspected on the basis of a biphasic reaction including an initial deterioration rapidly followed by a spontaneous recovery in well-defined echocardiographic territory. In all three cases, we were able to confirm spasm of angiography. The biphasic reaction may constitute a potential predictor of spasm in patients with positive dobutamine stress tests. PMID- 26602745 TI - [Acute pericarditis and tamponade: An unusual revelation of a visceral tuberculosis]. AB - Tuberculosis is a common pulmonary disease, which is still endemic in disadvantaged communities. Pericarditis is a rare but very lethal visceral localization. The authors report the case of a 58-year-old man, without neither medical history nor social risk, who presented a cardiac tamponade as the first and atypic manifestation of a visceral tuberculosis. PMID- 26602748 TI - Inhibiting Integrin alphavbeta5 Reduces Ischemia-Reperfusion Injury in an Orthotopic Lung Transplant Model in Mice. AB - Primary graft dysfunction after lung transplantation is the leading cause of morbidity and mortality in the immediate posttransplant period and is characterized by endothelial and epithelial barrier disruption and the leakage of protein-rich edema fluid. Integrins are cell surface receptors that have an important role in maintenance of the cell barrier, and inhibition of integrins, such as alphavbeta5, can diminish alveolar flooding in lung injury models. We hypothesized that inhibition of alphavbeta5 during donor lung cold ischemia would reduce endothelial permeability during reperfusion. Using an orthotopic single lung transplantation model with and without cold ischemia, donor lungs were perfused with alphavbeta5-blocking antibody (ALULA) or control antibody at the time of collection, followed by transplantation, 8 h of reperfusion, and the measurement of lung injury parameters. Prolonged cold ischemia (18 h) produced increases in extravascular lung water, protein permeability, and neutrophilic alveolitis and decreased oxygenation compared with lungs without cold ischemia. Perfusion of lungs with alphavbeta5 antibody versus control antibody protected donor lungs from injury and significantly improved oxygenation. In summary, alphavbeta5 integrin blockade protects from the development of ischemia reperfusion lung injury and is a promising approach to preventing primary graft dysfunction in human lung transplant procedures. PMID- 26602749 TI - Serological, genomic and structural analyses of the major mite allergen Der p 23. AB - BACKGROUND: Der p 23 was recently identified in a European population as a major allergen and potentially a chitin binding protein. OBJECTIVE: This study sought to assess the importance of Der p 23 among other Dermatophagoides allergens in a North American population and to determine the structure for functional characterization. METHODS: IgE binding to Der p 23, Der p 1, Der p 2, Der p 5, Der p 7 and Der p 8 was measured by ELISA. RNA-seq data from D. pteronyssinus were compared as estimates of allergen expression levels. The structure was analysed by X-ray crystallography and NMR. RESULTS: Despite a high prevalence of Der p 23, (75% vs. 87% and 79% for Der p 1 and Der p 2, respectively), the anti Der p 23 IgE levels were relatively low. The patient response to the 6 allergens tested was variable (n = 47), but on average anti-Der p 1 and anti-Der p 2 together accounted for 85% of the specific IgE. In terms of abundance, the RNA expression level of Der p 23 is the lowest of the major allergens, thirty fold less than Der p 1 and sevenfold less than Der p 2. The structure of Der p 23 is a small, globular protein stabilized by two disulphide bonds, which is structurally related to allergens such as Blo t 12 that contain carbohydrate binding domains that bind chitin. Functional assays failed to confirm chitin binding by Der p 23. CONCLUSIONS AND CLINICAL RELEVANCE: Der p 23 accounts for a small percentage of the IgE response to mite allergens, which is dominated by Der p 1 and Der p 2. The prevalence and amount of specific IgE to Der p 23 and Der p 2 are disproportionately high compared to the expression of other Dermatophagoides allergens. PMID- 26602751 TI - Association of beta-Adrenergic Receptor Gene Polymorphisms With Acute Coronary Syndrome and Cardiovascular Risk Factors in an Arab Population. AB - We evaluated the association between beta-adrenergic receptor genes (ADRB1 and ADRB2) polymorphism, cardiovascular risk, and acute coronary syndrome (ACS) in individuals from an Arab ethnicity. A total of 388 Qatari participants were assessed and genotyped for ADRB1 (rs1801252 & rs1801253) and ADRB2 (rs1042718 & rs1042713) polymorphisms using allele-specific PCR. Minor allele frequencies (MAF) in each single-nucleotide polymorphisms (SNPs) did not show statistically significant difference between cases and controls. A higher proportion of patients with ACS had homozygous minor alleles (GG) for rs1801253 (28.8% vs 17.1%; P = .019) compared with controls. Among cases with ACS, there was an association of minor allele frequency (G) for rs1801253 with severe coronary artery stenosis (0.485 vs 0.428; P = .04) than that of insignificant stenosis (<50% stenosis). There was a 3-fold increased risk of significant coronary stenosis in patients with diabetes mellitus (DM) and carrier of rs1801253 genotypes with dominant model (P = .01) and recessive model (P = .05). There is a possible synergic association between DM, carrier of ADRB1 (Arg389Gly) variants, and significant coronary artery stenosis among Arabs. Further prospective studies with larger sample sizes are warranted to support our findings. PMID- 26602750 TI - Therapeutic targeting of autophagy in cardiovascular disease. AB - Autophagy is an evolutionarily ancient process of intracellular catabolism necessary to preserve cellular homeostasis in response to a wide variety of stresses. In the case of post-mitotic cells, where cell replacement is not an option, finely tuned quality control of cytoplasmic constituents and organelles is especially critical. And due to the ubiquitous and critical role of autophagic flux in the maintenance of cell health, it comes as little surprise that perturbation of the autophagic process is observed in multiple disease processes. A large body of preclinical evidence suggests that autophagy is a double-edged sword in cardiovascular disease, acting in either beneficial or maladaptive ways, depending on the context. In light of this, the autophagic machinery in cardiomyocytes and other cardiovascular cell types has been proposed as a potential therapeutic target. Here, we summarize current knowledge regarding the dual functions of autophagy in cardiovascular disease. We go on to analyze recent evidence suggesting that titration of autophagic flux holds potential as a novel treatment strategy. PMID- 26602752 TI - Drug-Eluting Stent Type and Long-Term Outcomes. PMID- 26602753 TI - Surgical versus medical management of patients with acute ischemic mitral regurgitation: a systematic review. AB - AIMS: Acute ischemic mitral regurgitation (MR) is seen in patients with myocardial infarction and is associated with increased morbidity and mortality. The optimal treatment strategy of this condition however, is not well established. The aim of this manuscript is to conduct a systematic review of the medical literature to assess the relative benefits and harms of mitral valve surgery with medical therapy versus medical management alone for patients with acute ischemic MR of at least moderate severity. METHODS: We performed a literature search in MEDLINE, Embase.com, and Cochrane Central Register of Controlled Trials. We restricted the search to randomized clinical trials comparing surgical to medical management of acute ischemic MR. Exclusion criteria included non-randomized trials, trials enrolling patients with non-ischemic MR, and trials excluding acute ischemic MR. The primary outcomes were short-term and long term mortality. Two reviewers (WA, WA) screened titles and abstracts of identified citations independently and in duplicate using calibration exercises and standardized screening forms. RESULTS: The search strategy identified 887 citations (137 were duplicates and removed). Of the 750 titles, 709 were excluded (519 were non-relevant and 190 were review articles and case reports). Of the 41 remaining abstracts, 37 were retrospective cohorts and four excluded acute MR, leaving no eligible study for analysis. An ongoing study that is being conducted at Southern Illinois University entitled by "Medical Versus Surgical Management of Patients With Moderate Mitral Regurgitation Following Percutaneous Coronary Intervention for Myocardial Infarction: A Pilot Prospective Randomized Trial" was identified; however, it was just withdrawn after failing to enroll patients during 4 years. CONCLUSION: This is an empty systematic review that identified no published randomized trials for the management of acute MR complicating acute MI. The only ongoing randomized study that was identified was just withdrawn after failing to enroll patients. There is an urgent need for conducing proper randomized trials in order to guide informed decision making in the treatment of acute ischemic MR. PROSPERO registration number CRD42013005843. PMID- 26602754 TI - Comparison of effects of extra-thoracic paraaortic counterpulsation to intraaortic balloon pump on circulatory support in acute heart failure. AB - BACKGROUND: Previously designed intra-thoracic paraaortic counterpulsation device has limited stroke volume and may depress the lung to cause complications. The purpose of this study was to evaluate the hemodynamic effects of an extra thoracic paraaortic counterpulsation device (ETPACD) in comparison to intraaortic balloon pump (IABP) in an animal model with acute heart failure. METHODS: The acute heart failure model was successfully induced by snaring branch of anterior descending coronary artery in sheep (weighting, 38-50 kg, n = 8). The ETPACD is a single port, 65-ml stroke volume blood chamber designed to be connected to descending aorta through a valveless graft and placed extra-thorax. In comparison, a standard clinical 40-ml IABP was placed in the descending aorta. The hemodynamic indices of both devices were recorded during counterpulsation assistance. Two of the sheep were allowed to survive for 1 week to examine the prolonged effect. RESULTS: Both ETPACD and IABP increased cardiac output with higher effect of ETPACD (13.52 % vs. 8.19 % in IABP, P < 0.05) and on mean diastolic aortic pressure (26.73 % vs. 12.58 % in IABP, P < 0.01). Both ETPACD and IABP also produced a greater reduction in left ventricular end-diastolic pressure (26.77 % vs. 23.08 %, P > 0.05). The ETPACD increased left carotid artery flow more significantly the IABP (18.00 % vs. 9.19 % , P < 0.05). In two of the sheep allowed to survive for 1 week, the device worked well with no complications and there was no thrombus formation in the chamber of ETPACD. CONCLUSIONS: This study demonstrated that both ETPACD and IABP provided benefit of circulatory support in acute heart failure with better effect on hemodynamic parameters provided by ETPACD. Therefore, ETPACD with theoretical larger stroke volume may become a promising counterpulsation device for treatment of heart failure. PMID- 26602755 TI - Anti-Leukocyte Function-Associated Antigen 1 Therapy in a Nonhuman Primate Renal Transplant Model of Costimulation Blockade-Resistant Rejection. AB - Costimulation blockade with the fusion protein belatacept provides a desirable side effect profile and improvement in renal function compared with calcineurin inhibition in renal transplantation. This comes at the cost of increased rates of early acute rejection. Blockade of the integrin molecule leukocyte function associated antigen 1 (LFA-1) has been shown to be an effective adjuvant to costimulation blockade in a rigorous nonhuman primate (NHP) model of islet transplantation; therefore, we sought to test this combination in an NHP renal transplant model. Rhesus macaques received belatacept maintenance therapy with or without the addition of LFA-1 blockade, which was achieved using a murine-derived LFA-1-specific antibody TS1/22. Additional experiments were performed using chimeric rhesus IgG1 (TS1/22R1) or IgG4 (TS1/22R4) variants, each engineered to limit antibody clearance. Despite evidence of proper binding to the target molecule and impaired cellular egress from the intravascular space indicative of a therapeutic effect similar to prior islet studies, LFA-1 blockade failed to significantly prolong graft survival. Furthermore, evidence of impaired protective immunity against cytomegalovirus was observed. These data highlight the difficulties in translating treatment regimens between organ models and suggest that the primarily vascularized renal model is more robust with regard to belatacept-resistant rejection than the islet model. PMID- 26602756 TI - Multimorbidity in older adults: magnitude and challenges for the Brazilian health system. AB - BACKGROUND: Multimorbidity is a public health problem with high prevalence and important consequences. The aim of this paper was to verify the prevalence and distribution of multimorbidity in Brazilian older adults. METHODS: A population based survey was carried out in 2008 through face-to-face interviews with 1593 older adults (aged 60 or over) living in Bage, a medium-sized city in Southern Brazil. Multimorbidity was evaluated by 17 morbidities and operationalized according to two cutoff points: 2 or more and 3 or more morbidities. Descriptive analysis examined the occurrence of multimorbidity by demographic, socioeconomic and health services variables. Observed and expected dyads and triads of diseases were calculated. RESULTS: From total sample, 6 % did not have morbidities. Mean morbidity was 3.6. Morbidities showing higher prevalence were high blood pressure - HBP - (55.3 %) and spinal column disease (37.4 %). The percent of participants with multimorbidity was 81.3 % (95 % CI: 79.3; 83.3) for 2 or more morbidities and 64.0 % (95 % CI: 61.5; 66.4) for 3 or more morbidities. In both measures occurrence was higher among women, the more elderly, less socioeconomic status, the bedridden, those who did not have a health private plan, those who used health services and those living in Family Health Strategy catchment areas. We found 22 dyads of morbidities with prevalence 10 % or more and 35 triads with prevalence 5 % or more. The most prevalent observed pair and triplet of morbidities were HBP and spinal column disease (23.6 %) and HBP, rheumatism/arthritis/arthrosis and spinal column disease (10.6 %), respectively. CONCLUSIONS: Multimorbidity frequency was high in the sample studied, in keeping with percentage found in other countries. The social inequities identified increase the health system challenges for the management of multimorbidity, requiring a comprehensive and multidimensional care. The combinations of diseases can provide initial input to include multimorbidity in Brazilian clinical protocols. PMID- 26602757 TI - Management of the 2014 Enterovirus 68 Outbreak at a Pediatric Tertiary Care Center. AB - PURPOSE: Enterovirus 68 (EV-D68) is an uncommonly recognized cause of acute respiratory tract infections. During the late summer of 2014, an international EV D68 outbreak occurred. We review the steps of outbreak recognition and management in the context of 1 hospital's experience with the EV-D68 outbreak. METHODS: We reviewed the role of Children's Mercy Hospital as one of the first hospitals to recognize the 2014 EV-D68 outbreak in the United States. The steps of outbreak management were applied to real-life examples as the outbreak unfolded at our hospital. FINDINGS: Management of the 2014 EV-D68 outbreak was a multifaceted effort requiring close coordination with hospitals, local and state health departments, and the Centers for Disease Control and Prevention. The importance of clear and frequent communication is highlighted both intra- and interinstitutionally. Increased respiratory disease-related pediatric admissions at hospitals nationally were attributed to EV-D68. Outcomes for these children, including the association of EV-D68 with acute flaccid myelitis, remain under investigation. IMPLICATIONS: Following the steps of outbreak management is critical to providing optimal patient care and ensuring the health of the public. During the 2014 EV-D68 outbreak, close adherence to outbreak principles led to swift recognition of illness, rapid diagnostic measures, institution of appropriate therapies, and dissemination of information to health care providers and the public. Equally important was the subsequent identification of an increase in acute flaccid myelitis cases against the backdrop of an increase in EV-D68 detections nationally. Future prospective studies are needed to determine the true burden of EV-D68 disease, potential vaccines and therapeutics, and outcomes of children with EV-D68 infection. PMID- 26602758 TI - An economic evaluation of two interventions for the prevention of post-surgical infections in cardiac surgery. AB - OBJECTIVE: To conduct a cost-effectiveness analysis that compares two prophylactic protocols for treating post-surgical infections in cardiac surgery. METHODS: A cost effectiveness analysis was done by using a decision tree to compare two protocols for prophylaxis of post-surgical infections (Protocol A: Those patient with positive test to methicillin-resistant Staphylococcus aureus (MRSA) colonization received muripocin (twice a day during a two-week period), with no follow-up verification. Those who tested negative did not receive the prophylaxis treatment; Protocol B: all patients received the mupirocin treatment). The number of post-surgical infections averted was the measure of effectiveness from the health system's perspective, 30 days following the surgery. The incidence of infections and complications was obtained from two cohorts of patients who underwent cardiac surgery Hospital. The times for applying the two protocols were validated by experts. They cost were calculated from the hospital's analytical accounting management system and Pharmaceutical Service. Only direct costs were taken into account, no discount rates were applied. Incremental cost-effectiveness ratio (ICER) was calculated. A probabilistic sensitivity analysis was performed. RESULTS: A total of 1118 patients were included (721 in Protocol A and 397 in Protocol B). No statistically significant differences were found in age, sex, diabetes, exitus or length of hospital stay between the two protocols. In the control group the rate of infection was 15.3%, compared with 11.3% in the intervention group. Protocol B proves to be more effective and at a lower cost, yielding an ICER of ?32,506. CONCLUSION: Universal mupirocin prophylaxis against surgical site infections (SSI) in cardiac surgery as a dominant strategy, because it shows a lower incidence of infections and cost savings, versus the strategy to treat selectively patients according to their test results prior screening. PMID- 26602759 TI - [Catheter ablation of ventricular arrhythmias. Complications and emergency situations]. AB - Catheter ablation of ventricular arrhythmias is an established treatment for patients with and without structural heart disease. For patients without structural heart disease, the aim is symptomatic relief, while the ultimate goals for patients with underlying structural heart disease are reduction of ICD therapies and improved prognosis. Rates for major complications range between 6 10% in patients with structural heart disease. Vascular complications are most common; life-threatening complications (e.g., pericardial tamponade and stroke) are less frequent. Procedure-associated mortality is reported to be 0-3%. In patients with idiopathic ventricular tachycardia, the complication rate is much lower compared to patients with structural heart disease. PMID- 26602760 TI - Predicting Adverse Health Outcomes in Nursing Homes: A 9-Year Longitudinal Study and Development of the FRAIL-Minimum Data Set (MDS) Quick Screening Tool. AB - OBJECTIVES: To examine the predictive validity of a quick frailty screening tool, the FRAIL-NH, for adverse health outcomes in nursing home residents, using variables from the Minimum Data Set (MDS). The screening items were compiled from the MDS for potential direct application in long-term care facilities using this health information system. DESIGN: Longitudinal follow-up study of nursing home residents with annual clinical assessment using the MDS and mortality data between 2005 and 2013. SETTING: Six nursing homes operated by a nongovernmental organization in Hong Kong. PARTICIPANTS: Participants included 2380 nursing home residents aged 65 years or older at study baseline. MEASUREMENTS: Frailty assessed using the FRAIL-NH model with items from the MDS. The model covers 8 areas: fatigue, resistance, ambulation, incontinence, polypharmacy, weight loss, nutritional approach, and help with dressing. Adverse health outcomes in subsequent years were measured: incident falls, worsening activities of daily living (ADL) function, hospitalization, and death. RESULTS: Using a cutoff score of 5 on the FRAIL-NH, the prevalence of frailty was 58.5% in this nursing home sample. Frailty as identified using the FRAIL-NH predicts incident falls, worsening ADL function, hospitalization, and death (hazard ratios [HR] 2.00 3.73). This remained significant after adjusting for sociodemographic and other clinical characteristics. Each level of increase on the FRAIL-NH has strong distinguishing power on the incidence of adverse outcomes. Intermediate frailty status (score 1-4) also significantly predicts adverse health outcomes (HR 1.57 2.06). CONCLUSION: The FRAIL-NH is a quick screening tool that can be used to identify frail and prefrail nursing home residents at risk of adverse health outcomes. It can be applied using variables from the MDS, allowing direct adoption in long-term care facilities already using this health information system. PMID- 26602761 TI - RAG Off-Target Activity Is in the Loop. AB - The 'off-target' activity of RAG recombinases contributes to mutations and cancer. Recent studies show that the influence of DNA regulatory elements is largely constrained by the formation of chromatin loops and interaction frequencies. Now, the Alt lab has identified major RAG off-target activity bearing similar limitations, with joining events restricted to convergent paired RSS elements in loop domains. PMID- 26602762 TI - Variability in Humoral Immunity to Measles Vaccine: New Developments. AB - Despite the existence of an effective measles vaccine, resurgence in measles cases in the USA and across Europe has occurred, including in individuals vaccinated with two doses of the vaccine. Host genetic factors result in inter individual variation in measles vaccine-induced antibodies, and play a role in vaccine failure. Studies have identified HLA (human leukocyte antigen) and non HLA genetic influences that individually or jointly contribute to the observed variability in the humoral response to vaccination among healthy individuals. In this exciting era, new high-dimensional approaches and techniques including vaccinomics, systems biology, GWAS, epitope prediction and sophisticated bioinformatics/statistical algorithms provide powerful tools to investigate immune response mechanisms to the measles vaccine. These might predict, on an individual basis, outcomes of acquired immunity post measles vaccination. PMID- 26602765 TI - Controlling Cerebellar Output to Treat Refractory Epilepsy. AB - Generalized epilepsy is characterized by recurrent seizures caused by oscillatory neuronal firing throughout thalamocortical networks. Current therapeutic approaches often intervene at the level of the thalamus or cerebral cortex to ameliorate seizures. We review here the therapeutic potential of cerebellar stimulation. The cerebellum forms a prominent ascending input to the thalamus and, whereas stimulation of the foliated cerebellar cortex exerts inconsistent results, stimulation of the centrally located cerebellar nuclei (CN) reliably stops generalized seizures in experimental models. Stimulation of this area indicates that the period of stimulation with respect to the phase of the oscillations in thalamocortical networks can optimize its effect, opening up the possibility of developing on-demand deep brain stimulation (DBS) treatments. PMID- 26602763 TI - De novo assembly and functional annotation of Myrciaria dubia fruit transcriptome reveals multiple metabolic pathways for L-ascorbic acid biosynthesis. AB - BACKGROUND: Myrciaria dubia is an Amazonian fruit shrub that produces numerous bioactive phytochemicals, but is best known by its high L-ascorbic acid (AsA) content in fruits. Pronounced variation in AsA content has been observed both within and among individuals, but the genetic factors responsible for this variation are largely unknown. The goals of this research, therefore, were to assemble, characterize, and annotate the fruit transcriptome of M. dubia in order to reconstruct metabolic pathways and determine if multiple pathways contribute to AsA biosynthesis. RESULTS: In total 24,551,882 high-quality sequence reads were de novo assembled into 70,048 unigenes (mean length = 1150 bp, N50 = 1775 bp). Assembled sequences were annotated using BLASTX against public databases such as TAIR, GR-protein, FB, MGI, RGD, ZFIN, SGN, WB, TIGR_CMR, and JCVI-CMR with 75.2 % of unigenes having annotations. Of the three core GO annotation categories, biological processes comprised 53.6 % of the total assigned annotations, whereas cellular components and molecular functions comprised 23.3 and 23.1 %, respectively. Based on the KEGG pathway assignment of the functionally annotated transcripts, five metabolic pathways for AsA biosynthesis were identified: animal-like pathway, myo-inositol pathway, L-gulose pathway, D mannose/L-galactose pathway, and uronic acid pathway. All transcripts coding enzymes involved in the ascorbate-glutathione cycle were also identified. Finally, we used the assembly to identified 6314 genic microsatellites and 23,481 high quality SNPs. CONCLUSIONS: This study describes the first next-generation sequencing effort and transcriptome annotation of a non-model Amazonian plant that is relevant for AsA production and other bioactive phytochemicals. Genes encoding key enzymes were successfully identified and metabolic pathways involved in biosynthesis of AsA, anthocyanins, and other metabolic pathways have been reconstructed. The identification of these genes and pathways is in agreement with the empirically observed capability of M. dubia to synthesize and accumulate AsA and other important molecules, and adds to our current knowledge of the molecular biology and biochemistry of their production in plants. By providing insights into the mechanisms underpinning these metabolic processes, these results can be used to direct efforts to genetically manipulate this organism in order to enhance the production of these bioactive phytochemicals. The accumulation of AsA precursor and discovery of genes associated with their biosynthesis and metabolism in M. dubia is intriguing and worthy of further investigation. The sequences and pathways produced here present the genetic framework required for further studies. Quantitative transcriptomics in concert with studies of the genome, proteome, and metabolome under conditions that stimulate production and accumulation of AsA and their precursors are needed to provide a more comprehensive view of how these pathways for AsA metabolism are regulated and linked in this species. PMID- 26602764 TI - The Yin and Yang of Sleep and Attention. AB - Sleep is not a single state, but a complex set of brain processes that supports several physiological needs. Sleep deprivation is known to affect attention in many animals, suggesting that a key function of sleep is to regulate attention. Conversely, tasks that require more attention drive sleep need and sleep intensity. Attention involves the ability to filter incoming stimuli based on their relative salience, and this is likely to require coordinated synaptic activity across the brain. This capacity may have only become possible with the evolution of related neural mechanisms that support two key sleep functions: stimulus suppression and synaptic plasticity. We argue here that sleep and attention may have coevolved as brain states that regulate each other. PMID- 26602768 TI - UCD (SMMS) SSRA 2015. PMID- 26602766 TI - Intestinal Permeability of beta-Lapachone and Its Cyclodextrin Complexes and Physical Mixtures. AB - BACKGROUND AND OBJECTIVES: beta-Lapachone (betaLAP) is a promising, poorly soluble, antitumoral drug. betaLAP combination with cyclodextrins (CDs) improves its solubility and dissolution but there is not enough information about the impact of cyclodextrins on betaLAP intestinal permeability. The objectives of this work were to characterize betaLAP intestinal permeability and to elucidate cyclodextrins effect on the dissolution properties and on the intestinal permeability. The final goal was to evaluate CDs influence on the oral absorption of betaLAP. METHODS: Binary systems (physical mixtures and inclusion complexes) including betaLAP and CDs (beta-cyclodextrin: betaCD, random-methyl-beta cyclodextrin: RMbetaCD and sulfobutylether-beta-cyclodextrin: SBEbetaCD) have been prepared and analysed by differential scanning calorimetry. betaLAP (and its combinations with CDs) absorption rate coefficients and effective permeability values have been determined in vitro in MDCK or MDCK-Mdr1 monolayers and in situ in rat by a closed loop perfusion technique. RESULTS: DSC results confirmed the formation of the inclusion complexes. betaLAP-CDs inclusion complexes improve drug solubility and dissolution rate in comparison with physical mixtures. betaLAP presented a high permeability value which can provide complete oral absorption. Its oral absorption is limited by its low solubility and dissolution rate. Cyclodextrin (both as physical mixtures and inclusion complexes) showed a positive effect on the intestinal permeability of betaLAP. Complexation with CDs does not reduce betaLAP intestinal permeability in spite of the potential negative effect of the reduction in free fraction of the drug. CONCLUSIONS: The use of RMbetaCD or SBEbetaCD inclusion complexes could benefit betaLAP oral absorption by enhancing its solubility, dissolution rate and permeability. PMID- 26602769 TI - Tularemia and plague survey in rodents in an earthquake zone in southeastern Iran. AB - OBJECTIVES: Earthquakes are one the most common natural disasters that lead to increased mortality and morbidity from transmissible diseases, partially because the rodents displaced by an earthquake can lead to an increased rate of disease transmission. The aim of this study was to evaluate the prevalence of plague and tularemia in rodents in the earthquake zones in southeastern Iran. METHODS: In April 2013, a research team was dispatched to explore the possible presence of diseases in rodents displaced by a recent earthquake magnitude 7.7 around the cities of Khash and Saravan in Sistan and Baluchestan Province. Rodents were trapped near and in the earthquake zone, in a location where an outbreak of tularemia was reported in 2007. Rodent serums were tested for a serological survey using an enzyme-linked immunosorbent assay. RESULTS: In the 13 areas that were studied, nine rodents were caught over a total of 200 trap-days. Forty-eight fleas and 10 ticks were obtained from the rodents. The ticks were from the Hyalomma genus and the fleas were from the Xenopsylla genus. All the trapped rodents were Tatera indica. Serological results were negative for plague, but the serum agglutination test was positive for tularemia in one of the rodents. Tatera indica has never been previously documented to be involved in the transmission of tularemia. CONCLUSIONS: No evidence of the plague cycle was found in the rodents of the area, but evidence was found of tularemia infection in rodents, as demonstrated by a positive serological test for tularemia in one rodent. PMID- 26602767 TI - Histopathological gallbladder morphometric measurements in geriatric patients with symptomatic chronic cholecystitis. AB - INTRODUCTION: Cholecystectomy for symptomatic cholecystitis is one of the common surgical procedures in the geriatric patients. Increased gallbladder wall thickness is expected due to acute cholecystitis and in some other clinical conditions. Routine histopathological evaluation of cholecystectomy materials are required to confirm the diagnosis and document other pathologies. The aim of this study was to evaluate age-related histopathological gallbladder morphometric measurements. METHODS: A retrospective chart review of 371 cholecystectomy materials was performed. Two groups were designed according to age (<65 and >=65 years old, respectively). Age and gender analyses for histopathological gallbladder length, diameter and wall thickness were performed. In addition, pathologically confirmed acute inflammation rates were evaluated in this case control study. RESULTS: Gallbladder morphometric measurements and pathologically confirmed acute inflammation rates were similar in males and females. Histopathological gallbladder diameter was higher with acute inflammatory changes, but no differences were observed in gallbladder length and wall thickness. Gallbladder wall thickness and pathologically confirmed acute inflammation rates were not comparable between the control and geriatric patients (2.8 +/- 1.3 vs 2.6 +/- 1.2 mm, and 30/281 (10.7 %) vs 10/74 (13.5 %), respectively, p > 0.05). However, higher gallbladder length and diameter were observed in geriatric group. CONCLUSION: Age is an independent factor on histopathological gallbladder length and diameter, but not for gallbladder wall thickness. In addition, pathologically confirmed acute inflammation rate is not higher in geriatric patients. Clinical significance of these findings merits further investigation. PMID- 26602770 TI - Human papillomavirus infection and risk of lung cancer in never-smokers and women: an 'adaptive' meta-analysis. AB - OBJECTIVES: The incidence of lung cancer in Koreans is increasing in women and in both men and women with a never-smoking history. Human papillomavirus (HPV) infection has been suggested as a modifiable risk factor of lung cancer in never smokers and women (LCNSW). This systematic review (SR) aimed to evaluate an association between HPV infection and lung cancer risk in LCNSW. METHODS: Based on a prior SR and some expert reviews, we identified refereed, cited, or related articles using the PubMed and Scopus databases. All case-control studies that reported the odds ratio of HPV infection in LCNSW were selected. An estimate of the summary odds ratio (SOR) with 95% confidence intervals (CI) was calculated. RESULTS: A total of four case-control studies were included. The fixed-effect model was applied because of homogeneity (I-squared=0.0%). The SORs in women and in never-smokers were 5.32 (95% CI, 1.75 to 16.17) and 4.78 (2.25 to 10.15) respectively. CONCLUSIONS: These results showed a significant effect of HPV infection in LCNSW. It is evident that developing a preventive plan against LCNSW may be necessary. PMID- 26602771 TI - Heat stress impairs mice granulosa cell function by diminishing steroids production and inducing apoptosis. AB - Ovarian injury can be induced by heat stress. Mice granulosa cells (GCs) are critical for normal ovarian function and they synthesize a variety of growth factors and steroids for the follicle. Furthermore, the growth, differentiation, and maturate of theca cells and oocyte are dependent upon the synthesis of GCs. Due to the critical biological functions of GCs, we hypothesized that the apoptosis and dysfunction of GCs could also be induced by heat stress. We analyzed GCs apoptosis and evaluated the expression of apoptosis-related genes (caspase-3, Bax, Bcl-2) after heat treatment. Radio immunity assay was used to measure the secretion of 17beta-estradiol (E2) and progesterone (P4). RT-PCR was used to evaluate the expression of steroids-related genes (Star, CYP11A1, CYP19A1). Our data suggested that heat stress inhibited GCs proliferation, induced GCs apoptosis, decreased E2 and P4 secretion, reduced the steroids related genes mRNA expression. Besides, our results indicated that heat treatment induced apoptosis of GCs through the mitochondrial pathway, which involved caspase-3 and Bax. The reduction in steroids secretion and mRNA expression of Star, CYP11A1, and CYP19A1 might also play a role in heat-induced GCs apoptosis and ovarian injury. PMID- 26602772 TI - The Experience of Peer Mentors in an Intervention to Promote Smoking Cessation in Persons with Psychiatric Illness. AB - Peer support is an important component of services for persons with psychiatric illness but the experience of peer mentors is not well understood. This study explored the experiences of peer mentors, all former smokers and persons with psychiatric illness, who provided smoking cessation counseling as part of a 6 month professionally-led intervention. Data was obtained from 383 contact log entries and in-depth interviews with eight peer mentors. Qualitative analysis indicated that mentor roles were unexpectedly varied beyond the focus on smoking cessation. Of the two aspects of "peer-ness," shared smoking history was more prominent, while the shared experience of psychiatric illness was sometimes overlooked. Peer mentors experienced multiple challenges trying to help participants to change their smoking behaviors. Nonetheless, they described their experience as personally rewarding. Future interventions may be improved by anticipating peer mentor role complexity and the inherent tension between providing person-centered support and promoting behavior change. PMID- 26602773 TI - Imprisoned Husbands: Palestinian Wives and Experiences of Difficulties. AB - This study aimed to investigate difficulties experienced by the wives of Palestinian men arrested and held in Israeli prisons. 16 captives' wives were interviewed using a semi-structured interview to provide them with a greater opportunity to speak about their experiences. Three main research questions were discussed; community difficulties, social support, and coping strategies. A thematic analysis was used throughout the interviews. We concluded that in addition to the stress of being separated from their husbands, the frustrating visitation process to prison and the ongoing political conflict, the wives expressed a frustrating social network characterized by constant interferences in their personal lives and the choices they make. Most women expressed a lack in psychosocial support given through governmental and non-governmental organizations; in addition they expressed a need for that kind of support. Coping strategies ranged from religious, acceptance, distraction, to planning strategies. PMID- 26602774 TI - Integration between oncology and palliative care: does one size fit all? PMID- 26602775 TI - Reply to the letter to the editor 'How much evidence isn't in evidence-based guidelines?' by Johnson et al. PMID- 26602777 TI - Trabectedin is an effective second-line treatment in soft tissue sarcoma patients. PMID- 26602776 TI - Reply to the letter to the editor 'Integration between oncology and palliative care: does one size fit all?' by Verna et al. PMID- 26602778 TI - Idiopathic thrombocytopenic purpura induced by nivolumab in a metastatic melanoma patient with elevated PD-1 expression on B cells. PMID- 26602779 TI - Potential New Associations of North American Parasitoids With the Invasive Asian Longhorned Beetle (Coleoptera: Cerambycidae) for Biological Control. AB - The Asian longhorned beetle, Anoplophora glabripennis (Motschulsky), is a polyphagous wood-boring insect native to Asia. Since it invaded North America in the 1990s, the beetle has been continuously targeted by quarantines and eradication programs in the United States and Canada. We examined the potential for development of new species-associations between A. glabripennis and hymenopteran parasitoids collected from cerambycids and other wood-boring insects infesting red maple (Acer rubrum L.) trees in the mid-Atlantic region of the United States. Results of our study showed that five groups of braconid parasitoids (Ontsira mellipes Ashmead, Rhoptrocentrus piceus Marsh, Spathius laflammei Provancher, Heterospilus spp., and Atanycolus spp.) successfully attacked early instars of A. glabripennis larvae infesting red maple logs and produced both male and female progenies. One species, O. mellipes, was continuously reared on A. glabripennis larvae inserted inside small red maple sticks for over 50 generations, and produced female-biased progeny (~6:1 female to male ratio) at each generation. Continuous rearing of O. mellipes on A. glabripennis larvae did not significantly increase the parasitism and mean number of progeny produced per parasitized host. Together, these findings demonstrate that some North American parasitoids may be able to develop new associations with A. glabripennis and thus should be further studied under semifield or field conditions for possible use in biocontrol. PMID- 26602781 TI - Tolerance to sedative drugs in PICU: can it be moderated or is it immutable? PMID- 26602783 TI - The ethics of migration and critical illness. PMID- 26602782 TI - A randomized controlled trial of daily sedation interruption in critically ill children. AB - PURPOSE: To compare daily sedation interruption plus protocolized sedation (DSI + PS) to protocolized sedation only (PS) in critically ill children. METHODS: In this multicenter randomized controlled trial in three pediatric intensive care units in the Netherlands, mechanically ventilated critically ill children with need for sedative drugs were included. They were randomly assigned to either DSI + PS or PS only. Children in both study arms received sedation adjusted on the basis of validated sedation scores. Provided a safety screen was passed, children in the DSI + PS group received daily blinded infusions of saline; children in the PS group received blinded infusions of the previous sedatives/analgesics. If a patient's sedation score indicated distress, the blinded infusions were discontinued, a bolus dose of midazolam was given and the 'open' infusions were resumed: DSI + PS at half of infusion rate, PS at previous infusion rate. The primary endpoint was the number of ventilator-free days at day 28. Data were analyzed by intention to treat. RESULTS: From October 2009 to August 2014, 129 children were randomly assigned to DSI + PS (n = 66) or PS (n = 63). The study was terminated prematurely due to slow recruitment rates. Median number of ventilator-free days did not differ: DSI + PS 24.0 days (IQR 21.6-25.8) versus PS 24.0 days (IQR 20.6-26.0); median difference 0.02 days (95 % CI -0.91 to 1.09), p = 0.90. Median ICU and hospital length of stay were similar in both groups: DSI + PS 6.9 days (IQR 5.2-11.0) versus PS 7.4 days (IQR 5.3-12.8), p = 0.47, and DSI + PS 13.3 days (IQR 8.6-26.7) versus PS 15.7 days (IQR 9.3-33.2), p = 0.19, respectively. Mortality at 30 days was higher in the DSI + PS group than in the PS group (6/66 versus 0/63, p = 0.03), though no causal relationship to the intervention could be established. Median cumulative midazolam dose did not differ: DSI + PS 14.1 mg/kg (IQR 7.6-22.6) versus PS 17.0 mg/kg (IQR 8.2-39.8), p = 0.11. CONCLUSION: In critically ill children, daily sedation interruption in addition to protocolized sedation did not improve clinical outcome and was associated with increased mortality compared with protocolized sedation only. PMID- 26602784 TI - Incidence and associations of acute kidney injury after major abdominal surgery. AB - PURPOSE: Acute kidney injury (AKI) is a recognised risk factor for adverse outcomes in critical illness and hospitalised patients in general. To understand the incidence and associations of AKI as a peri-operative complication of major abdominal surgery, we conducted a systematic literature review and meta-analysis. METHODS: Using a systematic strategy, we searched the electronic reference databases for articles describing post-operative renal outcomes using consensus criteria for AKI diagnosis (RIFLE, AKIN or KDIGO) in the setting of major abdominal surgery. Pooled incidence of AKI and, where reported, pooled relative risk of death after post-operative AKI were estimated using random effects models. RESULTS: From 4287 screened titles, 19 articles met our inclusion criteria describing AKI outcomes in 82,514 patients undergoing abdominal surgery. Pooled incidence of AKI was 13.4% (95% CI 10.9-16.4%). In eight studies that reported the short-term mortality, relative risk of death in the presence of post operative AKI was 12.6 fold (95% CI, 6.8-23.4). Where reported, length of stay was greater and non-renal post-operative complications were also more frequent in patients experiencing AKI. CONCLUSIONS: Using modern consensus definitions, AKI is a common complication of major abdominal surgery that is associated with adverse patient outcomes including death. While a causative role for AKI cannot be concluded from this analysis, as an important signal of peri-operative harm, AKI should be regarded as an important surgical outcome measure and potential target for clinical interventions. PMID- 26602785 TI - Can this patient be safely discharged from the ICU? PMID- 26602787 TI - Heritage ethics: Toward a thicker account of nursing ethics. AB - The key to understanding the moral identity of modern nursing and the distinctiveness of nursing ethics resides in a deeper examination of the extensive nursing ethics literature and history from the late 1800s to the mid 1960s, that is, prior to the "bioethics revolution". There is a distinctive nursing ethics, but one that falls outside both biomedical and bioethics and is larger than either. Were, there a greater corpus of research on nursing's heritage ethics it would decidedly recondition the entire argument about a distinctive nursing ethics. It would also provide a thicker account of nursing ethics than has been afforded thus far. Such research is dependent upon identifying, locating, accessing and, more importantly, sharing these resources. A number of important heritage ethics sources are identified so that researchers might better locate them. In addition, a bibliography of heritage ethics textbooks and a transcript of the earliest known journal article on nursing ethics in the US are provided. PMID- 26602788 TI - Nursing instructors' perception of students' uncivil behaviors: A qualitative study. AB - BACKGROUND: Uncivil behavior is a serious issue in nursing education around the world, and is frequently faced by instructors and students. There is no study in relation to explain the concept and dimensions of uncivil behavior in nursing education of Iran. AIM: The aim of this study was to determine the perception of nursing educators about student incivility behavior. METHODS: This was a qualitative study. Data from 11 semi-structured interviews were analyzed using conventional content analysis. Participants and research context: In all, 11 nursing educators of 5 various nursing schools in Tehran, capital of Iran, participated. Ethical considerations: Organizational approval by the Universities, and informed consent were ensured before conducting the research. The principles of voluntariness, confidentiality, and anonymity were respected during the research process. RESULTS: Three themes were found: disruptive behavior affecting communication climate, disruptive behavior affecting ethical climate, and disruptive behavior affecting learning climate. Discussion and final considerations: The results of this study demonstrated that uncivil behavior affects every ethical, communicational, and learning climate and threaten peace of the instructors, students, and the academic community. With the consideration of mutuality in incivility behaviors, the authors propose to examine students' perceptions and identify dimensions of uncivil behavior of instructors for formulating strategies to minimize such behaviors in nursing educational society. PMID- 26602789 TI - Folic acid fortification for Europe? PMID- 26602790 TI - Pollutant exposure at wastewater treatment works affects the detoxification organs of an urban adapter, the Banana Bat. AB - The Banana Bat, Neoromicia nana, exploits pollution-tolerant chironomids at wastewater treatment works (WWTWs). We investigated how pollutant exposure impacts the detoxification organs, namely the liver and kidney of N. nana. (i) We performed SEM-EDS to quantify metal content and mineral nutrients, and found significant differences in essential metal (Fe and Zn) content in the liver, and significant differences in Cu and one mineral nutrient (K) in the kidneys. (ii) We performed histological analysis and found more histopathological lesions in detoxification organs of WWTW bats. (iii) We calculated hepatosomatic/renalsomatic indices (HSI/RSI) to investigate whole organ effects, and found significant increases in organ size at WWTWs. (iv) We quantified metallothionein 1E (MT1E), using Western Blot immunodetection. Contrary to predictions, we found no significant upregulation of MT1E in bats at WWTWs. Ultimately, N. nana exploiting WWTWs may suffer chronic health problems from sub lethal damage to organs responsible for detoxifying pollutants. PMID- 26602786 TI - Aerosol therapy in intensive and intermediate care units: prospective observation of 2808 critically ill patients. AB - PURPOSE: Unlike in the outpatient setting, delivery of aerosols to critically ill patients may be considered complex, particularly in ventilated patients, and benefits remain to be proven. Many factors influence aerosol delivery and recommendations exist, but little is known about knowledge translation into clinical practice. METHODS: Two-week cross-sectional study to assess the prevalence of aerosol therapy in 81 intensive and intermediate care units in 22 countries. All aerosols delivered to patients breathing spontaneously, ventilated invasively or noninvasively (NIV) were recorded, and drugs, devices, ventilator settings, circuit set-up, humidification and side effects were noted. RESULTS: A total of 9714 aerosols were administered to 678 of the 2808 admitted patients (24 %, CI95 22-26 %), whereas only 271 patients (10 %) were taking inhaled medication before admission. There were large variations among centers, from 0 to 57 %. Among intubated patients 22 % (n = 262) received aerosols, and 50 % (n = 149) of patients undergoing NIV, predominantly (75 %) inbetween NIV sessions. Bronchodilators (n = 7960) and corticosteroids (n = 1233) were the most frequently delivered drugs (88 % overall), predominantly but not exclusively (49 %) administered to patients with chronic airway disease. An anti-infectious drug was aerosolized 509 times (5 % of all aerosols) for nosocomial infections. Jet nebulizers were the most frequently used device (56 %), followed by metered dose inhalers (23 %). Only 106 (<1 %) mild side effects were observed, despite frequent suboptimal set-ups such as an external gas supply of jet nebulizers for intubated patients. CONCLUSIONS: Aerosol therapy concerns every fourth critically ill patient and one-fifth of ventilated patients. PMID- 26602791 TI - Enhancing tetrabromobisphenol A biodegradation in river sediment microcosms and understanding the corresponding microbial community. AB - In situ remediation of contaminated sediment using microbes is a promising environmental treatment method. This study used bioaugmentation to investigate the biodegradation of tetrabromobisphenol A (TBBPA) in sediment microcosms collected from an electronic-waste recycling site. Treatments included adding possible biodegradation intermediates of TBBPA, including 2,4-dibromophenol (2,4 DBP), 2,4,6-tribromophenol (TBP), and bisphenol A (BPA) as co-substrates. Bioaugmentation was done with Ochrobactrum sp. T (TBBPA-degrader) and a mixed culture of Ochrobactrum sp. T, Bacillus sp. GZT (TBP-degrader) and Bacillus sp. GZB (BPA-degrader). Results showed that bioaugmentation with Ochrobactrum sp. T significantly improved TBBPA degradation efficiencies in sediment microcosms (P < 0.01); aerobic conditions increased the microbes' degradation activities. Co substrates 2,4-DBP, TBP and BPA inhibited biodegradation of TBBPA. A metagenomic analysis of total 16S rRNA genes from the treated sediment microcosms showed that the following dominant genera: Ochrobactrum, Parasegetibacter, Thermithiobacillus, Phenylobacterium and Sphingomonas. The genus level of Ochrobactrum increased with increased degradation time, within 10-week of incubation. Microbes from genus Ochrobactrum are mainly linked to enhance the TBBPA biodegradation. PMID- 26602792 TI - Ten-year trends in urinary concentrations of triclosan and benzophenone-3 in the general U.S. population from 2003 to 2012. AB - Despite their popular use and emerging evidences of adverse health effects, consequent trends in population level triclosan and benzophenone-3 exposure have been poorly evaluated. Therefore, we examined temporal trends of urinary triclosan and benzophenone-3 concentration in the general U.S. population by combining five cycles of National Health and Nutritional Examination Survey (NHANES, 2003-2012) data. We calculated percent changes and the least square geometric means (LSGMs) of urinary triclosan and benzophenone-3 concentration from 10,232 participants by using multivariable regression models. As a result, LSGM concentration of urinary triclosan and benzophenone-3 did not show statistically significant changes over the study period. [Percent change (95% CI): Triclosan, -7.35% (-20.86, 8.47); Benzophenone-3, 7.08% (-27.88, 58.99)] However, we found decreasing trend of urinary triclosan concentration and increasing trend of urinary benzophenone-3 concentration since 2005-2006. Socio demographic factors which affected urinary concentration of triclosan and benzophenone-3 persisted throughout 10 year study period. Highest income group showed higher level of urinary triclosan and benzophenone-3 concentration. Overall concentration of benzophenone-3 was higher in female than in male, and higher in non-Hispanic Whites than any other races/ethnicities. PMID- 26602793 TI - [Cutaneous larva migrans in Mauritania]. PMID- 26602794 TI - Highly virulent M1 Streptococcus pyogenes isolates resistant to clindamycin. AB - CONTEXT: Emm1-type group A Streptococcus (GAS), or Streptococcus pyogenes, is mostly responsible for invasive infections such as necrotizing fasciitis (NF) and streptococcal toxic shock syndrome (STSS). The recommended treatment of severe invasive GAS infections is a combination of clindamycin and penicillin. Until 2012, almost all emm1 isolates were susceptible to clindamycin. OBJECTIVES: We aimed to identify the phenotypic and genotypic characteristics of emm1 GAS clone resistant to clindamycin. METHODS: GAS strains were characterized by emm sequence typing, detection of genes encoding pyrogenic exotoxins or superantigens. Cluster analysis was performed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Antibiotic susceptibility was assessed using disk diffusion and resistance genes were detected by PCR. RESULTS: A total of 1321 GAS invasive isolates were analyzed between January 2011 and December 2012. The overall number of invasive isolates resistant to clindamycin was 52 (3.9%); seven of them were emm1 isolates. All isolates had the same genomic markers: macrolide resistance due to the presence of the erm(B) gene, emm subtype 1.0, the same toxin or superantigen profile, PFGE pattern and sequence type. CONCLUSION: This is the first description of highly virulent GAS emm1 isolates resistant to clindamycin in France. This article strengthens the need for monitoring the epidemiology of invasive GAS strains as they could lead to changes in treatment guidelines. PMID- 26602795 TI - Five-year follow-up of a randomized, controlled trial comparing saphenofemoral ligation and stripping of the great saphenous vein with endovenous laser ablation (980 nm) using local tumescent anesthesia. AB - OBJECTIVE: The objective of this study was to compare the long-term results (groin-related recurrence, great saphenous vein [GSV] occlusion rate, Clinical class, Etiology, Anatomy, and Pathophysiology [CEAP] staging, and quality of life [QoL]) after the treatment of a GSV incompetence by saphenofemoral ligation and stripping (SFL/S) with endovenous laser ablation bare fiber, 980 nm (EVLA). METHODS: Patients with GSV insufficiency and varicose veins were randomized to either undergo SFL/S or EVLA, both of which were performed under tumescent anesthesia. The long-term results, which included the anatomic occlusion rate, varicose vein recurrence at the saphenofemoral junction (SFJ), relief of venous symptoms and QoL, were compared up to 5 years after treatment. RESULTS: A total of 130 legs of 121 patients were treated with either SFL/S (n = 68) or EVLA (n = 62). In the first 12 months, three recanalizations of the GSV were observed after EVLA. Up to 5 years later, more recurrent varicose veins caused by neoreflux in incompetent tributaries of the SFJ were observed in after EVLA (31%; 19/61) compared with SFL/S (7%; 4/60; P < .01). Neovascularization in the groin with clinically visible recurrence identified at 3 and 5 years post-treatment follow up was only observed in the SFL/S group (n = 6). After 5 years, clinically visible recurrences originating from the SFJ region after EVLA were observed 33% (20/61) compared with 17% of patients (10/60) after SFL/S (P < .04). In both treatment groups, venous symptoms improved significantly. Patients in both groups reported a continuing significant cosmetic improvement measured on a visual analog scale of 1 to 10 (mean, 7.49; P < .01). There was no difference in the CEAP staging and a standardized, non-disease-specific instrument for describing and valuing health states (EuroQol-5D), between the groups up to 5 years after follow-up. CONCLUSIONS: At the 5-year follow-up, a significantly higher varicose vein recurrence rate originated at the SFJ region after EVLA compared with SFL/S. There were no differences in the relief of venous symptoms, CEAP staging, or general QoL between the groups. PMID- 26602796 TI - The snuffbox fistula should be preferred over the wrist arteriovenous fistula. AB - OBJECTIVE: The snuffbox arteriovenous fistula (SBAVF) is the most distal native vascular access. Although published data show a favorable outcome, the SBAVF is not strongly recommended by the guidelines. The present study compared the patency of SBAVFs and wrist AVFs (WAVFs). METHODS: All 416 AVFs created by the same nephrologist from March 2006 to October 2014 were reviewed. From 416 procedures, 47 SBAVFs and 77 WAVFs with vessels suitable for a SBAVF were selected. RESULTS: Although vessel diameters used for construction of the SBAVFs were smaller than those used for WAVFs, the outcome of vascular access was similar. At 18 months, primary patency was 72% for SBAVF and 65% for WAVF (P = .48), and secondary patency was 93% for SBAVF and 94% for WAVF (P = .89). CONCLUSIONS: In our experience, a SBAVF performs as well as a WAVF up to 18 months after creation. We suggest favoring SBAVF, especially in young patients without comorbidities, as the primary vascular access. PMID- 26602797 TI - Methyl jasmolate treated buckwheat sprout powder enhances glucose metabolism by potentiating hepatic insulin signaling in estrogen-deficient rats. AB - OBJECTIVES: Methyl jasmolate (MeJA)-treated vegetables produce higher concentrations of various bioactive compounds. We investigated whether long-term oral consumption of MeJA-treated and untreated buckwheat sprout powder improves energy, glucose, lipid, and bone metabolism induced by estrogen deficiency in ovariectomized (OVX) rats fed high-fat diets, and explored the mechanisms involved. METHODS: OVX rats were divided into four groups and fed high-fat diets supplemented with 3% dextrin (OVX-control), buckwheat sprout powder (BWS), or MeJA-treated buckwheat sprout powder (MJ-BWS) for 12 wk. Sham rats without estrogen deficiency had a control diet as a normal-control. RESULTS: MeJA treatment increased total polyphenols and flavonoids by about 1.6 fold and isoorientin, orientin, rutin, and vitexin were elevated by about 18% in buckwheat. After 12 wk, OVX rats exhibited increased weight gain, fat mass, skin temperature, hyperglycemia, and decreased bone mineral density (BMD) compared to sham rats. BWS prevented the increase of skin temperature and decrease of femur BMD, but did not improve energy glucose homeostasis as much as MJ-BWS. MJ-BWS prevented increases in body weight and fat mass. Energy expenditure was lowest in OVX-control, followed by BWS, MJ-BWS, and normal-control. Furthermore, MJ-BWS exhibited greater improvements in glucose and insulin tolerance than OVX-control and BWS. Phosphorylation of hepatic Akt and AMPK was potentiated, in ascending order of OVX-control, BWS, MJ-BWS, and normal-control, whereas PEPCK expression was decreased. CONCLUSIONS: MJ-BWS prevented and ameliorated the disturbances in energy and glucose metabolism in estrogen-deficient animals better than BWS. Therefore, besides flavonoids in BWS, other components such as phytoalexins produced in MJ-BWS during MeJA-treatment might play a crucial role in the improvement. PMID- 26602798 TI - Intracranial dural based chondroma. AB - Intracranial chondromas are benign, slow-growing, cartilaginous tumors, which comprise only about 0.2% of all intracranial tumors. The majority of these lesions occur at the base of the skull, where they are thought to arise from residual embryonic chondrogenic cells along the basal synchondrosis. Very rarely, they may also originate from the convexity dura, falx cerebri, or the brain parenchyma. We present a patient with a dural based chondroma to highlight the technical considerations of surgical resection. The recent literature on intracranial chondromas regarding incidence, pathophysiologic origin, clinical symptoms, imaging, histopathology and prognosis is reviewed. PMID- 26602799 TI - Manual muscle test at C5 palsy onset predicts the likelihood of and time to C5 palsy resolution. AB - The primary objective of this study was to identify time to and prognostic factors of C5 palsy resolution. All patients over a 7 year period who experienced C5 palsy following a posterior decompression and instrumented fusion surgery were retrospectively reviewed. C5 palsy resolution was defined as a recovery of deltoid muscle function equal to or greater than the preoperative condition as defined by the manual muscle test (MMT). Of the 511 patients who met the selection criteria, 8.6% (n=44) experienced C5 palsy. MMT information was available for 43 patients; 81.4% (n=35) had full resolution from their condition. Of the 35 patients who resolved, the median MMT score at onset was 3-. Following a discrete-time proportional hazards model, the hazards of C5 palsy resolution increased by 19% for every one-grade increase in MMT score at symptom onset (hazard ratio [HR]=1.19, p=0.005). Moreover, males displayed a 71% lower hazard of resolution than females (HR=0.29, p=0.003). Following an adjusted Kaplan-Meier analysis, the median time to C5 palsy resolution was between 6 months and 1 year. In a multiple linear regression, a lower MMT score at the onset of C5 palsy predicted a longer time to C5 palsy resolution (coefficient=-0.19, p=0.003). Time to C5 palsy onset was not statistically associated with hazards of palsy resolution (p=0.381) or time to resolution (p=0.121). A higher MMT score at the onset of C5 palsy statistically significantly predicted a higher chance of resolution and a shorter recovery time. Female sex was also associated with a higher hazard of resolution. PMID- 26602800 TI - Varicella zoster virus rhombencephalomyelitis following radiation therapy for oropharyngeal carcinoma. AB - We report a 64-year-old man with a history of stage IV oropharyngeal squamous cell carcinoma treated with cisplatin and cetuximab followed by radiation therapy who developed a rapidly advancing rhombencephalomyelitis 11 months after the completion of radiation to the base of his tongue. His initial symptoms were left ear paresthesias, dysphagia, and progressive descending weakness. Routine cerebrospinal fluid (CSF) analysis was unremarkable. Initial MRI of the brain and cervical spinal cord revealed a demarcated symmetrical heterogeneously enhancing intramedullary lesion involving the cervicomedullary spinal cord. Progressive neurological worsening included increasing weakness of his limbs, facial weakness and ocular motility disorders and MRI revealed that the lesion was advancing into his pons and cervical spinal cord. Empiric treatment for radiation myelitis was initiated. Although CSF polymerase chain reaction was negative for varicella zoster virus (VZV), antibody studies revealed intrathecal synthesis of antibody to VZV and treatment for VZV was started as well. Improvement was slow and incomplete with subsequent worsening resulting in death in 5.5 weeks. The diagnosis of rhombencephalitis and myelitis following radiation therapy may be exquisitely challenging. The possibility of VZV, a treatable disorder, should be included in the differential diagnosis. PMID- 26602801 TI - Iatrogenic intradural arachnoid cyst following tethered cord release in a child. AB - Iatrogenic arachnoid cysts represent uncommon complications of intradural spinal procedures. Here we present the case of a 7-year-old girl who was found to have a symptomatic, pathologically proven, intradural arachnoid cyst 3 years following tethered cord release. The patient originally presented with abnormal urodynamics testing and was found to have fatty infiltration in her filum terminale. She underwent sectioning of the filum terminale without complications. The patient presented 3 years later with pain and neurogenic claudication. The patient was successfully treated with subarachnoid cyst fenestration with resolution of her bilateral lower extremity pain. Spinal intradural arachnoid cysts represent an important, though rare, postoperative complication of dural opening. PMID- 26602802 TI - [Arteriovenous malformations of the brain: personal experience with 121 patients treated with microsurgery]. AB - INTRODUCTION: Arteriovenous malformations (AVM) can be found in 0.1% of the population, and the most frequent presenting symptom is intracranial haemorrhage. AIM: To conduct a descriptive analysis of a series of cases of AVM that had been treated surgically by a neurosurgeon. PATIENTS AND METHODS: The cases of AVM treated surgically by the author over the period 1990 to May 2014 were selected from a hospital register, and then the clinical, demographic and angiographic aspects were reviewed, together with the clinico-radiological findings six months after surgery. RESULTS: Of the 400 patients treated over that same period, 121 were operated on by the author, their mean age being 34.3 years (range: 5-75 years). 61.7% of the patients were diagnosed due to a brain haemorrhage, and the second most frequent presenting symptom, in 19.8% of them, was because of epileptic seizures. A superficial supratentorial localisation, occurring in 97 cases (80.2%), was the most common. Over half the patients presented a low-grade AVM, I-II, according to the Spetzler and Martin scale. Twelve patients (10%) had associated non-intranidal aneurysms. In most cases, 109 (90.1%), elective surgery was performed. Complete resection of the AVM after the last angiographic examination was achieved in 118 patients (97.5%). The clinical results were good (good recovery and moderate disability) in 114 cases (95%), and poor (great disability and death), in six (5%). CONCLUSIONS: Surgery is the best therapeutic option for many patients with AVM, if appropriate selection criteria are used. PMID- 26602803 TI - [Experience in molecular diagnostic in hereditary neuropathies in a pediatric tertiary hospital]. AB - INTRODUCTION: Charcot-Marie-Tooth (CMT) is the most common hereditary sensory motor neuropathy. Advances in molecular diagnosis have increased the diagnostic possibilities of these patients. PATIENTS AND METHODS: Retrospective study of 36 pediatric patients diagnosed with CMT in a tertiary center in 2003-2015. RESULTS: We found 16 patients were diagnosed by a duplication in PMP22; two cases were diagnosed of hereditary neuropathy with liability to pressure palsies, one with a point mutation in PMP22; a male with a mild demyelinating phenotype, without family history, was diagnosed with GJB1 mutation; in a patient with a peripheral hypotonia at birth and axonal pattern in EMG by mutation in MFN2; a gypsy patient, with consanguineous family, CMT4D, was identified by a mutation in the gene NDRG1; a patient with multiplex congenital arthrogryposis and vocal cord paralysis, whose mother had a scapular-peroneal syndrome, had a congenital spinal muscular atrophy with mild distal axonal neuropathy by mutation in gene TRPV4; three girls, from a gypsy consanguineous family, with axonal CMT with neuromyotonic discharges were diagnosed by a mutation in the gene HINT1; twelve patients haven't molecular diagnosis currently. CONCLUSIONS: CMT1A predominated in our series (44%), as previous studies. We emphasize the description of a patient with a mutation in TRPV4 recently described as a cause of CMT2C and three cases, of gypsy consanguineous family, with the same mutation in HINT1 gene, recently described as a cause of axonal neuropathy with neuromyotonia, autosomal recessive (AR-CMT2). The proportion of patients without molecular diagnosis is similar to main European series. PMID- 26602805 TI - [Affective and psychotic disorders in multiple sclerosis]. AB - INTRODUCTION: Multiple sclerosis (MS) is the second most important cause of disability of a neurological origin in young adults. Both the physical and the psychiatric (affective and psychotic disorders) clinical signs and symptoms have a negative impact on the patients' health-related quality of life. AIM: To shed light on the prevalence and pathogenesis of the affective and psychotic symptoms present in MS. DEVELOPMENT: This review includes an update of the most significant studies published in the literature that have analysed the prevalence and pathogenesis of affective and psychotic signs and symptoms in patients with MS. The evidence available to date was reviewed in order to explore the association between the affective and psychotic symptoms of MS. CONCLUSIONS: Depression is the most frequent psychiatric disorder in MS. Further research is needed to clarify the underlying mechanisms that can trigger affective and psychotic symptoms in MS. Controlling those symptoms in patients with MS could improve their health-related quality of life. PMID- 26602804 TI - Spondylotic myelopathy mimicking myelitis: diagnostic clues by magnetic resonance imaging. AB - INTRODUCTION: Spondylotic myelopathy is the commonest cause of nontraumatic myelopathy. Radiological features of spondylotic myelopathy can often overlap with inflammatory myelopathies which may lead to a delayed or incorrect diagnosis and therapy. A distinctive gadolinium enhancement pattern recently described may help to differentiate spondylotic from inflammatory myelopathy. CASE REPORTS: Case 1: a 38-years-old man presented with a 2-year history of paresthesias in the upper extremities, and one year later cramps on the right limbs and numbness over right C5 and C6 dermatomes, related to movement of the neck. Case 2: a 44-year old man presented with a 1-year history of progressive gait difficulties and sensory disturbance in the hands, and a recent onset of bladder dysfunction. In both cases, spinal cord MRI identified a longitudinal cervical T2-signal hyperintensity associated with a pancakelike transverse band of gadolinium enhancement just below the site of maximum spinal stenosis, and circumferential or hemicord enhancement on axial images. CONCLUSIONS: The radiological features of spondylotic myelopathy may resemble those of inflammatory origin. The recognition of a transverse pancakelike gadolinium enhancement immediately below the site of maximal compression as a typical radiological pattern of spondylotic myelopathy is important to reduce the risk of misdiagnosis and to help in the management of these patients. PMID- 26602807 TI - [52.a Reunion de la Sociedad Espanola de Neurofisiologia Clinica (I). Communications]. PMID- 26602806 TI - Brain-to-brain embolism: an unknown pathway to consider in ischemic strokes. PMID- 26602808 TI - [Idiopathic intracranial hypotension associated with occult spinal dysraphism]. PMID- 26602809 TI - [Acute rhabdomyolysis in a female heterozygotic carrier of an undescribed mutation in the PNPLA2 gene]. PMID- 26602810 TI - [Toxic demyelinating neuropathy and leukoencephalopathy in patients who take the slimming products Thermatrim (r) and Pura Alegria (r)]. PMID- 26602812 TI - The role of fathers during pregnancy: A qualitative exploration of Arabic fathers' beliefs. AB - OBJECTIVE: to gain a deeper understanding of Arabic fathers' involvement in maternity care during their wives' pregnancy, and to give a descriptive interpretative explanation of their lived experience. DESIGN AND METHOD: a phenomenological study was undertaken to understand the perspectives of Arabic fathers regarding their involvement in maternity care. In-depth, semi-structured, audio taped interviews were conducted with 19 Arabic fathers. The analysis was done using Interpretative Phenomenological Analysis. FINDINGS: the main theme of our findings can be expressed as 'the role of fathers during pregnancy,' which encompasses the degree and type of support that fathers offered to their wives. Four sub-themes emerged from the data: sharing of responsibility, compassion and attention, the father is the guardian of the wife, and prayer and supplication. KEY CONCLUSION AND IMPLICATIONS FOR PRACTICE: the study revealed the perspectives of Arabic fathers about the degree and type of support they offered to their wives during pregnancy. The present maternity health policies in Arabic countries need revision to allow for fathers' inclusion. The findings of this study may offer insight that helps stakeholders of maternal health programs to support the meaningful involvement of fathers in maternity care. PMID- 26602811 TI - Hydrogen sulfide-induced itch requires activation of Cav3.2 T-type calcium channel in mice. AB - The contributions of gasotransmitters to itch sensation are largely unknown. In this study, we aimed to investigate the roles of hydrogen sulfide (H2S), a ubiquitous gasotransmitter, in itch signaling. We found that intradermal injection of H2S donors NaHS or Na2S, but not GYY4137 (a slow-releasing H2S donor), dose-dependently induced scratching behavior in a MU-opioid receptor dependent and histamine-independent manner in mice. Interestingly, NaHS induced itch via unique mechanisms that involved capsaicin-insensitive A-fibers, but not TRPV1-expressing C-fibers that are traditionally considered for mediating itch, revealed by depletion of TRPV1-expressing C-fibers by systemic resiniferatoxin treatment. Moreover, local application of capsaizapine (TRPV1 blocker) or HC 030031 (TRPA1 blocker) had no effects on NaHS-evoked scratching. Strikingly, pharmacological blockade and silencing of Cav3.2 T-type calcium channel by mibefradil, ascorbic acid, zinc chloride or Cav3.2 siRNA dramatically decreased NaHS-evoked scratching. NaHS induced robust alloknesis (touch-evoked itch), which was inhibited by T-type calcium channels blocker mibefradil. Compound 48/80 induced itch was enhanced by an endogenous precursor of H2S (L-cysteine) but attenuated by inhibitors of H2S-producing enzymes cystathionine gamma-lyase and cystathionine beta-synthase. These results indicated that H2S, as a novel nonhistaminergic itch mediator, may activates Cav3.2 T-type calcium channel, probably located at A-fibers, to induce scratching and alloknesis in mice. PMID- 26602813 TI - Freestanding carbon-coated CNT/Sn(O2) coaxial sponges with enhanced lithium-ion storage capability. AB - Carbon-coated, carbon nanotube (CNT)/tin(oxide) spongy coaxial nanostructures, CNT/Sn(O(2))@C, with large areal mass loadings have been developed by employing a three-dimensional CNT sponge as a backbone. The freestanding spongy coaxial nano architecture demonstrates exceptional electrochemical characteristics of tin based anode materials with appropriate structural engineering for energy storage application. PMID- 26602814 TI - Combination of anti-tuberculosis drugs with vitamin C or NAC against different Staphylococcus aureus and Mycobacterium tuberculosis strains. AB - BACKGROUNDS: Hepatotoxicity due to anti tuberculosis drugs, rifampin and isoniazid, is a major problem in tuberculosis patients. Vitamin C, an antioxidant, and N-acetyl cysteine (NAC), a scavenger of active metabolites, reduce the hepatotoxicity. The aim of present study was to investigate the effect of vitamin C and NAC individually on the antibacterial activity of anti tuberculosis drugs against Mycobacterium tuberculosis and Staphylococcus aureus strains. METHODS: The MICs of each compound against all strains were determined in 96 wells plate. Rifampin was tested at serial two fold concentrations alone or in combination with NAC or vitamin C. RESULTS: The MIC of rifampin against different strains of S. aureus was 0.008-0.032 MUg/ml. The MIC of rifampin and isoniazid against M. tuberculosis strains were 40 and 0.2 MUg/ml, respectively. Vitamin C and NAC had no antibacterial activity against all strains. MIC of rifampin was reduced two fold by combination with vitamin C for all S. aureus strains, while NAC did not affect the antibacterial activity of rifampin. Vitamin C and NAC had remarkable effects on the antibacterial activity of anti tuberculosis drugs against M. tuberculosis. CONCLUSIONS: Synergistic effects were observed between rifampin or isoniazid and vitamin C against all tested strains. However, combination therapy of rifampin and isoniazid with NAC was not being effective. This study highlighted the advantages of combination of anti tuberculosis drugs and vitamin C to eradicate the microbial infections. PMID- 26602818 TI - Molecular characterization of Galectin-8 from Nile tilapia (Oreochromis niloticus Linn.) and its response to bacterial infection. AB - Galectins belong to the family of galactoside-binding proteins and play a major role in the immune and inflammatory responses of vertebrates and invertebrates. The galectin family is divided into three subtypes based on molecular structure; prototypes, chimera types, and tandem-repeated types. We isolated and characterized the cDNA of galectin-8 (OnGal-8) in Nile tilapia (Oreochromis niloticus). OnGal-8 consisted of a 966 bp open reading frame (ORF) that encoded a 321 amino acid protein (43.47 kDa). Homology and phylogenetic tree analysis suggested the protein was clustered with galectin-8s from other animal species and shared at least 56.8% identity with salmon galectin-8. Structurally, the amino acid sequence included two distinct N- and C- terminus carbohydrate recognition domains (CRDs) of 135 and 133 amino acids, respectively, that were connected by a 39 amino acid polypeptide linker. The N- and C-CRDs contained two conserved WG-E-I and WG-E-T motifs, suggesting they have an important role in mediating the specific interactions between OnGal-8 and saccharide moieties such as beta-galactoside. The structure of OnGal-8 was characterized by a two-fold symmetric pattern of 10-and 12-stranded antiparallel beta-sheets of both N- and C CRDs, and the peptide linker presumably formed a random coil similar to the characteristic tandem-repeat type galectin. The expression of OnGal-8 in healthy fish was highest in the skin, intestine, and brain. Experimental challenge of Nile tilapia with S. agalactiae resulted in significant up-regulation of OnGal 8in the spleen after 5 d. Our results suggest that OnGal-8 is involved in the immune response to bacterial infection. PMID- 26602817 TI - Filling the gap: Developing health economics competencies for baccalaureate nursing programs. AB - BACKGROUND: The need for greater involvement of the nursing profession in cost containment efforts has been documented extensively. More thorough education of nurses in the subject of health economics (HE) is one of the factors that could contribute toward achievement of that goal. PURPOSE: The project's main contribution is the development of the unique list of essential HE competencies for baccalaureate nursing students. METHODS: The proposed competencies were developed and validated using the protocol by Lynn (1986) for two-stage content validation of psychometric instruments. An additional validation step that included a nationwide survey of nurse administrators was conducted to measure the value they place on the health economics-related skills and knowledge of their employees. RESULTS: A set of six HE competencies was developed. Their validity was unanimously approved by the panel of five experts and additionally supported by the survey results (with individual competencies' approval rates of 67% or higher). CONCLUSIONS: The incorporation of economic thinking into the nationwide standards of baccalaureate nursing education, and professional nursing competencies, will enhance the capacity of the nursing workforce to lead essential change in the delivery of high-value affordable health care nationwide. PMID- 26602815 TI - Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation. AB - Histone H3K36 trimethylation (H3K36me3) is frequently lost in multiple cancer types, identifying it as an important therapeutic target. Here we identify a synthetic lethal interaction in which H3K36me3-deficient cancers are acutely sensitive to WEE1 inhibition. We show that RRM2, a ribonucleotide reductase subunit, is the target of this synthetic lethal interaction. RRM2 is regulated by two pathways here: first, H3K36me3 facilitates RRM2 expression through transcription initiation factor recruitment; second, WEE1 inhibition degrades RRM2 through untimely CDK activation. Therefore, WEE1 inhibition in H3K36me3 deficient cells results in RRM2 reduction, critical dNTP depletion, S-phase arrest, and apoptosis. Accordingly, this synthetic lethality is suppressed by increasing RRM2 expression or inhibiting RRM2 degradation. Finally, we demonstrate that WEE1 inhibitor AZD1775 regresses H3K36me3-deficient tumor xenografts. PMID- 26602816 TI - A Pleiotropic RNA-Binding Protein Controls Distinct Cell Cycle Checkpoints to Drive Resistance of p53-Defective Tumors to Chemotherapy. AB - In normal cells, p53 is activated by DNA damage checkpoint kinases to simultaneously control the G1/S and G2/M cell cycle checkpoints through transcriptional induction of p21(cip1) and Gadd45alpha. In p53-mutant tumors, cell cycle checkpoints are rewired, leading to dependency on the p38/MK2 pathway to survive DNA-damaging chemotherapy. Here we show that the RNA binding protein hnRNPA0 is the "successor" to p53 for checkpoint control. Like p53, hnRNPA0 is activated by a checkpoint kinase (MK2) and simultaneously controls both cell cycle checkpoints through distinct target mRNAs, but unlike p53, this is through the post-transcriptional stabilization of p27(Kip1) and Gadd45alpha mRNAs. This pathway drives cisplatin resistance in lung cancer, demonstrating the importance of post-transcriptional RNA control to chemotherapy response. PMID- 26602819 TI - Docetaxel (DTX)-loaded polydopamine-modified TPGS-PLA nanoparticles as a targeted drug delivery system for the treatment of liver cancer. AB - Polydopamine-based surface modification is a simple way to functionalize polymeric nanoparticle (NP) surfaces with ligands and/or additional polymeric layers. In this work, we developed DTX-loaded formulations using polydopamine modified NPs synthesized using D-alpha-tocopherol polyethylene glycol 1000 succinate-poly(lactide) (pD-TPGS-PLA/NPs). To target liver cancer cells, galactosamine was conjugated on the prepared NPs (Gal-pD-TPGS-PLA/NPs) to enhance the delivery of DTX via ligand-mediated endocytosis. The size and morphology of pD-TPGS-PLA/NPs and Gal-pD-TPGS-PLA/NPs changed obviously compared with TPGS PLA/NPs. In vitro studies showed that TPGS-PLA/NPs, pD-TPGS-PLA/NPs and Gal-pD TPGS-PLA/NPs had similar release profiles of DTX. Both confocal laser scanning microscopy and flow cytometric results showed that coumarin 6-loaded Gal-pD-TPGS PLA/NPs had the highest cellular uptake efficiency in liver cancer cell line HepG2. Moreover, DTX-loaded Gal-pD-TPGS-PLA/NPs inhibited the growth of HepG2 cells more potently than TPGS-PLA/NPs, pD-TPGS-PLA/NPs, and a clinically available DTX formulation (Taxotere(r)). The in vivo biodistribution experiments show that the Gal-pD-TPGS-PLA/NPs are specifically targeted to the tumor. Furthermore, the in vivo anti-tumor effects study showed that injecting DTX loaded Gal-pD-TPGS-PLA/NPs reduced the tumor size most significantly on hepatoma bearing nude mice. These results suggest that Gal-pD-TPGS-PLA/NPs prepared in the study specifically interacted with the hepatocellular carcinoma cells through ligand-receptor recognition and they may be used as a potentially eligible drug delivery system targeting liver cancers. STATEMENT OF SIGNIFICANCE: Polydopamine based surface modification is a simple way to functionalize polymeric nanoparticle surfaces with ligands and/or additional polymeric layers. In this work, we developed docetaxel (DTX)-loaded formulations using polydopamine modified NPs synthesized from D-alpha-tocopherol polyethylene glycol 1000 succinate-poly(lactide) (pD-TPGS-PLA/NPs). To target liver cancer cells, galactosamine was conjugated on the prepared NPs (Gal-pD-TPGS-PLA/NPs) to enhance the delivery of DTX via ligand-mediated endocytosis. Both confocal laser scanning microscopy and flow cytometric results showed that coumarin 6-loaded Gal-pD-TPGS PLA/NPs had the highest cellular uptake efficiency for liver cancer cell line HepG2. The in vivo biodistribution experiments show that the Gal-pD-TPGS-PLA/NPs are specifically targeted to the tumor. Furthermore, the in vivo anti-tumor effects study showed that injecting DTX-loaded Gal-pD-TPGS-PLA/NPs reduced the tumor size most significantly on hepatoma-bearing nude mice. These results suggest that Gal-pD-TPGS-PLA/NPs prepared in the study specifically interacted with the hepatocellular carcinoma cells through ligand-receptor recognition and they could be used as a potentially eligible drug delivery system targeting liver cancers. PMID- 26602820 TI - Mesoporous manganese silicate coated silica nanoparticles as multi-stimuli responsive T1-MRI contrast agents and drug delivery carriers. AB - A novel kind of monodisperse mesoporous manganese silicate coated silica nanoparticle (MMSSN) as a highly efficient T1-weighted MRI contrast agent (CA) and drug carrier for cancer diagnosis and chemotherapy has been constructed by a modified "SiO2 sacrifice and in situ silicate growth" approach under a relatively low hydrothermal temperature and alkali-free condition. The mesoporous manganese silicate shell provides a large specific surface area and abundant exposed Mn paramagnetic centers to water molecules, which endows the MMSSNs with extraordinarily high longitudinal relaxivity. Meanwhile, the MMSSNs presented an efficient pH/redox-responsive T1-MRI feature based on the significant enhancement of relaxation rate (r1) stimulated by mild acidic environment or reducing agent (GSH) both in vitro and in vivo. Furthermore, the mesoporous structure and negatively charged pore surface of the manganese silicate shell enable the MMSSNs to attain anti-cancer drug (DOX) storage and a pH-responsive release, which is suitable for on-demand drug release for the chemotherapy of tumors. Therefore, the mesoporous manganese silicate-based nanomaterial is a promising candidate as T1-MRI CAs and anticancer-drug delivery carriers for the theranostics of tumor in an intelligent and on-demand manner. STATEMENT OF SIGNIFICANCE: MRI is one of the most frequently used imaging techniques in daily clinics for cancer diagnosis. Using contrast agents (CAs) in MRI can afford much clearer and enlarged images of detectable organs. Gadolinium (Gd(3+))-based T1-positive CAs are widely used but associated with the risk of nephrogenic systemic fibrosis. To achieve much safer CAs, various Mn(2+)-based T1-positive CAs have been reported, such as MnO or core shell MnOx-based nanoparticles. However, the efficiency of these CAs is still lower. Herein, we report a novel kind of mesoporous manganese silicate coated silica nanoparticle as CA and anti-cancer drug carrier. Results obtained from this study, especially the pH/redox-responsive T1-MRI feature are helpful for us to further design efficient MnSiO3-based materials for clinical MRI applications. PMID- 26602821 TI - Silk protein-based hydrogels: Promising advanced materials for biomedical applications. AB - Hydrogels are a class of advanced material forms that closely mimic properties of the soft biological tissues. Several polymers have been explored for preparing hydrogels with structural and functional features resembling that of the extracellular matrix. Favourable material properties, biocompatibility and easy processing of silk protein fibers into several forms make it a suitable material for biomedical applications. Hydrogels made from silk proteins have shown a potential in overcoming limitations of hydrogels prepared from conventional polymers. A great deal of effort has been made to control the properties and to integrate novel topographical and functional characteristics in the hydrogel composed from silk proteins. This review provides overview of the advances in silk protein-based hydrogels with a primary emphasis on hydrogels of fibroin. It describes the approaches used to fabricate fibroin hydrogels. Attempts to improve the existing properties or to incorporate new features in the hydrogels by making composites and by improving fibroin properties by genetic engineering approaches are also described. Applications of the fibroin hydrogels in the realms of tissue engineering and controlled release are reviewed and their future potentials are discussed. STATEMENT OF SIGNIFICANCE: This review describes the potentiality of silk fibroin hydrogel. Silk Fibroin has been widely recognized as an interesting biomaterial. Due to its properties including high mechanical strength and excellent biocompatibility, it has gained wide attention. Several groups are exploring silk-based materials including films, hydrogels, nanofibers and nanoparticles for different biomedical applications. Although there is a good amount of literature available on general properties and applications of silk based biomaterials, there is an inadequacy of extensive review articles that specifically focus on silk based hydrogels. Silk-based hydrogels have a strong potential to be utilized in biomedical applications. Our work is an effort to highlight the research that has been done in the area of silk-based hydrogels. It aims to provide an overview of the advances that have been made and the future course available. It will provide an overview of the silk-based hydrogels as well as may direct the readers to the specific areas of application. PMID- 26602823 TI - Biomimetic fibroblast-loaded artificial dermis with "sandwich" structure and designed gradient pore sizes promotes wound healing by favoring granulation tissue formation and wound re-epithelialization. AB - The structure of dermal scaffolds greatly affects the engineered tissue's functions and the activities of seeded cells. Current strategies of dermal scaffold design tend to yield a homogeneous architecture with a uniform pore size. However, the structures of the human dermis are not homogeneous in terms of either interstitial spaces or architecture at different dermal depths. In the present study, a biomimetic fibroblasts-loaded artificial dermis composed of three-layer scaffolds with different pore sizes was prepared. The three-layer scaffolds, which look similar to a sandwich, mimic the natural structures of the human dermis, which has comparatively larger pores in the outer layers and smaller pores in the middle layer. The fibroblasts-loaded artificial dermis were shown to favor wound healing by promoting granulation tissue formation and wound re-epithelialization, as determined by a histological study and Western blotting. Our data indicated that the biomimetic fibroblasts-loaded artificial dermis with "Sandwich" structure and designed gradient pore sizes may hold promise as tissue engineered dermis. STATEMENT OF SIGNIFICANCE: Pore size effect on wound healing had been extensively studied. However, it is still not well understood whether dermal scaffolds with a uniform pore size are better than that with varied pore sizes, which are similar to human dermis as determined by our previous work. In our study, we demonstrated that the "sandwich" collagen scaffolds mimicking the natural structures of the human dermis significantly promoted wound healing compared with the "Homogeneous" scaffolds with a uniform pore size. These results may be helpful in the design of dermal scaffolds. PMID- 26602822 TI - Cell penetrating peptide-modified poly(lactic-co-glycolic acid) nanoparticles with enhanced cell internalization. AB - The surface modification of nanoparticles (NPs) can enhance the intracellular delivery of drugs, proteins, and genetic agents. Here we studied the effect of different surface ligands, including cell penetrating peptides (CPPs), on the cell binding and internalization of poly(lactic-co-glycolic) (PLGA) NPs. Relative to unmodified NPs, we observed that surface-modified NPs greatly enhanced cell internalization. Using one CPP, MPG (unabbreviated notation), that achieved the highest degree of internalization at both low and high surface modification densities, we evaluated the effect of two different NP surface chemistries on cell internalization. After 2h, avidin-MPG NPs enhanced cellular internalization by 5 to 26-fold relative to DSPE-MPG NP formulations. Yet, despite a 5-fold increase in MPG density on DSPE compared to Avidin NPs, both formulations resulted in similar internalization levels (48 and 64-fold, respectively) after 24h. Regardless of surface modification, all NPs were internalized through an energy-dependent, clathrin-mediated process, and became dispersed throughout the cell. Overall both Avidin- and DSPE-CPP modified NPs significantly increased internalization and offer promising delivery options for applications in which internalization presents challenges to efficacious delivery. PMID- 26602824 TI - cRGDyK modified pH responsive nanoparticles for specific intracellular delivery of doxorubicin. AB - Stimuli-responsive nanocarriers attract wide attention because of the unique differences in microenvironment between solid tumors and normal tissues. Herein, we reported a novel cRGDyK peptide modified pH-sensitive nanoparticle system based on poly(ethylene glycol)-poly(2,4,6-trimethoxy benzylidene-pentaerythritol carbonate) (PEG-PTMBPEC) diblock copolymer, which was expected to destroy tumor angiogenesis and kill tumor cells simultaneously. Doxorubicin (DOX)-loaded nanoparticles (NPs) were characterized to have a uniform size distribution, high entrapment efficiency, good stability in plasma as well as a pH dependent drug release pattern. Blank NPs were non-toxic to both tumor cells and normal cells, while DOX-loaded cRGDyK peptide modified NPs (cRGDyK-NPs) exhibited the pronounced cytotoxicity against B16 cells and human umbilical vein endothelial cells (HUVEC) overexpressing alphavbeta3 integrin receptors. Cellular uptake studies revealed that the highly efficient uptake of cRGDyK-NPs was attributed to the receptor-mediated endocytosis and acidic-triggered drug release. Importantly, cRGDyK-NPs could dramatically reduce the systemic toxicity of DOX and exert excellent tumor killing activity in vivo. The cRGDyK modified pH-sensitive nanocarrier is a promising vehicle for intracellular drug delivery to alphavbeta3 integrin receptor overexpressed tumor cells and neovascular cells. STATEMENT OF SIGNIFICANCE: Slow intracellular drug release and poor tumor targeting capacity are still the critical barriers of polymeric nanoparticles (NPs) for the treatment efficiency of chemotherapy. In the present study, we designed cRGDyK peptide modified poly(ethylene glycol)-poly(2,4,6-trimethoxybenzylidene pentaerythritol carbonate) (cRGDyK-PEG-PTMBPEC) NPs with active targeting and fast pH-triggered drug release. Doxorubicin (DOX)-loaded cRGDyK-PEG-PTMBPEC NPs exhibited pronounced cytotoxicity and enhanced cellular uptake against B16 cells and human umbilical vein endothelial cells overexpressing alphavbeta3 integrin receptors. Moreover, the active targeted pH-sensitive NPs can enhance the antitumor activity and reduce the systematic toxicity of DOX in vivo. PMID- 26602825 TI - Semaphorin-3a, neuropilin-1 and plexin-A1 in prosthetic-particle induced bone loss. AB - Peri-prosthetic osteolysis (PPO) occurs in response to prosthetic wear particles causing an inflammatory reaction in the surrounding tissue that leads to subsequent bone loss. Semaphorin-3a (SEM3A), neuropilin-1 (NRP1) and plexin-A1 (PLEXA1) are axonal guidance molecules that have been recently implicated in regulating bone metabolism. This study investigated SEM3A, NRP1 and PLEXA1 protein and mRNA expression in human PPO tissue and polyethylene (PE) particle stimulated human peripheral blood mononuclear cell (PBMC)-derived osteoclasts in vitro. In addition, the effects of tumour necrosis factor alpha (TNFalpha) on cultured osteoclasts was assessed. In PPO tissues, a granular staining pattern of SEM3A and NRP1 was observed within large multi-nucleated cells that contained prosthetic wear particles. Immunofluorescent staining confirmed the expression of SEM3A, NRP1 and PLEXA1 in large multi-nucleated human osteoclasts in vitro. Furthermore, SEM3A, NRP1 and PLEXA1 mRNA levels progressively increased throughout osteoclast differentiation induced by receptor activator of nuclear factor kappaB ligand (RANKL), and the presence of PE particles further increased mRNA expression of all three molecules. Soluble SEM3A was detected in human osteoclast culture supernatant at days 7 and 17 of culture, as assessed by ELISA. TNFalpha treatment for 72h markedly decreased the mRNA expression of SEM3A, NRP1 and PLEXA1 by human osteoclasts in vitro. Our findings suggest that SEM3A, NRP1 and PLEXA1 may have important roles in PPO, and their interactions, alone or as a complex, may have a role in pathological bone loss progression. STATEMENT OF SIGNIFICANCE: Peri-prosthetic osteolysis occurs in response to prosthetic wear particles causing an inflammatory reaction in the surrounding tissue that leads to subsequent bone loss. The rate of hip and knee arthroplasty is increasing by at least 5% per year. However, these joint replacements have a finite lifespan, with data from the National Joint Replacement Registry (Australia) showing that the major cause of failure of total hip replacements is aseptic loosening. In aseptic loosening, wear particles liberated from prostheses are phagocytosed by macrophages, leading to release of inflammatory cytokines and up-regulation of osteoclast formation and activity. Semaphorin-3a, neuropilin-1 and plexin-A1 are axonal guidance molecules that have been recently implicated in regulating bone metabolism. This is the first report to show that these molecules may be involved in the implant failure. PMID- 26602826 TI - A micro-architecturally biomimetic collagen template for mesenchymal condensation based cartilage regeneration. AB - The unique arcade-like orientation of collagen fibers enables cartilage to bear mechanical loads. In this study continuous-length aligned collagen threads were woven to emulate the interdigitated arcade structure of the cartilage. The weaving pattern provided a macropore network within which micromass cell pellets were seeded to take advantage of mesenchymal condensation driven chondrogenesis. Compression tests showed that the baseline scaffold had a modulus of 0.83+/ 0.39MPa at a porosity of 80%. The modulus of pellet seeded scaffolds increased by 60% to 1.33+/-0.37MPa after 28days of culture, converging to the modulus of the native cartilage. The scaffolds displayed duress under displacement controlled low-cycle fatigue at 15% strain amplitude such that load reduction stabilized at 8% after 4500 cycles of loading. The woven structure demonstrated a substantial elastic recoil where 40% mechanical strain was close to completely recovered following unloading. A robust chondrogenesis was observed as evidenced by positive staining for GAGs and type II collagen and aggrecan. Dimethyl methylene blue and sircol assays showed GAGs and collagen productions to increase from 3.36+/-1.24 and 31.46+/-3.22 at day 3 to 56.61+/-12.12 and 136.70+/-12.29MUg/MUg of DNA at day 28 of culture. This woven collagen scaffold holds a significant potential for cartilage regeneration with shorter in vitro culture periods due to functionally sufficient mechanical robustness at the baseline. In conclusion, the mimicry of cartilage's arcade architecture resulted in substantial improvement of mechanical function while enabling one of the first pellet delivery platforms enabled by a macroporous network. STATEMENT OF SIGNIFICANCE: Mesenchymal condensation is critical for driving chondrogenesis, making high density cell seeding a standard in cartilage tissue engineering. Efforts to date have utilized scaffold free delivery of MSCs in pellet form. This study developed a macroporous scaffold that is fabricated by weaving highly aligned collagen threads. The scaffold can deliver high density cell condensates while providing mechanical stiffness comparable to that of cartilage. The scaffold also mimicked the arcade like orientation of collagen fibers in cartilage. A highly robust chondrogenesis was observed in this mesenchymal cell pellet delivery system. Baseline mechanical robustness of this scaffold system will enable delivery of cell pellets as early as three days. PMID- 26602827 TI - Synthesis and bio-evaluation of novel quinolino-stilbene derivatives as potential anticancer agents. AB - A series of 25 novel quinolino-stilbene derivatives were designed, synthesized and evaluated for their potential as anticancer agents. Three of them not only displayed quite potent antiproliferative activity with IC50 values<4MUM but also showed approximately twofold selectivity against cancer cells, compared to non cancerous cells. Three other compounds exhibited comparatively good activity with IC50 values in the range of 4-10MUM, and the rest was moderately active or inactive. One of these viz. 3-[E-(4-fluorostyryl)]-2-chloroquinoline (compound 7B) caused substantial DNA damage and arrested cell cycle in S phase. Interestingly, 7B was very active against MDA-MB468 (IC50=0.12MUM), but not against other cell lines examined. Compound 3-[Z-(3-(trifluoromethyl)styryl)]-2 chloroquinoline (12A), the most effective against all cancer cell lines examined, caused prolonged cell cycle arrest at mitosis and eventually apoptosis. Data from an in vitro study showed that compound 12A inhibited microtubule polymerization in a similar fashion to nocodazole. Further study using in silico molecular modeling revealed that 12A causes the impediment of microtubule polymerization by binding to tubulin at the same cavity where podophyllotoxin binds. PMID- 26602828 TI - Localization-dependent cell-killing effects of protoporphyrin (PPIX)-lipid micelles and liposomes in photodynamic therapy. AB - The protoporphyron (PPIX)-lipid (PL-C17) liposomes were successfully prepared from the corresponding micelles by post-inserted method. Both the PL-C17 micelles and liposomes were distributed in plasma membrane and cytoplasm after incubation of the cells with PL-C17 liposomes for 1h. They translocated from plasma membrane into a certain organelle in the cells after incubation in the photosensitizer free medium. Higher photo-cytotoxicity was observed in the PL-C17 micelles and liposomes localized in plasma membrane in comparison with those localized in the cytoplasm under light irradiation. The LDH assay revealed that cytopathic damages of the plasma membrane were observed in the PL-C17 micelles and liposomes highly localized in plasma membrane. The fluorescent intensity of the calcein encapsulating DOPC liposomes post-inserted with PL-C17 increased after light irradiation, suggesting that the membrane disruption is possibly caused by oxidation of membrane lipids with ROS generated from photosensitizers and affects the photo-cytotoxicity in PDT. PMID- 26602830 TI - Prognostic significance of distal subtotal gastrectomy with standard D2 and extended D2 lymphadenectomy for locally advanced gastric cancer. AB - This study was conducted to investigate prognosis and survival of patients undergoing distal subtotal gastrectomy with D2 and D2+ lymphadenectomy for patients with locally advanced gastric cancer. Overall survival rates of 416 patients with locally advanced gastric cancer were compared between D2 and D2+ lymphadenectomy. Univariate analysis and multivariate analysis was used to identify significant prognostic factors correlated with LN metastasis and prognosis. Univariate analysis identified tumor size, lymphatic vessel invasion, pT stage, pN stage, TNM stage, locoregional recurrence, and distant recurrence, to significantly correlate with prognosis; Tumor size, LVI, and pT stage were identified as independent factors correlating with LN metastasis. Multivariate analysis demonstrated that tumor size, pT stage, pN stage, locoregional recurrence, and distant recurrence were independent prognostic factors; Tumor size and pT stage were independent prognostic factors predicting LN metastasis. When comparing 5-year survival rates of patients who underwent D2 and D2+ lymphadenectomy, as stratified by pT stage and pN stage, a significant difference was found in pN3 patients, but not for pT2-4 and pN0-2 patients, or the patient cohort as a whole. In conclusion, D2 lymphadenectomy for patients with locally advanced gastric cancer undergoing distal subtotal gastrectomy was recommended, especially in eastern Asia. PMID- 26602829 TI - Synthesis, antiviral activity and resistance of a novel small molecule HIV-1 entry inhibitor. AB - One of the most critical requirements of the infection of the human immunodeficiency virus type 1 (HIV-1) is the interaction of its surface envelope glycoprotein gp120 with the cellular receptor CD4, which initiates virus entry to cells. Therefore, envelope glycoprotein gp120 has been validated as a potential target to develop HIV-1 entry inhibitors. Here we report the evaluation of a novel non-natural amino acid, termed 882376, reported earlier as a precursor of a CD4-mimetic miniprotein, as HIV-1 entry inhibitor. 882376 showed HIV-1 inhibitory activity against a large panel of primary isolates of different subtype. Moreover, genotyping of 882376 resistant HIV-1 virus revealed three amino acid substitutions in the gp120 including one in the CD4 binding site suggesting that this molecule may bind to gp120 and prevent its binding to CD4. Additional neutralization experiments indicate that 882376 is not active against mutant pseudoviruses carrying the amino acid substitutions S375H and S375Y located in the 'Phe43 cavity' which is the major site of CD4 binding, suggesting that this compound may interfere with the interaction between gp120 and CD4. The unnatural amino acid, 882376, is expected to serve as a lead for further optimization to more potent HIV-1 entry inhibitors. PMID- 26602831 TI - Implementation and evaluation of linked parenting models in a large urban child welfare system. AB - During the past decade, there have been increased efforts to implement evidence based practices into child welfare systems to improve outcomes for children in foster care and their families. In this paper, the implementation and evaluation of a policy-driven large system-initiated reform is described. Over 250 caseworkers and supervisors were trained and supported to implement two evidence based parent focused interventions in five private agencies serving over 2,000 children and families. At the request of child welfare system leaders, a third intervention was developed and implemented to train the social work workforce to use evidence-based principles in everyday interactions with caregivers (including foster, relative, adoptive, and biological parents). In this paper, we describe the policy context and the targeted outcomes of the reform. We discuss the theory of the interventions and the logistics of how they were linked to create consistency and synergy. Training and ongoing consultation strategies used are described as are some of the barriers and opportunities that arose during the implementation. The strategy for creating a path to sustainability is also discussed. The reform effort was evaluated using both qualitative and quantitative methods; the evaluation design, research questions and preliminary results are provided. PMID- 26602832 TI - Mitotic cells contract actomyosin cortex and generate pressure to round against or escape epithelial confinement. AB - Little is known about how mitotic cells round against epithelial confinement. Here, we engineer micropillar arrays that subject cells to lateral mechanical confinement similar to that experienced in epithelia. If generating sufficient force to deform the pillars, rounding epithelial (MDCK) cells can create space to divide. However, if mitotic cells cannot create sufficient space, their rounding force, which is generated by actomyosin contraction and hydrostatic pressure, pushes the cell out of confinement. After conducting mitosis in an unperturbed manner, both daughter cells return to the confinement of the pillars. Cells that cannot round against nor escape confinement cannot orient their mitotic spindles and more likely undergo apoptosis. The results highlight how spatially constrained epithelial cells prepare for mitosis: either they are strong enough to round up or they must escape. The ability to escape from confinement and reintegrate after mitosis appears to be a basic property of epithelial cells. PMID- 26602833 TI - Low muscle mass is associated with metabolic syndrome only in nonobese young adults: the Korea National Health and Nutrition Examination Survey 2008-2010. AB - Little is known about the relationship between body composition and metabolic risk factors in young adults. We hypothesized that low muscle mass (LMM) is associated with metabolic syndrome (MetS) and its components in young adults and that the associations vary by obesity. A cross-sectional analysis was conducted using the Korea National Health and Nutrition Examination Survey data. In total, 5300 young adults aged 19 to 39 years were evaluated. Low muscle mass was defined as an appendicular skeletal muscle mass/weight less than 1 SD below the mean for each participant's corresponding sex and age group. Obesity was defined as a body mass index greater than or equal to 25 kg/m2. The prevalence of LMM was higher in obese than nonobese participants (37.6% vs. 9.6%). In the nonobese participants, the prevalence of MetS, high waist circumference, high triglycerides, and high blood pressure was significantly greater in the LMM group than in the high muscle mass group. In the nonobese group, compared with high muscle mass participants, those with LMM had odds ratios for MetS of 3.6 (95% confidence interval, 1.48 8.76; P < .001) and 3.6 (95% confidence interval, 1.48-8.71; P < .001) in men and women, respectively, after adjusting for confounding factors. However, no significant association of LMM with MetS or its components was found in obese participants. In conclusion, our results suggest that young adults with LMM may have a high risk of MetS, especially when they are nonobese. Interventions aimed at increasing muscle mass at younger ages may have the potential to reduce MetS. PMID- 26602834 TI - Compliance with risk management plan recommendations on laboratory monitoring of antitumor necrosis factor-alpha therapy in clinical practice. AB - BACKGROUND/PURPOSE: A risk management plan (RMP) was introduced to monitor the association between initiation of antitumor necrosis factor-alpha (anti-TNF alpha) therapy and tuberculosis (TB) and viral hepatitis infections. The aim of this study was to assess adherence and predictors of laboratory-testing rates among patients treated with anti-TNF-alpha therapy. METHODS: Data on patients receiving anti-TNF-alpha therapy between January 1, 2005, and November 31, 2013, were retrieved from a large medical organization in Taiwan. Newly-treated patients were categorized into pre- and post-RMP groups. Laboratory testing for TB and hepatitis B and C was ascertained and the proportion of new users receiving the test was compared between the pre- and post-RMP groups. Patient characteristics and concomitant medications used were investigated using multivariate logistic regression to determine the impact of each factor on laboratory testing. RESULTS: Among 1128 new users, the initial testing rate of chest X-ray (CXR) for latent TB infection increased from 60.26% before RMP to 76.38% after RMP implementation; hepatitis B surface antigen (HBsAg) increased from 31.13% to 51.42%; and hepatitis C virus antibody (HCVAb) increased from 32.2% to 54.10%. CXR was significantly associated with age >60 years, higher Quan Charlson comorbidity index score, psoriasis, and use of prednisolone (>=7.5 mg/d). Patients aged 40-60 years and with prednisolone doses of >=7.5 mg/d and history of cancer were more likely to receive HBsAg or HCVAb tests than their counterparts. CONCLUSION: The rate of laboratory test monitoring for anti-TNF alpha therapy increased after RMP implementation. A strategy that integrates efforts from patient's education, health profession, and regulatory agencies is needed to improve safety screening and access to laboratory resources for the at risk group of patients. PMID- 26602836 TI - Short Communication: Population-Based Surveillance of HIV-1 Drug Resistance in Cameroonian Adults Initiating Antiretroviral Therapy According to the World Health Organization Guidelines. AB - With ongoing earlier enrollment on and rapid scale-up of antiretroviral therapy (ART) in Cameroon, there are increasing risks of transmitted HIV drug resistance (HIVDR) at population levels. We, therefore, evaluated the threshold of HIVDR in a population initiating ART, to inform on the effectiveness of first-line regimens, considering HIV-1 diversity, plasma viral load (PVL), and CD4-based disease progression. A total of 53 adults [median (interquartile range, IQR) CD4: 162 cell/mm(3) (48-284); median (IQR) PVL: 5.34 log10 RNA (4.17-6.42) copies/ml] initiating ART in 2014 at the Yaounde Central Hospital were enrolled for HIV-1 protease-reverse transcriptase sequencing. Drug resistance mutations (DRMs) were interpreted using the 2009 World Health Organization (WHO) list versus the Stanford HIVdb algorithm version 7.0. Level of DRMs was low (3.77%) versus moderate (7.55%), respectively, following the WHO list (T69D, K103N) versus Stanford HIVdb (T69D, A98G, K103N, K238T), respectively. Prevailing clade was CRF02_AG (71.70%). Based on Stanford HIVdb, a slightly higher proportion of patients with DRMs were found among ones infected with CRF02_AG than in those non CRF02_AG infected (7.89% vs. 6.67%, p = 1.000), with lower PVL (7.69% <5.5 vs. 0% >=5.5 log10 RNA copies/ml, p = .488) and with higher CD4 counts (9.52% CD4 >=200 vs. 3.33% CD4 <200 cells/mm(3), p = .749). Thresholds of DRMs suggest that standard first-line regimens currently used in Cameroon may remain effective at population levels, despite scale-up of ART in the country, pending adherence, and closed virological monitoring. With an intent-to-diagnose approach, the discrepant levels of DRMs support using Stanford HIVdb to evaluate initial ART, while revising the WHO list for surveillance. PMID- 26602837 TI - Fear learning, fear memory, and psychopathology. PMID- 26602835 TI - Impact of Mycobacterium tuberculosis RD1-locus on human primary dendritic cell immune functions. AB - Modern strategies to develop vaccines against Mycobacterium tuberculosis (Mtb) aim to improve the current Bacillus Calmette-Guerin (BCG) vaccine or to attenuate the virulence of Mtb vaccine candidates. In the present study, the impact of wild type or mutated region of difference 1 (RD1) variants on the immunogenicity of Mtb and BCG recombinants was investigated in human primary dendritic cells (DC). A comparative analysis of transcriptome, signalling pathway activation, maturation, apoptosis, cytokine production and capacity to promote Th1 responses demonstrated that DC sense quantitative and qualitative differences in the expression of RD1-encoded factors--ESAT6 and CFP10--within BCG or Mtb backgrounds. Expansion of IFN-gamma producing T cells was promoted by BCG::RD1 challenged DC, as compared to their BCG-infected counterparts. Although Mtb recombinants acted as a strong Th-1 promoting stimulus, even with RD1 deletion, the attenuated Mtb strain carrying a C-terminus truncated ESAT-6 elicited a robust Th1 promoting phenotype in DC. Collectively, these studies indicate a necessary but not sufficient role for the RD1 locus in promoting DC immune regulatory functions. Additional mycobacterial factors are likely required to endow DC with a high Th1 polarizing capacity, a desirable attribute for a successful control of Mtb infection. PMID- 26602838 TI - Intolerance of uncertainty and startle potentiation in relation to different threat reinforcement rates. AB - Fear conditioning research on threat predictability has primarily examined the impact of temporal (i.e., timing) predictability on the startle reflex. However, there are other key features of threat that can vary in predictability. For example, the reinforcement rate (i.e., frequency) of threat is a crucial factor underlying fear learning. The present study examined the impact of threat reinforcement rate on the startle reflex and self-reported anxiety during a fear conditioning paradigm. Forty-five participants completed a fear learning task in which the conditioned stimulus was reinforced with an electric shock to the forearm on 50% of trials in one block and 75% of trials in a second block, in counter-balanced order. The present study also examined whether intolerance of uncertainty (IU), the tendency to perceive or experience uncertainty as stressful or unpleasant, was associated with the startle reflex during conditions of low (50%) vs. high (75%) reinforcement. Results indicated that, across all participants, startle was greater during the 75% relative to the 50% reinforcement condition. IU was positively correlated with startle potentiation (i.e., increased startle response to the CS+ relative to the CS-) during the 50%, but not the 75%, reinforcement condition. Thus, despite receiving fewer electric shocks during the 50% reinforcement condition, individuals with high IU uniquely demonstrated greater defense system activation when impending threat was more uncertain. The association between IU and startle was independent of state anxiety. The present study adds to a growing literature on threat predictability and aversive responding, and suggests IU is associated with abnormal responding in the context of uncertain threat. PMID- 26602840 TI - Survival of patients with resectable pancreatic cancer who received neoadjuvant therapy. AB - BACKGROUND: Enthusiasm for neoadjuvant therapy is growing from the emerging consensus that pancreatic cancer is a systemic disease at the time of diagnosis. Those who remain in favor of upfront surgery often cite the lack of reported data to support alternative treatment sequencing. We therefore report the results of all patients treated outside of a clinical trial under the direction of a multidisciplinary pancreatic cancer working group. METHODS: We reviewed all patients with resectable pancreatic cancer treated with neoadjuvant therapy (NeoTx) from 2009 to 2013; we excluded those patients treated on prospective clinical trials as they will be the subject of subsequent reports. Data regarding demographics, NeoTx, operative outcomes, pathology, and survival data were abstracted from a prospective database. RESULTS: NeoTx was initiated in 69 patients; median age was 65 years (interquartile range [IQR]: 11) and median carbohydrate antigen 19-9 at diagnosis was 96.5 (IQR 210). NeoTx consisted of chemotherapy alone (n = 10, 14%), chemotherapy and radiation (chemoradiation, n = 53, 77%), or both (n = 6, 9%). Median carbohydrate antigen 19-9 after NeoTx was 39 (IQR 104) corresponding to a median decrease of 60%. Operative resection was completed in 60 (87%) of the 69 patients. At restaging after NeoTx, 5 (7%) of 69 patients were not considered candidates for surgery because of the development of metastatic disease (n = 4) or an inadequate performance status (n = 1). At the time of surgery, 4 (6%) of 64 patients had metastatic disease found at laparoscopy. Of the 60 patients who underwent surgical resection, a complete pathologic response was observed in 2 (3%) patients; 20 (33%) had positive lymph nodes, and the median number of positive lymph nodes was 2 (IQR 3). R0 resections were achieved in 58 (97%) of the 60 patients. Additional postoperative adjuvant therapy was administered to 37 (62%) of the 60 patients. Median survival of all 69 patients was 31.5 months; 44.9 months for the 60 patients who completed all NeoTx and resection compared with 8.1 months for the 9 patients who were not resected (log rank P < .001). CONCLUSION: NeoTx for resectable pancreatic cancer was associated with a median overall survival of 32 months; something not reported for patients treated with surgery first if based on intent-to-treat analysis. Treatment sequencing may provide an oncologic benefit beyond that of the selection bias afforded surgery after a period of induction therapy. PMID- 26602839 TI - Could BDNF be involved in compensatory mechanisms to maintain cognitive performance despite acute sleep deprivation? An exploratory study. AB - BACKGROUND: Neuroimaging studies suggest that acute sleep deprivation can lead to adaptations, such as compensatory recruitment of cerebral structures, to maintain cognitive performance despite sleep loss. However, the understanding of the neurochemical alterations related to these adaptations remains incomplete. OBJECTIVE: Investigate BDNF levels, cognitive performance and their relations in healthy subjects after acute sleep deprivation. METHODS: Nineteen sleep deprived (22.11+/-3.21years) and twenty control (25.10+/-4.42years) subjects completed depression, anxiety and sleep quality questionnaires. Sleep deprived group spent a full night awake performing different playful activities to keep themselves from sleeping. Attention, response inhibition capacity and working memory (prefrontal cortex-dependent) were assessed with Stroop and Digit Span tests. Declarative memory (hippocampus-dependent) was assessed with Logical Memory test. Serum BDNF was measured by sandwich ELISA. Data were analyzed with independent samples T-test, ANOVA, ANCOVA and curve estimation regressions. p<0.05 was deemed statistically significant. RESULTS: The sleep deprived group showed higher BDNF levels and normal performance on attention, response inhibition capacity and working memory. However, declarative memory was impaired. A sigmoidal relation between BDNF and Stroop Test scores was found. CONCLUSIONS: Increased BDNF could be related, at least in part, to the maintenance of normal prefrontal cognitive functions after sleep deprivation. This potential relation should be further investigated. PMID- 26602841 TI - Long-term outcomes and prognostic factors in neuroendocrine carcinomas of the pancreas: Morphology matters. AB - BACKGROUND: Limited data are available for pancreatic neuroendocrine carcinomas (NEC) defined by 2010 World Health Organization (WHO) criteria (mitotic count >20 mitoses/10 high-power fields and/or a Ki67 index of >20%), because most studies encompass heterogeneous cohorts of extrapulmonary/gastrointestinal NEC. Our aim was to evaluate the clinicopathologic characteristics, treatment, and prognosis of patients with pancreatic NEC defined by the 2010 WHO criteria. METHODS: We conducted a retrospective analysis of 59 patients with a histologic diagnosis of NEC between 1990 and 2012. All cases were re-reviewed and classified according to the WHO 2010 classification and the WHO 2000 criteria. RESULTS: All patients had stage III pancreatic NEC (n = 34; 58%) or IV pancreatic NEC (n = 25; 43%). Overall, 49 (83%) had poorly differentiated (PD) and 10 (17%) had a well differentiated (WD) morphology. Fifteen patients (26%) were operated with curative intent (R0/R1), and 8 (14%) were R2 resections. Median disease-specific survival (DSS) for the entire cohort was 14 months. Median DSS did not differ between patient not undergoing resection and those undergoing R2 resection (10 vs 12 months; P > .46), but DSS was greater for patients who underwent R0/R1 resection compared with those with no resection/R2 resection (35 vs 11 months; P < .005). WD morphologic NEC had a greater survival than PD ones (43 vs 12 months; P = .004). Performance status, R2 resection/no resection, PD morphologic NEC, and no medical treatment were independent predictors of poor survival. CONCLUSION: Pancreatic NEC constitute a heterogeneous group of tumors. Although NEC is an aggressive disease, curative resection in localized disease is associated with improved survival. Morphologic WD pancreatic NEC represents a subgroup with what seems to be a markedly improved survival. Within the NEC category, tumor treatment should be individualized considering tumor morphology as well as the other 2010 WHO criteria. PMID- 26602843 TI - Chip-Based Magnetic Solid-Phase Microextraction Online Coupled with MicroHPLC ICPMS for the Determination of Mercury Species in Cells. AB - Trace mercury speciation in cells is critical to understand its cytotoxicity and cell protection mechanism. In this work, we fabricated a chip-based magnetic solid-phase microextraction (MSPME) system, integrating a cell lysis unit as well as a sample extraction unit, and online combined it with micro high-performance liquid chromatography (microHPLC)-inductively coupled plasma mass spectrometry (ICPMS) for the speciation of mercury in HepG2 cells. Magnetic nanoparticles with sulfhydryl functional group were synthesized and self-assembled in the microchannels for the preconcentration of mercury species in cells under an external magnetic field. The enrichment factors are ca. 10-fold, and the recoveries for the spiked samples are in the range of 98.3-106.5%. The developed method was used to analyze target mercury species in Hg(2+) or MeHg(+) incubated HepG2 cells. The results demonstrated that MeHg(+) entered into the HepG2 cells more easily than Hg(2+), and part of the MeHg(+) might demethylate into Hg(2+) in HepG2 cells. Besides, comprehensive speciation of mercury in incubated cells revealed different detoxification mechanisms of Hg(2+) and MeHg(+) in Hg(2+) or MeHg(+) incubated HepG2 cells. PMID- 26602842 TI - Ex vivo peripheral nerve detection of rats by spontaneous Raman spectroscopy. AB - Nerve-sparing surgery is increasingly being applied to avoid functional deficits of the limbs and organs following surgery. Peripheral nerves that should be preserved are, however, sometimes misidentified due to similarity of shape and color to non-nerve tissues. To avoid misidentification of peripheral nerves, development of an in situ nerve detection method is desired. In this study, we report the label-free detection of ex vivo peripheral nerves of Wistar rats by using Raman spectroscopy. We obtained Raman spectra of peripheral nerves (myelinated and unmyelinated nerves) and their adjacent tissues of Wistar rats without any treatment such as fixation and/or staining. For the identification of tissue species and further analysis of spectral features, we proposed a principal component regression-based discriminant analysis with representative Raman spectra of peripheral nerves and their adjacent tissues. Our prediction model selectively detected myelinated nerves and unmyelinated nerves of Wistar rats with respective sensitivities of 95.5% and 88.3% and specificities of 99.4% and 93.5%. Furthermore, important spectral features for the identification of tissue species were revealed by detailed analysis of principal components of representative Raman spectra of tissues. Our proposed approach may provide a unique and powerful tool for peripheral nerve detection for nerve-sparing surgery in the future. PMID- 26602844 TI - The roles of different titanium species in TS-1 zeolite in propylene epoxidation studied by in situ UV Raman spectroscopy. AB - Titanium silicalite (TS-1) zeolites with different titanium species were synthesized and characterized by ultraviolet (UV)-Raman, ultraviolet visible (UV Vis) diffuse reflectance spectroscopies and by the NH3 temperature programmed desorption (NH3-TPD) method. The roles of different titanium species in TS-1 samples have been investigated by gas chromatography-Raman spectrometry (GC Raman) during the propylene epoxidation process. For the first time, a positive correlation was found among the concentration of framework Ti species, the amount of active intermediate Ti-OOH (eta(2)) and the conversion of propylene by the in situ GC-Raman technique. The results give evidence that the framework titanium species is the active center and Ti-OOH (eta(2)) is the active intermediate. The presence of extra-framework Ti species is harmful to propylene epoxidation. Furthermore, the amorphous Ti species has a more negative effect on the yield of propylene oxide (PO) than the anatase TiO2. The NH3-TPD results reveal that the amorphous Ti species are more acidic and thus should be mainly responsible for the further conversion of PO. PMID- 26602845 TI - [Cardiac rehabilitation must take place in a multidisciplinary team]. PMID- 26602846 TI - [CME: WPW syndrome]. PMID- 26602848 TI - [Cardiac Rehabilitation 2015]. AB - The goals of cardiac rehabilitation are (re-)conditioning and secondary prevention in patients with heart disease or an elevated cardiovascular risk profile. Rehabilitation is based on motivation through education, on adapted physical activity, instruction of relaxation techniques, psychological support and optimized medication. It is performed preferably in groups either in outpatient or inpatient settings. The Swiss working group on cardiac rehabilitation provides a network of institutions with regular quality auditing. Positive effects of rehabilitation programs on mortality and morbidity have been established by numerous studies. Although a majority of patients after cardiac surgery are being referred to rehabilitation, these services are notoriously underused after catheter procedures. PMID- 26602849 TI - [Obsessive-compulsive Disorder: Prevalence, Comorbidity and Remission from the Ages of 20 to 50]. AB - Individuals with obsessive-compulsive disorder (OCD) experience recurrent obsessive and/or compulsive thoughts and behaviours which cause them distress, and significantly impair their daily lives. The disorder is thought to have a chronic course and a low rate of remission, as evidenced by mainly clinical samples. Longitudinal psychiatric epidemiological studies are few and far between. This article presents the findings relating to OCD from one such study, the Zurich Study: OCD defined according to DSM-5 criteria had a high prevalence rate and frequently a chronic course but it had a long-term remission rate of almost 60%, which is higher than hitherto believed. OCD was generally highly comorbid with other disorders and particularly closely associated with social phobia. PMID- 26602850 TI - [Prevention of Postthrombotic Syndrom]. AB - Post-thrombotic syndrome (PTS) is a complication which occurs after deep vein thrombosis in spite of optimal anticoagulation. The term 'post-thrombotic syndrome' summarizes all clinical symptoms and skin lesions developing in the aftermath of deep vein thrombosis. In order to prevent PTS various therapeutic options exist, the choice is depending on the time lapse since the event of thrombosis. At the acute phase of pelvic vein thrombosis catheter-directed lysis has proved to be an efficient therapy. Starting from the acute phase up to the chronic phase compression therapy should be administered. In the chronic phase clinically relevant improvement of PTS can be achieved by recanalisation of the venous outflow tract in the pelvic axis by endovascular stenting. Surgery or endovenous thermal ablation of the insufficient superficial venous system are further and supplementary sensible treatment options. PMID- 26602851 TI - [Erectile and Ejaculatory Dysfunction]. AB - The inability to achieve an erection of the penis sufficient for sexual activity is called erectile dysfunction (ED). In most cases, the diagnosis can be made by medical history. The prevalence of ED in men at the age of 65 has been reported to be up to 50%. Premature ejaculation has a prevalence, up to 20% and is the most frequent ejaculatory dysfunction. The etiology of ED can involve psychological, vascular, neurogenic, hormonal or urogenital pathologies. The main pathophysiological mechanisms of ED are vascular disorders such as diabetes mellitus and atherosclerosis. Because of the common pathophysiology, patients diagnosed with ED should have a diagnostic work-up for systemic vascular pathologies to prevent concomitant cardiac events. Treatment options include invasive and non-invasive procedures. PMID- 26602852 TI - The Silent Giant. AB - SFT is a rare spindle cell neoplasm arising mostly at pleural and in rare cases at extrapleural sites. Histology and immunohistology are diagnostic tools. It is crucial to consider SFT as differential diagnosis in pulmonary nodules since they often remain clinically silent until they reach large dimension and to proceed with curative resection without delay. It is essential to follow up patients for a long period of time as recurrence may occur. PMID- 26602853 TI - [Conservative therapies effective in chronic sinusitis]. PMID- 26602854 TI - [Modified Valsalva maneuver in patients with supraventricular tachycardia]. PMID- 26602858 TI - Non-invasive experimental determination of a CT source model. AB - Non-invasive methods to determine equivalent X-ray source models of a CT scanner are presented. A high-precision technique called TRIC ("Time Resolved Integrated Charge") was developed and used to characterize the bow tie filters (BT) of the CT scanner installed at Physikalisch-Technische Bundesanstalt (PTB). Aluminum (Al) and polymethyl methacrylate (PMMA) equivalent thicknesses of the BT filters at all tube high voltages were evaluated, assuming that those consist of only one material. Thereby two different dose probes were used, a solid state detector and an ionization chamber, the former characterized by a significant and the latter by an almost negligible energy dependence of the air kerma response. A method was developed to correct for the energy dependence of the solid state dose probe. Next, a two-component material was assumed and equivalent BT filters were evaluated. The latter method was also applied using the known real BT filter materials and compared with the shape of the real BT filters. Finally, the results obtained by the TRIC method were compared with those obtained by using the so-called COBRA method ("Characterization Of Bow tie Relative Attenuation"), the latter being more suitable for measurements in a clinical environment. PMID- 26602859 TI - Improving the time efficiency of the Fourier synthesis method for slice selection in magnetic resonance imaging. AB - The design of slice selective pulses for magnetic resonance imaging can be cast as an optimal control problem. The Fourier synthesis method is an existing approach to solve these optimal control problems. In this method the gradient field as well as the excitation field are switched rapidly and their amplitudes are calculated based on a Fourier series expansion. Here, we provide a novel insight into the Fourier synthesis method via representing the Bloch equation in spherical coordinates. Based on the spherical Bloch equation, we propose an alternative sequence of pulses that can be used for slice selection which is more time efficient compared to the original method. Simulation results demonstrate that while the performance of both methods is approximately the same, the required time for the proposed sequence of pulses is half of the original sequence of pulses. Furthermore, the slice selectivity of both sequences of pulses changes with radio frequency field inhomogeneities in a similar way. We also introduce a measure, referred to as gradient complexity, to compare the performance of both sequences of pulses. This measure indicates that for a desired level of uniformity in the excited slice, the gradient complexity for the proposed sequence of pulses is less than the original sequence. PMID- 26602860 TI - Surgery: no profession for a lady. AB - There are currently over 700 active female Fellows of the Royal Australasian College of Surgeons, accounting for just less than 10% of the surgical workforce. The first female Fellow of the College was Lillian Violet Cooper, of Queensland, who was admitted to Fellowship on 17 June 1927. Over the following half century, 32 women obtained Fellowships, initially awarded on the basis of experience and clinical practice and then, from 1947, by passing the Fellowship examination. This paper will examine the contribution of some of these early pioneer women, not just as surgeons, but as role models, advocates of women in professional life and champions of equality. PMID- 26602862 TI - Relocating an intensive care unit: An exploratory qualitative study. AB - BACKGROUND: As new hospitals are built to replace old and ageing facilities, intensive care units are being constructed with single patient rooms rather than open plan environments. While single rooms may limit hospital infections and promote patient privacy, their effect on patient safety and work processes in the intensive care unit requires greater understanding. Strategies to manage changes to a different physical environment are also unknown. OBJECTIVES: This study aimed to identify challenges and issues as perceived by staff related to relocating to a geographically and structurally new intensive care unit. METHODS: This exploratory ethnographic study, underpinned by Donabedian's structure, process and outcome framework, was conducted in an Australian tertiary hospital intensive care unit. A total of 55 participants including nurses, doctors, allied health professionals, and support staff participated in the study. We conducted 12 semi-structured focus group and eight individual interviews, and reviewed the hospital's documents specific to the relocation. After sorting the data deductively into structure, process and outcome domains, the data were then analysed inductively to identify themes. FINDINGS: Three themes emerged: understanding of the relocation plan, preparing for the uncertainties and vulnerabilities of a new work environment, and acknowledging the need for change and engaging in the relocation process. DISCUSSION AND CONCLUSIONS: A systematic change management strategy, dedicated change leadership and expertise, and an effective communication strategy are important factors to be considered in managing ICU relocation. Uncertainty and staff anxiety related to the relocation must be considered and supports put in place for a smooth transition. Work processes and model of care that are suited to the new single room environment should be developed, and patient safety issues in the single room setting should be considered and monitored. Future studies on managing multidisciplinary work processes during intensive care unit relocation will add to the learnings we report here. PMID- 26602861 TI - RNF121 Inhibits Angiogenic Growth Factor Signaling by Restricting Cell Surface Expression of VEGFR-2. AB - Ligand stimulation promotes downregulation of RTKs, a mechanism by which RTKs, through the ubiquitination pathway are removed from the cell surface, causing a temporary termination of RTK signaling. The molecular mechanisms governing RTK trafficking and maturation in the endoplasmic reticulum (ER)/Golgi compartments are poorly understood. Vascular endothelial growth factor receptor-2 (VEGFR-2) is a prototypic RTK that plays a critical role in physiologic and pathologic angiogenesis. Here we demonstrate that Ring Finger Protein 121 (RNF121), an ER ubiquitin E3 ligase, is expressed in endothelial cells and regulates maturation of VEGFR-2. RNF121 recognizes newly synthesized VEGFR-2 in the ER and controls its trafficking and maturation. Over-expression of RNF121 promoted ubiquitination of VEGFR-2, inhibited its maturation and resulted a significantly reduced VEGFR-2 presence at the cell surface. Conversely, the shRNA-mediated knockdown of RNF121 in primary endothelial cells reduced VEGFR-2 ubiquitination and increased its cell surface level. The RING Finger domain of RNF121 is required for its activity toward VEGFR-2, as its deletion significantly reduced the effect of RNF121 on VEGFR-2. Additionally, RNF121 inhibited VEGF-induced endothelial cell proliferation and angiogenesis. Taken together, these data identify RNF121 as a key determinant of angiogenic signaling that restricts VEGFR-2 cell surface presence and its angiogenic signaling. PMID- 26602863 TI - Fibroblast growth factor 23 correlates with volume status in haemodialysis patients and is not reduced by haemodialysis. AB - BACKGROUND: Recent data suggest a role for fibroblast growth factor 23 (FGF-23) in volume regulation. In haemodialysis patients, a large ultrafiltration volume (UFV) reflects poor volume control, and both FGF-23 and a large UFV are risk factors for mortality in this population. We studied the association between FGF 23 and markers of volume status including UFV, as well as the intradialytic course of FGF-23, in a cohort of haemodialysis patients. METHODS: We carried out observational, post hoc analysis of 109 prevalent haemodialysis patients who underwent a standardized, low-flux, haemodialysis session with constant ultrafiltration rate. We measured UFV, plasma copeptin and echocardiographic parameters including cardiac output, end-diastolic volume and left ventricular mass index at the onset of the haemodialysis session. We measured the intradialytic course of plasma C-terminal FGF-23 (corrected for haemoconcentration) and serum phosphate levels at 0, 1, 3 and 4 h after onset of haemodialysis and analysed changes with linear mixed effect model. RESULTS: Median age was 66 (interquartile range: 51-75) years, 65% were male with a weekly Kt/V 4.3 +/- 0.7 and dialysis vintage of 25.4 (8.5-52.5) months. In univariable analysis, pre-dialysis plasma FGF-23 was associated with UFV, end-diastolic volume, cardiac output, early diastolic velocity e' and plasma copeptin. In multivariable regression analysis, UFV correlated with FGF-23 (standardized beta: 0.373, P < 0.001, model R(2): 57%), independent of serum calcium and phosphate. The association between FGF-23 and echocardiographic volume markers was lost for all but cardiac output upon adjustment for UFV. Overall, FGF-23 levels did not change during dialysis [7627 (3300-13 514) to 7503 (3109-14 433) RU/mL; P = 0.98], whereas phosphate decreased (1.71 +/- 0.50 to 0.88 +/- 0.26 mmol/L; P < 0.001). CONCLUSIONS: FGF-23 was associated with volume status in haemodialysis patients. The strong association with UFV suggests that optimization of volume status, for example by more intensive haemodialysis regimens, may also benefit mineral homeostasis. A single dialysis session did not lower FGF-23 levels. PMID- 26602864 TI - In Vivo and In Silico Investigation Into Mechanisms of Frequency Dependence of Repolarization Alternans in Human Ventricular Cardiomyocytes. AB - RATIONALE: Repolarization alternans (RA) are associated with arrhythmogenesis. Animal studies have revealed potential mechanisms, but human-focused studies are needed. RA generation and frequency dependence may be determined by cell-to-cell variability in protein expression, which is regulated by genetic and external factors. OBJECTIVE: To characterize in vivo RA in human and to investigate in silico using human models, the ionic mechanisms underlying the frequency dependent differences in RA behavior identified in vivo. METHODS AND RESULTS: In vivo electrograms were acquired at 240 sites covering the epicardium of 41 patients at 6 cycle lengths (600-350 ms). In silico investigations were conducted using a population of biophysically detailed human models incorporating variability in protein expression and calibrated using in vivo recordings. Both in silico and in vivo, 2 types of RA were identified, with Fork- and Eye-type restitution curves, based on RA persistence or disappearance, respectively, at fast pacing rates. In silico simulations show that RA are strongly correlated with fluctuations in sarcoplasmic reticulum calcium, because of strong release and weak reuptake. Large L-type calcium current conductance is responsible for RA disappearance at fast frequencies in Eye-type (30% larger in Eye-type versus Fork type; P<0.01), because of sarcoplasmic reticulum Ca(2+) ATPase pump potentiation caused by frequency-induced increase in intracellular calcium. Large Na(+)/Ca(2+) exchanger current is the main driver in translating Ca(2+) fluctuations into RA. CONCLUSIONS: In human in vivo and in silico, 2 types of RA are identified, with RA persistence/disappearance as frequency increases. In silico, L-type calcium current and Na(+)/Ca(2+) exchanger current determine RA human cell-to-cell differences through intracellular and sarcoplasmic reticulum calcium regulation. PMID- 26602865 TI - Uncoupling Caveolae From Intracellular Signaling In Vivo. AB - RATIONALE: Caveolin-1 (Cav-1) negatively regulates endothelial nitric oxide (NO) synthase-derived NO production, and this has been mapped to several residues on Cav-1, including F92. Herein, we reasoned that endothelial expression of an F92ACav-1 transgene would let us decipher the mechanisms and relationships between caveolae structure and intracellular signaling. OBJECTIVE: This study was designed to separate caveolae formation from its downstream signaling effects. METHODS AND RESULTS: An endothelial-specific doxycycline-regulated mouse model for the expression of Cav-1-F92A was developed. Blood pressure by telemetry and nitric oxide bioavailability by electron paramagnetic resonance and phosphorylation of vasodilator-stimulated phosphoprotein were determined. Caveolae integrity in the presence of Cav-1-F92A was measured by stabilization of caveolin-2, sucrose gradient, and electron microscopy. Histological analysis of heart and lung, echocardiography, and signaling were performed. CONCLUSIONS: This study shows that mutant Cav-1-F92A forms caveolae structures similar to WT but leads to increases in NO bioavailability in vivo, thereby demonstrating that caveolae formation and downstream signaling events occur through independent mechanisms. PMID- 26602867 TI - Organocatalytic Asymmetric Conjugate Additions to Cyclopent-1-enecarbaldehyde: A Critical Assessment of Organocatalytic Approaches towards the Telaprevir Bicyclic Core. AB - In the context of a programme directed at the manufacture of telaprevir, eight possible approaches to its bicyclic alpha-amino acid core, based on organocatalytic enantioselective conjugate additions to cyclopent-1 enecarbaldehyde, were identified and preliminarily explored. Four reactions, delivering advanced intermediates en route to the target amino acid, were selected for a thorough optimisation. Three of this reactions involved iminium ion catalysis with a prolinol catalyst (addition of nitromethane, nitroacetate and acetamidomalonate) and one was based on a Cinchona-derived phase-transfer catalyst (addition of glycine imines). A careful choice of additives allowed lowering of the catalyst loading to 0.5 mol% in some cases. The preparation of intermediates that would give access to the core of telaprevir in good yields and enantioselectivities by exploiting readily available substrates and catalysts, highlights the potential of organocatalytic technology for a cost-effective preparation of pharmaceuticals. PMID- 26602866 TI - Circadian Characteristics of Older Adults and Aerobic Capacity. AB - BACKGROUND: Alteration of circadian rhythmicity with aging might depend on physical aerobic capacity. METHODS: Three groups of participants were established based on their peak oxygen consumption (Group 1 < 20mL/min/kg; Group 2 > 20mL/min/kg and <30mL/min/kg; Group 3 > 30mL/min/kg). Each participant had an individual evaluation of their circadian rhythmicity characteristics through two well-known circadian rhythms: core temperature and rest/activity cycles. Nocturnal sleep was also recorded using actimetry and diurnal vigilance tested in a car driving simulator. RESULTS: The amplitude of the oral temperature fluctuations for Group 1 is significantly lower (p < .05) than that of Group 3. Group 2 (p < .01) and Group 3 (p < .05) were significantly more active during the day than Group 1. The index of inactivity during the night for Groups 2 (p < .05) and 3 (p < .01) was higher than Group 1. Results of the car driving simulation showed that for Group 1, the number of lane crossings was significantly higher than Groups 2 (p < .01) and 3 (p < .01). In addition, diurnal vigilance was lower in Group 1. CONCLUSIONS: The biological clock seems to be enhanced in older participants with a higher level of physical capacity. PMID- 26602868 TI - Gender differences in the prevalence and treatment of coronary chronic total occlusions. AB - BACKGROUND: Gender differences exist in the presentation and outcomes of patients with coronary artery disease (CAD). Our study objective was to compare gender differences in prevalence, co-morbidities, and revascularization treatment in CAD patients with chronic total occlusions (CTOs). METHODS: A retrospective analysis using the Canadian Multicenter CTO Registry, which included 1,690 consecutive CTO patients identified at coronary angiography and a control group of 7,682 non-CTO patients. RESULTS: The prevalence of women in the CTO group was significantly lower compared to the control group (19% vs. 30%, P < 0.001). Within the overall CTO group, women were significantly older than men (70 +/- 12 vs. 66 +/- 11 years, P < 0.001) with more comorbidities, including hypertension and heart failure. Rates of PCI in the CTO group were similar between gender (10%), however, women with CTO were treated significantly less by CABG compared to men (19% vs. 27%, P = 0.003). Moreover, compared to male patients, significantly fewer women undergoing CABG had revascularization of the CTO artery (84% vs. 93%, P = 0.03). Multivariable analysis indicated that female gender (along with age, chronic renal failure, prior MI and cerebro-vascular disease) were independent predictors for not receiving CABG treatment for CTO. CONCLUSIONS: Female gender differences exist in CTO patients with both lower prevalence of CTOs at angiography and lower revascularization rates of CTOs by CABG. (c) 2015 Wiley Periodicals, Inc. PMID- 26602869 TI - Effect of microtubule-associated protein-4 on epidermal cell migration under different oxygen concentrations. AB - After skin trauma, regional epidermal cell migration mediates the re epithelialization of the wound surface, which is an important step for wound healing, yet the underlying molecular regulatory mechanism is unclear. In the current study, HaCaT cells were maintained under different oxygen concentrations (1%, 21%, 40% and 65%). Technologies including immunofluorescence staining, wound scratch, transwell invasion, western blot and low-expression lentiviral vector were utilized to observe the changes in microtubule dynamics and the microtubule associated protein (MAP)4 expression. MAP4's effect on cell migration under different oxygen concentrations was also studied. The results showed that under hyperoxic (40% and 65%) and hypoxic (1%) conditions, HaCaT cells were able to regulate cell microtubule dynamics by MAP4, thus promoting cell migration. On the other hand, MAP4 silencing through targeted shRNA attenuated HaCaT cell migration under the above oxygen concentrations. These results imply that MAP4 plays an important role in epidermal cell migration under different oxygen concentrations. PMID- 26602870 TI - Leishmania amazonensis DNA in wild females of Lutzomyia cruzi (Diptera: Psychodidae) in the state of Mato Grosso do Sul, Brazil. AB - Studies on natural infection by Leishmania spp of sandflies collected in endemic and nonendemic areas can provide important information on the distribution and intensity of the transmission of these parasites. This study sought to investigate the natural infection by Leishmaniain wild female sandflies. The specimens were caught in the city of Corumba, state of Mato Grosso do Sul (Brazil) between October 2012-March 2014, and dissected to investigate flagellates and/or submitted to molecular analysis to detect Leishmania DNA. A total of 1,164 females (77.56% of which were Lutzomyia cruzi) representing 11 species were investigated using molecular analysis; 126 specimens of Lu. cruziwere dissected and also submitted to molecular analysis. The infection rate based on the presence of Leishmania DNA considering all the sandfly species analysed was 0.69%; only Leishmania (Leishmania) amazonensis was identified in Lu. cruzi by the molecular analysis. The dissections were negative for flagellates. This is the first record of the presence of L. (L.) amazonensis DNA in Lu. cruzi, and the first record of this parasite in this area. These findings point to the need for further investigation into the possible role of this sandfly as vector of this parasite. PMID- 26602871 TI - New insights on the development of fungal vaccines: from immunity to recent challenges. AB - Fungal infections are emerging as a major problem in part due to high mortality associated with systemic infections, especially in the case of immunocompromised patients. With the development of new treatments for diseases such as cancer and the acquired immune deficiency syndrome pandemic, the number of immunosuppressed patients has increased and, as a consequence, also the number of invasive fungal infections has increased. Several studies have proposed new strategies for the development of effective fungal vaccines. In addition, better understanding of how the immune system works against fungal pathogens has improved the further development of these new vaccination strategies. As a result, some fungal vaccines have advanced through clinical trials. However, there are still many challenges that prevent the clinical development of fungal vaccines that can efficiently immunise subjects at risk of developing invasive fungal infections. In this review, we will discuss these new vaccination strategies and the challenges that they present. In the future with proper investments, fungal vaccines may soon become a reality. PMID- 26602873 TI - Antileishmanial activity of the essential oil from Tetradenia riparia obtained in different seasons. AB - The herbaceous shrub Tetradenia riparia has been traditionally used to treat inflammatory and infectious diseases. Recently, a study showed that T. riparia essential oil (TrEO) obtained in summer has antileishmanial effects, although these results could be influenced by seasonal variation. This study evaluated the activity of the TrEO obtained in different seasons against Leishmania (Leishmania) amazonensis, in vitro and in vivo. The compounds in the TrEO were analysed by gas chromatography-mass spectrometry; terpenoids were present and oxygenated sesquiterpenes were the majority compounds (55.28%). The cytotoxicity and nitric oxide (NO) production were also tested after TrEO treatment. The TrEO from all seasons showed a 50% growth inhibitory concentration for promastigotes of about 15 ng/mL; at 30 ng/mL and 3 ng/mL, the TrEO reduced intracellular amastigote infection, independently of season. The TrEO from plants harvested in summer had the highest 50% cytotoxic concentration, 1,476 ng/mL for J774.A1 macrophages, and in spring (90.94 ng/mL) for murine macrophages. NO production did not change in samples of the TrEO from different seasons. The antileishmanial effect in vivo consisted of a reduction of the parasite load in the spleen. These results suggest that the TrEO has potential effects on L. (L.) amazonensis, consonant with its traditional use to treat parasitic diseases. PMID- 26602872 TI - Exploring the environmental diversity of kinetoplastid flagellates in the high throughput DNA sequencing era. AB - The class Kinetoplastea encompasses both free-living and parasitic species from a wide range of hosts. Several representatives of this group are responsible for severe human diseases and for economic losses in agriculture and livestock. While this group encompasses over 30 genera, most of the available information has been derived from the vertebrate pathogenic genera Leishmaniaand Trypanosoma. Recent studies of the previously neglected groups of Kinetoplastea indicated that the actual diversity is much higher than previously thought. This article discusses the known segment of kinetoplastid diversity and how gene-directed Sanger sequencing and next-generation sequencing methods can help to deepen our knowledge of these interesting protists. PMID- 26602874 TI - Opisthorchiasis in infant remains from the medieval Zeleniy Yar burial ground of XII-XIII centuries AD. AB - We present a paleoparasitological analysis of the medieval Zeleniy Yar burial ground of the XII-XII centuries AD located in the northern part of Western Siberia. Parasite eggs, identified as eggs of Opisthorchis felineus, were found in the samples from the pelvic area of a one year old infant buried at the site. Presence of these eggs in the soil samples from the infant's abdomen suggests that he/she was infected with opisthorchiasis and imply consumption of undercooked fish. Ethnographic records collected among the population of the northern part of Western Siberia reveal numerous cases of feeding raw fish to their children. Zeleniy Yar case of opisthorchiasis suggests that this dietary custom has persisted from at least medieval times. PMID- 26602875 TI - Antiplasmodial activity of iron(II) and ruthenium(II) organometallic complexes against Plasmodium falciparum blood parasites. AB - This work reports the in vitro activity against Plasmodium falciparum blood forms (W2 clone, chloroquine-resistant) of tamoxifen-based compounds and their ferrocenyl (ferrocifens) and ruthenocenyl (ruthenocifens) derivatives, as well as their cytotoxicity against HepG2 human hepatoma cells. Surprisingly with these series, results indicate that the biological activity of ruthenocifens is better than that of ferrocifens and other tamoxifen-like compounds. The synthesis of a new metal-based compound is also described. It was shown, for the first time, that ruthenocifens are good antiplasmodial prototypes. Further studies will be conducted aiming at a better understanding of their mechanism of action and at obtaining new compounds with better therapeutic profile. PMID- 26602878 TI - Reliability and validity of the March of dimes preconception/prenatal family health history questionnaire: The Persian version. AB - In recent years, there has been a remarkable gap between rapid advancements in genetic technology and public health practice. Looking at the familial health history may bridge this gap for easier and cheaper diagnosis and prevention of congenital anomalies. The aim of this study was to validate and culturally adapt the March of Dimes Preconception/Prenatal Family Health History Questionnaire for the Iranian population. After obtaining written permission from March of Dimes, the translation-back translation of the original questionnaire was performed. The content validity was assessed by a team of 12 experts. Based on a sample of 50 general practitioners and 100 subjects referred to health centers from September to November 2014 in Tabriz, Iran, test-retest reliability and inter-rater reliability were evaluated by Kappa and Intra-class Correlation Coefficient (ICC). Content validity of the Persian version of the questionnaire was confirmed according to the modified kappa value above 0.76 for all the items included in this tool. Inter-rater reliability assessment yielded a kappa value between 0.62 and 0.92 for variables with dichotomous measurement scales and ICC ranged from 0.6 to 0.9 for variables with numeric scales. Test-retest re-administration produced kappa ranging from 0.62 to 0.92 for variables with dichotomous measurement scales and ICC from 0.6 to 0.9 for variables with numeric scales. The Persian version of the March of Dimes preconception/prenatal family health history questionnaire showed acceptable reliability and validity and may be used as a simple tool for the detection of risk factors of birth defects in Iranian population. PMID- 26602876 TI - Co-administration of plasmid-encoded granulocyte-macrophage colony-stimulating factor increases human immunodeficiency virus-1 DNA vaccine-induced polyfunctional CD4+ T-cell responses. AB - T-cell based vaccines against human immunodeficiency virus (HIV) generate specific responses that may limit both transmission and disease progression by controlling viral load. Broad, polyfunctional, and cytotoxic CD4+T-cell responses have been associated with control of simian immunodeficiency virus/HIV-1 replication, supporting the inclusion of CD4+ T-cell epitopes in vaccine formulations. Plasmid-encoded granulocyte-macrophage colony-stimulating factor (pGM-CSF) co-administration has been shown to induce potent CD4+ T-cell responses and to promote accelerated priming and increased migration of antigen-specific CD4+ T-cells. However, no study has shown whether co-immunisation with pGM-CSF enhances the number of vaccine-induced polyfunctional CD4+ T-cells. Our group has previously developed a DNA vaccine encoding conserved, multiple human leukocyte antigen (HLA)-DR binding HIV-1 subtype B peptides, which elicited broad, polyfunctional and long-lived CD4+ T-cell responses. Here, we show that pGM-CSF co-immunisation improved both magnitude and quality of vaccine-induced T-cell responses, particularly by increasing proliferating CD4+ T-cells that produce simultaneously interferon-gamma, tumour necrosis factor-alpha and interleukin-2. Thus, we believe that the use of pGM-CSF may be helpful for vaccine strategies focused on the activation of anti-HIV CD4+ T-cell immunity. PMID- 26602877 TI - Quantitative DNA metabarcoding: improved estimates of species proportional biomass using correction factors derived from control material. AB - DNA metabarcoding is a powerful new tool allowing characterization of species assemblages using high-throughput amplicon sequencing. The utility of DNA metabarcoding for quantifying relative species abundances is currently limited by both biological and technical biases which influence sequence read counts. We tested the idea of sequencing 50/50 mixtures of target species and a control species in order to generate relative correction factors (RCFs) that account for multiple sources of bias and are applicable to field studies. RCFs will be most effective if they are not affected by input mass ratio or co-occurring species. In a model experiment involving three target fish species and a fixed control, we found RCFs did vary with input ratio but in a consistent fashion, and that 50/50 RCFs applied to DNA sequence counts from various mixtures of the target species still greatly improved relative abundance estimates (e.g. average per species error of 19 +/- 8% for uncorrected vs. 3 +/- 1% for corrected estimates). To demonstrate the use of correction factors in a field setting, we calculated 50/50 RCFs for 18 harbour seal (Phoca vitulina) prey species (RCFs ranging from 0.68 to 3.68). Applying these corrections to field-collected seal scats affected species percentages from individual samples (Delta 6.7 +/- 6.6%) more than population level species estimates (Delta 1.7 +/- 1.2%). Our results indicate that the 50/50 RCF approach is an effective tool for evaluating and correcting biases in DNA metabarcoding studies. The decision to apply correction factors will be influenced by the feasibility of creating tissue mixtures for the target species, and the level of accuracy needed to meet research objectives. PMID- 26602879 TI - Effect and mechanism of waterborne prolonged Zn exposure influencing hepatic lipid metabolism in javelin goby Synechogobius hasta. AB - The present study was conducted to determine the effect and mechanism of waterborne Zn exposure influencing hepatic lipid deposition and metabolism in javelin goby Synechogobius hasta. S. hasta were exposed to four waterborne Zn concentrations (Zn 0.005 [control], 0.18, 0.36 and 0.55 mg l(-1) , respectively) for 60 days. Sampling occurred at days 20, 40 and 60, respectively. Zn exposure increased Zn content, declined hepatic lipid content and reduced viscerosomatic and hepatosomatic indices and lipogenic enzyme activities, including 6 phosphogluconate dehydrogenase (6PGD), glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME) and fatty acid synthase (FAS). At days 20 and 60, Zn exposure decreased hepatic mRNA levels of 6PGD, G6PD, ME, FAS, acetyl-CoA carboxylase (ACC)alpha, ACCbeta, hormone-sensitive lipase (HSL)a, HSLb, sterol-regulator element-binding protein (SREBP)-1, peroxisome proliferators-activated receptor (PPAR)alpha and PPARgamma. However, the mRNA levels of CPT 1 and adipose triglyceride lipase increased following Zn exposure. On day 40, Zn exposure reduced hepatic mRNA expression of 6PGD, G6PD, ME, FAS, ACCalpha, ACCbeta, HSLa, HSLb, SREBP-1 and PPARgamma but increased mRNA expression of CPT 1, adipose triglyceride lipase and PPARalpha. General speaking, Zn exposure reduced hepatic lipid content by inhibiting lipogenesis and stimulating lipolysis. For the first time, the present study provided evidence that chronic Zn exposure differentially influenced mRNA expression and activities of genes and enzymes involved in lipogenic and lipolytic metabolism in a duration-dependent manner, and provided new insight into the relationship between metal elements and lipid metabolism. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26602880 TI - [Dosing adjustment and renal function: Which equation(s)?]. AB - While the CKD-EPI (for Chronic Kidney Disease Epidemiology) equation is now implemented worldwide, utilization of the Cockcroft formula is still advocated by some physicians for drug dosage adjustment. Justifications for this recommendation are that the Cockcroft formula was preferentially used to determine dose adjustments according to renal function during the development of many drugs, better predicts drugs-related adverse events and decreases the risk of drug overexposure in the elderly. In this opinion paper, we discuss the weaknesses of the rationale supporting the Cockcroft formula and endorse the French HAS (Haute Autorite de sante) recommendation regarding the preferential use of the CKD-EPI equation. When glomerular filtration rate (GFR) is estimated in order to adjust drug dosage, the CKD-EPI value should be re-expressed for the individual body surface area (BSA). Given the difficulty to accurately estimate GFR in the elderly and in individuals with extra-normal BSA, we recommend to prescribe in priority monitorable drugs in those populations or to determine their "true" GFR using a direct measurement method. PMID- 26602881 TI - Thyroid tuberculosis: a new case and review of the literature. PMID- 26602882 TI - A strategy for tuning achiral main-chain polymers into helical assemblies and chiral memory systems. AB - A general strategy to tune the achiral main chain polymers into helical nanoassemblies was proposed based on the co-gelation approach. As an example, two achiral main chain polymers, PCz8 and PSi8, were selected, and their co-assembly with an amphiphilic l- or d-glutamide gelator was investigated. Although the polymers could not form gels individually, they could form co-gels with the gelator and the resultant gels exhibited macroscopic supramolecular chirality, which could be confirmed by CD spectra and SEM observations. Moreover, the supramolecular chirality can be memorized even after the gelator molecules were removed. Remarkably, either the gelator-containing or gelator-free chiral polymer assemblies showed circularly polarized luminescence (CPL), which is usually inherent to intrinsic chiral polymers. It was suggested that during the co gelation, the chirality of the gelator was transferred to and memorized by the achiral polymers. The approach seems to be general and we provided the first example to tune the achiral polymers into helical assemblies through the co gelation. PMID- 26602883 TI - Evaluating the association of common UBE2Z variants with coronary artery disease in an Iranian population. AB - Coronary artery disease (CAD) is the leading cause of cardiovascular mortality worldwide. Genome-wide association studies have discovered several variants associated with CAD. Notably, a recent study has identified UBE2Z rs46522 at 17q21.32 as a CAD-susceptibility variant in Europeans. However, association of this locus with CAD in non-Europeans has not been investigated. Herein, we evaluated the contribution of rs46522 and a variant in high linkage disequilibrium in UBE2Z 3'-UTR (rs1057897) to the CAD susceptibility by performing association study in an Iranian population. This study recruited 300 angiographically-confirmed CAD patients and 300 asymptomatic controls. Genotypes were determined by TaqMan genotyping assay. Multivariate logistic regression analysis revealed that rs46522 was associated with the susceptibility to CAD assuming codominant [TT vs. CC: 2.68 (1.36-5.31), P: 1.1717e-2], dominant [CT+TT vs. CC: 1.74 (1.12-2.69), P: 1.2675e-2], recessive [TT vs. CC+CT: 2.12 (1.13 3.98), P: 1.9369e-2] and log-additive [1.61 (1.17-2.21), P: 2.967e-3] models. However, no association was observed for rs1057897 under any genetic models. In conclusion, we provide the first evidence for association of rs46522 with the susceptibility to CAD in an Iranian population and discussed about regulatory potential and functional role of the studied variants to provide clues for its association with CAD and promote further research. PMID- 26602884 TI - Ferritin is associated with neural differentiation of bone marrow-derived mesenchymal stem cells under extremely low-frequency electromagnetic field. AB - Extremely low-frequency electromagnetic field (ELFEF) is a well-known mechanical stimulation that induces neural differentiation. It is potentially an effective treatment for neurodegenerative diseases. In a previous study, ferritin light chain was upregulated in ELFEF-exposed human bone marrow-derived mesenchymal stem cells (BM-MSCs). Ferritin light chain is a component of ferritin, a highly conserved iron-binding protein. In this study, to identify molecules associated with ferritin during neural differentiation of BM-MSCs, we performed reverse transcription polymerase chain reaction (RT-PCR), western blotting, and ATP analysis. Our data indicated that ELFEF triggers the upregulation of ferritin light chain (FLC) and ferritin heavy chain (FHC) in BM-MSCs. The elevated levels of FLC and FHC correlated positively with the differentiation of BM-MSCs into neural cells. Moreover ELFEF induced the activation of iron regulatory protein-1 (IRP-1) and cofilin, which are downstream targets of ferritin. These results suggest that ELFEF induces neural differentiation through activation of a ferritin-regulated mechanism. PMID- 26602885 TI - Encapsulation and in vitro release of erythromycin using biopolymer micelle. AB - An amphiphilic block copolymer poly(ethylene glycol)-block-poly[2-(2 methoxyethoxy)ethyl methacrylate] (PEG-b-PMEO2MA) was prepared and the polymer micelle was applied to encapsulate erythromycin. The Critical Micelle Concentration (CMC) of PEG-b-PMEO2MA was determined by the fluorescent probe pyrene. The effects of addition of erythromycin on encapsulation efficiency and drug loading content were investigated. Drug release was also studied in a phosphate buffer solution with a pH of 7.5. The CMC of PEG-b-PMEO2MA is 0.065 mg/mL when the monomer ratio of the hydrophobic block PMEO2MA to the hydrophilic block PEG is equal to 6:4. The encapsulation efficiency and drug loading were 87.1% and 16.8%, respectively, as the loading content of erythromycin in polymeric micelle is equal to 28%. After erythromycin is loaded into the micelle, the size of PEG-b-PMEO2MA micelle becomes approximately thrice the size of unloaded micelle. The loading micelles stably release erythromycin within 180 hours in phosphate buffer, suggesting that the micelle loaded with erythromycin have a good sustained-release effect. PMID- 26602886 TI - Renal Transplantation With Final Allocation Based on the Virtual Crossmatch. AB - Solid phase immunoassays (SPI) are now routinely used to detect HLA antibodies. However, the flow cytometric crossmatch (FCXM) remains the established method for assessing final donor-recipient compatibility. Since 2005 we have followed a protocol whereby the final allocation decision for renal transplantation is based on SPI (not the FCXM). Here we report long-term graft outcomes for 508 consecutive kidney transplants using this protocol. All recipients were negative for donor-specific antibody by SPI. Primary outcomes are graft survival and incidence of acute rejection within 1 year (AR <1 year) for FCXM+ (n = 54) and FCXM- (n = 454) recipients. Median follow-up is 7.1 years. FCXM+ recipients were significantly different from FCXM- recipients for the following risk factors: living donor (24% vs. 39%, p = 0.03), duration of dialysis (31.0 months vs. 13.5 months, p = 0.008), retransplants (17% vs. 7.3%, p = 0.04), % sensitized (63% vs. 19%, p = 0.001), and PRA >80% (20% vs. 4.8%, p = 0.001). Despite these differences, 5-year actual graft survival rates are 87% and 84%, respectively. AR <1 year occurred in 13% FCXM+ and 12% FCXM- recipients. Crossmatch status was not associated with graft outcomes in any univariate or multivariate model. Renal transplantation can be performed successfully, using SPI as the definitive test for donor-recipient compatibility. PMID- 26602887 TI - Subtypes of firesetters. AB - BACKGROUND: Prior research has classified firesetters by motive. The multi trajectory theory of adult firesetting (M-TTAF) takes a more aetiological perspective, differentiating between five hypothesised trajectories towards firesetting: antisocial cognition, grievance, fire interest, emotionally expressive/need for recognition and multifaceted trajectories. AIM: The objective of this study was to validate the five routes to firesetting as proposed in the M TTAF. METHODS: All 389 adult firesetters referred for forensic mental health assessment to one central clinic in the Netherlands between 1950 and 2012 were rated on variables linked to the M-TTAF. Cluster analysis was then applied. RESULTS: A reliable cluster solution emerged revealing five subtypes of firesetters - labelled instrumental, reward, multi-problem, disturbed relationship and disordered. Significant differences were observed regarding both offender and offence characteristics. DISCUSSION: Our five-cluster solution with five subtypes of firesetters partially validates the proposed M-TTAF trajectories and suggests that for offenders with and without mental disorder, this classification may be useful. If further validated with larger and more diverse samples, the M-TTAF could provide guidance on staging evidence-based treatment. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26602888 TI - Genomic Copy Number Alterations in Renal Cell Carcinoma with Sarcomatoid Features. AB - PURPOSE: Sarcomatoid changes in renal cell carcinoma are associated with a poor prognosis. The identification of genetic alterations that drive this aggressive phenotype could aid in the development of more effective targeted therapies. In this study we aimed to pinpoint unique copy number alterations in sarcomatoid renal cell carcinoma compared to classical renal cell carcinoma subtypes. MATERIALS AND METHODS: Genomic copy number analysis was performed using single nucleotide polymorphism based microarrays on tissue extracted from the tumors of 81 patients who underwent renal mass excision, including 17 with sarcomatoid renal cell carcinoma. RESULTS: Sarcomatoid renal cell carcinoma showed a significantly higher number of copy number alterations than clear cell, papillary and chromophobe renal cell carcinoma (mean 18.0 vs 5.8, 6.5 and 7.2, respectively, p <0.0001). Copy number losses of chromosome arms 9q, 15q, 18p/q and 22q, and gains of 1q and 8q occurred in a significantly higher proportion of sarcomatoid renal cell carcinomas than in the other 3 histologies. Patients with sarcomatoid renal cell carcinoma demonstrated significantly worse overall survival compared to those without that condition on Kaplan-Meier analysis (p = 0.0001). Patients with 9 or more copy number alterations also demonstrated significantly worse overall survival than those with fewer than 9 copy number alterations (p = 0.004). CONCLUSIONS: Sarcomatoid changes in renal cell carcinoma are associated with a high rate of chromosomal imbalances with losses of 9q, 15q, 18p/q and 22q, and gains of 1q and 8q occurring at significantly higher frequencies in comparison to nonsarcomatoid renal cell carcinoma. Identifying candidate driver genes or tumor suppressor loci in these chromosomal regions may help identify targets for future therapies. PMID- 26602889 TI - Factors Influencing Readmission after Elective Ureteroscopy. AB - PURPOSE: Ureteroscopy is increasingly used to manage nephrolithiasis, upper urinary tract urothelial carcinoma and other urological conditions. In this study we determine the rate of readmission and emergency department visits after ureteroscopy in an underserved population, as well as factors associated with these unplanned visits. MATERIALS AND METHODS: A retrospective chart review from 2010 to 2014 of all elective ureteroscopies was conducted at a single tertiary hospital serving an underserved population in a major metropolis. Demographic, operative and discharge characteristics were collected and analyzed. RESULTS: A total of 276 ureteroscopies were performed with 15.6% presenting to the emergency department within 30 days. Overall 5.8% were readmitted. Readmitted patients were more likely to have hypertension (OR 3.64, p=0.02), asthma or chronic obstructive pulmonary disease (OR 5.54, p=0.001), 2 or more comorbidities (OR 3.65, p=0.12), or a complication associated with ureteroscopy (OR 7.27, p=0.007). The patients who sought care in the emergency department after ureteroscopy were less likely to have had a ureteral stent in place before ureteroscopy (OR 0.35, p=0.017) or an endoscopic urological procedure within the last 30 days (OR 0.35, p=0.045). About two-thirds of patients who presented to the emergency department complained of pain alone, while the most common complaints for readmitted patients were fever and pain (43.8%). CONCLUSIONS: The majority of emergency department visits after ureteroscopy were due to pain. These patients were less likely to have a preoperative ureteral stent placed or a history of recent urological procedures. Readmission rates were associated with overall comorbidities and complications. PMID- 26602890 TI - Dorsal Onlay Urethroplasty for Membranous Urethral Strictures: Urinary and Erectile Functional Outcomes. AB - PURPOSE: We evaluated urinary and erectile functional outcomes after dorsal onlay urethroplasty for bulbomembranous urethral strictures. Our aim was to understand the functional implications of dissection of the posterior urethra. MATERIALS AND METHODS: We report on men who underwent membranous urethral stricture repair by buccal mucosal graft dorsal onlay substitution urethroplasty. Continence and erectile function were assessed preoperatively and postoperatively. Tissue routinely excised from the intercrural space during dissection of the dorsal aspect of the membranous urethra was evaluated for scar, striated muscle and nerves. RESULTS: A total of 16 consecutive men with a mean age of 48.3 years (range 26 to 72) who had strictures with a mean length of 56 mm (range 15 to 170) involving the membranous urethra were included in analysis. Of the 16 men 15 were continent preoperatively and remained continent postoperatively. Three of 10 men (30%) with a preoperative SHIM (Sexual Health Inventory for Men) score of 17 to 25 had a decrease after urethroplasty. All 16 men had an improved maximum urinary flow rate with a mean improvement of 22 ml per second. I-PSS (International Prostate Symptom Score) improved from a median of 23 to 4 postoperatively with a median bother score improvement of 5 to 0. Histopathological assessment identified striated muscle and nerves in 6 (46%) and 9 (69%) of 13 specimens. Overall nerves and muscle comprised an average of less than 15% of the specimen. CONCLUSIONS: The dorsal onlay technique with a buccal mucosal graft for membranous urethral stricture repair does not compromise continence or erectile function in most patients. Dissection at the level of the membranous urethra should be limited because striated muscle and cavernous nerves are present. PMID- 26602891 TI - Multi-Institutional Experience with Robotic Nephrectomy with Inferior Vena Cava Tumor Thrombectomy. AB - PURPOSE: Since the first report of robotic management of renal tumors with inferior vena cava tumor thrombi, few additional cases have been reported in the literature. We report our combined experience with this procedure, to our knowledge the first multi-institutional and largest series reported to date. MATERIALS AND METHODS: A retrospective, multi-institutional review of robotic nephrectomy with inferior vena cava tumor thrombectomy was performed with institutional review board approval. RESULTS: A total of 32 cases were performed among 9 surgeons at 9 institutions since the first known procedure in 2008. Of these cases 30 were level II and 2 were level III thrombi with no level I thrombi (renal vein only) included in the analysis. Each surgeon performed between 1 and 10 procedures. Mean patient age was 63 years (range 43 to 81) with a mean body mass index of 30 kg/m(2) (range 17 to 43) and mean maximal tumor diameter of 9.6 cm (range 5.4 to 20). The length of inferior vena cava tumor thrombi ranged from 1 to 11 cm (median 4.2) on preoperative imaging. The inferior vena cava required cross-clamping in 24 cases. One patient had 2 renal veins with 2 caval thrombi and 1 patient required synthetic patch cavoplasty. Mean operative time was 292 minutes (range 180 to 411) with a mean blood loss of 399 cc (range 25 to 2,000). There were no conversions to open surgery or aborted procedures and there were 3 transfusions of 1 to 3 units. All but 2 patients ambulated by postoperative day 1 and mean hospital stay was 3.2 days (range 1 to 7). Lymphadenectomy in 24 patients yielded a mean of 11 nodes and 8 patients had node positive disease. There were 7 patients who experienced distant recurrence at a mean followup of 15.4 months, including 4 who had node positive disease on postoperative pathological examination. CONCLUSIONS: Robotic nephrectomy in the setting of inferior vena cava tumor thrombus is feasible and was performed safely in selected patients. Despite the complex and critical nature of these procedures, our series demonstrates favorable outcomes and reproducibility with adequate robotic experience. PMID- 26602892 TI - Serological makers of rubella infection in Africa in the pre vaccination era: a systematic review. AB - BACKGROUND: Rubella infections in susceptible women during early pregnancy often results in congenital rubella syndrome (CRS). World Health Organisation (WHO) recommends that countries without vaccination programmes to assess the burden of rubella infection and CRS. However; in many African countries there is limited data on epidemiology of rubella infection and CRS. This review was undertaken to assess the serological markers and genotypes of rubella virus on the African continent in order to ascertain the gap for future research. FINDINGS: A systematic search of original literatures from different electronic databases using search terms such as 'rubella' plus individual African countries such as 'Tanzania', 'Kenya', 'Nigeria' etc. and different populations such as 'children', 'pregnant women' etc. in different combinations was performed. Articles from countries with rubella vaccination programmes, outbreak data and case reports were excluded. Data were entered in a Microsoft Excel sheet and analyzed. A total of 44 articles from 17 African countries published between 2002 and 2014 were retrieved; of which 36 were eligible and included in this review. Of all population tested, the natural immunity of rubella was found to range from 52.9 to 97.9 %. In these countries, the prevalence of susceptible pregnant women ranged from 2.1 to 47.1 %. Rubella natural immunity was significantly higher among pregnant women than in general population (P < 0.001). Acute rubella infection was observed to be as low as 0.3 % among pregnant women to 45.1 % among children. All studies did not ascertain the age-specific prevalence, thus it was difficult to calculate the rate of infection with increase in age. Only two articles were found to report on rubella genotypes. Of 15 strains genotyped; three rubella virus genotypes were found to circulate in four African countries. CONCLUSION: Despite variations in serological assays, the seroprevalence of IgG rubella antibodies in Africa is high with a substantial number of women of childbearing age being susceptible to rubella infection. Standardized sero epidemiological data in various age groups as well as CRS data are important to implement cost-effective vaccination campaigns and control strategies. PMID- 26602893 TI - Population-based survey of overweight and obesity and the associated factors in peri-urban and rural Eastern Uganda. AB - BACKGROUND: In sub-Saharan Africa (SSA), the rising prevalence of overweight, obesity and non-communicable diseases co-exists with the high burden of under nutrition. The paucity of data on adulthood overweight and obesity, disaggregated by socio-demographic characteristics and in rural settings in SSA calls for research. We determined the prevalence of underweight, overweight/obesity and associated factors among adults in peri-urban and rural Uganda. METHODS: A cross sectional study of 1210 randomly selected adults aged >= 18 years was conducted in Iganga-Mayuge Health and Demographic Surveillance Site in eastern Uganda in 2013. Height, weight and socio-demographic variables were assessed. Overweight was defined as BMI = 25.0-29.99 kg/m(2), obesity >= 30 kg/m(2) and overweight/obesity >= 25 kg/m(2). Logistic regression was used to identify factors associated with overweight/obesity. RESULTS: Of the participants, 7 % were underweight (8.1 % of men; 5.9 % of women, p = 0.99); 17.8 % were overweight (12.4 % of men; 23.1 % of women, p < 0.001); and 7 % were obese (2.0 % of men; 12.7 % of women, p < 0.001). Overweight prevalence was 15.8 % and 23.8 % among rural and peri-urban adults, respectively (p < 0.001). Obesity prevalence was 3.9 % and 17.8 % among rural and peri-urban adults, respectively (p < 0.001). Factors associated with overweight/obesity were: being female, adjusted odds ratio (AOR) 4.3 (95 % confidence interval (PloS one 8:e75640, 20013) 3.2-5.9); peri-urban residence AOR 2.6 (1.9-3.6); being in age group 35-44, AOR 3.1 (1.8-5.3); 45-54 AOR 4.1 (2.3-7.3); 55-64 AOR 2.6 (1.4-5.0); >= 65 years AOR 3.1 (1.6-6.0); and having socio-economic status (SES) in the third AOR 2.8 (1.7-4.6), fourth 2.5 (1.5-4.2) and fifth 2.7 (1.6-4.4) quintile. CONCLUSIONS: Overweight/obesity was prevalent among adults. Overweight/obese was associated with being female, being aged 35 years and older, residing in a peri-urban area and having a higher SES. The time has come to develop interventions to prevent and control overweight/obesity. PMID- 26602894 TI - Augmentation of Transient Donor Cell Chimerism and Alloantigen-Specific Regulation of Lung Transplants in Miniature Swine. AB - Donor alloantigen infusion induces T cell regulation and transplant tolerance in small animals. Here, we study donor splenocyte infusion in a large animal model of pulmonary transplantation. Major histocompatibility complex-mismatched single lung transplantation was performed in 28 minipigs followed by a 28-day course of methylprednisolone and tacrolimus. Some animals received a perioperative donor or third party splenocyte infusion, with or without low-dose irradiation (IRR) before surgery. Graft survival was significantly prolonged in animals receiving both donor splenocytes and IRR compared with controls with either donor splenocytes or IRR only. In animals with donor splenocytes and IRR, increased donor cell chimerism and CD4(+) CD25(high+) T cell frequencies were detected in peripheral blood associated with decreased interferon-gamma production of leukocytes. Secondary third-party kidney transplants more than 2 years after pulmonary transplantation were acutely rejected despite maintained tolerance of the lung allografts. As a cellular control, additional animals received third party splenocytes or donor splenocyte protein extracts. While animals treated with third-party splenocytes showed significant graft survival prolongation, the subcellular antigen infusion showed no such effect. In conclusion, minipigs conditioned with preoperative IRR and donor, or third-party, splenocyte infusions may develop long-term donor-specific pulmonary allograft survival in the presence of high levels of circulating regulatory T cells. PMID- 26602895 TI - Early- and intermediate-term results of surgical correction in 122 patients with total anomalous pulmonary venous connection and biventricular physiology. AB - BACKGROUND: We retrospectively reported our 26-year experience with operative repair of total anomalous pulmonary venous connection (TAPVC) with biventricular physiology. METHODS: Between December 1982 and December 2008, 122 TAPVC patients with biventricular heart underwent surgical repair in our department. Moderate or deep hypothermia was induced at the time of cardiopulmonary bypass (CPB). Follow up was conducted for 5 postoperative years. Surgical outcomes of early and intermediate deaths after TAPVC repair were retrospectively analyzed. RESULTS: Six deaths occurred operatively; and three deaths, during follow-up. The 5-year survival rates after TAPVC repair was 92.6 %, without gradient across the anastomosis. The survival rate of the patients who were younger was 78.8 %, significantly lower than those older than 1 year. It was also lower in those who were less than 6 kg in weight. Three patients died during follow-up. Three patients died of ventricular arrhythmia, right heart failure, and pneumonia, respectively, during follow-up. If the left atrium pressure was higher than 15 mm Hg, the snare of the vertical vein was loosened after CPB ceased in the patients with supracardiac connection. It decreased from 21 +/- 5 to 13 +/- 3 mm Hg. The vertical vein was ligated in 57 cases and left open in 20 cases. A patient with an intact vertical vein had a large shunt and was cured by intervention afterward. Supraventricular arrhythmia occurred in 19 patients with the supercardiac type repaired through a biatrial incision. One patient died of ventricular arrhythmia, and none of the remaining patients had arrhythmias. CONCLUSION: Surgical treatment of TAPVC carried a low operative risk and had satisfactory immediate and intermediate results. Age younger than 1 year and weight less than 6 kg were risk factors. It was a good choice to leave the vertical vein open in the patients with a left atrial pressure higher than 15 mm Hg. PMID- 26602896 TI - A systematic approach to initial data analysis is good research practice. AB - Initial data analysis is conducted independently of the analysis needed to address the research questions. Shortcomings in these first steps may result in inappropriate statistical methods or incorrect conclusions. We outline a framework for initial data analysis and illustrate the impact of initial data analysis on research studies. Examples of reporting of initial data analysis in publications are given. A systematic and careful approach to initial data analysis is needed as good research practice. PMID- 26602897 TI - Historical perspectives of The American Association for Thoracic Surgery: Floyd D. Loop (1936-2015). PMID- 26602898 TI - Multidisciplinary motion economy in the cardiothoracic intensive care unit. PMID- 26602899 TI - Complex congenital aortic arch disease: The need for mandatory long-term follow up. PMID- 26602900 TI - A composite semiresorbable armoured scaffold stabilizes pulmonary autograft after the Ross operation: Mr Ross's dream fulfilled. AB - OBJECTIVES: Use of resorbable external reinforcement of the pulmonary autograft during the Ross operation has been suggested, but the differential regional potential for dilation of the aorta, mainly regarding the neo-root and the neo Valsalva sinuses, represents an unresolved issue. Auxetic materials could be useful in preventing dilation given their favorable mechanical properties. We designed a composite semiresorbable armoured bioprosthesis constituted by polydioxanone and expanded polytetrafluoroethylene and evaluated its effectiveness as a pulmonary autograft reinforcement device in an animal model of the Ross procedure. METHODS: An experimental model of the Ross procedure was performed in 20 three-month-old growing lambs. The pulmonary autograft was alternatively nonreinforced (control group n = 10) or reinforced with composite bioprosthesis (reinforced group n = 10). Animals were followed up during growth for 6 months by angiography and echocardiography. Specific stainings for extracellular matrix and immunohistochemistry for metalloproteinase-9 were performed. RESULTS: Reference aortic diameter increased from 14 +/- 1 mm to 19 +/ 2 mm over 6 months of growth. In the control group, pulmonary autograft distension (28 +/- 2 mm) was immediately noted, followed by aneurysm development at 6 months (40 +/- 2 mm, P < .001 vs reference). In the reinforced group, an initial dilation to 18 +/- 1 mm was detected and the final diameter was 27 +/- 2 mm (42% increase). Two deaths due to pulmonary autograft rupture occurred in the control group. On histology, the control group showed medial disruption with connective fibrous replacement, whereas in the reinforced group compensatory intimal hyperplasia was present in the absence of intimal tears. The bioprosthesis promoted a positive matrix rearrangement process favoring neoarterialization and elastic remodeling as demonstrated on specific staining for elastin collagen and metalloproteinase-9. CONCLUSIONS: The device adapted and functionally compensated for the characteristics of autograft growth, guaranteeing a reasonable size of the autograft at 6 months, but more important, because the device is biocompatible, it did not disrupt the biological process of growth or cause inflammatory damage to the wall. PMID- 26602901 TI - Preventative medicine: The next revolution in the treatment of aortic stenosis. PMID- 26602902 TI - Pulmonary vein stenosis: Plea for a multi-institutional registry. PMID- 26602903 TI - Characterization of the healing process in non-stabilized and stabilized femur fractures in mice. AB - BACKGROUND: Although a variety of suitable fracture models for mice exist, in many studies bone healing was still analyzed without fracture stabilization. Because there is little information whether the healing of non-stabilized fractures differs from that of stabilized fractures, we herein studied the healing process of non-stabilized compared to stabilized femur fractures. MATERIALS AND METHODS: Twenty-one CD-1 mice were stabilized after midshaft fracture of the femur with an intramedullary screw allowing micromovements and endochondral healing. In another 22 mice the femur fractures were left unstabilized. Bone healing was studied by radiological, biomechanical, histomorphometric and protein expression analyses. RESULTS: Non-stabilized femur fractures revealed a significantly lower biomechanical stiffness compared to stabilized fractures. During the early phase of fracture healing non-stabilized fractures demonstrated a significantly lower amount of osseous tissue and a higher amount of cartilage tissue. During the late phase of fracture healing both non-stabilized and stabilized fractures showed almost 100 % osseous callus tissue. However, in stabilized fractures remodeling was almost completed with lamellar bone while non-stabilized fractures still showed large callus with great amounts of woven bone, indicating a delay in bone remodeling. Of interest, western blot analyses of callus tissue demonstrated in non-stabilized fractures a significantly reduced expression of vascular endothelial growth factor and a slightly lowered expression of bone morphogenetic protein-2 and collagen-10. CONCLUSION: Non-stabilized femur fractures in mice show a marked delay in bone healing compared to stabilized fractures. Therefore, non-stabilized fracture models may not be used to analyze the mechanisms of normal bone healing. PMID- 26602904 TI - Proton Mobility in b2 Ion Formation and Fragmentation Reactions of Histidine Containing Peptides. AB - A detailed energy-resolved study of the fragmentation reactions of protonated histidine-containing peptides and their b2 ions has been undertaken. Density functional theory calculations were utilized to predict how the fragmentation reactions occur so that we might discern why the mass spectra demonstrated particular energy dependencies. We compare our results to the current literature and to synthetic b2 ion standards. We show that the position of the His residue does affect the identity of the subsequent b2 ion (diketopiperazine versus oxazolone versus lactam) and that energy-resolved CID can distinguish these isomeric products based on their fragmentation energetics. The histidine side chain facilitates every major transformation except trans-cis isomerization of the first amide bond, a necessary prerequisite to diketopiperazine b2 ion formation. Despite this lack of catalyzation, trans-cis isomerization is predicted to be facile. Concomitantly, the subsequent amide bond cleavage reaction is rate-limiting. PMID- 26602905 TI - Quantitative Measures of Swallowing Deficits in Patients With Parkinson's Disease. AB - OBJECTIVE: Dysphagia and associated aspiration pneumonia are commonly reported sequelae of Parkinson's disease (PD). Previous studies of swallowing in patients with PD have described prolonged pharyngeal transit time, delayed onset of pharyngeal transit, cricopharyngeal (CP) achalasia, reduced pharyngeal constriction, and slowed hyolaryngeal elevation. These studies were completed using inconsistent evaluation methodology, reliance on qualitative analysis, and a lack of a large control group, resulting in concerns regarding diagnostic precision. The purpose of this study was to investigate swallowing function in patients with PD using a norm-referenced, quantitative approach. METHODS: This retrospective study includes 34 patients with a diagnosis of PD referred to a multidisciplinary voice and swallowing clinic. Modified barium swallow studies were performed using quantitative measures of pharyngeal transit time, hyoid displacement, CP sphincter opening, area of the pharynx at maximal constriction, and timing of laryngeal vestibule closure relative to bolus arrival at the CP sphincter. RESULTS: Reduced pharyngeal constriction was found in 30.4%, and a delay in airway closure relative to arrival of the bolus at the CP sphincter was the most common abnormality, present in 62% of patients. Previously reported findings of prolonged pharyngeal transit, poor hyoid elevation, and CP achalasia were not identified as prominent features. PMID- 26602906 TI - Long-term Follow-up Results of Regeneration Process of Fungiform Taste Buds After Severing the Chorda Tympani Nerve During Middle Ear Surgery. AB - OBJECTIVE: To elucidate the regeneration process of fungiform taste buds after severing the chorda tympani nerve (CTN) by confocal laser scanning microscopy in vivo. METHODS: In 7 consecutive patients whose CTN was severed during tympanoplasty, an average of 10 fungiform papillae in the midlateral region of the tongue were periodically observed, and the number of taste buds was counted until 12 to 24 months after surgery. Gustatory function was assessed by EGM. RESULTS: EGM thresholds showed no response within 1 month after surgery in any patient. All taste buds had disappeared until 13 to 71 days after surgery. Regenerated taste buds were first detected 5 to 8 months after surgery in 5 of the 7 patients. EGM thresholds recovered to their preoperative values in 2 patients. In these 2 patients, the number of regenerated taste buds gradually increased in combination with a recovered taste function. However, a time lag existed between taste bud regeneration and taste function recovery. EGM thresholds did not recover in the other 3 patients with regenerated taste buds, suggesting that these taste buds were immature without gustatory function. CONCLUSION: The long-term regeneration process of fungiform taste buds could be clarified using confocal laser scanning microscopy. PMID- 26602907 TI - Medicalization in psychiatry: the medical model, descriptive diagnosis, and lost knowledge. AB - Medicalization was the theme of the 29th European Conference on Philosophy of Medicine and Health Care that included a panel session on the DSM and mental health. Philosophical critiques of the medical model in psychiatry suffer from endemic assumptions that fail to acknowledge the real world challenges of psychiatric nosology. The descriptive model of classification of the DSM 3-5 serves a valid purpose in the absence of known etiologies for the majority of psychiatric conditions. However, a consequence of the "atheoretical" approach of the DSM is rampant epistemological confusion, a shortcoming that can be ameliorated by importing perspectives from the work of Jaspers and McHugh. Finally, contemporary psychiatry's over-reliance on neuroscience and pharmacotherapy has led to a reductionist agenda that is antagonistic to the inherently pluralistic nature of psychiatry. As a result, the field has suffered a loss of knowledge that may be difficult to recover. PMID- 26602908 TI - Research in Emergency and Critical Care Settings: Debates, Obstacles and Solutions. AB - Research is an integral part of evidence-based practice in the emergency department and critical care unit that improves patient management. It is important to understand the need and major obstacles for conducting research in emergency settings. Herein, we review the literature for the obligations, ethics and major implications of emergency research and the associated limiting factors influencing research activities in critical care and emergency settings. We reviewed research engines such as PubMed, MEDLINE, and EMBASE for the last two decades using the key words "emergency department", "critical care", "research", "consent", and "ethics" as the search terms. Research within emergency settings is slow or non-existent due to time and financial constraints as well as the lack of a research tradition. There are several barriers to conducting research studies in emergency situations such as who, what, when, and how to obtain patient consent. The emergency environment is highly pressurized, emotional, and overburdened. The time taken for research is a particular risk that could delay the desired immediate interventions. Ethical issues abound, particularly relating to informed consent. Research in emergency settings is still in its infancy. Thus, there is a strong need for extensive research in the emergency setting through community awareness, resource management, ethics, collaborations, capacity building, and the development of a research interest for the improvement of patient care and outcomes. We need to establish a well-structured plan to assess and track the decision-making capacity, consider a multistep enrolment and consent strategy, and develop an integrated approach for recruitment into studies. PMID- 26602909 TI - A Different Trolley Problem: The Limits of Environmental Justice and the Promise of Complex Moral Assessments for Transportation Infrastructure. AB - Transportation infrastructure tremendously affects the quality of life for urban residents, influences public and mental health, and shapes social relations. Historically, the topic is rich with social and political controversy and the resultant transit systems in the United States cause problems for minority residents and issues for the public. Environmental justice frameworks provide a means to identify and address harms that affect marginalized groups, but environmental justice has limits that cannot account for the mainstream population. To account for this condition, I employ a complex moral assessment measure that provides a way to talk about harms that affect the public. PMID- 26602910 TI - A case of osteoclast-like giant cell-rich epithelioid glioblastoma with BRAF V600E mutation. AB - Epithelioid glioblastomas (E-GBMs) are rare, highly aggressive tumors consisting of closely packed tumor cells with smooth, round cell borders and abundant eosinophilic cytoplasm. They tend to affect younger patients compared with conventional GBM. BRAF V600E mutation is characteristically found in approximately 50% of all E-GBMs, compared with a low frequency of this mutation in conventional GBM. Here, we report an unusual case of glioma involving the right frontal lobe, basal ganglia and thalamus in an HIV-positive 30-year-old man on antiretroviral therapy. The lesion was composed of abundant discohesive, monotonous epithelioid cells with extensive necrosis, spindle and polyhedral cells, low-grade oligoastrocytoma-like areas, sarcomatous components, and numerous osteoclast-like giant cells (OLGCs) intermingled with epithelioid tumor cells. As the epithelioid cells accounted for more than one-third of the tumor, a pathological diagnosis of E-GBM was made. BRAF V600E mutation was detected in both oligoastrocytoma-like and epithelioid cell components. Similar to previously reported findings on E-GBM associated with low-grade glioma, this case suggested that low-grade astrocytic glioma with BRAF V600E mutation progressed to E-GBM. OLGCs are rarely observed in gliomas, and this is the first case report of E-GBM associated with abundant OLGC infiltration. PMID- 26602911 TI - Universal Screening of Colorectal Cancers for Lynch Syndrome: Challenges and Opportunities. AB - Lynch syndrome (LS) is the most common heritable colorectal cancer (CRC) syndrome, accounting for approximately 3 % of CRC cases in the USA each year. LS results from a genetic mutation in one of the four mismatch repair genes, and clinically LS is associated with CRC and other gastrointestinal and extra gastrointestinal malignancies. In this review, we describe the various clinical criteria utilized for the identification of LS patients and the inherent flaws with these criteria. We discuss the concept of universal testing for LS in all cases of newly diagnosed CRC, along with the potential benefits and challenges of universal testing. Several studies have shown that universal tumor testing is cost-effective and identifies cases of LS that are missed using traditional clinical criteria, which may result in reduced cancer mortality for probands and their families. Yet the full benefits of universal tumor testing may be limited by the availability and patient acceptance of genetic testing, and by logistical obstacles affecting the implementation of universal testing programs. Lastly, we comment on developing technologies such as massively parallel next-generation sequencing, which permits simultaneous sequencing of multiple genes involved in LS and other inherited colon cancer syndromes. PMID- 26602912 TI - Cystic Fibrosis Associated with Worse Survival After Liver Transplantation. AB - BACKGROUND: Survival in cystic fibrosis patients after liver transplantation and liver-lung transplantation is not well studied. AIMS: To discern survival rates after liver transplantation and liver-lung transplantation in patients with and without cystic fibrosis. METHODS: The United Network for Organ Sharing database was queried from 1987 to 2013. Univariate Cox proportional hazards, multivariate Cox models, and propensity score matching were performed. RESULTS: Liver transplant and liver-lung transplant were performed in 212 and 53 patients with cystic fibrosis, respectively. Univariate Cox proportional hazards regression identified lower survival in cystic fibrosis after liver transplant compared to a reference non-cystic fibrosis liver transplant cohort (HR 1.248; 95 % CI 1.012, 1.541; p = 0.039). Supplementary analysis found graft survival was similar across the 3 recipient categories (log-rank test: chi(2) 2.68; p = 0.262). Multivariate Cox models identified increased mortality hazard among cystic fibrosis patients undergoing liver transplantation (HR 2.439; 95 % CI 1.709, 3.482; p < 0.001) and liver-lung transplantation (HR 2.753; 95 % CI 1.560, 4.861; p < 0.001). Propensity score matching of cystic fibrosis patients undergoing liver transplantation to non-cystic fibrosis controls identified a greater mortality hazard in the cystic fibrosis cohort using a Cox proportional hazards model stratified on matched pairs (HR 3.167; 95 % CI 1.265, 7.929, p = 0.014). CONCLUSIONS: Liver transplantation in cystic fibrosis is associated with poorer long-term patient survival compared to non-cystic fibrosis patients, although the difference is not due to graft survival. PMID- 26602913 TI - Recurrent Pyogenic Cholangitis: Got Stones? PMID- 26602915 TI - Agreement between physicians' and nurses' clinical decisions for the management of the fracture liaison service (4iFLS): the Lucky BoneTM program. AB - We determined if nurses can manage osteoporotic fractures in a fracture liaison service by asking a rheumatologist and an internist to assess their clinical decisions. Experts agreed on more than 94 % of all nurses' actions for 525 fragility fracture patients, showing that their management is efficient and safe. INTRODUCTION: A major care gap exists in the investigation of bone fragility and initiation of treatment for individuals who have sustained a fragility fracture. The implementation of a fracture liaison service (FLS) managed by nurses could be the key in resolving this problem. The aim of this project was to obtain agreement between physicians' and nurses' clinical decisions and evaluate if the algorithm of care is efficient and reliable for the management of a FLS. METHODS: Clinical decisions of nurses for 525 subjects in a fracture liaison service between 2010 and 2013 were assessed by two independent physicians with expertise in osteoporosis treatment. RESULTS: Nurses succeeded in identifying all patients at risk and needed to refer 27 % of patients to an MD. Thereby, they managed autonomously 73 % of fragility fracture patients. No needless referrals were made according to assessing physicians. Agreement between each evaluator and nurses was of >97 %. Physicians' decisions were the same in >96 %, and Gwet AC11 coefficient was of >0.960 (almost perfect level of agreement). All major comorbidities were adequately managed. CONCLUSIONS: High agreement between nurses' and physicians' clinical decisions indicate that the independent management by nurses of a fracture liaison service is safe and should strongly be recommended in the care of patients with a fragility fracture. This kind of intervention could help resolve the existing care gap in bone fragility care as well as the societal economic burden associated with prevention and treatment of fragility fractures. PMID- 26602916 TI - Proton pump inhibitors and fracture risk: response to comments. PMID- 26602914 TI - Optimal serum cholesterol concentrations are associated with accelerated bone loss in African ancestry men. AB - We tested if serum lipid and lipoprotein cholesterol levels are associated with longitudinal measures of bone mineral density (BMD) in 1289 African ancestry men. After 6 years of mean follow-up, men with clinically optimal levels of low density lipoprotein (LDL), high-density lipoprotein (HDL), or triglycerides at baseline experienced the greatest BMD loss, independent of potential confounding factors (all p < 0.05). INTRODUCTION: Studies of lipid and lipoprotein cholesterol associations with bone mineral density (BMD) and bone loss have been inconclusive, and longitudinal data are sparse. Therefore, the aim of this study was to test if fasting serum lipid and lipoprotein cholesterol levels are associated with areal and volumetric BMD and BMD change. METHODS: We determined the association of serum triglycerides, high-density lipoprotein (HDL), and low density lipoprotein (LDL) cholesterol concentrations with cross-sectional and longitudinal (mean follow-up, 6.1 years) measures of BMD in a cohort of 1289 in African ancestry men (mean age, 56.4 years). Fasting serum triglycerides, HDL, and LDL were measured at baseline concurrent with BMD assessments. Dual-energy X ray absorptiometry was used to quantify integral hip BMD, and peripheral quantitative computed tomography at the radius and tibia was used to quantify volumetric BMD. Men were categorized as optimal, borderline, or high risk for triglyceride, HDL, and LDL concentrations based on Adult Treatment Panel III guidelines. RESULTS: Lower serum triglyceride or LDL and higher HDL concentrations were associated with lower trabecular BMD at baseline (all p < 0.05). Similarly, men classified as having optimal levels of LDL, HDL, or triglycerides at baseline experienced the greatest integral BMD loss at the hip and trabecular BMD loss at the tibia (all p < 0.05), independent of potential confounding factors. CONCLUSIONS: We found that clinically optimal serum lipid and lipoprotein cholesterol concentrations were associated with accelerated bone loss among Afro-Caribbean men. Further studies are needed to better understand the mechanisms involved and potential clinical significance of these findings. PMID- 26602917 TI - Application of Green Tea Catechin for Inducing the Osteogenic Differentiation of Human Dedifferentiated Fat Cells in Vitro. AB - Despite advances in stem cell biology, there are few effective techniques to promote the osteogenic differentiation of human primary dedifferentiated fat (DFAT) cells. We attempted to investigate whether epigallocatechin-3-gallate (EGCG), the main component of green tea catechin, facilitates early osteogenic differentiation and mineralization on DFAT cells in vitro. DFAT cells were treated with EGCG (1.25-10 MUM) in osteogenic medium (OM) with or without 100 nM dexamethasone (Dex) for 12 days (hereafter two osteogenic media were designated as OM(Dex) and OM). Supplementation of 1.25 MUM EGCG to both the media effectively increased the mRNA expression of collagen 1 (COL1A1) and runt-related transcription factor 2 (RUNX2) and also increased proliferation and mineralization. Compared to OM(Dex) with EGCG, OM with EGCG induced earlier expression for COL1A1 and RUNX2 at day 1 and higher mineralization level at day 12. OM(Dex) with 10 MUM EGCG remarkably hampered the proliferation of the DFAT cells. These results suggest that OM(without Dex) with EGCG might be a preferable medium to promote proliferation and to induce osteoblast differentiation of DFAT cells. Our findings provide an insight for the combinatory use of EGCG and DFAT cells for bone regeneration and stem cell-based therapy. PMID- 26602919 TI - Does Lysosomial Acid Lipase Reduction Play a Role in Adult Non-Alcoholic Fatty Liver Disease? AB - Lysosomal Acid Lipase (LAL) is a key enzyme involved in lipid metabolism, responsible for hydrolysing the cholesteryl esters and triglycerides. Wolman Disease represents the early onset phenotype of LAL deficiency rapidly leading to death. Cholesterol Ester Storage Disease is a late onset phenotype that occurs with fatty liver, elevated aminotransferase levels, hepatomegaly and dyslipidaemia, the latter characterized by elevated LDL-C and low HDL-C. The natural history and the clinical manifestations of the LAL deficiency in adults are not well defined, and the diagnosis is often incidental. LAL deficiency has been suggested as an under-recognized cause of dyslipidaemia and fatty liver. Therefore, LAL activity may be reduced also in non-obese patients presenting non alcoholic fatty liver disease (NAFLD), unexplained persistently elevated liver transaminases or with elevation in LDL cholesterol. In these patients, it could be indicated to test LAL activity. So far, very few studies have been performed to assess LAL activity in representative samples of normal subjects or patients with NAFLD. Moreover, no large study has been carried out in adult subjects with NAFLD or cryptogenic cirrhosis. PMID- 26602918 TI - Adjuvant Immune Enhancement of Subunit Vaccine Encoding pSCPI of Streptococcus iniae in Channel Catfish (Ictalurus punctatus). AB - Channel catfish (Ictalurus punctatus) is an important agricultural fish that has been plagued by Streptococcus iniae (S. iniae) infections in recent years, some of them severe. C5a peptidase is an important virulent factor of S. iniae. In this study, the subunit vaccine containing the truncated part of C5a peptidase (pSCPI) was mixed with aluminum hydroxide gel (AH), propolis adjuvant (PA), and Freund's Incomplete Adjuvant (FIA). The immunogenicity of the pSCPI was detected by Western-blot in vitro. The relative percent survival (RPS), lysozyme activity, antibody titers, and the expression of the related immune genes were monitored in vivo to evaluate the immune effects of the three different adjuvants. The results showed that pSCPI exerted moderate immune protection (RPS = 46.43%), whereas each of the three adjuvants improved the immune protection of pSCPI. The immunoprotection of pSCPI + AH, pSCPI + PA, and pSCPI + FIA was characterized by RPS values of 67.86%, 75.00% and, 85.71%, respectively. Further, each of the three different adjuvanted pSCPIs stimulated higher levels of lysozyme activity and antibody titers than the unadjuvanted pSCPI and/or PBS buffer. In addition, pSCPI + FIA and pSCPI + PA induced expression of the related immune genes under investigation, which was substantially higher than the levels stimulated by PBS. pSCPI + AH significantly stimulated the induction of MHC II beta, CD4-L2, and IFN gamma, while it induced slightly higher production of TNF-alpha and even led to a decrease in the levels of IL-1beta, MHC I alpha, and CD8 alpha. Therefore, we conclude that compared with the other two adjuvants, FIA combined with pSCPI is a more promising candidate adjuvant against S. iniae in channel catfish. PMID- 26602920 TI - Genotypic Variation under Fe Deficiency Results in Rapid Changes in Protein Expressions and Genes Involved in Fe Metabolism and Antioxidant Mechanisms in Tomato Seedlings (Solanum lycopersicum L.). AB - To investigate Fe deficiency tolerance in tomato cultivars, quantification of proteins and genes involved in Fe metabolism and antioxidant mechanisms were performed in "Roggusanmaru" and "Super Doterang". Fe deficiency (Moderate, low and -Fe) significantly decreased the biomass, total, and apoplastic Fe concentration of "Roggusanmaru", while a slight variation was observed in "Super Doterang" cultivar. The quantity of important photosynthetic pigments such as total chlorophyll and carotenoid contents significantly decreased in "Roggusanmaru" than "Super Doterang" cultivar. The total protein profile in leaves and roots determines that "Super Doterang" exhibited an optimal tolerance to Fe deficiency compared to "Roggusanmaru" cultivar. A reduction in expression of PSI (photosystem I), PSII (photosystem II) super-complexes and related thylakoid protein contents were detected in "Roggusanmaru" than "Super Doterang" cultivar. Moreover, the relative gene expression of SlPSI and SlPSII were well maintained in "Super Doterang" than "Roggusanmaru" cultivar. The relative expression of genes involved in Fe-transport (SlIRT1 and SlIRT2) and Fe(III) chelates reductase oxidase (SlFRO1) were relatively reduced in "Roggusanmaru", while increased in "Super Doterang" cultivar under Fe deficient conditions. The H+-ATPase relative gene expression (SlAHA1) in roots were maintained in "Super Doterang" compared to "Roggusanmaru". Furthermore, the gene expressions involved in antioxidant defense mechanisms (SlSOD, SlAPX and SlCAT) in leaves and roots showed that these genes were highly increased in "Super Doterang", whereas decreased in "Roggusanmaru" cultivar under Fe deficiency. The present study suggested that "Super Doterang" is better tomato cultivar than "Roggusanmaru" for calcareous soils. PMID- 26602921 TI - A Multiple Interaction Analysis Reveals ADRB3 as a Potential Candidate for Gallbladder Cancer Predisposition via a Complex Interaction with Other Candidate Gene Variations. AB - Gallbladder cancer is the most common and a highly aggressive biliary tract malignancy with a dismal outcome. The pathogenesis of the disease is multifactorial, comprising the combined effect of multiple genetic variations of mild consequence along with numerous dietary and environmental risk factors. Previously, we demonstrated the association of several candidate gene variations with GBC risk. In this study, we aimed to identify the combination of gene variants and their possible interactions contributing towards genetic susceptibility of GBC. Here, we performed Multifactor-Dimensionality Reduction (MDR) and Classification and Regression Tree Analysis (CRT) to investigate the gene-gene interactions and the combined effect of 14 SNPs in nine genes (DR4 (rs20576, rs6557634); FAS (rs2234767); FASL (rs763110); DCC (rs2229080, rs4078288, rs7504990, rs714); PSCA (rs2294008, rs2978974); ADRA2A (rs1801253); ADRB1 (rs1800544); ADRB3 (rs4994); CYP17 (rs2486758)) involved in various signaling pathways. Genotyping was accomplished by PCR-RFLP or Taqman allelic discrimination assays. SPSS software version 16.0 and MDR software version 2.0 were used for all the statistical analysis. Single locus investigation demonstrated significant association of DR4 (rs20576, rs6557634), DCC (rs714, rs2229080, rs4078288) and ADRB3 (rs4994) polymorphisms with GBC risk. MDR analysis revealed ADRB3 (rs4994) to be crucial candidate in GBC susceptibility that may act either alone (p < 0.0001, CVC = 10/10) or in combination with DCC (rs714 and rs2229080, p < 0.0001, CVC = 9/10). Our CRT results are in agreement with the above findings. Further, in-silico results of studied SNPs advocated their role in splicing, transcriptional and/or protein coding regulation. Overall, our result suggested complex interactions amongst the studied SNPs and ADRB3 rs4994 as candidate influencing GBC susceptibility. PMID- 26602922 TI - Identification of Pathogenicity-Related Genes in Biofilm-Defective Acidovorax citrulli by Transposon Tn5 Mutagenesis. AB - Biofilm formation is important for virulence of a large number of plant pathogenic bacteria. Indeed, some virulence genes have been found to be involved in the formation of biofilm in bacterial fruit blotch pathogen Acidovorax citrulli. However, some virulent strains of A. citrulli were unable to format biofilm, indicating the complexity between biofilm formation and virulence. In this study, virulence-related genes were identified in the biofilm-defective strain A1 of A. citrulli by using Tn5 insertion, pathogenicity test, and high efficiency thermal asymmetric interlaced PCR (hiTAIL-PCR). Results from this study indicated that 22 out of the obtained 301 mutants significantly decreased the virulence of strain A1 compared to the wild-type. Furthermore, sequence analysis indicated that the obtained 22 mutants were due to the insertion of Tn5 into eight genes, including Aave 4244 (cation diffusion facilitator family transporter), Aave 4286 (hypothetical protein), Aave 4189 (alpha/beta hydrolase fold), Aave 1911 (IMP dehydrogenase/GMP reductase domain), Aave 4383 (bacterial export proteins, family 1), Aave 4256 (Hsp70 protein), Aave 0003 (histidine kinase, DNA gyrase B, and HSP90-like ATPase), and Aave 2428 (pyridoxal-phosphate dependent enzyme). Furthermore, the growth of mutant Aave 2428 was unaffected and even increased by the change in incubation temperature, NaCl concentration and the pH of the LB broth, indicating that this gene may be directly involved in the bacterial virulence. Overall, the determination of the eight pathogenicity related genes in strain A1 will be helpful to elucidate the pathogenesis of biofilm-defective A. citrulli. PMID- 26602924 TI - Critical Role of Endoplasmic Reticulum Stress in Cognitive Impairment Induced by Microcystin-LR. AB - Recent studies showed that cyanobacteria-derived microcystin-leucine-arginine (MCLR) can cause hippocampal pathological damage and trigger cognitive impairment; but the underlying mechanisms have not been well understood. The objective of the present study was to investigate the mechanism of MCLR-induced cognitive deficit; with a focus on endoplasmic reticulum (ER) stress. The Morris water maze test and electrophysiological study demonstrated that MCLR caused spatial memory injury in male Wistar rats; which could be inhibited by ER stress blocker; tauroursodeoxycholic acid (TUDCA). Meanwhile; real-time polymerase chain reaction (real-time PCR) and immunohistochemistry demonstrated that the expression level of the 78-kDa glucose-regulated protein (GRP78); C/EBP homologous protein (CHOP) and caspase 12 were significantly up-regulated. These effects were rescued by co-administration of TUDCA. In agreement with this; we also observed that treatment of rats with TUDCA blocked the alterations in ER ultrastructure and apoptotic cell death in CA1 neurons from rats exposed to MCLR. Taken together; the present results suggested that ER stress plays an important role in potential memory impairments in rats treated with MCLR; and amelioration of ER stress may serve as a novel strategy to alleviate damaged cognitive function triggered by MCLR. PMID- 26602923 TI - MicroRNAs: Clinical Relevance in Colorectal Cancer. AB - Colorectal cancer is one of the most common cancer diagnoses and causes of mortality worldwide. MicroRNAs are a class of small, non-coding regulatory RNAs that have shown strong associations with colorectal cancer. Through the repression of target messenger RNAs, microRNAs modulate many cellular pathways, such as those involved in cell proliferation, apoptosis, and differentiation. The utilization of microRNAs has shown significant promise in the diagnosis and prognosis of colorectal cancer, owing to their unique expression profile associations with cancer types and malignancies. Moreover, microRNA therapeutics with mimics or antagonists show great promise in preclinical studies, which encourages further development of their clinical use for colorectal cancer patients. The unique ability of microRNAs to affect multiple downstream pathways represents a novel approach for cancer therapy. Although still early in its development, we believe that microRNAs can be used in the near future as biomarkers and therapeutic targets for colorectal cancer. PMID- 26602925 TI - Transcriptome Profiling of Louisiana iris Root and Identification of Genes Involved in Lead-Stress Response. AB - Louisiana iris is tolerant to and accumulates the heavy metal lead (Pb). However, there is limited knowledge of the molecular mechanisms behind this feature. We describe the transcriptome of Louisiana iris using Illumina sequencing technology. The root transcriptome of Louisiana iris under control and Pb-stress conditions was sequenced. Overall, 525,498 transcripts representing 313,958 unigenes were assembled using the clean raw reads. Among them, 43,015 unigenes were annotated and their functions classified using the euKaryotic Orthologous Groups (KOG) database. They were divided into 25 molecular families. In the Gene Ontology (GO) database, 50,174 unigenes were categorized into three GO trees (molecular function, cellular component and biological process). After analysis of differentially expressed genes, some Pb-stress-related genes were selected, including biosynthesis genes of chelating compounds, metal transporters, transcription factors and antioxidant-related genes. This study not only lays a foundation for further studies on differential genes under Pb stress, but also facilitates the molecular breeding of Louisiana iris. PMID- 26602928 TI - Balloon pulmonary angioplasty attenuates ongoing myocardial damage in patients with chronic thromboembolic pulmonary hypertension. PMID- 26602927 TI - Results of a Saxitoxin Proficiency Test Including Characterization of Reference Material and Stability Studies. AB - A saxitoxin (STX) proficiency test (PT) was organized as part of the Establishment of Quality Assurance for the Detection of Biological Toxins of Potential Bioterrorism Risk (EQuATox) project. The aim of this PT was to provide an evaluation of existing methods and the European laboratories' capabilities for the analysis of STX and some of its analogues in real samples. Homogenized mussel material and algal cell materials containing paralytic shellfish poisoning (PSP) toxins were produced as reference sample matrices. The reference material was characterized using various analytical methods. Acidified algal extract samples at two concentration levels were prepared from a bulk culture of PSP toxins producing dinoflagellate Alexandrium ostenfeldii. The homogeneity and stability of the prepared PT samples were studied and found to be fit-for-purpose. Thereafter, eight STX PT samples were sent to ten participating laboratories from eight countries. The PT offered the participating laboratories the possibility to assess their performance regarding the qualitative and quantitative detection of PSP toxins. Various techniques such as official Association of Official Analytical Chemists (AOAC) methods, immunoassays, and liquid chromatography-mass spectrometry were used for sample analyses. PMID- 26602929 TI - Sphenopalatine Artery Ligation for Epistaxis: Factors Influencing Outcome and Impact of Timing of Surgery. AB - OBJECTIVE: Sphenopalatine artery ligation is a commonly employed surgical intervention for control of posterior epistaxis unresponsive to nasal packing. The objective of the present study was to evaluate the outcome of sphenopalatine artery ligation for control of epistaxis at our institution and the impact of timing and other factors on outcome. STUDY DESIGN: Case series with chart review. SETTING: Academic tertiary referral center. SUBJECTS AND METHODS: Case notes were reviewed for 45 consecutive patients undergoing sphenopalatine artery ligation for control of epistaxis between October 2008 and October 2014. RESULTS: Forty one patients had nasal packing prior to sphenopalatine artery ligation, with 33 undergoing >=2 packings. Postoperatively, 6 patients had rebleeding, which was treated with repacking (n = 4) and return to the operating room (n = 2). The overall success rate of sphenopalatine artery ligation was 87% (39 of 45). Rebleeding rate was not affected by concomitant septoplasty, anterior ethmoidal artery ligation, or postoperative nasal packing. Patients undergoing SPA ligation within the first 24 hours of admission had a significantly shorter hospital length of stay (3 vs 6 days, P = .02) and treatment cost (?5905 vs ?10,001, P = .03). Length of stay was not influenced by sphenopalatine artery ligation after <=1 nasal pack versus >=2 packs. Timing of sphenopalatine artery ligation did not affect blood transfusion requirement (P = .84). CONCLUSION: Sphenopalatine artery ligation is an effective management strategy for surgical control of refractory epistaxis. Early timing of sphenopalatine artery ligation may lead to reductions in length of stay. PMID- 26602926 TI - Dermal Contributions to Human Interfollicular Epidermal Architecture and Self Renewal. AB - The human interfollicular epidermis is renewed throughout life by populations of proliferating basal keratinocytes. Though interfollicular keratinocyte stem cells have been identified, it is not known how self-renewal in this compartment is spatially organized. At the epidermal-dermal junction, keratinocytes sit atop a heterogeneous mix of dermal cells that may regulate keratinocyte self-renewal by influencing local tissue architecture and signalling microenvironments. Focusing on the rete ridges and complementary dermal papillae in human skin, we review the identity and organisation of abundant dermal cells types and present evidence for interactions between the dermal microenvironment and the interfollicular keratinocytes. PMID- 26602930 TI - In the digital era, architectural distortion remains a challenging radiological task. AB - AIM: To compare readers' performance in detecting architectural distortion (AD) compared with other breast cancer types using digital mammography. MATERIALS AND METHODS: Forty-one experienced breast screen readers (20 US and 21 Australian) were asked to read a single test set of 30 digitally acquired mammographic cases. Twenty cases had abnormal findings (10 with AD, 10 non-AD) and 10 cases were normal. Each reader was asked to locate and rate any abnormalities. Lesion and case-based performance was assessed. For each collection of readers (US; Australian; combined), jackknife free-response receiver operating characteristic (JAFROC), figure of merit (FOM), and inferred receiver operating characteristic (ROC), area under curve (Az) were calculated using JAFROC v.4.1 software. Readers' sensitivity, location sensitivity, JAFROC, FOM, ROC, Az scores were compared between cases groups using Wilcoxon's signed ranked test statistics. RESULTS: For lesion-based analysis, significantly lower location sensitivity (p=0.001) was shown on AD cases compared with non-AD cases for all reader collections. The case-based analysis demonstrated significantly lower ROC Az values (p=0.02) for the first collection of readers, and lower sensitivity for the second collection of readers (p=0.04) and all-readers collection (p=0.008), for AD compared with non-AD cases. CONCLUSIONS: The current work demonstrates that AD remains a challenging task for readers, even in the digital era. PMID- 26602931 TI - Heterotopic ossification related to the radial tuberosity: a tumour mimic. AB - AIM: To present the imaging features of heterotopic ossification (HO) related to the radial tuberosity initially referred as a suspected sarcoma. MATERIALS AND METHODS: Local institutional review board approval was obtained. A retrospective search of the oncology database was conducted to identify cases of ossification related to the radial tuberosity, referred to the supra-regional orthopaedic oncology centre as a suspected sarcoma. Furthermore, cases of soft-tissue sarcoma (STS) of the proximal forearm were also identified. The imaging findings were reviewed for all relevant cases. RESULTS: Over a 10-year period, 50 cases of STS of the forearm were identified with 23 involving the proximal forearm. STS was intimately related to the radial tuberosity in 52% (12/23) of these cases. There was no calcification or ossification related to the radial tuberosity in any of these sarcomas. During the same 10-year period, five cases of HO related to the radial tuberosity were identified. Demographics of these five cases revealed no significant sex predominance with a median age of 60 years. No obvious precipitating cause or predisposing condition was demonstrated. All five cases had radiographic evidence of ossification ranging from 20-53 mm in maximal dimension. Apart from one patient who had extensive ossification extending up the distal biceps tendon, the biceps tendon was otherwise normal on magnetic resonance imaging (MRI). There was only one case of mild osseous oedema of the proximal radius. CONCLUSION: No STS adjacent to the radial tuberosity was associated with ossification related to the radial tuberosity. Ossification related to the radial tuberosity is a benign entity and radiologists need to be aware of this tumour mimic. PMID- 26602932 TI - Gallbladder carcinoma: causes of misdiagnosis at CT. AB - Gallbladder carcinomas can present with varied imaging features on computed tomography. The three major imaging features include (1) focal or diffuse wall thickening with or without irregularity of the gallbladder; (2) polypoidal intraluminal mass; and (3) large mass obscuring and replacing the gallbladder, often extending to the liver. Patterns of wall thickening or polypoid growth are often confused with various benign gallbladder diseases due to overlap of imaging findings. Moreover, gallbladder carcinomas that coexist with benign gallbladder diseases make accurate preoperative diagnosis more difficult. Recently, high resolution ultrasound (HRUS) has been regarded as a problem-solving tool for gallbladder diseases. In this article, we will illustrate various imaging presentations of gallbladder cancer, along with imaging pitfalls and recently updated HRUS findings. PMID- 26602933 TI - Acute pancreatitis: international classification and nomenclature. AB - The incidence of acute pancreatitis (AP) is increasing and it is associated with a major healthcare concern. New insights in the pathophysiology, better imaging techniques, and novel treatment options for complicated AP prompted the update of the 1992 Atlanta Classification. Updated nomenclature for pancreatic collections based on imaging criteria is proposed. Adoption of the newly Revised Classification of Acute Pancreatitis 2012 by radiologists should help standardise reports and facilitate accurate conveyance of relevant findings to referring physicians involved in the care of patients with AP. This review will clarify the nomenclature of pancreatic collections in the setting of AP. PMID- 26602934 TI - PI-RADS: past, present and future. PMID- 26602935 TI - Multidetector computed tomography sizing of bioprosthetic valves: guidelines for measurement and implications for valve-in-valve therapies. AB - AIM: To describe a technique for bioprosthetic multidetector computed tomography (MDCT) sizing and to compare MDCT-derived values against manufacturer-provided sizing. MATERIALS AND METHODS: Fourteen bioprosthetic stented valves commonly used in the aortic valve position were evaluated using a Philips 256 MDCT system. All valves were scanned using a dedicated cardiac CT protocol with a four-channel electrocardiography (ECG) simulator. Measurements were made of major and minor axes and the area and perimeter of the internal stent using varying reconstruction kernels and window settings. Measurements derived from MDCT (MDCT ID) were compared against the stent internal diameter (Stent ID) as provided by the valve manufacturer and the True ID (Stent ID + insertion of leaflets). All data were collected and analysed using SPSS for Mac (version 21). RESULTS: The mean difference between the MDCT ID and Stent ID was 0.6+/-1.9 mm (r=0.649, p=0.012) and between MDCT ID and True ID 2.1+/-2 mm (r=0.71, p=0.005). There was no difference in the major (p=0.90), minor (p=0.87), area (p=0.92), or perimeter (p=0.92) measurements when sharp, standard, and detailed stent kernels were used. Similarly, the measurements remained consistent across differing windowing levels. CONCLUSION: Bioprosthetic stented valves may be reliably sized using MDCT in patients requiring valve-in-valve (VIV) interventions where the valve type and size are unknown. In these cases, clinicians should be aware that MDCT has a tendency to overestimate the True ID size. PMID- 26602936 TI - C-arm CT-guided renal arterial embolisation followed by radiofrequency ablation for treatment of patients with unresectable renal cell carcinoma. AB - AIM: To explore the value of using flat detector (FD) equipped angiographic C-arm CT (CACT) systems in treating unresectable renal cell carcinoma (RCC) by selective renal arterial embolisation (RAE) followed by radiofrequency ablation (RFA) (RAE-RFA). MATERIALS AND METHODS: A total of 28 patients who were not candidates for surgery were enrolled. The average size of tumours was 6.7+/-2.2 cm (range 4.1-9.6 cm). Twenty-eight tumours were treated with CACT-guided RFA, 5 7 days after CACT-guided RAE. RESULTS: CACT-guided RAE-RFA was technically successful in all patients. Tumour enhancement disappeared after a single RAE-RFA session in 20 patients, after two RAE-RFA sessions in four patients and after three RAE-RFA sessions in the other four patients. One patient died of lung metastasis and haematuria 13 months after RAE-RFA, and another patient died of pulmonary heart disease 23 months after repeat RAE-RFA. In the 26 living patients, tumours remained controlled during a mean follow-up period of 27 months and showed significant reduction in tumour size (6.7+/-2.2 cm to 3.9+/-1.7 cm, p<0.01). There were no significant changes in creatinine levels or urea nitrogen concentrations before and after the last RAE-RFA (p>0.05). There were no serious complications during and after the procedure. CONCLUSION: CACT-guided RAE followed by RFA appears to be a safe and effective technique for treating patients with inoperable RCC. PMID- 26602937 TI - Orbital lesions with low signal intensity on T2-weighted imaging. AB - The purpose of the present review is to discuss and display orbital lesions that demonstrate hypo-intense signal on T2-weighted images (T2WI). The physical basis for hypo-intense signal on T2WI produced by various substances is discussed. Orbital lesions that are hypo-intense on T2WI are subsequently reviewed, including a discussion on their composition as well as relevant clinical and imaging clues that may aid in their diagnosis. PMID- 26602938 TI - Diagnosing chronic obstructive pulmonary disease. PMID- 26602939 TI - [Level of control and treatment adherence of anticoagulation with acenocoumarol in Primary Care]. AB - OBJECTIVES: To determine the level of control in treatment compliance in a sample of patients who were treated with acenocoumarol attended in Primary Care settings. MATERIAL AND METHODS: Cross-sectional study. Patients with non-valvular atrial fibrillation treated with acenocoumarol were included. The sample size was calculated based on previous studies. Data of patients who possessed International Normalized Ratio (INR) values in last 6 months in medical consult were collected. It was considered that the INR control was inadequate when the percentage of INR values within the therapeutic range was less than 60% in the last 6 months. Assessment of compliance by telephone interview was conducted by the Morisky-Green Test. RESULTS: One hundred and ninety-one patients, 110 women (57.6%) with an average age of 76.5+/-9.4 years were included. Seventy-six patients (39.8%) were in therapeutic range (INR: 2-3) and 115 patients (60.2%) were out of range (below 2 the 20.9% and above 3 the 39.3%). Poor control of INR increased to the age of 85 years (<75 years: 57.8%; 75-85 years: 67.6%;>85 years: 61.5%). Ninety patients responded to the compliance questionnaire (78.3%), being compliant 74 (82.2%) and non-compliant 16 (17.8%). CONCLUSIONS: Six of 10 patients undergoing treatment with acenocoumarol are out of range and nearly 2 of each 10 patients out of range does not accomplish the treatment. We call attention to the need to make a systematically review of adherence in anticoagulated patients attended in Primary Care settings. PMID- 26602940 TI - [Diabetic retinopathy screening programme in primary health care. Diagnostic concordance between family and eye care practitioners]. AB - AIM: To evaluate the diagnostic concordance in retinography interpretation between primary care and eye care practitioners and assess the soundness index of a diabetic retinography screening programme during its implementation stage. MATERIAL AND METHODS: Descriptive, observational study was conducted on a sample of 243 patients with diabetes mellitus (type 1 and 2) over age 14, in 2 urban health care centers, gathered in an opportunistic manner between the dates of 21/07/2011 and 26/01/2012. A 45 degrees digital bilateral retinography, intraocular pressure and visual acuity were obtained from each patient. The primary care practitioners prepared a report for each patient, which was telematically sent to the eye care doctor within the corresponding retinographies. A new diagnostic report was prepared then by the eye care doctor after revising the images. The lack of retinographies and/or reports were considered both as losses. The diagnostic concordance between the observers and the validity and reliability from the screening programme were estimated. RESULTS: The kappa value obtained was 0.62 (95% CI 0.42-0.82) and 0.89 PABAK. The following validity indexes were obtained: Sensitivity 68.8%, specificity 96.5%, positive and negative predictive values: 61.1 and 97.5%, respectively. A percentage of 57.2 of the patients were not observed any pathology requiring referral to a eye care doctor. CONCLUSIONS: The concordance value obtained varied between considerable and almost perfect, depending on the index used for the analysis (kappa/PABAK, respectively). It's worth highlighting that carrying out retinographies in the primary care centers enhances patient-treatment capacity of the primary care doctors and the patients accessibility to screening. PMID- 26602941 TI - Interactive Web-Based Learning: Translating Health Policy Into Improved Diabetes Care. AB - In August 2014, the U.S. DHHS's Office of Disease Prevention and Health Promotion released the National Action Plan for Adverse Drug Event Prevention, highlighting prevention of diabetes agent-related hypoglycemia as a key area for improvement. In support of the Action Plan, the Office of Disease Prevention and Health Promotion then developed a web-based interactive module, or eLearning lesson, based on formative research and stakeholder feedback to educate healthcare professionals on strategies to prevent adverse drug events from diabetes agents. The training incorporates health literacy principles by demonstrating, through video scenarios, how to apply shared decision making when setting individualized glycemic targets, and how to use the teach-back method to confirm patients' understanding. Prior to release in September 2014, the training went through intensive usability testing and was pilot tested using a 36-item evaluation. Six months after its release (September 2014 to March 2015), the training landing page on health.gov had 24,334 unique page views. More than 90% of the 234 participants who earned continuing education credit agreed that they will be able to apply the knowledge gained from the lesson to their practice. Online trainings that model key prevention strategies are well received by health professional users and may play an important role in translating policy into improved outcomes. PMID- 26602942 TI - Baby factories taint surrogacy in Nigeria. AB - The practice of reproductive medicine in Nigeria is facing new challenges with the proliferation of 'baby factories'. Baby factories are buildings, hospitals or orphanages that have been converted into places for young girls and women to give birth to children for sale on the black market, often to infertile couples, or into trafficking rings. This practice illegally provides outcomes (children) similar to surrogacy. While surrogacy has not been well accepted in this environment, the proliferation of baby factories further threatens its acceptance. The involvement of medical and allied health workers in the operation of baby factories raises ethical concerns. The lack of a properly defined legal framework and code of practice for surrogacy makes it difficult to prosecute baby factory owners, especially when they are health workers claiming to be providing services to clients. In this environment, surrogacy and other assisted reproductive techniques urgently require regulation in order to define when ethico-legal lines have been crossed in providing surrogacy or surrogacy-like services. PMID- 26602943 TI - Regulation of inflammatory and angiogenesis mediators in a functional model of decidualized endometrial stromal cells. AB - The mechanisms involving the expression of interleukin (IL) 1 family members in the process of preparing the endometrium to receive an embryo remain unclear. In this study, decidualization differentially skewed the balance of IL1 family receptor expression in a pattern that increases endometrial stromal cell receptivity to IL1, IL18 and IL33. Additionally, endometrial cells showed increased expression of homeobox HOXA10 and HOXA11 and LIFR, which are known to be involved in endometrial embryo receptivity. Further analyses of decidual endometrial cells revealed a significant increase in the release of potent proinflammatory, remodelling and angiogenic factors implicated in the embryo invasion process, such as VEGF (P = 0.0305), MMP9 (P = 0.0003), TIMP3 (P = 0.0001), RANTES (P = 0.0020), MCP1 (P = 0.0001) and MIF (P = 0.0068). No significant changes in endogenous IL1B secretion were observed. Decreased secretion of IL18 and decidualization increased secretion of IL33. These findings reveal a significant modulation of endometrial cell receptivity to IL1 family members during endometrial stromal cell decidualization, and suggest that the involvement of IL1 family members is important in physiological processes of endometrial receptivity, including adaptive immunology. This may be relevant to establishing a favourable uterine microenvironment for embryo implantation. PMID- 26602944 TI - Implementation of cleanroom technology in reproductive laboratories: the question is not why but how. AB - Two articles recently published in Reproductive BioMedicine Online described how fertility centres in the USA and Brazil implemented air quality control to newly designed facilities. In both case scenarios, a highly efficient air filtration was achieved by installing a centred system supplying filtered air to the IVF laboratory and other critical areas, combining air particulate and volatile organic compound (VOC) filtration. Evaluating retrospective data of over 3000 cycles from both centres, live birth rates were increased by improvements in air quality and laboratory environment. This commentary discusses some of the key aspects of air contamination in the IVF settings, and highlights the fact that a risk management analysis taking into consideration all variables that play a role in air contamination is paramount for the reduction of the risk of poor IVF outcomes due to improper air quality conditions. PMID- 26602945 TI - Live birth resulting from a conjoined oocyte confirmed as euploid using array CGH: a case report. AB - The significance of conjoined oocytes in the clinical IVF laboratory setting has been of question due to the extremely limited data available. The most reliable criterion for true binovularity is the inclusion of two oocytes within a common zona pellucida or their fusion in the zonal region. This is a relatively rare event and owing to the limited number of embryo transfers performed and information on their outcomes, it is highly probable that these oocytes would be discarded without attempts at fertilization and subsequent embryo culture. To our knowledge, this is the first reported pregnancy resulting from a conjoined oocyte. Our experience involved a blastocyst transfer of a genetically screened embryo, performed after removal of the germinal vesicle from the conjoined oocyte/embryo on day 3. A clinical pregnancy with a gestational sac and fetal heartbeat was achieved and a healthy baby girl was delivered via Caesarean section at 37 weeks' gestation. PMID- 26602946 TI - Transcriptomics and physiological analyses reveal co-ordinated alteration of metabolic pathways in Jatropha curcas drought tolerance. AB - Jatropha curcas, a multipurpose plant attracting a great deal of attention due to its high oil content and quality for biofuel, is recognized as a drought-tolerant species. However, this drought tolerance is still poorly characterized. This study aims to contribute to uncover the molecular background of this tolerance, using a combined approach of transcriptional profiling and morphophysiological characterization during a period of water-withholding (49 d) followed by rewatering (7 d). Morphophysiological measurements showed that J. curcas plants present different adaptation strategies to withstand moderate and severe drought. Therefore, RNA sequencing was performed for samples collected under moderate and severe stress followed by rewatering, for both roots and leaves. Jatropha curcas transcriptomic analysis revealed shoot- and root-specific adaptations across all investigated conditions, except under severe stress, when the dramatic transcriptomic reorganization at the root and shoot level surpassed organ specificity. These changes in gene expression were clearly shown by the down regulation of genes involved in growth and water uptake, and up-regulation of genes related to osmotic adjustments and cellular homeostasis. However, organ specific gene variations were also detected, such as strong up-regulation of abscisic acid synthesis in roots under moderate stress and of chlorophyll metabolism in leaves under severe stress. Functional validation further corroborated the differential expression of genes coding for enzymes involved in chlorophyll metabolism, which correlates with the metabolite content of this pathway. PMID- 26602947 TI - Chloride regulates leaf cell size and water relations in tobacco plants. AB - Chloride (Cl(-)) is a micronutrient that accumulates to macronutrient levels since it is normally available in nature and actively taken up by higher plants. Besides a role as an unspecific cell osmoticum, no clear biological roles have been explicitly associated with Cl(-) when accumulated to macronutrient concentrations. To address this question, the glycophyte tobacco (Nicotiana tabacum L. var. Habana) has been treated with a basal nutrient solution supplemented with one of three salt combinations containing the same cationic balance: Cl(-)-based (CL), nitrate-based (N), and sulphate+phosphate-based (SP) treatments. Under non-saline conditions (up to 5 mM Cl(-)) and no water limitation, Cl(-) specifically stimulated higher leaf cell size and led to a moderate increase of plant fresh and dry biomass mainly due to higher shoot expansion. When applied in the 1-5 mM range, Cl(-) played specific roles in regulating leaf osmotic potential and turgor, allowing plants to improve leaf water balance parameters. In addition, Cl(-) also altered water relations at the whole-plant level through reduction of plant transpiration. This was a consequence of a lower stomatal conductance, which resulted in lower water loss and greater photosynthetic and integrated water-use efficiency. In contrast to Cl(-), these effects were not observed for essential anionic macronutrients such as nitrate, sulphate, and phosphate. We propose that the abundant uptake and accumulation of Cl(-) responds to adaptive functions improving water homeostasis in higher plants. PMID- 26602948 TI - In vitro activity of ceftaroline against staphylococci from prosthetic joint infection. AB - We tested the in vitro activity of ceftaroline by Etest against staphylococci recovered from patients with prosthetic joint infection, including 97 Staphylococcus aureus isolates (36%, oxacillin resistant) and 74 Staphylococcus epidermidis isolates (74%, oxacillin resistant). Ceftaroline inhibited all staphylococci at <=0.5 MUg/mL. The ceftaroline MIC(90/50) values for methicillin susceptible S. aureus, methicillin-susceptible S. epidermidis, methicillin resistant S. aureus, and methicillin-resistant S. epidermidis were 0.19/0.125, 0.094/0.047, 0.5/0.38, and 0.38/0.19 MUg/mL, respectively. Based on these in vitro findings, ceftaroline should be further evaluated as a potential therapeutic option for the treatment of prosthetic joint infection caused by methicillin-susceptible and methicillin-resistant S. aureus and S. epidermidis. PMID- 26602949 TI - Utility of microbiological testing of thoracic lymph nodes sampled by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in patients with mediastinal lymphadenopathy. AB - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) represents a minimally invasive technique to sample peribronchial and mediastinal lymph nodes for diagnosis of cancer, lymphoma, or sarcoidosis. However, the value of EBUS-TBNA in diagnosis of respiratory infections has not been well explored. Here, microbiologic testing data for EBUS-TBNA samples collected from 82 patients over a 30-month period were retrospectively reviewed. No organisms were identified on Gram, acid-fast, or fungal stains. Bacterial cultures were positive in 52% of samples; however, all but 1 culture were considered contaminants. Mycobacterial cultures yielded Mycobacterium avium-intracellulare not identified in a concurrent bronchoalveolar lavage sample in 1 patient. Fungal cultures were negative. Overall, routine microbiologic tests on EBUS-TBNA samples do not appear sufficiently sensitive to rule out infectious causes of adenopathy. High clinical suspicion for infection may require modification of sampling techniques or more sensitive detection methods. PMID- 26602950 TI - New findings about trichodysplasia spinulosa-associated polyomavirus (TSPyV)- novel qPCR detects TSPyV-DNA in blood samples. AB - A new real-time PCR assay for trichodysplasia spinulosa-associated polyomavirus (TSPyV) DNA detection was designed, and blood samples from kidney transplant recipients and healthy individuals were screened. TSPyV-DNA was not detected in blood from healthy individuals, but 26.8% of kidney recipients presented TSPyV DNA. This is the first report of TSPyV viremia. PMID- 26602951 TI - The prevalence of obstructive sleep apnea in symptomatic patients with syndromic craniosynostosis. AB - The reported prevalence of obstructive sleep apnea (OSA) in patients with syndromic craniosynostosis (SCS) varies due to inconsistent definitions of OSA, lack of uniform diagnostic testing, and different mixes of syndromic diagnoses. The purpose of this study was to determine the prevalence of OSA in symptomatic patients with SCS, and to determine whether this differs by phenotypic diagnosis. A retrospective cohort study of children with SCS was conducted. The primary outcome was presence of OSA diagnosed by polysomnography. The prevalence of OSA was calculated and stratified by diagnosis to compare differences in prevalence and severity (mild, moderate, or severe). The prevalence of OSA in symptomatic patients was 74.2%. Patients with Apert syndrome had the highest prevalence (80.6%), followed by Pfeiffer, Crouzon with acanthosis nigricans, and Crouzon syndromes (72.7%, 66.7%, and 64.7%, respectively). Severe OSA was most common in patients with Pfeiffer syndrome (45.5%), while patients with Apert and Crouzon syndromes were more likely to have moderate OSA (29.0% and 23.5%, respectively). Given that 56.4% of patients with SCS are symptomatic and that 74.2% of these symptomatic patients have OSA, it is recommended that a screening level I polysomnography be part of the clinical care for all patients with SCS. PMID- 26602952 TI - Part One: For the Motion. Branched/Fenestrated EVAR Procedures are Better than Snorkels, Chimneys, or Periscopes in the Treatment of Most Thoracoabdominal and Juxtarenal Aneurysms. PMID- 26602953 TI - Part Two: Against the Motion. Fenestrated EVAR Procedures are not Better than Snorkels, Chimneys, or Periscopes in the Treatment of Most Thoracoabdominal and Juxtarenal Aneurysms. PMID- 26602954 TI - Choice-impulsivity in children and adolescents with attention deficit/hyperactivity disorder (ADHD): A meta-analytic review. AB - Impulsive behavior is a core DSM-5 diagnostic feature of attention deficit/hyperactivity disorder (ADHD) that is associated with several pejorative outcomes. Impulsivity is multidimensional, consisting of two sub-constructs: rapid-response impulsivity and reward-delay impulsivity (i.e., choice impulsivity). While previous research has extensively examined the presence and implications of rapid-response impulsivity in children with ADHD, reviews of choice-impulsive behavior have been both sparse and relatively circumscribed. This review used meta-analytic methods to comprehensively examine between-group differences in choice-impulsivity among children and adolescents with and without ADHD. Twenty-eight tasks (from 26 studies), consisting of 4320 total children (ADHD=2360, TD=1,960), provided sufficient information to compute an overall between-group effect size for choice-impulsivity performance. Results revealed a medium-magnitude between-group effect size (g=.47), suggesting that children and adolescents with ADHD exhibited moderately increased impulsive decision-making compared to TD children and adolescents. Further, relative to the TD group, children and adolescents with ADHD exhibited similar patterns of impulsive decision-making across delay discounting and delay of gratification tasks. However, the use of single-informant diagnostic procedures relative to multiple informants yielded larger between-group effects, and a similar pattern was observed across samples that excluded females relative to samples that included females. PMID- 26602955 TI - In the presence of others: Self-location, balance control and vestibular processing. AB - The degree to which others in our environment influence sensorimotor processing has been a particular focus of cognitive neuroscience for the past two decades. This process of self-other resonance, or shared body representation, has only recently been extended to more global bodily processes such as self-location, self-motion perception, balance and perspective taking. In this review, we outline these previously overlooked areas of research to bridge the distinct field of social neuroscience with global self-perception, vestibular processing and postural control. Firstly, we outline research showing that the presence and movement of others can modulate two fundamental experiences of the self: self location (the experience of where the self is located in space) and self-motion perception (the experience that oneself has moved or has been moved in space). Secondly, we outline recent research that has shown perturbations in balance control as a result of instability in others in our environment. Conversely to this, we also highlight studies in virtual reality demonstrating the potential benefits of the presence of others in our environment for those undergoing vestibular rehabilitation. Thirdly, we outline studies of first- and third-person perspective taking, which is the ability to have or take a visuo-spatial perspective within and out-with the confines of our own body. These studies demonstrate a contamination of perspective taking processes (i.e. automatic, implicit, third-person perspective taking) in the presence of others. This collection of research highlights the importance of social cues in the more global processing of the self and its accompanying sensory inputs, particularly vestibular signals. Future research will need to better determine the mechanisms of self-other resonance within these processes, including the role of individual differences in the susceptibility to the influence of another. PMID- 26602956 TI - Use of biochemical tests of placental function for improving pregnancy outcome. AB - BACKGROUND: The placenta has an essential role in determining the outcome of pregnancy. Consequently, biochemical measurement of placentally-derived factors has been suggested as a means to improve fetal and maternal outcome of pregnancy. OBJECTIVES: To assess whether clinicians' knowledge of the results of biochemical tests of placental function is associated with improvement in fetal or maternal outcome of pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised, cluster-randomised or quasi randomised controlled trials assessing the merits of the use of biochemical tests of placental function to improve pregnancy outcome.Studies were eligible if they compared women who had placental function tests and the results were available to their clinicians with women who either did not have the tests, or the tests were done but the results were not available to the clinicians. The placental function tests were any biochemical test of placental function carried out using the woman's maternal biofluid, either alone or in combination with other placental function test/s. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted data and assessed trial quality. Authors of published trials were contacted for further information. MAIN RESULTS: Three trials were included, two quasi-randomised controlled trials and one randomised controlled trial. One trial was deemed to be at low risk of bias while the other two were at high risk of bias. Different biochemical analytes were measured - oestrogen was measured in one trial and the other two measured human placental lactogen (hPL). One trial did not contribute outcome data, therefore, the results of this review are based on two trials with 740 participants.There was no evidence of a difference in the incidence of death of a baby (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.36 to 2.13, two trials, 740 participants (very low quality evidence)) or the frequency of a small-for-gestational-age infant (RR 0.44, 95% CI 0.16 to 1.19, one trial, 118 participants (low quality evidence)).In terms of this review's secondary outcomes, there was no evidence of a clear difference between women who had biochemical tests of placental function compared with standard antenatal care for the incidence of stillbirth (RR 0.56, 95% CI 0.16 to 1.88, two trials, 740 participants (very low quality evidence)) or neonatal death (RR 1.62, 95% CI 0.39 to 6.74, two trials, 740 participants, very low quality evidence)) although the directions of any potential effect were in opposing directions. There was no evidence of a difference between groups in elective delivery (RR 0.98, 95% CI 0.84 to 1.14, two trials, 740 participants (low quality evidence)), caesarean section (one trial, RR 0.48, 95% CI 0.15 to 1.52, one trial, 118 participants (low quality evidence)), change in anxiety score (mean difference -2.40, 95% CI -4.78 to -0.02, one trial, 118 participants), admissions to neonatal intensive care (RR 0.32, 95% CI 0.03 to 3.01, one trial, 118 participants), and preterm birth before 37 weeks' gestation (RR 2.90, 95% CI 0.12 to 69.81, one trial, 118 participants). One trial (118 participants) reported that there were no cases of serious neonatal morbidity. Maternal death was not reported.A number of this review's secondary outcomes relating to the baby were not reported in the included studies, namely: umbilical artery pH < 7.0, neonatal intensive care for more than seven days, very preterm birth (< 32 weeks' gestation), need for ventilation, organ failure, fetal abnormality, neurodevelopment in childhood (cerebral palsy, neurodevelopmental delay). Similarly, a number of this review's maternal secondary outcomes were not reported in the included studies (admission to intensive care, high dependency unit admission, hospital admission for > seven days, pre-eclampsia, eclampsia, and women's perception of care). AUTHORS' CONCLUSIONS: There is insufficient evidence to support the use of biochemical tests of placental function to reduce perinatal mortality or increase identification of small-for-gestational-age infants. However, we were only able to include data from two studies that measured oestrogens and hPL. The quality of the evidence was low or very low.Two of the trials were performed in the 1970s on women with a variety of antenatal complications and this evidence cannot be generalised to women at low-risk of complications or groups of women with specific pregnancy complications (e.g. fetal growth restriction). Furthermore, outcomes described in the 1970s may not reflect what would be expected at present. For example, neonatal mortality rates have fallen substantially, such that an infant delivered at 28 weeks would have a greater chance of survival were those studies repeated; this may affect the primary outcome of the meta-analysis.With data from just two studies (740 women), this review is underpowered to detect a difference in the incidence of death of a baby or the frequency of a small-for-gestational-age infant as these have a background incidence of approximately 0.75% and 10% of pregnancies respectively. Similarly, this review is underpowered to detect differences between serious and/or rare adverse events such as severe neonatal morbidity. Two of the three included studies were quasi-randomised, with significant risk of bias from group allocation. Additionally, there may be performance bias as in one of the two studies contributing data, participants receiving standard care did not have venepuncture, so clinicians treating participants could identify which arm of the study they were in. Future studies should consider more robust randomisation methods and concealment of group allocation and should be adequately powered to detect differences in rare adverse events.The studies identified in this review examined two different analytes: oestrogens and hPL. There are many other placental products that could be employed as surrogates of placental function, including: placental growth factor (PlGF), human chorionic gonadotrophin (hCG), plasma protein A (PAPP-A), placental protein 13 (PP-13), pregnancy-specific glycoproteins and progesterone metabolites and further studies should be encouraged to investigate these other placental products. Future randomised controlled trials should test analytes identified as having the best predictive reliability for placental dysfunction leading to small-for-gestational-age infants and perinatal mortality. PMID- 26602957 TI - Dorsal anterior cingulate cortex in typically developing children: Laterality analysis. AB - We aimed to elucidate the dACC laterality in typically developing children and their sex/age-related differences with a sample of 84 right-handed children (6-16 years, 42 boys). We first replicated the previous finding observed in adults that gray matter density asymmetry in the dACC was region-specific: leftward (left > right) in its superior part, rightward (left < right) in its inferior part. Intrinsic connectivity analysis of these regions further revealed region-specific asymmetric connectivity profiles in dACC as well as their sex and age differences. Specifically, the superior dACC connectivity with frontoparietal network and the inferior dACC connectivity with visual network are rightward. The superior dACC connectivity with the default network (lateral temporal cortex) was more involved in the left hemisphere. In contrast, the inferior dACC connectivity with the default network (anterior medial prefrontal cortex) was more lateralized towards the right hemisphere. The superior dACC connectivity with lateral visual cortex was more distinct across two hemispheres in girls than that in boys. This connection in boys changed with age from right-prominent to left-prominent asymmetry whereas girls developed the connection from left-prominent to no asymmetry. These findings not only highlight the complexity and laterality of the dACC but also provided insights into dynamical structure-function relationships during the development. PMID- 26602959 TI - Perception of Jordanian nurses regarding involvement in decision-making. AB - BACKGROUND: Nurses in any organizational context are members of a team and cannot work independently. Teamwork requires making decisions frequently, and these decisions affect team performance on a regular basis. Ultimately, the team shapes the quality of patient care. AIM: This study examines nurse decision-making related to patient care, self-management and the work environment. METHOD: Qualitative descriptive design was used to collect data. Eighteen staff nurses participated in semi-structured interviews to explore the perception of Jordanian staff nurses regarding their participation in decision-making. RESULTS: Variation in decision-making involvement was found to exist across unit types and from hospital to hospital. In general, the participants were not satisfied with their level of decision-making involvement and believed that they could participate more. CONCLUSION: The results have implications for nurse managers in facilitating the engagement of staff nurses in decision-making and creating an organizational culture to facilitate this engagement. PMID- 26602958 TI - Longitudinal changes in white matter microstructure after heavy cannabis use. AB - Diffusion tensor imaging (DTI) studies of cannabis users report alterations in brain white matter microstructure, primarily based on cross-sectional research, and etiology of the alterations remains unclear. We report findings from longitudinal voxelwise analyses of DTI data collected at baseline and at a 2-year follow-up on 23 young adult (18-20 years old at baseline) regular cannabis users and 23 age-, sex-, and IQ-matched non-using controls with limited substance use histories. Onset of cannabis use was prior to age 17. Cannabis users displayed reduced longitudinal growth in fractional anisotropy in the central and parietal regions of the right and left superior longitudinal fasciculus, in white matter adjacent to the left superior frontal gyrus, in the left corticospinal tract, and in the right anterior thalamic radiation lateral to the genu of the corpus callosum, along with less longitudinal reduction of radial diffusion in the right central/posterior superior longitudinal fasciculus, corticospinal tract, and posterior cingulum. Greater amounts of cannabis use were correlated with reduced longitudinal growth in FA as was relatively impaired performance on a measure of verbal learning. These findings suggest that continued heavy cannabis use during adolescence and young adulthood alters ongoing development of white matter microstructure, contributing to functional impairment. PMID- 26602960 TI - The prognostic values of CYP2B6 genetic polymorphisms and metastatic sites for advanced breast cancer patients treated with docetaxel and thiotepa. AB - This study investigated interactive effects of CYP2B6 genotypes and liver metastasis on the prognosis of metastatic breast cancer patients who received combined chemotherapy of docetaxel and thiotepa. Totally 153 patients were retrospectively genotyped rs8192719 (c.1294 + 53C > T) and rs2279343 (c.785A > G). Kaplan-Meier method and Cox Proportional Hazard Regression model were used to estimate the survival. Patients with liver metastasis had worsen prognosis, conferring a 2.26-fold high risk of progression and 1.93-fold high risk of death (p < 0.05). Both CT/TT genotype of rs8192719 (c.1294 + 3C > T) and AG genotype of rs2279343 (c.785A > G) prolonged survival (p < 0.05). Furthermore, among liver metastatic patients, AG genotype of rs2279343 (c.785A > G) was associated with a 47% reduced risk of death and a 6-month-longer overall survival (p < 0.05). Among non-liver metastatic patients, hazard ratios of CT/TT genotype of rs8192719 (c.1294 + 53C > T) were 0.45 for progression and 0.40 for death; and the corresponding survival was improved by 6 months and 16 months, respectively (p < 0.05). Genotypes of CYP2B6 had an interaction with clinical efficacy of docetaxel and thiotepa on metastatic breast cancer patients; and metastatic sites also affected clinical responses. Further therapies should take into account of chemotherapy regimen, genotypes of metabolizing enzymes and metastatic sites for the particular subpopulation. PMID- 26602962 TI - Reconfigurable and resettable arithmetic logic units based on magnetic beads and DNA. AB - Based on the characteristics of magnetic beads and DNA, a simple and universal platform was developed for the integration of multiple logic gates to achieve resettable half adder and half subtractor functions. The signal reporter was composed of a split G-quadruplex DNAzyme and AuNP-surface immobilized molecular beacon molecule. The novel feature of the designed system is that the inputs (split G-quadruplexes) can interact with hairpin-modified Au NPs linked to magnetic particles. Another novel feature is that the logic operations can be reset by heating the output system and by using the magnetic separation of the computing modules. Moreover, the developed half adder and half subtractor are realized on a simple DNA/magnetic bead platform in an enzyme-free system and share a constant threshold setpoint. Due to the diversity and design flexibility of DNA, these investigations may provide a new method for the development of resettable DNA-based arithmetic operations. PMID- 26602961 TI - Patellar taping alters knee kinematics during step descent in individuals with a meniscal injury: An exploratory study. AB - BACKGROUND: Meniscus lesions are common musculoskeletal knee injuries which often lead to pain, limitation and compensations during functional tasks, such as descending stairs. This study investigated the effect of patellar taping with tension and without tension on three-dimensional (3D) kinematics of the knee during a slow step descent task in patients with meniscal lesions. METHODS: Ten patients diagnosed with a meniscal lesion, confirmed by magnetic resonance imaging, underwent five, step descent movements at slow speed under three different conditions: 1) no taping; 2) tension-free taping; and 3) patellar taping with medial tension. 3D kinematic data were recorded from the injured knee using an eight-camera infrared Vicon motion analysis system. Maximum and minimum angle values and total range of motion (maximum/minimum value) in three movement planes during single-limb stance were compared using a repeated measure ANOVA. FINDINGS: Results showed a significant increase in the maximum and minimum angle value in the sagittal plane (mean differences=2.4 degrees and 4.2 degrees , respectively) and a decrease in the transverse plane (-6.3 degrees and -2.2 degrees , respectively) for the patellar taping condition compared to the no taping condition. A decreased rotational angle range when comparing the patellar taping to the no taping (-4.1 degrees ) and tension-free taping (-3.1 degrees ) conditions was also observed. These changes remained significant when pain was considered as a covariate in the analysis. The tension applied to the patellar tape played a role in controlling the sagittal and transverse plane step-down movement among patients in our study. INTERPRETATION: These results support the use of patellar taping with a medially oriented tension to help to reduce the transversal plane movement of the knee in this population and they bring new light to the taping effect. PMID- 26602963 TI - Bisphenol A and other phenols in human placenta from children with cryptorchidism or hypospadias. AB - Embryo-foetal exposure to low doses of endocrine disrupting chemicals (EDCs) has been related to reproductive tract diseases in experimental animals but not convincingly in human populations. The aim of this case-control study was to explore the relationship between exposure to non-persistent EDCs during pregnancy and male genital development. Exposure to bisphenol-A (BPA), benzophenones (BPs) [BP-1, BP-2, BP-3, BP-6, BP-8 and 4-hydroxybenzophenone (4-OH-BP),] and parabens (PBs) [methyl-, ethyl-, propyl- and butyl-PB] was analyzed by means of ultra-high performance liquid chromatography-tandem mass spectrometry in placenta samples from a subsample of 28 cases and 51 healthy controls nested in a cohort of newborns recruited between 2000 and 2002. The multivariable regression analyses indicated a statistically significant association between exposure to BPA and propyl-PB and the risk of malformations [adjusted odd ratio (95% CIs) in the third tertile of exposure: 7.2 (1.5-35.5) and 6.4 (1.2-35.5) for BPA and propyl PB, respectively]. PMID- 26602965 TI - Photon beam quality correction factors for the NE2571A and NE2581A thimble ionization chambers using PENELOPE. AB - The beam quality correction factor kQ,Q0 and the perturbation factor pQ for photon beams were calculated for the NE2571A and NE2581A ionization chambers, using the Monte Carlo simulation code PENELOPE. Results are compared to those quoted for the NE2571 and NE2581 chambers in previous works. Both kQ,Q0 and pQ obtained for NE2571A and NE2581A chambers agree with those of their predecessors NE2571 and NE2581 ones. PMID- 26602964 TI - Hybrid (CT/MRI based) vs. MRI only based image-guided brachytherapy in cervical cancer: Dosimetry comparisons and clinical outcome. AB - PURPOSE: Limited access to MRI has restricted implementation of MRI-based image guided brachytherapy (IGBT) in line with GEC-ESTRO guidelines in many centers. This work reports our experience using an alternative CT/MRI based (hybrid) approach for IGBT, dosimetry comparisons, and its impact on long-term clinical outcome and major toxicity. METHODS AND MATERIALS: Seventy-six patients diagnosed with locally advanced cervical cancer between May 2008 and May 2012 treated with IGBT were analyzed. The hybrid approach is the default IGBT approach during this study period. Forty-nine had hybrid approach and 27 patients had "3-fraction conformal MRI" approach (17 within EMBRACE study). Treatment consisted of 48 Gy in 24 fractions of conformally planned external beam radiotherapy with weekly cisplatin followed by three weekly fractions of brachytherapy to high-risk clinical target volume (HR-CTV). All patients have a prebrachytherapy MRI 4 days before treatment and with the applicators in place on Fraction 1. MRI only or CT is used for subsequent fractions. Using image registration techniques and the assumption that the HR-CTV is fixed with respect to the applicator, the HR-CTV from MRI at Fraction 1 is transferred onto subsequent fraction CT image sets for the hybrid approach. RESULTS: Median follow-up was 41 months (range, 23-71 months). Excellent 3-year local control, overall progression-free survival, and overall survival of 92.6%, 78.8%, and 77.7% were seen with the hybrid approach and 92.2%, 66.3%, and 69.6% with a 3-fraction conformal MRI approach, respectively. Dosimetry achieved and late toxicity rates were comparable in the two groups. CONCLUSIONS: Hybrid IGBT in locally advanced cervical cancer offers an alternative approach when access to MRI restricts implementation of IGBT. PMID- 26602966 TI - Portal imaging: Performance improvement in noise reduction by means of wavelet processing. AB - This paper discusses the suitability, in terms of noise reduction, of various methods which can be applied to an image type often used in radiation therapy: the portal image. Among these methods, the analysis focuses on those operating in the wavelet domain. Wavelet-based methods tested on natural images--such as the thresholding of the wavelet coefficients, the minimization of the Stein unbiased risk estimator on a linear expansion of thresholds (SURE-LET), and the Bayes least-squares method using as a prior a Gaussian scale mixture (BLS-GSM method)- are compared with other methods that operate on the image domain--an adaptive Wiener filter and a nonlocal mean filter (NLM). For the assessment of the performance, the peak signal-to-noise ratio (PSNR), the structural similarity index (SSIM), the Pearson correlation coefficient, and the Spearman rank correlation (rho) coefficient are used. The performance of the wavelet filters and the NLM method are similar, but wavelet filters outperform the Wiener filter in terms of portal image denoising. It is shown how BLS-GSM and NLM filters produce the smoothest image, while keeping soft-tissue and bone contrast. As for the computational cost, filters using a decimated wavelet transform (decimated thresholding and SURE-LET) turn out to be the most efficient, with calculation times around 1 s. PMID- 26602967 TI - The perception of scar cosmesis following thyroid and parathyroid surgery: A prospective cohort study. AB - INTRODUCTION: Various "scarless" approaches have been described for thyroid and parathyroid surgery. The objective of the current study was to investigate patients' perception of neck scar cosmesis, its impact on quality of life (QoL) and evaluate patient preference with regards to scar location. METHODS: 120 patients undergoing thyroid or parathyroid surgery were followed-up over a 5-year period (2008-2013). Validated tools were used to assess scar perception and its impact on QoL. These were evaluated against sex, age, ethnicity, operation type, histopathology, time following surgery and scar length. RESULTS: Mean follow-up was 2.6 +/- 3.8 years. One of the most common post-operative problems was scar related (n = 18). Caucasian patients and those with benign histology expressed a lower impact on QoL (p < 0.001, p = 0.038). Sex and scar length did not significantly affect patients' perception for scar cosmesis (p > 0.05). Clinicians tended to score scar cosmesis higher than patients (p = 0.02). Most participants (75%) expressed a clear preference for an extracervical "scar-less in the neck" approach. DISCUSSION: Scar-related issues are frequently reported following thyroid and parathyroid surgery. The negative impact, often underestimated by clinicians, is more apparent amongst Asian and Afro-Caribbean patients and can significantly impact on their QoL. This, combined with the lack of correlation between scar length and patient satisfaction, indicates the need to divert research from miniaturising neck scars to concealing them in extracervical sites. CONCLUSION: Patients prefer a scar-less in the neck approach when given the option. A prospective comparative study is required to compare the cervical and extracervical approaches. PMID- 26602968 TI - Robotic-assisted selective and modified radical neck dissection in head and neck cancer patients. AB - INTRODUCTION: Recently, several authors introduced various methods and published feasibility studies on novel robotic-assisted neck dissection techniques for head and neck cancer patients. Cosmesis and general appearance have become important concerns of cancer patients today. Especially in the head and neck area, a conspicuous scar can reduce patient satisfaction after surgery. With conventional neck dissection techniques, a long scar in the neck is unavoidable. Therefore, the development of robotic assisted neck dissection provides the patients with a scarless neck in these situations. However, there are some limitations of the application of these techniques in their current stage of development. METHODS: This study was performed using a systematic literature review. RESULTS: The reviewed clinical studies show that robotic-assisted neck dissection yields similar functional and early oncologic outcomes to that of conventional neck dissection, as well as excellent cosmetic satisfaction of patients. Despite these benefits, some disadvantages can be observed, in terms of longer operation times as well as higher procedure costs. CONCLUSION: Besides the similar oncologic and functional outcomes compared with the open procedure so far, more prospective, controlled, multicenter studies are required to establish robotic-assisted neck dissection as an alternative standard and to justify its added costs beyond the cosmetic advantages. PMID- 26602969 TI - Nationwide analysis of short-term surgical outcomes of minimally invasive esophagectomy for malignancy. AB - BACKGROUND: Minimally invasive esophagectomy (MIE) is being increasingly utilized for esophageal cancer. It is unclear if MIE if being safely performed with satisfactory outcomes across the USA. We aimed to analyze the short-term surgical outcomes of MIE as compared to open esophagectomy (OE). METHODS: The National Cancer Database (NCDB) was queried for patients who underwent MIE or OE for esophageal malignancy between 2010 and 2011. Margin positivity, lymph node retrieval, 30-day mortality, 30-day unplanned readmission rate and hospital length of stay. RESULTS: A total of 4047 patients were identified; 3050 (75.4%) underwent OE, and 997 (24.6%) underwent MIE. The proportion of MIE increased from 21.9% in 2010 to 27.4% in 2011 (p < 0.001). The conversion rate was 13.7%. There were no differences in-patient or tumor characteristics between the two cohorts. OE and MIE were comparable in terms of margin positive resection rate (7.4% vs. 8.1%, p = 0.48), 30-day unplanned readmission rate (7.6% vs. 7.2%, p = 0.64) and 30-day mortality rate (4.3% vs. 3.3%, p = 0.71). Compared to OE, MIE was associated with higher node retrieval (median 12 vs 14, p < 0.001), and shorter hospital stay (median 11.0 vs 10.0 days, p < 0.001). Logistic regression analysis showed that surgical approach (OE vs MIE) was not associated with 30-day mortality rate. In an ANCOVA analysis, MIE was independently associated with a shorter hospital stay compared to OE (estimated mean difference 1.57 +/- 0.53 days, p = 0.003). MIE patients who underwent conversion had a longer hospital stay compared to those who did not (11.0 vs 10.0 days, p = 0.02). CONCLUSION: MIE is being offered more frequently to patients with esophageal cancer, and maybe accompanied with better short-term outcomes including shorter hospital stay when compared to open esophagectomy. PMID- 26602970 TI - Trabeculectomy Can Improve Long-Term Visual Function in Glaucoma. AB - PURPOSE: To measure the magnitude and direction of visual field (VF) rates of change in glaucoma patients after intraocular pressure (IOP) reduction with trabeculectomy. DESIGN: Retrospective, comparative, longitudinal cohort study. PARTICIPANTS: Patients with open-angle glaucoma. METHODS: Patients who underwent trabeculectomy (Trab) with mitomycin-C (74 eyes of 64 patients) with >=4 reliable VF measurements before and after trabeculectomy and at least 4 years of follow-up before and after surgery were included. Decay or improvement exponential models were used to calculate pointwise rates of perimetric change before and after surgery. A separate comparison (Comp) group with unoperated glaucoma (71 eyes of 65 patients) with similar baseline damage, number of VF tests, and follow-up was used to address possible regression to the mean. Proportions of VF locations decaying or improving before and after surgery in the Trab group, and during the first and second halves of follow-up in the Comp group, were calculated. A multivariate analysis was used to explore variables associated with VF improvement. MAIN OUTCOME MEASURES: The rate of pointwise VF change before and after surgery in the Trab group and Comp group. RESULTS: Patients in the Trab group were followed for 5.1+/-2.1 years (mean +/- standard deviation) before and 5.4+/-2.3 years after surgery, with 8.9+/-4.7 VF tests before and 9.0+/-4.4 VF tests after surgery. The mean rate of change for all VF locations slowed from 2.5+/-9.3%/year before surgery to -0.10+/-13.1%/year after surgery (P < 0.001). In the Trab group, 70% of locations decayed and 30% improved preoperatively; postoperatively, 56% decayed and 44% improved. The differences between the Trab and Comp groups were significant (P < 0.0001, chi-square test). The magnitude of IOP reduction correlated with the excess number of VF locations that exhibited long-term improvement postoperatively (P = 0.009). In the Trab group, 57% of eyes had >=10 improving VF locations postoperatively. CONCLUSIONS: The results show that trabeculectomy slows the rate of perimetric decay and provide evidence of sustained, long-term improvement of visual function in glaucoma. These findings suggest the possibility of reversal of glaucomatous dysfunction of retinal ganglion cells and their central projections. PMID- 26602971 TI - Peripheral sensitization reduces laser-evoked potential habituation. AB - OBJECTIVE: Laser-evoked potential (LEP) habituation was investigated under the influence of capsaicin-induced peripheral and central sensitization. MATERIAL AND METHODS: Fifteen subjects received 100 repetitive painful laser stimuli at the right hand dorsum at primary (application area; condition I) and secondary areas (beyond application area; condition II) in two different sessions after applying capsaicin topically. Conditions I and II were compared to a control condition without capsaicin application. N1, N2, and P2 latencies and N1 and N2/P2 amplitudes were recorded by EEG. Quantitative sensory testing (QST) and the Liewald Diary reaction time experiment were used as control tests. RESULTS: QST documented heat hyperalgesia as a sign of peripheral sensitization in the primary area and pinprick hyperalgesia in the primary and secondary area as a sign of central sensitization, after applying capsaicin. The N2/P2 amplitude habituation was significantly reduced in the primary area compared to controls (the primary area represents peripheral sensitization). The LEPs of the secondary area (the secondary area represents central sensitization) showed no significant N2/P2 amplitude habituation compared to controls. The comparison between conditions I vs. II showed no significant difference regarding N2/P2 amplitude and laser pain rating. CONCLUSION: Capsaicin-induced central sensitization does not alter LEP habituation. The physiological habituation of LEP amplitudes is reduced due to peripheral mechanisms after applying capsaicin topically. These findings form a basis for future studies, which use the habituation paradigm to investigate pain conditions promoted by sensitization phenomena. PMID- 26602972 TI - Early perceptual anomaly of negative facial expression in depression: An event related potential study. AB - Depressed patients have a demonstrated cognitive bias in emotional information processing. However, it is unknown how early perceptual processing is modulated by emotional stimuli in depression. To examine this question, we studied 22 depressed patients and 22 healthy controls performing a cued target-response task with emotional facial expression as the cue. The early perceptual processes were examined using event-related potential (ERP) components, i.e., P1 and N170. Results showed that depressed patients had larger P1 amplitudes than healthy controls, implying that early perceptual abnormality for face processing in depression may occur as early as the P1 stage. There was no significant interaction between emotion types and groups on P1 amplitudes, which suggested that cognitive biases in depression might not yet have arisen. Following the P1 stage, N170 amplitudes for sad faces were larger than for other emotion types in depressed patients, whereas N170 amplitudes for happy faces were larger than for other emotion types in healthy controls. These results implied that depressed patients might have a perceptual bias associated with sad emotions, which may be detectable from the N170 time window. In summary, this study provides new insights for understanding the negative cognitive bias in depression using the electroneurophysiological biomarker N170. PMID- 26602973 TI - Bottom pressure scaling of vibro-fluidized granular matter. AB - Vibrated granular beds show various interesting phenomena such as convection, segregation, and so on. However, its fundamental physical properties (e.g., internal pressure structure) have not yet been understood well. Thus, in this study, the bottom wall pressure in a vertically vibrated granular column is experimentally measured and used to reveal the nature of granular fluidization. The scaling method allows us to elucidate the fluidization (softening) degree of a vibrated granular column. The peak value of the bottom pressure pm is scaled as [formula in text], where pJ, d, g, omega, H, and Gamma are the Janssen pressure, grain diameter, gravitational acceleration, angular frequency, height of the column, and dimensionless vibrational acceleration, respectively. This scaling implies that the pressure of vibrated granular matter is quite different from the classical pressure forms: static and dynamic pressures. This scaling represents the importance of geometric factors for discussing the behavior of vibro fluidized granular matter. The scaling is also useful to evaluate the dissipation degree in vibro-fluidized granular matter. PMID- 26602974 TI - High adsorption capacity of heavy metals on two-dimensional MXenes: an ab initio study with molecular dynamics simulation. AB - Density functional theory (DFT) calculation is employed to study the adsorption properties of Pb and Cu on recently synthesized two-dimensional materials MXenes, including Ti3C2, V2C1 and Ti2C1. The influence of surface decoration with functional groups such as H, OH and F have also been investigated. Most of these studied MXenes exhibit excellent capability to adsorb Pb and Cu, especially the adsorption capacity of Pb on Ti2C1 is as high as 2560 mg g(-1). Both the binding energies and the adsorption capacities are sensitive to the functional groups attached to the MXenes' surface. Ab initio molecular dynamics (ab-init MD) simulation confirms that Ti2C1 remains stable at room temperature after adsorbing Pb atoms. Our calculations imply that these newly emerging two-dimensional MXenes are promising candidates for wastewater treatment and ion separation. PMID- 26602975 TI - Outbreak Management. PMID- 26602976 TI - An Indirect Comparison of Everolimus Versus Axitinib in US Patients With Advanced Renal Cell Carcinoma in Whom Prior Sunitinib Therapy Failed. AB - PURPOSE: The purpose of this study was to perform a weight-adjusted indirect comparison to approximate the relative efficacy of everolimus versus axitinib among patients with second-line metastatic renal cell carcinoma in whom sunitinib therapy previously failed. METHODS: Individual patient data from the RECORD-1 (Renal Cell Cancer Treatment With Oral RAD001 Given Daily) Phase III clinical trial provided information for patients taking everolimus. Summary baseline clinical and demographic characteristics and progression-free survival (PFS) outcomes were available for patients taking axitinib who were included in the AXIS (axitinib versus sorafenib) Phase III clinical trial. A Bayesian latent class mixture model differentiating responders and nonresponders and with imbedded Weibull regression on PFS was used to identify sex, Memorial Sloan Kettering Cancer Center risk score, and time receiving prior sunitinib therapy as prognostic factors for PFS based on posterior probability >95%. Patients taking everolimus were weighted up or down based on their combination of prognostic variables. Weights were calculated by dividing the proportion of patients observed in AXIS for a given characteristic by the proportion observed in RECORD 1 and taking the product of the values derived for all three weighting variables considered. Weighted PFS distributions were derived with bootstrapped 95% CIs and compared with those reported for the AXIS trial. FINDINGS: After weighting, distributions of the 3 key baseline characteristics were more closely aligned between the 2 studies; however, some differences remained. A slightly lower rate of poor-risk patients was evident in RECORD-1 (30%) versus AXIS (36%), and a 9% lower proportion of males was observed in the everolimus group compared with the axitinib group. Distributions of time receiving prior sunitinib therapy were almost equivalent between the treatment arms. A median PFS of 4.7 months (95% CI, 3.5-10.6 months) was observed for patients in the weighted everolimus group compared with 4.8 months (95% CI, 4.5-6.4 months) in the AXIS trial. IMPLICATIONS: Similar median PFS point estimates and overlapping CIs suggest that everolimus and axitinib have similar efficacy. Although these results do not negate the need for direct comparison, this study may be used to inform clinical and reimbursement decisions until such evidence is available. PMID- 26602977 TI - Confocal multiview light-sheet microscopy. AB - Selective-plane illumination microscopy has proven to be a powerful imaging technique due to its unsurpassed acquisition speed and gentle optical sectioning. However, even in the case of multiview imaging techniques that illuminate and image the sample from multiple directions, light scattering inside tissues often severely impairs image contrast. Here we combine multiview light-sheet imaging with electronic confocal slit detection implemented on modern camera sensors. In addition to improved imaging quality, the electronic confocal slit detection doubles the acquisition speed in multiview setups with two opposing illumination directions allowing simultaneous dual-sided illumination. Confocal multiview light-sheet microscopy eliminates the need for specimen-specific data fusion algorithms, streamlines image post-processing, easing data handling and storage. PMID- 26602978 TI - Antiferromagnetic structure in tetragonal CuMnAs thin films. AB - Tetragonal CuMnAs is an antiferromagnetic material with favourable properties for applications in spintronics. Using a combination of neutron diffraction and x-ray magnetic linear dichroism, we determine the spin axis and magnetic structure in tetragonal CuMnAs, and reveal the presence of an interfacial uniaxial magnetic anisotropy. From the temperature-dependence of the neutron diffraction intensities, the Neel temperature is shown to be (480 +/- 5) K. Ab initio calculations indicate a weak anisotropy in the (ab) plane for bulk crystals, with a large anisotropy energy barrier between in-plane and perpendicular-to-plane directions. PMID- 26602979 TI - Endotoxemia Engages the RhoA Kinase Pathway to Impair Cardiac Function By Altering Cytoskeleton, Mitochondrial Fission, and Autophagy. AB - AIMS: The RhoA/ROCK pathway controls crucial biological processes involved in cardiovascular pathophysiology, such as cytoskeleton dynamics, vascular smooth muscle contraction, and inflammation. In this work, we tested whether Rho kinase inhibition would beneficially impact cardiac cytoskeleton organization, bioenergetics, and autophagy in experimental endotoxemia induced by lipopolysaccharides (LPSs) in mice. RESULTS: Fasudil, a potent ROCK inhibitor, prevented LPS-induced cardiac inflammation, oxidative stress, cytoskeleton disarray, and mitochondrial injury. ROCK inhibition prevented phosphorylation of cofilin and dynamin-related protein-1, which promotes stabilization polymerization of F-actin and mediates mitochondrial fission, respectively. Pyr1, which exclusively alters actin dynamics, prevented LPS-induced myocardial dysfunction, suggesting that beneficial impact of ROCK inhibition was not mainly related to pleiotropic effects of fasudil on cardiac inflammation and oxidative stress. Fasudil reduced mitochondrial fragmentation, stimulated initiation of autophagy, and elicited cardioprotection in LPS heart. Mdivi-1, a potent mitochondria fission inhibitor, converted cardioprotective autophagy to an inefficient form due to cargo loading failure in which autophagic vacuoles fail to trap cytosolic cargo, despite their formation at enhanced rates and lysosomal elimination. INNOVATION: In experimental endotoxemia, cardioprotection by RhoA/ROCK inhibition may be related to changes in actin cytoskeleton reorganization and mitochondrial homeostasis. Improvement of LPS-induced mitochondrial dysfunction by fasudil was attributed to inhibition of ROCK dependent Drp1 phosphorylation and activation of autophagic processes that can limit mitochondrial fragmentation and enhance degradation of damaged mitochondria, respectively. CONCLUSION: Fasudil prevented LPS-induced heart oxidative stress, abnormal F-actin distribution, and oxidative phosphorylation, which concur to improve cardiac contractile and bioenergetic function. We suggest that fasudil may represent a valuable therapy for patients with sepsis. PMID- 26602980 TI - Organizing motor imageries. AB - Over the last few decades, motor imagery has attracted the attention of researchers as a prototypical example of 'embodied cognition' and also as a basis for neuro-rehabilitation and brain-machine interfaces. The current definition of motor imagery is widely accepted, but it is important to note that various abilities rather than a single cognitive entity are dealt with under a single term. Here, motor imagery has been characterized based on four factors: (1) motor control, (2) explicitness, (3) sensory modalities, and (4) agency. Sorting out these factors characterizing motor imagery may explain some discrepancies and variability in the findings from previous studies and will help to optimize a study design in accordance with the purpose of each study in the future. PMID- 26602981 TI - The role of functionality in the body model for self-attribution. AB - Bodily self-attribution, the feeling that a body (or parts of it) is owned by me, is a fundamental component of one's self. Previous studies have suggested that, in addition to a necessary multi-sensory stimulation, the sense of body ownership is determined by the body model, a representation of our body in the brain. It is however unclear what features constitute the body representation. To examine this issue, we first briefly review results on embodiment of artificial limbs, whole bodies and virtual avatars to understand the apparent anatomical, volumetric and spatial constraints associated with the sense of ownership toward external entities. We then discuss how considering limb functionality in the body model can provide an integrated explanation for most of the varied embodiment results in literature. We propose that the self-attribution of an entity may be determined, not just by its physical features, but by whether the entity can afford actions that the brain has associated with the limb which it replaces. PMID- 26602982 TI - Molecular characterization of the human microbiome from a reproductive perspective. AB - The process of reproduction inherently poses unique microbial challenges because it requires the transfer of gametes from one individual to the other, meanwhile preserving the integrity of the gametes and individuals from harmful microbes during the process. Advances in molecular biology techniques have expanded our understanding of the natural organisms living on and in our bodies, including those inhabiting the reproductive tract. Over the past two decades accumulating evidence has shown that the human microbiome is tightly related to health and disease states involving the different body systems, including the reproductive system. Here we introduce the science involved in the study of the human microbiome. We examine common methods currently used to characterize the human microbiome as an inseparable part of the reproductive system. Finally, we consider a few limitations, clinical implications, and the critical need for additional research in the field of human fertility. PMID- 26602983 TI - Development and validation of concurrent preimplantation genetic diagnosis for single gene disorders and comprehensive chromosomal aneuploidy screening without whole genome amplification. AB - OBJECTIVE: To develop a novel and robust protocol for multifactorial preimplantation genetic testing of trophectoderm biopsies using quantitative polymerase chain reaction (qPCR). DESIGN: Prospective and blinded. SETTING: Not applicable. PATIENT(S): Couples indicated for preimplantation genetic diagnosis (PGD). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Allele dropout (ADO) and failed amplification rate, genotyping consistency, chromosome screening success rate, and clinical outcomes of qPCR-based screening. RESULT(S): The ADO frequency on a single cell from a fibroblast cell line was 1.64% (18/1,096). When two or more cells were tested, the ADO frequency dropped to 0.02% (1/4,426). The rate of amplification failure was 1.38% (55/4,000) overall, with 2.5% (20/800) for single cells and 1.09% (35/3,200) for samples that had two or more cells. Among 152 embryos tested in 17 cases by qPCR-based PGD and CCS, 100% were successfully given a diagnosis, with 0% ADO or amplification failure. Genotyping consistency with reference laboratory results was >99%. Another 304 embryos from 43 cases were included in the clinical application of qPCR-based PGD and CCS, for which 99.7% (303/304) of the embryos were given a definitive diagnosis, with only 0.3% (1/304) having an inconclusive result owing to recombination. In patients receiving a transfer with follow-up, the pregnancy rate was 82% (27/33). CONCLUSION(S): This study demonstrates that the use of qPCR for PGD testing delivers consistent and more reliable results than existing methods and that single gene disorder PGD can be run concurrently with CCS without the need for additional embryo biopsy or whole genome amplification. PMID- 26602984 TI - Fastest predators in the plant kingdom: functional morphology and biomechanics of suction traps found in the largest genus of carnivorous plants. AB - Understanding the physics of plant movements, which describe the interplay between plant architecture, movement speed and actuation principles, is essential for the comprehension of important processes like plant morphogenesis. Recent investigations especially on rapid plant movements at the interface of biology, physics and engineering sciences highlight how such fast motions can be achieved without the presence of muscles, nerves and technical hinge analogies. The suction traps (bladders) of carnivorous bladderworts (Utricularia spp., Lentibulariaceae, Lamiales) are considered as some of the most elaborate moving structures in the plant kingdom. A complex interplay of morphological and physiological adaptations allows the traps to pump water out of their body and to store elastic energy in the deformed bladder walls. Mechanical stimulation by prey entails opening of the otherwise watertight trapdoor, followed by trap wall relaxation, sucking in of water and prey, and consecutive trapdoor closure. Suction can also occur spontaneously in non-stimulated traps. We review the current state of knowledge about the suction trap mechanism with a focus on architectonically homogeneous traps of aquatic bladderwort species from section Utricularia (the so-called 'Utricularia vulgaris trap type'). The functional morphology and biomechanics of the traps are described in detail. We discuss open questions and propose promising aspects for future studies on these sophisticated ultra-fast trapping devices. PMID- 26602986 TI - Topographic patterns in the phylogenetic structure of temperate forests on steep mountainous terrain. AB - In rugged terrain subject to active geomorphological processes, the species composition of forest communities changes along topographic gradients over short distances. However, the phylogenetic structure of forests on rugged terrain has rarely been examined. Understanding such structures provides insight into community assembly rules dependent on local environmental conditions. To this end, we tested the topographic trends of measurements of phylogenetic community structure [net relatedness index (NRI) and nearest taxon index] in a catchment covered by temperate forests with complex relief in Japan. We found that phylogenetic structure changed from over-dispersion to clustering with increasing slope inclination, change of slope aspect from south to north and decreasing soil depth. This result suggested that environmental filtering tended to restrict community composition at relatively stressful sites, whereas species interaction functioned more strongly at relatively stress-free sites. Relatively stressful sites were characterized by early-successional species that tended to assemble in certain phylogenetic clades, whereas highly competitive late-successional species associated with lower NRI at relatively stress-free sites. However, despite this significant topographic tendency, phylogenetic community structures were not statistically different from random assumptions in most plots. This obscuration of the phylogenetic structures at the plot level could be interpreted as species adapting to disturbances because they were abundant in this catchment. Accordingly, we suggest that a stochastic process was also important for this community at the plot level, although biotic and abiotic environmental filtering controlled the vegetation structure in the catchment, where disturbances occur frequently because of geomorphological mountain denudation processes owing to active crustal movements and abundant rainfall. PMID- 26602985 TI - Root hydraulic conductivity and adjustments in stomatal conductance: hydraulic strategy in response to salt stress in a halotolerant species. AB - Recent advances at the molecular level are introducing a new scenario that needs to be integrated into the analysis of plant hydraulic properties. Although it is not yet clear to what extent this scenario alters the current proposal for the hydraulic circuit models, it introduces new insights when studying plants that are able to easily overcome water restrictions. In this context, our aim was to explore water adjustments in a halotolerant model (Beta vulgaris) by studying the coordination between the root in terms of root hydraulic conductivity (Lpr) and the shoot as reflected in the stomatal conductance (gs). The root water pathways were also analysed in terms of root suberization (apoplastic barrier) and aquaporin transcript levels (cell-to-cell pathway). Beta vulgaris showed the ability to rapidly lose (4 h) and gain (24 h) turgor when submitted to salt stress (200 mM). The reduction profile observed in Lpr and gs was consistent with a coupled process. The tuning of the root water flow involved small variations in the studied aquaporin's transcripts before anatomical modifications occurred. Exploring Lpr enhancement after halting the stress contributed to show not only a different profile in restoring Lpr but also the capacity to uncouple Lpr from gs. Beta vulgaris root plays a key role and can anticipate water loss before the aerial water status is affected. PMID- 26602987 TI - Ecophysiology of four co-occurring lycophyte species: an investigation of functional convergence. AB - Lycophytes are the most early divergent extant lineage of vascular land plants. The group has a broad global distribution ranging from tundra to tropical forests and can make up an important component of temperate northeast US forests. We know very little about the in situ ecophysiology of this group and apparently no study has evaluated if lycophytes conform to functional patterns expected by the leaf economics spectrum hypothesis. To determine factors influencing photosynthetic capacity (Amax), we analysed several physiological traits related to photosynthesis to include stomatal, nutrient, vascular traits, and patterns of biomass distribution in four coexisting temperate lycophyte species: Lycopodium clavatum, Spinulum annotinum, Diphasiastrum digitatum and Dendrolycopodium dendroideum. We found no difference in maximum photosynthetic rates across species, yet wide variation in other traits. We also found that Amax was not related to leaf nitrogen concentration and is more tied to stomatal conductance, suggestive of a fundamentally different sets of constraints on photosynthesis in these lycophyte taxa compared with ferns and seed plants. These findings complement the hydropassive model of stomatal control in lycophytes and may reflect canalization of function in this group. Our data also demonstrate functional ecological similarities: De. dendroideum and D. digitatum are species that have substantial belowground biomass investment and are consistently more similar to each other across multiple traits than either is to the more surficial S. annotinum and L. clavatum. Such differences may partition environments in ways that allow for the close coexistence of these species. PMID- 26602988 TI - Influence of plant size on female-biased sex allocation in a single-flowered, nectarless herb. AB - Relative allocation to female and male function in hermaphroditic species often departs from strict equisexuality. Increased femaleness with plant size in animal pollinated species has been proposed in theory and demonstrated in empirical studies. However, such size-dependent sex allocation (SDS) has not been observed in some insect-pollinated species, throwing doubt on the generalization of SDS, that large plants have decelerated male function investment. Himalayan mayapple Podophyllum hexandrum (Berberidaceae) produces a single terminal flower and no nectar, providing a simple system for studying SDS without the confounding effects of flower number and nectar production. To investigate the SDS in P. hexandrum, plant size, biomass of floral organs (stamens, pistils and petals) and gamete production (pollen and ovule number) were measured in four populations in Yunnan Province, northwest China. Isometric allocation to female and male function with plant size was found in two populations, but the prediction of SDS was supported in the other two populations. Using pollen and ovule production as the allocation currency, allocation to female and male function was isometric in all studied populations. Resources allocated to attractive (petals) and sexual (pistils and stamens) structures did not show a significantly disproportionate increase with plant size in three of the four studied populations. The general pattern of isometric allocation to female and male function and to attractive and sexual structures could be attributed to the species being capable of automatic self-pollination, related to low pollen loss, minor deleterious effect of selfing and low importance of attractive structures. However, in further studies, careful consideration should be given to the different currencies used to estimate sex allocation. PMID- 26602990 TI - Scale quality: alpha is an inadequate estimate and factor-analytic evidence is needed first of all. AB - Cronbach's alpha is a commonly reported estimate to assess scale quality in health psychology and related disciplines. In this paper, we argue that alpha is an inadequate estimate for both validity and reliability - two key elements of scale quality. Omega is a readily available alternative that can be used for both interval and ordinal data. More importantly, we argue that factor-analytic evidence should be presented before assessing the internal structure of a scale. Finally, pointers for readers and reviewers of manuscripts on making judgements about scale quality are provided and illustrated by examples from the field of health psychology. PMID- 26602989 TI - Female genetic distribution bias in mitochondrial genome observed in Parkinson's Disease patients in northern China. AB - Genetic polymorphisms associated with susceptibility to Parkinson's disease (PD) have been described in mitochondrial DNA (mtDNA). To explore the potential contribution of mtDNA mutations to the risk of PD in a Chinese population, we examined the linkage relationship between several single nucleotide polymorphisms (SNPs) and haplotypes in mtDNA and PD. We genotyped 5 SNPs located on coding genes using PCR-RFLP analysis. A specific allele 10398G demonstrated an increased risk of PD (OR 1.30; 95% CI 0.95-1.76; P = 0.013). After stratification by gender, the increased risk appeared to be more significant in females (OR 1.91; 95% CI 1.16-3.16; P = 0.001). But the significance only appeared in females under Bonferroni correction. No significant differences were detected for other SNPs (T4336C, G5460A, G9055A, and G13708A). Individual haplotype composed of 4336T 5460G-9055G-10398A-13708G was found to be associated with protective effect regarding PD (P = 0.0025). The haplotypes 4336T-5460G-9055G-10398G-13708G and 4336T-5460G-9055G-10398A-13708G were more significantly associated in females (P = 0.0036 for risk and P = 0.0006 for protective effects). These data suggest that the A10398G and two haplotypes coupled with 10398A or 10398G are closely associated with susceptibility to PD in a northern Chinese population. This association demonstrated a female genetic distribution bias. PMID- 26602991 TI - Mastectomy with tears: breast cancer surgery in the early nineteenth century. AB - BACKGROUND: By the early nineteenth century, breast cancer was better understood and surgical treatment was emerging as a more favoured option although anaesthesia had yet to be discovered. Many questions would have arisen for a woman advised to have surgery, including possible alternatives, what the operation would entail, pain and risks involved and the competence, ethical and professional behaviour of the surgeon. This paper addresses these questions in the context of the contemporary environment, focusing in particular on the personal experiences of the women involved. METHODS: A review of the surviving personal letters and information regarding three women who had breast surgery, and of the contemporary surgical writings on breast cancer, training of surgeons, ethical and professional expectations and the concurrent status of women in society. RESULTS: Surgical training was in its infancy and the first pronouncements on medical ethics had just been published. Pain, bleeding and infection presented formidable challenges and carried significant risks. Women were frequently devoid of information, suffered a loss of their dignity and were progressively stripped of their authority. CONCLUSIONS: Breast cancer surgery was accompanied by enormous emotional and physical distress and significant risks from bleeding and infection. Although efforts were being made to give women a greater voice and autonomy in society, their position when receiving health care remained largely a submissive one. Lack of information, feelings of vulnerability, helplessness and loss of control occurred. The public perception of detachment most likely accounted for the occasional negative stigma then associated with the surgical profession. PMID- 26602993 TI - Water-Enhanced Synthesis of Higher Alcohols from CO2 Hydrogenation over a Pt/Co3O4 Catalyst under Milder Conditions. AB - The effect of water on CO2 hydrogenation to produce higher alcohols (C2-C4) was studied. Pt/Co3O4, which had not been used previously for this reaction, was applied as the heterogeneous catalyst. It was found that water and the catalyst had an excellent synergistic effect for promoting the reaction. High selectivity of C2-C4 alcohols could be achieved at 140 degrees C (especially with DMI (1,3 dimethyl-2-imidazolidinone) as co-solvent), which is a much lower temperature than reported previously. The catalyst could be reused at least five times without reducing the activity and selectivity. D2O and (13)CH3OH labeling experiments indicated that water involved in the reaction and promoted the reaction kinetically, and ethanol was formed via CH3OH as an intermediate. PMID- 26602992 TI - Long-Read Single Molecule Real-Time Full Gene Sequencing of Cytochrome P450-2D6. AB - The cytochrome P450-2D6 (CYP2D6) enzyme metabolizes ~25% of common medications, yet homologous pseudogenes and copy number variants (CNVs) make interrogating the polymorphic CYP2D6 gene with short-read sequencing challenging. Therefore, we developed a novel long-read, full gene CYP2D6 single molecule real-time (SMRT) sequencing method using the Pacific Biosciences platform. Long-range PCR and CYP2D6 SMRT sequencing of 10 previously genotyped controls identified expected star (*) alleles, but also enabled suballele resolution, diplotype refinement, and discovery of novel alleles. Coupled with an optimized variant-calling pipeline, CYP2D6 SMRT sequencing was highly reproducible as triplicate intra- and inter-run nonreference genotype results were completely concordant. Importantly, targeted SMRT sequencing of upstream and downstream CYP2D6 gene copies characterized the duplicated allele in 15 control samples with CYP2D6 CNVs. The utility of CYP2D6 SMRT sequencing was further underscored by identifying the diplotypes of 14 samples with discordant or unclear CYP2D6 configurations from previous targeted genotyping, which again included suballele resolution, duplicated allele characterization, and discovery of a novel allele and tandem arrangement. Taken together, long-read CYP2D6 SMRT sequencing is an innovative, reproducible, and validated method for full-gene characterization, duplication allele-specific analysis, and novel allele discovery, which will likely improve CYP2D6 metabolizer phenotype prediction for both research and clinical testing applications. PMID- 26602994 TI - Metal-Directed Self-Assembly of a Polyoxometalate-Based Molecular Triangle: Using Powerful Analytical Tools to Probe the Chemical Structure of Complex Supramolecular Assemblies. AB - A polyoxometalate-based molecular triangle has been synthesized through the metal driven self-assembly of covalent organic/inorganic hybrid oxo-clusters with remote pyridyl binding sites. The new metallomacrocycle was unambiguously characterized by using a combination of (1)H NMR spectroscopy, 2D diffusion NMR spectroscopy (DOSY), electrospray ionization travelling wave ion mobility mass spectrometry (ESI-TWIM-MS), small-angle X-ray scattering (SAXS) and molecular modelling. The collision cross-sections obtained from TWIM-MS and the hydrodynamic radii derived from DOSY are in good agreement with the geometry optimized structures obtained by using theoretical calculations. Furthermore, SAXS was successfully employed and proved to be a powerful technique for characterizing such large supramolecular assemblies. PMID- 26602995 TI - Patent ductus arteriosus balloon sizing: A new technique to evaluate the size in complex cases. AB - Patent ductus arteriosus (PDA) transcatheter closure is a widespread procedure. However in some cases PDA measurements may be unclear and choice of the proper device could be quite difficult. This may happen in large PDA and in particular in adults. We have developed a new technique using an ASD sizing balloon to measure the PDA in order to better understand PDA anatomy and size. The first step is to create an artero-venous circuit across the PDA. A 24 or a 34 mm Amplatzer balloon sizing for ASD closure is placed over the wire from the venous access in the descending aorta. Then, the balloon is inflated and gently pulled back across the PDA toward the pulmonary artery. The frame where the balloon is exactly across the PDA is chosen and measurements performed. In conclusion, a new method for PDA measurement in large PDA is reported. The procedure is safe and reliable. (c) 2015 Wiley Periodicals, Inc. PMID- 26602996 TI - Hematopoietic stem cell transplantation for cutaneous T-cell lymphoma: Summary of 11 cases from two facilities in Japan and Brazil. AB - Some patients with cutaneous T-cell lymphoma (CTCL) show a miserable clinical course and the only option that can induce long-term remission for advanced CTCL may be hematopoietic stem cell transplantation (HSCT). So far, studies on HSCT for CTCL patients have been limited. In this study, we summarized 11 cases with CTCL treated with HSCT, including nine cases in Japan and two cases in Brazil. The patients were five cases with mycosis fungoides (MF), two cases with Sezary syndrome (SS), three cases with anaplastic large cell lymphoma, and one case with primary cutaneous peripheral T-cell lymphoma, not otherwise specified (PTL-NOS). Currently, seven out of 11 cases are alive (at 13-108 months after transplantation) and four died at 15 days to 14 months after transplantation. When focusing on the eight patients who received allogeneic HSCT for MF/SS and PTL-NOS, all four patients at 45 years old or under are alive at present. One case showed relapse in the skin. On the other hand, one out of the other four patients at over 45 years old survived. Engraftment failure was seen in one case and all the other three cases experienced relapse. Although this is only a case series with a small number, our study has suggested that we should be careful about age when treating patients with MF/SS by allogeneic HSCT. PMID- 26602999 TI - Elective cesarean section for term breech delivery. PMID- 26603000 TI - The future of physicians and their relationship with patients. PMID- 26603001 TI - Complication of post-infectious bronchiolitis obliterans (Swyer-James syndrome). AB - Swyer-James syndrome is a complication of post-infectious bronchiolitis obliterans that causes inflammation and fibrosis of the bronchial walls. There are two types: asymptomatic, with most cases diagnosed in adults during routine radiological examinations; and symptomatic, most commonly found in children. Here, we report the case of a 6-year-old child with recurrent dyspnea since the age of 3, who showed signs and symptoms of bronchiolitis obliterans and radiological signs of bronchial wall thickening and air trapping. The clinical and radiological findings led to the diagnosis of Swyer-James syndrome. Treatment of this syndrome is intended to reduce the pulmonary lesions and improve the patient's quality of life. PMID- 26603002 TI - Menkes disease: importance of diagnosis with molecular analysis in the neonatal period. AB - Menkes disease is a congenital disorder caused by changes in copper metabolism derived from mutations in the ATP7A gene. It is characterized by physical and neurological alterations. In the neonatal period, these alterations can be nonspecific, which makes early diagnosis a challenge. Diagnosis can be suspected when there are low levels of ceruloplasmin and serum copper. Molecular analysis confirms the diagnosis. Treatment is parenteral administration of copper histidine. We report a familial case with molecular confirmation. The proband had clinical and biochemical suspicious. Treatment with copper histidine was indicated, but initiated at the age of 2 months and 27 days only. He did not present improvements and died at 6 months. The mother became pregnant again, a male fetus was identified and copper histidine was manufactured during pregnancy. He was born healthy, biochemical markers were reduced and treatment was indicated. Molecular analysis was performed confirming mutation in both the mother and the proband, while the other son did not have mutation, so treatment was discontinued. We support the clinical relevance of molecular confirmation for the correct diagnosis and genetic counseling, once clinical findings in the neonatal period are nonspecific and early treatment with parenteral copper histidine must be indicated. PMID- 26603003 TI - Adjuvant treatment delay in breast cancer patients. AB - BACKGROUND: to evaluate if time between surgery and the first adjuvant treatment (chemotherapy, radiotherapy or hormone therapy) in patients with breast cancer is a risk factor for lower overall survival (OS). METHOD: data from a five-year retrospective cohort study of all women diagnosed with invasive breast cancer at an academic oncology service were collected and analyzed. RESULTS: three hundred forty-eight consecutive women were included. Time between surgery and the first adjuvant treatment was a risk factor for shorter overall survival (HR=1.3, 95CI 1.06-1.71, p=0.015), along with negative estrogen receptor, the presence of lymphovascular invasion and greater tumor size. A delay longer than 4 months between surgery and the first adjuvant treatment was also associated with shorter overall survival (cumulative survival of 80.9% for delays <= 4 months vs. 72.6% for delays > 4 months; p=0.041, log rank test). CONCLUSION: each month of delay between surgery and the first adjuvant treatment in women with invasive breast cancer increases the risk of death in 1.3-fold, and this effect is independent of all other well-established risk factors. Based on these results, we recommend further public strategies to decrease this interval. PMID- 26603004 TI - Outcome of children and adolescents with lymphoblastic lymphoma. AB - INTRODUCTION: lymphoblastic lymphoma (LBL) is the second most common subtype of non-Hodgkin lymphoma in children. The aim of this study was to characterize the clinical course of children and adolescents with LBL treated at a tertiary center. METHODS: this is a retrospective cohort study of 27 patients aged 16 years or younger with LBL admitted between January 1981 and December 2013. Patients were treated according to the therapy protocol used for acute lymphoblastic leucemia. Diagnosis was based on biopsy of tumor and/or cytological examination of pleural effusions. The overall survival was analyzed using the Kaplan-Meier method. RESULTS: the median age at diagnosis was 11.6 years (interquartile range, 4.6- 13.8). LBL had T-cell origin in 16 patients (59%). The most common primary manifestation in T-cell LBL was mediastinal involvement, in 9 patients (56%). Intra-abdominal tumor was the major site of involvement in patients with precursor B-LBL. Most patients had advanced disease (18 patients - 67%) at diagnosis. Twenty-four patients (89%) achieved complete clinical remission. After a median follow-up of 43 months (interquartile range, 6.4-95), 22 patients (81%) were alive in first complete remission. Five children (18.5%) died, three of them soon after admission and two after relapsing. The probability of survival at five years for 20 patients with de novo LBL was 78% (SD 9.4). CONCLUSION: our findings confirm the favorable prognosis of children with LBL with an intensive chemotherapy regimen derived from ALL therapy. PMID- 26603005 TI - Quality of life evaluation of frail elderly in Campinas, Sao Paulo. AB - OBJECTIVE: describe the quality of life of frail elderly assisted by the Centro de Referencia a Saude do Idoso (CRI), Campinas, Sao Paulo, Brazil. METHODS: the convenience sample included 122 frail elderly being treated from January 2010 to July 2011, out of a total of 668 frail elderly who were referred to the CRI after application of the brief evaluation form of the elderly, recommended by Ministry of Health, which identifies the elderly with some degree of frailty. Descriptive observational study collected data through sociodemographic questionnaire and quality of life questionnaires: WHOQOL-BREF, WHOQOLOLD and SF-36. RESULTS: the study included 122 frail elderly. Of these, 74.6% (91) were female, mean age 73 years, 46.7% (57) were married, 51.6% (63) had less than 3 years of schooling and 87.7% (107) reported income of one to four minimum wages. The mean total score of the WHOQOL-BREF was 56.6, the WHOQOL-OLD 57.6 and SF-36 Physical Component Summary 34.5 and Mental Component Summary 43.6. CONCLUSION: knowledge of the impairment profile of quality of life among frail elderly is, therefore, essential for planning health care to this population. PMID- 26603006 TI - Brachytherapy and radical prostatectomy in patients with early prostate cancer. AB - OBJECTIVE: this study analyzes the survival of prostate cancer patients cared for at a hospital in Minas Gerais, Brazil according to one of the following treatments: iodine-125 seed implantation or radical prostatectomy. From January 2002 to December 2005, 129 patients underwent either brachytherapy (64 patients) or surgery (65 patients). METHODS: all had prostate-specific antigen, Gleason scores and clinical stage recorded prior to treatment. Biochemical relapse was defined as prostate-specific antigen (PSA)>0.4 ng/mL for radical prostatectomy, and any elevation equal or higher than 2 ng/mL over the PSA nadir for implanted patients. To analyze the effect of treatment on biochemical recurrence-free survival (BRFS), Kaplan-Meier curves and Cox regression were generated. Mean follow-up time was 56.1 months for patients with the implant, and 26.6 months for those operated on. BRFS in 5 years was 69% (95% CI: 58.18-77.45) for the whole cohort. DISCUSSION: when stratified according to treatment, survival of patients who had undergone brachytherapy (79.70%) was higher to those operated on (44.30%; p value= 0.0056). Upon multivariate analysis, independent predictors were iPSA (HR: 2.91, 95% CI: 1,32-6,42), Gleason score (HR: 2.18, 95% CI: 1,00-4,81) and treatment modality (HR: 2.61, 95% CI: 1.18-5,75). Risk of biochemical failure was higher with surgery than brachytherapy, which may be related to the failure criteria adopted, which is different for each therapy, as well as the high rate of histological progression between preoperative prostate biopsy and surgical specimen. CONCLUSION: it was found that brachytherapy is a good therapeutic option for low risk prostate cancer. PMID- 26603007 TI - Management of exogenous intoxication by carbamates and organophosphates at an emergency unit. AB - OBJECTIVES: to evaluate and indicate the procedure to be followed in the health unit, both for diagnosis and the treatment of acute exogenous intoxications by carbamates or organophosphates. METHODS: a descriptive study based on retrospective analysis of the clinical history of patients diagnosed with intoxication by carbamates or organophosphates admitted at the emergency unit of the Hospital de Urgencias de Sergipe Governador Joao Alves (HUSE) between January and December of 2012. Some criteria were evaluated, such as: intoxicating agent; patient's age and gender; place of event, cause, circumstances and severity of the intoxication; as well as signs and symptoms of the muscarinic, nicotinic and neurological effects. RESULTS: seventy patients (average age: 25 +/- 19.97) formed the study's population. It was observed that 77.14% of them suffered carbamate intoxication. However, organophosphate intoxications were more severe, with 68.75% of patients presenting moderate to severe forms. Suicide attempt was the leading cause of poisoning, with 62 cases (88.57% of total). Atropine administration was an effective therapeutic approach for treating signs and symptoms, which included sialorrhea (p = 0.0006), nausea (p = 0. 0029) and emesis (p < 0.0001). The use of activated charcoal was shown effective, both in combating the signs and symptoms presented by both patient groups (p < 0.0001). CONCLUSION: it is concluded that the use of atropine and activated charcoal is highly effective to treat the signs and symptoms developed by patients presenting acute exogenous intoxication by carbamates or organophosphates. PMID- 26603008 TI - Single-port laparoscopic hysterectomy: preliminary results. AB - OBJECTIVE: to describe the initial results of a laparoscopic single port access hysterectomy and also to evaluate the feasibility and safety of this access. METHODS: a prospective study was performed at a tertiary university medical center (Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo) between March 2013 and June 2014. A total of 20 women, referred for hysterectomy due to benign uterine disease, were included in the study after they had signed an informed consent. Outcome measures, including operating time, blood loss, rate of complications, febrile morbidity, visual analogical pain score and length of hospital stay were registered. RESULTS: mean patient age and body mass index (BMI) were 47.8 years and 27.15 kg/m2, respectively. Mean operating time was 165.5 min. Blood loss was minimal, with no blood transfusion. All procedures but one were successfully performed via a single incision and no post-operative complications occurred. We experienced one conversion to multiport laparoscopic hysterectomy due to extensive pelvic adhesions. There was no conversion to "open" total abdominal hysterectomy. None of the patients required narcotics or NSAD post-operatively. CONCLUSION: single-port hysterectomy is a feasible and safe technique, with no major complications. PMID- 26603009 TI - Knowledge and attitudes of nurses regarding patient rights: a Corum/Turkey sample. AB - OBJECTIVE: patient rights are defined as the rules of conduct between the people who benefit from health services and the health institutions and personnel who provide them. As the protection and provision of these rights are closely related to the nursing trade, these professionals must have thorough knowledge about this issue. The purpose of this study was to evaluate the acquaintance and attitudes of working nurses in Corum/Turkey regarding patient rights and to create the basis for a planned educational program. METHODS: sample selection was not performed in this study, but all nurses (n=939) who were working in the course of this study constituted the sample. Survey forms were used as data collection tools. RESULTS: the study revealed that 92.3% had received education about patient rights, 2.2% had never heard anything about this term and 86.6% became aware of it through sources from outside of school. It was established that the attitudes of nurses regarding patient rights differ for every patient and that this rate ranges from 35.8 to 98.1%. CONCLUSION: there is a requirement for more studies on the subject of patient rights, as they play an important role in the development of health services. In that regard, patient rights centers should be established and carried out according to the foreseen model set by national and international health systems. Studies aiming to teach health personnel, patients and their relatives about patient rights must be carried out. PMID- 26603010 TI - Single-nucleotide polymorphisms: a perspective of cardiovascular prevention. AB - INTRODUCTION: several studies have evaluated the utilization of lipid biomarkers in an attempt to correlate them with clinical cardiovascular events. Nevertheless, the investigation of clinical conditions under specific plasmatic levels of lipoproteins for long periods presents limitations due to inherent difficulties that are related to the follow-up of individuals throughout their lives. Better understanding of the clinical response and occasional resistance to the action of hypolipidemic drugs in several clinic scenarios is also necessary. OBJECTIVES: to determine the role of evaluation of single-nucleotide polymorphisms (SNPs) related to the metabolism of lipids, and its implications in different clinical scenarios. METHODS: a search of the literature in English and Spanish languages was performed in Medline, Lilacs via Bireme, IBECS via Bireme, and Cochrane databases. The expected results included information regarding plasmatic lipid profile and SNPs, cardiovascular clinical outcomes and polymorphisms related to the effectiveness of statins in the treatment of hypercholesterolemia. RESULTS: in order to perform this analysis, 19 studies were included from a total of 89 identified citations. The evaluation of the results suggests that low plasmatic levels of LDL-c are associated with a reduction in the risk of heart attacks, although this was not observed for the rise of plasmatic levels of HDL-c. CONCLUSION: polymorphisms in different populations and clinical perspectives may bring important contributions for a better understanding and adequacy of plasmatic lipoproteins aiming at reducing cardiovascular risk. PMID- 26603011 TI - Clinical management of incidental findings on pelvic adnexal masses. AB - Due to widespread use of pelvic and transvaginal ultrasound in routine gynecological evaluation, the incidental finding of adnexal masses has led to discussions about management in asymptomatic patients regarding the risk of ovarian cancer. Transvaginal ultrasonography remains the modality of choice in the evaluation of suspicious characteristics. The combined analysis of ultrasound morphological parameters with Doppler study, serum carcinoma antigen 125 and investigation of a symptom index may improve diagnosis. Surgical approach should be considered whenever there are suspicious images, rapid growth of cysts, changes in the appearance compared to the initial evaluation or when the patient has symptoms. Future studies on genetic and molecular mechanisms may help explain the pathophysiology of ovarian cancer, improving early diagnosis and treatment. PMID- 26603012 TI - Somatic mutations in breast and serous ovarian cancer young patients: a systematic review and meta-analysis. AB - OBJECTIVE: our aim was to evaluate whether somatic mutations in five genes were associated with an early age at presentation of breast cancer (BC) or serous ovarian cancer (SOC). METHODS: COSMIC database was searched for the five most frequent somatic mutations in BC and SOC. A systematic review of PubMed was performed. Young age for BC and SOC patients was set at <= 35 and <= 40 years, respectively. Age groups were also classified in < 30 years and every 10 years thereafter. RESULTS: twenty six (1,980 patients, 111 younger) and 16 studies (598, 41 younger), were analyzed for BC and SOC, respectively. In BC, PIK3CA wild type tumor was associated with early onset, not confirmed in binary regression with estrogen receptor (ER) status. In HER2-negative tumors, there was increased frequency of PIK3CA somatic mutation in older age groups; in ER-positive tumors, there was a trend towards an increased frequency of PIK3CA somatic mutation in older age groups. TP53 somatic mutation was described in 20% of tumors from both younger and older patients; PTEN, CDH1 and GATA3 somatic mutation was investigated only in 16 patients and PTEN mutation was detected in one of them. In SOC, TP53 somatic mutation was rather common, detected in more than 50% of tumors, however, more frequently in older patients. CONCLUSION: frequency of somatic mutations in specific genes was not associated with early-onset breast cancer. Although very common in patients with serous ovarian cancer diagnosed at all ages, TP53 mutation was more frequently detected in older women. PMID- 26603013 TI - Natural hair color and questionnaire-reported pain among women in the United States. PMID- 26603014 TI - Novel PORCN mutation in a severe case of Focal Dermal Hypoplasia. AB - Focal dermal hypoplasia is a rare genetic disease characterized 8-year-old female who sought genetic counseling for multiple malformations, aggressive behavior and intellectual disability. Gene analysis confirmed focal dermal hypoplasia. PMID- 26603015 TI - Occupational exposure to carcinogens in Australian road transport workers. AB - BACKGROUND: Road transport workers (RTWs) are at high risk of exposure to several occupational carcinogens. However, there are gaps in knowledge regarding the extent and the circumstances of exposure. As a sub-study of the Australian Work Exposures Study, this study investigated the prevalence of occupational exposure in Australian RTWs. METHODS: A random sample of Australian working population was invited to a telephone interview regarding their current jobs. An automated expert-assessment procedure was applied to self-reported job-related tasks using a web-based application. 162 RTWs were included in this study. RESULTS: RTWs were exposed to diesel exhaust (97%), solar ultraviolet radiation (78%), environmental tobacco smoke (55%), benzene (29%), silica (15%), and asbestos (10%) at work. Besides driving on roads, vehicle maintenance-related tasks were the major source of carcinogen exposures among RTWs. DISCUSSION: Most RTWs are exposed to at least one carcinogen at work. We have identified tasks where the use of control measures could potentially reduce exposures. PMID- 26603016 TI - Implementing caseload midwifery: Exploring the views of maternity managers in Australia - A national cross-sectional survey. AB - BACKGROUND: The benefits of caseload midwifery care are clearly documented, and many policy documents in Australia support its expansion. Despite this, little is known about the availability of caseload across Australia, nor about what proportion of women have access to a caseload model. This paper describes caseload midwifery in the public maternity system in Australia; its prevalence, and factors associated with implementation and sustainability. METHODS: A cross sectional online survey of maternity managers of public hospitals that provide birthing services throughout Australia. FINDINGS: Sixty-three percent (149/235) of eligible participants responded. Respondents were from all states and territories, metropolitan, regional and remote areas, and from hospitals with very small to very large birth numbers. Only 31% reported that their hospital offers caseload midwifery, and an estimated eight percent of women received caseload care at the time of the survey, most of whom were considered to be of 'low obstetric risk'. Many respondents were planning to implement or expand caseload. Key factors associated with the implementation of caseload were funding to establish the model, the interest and availability of staff to work in the model, organisational support and perceived consumer demand. CONCLUSION: This is the first study to explore caseload implementation at a national level. Although the number of services offering caseload midwifery care has increased nationally, access remains relatively limited. Women who live in metropolitan areas and who are considered at 'low obstetric risk' are most likely to be able to access this model. Funding and support for establishing new models are the main barriers to implementation. PMID- 26603017 TI - Limited Benefits of Heterogeneous Dual-Task Training on Transfer Effects in Older Adults. AB - Objectives: It has often been reported that cognitive training has limited transfer effects. The present study addresses training context variability as a factor that could increase transfer effects, as well as the manifestation through time of transfer effects. Method: Fifty-eight older adults were assigned to an active placebo or two dual-task training conditions, one in which the training context varies between sessions (heterogeneous training) and the other in a fixed training context (homogeneous training). Transfer was assessed with near and far modality transfer tasks. Results: Results show that heterogeneous and homogeneous training led to larger near-modality transfer effects than an active placebo (computer lessons). Transfer effects were roughly comparable in both training groups, but heterogeneous training led to a steeper improvement of the dual-task coordination learning curve within training sessions. Also, results indicated that dual-task cost did not improve in the active placebo group from the pre- to the post-training sessions. Discussion: Heterogeneous training showed modest advantages over homogeneous training. Results also suggest that transfer effects on dual-task cost induced by training take place early on in the post-training session. These findings provide valuable insights on benefits arising from variability in the training protocol for maximizing transfer effects. PMID- 26603018 TI - Design and setup of intermittent-flow respirometry system for aquatic organisms. AB - Intermittent-flow respirometry is an experimental protocol for measuring oxygen consumption in aquatic organisms that utilizes the best features of closed (stop flow) and flow-through respirometry while eliminating (or at least reducing) some of their inherent problems. By interspersing short periods of closed-chamber oxygen consumption measurements with regular flush periods, accurate oxygen uptake rate measurements can be made without the accumulation of waste products, particularly carbon dioxide, which may confound results. Automating the procedure with easily available hardware and software further reduces error by allowing many measurements to be made over long periods thereby minimizing animal stress due to acclimation issues. This paper describes some of the fundamental principles that need to be considered when designing and carrying out automated intermittent-flow respirometry (e.g. chamber size, flush rate, flush time, chamber mixing, measurement periods and temperature control). Finally, recent advances in oxygen probe technology and open source automation software will be discussed in the context of assembling relatively low cost and reliable measurement systems. PMID- 26603019 TI - Ross Procedure in Neonates and Infants: A European Multicenter Experience. AB - BACKGROUND: Infants and neonates with severe left ventricular outflow tract obstruction may require pulmonary autograft replacement of the aortic root. In this retrospective multicenter cohort study, we present our experience with the Ross procedure in neonates and infants with a focus on midterm survival and pulmonary autograft durability. METHODS: A retrospective observational study was performed in 76 infants (aged less than 1 year) operated on in six congenital cardiac centers in The Netherlands and Germany between 1990 and 2013. RESULTS: Patients had a pulmonary autograft replacement of the aortic valve with (68%) or without (32%) septal myectomy. Median patient age was 85 days (range, 6 to 347). Early mortality (n = 13, 17%) was associated with neonatal age, preoperative use of intravenous inotropic drugs, and congenital aortic arch defects. Five patients (9%) died during follow-up. Freedom from autograft reintervention was 98% at 10 years. Echocardiography demonstrated good valve function, with no or trace regurgitation in 73% of patients. Freedom from right ventricular outflow tract reintervention was 51% at 10 years. Univariable analysis demonstrated superior freedom from reintervention of pulmonary homografts compared with aortic homografts or xenografts. CONCLUSIONS: Pulmonary autograft replacement of the aortic valve in neonates and infants is a high-risk operation but offers a durable neoaortic valve. Midterm durability reflects successful adaptation of the autograft to the systemic circulation. Late mortality associated with heart failure was an unexpected finding. PMID- 26603020 TI - Thirty-Day Mortality After Lobectomy in Elderly Patients Eligible for Lung Cancer Screening. AB - BACKGROUND: Whether US surgeons have been able to replicate the low mortality rate of 1% after lobectomy experienced by patients treated in the National Lung Screening Trial is unknown. METHODS: To determine current operative 30-day mortality rates after lobectomy, we analyzed American College of Surgeons National Surgical Quality Improvement Program data files from 2005 to 2012. RESULTS: Of the 2,690 patients analyzed, 1,595 underwent open thoracotomy lobectomy and 1,095 underwent video-assisted thoracoscopic lobectomy. Sixty-three postoperative deaths occurred among the 2,690 patients (2.34% overall). The mortality rate for open lobectomy was 3.13% (50 cases) and that for video assisted thoracoscopic lobectomy was 1.19% (13 cases [odds ratio 2.69, 95% confidence interval: 1.43 to 5.43, p < 0.05). Evaluation of mortality rates between surgical approaches (open versus video-assisted thoracoscopic) was performed by age group: group 1, aged 65 to 69 years (odds ratio 2.72, 95% confidence interval: 1 to 9.4, p < 0.05); group 2, aged 70 to 74 years (odds ratio 4.41, 95% confidence interval: 1.28 to 23.4, p < 0.05); and group 3, aged 75 to 80 years (no difference was found in group 3, p = 0.45). CONCLUSIONS: Among the hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program, operative mortality rates after lobectomy are comparable to the operative mortality rates in the National Lung Screening Trial. PMID- 26603021 TI - What Is the Role of Minimally Invasive Mitral Valve Surgery in High-Risk Patients? A Meta-Analysis of Observational Studies. AB - BACKGROUND: Minimally invasive valve surgery is related to certain better postoperative outcomes. We aimed to assess the role of minimally invasive mitral valve surgery in high-risk patients. METHODS: A systematic literature review identified eight studies of which seven fulfilled criteria for meta-analysis. Outcomes for a total of 1,254 patients (731 were conventional standard sternotomy and 523 were minimally invasive mitral valve surgery) were submitted to meta analysis using random effects modeling. Heterogeneity and subgroup analysis with quality scoring were assessed. The primary end point was early mortality. Secondary end points were intraoperative and postoperative outcomes and long-term follow-up. RESULTS: Minimally invasive mitral valve surgery conferred comparable early mortality to standard sternotomy (p = 0.19); it was also associated with a lower number of units of blood transfused (weighted mean difference, -1.93; 95% confidence interval [CI], -3.04 to -0.82; p = 0.0006) and atrial fibrillation rate (odds ratio, 0.49; 95% CI, 0.32 to 0.74; p = 0.0007); however, cardiopulmonary bypass time was longer (weighted mean difference, 20.88; 95% CI, 1.90 to 43.65; p = 0.07). There was no difference in terms of valve repair rate (odds ratio, 1.51; 95% CI, 0.89 to 2.54; p = 0.12), and the incidence of stroke was significantly lower in the high-quality analysis with no heterogeneity (odds ratio, 0.35; 95% CI, 0.15 to 0.82; p = 0.02; chi(2), 1.67; I(2), 0%; p = 0.43). CONCLUSIONS: Minimally invasive mitral valve surgery is a safe and comparable alternative to standard sternotomy in patients at high risk, with similar early mortality and repair rate and better postoperative outcomes, although a longer cardiopulmonary bypass time is required. PMID- 26603022 TI - Half a Century's Experience With the Superior Cavopulmonary (Classic Glenn) Shunt. AB - BACKGROUND: Five decades after its introduction, the Glenn shunt remains an integral step for patients undergoing single-ventricle palliation. We performed a longitudinal follow-up of the original cohort of patients who underwent Glenn shunt. METHODS: We performed a retrospective study of the original cohort of patients who underwent Glenn shunt at Yale between 1958 and 1988. Electronic medical records and chart review up to current era were used to collect data. RESULTS: Ninety-one patients underwent a Glenn shunt at an average age of 6.6 +/- 2.5 years, of which 89 were classic Glenn shunts. Median overall survival was 43 years (range, 2 to 56; 95% confidence interval [CI], 39.5 to 46.5) while median survival from the Glenn shunt was 31.4 years (range, 0 to 45; 95% CI, 23.9 to 38.9). Forty-six patients died, 7 in the early postoperative period and 39 late deaths. Twenty-six patients were lost to follow-up. Nineteen patients remain alive with active clinical follow-up, 6 of whom still live with their classic Glenn shunt without conversion to bidirectional Glenn. Twenty-six patients (31%) developed pulmonary arteriovenous fistula with 11 patients (42%) requiring coil embolization. No patient developed thrombosis of the Glenn shunt. There were a total of 28 patients who developed arrhythmias, mostly in the tricuspid atresia group (n = 16), with the majority being atrial tachyarrhythmias (48%). Sixteen patients required permanent pacemaker placement for sinus node dysfunction. CONCLUSIONS: The Glenn shunt continues to provide excellent staged palliation in single-ventricle patients and a bridge to two-ventricle repair. Arrhythmias and pulmonary arteriovenous fistulas were common among single-ventricle cohort. Quality-of-life evaluation of the surviving patients would be an important outcome measure for future investigation. PMID- 26603023 TI - Changes in the Hemostatic System of Patients With Acute Aortic Dissection Undergoing Aortic Arch Surgery. AB - BACKGROUND: Aortic arch surgery for patients with acute aortic dissection is frequently complicated by excessive bleeding and transfusion of allogeneic blood products. However, the physiopathology of acute aortic dissection and surgery induced coagulopathy has never been precisely studied. The aim of the present study is to describe the changes of the perioperative hemostatic system in patients with acute aortic dissection undergoing aortic arch surgery. METHODS: Sixty-two patients undergoing emergent aortic arch surgery for Stanford type A acute aortic dissection were enrolled in this study from January 2013 to September 2014. The hemostatic system was evaluated using standard laboratory tests, plasma fibrinogen levels, and thromboelastogragh at 5 time points: anesthesia induction (T0), lowest nasopharyngeal temperature (T1), protamine reversal (T2), 4 h after surgery (T3), and on the first postoperative day (T4). RESULTS: The study results revealed that clotting factors had a tendency to be consumed in the preoperative period. Surgery and hypothermia resulted in a progressive reduction in clotting factors, platelet counts, and function, as well as fibrinogen concentration and function. After hemostatic therapy, although platelet counts were constantly low, clotting factors and platelet function returned to nearly preoperative levels. In contrast, fibrinogen concentration and function were still significantly lower than preoperative levels. CONCLUSIONS: The results of this prospective analysis showed that acute aortic dissection itself activated the hemostatic system even before surgery. After hemostatic therapy, fibrin formation was more impaired than platelet function. In this setting, we proposed that hemostatic therapy should focus on rapid and sufficient supplementation of fibrinogen. Thus, we recommend further increases in fibrinogen concentration to improve coagulopathy in patients with acute aortic dissection. PMID- 26603024 TI - Pretreatment Dysphagia in Esophageal Cancer Patients May Eliminate the Need for Staging by Endoscopic Ultrasonography. AB - BACKGROUND: Neoadjuvant therapy is commonly administered to patients with localized disease who have T3-4 esophageal disease as staged by endoscopic ultrasound (EUS). Previously, we noted that patients who present with dysphagia have a higher EUS T stage. We hypothesized that the presence of dysphagia is predictive of EUS T3-4 disease and that staging EUS could be forgone for esophageal cancer patients with dysphagia. METHODS: We performed a prospective, intent-to-treat, single-cohort study in which patients with potentially resectable esophageal cancer completed a standardized four-tier dysphagia score survey. EUS was performed as part of our standard evaluation. To determine whether the presence of dysphagia predicted EUS T3-4 disease, the dysphagia score was compared with EUS T stage. RESULTS: The study enrolled 114 consecutive patients between August 2012 and February 2014: 77% (88 of 114) received neoadjuvant therapy, 18% (20 of 114) did not, and 5% (6 of 114) pursued treatment elsewhere. In total, 70% (80 of 114) underwent esophagectomy; of these, 54% (61 of 114) had dysphagia and 46% (53 of 114) did not. Dysphagia scores were 66% (40 of 61) grade 1, 25% (15 of 61) grade 2, and 10% (6 of 61) grade 3 to 4. Among patients with dysphagia, 89% (54 of 61) had T3-4 disease by EUS; among those without dysphagia, only 53% (28 of 53) had T3-4 disease by EUS (p < 0.001). CONCLUSIONS: The presence of dysphagia in patients with esophageal cancer was highly predictive of T3-4 disease by EUS. On the basis of this finding, approximately 50% of patients currently undergoing staging EUS at our institution could potentially forgo EUS before neoadjuvant therapy. Patients without dysphagia, however, should still undergo EUS. PMID- 26603025 TI - Intermediate Clinical and Hemodynamic Outcomes After Transcatheter Aortic Valve Implantation. AB - BACKGROUND: Concerns still exist regarding long-term results and freedom from valve-related adverse events in transcatheter aortic valve implantation (TAVI). The aim of this single-center retrospective study was to assess intermediate-term (up to 5-year) clinical and hemodynamic outcomes in patients undergoing TAVI. METHODS: From 2007 through 2013, 338 consecutive patients underwent TAVI at our institution. Preoperative variables were defined according to the European System for Cardiac Operative Risk Evaluation (EuroSCORE) definitions, and outcomes were reported according to the Valve Academic Research Consortium (VARC)-2 definitions. Multivariate logistic regression analysis was performed to identify independent predictors of mortality at follow-up. RESULTS: transfemoral (TF) and transapical (TA) TAVI were performed in 233 (69%) and 105 (31%) patients, respectively. All-cause 30-day mortality was 4.4%, with no differences between TA and TF procedures. Thirty-day cardiovascular death, stroke, and myocardial infarction were not different between groups. The acute kidney injury (AKI) rate was higher in the TA group (30.5% versus 11.2%; p < 0.001). Access-related complications were more frequent in the TF group (36.1% versus 11.4%; p < 0.001). Mean follow-up was 22.3 +/- 17.8 months (range, 1-74 months). Overall survival rates at 1, 3, and 5 years were 85.5% +/- 2.1%, 69.9% +/- 3.2%, and 61% +/- 4.3%, respectively. Independent predictors of all-cause mortality at follow-up were previous myocardial infarction (odds ratio [OR], 2.7), any grade of paravalvular leak (PVL) (OR, 2.5), and AKI (OR, 3.1). Mean gradient and effective orifice area at follow-up were 10.7 +/- 12.0 mm Hg and 1.1 +/- 0.9 cm(2)/m(2), respectively. CONCLUSIONS: Our data show that TAVI has good early and intermediate-term clinical and hemodynamic outcomes in high-risk or inoperable patients with severe symptomatic aortic valve stenosis. PVL of any grade has a significant impact on survival. PMID- 26603027 TI - Risky business or not? FIFOs, sexual risk taking and the Australian mining industry. AB - Issue addressed The fly-in, fly-out (FIFO) and drive-in, drive-out (DIDO) models of mining in Australia have led to concerns about adverse health and psychosocial impacts. Despite speculation that increased levels of sexually transmitted infections (STIs) in Australia, including HIV, are associated with FIFO/DIDO work, we know little about sexual risk-taking behaviours in mining populations. This study explores differences in sexual risk taking and perceptions of risk between FIFO/DIDO miners and residential miners. Methods A cross-sectional survey was administered to a sample (n=444) of male miners working in Queensland, Australia. The self-completed survey contained 49 questions relating to knowledge, attitudes and behaviour and included demographic information and specific items related to sex and relationships. Results FIFO/DIDO status was not associated with any differential sexual risk-taking behaviours, except for an increased probability of reporting 'ever being diagnosed with an STI'; 10.8% of FIFO/DIDO respondents versus 3.6% of others (x(2) (1)=4.43, P=0.35). Conclusions Our results appear to counter anecdotal evidence that FIFO/DIDO miners engage in higher sexual risk behaviours when compared with residential miners. So what? Anecdotal evidence linking the rise of sexually transmitted infections with the FIFO/DIDO mining workforce could drive costly and unnecessary approaches to prevention. Further research, surveillance and monitoring are required to inform health promotion interventions. PMID- 26603026 TI - Quantification of CD4(+) T Cell Alloreactivity and Its Control by Regulatory T Cells Using Time-Lapse Microscopy and Immune Synapse Detection. AB - Assays designed to select transplant recipients for immunosuppression withdrawal have met with limited success, perhaps because they measure events downstream of T cell-alloantigen interactions. Using in vitro time-lapse microscopy in a mouse transplant model, we investigated whether transplant outcome would result in changes in the proportion of CD4(+) T cells forming prolonged interactions with donor dendritic cells. By blocking CD4-MHC class II and CD28-B7 interactions, we defined immunologically relevant interactions as those >=500 s. Using this threshold, T cell-dendritic cell (T-DC) interactions were examined in rejection, tolerance and T cell control mediated by regulatory T cells. The frequency of T DC contacts >=500 s increased with T cells from mice during acute rejection and decreased with T cells from mice rendered unresponsive to alloantigen. Regulatory T cells reduced prolonged T-DC contacts. Importantly, this effect was replicated with human polyclonally expanded naturally occurring regulatory T cells, which we have previously shown can control rejection of human tissues in humanized mouse models. Finally, in a proof-of-concept translational context, we were able to visualize differential allogeneic immune synapse formation in polyclonal CD4(+) T cells using high-throughput imaging flow cytometry. PMID- 26603028 TI - Nuclear-localized AtHSPR links abscisic acid-dependent salt tolerance and antioxidant defense in Arabidopsis. AB - Salt stress from soil or irrigation water limits plant growth. A T-DNA insertion mutant in C24, named athspr (Arabidopsis thaliana heat shock protein-related), showed several phenotypes, including reduced organ size and enhanced sensitivity to environmental cues. The athspr mutant is severely impaired under salinity levels at which wild-type (WT) plants grow normally. AtHSPR encodes a nuclear localized protein with ATPase activity, and its expression was enhanced by high salinity and abscisic acid (ABA). Overexpression (OE) of AtHSPR significantly enhanced tolerance to salt stress by increasing the activities of the antioxidant system and by maintaining K(+) /Na(+) homeostasis. Quantitative RT-PCR analyses showed that OE of AtHSPR increased the expression of ABA/stress-responsive, salt overly sensitive (SOS)-related and antioxidant-related genes. In addition, ABA content was reduced in athspr plants with or without salt stress, and exogenous ABA restored WT-like salt tolerance to athspr plants. athspr exhibited increased leaf stomatal density and stomatal index, slower ABA-induced stomatal closure and reduced drought tolerance relative to the WT. AtHSPR OE enhanced drought tolerance by reducing leaf water loss and stomatal aperture. Transcript profiling in athspr showed a differential salt-stress response for genes involved in accumulation of reactive oxygen species (ROS), ABA signaling, cell death, stress response and photosynthesis. Taken together, our results suggested that AtHSPR is involved in salt tolerance in Arabidopsis through modulation of ROS levels, ABA dependent stomatal closure, photosynthesis and K(+) /Na(+) homeostasis. PMID- 26603029 TI - Asymmetrical cross-talk between the endoplasmic reticulum stress and oxidative stress caused by dextrose. AB - AIMS: Oxidative and endoplasmic reticulum (ER) stresses are implicated in premature cardiovascular disease in people with diabetes. The aim of the present study was to characterize the nature of the interplay between the oxidative and ER stresses to facilitate the development of therapeutic agents that can ameliorate these stresses. MAIN METHODS: Human coronary artery endothelial cells were treated with varying concentrations of dextrose in the presence or absence of three antioxidants (alpha tocopherol, ascorbate and ebselen) and two ER stress modifiers (ERSMs) (4-phenylbutyrate and taurodeoxycholic acid). ER stress was measured using the placental alkaline phosphatase assay and superoxide (SO) generation was measured using the superoxide-reactive probe 2-methyl-6-(4 methoxyphenyl)-3,7-dihydroimidazo[1,2-A]pyrazin-3-one hydrochloride chemiluminescence. KEY FINDINGS: The SO generation was increased with increasing concentrations of dextrose. The ER stress was increased with both low (0 and 2.75 mM) and high (13.75 and 27.5 mM) concentrations of dextrose. The antioxidants inhibited the dextrose induced SO production while in high concentrations they aggravated ER stress. The ERSM reduced ER stress and potentiated the efficacy of the three antioxidants. Tunicamycin-induced ER stress was not associated with increased SO generation. Time course experiments with a high concentration of dextrose or by overexpressing glucose transporter one in endothelial cells revealed that dextrose induced SO generation undergoes adaptive down regulation within 2 h while the ER stress is sustained throughout 72 h of observation. SIGNIFICANCE: The nature of the cross talk between oxidative stress and ER stress induced by dextrose may explain the failure of antioxidant therapy in reducing diabetes complications. PMID- 26603030 TI - Pipeline embolization device thrombosis induced peri-construct collateral channels. AB - More than half a decade of experience and follow-up has now been accumulated with regard to flow diversion as a treatment for intracranial aneurysms; however, many uncertainties, such as the nature of aneurysmal remnants and the meaning of non regressed, non-perfused aneurysmal masses, are still unknown. Here we discuss a 22-year-old man who presented with a grade 1 subarachnoid hemorrhage secondary to a dissecting right anterior cerebral artery aneurysm who was subsequently treated with a Pipeline Embolization Device construct. After ceasing dual antiplatelet therapy himself, he was found on MRI to have an area of increased aneurysmal remnant reperfusion. This was found to connect to multiple channels which reconstituted flow within the distal construct on angiography. The central area of construct thrombosis could not be visualized on MRI. The finding suggests that non-opacified aneurysmal remnants that have not regressed are biologically active and raises concerns regarding using MRI for long term follow-up. PMID- 26603031 TI - Headway Duo microcatheter for cerebral arteriovenous malformation embolization with n-BCA. AB - BACKGROUND: Cerebral arteriovenous malformations (AVMs) are uncommon vascular lesions, and hemorrhage secondary to AVM rupture results in significant morbidity and mortality. AVMs may be treated by endovascular embolization, and technical advances in microcatheter design are likely to improve the success and safety of endovascular embolization of cerebral AVMs. OBJECTIVE: To describe our early experience with the Headway Duo microcatheter for embolization of cerebral AVMs with n-butyl-cyanoacrylate (n-BCA). METHODS: Consecutive patients treated by endovascular embolization of a cerebral AVM with n-BCA delivered intra-arterially through the Headway Duo microcatheter (167 cm length) were identified. Patient demographic information, procedural details, and patient outcome were determined from electronic medical records. RESULTS: Ten consecutive patients undergoing cerebral AVM embolization using n-BCA injected through the Headway Duo microcatheter were identified. Presenting symptoms included headache, hemorrhage, seizures, and weakness. Spetzler Martin grades ranged from 1 to 5, and AVMs were located in the basal ganglia (2 patients), parietal lobe (4 patients), frontal lobe (1 patient), temporal lobe (1 patient), an entire hemisphere (1 patient), and posterior fossa (1 patient). 50 arterial pedicles were embolized, and all procedures were technically successful. There was one post-procedural hemorrhage that was well tolerated by the patient, and no other complications occurred. Additional AVM treatment was performed by surgery and radiation therapy. CONCLUSIONS: The Headway Duo microcatheter is safe and effective for embolization of cerebral AVMs using n-BCA. The trackability and high burst pressure of the Headway Duo make it an important and useful tool for the neurointerventionalist during cerebral AVM embolization. PMID- 26603032 TI - Association of Hospital and Physician Characteristics and Care Processes With Racial Disparities in Procedural Outcomes Among Contemporary Patients Undergoing Coronary Artery Bypass Grafting Surgery. AB - BACKGROUND: Previous studies have reported that black patients undergoing coronary artery bypass surgery had worse outcomes than white patients, even after accounting for patient factors. The degree to which clinician, hospital, and care factors account for these outcome differences remains unclear. METHODS AND RESULTS: We evaluated procedural outcomes in 11,697 blacks and 136,362 whites undergoing isolated coronary artery bypass surgery at 663 Society of Thoracic Surgery Database participating sites (January 1, 2010 to June 30, 2011) adjusted for patients' clinical and socioeconomic features, hospital and surgeon effects, and care processes (internal mammary artery graft and perioperative medications use). Relative to whites, blacks undergoing coronary artery bypass surgery were younger, yet had higher comorbidities and more adverse presenting features. Blacks were also more likely to be treated at hospitals with higher risk-adjusted mortality. The use of internal mammary artery was marginally lower in blacks than in whites (93.3% versus 92.2%, P<0.0001). Unadjusted mortality and major morbidity rates were higher in blacks than in whites (1.8% versus 2.5%, P<0.0001) and (13.6% versus 19.4%, P<0.0001), respectively. These racial differences in outcomes narrowed but still persisted after adjusting for surgeon, hospital, and care processes in addition to patient and socioeconomic factors (odds ratio, 1.17; 95% confidence interval, 1.00-1.36 and odds ratio, 1.26; 95% confidence interval, 1.19-1.34, respectively). CONCLUSIONS: The risks of procedural mortality and morbidity after coronary artery bypass surgery were higher among black patients than among white patients. These differences were in part accounted for by patient comorbidities, socioeconomic status, and surgeon, hospital, and care factors, as well, as suggested by the reduction in the strength of the race-outcomes association. However, black race remained an independent predictor of outcomes even after accounting for these differences. PMID- 26603033 TI - Black Lives Do Matter. PMID- 26603034 TI - Under Utilization of Pancreas Transplants in Cystic Fibrosis Recipients in the United Network Organ Sharing (UNOS) Data 1987-2014. AB - Despite a high prevalence of pancreatic endocrine and exocrine insufficiency in cystic fibrosis (CF), pancreas transplantation is rarely reported. United Network for Organ Sharing (UNOS) data were used to examine utilization of pancreas transplant and posttransplant outcomes in CF patients. Between 1987-2014, CF patients (N = 4600) underwent 17 liver-pancreas, three lung-pancreas, one liver lung pancreas, four kidney-pancreas, and three pancreas-only transplants. Of the 303 CF patients who received liver transplantation, 20% had CF-related diabetes (CFRD) before transplantation, and nine of those received a liver-pancreas transplant. Of 4241 CF patients who underwent lung transplantation, 33% had CFRD before transplantation, and three of those received a pancreas transplant. Of 49 CF patients who received a liver-lung transplant, 57% had CFRD before transplantation and one received a pancreas transplant. Posttransplantation diabetes developed in 7% of CF pancreas transplant recipients versus 24% of CF liver and 29% of CF lung recipients. UNOS has no data on pancreas exocrine insufficiency. Two-year posttransplantation survival was 88% after liver-pancreas transplant, 33% after lung-pancreas transplant, and 100% after pancreas-kidney and pancreas-only transplants. Diabetes is common pretransplantation and posttransplantation in CF solid organ transplant recipients, but pancreas transplantation remains rare. Further consideration of pancreas transplant in CF patients undergoing other solid organ transplant may be warranted. PMID- 26603035 TI - Kidney transplantation in infantile myofibromatosis and fibromuscular dysplasia: a case report. AB - INTRODUCTION: We report what we believe to be the first case of a child affected by two rare vascular diseases complicated by kidney failure and successfully treated by kidney transplantation. CASE PRESENTATION: A 3-year-old Caucasian girl with fibromuscular dysplasia and infantile myofibromatosis presented with arterial hypertension and renal failure. She received a deceased donor kidney transplantation distal to an iliac graft. The technical peculiarities of this transplantation are described, as well as her favorable long-term outcome. CONCLUSION: Kidney transplantation may be considered in a patient with vascular diseases and a history of iliac surgery. PMID- 26603036 TI - Social support and HIV/STDs infections among a probability-based sample of rural married migrant women in Shandong Province, China. AB - BACKGROUND: The increasing population of marriage-based migrant women is disproportionally affected by AIDS/STDs in China, and social support plays a critical role. This study aims to describe the social support level received by married migrant women in rural areas in Shandong province in comparison to non migrant local women, identifies the relevant factors of this social support condition among married migrant women, and observes the correlation between social support level and infection status of AIDS and STDs among this group. METHODS: A probability-based sample of 1,076 migrant and 1,195 local women were included in the study. A pre-tested field questionnaire was administered to participants through a direct face-to-face interview. Questionnaire contained questions on socio-demographic information, AIDS and STDs prevalence information and Social Support Rating Scale (SSRS) which measures objective support, subjective support, and utilization of social support. RESULTS: Compared to local women, married migrant women had lower levels of social support in most dimensions. Multi-variable analysis revealed that relationship with spouse, family average income, number of children, education, engagement and claimed reasons of moving have various correlations with one or all dimensions of social support scores. Higher social support is also related to awareness of infection status of HIV and STDs among this group. CONCLUSION: Our findings provide further evidence that married migrant women have lower levels of social support which may be related to some social characteristics and their awareness status of AIDS and STDs infection status and that targeted interventions need to be developed for this population. PMID- 26603037 TI - High quality, patient centred and coordinated care for Alstrom syndrome: a model of care for an ultra-rare disease. AB - BACKGROUND: Patients with rare and ultra-rare diseases make heavy demands on the resources of both health and social services, but these resources are often used inefficiently due to delays in diagnosis, poor and fragmented care. We analysed the national service for an ultra-rare disease, Alstrom syndrome, and compared the outcome and cost of the service to the standard care. METHODS: Between the 9th and 26th of March 2014 we undertook a cross-sectional study of the UK Alstrom syndrome patients and their carers. We developed a semi-structured questionnaire to assess our rare patient need, quality of care and costs incurred to patients and their careers. In the UK all Alstrom syndrome patients are seen in two centres, based in Birmingham, and we systematically evaluated the national service and compared the quality and cost of care with patients' previous standard of care. RESULTS: One quarter of genetically confirmed Alstrom syndrome UK patients were enrolled in this study. Patients that have access to a highly specialised clinical service reported that their care is well organised, personalised, holistic, and that they have a say in their care. All patients reported high level of satisfaction in their care. Patient treatment compliance and clinic attendance was better in multidisciplinary clinic than the usual standard of NHS care. Following a variable costing approach based on personnel and consumables' cost, our valuation of the clinics was just under L700/patient/annum compared to the standard care of L960/patient/annum. Real savings, however, came in terms of patients' quality of life. Furthermore there was found to have been a significant reduction in frequency of clinic visits and ordering of investigations since the establishment of the national service. CONCLUSIONS: Our study has shown that organised, multidisciplinary "one stop" clinics are patient centred and individually tailored to the patient need with a better outcome and comparable cost compared with the current standard of care for rare disease. Our proposed care model can be adapted to several other rare and ultra-rare diseases. PMID- 26603038 TI - Comments on the relationship between green tea consumption and the risk of endometrial cancer. PMID- 26603039 TI - Thromboelastometry versus free-oscillation rheometry and enoxaparin versus tinzaparin: an in-vitro study comparing two viscoelastic haemostatic tests' dose responses to two low molecular weight heparins at the time of withdrawing epidural catheters from ten patients after major surgery. AB - BACKGROUND: Monitoring low molecular weight heparins (LMWH's) in the perioperative period is prudent in patients at high risk of coagulative complications, especially when the patient has an epidural catheter requiring withdrawal, which is associated with the risk of spinal haematoma. The aim of this study was to evaluate the in vitro dose-responses of two different LMWH's on two different viscoelastic haemostatic tests, using blood sampled from patients with normal routine coagulation parameters, on the day after major surgery when their epidural catheters were due to be withdrawn. METHODS: Enoxaparin or tinzaparin were added in vitro to blood from ten patients who had undergone oesophageal resection, to obtain plasma concentrations of approximately 0, 0.5, 1.0 and 1.5 IU/mL. Coagulation was monitored using thromboelastometry (ROTEM(r)) using the InTEM(r) activating reagent; and free oscillation rheometry (FOR: ReoRox(r)), activated using thromboplastin. Clot initiation was measured using ROTEM-CT, ReoRox-COT1 and ReoRox-COT2. Clot propagation was measured using ROTEM CFT, ROTEM-Alpha Angle and ReoRox-Slope. Clot stability was measured using ROTEM MCF and ReoRox-G'max, and clot lysis was measured using ROTEM-ML and ReoRox ClotSR. RESULTS: Clot initiation time assessed by thromboelastometry and FOR was prolonged by increasing concentrations of both LMWH's (P < 0.01). Equivalent doses of tinzaparin in international units (anti-FXa units) per millilitre prolonged clot initiation more than enoxaparin (P < 0.05). There was significant inter-individual variation - the ranges of CT and COT1 at LMWH-concentrations of 0 and 1.5 IU/mL overlapped. None of the tests reflecting clot formation rate or stability showed a dose-response to either LMWH but clot lysis showed a tentative negative dose-response to the LMWH's. CONCLUSIONS: Clot initiation time's dose dependent prolongation by LMWH's in this study agrees with previous research, as does tinzaparin's stronger anti-coagulative effect than enoxaparin at equivalent levels of anti-FXa activity. This casts doubt on the validity of using anti-FXa assays alone to guide dosage of LMWH's. The significant inter-individual variation in dose-response suggests that the relationship between dose and effect in the postoperative period is complicated. While both ROTEM and FOR may have some role in postoperative monitoring, more research is needed before any conclusion can be made about their clinical usefulness. PMID- 26603041 TI - Palm board and verbal estimates of slant reflect the same perceptual representation. AB - People verbally overestimate the orientation of slanted surfaces, but accurately estimate or underestimate slanted surfaces using a palm board. We demonstrate a fundamental issue that explains why the two different values typically given for palm board and verbal/visual matching estimates express similar perceptual representations of slanted surfaces. The fundamental problem in studies measuring palm board and verbal estimates is that the "measure"-either (1) reproducing a verbally given angle or the orientation of a slanted surface with an unseen hand or (2) verbally or visually estimating a visually perceived surface-has always been confounded with the "surface"-either using (1) a palm board or (2) a hill or ramp. Although reproduction has exclusively been used with palm boards in these studies, at the same time verbal estimation or visual matching has exclusively been used with hills/ramps. In three experiments, we showed that verbally estimating palm board orientations produces overestimates by a factor of 1.5, whereas reproducing the orientation of the surface of a ramp to verbally given angles produces gains of ~0.6. These values are similar to those seen for verbal overestimates of slanted surfaces, and to palm board gains for near surfaces and the relative palm-board-to-verbal gains for outdoor hills, respectively. Eliminating this confound eliminated the difference previously seen across surfaces. We discuss how and why different measures should produce different results if we overestimate slant in general and perceptually represent slant in the same way, both haptically and visually. PMID- 26603040 TI - The whole is faster than its parts: evidence for temporally independent attention to distinct spatial locations. AB - Behavioral and electrophysiological evidence suggests that visual attention operates in parallel at distinct spatial locations and samples the environment in periodic episodes. This combination of spatial and temporal characteristics raises the question of whether attention samples locations in a phase-locked or temporally independent manner. If attentional sampling rates were phase locked, attention would be limited by a global sampling rate. However, if attentional sampling rates were temporally independent, they could operate additively to sample higher rates of information. We tested these predictions by requiring participants to identify targets in 2 or 4 rapid serial visual presentation (RSVP) streams, synchronized or asynchronized to manipulate the rate of new information globally (across streams). Identification accuracy exhibited little or no change when the global rate of new information doubled from 7.5 to 15 Hz (Experiment 1) or quadrupled to 30 Hz (Experiment 2). This relatively stable identification accuracy occurred even though participants reliably discriminated 7.5 Hz synchronous displays from displays globally asynchronized at 15 and 30 Hz (Metamer Control Experiment). Identification accuracy in the left visual field also significantly exceeded that in the right visual field. Overall, our results are consistent with temporally independent attention across distinct spatial locations and support previous reports of a right parietal "when" pathway specialized for temporal attention. PMID- 26603042 TI - The Simon effect based on the egocentric and allocentric reference frame. AB - The classic Simon effect refers to the phenomenon that responses are faster when the task-irrelevant egocentric stimulus location is on the same side as the response hand than when not. However, the spatial location of an object often varies according to which reference frame the object location was represented in, e.g., egocentric versus allocentric reference frame. It has been unknown, however, whether and how the Simon effect based on the egocentric and the allocentric reference interact, and whether the potential interaction between them is affected by task demands. To investigate these questions, we orthogonally crossed the stimulus-response compatibility induced by the egocentric and the allocentric positions during the Simon effect. Moreover, the irrelevant egocentric and allocentric positions were either explicitly represented via interleaving spatial and non-spatial tasks in Experiment 1 or not in Experiment 2. The results suggested that the Simon effect based on the egocentric locations occurred irrespective of whether the egocentric representations were explicitly coded based on current task demands or not. The Simon effect based on allocentric locations, however, seemed to occur only when the allocentric representations were explicitly induced. Moreover, the egocentric and allocentric Simon effect interacted in a similar way irrespective of task demands, with significantly delayed responses when both the egocentric and the allocentric locations were incongruent with the response code. PMID- 26603043 TI - Revisiting the importance of common body motion in human action perception. AB - Human actions are complex dynamic stimuli comprised of two principle motion components: 1) common body motion, which represents the translation of the body when a person moves through space, and 2) relative limb movements, resulting from articulation of limbs after factoring out common body motion. Historically, most research in biological motion has focused primarily on relative limb movements while discounting the role of common body motion in human action perception. The current study examined the relative contribution of posture change resulting from relative limb movements and translation of body position resulting from common body motion in discriminating human walking versus running actions. We found that faster translation speeds of common body motion evoked significantly more responses consistent with running when discriminating ambiguous actions morphed between walking and running. Furthermore, this influence was systematically modulated by the uncertainty associated with intrinsic cues as determined by the degree of limited-lifetime spatial sampling. The contribution of common body motion increased monotonically as the reliability of inferring posture changes on the basis of intrinsic cues decreased. These results highlight the importance of translational body movements and their interaction with posture change as a result of relative limb movements in discriminating human actions when visual input information is sparse and noisy. PMID- 26603045 TI - Homicide in Greenland 1985-2010. AB - PURPOSE: Homicide in Greenland has not often been investigated. The latest published study documented a dramatic rise in the homicide rate from around 1/100,000 inhabitants to more than 23/100,000 inhabitants from 1946 to 1984. The aim of our study was to characterize homicides in Greenland from 1985 to 2010 and to compare trends during this period with those in previous studies and with homicide characteristics in Denmark, northern Europe, and other Arctic regions. METHODS: We identified a total of 281 homicides by legal definition and 194 by medical definition, the latter from the years 1990 to 2010. We procured case files for a total of 129 victims (71 male, 58 female) and 117 perpetrators (85 male, 32 female). RESULTS: We identified an overall decrease in the homicide rate during our study period. The decrease in the medical homicide rate was significant (p = 0.007). The homicide rate ranged from 25/100,000 inhabitants to 13/100,000 inhabitants when results were grouped within 5-year periods. There were significantly more male perpetrators (p < 0.001) and among female perpetrators there were significantly more male victims (p < 0.001). Sharp force and gunshot-related killings dominated homicide methods (41 and 29% respectively), with sharp force deaths increasing throughout the investigation period. Altercations were the main motive (49%). Alcohol-related homicides decreased in our study period. CONCLUSIONS: While the Greenlandic homicide rate has decreased, it is markedly higher compared to that seen in Denmark and northern Europe. However, it resembles the rate seen in the rest of the Arctic. Liberal gun laws do not affect the proportion of gun-related killings. Despite the high homicide rate, women account for almost half the victims. PMID- 26603046 TI - Born to roam? Surveying cat owners in Tasmania, Australia, to identify the drivers and barriers to cat containment. AB - Free-roaming domestic cats, Felis catus, are a major public nuisance in neighbourhoods across the world, and have been linked to biodiversity loss and a host of community health problems. Owners who let their cats roam, also place their cats at risk of serious injury. One management strategy that is gaining considerable support involves encouraging cat owners to contain their pets within their property. Contemporary behaviour change models highlight the importance of identifying drivers and barriers that encourage and discourage target behaviours such as cat containment. Results from a random dial phone survey of 356 cat owners in northern Tasmania identified four distinct cat containment profiles: owners who contained their cat all the time, owners who only contained their cat at night, owners who sporadically contained their cat with no set routine, and owners who made no attempt to contain their pet. Our results indicated that cat owners' decisions to contain or not contain their cats were guided by a range of factors including owners' beliefs about their ability to implement an effective containment strategy and their views about the physical and psychological needs of their cats. The results are discussed in terms of improving the behavioural effectiveness of cat containment interventions by selecting appropriate behavioural change tools for the identified drivers and barriers, and developing targeted engagement strategies and messaging. PMID- 26603044 TI - Response of Cytokines and Hydrogen Peroxide to Sporothrix schenckii Exoantigen in Systemic Experimental Infection. AB - The response of hydrogen peroxide (H2O2) and cytokines during an experimental sporotrichosis in male Swiss mice was assessed over a period of 10 weeks by monitoring macrophage activation challenged with exoantigen (ExoAg) from the fungus Sporothrix schenckii. The studied endpoints were: H2O2 production, fungal burden at spleen, apoptosis in peritoneal macrophages, and IL-1beta, IL-6, IL-2, IL-10 production. During the two first weeks of infection was observed low burden of yeast in spleen and high response of H2O2, IL-2, and IL-1beta. The weeks of highest fungal burden (fourth-sixth) coincided with major apoptosis in peritoneal macrophages, normal production of IL-6 and lower production of H2O2, IL-2, and IL 1beta, suggesting a role for these three last in the early control of infection. On the other hand, IL-1beta (but not IL-6) was recovered since the sixth week, suggesting a possible role in the late phase of infection, contributing to the fungal clearance in conjunction with the specific mechanisms. The IL-10 was elevated until the sixth, principally in the second week. These results evidences that ExoAg is involved in the host immune modulation, influencing the S. Schenckii virulence, and its role is related with the time of the infection in the model used. PMID- 26603047 TI - The causes and prognoses of different types of fractures in wild koalas submitted to wildlife hospitals. AB - Fractures are a major problem in wild koalas of great veterinary and conservation importance as their occurrence in different locations of the body might result in varying healing success. The aim of this study was to determine the fracture types (defined by location of the fracture) occurring in wild koalas, temporal patterns, possible causes and risk factors of fracture types, and the prognosis for successfully releasing kolas with healed fracture types into the wild. Data from a total of 2031 wild koalas submitted to wildlife hospitals in South-East Queensland, Australia, over a period of 13 years were analysed. Approximately 56.7% of koalas experienced head fractures, 13.4% had torso fractures, 14.9% had limb fractures and 15% had combination fractures. A total of 84.1% of fractures were caused by vehicle collisions, 9.1% by dog attacks, 3.3% by falls from trees, 1.3% by train collisions, 0.2% by livestock trampling and 1.8% due to unknown causes. Multinominal logistic regression was used to identify risk factors (cause of fracture, age category, sex, year, three-year admission period and season of fracture event) by fracture type. The type of fracture was associated with both the cause of the fracture and the season when it occurred: for example torso fractures (compared to combination fractures) were associated with dog attacks (OR=10.98; 95% CI6.03, 20.01) and falls from trees (OR=4.79; 95% CI2.26, 10.19) relative to vehicle collisions. More submissions of koalas with head fractures due to vehicle collisions occurred in spring compared to autumn and winter, coinciding with the breeding season of koalas and increased animal movement. Prognosis for koalas with fractures was poor, with approximately 63.8% of koalas admitted dead on arrival, 34.2% euthanised, and only 2.0% of koalas able to be released. Given this data, further research into mitigation strategies to decrease the risk of fractures and to increase the observed low recovery rate should be considered. PMID- 26603048 TI - Retrospective testing and case series study of porcine delta coronavirus in U.S. swine herds. AB - Porcine deltacoronavirus (PDCoV) was first reported in the United States (US) in February 2014. This was the second novel swine enteric coronavirus detected in the US since May 2013. In this study, we conducted retrospective testing of samples submitted to three veterinary diagnostic laboratories where qualifying biological samples were derived from previously submitted diagnostic case submissions from US commercial swine farms with a clinical history of enteric disease or from cases that had been previously tested for transmissible gastroenteritis virus, PEDV, or rotavirus. Overall, 2286 banked samples were tested from 27 States. Samples were collected in 3 separate years and in 17 different months. Test results revealed 4 positive samples, 3 collected in August 2013 and 1 collected in October 2013. In addition, a case series including 42 operations in 10 States was conducted through administration of a survey. Survey data collected included information on characteristics of swine operations that had experienced PDCoV clinical signs. Special emphasis was placed on obtaining descriptive estimates of biosecurity practices and disease status over time of each operation. Clinical signs of PDCoV were reported to be similar to those of PEDV. The average number of animals on each operation exhibiting clinical signs (morbidity) and the average number of case fatalities was greatest for suckling and weaned pigs. Average operation-level weaned pig morbidity was greatest in the first week of the outbreak while average operation-level suckling pig case fatality was greatest in the second week of the outbreak. The survey included questions regarding biosecurity practices for visitors and operation employees; trucks, equipment and drivers; and feed sources. These questions attempted to identify a likely pathway of introduction of PDCoV onto the operations surveyed. PMID- 26603049 TI - Evaluation of cognitive functions of juvenile myoclonic epileptic patients by magnetic resonance spectroscopy and neuropsychiatric cognitive tests concurrently. AB - Our aim in this research is investigating the hypothesis of biochemical changes in frontal cortex and thalamocortical pathways in juvenile myoclonic epilepsy (JME) and the interaction between the biochemical changes and cortical functions. Magnetic resonance spectroscopy (MRS) was applied to 20 JME patients and 20 controls for measuring N-acetyl aspartate (NAA), N-acetyl aspartate to creatine ratio (NAA/Cr), Glutamine and Glutamate (GLX), Glutamine-Glutamate to creatine (GLX/Cr), Choline containing compounds (Cho) and Choline to creatine (Cho/Cr) levels. Neuropsychological cognitive tests for linguistic and visual attention, linguistic and visual memory, visuospatial and executive functions were applied to all participants. NAA and NAA/Cr concentrations were found lower in bilateral frontal and thalamic regions in JME group as compared with the control group (p < 0.05). There was no difference in frontal and thalamic GLX, GLX/Cr, Cho, Cho/Cr levels in between JME patients and controls (p > 0.05). JME patients were found more unsuccessful than the controls in attention, memory, visuospatial function, verbal fluency, Trail B test and executive functions, stroop test, clock drawing test and Trail A test (p < 0.05). Prefrontal NAA/Cr level was positively related to visual attention, memory, stroop test and thalamic NAA/Cr level was positively related to linguistic memory and Wisconsin card sorting test in JME patients. This research highlights regional brain changes and cognitive decline in JME patients and suggests that MRS may be a sensitive technique for showing subclinical cognitive changes. PMID- 26603050 TI - Minimally Invasive Unilateral vs. Bilateral Pedicle Screw Fixation and Lumbar Interbody Fusion in Treatment of Multi-Segment Lumbar Degenerative Disorders. AB - BACKGROUND The choice for instrumentation with minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) in treatment of degenerative lumbar disorders (DLD) remains controversial. The goal of this study was to investigate clinical outcomes in consecutive patients with multi-segment DLD treated with unilateral pedicle screw (UPS) vs. bilateral pedicle screw (BPS) instrumented TLIF. MATERIAL AND METHODS Eighty-four consecutive patients who had multi-level MIS-TLIF were retrospectively reviewed. All data were collected to compare the clinical outcomes between the 2 groups. RESULTS Both groups showed similar clinical function scores in VAS and ODI. The two groups differed significantly in operative time (P<0.001), blood loss (P<0.001), and fusion rate (P=0.043), respectively. CONCLUSIONS This study demonstrated similar clinical outcomes between UPS fixation and BPS procedure after MIS-TLIF for multi-level DLD. Moreover, UPS technique was superior in operative time and blood loss, but represented lower fusion rate than the BPS construct did. PMID- 26603052 TI - Highlight report: critical evaluation of key evidence on health hazards of the general European population by exposure to arsenic. PMID- 26603051 TI - Effect of some commonly used pesticides on seed germination, biomass production and photosynthetic pigments in tomato (Lycopersicon esculentum). AB - Pesticides are highly toxic substances. Their toxicity may not be absolutely specific to the target organisms but can adversely affect different processes in the non-target host plants. In the present study, the effect of over application of four commonly used pesticides (emamectin benzoate, alpha-cypermethrin, lambda cyhalothrin and imidacloprid) was evaluated on the germination, seedling vigor and photosynthetic pigments in tomato. The obtained results revealed that seed germination was decreased by the pesticides and this effect was more prominent at early stages of exposure. All the tested pesticides reduced the growth of tomato when applied in higher concentration than the recommended dose, but at lower doses the pesticides had some stimulatory effects on growth as compared to the control. A similar effect of pesticides was observed on the photosynthetic pigments, i.e. a decrease in pigments concentrations was caused at higher doses but an increase was observed at lower doses of pesticides. The calculation of EC50 values for different parameters revealed the lowest EC50 values for emamectin (ranged as 51-181 mg/L) followed by alpha-cypermethrin (191.74-374.39), lambda-cyhalothrin (102.43-354.28) and imidacloprid (430.29-1979.66 mg/L). A comparison of the obtained EC50 values for different parameters of tomato with the recommended doses revealed that over application of these pesticides can be harmful to tomato crop. In a few cases these pesticides were found toxic even at the recommended doses. However, a field based study in this regard should be conducted to further verify these results. PMID- 26603053 TI - Efficacy of a 2% climbazole shampoo for reducing Malassezia population sizes on the skin of naturally infected dogs. AB - OBJECTIVE OF THE STUDY: Shampoo therapy is often recommended for the control of Malassezia overgrowth in dogs. The aim of this study was to evaluate the in vivo activity of a 2% climbazole shampoo against Malassezia pachydermatis yeasts in naturally infected dogs. ANIMALS: Eleven research colony Beagles were used. MATERIALS AND METHODS: The dogs were distributed randomly into two groups: group A (n=6) and group B (n=5). Group A dogs were washed with a 2% climbazole shampoo, while group B dogs were treated with a physiological shampoo base. The shampoos were applied once weekly for two weeks. The population size of Malassezia yeasts on skin was determined by fungal culture through modified Dixon's medium contact plates pressed on left concave pinna, axillae, groins, perianal area before and after shampoo application. Samples collected were compared by Wilcoxon rank sum test. RESULTS: Samples collected after 2% climbazole shampoo application showed a significant and rapid reduction of Malassezia population sizes. One hour after the first climbazole shampoo application, Malassezia reduction was already statistically significant and 15 days after the second climbazole shampoo, Malassezia population sizes were still significantly decreased. No significant reduction of Malassezia population sizes was observed in group B dogs. CONCLUSION: The application of a 2% climbazole shampoo significantly reduced Malassezia population sizes on the skin of naturally infected dogs. Application of 2% climbazole shampoo may be useful for the control of Malassezia overgrowth and it may be also proposed as prevention when recurrences are frequent. PMID- 26603054 TI - Trends in percutaneous coronary intervention from 2004 to 2013 according to the Portuguese National Registry of Interventional Cardiology. AB - INTRODUCTION AND OBJECTIVES: The aim of the present paper is to report trends in Portuguese interventional cardiology from 2004 to 2013 and to compare them with other European countries. METHODS: Based on the Portuguese National Registry of Interventional Cardiology and on official data from the Directorate-General of Health, we give an overview of developments in coronary interventions from 2004 to 2013. RESULTS: In 2013, 36 810 diagnostic catheterization procedures were performed, representing an increase of 34% compared to 2007 and a rate of 3529 coronary angiograms per million population. Coronary interventions increased by 65% in the decade from 2004 to 2013, with a total of 13 897 procedures and a rate of 1333 coronary interventions per million population in 2013. Primary percutaneous coronary intervention (PCI) increased by 265% from 2004 to 2013 (1328 vs. 3524), an adjusted rate of 338 primary PCIs per million, representing 25% of total angioplasties. Stents were the most frequently used devices, drug eluting stents being used in 73% in 2013. Radial access increased from 4.1% in 2004 to 57.9% in 2013. CONCLUSION: Interventional cardiology in Portugal has been expanding since 2004. We would emphasize the fact that in 2013 all Portuguese interventional cardiology centers were participating in the National Registry of Interventional Cardiology, as well as the growth in primary PCI and increased use of radial access. PMID- 26603055 TI - Therapy-Induced Cellular Senescence Induces Epithelial-to-Mesenchymal Transition and Increases Invasiveness in Rectal Cancer. AB - INTRODUCTION: DNA damaging agents and ionizing radiation used in the therapy of human cancers can induce senescence of cancer cells. Senescent cells exhibit a secretory phenotype (senescence-associated secretome [SAS]) that can affect cancer cell behavior and, eventually, clinical prognosis. We assessed the effects of the SAS on the induction of epithelial-to-mesenchymal transition (EMT) in vitro and in clinical samples from patients with rectal cancer who had undergone neoadjuvant chemoradiotherapy (CRT). MATERIALS AND METHODS: Colorectal cancer cells (HCT 116) were induced into senescence by exposure to either 5-fluorouracil (5-FU) or doxorubicin. The senescent state was confirmed by staining for senescence-associated beta-galactosidase (SA-beta-Gal). The paracrine effects of SASs were assessed on proliferating HCT 116 cells. The quantified parameters were cell proliferation, invasive capacity, and induction of EMT. Senescence and EMT in clinical samples were assessed by the expression levels (reverse transcriptase quantitative polymerase chain reaction) of genes related to senescence and EMT after laser-assisted microdissection of cancer cell clusters that stained either positive or negative for SA-beta-Gal. RESULTS: We have shown that cultured colon cancer cells induced into senescence by exposure to 5-FU exhibit a SAS capable of paracrine induction of EMT in colon and rectal cancer cell lines and increased cell invasion in vitro. Using laser-assisted microdissection, we found that in rectal cancer samples from patients treated with neoadjuvant CRT, tumor cell niches enriched for senescent cells bookmark regions of increased mRNA expression levels of EMT-related proteins (Slug, Snail, vimentin) compared with the nearby senescent-null tumor cell niches. CONCLUSION: We have provided, first-hand, strongly suggestive evidence that senescent cancer cells emerging in the context of neoadjuvant CRT for rectal cancer influenced the tumor microenvironment by promoting EMT by way of short-range interactions. PMID- 26603056 TI - Rationale and Design for the LUME-Colon 1 Study: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Nintedanib Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in Patients With Advanced Colorectal Cancer Refractory to Standard Treatment. AB - BACKGROUND: Clinical studies of antivascular endothelial growth factor (anti VEGF) agents have demonstrated that angiogenesis is critical to colorectal cancer (CRC) tumor growth and metastasis. Nintedanib is a triple angiokinase inhibitor of VEGF, platelet-derived growth factor, and fibroblast growth factor signaling. Nintedanib, combined with docetaxel, has been approved in the European Union for the treatment of patients with non-small-cell lung cancer with adenocarcinoma tumor histologic type after first-line chemotherapy. The objective of the present study (1199.52; clinicaltrials.gov identifier NCT02149108; LUME-Colon 1) is to evaluate the efficacy and safety of nintedanib plus best supportive care (BSC) in patients with advanced colorectal cancer refractory to standard chemotherapy regimens and biologic agents. PATIENTS AND METHODS: A total of 764 patients worldwide will be randomized 1:1 to receive either nintedanib 200 mg twice daily plus BSC or placebo plus BSC in 21-day courses until disease progression, undue toxicity, or withdrawal of informed consent. The primary endpoints are progression-free survival (PFS) and overall survival (OS). The secondary endpoints are the objective tumor response and disease control. PFS and OS will be evaluated using a log-rank test to determine the effect of nintedanib independently at the 2-sided alpha-level of 0.05. Other assessments will include the frequency and severity of adverse events and changes in laboratory parameters to measure the safety, health-related quality of life, and pharmacogenomic analyses, focusing on exploring the predictive biomarkers and drug-resistance mechanisms. The results are expected in 2016. PMID- 26603057 TI - Tips and tricks for flow cytometry-based analysis and counting of microparticles. AB - Submicron-sized extra-cellular vesicles generated by budding from the external cell membranes, microparticles (MPs) are important actors in transfusion as well as in other medical specialties. After briefly positioning their role in the characterization of labile blood products, this technically oriented chapter aims to review practical points that need to be considered when trying to use flow cytometry for the analysis, characterization and absolute counting of MP subsets. Subjects of active discussions relative to instrumentation will include the choice of the trigger parameter, possible standardization approaches requiring instrument quality-control, origin and control of non-specific background and of coincidence artifacts, choice of the type of electronic signals, optimal sheath fluid and sample speed. Questions related to reagents will cover target antigens and receptors, multi-color reagents, negative controls, enumeration of MPs and limiting artifacts due to unexpected (micro-) coagulation of plasma samples. Newly detected problems are generating innovative solutions and flow cytometry will continue to remain the technology of choice for the analysis of MPs, in the domain of transfusion as well as in many diverse specialties. PMID- 26603059 TI - Phenomenology and neurobiology of self disorder in schizophrenia: Secondary factors. AB - Schizophrenia is a diverse and varying syndrome that defies most attempts at classification and pathogenetic explanation. This is the second of two articles offering a comprehensive model meant to integrate an understanding of schizophrenia-related forms of subjectivity, especially anomalous core-self experience (disturbed ipseity), with neurocognitive and neurodevelopmental findings. Previously we discussed the primary or foundational role of disturbed intermodal perceptional integration ("perceptual dys-integration"). Here we discuss phenomenological alterations that can be considered secondary in a pathogenetic sense--whether as consequential products downstream from a more originary disruption, or as defensive reactions involving quasi-intentional or even volitional compensations to the more primary disruptions. These include secondary forms of: 1, hyperreflexivity, 2, diminished self-presence (self affection), and 3. disturbed "rip" or "hold" on the cognitive/perceptual field of awareness. We consider complementary relations between these secondary abnormal experiences while also considering their temporal relationships and pathogenetic intertwining with the more primary phenomenological alterations discussed previously, all in relation to the neurodevelopmental model. The secondary phenomena can be understood as highly variable factors involving overall orientations or attitudes toward experience; they have some affinities with experiences of meditation, introspectionism, and depersonalization defense. Also, they seem likely to become more pronounced during adolescence as a result of new cognitive capacities related to development of the prefrontal lobes, especially attention allocation, executive functions, abstraction, and meta-awareness. Heterogeneity in these secondary alterations might help explain much of the clinical diversity in schizophrenia, both between patients and within individual patients over time--without however losing sight of key underlying commonalities. PMID- 26603058 TI - Subcomponents of brain T2* relaxation in schizophrenia, bipolar disorder and siblings: A Gradient Echo Plural Contrast Imaging (GEPCI) study. AB - Investigating brain tissue T2* relaxation properties in vivo can potentially guide the uncovering of neuropathology in psychiatric illness, which is traditionally examined post mortem. We use an MRI-based Gradient Echo Plural Contrast Imaging (GEPCI) technique that produces inherently co-registered images allowing quantitative assessment of tissue cellular and hemodynamic properties. Usually described as R2* (=1/T2*) relaxation rate constant, recent developments in GEPCI allow the separation of cellular-specific (R2*C) and hemodynamic (BOLD) contributions to the MRI signal decay. We characterize BOLD effect in terms of tissue concentration of deoxyhemoglobin, i.e. CDEOXY, which reflects brain activity. 17 control (CON), 17 bipolar disorder (BPD), 16 schizophrenia (SCZ), and 12 unaffected schizophrenia sibling (SIB) participants were scanned and post processed using GEPCI protocols. A MANOVA of 38gray matter regions ROIs showed significant group effects for CDEOXY but not for R2*C. In the three non-control groups, 71-92% of brain regions had increased CDEOXY. Group effects were observed in the superior temporal cortex and the thalamus. Increased superior temporal cortex CDEOXY was found in SCZ (p=0.01), BPD (p=0.01) and SIB (p=0.02), with bilateral effects in SCZ and only left hemisphere effects in BPD and SIB. Thalamic CDEOXY abnormalities were observed in SCZ (p=0.003), BPD (p=0.03) and SIB (p=0.02). Our results suggest that increased activity in certain brain regions is part of the underlying pathophysiology of specific psychiatric disorders. High CDEOXY in the superior temporal cortex suggests abnormal activity with auditory, language and/or social cognitive processing. Larger studies are needed to clarify the clinical significance of relaxometric abnormalities. PMID- 26603061 TI - A new 3D approach to evaluate facial profile changes following BSSO. AB - The purpose of this study was to evaluate changes in the soft tissue facial profile in patients who underwent bilateral sagittal split osteotomy (BSSO) using 3D stereophotogrammetry and principal component analysis (PCA). Twenty-five female patients (mean age, 24 years; range: 18-26) who underwent BSSO and 70 female controls (mean age, 24 years; range: 18-26) participated in this prospective study. Three-dimensional photographs of all patients and controls were acquired. PCA was used to determine the unique morphological variations (UV) between the dysgnathic group and the control group. The most prominent facial morphologic difference between the dysgnathic group and the control group (UV1) was a clockwise rotation of the mandible and shortening of the lower part of the face, followed by a protrusion of the upper lip, retrusion of the mandible and over-accentuation of the labial-mental fold (UV2). The combination of UV1 and UV2 could be used to simulate a typical Class II facial profile and to automatically differentiate between the preoperative patients, postoperative patients and the control group. Based on the applied PCA method, this study demonstrated that BSSO advancement surgery could only provide a suboptimal improvement of the soft tissue facial profile in the majority of cases. PMID- 26603060 TI - Neuroimaging predictors of functional outcomes in schizophrenia at baseline and 6 month follow-up. AB - PURPOSE: Studies show that deficit syndrome schizophrenia patients, characterized by primary negative symptoms and poor functional outcome, have impairment in specific neural circuits. We assessed whether these same neural circuits are directly linked to functional outcomes across schizophrenia patients. METHODS: T1 and diffusion-weighted MR images were obtained for schizophrenia (n=30) and matched healthy control participants (n=30). Negative symptoms and functional outcome were assessed at baseline and 6-month follow-up. Cortical thickness and tract-wise fractional anisotropy (FA) were compared between groups. To assess relationships of neuroimaging measures with functional outcome, principal component analysis (PCA) was performed on tract-wise FA values and components were entered into a multiple regression model for schizophrenia participants. RESULTS: Consistent with the literature, schizophrenia participants showed frontotemporal reductions in cortical thickness and tract-wise FA compared to controls. The top two components from PCA explained 71% of the variance in tract wise FA values. The second component (associated with inferior longitudinal and arcuate fasciculus FA) was significantly correlated with functional outcome (baseline: beta=0.54, p=0.03; follow-up: beta=0.74, p=0.047); further analysis revealed this effect was mediated by negative symptoms. Post-hoc network analysis revealed increased cortical coupling between right inferior frontal and supramarginal gyri (connected by the arcuate fasciculus) in schizophrenia participants with poorer functional outcome. CONCLUSIONS: Our findings indicate that impairment in the same neural circuitry susceptible in deficit syndrome schizophrenia predicts functional outcome in a continuous manner in schizophrenia participants. This relationship was mediated by negative symptom burden. Our findings provide novel evidence for brain-based biomarkers of longitudinal functional outcome in people with schizophrenia. PMID- 26603062 TI - Reliability of a Method to Evaluate Frailty Using Medical Records of Hospitalized Octogenarians. PMID- 26603063 TI - Mild Depressive Symptoms Predict Mortality from Heart Failure in Elderly Men but Not Women. PMID- 26603064 TI - Predictors of Long-Term Survival of Individuals with Acute Coronary Syndrome Aged 90 and Older Admitted to a Tertiary Care Center. PMID- 26603065 TI - Low-Frequency High-Intensity Interval Training is an Effective Method to Improve Muscle Power in Lifelong Sedentary Aging Men: A Randomized Controlled Trial. PMID- 26603066 TI - Values of a Body Mass Index Surrogate in Older Adults Using Knee Height Instead of Height. PMID- 26603067 TI - Real-World Accuracy and Use of a Wearable Fall Detection Device by Older Adults. PMID- 26603068 TI - Transdermal Dopamine Agonist Ameliorates Gastric Emptying in Parkinson's Disease. PMID- 26603069 TI - Is Long-Term Anti-Osteoporotic Treatment Associated with Greater Risk of Cancer in People with Severe Vertebral Fractures? A Hospital-Based Cohort Study. PMID- 26603070 TI - Survey Mode Biases Reporting of Activities of Daily Living and Instrumental Activities of Daily Living. PMID- 26603071 TI - Healthcare Costs in Older Adults with Diabetes Mellitus: Challenges for Health Systems and for Society. PMID- 26603072 TI - Informed Consent in Older Medical Inpatients: Assessment of Decision-Making Capacity. PMID- 26603073 TI - Long-Term Changes in Stroke-Related Hospital Admissions After the Fukushima Triple Disaster. PMID- 26603074 TI - Reducing the Risks of Morbidity, Disability, and Mortality Using Successful Aging Strategies. PMID- 26603075 TI - Metaiodobenzylguanidine Myocardial Scintigraphy Identifies Premotor Parkinson's Disease During a Negative Dopamine Transporter Scan. PMID- 26603076 TI - Social Network Size and Cranial Magnetic Resonance Imaging Findings in Older Adults: The Cardiovascular Health Study. PMID- 26603077 TI - Feasibility of Recommended Cognitive Screening Tools for Older Adults in Carehomes. PMID- 26603078 TI - Superficial Vein Thrombosis in Frail Elderly Adults. PMID- 26603079 TI - Progressive Supranuclear Palsy-An Unusual Cause of Memory Loss and Falling. PMID- 26603080 TI - Sleuthing and Syncope: The Case for Implantable Loop Recorders in Elderly Adults. PMID- 26603081 TI - Formative Clinical Geriatrics Experiences for First- and Second-Year Medical Students: An Elusive Goal. PMID- 26603082 TI - Ebola and Age: We May Be Missing a Critical Biological Aspect of the Ebola Infection. PMID- 26603083 TI - Improving the Quality of Auscultation for Individuals with Cachexia. PMID- 26603084 TI - Comment on "Development and Validation of the Geriatric In-Hospital Nursing Care Questionnaire". PMID- 26603085 TI - Response to Dikken and Colleagues. PMID- 26603087 TI - Erratum. PMID- 26603088 TI - Influence of Gender and Cardiovascular Risk on the Control of Low-density Lipoprotein in a Population From Extremadura. PMID- 26603089 TI - Surgical Repair of Total Anomalous Pulmonary Venous Connection in a Neonate With Mosaic Trisomy 8. AB - Trisomy 8 mosaicism is a relatively rare chromosomal abnormality and has extremely variable phenotype with a wide range of clinical manifestations. Although no well-defined criteria for cardiac surgical indications are available for patients with mosaic trisomy 8, we present a case of hypoplastic left heart syndrome with total anomalous pulmonary venous connection (TAPVC) in a neonate with mosaic trisomy 8. Although primary sutureless repair of TAPVC with concomitant bilateral pulmonary artery banding was performed successfully in this case, the indications for cardiac surgery in patients with mosaic trisomy 8 should be carefully individualized. The entire dialog with parents and family, including the process of informed consent, is of great importance. PMID- 26603090 TI - Double Outlet Right Ventricle With Intact Ventricular Septum: Avulsion or Exclusion. AB - Double outlet right ventricle (DORV) is almost always associated with a ventricular septal defect. The variant of DORV with intact ventricular septum is very uncommon and may be associated with fetal demise or death immediately after birth. Reports of successful palliation of these patients to the stage of superior cavopulmonary anastomosis (bidirectional Glenn shunt) are rare. We describe the case of a child with DORV with intact ventricular septum who underwent successful palliation. This condition often provides a diagnostic, interventional, and surgical challenge. Patients generally require either balloon atrial septostomy or surgical atrial septectomy for survival, with the addition of a Blalock-Tausig shunt or pulmonary artery band depending on the pulmonary blood flow. Very few patients survive to a Glenn procedure. For those who do survive, a decision must be made regarding the management of the hypertensive and hypoplastic left ventricle (LV) and associated mitral regurgitation. The LV can be excluded by either mitral valve avulsion or closure (exclusion) of the mitral valve with a patch. The choice of the technique should be carefully made and depends in part on the size of the LV. In our patient, who was successfully palliated by bidirectional Glenn shunt, the LV was managed by means of mitral valve avulsion. PMID- 26603091 TI - Low prevalence of unexpected popliteal DVT detected on routine MRI assessment of the knee. AB - OBJECTIVE: The purpose of this study was to document the appearance and determine the prevalence of findings suspicious for popliteal vein thrombosis on magnetic resonance (MR) assessment of the knee joint. METHODS: A total of 2888 MR examinations were retrospectively reviewed and classified as illustrating either normal appearing popliteal vein or findings suspicious for popliteal vein thrombosis. RESULTS: A total of 2879 MR studies were assessed as having a normal appearing popliteal vein. Nine studies illustrated findings suspicious for popliteal vein thrombosis. CONCLUSION: Although the prevalence of MR findings is low (0.3%), our findings reiterate the need to interrogate the popliteal vein for evidence of thrombosis. PMID- 26603092 TI - A new Approach to El Nino Prediction beyond the Spring Season. AB - The enormous societal importance of accurate El Nino forecasts has long been recognized. Nonetheless, our predictive capabilities were once more shown to be inadequate in 2014 when an El Nino event was widely predicted by international climate centers but failed to materialize. This result highlighted the problem of the opaque spring persistence barrier, which severely restricts longer-term, accurate forecasting beyond boreal spring. Here we show that the role played by tropical seasonality in the evolution of the El Nino is changing on pentadal (five-year) to decadal timescales and thus that El Nino predictions beyond boreal spring will inevitably be uncertain if this change is neglected. To address this problem, our new coupled climate simulation incorporates these long-term influences directly and generates accurate hindcasts for the 7 major historical El Ninos. The error value between predicted and observed sea surface temperature (SST) in a specific tropical region (5 degrees N-5 degrees S and 170 degrees -120 degrees W) can consequently be reduced by 0.6 Kelvin for one-year predictions. This correction is substantial since an "El Nino" is confirmed when the SST anomaly becomes greater than +0.5 Kelvin. Our 2014 forecast is in line with the observed development of the tropical climate. PMID- 26603093 TI - Metal accumulation in roadside soil in Melbourne, Australia: Effect of road age, traffic density and vehicular speed. AB - Concentrations of vehicular emitted heavy metals in roadside soils result in long term environmental damage. This study assessed the relationships between traffic characteristics (traffic density, road age and vehicular speed) and roadside soil heavy metals. Significant levels were recorded for Cd (0.06-0.59 mg/kg), Cr (18 29 mg/kg), Cu (4-12 mg/kg), Ni (7-20 mg/kg), Mn (92-599 mg/kg), Pb (16-144 mg/kg) and Zn (10.36-88.75 mg/kg), with Mn concentrations exceeding the Ecological Investigation Level. Significant correlations were found between roadside soil metal concentration and vehicular speed (R = 0.90), road age (R = 0.82) and traffic density (R = 0.68). Recently introduced metals in automotive technology (e.g. Mn and Sb) were higher in younger roads, while the metals present for many years (e.g. Cd, Cu, Pb, Zn) were higher in medium and old age roads confirming the risk of significant metal deposition and soil metal retention in roadside soils. PMID- 26603094 TI - Exciton band structure in layered MoSe2: from a monolayer to the bulk limit. AB - We present the micro-photoluminescence (MUPL) and micro-reflectance contrast (MURC) spectroscopy studies on thin films of MoSe(2) with layer thicknesses ranging from a monolayer (1L) up to 5L. The thickness dependent evolution of the ground and excited state excitonic transitions taking place at various points of the Brillouin zone is determined. Temperature activated energy shifts and linewidth broadenings of the excitonic resonances in 1L, 2L and 3L flakes are accounted for by using standard formalisms previously developed for semiconductors. A peculiar shape of the optical response of the ground state (A) exciton in monolayer MoSe(2) is tentatively attributed to the appearance of a Fano-type resonance. Rather trivial and clearly decaying PL spectra of monolayer MoSe(2) with temperature confirm that the ground state exciton in this material is optically bright in contrast to a dark exciton ground state in monolayer WSe(2). PMID- 26603095 TI - Hydrogen peroxide regulates cell adhesion through the redox sensor RPSA. AB - To become metastatic, a tumor cell must acquire new adhesion properties that allow migration into the surrounding connective tissue, transmigration across endothelial cells to reach the blood stream and, at the site of metastasis, adhesion to endothelial cells and transmigration to colonize a new tissue. Hydrogen peroxide (H2O2) is a redox signaling molecule produced in tumor cell microenvironment with high relevance for tumor development. However, the molecular mechanisms regulated by H2O2 in tumor cells are still poorly known. The identification of H2O2-target proteins in tumor cells and the understanding of their role in tumor cell adhesion are essential for the development of novel redox-based therapies for cancer. In this paper, we identified Ribosomal Protein SA (RPSA) as a target of H2O2 and showed that RPSA in the oxidized state accumulates in clusters that contain specific adhesion molecules. Furthermore, we showed that RPSA oxidation improves cell adhesion efficiency to laminin in vitro and promotes cell extravasation in vivo. Our results unravel a new mechanism for H2O2-dependent modulation of cell adhesion properties and identify RPSA as the H2O2 sensor in this process. This work indicates that high levels of RPSA expression might confer a selective advantage to tumor cells in an oxidative environment. PMID- 26603096 TI - Vascular Ultrasound and Noninvasive Physiological Testing for Peripheral Arterial Disease: Are These Tests Being Overused? AB - PURPOSE: To examine recent trends in the use of duplex ultrasound and noninvasive physiologic tests (NPTs) for determining the presence of peripheral arterial disease (PAD). METHODS: Medicare Part B databases for 2001-2013 were used. The two Current Procedural Terminology, version four codes for duplex ultrasound of lower-extremity arteries, and the three codes for NPTs of extremity arteries were selected. Procedure volumes of both types of examinations were determined, and utilization rates per 100,000 beneficiaries were calculated. Medicare specialty codes were used to determine what proportions were performed by the major specialty groups involved in these examinations: surgeons, cardiologists, radiologists, and primary care physicians (PCPs). RESULTS: Between 2001 and 2010 (the peak year), the total utilization rates per 100,000 of duplex ultrasound and NPTs increased by 94% and 84%, respectively. During the ensuing three years, small declines occurred in both. In 2013, utilization rates of both types of tests were far higher than they had been in 2001 (88% higher for duplex ultrasound; 63% higher for NPTs). From 2001 to 2013, use of duplex ultrasound increased 235% among cardiologists, 90% among surgeons, 76% among radiologists, and 53% among PCPs. Utilization rates of NPTs among surgeons were already high in 2001 and increased an additional 23% by 2013. The NPT utilization rates increased 180% among PCPs, 179% among cardiologists, and 61% among radiologists. CONCLUSIONS: During a period when little growth occurred in the incidence of PAD, sharp growth occurred in testing for the disease. PMID- 26603097 TI - Identification of Neuroradiology MRI Protocol Errors via a Quality-Driven Categorization Approach. PMID- 26603098 TI - Electronic Health Record-Driven Workflow for Diagnostic Radiologists. AB - In most settings, radiologists maintain a high-throughput practice in which efficiency is crucial. The conversion from film-based to digital study interpretation and data storage launched the era of PACS-driven workflow, leading to significant gains in speed. The advent of electronic health records improved radiologists' access to patient data; however, many still find this aspect of workflow to be relatively cumbersome. Nevertheless, the ability to guide a diagnostic interpretation with clinical information, beyond that provided in the examination indication, can add significantly to the specificity of a radiologist's interpretation. Responsibilities of the radiologist include, but are not limited to, protocoling examinations, interpreting studies, chart review, peer review, writing notes, placing orders, and communicating with referring providers. Most of the aforementioned activities are not PACS-centric and require a login to one or more additional applications. Consolidation of these tasks for completion through a single interface can simplify workflow, save time, and potentially reduce the incidence of errors. Here, the authors describe diagnostic radiology workflow that leverages the electronic health record to significantly add to a radiologist's ability to be part of the health care team, provide relevant interpretations, and improve efficiency and quality. PMID- 26603099 TI - Antidermatophytic activity of hydroalcoholic extracts from Rosmarinus officinalis and Tetradenia riparia. AB - Rosmarinus officinalis and Tetradenia riparia are used in folk medicine for the treatment of disease, including infectious diseases and skin disorders. The purpose of this study was to investigate the antifungal activity of hydroalcoholic extracts from R. officinalis and T. riparia against strains of Trichophyton rubrum, T. mentagrophytes and Microsporum gypseum. Hydroalcoholic extracts prepared with dried leaves from R. officinalis, Psidium guajava and T. riparia were assayed against dermatophyte species by the microdilution technique and by microscopy. R. officinalis and T. riparia were the most active against dermatophytes, as determined from the minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC), and were investigated further. Fluorescence microscopy and scanning electron microscopy were used to investigate inhibition of hyphal growth by the two extracts, and showed a strong inhibition and an irregular growth pattern. Both extracts showed good action against dermatophytes, inhibiting fungal growth and causing alterations in their hyphae. Therefore, R. officinalis and T. riparia are potential sources of new compounds for the development of antifungal drugs. PMID- 26603100 TI - [Allergic fungal rhinosinusitis]. AB - INTRODUCTION: Definition, diagnosis and treatment of allergic fungal sinusitis remain difficult and controversial despite the increasing number of publications. We report a case of an allergic fungal sinusitis with a review of the literature. CLINICAL CASE: A 45-year-old man consulted for sinusal polyposis resistant to steroid therapy, clinical examination objectified bilateral nasal polyps and covered with scabs. CT scan of the sinuses disclosed a sinuse filled with a tissue density material containing air with lysis of the left maxillary sinus, hypereosinophilia, the IgE levels were high. Finally, mycological investigation allowed the identification of Aspergillus fumigatus. The patient underwent total ethmoidectomy, histological study found an allergic mucin and inflammatory mucosa with numerous eosinophils. The postoperative course was good and the patient was given oral steroids. The clinical and radiological evolution was favorable without recurrence with a follow-up of three years. DISCUSSION: A set of clinical, radiological, histopathological, immunoallergological and mycological criteria is necessary for precise diagnosis and to avoid fungal drift. The treatment is based on endoscopic surgery associated with corticosteroid. PMID- 26603101 TI - Cochlear labyrinth volume in Krapina Neandertals. AB - Research with extant primate taxa suggests that cochlear labyrinth volume is functionally related to the range of audible frequencies. Specifically, cochlear volume is negatively correlated with both the high and low frequency limits of hearing so that the smaller the cochlea, the higher the normal range of audible frequencies. The close anatomical relationship between the membranous cochlea and the bony cochlear labyrinth allows for the determination of cochlear size from fossil specimens. This study compares Krapina Neandertal cochlear volumes to extant taxa cochlear volumes. Cochlear volumes were acquired from high-resolution computed tomography scans of temporal bones of Krapina Neandertals, chimpanzees, gorillas, and modern humans. We find that Krapina Neandertals' cochlear volumes are similar to modern Homo sapiens and are significantly larger than chimpanzee and gorilla cochlear volumes. The measured cochlear volume in Krapina Neandertals suggests they had a range of audible frequencies similar to the modern human range. PMID- 26603102 TI - Neuronal gene repression in Niemann-Pick type C models is mediated by the c Abl/HDAC2 signaling pathway. AB - BACKGROUND: Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of free cholesterol in lysosomes. There are currently no effective FDA-approved treatments for NPC, although in the last years the inhibition of histone deacetylases (HDACs) has emerged as a potential treatment for this disease. However, the molecular mechanisms that deregulate HDAC activity in NPC disease are unknown. Previously our group had shown that the proapoptotic tyrosine kinase c-Abl signaling is activated in NPC neurons. Here, we demonstrate that c-Abl activity increases HDAC2 levels inducing neuronal gene repression of key synaptic genes in NPC models. RESULTS: Our data show that: i) HDAC2 levels and activity are increased in NPC neuronal models and in Npc1(-/-) mice; ii) inhibition of c-Abl or c-Abl deficiency prevents the increase of HDAC2 protein levels and activity in NPC neuronal models; iii) c-Abl inhibition decreases the levels of HDAC2 tyrosine phosphorylation; iv) treatment with methyl-beta-cyclodextrin and vitamin E decreases the activation of the c Abl/HDAC2 pathway in NPC neurons; v) in vivo treatment with two c-Abl inhibitors prevents the increase of HDAC2 protein levels in the brain of Npc1(-/-) mice; and vi) c-Abl inhibition prevents HDAC2 recruitment to the promoter of neuronal genes, triggering an increase in their expression. CONCLUSION: Our data show the involvement of the c-Abl/HDAC2 signaling pathway in the regulation of neuronal gene expression in NPC neuronal models. Thus, inhibition of c-Abl could be a pharmacological target for preventing the deleterious effects of increased HDAC2 levels in NPC disease. PMID- 26603103 TI - Wnt/beta-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance. AB - The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is commonly overexpressed in cancers and is implicated in the development of chemoresistance. The use of drugs inhibiting MGMT has been hindered by their haematologic toxicity and inefficiency. As a different strategy to inhibit MGMT we investigated cellular regulators of MGMT expression in multiple cancers. Here we show a significant correlation between Wnt signalling and MGMT expression in cancers with different origin and confirm the findings by bioinformatic analysis and immunofluorescence. We demonstrate Wnt-dependent MGMT gene expression and cellular co-localization between active beta-catenin and MGMT. Pharmacological or genetic inhibition of Wnt activity downregulates MGMT expression and restores chemosensitivity of DNA-alkylating drugs in mouse models. These findings have potential therapeutic implications for chemoresistant cancers, especially of brain tumours where the use of temozolomide is frequently used in treatment. PMID- 26603106 TI - Prediction of carotid artery in-stent restenosis by quantitative assessment of vulnerable plaque using computed tomography. AB - BACKGROUND AND PURPOSE: To assess the relationship between plaque volume evaluated by multidetector computed tomographic angiography (MDCT) and in-stent restenosis (ISR) after carotid artery stenting (CAS). MATERIALS AND METHODS: From a retrospectively maintained database, data were collected for 52patients with carotid artery stenosis treated with CAS between 2007 and 2012. We defined ISR of>=50% as a peak systolic velocity>=200cm/s on echo-duplex scan. Carotid plaques were subdivided into four components according to radiodensity in Hounsfield units (HU) as follows: <0, 0-60, 60-130, and>600HU. Risk factors that influenced ISR were compared using univariate and multivariate Cox regression analyses. RESULTS: During a median follow-up period of 36months, ISR of>=50% was detected in five patients (9.6%). In the univariate Cox proportional hazard regression analysis, renal insufficiency, coronary artery disease, total plaque volume, and plaque volumes with radiodensities<0 and>=600HU increased the risk for ISR (P<0.10). When the significant risk factors determined from the univariate analysis were subjected to a multivariate analysis, only the volumes of the plaque components with radiodensities<0 HU independently predicted the development of ISR (hazard ratio: 1.041; 95% confidence interval: 1.006-1.078; P=0.021). CONCLUSION: Our data suggest that the high volume of the plaque components with radiodensities<0HU was independently associated with the increased risk of ISR after CAS. Quantitative and qualitative tissue characterizations of carotid plaques using MDCT might be a useful predictive tool of the development of ISR. PMID- 26603105 TI - Integrated network model provides new insights into castration-resistant prostate cancer. AB - Castration-resistant prostate cancer (CRPC) is the main challenge for prostate cancer treatment. Recent studies have indicated that extending the treatments to simultaneously targeting different pathways could provide better approaches. To better understand the regulatory functions of different pathways, a system-wide study of CRPC regulation is necessary. For this purpose, we constructed a comprehensive CRPC regulatory network by integrating multiple pathways such as the MEK/ERK and the PI3K/AKT pathways. We studied the feedback loops of this network and found that AKT was involved in all detected negative feedback loops. We translated the network into a predictive Boolean model and analyzed the stable states and the control effects of genes using novel methods. We found that the stable states naturally divide into two obvious groups characterizing PC3 and DU145 cells respectively. Stable state analysis further revealed that several critical genes, such as PTEN, AKT, RAF, and CDKN2A, had distinct expression behaviors in different clusters. Our model predicted the control effects of many genes. We used several public datasets as well as FHL2 overexpression to verify our finding. The results of this study can help in identifying potential therapeutic targets, especially simultaneous targets of multiple pathways, for CRPC. PMID- 26603107 TI - Influence of setback and advancement osseous genioplasty on facial outcome: A computer-simulated study. AB - The aim of this virtual study was to investigate the influence of angular deviation and displacement distance on the overlying soft tissue during chin genioplasty. Computed tomography data from 21 patients were read using ProPlan CMF software. Twelve simulated genioplasties were performed per patient with variable osteotomy angles and displacement distances. Soft-tissue deformations and cephalometric analysis were compared. Changes in anterior and inferior soft tissue of the chin along with resultant lower facial third area were determined. Maximum average changes in soft-tissue were obtained anterior after 10-mm advancement about 4.19 SD 0.84 mm and inferior about -1.55 SD 0.96 mm. After 10 mm setback anterior -4.63 SD 0.56 mm and inferior 0.75 SD 1.16 mm were deviations found. The anterior soft tissue showed a statistically significant change with bony displacement in both directions independent of osteotomy angle (p < 0.001) and only after a 10-mm advancement with an angle of -5 degrees significant differences at inferior soft-tissue were noted (p = 0.0055). The average area of the total lower third of the face was 24,807.80 SD 4,091.72 mm(2) and up to 62.75% was influenced. Advanced genioplasty leads to greater changes in the overlying soft tissue, whereas the affected area is larger after setback displacement. The ratio between soft and hard tissue movements largely depends on the displacement distance. PMID- 26603108 TI - Custom-made titanium devices as membranes for bone augmentation in implant treatment: Clinical application and the comparison with conventional titanium mesh. AB - OBJECTIVE: Development of new custom-made devices to reconstruct alveolar bone for implantation, and comparison with conventional methods were the goals of this study. MATERIALS AND METHODS: Using a computer-aided design technique, three dimensional images were constructed. From these data, custom-made devices were produced by a selective laser melting method with pure titanium. Clinical trials also have been conducted with 26 participants who needed bone reconstruction before implantation; they were divided into 2 groups with 13 patients each. The first group uses custom-made devices; the other uses commercial titanium meshes that need to bend during operation. Some clinical aspects are evaluated after the trial. RESULTS: The custom-made devices can be produced closely by following the data precisely. Devices are fit for bone defect site. Moreover, the operation time of the custom-made group (75.4 +/- 11.6 min) was significantly shorter than that of the conventional group (111.9 +/- 17.8 min) (p < 0.01). Mucosal rupture occurs, without significant difference (p = 0.27), in a patient in the custom made without severe infection (7.7%), and 3 in conventional (23.1%), respectively. The retaining screw is significantly fewer in the custom-made group than commercial mesh group (p < 0.01). CONCLUSION: These results indicate that our novel protocol could be simple and safe for providing powerful support for guided bone regeneration. PMID- 26603109 TI - Serratus anterior plane block for breast surgery in a morbidly obese patient. PMID- 26603110 TI - Remifentanil infusion during emergence moderates hemodynamic and cough responses to the tracheal tube: A randomized controlled trial. AB - OBJECTIVE: To examine the severity of cough and straining at the time of emergence from anesthesia. DESIGN: Double-blind randomized, placebo-controlled study. SETTING: University-affiliated hospital. PATIENTS: Sixty-two American Society of Anesthesiologists 2 patients undergoing craniotomy and excision of supratentorial cerebral tumors. INTERVENTION: Intravenous infusion of remifentanil (REM) at 0.05 MUg/kg/min or normal saline (NS) upon termination of the surgical procedure. MEASUREMENTS: Heart rate (HR) and mean arterial pressure (MAP) along with the frequency and severity of cough response (Modified Minogue Scale) to the endotracheal tube were recorded at different time points. The frequency of cough and straining was analyzed with chi(2) tests. HRs and MAP were analyzed by repeated-measures analysis of variance between REM and NS groups. MAIN RESULTS: There was no case of significant cough in the REM group, and all of the patients in the NS group developed some extent of cough varying from mild retching to severe coughing episodes (P < .001). Both the HR and MAPs were consistently lower in the REM group compared to the NS group. CONCLUSION: Infusion of REM at the end of craniotomy procedures results in significant reduction of the frequency and severity of coughing and straining. Compared to placebo, REM moderates increases in MAP upon emergence from general anesthesia until the time of extubation. PMID- 26603111 TI - Responsibility to Protect at age 10--still worthy of support? PMID- 26603112 TI - Optically Transparent Microwave Polarizer Based On Quasi-Metallic Graphene. AB - In this paper, we report on the engineering and the realization of optically transparent graphene-based microwave devices using Chemical Vapour Deposition (CVD) graphene whose sheet resistance may be tailored down to values below 30 Omega/sq. In particular, we show that the process was successfully used to realize and characterize a simple, optically transparent graphene-based wire-grid polarizer at microwave frequencies (X band). The availability of graphene operating in a quasi-metallic region may allow the integration of graphene layers in several microwave components, thus leading to the realization of fully transparent (and flexible) microwave devices. PMID- 26603113 TI - Exploratory Higher Order Analysis of the Luria Interpretive Model on the Kaufman Assessment Battery for Children-Second Edition (KABC-II) School-Age Battery. AB - Higher order factor structure of the Luria interpretive scheme on the Kaufman Assessment Battery for Children-Second Edition (KABC-II) for the 7- to 12-year and the 13- to 18-year age groups in the KABC-II normative sample ( N = 2,025) is reported. Using exploratory factor analysis, multiple factor extraction criteria, and hierarchical exploratory factor analysis not included in the KABC-II manual, two-, three-, and four-factor extractions were analyzed to assess the hierarchical factor structure by sequentially partitioning variance appropriately to higher order and lower order dimensions as recommended by Carroll. No evidence for a four-factor solution was found. Results showed that the largest portions of total and common variance were accounted for by the second-order general factor and that interpretation should focus primarily, if not exclusively, at that level of measurement. PMID- 26603114 TI - Corrigendum. AB - Chrysikou, E. G., & Thompson, W. J. (2016). Assessing cognitive and affective empathy through the interpersonal reactivity index: An argument against a two factor model. Assessment, 23(6), 769-777. doi:1073191115599055. PMID- 26603115 TI - The Dissociative Subtype of PTSD Scale: Initial Evaluation in a National Sample of Trauma-Exposed Veterans. AB - The fifth edition of the Diagnostic and Statistical Manual includes a dissociative subtype of posttraumatic stress disorder, but no existing measures specifically assess it. This article describes the initial evaluation of a 15 item self-report measure of the subtype called the Dissociative Subtype of Posttraumatic Stress Disorder Scale (DSPS) in an online survey of 697 trauma exposed military veterans representative of the U.S. veteran population. Exploratory factor analyses of the lifetime DSPS items supported the intended structure of the measure consisting of three factors reflecting derealization/depersonalization, loss of awareness, and psychogenic amnesia. Consistent with prior research, latent profile analyses assigned 8.3% of the sample to a highly dissociative class distinguished by pronounced symptoms of derealization and depersonalization. Overall, results provide initial psychometric support for the lifetime DSPS scales; additional research in clinical and community samples is needed to further validate the measure. PMID- 26603116 TI - Evaluation of the Psychometric Properties of the Asian Adolescent Depression Scale and Construction of a Short Form: An Item Response Theory Analysis. AB - The present study applied item response theory to examine the psychometric properties of the Asian Adolescent Depression Scale and to construct a short form among 1,084 teenagers recruited from secondary schools in Hong Kong. Findings suggested that some items of the full form reflected higher levels of severity and were more discriminating than others, and the Asian Adolescent Depression Scale was useful in measuring a broad range of depressive severity in community youths. Differential item functioning emerged in several items where females reported higher depressive severity than males. In the short form construction, preliminary validation suggested that, relative to the 20-item full form, our derived short form offered significantly greater diagnostic performance and stronger discriminatory ability in differentiating depressed and nondepressed groups, and simultaneously maintained adequate measurement precision with a reduced response burden in assessing depression in the Asian adolescents. Cultural variance in depressive symptomatology and clinical implications are discussed. PMID- 26603117 TI - Using Item Response Theory to Develop Measures of Acquisitive and Protective Self Monitoring From the Original Self-Monitoring Scale. AB - For the past 40 years, the conventional univariate model of self-monitoring has reigned as the dominant interpretative paradigm in the literature. However, recent findings associated with an alternative bivariate model challenge the conventional paradigm. In this study, item response theory is used to develop measures of the bivariate model of acquisitive and protective self-monitoring using original Self-Monitoring Scale (SMS) items, and data from two large, nonstudent samples ( Ns = 13,563 and 709). Results indicate that the new acquisitive (six-item) and protective (seven-item) self-monitoring scales are reliable, unbiased in terms of gender and age, and demonstrate theoretically consistent relations to measures of personality traits and cognitive ability. Additionally, by virtue of using original SMS items, previously collected responses can be reanalyzed in accordance with the alternative bivariate model. Recommendations for the reanalysis of archival SMS data, as well as directions for future research, are provided. PMID- 26603118 TI - Measurement Invariance and Convergent Validity of Anger and Sadness Self Regulation Among Youth From Six Cultural Groups. AB - The present study examined measurement invariance and convergent validity of a novel vignette-based measure of emotion-specific self-regulation that simultaneously assesses attributional bias, emotion-regulation, and self-efficacy beliefs about emotion regulation. Participants included 541 youth-mother dyads from three countries (Italy, the United States, and Colombia) and six ethnic/cultural groups. Participants were 12.62 years old ( SD = 0.69). In response to vignettes involving ambiguous peer interactions, children reported their hostile/depressive attribution bias, self-efficacy beliefs about anger and sadness regulation, and anger/sadness regulation strategies (i.e., dysregulated expression and rumination). Across the six cultural groups, anger and sadness self-regulation subscales had full metric and partial scalar invariance for a one factor model, with some exceptions. We found support for both a four- and three factor oblique model (dysregulated expression and rumination loaded on a second order factor) for both anger and sadness. Anger subscales were related to externalizing problems, while sadness subscales were related to internalizing symptoms. PMID- 26603119 TI - Complete genome sequence of Enterococcus durans KLDS6.0930, a strain with probiotic properties. AB - Enterococcus durans KLDS6.0930 strain was originally isolated from traditional naturally fermented cream in Inner Mongolia of China. The complete genome sequence of E. durans KLDS6.0930 was carried out using the PacBio RSII platform. The genome contains a circular chromosome and two circular plasmids. Genome sequencing information provides the genetic basis for bioinformatics analysis of bile salt and acid tolerance, cell adhesion, and molecular mechanisms responsible for lipid metabolism. PMID- 26603120 TI - Complete genome sequence of Pandoraea thiooxydans DSM 25325(T), a thiosulfate oxidizing bacterium. AB - Pandoraea thiooxydans DSM 25325(T) is a thiosulfate-oxidizing bacterium isolated from rhizosphere soils of a sesame plant. Here, we present the first complete genome of P. thiooxydans DSM 25325(T). Several genes involved in thiosulfate oxidation and biodegradation of aromatic compounds were identified. PMID- 26603121 TI - Efficient targeted mutagenesis in soybean by TALENs and CRISPR/Cas9. AB - Gene targeting (GT) is of great significance for advancing basic plant research and crop improvement. Both TALENs (transcription activator-like effectors nucleases) and CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated 9) systems have been developed for genome editing in eukaryotes, including crop plants. In this work, we present the comparative analysis of these two technologies for two soybean genome editing targets, GmPDS11 and GmPDS18. We found GT in soybean hairy roots with a single targeting efficiency range of 17.5-21.1% by TALENs, 11.7-18.1% by CRISPR/Cas9 using the AtU6-26 promoter, and 43.4-48.1% by CRISPR/Cas9 using the GmU6-16g-1 promoter, suggesting that the CRISPR/Cas9 using the GmU6-16g-1 promoter is probably a much more efficient tool compared to the other technologies. Similarly, our double mutation GT efficiency experiment with these three technologies displayed a targeting efficiency of 6.25% by TALENs, 12.5% by CRISPR/Cas9 using the AtU6-26 promoter, and 43.4-48.1% by CRISPR/Cas9 using the GmU6-16g-1 promoter, suggesting that CRISPR/Cas9 is still a better choice for simultaneous editing of multiple homoeoalleles. Furthermore, we observed albino and dwarf buds (PDS knock-out) by soybean transformation in cotyledon nodes. Our results demonstrated that both TALENs and CRISPR/Cas9 systems are powerful tools for soybean genome editing. PMID- 26603122 TI - Improved polysaccharide production in a submerged culture of Ganoderma lucidum by the heterologous expression of Vitreoscilla hemoglobin gene. AB - Expression of Vitreoscilla hemoglobin (VHb) gene was used to improve polysaccharide production in Ganoderma lucidum. The VHb gene, vgb, under the control of the constitutive glyceraldehyde-3-phosphate dehydrogenase gene promoter was introduced into G. lucidum. The activity of expressed VHb was confirmed by the observation of VHb specific CO-difference spectrum with a maximal absorption at 419 nm for the transformant. The effects of VHb expression on intracellular polysaccharide (IPS) content, extracellular polysaccharide (EPS) production and transcription levels of three genes encoding the enzymes involved in polysaccharide biosynthesis, including phosphoglucomutase (PGM), uridine diphosphate glucose pyrophosphorylase (UGP), and beta-1,3-glucan synthase (GLS), were investigated. The maximum IPS content and EPS production in the vgb-bearing G. lucidum were 26.4 mg/100mg dry weight and 0.83 g/L, respectively, which were higher by 30.5% and 88.2% than those of the wild-type strain. The transcription levels of PGM, UGP and GLS were up-regulated by 1.51-, 1.55- and 3.83-fold, respectively, in the vgb-bearing G. lucidum. This work highlights the potential of VHb to enhance G. lucidum polysaccharide production by large scale fermentation. PMID- 26603123 TI - Metabolic engineering of CHO cells to alter lactate metabolism during fed-batch cultures. AB - Recombinant yeast pyruvate carboxylase (PYC2) expression was previously shown to be an effective metabolic engineering strategy for reducing lactate formation in a number of relevant mammalian cell lines, but, in the case of CHO cells, did not consistently lead to significant improvement in terms of cell growth, product titer and energy metabolism efficiency. In the present study, we report on the establishment of a PYC2-expressing CHO cell line producing a monoclonal antibody and displaying a significantly altered lactate metabolism compared to its parental line. All clones exhibiting strong PYC2 expression were shown to experience a significant and systematic metabolic shift toward lactate consumption, as well as a prolonged exponential growth phase leading to an increased maximum cell concentration and volumetric product titer. Of salient interest, PYC2-expressing CHO cells were shown to maintain a highly efficient metabolism in fed-batch cultures, even when exposed to high glucose levels, thereby alleviating the need of controlling nutrient at low levels and the potential negative impact of such strategy on product glycosylation. In bioreactor operated in fed-batch mode, the higher maximum cell density achieved with the PYC2 clone led to a net gain (20%) in final volumetric productivity. PMID- 26603124 TI - Development of living cell microarrays using non-contact micropipette printing. AB - During the last 30 years cellular screening systems were unidirectional developed towards high throughput applications on single cell level. We developed living cell microarrays, which provide an in vivo-like microenvironment for an advanced method to measure cellular response to external stimuli. To print living cells on glass slides, the classic microarray equipment, which involves printer and scanner, was fully transferred to suspensions of living cells. The microarray production was optimized using a contact-free spotting procedure in order to enhanced cell adhesion and growth rates. The printed model cells, A-549 (lung cancer cell line), were analyzed with conventional cell staining assays like DAPI (cell nuclei staining), calcein acetoxymethyl ester (viable cell staining), and CellTiter-Blue((r)) Cell Viability Assay. After optimization, a reproducible (spot-to-spot variation: +/- 8.6 cells) printing method for small living cell amounts (1200 cells and fewer) was established that achieved cell viabilities of up to 88% for >= 0.6 MUL and good proliferation characteristics. Hence, this method could be advantageous for use in biomedical and diagnostic applications. PMID- 26603126 TI - Intra-Bone Marrow Transplantation Confers Superior Multilineage Engraftment of Murine Aorta-Gonad Mesonephros Cells Over Intravenous Transplantation. AB - Hematopoietic stem cell (HSC) engraftment has been achieved using single-cell transplantation of prospectively highly purified adult HSC populations. However, bulk transplants are still performed when assessing the HSC potential of early embryonic hematopoietic tissues such as the aorta-gonad mesonephros (AGM) due to very low HSC activity content early in development. Intra-bone marrow transplantation (IBMT) has emerged as a superior administration route over intravenous (IV) transplantation for assessing the reconstituting ability of human HSCs in the xenotransplant setting since it bypasses the requirement for homing to the BM. In this study, we compared the ability of IBMT and IV administration of embryonic day 11.5 AGM-derived cells to reconstitute the hematopoietic system of myeloablated recipients. IBMT resulted in higher levels of AGM HSC long-term multilineage engraftment in the peripheral blood, BM, spleen, and thymus of primary and secondary recipients, and in limiting dilution experiments. The administration route did not skew the multilineage contribution pattern, but IBMT conferred higher Lineage(-)Sca-1(+)c-kit(+) long-term engraftment, in line with the superior IBMT reconstitution. Therefore, IBMT represents a superior administration route to detect HSC activity from developmentally early sources with limited HSC activity content, such as the AGM. PMID- 26603125 TI - Spatial-frequency dependent binocular imbalance in amblyopia. AB - While amblyopia involves both binocular imbalance and deficits in processing high spatial frequency information, little is known about the spatial-frequency dependence of binocular imbalance. Here we examined binocular imbalance as a function of spatial frequency in amblyopia using a novel computer-based method. Binocular imbalance at four spatial frequencies was measured with a novel dichoptic letter chart in individuals with amblyopia, or normal vision. Our dichoptic letter chart was composed of band-pass filtered letters arranged in a layout similar to the ETDRS acuity chart. A different chart was presented to each eye of the observer via stereo-shutter glasses. The relative contrast of the corresponding letter in each eye was adjusted by a computer staircase to determine a binocular Balance Point at which the observer reports the letter presented to either eye with equal probability. Amblyopes showed pronounced binocular imbalance across all spatial frequencies, with greater imbalance at high compared to low spatial frequencies (an average increase of 19%, p < 0.01). Good test-retest reliability of the method was demonstrated by the Bland-Altman plot. Our findings suggest that spatial-frequency dependent binocular imbalance may be useful for diagnosing amblyopia and as an outcome measure for recovery of binocular vision following therapy. PMID- 26603127 TI - Noncollapsibility in studies based on nonrepresentative samples. AB - BACKGROUND: It is common to use nonrepresentative samples in observational epidemiologic studies, but there has been debate about whether this introduces bias. In this article, we consider the consequences on noncollapsibility of a sample selection related to a relevant outcome-risk factor. METHODS: We focused on the odds ratio and defined the noncollapsibility effect as the difference between the marginal and the conditional (with respect to the outcome-risk factor) exposure-outcome association. We consider a situation in which the aims of the study require the estimate of a conditional effect. RESULTS: Using a classical numerical example, which assumes that all variables are binary and that the outcome-risk factor is not an effect modifier, we illustrate that in the selected sample the noncollapsibility effect can either be larger or smaller than in the population-based study, according to whether the selection moves the prevalence of the risk factor closer to or away from 50%. When the outcome-risk factor is also a confounder, the magnitude of the noncollapsibility effect in the selected sample depends on the effects of the selection on both noncollapsibility and confounding. CONCLUSIONS: When a key outcome-risk factor is unmeasured, in presence of noncollapsibility neither a population-based nor a selected study can directly estimate the conditional effect; whether the computable marginal is closer to the conditional in the selected or in the population-based study depends on the underlying population and the selection process. PMID- 26603128 TI - Change in cardiometabolic score and incidence of cardiovascular disease: the multi-ethnic study of atherosclerosis. AB - PURPOSE: Examine the relationship between changes in cardiometabolic risk profiles and subsequent cardiovascular disease (CVD). METHODS: The study sample included 5557 Multi-Ethnic Study of Atherosclerosis participants, recruited in 2000 from six U.S. counties. Standardized scores were calculated for metabolic and cardiovascular components relative to accepted clinical cut points and summed to create an index of cardiometabolic risk. CVD events and/or deaths were assessed after examination 3 (years, 2004-2005) through December 2011. Cox proportional hazards models were used to examine the association between change in the cardiometabolic index (examination 3 minus examination 1) and subsequent cardiovascular outcomes adjusted for demographics, socioeconomic status, medication, and stratified by tertiles of baseline cardiometabolic risk. RESULTS: We found a 31% relative increase in the CVD event rate per SD change in the cardiometabolic index among those in the highest tertile of baseline cardiometabolic risk (Hazard ratio = 1.31, 95% CI = 1.14-1.50); associations were not statistically significant in the lower tertiles of baseline risk. CONCLUSIONS: We found that larger increases in the cardiometabolic index over time were significantly associated with higher risk for subsequent CVD events among those with elevated cardiometabolic risk at baseline. These findings highlight the importance of monitoring temporal changes in risk factor profiles for predicting cardiovascular outcomes. PMID- 26603129 TI - Synthesis and Testing of Modular Dual-Modality Nanoparticles for Magnetic Resonance and Multispectral Photoacoustic Imaging. AB - Magnetic resonance (MR) and photoacoustic (PA) imaging are currently being investigated as complementing strategies for applications requiring sensitive detection of cells in vivo. While combined MR/PAI detection of cells requires biocompatible cell labeling probes, water-based synthesis of dual-modality MR/PAI probes presents significant technical challenges. Here we describe facile synthesis and characterization of hybrid modular dextran-stabilized gold/iron oxide (Au-IO) multimetallic nanoparticles (NP) enabling multimodal imaging of cells. The stable association between the IO and gold NP was achieved by priming the surface of dextran-coated IO with silver NP resulting from silver(I) reduction by aldehyde groups, which are naturally present within the dextran coating of IO at the level of 19-23 groups/particle. The Au-IO NP formed in the presence of silver-primed Au-IO were stabilized by using partially thiolated MPEG5-gPLL graft copolymer carrying residual amino groups. This stabilizer served as a carrier of near-infrared fluorophores (e.g., IRDye 800RS) for multispectral PA imaging. Dual modality imaging experiments performed in capillary phantoms of purified Au-IO-800RS NPs showed that these NPs were detectible using 3T MRI at a concentration of 25 MUM iron. PA imaging achieved approximately 2.5-times higher detection sensitivity due to strong PA signal emissions at 530 and 770 nm, corresponding to gold plasmons and IRDye integrated into the coating of the hybrid NPs, respectively, with no "bleaching" of PA signal. MDA-MB-231 cells prelabeled with Au-IO-800RS retained plasma membrane integrity and were detectable by using both MR and dual-wavelength PA at 49 +/- 3 cells/imaging voxel. We believe that modular assembly of multimetallic NPs shows promise for imaging analysis of engineered cells and tissues with high resolution and sensitivity. PMID- 26603130 TI - Interventional management of necrotizing pancreatitis: an Australian experience. AB - BACKGROUND: The interventional management of necrotizing pancreatitis has evolved from early open surgery to delayed endoscopic or percutaneous intervention. However, few studies have directly compared the three treatment modalities. We aim to compare the outcomes of patients who had endoscopic, percutaneous or surgical interventions for necrotizing pancreatitis at our institution. METHODS: This is a retrospective cohort study of patients who had interventions for necrotizing pancreatitis at our institution from 2005 to 2014. Primary outcome was length of stay (LOS); secondary outcomes were complication rate and number of procedures required for resolution of necrosis. RESULTS: Thirty patients were included. Mortality rate was 13% (four patients). Median LOS and time to intervention was 88 and 28 days, respectively. There were no significant differences in the computed tomography severity indices and 48-h C-reactive protein levels among the three groups. Initial endoscopic intervention was associated with a median LOS of 62 days compared with 101 days in the percutaneous group and 91 days in the surgical group (P = 0.04). There were higher rates of pancreatic fistulae (40%) (P = 0.012) and new onset diabetes (30%) (P = 0.046) in the surgical group. Median number of procedures was similar among the three groups. Median LOS for patients with delayed intervention (fourth to sixth week of pancreatitis) was 66 days, compared with 137 days in patients with early intervention (first to third week) and 104 days in patients with late intervention (seventh week onwards) (P <= 0.001). CONCLUSION: A delayed, endoscopy first approach appears to be a reasonable strategy as it is associated with decreased LOS and low complication rate. PMID- 26603131 TI - Childhood trauma and dimensions of depression: a specific association with the cognitive domain. AB - OBJECTIVE: To investigate associations between a history of childhood trauma and dimensions of depression in a sample of clinically depressed patients. METHODS: A sample of 217 patients from a mood-disorder outpatient unit was investigated with the Beck Depression Inventory, the Hamilton Depression Rating Scale, the CORE Assessment of Psychomotor Change, and the Childhood Trauma Questionnaire. A previous latent model identifying six depressive dimensions was used for analysis. Path analysis and Multiple Indicators Multiple Causes (MIMIC) models were used to investigate associations between general childhood trauma and childhood maltreatment modalities (emotional, sexual, and physical abuse; emotional and physical neglect) with dimensions of depression (sexual, cognition, insomnia, appetite, non-interactiveness/retardation, and agitation). RESULTS: The overall childhood trauma index was uniquely associated with cognitive aspects of depression, but not with any other depressive dimension. An investigation of childhood maltreatment modalities revealed that emotional abuse was consistently associated with depression severity in the cognitive dimension. CONCLUSION: Childhood trauma, and specifically emotional abuse, could be significant risk factors for the subsequent development of cognitive symptoms of major depression. These influences might be specific to this depressive dimension and not found in any other dimension, which might have conceptual and therapeutic implications for clinicians and researchers alike. PMID- 26603132 TI - Orbital implants in retinoblastoma patients: 23 years of experience and a review of the literature. AB - PURPOSE: To evaluate complications of different types of orbital implants following enucleation for retinoblastoma. METHODS: We performed a retrospective chart study of all patients that underwent enucleation as treatment of retinoblastoma between April 1991 and June 2013. Events of implant exposure, extrusion (defined as a complete loss of the implant, or a major exposure that could not be closed) and socket abnormalities were analysed for association with implant type and influence of additional external beam radiation therapy (EBRT) and/or chemotherapy. RESULTS: A total of 224 enucleations in 216 patients (eight bilateral) were identified. Mean age at surgery was 1.9 (median 1.5) years. Of the 219 included enucleated eyes, 20 were not replaced by a primary implant and 18 were replaced by an Allen implant. Scleral wrapped hydroxyapatite (HA) and acrylic implants (polymethylmethacrylate) were inserted in, respectively, 79 and 102 cases. In the total population, 29 treatment or implant-specific events (13.2%) were registered. Main complications were implant exposure n = 10 (4.6%) and extrusion n = 6 (2.7%). The acrylic/sclera group had less exposures or extrusions (5 of 102, 4.9%) compared to the HA/sclera group (10 of 79, 12.7%), although this difference did not quite reach statistical significance (p = 0.06). Additional treatment (chemotherapy and/or EBRT for the fellow eye) was administered in 78 cases (35.8%). The overall complication rate in the entire study population was significantly higher (16.7% versus 5.7%) in the group exposed to additional therapy (OR 3.3; 95% CI 1.30-8.36 p = 0.008). This negative effect of additional therapy was also significant in the combined acrylic/HA group (OR 2.9; 95% CI 0.97-8.46 p = 0.048). CONCLUSION: Our results suggest a favourable outcome for acrylic implants compared to the HA implant. Additional treatment with chemotherapy and/or EBRT is associated with an increased risk of complications. PMID- 26603133 TI - Impact of preparing for OSHA local emphasis program inspections of New York dairy farms: Case studies and financial cost analysis. AB - BACKGROUND: OSHA inspection of dairy farms began in July 1, 2014 in New York State. As of September 2014, a total of eight farms were randomly selected for inspection. This case study addresses how dairy farm managers prepared for these inspections, and identifies farm level costs preparing for inspection and/or being inspected. METHODS: Four farms that were OSHA inspected and 12 farms that were not inspected were included in this mixed method evaluation using a multimodal (telephone, email, or mail) survey. Descriptive analysis was carried out using frequencies, proportions, means, and medians. RESULTS: Overall, the impact of OSHA inspections was positive, leading to improved safety management and physical changes on the farm and worker trainings, although the farmers' perspectives about OSHA inspection were mixed. CONCLUSIONS: The cost of compliance was low relative to estimated overall production costs. Clarifications and engineering solutions for specific dairy farm hazard exposures are needed to facilitate compliance with OSHA regulations. PMID- 26603134 TI - Modular Synthesis of Spirocyclic Germafluorene-Germoles: A New Family of Tunable Luminogens. AB - The zirconium-mediated synthesis of a new class of air-stable spirocyclic germafluorene-germole (SGG) luminogens is reported. These species contain ring fused germafluorene and germole units that display color-tunable fluorescence when peripheral aryl substituents are appended. Three distinct pathways are introduced for SGG modification (Stille, Suzuki-Miyaura, and zirconocene-mediated couplings), which enable the preparation of new libraries of molecular and polymeric SGG light-emitters with tunable luminescence and desirable thermal- and photo-stability. PMID- 26603135 TI - The influence of advancing age on implantation of drug-eluting stents. AB - BACKGROUND: The influence of age upon the use of drug-eluting stents (DES) in patients aged >= 65 years is uncertain. The aim of this study is to investigate the impact of age increase in patients aged >= 65 years in the use of DES in patients undergoing percutaneous coronary intervention (PCI). METHOD: The study cohort comprised 8,598 patients >= 65 years of age who underwent stent implantation from April 2003 to March 2014. We defined the first DES era as the period April 2003 to July 2008 and the second DES era as the period July 2008 to March 2014. Multivariable logistic regression was performed for both eras to assess the impact of age increase and analyze independent factors associated with DES implantation. RESULTS: In the first DES era cohort, the two groups of patients differed in their risk factor profile with lower rates of male sex, diabetes, smokers, and hypercholesterolemia in those aged >= 75 years. There were more Caucasian and less African-Americans in this age group. Furthermore, patients aged >= 75 years had lower left ventricular ejection fraction (LVEF) and baseline haematocrit concentration were more likely to present with an acute myocardial infarction (MI) than stable or unstable angina and had higher rates of a previous history for congestive heart failure (CHF), chronic renal insufficiency (CRI), and peripheral vascular disease (PVD). These differences were broadly similar for patients in the second DES era except for similarities in LVEF, presentation with unstable angina, and PVD, as well as a lower rate for previous PCI. DES use was reduced with increasing age in both the first (OR=0.78; 95% CI=0.69-0.89) and second DES era (OR=0.53; 95% CI=0.47-0.58). In both eras, DES use was less likely in current smokers, patients presenting with acute MI and cardiogenic shock, and those with a previous history of CHF. CONCLUSION: In patients aged >= 65 years, the use of DES decreased with increasing age. This observation was apparent in both the first and second DES era. (c) 2015 Wiley Periodicals, Inc. PMID- 26603136 TI - Impact of rapid identification of Acinetobacter Baumannii via matrix-assisted laser desorption ionization time-of-flight mass spectrometry combined with antimicrobial stewardship in patients with pneumonia and/or bacteremia. AB - We evaluated the clinical and economic outcomes of matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) with stewardship intervention in patients with Acinetobacter baumannii (AB) pneumonia and/or bacteremia. 66 patients were included in the pre-intervention group and 53 in the intervention group. The combination of AB identification via MALDI-TOF MS and ID PharmD intervention significantly reduced the median time to effective therapy compared to conventional identification without intervention [77.7 (95% CI: 73.1-84.8) to 36.6 (95% CI: 25.9-50.9) hours (P < 0.0001)]. Rapid organism identification along with ID PharmD intervention was also associated with a 19% increase in clinical cure (15% versus 34%, P = 0.016) and a decreased length of stay during antibiotic therapy (13 [8-18] versus 11 [7-15] days, P = 0.021). No difference in 14-day mortality was observed (20% versus 25%, P = 0.526). Median costs during infection were approximately $6500 less in the intervention group ($49,402 [35,307-86,566] versus $42,872 [26,966-74,506]; P = 0.243). AB identification via MALDI-TOF MS combined with stewardship intervention allows for timely, effective antimicrobial therapy and is associated with increased clinical cure. PMID- 26603137 TI - Diet-Induced Obesity Enhances Progression of Hepatocellular Carcinoma through Tenascin-C/Toll-Like Receptor 4 Signaling. AB - Obesity is an independent risk factor for the development of liver fibrosis/cirrhosis and hepatocellular carcinoma (HCC). Tenascin-C (TnC), an extracellular matrix protein, is transiently expressed during tissue injury and plays a role in fibrogenesis and tumorigenesis. However, the mechanistic role of TnC signaling in the development of HCC remains unknown. We developed a diet induced obesity HCC mouse model and examined TnC expression and liver injury. To determine the cellular mechanism of TnC signaling in promoting inflammation and hepatocyte epithelial-mesenchymal transition and migration, we used primary hepatocytes and hepatoma and macrophage cell lines. Further, to determine whether elevated TnC expression correlated with obesity-associated HCC, we measured plasma TnC in obese patients with various levels of liver injury. Increased tissue inflammation accompanied with elevated hepatic stellate cell-derived TnC and Toll-like receptor 4 expression was observed in the diet-induced obesity HCC animal model. In vitro studies found enhanced Toll-like receptor 4 signaling activated by TnC, promoting an increased inflammatory response, hepatocyte transformation, and migration. Further, obese patients with cirrhosis alone and in combination with HCC showed significant increases in plasma TnC compared with healthy volunteers and patients with less severe liver injury. Overall, these studies suggest TnC/Toll-like receptor 4 signaling as an important regulator in HCC; inhibiting this signaling axis may be a viable therapeutic target for impeding HCC. PMID- 26603138 TI - Neurogenic effect of VEGF is related to increase of astrocytes transdifferentiation into new mature neurons in rat brains after stroke. AB - To study the cellular mechanism of vascular endothelial growth factor (VEGF) enhanced neurogenesis in ischemic brain injury, we used middle cerebral artery occlusion (MCAO) model to induce transient focal ischemic brain injury. The results showed that ischemic injury significantly increased glial fibrillary acidic protein immunopositive (GFAP(+)) and nestin(+) cells in ipsilateral striatum 3 days following MCAO. Most GFAP(+) cells colocalized with nestin (GFAP(+)-nestin(+)), Pax6 (GFAP(+)-Pax6(+)), or Olig2 (GFAP(+)-Olig2(+)). VEGF further increased GFAP(+)-nestin(+) and GFAP(+)-Pax6(+) cells, and decreased GFAP(+)-Olig2(+) cells. We used striatal injection of GFAP targeted enhanced green fluorescence protein (pGfa2-EGFP) vectors combined with multiple immunofluorescent staining to trace the neural fates of EGFP-expressing (GFP(+)) reactive astrocytes. The results showed that MCAO-induced striatal reactive astrocytes differentiated into neural stem cells (GFP(+)-nestin(+) cells) at 3 days after MCAO, immature (GFP(+)-Tuj-1(+) cells) at 1 week and mature neurons (GFP(+)-MAP-2(+) or GFP(+)-NeuN(+) cells) at 2 weeks. VEGF increased GFP(+) NeuN(+) and BrdU(+)-MAP-2(+) newborn neurons after MCAO. Fluorocitrate, an astrocytic inhibitor, significantly decreased GFAP and nestin expression in ischemic brains, and also reduced VEGF-enhanced neurogenic effects. This study is the first time to report that VEGF-mediated increase of newly generated neurons is dependent on the presence of reactive astrocytes. The results also illustrate cellular mechanism of VEGF-enhanced neural repair and functional plasticity in the brains after ischemic injury. We concluded that neurogenic effect of VEGF is related to increase of striatal astrocytes transdifferentiation into new mature neurons, which should be very important for the reconstruction of neurovascular units/networks in non-neurogenic regions of the mammalian brain. PMID- 26603139 TI - Effects of extended lay-off periods on performance and operator trust under adaptable automation. AB - Little is known about the long-term effects of system reliability when operators do not use a system during an extended lay-off period. To examine threats to skill maintenance, 28 participants operated twice a simulation of a complex process control system for 2.5 h, with an 8-month retention interval between sessions. Operators were provided with an adaptable support system, which operated at one of the following reliability levels: 60%, 80% or 100%. Results showed that performance, workload, and trust remained stable at the second testing session, but operators lost self-confidence in their system management abilities. Finally, the effects of system reliability observed at the first testing session were largely found again at the second session. The findings overall suggest that adaptable automation may be a promising means to support operators in maintaining their performance at the second testing session. PMID- 26603140 TI - The dipeptidyl peptidase IV inhibitor vildagliptin suppresses development of neuropathy in diabetic rodents: effects on peripheral sensory nerve function, structure and molecular changes. AB - Incretin-related therapy was found to be beneficial for experimental diabetic neuropathy, but its mechanism is obscure. The purpose of this study is to explore the mechanism through which dipeptidyl peptidase IV inhibitor, vildagliptin (VG), influences neuropathy in diabetic rodents. To this end, non-obese type 2 diabetic Goto-Kakizaki rats (GK) and streptozotocin (STZ)-induced diabetic mice were treated with VG orally. Neuropathy was evaluated by nerve conduction velocity (NCV) in both GK and STZ-diabetic mice, whereas calcitonin-gene-related peptide expressions, neuronal cell size of dorsal root ganglion (DRG) and intraepidermal nerve fiber density were examined in GK. DRG from GK and STZ-diabetic mice served for the analyses of GLP-1 and insulin signaling. As results, VG treatment improved glucose intolerance and increased serum insulin and GLP-1 in GK accompanied by the amelioration of delayed NCV and neuronal atrophy, reduced calcitonin-gene-related peptide expressions and intraepidermal nerve fiber density. Diet restriction alone did not significantly influence these measures. Impaired GLP-1 signals such as cAMP response element binding protein, protein kinase B/Akt (PKB/Akt) and S6RP in DRG of GK were restored in VG-treated group, but the effect was equivocal in diet-treated GK. Concurrently, decreased phosphorylation of insulin receptor substrate 2 in GK was corrected by VG treatment. Consistent with the effect on GK, VG treatment improved NCV in diabetic mice without influence on hyperglycemia. DRG of VG-treated diabetic mice were characterized by correction of GLP-1 signals and insulin receptor substrate 2 phosphorylation without effects on insulin receptor beta expression. The results suggest close association of neuropathy development with impaired signaling of insulin and GLP-1 in diabetic rodents. Diabetic neurons are resistant to insulin and such insulin resistance may contribute to development of neuropathy. DPP-IV inhibitor, vildagliptin, corrected insulin resistance and improved neuropathy irrespective of blood glucose via augmented action of GLP-1. PMID- 26603141 TI - Serotonin attenuates biotic stress and leads to lesion browning caused by a hypersensitive response to Magnaporthe oryzae penetration in rice. AB - The hypersensitive response (HR) of plants is one of the earliest responses to prevent pathogen invasion. A brown dot lesion on a leaf is visual evidence of the HR against the blast fungus Magnaporthe oryzae in rice, but tracking the browning process has been difficult. In this study, we induced the HR in rice cultivars harboring the blast resistance gene Pit by inoculation of an incompatible M. oryzae strain, which generated a unique resistance lesion with a brown ring (halo) around the brown fungal penetration site. Inoculation analysis using a plant harboring Pit but lacking an enzyme that catalyzes tryptamine to serotonin showed that high accumulation of the oxidized form of serotonin was the cause of the browning at the halo and penetration site. Our analysis of the halo browning process in the rice leaf revealed that abscisic acid enhanced biosynthesis of serotonin under light conditions, and serotonin changed to the oxidized form via hydrogen peroxide produced by light. The dramatic increase in serotonin, which has a high antioxidant activity, suppressed leaf damage outside the halo, blocked expansion of the browning area and attenuated inhibition of plant growth. These results suggest that serotonin helps to reduce biotic stress in the plant by acting as a scavenger of oxygen radicals to protect uninfected tissues from oxidative damage caused by the HR. The deposition of its oxide at the HR lesion is observed as lesion browning. PMID- 26603142 TI - Simultaneous Liver-Kidney Allocation Policy: A Proposal to Optimize Appropriate Utilization of Scarce Resources. AB - The introduction of the Mayo End-Stage Liver Disease score into the Organ Procurement and Transplantation Network (OPTN) deceased donor liver allocation policy in 2002 has led to a significant increase in the number of simultaneous liver-kidney transplants in the United States. Despite multiple attempts, clinical science has not been able to reliably predict which liver candidates with renal insufficiency will recover renal function or need a concurrent kidney transplant. The problem facing the transplant community is that currently there are almost no medical criteria for candidacy for simultaneous liver-kidney allocation in the United States, and this lack of standardized rules and medical eligibility criteria for kidney allocation with a liver is counter to OPTN's Final Rule. Moreover, almost 50% of simultaneous liver-kidney organs come from a donor with a kidney donor profile index of <=0.35. The kidneys from these donors could otherwise be allocated to pediatric recipients, young adults or prior organ donors. This paper presents the new OPTN and United Network of Organ Sharing simultaneous liver-kidney allocation policy, provides the supporting evidence and explains the rationale on which the policy was based. PMID- 26603144 TI - Usefulness of docetaxel as first-line chemotherapy for metastatic extramammary Paget's disease. AB - In invasive extramammary Paget's disease (EMPD), distant metastases may develop and the condition may become fatal; however, no standardized treatment has been established. Although based on only a few cases, several chemotherapy regimens were reported to be promising. We conducted a multicenter, retrospective study to evaluate the efficacy of docetaxel for metastatic EMPD. We retrospectively collected data on 18 metastatic EMPD patients treated using docetaxel from 1998 to 2012 in 12 institutes in Japan. The following clinical data were collected: tumor response, time to progression, overall survival and adverse effects. Of those, three patients treated combined with S-1, one patient treated with weekly schedule and one patient treated combined with radiotherapy were excluded from the further analysis. All 13 patients received monthly docetaxel as the first line treatment. The average number of treatment cycles was 9.1. Among the 12 patients with a confirmed response, seven (58%) showed a partial response, three (25%) stable disease and two (17%) progressive disease. The disease control rate (partial response + stable disease) was as high as 83%. The time to progression and median overall survival were 7.1 and 16.6 months, respectively. The 1-year overall survival rate determined by the Kaplan-Meier method was 75.0%. All adverse effects were manageable and no treatment-related deaths were observed. The high disease control rate and overall survival shown by this study suggest that first-line use of docetaxel may be a promising treatment for metastatic EMPD. A prospective clinical trial is required to confirm our results. PMID- 26603145 TI - Enantioselective Synthesis of 3a-Amino-Pyrroloindolines by Copper-Catalyzed Direct Asymmetric Dearomative Amination of Tryptamines. AB - A direct asymmetric dearomative amination of tryptamines with O-(2,4 dinitrophenyl)hydroxylamine (DPH) was achieved using CuBr-bisoxazoline complex as a catalyst, affording 3a-amino-pyrroloindolines in good to excellent enantioselectivity under mild reaction conditions. Furthermore, the synthetic value of this method was demonstrated in the total synthesis of (-) psychotriasine in a highly concise manner. PMID- 26603146 TI - Editorial Comment from Dr Cai to Predictive value of urinary interleukin-6 for symptomatic urinary tract infections in a nursing home population. PMID- 26603147 TI - The Relationship Between Verified Organ Donor Designation and Patient Demographic and Medical Characteristics. AB - Previous studies on the correlates of organ donation consent have focused on self reported willingness to donate and on self-reported medical suitability to donate. However, these may be subject to social desirability bias and inaccurate assessments of medical suitability. The authors sought to overcome these limitations by directly verifying donor designation on driver's licenses and by abstracting comorbid conditions from electronic health records. Using a cross sectional study design, they reviewed the health records of 2070 randomly selected primary care patients at a large urban safety-net medical system to obtain demographic and medical characteristics. They also examined driver's licenses that were scanned into electronic health records as part of the patient registration process for donor designation. Overall, 943 (46%) patients were designated as a donor on their driver's license. On multivariate analysis, donor designation was positively associated with age 35-54 years, female sex, nonblack race, speaking English or Spanish, being employed, having private insurance, having an income >$45 000, and having fewer comorbid conditions. These demographic and medical characteristics resulted in patient subgroups with donor designation rates ranging from 21% to 75%. In conclusion, patient characteristics are strongly related to verified donor designation. Further work should tailor organ donation efforts to specific subgroups. PMID- 26603148 TI - Organic pollutants in the central and coastal Beibu Gulf, South China Sea. AB - Surface sediments from the central and coastal Beibu Gulf, southern China, were analyzed for persistent organic pollutants. The absence of polychlorinated biphenyls (PCB; generally below detection limit), low concentrations of polycyclic aromatic hydrocarbons (PAH; 24-647 ng g(-1)), and locally high contamination with organo-chloro pesticides (DDT; 0.03-92 ng g(-1)) reflect the early stages of development in southwest China, with human activities dominated by agriculture and low impact of industry. Concentrations of PCB and PAH indicate no ecological risk, while DDT accumulation poses a probable toxic risk in coastal but not in shelf sediments. Diagnostic ratios suggest PAH originating mainly from combustion of biomass and diesel fuels, and recent DDT use in agriculture and antifouling paint. Distribution patterns along the coastal-shelf-gradient indicate mainly airborne transport of PAH and waterborne transport of DDT. In the central Gulf, also water column samples reveal low concentrations of PAH (1.7-7.8 ng L(-1)) and DDT (0.006-0.053 ng L(-1)). PMID- 26603149 TI - The relevance of the side-view in body image scales for public health: an example from two African populations. AB - BACKGROUND: Body size scales are a common method for diagnosing body image disturbances and assessing the cultural valorisation of stoutness, a phenomenon that plays a role in the development of overweight, especially among African populations. Traditionally, body size scales present a front view. In this study, we evaluated a complementary model of representing body shape: the side view of body outlines. In particular, we examined the association between the side-view and a set of bio-anthropometric indices in men and women. METHODS: To cover the inter-ethnic variability in the Niger-Congo area, we selected a balanced sex ratio sample of 80 Cameroonians and 81 Senegalese. Individuals wearing close fitting clothes were photographed from the front-and side-view, and measured following a bio-anthropometric protocol synthesizing body shape variation: Body Mass Index, percentage body fat, somatotype profile, waist circumference, waist to-hip ratio, mean blood pressure and glycaemia. The shape of each front and side body outline was extracted and characterised by Normalized Elliptic Fourier Descriptors (NEFD). Finally, we assessed associations between NEFD and bio anthropometric indices. RESULTS: Variation in the shape of both front and side body outlines was associated with all bio-anthropometrics for at least one sex population combination. Overall, the side view best captured body shape variation related to changes in almost all bio-anthropometrics in both sexes and populations, with the exceptions of female mesomorphy, male blood pressure and glycaemia (in both sexes). We found that the details of the relationship between bio-anthropometrics and body shape differed between the two male populations, a finding that was reflected in side-views for all criteria, but not front-views. CONCLUSIONS: Variation in body shape assessed by several bio-anthropometrics related to health and nutritional status was larger for side than front body outlines. Integrating side views in body size scales would improve the accuracy of body size assessment and thus, the assessment of behaviours leading to overweight, as well as symptoms of body image disturbances, in Africa and potentially in other populations. PMID- 26603150 TI - Peripheral vascular reactivity and serum BDNF responses to aerobic training are impaired by the BDNF Val66Met polymorphism. AB - Besides neuronal plasticity, the neurotrophin brain-derived neurotrophic factor (BDNF) is also important in vascular function. The BDNF has been associated with angiogenesis through its specific receptor tropomyosin-related kinase B (TrkB). Additionally, Val66Met polymorphism decreases activity-induced BDNF. Since BDNF and TrkB are expressed in vascular endothelial cells and aerobic exercise training can increase serum BDNF, this study aimed to test the hypotheses: 1) Serum BDNF levels modulate peripheral blood flow; 2) The Val66Met BDNF polymorphism impairs exercise training-induced vasodilation. We genotyped 304 healthy male volunteers (Val66Val, n = 221; Val66Met, n = 83) who underwent intense aerobic exercise training on a running track three times/wk for 4 mo. We evaluated pre- and post-exercise training serum BDNF and proBDNF concentration, heart rate (HR), mean blood pressure (MBP), forearm blood flow (FBF), and forearm vascular resistance (FVR). In the pre-exercise training, BDNF, proBDNF, BDNF/proBDNF ratio, FBF, and FVR were similar between genotypes. After exercise training, functional capacity (Vo2 peak) increased and HR decreased similarly in both groups. Val66Val, but not Val66Met, increased BDNF (interaction, P = 0.04) and BDNF/proBDNF ratio (interaction, P < 0.001). Interestingly, FBF (interaction, P = 0.04) and the FVR (interaction, P = 0.01) responses during handgrip exercise (HG) improved in Val66Val compared with Val66Met, even with similar responses of HR and MBP. There were association between BDNF/proBDNF ratio and FBF (r = 0.64, P < 0.001) and FVR (r = -0.58, P < 0.001) during HG exercise. These results show that peripheral vascular reactivity and serum BDNF responses to exercise training are impaired by the BDNF Val66Met polymorphism and such responsiveness is associated with serum BDNF concentrations in healthy subjects. PMID- 26603151 TI - Pharmacodynamic modelling of in vitro activity of tetracycline against a representative, naturally occurring population of porcine Escherichia coli. AB - BACKGROUND: The complex relationship between drug concentrations and bacterial growth rates require not only the minimum inhibitory concentration but also other parameters to capture the dynamic nature of the relationship. To analyse this relationship between tetracycline concentration and growth of Escherichia coli representative of those found in the Danish pig population, we compared the growth of 50 randomly selected strains. The observed net growth rates were used to describe the in vitro pharmacodynamic relationship between drug concentration and net growth rate based on E max model with three parameters: maximum net growth rate (amax); concentration for a half-maximal response (E max); and the Hill coefficient (gamma). RESULTS: The net growth rate in the absence of antibiotic did not differ between susceptible and resistant isolates (P = 0.97). The net growth rate decreased with increasing tetracycline concentrations, and this decline was greater in susceptible strains than resistant strains. The lag phase, defined as the time needed for the strain to reach an OD600 value of 0.01, increased exponentially with increasing tetracycline concentration. The pharmacodynamic parameters confirmed that the alphamax between susceptible and resistant strains in the absence of a drug was not different. EC 50 increased linearly with MIC on a log-log scale, and gamma was different between susceptible and resistant strains. CONCLUSIONS: The in vitro model parameters described the inhibition effect of tetracycline on E. coli when strains were exposed to a wide range of tetracycline concentrations. These parameters, along with in vivo pharmacokinetic data, may be useful in mathematical models to predict in vivo competitive growth of many different strains and for development of optimal dosing regimens for preventing selection of resistance. PMID- 26603152 TI - Rituximab in paediatric onset multiple sclerosis: a case series. AB - Paediatric onset multiple sclerosis (POMS) is characterized by high inflammatory activity. No disease modifying treatment has been approved for POMS. The objective of this report was to report the use of rituximab, a B cell depleting monoclonal anti-CD20-antibody, in POMS. This is a retrospective case series at four specialized MS centres in Sweden. Participants were identified through the Swedish MS-registry and our own patient stocks. Data were collected through medical charts review. We identified 14 POMS patients treated with i.v. rituximab 500-1000 mg every 6th to 12th months. Median age at disease onset was 14.7 years, median age at rituximab treatment initiation was 16.5 years, and median treatment duration was 23.6 months. No relapses were reported, and the EDSS scores remained stable or decreased in 13 of 14 cases during rituximab treatment. Beyond 6 months from initiating rituximab treatment, only one new lesion was detected on MRI. No serious AEs were reported. The drug survival was 86%. Our data indicate that rituximab treatment is safe, effective and well tolerated in children with MS. Nine POMS cases treated with rituximab have previously been published. They had higher disease activity pre-rituximab, but similar safety and efficacy outcomes after treatment. An RCT of rituximab in POMS is warranted. PMID- 26603153 TI - Abdominal Aortic Calcification Identified on Lateral Spine Images From Bone Densitometers Are a Marker of Generalized Atherosclerosis in Elderly Women. AB - OBJECTIVE: Dual-energy x-ray absorptiometry is a low-cost, minimal radiation technique used to improve fracture prediction. Dual-energy x-ray absorptiometry machines can also capture single-energy lateral spine images, and abdominal aortic calcification (AAC) is commonly seen on these images. APPROACH AND RESULTS: We investigated whether dual-energy x-ray absorptiometry-derived measures of AAC were related to an established test of generalized atherosclerosis in 892 elderly white women aged >70 years with images captured during bone density testing in 1998/1999 and B-mode carotid ultrasound in 2001. AAC scores were calculated using a validated 24-point scale into low (AAC24 score, 0 or 1), moderate (AAC24 scores, 2-5), and severe AAC (AAC24 scores, >5) seen in 45%, 36%, and 19%, respectively. AAC24 scores were correlated with mean and maximum common carotid artery intimal medial thickness (rs=0.12, P<0.001 and rs=0.14, P<0.001). Compared with individuals with low AAC, those with moderate or severe calcification were more likely to have carotid atherosclerotic plaque (adjusted prevalence ratio (PR), 1.35; 95% confidence interval, 1.14-1.61; P<0.001 and prevalence ratio, 1.94; 95% confidence interval, 1.65-2.32; P<0.001, respectively) and moderate carotid stenosis (adjusted prevalence ratio, 2.22; 95% confidence interval, 1.39-3.54; P=0.001 and adjusted prevalence ratio, 4.82; 95% confidence interval, 3.09-7.050; P<0.001, respectively). The addition of AAC24 scores to traditional risk factors improved identification of women with carotid atherosclerosis as quantified by C-statistic (+0.075, P<0.001), net reclassification (0.249, P<0.001), and integrated discrimination (0.065, P<0.001). CONCLUSIONS: AAC identified on images from a dual-energy x-ray absorptiometry machine were strongly related to carotid ultrasound measures of atherosclerosis. This low-cost, minimal radiation technique used widely for osteoporosis screening is a promising marker of generalized extracoronary atherosclerosis. PMID- 26603154 TI - Myeloid-Derived Vascular Endothelial Growth Factor and Hypoxia-Inducible Factor Are Dispensable for Ocular Neovascularization--Brief Report. AB - OBJECTIVE: Ocular neovascularization (ONV) is a pathological feature of sight threatening human diseases, such as diabetic retinopathy and age-related macular degeneration. Macrophage depletion in mouse models of ONV reduces the formation of pathological blood vessels, and myeloid cells are widely considered an important source of the vascular endothelial growth factor A (VEGF). However, the importance of VEGF or its upstream regulators hypoxia-inducible factor-1alpha (HIF1alpha) and hypoxia-inducible factor-2alpha (HIF2alpha) as myeloid-derived regulators of ONV remains to be determined. APPROACH AND RESULTS: We used 2 mouse models of ONV, choroidal neovascularization and oxygen-induced retinopathy, to show that Vegfa is highly expressed by several cell types, but not myeloid cells during ONV. Moreover, myeloid-specific VEGF ablation did not reduce total ocular VEGF during choroidal neovascularization or oxygen-induced retinopathy. In agreement, the conditional inactivation of Vegfa, Hif1a, or Epas1 in recruited and resident myeloid cells that accumulated at sites of neovascularization did not significantly reduce choroidal neovascularization or oxygen-induced retinopathy. CONCLUSIONS: The finding that myeloid cells are not a significant local source of VEGF in these rodent models of ONV suggests that myeloid function in neovascular eye disease differs from skin wound healing and other neovascular pathologies. PMID- 26603155 TI - Tissue Factor Pathway Inhibitor: Multiple Anticoagulant Activities for a Single Protein. AB - Tissue factor (TF) pathway inhibitor (TFPI) is an anticoagulant protein that inhibits early phases of the procoagulant response. Alternatively spliced isoforms of TFPI are differentially expressed by endothelial cells and human platelets and plasma. The TFPIbeta isoform localizes to the endothelium surface where it is a potent inhibitor of TF-factor VIIa complexes that initiate blood coagulation. The TFPIalpha isoform is present in platelets. TFPIalpha contains a stretch of 9 amino acids nearly identical to those found in the B-domain of factor V that are well conserved in mammals. These amino acids provide exosite binding to activated factor V, which allows for TFPIalpha to inhibit prothrombinase during the initiation phase of blood coagulation. Endogenous inhibition at this point in the coagulation cascade was only recently recognized and has provided a biochemical rationale to explain the pathophysiological mechanisms underlying several clinical disorders. These include the east Texas bleeding disorder that is caused by production of an altered form of factor V with high affinity for TFPI and a paradoxical procoagulant effect of heparins. In addition, these findings have led to ideas for pharmacological targeting of TFPI that may reduce bleeding in hemophilia patients. PMID- 26603156 TI - S1P2/G12/13 Signaling Negatively Regulates Macrophage Activation and Indirectly Shapes the Atheroprotective B1-Cell Population. AB - OBJECTIVES: Monocyte/macrophage recruitment and activation at vascular predilection sites plays a central role in the pathogenesis of atherosclerosis. Heterotrimeric G proteins of the G12/13 family have been implicated in the control of migration and inflammatory gene expression, but their function in myeloid cells, especially during atherogenesis, is unknown. APPROACH AND RESULTS: Mice with myeloid-specific deficiency for G12/13 show reduced atherosclerosis with a clear shift to anti-inflammatory gene expression in aortal macrophages. These changes are because of neither altered monocyte/macrophage migration nor reduced activation of inflammatory gene expression; on the contrary, G12/13 deficient macrophages show an increased nuclear factor-kappaB-dependent gene expression in the resting state. Chronically increased inflammatory gene expression in resident peritoneal macrophages results in myeloid-specific G12/13 deficient mice in an altered peritoneal micromilieu with secondary expansion of peritoneal B1 cells. Titers of B1-derived atheroprotective antibodies are increased, and adoptive transfer of peritoneal cells from mutant mice conveys atheroprotection to wild-type mice. With respect to the mechanism of G12/13 mediated transcriptional control, we identify an autocrine feedback loop that suppresses nuclear factor-kappaB-dependent gene expression through a signaling cascade involving sphingosine 1-phosphate receptor subtype 2, G12/13, and RhoA. CONCLUSIONS: Together, these data show that selective inhibition of G12/13 signaling in macrophages can augment atheroprotective B-cell populations and ameliorate atherosclerosis. PMID- 26603157 TI - Prognostic impact of immunohistochemical expression of CK7 and CK20 in curatively resected ampulla of Vater cancer. AB - BACKGROUND: In the consideration of ampullary adenocarcinoma, T stage, lymph node metastases, perineural invasion, tumor differentiation, pancraticobiliary type, and lymph node ratio are considered prognostic factors. The objectives of this study were to investigate surgical outcomes and the clinicopathological predictors affecting survival and recurrence, and to examine the prognostic roles of histopathological subtype and immunohistochemical markers. METHODS: From April 2006 to September 2012, 37 patients who underwent curative resection of ampullar of Vater adenocarcinoma were enrolled in this study. A retrospective review was performed based on medical records. Immunohistochemical expression, histopathological type and clinicopathologic factors were analyzed. RESULTS: The 5-year overall survival rates and disease-free survival rates after surgery were 77.4 and 75.7 %, respectively. Multivariate Cox regression analysis showed that advanced T stage (p = 0.019) and positive expression of Cytokeratin 7 (CK7) with negative expression of Cytokeratin 20 (CK20) (p = 0.046) were identified as significant independent factors related to survival, and poor differentiation (p = 0.031) significantly influenced disease-free survival in multivariate analysis. CONCLUSIONS: Advanced T stage is a significant prognostic factor affecting survival in ampullary adenocarcinoma. Also, positive expression of CK7 with negative expression of CK20 is an independent factor related to overall survival. PMID- 26603158 TI - Socioeconomic-related inequalities in child malnutrition: evidence from the Ghana multiple indicator cluster survey. AB - BACKGROUND: Malnutrition is a prevalent public health concern in Ghana. While studies have identified factors that influence child malnutrition and related inequalities in Ghana, very little efforts have been made to decompose these inequalities across various household characteristics. This study examined the influence of socioeconomic factors on inequality in child malnutrition using a decomposition approach. METHODS: The study employed cross section data from the 2011 Multiple Indicator Cluster Survey (MICS). Analysis was done at three levels: First, concentration curves were constructed to explore the nature of inequality in child malnutrition. Secondly, concentration indices were computed to quantify the magnitude of inequality. Thirdly, decomposition analysis was conducted to determine the role of mother's education and health insurance coverage in inequality of child malnutrition. RESULTS: The concentration curves showed that there exists a pro-poor inequality in child malnutrition measured by stunting and wasting. The concentration indices of these measures indicated that the magnitude of inequality was higher and significant at 1 % for weight-for-age (WAZ) ( 0.1641), relative to height-for-age (HAZ) (-0.1613). The decomposition analyses show that whilst mother's education contributed about 13 and 11 % to inequality in HAZ, it contributed about 18.9 and 11.8 % to inequality in WAZ for primary and secondary or above education attainments, respectively. Finally, health insurance contributed about 1.91 and 1.03 % to inequality in HAZ and WAZ, respectively. CONCLUSION: The results suggest that there is the need to encourage critical policies directed towards improving female literacy in the country. The existence of a functional health insurance system and increasing universal coverage are recommended to mitigate child malnutrition. PMID- 26603159 TI - Quality assessment of economic evaluations of health promotion programs for children and adolescents-a systematic review using the example of physical activity. AB - An increasing number of primary prevention programs aimed at promoting physical exercise in children and adolescents are being piloted. As resources are limited, it is important to ascertain the costs and benefits of such programs. The aim of this systematic review is to evaluate the currently available evidence on the cost-effectiveness of programs encouraging physical activity in children and adolescents and to assess their quality. A systematic review was conducted searching in well established literature databases considering all studies before February 2015. Citation tracking in Google Scholar and a manual search of the reference lists of included studies were used to consolidate this. The fundamental methodological elements of the included economic evaluations were extracted, and the quality of the included studies was evaluated using the Pediatric Quality Appraisal Questionnaire (PQAQ). In total, 14 studies were included. Considering the performance of the economic evaluation, the studies showed wide variation. Most of the studies used a societal perspective for their analyses and discounted costs and effects. The findings ranged from US$11.59 for a person to become more active (cheapest intervention) up to US$669,138 for a disability adjusted life year (DALY) saved (most expensive intervention), with everything in between. Overall, the results of three studies are below a value of US$3061, with one of them even below US$200.00, for the achieved effects. For the other programs, the context-specific assessment of cost-effectiveness is problematic as there are different thresholds for cost-effectiveness in different countries or no clearly defined thresholds at all. There are multiple methodological difficulties involved in evaluating the cost-effectiveness of interventions aimed at increasing physical activity, which results in little consistency between different evaluations. The quality of the evaluations ranged from poor to excellent while a large majority of them was of very good methodological quality. Better comparability could be reached by greater standardization, especially regarding systematic consideration of implementation costs. PMID- 26603160 TI - Patient cost sharing and medical expenditures for the Elderly. AB - Despite the rapidly aging population, relatively little is known about how cost sharing affects the elderly's medical spending. Exploiting longitudinal claims data and the drastic reduction of coinsurance from 30% to 10% at age 70 in Japan, we find that the elderly's demand responses are heterogeneous in ways that have not been previously reported. Outpatient services by orthopedic and eye specialties, which will continue to increase in an aging society, are particularly price responsive and account for a large share of the spending increase. Lower cost sharing increases demand for brand-name drugs but not for generics. These high price elasticities may call for different cost-sharing rules for these services. Patient health status also matters: receiving medical services appears more discretionary for the healthy than the sick in the outpatient setting. Finally, we found no evidence that additional medical spending improved short-term health outcomes. PMID- 26603161 TI - Vascular access complications in endovascular procedures with large sheaths. AB - Endovascular procedures, such as transcatheter aortic valve implantation (TAVI), thoracic endovascular aortic repair (TEVAR), and endovascular abdominal aortic repair (EVAR) have been established as promising less invasive therapeutic options. However, despite continuous advances and device improvements, the use of large-sheaths still remains an important challenge, since significant coexisting arterial disease may be encountered in patients undergoing such procedures. Identification of coexisting arterial diseases by optimal preoperative imaging assessment is essential to anticipate these difficulties and avoid the complications by using adequate access options. Should a vascular complication such as iliac rupture occur, vascular interventionists must be aware of salvage procedures to control and treat major complications, such as maintaining wire access across the rupture for occlusion balloon placement and vessel control, while disruption is addressed either through an endovascular or an open approach. The aims of this review are to describe how to prevent vascular complications by optimal preoperative imaging assessment, to detail intraoperative options available for addressing difficult access issues and to discuss how to manage intraoperative major vascular complications. PMID- 26603162 TI - Antitumor action of temozolomide, ritonavir and aprepitant against human glioma cells. AB - In the effort to find better treatments for glioblastoma we tested several currently marketed non-chemotherapy drugs for their ability to enhance the standard cytotoxic drug currently used to treat glioblastoma- temozolomide. We tested four antiviral drugs- acyclovir, cidofovir, maraviroc, ritonavir, and an anti-emetic, aprepitant. We found no cytotoxicity of cidofovir and discussed possible reasons for discrepancy from previous findings of others. We also found no cytotoxicity from acyclovir or maraviroc also in contradistinction to predictions. Cytotoxicity to glioma cell line GAMG for temozolomide alone was 14%, aprepitant alone 7%, ritonavir alone 14%, while temozolomide + aprepitant was 19%, temozolomide + ritonavir 34%, ritonavir + aprepitant 64 %, and all three, temozolomide + ritonavir + aprepitant 78%. We conclude that a remarkable synergy exists between aprepitant and ritonavir. Given the long clinical experience with these two well-tolerated drugs in treating non-cancer conditions, and the current median survival of glioblastoma of 2 years, a trial is warranted of adding these two simple drugs to current standard treatment with temozolomide. PMID- 26603163 TI - Effect of 10 different polymorphisms on preoperative volumetric characteristics of glioblastoma multiforme. AB - There is a distinct diversity between the appearance of every glioblastoma multiforme (GBM) on pretreatment magnetic resonance imaging (MRI) with a potential impact on clinical outcome and survival of the patients. The object of this study was to determine the impact of 10 different single nucleotide polymorphisms (SNPs) on various volumetric parameters in patients harboring a GBM. We prospectively analyzed 20 steroid-naive adult patients who had been treated for newly diagnosed GBM. The volumetry was performed using MRI with the help of a semiautomated quantitative software measuring contrast enhancing tumor volume including necrosis, central necrosis alone and peritumoral edema (PTE). We calculated ratios between the tumor volume and edema (ETR), respectively necrosis (NTR). SNP analysis was done using genomic DNA extracted from peripheral blood genotyped via PCR and sequencing. There was a strong correlation between tumor volume and PTE (p < 0.001), necrosis (p < 0.001) and NTR (p = 0.003). Age and sex had no influence on volumetric data. The Aquaporin 4-31G > A SNP had a significant influence on the ETR (p = 0.042) by decreasing the measured edema compared with the tumor volume. The Interleukin 8-251A > T SNP was significantly correlated with an increased tumor (p = 0.048), PTE (p = 0.033) and necrosis volume (p = 0.028). We found two SNPs with a distinct impact on pretreatment tumor characteristics, presenting a potential explanation for the individual diversity of GBM appearance on MRI and influence on survival. PMID- 26603164 TI - Stereotactic radiosurgery (SRS) in high-grade glioma: judicious selection of small target volumes improves results. AB - We present a retrospective review of 55 Stereotactic Radiosurgery (SRS) procedures performed in 47 consecutive patients with high-grade glioma (HGG). Thirty-three (70.2%) patients were diagnosed with glioblastoma and 14 (29.8%) with grade III glioma. The indications for SRS were small (up to 30 mm in diameter) locally progressing lesions in 32/47 (68%) or new distant lesions in 15/47 (32%) patients. The median target volume was 2.2 cc (0.2-9.5 cc) and the median prescription dose was 18 Gy (14-24 Gy). Three patients (5.5% incidence in 55 treatments) developed radiation necrosis. In eight cases (17%) patients received a second salvage SRS treatment to nine new lesions detected during follow-up. In 22/55 SRS treatments (40.0%) patients received concurrent chemo- or biological therapy, including temozolamide (TMZ) (15 patients), bevacizumab (BVZ) (6 patients) and carboplatin in one patient. Median time to progression after SRS was 5.0 months (1.0-96.4). Median survival time after SRS was 15.9 months (2.3 109.3) overall median survival (since diagnosis) was 37.4 months (9.6-193.6 months). Long-lasting responses (>12 months) after SRS were observed in 25/46 (54.3%) patients. We compared a matched (histology, age, KPS) cohort of patients with recurrent HGG treated with BVZ alone with the current study group. Median survival was significantly longer for SRS treated patients compared to the BVZ only cohort (12.6 vs. 7.3 months, p = 0.0102). SRS may be considered an effective salvage procedure for selected patients with small volume, recurrent high-grade gliomas. Long-term radiological control was observed in more than 50% of the patients. PMID- 26603165 TI - The truth on IgD in the ploy of immune surveillance and inflammation. PMID- 26603166 TI - Subclinical intestinal inflammation in chronic granulomatous disease patients. AB - Chronic granulomatous disease is a primary immunodeficiency caused by impaired neutrophil production of reactive oxygen species. Non-infectious colitis is common in chronic granulomatous disease, and high levels of antimicrobial antibodies that are associated with Crohn's disease are common even without colitis. Fecal calprotectin concentration is a marker for intestinal inflammation. We sought to determine whether subclinical intestinal inflammation occurs in asymptomatic chronic granulomatous disease patients. Asymptomatic chronic granulomatous disease patients without overt gastrointestinal symptoms suggestive of colitis at the time of enrollment were studied for fecal calprotectin concentration, antibodies associated with Crohn's disease and systemic inflammatory markers. Eight patients were included, aged 54-176 months. In 7/8 (87.5 %) fecal calprotectin concentration was normal (<50) and elevated (137 mg/kg) in only one patient. This patient later developed colitis. In 7/8 (87.5 %) anti-Saccharomyces cerevisiae antibody was positive. C-reactive protein, albumin, complete blood count and p-anti-neutrophil cytoplasmic antibody were normal in all 8 patients. Subclinical colitis is not evident in most asymptomatic chronic granulomatous disease patients; however, in some patients, fecal calprotectin concentration may be elevated, possibly indicating the presence of subclinical colitis and predicting the occurrence of clinically relevant colitis. Serum anti-Saccharomyces cerevisiae antibody concentrations do not seem to correlate with fecal calprotectin concentration in asymptomatic chronic granulomatous disease patients. PMID- 26603167 TI - Positive association of genetic variations in the phospholipase C-like 1 gene with dermatomyositis in Chinese Han. AB - Idiopathic inflammatory myopathies (IIMs) are autoimmune diseases with an underlying yet undefined genetic component. Recently, phospholipase C-like 1 (PLCL1) has been identified as a potential genetic susceptibility locus for dermatomyositis (DM) in patients of European ancestry. Here, association between PLCL1 polymorphisms and IIMs was investigated in Chinese Han. Genomic DNA was isolated from blood samples (2 mL) collected from Chinese Han (>=18 years) with polymyositis (PM, n = 286) or dermatomyositis (DM, n = 535) and ethnically matched controls (n = 968). Patients and controls were genotyped for five SNPs (rs938929, rs1518364, rs6738825, rs2117339, and rs7572733) previously associated with DM, with the Sequenom MassARRAY system. SNPs rs6738825 and rs7572733 were found to be associated with the development of DM in Chinese Han (P c = 0.015; P c = 0.025, respectively) as well as the risk A allele of rs938929 and T allele of rs1518364 (P c = 0.030; P c = 0.029). None of the five SNPs were associated with PM (all P c > 0.05). The frequency of the two haplotypes of these five SNPs was also significantly different between DM patients and healthy controls. In addition, conditional analysis with rs6738825 revealed that these SNPs were not independent factors contributing to DM. Finally, a novel association between rs6738825 and rs7572733 and DM with complicating interstitial lung disease was observed (ILD; P c = 0.040; P c = 0.030, respectively). A positive association between PLCL1 polymorphisms and DM patients and DM patients with ILD was observed, indicating that PLCL1 might be the susceptibility gene for DM patients in Chinese Han. PMID- 26603168 TI - Role of immune tolerance in BALB/c mice with anaphylactic shock after Echinococcus granulosus infection. AB - This study tested the hypothesis that immune tolerance mediated by regulatory T (Treg) cells is protective against cystic echinococcosis (CE)-induced anaphylactic shock. BALB/c mice were inoculated with protoscoleces of Echinococcus granulosus. After 3 months, the presence of cysts in the peritoneal cavity was confirmed after which a subset of mice was sensitized using a cyst fluid suspension to induce anaphylactic shock. While IgE levels were significantly higher in both groups inoculated with E. granulosus as compared to the healthy control group (both P < 0.01), sensitized mice had higher IgE levels as compared with those with E. granulosus alone (P < 0.05). Mice inoculated with E. granulosus alone and sensitized mice both had significantly higher histamine levels as compared to the healthy controls. The proportion of CD4(+)CD25(+)Foxp3(+) Treg cells relative to CD4(+) cells was significantly higher in mice inoculated with E. granulosus alone (P < 0.0167); significantly higher interleukin-10 (IL-10) and tumor growth factor-beta (TGF-beta1) levels were also noted in this group (all P < 0.01). In contrast, IL-13 and IL-17A levels were significantly higher in the sensitized mice (both P < 0.05). Taken together, these data suggest that the biphasic changes in Treg cell and cytokine levels may be associated with anaphylactic shock induced by CE. PMID- 26603169 TI - Assessment of relative bioavailability of heavy metals in soil using in vivo mouse model and its implication for risk assessment compared with bioaccessibility using in vitro assay. AB - There is limited study to simultaneously determine the relative bioavailability of heavy metals such as Cd, Pb, Cu, Cr(VI), and Ni in soil samples. In the present study, the bioaccessibility of heavy metals using in vitro assay was compared with the relative bioavailability of heavy metals using in vivo mouse model. The bioaccessibility of heavy metals ranged from 9.05 +/- 0.97 % (Cr) to 42.8 +/- 3.52 % (Cd). The uptake profile of heavy metals in soil and solution samples in mouse revealed that the uptake kinetics could be fitted to a two compartment model. The relative bioavailability of heavy meals ranged from 34.8 +/- 7.0 % (Ni) to 131 +/- 20.3 % (Cu). Poor correlation between bioaccessibility and relative bioavailability of heavy metals was observed (r (2) = 0.11, p > 0.05). The relative bioavailability of heavy metals was significantly higher than the bioaccessibility of heavy metals (p < 0.05). The present study indicated that the in vitro digestion method should be carefully employed in risk assessment. PMID- 26603170 TI - Artemisinin-based combination therapy for knowlesi malaria. PMID- 26603171 TI - Colistin resistance: a major breach in our last line of defence. PMID- 26603172 TI - Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. AB - BACKGROUND: Until now, polymyxin resistance has involved chromosomal mutations but has never been reported via horizontal gene transfer. During a routine surveillance project on antimicrobial resistance in commensal Escherichia coli from food animals in China, a major increase of colistin resistance was observed. When an E coli strain, SHP45, possessing colistin resistance that could be transferred to another strain, was isolated from a pig, we conducted further analysis of possible plasmid-mediated polymyxin resistance. Herein, we report the emergence of the first plasmid-mediated polymyxin resistance mechanism, MCR-1, in Enterobacteriaceae. METHODS: The mcr-1 gene in E coli strain SHP45 was identified by whole plasmid sequencing and subcloning. MCR-1 mechanistic studies were done with sequence comparisons, homology modelling, and electrospray ionisation mass spectrometry. The prevalence of mcr-1 was investigated in E coli and Klebsiella pneumoniae strains collected from five provinces between April, 2011, and November, 2014. The ability of MCR-1 to confer polymyxin resistance in vivo was examined in a murine thigh model. FINDINGS: Polymyxin resistance was shown to be singularly due to the plasmid-mediated mcr-1 gene. The plasmid carrying mcr-1 was mobilised to an E coli recipient at a frequency of 10(-1) to 10(-3) cells per recipient cell by conjugation, and maintained in K pneumoniae and Pseudomonas aeruginosa. In an in-vivo model, production of MCR-1 negated the efficacy of colistin. MCR-1 is a member of the phosphoethanolamine transferase enzyme family, with expression in E coli resulting in the addition of phosphoethanolamine to lipid A. We observed mcr-1 carriage in E coli isolates collected from 78 (15%) of 523 samples of raw meat and 166 (21%) of 804 animals during 2011-14, and 16 (1%) of 1322 samples from inpatients with infection. INTERPRETATION: The emergence of MCR-1 heralds the breach of the last group of antibiotics, polymyxins, by plasmid mediated resistance. Although currently confined to China, MCR-1 is likely to emulate other global resistance mechanisms such as NDM-1. Our findings emphasise the urgent need for coordinated global action in the fight against pan-drug resistant Gram-negative bacteria. FUNDING: Ministry of Science and Technology of China, National Natural Science Foundation of China. PMID- 26603173 TI - Duration of BCG protection against tuberculosis and change in effectiveness with time since vaccination in Norway: a retrospective population-based cohort study. AB - BACKGROUND: Little is known about how long the BCG vaccine protects against tuberculosis. We assessed the long-term vaccine effectiveness (VE) in Norwegian born individuals. METHODS: In this retrospective population-based cohort study, we studied Norwegian-born individuals aged 12-50 years who were tuberculin skin test (TST) negative and eligible for BCG vaccination as part of the last round of Norway's mandatory mass tuberculosis screening and BCG vaccination programme between 1962 and 1975. We excluded individuals who had tuberculosis before or in the year of screening and those with unknown TST and BCG status. We obtained TST and BCG information and linked it to the National Tuberculosis Register, population and housing censuses, and the population register for emigrations and deaths. We followed individuals up to their first tuberculosis episode, emigration, death, or Dec 31, 2011. We used Cox regressions to estimate VE against all tuberculosis and just pulmonary tuberculosis by time since vaccination, adjusted for age, time, county-level tuberculosis rates, and demographic and socioeconomic indicators. FINDINGS: Median follow-up was 41 years (IQR 32-49) for 83 421 BCG-unvaccinated and 44 years (41-46) for 297 905 vaccinated individuals, with 260 tuberculosis episodes. Tuberculosis rates were 3.3 per 100 000 person-years in unvaccinated and 1.3 per 100 000 person-years in vaccinated individuals. The adjusted average VE during 40 year follow-up was 49% (95% CI 26-65), although after 20 years, the VE was not significant (up to 9 years VE [excluding tuberculosis episodes in the first 2 years] 61% [95% CI 24 80]; 10-19 years 58% [27-76]; 20-29 years 38% [-32 to 71]; 30-40 years 42% [-24 to 73]). VE against pulmonary tuberculosis up to 9 years (excluding tuberculosis episodes in the first 2 years) was 67% (95% CI 27-85), 10-19 years was 63% (32 80), 20-29 years was 50% (-19 to 79), and 30-40 years was 40% (-46 to 76). INTERPRETATION: Findings are consistent with long-lasting BCG protection, but waning of VE with time. The vaccine could be more cost effective than has been previously estimated FUNDING: Norwegian Institute of Public Health and London School of Hygiene & Tropical Medicine. PMID- 26603175 TI - Long-term protectiveness of BCG. PMID- 26603174 TI - Artesunate-mefloquine versus chloroquine for treatment of uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT KNOW): an open-label, randomised controlled trial. AB - BACKGROUND: The zoonotic parasite Plasmodium knowlesi has become the most common cause of human malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate-mefloquine with chloroquine to define the optimum treatment for uncomplicated P knowlesi malaria in adults and children. METHODS: We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P knowlesi malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate-mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876. FINDINGS: Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76-91]) of 115 patients in the artesunate mefloquine group versus 61 (55% [45-64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18.0-40.8]; p<0.0001). Parasite clearance was faster in patients given artesunate-mefloquine than in those given chloroquine (18.0 h [range 6.0-48.0] vs 24.0 h [6.0-60.0]; p<0.0001), with faster clearance of ring stages in the artesunate-mefloquine group (mean time to 50% clearance of baseline parasites 8.6 h [95% CI 7.9-9.4] vs 13.8 h [12.1-15.4]; p<0.0001). Risk of anaemia within 28 days was lower in patients in the artesunate mefloquine group (71 [62%; 95% CI 52.2-70.6]) than in those in the chloroquine group (83 [75%; 65.6-82.5]; p=0.035). Gametocytaemia as detected by PCR for pks25 was present in 44 (86%) of 51 patients in the artesunate-mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate-mefloquine group (mean 11.5 h [95% CI 8.3-14.6]) than in the chloroquine group (14.8 h [11.7-17.8]; p=0.034). Bed occupancy was 2426 days per 1000 patients in the artesunate-mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0.858 [95% CI 0.812-0.906]; p<0.0001). One (<1%) patient in the artesunate-mefloquine group had a serious neuropsychiatric event regarded as probably related to study drug. INTERPRETATION: Artesunate-mefloquine is highly efficacious for treatment of uncomplicated P knowlesi malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas. FUNDING: Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network. PMID- 26603177 TI - Sensitive and label-free detection of miRNA-145 by triplex formation. AB - The development of new strategies for detecting microRNAs (miRNAs) has become a crucial step in the diagnostic field. miRNA profiles depend greatly on the sample and the analytical platform employed, leading sometimes to contradictory results. In this work, we study the use of modified parallel tail-clamps to detect a miRNA sequence involved in tumor suppression by triplex formation. Thermal denaturing curves and circular dichroism (CD) measurements have been performed to confirm that parallel clamps carrying 8-aminoguanine form the most stable triplex structures with their target miRNA. The modified tail-clamps have been tested as bioreceptors in a surface plasmon resonance (SPR) biosensor for the detection of miRNA-145. The detection limit was improved 2.4 times demonstrating that a stable triplex structure is formed between target miRNA and 8-aminoguanine tail-clamp bioreceptor. This new approach is an essential step toward the label-free and reliable detection of miRNA signatures for diagnostic purposes. PMID- 26603176 TI - The National Cardiovascular Data Registry Voluntary Public Reporting Program: An Interim Report From the NCDR Public Reporting Advisory Group. AB - Public reporting of health care data continues to proliferate as consumers and other stakeholders seek information on the quality and outcomes of care. Medicare's Hospital Compare website, the U.S. News & World Report hospital rankings, and several state-level programs are well known. Many rely heavily on administrative data as a surrogate to reflect clinical reality. Clinical data are traditionally more difficult and costly to collect, but more accurately reflect patients' clinical status, thus enhancing the validity of quality metrics. We describe the public reporting effort being launched by the American College of Cardiology and partnering professional organizations using clinical data from the National Cardiovascular Data Registry (NCDR) programs. This hospital-level voluntary effort will initially report process of care measures from the percutaneous coronary intervention (CathPCI) and implantable cardioverter defibrillator (ICD) registries of the NCDR. Over time, additional process, outcomes, and composite performance metrics will be reported. PMID- 26603178 TI - Recent developments in methodology employed to study the interactions between nanomaterials and model lipid membranes. AB - With the boom of nanotechnology, nanomaterials (NMs) have been widely utilized in diverse applications, especially in biological and biomedical fields. Understanding how NMs interact with biomolecules, including proteins, DNA, and lipids, is of great importance for revealing the limitations posed and opportunities offered. Model lipid membrane, as a simplified cell membrane model, has been widely used to study the nanomaterial-lipid membrane interactions. In this article, current and emerging techniques, both experimental and theoretical, to investigate the interactions between NMs and model lipid membrane are summarized with each tool's capacities and limitations, along with future directions and challenges in this exciting area. This critical information will provide methodological guidance for researchers in this field. PMID- 26603179 TI - Keratins K2 and K10 are essential for the epidermal integrity of plantar skin. AB - BACKGROUND: K1 and K2 are the main type II keratins in the suprabasal epidermis where each of them heterodimerizes with the type I keratin K10 to form intermediate filaments. In regions of the ears, tail, and soles of the mouse, only K2 is co-expressed with K10, suggesting that these keratins suffice to form a mechanically resilient cytoskeleton. OBJECTIVE: To determine the effects of the suppression of both main keratins, K2 and K10, in the suprabasal plantar epidermis of the mouse. METHODS: Krt2(-/-) Krt10(-/-) mice were generated by crossing Krt2(-/-) and Krt10(-/-) mice. Epidermal morphology of soles of hind paws was examined macroscopically and histologically. Immunofluorescence analysis and quantitative PCR analysis were performed to analyze the expression of keratins in sole skin of wildtype and Krt2(-/-) Krt10(-/-) mice. Highly abundant proteins of the sole stratum corneum were determined by electrophoretic and chromatographic separation and subsequent mass spectrometry. RESULTS: K2 and K10 are the most prominent suprabasal keratins in normal mouse soles with the exception of the footpads where K1, K9 and K10 predominate. Mice lacking both K2 and K10 were viable and developed epidermal acanthosis and hyperkeratosis in inter-footpad epidermis of the soles. The expression of keratins K1, K9 and K16 was massively increased at the RNA and protein levels in the soles of Krt2(-/-) Krt10(-/-) mice. CONCLUSIONS: This study demonstrates that the loss of the main cytoskeletal components of plantar epidermis, i.e. K2 and K10, can be only partly compensated by the upregulation of other keratins. The thickening of the epidermis in the soles of Krt2(-/-) Krt10(-/-) mice may serve as a model for pathomechanistic aspects of palmoplantar keratoderma. PMID- 26603180 TI - Pyogenic granuloma caused by afatinib: Case report and review of the literature. AB - We report on the first case of pyogenic granulomas caused by afatinib. We also review the current literature concerning pyogenic granulomas caused by epidermal growth factor receptor tyrosine kinase inhibitors. PMID- 26603181 TI - Unmet Need for Help With Activities of Daily Living Disabilities and Emergency Department Admissions Among Older Medicare Recipients. AB - Purpose of the Study: This study determined whether self-reports of unmet need for help with activities of daily living (ADL) disabilities are prognostic of emergency department (ED) utilization. Design and Methods: This prospective cohort study of 2,194 community-living, ADL-disabled subjects combined 2004 National Long-Term Care Survey responses with linked Medicare data through 2005. A negative binomial count model was computed to assess the association between unmet ADL need and number of subsequent ED admissions while statistically adjusting for predisposing, enabling, and need characteristics associated with ED admissions among older adults. Results: The adjusted annual incidence rate (IR) for ED admissions was 19% higher for unmet versus met need (IR = 1.19; 95% confidence interval [CI] = 1.00-1.40; p = .047). The IR for ED admissions for falls and injuries was higher for those with unmet ADL versus met ADL need (IR = 1.43; 95% CI = 1.10-1.86), and trended toward significance for ED admissions for skin breakdown (IR = 2.02; 95% CI = 0.97-2.88), but was not significant for ED admissions for dehydration (IR = 1.13; 95% CI= 0.79-1.63). Implications: Unmet ADL need is prognostic of ED admissions, especially for falls and injuries. Future research is needed to determine whether resolution of unmet ADL need reduces ED utilization. PMID- 26603182 TI - Residents Perceptions of Friendship and Positive Social Networks Within a Nursing Home. AB - PURPOSE OF THE STUDY: (i) To describe nursing home residents' perceptions of their friendship networks using social network analysis (SNA) and (ii) to contribute to theory regarding resident friendship schema, network structure, and connections between network ties and social support. DESIGN AND METHODS: Cross sectional interviews, standardized assessments, and observational data were collected in three care units, including a Dementia Specific Unit (DSU), of a 94 bed Sydney nursing home. Full participation consent was obtained for 36 residents aged 63-94 years. Able residents answered open-ended questions about friendship, identified friendship ties, and completed measures of nonfamily social support. RESULTS: Residents retained clear concepts of friendship and reported small, sparse networks. Nonparametric pairwise comparisons indicated that DSU residents reported less perceived social support (median = 7) than residents from the other units (median = 17; U = 10.0, p = .034, r = -.51), (median = 14; U = 0.0, p = .003, r = -.82). Greater perceived social support was moderately associated with higher number of reciprocated ties [rho(25) = .49, p = .013]. IMPLICATIONS: Though some residents had friendships, many reported that nursing home social opportunities did not align with their expectations of friendship. Relationships with coresidents were associated with perceptions of social support. SNA's relational perspective elucidated network size, tie direction, and density, advancing understanding of the structure of residents' networks and flow of subjective social support through that structure. Understanding resident expectations and perceptions of their social networks is important for care providers wishing to improve quality of life in nursing homes. PMID- 26603183 TI - Care to Plan: An Online Tool That Offers Tailored Support to Dementia Caregivers. AB - PURPOSE OF THE STUDY: Even with the advent of evidence-based interventions, an ongoing concern in clinical practice is how to help dementia caregivers determine what type of support is best for them absent a laborious process of trial and error. To help address this practice gap, the present study developed and tested the feasibility of "Care to Plan" (CtP), an online resource for dementia caregivers (e.g., relatives or unpaid nonrelatives) that generates tailored support recommendations. DESIGN AND METHODS: Care to Plan was developed using an iterative prototype and testing process with the assistance of a 29-member Community Advisory Board. A parallel-convergent mixed methods design (quan + QUAL) was used that included a post-CtP survey and a brief semistructured interview to capture in-depth information on the utility and feasibility of CtP. The sample included 30 caregivers of persons with dementia. RESULTS: The integrated qualitative and quantitative data indicated that CtP was simple and easy to understand, the streamlined visual layout facilitated utility, and the individualized recommendations could meet the needs of users. Key barriers to use included the need for additional features (e.g., video introductions of caregiver support types) to further guide dementia caregivers' potential use of tailored support. IMPLICATIONS: The multiple data sources underscore the high feasibility and utility of CtP. By describing, identifying, and prioritizing support, CtP could help to improve the care planning process for dementia caregivers. Future dissemination efforts should aim to demonstrate how CtP can be implemented seamlessly within current family caregiver support systems. PMID- 26603184 TI - What Health and Aged Care Culture Change Models Mean for Residents and Their Families: A Systematic Review. AB - PURPOSE OF THE STUDY: A range of commercialized programs are increasingly being adopted which involve broad culture change within care organizations to implement person-centered care. These claim a range of benefits for clients; however, the published evidence for client and family outcomes from culture change is inconclusive and the evidence for these specific models is difficult to identify. The purpose of this review was to identify and evaluate the peer-reviewed evidence regarding consumer outcomes for these subscription-based models. DESIGN AND METHODS: The review followed the Joanna Briggs Institute procedure. The review considered peer-reviewed literature that reported on studies conducted with health and aged care services, their staff, and consumers, addressed subscription-based person-centered culture change models, and were published in English up to and including 2015. The review identified 19 articles of sufficient quality that reported evidence relating to consumer outcomes and experience. RESULTS: Resident outcomes and family and resident satisfaction and experiences were mixed. Findings suggest potential benefits for some outcomes, particularly related to quality of life and psychiatric symptoms, staff engagement, and functional ability. Although residents and families identified some improvements in residents' lives, both also identified problematic aspects of the change related to staff adjustment and staff time. IMPLICATIONS: Outcomes for these models are at best comparable with traditional care with limited suggestions that they result in poorer outcomes and sufficient potential for benefits to warrant further investigation. Although these models may have the potential to benefit residents, the implementation of person-centered principles may affect the outcomes. PMID- 26603185 TI - Use of Real-World Claim Databases to Assess Prevalence of Comorbid Conditions Relevant to the Treatment of Chronic Myelogenous Leukemia Based on National Comprehensive Network Treatment Guidelines. AB - BACKGROUND: The National Comprehensive Cancer Network (NCCN) guidelines state that based on toxicity profiles, 1 second-generation tyrosine kinase inhibitor (TKI) indicated for first-line therapy (ie, dasatinib, nilotinib) may be preferred over the other for treatment of chronic myelogenous leukemia (CML) patients with certain comorbidities. This study assessed the prevalence of comorbid conditions relevant to TKI treatment choice among CML patients in the US real-world setting. PATIENTS AND METHODS: Patients who had CML and initiated TKI treatment were identified from the MarketScan Commercial and Medicare databases (January 1, 2006, to June 30, 2013). Demographics and prevalence of comorbid conditions relevant to TKI treatment choice per NCCN guidelines (heart disease, arrhythmia, diabetes, pancreatitis, pleural effusion, lung disease) were assessed among the overall study population and among subgroups. RESULTS: The median age of the CML study population newly initiated on TKI treatment (ie, imatinib, dasatinib, or nilotinib; n = 2296) was 56 years. Approximately 41% of the CML study population had at least 1 comorbid condition that may influence the choice of TKI treatment as recommended by NCCN guidelines. The most prevalent comorbid condition was heart disease (23%), followed by diabetes (18%) and lung disease (13%). The prevalence of comorbid conditions relevant to TKI treatment choice varied among patients of different age groups, gender, and US regions. CONCLUSION: The results of this analysis provide real-world evidence that the prevalence of relevant comorbid conditions is substantial among CML patients in the US managed care setting and therefore needs to be considered throughout various health care decision-making processes related to CML. PMID- 26603186 TI - A cost-effectiveness study of person-centered integrated heart failure and palliative home care: Based on a randomized controlled trial. AB - BACKGROUND: Previous economic studies of person-centered palliative home care have been conducted mainly among patients with cancer. Studies on cost effectiveness of advanced home care for patients with severe heart failure are lacking when a diagnosis of heart failure is the only main disease as the inclusion criterion. AIM: To assess the cost-effectiveness of a new concept of care called person-centered integrated heart failure and palliative home care. DESIGN: A randomized controlled trial was conducted from January 2011 to 2013 at a center in Sweden. Data collection included cost estimates for health care and the patients' responses to the EQ-5D quality of life instrument. SETTING/PARTICIPANTS: Patients with chronic and severe heart failure were randomly assigned to an intervention (n = 36) or control (n = 36) group. The intervention group received the Palliative Advanced Home Care and Heart Failure Care intervention over 6 months. The control group received the same care that is usually provided by a primary health care center or heart failure clinic at the hospital. RESULTS: EQ-5D data indicated that the intervention resulted in a gain of 0.25 quality-adjusted life years, and cost analysis showed a significant cost reduction with the Palliative Advanced Home Care and Heart Failure Care intervention. Even if costs for staffing are higher than usual care, this is more than made up for by the reduced need for hospital-based care. This intervention made it possible for the county council to use ?50,000 for other needs. CONCLUSION: The Palliative Advanced Home Care and Heart Failure Care working mode saves financial resources and should be regarded as very cost-effective. PMID- 26603187 TI - Development of a panel of DNA Aptamers with High Affinity for Pancreatic Ductal Adenocarcinoma. AB - Pancreatic cancer costs nearly 40,000 lives in the U.S. each year and has one of the lowest survival rates among cancers. Effective treatment of pancreatic ductal adenocarcinoma is hindered by lack of a reliable biomarker. To address this challenge, aptamers were selected by cell-SELEX (Systematic Evolution of Ligands by EXponential enrichment) targeting human pancreatic ductal adenocarcinoma (PL45). Five promising aptamers presenting low Kd values and good specificity were generated. Among these five aptamers, one was tailored into a nanostructure carrying a high drug payload for specific drug delivery. The results show a viability of almost 80% for negative cells while only 50% of the target cells remained alive after 48 h incubation. These results lead to the conclusion that further research could reveal protein biomarkers specific to pancreatic adenocarcinoma, with probes available for early detection. PMID- 26603190 TI - Neuronal Regulation of Energy Homeostasis: Beyond the Hypothalamus and Feeding. AB - The essential role of the brain in maintaining energy homeostasis has motivated the drive to define the neural circuitry that integrates external and internal stimuli to enact appropriate and consequential metabolic and behavioral responses. The hypothalamus has received significant attention in this regard given its ability to influence feeding behavior, yet organisms rely on a much broader diversity and distribution of neuronal networks to regulate both energy intake and expenditure. Because energy balance is a fundamental determinant of survival and success of an organism, it is not surprising that emerging data connect circuits controlling feeding and energy balance with higher brain functions and degenerative processes. In this review, we will highlight both classically defined and emerging aspects of brain control of energy homeostasis. PMID- 26603188 TI - Mitochondrial Dynamics is a Distinguishing Feature of Skeletal Muscle Fiber Types and Regulates Organellar Compartmentalization. AB - Skeletal muscle fibers differentiate into specific fiber types with distinct metabolic properties determined by their reliance on oxidative phosphorylation (OXPHOS). Using in vivo approaches, we find that OXPHOS-dependent fibers, compared to glycolytic fibers, contain elongated mitochondrial networks with higher fusion rates that are dependent on the mitofusins Mfn1 and Mfn2. Switching of a glycolytic fiber to an oxidative IIA type is associated with elongation of mitochondria, suggesting that mitochondrial fusion is linked to metabolic state. Furthermore, we reveal that mitochondrial proteins are compartmentalized to discrete domains centered around their nuclei of origin. The domain dimensions are dependent on fiber type and are regulated by the mitochondrial dynamics proteins Mfn1, Mfn2, and Mff. Our results indicate that mitochondrial dynamics is tailored to fiber type physiology and provides a rationale for the segmental defects characteristic of aged and diseased muscle fibers. PMID- 26603189 TI - Fetuin B Is a Secreted Hepatocyte Factor Linking Steatosis to Impaired Glucose Metabolism. AB - Liver steatosis is associated with the development of insulin resistance and the pathogenesis of type 2 diabetes. We tested the hypothesis that protein signals originating from steatotic hepatocytes communicate with other cells to modulate metabolic phenotypes. We show that the secreted factors from steatotic hepatocytes induce pro-inflammatory signaling and insulin resistance in cultured cells. Next, we identified 168 hepatokines, of which 32 were differentially secreted in steatotic versus non-steatotic hepatocytes. Targeted analysis showed that fetuin B was increased in humans with liver steatosis and patients with type 2 diabetes. Fetuin B impaired insulin action in myotubes and hepatocytes and caused glucose intolerance in mice. Silencing of fetuin B in obese mice improved glucose tolerance. We conclude that the protein secretory profile of hepatocytes is altered with steatosis and is linked to inflammation and insulin resistance. Therefore, preventing steatosis may limit the development of dysregulated glucose metabolism in settings of overnutrition. PMID- 26603192 TI - A study into the role of surface capping on energy transfer in metal cluster semiconductor nanocomposites. AB - Metal cluster-semiconductor nanocomposite materials remain a frontier area of research for the development of optoelectronic, photovoltaic and light harvesting devices because metal nanoclusters and semiconductor QDs are promising candidates for photon harvesting. Here, we have designed well defined metal cluster semiconductor nanostructures using different surface capped negatively charged Au25 nanoclusters (Au NCs) and positively charged cysteamine capped CdTe quantum dots using electrostatic interactions. The main focus of this article is to address the impact of surface capping agents on the photophysical properties of Au cluster-CdTe QD hybrid nanocomposites. Steady state and time resolved spectroscopic studies reveal that photoluminescence quenching, radiative and nonradiative rate, and energy transfer between Au nanoclusters and CdTe QDs have been influenced by the nature of the capping agent. We have calculated the energy transfer related parameters such as the overlap integral, distance between donor and acceptor, Forster distance, efficiency of energy transfer and rate of energy transfer from CdTe QDs to three different Au NCs. Photoluminescence quenching varies from 73% to 43% when changing the capping agents from bovine serum albumin (BSA) to glutathione (GSH). The efficiency of the energy transfer from CdTe QDs to BSA-capped Au NCs is found to be 83%, for Cys-capped Au NCs it was 46% and for GSH-capped Au NCs it was 35%. The efficiency depends on the number of Au clusters attached per QD. This reveals that the nature of capping ligands plays a crucial role in the energy transfer phenomena from CdTe QDs to Au NCs. Interesting findings reveal that the efficient energy transfer in metal cluster-semiconductor nanocomposites may open up new possibilities in designing artificial light harvesting systems for future applications. PMID- 26603191 TI - IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome. AB - Interleukin-18 (IL-18) is activated by Caspase-1 in inflammasome complexes and has anti-obesity effects; however, it is not known which inflammasome regulates this process. We found that mice lacking the NLRP1 inflammasome phenocopy mice lacking IL-18, with spontaneous obesity due to intrinsic lipid accumulation. This is exacerbated when the mice are fed a high-fat diet (HFD) or a high-protein diet, but not when mice are fed a HFD with low energy density (high fiber). Furthermore, mice with an activating mutation in NLRP1, and hence increased IL 18, have decreased adiposity and are resistant to diet-induced metabolic dysfunction. Feeding these mice a HFD further increased plasma IL-18 concentrations and strikingly resulted in loss of adipose tissue mass and fatal cachexia, which could be prevented by genetic deletion of IL-18. Thus, NLRP1 is an innate immune sensor that functions in the context of metabolic stress to produce IL-18, preventing obesity and metabolic syndrome. PMID- 26603193 TI - Crystal structure of vespid phospholipase A(1) reveals insights into the mechanism for cause of membrane dysfunction. AB - Vespid phospholipase A1 (vPLA1) from the black-bellied hornet (Vespa basalis) catalyzes the hydrolysis of emulsified phospholipids and shows potent hemolytic activity that is responsible for its lethal effect. To investigate the mechanism of vPLA1 towards its function such as hemolysis and emulsification, we isolated vPLA1 from V. basalis venom and determined its crystal structure at 2.5 A resolution. vPLA1 belongs to the alpha/beta hydrolase fold family. It contains a tightly packed beta-sheet surrounded by ten alpha-helices and a Gly-X-Ser-X-Gly motif, characteristic of a serine hydrolyase active site. A bound phospholipid was modeled into the active site adjacent to the catalytic Ser-His-Asp triad indicating that Gln95 is located at hydrogen-bonding distance from the substrate's phosphate group. Moreover, a hydrophobic surface comprised by the side chains of Phe53, Phe62, Met91, Tyr99, Leu197, Ala167 and Pro169 may serve as the acyl chain-binding site. vPLA1 shows global similarity to the N-terminal domain of human pancreatic lipase (HPL), but with some local differences. The lid domain and the beta9 loop responsible for substrate selectivity in vPLA1 are shorter than in HPL. Thus, solvent-exposed hydrophilic residues can easily accommodate the polar head groups of phospholipids, thereby accounting for the high activity level of vPLA1. Our result provides a potential explanation for the ability of vPLA1 to hydrolyze phospholipids of cell membrane. PMID- 26603194 TI - Assessment of the changes in quality of life of patients with class II and III deformities during and after orthodontic-surgical treatment. AB - The aim of this longitudinal study was to assess and compare the oral health related quality of life (OHRQoL) of patients with class II and III deformities during and after orthodontic-surgical treatment. Thirty class III and 28 class II patients were evaluated at baseline (T0), just prior to surgery (T1), at 6 months after surgery (T2), and at 12 months after debonding (T3). OHRQoL was assessed using the Oral Health Impact Profile (OHIP-14). Friedman two-way analysis of variance and the Wilcoxon signed-rank test were performed to compare the relative changes in OHRQoL during treatment. Significant changes in the overall OHIP-14 scores were observed during and after orthodontic-surgical treatment in both groups. During the pre-surgical stage, psychological discomfort and psychological disability decreased in class III patients, and class II patients experienced a significant deterioration in psychological discomfort during the same period. Six months after surgery, patients in both groups showed improvements in psychological discomfort, social disability, and handicap. Physical disability and functional limitation showed further improvement at 12 months after debonding in class II patients. This study reaffirms that orthodontic-surgical treatment has a significant effect on the OHRQoL of class III and class II patients. PMID- 26603195 TI - Mandible-first sequence in bimaxillary orthognathic surgery: a systematic review. AB - The sequencing of bimaxillary orthognathic surgery remains controversial, although the traditional maxilla-first approach is performed routinely. The goal of this study was to present a systematic review of the mandible-first sequence in bimaxillary orthognathic surgery, to provide data that may assist in the decision as to which jaw should undergo osteotomy first in bimaxillary orthognathic surgery cases. A literature search was conducted for articles published in the English language, reporting the use of the altered sequence for bimaxillary orthognathic surgery (mandible-first), using the following descriptors: 'orthognathic' and 'double-jaw', 'orthognathic' and 'two-jaw', 'orthognathic' and 'mandible-first', 'orthognathic' and 'bimaxillary'. Eight hundred eighty-seven abstracts were initially identified and were evaluated for inclusion according to the proposed inclusion criteria. After evaluation of these abstracts and relevant references, six publications met the criteria for consideration. Performing mandible-first surgery in bimaxillary orthognathic cases dates back to the 1970s; however the decision regarding the jaw to be operated on first seems to rely on accurate preoperative planning based upon the surgeon's experience and preference. While there appear to be significant theoretical advantages to support the use of the altered orthognathic sequence (mandible-first), future prospective studies on its reliability, accuracy, and short- and long-term outcomes are required. PMID- 26603196 TI - Dual C-H functionalization of N-aryl tetrahydroisoquinolines: a highly diastereoselective synthesis of dibenzo[a,f]quinolizines via visible-light induced oxidation and inverse electron-demand aza-Diels-Alder reaction. AB - Described herein is the first example of the application of an iminium intermediate generated by visible-light photocatalyzed oxidation in an inverse electron-demand aza-Diels-Alder reaction. This dual functionalization of both C(sp(3))-H and C(sp(2))-H bonds of N-aryl tetrahydroisoquinolines represents a valuable example for access to polycycles with high diastereoselectivity. PMID- 26603197 TI - Psychological theories of aging. PMID- 26603198 TI - Solid-gaseous phase transformation of elemental contaminants during the gasification of biomass. AB - Disposal of plant biomass removed from heavy metal contaminated land via gasification achieves significant volume reduction and can recover energy. However, these biomass often contain high concentrations of heavy metals leading to hot-corrosion of gasification facilities and toxic gaseous emissions. Therefore, it is of significant interest to gain a further understanding of the solid-gas phase transition of metal(loid)s during gasification. Detailed elemental analyses (C, H, O, N and key metal/metalloid elements) were performed on five plant species collected from a contaminated site. Using multi-phase equilibria modelling software (MTDATA), the analytical data allows modelling of the solid/gas transformation of metal(loid)s during gasification. Thermodynamic modelling based on chemical equilibrium calculations was carried out in this study to predict the fate of metal(loid) elements during typical gasification conditions and to show how these are influenced by metal(loid) composition in the biomass and operational conditions. As, Cd, Zn and Pb tend to transform to their gaseous forms at relatively low temperatures (<1000 degrees C). Ni, Cu, Mn and Co converts to gaseous forms within the typical gasification temperature range of 1000-1200 degrees C. Whereas Cr, Al, Fe and Mg remain in solid phase at higher temperatures (>1200 degrees C). Simulation of pressurised gasification conditions shows that higher pressures increase the temperature at which solid-to-gaseous phase transformations takes place. PMID- 26603199 TI - Inter-rater Reliability of Real-Time Ultrasound to Measure Acromiohumeral Distance. AB - BACKGROUND: Real-time ultrasound (RTUS) has been suggested as a reliable measure of acromiohumeral distance. However, to date, no vigorous assessment and reporting of inter-rater reliability of this method has been performed with the shoulder in a neutral position or with active and passive arm abduction. OBJECTIVE: To assess intrasession inter-rater reliability of using RTUS to measure acromiohumeral distance with the shoulder in a neutral position and with 60 degrees active and passive abduction. STUDY DESIGN: Inter-rater intrasession reliability of repeated measures. SETTING: Human performance laboratory. PARTICIPANTS: Twenty persons (12 male and 8 female) with an average age of 29.86 years (standard deviation, 7.8). METHOD: In an inter-rater, intrasession study, RTUS was used to measure the acromiohumeral distance with the shoulder in a neutral position and with 60 degrees of both active and passive abduction. MAIN OUTCOME MEASURE: Acromiohumeral distance. RESULTS: Intraclass correlation coefficient (ICC)2.1 scores ranged between 0.65-0.88 (standard error of the mean = 0.81-1.2 mm and minimal detectable differences with 95% confidence = 2.2-2.3 mm) for inter-rater intrasession reliability. CONCLUSION: RTUS was found to have fair to good inter-rater reliability as a tool to measure acromiohumeral distance with the shoulder in a neutral position and with 60 degrees of both active and passive arm abduction. PMID- 26603200 TI - Outcomes of Inpatient Rehabilitation in Patients With Simultaneous Bilateral Total Knee Arthroplasty. AB - BACKGROUND: The number of total knee arthroplasty (TKA) procedures performed in the United States is increasing each year, and the number of bilateral TKA procedures has also increased during the past 2 decades. However, few studies in the literature have investigated the rehabilitation outcomes of patients who undergo bilateral TKA. This study was performed to provide information on the benefits and role of inpatient rehabilitation for patients after bilateral TKA. OBJECTIVE: To investigate the functional outcomes, complications, and transfer rates of patients in the inpatient rehabilitation setting who undergo simultaneous bilateral TKA. DESIGN: Retrospective cohort study. SETTING: Freestanding inpatient rehabilitation hospital. PATIENTS: Ninety-four patients admitted to an inpatient rehabilitation hospital after simultaneous bilateral TKA from 2008-2013. METHODS: Retrospective chart review of demographic, clinical, and functional data for patients admitted to inpatient rehabilitation after simultaneous bilateral TKA. MAIN OUTCOME MEASURES: Length of stay, admission and discharge Functional Independence Measure (FIM), and FIM efficiency. RESULTS: The study included 27 male (28.7%) and 67 female (71.3%) patients aged 42.0-86.9 years, with a mean of 65.6 +/- 10.2 years. Mean length of time between surgery and admission to inpatient rehabilitation was 4.5 +/- 3.3 days. Mean length of stay in rehabilitation was 11.7 +/- 4.2 days. Mean admission and discharge FIM scores were 87.3 +/- 11.7 and 113.4 +/- 4.8, respectively, with a mean FIM gain of 26.1 +/- 10.5. The mean FIM efficiency was 2.33 +/- 0.84. Eight patients required transfer to an acute care hospital. Complications leading to transfer to acute care facilities included sepsis, cardiac arrhythmias, knee dislocation, and suspected small bowel obstruction. Eighty-eight patients were discharged home, 4 patients were discharged to skilled nursing facilities, and 2 patients were transferred to an acute care hospital and did not return to the inpatient rehabilitation hospital. CONCLUSIONS: After undergoing simultaneous bilateral TKA, patients demonstrate functional gains when admitted to inpatient rehabilitation facilities based on FIM gains and FIM efficiency scores; 8.5% of patients in this cohort required transfer to an acute care facility as a result of complications during inpatient rehabilitation, and 93.6% of patients were discharged home. PMID- 26603201 TI - Effects of Exercise During Pregnancy on Maternal Heart Rate and Heart Rate Variability. AB - BACKGROUND: Pregnancy is associated with an increased sympathetic state, which can be exacerbated by gestational conditions. Research has shown that exercise during pregnancy lowers heart rate (HR) and can attenuate the symptoms of gestational conditions associated with increased sympathetic control. However, changes in maternal heart autonomic function in response to exercise have not been reported across multiple time points during pregnancy. This analysis is designed to address this gap. OBJECTIVE: To determine if exercise throughout gestation improves maternal cardiac autonomic nervous system functioning, as evidenced by decreased HR and increased heart rate variability (HRV) indices. DESIGN: Case control study. SETTING: Academic medical institution. PARTICIPANTS: A total of 56 women with healthy, singleton, low-risk pregnancies. METHODS: Participants were asked to complete 3 resting 18-minute HRV recordings at 28, 32, and 36 weeks' gestation, along with a physical activity questionnaire. MAIN OUTCOME MEASURES: HRV indices were calculated for time (R peak to R peak interval standard deviation and root mean squared of successive differences) and frequency (very low, low, and high frequency) domain measures. The differences between groups were compared for HRV indices at 28, 32, and 36 weeks. RESULTS: Resting HR was significantly lower in the exercise group at 28 weeks (P < .01) compared with the control group. The exercise group had significantly (P < .05) increased measures of resting HRV time domain measures at 28, 32, and 36 weeks' gestation compared with the control group. Resting HRV power was significantly increased (P < .05) in all frequency domain measures at 32 weeks in the exercise group relative to the control group. No differences occurred in sympathovagal balance (low frequency/high frequency ratio) between groups. CONCLUSION: Exercise throughout pregnancy can significantly improve cardiac autonomic control. More research is needed to determine if this adaptation to exercise may reduce the risk of adverse outcomes associated with gestational conditions with poor autonomic control, such as diabetes, hypertension, pre-eclampsia, and excessive weight gain. PMID- 26603202 TI - L159F and V321A Sofosbuvir-Associated Hepatitis C Virus NS5B Substitutions. AB - BACKGROUND: Sofosbuvir (SOF) exhibits a high barrier to resistance, with no S282T NS5B substitution or phenotypic resistance detected in phase 3 registration studies. METHODS: Here, emergence of the NS5B variants L159F and V321A and possible association with resistance was evaluated in 8 studies of SOF (NEUTRINO, FISSION, POSITRON, FUSION, VALENCE, PHOTON-1, PHOTON-2, and P7977-2025) and 5 studies of combination ledipasvir (LDV) and SOF (LDV/SOF; LONESTAR, ELECTRON [LDV/SOF arms], ION1, ION2, and ION3), using deep sequencing. RESULTS: Deep sequencing detected L159F in 15% (53 of 353) and V321A in 5% (17 of 353) of patients with virologic failure in the SOF studies. Intensification of SOF treatment with LDV reduced the emergence of L159F or V321A to 2% (1 of 50 each) at virologic failure. L159F and V321A did not influence the outcome of retreatment with SOF, ribavirin, and pegylated interferon. At baseline, L159F was detected only in genotype 1-infected patients (1%) and was only associated with increased virologic failure in patients treated for short durations with SOF and ribavirin. CONCLUSIONS: Deep-sequencing analysis confirmed that NS5B variants L159F and V321A emerged in a subset of patients treated with SOF at virologic failure. These variants had no impact on retreatment outcome with SOF, ribavirin, and pegylated interferon. Baseline L159F in genotype 1 did not affect the treatment outcome with LDV/SOF. PMID- 26603203 TI - Reply to Fernandez-Ruiz et al. PMID- 26603205 TI - Low Natural Killer Cell Counts and Onset of Invasive Fungal Disease After Solid Organ Transplantation. PMID- 26603204 TI - Toll-like Receptor 4 Signaling on Dendritic Cells Suppresses Polymorphonuclear Leukocyte CXCR2 Expression and Trafficking via Interleukin 10 During Intra abdominal Sepsis. AB - BACKGROUND: Toll-like receptor 4 (TLR4) is a critical receptor involved in the sensing of gram-negative bacterial infection. However, the roles of TLR4 in sepsis are cell-type specific. Dendritic cells (DCs) are known to play a central role in microbial detection, alerting the immune system to the presence of infection and coordinating adaptive immune response. The goal of this study was to investigate the impact of DC-specific TLR4 signaling on host defense against intra-abdominal polymicrobial sepsis. METHODS: C57BL/6, global Tlr4 knockout, cell-specific knockout control, and CD11c-specific Tlr4(-/-) mice underwent cecal ligation and puncture (CLP). RESULTS: Specific deletion of TLR4 on DCs in mice improved survival and enhanced bacterial clearance. Deletion of TLR4 on DCs was associated with lower levels of circulating interleukin 10 (IL-10), higher polymorphonuclear leukocyte (PMN) accumulation in the peritoneal cavity, and higher expression of chemokine (C-X-C motif) receptor 2 (CXCR2) on PMNs after CLP. In vitro studies of DC and neutrophil cocultures confirmed that TLR4 dependent secretion of IL-10 from DCs regulated neutrophil CXCR2 expression. CONCLUSIONS: Our data shed light on a previously unrecognized role for TLR4 signaling on DCs in driving IL-10 secretion during sepsis and, through this pathway, regulates PMN recruitment via suppression of CXCR2 expression. PMID- 26603207 TI - STAT5-regulated microRNA-193b controls haematopoietic stem and progenitor cell expansion by modulating cytokine receptor signalling. AB - Haematopoietic stem cells (HSCs) require the right composition of microRNAs (miR) for proper life-long balanced blood regeneration. Here we show a regulatory circuit that prevents excessive HSC self-renewal by upregulation of miR-193b upon self-renewal promoting thrombopoietin (TPO)-MPL-STAT5 signalling. In turn, miR 193b restricts cytokine signalling, by targeting the receptor tyrosine kinase c KIT. We generated a miR-193b knockout mouse model to unravel the physiological function of miR-193b in haematopoiesis. MiR-193b(-/-) mice show a selective gradual enrichment of functional HSCs, which are fully competent in multilineage blood reconstitution upon transplantation. The absence of miR-193b causes an accelerated expansion of HSCs, without altering cell cycle or survival, but by decelerating differentiation. Conversely, ectopic miR-193b expression restricts long-term repopulating HSC expansion and blood reconstitution. MiR-193b-deficient haematopoietic stem and progenitor cells exhibit increased basal and cytokine induced STAT5 and AKT signalling. This STAT5-induced microRNA provides a negative feedback for excessive signalling to restrict uncontrolled HSC expansion. PMID- 26603209 TI - [Fat grafting in breast reconstruction. Retrospective study of satisfaction and quality of life about 68 patients]. AB - BACKGROUND: Evaluate the aesthetic clinical results, satisfaction and quality of life related to health in patients who underwent breast reconstruction by exclusive lipofilling or in addition to other surgical techniques. MEANS AND METHODS: A retrospective observational study was carried between 2009 and 2014 in four groups of patients who underwent a lipofilling by the same operator either after a conservative treatment (group 1), or exclusively (group 2), or after a flap (group 3) or implants (group 4). The sociodemographic data related to lipofilling or tumor pathology were collected and reported in a software designed for this study. Satisfaction and quality of life after lipofilling was assessed using the questionnaire Q BREAST((c)) postoperative reconstruction module. RESULTS: One hundred and seventy lipofilling procedures were performed in 68 patients. The average volume transferred was 1421.2cm(3) for the exclusive lipofilling group and the average number of sessions was 4.9 spread over a period of 15.6months on average. In adjuvant technique or conservative surgery, the average total volume transferred was 212.2cm(3) and the average number of sessions was 1.4. The abdomen was the site most used donor and the posterior thigh exclusively used in exclusive reconstruction. The cytosteatonecrosis rate was 8.8 % (n=6). A single case of infection was noted. The tumor recurrence at ten months after lipofilling concerned two patients. The response rate was 80.8 %. The lipofilling improves the final cosmetic result with a rate of 91.1 % of patients satisfied or very satisfied with their breast. In all, 95.4 % of patients in the exclusive lipofilling group found a secondary benefit after surgery. Quality of life after lipofilling is also improved socially and sexually in the four groups with better results in patients who underwent conservative treatment. CONCLUSION: The lipofilling is a simple, reliable technique, requiring a learning curve, improving the final aesthetic result and the quality of life it is used exclusively or to complement other techniques. PMID- 26603208 TI - Streptococcus agalactiae Serotype Distribution and Antimicrobial Susceptibility in Pregnant Women in Gabon, Central Africa. AB - Neonatal invasive disease due to Streptococcus agalactiae is life threatening and preventive strategies suitable for resource limited settings are urgently needed. Protective coverage of vaccine candidates based on capsular epitopes will relate to local epidemiology of S. agalactiae serotypes and successful management of critical infections depends on timely therapy with effective antibiotics. This is the first report on serotype distribution and antimicrobial susceptibility of S. agalactiae in pregnant women from a Central African region. Serotypes V, III, and Ib accounted for 88/109 (81%) serotypes and all isolates were susceptible to penicillin and clindamycin while 13% showed intermediate susceptibility to erythromycin. PMID- 26603210 TI - Pulmonary embolism, acute coronary syndrome and ischemic stroke in the Spanish National Discharge Database. AB - BACKGROUND: Venous and arterial thrombosis share a number of pathogenic mechanisms, but the burden of pulmonary embolism (PE) has not been consistently compared with that in other arterial diseases. METHODS: We used the Spanish National Discharge Database to compare the frequency, clinical characteristics and mortality rate of all patients with PE, acute coronary syndrome (ACS) or ischemic stroke admitted from 2001 to 2010. Patients were classified as having primary diagnosis (the process leading to hospital admission) or secondary diagnosis (it appeared during hospital stay for other reasons) RESULTS: During the study period, 31,949,739 patients were discharged. Of these, 165,229 (0.52%) were diagnosed with PE, 562,837 (1.76%) with ACS and 495,427 (1.55%) with ischemic stroke. Overall, 31% of patients with PE, 8.4% with ACS and 13% with ischemic stroke had secondary diagnoses. The most common reasons for admission in patients with secondary PE were: cancer (21%), acute respiratory failure (11%), acute heart failure (6.4%) and stroke (5.5%). Mean hospital stay was: 14 +/- 13 days in PE patients, 9.7 +/- 9.7 in those with ACS and 13 +/- 14 days in those with stroke. In-hospital mortality rate was: 10.5%, 10.1% and 12.3% respectively in patients with primary diagnosis, and 36%, 34% and 29% in those with secondary diagnosis. CONCLUSIONS: Patients hospitalized with PE were 3-4 times less frequent than those with ACS or stroke, but had a higher mortality. One in every 3 patients with PE (but only one in every 10 with ACS or stroke) had secondary diagnosis, and these patients had the highest mortality. PMID- 26603212 TI - Afatinib-based combination regimens for the treatment of solid tumors: rationale, emerging strategies and recent progress. AB - In oncology, there is a clinical need for novel combination therapy regimens that maximize efficacy and delay resistance to individual treatment modalities. Given the role of aberrant ErbB receptor signaling in the pathogenesis of many human cancers, there is rationale for incorporating afatinib, an irreversible pan-ErbB tyrosine kinase inhibitor, into such combinations. This review focuses on: pharmacological properties of afatinib that facilitate its use in combination; preclinical rationale for the combination of afatinib with other agents; and recently completed, and ongoing, clinical trials of afatinib-based combinations across tumor types. Based on these data, we emphasize a number of areas of high unmet medical need that could benefit from afatinib-based combinations, including patients with relapsed/refractory non-small-cell lung cancer. PMID- 26603211 TI - Metagenomic insights into communities, functions of endophytes, and their associates with infection by root-knot nematode, Meloidogyne incognita, in tomato roots. AB - Endophytes are known to play important roles in plant's health and productivity. In this study, we investigated the root microbiome of tomato in association with infection by root knot nematodes. Our objectives were to observe the effects and response of the bacterial endophytes before nematode attacks and to reveal the functional attributes of microbes in plant health and nematode pathogenesis. Community analysis of root-associated microbiomes in healthy and nematode infected tomatoes indicated that nematode infections were associated with variation and differentiation of the endophyte and rhizosphere bacterial populations in plant roots. The community of the resident endophytes in tomato root was significantly affected by nemato-pathogenesis. Remarkably, some bacterial groups in the nematode feeding structure, the root gall, were specifically enriched, suggesting an association with nematode pathogenesis. Function-based metagenomic analysis indicated that the enriched bacterial populations in root gall harbored abundant genes related to degradation of plant polysaccharides, carbohydrate and protein metabolism, and biological nitrogen fixation. Our data indicated that some of the previously assumed beneficial endophytes or bacterial associates with nematode might be involved in nematode infections of the tomato roots. PMID- 26603213 TI - A multi-faceted, family-centred nutrition intervention to optimise nutrition intake of critically ill patients: The OPTICS feasibility study. AB - BACKGROUND: Critically ill patients are at risk of developing malnutrition which contributes to functional decline and hospital re-admission. Strategies to promote nutritional intake have had a modest effect on protein-calorie intake. None have addressed the recovery trajectory of critical illness or incorporated family as advocates. OBJECTIVES: We evaluated the feasibility and acceptability of a family-centred intervention designed to optimise nutrition during and following recovery from critical illness. DESIGN: A prospective cohort study. SETTING: Two Australian adult intensive care units. PARTICIPANTS: A convenience sample of 49 patients and their families was recruited. Patients >=18 years of age anticipated to require mechanical ventilation for at least 2 days were eligible, provided their family visited regularly and were able to communicate in English. Health care professionals including doctors (n=4), nurses (n=20) and dietitians (n=2) also participated. METHODS: Demographic data were obtained from participants. Recruitment and retention informed study feasibility. Individual and group interviews informed participant views on the acceptability, perception of and experience with the intervention. Inductive analysis was used to analyse qualitative data. RESULTS: 187 (15.8%) patients met the eligibility criteria; 49 patients and 51 family members consented to participate for a 20.3% consent failure rate. We interviewed 33 (67.3%) family members and 13 (43.4%) patients, all of whom considered the intervention acceptable and who would participate in a similar intervention again, given the opportunity. Inductive analysis of qualitative data from all participants identified three themes: variability in in hospital nutrition support, families as advocates for optimal nutrition, and partnering with health care providers. CONCLUSION: We described a feasible and acceptable family centred intervention that may be effective in promoting nutrition intake in critically ill patients. Further research is required to examine contextual factors impacting implementation of family-centred interventions, particularly those that involve active family participation and advocacy. PMID- 26603214 TI - Transcriptomic analysis of porcine PBMCs infected with Toxoplasma gondii RH strain. AB - Toxoplasma gondii is an obligate, intracellular protozoan that can infect virtually all warm-blooded animals. Humans can be infected through the consumption of undercooked meat of farm animals. However, there are few reports on pathogenic mechanism and immune regulation during the interaction between T. gondii and domesticated animals. RNA extracted from pig peripheral blood mononuclear cells (PBMCs) infected with T. gondii RH strain at different time points (0 h, 8 h, 24 h, and 48 h) were reverse transcribed into cDNA and sequenced using Illumina technology. After ruling out short-length and low quality sequences, more than 18 million clean reads and 14 million unique reads were acquired in each group. Clean reads were then mapped to the pig reference genome and differently expressed (DE) genes were identified. DE genes increased along with the extension of infection time. For function classification and pathway analysis, annotated DE genes were categorized into three Gene Ontology (GO) categories and assigned to six major Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Furthermore, 10 DE genes were identified to be involved in some important immune processes and signaling pathways at the early infection stage. This is the first transcriptomic analysis of pig PBMCs infected by T. gondii. Functional DE genes and KEGG pathways indentified at different time points in this study will help to better understand the host immunity and defense mechanisms and promote the prevention and control of T. gondii infection. PMID- 26603215 TI - alpha-Viniferin and resveratrol induced alteration in the activities of some energy metabolism related enzymes in the cestode parasite Raillietina echinobothrida. AB - alpha-Viniferin (AVF) and its monomer resveratrol (RESV) are natural phytostilbenes produced by several plants in response to injury or under the influence of pathogens such as bacteria or fungi. Our earlier studies have revealed that both the compounds exert anthelmintic activity through alterations of cestode tegument and its associated enzymes. The present study investigates the effects of these phytochemicals on some energy metabolism related enzymes in the fowl tapeworm, Raillietina echinobothrida. The phytostilbenes AVF, RESV and the reference drug praziquantel (PZQ) were tested against some selected enzymes i.e., phosphoenolpyruvate carboxykinase (PEPCK), lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) of R. echinobothrida. Exposure of the tapeworm to AVF, RESV and PZQ causes reduction in activity of PEPCK to the extent of 40.57/41.96, 24.58/23.75 and 41.11/13.47%, respectively, and LDH up to 48.95/16.25, 38.31/38.42 and 45.67/41.87%, respectively, at the time of paralysis. Whereas activity of MDH decreased by 34.22/37.7, 39.1/35.24 and 28.83/19.26%, respectively. Decrease in activities of LDH and MDH was also visible through histochemical observations. The results suggest that both the phytochemicals interfere with the energy transducing pathways by inhibiting the studied energy metabolism related enzymes of the parasite. PMID- 26603216 TI - Characterization of a novel Sclerotinia sclerotiorum RNA virus as the prototype of a new proposed family within the order Tymovirales. AB - Recent studies have shown that Sclerotinia sclerotiorum, an important plant pathogen fungus, harbors diverse mycoviruses. A new mycovirus, tentatively named as Sclerotinia sclerotiorum deltaflexivirus 1 (SsDFV1), was isolated from a S. sclerotiorum strain AX19 containing multiple dsRNA elements. The complete genome of SsDFV1 was shown to be 8178 nucleotides long excluding the poly (A) tail. SsDFV1 has a large putative open reading frame (ORF1) and three smaller ORFs (2 4). ORF1 encodes a putative methyltransferase-helicase-RdRp polyprotein of 2075 amino acids. ORFs (2-4) encode three putative small hypothetical proteins (<40kDa) with unknown biological functions. No evidence for a coat protein encoded by SsDFV1 was obtained. Multiple alignment suggested that three conserved domains, RdRp, methyltransferase, and helicase, from SsDFV1 have lower identity (approximately 25%) with all the reported viruses of four approved families, Alphaflexiviridae, Betaflexiviridae, Gammaflexiviridae and Tymoviridae in the order Tymovirales. Moreover, a phylogenetic tree also suggested that the SsDFV1 could not be phylogenetically placed in any of the approved families, and forms a separated cluster distinct from other known viruses. Therefore, these combined results suggest that SsDFV1 could represent a new positive-sense single-stranded RNA virus with some unique molecular features, and we propose to create a tentative family Deltaflexiviridae that accommodates SsDFV1. PMID- 26603217 TI - A prospective case-control study to investigate retinal microvascular changes in acute dengue infection. AB - Dengue infection can affect the microcirculation by direct viral infection or activation of inflammation. We aimed to determine whether measured retinal vascular parameters were associated with acute dengue infection. Patients with acute dengue were recruited from Communicable Diseases Center, Singapore and age gender-ethnicity matched healthy controls were selected from a population-based study. Retinal photographs were taken on recruitment and convalescence. A spectrum of quantitative retinal microvascular parameters (retinal vascular caliber, fractal dimension, tortuosity and branching angle) was measured using a semi-automated computer-based program. (Singapore I Vessel Assessment, version 3.0). We included 62 dengue patients and 127 controls. Dengue cases were more likely to have wider retinal arteriolar and venular calibers (158.3 MUm vs 144.3 MUm, p < 0.001; 227.7 MUm vs 212.8 MUm, p < 0.001; respectively), higher arteriolar and venular fractal dimensions (1.271 vs 1.249, p = 0.002; 1.268 vs. 1.230, p < 0.001, respectively), higher arteriolar and venular tortuosity (0.730 vs 0.546 [x10(4)], p < 0.001; 0.849 vs 0.658 [x10(4)], p < 0.001; respectively), compared to controls. Resolution of acute dengue coincided with decrease in retinal vascular calibers and venular fractal dimension. Dengue patients have altered microvascular network in the retina; these changes may reflect pathophysiological processes in the immune system. PMID- 26603218 TI - Isothiocyanate-Functionalized Bifunctional Chelates and fac-[M(I)(CO)3](+) (M = Re, (99m)Tc) Complexes for Targeting uPAR in Prostate Cancer. AB - Developing new strategies to rapidly incorporate the fac-[M(I)(CO)3](+) (M = Re, (99m)Tc) core into biological targeting vectors in radiopharmaceuticals continues to expand as molecules become more complex and as efforts to minimize nonspecific binding increase. This work examines a novel isothiocyanate-functionalized bifunctional chelate based on 2,2'-dipicolylamine (DPA) specifically designed for complexing the fac-[M(I)(CO)3](+) core. Two strategies (postlabeling and prelabeling) were explored using the isothiocyanate-functionalized DPA to determine the effectiveness of assembly on the overall yield and purity of the complex with amine containing biomolecules. A model amino acid (lysine) examined (1) amine conjugation of isothiocyanate-functionalized DPA followed by complexation with fac-[M(I)(CO)3](+) (postlabeling) and (2) complexation of fac [M(I)(CO)3](+) with isothiocyanate-functionalized DPA followed by amine conjugation (prelabeling). Conducted with stable Re and radioactive (99m)Tc analogs, both strategies formed the product in good to excellent yields under macroscopic and radiotracer concentrations. A synthetic peptide (AE105) which targets an emerging biomarker in CaP prognosis, urokinase-type plasminogen activator receptor (uPAR), was also explored using the isothiocyanate functionalized DPA strategy. In vitro PC-3 (uPAR+) cell uptake assays with the (99m)Tc-labeled peptide (8a) showed 4.2 +/- 0.5% uptake at 4 h. In a murine model bearing PC-3 tumor xenografts, in vivo biodistribution of 8a led to favorable tumor uptake (3.7 +/- 0.7% ID/g) at 4 h p.i. with relatively low accumulation (<2% ID/g) in normal organs not associated with normal peptide excretion. These results illustrate the promise of the isothiocyanate-functionalized approach for labeling amine containing biological targeting vectors with fac-[M(I)(CO)3](+). PMID- 26603220 TI - Chondrogenic Differentiation Could Be Induced by Autologous Bone Marrow Mesenchymal Stem Cell-Derived Extracellular Matrix Scaffolds Without Exogenous Growth Factor. AB - We previously found that the combination of an autologous bone mesenchymal stem cell-derived extracellular matrix (aBMSC-dECM) scaffold with bone marrow stimulation could enhance hyaline cartilage regeneration. We suspected that chondrogenic differentiation could be induced by the aBMSC-dECM scaffold. This study aimed to investigate whether aBMSC-dECM scaffolds could promote chondrogenic differentiation without exogenous growth factors. BMSCs were seeded on aBMSC-dECM scaffolds and cultured in vitro with or without transforming growth factor-beta3 (E(+) or E(-) group). Atelocollagen scaffolds were used as controls (C(+) or C(-) group). The chondrogenic differentiation was evaluated by histological, biochemical, and real-time polymerase chain reaction assays. After 3 weeks, cartilage-like tissue with a homogeneous structure, a high cartilaginous matrix content (proteoglycan and type II collagen), and high expression levels of cartilage-associated genes (COL2A1, ACAN, and SOX9) were observed in the E(+), E( ), and C(+) groups. In addition, BMSCs in each scaffold (E group or C group) were preconditioned with chondrogenic media in vitro for 1 week, and then implanted in the backs of nude mice for 3 weeks. Three weeks later, cartilage matrix formation (proteoglycan and type II collagen) was achieved only in the E group, confirmed by safranin O staining and immunohistochemical staining for type II collagen. Taken together, these results indicate that aBMSC-dECM scaffolds could induce chondrogenic differentiation. Thus, they could be successful candidate scaffolds for cartilage tissue engineering. PMID- 26603219 TI - The Effect of Hollyhock (Althaea officinalis L) Leaf Compresses Combined With Warm and Cold Compress on Breast Engorgement in Lactating Women: A Randomized Clinical Trial. AB - Breast engorgement affects lactation. The present study was conducted to determine the effect of hollyhock combined with warm and cold compresses on improving breast engorgement in lactating women. Participants included 40 women with breast engorgement divided into intervention and control groups, with participants in both groups being applied routine interventions and warm compress before nursing and a cold compress after nursing; however, the intervention group was also applied hollyhock compress. Both groups received these treatments 6 times during 2 days. The data collected were analyzed in SPSS-16 using a generalized estimating equation. According to the results, a significant difference was observed in the overall breast engorgement severity in the intervention group (P < .001). The severity of breast engorgement was also found to have a significant relationship with time (P < .001). According to the findings, hollyhock leaf compress combined with performing routine interventions for breast engorgement can improve breast engorgement. PMID- 26603221 TI - Transanal natural orifice specimen extraction in colorectal surgery: bacteriological and oncological concerns. AB - INTRODUCTION: Natural orifice techniques have been developed to reduce incision related morbidity in laparoscopic colorectal surgery. We describe our method of performing transanal specimen extraction in laparoscopic colorectal surgery, addressing bacteriological and oncological concerns in its implementation. METHODS: Data of consecutive patients undergoing natural orifice specimen extraction (NOSE) laparoscopic colorectal surgery in our institution were retrospectively analysed. All specimens were extracted transanally via a wound protector, followed by intracorporeal end-to-end colorectal anastomosis. Perioperative details, microbiological and oncological findings were reviewed. RESULTS: Between November 2014 and February 2015, five patients underwent NOSE laparoscopic colorectal procedures in our institution. All cases were completed laparoscopically and specimens were extracted transanally via a wound protector. There were no cases of post-operative anastomotic leaks, wound infections, intra abdominal sepsis or faecal incontinence. Oncological margins and lymph node harvest were adequate for malignant cases. Transanal specimen extraction did not result in a malignant yield on peritoneal fluid cytology. CONCLUSIONS: Early bacteriological, oncological and functional results show that NOSE is safe and feasible. Follow-up is required to establish that long-term oncological outcome is not compromised. PMID- 26603222 TI - HUMAN TOXOPLASMOSIS OUTBREAKS AND THE AGENT INFECTING FORM. FINDINGS FROM A SYSTEMATIC REVIEW. AB - Toxoplasmosis, a worldwide highly prevalent zoonotic infection, is transmitted either by the oocysts, from water and soil, or the tissue cysts, in raw or undercooked infected meat, of Toxoplasma gondii. An ongoing debate is whether there are differences between the clinical and epidemiological characteristics of the outbreaks due to one or the other infective form of the agent. We performed a systematic review, recovering 437 reported outbreaks of which 38 were selected. They were complete reports containing ascribed Toxoplasma infecting form, and clinical and demographic data. There was no gender or age group selection in the outbreaks, which were described more often in the Americas. A large number of individuals were affected when oocysts, associated with soil and water contaminated with cat feces, were considered the transmission source. Onset of symptoms occurred early when the infection was ascribed to meat tissue cysts (11.4 +/- 6.7 days) with sharpened temporal distribution of cases, while a broader and prolonged appearance of new cases was observed when oocysts in water were the source of the infection (20 +/- 7 days, p < 0.001). Such information may be useful in the design and implementation of control strategies. PMID- 26603223 TI - NEW PRIMERS FOR DETECTION OF Leishmania infantum USING POLYMERASE CHAIN REACTION. AB - Leishmania infantum causes visceral leishmaniasis (VL) in the New World. The diagnosis of VL is confirmed by parasitological and serological tests, which are not always sensitive or specific. Our aim was to design new primers to perform a Polymerase Chain Reaction (PCR) for detecting L. infantum. Sequences of the minicircle kinetoplast DNA (kDNA) were obtained from GenBank, and the FLC2/RLC2 primers were designed. Samples of DNA from L. infantum, Leishmania amazonensis, Leishmania braziliensis, Leishmania guyanensis, Leishmania naiffi, Leishmania lainsoni, Leishmania panamensis, Leishmania major and Trypanosoma cruzi were used to standardize the PCR. PCR with FLC2/RLC2 primers amplified a fragment of 230 bp and the detection limit was 0.2 fg of L. infantum DNA. Of the parasite species assayed, only L. infantum DNA was amplified. After sequencing, the fragment was aligned to GenBank sequences, and showed (99%) homology with L. infantum. In the analysis of blood samples and lesion biopsy from a dog clinically suspected to have VL, the PCR detected DNA from L. infantum. In biopsy lesions from humans and dogs with cutaneous leishmaniasis, the PCR was negative. The PCR with FLC2/RLC2 primers showed high sensitivity and specificity, and constitutes a promising technique for the diagnosis of VL. PMID- 26603224 TI - ADENOSINE DEAMINASE ACTIVITY AND SERUM C-REACTIVE PROTEIN AS PROGNOSTIC MARKERS OF CHAGAS DISEASE SEVERITY. AB - Chagas disease is a public health problem worldwide. The availability of diagnostic tools to predict the development of chronic Chagas cardiomyopathy is crucial to reduce morbidity and mortality. Here we analyze the prognostic value of adenosine deaminase serum activity (ADA) and C-reactive protein serum levels (CRP) in chagasic individuals. One hundred and ten individuals, 28 healthy and 82 chagasic patients were divided according to disease severity in phase I (n = 35), II (n = 29), and III (n = 18). A complete medical history, 12-lead electrocardiogram, chest X-ray, and M-mode echocardiogram were performed on each individual. Diagnosis of Chagas disease was confirmed by ELISA and MABA using recombinant antigens; ADA was determined spectrophotometrically and CRP by ELISA. The results have shown that CRP and ADA increased linearly in relation to disease phase, CRP being significantly higher in phase III and ADA at all phases. Also, CRP and ADA were positively correlated with echocardiographic parameters of cardiac remodeling and with electrocardiographic abnormalities, and negatively with ejection fraction. CRP and ADA were higher in patients with cardiothoracic index >= 50%, while ADA was higher in patients with ventricular repolarization disturbances. Finally, CRP was positively correlated with ADA. In conclusion, ADA and CRP are prognostic markers of cardiac dysfunction and remodeling in Chagas disease. PMID- 26603225 TI - ISOLATION AND MOLECULAR IDENTIFICATION OF POTENTIALLY PATHOGENIC Escherichia coli AND Campylobacter jejuni IN FERAL PIGEONS FROM AN URBAN AREA IN THE CITY OF LIMA, PERU. AB - Feral pigeons (Columbia livia) live in close contact with humans and other animals. They can transmit potentially pathogenic and zoonotic agents. The objective of this study was to isolate and detect strains of diarrheagenic Escherichia coli and Campylobacter jejuni of urban feral pigeons from an area of Lima, Peru. Fresh dropping samples from urban parks were collected for microbiological isolation of E. coli strains in selective agar, and Campylobacter by filtration method. Molecular identification of diarrheagenic pathotypes of E.coli and Campylobacter jejuni was performed by PCR. Twenty-two parks were sampled and 16 colonies of Campylobacter spp. were isolated. The 100% of isolates were identified as Campylobacter jejuni. Furthermore, 102 colonies of E. coli were isolated and the 5.88% resulted as Enteropathogenic (EPEC) type and 0.98% as Shiga toxin-producing E. coli (STEC). The urban feral pigeons of Lima in Peru can act as a reservoir or carriers of zoonotic potentially pathogenic enteric agents. PMID- 26603226 TI - CHEMICAL CHARACTERIZATION AND EVALUATION OF ANTIBACTERIAL, ANTIFUNGAL, ANTIMYCOBACTERIAL, AND CYTOTOXIC ACTIVITIES OF Talinum paniculatum. AB - In this study, the bioactivity of Talinum paniculatum was evaluated, a plant widely used in folk medicine. The extract from the T. paniculatum leaves (LE) was obtained by percolation with ethanol-water and then subjecting it to liquid liquid partitions, yielding hexane (HX), ethyl acetate (EtOAc), butanol (BuOH), and aqueous (Aq) fractions. Screening for antimicrobial activity of the LE and its fractions was evaluated in vitro through broth microdilution method, against thirteen pathogenic and non-pathogenic microorganisms, and the antimycobacterial activity was performed through agar diffusion assay. The cytotoxic concentrations (CC90) for LE, HX, and EtOAc were obtained on BHK-21 cells by using MTT reduction assay. The LE showed activity against Serratia marcescens and Staphylococcus aureus, with Minimum Inhibitory Concentration (MIC) values of 250 and 500 ug/mL, respectively. Furthermore, HX demonstrated outstanding activity against Micrococcus luteus and Candida albicans with a MIC of 31.2 ug/mL in both cases. The MIC for EtOAc also was 31.2 ug/mL against Escherichia coli. Conversely, BuOH and Aq were inactive against all tested microorganisms and LE proved inactive against Mycobacterium tuberculosis and Mycobacterium bovis as well. Campesterol, stigmasterol, and sitosterol were the proposed structures as main compounds present in the EF and HX/EtOAc fractions, evidenced by mass spectrometry. Therefore, LE, HX, and EtOAc from T. paniculatum showed potential as possible sources of antimicrobial compounds, mainly HX, for presenting low toxicity on BHK 21 cells with excellent Selectivity Index (SI = CC90/MIC) of 17.72 against C. albicans. PMID- 26603227 TI - MORBIDITY AND MORTALITY DUE TO AIDS: A STUDY OF BURDEN OF DISEASE AT A MUNICIPAL LEVEL. AB - INTRODUCTION: The purpose of measuring the burden of disease involves aggregating morbidity and mortality components into a single indicator, the disability adjusted life year (DALY), to measure how much and how people live and suffer the impact of a disease. OBJECTIVE: To estimate the global burden of disease due to AIDS in a municipality of southern Brazil. METHODS: An ecological study was conducted in 2009 to examine the incidence and AIDS-related deaths among the population residing in the city of Tubarao, Santa Catarina State, Brazil. Data from the Mortality Information System in the National Health System was used to calculate the years of life lost (YLL) due to premature mortality. The calculation was based on the difference between a standardized life expectancy and age at death, with a discount rate of 3% per year. Data from the Information System for Notifiable Diseases were used to calculate the years lived with disability (YLD). The DALY was estimated by the sum of YLL and YLD. Indicator rates were estimated per 100,000 inhabitants, distributed by age and gender. RESULTS: A total of 131 records were examined, and a 572.5 DALYs were estimated, which generated a rate of 593.1 DALYs/100,000 inhabitants. The rate among men amounted to 780.7 DALYs/100,000, whereas among women the rate was 417.1 DALYs/100,000. The most affected age groups were 30-44 years for men and 60-69 years for women. CONCLUSION: The burden of disease due to AIDS in the city of Tubarao was relatively high when considering the global trend. The mortality component accounted for more than 90% of the burden of disease. PMID- 26603228 TI - PATHOGENIC FUNGI IN BIRD EXCRETA: A FORGOTTEN PUBLIC HEALTH PROBLEM. PMID- 26603229 TI - RELATED FACTORS FOR COLONIZATION BY Candida SPECIES IN THE ORAL CAVITY OF HIV INFECTED INDIVIDUALS. AB - The colonization of the oral cavity is a prerequisite to the development of oropharyngeal candidiasis. AIMS: The aims of this study were: to evaluate colonization and quantify Candida spp. in the oral cavity; to determine the predisposing factors for colonization; and to correlate the levels of CD4+ cells and viral load with the yeast count of colony forming units per milliliter (CFU/mL) in HIV-positive individuals treated at a University Hospital. Saliva samples were collected from 147 HIV patients and were plated on Sabouraud Dextrose Agar (SDA) and chromogenic agar, and incubated at 30 oC for 72 h. Colonies with similar morphology in both media were counted and the result expressed in CFU/mL. RESULTS: Of the 147 HIV patients, 89 had positive cultures for Candida spp., with a total of 111 isolates, of which C. albicans was the most frequent species (67.6%), and the mean of colonies counted was 8.8 * 103 CFU/mL. The main predisposing factors for oral colonization by Candida spp. were the use of antibiotics and oral prostheses. The use of reverse transcriptase inhibitors appears to have a greater protective effect for colonization. A low CD4+ T lymphocyte count is associated with a higher density of yeast in the saliva of HIV patients. PMID- 26603230 TI - THE RELEVANCE OF NUTRITIONAL STATUS AND HISTOPATHOLOGICAL FINDINGS ON THE INFECTIOUS PROCESS OF BALB/C MICE INOCULATED WITH Lacazia loboi. AB - The aim of this study was to evaluate the effects of the protein-calorie malnutrition in BALB/c isogenic mice infected with Lacazia loboi, employing nutritional and histopathological parameters. Four groups were composed: G1: inoculated with restricted diet, G2: not inoculated with restricted diet, G3: inoculated with regular diet, G4: not inoculated with regular diet. Once malnutrition had been imposed, the animals were inoculated intradermally in the footpad and after four months, were sacrificed for the excision of the footpad, liver and spleen. The infection did not exert great influence on the body weight of the mice. The weight of the liver and spleen showed reduction in the undernourished groups when compared to the nourished groups. The macroscopic lesions, viability index and total number of fungi found in the footpads of the infected mice were increased in G3 when compared to G1. Regarding the histopathological analysis of the footpad, a global cellularity increase in the composition of the granuloma was observed in G3 when compared to G1, with large numbers of macrophages and multinucleated giant cells, discrete numbers of lymphocytes were present in G3 and an increase was observed in G1. The results suggest that there is considerable interaction between Jorge Lobo's disease and nutrition. PMID- 26603231 TI - IMMUNODIAGNOSIS OF HUMAN STRONGYLOIDIASIS: USE OF SIX DIFFERENT ANTIGENIC FRACTIONS FROM Strongyloides venezuelensis PARASITIC FEMALES. AB - The aim of this study was to evaluate six different antigenic fractions from Strongyloides venezuelensis parasitic females for the immunodiagnosis of human strongyloidiasis. Soluble and membrane fractions from S. venezuelensis parasitic females were prepared in phosphate-buffered saline (SSF and SMF, respectively), Tris-HCl (TSF and TMF, respectively), and an alkaline buffer (ASF and AMF, respectively). Serum samples obtained from patients with strongyloidiasis or, other parasitic diseases, and healthy individuals were analyzed by enzyme-linked immunosorbent assay (ELISA). Soluble fractions SSF, TSF, and ASF showed 85.0%, 75.0%, and 80.0% sensitivity and 93.1%, 93.1%, and 87.5% specificity, respectively. Membrane fractions SMF, TMF, and AMF showed 80.0%, 75.0%, and 85.0% sensitivity, and 95.8%, 90.3%, and 91.7% specificity, respectively. In conclusion, the present results suggest that the fractions obtained from parasitic females, especially the SSF and SMF, could be used as alternative antigen sources in the serodiagnosis of human strongyloidiasis. PMID- 26603232 TI - PREVALENCE OF CHAGAS DISEASE IN A RURAL AREA IN THE STATE OF CEARA, BRAZIL. AB - Chagas disease is caused by Trypanosoma cruzi and affects about two to three million people in Brazil, still figuring as an important public health problem. A study was conducted in a rural area of the municipality of Limoeiro do Norte - CE, northeastern Brazil, aiming to determine the prevalence of T. cruzi infection. Of the inhabitants, 52% were examined, among whom 2.6% (4/154) were seropositive in at least two serological tests. All seropositive individuals were older than 50 years, farmers, with a low education and a family income of less than three minimum wages. Active surveillance may be an alternative for early detection of this disease. PMID- 26603233 TI - GEOGRAPHICAL EXPANSION OF CANINE VISCERAL LEISHMANIASIS IN RIO DE JANEIRO STATE, BRAZIL. AB - Visceral Leishmaniasis (VL) is a vector-borne disease that affects humans, and domestic and wild animals. It is caused by the protozoan Leishmania (Leishmania) infantum (syn = Leishmania chagasi). The domestic dog (Canis familiaris) is considered the main reservoir of the etiologic agent of VL in domestic and peridomestic environments. In the past three years, although control actions involving domestic dogs are routinely performed in endemic areas of the Rio de Janeiro State, new cases of canine visceral leishmaniasis (CVL) have been reported in several municipalities. The objective of this short communication was to describe the geographical expansion of CVL in the Rio de Janeiro State, Brazil, through its reports in the scientific literature and studies performed by our group. From 2010 to 2013, autochthonous and allochthonous cases of CVL were reported in the municipalities of Mangaratiba, Marica, Niteroi, Barra Mansa, Cachoeiras de Macacu, Volta Redonda, Resende and Rio de Janeiro. These reports demonstrate that CVL is in intense geographical expansion around the state; therefore, a joint effort by public agencies, veterinarians and researchers is needed in order to minimize and/or even prevent the dispersion of this disease. PMID- 26603234 TI - Toxoplasma-SPECIFIC IgG SUBCLASS ANTIBODY RESPONSE IN CEREBROSPINAL FLUID SAMPLES FROM PATIENTS WITH CEREBRAL TOXOPLASMOSIS. AB - Cerebral toxoplasmosis can be highly debilitating and occasionally fatal in persons with immune system deficiencies. In this study, we evaluated the Toxoplasma gondii-specific IgG subclass antibody response in 19 cerebrospinal fluid (CSF) samples from patients with cerebral toxoplasmosis who had a positive IgG anti-T. gondii ELISA standardized with a cyst antigen preparation. There were no significant differences between the rates of positivity and the antibody concentrations (arithmetic means of the ELISA absorbances, MEA) for IgG1 and IgG2, but the rates of positivity and MEA values for these two IgG subclasses were significantly higher than those for IgG3 and IgG4. The marked IgG2 response in CSF from patients with cerebral toxoplasmosis merits further investigation. PMID- 26603235 TI - A NEW POSSIBILITY FOR SURVEILLANCE: DO WE IDENTIFY ALL CASES OF LEPTOSPIROSIS? AB - Leptospirosis is a febrile disease with a typically underestimated global incidence, especially in regions where dengue is endemic. Therefore, it is difficult to accurately determine the number of leptospirosis cases in these areas, which contributes to significant under-reporting this disease. In this study, we estimated the number of possible leptospirosis cases among dengue-like cases that were reported during 2008, 2010, and 2012 in the city of Fortaleza, northeast Brazil. Patients were evaluated for dengue and leptospirosis using immunoenzymatic tests for IgM antibodies that were specific to each pathogen. Among the suspected cases of dengue that resulted as negative in laboratory tests, 10.8% (2008), 19.2% (2010), and 30.8% (2012) were confirmed to be leptospirosis. Considering the cases reported by the surveillance authority as dengue that were subsequently discarded based on the laboratory test results, we estimate that the number of actual leptospirosis cases may be 26 to 49 times higher than those diagnosed and reported by the Health Services. Furthermore, we believe that approximately 20% of dengue-like cases may be leptospirosis cases in areas where the two diseases are endemic. PMID- 26603236 TI - FIRST CASE OF HUMAN INFECTION BY Bertiella studeri (Blanchard, 1891) Stunkard,1940 (Cestoda; Anoplocephalidae) IN BRAZIL. AB - Cestodes of the Bertiella genus are parasites of non-human primates found in Africa, Asia, Oceania and the Americas. Species Bertiella studeri and Bertiella mucronata could, accidentally, infect human beings. The infection occurs from ingestion of mites from the Oribatida order containing cysticercoid larvae of the parasite. The objective of this report is to register the first case of human infection by Bertiella studeri in Brazil. Proglottids of the parasite, found in the stool sample of a two-and-a-half-year-old child, were fixed, stained and microscopically observed to evaluate its morphological characteristics. Eggs obtained from the proglottids were also studied. The gravid proglottids examined matched the description of the genus Bertiella. The eggs presented a round shape, with the average diameter of 43.7 um, clearly showing the typical pyriform apparatus of B. studeri. The authors concluded that the child was infected with Bertiella studeri,based on Stunkard's (1940) description of the species. This is the fifth case of human Bertiellosis described in Brazil through morphometric analysis of the parasite, the third in Minas Gerais State and the first diagnosed case of Bertiella studeri in Brazil. PMID- 26603237 TI - FIRST REPORT OF CUTANEOUS LEISHMANIASIS CAUSED BY Leishmania (Leishmania) infantum chagasi IN AN URBAN AREA OF RIO DE JANEIRO, BRAZIL. AB - American tegumentary leishmaniasis (ATL) is an infectious disease caused by protozoa of the genus Leishmania, and transmitted by sandflies. In the state of Rio de Janeiro, almost all of the cases of American tegumentary leishmaniasis (ATL) are caused by Leishmania (Viannia) braziliensis, while cases of visceral leishmaniasis (VL) are caused by Leishmania (Leishmania) infantum chagasi. The resurgence of autochthonous VL cases in Rio de Janeiro is related to the geographic expansion of the vector Lutzomyia longipalpis and its ability to adapt to urban areas. We report the first case of leishmaniasis with exclusively cutaneous manifestations caused by L. (L.) infantum chagasi in an urban area of Rio de Janeiro. An eighty-one-year-old woman presented three pleomorphic skin lesions that were not associated with systemic symptoms or visceromegalies. Multilocus enzyme electrophoresis identified L. (L.) infantum chagasi, but direct smear and PCR of bone narrow were negative for Leishmania sp. (suggesting exclusively cutaneous involvement). We discuss the different dermatological presentations of viscerotropic leishmaniasis of the New and Old World, and the clinical and epidemiological importance of the case. Etiologic diagnosis of ATL based upon exclusive clinical criteria may lead to incorrect conclusions. We should be aware of the constant changes in epidemiological patterns related to leishmaniases. PMID- 26603239 TI - DIVERSITY AND INFECTIVITY POTENTIAL OF EMERGING FUNGI IN AN AREA OF BABACU TREES IN THE STATE OF MARANHAO, BRAZIL. PMID- 26603238 TI - PROTECTIVE LEVELS OF VARICELLA-ZOSTER ANTIBODY DID NOT EFFECTIVELY PREVENT CHICKENPOX IN AN X-LINKED AGAMMAGLOBULINEMIA PATIENT. AB - We describe the case of an eight-year-old boy with X-linked agammaglobulinemia who developed mild varicella despite regular intravenous immunoglobulin (IVIG) therapy. He maintained protective antibody levels against varicella and the previous batches of IVIG that he received had adequate varicella-specific IgG levels. The case illustrates that IVIG may not prevent VZV infection. PMID- 26603240 TI - Risk factors for the hypertensive phase after implantation of a glaucoma drainage device. AB - PURPOSE: To investigate risk factors for the development of the hypertensive phase after implantation of the Ahmed glaucoma valve (AGV). METHODS: A total of 128 patients who had undergone AGV implantation were included in this study. The hypertensive phase was defined as intraocular pressure (IOP) > 21 mmHg during the first 3 months after surgery. Failure was defined IOP > 21 mmHg or less than a 20% reduction from baseline on two consecutive study visits after 3 months. RESULTS: Mean age and preoperative IOP were not different between the hypertensive and non-hypertensive groups (p = 0.054, 0.065, respectively). Axial length (AL) was significantly longer in the hypertensive group (25.2 +/- 2.6 mm) than in the non-hypertensive group (23.6 +/- 1.6 mm; p = 0.006). AL was correlated with postoperative IOP at 1 and 3 months postoperatively (r = 0.176, p = 0.047; r = 0.363, p < 0.001), but not at 6 months and 1 year postoperatively (p = 0.105, 0.068). Only AL was significantly associated with development of the hypertensive phase (p = 0.026) in the binary logistic regression analysis. The development of hypertensive phase was higher in the high-myopia group (95.1%) than in the non-high myopia group (79.3%; p = 0.011). The cumulative probability of success at postoperative 1 year was 96.5% in the non-high myopia group and 95.1% in the high myopia group (p = 0.784). CONCLUSIONS: Eyes with high myopia were at the greatest risk for developing hypertension following implantation of a glaucoma drainage valve. PMID- 26603241 TI - Oral health status in children and adolescents with Fanconi anemia. AB - OBJECTIVE: The aim of the study was to investigate the caries experience, dental care level, and oral hygiene in children and adolescents with Fanconi anemia. METHODS: Decay-missing-filled teeth index, restorative index and simplified oral hygiene index were examined in two groups of children and adolescents: FA, diagnosed with Fanconi anemia (n = 35) and a healthy control group, non-FA (n = 35). Oral hygiene habits were assessed through questionnaires completed by parents. RESULTS: FA group presents higher decay-missing-filled teeth index values, dental care index, oral hygiene index. Nevertheless, no statistical difference was observed between the groups. Frequency of visits to the dentist was higher in the non-FA group. Frequency of tooth brushing was higher in FA group and it was performed by the subjects without the help of their parents. CONCLUSIONS: No difference was observed in caries experience, dental care level, and oral hygiene in children and adolescents with FA when compare with non-FA. PMID- 26603242 TI - A cross-sectional multicentre study of cardiac risk score use in the management of unstable angina and non-ST-elevation myocardial infarction. AB - OBJECTIVES: Quantitative risk assessment in unstable angina (UA) and non-ST elevation myocardial infarction (NSTEMI), by using cardiac risk scores, is recommended in international guidelines. However, a gap between recommended care and actual practice exists, as these instruments seem underused in practice. The present study aimed to determine the extent of cardiac risk score use and to study factors associated with lower or higher cardiac risk score use. SETTING: 13 hospitals throughout the Netherlands. PARTICIPANTS: A retrospective chart review of 1788 charts of patients with UA and NSTEMI, discharged in 2012. PRIMARY AND SECONDARY OUTCOMES: The extent of cardiac risk score use reflected in a documented risk score outcome in the patient's chart. Factors associated with cardiac risk score use determined by generalised linear mixed models. RESULTS: In 57% (n=1019) of the charts, physicians documented the use of a cardiac risk score. Substantial variation between hospitals was observed (16.7-87%), although this variation could not be explained by the presence of on-site revascularisation facilities or a hospitals' teaching status. Obese patients (OR=1.49; CI 95%1.03 to 2.15) and former smokers (OR=1.56; CI 95%1.15 to 2.11) were more likely to have a cardiac risk score documented. Risk scores were less likely to be used among patients diagnosed with UA (OR=0.60; CI 95% 0.46 to 0.77), in-hospital resuscitation (OR=0.23; CI 95% 0.09 to 0.64), in-hospital heart failure (OR=0.46; CI 95% 0.27 to 0.76) or tachycardia (OR=0.45; CI 95% 0.26 to 0.75). CONCLUSIONS: Despite recommendations in cardiac guidelines, the use of cardiac risk scores has not been fully implemented in Dutch practice. A substantial number of patients did not have a cardiac risk score documented in their chart. Strategies to improve cardiac risk score use should pay special attention to patient groups in which risk scores were less often documented, as these patients may currently be undertreated. PMID- 26603243 TI - Bone mineral density and fracture risk with long-term use of inhaled corticosteroids in patients with asthma: systematic review and meta-analysis. AB - OBJECTIVES: We aimed to assess the association between long-term use of inhaled corticosteroids (ICS) and bone adverse effects in patients with asthma. DESIGN: Systematic review and meta-analysis of fracture risk and changes in bone mineral density with long-term ICS use in asthma. METHODS: We initially searched MEDLINE and EMBASE in July 2013, and performed an updated PubMed search in December 2014. We selected randomised controlled trials (RCTs) and controlled observational studies of any ICS (duration at least 12 months) compared to non-ICS use in patients with asthma. We conducted meta-analysis of ORs for fractures, and mean differences in bone mineral density. Heterogeneity was assessed using the I(2) statistic. RESULTS: We included 18 studies (7 RCTs and 11 observational studies) in the systematic review. Meta-analysis of observational studies did not demonstrate any significant association between ICS and fractures in children (pooled OR 1.02, 95% CI 0.94 to 1.10, two studies), or adults (pooled OR 1.09, 95% CI 0.45 to 2.62, four studies). Three RCTs and three observational studies in children reported on bone mineral density at the lumbar spine, and our meta analysis did not show significant reductions with ICS use. Three RCTs and four observational studies in adults reported on ICS use and bone mineral density at the lumbar spine and femur, with no significant reductions found in the meta analysis compared to control. CONCLUSIONS: ICS use for >=12 months in adults or children with asthma was not significantly associated with harmful effects on fractures or bone mineral density. PMID- 26603244 TI - Comparison of birth weight between school health records and medical birth records in Denmark: determinants of discrepancies. AB - OBJECTIVE: To compare reported birth weight (BW) information in school health records with BW from medical birth records, and to investigate if maternal and offspring characteristics were associated with any discrepancies. DESIGN: Register-based cohort study. SETTING: Denmark, 1973-1991. PARTICIPANTS: The study was based on BW recorded in the Copenhagen School Health Records Register (CSHRR) and in The Medical Birth Register (MBR). The registers were linked via the Danish personal identification number. PRIMARY AND SECONDARY OUTCOME MEASURES: Statistical comparisons of BW in the registers were performed using t tests, Pearson's correlation coefficients, Bland-Altman plots and kappa coefficients. Odds of BW discrepancies >100 g were examined by logistic regressions. RESULTS: The study population included 47,534 children. From 1973 to 1979 when BW was grouped in 500 g intervals in the MBR, mean BW differed significantly between the registers. During 1979-1991 when BW was recorded in 10 and 1 g intervals, mean BW did not significantly differ between the two registers. BW from both registers was highly correlated (0.93-0.97). Odds of a BW discrepancy significantly increased with parity, the child's age at recall and by marital status (children of married women had the highest odds). CONCLUSIONS: Overall, BW information in school health records agreed very well with BW from medical birth records, suggesting that reports of BWs in school health records in Copenhagen, Denmark generally are valid. PMID- 26603246 TI - Neighbourhood walkability, daily steps and utilitarian walking in Canadian adults. AB - OBJECTIVES: To estimate the associations of neighbourhood walkability (based on Geographic Information System (GIS)-derived measures of street connectivity, land use mix, and population density and the Walk Score) with self-reported utilitarian walking and accelerometer-assessed daily steps in Canadian adults. DESIGN: A cross-sectional analysis of data collected as part of the Canadian Health Measures Survey (2007-2009). SETTING: Home neighbourhoods (500 m polygonal street network buffers around the centroid of the participant's postal code) located in Atlantic Canada, Quebec, Ontario, the Prairies and British Columbia. PARTICIPANTS: 5605 individuals participated in the survey. 3727 adults (>=18 years) completed a computer-assisted interview and attended a mobile clinic assessment. Analyses were based on those who had complete exposure, outcome and covariate data (n=2949). MAIN EXPOSURE MEASURES: GIS-derived walkability (based on land use mix, street connectivity and population density); Walk Score. MAIN OUTCOME MEASURES: Self-reported utilitarian walking; accelerometer-assessed daily steps. RESULTS: No important relationship was observed between neighbourhood walkability and daily steps. Participants who reported more utilitarian walking, however, accumulated more steps (<1 h/week: 6613 steps/day, 95% CI 6251 to 6975; 1 to 5 h/week: 6768 steps/day, 95% CI 6420 to 7117; >=6 h/week: 7391 steps/day, 95% CI 6972 to 7811). There was a positive graded association between walkability and odds of walking >=1 h/week for utilitarian purposes (eg, Q4 vs Q1 of GIS derived walkability: OR=1.66, 95% CI 1.31 to 2.11; Q3 vs Q1: OR=1.41, 95% CI 1.14 to 1.76; Q2 vs Q1: OR=1.13, 95% CI 0.91 to 1.39) independent of age, sex, body mass index, married/common law status, annual household income, having children in the household, immigrant status, mood disorder, perceived health, ever smoker and season. CONCLUSIONS: Contrary to expectations, living in more walkable Canadian neighbourhoods was not associated with more total walking. Utilitarian walking and daily steps were, however, correlated and walkability demonstrated a positive graded relationship with utilitarian walking. PMID- 26603245 TI - Effect of increased water intake on plasma copeptin in patients with chronic kidney disease: results from a pilot randomised controlled trial. AB - OBJECTIVES: Increased water intake may have a beneficial effect on the kidney through suppression of plasma vasopressin. We examined the effect of increased water intake on plasma copeptin (a marker of vasopressin) over 6 weeks in patients with chronic kidney disease. DESIGN: Secondary analysis of a randomised controlled parallel-group pilot trial. SETTING: Canada, 2012-2013. PARTICIPANTS: 28 patients with stage 3 chronic kidney disease randomised (2:1) to a hydration (n=17) or control group (n=11). INTERVENTION: The hydration group was coached to increase water intake by up to 1.5 L/day for 6 weeks. The control group was asked to maintain regular water intake. MEASURES AND OUTCOMES: Participants provided blood and 24 h urine samples at baseline and 6 weeks. Change in plasma copeptin was compared within and between study groups. RESULTS: Participants were 64% male with a mean age of 62 years and an estimated glomerular filtration rate of 40 mL/min/1.73 m(2). Between baseline and 6 weeks, 24 h urine volume increased by 0.7 L/day in the hydration group, rising from 2.3 to 3.0 L/day (p=0.01), while decreasing by 0.3 L/day among controls, from 2.0 to 1.7 L/day (p=0.07); between group difference: 0.9 L/day (95% CI 0.37 to 1.46; p=0.002). In the hydration group, median copeptin decreased by 3.6 pmol/L, from 15.0 to 10.8 pmol/L (p=0.005), while remaining stable among controls at 19 pmol/L (p=0.76; p=0.19 for the between-group difference in median change); the between-group difference in mean change was 5.4 pmol/L (95% CI -1.2 to 12.0; p=0.11). CONCLUSIONS: Adults with stage 3 chronic kidney disease can be successfully randomised to drink approximately 1 L more per day than controls. This increased water intake caused a significant decrease in plasma copeptin concentration. Our larger 12-month trial will examine whether increased water intake can slow renal decline in patients with chronic kidney disease. TRIAL REGISTRATION NUMBER: NCT01753466. PMID- 26603247 TI - Is acute idiopathic pericarditis associated with recent upper respiratory tract infection or gastroenteritis? A case-control study. AB - OBJECTIVES: The aim of this study was to assess the association of a clinical diagnosis of acute idiopathic pericarditis (AIP), and a reported upper respiratory tract infection (URTI) or gastroenteritis (GE) in the preceding month. DESIGN: Patients who were hospitalised with a first diagnosis of AIP were retrospectively compared with a control group of patients admitted with deep vein thrombosis (DVT), matched by gender and age. SETTING: Primary and secondary care level; one hospital serving a population of about 170,000. PARTICIPANTS: A total of 51 patients with AIP were included, of whom 46 could be matched with 46 patients with control DVT. Only patients with a complete review of systems on the admission note were included in the study. MAIN OUTCOME MEASURE: Conditional logistic regression was used to assess the association of a clinical diagnosis of AIP and an infectious episode (URTI or GE) in the month preceding AIP diagnosis. RESULTS: Patients with AIP had more often experienced a recent episode of URTI or GE than patients with DVT (39.1% vs 10.9%, p=0.002). The multivariate conditional regression showed that AIP was independently associated with URTI or GE in the last month preceding diagnosis (OR=37.18, 95% CI=1.91 to 724.98, p=0.017). CONCLUSIONS: This is, to the best of our knowledge, the first study demonstrating an association between a recent episode of URTI or GE and a clinical diagnosis of AIP. PMID- 26603249 TI - Discovery of URAT1 SNPs and association between serum uric acid levels and URAT1. AB - OBJECTIVES: Human urate transporter 1 (URAT1) is a member of the organic anion transporter family (SLC22A12) that primarily regulates the renal tubular reabsorption of uric acid. This case-control study was designed to analyse whether hURAT1 might also be a candidate gene for hyperuricaemia or hypouricaemia. SETTING: We recruited 68 healthy volunteers and divided them into two groups: a normal uric acid group and a hyperuricaemia group. We analysed the sequence of the URAT1 gene and found five significant single nucleotide polymorphisms (SNPs). We then selected 900 male subjects from the 262,200 enrolled in the Korean Cancer Prevention Study-II (KCPS-II) cohort for further genetic analysis. PARTICIPANTS: DNA samples from 36 individuals with normal uric acid (<4.5 mg/dL) and 32 individuals with hyperuricaemia (>8.5 mg/dL) were sequenced. Five significant SNPs (rs7929627, rs75786299, rs3825017, rs11602903 and rs121907892) were identified. We then chose 900 subjects from the KCPS-II cohort consisting of 450 subjects with normal uric acid (UA <4.1 mg/dL) and 450 subjects with hyperuricaemia (UA >8.7 mg/dL). The groups were matched by age, body mass index, metabolic syndrome and use of anti-hypertensive medication. PRIMARY OUTCOME MEASURES: We compared the OR of the incidence of hyperuricaemia by URAT1 genotype. RESULTS: The strongest association with hyperuricaemia was observed for rs75786299 (IVS3+11A/G) with an OR of 32.05. rs7929627 (IVS7-103A/G) and rs3825017 (N82N) showed an association with hyperuricaemia with ORs of 2.56 and 2.29, respectively. rs11602903 (788A/T) and rs121907892 (W258X) were negatively correlated with hyperuricaemia with ORs of 0.350 and 0.447, respectively. Individuals carrying the GATAG haplotype (n=32)-a relatively common variant consisting of rs7929627, rs75786299 and rs3825017-showed the highest risk for hyperuricaemia with an OR of 92.23 (p=9.55*10(-3)). CONCLUSIONS: These results indicate that five newly described SNPs in the hURAT1 gene are significantly associated with uric acid level (4-2008-0318 and 4-2011-0277). PMID- 26603250 TI - The PROblem Gambling RESearch Study (PROGRESS) research protocol: a pragmatic randomised controlled trial of psychological interventions for problem gambling. AB - INTRODUCTION: International prevalence rates for problem gambling are estimated at 2.3%. Problem gambling is a serious global public health concern due to adverse personal and social consequences. Previous research evaluating the effectiveness of psychological interventions for the treatment of problem gambling has been compromised by methodological limitations, including small sample sizes and the use of waitlist control groups. This article describes the study protocol for a pragmatic randomised controlled trial (RCT) evaluating the effectiveness of cognitive-behavioural therapy (CBT), behaviour therapy (BT), motivational interviewing (MI) against a non-directive supportive therapy (NDST) control, in treating problem gambling. METHODS AND ANALYSIS: This study was a mixed-methods design, with a parallel group, pragmatic RCT as the primary component, and embedded qualitative studies conducted alongside. A total of 297 participants were recruited from the community in Victoria, Australia. Individuals aged 18 years and over, could communicate in English and wished to receive treatment for a gambling problem were eligible. Participants were randomly allocated in to 1 of the 4 psychological interventions: CBT, BT, MI and NDST. Repeated measures were conducted at pretreatment and post-treatment, and 6 and 12 months post-treatment. The statistical analysis will use an intention-to treat approach. Multilevel mixed modelling will be used to examine changes in the primary outcome measures: gambling symptom severity, using the Gambling Symptom Assessment Scale, and gambling behaviours (frequency, time and expenditure). Secondary outcomes are depression, anxiety, stress and alcohol use. Individual semistructured qualitative interviews were conducted at pretreatment and post treatment and 12 months post-treatment for a subset of participants (n=66). ETHICS AND DISSEMINATION: This study was approved by the Victorian Department of Justice, Monash University and the University of Melbourne Human Research Ethics Committees. Findings will be reported in a government report, peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN01629698. PMID- 26603248 TI - Use of high doses of folic acid supplements in pregnant women in Spain: an INMA cohort study. AB - OBJECTIVES: We examined the use of low (<400 MUg/day, including no use) and high folic acid supplement (FAS) dosages (>=1000 MUg/day) among pregnant women in Spain, and explored factors associated with the use of these non-recommended dosages. DESIGN: Population-based cohort study. SETTING: Spain. PARTICIPANTS: We analysed data from 2332 pregnant women of the INMA study, a prospective mother child cohort study in Spain. MAIN OUTCOME MEASURES: We assessed usual dietary folate and the use of FAS from preconception to the 3rd month (first period) and from the 4th to the 7th month (second period), using a validated food frequency questionnaire. We used multinomial logistic regression to estimate relative risk ratios (RRRs). RESULTS: Over a half of the women used low dosages of FAS in the first and second period while 29% and 17% took high dosages of FAS, respectively. In the first period, tobacco smoking (RRR=1.63), alcohol intake (RRR=1.40), multiparous (RRR=1.44), unplanned pregnancy (RRR=4.20) and previous spontaneous abortion (RRR=0.58, lower use of high FAS dosages among those with previous abortions) were significantly associated with low FAS dosages. Alcohol consumption (RRR=1.42), unplanned pregnancy (RRR=2.66) and previous spontaneous abortion (RRR=0.68) were associated with high dosage use. In the second period, only tobacco smoking was significantly associated with high FAS dosage use (RRR=0.67). CONCLUSIONS: A high proportion of pregnant women did not reach the recommended dosages of FAS in periconception and a considerable proportion also used FAS dosages >=1000 MUg/day. Action should be planned by the Health Care System and health professionals to improve the appropriate periconceptional use of FAS, taking into consideration the associated factors. PMID- 26603251 TI - EVerT2-needling versus non-surgical debridement for the treatment of verrucae: study protocol for a single-centre randomised controlled trial. AB - INTRODUCTION: Verrucae are extremely common, and are experienced by most people at some time during their lives. Although most verrucae will spontaneously disappear without treatment, many patients seek treatment, often because they have persisted for many years, are unsightly or painful or prevent them from doing sports or other activities. There are many different treatments available; including the Falknor's needling procedure. To date, there has only been one small trial evaluating the clinical effectiveness of this treatment and no health economic analysis has been undertaken. The Effective Verruca Treatments (EVerT2) trial aims to evaluate the clinical and cost-effectiveness of the needling procedure for the treatment of verrucae. METHODS AND ANALYSIS: This single-centre randomised controlled trial will recruit 58 participants (aged 18 years and over with a plantar verruca) from Salford Podiatry Clinic patient lists and the surrounding area. If the participant presents with multiple verrucae, an 'index' verruca (largest and thickest lesion) will be identified and patients will be randomised 1:1 to the intervention group to receive the needling treatment or the control group to have the callus overlying the verruca debrided. The primary outcome is complete clearance of the index verruca at 12 weeks after randomisation. Secondary outcomes include clearance and recurrence of the treated verruca, clearance of all verrucae, number of verrucae remaining, change in size of the index verruca, pain, and participant satisfaction. A cost-effectiveness analysis of the needling versus callus debridement will be carried out from the perspective of health services over a time horizon of 12 weeks. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the University of Salford, Department of Health Sciences Ethical Approval Committee (HSCR15/24) and the University of York, Department of Health Sciences Research Governance Committee (HSRGC/2014/98/B). Findings will be disseminated through publication and conference presentations. TRIAL REGISTRATION NUMBER: ISRCTN16429440. PMID- 26603252 TI - Effect of iron supplementation on psychomotor development of non-anaemic, exclusively or predominantly breastfed infants: a randomised, controlled trial. AB - INTRODUCTION: Uncertainty exists regarding the effects of iron supplementation during infancy on neurodevelopmental outcomes in the absence of anaemia. The aim of the study is to establish whether psychomotor and mental development is influenced by early iron supplementation in healthy, non-anaemic, exclusively or predominantly breastfed infants. METHODS AND ANALYSIS: Healthy term infants will be recruited. If exclusively or predominantly breast fed (>50% of daily feedings) and not anaemic at 4 months, they will be randomised to receive either iron pyrophosphate (approximately 1 mg/kg) or placebo daily until 9 months of age. The primary outcome measure is neurodevelopment assessed with the Bayley Scales of Infant and Toddler Development (Bayley-III) at 12 months, and repeated at 24 and 36 months of age. Haematological parameters of iron metabolism also will be measured. ETHICS AND DISSEMINATION: The Bioethics Committee of the Medical University of Warsaw approved the study protocol before recruitment started. Study results will be submitted to peer-reviewed journals in the fields of paediatrics and nutrition, and presented at relevant conferences. TRIAL REGISTRATION NUMBER: NCT02242188. PMID- 26603254 TI - Changes in health-related quality of life (HRQoL) after discharge from intensive care unit: a protocol for a systematic review. AB - INTRODUCTION: Treatment on an intensive care unit (ICU) imposes a high treatment burden on patients, as well as an economic burden for the healthcare provider. Many studies have recorded health-related quality of life (HRQoL) in patients after treatment on an ICU. We propose a systematic review of these studies. METHODS: We will search the National Library of Medicine's PubMed electronic database (PubMed), the Cochrane database, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science and Open Grey to identify papers reporting quality of life after discharge from ICU. We will include papers including validated quality of life measures. We will examine three categories: populations of patients treated on general ICUs, patients with severe infections and patients with respiratory dysfunction. We will extract HRQoL data. We will assess papers for risk of bias using the QUADAS-2 tool. The strength of our conclusions will depend on the quality and number of papers showing uniform results. ETHICS AND DISSEMINATION: This review will use published literature and contains no primary data; so we do not need ethical approval. We will submit the outcome of the systematic review to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: PROSPERO CRD42015024700. PMID- 26603253 TI - An ecological analysis of PM2.5 concentrations and lung cancer mortality rates in China. AB - OBJECTIVE: To explore the association between Particulate Matter (PM)2.5 (particles with an aerodynamic diameter less than 2.5 um) and lung cancer mortality rates and to estimate the potential risk of lung cancer mortality related to exposure to high PM2.5 concentrations. DESIGN: Geographically weighted regression was performed to evaluate the relation between PM2.5 concentrations and lung cancer mortality for males, females and for both sexes combined, in 2008, based on newly available long-term data. Lung cancer fatalities from long term exposure to PM2.5 were calculated according to studies by Pope III et al and the WHO air quality guidelines (AQGs). SETTING: 31 provinces in China. RESULTS: PM2.5 was associated with the lung cancer mortality of males, females and both sexes combined, in China, although there were exceptions in several regions, for males and females. The number of lung cancer fatalities calculated by the WHO AQGs ranged from 531,036 to 532,004, whereas the number calculated by the American Cancer Society (ACS) reached 614,860 after long-term (approximately 3-4 years) exposure to PM2.5 concentrations since 2008. CONCLUSIONS: There is a positive correlation between PM2.5 and lung cancer mortality rate, and the relationship between them varies across the entire country of China. The number of lung cancer fatalities estimated by ACS was closer to the actual data than those of the WHO AQGs. Therefore, the ACS estimate of increased risk of lung cancer mortality from long-term exposure to PM2.5 might be more applicable for evaluating lung cancer fatalities in China than the WHO estimate. PMID- 26603255 TI - Influence of the practice setting on diagnostic prediction rules using FENO measurement in combination with clinical signs and symptoms of asthma. AB - OBJECTIVES: To evaluate the influence of the practice setting on diagnostic accuracy of fractional exhaled nitric oxide (FENO) for diagnosing asthma; and to develop prediction rules for diagnostic decision-making including clinical signs and symptoms (CSS). SETTING: Patients from 10 general practices and 1 private practice of 5 pneumologists in ambulatory care. PARTICIPANTS: 553 patients, 57.9% female. Consecutive inclusion of diagnostic-naive patients suspected of suffering from obstructive airway disease. Exclusion criteria were respiratory tract infections within the last 6 weeks. INTERVENTIONS: The index test was FENO measurement. Reference standard was the Tiffeneau ratio (forced expiratory volume in 1 s/vital capacity) or airway resistance as assessed by whole body plethysmography, with additional bronchoprovocation or bronchodilator testing. PRIMARY AND SECONDARY OUTCOME MEASURES: Asthma as determined by pneumologists, who were blind to FENO measurement results. Prediction rules were derived from multiple logistic regression analysis. A freely available calculator that allows computing all combinations was developed. RESULTS: The practice setting only had minor influence on sensitivities of FENO cut-off points. In the final model (n=472), allergic rhinitis, wheezing and previous medication were positively associated with asthma. Increasing age and recurrent respiratory tract infections were negatively associated. The area under the curve (AUC) of FENO (AUC=0.650; 95% CI 0.599 to 0.701) increased significantly (p<0.0001) when combined with CSS (AUC=0.753; 95% CI 0.707 to 0.798). Presence of wheezing and allergic rhinitis allowed ruling in asthma with FENO >30 ppb. Ruling out with FENO <16 ppb in patients <43 years was only possible without allergic symptoms when recurrent respiratory tract infections were present. CONCLUSIONS: FENO results should be interpreted in the context of CSS to enhance their diagnostic value in primary care. The final diagnostic model appears as a sound algorithm fitting well to the established diagnostic rules related to CSS of asthma. FENO appears more effective for ruling in asthma than for ruling it out. PMID- 26603256 TI - XPO1 Inhibition Enhances Radiation Response in Preclinical Models of Rectal Cancer. AB - PURPOSE: Combination of radiation with radiosensitizing chemotherapeutic agents improves outcomes for locally advanced rectal cancer. Current treatment includes 5-fluorouracil-based chemoradiation prior to surgical resection; however pathologic complete response varies from 15% to 20%, prompting the need to identify new radiosensitizers. Exportin 1 (XPO1, also known as chromosome region 1, CRM1) mediates the nuclear export of critical proteins required for rectal cancer proliferation and treatment resistance. We hypothesize that inhibition of XPO1 may radiosensitize cancer cells by altering the function of these critical proteins resulting in decreased radiation resistance and enhanced antitumoral effects. EXPERIMENTAL DESIGN: To test our hypothesis, we used the selective XPO1 inhibitor, selinexor, to inhibit nuclear export in combination with radiation fractions similar to that given in clinical practice for rectal cancer: hypofractionated short-course radiation dosage of 5 Gy per fraction or the conventional long-course radiation dosage of 1 Gy fractions. Single and combination treatments were tested in colorectal cancer cell lines and xenograft tumor models. RESULTS: Combination treatment of radiotherapy and selinexor resulted in an increase of apoptosis and decrease of proliferation compared with single treatment, which correlated with reduced tumor size. We found that the combination promoted nuclear survivin accumulation and subsequent depletion, resulting in increased apoptosis and enhanced radiation antitumoral effects. CONCLUSIONS: Our findings suggest a novel therapeutic option for improving radiation sensitivity in the setting of rectal cancer and provide the scientific rationale to evaluate this combination strategy for clinical trials. PMID- 26603257 TI - Identification of Developmental Endothelial Locus-1 on Circulating Extracellular Vesicles as a Novel Biomarker for Early Breast Cancer Detection. AB - PURPOSE: Currently, there are no molecular biomarkers for the early detection of breast cancer. This study focused on identifying surface proteins found on circulating extracellular vesicles (EVs) for detecting early-stage breast cancer. EXPERIMENTAL DESIGN: Circulating EVs, isolated from the plasma of 10 patients with breast cancer (stages I and II) and 5 healthy controls, were analyzed using LC-MS/MS. Developmental endothelial locus-1 protein (Del-1) was selected as a candidate biomarker. Two different ELISAs were used to measure Del-1 in plasma samples from healthy controls (n= 81), patients with breast cancer (n= 269), breast cancer patients after surgical resection (n= 50), patients with benign breast tumors (n= 64), and patients with noncancerous diseases (n= 98) in two cohorts. RESULTS: Plasma Del-1 levels were significantly higher (P< 0.0001) in patients with breast cancer than in all controls and returned to almost normal after tumor removal. The diagnostic accuracy of Del-1 was AUC, 0.961 [95% confidence interval (CI), 0.924-0.983], sensitivity of 94.70%, and specificity of 86.36% in test cohort and 0.968 (0.933-0.988), 92.31%, and 86.62% in validation cohort for early-stage breast cancer by one type of ELISA. Furthermore, Del-1 maintained diagnostic accuracy for patients with early-stage breast cancer using the other type of ELISA [0.946 (0.905-0.972), 90.90%, and 77.14% in the test cohort; 0.943 (0.900-0.971), 89.23%, and 80.99% in the validation cohort]. CONCLUSIONS: Del-1 on circulating EVs is a promising marker to improve identification of patients with early-stage breast cancer and distinguish breast cancer from benign breast tumors and noncancerous diseases. PMID- 26603258 TI - First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies. AB - PURPOSE: GSK2126458 (GSK458) is a potent inhibitor of PI3K (alpha, beta, gamma, and delta), with preclinical studies demonstrating broad antitumor activity. We performed a first-in-human phase I study in patients with advanced solid tumors. MATERIALS AND METHODS: Patients received oral GSK458 once or twice daily in a dose-escalation design to define the maximum tolerated dose (MTD). Expansion cohorts evaluated pharmacodynamics, pharmacokinetics, and clinical activity in histologically and molecularly defined cohorts. RESULTS: One hundred and seventy patients received doses ranging from 0.1 to 3 mg once or twice daily. Dose limiting toxicities (grade 3 diarrhea,n= 4; fatigue and rash,n= 1) occurred in 5 patients (n= 3 at 3 mg/day). The MTD was 2.5 mg/day (MTD with twice daily dosing undefined). The most common grade >=3 treatment-related adverse events included diarrhea (8%) and skin rash (5%). Pharmacokinetic analyses demonstrated increased duration of drug exposure above target level with twice daily dosing. Fasting insulin and glucose levels increased with dose and exposure of GSK458. Durable objective responses (ORs) were observed across multiple tumor types (sarcoma, kidney, breast, endometrial, oropharyngeal, and bladder cancer). Responses were not associated withPIK3CAmutations (OR rate: 5% wild-type vs. 6% mutant). CONCLUSIONS: Although the MTD of GSK458 was 2.5 mg once daily, twice-daily dosing may increase duration of target inhibition. Fasting insulin and glucose levels served as pharmacodynamic markers of drug exposure. Select patients achieved durable responses; however,PIK3CAmutations were neither necessary nor predictive of response. Combination treatment strategies and novel biomarkers may be needed to optimally target PI3K. PMID- 26603259 TI - Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models. AB - PURPOSE: To characterize the prevalence of hypoxia in the leukemic bone marrow, its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxia-activated prodrug TH-302 in leukemia models. EXPERIMENTAL DESIGN: Hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine acute myeloid leukemia (AML) model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated prodrug TH-302 was examined in the in vitro and in vivo leukemia models. RESULTS: Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared with healthy control mice, suggesting metabolic reprogramming of hypoxic bone marrow niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a "hypoxia index" compared with samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models, and reduced the leukemia stem cell pool in vivo In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater antileukemia effects than either drug alone. Importantly, residual leukemic bone marrow cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells. CONCLUSIONS: These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins. PMID- 26603260 TI - Defects in the Fanconi Anemia Pathway in Head and Neck Cancer Cells Stimulate Tumor Cell Invasion through DNA-PK and Rac1 Signaling. AB - PURPOSE: Head and neck squamous cell carcinoma (HNSCC) remains a devastating disease, and Fanconi anemia (FA) gene mutations and transcriptional repression are common. Invasive tumor behavior is associated with poor outcome, but relevant pathways triggering invasion are poorly understood. There is a significant need to improve our understanding of genetic pathways and molecular mechanisms driving advanced tumor phenotypes, to develop tailored therapies. Here we sought to investigate the phenotypic and molecular consequences of FA pathway loss in HNSCC cells. EXPERIMENTAL DESIGN: Using sporadic HNSCC cell lines with and without FA gene knockdown, we sought to characterize the phenotypic and molecular consequences of FA deficiency. FA pathway inactivation was confirmed by the detection of classic hallmarks of FA following exposure to DNA cross-linkers. Cells were subjected to RNA sequencing with qRT-PCR validation, followed by cellular adhesion and invasion assays in the presence and absence of DNA dependent protein kinase (DNA-PK) and Rac1 inhibitors. RESULTS: We demonstrate that FA loss in HNSCC cells leads to cytoskeletal reorganization and invasive tumor cell behavior in the absence of proliferative gains. We further demonstrate that cellular invasion following FA loss is mediated, at least in part, through NHEJ-associated DNA-PK and downstream Rac1 GTPase activity. CONCLUSIONS: These findings demonstrate that FA loss stimulates HNSCC cell motility and invasion, and implicate a targetable DNA-PK/Rac1 signaling axis in advanced tumor phenotypes. PMID- 26603261 TI - The Oncolytic Adenovirus VCN-01 as Therapeutic Approach Against Pediatric Osteosarcoma. AB - PURPOSE: Osteosarcoma is the most common malignant bone tumor in children and adolescents. Despite aggressive chemotherapy, more than 30% of patients do not respond and develop bone or lung metastasis. Oncolytic adenoviruses engineered to specifically destroy cancer cells are a feasible option for osteosarcoma treatment. VCN-01 is a replication-competent adenovirus specifically engineered to replicate in tumors with a defective RB pathway, presents an enhanced infectivity through a modified fiber and an improved distribution through the expression of a soluble hyaluronidase. The aim of this study is to elucidate whether the use of VCN-01 would be an effective therapeutic strategy for pediatric osteosarcoma. EXPERIMENTAL DESIGN: We used osteosarcoma cell lines established from patients with metastatic disease (531MII, 678R, 588M, and 595M) and a commercial cell line (143B). MTT assays were carried out to evaluate the cytotoxicity of VCN-01. Hexon assays were used to evaluate the replication of the virus. Western blot analysis was performed to assess the expression levels of viral proteins and autophagic markers. The antitumor effect of VCN-01 was evaluated in orthotopic and metastatic osteosarcoma murine animal models. RESULTS: This study found that VCN-01, a new generation genetically modified oncolytic adenovirus, administered locally or systemically, had a potent antisarcoma effect in vitro and in vivo in mouse models of intratibial and lung metastatic osteosarcoma. Moreover, VCN-01 administration showed a safe toxicity profile. CONCLUSIONS: These results uncover VCN-01 as a promising strategy for osteosarcoma, setting the bases to propel a phase I/II trial for kids with this disease. Clin Cancer Res; 22(9); 2217-25. (c)2015 AACR. PMID- 26603262 TI - Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression. AB - PURPOSE: To clarify the effects of cyclin E1 suppression on antitumor efficacy of sorafenib in hepatocellular carcinoma cells and to explore the potential of combining sorafenib with cyclin-dependent kinase (CDK) inhibition in therapy. EXPERIMENTAL DESIGN: The effects of cyclin E1 suppression on sorafenib-induced apoptosis were tested in both sorafenib-sensitive (Huh-7 and HepG2, IC50 5-6 MUmol/L) and sorafenib-resistant (Huh-7R and HepG2R, IC50 14-15 MUmol/L) hepatocellular carcinoma cells. The activity of pertinent signaling pathways and the expression of cell cycle and apoptosis-related proteins were measured using Western blotting. Efficacy of sorafenib combined with the pan-CDK inhibitor flavopiridol was tested both in vitro and in xenograft experiments. The pertinent downstream mediators of antitumor efficacy were tested in transient transfection and RNA interference experiments. RESULTS: Cyclin E1 mRNA and protein expressions were suppressed after sorafenib treatment in sorafenib-sensitive but not in sorafenib-resistant hepatocellular carcinoma cells. Changes in cyclin E2 or D1 were not correlated with sorafenib sensitivity. The knockdown of cyclin E1 expression reversed the resistance of hepatocellular carcinoma cells to sorafenib in terms of cell growth and apoptosis induction, whereas the overexpression of cyclin E1 increased the resistance to sorafenib. The growth-inhibitory and apoptosis-inducing effects of sorafenib were enhanced by flavopiridol, and Mcl-1 suppression was determined to play a critical role in mediating this enhancing effect. CONCLUSIONS: The cyclin E1 suppression in hepatocellular carcinoma cells may serve as a pharmacodynamic biomarker for predicting sorafenib efficacy. The combination of sorafenib and CDK inhibitors may improve the efficacy of sorafenib in hepatocellular carcinoma. Clin Cancer Res; 22(10); 2555-64. (c)2015 AACR. PMID- 26603263 TI - Resistive switching properties of epitaxial BaTiO(3-delta) thin films tuned by after-growth oxygen cooling pressure. AB - BaTiO3-delta, i.e. oxygen-deficient barium titanate (BaTiO3), thin films grown on GdScO3(110) substrates with SrRuO3 conductive electrodes by pulsed laser deposition are studied by X-ray diffraction and conductive AFM to characterize their structure and nanoscale electronic properties. Bias- and time-dependent resistive switching measurements reveal a strong dependence on the oxygen vacancy concentration, which can be tuned by after-growth oxygen cooling conditions of thin films. The results indicate that the resistive switching properties of BaTiO3-delta can be enhanced by controlling oxygen deficiency and provide new insight for potential non-volatile resistive random-access memory (RRAM) applications. PMID- 26603264 TI - Diazo Strategy for the Synthesis of Pyridazines: Pivotal Impact of the Configuration of the Diazo Precursor on the Process. AB - Phosphazenes of vinyldiazocarbonyl compounds having cis stereochemistry of the functional groups on the vinyl bond readily produce pyridazines by a diaza-Wittig process, whereas their counterparts with trans configuration remain intact under similar reaction conditions. Upon UV irradiation trans-phosphazenes furnish pyridazines through a tandem trans-to-cis isomerization followed by intramolecular cyclization. At elevated temperatures trans (triphenyl)phosphazenes dissociate to give the initial vinyldiazo compounds, which produce pyrazoles in high yields. The first theoretical study on the mechanism of the diaza-Wittig process by DFT calculations at the M06-2X/6-31G(d) level of theory suggest that for the cis-phosphazenes a rapid tandem [2+2] cycloaddition/cycloelimination process with low energy barriers is preferred over trans isomers. PMID- 26603267 TI - Chikungunya virus infection in patients on biotherapies. PMID- 26603266 TI - Vascular complication can be minimized with a balloon-expandable, re-collapsible sheath in TAVR with a self-expanding bioprosthesis. AB - OBJECTIVE: This study evaluates the feasibility and safety of a balloon expandable, re-collapsible sheath for TAVR patients, including those with small iliofemoral access (<=5.0 mm). BACKGROUND: The recommended iliofemoral diameter for the CoreValve TAVR system is >=6.0 mm, but the lowest limit has not been determined. METHODS: Of 322 consecutive patients who underwent TAVR from 1/2014 to 8/2015 at two institutions, 64 underwent transfemoral CoreValve implantation, using an 11/19-French balloon-expandable, re-collapsible sheath, which has a 4.45 mm outer diameter (OD) on arterial entry, expands to 7.67 mm, then re-collapses upon removal. Valve sizing and vascular access were determined by computed tomography, and outcomes were assessed using the Valve Academic Research Consortium 2 (VARC-2) definitions. RESULTS: Thirteen of 64 patients had a minimal iliofemoral artery luminal diameter (MLD) of <=5.0 mm (mean 4.38+/-0.59 mm, range 3.1-5.0 mm), with vessel calcification <=90 degrees to 360 degrees and tortuosity <45 degrees to >90 degrees . At the MLD point, the sheath-to-artery ratios, based on the fully expanded 7.67 mm OD, ranged 1.53-2.47, higher than previously reported ratios that risk vascular complications. Major comorbidities included chronic renal failure, severe chronic obstructive pulmonary disease, extreme thrombocytopenia, cirrhosis, prior cardiac surgery, poor ventricular function, and frailty. All 64 patients had TAVR with IV sedation and local anesthesia, with 0% sheath malfunction, 0% vascular complications, and 0% bleeding in-hospital and at 30 days per VARC-2 definitions. CONCLUSIONS: TAVR using a balloon-expandable, re-collapsible sheath is safe, including in small iliofemoral access <=5.0 mm, thus considerably expanding the population suitable for transfemoral approach. (c) 2015 Wiley Periodicals, Inc. PMID- 26603268 TI - Length of stay in EDs: variation across classifications of clinical condition and patient discharge disposition. AB - STUDY OBJECTIVE: Duration of a stay in an emergency department (ED) is considered a measure of quality, but current measures average lengths of stay across all conditions. Previous research on ED length of stay has been limited to a single condition or a few hospitals. We use a census of one state's data to measure length of ED stays by patients' conditions and dispositions and explore differences between means and medians as quality metrics. METHODS: The data source was the Healthcare Cost and Utilization Project 2011 State Emergency Department Databases and State Inpatient Databases for Florida. Florida is unique in collecting ED length of stay for both released and admitted patients. Clinical Classifications Software was used to group visits based on first-listed International Classification of Disease, Ninth Edition, Clinical Modification, diagnoses. RESULTS: For the 10 most common diagnoses, patients with relatively minor injuries typically required the shortest mean stay (3 hours or less); conditions resulting in admission or transfer tended to be more serious, resulting in longer stays. Patients requiring the longest stays, by disposition, had discharge diagnoses of nonspecific chest pain (mean 7.4 hours among discharged patients), urinary tract infections (4.8 hours among admissions), and schizophrenia (9.6 hours among transfers) among the top 10 diagnoses. CONCLUSION: Emergency department length of stay as a measure of ED quality should take into account the considerable variation by condition and disposition of the patient. Emergency department length of stay measurement could be improved in the United States by standardizing its definition; distinguishing visits involving treatment, observation, and boarding; and incorporating more distributional information. PMID- 26603269 TI - Expression of class II histone deacetylases in two mouse models of temporal lobe epilepsy. AB - Epigenetic mechanisms like altered histone acetylation may have a crucial role in epileptogenesis. In two mouse models of temporal lobe epilepsy, we investigated changes in the expression of class II histone deacetylases (HDAC), a group of signal transducers that shuttle between nucleus and cytoplasm. Intrahippocampal injection of kainic acid (KA) induced a status epilepticus, development of spontaneous seizures (after 3 days), and finally chronic epilepsy and granule cell dispersion. Expression of class II HDAC mRNAs was investigated at different time intervals after KA injection in the granule cell layers and in sectors CA1 and CA3 contralateral to the site of KA injection lacking neurodegeneration. Increased expression of HDAC5 and 9 mRNAs coincided with pronounced granule cell dispersion in the KA-injected hippocampus at late intervals (14-28 days after KA) and equally affected both HDAC9 splice variants. In contrast, in the pilocarpine model (showing no granule cell dispersion), we observed decreases in the expression of HDAC5 and 9 at the same time intervals. Beyond this, striking similarities between both temporal lobe epilepsy models such as fast decreases in HDAC7 and 10 mRNAs during the acute status epilepticus were observed, notably also in the contralateral hippocampus not affected by neurodegeneration. The particular patterns of HDAC mRNA expression suggest a role in epileptogenesis and granule cell dispersion. Reduced expression of HDACs may result in increased expression of pro- and anticonvulsive proteins. On the other hand, export of HDACs from the nucleus into the cytoplasm could allow for deacetylation of cytoplasmatic proteins involved in axonal and dendritic remodeling, like granule cell dispersion. HDAC 5 and HDAC 9 expression is highly increased in granule cells of the KA-injected hippocampus and parallels granule cell dispersion. Both HDACs are thought to be targeted to the cytoplasm and to act there by deacetylating cytoplasmatic (e.g. cytosceleton-related) proteins. PMID- 26603271 TI - A simple mechanism for the establishment of C2-specific gene expression in Brassicaceae. AB - The transition of C3 , via C2 towards C4 photosynthesis is an important example of stepwise evolution of a complex genetic trait. A common feature that was gradually emphasized during this trajectory is the evolution of a CO2 concentration mechanism around Rubisco. In C2 plants, this mechanism is based on tissue-specific accumulation of glycine decarboxylase (GDC) in bundle sheath (BS) cells, relative to global expression in the cells of C3 leaves. This limits photorespiratory CO2 release to BS cells. Because BS cells are surrounded by photosynthetically active mesophyll cells, this arrangement enhances the probability of re-fixation of CO2 . The restriction of GDC to BS cells was mainly achieved by confinement of its P-subunit (GLDP). Here, we provide a mechanism for the establishment of C2 -type gene expression by studying the upstream sequences of C3 Gldp genes in Arabidopsis thaliana. Deletion of 59 bp in the upstream region of AtGldp1 restricted expression of a reporter gene to BS cells and the vasculature without affecting diurnal variation. This region was named the 'M box'. Similar results were obtained for the AtGldp2 gene. Fusion of the M box to endogenous or exogenous promoters supported mesophyll expression. Nucleosome densities at the M box were low, suggesting an open chromatin structure facilitating transcription factor binding. In silico analysis defined a possible consensus for the element that was conserved across the Brassicaceae, but not in Moricandia nitens, a C2 plant. Collective results provide evidence that a simple mutation is sufficient for establishment of C2 -specific gene expression in a C3 plant. PMID- 26603270 TI - Are the leading drugs against Staphylococcus aureus really toxic to cartilage? AB - Many studies have shown that the toxic effects of local antibiotics on bone and cartilage limit orthopedic surgeons. In this study, we evaluated three antibacterial agents used locally to treat highly mortal and morbid diseases in the field of orthopedics, such as septic arthritis. Are vancomycin, teicoplanin, and linezolid, which are archenemies of Staphylococcus aureus, really toxic to chondrocytes? The purpose of the study was to investigate the effects of antibiotics, which are used against S. aureus, on human chondrocytes in vitro. Primary cell cultures obtained from gonarthrosis patients were divided into two main groups. One of these groups was designated as the control chondrocyte culture. The other group was divided into three subgroups, and each group was exposed to vancomycin, teicoplanin, or linezolid. Cell culture samples were characterized by immunophenotyping following incubation with the three different antibiotics. Before and after the agents were administered, the cultures were subjected to inverted and environmental scanning electron microscopy. The number of live cells and the proliferation rate were monitored with the MTT-assay. We found that vancomycin, teicoplanin, and linezolid do not have chondrotoxic effects. Vancomycin, teicoplanin, and linezolid had no chondrotoxic activity during in vitro culture, which supports the argument that these agents can safely be used in orthopedic surgery, especially against methicillin-resistant S. aureus agents. PMID- 26603272 TI - Case of bullous impetigo with enormous bulla developing into staphylococcal scalded skin syndrome. PMID- 26603273 TI - Targeting pancreatic cancer using a combination of gemcitabine with the omega-3 polyunsaturated fatty acid emulsion, LipidemTM. AB - SCOPE: Pancreatic cancer remains a disease of poor prognosis, with alternate strategies being sought to improve therapeutic efficacy. Omega-3 fatty acids have shown clinical benefit, and mechanisms of action are under investigation. METHODS AND RESULTS: Proliferation assays, flow cytometry, invasion assays, ELISA and western blotting were used to investigate efficacy of omega-3 fatty acids alone and in combination with gemcitabine. The docosahexanoic acid (DHA)/eicosapentanoic acid (EPA) combination, LipidemTM, in combination with gemcitabine inhibited growth in pancreatic cancer and pancreatic stellate cell (PSC) lines, with PSCs exhibiting greatest sensitivity to this combination. Invasion of pancreatic cancer cells and PSCs in a 3D spheroid model, was inhibited by combination of gemcitabine with LipidemTM. PSCs were required for cancer cell invasion in an organotypic co-culture model, with invasive capacity reduced by LipidemTM alone. Platelet-derived growth factor (PDGF) is a key cytokine in pro-proliferative and invasion signalling, and thus a critical regulator of interactions between pancreatic cancer cells and adjacent stroma. Platelet-derived growth factor (PDGF-BB) secretion was completely inhibited by the combination of LipidemTM with gemcitabine in cancer cells and PSCs. CONCLUSION: LipidemTM in combination with gemcitabine, has anti-proliferative and anti-invasive efficacy in vitro, with pancreatic stellate cells exhibiting the greatest sensitivity to this combination. PMID- 26603274 TI - Characterization of the relationship between spontaneous locomotor activity and cardiovascular parameters in conscious freely moving rats. AB - In freely behaving rats, variations in heart rate (HR) and blood pressure (BP) are coupled closely with changes in locomotor activity (Act). We have attempted to characterize this relationship mathematically. In 10- and 16-week-old rats, HR, BP and Act were recorded telemetrically every minute for 2 days under 12h:12h light-dark cycling. After examining data for individual rats, we found that the relationship between Act and HR could be approximated by the negative exponential function HR(Act)=HRmax-(HRmax-HRmin)*exp(-Act/Acte), where HRmax, HRmin, and Acte are constants. These constants were calculated separately for light and dark periods by non-linear curve fitting. HR corresponding to maximal locomotion was similar during the light and dark phases, while HR at rest during the dark phase was higher than during the light phase. The range of HR variability associated with Act during the dark phase was similar in young and older animals, but minimal HR was significantly lower in older rats. The relationship between Act and BP was approximated with a similar function. We have found no differences between BP at rest and at maximal locomotion between light and dark and between 10-week and 16-week-old rats. Our results indicate that in rats, cardiovascular parameters are coupled to locomotion to a high degree; however both the HR and the BP reach maximal values when locomotor activity is relatively low. We also found that the phase of daily cycle affects HR in conscious rats independent of locomotor activity. PMID- 26603275 TI - Blocking Deprotonation with Retention of Aromaticity in a Plant ent-Copalyl Diphosphate Synthase Leads to Product Rearrangement. AB - Substitution of a histidine, comprising part of the catalytic base group in the ent-copalyl diphosphate synthases found in all seed plants for gibberellin phytohormone metabolism, by a larger aromatic residue leads to rearrangements. Through a series of 1,2-hydride and methyl shifts of the initially formed bicycle predominant formation of (-)-kolavenyl diphosphate is observed. Further mutational analysis and quantum chemical calculations provide mechanistic insight into the basis for this profound effect on product outcome. PMID- 26603276 TI - Identification of leaf volatiles from olive (Olea europaea) and their possible role in the ovipositional preferences of olive fly, Bactrocera oleae (Rossi) (Diptera: Tephritidae). AB - The olive fly, Bactrocera oleae (Rossi), is a monophagous pest that displays an oviposition preference among cultivars of olive (Olea europaea L.). To clarify the oviposition preference, the olive leaf volatiles of three olive cultivars (Cobrancosa, Madural and Verdeal Transmontana) were assessed by headspace solid phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC/MS) at six different periods of olive fruit maturation and degrees of infestation. A total of 39 volatiles were identified, mainly esters and alcohols, with a minor percentage of aldehydes, ketones and terpenic compounds, including sesquiterpenes. At sampling dates with higher degrees of infestation, cv. Cobrancosa had, simultaneously, significantly lower infestation degrees and higher volatile amounts than the other two cultivars, with a probable deterrent effect for oviposition. The green leaf volatiles (GLVs) (Z)-3-hexen-1-ol and (Z) 3-hexen-1-ol acetate) were the main compounds identified in all cultivars, together with toluene. The abundance of GLVs decreased significantly throughout maturation, without significant differences among cultivars, while toluene showed a general increase and positive correlation with olive fly infestation levels. The results obtained could broaden our understanding of the roles of various types and amounts of olive volatiles in the environment, especially in olive fly host selection and cultivar preference. PMID- 26603277 TI - Scent emission profiles from Darwin's orchid--Angraecum sesquipedale: Investigation of the aldoxime metabolism using clustering analysis. AB - The display of scent is crucial for plants in attracting pollinating insects to flowers and ensuring successful pollination and reproduction. The large number of aldoxime volatile species present in the scent of the Madagascan orchid Angraecum sesquipedale has been suggested to play a primary role in attracting the sphingid moth Xanthopan morgani praedicta. By solid phase micro-extraction (SPME) coupled with gas chromatography-mass spectrometry (GC-MS), we monitored the scent release from different flowers of a single orchid, day and night throughout the entire flowering period. In separate experiments, the diurnal release was monitored in 3h intervals and the tissue specific release from the different floral parts was tracked. Numerous novel compounds related to the aldoxime metabolism not previously detected in A. sesquipedale were identified and positioned into a proposed pathway for aldoxime metabolism. From the results, we hypothesize that (E/Z)-phenylacetaldoxime and its derivatives could be important attractants for the pollinating moth X. morgani praedicta. By applying an untargeted Partitioning Around Medoids (PAM) cluster analysis to the metabolite profiles in the scent, the proposed pathways for the formation of aldoximes were substantiated. With this study, we demonstrate the powerful utility of a bioinformatics tool to aid in the elucidation of the routes of formation for volatiles and provide a benchmark and guidelines for future detailed observations of hawkmoth pollination of Angraecum species, and in particular A. sesquipedale, in the wild. PMID- 26603278 TI - Inpatient Treatment for Adolescents with Anorexia Nervosa: Clinical Significance and Predictors of Treatment Outcome. AB - This study evaluated the clinical significance as well as predictors of outcome for adolescents with severe anorexia nervosa (AN) treated in an inpatient setting. Body mass index (BMI), eating disorder (ED) symptoms [Eating Disorder Inventory-2 (EDI-2)], general psychopathology and depression were assessed in 238 patients at admission and discharge. BMI increased from 14.8 + 1.2 to 17.3 + 1.4 kg/m(2). Almost a fourth (23.6%) of the patients showed reliable changes, and 44.7% showed clinically significant changes (EDI-2). BMI change did not significantly differ between those with reliable or clinically significant change or no reliable change in EDI-2. Length of stay, depression and body dissatisfaction were negative predictors of a clinically significant change. Inpatient treatment is effective in about two thirds of adolescents with AN and should be considered when outpatient treatment fails. About one third of patients showed significant weight gain, but did not improve regarding overall ED symptomatology. Future studies should focus on treatment strategies for non responders. PMID- 26603279 TI - Editorial Comment from Dr Negoro to Propiverine increases urethral wall catecholamine levels and bladder leak point pressure in rats. PMID- 26603280 TI - Predictors of couple HIV counseling and testing among adult residents of Bukomero sub-county, Kiboga district, rural Uganda. AB - BACKGROUND: Studies have shown that couple HIV counseling and testing (CHCT) increased rates of sero-status disclosure and adoption of safer sexual behaviors with better linkage to treatment and care. However, current evidence suggests that new HIV infections are occurring among heterosexual couples in stable relationships where the majority of the individuals are not aware of their partner's serostatus. This study examined the predictors of CHCT uptake among married or cohabiting couples of Bukomero sub-county Kiboga district in Uganda. METHODS: This cross-sectional correlational study was conducted among 323 individuals who were either married or cohabiting, aged 18-49 years. Participants were enrolled from randomly selected households in Bukomero sub-county. Data were collected using an interviewer-administered questionnaire on socio-demographics, self-rating on awareness of CHCT benefits, couple discussion about HIV testing and CHCT practices. Couples were compared between those who had reported to have tested as a couple and those who had not. Binary logistic regression was performed to determine the adjusted odds ratio [aOR] and 95 % confidence intervals [CI] for CHCT uptake and the other independent variables. RESULTS: Of the participants 288 (89.2 %) reported to have ever taken an HIV test only 99 (34.4 %) did so as a couple. The predictors of testing for HIV as a couple were discussing CHCT with the partner (adjusted odds ratio 4.95[aOR], 95 % confidence interval [CI]:1.99-12.98; p < 0.001), awareness of CHCT benefits (aOR 3.23; 95 % CI 1.78-5.87; p < 0.001) and having time to test as a couple (aOR 2.61; 95 % CI 1.22-5.61; p < 0.05). CONCLUSION: Uptake of HIV counseling and testing among couples was low. Discussing CHCT with partner, awareness of CHCT benefits, and availability of time to test as a couple were predictive of CHCT uptake. Thus CHCT campaigns should emphasize communication and discussion of HIV counseling and testing among partners. PMID- 26603281 TI - Erratum to: Exercise training in adverse cardiac remodeling. PMID- 26603282 TI - Calcium homeostasis modulator (CALHM) ion channels. AB - Calcium homeostasis modulator 1 (CALHM1), formerly known as FAM26C, was recently identified as a physiologically important plasma membrane ion channel. CALHM1 and its Caenorhabditis elegans homolog, CLHM-1, are regulated by membrane voltage and extracellular Ca(2+) concentration ([Ca(2+)]o). In the presence of physiological [Ca(2+)]o (~1.5 mM), CALHM1 and CLHM-1 are closed at resting membrane potentials but can be opened by strong depolarizations. Reducing [Ca(2+)]o increases channel open probability, enabling channel activation at negative membrane potentials. Together, voltage and Ca(2+) o allosterically regulate CALHM channel gating. Through convergent evolution, CALHM has structural features that are reminiscent of connexins and pannexins/innexins/LRRC8 (volume-regulated anion channel (VRAC)) gene families, including four transmembrane helices with cytoplasmic amino and carboxyl termini. A CALHM1 channel is a hexamer of CALHM1 monomers with a functional pore diameter of ~14 A. CALHM channels discriminate poorly among cations and anions, with signaling molecules including Ca(2+) and ATP able to permeate through its pore. CALHM1 is expressed in the brain where it plays an important role in cortical neuron excitability induced by low [Ca(2+)]o and in type II taste bud cells in the tongue that sense sweet, bitter, and umami tastes where it functions as an essential ATP release channel to mediate nonsynaptic neurotransmitter release. CLHM-1 is expressed in C. elegans sensory neurons and body wall muscles, and its genetic deletion causes locomotion defects. Thus, CALHM is a voltage- and Ca(2+) o-gated ion channel, permeable to large cations and anions, that plays important roles in physiology. PMID- 26603283 TI - Successful Transplantation of Lungs From an Uncontrolled Donor After Circulatory Death Preserved In Situ by Alveolar Recruitment Maneuvers and Assessed by Ex Vivo Lung Perfusion. AB - We developed a protocol to procure lungs from uncontrolled donors after circulatory determination of death (NCT02061462). Subjects with cardiovascular collapse, treated on scene by a resuscitation team and transferred to the emergency room, are considered potential donors once declared dead. Exclusion criteria include unwitnessed collapse, no-flow period of >15 min and low flow >60 min. After death, lung preservation with recruitment maneuvers, continuous positive airway pressure, and protective mechanical ventilation is applied to the donor. After procurement, ex vivo lung perfusion (EVLP) is performed. From November 2014, 10 subjects were considered potential donors; one of these underwent the full process of procurement, EVLP, and transplantation. The donor was a 46-year-old male who died because of thoracic aortic dissection. Lungs were procured 4 h and 48 min after death, and deemed suitable for transplantation after EVLP. Lungs were then offered to a rapidly deteriorating recipient with cystic fibrosis (lung allocation score [LAS] 46) who consented to the transplant in this experimental setting. Six months after transplantation, the recipient is in good condition (forced expiratory volume in 1 s 85%) with no signs of rejection. This protocol allowed procurement of lungs from an uncontrolled donor after circulatory determination of death following an extended period of warm ischemia. PMID- 26603285 TI - Erratum to: self-reported psychopathy in the Middle East: a cross-national comparison across Egypt, Saudi Arabia, and the United States. PMID- 26603284 TI - Calcium/calmodulin-dependent kinase II and Alzheimer's disease. AB - CaMKII is a remarkably complex protein kinase, known to have a fundamental role in synaptic plasticity and memory formation. Further, CaMKII has also been suggested to be a tau kinase. CaMKII dysregulation may therefore be a modulator of toxicity in Alzheimer's disease, a dementia characterised by aberrant calcium signalling, synapse and neuronal loss, and impaired memory. Here, we first examine the evidence for CaMKII dysregulation in Alzheimer's patients and draw parallels to findings in disease models which recapitulate key aspects of the disease. We then put forward the hypothesis that these changes critically contribute to neurodegeneration and memory impairment in Alzheimer's disease. PMID- 26603286 TI - Measuring Methane Production from Ruminants. AB - Radiative forcing of methane (CH4) is significantly higher than carbon dioxide (CO2) and its enteric production by ruminant livestock is one of the major sources of greenhouse gas emissions. CH4 is also an important marker of farming productivity, because it is associated with the conversion of feed to product in livestock. Consequently, measurement of enteric CH4 is emerging as an important research topic. In this review, we briefly describe the conversion of carbohydrate to CH4 by the bacterial community within gut, and highlight some of the key host-microbiome interactions. We then provide a picture of current progress in techniques for measuring enteric CH4, the context in which these technologies are used, and the challenges faced. We also discuss solutions to existing problems and new approaches currently in development. PMID- 26603287 TI - Microfluidics: The Challenge Is to Bridge the Gap Instead of Looking for a 'Killer App'. PMID- 26603288 TI - [Position of French transfusion operator in the regulation of territorial care in a changing context]. AB - Since the first law regarding the French transfusion, the public service of blood transfusion has always evolved. Today, different factors are changing: consequences of combination of French laws and European rules, new regulations and required levels of blood products. Moreover, those changes lead us to look at the position of the EFS in his health's territory which is actually changing too. The study of the context and actual laws could draw a first picture of the opportunities available for the EFS to face those new challenges. PMID- 26603289 TI - Continuous control of tracheal cuff pressure for VAP prevention: a collaborative meta-analysis of individual participant data. AB - BACKGROUND: Underinflation of tracheal cuff is a risk factor for microaspiration of contaminated secretions and subsequent ventilator-associated pneumonia (VAP). The aim of this collaborative meta-analysis of individual participant data is to determine the impact of continuous control of P cuff on the incidence of VAP. METHODS: Studies were identified by searching PubMed and references of relevant articles. Data from 3 prospective controlled trials (two randomized and one quasi randomized), which evaluated the impact of continuous control of P cuff on the incidence of VAP, were obtained and pooled together. Three different devices were used to continuously control P cuff. VAP was diagnosed using clinical, radiologic, and quantitative microbiological criteria. The impact of continuous control of P cuff on VAP was assessed by Cox regression analysis, stratified on trial. RESULTS: 263 (48.4 %) patients received continuous control of P cuff, and 280 (51.5 %) patients received routine control of P cuff using a manometer. 36 (13.6 %) VAP were diagnosed in continuous control group, and 72 (25.7 %) in routine care group (HR 0.47, 95 % CI 0.31-0.71, p < 0.001). However, heterogeneity was apparent in continuous control effect size across trials (I (2) = 58 %, p = 0.085). The number of patients needed to treat to prevent one VAP episode was 8. No significant impact of continuous control of P cuff was found on duration of mechanical ventilation, ICU length of stay, or mortality. CONCLUSION: Continuous control of P cuff might be beneficial in reducing the risk for VAP. However, no significant impact of continuous control of P cuff was found on duration of mechanical ventilation, ICU length of stay, or mortality. PMID- 26603290 TI - Important drug classes associated with potential drug-drug interactions in critically ill patients: highlights for cardiothoracic intensivists. AB - BACKGROUND: Patients in the intensive care unit (ICU) are more prone to drug-drug interactions (DDIs). The software and charts that indicate all interactions may not be proper for clinical usage. This study aimed to identify the main drug classes associated with clinically significant DDIs in cardiothoracic ICU and categorize DDIs to make cardiothoracic intensivists aware of safe medication usage. METHODS: This prospective study was conducted over 6 months in a cardiothoracic ICU of a university-affiliated teaching hospital. The presence of potential drug-drug interactions (pDDIs) was assessed by a clinical pharmacologist using Lexi-Interact database. Clinically significant pDDIs were defined according to severity and reliability rating. Interacting drug classes, mechanisms, and recommendations were identified for each interaction. RESULTS: From 1780 administered drugs, 496 lead to major (D) and contraindicated (X) interactions. Nine drug classes were responsible for D and/or X interactions with excellent (E) and/or good (G) reliability. Anti-infective agents (45.87 %) were the main drug classes that caused clinically significant pDDIs followed by central nervous system drugs (14.67 %). Azole antifungals as the most interacting antimicrobial agents precipitated metabolism inhibition of CYP3A substrates. CONCLUSIONS: Clinically significant pDDIs as potential patient safety risks were prevalent in critically ill patients. The findings from current study help to improve knowledge and awareness of clinicians in this area and minimize adverse events due to pDDIs. PMID- 26603291 TI - Which carotid artery aneurysms need to be treated (and how)? AB - Extra-cranial carotid artery aneurysms (ECAA) are uncommon and represent a therapeutic challenge for clinicians. An ECAA is generally defined as a dilation of the internal carotid artery (ICA) or common carotid artery (CCA) greater than 150% of the diameter of the normal healthy artery. The presence of an ECAA is usually found by coincidence in asymptomatic patients. Symptomatic patient may present with neurological dysfunction or symptoms of local compression. The initial diagnosis of ECAA is often by echo/duplex ultrasound imaging. However, computerized tomographic angiography (CTA), with 3-dimensional reconstruction of the images (3D) can provide additional and valuable information, especially when considering surgical exclusion of the aneurysm. Recently, vessel wall imaging using contrast enhanced magnetic resonance with gadolinium administration was explored, which could potentially provide valuable information regarding aneurysm wall changes during clinical follow up. Location and accessibility of an ECAA is key information when considering the appropriate treatment. With the lack of evidence based treatment guidelines, a conservative approach with or without medicinal treatment is currently the standard of care for asymptomatic non growing ECAA. Open surgical repair has for long been the accepted treatment for patients with a growing aneurysms or aneurysm related symptoms. Endovascular interventions are increasingly applied, especially when surgical intervention is considered too risky or not possible due to patient comorbidities or anatomical restrictions. Data on the natural course, immediate and long-term results of surgical or endovascular therapy is scarce. Thus, there is a clear need for an international collaboration collecting data of ECAA within a registry. PMID- 26603292 TI - Consequences of Needle-Related Medical Procedures: A Hermeneutic Study With Young Children (3-7 Years). AB - Needle-related medical procedures (NRMPs) are often frightening and cause children anxiety and pain. Only a few studies have examined the perspectives of younger children. More knowledge is needed about younger children's experiences in caring situations such as NRMPs. AIM: The aim of this study was to explain and understand the consequences related to NRMPs from younger children's perspectives. METHODS: Participant observations and interviews with younger children who had experienced NRMPs were analysed using a lifeworld hermeneutic approach. RESULTS: Experiencing fear is central for younger children during an NRMP and interpretation of its consequences formed the basis for the following themes: seeking security, realizing the adult's power, struggling for control, feeling ashamed, and surrendering. A comprehensive understanding is presented wherein younger children's experiences of NRMPs vary across time and space related to weakening and strengthening their feelings of fear. CONCLUSIONS: Awareness is needed that adults' power becomes more obvious for children during an NRMP. Children's surrender does not necessarily imply acceptance of the procedure. Providing children with opportunities to control elements of the procedure creates a foundation for active participation, and vice versa. PMID- 26603293 TI - Increased Expression of Rac1 in Epilepsy Patients and Animal Models. AB - The mechanisms of epilepsy remain incompletely understood. Rac1 (ras-related C3 botulinum toxin substrate 1) belongs to the Rho family of small GTPases. Rac1 play important roles in cytoskeleton rearrangement and neuronal synaptic plasticity, which had also been implicated in epilepsy. However, little is known regarding the expression of Rac1 in the epileptic brain or whether Rac1-targeted interventions affect the progression of epilepsy. The aim of this study was to investigate the expression profile of Rac1 in brain tissues from patients suffering from temporal lobe epilepsy (TLE) and experimental epileptic rats and determine the possible role of Rac1 in epilepsy. We demonstrated that the expression of Rac1 is significantly increased in TLE patients and in lithium pilocarpine epilepsy model animals compared to the corresponding controls. Rac1 inhibitor NSC23766 reduced the severity of status epilepticus during the acute stage in a lithium-pilocarpine animal model. Consistent with these results, the latent period of a PTZ kindling animal model also increased. Our results demonstrated that the increased expression of Rac1 may contribute to pathophysiology of epilepsy. PMID- 26603294 TI - Current and Novel Aspects on the Non-lysosomal beta-Glucosylceramidase GBA2. AB - The non-lysosomal beta-glucosylceramidase GBA2 (EC3.2.1.45, GH116) is ubiquitously expressed in various mammal tissues and cell types where it catalyzes the hydrolysis of glucosylceramide into glucose and ceramide. Although it has been known for many years that the central nervous system is the main site of GBA2 expression and activity, little information has been available so far on the role of this protein in the neuronal development, senescence and homeostasis. In the present review, we summarize the state-of-the art of this enzyme and in particular, we focus on the current knowledge on its structure, its physico chemical properties and its subcellular localization. Data on the involvement of GBA2 in physiopathological processes are also described, with particular emphasis on the studies that have indicated the direct involvement of GBA2 in neuronal development and neurological disorders. A discussion of some open questions and future perspectives related to GBA2 are finally reported. We conclude that further investigations on this beta-glucosylceramidase will provide new clues about the physiology of the central nervous system. PMID- 26603295 TI - Treatment with a Global Methyltransferase Inhibitor Induces the Intranuclear Aggregation of ALS-Linked FUS Mutant In Vitro. AB - FUS/TLS (fused in sarcoma/translocated in liposarcoma) encodes a multifunctional DNA/RNA binding protein with non-classical carboxy (C)-terminal nuclear localization signal (NLS). A variety of ALS-linked mutations are clustered in the C-terminal NLS, resulting in the cytoplasmic mislocalization and aggregation. Since the arginine methylations are implicated in the nuclear-cytoplasmic shuttling of FUS, a methylation inhibitor could be one of therapeutic targets for FUS-linked ALS. We here examined effects of methylation inhibitors on the cytoplasmic mislocalization and aggregates of ALS-linked C-terminal FUS mutant in a cell culture system. Treatment with adenosine dialdehyde (AdOx), a representative global methyltransferase inhibitor, remarkably mitigated the cytoplasmic mislocalization and aggregation of FUS mutant, which is consistent with previous reports. However, AdOx treatment of higher concentration and longer time period evoked the intranuclear aggregation of the ectopic expressed FUS protein. The pull down assay and the morphological analysis indicated the binding between FUS and Transportin could be potentiated by AdOx treatment through modulating methylation status in RGG domains of FUS. These findings indicated the treatment with a methylation inhibitor at the appropriate levels could alleviate the cytoplasmic mislocalization but in excess this could cause the intranuclear aggregation of FUS C-terminal mutant. PMID- 26603296 TI - Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation. AB - c-Myc is known to promote glutamine usage by upregulating glutaminase (GLS), which converts glutamine to glutamate that is catabolized in the TCA cycle. Here we report that in a number of human and murine cells and cancers, Myc induces elevated expression of glutamate-ammonia ligase (GLUL), also termed glutamine synthetase (GS), which catalyzes the de novo synthesis of glutamine from glutamate and ammonia. This is through upregulation of a Myc transcriptional target thymine DNA glycosylase (TDG), which promotes active demethylation of the GS promoter and its increased expression. Elevated expression of GS promotes cell survival under glutamine limitation, while silencing of GS decreases cell proliferation and xenograft tumor growth. Upon GS overexpression, increased glutamine enhances nucleotide synthesis and amino acid transport. These results demonstrate an unexpected role of Myc in inducing glutamine synthesis and suggest a molecular connection between DNA demethylation and glutamine metabolism in Myc driven cancers. PMID- 26603297 TI - A phase II study of pemetrexed plus carboplatin followed by maintenance pemetrexed as first-line chemotherapy for elderly patients with advanced non squamous non-small cell lung cancer. AB - A phase I study recommended carboplatin (CBDCA, area under the curve = 5) plus pemetrexed (PEM, 500 mg/m(2)) for elderly patients (>=75-years old) with non squamous non-small cell lung cancer (NSCLC). PEM maintenance therapy was well tolerated. We conducted a multicenter phase II trial to evaluate the efficacy and safety of this regimen in elderly patients with NSCLC. Four courses of CBDCA plus PEM, followed by PEM, were administered. The primary endpoint was the 1-year overall survival (OS) rate, and the secondary endpoints were OS, progression-free survival (PFS), response rate (RR), and safety. Thirty-four patients (median age, 77 years) were enrolled between June 2012 and May 2013. The median observation time was 22.7 months. The primary endpoint of the 1-year OS rate was 58.0 % (95 % confidence interval (CI) 42.9-78.4 %), and RR and disease control rate were 41.2 and 85.3 %, respectively. Fourteen patients had partial responses, 15 had stable disease, 4 had disease progression, and 1 was not evaluated. The maintenance therapy rate was 58.8 %. The median PFS was 5.7 months (95 % CI 3.9-8.9 months), and median OS was 20.5 months (95 % CI 10.0-infinity months). Grade >=3 hematological adverse events included leucopenia (23.5 % of patients), neutropenia (55.9 %), anemia (35.3 %), and thrombocytopenia (20.6 %). Grade >=3 non-hematological adverse events included febrile neutropenia (8.8 %), elevated aminotransferases (5.9 %), infection (23.5 %), and anorexia/fatigue (5.9 %). Four patients had interstitial lung diseases (ILD) and one died due to ILD. CBDCA plus PEM, followed by PEM, was effective and reasonably tolerated in chemotherapy naive elderly patients with non-squamous NSCLC. Clinical Trial Registration This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry (Trial Number UMIN 000004810). PMID- 26603298 TI - Direct cost of pars plana vitrectomy for the treatment of macular hole, epiretinal membrane and vitreomacular traction: a bottom-up approach. AB - PURPOSE: The direct cost to the National Health Service (NHS) in England of pars plana vitrectomy (PPV) is unknown since a bottom-up costing exercise has not been undertaken. Healthcare resource group (HRG) costing relies on a top-down approach. We aimed to quantify the direct cost of intermediate complexity PPV. METHODS: Five NHS vitreoretinal units prospectively recorded all consumables, equipment and staff salaries during PPV undertaken for vitreomacular traction, epiretinal membrane and macular hole. Out-of-surgery costs between admission and discharge were estimated using a representative accounting method. RESULTS: The average patient time in theatre for 57 PPVs was 72 min. The average in-surgery cost for staff was L297, consumables L619, and equipment L82 (total L997). The average out-of-surgery costs were L260, including nursing and medical staff, other consumables, eye drops and hospitalisation. The total cost was therefore L1634, including 30 % overheads. This cost estimate was an under-estimate because it did not include out-of-theatre consumables or equipment. The average reimbursed HRG tariff was L1701. CONCLUSIONS: The cost of undertaking PPV of intermediate complexity is likely to be higher than the reimbursed tariff, except for hospitals with high throughput, where amortisation costs benefit from economies of scale. Although this research was set in England, the methodology may provide a useful template for other countries. PMID- 26603299 TI - Comparison of the residue persistence of trifloxystrobin (25%) + tebuconazole (50%) on gherkin and soil at two locations. AB - Residue study of trifloxystrobin and tebuconazole on gherkin was carried out at two locations (Bangalore and Gouribiddunur, India) after applications at the standard and double doses of 75 + 150 and of 150 + 300 g ha(-1) of the formulated product, trifloxystrobin (25%) + tebuconazole (50%) (Nativo 75 WG). The fungicides were determined by gas chromatography (GC) and confirmed by gas chromatography-mass spectrometry (GC-MS). Extraction and purification of the samples were carried out by Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) method after validating the analytical parameters. Initial residues of trifloxystrobin on gherkin fruits were 0.335 and 0.65 mg kg(-1) at Bangalore, and 0.34 and 0.615 mg kg(-1) at Gouribiddunur. Tebuconazole residues were 0.842 and 1.682 mg kg(-1) at Bangalore, and 0.71 and 1.34 mg kg(-1) at Gouribiddunur. Residue dissipation of the fungicides followed first-order rate kinetics. Trifloxystrobin residues dissipated at the half-life of 2.9-3.7 days, and tebuconazole at 3.2 days. At the standard dose treatment, trifloxystrobin residues dissipated to below the maximum residue limit (MRL) of 0.2 mg kg(-1) (European Union) within 3 days at both the locations. Residues of the metabolite CGA 321113 was less than the limit of quantification (LOQ; 0.05 mg kg(-1)) on all sampling days. Tebuconazole residues dissipated to below its MRL (0.05 mg kg(-1)) within 14 and 11 days, at Bangalore and Gouribiddunur, respectively. From the two trials, it was concluded that the required pre-harvest interval (PHI) for the combination formulation was 14 days. Application of Nativo 75 WG should be given before flowering to allow the residues to dissipate below the MRLs at harvest. PMID- 26603300 TI - Erratum to: Assessing environmental risks for high intensity agriculture using the material flow analysis method--a case study of the Dongting Lake basin in South Central China. PMID- 26603301 TI - Suitability Assessment of Printed Dietary Guidelines for Pregnant Women and Parents of Infants and Toddlers From 7 European Countries. AB - OBJECTIVES: To evaluate selected European printed dietary guidelines for pregnant women and parents of infants and toddlers using the suitability assessment of materials (SAM) method. METHODS: A descriptive study to determine the suitability of 14 printed dietary guidelines from 7 European countries based on deductive quantitative analyses. RESULTS: Materials varied greatly in format and content: 35.7% of materials were rated superior and 64.3% were rated adequate according to the overall SAM score for patient education material. None of the materials were scored not suitable. Among the categories, the highest average scores were for layout and typography and the lowest average scores were for cultural appropriateness and learning stimulation and motivation. Interrater reliability ranged from Cohen's kappa of 0.37 to 0.62 (mean, 0.41), indicating fair to moderate agreement among the 3 investigators. CONCLUSIONS AND IMPLICATIONS: Overall, the suitability of the assessed printed dietary guidelines was adequate. Based on the SAM methodology, printed dietary guidelines may increase in suitability by emphasizing aspects related to health literacy and accommodating the needs of different food cultures within a population. PMID- 26603302 TI - ED ultrasound-guided posterior tibial nerve blocks for calcaneal fracture analagesia. PMID- 26603303 TI - Effects of Sclerostin Antibody on the Healing of Femoral Fractures in Ovariectomised Rats. AB - The inhibition of sclerostin by the systemic administration of a monoclonal antibody (Scl-Ab) significantly increased bone mass and strength in fractured bones in animal models and non-fractured bones in ovariectomised (OVX) rats. In this study, the effects of Scl-Ab on healing were examined in a closed fracture model in OVX rats. Sixty Sprague-Dawley rats underwent an ovariectomy or a sham operation at 4 months of age, and a closed fracture of the right femur was performed 3 months later. Subcutaneous injections with Scl-Ab (25 mg/kg) or saline were then administered on day 1 after the fracture and twice a week for 8 weeks (n = 20 per group), at which time the fractured femurs were harvested for micro-computed tomography analysis, four-point bending mechanical testing and histomorphometric analysis to examine bone mass, bone strength and dynamic bone formation at the fracture site. The angiogenesis at the fracture site was also examined. Bone marrow stem cells were also isolated from the fractured bone to perform a colony-forming unit (CFU) assay and an alkaline phosphatase-positive (ALP(+)) CFU assay. OVX rats treated with Scl-Ab for 8 weeks had significantly increased bone mineral density and relative bone volume compared with OVX rats treated with saline. Similarly, maximum loading, energy to maximum load and stiffness in Scl-Ab-treated OVX rats were significantly higher than those in saline controls. The mineral apposition rate (MAR), mineralising surface (MS/BS) and bone formation rate (BFR/BS) were also significantly increased in Scl-Ab treated group compared with the saline-treated group in OVX rats. Furthermore, the Scl-Ab-treated group had more CFUs and ALP(+) CFUs than the saline-treated group in OVX rats. No significant difference in angiogenesis at the fracture site was found between the groups. Our study demonstrated that Scl-Ab helped to increase bone mass, bone strength and bone formation at the fracture site in a closed femoral fracture model in OVX rats. Bone marrow stem cells in OVX rats injected with Scl-Ab also had increased CFUs and ALP(+) CFUs. PMID- 26603304 TI - Thrice-weekly temocillin administered after each dialysis session is appropriate for the treatment of serious Gram-negative infections in haemodialysis patients. AB - In patients with end-stage renal disease (ESRD) treated with intermittent haemodialysis, a limited number of antibiotics have been studied for their suitability for parenteral administration after dialysis sessions only in a thrice-weekly regimen. Temocillin is a beta-lactam antibiotic with a long half live and enhanced activity against most Gram-negative bacteria, including extended-spectrum beta-lactamase-producers, thus making it an ideal candidate for use in this setting. This study aimed to evaluate the reliability of thrice weekly parenteral temocillin in haemodialysis patients by characterising the pharmacokinetics of total and free temocillin. Free and total temocillin concentrations were determined with a validated HPLC method in 448 samples derived from 48 administration cycles in 16 patients with ESRD treated with intermittent haemodialysis and temocillin. Pharmacokinetics were non-linear partly due to saturation in protein binding. Median clearance and half-life for the free drug during intradialysis and interdialysis periods were 113 mL/min vs. 26 mL/min and 3.6 h vs. 24 h, respectively, with dialysis extracting approximately one-half of the residual concentration. The free temocillin concentration remained >16 mg/L (MIC90 threshold for most Enterobacteriaceae) during 48%, 67% and 71% of the dosing interval for patients receiving 1 g q24h, 2 g q48h and 3 g q72h, respectively, suggesting appropriate exposure for the two latter therapeutic schemes. Temocillin administered on dialysis days only in a dosing schedule of 2 g q48h and 3 g q72h is appropriate for the treatment of serious and/or resistant Gram-negative infections in patients with ESRD undergoing intermittent haemodialysis. These doses are higher than those previously recommended. PMID- 26603305 TI - Preoperative pulmonary function and respiratory muscle strength in Portuguese adolescents with idiopathic scoliosis. PMID- 26603306 TI - Sleep disorders breathing in chronic heart failure. Is adaptive servoventilation really the answer? PMID- 26603307 TI - Overlap syndrome--Asthma and obstructive sleep apnea. AB - INTRODUCTION: Asthma is a chronic inflammatory disease with multiple phenotypes. There is still a major gap in the understanding of its complex causality. Obstructive sleep apnea (OSA) is a common condition that has been implicated as a risk factor for asthma exacerbations. OBJECTIVES: This study aims to characterize patients with the diagnosis of asthma and suspected OSA; identify the presence of OSA and review, on the current literature, the association between asthma and OSA, as an overlap syndrome. MATERIALS AND METHODS: The authors present a retrospective study that included patients diagnosed with asthma that underwent sleep study in a 3 year period. Demographic, clinical data, body mass index (BMI), sleep study parameters and treatments were analyzed. RESULTS: The sample consisted of 47 patients. The majority of population was females (68%) and the mean age was 55.65 +/- 13.04 years. The most common nighttime symptom was snoring (93.6%). Regarding BMI, values above the normal limit were observed in 89.36% of the patients. 68% underwent polysomnography and the others cardiorespiratory polygraphy. In 57.4% of the patients, OSA was confirmed with a higher prevalence in males (73.3%) compared to females (50%). The therapeutic approach in 81.8% of these patients was home ventilation therapy. CONCLUSION: The combination of asthma and OSA has become increasingly more frequent. In the described study, the prevalence of OSA was 57.4%, value that is in fact higher than in general population. After the therapeutic approach, all patients referred improvement of symptoms. It is therefore essential that OSA is investigated in patients with asthma when there is poor control of symptoms, in order to achieve a better control. PMID- 26603308 TI - Challenging the discourse of untreatability for borderline personality disorder: A call for comparative research. PMID- 26603309 TI - Uncertain prophecies: How practitioners negotiate the prognostic ambivalence of 'disability' in prenatal diagnosis consultations: Commentary on I. Ville & V. Mirlesse, 'prenatal diagnosis: From policy to practice. Two distinct ways of managing prognostic uncertainty and anticipating disability in Brazil and France'. PMID- 26603310 TI - Sexual and physical violence victimization among senior high school students in Ghana: Risk and protective factors. AB - Violence in all forms poses a concern because of associations with multiple adverse effects including injuries and mental health problems. There is however limited data on violence in general and youth violence in particular in Ghana. To explore the nature and scope of youth violence in Ghana, we used the nationwide Global School-based Health Survey, conducted among senior high school students in Ghana, to explore risk and protective factors at the individual, family, and environmental levels associated with sexual and physical violence victimization. A fifth of these students reported being forced to have sex in their lifetime while two out of five had been a victim of a physical attack in the year preceding the survey. In final multivariate analysis, for sexual violence victimization, history of sexual activity with or without condom use at last sex, feeling sad or hopeless, and being a victim of bullying and electronic bullying were identified as risk factors, while having friends who were not sexually active was protective. Independent risk factors for physical violence victimization were attempting suicide in the last year, alcohol use in the past month, and bullying other students in the past month. Parent respect for privacy just reached significance as a protective factor for physical violence victimization in the final model. Recognition of the magnitude of violence victimization among Ghanaian students and associated factors must be used to guide development and implementation of appropriate concrete measures to prevent and address the problem. PMID- 26603311 TI - Healthcare under siege: Geopolitics of medical service provision in the Gaza Strip. AB - Siege, a process of political domination aimed at isolating an entire population, represents a unique threat to healthcare provision. This study is a qualitative examination of the impacts of siege on the practices and systems that underlie health in Gaza. Data are from participant observation conducted over a period of six years (2009-2014), along over 20 interviews with doctors and health administrators in the Non-Governmental Organisation (NGO), Governmental, and United Nations sectors. Analyses were informed by two connected theories. First, the theory of surplus population was used, an idea that builds on Marx's conception of primitive accumulation and Harvey's accumulation by dispossession. Second, Roy's theory of de-development was used, particularly as it is connected to neoliberal trends in healthcare systems organizing and financing. Findings indicate that siege impinges on effective healthcare provision through two central, intertwined processes: withholding materials and resources and undermining healthcare at a systems level. These strains pose considerable threats to healthcare, particularly within the Ministry of Health but also within and among other entities in Gaza that deliver care. The strategies of de development described by participants reflect the ways the population that is codified as a surplus population. Gazan society is continually divested of any of the underpinnings necessary for a well-functioning sovereign health care infrastructure. Instead of a self-governing, independent system, this analysis of health care structures in Gaza reveals a system that is continually at risk of being comprised entirely of captive consumers who are entirely dependent on Israel, international bodies, and the aid industry for goods and services. This study points to the importance of foregrounding the geopolitical context for analysis of medical service delivery within conflict settings. Findings also highlight the importance of advocating for sovereignty and self-determination as related to health systems. PMID- 26603312 TI - Manipulating Water Wave Propagation via Gradient Index Media. AB - It is challenging to realise the perfect manipulation of water waves within a broad range of frequencies. By extending conformal transformation principles to water waves, their propagation can be controlled via gradually varying water depths, permitting the realisation of a desired refractive index profile for linear water surface waves. Wave bending, directional wave emission and wave focusing are analysed experimentally with accompanying simulations. The results demonstrate desired wave manipulations within a broad range of frequencies, confirming the accuracy and effectiveness of conformal transformation for water waves. PMID- 26603313 TI - The protective effect of neutralizing high-mobility group box1 against chronic cyclosporine nephrotoxicity in mice. AB - BACKGROUND: High-mobility group box1 (HMGB1) is known to be involved in innate immune response through interaction with receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs), besides its proper role within the nucleus. Immunological pathways, including TLR signaling, are also involved in chronic cyclosporine (CsA) nephrotoxicity. This study was designed to determine whether neutralizing HMGB1 prevents chronic CsA nephrotoxicity. METHODS: Chronic CsA nephrotoxicity was induced by CsA subcutaneous injection daily for 4weeks under salt-depletion in mice. Anti-HMGB1 neutralizing antibody for HMGB1 blockade (600mcg/mouse) was administered weekly to mice in the anti HMGB1 treatment group. The effects of HMGB1 neutralization were evaluated in terms of renal function as well as histological and immunopathological examination. RESULTS: Anti-HMGB1 administration prevented the increases in serum creatinine and 24h albuminuria and the decrease in creatinine clearance associated with CsA treatment. Increased tubulointerstitial fibrosis and transforming growth factor (TGF)-beta immunohistochemical staining associated with CsA treatment were also prevented by anti-HMGB1 administration. Anti-HMGB1 administration prevented the activation of the TLR4 signaling pathway, which resulted in the reduction of nuclear factor kappa B (NF-kappaB) expression. In cultured tubular cells, anti-HMGB1 pretreatment also prevented the increases in fibronectin and collagen IV levels associated with CsA treatment. CONCLUSIONS: Neutralizing HMGB1 with an anti-HMGB1 antibody ameliorated chronic CsA nephrotoxicity via inhibition of the TLR4 signaling pathway. Our study suggests that HMGB1 blockade can be beneficial for increasing allograft survival in renal transplant recipients by protecting against calcineurin inhibitor-induced nephrotoxicity. PMID- 26603314 TI - Impact of preformed and de novo anti-HLA DP antibodies in renal allograft survival. AB - The influence of antibodies against HLA-DP antigens detected with solid-phase assays on graft survival after kidney transplantation (KT) is uncertain. We evaluated with Luminex(r) the prevalence of pre- and posttransplant DP antibodies in 440 KT patients and their impact on graft survival. For 291 patients with available pretransplant samples, DP antibodies were present in 39.7% KT with pretransplant HLA antibodies and 47.7% with DSA. Graft survival of KT with pretransplant class-II DSA was worse than with non-DSA (p=0.01). DP antibodies did not influence graft survival. Of 346 patients monitored post-KT, 17.1% had HLA class-II antibodies, 56% with DP antibodies. Class-II DSA was detected in 39%, 60.9% of them had DP antibodies. Graft survival was worse in patients with class-II DSA (p=0.022). DP antibodies did not change these results. The presence of isolated DP antibodies was a rare event both pre- and posttransplantation (1.03 and 0.86%). The presence of pretransplant and posttransplant DSA is associated with a negative impact on graft survival. However, the presence of DP antibodies does not modify this impact significantly. PMID- 26603315 TI - Facile preparation of uniform FeSe2 nanoparticles for PA/MR dual-modal imaging and photothermal cancer therapy. AB - Recently, magnetic photothermal nanomaterials have emerged as a new class of bio nanomaterials for application in cancer diagnosis and therapy. Hence, we developed a new kind of magnetic nanomaterials, iron diselenide (FeSe(2)) nanoparticles, for multimodal imaging-guided photothermal therapy (PTT) to improve the efficacy of cancer treatment. By controlling the reaction time and temperature, FeSe(2) nanoparticles were synthesized by a simple solution-phase method. After modification with polyethylene glycol (PEG), the obtained FeSe(2) PEG nanoparticles showed high stability under various physiological conditions. FeSe(2)-PEG could serve as a T2-weighted magnetic resonance (MR) imaging contrast agent because of its strong superparamagnetic properties, with its r(2) relaxivity determined to be 133.38 mM(-1) S(-1), a value higher than that of the clinically used Feridex. On the other hand, with high absorbance in the near infrared (NIR) region, FeSe(2)-PEG also appeared to be a useful contrast agent for photoacoustic imaging (PA) as well as an effective photothermal agent for PTT cancer treatment, as demonstrated in our animal tumor model experiments. Moreover, long-term toxicity tests have proven that FeSe(2)-PEG nanoparticles after systematic administration rendered no appreciable toxicity to the treated animals, and could be gradually excreted from the major organs of mice. Our work indicates that FeSe(2)-PEG nanoparticles would be a new class of theranostic agents promising for application in bioimaging and cancer therapy. PMID- 26603316 TI - Comment on: Distal small bowel bypass for weight regain after gastric bypass: safety and efficacy threshold occurs at <70% bypass. PMID- 26603317 TI - Endometrial Receptivity Markers in Mice Stimulated With Raloxifene Versus Clomiphene Citrate and Natural Cycles. AB - Ovulation induction therapy with clomiphene citrate can suppress endometrial receptivity. Raloxifene may be an alternative therapeutic for women with ovulatory disorders. This study aimed to compare the expression of endometrial receptivity markers, including homeobox gene 10 (HOXA10), integrin beta3, and leukemia inhibitory factor (LIF), as well as pinopode production during the implantation window in mice stimulated with raloxifene and clomiphene citrate and natural cycles. Thirty-six 8-week-old female Kunming mice were randomly divided into 3 groups (n = 12) and administered daily raloxifene (22 mg/kg), clomiphene citrate (18 mg/kg), and normal saline (1 mL), respectively, by gavage. Two days later, mice were injected with 5 IU human chorionic gonadotropin and mated. Successfully mated female animals were identified with vaginal plugs designated gestation day 1. At day 4.5, pregnant donor mice were euthanized, and uterus samples were collected for immunohistochemistry, quantitative polymerase chain reaction, Western blot, and scanning electron microscopy analyses. Homeobox gene 10, integrin beta3, and LIF messenger RNA (mRNA) and protein levels were significantly higher in the raloxifene-treated animals compared with the clomiphene citrate group (all P < .05) but not significantly different from saline group values, except for LIF and integrin beta3 mRNA levels (P < .05). Pinopodes were abundant and well developed in the raloxifene and saline groups; however, in the clomiphene citrate-treated mice, fewer and poorly developed pinopodes were obtained. In mice, raloxifene had no effect on HOXA10, integrin beta3, and LIF expression as well as pinopode production, suggesting it has no adverse effects on endometrial receptivity. Raloxifene may provide a viable alternative oral ovulation induction agent to clomiphene citrate. PMID- 26603318 TI - Stability of Curcuma longa rhizome lectin: Role of N-linked glycosylation. AB - Curcuma longa rhizome lectin, a mannose-binding protein of non-seed portions of turmeric, is known to have antifungal, antibacterial and alpha-glucosidase inhibitory activities. We studied the role of complex-type glycans attached to asparagine (Asn) 66 and Asn 110 to elucidate the role of carbohydrates in lectin activity and stability. Apart from the native lectin, the characteristics of a deglycosylated Escherichia coli expressed lectin, high-mannose oligosaccharides at both asparagines and its glycosylation mutants N66Q and N110Q expressed in Pichia pastoris, were compared to understand the relationship between glycosylation and activity. Far UV circular dichroism (CD) spectra, fluorescence emission maximum, hemagglutination assay show no change in secondary or tertiary structures or sugar-binding properties between wild-type and aforementioned recombinant lectins under physiological pH. But reduced agglutination activity and loss of tertiary structure are observed in the acidic pH range for the deglycosylated and the N110Q protein. In thermal and guanidine hydrochloride (GdnCl)-induced unfolding, the wild-type and high-mannose lectins possess higher stability compared with the deglycosylated recombinant lectin and both mutants, as measured by a higher Tm of denaturation or a greater free energy change, respectively. Reversibility experiments after thermal denaturation reveal that deglycosylated proteins tend to aggregate during thermal inactivation but the wild type shows a much greater recovery to the native state upon refolding. These results suggest that N-glycosylation in turmeric lectin is important for the maintenance of its proper folding upon changes in pH, and that the oligosaccharides help in maintaining the active conformation and prevent aggregation in unfolded or partially folded molecules. PMID- 26603319 TI - "Nucleosome debris" provokes coagulation and inflammation. PMID- 26603320 TI - Conditional knockout of tissue factor pathway inhibitor 2 in vascular endothelial cells accelerates atherosclerotic plaque development in mice. AB - BACKGROUND: Tissue factor pathway inhibitor-2 (TFPI-2) regulates matrix metalloproteinases activation and extracellular matrix degradation. Over expression of TFPI-2 enhances atherosclerotic plaque stability. The aim of this study is to investigate the effect of conditional knockout (KO) of TFPI-2 in vascular endothelial cells on the initiation and development of atherosclerotic plaque. METHODS: A Cre/mloxP conditional KO system and Tek-Cre mice were used to generate offsprings with monoallelic deletion of the TFPI-2 gene in endothelial cells. TFPI-2(fl/+)/Tek-Cre mice, TFPI-2(fl/+) mice and ApoE(-/-) mice (n=6 for each group) were included. Arteries were obtained. HE, EVG and anti-alpha-SMA staining were used to examine the morphology of vessel and plaque. Protein expression and phosphorylation were detected by Western blot or immunohistochemistry. RESULTS: TFPI-2(fl/+)/Tek-Cre mice were generated. TFPI-2 level decreased to 40.68% in TFPI-2(fl/+)/Tek-Cre group. TFPI-2(fl/+)/Tek-Cre developed plaques when no plaque was found in TFPI-2(fl/+) mice. Compared with ApoE(-/-) group, TFPI-2(fl/+)/Tek-Cre group has smaller plaque area, decreased lipid content and less buried fibrous cap layers. MMP-2 and MMP-9 in TFPI 2(fl/+)/Tek-Cre group was higher than in TFPI-2(fl/+)group. The phosphorylation of PPAR-alpha and PPAR-gamma was decreased in TFPI-2(fl/+)/Tek-Cre group. CONCLUSIONS: A novel mouse model is presented and can be used to investigate the role of TFPI-2 in the process of atherosclerosis. Our findings suggest that monoallelic deletion of TFPI-2 gene in vascular endothelial cells leads to significant downregulation of TFPI-2. TFPI-2 deficiency may accelerate initiation of atherosclerotic lesion in mice. Elevated MMP-2 and 9 and decreased phosphorylation of PPAR-alpha and PPAR-gamma may contribute to this phenotype. PMID- 26603321 TI - Timing of pulmonary embolism diagnosis in the emergency department. AB - BACKGROUND: Patients with pulmonary embolism(PE) benefit from rapid diagnosis and treatment. The aim of the present study is to examine factors that contribute to the time between admission at the emergency department and diagnosis of PE (=time to diagnosis TTD). METHODS: This retrospective study included 241 patients with symptomatic PE that were admitted at the emergency department. Patient records were reviewed to obtain the relevant clinical information. Patients were assigned in one of three groups according to their TTD: short TTD <= 2 h; intermediate TTD N 2 h and <= 12 h; and prolonged TTD N 12 h. The groups were compared for differences in clinical factors. Furthermore multiple linear regression analyses based on TTD was performed. RESULTS: Factor that significantly contribute to a very short TTD b 2 h are tachycardia and a high embolus burden. Factors that significantly contribute to a diagnosis b12 h are embolus burden, no COPD present, patient admitted at day shift, and a less pathologic ratio of ventricle axis. Multiple regression analyses identified increased age and low embolus burden as the strongest, independent factors for prolonged TTD. CONCLUSIONS: Patients with higher embolus load or signs of severe PE including tachycardia were most likely diagnosed within 2 h after presentation.More effort should be put in a faster diagnostic process in older patients and in patients with COPD. PMID- 26603322 TI - When and how aortic stenosis is first diagnosed: A single-center observational study. AB - BACKGROUND: The development of clinical symptoms is associated with cardiovascular events in patients with aortic stenosis (AS). Thus, early diagnosis of AS is clinically important. However, there are few data on symptom status or the severity of AS when patients are first diagnosed, or on how AS is detected in routine practice. We aimed to investigate when and how AS patients are first diagnosed in our hospital. METHODS: We retrospectively enrolled 198 AS patients diagnosed from 1989 to 2009, and identified their symptoms and AS severity at the time of the first diagnosis. We also assessed the reasons why they came to the hospital based on their medical records. RESULTS: Of the 198 patients, 82 (41.6%) had voluntarily visited or been referred to our hospital after developing clinical symptoms (Symptomatic group). The remaining 116 patients (58.4%) had been asymptomatic, and cardiovascular disease was suspected during an annual or occasional health checkup (Asymptomatic group). The initial findings in the Asymptomatic group that led to the diagnosis of AS were: a systolic murmur on auscultation (62%), abnormal electrocardiography (27%), or abnormal echocardiography (11%). The Symptomatic group had significantly greater AS severity and an increased left ventricular mass index, and experienced more cardiac events (valve replacement or cardiac death) during the follow-up period. CONCLUSIONS: About 40% of the AS patients in this study were not diagnosed until they developed clinical symptoms, suggesting that many other patients in the community might have a latent risk of cardiovascular events. Auscultation plays an important role in the early diagnosis of AS. PMID- 26603323 TI - Biomarkers related to hemodynamic abnormalities with high shear stress. PMID- 26603324 TI - A-lipoic acid therapy mediated amelioration of sympathetic heart denervation in patients with takotsubo syndrome. PMID- 26603325 TI - Clinical impact of contact force and its regional variability on efficiency and effectiveness of pulmonary vein isolation for atrial fibrillation. AB - BACKGROUND: The purpose of this study is to analyze the impact of average contact force (CF) and its regional variability during pulmonary vein isolation (PVI) for atrial fibrillation (AF) on periprocedural parameters and midterm outcome. METHODS: This retrospective cohort study enrolled 57 drug-refractory AF patients who underwent initial PVI for AF using an open-irrigated CF catheter (SmartTouch Thermocool, Biosense Webster, Diamond Bar, CA, USA). Thirty patients were assigned to a lower CF (LCF) group (average CF<=10g) and 27 patients to a higher CF (HCF) group (average CF>10g). The relationship between CF and clinical outcome was analyzed. RESULTS: Patients were followed-up for 317+/-57 days after PVI. The CF was 8.1+/-1.3g in the LCF group and 12.4+/-1.5g in the HCF group. Higher average CF was associated with shorter ablation time (28+/-6min vs. 36+/-9min, p=0.0002) and lower radiofrequency energy delivery (79+/-18 vs. 99+/-26, p=0.0016) for PVI. The rate of acute PV reconnection (APVR) was similar in both groups (LCF group 60% vs. HCF group 44%, p=0.36). Four patients (13%) in the LCF group and nine patients (33%) in the HCF group experienced AF-recurrence. Average CF did not impact on AF-recurrence during midterm clinical outcome (p=0.09 by log rank test). In the non-recurrence group (n=44), average CF was higher at left posterosuperior PV and right anteroinferior PV than that in the recurrence group (n=13) (p=0.012 and p=0.004, respectively). CONCLUSIONS: Higher average CF decreased ablation time and radiofrequency energy delivery for PVI, but did not decrease APVR rate or improve midterm clinical outcome. PMID- 26603326 TI - Association between fractional flow reserve and coronary plaque characteristics assessed by optical coherence tomography. AB - BACKGROUND: The assessment of fractional flow reserve (FFR) in coronary lesions determines the strategy of percutaneous coronary intervention. However, the association between FFR and characteristics of the underlying coronary plaque has not been sufficiently investigated. METHODS: A total of 110 coronary lesions in 106 patients were evaluated using both FFR and optical coherence tomography (OCT). Coronary plaques were classified into fibrous, fibrocalcific, or fibroatheroma according to OCT evaluation at the site of minimal lumen area. Plaque microstructures such as cap thickness, macrophage accumulation, intimal vasculature, or cholesterol crystals were also evaluated. RESULTS: Lesions with FFR<=0.8 showed a higher frequency of fibroatheroma, macrophage accumulation, and cholesterol crystals when compared to those with FFR>0.8. The angle of lipid was wider in lesions with FFR<=0.8 (145.1+/-63.0 degrees vs. 120.7+/-48.9 degrees , p=0.047), and the longitudinal length was longer in those with FFR<=0.8 (4.2+/ 2.8mm vs. 2.5+/-2.9mm, p=0.007). However, multiple linear regression analysis revealed that the morphological characteristics of plaques assessed by OCT were not independently associated with FFR. Minimal lumen area [coefficient, 0.035; 95% confidence interval (CI), 0.022-0.048; p<0.001] and area stenosis (coefficient, -0.003; 95% CI, -0.005 to -0.001; p=0.001) assessed by OCT significantly correlated with FFR. CONCLUSION: The morphological characteristics of coronary plaque derived from OCT are not directly related to FFR. PMID- 26603327 TI - Increased T-wave alternans is associated with subclinical myocardial structural and functional abnormalities in patients with type 2 diabetes. AB - BACKGROUND: Increased T wave alternans (TWA) represents ventricular depolarization heterogeneity and is a non-invasive marker of sudden cardiac death. This study sought to determine whether myocardial structural alteration and dysfunction in patients with type 2 diabetes mellitus (T2DM) is associated with an increased TWA. METHODS: We recruited 108 T2DM patients (59.2+/-9.7 years and 52% male) without prior history of cardiovascular disease and normal treadmill stress testing. TWA was analyzed during treadmill testing in all standard precordial leads by time-domain method. Transthoracic echocardiography was performed to measure myocardial structural alteration by calibrated integrated backscatter (IBS), left ventricular (LV) systolic function by conventional method, and speckle tracking-derived global longitudinal strain (GLS), and LV diastolic function. RESULTS: A total of 29 (26.9%) patients had a high TWA of >=47mV (defined by >=75 percentile of the study population). Patients with and without elevated TWA had a similar LV dimension and ejection fraction. Nonetheless, patients with high TWA had a higher calibrated IBS (-15.8+/-4.0dB vs. -17.9+/-5.3dB, p=0.04), more impaired GLS (-18.4+/-2.0% vs. -19.3+/-1.4%, p=0.02), and a higher prevalence of diastolic dysfunction (60 vs. 33%, p=0.02). Multivariable analysis demonstrated that high TWA was independently associated with calibrated IBS, GLS, and LV diastolic dysfunction grading. CONCLUSIONS: Our results demonstrated that calibrated IBS, GLS, and LV diastolic dysfunction are independent predictors for high TWA in T2DM patients. These findings suggest that subclinical myocardial structural and functional abnormalities may contribute to high TWA in T2DM patients. PMID- 26603328 TI - Left ventricular diastolic dysfunction is associated with atrial remodeling and risk or presence of stroke in patients with paroxysmal atrial fibrillation. AB - BACKGROUND: Although the degree of electroanatomical remodeling of the left atrium (LA) is influenced by left ventricular (LV) diastolic function, clinical implications of estimated LV filling pressure (E/Em) are limited in patients with atrial fibrillation (AF). We hypothesized that increased E/Em is related to an advanced LA remodeling, a high CHA2DS2-VASc score, and the presence of stroke or transient ischemic attack (TIA) in patients with paroxysmal AF. METHODS: We included 1098 patients with paroxysmal AF (male 74.5%, 57.6+/-11.3 years old) who underwent AF catheter ablation. We compared E/Em to clinical parameters, echocardiography, and three-dimensional-computed tomography findings. RESULTS: The E/Em>15 group (n=98) was older (p<0.001) and had more females (p<0.001), greater LA volume index (p<0.001), higher CHA2DS2-VASc score (p<0.001), and stroke/TIA prevalence (p=0.001) than groups with an E/Em of 8-15 (n=676) or <8 (n=324). An E/Em was independently associated with the presence of stroke/TIA (OR 1.638, 95% CI 1.050-2.554, p=0.030) after adjusting for age, sex, body surface area, LA volume index, and LA appendage volume index. CONCLUSIONS: In patients with paroxysmal AF, the elevated LV filling pressure estimated by E/Em is independently associated with the presence of stroke or TIA. PMID- 26603329 TI - The use of static and dynamic haemodynamic parameters before volume expansion: A prospective observational study in six French intensive care units. AB - OBJECTIVE: The aim of the present study was to determine the use of static and dynamic haemodynamic parameters for predicting fluid responsiveness prior to volume expansion (VE) in intensive care unit (ICU) patients with systemic inflammatory response syndrome (SIRS). METHODS: We conducted a prospective, multicentre, observational study in 6 French ICUs in 2012. ICU physicians were audited concerning their use of static and dynamic haemodynamic parameters before each VE performed in patients with SIRS for 6 consecutive weeks. RESULTS: The median volume of the 566 VEs administered to patients with SIRS was 1000mL [500 1000mL]. Although at least one static or dynamic haemodynamic parameter was measurable before 99% (95% CI, 99%-100%) of VEs, at least one them was used in only 38% (95% CI, 34%-42%) of cases: static parameters in 11% of cases (95% CI, 10%-12%) and dynamic parameters in 32% (95% CI, 30%-34%). Static parameters were never used when uninterpretable. For 15% of VEs (95% CI, 12%-18%), a dynamic parameter was measured in the presence of contraindications. Among dynamic parameters, respiratory variations in arterial pulse pressure (PPV) and passive leg raising (PLR) were measurable and interpretable before 17% and 90% of VEs, respectively. CONCLUSIONS: Haemodynamic parameters are underused for predicting fluid responsiveness in current practice. In contrast to static parameters, dynamic parameters are often incorrectly used in the presence of contraindications. PLR is more frequently valid than PPV for predicting fluid responsiveness in ICU patients. PMID- 26603330 TI - [Interest of saline contrast sonohysterography for the diagnosis of cesarean scar defects]. AB - OBJECTIVES: To determine the interest of saline contrast sonohysterography in the evaluation of number, size and shape of cesarean scar defects in comparison with 3D-transvaginal ultrasound examination. METHODS: Patients who had surgical reparation of cesarean scar defect by operative hysteroscopy were included in this retrospective study. Before surgery, they all had 3D-transvaginal ultrasound examination and saline contrast sonohysterography to establish the diagnosis. Then those two exams were compared to determine which one is better for cesarean scar defect evaluation, in terms of diagnosis and severity. RESULTS: Fourteen patients were enrolled, they underwent transvaginal ultrasound and saline contrast sonohysterography before the surgery. 3D-transvaginal ultrasound examination made the diagnosis in 50% of patients with cesarean scar defect, whereas saline contrast sonohysterography enabled to detect 86% of defects, in comparison with hysteroscopy (100%). In 29% of patients, the size and depth of the cesarean scar defect was more important with saline contrast sonohysterography and hysteroscopy than expected by 3D-transvaginal ultrasound examination. After surgical repair, symptoms improvement was found in 82% of case (pain or abnormal uterine bleeding), and fertility was restored in 67%. CONCLUSION: Saline contrast sonohysterography is better to characterize cesarean scar defects than 3D-transvaginal ultrasound, with a higher sensibility. Moreover, it evaluates more precisely the size and shape of the defect, thus severity. PMID- 26603331 TI - [Predictive value of vitamin D plasma levels on pregnancy rates in a cohort of IVF patients]. AB - OBJECTIVE: To determine a possible correlation between plasma levels of vitamin D and pregnancy rates obtained by in vitro fertilization (IVF). PATIENTS AND METHODS: One hundred and ninety-eight womens participated in an IVF cycle from January to May 2012 in a prospective study. During the follicular phase locking, serum fluid was collected for vitamin D, calcium, FSH and estradiol analysis. The serum bhCG was checked 16 days after oocyte collect. Clinical pregnancy was confirmed by transvaginal sonography with at least one gestational sac in the uterine cavity. RESULTS: The mean levels of vitamin D was 31.7 nmol/L. A total of 169 patients (85.3%) had a vitamin D insufficiency (< 50 nmol/L). Only 29 patients (14.7%) had a sufficient vitamin D status (vitamin D 50 nmol/L). Pregnancy rate was 29.8% (59/198). There was no significant correlation between the levels of vitamin D and mean age (P = 0.92), BMI (P = 0.16) and etiology of infertility (P = 0.78). In contrast, the levels of vitamin D mean were significantly lower in patients from North Africa (P < 0.0001) and Black African (P = 0.0003) compared to Caucasian patients. DISCUSSION AND CONCLUSION: No correlation was found between serum vitamin D level and the pregnancy rate in IVF cycle. PMID- 26603332 TI - [Ultrasound appearance of the area of uterine closure in asymptomatic patients at 48 hours of uneventful cesarean section]. AB - OBJECTIVE: It seeks to assess the appearance of the hysterorrhaphy area and seeks hematoma in asymptomatic patients at 48hours of their cesarean. METHOD: It is common to see, ultrasound or CT scan, collection of images next to the hysterorrhaphy area in symptomatic patients after cesarean. Their interpretation remains difficult which led us to propose a prospective study looking for an evocative image collection or hematoma in asymptomatic patients at 48hours of their cesarean. It was directed suprapubic and transvaginal pelvic ultrasound with study area hysterorrhaphy and inter-uterine bladder space. RESULTS: The suprapubic ultrasound examination was performed in 31 asymptomatic patients after collecting their written consent. Twenty-eight patients also received an endovaginal examination. The studied area was easily identified by visualizing the path of hysterotomy and hyperechoic aspect of the hysterorrhaphy. In 28 cases there were no abnormal image in front of the hysterorrhaphy area. In 3 cases, an evocative image of a haematic collection was displayed and measured a maximum of only 49mm long axis with a weak Doppler signal. The exam was very well tolerated by patients, especially by transvaginal route. Also the duration of ultrasound never exceeded 58seconds and remained fastest vaginally. CONCLUSION: This preliminary work to a prospective double cohort (symptomatic patients and asymptomatic patients) has clarified the technique to use and focus in the search for a collection next to the hysterorrhaphy area. Ultrasound examination postoperatively, especially vaginally, is very fast, well tolerated with satisfactory image quality. Finally in this cohort of asymptomatic patients, it was very unusual for a collection, confirming the credit to be given to this type of image in case of symptoms after cesarean. PMID- 26603333 TI - [High doses of gonadotropins for controlled ovarian hyperstimulation: A case control study]. AB - OBJECTIVES: While assisted reproductive technology (ART) activity increases throughout the world, most teams have to face with the challenge of ovarian stimulation in poor responders. Despite a huge amount of literature available, no consensus currently exists on the best protocol, molecule or dose to use in these patients. The main objective of this case-control study was to compare ovarian stimulation and IVF outcome in patients at risk of poor ovarian response undergoing antagonist protocol with high doses of gonadotropins (>=450IU/day) versus patients undergoing stimulation at 300IU/day. METHODS: This retrospective monocentric study was conducted in 2013 on antagonist cycles performed with >=450IU/day. Each cycle was matched with a control antagonist cycle with 300IU/day injection, with strict matching for ART type, age, serum anti-mullerian hormone (AMH) and body mass index (BMI). RESULTS: A total of 82 high dose cycles were matched and compared with 82 control cycles. Both groups were comparable, except for poor responder prevalence and mean IVF rank, which were higher in high dose group than in control group. No significant difference was observed between the groups in terms of number of oocytes, embryos, fertilization rate, implantation and ongoing pregnancy rates. CONCLUSIONS: No ovarian stimulation protocol has demonstrated its superiority in expected poor responders up to now, especially regarding doses of gonadotropins to use. Accordingly, our study did not show any difference between high dose stimulation regimen (>=450IU/day) and conventional stimulation (300IU/day) in terms of IVF cycle outcome. PMID- 26603335 TI - Optically initialized robust valley-polarized holes in monolayer WSe2. AB - A robust valley polarization is a key prerequisite for exploiting valley pseudospin to carry information in next-generation electronics and optoelectronics. Although monolayer transition metal dichalcogenides with inherent spin-valley coupling offer a unique platform to develop such valleytronic devices, the anticipated long-lived valley pseudospin has not been observed yet. Here we demonstrate that robust valley-polarized holes in monolayer WSe2 can be initialized by optical pumping. Using time-resolved Kerr rotation spectroscopy, we observe a long-lived valley polarization for positive trion with a lifetime approaching 1 ns at low temperatures, which is much longer than the trion recombination lifetime (~10-20 ps). The long-lived valley polarization arises from the transfer of valley pseudospin from photocarriers to resident holes in a specific valley. The optically initialized valley pseudospin of holes remains robust even at room temperature, which opens up the possibility to realize room-temperature valleytronics based on transition metal dichalcogenides. PMID- 26603337 TI - Epidemiology of trauma: Childhood adversities, neighborhood problems, discrimination, chronic strains, life events, and daily hassles among people with a severe mental illness. AB - Trauma during childhood and adolescence is a common event among people with a serious psychological disorder. Few studies assess a wide range of stressors for this population. This is surprising given that these stressful events are implicated in poorer outcomes related to course and treatment of mental health problems. This study of 214 people with serious mental illness examines the prevalence of childhood traumas, perceived neighborhood problems, discrimination, chronic strains, negative life events, and daily hassles. We use regression analyses to determine if these stressors are associated with quality of life. Results show that 95% of the sample report at least one childhood adversity. Perceived neighborhood problems, experiences of discrimination, chronic strains, life events, and daily hassles were also common. Examining the relationship between demographic factors and stressors suggests that older respondents, Whites, those who have never been married, and people diagnosed with Schizophrenia reported fewer stressors compared to those who are older, non White, ever married, or suffering from other types of mental health problems. Finally, three of the six types of stressors were related to lower quality of life and depression. We discuss the implications of these findings for the treatment of severe psychological problems. PMID- 26603336 TI - A prospective study of leukocyte telomere length and risk of phobic anxiety among women. AB - We prospectively examined the relation of relative telomere lengths (RTLs), a marker of biological aging, to phobic anxiety in later-life. RTLs in peripheral blood leukocytes were measured among 3194 women in the Nurses' Health Study who provided blood samples in 1989/90. The Crown-Crisp Phobic Index (CCI, range=0-16) was assessed in 1988 and 2004. Only participants with CCI<=3 (consistent with no meaningful anxiety symptoms) in 1988 were included. We related baseline RTLs to odds ratios (ORs) of incident high phobic anxiety symptoms (CCI>=6). To enhance clinical relevance, we used finite mixture modeling (FMM) to relate baseline RTLs to latent classes of CCI in 2004. RTLs were not significantly associated with high phobic anxiety symptoms after 16 years of follow-up. However, FMM identified 3 groups of phobic symptoms in later-life: severe, minimal/intermediate, and non anxious. The severe group had non-significantly shorter multivariable-adjusted mean RTLs than the minimal/intermediate and non-anxious groups. Women with shorter telomeres vs. longest telomeres had non-significantly higher likelihood of being in the severe vs. non-anxious group. Overall, there was no significant association between RTLs and incident phobic anxiety symptoms. Further work is required to explore potential connections of telomere length and emergence of severe phobic anxiety symptoms during later-life. PMID- 26603338 TI - Recombination and selection in the major histocompatibility complex of the endangered forest musk deer (Moschus berezovskii). AB - The forest musk deer (Moschus berezovskii) is a high elevation species distributed across western China and northern Vietnam. Once abundant, habitat loss and poaching has led to a dramatic decrease in population numbers prompting the IUCN to list the species as endangered. Here, we characterized the genetic diversity of a Major Histocompatibility Complex (MHC) locus and teased apart driving factors shaping its variation. Seven DRB exon 2 alleles were identified among a group of randomly sampled forest musk deer from a captive population in the Sichuan province of China. Compared to other endangered or captive ungulates, forest musk deer have relatively low levels of MHC genetic diversity. Non synonymous substitutions primarily occurred in the putative peptide-binding region (PBR), with analyses suggesting that recombination and selection has shaped the genetic diversity across the locus. Specifically, inter-allelic recombination generated novel allelic combinations, with evidence for both positive selection acting on the PBR and negative selection on the non-PBR. An improved understanding of functional genetic variability of the MHC will facilitate better design and management of captive breeding programs for this endangered species. PMID- 26603339 TI - Differences in change in coping styles between good responders, moderate responders and non-responders to pulmonary rehabilitation. AB - INTRODUCTION: Pulmonary rehabilitation (PR) improves exercise tolerance and health status in patients with chronic obstructive pulmonary disease (COPD). Data on the effects of PR on coping styles are limited. Aim of the present study was to compare changes in coping styles between patients who had a good, moderate and no improvement in either exercise tolerance or health status after PR. METHODS: Coping styles of 439 COPD patients undergoing PR were assessed by the Utrecht Coping List (UCL) at baseline and after PR. Patients' pulmonary function, six minute walking distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) and Hospital Anxiety and Depression Scale (HADS-A and HADS-D) were recorded. Good, moderate and non-responders were defined on the basis of minimally clinically important difference (MCID) for SGRQ total score and/or 6MWD. RESULTS: Overall, 54.0% of the patients fulfilled the criteria for good responders, while 22.1% were moderate responders. Change in passive reaction pattern coping style differed significantly between good responders and non-responders following PR (p < 0.001). Moreover, within the groups, changes in coping styles after PR occurred among the good responders, whereas the majority of moderate responders' and non responders' coping styles were not significantly influenced by PR. CONCLUSION: Good responders decreased their passive reaction pattern coping style in contrast to non-responders after PR. In general, PR did not change the coping among moderate and non-responders. Further research is warranted to determine whether including interventions targeting coping styles may modify coping behaviour of COPD patients, as well as improvement in exercise tolerance or health status after PR. PMID- 26603340 TI - Emerging role of long noncoding RNAs in lung cancer: Current status and future prospects. AB - Lung cancer is the leading cause of cancer-related death worldwide with a 5-year survival rate of less than 15%, despite significant advances in both diagnostic and therapeutic approaches. Combined genomic and transcriptomic sequencing studies have identified numerous genetic driver mutations that are responsible for the development of lung cancer. Importantly, these approaches have also uncovered the widespread expression of "noncoding RNAs" including long noncoding RNAs (LncRNAs), which impact biologic responses through the regulation of mRNA transcription or translation. To date, most studies of the role of noncoding RNAs have focused on LncRNAs, which regulate mRNA translation via the RNA interference pathway. Although many of their attributes, such as patterns of expression, remain largely unknown, LncRNAs have key functions in transcriptional, post transcriptional, and epigenetic gene regulation. Recent research showed that LncRNAs regulate flowering time in the lung cancer. In this review, we discuss these investigations into long noncoding RNAs were performed almost exclusively in lung cancer. Future work will need to extend these into lung cancer and to analyze how LncRNAs interact to regulate mRNA expression. From a clinical perspective, the targeting of LncRNAs as a novel therapeutic approach will require a deeper understanding of their function and mechanism of action. PMID- 26603341 TI - Phenotypic and genomic comparisons of highly vancomycin-resistant Staphylococcus aureus strains developed from multiple clinical MRSA strains by in vitro mutagenesis. AB - The development of vancomycin (VCM) resistance in Staphylococcus aureus threatens global health. Studies of the VCM-resistance mechanism and alternative therapeutic strategies are urgently needed. We mutagenized S. aureus laboratory strains and methicillin-resistant S. aureus (MRSA) with ethyl methanesulfonate, and isolated mutants that exhibited high resistance to VCM (minimum inhibitory concentration = 32 MUg/ml). These VCM-resistant strains were sensitive to linezolid and rifampicin, and partly to arbekacin and daptomycin. Beta-lactams had synergistic effects with VCM against these mutants. VCM-resistant strains exhibited a 2-fold increase in the cell wall thickness. Several genes were commonly mutated among the highly VCM-resistant mutants. These findings suggest that MRSA has a potential to develop high VCM resistance with cell wall thickening by the accumulation of mutations. PMID- 26603342 TI - Early Cardiovascular Disease After the Diagnosis of Systemic Sclerosis. AB - PURPOSE: The purpose of this study is to assess risk and time trends of newly recorded myocardial infarction and stroke in cases with systemic sclerosis. METHODS: We conducted a matched incident cohort study (1996-2010) among patients satisfying at least one of the following: 1) diagnosis of systemic sclerosis on at least 2 visits within a 2-year period by a nonrheumatologist physician; or 2) diagnosis of systemic sclerosis on at least one visit by a rheumatologist or from hospitalization; as well as receiving no prior systemic sclerosis diagnosis between 1990 and 1995. Ten controls were matched by birth year, sex, and calendar year of exposure from the general population for each case. Incident myocardial infarction, stroke, and myocardial infarction or stroke was recorded from hospital or death certificates. We estimated incidence rate ratios and hazard ratios (HRs) after adjusting for confounders. RESULTS: Among 1239 individuals with systemic sclerosis and no history of myocardial infarction (83% female, 56 years old), the incidence rate for myocardial infarction was 13.0/1000 person years vs 4.1/1000 person-years in the comparison cohort. The incidence rate for stroke was 8.0/1000 person-years vs 3.7/1000 among controls. The adjusted HRs were 3.49 (95% confidence interval [CI], 2.52-4.83) and 2.35 (95% CI, 1.59-3.48) for myocardial infarction and stroke, respectively. For myocardial infarction and stroke, the risk was highest within the first year following diagnosis (HR 8.95; 95% CI, 5.43-14.74 and HR 5.25; 95% CI, 2.90-9.53, respectively). CONCLUSION: This large general population-based study indicates an increased risk of myocardial infarction and stroke in patients with systemic sclerosis, especially within the first year of diagnosis. PMID- 26603343 TI - MacroH2A1 associates with nuclear lamina and maintains chromatin architecture in mouse liver cells. AB - In the interphase nucleus, chromatin is organized into three-dimensional conformation to coordinate genome functions. The lamina-chromatin association is important to facilitate higher-order chromatin in mammalian cells, but its biological significances and molecular mechanisms remain poorly understood. One obstacle is that the list of lamina-associated proteins remains limited, presumably due to the inherent insolubility of lamina proteins. In this report, we identified 182 proteins associated with lamin B1 (a constitutive component of lamina) in mouse hepatocytes, by adopting virus-based proximity-dependent biotin identification. These proteins are functionally related to biological processes such as chromatin organization. As an example, we validated the association between lamin B1 and core histone macroH2A1, a histone associated with repressive chromatin. Furthermore, we mapped Lamina-associated domains (LADs) in mouse liver cells and found that boundaries of LADs are enriched for macroH2A. More interestingly, knocking-down of macroH2A1 resulted in the release of heterochromatin foci marked by histone lysine 9 trimethylation (H3K9me3) and the decondensation of global chromatin structure. However, down-regulation of lamin B1 led to redistribution of macroH2A1. Taken together, our data indicated that macroH2A1 is associated with lamina and is required to maintain chromatin architecture in mouse liver cells. PMID- 26603345 TI - Review of the current role of targeted therapies as maintenance therapies in first and second line treatment of epithelial ovarian cancer; In the light of completed trials. AB - Late and recurrent stage ovarian cancer has a high mortality and low response rate to therapy beyond first line treatment. Although first line platinum/taxane based regimens have a satisfactory response rate eventually in most cases disease recurrence is common and second-line treatments are not curative. Delaying progression or recurrence is the main goal of current ongoing clinical studies by means of establishing an effective maintenance regimen with acceptable toxicity profile. Clearly, the persistence of dormant and drug-resistant cells after front line treatments results in the inability to cure the disease. Over the past several years, the idea of prolongation of therapy for ovarian cancer has garnered clinical attention and academic debate. As a result of a greater understanding of the molecular pathways involved in carcinogenesis and tumor growth, a large number of potential therapeutic targets have been identified and drugs to block receptors, ligands or pathways are being developed. Currently, numerous clinical trials with targeted agents have just been completed or are ongoing involving patients achieving a complete or durable response after first line and beyond the first line chemotherapy in order to evaluate the efficacy of different therapeutic approaches in terms of progression-free survival and overall survival. PMID- 26603344 TI - Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease. AB - Pompe disease is a progressive neuromuscular disorder caused by lysosomal accumulation of glycogen from a deficiency in acid alpha-glucosidase (GAA). Replacement of the missing enzyme is available by repeated protein infusions; however, efficacy is limited by immune response and inability to restore enzymatic function in the central nervous system. An alternative therapeutic option is adeno-associated virus (AAV)-mediated gene therapy, which results in widespread gene transfer and prolonged transgene expression. Both enzyme replacement therapy (ERT) and gene therapy can elicit anti-GAA immune reactions that dampen their effectiveness and pose life-threatening risks to patient safety. To modulate the immune responses related to gene therapy, we show that a human codon-optimized GAA (coGAA) driven by a liver-specific promoter (LSP) using AAV9 is capable of promoting immune tolerance in a Gaa(-/-) mouse model. Copackaging AAV9-LSP-coGAA with the tissue-restricted desmin promoter (AAV9-DES coGAA) demonstrates the necessary cell autonomous expression in cardiac muscle, skeletal muscle, peripheral nerve, and the spinal cord. Simultaneous high-level expression in liver led to the expansion of GAA-specific regulatory T-cells (Tregs) and induction of immune tolerance. Transfer of Tregs into naive recipients prevented pathogenic allergic reactions after repeated ERT challenges. Copackaged AAV9 also attenuated preexisting humoral and cellular immune responses, which enhanced the biochemical correction. Our data present a therapeutic design in which simultaneous administration of two copackaged AAV constructs may provide therapeutic benefit and resolve immune reactions in the treatment of multisystem disorders. PMID- 26603346 TI - Identification of a novel de novo mutation of CREBBP in a patient with Rubinstein Taybi syndrome by targeted next-generation sequencing: a case report. AB - Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant congenital disorder (prevalence, 1:125000-720000) characterized by broad thumbs and halluces, facial dysmorphism, psychomotor development delay, skeletal defects, abnormalities in the posterior fossa, and short stature. The purpose of this study was to use targeted exome sequencing to identify the genetic cause of RSTS in a 6.5-year-old girl presenting typical features of this condition. Targeted exome sequencing of the patient DNA revealed de novo transition c.1066C>T corresponding to a novel nonsense mutation p.Q356X in the CREB-binding protein gene, CREBBP, whose haploinsufficiency is responsible for 50% to 60% of the RSTS cases. Based on comparing the clinical manifestations of our patient with those of patients carrying similar mutations, we supposed that haploinsufficiency is the possible functional consequence of p.Q356X mutation by creation of a loss-of-function CREBBP allele due to a premature stop codon and RSTS phenotype. Our findings expand the spectrum of mutations associated with this condition. PMID- 26603348 TI - Evidence That Compound I Is the Active Species in Both the Hydroxylase and Lyase Steps by Which P450scc Converts Cholesterol to Pregnenolone: EPR/ENDOR/Cryoreduction/Annealing Studies. AB - Cytochrome P450scc (CYP 11A1) catalyzes the conversion of cholesterol (Ch) to pregnenolone, the precursor to steroid hormones. This process proceeds via three sequential monooxygenation reactions: two hydroxylations of Ch first form 22(R) hydroxycholesterol (HC) and then 20alpha,22(R)-dihydroxycholesterol (DHC); a lyase reaction then cleaves the C20-C22 bond to form pregnenolone. Recent cryoreduction/annealing studies that employed electron paramagnetic resonance (EPR)/electron nuclear double resonance (ENDOR) spectroscopy [Davydov, R., et al. (2012) J. Am. Chem. Soc. 134, 17149] showed that compound I (Cpd I) is the active intermediate in the first step, hydroxylation of Ch. Herein, we have employed EPR and ENDOR spectroscopy to characterize the intermediates in the second and third steps of the enzymatic process, as conducted by 77 K radiolytic one-electron cryoreduction and subsequent annealing of the ternary oxy-cytochrome P450scc complexes with HC and DHC. This procedure is validated by showing that the cryoreduced ternary complexes of oxy-cytochrome P450scc with HC and DHC are catalytically competent and during annealing generate DHC and pregnenolone, respectively. Cryoreduction of the oxy-P450scc-HC ternary complex trapped at 77K produces the superoxo-ferrous P450scc intermediate along with a minor fraction of ferric hydroperoxo intermediates. The superoxo-ferrous intermediate converts into a ferric-hydroperoxo species after annealing at 145 K. During subsequent annealing at 170-180 K, the ferric-hydroperoxo intermediate converts to the primary product complex with the large solvent kinetic isotope effect that indicates Cpd I is being formed, and (1)H ENDOR measurements of the primary product formed in D2O demonstrate that Cpd I is the active species. They show that the primary product contains Fe(III) coordinated to the 20-O(1)H of DHC with the (1)H derived from substrate, the signature of the Cpd I reaction. Hydroperoxo ferric intermediates are the primary species formed during cryoreduction of the oxy-P450scc-DHC ternary complex, and they decay at 185 K with a strong solvent kinetic isotope effect to form low-spin ferric P450scc. Together, these observations indicated that Cpd I also is the active intermediate in the C20,22 lyase final step. In combination with our previous results, this study thus indicates that Cpd I is the active species in each of the three sequential monooxygenation reactions by which P450scc catalytically converts Ch to pregnenolone. PMID- 26603347 TI - Microneedle patches for vaccination in developing countries. AB - Millions of people die of infectious diseases each year, mostly in developing countries, which could largely be prevented by the use of vaccines. While immunization rates have risen since the introduction of the Expanded Program on Immunization (EPI), there remain major challenges to more effective vaccination in developing countries. As a possible solution, microneedle patches containing an array of micron-sized needles on an adhesive backing have been developed to be used for vaccine delivery to the skin. These microneedle patches can be easily and painlessly applied by pressing against the skin and, in some designs, do not leave behind sharps waste. The patches are single-dose, do not require reconstitution, are easy to administer, have reduced size to simplify storage, transportation and waste disposal, and offer the possibility of improved vaccine immunogenicity, dose sparing and thermostability. This review summarizes vaccination challenges in developing countries and discusses advantages that microneedle patches offer for vaccination to address these challenges. We conclude that microneedle patches offer a powerful new technology that can enable more effective vaccination in developing countries. PMID- 26603350 TI - Impact of falls on mental health outcomes for older adult mental health patients: An Australian study. AB - Sustaining a fall during hospitalization reduces a patient's ability to return home following discharge. It is well accepted that factors, such as alteration in balance, functional mobility, muscle strength, and fear of falling, are all factors that impact on the quality of life of elderly people following a fall. However, the impact that falls have on mental health outcomes in older adult mental health patients remains unexplored. The present study reports Health of the Nation Outcome Scale scores for people over the age of 65 (HoNOS65+), which were examined in a cohort of 65 patients who sustained a fall and 73 non-fallers admitted to an older adult mental health service (OAMHS). Results were compared with state and national HoNOS65+ data recorded in Australian National Outcome Casemix Collection data to explore the effect that sustaining a fall while hospitalized has on mental health outcomes. Australian state and national HoNOS65+ data indicate that older adults generally experience improved HoNOS65+ scores from admission to discharge. Mental health outcomes for patients who sustained a fall while admitted to an OAMHS did not follow this trend. Sustaining a fall while admitted to an OAMHS negatively affects discharge mental health outcomes. PMID- 26603349 TI - Looking Ahead to Engineering Epimorphic Regeneration of a Human Digit or Limb. AB - Approximately 2 million people have had limb amputations in the United States due to disease or injury, with more than 185,000 new amputations every year. The ability to promote epimorphic regeneration, or the regrowth of a biologically based digit or limb, would radically change the prognosis for amputees. This ambitious goal includes the regrowth of a large number of tissues that need to be properly assembled and patterned to create a fully functional structure. We have yet to even identify, let alone address, all the obstacles along the extended progression that limit epimorphic regeneration in humans. This review aims to present introductory fundamentals in epimorphic regeneration to facilitate design and conduct of research from a tissue engineering and regenerative medicine perspective. We describe the clinical scenario of human digit healing, featuring published reports of regenerative potential. We then broadly delineate the processes of epimorphic regeneration in nonmammalian systems and describe a few mammalian regeneration models. We give particular focus to the murine digit tip, which allows for comparative studies of regeneration-competent and regeneration incompetent outcomes in the same animal. Finally, we describe a few forward thinking opportunities for promoting epimorphic regeneration in humans. PMID- 26603351 TI - Vulnerabilities in snakebites in Sao Paulo, Brazil. AB - OBJECTIVE: To describe elements of vulnerability of victims of snakebite. METHODS: This qualitative, descriptive, cross-sectional study had, as theoretical framework, the concept of vulnerability in individual, social, and programmatic dimensions. We interviewed 21 patients admitted into a hospital specialized in the care of accidents caused by venomous animals. The interviews were analyzed according to a discourse analysis technique. RESULTS: Patients were mainly young men, living in remote countryside areas, where health services frequently have limited resources. We found social and individual conditions of vulnerability, such as precarious schooling, low professional qualification, housing without access to piped water, no sewage treated, and no regular garbage collection, and lack of knowledge on this health problem. Regarding the programmatic dimension, we found limited accessibility to the health services that could affect the prognosis and the frequency of sequelae and deaths. CONCLUSIONS: Considering such vulnerabilities evoke the need to improve the program for control the Accidents by Venomous Animals and the training of health workers, we highlight the potential use of the concept of vulnerability, which may amplify the understanding and the recommendations for the practice and education related to snakebites. PMID- 26603352 TI - Spatial patterns of leprosy in a hyperendemic state in Northern Brazil, 2001 2012. AB - OBJECTIVE: To describe the spatial patterns of leprosy in the Brazilian state of Tocantins. METHODS: This study was based on morbidity data obtained from the Sistema de Informacoes de Agravos de Notificacao (SINAN - Brazilian Notifiable Diseases Information System), of the Ministry of Health. All new leprosy cases in individuals residing in the state of Tocantins, between 2001 and 2012, were included. In addition to the description of general disease indicators, a descriptive spatial analysis, empirical Bayesian analysis and spatial dependence analysis were performed by means of global and local Moran's indexes. RESULTS: A total of 14,542 new cases were recorded during the period under study. Based on the annual case detection rate, 77.0% of the municipalities were classified as hyperendemic (> 40 cases/100,000 inhabitants). Regarding the annual case detection rate in < 15 years-olds, 65.4% of the municipalities were hyperendemic (10.0 to 19.9 cases/100,000 inhabitants); 26.6% had a detection rate of grade 2 disability cases between 5.0 and 9.9 cases/100,000 inhabitants. There was a geographical overlap of clusters of municipalities with high detection rates in hyperendemic areas. Clusters with high disease risk (global Moran's index: 0.51; p < 0.001), ongoing transmission (0.47; p < 0.001) and late diagnosis (0.44; p < 0.001) were identified mainly in the central-north and southwestern regions of Tocantins. CONCLUSIONS: We identified high-risk clusters for transmission and late diagnosis of leprosy in the Brazilian state of Tocantins. Surveillance and control measures should be prioritized in these high-risk municipalities. PMID- 26603353 TI - Impact of long-stay beds on the performance of a tertiary hospital in emergencies. AB - OBJECTIVE: To assess the impact of implementing long-stay beds for patients of low complexity and high dependency in small hospitals on the performance of an emergency referral tertiary hospital. METHODS: For this longitudinal study, we identified hospitals in three municipalities of a regional department of health covered by tertiary care that supplied 10 long-stay beds each. Patients were transferred to hospitals in those municipalities based on a specific protocol. The outcome of transferred patients was obtained by daily monitoring. Confounding factors were adjusted by Cox logistic and semiparametric regression. RESULTS: Between September 1, 2013 and September 30, 2014, 97 patients were transferred, 72.1% male, with a mean age of 60.5 years (SD = 1.9), for which 108 transfers were performed. Of these patients, 41.7% died, 33.3% were discharged, 15.7% returned to tertiary care, and only 9.3% tertiary remained hospitalized until the end of the analysis period. We estimated the Charlson comorbidity index - 0 (n = 28 [25.9%]), 1 (n = 31 [56.5%]) and >= 2 (n = 19 [17.5%]) - the only variable that increased the chance of death or return to the tertiary hospital (Odds Ratio = 2.4; 95%CI 1.3;4.4). The length of stay in long-stay beds was 4,253 patient days, which would represent 607 patients at the tertiary hospital, considering the average hospital stay of seven days. The tertiary hospital increased the number of patients treated in 50.0% for Intensive Care, 66.0% for Neurology and 9.3% in total. Patients stayed in long-stay beds mainly in the first 30 (50.0%) and 60 (75.0%) days. CONCLUSIONS: Implementing long-stay beds increased the number of patients treated in tertiary care, both in general and in system bottleneck areas such as Neurology and Intensive Care. The Charlson index of comorbidity is associated with the chance of patient death or return to tertiary care, even when adjusted for possible confounding factors. PMID- 26603354 TI - Glioblastomas with IDH1/2 mutations have a short clinical history and have a favorable clinical outcome. AB - OBJECTIVE: Glioblastomas with isocitrate dehydrogenase 1/2 mutations comprise a biologically distinct subgroup of glioblastomas. We studied isocitrate dehydrogenase 1/2 mutant glioblastomas at the clinical, molecular and radiological levels to define their clinical features, including the prognostic value of isocitrate dehydrogenase 1/2 mutations compared with isocitrate dehydrogenase 1/2 wild-type glioblastomas. METHODS: We investigated 128 newly diagnosed glioblastoma patients who were treated at our institute between January 2005 and May 2013. Isocitrate dehydrogenase 1/2 mutation status was determined using pyrosequencing. O-6-methylguanine deoxyribonucleic acid methyltransferase promoter methylation and 1p/19q co-deletions were also analyzed using pyrosequencing and multiplex ligation-dependent probe amplification, respectively. RESULTS: Isocitrate dehydrogenase 1/2 mutations were detected in 10 of 128 patients (7.8%). Isocitrate dehydrogenase 1/2 mutations were correlated with a younger age, the presence of an oligodendroglial component and 1p/19q co deletions and a longer survival time. The interval from initial symptom to initial operation did not differ according to isocitrate dehydrogenase 1/2 mutation status (median interval: 2.3 versus 1.2 months; P = 0.13). Two of three isocitrate dehydrogenase 1/2 mutant glioblastomas harboring 1p/19q co-deletions had an oligodendroglial component and were associated with a prolonged survival time. Multivariate analysis of 90 patients treated with temozolomide-based chemoradiotherapy indicated that age, extent of resection, postoperative Karnofsky performance score and O-6-methylguanine deoxyribonucleic acid methyltransferase promoter methylation were correlated with better survival. Isocitrate dehydrogenase 1/2 mutations showed a trend for improved survival (P = 0.068). CONCLUSIONS: Most isocitrate dehydrogenase 1/2 mutant glioblastomas have a short clinical history, and some isocitrate dehydrogenase 1/2 mutant glioblastomas harboring 1p/19q co-deletions behave like oligodendroglial tumors. Isocitrate dehydrogenase 1/2 mutations may have a positive prognostic impact on the Japanese population. PMID- 26603356 TI - Effect of interelectrode distance on surface electromyographic signals of vastus intermedius muscle in women and men. AB - We previously developed a novel technique to record surface electromyography (EMG) of the vastus intermedius (VI) in men. The purpose of the present study was to assess whether this technique can be applied to women in the same way. We measured the subcutaneous fat thickness at the site of electrode placement on VI using ultrasonography. Nine men and ten women performed isometric knee extensions at 25%, 50%, 75%, and 100% of the maximal voluntary contraction. During the tasks, surface EMG signals were recorded from the superficial region of VI with interelectrode distances (IEDs) of 10 mm (IED-10) and 20 mm (IED-20). The subcutaneous fat thickness in women was significantly greater than in men (women: 8.7 +/- 2.1 mm; men: 5.6 +/- 1.6 mm, p < 0.01). However, the amplitude and frequency of the EMG signal of VI at the different force levels were not affected by IEDs in either sex. These results suggest that surface EMG recording of VI with both IED-10 and IED-20 would be applicable to relatively lean women with a similar sensitivity to that in men. PMID- 26603355 TI - FOLFOX-4 as second-line therapy after failure of gemcitabine and platinum combination in advanced gall bladder cancer patients. AB - OBJECTIVE: There is no standard second-line chemotherapy after progression on first-line therapy including gemcitabine and platinum combination in advanced gall bladder cancer patients. So this study was undertaken to assess the efficacy and safety of FOLFOX-4 regimen in this setting. METHODS: In this observational study, patients with performance status <=2, who progressed on first-line therapy, were enrolled from May 2010 to June 2014. FOLFOX-4 based treatment was administered until progression, unacceptable toxicity or up to 12 cycles. RESULTS: A total of 66 patients were enrolled in this study. The median age of patients was 52.5 years (32-66 years),of which 24 (36.36%) were males and 42 (63.63%) were females. The median number of cycles could be given were 9.5 (2 12). Only 43.93% patients in this study completed full 12 cycles of chemotherapy. Sixteen patients (24.24%) in this study required the dose reduction at least in one cycle of chemotherapy due to toxicities. Disease control rate was seen in 39 (59.09%) patients, with complete response in none, partial response in 16 (24.24%), stable disease in 23 (34.84%) and progressive disease in 27 (40.90%) patients. The median progression free survival was 3.9 months; median overall survival was 7.6 months. The main Grade 3/4 side effects seen were hematological in 31.81% (n = 21) and gastrointestinal in 25.75% (n = 17) patients. Majority of patients (46%) had Grade 1/2 peripheral neuropathy. CONCLUSIONS: FOLFOX-4 is an effective and well-tolerated regimen as a second-line treatment in advanced gall bladder cancer patients. Further studies are required, especially in the Indian subcontinent. PMID- 26603357 TI - Trauma-Informed Care for Children in the Child Welfare System: An Initial Evaluation of a Trauma-Informed Parenting Workshop. AB - An essential but often overlooked component to promoting trauma-informed care within the child welfare system is educating and empowering foster, adoptive, and kinship caregivers (resource parents) with a trauma-informed perspective to use in their parenting as well as when advocating for services for their child. In this first evaluation of the National Child Traumatic Stress Network's trauma informed parenting workshop (Caring for Children who Have Experienced Trauma, also known as the Resource Parent Curriculum), participant acceptance and satisfaction and changes in caregiver knowledge and beliefs related to trauma informed parenting were examined. Data from 159 ethnically diverse resource parents were collected before and after they participated in the workshop. Results demonstrate that kinship and nonkinship caregivers showed significant increases in their knowledge of trauma-informed parenting and their perceived self-efficacy parenting a child who experienced trauma. Nonkinship caregivers increased on their willingness to tolerate difficult child behaviors, whereas kinship caregivers did not show a significant change. Participants also demonstrated high levels of satisfaction with the workshop. Although these preliminary results are important as the first empirical study supporting the workshop's effectiveness, the limitations of this study and the directions for future research are discussed. PMID- 26603358 TI - Carboranes as a Tool to Tune Phosphorescence. AB - Phosphorescent transition-metal complexes (PTMCs) have attracted great interest because of their excellent properties which may lead to promising applications in optoelectronics. In recent years, carboranes have been demonstrated to be a novel and effective tool to tune phosphorescence of PTMCs. This Concept article deals with the advances of carborane-functionalized PTMCs for potential optical applications. The discussions are focused on the design strategies and synthetic procedures leading to carborane-functionalized PTMCs, the influence of carboranes on the optical properties of PTMCs, and the promising optical applications of this interesting class of phosphorescent materials. PMID- 26603359 TI - The Relationship Between High-Sensitivity C-Reactive Protein Levels and Left Ventricular Hypertrophy in Patients With Newly Diagnosed Hypertension. AB - The authors aimed to evaluate the relationship between high-sensitivity C reactive protein (hs-CRP) and presence of left ventricular hypertrophy and diastolic dysfunction in patients with hypertension. A total of 95 newly diagnosed hypertensive patients (mean age, 54+/-10 years) and 20 controls were included in this study. Patients were divided into four groups according to relative wall thickness as normal, concentric remodeling, concentric, and eccentric hypertrophy. hs-CRP was measured in all patients and serum hs-CRP level was shown to be increased in patients with hypertension compared with controls (0.57 mg/dL vs 0.25 mg/dL, respectively; P<.001). The hs-CRP level was highest in patients with concentric hypertrophy. When compared with controls, serum hs-CRP level was significantly higher in patients with concentric remodeling (0.61+/-0.3 mg/dL vs 0.43+/-0.5 mg/dL, P<.030) and concentric hypertrophy (0.69+/-0.3 mg/dL vs 0.43+/-0.5 mg/dL, P<.032). The present study shows that serum hs-CRP is significantly associated with left ventricular diastolic function and concentric hypertrophy in patients with hypertension. PMID- 26603360 TI - Evaluation of Hematochezia in a Two-Day-Old Infant. AB - BACKGROUND: Hematochezia in the pediatric population, particularly infants, has a wide differential diagnosis ranging from benign to life-threatening causes. Obtaining a thorough history and identifying risk factors for more ominous disease is vital during the emergency department (ED) evaluation. CASE REPORT: The patient is a 2-day-old female who presented to the ED with 8-10 episodes of bright red blood in her stools. She was otherwise asymptomatic, with an uncomplicated pregnancy and delivery. Her history was significant for a sibling who recently tested positive for Escherichia coli O157:H7 in his stool and a family history of lactose intolerance. She was exclusively formula fed. An abdominal plain film was obtained and was normal. Milk protein enterocolitis was suspected and she was transitioned to hydrolyzed formula with resolution of her symptoms. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: As emergency physicians, we need to be aware of the life-threatening conditions that are associated with hematochezia, such as necrotizing enterocolitis, and act quickly. However, many patients will have benign conditions, and recognizing the key historical and diagnostic pieces of the infant's presentation will prevent unnecessary evaluations and consultations. PMID- 26603361 TI - Dermal Abrasion Experienced as an Adverse Effect of the EZ-IO((r)). AB - BACKGROUND: In 2007, an update was released to the pediatric and neonatal septic shock guidelines, which emphasized early use of therapies, specifically, first hour fluid resuscitation and inotrope therapy. This has led to increased use of intraosseous (IO) access as a source of vascular access. Previously, IO access could be obtained only via a manual IO placement. New semi-automatic devices, such as EZ-IO((r)) (Vidacare, Shavano Park, TX), allow for safer and quicker IO access. Data support the use of semi-automatic devices during the acute resuscitation period. CASE REPORT: The patient was a 7-month old girl with VACTERL association (Vertebral defects, Anal atresia, Cardiac defects, Tracheo Esophageal fistula, Renal anomalies, Limb abnormalities) and complex past medical history. The patient experienced a "choking episode," which led to subsequent apnea and cyanosis. The patient presented in shock to a local pediatric emergency department. After multiple unsuccessful intravenous line attempts, IO access was obtained using the EZ-IO((r)). Once in the pediatric intensive care unit with venous access, the IO device was removed and the site had "red bulls-eye target shape" damage to the skin, which appeared consistent with the EZ-IO((r)) flange. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: IO device use is increasing due to the most recent pediatric and neonatal septic shock guidelines, which emphasize first-hour fluid resuscitation and inotrope therapy. It is vital that emergency physicians be aware of the adverse effects of semi-automatic IO devices, including dermal abrasion, which has not been reported previously. With proper training and familiarity, it is possible to avoid dermal abrasion as an adverse effect of the semi-automatic IO device. PMID- 26603362 TI - Lymphoid Hyperplasia of the Tongue. PMID- 26603363 TI - Methylene Blue and Cardiovascular Collapse. PMID- 26603364 TI - Frontal Sinus TASER Dart Injury. PMID- 26603365 TI - Limb-threatening Deep Venous Thrombosis Complicating Warfarin Reversal with Three factor Prothrombin Complex Concentrate: A Case Report. AB - BACKGROUND: Three- and four-factor prothrombin complex concentrates (PCC) are gaining popularity for acute reversal of vitamin K antagonist-associated bleeding. Although acute thrombosis after PCC administration has been described, it seems to be rare. CASE REPORT: An 83-year-old woman on warfarin for history of deep venous thrombosis (DVT) presented to the Emergency Department with life threatening gastrointestinal bleeding, requiring urgent PCC administration. After stabilization, she subsequently developed a new limb-threatening upper-extremity DVT. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: As PCC therapy gains popularity for reversal of anticoagulant-induced bleeding in urgent bleeding scenarios, the emergency physician must be aware of the complications of PCC administration, including new limb-threatening DVT. PMID- 26603366 TI - Another Method for the Removal of Spherical Nasal Foreign Bodies in Pediatric Patients. PMID- 26603368 TI - Arthroscopic interposition in thumb carpometacarpal osteoarthritis: A series of 26 cases. AB - In 2011, we reported good results after a mean follow-up of 14 months for a series of 25 patients who underwent thumb carpometacarpal osteoarthritis surgery in which a poly-L-lactic acid implant was interposed arthroscopically. The aim of this study was to evaluate the outcomes after a longer follow-up. The new series consisted of 26 patients, whose average age was 60 years, operated with arthroscopy for the interposition of an implant made of poly-L-lactic acid in 12 cases and tendon interposition in 14 cases. After an average follow-up of 20 months, the pain assessed with a visual analog scale was on average 6.61/10 before surgery and 6.03/10 after, the QuickDASH score was 56.36/100 before and 53.65/100 after, grip strength was 15.34kg before and 12.8kg after, pinch strength was 3.7kg before and 2.18kg after, Kapandji thumb opposition score was 8.96/10 before and 8.26/10 after. The radiological stage did not change. We noted one case of type 1 complex regional pain syndrome and 12 poor results, 11 of which were reoperated by trapeziectomy. Given our results and the lack of published studies with a high level of evidence, the value of isolated arthroscopy with interposition in the surgical treatment of thumb carpometacarpal osteoarthritis remains to be demonstrated. PMID- 26603369 TI - Headache in acute ischaemic stroke: a lesion mapping study. AB - Headache is a common symptom in acute ischaemic stroke, but the underlying mechanisms are incompletely understood. The aim of this lesion mapping study was to identify brain regions, which are related to the development of headache in acute ischaemic stroke. Patients with acute ischaemic stroke (n = 100) were assessed by brain MRI at 3 T including diffusion weighted imaging. We included 50 patients with stroke and headache as well as 50 patients with stroke but no headache symptoms. Infarcts were manually outlined and images were transformed into standard stereotaxic space using non-linear warping. Voxel-wise overlap and subtraction analyses of lesions as well as non-parametric statistics were conducted. The same analyses were carried out by flipping of left-sided lesions, so that all strokes were transformed to the same hemisphere. Between the headache group as well as the non-headache there was no difference in infarct volumes, in the distribution of affected vascular beds or in the clinical severity of strokes. The headache phenotype was tension-type like in most cases. Subtraction analysis revealed that in headache sufferers infarctions were more often distributed in two well-known areas of the central pain matrix: the insula and the somatosensory cortex. This result was confirmed in the flipped analysis and by non-parametric statistical testing (whole brain corrected P-value < 0.01). To the best of our knowledge, this is the first lesion mapping study investigating potential lesional patterns associated with headache in acute ischaemic stroke. Insular strokes turned out to be strongly associated with headache. As the insular cortex is a well-established region in pain processing, our results suggest that, at least in a subgroup of patients, acute stroke-related headache might be centrally driven. PMID- 26603370 TI - Relapse of depression during pregnancy and postpartum periods in Japanese women associated with self-interruption of their medications: Selective serotonin reuptake inhibitors. PMID- 26603371 TI - Do patients on oral chemotherapy have sufficient knowledge for optimal adherence? A mixed methods study. AB - A new treatment paradigm has emerged with many patients now receiving oral chemotherapy (OC) as first-line treatment for cancer. Treatment with OC has resulted in reduced hospital costs, more autonomy for patients but with added responsibilities for patient self-management. Little is known about patient's knowledge following patient education to enable optimal adherence with OC. A mixed methods study was carried out using a self-report questionnaire to patients on OC for multiple myeloma (MM) followed by semi-structured interviews with patients at home. Analysis identifies high rates of adherence (92.2%) with OC for MM. However, statistically significant knowledge deficits were identified, which were related to patient ethnicity and to gender. There is the potential for non intentional non-adherence with OC due to deficits in knowledge of OC. Support at home needs to include primary care practitioners such as GPs, practice nurses and pharmacists so that timely support is easily accessible especially in the early phase of treatment. PMID- 26603372 TI - Activation of microglial Toll-like receptor 3 promotes neuronal survival against cerebral ischemia. AB - Emerging experimental evidence suggests that activation of Toll-like receptor 3 (TLR3) by its agonist polyinosinic polycytidylic acid (poly-ICLC) protects neurons against cerebral ischemia, but the underlying mechanisms remain largely unknown. In the brain, TLR3 is mostly expressed in glial cells. Therefore, we assess the hypothesis that TLR3 activation in microglia is required for neuroprotection against ischemia. After transient focal cerebral ischemia, microglia/macrophages (MMs) demonstrate a significant reduction in TLR3 and its downstream cytokine interleukin 6 (IL-6). Subsequently, activation of TLR3 by poly-ICLC restored TLR3 expression and decreased infarction. To further investigate these mechanisms, we turned to a primary cell culture system. Consistent with the in vivo findings, oxygen-glucose deprivation (OGD) significantly reduced TLR3 and IL-6 mRNA expression in microglia, but poly-ICLC significantly rescued TLR3 and IL-6 expression. Importantly, conditioned media from OGD-treated microglia increased neuronal death after OGD. In contrast, the conditioned media from microglia treated with poly-ICLC after OGD significantly protected against OGD-induced neuron death. Taken together, our findings provide proof-of-concept that activation of TLR3 in microglia may promote neuron survival after ischemia. We assessed the hypothesis that Toll-like receptor 3 (TLR3) activation in microglia is required for neuroprotection against ischemia. After transient focal cerebral ischemia, microglia/macrophage demonstrates a reduction in TLR3 and Interleukin 6 (IL-6). Also, oxygen-glucose deprivation (OGD) reduces TLR3 and IL-6 expression in microglia, but polyinosinic polycytidylic acid (poly ICLC) rescues TLR3 and IL-6. Importantly, conditioned media from microglia treated with poly-ICLC protects against OGD-induced neuron death. We propose that activation of TLR3 in microglia may promote neuron survival after ischemia. PMID- 26603373 TI - Bullous pemphigoid: What's ahead? AB - Bullous pemphigoid (BP) is an autoimmune subepidermal blistering skin disease mainly affecting older individuals. Pathogenic autoantibodies preferentially target the non-collagenous 16A domain of collagen XVII (also called BP antigen 2, BPAG2) present in hemidesmosomes. The pathogenic anti-BPAG2 antibodies cause the dermal-epidermal separation in neonatal and adult mice as well as in cryosections of human skin. These experimental BP models stress a pivotal role for neutrophils and the Fcgamma receptor of immunoglobulins. Mice that have been genetically manipulated in the pathogenic domain of BPAG2 spontaneously develop subepidermal blistering with pruritus and eosinophilic infiltration. BPAG2 is physiologically and aberrantly expressed in neuronal tissue and internal malignancies, and the associations of BP with Parkinson's disease, stroke and internal malignancies invites new investigations into the immunological dysregulation behind the comorbidity. PMID- 26603374 TI - Oral administration of oleuropein attenuates cisplatin-induced acute renal injury in mice through inhibition of ERK signaling. AB - SCOPE: Oleuropein possesses numerous health beneficial effects. We investigated the renoprotective effects of oleuropein against cisplatin (CP) induced kidney injury. METHODS AND RESULTS: Male BALB/cN mice were orally gavaged with 5, 10 and 20 mg oleuropein/kg body weight for 2 days, 48 h after intraperitoneal injection of CP (13 mg/kg). Four days after CP administration, serum creatinine and blood urea nitrogen (BUN) levels were significantly elevated, with histopathological changes in renal tissue. In addition, renal oxidative stress was evidenced by increased expression of 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE), cytochrome P450 E1 (CYP2E1) and heme oxygenase-1 (HO-1). The expression of nuclear factor-kappaB (NF-kappaB) p65, phospho-p65, tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2) in the kidneys increased upon CP treatment, suggesting renal inflammation. CP intoxication increased the expression of p53, Bax and caspase-3 and induced apoptosis in the kidneys. CP administration also resulted in enhanced phosphorylation of extracellular signal regulated kinases 1 and 2 (ERK1/2). All these effects were dose dependently diminished by oleuropein. Oral administration of PD0325901, an MEK inhibitor, coincided with the oleuropein-mediated suppression of apoptotic, inflammatory and antioxidant markers. CONCLUSION: The results of the current study suggest that oleuropein attenuated CP-induced acute renal injury, which was mediated through the inhibition of ERK signaling. PMID- 26603375 TI - Successful treatment of a fracture of a huge Achilles tendon ossification with autologous hamstring tendon graft and gastrocnemius fascia flap: a case report. AB - BACKGROUND: Fracture of an ossified Achilles tendon is a rare entity, and no standard treatment has been established. This is the first report to describe the use of a hamstring tendon graft and gastrocnemius fascia flap for Achilles tendon reconstruction. CASE PRESENTATION: We present the case of a 50-year-old woman with fracture of an ossified Achilles tendon. She presented to our clinic with acute right hindfoot pain, which started suddenly while going up the stairs. Plain radiography and magnetic resonance imaging revealed a massive ossification on the right Achilles tendon extending over 14 cm in length; the ossification was fractured at 5 cm proximal to the calcaneus insertion. Surgical treatment included removal of the ossified tendon and reconstruction with an autologous hamstring tendon graft and gastrocnemius fascia flap. One year after surgery, she was able to walk with little pain or discomfort and to stand on her right tiptoe. CONCLUSION: Our novel surgical procedure may be useful in the treatment of fractured ossified Achilles tendons and large Achilles tendon defects. PMID- 26603376 TI - A Catalyst Designed for the Enantioselective Construction of Methyl- and Alkyl Substituted Tertiary Stereocenters. AB - Tertiary methyl-substituted stereocenters are present in numerous biologically active natural products. Reported herein is a catalytic enantioselective method for accessing these chiral building blocks using the Mukaiyama-Michael reaction between silyl ketene thioacetals and acrolein. To enable remote enantioface control on the nucleophile, a new iminium catalyst, optimized by three-parameter tuning and by identifying substituent effects on enantioselectivity, was designed. The catalytic process allows rapid access to chiral thioesters, amides, aldehydes, and ketones bearing an alpha-methyl stereocenter with excellent enantioselectivities, and allowed rapid access to the C4-C13 segment of (-) bistramide A. DFT calculations rationalized the observed sense and level of enantioselectivity. PMID- 26603377 TI - Photopsia and a temporal visual field defect. AB - A 30-year-old woman presented with intermittent photopsia, a temporal visual field defect below the horizontal in her left eye, and flu-like symptoms. Slit lamp and fundus examinations were unremarkable. Humphrey 30-2 threshold perimetry and 120-point screening visual field demonstrated blind spot enlargement of the left eye and a normal field in the right eye. Fundus autofluorescence, optical coherence tomography of the macula, full-field electroretinogram, electrooculogram, and multifocal electroretinogram were normal. Swept-source optical coherence tomography scan of the left optic nerve showed an intact outer retina, a remarkably thinned nerve fiber layer nasally, and peripapillary vitreous traction. Goldmann kinetic perimetry revealed a sector-shaped dense defect breaking out from the blind spot to the temporal periphery just below the horizontal in the left eye. The patient had nasal hypoplasia of the optic nerve and peripapillary vitreous traction. PMID- 26603379 TI - Exploring Parental Bonding in BED and Non-BED Obesity Compared with Healthy Controls: Clinical, Personality and Psychopathology Correlates. AB - Early inadequate attachment experiences are relevant co-factors in the development of obesity and Binge Eating Disorder (BED), which often concurs with obesity. The relationship of parental bonding with personality and psychopathology may influence treatment strategies for obese subjects, either affected or not with BED. In this study, 443 obese women (BMI >= 30 kg/m(2)), including 243 with and 200 without BED, and 158 female controls were assessed with regards to attachment, personality and eating psychopathology measures. Clusters obtained using the scores of the Parental Bonding Instrument (PBI) were compared with each other and with a control subjects' group. Lower scores of parental bonding distinguished obese subjects with respect to healthy controls. The cluster analysis revealed two clusters of parenting among obese subjects. The larger one displayed intermediate care and overprotection between controls and the smaller cluster, with the exception of paternal overprotection which is similar to controls. This larger cluster was characterized by low persistence and levels of psychopathology which are intermediate between healthy controls and the smaller cluster. The smaller cluster displayed lower care and higher overcontrol from both parents. It also displays more extreme personality traits (high novelty seeking and harm avoidance, and lower self-directedness and cooperativeness) and more severe eating and general psychopathology. Different parenting dynamics relate to different personality patterns and eating psychopathology of obese subjects, but not to binge eating conducts. Personality differences between parenting clusters are more extensive than those between BED and non-BED subgroups. The two different typologies of obese subjects based on parenting may be relevant for treatment personalization. PMID- 26603378 TI - Identification of progressive mild cognitive impairment patients using incomplete longitudinal MRI scans. AB - Distinguishing progressive mild cognitive impairment (pMCI) from stable mild cognitive impairment (sMCI) is critical for identification of patients who are at risk for Alzheimer's disease (AD), so that early treatment can be administered. In this paper, we propose a pMCI/sMCI classification framework that harnesses information available in longitudinal magnetic resonance imaging (MRI) data, which could be incomplete, to improve diagnostic accuracy. Volumetric features were first extracted from the baseline MRI scan and subsequent scans acquired after 6, 12, and 18 months. Dynamic features were then obtained using the 18th month scan as the reference and computing the ratios of feature differences for the earlier scans. Features that are linearly or non-linearly correlated with diagnostic labels are then selected using two elastic net sparse learning algorithms. Missing feature values due to the incomplete longitudinal data are imputed using a low-rank matrix completion method. Finally, based on the completed feature matrix, we build a multi-kernel support vector machine (mkSVM) to predict the diagnostic label of samples with unknown diagnostic statuses. Our evaluation indicates that a diagnosis accuracy as high as 78.2 % can be achieved when information from the longitudinal scans is used-6.6 % higher than the case using only the reference time point image. In other words, information provided by the longitudinal history of the disease improves diagnosis accuracy. PMID- 26603380 TI - Editorial Comment from Dr Komai to Clinicopathological characteristics of Xp11.2 translocation renal cell carcinoma in adolescents and adults: Diagnosis using immunostaining of transcription factor E3 and fluorescence in situ hybridization analysis. PMID- 26603382 TI - Parental modelling and prompting effects on acceptance of a novel fruit in 2-4 year-old children are dependent on children's food responsiveness. AB - Few children consume the recommended portions of fruit or vegetables. This study examined the effects of parental physical prompting and parental modelling in children's acceptance of a novel fruit (NF) and examined the role of children's food-approach and food-avoidance traits on NF engagement and consumption. A total of 120 caregiver-child dyads (fifty-four girls, sixty-six boys) participated in this study. Dyads were allocated to one of the following three conditions: physical prompting but no modelling, physical prompting and modelling or a modelling only control condition. Dyads ate a standardised meal containing a portion of a fruit new to the child. Parents completed measures of children's food approach and avoidance. Willingness to try the NF was observed, and the amount of the NF consumed was measured. Physical prompting but no modelling resulted in greater physical refusal of the NF. There were main effects of enjoyment of food and food fussiness on acceptance. Food responsiveness interacted with condition such that children who were more food responsive had greater NF acceptance in the prompting and modelling conditions in comparison with the modelling only condition. In contrast, children with low food responsiveness had greater acceptance in the modelling control condition than in the prompting but no modelling condition. Physical prompting in the absence of modelling is likely to be detrimental to NF acceptance. Parental use of physical prompting strategies, in combination with modelling of NF intake, may facilitate acceptance of NF, but only in food-responsive children. Modelling consumption best promotes acceptance in children with low food responsiveness. PMID- 26603381 TI - CD57(+) CD4 T Cells Underlie Belatacept-Resistant Allograft Rejection. AB - Belatacept is a B7-specific fusion protein used to prevent allograft rejection by blocking T cell costimulation. Generally efficacious, it fails to prevent acute rejection in a sizable minority of patients. In experimental models, memory T cells mediate costimulation blockade-resistant rejection (CoBRR), but this remains undefined in humans. To explore relationships between individual patients' immune cell phenotypes and CoBRR, we studied patients receiving belatacept or conventional calcineurin inhibitor-based immunosuppression. We identified a population of CD57(+) PD1(-) CD4 T cells present prior to transplantation that correlated with CoBRR. Contrary to data recognizing CD57 as a marker of senescence on CD8 T cells, we discovered a nonsenescent, cytolytic phenotype associated with CD57 on CD4 T cells. Moreover, CD57(+) CD4 T cells expressed high levels of adhesion molecules implicated in experimental CoBRR, were CD28(-) , expressed a transcriptional phenotype broadly defining allograft rejection and were shown to be present in rejecting human kidney allografts. These data implicate CD57(+) CD4 T cells in clinical CoBRR. If prospectively validated, this characteristic could identify patients at higher risk for acute rejection on belatacept-based therapy. PMID- 26603383 TI - TimerQuant: a modelling approach to tandem fluorescent timer design and data interpretation for measuring protein turnover in embryos. AB - Studies on signalling dynamics in living embryos have been limited by a scarcity of in vivo reporters. Tandem fluorescent protein timers provide a generic method for detecting changes in protein population age and thus provide readouts for signalling events that lead to changes in protein stability or location. When imaged with quantitative dual-colour fluorescence microscopy, tandem timers offer detailed 'snapshot' readouts of signalling activity from subcellular to organismal scales, and therefore have the potential to revolutionise studies in developing embryos. Here we use computer modelling and embryo experiments to explore the behaviour of tandem timers in developing systems. We present a mathematical model of timer kinetics and provide software tools that will allow experimentalists to select the most appropriate timer designs for their biological question, and guide interpretation of the obtained readouts. Through the generation of a series of novel zebrafish reporter lines, we confirm experimentally that our quantitative model can accurately predict different timer responses in developing embryos and explain some less expected findings. For example, increasing the FRET efficiency of a tandem timer actually increases the ability of the timer to detect differences in protein half-life. Finally, while previous studies have used timers to monitor changes in protein turnover, our model shows that timers can also be used to facilitate the monitoring of gene expression kinetics in vivo. PMID- 26603385 TI - Hypothalamic radial glia function as self-renewing neural progenitors in the absence of Wnt/beta-catenin signaling. AB - The vertebrate hypothalamus contains persistent radial glia that have been proposed to function as neural progenitors. In zebrafish, a high level of postembryonic hypothalamic neurogenesis has been observed, but the role of radial glia in generating these new neurons is unclear. We have used inducible Cre mediated lineage labeling to show that a population of hypothalamic radial glia undergoes self-renewal and generates multiple neuronal subtypes at larval stages. Whereas Wnt/beta-catenin signaling has been demonstrated to promote the expansion of other stem and progenitor cell populations, we find that Wnt/beta-catenin pathway activity inhibits this process in hypothalamic radial glia and is not required for their self-renewal. By contrast, Wnt/beta-catenin signaling is required for the differentiation of a specific subset of radial glial neuronal progeny residing along the ventricular surface. We also show that partial genetic ablation of hypothalamic radial glia or their progeny causes a net increase in their proliferation, which is also independent of Wnt/beta-catenin signaling. Hypothalamic radial glia in the zebrafish larva thus exhibit several key characteristics of a neural stem cell population, and our data support the idea that Wnt pathway function may not be homogeneous in all stem or progenitor cells. PMID- 26603387 TI - Effect of cataract surgery on circadian rhythms. PMID- 26603384 TI - Two classes of matrix metalloproteinases reciprocally regulate synaptogenesis. AB - Synaptogenesis requires orchestrated intercellular communication between synaptic partners, with trans-synaptic signals necessarily traversing the extracellular synaptomatrix separating presynaptic and postsynaptic cells. Extracellular matrix metalloproteinases (Mmps) regulated by secreted tissue inhibitors of metalloproteinases (Timps), cleave secreted and membrane-associated targets to sculpt the extracellular environment and modulate intercellular signaling. Here, we test the roles of Mmp at the neuromuscular junction (NMJ) model synapse in the reductionist Drosophila system, which contains just two Mmps (secreted Mmp1 and GPI-anchored Mmp2) and one secreted Timp. We found that all three matrix metalloproteome components co-dependently localize in the synaptomatrix and show that both Mmp1 and Mmp2 independently restrict synapse morphogenesis and functional differentiation. Surprisingly, either dual knockdown or simultaneous inhibition of the two Mmp classes together restores normal synapse development, identifying a reciprocal suppression mechanism. The two Mmp classes co-regulate a Wnt trans-synaptic signaling pathway modulating structural and functional synaptogenesis, including the GPI-anchored heparan sulfate proteoglycan (HSPG) Wnt co-receptor Dally-like protein (Dlp), cognate receptor Frizzled-2 (Frz2) and Wingless (Wg) ligand. Loss of either Mmp1 or Mmp2 reciprocally misregulates Dlp at the synapse, with normal signaling restored by co-removal of both Mmp classes. Correcting Wnt co-receptor Dlp levels in both Mmp mutants prevents structural and functional synaptogenic defects. Taken together, these results identify an Mmp mechanism that fine-tunes HSPG co-receptor function to modulate Wnt signaling to coordinate synapse structural and functional development. PMID- 26603386 TI - Human induced pluripotent stem cell derived neurons as a model for Williams Beuren syndrome. AB - BACKGROUND: Williams-Beuren Syndrome (WBS) is caused by the microdeletion of approximately 25 genes on chromosome 7q11.23, and is characterized by a spectrum of cognitive and behavioural features. RESULTS: We generated cortical neurons from a WBS individual and unaffected (WT) control by directed differentiation of induced pluripotent stem cells (iPSCs). Single cell mRNA analyses and immunostaining demonstrated very efficient production of differentiated cells expressing markers of mature neurons of mixed subtypes and from multiple cortical layers. We found that there was a profound alteration in action potentials, with significantly prolonged WBS repolarization times and a WBS deficit in voltage activated K(+) currents. Miniature excitatory synaptic currents were normal, indicating that unitary excitatory synaptic transmission was not altered. Gene expression profiling identified 136 negatively enriched gene sets in WBS compared to WT neurons including gene sets involved in neurotransmitter receptor activity, synaptic assembly, and potassium channel complexes. CONCLUSIONS: Our findings provide insight into gene dysregulation and electrophysiological defects in WBS patient neurons. PMID- 26603388 TI - Outcomes of wavefront-guided laser in situ keratomileusis using a new-generation Hartmann-Shack aberrometer in patients with high myopia. AB - PURPOSE: To evaluate refractive and visual outcomes of wavefront-guided laser in situ keratomileusis (LASIK) to correct high myopia using a new Hartmann-Shack aberrometer. SETTING: Optical Express, Glasgow, United Kingdom. DESIGN: Retrospective noncomparative case series. METHODS: Data of eyes that had wavefront-guided LASIK for high myopia and myopic astigmatism (spherical equivalent [SE] between -6.00 diopters [D] and -10.25 D, up to 5.00 D of cylinder) were analyzed. The treatment profile was derived from a new-generation Hartmann-Shack aberrometer (iDesign Advanced Wavescan). Visual acuities, refractive outcomes, vector analysis of refractive cylinder, and patient satisfaction were assessed. Three-months data are presented. RESULTS: Data were obtained for 621 eyes. The mean manifest SE reduced from -7.28 D +/- 1.05 (SD) (range -10.25 to -6.00 D) preoperatively to -0.09 +/- 0.44 D (range -2.13 to +1.38 D) at 3 months. The mean manifest cylinder changed from -1.02 +/- 0.82 D (range -5.00 to 0.00 D) to -0.27 +/- 0.33 D (range -1.75 to 0.00 D) postoperatively. The percentage of eyes achieving an uncorrected distance visual acuity 20/20 or better was 82.4% monocularly and 92.5% binocularly. The mean correction ratio of refractive cylinder was 1.02 +/- 0.48, and the mean error of angle was -0.29 +/- 14.56 degrees. A postoperative questionnaire revealed high satisfaction with the outcomes of the procedure, with low scores for night-vision phenomena. CONCLUSION: The results in this study were promising in terms of safety, efficacy, and predictability in eyes with high degrees of myopia. FINANCIAL DISCLOSURE: Dr. Schallhorn is a consultant to Abbott Medical Optics, Inc. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 26603389 TI - Comparison of ocular aberrations measured by a Fourier-based Hartmann-Shack and Zernike-based Tscherning aberrometer before and after laser in situ keratomileusis. AB - PURPOSE: To assess agreement between a Hartmann-Shack aberrometer (Wavescan) and a Tscherning aberrometer (Wavelight Allegro Analyzer) and their respective agreement with manifest refraction before and after laser in situ keratomileusis (LASIK). SETTING: Stanford Eye Laser Center, California, USA. DESIGN: Prospective comparative observational study. METHODS: Multiple readings were obtained both aberrometers preoperatively and 12 months after wavefront-guided LASIK. Sphere, cylinder, spherical equivalent (SE), defocus Z(2,0), astigmatism Z(2,2), spherical aberration Z(4,0), coma Z(3,1), trefoil Z(3,3), and total higher-order aberrations (HOAs) were compared using intraclass correlation coefficients (ICCs) (perfect agreement = 1; disagreement = 0). RESULTS: In the 100 study eyes, preoperative agreement was good to excellent between the aberrometers for the parameters of defocus, astigmatism, and spherical aberration (ICC: 0.8, 0.9, and 0.7, respectively) but was poor for coma, trefoil, and total HOAs (ICC: 0.6, 0.2, and 0.4, respectively). At 12 months, ICCs worsened for all parameters (ICC: defocus = 0.6; astigmatism = 0.2; spherical aberration = 0.6; coma = 0.4; trefoil = -0.3; total HOAs = 0.4). Preoperative agreement of sphere, cylinder, and SE was good to excellent between the manifest refraction and both aberrometers (ICC Hartmann-Shack: 0.98, 0.95, and 0.97, respectively; ICC Tscherning: 0.97, 0.92, and 0.98, respectively). However, agreement was poor to fair between the manifest refraction and both aberrometers at 12 months (ICC Hartmann-Shack: 0.4, 0.1, and 0.4, respectively; ICC Tscherning: 0.03, 0.02, and 0.2, respectively). CONCLUSIONS: Although some HOAs measured with both aberrometers agreed preoperatively, such agreement might not persist after LASIK. Spherocylinder measurements with both aberrometers seemed to agree closely with the manifest refraction before LASIK, but not at 12 months. FINANCIAL DISCLOSURE: Dr. Manche has equity in Calhoun Vision, Inc., Krypton Vision, Seros Medical, LLC, and Veralas and is a consultant to Best Doctors, Gerson Lehrman Group. PMID- 26603390 TI - Prevalence of laser vision correction in ophthalmologists who perform refractive surgery. AB - PURPOSE: To determine the prevalence of laser corneal refractive surgery (laser vision correction [LVC]) among ophthalmologists who perform these procedures and to assess the willingness of these ophthalmologists to recommend LVC to immediate family members. SETTING: Online survey with results analyzed at Surgivision Consultants, Inc., Scottsdale, Arizona, USA. DESIGN: Prospective randomized questionnaire study. METHODS: The 22-question Global Survey on Refractive Surgery in Refractive Surgeons was sent by e-mail to 250 ophthalmologists randomly selected from a database of 2441 ophthalmologists known to have performed LVC at some point in the past decade. Responses were solicited by e-mail, with subsequent telephone reminders to nonresponders. RESULTS: Responses were received from 248 (99.2%) of 250 queried individuals, of which 232 (92.8%) met the protocol criteria of currently working as refractive surgeons. Of the 232 subjects, 161 (69.4%) reported that they had refractive errors potentially amenable to treatment with LVC, not including presbyopia. Of the 161 ophthalmologists with treatable refractive errors, 54 (33.5%) reported they were not candidates for LVC for a variety of reasons and 107 (66.5%) reported they were candidates for LVC. Of the LVC candidates, 62.6% reported that they had an LVC procedure in their own eyes. Of the overall 232 subjects, more than 90% recommend LVC for adult members of their immediate family. CONCLUSIONS: Ophthalmologists who perform LVC were significantly more likely than the general population to have LVC in their own eyes. The prevalence of refractive errors was significantly higher among ophthalmologists performing refractive surgery than in the general population. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26603391 TI - Femtosecond laser-assisted compared with standard cataract surgery for removal of advanced cataracts. AB - PURPOSE: To compare effective phacoemulsification time (EPT) for the removal of brunescent cataracts treated with femtosecond laser-assisted cataract surgery with standard cataract phacoemulsification techniques. SETTING: Ruhr University Eye Hospital, Bochum, Germany. DESIGN: Comparative prospective case study. METHODS: The Lens Opacities Classification System III (LOCS III) grading system was used to measure eyes divided into 4 groups having cataract surgery. Groups 1 and 2 contained eyes with LOCS III grade nuclear opalescence (NO) 3 cataracts treated with standard cataract surgery and femtosecond laser-assisted cataract surgery, respectively. Groups 3 and 4 contained brunescent cataracts, LOCS III grades NO5, treated with standard cataract surgery and femtosecond laser-assisted cataract surgery, respectively. RESULTS: There were 240 eyes, with 60 eyes in each group. The EPT in Group 1 ranged from 0.46 to 3.10 (mean 1.38); the EPT in all eyes in Group 2 was 0 (P < .001). The EPT in Groups 3 and 4 was 2.12 to 19.29 (mean 6.85) and 0 to 6.75 (mean 1.35), respectively (P < .001). A comparison between EPT in Groups 1 and 4 showed that EPT in Group 4 was also lower than in Group 1 (P = .013). Groups 4 and 1 were the most statistically similar of all groups compared, suggesting that EPT for a femtosecond laser-treated grade 5 cataract was most similar to that of a standard-treated grade 3 cataract. CONCLUSION: Femtosecond laser pretreatment for brunescent cataracts allowed for a significant reduction in EPT compared with manual standard phacoemulsification techniques. FINANCIAL DISCLOSURE: Drs. Hatch, Talamo, and Dick are consultants to Abbott Medical Optics, Inc. Dr. Schultz has no financial or proprietary interest in any material or method mentioned. PMID- 26603392 TI - Outcomes of glued foldable intraocular lens implantation in eyes with preexisting complications and combined surgical procedures. AB - PURPOSE: To evaluate the visual outcomes and complications of glued foldable intraocular lens (IOL) implantation in patients with a wide range of ocular pathologies and/or having combined surgical procedures. SETTING: New York Eye and Ear Infirmary of Mount Sinai, New York, New York, USA. DESIGN: Retrospective case series. METHODS: A chart review was conducted of all glued foldable IOL procedures performed in eyes with absent or insufficient capsule support. Patients with a postoperative follow-up less than 3 months were excluded from analysis. Intraoperative and postoperative complications, the postoperative course, and visual and refractive outcomes were analyzed. RESULTS: Sixty-five eyes (64 patients) were evaluated over a mean follow-up of 9.1 months +/- 6.2 (SD). Ocular comorbidities were present in 98.5% of eyes, and 95.4% had additional concurrent surgical procedures. There was a statistically significant improvement in corrected distance visual acuity (P = .046), with 89.2% of eyes achieving better or equal vision postoperatively. Intraoperative complications included ocular hemorrhage (10.8%), haptic deformation (10.8%), and haptic breakage (1.5%). Postoperative complications included elevated intraocular pressure (13.8%), optic capture (12.3%), persistent anterior chamber inflammation (6.2%), IOL tilt (4.6%), cystoid macular edema (3.1%), recurrent ocular hemorrhage (3.1%), and retinal detachment (1.5%). CONCLUSION: The glued foldable IOL technique resulted in favorable visual outcomes but with a moderate risk for IOL-related and other postoperative complications in eyes with complex ocular comorbidities having combined surgical procedures. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26603393 TI - Crossed versus conventional pseudophakic monovision: Patient satisfaction, visual function, and spectacle independence. AB - PURPOSE: To compare patient satisfaction, visual function, and spectacle independence in patients with crossed or conventional pseudophakic monovision. SETTING: Department of Ophthalmology, Henry Ford Health System, Taylor, Michigan, USA. DESIGN: Retrospective comparative cohort study. METHODS: Cataract surgery patient records from June 1999 to December 2013 were reviewed. Crossed monovision patients were identified. Control conventional monovision cases were matched for age, sex, general health, personal lifestyle/main hobbies, preoperative refractive status, postoperative refractive status, uncorrected distance visual acuity, uncorrected near visual acuity, astigmatism level, and anisometropia level. A survey was mailed to participants, and results were independently analyzed. RESULTS: The review comprised 7311 patient records. Forty-four crossed monovision patients were identified, and 30 of them were enrolled. Thirty matched pairs were surveyed. The mean anisometropia was 1.19 diopters (D) in the conventional and 1.12 D in the crossed monovision groups. No significant difference was identified for eye-hand coordination, eye-foot coordination, or sport-related depth perception, but satisfaction was slightly better in the crossed monovision group (P = .028). No significant difference was identified for 6 of 8 spectacle independence measures, but nighttime driving was a little easier for the crossed monovision group (P = .025). Seventy-seven percent of crossed and 50% of conventional monovision patients did not use glasses for intermediate distance activities (P = .037). CONCLUSION: Crossed pseudophakic monovision appears to work as well as conventional pseudophakic monovision in terms of patient satisfaction and spectacle independence in patients with a mild degree of anisometropic pseudophakia. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26603394 TI - Incidence of cystoid macular edema following secondary posterior chamber intraocular lens implantation. AB - PURPOSE: To investigate the incidence and risk factors for the occurrence of cystoid macular edema (CME) after secondary posterior chamber intraocular lens (PC IOL) fixation. SETTING: Eye Clinic Herzog Carl Theodor, Munich, Germany. DESIGN: Retrospective case series. METHODS: Eyes with secondary PC IOL implantation were included. Eyes in Group 1 were treated because of preexisting aphakia; eyes in Group 2 had reimplantation or refixation of a failed primary PC IOL (Group 2). Patients were followed for at least 12 months with measurement of corrected distance visual acuity (CDVA) and central retinal thickness with optical coherence tomography (OCT). Risk factors for CME occurrence were evaluated with standard statistical procedures. Cutoff points of sensitivity and specificity were calculated for the prediction of CME with the receiver operating characteristic (ROC) method. RESULTS: Forty-two eyes of 40 patients (16 men, 24 women; mean age 75.4 years +/- 13.7 [SD]) were included. There were 28 eyes in Group 1 and 14 eyes in Group 2. Seven eyes (16.7%) developed CME with significant impairment of CDVA and an increase in central retinal thickness on OCT. Five eyes in Group 1 and 2 eyes in Group 2 were affected, without a significant difference between groups. The CDVA after surgery had a significant influence, and there was a trend toward patient age as a risk factor. The ROC analysis yielded 83.9 years of age and a CDVA of 0.35 logMAR, respectively, as meaningful cutoff points. CONCLUSIONS: Secondary PC IOL fixation was performed with good results despite the inherent CME risk from the procedure. Advanced age and poor CDVA after surgery might predict CME occurrence. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26603395 TI - Clinical outcomes of the glued intraocular lens scaffold. AB - PURPOSE: To report the visual outcomes and complications of the glued intraocular lens (IOL) scaffold procedure in patients with intraoperative posterior capsule rupture and retained nuclear fragments, subluxated cataract, and Soemmerring ring associated with aphakia and deficient posterior capsule. SETTING: Dr. Agarwal's Eye Hospital, Chennai, India. DESIGN: Retrospective noncomparative interventional case series. METHODS: Medical records of patients who had a glued IOL scaffold procedure performed were reviewed. The main outcome measures were visual acuity at final follow-up and intraoperative and postoperative complications during the entire follow-up. RESULTS: The mean preoperative and mean final postoperative corrected distance visual acuity (CDVA) (Snellen decimal equivalent) in 19 eyes of 17 patients were 0.39 +/- 0.13 (SD) and 0.73 +/- 0.27, respectively (P = .002, Wilcoxon test). No eye lost CDVA. The CDVA was stable in 7 eyes, improved 1 line in 2 eyes, and improved 2 lines or more in 10 eyes. Postoperatively, 20/20 visual acuity was attained in 9 eyes. Intraoperatively, Soemmerring ring drop into the vitreous cavity in 1 eye and hyphema in 2 eyes were observed. Postoperative complications included corneal edema (2 eyes), choroidal detachment (1 eye), mild vitritis (1 eye), ocular hypertension (1 eye), and fibrin reaction in the anterior chamber that resolved with medical management (2 eyes). CONCLUSION: The glued IOL scaffold enabled a closed-chamber approach with proper placement of an IOL in cases with inadequate sulcus or iris support and allowed safe emulsification of the retained nuclear fragments with good visual outcomes. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26603396 TI - Measuring the cataractous lens. AB - PURPOSE: To evaluate the lens thickness, anterior cortex space, nucleus thickness, and posterior cortex space in cataractous eyes and compare them with those in eyes of younger patients with clear lenses. SETTING: Private practice, Lynwood, California, USA. DESIGN: Retrospective observational study. METHODS: The study evaluated a group of cataractous eyes and compared them with a group of eyes of younger patients with clear lenses. All measurements were performed with a biometer (Lenstar LS 900). RESULTS: The cataractous group (200 eyes) had a greater mean lens thickness (4.65 mm +/- 0.41 [SD]) than the control group (80 eyes) (4.09 +/- 0.33 mm). The mean measured values for the cataractous groups and control groups were 0.84 +/- 0.21 mm and 0.35 +/- 0.11 mm for anterior cortex space, 3.31 +/- 0.25 mm and 3.27 +/- 0.27 mm for mean nucleus thickness, and 0.51 +/- 0.16 mm and 0.48 +/- 0.13 mm for mean posterior cortex space, respectively. Anterior cortex space, nucleus thickness, and posterior cortex space correlated positively with lens thickness (r = 0.69, r = 0.69, and r = 0.59, respectively). Lens thickness, anterior cortex space, nucleus thickness, and posterior cortex space showed a weak inverse correlation with axial length (r = 0.06, r = 0.08, r = 0.10, and r = 0.10, respectively) and an inverse correlation with anterior chamber depth (r = 0.57, r = 0.43, r = 0.42, and r = 0.22, respectively). Lens thickness showed a positive correlation with age (r = 0.28), as did the anterior cortex space (r = 0.32) and posterior cortex space (r = 0.26), but nucleus thickness did not show a positive correlation (r = 0.02). CONCLUSION: Lens thickness increased with age and with cataract formation and was mostly attributable to an increase in the anterior cortex space. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 26603397 TI - Intraocular lens power calculation after myopic excimer laser surgery: Selecting the best method using available clinical data. AB - PURPOSE: To compare the results of methods to calculate intraocular lens (IOL) power after myopic excimer laser surgery. SETTING: G.B. Bietti Foundation-IRCCS, Rome, Italy. DESIGN: Prospective interventional case series. METHODS: Eyes were classified into 4 groups: Group 1 (preoperative keratometry available, refractive change known), Group 2 (preoperative keratometry available, refractive change uncertain), Group 3 (preoperative keratometry unavailable, refractive change known), and Group 4 (preoperative keratometry unavailable, refractive change unknown). The IOL power was calculated by 19 methods. The median absolute error in refraction prediction and the percentage of eyes with a refraction prediction error within +/-0.50 diopter (D) were calculated. RESULTS: In Group 1 (n = 30), the Savini, Seitz/Speicher/Savini, and Masket methods provided the lowest median absolute error (0.29 D, 0.35 D, and 0.34 D, respectively), with more than 70% of eyes within +/-0.50 D of the predicted refraction. In Group 2 (n = 16), the Seitz/Speicher method achieved the best result (median absolute error 0.37 D), with 75% of eyes within +/-0.50 D of the predicted refraction. In Group 3 (n = 18), the Masket method provided the lowest median absolute error (0.24 D), with 72.2% of eyes within +/-0.50 D of the predicted refraction. In Group 4 (n = 6), the Shammas no-history method had the lowest median absolute error (0.31 D), with 83% of eyes within +/-0.50 D of the predicted refraction. CONCLUSION: Intraocular lens power can be accurately calculated in post-laser surgery eyes when the preoperative corneal power and refractive change are known and when they are not. FINANCIAL DISCLOSURE: Dr. Hoffer receives book royalties for IOL Power and formula royalties from all manufacturers using the Hoffer Q formula to ensure it is programmed correctly. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 26603399 TI - Anterior chamber depth studies. AB - PURPOSE: To compare the anterior chamber depth (ACD; corneal epithelium to lens) using 3 modalities and compare the change 1 day and 3 months postoperatively. SETTING: Private practice, Santa Monica, California, USA. DESIGN: Nonrandomized prospective series. METHODS: The mean optical pachymetry and immersion ultrasound (US) of the ACD and partial coherence interferometry (PCI) were measured. Optical pachymetry ACD was measured in 675 eyes postoperatively at 1 day and 3 months. RESULTS: The optical pachymetry ACD in 492 eyes was 3.17 mm +/- 0.42 (SD); by immersion US, it was 2.99 +/- 0.51 mm (0.18 mm deeper; P < .0001). In 178 eyes, the optical pachymetry ACD was 3.23 +/- 0.45 mm; the PCI was 3.19 +/- 0.48 mm (0.04 mm deeper), which was not statistically different (P > .05). In 675 eyes, optical pachymetry ACD preoperatively was 3.19 +/- 0.40 mm. The postoperative 1 day optical pachymetry ACD was 4.35 +/- 0.35 mm with a mean refractive error of 0.30 diopter (D); the final 3-month optical pachymetry ACD was 4.47 +/- 0.31 mm, with a mean refractive error of -0.07 D (P < .0001). This is a mean intraocular lens (IOL) position shift of +0.12 mm posteriorly; the +0.23 D change represents a ratio of 1.92 D/mm of IOL axial movement. CONCLUSIONS: The PCI ACD was comparable with optical pachymetry, but careful immersion US led to a 0.18 mm shorter ACD reading that cannot be corrected by sound velocity. The posterior capsule contracted and moved the IOL posteriorly 0.12 mm, resulting in 0.23 D hyperopic shift. FINANCIAL DISCLOSURE: Dr. Hoffer owns the registered trademark name "Hoffer((r))" and receives royalties for its commercial use from Alcon Laboratories, Inc., Appasamy Associates, Carl Zeiss Meditec AG, DGH Technology, Inc., Ellex iScience, Inc., Haag-Streit AG, Nidek Co., Ltd., Tomey Corp., Topcon Medical Systems, Inc., and Ziemer USA, Inc., as well as royalties from Slack, Inc. for the textbook IOL Power. Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 26603398 TI - Accuracy of an automated refractor using a Hartmann-Shack sensor after corneal refractive surgery and cataract surgery. AB - PURPOSE: To evaluate the accuracy of a new automated refractor (HRK-8000A) using the Hartmann-Shack sensor in eyes with previous corneal refractive surgery or intraocular lens (IOLs) implantation. SETTING: Asan Medical Center, Seoul, South Korea. DESIGN: Retrospective nonrandomized clinical study. METHODS: Refractive errors were evaluated after more than 1 month postoperatively. Subjective refractive error measurements were obtained by the same practitioner. Refractive error measurements were obtained with the Hartmann-Shack sensor refractor and a conventional refractor (KR 8800). RESULTS: There were 121 eyes (121 patients) with previous corneal refractive surgery and 122 eyes (122 patients) with previous cataract surgery. The results of refractive error measured by the Hartmann-Shack sensor refractor were more similar to subjective refraction than those measured by the conventional refractor in both groups. In both groups, the mean spherical equivalent (SE) for the subjective refraction showed better agreement with the automated refraction measured by the Hartmann-Shack sensor refractor (limits of agreement [LoA], -0.66 to +0.65 diopters [D] and -0.47 to +0.41 D, respectively) than the automated refraction measured by the conventional refractor (LoA, -1.66 to +0.58 D and -1.34 to +0.60 D, respectively). In both groups, the Jackson cross-cylinder at axis 0 degrees and 45 degrees from the automated refraction by the Hartmann-Shack sensor refractor and conventional refractor showed similar agreement with the subjective refraction. CONCLUSION: The Hartmann-Shack sensor automated refractor gave reliable and valid objective refraction results in patients who have had cataract or corneal refractive surgery. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26603400 TI - Long-term postoperative outcomes after bilateral congenital cataract surgery in eyes with microphthalmos. AB - PURPOSE: To evaluate the long-term impact of bilateral cataract surgery on postoperative complications, influence of age at surgery on the pattern of axial growth and central corneal thickness (CCT), and visual and orthoptic assessment in microphthalmic eyes. SETTING: Iladevi Cataract and IOL Research Centre, Ahmedabad, India. DESIGN: Prospective longitudinal study. METHODS: This study assessed children with microphthalmos who had bilateral congenital cataract surgery. Microphthalmos was defined as an eye that has an axial length (AL) that was 2 standard deviations smaller than what is normally expected at that age. All eyes were left aphakic. One of the 2 eyes was randomly selected for analysis. Postoperative complications, AL, CCT, and visual acuity were documented. RESULTS: This study included 72 eys of 36 children. The mean age of the patients was 4.8 months +/- 6.2 (SD) (range 0.5 to 15 months). Postoperative complications included secondary glaucoma (11/36, 30.6%), visual axis obscuration (4/36, 11.1%), and posterior synechiae (10/36, 27.8%). A significant rate of change was observed in axial growth up to 4 years and in CCT up to 3 years postoperatively. When age at the time of surgery was correlated with the profile of the rate of change in AL and CCT at 1 month and 1, 2, and 4 years, statistically significant differences in AL and CCT at all timepoints were found. Loss of vision after surgery occurred in 2 eyes. CONCLUSION: After early surgical intervention, an acceptable rate of serious postoperative complications and good visual outcomes were obtained in microphthalmic eyes. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26603401 TI - Ultra-widefield retinal imaging through a black intraocular lens. AB - PURPOSE: To evaluate the feasibility of ultra-widefield retinal imaging in patients with near infrared (IR)-transmitting black intraocular lenses (IOLs). SETTING: Oxford Eye Hospital, Oxford, United Kingdom. DESIGN: Laboratory evaluation of a diagnostic technology with interventional case report. METHODS: The field of retinal imaging through a Morcher poly(methyl methacrylate) (PMMA) black IOL was determined in a purpose-built adult schematic model eye with the HRA2 Spectralis confocal scanning laser ophthalmoscope using standard imaging, Staurenghi retina lens-assisted imaging, and ultra-widefield noncontact imaging. Retinal imaging using each modality was then performed on a patient implanted with another Morcher PMMA black IOL model. RESULTS: Ultra-widefield noncontact imaging and lens-assisted imaging captured up to 150 degrees of field (versus 40 degrees with a standard confocal scanning laser ophthalmoscope). Ultra-widefield retinal images were successfully acquired in a patient eye with a black IOL. CONCLUSIONS: This study has identified the first ultra-widefield retinal imaging modalities for patients with near IR-transmitting black IOLs. Should larger studies confirm this finding, noncontact ultra-widefield confocal scanning laser ophthalmoscopy might be considered the gold standard imaging technique for retinal surveillance in patients with near IR-transmitting black IOLs. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26603402 TI - Outcomes of a modified capsular tension ring with a single black occluder paddle for eyes with congenital and acquired iris defects: Report 2. AB - PURPOSE: To evaluate the safety and efficacy of Morcher 96F iris diaphragm implantation to manage small defects of the human iris. SETTING: Jules Stein Eye Institute, UCLA, Los Angeles, California, USA. DESIGN: Prospective nonrandomized interventional case series. METHODS: Demographic, preoperative, and postoperative data of patients who had implantation of the modified capsular tension ring (CTR) and followed to 1 year were reviewed. Safety measures included loss of corrected distance visual acuity (CDVA), perioperative complications, adverse events, and secondary surgical interventions. Efficacy measures included CDVA with glare, daytime and nighttime glare symptom scores, and subjective cosmesis scores. RESULTS: Sixteen patients had CTR implantation. There was a statistically significant improvement in the median CDVA of 2.5 Snellen lines (P < .01), with 4 patients having minor decreases in CDVA for reasons unrelated to the device. There were no intraoperative complications. Three adverse events were reported: 1 ocular hypertension, 1 postoperative retinal detachment, and 1 25-degree rotation of the CTR. There were 4 secondary surgical interventions. There was a statistically significant improvement in the median CDVA with glare of 8 Snellen lines (P < .01), but 2 patients had a decrease in CDVA with glare for reasons unrelated to the device. There were statistically significant improvements in the median daytime and nighttime glare symptom scores of 5 points and 4 points, respectively (both P < .01). There was no change in cosmesis for most patients. CONCLUSION: Iris diaphragm CTR implantation was relatively safe and effective at reducing light and glare sensitivity in eyes with small iris defects. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26603403 TI - Height-, extent-, length-, and pupil-based (HELP) algorithm to manage post phacoemulsification Descemet membrane detachment. AB - PURPOSE: To analyze the functional and anatomic outcomes of management of Descemet membrane detachment after phacoemulsification using a protocol based on the detachment's height, extent, and chord length and its relation to the pupil. SETTING: Dr. Agarwal's Eye Hospital and Eye Research Centre, Chennai, India. DESIGN: Prospective comparative case series. METHODS: Eyes with post phacoemulsification Descemet membrane detachment were managed surgically or medically based on the detachment's height, extent, length (chord), and relation to the pupil (HELP protocol). Central corneal thickness (CCT), chord length, and detachment height were determined by anterior segment optical coherence tomography (AS-OCT) (Visante). RESULTS: Of 161 eyes, 96 were treated surgically (Group 1) and 65 medically (Group 2). The mean length and mean height of Descemet membrane detachment were 2.4 mm +/- 1.4 (SD) and 266 +/- 189.8 MUm, respectively, in Group 1 and 1.03 +/- 0.4 mm and 153.3 +/- 60.8 MUm, respectively, in Group 2. The complete reattachment rate was 95.8% in Group 1 and 96.9% in Group 2. The corrected distance visual acuity (CDVA) was 20/40 or better in 83.3% of eyes in Group 1 and 92.3% of eyes in Group 2. No eye lost CDVA as a result of a Descemet membrane scar in the central 5.0 mm of the cornea. The AS-OCT allowed visualization of the detachment in all eyes with a CCT of more than 800 MUm. There was no difference in the final CDVA between Group 1 and Group 2. CONCLUSIONS: The AS-OCT-based algorithm was effective for managing post-surgical Descemet membrane detachment in eyes with dense corneal edema. Early surgical intervention for detachments in the central cornea can reduce scarring-induced visual loss. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26603404 TI - Dexamethasone implant as an effective treatment option for macular edema due to Irvine-Gass syndrome. AB - PURPOSE: To investigate the effectiveness and safety of a dexamethasone implant (Ozurdex) to treat pseudophakic macular edema (Irvine-Gass syndrome). SETTING: Department of Ophthalmology, Ludwig-Maximilians-University Munich, Munich, Germany. DESIGN: Prospective nonrandomized study. METHODS: Preoperatively and in 12 monthly postoperative intervals, a complete ophthalmic examination was performed in study patients, including measurement of corrected distance visual acuity (CDVA) using the standard Early Treatment Diabetic Retinopathy Study chart, intraocular pressure, foveal thickness using spectral-domain optical coherence tomography (SD-OCT), and retinal sensitivity (mean defect depth) using microperimetry. Morphological aspects of the inner segment-outer segment junction and visual function were correlated. RESULTS: Twenty-three eyes (23 patients) with pseudophakic macular edema after uneventful cataract surgery were included. The mean duration of macular edema before treatment with a dexamethasone implant was 5.4 months (range 2 to 8 months). The CDVA increased in all patients from 30.2 letters +/- 4.3 (SD) at baseline to 50.4 +/- 4.9 letters at 12 months (P = .0016), regardless of the time of macular edema duration. Foveal thickness decreased from 520.8 +/- 71.4 MUm to 232.7 +/- 26.6 MUm (P < .002). Retinal sensitivity (mean defect depth) increased significantly over a 12-month follow up, correlating positively with a restored inner segment-outer segment junction on SD-OCT analyses. No relevant adverse events were reported, and 9 recurrences occurred with a peak after 3 months and required a second dexamethasone implant injection. CONCLUSION: The dexamethasone implant was safe and effective in treating pseudophakic macular edema regardless of the duration of the edema. FINANCIAL DISCLOSURE: Drs. Mayer and Haritoglou are consultants to Allergan, Inc. No author has a financial or proprietary interest in any material or method mentioned. PMID- 26603405 TI - Bifocal refractive corneal inlay implantation to improve near vision in emmetropic presbyopic patients. AB - PURPOSE: To evaluate the safety and effectiveness of the Flexivue Microlens corneal inlay for the improvement of near vision in emmetropic presbyopic patients. SETTING: Ophthalmology Department, Misericordia e Dolce Hospital, Prato, Italy. DESIGN: Prospective interventional case series. METHODS: Corneal inlay implantation was performed in nondominant eyes using a 150 kHz femtosecond laser (iFS). Refraction, uncorrected (UNVA) and corrected (CNVA) near visual acuities, uncorrected (UDVA) and corrected (CDVA) distance visual acuities, slitlamp evaluation, wavefront aberrometry, photopic and mesopic contrast sensitivity, anterior segment optical coherence tomography, endothelial cell density, and central corneal thickness measurements were assessed preoperatively and at each postoperative visit. RESULTS: The study evaluated 81 eyes. In 26 eyes, the mean preoperative UNVA and UDVA were 0.76 logMAR and 0.00 logMAR, respectively, compared with 0.10 logMAR and 0.15 logMAR, respectively, 36 months postoperatively. Sixteen (62%) of 26 treated eyes lost more than 1 line of UDVA, and 5 (19%) lost more than 2 lines of UDVA. Two eyes (8%) lost more than 1 line of CDVA at 36 months. The mean binocular UDVA was 0.00 logMAR preoperatively and 0.02 logMAR at 36 months. The mean spherical aberration increased after surgery. Statistically significant differences in the mean mesopic and photopic contrast sensitivities at higher spatial frequencies were found between treated eyes and nontreated eyes. Explantation was performed in 6 treated eyes because of halos, glare, and a reduced UDVA. CONCLUSION: The corneal inlay might be a safe and effective method of improving UNVA in emmetropic presbyopic patients. FINANCIAL DISCLOSURE: Dr. Fantozzi is a member of the Presbia medical advisory board. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 26603406 TI - Correction ratio and vector analysis of femtosecond laser arcuate keratotomy for the correction of post-mushroom profile keratoplasty astigmatism. AB - PURPOSE: To evaluate the refractive and keratometric effect of arcuate keratotomy using femtosecond technology in patients with high post-keratoplasty astigmatism with a mushroom profile. SETTING: Enaim Refractive Center, Tel-Aviv, Israel. DESIGN: Noncomparative prospective interventional case series. METHODS: The arcuate depth incision was set to 80% of the minimal graft thickness, with a 60 degree angle. The mean diameter was 5.79 mm +/- 0.32 (SD) according to the graft size. Patient evaluation included logMAR corrected distance visual acuity (CDVA), refraction, keratometry (K), and a complete eye examination. RESULTS: Twenty seven eyes of 27 patients after keratoplasty surgery were included. Both uncorrected distance visual acuity and logMAR CDVA improved after surgery. The preoperative mean logMAR CDVA was 0.29 +/- 0.37 (SD), which improved by 1 line (to 0.19 +/- 0.10; P = .01). The mean refractive astigmatism was -8.43 +/- 2.80 diopters (D) (range -4.5 to -15 D), and it declined at the 3-month postsurgical follow-up to -4.31 +/- 0.23 D (P < .001) and remained stable until the end of follow-up (-3.31 +/- 1.39 D; P = 1.00). The K value decreased by 1.18 D (P < .001). There were no complications or adverse effects during the follow-up period. CONCLUSIONS: Arcuate keratotomies performed with the femtosecond laser showed good results. There was a more than 50% decrease in post-mushroom profile keratoplasty astigmatism as well as stability of the results over 1 year. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26603407 TI - In vitro biofilm distribution on the intraocular lens surface of different biomaterials. AB - PURPOSE: To study the disposition of bacterial adhesion to intraocular lens (IOL) biomaterials depending on the material and region of the optic IOL surface: center or peripheral edge. SETTING: School of Medicine, University of Barcelona, Barcelona, Spain. DESIGN: Experimental study. METHODS: For the in vivo study, IOLs were explanted from donor ocular globes without clinical symptoms of endophthalmitis. Biofilm formation was qualitatively studied by scanning electron microscopy (SEM). For the in vitro study, 5 IOL biomaterials (hydrophilic acrylic, hydrophobic acrylic, poly[methyl methacrylate] [PMMA], heparinized PMMA, and silicone) were contaminated with a biofilm-producing strain of Staphylococcus epidermidis. Bacterial densities were quantitatively (colony-forming units per area) compared by SEM and direct counting of viable adherent bacteria, according to the biomaterial, region of the IOL optic surface, and time of incubation. For SEM, bacterial adhesion was also qualitatively classified according to the characteristics of biofilm observed: structure, cocci per cluster, homogeneity of cluster distribution, and extracellular matrix production. RESULTS: At 3 hours of incubation, bacterial counts for hydrophilic acrylic and PMMA IOLs were significantly lower, but at 72 hours there were no statistically significant differences among biomaterials. A higher density of bacteria was observed at the periphery of the IOL's optic of assayed biomaterials for in vitro and in vivo studies. Biofilm formation and the presence of extracellular matrix were predominantly restricted to the edges of IOL optic surface. CONCLUSION: Bacterial adhesion and biofilm development on the IOL optic surface depended on the region and biomaterial of the IOL. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 26603408 TI - Standard versus accelerated riboflavin-ultraviolet corneal collagen crosslinking: Resistance against enzymatic digestion. AB - PURPOSE: To examine the effect of standard and accelerated corneal collagen crosslinking (CXL) on corneal enzymatic resistance. SETTING: School of Optometry and Vision Sciences, Cardiff University, Cardiff, United Kingdom. DESIGN: Experimental study. METHODS: Sixty-six enucleated porcine eyes (with corneal epithelium removed) were assigned to 6 groups. Group 1 remained untreated, group 2 received dextran eyedrops, and groups 3 to 6 received riboflavin/dextran eyedrops. Group 4 had standard CXL (3 mW/cm(2) ultraviolet-A for 30 minutes), whereas groups 5 and 6 received accelerated CXL (9 mW/cm(2) for 10 minutes and 18 mW/cm(2) for 5 minutes, respectively). Trephined central 8.0 mm buttons from each cornea underwent pepsin digestion. Corneal diameter was measured daily, and the dry weight of 5 samples from each group was recorded after 12 days of digestion. RESULTS: All CXL groups (4 to 6) took longer to digest and had a greater dry weight at 12 days (P < .0001) than the nonirradiated groups (1 to 3) (P < .0001). The time taken for complete digestion to occur did not differ between the standard and accelerated CXL groups, but the dry weights at 12 days showed significant differences between treatments: standard CXL 3 mW > accelerated CXL 9 mW > accelerated CXL 18 mW (P < .0001). CONCLUSIONS: Standard and accelerated CXL both increased corneal enzymatic resistance; however, the amount of CXL might be less when accelerated CXL is used. The precise amount of CXL needed to prevent disease progression is not yet known. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26603409 TI - Effect of cataract surgery on regulation of circadian rhythms. AB - This review looked at the effect of cataract surgery on the regulation of circadian rhythms and compared the effect of blue light-filtering and clear intraocular lenses (IOLs) on circadian rhythms. A systematic review and metaanalysis were performed, and the level of evidence was evaluated based on the principles described in the Grading of Recommendations Assessment, Development, and Evaluation system. A literature search of PubMed, Embase, and Cochrane Library databases was performed, as well as a search for unpublished trials at the U.S. National Institutes of Health Clinical Trials web site. Trials that reported the effect of cataract surgery on circadian rhythms were included. Outcomes were the Pittsburgh Sleep Quality Index (PSQI) global score, number of poor sleepers, Epworth Sleepiness Score, sleep efficiency, and mean concentration of melatonin. Cataract surgery improved regulation of circadian rhythms measured by the PSQI questionnaire, but the clinical relevance is uncertain. There was no difference between the effect of the 2 IOL types. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26603410 TI - Unilateral corneal ectasia following small-incision lenticule extraction. AB - We describe a case of unilateral corneal ectasia in a 26-year-old man following small-incision lenticule extraction. The preoperative corneal topography was normal, with a minimum corneal thickness of 511 MUm and 513 MUm in the right eye and left eye, respectively. Lenticules of 85 MUm and 82 MUm were fashioned to offer a refractive correction of -3.75 -1.50 * 180 and -3.50 -1.50 * 165 in the right eye and left eye, respectively. Twelve months after small-incision lenticule extraction, the patient presented with early signs of ectasia in the left eye on corneal topography, which had worsened at the 18-month examination. Intrastromal corneal ring segment implantation with corneal collagen crosslinking was performed to arrest further progression and to improve uncorrected distance visual acuity. On the last examination, the corrected distance visual acuity was 20/20(-2). FINANCIAL DISCLOSURE: Dr. Mahipal S. Sachdev receives travel grants from Carl Zeiss Meditec AG. No author has a financial or proprietary interest in any material or method mentioned. PMID- 26603411 TI - Cardiovascular hazard of intracameral phenylephrine. PMID- 26603412 TI - Use of a single peripheral triangular mark to ensure correct graft orientation in Descemet membrane endothelial keratoplasty. PMID- 26603413 TI - Decreased vision after presbyopic laser surgery: What now?: September consultation #1. PMID- 26603414 TI - September consultation #2. PMID- 26603415 TI - September consultation #3. PMID- 26603416 TI - September consultation #4. PMID- 26603417 TI - September consultation #5. PMID- 26603418 TI - September consultation #6. PMID- 26603419 TI - September consultation #7. PMID- 26603420 TI - September consultation #8. PMID- 26603421 TI - September consultation #9. PMID- 26603422 TI - Reply: To PMID 26287892. PMID- 26603423 TI - Identification of surrogate endpoints in patients with locoregionally advanced nasopharyngeal carcinoma receiving neoadjuvant chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone. AB - BACKGROUND: In the era of intensity-modulated radiotherapy (IMRT), the efficacy of additional neoadjuvant chemotherapy (NACT) to concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal carcinoma (NPC) is currently being investigated in ongoing trials. Overall survival (OS) is the gold standard endpoint in NPC trials. We performed this analysis to identify surrogate endpoints for OS, which could shorten follow-up duration and speed up assessment of treatment effects. METHODS: We retrospectively analysed 208 matched-pair patients with locoregionally advanced NPC receiving NACT+CCRT or CCRT. Progression-free survival (PFS), failure-free survival (FFS), distant failure free survival (D-FFS) and locoregional failure-free survival (LR-FFS) at 2 and 3 years were assessed as surrogates for 5-year OS according to Prentice's criteria. The strength of the associations were assessed using Spearman's rank correlation coefficient. RESULTS: No significant differences were observed between treatment arms for any surrogate endpoint at 2 years, which rejected Prentice's second criterion. In contrast, 3-year LR-FFS, PFS, FFS and D-FFS were consistent with all four of Prentice's criteria; the rank correlation coefficient (0.730) between 3-year PFS and 5-year OS was highest. CONCLUSIONS: 3-year PFS, FFS and D-FFS could be valid surrogate endpoints for 5-year OS; 3-year PFS may be the most accurate. PMID- 26603424 TI - In vitro potency and combination testing of antimicrobial agents against Neisseria gonorrhoeae. AB - Antimicrobial resistant Neisseria gonorrhoeae is a major concern to public health due to decreased susceptibility to frontline antimicrobials. To find agents that are active against N. gonorrhoeae, we tested antimicrobials alone or in combination by Etest gradient strips. The potencies (as assessed by minimum inhibitory concentrations) of twenty-five antimicrobials were evaluated against nine reference strains of N. gonorrhoeae (WHO F, G, K, L, M, N, O, P and ATCC 49226). Potency was greatest for netilmicin, quinupristin-dalfopristin, ceftriaxone, ertapenem and piperacillin-tazobactam. Combinations of azithromycin, moxifloxacin, or gentamicin with ceftriaxone, doripenem, or aztreonam were tested against reference isolates and the fractional inhibitory concentration index (FICI) was calculated. All nine combinations resulted in indifference (>0.5 FICI <= 4). Combinations with FICI < 1 were further evaluated in nine clinical isolates which supported the finding of indifference. No antagonism was observed in any of the combinations tested. This is the first report in which the six combinations of azithromycin, moxifloxacin or gentamcin in combination with doripenem or aztreonam were tested in N. gonorrhoeae. These data on antimicrobials with higher potency and combinations that did not show antagonism can help to guide larger scale susceptibility studies for antimicrobial resistant N. gonorrhoeae. PMID- 26603425 TI - Anti-cancer and cardioprotective effects of indol-3-carbinol in doxorubicin treated mice. AB - Doxorubicin (DOX) is a broad-spectrum antitumor antibiotic used in treatment of cancer. Its effect may be complicated by increased risk of cardiotoxicity. It was suggested that natural compounds with anticancer properties can be used in combination with DOX to decrease its dose and side effects. Indole-3-carbinol (I3C) is one of the phytochemicals that was shown to have anti-cancer effect. Our aim was to detect the possible chemosensitizing effects of I3C in DOX-induced cytotoxicity and the possible cardioprotective effects of I3C in DOX-induced cardiotoxicity. One hundred mice were divided into five equal groups: Control untreated group, solid Ehrlich carcinoma (SEC), SEC + DOX, SEC + I3C, SEC + DOX + I3C. Tumor volume, serum creatinine kinase and lactate dehydrogenase were measured. Also, tissue malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), sphingosine kinase-1 (SphK1) activity and interleukin-6 (IL-6) were determined. Parts of the tumor and cardiac tissues were subjected to histopathological examination. DOX or I3C alone or in combination induced significant increase in tumor CAT and SOD with significant decrease in tumor volume, tumor MDA, SphK1 activity and IL-6 and alleviated the histopathological changes with significant increase in the apoptotic index and significant decrease in tissue bcl2 compared to SEC group. Also, DOX induced cardiotoxicity which was ameliorated by I3C. In conclusion, DOX/I3C combination had a better effect than each of DOX or I3C alone against SEC in mice with marked improvement of the cardiotoxicity induced by DOX. PMID- 26603426 TI - Successful treatment of Beauveria bassiana fungal keratitis with topical voriconazole. AB - We describe a 66-year-old woman who suffered from fungal keratitis after corneal transplantation. The causative organism was identified as Beauveria bassiana on the basis of morphological characteristics and the sequence of the internal transcribed spacer region of the ribosomal RNA gene. The patient was successfully treated with topical voriconazole (VRCZ) use only. We, hereby, present the first report of a case with B. bassiana fungal keratitis that responded to topical antifungal VRCZ treatment. PMID- 26603427 TI - Linezolid-resistant Staphylococcus epidermidis associated with long-term, repeated linezolid use in a pediatric patient. AB - We report an 8-year-old patient with catheter-related bacteremia caused by linezolid-resistant Staphylococcus epidermidis that was isolated after the long term, repeated use of linezolid. Three S. epidermidis strains isolated from this patient were bacteriologically analyzed. While the strain isolated prior to linezolid initiation was susceptible to linezolid, two strains after linezolid therapy displayed low-level linezolid susceptibility (MIC, 4 mg/L) and linezolid resistance (MIC, 16 mg/L). T2500A mutation in two copies and G2575T mutations in three copies of 23S rRNA were detected in the low-susceptible strain and the resistant strain, respectively. Linezolid-resistant S. epidermidis infection is rare, but may occur with the long-term administration of linezolid. PMID- 26603429 TI - An empirical analysis of the demand for sleep: Evidence from the American Time Use Survey. AB - Using data from the American Time Use Survey, this paper empirically examined the demand for sleep, with special attention to its opportunity cost represented by wages. Variation in the unemployment rate by state was also used to investigate the cyclical nature of sleep duration. We conducted separate estimations for males and females, as well as for those who received a fixed salary and hourly wages. The findings predominantly revealed no relationship between sleep duration and the business cycle. However, an inverse relationship between sleep duration and wages was detected. This is in accordance with sleep duration being an economic choice variable, rather than a predetermined subtraction of the 24-h day. Although the inverse relationship was not significant in all the estimations for salaried subjects, it was consistent and strong for subjects who received hourly wages. For instance, elasticity measures were -.03 for those who received hourly wages and -.003 for those who received a fixed salary. PMID- 26603428 TI - Thoracoscopic examination of empyema in a patient with sparganosis mansoni. AB - A 27-year-old man was admitted to our hospital with right pleural effusion. He had suffered from right chest and back pain and a high fever for one week prior to the admission. He had been treated with clarithromycin without improvement. Since thoracoscopy under local anesthesia revealed purulent effusion, synechiae and fibrous septa in the thoracic cavity, synechiotomy was performed and we started antibiotic treatment with the diagnosis of acute bacterial empyema. At the same time, we also suspected parasitic infection because of massive eosinophilic infiltration in pleural effusion and his dietary history of eating raw frogs. During the course of the disease, he had an infiltration in the right lower lobe and pneumothorax. Finally, we diagnosed him with sparganosis mansoni because his serum as well as pleural effusion was positive for the binding to sparganosis mansoni plerocercoid antigen, without any positive findings in bacteriology. His pleural effusion and lung infiltration were resolved after the administration of a high-dose praziquantel. We report this rare parasitic empyema with findings by thoracoscopic examination. PMID- 26603431 TI - Impact of preoperative evaluation by vascular physician on mortality in patients undergoing elective endovascular repair for abdominal aortic aneurysm. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) is a potentially life-threatening condition associated with increased cardiovascular mortality. This study aims to evaluate effects of medical assessment prior to endovascular repair (EVAR) for AAA on long term survival and causes of death. METHODS: A retrospective study comparing patients treated with EVAR for AAA from 1998 to 2006, having undergone standardized preoperative work-up including spirometry and echocardiography (group 1, N.=304), to patients undergoing EVAR 2007 to 2011 after individual assessment by a vascular physician aiming to optimize cardiovascular medication and reveal previously unknown illnesses (group 2, N.=201). Median follow-up was 84 months (Inter Quartile Range [IQR] 40-84) in group 1, and 60 months (IQR 45 75) in group 2. RESULTS: The use of lipid lowering agents (92%; P<0.001), anti platelet (85%; P<0.001), antihypertensive drugs (94%; P<0.001), and beta receptor blockers (78%; P<0.001) was higher in group 2. In multivariable analysis adjusting for AAA-size >=6.0 cm, signs of ischemia on ECG, and chronic kidney disease stage >=3, group 1 had significantly higher both 1-year (OR 3.2 [95% CI 1.2-9.0]) and 2-year mortality (OR 2.3 [95% CI 1.2-4.6]), whereas no differences were found between groups in survival beyond 2 years. Vascular disease was the most common cause of death in both groups (62% and 55%; P=0.29). CONCLUSIONS: Individualized preoperative evaluation by a vascular physician prior to elective EVAR was associated with reduced 1- and 2-year mortality, presumably related to more effective pharmacological cardiovascular prevention. PMID- 26603430 TI - Clinical potential of gene mutations in lung cancer. AB - Lung cancer is the most common cancer type worldwide and the leading cause of cancer related deaths in the United States. The majority of newly diagnosed patients present with late stage metastatic lung cancer that is inoperable and resistant to therapies. High-throughput genomic technologies have made the identification of genetic mutations that promote lung cancer progression possible. Identification of the mutations that drive lung cancer provided new targets for non-small cell lung cancer (NSCLC) treatment and led to the development of targeted therapies such as tyrosine kinase inhibitors that can be used to combat the molecular changes that promote cancer progression. Development of targeted therapies is not the only clinical benefit of gene analysis studies. Biomarkers identified from gene analysis can be used for early lung cancer detection, determine patient's prognosis and response to therapy, and monitor disease progression. Biomarkers can be used to identify the NSCLC patient population that would most benefit from treatment (targeted therapies or chemotherapies), providing clinicians tools that can be used to develop a personalized treatment plan. This review explores the clinical potential of NSCLC genetic studies on diagnosing and treating NSCLC. PMID- 26603432 TI - Venous thromboembolism: the prevailing approach to diagnosis, prevention and treatment among Internal Medicine practitioners. AB - BACKGROUND: Venous thromboembolism (VTE) is the third most common cause of death and the leading cause of sudden death in hospitalized medical patients. Despite the existence of guidelines for prevention and treatment of this disorder, their implementation in everyday life is not always accomplished. METHODS: We performed a survey among directors of Internal Medicine departments in our country in order to evaluate their attitude and approach to this issue. A questionnaire with pertinent questions regarding prevention and treatment of VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE) was sent to each one of the directors of Internal Medicine Departments around the country. RESULTS: Sixty nine out of 97 (71%) of the Internal Medicine departments directors responded the questionnaire. We found that several of the current guidelines were followed in a reasonable way. On the other hand, heterogeneity of responses was also present and the performance of current guidelines was imperfectly followed, and showed to be deficient in several aspects. CONCLUSIONS: An effort should be done in order to reemphasize and put in effect current guidelines for the prevention and treatment of VTE among hospitalists and Internal Medicine practitioners. PMID- 26603433 TI - Vitamins and abdominal aortic aneurysm. AB - INTRODUCTION: To summarize the association of vitamins (B6, B12, C, D, and E) and abdominal aortic aneurysm (AAA), we reviewed clinical studies with a comprehensive literature research and meta-analytic estimates. EVIDENCE ACQUISITION: To identify all clinical studies evaluating the association of vitamins B6/B12/C/D/E and AAA, databases including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched through April 2015, using Web-based search engines (PubMed and OVID). For each case-control study, data regarding vitamin levels in both the AAA and control groups were used to generate standardized mean differences (SMDs) and 95% confidence intervals (CIs). EVIDENCE SYNTHESIS: Pooled analyses of the 4 case-control studies demonstrated significantly lower circulating vitamin B6 levels (SMD, -0.33; 95% CI, -0.55 to 0.11; P=0.003) but non-significantly lower vitamin B12 levels (SMD, -0.42; 95% CI, -1.09 to 0.25; P=0.22) in patients with AAA than subjects without AAA. Pooled analyses of the 2 case-control studies demonstrated significantly lower levels of circulating vitamins C (SMD, -0.71; 95% CI, -1.23 to -0.19; P=0.007) and E (SMD, 1.76; 95% CI, -2.93 to 0.60; P=0.003) in patients with AAA than subjects without AAA. Another pooled analysis of the 3 case-control studies demonstrated significantly lower circulating vitamin D (25-hydroxyvitamin D) levels (SMD, 0.25; 95% CI, -0.50 to -0.01; P=0.04) in patients with AAA than subjects without AAA. In a double-blind controlled trial, 4.0-year treatment with a high-dose folic acid and vitamin B6/B12 multivitamin in kidney transplant recipients did not reduce a rate of AAA repair despite significant reduction in homocysteine level. In another randomized, double-blind, placebo-controlled trial, 5.8-year supplementation with alpha-tocopherol (vitamin E) had no preventive effect on large AAA among male smokers. CONCLUSIONS: In clinical setting, although low circulating vitamins B6/C/D/E (not B12) levels are associated with AAA presence, vitamins B6/B12/E supplementation may not reduce AAA incidence. PMID- 26603434 TI - Treatment of postmastectomy lymphedema by bypassing the armpit with implanted silicone tubings. AB - BACKGROUND: Women treated for breast cancer are facing a life-time risk of developing lymphedema in up to 40% of this population. In advanced cases of lymphedema main lymphatics are obstructed and tissue fluid accumulates in the interstitial spaces forming fluid "lakes"and "channels". The only solution for fluid drainage would be creating artificial channel for flow away to the non obstructed regions. The aim of this study was to form artificial pathways for edema fluid flow by subcutaneous implantation of silicone tubes into the swollen limb. METHODS: Implantation was carried out in ten patients with lymphedema after mastectomy, axillary lymphadenectomy and radiotherapy, stage II and III. Tubes were placed from hand dorsum, through forearm and arm to scapular region. Implantation was followed by routine arm sleeve compression. Prophylactic long term penicillin was administered. The follow-up is at present 10 months. RESULTS: We observed: implanted tubes brought about fast evacuation of excess tissue fluid; most decrease in circumference, volume and stiffness occurred within first two weeks; less limb heaviness and easier hand grip; lymphoscintigraphy tracer accumulated in tubes and around them; free fluid was seen on ultrasonography at both ends of tubes and in between; no postoperative complications. CONCLUSIONS: We propose a multimodality method including implantation, limb compression to generate fluid pressure gradient for flow and prevention of inflammation by administration of long-term penicillin. Simplicity of surgical procedure and lack of reaction to implant make the method worth applying in advanced stages of lymphedema in large cohorts of patients. PMID- 26603435 TI - VISTA: A MU-Thermogravimeter for Investigation of Volatile Compounds in Planetary Environments. AB - This paper presents the VISTA (Volatile In Situ Thermogravimetry Analyser) instrument, conceived to perform planetary in-situ measurements. VISTA can detect and quantify the presence of volatile compounds of astrobiological interest, such as water and organics, in planetary samples. These measurements can be particularly relevant when performed on primitive asteroids or comets, or on targets of potential astrobiological interest such as Mars or Jupiter's satellite Europa. VISTA is based on a micro-thermogravimetry technique, widely used in different environments to study absorption and sublimation processes. The instrument core is a piezoelectric crystal microbalance, whose frequency variations are affected by variations of the mass of the deposited sample, due to chemical processes such as sublimation, condensation or absorption/desorption. The low mass (i.e. 40 g), the low volume (less than 10 cm(3)) and the low power (less than 1 W) required makes this kind of instrument very suitable for space missions. This paper discusses the planetary applications of VISTA, and shows the calibration operations performed on the breadboard, as well as the performance tests which demonstrate the capability of the breadboard to characterize volatile compounds of planetary interests. PMID- 26603436 TI - Erratum to: Methylation of the miR-126 gene associated with glioma progression. PMID- 26603437 TI - Are lung cysts in renal cell cancer (RCC) patients an indication for FLCN mutation analysis? AB - Renal cell cancer (RCC) represents 2-3% of all cancers and is the most lethal of the urologic malignancies, in a minority of cases caused by a genetic predisposition. Birt-Hogg-Dube syndrome (BHD) is one of the hereditary renal cancer syndromes. As the histological subtype and clinical presentation in BHD are highly variable, this syndrome is easily missed. Lung cysts--mainly under the main carina--are reported to be present in over 90% of all BHD patients and might be an important clue in differentiating between sporadic RCC and BHD associated RCC. We conducted a retrospective study among patients diagnosed with sporadic RCC, wherein we retrospectively scored for the presence of lung cysts on thoracic CT. We performed FLCN mutation analysis in 8 RCC patients with at least one lung cysts under the carina. No mutations were identified. We compared the radiological findings in the FLCN negative patients to those in 4 known BHD patients and found multiple basal lung cysts were present significantly more frequent in FLCN mutation carriers and may be an indication for BHD syndrome in apparent sporadic RCC patients. PMID- 26603438 TI - Stress-shielding, growth and remodeling of pulmonary artery reinforced with copolymer scaffold and transposed into aortic position. AB - Ross operation, i.e., the use of autologous pulmonary artery to replace diseased aortic valve, has been recently at the center of a vivid debate regarding its unjust underuse in the surgical practice. Keystone of the procedure regards the use of an autologous biologically available graft which would preserve the anticoagulative and tissue homeostatic functions normally exerted by the native leaflets and would harmoniously integrate in the vascular system, allowing for progressive somatic growth of aortic structures. With this respect, recently, some of the authors have successfully pioneered a large animal model of transposition of pulmonary artery in systemic pressure load in order to reproduce the clinical scenario in which this procedure might be applied and allow for the development and testing of different devices or techniques to improve the pulmonary autograft (PA) performance, by testing a bioresorbable mesh for PA reinforcement. In the present work, to support and supplement the in vivo animal experimentation, a mathematical model is developed in order to simulate the biomechanical changes in pulmonary artery subjected to systemic pressure load and reinforced with a combination of resorbable and auxetic synthetic materials. The positive biological effects on vessel wall remodeling, the regional somatic growth phenomena and prevention of dilatative degeneration have been analyzed. The theoretical outcomes show that a virtuous biomechanical cooperation between biological and synthetic materials takes place, stress-shielding guiding the physiological arterialization of vessel walls, consequently determining the overall success of the autograft system. PMID- 26603439 TI - Upright Time and Sit-To-Stand Transition Progression After Total Hip Arthroplasty: An Inhospital Longitudinal Study. AB - BACKGROUND: Although early mobilization in hospital is a key element of post total hip arthroplasty rehabilitation, it is poorly documented. METHODS: To gain quantitative insight into inhospital mobilization, upright times and sit-to-stand transitions (STS) were measured using a thigh-mounted movement sensor in 44 participants (13 males and 31 females), age 50 to 82 years, in an observational, postsurgery, inhospital, longitudinal study. RESULTS: Some participants performed no activity in the first 24 hours after surgery. However, in the last 24 hours before discharge, participants performed a median of 40 (interquartile range [IQR], 15) STS and spent 134 minutes (IQR, 74 minutes) upright. Activity in rehabilitation constituted 19.4% (IQR, 15.8%) of STS and 13.3% (IQR, 5.5%) of upright time. Females spent longer in hospital (80 hours; IQR, 24) compared to males (54 hours; IQR, 26). CONCLUSION: Although there was considerable activity within rehabilitation periods, a large majority of STS and upright time occurred outside rehabilitation. Within the last 24 hours in hospital, all participants were upright for prolonged periods and completed numerous STS. PMID- 26603440 TI - Influence of the Medial Knee Structures on Valgus and Rotatory Stability in Total Knee Arthroplasty. AB - BACKGROUND: Precise biomechanical knowledge of individual components of the MCL is critical for proper MCL release during TKA. This study was to define the influences of the deep MCL and the POL on valgus and rotatory stability in TKA using cadaveric knees. METHODS: This study used six fresh-frozen cadaveric knees. All TKA procedures were performed using a cruciate-retaining TKA with a CT-free navigation system. We did a sequential sectioning on each knee, S1; femoral arthroplasty only, S2; medial half tibial resection with spacer, S3; anterior cruciate ligament cut, S4; tibial arthroplasty, S5; release of the dMCL, S6; release of the POL. The navigation system monitored motion after application of 10 N-m valgus loads and 5 N-m internal and external rotation torques to the tibia at 0 degrees , 20 degrees , 30 degrees , 60 degrees , and 90 degrees of knee flexion for each sequence. RESULTS: There were no significant differences in medial gaps. Internal rotation angles significantly increased after S2 at 0 degrees , 20 degrees , and 30 degrees , and after S6 at 90 degrees compared with those after S1. External rotation angles significantly increased after S3 at 0 degrees , S4 at 60 degrees , S5 at 0 degrees , 30 degrees and 90 degrees , and after S6 at 30 degrees , 60 degrees compared with those after S1. CONCLUSION: Significant increases of rotatory instability were seen on release of the dMCL, and then further increased after release of the POL. Surgical approach of retaining the dMCL and POL has a possibility to improve the outcome after primary TKA. PMID- 26603441 TI - Gene Cloning and Characterization of the Geobacillus thermoleovorans CCR11 Carboxylesterase CaesCCR11, a New Member of Family XV. AB - A gene encoding a carboxylesterase produced by Geobacillus thermoleovoras CCR11 was cloned in the pET-3b cloning vector, sequenced and expressed in Escherichia coli BL21(DE3). Gene sequence analysis revealed an open reading frame of 750 bp that encodes a polypeptide of 250 amino acid residues (27.3 kDa) named CaesCCR11. The enzyme showed its maximum activity at 50 degrees C and pH 5-8, with preference for C4 substrates, confirming its esterase nature. It displayed good resistance to temperature, pH, and the presence of organic solvents and detergents, that makes this enzyme biotechnologically applicable in the industries such as fine and oleo-chemicals, cosmetics, pharmaceuticals, organic synthesis, biodiesel production, detergents, and food industries. A 3D model of CaesCCR11 was predicted using the Bacillus sp. monoacyl glycerol lipase bMGL H 257 structure as template (PBD code 3RM3, 99 % residue identity with CaesCCR11). Based on its canonical alpha/beta hydrolase fold composed of 7 beta-strands and 6 alpha-helices, the alpha/beta architecture of the cap domain, the GLSTG pentapeptide, and the formation of distinctive salt bridges, we are proposing CaesCCR11 as a new member of family XV of lipolytic enzymes. PMID- 26603442 TI - Virus-Induced Gene Silencing in Cultivated Cotton (Gossypium spp.) Using Tobacco Rattle Virus. AB - The study described here has optimized the conditions for virus-induced gene silencing (VIGS) in three cultivated cotton species (Gossypium hirsutum, G. arboreum, and G. herbaceum) using a Tobacco rattle virus (TRV) vector. The system was used to silence the homolog of the Arabidopsis thaliana chloroplastos alterados 1 (AtCLA1) gene, involved in chloroplast development, in G. herbaceum, G. arboreum, and six commercial G. hirsutum cultivars. All plants inoculated with the TRV vector to silence CLA1 developed a typical albino phenotype indicative of silencing this gene. Although silencing in G. herbaceum and G. arboreum was complete, silencing efficiency differed for each G. hirsutum cultivar. Reverse transcriptase polymerase chain reaction (PCR) and real-time quantitative PCR showed a reduction in mRNA levels of the CLA1 homolog in all three species, with the highest efficiency (lowest CLA1 mRNA levels) in G. arboreum followed by G. herbaceum and G. hirsutum. The results indicate that TRV is a useful vector for VIGS in Gossypium species. However, selection of host cultivar is important. With the genome sequences of several cotton species recently becoming publicly available, this system has the potential to provide a very powerful tool for the rapid, large-scale reverse-genetic analysis of genes in Gossypium spp. PMID- 26603443 TI - Use of Cytotoxic Chemotherapy in Metastatic Breast Cancer: Putting Taxanes in Perspective. AB - Agents that target microtubule (MT) dynamics have been used extensively for the treatment of metastatic breast cancer (MBC). Among these agents are taxanes (solvent-based paclitaxel [sb-paclitaxel], docetaxel, and nab-paclitaxel) and non taxanes, such as eribulin and ixabepilone. Although these agents have been approved for the treatment of MBC, questions regarding the ideal agent, regimen (single agent vs. combination vs. sequential), and schedule still remain. This systematic review examined pivotal trials for taxanes, eribulin, and ixabepilone as well as first-line taxane trials in MBC. Only randomized trials that enrolled >= 100 patients were included. Publications on combination regimens with targeted agents were excluded unless they also included a comparison between nontargeted regimens. The studies were grouped into taxane versus taxane, sb-paclitaxel versus non-taxane, and docetaxel versus non-taxane regimens. In taxane versus taxane comparisons, the efficacy of sb-paclitaxel and docetaxel appeared similar, nab-paclitaxel every 3 weeks (q3w) appeared superior to sb-paclitaxel q3w, and weekly nab-paclitaxel appeared superior to docetaxel. In general, taxane regimens demonstrated higher overall response rates (ORRs) versus non-taxane regimens; however, only 2 trials demonstrated longer overall survival (OS) for taxane regimens. Taxanes will likely continue to be used in earlier lines of therapy, whereas eribulin and ixabepilone may be more appropriate for later lines of treatment. Ongoing research may identify biomarkers that could help in selecting the appropriate MT-targeted agent for a given patient. PMID- 26603444 TI - Antineutrophil cytoplasmic antibodies (ANCA)-negative vasculitis in a patient with alpha-1-antitrypsin deficiency. PMID- 26603445 TI - Graphical displays of patient-reported outcomes (PRO) for use in clinical practice: What makes a pro picture worth a thousand words? AB - Patient-reported outcomes (PROs) report patients' assessments of the impact of a health condition and its treatment, and can promote patient-centered care. OBJECTIVES: To address the effectiveness of graphic display of PRO data in clinical practice by reviewing existing literature, and current recommendations, regarding graphic presentations of PROs. METHODS: We performed an integrated literature review to identify themes and emerging principles guiding effective graphic display of PRO data. The findings were placed in the context of the literature informing graphical presentation of other clinical data. RESULTS: Although a large body of literature informs graphical presentation of clinical data, only nine empirical studies addressed presentation of PROs. Four major themes emerged: many patients and most clinicians can accurately interpret some PRO graphs; interpretation accuracy, personal preference, and perceived level of understanding are sometimes discordant; patient age and education may predict PRO graph comprehension; patients tend to prefer simpler graphs than do clinicians. CONCLUSIONS: Little empirical research specifically addresses graphic representation of PRO data. A single format may not work optimally for both clinicians and patients. PRACTICE IMPLICATIONS: Patients and clinicians may or may not comprehend PRO data when graphically presented. Further research to determine best practices for presenting PROs optimally is needed. PMID- 26603446 TI - Knowledge and values for cancer screening decisions: Results from a national survey. AB - BACKGROUND: Guidelines recommend shared decision making (SDM) for cancer screening decisions. SDM requires providers to ensure that patients are informed about screening issues and to support decisions that are concordant with patient values. We evaluated decision-quality factors for breast, colorectal, and prostate cancer screening decisions. METHODS: We conducted a national, population based Internet survey of adults aged 40+ to characterize perceptions about about cancer screening, the importance of information sources, cancer screening knowledge, values and preferences for screening, and the most influential drivers of decisions. RESULTS: Among 1452 participants who completed the survey, the mean age was 60, and 94% were insured. Most participants reported feeling well informed about cancer screening, though only 21% reported feeling extremely well informed. Most participants correctly answered about 50% of the knowledge questions, with the majority markedly overestimating lifetime risk of cancer diagnoses and mortality. Participants rated health care providers as the most important source of information. CONCLUSION: Although respondents considered themselves well informed about cancer they performed poorly on knowledge questions. This discordance suggests the potential for poor-quality decision making. PRACTICE IMPLICATIONS: To improve the quality of decision making, providers need training to utilize decision support tools and time to carry out SDM. PMID- 26603449 TI - The lymphocyte secretome from young adults enhances skeletal muscle proliferation and migration, but effects are attenuated in the secretome of older adults. AB - Older people experience skeletal muscle wasting, in part due to impaired proliferative capacity of quiescent skeletal muscle satellite cells which can be reversed by exposure to young blood. To investigate the role of immune cells in muscle regeneration, we isolated lymphocytes from whole blood of young and older healthy volunteers and cultured them with, or without, anti-CD3/CD28 activators to induce release of cytokines, interleukins, and growth factors into the media. The secreted proteins were collected to prepare a conditioned media, which was subsequently used to culture C2C12 myoblasts. The conditioned media from the activated young lymphocytes increased the rate of proliferation of myoblasts by around threefold (P < 0.005) and caused an approximate fourfold (P < 0.005) increase in migration compared with nonactivated lymphocyte control media. These responses were characterized by minimal myotube formation (2%), low fusion index (5%), low myosin heavy chain content, and substantial migration. In contrast, myoblasts treated with conditioned media from activated old lymphocytes exhibited a high degree of differentiation, and multi-nucleated myotube formation that was comparable to control conditions, thus showing no effect on proliferation or migration of myoblasts. These results indicate that secreted proteins from lymphocytes of young people enhance the muscle cell proliferation and migration, whereas secreted proteins from lymphocytes of older people may contribute to the attenuated skeletal muscle satellite cell proliferation and migration. PMID- 26603450 TI - Relationships between inflammatory cytokine and cortisol responses in firefighters exposed to simulated wildfire suppression work and sleep restriction. AB - The interplay between inflammatory and cortisol responses modulates an appropriate response to a stressor. Exposure to severe stressors, however, may alter the actions and relationships of these responses and contribute to negative health outcomes. Physical work and sleep restriction are two stressors faced by wildland firefighters, yet their influence on the relationship between inflammatory and cortisol responses is unknown. The aim of the present study was to quantify the relationship between the cytokine and cortisol responses to sleep restriction while performing simulated physical wildfire suppression work. Firefighters completed 3 days of simulated physical firefighting work separated by either an 8-h (Control condition; n = 18) or 4-h sleep (Sleep restriction condition; n = 17) opportunity on each of the two nights. Salivary cortisol and inflammatory cytokines (IL-6, IL-8, IL-1beta, TNF-alpha, IL-4, and IL-10) were measured throughout each day. An increase in morning IL-6 was related to a rise (6.2%, P = 0.043) in evening cortisol among firefighters in the sleep restriction condition. Higher morning IL-6 levels were related to increased (5.3%, P = 0.048) daily cortisol levels, but this relationship was not different between conditions. Less pronounced relationships were demonstrated between TNF-alpha, IL 10, IL-4, and cortisol independent of the sleep opportunity, but relationships did not persist after adjusting for demographic factors and other cytokines. These findings quantify the relationship between cytokine and cortisol responses among wildland firefighters exposed to simulated occupational stressors. Potential disturbances to the IL-6 and cortisol relationship among sleep restricted firefighters' supports further investigations into the negative health effects related to possible imbalances between these systems. PMID- 26603451 TI - Chloride-hydrogen antiporters ClC-3 and ClC-5 drive osteoblast mineralization and regulate fine-structure bone patterning in vitro. AB - Osteoblasts form an epithelium-like layer with tight junctions separating bone matrix from extracellular fluid. During mineral deposition, calcium and phosphate precipitation in hydroxyapatite liberates 0.8 mole of H(+) per mole Ca(+2). Thus, acid export is needed for mineral formation. We examined ion transport supporting osteoblast vectorial mineral deposition. Previously we established that Na/H exchangers 1 and 6 are highly expressed at secretory osteoblast basolateral surfaces and neutralize massive acid loads. The Na/H exchanger regulatory factor 1 (NHERF1), a pdz-organizing protein, occurs at mineralizing osteoblast basolateral surfaces. We hypothesized that high-capacity proton transport from matrix into osteoblast cytosol must exist to support acid transcytosis for mineral deposition. Gene screening in mineralizing osteoblasts showed dramatic expression of chloride-proton antiporters ClC-3 and ClC-5. Antibody localization showed that ClC-3 and ClC-5 occur at the apical secretory surface facing the bone matrix and in membranes of buried osteocytes. Surprisingly, the Clcn3(-/-) mouse has only mildly disordered mineralization. However, Clcn3(-/-) osteoblasts have large compensatory increases in ClC-5 expression. Clcn3(-/-) osteoblasts mineralize in vitro in a striking and novel trabecular pattern; wild-type osteoblasts form bone nodules. In mesenchymal stem cells from Clcn3(-/-) mice, lentiviral ClC-5 shRNA created Clcn3(-/-), ClC-5 knockdown cells, validated by western blot and PCR. Osteoblasts from these cells produced no mineral under conditions where wild-type or Clcn3(-/-) cells mineralize well. We conclude that regulated acid export, mediated by chloride-proton exchange, is essential to drive normal bone mineralization, and that CLC transporters also regulate fine patterning of bone. PMID- 26603453 TI - Exercise training is an effective alternative to estrogen supplementation for improving glucose homeostasis in ovariectomized rats. AB - The irreversible loss of estrogen (specifically 17-beta-estradiol; E2) compromises whole-body glucose tolerance in women. Hormone replacement therapy (HRT) is frequently prescribed to treat estrogen deficiency, but has several deleterious side effects. Exercise has been proposed as an HRT substitute, however, their relative abilities to treat glucose intolerance are unknown. Thirty ovariectomized (OVX) and 20 SHAM (control) rats underwent glucose tolerance tests (GTT) 10 weeks post surgery. Area under the curve (AUC) for OVX rats was 60% greater than SHAM controls (P = 0.0005). Rats were then randomly assigned to the following treatment groups: SHAM sedentary (sed) or exercise (ex; 60 min, 5*/weeks), OVX sed, ex, or E2 (28 MUg/kg bw/day) for 4 weeks. OVX ex rats experienced a ~45% improvement in AUC relative to OVX sed rats, whereas OVX E2 underwent a partial reduction (17%; P = 0.08). Maximal insulin-stimulated glucose uptake in soleus and EDL was not impaired in OVX rats, or augmented with exercise or E2. Akt phosphorylation did not differ in soleus, EDL, or liver of any group. However, OVX ex and OVX E2 experienced greater increases in p-Akt Ser473 in VAT and SQ tissues compared with SHAM and OVX sed groups. Mitochondrial markers CS, COXIV, and core1 were increased in soleus posttraining in OVX ex rats. The content of COXIV was reduced by 52% and 61% in SQ of OVX sed and E2 rats, compared to SHAM controls, but fully restored in OVX ex rats. In summary, exercise restores glucose tolerance in OVX rats more effectively than E2. This is not reflected by alterations in muscle maximal insulin response, but increased insulin signaling in adipose depots may underlie whole-body improvements. PMID- 26603454 TI - Antioxidant resveratrol restores renal sodium transport regulation in SHR. AB - Previously we have shown that in spontaneously hypertensive rats (SHR) renal angiotensin (Ang) II receptor (AT1R) upregulation leads to overstimulation of Na/K-ATPase by Ang II. There are reports that antioxidants can reduce oxidative stress and blood pressure (BP) in SHR, however the effect of these compounds on AT1R function remains to be determined. Therefore, we hypothesized that polyphenol antioxidant resveratrol would mitigate oxidative stress, normalize renal AT1R signaling, and reduce BP in SHR. SHR and wistar-kyoto (WKY) rats were treated with resveratrol for 8 weeks. Untreated SHR exhibited oxidative stress and enhanced renal proximal tubular Ang II-induced G-protein activation and Na/K ATPase stimulation. Treatment of SHR with resveratrol mitigated oxidative stress, reduced BP, and normalized renal AT1R signaling. In SHR, nuclear expression of transcription factor NF-kappaB was increased while expression of Nrf2 was reduced. SHR also exhibited a significant decrease in renal antioxidant capacity and activities of phase II antioxidant enzymes. Resveratrol treatment of SHR abolished renal NF-kappaB activation, restored Nrf2-phase II antioxidant signaling and Ang II-mediated Na/K-ATPase regulation. These data show that in SHR, oxidative stress via activation of NF-kappaB upregulates AT1R-G-protein signaling resulting in overstimulation Na/K-ATPase which contributes to hypertension. Resveratrol, via Nrf2, activates phase II antioxidant enzymes, mitigates oxidative stress, normalizes AT1R-G-protein signaling and Na/K-ATPase regulation, and decreases BP in SHR. PMID- 26603452 TI - Cytoskeletal changes induced by allosteric modulators of calcium-sensing receptor in esophageal epithelial cells. AB - The calcium-sensing receptor (CaSR), a G-protein-coupled receptor, plays a role in glandular and fluid secretion in the gastrointestinal tract, and regulates differentiation and proliferation of epithelial cells. We examined the expression of CaSR in normal and pathological conditions of human esophagus and investigated the effect of a CaSR agonist, cinacalcet (CCT), and antagonist, calhex (CHX), on cell growth and cell-cell junctional proteins in primary cultures of porcine stratified squamous esophageal epithelium. We used immunohistochemistry and Western analysis to monitor expression of CaSR and cell-cell adhesion molecules, and MTT assay to monitor cell proliferation in cultured esophageal cells. CCT treatment significantly reduced proliferation, changed the cell shape from polygonal to spindle-like, and caused redistribution of E-cadherin and beta catenin from the cell membrane to the cytoplasm. Furthermore, it reduced expression of beta-catenin by 35% (P < 0.02) and increased expression of a proteolysis cleavage fragment of E-cadherin, Ecad/CFT2, by 2.3 folds (P < 0.01). On the other hand, CHX treatment enhanced cell proliferation by 27% (P < 0.01), increased the expression of p120-catenin by 24% (P < 0.04), and of Rho, a GTPase involved in cytoskeleton remodeling, by 18% (P < 0.03). In conclusion, CaSR is expressed in normal esophagus as well as in Barrett's, esophageal adenocarcinoma, squamous cell carcinoma, and eosinophilic esophagitis. Long-term activation of CaSR with CCT disrupted the cadherin-catenin complex, induced cytoskeletal remodeling, actin fiber formation, and redistribution of CaSR to the nuclear area. These changes indicate a significant and complex role of CaSR in epithelial remodeling and barrier function of esophageal cells. PMID- 26603455 TI - Comparative adaptations in oxidative and glycolytic muscle fibers in a low voluntary wheel running rat model performing three levels of physical activity. AB - A unique polygenic model of rat physical activity has been recently developed where rats were selected for the trait of low voluntary wheel running. We utilized this model to identify differences in soleus and plantaris muscles of sedentary low voluntary wheel running rats and physically active low voluntary wheel running rats exposed to moderate amounts of treadmill training. Three groups of 28-day-old male Wistar rats were used: (1) rats without a running wheel (SEDENTARY, n = 7), (2) rats housed with a running wheel (WHEEL, n = 7), and (3) rats housed with a running wheel and exercised on the treadmill (5 days/week for 20 min/day at 15.0 m/min) (WHEEL + TREADMILL, n = 7). Animals were euthanized 5 weeks after the start of the experiment and the soleus and plantaris muscles were excised and used for analyses. Increases in skeletal muscle gene expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha and fibronectin type III domain-containing protein 5 in WHEEL + TREADMILL group were observed. Also, WHEEL + TREADMILL had higher protein levels of superoxide dismutase 2 and decreased levels of oxidative damage. Our data demonstrate that the addition of treadmill training induces beneficial muscular adaptations compared to animals with wheel access alone. Furthermore, our data expand our understanding of differential muscular adaptations in response to exercise in mitochondrial, antioxidant, and metabolic markers. PMID- 26603456 TI - MicroRNA-208b progressively declines after spinal cord injury in humans and is inversely related to myostatin expression. AB - The effects of long-term physical inactivity on the expression of microRNAs involved in the regulation of skeletal muscle mass in humans are largely unknown. MicroRNAs are short, noncoding RNAs that fine-tune target expression through mRNA degradation or by inhibiting protein translation. Intronic to the slow, type I, muscle fiber type genes MYH7 and MYH7b, microRNA-208b and microRNA-499-5p are thought to fine-tune the expression of genes important for muscle growth, such as myostatin. Spinal cord injured humans are characterized by both skeletal muscle atrophy and transformation toward fast-twitch, type II fibers. We determined the expression of microRNA-208b, microRNA-499-5p, and myostatin in human skeletal muscle after complete cervical spinal cord injury. We also determined whether these microRNAs altered myostatin expression in rodent skeletal muscle. A progressive decline in skeletal muscle microRNA-208b and microRNA-499-5p expression occurred in humans during the first year after spinal cord injury and with long-standing spinal cord injury. Expression of myostatin was inversely correlated with microRNA-208b and microRNA-499-5p in human skeletal muscle after spinal cord injury. Overexpression of microRNA-208b in intact mouse skeletal muscle decreased myostatin expression, whereas microRNA-499-5p was without effect. In conclusion, we provide evidence for an inverse relationship between expression of microRNA-208b and its previously validated target myostatin in humans with severe skeletal muscle atrophy. Moreover, we provide direct evidence that microRNA-208b overexpression decreases myostatin gene expression in intact rodent muscle. Our results implicate that microRNA-208b modulates myostatin expression and this may play a role in the regulation of skeletal muscle mass following spinal cord injury. PMID- 26603457 TI - Effect of imperceptible vibratory noise applied to wrist skin on fingertip touch evoked potentials - an EEG study. AB - Random vibration applied to skin can change the sense of touch. Specifically, low amplitude white-noise vibration can improve fingertip touch perception. In fact, fingertip touch sensation can improve even when imperceptible random vibration is applied to other remote upper extremity areas such as wrist, dorsum of the hand, or forearm. As such, vibration can be used to manipulate sensory feedback and improve dexterity, particularly during neurological rehabilitation. Nonetheless, the neurological bases for remote vibration enhanced sensory feedback are yet poorly understood. This study examined how imperceptible random vibration applied to the wrist changes cortical activity for fingertip sensation. We measured somatosensory evoked potentials to assess peak-to-peak response to light touch of the index fingertip with applied wrist vibration versus without. We observed increased peak-to-peak somatosensory evoked potentials with wrist vibration, especially with increased amplitude of the later component for the somatosensory, motor, and premotor cortex with wrist vibration. These findings corroborate an enhanced cortical-level sensory response motivated by vibration. It is possible that the cortical modulation observed here is the result of the establishment of transient networks for improved perception. PMID- 26603458 TI - Effects of donor age and proliferative aging on the phenotype stability of rat aortic smooth muscle cells. AB - Age-related effects of the vascular wall have been associated with several hemodynamic dysfunctions, including medial vascular calcification. Vascular aging has been traditionally addressed using proliferative senescence of vascular smooth muscle cells (VSMC) in vitro, which induces osteoblastic transition and favors calcification in vitro. In this work, we have analyzed the relationship between organismal aging and proliferative senescence by comparing the proliferative aging of VSMC obtained from young, mature, and old rats (2-, 12-, and 24-month cell lines [CL], respectively). VSMC proliferated to more than 100 cumulative population doublings (CPD) without evidence of proliferative senescence, most likely as a consequence of telomerase induction. The apoptosis rate increased with CPD in all three CL, but the oxidation status of the cells was not modified. The magnitude of all gene expression changes caused by CPD was higher than the magnitude of the changes caused by donor age: the expressions of VSMC markers alpha-actin and SM22alpha decreased, while the expressions of transcription factors Msx2 and Runx2 and of bone morphogenetic protein-2 increased. Treatment of the cells with 2 mmol/L Pi revealed that the intensity of the effect of CPD on calcium deposition was greater than the effect of donor age. In conclusion, the proliferative lifespan of VSMC magnifies the effect of donor age on the osteoblastic transition of VSMC, therefore suggesting that in vivo vascular aging changes can be less dramatic than what is shown by in vitro aging. PMID- 26603459 TI - Role of brain-derived neurotrophic factor in the excitatory-inhibitory imbalance during the critical period of postnatal respiratory development in the rat. AB - The critical period of respiratory development in rats is a narrow window toward the end of the second postnatal week (P12-13), when abrupt neurochemical, electrophysiological, and ventilatory changes occur, when inhibition dominates over excitation, and when the animals' response to hypoxia is the weakest. The goal of this study was to further test our hypothesis that a major mechanism underlying the synaptic imbalance during the critical period is a reduced expression of brain-derived neurotrophic factor (BDNF) and its TrkB receptors. Our aims were to determine (1) that the inhibitory dominance observed in hypoglossal motoneurons during the critical period was also demonstrable in a key respiratory chemosensor, NTSVL; (2) if in vivo application of a TrkB agonist, 7,8 DHF, would prevent, but a TrkB antagonist, ANA-12, would accentuate the synaptic imbalance; and (3) if hypoxia would also heighten the imbalance. Our results indicate that (1) the synaptic imbalance was evident in the NTSVL during the critical period; (2) intraperitoneal injections of 7,8-DHF prevented the synaptic imbalance during the critical period, whereas ANA-12 in vivo accentuated such an imbalance; and (3) acute hypoxia induced the weakest response in both the amplitude and frequency of sEPSCs during the critical period, but it increased the frequency of sIPSCs during the critical period. Thus, our findings are consistent with and strengthen our hypothesis that BDNF and TrkB play a significant role in inducing a synaptic imbalance during the critical period of respiratory development in the rat. PMID- 26603460 TI - Characterization of L-type calcium channel activity in atrioventricular nodal myocytes from rats with streptozotocin-induced Diabetes mellitus. AB - Cardiovascular complications are common in patients with Diabetes mellitus (DM). In addition to changes in cardiac muscle inotropy, electrical abnormalities are also commonly observed in these patients. We have previously shown that spontaneous cellular electrical activity is altered in atrioventricular nodal (AVN) myocytes, isolated from the streptozotocin (STZ) rat model of type-1 DM. In this study, utilizing the same model, we have characterized the changes in L-type calcium channel activity in single AVN myocytes. Ionic currents were recorded from AVN myocytes isolated from the hearts of control rats and from those with STZ-induced diabetes. Patch-clamp recordings were used to assess the changes in cellular electrical activity in individual myocytes. Type-1 DM significantly altered the cellular characteristics of L-type calcium current. A reduction in peak ICaL density was observed, with no corresponding changes in the activation parameters of the current. L-type calcium channel current also exhibited faster time-dependent inactivation in AVN myocytes from diabetic rats. A negative shift in the voltage dependence of inactivation was also evident, and a slowing of restitution parameters. These findings demonstrate that experimentally induced type-1 DM significantly alters AVN L-type calcium channel cellular electrophysiology. These changes in ion channel activity may contribute to the abnormalities in cardiac electrical function that are associated with high mortality levels in patients with DM. PMID- 26603461 TI - Placental ischemia increases seizure susceptibility and cerebrospinal fluid cytokines. AB - Eclampsia is diagnosed in preeclamptic patients who develop unexplained seizures and/or coma during pregnancy or postpartum. Eclampsia is one of the leading causes of maternal and infant morbidity and mortality, accounting for ~13% of maternal deaths worldwide. Little is known about the mechanisms contributing to the pathophysiology of eclampsia, partly due to the lack of suitable animal models. This study tested the hypothesis that placental ischemia, induced by reducing utero-placental perfusion, increases susceptibility to seizures, cerebrospinal fluid (CSF) inflammation, and neurokinin B (NKB) expression in brain and plasma. Pentylenetetrazol (PTZ), a pro-convulsive drug, was injected into pregnant and placental ischemic rats (40 mg/kg, i.p.) on gestational day 19 followed by video monitoring for 30 min. Seizure scoring was blindly conducted. Placental ischemia hastened the onset of seizures compared to pregnant controls but had no effect on seizure duration. Placental ischemia increased CSF levels of IL-2, IL-17, IL-18 and eotaxin (CCL11), had no effect on plasma NKB; however, PTZ increased plasma NKB in both pregnant and placental ischemic rats. NKB was strongly correlated with latency to seizure in normal pregnant rats (R(2) = 0.88 vs. 0.02 in placental ischemic rats). Lastly, NKB decreased in the anterior cerebrum in response to placental ischemia and PTZ treatment but was unchanged in the posterior cerebrum. These data demonstrate that placental ischemia is associated with increased susceptibility to seizures and CSF inflammation; thus provides an excellent model for elucidating mechanisms of eclampsia-like symptoms. Further studies are required to determine the role of CSF cytokines/chemokines in mediating increased seizure susceptibility. PMID- 26603462 TI - HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma. AB - The diagnosis and treatment of hepatocellular carcinoma (HCC) underwent a huge advancement in the last years. Recently, microRNAs (miRNAs) have been also studied to provide a new tool for early diagnosis of high risk patients, for prognostic classification to identify those patients who benefit cancer treatment and for predictive definition to select the right targeted drug. In this review we revised all the available data obtained to explore the role of miRNAs in HCC. This analysis led to identification of miRNAs which could gain a diagnostic, prognostic or predictive role. The results of studies on miRNAs involved in HCC are initial and far from providing scientific evidences to translate into clinical practice. We propose a classification of these miRNAs, that we could name HepatomiRNoma as a whole. Anyway prospective studies have to be designed to clarify the real clinical impact of this new tool. PMID- 26603463 TI - Somatic alterations of CDKN1B are associated with small bowel neuroendocrine tumors. AB - CDKN1B, a cyclin-dependent kinase inhibitor associated with G1 arrest, was recently proposed as an important tumor suppressor gene in small bowel neuroendocrine tumors (SBNETs). The rate of frameshift mutations in SBNET primaries are reportedly 7.4%, and hemizygous deletions are 6.7%. We set out to confirm the role of CDKN1B mutations and copy number variants (CNVs) in primary SBNETs, and whether these are also found in pancreatic neuroendocrine tumors (PNETs). Genomic DNA was isolated from 90 primary SBNETs and 67 PNETs. Coding exons of CDKN1B were amplified by PCR and sequenced. CNV analysis was performed by quantitative PCR, p27 expression was evaluated using immunohistochemistry. In SBNETS, three frameshifts, one missense mutation, and three CNVs were observed. The total rate of CDKN1B alterations was 7.0% (6 of 86; 95% confidence interval (CI) 3.2-4.4%). The frameshift rate was 3.5% (95% CI 1.1-9.8%). One SBNET patient had a hemizygous deletion of CDKN1B, and two patients had duplications (3.4%; 95% CI -0.41-7.2%). One PNET patient had a duplication, and two patients had hemizygous deletions (4.8%; 95% CI -0.44-10%). Alterations of cell-cycle control due to alterations in CDKN1B may be one mechanism by which SBNETs develop, which could have implications for new treatment modalities. PMID- 26603465 TI - Home cooking trends and dietary illness: nutritional compliance of recipes in a Swedish food magazine 1970-2010. AB - AIMS: To investigate the trends in nutritional compliance of recipes from a Swedish food magazine to offer a perspective on the effects of home cooking on public health. METHODS: The nutritional content of 654 recipes from magazine issues published in 1970, 1980, 2000, and 2010 were collected. The recipes were analyzed for macronutrient energy contribution, sodium content, and composition. RESULTS: The recipes were in poor agreement with nutritional recommendations (excessive fat, protein, and sodium and insufficient carbohydrate and fiber content). Significant changes between 1970 and 2010 were the increased calorific contribution of fat (from 38 to 46%) and the reduced contribution of proteins (from 27 to 21%). The calorific contribution from spreads, cheese, bread, and fruit and vegetables have increased significantly, whereas the contribution from meat has decreased significantly. CONCLUSIONS: The poor nutritional compliance identified in this work indicates that consumers using the recipes as norms for home cooking risk following an unhealthy diet. This might have adverse effects on public health. However, the recipes have not become less compliant over time and therefore the data do not show an adverse trend in these norms. PMID- 26603464 TI - Quantifying the Impact of Scenic Environments on Health. AB - Few people would deny an intuitive sense of increased wellbeing when spending time in beautiful locations. Here, we ask: can we quantify the relationship between environmental aesthetics and human health? We draw on data from Scenic-Or Not, a website that crowdsources ratings of "scenicness" for geotagged photographs across Great Britain, in combination with data on citizen-reported health from the Census for England and Wales. We find that inhabitants of more scenic environments report better health, across urban, suburban and rural areas, even when taking core socioeconomic indicators of deprivation into account, such as income, employment and access to services. Our results provide evidence in line with the striking hypothesis that the aesthetics of the environment may have quantifiable consequences for our wellbeing. PMID- 26603466 TI - Abnormal early brain responses during visual search are evident in schizophrenia but not bipolar affective disorder. AB - People with schizophrenia show deficits in processing visual stimuli but neural abnormalities underlying the deficits are unclear and it is unknown whether such functional brain abnormalities are present in other severe mental disorders or in individuals who carry genetic liability for schizophrenia. To better characterize brain responses underlying visual search deficits and test their specificity to schizophrenia we gathered behavioral and electrophysiological responses during visual search (i.e., Span of Apprehension [SOA] task) from 38 people with schizophrenia, 31 people with bipolar disorder, 58 biological relatives of people with schizophrenia, 37 biological relatives of people with bipolar disorder, and 65 non-psychiatric control participants. Through subtracting neural responses associated with purely sensory aspects of the stimuli we found that people with schizophrenia exhibited reduced early posterior task-related neural responses (i.e., Span Endogenous Negativity [SEN]) while other groups showed normative responses. People with schizophrenia exhibited longer reaction times than controls during visual search but nearly identical accuracy. Those individuals with schizophrenia who had larger SENs performed more efficiently (i.e., shorter reaction times) on the SOA task suggesting that modulation of early visual cortical responses facilitated their visual search. People with schizophrenia also exhibited a diminished P300 response compared to other groups. Unaffected first-degree relatives of people with bipolar disorder and schizophrenia showed an amplified N1 response over posterior brain regions in comparison to other groups. Diminished early posterior brain responses are associated with impaired visual search in schizophrenia and appear to be specifically associated with the neuropathology of schizophrenia. PMID- 26603467 TI - Cortical thickness and low insight into symptoms in enduring schizophrenia. AB - Poor insight is a common, multidimensional phenomenon in patients with schizophrenia, associated with poorer outcomes and treatment non-adherence. Yet scant research has investigated the neuronal correlates of insight into symptoms (IS), a dimension of insight that may be particularly significant in enduring schizophrenia. Sixty-six patients with enduring schizophrenia (duration >4years) and 33 healthy controls completed MRI scanning and IQ, depression, and anxiety assessments. The Scale to Assess Insight-Expanded (SAI-E) measured insight into patients' four most prominent symptoms and patients were classified into two groups: low IS (0-2; n=33), and high IS (>2; n=33). We evaluated the association between cortical thickness (CT) and insight into symptoms using two methods: (1) a between-patients region-of-interest analysis in the insula, superior temporal gyrus (STG) and frontal lobe; and (2) a whole-brain exploratory regression between patient and controls. Brain regions were segmented using a neuroanatomical atlas and vertex-wise CT analyses were conducted with CIVET, covaried for age and sex. ROI analysis revealed thinner insula cortex in patients with low IS (p<0.05, surviving FDR correction). Patients with low IS also showed significantly thinner right insula, STG, and parahippocampal cortex compared to healthy controls (p<0.05, surviving FDR correction). Regions of observed CT reductions have been hypothesized to subserve self-monitoring, error awareness, and ability to identify hallucinations. Results highlight an important association between right insula abnormalities and impaired IS in schizophrenia. The diverse clinical presentation of patients further suggests an independent relationship between symptomology and insight-related differences in CT that has been previously unexplored in enduring schizophrenia. PMID- 26603468 TI - BDNF polymorphisms are associated with schizophrenia onset and positive symptoms. AB - Numerous studies have showed that brain-derived neurotrophic factor (BDNF) may be involved in the pathogenesis and pathophysiology of schizophrenia. The purposes of this study were to investigate the potential association of BDNF gene polymorphisms with susceptibility to schizophrenia and the psychopathological symptoms in patients with schizophrenia in a Han Chinese population. Four polymorphisms (rs6265, rs12273539, rs10835210 and rs2030324) of the BDNF gene were analyzed in a case-control study of 1887 Han Chinese individuals (844 patients and 1043 controls). We assessed 825 patients for psychopathology using the Positive and Negative Syndrome Scale. In single marker analyses the BDNF rs10835210 mutant A allele was significantly associated with schizophrenia. Haplotype analyses revealed higher frequencies of haplotypes containing the mutant A allele of the rs10835210 in schizophrenia than controls. We also found that this polymorphism rs10835210 was associated with positive symptoms, and the patients carrying the mutational allele A showed more positive symptoms. These findings suggest the role of these BDNF gene variants in both susceptibility to schizophrenia and in clinical symptom severity. PMID- 26603469 TI - Photochemically re-bridging disulfide bonds and the discovery of a thiomaleimide mediated photodecarboxylation of C-terminal cysteines. AB - Described in this work is a novel method for photochemically manipulating peptides and proteins via the installation of cysteine-selective photoactive tags. Thiomaleimides, generated simply by the addition of bromomaleimides to reduced disulfide bonds, undergo [2 + 2] photocycloadditions to reconnect the crosslink between the two cysteine residues. This methodology is demonstrated to enable photoactivation of a peptide by macrocyclisation, and reconnection of the heavy and light chains in an antibody fragment to form thiol stable conjugates. Finally we report on an intriguing thiomaleimide mediated photochemical decarboxylation of C-terminal cysteines, discovered during this study. PMID- 26603470 TI - Different ossification patterns of intermuscular bones in fish with different swimming modes. AB - Intermuscular bones are found in the myosepta in teleosts. However, there is very little information on the development and ossification of these intermuscular bones. In this study, we performed an in-depth investigation of the ossification process during development in zebrafish (Danio rerio) and Japanese eel (Anguilla japonica). In Japanese eel, a typical anguilliform swimmer, the intermuscular bones ossified predominantly from the anterior to the posterior. By contrast, in the zebrafish, a sub-carangiform or carangiform swimmer, the intermuscular bones ossified predominantly from the posterior to the anterior regions of the fish. Furthermore, tail amputation affected the ossification of the intermuscular bones. The length of the intermuscular bones in the posterior area became significantly shorter in tail-amputated zebrafish and Japanese eels, and both had less active and lower swimming speeds; this indicates that swimming might induce the ossification of the intermuscular bones. Moreover, when a greater length of tail was amputated in the zebrafish, the intermuscular bones became even shorter. Tail amputation affected the length and ossification of intermuscular bones in the anterior part of the fish, close to the head, differently between the two fish: they became significantly shorter in the zebrafish, but did not in the Japanese eel. This might be because tail amputation did not significantly affect the undulations in the anterior of the Japanese eel, especially near the head. This study shows that the ossification of intermuscular bones might be induced through mechanical force loadings that are produced by swimming. PMID- 26603471 TI - The invisible fish: hydrodynamic constraints for predator-prey interaction in fossil fish Saurichthys compared to recent actinopterygians. AB - Recent pike-like predatory fishes attack prey animals by a quick strike out of rest or slow movement. This fast-start behaviour includes a preparatory, a propulsive and a final phase, and the latter is crucial for the success of the attack. To prevent prey from escape, predators tend to minimise the duration of the interaction and the disturbance caused to surrounding water in order to not be detected by the prey's lateral line sensory system. We compared the hydrodynamic properties of the earliest fossil representative of the pike-like morphotype, the Triassic actinopterygian Saurichthys, with several recent pike like predators by means of computational fluid dynamics (CFD). Rainbow trout has been used as a control example of a fish with a generalist body shape. Our results show that flow disturbance produced by Saurichthys was low and similar to that of the recent forms Belone and Lepisosteus, thus indicative of an effective ambush predator. Drag coefficients are low for all these fishes, but also for trout, which is a good swimmer over longer distances but generates considerable disturbance of flow. Second-highest flow disturbance values are calculated for Esox, which compensates the large disturbance with its extremely high acceleration performance (i.e. attacks at high speeds) and the derived teleostean protrusible mouth that allows prey catching from longer distances compared to the other fishes. We show CFD modelling to be a useful tool for palaeobiological reconstruction of fossil fishes, as it allows quantification of impacts of body morphology on a hypothesised lifestyle. PMID- 26603472 TI - S phase block following MEC1ATR inactivation occurs without severe dNTP depletion. AB - Inactivation of Mec1, the budding yeast ATR, results in a permanent S phase arrest followed by chromosome breakage and cell death during G2/M. The S phase arrest is proposed to stem from a defect in Mec1-mediated degradation of Sml1, a conserved inhibitor of ribonucleotide reductase (RNR), causing a severe depletion in cellular dNTP pools. Here, the casual link between the S phase arrest, Sml1, and dNTP-levels is examined using a temperature sensitive mec1 mutant. In addition to S phase arrest, thermal inactivation of Mec1 leads to constitutively high levels of Sml1 and an S phase arrest. Expression of a novel suppressor, GIS2, a conserved mRNA binding zinc finger protein, rescues the arrest without down-regulating Sml1 levels. The dNTP pool in mec1 is reduced by ~17% and GIS2 expression restores it, but only partially, to ~93% of a control. We infer that the permanent S phase block following Mec1 inactivation can be uncoupled from its role in Sml1 down-regulation. Furthermore, unexpectedly modest effects of mec1 and GIS2 on dNTP levels suggest that the S phase arrest is unlikely to result from a severe depletion of dNTP pool as assumed, but a heightened sensitivity to small changes in its availability. PMID- 26603473 TI - The primary cilium is a self-adaptable, integrating nexus for mechanical stimuli and cellular signaling. AB - Mechanosensation is crucial for cells to sense and respond to mechanical signals within their local environment. While adaptation allows a sensor to be conditioned by stimuli within the environment and enables its operation in a wide range of stimuli intensities, the mechanisms behind adaptation remain controversial in even the most extensively studied mechanosensor, bacterial mechanosensitive channels. Primary cilia are ubiquitous sensory organelles. They have emerged as mechanosensors across diverse tissues, including kidney, liver and the embryonic node, and deflect with mechanical stimuli. Here, we show that both mechanical and chemical stimuli can alter cilium stiffness. We found that exposure to flow stiffens the cilium, which deflects less in response to subsequent exposures to flow. We also found that through a process involving acetylation, the cell can biochemically regulate cilium stiffness. Finally, we show that this altered stiffness directly affects the responsiveness of the cell to mechanical signals. These results demonstrate a potential mechanism through which the cell can regulate its mechanosensing apparatus. PMID- 26603474 TI - Targeted re-sequencing of linkage region on 2q21 identifies a novel functional variant for hip and knee osteoarthritis. AB - OBJECTIVE: The aim of the study was to identify genetic variants predisposing to primary hip and knee osteoarthritis (OA) in a sample of Finnish families. METHODS: Genome wide analysis was performed using 15 independent families (279 individuals) originating from Central Finland identified as having multiple individuals with primary hip and/or knee OA. Targeted re-sequencing was performed for three samples from one 33-member, four-generation family contributing most significantly to the LOD score. In addition, exome sequencing was performed in three family members from the same family. RESULTS: Genome wide linkage analysis identified a susceptibility locus on chromosome 2q21 with a multipoint LOD score of 3.91. Targeted re-sequencing and subsequent linkage analysis revealed a susceptibility insertion variant rs11446594. It locates in a predicted strong enhancer element region with maximum LOD score 3.42 under dominant model of inheritance. Insertion creates a recognition sequence for ELF3 and HMGA1 transcription factors. Their DNA-binding affinity is highly increased in the presence of A-allele compared to wild type null allele. CONCLUSION: A potentially novel functional OA susceptibility variant was identified by targeted re sequencing. This variant locates in a predicted regulatory site and creates a recognition sequence for ELF3 and HMGA1 transcription factors that are predicted to play a significant role in articular cartilage homeostasis. PMID- 26603476 TI - Obstetric antiphospholipid syndrome. AB - Obstetric antiphospholipid syndrome is an acquired autoimmune disorder that is associated with various obstetric complications and, in the absence of prior history of thrombosis, with the presence of antiphospholipid antibodies directed against other phospholipids, proteins called cofactors or PL-cofactor complexes. Although the obstetric complications have been related to the procoagulant properties of antiphospholipid antibodies, pathological studies of human placenta have shown the proinflammatory capacity of antiphospholipid antibodies via the complement system and proinflammatory cytokines. There is no general agreement on which antiphospholipid antibodies profile (laboratory) confers the greatest obstetric risk, but the best candidates are categories I and IIa. Combined treatment with low doses of aspirin and heparin achieves good obstetric and maternal outcomes. In this study, we also review the therapeutic possibilities in refractory cases, although the likelihood of progressing to other autoimmune diseases is low. We briefly comment on incomplete obstetric antiphospholipid syndrome, also known as antiphospholipid antibody-mediated pregnancy morbidity syndrome. PMID- 26603475 TI - Factors secreted from dental pulp stem cells show multifaceted benefits for treating experimental rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and chronic inflammation, which lead to the progressive destruction of cartilage and bone in the joints. Numerous studies have reported that administrations of various types of MSCs improve arthritis symptoms in animal models, by paracrine mechanisms. However, the therapeutic effects of the secreted factors alone, without the cell graft, have been uncertain. Here, we show that a single intravenous administration of serum-free conditioned medium (CM) from human deciduous dental pulp stem cells (SHED-CM) into anti-collagen type II antibody-induced arthritis (CAIA), a mouse model of rheumatoid arthritis (RA), markedly improved the arthritis symptoms and joint destruction. The therapeutic efficacy of SHED-CM was associated with an induction of anti-inflammatory M2 macrophages in the CAIA joints and the abrogation of RANKL expression. SHED-CM specifically depleted of an M2 macrophage inducer, the secreted ectodomain of sialic acid-binding Ig-like lectin-9 (ED-Siglec-9), exhibited a reduced ability to induce M2-related gene expression and attenuate CAIA. SHED-CM also inhibited the RANKL-induced osteoclastogenesis in vitro. Collectively, our findings suggest that SHED-CM provides multifaceted therapeutic effects for treating CAIA, including the ED-Siglec-9-dependent induction of M2 macrophage polarization and inhibition of osteoclastogenesis. Thus, SHED-CM may represent a novel anti inflammatory and reparative therapy for RA. PMID- 26603477 TI - Activation of the Glucocorticoid Receptor in Acute Inflammation: the SEDIGRAM Concept. AB - Since the 1950s, glucocorticoids (GCs) have been a mainstay therapy for acute and chronic inflammatory disorders, although adverse effects limit their chronic use. Following the notion that the anti-inflammatory therapeutic and metabolic endocrine adverse effects of GCs may be based on different glucocorticoid receptor (GR)-dependent mechanisms, subsequent attempts to separate these mechanisms by trying to develop selective GR agonists and modulators (SEGRAMs) with an improved therapeutic benefit have yielded only a few molecules effective in clinical use. Recent new insights into the pro- and anti-inflammatory activities of GR support a more sophisticated drug discovery model. Here, we suggest that the way forward may include a need to redefine the pharmacological SEGRAM concept into selective monomerizing GR agonists and modulators (SEMOGRAMs) and selective dimerizing GR agonists or modulators (SEDIGRAMs) for selective therapeutic applications against chronic or acute inflammatory disorders, respectively. PMID- 26603479 TI - Construction of negatively charged and environment-sensitive nanomedicine for tumor-targeted efficient siRNA delivery. AB - A novel siRNA delivery system based on a triblock copolymer with pH and reduction dual-sensitivity was introduced. The polyplex, having high delivery efficiency not dependent on surface charge reversion in response to the pH value of tumor tissue, was used for target gene silencing in cancer therapy. PMID- 26603478 TI - Evolution and control of the phase competition morphology in a manganite film. AB - The competition among different phases in perovskite manganites is pronounced since their energies are very close under the interplay of charge, spin, orbital and lattice degrees of freedom. To reveal the roles of underlying interactions, many efforts have been devoted towards directly imaging phase transitions at microscopic scales. Here we show images of the charge-ordered insulator (COI) phase transition from a pure ferromagnetic metal with reducing field or increasing temperature in a strained phase-separated manganite film, using a home built magnetic force microscope. Compared with the COI melting transition, this reverse transition is sharp, cooperative and martensitic-like with astonishingly unique yet diverse morphologies. The COI domains show variable-dimensional growth at different temperatures and their distribution can illustrate the delicate balance of the underlying interactions in manganites. Our findings also display how phase domain engineering is possible and how the phase competition can be tuned in a controllable manner. PMID- 26603480 TI - Invasive pneumococcal diseases in children in Hokkaido, Japan from April 2000, to March 2015. AB - In Japan, the 7-valent pneumococcal conjugate vaccine (PCV-7) became commercially available as a voluntary vaccine in March 2010. It was included in the routine immunization schedule in April 2013 and was replaced by PCV-13 in November 2013. We evaluated 146 cases of invasive pneumococcal disease (IPD) in 142 children (2 developed the disease twice, and 1 developed it three times) treated in the northern district of Hokkaido, Japan from April 2000 to March 2015, before and after the introduction of PCV-7. The incidence rate per 100,000 people aged <5 years showed an increasing trend between April 2000 and March 2010, and reached 87.5 per 100,000 people per year between April 2009 and March 2010, which was immediately before the introduction of PCV-7. Subsequently, the incidence rate started to show a decreasing trend and reached as low as 9.5 per 100,000 people per year between April 2013 and March 2014. However, the incidence rate showed an increasing trend again between April 2014 and March 2015, reaching 33.4 per 100,000 people per year. Serotyping was performed for the 77 strains collected between April 2000 and March 2010. The most frequently isolated serotype was 6B (31.2%), followed by 23F (14.3%) and 19F (13.0%). Among them, 55 strains were covered by PCV-7 (71.4%), and 64 strains were covered by PCV-13 (83.1%). Of the 33 strains collected between April 2010 and March 2015, 14 were covered by PCV-7 (42.4%) and 16 were covered by PCV-13 (48.4%), showing a significant decrease (p < 0.01). PMID- 26603481 TI - Utility of the MALDI-TOF MS method to identify nontuberculous mycobacteria. AB - In comparison to the conventional real-time polymerase chain reaction method (PCR method) or the DNA-DNA hybridization method (DDH method), the utility of NTM identification by the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) method has seldom been reported. In this study, 75 clinical NTM isolates from our hospital between April 2013 and July 2014 were identified and analyzed using PCR, DDH, and MALDI-TOF MS methods, and the results for the MALDI-TOF MS method were compared with the others. Identification at the species level was in agreement for 71 (94.5%) of the 75 isolates. For further details, identification was possible for 23 (95.8%) of 24 Mycobacterium avium, 11 (100%) of 11 Mycobacterium intracellulare, and 1 (50%) of 2 isolates mixed with M. avium and M. intracellulare. Mycobacterium ksansasii, Mycobacterium abscessus, Mycobacterium fortuitum, Mycobacterium gordonae, and Mycobacterium chelonae identified by DDH method were same result by MALDI-TOF MS. Additionally, Mycobacterium mucogenicum, which could not be identified by the DDH method, was identified by the MALDI-TOF MS method. However, two isolates identified as Mycobacterium terrae by DDH method could not be identified by the MALDI-TOF MS method and were determined to be Mycobacterium arupense by 16S ribosomal RNA (rRNA) sequence analysis. The present findings show that, for rare bacterial species, identification is sometimes not possible, but, in most cases, the results of identification by the MALDI-TOF MS method have a high concordance rate with the results of the PCR and DDH methods. PMID- 26603482 TI - The impact of doping rates on the morphologies of silver and gold nanowires grown in helium nanodroplets. AB - Silver and gold nanowires are grown within superfluid helium nanodroplets and investigated by high resolution electron microscopy after surface deposition. The wire morphologies depend on the rate of metal atom doping in the pickup sequence. While high doping rates result in a polycrystalline face-centered cubic nanowire structure, at lower doping rates the initial fivefold-symmetry seems to be preserved. An explanation for this observation is given by computer simulations, which allow the derivation of timescales for the nanowire growth process inside helium nanodroplets. PMID- 26603483 TI - Size confinement of Si nanocrystals in multinanolayer structures. AB - Si nanocrystals (NCs) are often prepared by thermal annealing of multiple stacks of alternating sub-stoichiometric SiOx and SiO2 nanolayers. It is frequently claimed that in these structures, the NC diameter can be predefined by the thickness of the SiOx layer, while the NC concentration is independently controlled by the stoichiometry parameter x. However, several detailed structural investigations report that the NC size confinement to within the thickness of the SiOx layer is not strictly obeyed. In this study we address these contradicting findings: based on cross-correlation between structural and optical characterization of NCs grown in a series of purposefully prepared samples of different stoichiometry and layer thickness, we develop a comprehensive understanding of NC formation by Si precipitation in multinanolayer structures. We argue that the narrow NC size distribution generally observed in these materials appears due to reduction of the Si diffusion range, imposed by the SiO2 spacer layer. Therefore, both the SiOx layer thickness and composition as well as the actual thickness of the SiO2 spacer play an essential role in the NC formation. PMID- 26603484 TI - Everolimus immunosuppression in kidney transplantation: What is the optimal strategy? AB - Two main everolimus-based strategies have been pursued to facilitate calcineurin inhibitor (CNI) reduction after kidney transplantation: (i) everolimus with reduced CNI exposure from time of transplant and (ii) pre-emptive introduction of everolimus with CNI reduction or withdrawal at some point post-transplant. Randomized trials have shown no loss of immunosuppressive efficacy for everolimus (targeting 3-8 ng/mL) with reduced-exposure CNI versus standard-exposure CNI and mycophenolic acid (MPA) in low-to-moderate risk patients. Renal function has tended to be numerically, but not significantly, higher with everolimus and reduced-CNI versus MPA and standard-CNI. One study which used very low CsA exposure in everolimus-treated patients reported a substantial improvement in estimated GFR compared to controls, but this requires confirmation. Pre-emptive conversion to everolimus at three to six months after kidney transplantation significantly improves long-term renal function, but with an increased rate of mild acute rejection. Earlier conversion (up to two months post-transplant) can lead to an increase in rejection risk, while later conversion (more than six months post-transplant) is unproductive unless baseline renal function is good. This article considers the risks and benefits associated with either strategy, and reviews specific clinical situations that influence the optimal approach in individual patients. The balance of evidence suggests two options. De novo everolimus with reduced CNI, steroids and induction therapy ensures immunosuppressive efficacy in low- or standard-risk populations, and investigations into this strategy are ongoing. Conversion to everolimus with CNI withdrawal between three and six months post-transplant offers a long-term renoprotective effect if baseline graft function is good. PMID- 26603485 TI - Clinical risk factors of colorectal cancer in patients with serrated polyposis syndrome: a multicentre cohort analysis. AB - OBJECTIVE: Serrated polyposis syndrome (SPS) is accompanied by an increased risk of colorectal cancer (CRC). Patients fulfilling the clinical criteria, as defined by the WHO, have a wide variation in CRC risk. We aimed to assess risk factors for CRC in a large cohort of patients with SPS and to evaluate the risk of CRC during surveillance. DESIGN: In this retrospective cohort analysis, all patients with SPS from seven centres in the Netherlands and two in the UK were enrolled. WHO criteria were used to diagnose SPS. Patients who only fulfilled WHO criterion 2, with IBD and/or a known hereditary CRC syndrome were excluded. RESULTS: In total, 434 patients with SPS were included for analysis; 127 (29.3%) were diagnosed with CRC. In a per-patient analysis >=1 serrated polyp (SP) with dysplasia (OR 2.07; 95% CI 1.28 to 3.33), >=1 advanced adenoma (OR 2.30; 95% CI 1.47 to 3.67) and the fulfilment of both WHO criteria 1 and 3 (OR 1.60; 95% CI 1.04 to 2.51) were associated with CRC, while a history of smoking was inversely associated with CRC (OR 0.36; 95% CI 0.23 to 0.56). Overall, 260 patients underwent surveillance after clearing of all relevant lesions, during which two patients were diagnosed with CRC, corresponding to 1.9 events/1000 person-years surveillance (95% CI 0.3 to 6.4). CONCLUSION: The presence of SPs containing dysplasia, advanced adenomas and/or combined WHO criteria 1 and 3 phenotype is associated with CRC in patients with SPS. Patients with a history of smoking show a lower risk of CRC, possibly due to a different pathogenesis of disease. The risk of developing CRC during surveillance is lower than previously reported in literature, which may reflect a more mature multicentre cohort with less selection bias. PMID- 26603486 TI - An unusual cause of GI bleeding. PMID- 26603487 TI - Optical detection of individual ultra-short carbon nanotubes enables their length characterization down to 10 nm. AB - Ultrashort single-walled carbon nanotubes, i.e. with length below ~30 nm, display length-dependent physical, chemical and biological properties that are attractive for the development of novel nanodevices and nanomaterials. Whether fundamental or applicative, such developments require that ultrashort nanotube lengths can be routinely and reliably characterized with high statistical data for high-quality sample production. However, no methods currently fulfill these requirements. Here, we demonstrate that photothermal microscopy achieves fast and reliable optical single nanotube analysis down to ~10 nm lengths. Compared to atomic force microscopy, this method provides ultrashort nanotubes length distribution with high statistics, and neither requires specific sample preparation nor tip dependent image analysis. PMID- 26603488 TI - Clinical Characteristics of Dry Eye Patients With Chronic Pain Syndromes. AB - PURPOSE: To investigate clinical characteristics of dry eye disease (DED) patients with a chronic pain syndrome. DESIGN: Cross-sectional study. METHODS: Four hundred twenty-five patients of a tertiary care DED patient cohort in the Netherlands were included. Chronic pain syndromes irritable bowel syndrome, chronic pelvic pain, and fibromyalgia were assessed by questionnaires. Outcome variables were the Ocular Surface Disease Index (OSDI) symptom questionnaire, tear osmolarity, Schirmer test, tear breakup time, conjunctival hyperemia, staining of the cornea and conjunctiva, and amount of mucus. Outcomes were cross sectionally compared between DED patients with a chronic pain syndrome and those without. RESULTS: A total of 74 out of 425 DED patients (17%) had at least 1 chronic pain syndrome. The total symptom score was significantly higher in DED patients with a chronic pain syndrome than in those without (45.8 vs 33.8, P < .0005). Moreover, patients with a chronic pain syndrome scored higher on every single subscale of the 12-item OSDI symptom questionnaire. However, ocular signs were similar or even less severe in these patients. Similarly, in 64 DED patients from the population-based cohort TwinsUK, patients with a chronic pain syndrome (n = 24, 38%) had higher subscale and total (34.1 vs 14.4, P = .001) symptom scores. CONCLUSION: In DED patients, chronic pain syndromes are common and are associated with increased severity of DED symptoms across all domains of the OSDI, even though objective ocular surface signs are no worse. In clinical practice, more awareness of chronic pain syndromes might help in understanding the discrepancy between signs and symptoms in DED. PMID- 26603490 TI - Celiac disease: Autoimmunity in response to food antigen. AB - Celiac disease (CD) is an increasingly common disease of the small intestine that occurs in genetically susceptible subjects by ingestion of cereal gluten proteins. Gluten is highly abundant in the modern diet and well tolerated by most individuals. In CD, however, an erroneous but highly specific, adaptive immune response is mounted toward certain parts of the gluten proteome. The resulting intestinal destruction is reversible and resolved upon removal of gluten from the diet. Post-translational modification (deamidation) of gluten peptides by transglutaminase 2 (TG2) is essential for the peptides to act as HLA-DQ restricted T-cell antigens. Characteristically, deamidated gluten and the self protein TG2 both become targets of highly disease specific B-cell responses. These antibodies share several peculiar characteristics despite being directed against vastly different antigens, which suggests a common mechanism of development. Importantly, no clear function has been ascribed to the antibodies and their contribution to disease may relate to their function as antigen receptors of the B cells rather than as soluble immunoglobulins. Adaptive immunity against gluten and TG2 appears not to be sufficient for establishment of the disease lesion, and it has been suggested that stress responses in the intestinal epithelium are essential for the development of full-blown disease and tissue damage. In this review we will summarize current concepts of the immune pathology of CD with particular focus on recent advances in our understanding of disease specific B-cell responses. PMID- 26603489 TI - Astaxanthin prevents and reverses diet-induced insulin resistance and steatohepatitis in mice: A comparison with vitamin E. AB - Hepatic insulin resistance and nonalcoholic steatohepatitis (NASH) could be caused by excessive hepatic lipid accumulation and peroxidation. Vitamin E has become a standard treatment for NASH. However, astaxanthin, an antioxidant carotenoid, inhibits lipid peroxidation more potently than vitamin E. Here, we compared the effects of astaxanthin and vitamin E in NASH. We first demonstrated that astaxanthin ameliorated hepatic steatosis in both genetically (ob/ob) and high-fat-diet-induced obese mice. In a lipotoxic model of NASH: mice fed a high cholesterol and high-fat diet, astaxanthin alleviated excessive hepatic lipid accumulation and peroxidation, increased the proportion of M1-type macrophages/Kupffer cells, and activated stellate cells to improve hepatic inflammation and fibrosis. Moreover, astaxanthin caused an M2-dominant shift in macrophages/Kupffer cells and a subsequent reduction in CD4(+) and CD8(+) T cell recruitment in the liver, which contributed to improved insulin resistance and hepatic inflammation. Importantly, astaxanthin reversed insulin resistance, as well as hepatic inflammation and fibrosis, in pre-existing NASH. Overall, astaxanthin was more effective at both preventing and treating NASH compared with vitamin E in mice. Furthermore, astaxanthin improved hepatic steatosis and tended to ameliorate the progression of NASH in biopsy-proven human subjects. These results suggest that astaxanthin might be a novel and promising treatment for NASH. PMID- 26603491 TI - Interactions between adipose tissue and the immune system in health and malnutrition. AB - Adipose tissue provides the body with a storage depot of nutrients that is drained during times of starvation and replenished when food sources are abundant. As such, it is the primary sensor for nutrient availability in the milieu of an organism, which it communicates to the body through the excretion of hormones. Adipose tissue regulates a multitude of body functions associated with metabolism, such as gluconeogenesis, feeding and nutrient uptake. The immune system forms a vital layer of protection against micro-organisms that try to gain access to the nutrients contained in the body. Because infections need to be resolved as quickly as possible, speed is favored over energy-efficiency in an immune response. Especially when immune cells are activated, they switch to fast, but energy-inefficient anaerobic respiration to fulfill their energetic needs. Despite the necessity for an effective immune system, it is not given free rein in its energy expenditure. Signals derived from adipose tissue limit immune cell numbers and activity under conditions of nutrient shortage, whereas they allow proper immune cell activity when food sources are sufficiently available. When excessive fat accumulation occurs, such as in diet-induced obesity, adipose tissue becomes the site of pathological immune cell activation, causing chronic low-grade systemic inflammation. Obesity is therefore associated with a number of disorders in which the immune system plays a central role, such as atherosclerosis and non-alcoholic steatohepatitis. In this review, we will discuss the way in which adipose tissue regulates activity of the immune system under healthy and pathological conditions. PMID- 26603492 TI - The Promise of Gene Therapy for Pancreatic Cancer. AB - Unlike for other digestive cancer entities, chemotherapy, radiotherapy, and targeted therapies have, so far, largely failed to improve patient survival in pancreatic adenocarcinoma (PDAC), which remains the fourth leading cause of cancer-related death in Europe and the United States. In this context, gene therapy may offer a new avenue for patients with PDAC. In this review, we explore the research currently ongoing in French laboratories aimed at defeating PDAC using nonviral therapeutic gene delivery, targeted transgene expression, or oncolytic virotherapy that recently or will soon bridge the gap between experimental models of cancer and clinical trials. These studies are likely to change clinical practice or thinking about PDAC management, as they represent a major advance not only for PDAC but may also significantly influence the field of gene-based molecular treatment of cancer. PMID- 26603493 TI - Catheter-related thrombosis: Unresolved issues. PMID- 26603494 TI - The changes of lumbar muscle flexion-relaxation phenomenon due to antero posteriorly slanted ground surfaces. AB - Uneven ground surface is a common occupational injury risk factor in industries such as agriculture, fishing, transportation and construction. Studies have shown that antero-posteriorly slanted ground surfaces could reduce spinal stability and increase the risk of falling. In this study, the influence of antero-posteriorly slanted ground surfaces on lumbar flexion-relaxation responses was investigated. Fourteen healthy participants performed sagittally symmetric and asymmetric trunk bending motions on one flat and two antero-posteriorly slanted surfaces (-15 degrees (uphill facing) and 15 degrees (downhill facing)), while lumbar muscle electromyography and trunk kinematics were recorded. Results showed that standing on a downhill facing slanted surface delays the onset of lumbar muscle flexion relaxation phenomenon (FRP), while standing on an uphill facing ground causes lumbar muscle FRP to occur earlier. In addition, compared to symmetric bending, when performing asymmetric bending, FRP occurred earlier on the contralateral side of lumbar muscles and significantly smaller maximum lumbar flexion and trunk inclination angles were observed. Practitioner Summary: Uneven ground surface is a common risk factor among a number of industries. In this study, we investigated the influence of antero-posteriorly slanted ground surface on trunk biomechanics during trunk bending. Results showed the slanted surface alters the lumbar tissue load-sharing mechanism in both sagittally symmetric and asymmetric bending. PMID- 26603495 TI - Line-scanning confocal microscopy for high-resolution imaging of upconverting rare-earth-based contrast agents. AB - Rare-earth (RE) doped nanocomposites emit visible luminescence when illuminated with continuous wave near-infrared light, making them appealing candidates for use as contrast agents in biomedical imaging. However, the emission lifetime of these materials is much longer than the pixel dwell times used in scanning intravital microscopy. To overcome this limitation, we have developed a line scanning confocal microscope for high-resolution, optically sectioned imaging of samples labeled with RE-based nanomaterials. Instrument performance is quantified using calibrated test objects. NaYF4 : Er,Yb nanocomposites are imaged in vitro, and in ex vivo tissue specimens, with direct comparison to point-scanning confocal microscopy. We demonstrate that the extended pixel dwell time of line scanning confocal microscopy enables subcellular-level imaging of these nanomaterials while maintaining optical sectioning. The line-scanning approach thus enables microscopic imaging of this emerging class of contrast agents for preclinical studies, with the potential to be adapted for real-time in vivo imaging in the clinic. PMID- 26603496 TI - Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors--What Some May Have Forgotten or Would Rather Forget? AB - Hydroxamate-based histone deacetylase inhibitors (HDACIs) have been approved as therapeutic agents by the US Food and Drug Administration for use in oncology applications. While the potential utility of such HDACIs in other areas of medicinal chemistry is tremendous, there are significant concerns that "pan-HDAC inhibitors" may be too broadly acting and/or toxic for clinical use beyond oncology. In addition to the isozyme selectivity challenge, the potential mutagenicity of hydroxamate-containing HDAC inhibitors represents a major hindrance in their application to other therapeutic areas. Herein we report on the mutagenicity of known hydroxamates, discuss the mechanisms responsible for their genotoxicity, and review some of the current alternatives to hydroxamates. We conclude that the hydroxamate group, while providing high-potency HDACIs, is not necessarily the best zinc-binding group for HDACI drug discovery. PMID- 26603497 TI - Baseline and Early MR Apparent Diffusion Coefficient Quantification as a Predictor of Response of Unresectable Hepatocellular Carcinoma to Doxorubicin Drug-Eluting Bead Chemoembolization. AB - PURPOSE: To investigate baseline and early apparent diffusion coefficients (ADC) derived from diffusion-weighted imaging (DWI) as a predictor of objective response (OR) and survival in unresectable hepatocellular carcinoma (HCC) treated with doxorubicin drug-eluting bead (DEB) transcatheter arterial chemoembolization. MATERIALS AND METHODS: In a prospective study, 57 patients underwent DEB chemoembolization. Dynamic contrast-enhanced magnetic resonance imaging and DWI were performed at baseline and 1 and 3 months after DEB chemoembolization. OR was evaluated per modified Response Evaluation Criteria In Solid Tumors (mRECIST) and European Association for the Study of the Liver (EASL) guidelines. Baseline ADCs of tumors that showed OR at 1 and 3 months were compared with nonresponding tumor ADCs by two-sample t test and receiver operating characteristic curves. Additionally, ADC changes at 30 days were correlated with OR. Finally, Kaplan-Meier analysis was used to compare survival between patients with lesions demonstrating more restricted baseline diffusion and others. RESULTS: At 1 month, 33 patients (60%) showed OR (21 complete responses and 12 partial responses). At baseline, tumors with OR at 1 month showed significantly more restricted diffusion (0.731 * 10(-3) mm2/s) compared with others (1.057 * 10(-3) mm2/s; P = .031). No difference between response rates at 1 and 3 months according to mRECIST and EASL was observed. For an area under the curve of 0.965, the sensitivity and specificity of predicting objective tumor response at 1 month using a baseline HCC ADC of 0.83 * 10(-3) mm2/s were 91% and 96%, respectively. In addition, patients with lesions with a baseline ADC < 0.83 * 10(-3) mm2/s showed prolonged survival compared with others (P < .001). CONCLUSIONS: In unresectable HCC, a baseline ADC < 0.83 * 10(-3) mm2/s is a predictor of survival and treatment response at 1 and 3 months after DEB chemoembolization with high sensitivity and specificity. PMID- 26603498 TI - Safety and Efficacy of Radiofrequency Ablation for Hepatic Metastases from Gastrointestinal Stromal Tumor. AB - PURPOSE: To evaluate the safety and efficacy of radiofrequency (RF) ablation for hepatic metastases from gastrointestinal stromal tumor (GIST). MATERIALS AND METHODS: Retrospective review of a prospectively maintained database was performed between February 2002 and November 2010 and identified 29 patients with GISTs (18 male; age range, 35-77 y; median age, 61 y) who had undergone ultrasound-guided RF ablation for metastases detected in the liver. All patients had been treated with imatinib mesylate. Indications for RF ablation were tumor progression during medical therapy or the development of drug resistance after initial tumor control. The average number of target lesions per procedure was 2.3 (range, 1-8), and mean lesion diameter was 1.3 cm (range, 0.4-3.6 cm). RESULTS: For 69 lesions among 86 hepatic metastases, RF ablation was successfully performed according to the protocol currently in use. In 17 hepatic metastases in 13 patients, RF ablation was not performed because of poor lesion visibility or possible thermal damage to adjacent organs. Major complications included bleeding at the ablation site in one patient and peritoneal seeding near the ablation tract in another patient. Technical effectiveness was achieved for 66 of 69 lesions (95.6%). The median follow-up period was 33.1 months (range, 12.3-108.6 mo). Four of 66 lesions (6%) showed local recurrence at 3.2-10.5 months. Four patients died of disease progression. The median overall survival period was 90.2 months (range, 12.3-108.6 mo). CONCLUSIONS: RF ablation appears to be a safe and effective treatment for hepatic metastases of GIST when medical therapy fails. PMID- 26603499 TI - A Light-Activated Microheater for the Remote Control of Enzymatic Catalysis. AB - The remote control of enzymatic catalysis is of significant importance in disease treatment and industrial applications. Herein, we designed a microheater composed of a porous polylactic acid (PLA) matrix and polydopamine (PDA) with notable photothermal conversion capability. Starch hydrolysis, catalyzed by using alpha amylase, was accelerated in the presence of the microheater under illumination with near-infrared light or natural sunlight at room temperature. Additionally, the methodology was extended to the preparation of microwave-absorbing materials with the deposition of polyaniline on porous PLA matrix. The porous morphology improves the energy-conversion efficiency. PMID- 26603501 TI - Palladium(II)-Catalyzed Annulation of Alkynes with 2-(Cyanomethyl)phenylboronates Leading to 3,4-Disubstituted 2-Naphthalenamines. AB - 1,2-Bis(diphenylphosphino)ethane (dppe)-ligated palladium(II) complexes catalyze the annulation of internal alkynes with 2-(cyanomethyl)phenylboronates to provide 3,4-disubstituted-2-naphthalenamines in good yields. The annulation reaction proceeds under mild and neutral conditions and requires methanol as an essential solvent. In addition to symmetrical alkynes, unsymmetrical alkynes substituted by aryl, alkyl, and alkynyl groups participate in the annulation to afford the corresponding 2-naphthalenamines with electron-withdrawing sp(2)- and sp-carbons preferentially located at the C-3 position. Substituents including an alkyl or alkoxy group on the cyanomethyl moiety and a halogen atom on the benzene ring in the boronates are compatible with the reaction conditions. The annulation proceeds through the transmetalation of the palladium(II) complexes with the boronates and alkyne insertion followed by nucleophilic addition of the generated alkenylpalladium(II) species to the intramolecular cyano group. Stoichiometric reactions revealed that the methanol solvent was effective for both transmetalation and catalyst regeneration. PMID- 26603500 TI - Multivariate test power approximations for balanced linear mixed models in studies with missing data. AB - Multilevel and longitudinal studies are frequently subject to missing data. For example, biomarker studies for oral cancer may involve multiple assays for each participant. Assays may fail, resulting in missing data values that can be assumed to be missing completely at random. Catellier and Muller proposed a data analytic technique to account for data missing at random in multilevel and longitudinal studies. They suggested modifying the degrees of freedom for both the Hotelling-Lawley trace F statistic and its null case reference distribution. We propose parallel adjustments to approximate power for this multivariate test in studies with missing data. The power approximations use a modified non-central F statistic, which is a function of (i) the expected number of complete cases, (ii) the expected number of non-missing pairs of responses, or (iii) the trimmed sample size, which is the planned sample size reduced by the anticipated proportion of missing data. The accuracy of the method is assessed by comparing the theoretical results to the Monte Carlo simulated power for the Catellier and Muller multivariate test. Over all experimental conditions, the closest approximation to the empirical power of the Catellier and Muller multivariate test is obtained by adjusting power calculations with the expected number of complete cases. The utility of the method is demonstrated with a multivariate power analysis for a hypothetical oral cancer biomarkers study. We describe how to implement the method using standard, commercially available software products and give example code. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26603502 TI - Phrenic Nerve Injury After Radiofrequency Denervation of the Cervical Medial Branches. AB - Radiofrequency denervation of the cervical medial branches is a possible treatment for chronic cervical facet pain syndrome when conservative management has failed. According to the literature, complications after radiofrequency denervation of the cervical medial branches are rare. We report a case of possible phrenic nerve injury after ipsilateral radiofrequency denervation of the cervical medial branches following a posterolateral approach. PMID- 26603504 TI - Psycho-educational preparation of children for anaesthesia: A review of intervention methods. AB - OBJECTIVE: To systematically review the different methods available for the psycho-educational preparation of children for anaesthesia induction. METHODS: Articles were searched in Academic Search Premier, OvidSP, Web of Science, and PsycINFO. Inclusion criteria were psychological and educational preparation of children for anaesthesia and anxiety reduction. The titles of papers and abstracts were reviewed and full copies of selected papers were scrutinized. RESULTS: Forty-four empirical studies were identified. Twenty-one articles described preoperative preparation programmes, twelve examined the effects of distractive techniques and eleven reported the effect of parental presence during anaesthesia's induction. Some general characteristics of the different interventions are discussed together with some key psychological and educational factors mediating anxiety in children undergoing anaesthesia. CONCLUSION: The effectiveness of interventions were linked to several factors. Psychological and contextual aspects are discussed. Psycho-educational activities should be better described when reporting their effectiveness in children's preparation for an anaesthesia. PRACTICE IMPLICATIONS: Patient and family characteristics together with organizational and systemic aspects are described in order to guide the choice of the most appropriate preparation method for diverse health care setting. PMID- 26603505 TI - Medication adherence communications in community pharmacies: A naturalistic investigation. AB - OBJECTIVE: To describe the extent of pharmacy detection and monitoring of medication non-adherence, and solutions offered to improve adherence. METHODS: Participants were 60 residents of the Boston area who had a generic chronic medication with 30 day supplies from their usual pharmacy. Participants received a duplicate prescription which they filled at a different pharmacy. For 5 months, participants alternated between the two pharmacies, creating gaps in their refill records at both pharmacies but no gaps in their medication adherence. Participants followed a scripted protocol and after each pharmacy visit reported their own and the pharmacy staff's behavior. RESULTS: Across 78 unique community pharmacies and 260 pharmacy visits, pharmacies were inconsistent and inadequate in asking if participants had questions, discussing the importance of adherence, providing adequate consultations with new medication, and detecting and intervening on non-adherence. Insurers rarely contacted the participants about adherence concerns. CONCLUSION: There is a need for more structured intervention systems to ensure pharmacists are consistently and adequately educating patients and detecting/managing potential medication non-adherence. PRACTICE IMPLICATIONS: The present study calls for more attention to building infrastructure in pharmacy practice that helps pharmacists more consistently identify, monitor, and intervene on medication adherence. PMID- 26603506 TI - Increased minimum toe clearance variability in patients with peripheral arterial disease. AB - Individuals with peripheral arterial disease (PAD) report difficulty walking and experience 73% more falls than their healthy counterparts, but no studies have investigated functional mechanisms contributing to increased falls. Minimum toe clearance (MTC) is the minimum vertical distance between the toe of the swinging leg and the walking surface when the leg is swinging, and decreased values are associated with an increased risk for falls. This study is the first such analysis in patients with PAD. Eighteen individuals with PAD and eighteen healthy controls walked on a treadmill before and after the onset of claudication pain. Mean MTC and the standard deviation of MTC values across the trial were calculated. Mean MTC was not different between groups in the pain-free (P = 0.244) or pain conditions (P = 0.565). MTC variability was increased for patients with PAD in pain-free (P = 0.048) and pain conditions (P = 0.019). No significant differences existed between conditions for MTC mean (P = 0.134) or MTC variability (P = 0.123). Increased MTC variability is present before and after the onset of claudication pain, and may be a useful assessment for treatment and rehabilitation efficacy in these patients. PMID- 26603507 TI - Estimation of heart rate variability using a compact radiofrequency motion sensor. AB - Physiological indices that reflect autonomic nervous activity are considered useful for monitoring peoples' health on a daily basis. A number of such indices are derived from heart rate variability, which is obtained by a radiofrequency (RF) motion sensor without making physical contact with the user's body. However, the bulkiness of RF motion sensors used in previous studies makes them unsuitable for home use. In this study, a new method to measure heart rate variability using a compact RF motion sensor that is sufficiently small to fit in a user's shirt pocket is proposed. To extract a heart rate related component from the sensor signal, an algorithm that optimizes a digital filter based on the power spectral density of the signal is proposed. The signals of the RF motion sensor were measured for 29 subjects during the resting state and their heart rate variability was estimated from the measured signals using the proposed method and a conventional method. A correlation coefficient between true heart rate and heart rate estimated from the proposed method was 0.69. Further, the experimental results showed the viability of the RF sensor for monitoring autonomic nervous activity. However, some improvements such as controlling the direction of sensing were necessary for stable measurement. PMID- 26603508 TI - Multiple myeloma: the quality of care is linked to geographical and organisational determinants. A study in a French registry. AB - Multiple myeloma is a haematological malignancy whose care is spread over several specialities and provided by centres that various sizes, which raises the issue of equal opportunities in care access. Incident cases of myeloma between 2008 and 2010 were exhaustively identified by the Poitou-Charentes Cancer Registry. To ascertain the quality of care, the diagnosis, staging, and treatment administered were compared to international recommendations. Three hundred and sixty-seven patients were included. The diagnostic procedure exhibited 98% compliance, the staging 58%, and treatment 89%. Concerning diagnostic and staging, non-compliance with recommendations was associated to the failure to perform collegiate case assessments in multidisciplinary team (MDT) meetings [OR 2.15 (1.15-4.04)], care provided at a secondary centre, and a distance between home and the centre of 5 25 km [2.16 (1.06-4.40)] and 25-50 km [2.86 (1.37-6.01)]. Regarding treatment, non-compliance with recommendations was associated with care provided at a secondary centre [5.28 (2.03-13.75)]. Finally, diagnosis, staging and treatment quality improved over time. This study underlines the need to improve the organisation of the healthcare offer, so that patients can receive the best possible care. MDT seems to be the main means to improve quality of care. PMID- 26603509 TI - Detection of Angiostrongylus vasorum by quantitative PCR in bronchoalveolar lavage fluid in Belgian dogs. AB - OBJECTIVES: To describe Angiostrongylus vasorum infection in a series of clinical cases over a 12-month period, report the use of quantitative PCR on broncho alveolar lavage fluid and investigate the -possibility of previously undiagnosed angiostrongylosis in a retrospective cohort of coughing and healthy dogs. METHODS: Pulmonary angiostrongylosis was diagnosed based on compatible clinical signs and positive quantitative PCR on broncho-alveolar lavage fluid and/or positive Baermann examination. Quantitative PCR was also performed retrospectively on broncho-alveolar lavage fluid from 65 dogs (55 coughing and 10 healthy dogs), examined between 2008 and 2014; results of Baermann examination were also available in 33 dogs. RESULTS: Seven young adult dogs from Southeastern Belgium with respiratory clinical signs were diagnosed with angiostrongylosis between March 2013 and April 2014. Positive broncho-alveolar lavage fluid quantitative PCR results and positive Baermann examination were obtained in 5/5 and 2/5 dogs, respectively. In the remaining two dogs, only Baermann analysis was performed. Among the retrospective cohorts, only one broncho-alveolar lavage fluid from a coughing dog was quantitative PCR-positive whereas all faecal samples were negative. CLINICAL SIGNIFICANCE: Until recently, canine angiostrongylosis was not reported in Belgium. It should now be included in the differential diagnosis of coughing Belgian dogs. Identification of affected dogs may be aided by quantitative PCR on broncho-alveolar lavage fluid. PMID- 26603510 TI - Clinical outcomes of a simultaneous replantation technique for amputations of four or five digits. AB - PURPOSE: Replantation of amputations separated by more than four digits is challenging microsurgery because of the technical demands and long operation time. The purpose of this report was to present the clinical and functional outcomes in patients with amputations of four or five digits using a simultaneous replantation technique. PATIENTS AND METHODS: Among the 43 patients who visited our institution due to amputation of four or five digits from 2004 to 2013, 35 patients (28 males and seven females) underwent simultaneous replantation of four or five digits. The age range of the patients was 25-64 years (mean, 40.6 years). Simultaneous replantation technique included that bone was fixed and flexor tendons were repaired first and then digital vessels and nerves were simultaneously anastomosed for all amputated digits. The clinical and functional outcomes were evaluated at a minimum 1-year follow-up. RESULTS: Ischemic time was 150-510 min. Mean operation time was 313.2 min. In total, 127 of the 145 (87.5%) digits remained viable survived 2-weeks postoperatively, and four patients (16 digits) were lost to follow up. Of the 31 patients (129 digits), 19 (61.3%) had excellent and good outcomes using the criteria of Chen, and 21 patients (71%) were satisfied completely. Mean grip strength of the injured hand was 67% at the last follow-up. CONCLUSION: The results from this series of cases showed that the simultaneous replantation technique for four or five digit amputations may provide an alternative method to shorten surgical time, reduce complication rates, and enhance high survival rate. PMID- 26603511 TI - Dietary exposure to aflatoxin and micronutrient status among young children from Guinea. AB - SCOPE: Aflatoxin exposure coincides with micronutrient deficiencies in developing countries. Animal feeding studies have postulated that aflatoxin exposure may be exacerbating micronutrient deficiencies. Evidence available in human subjects is limited and inconsistent. The aim of the study was to investigate the relationship between aflatoxin exposure and micronutrient status among young Guinean children. METHODS AND RESULTS: A total of 305 children (28.8 +/- 8.4 months) were recruited at groundnut harvest (rainy season), of which 288 were followed up 6 months later postharvest (dry season). Blood samples were collected at each visit. Aflatoxin-albumin adduct levels were measured by ELISA. Vitamin A, vitamin E and beta-carotene concentrations were measured using HPLC methods. Zinc was measured by atomic absorption spectroscopy. Aflatoxin exposure and micronutrient deficiencies were prevalent in this population and were influenced by season, with levels increasing between harvest and postharvest. At harvest, children in the highest aflatoxin exposure group, compared to the lowest, were 1.98 (95%CI: 1.00, 3.92) and 3.56 (95%CI: 1.13, 11.15) times more likely to be zinc and vitamin A deficient. CONCLUSION: Although children with high aflatoxin exposure levels were more likely to be zinc and vitamin A deficient, further research is necessary to determine a cause and effect relationship. PMID- 26603513 TI - Grouping nanomaterials to predict their potential to induce pulmonary inflammation. AB - The rapidly expanding manufacturing, production and use of nanomaterials have raised concerns for both worker and consumer safety. Various studies have been published in which induction of pulmonary inflammation after inhalation exposure to nanomaterials has been described. Nanomaterials can vary in aspects such as size, shape, charge, crystallinity, chemical composition, and dissolution rate. Currently, efforts are made to increase the knowledge on the characteristics of nanomaterials that can be used to categorise them into hazard groups according to these characteristics. Grouping helps to gather information on nanomaterials in an efficient way with the aim to aid risk assessment. Here, we discuss different ways of grouping nanomaterials for their risk assessment after inhalation. Since the relation between single intrinsic particle characteristics and the severity of pulmonary inflammation is unknown, grouping of nanomaterials by their intrinsic characteristics alone is not sufficient to predict their risk after inhalation. The biokinetics of nanomaterials should be taken into account as that affects the dose present at a target site over time. The parameters determining the kinetic behaviour are not the same as the hazard-determining parameters. Furthermore, characteristics of nanomaterials change in the life-cycle, resulting in human exposure to different forms and doses of these nanomaterials. As information on the biokinetics and in situ characteristics of nanomaterials is essential but often lacking, efforts should be made to include these in testing strategies. Grouping nanomaterials will probably be of the most value to risk assessors when information on intrinsic characteristics, life-cycle, biokinetics and effects are all combined. PMID- 26603515 TI - Life or Limb: Family as Decision Makers for a Psychotic Patient With Life Threatening Gangrene. PMID- 26603514 TI - Tissue-specific in vivo genetic toxicity of nine polycyclic aromatic hydrocarbons assessed using the MutaTMMouse transgenic rodent assay. AB - Test batteries to screen chemicals for mutagenic hazard include several endpoints regarded as effective for detecting genotoxic carcinogens. Traditional in vivo methods primarily examine clastogenic endpoints in haematopoietic tissues. Although this approach is effective for identifying systemically distributed clastogens, some mutagens may not induce clastogenic effects; moreover, genotoxic effects may be restricted to the site of contact and/or related tissues. An OECD test guideline for transgenic rodent (TGR) gene mutation assays was released in 2011, and the TGR assays permit assessment of mutagenicity in any tissue. This study assessed the responses of two genotoxicity endpoints following sub-chronic oral exposures of male MutaTMMouse to 9 carcinogenic polycyclic aromatic hydrocarbons (PAHs). Clastogenicity was assessed via induction of micronuclei in peripheral blood, and mutagenicity via induction of lacZ transgene mutations in bone marrow, glandular stomach, small intestine, liver, and lung. Additionally, the presence of bulky PAH-DNA adducts was examined. Five of the 9 PAHs elicited positive results across all endpoints in at least one tissue, and no PAHs were negative or equivocal across all endpoints. All PAHs were positive for lacZ mutations in at least one tissue (sensitivity=100%), and for 8 PAHs, one or more initial sites of chemical contact (i.e., glandular stomach, liver, small intestine) yielded a greater response than bone marrow. Five PAHs were positive in the micronucleus assay (sensitivity=56%). Furthermore, all PAHs produced DNA adducts in at least one tissue. The results demonstrate the utility of the TGR assay for mutagenicity assessment, especially for compounds that may not be systemically distributed. PMID- 26603516 TI - INSPIRE (INvestigating Social and PractIcal suppoRts at the End of life): Pilot randomised trial of a community social and practical support intervention for adults with life-limiting illness. AB - BACKGROUND: For most people, home is the preferred place of care and death. Despite the development of specialist palliative care and primary care models of community based service delivery, people who are dying, and their families/carers, can experience isolation, feel excluded from social circles and distanced from their communities. Loneliness and social isolation can have a detrimental impact on both health and quality of life. Internationally, models of social and practical support at the end of life are gaining momentum as a result of the Compassionate Communities movement. These models have not yet been subjected to rigorous evaluation. The aims of the study described in this protocol are: (1) to evaluate the feasibility, acceptability and potential effectiveness of The Good Neighbour Partnership (GNP), a new volunteer-led model of social and practical care/support for community dwelling adults in Ireland who are living with advanced life-limiting illness; and (2) to pilot the method for a Phase III Randomised Controlled Trial (RCT). DESIGN: The INSPIRE study will be conducted within the Medical Research Council (MRC) Framework for the Evaluation of Complex Interventions (Phases 0-2) and includes an exploratory two-arm delayed intervention randomised controlled trial. Eighty patients and/or their carers will be randomly allocated to one of two groups: (I) Intervention: GNP in addition to standard care or (II) Control: Standard Care. Recipients of the GNP will be asked for their views on participating in both the study and the intervention. Quantitative and qualitative data will be gathered from both groups over eight weeks through face-to-face interviews which will be conducted before, during and after the intervention. The primary outcome is the effect of the intervention on social and practical need. Secondary outcomes are quality of life, loneliness, social support, social capital, unscheduled health service utilisation, caregiver burden, adverse impacts, and satisfaction with intervention. Volunteers engaged in the GNP will also be assessed in terms of their death anxiety, death self efficacy, self-reported knowledge and confidence with eleven skills considered necessary to be effective GNP volunteers. DISCUSSION: The INSPIRE study addresses an important knowledge gap, providing evidence on the efficacy, utility and acceptability of a unique model of social and practical support for people living at home, with advanced life-limiting illness. The findings will be important in informing the development (and evaluation) of similar service models and policy elsewhere both nationally and internationally. TRIAL REGISTRATION: ISRCTN18400594 18(th) February 2015. PMID- 26603517 TI - [Renovascular safety of bevacizumab in breast cancer patients. The prognostic value of hypertension and proteinuria]. AB - INTRODUCTION: The potential prognostic value of hypertension and proteinuria of anti-vascular endothelial growth factor (VEGF) drugs has not been assessed in routine clinical practice so far in breast cancer. The objectives of the MARS study were to assess the prevalence of proteinuria and hypertension at baseline, their incidence under anti-VEGF treatment, and to evaluate a possible link with overall survival. METHODS: Patients from 8 centres were included between 2009 and 2011 with a follow-up of 1 year. They were naive of any previous anti-VEGF treatment and planned to be started on one. The results of the group of patients with breast cancer receiving bevacizumab are presented. RESULTS: Four hundred and two patients with breast cancer and treated with bevacizumab were included. At inclusion, hypertension prevalence was 12.4%, proteinuria 23.9%. The incidence of de novo proteinuria and hypertension during the follow-up was 61.7% and 16.8%, respectively. Among patients with de novo proteinuria, 62.2% afterwards improved/normalized. No thrombotic microangiopathy was reported. Baseline or de novo proteinuria/hypertension were not associated with overall survival in breast cancer patients treated with bevacizumab. DISCUSSION: These results on the renovascular safety of bevacizumab in breast cancer patients showed that the prevalence of hypertension and proteinuria was high at baseline and, moreover, patients treated with bevacizumab frequently developed de novo hypertension and/or proteinuria. Finally, neither hypertension, nor proteinuria, neither at baseline, nor de novo, were associated with overall survival in our cohort of "real-life'' patients PMID- 26603518 TI - Expression and regulation of CacyBP/SIP in chronic lymphocytic leukemia cell balances of cell proliferation with apoptosis. AB - PURPOSE: Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, with incidence in Chinese populations also increasing. CLL involves an accumulation of abnormal B cells which result in dysregulation of cell proliferation and apoptosis rates. The calcyclin-binding protein/Siah-1 interacting protein (CacyBP/SIP) plays a pivotal role in tumorigenicity and cell apoptosis. Here, we investigated the function of CacyBP/SIP in CLL cell proliferation and apoptosis. METHODS: CacyBP/SIP expression levels were measured in peripheral blood mononuclear cells from 23 Chinese CLL patients and three healthy donors by western blotting. Correlation analysis was performed to assess associations between CacyBP/SIP expression and clinical stage, chromosome abnormalities and zeta-chain-associated protein kinase 70 (ZAP-70) expression. We silenced CacyBP/SIP expression in MEC-1 cells using a lentivirus system and analyzed cell vitality, cell cycle and tumorigenicity. Apoptosis was also analyzed following the upregulation of CacyBP/SIP expression in MEC-1 cells. RESULTS: Downregulation of CacyBP/SIP expression in CLL patients was negatively correlated with CLL clinical stage, but not with patient sex, age, del(13q14) or del(17q-) presence, or ZAP-70 expression. CacyBP/SIP silencing significantly enhanced cell proliferation and tumorigenicity. CacyBP/SIP silencing promoted accumulation of cells in S phase by upregulation of beta-catenin, cyclin D1 and cyclin E, and downregulation of p21. Moreover, CacyBP/SIP overexpression facilitated CLL apoptosis through the activation of pro-caspase-3. CONCLUSION: CacyBP/SIP is a useful indicator of CLL disease processes and plays an important role in sustaining the balance of cell proliferation and apoptosis. PMID- 26603519 TI - Predictive Power of f99 Repolarization Index for the Occurrence of Ventricular Arrhythmias. AB - BACKGROUND: Defects of cardiac repolarization, noninvasively identifiable by analyzing the electrocardiographic (ECG) ST segment and T wave, are among the major causes of sudden cardiac death. Still, no repolarization-based index has so far shown sufficient sensitivity and specificity to justify preventive treatments. Thus, the aim of this work was to evaluate the predictive power of our recently proposed f99 index for the occurrence of ventricular arrhythmias. METHODS: Our study populations included 170 patients with implanted cardiac defibrillator (ICD), 44 of which developed ventricular tachycardia and/or fibrillation during the 4-year follow-up (ICD_Cases) and 126 did not (ICD_Controls). The f99 index, defined as the frequency at which the repolarization normalized cumulative energy reaches 99%, was computed in each of the 15 (I to III, aVl, aVr, aVf, V1 -V6 , X, Y, Z) available ECG leads independently, and then maximized over the 6 precordial leads (f99_MaxV1 -V6 ), 12 standard leads (f99_Max12STD) and three orthogonal leads (f99_MaxXYZ) to avoid dispersion-related issues. Each index predictive power was quantified as the area under the receiving operating characteristic curve (AUC). RESULTS: Median f99_MaxV1 -V6 , f99_Max12STD and f99_MaxXYZ values were significantly higher in the ICD_Cases than in the ICD_Controls (48 Hz vs. 35 Hz, P<0.05; 51 Hz vs. 43 Hz, P<0.05; 45 Hz vs. 31 Hz, P<10(-3) ; respectively), indicating a more fragmented repolarization in the former group. The AUC values were 0.62, 0.63 and 0.68, respectively. CONCLUSIONS: The f99 represents a promising risk index for the occurrence of ventricular arrhythmias, especially when maximized over the three orthogonal leads. PMID- 26603520 TI - Editorial Comment from Dr Numakura to Clinicopathological characteristics of Xp11.2 translocation renal cell carcinoma in adolescents and adults: Diagnosis using immunostaining of transcription factor E3 and fluorescence in situ hybridization analysis. PMID- 26603521 TI - Cytomegalovirus-Associated CD4(+) CD28(null) Cells in NKG2D-Dependent Glomerular Endothelial Injury and Kidney Allograft Dysfunction. AB - Emerging data suggest that expansion of a circulating population of atypical, cytotoxic CD4(+) T cells lacking costimulatory CD28 (CD4(+) CD28(null) cells) is associated with latent cytomegalovirus (CMV) infection. The purpose of the current study was to increase the understanding of the relevance of these cells in 100 unselected kidney transplant recipients followed prospectively for a median of 54 months. Multicolor flow cytometry of peripheral blood mononuclear cells before transplantation and serially posttransplantation was undertaken. CD4(+) CD28(null) cells were found predominantly in CMV-seropositive patients and expanded in the posttransplantation period. These cells were predominantly effector-memory phenotype and expressed markers of endothelial homing (CX3CR1) and cytotoxicity (NKG2D and perforin). Isolated CD4(+) CD27(-) CD28(null) cells proliferated in response to peripheral blood mononuclear cells previously exposed to CMV-derived (but not HLA-derived) antigens and following such priming incubation with glomerular endothelium resulted in signs of endothelial damage and apoptosis (release of fractalkine and von Willebrand factor; increased caspase 3 expression). This effect was mitigated by NKG2D-blocking antibody. Increased CD4(+) CD28(null) cell frequencies were associated with delayed graft function and lower estimated glomerular filtration rate at end follow-up. This study suggests an important role for this atypical cytotoxic CD4(+) CD28(null) cell subset in kidney transplantation and points to strategies that may minimize the impact on clinical outcomes. PMID- 26603522 TI - Proteomic research on diapause-related proteins in the female ladybird, Coccinella septempunctata L. AB - In the experiments reported here, we used the female ladybird Coccinella septempunctata L. as a model to identify diapause-associated proteins using proteomics technology. Our results indicated that protein expression patterns of diapausing and nondiapausing individuals were highly differentiated. A total of 58 spots showed significant differences in abundance (Ratio > 2 and P < 0.05) according to two-dimensional electrophoresis and GE Image Scanner III analysis. Sixteen protein spots were further investigated using mass spectrometry. Eight proteins were characterized, including chaperones and proteins involved in glucose metabolism, lipid metabolism, and the tricarboxylic acid cycle. Among these proteins, five proteins were upregulated in diapausing female adults, including a chaperone (Symbionin symL), malate dehydrogenase (putative), two proteins linked to lipid metabolism (unknown and conserved hypothetical protein) and phosphoglyceromutase (partial). By contrast, isocitrate dehydrogenase (RH49423p), fumarylacetoacetate hydrolase (AGAP001942-PA), and a putative medium chain acyl-CoA dehydrogenase were downregulated. These results contribute to the understanding of diapause mechanisms of the ladybird C. septempunctata and may suggest methods for improving the application of this natural enemy insect. PMID- 26603523 TI - Non-invasive tests for liver fibrosis progression and regression. PMID- 26603524 TI - TRK Inhibitor Shows Early Promise. AB - Results from a phase I study show that the TRK inhibitor LOXO-101 is well tolerated and effective, with patients whose tumors bear NTRK fusions responding well and durably to this targeted therapy. PMID- 26603525 TI - Targeting p300 Addiction in CBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation of MYC Expression. AB - Loss-of-function mutations in the CBP/CREBBP gene, which encodes a histone acetyltransferase (HAT), are present in a variety of human tumors, including lung, bladder, gastric, and hematopoietic cancers. Consequently, development of a molecular targeting method capable of specifically killing CBP-deficient cancer cells would greatly improve cancer therapy. Functional screening of synthetic lethal genes in CBP-deficient cancers identified the CBP paralog p300/EP300 Ablation of p300 in CBP-knockout and CBP-deficient cancer cells induced G1-S cell cycle arrest, followed by apoptosis. Genome-wide gene expression analysis revealed that MYC is a major factor responsible for the synthetic lethality. Indeed, p300 ablation in CBP-deficient cells caused downregulation of MYC expression via reduction of histone acetylation in its promoter, and this lethality was rescued by exogenous MYC expression. The p300-HAT inhibitor C646 specifically suppressed the growth of CBP-deficient lung and hematopoietic cancer cells in vitro and in vivo; thus p300 is a promising therapeutic target for treatment of CBP-deficient cancers. SIGNIFICANCE: Targeting synthetic-lethal partners of genes mutated in cancer holds great promise for treating patients without activating driver gene alterations. Here, we propose a "synthetic lethal based therapeutic strategy" for CBP-deficient cancers by inhibition of the p300 HAT activity. Patients with CBP-deficient cancers could benefit from therapy using p300-HAT inhibitors. PMID- 26603526 TI - Matrix Biology Highlights. PMID- 26603528 TI - Stereoselective metabolism of donepezil and steady-state plasma concentrations of S-donepezil based on CYP2D6 polymorphisms in the therapeutic responses of Han Chinese patients with Alzheimer's disease. AB - The therapeutic response rates of patients to donepezil vary from 20% to 60%, one of the reasons is their genetic differences in donepezil-metabolizing enzymes, which directly influence liver metabolism. However, the mechanism of donepezil metabolism and that of its enantiomers is unknown. This study evaluated CYP2D6 polymorphisms to elucidate the stereoselective metabolism of donepezil and to confirm the association between the steady-state plasma concentrations of the pharmaco-effective S-donepezil and the therapeutic responses of Han Chinese patients with Alzheimer's disease. The in vitro study of the stereoselective metabolism demonstrated that CYP2D6 is the predominant P450 enzyme that metabolizes donepezil and that different CYP2D6 alleles differentially affect donepezil enantiomers metabolism. A total of 77 Han Chinese patients with Alzheimer's disease were recruited to confirm these results, by measuring their steady-state plasma concentrations of S-donepezil. The related CYP2D6 genes were genotyped. Plasma concentrations of S-donepezil (based on CYP2D6 polymorphisms) were significantly associated with therapeutic responses. This finding suggests that plasma concentrations of S-donepezil influence therapeutic outcomes following treatment with donepezil in Han Chinese patients with Alzheimer's disease. Therefore, determining a patient's steady-state plasma concentration of S-donepezil in combination with their CYP2D6 genotype might be useful for clinically monitoring the therapeutic efficacy of donepezil. PMID- 26603529 TI - Angiostatin prevents IL-1beta-induced down-regulation of eNOS expression by inhibiting the NF-kappaB cascade. AB - This study aimed to elucidate the protective potential of angiostatin in inflamed endothelial cells in culture. We assessed the effect of angiostatin on the expression of ICAM-1 and eNOS. Angiostatin prevented IL-1beta-induced down regulation of eNOS expression, but produced no significant changes on IL-1beta induced up-regulation of ICAM-1. We then explored the effect of angiostatin on IL 1beta-mediated inflammatory signaling and found that angiostatin inhibited IL 1beta-mediated nuclear translocation of NF-kappaB. Thus, our results suggest that angiostatin prevents IL-1beta-induced down-regulation of eNOS expression via inhibition of the NF-kappaB cascade; this may be the anti-inflammatory mechanism of angiostatin. PMID- 26603531 TI - Plasma Prekallikrein Is Associated With Carotid Intima-Media Thickness in Type 1 Diabetes. AB - The hypothesis that plasma prekallikrein (PK) is a risk factor for the development of vascular complications was assessed in a study using the Diabetes Control and Complications Trial (DCCT)/Epidemiology and Diabetes Interventions and Complications (EDIC) cohort of subjects with type 1 diabetes. The circulating levels of plasma PK activity were measured in the plasma of 636 subjects with type 1 diabetes (EDIC years 3-5). Common and internal carotid intima-media thickness (IMT) were measured by B-mode ultrasonography in EDIC years 1 and 6. Plasma PK levels were positively and significantly associated with BMI, hemoglobin A1c, systolic blood pressure, total cholesterol, LDL cholesterol, and triglycerides but not with age, sex, duration of diabetes, or HDL cholesterol. Univariate and multivariable statistical models after controlling for other risk factors consistently demonstrated a positive association between plasma PK and progression of internal carotid IMT. Multivariate analysis using a general linear model showed plasma PK to be significantly associated with progression of both internal and combined IMT (Wilks Lambda P value of 0.005). In addition, the mean internal carotid IMT levels were higher in subjects with plasma PK levels in the highest 10th percentile compared with subjects with plasma PK levels in the lower 10th percentile (P = 0.048). These novel findings implicate plasma PK as a risk factor for vascular disease in type 1 diabetes. PMID- 26603530 TI - Plasma fractalkine is a sustained marker of disease severity and outcome in sepsis patients. AB - INTRODUCTION: Fractalkine is a chemokine implicated as a mediator in a variety of inflammatory conditions. Knowledge of fractalkine release in patients presenting with infection to the Intensive Care Unit (ICU) is highly limited. The primary objective of this study was to establish whether plasma fractalkine levels are elevated in sepsis and associate with outcome. The secondary objective was to determine whether fractalkine can assist in the diagnosis of infection upon ICU admission. METHODS: Fractalkine was measured in 1103 consecutive sepsis patients (including 271 patients with community-acquired pneumonia (CAP)) upon ICU admission and at days 2 and 4 thereafter; in 73 ICU patients treated for suspected CAP in whom this diagnosis was refuted in retrospect; and in 5 healthy humans intravenously injected with endotoxin. RESULTS: Compared to healthy volunteers, sepsis patients had strongly elevated fractalkine levels. Fractalkine levels increased with the number of organs failing, were higher in patients presenting with shock, but did not vary by site of infection. Non-survivors had sustained elevated fractalkine levels when compared to survivors. Fractalkine was equally elevated in CAP patients and patients treated for CAP but in whom the diagnosis was retrospectively refuted. Fractalkine release induced by intravenous endotoxin followed highly similar kinetics as the endothelial cell marker E selectin. CONCLUSIONS: Plasma fractalkine is an endothelial cell derived biomarker that, while not specific for infection, correlates with disease severity in sepsis patients admitted to the ICU. PMID- 26603533 TI - Endoscopic skull base surgery: evaluation of current clinical outcomes. AB - INTRODUCTION: Endoscopic skull base surgery is one of the most recent fields of neurosurgery. Successive innovations were developed throughout history so that the current concepts that rule this surgical field could be reached. The current paper presents the evolution of endoscopic surgery and its current results on the treatment of skull base tumor, based on a review of meta-analysis and clinical series. METHODS: A PubMed search for articles published between January 1990 and January 2014 about "endoscopic skull base surgery", "endoscopic transsphenoidal approach", "endoscopic treatment of parasellar tumors" and "suprasellar lesions" was performed. RESULTS: According to the current data, endoscopic surgery seems to be superior to open and transsphenoidal microscopic removal of giant pituitary adenomas. Endoscopy is at least as successful as transsphenoidal microsurgery for the removal of pituitary adenomas and craniopharyngiomas. Transcranial open approaches, in the context of anterior midline skull base meningiomas, present higher rates of gross total resection, fewer complications and better clinical results than endoscopy approaches. The rate of postoperative CSF leakage has been significantly reduced with the introduction of new techniques such as the Hadad- Bassagasteguy flap but still represent one of the most important complications of this technique. CONCLUSION: Currently, selected tumors located at the anterior, middle and posterior fossa can be adequately assessed using the endoscope with low rates of postoperative CSF leaks. Endoscopic surgery has substantially evolved in the last decades through the collaboration of different teams around the world. The endoscope is now an essential tool in the neurosurgery armamentarium with great potential for new applications in the nearby future. PMID- 26603532 TI - Using second harmonic generation to predict patient outcome in solid tumors. AB - BACKGROUND: Over-treatment of estrogen receptor positive (ER+), lymph node negative (LNN) breast cancer patients with chemotherapy is a pressing clinical problem that can be addressed by improving techniques to predict tumor metastatic potential. Here we demonstrate that analysis of second harmonic generation (SHG) emission direction in primary tumor biopsies can provide prognostic information about the metastatic outcome of ER+, LNN breast cancer, as well as stage 1 colorectal adenocarcinoma. METHODS: SHG is an optical signal produced by fibrillar collagen. The ratio of the forward-to-backward emitted SHG signals (F/B) is sensitive to changes in structure of individual collagen fibers. F/B from excised primary tumor tissue was measured in a retrospective study of LNN breast cancer patients who had received no adjuvant systemic therapy and related to metastasis-free survival (MFS) and overall survival (OS) rates. In addition, F/B was studied for its association with the length of progression-free survival (PFS) in a subgroup of ER+ patients who received tamoxifen as first-line treatment for recurrent disease, and for its relation with OS in stage I colorectal and stage 1 lung adenocarcinoma patients. RESULTS: In 125 ER+, but not in 96 ER-negative (ER-), LNN breast cancer patients an increased F/B was significantly associated with a favorable MFS and OS (log rank trend for MFS: p = 0.004 and for OS: p = 0.03). On the other hand, an increased F/B was associated with shorter PFS in 60 ER+ recurrent breast cancer patients treated with tamoxifen (log rank trend p = 0.02). In stage I colorectal adenocarcinoma, an increased F/B was significantly related to poor OS (log rank trend p = 0.03), however this relationship was not statistically significant in stage I lung adenocarcinoma. CONCLUSION: Within ER+, LNN breast cancer specimens the F/B can stratify patients based upon their potential for tumor aggressiveness. This offers a "matrix-focused" method to predict metastatic outcome that is complementary to genomic "cell-focused" methods. In combination, this and other methods may contribute to improved metastatic prediction, and hence may help to reduce patient over-treatment. PMID- 26603534 TI - Near-infrared spectroscopy to assess microvascular dysfunction: A prospective pilot study in cardiac surgery patients. AB - PURPOSE: The diagnosis of microvascular dysfunction remains challenging after cardiac surgery. We hypothesized that peripheral near-infrared spectroscopy (NIRS) monitoring in combination with a vascular occlusion test could reliably assess postoperative microvascular dysfunction in that setting. MATERIALS AND METHODS: Twenty-two patients undergoing cardiac surgery with cardiopulmonary bypass and 10 healthy volunteers were prospectively investigated. Relevant NIRS parameters (regional tissue oxygen saturation, desaturation, and resaturation rates) were recorded the day before surgery (D-1), at the arrival in the intensive care unit (postoperative day [POD] 0) and on POD 1 and POD 2. RESULTS: No difference in NIRS parameters was found at baseline between healthy volunteers and cardiac surgical patients. Absolute values of regional tissue oxygen saturation significantly increased at POD 0 and POD 1 when compared with D-1: 78% (75%-81%) and 75% (73%-78%) vs 68% (64%-72%), P < .001. No statistical difference was evidenced within the postoperative period in desaturation and resaturation rates compared with D-1: desaturation rate, 0.11% . s(-1) (0.08-0.14) and 0.15% . s(-1) (0.08-0.22) vs 0.14% . s(-1) (0.10-0.17), P = .233, and resaturation rate, 0.76% . s(-1) (0.41-1.11) and 0.77% . s(-1) (0.53-1.02) vs 0.79% . s(-1) (0.61 0.97), P = .453. The use of postoperative norepinephrine infusion did not change the results. CONCLUSIONS: Peripheral NIRS monitoring in combination with a vascular occlusion test failed to assess cardiopulmonary bypass-induced microvascular dysfunction. PMID- 26603535 TI - [In Process Citation]. PMID- 26603536 TI - Effects of lanreotide Autogel primary therapy on symptoms and quality-of-life in acromegaly: data from the PRIMARYS study. AB - PURPOSE: To evaluate the effects of lanreotide Autogel on patient-reported outcomes and association with biochemical control, using PRIMARYS data. METHODS: PRIMARYS was a 1-year, open-label study of lanreotide Autogel (Depot in USA) 120 mg every 4 weeks in 90 treatment-naive patients with acromegaly. Symptoms were assessed using Patient-assessed Acromegaly Symptom Questionnaire (PASQ) and health-related quality of life (HRQoL) using the AcroQoL questionnaire. Correlations between PASQ and AcroQoL scores, and between PASQ/AcroQoL and growth hormone (GH)/insulin-like growth factor-1 (IGF-1) levels were also evaluated (post hoc). RESULTS: Acromegaly symptoms and HRQoL significantly improved from week 12 to week 48, with modest correlations at week 48 between PASQ total score (R = -0.55, p < 0.0001) and AcroQoL global and physical scores (R = -0.67, p < 0.0001). Approximately 60% of patients achieved a minimal important difference (MID; improvement >50% of baseline standard deviation) in PASQ total score and >40% achieved a MID in AcroQoL global score (post hoc). Changes in PASQ scores were similar in biochemically controlled (GH levels <=2.5 MUg/L and normal IGF-1 levels) and uncontrolled groups, while changes in global and psychological AcroQoL scores were greater in the controlled group. There was no correlation between changes in PASQ or AcroQoL scores and changes in GH or IGF-1 levels. CONCLUSIONS: Primary treatment with lanreotide Autogel over 1 year was associated with rapid and sustained improvements in clinical signs and symptoms and HRQoL in patients with acromegaly. Improvements in HRQoL, but not symptoms, were greater in those achieving biochemical control (ClinicalTrials.gov: NCT00690898; EudraCT: 2007-000155-34). PMID- 26603537 TI - Structural studies of novel glycoconjugates from polymerized allergens (allergoids) and mannans as allergy vaccines. AB - Immunotherapy for treating IgE-mediated allergies requires high doses of the corresponding allergen. This may result in undesired side effects and, to avoid them, hypoallergenic allergens (allergoids) polymerized with glutaraldehyde are commonly used. Targeting allergoids to dendritic cells to enhance cell uptake may result in a more effective immunotherapy. Allergoids coupled to yeast mannan, as source of polymannoses, would be suitable for this purpose, since mannose-binding receptors are expressed on these cells. Conventional conjugation procedures of mannan to proteins use oxidized mannan to release reactive aldehydes able to bind to free amino groups in the protein; yet, allergoids lack these latter because their previous treatment with glutaraldehyde. The aim of this study was to obtain allergoids conjugated to mannan by an alternative approach based on just glutaraldehyde treatment, taking advantage of the mannoprotein bound to the polymannose backbone. Allergoid-mannan glycoconjugates were produced in a single step by treating with glutaraldehyde a defined mixture of allergens derived from Phleum pratense grass pollen and native mannan (non-oxidized) from Saccharomyces cerevisae. Analytical and structural studies, including 2D-DOSY and (1)H-(13)C HSQC nuclear magnetic resonance spectra, demonstrated the feasibility of such an approach. The glycoconjugates obtained were polymers of high molecular weight showing a higher stability than the native allergen or the conventional allergoid without mannan. The allergoid-mannan glycoconjugates were hypoallergenic as detected by the IgE reactivity with sera from grass allergic patients, even with lower reactivity than conventional allergoid without mannan. Thus, stable hypoallergenic allergoids conjugated to mannan suitable for using in immunotherapy can be achieved using glutaraldehyde. In contrast to mannan oxidation, the glutaraldehyde approach allows to preserve mannoses with their native geometry, which may be functionally important for its receptor-mediated recognition. PMID- 26603539 TI - Spatial variation of vessel grouping in the xylem of Betula platyphylla Roth. AB - Vessel grouping in angiosperms may improve hydraulic integration and increase the spread of cavitations through redundancy pathways. Although disputed, it is increasingly attracting research interest as a potentially significant hydraulic trait. However, the variation of vessel grouping in a tree is poorly understood. I measured the number of solitary and grouped vessels in the xylem of Betula platyphylla Roth. from the pith to the bark along the water flow path. The vessel grouping parameters included the mean number of vessels per vessel group (VG), percentage of solitary vessels (SVP), percentage of radial multiple vessels (MVP), and percentage of cluster vessels (CVP). The effects of cambial age (CA) and flow path-length (PL) on the vessel grouping were analyzed using a linear mixed model.VG and CVP increased nonlinearly, SVP decreased nonlinearly with PL. In trunks and branches, VG and CVP decreased nonlinearly, and SVP increased nonlinearly with CA. In roots, the parameters had no change with CA. MVP was almost constant with PL or CA. The results suggest that vessel grouping has a nonrandom variation pattern, which is affected deeply by cambial age and water flow path. PMID- 26603540 TI - Abstracts from the 2nd Annual Fetal Cardiac Symposium Chicago, Illinois, United States September 10-12, 2015. PMID- 26603538 TI - What is the evidence for the role of TRP channels in inflammatory and immune cells? AB - A complex network of many interacting mechanisms orchestrates immune and inflammatory responses. Among these, the cation channels of the transient receptor potential (TRP) family expressed by resident tissue cells, inflammatory and immune cells and distinct subsets of primary sensory neurons, have emerged as a novel and interrelated system to detect and respond to harmful agents. TRP channels, by means of their direct effect on the intracellular levels of cations and/or through the indirect modulation of a large series of intracellular pathways, orchestrate a range of cellular processes, such as cytokine production, cell differentiation and cytotoxicity. The contribution of TRP channels to the transition of inflammation and immune responses from a defensive early response to a chronic and pathological condition is also emerging as a possible underlying mechanism in various diseases. This review discusses the roles of TRP channels in inflammatory and immune cell function and provides an overview of the effects of inflammatory and immune TRP channels on the pathogenesis of human diseases. PMID- 26603542 TI - Open surgical or endovascular revascularization for acute limb ischemia. AB - Acute limb ischemia (ALI) is one of the most common vascular emergencies, with high risk for limb loss if it is not treated expediently. Endovascular therapy is less invasive and used increasingly because of patient factors that disfavor open surgery despite limited quality data to support its safety and efficacy. This evidence summary reviews literature from 1990 to 2014, comparing contemporary surgical and endovascular revascularization. Systematic review was performed with emphasis on acuity of presentation, study design, revascularization techniques, limb salvage and mortality rates, and complications. There were 2999 articles identified and 563 abstracts reviewed; 68 articles were reviewed fully and 26 critically appraised. Limb salvage, amputation-free survival, overall survival and mortality, and treatment complications were elucidated, including Medicare outcomes data. Risk factors for amputation and mortality were identified. Surgical or endovascular revascularization for ALI is achievable with acceptable limb salvage and amputation rates, which are not markedly different between the two modalities in the short term. Endovascular therapy and surgery are complementary rather than competing strategies for ALI. Further good-quality clinical trial data are needed to define longer term outcomes. PMID- 26603541 TI - Late liver function test abnormalities post-adult liver transplantation: a review of the etiology, investigation, and management. AB - Approximately 24,000 liver transplants are performed annually worldwide, almost 7000 of which are performed in the USA. Survival is excellent and continues to improve, with 1-year survival currently exceeding 85 %, but effective management of patients after liver transplantation is critical to achieve optimal results. A plethora of diseases can affect the transplanted allograft, ranging from recurrence of the original disease to de novo liver pathology, and diagnosis can be complicated by nonclassical presentation, de novo disease, or inconclusive histology. Patients can remain asymptomatic despite significant damage to the transplanted liver, so prompt identification and treatment of liver disease after transplantation is crucial to preserve allograft function. Liver function tests are routinely taken throughout the postoperative period to monitor the graft. Although nonspecific, they are inexpensive, noninvasive, and sensitive for allograft disease and can quickly alert physicians to the presence of asymptomatic pathology. This review will outline possible causes of liver function test abnormalities in the late posttransplant period and provide guidance for investigation, diagnosis, and management. PMID- 26603543 TI - Renin-angiotensin-aldosterone-system inhibition is safe in the preoperative period surrounding carotid endarterectomy. AB - OBJECTIVE: Discontinuation of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) medications before surgery has been suggested because of the potentially deleterious effects of hypotension. We investigated the effect of preoperative ACEI and/or ARB use on early outcomes after carotid endarterectomy (CEA). METHODS: We examined 3752 consecutive CEA patients within the Vascular Study Group of New England from September 2012 to September 2014 and compared outcomes for patients treated (n = 1772) or not treated (n = 1980) with ACEI and/or ARB preoperatively. Outcomes included perioperative need for intravenous vasoactive medication (IVBPmed) for hypotension or hypertension (HTN), major adverse cardiac events (MACEs), and the combined outcome of stroke or death. Adjusted analysis was performed using multivariable logistic regression of the crude cohort and by constructing a propensity score matched cohort (n = 1441). RESULTS: ACEI and/or ARB users were more likely to be male (64% vs 59%; P = .001), with a higher prevalence of diabetes (41% vs 28%; P < .0001), HTN (97% vs 82%; P < .0001), coronary artery disease (31% vs 25%; P = .0001), congestive heart failure (10% vs 8%; P = .02), and asymptomatic carotid disease (59% vs 54%; P = .004). Patients who received ACEI and/or ARB preoperatively were more likely to be treated with aspirin (92% vs 88%; P = .0002) and statins (89% vs 85%; P = .001) preoperatively. In the unadjusted analysis, no significant differences were identified in hypotension that required IVBPmed (12% vs 11%; odds ratio [OR], 1.1; 95% confidence interval [CI], 0.9-1.4; P = .22), MACE (3% vs 2%; OR, 1.3; 95% CI, 0.8-1.9; P = .32), or stroke or death (3% vs 3%; OR, 1.0; 95% CI, 0.7 1.6; P = .89) for preoperative ACEI and/or ARB treated and nontreated patients, respectively. Preoperative ACEI and/or ARB usage was, however, associated with HTN that required IVBPmed (13% vs 10%; OR, 1.3; 95% CI, 1.1-1.6; P = .01). Analysis of the propensity score matched cohort revealed no significant differences in hypotension that required IVBPmed (12% vs 12%; OR, 1.0; 95% CI, 0.8-1.3; P = .86), MACE (3% vs 2%; OR, 1.1; 95% CI, 0.7-1.8; P = .62; ), or stroke or death (3% vs 3%; OR, 1.0; 95% CI, 0.7-1.6; P = .91) for patients treated or not treated with preoperative ACEI and/or ARB, respectively. ACEI and/or ARB remained associated with HTN that required IVBPmed (13% vs 10%; OR, 1.3; 95% CI, 1.0-1.7; P = .02). Results were similar after adjustment using logistic regression. The incidence of hospital length of stay >1 day was similar between ACEI and/or ARB treated and not treated patients (29% vs 32%; OR, 0.9; 95% CI, 0.8-1.1; P = .21). CONCLUSIONS: Preoperative ACEI and/or ARB use was associated with marginally increased use of IVBPmed for HTN but not for hypotension and was not associated with increased MACE, stroke, or death. On the basis of these metrics, the use of preoperative ACEI and/or ARB appears safe before CEA. PMID- 26603544 TI - Perigraft vascularization and incorporation of implanted Dacron prostheses are affected by rifampicin coating. AB - BACKGROUND: Prosthetic vascular grafts are increasingly implanted to replace damaged arteries. However, their microbial contamination is highly problematic and often results in devastating clinical complications. To reduce the risk of infection, Dacron grafts may be coated with rifampicin. In this experimental study we analyzed whether this coating affects the early tissue incorporation of the grafts. METHODS: Saline- and rifampicin-coated Dacron (Dacron-Rifamp) grafts were implanted into dorsal skinfold chambers of C57BL/6 mice (n = 8 per group) to study vascularization, inflammation, cell proliferation, and apoptosis at the implantation site using repetitive intravital fluorescence microscopy and immunohistochemistry over an observation period of 14 days. RESULTS: Implanted Dacron-Rifamp grafts exhibited a impaired vascularization, indicated by a significantly lower functional capillary density (85 +/- 1 cm/cm2) compared with controls (113 +/- 1 cm/cm2; P < .05). This was associated with a reduced number of Ki-67-positive proliferating cells (9.4% +/- 1.1% vs 13.5 +/- 0.4%; P < .05) and an increased number of cleaved caspase-3-positive apoptotic cells (2.7% +/- 0.3% vs 1.3% +/- 0.3%; P < .05) in the newly developing granulation tissue surrounding the implants. In addition, the neutrophilic (652 +/- 84 mm2 vs 934 +/ 117 mm2; P = .06), lymphatic (26 +/- 6 mm2 vs 39 +/- 9 mm2; P = .24) and macrophage response (177 +/- 42 mm2 vs 233 +/- 86 mm2; P = .57) was decreased by trend in the group with Dacron-Rifamp grafts. CONCLUSIONS: Our novel findings show that early perigraft vascularization and incorporation of implanted Dacron prostheses are affected by the rifampicin coating. Because rapid graft vascularization and incorporation are thought to reduce the risk of infection, the use of Dacron-Rifamp Dacron grafts for antibacterial prophylaxis should be reconsidered particularly in cases of elective arterial reconstruction in a noninfected environment. PMID- 26603545 TI - Attainment of low-density lipoprotein cholesterol goal after endovascular treatment is associated with reduced cardiovascular events in patients with peripheral arterial disease. AB - OBJECTIVE: The relationship between attainment of low-density lipoprotein cholesterol (LDL-C) levels and clinical outcomes in patients with peripheral arterial disease (PAD) has received little attention. We sought to investigate clinical outcomes in relation to attainment of LDL-C goals in patients with PAD after endovascular treatment. METHODS: We reviewed 342 PAD patients treated with endovascular therapy from 2010 through 2012. We categorized patients into two groups based on the attained LDL-C levels at short-term follow-up (mean, 4.8 +/- 2.8 months): group A (n = 160), with LDL-C <70 mg/dL; and group B (n = 182), with LDL-C >=70 mg/dL. The primary end point was major adverse cardiovascular events (MACEs), a composite of all-cause death, nonfatal myocardial infarction, and stroke. RESULTS: Baseline characteristics were similar between group A and group B except for obstructive pulmonary disease (0% vs 7%; P = .001). More patients in group A received statin therapy than those in group B (93% vs 76%; P < .001). MACEs (4% vs 10%; P = .002) and all-cause mortality (2% vs 7%; P = .007) occurred less frequently in group A than in group B at 2 years. A Cox proportional hazards multivariate regression model identified attainment of LDL-C goal <70 mg/dL at short-term follow-up as an independent predictor of reduced MACEs (hazard ratio, 0.25; 95% confidence interval, 0.09-0.67; P = .006) along with age as a predictor of increased MACEs (hazard ratio, 1.04; 95% confidence interval, 1.00-1.08; P = .031). CONCLUSIONS: Attainment of LDL-C goal <70 mg/dL at short-term follow-up is an independent predictor of reduced mortality and cardiovascular events after endovascular therapy in patients with PAD. PMID- 26603546 TI - Patency of the contralateral internal iliac artery in aortouni-iliac endografting. AB - OBJECTIVE: This study determined the outcome of the contralateral internal iliac artery (IIA) in patients undergoing aortouni-iliac (AUI) endovascular abdominal aortic aneurysm repair (EVAR) with a femorofemoral bypass. METHODS: This retrospective study evaluated 131 consecutive patients undergoing AUI EVAR with femorofemoral bypass at the McGill University Health Center from October 2001 to November 2010. One hundred patients with preoperatively patent contralateral IIA met inclusion criteria for the study. Preoperative demographics and preoperative and postoperative contrast-enhanced computed tomography (CT) scans with multiplanar reconstruction were reviewed for all patients. The last available postoperative CT imaging for all patients was identified and evaluated for contralateral IIA patency. Patency in preoperative and postoperative CT scans was defined as contrast enhancement of the IIA in continuity with the external iliac artery and absence of >50% stenosis at the origin of the IIA. Clinical outcome focused on postoperative pelvic ischemia and reported symptoms of buttock claudication. RESULTS: Mean age at the time of operation was 77.6 +/- 6.7 years, and 78% were male. Mean clinical follow-up was 29.2 months after surgery, and mean follow-up of imaging with intravenous contrast was 30.6 months. The last imaging follow-up showed 67 patients (67%) had a patent contralateral IIA and that the IIAs in 33 patients (33%) were occluded (25 [76%]) or stenotic (8 [24%]). Of the patients with IIA occlusion, 80% (20 of 25) were occluded on the first postoperative imaging (median, 8.5 days). Buttock claudication was reported in 18% (6 of 33 patients) with an occluded IIA compared with only 3% (2 of 67 patients) of patients with a patent contralateral IIA on final imaging follow-up (18% vs 3%; P = .014). There were no observed cases of buttock necrosis, spinal ischemia, or colonic ischemia. CONCLUSIONS: Our findings suggest that AUI EVAR with femorofemoral bypass is associated with a significant incidence of contralateral IIA malperfusion on postoperative CT imaging. Occlusion appears to occur early in the postoperative period in most patients, and patient-reported buttock claudication is observed significantly more frequently in patients with an occluded IIA compared with those with a patent IIA. More serious pelvic ischemic complications were not seen in this series. Further study is required to determine whether modification of the procedure can prevent contralateral IIA occlusion and the development of buttock claudication. PMID- 26603547 TI - A comparative evaluation of risk-adjustment models for benchmarking amputation free survival after lower extremity bypass. AB - BACKGROUND: Providing patients and payers with publicly reported risk-adjusted quality metrics for the purpose of benchmarking physicians and institutions has become a national priority. Several prediction models have been developed to estimate outcomes after lower extremity revascularization for critical limb ischemia, but the optimal model to use in contemporary practice has not been defined. We sought to identify the highest-performing risk-adjustment model for amputation-free survival (AFS) at 1 year after lower extremity bypass (LEB). METHODS: We used the national Society for Vascular Surgery Vascular Quality Initiative (VQI) database (2003-2012) to assess the performance of three previously validated risk-adjustment models for AFS. The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL), Finland National Vascular (FINNVASC) registry, and the modified Project of Ex-vivo vein graft Engineering via Transfection III (PREVENT III [mPIII]) risk scores were applied to the VQI cohort. A novel model for 1-year AFS was also derived using the VQI data set and externally validated using the PIII data set. The relative discrimination (Harrell c-index) and calibration (Hosmer-May goodness-of-fit test) of each model were compared. RESULTS: Among 7754 patients in the VQI who underwent LEB for critical limb ischemia, the AFS was 74% at 1 year. Each of the previously published models for AFS demonstrated similar discriminative performance: c indices for BASIL, FINNVASC, mPIII were 0.66, 0.60, and 0.64, respectively. The novel VQI-derived model had improved discriminative ability with a c-index of 0.71 and appropriate generalizability on external validation with a c-index of 0.68. The model was well calibrated in both the VQI and PIII data sets (goodness of fit P = not significant). CONCLUSIONS: Currently available prediction models for AFS after LEB perform modestly when applied to national contemporary VQI data. Moreover, the performance of each model was inferior to that of the novel VQI-derived model. Because the importance of risk-adjusted outcome reporting continues to increase, national registries such as VQI should begin using this novel model for benchmarking quality of care. PMID- 26603548 TI - Twisted parietal peritoneal lipomatous appendage incarcerated in a linea arcuata hernia: Imaging findings. PMID- 26603549 TI - PSMA-Based Detection of Prostate Cancer Bone Lesions With 18F-DCFPyL PET/CT: A Sensitive Alternative to (99m)Tc-MDP Bone Scan and Na18F PET/CT? PMID- 26603551 TI - A novel C,D-spirodioxene taxoid synthesized through an unexpected Pd-mediated ring cyclization. AB - A novel C,D-spirodioxene taxoid (6) was prepared from paclitaxel (1a), with the key steps including an unexpected Pd-mediated ring cyclization. The anti-tubulin activity of 6 was decreased relative to that of 1a and a previously reported C,D spirolactone taxane (5). These observations could be rationalized on the basis of molecular modeling results. To the best of our knowledge, this is the first example indicating that 1,4-dioxenes can be synthesized from a mono-allyl vicinal diol through a Wacker-type cyclization. This strategy may be applicable to the synthesis of other C,D-spiro taxoids. PMID- 26603550 TI - Ganoderma lucidum polysaccharide peptide prevents renal ischemia reperfusion injury via counteracting oxidative stress. AB - Ganoderma lucidum polysaccharide peptide (GLPP) scavenges oxygen free radicals that are a key factor in the pathogenesis of renal ischemia reperfusion injury (RIRI). The aim of this study was to determine whether GLPP could attenuate RIRI by counteracting the oxidative stress. The mechanism involved was assessed by an in vivo mouse RIRI model and an in vitro hypoxia/reoxygenation model, and tunicamycin-stimulated NRK-52E cells were used to explore the GLPP-mediated alleviation of ER stress. Experimental results showed that renal dysfunction and morphological damage were reduced in GLPP-treated group. The imbalance of redox status was reversed and production of ROS was reduced by GLPP. RIRI-induced mitochondrial- and ER stress-dependent apoptosis were dramatically inhibited in GLPP-treated group. Intriguingly, JNK activation in the kidney with RIRI or hypoxia/reoxygenation was inhibited by GLPP. These results suggest that the protective effect of GLPP against RIRI may be due to reducing oxidative stress, alleviating the mitochondrial and ER stress-dependent apoptosis caused by excessive ROS. PMID- 26603552 TI - Is fucose the answer to the immunomodulatory paradox of Quillaja saponins? AB - Quillaja saponins, e.g. QS-21, are immunomodulating aldehyde-carrying triterpene glycosides, which depending on the acylation state of their single fucosyl residue (Fucp) induce either Th1/Th2 or Th2 immunity. Indeed, their changes in immunomodulation or adjuvanticity from Th1/Th2 to sole Th2 immunity, correlate with the presence of acylated and de-acylated Fucp residues, respectively. Thus, it is possible to infer that the single Fucp residue is responsible for the Th2 immunity biasing induced by de-acylated Q. saponins (QT-0101). That removal of the fucosylated oligosaccharide from de-acylated Q. saponins results once more in the induction of Th1/Th2 immunity supports the Fucp role in polarizing the response toward Th2 immunity. From structural and functional analogies with the helminths' fucosylated glycans, it is possible to infer that these saponins' Fucp must bind to the lectin DC-SIGN on dendritic cells (DC). This binding to DC-SIGN, a C-type lectin that shows significant pliability in its binding interactions, must result in polarization toward Th2 while inhibiting Th1 immunity. Apparently, acylation of the Fucp by large fatty acids sterically hinders this sugar from binding to DC-SIGN, preventing a biasing to Th2 immunity. Evidently, de-acylation of Q. saponins may negatively affect vaccines requiring Th1 immunity for immune protection, particularly those against pathogens that use DC-SIGN to infect DCs and modulate Th2 immunity. However, it could be valuable in vaccines that require a sole Th2 immunity, like those against proteinopathies, e.g. Alzheimer's disease. Hence, it would valuable to elucidate the possible interactions between DC-SIGN and the QT-0101 immunomodulator. PMID- 26603553 TI - Postoperative Infection After Anterior Cruciate Ligament Reconstruction. AB - CONTEXT: Infection after anterior cruciate ligament reconstruction (ACLR) is uncommon; if it occurs, it can lead to disastrous complications. OBJECTIVE: To analyze post-ACLR infections and identify related complications to provide the most effective treatment protocol. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Among approximately 1850 ACLRs performed by a single surgeon over the past 20 years, 7 cases of post-ACLR infection were identified (incidence, 0.37%). Five patients presenting with low-severity infection were successfully treated without any complication or residual functional disability. The remaining 2 patients, although successfully treated, presented with minor residual limitations. From a literature review, 16 studies including 246 cases of infection were reported among 35,795 ACLRs, making the rate of infection 0.68% (range, 0.14%-2.6%). CONCLUSION: With proper treatment protocols, post-ACLR infection is rare but can compromise outcomes. PMID- 26603554 TI - Effects of wintertime fasting and seasonal adaptation on AMPK and ACC in hypothalamus, adipose tissue and liver of the raccoon dog (Nyctereutes procyonoides). AB - The raccoon dog (Nyctereutes procyonoides) is a canid with autumnal fattening and passive wintering strategy. We examined the effects of wintertime fasting and seasonality on AMP-activated protein kinase (AMPK), a regulator of metabolism, and its target, acetyl-CoA carboxylase (ACC) on the species. Twelve farmed raccoon dogs (eleven females/one male) were divided into two groups: half were fasted for ten weeks in December-March (winter fasted) and the others were fed ad libitum (winter fed). A third group (autumn fed, eight females) was fed ad libitum and sampled in December. Total AMPK, ACC and their phosphorylated forms (pAMPK, pACC) were measured from hypothalamus, liver, intra-abdominal (iWAT) and subcutaneous white adipose tissues (sWAT). The fasted animals lost 32% and the fed 20% of their body mass. Hypothalamic AMPK expression was lower and pACC levels higher in the winter groups compared to the autumn fed group. Liver pAMPK was lower in the winter fasted group, with consistently decreased ACC and pACC. AMPK and pAMPK were down-regulated in sWAT and iWAT of both winter groups, with a parallel decline in pACC in sWAT. The responses of AMPK and ACC to fasting were dissimilar to the effects observed previously in non-seasonal mammals and hibernators. Differences between the winter fed and autumn fed groups indicate that the functions of AMPK and ACC could be regulated in a season-dependent manner. Furthermore, the distinctive effects of prolonged fasting and seasonal adaptation on AMPK-ACC pathway could contribute to the wintering strategy of the raccoon dog. PMID- 26603555 TI - The potential impacts of migratory difficulty, including warmer waters and altered flow conditions, on the reproductive success of salmonid fishes. AB - Climate change and urbanisation of watercourses affect water temperatures and current flow velocities in river systems on a global scale. This represents a particularly critical issue for migratory fish species with complex life histories that use rivers to reproduce. Salmonids are migratory keystone species that provide substantial economical value to ecosystems and human societies. Consequently, a comprehensive understanding of the effects of environmental stressors on their reproductive success is critical in order to ensure their continued abundance during future climatic change. Salmonids are capital breeders, relying entirely on endogenous energy stores to fuel return migration to their natal spawning sites and reproduction upon arrival. Metabolic rates and cost of transport en-route increase with temperature and at extreme temperatures, swimming is increasingly fuelled anaerobically, resulting in an oxygen debt and reduced capacity to recover from exhaustive exercise. Thermally challenged salmonids also produce less viable gametes, which themselves are affected by water temperature after release. Passage through hydrological barriers and temperature changes both affect energy expenditure. As a result, important energetic tradeoffs emerge between extra energy used during migration and that available for other facets of the reproductive cycle, such as reproductive competition and gamete production. However, studies identifying these tradeoffs are extremely sparse. This review focuses on the specific locomotor responses of salmonids to thermal and hydrological challenges, identifying gaps in our knowledge and highlighting the potential implications for key aspects of their reproduction. PMID- 26603556 TI - Impact of different temperatures on survival and energy metabolism in the Asian citrus psyllid, Diaphorina citri Kuwayama. AB - Temperature influences the life history and metabolic parameters of insects. Asian citrus psyllid (ACP), Diaphorina citri is a tropical and subtropical pest. ACP invaded new regions around the world and threatened the citrus industry as a vector for Huanglongbing (HLB) disease. ACP is widely distributed and can survive high (up to 45 degrees C) and low temperatures (as low as -6 degrees C). The precise mechanism of temperature tolerance in ACP is poorly understood. We investigated adult survival, cellular energy balance, gene expression, and nucleotide and sugar-nucleotide changes under the effect of different temperature regimes (0 degrees C to 45 degrees C with 5 degrees C intervals). The optimum temperatures for survival were 20 and 25 degrees C. Low temperatures of 0 degrees C and 5 degrees C caused 50% mortality after 2 and 4 days respectively, while one day at high temperature (40 degrees C and 45 degrees C) caused more than 95% mortality. The lowest quantity of ATP (3.69 +/- 1.6 ng/insect) and the maximum ATPase enzyme activities (57.43 +/- 7.6 MUU/insect) were observed at 25 degrees C. Correlation between ATP quantities and ATPase activity was negative. Gene expression of hsp 70, V-type proton ATPase catalytic subunit A and ATP synthase alpha subunit matched these results. Twenty-four nucleotides and sugar nucleotides were quantified using HPLC in ACP adults maintained at low, high, and optimum temperatures. The nucleotide profiles were different among treatments. The ratios between AMP:ATP and ADP:ATP were significantly decreased and positively correlated to adults survival, whereas the adenylate energy charge was increased in response to low and high temperatures. Exploring energy metabolic regulation in relation with adult survival might help in understanding the physiological basis of how ACP tolerates newly invaded regions. PMID- 26603557 TI - Salinity effects on plasma ion levels, cortisol, and osmolality in Chinook salmon following lethal sampling. AB - Studies on hydromineral balance in fishes frequently employ measurements of electrolytes following euthanasia. We tested the effects of fresh- or salt-water euthanasia baths of tricaine mesylate (MS-222) on plasma magnesium (Mg(2+)) and sodium (Na(+)) ions, cortisol and osmolality in fish exposed to saltwater challenges, and the ion and steroid hormone fluctuations over time following euthanasia in juvenile spring Chinook salmon (Oncorhynchus tshawytscha). Salinity of the euthanasia bath affected plasma Mg(2+) and Na(+) concentrations as well as osmolality, with higher concentrations in fish euthanized in saltwater. Time spent in the bath positively affected plasma Mg(2+) and osmolality, negatively affected cortisol, and had no effect on Na(+) concentrations. The difference of temporal trends in plasma Mg(2+) and Na(+) suggests that Mg(2+) may be more sensitive to physiological changes and responds more rapidly than Na(+). When electrolytes and cortisol are measured as endpoints after euthanasia, care needs to be taken relative to time after death and the salinity of the euthanasia bath. PMID- 26603558 TI - Early versus delayed intravitreal betamethasone as an adjuvant in the treatment of presumed postoperative endophthalmitis: a randomised trial. AB - AIM: To compare early versus delayed intravitreal betamethasone as an adjuvant in the treatment of presumed acute postoperative endophthalmitis after phacoemulsification. METHODS: Patients with presumed postcataract surgery endophthalmitis were included in this prospective, randomised, multicentre study. On admission, patients received intravitreal vancomycin and ceftazidime, and were randomly assigned to intravitreal betamethasone injection (early-IVB) group or no immediate injection (delayed-IVB) group. After 48 h, a second intravitreal antibiotic injection associated with intravitreal betamethasone was given to all patients. In patients with severe endophthalmitis or clinical deterioration, a prompt or delayed vitrectomy was performed. The primary outcome was the proportion of patients achieving a visual acuity (VA) of 20/40 or better at 12 months. The secondary outcomes were the rate of delayed vitrectomy and the rate of complications (retinal detachment and phthisis). RESULTS: Ninety-seven eyes of 97 patients were included, 45 in the early-IVB group and 52 in the delayed-IVB group. Overall, 62.9% of patients achieved a VA >=20/40 at 1 year. There was no statistically significant difference in the visual outcome between the two groups at 1 year, whatever their baseline VA or light perception or hand motion or more (p=0.55 and p=0.10, respectively). The rates of delayed vitrectomy, retinal detachment and phthisis bulbi were not significantly different between the two groups (p=0.42, p=0.37 and p=0.44, respectively). CONCLUSIONS: Early intravitreal betamethasone had no clear advantage versus delayed injection in the management of presumed postoperative endophthalmitis. PMID- 26603559 TI - Transcriptome-Wide Identification of RNA Targets of Arabidopsis SERINE/ARGININE RICH45 Uncovers the Unexpected Roles of This RNA Binding Protein in RNA Processing. AB - Plant SR45 and its metazoan ortholog RNPS1 are serine/arginine-rich (SR)-like RNA binding proteins that function in splicing/postsplicing events and regulate diverse processes in eukaryotes. Interactions of SR45 with both RNAs and proteins are crucial for regulating RNA processing. However, in vivo RNA targets of SR45 are currently unclear. Using RNA immunoprecipitation followed by high-throughput sequencing, we identified over 4000 Arabidopsis thaliana RNAs that directly or indirectly associate with SR45, designated as SR45-associated RNAs (SARs). Comprehensive analyses of these SARs revealed several roles for SR45. First, SR45 associates with and regulates the expression of 30% of abscisic acid (ABA) signaling genes at the postsplicing level. Second, although most SARs are derived from intron-containing genes, surprisingly, 340 SARs are derived from intronless genes. Expression analysis of the SARs suggests that SR45 differentially regulates intronless and intron-containing SARs. Finally, we identified four overrepresented RNA motifs in SARs that likely mediate SR45's recognition of its targets. Therefore, SR45 plays an unexpected role in mRNA processing of intronless genes, and numerous ABA signaling genes are targeted for regulation at the posttranscriptional level. The diverse molecular functions of SR45 uncovered in this study are likely applicable to other species in view of its conservation across eukaryotes. PMID- 26603561 TI - Magnetic anisotropy in Shiba bound states across a quantum phase transition. AB - The exchange coupling between magnetic adsorbates and a superconducting substrate leads to Shiba states inside the superconducting energy gap and a Kondo resonance outside the gap. The exchange coupling strength determines whether the quantum many-body ground state is a Kondo singlet or a singlet of the paired superconducting quasiparticles. Here we use scanning tunnelling spectroscopy to identify the different quantum ground states of manganese phthalocyanine on Pb(111). We observe Shiba states, which are split into triplets by magnetocrystalline anisotropy. Their characteristic spectral weight yields an unambiguous proof of the nature of the quantum ground state. Our results provide experimental insights into the phase diagram of a magnetic impurity on a superconducting host and shine light on the effects induced by magnetic anisotropy on many-body interactions. PMID- 26603560 TI - Brain Circuits Encoding Reward from Pain Relief. AB - Relief from pain in humans is rewarding and pleasurable. Primary rewards, or reward-predictive cues, are encoded in brain reward/motivational circuits. While considerable advances have been made in our understanding of reward circuits underlying positive reinforcement, less is known about the circuits underlying the hedonic and reinforcing actions of pain relief. We review findings from electrophysiological, neuroimaging, and behavioral studies supporting the concept that the rewarding effect of pain relief requires opioid signaling in the anterior cingulate cortex (ACC), activation of midbrain dopamine neurons, and the release of dopamine in the nucleus accumbens (NAc). Understanding of circuits that govern the reward of pain relief may allow the discovery of more effective and satisfying therapies for patients with acute or chronic pain. PMID- 26603562 TI - Correction: Acid-labile boronate-bridged dextran-bortezomib conjugate with up regulated hypoxic tumor suppression. AB - Correction for 'Acid-labile boronate-bridged dextran-bortezomib conjugate with up regulated hypoxic tumor suppression' by Weiguo Xu et al., Chem. Commun., 2015, 51, 6812-6815. PMID- 26603563 TI - The Origins of Tropical Rainforest Hyperdiversity. AB - Traditional models for tropical species richness contrast rainforests as "museums" of old species or "cradles" of recent speciation. High plant species diversity in rainforests may be more likely to reflect high episodic evolutionary turnover of species--a scenario implicating high rates of both speciation and extinction through geological time. PMID- 26603564 TI - Ultra-thin and porous MoSe2 nanosheets: facile preparation and enhanced electrocatalytic activity towards the hydrogen evolution reaction. AB - In this study, ultra-thin and porous molybdenum selenide (MoSe2) nanosheets were prepared through a modified liquid exfoliation method as efficient electrocatalysts for the hydrogen evolution reaction (HER). This novel structure enables the exposure of more catalytically active sites and moreover maintains effective electron transport, resulting in a small peak potential of ~75 mV as well as long-term durability. In addition, due to the facile and economical preparation method as well as its eco-friendly synthetic conditions, this study provides a high-performance HER catalyst with promising commercial application prospects. PMID- 26603566 TI - Prenatal diagnosis of thrombosed dural sinus malformation with periorbital hemangioma: a case report. PMID- 26603565 TI - An Insight into Recombination with Enterovirus Species C and Nucleotide G-480 Reversion from the Viewpoint of Neurovirulence of Vaccine-Derived Polioviruses. AB - A poliomyelitis outbreak caused by type 1 circulating vaccine-derived polioviruses (cVDPVs) was identified in China in 2004. Six independent cVDPVs (eight isolates) could be grouped into a single cluster with pathways of divergence different from a single cVDPV progenitor, which circulated and evolved into both a highly neurovirulent lineage and a less neurovirulent lineage. They were as neurovirulent as the wild type 1 Mahoney strain, recombination was absent, and their nucleotide 480-G was identical to that of the Sabin strain. The Guizhou/China cVDPV strains shared 4 amino acid replacements in the NAg sites: 3 located at the BC loop, which may underlie the aberrant results of the ELISA intratypic differentiation (ITD) test. The complete ORF tree diverged into two main branches from a common ancestral infection estimated to have occurred in about mid-September 2003, nine months before the appearance of the VDPV case, which indicated recently evolved VDPV. Further, recombination with species C enteroviruses may indicate the presence and density of these enteroviruses in the population and prolonged virus circulation in the community. The aforementioned cVDPVs has important implications in the global initiative to eradicate polio: high quality surveillance permitted earliest detection and response. PMID- 26603567 TI - Kinetic model of the thermal pyrolysis of chrome tanned leather treated with NaOH under different conditions using thermogravimetric analysis. AB - The thermal decomposition of chrome tanned leather before and after a soaking treatment with NaOH was studied using thermogravimetric analysis (TGA). The effect of the solution concentration (0.2M and 0.5M) and the soaking time (5min and 15min) was evaluated. TGA experiments at four heating rates (5, 10, 15 and 20 degrees Cmin(-1)) were run in a nitrogen atmosphere for every treatment condition. A kinetic model was developed considering the effect of the three variables studied, i.e.: the NaOH solution concentration, the soaking time and the heating rate. The proposed model for chrome tanned leather pyrolysis involves a set of four reactions, i.e.: three independent nth order reactions, yielding the corresponding products and one of them undergoing a successive cero order reaction. The model was successfully applied simultaneously to all the experimental data obtained. The evaluation of the kinetic parameters obtained (activation energy, pre-exponential factor and reaction order) allowed a better understanding of the effect of the alkali treatment on these wastes. PMID- 26603568 TI - Circulating HIV DNA Correlates With Neurocognitive Impairment in Older HIV infected Adults on Suppressive ART. AB - Older HIV-infected adults have a higher risk of neurocognitive impairment, but the underlying mechanisms are poorly understood. Here, we investigated the associations between levels of HIV DNA in peripheral blood, soluble markers of inflammation and cellular trafficking in blood and cerebrospinal fluid (CSF) and neurocognitive functioning among 18 younger (22-40 years) and 26 older (50-71 years) HIV-infected subjects, who were administered a comprehensive neurocognitive battery. Older HIV-infected individuals presented higher levels of inflammation in CSF and blood compared to younger individuals, but no difference was observed in HIV DNA levels. Among older participants, higher HIV DNA levels were significantly associated with more severe neurocognitive impairment (p = 0.005), particularly in the Executive Functions domain (p = 0.004). No association was observed between HIV DNA and neurocognition among younger individuals. Despite significantly increased inflammation observed in the older group, none of the inflammatory markers were associated with neurocognitive impairment among older HIV+ individuals (p > 0.05). Our study supports the involvement of peripheral HIV DNA reservoir in the pathogenesis of neurocognitive disorder during suppressive ART. Correlates of neurocognitive impairment might differ between younger and older adults, suggesting that future treatment and prevention strategies for HIV-associated neurocognitive disorders likely need to be tailored based on age. PMID- 26603569 TI - ORMDL3 contributes to the risk of atherosclerosis in Chinese Han population and mediates oxidized low-density lipoprotein-induced autophagy in endothelial cells. AB - ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) is a universally confirmed susceptibility gene for asthma and has recently emerged as a crucial modulator in lipid metabolism, inflammation and endoplasmic reticulum (ER) stress-the mechanisms also closely involved in atherosclerosis (AS). Here we first presented the evidence of two single nucleotide polymorphisms regulating ORMDL3 expression (rs7216389 and rs9303277) significantly associated with AS risk and the evidence of increased ORMDL3 expression in AS cases compared to controls, in Chinese Han population. Following the detection of its statistical correlation with AS, we further explored the functional relevance of ORMDL3 and hypothesized a potential role mediating autophagy as autophagy is activated upon modified lipid, inflammation and ER stress. Our results demonstrated that in endothelial cells oxidized low-density lipoprotein (ox-LDL) up-regulated ORMDL3 expression and knockdown of ORMDL3 alleviated not only ox-LDL-induced but also basal autophagy. BECN1 is essential for autophagy initiation and silencing of ORMDL3 suppressed ox LDL-induced as well as basal BECN1 expression. In addition, deletion of ORMDL3 resulted in greater sensitivity to ox-LDL-induced cell death. Taken together, ORMDL3 might represent a causal gene mediating autophagy in endothelial cells in the pathogenesis of AS. PMID- 26603570 TI - Cone-Specific Promoters for Gene Therapy of Achromatopsia and Other Retinal Diseases. AB - Adeno-associated viral (AAV) vectors containing cone-specific promoters have rescued cone photoreceptor function in mouse and dog models of achromatopsia, but cone-specific promoters have not been optimized for use in primates. Using AAV vectors administered by subretinal injection, we evaluated a series of promoters based on the human L-opsin promoter, or a chimeric human cone transducin promoter, for their ability to drive gene expression of green fluorescent protein (GFP) in mice and nonhuman primates. Each of these promoters directed high-level GFP expression in mouse photoreceptors. In primates, subretinal injection of an AAV-GFP vector containing a 1.7-kb L-opsin promoter (PR1.7) achieved strong and specific GFP expression in all cone photoreceptors and was more efficient than a vector containing the 2.1-kb L-opsin promoter that was used in AAV vectors that rescued cone function in mouse and dog models of achromatopsia. A chimeric cone transducin promoter that directed strong GFP expression in mouse and dog cone photoreceptors was unable to drive GFP expression in primate cones. An AAV vector expressing a human CNGB3 gene driven by the PR1.7 promoter rescued cone function in the mouse model of achromatopsia. These results have informed the design of an AAV vector for treatment of patients with achromatopsia. PMID- 26603571 TI - MicroRNA-125b-5p attenuates lipopolysaccharide-induced monocyte chemoattractant protein-1 production by targeting inhibiting LACTB in THP-1 macrophages. AB - BACKGROUND: Increasing evidence has shown that gene beta-lactamases (LACTB) has effect on obesity. Recent studies demonstrate that miR-125b-5p is a potential small molecular target to prevent atherosclerosis obliterans which may be inflammation-associated. However, the mechanism underlying miR-125b-5p on arteriosclerosis development, the association between miR-125b-5p and LACTB is still unknown. METHODS AND RESULTS: In this study, we found that miR-125b-5p was down-regulated while LACTB was up-regulated in atherosclerotic plaques. Our results showed that LACTB was a potential target of miR-125b-5p based on bioinformatics analyses and dual-luciferase reporter assays. Moreover, miR-125b 5p directly inhibited LACTB protein and mRNA expression by targeting LACTB 3'UTR. Meanwhile, the expression of monocyte chemotactic protein-1 (MCP-1) was decreased by miR-125b-5p mimics treatment in THP-1 macrophages. We also demonstrated that the level of MCP-1 was markedly increased when transfected with LACTB. In addition, the upregulation of MCP-1 expression through miR-125b-5p inhibitors was attenuate by siRNA-LACTB treatment in LPS-stimulated THP-1 macrophages. CONCLUSIONS: MiR-125b-5p attenuates the secretion of MCP-1 by directly targeting inhibiting LACTB in LPS-stimulated THP-1 macrophages. PMID- 26603572 TI - Evaluating Biomaterial- and Microfluidic-Based 3D Tumor Models. AB - Cancer is a major cause of morbidity and mortality worldwide, with a disease burden estimated to increase over the coming decades. Disease heterogeneity and limited information on cancer biology and disease mechanisms are aspects that 2D cell cultures fail to address. Here, we review the current 'state-of-the-art' in 3D tissue-engineering (TE) models developed for, and used in, cancer research. We assess the potential for scaffold-based TE models and microfluidics to fill the gap between 2D models and clinical application. We also discuss recent advances in combining the principles of 3D TE models and microfluidics, with a special focus on biomaterials and the most promising chip-based 3D models. PMID- 26603573 TI - Household food insecurity as a determinant of overweight and obesity among low income Hispanic subgroups: Data from the 2011-2012 California Health Interview Survey. AB - An estimated 78% of Hispanics in the United States (US) are overweight or obese. Household food insecurity, a condition of limited or uncertain access to adequate food, has been associated with obesity rates among Hispanic adults in the US. However, the Hispanic group is multi-ethnic and therefore associations between obesity and food insecurity may not be constant across Hispanic country of origin subgroups. This study sought to determine if the association between obesity and food insecurity among Hispanics is modified by Hispanic ancestry across low income (<=200% of poverty level) adults living in California. Data are from the cross-sectional 2011-12 California Health Interview Survey (n = 5498). Rates of overweight or obesity (BMI >= 25), Calfresh receipt (California's Supplemental Nutrition Assistance Program), and acculturation were examined for differences across subgroups. Weighted multiple logistic regressions examined if household food insecurity was significantly associated with overweight or obesity and modified by country of origin after controlling for age, education, marital status, country of birth (US vs. outside of US), language spoken at home, and Calfresh receipt (P < .05). Significant differences across subgroups existed for prevalence of overweight or obesity, food security, Calfresh receipt, country of birth, and language spoken at home. Results from the adjusted logistic regression models found that food insecurity was significantly associated with overweight or obesity among Mexican-American women (beta (SE) = 0.22 (0.09), p = .014), but not Mexican-American men or Non-Mexican groups, suggesting Hispanic subgroups behave differently in their association between food insecurity and obesity. By highlighting these factors, we can promote targeted obesity prevention interventions, which may contribute to more effective behavior change and reduced chronic disease risk in this population. PMID- 26603574 TI - Relative validity of a tool to measure food acculturation in children of Mexican descent. AB - The purpose of this study was to examine relative validity of a food frequency questionnaire (FFQ) to measure food acculturation in young Mexican-origin children. In 2006, Spanish-speaking staff interviewed mothers in a community based sample of households from Ventura, California (US) (n = 95) and Guanajuato, Mexico (MX) (n = 200). Data included two 24-h dietary recalls (24-DR); a 30-item FFQ; and anthropometry of the children. To measure construct, convergent, and discriminant validity, data analyses included factor analysis, Spearman correlations, t-test, respectively. Factor analysis revealed two constructs: 1) a US food pattern including hamburgers, pizza, hot dogs, fried chicken, juice, cereal, pastries, lower fat milk, quesadillas, and American cheese and 2) a MX food pattern including tortillas, fried beans, rice/noodles, whole milk, and pan dulce (sweet bread). Out of 22 food items that could be compared across the FFQ and mean 24-DRs, 17 were significantly, though weakly, correlated (highest r = 0.62, for whole milk). The mean US food pattern score was significantly higher, and the MX food pattern score, lower in US children than in MX children (p < 0.0001). After adjusting for child's age and gender; mother's education; and household size, the US food pattern score was positively related to body mass index (BMI) z-scores (beta coefficient: +0.29, p = - 0.004), whereas the MX food pattern score was negatively related to BMI z-scores (beta coefficient: -0.28, p = 0.002). This tool may be useful to evaluate nutrition education interventions to prevent childhood obesity on both sides of the border. PMID- 26603575 TI - Promotion or Inhibition of Islet Amyloid Polypeptide Aggregation by Zinc Coordination Depends on Its Relative Concentration. AB - Zinc is reported to play a complex role in islet amyloid polypeptide (IAPP) aggregation, which is associated with beta-cell death in type II diabetes (T2D). Depending on their relative concentrations in vitro, zinc could either promote or inhibit IAPP aggregation. Interestingly, genomewide association studies suggested both positive and negative correlations between T2D risks and activities of a beta-cell-specific zinc transporter upon mutations, which determines zinc concentration in vivo. To decipher the effect of zinc coordination on IAPP aggregation, we performed atomistic discrete molecular dynamics simulations to systemically study aggregation propensities of zinc-coordinated IAPP oligomers with different molecular weights (MWs), whose populations are determined by zinc concentration. We find that at low zinc:IAPP stoichiometry, zinc coordination promotes aggregation by forming high-MW oligomers. The aggregation is inhibited when the stoichiometry increases and zinc binds individual peptides. Our computationally derived predictions are validated by the complementary thioflavin T fluorescence assay measuring the dependence of IAPP aggregation on a wide range of zinc concentrations. Our combined computational and experimental study offers detailed mechanistic insight into the complex role of zinc on IAPP aggregation and T2D development. PMID- 26603576 TI - Allogeneic adipose-derived stem cells for the treatment of perianal fistula in Crohn's disease: a pilot clinical trial. AB - AIM: Many perianal fistulae in Crohn's disease do not respond to conventional surgical and medical management and recurrence rates are high. The study evaluated the safety and feasibility of allogeneic adipose-derived stem cells for the treatment of perianal fistula in Crohn's disease. METHOD: A multicentre, open label, dose escalation pilot study was performed. The first three patients (group 1) were administered 1 * 10(7) cells/ml based on the size of the fistula tract. Four weeks later, after which time this dose had been confirmed to be safe, the next three patients (group 2) were administered 3 * 10(7) cells/ml. The end-point was complete closure at 8 weeks after the injection. Patients who attended for the 8 week assessment were followed for an additional 6 months. RESULTS: There were no adverse events of Grade 3 or 4 severity and no adverse events related to the treatment with allogeneic adipose-derived stem cells. Two patients in group 1 achieved complete closure of the fistula at month 4 and month 6, and one patient in group 2 achieved complete closure at 8 weeks. The closure was sustained up to month 8 in all three of those patients. CONCLUSION: These data suggest that allogeneic adipose-derived stem cells may be a feasible treatment option for perianal fistula in Crohn's disease. PMID- 26603577 TI - Advancements in the Synthesis and Applications of Cationic N-Heterocycles through Transition Metal-Catalyzed C-H Activation. AB - Cationic N-heterocycles are an important class of organic compounds largely present in natural and bioactive molecules. They are widely used as fluorescent dyes for biological studies, as well as in spectroscopic and microscopic methods. These compounds are key intermediates in many natural and pharmaceutical syntheses. They are also a potential candidate for organic light-emitting diodes (OLEDs). Because of these useful applications, the development of new methods for the synthesis of cationic N-heterocycles has received a lot of attention. In particular, many C-H activation methodologies that realize high step- and atom economies toward these compounds have been developed. In this review, recent advancements in the synthesis and applications of cationic N-heterocycles through C-H activation reactions are summarized. The new C-H activation reactions described in this review are preferred over their classical analogs. PMID- 26603578 TI - Re: Semen Parameters in Adolescents with Varicocele: Association with Testis Volume Differential and Total Testis Volume: M. P. Kurtz, D. Zurakowski, I. Rosoklija, S. B. Bauer, J. G. Borer, K. L. Johnson, M. Migliozzi and D. A. Diamond J Urol, suppl., 2015;193:1843-1847. PMID- 26603579 TI - Solid-State Molecular Nanomagnet Inclusion into a Magnetic Metal-Organic Framework: Interplay of the Magnetic Properties. AB - Single-ion magnets (SIMs) are the smallest possible magnetic devices and are a controllable, bottom-up approach to nanoscale magnetism with potential applications in quantum computing and high-density information storage. In this work, we take advantage of the promising, but yet insufficiently explored, solid state chemistry of metal-organic frameworks (MOFs) to report the single-crystal to single-crystal inclusion of such molecular nanomagnets within the pores of a magnetic MOF. The resulting host-guest supramolecular aggregate is used as a playground in the first in-depth study on the interplay between the internal magnetic field created by the long-range magnetic ordering of the structured MOF and the slow magnetic relaxation of the SIM. PMID- 26603580 TI - Predictors of Complications of Tonsillectomy With or Without Adenoidectomy in Hospitalized Children and Adolescents in the United States, 2001-2010: A Population-Based Study. AB - Outcomes of tonsillectomy (with or without adenoidectomy [w/woA]) in hospitalized children are unclear. We sought, to describe the characteristics of hospitalized children who underwent tonsillectomy (w/woA), to estimate the prevalence of complications and to evaluate the relative impact of different comorbid conditions (CMC) on the risk of occurrence of common complications following these procedures. All patients aged <=21years who underwent a tonsillectomy (w/woA) were selected from the Nationwide Inpatient Sample (NIS 2001-2010). The associations between several patient/hospital-level factors and occurrence of complications were generated using multivariable logistic regression models. Over a decade, a total of 141 599 hospitalized patients underwent tonsillectomy (w116 319; woA 25 280). A total of 58.1% were males. Majority of the procedures were performed in teaching hospitals (TH, 73.7%), in large (bed-size) hospitals (LH, 57.8%), and in those who were electively admitted (EA, 67.3%). Frequently present CMC in patients included obstructive sleep apnea (OSA, 26.4%), chronic pulmonary disease (CPD, 14.6%), neurological disorders (ND, 6.7%), and obesity (4.8%). Majority of patients were discharged routinely (98%). Overall complication rate was 6.4% with common complications being postoperative pneumonia (2.3%), bacterial infections (1.4%), respiratory complications (1.3%), and hemorrhage (1.2%). All-cause mortality included a total of 60 patients. Patients in TH (odds ratio [OR] = 0.72, 95%CI = 0.62-0.85), LH (OR = 0.80, 95% CI = 0.69-0.93), and those who had the procedures during EA (OR = 0.64, 95% CI = 0.56-0.74) had significantly lower odds of complications compared with their counterparts. CMC such as anemia, CPD, coagulopathy, HT, ND, and fluid/electrolyte disorders were independent predictors of significantly higher complication risk (P < .05). In conclusion, hospitalized children who underwent tonsillectomy (w/woA) in large or teaching hospitals, or during elective admissions had lower risk of complications. Comorbidity is an important independent predictor of complications in this cohort. PMID- 26603581 TI - Human Papillomavirus Vaccination Coverage Among Girls Before 13 Years: A Birth Year Cohort Analysis of the National Immunization Survey-Teen, 2008-2013. AB - Routine human papillomavirus (HPV) vaccination is recommended at 11 or 12 years by the Advisory Committee on Immunization Practices. National Immunization Survey Teen data were analyzed to evaluate, among girls, coverage with one or more doses of HPV vaccination, missed opportunities for HPV vaccination, and potential achievable coverage before 13 years. Results were stratified by birth year cohorts. HPV vaccination coverage before 13 years (>=1 HPV dose) increased from 28.4% for girls born in 1995 to 46.8% for girls born in 2000. Among girls born during 1999-2000 who had not received HPV vaccination before 13 years (57.2%), 80.1% had at least 1 missed opportunity to receive HPV vaccination before 13 years. Opportunities to vaccinate for HPV at age 11 to 12 years are missed. Strategies are needed to decrease these missed opportunities for HPV vaccination. This can be facilitated by the administration of all vaccines recommended for adolescents at the same visit. PMID- 26603582 TI - Physician Perspectives on Obesity Screening in Hospitalized Children. AB - Nearly one-third of the children in the United States are obese or overweight and face associated physical and mental health issues.(1,2) Parents often misperceive and underreport their child's weight status.(3-5) This misperception is a major barrier to increasing healthy lifestyle choices, such as limiting screen time, increasing physical activity, improving diet, and participating in prevention programs.(6-8) Increasing parental awareness of children's weight status is an important initial step in addressing the obesity epidemic. PMID- 26603583 TI - Language Choices for Deaf Infants: Advice for Parents Regarding Sign Languages. PMID- 26603584 TI - Long-term Follow-up of Observation-Only Management of Nontuberculous Mycobacterial Lymphadenitis. AB - A total of 21 children with clinically and microbiologically proven craniofacial nontuberculous mycobacterial lymphadenitis managed by observation only at a tertiary medical center in 1993-2005 were evaluated for scar parameters at least 2 years after diagnosis. Parents completed a satisfaction questionnaire. Median follow-up time from presentation was 6.8 years (range = 2.3-16.9 years). In all, 18 patients showed scar formation, for a total of 26 scars; 21 scars (81%) had a maximal length of <=3 cm. Vascularity was normal in 20 scars (77%), and pigmentation was normal in 18 (69%); 21 scars (81%) had a normal to only mildly uneven surface. Although 8 parents (44%) reported that the presence of the scar disturbed them, all responders but one (94%) expressed overall contentment of observation only as a conceivable management alternative. In conclusion, an observation-only approach to craniofacial nontuberculous mycobacterial lymphadenitis is associated with an acceptable outcome and may be an alternative to patients who wish to avoid surgery. PMID- 26603585 TI - Adverse Effects of Tattoos and Piercing on Parent/Patient Confidence in Health Care Providers. AB - First impressions based on practitioner appearance often form the basis for preliminary assumptions regarding trust, confidence, and competence, especially in situations where patients or family members do not have an established relationship with the physician. Given their growing prevalence, we strove to further investigate whether visible tattoos or piercings on a medical provider affects a patient's perception of the provider's capabilities and their trust in the care that would be provided. A survey using photographs of simulated practitioners was administered to 314 participants split between rural and urban locations. Study volunteers rated tattooed practitioners with lower confidence ratings when compared with nontattooed practitioners and reported greater degrees of discomfort with greater degrees of facial piercing. We concluded that these factors adversely affect the clinical confidence ratings of practitioners, regardless of the gender, age group, or location of participants. PMID- 26603586 TI - A Case of Bullous Pemphigoid in an Infant. PMID- 26603587 TI - Incidence, Trends, and Outcomes of Cerebral Edema Among Children With Diabetic Ketoacidosis in the United States. AB - INTRODUCTION: There are limited data regarding the incidence, trends, and outcomes of cerebral edema among patients with diabetic ketoacidosis (DKA). METHODS: NIS database was used from year 2002 to 2012. Cases with primary diagnosis of DKA were identified using International Classification of Diseases, Ninth Revision-Clinical Modification (ICD-9 CM) code 250.1 x. Cerebral edema patients were identified using ICD-9 CM code 348.5. We compared the baseline characteristics of both groups to estimate differences using the chi(2) test, Student's t test, Wilcoxon rank-sum test, and survey regression depending on the distributions of variables. For trend analysis, the chi(2) test of trend for proportions was used using the Cochrane Armitage test via the "trend" command in Statistical Analysis Software (SAS). Multivariate odds ratios were calculated. P value for <0.05 was considered as significant for all analysis. RESULTS: In all, 205 (weighted n = 974) cases of cerebral edema were identified among 52 049 (weighted n = 246 925) DKA patients, which estimates the incidence of cerebral edema at 0.39%. Trends of incidence of developing cerebral edema increased almost 2 times, from 0.34 in 2002 to 0.64 in 2012 (P < 0.001). Univariate analysis showed that both length of stay (LOS; 3 vs 2; P < 0.001) and cost of hospitalization ($10 530 vs $3953; P < 0.001) were statistically higher among those who developed cerebral edema. CONCLUSION: Our study shows that over the study period, trend in incidence of cerebral edema among DKA patients has increased. Patients with cerebral edema were found to have longer LOS and higher cost of hospitalization. PMID- 26603588 TI - Syncopal Event During a Soccer Game. PMID- 26603589 TI - A [3Fe-3S](3+) cluster with exclusively MU-sulfide donors. AB - A [3Fe-3(MU-S)](3+) cluster is reported in which each ferric center has a distorted trigonal pyramidal geometry, with an S = 1/2 ground state for the cluster and unusually anisotropic hyperfine coupling constants as determined by variable temperature magnetometry and Mossbauer spectroscopy. PMID- 26603590 TI - Coblation of Femoral and Sciatic Nerve for Stump Pain and Phantom Limb Pain: A Case Report. AB - BACKGROUND: There is currently no reliable treatment for stump pain and phantom limb pain. Peripheral factors play a significant role in the pathophysiology of stump pain and phantom limb pain. Coblation technology is a relatively new technology that has shown promise in treating neuropathic pain. CASE REPORT: This report describes the use of coblation technology on femoral and sciatic nerve for stump pain and phantom limb pain. An ultrasound-guided perineural infiltration anesthesia surrounding the neuroma was first performed and achieved approximately 60% stump pain relief that lasted for 2 hours, but no relief of the phantom limb pain. An ultrasound-guided femoral and sciatic nerve block was performed to obtain longer pain relief. The patient reported approximately 80% pain relief in both stump pain and phantom limb pain that lasted for 40 hours. This finding suggested other factors in addition to the ultrasound-detected neuroma in the residual limb generating pain for this patient. Coblation of femoral and sciatic nerves was performed. The stump pain was completely relieved immediately after operation. At 1, 3, and 6 months postoperative review, 80% relief of both stump and phantom limb pain was achieved. Overall activity was improved and there was no need for pain medications. The analgesic effect was stable during the 6-month follow-up period. CONCLUSION: Our report suggests that coblation technology may be useful treatment for stump pain and phantom limb pain. Treatments focusing on peripheral nerves may be more effective than those focusing on the neuroma. This finding needs additional study for confirmation. PMID- 26603591 TI - PASCAR 2015 Mauritius Scientific Programme. PMID- 26603592 TI - PASCAR 2015: French Abstracts. PMID- 26603593 TI - PASCAR 2015: English Abstracts. PMID- 26603594 TI - Pseudotumors of the placenta. AB - The placenta is one of the most common gross pathology specimens encountered by surgical pathologists, yet primary tumors are exceptionally rare and even rarer are entities with the potential to mimic malignancy. There are many nonneoplasticmass forming lesions in the placenta that are important to be aware of as many of these can be associated with adverse outcomes in the mother and fetus. Also important are entities which may be observed microscopically in the placenta and potentially confused as a malignancy. Knowledge of these potential pitfalls is essential to avoid making an incorrect diagnosis and causing undue alarm. PMID- 26603595 TI - Health-related quality of life in patients with lower rectal cancer after sphincter-saving surgery: a prospective 6-month follow-up study. AB - This longitudinal descriptive study examined whether rectal cancer patients report changes in health-related quality of life (HRQOL) over a 6-month period after different types of sphincter-saving surgery (SSS): intersphincteric resection (ISR), ultra-low anterior resection (ULAR) and low anterior resection (LAR). It also compares HRQOL among the three groups of patients. Seventy-three patients from two hospitals in Japan completed questionnaires on HRQOL and defecation symptoms immediately before surgery and 1 and 6 months afterwards. Results showed that ISR patients had significantly worse HRQOL scores than ULAR and LAR patients and more defecation symptoms that persisted during the 6 months post-SSS. Thus, patients undergoing ISR require psychological and social support, including skills in competent self-management, during the early post-operative period. Furthermore, defecation problems substantially influence HRQOL. The first month post-SSS is particularly challenging. The assumption that HRQOL is better after SSS compared to living with a permanent stoma might not be valid. PMID- 26603596 TI - Evaluation of initial setup accuracy and intrafraction motion for spine stereotactic body radiation therapy using stereotactic body frames. AB - PURPOSE: The purposes of this study were (1) to evaluate the initial setup accuracy and intrafraction motion for spine stereotactic body radiation therapy (SBRT) using stereotactic body frames (SBFs) and (2) to validate an in-house developed SBF using a commercial SBF as a benchmark. METHODS AND MATERIALS: Thirty-two spine SBRT patients (34 sites, 118 fractions) were immobilized with the Elekta and in-house (BHS) SBFs. All patients were set up with the Brainlab ExacTrac system, which includes infrared and stereoscopic kilovoltage x-ray-based positioning. Patients were initially positioned in the frame with the use of skin tattoos and then shifted to the treatment isocenter based on infrared markers affixed to the frame with known geometry relative to the isocenter. ExacTrac kV imaging was acquired, and automatic 6D (6 degrees of freedom) bony fusion was performed. The resulting translations and rotations gave the initial setup accuracy. These translations and rotations were corrected for by use of a robotic couch, and verification imaging was acquired that yielded residual setup error. The imaging/fusion process was repeated multiple times during treatment to provide intrafraction motion data. RESULTS: The BHS SBF had greater initial setup errors (mean+/-SD): -3.9+/-5.5mm (0.2+/-0.9 degrees ), -1.6+/-6.0mm (0.5+/-1.4 degrees ), and 0.0+/-5.3mm (0.8+/-1.0 degrees ), respectively, in the vertical (VRT), longitudinal (LNG), and lateral (LAT) directions. The corresponding values were 0.6+/-2.7mm (0.2+/-0.6 degrees ), 0.9+/-5.3mm (-0.2+/-0.9 degrees ), and 0.9+/-3.0mm (0.3+/-0.9 degrees ) for the Elekta SBF. The residual setup errors were essentially the same for both frames and were -0.1+/-0.4mm (0.1+/-0.5 degrees ), -0.2+/-0.4mm (0.0+/-0.4 degrees ), and 0.0+/-0.4mm (0.0+/-0.4 degrees ), respectively, in VRT, LNG, and LAT. The intrafraction shifts in VRT, LNG, and LAT were 0.0+/-0.4mm (0.0+/-0.3 degrees ), 0.0+/-0.5mm (0.0+/-0.4 degrees ), and 0.0+/-0.4mm (0.0+/-0.3 degrees ), with no significant difference observed between the 2 frames. CONCLUSIONS: These results showed that the combination of the ExacTrac system with either SBF was highly effective in achieving both setup accuracy and intrafraction stability, which were on par with that of mask-based cranial radiosurgery. PMID- 26603597 TI - US radiation oncology practice patterns for posttreatment survivor care. AB - PURPOSE: Increasing numbers of cancer survivors have driven a greater focus on care of cancer patients after treatment. Radiation oncologists have long considered follow-up of patients an integral part of practice. We sought to document current survivor-focused care patterns and identify barriers to meeting new regulatory commission guidelines for survivorship care plans (SCPs) and provide guidance for survivorship care. METHODS AND MATERIALS: A 23-question electronic survey was e-mailed to all practicing US physician American Society of Radiation Oncology members. Responses were collected for 25 days in March 2014. Survey data were descriptively analyzed. RESULTS: A total of 574 eligible providers responded, for a response percentage of 14.7%. Almost all providers follow their patients after treatment (97%). Length of follow-up was frequently extensive: 17% followed up to 2 years, 40% for 3-5 years, 12% for 6-10 years, and 31% indefinitely. Ancillary services, particularly social work and nutrition services, are commonly available onsite to patients in follow-up. Fewer than half of respondents (40%) indicated that they currently use SCPs for curative intent patients and those who do generally use internally developed templates. SCPs typically go to patients (91%), but infrequently to primary care providers (22%). The top 3 barriers to implementation of SCPs were cost (57%), duplicative survivorship care plans provided by other physicians (43%), and lack of consensus or professional guidelines (40%). Eighty-seven percent indicated that SCPs built into an electronic medical record system would be useful. CONCLUSIONS: A significant part of radiation oncology practice includes the care of those in the surveillance of follow-up phase of care. SCPs may be beneficial in improving communication with the patient and other care but are not widely used within our field. This survey identified key barriers to use of SCPs and provides specialty guidance for important information to be included in a radiation oncology oriented SCP. PMID- 26603598 TI - Natural history and treatment trends in hepatocellular carcinoma subtypes: Insights from a national cancer registry. AB - BACKGROUND: Histopathologic advancements have identified several rare subtypes of hepatocellular carcinoma (HCC), but the clinical significance of these distinctions is incompletely understood. Our aim was to investigate pathologic and treatment differences between HCC variants. METHODS: The American College of Surgeons National Cancer Data Base (1998-2011) was queried to identify 784 patients with surgical management of six rare HCC subtypes: fibrolamellar (FL, n = 206), scirrhous (SC, n = 29), spindle cell (SP, n = 20), clear cell (CC, n = 169), mixed type (M, n = 291), and trabecular (T, n = 69). We examined associations between demographic, tumor and treatment-specific variables, and overall survival (OS). RESULTS: Patients with FL-HCC were younger than other variants (median age 27 vs. 54-61, P < 0.001), more commonly female (56.3%, P < 0.001), and less likely to receive a transplant (3.66%, P < 0.001). Patients with FL- and Sp-HCC presented more frequently with larger tumors (>5 cm, P < 0.001) and node-positive disease (P < 0.001). Better OS was associated with lower pathologic stage, node-negative disease, FL-HCC, and liver transplant. Adjuvant therapy (11% of patients) was not associated with better OS. CONCLUSIONS: This largest series of recognized HCC variants demonstrates distinct differences in presentation, treatment, and prognosis. These findings can provide a valuable reference for clinicians and patients who encounter these rare clinical entities. PMID- 26603599 TI - Origin of Improved Optical Quality of Monolayer Molybdenum Disulfide Grown on Hexagonal Boron Nitride Substrate. AB - Monolayer MoS2 is synthesized on hexagonal boron nitride (h-BN) flakes with a simple, high-yield method. Monolayer MoS2 on h-BN exhibits improved optical quality. Combining the theoretical and experimental analysis, it is concluded that the enhanced photoluminescence and Raman intensities of monolayer MoS2 probably originate from the relatively weak doping effect from the h-BN substrate rather than the optical interference effect. PMID- 26603600 TI - Cell-Like Nanostructured Environments Alter Diffusion and Reaction Kinetics in Cell-Free Gene Expression. AB - In highly crowded and viscous intracellular environments, the kinetics of complex enzymatic reactions are determined by both reaction and diffusion rates. However in vitro studies on transcription and translation often fail to take into account the density of the prokaryotic cytoplasm. Here we mimic the cellular environment by using a porous hydrogel matrix, to study the effects of macromolecular crowding on gene expression. We found that within microgels gene expression is localized, transcription is enhanced up to fivefold, and translation is enhanced up to fourfold. Our results highlight the need to consider the role of the physical environment on complex biochemical reactions, in this case macromolecular crowding, nanoscale spatial organization, and confinement. PMID- 26603601 TI - Determination of toxicity in rabbits and corresponding detection of monofluoroacetate in four Palicourea (Rubiaceae) species from the Amazonas state, Brazil. AB - Numerous monofluoroacetate (MFA)-containing plants in Brazil cause sudden death syndrome precipitated by exercise in livestock, which is characterized by loss of balance, ataxia, labored breathing, muscle tremors, and recumbence leading to death. Four species of Palicourea collected at six farms were tested for the presence of MFA and their toxicity to rabbits. Palicourea longiflora and Palicourea barraensis contained MFA and caused sudden death in the rabbits. Palicourea croceoides and Palicourea nitidella did not contain MFA and were not toxic to rabbits. P. longiflora and P. barraensis were collected at three farms with a history of sudden death in their cattle. This is the first report of toxicity in regard to these two species. PMID- 26603602 TI - Who is sceptical about emerging public health threats? Results from 39 national surveys in the United Kingdom. AB - OBJECTIVES: Members of the public are often sceptical about warnings of an impending public health crisis. Breaking through this scepticism is important if we are to convince people to take urgent protective action. In this paper we explored correlates of perceiving that 'too much fuss' was being made about the 2009/10 influenza A H1N1v ('swine flu') pandemic. STUDY DESIGN: A secondary analysis of data from 39 nationally representative telephone surveys conducted in the UK during the pandemic. METHODS: Each cross-sectional survey (combined n = 42,420) collected data over a three day period and asked participants to state whether they agreed or disagreed that 'too much fuss is being made about the risk of swine flu.' RESULTS: Overall, 55.1% of people agreed or strongly agreed with this sentiment. Perceiving that too much fuss was being made was associated with: being male, being white, being generally healthy, trusting most in a primary care physician to provide advice, not knowing someone who had contracted the illness, believing you know a lot about the outbreak, not wishing to receive additional information about the outbreak and possessing worse factual knowledge about the outbreak than other people. CONCLUSIONS: In future disease outbreaks merely providing factual information is unlikely to engage people who are sceptical about the need to take action. Instead, messages which challenge their perceived knowledge and which present case studies of people who have been affected may prove more effective, especially when delivered through trusted channels. PMID- 26603603 TI - Socio-economic mortality inequalities in Lithuania during 2001-2009: the record linkage study. AB - OBJECTIVES: To present socio-economic inequalities in mortality and their trends in Lithuania using routinely collected data and record linkage for the years 2001 2009, as related to educational level, occupation, economic activity, marital status and household size. STUDY DESIGN: Retrospective cohort study. METHODS: Record linkage was performed using personal identification number between three data sources: 2001 population census, national mortality register for years 2001 2009 and population register, including individuals of age 30 years and older. The linked data set consisted of 2,061,481 records, including 338,652 death cases. Age-standardized mortality rates were calculated for socio-economic groups and compared in terms of rate differences (RD) and rate ratios (RR). RESULTS: Significant mortality inequalities were found for all socio-economic variables. Both among males and females the highest RR were observed for the occupation (males--3.4, females--2.8) and economic activity status (males--2.7, females- 3.1). RR were the highest in mid-ages and declined with ageing. RD increased with the increase in total mortality during 2005-2007, while decline in inequalities was observed in later years. CONCLUSIONS: Lower education, manual occupations, unemployed, economically inactive and unmarried groups of population appeared in the most unfavourable position in terms of mortality and contributed most to the mortality increase in Lithuania throughout 2005-2007. PMID- 26603604 TI - Group psychological intervention for postnatal depression: a nested qualitative study with British South Asian women. AB - BACKGROUND: Postnatal depression affects 10-15 % of all mothers in Western societies and remains a major public health concern for women from diverse cultures. British Pakistani and Indian women have a higher prevalence of depression in comparison to their white counterparts. Research has shown that culturally adapted interventions using Cognitive Behavioural Therapy (CBT) may be acceptable and may help to address the needs of this population. The aim of this study was to assess the acceptability and overall experience of the Positive Health Programme by British South Asian mothers. METHODS: This was a nested qualitative study, part of an exploratory randomized controlled trial (RCT) conducted to test the feasibility and acceptability of a culturally-adapted intervention (Positive Health Programme or PHP) for postnatal depression in British South Asian women. In-depth interviews (N = 17) were conducted to determine the views of the participants on the feasibility and acceptability of the intervention. RESULTS: The participants found the intervention acceptable and experienced an overall positive change in their attitudes, behaviour, and increased self-confidence. CONCLUSIONS: The findings suggest that the culturally adapted Positive Health Programme is acceptable to British South Asian women. These results support that culturally sensitive interventions may lead to better health outcomes and overall satisfaction. TRIAL REGISTRATION: Protocol registered on Clinicaltrials.gov NCT01838889. PMID- 26603605 TI - Increase of Electrical Impedance Following Hemodialysis Is Not the Reason for QRS Augmentation. PMID- 26603607 TI - Is Informed Consent Enough? PMID- 26603606 TI - The origin of exon 3 skipping of paternal GLOBOSA pre-mRNA in some Nicotiana tabacum lines correlates with a point mutation of the very last nucleotide of the exon. AB - In plants, genome duplication followed by genome diversification and selection is recognized as a major evolutionary process. Rapid epigenetic and genetic changes that affect the transcription of parental genes are frequently observed after polyploidization. The pattern of alternative splicing is also frequently altered, yet the related molecular processes remain largely unresolved. Here, we study the inheritance and expression of parental variants of three floral organ identity genes in allotetraploid tobacco. DEFICIENS and GLOBOSA are B-class genes, and AGAMOUS is a C-class gene. Parental variants of these genes were found to be maintained in the tobacco genome, and the respective mRNAs were present in flower buds in comparable amounts. However, among five tobacco cultivars, we identified two in which the majority of paternal GLOBOSA pre-mRNA transcripts undergo exon 3 skipping, producing an mRNA with a premature termination codon. At the DNA level, we identified a G-A transition at the very last position of exon 3 in both cultivars. Although alternative splicing resulted in a dramatic decrease in full length paternal GLOBOSA mRNA, no phenotypic effect was observed. Our finding likely serves as an example of the initiation of homoeolog diversification in a relatively young polyploid genome. PMID- 26603608 TI - Large Enhancement of Carrier Transport in Solution-Processed Field-Effect Transistors by Fluorinated Dielectric Engineering. AB - The universal role of high-k fluorinated dielectrics in assisting the carrier transport in transistors for a broad range of printable semiconductors is explored. These results present general rules for how to design dielectric materials and achieve devices with a high carrier concentration, low disorder, reliable operation, and robust properties. PMID- 26603609 TI - Molecular characterization of Urocleidoides cuiabai and U. malabaricusi (Monogenea: Dactylogyridae) from the trahira fish Hoplias aff. malabaricus in the Parana River, Brazil. AB - Urocleidoides ectoparasites are mainly found on fish of the neotropical regions. Although molecular research on monogeneans is available, no genetic data exist characterizing species in the Urocleidoides genus. Some DNA sequences have been efficacious in systematic studies and in the reconstruction of phylogenies of fish parasites. Relevant roles have been given to the sequence of the mitochondrial gene of cytochrome c oxidase I (COI). This study characterized COI sequences of the parasites Urocleidoides malabaricusi and U. cuiabai in trahira fish Hoplias aff. malabaricus of the flood plain of the Upper River Parana, Brazil. The two species under analysis were distinguished by sequencing and analysing a 420-bp fragment of the COI gene, which suggested the existence of the cryptic species U. malabaricusi. PMID- 26603610 TI - Genomics and the Contrasting Dynamics of Annual and Perennial Domestication. AB - Plant domestication modifies a wild species genetically for human use. Among thousands of domesticated plants, a major distinction is the difference between annual and perennial life cycles. The domestication of perennials is expected to follow different processes than annuals, with distinct genetic outcomes. Here we examine domestication from a population genetics perspective, with a focus on three issues: genetic bottlenecks during domestication, introgression as a source of local adaptation, and genetic load. These three issues have been studied nominally in major annual crops but even less extensively in perennials. Here we highlight lessons from annual plants, motivations to study these issues in perennial plants, and new approaches that may lead to further progress. PMID- 26603611 TI - Three-dimensional fuse deposition modeling of tissue-simulating phantom for biomedical optical imaging. AB - Biomedical optical devices are widely used for clinical detection of various tissue anomalies. However, optical measurements have limited accuracy and traceability, partially owing to the lack of effective calibration methods that simulate the actual tissue conditions. To facilitate standardized calibration and performance evaluation of medical optical devices, we develop a three-dimensional fuse deposition modeling (FDM) technique for freeform fabrication of tissue simulating phantoms. The FDM system uses transparent gel wax as the base material, titanium dioxide (TiO2 ) powder as the scattering ingredient, and graphite powder as the absorption ingredient. The ingredients are preheated, mixed, and deposited at the designated ratios layer-by-layer to simulate tissue structural and optical heterogeneities. By printing the sections of human brain model based on magnetic resonance images, we demonstrate the capability for simulating tissue structural heterogeneities. By measuring optical properties of multilayered phantoms and comparing with numerical simulation, we demonstrate the feasibility for simulating tissue optical properties. By creating a rat head phantom with embedded vasculature, we demonstrate the potential for mimicking physiologic processes of a living system. PMID- 26603612 TI - Impact of acoustic cavitation on food emulsions. AB - The work explores the experimental and theoretical aspects of emulsification capability of ultrasound to deliver stable emulsions of sunflower oil in water and meat sausages. In order to determine optimal parameters for direct ultrasonic emulsification of food emulsions, a model was developed based on the stability of emulsion droplets in acoustic cavitation field. The study is further extended to investigate the ultrasound induced changes to the inherent properties of raw materials under the experimental conditions of sono-emulsification. PMID- 26603613 TI - Medical thermography (digital infrared thermal imaging - DITI) in paediatric forearm fractures - A pilot study. AB - Trauma is the most common cause of hospitalisation in children, and forearm fractures comprise 35% of all paediatric fractures. One-third of forearm fractures are distal forearm fractures, which are the most common fractures in the paediatric population. This type of fracture represents an everyday problem for the paediatric surgeon. The three phases of fracture healing in paediatric trauma are associated with skin temperature changes that can be measured and then compared with standard plain radiographs of visible callus formation, and eventually these methods can be used in everyday practice. Thermographic assessment of temperature distribution within the examined tissues enables a quick, non-contact, non-invasive measurement of their temperature. Medical thermography is used as a screening method in other parts of medicine, but the use of this method in traumatology has still not been researched. PMID- 26603614 TI - Histological analysis of cross-sectional area of quadruple hamstring tendons and patellar ligament samples in relation to age and gender. AB - AIMS: The middle of the patellar ligament and the quadruple hamstring tendons (gracilis and semitendinosus) are two types of graft predominantly used in anterior cruciate ligament (ACL) reconstruction. The aim of this study was to determine the morphometric characteristics of patellar ligament grafts and hamstring tendon grafts and to compare the results according to subject age and gender. MATERIALS AND METHODS: The study was conducted on a total of 120 samples: 40 of gracilis tendon, 40 of semitendinosus tendon and 40 of patellar ligament, distributed equally according to gender, age (50-75 years) and the side of the body from which the sample was harvested. RESULTS: Morphometric and histological analyses showed that patellar ligament samples had less cross-sectional area than quadruple tendon samples (49.29 mm(2) compared with 51.46 mm(2), respectively). Sexual dimorphism was noticed in distal cross-sections of gracilis tendons (p=0.09), cross-sections of quadruple tendons (p=0.07) and patellar ligament samples (p=0.01) because of different muscular build. CONCLUSIONS: All samples obtained from male subjects had larger cross-sectional areas compared with the samples taken from females. Furthermore, samples obtained from subjects aged 60 years or under had larger cross-sectional areas than samples obtained from subjects aged at least 61 years for all types of graft. PMID- 26603615 TI - Variations of treatment in selected proximal femur fractures among surgeons with different surgical experience--A survey at an international AO course. AB - INTRODUCTION: Different modalities of treatment for hip fractures have been discussed in the literature; however, practice may vary between centres. A survey was conducted on participants at an international AO course to assess the current management of pertrochanteric fractures (AO/OTA 31-A2) and displaced, non impacted, subcapital fractures (AO/OTA 31-B3) in a 35-year-old patient and an 85 year-old patient. METHODS: Surgeons taking part in an international orthopaedic course were invited to participate in a survey and were divided into two groups: inexperienced (one-to-three years since qualification) and experienced (four or more years). A survey was conducted to assess the management modalities used for pertrochanteric fractures (AO/OTA 31-A2) and displaced, non-impacted, subcapital fractures (AO/OTA 31-B3) in a 35-year-old patient and an 85-year-old patient. RESULTS: Fifty-two surgeons participated: 18 were inexperienced and 34 were experienced. The method of operative fixation for the pertrochanteric fracture was gamma-nailing for 95% of the surgeons in the inexperienced group; in the experienced group, 56% opted for gamma-nailing and 38% for dynamic hip screw (DHS). For the displaced subcapital fracture in a 35-year-old, screw fixation was the dominant treatment option for both groups. For the displaced subcapital fracture in an 85-year-old, most of the surgeons in both groups preferred hemiarthroplasty: 59% in the inexperienced group chose cemented bipolar hemiarthroplasty and 12% uncemented, whereas 56% of the experienced group suggested cemented bipolar hemiarthroplasty and 25% uncemented. DISCUSSION: This survey shows that a variety of methods are used to treat femoral neck fractures. A prospective randomised trial has shown the DHS to be the implant of choice for pertrochanteric fractures; however, this was not considered an option in the inexperienced group of surgeons and was the treatment of choice in only 13 out of 34 experienced surgeons. There is a general consensus for femoral head-conserving surgery in young patients with displaced subcapital fractures. Replacement arthroplasty was considered in the 85-year-old with a subcapital fracture. In the inexperienced group, 10 of 17 surgeons would cement the prosthesis, as would 27 of 36 in the experienced group. PMID- 26603616 TI - The predictive value of plasma biomarkers in discharged heart failure patients: role of troponin I/T. AB - Hospitalization for heart failure (HHF) is a frequent manifestation of chronic heart failure (CHF), and represents the moment of greatest impact on costs and on risk for the patient, in particular after discharge. Contributing factors to this disappointingly high postdischarge event rate include the incomplete relief of fluid overload, insufficient patient education, the lack of implementation of evidence-based therapies, poor follow-up and inadequate risk stratification before leaving hospital. Among available tools, different biomarkers have been tested, including cardiac troponin (cTn). The value of cTn to monitoring and to stratifying risk before discharge has been evaluated by mean of three strategies: a single measurement before discharge, monitoring with serial sampling during hospitalization, and comparing admission and predischarge values to establishing the cTn "delta". Acute heart failure syndrome (AHFS) is an active and continuing process, which starts at admission, but its evolution might be unpredictable, and the prevention of ongoing myocardial damage (OMD) might be one of the important targets to improve prognosis. OMD is also a dynamic process and can be detected in CHF and HHF, at different moments and in diverse magnitudes, justifying the cTn monitoring. The favorable effect of drugs on cTn release and its association with better prognosis have increased our expectation for the role of serial determination in HHF patients. PMID- 26603617 TI - Thrombus aspiration in ST-segment elevation myocardial infarction. AB - Primary percutaneous coronary intervention (PCI) has become the treatment of choice in patients with ST-segment elevation myocardial infarction (STEMI) throughout the last years. A significant number of studies have demonstrated a morbidity and mortality benefit over thrombolysis, which has been attributed to better coronary perfusion in patients undergoing primary PCI. Even though it usually achieves normal flow in the affected epicardial vessel, myocardial reperfusion is not fully restored in a significant percentage of patients. This is commonly the result of distal thrombus embolization with subsequent impairment of myocardial microcirculation. Recognition of this has led to the development of a number of devices with different mechanisms, including thrombus aspiration catheters, in order to reduce distal embolization and therefore improve myocardial perfusion. Recent studies indeed demonstrate that the use of such devices offer additional clinical advantage in patients undergoing primary PCI in comparison to the standard PCI, whether in other trials it could not be proved. This paper focuses on general mechanisms of thrombus formation and discusses favorable and unfavorable studies towards thrombus aspiration in STEMI and its main aspects and it comes up with specific subjects that could benefit or not from the procedure of thrombus aspiration. PMID- 26603618 TI - Association of perioperative intravenous fluid strategy with acute kidney injury following off-pump coronary artery bypass surgery. PMID- 26603619 TI - Involvement of transglutaminase 2 and voltage-gated potassium channels in cystamine vasodilatation in rat mesenteric small arteries. AB - BACKGROUND AND PURPOSE: Vasodilatation may contribute to the neuroprotective and vascular anti-remodelling effect of the tissue transglutaminase 2 (TG2) inhibitor cystamine. Here, we hypothesized that inhibition of TG2 followed by blockade of smooth muscle calcium entry and/or inhibition of Rho kinase underlies cystamine vasodilatation. EXPERIMENTAL APPROACH: We used rat mesenteric small arteries and RT-PCR, immunoblotting, and measurements of isometric wall tension, intracellular Ca(2+) ([Ca(2+)]i ), K(+) currents (patch clamp), and phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and myosin regulatory light chain, in our experiments. KEY RESULTS: RT-PCR and immunoblotting revealed expression of TG2 in mesenteric small arteries. Cystamine concentration-dependently inhibited responses to phenylephrine, 5-HT and U46619 and for extracellular potassium. Selective inhibitors of TG2, LDN 27129 and T101, also inhibited phenylephrine contraction. An inhibitor of PLC suppressed cystamine relaxation. Cystamine relaxed and reduced [Ca(2+)]i in phenylephrine-contracted arteries. In potassium contracted arteries, cystamine induced less relaxation without changing [Ca(2+)]i , and these relaxations were blocked by mitochondrial complex inhibitors. Blockers of Kv 7 channels, XE991 and linopirdine, inhibited cystamine relaxation and increases in voltage-dependent smooth muscle currents. Cystamine and the Rho kinase inhibitor Y27632 reduced basal MYPT1-Thr(855) phosphorylation, but only Y27632 reduced phenylephrine-induced increases in MYPT1-Thr(855) and myosin regulatory light chain phosphorylation. CONCLUSIONS AND IMPLICATIONS: Cystamine induced vasodilatation by inhibition of receptor-coupled TG2, leading to opening of Kv channels and reduction of intracellular calcium, and by activation of a pathway sensitive to inhibitors of the mitochondrial complexes I and III. Both pathways may contribute to the antihypertensive and neuroprotective effect of cystamine. PMID- 26603620 TI - Dietary Consumption of Black Raspberries or Their Anthocyanin Constituents Alters Innate Immune Cell Trafficking in Esophageal Cancer. AB - Freeze-dried black raspberries (BRB), their component anthocyanins (AC), and a metabolite of BRB ACs, protocatechuic acid (PCA), inhibit the development of esophageal cancer in rats induced by the carcinogen, N-nitrosomethylbenzylamine (NMBA). All three components reduce inflammation in the esophagus and in plasma. The present study determined the relation of changes in inflammatory markers to infiltration of innate immune cells into NMBA-treated esophagus. Rats were injected with NMBA (0.35 mg/kg) for 5 weeks while on control diet. Following NMBA treatment, rats were fed diets containing 6.1% BRB powder, an AC-rich fraction of BRBs (3.8 MUmol/g), or 500 ppm PCA. At weeks 15, 25, and 35, inflammatory biomarker expression in the plasma and esophagus was quantified, and infiltration of immune cells in the esophagus was examined. At all three time points, BRB, AC, and PCA similarly affected cytokine production in the esophagus and plasma of NMBA-treated rats, relative to the NMBA-only control. These included decreased expression of the proinflammatory cytokine IL1beta and increased expression of the anti-inflammatory cytokine IL10. Moreover, all three diets also increased the expression of IL12, a cytokine that activates both cytolytic natural killer and CD8(+) T cells. In addition, the three diets also decreased infiltration of both macrophages and neutrophils into the esophagus. Overall, our results suggest that another mechanism by which BRBs, ACs, and PCA inhibit NMBA-induced esophageal tumorigenesis is by altering cytokine expression and innate immune cell trafficking into tumor tissues. PMID- 26603622 TI - Recurrent Streptococcus Pneumoniae 23 F meningitis due to cerebrospinal fluid leakage from the ear cannel: a case report. AB - BACKGROUND: Bacterial meningitis is a medical emergency, and immediate diagnostic steps must be taken to establish the specific cause. Recurrence of bacterial meningitis in children is not only potentially life-threatening, but also involves or induces psychological trauma to the patients through repeated hospitalization with many invasive investigations. CASE PRESENTATION: A 6-year old boy was diagnosed with recurrent bacterial meningitis caused by Streptococcus Pneumonia 23 F. He had received serial imaging studies for identifying the cause. The initial sinus computed tomography (CT) also showed sinusitis without bony defect of sinus. However, after performing nuclear scan, the results showed cerebrospinal fluid (CSF) leaked originating from the right petrooccpital region into the middle ear. Subsequent high resolution CT (HRCT) reports showed focal enlargement of the right facial nerve canal, erosion of the bony canal at geniculate ganglion and tympanic segment with tiny high-density spots. The reconstruction HRCT showed multiple bony defects at temporal bone. The magnetic resonance imaging revealed multifocal bony destruction with CSF collection in the right petrous ridge, carotid canal and jugular foramen. Eventually, CSF leakage to the right middle ear was confirmed and this could be the cause of the recurrent bacteria meningitis in this patient. CONCLUSION: Although recurrent bacterial meningitis in childhood is not common, this case report illustrates that recurrence of meningitis within a short period should be considered as cause of underline immunologic or anatomic defect. PMID- 26603621 TI - MIF Is Necessary for Late-Stage Melanoma Patient MDSC Immune Suppression and Differentiation. AB - Highly aggressive cancers "entrain" innate and adaptive immune cells to suppress antitumor lymphocyte responses. Circulating myeloid-derived suppressor cells (MDSC) constitute the bulk of monocytic immunosuppressive activity in late-stage melanoma patients. Previous studies revealed that monocyte-derived macrophage migration inhibitory factor (MIF) is necessary for the immunosuppressive function of tumor-associated macrophages and MDSCs in mouse models of melanoma. In the current study, we sought to determine whether MIF contributes to human melanoma MDSC induction and T-cell immunosuppression using melanoma patient-derived MDSCs and an ex vivo coculture model of human melanoma-induced MDSC. We now report that circulating MDSCs isolated from late-stage melanoma patients are reliant upon MIF for suppression of antigen-independent T-cell activation and that MIF is necessary for maximal reactive oxygen species generation in these cells. Moreover, inhibition of MIF results in a functional reversion from immunosuppressive MDSC to an immunostimulatory dendritic cell (DC)-like phenotype that is at least partly due to reductions in MDSC prostaglandin E(2) (PGE(2)). These findings indicate that monocyte-derived MIF is centrally involved in human monocytic MDSC induction/immunosuppressive function and that therapeutic targeting of MIF may provide a novel means of inducing antitumor DC responses in late-stage melanoma patients. PMID- 26603623 TI - The Association Between Psychological Distress and Decision Regret During Armed Conflict Among Hospital Personnel. AB - The association between psychological distress and decision regret during armed conflict among hospital personnel is of interest. The objective of this study was to learn of the association between psychological distress and decision regret during armed conflict. Data was collected from 178 hospital personnel in Barzilai Medical Center in Ashkelon, Israel during Operation Protective Edge. The survey was based on intranet data collection about: demographics, self-rated health, life satisfaction, psychological distress and decision regret. Among hospital personnel, having higher psychological distress and being young were associated with higher decision regret. This study adds to the existing knowledge by providing novel data about the association between psychological distress and decision regret among hospital personnel during armed conflict. This data opens a new venue of future research to other potentially detrimental factor on medical decision making and medical error done during crisis. PMID- 26603624 TI - Cognitive Impairment in Schizophrenia: Interplay of BDNF and Childhood Trauma? A Review of Literature. AB - Cognitive impairment is a core feature of schizophrenia. These deficits can also serve as an endophenotype for the illness in genetic studies. There is evidence that suggests that cognition can be considered a reasonable target for intervention in both schizophrenia and bipolar disorder. One of the most studied genetic phenotypes for psychosis is brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms. BDNF has an established role in neuronal development and cell survival in response to stress and is abnormally expressed in schizophrenia. Studies have shown that childhood trauma is associated with poor prognosis of schizophrenic patients. BDNF-Val66Met polymorphism has been shown to moderate the impact of childhood adversity on later expression of affective symptoms, suggesting the possibility of gene environment interactions. Considering the recent advances of neuroscience an up to date review of relevant literature is warranted in this field. This article reviews the current literature available regarding associations between the Val66Met polymorphism, childhood trauma and cognitive dysfunction in schizophrenia. PMID- 26603625 TI - A Novel Perspective of Neoadjuvant Chemotherapy in Locally Advanced Cervical Cancer. PMID- 26603626 TI - Assessing the Quality of Goal Setting in Behavioural Support for Smoking Cessation and its Association with Outcomes. AB - BACKGROUND: Smoking cessation behavioural support can be effective but practitioners differ markedly in effectiveness, possibly due to variation in the quality of delivery of key behaviour change techniques, such as goal setting (i.e. setting a quit date). OBJECTIVES: This study aimed to (i) develop a reliable method for assessing the quality of practitioners' support in setting quit dates and (ii) assess whether quality predicts initiation of abstinence as a first step to quitting. METHODS: A scale for scoring the quality of goal setting was developed from national guidance documents and applied to 85 transcribed behavioural support sessions. Inter-rater reliability was assessed. Associations between quality scores and quit attempts were assessed. RESULTS: The 10-item scale produced had good inter-rater reliability (Kappa = 0.68). Higher quality goal setting was associated with increased self-reported quit attempts (p < .001; OR = 2.60, 95 % CI 1.54-4.40). The scale components 'set a clear quit date' (chi (2) (2, N = 85) = 22.3, p < .001) and 'within an appropriate timeframe' (chi (2) (2, N = 85) = 15.5, p < .001) were independently associated with quit attempts. CONCLUSIONS: It is possible to reliably assess the quality of goal setting in smoking cessation behavioural support. Higher quality of goal setting is associated with greater likelihood of initiating quit attempts. PMID- 26603627 TI - When Different Message Frames Motivate Different Routes to the Same Health Outcome. AB - BACKGROUND: Message framing is an effective strategy for promoting health behavior. PURPOSE: We examined the relative effectiveness of framed messages that simultaneously promoted two different health behaviors-eating a calcium-rich diet and taking calcium supplements-for preventing osteoporosis. Because those behaviors are associated with different perceptions of risk, we predicted that gain- and loss-framed messages would have opposite effects. METHODS: In two experiments, participants (N1 = 69; N2 = 219) were randomly assigned to a gain- or loss-framed message presenting two osteoporosis prevention behaviors. RESULTS: A gain-framed advantage was observed for dietary calcium consumption, but the opposite-a loss-framed advantage-was observed for use of calcium supplements. Message frame interacted with baseline calcium consumption behavior for some outcomes. CONCLUSIONS: Both gain- and loss-framed messages increased osteoporosis prevention behavior, but their relative effectiveness depended on the type of behavior. Framed messages can have opposite effects on different behaviors used to achieve a common health goal. PMID- 26603629 TI - [Intussusception in infancy and childhood: Radiological and surgical management]. AB - Ileocolic intussusception in infants and children requires emergency treatment and has a very good prognosis. Abdominal ultrasonography imaging has a high sensitivity and specificity in its detection. Management of ileocolic intussusceptions now requires fewer surgical procedures because interventional radiology is usually efficient. Surgery (laparoscopy or laparotomy) is reserved for failed radiological reductions and advanced or immediately complicated intussusceptions (pneumoperitoneum, acute peritonitis, shock). Radiology teams have two reduction techniques: hydrostatic barium enema under fluoroscopic or sonographic guidance and air enema under fluoroscopic guidance. The superiority of one radiological reduction technique over the other cannot be asserted, and the choice depends on experience and available equipment. Current management of intussusceptions should be performed by pediatric radiology, anesthesiology and surgery teams. PMID- 26603628 TI - Dynamic Behavior of Microbubbles during Long Ultrasound Tone-Burst Excitation: Mechanistic Insights into Ultrasound-Microbubble Mediated Therapeutics Using High Speed Imaging and Cavitation Detection. AB - Ultrasound (US)-microbubble (MB)-mediated therapies have been found to restore perfusion and enhance drug/gene delivery. On the presumption that MBs do not persist during long US exposure under high acoustic pressures, most schemes use short US pulses when a high US pressure is employed. However, we recently observed an enhanced thrombolytic effect using long US pulses at high acoustic pressures. Therefore, we explored the fate of MBs during long tone-burst exposures (5 ms) at various acoustic pressures and MB concentrations via direct high-speed optical observation and passive cavitation detection. MBs first underwent stable or inertial cavitation depending on the acoustic pressure and then formed gas-filled clusters that continued to oscillate, break up and form new clusters. Cavitation detection confirmed continued, albeit diminishing, acoustic activity throughout the 5-ms US excitation. These data suggest that persisting cavitation activity during long tone bursts may confer additional therapeutic effects. PMID- 26603630 TI - [Implementation of meningococcal B vaccination (Bexsero(r)) in France: Physicians' perceptions and experiences of a few months after marketing approval]. AB - BACKGROUND: In December 2013, the French public health authorities recommended the use of Bexsero(r) (meningococcus B vaccine) in areas with endemic risk and for patients at risk for invasive meningococcal B disease. In this context, InfoVac-France performed a national survey a few months after the implementation of the vaccine to evaluate physicians' perceptions and experiences with this new vaccine. METHODS: This survey was proposed by email in April 2014 to the InfoVac network. An initial email explained the purpose of this study and proposed an online questionnaire. RESULTS: Between April 29 and May 16, 2014, 1502 physicians answered online: 502 GPs (33%), 939 pediatricians (63%), and 61 other specialists (4%). In response, 91% of physicians would like to use this vaccine and 87% of pediatricians versus 50% of GPs knew that the vaccine was marketed. Physicians had been informed of the vaccine mostly via the InfoVac network (61%). The immunization schedules for all ages were slightly known by physicians (9% for GPs and 43% of pediatricians). This vaccination was still rarely proposed (18%) more often because it was not reimbursed to patients (62%). Although 39% of physicians were planning to propose the vaccine to their patients, 54% remained undecided. A total of 9% of pediatricians and 2% of GPs had already used this vaccination. CONCLUSION: This InfoVac-France survey shows that physicians would support the implementation of this vaccine, but questions persist as to its effectiveness, impact on carriage, and duration of protection. PMID- 26603631 TI - Diversity and Distribution of Arsenic-Related Genes Along a Pollution Gradient in a River Affected by Acid Mine Drainage. AB - Some microorganisms have the capacity to interact with arsenic through resistance or metabolic processes. Their activities contribute to the fate of arsenic in contaminated ecosystems. To investigate the genetic potential involved in these interactions in a zone of confluence between a pristine river and an arsenic-rich acid mine drainage, we explored the diversity of marker genes for arsenic resistance (arsB, acr3.1, acr3.2), methylation (arsM), and respiration (arrA) in waters characterized by contrasted concentrations of metallic elements (including arsenic) and pH. While arsB-carrying bacteria were representative of pristine waters, Acr3 proteins may confer to generalist bacteria the capacity to cope with an increase of contamination. arsM showed an unexpected wide distribution, suggesting biomethylation may impact arsenic fate in contaminated aquatic ecosystems. arrA gene survey suggested that only specialist microorganisms (adapted to moderately or extremely contaminated environments) have the capacity to respire arsenate. Their distribution, modulated by water chemistry, attested the specialist nature of the arsenate respirers. This is the first report of the impact of an acid mine drainage on the diversity and distribution of arsenic (As) related genes in river waters. The fate of arsenic in this ecosystem is probably under the influence of the abundance and activity of specific microbial populations involved in different As biotransformations. PMID- 26603634 TI - Anaphylaxis during rapid oral desensitization to rifampicin. PMID- 26603633 TI - Chronic alcohol increases CD8+ T-cell immunosenescence in simian immunodeficiency virus-infected rhesus macaques. AB - Activated CD8+ T-cells correlate with viral load and may foretell antiretroviral therapy (ART) failure. HIV infection has been suggested to accelerate immunosenescence through chronic persistent inflammation. Alcohol-use disorders (AUD) are prevalent in persons living with HIV/AIDS (PLWHA). We tested the hypothesis that hazardous alcohol consumption accelerates immune activation and immunosenescence. Immune activation and immunosenescence were examined in CD8+ T lymphocytes (CD3+CD4-CD8+) isolated from intestinal biopsies, axillary lymph nodes, and peripheral blood mononuclear cells (PBMCs) of chronic binge alcohol (CBA)-consuming simian immunodeficiency virus (SIV)-infected male rhesus macaques with and without antiretroviral therapy (ART; CBA/ART+, CBA/ART-) and in PBMCs isolated from a cohort of PLWHA. Polychromatic flow cytometry was used to phenotype cells isolated from intestinal biopsies, lymph nodes, and peripheral blood from rhesus macaques and PLWHA. The Alcohol Use Disorders Identification Test (AUDIT) identified hazardous alcohol drinking in PLWHA. Viral load was determined by RT-qPCR and telomere length was measured using qPCR. PBMC CD8+ T cell activation (CD38+HLA-DR+) and immunosenescence (CD28-) were increased over baseline levels (857% +/- 334, p < 0.05; 398% +/- 80, p < 0.05, respectively) only in CBA animals not receiving ART. Viral load correlated with CD8+ T-cell immunosenescence in macaque PBMCs (r(s) = 0.49, p = 0.02). Activated immunosenescent T-cell (CD8+CD38+CD28-) frequencies in PBMCs from PLWHA significantly correlated with AUDIT scores (r(s) = 0.75, p = 0.001), while no correlation was observed with CD4+ T-cell and AUDIT scores (r(s) = -0.24, p = 0.38). Activated immunosenescent T-cells had shorter telomeres than CD8+ T-cells (CD8+CD28+) from PLWHA. Our results suggest that CBA and AUD augment immune activation and immunosenescence in SIV-infected macaques and PLWHA. PMID- 26603632 TI - Interactions between ethanol and the endocannabinoid system at GABAergic synapses on basolateral amygdala principal neurons. AB - The basolateral amygdala (BLA) plays crucial roles in stimulus value coding, as well as drug and alcohol dependence. Ethanol alters synaptic transmission in the BLA, while endocannabinoids (eCBs) produce presynaptic depression at BLA synapses. Recent studies suggest interactions between ethanol and eCBs that have important consequences for alcohol drinking behavior. To determine how ethanol and eCBs interact in the BLA, we examined the physiology and pharmacology of GABAergic synapses onto BLA pyramidal neurons in neurons from young rats. Application of ethanol at concentrations relevant to intoxication increased, in both young and adult animals, the frequency of spontaneous and miniature GABAergic inhibitory postsynaptic currents, indicating a presynaptic site of ethanol action. Ethanol did not potentiate sIPSCs during inhibition of adenylyl cyclase while still exerting its effect during inhibition of protein kinase A. Activation of type 1 cannabinoid receptors (CB1) in the BLA inhibited GABAergic transmission via an apparent presynaptic mechanism, and prevented ethanol potentiation. Surprisingly, ethanol potentiation was also prevented by CB1 antagonists/inverse agonists. Brief depolarization of BLA pyramidal neurons suppressed GABAergic transmission (depolarization-induced suppression of inhibition [DSI]), an effect previously shown to be mediated by postsynaptic eCB release and presynaptic CB1 activation. A CB1-mediated suppression of GABAergic transmission was also produced by combined afferent stimulation at 0.1 Hz (LFS), and postsynaptic loading with the eCB arachidonoyl ethanolamide (AEA). Both DSI and LFS-induced synaptic depression were prevented by ethanol. Our findings indicate antagonistic interactions between ethanol and eCB/CB1 modulation at GABAergic BLA synapses that may contribute to eCB roles in ethanol seeking and drinking. PMID- 26603635 TI - Serum trough infliximab levels: A comparison of three different immunoassays for the monitoring of CT-P13 (infliximab) treatment in patients with inflammatory bowel disease. AB - BACKGROUND: CT-P13 is a biosimilar drug of reference infliximab and is approved in some countries for use in some indications for which reference infliximab is approved, including inflammatory bowel disease (IBD). The CT-P13 formulation is identical to that of reference infliximab and has similar physiochemical characteristics. However, even a small molecular distinction could lead to different behavior of CT-P13 in immunoanalytical detection systems. AIM: To determine the correlation between three different enzyme-linked immunosorbent assays for infliximab detection in the measurement of CT-P13 trough serum levels. METHODS: Serum samples (n = 42) from IBD patients (n = 22) treated with CT-P13 RemsimaTM (Celltrion, Korea) were evaluated in a blinded way in infliximab assays manufactured by (A) Matriks Biotek (Turkey), (B) Theradiag (France), and (C) R Biopharm (Germany). RESULTS: All assays showed excellent qualitative correlation (Cohen's kappa = 0.90 for A vs. B, 0.76 for A vs. C, and 0.83 for B vs. C). A linear quantitative correlation was satisfactory as well (Spearman's r = 0.91 for A vs. B, 0.86 for A vs. C and 0.92 for B vs. C). Assay C did not detect CT-P13 in 6 samples detected by A and/or B. CONCLUSION: There is a good correlation of CT P13 serum level detection between these assays. PMID- 26603636 TI - Cancer immunotherapy via nucleic acid aptamers. AB - Over the past decade, immune therapy has become a standard treatment for a variety of cancers. Monoclonal antibodies, immune adjuvants and vaccines against oncogenic viruses are now well-established cancer therapies. Immune modulation is a principal element of supportive care for many high-dose chemotherapy regimens. Aptamers are short nucleic acids that bind to defined targets with high affinity and specificity. The first aptamers have been selected around two decades ago by an in vitro process named SELEX (systematic evolution of ligands by exponential enrichment). Since then, numerous aptamers with specificities for a variety of targets from small molecules to proteins or even whole cells have been selected. Targeting immunomodulatory ligands in the progressive tumor lesions of the patients would be prophylactic or therapeutic and may reduce drug-associated toxicities. A new class of inhibitory and agonistic ligands composed of short oligonucleotide (ODN) aptamers was developed recently that exhibited bioactivities comparable or superior to that of antibodies. This paper addressed progress in cancer immunotherapy with nucleic acid aptamers and highlighted recent developments either in immune system targeting or in immunotherapy methods involved aptamers. We discussed aptamer limitations when used as therapeutic agents for cancer treatment and suggested ways to overcome those limitations. PMID- 26603637 TI - Laquinimod ameliorates spontaneous colitis in interleukin-10-gene-deficient mice with improved barrier function. AB - BACKGROUND AND AIMS: Crohn's disease is an autoimmune disease associated with imbalanced mucosal immunity, mediated with increased Th1 and Th17 cells. Laquinimod, an immunomodulatory drug, has shown efficacy in regulating the differentiation of T cells. The aim of the study was to investigate the therapeutic effect of laquinimod on spontaneous colitis in interleukin-10-gene deficient mice, an animal model of Crohn's disease. METHODS: Male Il10(-/-) mice aged 16weeks in the laquinimod group were treated with laquinimod with distilled water at a dose of 25mg/kg by oral gavage, 3 times a week. Il10(-/-) mice in the IL-10-KO group and wild type mice received equal volume of phosphate buffered saline by oral gavage, 3 times a week. After 4weeks, mice were sacrificed for analysis. Severity of colitis, epithelial expression of T-cell-associated cytokines, expression and distribution of tight junction proteins in the lamina propria and NF-kappaB signaling pathway associated mRNA expression were measured at the end of the experiment. RESULTS: Laquinimod treatment ameliorated spontaneous colitis in Il10(-/-) mice, which was associated with decreased T-cell associated pro-inflammatory cytokines. Increased expression and correct distribution of tight junction proteins (occludin and ZO-1) were found in Il10(-/ ) mice treated with laquinimod. In addition, in mice treated with laquinimod, NF kappaB signaling pathway associated mRNA in the colon was also downregulated. CONCLUSIONS: Our results indicated that laquinimod treatment ameliorates colitis in Il10(-/-) mice and improves intestinal barrier function, which may support a new therapeutic approach to Crohn's disease. PMID- 26603638 TI - Respiratory macrophages and dendritic cells mediate respiratory syncytial virus induced IL-33 production in TLR3- or TLR7-dependent manner. AB - Respiratory syncytial virus (RSV) infection can increase the production of IL-33 in lungs of mice. However, little is known about cellular source of IL-33, particularly the types of IL-33-producing cells in innate immune cells during RSV infection. In this study, by using BALB/c mice that were infected intranasally with RSV, it became clear that RSV infection can enhance not only the number of IL-33(+)-alveolar macrophages (AMs) and dendritic cells (DCs), but also the expression of IL-33 mRNA in these cells, suggesting that innate immune cells participate in the production of IL-33. Indeed, in vitro experiments by using murine cell lines found that RSV infection results in more expression of IL-33 mRNA in AMs and DCs, further confirming that these cell types may be an important source of IL-33 during RSV infection. It should be noted that the expression of mRNA for TLR3 and TLR7 was up-regulated in pulmonary AMs during RSV infection. Blockade of TLRs by TLR3 or TLR7 antagonist significantly reduces the levels of IL-33 mRNA in AMs and DCs, suggesting that RSV-induced IL-33 production might be TLRs-dependent manner. Although the expression of TLRs mRNA in pulmonary interstitial macrophages (IMs) was enhanced after RSV infection, stimulation with agonists or inactivated RSV cannot alter the expression of IL-33 mRNA in IMs, suggesting that pulmonary IMs may not be a source of IL-33 during RSV infection. Thus, these results demonstrate that during RSV infection, respiratory macrophages and dendritic cells mediate the production of IL-33 in a TLR dependent manner. PMID- 26603640 TI - suPAR: The unspecific marker for disease presence, severity and prognosis. AB - Investigation of biomarkers that can promptly predict unfavourable outcome of critically illness is an emerging necessity taking into consideration the need for early intervention, the shortage of available beds in intensive care units and the considerable cost of hospitalisation. The most promising biomarker is soluble urokinase-type plasminogen activator receptor (suPAR). Three studies in large populations of critically ill patients and patients admitted to the emergency department have shown that concentrations >12 ng/mL can safely predict unfavourable outcome. This review presents a thorough analysis of the data from these studies. PMID- 26603639 TI - Revisiting the role of phospholipases C in virulence and the lifecycle of Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis, the agent of human tuberculosis has developed different virulence mechanisms and virulence-associated tools during its evolution to survive and multiply inside the host. Based on previous reports and by analogy with other bacteria, phospholipases C (PLC) of M. tuberculosis were thought to be among these tools. To get deeper insights into the function of PLCs, we investigated their putative involvement in the intracellular lifestyle of M. tuberculosis, with emphasis on phagosomal rupture and virulence, thereby re visiting a research theme of longstanding interest. Through the construction and use of an M. tuberculosis H37Rv PLC-null mutant (DeltaPLC) and control strains, we found that PLCs of M. tuberculosis were not required for induction of phagosomal rupture and only showed marginal, if any, impact on virulence of M. tuberculosis in the cellular and mouse infection models used in this study. In contrast, we found that PLC-encoding genes were strongly upregulated under phosphate starvation and that PLC-proficient M. tuberculosis strains survived better than DeltaPLC mutants under conditions where phosphatidylcholine served as sole phosphate source, opening new perspectives for studies on the role of PLCs in the lifecycle of M. tuberculosis. PMID- 26603641 TI - Copper-catalyzed direct C-H fluoroalkenylation of heteroarenes. AB - Copper-catalyzed direct C-H fluoroalkenylation of heterocycles using various gem bromofluoroalkenes as electrophiles is reported. This efficient method offers step-economical, low-cost and stereocontrolled access to relevant heteroarylated monofluoroalkenes. The synthesis of fluorinated analogues of biomolecules and therapeutic agents for the treatment of Duchenne muscular dystrophy as application is reported. PMID- 26603642 TI - IV-treated pulmonary exacerbations in the prior year: An important independent risk factor for future pulmonary exacerbation in cystic fibrosis. AB - BACKGROUND: Single-center analyses have suggested that the number of CF pulmonary exacerbations (PEx) treated with intravenous antibiotics an individual has experienced in the prior year is significantly associated with their future PEx hazard. METHODS: We studied Prior-year PEx association with future PEx hazard by Cox proportional hazards regression among CF Foundation Patient Registry patients who experienced PEx after Jan 1, 2010. RESULTS: Among 13,579 patients, those with 1, 2, 3, or >=4 Prior-year PEx treated with intravenous antibiotics were at 1.8, 2.9, 4.8, and 8.7 higher PEx hazard vs those without (P<.0001). Adjustment with significant demographic and clinical covariates (univariate P<=.0001) reduced Prior-year PEx hazard ratios to 1.6, 2.4, 3.6, and 6.0 (P<.0001). No other covariates had adjusted hazard ratios of >1.7. CONCLUSIONS: Prior-year PEx strongly associate with future PEx hazard and should be accounted for in prospective trials where treatment-associated change in PEx hazard is an efficacy outcome. PMID- 26603643 TI - Multilocus enzyme electrophoresis analysis of rapidly-growing mycobacteria: an alternative tool for identification and typing. AB - OBJECTIVES: Rapidly growing mycobacteria (RGM) have emerged as important pathogens in clinical settings, associated with esthetic procedures and postsurgical infections, pulmonary infections among cystic fibrosis patients, and other structural pulmonary diseases. Microorganisms belonging to Mycobacterium abscessus-Mycobacterium chelonae and to Mycobacterium fortuitum groups have frequently been associated with outbreaks and various epidemics. In the present study, RGM strains were characterized in order to investigate molecular markers based on proteomic analysis. METHODS: Multilocus enzyme electrophoresis (MLEE) was used for species identification and clonal analysis of RGM recovered from postsurgical wound infections during an epidemic. The study included 30M. abscessus subsp. bolletii clinical isolates, most belonging to the BRA100 clone (epidemic in Rio de Janeiro city), as well as 16 RGM ATCC reference strains. RESULTS: Molecular typing allowed the detection of diversity in the studied population and revealed species-specific isoenzymatic patterns. Additionally, the clonal relationship among M. abscessus subsp. bolletii outbreak isolates, as examined using MLEE, was markedly consistent. CONCLUSIONS: Isoenzymatic characterization was found to be a useful molecular tool to identify RGM species and to determine the relatedness among closely related M. abscessus subsp. bolletii isolates. This may be considered a powerful approach for epidemiological studies on RGM. PMID- 26603644 TI - Isoniazid-resistant Mycobacterium kansasii in an HIV-positive patient, and possible development of immune reconstitution inflammatory syndrome after initiation of highly active antiretroviral therapy: case report. AB - Non-tuberculous mycobacteria are rare but important causes of infection in HIV positive individuals. A 28-year-old HIV-positive male presented with a high fever, non-productive cough, right subcostal pain, splenomegaly, a very low CD4 count, elevated C-reactive protein and erythrocyte sedimentation rate, and a normal white blood cell count. The suspicion of tuberculosis (TB) was very high, and sputum samples were positive for acid-fast bacilli. Standard quadruple anti TB therapy was initiated, but once culture of the sample revealed Mycobacterium kansasii, pyrazinamide was withdrawn. Highly active antiretroviral therapy (HAART) was initiated soon after, consisting of abacavir/lamivudine and efavirenz. The patient's general condition deteriorated 2 weeks after HAART initiation, which could have been due to the development of immune reconstitution inflammatory syndrome (IRIS). The patient recovered and was discharged in good condition. However, the results of resistance testing of the isolated organism arrived after discharge, and showed isoniazid and streptomycin resistance. This is the first case report of M. kansasii infection from Serbia and shows the difficulties encountered during the course of treatment. PMID- 26603645 TI - Psychogenic movement disorder in human T-lymphotropic virus type 1 associated myelopathy. AB - Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory disorder of the spinal cord. Acute cases of HAM/TSP and those complicated by movement disorders are rarely reported. Otherwise, psychiatric disturbances are very frequent in infected patients. It can evolve to psychogenic disorders. The case of a 46-year-old woman with acute HAM/TSP complicated by depression and psychogenic movement disorders (chorea of the hands and dystonia-like facial symptoms) is reported. Brain magnetic resonance imaging revealed non-specific small white matter lesions. The involuntary movements arose suddenly and disappeared when the patient was distracted. Two years of psychotherapy and psychiatric follow-up induced complete remission of the symptoms. The association of psychogenic movement disorders and HAM/TSP, increasing the range of neurological manifestations associated with HTLV 1, is related here. Early diagnosis of psychogenic movement disorders is very important to improve the prognosis and treatment of the two conditions, thereby improving the quality of life of HAM/TSP patients and avoiding irreversible sequelae. PMID- 26603646 TI - Onychomycosis caused by Trichosporon mucoides. AB - A case of onychomycosis caused by Trichosporon mucoides in a man with diabetes is presented. The infection was characterized by a brown-black pigmentation of the nail plates and subungual hyperkeratosis of the first three toes of both feet. Onychogryphosis was also visible on the third left toe. Direct microscopic examinations revealed wide and septate hyphae and spores. Three cultures on Sabouraud-gentamicin-chloramphenicol 2 agar and chromID Candida agar produced white, creamy, and smooth colonies that were judged to be morphologically typical of T. mucoides. Microscopic examinations of the colonies showed arthroconidia and blastoconidia. The urease test was positive. A sugar assimilation test on yeast nitrogen base agar showed assimilation of galactitol, sorbitol, and arabinitol. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) confirmed the diagnosis of T. mucoides infection. The patient was treated with topical urea and oral itraconazole. Three months later, a mild improvement was observed. The patient was subsequently lost to follow-up. PMID- 26603647 TI - Effect of ski geometry on aggressive ski behaviour and visual aesthetics: equipment designed to reduce risk of severe traumatic knee injuries in alpine giant slalom ski racing. AB - BACKGROUND/AIM: Aggressive ski-snow interaction is characterised by direct force transmission and difficulty of getting the ski off its edge once the ski is carving. This behaviour has been suggested to be a main contributor to severe knee injuries in giant slalom (GS). The aim of the current study was to provide a foundation for new equipment specifications in GS by considering two perspectives: Reducing the ski's aggressiveness for injury prevention and maintaining the external attractiveness of a ski racer's technique for spectators. METHODS: Three GS ski prototypes were defined based on theoretical considerations and were compared to a reference ski (Pref). Compared to Pref, all prototypes were constructed with reduced profile width and increased ski length. The construction radius (sidecut radius) of Pref was >= 27 m and was increased for the prototypes: 30 m (P30), 35 m (P35), and 40 m (P40). Seven World Cup level athletes performed GS runs on each of the three prototypes and Pref. Kinetic variables related to the ski-snow interaction were assessed to quantify the ski's aggressiveness. Additionally, 13 athletes evaluated their subjective perception of aggressiveness. 15 sports students rated several videotaped runs to assess external attractiveness. RESULTS: Kinetic variables quantifying the ski's aggressiveness showed decreased values for P35 and P40 compared to Pref and P30. Greater sidecut radius reduced subjectively perceived aggressiveness. External attractiveness was reduced for P40 only. CONCLUSIONS: This investigation revealed the following evaluation of the prototypes concerning injury prevention and external attractiveness: P30: no preventative gain, no loss in attractiveness; P35: substantial preventative gain, no significant loss in attractiveness; P40: highest preventative gain, significant loss in attractiveness. PMID- 26603648 TI - IgG4-related disease with coronary arteritis. PMID- 26603649 TI - C-reactive protein levels and aortic aneurysmal disease progression after endovascular repair: The jury is still out. PMID- 26603650 TI - A mechanism of glucose tolerance and stimulation of GH1 beta-glucosidases. AB - beta-Glucosidases are enzymes that hydrolyze beta-glycosidic bonds to release non reducing terminal glucosyl residues from glycosides and oligosaccharides, and thus have significant application potential in industries. However, most beta glucosidases are feedback inhibited by the glucose product, which restricts their application. Remarkably, some beta-glucosidases of the glycoside hydrolase (GH) 1 family are tolerant to or even stimulated by glucose. Elucidation of the mechanisms of glucose tolerance and stimulation of the GH1 beta-glucosidases will be crucial to improve their application through enzyme engineering. In this study, by comparing the primary and tertiary structures of two GH1 beta glucosidases with distinct glucose dependence, some putative glucose-dependence relevant sites were mutated to investigate their exact roles. Both biochemical and structural characterization of the mutants suggested that some sites at the entrance and middle of the substrate channel regulate the effects of glucose, and the relative binding affinity/preference of these sites to glucose modulates the glucose dependence. A mechanism was therefore proposed to interpret the glucose dependence of GH1 beta-glucosidases. This research provides fresh insight into our current understanding of the properties and mechanisms of GH1 beta glycosidases and related enzymes that modulate their activity via feedback control mechanism. PMID- 26603651 TI - EEG characteristics in "eyes-open" versus "eyes-closed" conditions: Small-world network architecture in healthy aging and age-related brain degeneration. AB - OBJECTIVE: Applying graph theory, we investigated how cortical sources small worldness (SW) of resting EEG in eyes-closed/open (EC/EO) differs in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) subjects with respect to normal elderly (Nold). METHODS: EEG was recorded in 30 Nold, 30 aMCI, and 30 AD during EC and EO. Undirected and weighted cortical brain network was built to evaluate graph core measures. eLORETA lagged linear connectivity was used to weight the network. RESULTS: In Nold, in EO condition, the brain network is characterized by more SW (higher SW) in alpha bands and less SW (lower SW) in beta2 and gamma bands. In aMCI, SW has the same trend, except for delta and theta bands where the network shows less small worldness. AD shows a similar trend of Nold, but with less fluctuations between EO/EC conditions. Furthermore, in both conditions, aMCI SW architecture presents midway properties between AD and Nold. At low frequencies (delta e theta bands) in EC, aMCI group presents network's architecture similar to Nold, while in EO aMCI, SW is superimposable to AD ones. CONCLUSIONS: In resting state condition, aMCI small-world architecture presents midway topological properties between AD subjects and healthy controls, confirming the hypothesis that aMCI is an intermediate step along the disease progression. SIGNIFICANCE: We proposed the application of graph theory to EEG in reactivity to EO in order to find a marker of diagnosis that - in association with other techniques of neuroimaging - could be sensitive to the progression of MCI or conversion into AD. PMID- 26603652 TI - Eigencentrality based on dissimilarity measures reveals central nodes in complex networks. AB - One of the most important problems in complex network's theory is the location of the entities that are essential or have a main role within the network. For this purpose, the use of dissimilarity measures (specific to theory of classification and data mining) to enrich the centrality measures in complex networks is proposed. The centrality method used is the eigencentrality which is based on the heuristic that the centrality of a node depends on how central are the nodes in the immediate neighbourhood (like rich get richer phenomenon). This can be described by an eigenvalues problem, however the information of the neighbourhood and the connections between neighbours is not taken in account, neglecting their relevance when is one evaluates the centrality/importance/influence of a node. The contribution calculated by the dissimilarity measure is parameter independent, making the proposed method is also parameter independent. Finally, we perform a comparative study of our method versus other methods reported in the literature, obtaining more accurate and less expensive computational results in most cases. PMID- 26603655 TI - N-Heterocyclic olefin stabilized boron dication. AB - Boron mono- and di-cations featuring a nucleophilic N-heterocyclic olefin and the pentamethylcyclopentadienyl substituent have been prepared and structurally characterized. Experimental and theoretical investigations show that [eta(5)-Cp*B NHO](2+) is considerably more Lewis acidic than [eta(5)-Cp*B-IMes](2+) due to the steric congestion imposed by the bent geometry of NHO around the central boron atom. PMID- 26603653 TI - Differential Costs of Two Distinct Resistance Mechanisms Induced by Different Herbivore Species in Arabidopsis. AB - Plants respond to herbivory with the induction of resistance, mediated by distinct phytohormonal signaling pathways and their interactions. Phloem feeders are known to induce plant resistance via the salicylic acid pathway, whereas biting-chewing herbivores induce plant resistance mainly via the jasmonate pathway. Here, we show that a specialist caterpillar (biting-chewing herbivore) and a specialist aphid (phloem feeder) differentially induce resistance against Pieris brassicae caterpillars in Arabidopsis (Arabidopsis thaliana) plants. Caterpillar feeding induces resistance through the jasmonate signaling pathway that is associated with the induction of kaempferol 3,7-dirhamnoside, whereas aphid feeding induces resistance via a novel mechanism involving sinapoyl malate. The role of sinapoyl malate is confirmed through the use of a mutant compromised in the biosynthesis of this compound. Caterpillar-induced resistance is associated with a lower cost in terms of plant growth reduction than aphid induced resistance. A strong constitutive resistance against P. brassicae caterpillars in combination with a strong growth attenuation in plants of a transfer DNA (T-DNA) insertion mutant of WRKY70 (wrky70) suggest that the WRKY70 transcription factor, a regulator of downstream responses mediated by jasmonate salicylic acid signaling cross talk, is involved in the negative regulation of caterpillar resistance and in the tradeoff between growth and defense. In conclusion, different mechanisms of herbivore-induced resistance come with different costs, and a functional WRKY70 transcription factor is required for the induction of low-cost resistance. PMID- 26603656 TI - Optimization of a vitrification protocol for hatched blastocysts from the dromedary camel (Camelus dromedarius). AB - The objective of this study was to modify and optimize a vitrification protocol (open pulled straw) that was originally designed for human oocytes and embryos, to make it suitable for the cryopreservation of camel hatched blastocysts. The original open pulled straw protocol was a complex process with 15-minute exposure of oocytes/embryos in 7.5% ethylene glycol (EG) and 7.5% dimethyl sulfoxide (Me2SO) for equilibration, and cooling in 16% EG + 16% Me2SO + 1 M sucrose. Recognizing a need to better control the cryoprotectant (CPA) concentrations, while avoiding toxicity to the embryos, the effects on the survival rate and developmental potential of camel embryos in vitro were investigated using two different methods of loading the CPAs into the embryos (stepwise and semicontinuous increase in concentration), two different loading temperature/time (room temperature ~24 degrees C/15 min and body 37 degrees C/3 min), and the replacement of Me2SO with EG alone or in combination with glycerol (Gly). A total of 145 in vivo-derived embryos were subjected to these processes, and after warming their morphological quality and integrity, and re-expansion was assessed after 0, 2, 24, 48, 72, and 96 hours of culture. Exposure of embryos in a stepwise method was more beneficial to the survival of embryos than was the semicontinuous process, and loading of CPAs at 37 degrees C with a short exposure time (3 minutes) resulted in an outcome comparable to the original processing at room temperature with a longer exposure time (15 minutes). The replacement of the Me2SO + EG mixture with EG only or a combination of EG + Gly in the vitrification medium significantly improved the outcome of all these evaluation criteria (P < 0.05). The modified protocol of loading EG at 37 degrees C for 3 minutes has increased the embryo survival of the original protocol from 67% to 91% and the developmental rate from 57% to 83% at 5-day culture. These results were comparable to or better than those reported in human or other species, indicating that this optimized method is well suited to any commercial embryo transfer program in the dromedary camel. PMID- 26603654 TI - Engineering Triterpene and Methylated Triterpene Production in Plants Provides Biochemical and Physiological Insights into Terpene Metabolism. AB - Linear, branch-chained triterpenes, including squalene (C30), botryococcene (C30), and their methylated derivatives (C31-C37), generated by the green alga Botryococcus braunii race B have received significant attention because of their utility as chemical and biofuel feedstocks. However, the slow growth habit of B. braunii makes it impractical as a production system. In this study, we evaluated the potential of generating high levels of botryococcene in tobacco (Nicotiana tabacum) plants by diverting carbon flux from the cytosolic mevalonate pathway or the plastidic methylerythritol phosphate pathway by the targeted overexpression of an avian farnesyl diphosphate synthase along with two versions of botryococcene synthases. Up to 544 ug g(-1) fresh weight of botryococcene was achieved when this metabolism was directed to the chloroplasts, which is approximately 90 times greater than that accumulating in plants engineered for cytosolic production. To test if methylated triterpenes could be produced in tobacco, we also engineered triterpene methyltransferases (TMTs) from B. braunii into wild-type plants and transgenic lines selected for high-level triterpene accumulation. Up to 91% of the total triterpene contents could be converted to methylated forms (C31 and C32) by cotargeting the TMTs and triterpene biosynthesis to the chloroplasts, whereas only 4% to 14% of total triterpenes were methylated when this metabolism was directed to the cytoplasm. When the TMTs were overexpressed in the cytoplasm of wild-type plants, up to 72% of the total squalene was methylated, and total triterpene (C30+C31+C32) content was elevated 7-fold. Altogether, these results point to innate mechanisms controlling metabolite fluxes, including a homeostatic role for squalene. PMID- 26603657 TI - Characterization of Compensatory Stepping in People With Multiple Sclerosis. AB - OBJECTIVE: To characterize postural responses to forward and backward external perturbations in people with multiple sclerosis (PwMS), and to relate performance to commonly used clinical outcomes. DESIGN: Cross-sectional study. Postural responses were tested during large stepping and smaller feet-in-place perturbations in forward and backward directions. SETTING: University research laboratory. PARTICIPANTS: PwMS (n=54) and age-matched controls (n=21) (N=75). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Center of mass displacement and step latency after external perturbations. RESULTS: PwMS exhibited larger center of mass displacements and step latencies than control participants in response to stepping perturbations (P=.003 and P=.028, respectively). Stepping deficits were more pronounced during backward stepping and were significantly correlated to increased severity on clinical measures (European Database for Multiple Sclerosis disability score and Timed 25-Foot Walk). CONCLUSIONS: Compensatory stepping is impaired in PwMS and correlates with clinical disability. Measurement of backward compensatory stepping may be more effective at identifying postural dysfunction in PwMS than forward compensatory steps. Prolonged step latencies, large anticipatory postural adjustments, and multiple compensatory steps are especially altered in PwMS, suggesting possible targets for neurorehabilitation. PMID- 26603658 TI - Widespread Positive Selection Drives Differentiation of Centromeric Proteins in the Drosophila melanogaster subgroup. AB - Rapid evolution of centromeric satellite repeats is thought to cause compensatory amino acid evolution in interacting centromere-associated kinetochore proteins. Cid, a protein that mediates kinetochore/centromere interactions, displays particularly high amino acid turnover. Rapid evolution of both Cid and centromeric satellite repeats led us to hypothesize that the apparent compensatory evolution may extend to interacting partners in the Condensin I complex (i.e., SMC2, SMC4, Cap-H, Cap-D2, and Cap-G) and HP1s. Missense mutations in these proteins often result in improper centromere formation and aberrant chromosome segregation, thus selection for maintained function and coevolution among proteins of the complex is likely strong. Here, we report evidence of rapid evolution and recurrent positive selection in seven centromere-associated proteins in species of the Drosophila melanogaster subgroup, and further postulate that positive selection on these proteins could be a result of centromere drive and compensatory changes, with kinetochore proteins competing for optimal spindle attachment. PMID- 26603659 TI - Computer-Aided Segmentation of the Mid-Brain in Trans-Cranial Ultrasound Images. AB - This paper presents a novel and rapid method developed for semi-automated segmentation of the mid-brain region in B-mode trans-cranial ultrasound (TCS) images. TCS is a relatively new neuroimaging tool having promising application in early diagnosis of Parkinson's disease. The quality of TCS images is much lower compared with the ultrasound images obtained during scanning of the soft tissues; the structures of interest in TCS are difficult to extract and to evaluate. The combination of an experience-based statistical shape model and intensity amplitude invariant edge detector was proposed for the extraction of fuzzy boundaries of the mid-brain in TCS images. A statistical shape model was constructed using 90 manual delineations of the mid-brain region made by professional neurosonographer. Local phase-based edge detection strategy was applied for determination of plausible mid-brain boundary points used for statistical shape fitting. The proposed method was tested on other 40 clinical TCS images evaluated by two experts. The obtained averaged results of segmentation revealed that the differences between manual and automated measurements are statistically insignificant (p > 0.05). PMID- 26603660 TI - The Sonographic Features of the Thyroid Gland After Treatment with Radioiodine Therapy in Patients with Graves' Disease. AB - The aim of the study was to describe the typical sonographic features of the thyroid gland in patients with Graves' hyperthyroidism after radioiodine therapy (RIT). Thirty patients (21 female and 9 male) with a mean age of 53 y (standard deviation [SD] +/- 11.3) and with previous Graves' disease who had been successfully treated with RIT were enrolled in the study. All were hypothyroid or euthyroid after treatment. The thyroid ultrasound was carried out by a single experienced operator with an 8-MHz linear transducer. Volume, vascularity, echogenicity and echotexture of the glands were noted. The presence of nodules and lymph nodes was also documented. The mean volumes of the right lobe were 2.4 mL +/- 2.9 SD (0.6-14) and the left lobe were 1.8 mL +/- 1.9 SD (0.4-9.1), with a mean total volume of 4.2 mL +/- 4.7 SD (1.3-19.1). Of those who had a pre treatment ultrasound (23%), the percentage reduction in volume was 87% (p < 0.05); 93% of the glands were hypovascular, with the remaining 7% showing normal vascularity. The glands were hyperechoic and of coarse echotexture. Overall, the sonographic features of the post-RIT gland included a significantly reduced mean total volume of 4.2 mL, hypovascularity, coarse echotexture and hyperechogenicity. PMID- 26603661 TI - Cardiac arrest and therapeutic hypothermia. AB - Therapeutic hypothermia for patients who remain comatose following resuscitation from a cardiac arrest improves both survival and neurologic outcomes. Although this therapy has been incorporated into the guidelines for routine post resuscitation care and has been in clinical use for over a decade, significant questions and controversies remain. In this review, we discuss these questions in the context of the current evidence and provide a practical framework to help guide clinicians. PMID- 26603662 TI - Defining the timing and causes of death amongst patients undergoing colorectal resection in England. AB - AIM: Historically, postoperative deaths have been reported up to 30 days following surgery. There is, however, emerging evidence that deaths attributable to surgery continue to occur much later than this time frame. This aim of this study was to analyse the timing and causes of mortality following colorectal resection. METHOD: Data were obtained from the Hospital Episode Statistics database with linkage to mortality data from the Office for National Statistics. Patients who underwent colorectal resection between April 2001 and February 2007 were included. Causes of death were classified into colorectal cancer (CRC), other malignancy, cardiac, respiratory, gastrointestinal, neurological and other. RESULTS: During the study period 171 791 patients underwent a colorectal resection. Thirty-day mortality rates for elective procedures were 1.3, 3.5, 7.0 and 12.1% for the <= 65, 66-75, 76-85 and > 85 year age groups, respectively, compared with 2.2, 5.4, 9.8 and 16.7% at 90 days. For elective operations, at 30 days, 38.6% of patients who died had CRC recorded as the primary cause of death, whilst 25.4% died of cardiac causes. In the younger population undergoing a resection, deaths due to cardiac causes were significantly higher than the national average for the same age group even beyond 30 days (13.5% at 30 days, 11.1% at 90 days and 5.7% at 1 year). CONCLUSION: This study shows that deaths attributable to colorectal surgery occur beyond the conventionally utilized 30 day period. Information presented to patients on the basis of 30-day mortality estimates is likely to underestimate the true risk of surgical intervention. PMID- 26603671 TI - Copper-Catalyzed Aerobic Oxidative Reaction of Sulfonyl Hydrazides with Alcohols: An Easy Access to Sulfinates. AB - A Cu-catalyzed aerobic oxidative reaction between sulfonyl hydrazides and alcohols has been developed. In this reaction, sulfonyl hydrazides act as the sulfinic acid precursors to react with alcohols, resulting in sulfinic esters with up to 72 % yield. This catalytic system tolerates a wide range of sulfonyl hydrazide substrates, and represents a new strategy for the transformation of readily available sulfonyl hydrazides. PMID- 26603672 TI - Microwave-Assisted Synthesis and Physicochemical Characterization of Tetrafuranylporphyrin-Grafted Reduced-Graphene Oxide. AB - This work describes the design of a modified porphyrin that bears four furan rings linked by 1,2-bis-(2-aminoethoxy)ethane spacers. This unit is a well-suited scaffold for a Diels-Alder reaction with commercial reduced-graphene oxide, which is also described in this paper. A new hybrid material is obtained, thanks to efficient grafting under microwave irradiation, and fully characterized in terms of structure (UV, TGA, Raman) and morphology (HR-TEM and AFM). Potential applications in photo- and sonodynamic therapy are envisaged. PMID- 26603673 TI - Circadian variation in serum cortisol during hydrocortisone replacement is not attributable to changes in cortisol-binding globulin concentrations. AB - BACKGROUND: Patients taking hydrocortisone (HC) replacement for primary or secondary adrenal failure require individual adjustment of their dose. In addition to modifying the administered doses of HC for each patient, physicians are increasingly interested in variations in the bioavailability of glucocorticoid replacement. One potential determinant of the bioavailability of replaced HC is a variation in serum cortisol-binding globulin (CBG) concentration, which may, in turn, affect interpretation of cortisol profiles and individual dose selection for patients on hydrocortisone replacement therapy. AIM: To investigate the hypothesis that there is a circadian variation in CBG levels. METHODS AND RESULTS: A total of 34 male patients divided into 3 groups (10 patients with non-somatotroph structural pituitary disease on HC replacement, 11 patients with treated acromegaly on HC replacement and 13 patients with treated acromegaly not on HC replacement) and 10 healthy volunteers were included. Cortisol and CBG levels were measured at 6 time points (0800, 1100, 1300, 1500, 1700 and 1900). No significant circadian variation in CBG concentration was found in any of the 4 groups. CONCLUSION: Circadian variation in serum cortisol during hydrocortisone replacement is not attributable to changes in cortisol-binding globulin concentration. Changes in serum cortisol levels may thus be explained by other factors including 11 beta-hydroxysteroid dehydrogenase type 1 activity or circadian changes in the binding properties of CBG. PMID- 26603674 TI - The Perception of Female Smokers with Fibromyalgia on the Effects of Smoking on Fibromyalgia Symptoms. AB - OBJECTIVE: Smokers with fibromyalgia have greater pain intensity and function impairment compared to nonsmokers. Patients' perceptions of interactions between smoking and fibromyalgia symptoms have not been described. The primary aim of this study was to report the perceptions of female smokers with fibromyalgia on how smoking affects symptoms. METHODS: Forty-eight daily smokers with fibromyalgia enrolled in the Mayo Clinic Fibromyalgia Treatment Center completed the Fibromyalgia Impact Questionnaire, Fagerstrom Test for Nicotine Dependence, Patient Health Questionnaire-9, General Anxiety Disorder-7 and a Fibromyalgia Symptoms and Smoking Survey which queried how smoking directly affected fibromyalgia symptoms (eg, pain, tiredness/fatigue, stiffness, nervousness/anxiety, depression/blueness, irritability, concentration, and overall) or indirectly as a coping mechanism. RESULTS: The majority of subjects reported smoking had no direct effect on fibromyalgia physical symptoms (pain [60% reported no effect], fatigue [56%], stiffness [81%]) but direct improvement of emotional symptoms (anxiety [62% reported improvement], irritability [64%]). The majority of subjects used smoking to cope with pain (69%) via distraction (83%) and relaxation (77%), lessening emotional distress by reducing a sense of frustration (83%) or sadness (54%) because of pain, and as a justification for resting vis-a-vis "smoke breaks" (69%). Thirty-one smokers were mildly and 17 moderately/severely dependent on tobacco, and no difference in fibromyalgia impact score (P = 0.70), pain (P = 0.39), depression (P = 0.20), and anxiety (P = 0.64) scores were detected, but more moderately/severely dependent subjects reported smoking improved pain (50% vs. 17%, P = 0.04). DISCUSSION: Smokers with fibromyalgia reported smoking helped to cope with fibromyalgia pain but generally did not directly ameliorate fibromyalgia physical symptoms. PMID- 26603675 TI - [Clinical anatomy of the horse: teeth and dentition]. AB - The routine inspection of the equine oral cavity allows a numerical assessment of the teeth and provides information about positional changes within the dentition. By use of appropriate dental equipment, the occlusal surfaces of all teeth can be inspected and diagnosed. However, neither the teeth nor their occlusal surfaces are constant structures. Instead, equine teeth and, in particular, their occlusal surfaces are subjected to continuous morphological and positional changes due to the effects of aging and the equine-specific high amount of occlusal wear. Therefore, it is mandatory to define anatomical criteria, which allow us to distinguish between anatomical variations and pathological conditions. Moreover, an unambiguous nomenclature with regard to the equine-specific dental anatomy is essential. This article provides a tutorial overview of the equine dental anatomy as well as recent findings in the field of equine dentistry. Special attention is paid to dynamic changes within both individual teeth and dentition. PMID- 26603676 TI - Posterior decompression and spine stabilization for metastatic spinal cord compression in the cervical spine. A matched pair analysis. AB - PURPOSE: This study aims to compare clinical outcome of cervical spine metastasis with those of thoracic and lumbar spine metastasis after surgery for metastatic spinal cord compression (MSCC). PATIENTS AND METHODS: Data from nineteen patients with cervical spine metastasis were matched to thirty-eight patients with thoracic spine metastasis and thirty-eight patients with lumbar spine metastasis from a cohort of 183 patients with MSCC treated with posterior decompression and spine stabilization. Three groups were matched for eleven potential prognostic characteristics, and at least nine of eleven characteristics should match between the matched patients. RESULTS: Deterioration of motor function was observed in 37% patients with cervical spine metastasis, 18% patients with thoracic spine metastasis, and 13% patients with lumbar spine metastasis after surgery (P = 0.02). Postoperative median survival was 11.5 months for cervical spine metastasis, 10.9 months for thoracic spine metastasis, and 10.7 months for lumbar spine metastasis (P = 0.64). Surgery-related complications occurred in 18.9% of all patients and showed no significant difference between the three groups (P = 0.63). Each group experienced improvement in pain outcome when compared between pre- and post-operative pain scores (P < 0.01), while the differences had no significance between the three groups (P > 0.05). CONCLUSIONS: MSCC in cervical spine is less likely to improve or maintain motor function as compared with MSCC in thoracic and lumbar spine after surgery. However, its clinical outcomes appear similar to those of thoracic and lumbar spine metastasis in terms of postoperative survival, surgery-related complication, and pain outcome. PMID- 26603677 TI - Incidental findings in CT angiograms for free DIEP flap breast reconstruction - Do they change our management? AB - BACKGROUND: Abdominal CT angiography (CTA) has become an integral part of the pre operative evaluation of patients undergoing free Deep Inferior Epigastric Perforator (DIEP) flap breast reconstruction. It aids accurate delineation of perforator anatomy, assists pre-operative decision making and reduces operative time. However, such detailed imaging invariably yields a variety of incidental findings, with quoted figures of 13-36% in this setting. The purpose of this study was to identify the rate of "incidentalomas" when using DIEP CT angiography and, review how such findings influence our management. METHOD: A retrospective review was performed, looking at pre-operative scan reports of 154 consecutive patients undergoing free DIEP flap breast reconstructions between July 2008 and June 2012. RESULTS: Of 154 CTA's reviewed, 116 (75.3%) demonstrated incidental findings. In 71 patients (46.1%), these "incidentalomas" were inconsequential. However, in 37 patients (24.0%) the CTA prompted further investigations, and notably in a further 8 patients (5.2%) metastatic disease or other significant pathology was discovered which changed the operative plan. CONCLUSION: The overall rate of "incidentalomas" presented in this study is substantially higher than other similar published series, and most importantly, significantly altered the surgical management plan in 5.2% of cases. As such we would advocate that a pre-operative "staging" CTA, imaging the chest, abdomen and pelvis is useful for more than just delineation of vascular anatomy in patients undergoing DIEP flap reconstruction. PMID- 26603678 TI - Laparoscopic gastrectomy in Western European patients with advanced gastric cancer. AB - BACKGROUND: The advantage of laparoscopic gastrectomy compared to open gastrectomy has been established in Asian patient series with early gastric cancer. However, its feasibility in Western European patients with locally advanced gastric cancer is unknown. METHODS: Between 2006 and 2014 70 consecutive patients with advanced gastric cancer underwent laparoscopic gastrectomy with D2 lymph node dissection. A Billroth II reconstruction was performed after distal gastrectomy. In case of total gastrectomy a jejunal J-pouch reconstruction was performed. RESULTS: Total gastrectomy was performed in 56 patients and distal gastrectomy in 14 patients. Perioperative chemotherapy was administered in 45/70 (64%) patients. A radical resection was achieved in 63/70 (90%). The median number of dissected lymph nodes was 17 (2-62). The median intraoperative blood loss was 305 (30-2700) milliliters. The median postoperative hospital stay was 11 (5-91) days. The 30-day mortality was 4.3%. CONCLUSIONS: Laparoscopic gastrectomy can be performed in Western European patients with advanced gastric cancer and meets the oncologic standard with low intraoperative blood loss and short hospital stay. PMID- 26603679 TI - Neck muscle endurance and head posture: A comparison between adolescents with and without neck pain. AB - OBJECTIVE: The main aims of this study were to compare the neck flexor and extensor endurance and forward head posture between adolescents with and without neck pain. The secondary aims were to explore potential associations between muscles endurance, head posture and neck pain characteristics and to assess intra rater reliability of the measurements used. METHODS: Adolescents with neck pain (n = 35) and age-matched asymptomatic adolescents (n = 35) had their forward head posture, neck flexor endurance and neck extensor endurance measured using clinical tests. Intra-rater reliability was also assessed. RESULTS: Forward head posture and neck flexor and extensor endurance tests showed moderate to almost perfect intra-rater reliability (ICC between 0.58 and 0.88). Adolescents with neck pain showed significantly less forward head posture (neck pain = 46.62 +/- 4.92; asymptomatic = 44.18 degrees +/- 3.64 degrees , p > 0.05) and less neck flexor (neck pain = 24.50 +/- 23.03s; asymptomatic = 35.89 +/- 21.53s, p > 0.05) and extensor endurance (neck pain = 12.6.64 +/- 77.94s; asymptomatic = 168.66 +/- 74.77s, p > 0.05) than asymptomatic adolescents. CONCLUSIONS: Results suggest that changes in posture and neck muscle endurance are a feature of adolescents with neck pain. PMID- 26603680 TI - Serelaxin and acute heart failure. AB - Attempts at developing novel therapeutic agents for acute heart failure (AHF) over the past two decades have been marked by disappointment. Relaxin is a human peptide hormone believed to mediate many adaptive haemodynamic changes that occur during pregnancy. Because these effects may be useful for treating AHF, a recombinant version of human relaxin-2, serelaxin, has been developed as a novel therapeutic agent. Studies have confirmed serelaxin's haemodynamic effects of decreasing pulmonary and systemic resistance and increasing renal blood flow. A 1161-patient, placebo-controlled Phase III trial, RELAX-AHF, demonstrated significant improvement in symptoms, reduced worsening of heart failure, decreased hospital length of stay and increased 180-day survival after index hospitalisation. Additional Phase III trials (RELAX-AHF-2; RELAX-AHF-ASIA) are underway to further evaluate the efficacy of serelaxin in patients with AHF. This article will review the physiological function, mechanism of action, clinical trial results and future directions of serelaxin in the treatment of AHF. PMID- 26603681 TI - A 56-year-old man with exercise-induced chest pains. PMID- 26603682 TI - New approach to accuracy verification of 3D surface models: An analysis of point cloud coordinates. AB - PURPOSE: The precision of two types of surface digitization devices, i.e., a contact probe scanner and an optical scanner, and the trueness of two types of stone replicas, i.e., one without an imaging powder (SR/NP) and one with an imaging powder (SR/P), were evaluated using a computer-aided analysis. METHODS: A master die was fabricated from stainless steel. Ten impressions were taken, and ten stone replicas were prepared from Type IV stone (Fujirock EP, GC, Leuven, Belgium). The precision of two types of scanners was analyzed using the root mean square (RMS), measurement error (ME), and limits of agreement (LoA) at each coordinate. The trueness of the stone replicas was evaluated using the total deviation. A Student's t-test was applied to compare the discrepancies between the CAD-reference-models of the master die (m-CRM) and point clouds for the two types of stone replicas (alpha=.05). RESULTS: The RMS values for the precision were 1.58, 1.28, and 0.98MUm along the x-, y-, and z-axes in the contact probe scanner and 1.97, 1.32, and 1.33MUm along the x-, y-, and z-axes in the optical scanner, respectively. A comparison with m-CRM revealed a trueness of 7.10MUm for SR/NP and 8.65MUm for SR/P. CONCLUSIONS: The precision at each coordinate (x-, y , and z-axes) was revealed to be higher than the one assessed in the previous method (overall offset differences). A comparison between the m-CRM and 3D surface models of the stone replicas revealed a greater dimensional change in SR/P than in SR/NP. PMID- 26603683 TI - Barriers and facilitators for return to work in cancer survivors with job loss experience: a focus group study. AB - Over 50% of cancer survivors lose their job or quit working. Cancer survivors who experience job loss may face different challenges regarding return to work, compared to cancer survivors with employers. This qualitative study aimed to explore barriers and facilitators for return to work in cancer survivors with job loss and in insurance physicians who assist cancer survivors in their return to work. We conducted five focus groups and one interview (cancer survivors, N = 17; insurance physicians, N = 23). Topics included, among others, experience of job loss and barriers and facilitators for return to work. Data were audio recorded and analysed using thematic analysis. Our main finding was that cancer survivors experienced a double loss: loss of job on top of loss of health. As a result, cancer survivors feared for job applications, lacked opportunities to gradually increase work ability, and faced reluctance from employers in hiring them. Insurance physicians expressed a need for more frequent and longer consultations with cancer survivors with job loss. We conclude that cancer survivors who experience double loss encounter specific barriers in the return to work process. This calls for a tailored approach regarding return to work support. PMID- 26603684 TI - Prognosis of gastric adenocarcinoma patients with various burdens of peritoneal metastases. AB - BACKGROUND: Peritoneal metastases (PM) in patients with gastric adenocarcinoma (GAC) may be identified by diagnostic laparoscopy (DL) or imaging (I). Although prognosis is poor, some patients have excellent outcome. We compared the overall survival (OS) of patients in 3 groups: those with positive cytology (CY+) by DL (DL-CY+), those with gross PM (GPM) by DL (DL-GPM+) and with GPM obvious on I (I GPM+). METHODS: 146 GAC patients were identified. The Kaplan-Meier analysis, univariate, and multivariate Cox proportional hazards regression models were employed. RESULTS: Patients were primarily men (67%), with good ECOG scores (0-1; 89%), had DL (84%), had poorly differentiated GAC (92%), and had received chemotherapy (89%). The median OS for all patients was 15 months (5% CI, 12.9 18.2 months). The DL-CY+ group had median OS of 22.5 months (95% CI, 15-29.3 months). Patients with I-GPM+ had four times the risk of death than those with DL CY+ (P < 0.001) and patients with DL-GPM+ had two times the risk of death than those with DL-CY+ (P = 0.001). At 36 months, all DL-GPM+ and I-GPM+ had died but 8 patients with DL-CY+ remained alive. CONCLUSIONS: Some GAC patients with DL-CY+ have long OS; therefore, novel strategies to further prolong their OS are needed. PMID- 26603685 TI - Extrinsic Esophageal Compression by Cervical Osteophytes in Diffuse Idiopathic Skeletal Hyperostosis: A Contraindication to Transesophageal Echocardiography? AB - Contraindications to transesophageal echocardiography (TEE) include various esophageal pathologies, but compression of the esophagus by vertebral osteophytes is not listed in the current American Society of Echocardiography guidelines. We report a case of diffuse idiopathic skeletal hyperostosis (DISH) in an 81-year old man who had incidentally been found to have extrinsic esophageal compression by cervical osteophytes prior to a proposed TEE. The incidence of esophageal perforation in patients with DISH and vertebral osteophytes is not well documented. We believe these patients are at increased risk of esophageal perforation during TEE, and thus, TEE may be relatively contraindicated in patients with DISH. PMID- 26603686 TI - Determination of polycyclic aromatic hydrocarbons in soy isoflavone nutraceutical products by gas chromatography coupled to triple quadrupole tandem mass spectrometry. AB - Thirteen polycyclic aromatic hydrocarbons have been determined in soy-based nutraceutical products. First, an optimization of extraction procedure was performed, and a solid-liquid extraction assisted by sonication and a dilute and shoot procedure were compared, selecting the dilute and shoot approach for the extraction of target compounds, utilizing a mixture of acetone/n-hexane (1:1 v/v) as extractant solvent. After this, a clean-up step was needed bearing in mind the complexity of these matrices. Dispersive solid-phase extraction, using a mixture of C18 and Zr-Sep+ (25 mg/mL each) was used. The separation was achieved by gas chromatography and detection with triple quadrupole tandem mass spectrometry. For quantification purposes, matrix-matched calibration was used. The validation was applied at three concentration levels (20, 100 and 250 MUg/kg), obtaining recoveries between 70 and 120% and precision values equal to or lower than 23%. Limits of detection and quantification were below 8 and 20 MUg/kg, respectively. The method was applied in 11 samples, detecting five polycyclic aromatic hydrocarbons at concentrations ranging from 4.1 to 18.5 MUg/kg. PMID- 26603687 TI - Exposing Differences in Monomer Exchange Rates of Multicomponent Supramolecular Polymers in Water. AB - The formation of multicomponent and bioactive supramolecular polymers is a promising strategy for the formation of biomaterials that match the dynamic and responsive nature of biological systems. In order to fully realize the potential of this strategy, knowledge of the location and behavior of bioactive components within the system is crucial. By employing synthetic strategies to create multifunctional monomers, coupled with FRET and STORM techniques, we have investigated the formation and behavior of a bioactive and multicomponent supramolecular polymer. By creating a peptide-dye-monomer conjugate, we were able to measure high degrees of monomer incorporation and to visualize the equal distribution of monomers within the supramolecular polymer. Furthermore, by tracking the movement of monomers, we uncovered small differences in the dynamics of the bioactive monomers. PMID- 26603688 TI - Is the role of human RNase H2 restricted to its enzyme activity? AB - In human cells, ribonuclease (RNase) H2 complex is the predominant source of RNase H activities with possible roles in nucleic acid metabolism to preserve genome stability and to prevent immune activation. Dysfunction mutations in any of the three subunits of human RNase H2 complex can result in embryonic/perinatal lethality or cause Aicardi-Goutieres syndrome (AGS). Most recently, increasing findings have shown that human RNase H2 proteins play roles beyond the RNase H2 enzymatic activities in health and disease. Firstly, the biochemical and structural properties of human RNase H2 proteins allow their interactions with various partner proteins that may support functions other than RNase H2 enzymatic activities. Secondly, the disparities of clinical presentations of AGS with different AGS-mutations and the biochemical and structural analysis of AGS mutations, especially the results from both AGS-knockin and RNase H2-null mouse models, suggest that human RNase H2 complex has certain cellular functions beyond the RNase H2 enzymatic activities to prevent the innate-immune-mediated inflammation. Thirdly, the subunit proteins RNASEH2A and RNASEH2B respectively, not related to the RNase H2 enzymatic activities, have been shown to play a certain role in the pathophysiological processes of different cancer types. In this minireview, we aims to provide a brief overview of the most recent investigations into the biological functions of human RNase H2 proteins and the underlying mechanisms of their actions, emphasizing on the new insights into the roles of human RNase H2 proteins playing beyond the RNase H2 enzymatic activities in health and disease. PMID- 26603689 TI - Influence of acute kidney injury on the time to complete remission in adult minimal change nephrotic syndrome: a single-centre study. AB - AIM: Acute kidney injury (AKI) is a common complication of minimal change nephrotic syndrome (MCNS), particularly in adults. We evaluated the prevalence of AKI at the onset of adult MCNS and analyzed the influence of AKI on the duration of achieving complete remission (CR). METHODS: A retrospective, single-centre, dynamic cohort study was conducted with biopsy-proven, first-onset, adult MCNS patients treated with corticosteroids. Fifty-three consecutive patients diagnosed with MCNS from January 2000 to April 2014 were enrolled. Age, gender, daily urinary protein excretion, and serum creatinine levels were measured. To evaluate AKI during induction, we used the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for AKI and judged AKI stage according to the fluctuations in serum creatinine levels during the first 4 weeks of starting corticosteroid therapy. RESULTS: Twenty patients (37.7%) met the AKI criteria and all 53 patients achieved CR within 1 year. Kaplan-Meier analysis showed that the median time to CR was significantly longer in patients with AKI than in patients without AKI. Cox proportional hazard analysis showed that the hazard ratio (HR) associated with the presence of AKI for achieving CR within 4 weeks was 0.36 after adjustment for age, gender, serum albumin, daily urinary protein excretion, hypertension, administration of 25% albumin, and methylprednisolone pulse therapy. A graded association was also observed between AKI stage and HR for achieving CR. CONCLUSIONS: The prevalence of AKI is high in adult patients with MCNS during induction therapy. AKI is an independent factor that delays the time to CR. PMID- 26603691 TI - Improving Surgical Resection of Metastatic Liver Tumors With Near-Infrared Optical-Guided Fluorescence Imaging. AB - Objective The aim of this study was to investigate the feasibility and future clinical applications of near-infrared (NIR) fluorescence imaging to guide liver resection surgery for metastatic cancer to improve resection margins. Summary Background Data A subset of patients with metastatic hepatic tumors can be cured by surgery. The degree of long-term and disease-free survival is related to the quality of surgery, with the best resection defined as "R0" (complete removal of all tumor cells, as evidenced by microscopic examination of the margins). Although intraoperative ultrasonography can evaluate the surgical margins, surgeons need a new tool to perfect the surgical outcome. Methods A preliminary study was performed on 3 patients. We used NIR imaging postoperatively "ex vivo" on the resected liver tissue. The liver tumors were preoperatively labelled by intravenously injecting the patient with indocyanine green (ICG), a NIR fluorescent agent (24 hours before surgery, 0.25 mg/kg). Fluorescent images were obtained using a miniaturized fluorescence imaging system (FluoStic, Fluoptics, Grenoble, France). Results After liver resection, the surgical specimens from each patient were sliced into 10-mm sections in the operating room and analyzed with the FluoStic. All metastatic tumors presented rim-type fluorescence. Two specimens had incomplete rim fluorescence. The pathologist confirmed the presence of R1 margins (microscopic residual resection), even though the ultrasonographic analysis indicated that the result was R0. Conclusions Surgical liver resection guided by NIR fluorescence can help detect potentially uncertain anatomical areas that may be missed by preoperative imaging and by ultrasonography during surgery. These preliminary results will need to be confirmed in a larger prospective patient series. PMID- 26603690 TI - Economic Impacts of ABO-Incompatible Live Donor Kidney Transplantation: A National Study of Medicare-Insured Recipients. AB - The infrequent use of ABO-incompatible (ABOi) kidney transplantation in the United States may reflect concern about the costs of necessary preconditioning and posttransplant care. Medicare data for 26 500 live donor kidney transplant recipients (2000 to March 2011), including 271 ABOi and 62 A2-incompatible (A2i) recipients, were analyzed to assess the impact of pretransplant, transplant episode and 3-year posttransplant costs. The marginal costs of ABOi and A2i versus ABO-compatible (ABOc) transplants were quantified by multivariate linear regression including adjustment for recipient, donor and transplant factors. Compared with ABOc transplantation, patient survival (93.2% vs. 88.15%, p = 0.0009) and death-censored graft survival (85.4% vs. 76.1%, p < 0.05) at 3 years were lower after ABOi transplant. The average overall cost of the transplant episode was significantly higher for ABOi ($65 080) compared with A2i ($36 752) and ABOc ($32 039) transplantation (p < 0.001), excluding organ acquisition. ABOi transplant was associated with high adjusted posttransplant spending (marginal costs compared to ABOc - year 1: $25 044; year 2: $10 496; year 3: $7307; p < 0.01). ABOi transplantation provides a clinically effective method to expand access to transplantation. Although more expensive, the modest increases in total spending are easily justified by avoiding long-term dialysis and its associated morbidity and cost. PMID- 26603692 TI - Postoperative Hemodynamic Index Measurement With Miniaturized Dynamic Light Scattering Predicts Colorectal Anastomotic Healing. AB - INTRODUCTION: Perioperative bowel perfusion (local hemodynamic index [LHI]) was measured with a miniaturized dynamic light scattering (mDLS) device, aiming to determine whether anastomotic perfusion correlates with the anastomotic healing process and whether LHI measurement assists in the detection of anastomotic leakage (AL) in colorectal surgery. METHODS: A partial colectomy was performed in 21 male Wistar rats. Colonic and anastomotic LHIs were recorded during operation. On postoperative day (POD) 3, the rats were examined for AL manifestations. Anastomotic LHI was recorded before determining the anastomotic bursting pressure (ABP). The postoperative LHI measurements were repeated in 15 other rats with experimental colitis. Clinical manifestations and anastomotic LHI were also determined on POD3. Diagnostic value of LHI measurement was analyzed with the combined data from both experiments. RESULTS: Intraoperative LHI measurement showed no correlation with the ABP on POD3. Postoperative anastomotic LHI on POD3 was significantly correlated with ABP in the normal rats (R(2) = 0.52; P < .001) and in the rats with colitis (R(2) = 0.63; P = .0012). Anastomotic LHI on POD3 had high accuracy for identifying ABP <50 mm Hg (Area under the curve = 0.86; standard error = 0.065; P < .001). A cutoff point of 1236 yielded a sensitivity of 100% and a specificity of 65%. On POD3, rats with LHIs <1236 had significantly higher dehiscence rates (40% vs 0%), more weight loss, higher abscess severity, and lower ABPs (P < .05); worse anastomotic inflammation and collagen deposition were also found in the histological examination. CONCLUSION: Our data suggest that postoperative evaluation of anastomotic microcirculation with the mDLS device assists in the detection of AL in colorectal surgery. PMID- 26603693 TI - Ammar ibn Ali al-Mawsili and His Innovating Suction Method for the Treatment of Cataract. PMID- 26603694 TI - Laparoscopic Transversus Abdominis Release, a Novel Minimally Invasive Approach to Complex Abdominal Wall Reconstruction. AB - BACKGROUND: Open abdominal wall reconstruction is used to repair complex abdominal wall hernias with contour abnormalities. We present a novel minimally invasive approach to address these types of defects, completed entirely laparoscopically. METHODS: Three patients underwent laparoscopic abdominal wall reconstruction for complex hernias in August and September of 2015. Operative approach consisted of laparoscopic transversus abdominis components separation, defect closure, and wide mesh implantation in the retromuscular space. RESULTS: Two males and one female with mean age and body mass index of 70 and 30.1, respectively, underwent a mean operation room time of 329 minutes. Estimated blood loss and length of stay were 91.7 cc and 4.7 days, respectively. No subcutaneous flaps were raised avoiding the need for subcutaneous drains. There were no perioperative complications. All of the subfascial drains were removed prior to patient discharge. On initial follow-up visit at 3 weeks, there was no evidence of wound complications, bulging, or hernia recurrences. CONCLUSION: Laparoscopic abdominal wall reconstruction with transversus abdominis release is a unique and feasible approach to complex abdominal wall defects with the potential to reduce pain, facilitate recovery, and decrease length of hospital stay for patients. PMID- 26603695 TI - Feasibility of an Intraluminal Bypass Device in Low Colorectal Anastomosis: Preliminary Results in a Porcine Model. AB - BACKGROUND: The Cologuard CG-100 is a novel intraluminal bypass device designed to reduce the clinical outcomes associated with low colorectal anastomotic leak. The device is inserted transanally, anchored to the colon above the anastomosis, and deployed intraluminally to cover the anastomosis from within. The purpose of this study was to evaluate the safety and performance of the device in a porcine model. METHOD: Twelve pigs underwent low colorectal anastomosis with insertion of the Cologuard CG-100 device. Contrast material injection, abdominal X-ray, and histologic studies were used to evaluate sealing quality, device positioning, and tissue damage, respectively. The surgeons completed a usability and satisfaction questionnaire after completion of the procedure. RESULTS: Absolute sealing was observed in all 4 animals euthanized immediately after surgery. In the other 8 animals, the device was kept in situ for 10 days and then extracted. X-ray films with injection of contrast material through a designated injection tube before device removal showed that the sheath and ring were correctly placed. No leak was demonstrated. There were no device-related adverse events, and no critical histological abnormalities were noted in the bowel area that was compressed by the device. The device was found to be easy to insert, position, and extract. CONCLUSION: The Cologuard CG-100 device efficiently reduced contact between fecal content and low colorectal anastomosis in a porcine model and is easily deployed and extracted. It holds promise for possible clinical use pending further studies. PMID- 26603696 TI - Laparoscopic Extraction of Solid Viscera by a Vacuum-Bag System. PMID- 26603697 TI - Treatment of Provoked Vulvodynia in a Swedish cohort using desensitization exercises and cognitive behavioral therapy. AB - BACKGROUND: Problems related to pain during vaginal penetration are complex and the etiology is multi-factorial. It was the aim of the present study to measure whether treatment using desensitization exercises and cognitive behavioral therapy (CBT) for women with provoked vulvodynia (PVD) could increase sexual interest, sexual satisfaction and response whilst decreasing experiences of sexual pain. METHODS AND OUTCOME MEASURES: Sixty women suffering from PVD were treated during a 10-week period with a combination of mucosal desensitization and pelvic floor exercises and CBT. The McCoy Female Sexuality Questionnaire (MFSQ) was used to measure efficacy of the treatment. The Hospital Anxiety and Depression Scale (HADS) was used to measure psychological distress. The primary outcome measurements were changes in scores for the MFSQ and changes in individual items on the MFSQ directly after treatment completion. Secondary outcome measurements were changes in the MFSQ items 6 months after treatment and changes in HADS sub-scales 6 months after treatment. Statistical comparisons of answers to the MFSQ were carried out using the Wilcoxon signed rank test (paired). Validity of the MFSQ in this study was measured by testing one global question about sexuality and total scores on MFSQ using Spearman's correlation test. RESULTS: Study participants reported a statistically significant increase in sexual fantasies, increased sexual pleasure, excitement and vaginal lubrication after treatment was completed. PVD occurred less often which resulted in significantly less avoidance of sexual intercourse, increased frequency of masturbation and intercourse. All improvements were sustained at 6 months after treatment ended. Two questions showed no significant changes, these pertained to the individual's contentment with her partner as a lover and a friend. The anxiety sub-scale of the HADS showed a significantly decreased level of anxiety at 6 months follow-up but no change in the scores on the depression sub-scale. CONCLUSION: Treatment for PVD using desensitization exercises and cognitive behavioral therapy significantly improved sexual interest, response and activity and decreased the experience of pain. Larger studies and RCTs are required in order to draw conclusions about treatment and long term effects should be studied. Partners should be encouraged to participate in treatment regimes. TRIAL REGISTRATION: The study is registered with ISRCTN registry, ID ISRCTN40416405. PMID- 26603698 TI - Realization of Room-Temperature Phonon-Limited Carrier Transport in Monolayer MoS2 by Dielectric and Carrier Screening. AB - By combining a high-kappa dielectric substrate and a high density of charge carriers, Coulomb impurities in MoS2 can be effectively screened, leading to an unprecedented room-temperature mobility of ~150 cm(2) V(-1) s(-1) and room temperature phonon-limited transport in a monolayer MoS2 transistor for the first time. PMID- 26603699 TI - EDARV370A associated facial characteristics in Uyghur population revealing further pleiotropic effects. AB - An adaptive variant of human Ectodysplasin receptor, EDARV370A, had undergone strong positive selection in East Asia. In mice and humans, EDARV370A was found to affect ectodermal-derived characteristics, including hair thickness, hair shape, active sweat gland density and teeth formation. Facial characteristics are also largely ectodermal derived. In this study, taking advantage of an admixed population of East Asian and European ancestry-the Uyghur, we aim to test whether EDARV370A is affecting facial characteristics and to investigate its pleiotropic nature and genetic model. In a sample of 1027 Uyghurs, we discover that EDARV370A is significantly associated with several facial characteristics, in particular shape of earlobe (P = 3.64 * 10 (-6) ) and type of chin (P = 9.23 * 10 (-5) ), with successful replication in other East Asian populations. Additionally, in this Uyghur population, we replicate previous association findings of incisors shoveling (P = 1.02 * 10 (-7) ), double incisors shoveling (P = 1.86 * 10 (-12) ) and hair straightness (P = 3.99 * 10 (-16) ), providing strong evidence supporting an additive model for the EDARV370A associations. Partial least square path model confirms EDARV370A systematically affect these weakly related ectodermal-derived characteristics, suggesting the pleiotropic effect of EDARV370A mainly plays roles in early embryo development. This study extends our knowledge about the pleiotropic nature of EDARV370A and provides potential clues to its adaptation fitness in human evolution. PMID- 26603700 TI - DSM-IV post-traumatic stress disorder among World Trade Center responders 11-13 years after the disaster of 11 September 2001 (9/11). AB - BACKGROUND: Post-traumatic symptomatology is one of the signature effects of the pernicious exposures endured by responders to the World Trade Center (WTC) disaster of 11 September 2001 (9/11), but the long-term extent of diagnosed Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) post traumatic stress disorder (PTSD) and its impact on quality of life are unknown. This study examines the extent of DSM-IV PTSD 11-13 years after the disaster in WTC responders, its symptom profiles and trajectories, and associations of active, remitted and partial PTSD with exposures, physical health and psychosocial well-being. METHOD: Master's-level psychologists administered sections of the Structured Clinical Interview for DSM-IV and the Range of Impaired Functioning Tool to 3231 responders monitored at the Stony Brook University World Trade Center Health Program. The PTSD Checklist (PCL) and current medical symptoms were obtained at each visit. RESULTS: In all, 9.7% had current, 7.9% remitted, and 5.9% partial WTC-PTSD. Among those with active PTSD, avoidance and hyperarousal symptoms were most commonly, and flashbacks least commonly, reported. Trajectories of symptom severity across monitoring visits showed a modestly increasing slope for active and decelerating slope for remitted PTSD. WTC exposures, especially death and human remains, were strongly associated with PTSD. After adjusting for exposure and critical risk factors, including hazardous drinking and co-morbid depression, PTSD was strongly associated with health and well-being, especially dissatisfaction with life. CONCLUSIONS: This is the first study to demonstrate the extent and correlates of long-term DSM-IV PTSD among responders. Although most proved resilient, there remains a sizable subgroup in need of continued treatment in the second decade after 9/11. PMID- 26603707 TI - 1400 Miles. PMID- 26603708 TI - 50 Years Ago in The Journal of Pediatrics: Imbalance of Liver Phosphorylase and Accumulation of Hepatic Glycogen in a Girl with Progressive Disease of the Brain. PMID- 26603709 TI - 50 Years Ago in The Journal of Pediatrics: Congenital Cystic Adenomatoid Malformation of the Lung. PMID- 26603710 TI - 50 Years Ago in The Journal of Pediatrics: Cor Pulmonale in Cystic Fibrosis of the Pancreas. PMID- 26603711 TI - Efficacy of hand washing and nail clipping on parasitic infection. PMID- 26603712 TI - Allergic rhinitis treatment with sublingual immunotherapy. PMID- 26603713 TI - Pimecrolimus is safe and effective in treating atopic dermatitis. PMID- 26603714 TI - Minority of college rapes committed by serial rapists. PMID- 26603715 TI - Multivariate survival factors in congenital heart disease. PMID- 26603716 TI - Opening the Debate on Pediatric Subspecialties and Specialist Centers: Opportunities for Better Care or Risks of Care Fragmentation? PMID- 26603717 TI - Serum YKL-40 in young patients with beta-thalassemia major: Relation to hepatitis C virus infection, liver stiffness by transient elastography and cardiovascular complications. AB - BACKGROUND: YKL-40 is an inflammatory glycoprotein involved in endothelial dysfunction and elevated in sera of patients with liver diseases. AIM: To determine serum YKL-40 among 50 children and adolescents with beta-thalassemia major (beta-TM) compared to 35 healthy controls and assess its relation to liver stiffness by transient elastography (TE), markers of hemolysis, iron overload and various hemolysis-associated complications. METHODS: beta-TM patients asymptomatic for heart disease were studied stressing on chelation therapy, serum ferritin, liver iron concentration (LIC), cardiac T2* and YKL-40. Echocardiography and TE were performed. RESULTS: Liver cirrhosis (METAVIR F4; TE values>12.5kPa) was encountered in 32%. HCV-positive patients had significantly higher WBC count, alanine transaminase (ALT) and serum ferritin than HCV-negative patients. YKL-40 levels were significantly higher in beta-TM patients compared with control (p<0.001). YKL-40 was significantly higher among patients with heart disease (p=0.014) or hepatitis C virus (p=0.004) than those without. YKL-40 was correlated with liver stiffness and the degree of hepatic fibrosis being highest among patients with F4 stage (p<0.001). The YKL-40 cutoff to identify beta-TM patients with liver cirrhosis or heart disease was determined. Patients treated with combined chelation therapy had significantly lower levels of YKL-40 than the monotherapy group (p<0.001). YKL-40 was positively correlated with transfusion index, ALT, lactate dehydrogenase, serum ferritin and LIC but negatively correlated with cardiac T2*. CONCLUSION: YKL-40 is a promising marker of cardiovascular disease and liver siderosis in beta-TM patients. The combination of YKL-40 and TE provides a reliable method to assess hepatic fibrosis in young beta-TM patients. PMID- 26603718 TI - Diagnostic tool for red blood cell membrane disorders: Assessment of a new generation ektacytometer. AB - Inherited red blood cell (RBC) membrane disorders, such as hereditary spherocytosis, elliptocytosis and hereditary ovalocytosis, result from mutations in genes encoding various RBC membrane and skeletal proteins. The RBC membrane, a composite structure composed of a lipid bilayer linked to a spectrin/actin-based membrane skeleton, confers upon the RBC unique features of deformability and mechanical stability. The disease severity is primarily dependent on the extent of membrane surface area loss. RBC membrane disorders can be readily diagnosed by various laboratory approaches that include RBC cytology, flow cytometry, ektacytometry, electrophoresis of RBC membrane proteins and genetics. The reference technique for diagnosis of RBC membrane disorders is the osmotic gradient ektacytometry. However, in spite of its recognition as the reference technique, this technique is rarely used as a routine diagnosis tool for RBC membrane disorders due to its limited availability. This may soon change as a new generation of ektacytometer has been recently engineered. In this review, we describe the workflow of the samples shipped to our Hematology laboratory for RBC membrane disorder analysis and the data obtained for a large cohort of French patients presenting with RBC membrane disorders using a newly available version of the ektacytomer. PMID- 26603719 TI - Patients with type 1 Gaucher disease in Spain: A cross-sectional evaluation of health status. AB - A multicentre, cross-sectional epidemiological survey was conducted to describe the health status of patients with type 1 Gaucher disease (GD1) in Spain. Patient data were collected retrospectively from clinical records. Therapeutic goals for seven clinical parameters were chosen as primary outcome measures. 108 GD1 patients (mean age 44.8 years; 53% male) were recruited from 28 hospitals. Ninety five patients (88%) were receiving treatment for GD1. Hemoglobin concentration was the therapeutic goal with the highest level of achievement, being met by 105 of 108 patients (97%), followed by the goals for liver volume (86/98 patients; 88%), spleen volume (67/77 patients; 87%) and platelet count (81/108 patients; 75%). The goal for bone mineral density (BMD) was met by 48 of 75 patients (64%), and the goal for quality of life was met by 65 of 103 patients (63%). Bone pain was the parameter with the lowest level of achievement (goal met by 50/94 patients; 53%). The clinical information most often missing from patient records was the BMD Z-score (missing for 31% of patients). These data suggest that most Spanish GD1 patients have good control over hematological and visceral parameters, but there is a need to improve monitoring and treatment of GD-related bone disease. PMID- 26603720 TI - Isocitrate treatment of acute anemia of inflammation in a mouse model. AB - Acute and severe anemia of inflammation (AI) is a common complication of various clinical syndromes, including fulminant infections, critical illness with multiorgan failure, and exacerbations of autoimmune diseases. Building on recent data showing beneficial results with isocitrate treatment for chronic low-grade AI in a rat model, we used a mouse model of acute and severe AI induced by intraperitoneal heat-killed Brucella abortus to determine if isocitrate would be effective in this more stringent application. Inflamed mice treated with isocitrate developed an early but transient improvement in hemoglobin compared to solvent-treated controls, with a robust improvement on day 7, and only a trend towards improvement by day 14. Reticulocyte counts were increased in treated mice transiently, with no significant difference by day 21. Serum erythropoietin (EPO) levels were similar in treated versus control mice, indicating that isocitrate increased sensitivity to EPO. Serum and tissue iron levels showed no significant differences between the treated and control mice, ruling out improved iron availability as the cause of the increased response to endogenous EPO. Compared to the milder rat model, much higher doses of isocitrate were required for a relatively modest benefit. PMID- 26603721 TI - Isolated polyglobulia as an uncommon presentation of chronic myeloid leukaemia. PMID- 26603722 TI - Interactions of sickle red blood cells with neutrophils are stabilized on endothelial cell layers. PMID- 26603723 TI - Which side of the balance determines the frequency of vaso-occlusive crises in children with sickle cell anemia: Blood viscosity or microvascular dysfunction? AB - Vascular resistance and tissue perfusion may be both affected by impaired vascular function and increased blood viscosity. Little is known about the effects of vascular function on the occurrence of painful vaso-occlusive crises (VOC) in children with sickle cell anemia (SCA). The aim of the present study was to determine which side of the balance (blood viscosity or vascular function) is the most deleterious in SCA and increases the risk for frequent hospitalized VOC. Microvascular function, microcirculatory oxygenation and blood viscosity were determined in a group of 22 SCA children/adolescents at steady state and a group of 13 healthy children/adolescents. Univariate analyses demonstrated blunted microvascular reactivity during local thermal heating test and decreased microcirculatory oxygenation in SCA children compared to controls. Multivariate analysis revealed that increased blood viscosity and decreased microcirculatory oxygenation were independent risk factors of frequent VOC in SCA. In contrast, the level of microvascular dysfunction does not predict VOC rate. In conclusion, increased blood viscosity is usually well supported in healthy individuals where vascular function is not impaired. However, in the context of SCA, microvascular function is impaired and any increase of blood viscosity or decrease in microcirculatory oxygenation would increase the risks for frequent VOC. PMID- 26603724 TI - Tanshinone IIA inhibits acute promyelocytic leukemia cell proliferation and induces their apoptosis in vivo. AB - Tanshinone IIA (TanIIA) is a traditional Chinese agent and has been widely used for treatment of cardiovascular diseases. Our previous study has shown that TanIIA can induce the differentiation of acute promyelocytic leukemia (APL) cells by increasing C/EBPbeta expression and induce APL cell apoptosis in vitro. In this study, we evaluated the activity of TanIIA against APL in vivo. We found that treatment with TanIIA prevented APL-mediated reduction in body weights. Treatment with TanIIA inhibited the proliferation of APL cells and triggered APL cell apoptosis and differentiation in vivo. Treatment with TanIIA significantly prolonged the survival of APL-bearing mice. Our data indicate that TanIIA has potent anti-APL activity with little adverse effect. PMID- 26603725 TI - Red blood cells in retinal vascular disorders. AB - Microvascular circulation plays a vital role in regulating physiological functions, such as vascular resistance, and maintaining organ health. Pathologies such as hypertension, diabetes, or hematologic diseases affect the microcirculation posing a significant risk to human health. The retinal vasculature provides a unique window for non-invasive visualisation of the human circulation in vivo and retinal vascular image analysis has been established to predict the development of both clinical and subclinical cardiovascular, metabolic, renal and retinal disease in epidemiologic studies. Blood viscosity which was otherwise thought to play a negligible role in determining blood flow based on Poiseuille's law up to the 1970s has now been shown to play an equally if not a more important role in controlling microcirculation and quantifying blood flow. Understanding the hemodynamics/rheology of the microcirculation and its changes in diseased states remains a challenging task; this is due to the particulate nature of blood, the mechanical properties of the cells (such as deformability and aggregability) and the complex architecture of the microvasculature. In our review, we have tried to postulate a possible role of red blood cell (RBC) biomechanical properties and laid down future framework for research related to hemorrheological aspects of blood in patients with retinal vascular disorders. PMID- 26603727 TI - Pelvic floor dysfunction in inflammatory bowel disease. AB - Advances in tailored medical therapy and introduction of biologic agents for inflammatory bowel disease (IBD) treatment have ensured long-term disease remission. Some patients, however, still report defecatory symptoms. Patients present with a wide spectrum of conditions - anal incontinence, obstructed defecation and pelvic pain among the most frequent - that have a great impact on their quality of life. Due to IBD diagnosis, little relevance is attributed to this type of symptoms and their epidemiologic distribution is unknown. Pathogenetic hypotheses are currently under investigation. Routine diagnostic workflow and therapeutic options in pelvic floor service are often underused. The evaluation of these disorders starts with an endoscopy to rule out ongoing disease; the following diagnostic workflow is the same as in patients without IBD. For fecal incontinence and obstructed defecation, simple conservative therapy with dietary modifications and appropriate fluid intake is effective in most cases. In non-responding patients, anorectal physiology tests and imaging are required to select patients for pelvic floor muscle training and biofeedback. These treatments have been proven effective in IBD patients. Some new minimally invasive alternative strategies are available for IBD patients, as sacral nerve and posterior tibial nerve stimulation; for other ones (e.g., bulking agent implantation) IBD still remains an exclusion criterion. In order to preserve anatomical areas that could be useful for future reconstructive techniques, surgical options to cure pelvic floor dysfunction are indicated only in a small group of IBD patients, due to the high risk of failure in wound healing and to the possible side effects of surgery, which can lead to anal incontinence or to a possible proctectomy. A particular issue among defecatory symptoms in patients with IBD is paradoxical puborectalis contraction after restorative proctocolectomy: if this disorder is properly diagnosed, a conservative treatment is indicated, thus avoiding unnecessary laparotomy for small bowel occlusion. Pelvic pain management, coordinated by a specialist with expertise in pelvic floor disorders, includes many options, which vary from oral or local therapies to pelvic floor rehabilitation and sacral nerve stimulation. Surgical procedures often have unsatisfactory outcomes. Diagnosis and investigation of anorectal functional disorders in patients with IBD is important in order to implement better-suited diagnostic and therapeutic strategies, so as to avoid unnecessary and potentially detrimental medical and surgical therapies, with the final aim of improving patients' quality of life. PMID- 26603726 TI - Therapeutic fetal-globin inducers reduce transcriptional repression in hemoglobinopathy erythroid progenitors through distinct mechanisms. AB - Pharmacologic augmentation of gamma-globin expression sufficient to reduce anemia and clinical severity in patients with diverse hemoglobinopathies has been challenging. In studies here, representative molecules from four chemical classes, representing several distinct primary mechanisms of action, were investigated for effects on gamma-globin transcriptional repressors, including components of the NuRD complex (LSD1 and HDACs 2-3), and the downstream repressor BCL11A, in erythroid progenitors from hemoglobinopathy patients. Two HDAC inhibitors (MS-275 and SB939), a short-chain fatty acid derivative (sodium dimethylbutyrate [SDMB]), and an agent identified in high-throughput screening, Benserazide, were studied. These therapeutics induced gamma-globin mRNA in progenitors above same subject controls up to 20-fold, and increased F reticulocytes up to 20%. Cellular protein levels of BCL11A, LSD-1, and KLF1 were suppressed by the compounds. Chromatin immunoprecipitation assays demonstrated a 3.6-fold reduction in LSD1 and HDAC3 occupancy in the gamma-globin gene promoter with Benserazide exposure, 3-fold reduction in LSD-1 and HDAC2 occupancy in the gamma-globin gene promoter with SDMB exposure, while markers of gene activation (histone H3K9 acetylation and H3K4 demethylation), were enriched 5.7-fold. These findings identify clinical-stage oral therapeutics which inhibit or displace major co-repressors of gamma-globin gene transcription and may suggest a rationale for combination therapy to produce enhanced efficacy. PMID- 26603728 TI - The aged gut in inflammatory bowel diseases. AB - Senescence is accompanied by various anatomical and functional alterations starting from mastication and deglutition and consequent modifications of nutrition. In addition, the widespread use of proton pump inhibitors and non steroidal anti-inflammatory drugs in aged subjects weakens the gastric barrier, thus contributing to easier entry of microbes into the gastrointestinal tract. The microbiota of the elderly is less stable than that of younger adults, therefore, gut dysbiosis is more frequent. Dysbiosis represents a key factor for infections, e.g. Clostridium difficile, especially after antibiotic treatment, but also represents an important step for the development of inflammatory bowel diseases (IBD). IBD onset in the elderly needs careful evaluation in order to distinguish this entity from other pathologies that may affect the gut in senescence. Colitis associated with diverticula, drug-induced, ischemic, and microscopic colitides are among the possible diseases and, therefore, a careful macroscopic and histologic evaluation is mandatory. Finally, late onset IBD represents an important challenge for physicians since it occurs in subjects with frequent comorbidities and relative concomitant treatments. Although there is some evidence that disease course of elderly-onset IBD follows a milder course, overall morbidity, hospitalization rates and even mortality, the latter mostly due to comorbidities, are increased, especially in emergency settings. PMID- 26603729 TI - The state of readiness for evidence-based practice among nurses: An integrative review. AB - OBJECTIVES: To review factors related to nurses' individual readiness for evidence-based practice and to determine the current state of nurses' evidence based practice competencies. DESIGN: An integrative review study. DATA SOURCES: Thirty-seven (37) primary research studies on nurses' readiness for evidence based practice, of which 30 were descriptive cross-sectional surveys, 5 were pretest-posttest studies, and one study each was an experimental pilot study and a descriptive qualitative study. Included studies were published from the beginning of 2004 through end of January 2015. REVIEW METHODS: The integrative review study used thematic synthesis, in which the quantitative studies were analyzed deductively and the qualitative studies inductively. Outcomes related to nurses' readiness for evidence-based practice were grouped according to the four main themes that emerged from the thematic synthesis: (1) nurses' familiarity with evidence-based practice (EBP); (2) nurses' attitudes toward and beliefs about evidence-based practice; (3) nurses' evidence-based practice knowledge and skills; and (4) nurses' use of research in practice. Methodological quality of the included studies was evaluated with Joanna Briggs Institute critical appraisal tools. RESULTS: Although nurses were familiar with, had positive attitudes toward, and believed in the value of EBP in improving care quality and patient outcomes, they perceived their own evidence-based practice knowledge and skills insufficient for employing evidence-based practice, and did not use best evidence in practice. The vast majority (81%) of included studies were descriptive cross-sectional surveys, 84% used a non-probability sampling method, sample sizes were small, and response rates low. Most included studies were of modest quality. CONCLUSIONS: More robust, theoretically-based and psychometrically sound nursing research studies are needed to test and evaluate the effectiveness of interventions designed to advance nurses' evidence-based practice competencies, especially teaching them how to integrate evidence-based practice into clinical decision-making. All efforts should be focused on systematically using knowledge transformation strategies shown to be effective in rigorous studies, to translate best evidence into practice-friendly, readily usable forms that are easily accessible to nurses to integrate into their clinical practice. PMID- 26603730 TI - Work environment antecedents of bullying: A review and integrative model applied to registered nurses. AB - OBJECTIVES AND DESIGN: This review paper provides an overview of the current state of knowledge on work environment antecedents of workplace bullying and proposes an integrative model of bullying applied to registered nurses. DATA SOURCES AND REVIEW METHODS: A literature search was conducted on the databases PsycInfo, ProQuest, and CINAHL. Included in this review were empirical studies pertaining to work-related antecedents of workplace bullying in nurses. RESULTS: A total of 12 articles were maintained in the review. An examination of these articles highlights four main categories of work-related antecedents of workplace bullying: job characteristics, quality of interpersonal relationships, leadership styles, and organizational culture. A conceptual model depicting the interplay between these factors in relation to bullying is also presented. Suggestions regarding other factors to incorporate within the model (e.g., individual factors, outcomes of bullying) are provided to increase our understanding of bullying in registered nurses. CONCLUSIONS: This paper hopes to guide future efforts in order to effectively prevent and/or address this problem and ultimately ensure patient safety and quality of care provided by health care organizations. PMID- 26603731 TI - An evaluation of calprotectin as serum marker of preeclampsia: a systematic review of observational studies. AB - BACKGROUND: Calprotectin is calcium-binding protein which can be found in the cytosol of neutrophils. Several studies have studied its levels in preeclamptic women; however, to date there is no consensus regarding its effectiveness in the field. PURPOSE: To investigate whether serum calprotectin levels are elevated among preeclamptic women compared to healthy controls. MATERIALS AND METHODS: We used Medline (1966-2015), Scopus (2004-2015), ClinicalTrials.gov (2008-2015), Cochrane Central Register of Controlled Trials CENTRAL (1999-2015) and Google Scholar (2004-2015) search engines in our primary search, together with reference lists from included studies. RESULTS: Seven studies were finally included in our systematic review which recruited 439 women (245 with preeclampsia and 194 healthy controls). Their methodological quality was relatively high as they reached a score that ranged between 6 and 7 according to the Ottawa-Newcastle classification. All included studies reported that the serum calprotectin levels were significantly elevated among preeclamptic patients (p < 0.05). One study suggested that patients with severe preeclampsia have significantly higher levels of calprotectin than patients with mild preeclampsia (p = 0.01). However, to date there is no evidence regarding specific cut-off values which would help screen women for preeclampsia, or even follow the course of the disease. CONCLUSION: Current evidence suggests that serum calprotectin is significantly raised among women with preeclampsia during the third trimester. Future research is needed to reach firm conclusions regarding its use as a potential screening and surveillance marker during the pregnancy course of women at risk of developing preeclampsia. PMID- 26603733 TI - Longer term effects of the Angelina Jolie effect: increased risk-reducing mastectomy rates in BRCA carriers and other high-risk women. PMID- 26603732 TI - Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4. AB - BACKGROUND AND PURPOSE: The toll-like receptor TLR4 is involved in neuropathic pain and in drug reward and reinforcement. The opioid inactive isomers (+) naltrexone and (+)-naloxone act as TLR4 antagonists, reversing neuropathic pain and reducing opioid and cocaine reward and reinforcement. However, how these agents modulate TLR4 signalling is not clear. Here, we have elucidated the molecular mechanism of (+)-naltrexone and (+)-naloxone on TLR4 signalling. EXPERIMENTAL APPROACH: BV-2 mouse microglial cell line, primary rat microglia and primary rat peritoneal macrophages were treated with LPS and TLR4 signalling inhibitors. Effects were measured using Western blotting, luciferase reporter assays, fluorescence microscopy and ELISA KEY RESULTS: (+)-Naltrexone and (+) naloxone were equi-potent inhibitors of the LPS-induced TLR4 downstream signalling and induction of the pro-inflammatory factors NO and TNF-alpha. Similarly, (+)-naltrexone or (+)-naloxone inhibited production of reactive oxygen species and increased microglial phagocytosis, induced by LPS. However, (+) naltrexone and (+)-naloxone did not directly inhibit the increased production of IL-1beta, induced by LPS. The drug interaction of (+)-naloxone and (+)-naltrexone was additive. (+)-Naltrexone or (+)-naloxone inhibited LPS-induced activation of IFN regulatory factor 3 and production of IFN-beta. However, they did not inhibit TLR4 signalling via the activation of either NF-kappaB, p38 or JNK in these cellular models. CONCLUSIONS AND IMPLICATIONS: (+)-Naltrexone and (+)-naloxone were TRIF-IFN regulatory factor 3 axis-biased TLR4 antagonists. They blocked TLR4 downstream signalling leading to NO, TNF-alpha and reactive oxygen species. This pattern may explain, at least in part, the in vivo therapeutic effects of (+) naltrexone and (+)-naloxone. PMID- 26603734 TI - Foreword: Updates on Obstructive Sleep Apnea Syndrome (OSAS). PMID- 26603735 TI - Design of a Subtarsal Ultrasonic Transducer for Mild Hyperthermia Treatment of Dry Eye Disease. AB - Dry eye disease is a disorder of the ocular surface that causes pain and low vision in a significant portion of the adult population. A common cause is obstructive Meibomian gland dysfunction, whereby the Meibomian glands secrete abnormal meibum with a melting point elevated by 3 degrees C-4 degrees C; hence, hyperthermia is the typical treatment. A design is proposed for an ultrasound hyperthermia device made of a transducer contained inside a contact lens with an internal air gap. The transducer heats the posterior of the tarsus, and the air gap provides an air backing to the transducer, preventing direct heating of the cornea. A prototype device was built, and hyperthermia experiments were performed on a porcine subject in vivo. A therapeutic temperature rise of 5 degrees C-7 degrees C was achievable in 10-15 min. The temperature of the cornea did not rise more than 2 degrees C during any of the experiments. PMID- 26603736 TI - Reversibility of Left Ventricle Longitudinal Strain Alterations Induced by Adjuvant Therapy in Early Breast Cancer Patients. AB - Left ventricular ejection fraction (LV-EF), despite its high feasibility, is not sensitive enough to detect early and subtle LV systolic dysfunction during oncologic treatments. Therefore, we used systolic global longitudinal strain (GLS) by speckle tracking echocardiography to verify whether early LV systolic dysfunction induced by adjuvant therapy in early breast cancer patients at low risk for cardiotoxicity can be reversed. Thirty patients (aged 53 +/- 11 y) with no previous cardiac and oncologic disease who were receiving adjuvant trastuzumab and taxane (group HER2+, n = 15) or taxane only (group HER2-, n = 15), after treatment with anthracyclines, were studied. LV-EF and GLS were measured at baseline, after anthracyclines (end of week 7 or 8), short term after trastuzumab and/or taxane (end of week 18) and after completion of therapy. Significant LV systolic dysfunction was defined as a relative reduction in GLS of >10% with respect to baseline values. Mean and individual LV-EFs did not change significantly during the oncologic treatment and after completion of therapy, although GLS varied significantly. In particular, during the course of therapy, four patients in the trastuzumab-docetaxel HER2+ subgroup and two patients in the taxane HER2- subgroup had a relative decrease (>10%) in GLS. However, after the end of adjuvant treatment, strain modification was fully or partially reversible. Speckle tracking echocardiography is more sensitive than LV-EF in recognizing subtle myocardial impairment during adjuvant chemotherapy. However, in patients at low risk for cardiotoxicity, these alterations may be reversible and not associated with clinically significant cardiotoxicity or late development of decreased LV-EF. PMID- 26603737 TI - Validity of standard gamble utilities in patients referred for aortic valve replacement. AB - PURPOSE: Standard gamble (SG) is the preferred method of assessing preferences in situations with uncertainty and risk, which makes it relevant to patients considered for aortic valve replacement (AVR). The present study assesses SG preferences in patients with severe aortic stenosis (AS). METHODS: All patients >18 years old with severe AS referred for AVR to our institution were invited to enroll in the study. The SG was administered by a clinical research nurse. The SF 36, EQ-5D 3L, Hospital Anxiety and Depression Scale (HADS), and AS symptoms were administered by self-completed questionnaire. We hypothesized that SG utilities would have low-to-moderate correlations with physical and mental aspects of health based on our pathophysiological understanding of severe AS. No correlations were expected with echocardiographic measures of the aortic valve. RESULTS: The response rate for SG was 98 %. SG moderately correlated with physical aspects of SF-36 (PCS, role-physical, vitality), health transition, AS symptoms, and EQ-VAS (rho S = 0.31-0.39, p < 0.001) and had low correlation with mental aspects of SF-36 and EQ-5D (rho S = 0.17-0.28, p < 0.001). No correlation was found between SG and HADS, echocardiographic measures, age, gender, or education level (rho S = 0.01-0.06). CONCLUSIONS: SG is an acceptable and feasible method of assessing preferences in patients with severe AS that has evidence for validity. The inclusion of uncertainty lends the SG face validity in this population as a direct approach to assessing preferences and basis for QALY calculations. PMID- 26603738 TI - Quality of life across medical conditions and psychological factors: implications for population health management. AB - PURPOSE: To identify the contributions of medical conditions and psychological distress to well-being within a non-clinical sample, stratified by age. It was predicted that medical conditions and psychological distress would be negatively associated with well-being. It was also predicted that psychological distress and medical conditions would account for significant variance in well-being. It was further predicted that psychological distress would mediate the relationship between medical conditions and well-being across the life span. METHODS: 1,424,307 employees/health plan members that completed an HRA. SEM was used to characterize relationships among medical conditions and psychological distress in predicting well-being (QoL, HRQoL, and impairments in ADLs) in five adult age groups. RESULTS: Medical conditions and psychological distress were negatively associated with well-being. As age increased, psychological distress was less associated with well-being. However, in those >75 years old, psychological distress had the largest association with well-being. All medical conditions, except cancer, were negatively associated with well-being. There were decreasing effects of medical conditions across the life span, with the exception of pulmonary disease which increased. Psychological distress mediated the relationship between medical conditions and well-being, with chronic pain having the greatest mediation across the life span. CONCLUSIONS: The analysis revealed differences in the contribution of psychological distress and medical conditions to well-being by age group. Additionally, the contribution of psychological distress was equitable to that of medical conditions, thus highlighting the importance of addressing psychological distress in medical populations for well being. Findings suggest the relevance of age in well-being and the need for further longitudinal investigation. PMID- 26603739 TI - Health literacy and health-related quality of life in adults with type 2 diabetes: a longitudinal study. AB - PURPOSE: To examine the association of health literacy (HL) with changes in health-related quality of life (HRQL) among patients with type 2 diabetes. METHODS: Data from a cohort study of type 2 diabetes patients were used. HL was assessed using 3 previously validated screening questions and HRQL using the EQ 5D-5L and SF-12 [physical and mental composite summary scores (PCS, MCS)]. The associations of baseline HL with changes in EQ-5D, PCS, and MCS scores over 1 year and with directions of changes (no change; declined; improved) were examined. Missing data were handled with multiple imputation and sensitivity analyses. RESULTS: Average age of participants (N = 1948) was 64.6 +/- 10.9 years, 45 % were female, and 12.6 % had inadequate HL. Participants had mean decrements of 0.01 in EQ-5D, 1.0 in PCS, and 1.2 in MCS over 1 year. In adjusted analysis, HL was not associated with changes in EQ-5D over 1 year (beta = 0.01, P = 0.146); however, patients with adequate HL had 2.1 points greater increase in PCS (P < 0.001) and 3.1 points in MCS (P < 0.001) compared to those with inadequate HL. Patients with adequate HL were less likely to have a decline in EQ 5D (RR 0.66; 95 % CI 0.44, 0.98), PCS (RR 0.51; 95 % CI 0.34, 0.76), and MCS (RR 0.49; 95 % CI 0.33, 0.72) compared to those with inadequate HL. Patients with adequate HL were more likely to have an improvement in MCS compared to those with inadequate HL (RR 1.78; 95 % CI 1.04, 3.04); such associations were not observed for PCS or EQ-5D. All results were robust in sensitivity analyses. CONCLUSIONS: Inadequate HL was independently associated with worsening HRQL in adults with type 2 diabetes, particularly in the mental health domain. PMID- 26603740 TI - Inflammatory Marker Changes in Postmenopausal Women after a Year-long Exercise Intervention Comparing High Versus Moderate Volumes. AB - This randomized dose comparison trial examined if higher exercise volume decreased inflammatory biomarkers, associated with postmenopausal breast cancer risk, more than moderate exercise volume. The Breast Cancer and Exercise Trial in Alberta was a two-center, two-armed randomized trial in 400 inactive, healthy, postmenopausal women, aged 50 to 74 years, with a body mass index of 22 to 40 kg/m(2). Participants were randomized to high (300 minutes/week) or moderate (150 minutes/week) volumes of aerobic exercise while maintaining usual diet. Fasting blood concentrations of C-reactive protein (CRP), IL6, and TNFalpha were measured at baseline, 6 and 12 months. Intention-to-treat (ITT) analysis was performed using linear mixed models adjusted for baseline biomarker concentrations. ITT analyses of 386 (97%) participants showed no statistically significant group differences for changes in biomarker levels at 6 and 12 months. In addition, we did not observe any modification of this effect by baseline characteristics of participants. In post hoc analyses based on self-selected exercise level (measured in minutes/week), CRP decreased by 22.45% for participants who exercised >246 minutes/week (highest quintile) and increased by 0.07% for those who exercised <110 minutes/week (lowest quintile, Ptrend = 0.04), adjusted for baseline covariates. When this analysis was restricted to include exercise time in the target heart rate zone only, statistically significant trends were observed for both CRP (P < 0.01) and IL6 (P = 0.04). Prescribing 300 minutes/week of moderate-to-vigorous aerobic exercise did not improve inflammatory markers compared with 150 minutes/week in postmenopausal women. Decreases in CRP were observed with higher self-selected exercise volume. PMID- 26603742 TI - Efficacy of disintegrating aspirin in two different models for acute mild-to moderate pain: sore throat pain and dental pain. AB - A recently developed fast-release aspirin tablet formulation has been evaluated in two different pain models. The dental impaction pain model and the sore throat pain model are widely used for assessing analgesia, including acute mild-to moderate pain. Both studies were double-blind, randomized, parallel group and compared a single dose of 1000 mg aspirin with 1000 mg paracetamol and with placebo and investigated the onset and overall time course of pain relief. Speed of onset was measured by the double-stopwatch method for time to meaningful pain relief and time to first perceptible pain relief. Pain intensity and pain relief were rated subjectively over a 6-h (dental pain) and 2-h (sore throat pain) time period. In both models fast-release aspirin and commercial paracetamol were statistically significantly different from placebo for onset of action, summed pain intensity differences and total pain relief. Meaningful pain relief was achieved within a median of 42.3 and 42.9 min for aspirin and paracetamol, respectively, in the dental pain model. The corresponding numbers in sore throat pain were 48.0 and 40.4 min. All treatments in both studies were safe and well tolerated. No serious adverse events were reported and no subject was discontinued due to an adverse event. Overall the two studies clearly demonstrated efficacy over placebo in the two pain models and a comparable efficacy and safety profile between aspirin and an equivalent dose of paracetamol under the conditions of acute dental pain and acute sore throat pain. Trial registration These trials were registered with ClinicalTrials.gov, registration number: NCT01420094, registration date: July 27, 2011 and registration number: NCT01453400, registration date: October 13, 2011. PMID- 26603741 TI - Intravenous and Intramuscular Formulations of Antiseizure Drugs in the Treatment of Epilepsy. AB - Intravenous and intramuscular antiseizure drugs (ASDs) are essential in the treatment of clinical seizure emergencies as well as in replacement therapy when oral administration is not possible. The parenteral formulations provide rapid delivery and complete (intravenous) or nearly complete (intramuscular) bioavailability. Controlled administration of the ASD is feasible with intravenous but not intramuscular formulations. This article reviews the literature and discusses the chemistry, pharmacology, pharmacokinetics, and clinical use of currently available intravenous and intramuscular ASD formulations as well as the development of new formulations and agents. Intravenous or intramuscular formulations of lorazepam, diazepam, midazolam, and clonazepam are typically used as the initial treatment agents in seizure emergencies. Recent studies also support the use of intramuscular midazolam as easier than the intravenous delivery of lorazepam in the pre-hospital setting. However, benzodiazepines may be associated with hypotension and respiratory depression. Although loading with intravenous phenytoin was an early approach to treatment, it is associated with cardiac arrhythmias, hypotension, and tissue injury at the injection site. This has made it less favored than fosphenytoin, a water-soluble, phosphorylated phenytoin molecule. Other drugs being used for acute seizure emergencies are intravenous formulations of valproic acid, levetiracetam, and lacosamide. However, the comparative effectiveness of these for status epilepticus (SE) has not been evaluated adequately. Consequently, guidelines for the medical management of SE continue to recommend lorazepam followed by fosphenytoin, or phenytoin if fosphenytoin is not available. Intravenous solutions for carbamazepine, lamotrigine, and topiramate have been developed but remain investigational. The current ASDs were not developed for use in emergency situations, but were adapted from ASDs approved for chronic oral use. New approaches for bringing drugs from experimental models to treatment of human SE are needed. PMID- 26603743 TI - Association between low-dose acetylsalicylic acid reinitiation and the risk of myocardial infarction or coronary heart disease death. AB - BACKGROUND: In secondary cardiovascular prevention, discontinuation of acetylsalicylic acid (ASA) is associated with an increased risk of cardiovascular events. This study assessed the impact of ASA reinitiation on the risk of myocardial infarction and coronary heart disease death. METHODS: Patients prescribed ASA for secondary cardiovascular prevention and who had had a period of ASA discontinuation of >=90 days in 2000-2007 were identified from The Health Improvement Network (N = 10,453). Incidence of myocardial infarction/coronary heart disease death was calculated. Survival analyses using adjusted Cox proportional hazard models were performed to calculate hazard ratios and 95% confidence intervals for the risk of myocardial infarction/coronary heart disease death associated with ASA use patterns after the initial period of discontinuation. Individuals who were prescribed ASA during follow-up were considered reinitiators. RESULTS: The incidence of myocardial infarction/coronary heart disease death was 8.90 cases per 1000 person-years. Risk of myocardial infarction/coronary heart disease death was similar for current ASA users, who had been continuously exposed since reinitiation, and patients who had not reinitiated ASA (hazard ratio 1.27, 95% confidence interval 0.93-1.73). Among reinitiators, an additional period of ASA discontinuation was associated with increased risk of myocardial infarction/coronary heart disease death compared with no reinitiation (current users: hazard ratio 1.46, 95% confidence interval 1.13-1.90; noncurrent users: hazard ratio 1.70, 95% confidence interval 1.31 2.21). CONCLUSIONS: ASA reinitiation was not associated with a decreased risk of myocardial infarction/coronary heart disease death. This may be explained by confounding by indication/comorbidity, whereby higher-risk patients are more likely to reinitiate therapy. An additional period of ASA discontinuation among reinitiators was associated with an increased risk of myocardial infarction/coronary heart disease death. PMID- 26603744 TI - Risk stratification and treatment effect of statins in secondary cardiovascular prevention in old age: Additive value of N-terminal pro-B-type natriuretic peptide. AB - BACKGROUND: To date, no validated risk scores exist for prediction of recurrence risk or potential treatment effect for older people with a history of a cardiovascular event. Therefore, we assessed predictive values for recurrent cardiovascular disease of models with age and sex, traditional cardiovascular risk markers, and 'SMART risk score', all with and without addition of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Treatment effect of pravastatin was assessed across low and high risk groups identified by the best performing models. DESIGN AND METHODS: Post-hoc analysis in 2348 participants (age 70-82 years) with a history of cardiovascular disease within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. Composite endpoint was a recurrent cardiovascular event/cardiovascular mortality. RESULTS: The models with age and sex, traditional risk markers and SMART risk score had comparable predictive values (area under the curve (AUC) 0.58, 0.61 and 0.59, respectively). Addition of NT-proBNP to these models improved AUCs with 0.07 (p for difference ((pdiff)) = 0.003), 0.05 (pdiff = 0.009) and 0.06 (pdiff < 0.001), respectively. For the model with age, sex and NT-proBNP, the hazard ratio for the composite endpoint in pravastatin users compared with placebo was 0.67 (95% confidence interval 0.49-0.90) for those in the highest third of predicted risk and 0.91 (0.57-1.46) in the lowest third, number needed to treat 12 and 115 (pdiff = 0.038) respectively. CONCLUSION: In secondary cardiovascular prevention in old age addition of NT-proBNP improves prediction of recurrent cardiovascular disease, cardiovascular mortality and treatment effect of pravastatin. A minimal model including age, sex and NT-proBNP predicts as accurately as complex risk models including NT-proBNP. PMID- 26603745 TI - Cost-effectiveness of self-management of blood pressure in hypertensive patients over 70 years with suboptimal control and established cardiovascular disease or additional cardiovascular risk diseases (TASMIN-SR). AB - BACKGROUND: A previous economic analysis of self-management, that is, self monitoring with self-titration of antihypertensive medication evaluated cost effectiveness among patients with uncomplicated hypertension. This study considered cost-effectiveness of self-management in those with raised blood pressure plus diabetes, chronic kidney disease and/or previous cardiovascular disease. DESIGN AND METHODS: A Markov model-based economic evaluation was undertaken to estimate the long-term cost-effectiveness of self-management of blood pressure in a cohort of 70-year-old 'high risk' patients, compared with usual care. The model used the results of the TASMIN-SR trial. A cost-utility analysis was undertaken from a UK health and social care perspective, taking into account lifetime costs of treatment, cardiovascular events and quality adjusted life years. A subgroup analysis ran the model separately for men and women. Deterministic sensitivity analyses examined the effect of different time horizons and reduced effectiveness of self-management. RESULTS: Base-case results indicated that self-management was cost-effective compared with usual care, resulting in more quality adjusted life years (0.21) and cost savings (-L830) per patient. There was a 99% chance of the intervention being cost-effective at a willingness to pay threshold of L20,000 per quality adjusted life year gained. Similar results were found for separate cohorts of men and women. The results were robust to sensitivity analyses, provided that the blood pressure lowering effect of self-management was maintained for more than a year. CONCLUSION: Self management of blood pressure in high-risk people with poorly controlled hypertension not only reduces blood pressure, compared with usual care, but also represents a cost-effective use of healthcare resources. PMID- 26603746 TI - Burden of hypertension in China over the past decades: Systematic analysis of prevalence, treatment and control of hypertension. AB - AIMS: To review comprehensively the prevalence, treatment and control of hypertension; and to estimate the burden of hypertension in China, thereby aiding Chinese health policies for better prevention and control of this condition. METHODS AND RESULTS: PubMed, EMbase, China National Knowledge Infrastructure, Wanfang and Chongqing VIP databases were searched for population-based studies published in English and Chinese that described prevalence, treatment and control of hypertension in China, as well as deaths and disabilities attributed to hypertension. All research papers were published between January 1999 and May 2014. Data from 178 studies involving over 2,901,464 participants covering 30 provinces were pooled. Overall, rates of prevalence, treatment and control of hypertension were 28.9%, 35.3% and 13.4% in China. A statistically significant association was observed between temperature gradient and the prevalence of hypertension. There were 10,667 (95% confidence interval 8063-13,345) disability adjusted life years per 100,000 people. In total, 78.3% of disability-adjusted life years were from years lived with disability and 21.7% from years of life lost due to premature mortality. CONCLUSIONS: Although there has been a slight improvement in rates for the treatment and control of hypertension, these rates were still suboptimal, especially for men and people living in rural areas. Low and middle-income provinces had a comparatively huge burden of hypertension, which is a considerable risk factor for reducing life expectancy. Our analysis may be helpful in generating a current overview of hypertension in China. PMID- 26603747 TI - Advantages and disadvantages of unstructured cardiovascular risk factor screening for follow-up in primary care. AB - BACKGROUND: In contrast to structured, integrated risk assessment in primary care, unstructured risk factor screening outside primary care and corresponding recommendations to consult a general practitioner (GP) are often based on one abnormal value of a single risk factor. This study investigates the advantages and disadvantages of unstructured screening of blood pressure and cholesterol outside primary care. METHODS: After the baseline visit of the Netherlands Epidemiology of Obesity study (population-based prospective cohort study in persons aged 45-65 years, recruited 2008-2012) all participants received a letter with results of blood pressure and cholesterol, and a recommendation to consult a GP if results were abnormal. Four years after the start of the study, participants received a questionnaire about the follow-up of their results. RESULTS: The study population consisted of 6343 participants, 48% men, mean age 56 years, mean body mass index 30 kg/m(2). Of all participants 66% had an abnormal result and, of these, 49% had a treatment indication based on the risk estimation system SCORE-NL 2006. Of the 25% of the participants who did not consult a GP, 40% had a treatment indication. Of the participants with an abnormal result 19% were worried, of whom 60% had no treatment indication. CONCLUSIONS: In this population 51% of the participants with an abnormal result had unnecessarily received a recommendation to consult a GP, and 10% were unnecessarily worried. GPs should be informed about the complete risk assessment, and only participants at intermediate or high risk should receive a recommendation to consult a GP. PMID- 26603748 TI - Enterococci isolated from farm ostriches and their relation to enterocins. AB - The present study focuses on the detection of enterococci in ostrich faeces. Forty-six bacterial colonies from 140 ostriches were identified at the species level using the MALDI-TOF MS identification system. According to the score value evaluation, they were allotted to the species Enterococcus hirae, Enterococcus faecium and Enterococcus mundtii confirmed also by phenotypic testing. Dominated species E. hirae (34 strains) were submitted to more detailed testing. Those strains E. hirae produced either no or only slight amount of the enzymes related to disorders (N-acetyl-beta-glucosaminidase, beta-glucuronidase, alpha chymotrypsin, trypsin). Most of the strains were not hemolytic. They did not harbour the hiracin-producing gene. Five E. hirae strains harboured virulence factor gene gelE; however, they were phenotypically gelatinase negative. They also harboured other virulence factor genes such as esp, efaAfm and ccf. E. hirae strains were mostly sensitive to antibiotics and those resistant at least to one antibiotic were sensitive to enterocins (200-25,600 AU/mL). This study represents original and novel results concerning the enterococcal microflora in ostriches; enterococci in ostriches have not been described in detail up to now; sensitivity to enterocins of E. hirae strains harbouring virulence factor genes to enterocins is also new. PMID- 26603749 TI - Synthesis of silver nanoparticles on the basis of low and high molar mass exopolysaccharides of Bradyrhizobium japonicum 36 and its antimicrobial activity against some pathogens. AB - Silver nanoparticles (SNPs) were synthesized on the basis of exopolysaccharides (low and high molar mass) of diazotrophic Bradyrhizobium japonicum 36 strain. The synthesis of SNPs was carried out by direct reduction of silver nitrate with ethanol-insoluble (high molar mass, HMW) and ethanol-soluble (low molar mass, LMW) fractions of exopolysaccharides (EPS), produced by diazotrophic strain B. japonicum 36. SNPs were characterized using UV-vis spectroscopy, transmission electron microscopy (TEM), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). SNPs synthesized on the basis of LMW EPS absorbed radiation in the visible regions of 420 nm, whereas SNPs based on the HMW EPS have a wavelength maximum at 450 nm because of the strong SPR transition. Moreover, the antibacterial and antifungal activities of the SNPs were examined in vitro against Escherichia coli, Staphylococcus aureus, and Candida albicans. SNPs synthesized on the basis of LMW EPS were active than those synthesized on the basis of HMW EPS. Besides, UV-visible spectroscopic evaluation confirmed that SNPs synthesized on the basis of LMW EPS were far more stable than those obtained on the basis of HMW EPS. PMID- 26603750 TI - Using Arden Syntax for the creation of a multi-patient surveillance dashboard. AB - OBJECTIVE: Most practically deployed Arden-Syntax-based clinical decision support (CDS) modules process data from individual patients. The specification of Arden Syntax, however, would in principle also support multi-patient CDS. The patient data management system (PDMS) at our local intensive care units does not natively support patient overviews from customizable CDS routines, but local physicians indicated a demand for multi-patient tabular overviews of important clinical parameters such as key laboratory measurements. As our PDMS installation provides Arden Syntax support, we set out to explore the capability of Arden Syntax for multi-patient CDS by implementing a prototypical dashboard for visualizing laboratory findings from patient sets. METHODS AND MATERIAL: Our implementation leveraged the object data type, supported by later versions of Arden, which turned out to be serviceable for representing complex input data from several patients. For our prototype, we designed a modularized architecture that separates the definition of technical operations, in particular the control of the patient context, from the actual clinical knowledge. Individual Medical Logic Modules (MLMs) for processing single patient attributes could then be developed according to well-tried Arden Syntax conventions. RESULTS: We successfully implemented a working dashboard prototype entirely in Arden Syntax. The architecture consists of a controller MLM to handle the patient context, a presenter MLM to generate a dashboard view, and a set of traditional MLMs containing the clinical decision logic. Our prototype could be integrated into the graphical user interface of the local PDMS. We observed that with realistic input data the average execution time of about 200ms for generating dashboard views attained applicable performance. CONCLUSION: Our study demonstrated the general feasibility of creating multi-patient CDS routines in Arden Syntax. We believe that our prototypical dashboard also suggests that such implementations can be relatively easy, and may simultaneously hold promise for sharing dashboards between institutions and reusing elementary components for additional dashboards. PMID- 26603751 TI - Quantification of Malignant Breast Cancer Cell MDA-MB-231 Transmigration Across Brain and Lung Microvascular Endothelium. AB - Tumor cell extravasation through the endothelial barrier forming the microvessel wall is a crucial step during tumor metastasis. However, where, how and how fast tumor cells transmigrate through endothelial barriers remain unclear. Using an in vitro transwell model, we performed a transmigration assay of malignant breast tumor cells (MDA-MB-231) through brain and lung microvascular endothelial monolayers under control and pathological conditions. The locations and rates of tumor cell transmigration as well as the changes in the structural components (integrity) of endothelial monolayers were quantified by confocal microscopy. Endothelial monolayer permeability to albumin P (albumin) was also quantified under the same conditions. We found that about 98% of transmigration occurred at the joints of endothelial cells instead of cell bodies; tumor cell adhesion and transmigration degraded endothelial surface glycocalyx and disrupted endothelial junction proteins, consequently increased P (albumin); more tumor cells adhered to and transmigrated through the endothelial monolayer with higher P (albumin); P (albumin) and tumor transmigration were increased by vascular endothelial growth factor, a representative of cytokines, and lipopolysaccharides, a typical systemic inflammatory factor, but reduced by adenosine 3',5'-cyclic monophosphate. These results suggest that reinforcing endothelial structural integrity is an effective approach for inhibiting tumor extravasation. PMID- 26603752 TI - [Study of the normality of the orbito-naso-frontal bandeau]. AB - INTRODUCTION: Craniosynostoses are cranio-facial malformations affecting about 1/2100 newborns in France. The involvement of anterior sutures (coronal and metopic) leads to orbito-frontal deformities. The treatment calls upon surgery the goal being, on an esthetic point of view, to restore a normal anatomy. The purpose of our work was to establish if some facial and/or frontal measures easy to perform on a CT are correlated to the global shape of the normal orbito-naso frontal bandeau (ONFB). MATERIAL AND METHOD: Cranial CTs of 123 consecutive non malformed children aged between 4 and 12 months were selected in the database of Department of Radiology of the University Hospital of Besancon - France. The CTs were all relocated by rigid transformation in an orthonormal coordinate system. On each of the 123 CTs, 21 reproducible measures representative of the global shape of the ONFB were made. Statistical analyses of these measures were achieved, considering age and gender, in order to determine the correlation between each measure and the ONFB shape. RESULTS: The only measure statistically correlated to the ONFB shape was the distance between the fronto-zygomatic sutures (FZD). The FZD was independent from age (in an interval of 4 months) and from gender. The 20 other measures did not show any correlation with age or gender. DISCUSSION: The FZD allows in itself to determine the ONFB global shape. This measure, easily available on a CT, can help the surgeon to perform a customized reshaping of the ONFB. The development of a surgical template using this measure is ongoing. PMID- 26603753 TI - Prevalence of Lateral Meniscal Extrusion for Posterior Lateral Meniscal Root Lesion With and Without Concomitant Midbody Radial Tear in Anterior Cruciate Ligament Injury. AB - PURPOSE: To investigate the prevalence of lateral meniscal extrusion for patients with posterior lateral meniscal root lesions (PLMRLs) and for those with concomitant midbody radial tears (MRTs) in anterior cruciate ligament (ACL) injuries. METHODS: A database of consecutive patients undergoing primary ACL reconstruction between 2011 and 2013 was retrospectively reviewed to identify patients with isolated ACL injuries and those with associated PLMRLs. Patients with (1) unavailable preoperative magnetic resonance imaging scans, (2) other concomitant ligamentous injuries, (3) severe degeneration or malalignment, (4) infection or tumor, or (5) history of surgery on the injured side were excluded. For patients with associated PLMRLs (study group), degree of concomitant MRTs and status of meniscofemoral ligaments (MFLs) were verified arthroscopically. Prevalence of lateral meniscal extrusion was compared between (1) patients in the study group and those with isolated ACL injuries and between (2) those with and without concomitant MRTs in the study group. RESULTS: Of the 1,021 consecutive patients, 412 met the inclusion and exclusion criteria. Of those, 52 (5.1%) had an associated PLMRL (study group) and another 52 were randomly chosen from the 360 isolated ACL injuries as the control group. In the study group, 33 (63.5%) were arthroscopically verified to have concomitant MRTs. Prevalence of lateral meniscal extrusion was significantly higher (P < .0001) in the study group (30.8%; 95% confidence interval [CI], 18.3 to 43.3) than in the control group (1.9%; 95% CI, -1.8 to 5.6), whereas there was no significant difference (P = .758) between patients with (33.3%; 95% CI, 17.3 to 49.3) and without (26.3%; 95% CI, 6.5 to 46.1) concomitant MRTs in the study group. However, the 7 patients who showed either complete concomitant MRTs or absence of MFLs were all diagnosed to have lateral meniscal extrusion. CONCLUSIONS: The PLMRLs, identified in 5.1% of ACL injuries, appeared to result in lateral meniscal extrusion. Although the presence of a concomitant MRT did not further increase the prevalence of lateral meniscal extrusion in the setting of a PLMRL, surgical repair might still be necessary if a complete concomitant MRT or an absence of MFL was identified to restore normal meniscal functions. LEVEL OF EVIDENCE: Level III, prognostic case control study. PMID- 26603754 TI - Efficient Test and Visualization of Multi-Set Intersections. AB - Identification of sets of objects with shared features is a common operation in all disciplines. Analysis of intersections among multiple sets is fundamental for in-depth understanding of their complex relationships. However, so far no method has been developed to assess statistical significance of intersections among three or more sets. Moreover, the state-of-the-art approaches for visualization of multi-set intersections are not scalable. Here, we first developed a theoretical framework for computing the statistical distributions of multi-set intersections based upon combinatorial theory, and then accordingly designed a procedure to efficiently calculate the exact probabilities of multi-set intersections. We further developed multiple efficient and scalable techniques to visualize multi-set intersections and the corresponding intersection statistics. We implemented both the theoretical framework and the visualization techniques in a unified R software package, SuperExactTest. We demonstrated the utility of SuperExactTest through an intensive simulation study and a comprehensive analysis of seven independently curated cancer gene sets as well as six disease or trait associated gene sets identified by genome-wide association studies. We expect SuperExactTest developed by this study will have a broad range of applications in scientific data analysis in many disciplines. PMID- 26603755 TI - Complex-system causality in large-scale brain networks: Comment on "Foundational perspectives on causality in large-scale brain networks" by M. Mannino and S.L. Bressler. PMID- 26603756 TI - Stochastic causality, criticality, and non-locality in brain networks: Comment on "Foundational perspectives on causality in large-scale brain networks" by M. Mannino and S.L. Bressler. PMID- 26603757 TI - The impact of information spreading on disease dynamics: Comment on "Coupled disease-behavior on complex networks: A review" by Z. Wang et al. PMID- 26603758 TI - Characterization of a gamma-butyrolactone synthetase gene homologue (stcA) involved in bafilomycin production and aerial mycelium formation in Streptomyces sp. SBI034. AB - Streptomyces SBI034 produces several bafilomycin derivatives. Its afsA homologue (stcA) and putative gamma-butyrolactone receptor gene (stcB) were cloned. Construction of a stcA disruptant (stcA gene knockout) resulted in complete abolishment of all bafilomycin production. Electron microscopic analysis showed a defect of aerial mycelium formation and sporulation in the stcA disruptant. Restoration of all phenotypic defects and bafilomycin production was observed in a stcA complemented strain. Addition of exogenous gamma-butyrolactone (GBL) extracted from the culture broth of the wild-type strain could stimulate the aerial mycelium and spore formation of the stcA disruptant. These results suggest that stcA plays a role in GBL-mediated regulation of bafilomycin biosynthesis and morphological development in Streptomyces strain SBI034. PMID- 26603759 TI - Rapid onsite detection of bacterial spores of biothreat importance by paper-based colorimetric method using erbium-pyrocatechol violet complex. AB - Dipicolinic acid (DPA) is an important chemical marker for the detection of bacterial spores. In this study, complexes of lanthanide series elements such as erbium, europium, neodymium, and terbium were prepared with pyrocatechol violet and effectively immobilized the pyrocatechol violet (PV)-metal complex on a filter paper using polyvinyl alcohol. These filter paper strips were employed for the onsite detection of bacterial spores. The test filter papers were evaluated quantitatively with different concentrations of DPA and spores of various bacteria. Among the four lanthanide ions, erbium displayed better sensitivity than the other ions. The limit of detection of this test for DPA was 60 MUM and 5 * 10(6) spores. The effect of other non-spore-forming bacteria and interfering chemicals on the test strips was also evaluated. The non-spore-forming bacteria did not have considerable effect on the test strip whereas chemicals such as EDTA had significant effects on the test results. The present test is rapid and robust, capable of providing timely results for better judgement to save resources on unnecessary decontamination procedures during false alarms. PMID- 26603760 TI - Induction of secondary metabolism of Aspergillus terreus ATCC 20542 in the batch bioreactor cultures. AB - Cultivation of Aspergillus terreus ATCC 20542 in a stirred tank bioreactor was performed to induce the biosynthesis of secondary metabolites and provide the bioprocess-related insights into the metabolic capabilities of the investigated strain. The activation of biosynthetic routes was attempted by the diversification of process conditions and growth media. Several strategies were tested, including the addition of rapeseed oil or inulin, changing the concentration of nitrogen source, reduction of chlorine supply, cultivation under saline conditions, and using various aeration schemes. Fifteen secondary metabolites were identified in the course of the study by using ultra-high performance liquid chromatography coupled with mass spectrometry, namely mevinolinic acid, 4a,5-dihydromevinolinic acid, 3alpha-hydroxy-3,5 dihydromonacolin L acid, terrein, aspulvinone E, dihydroisoflavipucine, (+) geodin, (+)-bisdechlorogeodin, (+)-erdin, asterric acid, butyrolactone I, desmethylsulochrin, questin, sulochrin, and demethylasterric acid. The study also presents the collection of mass spectra that can serve as a resource for future experiments. The growth in a salt-rich environment turned out to be strongly inhibitory for secondary metabolism and the formation of dense and compact pellets was observed. Generally, the addition of inulin, reducing the oxygen supply, and increasing the content of nitrogen source did not enhance the production of examined molecules. The most successful strategy involved the addition of rapeseed oil to the chlorine-deficient medium. Under these conditions, the highest levels of butyrolactone I, asterric acid, and mevinolinic acid were achieved and the presence of desmethylsulochrin and (+) bisdechlorogeodin was detected in the broth. The constant and relatively high aeration rate in the idiophase was shown to be beneficial for terrein and (+) geodin biosynthesis. PMID- 26603761 TI - High production in E. coli of biologically active recombinant human fibroblast growth factor 20 and its neuroprotective effects. AB - Fibroblast growth factor 20 (FGF20) has a wide range of biological activities; its expression is most pronounced in neural tissues where it has functions in development and neuroprotection. Given these activities, interest in the clinical applications of FGF20 is rising, which will lead to increasing demand for active recombinant human FGF20 (rhFGF20). To improve the production of rhFGF20, an artificial gene encoding fgf20 was cloned into pET3a and expressed in E. coli BL21(DE3)pLysS. By optimizing induction conditions, we successfully induced large amounts of insoluble rhFGF20. Following solubilization and refolding of the rhFGF20 from inclusion bodies, it was purified by HiTrap heparin affinity chromatography to a purity of over 96% with a yield of 218 mg rhFGF20/100 g wet cells. The purified rhFGF20 could stimulate proliferation of both NIH 3T3 cells and PC-12 cells, measured by the MTT assay. In a model of Abeta25-35-induced apoptosis on PC-12 cells, rhFGF20 had a clear protective effect. RT-PCR and Western blot analysis of apoptosis-related genes and proteins revealed that the FGF20-derived protective mechanism was likely due to the relief of endoplasmic reticulum stress (ER stress). In conclusion, the approach described here may be a better means to produce active rhFGF20 in good quantity, thereby allowing for its future pharmacological and clinical use. PMID- 26603762 TI - Xylose fermentation efficiency and inhibitor tolerance of the recombinant industrial Saccharomyces cerevisiae strain NAPX37. AB - Industrial yeast strains with good xylose fermentation ability and inhibitor tolerance are important for economical lignocellulosic bioethanol production. The flocculating industrial Saccharomyces cerevisiae strain NAPX37, harboring the xylose reductase-xylitol dehydrogenase (XR-XDH)-based xylose metabolic pathway, displayed efficient xylose fermentation during batch and continuous fermentation. During batch fermentation, the xylose consumption rates at the first 36 h were similar (1.37 g/L/h) when the initial xylose concentrations were 50 and 75 g/L, indicating that xylose fermentation was not inhibited even when the xylose concentration was as high as 75 g/L. The presence of glucose, at concentrations of up to 25 g/L, did not affect xylose consumption rate at the first 36 h. Strain NAPX37 showed stable xylose fermentation capacity during continuous ethanol fermentation using xylose as the sole sugar, for almost 1 year. Fermentation remained stable at a dilution rate of 0.05/h, even though the xylose concentration in the feed was as high as 100 g/L. Aeration rate, xylose concentration, and MgSO4 concentration were found to affect xylose consumption and ethanol yield. When the xylose concentration in the feed was 75 g/L, a high xylose consumption rate of 6.62 g/L/h and an ethanol yield of 0.394 were achieved under an aeration rate of 0.1 vvm, dilution rate of 0.1/h, and 5 mM MgSO4. In addition, strain NAPX37 exhibited good tolerance to inhibitors such as weak acids, furans, and phenolics during xylose fermentation. These findings indicate that strain NAPX37 is a promising candidate for application in the industrial production of lignocellulosic bioethanol. PMID- 26603763 TI - Synthesis and characterization of the fluorescent probes for the labeling of Microthrix parvicella. AB - Although the fluorescent in situ hybridization (FISH) has been widely used to identify the Microthrix parvicella (M. parvicella), there are a few disadvantages and difficulties, such as complicated process, time consuming, etc. In this work, a series of fluorescent probes, which were modified by long-chain alkane with hydrophobic property and based on the property of M. parvicella utilizing long chain fatty acids (LCFA), for the labeling of M. parvicella in bulking sludge were designed, synthesized, and characterized. The probes were characterized by ultraviolet-visible (UV-Vis) absorption spectra, fluorescence spectra, (1)H NMR spectra, and mass spectra, and the photostability and hydrophobic property of probes were investigated. All the results showed that the probes were quite stable and suitable for the fluorescent labeling. The probes had a large stoke shift of 98-137 nm, which was benefit for the fluorescent labeling. In the fluorescent labeling of M. parvicella by the synthesized probes, the probes had excellent labeling effects. By comparison of the images and the Image Pro Plus 6.0 analysis, the optimal concentration of the probes in the activated sludge sample for labeling was 0.010 mmol/L and the probe 3d had the best labeling. In addition, the effect of the duration time of probes was also investigated, and the results showed that the fluorescent intensity of probes hardly changed in a long period of time and it was suitable for labeling. PMID- 26603764 TI - Effect of dissolved oxygen on elemental sulfur generation in sulfide and nitrate removal process: characterization, pathway, and microbial community analysis. AB - Microaerobic bioreactor treatment for enriched sulfide and nitrate has been demonstrated as an effective strategy to improve the efficiencies of elemental sulfur (S(0)) generation, sulfide oxidation, and nitrate reduction. However, there is little detailed information for the effect and mechanism of dissolved oxygen (DO) on the variations of microbial community in sulfur generation, sulfide oxidation, and nitrate reduction systems. Polymerase chain reaction denaturing gradient gel electrophoresis (PCR-DGGE) was employed to evaluate the variations of microbial community structures in a sulfide oxidation and nitrate reduction reactor under different DO conditions (DO 0-0.7 mg . L(-1)). Experimental results revealed that the activity of sulfide-oxidizing bacteria (SOB) and nitrate-reducing bacteria (NRB) could be greatly stimulated in 0.1-0.3 mg-DO . L(-1). However, when the DO concentration was further elevated to more than 0.5 mg . L(-1), the abundance of NRB was markedly decreased, while the heterotrophic microorganisms, especially carbon degradation species, were enriched. The reaction pathways for sulfide and nitrate removal under microaerobic conditions were also deduced by combining batch experiments with functional species analysis. It was likely that the oxidation of sulfide to sulfur could be performed by both aerobic heterotrophic SOB and sulfur-based autotrophic denitrification bacteria with oxygen and nitrate as terminal electron acceptor, respectively. The nitrate could be reduced to nitrite by both autotrophic and heterotrophic denitrification, and then the generated nitrite could be completely converted to nitrogen gas via heterotrophic denitrification. This study provides new insights into the impacts of microaerobic conditions on the microbial community functional structures of sulfide-oxidizing, nitrate reducing, and sulfur-producing bioreactors, which revealing the potential linkage between functional microbial communities and reactor performance. PMID- 26603765 TI - Gas-phase synthesis of Mg-Ti nanoparticles for solid-state hydrogen storage. AB - Mg-Ti nanostructured samples with different Ti contents were prepared via compaction of nanoparticles grown by inert gas condensation with independent Mg and Ti vapour sources. The growth set-up offered the option to perform in situ hydrogen absorption before compaction. Structural and morphological characterisation was carried out by X-ray diffraction, energy dispersive spectroscopy and electron microscopy. The formation of an extended metastable solid solution of Ti in hcp Mg was detected up to 15 at% Ti in the as-grown nanoparticles, while after in situ hydrogen absorption, phase separation between MgH2 and TiH2 was observed. At a Ti content of 22 at%, a metastable Mg-Ti-H fcc phase was observed after in situ hydrogen absorption. The co-evaporation of Mg and Ti inhibited nanoparticle coalescence and crystallite growth in comparison with the evaporation of Mg only. In situ hydrogen absorption was beneficial to subsequent hydrogen behaviour, studied by high pressure differential scanning calorimetry and isothermal kinetics. A transformed fraction of 90% was reached within 100 s at 300 degrees C during both hydrogen absorption and desorption. The enthalpy of hydride formation was not observed to differ from bulk MgH2. PMID- 26603766 TI - Wiener-Granger causality for effective connectivity in the hidden states: Indication from probabilistic causality: Comment on "Foundational perspectives on causality in large-scale brain net"orks" by M. Mannino and S.L. Bressler. PMID- 26603767 TI - Modelling real disease dynamics with behaviourally adaptive complex networks: Comment on "Coupled disease-behavior dynamics on complex networks: A review" by Z. Wang et al. PMID- 26603768 TI - Empathy beyond the head: Comment on "Music, empathy, and cultural understanding" by E. Clarke et al. PMID- 26603769 TI - Evaluation of Composite Adaptation to Pulpal Chamber Floor Using Optical Coherence Tomography. AB - INTRODUCTION: A coronal seal is fundamental for a positive outcome to endodontic therapy. In this in vitro study, we evaluated the adaptation of composite resins in postendodontic restorations using optical coherence tomographic (OCT) imaging. Our null hypothesis was that there would be no difference in marginal adaptation to the pulp chamber floor between resin composites of different viscosities. METHODS: Thirty intact upper molars extracted for periodontal reasons were selected, endodontically treated, and filled with gutta-percha. The excess gutta percha was entirely removed from the pulp chamber floor, and teeth were randomly divided into 3 groups (n = 10) according to the material used for the restoration: group 1: 0.5-mm horizontal layer of flowable composite followed by nanohybrid composite, group 2: bulk layering of bulk fill flowable composite; and group 3: oblique layering of nanohybrid composite. The degree of adaptation to the cavity floor was assessed using OCT imaging, and images were analyzed with the software program ImageJ (National Institutes of Health, Bethesda, MD) to assess the marginal gap between the composite and the pulp chamber floor. Collected data were statistically analyzed using analysis of variance testing, and statistical significance was set at P < .05. RESULTS: Flowable composites showed significantly better adaptation than traditional packable nanohybrid composites (P < .05). All significant differences were found between groups 1 and 2. CONCLUSIONS: Within the limitations of this OCT imaging-based in vitro study, it was concluded that the flowable composite (flow + nanofilled; flow bulk fill composite) adapted better to the pulp chamber floor than the packable nanohybrid composite resin. Further studies are necessary to confirm these results. PMID- 26603770 TI - Age-related Changes in the Alkaline Phosphatase Activity of Healthy and Inflamed Human Dental Pulp. AB - INTRODUCTION: Alkaline phosphatase (ALP) plays an important role in inducing mineralization events in the dental pulp. This study investigated and compared the ALP levels in healthy and inflamed pulp in young and old human pulp. METHODS: Tissue samples were collected from young (<30 years) and old (>60 years) donors. In both age groups, healthy human pulp (n = 18) were collected from extracted wisdom teeth. For reversible and irreversible pulpitis, pulp samples (n = 18 each) were obtained during endodontic treatment. ALP activity was assessed by spectrophotometry and immunhistochemistry. RESULTS: Regardless of age, reversible pulpitis group samples showed a slight elevation in ALP activity compared with normal healthy pulp. In elderly patients, ALP expression with irreversible pulpitis was significantly higher than those with a healthy pulp (P < .05). CONCLUSIONS: In the hyperemic state, both the young and old pulp shows a slight increase in ALP activity, whereas in irreversible pulpitis, only the old pulp shows significantly elevated ALP levels. Such an increase may trigger calcification events, which may eventually cause difficulties in endodontic treatment procedures in elderly individuals. PMID- 26603771 TI - Randomized Clinical Trial of Intraosseous Methylprednisolone Injection for Acute Pulpitis Pain. AB - INTRODUCTION: The present study reports the results of a randomized clinical trial comparing local intraosseous methylprednisolone injection and emergency pulpotomy in the management of acute pulpitis on efficacy, safety, and efficiency end points. METHODS: After providing prior informed written consent, 94 patients consulting for acute irreversible pulpitis pain at university-affiliated teaching hospital dental clinics in Dakar, Senegal were randomly assigned to either the methylprednisolone treatment group (n = 47) or the pulpotomy treatment group (n = 47). Patients were followed up at 1 week and assessed 6 months later to evaluate the therapeutic outcome of their treatment. RESULTS: At day 7 the patients in the methylprednisolone group reported less intense spontaneous and percussion pain in the day 0-day 7 period than the patients in the pulpotomy group. Methylprednisolone treatment took approximately 7 minutes (4.6-9.3) less to accomplish than pulpotomy (or about half the time). No difference in the therapeutic outcome was found between the 2 treatment groups at 6 months (all credible intervals span 0). CONCLUSIONS: This study establishes that methylprednisolone injection for acute pulpitis is relieved by a minimally invasive pharmacologic approach more effectively than by the reference pulpotomy and conserves scarce dental resources (ie, endodontic equipment and supplies, dental surgeon's time). PMID- 26603772 TI - Abnormal pancreatic enzymes and their prognostic role after acute paraquat poisoning. AB - Ingestion of paraquat causes multi-organ failure. Prognosis is best estimated through measurement of blood paraquat concentrations but this facility is not available in most hospitals. We studied the prognostic significance of abnormal pancreatic enzymes for survival. Patients with acute paraquat poisoning were recruited. An extensive series of blood tests including serum amylase were serially checked. Patients were sorted according to their serum amylase activity (normal [<220 U/L], mildly elevated [220 to 660 U/L], elevated [>660 U/L]), and survival compared between groups. 177 patients were enrolled to the study, of whom 67 died and 110 survived. 122 (70.62%), 27 (15.25%) and 25 (14.13%) patients were in the normal, mildly elevated and elevated amylase activity groups, respectively. The case fatality in the elevated group was 100% compared to 17% in the normal group (P < 0.001). We found four independent factors for paraquat death prediction: amylase, PaCO2, leukocyte number, and neutrophil percentage. Models using pancreatic enzyme activity showed good prediction power. We have found that abnormal pancreatic enzymes are useful prognostic marker of death after acute paraquat poisoning. Including serum amylase activity into a prognostic model provides a good prognostication. PMID- 26603773 TI - Measuring radiotherapy setup errors at multiple neck levels in nasopharyngeal cancer (NPC): A case for differential PTV expansion. AB - BACKGROUND AND PURPOSE: We aim to quantify the magnitude of the systematic and random setup errors at three different anatomical levels of the neck in Nasopharyngeal Carcinoma (NPC) when clivus matching is used, and recommend appropriate PTV margins for each level. MATERIAL AND METHODS: Thirty-six patients undergoing image-guided radiotherapy (IGRT) each with 9 scheduled CBCTs were reviewed. The magnitude of setup errors were measured at the level of the clivus, C4 and C7 vertebrae, before and after CBCT correction. The 3D displacements, systematic and random errors were calculated for each level. The appropriate PTV expansion was determined using Van Herk's formula. RESULTS: Mean 3D displacement was 1.88, 2.66 and 3.35 mm at the clivus, C4 and C7 before correction. The differences were statistically significant (p<0.05). The PTV margin required without correction was 2.33, 4.33 and 6.52 mm respectively. These were reduced to 1.20, 3.72 and 6.08 mm after CBCT corrections. CONCLUSIONS: Variability is seen in setup errors at the clivus, C4 and C7 vertebral levels. A variable planning margin approach with reduced margin at the clivus is recommended. Use of daily CBCT allows the PTV expansion to be reduced to 1.2 mm. PMID- 26603775 TI - Intestinal tract: DLL4 signalling maintains organization and function of lacteals. PMID- 26603776 TI - Achieving high strength and high ductility in magnesium alloy using hard-plate rolling (HPR) process. AB - Magnesium alloys are highly desirable for a wide range of lightweight structural components. However, rolling Mg alloys can be difficult due to their poor plasticity, and the strong texture yielded from rolling often results in poor plate forming ability, which limits their further engineering applications. Here we report a new hard-plate rolling (HPR) route which achieves a large reduction during a single rolling pass. The Mg-9Al-1Zn (AZ91) plates processed by HPR consist of coarse grains of 30-60 MUm, exhibiting a typical basal texture, fine grains of 1-5 MUm and ultrafine (sub) grains of 200-500 nm, both of the latter two having a weakened texture. More importantly, the HPR was efficient in gaining a simultaneous high strength and uniform ductility, i.e., ~371 MPa and ~23%, respectively. The superior properties should be mainly attributed to the cooperation effect of the multimodal grain structure and weakened texture, where the former facilitates a strong work hardening while the latter promotes the basal slip. The HPR methodology is facile and effective, and can avoid plate cracking that is prone to occur during conventional rolling processes. This strategy is applicable to hard-to-deform materials like Mg alloys, and thus has a promising prospect for industrial application. PMID- 26603777 TI - The design of second generation MOP-phosphonites: efficient chiral hydrosilylation of functionalised styrenes. AB - A series of enantiopure MOP-phosphonite ligands, with tailored steric profiles, have been synthesised and are proven to be very successful in high-yielding, regio- and enantioselective catalytic hydrosilylation reactions of substituted styrenes, affording important chiral secondary alcohols. PMID- 26603774 TI - Uncertainty in the Timing of Origin of Animals and the Limits of Precision in Molecular Timescales. AB - The timing of divergences among metazoan lineages is integral to understanding the processes of animal evolution, placing the biological events of species divergences into the correct geological timeframe. Recent fossil discoveries and molecular clock dating studies have suggested a divergence of bilaterian phyla >100 million years before the Cambrian, when the first definite crown-bilaterian fossils occur. Most previous molecular clock dating studies, however, have suffered from limited data and biases in methodologies, and virtually all have failed to acknowledge the large uncertainties associated with the fossil record of early animals, leading to inconsistent estimates among studies. Here we use an unprecedented amount of molecular data, combined with four fossil calibration strategies (reflecting disparate and controversial interpretations of the metazoan fossil record) to obtain Bayesian estimates of metazoan divergence times. Our results indicate that the uncertain nature of ancient fossils and violations of the molecular clock impose a limit on the precision that can be achieved in estimates of ancient molecular timescales. For example, although we can assert that crown Metazoa originated during the Cryogenian (with most crown bilaterian phyla diversifying during the Ediacaran), it is not possible with current data to pinpoint the divergence events with sufficient accuracy to test for correlations between geological and biological events in the history of animals. Although a Cryogenian origin of crown Metazoa agrees with current geological interpretations, the divergence dates of the bilaterians remain controversial. Thus, attempts to build evolutionary narratives of early animal evolution based on molecular clock timescales appear to be premature. PMID- 26603778 TI - Radicular Cyst: An Update of the Biological Factors Related to Lining Epithelium. AB - INTRODUCTION: Radicular cysts are common lesions in daily dentistry practice. However, the mechanisms related to epithelial lining formation and cavity growth are not fully understood. Therefore, the purpose of this article was to review the biological factors implicated in these process. METHODS: Literature was selected through a search of PubMed electronic databases matching the following key words in the title or abstract: "cyst" OR "granuloma" OR "abscess" AND "radicular" OR "apical" OR "periapical" AND "epithelium" OR "epithelial" OR "epithelial lining." The PubMed database was searched for articles published between 1975 and 2014. Only English language was applied to the search. RESULTS: The literature search yielded a total of 187 articles. After duplicate references were discarded, a subsequent search at the title and abstract level revealed 42 articles for full-text reading. The articles were categorized into 5 main subtopics: (1) cell proliferation, cell cycle, and apoptosis; (2) extracellular matrix constituents; (3) inflammatory components; (4) bone metabolic factors and; (5) others. These subtopics described the characteristics of radicular cysts focusing on the epithelial tissue effects. CONCLUSIONS: Several factors from different sources (epithelial cells, stromal cells, extracellular matrix, and bone matrix) were implicated on apical cyst pathogenesis. Probably a combination of many factors involving an epithelial-stromal interaction is responsible for the sustenance and growth of apical cysts. PMID- 26603779 TI - Influence of lipidation on the mode of action of a small RW-rich antimicrobial peptide. AB - Antimicrobial peptides are a potent class of antibiotics. In the Gram-positive model organism Bacillus subtilis the synthetic peptide RWRWRW-NH2 integrates into the bacterial membrane and delocalizes essential peripheral membrane proteins involved in cell wall biosynthesis and respiration. A lysine residue has been added to the hexapeptide core structure, either C or N-terminally. Lipidation of the lysine residues by a C8-acyl chain significantly improved antibacterial activity against both Gram-positive and Gram-negative bacteria. Here, we report a comparative proteomic study in B. subtilis on the mechanism of action of the lipidated and non-lipidated peptides. All derivatives depolarized the bacterial membrane without forming pores and all affected cell wall integrity. Proteomic profiling of the bacterial stress responses to the small RW-rich antimicrobial peptides was reflective of non-disruptive membrane integration. Overall, our results indicate that antimicrobial peptides can be derivatized with lipid chains enhancing antibacterial activity without significantly altering the mechanism of action. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert. PMID- 26603780 TI - A new application of click chemistry in situ: development of fluorescent probe for specific G-quadruplex topology. AB - Target-guided synthesis is an approach to drug discovery that allows the target to self-assemble its own binding agents. So far, target-guided synthesis and especially in situ click chemistry have attracted extensive attention and have led to the identification of highly potent inhibitors for proteins. In this study, we expand the application of in situ click chemistry and present a procedure using this approach to identify selective fluorescent probes for a specific topology of G-quadruplex nucleic acids, the parallel G-quadruplexes. On this basis, compound 15 assembled by triarylimidazole scaffold and carboxyl side chain was a positive hit, demonstrating highly potential in the sensitive and selective detection of parallel G-quadruplexes. Such selective fluorescence response can be rationalized in terms of different binding affinities between 15 and G-quadruplexes. Our work accordingly represents a new development towards the application of in situ click chemistry to develop selective fluorescent probes and may also shed light on the search for probes for a specific G-quadruplex topology. PMID- 26603781 TI - Long-term Use of Statins and Risk of Renal Cell Carcinoma: A Population-based Case-Control Study. AB - BACKGROUND: Use of statins has been suggested to protect against renal cell carcinoma (RCC); however, studies have typically been underpowered, and the results are conflicting. OBJECTIVE: To determine whether the use of statins is associated with a reduced risk of RCC using high-quality registry data. DESIGN, SETTING, AND PARTICIPANTS: We conducted a nationwide case-control study based on all histologically verified cases of RCC in Denmark between 2002 and 2012 (n=4606) matched 1:10 to cancer-free controls. Data on drug use, comorbidity, and educational level were obtained from Danish nationwide prescription, patient, and demographic registries. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) and 95% confidence intervals (CIs) for RCC associated with long-term use (>=5 yr) of statins were estimated using conditional logistic regression, adjusting for potential confounders. RESULTS AND LIMITATIONS: The adjusted OR for RCC associated with long-term use of statins was 1.06 (95% CI, 0.91-1.23). Analyses stratified by duration of statin use, type of statin, and patient characteristics all yielded ORs close to unity, except for a slightly increased OR for RCC associated with long-term statin use among women (OR: 1.25; 95% CI, 0.96-1.62). The main limitation of our study was lack of information on lifestyle factors, notably obesity, which may have biased the risk estimates upward. CONCLUSIONS: Our study does not support an important chemopreventive effect of long-term statin use against RCC. The marginally increased and statistically insignificant risk estimates can readily be interpreted as a null finding, considering the lack of control for obesity and other lifestyle risk factors. PATIENT SUMMARY: Previous studies have shown that the use of cholesterol-lowering drugs (statins) may protect against renal cancer. In a large study including all Danish renal cancers during an 11-yr period, we found no evidence of such an effect. PMID- 26603782 TI - Another Reason to Consider Active Surveillance. PMID- 26603783 TI - Review of achievements of the OECD Working Party on Manufactured Nanomaterials' Testing and Assessment Programme. From exploratory testing to test guidelines. AB - This paper charts the almost ten years of history of OECD's work on nanosafety, during which the programme of the OECD on the Testing and Assessment of Manufactured Nanomaterials covered the testing of eleven nanomaterials for about 59 end-points addressing physical-chemical properties, mammalian and environmental toxicity, environmental fate and material safety. An overview of the materials tested, the test methods applied and the discussions regarding the applicability of the OECD test guidelines, which are recognised methods for regulatory testing of chemicals, are given. The results indicate that many existing OECD test guidelines are suitable for nanomaterials and consequently, hazard data collected using such guidelines will fall under OECD's system of Mutual Acceptance of Data (MAD) which is a legally binding instrument to facilitate the international acceptance of information for the regulatory safety assessment of chemicals. At the same time, some OECD test guidelines and guidance documents need to be adapted to address nanomaterials while new test guidelines and guidance documents may be needed to address endpoints that are more relevant to nanomaterials. This paper presents examples of areas where test guidelines or guidance for nanomaterials are under development. PMID- 26603784 TI - A Prospective Study of the Timing and Accuracy of Neutrophil Gelatinase Associated Lipocalin Levels in Predicting Acute Kidney Injury in High-Risk Cardiac Surgery Patients. AB - OBJECTIVES: Neutrophil gelatinase-associated lipocalin (NGAL) appears to be a promising biomarker in the effort to predict acute kidney injury (AKI) after cardiac surgery. The authors aimed to identify the specific time point in the perioperative period at which measurement of either urinary or serum concentrations of NGAL would have the highest predictive power for AKI. The authors also investigated whether change in NGAL from baseline was a better predictor of AKI than absolute NGAL values. DESIGN: A prospective, investigator blinded observational study. SETTING: The cardiac surgical unit of a university teaching hospital. PARTICIPANTS: The study consisted of 50 patients undergoing cardiac surgery who were classified preoperatively as high risk for developing postoperative AKI. INTERVENTIONS: No changes to standard practice were required. MEASUREMENTS AND MAIN RESULTS: The authors performed serial measurements of urinary and serum NGAL concentrations at 18 time points throughout the first 48 postoperative hours and assessed the variables required to diagnose AKI with standard criteria. Statistical analysis of predictive ability was performed using the area under receiver operator curves (AUROC) calculated for each time point. It was demonstrated that urinary NGAL performed marginally better than serum NGAL in predicting AKI. Urinary sampling at 4 and 24 hours after initiation of cardiopulmonary bypass provided the greatest diagnostic ability (AUROC, 0.702 and 0.712, respectively). Absolute NGAL values performed better than changes in NGAL values in predicting AKI. CONCLUSIONS: Urinary NGAL performed better than serum NGAL in predicting AKI and was most accurate when measured at 24 hours after initiation of cardiopulmonary bypass; however, NGAL appeared to be at best only a fair predictor of cardiac surgery-associated AKI. PMID- 26603785 TI - Ongoing challenges in the diagnosis of hepatocellular carcinoma. AB - In 2001, the European Association for the Study of the Liver (EASL) endorsed the possibility of achieving a non-invasive diagnosis of Hepatocellular Carcinoma (HCC) for the first time. Since then, various refinements of the criteria and techniques capable of achieving this diagnosis and the role of plasma and tissue oncomarkers have been reported in the literature and have been accepted to different extents in various geographical areas. Such tools can also potentially imply prognostic significance. The present article critically discusses some of the most relevant and debated challenges which have emerged in this field, including the role of contrast-enhanced ultrasound, and of hepatocyte-specific magnetic resonance contrast agents, the pitfall of transient hepatic attenuation differences, the reliability of biopsy and the status of biomarkers. PMID- 26603786 TI - Transanal vs laparoscopic total mesorectal excision for rectal cancer: initial experience from Denmark. AB - AIM: Laparoscopic total mesorectal excision (LaTME) has improved short-term outcomes of rectal cancer surgery with comparable oncological results to open approach. LaTME can be difficult in the lowermost part of the rectum, leading potentially to higher rates of complications, conversion to open surgery and probably suboptimal oncological quality. Transanal TME (TaTME) can potentially solve these problems. The aim of this study was to compare the short-term results after TaTME with those after LaTME. METHOD: A prospectively collected database of consecutive patients who underwent TaTME was maintained. Results were compared with those who underwent LaTME in the preceding period. Patients who underwent low anterior resection or intersphincteric abdominoperineal excision were included. Primary end-points were radical resection and specimen quality. Secondary end-points were complications, rates of conversion, operating time and hospital stay. RESULTS: In total, 50 patients were included (TaTME = 25, LaTME = 25). The groups were comparative in demographic data and tumour characteristics. Circumferential resection margin was positive in one patient in the TaTME group vs four patients in the LaTME group (P = 0.349). All patients in the TaTME group had either complete or nearly complete specimen quality, while four patients in the LaTME group had incomplete specimen quality (P = 0.113). Less blood loss, shorter operating time and shorter hospital stay were found in the TaTME group (P values 0.016, 0.002 and 0.020 respectively). Intra-operative complications were comparable (P = 0.286). CONCLUSION: The TaTME procedure had comparable pathological results and acceptable short-term postoperative outcomes compared to LaTME. PMID- 26603787 TI - Full Characterization and Photoelectrochemical Behavior of Pyrene-fused Octaazadecacene and Tetraazaoctacene. AB - The preparation of large azaacenes is very important because of their great potential in organic electronics. In this report, we successfully synthesized and fully characterized two stable pyrene-fused large azaacenes: octaazadecacene and tetraazaoctacene through employing a relatively moderate aromatic unit pyrene as imbedded species in the backbone of azaacenes to ensure large conjugation and stability. The photoelectrochemical (PEC) studies indicate that both azaacenes display n-type semiconductor behavior. PMID- 26603788 TI - Videos in laryngoscopy. PMID- 26603789 TI - Rod Westhorpe-covering a historical moment. PMID- 26603790 TI - Does hyperbaric oxygen improve survival in necrotising soft tissue infections? PMID- 26603791 TI - Necrotising soft tissue infections: the effect of hyperbaric oxygen on mortality. AB - In a single-centre, retrospective, case-controlled study of patients attending the Alfred Hospital in Prahran, Victoria, we assessed the effect of hyperbaric oxygen therapy (HBOT) in reducing mortality or morbidity in patients with necrotising fasciitis (NF) over a 13-year period from 2002 to 2014. A total of three hundred and forty-one patients with NF were included in the study, of whom 275 received HBOT and 66 did not. The most commonly involved sites were the perineum (33.7%), lower limb (29.9%) and trunk (18.2%). The commonest predisposing factor was diabetes mellitus (34.8%). Polymicrobial NF (type 1 NF) occurred in 50.7% and Group A streptococcal fasciitis (type 2 NF) occurred in 25.8% of patients. Mortality was 14.4% overall, 12% in those treated with, and 24.3% in those not treated with, HBOT. ICU support was required in 248 (72.7%) patients. Independent factors impacting on mortality included HBOT (odds ratio [OR] 0.42 [0.22 to 0.83], P=0.01), increased age (OR 1.06 [1.03 to 1.08], P=0.001) and immunosuppression (OR 2.6 [1.23 to 5.51], P=0.01). Mortality was linked to illness severity at presentation, however when adjusted for severity score and need for intensive care management, HBOT was associated with significant reduction in mortality. PMID- 26603792 TI - The incidence of ocular candidiasis and evaluation of routine opthalmic examination in critically ill patients with candidaemia. AB - Despite a paucity of data regarding both the incidence of ocular candidiasis and the utility of ophthalmic examination in critically ill patients, routine ophthalmic examination is recommended for critically ill patients with candidaemia. The objectives were to estimate the incidence of ocular candidiasis and evaluate whether ophthalmic examination influenced subsequent management of these patients. We conducted a ten-year retrospective observational study. Data were extracted for all ICU patients who were blood culture positive for fungal infection. Risk factors for candidaemia and eye involvement were quantified and details regarding ophthalmic examination were reviewed. Candida species were cultured in 93 patients. Risk factors for ocular candidiasis were present in 57% of patients. Forty-one percent of patients died prior to ophthalmology examination and 2% of patients were discharged before candidaemia was identified. During examination, signs of ocular candidiasis were only present in one (2.9%) patient, who had a risk factor for ocular candidiasis. Based on these findings, the duration of antifungal treatment for this patient was increased. Ocular candidiasis occurs rarely in critically ill patients with candidaemia, but because treatment regimens may be altered when diagnosed, routine ophthalmic examination is still indicated. PMID- 26603793 TI - Deviation from accepted drug administration guidelines during anaesthesia in twenty highly realistic simulated cases. AB - Deviations from accepted practice guidelines and protocols are poorly understood, yet some deviations are likely to be deliberate and carry potential for patient harm. Anaesthetic teams practice in a complex work environment and anaesthetists are unusual in that they both prescribe and administer the drugs they use, allowing scope for idiosyncratic practise. We aimed to better understand the intentions underlying deviation from accepted guidelines during drug administration in simulated cases. An observer recorded events that may have increased the risk of patient harm ('Events of Interest' [EOIs]) during 20 highly realistic simulated anaesthetic cases. In semi-structured interviews, details of EOIs were confirmed with participating anaesthetic teams, and intentions and reasoning underlying the confirmed deviations were discussed. Confirmed details of EOIs were tabulated and we undertook qualitative analysis of interview transcripts. Twenty-four EOIs (69% of 35 recorded) were judged by participants to carry potential for patient harm, and 12 (34%) were judged to be deviations from accepted guidelines (including one drug administration error). Underlying reasons for deviations included a strong sense of clinical autonomy, poor clinical relevance and a lack of evidence for guidelines, ingrained habits learnt in early training, and the influence of peers. Guidelines are important in clinical practice, yet self-identified deviation from accepted guidelines was common in our results, and all but one of these events was judged to carry potential for patient harm. A better understanding of the reasons underlying deviation from accepted guidelines is essential to the design of more effective guidelines and to achieving compliance. PMID- 26603794 TI - Idiopathic interstitial pneumonia in the ICU: an observational cohort. AB - In the absence of a clearly identifiable cause, the prognosis of patients with interstitial lung disease is grim. This study describes our institutional experience in management of patients who are admitted to an ICU with respiratory insufficiency secondary to idiopathic interstitial pneumonia (IIP). This study was performed to obtain Australian data on patients admitted to an ICU with respiratory insufficiency secondary to IIP. This is a retrospective cohort study of patients with IIP who were admitted to the ICU between December 2007 and December 2013 at one of two university-affiliated academic hospitals in Newcastle, New South Wales. Thirty-six patients (69% male) were admitted to the ICU in respiratory insufficiency from IIP. The median age of the cohort was 71 (66 to 77) years. The median APACHE III score was 68 (56 to 97). Sixty-nine percent (25/36) of patients died in hospital. The median ICU and hospital lengths of stay were 6 (2 to 13.5) and 12 (4.8 to 18.3) days respectively. No significant difference was observed between admission characteristics and mortality. Patients admitted to ICU with respiratory failure secondary to IIP are aggressively investigated and treated, but still have a high mortality rate. Accurate predictors of mortality would be useful in offering aggressive treatment to patients who would benefit from it. PMID- 26603795 TI - Fast-track rapid warfarin reversal for elective surgery: extending the efficacy profile to high-risk patients with cancer. AB - Periprocedural management of patients on long-term warfarin therapy remains a common and important clinical issue, with little high-quality data to guide this complex process. The current accepted practice is cessation of warfarin five days preoperatively, but this is not without risk and can be complicated, particularly if bridging is required. An alternative method utilising low-dose intravenous vitamin K the day before surgery has been shown previously to be efficacious, safe and convenient in an elective surgical population receiving chronic warfarin therapy. The efficacy and utility of this 'fast-track' warfarin reversal protocol in surgical patients with cancer, who were at high risk of both thromboembolism and bleeding was investigated in a prospective, single-arm study at a dedicated cancer centre. Seventy-one patients underwent 82 episodes of fast-track warfarin reversal (3 mg intravenous vitamin K 18 to 24 hours before surgery). No patient suffered an adverse reaction to intravenous vitamin K, all but one achieved an International Normalized Ratio =1.5 on the day of surgery, and no surgery was deferred. Assays of vitamin K-dependent factor levels pre- and post-vitamin K demonstrated restoration of functional activity to within an acceptable range for surgical haemostasis. While this alternative method requires further validation in a larger prospective randomised study, we have now extended our use of fast track warfarin reversal using vitamin K to patients with cancer, on the basis of our experience of its safety, convenience, reliability and efficacy. PMID- 26603796 TI - Overcoming barriers to the mobilisation of patients in an intensive care unit. AB - We conducted a quality improvement project aimed at increasing the frequency of mobilisation in our ICU. We designed a four-part quality improvement project comprising: an audit documenting the baseline frequency of mobilisation; a staff survey evaluating perceptions of the barriers to mobilisation; identification of barriers that were amenable to change and implementation of strategies to address these; and a follow-up audit to determine their effectiveness. The setting was a tertiary care, urban, public hospital ICU in South Australia. All patients admitted to the ICU during the two audit periods were included in the audits, while all permanent/semi-permanent ICU staff were eligible for inclusion in the staff survey. We found that patient- and institution-related factors had the greatest impact on the mobilisation of patients in our ICU. Barriers identified as being amenable to change included insufficient staff education about the benefits of mobilisation, poor interdisciplinary communication and lack of leadership regarding mobilisation. Various strategies were implemented to address these barriers over a three-month period. Multivariable analyses showed that three out of four mobility outcomes did not significantly change between the baseline and follow-up audits, with a significant difference in favour of the baseline audit found for the fourth mobility outcome (maximum level of mobility). We concluded that implementing relatively simple measures to improve staff education, interdisciplinary communication and leadership regarding early progressive mobilisation was ineffective at improving mobility outcomes for patients in a large tertiary-level Australian ICU. Other strategies, such as changing sedation practices and/or increasing staffing, may be required to improve mobility outcomes of these patients. PMID- 26603797 TI - High-risk residual gastric content in fasted patients undergoing gastrointestinal endoscopy: a prospective cohort study of prevalence and predictors. AB - In this prospective cohort study, we examined the residual gastric contents of 255 fasted patients undergoing gastrointestinal endoscopy. The volume and pH of residual gastric contents collected by suction under direct visualisation during gastroscopy were accurately quantified. All patients completed the minimum two hour fast for clear fluids and 97.2% of patients completed the minimum six-hour fast for solids. High-risk residual gastric content, defined as volume >25 ml and pH <2.5, was present in 12.2% (95% CI 8.7% to 16.7%) of patients. We used multiple logistic regression analysis to identify demographic and clinical factors associated with high-risk residual gastric content. The odds of having high-risk residual gastric content were reduced with increase in age (adjusted odds ratio 0.77, 95% CI 0.61 to 0.96, P=0.0230), and use of a proton pump inhibitor or histamine type 2 receptor antagonist (adjusted odds ratio 0.24, 95% CI 0.10 to 0.55, P=0.0013), and were increased in male patients (adjusted odds ratio 2.36, 95% CI 1.06 to 5.28, P=0.0348). Notably, residual gastric content was classified as high-risk in 20.4% of patients who did not take a proton pump inhibitor or histamine type 2 receptor antagonist versus only 5.6% of those who did. Our findings suggest that, despite currently recommended fasting, males presenting for endoscopy are more likely to have high-risk gastric content than females, and that the incidence appears to be reduced with increasing age, and by the use of proton pump inhibitors or histamine type 2 receptor antagonists, we were unable to confirm or exclude an effect of body mass index, peptic pathology, diabetes or other clinical or demographic factors in our study population. PMID- 26603798 TI - The effects of haemodilution with hydroxyethyl starch 130/0.4 solution on coagulation as assessed by thromboelastography and platelet receptor function studies in vitro. AB - This study evaluated the effects of haemodilution with either 6% hydroxyethyl starch (HES) 130/0.4 (Voluven((r))) or 0.9% normal saline (NS) on blood coagulation in vitro. Haemodilution with 6% HES 130/0.4 impaired coagulation, as indicated by the changes in thromboelastographic parameters k-time, alpha-angle and maximum amplitude. Light transmission aggregometry and multiple electrode aggregometry demonstrated that impaired platelet receptor function occurred only at high levels of haemodilution (40%) with both fluids, but there was no significant difference between the two fluids (P=0.05). The thromboelastographic functional fibrinogen assay showed that the fibrinogen component of clot strength was significantly impaired with haemodilution with HES 130/0.4 compared with haemodilution with NS (whole blood [14.4 +/- 4.6 mm] versus 40% HES dilution [3.7 +/- 1.9], [P=0.001]; versus 40% NS dilution [10.4 +/- 4.6], [P=0.129]). These findings suggest that there is little difference between HES or NS in relation to coagulation or platelet function during minor or moderate haemodilution, but at high levels of haemodilution with HES, fibrinogen activity is more impaired compared with NS. PMID- 26603799 TI - Teaching and learning in undergraduate anaesthesia: a quantitative and qualitative analysis of practice at the University of Auckland. AB - Anaesthesia encompasses a broad range of knowledge and skills of relevance to graduating doctors. For the majority of new doctors, an undergraduate clinical rotation is their only exposure to anaesthesia practice. However, the content and approach to undergraduate anaesthesia education varies between institutions. We explored our students' views and experiences, and teaching approaches and expectations of consultant anaesthetists during a clinical attachment in anaesthesia. Our mixed-method design included student and staff surveys, logbook analysis and student focus groups. Logbook analysis of all 202 students showed mean numbers of attempts for bag-mask ventilation, laryngeal mask insertion, tracheal intubation and IV cannulation were 6.8, 3.9, 3.3 and 4.5, respectively. Focus group responses (11 students, three groups) suggested a mismatch between students' expectations of performing clinical skills and the available opportunities, particularly for IV cannulation. Students often felt reluctant to ask anaesthetists to teach them, and appreciated clinician-led engagement in all aspects of learning patient management. Among the 78 anaesthetists (29.3%) responding to the survey, the five tasks most frequently identified as suitable for teaching to students all related to airway management. Our study found much unanticipated variability in student exposure, teaching practice and attitudes to teaching various skills or procedures between anaesthetists, and student opinion of their clinical attachment. The findings resulted in a review of many aspects of the attachment. It is likely that other institutions will have similar variability and we recommend they undertake similar exercises to optimise teaching and learning opportunities for undergraduate anaesthesia. PMID- 26603800 TI - Characteristics and expectations of fluid bolus therapy: a bi-national survey of acute care physicians. AB - There is little consensus on the definition or optimal constituents of fluid bolus therapy (FBT), and there is uncertainty regarding its physiological effects. The aims of this study were to determine clinician-reported definitions of FBT and to explore the physiological responses clinicians expect from such FBT. In June and October 2014, intensive care and emergency physicians in Australia and New Zealand were asked to participate in an electronic questionnaire of the reported practice and expectations of FBT. Two hundred and fifty-one questionnaires were completed, 65.3% from intensivists. We identified the prototypical FBT given by intensivists is more than 250 ml of compound sodium lactate, saline or 4% albumin given in less than 30 minutes, while that given by emergency department physicians is a similar volume of saline delivered over a similar time frame. Intensive care and emergency physicians expected significantly different changes in mean arterial pressure (P=0.001) and heart rate (P=0.033) following FBT. Substantial variation was demonstrated in the magnitude of expected response within both specialties for each variable. Major variations exist in self-reported FBT practice, both within and between acute specialties, and wide variation can be demonstrated in the expected physiological responses to FBT. International explorations of practice and prospective quantification of the actual physiological response to FBT are warranted. PMID- 26603801 TI - Evaluation of perioperative predictors of acute kidney injury post orthotopic liver transplantation. AB - Acute kidney injury (AKI) is a common complication following orthotopic liver transplantation. It is associated with increased morbidity and mortality, as well as increased healthcare costs. The aetiology of AKI post liver transplantation is multifactorial and understanding these factors is pivotal in developing risk stratification and prevention strategies. This study aims to investigate the preoperative and intraoperative factors that may be associated with AKI in patients undergoing liver transplantation at the Princess Alexandra Hospital, Brisbane, Queensland. In our study, retrospective data of 97 consecutive orthotopic liver transplantations performed between January 2009 and August 2012 were recorded. Univariate and multivariate analyses were performed to investigate the preoperative and intraoperative risk factors for the development of AKI in this cohort. In the cohort of 97 patients who underwent orthotopic liver transplantation, 24 patients (25%) developed postoperative AKI. Univariate analysis demonstrated that high preoperative body mass index and intraoperative noradrenaline use were both associated with AKI. Multivariate analysis demonstrated that high body mass index, high Model for End-stage Liver Disease score and intraoperative noradrenaline use were associated with AKI. Overall mortaility was 4.1% during the study period and was not significantly different between the two groups. The high incidence of AKI following liver transplantation in this study cohort highlights the importance of this issue. This study has identified several potential pre- and intraoperative risk factors, providing a focus for patient surveillance and future research. PMID- 26603803 TI - A survey of educator needs to support the implementation of the intrinsic ANZCA Roles in Practice. AB - The 'Roles in Practice' framework was introduced into the revised ANZCA curriculum in 2013. We conducted an online survey of Supervisors of Training in Australia and New Zealand to assess understanding of this framework, and teaching and perceived value of the non-scholar intrinsic roles within the framework. One hundred and forty-three survey responses were received (response rate 60.8%). The majority of respondents (52.1%) reported only a fair understanding of the framework. Formal teaching of all the roles was consistently reported as infrequent, with most teaching occurring through the informal curriculum. The Communicator, Collaborator and Professional Roles were rated as better taught and more important to teach than the roles of Health Advocate and Manager. The Communicator Role was perceived as being the role for which the development of resources would be most valuable. Respondents overwhelmingly nominated small group teaching as the preferred medium for resource development of all intrinsic roles. Our survey indicates that there is a need to increase both the understanding of the Roles in Practice framework and the teaching resources available in the ANZCA Supervisor of Training community. PMID- 26603802 TI - Effects of dialysis modality on blood loss, bleeding complications and transfusion requirements in critically ill patients with dialysis-dependent acute renal failure. AB - Blood loss and bleeding complications may often be observed in critically ill patients on renal replacement therapies (RRT). Here we investigate procedural (i.e. RRT-related) and non-procedural blood loss as well as transfusion requirements in regard to the chosen mode of dialysis (i.e. intermittent haemodialysis [IHD] versus continuous veno-venous haemofiltration [CVVH]). Two hundred and fifty-two patients (122 CVVH, 159 male; aged 61.5+/-13.9 years) with dialysis-dependent acute renal failure were analysed in a sub-analysis of the prospective randomised controlled clinical trial-CONVINT-comparing IHD and CVVH. Bleeding complications including severity of bleeding and RRT-related blood loss were assessed. We observed that 3.6% of patients died related to severe bleeding episodes (between group P=0.94). Major all-cause bleeding complications were observed in 23% IHD versus 26% of CVVH group patients (P=0.95). Under CVVH, the rate of RRT-related blood loss events (57.4% versus 30.4%, P=0.01) and mean total blood volume lost was increased (222.3+/-291.9 versus 112.5+/-222.7 ml per patient, P <0.001). Overall, transfusion rates did not differ between the study groups. In patients with sepsis, transfusion rates of all blood products were significantly higher when compared to cardiogenic shock (all P <0.01) or other conditions. In conclusion, procedural and non-procedural blood loss may often be observed in critically ill patients on RRT. In CVVH-treated patients, procedural blood loss was increased but overall transfusion rates remained unchanged. Our data show that IHD and CVVH may be regarded as equivalent approaches in critically ill patients with dialysis-dependent acute renal failure in this regard. PMID- 26603804 TI - Anaphylaxis following intravenous paracetamol: the problem is the solution. AB - Paracetamol is a ubiquitous analgesic and antipyretic that is widely administered, including by anaesthetists. Immediate hypersensitivity reactions to intravenous paracetamol are particularly rare. We report two cases involving four separate episodes of anaphylaxis to intravenous paracetamol in different perioperative settings without a past history of intolerance to the oral form. The allergological investigations are described, during which it became evident that both patients were allergic to an excipient (mannitol) present in the formulation and that neither was allergic to the principal agent (paracetamol). The importance of referral and investigation of perioperative drug reactions is underscored by these two cases. PMID- 26603805 TI - Hereditary antithrombin III deficiency and neuraxial anaesthesia. AB - Antithrombin III (ATIII) deficiency offers unique challenges to the anaesthetist in the perioperative setting due to the inherent thrombophilia, the anticoagulant therapies instituted and replacement of the deficient intrinsic natural anticoagulant. A particular challenge is the use of intrathecal anaesthesia, which requires a safe level of coagulation at the time of subarachnoid puncture. We describe the use of intrathecal anaesthesia on two occasions in a patient with ATIII deficiency who received human-derived ATIII concentrate as part of a perioperative anticoagulant regimen. The patient sustained no thrombotic or bleeding events. Our experience suggests that ATIII deficiency does not preclude the use of regional anaesthetic techniques so long as there is timely referral to a multidisciplinary perioperative service for anticoagulant management and that ATIII concentrate is used to ensure safe levels of ATIII throughout the perioperative period. PMID- 26603806 TI - Comparing disposable and reusable fibreoptic bronchoscopes. PMID- 26603808 TI - Idiopathic thoracic spinal cord herniation: the unknown anaesthetic implications. PMID- 26603807 TI - In response to Sun et al. PMID- 26603809 TI - Sevoflurane 2000 Drager Vaporiser 'locked on' during maintenance of anaesthesia. PMID- 26603810 TI - Postpartum seizure following epidural anaesthesia and post-dural puncture headache. PMID- 26603811 TI - CUSUM analysis-a simple method to audit own clinical skills and description of a CUSUM app. PMID- 26603812 TI - English and Mandarin translation using Google Translate software for pre anaesthetic consultation. PMID- 26603814 TI - Major leak from bottom-loading soda lime canister on a GE Healthcare Datex-Ohmeda AespireTM 7900. PMID- 26603813 TI - Hyperthyroidism and propylthiouracil-induced liver failure in pregnancy. PMID- 26603815 TI - Pacemaker-induced R-on-T phenomenon leading to ventricular fibrillation post cardiac surgery. PMID- 26603817 TI - In reply to Cross et al. PMID- 26603816 TI - Effect of a U-shape or non-linear continuous predictor on performance of an ROC curve in differentiating a dichotomised outcome: a simulation study. PMID- 26603818 TI - A renewed call for environmentally responsible anaesthesia. PMID- 26603819 TI - Jahn-Teller Effect in the B12F12 Radical Anion and Energetic Preference of an Octahedral B6(BF2)6 Cluster Structure over an Icosahedral Structure for the Elusive Neutral B12F12. AB - The B12F12(-) radical anion was generated by oxidation of [CoCp2(+)]2B12F12(2-) with AsF5 in SO2. In the crystal structure of [CoCp2(+)]B12F12(-), the anion displays a lowered symmetry (D2h) instead of an Ih-symmetric dianion as a result of Jahn-Teller distortion. Moreover, shortening of the B-F bonds and subtle changes of the B-B bonds are observed. DFT calculations show that, for the unknown neutral B12F12, unprecedented structural isomers [e.g., octahedral B6(BF2)6] are energetically favored instead of an icosahedral structure. The structures and energetics are compared with those of the analogous chlorine compounds. PMID- 26603820 TI - Electrospun N-Substituted Polyurethane Membranes with Self-Healing Ability for Self-Cleaning and Oil/Water Separation. AB - Membranes with special functionalities, such as self-cleaning, especially those for oil/water separation, have attracted much attention due to their wide applications. However, they are difficult to recycle and reuse after being damaged. Herein, we put forward a new N-substituted polyurethane membrane concept with self-healing ability to address this challenge. The membrane obtained by electrospinning has a self-cleaning surface with an excellent self-healing ability. Importantly, by tuning the membrane composition, the membrane exhibits different wettability for effective separation of oil/water mixtures and water-in oil emulsions, whilst still displaying a self-healing ability and durability against damage. To the best of our knowledge, this is the first report to demonstrate a self-healing membrane for oil/water separation, which provides the fundamental research for the development of advanced oil/water separation materials. PMID- 26603821 TI - Luteal-phase ovarian stimulation vs conventional ovarian stimulation in patients with normal ovarian reserve treated for IVF: a large retrospective cohort study. AB - OBJECTIVE: We have previously reported a new luteal-phase ovarian stimulation (LPS) strategy for infertility treatment. The purpose of this study was to systematically assess the efficiency and safety of this strategy by comparing it with conventional ovarian stimulation protocols. DESIGN: Retrospective cohort study. SUBJECTS: Patients with normal ovarian reserve undergoing ovum pick-up (OPU) cycles between April 2012 and September 2013 were enrolled: 708 patients underwent the LPS protocol compared with 745 patients who underwent the mild treatment protocol and 1287 patients who underwent the short-term protocol. MEASUREMENTS: Number of mature oocytes retrieved and top-quality embryos obtained, implantation rate, pregnancy rate, live birth and ongoing pregnancy rate and neonatal outcomes. RESULTS: The numbers of mature oocytes retrieved and top-quality embryos obtained per OPU cycle were significantly increased in the LPS group (10.9 +/- 7.6 and 4.6 +/- 4.3, respectively) compared with the mild treatment group (3.7 +/- 3.0 and 1.8 +/- 1.8, respectively, both P < 0.001) or the short-term group (9.1 +/- 5.5 and 3.7 +/- 3.1, respectively, both P < 0.001). Moreover, the total gonadotrophin used was also the highest in the LPS group. No significant differences were identified in the implantation rate (35.5% vs 34.8%, P > 0.05), pregnancy rate (46.2% vs 43.7%, P > 0.05) or live birth and ongoing pregnancy rate (44.4% vs 41.7%, P > 0.05) per frozen-thawed embryo transfer (FET) cycle in the LPS and mild treatment groups, respectively. However, the LPS protocol achieved a higher implantation rate (35.5% vs 31.8%, P = 0.012), pregnancy rate (46.2% vs 41.9%, P = 0.041), and live birth and ongoing pregnancy rate (44.4% vs 39.2%, P = 0.012) compared with the short-term protocol. Neonatal outcomes in the LPS group were similar to the other two groups. CONCLUSIONS: The available data suggest that LPS is a feasible strategy for infertility treatment and complements the available follicular-phase ovarian stimulation strategies. PMID- 26603822 TI - Some Non-FDA Approved Uses for Neuromodulation: A Review of the Evidence. AB - INTRODUCTION: Neuromodulation, including spinal cord stimulation and peripheral nerve field stimulation, has been used with success in treating several painful conditions. The FDA approved the use of neuromodulation for a few indications. We review evidence for neuromodulation in treating some important painful conditions that are not currently FDA approved. METHODS: This review included an online web search for only clinical trials testing the efficacy of neuromodulation in treating coronary artery disease, peripheral vascular disease (PVD), headache, and peripheral field stimulation. RESULTS: Our systematic literature search found 10, 6, and 3 controlled studies relating to coronary artery disease, PVD, and headache, respectively. Our review also included 5 noncontrolled studies relating to peripheral field stimulation, as no controlled studies had been completed. CONCLUSION: This review article shows compelling evidence based on clinical trials that neuromodulation can be of benefit for patients with serious painful conditions that are not currently approved by the FDA. PMID- 26603823 TI - Assessment of canine autologous platelet-rich plasma produced with a commercial centrifugation and platelet recovery kit. AB - OBJECTIVES: To characterize the cellular composition (platelets, erythrocytes, and leukocytes) and confirm reproducibility of platelet enrichment, as well as determine the platelet activation status in the final product of a commercial platelet-rich plasma kit using canine blood. METHODS: Venous blood from 20 sedated client-owned dogs was used to prepare platelet-rich plasma (PRP) from a commercial kit. Complete blood counts were performed to determine erythrocyte, leukocyte, and platelet numbers in both whole blood (WB) and resultant PRP. The WB and PRP samples from jugular (fast collection) and cephalic (slow collection) venipuncture were also compared. P-selectin externalization was measured in WB and PRP samples from 15 of 20 dogs. RESULTS: This commercial kit produced an average percent recovery in platelets of 64.7 +/- 17.4; erythrocytes of 3.7 +/- 0.8, and leukocytes of 31.6 +/- 10.0. Neutrophil, monocyte, and lymphocyte percent recovery was 19.6 +/- 7.2, 44.89 +/- 19.8, and 57.5 +/- 10.6, respectively. The recovery of platelets from jugular venipuncture (59.7 +/- 13.6%) was lower than from cephalic recovery (68.8 +/- 19.1%). The mean percent P Selectin externalization for WB, PRP, and PRP with thrombin was 25.5 +/- 30.9, 4.5 +/- 6.4, and 90.6 +/- 4.4 respectively. CLINICAL SIGNIFICANCE: Cellular reproducibility of this kit was confirmed and platelets were concentrated within autologous serum. Additionally, measurements of P-selectin externalization showed that platelets are inactive in PRP unless stimulated to degranulate. PMID- 26603824 TI - Comparative Magnetic Resonance Imaging Study of Cross-Sectional Area of Anatomic Double Bundle Anterior Cruciate Ligament Reconstruction Grafts and the Contralateral Uninjured Knee. AB - PURPOSE: To evaluate the differences between cross-sectional area of the reconstructed graft by 2 anatomic double-bundle anterior cruciate ligament (ACL) reconstruction techniques, transportal and outside-in and contralateral uninjured knee. METHODS: In prospective, randomized controlled trials, magnetic resonance imaging of both the reconstructed anatomic double-bundle ACL graft side and the contralateral uninjured knee of 92 patients (mean age, 34.7 +/- 10.7 years) between November 2010 and January 2013 were compared. The 3-dimensional curved multiplanar reconstruction function of OsiriX v5.6 was used. Cross-sectional area was measured from the femoral insertion site to the tibial insertion site at 5 different locations, including the midsubstance. RESULTS: A significant difference was observed between areas of the uninjured side and reconstructed side at the 5 locations. The area of the reconstructed graft at the femoral insertion site (64 +/- 13 mm(2)) and midsubstance (62 +/- 11 mm(2)) was larger that of the normal ACL (femoral insertion site; 60 +/- 13 mm(2), P = .005 and midsubstance; 47 +/- 13 mm(2), P = .0001), whereas at the tibial insertion site (71 +/- 13 mm(2)) it was smaller than normal ACL (97 +/- 22 mm(2), P = .0001). The measured area between the reconstructed graft and normal uninjured side at the femoral insertion site was relatively closer than that at midsubstance and the tibial insertion-site area. CONCLUSIONS: A double-bundle anterior cruciate ligament reconstruction graft relatively closely restored the cross-sectional area of the femoral footprint area but was smaller than that of the tibial footprint area; however, the cross-sectional area of graft was much larger than that of the midsubstance. PMID- 26603825 TI - Alterations in Glenohumeral Kinematics in Patients With Rotator Cuff Tears Measured With Biplane Fluoroscopy. AB - PURPOSE: To quantitatively measure the 3-dimensional (3D) glenohumeral translations during dynamic shoulder abduction in the scapular plane, using a biplane fluoroscopy system, in patients with supraspinatus rotator cuff tears. METHODS: A custom biplane fluoroscopy system was used to measure the 3D position and orientation of the scapula and humerus of 14 patients with full-thickness supraspinatus or supraspinatus and infraspinatus rotator cuff tears and 10 controls as they performed shoulder abduction over their full range of motion. The 3D geometries of the scapula and humerus were extracted from a computed tomography scan of each shoulder. For each frame, the 3D bone position and orientation were estimated using a contour-based matching algorithm, and the 3D position of the humeral head center was determined relative to the glenoid. For each subject the superior-inferior and anterior-posterior translation curves were determined from 20 degrees through 150 degrees of arm elevation. RESULTS: The humeral head in shoulders with rotator cuff tears was positioned significantly inferior compared with controls for higher elevation angles of 80 degrees to 140 degrees (P < .05). For both groups the humeral head translated inferiorly during shoulder abduction from 80 degrees (P = .044; rotator cuff tear v controls: -0.2 +/- 1.3 v 1.2 +/- 1.4 mm) up to 140 degrees (P = .047; rotator cuff tear v controls: -1.3 +/- 2.2 v 0.44 +/- 1.4 mm). There was no significant translation in the anterior- posterior direction. CONCLUSIONS: Patients with well-compensated single or 2-tendon rotator cuff tears show no dynamic superior humeral head migration but unexpectedly show an inferior shift during active elevation. It is unclear whether the size of the translational differences found in this study, while statistically significant, are also of clinical significance. LEVEL OF EVIDENCE: Level III, comparative study. PMID- 26603826 TI - Clinical and Functional Outcome of All-Inside Anterior Cruciate Ligament Reconstruction at a Minimum of 2 Years' Follow-up. AB - PURPOSE: To evaluate the clinical and functional outcomes for anatomic anterior cruciate ligament (ACL) reconstruction using the all-inside technique with a minimum follow-up of 24 months. METHODS: Patients undergoing anatomic ACL reconstruction via the all-inside technique between January 2011 and October 2012 were reviewed for inclusion in this study. Functional outcome measures, including the Lysholm score, International Knee Documentation Committee score, visual analog scale score, and Tegner Activity Scale, were used to evaluate outcomes before surgery and at 3, 6, 12, and > 24 months. At final follow-up, anteroposterior knee stability was assessed with KT-2000 (MEDmetric, San Diego, CA) measurements. RESULTS: Of the 92 patients who underwent primary all-inside ACL reconstruction, 79 patients returned to final follow-up with a minimum of 2 years. There were 53 men and 26 women with a mean age of 29 years (range, 18 to 54 years) and a mean follow-up of 29 months (range, 24 to 45 months). The International Knee Documentation Committee score (44.6 v 89.7, P < .0001), Lysholm score (53.4 v 93.1, P < .001), visual analog scale score (5 v 0.1, P < .001), and Tegner activity score (2 v 6, P < .001) showed a significant improvement between baseline and final clinical follow-up. The mean side-to-side KT-2000 difference at final follow-up was 1.7 mm (range; 0 to 6 mm). Overall 10 patients (12.7%) sustained an ACL graft rerupture after a mean of 17.6 months (range, 6.9 to 28.6 months). CONCLUSIONS: The current data support our first hypothesis that primary anatomic ACL reconstruction using the all-inside technique leads to improved functional outcomes between baseline and clinical follow-up at 24 months. Further, there was no difference in knee stability between the ACL reconstructed- and the contralateral normal knee at 24 months, which confirms our second hypothesis. PMID- 26603827 TI - Coronary Artery Dominance as a Prognostic Factor: In Anterior Myocardial Infarctions as Well? Response. PMID- 26603829 TI - The importance of surgical margins in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a grim prognosis. Surgical resection offers the best chance for long-term survival, yet recurrence rates are high and outcomes are poor. The influence of margin status in PDAC is controversial, as conflicting data have been plagued by a lack of standardization in margin definitions, pathologic analysis, and reporting. Despite recent efforts, international consensus is still needed for this disease. PMID- 26603830 TI - Multimodality Imaging Diagnostic Approach of Systemic-to-Pulmonary Vein Fistulae. AB - A 26-year-old man with a history of bilateral lung transplantation for pulmonary cystic fibrosis 6 months before was admitted in our institution for acute heart failure. Cardiac magnetic resonance imaging (CMR) showed an increased aortic output, as aortic flow assessed by velocity mapping was twofold the pulmonary flow, an occluded superior vena cava (SVC), and enlarged azygos vein. A systemic to-pulmonary vein fistula (SAPVF) was suspected. The selective angiography showed numerous fistulae between intercostals, thyro-cervical, internal mammary arteries and pulmonary veins. The thoracic CT performed before the CMR, which was initially considered as normal, showed well these arteriovenous fistulae after 3D MIP reconstruction. This particular observation highlights the great value of multimodality imaging for the diagnosis of this rare pathology. The MR velocity mapping is a noninvasive imaging technique of great interest to guide the diagnosis of arteriovenous fistulae, and further indicating more invasive complementary imaging modalities like selective arterial angiography. PMID- 26603828 TI - Predictors of duloxetine response in patients with oxaliplatin-induced painful chemotherapy-induced peripheral neuropathy (CIPN): a secondary analysis of randomised controlled trial - CALGB/alliance 170601. AB - Duloxetine is an effective treatment for oxaliplatin-induced painful chemotherapy induced peripheral neuropathy (CIPN). However, predictors of duloxetine response have not been adequately explored. The objective of this secondary and exploratory analysis was to identify predictors of duloxetine response in patients with painful oxaliplatin-induced CIPN. Patients (N = 106) with oxaliplatin-induced painful CIPN were randomised to receive duloxetine or placebo. Eligible patients had chronic CIPN pain and an average neuropathic pain score >=4/10. Duloxetine/placebo dose was 30 mg/day for 7 days, then 60 mg/day for 4 weeks. The Brief Pain Inventory-Short Form and the EORTC QLQ-C30 were used to assess pain and quality of life, respectively. Univariate and multiple logistic regression analyses were performed to identify demographic, physiologic and psychological predictors of duloxetine response. Higher baseline emotional functioning predicted duloxetine response (>=30% reduction in pain; OR 4.036; 95% CI 0.999-16.308; p = 0.050). Based on the results from a multiple logistic regression using patient data from both the duloxetine and placebo treatment arms, duloxetine-treated patients with high emotional functioning are more likely to experience pain reduction (p = 0.026). In patients with painful, oxaliplatin induced CIPN, emotional functioning may also predict duloxetine response. ClinicalTrials.gov, Identifier NCT00489411. PMID- 26603831 TI - Proteomic analyses provide new insights into the responses of Pinus massoniana seedlings to phosphorus deficiency. AB - Phosphorus is an essential macronutrient for plant growth and development. Plants can respond defensively to phosphorus deficiency by modifying their morphology and metabolic pathways via the differential expression of low phosphate responsive genes. To better understand the mechanisms by which the Masson pine (Pinus massoniana) adapts to phosphorus deficiency, we conducted comparative proteomic analysis using an elite line exhibiting high tolerance to phosphorus deficiency. The selected seedlings were treated with 0.5 mM KH2PO4 (control), 0.01 mM KH2PO4 (P1), or 0.06 mM KH2PO4 (P2) for 48 days. Total protein samples were separated via 2DE. A total of 98 differentially expressed proteins, which displayed at least 1.7-fold change expression compared to the control levels (p <= 0.05), were identified by MALDI-TOF/TOF MS. These phosphate starvation responsive proteins were implicated in photosynthesis, defense, cellular organization, biosynthesis, energy metabolism, secondary metabolism, signal transduction etc. Therefore, these proteins might play important roles in facilitating internal phosphorus homeostasis. Additionally, the obtained data may be useful for the further characterization of gene function and may provide a foundation for a more comprehensive understanding of the adaptations of the Masson pine to phosphorus-deficient conditions. PMID- 26603832 TI - A Structuring Repeat for Peptide Design: Long Beta Ribbons. AB - Beta sheets are inherently length-limited; adding residues to the ends of model beta-sheets does not necessarily grow the beta-sheet. Here, we present a method for extending beta-sheets to any length with a stabilizing repeat unit containing cross-strand Trp residues. Beta ribbons as long as 35 residues (approaching 100 A in length) are reported and characterized. PMID- 26603833 TI - Giant Prostatic Hyperplasia: Case Report of 3987 mL. AB - We present herein a 72-year-old male with a long history of mild lower urinary tract symptoms, with a serum prostate-specific antigen level value of 87.9 ng/mL and an estimated prostate size of 3987 mL, according to magnetic resonance imaging. Prostatic biopsies showed benign prostatic hyperplasia. Prostatic surgery has not been required. To the best of our knowledge, this is the highest prostate volume reported in the medical literature. PMID- 26603834 TI - IgG4-related disease manifesting the gastric wall thickening. AB - IgG4-related disease (IgG4-RD) is a recently designated disease entity and its full picture has not yet been elucidated. Here, we report an unusual case of a patient with gastric wall thickening secondary to IgG4-RD. A 68-year-old male visited our hospital with itchy skin lesions and an episode of organizing pneumonia. On the suspicion of malignancy-associated skin lesions, computed tomography (CT) was performed. The CT revealed prominent thickening of the gastric wall. Due to the possibility of malignancy, the patient underwent distal gastrectomy. Histopathological examination showed fibrosis of the submucosa and prominent thickening of the muscularis propria. Most of infiltrating cells were IgG4-positive plasma cells. Post-operative blood test revealed significantly high serum levels of total IgG and IgG4. Based on these histological features, the patient was given a definitive diagnosis of IgG4-RD. Further accumulation of cases like the present case that develop IgG4-RD with rare manifestations would lead to the elucidation of pathogenesis. PMID- 26603835 TI - Hepatic Infiltrates in Operational Tolerant Patients After Liver Transplantation Show Enrichment of Regulatory T Cells Before Proinflammatory Genes Are Downregulated. AB - Immunosuppression can be discontinued from selected and stable patients after liver transplantation resulting in spontaneous operational tolerance (SOT), although the underlying mechanisms remain elusive. Thus, we analyzed serial liver biopsy specimens from adult liver recipients enrolled in a prospective multicenter immunosuppression withdrawal trial that used immunophenotyping and transcriptional profiling. Liver specimens were collected before the initiation of weaning, at the time of rejection, or at 1 and 3 years after complete drug discontinuation. Unexpectedly, the tolerated grafts developed portal tract expansion with increased T cell infiltration after immunosuppression withdrawal. This was associated with transient and preferential accumulation of CD4(+) FOXP3(+) cells and a trend toward upregulation of immune activation and regulatory genes, without signs of rejection. At the same time, no markers of endothelial damage or activation were noted. Portal infiltrates persisted at 3 years but were characterized by decreased expression of genes associated with chronic immunological damage. Further, SOT was not associated with a progressive liver fibrosis up to 5 years. These data suggest that SOT involves several mechanisms: a long-lasting local immune cell persistence with a transient regulatory T cells accumulation followed by a downregulation of immune-activated genes over years. These results have important implications for designs and follow-up of weaning trials. PMID- 26603836 TI - Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas. AB - Aggressive double- and triple-hit (DH/TH) diffuse large B-cell lymphomas (DLBCLs) feature activation of Hsp90 stress pathways. Herein, we show that Hsp90 controls posttranscriptional dynamics of key messenger RNA (mRNA) species including those encoding BCL6, MYC, and BCL2. Using a proteomics approach, we found that Hsp90 binds to and maintains activity of eIF4E. eIF4E drives nuclear export and translation of BCL6, MYC, and BCL2 mRNA. eIF4E RNA-immunoprecipitation sequencing in DLBCL suggests that nuclear eIF4E controls an extended program that includes B cell receptor signaling, cellular metabolism, and epigenetic regulation. Accordingly, eIF4E was required for survival of DLBCL including the most aggressive subtypes, DH/TH lymphomas. Indeed, eIF4E inhibition induces tumor regression in cell line and patient-derived tumorgrafts of TH-DLBCL, even in the presence of elevated Hsp90 activity. Targeting Hsp90 is typically limited by counterregulatory elevation of Hsp70B, which induces resistance to Hsp90 inhibitors. Surprisingly, we identify Hsp70 mRNA as an eIF4E target. In this way, eIF4E inhibition can overcome drug resistance to Hsp90 inhibitors. Accordingly, rational combinatorial inhibition of eIF4E and Hsp90 inhibitors resulted in cooperative antilymphoma activity in DH/TH DLBCL in vitro and in vivo. PMID- 26603837 TI - Kinetics and mechanics of clot contraction are governed by the molecular and cellular composition of the blood. AB - Platelet-driven blood clot contraction (retraction) is thought to promote wound closure and secure hemostasis while preventing vascular occlusion. Notwithstanding its importance, clot contraction remains a poorly understood process, partially because of the lack of methodology to quantify its dynamics and requirements. We used a novel automated optical analyzer to continuously track in vitro changes in the size of contracting clots in whole blood and in variously reconstituted samples. Kinetics of contraction was complemented with dynamic rheometry to characterize the viscoelasticity of contracting clots. This combined approach enabled investigation of the coordinated mechanistic impact of platelets, including nonmuscle myosin II, red blood cells (RBCs), fibrin(ogen), factor XIIIa (FXIIIa), and thrombin on the kinetics and mechanics of the contraction process. Clot contraction is composed of 3 sequential phases, each characterized by a distinct rate constant. Thrombin, Ca(2+), the integrin alphaIIbbeta3, myosin IIa, FXIIIa cross-linking, and platelet count all promote 1 or more phases of the clot contraction process. In contrast, RBCs impair contraction and reduce elasticity, while increasing the overall contractile stress generated by the platelet-fibrin meshwork. A better understanding of the mechanisms by which blood cells, fibrin(ogen), and platelet-fibrin interactions modulate clot contraction may generate novel approaches to reveal and to manage thrombosis and hemostatic disorders. PMID- 26603838 TI - Active IKKbeta promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma. AB - GLI1 oncogene has been implicated in the pathobiology of several neoplasms including diffuse large B-cell lymphoma (DLBCL). However, mechanisms underlying GLI1-increased activity in DLBCL are poorly characterized. Herein, we demonstrate that IKKbeta phosphorylates GLI1 in DLBCL. IKKbeta activation increased GLI1 protein levels and transcriptional activity, whereas IKKbeta silencing decreased GLI1 levels and transcriptional activity. Tumor necrosis factor-alpha (TNFalpha) mediated IKKbeta activation-impaired GLI1 binding with the E3 ubiquitin ligase ITCH, leading to decreased K48-linked ubiquitination/degradation of GLI1. We found 8 IKKbeta-dependent phosphorylation sites that mediate GLI1 stability. Mutating or deleting these residues facilitated GLI1-ITCH interaction and decreased the protective effect of TNFalpha on GLI1 stability. IKKbeta-GLI1 crosstalk is significant because combined inhibition of both molecules resulted in synergistic suppression of DLBCL viability in vivo and in vitro. By linking IKKbeta-mediated nuclear factor-kappaB activity with GLI1, we identified a crosstalk between these 2 pathways that can inform the design of novel therapeutic strategies in DLBCL. PMID- 26603839 TI - Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients. AB - BCR-ABL1 kinase domain mutations can confer resistance to first- and second generation tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). In preclinical studies, clinically achievable concentrations of the third generation BCR-ABL1 TKI ponatinib inhibit T315I and all other single BCR-ABL1 mutants except T315M, which generates a single amino acid exchange, but requires 2 sequential nucleotide exchanges. In addition, certain compound mutants (containing >=2 mutations in cis) confer resistance. Initial analyses based largely on conventional Sanger sequencing (SS) have suggested that the preclinical relationship between BCR-ABL1 mutation status and ponatinib efficacy is generally recapitulated in patients receiving therapy. Thus far, however, such analyses have been limited by the inability of SS to definitively identify compound mutations or mutations representing less than ~20% of total alleles (referred to as "low-level mutations"), as well as limited patient follow-up. Here we used next-generation sequencing (NGS) to define the baseline BCR-ABL1 mutation status of 267 heavily pretreated chronic phase (CP)-CML patients from the PACE trial, and used SS to identify clonally dominant mutants that may have developed on ponatinib therapy (30.1 months median follow-up). Durable cytogenetic and molecular responses were observed irrespective of baseline mutation status and included patients with compound mutations. No single or compound mutation was identified that consistently conferred primary and/or secondary resistance to ponatinib in CP-CML patients. Ponatinib is effective in CP-CML irrespective of baseline mutation status. PMID- 26603841 TI - Correction. PMID- 26603843 TI - Discussion. PMID- 26603842 TI - Living with constant leaking of urine and odour: thematic analysis of socio cultural experiences of women affected by obstetric fistula in rural Tanzania. AB - BACKGROUND: Obstetric fistula is a worldwide problem that affects women and girls mostly in Sub Saharan Africa. It is a devastating medical condition consisting of an abnormal opening between the vagina and the bladder or rectum, resulting from unrelieved obstructed labour. Obstetric fistula has devastating social, economic and psychological effect on the health and wellbeing of the women living with it. This study aimed at exploring social-cultural experiences of women living with obstetric fistula in rural Tanzania. METHODS: Women living with obstetric fistula were identified from the fistula ward at CCBRT hospital. Sixteen individual semi structured interviews and two (2) focus group discussions were conducted among consenting women. Interviews were transcribed verbatim and transcripts analysed independently by two researchers using a thematic analysis approach. Themes related to the experiences of living with obstetric fistula were identified. RESULTS: Four themes illustrating the socio-cultural experiences of women living with obstetric fistula emerged from the analysis of women experiences of living with incontinence and odour. These were keeping clean and neat, earning an income, maintaining marriage, and keeping association. Women experiences of living with fistula were largely influenced by perceptions of people around them basing on their cultural understanding of a woman. CONCLUSION: Living with fistula reveals women's day-to-day experiences of social discrimination and loss of control due to incontinence and odour. They cannot work and contribute to the family income, cannot satisfy their husband's sexual needs and or bear children, and cannot interact with members of the community in social activities. Women experience of living with fistula was influenced by perceptions of people around them. In the eyes of these people, women who leak urine were of less value since they were not capable of carrying out ascribed social roles. PMID- 26603840 TI - The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. AB - Transplant-associated thrombotic microangiopathy (TA-TMA) occurs frequently after hematopoietic stem cell transplantation (HSCT) and can lead to significant morbidity and mortality. There are no data addressing individual susceptibility to TA-TMA. We performed a hypothesis-driven analysis of 17 candidate genes known to play a role in complement activation as part of a prospective study of TMA in HSCT recipients. We examined the functional significance of gene variants by using gene expression profiling. Among 77 patients undergoing genetic testing, 34 had TMA. Sixty-five percent of patients with TMA had genetic variants in at least one gene compared with 9% of patients without TMA (P < .0001). Gene variants were increased in patients of all races with TMA, but nonwhites had more variants than whites (2.5 [range, 0-7] vs 0 [range, 0-2]; P < .0001). Variants in >=3 genes were identified only in nonwhites with TMA and were associated with high mortality (71%). RNA sequencing analysis of pretransplantation samples showed upregulation of multiple complement pathways in patients with TMA who had gene variants, including variants predicted as possibly benign by computer algorithm, compared with those without TMA and without gene variants. Our data reveal important differences in genetic susceptibility to HSCT-associated TMA based on recipient genotype. These data will allow prospective risk assessment and intervention to prevent TMA in highly susceptible transplant recipients. Our findings may explain, at least in part, racial disparities previously reported in transplant recipients and may guide treatment strategies to improve outcomes. PMID- 26603844 TI - Remnant pancreatic parenchymal volume predicts postoperative pancreatic exocrine insufficiency after pancreatectomy. AB - BACKGROUND: Pancreatectomy, including pancreatoduodenectomy and distal pancreatectomy, often causes postoperative pancreatic exocrine insufficiency (PEI). Our aim was to clarify a relationship between remnant pancreatic volume and postoperative PEI. METHODS: A total of 227 patients who underwent pancreatoduodenectomy or distal pancreatectomy were enrolled in this study. All patients underwent a (13)C-labeled mixed triglyceride breath test to assess pancreatic exocrine function and abdominal dynamic computed tomography for assessing remnant pancreatic volume after pancreatectomy at a median of 7 months postoperatively. The percent (13)CO2 cumulative dose at 7 hours (% dose (13)C cum 7 h) < 5% on the (13)C-labeled mixed triglyceride breath test was considered diagnostic of postoperative PEI. Relationships between postoperative PEI and clinicopathologic factors including remnant pancreatic volume were analyzed. RESULTS: Pancreatoduodenectomy and distal pancreatectomy were performed in 174 (76.7%) and 53 (23.3%) patients, respectively. Of the 227 patients, 128 (56.3%) developed postoperative PEI. Postoperative % dose (13)C cum 7 h was strongly correlated with remnant pancreatic volume (r = .509, P < .001). The cut-off value of remnant pancreatic volume for predicting postoperative PEI was 24.1 mL by receiver operating characteristic curve analysis. Multivariate analysis revealed that remnant pancreatic volume < 24.1 mL was the only independent predictive factor for the development of postoperative PEI in patients who underwent pancreatectomy (P < .001, hazard ratio; 5.94, 95% confidence interval; 2.96 12.3). CONCLUSION: Remnant pancreatic volume is associated closely with postoperative PEI after pancreatectomy. Remnant pancreatic volume may predict postoperative PEI in patients who undergo pancreatectomy. PMID- 26603845 TI - Ultrasound-guided radiofrequency ablation of the segmental Glissonian pedicle: A new technique for anatomic liver resection. AB - BACKGROUND: Anatomic liver resection is widely accepted as the optimal surgical treatment for hepatocellular carcinoma (HCC); however, the complexity of conventional operative methods limits their use. To explore the possibility of using modern techniques to achieve a simpler approach, we have evaluated ultrasound-guided segmental radiofrequency ablation (RFA) of the Glissonian pedicle before liver resection in a porcine model and in HCC patients. METHODS: This study had 2 stages. First, we piloted anatomic liver resection using ultrasound-guided RFA of the segmental Glissonian pedicle in 6 Bama miniature pigs. Having found this technique safe and effective, we selected 21 HCC patients to treat with the same approach. RESULTS: The pigs had no postoperative mortality or morbidity. Demarcation areas were apparent in all targeted segments. The mean length of segmental portal, arterial, and biliary tract branches ablated was 1.7, 1.4, and 1.6 cm, respectively. Human HCC operations consisted of 8 subsegmentectomies, 8 segmentectomies, and 5 multisegmentectomies. The procedure was feasible in all patients, with no mortality, morbidity, or need for blood transfusions. A demarcation area was apparent in all patients within 157 seconds of RF application for each target feeding vessel. The mean number of target feeding vessels was 2 (range, 1-7). CONCLUSION: Our study demonstrates that ultrasound-guided RFA ablation of the segmental Glissonian pedicle is expedient, safe, and effective, and is suitable for resection of any hepatic segments or subsegments, from segments 2 to 8. PMID- 26603846 TI - Continuous infusion of octreotide combined with perioperative octreotide bolus does not prevent intraoperative carcinoid crisis. AB - BACKGROUND: Operations and anesthesia in carcinoid patients can provoke carcinoid crises, which can have serious sequelae, including death. Prophylactic octreotide is recommended to prevent crises. Recommended prophylaxis regimens vary from octreotide long-acting repeatable to preoperative bolus to continuous octreotide infusion; however, efficacy data are lacking. We have shown previously that crises correlated with major complications and that octreotide long-acting repeatable and preoperative bolus failed to prevent crises. This study examines the impact of continuous octreotide infusion. METHODS: A total of 127 patients (71% with liver metastases, 74% with carcinoid syndrome) who underwent 150 operations with continuous octreotide infusions were enrolled in this prospective case series. Our main outcome measures were the occurrence of intraoperative carcinoid crises and post-operative complications. RESULTS: Crises occurred at a rate of 30% as compared with 24% in our previous series, which examined the impact of preoperative octreotide bolus. Crises were significantly associated with the presence of hepatic metastases (P = .02) or history of carcinoid syndrome (P = .006), although neither was required for crises. Prompt vasopressor treatment shortened the mean duration of hypotension to 8.7 minutes, compared with 19 minutes in our prior series. Crises no longer correlated with major complications (P = .481) unless instability persisted for greater than 10 minutes (P = .011). CONCLUSION: Octreotide infusions do not prevent intraoperative crises. Patients without liver metastases or carcinoid syndrome can have intraoperative crises. Postoperative complications can be decreased by reducing the duration of crises. Further study is needed to determine how best to shorten hemodynamic instability during crises. PMID- 26603847 TI - Postoperative pancreatic fistula: We need to redefine grades B and C. AB - BACKGROUND: Postoperative pancreatic fistula (POPF) is the most important complication after pancreatic surgery. In 2005, the International Study Group of Pancreatic Surgery (ISGPS) introduced a standardized POPF definition with severity grading from A to C. In recent years, interventional drainage (ID) has become the standard of care for symptomatic postoperative fluid collections or undrained POPF. From the original definition, it is unclear whether ID is categorized as POPF grade B or C. Therefore, international authors shift ID between grades B and C. The aim of the study was to analyze patients with ID (proposed new grade B) versus patients who underwent reoperation (grade C) for POPF. METHODS: Between 2005 and 2013, all patients undergoing pancreatic resection were analyzed regarding POPF grade A-C. Demographic data, type of operation, postoperative complications, therapies and outcome were examined with focus on ID versus reoperation. RESULTS: Of the 2,955 patients included, 403 developed POPF (13.6%). Among all POPF, 11% were grade A, 17% grade B (clinically symptomatic without ID), and 72% grade C. These patients underwent either ID (n = 165) or reoperation (n = 123). Patients with ID had an average hospital stay of 33 days and POPF-associated mortality of 0%. This was strikingly different from patients undergoing reoperation with a hospital stay of 47 days and POPF associated mortality of 37% (P < .0001). CONCLUSION: After 10 years of the ISGPS classification, there is a clear-cut outcome difference between patients undergoing POPF-associated ID or reoperation. We propose assigning all patients undergoing ID as POPF grade B. Patients undergoing reoperation should definitely remain within category C. PMID- 26603848 TI - Helicopter transport improves survival following injury in the absence of a time saving advantage. AB - BACKGROUND: Although survival benefits have been shown at the population level, it remains unclear what drives the outcome benefits for helicopter emergency medical services (HEMS) in trauma. Although speed is often cited as the vital factor of HEMS, we hypothesized a survival benefit would exist in the absence of a time savings over ground emergency medical services (GEMS). The objective was to examine the association of survival with HEMS compared with GEMS transport across similar prehospital transport times. METHODS: We used a retrospective cohort of scene HEMS and GEMS transports in the National Trauma Databank (2007 2012). Propensity score matching was used to match HEMS and GEMS subjects on the likelihood of HEMS transport. Subjects were stratified by prehospital transport times in 5-minute increments. Conditional logistic regression determined the association of HEMS with survival across prehospital transport times strata controlling for confounders. Transport distance was estimated from prehospital transport times and average HEMS/GEMS transport speeds. RESULTS: There were 155,691 HEMS/GEMS pairs matched. HEMS had a survival benefit over GEMS for prehospital transport times between 6 and 30 minutes. This benefit ranged from a 46% increase in odds of survival between 26 and 30 minutes (adjusted odds ratio [AOR], 1.46; 95% CI, 1.11-1.93; P < .01) to an 80% increase in odds of survival between 16 and 20 minutes (AOR, 1.80; 95% CI, 1.51-2.14; P < .01). This prehospital transport times window corresponds to estimated transport distance between 14.3 and 71.3 miles for HEMS and 3.3 and 16.6 miles for GEMS. CONCLUSION: When stratified by prehospital transport times, HEMS had a survival benefit concentrated in a window between 6 and 30 minutes. Because there was no time savings advantage for HEMS, these findings may reflect care delivered by HEMS providers. PMID- 26603849 TI - Impact of the preoperative quantity and quality of skeletal muscle on outcomes after resection of extrahepatic biliary malignancies. AB - BACKGROUND: Skeletal muscle depletion, referred to as sarcopenia, predicts mortality after major surgery. This study investigated the impact of preoperative skeletal muscle quantity and quality on outcomes in patients undergoing resection of extrahepatic biliary cancer. METHODS: We performed a retrospective analysis of 207 patients undergoing resection for biliary cancer between 2004 and 2013. The quantity and quality of skeletal muscle, indicated by the psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC), were measured on preoperative images of computed tomography. Overall survival (OS) and recurrence free survival (RFS) rates were compared by PMI and IMAC, and prognostic factors after operation were assessed. RESULTS: The OS and RFS rates were less in patients with low PMI (low muscle quantity) than in those with normal PMI (P < .001 and P < .001; 5-year OS, 15.7 vs 53.5%). The OS and RFS rates were also less in patients with high IMAC (low muscle quality) than in those with normal IMAC (P < .001 and P < .001; 5-year OS, 23.8 vs 55.9%). Low PMI and high IMAC were independent factors predictive of poor OS (hazard ratio [HR], 2.921 [95% CI, 1.920-4.470; P < .001] and HR, 1.725 [95% CI, 1.159-2.590; P = .007]) and RFS (HR, 2.141 [95% CI, 1.464-3.129, P < .001] and HR, 1.492 [95% CI, 1.032-2.166, P = .034]). CONCLUSION: Preoperative sarcopenia, indicating a low quantity and quality of skeletal muscle, is related closely to mortality after resection of biliary cancer. PMID- 26603850 TI - Parathyroidectomy is underused in patients with tertiary hyperparathyroidism after renal transplantation. AB - BACKGROUND: Parathyroidectomy (PTX) is the only curative treatment for tertiary hyperparathyroidism (3HPT). With the introduction of calcimimetics (cinacalcet), PTX can sometimes be delayed or avoided. The purpose of this study was to determine the current incidence of utilization of PTX in patients with posttransplant 3HPT with the advent of cinacalcet. METHODS: We evaluated renal transplant patients between January 1, 2004, and June 30, 2012, with a minimum of 24 months follow-up who had persistent allograft function. Patients with an increased serum level of parathyroid hormone (PTH) at 1 year after successful renal transplantation with normocalcemia or hypercalcemia were defined as having 3HPT. A multivariate logistic regression model was constructed to determine factors associated with undergoing PTX. RESULTS: We identified 618 patients with 3HPT, only 41 (6.6%) of whom underwent PTX. Patients with higher levels of serum calcium (P < .001) and PTH (P = .002) posttransplant were more likely to be referred for PTX. Importantly, those who underwent PTX had serum calcium and PTH values distributed more closely to the normal range on most recent follow-up. PTX was not associated with rejection (P = .400) or with worsened allograft function (P = .163). CONCLUSION: PTX seems to be underused in patients with 3HPT at our institution. PTX is associated with high cure rates, improved serum calcium and PTH levels, and is not associated with rejection. PMID- 26603851 TI - Discussion. PMID- 26603853 TI - Impact of vocal cord ultrasonography on endocrine surgery practices. AB - BACKGROUND: It is common practice to perform flexible laryngoscopy (FL) to ensure true vocal cord (TVC) mobility in patients with previous neck operations or patients with suspected VC dysfunction. Vocal cord ultrasonography (VCUS) is accurate in identifying TVC paralysis. The goal of this study is to evaluate the impact of VCUS as the initial study to confirm TVC mobility in patients requiring preoperative FL. METHODS: A total of 194 consecutive patients with indications for preoperative FL underwent VCUS. In group 1, 52 patients had FL regardless of the results of VCUS, whereas in group 2, 142 patients had VCUS followed by FL only when VCUS was unsatisfactory. RESULTS: VCUS visualized TVC/arytenoids in 164 of 194 (85%) patients. TVC visualization was more common in women (95%) and in patients without thyroid cartilage calcification (92%) (P < .0005). VCUS predicted all paralyzed TVC. In group 2, 76% of patients had adequate VCUS and avoided preoperative FL. Among 24% of patients in whom VCUS was inadequate, 16 had preoperative FL attributable to a lack of TVC visualization, 6 had abnormal TVC mobility, 11 needed additional confirmations, and 2 had previous FL for another reason. CONCLUSION: VCUS changed surgeon practices by avoiding the need for preoperative FL in the majority of patients. This noninvasive and sensitive method demonstrates TVC mobility and safely precludes preoperative FL in most patients. PMID- 26603852 TI - Integrating "big data" into surgical practice. AB - 'Big data' is the next frontier of medicine. We now have the ability to generate and analyze large quantities of healthcare data. Although interpreting and integrating this information into clinical practice poses many challenges, the potential benefits of personalized medicine are seemingly without limit. PMID- 26603854 TI - Association of perioperative transfusion with outcomes after amputation. PMID- 26603855 TI - Discussion. PMID- 26603856 TI - Degradable Magnetic Composites for Minimally Invasive Interventions: Device Fabrication, Targeted Drug Delivery, and Cytotoxicity Tests. AB - Superparamagnetic nanoparticles and a functional, degradable polymer matrix based on poly(ethylene glycol) are combined to enable fully degradable magnetic microdevices for minimally invasive biomedical applications. A bioinspired helical microrobot platform mimicking Escherichia coli bacteria is fabricated and actuated using weak rotating magnetic fields. Locomotion based on corkscrew propulsion, targeted drug delivery, and low-degradation-product cytotoxicity are demonstrated. PMID- 26603857 TI - ALK-rearranged squamous cell lung carcinoma responding to crizotinib: A missing link in the field of non-small cell lung cancer? AB - ALK-rearrangements are mainly encountered in lung adenocarcinomas and allow treating patients with anti-ALK targeted therapy. ALK-rearranged squamous cell lung carcinomas are rare tumors that can also respond to anti-ALK-targeted therapy. Nevertheless, ALK screening is not always performed in patients with squamous cell lung carcinomas making the identification and treatment of this molecular tumor subtype challenging. We intend to report a rare case of ALK rearranged lung squamous cell carcinoma with response to crizotinib therapy. We report clinical, pathological, immunohistochemical and fluorescent in situ hybridization data concerning a patient having an ALK-rearranged squamous cell lung cancer diagnosed in our institution. The patient was a 58-year old woman with a metastatic-stage lung cancer. Histopathological and immunohistochemical analyses were performed on a bronchial biopsy sample and concluded in a non keratinizing squamous cell lung carcinoma expressing strongly cytokeratin 5/6, p63 and p40, which are classic hallmarks of lung squamous cell carcinomas, but also cytokeratin 7 which is more commonly expressed in lung adenocarcinomas. The tumor did not express thyroid transcription factor-1. ALK rearrangement was searched because of the never-smoker status of the patient and resulted in strong positive fluorescent in situ hybridization test and ALK/p80 immunohistochemistry. The patient responded to crizotinib therapy during 213 days. Our observation points out the interest of considering ALK screening in patients with metastatic lung squamous cell carcinomas, especially in patients lacking a usual heavy smoker clinical history. The histopathological and immunohistochemical features of this particular tumor highlighting the overlapping criteria between lung adenocarcinomas and rare ALK-rearranged squamous cell lung carcinomas could also be relevant to extend ALK screening to tumors with intermediate phenotypes between squamous cell carcinomas and adenocarcinomas and/or arising in non smokers. PMID- 26603859 TI - Turn-taking, timing, and planning in early language acquisition. AB - Young children answer questions with longer delays than adults do, and they don't reach typical adult response times until several years later. We hypothesized that this prolonged pattern of delay in children's timing results from competing demands: to give an answer, children must understand a question while simultaneously planning and initiating their response. Even as children get older and more efficient in this process, the demands on them increase because their verbal responses become more complex. We analyzed conversational question-answer sequences between caregivers and their children from ages 1;8 to 3;5, finding that children (1) initiate simple answers more quickly than complex ones, (2) initiate simple answers quickly from an early age, and (3) initiate complex answers more quickly as they grow older. Our results suggest that children aim to respond quickly from the start, improving on earlier-acquired answer types while they begin to practice later-acquired, slower ones. PMID- 26603860 TI - Editorial. PMID- 26603858 TI - Secondary bacterial symbiont community in aphids responds to plant diversity. AB - Biodiversity is important for ecosystem functioning and biotic interactions. In experimental grasslands, increasing plant species richness is known to increase the diversity of associated herbivores and their predators. If these interactions can also involve endosymbionts that reside within a plant or animal host is currently unknown. In plant-feeding aphids, secondary bacterial symbionts can have strong fitness effects on the host, e.g. resistance to natural enemies or fungal pathogens. We examined the secondary symbiont community in three species of aphid, each feeding on a unique host plant across experimental plots that varied in plant species richness. Aphids were collected in May and June, and the symbiont community identified using species-specific PCR assays. Aphis fabae aphids were found to host six different symbiont species with individual aphids co-hosting up to four symbionts. Uroleucon jaceae and Macrosiphum rosae hosted two and three symbiont species, respectively. We found that, at the aphid population level, increasing plant species richness increased the diversity of the aphid symbiont community, whereas at the individual aphid level, the opposite was found. These effects are potentially driven by varying selective pressures across different plant communities of varying diversities, mediated by defensive protection responses and a changing cost-benefit trade-off to the aphid for hosting multiple secondary symbionts. Our work extends documented effects of plant diversity beyond visible biotic interactions to changes in endosymbiont communities, with potentially far-reaching consequences to related ecosystem processes. PMID- 26603861 TI - Pax genes: Master regulators of development and tissue homeostasis. PMID- 26603862 TI - Combined retrograde-antegrade arterial wiring: Peroneal artery can be a bridge to cross infrapopliteal Trans Atlantic Inter Society Consensus D lesions. AB - BACKGROUND: Percutaneous transluminal angioplasty of complex infrapopliteal lesions might be a true and complex challenge. Success rates remain suboptimal when employing standard approaches. Thus, recanalization techniques for infrapopliteal disease remain a seat of continuous evolution. AIM OF THE STUDY: We report our results of Trans Atlantic Inter Society Consensus D infrapopliteal disease recanalization using combined antegrade-retrograde approach through peroneal artery branches. PATIENTS AND METHODS: A total of 27 patients with infrapopliteal Trans Atlantic Inter Society Consensus D lesions underwent recanalization of at least one of the tibial arteries by combined retrograde antegrade route using the peroneal artery normal anastomosis channels. RESULTS: Technical success was achieved in 22 patients who were followed for 6-24 months. Healing of ischemic ulcers or spontaneous separation of ischemic gangrenous patches in 13 patients. Minor amputation in nine patients. No major amputation in the follow-up period. CONCLUSION: Although demanding, the technique can be reserved for selected cases with failed antegrade recanalization. This technique is valuable when a proximal occlusion is not crossable, when a dissection flap or a perforation in the proximal portion of a target vessel hinders guide-wire advancement. This technique may represent a feasible endovascular option to avoid second distal puncture exhausting the landing zone of a future distal bypass. PMID- 26603863 TI - Results of isolated infrapopliteal percutaneous transluminal angioplasty for critical limb ischemia in high-risk diabetic patients. AB - AIM: Infrapopliteal occlusive arterial lesions mostly characterize diabetic patients arteriopathy. Diabetic patients are prone to multiple comorbidities that make them candidates for low-invasive therapeutic options. The aim of this study was to evaluate the safety of infrapopliteal angioplasty in high-risk diabetic patients. METHODS: We undertook a study (retrospective study of a prospectively collected database) of all infrapopliteal endovascular revascularizations performed for critical limb ischemia in high-risk (>=3 major comorbidities) diabetic patients in our institution between 2008 and 2010. Study end points were safety, technical success rate, healing rate, overall 1-year survival, primary patency, secondary patency and limb salvage rates. RESULTS: A total of 101 high risk diabetic patients (160 arterial lesions: 94 stenosis and 66 occlusions) underwent infrapopliteal endovascular surgery. No major adverse cardiovascular or cerebrovascular event was recorded within 30 days. Two major adverse limb events (two thromboses requiring major amputation) and seven minor adverse events were recorded. Technical and healing rates were, respectively, 83% and 78%. The 1-year survival, primary patency, secondary patency and limb salvage rates were, respectively, 86%, 67%, 83% and 84%. CONCLUSION: Infrapopliteal angioplasty can be considered as a safe and feasible option for high-risk diabetic patients with critical limb ischemia. PMID- 26603864 TI - Stent failure due to simultaneous aggressive neoatherosclerosis of first- and current-generation drug-eluting stents. PMID- 26603865 TI - A very late thrombosis in a bioresorbable vascular scaffold. PMID- 26603866 TI - Neonatal tricuspid stenosis caused by device closure of a large coronary fistula. PMID- 26603867 TI - Impact of CT-guided balloon pulmonary angioplasty with identification of pulmonary arterial structures distal to target lesions. PMID- 26603868 TI - An atypical clinical presentation of a broken guidewire left in the venous system. PMID- 26603869 TI - Wealth index and risk of childhood overweight and obesity: evidence from four prospective cohorts in Peru and Vietnam. AB - OBJECTIVES: To estimate the incidence and risk of childhood overweight and obesity according to socioeconomic status in Peruvian and Vietnamese school-aged children. METHODS: Longitudinal data from the Young Lives study were analyzed. Exposure was wealth index in tertiles. Outcome was overweight and obesity. Cumulative incidence per 100 children-years, relative risks (RR), and 95 % confidence intervals (95 % CI) were calculated. A hierarchical approach, including child- and family-related variables, was followed to construct multivariable models. RESULTS: The cumulative incidence of overweight and obesity was 4.8 (95 % CI 4.1-5.5) and 1.7 (95 % CI 1.3-2.2) in the younger and older Peruvian cohort, respectively; and in Vietnam 1.5 (95 % CI 1.2-1.8) and 0.3 (95 % CI 0.2-0.5), respectively. The incidence of overweight and obesity was higher at the top wealth index tertile in all samples. In the older cohorts, comparing highest versus bottom wealth index tertile, RR of overweight and obesity was four to nine times higher: 4.25 in Peru (95 % CI 2.21-8.18) and 9.11 in Vietnam (95 % CI 1.07-77.42). CONCLUSIONS: The results provide important information for childhood obesity prevention in countries moving ahead with economic, epidemiological and nutritional transitions. PMID- 26603870 TI - Erratum to: Quantitative assessment of background parenchymal enhancement in breast MRI predicts response to risk-reducing salpingo-oophorectomy: preliminary evaluation in a cohort of BRCA1/2 mutation carriers. PMID- 26603871 TI - Serum cardiac troponin T and effective blood flow in stable extracorporeal dialysis patients. AB - PURPOSE: We examined the association between extracorporeal dialysis (ED)-related effective blood flow (eQB) and serum cardiac troponin T (cTnT) as a possible indicator of silent myocardial damage in stable ED patients. METHODS: In a cross sectional study, cTnT was determined in 247 ED patients dialyzed using stable eQB and dialysate flow (QD). In a prospective study, 91 patients were switched from low-flux (LF) to high-flux (HF) hemodialysis (HD), and subsequently, the eQB increased, and the QD decreased; 65 patients continued LF-HD with stable eQB and QD. Clinical/laboratory evaluations were performed at 0, 15, 36, and 53 weeks from the start of the study. RESULTS: In the cross-sectional study, the main cTnT predictors were dialysis vintage, age, eQB, phosphorus, and C-reactive protein. Patients with cTnT levels in the highest quartile were excluded from the analysis, and subjects dialyzed with eQB <=316 ml/min exhibited lower cTnT levels compared with patients dialyzed with higher eQB (P = 0.002). The all-cause and cardiac mortality rates of 154 patients, without changes in ED modality for up to 42 months, were associated with the initial cTnT concentrations but not with the initial eQB. In the prospective study, higher values for eQB and cTnT were observed during HF-HD at weeks 36 (P = 0.045) and 53 (P = 0.01) of the present study. The initial cTnT, ?eQB, and ?albumin influenced the ?cTnT. The all-cause and cardiac mortality rates were not different between LF and HF groups at 21 months after the prospective study was completed. CONCLUSION: In stable ED patients, higher eQB rates and QB/QD values might contribute to silent myocardial injury, particularly in patients with lower cTnT levels, but do not affect the outcome of ED patients. PMID- 26603872 TI - In vivo loads on a vertebral body replacement during different lifting techniques. AB - The repeated lifting of heavy weights has been identified as a risk factor for low back pain (LBP). Whether squat lifting leads to lower spinal loads than stoop lifting and whether lifting a weight laterally results in smaller forces than lifting the same weight in front of the body remain matters of debate. Instrumented vertebral body replacements (VBRs) were used to measure the in vivo load in the lumbar spine in three patients at level L1 and in one patient at level L3. Stoop lifting and squat lifting were compared in 17 measuring sessions, in which both techniques were performed a total of 104 times. The trunk inclination and amount of knee bending were simultaneously estimated from recorded images. Compared with the aforementioned lifting tasks, the patients additionally lifted a weight laterally with one hand 26 times. Only a small difference (4%) in the measured resultant force was observed between stoop lifting and squat lifting, although the knee-bending angle (stoop 10 degrees , squat 45 degrees ) and trunk inclination (stoop 52 degrees , squat 39 degrees ) differed considerably at the time points of maximal resultant forces. Lifting a weight laterally caused 14% less implant force on average than lifting the same weight in front of the body. The current in vivo biomechanical study does not provide evidence that spinal loads differ substantially between stoop and squat lifting. The anterior-posterior position of the lifted weight relative to the spine appears to be crucial for spinal loading. PMID- 26603873 TI - Mepolizumab: First Global Approval. AB - Mepolizumab (Nucala((r))) is a fully humanized monoclonal antibody against interleukin-5 (IL-5) that is being developed by GlaxoSmithKline. Subcutaneous mepolizumab is approved in the USA for the add-on maintenance treatment of patients aged >=12 years with severe asthma and an eosinophilic phenotype, and is awaiting approval in the EU. Mepolizumab blocks IL-5 and reduces blood and sputum eosinophil counts in patients with asthma. In the phase III MENSA trial in patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high-dose inhaled glucocorticoid therapy, mepolizumab significantly reduced the annualized exacerbation rate. In the phase III SIRIUS trial, mepolizumab had an oral glucocorticoid-sparing effect in patients with severe eosinophilic asthma requiring systemic glucocorticoid maintenance therapy. This article summarizes the milestones in the development of mepolizumab leading to this first approval for severe asthma with an eosinophilic phenotype. PMID- 26603875 TI - The Challenges of Interstitial Cystitis: Current Status and Future Prospects. AB - Interstitial cystitis/bladder pain syndrome (IC/BPS) is a syndrome of unpleasant bladder sensations and lower urinary tract symptoms. The three main proposed etiologies are bladder urothelial dysfunction, bladder inflammation (possible neurogenic), and neuropathic pain. Despite decades of basic and clinical research, IC/BPS remains difficult to treat. A variety of treatments are used, each aimed towards one etiology. For example, glycosaminoglycans are thought to improve the urothelial permeability barrier, anti-inflammatory agents are used to decrease general inflammation, and mast cell stabilizers and/or antagonists of mast cell products are used in the treatment of neurogenic inflammation. In the (unfortunately frequent) event that a treatment fails, possible reasons are that (1) the clinician is aiming towards the wrong etiology for that patient (i.e., the treatment is off target) or (2) the correct etiology is being targeted, but the treatment is not ameliorating it (i.e., the treatment is sub-therapeutic). This is a crucial distinction, because an off-target treatment should be abandoned, but a sub-therapeutic treatment should be escalated. Currently, our inability to make this crucial distinction is the greatest obstacle to effective treatment. An important future advance would be to identify urine or serum biomarkers specific to each etiologic target. Then, each biomarker could be used to select appropriate patients for each treatment and monitor the treatment's effect on its intended target. PMID- 26603876 TI - Assessment of selenium nutritional status of school-age children from rural areas of China in 2002 and 2012. AB - BACKGROUND/OBJECTIVES: To assess the selenium nutritional status of 3458 school age children recruited from rural areas using the China Nutrition and Health Survey 2002 and 2012 (CNHS 2002 and CNHS 2012). SUBJECTS/METHODS: The serum selenium concentration was determined by high-resolution inductively coupled plasma mass spectrometry. The prevalence of dietary selenium intake insufficiency was calculated according to the formula suggested by and the estimated average requirements of the new Chinese Dietary Reference Intakes. The percentage of low selenium was based on the cutoff values with a serum selenium concentration below the threshold limit of clinical importance in coronary and cardiovascular diseases (<45 MUg/l) and in abnormal physiological functions (<60 MUg/l). RESULTS: The overall median serum selenium concentration was 64.3 MUg/l in the CNHS 2002 and 74.2 MUg/l in the CNHS 2012. The median calculated dietary selenium intake was 26.7 MUg/day in the CNHS 2002 and 33.2 MUg/day in the CNHS 2012 together with a 61.1% and 52.8% dietary selenium intake insufficiency in the CNHS 2002 and in the CNHS 2012. In addition, the percentages of low selenium (<45 MUg/l and <60 MUg/l) were 25.1 and 43.8% in the CNHS 2002 but 9.4 and 25.6% in the CHNS 2012. CONCLUSIONS: The selenium nutritional status of school-age children was significantly improved in the CNHS 2012 versus the CNHS 2002. However, the health risk for selenium malnutrition in school-age children remains a potential problem affecting children's health. PMID- 26603874 TI - Lipoglycopeptide Antibacterial Agents in Gram-Positive Infections: A Comparative Review. AB - Oritavancin, telavancin, and dalbavancin are recently marketed lipoglycopeptides that exhibit remarkable differences to conventional molecules. While dalbavancin inhibits the late stages of peptidoglycan synthesis by mainly impairing transglycosylase activity, oritavancin and telavancin anchor in the bacterial membrane by the lipophilic side chain linked to their disaccharidic moiety, disrupting membrane integrity and causing bacteriolysis. Oritavancin keeps activity against vancomycin-resistant enterocococci, being a stronger inhibitor of transpeptidase than of transglycosylase activity. These molecules have potent activity against Gram-positive organisms, most notably staphylococci (including methicillin-resistant Staphylococcus aureus and to some extent vancomycin intermediate S. aureus), streptococci (including multidrug-resistant pneumococci), and Clostridia. All agents are indicated for the treatment of acute bacterial skin and skin structure infections, and telavancin, for hospital acquired and ventilator-associated bacterial pneumonia. While telavancin is administered daily at 10 mg/kg, the remarkably long half-lives of oritavancin and dalbavancin allow for infrequent dosing (single dose of 1200 mg for oritavancin and 1000 mg at day 1 followed by 500 mg at day 8 for dalbavancin), which could be exploited in the future for outpatient therapy. Among possible safety issues evidenced during clinical development were an increased risk of developing osteomyelitis with oritavancin; taste disturbance, nephrotoxicity, and risk of corrected QT interval prolongation (especially in the presence of at-risk co medications) with telavancin; and elevation of hepatic enzymes with dalbavancin. Interference with coagulation tests has been reported with oritavancin and telavancin. These drugs proved non-inferior to conventional treatments in clinical trials but their advantages may be better evidenced upon future evaluation in more severe infections. PMID- 26603878 TI - Association between bariatric surgery and quality of life. PMID- 26603877 TI - High respiratory quotient is associated with increases in body weight and fat mass in young adults. AB - BACKGROUND/OBJECTIVES: Metabolic disturbances, such as reduced rates of fat oxidation (high respiratory quotient (RQ)) or low energy expenditure (low resting metabolic rate (RMR)), may contribute to obesity. The objective was to determine the association between a high RQ or a low RMR and changes in body weight and body composition over 1 year. SUBJECTS/METHODS: We measured RQ and RMR in 341 adults using indirect calorimetry, along with body weight/body composition using dual-energy X-ray absorptiometery, energy expenditure using an arm-based activity monitor and energy intake using dietary recalls. Participants were classified into low, moderate or high RQ and RMR (adjusted for age, sex, race and body composition) groups according to tertiles by sex. Follow-up measurements were completed every 3 months. RESULTS: Individuals with a high RQ had larger gains in body weight and fat mass compared with individuals with a low/moderate RQ at month 3, and increases in fat mass were more than double among individuals with a high RQ at 12 months (1.3+/-3.0 vs 0.6+/-3.7 kg, P=0.03). Individuals with a low RMR did not gain more body weight nor fat mass compared with individuals with a moderate/high RMR. CONCLUSION: The primary finding is a high RQ is predictive of gains in body weight and fat mass over a 12-month period among young adults, with changes occurring as soon as 3 months. In addition, a low RMR was not associated with gains in body weight or fat mass over the same period. PMID- 26603879 TI - Malnutrition, functional ability and mortality among older people aged ? 60 years: a 7-year longitudinal study. AB - BACKGROUND/OBJECTIVES: This study aimed to assess the association between risk of malnutrition and 7-year mortality, controlling for functional ability, socio demographics, lifestyle behavior and diseases, and investigate the interaction between risk of malnutrition and functional ability on the risk of mortality. SUBJECTS/METHODS: A longitudinal study on home-living and special-housing residents aged ? 60 years was conducted. Of 2312 randomly invited participants, 1402 responded and 1203 provided information on both nutritional status and functional ability. The risk of malnutrition was estimated by the occurrence of at least one anthropometric measure (BMI, MAC and CC) below cut-off in addition to the presence of at least one subjective measure (decreased food intake, weight loss and eating difficulty). RESULTS: At baseline, 8.6% of subjects were at risk of malnutrition and during the 7-year follow-up 34.6% subjects died. The risk of malnutrition was independently associated with 7-year mortality (hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.28-2.65). Additional independent predictors were dementia (HR 2.76, 95% CI 1.85-4.10), activity of daily living (ADL) dependence (HR 2.08, 95% CI 1.62-2.67), heart disease (HR 1.44, 95% CI 1.16 1.78), diabetes (HR 1.41, 95% CI 1.03-1.93) and older age (HR 1.09, 95% CI 1.07 1.10). Moreover, the risk of malnutrition and ADL dependence in combination predicted the poorest survival rate (18.7%, P<0.001). CONCLUSIONS: The risk of malnutrition significantly increases the risk of mortality in older people. Moreover, risk of malnutrition and ADL dependence together explain a significantly poorer survival rate; however, the importance of this interaction decreased in the multivariable model and risk of malnutrition and ADL dependence independently explained a significant risk of mortality. PMID- 26603880 TI - Dietary guidance normalizes large intestinal endocrine cell densities in patients with irritable bowel syndrome. AB - BACKGROUND/OBJECTIVES: To determine the large intestinal endocrine cell types affected following dietary guidance in patients with irritable bowel syndrome (IBS). SUBJECTS/METHODS: The study included 13 IBS patients and 13 control subjects. The patients received three sessions of individualized dietary guidance. Both the control subjects and the patients were scheduled for colonoscopies at baseline and again for the patients at 3-9 months after dietary guidance. Biopsy samples were taken from the colon and rectum and were immunostained for all types of large intestinal endocrine cells. The endocrine cells were quantified using computerized image analysis. RESULTS: The daily total consumption (mean+/-s.e.m. values) of fruits and vegetables rich in FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) decreased significantly from 16.2+/-5.3 g before receiving dietary guidance to 9.2+/-3.2 g after receiving dietary guidance (P=0.02). In the total colon, the densities of serotonin cells were 46.8+/-8.9, 10.5+/-2.1 and 22.6+/-3.2 cells/mm(2) in control subjects and in IBS patients before and after receiving dietary guidance, respectively (P=0.007); the corresponding densities of peptide YY cells were 11.6+/-1.8, 10.8+/-1.7 and 16.8+/-2.1 cells/mm(2), respectively (P=0.06). The cell densities for both serotonin and peptide YY did not change significantly in the rectum. The densities of somatostatin cells in the rectum were 13.5+/-3.0, 13.2+/-3.0, and 22.3+/-3.2 cells/mm(2) for control subjects and for IBS patients before and after receiving dietary guidance, respectively (P=0.01). CONCLUSIONS: The densities of the large intestinal endocrine cells tend to normalize following dietary guidance that may have contributed to the improvement of the patients with IBS symptoms. PMID- 26603882 TI - Intermittent energy restriction and weight loss: a systematic review. AB - BACKGROUND/OBJECTIVES: Intermittent energy restriction (IER) is an eating pattern of regular daily periods of restricted energy intake followed by periods of unrestricted energy intake. This is gaining prominence as an alternative weight loss strategy to daily energy restriction (DER). The aim of this systematic review was to determine the effectiveness of IER on weight loss in overweight and obese adults and compare this with DER. SUBJECTS/METHODS: A systematic literature search was conducted using the CINAHL, Embase, Medline, PsycINFO, Cochrane and Scopus databases. Eight studies that assigned overweight or obese adults to IER or to a DER 'control' were deemed eligible for inclusion. RESULTS: All studies reported significant weight loss for IER groups. Average weight loss was approximately 0.2-0.8 kg per week. IER resulted in comparable weight loss to DER when overall energy restriction remained similar between diets. The majority of studies that reported body composition outcomes have shown equal efficacy for fat mass, fat-free mass and waist circumference. CONCLUSIONS: Weight loss was achieved in overweight and obese adults following IER and this loss was comparable to a DER diet. IER may be an effective alternative strategy for health practitioners to promote weight loss for selected overweight and obese people. PMID- 26603881 TI - Effect of inulin and fructo-oligosaccharide on the prevention of acute radiation enteritis in patients with gynecological cancer and impact on quality-of-life: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND/OBJECTIVES: The pathogenesis of enteritis after abdominal radiotherapy (RT) is unknown, although changes in fecal microbiota may be involved. Prebiotics stimulate the proliferation of Lactobacillus spp and Bifidobacterium spp, and this may have positive effects on the intestinal mucosa during abdominal RT. SUBJECTS/METHODS: We performed a randomized, double-blind, placebo-controlled trial involving patients with gynecological cancer who received abdominal RT after surgery. Patients were randomized to receive prebiotics or placebo. The prebiotic group received a mixture of fiber (50 inulin and 50% fructo oligosaccharide), and the placebo group received 6 g of maltodextrin twice daily from 1 week before to 3 weeks after RT. The number of bowel movements and stool consistency was recorded daily. Diarrhea was evaluated according to the Common Toxicity Criteria of the National Cancer Institute. Stool consistency was assessed using the 7-point Bristol scale. Patients' quality-of-life was evaluated at baseline and at completion of RT using the EORTC-QLQ-C30 (European Organization for Research and Treatment of Cancer quality-of-life Questionnaire C30) test. RESULTS: Thirty-eight women with a mean age of 60.3+/-11.8 years participated in the study. Both groups (prebiotic (n=20) and placebo (n=18)) were comparable in their baseline characteristics. The number of bowel movements per month increased in both groups during RT. The number of bowel movements per day increased in both groups. The number of days with watery stool (Bristol score 7) was lower in the prebiotic group (3.3+/-4.4 to 2.2+/-1.6) than in the placebo group (P=0.08). With respect to quality-of-life, the symptoms with the highest score in the placebo group were insomnia at baseline and diarrhea toward the end of the treatment. In the prebiotic group, insomnia was the symptom with the highest score at both assessments, although the differences were not statistically significant. CONCLUSIONS: Prebiotics can improve the consistency of stools in gynecologic cancer patients on RT. This finding could have important implications in the quality-of-life of these patients during treatment. PMID- 26603883 TI - Cosinor modelling of seasonal variation in 25-hydroxyvitamin D concentrations in cardiovascular patients in Norway. AB - BACKGROUND/OBJECTIVES: Seasonal variation may reduce the validity of 25 hydroxyvitamin D (25OHD) as a biomarker of vitamin D status. Here we aimed to identify potential determinants of seasonal variation in 25OHD concentrations and to evaluate cosinor modelling as a method to adjust single 25OHD measurements for seasonal variation. SUBJECTS/METHODS: In Caucasian cardiovascular patients (1999 2004), we measured 25OHD by liquid chromatography tandem mass spectrometry in 4116 baseline and 528 follow-up samples. To baseline values, we fitted a cosinor model for monthly concentrations of 25OHD. Using the model, we estimated each patient's adjusted annual 25OHD value. Further, we studied how covariates affected the annual mean 25OHD concentration and seasonal variation of the study cohort. To evaluate the model, we predicted follow-up measurements with and without covariates and compared accuracy with carrying forward baseline values and linear regression adjusting for season, common approaches in research and clinical practice, respectively. RESULTS: The annual mean (59.6 nmol/l) was associated with participants' age, gender, smoking status, body mass, physical activity level, diabetes diagnosis, vitamin D supplement use and study site (adjusted models, P<0.05). Seasonal 25OHD variation was 15.8 nmol/l, and older age (>62 years) was associated with less variation (adjusted model, P=0.025). Prediction of follow-up measurements was more accurate with the cosinor model compared with the other approaches (P<0.05). Adding covariates to cosinor models did not improve prediction (P>0.05). CONCLUSIONS: We find cosinor models suitable and flexible for analysing and adjusting for seasonal variation in 25OHD concentrations, which is influenced by age. PMID- 26603884 TI - Toward diversity-responsive medical education: taking an intersectionality-based approach to a curriculum evaluation. AB - Recent years have seen a rise in the efforts to implement diversity topics into medical education, using either a 'narrow' or a 'broad' definition of culture. These developments urge that outcomes of such efforts are systematically evaluated by mapping the curriculum for diversity-responsive content. This study was aimed at using an intersectionality-based approach to define diversity related learning objectives and to evaluate how biomedical and sociocultural aspects of diversity were integrated into a medical curriculum in the Netherlands. We took a three-phase mixed methods approach. In phase one and two, we defined essential learning objectives based on qualitative interviews with school stakeholders and diversity literature. In phase three, we screened the written curriculum for diversity content (culture, sex/gender and class) and related the results to learning objectives defined in phase two. We identified learning objectives in three areas of education (medical knowledge and skills, patient-physician communication, and reflexivity). Most diversity content pertained to biomedical knowledge and skills. Limited attention was paid to sociocultural issues as determinants of health and healthcare use. Intersections of culture, sex/gender and class remained mostly unaddressed. The curriculum's diversity-responsiveness could be improved by an operationalization of diversity that goes beyond biomedical traits of assumed homogeneous social groups. Future efforts to take an intersectionality-based approach to curriculum evaluations should include categories of difference other than culture, sex/gender and class as separate, equally important patient identities or groups. PMID- 26603885 TI - Early Predictors of Growth in Diversity of Key Consonants Used in Communication in Initially Preverbal Children with Autism Spectrum Disorder. AB - Diversity of key consonants used in communication (DKCC) is a value-added predictor of expressive language growth in initially preverbal children with autism spectrum disorder (ASD). Studying the predictors of DKCC growth in young children with ASD might inform treatment of this under-studied aspect of prelinguistic development. Eighty-seven initially preverbal preschoolers with ASD and their parents were observed at five measurement periods. In this longitudinal correlational investigation, we found that child intentional communication acts and parent linguistic responses to child leads predicted DKCC growth, after controlling for two other predictors and two background variables. As predicted, receptive vocabulary mediated the association between the value-added predictors and endpoint DKCC. PMID- 26603886 TI - How Easy is it to Read the Minds of People with Autism Spectrum Disorder? AB - How well can neurotypical adults' interpret mental states in people with ASD? 'Targets' (ASD and neurotypical) reactions to four events were video-recorded then shown to neurotypical participants whose task was to identify which event the target had experienced. In study 1 participants were more successful for neurotypical than ASD targets. In study 2, participants rated ASD targets equally expressive as neurotypical targets for three of the events, while in study 3 participants gave different verbal descriptions of the reactions of ASD and neurotypical targets. It thus seems people with ASD react differently but not less expressively to events. Because neurotypicals are ineffective in interpreting the behaviour of those with ASD, this could contribute to the social difficulties in ASD. PMID- 26603888 TI - Neonatal Immune Tolerance Induction to Allow Long-Term Studies With an Immunogenic Therapeutic Monoclonal Antibody in Mice. AB - The purpose of this study is to test the feasibility of neonatal immune tolerance induction in mice to enable long-term pharmacokinetic studies with immunogenic therapeutic monoclonal antibodies (mAb). Neonatal immune tolerance was induced by transfer of a mAb to neonatal mice via colostrum from nursing mother mice treated with two subcutaneous doses of a tolerogen starting within the first 24 h after delivery. Adalimumab and efalizumab were administered as tolerogens at various dose levels. Tolerance induction was evaluated in the offspring after reaching adulthood at 8 weeks of age. After a single intravenous injection of the same mAb as used for tolerance induction, the pharmacokinetics of the mAb and formation of anti-drug antibodies (ADA) in plasma were assessed using ELISA. Tolerance induction to adalimumab was achieved in a maternal dose-dependent manner. Adalimumab immune-tolerant offspring showed a slower adalimumab clearance (4.24 +/- 0.32 mL/day/kg) as compared to the control group (12.09 +/- 3.81 mL/day/kg). In the control group, accelerated clearance started 7 days after adalimumab dosing, whereas immune-tolerant offspring showed a log-linear terminal concentration-time course. In the offspring, the absence of predose ADA levels was indicative of successful tolerance induction. The second test compound efalizumab was not immunogenic in mice under our experimental conditions. Overall, the present study demonstrated the suitability of neonatal immune tolerance induction for a 4-week single dose study in adult mice with a human therapeutic mAb that is otherwise immunogenic in laboratory animals. PMID- 26603889 TI - Development of a Tumour Growth Inhibition Model to Elucidate the Effects of Ritonavir on Intratumoural Metabolism and Anti-tumour Effect of Docetaxel in a Mouse Model for Hereditary Breast Cancer. AB - In a mouse tumour model for hereditary breast cancer, we previously explored the anti-cancer effects of docetaxel, ritonavir and the combination of both and studied the effect of ritonavir on the intratumoural concentration of docetaxel. The objective of the current study was to apply pharmacokinetic (PK) pharmacodynamic (PD) modelling on this previous study to further elucidate and quantify the effects of docetaxel when co-administered with ritonavir. PK models of docetaxel and ritonavir in plasma and in tumour were developed. The effect of ritonavir on docetaxel concentration in the systemic circulation of Cyp3a knock out mice and in the implanted tumour (with inherent Cyp3a expression) was studied, respectively. Subsequently, we designed a tumour growth inhibition model that included the inhibitory effects of both docetaxel and ritonavir. Ritonavir decreased docetaxel systemic clearance with 8% (relative standard error 0.4%) in the co-treated group compared to that in the docetaxel only-treated group. The docetaxel concentration in tumour tissues was significantly increased by ritonavir with mean area under the concentration-time curve 2.5-fold higher when combined with ritonavir. Observed tumour volume profiles in mice could be properly described by the PK/PD model. In the co-treated group, the enhanced anti tumour effect was mainly due to increased docetaxel tumour concentration; however, we demonstrated a small but significant anti-tumour effect of ritonavir addition (p value <0.001). In conclusion, we showed that the increased anti tumour effect observed when docetaxel is combined with ritonavir is mainly caused by enhanced docetaxel tumour concentration and to a minor extent by a direct anti tumour effect of ritonavir. PMID- 26603891 TI - Intravascular papillary endothelial hyperplasia: magnetic resonance imaging of finger lesions. AB - OBJECTIVE: To describe magnetic resonance imaging (MRI) features of intravascular papillary endothelial hyperplasia (IPEH), to identify findings differentiating IPEH of the finger from that of other locations, and to correlate these with pathology. MATERIALS AND METHODS: Nineteen patients with 20 I.E. masses of the finger (n = 13) and other locations (n = 7) were evaluated. All patients underwent MRI, and the results were correlated with pathology. RESULTS: Seventeen IPEHs, including all IPEHs of the finger, were located in the subcutis, the three other lesions in the muscle layer. On T1WI, all masses were isointense or slightly hyperintense. IPEHs of the finger (n = 13) revealed focal hyperintense nodules (n = 2) or central hypointensity (n = 2) on T1WI, hypointensity with a hyperintense rim (n = 7), hyperintensity with hypointense nodules (n = 5), or isointensity with a hypointense rim (n = 1) on T2WI, and rim enhancement (n = 5), heterogeneous enhancement with nodular nonenhanced areas (n = 6), peripheral nodular enhancement (n = 1), or no enhancement (n = 1) on gadolinium-enhanced T1WI. IPEHs of other locations (n = 7) demonstrated focal hyperintense nodules (n = 5) on T1WI, hyperintensity with hypointense nodules (n = 5) or heterogeneous signal intensity (n = 2) on T2WI, and rim or rim and septal enhancement (n = 6) or peripheral nodular enhancement (n = 1). Microscopically, IPEHs were composed of thrombi that were hypointense on T2WI and papillary endothelial proliferations that showed T2 hyperintensity and enhancement. CONCLUSION: MRI of finger IPEH reveals well-demarcated subcutaneous masses with hypointensity or hypointense nodules with peripheral hyperintensity on T2WI, as well as peripheral enhancement. T1 hyperintense nodules, internal heterogeneity on T2WI, and septal enhancement are more common in IPEH of other locations. PMID- 26603890 TI - Effects of Surface Composition on the Aerosolisation and Dissolution of Inhaled Antibiotic Combination Powders Consisting of Colistin and Rifampicin. AB - Colistin is often the only effective antibiotic against the respiratory infections caused by multidrug-resistant Gram-negative bacteria. However, colistin-resistant multidrug-resistant isolates have been increasingly reported and combination therapy is preferred to combat resistance. In this study, five combination formulations containing colistin (COL) and rifampicin (RIF) were prepared by spray drying. The lowest minimum inhibitory concentration (MIC) value against Pseudomonas aeruginosa PAO1 was measured for the formulation of COL/RIF = 4:1 with relatively high emitted doses (over 80%) and satisfactory fine particle fractions (over 60%). Data from X-ray photoelectron spectroscopy (XPS) and nano time-of-flight secondary ion mass spectrometry (ToF-SIMS) showed the surfaces of particles were mainly covered by rifampicin even for the formulation with a mass ratio of COL/RIF = 4:1. Because colistin is hygroscopic and rifampicin is hydrophobic, moisture absorption of combination formulations was significantly lower than the pure colistin formulation in the dynamic vapour sorption results. To investigate the dissolution characteristics, four dissolution test methods (diffusion Franz cell, modified Franz cell, flow-through and beaker methods) were employed and compared. The modified Franz cell method was selected to test the dissolution behaviour of aerosolised powder formulations to eliminate the effect of membrane on dissolution. The results showed that surface enrichment of hydrophobic rifampicin neither affected aerosolisation nor retarded dissolution rate of colistin in the combination formulations. For the first time, advanced surface characterisation techniques of XPS and ToF-SIMS have shown their capability to understand the effect of surface composition on the aerosolisation and dissolution of combination powders. PMID- 26603892 TI - Motivational interviewing increases physical activity and self-efficacy in people living in the community after hip fracture: a randomized controlled trial. AB - OBJECTIVE: To investigate if motivational interviewing improved physical activity, self-efficacy, quality of life, mobility and mental health in people living in the community after hip fracture. DESIGN: Single-blind randomized controlled trial. SETTING: Community. PARTICIPANTS: A total of 30 adults after hip fracture who had been discharged from rehabilitation to independent living in the community and allocated to a control group ( n = 14) or an intervention group ( n = 16). INTERVENTION: All participants received usual care. The intervention group also received eight weekly sessions of motivational interviewing as additional input, with the control group having no additional matching input. MAIN OUTCOMES: The primary outcome was physical activity levels as measured by an accelerometer (steps taken per day, time spent walking per day, and time spent sitting or lying each day). Secondary outcomes included self-efficacy (confidence about walking and not falling), health-related quality of life, mobility and mental health. RESULTS: Relative to usual care, the motivational interviewing group took significantly more steps per day (mean = 1237 steps, 95% confidence interval (CI) 12 to 2463), walked for longer per day (mean = 14.4 minutes, 95% CI 0.6 to 28.8), had improved self-efficacy evidenced by being more confident about walking (mean = 1.6 units out of 10, 95% CI 0.3 to 2.9) and not falling (mean = 1.1 units out of 10, 95% CI 0.3 to 1.9) and improved health-related quality of life and mental health. CONCLUSION: This study provides preliminary evidence that motivational interviewing can result in clinically meaningful improvements in physical activity and psychosocial outcomes for people recovering from hip fracture. PMID- 26603893 TI - Validation and internal consistency of the Swedish version of the Valued Life Activities scale. AB - OBJECTIVE: The objective was to create a linguistically and culturally validated Swedish version of the Valued Life Activities scale. The aim was also to describe its content and concurrent validity and its internal consistency in persons with rheumatoid arthritis. METHODS: The Valued Life Activities scale was translated to Swedish and culturally adapted. In order to describe the content validity, both the Swedish and original Valued Life Activities scale were linked to the International Classification of Functioning, Disability and Health. The concurrent validity and internal consistency were evaluated in 737 patients with rheumatoid arthritis. To establish concurrent validity, the scale was correlated to disease activity, activity limitations, and life satisfaction. Internal consistency was assessed with Cronbach's alpha. RESULTS: The equivalence of meaning between the Swedish and the original Valued Life Activities scale was ensured by harmonization review. Content validity was high when linked to the International Classification of Functioning, Disability and Health. Concurrent validity showed a strong correlation with the activity limitations (r = 0.87), moderate with life satisfaction (r = -0.61), and weak with disease activity (r = 0.38). Internal consistency was excellent (Cronbach's alpha = 0.97). CONCLUSIONS: The Swedish Valued Life Activities scale has been tested in a large and well characterized sample and found to be a linguistically valid and culturally adapted self-reported measure of participation. Content validity of the Valued Life Activities scale was excellent, concurrent validity strong, and the internal consistency excellent. Since both individual preferences and International Classification of Functioning, Disability and Health concepts of disability are taken into account, the Swedish Valued Life Activities scale appears to be a promising new scale addressing important aspects of participation. PMID- 26603894 TI - An unexpected role for mixotrophs in the response of peatland carbon cycling to climate warming. AB - Mixotrophic protists are increasingly recognized for their significant contribution to carbon (C) cycling. As phototrophs they contribute to photosynthetic C fixation, whilst as predators of decomposers, they indirectly influence organic matter decomposition. Despite these direct and indirect effects on the C cycle, little is known about the responses of peatland mixotrophs to climate change and the potential consequences for the peatland C cycle. With a combination of field and microcosm experiments, we show that mixotrophs in the Sphagnum bryosphere play an important role in modulating peatland C cycle responses to experimental warming. We found that five years of consecutive summer warming with peaks of +2 to +8 degrees C led to a 50% reduction in the biomass of the dominant mixotrophs, the mixotrophic testate amoebae (MTA). The biomass of other microbial groups (including decomposers) did not change, suggesting MTA to be particularly sensitive to temperature. In a microcosm experiment under controlled conditions, we then manipulated the abundance of MTA, and showed that the reported 50% reduction of MTA biomass in the field was linked to a significant reduction of net C uptake (-13%) of the entire Sphagnum bryosphere. Our findings suggest that reduced abundance of MTA with climate warming could lead to reduced peatland C fixation. PMID- 26603895 TI - The lived experiences of patients and ambulance ramping in a regional Australian emergency department: An interpretive phenomenology study. AB - BACKGROUND: Internationally, the workload of emergency departments (ED) has increased, resulting in overcrowding and frequent delays in the offloading of patients arriving via ambulance--referred to in Australia as 'ambulance ramping'. METHODS: Using interpretive phenomenology, this study sought to understand the experience of ambulance ramping from the perspective of patients. Semi-structured interviews were undertaken with seven patients who presented to a regional Queensland ED via ambulance, and experienced an ambulance offload delay of >30 min. RESULTS: Ambulance ramping in the ED was described as 'Being a patient, patient', and three major themes emerged: Understanding the emergency healthcare system; Making do within the emergency healthcare system; and Being 'in the dark' during ambulance ramping. Most participants did not understand the antecedents to ambulance ramping, but understood some of the consequences. Most were happy to wait with paramedics for a bed and, although without privacy, felt safe. However, most participants felt 'in the dark' during ambulance ramping, due to communication difficulties regarding bed availability, and this led to frustration. CONCLUSIONS: In light of the Australian Charter of Healthcare Rights, service improvement opportunities exist for patients arriving to the ED by ambulance to ensure delays are minimised and quality care is delivered. PMID- 26603896 TI - DNA-PKcs and PARP1 Bind to Unresected Stalled DNA Replication Forks Where They Recruit XRCC1 to Mediate Repair. AB - A series of critical pathways are responsible for the detection, signaling, and restart of replication forks that encounter blocks during S-phase progression. Small base lesions may obstruct replication fork progression and processing, but the link between repair of small lesions and replication forks is unclear. In this study, we investigated a hypothesized role for DNA-PK, an important enzyme in DNA repair, in cellular responses to DNA replication stress. The enzyme catalytic subunit DNA-PKcs was phosphorylated on S2056 at sites of stalled replication forks in response to short hydroxyurea treatment. Using DNA fiber experiments, we found that catalytically active DNA-PK was required for efficient replication restart of stalled forks. Furthermore, enzymatically active DNA-PK was also required for PARP-dependent recruitment of XRCC1 to stalled replication forks. This activity was enhanced by preventing Mre11-dependent DNA end resection, suggesting that XRCC1 must be recruited early to an unresected stalled fork. We also found that XRCC1 was required for effective restart of a subset of stalled replication forks. Overall, our work suggested that DNA-PK and PARP dependent recruitment of XRCC1 is necessary to effectively protect, repair, and restart stalled replication forks, providing new insight into how genomic stability is preserved. PMID- 26603897 TI - SBI-0640756 Attenuates the Growth of Clinically Unresponsive Melanomas by Disrupting the eIF4F Translation Initiation Complex. AB - Disrupting the eukaryotic translation initiation factor 4F (eIF4F) complex offers an appealing strategy to potentiate the effectiveness of existing cancer therapies and to overcome resistance to drugs such as BRAF inhibitors (BRAFi). Here, we identified and characterized the small molecule SBI-0640756 (SBI-756), a first-in-class inhibitor that targets eIF4G1 and disrupts the eIF4F complex. SBI 756 impaired the eIF4F complex assembly independently of mTOR and attenuated growth of BRAF-resistant and BRAF-independent melanomas. SBI-756 also suppressed AKT and NF-kappaB signaling, but small-molecule derivatives were identified that only marginally affected these pathways while still inhibiting eIF4F complex formation and melanoma growth, illustrating the potential for further structural and functional manipulation of SBI-756 as a drug lead. In the gene expression signature patterns elicited by SBI-756, DNA damage, and cell-cycle regulatory factors were prominent, with mutations in melanoma cells affecting these pathways conferring drug resistance. SBI-756 inhibited the growth of NRAS, BRAF, and NF1 mutant melanomas in vitro and delayed the onset and reduced the incidence of Nras/Ink4a melanomas in vivo. Furthermore, combining SBI-756 and a BRAFi attenuated the formation of BRAFi-resistant human tumors. Taken together, our findings show how SBI-756 abrogates the growth of BRAF-independent and BRAFi resistant melanomas, offering a preclinical rationale to evaluate its antitumor effects in other cancers. PMID- 26603898 TI - T cells: CiShh... PMID- 26603899 TI - Regulation of macrophage development and function in peripheral tissues. AB - Macrophages are immune cells of haematopoietic origin that provide crucial innate immune defence and have tissue-specific functions in the regulation and maintenance of organ homeostasis. Recent studies of macrophage ontogeny, as well as transcriptional and epigenetic identity, have started to reveal the decisive role of the tissue stroma in the regulation of macrophage function. These findings suggest that most macrophages seed the tissues during embryonic development and functionally specialize in response to cytokines and metabolites that are released by the stroma and drive the expression of unique transcription factors. In this Review, we discuss how recent insights into macrophage ontogeny and macrophage-stroma interactions contribute to our understanding of the crosstalk that shapes macrophage function and the maintenance of organ integrity. PMID- 26603902 TI - Replacement of two amino acids of 9R-dioxygenase-allene oxide synthase of Aspergillus niger inverts the chirality of the hydroperoxide and the allene oxide. AB - The genome of Aspergillus niger codes for a fusion protein (EHA25900), which can be aligned with ~50% sequence identity to 9S-dioxygenase (DOX)-allene oxide synthase (AOS) of Fusarium oxysporum, homologues of the Fusarium and Colletotrichum complexes and with over 62% sequence identity to homologues of Aspergilli, including (DOX)-9R-AOS of Aspergillus terreus. The aims were to characterize the enzymatic activities of EHA25900 and to identify crucial amino acids for the stereospecificity. Recombinant EHA25900 oxidized 18:2n-6 sequentially to 9R-hydroperoxy-10(E),12(Z)-octadecadienoic acid (9R-HPODE) and to a 9R(10)-allene oxide. 9S- and 9R-DOX-AOS catalyze abstraction of the pro-R hydrogen at C-11, but the direction of oxygen insertion differs. A comparison between twelve 9-DOX domains of 9S- and 9R-DOX-AOS revealed conserved amino acid differences, which could contribute to the chirality of products. The Gly616Ile replacement of 9R-DOX-AOS (A. niger) increased the biosynthesis of 9S-HPODE and the 9S(10)-allene oxide, whereas the Phe627Leu replacement led to biosynthesis of 9S-HPODE and the 9S(10)-allene oxide as main products. The double mutant (Gly616Ile, Phe627Leu) formed over 90% of the 9S stereoisomer of HPODE. 9S-HPODE was formed by antarafacial hydrogen abstraction and oxygen insertion, i.e., the original H-abstraction was retained but the product chirality was altered. We conclude that 9R-DOX-AOS can be altered to 9S-DOX-AOS by replacement of two amino acids (Gly616Ile, Phe627Leu) in the DOX domain. PMID- 26603901 TI - STING: infection, inflammation and cancer. AB - The rapid detection of microbial agents is essential for the effective initiation of host defence mechanisms against infection. Understanding how cells detect cytosolic DNA to trigger innate immune gene transcription has important implications - not only for comprehending the immune response to pathogens but also for elucidating the causes of autoinflammatory disease involving the sensing of self-DNA and the generation of effective antitumour adaptive immunity. The discovery of the STING (stimulator of interferon genes)-controlled innate immune pathway, which mediates cytosolic DNA-induced signalling events, has recently provided important insights into these processes, opening the way for the development of novel immunization regimes, as well as therapies to treat autoinflammatory disease and cancer. PMID- 26603900 TI - New insights into the immunopathology and control of dengue virus infection. AB - Dengue virus poses a major threat to global public health: two-thirds of the world's population is now at risk from infection by this mosquito-borne virus. Dengue virus causes a range of diseases with a small proportion of infected patients developing severe plasma leakage that leads to dengue shock syndrome, organ impairment and bleeding. Infection with one of the four viral serotypes results in the development of homotypic immunity to that serotype. However, subsequent infection with a different serotype is associated with an increased risk of developing severe disease, which has led to the suggestion that severe disease is triggered by immunopathology. This Review outlines recent advances in the understanding of immunopathology, vaccine development and human monoclonal antibodies produced against dengue virus. PMID- 26603903 TI - Lack of phosphatidylethanolamine N-methyltransferase in mice does not promote fatty acid oxidation in skeletal muscle. AB - Phosphatidylethanolamine N-methyltransferase (PEMT) converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC) in the liver. Mice lacking PEMT are protected from high-fat diet-induced obesity and insulin resistance, and exhibit increased whole-body energy expenditure and oxygen consumption. Since skeletal muscle is a major site of fatty acid oxidation and energy utilization, we determined if rates of fatty acid oxidation/oxygen consumption in muscle are higher in Pemt(-/-) mice than in Pemt(+/+) mice. Although PEMT is abundant in the liver, PEMT protein and activity were undetectable in four types of skeletal muscle. Moreover, amounts of PC and PE in the skeletal muscle were not altered by PEMT deficiency. Thus, we concluded that any influence of PEMT deficiency on skeletal muscle would be an indirect consequence of lack of PEMT in liver. Neither the in vivo rate of fatty acid uptake by muscle nor the rate of fatty acid oxidation in muscle explants and cultured myocytes depended upon Pemt genotype. Nor did PEMT deficiency increase oxygen consumption or respiratory function in skeletal muscle mitochondria. Thus, the increased whole body oxygen consumption in Pemt(-/-) mice, and resistance of these mice to diet-induced weight gain, are not primarily due to increased capacity of skeletal muscle for utilization of fatty acids as an energy source. PMID- 26603904 TI - A Systematic Approach to Identify Candidate Transcription Factors that Control Cell Identity. AB - Hundreds of transcription factors (TFs) are expressed in each cell type, but cell identity can be induced through the activity of just a small number of core TFs. Systematic identification of these core TFs for a wide variety of cell types is currently lacking and would establish a foundation for understanding the transcriptional control of cell identity in development, disease, and cell-based therapy. Here, we describe a computational approach that generates an atlas of candidate core TFs for a broad spectrum of human cells. The potential impact of the atlas was demonstrated via cellular reprogramming efforts where candidate core TFs proved capable of converting human fibroblasts to retinal pigment epithelial-like cells. These results suggest that candidate core TFs from the atlas will prove a useful starting point for studying transcriptional control of cell identity and reprogramming in many human cell types. PMID- 26603905 TI - Paraquat induce pulmonary epithelial-mesenchymal transition through transforming growth factor-beta1-dependent mechanism. AB - Pulmonary fibrosis is prevalent in Paraquat (PQ) poisoning. Transforming growth factor beta1 (TGF-beta1)-induced epithelial-mesenchymal transition (EMT) of Type II alveolar epithelial cells (AT2) contributed to the pulmonary fibrosis in some pulmonary disease. In this study, we investigated whether PQ could induce EMT in AT2 through transforming growth factor beta1 (TGF-beta1) signal pathway in vitro. Morphological and phenotypic characterizations were evaluated on AT2 cell lines A549 cells in the presence of PQ with or without TGF-beta1 inhibitors SB431542 for 5 days. As a result, PQ induced the transition of A549 cells from epithelial morphology to fibroblast-like morphology, associated with the acquisition of migratory properties. Phenotypically, PQ induced-EMT was characterized by loss of epithelial cell markers including E-cadherin and zonula occludens (ZO-1), while up-expressions of mesenchymal cell markers including alpha-smooth muscle actin (alpha-SMA) and vimentin, concurrent with increased type I collagen (Col I). SB431542 suppressed PQ-induced EMT via inhibiting expressions of phospho-Smad2 and phospho-Smad3. These findings conclusively demonstrated that the cultured A549 cells underwent EMT in the presence of PQ, and suggested that TGF-beta1 played a central role in PQ-induced EMT. PMID- 26603906 TI - NVP-TAE684 reverses multidrug resistance (MDR) in human osteosarcoma by inhibiting P-glycoprotein (PGP1) function. AB - BACKGROUND AND PURPOSE: Increased expression of P-glycoprotein (PGP1) is one of the major causes of multidrug resistance (MDR) in cancer, including in osteosarcoma, which eventually leads to the failure of cancer chemotherapy. Thus, there is an urgent need to develop effective therapeutic strategies to override the expression and function of PGP1 to counter MDR in cancer patients. EXPERIMENTAL APPROACH: In an effort to search for new chemical entities targeting PGP1-associated MDR in osteosarcoma, we screened a 500+ compound library of known kinase inhibitors with established kinase selectivity profiles. We aimed to discover potential drug synergistic effects among kinase inhibitors and general chemotherapeutics by combining inhibitors with chemotherapy drugs such as doxorubicin and paclitaxel. The human osteosarcoma MDR cell lines U2OSR2 and KHOSR2 were used for the initial screen and secondary mechanistic studies. KEY RESULTS: After screening 500+ kinase inhibitors, we identified NVP-TAE684 as the most effective MDR reversing agent. NVP-TAE684 significantly reversed chemoresistance when used in combination with doxorubicin, paclitaxel, docetaxel, vincristine, ET-743 or mitoxantrone. NVP-TAE684 itself is not a PGP1 substrate competitive inhibitor, but it can increase the intracellular accumulation of PGP1 substrates in PGP1-overexpressing cell lines. NVP-TAE684 was found to inhibit the function of PGP1 by stimulating PGP1 ATPase activity, a phenomenon reported for other PGP1 inhibitors. CONCLUSIONS AND IMPLICATIONS: The application of NVP TAE684 to restore sensitivity of osteosarcoma MDR cells to the cytotoxic effects of chemotherapeutics will be useful for further study of PGP1-mediated MDR in human cancer and may ultimately benefit cancer patients. PMID- 26603907 TI - Relation of Risk of Atrial Fibrillation With Systolic Blood Pressure Response During Exercise Stress Testing (from the Henry Ford ExercIse Testing Project). AB - Decreases in systolic blood pressure during exercise may predispose to arrhythmias such as atrial fibrillation (AF) because of underlying abnormal autonomic tone. We examined the association between systolic blood pressure response and incident AF in 57,442 (mean age 54 +/- 13 years, 47% women, and 29% black) patients free of baseline AF who underwent exercise treadmill stress testing from the Henry Ford ExercIse Testing project. Exercise systolic blood pressure response was examined as a categorical variable across clinically relevant categories (>20 mm Hg: referent; 1 to 20 mm Hg, and <=0 mm Hg) and per 1 SD decrease. Cox regression, adjusting for demographics, cardiovascular risk factors, medications, history of coronary heart disease, history of heart failure, and metabolic equivalent of task achieved, was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between systolic blood pressure response and incident AF. Over a median follow-up of 5.0 years, a total of 3,381 cases (5.9%) of AF were identified. An increased risk of AF was observed with decreasing systolic blood pressure response (>20 mm Hg: HR 1.0, referent; 1 to 20 mm Hg: HR 1.09, 95% CI 0.99, 1.20; <=0 mm Hg: HR 1.22, 95% CI 1.06 to 1.40). Similar results were obtained per 1-SD decrease in systolic blood pressure response (HR 1.08, 95% CI 1.04 to 1.12). The results were consistent when stratified by age, sex, race, hypertension, and coronary heart disease. In conclusion, our results suggest that a decreased systolic blood pressure response during exercise may identify subjects who are at risk for developing AF. PMID- 26603908 TI - [Thyroid and the environment]. AB - It has long been known that the thyroid depends upon the environment for regular iodine supply, avoiding iodine deficiency or excess. Thyroid function may be altered by natural compounds present in water or foodstuff (such as iodine or phyto-goitrogens), or by synthetic compounds, either administered knowingly (in case of medicine), or as an untoward event in case of exposure to industrial products and pesticides, massively produced and polluting the environment. Compounds with an impact on thyroid homeostasis are called thyroid disruptors (TD). TD may disrupt the thyroid economy at any level of regulation: thyroid hormone synthesis, metabolism, or transport; cellular level including thyroid hormone signaling; tumorigenesis or more indirectly via the triggering of an autoimmune process. Compounds such as polychlorinated biphenyls (PCBs) may act at multiple levels. PT effects on human health depend on parameters linked to the individual person (age at exposure, iodine status, diet, professional exposure, place of living, family history of thyroid disease, detoxification enzyme genetic variants) and on parameters linked to the compounds themselves (chemical structure, lipo- or hydro-solubility, modes of exposure, metabolites activity, "cocktail effect"). The toxic effects of TD do not necessarily follow the rules of classical toxicology (low-dose effects, non-monotonic curves). The main clinical risks are the deleterious impact on neurocognition and behavior for the fetus and the young child, and possibly the elderly, while in adults the main concerns are tumori/goitrogenesis and autoimmune thyroid disease. The potential socioeconomic impact for society warrants an active and major involvement in research to find solutions in a multidisciplinary approach. PMID- 26603909 TI - Brief report: Academic amotivation in light of the dark side of identity formation. AB - The study intended to determine motivational profiles of first-year undergraduates and aimed their characterization in terms of identity processes. First, a cluster analysis revealed five motivational profiles: combined (i.e., high quantity of motivation, low amotivation); intrinsic (i.e., high intrinsic, low introjected and external regulation, low amotivation); "demotivated" (i.e., very low quantity of motivation and amotivation); extrinsic (i.e., high extrinsic and identified regulation and low intrinsic and amotivation); and "amotivated" (i.e., low intrinsic and identified, very high amotivation). Second, using Lebart's (2000) methodology, the most characteristic identity processes were listed for each motivational cluster. Demotivated and amotivated profiles were refined in terms of adaptive and maladaptive forms of exploration. Notably, exploration in breadth and in depth were underrepresented in demotivated students compared to the total sample; commitment and ruminative exploration were under and overrepresented respectively in amotivated students. Educational and clinical implications are proposed and future research is suggested. PMID- 26603910 TI - Vocational identity and psychological adjustment: a study in French adolescents and emerging adults. AB - The aim of the present research was to study vocational identity in French adolescent and emerging adult students by using a French adaptation of the Vocational Identity Status Assessment (VISA), and to analyze the links between vocational identity formation and negative and positive psychological adjustment. Participants were 1077 French students who completed self-report scales about vocational identity, depression and satisfaction with life. The French version of the VISA showed good psychometric properties and six identity statuses were derived by means of cluster analysis: achievement, foreclosure, moratorium, searching moratorium, diffused diffusion and carefree diffusion. The main findings show that diffused diffusion and moratorium represent the dark sides of identity because of their negative psychological adjustment, and that the two processes of reconsideration of commitment were differently associated with psychological adjustment. These findings demonstrate that clinical interventions should be adapted to the individual's identity profile. PMID- 26603911 TI - Author reply to: "Depressive symptomatology, serotonergic activity, and neuroticism: A methodological recommendation". PMID- 26603912 TI - Self-inflicted Burns: 10 year review and comparison to national guidelines. AB - INTRODUCTION: There is an increasing trend of self-inflicted burns noted in the literature, often seen in patients with complex psychosocial backgrounds. These patients are challenging to manage as the recovery from the acute burn may be compounded by difficult rehabilitation and suboptimal coping strategies. We aimed to review patients presenting to our burns unit with self-inflicted burns, the management strategies and examine the complexities surrounding their management. We assessed patient outcomes with a particular interest in psychosocial support given. METHODS: A retrospective review of all patients presenting with self inflicted burns over a 10 year period (2005-2014 inclusive) was conducted. Patients were identified through IBID database coded as either 'self-inflicted' or 'suicidal.' We reviewed patient and burn demographics, the clinical management, psychosocial management and patient outcomes such as wound healing, re-admission rates, and survival. RESULTS: We identified 118 self-inflicted burns in total. 50/118 (42%) were admitted. 64 (54%) were male and the total body surface burn area ranged from <0.5% to 99% with a median of 14%. 60/118 (51%) had TBSA <10% and 58/118 (49%) had TBSA >10%. 24 (48%) underwent admission to the Burn Intensive Care Unit (BITU). All patients admitted to BITU had TBSA >10%. Of those admitted to BITU 6 were palliative, 18 had full resuscitation and surgical management. Of those 18 patients who had active treatment, 10/18 (56%) died. Mean total length of stay was 31 days, range 1-130 days. 9% of patients sustained injuries whilst being a current inpatient at a psychiatric institution. Of all patients reviewed, 16% (n=19) had a previous history of deliberate self-harm through burns. Of those patients admitted, 98% of were reviewed by the mental health team during their admission with time to psychological review varying depending on fitness for assessment. The overall mean length of stay for all admitted patients who were actively treated but who subsequently died was 53 days. 84% of admitted patients were managed surgically. CONCLUSION: Self inflicted burns patients would benefit from a more complex pathway of treatment as their management aims to achieve not only physical health but also psychological health. They would benefit from enhanced care to manage the acute burn but also psychiatric support to ensure patients do not re-offend. PMID- 26603913 TI - Silver- and fluoride-containing mesoporous bioactive glasses versus commonly used antibiotics: Activity against multidrug-resistant bacterial strains isolated from patients with burns. AB - The wound healing process is frequently associated with a number of major clinical challenges, due to the failure of commonly used antibiotics as a remedy for wounds. There have always been fascinating questions about the novel applications of bioactive glasses (BGs) and it is expected that in the next few years these types of materials may play an important role in many aspects of soft tissue regeneration. This research focuses on the feasibility of using silver- and fluoride-containing BGs against multidrug-resistant bacterial strains isolated from patients with burns. According to the results obtained, fluoride did not exhibit antibacterial activity against the tested bacteria, while both 1% and 2% silver-containing BGs inhibited the bacterial growth. It is an important finding that 1% silver-containing BGs showed a potential antibacterial activity without any toxicity against fibroblasts, suggesting that this class of BGs could play a key role in the prevention of infection, reduction of pain, and removal of excessive exudates. PMID- 26603914 TI - Comparative genomics and genome biology of invasive Campylobacter jejuni. AB - Campylobacter jejuni is a major pathogen in bacterial gastroenteritis worldwide and can cause bacteremia in severe cases. C. jejuni is highly structured into clonal lineages of which the ST677CC lineage has been overrepresented among C. jejuni isolates derived from blood. In this study, we characterized the genomes of 31 C. jejuni blood isolates and 24 faecal isolates belonging to ST677CC in order to study the genome biology related to C. jejuni invasiveness. We combined the genome analyses with phenotypical evidence on serum resistance which was associated with phase variation of wcbK; a GDP-mannose 4,6-dehydratase involved in capsular biosynthesis. We also describe the finding of a Type III restriction modification system unique to the ST-794 sublineage. However, features previously considered to be related to pathogenesis of C. jejuni were either absent or disrupted among our strains. Our results refine the role of capsule features associated with invasive disease and accentuate the possibility of methylation and restriction enzymes in the potential of C. jejuni to establish invasive infections. Our findings underline the importance of studying clinically relevant well-characterized bacterial strains in order to understand pathogenesis mechanisms important in human infections. PMID- 26603915 TI - Three-dimensional direct cell patterning in collagen hydrogels with near-infrared femtosecond laser. AB - We report a methodology for three-dimensional (3D) cell patterning in a hydrogel in situ. Gold nanorods within a cell-encapsulating collagen hydrogel absorb a focused near-infrared femtosecond laser beam, locally denaturing the collagen and forming channels, into which cells migrate, proliferate, and align in 3D. Importantly, pattern resolution is tunable based on writing speed and laser power, and high cell viability (>90%) is achieved using higher writing speeds and lower laser intensities. Overall, this patterning technique presents a flexible direct-write method that is applicable in tissue engineering systems where 3D alignment is critical (such as vascular, neural, cardiac, and muscle tissue). PMID- 26603916 TI - Improving HIV pre-exposure prophylaxis for infants. PMID- 26603918 TI - Access to effective antimicrobials: a worldwide challenge. AB - Recent years have seen substantial improvements in life expectancy and access to antimicrobials, especially in low-income and lower-middle-income countries, but increasing pathogen resistance to antimicrobials threatens to roll back this progress. Resistant organisms in health-care and community settings pose a threat to survival rates from serious infections, including neonatal sepsis and health care-associated infections, and limit the potential health benefits from surgeries, transplants, and cancer treatment. The challenge of simultaneously expanding appropriate access to antimicrobials, while restricting inappropriate access, particularly to expensive, newer generation antimicrobials, is unique in global health and requires new approaches to financing and delivering health care and a one-health perspective on the connections between pathogen transmission in animals and humans. Here, we describe the importance of effective antimicrobials. We assess the disease burden caused by limited access to antimicrobials, attributable to resistance to antimicrobials, and the potential effect of vaccines in restricting the need for antibiotics. PMID- 26603919 TI - Maximising access to achieve appropriate human antimicrobial use in low-income and middle-income countries. AB - Access to quality-assured antimicrobials is regarded as part of the human right to health, yet universal access is often undermined in low-income and middle income countries. Lack of access to the instruments necessary to make the correct diagnosis and prescribe antimicrobials appropriately, in addition to weak health systems, heightens the challenge faced by prescribers. Evidence-based interventions in community and health-care settings can increase access to appropriately prescribed antimicrobials. The key global enablers of sustainable financing, governance, and leadership will be necessary to achieve access while preventing excess antimicrobial use. PMID- 26603917 TI - Extended pre-exposure prophylaxis with lopinavir-ritonavir versus lamivudine to prevent HIV-1 transmission through breastfeeding up to 50 weeks in infants in Africa (ANRS 12174): a randomised controlled trial. AB - BACKGROUND: Strategies to prevent postnatal mother-to-child transmission of HIV-1 in Africa, including infant prophylaxis, have never been assessed past 6 months of breastfeeding, despite breastfeeding being recommended up to 12 months after birth. We aimed to compare the efficacy and safety of infant prophylaxis with the two drug regimens (lamivudine or lopinavir-ritonavir) to prevent postnatal HIV-1 transmission up to 50 weeks of breastfeeding. METHODS: We did a randomised controlled trial in four sites in Burkina Faso, South Africa, Uganda, and Zambia in children born to HIV-1-infected mothers not eligible for antiretroviral therapy (CD4 count >350 cells per MUL). An independent researcher electronically generated a randomisation schedule; we then used sequentially numbered envelopes to randomly assign (1:1) HIV-1-uninfected breastfed infants aged 7 days to either lopinavir-ritonavir or lamivudine (paediatric liquid formulations, twice a day) up to 1 week after complete cessation of breastfeeding or at the final visit at week 50. We stratified the randomisation by country and used permuted blocks of four and six. We used a study label on drug bottles to mask participants, study physicians, and assessors to the treatment allocation. The primary outcome was infant HIV-1 infection between age 7 days and 50 weeks, diagnosed every 3 months with HIV-1 DNA PCR, in the modified intention-to-treat population (all who attended at least one follow-up visit). This trial is registered with ClinicalTrials.gov, number NCT00640263. FINDINGS: Between Nov 16, 2009, and May 7, 2012, we enrolled and randomised 1273 infants and analysed 1236; 615 assigned to lopinavir-ritonavir or 621 assigned to lamivudine. 17 HIV-1 infections were diagnosed in the study period (eight in the lopinavir-ritonavir group and nine in the lamivudine group), resulting in cumulative HIV-1 infection of 1.4% (95% CI 0.4-2.5) and 1.5% (0.7-2.5), respectively. Infection rates did not differ between the two drug regimens (hazard ratio [HR] of lopinavir-ritonavir versus lamivudine of 0.90, 95% CI 0.35-2.34; p=0.83). Clinical and biological severe adverse events did not differ between groups; 251 (51%) infants had a grade 3-4 event in the lopinavir-ritonavir group compared with 246 (50%) in the lamivudine group. INTERPRETATION: Infant HIV-1 prophylaxis with lopinavir-ritonavir was not superior to lamivudine and both drugs led to very low rates of HIV-1 postnatal transmission for up to 50 weeks of breastfeeding. Infant pre-exposure prophylaxis should be extended until the end of HIV-1 exposure and mothers should be informed about the persistent risk of transmission throughout breastfeeding. FUNDING: INSERM/National Agency for Research on AIDS and Viral Hepatitis (including funds from the Total Foundation), European Developing Countries Clinical Trials Partnership, Research Council of Norway. PMID- 26603920 TI - International cooperation to improve access to and sustain effectiveness of antimicrobials. AB - Securing access to effective antimicrobials is one of the greatest challenges today. Until now, efforts to address this issue have been isolated and uncoordinated, with little focus on sustainable and international solutions. Global collective action is necessary to improve access to life-saving antimicrobials, conserving them, and ensuring continued innovation. Access, conservation, and innovation are beneficial when achieved independently, but much more effective and sustainable if implemented in concert within and across countries. WHO alone will not be able to drive these actions. It will require a multisector response (including the health, agriculture, and veterinary sectors), global coordination, and financing mechanisms with sufficient mandates, authority, resources, and power. Fortunately, securing access to effective antimicrobials has finally gained a place on the global political agenda, and we call on policy makers to develop, endorse, and finance new global institutional arrangements that can ensure robust implementation and bold collective action. PMID- 26603921 TI - Exploring the evidence base for national and regional policy interventions to combat resistance. AB - The effectiveness of existing policies to control antimicrobial resistance is not yet fully understood. A strengthened evidence base is needed to inform effective policy interventions across countries with different income levels and the human health and animal sectors. We examine three policy domains-responsible use, surveillance, and infection prevention and control-and consider which will be the most effective at national and regional levels. Many complexities exist in the implementation of such policies across sectors and in varying political and regulatory environments. Therefore, we make recommendations for policy action, calling for comprehensive policy assessments, using standardised frameworks, of cost-effectiveness and generalisability. Such assessments are especially important in low-income and middle-income countries, and in the animal and environmental sectors. We also advocate a One Health approach that will enable the development of sensitive policies, accommodating the needs of each sector involved, and addressing concerns of specific countries and regions. PMID- 26603922 TI - Understanding the mechanisms and drivers of antimicrobial resistance. AB - To combat the threat to human health and biosecurity from antimicrobial resistance, an understanding of its mechanisms and drivers is needed. Emergence of antimicrobial resistance in microorganisms is a natural phenomenon, yet antimicrobial resistance selection has been driven by antimicrobial exposure in health care, agriculture, and the environment. Onward transmission is affected by standards of infection control, sanitation, access to clean water, access to assured quality antimicrobials and diagnostics, travel, and migration. Strategies to reduce antimicrobial resistance by removing antimicrobial selective pressure alone rely upon resistance imparting a fitness cost, an effect not always apparent. Minimising resistance should therefore be considered comprehensively, by resistance mechanism, microorganism, antimicrobial drug, host, and context; parallel to new drug discovery, broad ranging, multidisciplinary research is needed across these five levels, interlinked across the health-care, agriculture, and environment sectors. Intelligent, integrated approaches, mindful of potential unintended results, are needed to ensure sustained, worldwide access to effective antimicrobials. PMID- 26603923 TI - Antibiotics: achieving the balance between access and excess. PMID- 26603924 TI - National action for global gains in antimicrobial resistance. PMID- 26603925 TI - Animal production and antimicrobial resistance in the clinic. PMID- 26603926 TI - Yusuf Hamied: leader in the Indian generic drug industry. PMID- 26603927 TI - QSAR and Docking Studies of N-hydroxy Urea Derivatives as Flap Endonuclease-1 Inhibitors. AB - Flap endonuclease-I (FEN-1) is involved in DNA repair and considered to be a novel target for the development of anticancer agents. N-hydroxy urea derivatives have been reported as FEN-1 inhibitors. To derive in vitro and in silico correlation, we have performed 2D-quantitative structure activity relationship (QSAR) analysis and docking studies on these compounds. 2D-QSAR models were developed using multiple linear regression (MLR) analysis and cross-validation using leave one out (LOO) method. The best model displayed R(2) of 0.806 and Q(2) of 0.607. Docking study revealed key interactions with desired amino acids and compare well with the in vitro potency of the reported compounds. Both studies reveal a link between FEN-1 inhibition and physicochemical descriptors or interactions with amino acids in active site. The information generated is first of its kind and may be helpful in the design of novel FEN-1 inhibitors. PMID- 26603928 TI - 3D Structure Generation, Molecular Dynamics and Docking Studies of IRHOM2 Protein Involved in Cancer & Rheumatoid Arthritis. AB - A short-lived membrane protein IRHOM2 pedals a cascade of events by regulating Epidermal Growth Factor Receptor (EGFR) signalling in parallel with metalloproteases which results their involvement in cancer as well as in rheumatoid arthritis. Therefore, IRHOM2 is a potential therapeutic drug target for these diseases, but its 3D-structure has not been reported yet. In this study, the three-dimensional structure of the IRHOM2 protein was generated using I-TASSER (Iterative Threading Assembly Refinement) server. The modeled structure of IRHOM2 receptor was validated using various Structural Analysis and Verification Server (SAVES) in which 99.7% of amino acid residues are present in the favoured regions of the Ramachandran Plot. Further, the refined modeled structure was subjected to molecular dynamics simulation & docking analysis. Virtual screening studies were carried out using Glide with various selective libraries containing 24552 compounds and the analysis indicated extensive hydrogen bonding network and hydrophobic interactions which play a significant role in its binding. Docking results were analyzed for high ranking compounds using a consensus based docking score to calculate the binding affinity as a measure of protein-ligand interactions. The top ranking molecule against IRHOM2 active site has a glide g-score of -12.565 kcal/mol and glide e-model score of 74.967 with 3 hydrogen bonds and 11 hydrophobic contacts. This compound may act as probable inhibitor against these chronic diseases but further in vitro studies are required. PMID- 26603929 TI - Water Molecules Increases Binding Affinity of Natural PI3Kgamma Inhibitors Against Cancer. AB - The PI3K pathway is a signal transduction process including oncogenes and receptor tyrosine kinase regulating cellular functions i.e., survival, protein synthesis, and metabolism. In the present work, we have investigated the role of water molecules on inhibitor's binding orientation in crystal structures of PI3K pathway targets using molecular docking approach. AutoDock v4.2 docking software was employed to dock PI3Kgamma and its known inhibitors viz., wortmannin, quercetin, myricetin and pyridyl-triazine. Besides, serpentine was also docked on the same binding pocket, subsequently its anticancer activity was evaluated through in vitro experiment. Docking studies have been performed in the presence as well as in absence of water molecules at the binding pocket, and results were compared with crystallographic structural data. The comparison was done on the basis of binding energy, RMSD, inhibition constant (Ki), conserved and bridging water molecules, and found that, while considering water molecules during docking experiments, it increases the binding affinity of PI3K inhibitors. PMID- 26603931 TI - Refractory celiac disease. AB - Refractory celiac disease (RCD) affects patients who have failed to heal after 6 12 months of a strict gluten-free diet (GFD) and when other causes of symptoms (including malignancy) have been ruled out. It may also occur in patients who previously had responded to a long-term GFD. RCD may be categorized as RCD1 (normal immunophenotype) and RCD2 (aberrant immunophenotype). RCD1 usually responds to a continued GFD, nutritional support, and therapeutic agents such as corticosteroids. In contrast, clinical response in RCD2 is incomplete and prognosis is often poor. RCD (particularly RCD2) is associated with serious complications, such as ulcerative jejunitis and enteropathy-associated T-cell lymphoma (EATL). Strict clinical and laboratory criteria should be used to diagnose RCD and specialized tests for aberrancy and clonality should be interpreted in the context of their sensitivity and specificity. Adequate nutritional support and anti-inflammatory treatment may even allow patients with RCD2 to attain a clinical remission. PMID- 26603932 TI - Anti-fibrotic effects of a novel small compound on the regulation of cytokine production in a mouse model of colorectal fibrosis. AB - Intestinal fibrotic stricture is a major complication of inflammatory bowel disease. Despite its clinical importance, anti-fibrotic therapy has not been implemented. Transforming growth factor-beta (TGF-beta) is considered to be a major factor contributing to tissue fibrosis. We have previously shown that the administration of a small compound, HSc025, which promotes the nuclear translocation of YB-1 as a downstream effector of IFN-gamma and antagonizes TGF beta/Smad signaling, improves fibrosis in several murine tissues. In this study, we evaluated the anti-fibrotic effect of HSc025 on colorectal fibrosis in TNBS induced murine chronic colitis. Daily oral administration of HSc025 (3, 15 and 75 mg/kg) suppressed collagen production and decreased the severity of colorectal fibrosis in a dose-dependent manner. In addition, the local production of TGF beta was decreased after HSc025 treatment, whereas that of IL-13 and TNF-alpha was not affected. HSc025 administration maintained the level of IFN-gamma production, even at a late stage when IFN-gamma production was lost without the drug treatment. These results demonstrate that HSc025 could be a therapeutic candidate for intestinal fibrosis in inflammatory bowel disease that acts by altering the local production of cytokines, as well as by directly suppressing collagen production. PMID- 26603933 TI - Glucagon-like peptide 1 (GLP-1)-based therapy upregulates LXR-ABCA1/ABCG1 cascade in adipocytes. AB - A promising treatment for obesity involves the use of therapeutic agents that increase the level of the glucagon-like peptide (GLP-1) which reduces appetite and food intake. Native GLP-1 is rapidly metabolized by the dipeptidyl peptidase 4 (DPP-4) enzyme and, as such, GLP-1 mimetics or DPP-4 inhibitors represent promising treatment approaches. Interestingly, obese patient receiving such medications showed improved lipid profiles and cholesterol homeostasis, however the mechanism(s) involved are not known. Members of the ATP-binding cassette (ABC) transporters, including ABCA1 and ABCG1, play essential roles in reverse cholesterol transport and in high density lipoprotein (HDL) formation. These transporters are under the transcriptional regulation of liver X receptor alpha (LXR-alpha). We hypothesize that GLP-1 mimetics and/or DPP-4 inhibitors modulate ABCA1/ABCG1 expression in adipocytes through an LXR-alpha mediated process and thus affecting cholesterol homeostasis. 3T3-L1 adipocytes were treated with the DPP-4 inhibitor vildagliptin (2 nM) or the GLP-1 mimetic exendin-4 (5 nM). Gene and protein expression of ABCA1, ABCG1 and LXR-alpha were determined and correlated with cholesterol efflux. Expression levels of interleukin-6 (IL-6), leptin and the glucose transporter-4 (GLUT-4) were also determined. Treatment with both medications significantly increased the expression of ABCA1, ABCG1, LXR alpha and GLUT-4, decreased IL-6 and leptin, and improved cholesterol efflux from adipocytes (P < 0.05). Our data suggest that GLP-1-based therapy modulate ABCA1/ABCG1 expression in adipocytes potentially through an LXR-alpha mediated process. PMID- 26603934 TI - Carboxypeptidase X-1 (CPX-1) is a secreted collagen-binding glycoprotein. AB - Carboxypeptidase X-1 (CPX-1) is an atypical member of the carboxypeptidase (CP) family of proteins involved in a variety of physiological and pathological processes. However, unlike most other family members CPX-1 lacks catalytic activity making its biological function unclear. CPX-1 contains a 160 amino acid discoidin domain (DSD) that serves as a binding domain in other proteins prompting us to investigate a putative functional role for this domain in CPX-1. Sequence alignment confirmed the overarching homology between the DSD of CPX-1 and other DSDs whilst more detailed analysis revealed conservation of the residues known to form the collagen-binding trench within the DSD of the discoidin domain receptors (DDRs) 1 and 2. Biochemical characterisation of transiently expressed human CPX-1 revealed that CPX-1 was secreted in an N glycosylation-dependent manner as treatment with the N-glycosylation inhibitor tunicamycin inhibited secretion concomitant with a reduction in CPX-1 mobility on Western blot. Using a collagen pull-down assay we found that secreted CPX-1 bound collagen and this appeared independent of N-glycosylation as treatment with PNGaseF did not affect binding. Further analysis under non-reducing and reducing (+DTT) conditions revealed that CPX-1 was secreted in both monomeric and dimeric forms and only the former bound collagen. Finally, mutation of a key residue situated within the putative collagen-binding trench within the DSD of CPX-1 (R192A) significantly reduced secretion and collagen-binding by 40% and 60%, respectively. Collectively these results demonstrate that CPX-1 is a secreted collagen-binding glycoprotein and provide a foundation for future studies investigating the function of CPX-1. PMID- 26603935 TI - Upregulation of lncRNA MEG3 promotes hepatic insulin resistance via increasing FoxO1 expression. AB - BACKGROUND: Hepatic insulin resistance is a major characteristic of type 2 diabetes mellitus. LncRNA MEG3 has been shown to correlate to hepatic glucose production; however, the underlying mechanism remains unclear. This study aims to investigate the role of MEG3 in hepatic insulin resistance. METHODS: High-fat diet mice, ob/ob mice and mice primary hepatocytes were used in this study. Expression of MEG3, FoxO1, G6pc and Pepck were determined by real-time PCR. FoxO1, G6pc, Pepck, HDAC1 and HDAC3 protein levels were analyzed by western blotting. Hepatic gluconeogenesis, glycogen accumulation, triglyceride and glycogen contents were measured by corresponding assay or kit, and body weight was monitored after an overnight fast. RESULTS: Gene expression of MEG3 was upregulated in high-fat diet and ob/ob mice and increased by palmitate, oleate or linoleate. MEG3 overexpression significantly increased FoxO1, G6pc, Pepck mRNA expressions and hepatic gluconeogenesis and suppressed insulin-stimulated glycogen synthesis in primary hepatocytes, whereas palmitate-induced increase of FoxO1, G6pc and Pepck protein expressions could be reversed by MEG3 interference. In addition, high fat enhanced expression of lncRNA MEG3 in hepatocytes through histone acetylation. Furthermore, MEG3 interference could reverse the up regulation of triglyceride as well as impaired glucose tolerance and down regulation of glucogen content in high-fat diet mice or ob/ob mice. CONCLUSION: Upregulation of lncRNA MEG3 enhances hepatic insulin resistance via increasing foxO1expression, suggesting that MEG3 may be a potential target and therapeutic strategy for diabetes. PMID- 26603936 TI - IL-9 antibody injection suppresses the inflammation in colitis mice. AB - Diverse T help (Th) cells play a crucial role in the processing and maintaining of chronic inflammation as seen in ulcerative colitis (UC). Th9, a novel subset of Th cells that primarily produces interleukin (IL)-9, has recently been associated with the development of inflammatory diseases. In this study, we evaluated the presentation of Th9 cells in inflamed tissues of human and experimental mouse UC, and examined the therapeutic efficiency of anti Th9 cytokine IL-9 in the experimental mouse UC. Using immunohistochemistry (IHC), we evaluated the presentation of Th9 cells labelled by transcriptional factor PU.1 in both human and dextran sulfate sodium (DSS) induced mouse colitis biopsies. The results showed that increased PU.1 positive Th9 cells were mainly located in the lamina propria in relative with the controls, intraepithelial Th9 cells can also be observed but at low density. Double IHCs revealed that most of PU.1 positive cells were CD3 positive lymphocytes in human UC specimens. Anti-IL-9 antibody injection for 2 weeks reduced the severity of inflammation in DSS induced colitis mice. Our results suggest that The Th9/IL-9 is involved in the pathogenesis of UC. PMID- 26603937 TI - Biochemical and structural characterization of a keratin-degrading M32 carboxypeptidase from Fervidobacterium islandicum AW-1. AB - Comparative genomics of the keratin-degrading extremophilic eubacterium Fervidobacterium islandicum AW-1 and the closely related Fervidobacterium nodosum with no keratinolytic activity suggested that the FIAW1_1600 gene encoding a carboxypeptidase (CP) plays an important role in keratin degradation. The presumptive 489 amino acid sequence of the gene showed a conserved HEXXH motif with low levels of sequence identity (<38%) to reported thermostable M32 CPs. To identify its functional role, the FIAW1_1600 gene was overexpressed in Escherichia coli, and the recombinant enzyme was purified and characterized in detail. F. islandicum AW-1 CP (FisCP) formed a homodimer with a molecular mass of 107 kDa, and its apoenzyme exhibited maximal activity at 80 degrees C and pH 7.0 in the presence of Co(2+). This metalloenzyme mainly cleaved the C-termini of peptides with a basic amino acid sequence. The crystal structure of FisCP at 2.2 A resolution showed high levels of structural similarities (root-mean-square deviations of <1.7 A) to those of other M32 CP homologs. Remarkably, the enzyme significantly enhanced the degradation of native chicken feathers. This study suggests that FisCP, a keratinolytic member of the thermostable M32 CP family, plays an important role in keratin degradation for cellular metabolism in F. islandicum AW-1. PMID- 26603938 TI - N-Myristoyltransferase 1 interacts with calnexin at the endoplasmic reticulum. AB - Calnexin is a type 1 integral endoplasmic reticulum (ER) membrane molecular chaperone with a highly conserved C-terminal domain oriented to the cytoplasm. Protein N-myristoylation plays an important role in a wide variety of cellular signal transduction pathways and it is catalyzed by N-myristoyltransferase (NMT), a cytoplasmic and ER associated enzyme. Here using yeast two-hybrid screen, Western blot analysis, immunoprecipitation, immunolocalization and cellular fractionation we discovered that N-myristoyltransferase 1 interacts with calnexin at the ER. These observations point at a previously unrecognized contribution of calnexin to the retention of NMT1 at the ER membrane. PMID- 26603930 TI - Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots. AB - Brain has exceptional high requirement for energy metabolism with glucose as the exclusive energy source. Decrease of brain energy metabolism and glucose uptake has been found in patients of Alzheimer's, Parkinson's and other neurodegenerative diseases, providing a clear link between neurodegenerative disorders and energy metabolism. On the other hand, cancers, including glioblastoma, have increased glucose uptake and rely on aerobic glycolysis for energy metabolism. The switch of high efficient oxidative phosphorylation to low efficient aerobic glycolysis pathway (Warburg effect) provides macromolecule for biosynthesis and proliferation. Current research indicates that methylene blue, a century old drug, can receive electron from NADH in the presence of complex I and donates it to cytochrome c, providing an alternative electron transfer pathway. Methylene blue increases oxygen consumption, decrease glycolysis, and increases glucose uptake in vitro. Methylene blue enhances glucose uptake and regional cerebral blood flow in rats upon acute treatment. In addition, methylene blue provides protective effect in neuron and astrocyte against various insults in vitro and in rodent models of Alzheimer's, Parkinson's, and Huntington's disease. In glioblastoma cells, methylene blue reverses Warburg effect by enhancing mitochondrial oxidative phosphorylation, arrests glioma cell cycle at s-phase, and inhibits glioma cell proliferation. Accordingly, methylene blue activates AMP activated protein kinase, inhibits downstream acetyl-coA carboxylase and cyclin dependent kinases. In summary, there is accumulating evidence providing a proof of concept that enhancement of mitochondrial oxidative phosphorylation via alternative mitochondrial electron transfer may offer protective action against neurodegenerative diseases and inhibit cancers proliferation. PMID- 26603939 TI - A serum-free and defined medium for the culture of mammalian postimplantation embryos. AB - Whole embryo culture (WEC) of postimplantation rodent embryos is widely used for the study of mammalian embryogenesis and developmental toxicity testing. Its major advantage is that it allows direct access to embryos for experimental manipulations and the monitoring of their consequences that would otherwise not be possible or technically difficult to perform in utero. However, a major drawback of mammalian WEC is that the culture media currently in use display batch variations and are undefined, as they contain serum or serum replacements of unknown composition. Moreover, these media possess cell-signalling activities important for embryogenesis. Therefore, reproducibility of mammalian postimplantation WEC results may be affected by batch variation and their interpretation is complicated because the experimenter is unsure whether the embryo response to experimental perturbations is solely due to their action, or modified as a result of influences from undefined substances/signaling activities present in culture media. To alleviate these problems we investigated whether N2B27, a serum-free and defined medium, can support the in vitro development of postimplantation mammalian embryos. We show that N2B27 allows pre-gastrulation mouse embryos isolated at embryonic day 5.5 to develop to advanced gastrulation, reaching the mid- and late primitive streak stages. This is the first demonstration that postimplantation mammalian embryos can develop in vitro in a defined medium in the absence of serum and provides a novel WEC system for studying developmental mechanisms and testing for developmental toxicity during the early postimplantation period. PMID- 26603940 TI - Water and Ethanol Droplet Wetting Transition during Evaporation on Omniphobic Surfaces. AB - Omniphobic surfaces with reentrant microstructures have been investigated for a range of applications, but the evaporation of high- and low-surface-tension liquid droplets placed on such surfaces has not been rigorously studied. In this work, we develop a technique to fabricate omniphobic surfaces on copper substrates to allow for a systematic examination of the effects of surface topography on the evaporation dynamics of water and ethanol droplets. Compared to a water droplet, the ethanol droplet not only evaporates faster, but also inhibits Cassie-to-Wenzel wetting transitions on surfaces with certain geometries. We use an interfacial energy-based description of the system, including the transition energy barrier and triple line energy, to explain the underlying transition mechanism and behaviour observed. Suppression of the wetting transition during evaporation of droplets provides an important metric for evaluating the robustness of omniphobic surfaces requiring such functionality. PMID- 26603941 TI - The diagnostic line: A novel criterion for condition monitoring of rotating machinery. AB - This study examined scaling properties of an increment series from rotating machinery. Moreover, two fluctuation parameters for the smallest and largest time scales of a scaling range served as a pair of fluctuation parameters to describe system conditions. Therefore, an interesting phenomenon is observed: the data points, each representing a pair of fluctuation parameters, for fault conditions almost form a straight line, while those for normal clearly depart from the straight line. To describe the phenomenon, a novel concept termed the diagnostic line was introduced. Subsequently, properties of the diagnostic line were carefully investigated theoretically and numerically. Consequently, a decisive role of noise in forming the diagnostic line was determined. Accordingly, this study develops a novel criterion for condition monitoring of rotating machinery. PMID- 26603942 TI - Further results on stochastic admissibility for singular Markov jump systems using a dissipative constrained condition. AB - In this paper, the stochastic admissibility analysis problem is investigated for a class of singular Markov jump delayed systems (SMJDSs). The purpose is to establish some conditions such that the SMJDSs are stochastically admissible and strictly (X, Y, Z)-MU-dissipative. A mode-dependent Lyapunov functional and some novel inequalities are proposed for the considered SMJDSs. Based on these, some new stochastic admissibility conditions are established. In comparison with the existing results, the advantage of the obtained conditions lies in the fact that they are not only less conservatism but also more general. Four numerical examples borrowed from some existing papers are given to demonstrate the effectiveness and the reduced conservatism of the presented method. PMID- 26603943 TI - Quantifying Modes of 3D Cell Migration. AB - Although it is widely appreciated that cells migrate in a variety of diverse environments in vivo, we are only now beginning to use experimental workflows that yield images with sufficient spatiotemporal resolution to study the molecular processes governing cell migration in 3D environments. Since cell migration is a dynamic process, it is usually studied via microscopy, but 3D movies of 3D processes are difficult to interpret by visual inspection. In this review, we discuss the technologies required to study the diversity of 3D cell migration modes with a focus on the visualization and computational analysis tools needed to study cell migration quantitatively at a level comparable to the analyses performed today on cells crawling on flat substrates. PMID- 26603944 TI - DPD deficiency in patients treated with fluorouracil. PMID- 26603946 TI - Postabortion Initiation of Long-Acting Reversible Contraception by Adolescent and Nulliparous Women in New Zealand. AB - PURPOSE: To describe changes in receipt of immediate postabortion long-acting reversible contraception (LARC) by adolescent and nulliparous women in New Zealand. METHODS: Nationally collected data on immediate postabortion receipt of an intrauterine method (intrauterine device [IUD]/intrauterine system [IUS]) or contraceptive implant were analyzed to describe proportions and demographic characteristics of women receiving LARC between 2007 and 2013. Changes in uptake over time were presented for adolescent, nulliparous, and parous women. RESULTS: Postabortion LARC uptake increased between 2007 and 2013, rising from 7.9% to 42.7% for adolescents and from 8.8% to 36.9% for nulliparous women. The increase was highest among nulliparous adolescents with a seven-fold increase in LARC uptake between 2007 and 2013. Adolescents had a five-fold increase and nulliparous women (of all ages) a four-fold increase. In 2013, IUD/IUS use was lowest among adolescents (22.4%) and increased with increasing age (43% by ages 40+ years), whereas implant use was highest among adolescents (20.3%) and decreased with increasing age (to 4.6% by age 40+ years). Nulliparous women had the lowest use of both IUD/IUS and implants in 2013, with 24.6% receiving an intrauterine method (compared with 43.2% for para 3+), and 12.3% an implant (compared with 17.5% for para 3+). CONCLUSIONS: Despite an overall trend toward increased uptake of postabortion LARC by adolescent and nulliparous women, uptake in these groups still lags behind that of parous and older women. Reasons for differential uptake need to be explored and addressed if necessary to ensure all women have equitable access to the most effective methods of contraception. PMID- 26603945 TI - Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. AB - BACKGROUND: The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD (DPYD), including DPYD*2A and c.2846A>T. Three other variants-DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity. METHODS: We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade >=3) fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0.0167 (Bonferroni correction). FINDINGS: 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4.40, 95% CI 2.08-9.30, p<0.0001), as was c.1236G>A/HapB3 (1.59, 1.29-1.97, p<0.0001). The association between c.1601G>A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1.52, 95% CI 0.86-2.70, p=0.15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5.72, 95% CI 1.40-23.33, p=0.015; and 2.04, 1.49-2.78, p<0.0001, respectively) and haematological toxicity (adjusted RR 9.76, 95% CI 3.03-31.48, p=0.00014; and 2.07, 1.17-3.68, p=0.013, respectively), but not with hand-foot syndrome. DPYD*2A and c.2846A>T were also significantly associated with severe fluoropyrimidine associated toxicity (adjusted RR 2.85, 95% CI 1.75-4.62, p<0.0001; and 3.02, 2.22 4.10, p<0.0001, respectively). INTERPRETATION: DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD*2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines. FUNDING: None. PMID- 26603947 TI - Problems with the electronic health record. AB - One of the most significant changes in modern healthcare delivery has been the evolution of the paper record to the electronic health record (EHR). In this paper we argue that the primary change has been a shift in the focus of documentation from monitoring individual patient progress to recording data pertinent to Institutional Priorities (IPs). The specific IPs to which we refer include: finance/reimbursement; risk management/legal considerations; quality improvement/safety initiatives; meeting regulatory and accreditation standards; and patient care delivery/evidence based practice. Following a brief history of the transition from the paper record to the EHR, the authors discuss unintended or contested consequences resulting from this change. These changes primarily reflect changes in the organization and amount of clinician work and clinician patient relationships. The paper is not a research report but was informed by an institutional ethnography the aim of which was to understand how the EHR impacted clinicians and administrators in a large, urban hospital in the United States. The paper was also informed by other sources, including the philosophies of Jacques Ellul, Don Idhe, and Langdon Winner. PMID- 26603948 TI - Prevention of Surgical Site Infection After Ankle Surgery Using Vacuum-Assisted Closure Therapy in High-Risk Patients With Diabetes. AB - Patients with diabetes have a high risk of surgical site infection (SSI) after ankle surgery. The aim of the present study was to investigate the efficacy of vacuum-assisted closure (VAC) in the prevention of SSI after ankle surgery compared with the efficacy of standard moist wound care (SMWC). A retrospective study was performed of unstable ankle fractures for surgical fixation in patients with diabetes from January 2012 to December 2014. VAC and SMWC were used for surgical incision coverage. The primary outcome was the incidence of SSI, and the secondary outcomes were the length of hospital stay and crude hospital costs. The data from 76 patients were analyzed, with 22 (28.95%) in the VAC group and 54 (71.05%) in the SMWC group. The incidence of SSI was 4.6% in the VAC group compared with 27.8% in the SMWC group (chi-square 5.076; p = .024), and the crude odds ratio for SSI in the VAC group was 0.124 (95% confidence interval 0.002 to 0.938). The length of hospital stay was lower in the VAC group than in the SMWC group (12.6 +/- 2.7 days and 15.2 +/- 3.5 days, respectively; t = 3.122, p = .003). The crude hospital costs were also lower in the VAC group than in the SMWC group (Chinese yuan 8643.2 +/- 1195.3 and 9456.2 +/- 1106.3, respectively; t = 2.839, p = .006). After logistic regression analysis, the adjusted odds ratio for the total SSI rate comparing VAC and SMWC was 0.324 (95% confidence interval 0.092 to 0.804; p = .021). Compared with SMWC, VAC can decrease the SSI rate after ankle surgery in patients with diabetes. This finding should be confirmed by prospective, randomized controlled clinical trials. PMID- 26603949 TI - Seroprevalence in Chickens against Campylobacter jejuni Flagellar Capping Protein (FliD) in Selected Areas of the United States. AB - Campylobacter jejuni is a causative pathogen of human acute bacterial gastroenteritis. Infected poultry products are regarded as a major source for human C. jejuni infection. The flagellar capping protein (FliD) is highly conserved among C. jejuni strains/isolates and is antigenic as analysed by immunoblot. In this study, we used the FliD protein as a probe to survey the prevalence of C. jejuni antibodies in chickens from two areas in the United States. A total of 394 samples were tested. Sera from layer breeders of 44-52 weeks of age tested 100% positive, while 4- to 6-week broilers from 22 premises showed 7-100% positivity. These results demonstrate that anti-FliD antibodies were prevalent in the poultry population in the areas of serum samples collected. PMID- 26603950 TI - Papain-Based Vaccination Modulates Schistosoma mansoni Infection-Induced Cytokine Signals. AB - We have previously shown that immunization of outbred rodents with cysteine peptidases-based vaccine elicited type 2-biased immune responses associated with consistent and reproducible protection against challenge Schistosoma mansoni. We herein start to elucidate the molecular basis of C57BL/6 mouse resistance to S. mansoni following treatment with the cysteine peptidase, papain. We evaluated the early cytokine signals delivered by epidermal, dermal, and draining lymph node cells of naive, and S. mansoni -infected mice treated 1 day earlier with 0 or 50 MUg papain, or immunized twice with papain only (10 MUg/mouse), papain-free recombinant S. mansoni glyceraldehyde 3-phosphate dehydrogenase and 2-Cys peroxiredoxin peptide (10 and 15 MUg/mouse, respectively = antigen Mix), or papain-adjuvanted antigen Mix. Schistosoma mansoni infection induced epidermal and lymph node cells to release type 1, type 2 and type 17 cytokines, known to counteract each other. Expectedly, humoral immune responses were negligible until patency. Papain pretreatment or papain-based vaccination diminished or shut off S. mansoni infection early induction of type 1, type 17 and type 2 cytokines except for thymic stromal lymphopoietin and programmed the immune system towards a polarized type 2 immune milieu, associated with highly significant (P < 0.005 - <0.0001) resistance to S. mansoni infection. PMID- 26603951 TI - Metaphyseal osteopathy-like disease in two sibling kittens. AB - This report describes the diagnosis and treatment of a growth plate disturbance resembling canine metaphyseal osteopathy in two, two-month-old, sibling, intact, female Domestic Shorthair cats. Clinical signs and radiographic lesions resolved spontaneously after three months. Follow-up examination at six months of age showed complete recovery and no radiographic abnormalities. PMID- 26603952 TI - A Dual Colorimetric/Fluorescence System for Determining pH Based on the Nucleophilic Addition Reaction of an o-Hydroxymerocyanine Dye. AB - Owing to their ability to monitor pH in a precise and rapid manner, optical probes have widely been developed for biological and nonbiological applications. The strategies thus far employed to determine pH rely on two types of processes including reversible protonation of amine nitrogen atoms and deprotonation of phenols. We have developed a novel dual, colorimetric/fluorescence system for determining the pH of a solution. This system utilizes an o-hydroxymerocyanine dye that undergoes a nucleophilic addition reaction that subsequently causes reversible structural changes interconverting a merocyanine to a spirocyanine and a spirocyanine to a spiropyran. It was demonstrated that the dye can be employed to measure the pH of solutions in the 2.5-5.75 and 9.6-11.8 ranges with color changes from yellow to dark blue and then to lavender. Moreover, the fluorescence response associated with the spirocyanine-spiropyran transformation of the dye occurring in alkaline solutions provides a precise method. PMID- 26603953 TI - Formation of environmentally persistent free radicals from the heterogeneous reaction of ozone and polycyclic aromatic compounds. AB - In the 1980s long-lived radical species were identified in cigarette tar. Since then, environmentally persistent free radicals (EPFRs) have been observed in ambient particulate matter, and have been generated in particulate matter generated from internal combustion engines. For the first time, we measure in situ the formation and decay of EPFRs through the heterogeneous reaction of ozone and several polycyclic aromatic compounds (PAC). Solid anthracene (ANT), pyrene (PY), benzo[a]pyrene (BAP), benzo[ghi]perylene (BGHIP), 1,4-naphthoquinone (1,4NQ), and 9,10-anthraquinone (AQ) were reacted with gas-phase ozone in a flow system placed in the active cavity of an electron paramagnetic resonance (EPR) spectrometer, and the formation of radicals was measured on the timescale of tens of minutes at ambient levels of ozone down to 30 ppb. For most substrates the net radical production is initially rapid, slows at intermediate times, and is followed by a slow decay. For oxidized solid BAP, radical signal persists for many days in the absence of ozone. To evaluate the effect of substrate phase, the solid PAHs were also dissolved in squalane, an organic oil inert to ozone, which yielded a much higher maximum radical concentration and faster radical decay when exposed to ozone. With higher mobility, reactants were apparently able to more easily diffuse and react with each other, yielding the higher radical concentrations. The EPR spectra exhibit three radicals types, two of which have been assigned to semiquinone species and one to a PAH-derived, carbon-centered radical. Although our system uses levels of PAC not typically found in the environment it is worth noting that the amounts of radical formed, on the order of 10(18) radicals per g, are comparable to those observed in ambient particulate matter. PMID- 26603954 TI - Quantifying the risk of pandemic influenza virus evolution by mutation and re assortment. AB - Large outbreaks of zoonotic influenza A virus (IAV) infections may presage an influenza pandemic. However, the likelihood that an airborne-transmissible variant evolves upon zoonotic infection or co-infection with zoonotic and seasonal IAVs remains poorly understood, as does the relative importance of accumulating mutations versus re-assortment in this process. Using discrete-time probabilistic models, we determined quantitative probability ranges that transmissible variants with 1-5 mutations and transmissible re-assortants evolve after a given number of zoonotic IAV infections. The systematic exploration of a large population of model parameter values was designed to account for uncertainty and variability in influenza virus infection, epidemiological and evolutionary processes. The models suggested that immunocompromised individuals are at high risk of generating IAV variants with pandemic potential by accumulation of mutations. Yet, both immunocompetent and immunocompromised individuals could generate high viral loads of single and double mutants, which may facilitate their onward transmission and the subsequent accumulation of additional 1-2 mutations in newly-infected individuals. This may result in the evolution of a full transmissible genotype along short chains of contact transmission. Although co-infection with zoonotic and seasonal IAVs was shown to be a rare event, it consistently resulted in high viral loads of re-assortants, which may facilitate their onward transmission among humans. The prevention or limitation of zoonotic IAV infection in immunocompromised and contact individuals, including health care workers, as well as vaccination against seasonal IAVs-limiting the risk of co-infection-should be considered fundamental tools to thwart the evolution of a novel pandemic IAV by accumulation of mutations and re-assortment. PMID- 26603955 TI - The actual and potential costs of meningitis surveillance in the African meningitis belt: Results from Chad and Niger. AB - BACKGROUND: The introduction of serogroup A meningococcal conjugate vaccine in the African meningitis belt required strengthened surveillance to assess long term vaccine impact. The costs of implementing this strengthening had not been assessed. METHODOLOGY: The ingredients approach was used to retrospectively determine bacterial meningitis surveillance costs in Chad and Niger in 2012. Resource use and unit cost data were collected through interviews with staff at health facilities, laboratories, government offices and international partners, and by reviewing financial reports. Sample costs were extrapolated to national level and costs of upgrading to desired standards were estimated. RESULTS: Case based surveillance had been implemented in all 12 surveyed hospitals and 29 of 33 surveyed clinics in Niger, compared to six out of 21 clinics surveyed in Chad. Lumbar punctures were performed in 100% of hospitals and clinics in Niger, compared to 52% of the clinics in Chad. The total costs of meningitis surveillance were US$ 1,951,562 in Niger and US$ 338,056 in Chad, with costs per capita of US$ 0.12 and US$ 0.03, respectively. Laboratory investigation was the largest cost component per surveillance functions, comprising 51% of the total costs in Niger and 40% in Chad. Personnel resources comprised the biggest expense type: 37% of total costs in Niger and 26% in Chad. The estimated annual, incremental costs of upgrading current systems to desired standards were US$ 183,299 in Niger and US$ 605,912 in Chad, which are 9% and 143% of present costs, respectively. CONCLUSIONS: Niger's more robust meningitis surveillance system costs four times more per capita than the system in Chad. Since Chad spends less per capita, fewer activities are performed, which weakens detection and analysis of cases. Countries in the meningitis belt are diverse, and can use these results to assess local costs for adapting surveillance systems to monitor vaccine impact. PMID- 26603956 TI - [Functional evaluation and quality of life in patients treated for pulmonary tuberculosis: An underestimated issue in countries with limited resources]. PMID- 26603957 TI - [Script concordance test for knowledge assessment of lung cancer screening]. AB - BACKGROUND: Annual screening for lung cancer using low-dose CT-scans is associated with decreased mortality. A survey conducted in Rhone-Alpes area in France found that clinicians need education and information on this topic. Script concordance tests (SCT) are a tool for assessing clinical reasoning in situations of uncertainty. They have not previously been used in France in the context of continuing medical education. METHOD: We created a questionnaire with 5 multiple choice questions (MCQ) and two SCT scenarios. The questionnaire was sent to all clinicians and residents who are members of French-Speaking Respiratory Society or the French Young Pulmonologist Association. RESULTS: One hundred and ninety answers were analyzed. Seventy percent stated that decreasing mortality was the best criterion for assessing the effectiveness of a cancer screening policy, and 75% that low-dose CT scan was the best test to achieve this in lung cancer screening. Forty-five percent knew the eligibility criteria of the population, and 62% that low-dose CT scan should be performed annually. Participation in tumor boards and certification in oncology were significantly associated with a better score at MCQ and SCT. SCT and MCQ scores were significantly correlated (Spearman's Rho 0.339; P<0.0001). CONCLUSION: SCT are feasible by electronic survey and seem relevant. Improving knowledge of clinicians on lung cancer screening is still critical. PMID- 26603958 TI - [E-cigarette use in university students and its relationship to cigarette smoking]. AB - INTRODUCTION: There is concern that e-cigarette use could be a risk factor for subsequent cigarette smoking. METHODS: This survey included a group of 1220 students at Aix-Marseille University who attended a check-up visit and volunteered to participate to the survey. They answered a standardized questionnaire relating to e-cigarette use, smoking habits and the relationship between both habits. Mean age of participants was 19.9 years and 56% of them were female. RESULTS: All students invited to the check-up examination attended and agreed to participate in the survey. 13.3% of students answered they had already used e-cigarettes, a higher proportion of boys (17.5%) than girls (10.0%), starting at a mean age equal to 19.2 years. Forty-six percent of them had already smoked cigarettes, more girls (55.0%) than boys (45.0%). Among current cigarette smokers, e-cigarette use had induced giving up smoking in 12.6% and a decrease in the number of cigarettes smoked in 30.1%. Twenty percent said they begun to smoke cigarettes after using e-cigarettes. DISCUSSION: E-cigarette use is much less prevalent than smoking conventional tobacco cigarettes. There is a strong link between both. E-cigarette use had allowed a cessation or reduction in tobacco smoking in half of users. E-cigarette users may go on to start tobacco smoking but prospective surveys are needed to know how this will evolve over time. E cigarette use could also be a means to prevent or postpone cigarette smoking. PMID- 26603959 TI - [Sleep duration and metabolism]. AB - Sleep duration has gradually diminished during the last decade while obesity and type 2 diabetes have become epidemics. Experimental sleep curtailment leads to increased appetite, hormonal disturbances and, especially, insulin resistance. Numerous epidemiological studies have therefore examined whether habitual short sleep is associated with obesity and type 2 diabetes. A large majority of cross sectional studies have confirmed an association between short, and also long sleep duration and obesity in adults more than in the elderly. Short sleep is strongly associated to obesity in children and adolescents. Prospective studies, including studies in children, are not conclusive with regard to the effect of short sleep on the incidence of obesity. Both short and long sleep durations are associated with diabetes, but only short sleep duration seems predictive of future diabetes. Insomnia seems to be a strong contributor to short sleep duration but the association of insomnia with obesity is not clear. Insomnia is associated with type 2 diabetes and also predictive of a higher incidence. Other studies have shown that short sleep duration and insomnia are associated with, and sometime predictive of, other components of the metabolic syndrome, especially hypertension and the risk of coronary disease. The treatment of short sleep duration and insomnia with regard to their effects on the metabolic syndrome merits further study. PMID- 26603961 TI - Starred. PMID- 26603960 TI - [Angiosarcoma mimicking recurrent pulmonary embolism]. AB - INTRODUCTION: Pulmonary artery sarcoma is a rare disease with non-specific symptoms. The clinical and radiological presentation can mimic pulmonary embolism with chronic thromboembolic pulmonary hypertension. Management is essentially surgical but the prognosis remains poor. CASE REPORT: A patient presented with symptoms of pulmonary embolism. Despite vitamin K antagonist therapy, he suffered from extension of the endovascular defects and his pulmonary hypertension increased. Suspicious results of positron emission tomography suggested the diagnosis of pulmonary artery sarcoma that was confirmed by surgery. However, the outcome was unfavourable, leading to death of the patient. CONCLUSION: This case reinforces the idea that the clinical and tomodensitometric presentations of pulmonary arterial sarcoma and chronic thromboembolic pulmonary hypertension are similar. The positron emission tomography seems to be a key to distinguishing these two diagnoses. PMID- 26603962 TI - Does Microbial Diversity Confound General Predictions? AB - Microbes show more geographic diversity than previously expected, a serious challenge for ecological prediction. However, a recent study shows that microbial communities from a global grassland plot network responded consistently to nutrient addition. These results highlight the risks of nutrient deposition, but also hope for generalized understanding of microbial communities. PMID- 26603963 TI - Trigeminal Nerve Stimulation (TNS) for Panic Disorder: An Open Label Proof-of Concept Trial. PMID- 26603964 TI - Case Report: Repetitive Transcranial Magnetic Stimulation (rTMS) Treatment of Depression in a Patient with Myasthenia Gravis. PMID- 26603966 TI - Coronary Flow Reserve Predicts Longitudinal Myocardial Deformation Capacity in Heart-Transplanted Patients. AB - AIMS: This study aimed to evaluate the role of microvascular dysfunction on left ventricular (LV) longitudinal deformation, filling pressures, and exercise capacity in heart-transplanted (HTx) patients. METHODS AND RESULTS: Fifty-seven HTx patients underwent comprehensive echocardiographic graft function assessment during symptom-limited, semisupine exercise test with simultaneous right heart catheterization. Coronary flow velocity reserve (CFVR) was measured in the left anterior descending artery using pulsed Doppler echocardiography. We divided patients into two groups based on upper and lower median of CFVR. Twenty-six healthy subjects served as controls. Compared with healthy controls, HTx patients had reduced CFVR (P < 0.0001), exercise capacity (P < 0.0001), and LV longitudinal deformation capacity (P < 0.0001). HTx patients in the reduced CFVR group (CFVR < 2.73) were more symptomatic (P < 0.0001) and had higher prevalence of coronary cardiac allograft vasculopathy (CAV) (P < 0.0001) than patients in the high CFVR group. Systolic function improved in both HTx groups during exercise. However, LV longitudinal myocardial deformation improved significantly more in the high CFVR group (P < 0.0001). Peak exercise LV global longitudinal strain and CFVR were strongly correlated (r = 0.8, P < 0.0001). A weak correlation was observed between CFVR and invasive cardiac index at peak exercise (r = 0.35, P < 0.01) and CFVR and LV filling measured by E/e' ratio (r = -0.41, P < 0.01) and pulmonary capillary wedge pressure (r = -0.30, P < 0.05). CONCLUSION: HTx patients have reduced CFVR, exercise capacity, and LV longitudinal myocardial deformation capacity compared with healthy individuals. HTx patients with reduced CFVR are more symptomatic and have increased prevalence of CAV. Furthermore, reduced CFVR is correlated with reduced LV longitudinal myocardial deformation and exercise capacity. PMID- 26603965 TI - Use of a mobile tower-based robot--The initial Xi robot experience in surgical oncology. AB - BACKGROUND AND OBJECTIVES: The da Vinci Xi platform provides expanded movement of the arms relative to the base, theoretically allowing increased versatility in complex multi-field or multi-quadrant surgery. We describe the initial Xi experience in oncologic surgery at a tertiary cancer center. METHODS: One hundred thirty unique robot-assisted procedures were performed using the Xi between 2014 and 2015, 112 of which were oncology surgeries. For procedures involving multiple quadrants, the robot was re-targeted. Complications were assessed according to Martin criteria and the Clavien-Dindo classification up to 90 days after operation. RESULTS: Thirteen different operations were performed in five oncology subspecialties (urology, gynecology, thoracic, hepatobiliary, and gastrointestinal surgery). Median operative times ranged from 183 min for nephroureterectomy to 543 min for esophagogastrectomy. Median estimated blood loss did not exceed 200 ml for any of the categorized procedures . No patients were transfused intraoperatively and no positioning injuries occurred. Conversions to open operation occurred in three cases (2.7%), though not related to complications or technical considerations. Overall complication rate was 26% with major complication rate of 4%. Readmissions were necessary in 11 (10%) patients. CONCLUSIONS: The da Vinci Xi can be safely assimilated into a surgical oncology program. The Xi offers versatility to various oncologic procedures with satisfactory complication and readmission rates. PMID- 26603967 TI - Distinguishing Protonation States of Histidine Ligands to the Oxidized Rieske Iron-Sulfur Cluster through (15) N Vibrational Frequency Shifts. AB - The Rieske [2Fe-2S] cluster is a vital component of many oxidoreductases, including mitochondrial cytochrome bc1; its chloroplast equivalent, cytochrome b6f; one class of dioxygenases; and arsenite oxidase. The Rieske cluster acts as an electron shuttle and its reduction is believed to couple with protonation of one of the cluster's His ligands. In cytochromes bc1 and b6f, for example, the Rieske cluster acts as the first electron acceptor in a modified Q cycle. The protonation states of the cluster's His ligands determine its ability to accept a proton and possibly an electron through a hydrogen bond to the electron carrier, ubiquinol. Experimental determination of the protonation states of a Rieske cluster's two His ligands by NMR spectroscopy is difficult, due to the close proximity of the two paramagnetic iron atoms of the cluster. Therefore, this work reports density functional calculations and proposes that difference vibrational spectroscopy with (15) N isotopic substitution may be used to assign the protonation states of the His ligands of the oxidized Rieske [2Fe-2S] complex. PMID- 26603968 TI - Proteomics in food: Quality, safety, microbes, and allergens. AB - Food safety and quality and their associated risks pose a major concern worldwide regarding not only the relative economical losses but also the potential danger to consumer's health. Customer's confidence in the integrity of the food supply could be hampered by inappropriate food safety measures. A lack of measures and reliable assays to evaluate and maintain a good control of food characteristics may affect the food industry economy and shatter consumer confidence. It is imperative to create and to establish fast and reliable analytical methods that allow a good and rapid analysis of food products during the whole food chain. Proteomics can represent a powerful tool to address this issue, due to its proven excellent quantitative and qualitative drawbacks in protein analysis. This review illustrates the applications of proteomics in the past few years in food science focusing on food of animal origin with some brief hints on other types. Aim of this review is to highlight the importance of this science as a valuable tool to assess food quality and safety. Emphasis is also posed in food processing, allergies, and possible contaminants like bacteria, fungi, and other pathogens. PMID- 26603969 TI - Guidelines for pre- and intra-operative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS(r)) Society recommendations--Part I. PMID- 26603970 TI - The role of racial genetic admixture with endometrial cancer outcomes: An NRG Oncology/Gynecologic Oncology Group study. AB - PURPOSE: Racial genetic admixture (RGA), a measure to account for ancestral genetic background that correlates with individual's racial classification, could provide insights on causation of racial disparity in endometrial cancer (EC). Our objective is to evaluate the association of RGA with EC outcomes. METHODS: EC patients enrolled onto the GOG-210 protocol were eligible. A randomized subcohort stratified by stage and self-reported race/ethnicity of black or white was used. Genotyping was performed using custom-selected Ancestry Informative Markers to calculate individual admixture estimates of African and European ancestral background. RESULTS: A total of 149 patients were evaluated (self-reported race: 70 black & 79 white). Mean RGA for African ancestry for self-reported black patients was 0.65 (range 0.04-0.86); while mean RGA for European ancestry for self-reported white patients was 0.77 (range 0.12-0.88). Progression-free survival (PFS) analysis using proportional hazards models stratified by stage and race revealed that each 0.10 increase in African ancestry was associated with worse PFS with hazard ratio (HR) of 1.11 (95% CI 0.90-1.37). Each 0.10 increase in European RGA was associated with improved PFS with HR of 0.86 (95% CI 0.69 1.07). Using tertiles of African RGA showed increasing risk of progression of death with increasing African RGA (with 0-5% as reference), HR (95% CIs) for top two tertiles are: 6%-66%: 1.38 (0.64, 2.97), and 67%-86%: 2.27 (0.74, 6.95). CONCLUSION: RGA demonstrated a trend with PFS in self-reported black and white patients with EC. Patients with increased levels of African ancestry showed a trend towards worse survival after stratifying by stage/race. PMID- 26603971 TI - Differences in baseline factors and survival between normocapnia, compensated respiratory acidosis and decompensated respiratory acidosis in COPD exacerbation: A pilot study. AB - BACKGROUND AND OBJECTIVE: Patients with chronic obstructive pulmonary disease (COPD) experiencing acute exacerbation (AE-COPD) with decompensated respiratory acidosis are known to have poor outcomes in terms of recurrent respiratory failure and death. However, the outcomes of AE-COPD patients with compensated respiratory acidosis are not known. METHODS: We performed a 1-year prospective, single-centre, cohort study in patients surviving the index admission for AE-COPD to compare baseline factors between groups with normocapnia, compensated respiratory acidosis and decompensated respiratory acidosis. Survival analysis was done to examine time to readmissions, life-threatening events and death. RESULTS: A total of 250 patients fulfilling the inclusion and exclusion criteria were recruited and 245 patients were analysed. Compared with normocapnia, both compensated and decompensated respiratory acidosis are associated with lower FEV1 % (P < 0.001), higher GOLD stage (P = 0.003, <0.001) and higher BODE index (P = 0.038, 0.001) and a shorter time to life-threatening events (P < 0.001). Comparing compensated and decompensated respiratory acidosis, there was no difference in FEV1 (% predicted) (P = 0.15), GOLD stage (P = 0.091), BODE index (P = 0.158) or time to life-threatening events (P = 0.301). High PaCO2 level (P = 0.002) and previous use of non-invasive ventilation (NIV) in acute setting (P < 0.001) are predictive factors of future life-threatening events by multivariate analysis. CONCLUSIONS: Compared with normocapnia, both compensated and decompensated respiratory acidosis are associated with poorer lung function and higher risk of future life-threatening events. High PaCO2 level and past history of NIV use in acute settings were predictive factors for future life-threatening events. Compensated respiratory acidosis warrants special attention and optimization of medical therapy as it poses risk of life-threatening events. PMID- 26603972 TI - [A manner of voicing, the mass hysteria]. AB - INTRODUCTION: Mass hysteria is defined as the epidemic occurrence of a succession of physical symptoms without organic disorder or identifiable illness agents. The hysteria epidemic has been described since the Middle Ages, reported in different cultures and religions and affects different populations throughout the world. Few studies on the subject have been under takenin Madagascar. We aim at describing in this study the clinical and therapeutic aspects of a mass hysteria that has occurred in the South of Madagascar. METHODOLOGY: The study is retrospective and prospective at the same time. It concerns the victims of a mass hysteria that had occurred in a village (Ikalahazo) in the South of Madagascar,from the 6th of April 2009 to the 7th of May 2009. Patients exhibiting clinical symptoms ofconversive behavior and having undergone an assessment in hospital surroundings represent the object of this study. During the study period, 27 cases of young women were reported, 22 ofthem were sent to the University Hospital Center of Fianarantsoa (UHCF), a referring center o fthe region, for a thorough clinical examination. Demographic data, the clinical aspects and thecare and treatment provided are the studied parameters. RESULT: During a land ownership dissension that drags on endlessly in Ikalahazo village, exclusively 27 young women, between 8 and 21 years old, presented atypical symptoms, strangedisorders. A first case appeared on the 6th of April 2009, that is to say a month before alarge manifestation of the crisis. A similar case was observed two years ago, but it was an isolated case. The symptoms, primarily with motive manifestation, extended rapidly but remainedhowever limited, susceptible to the "Mpiandry" (literally "shepherds") advice. As the villagers believed that spiteful spirits were at the origin of the deeds, they appealed to the latter. Facing the symptoms persistence, the Neuropsychiatry Unit employees of the CHUF were sent to the village on the 6th of May 2009. The intense adhesion of villagers to a belief in satanic misdeedscomplicated their somatic assessment, the results of which showed no distinctive features. At the end of the land dissension proceedings that was resolved in favor of the villagers, and after the isolation of the "madwomen" in the Mpiandry's camp, no more pathological cases related to the above occurrence were reported. CONCLUSION: A mass hysteria diagnosis is retained. It is favored and kept up by local dissensions,by the villagers' belief and its large media casting, thanks to the shepherds' presence. It mingles culture, tradition and modern psychiatry. Therefore, care and treatment of the disorder to be appropriate and optimal require the cooperation between these three spheres. PMID- 26603973 TI - [Long-term efficacy and safety of lurasidone in the treatment of schizophrenia]. AB - Lurasidone is a new second-generation antipsychotic approved in March 2014 by the European Medicines Agency for the treatment of schizophrenia. Lurasidone has demonstrated its efficacy in long-term studies. It has been shown to reduce significantly the risk of relapse in comparison with placebo in patients with schizophrenia. In comparator study, lurasidone was noninferior to quetiapine XR in risk for relapse. In open-label studies, lurasidone was associated with sustained improvement in efficacy measures observed and well-tolerated inpatients with schizophrenia who had switched to lurasidone from another antipsychotic. Available evidence showed also that lurasidone might be involved in the long-term improvement of cognitive performance in schizophrenic patients. Lurasidone differs from the other second-generation antipsychotics by a good tolerability profile, in particular in terms of metabolic and cardiovascular profiles. Lurasidone seems to have a moderate link with the occurrence of akathisia and extrapyramidal symptoms. Although lurasidone long-acting formulation is lacking, the long-term profile of lurasidone appears compatible with a good acceptability and consequently a good compliance to treatment of patients with schizophrenia. PMID- 26603974 TI - Virus-Specific CD8(+) T Cells Cross-Reactive to Donor-Alloantigen Are Transiently Present in the Circulation of Kidney Transplant Recipients Infected With CMV and/or EBV. AB - T cells play a dual role in transplantation: They mediate transplant rejection and are crucial for virus control. Memory T cells generated in response to pathogens can cross-react to alloantigen, a phenomenon called heterologous immunity. Virus-specific CD8(+) T cells cross-reacting to donor-alloantigen might affect alloimmune responses and hamper tolerance induction following transplantation. Here, we longitudinally studied these cross-reactive cells in peripheral blood of 25 kidney transplant recipients with a cytomegalovirus and/or Epstein-Barr virus infection. Cross-reactive T cells were identified by flow cytometry as virus-specific T cells that proliferate in response to donor cells in a mixed-lymphocyte reaction. In 13 of 25 patients, we found cross-reactivity to donor cells for at least 1 viral epitope before (n = 7) and/or after transplantation (n = 8). Cross-reactive T cells were transiently present in the circulation, and their precursor frequency did not increase following transplantation or viral infection. Cross-reactive T cells expressed interferon gamma and CD107a in response to both alloantigen and viral peptide and resembled virus-specific T cells in phenotype and function. Their presence was not associated with impaired renal function, proteinuria, or rejection. In conclusion, virus-specific T cells that cross-react to donor-alloantigen are transiently detectable in the circulation of kidney transplant recipients. PMID- 26603975 TI - Immunohistochemical localization of Nox in mouse circumvallate papillae. AB - Recently it has been reported that reactive oxygen species plays an important role in several physiological processes. Reactive oxygen species are generated by reactive oxygen-synthesizing enzymes (Nox). We immunohistochemically investigated expression and localization of the Nox family in a mouse circumvallate papillae. In the epithelium of the circumvallate papilla, Nox 1, 2, 3, and 4, Noxo1, and Noxa1 were expressed. In the circumvallate papilla, Nox2 was more weakly expressed in the lateral than in the upper part, and Nox3 was not expressed. In the taste buds, Nox 1, 2, 3, and 4, Noxo1, and Noxa1 were expressed; the Nox expression pattern varied with the cell type. In type II cells, Nox 1, 3, and 4, Noxo1, and Noxa1 were expressed. In type III cells, Nox2, besides Nox 1, 3, and 4, Noxo1, and Noxa1, were specifically expressed, unlike in other taste bud cells. In the mouse circumvallate papilla, Nox is always expressed, suggesting the generation of reactive oxygen species. Of note, all cells comprising taste buds expressed Nox, with each showing a specific Nox expression pattern. PMID- 26603976 TI - Expression and localization of collectins in feto-maternal tissues of human first trimester spontaneous abortion and abortion prone mouse model. AB - Dysregulation of immune response at the feto-maternal interface during first trimester of pregnancy is one of the leading causes of spontaneous abortion. Previously, we reported differential expression of collectins, soluble pattern recognition molecules involved in immunoregulation, in placental and decidual tissues during spontaneous labor. In the present pilot study, the expression of collectins was analyzed in the inflamed human gestational tissues of spontaneous abortion ('SA') and in 13.5 dpc placental tissues from resorption survived embryos of murine model (CBA/J X DBA/2J). Transcripts of SP-A were significantly down-regulated and SP-D were significantly up-regulated in placental and decidual tissues of 'SA' group compared to that of 'normal' group. Immunostaining for SP-D and MBL proteins was positive in placental and decidual tissues. However, levels of SP-D and MBL proteins were not significantly altered in placental as well as in decidual tissues of 'SA' group in comparison to the 'normal' group. Placental tissues of viable embryos from the abortion prone mouse model showed significantly enhanced expression of mSP-A and mSP-D transcripts at 13.5 day post coitus (dpc) and 14.5 dpc compared to the control group (CBA/J X Balb/c). Mouse collectins were localized in placental tissues (13.5 dpc), with increased staining in murine model compared to control. Human and murine data together indicate that SP-A, SP-D and MBL are synthesised in early gestational tissues, and may contribute to regulation of immune response at the feto-maternal interface during pregnancy. PMID- 26603977 TI - Electronic Structure and Properties of Organic Bulk-Heterojunction Interfaces. AB - The electronic structure and physical mechanisms of carrier generation and transport in the organic bulk heterojunction are reviewed. The electronic structure describes the bands and band-tail states, the band alignment at the bulk-heterojunction interface, and the overall density-of-states model. The different electronic character of excitons and mobile charge is discussed, the former being highly molecular and the latter more delocalized. Dissociation of the exciton via the charge-transfer (CT) states is attributed to weak binding of the CT state arising from charge delocalization. Carrier transport and charge collection is strongly influenced by the presence of localized band-tail states. Recombination is attributed primarily to transitions from mobile carriers to band tail or deep trap states. PMID- 26603979 TI - Breast feeding may cut risk of diabetes in high risk women. PMID- 26603978 TI - Shenmai injection as an adjuvant treatment for chronic cor pulmonale heart failure: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Shenmai injection (SM), as a traditional Chinese medicine injection, is widely used for chronic cor pulmonale heart failure in mainland China. It is essential to systematically assess the efficacy and safety of SM as an adjuvant treatment for chronic cor pulmonale heart failure. METHODS: Eight English and Chinese electronic databases were searched, from inception to December 2014, to identify randomized controlled trials (RCTs) of SM for chronic cor pulmonale heart failure. The Cochrane Risk of Bias tool was used to evaluate the methodological quality of eligible studies. Meta-analysis was performed by Review Manager 5.2. RESULTS: Twenty-seven RCTs with 2045 participants were identified. The methodological quality of the included studies was generally low. Only one trial reported data on death. None of the included trials reported quality of life. The meta-analysis indicated that compared to conventional treatment, the combination of SM and conventional treatment was more effective in terms of the New York Heart Association classification (RR, 1.26; 95% CI, 1.20-1.32; P < 0.00001), Left Ventricular Ejection Fraction (MD, 11.33; 95% CI, 8.59-14.07; p < 0.00001), partial pressure of oxygen (MD, 1.00; 95% CI, 0.64-1.36; P < 0.00001) and partial pressure of carbon dioxide (MD, 0.83; 95 % CI, 0.58-1.08; p < 0.00001). In addition, two trials reported that SM plus conventional treatment was superior to the conventional treatment alone to reduce B-type natriuretic peptide. No serious adverse drug events or reactions were reported. CONCLUSIONS: SM plus conventional treatment appeared to be effective and relatively safe for chronic cor pulmonale heart failure. However, due to the generally low methodological quality and small sample size, this review didn't find evidence to support routine use of SM as an adjuvant treatment for chronic cor pulmonale heart failure. PMID- 26603980 TI - Source-Sink Communication: Regulated by Hormone, Nutrient, and Stress Cross Signaling. AB - Communication between source organs (exporters of photoassimilates) and sink organs (importers of fixed carbon) has a pivotal role in carbohydrate assimilation and partitioning during plant growth and development. Plant productivity is enhanced by sink strength and source activity, which are regulated by a complex signaling network encompassing sugars, hormones, and environmental factors. However, key components underlying the signaling pathways that regulate source-sink communication are only now beginning to be discovered. Here, we discuss recent advances in our understanding of the molecular mechanisms regulating sugar mobilization during seed development and seedling establishment in cereals, which provide the majority of nutrition for humans. Insights into these mechanisms may provide strategies for improving crop productivity. PMID- 26603981 TI - In situ heating SEM observation of the bainitic transformation process in Cu-17Al 11Mn (at.%) alloys. AB - To understand the bainitic transformation behavior in Cu-17Al-11Mn (at.%) alloys, dynamicin situobservation during heating was carried out in a scanning electron microscope (SEM). In this study, after optimizing the sample preparation method and observation conditions, we successfully observed the transformation process with sufficient resolution and contrast. From the observation results, bainite is first formed preferentially at the grain boundaries of the parent phase. Bainite is also formed inside the grains to relax the elastic strain generated by the initial bainite. Regarding the growth mode, in the early stage of the transformation, bainite grows along the longitudinal direction, and in the late stage, it grows along the lateral direction. The growth rate of the bainite was also evaluated by continuous observation of the same plate. Dynamicin situobservation of a martensitic transformation in the same alloy was also performed to compare the growth mode with that of bainite, and it was found that the behavior is considerably different between bainitic and the martensitic transformations. PMID- 26603982 TI - Peripheral vascular disease: shaping a new panvascular interventional approach. PMID- 26603983 TI - Prevention of radial artery occlusion: it's the right thing to do. PMID- 26603984 TI - The EAPCI Elections 2016: making a fundamental contribution to the advancement of our Association. PMID- 26603985 TI - Facilitated patent haemostasis after transradial catheterisation to reduce radial artery occlusion. AB - AIMS: This study sought to evaluate the feasibility of a rapid deflation technique (RDT) after transradial catheterisation to achieve patent haemostasis and to assess whether this could reduce radial artery occlusion (RAO). Ensuring patent haemostasis is the most important factor in reducing RAO. The use of larger sheath sizes and antiplatelet and antithrombotic agents limits achieving patent haemostasis immediately after transradial intervention. METHODS AND RESULTS: A feasibility assessment was first performed in 105 patients to assess whether RDT could be performed safely and consistently achieve patent haemostasis after transradial catheterisation. Prospective data were then collected on 201 patients who underwent either rapid or standard deflation technique and had RAO assessment at 24 hours. Acute coronary syndrome was the indication for transradial catheterisation in 62.7% of patients. Baseline patent haemostasis increased from 40% to 95% after RDT. RAO at 24 hours was seen in two (2.0%) patients in the RDT group and 15 (14.9%) in the standard deflation group (OR 0.117; 95% CI: 0.026 to 0.526, p=0.005). Other independent predictors of RAO included body surface area (OR 0.022; 95% CI: 0.002 to 0.273, p=0.003) and male sex (OR 0.298; 95% CI: 0.108 to 0.824, p=0.020). No significant difference was found in safety outcomes: need to re-inflate compression band (2% versus 1.8%) or haematoma (0% versus 0.9%). CONCLUSIONS: Rapid deflation of the compression band after transradial catheterisation is a safe and effective method of achieving patent haemostasis that reduces RAO. PMID- 26603986 TI - Modified flower petal technique in the treatment of Medina type 0,0,1 or 0,1,0 lesions. AB - AIMS: The optimal strategy for patients with isolated ostial bifurcation lesions has not yet been determined. We propose the modified flower petal technique for the treatment of Medina type 0,0,1 or 0,1,0 coronary bifurcation lesions. METHODS AND RESULTS: We selected 64 patients who had Medina type 0,0,1 or 0,1,0 coronary bifurcation lesions. Percutaneous coronary intervention (PCI) was performed with the modified flower petal technique in all patients. After PCI, all patients were followed up to nine months after the intervention. Quantitative coronary angiography (QCA) analyses were performed for both the main and the side branch at baseline, after the stent implantation and at nine-month follow-up. Twenty patients (31.2%) had ostial left anterior descending artery lesions, nine patients (14.1%) had ostial circumflex artery lesions and the other patients had isolated ostial non-left main bifurcation lesions. The procedural success rate was 100%. There was no death, myocardial infarction, subacute or late stent thrombosis at nine-month follow-up. In one patient, in-stent restenosis requiring reintervention was noted. CONCLUSIONS: The modified flower petal technique has excellent acute results and midterm clinical outcomes in the management of Medina type 0,0,1 or 0,1,0 coronary bifurcation lesions. PMID- 26603987 TI - Guidewires for lower extremity artery angioplasty: a review. AB - The guidewire (GW) is probably the most important tool for the endovascular treatment of arterial obstructions. In fact, the treatment of a lesion is only possible when the GW is passed beyond the target lesion. Lower limb percutaneous arterial revascularisation can be achieved using a variety of GWs which may differ in calibre, body, tip or coating. As the choice of an appropriate GW is critical for the success of a lower limb artery angioplasty, knowledge of the properties and performances of different GWs should be well known in order to tailor the choice of the device to the lesion characteristics and location, as well as to the intended revascularisation strategy. The aim of the present paper is to describe the constructive characteristics of GWs for lower limb arterial revascularisation, and to evaluate groups of GWs for each segment of the lower limb arterial vasculature. PMID- 26603988 TI - History of transient ischaemic attack, myocardial infarction and hyperlipidaemia affects outcome following carotid artery stenting. AB - AIMS: This prospective registry study was intended to evaluate outcomes and predictors of adverse events following carotid artery stenting (CAS). METHODS AND RESULTS: Patients received neurological and duplex exams before CAS, prior to discharge and at 30- and 180-day follow-up. Multiple regression analysis included patient- and procedure-related characteristics. The MACCE endpoint comprised stroke, myocardial infarction and death. Three hundred and seventy-five consecutive patients underwent CAS between 1998 and 2011. Mean age was 69+/-9.1 years; 53% were symptomatic within the preceding six months. Mean time to CAS was 23 days in patients with TIA and 31 days with stroke (p=0.029). The MACCE rate was 1.6% during intervention and 4.0%, 5.6% and 5.9% at discharge, day 30 and day 180, respectively. TIA occurred in 31 cases (9.6%) within 30 days. A history of TIA was independently associated with MACCE (OR: 2.88; p=0.04). Furthermore, a history of hyperlipidaemia (OR: 4.02, p=0.029), MI (OR: 2.93, p=0.007) and age >=70 (OR: 1.89, p=0.033) were independent predictors for the combined endpoint MACCE plus TIA. CONCLUSIONS: TIA is an underappreciated adverse event following CAS. Pre-procedural TIA was an independent risk factor for adverse outcomes, while stroke was not, probably related to the timing of the procedure relative to the index event. PMID- 26603989 TI - Incidence, predictors, and treatment options of critical limb ischaemia after use of collagen plug-based vascular closure devices. AB - AIMS: Limited data are available on the frequency and predictors of vascular closure device (VCD) failure with subsequent vascular complications. The aim of this study was to investigate the incidence, clinical characteristics, and treatment options in patients with critical limb ischaemia (CLI) after use of a collagen plug-based VCD. METHODS AND RESULTS: A high-volume, single-centre prospectively maintained database was retrospectively interrogated, and cases of collagen plug-based VCD-related CLI were identified between June 2006 and December 2013. CLI was defined as acute onset of rest pain after VCD application requiring endovascular or surgical treatment. Among 13,595 coronary procedures, 43 patients (0.3%) were identified with an Angio-Seal-related CLI. In a multivariable logistic regression analysis, peripheral artery disease and renal insufficiency were identified as independent predictors for CLI after Angio-Seal application. Treatment was performed in 27 patients (63%) by surgery and in 16 patients (37%) with endovascular angioplasty. CONCLUSIONS: CLI after use of a collagen plug-based VCD is rare. Peripheral artery disease was identified as an independent predictor of CLI. Interventional cardiologists should be aware of potentially high-risk patients and complications after use of a VCD to provide prompt and adequate therapy. PMID- 26603990 TI - Intraprocedural reduction of the veno-arterial norepinephrine gradient correlates with blood pressure response after renal denervation. AB - AIMS: No intraprocedural assessment is currently available to evaluate the extent of nerve ablation by renal denervation (RDN). We prospectively evaluated the association of intraprocedural reduction of renal veno-arterial norepinephrine gradient with blood pressure (BP) response after RDN. METHODS AND RESULTS: In 46 consecutive RDN patients, the periprocedural norepinephrine veno-arterial difference was defined as veno-arterial norepinephrine gradient. We observed a reduction of the office systolic BP from 176+/-19 mmHg to 165+/-24 mmHg (p=0.02) at three months and 163+/-22 mmHg (p=0.02) at six months. The mean and maximum systolic ABP decreased by 5 mmHg (p=0.03) and 9 mmHg (p=0.02), respectively. There was a decrease of the norepinephrine RV-RA difference from pre- to post procedural levels (median 186 pg/ml [54;466] vs. 81 pg/ml [0;182], p=0.02). OBP responders (office systolic BP reduction >=10 mmHg) showed a greater reduction of the norepinephrine gradient compared to non-responders (-290+/-450 pg/ml vs. -4+/ 106 pg/ml, p=0.01). Patients with a reduction of norepinephrine gradient in both kidneys showed the most pronounced decrease of the systolic OBP (-24+/-14 mmHg) compared to patients with a reduction of norepinephrine gradient in only one kidney (-7+/-15 mmHg) or patients without a norepinephrine reduction (-3+/-19 mmHg, p=0.03 vs. bilateral reduction). CONCLUSIONS: Measuring renal norepinephrine gradient during RDN may be a method to gauge the extent of renal nerve ablation. PMID- 26603991 TI - The PulseCath iVAC 2L left ventricular assist device: conversion to a percutaneous transfemoral approach. AB - AIMS: This technical report describes the essentials and practical implantation technique of the completely percutaneous PulseCath iVAC 2L left ventricular assist device. METHODS AND RESULTS: Percutaneously inserted mechanical left ventricular assist devices are used for circulatory support during cardiogenic shock or high-risk percutaneous coronary interventions. The PulseCath concept is a novel pulsatile design that consists of an extracorporeal membrane pump connected to a large-bore catheter which is inserted across the aortic valve retrogradely into the left ventricle. A genuine intra-aortic balloon pump (IABP) console drives the pulsatile pump. CONCLUSIONS: The percutaneous PulseCath iVAC 2L is driven by a genuine IABP console and provides more left ventricular support. PMID- 26603992 TI - Tools and Techniques - Clinical: Fluoroscopic balloon sizing of the aortic annulus before transcatheter aortic valve replacement (TAVR) - follow the "right cusp rule". PMID- 26603993 TI - How should I treat multiple coronary aneurysms with severe stenoses? PMID- 26603994 TI - High throughput de novo RNA sequencing elucidates novel responses in Penicillium chrysogenum under microgravity. AB - In this study, the transcriptional alterations in Penicillium chrysogenum under simulated microgravity conditions were analyzed for the first time using an RNA Seq method. The increasing plethora of eukaryotic microbial flora inside the spaceship demands the basic understanding of fungal biology in the absence of gravity vector. Penicillium species are second most dominant fungal contaminant in International Space Station. Penicillium chrysogenum an industrially important organism also has the potential to emerge as an opportunistic pathogen for the astronauts during the long-term space missions. But till date, the cellular mechanisms underlying the survival and adaptation of Penicillium chrysogenum to microgravity conditions are not clearly elucidated. A reference genome for Penicillium chrysogenum is not yet available in the NCBI database. Hence, we performed comparative de novo transcriptome analysis of Penicillium chrysogenum grown under microgravity versus normal gravity. In addition, the changes due to microgravity are documented at the molecular level. Increased response to the environmental stimulus, changes in the cell wall component ABC transporter/MFS transporters are noteworthy. Interestingly, sustained increase in the expression of Acyl-coenzyme A: isopenicillin N acyltransferase (Acyltransferase) under microgravity revealed the significance of gravity in the penicillin production which could be exploited industrially. PMID- 26603995 TI - High temperature diaphragm valve-based comprehensive two-dimensional gas chromatography. AB - A high-temperature diaphragm valve-based comprehensive two-dimensional gas chromatography (GC*GC) instrument is demonstrated which readily allows separations up to 325 degrees C. Previously, diaphragm valve-based GC*GC was limited to 175 degrees C if the valve was mounted in the oven, or limited to 265 degrees C if the valve was faced mounted on the outside of the oven. A new diaphragm valve has been commercially developed, in which the temperature sensitive O-rings that previously limited the separation temperatures have been replaced with Kalrez O-rings, a perfluoroelastomer, allowing for significantly higher temperatures permitting a greater range of volatile and semi-volatile compounds to be readily separated. In the current investigation, a separation temperature up to 325 degrees C is demonstrated with the valve mounted directly in the oven. Since the temperature limit for most commonly used GC columns is at or below 325 degrees C, the scope of diaphragm valve-based GC*GC is now dramatically broadened to encompass a majority of all column stationary phase chemistries. A 44-component mixture of alkanes, alcohols, and polyaromatic hydrocarbons is used to study this new configuration whose boiling points range from 98 degrees C (n-heptane) to 450 degrees C (n-triacontane). For the test mixture using a modulation period PM of 1.0s, peak shapes on second dimension separations, (2)D, are symmetric with average widths at base of 79.4ms, producing a (2)D peak capacity of (2)nc~12. Based on the average peak width of 2.4s for the first dimension separation with a run time of 32.5min, the (1)D peak capacity is (1)nc~800. Thus, the ideal two-dimensional peak capacity [Formula: see text] is 9600. Little variation in within-analyte (2)D peak width was observed with an average %RSD of less than 3.0%. Furthermore, retention time on (2)D was very reproducible with an average %RSD less than 0.5%. Measured peak areas (sum of all (2)D peaks for given analyte) had an average %RSD of 4.4%. The transfer fraction from (1)D to (2)D was experimentally determined to be ~30%, while the detection sensitivity for valve-based GC*GC was ~8 times higher than one dimensional GC due to zone compression. After a year of use with temperatures consistently up to 325 degrees C, there has been no deterioration of the valve or its performance for GC*GC. Separations of vacuum pump oil and orange oil are also reported to demonstrate practical utility. PMID- 26603996 TI - Determination of nitroalkanes in mainstream cigarette smoke by heart-cutting multidimensional gas chromatography system coupled with mass spectrometry detection. AB - In this paper, heart-cutting two-dimensional GC/MS (GC-GC/MS) method in combination with a simple sample collection procedure was developed for the determination of 6 nitroalkanes in mainstream cigarette smoke. The method could remove large amounts of impurities on-line in the first polar column by heart cuts and separate from the left interferences in a second mid-polar column. And the target compounds could be focused at the inlet of the second column by cryo concentration. Compared to conventional GC/MS, GC-GC/MS achieved a lower noise level and sensitivity at least an order of magnitude higher. Furthermore, the GC GC/MS method could avoid the false negative and false positive results that appeared in the compared conventional GC/MS analysis. By trapping the vapor phase of 20 cigarettes smoke, the LODs and LOQs of the nitroalkanes were 1.3 to 9.8 and 4.3 to 32.6ng/cigarette, respectively, and all linear correlation efficiencies were larger than 0.999. The validation results also indicate that the method has high accuracy (spiked recoveries between 84% and 102%) and good repeatability (RSD between 7.2% and 9.4%). The developed method was applied to analyze 1 Kentucky reference cigarette (3R4F) and 10 Chinese commercial brands of cigarettes. The research results indicated that nitromethane, nitroethane, 2 nitropropane and 1-nitro-n-pentane were detected in mainstream cigarette smoke, but 1-nitro-n-butane and 2-nitropropane, which were reported by one previous study, were not detected in all cigarette samples. PMID- 26603997 TI - Considerations about Occlusion of the Intracranial Distal Internal Carotid Artery. AB - Occlusion of the intracranial distal internal carotid artery (ICA) is one of the most critical conditions among the cases of acute stroke in the anterior circulation. The introduction of selective endovascular treatment first using thrombolytic agents replaced later by the mechanical thrombectomy using various devices has improved the prognosis in a certain number of these patients. Among the factors influencing the prognosis of these patients, one is the collateral circulation which in these cases is mainly characterized by leptomeningeal anastomoses. The collateral can, however, be impaired, by distal embolization and by anomalies of the Circle of Willis: the aim of this study is to describe these aspects. PMID- 26603998 TI - Rapid and Accurate MRI Segmentation of Peritumoral Brain Edema in Meningiomas. AB - PURPOSE: The extent of peritumoral brain edema (PTBE) in meningiomas commonly affects the clinical outcome. Despite its importance, edema volume is usually highly inaccurately approximated to a spheroid shape. We tested the accuracy and the reproducibility of semiautomatic lesion management software for the analysis of PTBE in a homogeneous case series of surgically confirmed intracranial meningiomas. METHODS: PTBE volume was calculated on magnetic resonance images in 50 patients with intracranial meningiomas using commercial lesion management software (Vue PACS Livewire, Carestream, Rochester, NY, USA). Inter and intraobserver agreement evaluation and a comparison between manual volume calculation, the semiautomatic software and spheroid approximation were performed in 22 randomly selected patients. RESULTS: The calculation of edema volume was possible in all cases irrespective of the extent of the signal changes. The median time for each calculation was 3 min. Interobserver and intraobserver agreement confirmed the reproducibility of the method. Comparison with standard (fully manual) calculation confirmed the accuracy of this software. CONCLUSIONS: Our study showed a high level of reproducibility of this semiautomatic computational method for peritumoral brain edema. It is rapid and easy to use after relatively short training and is suitable for implementation in clinical practice. PMID- 26603999 TI - Lessons learned from gene identification studies in Mendelian epilepsy disorders. AB - Next-generation sequencing (NGS) technologies are now routinely used for gene identification in Mendelian disorders. Setting up cost-efficient NGS projects and managing the large amount of variants remains, however, a challenging job. Here we provide insights in the decision-making processes before and after the use of NGS in gene identification studies. Genetic factors are thought to have a role in ~70% of all epilepsies, and a variety of inheritance patterns have been described for seizure-associated gene defects. We therefore chose epilepsy as disease model and selected 35 NGS studies that focused on patients with a Mendelian epilepsy disorder. The strategies used for gene identification and their respective outcomes were reviewed. High-throughput NGS strategies have led to the identification of several new epilepsy-causing genes, enlarging our knowledge on both known and novel pathomechanisms. NGS findings have furthermore extended the awareness of phenotypical and genetic heterogeneity. By discussing recent studies we illustrate: (I) the power of NGS for gene identification in Mendelian disorders, (II) the accelerating pace in which this field evolves, and (III) the considerations that have to be made when performing NGS studies. Nonetheless, the enormous rise in gene discovery over the last decade, many patients and families included in gene identification studies still remain without a molecular diagnosis; hence, further genetic research is warranted. On the basis of successful NGS studies in epilepsy, we discuss general approaches to guide human geneticists and clinicians in setting up cost-efficient gene identification NGS studies. PMID- 26604000 TI - DNM1L-related mitochondrial fission defect presenting as refractory epilepsy. AB - Mitochondrial fission and fusion are dynamic processes vital to mitochondrial quality control and the maintenance of cellular respiration. In dividing mitochondria, membrane scission is accomplished by a dynamin-related GTPase, DNM1L, that oligomerizes at the site of fission and constricts in a GTP-dependent manner. There is only a single previous report of DNM1L-related clinical disease: a female neonate with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF; OMIM #614388), a lethal disorder characterized by cerebral dysgenesis, seizures, lactic acidosis, elevated very long chain fatty acids, and abnormally elongated mitochondria and peroxisomes. Here, we describe a second individual, diagnosed via whole-exome sequencing, who presented with developmental delay, refractory epilepsy, prolonged survival, and no evidence of mitochondrial or peroxisomal dysfunction on standard screening investigations in blood and urine. EEG was nonspecific, showing background slowing with frequent epileptiform activity at the frontal and central head regions. Electron microscopy of skeletal muscle showed subtle, nonspecific abnormalities of cristal organization, and confocal microscopy of patient fibroblasts showed striking hyperfusion of the mitochondrial network. A panel of further bioenergetic studies in patient fibroblasts showed no significant differences versus controls. The proband's de novo DNM1L variant, NM_012062.4:c.1085G>A; NP_036192.2:p.(Gly362Asp), falls within the middle (oligomerization) domain of DNM1L, implying a likely dominant-negative mechanism. This disorder, which presents nonspecifically and affords few diagnostic clues, can be diagnosed by means of DNM1L sequencing and/or confocal microscopy. PMID- 26604001 TI - The effectiveness and cost-effectiveness of the peer-delivered Thinking Healthy Programme for perinatal depression in Pakistan and India: the SHARE study protocol for randomised controlled trials. AB - BACKGROUND: Rates of perinatal depression (antenatal and postnatal depression) in South Asia are among the highest in the world. The delivery of effective psychological treatments for perinatal depression through existing health systems is a challenge due to a lack of human resources. This paper reports on a trial protocol that aims to evaluate the effectiveness and cost-effectiveness of the Thinking Healthy Programme delivered by peers (Thinking Healthy Programme Peer delivered; THPP), for women with moderate to severe perinatal depression in rural and urban settings in Pakistan and India. METHODS/DESIGN: THPP is evaluated with two randomised controlled trials: a cluster trial in Rawalpindi, Pakistan, and an individually randomised trial in Goa, India. Trial participants are pregnant women who are registered with the lady health workers in the study area in Pakistan and pregnant women attending outpatient antenatal clinics in India. They will be screened using the patient health questionnaire-9 (PHQ-9) for depression symptoms and will be eligible if their PHQ-9 is equal to or greater than 10 (PHQ 9 >= 10). The sample size will be 560 and 280 women in Pakistan and India, respectively. Women in the intervention arm (THPP) will be offered ten individual and four group sessions (Pakistan) or 6-14 individual sessions (India) delivered by a peer (defined as a mother from the same community who is trained and supervised in delivering the intervention). Women in the control arm (enhanced usual care) will receive health care as usual, enhanced by providing the gynaecologist or primary-health facilities with adapted WHO mhGAP guidelines for depression treatment, and providing the woman with her diagnosis and information on how to seek help for herself. The primary outcomes are remission and severity of depression symptoms at the 6-month postnatal follow-up. Secondary outcomes include remission and severity of depression symptoms at the 3-month postnatal follow-up, functional disability, perceived social support, breastfeeding rates, infant height and weight, and costs of health care at the 3- and 6-month postnatal follow-ups. The primary analysis will be intention-to-treat. DISCUSSION: The trials have the potential to strengthen the evidence on the effectiveness and cost-effectiveness of an evidence-based psychological treatment recommended by the World Health Organisation and delivered by peers for perinatal depression. The trials have the unique opportunity to overcome the shortage of human resources in global mental health and may advance our understanding about the use of peers who work in partnership with the existing health systems in low resource settings. TRIAL REGISTRATION: Pakistan Trial: ClinicalTrials.gov Identifier: NCT02111915 (9 April 2014) India Trial: ClinicalTrials.gov Identifier: NCT02104232 (1 April 2014). PMID- 26604004 TI - Feasibility of Real Time Medication Monitoring Among HIV Infected and TB Patients in a Resource-Limited Setting. AB - HIV infected and tuberculosis (TB) patients need high levels of treatment adherence to achieve optimal treatment outcomes. We conducted a pilot-study on real time medication monitoring (RTMM) in a resource-limited setting. We enrolled five HIV infected and five TB patients from Kilimanjaro, Tanzania. They took their medication using RTMM. When the device was not opened on time, patients received a reminder SMS. After 3 months, we interviewed patients. Six patients (60 %) reached adherence of >95 %. Nine-hundred-twenty-two of 1104 intakes (84 %) were on time. Five-hundred reminders (45 %) were sent, of which 202 (40 %) were incorrect, because of an unstable mobile network. Nine patients found the device helpful and nine mentioned it keeps medication safe. Six patients reported that the size was too big. Five patients mentioned they received incorrect reminders. The device is considered useful in Kilimanjaro. Optimization of the device should consider network connectivity and the size of the device. PMID- 26604002 TI - Bufavirus Protoparvovirus in feces of wild rats in China. AB - Bufavirus (BuV) was first discovered from feces of children with acute diarrhea. It was subsequently detected from several animal species including shrews, bats, and nonhuman primates. In this study, we identified a novel Protoparvovirus, designated RatBuV, from the intestinal contents of wild rats using viral metagenomics. The near complete genome was 4643 nt encoding NS1, VP1, and VP2 proteins. Phylogenetic analysis over the complete genome showed that RatBuV clustered with Mpulungu BuV from shrews. Sequence analysis indicated that the putative protein sequences of NS1, VP1, and VP2 of RatBuV shared identities of 50.6-77.2, 48.3-77.3, and 47.1-78.3 %, respectively, with those of human BuVs, MpBuV, and WUHARV parvovirus, suggesting RatBuV belongs to a new species of Protoparvovirus. Our epidemiologic study indicated that the prevalence rate of RatBuV in the cohort of 40 wild rats is 12.5 % (5/40), which is higher than that of BuV in humans in a previous study. PMID- 26604006 TI - Affect, work-goal schemas, and work-goal striving among adults with chronic pain: a multilevel structural equation analysis. AB - For individuals with chronic pain, the within-person influence of affect and goal cognition on daily work-related goal striving is not yet well understood. The present study tested the hypothesis that anticipatory goal cognition in the form of a morning work goal schema mediates the relations between morning affect and later (afternoon and evening) work goal striving. Working adults with chronic pain (N = 131) completed a 21-day diary with morning, afternoon, and evening assessments analyzed via multi-level structural equation modeling. At the within person level, morning positive and negative affect were positively associated with morning work goal schemas; and morning work goal schemas, in turn, positively predicted both afternoon and evening work goal striving. Our findings underscore the complex dynamics over time of the relationship between affect and self-regulatory processes and have implications for future studies and for interventions to assist working adults with chronic pain. PMID- 26604005 TI - Pharmacist work stress and learning from quality related events. AB - BACKGROUND: Among the many stresses faced by pharmacy staff, quality related event (QRE) learning can be among the most significant. In the absence of a supportive organizational culture, the potential for blaming individuals, versus identifying key process flaws, is significant and can be very intimidating to those involved in such discussions and may increase an already stressful work environment. OBJECTIVE: This research develops and tests a model of the relationship between the work stress faced by pharmacists and the extent of QRE learning in community pharmacies. Building upon recent research models that explore job characteristics and safety climate, the model proposes that work stress captured by the effort that the pharmacist invests into job performance, the extent to which the pharmacist is rewarded for such efforts, and the extent of pharmacist work-related commitment to their job, influence pharmacist assessment of the working conditions within their community pharmacy. It is further proposed that working conditions influence the extent of a blame culture and safety focus in the pharmacy, which, in turn, influences organizational learning from QREs. METHODS: This research formed part of a larger study focused on QRE reporting in community pharmacies. As part of the larger study, a total of 1035 questionnaires were mailed to community pharmacists, pharmacy managers, and pharmacy owners in the Canadian province of Saskatchewan during the fall of 2013 and winter and spring of 2014. Partial least squares (PLS) using SmartPLS was selected to test and further develop the proposed model. An examination of the statistical significance of latent variable paths, convergent validity, construct reliability, discriminant validity, and variance explained was used to assess the overall quality of the model. RESULTS: Of the 1035 questionnaire sent, a total of 432 questionnaires were returned for an initial response rate of approximately 42%. However, for this research, only questionnaires from staff pharmacists were used thereby reducing the number of usable questionnaires to 265. The final model highlights that pharmacist work stress greatly influences perceptions of the working conditions in the pharmacy (R(2) = 0.52), which, in turn, influence assessments of the safety focus (R(2) = 0.27) and blame culture (R(2) = 0.14) in the pharmacy. The model also found that the extent of a safety focus and blame culture within the pharmacy both influence the extent of organizational learning from QREs (R(2) = 0.44) within the pharmacy. CONCLUSIONS: In an environment where financial rewards are not always possible, ensuring that pharmacy staff feel respected and encouraged in providing safe care may help enhance QRE learning. Given the importance placed on organizational reporting of, and learning from, QREs in many jurisdictions in North America, the findings from this study suggest that a number of working conditions and perceptions of blame culture and organizational safety need to be explored before such processes can become entrenched in work flow. PMID- 26604007 TI - In-line ATR-UV and Raman Spectroscopy for Monitoring API Dissolution Process During Liquid-Filled Soft-Gelatin Capsule Manufacturing. AB - Complete dissolution of the active pharmaceutical ingredient (API) is critical in the manufacturing of liquid-filled soft-gelatin capsules (SGC). Attenuated total reflectance UV spectroscopy (ATR-UV) and Raman spectroscopy have been investigated for in-line monitoring of API dissolution during manufacturing of an SGC product. Calibration models have been developed with both techniques for in line determination of API potency. Performance of both techniques was evaluated and compared. The ATR-UV methodology was found to be able to monitor the dissolution process and determine the endpoint, but was sensitive to temperature variations. The Raman technique was also capable of effectively monitoring the process and was more robust to the temperature variation and process perturbations by using an excipient peak for internal correction. Different data preprocessing methodologies were explored in an attempt to improve method performance. PMID- 26604008 TI - Trophic State Evolution and Nutrient Trapping Capacity in a Transboundary Subtropical Reservoir: A 25-Year Study. AB - Artificial reservoirs have been used for drinking water supply, other human activities, flood control and pollution abatement worldwide, providing overall benefits to downstream water quality. Most reservoirs in Brazil were built during the 1970s, but their long-term patterns of trophic status, water chemistry, and nutrient removal are still not very well characterized. We aimed to evaluate water quality time series (1985-2010) data from the riverine and lacustrine zones of the transboundary Itaipu Reservoir (Brazil/Paraguay). We examined total phosphorus and nitrogen, chlorophyll a concentrations, water transparency, and phytoplankton density to look for spatial and temporal trends and correlations with trophic state evolution and nutrient retention. There was significant temporal and spatial water quality variation (P < 0.01, ANCOVA). The results indicated that the water quality and structure of the reservoir were mainly affected by one internal force (hydrodynamics) and one external force (upstream cascading reservoirs). Nutrient and chlorophyll a concentrations tended to be lower in the lacustrine zone and decreased over the 25-year timeframe. Reservoir operational features seemed to be limiting primary production and phytoplankton development, which exhibited a maximum density of 6050 org/mL. The relatively small nutrient concentrations in the riverine zone were probably related to the effect of the cascade reservoirs upstream of Itaipu and led to relatively low removal percentages. Our study suggested that water quality problems may be more pronounced immediately after the filling phase of the artificial reservoirs, associated with the initial decomposition of drowned vegetation at the very beginning of reservoir operation. PMID- 26604009 TI - Urban Rights-of-Way as Reservoirs for Tall-Grass Prairie Plants and Butterflies. AB - Urban rights-of-way may be potential reservoirs of tall-grass prairie plants and butterflies. To determine if this is true, in 2007-2008, we conducted vegetation surveys of species richness and cover, and butterfly surveys of species richness and abundance, along 52 transmission lines and four remnant prairies in Winnipeg, Manitoba. We detected many prairie plants and butterflies within transmission lines. Some unmowed and infrequently managed transmission lines had native plant species richness and total percent cover of native plants comparable to that of similar-sized remnant tall-grass prairies in the region. Although we did not find significant differences in overall native butterfly numbers or species richness between rights-of-way and remnant prairies, we found lower numbers of some prairie butterflies along frequently mowed rights-of-way than within remnant tall grass prairies. We also observed higher butterfly species richness along sites with more native plant species. By reducing mowing and spraying and reintroducing tall-grass prairie plants, urban rights-of-way could serve as extensive reservoirs for tall-grass prairie plants and butterflies in urban landscapes. Eventually, managing urban rights-of-way as reservoirs for tall-grass prairie plants and animals could contribute to the restoration of tall-grass prairie in the North American Midwest. PMID- 26604010 TI - Correlation Between the Position of the Hyoid Bone on Lateral Cephalographs and Formant Frequencies. AB - OBJECTIVES: The objective of this study is to examine the F1, F2, F3, and F4 during sustained vowels /alpha/, /i/, /o/, /u/. STUDY DESIGN: Prospective cross sectional study. METHODS: Fifty-two consecutive patients aged between 9 years and 38 years were invited to participate in this study. Linear measurements included linear vertical distance from the hyoid bone to the sella turcica (H-S); linear vertical distance from the hyoid bone to the posterior nasal spine (H-PNS); linear measure from the hyoid bone to the most anterior point of the cervical vertebra C3 (H-C3); and linear vertical distance from the hyoid bone to the mandibular plane (H-MP). RESULTS: The results showed a moderate and statistically significant correlation between the average fundamental frequency for the vowel /alpha/ and H-C3, H-S, and H-PNS and another moderate negative correlation between F3 and F4, and the vertical position of the hyoid bone H-C3 and H-S. For the vowel /i/, there was a moderate negative correlation between F1, F3, and F4 and H-S and also a moderate negative correlation between F3 and F4 and H-C3. For the vowel /o/, there was a moderate negative correlation between F4 and H-S and H PNS. For the vowel /u/, only F4 correlated significantly with H-S. CONCLUSION: There is a moderate correlation between the high formants, mostly F4, and the cephalo-caudal position of the hyoid bone. PMID- 26604012 TI - Specific HDAC6 inhibition by ACY-738 reduces SLE pathogenesis in NZB/W mice. AB - We sought to determine if a selective HDAC6 inhibitor (ACY-738) decreases disease in NZB/W mice. From 22 to 38weeks-of-age, mice were injected intraperitoneally with 5 or 20mg/kg of ACY-738, or vehicle control. Body weight and proteinuria were measured every 2weeks, while sera anti-dsDNA, Ig isotypes, and cytokine levels were measured every 4weeks. Kidney disease was determined by evaluation of sera, urine, immune complex deposition, and renal pathology. Flow cytometric analysis assessed thymic, splenic, bone marrow, and peripheral lymphocyte differentiation patterns. Our results showed HDAC6 inhibition decreased SLE disease by inhibiting immune complex-mediated glomerulonephritis, sera anti-dsDNA levels, and inflammatory cytokine production and increasing splenic Treg cells. Inhibition of HDAC6 increased the percentage of cells in the early-stage developmental fractions of both pro- and pre-B cells. These results suggest that specific HDAC6 inhibition may be able to decrease SLE disease by altering aberrant T and B cell differentiation. PMID- 26604011 TI - Harnessing adaptive natural killer cells in cancer immunotherapy. AB - Natural killer (NK) cells are innate lymphocytes with a refined ability to recognize transformed cells through a broad array of activating receptors in combination with stochastically expressed inhibitory receptors that recognize MHC class I. Recent advances in NK cell biology have revealed a high degree of functional plasticity that can be attributed to dynamic cell-to-cell interactions in concert with transcriptional and epigenetic reprogramming. Here, we discuss how new insights into the adaptive behavior of NK cells pave the way for next generation cell therapy based on guided differentiation and selective expansion of particularly cytotoxic NK cell subsets. PMID- 26604013 TI - The role of icaritin in regulating Foxp3/IL17a balance in systemic lupus erythematosus and its effects on the treatment of MRL/lpr mice. AB - Systemic lupus erythematosus (SLE) is a female predominant autoimmune disease characterized by multi-organ dysfunctions. However, current available therapies control the disease at the cost of many potential adverse effects. The development of safer and more effective therapies for SLE is a critical unmet need. Icaritin (ICT) is an active monomer extracted from Chinese herbals named the Epimedium genus. In this study, we found that ICT exhibited the capacity of regulating Foxp3/IL17a balance, enhancing Treg cell suppressive activities, and inhibiting over-activation of CD4(+)T cells from SLE. We also observed that ICT regulated Foxp3/IL17a balance by increasing STAT5b expression and histone methylation modification. Subsequent experiments further confirmed that ICT treated mice exhibited amelioration of renal damages and suggested that ICT may be a potential new drug for the treatment of SLE. PMID- 26604014 TI - Successful use of spinal anesthesia for inguinal hernia repair in a child with Hunter syndrome with difficult airway. PMID- 26604015 TI - Postoperative delirium: age and low functional reserve as independent risk factors. AB - STUDY OBJECTIVE: The aim of this study was to determine the incidence of postoperative delirium (POD) and the presence of previous conditions related to its development. DESIGN: Prospective observational study. SETTINGS: The study was performed in adult patients (n=221) scheduled for elective surgery and admitted to the postanesthesia care unit (PACU). MEASUREMENTS: The presence of POD was assessed by the Nursing Delirium Screening Scale at discharge from the PACU and 24hours after surgery. Descriptive analyses were carried out, and statistical comparisons were performed with Mann-Whitney U, chi(2), or Fisher exact test. Logistic regression analysis was used for evaluation of independent determinants of POD. MAIN RESULTS: POD was found in 25 patients (11%). Patients who developed POD were older (median age, 69 vs 57years; P<.001); had a higher American Society of Anesthesiologists physical status score (>=3) (60% vs 19%, respectively, had American Society of Anesthesiologists physical status III/IV; P<.001); and showed higher incidences of ischemic heart disease (24% vs 6%; P=.001), chronic kidney disease (20% vs 5%; P=.005), hypertension (80% vs 45%; P=.001), chronic obstructive pulmonary disease (20% vs 6%; P=.009), and low functional reserve (LFR) (24% vs 2%; P<.001). Age (odds ratio, 1.06; 95% confidence interval, 1.02 1.10; P=.003) and LFR (odds ratio, 8.04; 95% confidence interval, 3.95-32.27; P=.003) were considered independent risk factors for POD. CONCLUSIONS: The incidence of POD in the study population (11%) is consistent with that described in the literature (5%-15%). The comorbidities associated with its development were ischemic heart disease, hypertension, chronic kidney disease, LFR, and chronic obstructive pulmonary disease. Age >=65years and LFR were independent risk factors for POD development. PMID- 26604016 TI - The sleep architecture of Australian volunteer firefighters during a multi-day simulated wildfire suppression: Impact of sleep restriction and temperature. AB - Wildland firefighting exposes personnel to combinations of occupational and environmental stressors that include physical activity, heat and sleep restriction. However, the effects of these stressors on sleep have rarely been studied in the laboratory, and direct comparisons to field scenarios remain problematic. The aim of this study was to examine firefighters' sleep during a three-day, four-night simulated wildfire suppression that included sleep restriction and physical activity circuits representative of firefighting wildfire suppression tasks in varied temperatures. Sixty-one volunteer firefighters (37.5+/-14.5 years of age, mean+/-SD) were assigned to one of three conditions: control (n=25; 8h sleep opportunities and 18-20 degrees C), awake (n=25; 4h sleep opportunities and 18-20 degrees C) or awake/hot (n=11; 4h sleep opportunities and 33-35 degrees C during the day and 23-25 degrees C during the night). Results demonstrated that amounts of N1, N2 and R sleep, TST, SOL and WASO declined, whilst sleep efficiency increased significantly in the awake and awake/hot conditions compared to the control condition. Results also demonstrated that SWS sleep remained relatively stable in the awake and awake/hot conditions compared to control values. Most importantly, no significant differences were found for any of the sleep measures between the awake and awake/hot conditions. Thus, working in hot daytime temperatures in combination with sleep restriction during the night did not affect patterns of sleep compared to working in temperate conditions in combination with sleep restriction during the night. However, the effects on sleep of high (>25 degrees C) night-time temperatures with sleep restriction in addition to physical activity remains to be studied. PMID- 26604017 TI - Gender Differences in Outcome of an Attempt to Stop Smoking Among Smokers Attending a Smoking Cessation Clinic in Taiwan: 3-Year Follow-Up Study. AB - Studies that have examined gender differences in smoking cessation have produced mixed results. The purpose of the study was to examine whether there are gender differences in long-term smoking abstinence rates in smokers treated with nicotine patches at a smoking cessation clinic in Taiwan, where 39% of men and 5% of women smoke. This study included 1,065 smokers, comprising of 940 men and 125 women. Smokers were invited to attend the clinic every 1-2 weeks for a maximum of eight visits over 90 days, where they received prescriptions for nicotine patches, counseling, and educational materials. Participants were contacted by telephone at 1 and 3 years after the first visit and were asked whether they had smoked at all over the past 7 days. The results showed that women were significantly less likely than men to be abstinent at 1 year (adjusted odds ratio [aOR] = 0.64; 95% CI [confidence interval] = [0.41, 0.99]; p = .044) and 3 years (aOR = 0.44; 95% CI = [0.27, 0.74]; p = .02). More effective ways are needed to help female smokers quit in societies where smoking in women is rare and may be associated with social stigma. PMID- 26604018 TI - Clinical and morphometric parameters of frailty for prediction of mortality following hepatopancreaticobiliary surgery in the elderly. AB - BACKGROUND: Although frailty is a known determinant of poor postoperative outcomes, it can be difficult to identify in patients before surgery. The authors sought to develop a preoperative frailty risk model to predict mortality among patients aged 65 years or more. METHODS: Clinical and morphometric data including total psoas area (TPA), total psoas volume (TPV) and psoas density (Hounsfield unit average calculation, HUAC) were collected for patients undergoing hepatopancreaticobiliary (HPB) surgery between 2012 and 2014. Multivariable Cox proportional hazards regression was used to identify preoperative risk factors associated with 1-year mortality. RESULTS: The median age of the 518 patients included in the study was 72 (i.q.r. 68-76) years; 55.6 per cent of patients were men, and half of the cohort had multiple co-morbidities (Charlson co-morbidity index (CCI) of 4 or more, 55.6 per cent). TPA cut-offs to define sarcopenia were 552.7 mm(2) /m(2) in women and 702.9 mm(2) /m(2) in men; cut-offs for TPV were 18.2 cm(3) /m(2) in women and 26.2 cm(3) /m(2) in men, whereas HUAC cut-offs were 31.1 HU in women and 33.3 HU in men. The overall 1-year mortality rate was 14.1 per cent. In multivariable analysis, risk factors associated with 1-year mortality included CCI of 4 or above (hazard ratio (HR) 2.91, 95 per cent c.i. 1.47 to 5.77; P = 0.002), malignant disease (HR 3.94, 1.17 to 13.30; P = 0.027) and sarcopenia by HUAC (HR 1.85, 1.10 to 3.10; P = 0.021). A weighted 25-point composite score was developed to stratify patients at risk of 1-year postoperative mortality. The 1-year mortality rate was noted to be 2.5 per cent among patients scoring 0-10 (low risk), 17.3 per cent among patients scoring 11 20 (intermediate risk) and 29.2 per cent among those scoring between 21 and 25 (high risk) (P < 0.001). CONCLUSION: Clinical and morphometric measures of frailty accurately predict the risk of 1-year mortality following HPB surgery in elderly patients, and can be used to risk-stratify patients appropriately. PMID- 26604019 TI - [Pulmonary lymphangioleiomyomatosis: From pathogenesis to management]. AB - INTRODUCTION: Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease affecting mainly young women. BACKGROUND: The respiratory manifestations are characterized by a progressive cystic destruction of the lung parenchyma. Extrapulmonary involvement includes benign renal tumours called angiomyolipomas and abdominal lymphatic masses called lymphangioleiomyomas. At the pathological level, the cellular proliferation found in LAM is in part due to the presence of mutations in the tumour suppressor genes TSC1 and TSC2 (Tuberous Sclerosis Complex). These mutations lead to the activation of the mTOR pathway, which is currently the main therapeutic target. mTOR inhibitors such as sirolimus or everolimus have shown a beneficial effect on the decline in pulmonary function and a reduction of angiomyolipoma size, but are necessary in only some patients. PERSPECTIVES: LAM cells have migratory properties mediated by the formation of new lymphatic vessels. They are also able to secrete metalloproteases, which enhance their invasiveness. Moreover, the expression of estrogen and progesterone receptors by LAM cells suggests a possible role for sex hormones in the pathogenesis of the disease. CONCLUSION: A better understanding of mTOR independent mechanisms would allow the development of novel therapeutic approaches. PMID- 26604020 TI - [Alpha-1 antitrypsin deficiency caused by Null mutation]. AB - INTRODUCTION: Alpha-1 antitrypsin deficiency is a hereditary disease defined at the biological level by a serum alpha-1 antitrypsin level below 11MUM/L. The null variants are characterized by undetectable circulating alpha-1 antitrypsin levels. Suspicion of a null variant requires the use of appropriate diagnostic techniques. CASE REPORT: We report the case of a 33-year old patient presenting with dyspnea on exertion, associated with a moderate airflow obstruction, incompletely reversible. His tobacco use was less than 3pack-years. The thoracic CT-scan showed emphysema. The serum alpha-1 antitrypsin level was collapsed. Phenotyping by isoelectrofocusing on agarose gels did not show any band. The study of the SERPINA1 gene, by PCR-sequence of the II, III, IV and V exons and the flanking intronic sequences, allowed identification of the NullQ0ourem allele in homozygous state. This mutation was found in heterozygous state in both parents of the index case and in one of his brothers. The index case showed a rapid aggravation of the airflow obstruction. CONCLUSION: In the case of a serum alpha-1 antitrypsin deficiency, the analysis of the phenotype of the protein by isoelectrofocusing must be performed as a first-line investigation. The detection of an atypical profile may suggest the presence of deficient alleles other than the PI S and PI Z alleles that can only be characterized by sequencing of the whole SERPINA1 gene. The patients carrying a null mutation have a high risk of severe chronic obstructive pulmonary disease. PMID- 26604021 TI - [Multidisciplinarity, education, and training in pediatric oncology-hematology]. AB - INTRODUCTION: According to the European Society of Pediatric Oncology (SIOPE) standard of care guidelines, high-quality care of children and adolescents with cancer needs to be delivered by well-trained multidisciplinary teams in specialist centers working with designated shared-care local centers in a so called hub-and-spoke model. The Diplome Inter-Universitaire d'Oncologie Pediatrique (DIUOP) is the only European training program in pediatric oncology in French for all physicians involved in care of patients with pediatric malignancies. In agreement with the SIOPE syllabus, the DIUOP is composed of training courses (120h), on-site practical training in a specialist center, and a research project to be defended before an examining board. METHOD: All graduates received a questionnaire to describe their current professional position. A comprehensive PubMed analysis retrieved all papers published form DIUOP research projects. RESULTS: From 2000 to 2011, 290 physicians were trained: 242 pediatricians, 21 surgeons, and 19 radiation therapists. Eight had another specialty including imaging, hematology, and pathology. Ninety-two were initially trained outside of France: 50% in Europe (mainly in Italy, Belgium, and Switzerland), 42% in Africa and the Middle East, and 8% in South America. Of the 266 graduates, 74% answered the questionnaire, and 90% of them take care of children and adolescents with cancer. Sixty-nine articles, i.e., one out of four research projects, were published in 34 journals with a median impact factor of 3.5 (0-22.6), 85% in English. CONCLUSION: DIUOP is the only French-speaking European education program providing a high-quality, professionalizing, and comprehensive multidisciplinary training program for French and international specialists taking care of children and adolescents with cancer. PMID- 26604022 TI - Immunological responses in the mussel Mytilus trossulus transplanted at the coastline of the northern Baltic Sea. AB - The applicability of immune responses in transplanted Baltic blue mussels (Mytilus trossulus) as biomarkers of immunotoxic effects was studied at differently contaminated locations in the Gulf of Bothnia (northern Baltic Sea). Here, we present a detailed report on the immune responses measured as complementary part of transplantation study by Turja et al. (2014).Various immunological endpoints such as total and differential cell count, morphological alterations,phagocytic activity, and caspase 3/7 activity of mussel haemocytes as well as haemolytic activity of the haemolymph were used. Mussels collected at a reference site at a Finnish coastal site (Hanko, H) were transplanted at the Swedish coast near industrial and urban regions of the cities Sundsvall (S1, S2) and Gavle (G1, G2), respectively. Based on the measured immunological responses, multivariate statistical analysis (PCA biplot) showed a clear separation of the most polluted site S1, indicating immunotoxic impacts of the mixture of contaminants present at this location. Based on these observations and results from Turja et al. (2014), we suggest the implementation of immunotoxic biomarkers for the evaluation of ecosystem health. However, these should be accompanied by complementary endpoints of biological effects encompassing i.e., physiological, antioxidant and bioenergetic markers. PMID- 26604024 TI - Fatty acyl composition of lysophosphatidylcholine is important in atherosclerosis. AB - Atherosclerosis is a major cause of death for mankind. Although the pathophysiology of atherosclerosis is a complex and multifactorial process, growing body of evidence has identified phospholipids-mediated signaling as an important factor in the induction and progression of atherosclerosis. Lysophosphatidylcholine (LPC) is a major phospholipid in oxidized low-density lipoprotein, and is generally considered to be atherogenic. However, some studies have shown anti-atherogenic properties of LPC. The controversial findings surrounding the pro- or anti-atherogenic properties of LPC appear to be due to the chain length and the degree of saturation of the fatty acyl moiety of LPC. Studies have suggested that the presence of omega (n)-polyunsaturated fatty acids (PUFA) at the sn-1 position of LPC modulates the inflammatory response thereby making LPC anti-atherogenic. We have recently shown that feeding a diet high in n 3 PUFA resulted in the enrichment of LPC in both plasma and liver of C57BL/6 mice with n-3 PUFA. Others have also shown that supplementation with fish oil leads to preferential incorporation of n-3 PUFA into LPC. We also found that plasma obtained from mice fed a diet high in n-3 PUFA showed higher cholesterol efflux capacity compared to animals fed a low n-3 PUFA diet, despite no changes in high density lipoprotein concentrations. We are therefore hypothesizing that n-3 PUFA enriched LPC has anti-atherogenic properties by promoting cholesterol efflux from macrophages and by reducing inflammation. Our anticipated long term objective is to establish that the fatty acyl moiety of LPC can be used as a potential biomarker for the risk of developing atherosclerosis. Validating this hypothesis would have a substantial impact on the public health with respect to early diagnosis of cardiovascular risks, and designing dietary based therapeutic strategies for the prevention and management of atherosclerosis and other heart related diseases. PMID- 26604023 TI - Integrated indicator framework and methodology for monitoring and assessment of hazardous substances and their effects in the marine environment. AB - Many maritime countries in Europe have implemented marine environmental monitoring programmes which include the measurement of chemical contaminants and related biological effects. How best to integrate data obtained in these two types of monitoring into meaningful assessments has been the subject of recent efforts by the International Council for Exploration of the Sea (ICES) Expert Groups. Work within these groups has concentrated on defining a core set of chemical and biological endpoints that can be used across maritime areas, defining confounding factors, supporting parameters and protocols for measurement. The framework comprised markers for concentrations of, exposure to and effects from, contaminants. Most importantly, assessment criteria for biological effect measurements have been set and the framework suggests how these measurements can be used in an integrated manner alongside contaminant measurements in biota, sediments and potentially water. Output from this process resulted in OSPAR Commission (www.ospar.org) guidelines that were adopted in 2012 on a trial basis for a period of 3 years. The developed assessment framework can furthermore provide a suitable approach for the assessment of Good Environmental Status (GES) for Descriptor 8 of the European Union (EU) Marine Strategy Framework Directive (MSFD). PMID- 26604025 TI - Baicalin may have a therapeutic effect in attention deficit hyperactivity disorder. AB - Baicalin is a flavonoid purified from Scutellaria baicalensis Georgi. It possesses a variety of pharmacological properties, such as anti-inflammatory, antioxidant, antiapoptotic, and neuro-protective properties, and provides protection against cerebral hemorrhage. However, it is seldom considered a therapeutic in mental disorders. Recent studies showed that baicalin protects cerebral functions against ischemia and has sedative and anxiolytic-like effects. Animal experiments showed that it protects dopaminergic neurons in the striatum, hippocampus and substantia nigra. It also has effects such as anti-depressive and anti-epileptic and offers resistance to Parkinson's disease. Attention deficit hyperactivity disorder (ADHD) pathogenesis is closely related to dopamine deficiency. However, the therapeutic effect of baicalin in ADHD has not been studied. We hypothesize that baicalin may protect dopaminergic neurons and increase brain dopamine levels, thus serving as an effective novel treatment for ADHD. PMID- 26604026 TI - Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease. AB - The etiology of myalgic encephalomyelitis also known as chronic fatigue syndrome or ME/CFS has not been established. Controversies exist over whether it is an organic disease or a psychological disorder and even the existence of ME/CFS as a disease entity is sometimes denied. Suggested causal hypotheses have included psychosomatic disorders, infectious agents, immune dysfunctions, autoimmunity, metabolic disturbances, toxins and inherited genetic factors. Clinical, immunological and epidemiological evidence supports the hypothesis that: ME/CFS is an infectious disease; the causal pathogen persists in patients; the pathogen can be transmitted by casual contact; host factors determine susceptibility to the illness; and there is a population of healthy carriers, who may be able to shed the pathogen. ME/CFS is endemic globally as sporadic cases and occasional cluster outbreaks (epidemics). Cluster outbreaks imply an infectious agent. An abrupt flu-like onset resembling an infectious illness occurs in outbreak patients and many sporadic patients. Immune responses in sporadic patients resemble immune responses in other infectious diseases. Contagion is shown by finding secondary cases in outbreaks, and suggested by a higher prevalence of ME/CFS in sporadic patients' genetically unrelated close contacts (spouses/partners) than the community. Abortive cases, sub-clinical cases, and carrier state individuals were found in outbreaks. The chronic phase of ME/CFS does not appear to be particularly infective. Some healthy patient-contacts show immune responses similar to patients' immune responses, suggesting exposure to the same antigen (a pathogen). The chronicity of symptoms and of immune system changes and the occurrence of secondary cases suggest persistence of a causal pathogen. Risk factors which predispose to developing ME/CFS are: a close family member with ME/CFS; inherited genetic factors; female gender; age; rest/activity; previous exposure to stress or toxins; various infectious diseases preceding the onset of ME/CFS; and occupational exposure of health care professionals. The hypothesis implies that ME/CFS patients should not donate blood or tissue and usual precautions should be taken when handling patients' blood and tissue. No known pathogen has been shown to cause ME/CFS. Confirmation of the hypothesis requires identification of a causal pathogen. Research should focus on a search for unknown and known pathogens. Finding a causal pathogen could assist with diagnosis; help find a biomarker; enable the development of anti-microbial treatments; suggest preventive measures; explain pathophysiological findings; and reassure patients about the validity of their symptoms. PMID- 26604027 TI - Review of Amyotrophic Lateral Sclerosis, Parkinson's and Alzheimer's diseases helps further define pathology of the novel paradigm for Alzheimer's with heavy metals as primary disease cause. AB - Pathologies of neurological diseases are increasingly recognized to have common structural and molecular events that can fit, sometimes loosely, into a central pathological theme. A better understanding of the genetic, proteomic and metabolic similarities between three common neurodegenerative diseases - Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD) - and how these similarities relate to their unique pathological features may shed more light on the underlying pathology of each. These are complex multigenic neuroinflammatory diseases caused by a combined action by multiple genetic mutations, lifestyle factors and environmental elements including a proposed contribution by transition metals. This comprehensive dynamic makes disease decoding and treatment difficult. One case of ALS, for example, can manifest from a very different pool of genetic mutations than another. In the case of ALS multiple genes in addition to SOD1 are implicated in the pathogenesis of both sporadic and familial variants of the disease. These genes play different roles in the processing and trafficking of signalling, metabolic and structural proteins. However, many of these genetic mutations or the cellular machinery they regulate can play a role in one form or another in PD and AD as well. In addition, the more recent understanding of how TREM-2 mutations factor into inflammatory response has shed new light on how chronic inflammatory activity can escalate to uncontrolled systemic levels in a variety of inflammatory diseases from neurodegenerative, auto-inflammatory and autoimmune diseases. TREM-2 mutations represent yet another complicating element in these multigenic disease pathologies. This review takes us one step back to discuss basic pathological features of these neurodegenerative diseases known to us for some time. However, the objective is to discuss the possibility of related or linked mechanisms that may exist through these basic disease hallmarks that we often classify as absolute signatures of one disease. These new perspectives will be discussed in the context of a new paradigm for Alzheimer's disease that implicates heavy metals as a primary cause. Plausible links between these distinctly different pathologies are presented showing intersections of their distinct pathologies that hinge on metal interactions. PMID- 26604028 TI - Non-pharmacological treatment for neuropathic pain in children with cancer. AB - Neuropathic pain (NP) associated with childhood cancer is currently a difficult problem to control. It is treated with drugs that not only fail to provide the expected improvements, but which also have side effects. Therefore, the main aim of this pilot study is to assess whether non-pharmacological treatments, Graded Motor Imagery (GMI) and Neural Mobilization (NM), have a positive effect on this pain, thus improving the associated comorbid factors and, consequently, the quality of life of the children. In an n = 6, the results after 4 weeks of treatment show a 10-point improvement in the pain threshold and a 3.1-point improvement in the perception of pain. PMID- 26604029 TI - Triclosan and bisphenol a affect decidualization of human endometrial stromal cells. AB - In recent years, impaired fertility and endometrium related diseases are increased. Many evidences suggest that environmental pollution might be considered a risk factor for endometrial physiopathology. Among environmental pollutants, endocrine disrupting chemicals (EDCs) act on endocrine system, causing hormonal imbalance which, in turn, leads to female and male reproductive dysfunctions. In this work, we studied the effects of triclosan (TCL) and bisphenol A (BPA), two widespread EDCs, on human endometrial stromal cells (ESCs), derived from endometrial biopsies from woman not affected by endometriosis. Cell proliferation, cell cycle, migration and decidualization mechanisms were investigated. Treatments have been performed with both the EDCs separately or in presence and in absence of progesterone used as decidualization stimulus. Both TCL and BPA did not affect cell proliferation, but they arrested ESCs at G2/M phase of cell cycle enhancing cell migration. TCL and BPA also increased gene expression and protein levels of some decidualization markers, such as insulin growth factor binding protein 1 (IGFBP1) and prolactin (PRL), amplifying the effect of progesterone alone. All together, our data strongly suggest that TCL and BPA might alter human endometrium physiology so affecting fertility and pregnancy outcome. PMID- 26604031 TI - RECIST progression patterns during EGFR tyrosine kinase inhibitor treatment of advanced non-small cell lung cancer patients harboring an EGFR mutation. AB - BACKGROUND: Progression patterns at the response evaluation criteria in solid tumors-progressive disease (RECIST-PD) during treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for advanced non-small cell lung cancer (NSCLC) in patients harboring an EGFR mutation are clinically heterogeneous. We evaluated the association between progression patterns during EGFR-TKI treatment and prognosis after treatment in such patients. METHODS: From 2008 to 2012, 160 consecutive patients with advanced NSCLC harboring an EGFR mutation were treated with EGFR-TKIs (erlotinib or gefitinib). Among these, 104 who experienced RECIST-PD were retrospectively evaluated for initial response to EGFR-TKIs, progression sites, focus of progression (solitary lesion or multiple lesions), symptom status at RECIST-PD evaluation, and post-progression survival (PPS). RESULTS: Of 104 patients, 96 (92%) had an EGFR major mutation, and 50 (48%) received EGFR-TKIs as first-line treatment. Overall response rate and median time to RECIST-PD on EGFR-TKIs were 68% and 8.2 months, respectively. At the time of attaining RECIST-PD status, 44 (42%) patients were symptomatic, and 60 (58%) were asymptomatic. Progression sites at RECIST-PD were isolated brain in 17 (16%) patients and systemic in 87 (84%): 24 (23%) had a solitary lesion, and 80 (77%) had multiple lesions. After RECIST-PD assessment, 40 (38%) patients continued EGFR-TKIs, and 25 (24%) switched to cytotoxic agents; 10 (10%) received local radiotherapy for an isolated progression site (brain 6; bone 3; lung 1). Median PPS was 10.8 months. Multivariate analysis revealed that asymptomatic or solitary lesion status was associated with significantly longer PPS (asymptomatic: HR 0.36, 95% CI 0.21-0.62, P<0.01; solitary progression lesion: HR 0.45, 95% CI 0.18-99, P=0.04). CONCLUSIONS: Progression patterns at the RECIST-PD during EGFR-TKI treatment of advanced NSCLC in patients harboring an EGFR mutation are widely diverse, and might be associated with clinical outcome after treatment failure. PMID- 26604030 TI - Short-Circuiting Gene Regulatory Networks: Origins of B Cell Lymphoma. AB - B cell lymphomas (BCLs) are characterized by widespread deregulation of gene expression compared with their normal B cell counterparts. Recent epigenomic studies defined cis-regulatory elements (REs) whose activities are altered in BCL to drive some of these pathogenic expression changes. During transformation, multiple mechanisms are employed to alter RE activities, including perturbations in the function of chromatin modifiers, which can lead to revision of the B cell epigenome. Inherited and somatic variants also alter RE function via disruption of transcription factor (TF) binding. Aberrant expression of noncoding RNAs (ncRNAs) deregulates genes involved in B cell differentiation via direct repression and post-transcriptional targeting. These discoveries have established epigenetic etiologies for B cell transformation that are being exploited in novel therapeutic approaches. PMID- 26604032 TI - Prognostic impact of clinical variables on surgically resected small-cell lung cancer: Results of a retrospective multicenter analysis (FIGHT002A and HOT1301A). AB - OBJECTIVES: Several American and Japanese guidelines recommend surgery for patients with c-stage I small-cell lung cancer (SCLC), whereas the European Society of Medical Oncology (ESMO) guidelines recommend surgery for patients with not only c-stage I but also c-stage II (T2N1) SCLC. In addition, previous studies identified various factors other than clinical stage that are related to survival in these patients. Thus, further validation and examination of the association of clinical stage and other clinical variables with survival are required for establishing practical management of early-stage SCLC. PATIENTS AND METHODS: We reviewed the clinical courses of 156 SCLC patients who had undergone surgery at 17 institutions between January 2003 and January 2013. RESULTS: Clinical stages (tumor-node-metastasis [TNM] version 7) of the 156 patients were 98 cases in IA, 14 in IB, 16 in IIA, 7 in IIB, 18 in IIIA, and 3 in IIIB. Median overall survival (OS) was 33.3 months (95% confidence interval: 20.9-45.8). Multivariate analysis revealed that OS was longer in patients either at c-stage II and under, with a maximum tumor diameter of <20mm, with preoperative diagnosis, without a history or presence of other types of cancer, or who underwent prophylactic cranial irradiation (PCI). CONCLUSION: These results indicate that a history or presence of other types of cancer might be a major decisive factor for surgery. Patients with c-stages I and II (c-T2N1) can be considered for surgery, and PCI may be useful in patients undergoing surgery in a practical setting, partly supporting the ESMO guidelines.(1). PMID- 26604033 TI - Influence of encoding focus and stereotypes on source monitoring event-related potentials. AB - Source memory, memory for the origin of a memory, can be influenced by stereotypes and the information of focus during encoding processes. Participants studied words from two different speakers (male or female) using self-focus or other-focus encoding. Source judgments for the speaker's voice and Event-Related Potentials (ERPs) were recorded during test. Self-focus encoding increased dependence on stereotype information and the Late Posterior Negativity (LPN). The results link the LPN with an increase in systematic decision processes such as consulting prior knowledge to support an episodic memory judgment. In addition, other-focus encoding increased conditional source judgments and resulted in weaker old/new recognition relative to the self-focus encoding. The putative correlate of recollection (LPC) was absent during this condition and this was taken as evidence that recollection of partial information supported source judgments. Collectively, the results suggest that other-focus encoding changes source monitoring processing by altering the weight of specific memory features. PMID- 26604034 TI - Cyclization of polyketides and non-ribosomal peptides on and off their assembly lines. AB - Modular polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) are multifunctional megaenzymes that serve as templates to program the assembly of short carboxylic acids and amino acids in a primarily co-linear manner. The variation, combination, permutation and evolution of their functional units (e.g., modules, domains and proteins) along with their association with external enzymes have resulted in the generation of numerous versions of templates, the roles of which have not been fully recognized in the structural diversification of polyketides, non-ribosomal peptides and their hybrids present in nature. In this Highlight, we focus on the assembly-line enzymology and associated chemistry by providing examples of some newly characterized cyclization reactions that occur on and off the assembly lines during and after chain elongation for the purpose of elucidating the template effects of PKSs and NRPSs. A fundamental understanding of the underlying biosynthetic logic would facilitate the elucidation of chemical information contained within the PKS or NRPS templates and benefit the development of strategies for genome mining, biosynthesis inspired chemical synthesis and combinatorial biosynthesis. PMID- 26604035 TI - Defining reference levels for intra-operative radiation exposure in orthopaedic trauma: A retrospective multicentre study. AB - There is currently limited data to define reference levels for the use of ionising radiation in orthopaedic trauma surgery. In this multicentre study, we utilise methodology employed by the Health Protection Agency in establishing reference levels for diagnostic investigations in order to define analogous levels for common and reproducible orthopaedic trauma procedures. Four hundred ninety-five procedures were identified across four Greater London hospitals over a 1-year period. Exposure was defined in terms of both time and dose area product (DAP). Third quartile mean values for either parameter were used to define reference levels. Variations both between centres and grades of lead surgeon were analysed as secondary outcomes. Reference levels; dynamic hip screw (DHS) 1.9225000 Gycm(2)/70.50 s, intramedullary (IM) femoral nail 1.5837500 Gycm(2)/126.00 s, open reduction internal fixation (ORIF) clavicle 0.2042500 Gycm(2)/21.50 s, ORIF lateral malleolus 0.32250500 Gycm(2)/35.00 s, ORIF distal radius 0.1300000 Gycm(2)/56.00 s. Grade of surgeon did not influence exposure in dynamic hip screw, and was inversely related to exposure in intramedullary femoral nails. Less variation was observed with exposure time than with DAP. This study provides the most comprehensive reference to guide fluoroscopy use in orthopaedic trauma to date, and is of value both at the point of delivery and for audit of local practice. PMID- 26604036 TI - Impact of length of red blood cells transfusion on postoperative delirium in elderly patients undergoing hip fracture surgery: A cohort study. AB - PURPOSE: The purpose of the present study was to test whether older red blood cells (RBCs) transfusion results in an increased risk of postoperative delirium (POD) and various in-hospital postoperative complications in elderly patients undergoing hip fracture surgery. MATERIALS AND METHODS: Patients (>=65 years) who underwent hip fracture surgery were enrolled, 179 patients were divided into two groups according to the storage time of the RBCs. The shorter storage time of RBCs transfusion group comprised patients who received RBCs <=14 days old and the longer storage time of RBCs transfusion group comprised patients who received RBCs >14 days old. The blood samples were collected before anaesthesia induction, 4 and 24 h after RBCs transfusion for the determination of proinflammatory mediators, malondialdehyde, and superoxide dismutase activity. RESULTS: There was no difference in the baseline characteristics, the incidence of POD, and the in hospital postoperative complications between the shorter storage time of RBCs transfusion group and the longer storage time of RBCs transfusion groups (P>0.05). Compared with the shorter storage time of RBCs transfusion group, the longer storage time of RBCs transfusion caused significantly longer duration of POD (P<0.05). There were significantly increased plasma levels of IL-8 and malondialdehyde at 24 h and IL-1beta at 4 h after RBCs transfusion in the POD group compared with the non-POD group (P<0.05). CONCLUSION: Transfusion of the longer storage RBCs is not associated with a higher incidence of POD or in hospital postoperative complications, but with longer duration of POD in elderly patients undergoing hip fracture surgery. PMID- 26604038 TI - 'Hypoxio-spondin': thrombospondin and its emerging role in pulmonary hypertension. PMID- 26604037 TI - A CD1d-dependent lipid antagonist to NKT cells ameliorates atherosclerosis in ApoE-/- mice by reducing lesion necrosis and inflammation. AB - AIMS: Atherosclerosis-related deaths from heart attacks and strokes remain leading causes of global mortality, despite the use of lipid-lowering statins. Thus, there is an urgent need to develop additional therapies. METHODS AND RESULTS: Reports that NKT cells promote atherosclerosis and an NKT cell CD1d dependent lipid antagonist (DPPE-PEG350, 1,2-dipalmitoyl-sn-glycero-3 phosphoethanolamine-N[methoxy(polyethyleneglycol)-350]) reduces allergen-induced inflammation led us to investigate its therapeutic potential in preventing the development and progression of experimental atherosclerosis. DPPE-PEG350 was administered to hyperlipidaemic ApoE(-/-) mice with/without established atherosclerosis. Atherosclerosis and immune cells were assessed in the aortic sinus lesions. Lesion expression of monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion protein-1 (VCAM-1) responsible for inflammatory immune cell recruitment as well as mRNA expression of IFNgamma and its plasma levels were investigated. Necrotic cores and lesion smooth muscle and collagen contents important in plaque stability were determined as were plasma lipid levels. DPPE PEG350 reduced atherosclerosis development and delayed progression of established atherosclerosis without affecting plasma lipids. CD4 and CD8 T cells and B cells in atherosclerotic lesions were decreased in DPPE-PEG350-treated mice. Lesion MCP 1 and VCAM-1 protein expression and necrotic core size were reduced without affecting lesion smooth muscle and collagen content. IFNgamma and lymphocytes were unaffected by the treatment. CONCLUSION: The attenuation of progression of established atherosclerosis together with reduced development of atherosclerosis in hyperlipidaemic mice by the NKT antagonist, without affecting NKT cell or other lymphocyte numbers, suggests that targeting lesion inflammation via CD1d dependent activation of NKT cells using DPPE-PEG350 has a therapeutic potential in treating atherosclerosis. PMID- 26604039 TI - Interventions for the prevention of catheter associated urinary tract infections in intensive care units: An integrative review. AB - Catheter associated urinary tract infections (CAUTIs) put an unnecessary burden on patients and health care systems. The purpose of this integrative review was to examine existing evidence on preventative interventions and protocols currently implemented in intensive care units (ICUs) and the impact they have on CAUTI rates and patient outcomes. This review analysed 14 research articles obtained from electronic databases and included adult patients with urinary catheters in an ICU setting. Evidence demonstrated interventions that included criteria for catheter use, daily review of catheter necessity and discontinuation of catheter prior to day seven were successful in decreasing CAUTI rates. This review provides a scientific basis for the effectiveness of these interventions and protocols. Identification and use of interventions with the greatest positive impact on CAUTI rates are an asset to healthcare professional caring for patients with indwelling catheters and nurse clinicians developing policies. PMID- 26604040 TI - Changes in patient safety culture after restructuring of intensive care units: Two cross-sectional studies. AB - OBJECTIVES: Compare changes in registered nurses' perception of the patient safety culture in restructured and not restructured intensive care units during a four-year period. METHODOLOGY/DESIGN: Two cross-sectional surveys were performed, in 2008/2009 (time 1) and 2012/2013 (time 2). During a period of 0-3 years after time 1, three of six hospitals merged their general and medical intensive care units (restructured). The other hospitals maintained their structure of the intensive care units (not restructured). SETTING: Intensive care units in hospitals at one Norwegian hospital trust. OUTCOME MEASURE: The safety culture was measured with Hospital Survey on Patient Safety Culture. RESULTS: At times 1 and 2, 217/302 (72%) and 145/289 (50%) registered nurses participated. Restructuring was negatively associated with change in the safety culture, in particular, the dimensions of the safety culture within the unit level. The dimensions most vulnerable for restructuring were manager expectations and actions promoting safety, teamwork within hospital units and staffing. CONCLUSION: In this study, the restructuring of intensive care units was associated with a negative impact on the safety culture. When restructuring, the management should be particularly aware of changes in the safety culture dimensions manager expectations and actions promoting safety, teamwork within hospital units and staffing. PMID- 26604041 TI - Tasks completed by nursing members of a teaching hospital Medical Emergency Team. AB - OBJECTIVES: To assess tasks completed by intensive care medical emergency team nurses. RESEARCH DESIGN: Prospective observational study. SETTING: Australian teaching hospital. MAIN OUTCOME MEASURES: Nursing-related technical and non technical tasks and level of self-reported confidence and competence. RESULTS: Amongst 400 calls, triggers and nursing tasks were captured in 93.5% and 77.3% of cases, respectively. The median patient age was 73 years. The four most common triggers were hypotension (22.0%), tachycardia (21.1%), low SpO2 (17.4%), and altered conscious state (10.1%). Non-technical skills included investigation review (33.7%), history acquisition (18.4%), contribution to the management plan (40.5%) and explanation to bedside nurses (78.3%), doctors (13.6%), allied health (3.9%) or patient/relative (39.5%). Technical tasks included examining the circulation (32%), conscious state (29.4%), and chest (26.5%). Additional tasks included adjusting oxygen (23.9%), humidification (8.4%), non-invasive ventilation (6.5%), performing an ECG (22%), and administrating fluid as a bolus (17.5%) or maintenance (16, 5.2%), or medication as a statim dose (16.8%) or infusion (5.2%). Self-reported competence and confidence appeared to be high overall amongst our MET nurses. CONCLUSION: Our findings provide important information on the tasks completed by Medical Emergency Team nurses and will guide future training. PMID- 26604042 TI - Interferons and the Immunogenic Effects of Cancer Therapy. AB - Much of our understanding on resistance mechanisms to conventional cancer therapies such as chemotherapy and radiation has focused on cell intrinsic properties that antagonize the detrimental effects of DNA and other cellular damage. However, it is becoming clear that the immune system and/or innate immune signaling pathways can integrate with these intrinsic mechanisms to profoundly influence treatment efficacy. In this context, recent evidence indicates that interferon (IFN) signaling has an important role in this integration by influencing immune and intrinsic/non-immune determinants of therapy response. However, IFN signaling can be both immunostimulatory and immunosuppressive, and the factors determining these outcomes in different disease settings are unclear. Here I discuss the regulation and molecular events in cancer that are associated with these dichotomous functions. PMID- 26604043 TI - The Health Belief Model: A Qualitative Study to Understand High-risk Sexual Behavior in Chinese Men Who Have Sex With Men. AB - The Health Belief Model (HBM) has been widely used to explain rationales for health risk-taking behaviors. Our qualitative study explored the applicability of the HBM to understand high-risk sexual behavior in Chinese men who have sex with men (MSM) and to elaborate each component of the model. HIV knowledge and perception of HIV prevalence contributed to perceived susceptibility. An attitude of treatment optimism versus hard life in reality affected perceived severity. Perceived barriers included discomfort using condoms and condom availability. Perceived benefits included prevention of HIV and other sexually transmitted illnesses. Sociocultural cues for Chinese MSM were elaborated according to each component. The results demonstrated that the HBM could be applied to Chinese MSM. When used with this group, it provided information to help develop a population- and disease-specific HBM scale. Results of our study also suggested behavioral interventions that could be used with Chinese MSM to increase condom use. PMID- 26604044 TI - Refining prognosis after trans-arterial chemo-embolization for hepatocellular carcinoma. AB - BACKGROUND & AIMS: To develop an individual prognostic calculator for patients with unresectable hepatocellular carcinoma (HCC) undergoing trans-arterial chemo embolization (TACE). METHODS: Data from two prospective databases, regarding 361 patients who received TACE as first-line therapy (2000-2012), were reviewed in order to refine available prognostic tools and to develop a continuous individual web-based prognostic calculator. Patients with neoplastic portal vein invasion were excluded from the analysis. The model was built following a bootstrap resampling procedure aimed at identifying prognostic predictors and by carrying out a 10-fold cross-validation for accuracy assessment by means of Harrell's c statistic. RESULTS: Number of tumours, serum albumin, serum total bilirubin, alpha-foetoprotein and maximum tumour size were selected as predictors of mortality following TACE with the bootstrap resampling technique. In the 10-fold cross-validation cohort, the model showed a Harrell's c-statistic of 0.649 (95% CI: 0.610-0.688), significantly higher than that of the Hepatoma Arterial embolization Prognostic (HAP) score (0.589; 95% CI: 0.552-0.626; P = 0.001) and of the modified HAP-II score (0.611; 95% CI: 0.572-0.650; P = 0.005). Akaike's information criterion for the model was 2520; for the mHAP-II it was 2544 and for the HAP score it was 2554. A web-based calculator was developed for quick consultation at http://www.livercancer.eu/mhap3.html. CONCLUSIONS: The proposed individual prognostic model can provide an accurate prognostic prediction for each patient with unresectable HCC following treatment with TACE without class stratification. The availability of an online calculator can help physicians in daily clinical practice. PMID- 26604045 TI - Detection of Zoonotic Protozoa Toxoplasma gondii and Sarcocystis suihominis in Wild Boars from Spain. AB - Food safety regulations require the control of the presence of protozoa in meats destined for human consumption. Wild boar (Sus scrofa) meat may constitute a source of zoonoses. A 23.8% (688/2881) seroprevalence of anti-Toxoplasma gondii antibodies and 72.2% (662/910) Sarcocystis sarcocysts prevalence were detected among wild boars hunted in Southwestern areas of Spain. Identity of Sarcocystis spp. was performed by RFLP-PCR and sequencing, detecting S. miescheriana (7/8) and the zoonotic S. suihominis (1/8). Risk assessment studies of these coccidian in meats destined to human consumption are needed. PMID- 26604046 TI - Dual Effect of Manganese Oxide Micromotors: Catalytic Degradation and Adsorptive Bubble Separation of Organic Pollutants. AB - Manganese oxide (MnO2 ) based micromotors exhibiting a dual effect, that is, catalytic degradation and adsorptive bubble separation, were employed for water remediation. The dual effect of MnO2 microparticles led to a greater than 90 % of decolorization of non-biodegradable organic dyes in just 1 h, without the need for external agitation or bubble generation. These findings suggest high potential of MnO2 micromotors for decontamination of organic pollutants from wastewaters or natural water reserves. PMID- 26604047 TI - Observations of sacrocaudal fusion in Greyhounds and other dogs. AB - OBJECTIVES: To describe the incidence and forms of nonpathological sacrocaudal fusion in racing Greyhounds and compare them with those in a variety of other domestic dog breeds. METHODS: This retrospective observational study used archived anatomical specimens from 81 racing Greyhounds and 10 Beagles, and archived clinical radiographs from 81 non-Greyhound dogs representing 37 other breeds. Dogs less than two years of age and dogs with evidence of soft tissue or osseous pathology involving the sacrocaudal region were excluded. The incidence of osseous sacrocaudal fusion (any type and complete fusion) was compared between Greyhounds and all of the other dogs combined, using the Fisher's exact test. RESULTS: Sacrocaudal fusion of some type was found in 33 (41%) of 81 Greyhounds but in only 14 (15%) of 91 non-Greyhound dogs (p <0.01). Complete fusion (osseous fusion of vertebral bodies and both transverse and articular processes) between the sacrum and the first caudal vertebra was the most common form in Greyhounds, found in 27 (33%) of 81 Greyhounds, but in only three (3.3%) of 91 non-Greyhound dogs (p <0.01). CLINICAL SIGNIFICANCE: Sacrocaudal fusion appears to be more prevalent in Greyhounds than in other domestic dog breeds and may be attributable to selection pressure for speed on a region of the spine that is naturally prone to variation. Its significance for performance and soundness requires further study. PMID- 26604048 TI - Inferior Turbinate Asymmetry Is a Feature of the Unilateral Complete Cleft Lip and Palate Nasal Deformity. AB - PURPOSE: Patients with unilateral complete cleft lip and palate (UCLP) have a characteristic bilateral septal deformity, and septal deviation can be associated with turbinate hyperplasia, leading to paradoxical nasal obstruction. The purpose of the present study was to measure and compare the bony and mucosal dimensions of the inferior turbinate on the cleft and non-cleft sides in patients with UCLP. PATIENTS AND METHODS: We implemented a retrospective cohort study of patients with UCLP who had undergone computed tomography (CT) scan between 2002 to 2013. Subjects who had undergone nasal revision, septoplasty, turbinectomy, or Le Fort I osteotomy before the imaging date were excluded. The primary predictor variable was the subject side (cleft vs noncleft side), and the primary outcome variable was the turbinate cross-sectional area. The secondary predictor variables included the site of measurement along the sagittal axis of the turbinate (anterior, middle, posterior) and tissue type (turbinate whole, bone, mucosa). The Wilcoxon signed rank test for paired samples compared the turbinate dimensions on the cleft and noncleft sides, with statistical significance set at P <= .05. RESULTS: The sample included 53 patients (32 females and 21 males). The inferior turbinates were measured bilaterally on CT images obtained at a mean age of 12.2 +/- 0.8 years. The inferior turbinate on the noncleft side was significantly larger in both bone and mucosa (P = .003). This relationship did not change when controlling for age and gender. CONCLUSIONS: The results of the present study have confirmed bony and mucosal enlargement of the inferior turbinate on the noncleft side in patients with UCLP. This might contribute to bilateral nasal obstruction and should be considered during treatment planning for nasopharyngeal and orthognathic surgery. PMID- 26604049 TI - Short- and long-term need for permanent pacemaker after transcatheter implantation of the Edwards Sapien aortic valve prosthesis. AB - INTRODUCTION: A permanent pacemaker is frequently needed after transcatheter aortic valve implantation, but the available data are mainly on the CoreValve system. OBJECTIVE: To evaluate the need for new permanent pacemaker after implantation of the Edwards Sapien device, as well as related factors. METHODS: We included the first 100 patients treated with the Edwards Sapien device at our institution. Of these, 12 had a permanent pacemaker before the procedure, and thus our study population was the remaining 88 patients. RESULTS: A permanent pacemaker was indicated in eight patients (9.1%) during hospitalization or at 30 days. After discharge, another four patients needed a pacemaker (at 42 days and three, 18, and 30 months). Two variables were associated with the need for pacemaker during hospitalization: previous dialysis (13% vs. 1%, p=0.042) and complete right bundle branch block before the procedure (25% vs. 5%, p=0.032). More than one month after the procedure, the characteristics associated with the need for pacemaker were plasma creatinine level (2.5+/-1.7 vs. 1.3+/-0.6 mg/dl, p=0.001) and previous myocardial infarction (50% vs. 10%, p=0.013). CONCLUSION: The rate of pacemaker implantation with the Edwards Sapien device was 9.1%. Right bundle branch block and dialysis were associated with this complication. PMID- 26604050 TI - Multidimensional indices of clinical oral conditions from a population perspective: a systematic review. AB - OBJECTIVE: To conduct a systematic review of the literature on indices that assess different clinical oral conditions simultaneously from a population perspective. METHODS: A search of the literature was carried out considering articles indexed in PubMed/MEDLINE, Web of Science, Scopus, SciELO, and LILACS, using search queries containing free and controlled vocabulary. The search included validity and reproducibility studies on the development of indices that assessed, simultaneously, at least two of the following oral morbidities: dental caries, periodontal status, and occlusal conditions, regardless of their indication for specific age or age groups. RESULTS: Of the 2240 studies identified, 21 were considered eligible to be included in this study. Most studies (70% n = 14) were published between the 1960s and the 1990s. Eight indices were identified and half of these originated from the United States. For most indices, the minimum age indicated was 19 years and above. All the indices evaluated dental caries, and more than 2/3 evaluated periodontal status. None evaluated need for prosthesis and one included need for treatment. Interobserver and intra-observer reliability values were 0.7 or above. Most studies only presented content validity. CONCLUSIONS: Although few normative oral health indices and validation studies were developed after the 1990s, the reliability values of all the reviewed studies were satisfactory; however, they did not present a refinement in terms of validity. This evidence suggests that further studies are needed to demonstrate the validity and/or reproducibility of multidimensional measures of clinical oral conditions. PMID- 26604052 TI - Effect of orthokeratology in patients with myopic regression after refractive surgery. AB - PURPOSE: To evaluate the clinical effect of orthokeratology (ortho-K) lenses and to introduce the fitting steps of ortho-K lens for myopic regression after keratorefractive surgery. METHODS: Twenty-one eyes from 12 patients with myopic regression after keratorefractive surgery were fitted with ortho-K lenses and followed up for 12.11+/-3.68 months. The mean K value of the peripheral cornea was used to speculate preoperative central corneal K value, estimated K. After dispensing the lenses according to estimated K, biomicroscopic examination including fluorescein staining and over-refraction were performed to determine the final K and final lens power. RESULTS: LogMAR uncorrected visual acuity was 0.48+/-0.39 before and 0.00+/-0.00 after wearing ortho-K lenses (p<0.001). Pre fitted refractive error was -1.87+/-1.05 diopters (D) in myopia, 0.54+/-0.42 D in astigmatism, and spherical equivalent of -2.14+/-1.01 D. At the final visit myopia level and spherical equivalent significantly decreased to -0.73+/-0.84 D (p<0.001) and -1.01+/-0.87 D (p<0.001), respectively. Estimated K was 8.07+/-0.36 mm, and final K used for ortho-K prescription was 8.19+/-0.30 mm. Final K significantly correlated with K value of pre-fitted peripheral cornea (r=0.737, p<0.001) and estimated K (r=0.721, p<0.001), respectively. There was no correlation between pre-fitted degree of myopia and the Final lens power (r=0.429, p=0.053). CONCLUSIONS: Ortho-K lenses may be an effective solution for patients with myopic regression following keratorefractive surgery. Estimated K value can be used as reference value in ortho-K prescription. PMID- 26604053 TI - Backward Migration of a MitraClip Through a Patent Transseptal Orifice: The Salmon Syndrome. PMID- 26604054 TI - Not Your Typical Hole-in-the-Wall: Percutaneous Closure of an Acquired Post Myocardial Infarction Ventriculoatrial Gerbode Defect. PMID- 26604055 TI - Simple Solution for an Undeflatable Stent Balloon in the Left Main Stem. PMID- 26604056 TI - A New Transcatheter Aortic Valve Replacement System for Predominant Aortic Regurgitation Implantation of the J-Valve and Early Outcome. AB - OBJECTIVES: This study introduces a newly designed transcatheter aortic valve system, the J-Valve system, and evaluates its application in patients with predominant aortic regurgitation without significant valve calcification. We also report the early results of one of the first series of transapical implantations of this device and aim to offer guidance on the technical aspects of the procedure. BACKGROUND: Transcatheter aortic valve replacement (TAVR) has been widely used in high-risk patients for surgical aortic valve replacement. However, the majority of the TAVR devices were designed for aortic valve stenosis with significant valve calcification. METHODS: Six patients with native aortic regurgitation without significant valve calcification (age, 61 to 83 years; mean age, 75.50 +/- 8.14 years) underwent transapical implantation of the J-Valve prosthesis (JieCheng Medical Technology Co., Ltd., Suzhou, China), a self expandable porcine valve, in the aortic position at our institution. All patients were considered to be prohibitive or high risk for surgical valve replacement (logistic EuroSCORE [European System for Cardiac Operative Risk Evaluation], 22.15% to 44.44%; mean, 29.32 +/- 7.70%) after evaluation by an interdisciplinary heart team. Procedural and clinical outcomes were analyzed. RESULTS: Implantations were successful in all patients. During the follow-up period (from 31 days to 186 days, mean follow-up was 110.00 +/- 77.944 days), only 1 patient had trivial prosthetic valve regurgitation, and none of these patients had paravalvular leak of more than mild grade. There were no major post-operative complications or mortality during the follow-up. CONCLUSIONS: Our study demonstrated the feasibility of transapical implantation of the J-Valve system in high-risk patients with predominant aortic regurgitation. PMID- 26604057 TI - Proficiency With Vascular Access: Don't Rob Peter to Pay Paul. PMID- 26604058 TI - Imaging-Guided Lower Extremity Endovascular Interventions: Is Now the Time? PMID- 26604059 TI - Complete Transcatheter Treatment of Degenerated Bioprosthetic Mitral Regurgitation: Transapical Paravalvular Leak Closure Followed by Transseptal Mitral Valve-in-Valve Replacement. PMID- 26604060 TI - Transcatheter Options for the Treatment of Noncalcified Aortic Regurgitation. PMID- 26604061 TI - 15-Year Patency and Life Expectancy After Primary Stenting Guided by Intravascular Ultrasound for Iliac Artery Lesions in Peripheral Arterial Disease. AB - OBJECTIVES: The purpose of this study was to evaluate 15-year patency and life expectancy after endovascular treatment (EVT) with primary stenting guided by intravascular ultrasound (IVUS) for iliac artery lesions. BACKGROUND: Fifteen year patency, factors causing restenosis, and survival after IVUS-guided EVT are unclear based on the TransAtlantic Inter-Society Consensus II (TASC-II) classification in peripheral arterial disease (PAD). METHODS: EVT was performed for 507 lesions in 455 patients with PAD. The 15-year endpoints were primary, primary-assisted, and secondary patency; overall survival; freedom from major adverse cardiovascular events (MACE); and freedom from major adverse cardiovascular and limb events (MACLE). RESULTS: The 5-, 10-, and 15-year primary and secondary patencies were 89%, 83%, and 75%, respectively, and 92%, 91%, and 91%, respectively. There were no significant differences among TASC-II categories. CONCLUSIONS: IVUS-guided stenting for the iliac artery had favorable 15-year patency in all TASC categories. Life expectancy after EVT was poor, but stenting is feasible for patients with PAD. PMID- 26604062 TI - Transfemoral Implantation of a Fully Repositionable and Retrievable Transcatheter Valve for Noncalcified Pure Aortic Regurgitation. AB - OBJECTIVES: This study sought to evaluate the use of the Direct Flow Medical (DFM) transcatheter heart valve (Direct Flow Medical, Santa Rosa, California) for the treatment of noncalcific pure aortic regurgitation (AR). BACKGROUND: The treatment of noncalcific AR has remained a relative contraindication with transcatheter heart valves due to challenges in anchoring devices in the absence of calcium, concerns of valve embolization, and the high risk of significant residual paravalvular leak. METHODS: The study population consisted of patients treated for severe noncalcific pure AR with transfemoral implantation of a DFM transcatheter heart valve at 6 European centers. The primary endpoint was the composite endpoint of device success and the secondary endpoint was the composite early safety endpoint (according to the VARC-2 criteria). RESULTS: Eleven high risk (STS score 8.84 +/- 8.9, Logistic EuroSCORE 19.9 +/- 7.1) patients (mean age 74.7 +/- 12.9 years) were included. Device success was achieved in all patients. In 1 patient, the initial valve prosthesis was retrieved after pull-through, and a second valve was successfully deployed. The early safety endpoint was reached in 91% of the patients, with 1 patient requiring surgical aortic valve replacement secondary to downward dislocation of the prosthesis that was successfully managed with surgical aortic valve replacement. DFM implantation resulted in excellent hemodynamics with none or trivial paravalvular regurgitation in 9 patients and a transprosthetic gradient of 7.7 +/- 5.1 mm Hg at 30-day follow up. All patients derived symptomatic benefit following the procedure, with 72% in New York Heart Association functional class I or II. CONCLUSIONS: This study reports the feasibility of treating severe noncalcific AR with the Direct Flow prosthesis via the transfemoral route. PMID- 26604063 TI - The Benefits Conferred by Radial Access for Cardiac Catheterization Are Offset by a Paradoxical Increase in the Rate of Vascular Access Site Complications With Femoral Access: The Campeau Radial Paradox. AB - OBJECTIVES: The purpose of this study was to assess whether the benefits conferred by radial access (RA) at an individual level are offset by a proportionally greater incidence of vascular access site complications (VASC) at a population level when femoral access (FA) is performed. BACKGROUND: The recent widespread adoption of RA for cardiac catheterization has been associated with increased rates of VASCs when FA is attempted. METHODS: Logistic regression was used to calculate the adjusted VASC rate in a contemporary cohort of consecutive patients (2006 to 2008) where both RA and FA were used, and compared it with the adjusted VASC rate observed in a historical control cohort (1996 to 1998) where only FA was used. We calculated the adjusted attributable risk to estimate the proportion of VASC attributable to the introduction of RA in FA patients of the contemporary cohort. RESULTS: A total of 17,059 patients were included. At a population level, the VASC rate was higher in the overall contemporary cohort compared with the historical cohort (adjusted rates: 2.91% vs. 1.98%; odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.17 to 1.89; p = 0.001). In the contemporary cohort, RA patients experienced fewer VASC than FA patients (adjusted rates: 1.44% vs. 4.19%; OR: 0.33, 95% CI: 0.23 to 0.48; p < 0.001). We observed a higher VASC rate in FA patients in the contemporary cohort compared with the historical cohort (adjusted rates: 4.19% vs. 1.98%; OR: 2.16, 95% CI: 1.67 to 2.81; p < 0.001). This finding was consistent for both diagnostic and therapeutic catheterizations separately. The proportion of VASCs attributable to RA in the contemporary FA patients was estimated at 52.7%. CONCLUSIONS: In a contemporary population where both RA and FA were used, the safety benefit associated with RA is offset by a paradoxical increase in VASCs among FA patients. The existence of this radial paradox should be taken into consideration, especially among trainees and default radial operators. PMID- 26604065 TI - Successful elective and medically indicated oocyte vitrification and warming for autologous in vitro fertilization, with predicted birth probabilities for fertility preservation according to number of cryopreserved oocytes and age at retrieval. AB - OBJECTIVE: To evaluate a single treatment center's experience with autologous IVF using vitrified and warmed oocytes, including fertilization, embryonic development, pregnancy, and birth outcomes, and to estimate the likelihood of live birth of at least one, two, or three children according to the number of mature oocytes cryopreserved by elective fertility preservation patients. DESIGN: Retrospective cohort study. SETTING: Private practice clinic. PATIENT(S): Women undergoing autologous IVF treatment using vitrified and warmed oocytes. Indications for oocyte vitrification included elective fertility preservation, desire to limit the number of oocytes inseminated and embryos created, and lack of available sperm on the day of oocyte retrieval. INTERVENTION(S): Oocyte vitrification, warming, and subsequent IVF treatment. MAIN OUTCOME MEASURE(S): Post-warming survival, fertilization, implantation, clinical pregnancy, and live birth rates. RESULT(S): A total of 1,283 vitrified oocytes were warmed for 128 autologous IVF treatment cycles. Postthaw survival, fertilization, implantation, and birth rates were all comparable for the different oocyte cryopreservation indications; fertilization rates were also comparable to fresh autologous intracytoplasmic sperm injection cycles (70% vs. 72%). Implantation rates per embryo transferred (43% vs. 35%) and clinical pregnancy rates per transfer (57% vs. 44%) were significantly higher with vitrified-warmed compared with fresh oocytes. However, there was no statistically significant difference in live birth/ongoing pregnancy (39% vs. 35%). The overall vitrified-warmed oocyte to live born child efficiency was 6.4%. CONCLUSION(S): Treatment outcomes using autologous oocyte vitrification and warming are as good as cycles using fresh oocytes. These results are especially reassuring for infertile patients who must cryopreserve oocytes owing to unavailability of sperm or who wish to limit the number of oocytes inseminated. Age-associated estimates of oocyte to live-born child efficiencies are particularly useful in providing more explicit expectations regarding potential births for elective oocyte cryopreservation. PMID- 26604064 TI - A phase II study of neoadjuvant chemotherapy with S-1 and cisplatin for stage III gastric cancer: KUGC03. AB - OBJECTIVES: A multi-center phase II study was conducted to evaluate the safety and efficacy of neoadjuvant chemotherapy (NAC) with S-1 plus cisplatin for advanced gastric cancer. METHODS: The eligibility criteria were clinical T3/T4 or N2, not Stage IV. Patients received two 35-day cycles of S-1 plus cisplatin, and then underwent D2 gastrectomy. The primary endpoint was 3-year progression free survival (PFS). Secondary endpoints were ratio of R0 resection, response rate, adverse events, and overall survival. A sample size of 49 was determined to have 80% power for detecting 15% improvement in the 3-year PFS over 55% at a one-sided alpha of 0.1. RESULTS: Among 53 patients enrolled, 44 patients completed two cycles of NAC (83%), and 48 patients underwent R0 resection (91%). Postoperative complications occurred in 13 patients (26%). A pathological response was confirmed in 24 patients (45%), including four complete responses. The 3-year PFS was 50.7%, while the 3-year OS was 74.9%. CONCLUSIONS: Although the observed 3 year PFS rate was worse than expected, NAC with S1 plus cisplatin was safe and led to a high rate of R0 resection. A randomized controlled trial is needed to make conclusions about the effectiveness of NAC in Japanese patients undergoing D2 resection. PMID- 26604066 TI - Does the time interval between hysteroscopic polypectomy and start of in vitro fertilization affect outcomes? AB - OBJECTIVE: To investigate whether the time interval between hysteroscopic polypectomy and the start of IVF-ET cycles affect IVF cycle outcomes. DESIGN: Retrospective cohort. SETTING: Academic center. PATIENT(S): All patients diagnosed with endometrial polyps undergoing hysteroscopic polypectomy before fresh IVF-ET. INTERVENTION(S): Hysteroscopic polypectomy. MAIN OUTCOME MEASURE(S): Patients were divided into three groups based on the time interval between hysteroscopic polypectomy and the start of a fresh IVF-ET cycle. Group 1 consisted of patients who underwent IVF-ET after their next menses, group 2 after two or three menstrual cycles, and group 3 after more than three menstrual cycles. Demographics, baseline IVF characteristics, controlled ovarian stimulation response, and pregnancy outcomes after ET were compared among the groups. RESULT(S): A total of 487 patients met inclusion criteria: 241 in group 1 (49.5%), 172 in group 2 (35.3%), and 74 in group 3 (15.2%). There were no differences in the baseline characteristics of the three groups. Ovarian stimulation outcomes, specifically total stimulation days, total gonadotropins administered, and number of oocytes retrieved, were similar between groups. There were no differences in the mean number of embryos transferred. The overall pregnancy outcomes were similar for groups 1, 2, and 3: implantation rate (42.4%, 41.2%, and 42.1%, respectively), clinical pregnancy rate (48.5%, 48.3%, and 48.6%), spontaneous miscarriage rate (4.56%, 4.65%, and 4.05%), and live birth rate (44.0, 43.6%, and 44.6%). CONCLUSION(S): Because waiting for two or more menstrual cycles after hysteroscopic polypectomy does not necessarily yield superior outcomes, patients can undergo ovarian stimulation after their next menses without affecting IVF-ET outcomes. PMID- 26604067 TI - Expression of microtubule associated protein 2 and synaptophysin in endometrium: high levels in deep infiltrating endometriosis lesions. AB - OBJECTIVE: To assess whether healthy endometrium, eutopic endometrium, and endometriotic lesions express nerve growth factor (NGF), microtubule-associated protein 2 (MAP-2), and synaptophysin (SYP). DESIGN: Molecular study in tissue extracts. SETTING: University hospital. PATIENT(S): A group of women (n = 70), divided as [1] healthy controls (n = 30) and [2] with endometriosis (n = 40), was included. INTERVENTION(S): From the healthy control group an endometrial specimen was collected by hysteroscopy (proliferative phase, n = 16; secretive phase, n = 14). Endometriotic and endometrial specimens were collected from women undergoing laparoscopic surgery for endometriosis, endometrioma (OMA) (n = 20), or deep infiltrating endometriosis (DIE) (n = 20). MAIN OUTCOME MEASURE(S): To assess expression of NGF, MAP-2, and SYP messenger RNA (mRNA) levels in endometrium and in endometriosis by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and protein localization by immunofluorescence. Cultures of human endometrial stromal cells were used to evaluate the effect of tumor necrosis factor (TNF)-alpha on NGF and SYP. RESULT(S): Endometrial tissue from control expressed mRNA for NGF, MAP-2, and SYP, without any difference between proliferative and secretive phase. The DIE and OMA lesions showed the highest NGF mRNA expression, significantly higher than in eutopic endometrium and control. In DIE lesions SYP mRNA expression was higher than in OMA or in eutopic endometrium or controls. Immunofluorescence analysis of NGF, MAP-2, and SYP showed a slightly more intense positive signal in endometriotic lesions. Exposure to TNF-alpha increased NGF and SYP mRNA expression in endometrial culture cells. CONCLUSION(S): The present study revealed the presence of two selected neuronal markers, MAP-2 and SYP mRNAs and protein expression, in eutopic endometrium and in endometriotic lesions. PMID- 26604068 TI - Costs of achieving live birth from assisted reproductive technology: a comparison of sequential single and double embryo transfer approaches. AB - OBJECTIVE: To assess treatment and pregnancy/infant-associated medical costs and birth outcomes for assisted reproductive technology (ART) cycles in a subset of patients using elective double embryo (ET) and to project the difference in costs and outcomes had the cycles instead been sequential single ETs (fresh followed by frozen if the fresh ET did not result in live birth). DESIGN: Retrospective cohort study using 2012 and 2013 data from the National ART Surveillance System. SETTING: Infertility treatment centers. PATIENT(S): Fresh, autologous double ETs performed in 2012 among ART patients younger than 35 years of age with no prior ART use who cryopreserved at least one embryo. INTERVENTION(S): Sequential single and double ETs. MAIN OUTCOME MEASURE(S): Actual live birth rates and estimated ART treatment and pregnancy/infant-associated medical costs for double ET cycles started in 2012 and projected ART treatment and pregnancy/infant-associated medical costs if the double ET cycles had been performed as sequential single ETs. RESULT(S): The estimated total ART treatment and pregnancy/infant-associated medical costs were $580.9 million for 10,001 double ETs started in 2012. If performed as sequential single ETs, estimated costs would have decreased by $195.0 million to $386.0 million, and live birth rates would have increased from 57.7%-68.0%. CONCLUSION(S): Sequential single ETs, when clinically appropriate, can reduce total ART treatment and pregnancy/infant-associated medical costs by reducing multiple births without lowering live birth rates. PMID- 26604069 TI - Improved implantation rates of day 3 embryo transfers with the use of an automated time-lapse-enabled test to aid in embryo selection. AB - OBJECTIVE: To determine if an automated time-lapse test (TL-test) combined with traditional morphology for embryo selection and day 3 transfer results in improved clinical outcomes. DESIGN: Prospective concurrent-controlled pilot study. SETTING: IVF clinic and laboratory. PATIENT(S): A total of 319 female patients <41 years old, with day 3 embryo transfer, fewer than three failed IVF cycles, and at least four zygotes (2-pronuclear) on day 1. INTERVENTION(S): Automated time-lapse embryo assessment combined with morphologic assessment in the study (test) group compared with morphologic assessment only (control group). MAIN OUTCOME MEASURE(S): Embryo implantation, pregnancy, and multiple pregnancy rates. Subanalysis of implantation potential of embryos based on the TL-test (TL high vs. TL-low) scores. RESULT(S): Implantation and clinical pregnancy rates were significantly higher in the test group compared with the control group (implantation rates 30.2% vs. 19.0%, clinical pregnancy rates 46.0% vs. 32.1%, respectively). Multiple pregnancy rates were not statistically different (26.7% vs. 18.3%). Test group patients receiving at least one TL-high embryo had significantly higher implantation rates than patients receiving only TL-low embryos (36.8% vs. 20.6%). TL-high compared with TL-low embryos had significantly higher implantation rates (44.7% vs. 20.5%). Among morphologically good embryos, TL-high embryos were more likely to implant than TL-low embryos (44.1% vs. 20.6%). CONCLUSION(S): This is the first report demonstrating improved implantation rates in patients receiving day 3 embryo transfers based on the combined use of a TL-test along and traditional morphology. Our findings confirm that the noninvasive TL-test adds valuable information to traditional morphologic grading. CLINICAL TRIAL REGISTRATION NUMBER: NCT01671657. PMID- 26604070 TI - Subfertility increases risk of testicular cancer: evidence from population-based semen samples. AB - OBJECTIVE: To further understand the association between semen quality and cancer risk by means of well defined semen parameters. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 20,433 men who underwent semen analysis (SA) and a sample of 20,433 fertile control subjects matched by age and birth year. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Risk of all cancers as well as site-specific results for prostate cancer, testicular cancer, and melanoma. RESULT(S): Compared with fertile men, men with SA had an increased risk of testicular cancer (hazard rate [HR] 3.3). When the characterization of infertility was refined using individual semen parameters, we found that oligozoospermic men had an increased risk of cancer compared with fertile control subjects. This association was particularly strong for testicular cancer, with increased risk in men with oligozoospermia based on concentration (HR 11.9) and on sperm count (HR 10.3). Men in the in the lowest quartile of motility (HR 4.1), viability (HR 6.6), morphology (HR 4.2), or total motile count (HR 6.9) had higher risk of testicular cancer compared with fertile men. Men with sperm concentration and count in the 90th percentiles of the distribution (>=178 and >=579 * 10(6)/mL, respectively), as well as total motile count, had an increased risk of melanoma (HRs 2.1, 2.7, and 2.0, respectively). We found no differences in cancer risk between azoospermic and fertile men. CONCLUSION(S): Men with SA had an increased risk of testicular cancer which varied by semen quality. Unlike earlier work, we did not find an association between azoospermia and increased cancer risk. PMID- 26604071 TI - Influence of medically assisted reproduction techniques on crown-rump length and biochemical markers of trisomy 21 in the first trimester of pregnancy. AB - OBJECTIVE: To determine whether there is a difference between the known gestational age in pregnancies conceived after IVF and the estimated gestational age based on the crown-rump length (CRL) measurement during the first trimester. DESIGN: We retrospectively (between 2007 and 2012) studied a cohort of 6,739 patients who underwent ultrasonography between 11 and 13+6 weeks of amenorrhea. SETTING: Hospital. PATIENT(S): Group A consisted of 6,621 patients with regular menses whose term was calculated based on the date of their last menstrual period (LMP). Group B consisted of 529 patients whose pregnancies had been achieved by IVF and in whom term was calculated based on the date of fresh or frozen ET. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The gestational age difference was obtained by comparing the age obtained by measuring the CRL (Robinson's curve) with the gestational age calculated in accordance with LMP in group A or with ET day in group B. RESULT(S): The gestational age difference was significantly more in group B (2.3 days vs. 0.84 days in group A). We found a significant difference regarding biochemical markers for trisomy 21 to the detriment of group B with a significantly reduced pregnancy-associated protein P A multiple of median (0.78 vs. 0.92). CONCLUSION(S): There appears to be a small difference in CRL development between spontaneous pregnancies and pregnancies conceived by assisted reproductive technology (ART). Specific ultrasonographic curves for pregnancies conceived by ART would be more relevant and precise. The underlying pathophysiological mechanisms are not very clear and offer possibilities for future research. PMID- 26604072 TI - Pharmacokinetics, safety and tolerability of the novel, selective mineralocorticoid receptor antagonist finerenone - results from first-in-man and relative bioavailability studies. AB - The safety, tolerability and pharmacokinetics of the selective nonsteroidal mineralocorticoid receptor antagonist finerenone were evaluated in healthy male volunteers in two randomized, single-centre studies. Study 1 was a first-in-man, single-blinded, placebo-controlled, parallel-group, dose-escalation study. Fasted participants (n = 45) received single oral doses of finerenone 1-40 mg polyethylene glycol (PEG) solution or placebo. Study 2 was a relative bioavailability study comparing a finerenone 10 mg immediate-release (IR) tablet with finerenone 10 mg PEG solution in the fasted state, investigating the effect of a high-fat/high-calorie meal on the pharmacokinetics of the IR tablet and assessing a further dose escalation to finerenone 80 mg (eight * finerenone 10 mg IR tablets), in an open-label, fourfold crossover design (n = 15). Finerenone was rapidly absorbed from PEG solution (median time to maximum plasma concentration [tmax ]: 0.500-1.00 h), exhibited dose-linear pharmacokinetics and was rapidly eliminated from plasma (geometric mean terminal half-life [t1/2 ]: 1.70-2.83 h). Finerenone IR tablets demonstrated similar pharmacokinetics (median tmax : 0.750 2.50 h; geometric mean t1/2 : 1.89-4.29 h) with, however, enhanced bioavailability versus PEG solution (least-squares mean tablet/solution ratio of 187% for area under the plasma-concentration curve [AUC] and maximum plasma concentration [Cmax ]). High-fat/high-calorie food affected the rate but not the extent of finerenone absorption. Finerenone was well tolerated and did not influence clinical laboratory parameters, blood pressure, heart rate, urinary electrolytes or neurohormones, including serum aldosterone and angiotensin II. In conclusion, finerenone has favourable pharmacokinetics and tolerability in healthy men, and is suitable for dosing independent of food intake. PMID- 26604073 TI - Controlled Directional Motions of Molecular Vehicles, Rotors, and Motors: From Metallic to Silicon Surfaces, a Strategy to Operate at Higher Temperatures. AB - In the last decade, many nanomachines with controlled molecular motions have been studied, mainly on metallic surfaces, which are easy to obtain very clean, and are stable over months. However, the studies of mechanical properties of nanomachines are mainly performed at very low temperatures, usually between 5 and 80 K, which prevents any kind of applications. In this Minireview, we will present our strategy to operate at higher temperatures, in particular through the use of semiconducting silicon surfaces. We also review our best achievements in the field through some examples of rotating molecular machines that have been designed, synthesized, and studied in our groups. On metallic surfaces, the nanovehicles are molecules with two or four triptycenes as wheels and the molecular motor is built around a ruthenium organometallic center with a piano stool geometry and peripheric ferrocenyl groups. On semiconducting silicon surfaces, vehicles are also made from triptycene fragments and the rotor is a pentaphenylbenzene molecule. PMID- 26604074 TI - Secretome profiling of cytokines and growth factors reveals that neuro-glial differentiation is associated with the down-regulation of Chemokine Ligand 2 (MCP 1/CCL2) in amniotic fluid derived-mesenchymal progenitor cells. AB - Secreted cytokines and growth factors play a key role in the modulation of stem cell proliferation, differentiation and survival. To investigate the interplay between the changes in their expression levels, we used the newly characterized human amniotic fluid derived-mesenchymal progenitor MePR-2B cell line differentiated to a neuro-glial phenotype and exploited the very high sensitivity and versatility of magnetic beads-based immunoassays. We found that a sub-set of proteins, including the cytokines IL-6, TNFalpha, IL-15, IFNgamma, IL-8, IL-1ra, MCP-1/CCL2, RANTES and the growth factor PDGFbb, underwent a significant down regulation following neuro-glial differentiation, whereas the expression levels of IL-12 p70, IL-5, IL-7, bFGF, VEGF and G-CSF were increased. The role of MCP 1/CCL2, previously identified as a regulator of neural progenitor stem cell differentiation, has been further investigated at transcriptional level, revealing that both the chemokine and its receptor are co-expressed in MePR-2B cells and that are regulated upon differentiation, suggesting the presence of an autocrine and paracrine loop in differentiating cells. Moreover, we demonstrated that exogenous CCL2 is capable to affect neuro-glial differentiation in MePR-2B cells, thus providing novel evidences for the potential involvement of chemokine mediated signaling in progenitor/stem cells differentiation processes and fate specification. PMID- 26604075 TI - Involvement of N-methyl-d-aspartate receptors in the antidepressant-like effect of 5-hydroxytryptamine 3 antagonists in mouse forced swimming test and tail suspension test. AB - Recent evidence indicates that 5-hydroxytryptamine 3 (5-HT3) antagonists such as ondansetron and tropisetron exert positive behavioral effects in animal models of depression. Due to the ionotropic nature of 5-HT3 and N-methyl-d-aspartate (NMDA) receptors, plus their contribution to the pathophysiology of depression, we investigated the possible role of NMDA receptors in the antidepressant-like effect of 5-HT3 receptor antagonists in male mice. In order to evaluate the animals' behavior in response to different treatments, we performed open-field test (OFT), forced swimming test (FST), and tail-suspension test (TST), which are considered as valid tasks for measuring locomotor activity and depressive-like behaviors in mice. Our data revealed that intraperitoneal (i.p.) administration of tropisetron (5, 10, and 30mg/kg) and ondansetron (0.01, and 0.1MUg/kg) significantly decreased the immobility time in FST and TST. Also, co administration of subeffective doses of tropisetron (1mg/kg, i.p.) or ondansetron (0.001MUg/kg, i.p.) with subeffective doses of NMDA receptor antagonists, ketamine (1mg/kg, i.p.), MK-801 (0.05mg/kg, i.p.) and magnesium sulfate (10mg/kg, i.p.) resulted in a reduced immobility time both in FST and TST. The subeffective dose of NMDA (NMDA receptor agonist, 75mg/kg, i.p.) abolished the effects of 5 HT3 antagonists in FST and TST, further supporting the presumed interaction between 5-HT3 and NMDA receptors. These treatments did not affect the locomotor behavior of animals in OFT. Finally, the results of our study suggest that the positive effects of 5-HT3 antagonists on the coping behavior of mice in FST and TST are at least partly mediated through NMDA receptors participation. PMID- 26604076 TI - Administration of caffeine inhibited adenosine receptor agonist-induced decreases in motor performance, thermoregulation, and brain neurotransmitter release in exercising rats. AB - We examined the effects of an adenosine receptor agonist on caffeine-induced changes in thermoregulation, neurotransmitter release in the preoptic area and anterior hypothalamus, and endurance exercise performance in rats. One hour before the start of exercise, rats were intraperitoneally injected with either saline alone (SAL), 10 mg kg(-1) caffeine and saline (CAF), a non-selective adenosine receptor agonist (5'-N-ethylcarboxamidoadenosine [NECA]: 0.5 mg kg(-1)) and saline (NECA), or the combination of caffeine and NECA (CAF+NECA). Rats ran until fatigue on the treadmill with a 5% grade at a speed of 18 m min(-1) at 23 degrees C. Compared to the SAL group, the run time to fatigue (RTTF) was significantly increased by 52% following caffeine administration and significantly decreased by 65% following NECA injection (SAL: 91 +/- 14.1 min; CAF: 137 +/- 25.8 min; NECA: 31 +/- 13.7 min; CAF+NECA: 85 +/- 11.8 min; p<0.05). NECA decreased the core body temperature (Tcore), oxygen consumption, which is an index of heat production, tail skin temperature, which is an index of heat loss, and extracellular dopamine (DA) release at rest and during exercise. Furthermore, caffeine injection inhibited the NECA-induced decreases in the RTTF, Tcore, heat production, heat loss, and extracellular DA release. Neither caffeine nor NECA affected extracellular noradrenaline or serotonin release. These results support the findings of previous studies showing improved endurance performance and overrides in body limitations after caffeine administration, and imply that the ergogenic effects of caffeine may be associated with the adenosine receptor blockade-induced increases in brain DA release. PMID- 26604078 TI - Deforestation scenarios for the Bolivian lowlands. AB - Tropical forests in South America play a key role in the provision of ecosystem services such as carbon sinks, biodiversity conservation, and global climate regulation. In previous decades, Bolivian forests have mainly been deforested by the expansion of agricultural frontier development, driven by the growing demands for beef and other productions. In the mid-2000s the Movimiento al Socialismo (MAS) party rose to power in Bolivia with the promise of promoting an alternative development model that would respect the environment. The party passed the world's first laws granting rights to the environment, which they termed Mother Earth (Law No. 300 of 2012), and proposed an innovative framework that was expected to develop radical new conservation policies. The MAS conservationist discourse, policies, and productive practices, however, have since been in permanent tension. The government continues to guarantee food production through neo-extractivist methods by promoting the notion to expand agriculture from 3 to 13 million ha, risking the tropical forests and their ecosystem services. These actions raise major environmental and social concerns, as the potential impacts of such interventions are still unknown. The objective of this study is to explore an innovative land use modeling approach to simulate how the growing demand for land could affect future deforestation trends in Bolivia. We use the LuccME framework to create a spatially-explicit land cover change model and run it under three different deforestation scenarios, spanning from the present-2050. In the Sustainability scenario, deforestation reaches 17,703,786 ha, notably in previously deforested or degraded areas, while leaving forest extensions intact. In the Middle of the road scenario, deforestation and degradation move toward new or paved roads spreading across 25,698,327 ha in 2050, while intact forests are located in Protected Areas (PAs). In the Fragmentation scenario, deforestation expands to almost all Bolivian lowlands reaching 37,944,434 ha and leaves small forest patches in a few PAs. These deforestation scenarios are not meant to predict the future but to show how current and future decisions carried out by the neo-extractivist practices of MAS government could affect deforestation and carbon emission trends. In this perspective, recognizing land use systems as open and dynamic systems is a central challenge in designing efficient land use policies and managing a transition towards sustainable land use. PMID- 26604077 TI - Lack of endogenous cholecystokinin promotes cholelithogenesis in mice. AB - BACKGROUND: Celiac disease is an autoimmune enteropathy caused by a permanent intolerance to dietary gluten in genetically predisposed individuals. Cholecystokinin (CCK) release from the proximal small intestine and gallbladder emptying in response to a fatty meal are greatly reduced in celiac patients before they start the gluten-free diet, showing a genetic predisposition to gallstones. METHODS: To elucidate the complex pathophysiological mechanisms determining the biliary characteristic of celiac disease, we investigated the effect of the absence of endogenous CCK on cholesterol crystallization and gallstone formation in mice fed a lithogenic diet for 28 days. KEY RESULTS: Fasting gallbladder volumes were increased and the response of gallbladder emptying to the high-fat diet was impaired in CCK knockout (KO) mice compared to wild-type mice. Because of the absence of CCK, small intestinal transit time was prolonged and intestinal cholesterol absorption was increased. During 28 days of feeding, elevated biliary cholesterol concentrations and gallbladder stasis promoted the growth and agglomeration of solid cholesterol crystals into microlithiasis and stones. Thus, cholesterol crystallization and gallstone formation were accelerated in CCK KO mice. In contrast, daily intraperitoneal administration of CCK-8 reduced gallstone formation in CCK KO mice even on the lithogenic diet. CONCLUSIONS & INFERENCES: The lack of endogenous CCK enhances susceptibility to gallstones by impairing gallbladder contractile function and small intestinal motility function. These findings show that celiac disease is an important risk factor for gallstone formation and the gallbladder motility function should be routinely examined by ultrasonography and gallbladder stasis should be prevented in celiac patients. PMID- 26604079 TI - Liver Transplant Patients With Operational Tolerance: What Can the Graft Itself Tell Us? PMID- 26604080 TI - Impact of Film Stoichiometry on the Ionization Energy and Electronic Structure of CH3 NH3 PbI3 Perovskites. AB - The electronic structure of a large sample set of CH3 NH3 PbI3 -based perovskites is studied. Combined investigations by UV/X-ray photoelectron spectroscopy and X ray diffraction reveal that interstitials present in the film lead to changes in the occupied density of states close to the valence band, which in turn influences the performance of solar cells. Changes in elemental composition tune the ionization energy of the perovskite film by almost 1 eV without introducing significant amounts of gap states. PMID- 26604082 TI - EZH2 is associated with poor prognosis in head-and-neck squamous cell carcinoma via regulating the epithelial-to-mesenchymal transition and chemosensitivity. AB - OBJECTIVES: Increasing evidence suggests that epigenetic regulation is responsible for tumor initiation and progression in head and neck squamous cell carcinoma (HNSCC). Although the polycomb group protein enhancer zeste homolog 2 (EZH2) is upregulated and a key epigenetic modifier implicated in various cancers, its molecular mechanism in HNSCC remains unknown. Herein, we investigated the role of EZH2 in HNSCC progression and its clinical implication as an HNSCC risk predictor. MATERIALS AND METHOD: A retrospective analysis was performed on 90 HNSCC patients who had curative surgery between 1999 and 2011. Patients with high and low EZH2 expression were compared by the various clinicopathological factors. Survival rates were estimated by the Kaplan-Meier method and log-rank test was used to determine significance. For functional in vitro analysis, migration/invasion assay and Western blotting were performed after EZH2 knockdown using siRNA. In addition, cell proliferation was measured to clarify the role of EZH2 on cisplatin chemotherapy. RESULTS: In patients with HNSCC, high EZH2 expression was correlated with advanced T stage and poor survival outcome. RNAi analysis revealed that EZH2 silencing increased E-cadherin expression while decreasing that of N-cadherin and Vimentin without altering Snail/Slug signaling, which led to decreased cell migration/invasion. EZH2 is also associated with tumor aggressiveness via regulating the epithelial-to mesenchymal transition. Furthermore, we show that high EZH2 expression decreases sensitivity to cisplatin-based chemotherapy. CONCLUSION: Our results indicate that EZH2 may not be only a predictive and prognostic biomarker but also a potential personalized therapeutic target for the treatment of HNSCC. PMID- 26604081 TI - [Rationale for a diagnostic approach in non-Graves' orbital inflammation--Report of 61 patients]. AB - INTRODUCTION: Orbital inflammatory syndromes include a wide variety of inflammatory intraorbital processes which are very different in terms of clinical presentation and prognosis. We currently prefer to differentiate so-called "specific" inflammations, for which an etiology is able to be identified, from idiopathic orbital inflammatory syndromes (IOIS), for which the etiology remains unknown and the histology is nonspecific. PURPOSE: To propose an efficient diagnostic approach for clinicians managing patients with non-Graves' orbital inflammations. MATERIALS AND METHODS: This is a retrospective and prospective study concerning 61 patients managed by the medical team for non-Graves' orbital inflammations between May, 1999 and May, 2013 in the ophthalmology departments of Nice and Limoges university hospitals in France. Seventeen specific inflammations, 19 orbital lymphomas and 25 idiopathic orbital inflammatory syndromes were included. Patients were divided into two groups. Thirty-six patients (group 1) underwent primary biopsy, while for the other 25 (group 2), therapy was begun empirically without biopsy. We could therefore compare both approaches in terms of diagnostic efficiency and time until identification of a specific etiology. RESULTS: Our statistical results show that an approach without primary biopsy leads to a number of specific diagnoses statistically much lower than that obtained by the approach with primary biopsy. Also, the risk of missing a specific inflammation (with as a consequence an inappropriate treatment and a risk of functional sequelae as well as a fatal risk of missing a lymphoproliferative pathology) is very clearly higher in the case of not performing primary biopsy. Finally, the average time elapsed between the initial consultation with the ophthalmologist and a specific diagnosis was one month in the case of the first approach, while this delay was almost three times higher with the second approach, with a mean of 2.91 months (P<0.01). DISCUSSION: Our study shows that biopsy should be the mainstay of diagnostic management. A trial of empiric treatment is only performed first in myositis or in locations where biopsy could jeopardize functional prognosis. It should only be done after biopsy in all other cases. Of course, in all cases of relapse or recurrence after treatment, biopsy should be performed or repeated. CONCLUSION: The diagnostic work-up of a patient with an orbital inflammatory process must of course include blood testing and orbital imaging, but also a systematic primary biopsy for histological examination in the vast majority of cases. It must be repeated at least in the case of any doubt about the diagnosis or in the case of any recurrence or resistance to treatment. PMID- 26604083 TI - Transplacental Transmission of Ovine Herpesvirus 2 in Cattle with Sheep associated Malignant Catarrhal Fever. AB - Sheep-associated malignant catarrhal fever (SA-MCF) is an important infectious disease of ruminants worldwide that is caused by ovine herpesvirus 2 (OvHV-2). OvHV-2 is transmitted predominantly by contact between infected and susceptible hosts, while the documentation of vertical transmission is rare. This report presents the pathological and molecular findings associated with transplacental transmission of OvHV-2 in cattle. Two Girolanda cows with corneal oedema, lethargy, mucopurulent nasal discharge and ulcerative stomatitis died spontaneously; one of these was pregnant with a 4-month-old fetus. Significant pathological findings included widespread lymphoplasmacytic necrotizing vasculitis and lymphoplasmacytic accumulations in several organs of both cows and the fetus. A polymerase chain reaction that targeted the tegument protein gene of OvHV-2 amplified viral DNA from the brain of the pregnant cow and her fetus, as well as from the kidney of the pregnant cow. The pathological findings observed in the cow and her fetus, together with the presence of OvHV-2 DNA in tissues of these animals, are suggestive of transplacental transmission of OvHV-2 in SA-MCF in cattle. PMID- 26604084 TI - Climate science: frequently asked questions. PMID- 26604085 TI - A child with white urine: Questions. PMID- 26604086 TI - A child with white urine: Answers. PMID- 26604087 TI - Liver transplantation for aHUS: still needed in the eculizumab era? AB - BACKGROUND: The risk of disease recurrence after a kidney transplant is high in patients with atypical hemolytic uremic syndrome (aHUS) and mutations in the complement factor H (FH) gene (CFH). Since FH is mostly produced by the liver, a kidney transplant does not correct the genetic defect. The anti-C5 antibody eculizumab prevents post-transplant aHUS recurrence, but it does not cure the disease. Combined liver-kidney transplantation has been performed in few patients with CFH mutations based on the rationale that liver replacement provides a source of normal FH. METHODS: We report the 9-year follow-up of a child with aHUS and a CFH mutation, including clinical data, extensive genetic characterization, and complement profile in the circulation and at endothelial level. The outcome of kidney and liver transplants performed separately 3 years apart are reported. RESULTS: The patient showed incomplete response to plasma, with relapsing episodes, progression to end-stage renal disease, and endothelial-restricted complement dysregulation. Eculizumab prophylaxis post-kidney transplant did not achieve sustained remission, leaving the child at risk of disease recurrence. A liver graft given 3 years after the kidney transplant completely abrogated endothelial complement activation and allowed eculizumab withdrawal. CONCLUSIONS: Liver transplant may definitely cure aHUS and represents an option for patients with suboptimal response to eculizumab. PMID- 26604088 TI - Lentivirus expressing soluble ST2 alleviates bleomycin-induced pulmonary fibrosis in mice. AB - It has been shown that the expression of ST2, a receptor of interleukin (IL)-33, is elevated in the lungs of idiopathic pulmonary fibrosis patients and bleomycin induced mouse models, however its contribution to the development of pulmonary fibrosis has yet to be tested. In the present study, we treated mice by intranasal instillation of lentivirus expressing soluble ST2 and evaluated lung inflammation and fibrosis in the bleomycin-induced pulmonary fibrosis mouse model. We found that ST2 lentivirus treatment significantly improved survival rate and reduced weight loss compared with controls treated with empty lentivirus. Furthermore, ST2 treatment profoundly attenuated the pulmonary inflammatory cell infiltration and fibrotic changes. Finally, ST2 treatment markedly lowered the levels of IL-4, IL-6, IL-13, IL-33, monocyte chemoattractant protein-1, and transforming growth factor-beta1, whereas it increased the levels of interferon-gamma in bronchoalveolar lavage fluid. The results indicate that ST2 might prevent bleomycin-induced pulmonary fibrosis possibly through downregulating proinflammatory and profibrotic mediators. This study suggests that lentivirus expressing soluble ST2 might represent an effective therapeutic approach in the treatment of pulmonary fibrotic diseases. PMID- 26604089 TI - Protective effect of butyrate against ethanol-induced gastric ulcers in mice by promoting the anti-inflammatory, anti-oxidant and mucosal defense mechanisms. AB - Gastric ulcers (GUs) are a common type of peptic ulcer. Alcohol overdose is one of the main causes of GU, which is difficult to prevent. Although the protective effect of butyrate on inflammation-related diseases is well understood, its effect on GUs has not been reported. We investigated the protective effects of butyrate against ethanol-induced lesions to the gastric mucosa in mice and the underlying mechanisms. BALB/c mice were orally pretreated with butyrate for 30min prior to the establishment of the GU model by challenge with absolute ethanol. Ethanol administration produced apparent mucosal injuries with morphological and histological damage, whereas butyrate pretreatment reduced the gastric mucosal injuries in a dose-dependent manner. Butyrate pretreatment also significantly ameliorated contents of malondialdehyde (MDA) and carbonyl proteins, and decreased levels of IL-1beta, TNF-alpha and IL-6. The Western blot results consistently demonstrated that butyrate pretreatment attenuated the phosphorylation of NF-kappaB p65, p38 MAPK and ERKs in the gastric tissues. Additionally, gastric wall mucus (GWM), a parameter reflecting mucosal defense, was clearly increased by butyrate pretreatment. Butyrate pretreatment protects the gastric mucosa against ethanol-induced lesions by strengthening the mucosal defense and anti-oxidant and anti-inflammatory activities. As a necessary substance for the body, butyrate may be applied to the prevention and treatment of GUs. PMID- 26604090 TI - Synthesized peptides 705-734 from hepatitis C virus E2 glycoprotein induce dendritic cell maturation by activating p38 MAPK signaling. AB - Hepatitis C virus (HCV) envelope E2 is a glycoprotein that are implicated in HCV infection by facilitating its entry and immune evasion, which in turn leads to hepatitis, hepatocellular carcinoma and other chronic liver diseases. It is reported that the HCV E2 stem region comprise a functional region for HCV entry; however, the roles and underlying mechanism of these conserved residues on the E2 protein in the immune response after HCV infection are still not well defined. In this study, we synthesized 30 aa peptides containing residues 705-734 (E2-705) of HCV E2 using the solid-phase peptide synthesis (SPPS) method. The characteristics of the synthesized peptides were identified by Western blot and cell culture derived HCV particles (HCVcc) infection blocking assay. ELISA and flow cytometry assays were employed to determine the effect of the synthesized peptide on dendritic cells (DCs) response and CD4(+) T cell activation. Results showed that the synthesized E2-705 peptides binds to DCs by interaction with DC-SIGN receptor. E2-705 peptides induced the maturation of infected DCs to a similar extent with recombinant HCV E2 as reflected by the antigen uptake potential and allostimulatory capacity. Furthermore, the E2-705 peptides increased the production of IL-12, CD80 and CD86 but reduced the IL-10 in DCs, in which p38 MAPK signaling might be involved. These results suggest that the carboxyl terminus beyond the core ectodomain of HCV E2 protein may play a key role in immunoreaction of HCV infection, giving a new understanding of HCV E2 and a novel target for the design of HCV vaccines or inhibitors. PMID- 26604091 TI - [Plasma exchange in treatment refractory septic shock : Presentation of a therapeutic add-on strategy]. AB - Sepsis is defined as a systemic inflammatory response of the body to an infection. Besides anti-infective drugs and removal of the site of infection, no specific therapeutics that target the overwhelming host response are available. Clinical researchers are currently evaluating the extracorporeal elimination of circulating cytokines. Modern adsorbing techniques have increasingly been used for this purpose allowing an unselective but highly effective removal of the vast majority of circulating cytokines but also fail to replace used protective factors in patients' plasma. Therapeutic plasma exchange (TPE) however might represent a novel method to remove pathologically elevated cytokines and simultaneously to replace protective plasmatic factors. Here we report the case of a septic shock patient treated with TPE and review the available literature with respect to TPE as an adjunctive therapy in sepsis. PMID- 26604092 TI - [Medicolegal aspects in emergency medical care : Analysis of the frequency of advance health care directives and the influence on decision making in emergency medicine]. AB - BACKGROUND: Medical decisions in an emergency medical services (EMS) situation are always extremely time- critical and sensitive, potentially leading to medicolegal consequences. Advance health care directives (AHCDs) are crucial components in the patients' participative decision making. When a patient refuses resuscitation, and/or other life-extending treatments, emergency physicians face possible ethical, medical, and medicolegal conflicts. METHODS: As part of the RIMANO II Study [Risk Management Praklinische (prehospital) Notfallmedizin (emergency medicine)], all 18 "emergency physician bases" of the Berlin Fire Department were polled regarding the influence of AHCDs in regard to emergency medical decision making. The assessment was based on anonymous questionnaires. Furthermore, emergency medical suggestions for improvement of AHCDs were gathered. Descriptive statistics and qualitative methods were used for evaluation. RESULTS: A total of 112 responses from emergency physicians could be incorporated into the study. Anesthesiologists represented the largest group (n = 55, 49 %), followed by internists (n = 40, 36 %). The median length of experience in EMS was 7 years [interquartile range (IQR) 4-14 years]. Patients' "do not resuscitate" orders were obeyed in 78/112 cases (70 %, 95 % CI 69-78 %). In 49/112 cases (44 %, 95 % CI 34-53 %), the request to not be hospitalized was granted. The length of EMS experience, type of medical specialty, the number of EMS cases and ways in which AHCDs were handled were all contributing factors to the various emergency medical interventions. CONCLUSION: AHCDs appear to have an influence in the emergency medical decision process. However, it is presently unclear as to what a standardized and universally comprehensible AHCD should look like, in order to provide a framework that is both acceptable and necessary in a prehospital emergency medicine environment, ensuring medicolegal certainty for the parties involved. PMID- 26604093 TI - Prognostic role of pretreatment plasma fibrinogen in patients with solid tumors: A systematic review and meta-analysis. AB - BACKGROUND: Plasma fibrinogen may be involved in several stages of cancer progression. Clinical studies have demonstrated that pretreatment plasma fibrinogen is associated with poor survival in various cancers. The aim of this meta-analysis was to examine the prognostic effect of circulating fibrinogen in solid tumors. MATERIALS AND METHODS: We searched Medline, EMBASE, Cochrane Database of Systematic Reviews, and meeting proceedings to identify studies assessing the effect of pretreatment plasma fibrinogen on survival of cancer patients. Pooled multivariable-adjusted hazard ratios (HRs) for overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) were estimated using random-effects models. RESULTS: Data from 52 observational studies and 15,371 patients were summarized. An elevated baseline plasma fibrinogen was significantly associated with worse OS (pooled HR = 1.69; 95% CI = 1.48-1.92). The highest negative effect of elevated plasma fibrinogen on OS was demonstrated in renal cell carcinoma (pooled HR = 2.22), followed by head and neck cancer (pooled HR = 2.02), and colorectal cancer (pooled HR = 1.89). The adverse prognostic impact of high plasma fibrinogen remained in both non metastatic and metastatic disease and patients of different ethnicity. Patients with high baseline fibrinogen had a significantly shorter DFS (pooled HR = 1.52) and CSS (pooled HR = 2.50). CONCLUSIONS: An elevated pretreatment plasma fibrinogen significantly correlates with decreased survival in patients with solid tumors. Future clinical trials are warranted to determine whether plasma fibrinogen could be incorporated in cancer staging systems and whether fibrinogen lowering therapies have a favorable effect on disease recurrence and mortality. PMID- 26604094 TI - The cortisol awakening response at its best. PMID- 26604095 TI - Generalisation, decision making, and embodiment effects in mental rotation: A neurorobotic architecture tested with a humanoid robot. AB - Mental rotation, a classic experimental paradigm of cognitive psychology, tests the capacity of humans to mentally rotate a seen object to decide if it matches a target object. In recent years, mental rotation has been investigated with brain imaging techniques to identify the brain areas involved. Mental rotation has also been investigated through the development of neural-network models, used to identify the specific mechanisms that underlie its process, and with neurorobotics models to investigate its embodied nature. Current models, however, have limited capacities to relate to neuro-scientific evidence, to generalise mental rotation to new objects, to suitably represent decision making mechanisms, and to allow the study of the effects of overt gestures on mental rotation. The work presented in this study overcomes these limitations by proposing a novel neurorobotic model that has a macro-architecture constrained by knowledge held on brain, encompasses a rather general mental rotation mechanism, and incorporates a biologically plausible decision making mechanism. The model was tested using the humanoid robot iCub in tasks requiring the robot to mentally rotate 2D geometrical images appearing on a computer screen. The results show that the robot gained an enhanced capacity to generalise mental rotation to new objects and to express the possible effects of overt movements of the wrist on mental rotation. The model also represents a further step in the identification of the embodied neural mechanisms that may underlie mental rotation in humans and might also give hints to enhance robots' planning capabilities. PMID- 26604096 TI - Bioluminescence Imaging to Monitor the Effects of the Hsp90 Inhibitor NVP-AUY922 on NF-kappaB Pathway in Endometrial Cancer. AB - PURPOSE: In this study, we first aimed to evaluate the effects in vitro and in vivo, of the Hsp90 inhibitor NVP-AUY922, in endometrial cancer (EC). We also aimed to track nuclear factor kappa B (NF-kappaB) signalling, a key pathway involved in endometrial carcinogenesis and to check whether NVP-AUY922 treatment modulates it both in vitro and in vivo. PROCEDURES: I n vitro effects of NVP AUY922 on EC cell growth and the signalling pathways were assessed by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clonogenic assays, Western Blot and luciferase assay. NVP-AUY922 effect on Ishikawa (IK) xenograft growth was evaluated in vivo, and NF-kappaB activity was monitored using bioluminescence imaging. RESULTS: NVP-AUY922 inhibited the growth of three endometrial cell lines tested in vitro. In vivo, NVP-AUY922 reduced tumour growth of 47 % (p = 0.042) compared to control condition. Moreover, the bioluminescence signal of the tumours harbouring IK NF-kappaB-LUC cells was significantly reduced in NVP-AUY922-treated animals compared to untreated ones. CONCLUSIONS: NVP-AUY922 reduced EC tumour growth and NF-kappaB signalling both in vitro and in vivo. As therapeutic resistance of EC remains a challenge for oncologists nowadays, we think that NVP-AUY922 represents a valid alternative to conventional chemotherapy, and we believe that this approach for assessing and tracking the activation of NF-kappaB pathway may be of therapeutic benefit. PMID- 26604097 TI - Placebo Use in Pain Management: A Mechanism-Based Educational Intervention Enhances Placebo Treatment Acceptability. AB - Health care providers use treatments whose effectiveness derives partially or completely from 'nonspecific' factors, frequently referred to as placebo effects. Although the ethics of interventional placebo use continues to be debated, evidence suggests that placebos can produce clinically meaningful analgesic effects. Burgeoning evidence suggest that patients with chronic pain might be open to placebo treatments in certain contexts despite limited knowledge of their well-established psychoneurobiological underpinnings. In this investigation we sought to examine the effects of a brief, mechanism-based placebo analgesia educational intervention on aspects placebo knowledge and acceptability. Participants with chronic musculoskeletal pain completed a web-based survey in which they rated their knowledge of placebo analgesia, assessed placebo acceptability across different medical contexts, and evaluated 6 unique patient provider treatment scenarios to assess the role of treatment effectiveness and deception on patient-provider attributions. Using a pre-post design, participants were randomized to receive either a placebo educational intervention or an active control education. Results showed that the educational intervention greatly improved perceptions of placebo knowledge, effectiveness, and acceptability, even in deceptive treatment contexts. This was the first study of its kind to show the value of an educational intervention in increasing openness to and knowledge of placebo analgesic interventions among patients with chronic musculoskeletal pain. PERSPECTIVE: In this we article highlight how patients with chronic pain might be open to placebo interventions, particularly adjunct and/or complementary treatments, when provided education on the neurobiological and psychological mechanisms that underlie placebo effects. Study findings highlight ethically acceptable ways to potentially use placebo factors to enhance existing pain treatments and improve patient health outcomes. PMID- 26604098 TI - Repetitive Acupuncture Point Treatment with Diluted Bee Venom Relieves Mechanical Allodynia and Restores Intraepidermal Nerve Fiber Loss in Oxaliplatin-Induced Neuropathic Mice. AB - The chemotherapeutic agent, oxaliplatin, produces a robust painful neuropathy that results in the loss of intraepidermal nerve fibers (IENFs). We have previously reported that an acupuncture point (acupoint) injection of diluted bee venom (DBV) produces a temporary antiallodynic effect in oxaliplatin-induced neuropathic mice. Herein we show a significant long-lasting antinociceptive effect of repetitive DBV acupoint treatment on oxaliplatin-induced mechanical allodynia and a significant reduction in the loss of IENFs. DBV (0.1 mg/kg, subcutaneous) was administered once a day for 18 days beginning on day 15 after oxaliplatin injection. Immunohistochemistry for IENF was performed on the glabrous skin of the hind paw footpad using the pan-neuronal marker, protein gene product 9.5. A temporary increase in mechanical threshold was observed 60 minutes after a single DBV injection into the Zusanli acupoint, and this effect was enhanced over time with repetitive DBV treatments. The basal mechanical threshold before daily DBV injection also increased from day 7 after DBV injections, and peaked at day 14 after DBV treatment. Moreover, the oxaliplatin-induced loss of IENFs was significantly reduced in mice treated repetitively with DBV. Repetitive pretreatment with the alpha-2 adrenoceptor antagonist, yohimbine, (5 mg/kg, subcutaneous) completely prevented the antiallodynic effects and the increase in IENFs observed in mice treated repetitively with DBV. PERSPECTIVE: We showed that repetitive acupoint stimulation with DBV gradually and significantly reduced oxaliplatin-induced mechanical allodynia and restored the loss of IENFs in neuropathic mice via an alpha-2 adrenoceptor mechanism. Collectively, results of this study suggest that repetitive acupoint treatment with DBV can be a potential strategy for the management of chemotherapy-induced neuropathy. PMID- 26604100 TI - In Search of the Ideal Resistance Training Program to Improve Glycemic Control and its Indication for Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Resistance training (RT) is effective for glycemic control in type 2 diabetes mellitus (T2DM) patients. However, the characteristics of an RT program that will maximize its effect and those of patients that will especially benefit from RT are unknown. OBJECTIVE: The objectives of this systematic review were to identify via a comprehensive meta-analysis the characteristics of an RT program for patients with T2DM that might increase the patients' improvement in glycemic control and the characteristics of patients that will benefit from RT. DATA SOURCES: Electronic-based literature searches of MEDLINE and EMBASE entries from 1 January 1966 to 25 August 2014 were conducted to identify clinical trials examining the effect of RT on glycemic control among patients with T2DM. Study keywords were text words and thesaurus terms related to RT and T2DM. STUDY SELECTION: Studies were included if they (1) were clinical trials consisting of two groups with and without RT exercise intervention; (2) had an intervention period of at least 5 weeks; (3) clarified that all patients had T2DM; and (4) reported or made it possible to estimate the effect size [i.e., change in glycosylated hemoglobin (HbA1c) in the RT group minus that in the control group] and its corresponding standard error. STUDY APPRAISAL AND SYNTHESIS METHODS: The effect size in each study was pooled with a random-effects model. Analyses were stratified by several key characteristics of the patients and RT exercise programs; meta-regression analysis was then used to detect a difference in the effect size among strata within each factor. Linear regression analyses were added by entering each of the following profiles: patients' baseline characteristics [mean baseline age, body mass index (BMI), and HbA1c levels] and exercise characteristics (total sets per week, total sets per bout of exercise, frequency, and intensity). RESULTS: There were 23 eligible studies comprising 954 patients with T2DM. The pooled effect size (95% confidence interval) was -0.34% ( 0.53 to -0.16). A program with multiple sets (>=21 vs. <21) per one RT bout was associated with a large effect size (P = 0.03); however, the linear correlation between the number of sets and effect size was not significant (P = 0.56). A larger effect size was observed in studies with participants with diabetes of a relatively short duration (<6 vs. >=6 years; P = 0.04) or a high baseline HbA1c [>=7.5% (58 mmol/mol) vs. <7.5 %; P = 0.01] while a smaller effect size was observed in studies with a particularly high mean baseline BMI value (>=32 vs. <32 kg/m(2); P = 0.03). Linear regression analyses predicted that each increment of 1% in the baseline HbA1c would enlarge the effect size by 0.036%, while each increment of 1 kg/m2 in the baseline BMI decreased it by 0.070% in the range between 22.3 and 38.8 kg/m2. CONCLUSION: In terms of glycemic control, RT could be recommended in the early stage of T2DM, especially for patients with relatively poor glycemic control. More benefit would be elicited in less obese patients within a limited range of the BMI. A substantial amount of exercise might be required to stimulate post-exercise glucose uptake, although the dose dependency was not specifically clarified. PMID- 26604099 TI - Use of Objective Neurocognitive Measures to Assess the Psychological States that Influence Return to Sport Following Injury. AB - There is growing interest in the effects of psychological states on human performance, especially with those who have suffered debilitating injury and are attempting to return to sport (RTS). Current research methods measure psychological states through validated questionnaires; however, these outcomes only allow for subjective assessment and may be unintentionally biased. Application of objective neurocognitive measures correlated with psychological states will advance understanding of injury outcomes by identifying human behavior and avoiding vague assumptions from subjective measures. PMID- 26604101 TI - Coordination in Climbing: Effect of Skill, Practice and Constraints Manipulation. AB - BACKGROUND: Climbing is a physical activity and sport involving many subdisciplines. Minimization of prolonged pauses, use of a relatively simple path through a route and smooth transitions between movements broadly define skilled coordination in climbing. OBJECTIVES: To provide an overview of the constraints on skilled coordination in climbing and to explore future directions in this emerging field. METHODS: A systematic literature review was conducted in 2014 and retrieved studies reporting perceptual and movement data during climbing tasks. To be eligible for the qualitative synthesis, studies were required to report perceptual or movement data during climbing tasks graded for difficulty. RESULTS: Qualitative synthesis of 42 studies was carried out, showing that skilled coordination in climbing is underpinned by superior perception of climbing opportunities; optimization of spatial-temporal features pertaining to body-to wall coordination, the climb trajectory and hand-to-hold surface contact; and minimization of exploratory behaviour. Improvements in skilled coordination due to practice are related to task novelty and the difficulty of the climbing route relative to the individual's ability level. CONCLUSION: Perceptual and motor adaptations that improve skilled coordination are highly significant for improving the climbing ability level. Elite climbers exhibit advantages in detection and use of climbing opportunities when visually inspecting a route from the ground and when physically moving though a route. However, the need to provide clear guidelines on how to improve climbing skill arises from uncertainties regarding the impacts of different practice interventions on learning and transfer. PMID- 26604103 TI - Bacillus lindianensis sp. nov., a novel alkaliphilic and moderately halotolerant bacterium isolated from saline and alkaline soils. AB - Two alkaliphilic and halotolerant Gram-stain positive, rod-shaped and endospore forming bacteria, designated strains 12-3(T) and 12-4, were isolated from saline and alkaline soils collected in Lindian county, Heilongjiang province, China. Both strains were observed to grow well at a wide range of temperature and pH values, 10-45 degrees C and pH 8-12, with optimal growth at 37 degrees C and pH 9.0, respectively. Growth of the two strains was found to occur at total salt concentrations of 0-12 % (w/v), with an optimum at 4 % (w/v). The G+C contents of the genomic DNA of strains 12-3(T) and 12-4 were determined to be 42.7 and 42.4 mol%, respectively, and the major cellular fatty acids were identified as anteiso C15:0 and anteiso-C17:0. In isolate 12-3(T), meso-diaminopimelic acid was found to be the diagnostic diamino acid of the cell wall peptidoglycan; diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol were identified as the major cellular polar lipids; and menaquinone-7 was identified as the predominant isoprenoid quinone. Strains 12-3(T) and 12-4 share very close 16S rRNA gene sequence similarity (99.74 %) and their DNA-DNA relatedness was 95.3 +/- 0.63 %, meaning that the two strains can be considered to belong to the same species. 16S rRNA gene sequence-based phylogenetic analysis revealed strains 12-3(T) and 12-4 exhibit high similarities to Bacillus pseudofirmus DSM 8715(T) (98.7 %), Bacillus marmarensis DSM 21297(T) (97.2 %) and Bacillus nanhaiisediminis CGMCC 1.10116(T) (97.1 and 97.0 %, respectively). DNA-DNA hybridization values between isolate 12-3(T) and the type strains of closely related Bacillus species were below 30 %. On the basis of the polyphasic evidence presented, strains 12-3(T) and 12-4 are considered to represent a novel species of the genus Bacillus, for which the name Bacillus lindianensis sp. nov. is proposed. The type strain is 12-3(T) (DSM 26864(T) = CGMCC 1.12717(T)). PMID- 26604102 TI - The Biomechanics of the Modern Golf Swing: Implications for Lower Back Injuries. AB - The modern golf swing is a complex and asymmetrical movement that places an emphasis on restricting pelvic turn while increasing thorax rotation during the backswing to generate higher clubhead speeds at impact. Increasing thorax rotation relative to pelvic rotation preloads the trunk muscles by accentuating their length and allowing them to use the energy stored in their elastic elements to produce more power. As the thorax and pelvis turn back towards the ball during the downswing, more skilled golfers are known to laterally slide their pelvis toward the target, which further contributes to final clubhead speed. However, despite the apparent performance benefits associated with these sequences, it has been argued that the lumbar spine is incapable of safely accommodating the forces they produce. This notion supports a link between the repeated performance of the golf swing and the development of golf-related low back injuries. Of the complaints reported by golfers, low back injuries continue to be the most prevalent, but the mechanism of these injuries is still poorly understood. This review highlights that there is a paucity of research directly evaluating the apparent link between the modern golf swing and golf-related low back pain. Furthermore, there has been a general lack of consensus within the literature with respect to the methods used to objectively assess the golf swing and the methods used to derived common outcome measures. Future research would benefit from a clear set of guidelines to help reduce the variability between studies. PMID- 26604105 TI - New ethanol extraction improves the anti-obesity effects of black tea. AB - Black tea has been reported to have anti-obesity effects in both rodents and humans. Gallic acid, an active component of black tea, decomposes quickly into pyrogallol in high-temperature solutions. This study introduced a new, aqueous ethanol extraction of black tea, which resulted in extracts with higher concentrations of gallic acid than conventional black tea extracts prepared by hot-water extraction or hot-ethanol extraction. We confirmed that, compared with the hot-water extract of black tea, the cold-ethanol extract of black tea (CE BTE) had greater effects on reducing body weight and body fat, improving fatty liver, regulating blood glucose, and reducing blood cholesterol in the high-fat diet-induced obese mouse model. Nonetheless, although CE-BTE significantly reduced fat content, it did not reduce peroxisome proliferator-activated receptor (PPARgamma) protein in epididymal fat tissue of HFD mice. We also showed that CE BTE did not inhibit the function of PPARgamma protein to drive adipogenesis of mouse 3T3-L1 preadipocytes. Considering that PPARgamma is a master transcription factor not only for adipocyte differentiation, but also for adipose tissue function, such as glucose and lipid metabolism and insulin sensitivity, these results suggest that CE-BTE reduced fat mass and body weight without dampening fat cell homeostasis and insulin sensitivity. PMID- 26604106 TI - Characteristics and temporal pattern of the readmissions of patients with multiple hospital admissions in the medical departments of a general hospital. AB - INTRODUCTION: Patients with multiple hospital admissions represent a small percentage of total hospitalizations but result in a considerable proportion of the healthcare expenditure. There are no studies that have analyzed their long term clinical evolution. OBJECTIVES: To study the characteristics, temporal patterns of readmissions and clinical evolution of patients with multiple hospital admission in the long term. METHODS: A retrospective study was conducted of all hospital admissions in the medical area of the Hospital of Lugo (Spain) between January 1, 2000 and December 31, 2012, based on data from the center's minimum basic data set. RESULTS: A total of 139,249 hospital admissions for 62,515 patients were studied. Six hospital admissions were recorded for 6.4% of the patients. The overall mortality rate was 16% (9982 patients). The readmissions rate steadily increased with each new admission, from 48% after the first event to 74.6% after the fifth. The rate of hospital readmission before 30days increased from 18.3% in the second admission to 36.3% in the sixth. The number of chronic diseases increased from 3.1 (SD, 2) in the first hospital admission up to 4.9 (2.8) in the sixth. The Department of Internal Medicine treated a third of all hospital admissions. In the sixth hospitalization, conditions associated with admission in Internal Medicine were CIRS score, age, heart failure, COPD, dementia, diabetes, atrial fibrillation and anemia. CONCLUSIONS: Patients with multiple hospital admissions are complex patients whose temporal pattern of readmissions changes with time, such that each hospital admission constitutes a factor facilitating the next. PMID- 26604104 TI - The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1. AB - PURPOSE: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients. METHODS: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-alpha, IFN gamma or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients. RESULTS: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61%). Out of 39 familial cases from 11 families, 26 patients (67%) from 9 families and out of 18 sporadic cases, 9 patients (50%) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients. CONCLUSION: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing. PMID- 26604107 TI - Risk and mortality of gastrointestinal hemorrhage in patients with thrombocytopenia: Two nationwide retrospective cohort studies. AB - INTRODUCTION: The association between thrombocytopenia (TP) and gastrointestinal hemorrhage was not completely understood. The purpose of this study is to evaluate the risk of gastrointestinal hemorrhage and post-hemorrhage mortality in patients with TP. METHODS: Using the Taiwan National Health Insurance Research Database, we identified 1033 adults aged >=18 years diagnosed with TP in 2000 2003. Non-TP cohort consisted of 10,330 adults randomly selected and matched by age and sex from the same dataset. Incident events of gastrointestinal hemorrhage occurring after TP from January 1, 2000, through December 31, 2008, were ascertained from medical claims. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of gastrointestinal hemorrhage associated with TP were calculated. Another nested cohort study consisted of 27,369 patients with hospitalization due to gastrointestinal hemorrhage between January 1, 2004, and December 31, 2010. We calculated the adjusted odds ratios (ORs) and 95% CIs of 30 day mortality after gastrointestinal hemorrhage in patients with and without TP during admission. RESULTS: The incidences of gastrointestinal hemorrhage for people with and without TP were 14.5 and 5.07 per 1000 person-years, respectively (P<0.0001). Compared to people without TP, patients with TP had increased risk of gastrointestinal hemorrhage (HR, 2.61; 95% CI, 2.05-3.32). In the nested cohort study, TP was associated with post-hemorrhage mortality (OR, 1.98; 95% CI, 1.09 3.59). CONCLUSION: Patients with TP showed higher risks of gastrointestinal hemorrhage and post-hemorrhage mortality. Our findings suggest the urgency of preventing and managing gastrointestinal hemorrhage by a multidisciplinary medical team for this specific population. PMID- 26604109 TI - Erratum to: Fluoroscopy-Guided Percutaneous Vertebral Body Biopsy Using a Novel Drill-Powered Device: Technical Case Series. PMID- 26604108 TI - Burden of Stroke in Qatar. AB - BACKGROUND: Qatar is located on the northeastern coast of the Arabian Peninsula. The total population is over 2.1 million with around 15% being Qatari citizens. Hamad General Hospital (HGH) is the only tertiary referral governmental hospital in Qatar which admits acute (thrombolysis-eligible) stroke patients. OBJECTIVE: To provide an overview of the burden of stroke in Qatar. METHODS: Data from literature databases, online sources and our stroke registry were collated to identify information on the burden of stroke in Qatar. RESULTS: Overall, over 80% of all stroke patients in Qatar are admitted in HGH. In 2010, the age standardized incidence for first-ever ischemic stroke was 51.88/100,000 person years. To date our stroke registry reveals that 79% of all stroke patients are male and almost 50% of stroke patients are 50 years or less. Hypertension, diabetes and dyslipidemia are the main predisposing factors for stroke, with ischemic stroke being more common (87%) than hemorrhagic stroke (13%). Despite the lack of a stroke unit, 9% of ischemic stroke patients are being thrombolyzed. However the presence of a stroke ward allows swift turnover of patients with a length of stay of less than 5 days before discharge or, if required, transfer to the fully-equipped hospital-based rehabilitation service. Several community awareness programs are ongoing, in addition to several research programs funded by the Qatar National Research Fund and Hamad Medical Corporation. CONCLUSION: In a country where over 15% of the population suffers from diabetes there is continuous need for national community-based awareness campaigns, prevention and educational programs particularly targeting patients and health care workers. PMID- 26604111 TI - Cryoablation Does Not Prevent from Diaphragmatic Hernia. PMID- 26604112 TI - Risk Factors for Immediate and Delayed-Onset Fever After Percutaneous Transhepatic Biliary Drainage. AB - OBJECTIVES: To prospectively investigate the pre and intra-procedural risk factors for immediate (IF) and delayed-onset (DOF) fever development after percutaneous transhepatic biliary drainage (PTBD). METHODS: Institutional review board approval and informed patient consent were obtained. Between February 2013 and February 2014, 97 afebrile patients (77 at the Sapienza University of Rome, Italy and 20 at the Sun Yat-sen University of Guangzhou, China) with benign (n = 31) and malignant (n = 66) indications for a first PTBD were prospectively enrolled. Thirty pre- and intra-procedural clinical/radiological characteristics, including the amount of contrast media injected prior to PTBD placement, were collected in relation to the development of IF (within 24 h) or DOF (after 24 h). Fever was defined as >=37.5 degrees C. Binary logistic regression analysis was used to assess independent associations with IF and DOF. RESULTS: Fourteen (14.4%) patients developed IF and 17 (17.5%) developed DOF. At multivariable analysis, IF was associated with pre-procedural absence of intrahepatic bile duct dilatation (OR 63.359; 95% CI 2.658-1510.055; P = 0.010) and low INR (OR 4.7 * 10(-4); 95% CI 0.000-0.376; P = 0.025), while DOF was associated with unsatisfactory biliary drainage at the end of PTBD (OR 4.571; 95% CI 1.161 17.992; P = 0.030). CONCLUSIONS: The amount of contrast injected is not associated with post-PTBD fever development. Unsatisfactory biliary drainage at the end of PTBD is associated with DOF, suggesting that complete biliary tree decompression should be pursued within the first PTBD. Patients with unsatisfactory drainage and those with the absence of pre-procedural intrahepatic bile duct dilatation, which is associated with IF, require tailored post-PTBD management. PMID- 26604113 TI - Treatment of Osteoid Osteomas Using a Navigational Bipolar Radiofrequency Ablation System. AB - BACKGROUND: Percutaneous CT-guided radiofrequency ablation is a safe and effective minimally invasive treatment for osteoid osteomas. This technical case series describes the use of a recently introduced ablation system with a probe that can be curved in multiple directions, embedded thermocouples for real-time monitoring of the ablation volume, and a bipolar design that obviates the need for a grounding pad. METHODS: Medical records of all patients who underwent radiofrequency ablation of an osteoid osteoma with the STAR Tumor Ablation System (DFINE; San Jose, CA) were reviewed. The location of each osteoid osteoma, nidus volume, and procedural details were recorded. Treatment efficacy and long-term complications were assessed at clinical follow-up. RESULTS: During the study period, 18 osteoid osteomas were radiofrequency ablated with the multidirectional bipolar system. Lesion locations included the femur (50%; 9/18), tibia (22%; 4/18), cervical spine (11%; 2/18), calcaneus (5.5%; 1/18), iliac bone (5.5%; 1/18), and fibula (5.5%; 1/18). The median nidus volume of these cases was 0.33 mL (range 0.12-2.0 mL). All tumors were accessed via a single osseous channel. Median cumulative ablation time was 5 min and 0 s (range 1 min and 32 s-8 min and 50 s). All patients with clinical follow-up reported complete symptom resolution. No complications occurred. CONCLUSION: Safe and effective CT-guided radiofrequency ablation of osteoid osteomas can be performed in a variety of locations using a multidirectional bipolar system. PMID- 26604114 TI - MRI-Guided Percutaneous Biopsy of Mediastinal Masses Using a Large Bore Magnet: Technical Feasibility. AB - OBJECTIVE: To evaluate the diagnostic accuracy and safety of magnetic resonance imaging (MRI)-guided percutaneous biopsy of mediastinal masses performed using a wide-bore high-field scanner. MATERIALS AND METHODS: This is a retrospective study of 16 consecutive patients (8 male, 8 female; mean age 74 years) who underwent MRI-guided core needle biopsy of a mediastinal mass between February 2010 and January 2014. Size and location of lesion, approach taken, time for needle placement, overall duration of procedure, and post-procedural complications were evaluated. Technical success rates and correlation with surgical pathology (where available) were assessed. RESULTS: Target lesions were located in the anterior (n = 13), middle (n = 2), and posterior mediastinum (n = 1), respectively. Mean size was 7.2 cm (range 3.6-11 cm). Average time for needle placement was 9.4 min (range 3-18 min); average duration of entire procedure was 42 min (range 27-62 min). 2-5 core samples were obtained from each lesion (mean 2.6). Technical success rate was 100%, with specimens successfully obtained in all 16 patients. There were no immediate complications. Histopathology revealed malignancy in 12 cases (4 of which were surgically confirmed), benign lesions in 3 cases (1 of which was false negative following surgical resection), and one inconclusive specimen (treated as inaccurate since repeat CT-guided biopsy demonstrated thymic hyperplasia). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in our study were 92.3, 100, 100, 66.7, and 87.5%, respectively. CONCLUSION: MRI-guided mediastinal biopsy is a safe procedure with high diagnostic accuracy, which may offer a non-ionizing alternative to CT guidance. PMID- 26604115 TI - Amplatzer Vascular Plug Anchoring Technique to Stabilize the Delivery System for Microcoil Embolization. AB - PURPOSE: To evaluate the feasibility of a novel embolization technique, the Amplatzer vascular plug (AVP) anchoring technique, to stabilize the delivery system for microcoil embolization. MATERIALS AND METHODS: Three patients were enrolled in this study, including two cases of internal iliac artery aneurysms and one case of internal iliac arterial occlusion prior to endovascular aortic repair. An AVP was used in each case for embolization of one target artery, and the AVP was left in place. The AVP detachment wire was then used as an anchor to stabilize the delivery system for microcoil embolization to embolize the second target artery adjacent to the first target artery. The microcatheter for the microcoils was inserted parallel to the AVP detachment wire in the guiding sheath or catheter used for the AVP. RESULTS: The AVP anchoring technique was achieved and the microcatheter was easily advanced to the second target artery in all three cases. CONCLUSION: The AVP anchoring technique was found to be feasible to advance the microcatheter into the neighboring artery of an AVP-embolized artery. PMID- 26604116 TI - Percutaneous Puncture of the Superior Vena Cava with Insertion of a Cuff Catheter to Address Multiple-Site Venous Occlusion in Hemodialysis Patients. PMID- 26604117 TI - An Approach to Endovascular and Percutaneous Management of Transjugular Intrahepatic Portosystemic Shunt (TIPS) Dysfunction: A Pictorial Essay and Clinical Practice Algorithm. AB - Transjugular intrahepatic portosystemic shunts (TIPS) have evolved as an effective and durable nonsurgical option in the treatment of portal hypertension (PH). It has been shown to improve survival in decompensated cirrhosis and may also serve as a bridge to liver transplantation. In spite of the technical improvements in the procedure, problems occur with the shunt which jeopardizes effective treatment of the PH. Appropriate management is vital to ensure the longevity of the conduit. Shunt revision techniques include endovascular revision techniques and new shunt creation or, in the appropriate patients, alternative/rescue therapies. The ability of interventional radiologists to restore adequate TIPS function has enormous implications for quality of life with palliation, morbidity/mortality related to variceal bleeding and survival if transplant candidates can live long enough to receive a new liver. As such, it is imperative that these treatment strategies are understood and employed when these patients are encountered. In this review, the restoration of appropriate shunt function using various techniques will be discussed as they apply to a variety of clinical scenarios, based on literature. In addition, illustrative case examples highlighting our experience at an academic tertiary medical center will be included. It is the intent to have this document serve as a concise and informative reference to be used by those who may encounter patients with suboptimal functioning TIPS. PMID- 26604118 TI - Therapy for young children with cerebral palsy: what, when, where, and how? PMID- 26604119 TI - Herbal Cardiotoxicity: Can Mother Nature Hurt the Heart? PMID- 26604120 TI - An Unusual Etiology for Bidirectional Ventricular Tachycardia. AB - Bidirectional ventricular tachycardia is a rare variety of tachycardia with a morphologically distinct presentation. The QRS axis and/or morphology alternate in the frontal plane leads. We report a patient with bidirectional ventricular tachycardia in association with aconitine poisoning. PMID- 26604122 TI - Genetic Testing in Thoracic Aortic Disease--When, Why, and How? AB - Advances in genetic technology over the past 10 years have revealed the polygenic basis of thoracic aortic aneurysm and thoracic aortic acute dissection (TAAD) in a subset of patients. There is mounting evidence to show that clinical risk stratification for aneurysmal dilatation and acute dissection can be based on genotype for some of the known genes, allowing individualized medical and surgical management with the aim of reducing morbidity and mortality. This evidence has led to a recommendation by the American College of Cardiology Foundation and the American Heart Association that the underlying genetic mutation should dictate the timing of aortic repair. Other benefits of identifying a specific genetic cause include prediction of multisystem involvement in syndromic forms of TAAD and cascade screening for other at-risk family members. Mutation analysis for genes associated with TAAD in a clinical setting is typically ordered by geneticists or cardiologists with an interest or expertise in cardiac genetics. We present an approach to assist cardiologists and vascular surgeons in recognizing which patients would benefit from genetic testing, provide justification for such testing, and outline a practical approach to ordering the tests. PMID- 26604121 TI - Bicuspid Aortic Stenosis Treated With the Repositionable and Retrievable Lotus Valve. AB - Transcatheter aortic valve implantation (TAVI) for severe aortic stenosis is a well-established and safe therapeutic option. However, data on TAVI in bicuspid aortic valve stenosis are limited and show a higher rate of moderate-severe aortic regurgitation compared with TAVI for tricuspid aortic valve stenosis. We report for the first time, to our knowledge, the use of the mechanically deployed Lotus valve in bicuspid aortic stenosis. In our patient who had severe bicuspid aortic stenosis and was at high surgical risk, the implantation of the repositionable and completely retrievable Lotus valve was a safe and controlled procedure resulting in no relevant aortic regurgitation. PMID- 26604123 TI - State-of-the-Art Surgical Management of Acute Type A Aortic Dissection. AB - Acute type A aortic dissections still present a major challenge to cardiac surgeons. Although surgical management remains the gold standard, operative mortality remains high, including in experienced centres. Nevertheless, recent advances in the understanding and management of various aspects of these complex operations are expected to improve overall patient outcomes. The Canadian Thoracic Aortic Collaborative (CTAC) represents a group of surgeons with interest and expertise in the management of patients with aortic diseases. The purpose of this state-of-the-art review is to detail our approach to the contemporary surgical management of acute type A aortic dissections. We focus specifically on cannulation strategies, cerebral protection, and extent of proximal and distal resection. In addition, specific clinical scenarios-including malperfusion, intramural hematomas, and surgery in octogenarians-are explored. PMID- 26604124 TI - Pregnancy and Thoracic Aortic Disease: Managing the Risks. AB - The most common aortopathies in women of childbearing age are bicuspid aortic valve, coarctation of the aorta, Marfan syndrome, Ehlers-Danlos syndrome, Loeys Dietz syndrome, SMAD3 aortopathy, Turner syndrome, and familial thoracic aneurysm and dissection. The hemodynamic and hormonal changes of pregnancy increase the risk of progressive dilatation or dissection of the aorta in these women. The presence of hypertension increases the risk further. Therefore, appropriate preconception counselling is advised. For women who become pregnant, serial follow-up by a specialized multidisciplinary team throughout pregnancy and postpartum period is required. In this review we discuss risk assessment and management strategies for women with aortopathies. PMID- 26604125 TI - Comparison of Contrast Sensitivity and Through Focus in Small-Aperture Inlay, Accommodating Intraocular Lens, or Multifocal Intraocular Lens Subjects. PMID- 26604126 TI - Validation of Concentric Rings Method as a Topographic Measure of Retinal Nonperfusion in Ultra-widefield Fluorescein Angiography. PMID- 26604127 TI - Dynamic, conjugated microporous polymers: visible light harvesting via guest responsive reversible swelling. AB - The light-harvesting properties of two fluorescent dynamic conjugated microporous organic polymers (Py-PP and Py-BPP) rendered with pyrene chromophores are described. The hydrophobic and dynamic nature of these porous frameworks allows the selective capture of various organic solvents by instantaneous swelling at room temperature. Moreover, the dynamic nature of these frameworks indicates the swelling process with visible volume expansion and enhanced fluorescence. This was further explored for the rapid encapsulation of various fluorescent chromophoric guests at room temperature and investigated for photoinduced energy transfer process. The resultant host-guest antenna materials showed efficient light-harvesting and funnelling of excitation energy of host framework towards the entrapped guest molecule. This process further yielded solid-state luminescent materials with tunable emission. This work holds a great promise on the design of smart porous organic solids from pi-conjugated small molecules for optoelectronics, sensing and separation. PMID- 26604128 TI - Promoting walking in older adults: Perceived neighborhood walkability influences the effectiveness of motivational messages. AB - Positively framed messages seem to promote walking in older adults better than negatively framed messages. This study targeted elderly people in communities unfavorable to walking. Walking was measured with pedometers during baseline (1 week) and intervention (4 weeks). Participants ( n = 74) were informed about either the benefits of walking or the negative consequences of not walking. Perceived neighborhood walkability was assessed with a modified version of the Neighborhood Walkability Scale. When perceived walkability was high, positively framed messages were more effective than negatively framed messages in promoting walking; when perceived walkability was low, negatively framed messages were comparably effective to positively framed messages. PMID- 26604129 TI - Changes in the enhancer landscape during early placental development uncover a trophoblast invasion gene-enhancer network. AB - INTRODUCTION: Trophoblast invasion establishes adequate blood flow between mother and fetus in early placental development. However, little is known about the cis regulatory mechanisms underlying this important process. We aimed to identify enhancer elements that are active during trophoblast invasion, and build a trophoblast invasion gene-enhancer network. METHODS: We carried out ChIP-Seq for an enhancer-associated mark (H3k27Ac) at two time points during early placental development in mouse. One time point when invasion is at its peak (e7.5) and another time point shortly afterwards (e9.5). We use computational analysis to identify putative enhancers, as well as the transcription factor binding sites within them, that are specific to the time point of trophoblast invasion. RESULTS: We compared read profiles at e7.5 and e9.5 to identify 1,977 e7.5 specific enhancers. Within a subset of e7.5-specific enhancers, we discovered a cell migration associated regulatory code, consisting of three transcription factor motifs: AP1, Ets, and Tcfap2. To validate differential expression of the transcription factors that bind these motifs, we performed RNA-Seq in the same context. Finally, we integrated these data with publicly available protein protein interaction data and constructed a trophoblast invasion gene-enhancer network. DISCUSSION: The data we generated and analysis we carried out improves our understanding of the regulatory mechanisms of trophoblast invasion, by suggesting a transcriptional code exists in the enhancers of cell migration genes. Furthermore, the network we constructed highlights novel candidate genes that may be critical for trophoblast invasion. PMID- 26604132 TI - Corrigendum. PMID- 26604130 TI - Bovine milk-derived exosomes for drug delivery. AB - Exosomes are biological nanovesicles that are involved in cell-cell communication via the functionally-active cargo (such as miRNA, mRNA, DNA and proteins). Because of their nanosize, exosomes are explored as nanodevices for the development of new therapeutic applications. However, bulk, safe and cost effective production of exosomes is not available. Here, we show that bovine milk can serve as a scalable source of exosomes that can act as a carrier for chemotherapeutic/chemopreventive agents. Drug-loaded exosomes showed significantly higher efficacy compared to free drug in cell culture studies and against lung tumor xenografts in vivo. Moreover, tumor targeting ligands such as folate increased cancer-cell targeting of the exosomes resulting in enhanced tumor reduction. Milk exosomes exhibited cross-species tolerance with no adverse immune and inflammatory response. Thus, we show the versatility of milk exosomes with respect to the cargo it can carry and ability to achieve tumor targetability. This is the first report to identify a biocompatible and cost effective means of exosomes to enhance oral bioavailability, improve efficacy and safety of drugs. PMID- 26604131 TI - The disulfide compound alpha-lipoic acid and its derivatives: A novel class of anticancer agents targeting mitochondria. AB - The endogenous disulfide alpha-lipoic acid (LA) is an essential mitochondrial co factor. In addition, LA and its reduced counterpart dihydro lipoic acid form a potent redox couple with antioxidative functions, for which it is used as dietary supplement and therapeutic. Recently, it has gained attention due to its cytotoxic effects in cancer cells, which is the key aspect of this review. We initially recapitulate the dietary occurrence, gastrointestinal absorption and pharmacokinetics of LA, illustrating its diverse antioxidative mechanisms. We then focus on its mode of action in cancer cells, in which it triggers primarily the mitochondrial pathway of apoptosis, whereas non-transformed primary cells are hardly affected. Furthermore, LA impairs oncogenic signaling and displays anti metastatic potential. Novel LA derivatives such as CPI-613, which target mitochondrial energy metabolism, are described and recent pre-clinical studies are presented, which demonstrate that LA and its derivatives exert antitumor activity in vivo. Finally, we highlight clinical studies currently performed with the LA analog CPI-613. In summary, LA and its derivatives are promising candidates to complement the arsenal of established anticancer drugs due to their mitochondria-targeted mode of action and non-genotoxic properties. PMID- 26604133 TI - Rheumatoid arthritis-associated RBPJ polymorphism alters memory CD4+ T cells. AB - Notch signaling has recently emerged as an important regulator of immune responses in autoimmune diseases. The recombination signal-binding protein for immunoglobulin kappa J region (RBPJ) is a transcriptional repressor, but converts into a transcriptional activator upon activation of the canonical Notch pathway. Genome-wide association studies of rheumatoid arthritis (RA) identified a susceptibility locus, rs874040(CC), which implicated the RBPJ gene. Here, chromatin state mapping generated using the chromHMM algorithm reveals strong enhancer regions containing DNase I hypersensitive sites overlapping the rs874040 linkage disequilibrium block in human memory, but not in naive CD4(+) T cells. The rs874040 overlapping this chromatin state was associated with increased RBPJ expression in stimulated memory CD4(+) T cells from healthy subjects homozygous for the risk allele (CC) compared with memory CD4(+) T cells bearing the protective allele (GG). Transcriptomic analysis of rs874040(CC) memory T cells showed a repression of canonical Notch target genes IL (interleukin)-9, IL-17 and interferon (IFN)gamma in the basal state. Interestingly, activation of the Notch pathway using soluble Notch ligand, Jagged2-Fc, induced IL-9 and IL-17A while delta-like 4Fc, another Notch ligand, induced higher IFNgamma expression in the rs874040(CC) memory CD4(+) T cells compared with their rs874040(GG) counterparts. In RA, RBPJ expression is elevated in memory T cells from RA patients compared with control subjects, and this was associated with induced inflammatory cytokines IL-9, IL-17A and IFNgamma in response to Notch ligation in vitro. These findings demonstrate that the rs874040(CC) allele skews memory T cells toward a pro-inflammatory phenotype involving Notch signaling, thus increasing the susceptibility to develop RA. PMID- 26604134 TI - MRI phenotypes with high neurodegeneration are associated with peripheral blood B cell changes. AB - Little is known about the mechanisms leading to neurodegeneration in multiple sclerosis (MS) and the role of peripheral blood cells in this neurodegenerative component. We aimed to correlate brain radiological phenotypes defined by high and low neurodegeneration with gene expression profiling of peripheral blood mononuclear cells (PBMC) from MS patients. Magnetic resonance imaging (MRI) scans from 64 patients with relapsing-remitting MS (RRMS) were classified into radiological phenotypes characterized by low (N = 27) and high (N = 37) neurodegeneration according to the number of contrast-enhancing lesions, the relative volume of non-enhancing black holes on T1-weighted images, and the brain parenchymal fraction. Gene expression profiling was determined in PBMC using microarrays, and validation of selected genes was performed by polymerase chain reaction (PCR). B-cell immunophenotyping was conducted by flow cytometry. Microarray analysis revealed the B-cell specific genes FCRL1, FCRL2, FCRL5 (Fc receptor-like 1, 2 and 5 respectively), and CD22 as the top differentially expressed genes between patients with high and low neurodegeneration. Levels for these genes were significantly down-regulated in PBMC from patients with MRI phenotypes characterized by high neurodegeneration and microarray findings were validated by PCR. In patients with high neurodegeneration, immunophenotyping showed a significant increase in the expression of the B-cell activation markers CD80 in naive B cells (CD45+/CD19+/CD27-/IgD+), unswitched memory B cells (CD45+/CD19+/CD27+/IgD+), and switched memory B cells (CD45+/CD19+/CD27+/IgD-), and CD86 in naive and switched memory B cells. These results suggest that RRMS patients with radiological phenotypes showing high neurodegeneration have changes in B cells characterized by down-regulation of B-cell-specific genes and increased activation status. PMID- 26604135 TI - Dasatinib as a treatment for Duchenne muscular dystrophy. AB - Identification of a systemically acting and universal small molecule therapy for Duchenne muscular dystrophy would be an enormous advance for this condition. Based on evidence gained from studies on mouse genetic models, we have identified tyrosine phosphorylation and degradation of beta-dystroglycan as a key event in the aetiology of Duchenne muscular dystrophy. Thus, preventing tyrosine phosphorylation and degradation of beta-dystroglycan presents itself as a potential therapeutic strategy. Using the dystrophic sapje zebrafish, we have investigated the use of tyrosine kinase and other inhibitors to treat the dystrophic symptoms in this model of Duchenne muscular dystrophy. Dasatinib, a potent and specific Src tyrosine kinase inhibitor, was found to decrease the levels of beta-dystroglycan phosphorylation on tyrosine and to increase the relative levels of non-phosphorylated beta-dystroglycan in sapje zebrafish. Furthermore, dasatinib treatment resulted in the improved physical appearance of the sapje zebrafish musculature and increased swimming ability as measured by both duration and distance of swimming of dasatinib-treated fish compared with control animals. These data suggest great promise for pharmacological agents that prevent the phosphorylation of beta-dystroglycan on tyrosine and subsequent steps in the degradation pathway as therapeutic targets for the treatment of Duchenne muscular dystrophy. PMID- 26604136 TI - Modeling structural and functional deficiencies of RBM20 familial dilated cardiomyopathy using human induced pluripotent stem cells. AB - Dilated cardiomyopathy (DCM) is a leading cause of heart failure. In families with autosomal-dominant DCM, heterozygous missense mutations were identified in RNA-binding motif protein 20 (RBM20), a spliceosome protein induced during early cardiogenesis. Dermal fibroblasts from two unrelated patients harboring an RBM20 R636S missense mutation were reprogrammed to human induced pluripotent stem cells (hiPSCs) and differentiated to beating cardiomyocytes (CMs). Stage-specific transcriptome profiling identified differentially expressed genes ranging from angiogenesis regulator to embryonic heart transcription factor as initial molecular aberrations. Furthermore, gene expression analysis for RBM20-dependent splice variants affected sarcomeric (TTN and LDB3) and calcium (Ca(2+)) handling (CAMK2D and CACNA1C) genes. Indeed, RBM20 hiPSC-CMs exhibited increased sarcomeric length (RBM20: 1.747 +/- 0.238 um versus control: 1.404 +/- 0.194 um; P < 0.0001) and decreased sarcomeric width (RBM20: 0.791 +/- 0.609 um versus control: 0.943 +/- 0.166 um; P < 0.0001). Additionally, CMs showed defective Ca(2+) handling machinery with prolonged Ca(2+) levels in the cytoplasm as measured by greater area under the curve (RBM20: 814.718 +/- 94.343 AU versus control: 206.941 +/- 22.417 AU; P < 0.05) and higher Ca(2+) spike amplitude (RBM20: 35.281 +/- 4.060 AU versus control:18.484 +/- 1.518 AU; P < 0.05). beta adrenergic stress induced with 10 um norepinephrine demonstrated increased susceptibility to sarcomeric disorganization (RBM20: 86 +/- 10.5% versus control: 40 +/- 7%; P < 0.001). This study features the first hiPSC model of RBM20 familial DCM. By monitoring human cardiac disease according to stage-specific cardiogenesis, this study demonstrates RBM20 familial DCM is a developmental disorder initiated by molecular defects that pattern maladaptive cellular mechanisms of pathological cardiac remodeling. Indeed, hiPSC-CMs recapitulate RBM20 familial DCM phenotype in a dish and establish a tool to dissect disease relevant defects in RBM20 splicing as a global regulator of heart function. PMID- 26604138 TI - Preferential PPAR-alpha activation reduces neuroinflammation, and blocks neurodegeneration in vivo. AB - Neuroinflammation, immune reactivity and mitochondrial abnormalities are considered as causes and/or contributors to neuronal degeneration. Peroxisome proliferator-activated receptors (PPARs) regulate both inflammatory and multiple other pathways that are implicated in neurodegeneration. In the present study, we investigated the efficacy of fenofibrate (Tricor), a pan-PPAR agonist that activates PPAR-alpha as well as other PPARs. We administered fenofibrate to superoxide dismutase 1 (SOD1(G93A)) mice daily prior to any detectable phenotypes and then animal behavior, pathology and longevity were assessed. Treated animals showed a significant slowing of the progression of disease with weight loss attenuation, enhanced motor performance, delayed onset and survival extension. Histopathological analysis of the spinal cords showed that neuronal loss was significantly attenuated in fenofibrate-treated mice. Mitochondria were preserved as indicated by Cytochrome c immunostaining in the spinal cord, which maybe partly due to increased expression of the PPAR-gamma co-activator 1-alpha. The total mRNA analysis revealed that neuroprotective and anti-inflammatory genes were elevated, while neuroinflammatory genes were down-regulated. This study demonstrates that the activation of PPAR-alpha action via fenofibrate leads to neuroprotection by both reducing neuroinflammation and protecting mitochondria, which leads to a significant increase in survival in SOD1(G93A) mice. Therefore, the development of therapeutic strategies to activate PPAR-alpha as well as other PPARs may lead to new therapeutic agents to slow or halt the progression of amyotrophic lateral sclerosis. PMID- 26604137 TI - Whole-exome sequencing of over 4100 men of African ancestry and prostate cancer risk. AB - Prostate cancer is the most common non-skin cancer in males, with a ~1.5-2-fold higher incidence in African American men when compared with whites. Epidemiologic evidence supports a large heritable contribution to prostate cancer, with over 100 susceptibility loci identified to date that can explain ~33% of the familial risk. To explore the contribution of both rare and common variation in coding regions to prostate cancer risk, we sequenced the exomes of 2165 prostate cancer cases and 2034 controls of African ancestry at a mean coverage of 10.1*. We identified 395 220 coding variants down to 0.05% frequency [57% non-synonymous (NS), 42% synonymous and 1% gain or loss of stop codon or splice site variant] in 16 751 genes with the strongest associations observed in SPARCL1 on 4q22.1 (rs13051, Ala49Asp, OR = 0.78, P = 1.8 * 10(-6)) and PTPRR on 12q15 (rs73341069, Val239Ile, OR = 1.62, P = 2.5 * 10(-5)). In gene-level testing, the two most significant genes were C1orf100 (P = 2.2 * 10(-4)) and GORAB (P = 2.3 * 10(-4)). We did not observe exome-wide significant associations (after correcting for multiple hypothesis testing) in single variant or gene-level testing in the overall case-control or case-case analyses of disease aggressiveness. In this first whole-exome sequencing study of prostate cancer, our findings do not provide strong support for the hypothesis that NS coding variants down to 0.5 1.0% frequency have large effects on prostate cancer risk in men of African ancestry. Higher-coverage sequencing efforts in larger samples will be needed to study rarer variants with smaller effect sizes associated with prostate cancer risk. PMID- 26604139 TI - Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome. AB - Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia. We show that de novo missense mutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio cutaneous disorder, which we term erythrokeratodermia-cardiomyopathy (EKC) syndrome. We demonstrate that DSP mutations in our EKC syndrome subjects affect localization of desmosomal proteins and connexin 43 in the skin, and result in desmosome aggregation, widening of intercellular spaces, and lipid secretory defects. DSP encodes desmoplakin, a primary component of desmosomes, intercellular adhesion junctions most abundant in the epidermis and heart. Though mutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severe whole-body erythrokeratodermia, with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndrome featuring erythrokeratodermia and cardiomyopathy to the spectrum of disease caused by mutation in DSP, and identify a specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin. PMID- 26604140 TI - Urogenital development in Pallister-Hall syndrome is disrupted in a cell-lineage specific manner by constitutive expression of GLI3 repressor. AB - Pallister-Hall syndrome (PHS) is a rare disorder caused by mutations in GLI3 that produce a transcriptional repressor (GLI3R). Individuals with PHS present with a variably penetrant variety of urogenital system malformations, including renal aplasia or hypoplasia, hydroureter, hydronephrosis or a common urogenital sinus. The embryologic mechanisms controlled by GLI3R that result in these pathologic phenotypes are undefined. We demonstrate that germline expression of GLI3R causes renal hypoplasia, associated with decreased nephron number, and hydroureter and hydronephrosis, caused by blind-ending ureters. Mice with obligate GLI3R expression also displayed duplication of the ureters that was caused by aberrant common nephric duct patterning and ureteric stalk outgrowth. These developmental abnormalities are associated with suppressed Hedgehog signaling activity in the cloaca and adjacent vesicular mesenchyme. Mice with conditional expression of GLI3R were utilized to identify lineage-specific effects of GLI3R. In the ureteric bud, GLI3R expression decreased branching morphogenesis. In Six2 positive nephrogenic progenitors, GLI3R decreased progenitor cell proliferation reducing the number of nephrogenic precursor structures. Using mutant mice with Gli3R and Gli3 null alleles, we demonstrate that urogenital system patterning and development is controlled by the levels of GLI3R and not by an absence of full length GLI3. We conclude that the urogenital system phenotypes observed in PHS are caused by GLI3R-dependent perturbations in nephric duct patterning, renal branching morphogenesis and nephrogenic progenitor self-renewal. PMID- 26604141 TI - Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration. AB - Zinc finger motifs are distributed amongst many eukaryotic protein families, directing nucleic acid-protein and protein-protein interactions. Zinc finger protein 106 (ZFP106) has previously been associated with roles in immune response, muscle differentiation, testes development and DNA damage, although little is known about its specific function. To further investigate the function of ZFP106, we performed an in-depth characterization of Zfp106 deficient mice (Zfp106(-/-)), and we report a novel role for ZFP106 in motor and sensory neuronal maintenance and survival. Zfp106(-/-) mice develop severe motor abnormalities, major deficits in muscle strength and histopathological changes in muscle. Intriguingly, despite being highly expressed throughout the central nervous system, Zfp106(-/-) mice undergo selective motor and sensory neuronal and axonal degeneration specific to the spinal cord and peripheral nervous system. Neurodegeneration does not occur during development of Zfp106(-/-) mice, suggesting that ZFP106 is likely required for the maintenance of mature peripheral motor and sensory neurons. Analysis of embryonic Zfp106(-/-) motor neurons revealed deficits in mitochondrial function, with an inhibition of Complex I within the mitochondrial electron transport chain. Our results highlight a vital role for ZFP106 in sensory and motor neuron maintenance and reveal a novel player in mitochondrial dysfunction and neurodegeneration. PMID- 26604142 TI - Large-scale probabilistic 3D organization of human chromosome territories. AB - There is growing evidence that chromosome territories (CT) have a probabilistic non-random arrangement within the cell nucleus of mammalian cells including radial positioning and preferred patterns of interchromosomal interactions that are cell-type specific. While it is generally assumed that the three-dimensional (3D) arrangement of genes within the CT is linked to genomic regulation, the degree of non-random organization of individual CT remains unclear. As a first step to elucidating the global 3D organization (topology) of individual CT, we performed multi-color fluorescence in situ hybridization using six probes extending across each chromosome in human WI38 lung fibroblasts. Six CT were selected ranging in size and gene density (1, 4, 12, 17, 18 and X). In-house computational geometric algorithms were applied to measure the 3D distances between every combination of probes and to elucidate data-mined structural patterns. Our findings demonstrate a high degree of non-random arrangement of individual CT that vary from chromosome to chromosome and display distinct changes during the cell cycle. Application of a classic, well-defined data mining and pattern recognition approach termed the 'k-means' generated 3D models for the best fit arrangement of each chromosome. These predicted models correlated well with the detailed distance measurements and analysis. We propose that the unique 3D topology of each CT and characteristic changes during the cell cycle provide the structural framework for the global gene expression programs of the individual chromosomes. PMID- 26604144 TI - Rescue of neurodegeneration in the Fig4 null mouse by a catalytically inactive FIG4 transgene. AB - The lipid phosphatase FIG4 is a subunit of the protein complex that regulates biosynthesis of the signaling lipid PI(3,5)P2. Mutations of FIG4 result in juvenile lethality and spongiform neurodegeneration in the mouse, and are responsible for the human disorders Charcot-Marie-Tooth disease, Yunis-Varon syndrome and polymicrogyria with seizures. We previously demonstrated that conditional expression of a wild-type FIG4 transgene in neurons is sufficient to rescue most of the abnormalities of Fig4 null mice, including juvenile lethality and extensive neurodegeneration. To evaluate the contribution of the phosphatase activity to the in vivo function of Fig4, we introduced the mutation p.Cys486Ser into the Sac phosphatase active-site motif CX5RT. Transfection of the Fig4(Cys486Ser) cDNA into cultured Fig4(-/-) fibroblasts was effective in preventing vacuolization. The neuronal expression of an NSE-Fig4(Cys486Ser) transgene in vivo prevented the neonatal neurodegeneration and juvenile lethality seen in Fig4 null mice. These observations demonstrate that the catalytically inactive FIG4 protein provides significant function, possibly by stabilization of the PI(3,5)P2 biosynthetic complex and/or localization of the complex to endolysosomal vesicles. Despite this partial rescue, later in life the NSE Fig4(Cys486Ser) transgenic mice display significant abnormalities that include hydrocephalus, defective myelination and reduced lifespan. The late onset phenotype of the NSE-Fig4(Cys486Ser) transgenic mice demonstrates that the phosphatase activity of FIG4 has an essential role in vivo. PMID- 26604146 TI - Extracellular cleavage of collagen XVII is essential for correct cutaneous basement membrane formation. AB - In skin, basal keratinocytes in the epidermis are tightly attached to the underlying dermis by the basement membrane (BM). The correct expression of hemidesmosomal and extracellular matrix (ECM) proteins is essential for BM formation, and the null-expression of one molecule may induce blistering diseases associated with immature BM formation in humans. However, little is known about the significance of post-translational processing of hemidesmosomal or ECM proteins in BM formation. Here we show that the C-terminal cleavage of hemidesmosomal transmembrane collagen XVII (COL17) is essential for correct BM formation. The homozygous p.R1303Q mutation in COL17 induces BM duplication and blistering in humans. Although laminin 332, a major ECM protein, interacts with COL17 around p.R1303, the mutation leaves the binding of both molecules unchanged. Instead, the mutation hampers the physiological C-terminal cleavage of COL17 in the ECM. Consequently, non-cleaved COL17 ectodomain remnants induce the aberrant deposition of laminin 332 in the ECM, which is thought to be the major pathogenesis of the BM duplication that results from this mutation. As an example of impaired cleavage of COL17, this study shows that regulated processing of hemidesmosomal proteins is essential for correct BM organization in skin. PMID- 26604145 TI - Early-onset sleep defects in Drosophila models of Huntington's disease reflect alterations of PKA/CREB signaling. AB - Huntington's disease (HD) is a progressive neurological disorder whose non-motor symptoms include sleep disturbances. Whether sleep and activity abnormalities are primary molecular disruptions of mutant Huntingtin (mutHtt) expression or result from neurodegeneration is unclear. Here, we report Drosophila models of HD exhibit sleep and activity disruptions very early in adulthood, as soon as sleep patterns have developed. Pan-neuronal expression of full-length or N-terminally truncated mutHtt recapitulates sleep phenotypes of HD patients: impaired sleep initiation, fragmented and diminished sleep, and nighttime hyperactivity. Sleep deprivation of HD model flies results in exacerbated sleep deficits, indicating that homeostatic regulation of sleep is impaired. Elevated PKA/CREB activity in healthy flies produces patterns of sleep and activity similar to those in our HD models. We were curious whether aberrations in PKA/CREB signaling were responsible for our early-onset sleep/activity phenotypes. Decreasing signaling through the cAMP/PKA pathway suppresses mutHtt-induced developmental lethality. Genetically reducing PKA abolishes sleep/activity deficits in HD model flies, restores the homeostatic response and extends median lifespan. In vivo reporters, however, show dCREB2 activity is unchanged, or decreased when sleep/activity patterns are abnormal, suggesting dissociation of PKA and dCREB2 occurs early in pathogenesis. Collectively, our data suggest that sleep defects may reflect a primary pathological process in HD, and that measurements of sleep and cAMP/PKA could be prodromal indicators of disease, and serve as therapeutic targets for intervention. PMID- 26604143 TI - Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index. AB - A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 * 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 * 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index. PMID- 26604147 TI - Altered microtubule dynamics and vesicular transport in mouse and human MeCP2 deficient astrocytes. AB - Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder, characterized by normal post-natal development followed by a sudden deceleration in brain growth with progressive loss of acquired motor and language skills, stereotypic hand movements and severe cognitive impairment. Mutations in the methyl-CpG binding protein 2 (MECP2) cause more than 95% of classic cases. Recently, it has been shown that the loss of Mecp2 from glia negatively influences neurons in a non-cell-autonomous fashion, and that in Mecp2-null mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern and greatly prolonged lifespan compared with globally null mice. We now report that microtubule (MT)-dependent vesicle transport is altered in Mecp2-deficient astrocytes from newborn Mecp2-deficient mice compared with control wild-type littermates. Similar observation has been made in human MECP2 p.Arg294* iPSC derived astrocytes. Importantly, administration of Epothilone D, a brain penetrant MT-stabilizing natural product, was found to restore MT dynamics in Mecp2-deficient astrocytes and in MECP2 p.Arg294* iPSC-derived astrocytes in vitro. Finally, we report that relatively low weekly doses of Epothilone D also partially reversed the impaired exploratory behavior in Mecp2(308/y) male mice. These findings represent a first step toward the validation of an innovative treatment for RTT. PMID- 26604148 TI - Mitochondrial defects and neurodegeneration in mice overexpressing wild-type or G399S mutant HtrA2. AB - The protease HtrA2 has a protective role inside mitochondria, but promotes apoptosis under stress. We previously identified the G399S HtrA2 mutation in Parkinson's disease (PD) patients and reported mitochondrial dysfunction in vitro. Mitochondrial dysfunction is a common feature of PD and related to neurodegeneration. Complete loss of HtrA2 has been shown to cause neurodegeneration in mice. However, the full impact of HtrA2 overexpression or the G399S mutation is still to be determined in vivo. Here, we report the first HtrA2 G399S transgenic mouse model. Our data suggest that the mutation has a dominant-negative effect. We also describe a toxic effect of wild-type (WT) HtrA2 overexpression. Only low overexpression of the G399S mutation allowed viable animals and we suggest that the mutant protein is likely unstable. This is accompanied by reduced mitochondrial respiratory capacity and sensitivity to apoptotic cell death. Mice overexpressing WT HtrA2 were viable, yet these animals have inhibited mitochondrial respiration and significant induction of apoptosis in the brain leading to motor dysfunction, highlighting the opposing roles of HtrA2. Our data further underscore the importance of HtrA2 as a key mediator of mitochondrial function and its fine regulatory role in cell fate. The location and abundance of HtrA2 is tightly controlled and, therefore, human mutations leading to gain- or loss of function could provide significant risk for PD related neurodegeneration. PMID- 26604149 TI - Sarcolemmal targeting of nNOSMU improves contractile function of mdx muscle. AB - Nitric oxide (NO) is a key regulator of skeletal muscle function and metabolism, including vasoregulation, mitochondrial function, glucose uptake, fatigue and excitation-contraction coupling. The main generator of NO in skeletal muscle is the muscle-specific form of neuronal nitric oxide synthase (nNOSMU) produced by the NOS1 gene. Skeletal muscle nNOSMU is predominantly localized at the sarcolemma by interaction with the dystrophin protein complex (DPC). In Duchenne muscular dystrophy (DMD), loss of dystrophin leads to the mislocalization of nNOSMU from the sarcolemma to the cytosol. This perturbation has been shown to impair contractile function and cause muscle fatigue in dystrophic (mdx) mice. Here, we investigated the effect of restoring sarcolemmal nNOSMU on muscle contractile function in mdx mice. To achieve this, we designed a modified form of nNOSMU (NOS-M) that is targeted to the sarcolemma by palmitoylation, even in the absence of the DPC. When expressed specifically in mdx skeletal muscle, NOS-M significantly attenuates force loss owing to damaging eccentric contractions and repetitive isometric contractions (fatigue), while also improving force recovery after fatigue. Expression of unmodified nNOSMU at similar levels does not lead to sarcolemmal association and fails to improve muscle function. Aside from the benefits of sarcolemmal-localized NO production, NOS-M also increased the surface membrane levels of utrophin and other DPC proteins, including beta-dystroglycan, alpha-syntrophin and alpha-dystrobrevin in mdx muscle. These results suggest that the expression of NOS-M in skeletal muscle may be therapeutically beneficial in DMD and other muscle diseases characterized by the loss of nNOSMU from the sarcolemma. PMID- 26604151 TI - Gene therapy for lysosomal storage disorders: a good start. AB - Lysosomal storage disorders (LSDs) are a heterogeneous group of inherited diseases with a collective frequency of ~1 in 7000 births, resulting from the deficiency in one or more enzymes or transporters that normally reside within the lysosomes. Pathology results from the progressive accumulation of uncleaved lipids, glycoproteins and/or glycosaminoglycans in the lysosomes and secondary damages that affect the brain, viscera, bones and connective tissues. Most treatment modalities developed for LSD, including gene therapy (GT), are based on the lysosome-specific cross-correction mechanism, by which close proximity of normal cells leads to the correction of the biochemical consequences of enzymatic deficiency within the neighboring cells. Here, GT efforts addressing these disorders are reviewed with an up-to-date discussion of their impact on the LSD disease phenotype in animal models and patients. PMID- 26604150 TI - Genome-wide association study identifies common and low-frequency variants at the AMH gene locus that strongly predict serum AMH levels in males. AB - Anti-Mullerian hormone (AMH) is an essential messenger of sexual differentiation in the foetus and is an emerging biomarker of postnatal reproductive function in females. Due to a paucity of adequately sized studies, the genetic determinants of circulating AMH levels are poorly characterized. In samples from 2815 adolescents aged 15 from the ALSPAC study, we performed the first genome-wide association study of serum AMH levels across a set of ~9 m '1000 Genomes Reference Panel' imputed genetic variants. Genetic variants at the AMH protein coding gene showed considerable allelic heterogeneity, with both common variants [rs4807216 (P(Male) = 2 * 10(-49), Beta: ~0.9 SDs per allele), rs8112524 (P(Male) = 3 * 10(-8), Beta: ~0.25)] and low-frequency variants [rs2385821 (P(Male) = 6 * 10(-31), Beta: ~1.2, frequency 3.6%)] independently associated with apparently large effect sizes in males, but not females. For all three SNPs, we highlight mechanistic links to AMH gene function and demonstrate highly significant sex interactions (P(Het) 0.0003-6.3 * 10(-12)), culminating in contrasting estimates of trait variance explained (24.5% in males versus 0.8% in females). Using these SNPs as a genetic proxy for AMH levels, we found no evidence in additional datasets to support a biological role for AMH in complex traits and diseases in men. PMID- 26604152 TI - The ASK1-specific inhibitors K811 and K812 prolong survival in a mouse model of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure. To develop effective treatments for this devastating disease, an appropriate strategy for targeting the molecule responsible for the pathogenesis of ALS is needed. We previously reported that mutant SOD1 protein causes motor neuron death through activation of ASK1, a mitogen-activated protein kinase kinase kinase. Additionally, we recently developed K811 and K812, which are selective inhibitors for ASK1. Here, we report the effect of K811 and K812 in a mouse model of ALS (SOD1(G93A) transgenic mice). Oral administration of K811 or K812 significantly extended the life span of SOD1(G93A) transgenic mice (1.06 and 1.08% improvement in survival). Moreover, ASK1 activation observed in the lumbar spinal cord of mice at the disease progression stage was markedly decreased in the K811- and K812-treated groups. In parallel, immunohistochemical analysis revealed that K811 and K812 treatment inhibited glial activation in the lumbar spinal cord of SOD1(G93A) transgenic mice. These results reinforce the importance of ASK1 as a therapeutic target for ALS treatment. PMID- 26604153 TI - Beta-cyfluthrin induced neurobehavioral impairments in adult rats. AB - Beta-cyfluthrin (CYF) is a commonly used synthetic pyrethroid having both agricultural and domestic applications. The present study aimed to evaluate the neurobehavioural effects of beta-cyfluthrin in adult rats administered at doses 25 mg/kg body weight/day and 12.5 mg/kg body weight/day for a period of 30 days. Motor coordination and spatial memory were found to be impaired by beta cyfluthrin. Levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), epinephrine (EPN), and serotonin (5-HT) decreased in frontal cortex, corpus striatum and hippocampus of treated rats. At the same time, significantly elevated levels of homovanillic acid (HVA) and nor-epinephrine (NE) were measured. Beta-cyfluthrin inhibited the activity of acetylcholinesterase (AChE) in all the regions of the brain. Hippocampal choline acetyltransferase (ChAT) expression was reduced 3.1 and 4.7 fold by the two doses respectively. Impairment of the antioxidant defense system, evident by decrease in the levels of antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) was seen in the treated rats. The neurochemical alterations manifested were more pronounced in the high dose group as the effects persisted even after withdrawal of exposure. PMID- 26604154 TI - Advances in Equipment and Instrumentation in Laparoscopic Surgery. AB - The practice of veterinary laparoscopic surgery has grown in the past decade. Surgical devices routinely used in human laparoscopy have become available to the veterinary surgeon, at a cost the veterinary market can bear. This includes electrosurgical generators, access ports, stapling devices, tissue dissectors, and a wide array of laparoscopic handpieces. With the development of the laparoscopic clip applier in the 1990s, laparoscopic cholecystectomy came to be commonly performed in people. During this time, numerous training programs were developed to rapidly bring human surgeons up to speed. PMID- 26604155 TI - Advances in Laparoscopic Surgery. AB - Recently, a new platform of abdominal access, called single-port surgery, has emerged in human and veterinary laparoscopy. The single-port platform enables all laparoscopic instruments, including the telescope, to pass individually through the same abdominal incision. Recently, there have been several published reports documenting the efficacy and safety of single-port procedures in veterinary patients. This article discusses the common single-port devices and instrumentation, as well as procedures now routinely offered in veterinary minimally invasive surgery. PMID- 26604156 TI - Advances in Flexible Endoscopy. AB - Flexible endoscopy, a minimally invasive diagnostic and potentially therapeutic tool, has become more available over the past decades. A fiberscope is used to visualize the lumen of the area of interest and collect tissue or fluid samples for evaluation. Samples can be submitted for histopathology, cytologic analysis, and bacterial culture. Flexible endoscopy is being investigated. This article provides a brief review of equipment and basic flexible endoscopy followed by an overview of advanced flexible endoscopic procedures that focuses on the gastrointestinal tract. The procedures included here may become more readily available and improve diagnosis and treatment. PMID- 26604157 TI - A review of large-area bilayer graphene synthesis by chemical vapor deposition. AB - Bilayer graphene has attracted considerable attention due to its potential as a tunable band gap in AB-stacked bilayers. Recently, great advancements have been made in the synthesis of chemical-vapor-deposited bilayer graphene. This featured article provides a detailed and up-to-date review of the synthesis of bilayer graphene by chemical vapor deposition (CVD). We will discuss various approaches to synthesize bilayer graphene and the corresponding growth dynamics. Methods for identifying the growth mechanism of bilayer graphene on Cu enclosures are highlighted for a deeper understanding of better control over uniformity and thickness. PMID- 26604158 TI - Client-pharmacy worker interactions regarding medical abortion in Zambia in 2009 and 2011. AB - OBJECTIVE: To examine sales practices, knowledge, and behavior of pharmacy workers regarding medical abortion in 2009 and 2011 in Zambia, where hostile and stigmatizing attitudes still result in high rates of unsafe abortion. METHODS: Four mystery clients visited pharmacies during 2009 and 2011, and recorded their experiences following their interactions using a standardized form. Bivariate analysis examined pharmacy workers' attitudes, behavior, and medical abortion dispensing practices. RESULTS: Mystery clients visited 76 pharmacies in 2009 and 80 pharmacies in 2011. In 2011, mystery clients reported hostile interactions with pharmacy workers at 8 (10%) pharmacy visits, a relative decrease from 7 (22%) in 2009 (P=0.0353). In 2009, less than half (35 [46%]) of clients received information or had the opportunity to purchase medical abortion drugs in comparison with 53 (66%) in 2011 (P=0.0110). In 2011, more pharmacy workers mentioned a valid medical abortion drug in comparison with 2009 (42 [53%] vs 31 [41%], respectively); however, guidance for women on misoprostol use was minimal. CONCLUSION: Pharmacy workers exhibited increased awareness of misoprostol, less hostility, and a willingness to sell medical abortion drugs; however, they continued to provide inadequate information on misoprostol for medical abortion. Effective training of pharmacy employees is vital in increasing access to safe induced-abortion care. PMID- 26604159 TI - Maternal outcomes after 12hours and 24hours of magnesium sulfate therapy for eclampsia. AB - OBJECTIVE: To assess the effectiveness of a reduced duration (12hours) of magnesium sulfate (MgSO4) administration for eclampsia. METHODS: In a prospective randomized study, women with eclampsia (prepartum, intrapartum, or postpartum) attending Jawaharlal Nehru Medical College, Aligarh, India, between January 2012 and September 2013 were enrolled. The inclusion criteria were blood pressure of at least 140/90mm Hg after 20weeks, proteinuria (dipstick value>=+1), and seizures not attributed to other causes. Participants were assigned to control and study groups according to the time of enrollment (6-month blocks). All patients received a MgSO4 loading dose (4g, intravenously), followed by maintenance doses (1g/hour) for 12hours (study group) and 24hours (control group). The primary outcome was recurrent convulsions after completion of MgSO4 therapy. Patients with treatment failure were excluded from analyses. RESULTS: Analyses included 132 patients in the study group and 72 patients in the control group. No convulsions recurred in either group after the completion of treatment. CONCLUSION: For women with eclampsia, 12hours of magnesium sulfate could effectively prevent recurrent convulsions. PMID- 26604160 TI - Clinical and prognostic value of combined measurement of cytokines and vascular cell adhesion molecule-1 in premature rupture of membranes. AB - OBJECTIVE: To evaluate whether levels of interleukin 6 (IL-6), interleukin 8 (IL 8), and vascular cell adhesion molecule-1 (VCAM-1) in women with premature rupture of membranes (PROM) differ from those in women without PROM. METHODS: An observational study of full-term primiparous pregnant women with PROM (PROM group) and those undergoing elective cesarean delivery (control group) was performed at a center in Yangzhou, China, between January 2003 and July 2006. IL 6, IL-8, and VCAM-1 levels were measured in maternal blood, cord blood, and amniotic fluid. A pathologic examination of fetal membranes was conducted. RESULTS: The IL-6, IL-8, and VCAM-1 levels in maternal serum, amniotic fluid, and cord blood were significantly higher in the PROM group (n=58) than in the control group (n=38; P<0.05 for all comparisons). In the PROM group, the levels increased with duration of membrane rupture (P<0.05 for all). Women with chorioamnionitis had significantly higher levels than women without chorioamnionitis (P<0.05 for all), and women with PROM whose newborns had low Apgar score (<=7) had higher levels than those whose newborns had a higher Apgar score (P<0.05 for all). CONCLUSION: Combined measurements of IL-6, IL-8, and VCAM-1 might help to improve early diagnosis of PROM and chorioamnionitis, and to evaluate the prognosis of newborns. PMID- 26604161 TI - The Burden of Livestock Parasites on the Poor. AB - Parasitic diseases of humans and livestock are ubiquitous in the developing world and have substantial impacts on human wellbeing. For the estimated one billion people living in poverty who rely on livestock for their livelihoods, parasites steal valuable nutritional resources through multiple pathways. This diversion of nutrients ultimately contributes to chronic malnutrition, greater human disease burdens, and decreased productivity of both humans and livestock. PMID- 26604162 TI - Can Helminth Infection Reverse Microbial Dysbiosis? AB - There is growing interest in treating inflammatory conditions with helminth infection. Recently, Loukas and colleagues have reported promising results from using experimental hookworm infection to reduce gluten sensitivity in celiac disease patients. Analysis of microbiota samples from the trial is contributing to our understanding of the complexity underlying helminth-microbiota-host relationships. PMID- 26604163 TI - Progress and Challenges in Infectious Disease Cartography. AB - Quantitatively mapping the spatial distributions of infectious diseases is key to both investigating their epidemiology and identifying populations at risk of infection. Important advances in data quality and methodologies have allowed for better investigation of disease risk and its association with environmental factors. However, incorporating dynamic human behavioural processes in disease mapping remains challenging. For example, connectivity among human populations, a key driver of pathogen dispersal, has increased sharply over the past century, along with the availability of data derived from mobile phones and other dynamic data sources. Future work must be targeted towards the rapid updating and dissemination of appropriately designed disease maps to guide the public health community in reducing the global burden of infectious disease. PMID- 26604164 TI - Lifetime depression history and depression risk in type 2 diabetes: A case control study. AB - AIMS: To assess whether a personal history of depression assists in risk prediction for depression in type 2 diabetes. METHODS: Age- and sex-matched participants with and without diabetes from the Busselton Health Survey were assessed for current and previous depression using the 9-item Patient Health Questionnaire and the Brief Lifetime Depression Scale (BLDS). In the diabetic participants, the temporal relationship between first depression episode and diabetes onset was also explored. RESULTS: In 184 paired participants (age 70.2+/ 10.1years, 50% female), those with diabetes had a higher prevalence of any current depression (12.5% vs 4.3%, P<0.01) and lifetime history of major depression (30.6% vs 21.1%, P=0.06) compared to those without diabetes. After adjustment, lifetime major depression history was independently associated with any current depression in the combined sample (odds ratio (95% CI): 5.55 (3.09 9.98), P<0.001), in those with diabetes (4.17 (2.00-8.71), P<0.001), in those without diabetes (8.29 (3.24-21.23), P<0.001) and in diabetes whether sub-divided by depression first occurring before or after diabetes onset (before: 3.16 (1.38 7.24), P=0.007; after: 2.77 (1.00-7.70), P=0.051). CONCLUSIONS: Obtaining a lifetime history of major depression using the BLDS assists in depression risk prediction in type 2 diabetes regardless of whether depression preceded diabetes onset or not. PMID- 26604165 TI - Subjective parameters markedly limit the referral of transplantation candidates to liver transplant centres. AB - BACKGROUND & AIMS: Equality of access to organ transplantation is a mandatory public health requirement. Referral from a local to a university hospital and then registration on the national waiting list are the two key steps enabling access to liver transplantation (LT). Although the latter procedure is well defined using the Model for End-stage Liver Disease score that improves equality of access, the former is mostly reliant on the practices of referring physicians. The aim of this study was to clarify the factors determining this initial step. METHODS: This observational study included consecutive inpatients with cirrhosis of whatever origin in a cohort constituted between 2003 and 2008, using medical records and structured questionnaires concerning patient characteristics and the opinions of hospital clinicians. Candidates for LT were defined in line with these opinions. RESULTS: Four hundred and thirty-three patients, mostly affected by alcoholic cirrhosis, were included, 21.0% of whom were considered to be candidates for LT. Factors independently associated with their candidature were: physician empathy [odds ratio (OR) = 10.8; 95% CI: 4.0-29.5], adherence to treatment (OR = 16.6; 95% CI: 3.7-75.2), geographical area (OR = 6.8; 95% CI: 2.2 21.3) and the patient's physiological age (OR = 2.3; 95% CI: 1.1-4.7). CONCLUSIONS: Several subjective markers restrict the referral of patients from local hospitals to liver transplant centres. Their advancement to this second step is thus markedly weakened by initial subjectivity. The development of objective guidelines for local hospital physicians to assist them with their initial decision-making on LT is now necessary. PMID- 26604166 TI - A novel fluorescence-based assay for measuring A2E removal from human retinal pigment epithelial cells to screen for age-related macular degeneration inhibitors. AB - Age-related macular degeneration (AMD) is a common retinal disease that leads to irreversible central vision loss in the elderly population. Recent studies have identified many factors related to the development of dry AMD, such as aging, cigarette smoking, genetic predispositions, and oxidative stress, eventually inducing the accumulation of lipofuscin, which is one of the most critical risk factors. One of the major lipofuscins in retinal pigment epithelial (RPE) cells is N-retinylidene-N-retinylethanolamine (also known as A2E), a pyridinium bis retinoid. Currently there is a lack of effective therapy to prevent or restore vision loss caused by dry AMD. Recent studies have shown that 430 nm blue light induces the oxidation of A2E and the activation of caspase-3 to subsequently cause the death of RPE cells, suggesting that removal of A2E from retinal pigment cells might be critical for preventing AMD. Here, we developed a fluorescence labeled A2E analog (A2E-BDP) that functions similar to A2E in RPE cells, but is more sensitive to detection than A2E. A2E-BDP-based tracing of intracellular A2E will be helpful, not only for studying the accumulation and removal of A2E in human RPE cells but also for identifying possible inhibitors of AMD. PMID- 26604167 TI - Prediction of dissolution profiles by non-destructive near infrared spectroscopy in tablets subjected to different levels of strain. AB - This study describes how the strain on formulation components affects dissolution and how near infrared spectroscopy can be used to predict dissolution. Strain (exposure to shear stress) applied during powder mixing affects the interaction between formulation components. Particles experience shear strain when they move relative to each other in a process affecting the properties of the final product. This stress affects the dissolution of oral solid dosages forms. However, dissolution testing destroys the entire tablet, making it impossible to further evaluate tablet properties when an out of specification result is obtained. Thus, a nondestructive technique such as near infrared spectroscopy is desirable to predict dissolution. The aim of this study was to predict dissolution on tablets with different levels of strain (shear) using near infrared spectroscopy in combination with multivariate data analysis. Shear was induced using a modified Couette cell on the powder mixture and tablets from these mixtures were produced using a tablet press emulator. Tablets produced with different strain levels were measured using near infrared spectroscopy. Spectra were obtained in diffuse reflectance mode and pretreated with baseline correction to maintain the physical and chemical information of the tablets. Dissolution profiles were obtained using USP Apparatus 2 as a reference method. Principal component analysis was used to study the sources of variation in the spectra obtained. Partial least squares 2 was used to predict dissolution on tablets with different levels of strain. PMID- 26604168 TI - Multi-modal optical imaging characterization of atherosclerotic plaques. AB - We combined cross-polarization optical coherence tomography (CP OCT) and non linear microscopy based on second harmonic generation (SHG) and two-photon excited fluorescence (2PEF) to assess collagen and elastin fibers and other vascular structures in the development of atherosclerosis, including identification of vulnerable plaques, which remains an important clinical problem and imaging application. CP OCT's ability to visualize tissue birefringence and cross-scattering adds new information about the microstructure and composition of the plaque. However its interpretation can be ambiguous, because backscattering contrast may have a similar appearance to the birefringence related fringes. Our results represent a step towards minimally invasive characterization and monitoring of different stages of atherosclerosis, including vulnerable plaques. CP OCT image of intimal thickening in the human coronary artery. The dark stripe in the cross-polarization channel (arrow) is a polarization fringe related to the phase retardation between two eigen polarization states. It is histologically located in the area of the lipid pool, however this stripe is a polarization artifact, rather than direct visualization of the lipid pool. PMID- 26604170 TI - ANP-ing Up Diabetes: Impaired Natriuretic Peptide Action in Muscle Forms a Mechanistic Link Between Obesity and Diabetes. PMID- 26604171 TI - RAGE Against the ABCs. PMID- 26604172 TI - Maintenance of Subcutaneous Fat Homeostasis Improves Systemic Metabolic Dysfunction in Obesity. PMID- 26604173 TI - Is Diabetic Nerve Pain Caused by Dysregulated Ion Channels in Sensory Neurons? PMID- 26604174 TI - Back From the Brink: The Uses of Targeting the CXCL10:CXCR3 Axis in Type 1 Diabetes. PMID- 26604175 TI - Dissecting the Etiology of Type 2 Diabetes in the Pima Indian Population. PMID- 26604178 TI - Comment on Frances et al. Hepatic Cyclooxygenase-2 Expression Protects Against Diet-Induced Steatosis, Obesity, and Insulin Resistance. Diabetes 2015;64:1522 1531. PMID- 26604179 TI - Response to Comment on Frances et al. Hepatic Cyclooxygenase-2 Expression Protects Against Diet-Induced Steatosis, Obesity, and Insulin Resistance. Diabetes 2015;64:1522-1531. PMID- 26604176 TI - Measurements of Gluconeogenesis and Glycogenolysis: A Methodological Review. AB - Gluconeogenesis is a complex metabolic process that involves multiple enzymatic steps regulated by myriad factors, including substrate concentrations, the redox state, activation and inhibition of specific enzyme steps, and hormonal modulation. At present, the most widely accepted technique to determine gluconeogenesis is by measuring the incorporation of deuterium from the body water pool into newly formed glucose. However, several techniques using radioactive and stable-labeled isotopes have been used to quantitate the contribution and regulation of gluconeogenesis in humans. Each method has its advantages, methodological assumptions, and set of propagated errors. In this review, we examine the strengths and weaknesses of the most commonly used stable isotopes methods to measure gluconeogenesis in vivo. We discuss the advantages and limitations of each method and summarize the applicability of these measurements in understanding normal and pathophysiological conditions. PMID- 26604180 TI - Nanoparticles self-assembled from multiple interactions: a novel near-infrared fluorescent sensor for the detection of serum albumin in human sera and turn-on live-cell imaging. AB - A novel pyrene-conjugated squaraine fluorescent probe SQ-P, which could self assemble into nanoparticles in aqueous solution through multiple interactions, was designed to selectively detect serum albumin with a turn-on response in the near infrared (NIR) region. More importantly, the probe can quantitatively detect serum albumin in human sera, and be used for imaging in living cells. PMID- 26604181 TI - Reaction between Azidyl Radicals and Alkynes: A Straightforward Approach to NH 1,2,3-Triazoles. AB - Reaction between nitrogen-centered radicals and unsaturated C-C bonds is an effective synthetic strategy for the construction of nitrogen-containing molecules. Although the reactions between nitrogen-centered radicals and alkenes have been studied extensively, their counterpart reactions with alkynes are extremely rare. Herein, the first example of reactions between azidyl radicals and alkynes is described. This reaction initiated an efficient cascade reaction involving inter-/intramolecular radical homolytic addition toward a C-C triple bond and a hydrogen-atom transfer step to offer a straightforward approach to NH 1,2,3-triazoles under mild reaction conditions. Both the internal and terminal alkynes work well for this transformation and some heterocyclic substituents on alkynes are compatible. This mechanistically distinct strategy overcomes the inherent limitations associated with azide anion chemistry and represents a rare example of reactions between a nitrogen-centered radicals and alkynes. PMID- 26604182 TI - Successful Treatment of Hepatitis C in Renal Transplant Recipients With Direct Acting Antiviral Agents. AB - The direct-acting antivirals (DAAs) constitute an emerging group of small molecule inhibitors that effectively treat hepatitis C virus (HCV) infection, a common comorbidity in end-stage renal disease patients. To date, there are no data to guide use of these agents in kidney transplant patients. The authors collected data from 20 consecutive kidney recipients treated with interferon-free treatment regimens for HCV at their center: 88% were infected with genotype 1; 50% had biopsy-proved advanced hepatic fibrosis on their most recent liver biopsy preceding treatment (Metavir stage 3 fibrosis [F3] or F4); and 60% had failed treatment pretransplantation with interferon-based therapy. DAA treatment was initiated a median of 888 days after renal transplantation. All patients cleared the virus while on therapy, and 100% have achieved a sustained virologic response at 12 weeks after completion of DAA therapy. The most commonly used regimen was sofosbuvir 400 mg daily in combination with simeprevir 150 mg daily. However, four different treatment approaches were used, with comparable results. The DAAs were well tolerated, and less than half of patients required calcineurin inhibitor dose adjustment during treatment. Eradication of HCV infection with DAAs is feasible after kidney transplantation with few treatment-related side effects. PMID- 26604183 TI - Synthesis of Plasmonic Cu2-x Se@ZnS Core@Shell Nanoparticles. AB - We report the synthesis of plasmonic Cu2-x Se@ZnS core@shell nanoparticles (NPs). We used a shell growth approach, starting from Cu2-x Se NPs that have been shown before to exhibit a localized surface plasmon resonance (LSPR). By careful synthesis planning we avoided cation exchange reactions and received core@shell nanoparticles that, after oxidation under air, exhibit a strong LSPR in the NIR. Interestingly, the crystalline, closed ZnS shell that we grew with variable thickness still allowed a slow oxidation of the core under ambient conditions, while the core was effectively protected from reduction, even in the presence of reducing agents such as borane tert-butyamine complex and diisobutylaluminum hydride, giving rise to a stable particle LSPR, also under strongly reducing conditions. PMID- 26604184 TI - Recall memory in children with Down syndrome and typically developing peers matched on developmental age. AB - BACKGROUND: Whereas research has indicated that children with Down syndrome (DS) imitate demonstrated actions over short delays, it is presently unknown whether children with DS recall information over lengthy delays at levels comparable with typically developing (TD) children matched on developmental age. METHOD: In the present research, 10 children with DS and 10 TD children participated in a two session study to examine basic processes associated with hippocampus-dependent recall memory. At the first session, the researcher demonstrated how to complete a three-step action sequence with novel stimuli; immediate imitation was permitted as an index of encoding. At the second session, recall memory was assessed for previously modelled sequences; children were also presented with two novel three-step control sequences. RESULTS: The results indicated that group differences were not apparent in the encoding of the events or the forgetting of information over time. Group differences were also not observed when considering the recall of individual target actions at the 1-month delay, although TD children produced more target actions overall at the second session relative to children with DS. Group differences were found when considering memory for temporal order information, such that TD children evidenced recall relative to novel control sequences, whereas children with DS did not. CONCLUSIONS: These findings suggest that children with DS may have difficulty with mnemonic processes associated with consolidation/storage and/or retrieval processes relative to TD children. PMID- 26604185 TI - Carotid stenosis and cognitive impairment amongst older Chinese adults living in a rural area: a population-based study. AB - BACKGROUND AND PURPOSE: The possible association between carotid stenosis and cognitive impairment in the Chinese population has been rarely investigated. The association between the severity of carotid stenosis and cognitive impairment amongst older Chinese people living in a rural area was assessed. METHODS: This cross-sectional study included 1375 participants (age >=60 years) from the Confucius Hometown Aging Project in Shandong. In 2010-2011, data were collected through interviews and clinical examinations. Carotid stenosis was assessed using ultrasonography. Cognitive impairment was defined according to the education specific cutoff scores of the Mini-Mental State Examination. Data were analyzed using multinomial logistic models. RESULTS: The overall prevalence was 7.0% for moderate carotid stenosis, 2.0% for severe stenosis and 6.0% for cognitive impairment. The multi-adjusted odds ratio of cognitive impairment was 1.43 (95% confidence interval 0.63-3.22) for moderate carotid stenosis and 3.75 (1.24 11.40) for severe carotid stenosis (P(trend) = 0.023). Similar results were obtained in people without a history of cerebrovascular disease. CONCLUSIONS: Severe carotid stenosis, even asymptomatic, is associated with cognitive impairment independent of atherosclerotic risk factors and disorders amongst older Chinese people. PMID- 26604186 TI - Practical guide to sample size calculations: non-inferiority and equivalence trials. AB - A sample size justification is a vital part of any trial design. However, estimating the number of participants required to give a meaningful result is not always straightforward. A number of components are required to facilitate a suitable sample size calculation. In this paper, the steps for conducting sample size calculations for non-inferiority and equivalence trials are summarised. Practical advice and examples are provided that illustrate how to carry out the calculations by hand and using the app SampSize. PMID- 26604187 TI - Tumor necrosis factor inhibitors added to nonbiological immunosuppressants vs. nonbiological immunosuppressants alone: a different signal of cancer risk according to the condition. A disproportionality analysis in a nationwide pharmacovigilance database. AB - We aimed at detecting a signal of an increased risk of cancer in patients treated with TNF inhibitor (TNFi) and nonbiological immunosuppressant (NBIS), compared with NBIS alone for autoimmune diseases. Secondly, we aimed at comparing this risk between the different TNFis. We conducted a disproportionality analysis (case/noncase study) from the French National PharmacoVigilance Database. We selected all the reports of serious adverse drug reactions from 2000 to 2010 in patients treated with NBIS for labeled indications of TNFi. Cases were all the reports of cancer that occurred after a minimal 3-month exposure to NBIS. Noncases were all the other reports. We searched for exposure to TNFi and calculated reporting odds ratios (RORs), stratified by condition and type of cancer and adjusted by age, gender, history of cancer, type of NBIS and year of reporting. Of the 1918 reports included in the study population, 217 were cases (135 solid and 82 blood cancers). A safety signal was found in rheumatoid arthritis (RA) (ROR: 5.43, 95% CI[3.52-8.38]) particularly for nonmelanoma skin cancer (NMSC) (20.17[2.49-163.36]), and in psoriasis/psoriatic arthritis (3.45[1.09-10.92]). No signal was found in inflammatory bowel diseases (IBD) and ankylosing spondylitis, whatever the type of cancer. There was no difference between TNFis. This study puts the argument of an increased risk of cancer (particularly NMSC) in patients with rheumatoid arthritis exposed to TNFi and NBIS compared with NBIS alone, but not in IBD and ankylosing spondylitis patients. No signal was detected for melanoma potentially related to the lack of power. The signal seems similar whatever the TNFi. PMID- 26604188 TI - Effect of physicochemical parameters on the polygalacturonase of an Aspergillus sojae mutant using wheat bran, an agro-industrial waste, via solid-state fermentation. AB - BACKGROUND: Polygalacturonases (PGs) are valuable enzymes of the food industry; therefore it is of great importance to discover new and GRAS PG-producing microbial strains. In this study, PG enzyme produced from a high PG activity producer mutant Aspergillus sojae using wheat bran at the flask scale under pre optimized conditions of solid-state fermentation (SSF) was biochemically characterized. RESULTS: The crude PG enzyme showed optimum activity in the pH range 4.0-5.0 and was stable in the pH range 3.0-7.0. The optimum temperature for the PG was 40 degrees C and it retained 99% of its activity at 50 degrees C. The mutant A. sojae PG could preserve more than 50% of its stability between 25 and 50 degrees C, both for 30 and 60 min, and was found to be stable in the presence of most of the tested compounds and metal ions. The inactivation energy (Ed ) was determined as 125.3 kJ mol(-1) . The enthalpy (DeltaH*), free energy (DeltaG*) and entropy (DeltaS*) of inactivation were found to be stable with increasing temperature. CONCLUSION: The mutant A. sojae PG could be suitable for the clarification (depectinization) of orange and grape juices and wine. (c) 2015 Society of Chemical Industry. PMID- 26604189 TI - Genetic differentiation and admixture between sibling allopolyploids in the Dactylorhiza majalis complex. AB - Allopolyploidization often happens recurrently, but the evolutionary significance of its iterative nature is not yet fully understood. Of particular interest are the gene flow dynamics and the mechanisms that allow young sibling polyploids to remain distinct while sharing the same ploidy, heritage and overlapping distribution areas. By using eight highly variable nuclear microsatellites, newly reported here, we investigate the patterns of divergence and gene flow between 386 polyploid and 42 diploid individuals, representing the sibling allopolyploids Dactylorhiza majalis s.s. and D. traunsteineri s.l. and their parents at localities across Europe. We make use in our inference of the distinct distribution ranges of the polyploids, including areas in which they are sympatric (that is, the Alps) or allopatric (for example, Pyrenees with D. majalis only and Britain with D. traunsteineri only). Our results show a phylogeographic signal, but no clear genetic differentiation between the allopolyploids, despite the visible phenotypic divergence between them. The results indicate that gene flow between sibling Dactylorhiza allopolyploids is frequent in sympatry, with potential implications for the genetic patterns across their entire distribution range. Limited interploidal introgression is also evidenced, in particular between D. incarnata and D. traunsteineri. Altogether the allopolyploid genomes appear to be porous for introgression from related diploids and polyploids. We conclude that the observed phenotypic divergence between D. majalis and D. traunsteineri is maintained by strong divergent selection on specific genomic areas with strong penetrance, but which are short enough to remain undetected by genotyping dispersed neutral markers. PMID- 26604190 TI - Reduction in the cumulative effect of stress-induced inbreeding depression due to intragenerational purging in Drosophila melanogaster. AB - Environmental stress generally exacerbates the harmful effects of inbreeding and it has been proposed that this could be exploited in purging deleterious alleles from threatened inbred populations. However, understanding what factors contribute to variability in the strength of inbreeding depression (ID) observed across adverse environmental conditions remains a challenge. Here, we examined how the nature and timing of stress affects ID and the potential for purging using inbred and outbred Drosophila melanogaster larvae exposed to biotic (larval competition, bacteria infection) and abiotic (ethanol, heat) stressors compared with unstressed controls. ID was measured during (larval survival) and after (male mating success) stress exposure. The level of stress imposed by each stressor was approximately equal, averaging a 42% reduction in outbred larval survival relative to controls. All stressors induced on average the same ID, causing a threefold increase in lethal equivalents for larval survival relative to controls. However, stress-induced ID in larval success was followed by a 30% reduction in ID in mating success of surviving males. We propose that this fitness recovery is due to 'intragenerational purging' whereby fitness correlations facilitate stress-induced purging that increases the average fitness of survivors in later life history stages. For biotic stressors, post-stress reductions in ID are consistent with intragenerational purging, whereas for abiotic stressors, there appeared to be an interaction between purging and stress induced physiological damage. For all stressors, there was no net effect of stress on lifetime ID compared with unstressed controls, undermining the prediction that stress enhances the effectiveness of population-level purging across generations. PMID- 26604191 TI - Individual spatial aggregation correlates with between-population variation in fine-scale genetic structure of Silene ciliata (Caryophyllaceae). AB - Fine-scale genetic structure (FSGS) can vary among populations within species depending on multiple demographic and environmental factors. Theoretical models predict that FSGS should decrease in high-density populations and increase in populations where individuals are spatially aggregated. However, few empirical studies have compared FSGS between populations with different degrees of individual spatial aggregation and microhabitat heterogeneity. In this work, we studied the relationship between spatial and genetic structure in five populations of alpine specialist Silene ciliata Poiret (Caryophyllaceae). We mapped all individuals in each population and genotyped 96 of them using 10 microsatellite markers. We found significant FSGS consistent with an isolation-by distance process in three of the five populations. The intensity of FSGS was positively associated with individual spatial aggregation. However, no association was found between FSGS and global population density or microhabitat heterogeneity. Overall, our results support theoretical studies indicating that stronger spatial aggregation tends to increase the magnitude of FSGS. They also highlight the relevance of characterizing local plant distribution and microhabitat to better understand the mechanisms that generate intraspecific variation in FSGS across landscapes. PMID- 26604192 TI - Chemotherapy at end-of-life: an integration of oncology and palliative team. AB - Palliative chemotherapy is increasingly used in cancer patients near end of life. With the development of newer anticancer agents which have less side effects and higher expected efficacy, the decision on palliative chemotherapy in patients near end of life is complex. This article illustrates how oncologist and palliative care physicians can work together effectively. This article also gives an overview about the risks of palliative chemotherapy near end of life, patients' and physicians' perspectives in choosing the aggressive treatment and describes what an oncologist should do when facing this challenging situation. PMID- 26604193 TI - [Metastasized occult melanomas?]. AB - CASE REPORTS: We present two patients who were referred to us from other hospitals for further therapy as metastasized occult melanoma patients with extensive stage III and stage IV disease, respectively. On thorough clinical examination, we found a slightly thickened nail plate on the right thumb with barely visible pigmentation and a tiny skin-colored tumor at the proximal nail fold of a 60-year-old man. In a 60-year-old woman, we saw an anatomically almost hidden small nonpigmented tumor on the labia majora close to the posterior commissure. The patients were histologically diagnosed with an ulcerated acrolentigineous melanoma and a nodular mucosal melanoma, respectively. CONCLUSION: With these two case reports we want to emphasize that although extensive radiographic and invasive diagnostic procedures to detect a primary in patients with suspected melanoma of unknown primary are no longer recommended by current guidelines, repeated and thorough clinical examinations can sometimes revise the diagnosis metastasized "occult" melanoma. PMID- 26604194 TI - British American Tobacco puts tobacco in new e-cigarette. PMID- 26604196 TI - Remediation of radiocesium-contaminated liquid waste, soil, and ash: a mini review since the Fukushima Daiichi Nuclear Power Plant accident. AB - The radiation contamination after the Fukushima Daiichi Nuclear Power Plant accident attracts considerable concern all over the world. Many countries, areas, and oceans are greatly affected by the emergency situation other than Japan. An effective remediation strategy is in a highly urgent demand. Though plenty of works have been carried out, progressive achievements have not yet been well summarized. Here, we review the recent advances on the remediation of radiocesium contaminated liquid waste, soil, and ash. The overview of the radiation contamination is firstly given. Afterwards, the current remediation strategies are critically reviewed in terms of the environmental medium. Special attentions are paid on the adsorption/ion exchange and electrically switched ion exchange methods. Finally, the present review outlines the possible works to do for the large-scale application of the novel remediation strategies. PMID- 26604197 TI - Assessment of fertilizer potential of the struvite produced from the treatment of methanogenic landfill leachate using low-cost reagents. AB - Leachates generated in methanogenic landfills contain high strength of ammonium nitrogen which removal is hard to be accomplished by means of conventional techniques. The chemical precipitation of struvite, which is a mineral that could be reused as a slow-release fertilizer, is an effective process in the removal and recovery of NH4 amount of high-concentrated wastewaters. In this paper, a struvite precipitation process using unconventional reagents is proposed for a sustainable recovery of nitrogen content. In particular, seawater bittern, a by product of marine salt manufacturing, and bone meal, a by-product of the thermal treatment of meat waste, have been used as low-cost sources of magnesium and phosphorus, respectively. The process enables the removal of more than 98 % ammonia load, the recovery about 99 and 95 % of phosphorus and magnesium, respectively, and the production of a precipitate containing struvite crystals. Heavy metals concentrations of produced precipitate were below the threshold values specified by the EC Directive for use of sewage sludges as fertilizers. Specific agronomic tests were conducted to investigate the fertilizing value of precipitate recovered from landfill leachate. The fertilizing effect of struvite deposit in cultivating Spinacia oleracea was compared with that of vegetable soil and commercial fertilizer. The growth of selected vegetable in the pots with struvite precipitate resulted significantly greater in both than those in the control pots and in the pots with the complex fertilizer. Furthermore, the struvite application as fertilizer did not result in more heavy metals in the vegetables respect those from soil and model fertilizer. PMID- 26604198 TI - Microbial and mineral evolution in zero valent iron-based permeable reactive barriers during long-term operations. AB - Impacts of subsurface biogeochemical processes over time have always been a concern for the long-term performance of zero valent iron (Fe(0))-based permeable reactive barriers (PRBs). To evaluate the biogeochemical impacts, laboratory experiments were performed using flow-through glass columns for 210 days at controlled temperature (20 degrees C). Two different particle sizes of Fe(0) were used in the columns, and to simulate indigenous microbial activity, extra carbon source was provided in the two columns (biotic columns) and the remaining two columns were kept abiotic using gamma radiations. Heavy metals (Zn, As) were removed efficiently in all the columns, and no exhaustion of treatment capability or clogging was observed during our experimental duration. Newly formed Fe mineral phases and precipitates were characterized using X-ray diffraction (XRD), scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX), and micro-XRF techniques in solid phase at the end of the experiment. In addition, 16S rRNA gene extraction was used for microbial community identification in biotic columns. During the incubation, microbial population shifted in favor of Desulfosporosinus species (sulfate-reducing bacteria) from initial dominance of Acidithiobacillus ferrooxidans in sediments. Dominant mineral phases detected in biotic columns were mackinawite (FeS) and sulfate green rust, while in abiotic columns, magnetite/maghemite phases were more prevalent. PMID- 26604200 TI - Effects of organic matter content and composition on ammonium adsorption in lake sediments. AB - The nature of the influence of organic matter (OM) on ammonium adsorption in lake sediments remains disputed. In this study, the kinetics and thermodynamics of ammonium adsorption were investigated on sediment samples with different OM contents (ignoring the effects of OM mineralization) previously collected from Lake Wuli, a northern bay of Lake Taihu, a shallow lake in southern China. The mechanisms of ammonium adsorption in these samples were characterized by Fourier transform infrared spectrometry and scanning electron microscopy. The results show that the ammonium adsorption capacity of the sediments is highly correlated with their OM content and with the humic content of the OM. The ammonium adsorption capacity of OM varies with its composition, i.e., with the surface properties of the different functional groups present. Indeed, humic acid was found to have a greater ammonium adsorption capacity by itself than when mixed with kerogen and black carbon, the mixture of the latter two components proving a better adsorbent than pure black carbon. PMID- 26604199 TI - Environmental materials for remediation of soils contaminated with lead and cadmium using maize (Zea mays L.) growth as a bioindicator. AB - Heavy metal pollution is a severe environmental problem. Remediation of contaminated soils can be accomplished using environmental materials that are low cost and environmentally friendly. We evaluated the individual and combination effects of humic acid (HA), super absorbent polymer (SAP), zeolite (ZE), and fly ash composites (FC) on immobilization of lead (Pb) and cadmium (Cd) in contaminated soils. We also investigated long-term practical approaches for remediation of heavy metal pollution in soil. The biochemical and morphological properties of maize (Zea mays L.) were selected as biomarkers to assess the effects of environmental materials on heavy metal immobilization. The results showed that addition of test materials to soil effectively reduced heavy metal accumulation in maize foliage, improving chlorophyll levels, plant growth, and antioxidant enzyme activity. The test materials reduced heavy metal injury to maize throughout the growth period. A synergistic effect from combinations of different materials on immobilization of Pb and Cd was determined based on the reduction of morphological and biochemical injuries to maize. The combination of zeolite and humic acid was especially effective. Treatment with a combination of HA + SAP + ZE + FC was superior for remediation of soils contaminated with high levels of Pb and Cd. PMID- 26604201 TI - "The next mouthful will be the best": influence of prevision of the pleasure on the decision of having a second helping of a just eaten food. AB - PURPOSE: Firstly, to see if the decision to have a second helping of food is related to the current evaluation of its palatability or to the predicted pleasure of a second helping of the same food. Secondly, to see if there is any relationship between subjects' BMI, their current or predicted evaluation of food palatability and their decision to have a second helping. METHODS: 128 guests attended a village festival with the specific purpose of eating a traditional, local soup made of beans and bacon. Subjects were asked to indicate the pleasure they felt eating the soup and the pleasure they predicted they would feel by having a second helping of the same food. Subjects were then offered a second identical portion of the above described soup. RESULTS: 72 subjects accepted a second helping of the soup. We discovered a significant correlation between predicted pleasure and the decision to have a second helping of the same food. There was also a significant correlation between BMI and the level of predicted pleasure of a second helping. CONCLUSIONS: The decision to have a second helping of food was related to predicted pleasure and not to the pleasure that was experienced during the first helping. PMID- 26604202 TI - At the Intersection of Health Information Technology and Decision Support: Measurement Feedback Systems... and Beyond. AB - We select and comment on concepts and examples from the target articles in this special issue on measurement feedback systems, placing them in the context of some of our own insights and ideas about measurement feedback systems, and where those systems lie at the intersection of technology and decision making. We contend that, connected to the many implementation challenges relevant to many new technologies, there are fundamental design challenges that await a more elaborate specification of the clinical information and decision models that underlie these systems. Candidate features of such models are discussed, which include referencing multiple evidence bases, facilitating observed and expected value comparisons, fostering collaboration, and allowing translation across multiple ontological systems. We call for a new metaphor for these technologies that goes beyond measurement feedback and encourages a deeper consideration of the increasingly complex clinical decision models needed to manage the uncertainty of delivering clinical care. PMID- 26604203 TI - Impact of Mental Health Services on Resilience in Youth with First Episode Psychosis: A Qualitative Study. AB - The purpose of this qualitative study is to understand how mental health and related services support and hinder resilience in young people diagnosed with first-episode psychosis. Seventeen youth between the ages of 18-24 were recruited and 31 in-depth interviews were conducted. Findings illustrated that informational and meaning making, instrumental, and emotional supports were experienced positively (i.e., resilience-enhancing); whereas services with ghettoizing, engulfing, regulating, and out of tune practices were experienced negatively (i.e., resilience-hindering). These results demonstrate how various types of service-related practices influence resilience in youth and can inform future planning of services for psychosis. PMID- 26604204 TI - Introduction to the Special Issue: Invited Papers from the 2015 APAHC Conference. AB - The 7th biennial National Conference of APAHC, the Association of Psychologists in Academic Health Centers, was held in Atlanta, Georgia, February 5-7, 2015. Speakers were invited to contribute manuscripts based on their conference presentations, and many submitted manuscripts for this special edition of the Journal of Clinical Psychology in Medical Settings. Some papers will appear in the December 2015 issue of JCPMS; others will appear in the March 2016 issue. All papers have undergone a rigorous peer review process. The Conference Co-Chairs, Drs. Laura Shaffer and Amit Shahane, are Guest Editors for the special issue. In this article, they provide an overview of the conference's major themes, and also discuss some aspects of conference planning. PMID- 26604205 TI - Leadership in Academic Health Centers: Transactional and Transformational Leadership. AB - Leadership is a crucial component to the success of academic health science centers (AHCs) within the shifting U.S. healthcare environment. Leadership talent acquisition and development within AHCs is immature and approaches to leadership and its evolution will be inevitable to refine operations to accomplish the critical missions of clinical service delivery, the medical education continuum, and innovations toward discovery. To reach higher organizational outcomes in AHCs requires a reflection on what leadership approaches are in place and how they can better support these missions. Transactional leadership approaches are traditionally used in AHCs and this commentary suggests that movement toward a transformational approach is a performance improvement opportunity for AHC leaders. This commentary describes the transactional and transformational approaches, how they complement each other, and how to access the transformational approach. Drawing on behavioral sciences, suggestions are made on how a transactional leader can change her cognitions to align with the four dimensions of the transformational leadership approach. PMID- 26604206 TI - Traumatic endophthalmitis caused by Nocardia kruczakiae in a patient with traumatic eye injury. AB - BACKGROUND: We describe a case of traumatic ocular endophthalmitis caused by Nocardia kruczakiae after vegetable trauma in an immunocompetent child. FINDINGS: A 5-year-old boy suffered from a trauma with a palm tree leaflet. Two months later, he was diagnosed with traumatic infectious uveitis and intumescent cataract with anterior capsule rupture. Intensive treatment with systemic and topical vancomycin, ceftazidime and methylprednisolone began. After 1 month, he underwent phacoemulsification with intraocular lens implantation (IOL). After some episodes of reactivation, he was diagnosed with traumatic nocardial endophthalmitis from aqueous humour samples. Several operations and specific antibiotic therapy resolved the infection. CONCLUSIONS: In cases of traumatic endophthalmitis and several recurrences, it is extremely useful to make an etiologic diagnosis in order to treat the patient with specific antibiotics. PMID- 26604207 TI - Pharmacodynamic modeling of combined chemotherapeutic effects predicts synergistic activity of gemcitabine and trabectedin in pancreatic cancer cells. AB - PURPOSE: This study investigates the combined effects of gemcitabine and trabectedin (ecteinascidin 743) in two pancreatic cancer cell lines and proposes a pharmacodynamic (PD) model to quantify their pharmacological interactions. METHODS: Effects of gemcitabine and trabectedin upon the pancreatic cancer cell lines MiaPaCa-2 and BxPC-3 were investigated using cell proliferation assays. Cells were exposed to a range of concentrations of the two drugs, alone and in combination. Viable cell numbers were obtained daily over 5 days. A model incorporating nonlinear cytotoxicity, transit compartments, and an interaction parameter psi was used to quantify the effects of the individual drugs and combinations. RESULTS: Simultaneous fitting of temporal cell growth profiles for all drug concentrations provided reasonable cytotoxicity parameter estimates (the cell killing rate constant K max and the sensitivity constant KC50) for each drug. The interaction parameter psi was estimated as 0.806 for MiaPaCa-2 and 0.843 for BxPC-3 cells, suggesting that the two drugs exert modestly synergistic effects. CONCLUSIONS: The proposed PD model enables quantification of the temporal profiles of drug combinations over a range of concentrations with drug specific parameters. Based upon these in vitro studies, trabectedin may have augmented benefit in combination with gemcitabine. The PD model may have general relevance for the study of other cytotoxic drug combinations. PMID- 26604208 TI - Hypoxia-inducible factor-1alpha perpetuates synovial fibroblast interactions with T cells and B cells in rheumatoid arthritis. AB - Synovial fibroblast hyperplasia, T-cell hyperactivity, B-cell overactivation, and the self-perpetuating interactions among these cell types are major characteristics of rheumatoid arthritis (RA). The inflamed joints of RA patients are hypoxic, with upregulated expression of hypoxia-inducible factor-1alpha (HIF 1alpha) in RA synovial fibroblasts (RASFs). It remains unknown whether HIF-1alpha regulates interactions between RASFs and T cells and B cells. We report here that HIF-1alpha promotes the expression of inflammatory cytokines IL-6, IL-8, TNF alpha, and IL-1beta, and cell-cell contact mediators IL-15, vascular cell adhesion molecule (VCAM)-1, thrombospondin (TSP)-1, and stromal cell-derived factor (SDF)-1 in RASFs. Furthermore, HIF-1alpha perpetuates RASF-mediated inflammatory Th1- and Th17-cell expansion while differentially inhibiting regulatory B10 and innate-like B cells, leading to increased IFN-gamma, IL-17, and IgG production and decreased protective natural IgM secretion. Our findings suggest that HIF-1alpha perpetuates the interactions between RASFs and T cells and B cells to induce inflammatory cytokine and autoantibody production, thus exacerbating the severity of RA. Targeting HIF-1alpha may provide new therapeutic strategies for overcoming this persistent disease. PMID- 26604209 TI - Age and diabetes related changes of the retinal capillaries: An ultrastructural and immunohistochemical study. AB - Normal human aging and diabetes are associated with a gradual decrease of cerebral flow in the brain with changes in vascular architecture. Thickening of the capillary basement membrane and microvascular fibrosis are evident in the central nervous system of elderly and diabetic patients. Current findings assign a primary role to endothelial dysfunction as a cause of basement membrane (BM) thickening, while retinal alterations are considered to be a secondary cause of either ischemia or exudation. The aim of this study was to reveal any initial retinal alterations and variations in the BM of retinal capillaries during diabetes and aging as compared to healthy controls. Moreover, we investigated the potential role of vascular endothelial growth factor (VEGF) and pro-inflammatory cytokines in diabetic retina.Transmission electron microscopy (TEM) was performed on 46 enucleated human eyes with particular attention to alterations of the retinal capillary wall and Muller glial cells. Inflammatory cytokines expression in the retina was investigated by immunohistochemistry.Our electron microscopy findings demonstrated that thickening of the BM begins primarily at the level of the glial side of the retina during aging and diabetes. The Muller cells showed numerous cytoplasmic endosomes and highly electron-dense lysosomes which surrounded the retinal capillaries. Our study is the first to present morphological evidence that Muller cells start to deposit excessive BM material in retinal capillaries during aging and diabetes. Our results confirm the induction of pro-inflammatory cytokines TNF-alpha and IL-1beta within the retina as a result of diabetes.These observations strongly suggest that inflammatory cytokines and changes in the metabolism of Muller glial cells rather than changes in of endothelial cells may play a primary role in the alteration of retinal capillaries BM during aging and diabetes. PMID- 26604210 TI - Polycystic ovary syndrome and pregnancy. PMID- 26604211 TI - Letter to the Editor. PMID- 26604212 TI - A Systematic Method for Categorizing GN. PMID- 26604214 TI - The effect of intravenous iloprost on pulmonary artery hypertension after paediatric congenital heart surgery. AB - OBJECTIVES: To investigate the effects of intravenous iloprost on pulmonary artery hypertension (PAH) in infants undergoing congenital heart surgery. METHODS: In this prospective, randomized study, the study group (n = 15) received a continuous infusion of iloprost (2.0 ng/kg/min) that was delivered immediately after weaning from cardiopulmonary bypass and continued for 72 h postoperatively. Patients in the control group (n = 12) were managed conventionally. The groups were compared in terms of postoperative data, including systolic and mean pulmonary artery (PA) pressures, PA/systemic pressure ratio, lactate level, PAH crisis, ventilation time, reintubation and lengths of intensive care unit (ICU) and hospital stay. Transthoracic echocardiography was used to assess PA pressures at 1 day, 7 days and 30 days after surgery. RESULTS: No mortality occurred. PAH crisis occurred in 2 (16.6%) patients in the control group and 4 (26.7%) patients in the study group (P = 0.53). Postoperative PA pressures and PA/systemic pressure ratios were similar between the groups (P > 0.05). The durations of ICU (P = 0.40) and hospital (P = 0.98) stays were similar between the groups. Echocardiographic studies demonstrated a significant decrease in postoperative PA pressures in the control (P = 0.001) and study (P = 0.0001) groups. However, no significant change was observed between the groups (P > 0.05). The Tukey multiple comparison test showed a significant decrease in PA pressures at each follow-up in both groups (P < 0.05). CONCLUSIONS: Intravenous iloprost demonstrated no additional benefit over the conventional management of infants with PAH after repair of intracardiac defects. Clinicians may prefer other alternative agents in infants with a high risk of PAH crisis. PMID- 26604213 TI - Change in Measured GFR Versus eGFR and CKD Outcomes. AB - Measured GFR (mGFR) has long been considered the gold standard measure of kidney function, but recent studies have shown that mGFR is not consistently superior to eGFR in explaining CKD-related comorbidities. The associations between longitudinal changes in mGFR versus eGFR and adverse outcomes have not been examined. We analyzed a subset of 942 participants with CKD in the Chronic Renal Insufficiency Cohort Study who had at least two mGFRs and two eGFRs determined concurrently by iothalamate and creatinine (eGFRcr) or cystatin C, respectively. We compared the associations between longitudinal changes in each measure of kidney function over 2 years and risks of ESRD, nonfatal cardiovascular events, and all-cause mortality using univariate Cox proportional hazards models. The associations for all outcomes except all-cause mortality associated most strongly with longitudinal decline in eGFRcr. Every 5-ml/min per 1.73 m(2) decline in eGFRcr over 2 years associated with 1.54 (95% confidence interval, 1.44 to 1.66; P<0.001) times higher risk of ESRD and 1.23 (95% confidence interval, 1.12 to 1.34; P<0.001) times higher risk for cardiovascular events. All-cause mortality did not associate with longitudinal decline in mGFR or eGFR. When analyzed by tertiles of renal function decline, mGFR did not outperform eGFRcr in the association with any outcome. In conclusion, compared with declines in eGFR, declines in mGFR over a 2-year period, analyzed either as a continuous variable or in tertiles, did not consistently show enhanced association with risk of ESRD, cardiovascular events, or death. PMID- 26604215 TI - Strain- and Diet-Related Lesion Variability in Aging DBA/2, C57BL/6, and DBA/2xC57BL/6 F1 Mice. AB - Genetic and environmental factors both play a role in the occurrence of age related disease. To examine the genetic contribution to the development of spontaneous lesions in aging animals, a complete range of tissues was comprehensively analyzed by histopathology from 180 individually housed ad libitum-fed or 40% calorically restricted 24-month-old male and female mice of 2 parental strains-DBA/2NNia (D2) and C57BL/6NNia (B6)-and the F1 cross B6D2F1/NNia. Several strain- and diet-dependent patterns of lesions were identified. Many lesions were genotype dependent and exhibited recessive phenotypic expression, defined as being common in 1 parental strain but infrequently observed in the F1 cross (eg, glomerulonephritis in B6 mice), while others were maintained from 1 parental strain to the F1 with similar frequencies (eg, reproductive tract leiomyoma in D2 mice). Other lesions were common regardless of genotype (osteoarthritis, periodontitis). Only rare lesions were more common in the F1 but underrepresented in the 2 parental strains. Furthermore, F1 mice had a lower number of overall total lesions and a lower number of tumors than either parental strain. Caloric restriction reduced the total number of lesions and neoplasms regardless of genotype but differentially affected genotype-dependent lesions in B6 and D2 mice, with B6 mice more sensitive to the effects of caloric restriction than D2 mice. In summary, genetics and environmental factors (eg, dietary restriction) both substantially contribute to the pattern of lesions that develop as animals age. PMID- 26604216 TI - Extra L3.8bn for NHS will be undermined by public health and social care cuts, experts predict. PMID- 26604217 TI - The relationship between Executive Functions and Theory of Mind: a Long and Winding Road. PMID- 26604218 TI - Studying city life, improving population health. PMID- 26604219 TI - Chronic Pain and Cognitive Behavioral Therapy: An Integrative Review. AB - Cognitive behavioral therapy (CBT) is often used to treat chronic pain; however, more information is needed about what are the most efficacious dose and delivery methods. The aims of this review were to determine (a) which CBT doses, delivery methods, strategies, and follow-up periods have been explored in recent intervention studies of individuals with chronic pain and (b) whether the outcomes described in the selected studies were consistent with recommendations by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials. The CINAHL, EMBASE, PubMed, PsycInfo, and SCOPUS databases were searched for randomized controlled trials published from 2009 to 2015 testing CBT for adults with chronic pain. Thirty-five studies were included in this review. Results revealed that CBT reduced pain intensity in 43% of trials, the efficacy of online and in-person formats were comparable, and military veterans and individuals with cancer-related chronic pain were understudied. PMID- 26604220 TI - Risk Prediction Tools for Hip and Knee Arthroplasty. AB - The current healthcare environment in America is driven by the concepts of quality, cost containment, and value. In this environment, primary hip and knee arthroplasty procedures have been targeted for cost containment through quality improvement initiatives intended to reduce the incidence of costly complications and readmissions. Accordingly, risk prediction tools have been developed in an attempt to quantify the patient-specific assessment of risk. Risk prediction tools may be useful for the informed consent process, for enhancing risk mitigation efforts, and for risk-adjusting data used for reimbursement and the public reporting of outcomes. The evaluation of risk prediction tools involves statistical measures such as discrimination and calibration to assess accuracy and utility. Furthermore, prediction tools are tuned to the source dataset from which they are derived, require validation with external datasets, and should be recalibrated over time. However, a high-quality, externally validated risk prediction tool for adverse outcomes after primary total joint arthroplasty remains an elusive goal. PMID- 26604222 TI - FGF control of E-cadherin targeting in the Drosophila midgut impacts on primordial germ cell motility. AB - Embryo formation requires tight regulation and coordination of adhesion in multiple cell types. By undertaking imaging, three-dimensional (3D) reconstructions and genetic analysis during posterior midgut morphogenesis in Drosophila, we find a new requirement for the conserved fibroblast growth factor (FGF) signaling pathway in the maintenance of epithelial cell adhesion through FGF modulation of zygotic E-cadherin. During Drosophila gastrulation, primordial germ cells (PGCs) are transported with the posterior midgut while it undergoes dynamic cell shape changes. In embryos mutant for the FGF signaling pathway components Branchless and Breathless, zygotic E-cadherin is not targeted to adherens junctions, causing midgut pocket collapse, which impacts on PGC movement. We find that the ventral midline also requires FGF signaling to maintain cell-cell adhesion. We show that FGF signaling regulates the distribution of zygotic E-cadherin during early embryonic development to maintain cell-cell adhesion in the posterior midgut and the ventral midline, a role that is likely crucial in other tissues undergoing active cell shape changes with higher adhesive needs. PMID- 26604224 TI - Srv2/CAP is required for polarized actin cable assembly and patch internalization during clathrin-mediated endocytosis. AB - The dynamic assembly and disassembly of actin filaments is essential for the formation and transport of vesicles during endocytosis. In yeast, two types of actin structures, namely cortical patches and cytoplasmic cables, play a direct role in endocytosis, but how their interaction is regulated remains unclear. Here, we show that Srv2/CAP, an evolutionarily conserved actin regulator, is required for efficient endocytosis owing to its role in the formation of the actin patches that aid initial vesicle invagination and of the actin cables that these move along. Deletion of the SRV2 gene resulted in the appearance of aberrant fragmented actin cables that frequently moved past actin patches, the sites of endocytosis. We find that the C-terminal CARP domain of Srv2p is vitally important for the proper assembly of actin patches and cables; we also demonstrate that the N-terminal helical folded domain of Srv2 is required for its localization to actin patches, specifically to the ADP-actin rich region through an interaction with cofilin. These results demonstrate the in vivo roles of Srv2p in the regulation of the actin cytoskeleton during clathrin-mediated endocytosis. PMID- 26604221 TI - LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1. AB - Cardiolipin (also known as PDL6) is an indispensable lipid required for mitochondrial respiration that is generated through de novo synthesis and remodeling. Here, the cardiolipin remodeling enzyme, acyl-CoA:lysocardiolipin acyltransferase-1 (Alcat1; SwissProt ID, Q6UWP7) is destabilized in epithelia by lipopolysaccharide (LPS) impairing mitochondrial function. Exposure to LPS selectively decreased levels of carbon 20 (C20)-containing cardiolipin molecular species, whereas the content of C18 or C16 species was not significantly altered, consistent with decreased levels of Alcat1. Alcat1 is a labile protein that is lysosomally degraded by the ubiquitin E3 ligase Skp-Cullin-F-box containing the Fbxo28 subunit (SCF-Fbxo28) that targets Alcat1 for monoubiquitylation at residue K183. Interestingly, K183 is also an acetylation-acceptor site, and acetylation conferred stability to the enzyme. Histone deacetylase 2 (HDAC2) interacted with Alcat1, and expression of a plasmid encoding HDAC2 or treatment of cells with LPS deacetylated and destabilized Alcat1, whereas treatment of cells with a pan-HDAC inhibitor increased Alcat1 levels. Alcat1 degradation was partially abrogated in LPS-treated cells that had been silenced for HDAC2 or treated with MLN4924, an inhibitor of Cullin-RING E3 ubiquitin ligases. Thus, LPS increases HDAC2-mediated Alcat1 deacetylation and facilitates SCF-Fbxo28-mediated disposal of Alcat1, thus impairing mitochondrial integrity. PMID- 26604223 TI - Localisation-based imaging of malarial antigens during erythrocyte entry reaffirms a role for AMA1 but not MTRAP in invasion. AB - Microscopy-based localisation of proteins during malaria parasite (Plasmodium) invasion of the erythrocyte is widely used for tentative assignment of protein function. To date, however, imaging has been limited by the rarity of invasion events and the poor resolution available, given the micron size of the parasite, which leads to a lack of quantitative measures for definitive localisation. Here, using computational image analysis we have attempted to assign relative protein localisation during invasion using wide-field deconvolution microscopy. By incorporating three-dimensional information we present a detailed assessment of known parasite effectors predicted to function during entry but as yet untested or for which data are equivocal. Our method, termed longitudinal intensity profiling, resolves confusion surrounding the localisation of apical membrane antigen 1 (AMA1) at the merozoite-erythrocyte junction and predicts that the merozoite thrombospondin-related anonymous protein (MTRAP) is unlikely to play a direct role in the mechanics of entry, an observation supported with additional biochemical evidence. This approach sets a benchmark for imaging of complex micron-scale events and cautions against simplistic interpretations of small numbers of representative images for the assignment of protein function or prioritisation of candidates as therapeutic targets. PMID- 26604226 TI - Elderly care between global and local services: the use of somatic care practices. AB - Israel's population is ageing alongside the worldwide ageing population. As the population ages and the number of older people who are 'ageing in place' increases, the system of elderly care will face new opportunities and challenges in responding to non-institutional services for elderly care. There is an increasing demand for foreign caregivers despite differences in language and cultural background. This case report describes the global care services provided in Israel by caregivers from the Philippines to emphasis the cultural and social components of elderly care. The following case analyses the use of somatic care practices as culturally intuitive sensitivity practices adjustable to the local culture, especially since the caregiver from the Philippines and her Israeli patient do not share a common language or cultural background. PMID- 26604225 TI - Extremely high HIV-1 viral load in a patient with undiagnosed clinical indicator disease for HIV infection. AB - We report a case of a new diagnosis of HIV with an extremely high viral load presenting with HIV encephalopathy, in a 54-year-old woman who had been treated with 2 years of extended high-dose immunosuppressant therapy for a recalcitrant pruritic rash before diagnosis. PMID- 26604227 TI - A 43-year-old woman presenting with subacute, bilateral, sequential facial nerve palsies, then developing pseudotumour cerebri. AB - A patient presented elsewhere with what appeared to be a simple, unilateral, chronic suppurative otitis media and then developed an ipsilateral facial palsy. She soon developed the same problem on the other side. At the time, a brain MRI had been ordered but the clinician did not review it with a radiologist. The surgical specimens were not sent for histopathology. When transferred to our institution 3 months later, the patient had severe bilateral papilloedema due to intracranial hypertension due to missed cerebral venous sinus thrombosis. Further surgery revealed that the pathology in the temporal bone was B-cell lymphoma, which, fortunately, responded to chemoradiotherapy. There was good resolution of the facial palsies, but the patient has severe permanent visual loss due to optic atrophy. PMID- 26604228 TI - Ulnar artery aneurysm and hypothenar hammer syndrome. PMID- 26604229 TI - An example of prompt and appropriate multidisciplinary management leading to an exceptionally good outcome: a case complicated by amniotic fluid embolism. AB - Amniotic fluid embolism (AFE) is a rare and serious phenomenon; we describe a rare case of AFE occurring after a second trimester surgical termination in a private clinic, which, with prompt transfer and appropriate multidisciplinary management, had an exceptionally good outcome. The patient developed hypotension, respiratory arrest and disseminated intravascular coagulopathy following the procedure but with aggressive management she made a full recovery without any neurological or long-term sequelae. PMID- 26604230 TI - Postpartum vertebral artery dissection. AB - We report a case of a right vertebral artery dissection in a 35-year-old woman, 3 weeks post partum, with manifestations of vertebrobasilar disease. She was 3 weeks out from the uneventful delivery of her fourth child, with presentation of acute neurological symptoms, predominantly intractable vertigo. Vertigo can have many non-specific generalised symptoms and clinical findings. Postpartum women have a lengthy list of possible aetiologies of vertigo not limited to our initially suspected preeclampsia, dural venous thrombosis and vertebral dissection. PMID- 26604231 TI - Septic arthritis and subsequent fatal septic shock caused by Vibrio vulnificus infection. AB - Vibrio vulnificus is a rare but potential fatal bacterium that can cause severe infections. Wound infections, primary sepsis and gastroenteritis are the most common clinical features. Septic arthritis caused by V. vulnificus is an atypical presentation that has been reported in only two case reports; however, it has not been previously noted in Denmark. The authors report a case of septic arthritis caused by V. vulnificus in an immunocompromised patient. The disease progressed to severe sepsis and subsequent death within 10 h of admission. PMID- 26604232 TI - Salmonella newport causing osteomyelitis in a patient with diabetes. AB - Salmonella is a foodborne pathogen that commonly causes intestinal symptoms. Bacteraemia and extraintestinal infections have been documented within the literature, and are more frequently associated with immunodeficiency and general debilitation. We discuss the case of a previously well 36-year-old man who presented with a septic knee and new-onset diabetes. Imaging confirmed osteomyelitis and a Brodie's abscess, with blood and tissue cultures revealing the isolate Salmonella enterica newport. He denied any previous gastrointestinal symptoms, recent travel, change in usual dietary habit or symptoms of diabetes. So far there have only been three reported cases of S. newport causing osteomyelitis. We discuss the incidence of Salmonella infections, including extraintestinal symptoms, its relation to immunodeficiency and the disease burden of S. newport. PMID- 26604233 TI - Recurrent pericardial effusion and tamponade in a patient with Erdheim-Chester disease (ECD). AB - Erdheim-Chester disease (ECD) is a rare xanthogranulomatous disorder characterised by the proliferation of lipid laden histiocytes along with infiltration of various organs of the body. Although commonly presenting with bone pains secondary to bony infiltration, cardiac involvement in the form of periaortic fibrosis and pericardial involvement may be seen in a subgroup of patients. We report a case of ECD presenting as recurrent pericardial effusion along with pericardial tamponade. PMID- 26604234 TI - Inferior mesenteric vein pylephlebitis due to sigmoid diverticulitis. PMID- 26604235 TI - Successful re-implantation of implantable collamer lens after management of post ICL methicillin-resistant Staphylococcus epidermidis endophthalmitis. AB - A 29-year-old man presented with acute onset pain, redness and diminution of vision in the right eye 5 days after implantation of an implantable collamer lens (ICL). A diagnosis of postoperative endophthalmitis was made based on examination and ultrasonography. A vitreous tap was taken and intravitreal antibiotics (vancomycin 1 mg/0.1 ml+piperacillin-tazobactam 225 ug/0.1 mL) were administered. The vitreous culture revealed presence of methicillin-resistant Staphylococcus epidermidis. There was minimal improvement after 48 h; hence the ICL was explanted and repeat injection of intravitreal antibiotics administered. Following this, the endophthalmitis resolved and the patient achieved a corrected distance visual acuity of 20/25 4 weeks later. A repeat implantation of ICL was performed 9 months after the first surgery, following which the patient regained uncorrected distance visual acuity of 20/20. To our knowledge, this is the first case in which an ICL was re-implanted after successful resolution of endophthalmitis. PMID- 26604236 TI - Transcatheter closure of direct right pulmonary artery to left atrial communication using vascular plug. AB - A direct right pulmonary artery to left atrial fistula is a rare congenital condition in which patients usually present with isolated cyanosis in the absence of abnormal cardiovascular findings. We report the percutaneous closure of such a defect in a young woman who presented with severe cyanosis. This was achieved without making a conventional venovenous loop and was performed using an Amplatzer vascular plug. We believe, in patients with a suitable anatomy, closure with vascular plug without a venovenous loop should be the method of choice for treating this malady in view of the technical ease. PMID- 26604237 TI - Persistent thrombocytopaenia in a young man with splenomegaly, rebound thrombocytosis after splenectomy and subsequent pulmonary embolism: splenic littoral cell angioma and associated events. AB - Littoral cell angioma (LCA) is a rare endothelial cell neoplasm in the spleen. Although many cases of LCA are asymptomatic, some present with signs and symptoms related to splenomegaly, whereas others manifest with haematological abnormalities, including anaemia and/or thrombocytopaenia (ie, hypersplenism). We report a case of LCA presenting with chronic thrombocytopaenia, probably due to splenic sequestration of platelets or phagocytosis of platelets by neoplastic cells. Following therapeutic splenectomy, the patient suffered from a marked rebound thrombocytosis and subsequently developed pulmonary embolisms. He was treated with anticoagulant therapy combined with antiplatelet therapy, and his symptoms were quickly resolved. This case emphasises an exclusion of primary splenic disorders in patients with chronic thrombocytopaenia, especially in those with splenomegaly and the contemplation of thromboembolism prophylaxis postsplenectomy. PMID- 26604238 TI - Interhemispheric epidermoid cyst. PMID- 26604239 TI - Seizures with an atypical aetiology in an elderly patient: Eagle's syndrome--how does one treat it? AB - Onset of epilepsy can occur at any age, but it is relatively rare in the elderly. Late onset epilepsy is usually secondary to stroke, tumour, trauma or neurodegenerative disorders. A 62-year-old Indian woman presented with frequent drop attacks sometimes leading to unconsciousness and, rarely, associated with seizure. Her epilepsy work up was unremarkable. As the disease progressed, she was diagnosed as having idiopathic epilepsy, syncope or pseudo-seizure, on different occasions, and was treated at length with no response. Finally, detailed history-taking revealed her as having glossopharyngeal neuralgia leading to syncope and seizures. She subsequently improved. In clinical practice, such rare entities should also be considered for proper management of patients' ailments. PMID- 26604240 TI - Filarial hydropneumothorax: a strange journey. AB - Filarial infection can have varied manifestations, but hydropneumothorax at presentation has not yet been reported. A 28-year-old man presented to our hospital with heaviness of the left chest for the past 10 days, which was preceded by a sudden, short stabbing pain in the left chest after straining. Chest X-ray revealed left-sided hydropneumothorax. A peripheral blood picture revealed significant eosinophilia. A pleural fluid report also showed eosinophilia and a few motile microfilaria of Wuchereria bancrofti. Microfilaria was also documented in peripheral blood. There was no evidence of other organ system involvement. The patient was diagnosed with 'Filarial Hydropneumothorax'. After treatment with a temporary chest drain and oral diethylcarbamazine citrate, there was dramatic relief of symptoms and radiological improvement. The patient has been symptom free with no features of recurrence through 8 months of follow up. PMID- 26604241 TI - Comparison of serological responses to single-dose azithromycin (2 g) versus benzathine penicillin G in the treatment of early syphilis in HIV-infected patients in an area of low prevalence of macrolide-resistant Treponema pallidum infection. AB - OBJECTIVES: Effectiveness of single-dose azithromycin (2 g) in the treatment of early syphilis among HIV-infected patients has rarely been evaluated in the era of combination ART. METHODS: Consecutive HIV-infected patients with early syphilis, who received 2 g single-dose azithromycin or 2.4 MU benzathine penicillin G, between 2007 and 2014, were prospectively observed. Genotypic resistance to macrolides was determined in Treponema pallidum isolates identified from clinical specimens using PCR assays. Rapid plasma reagin (RPR) titres were determined at baseline and every 3 months after treatment. Primary outcome was a decline of RPR titre by >=4-fold at 12 months after treatment. RESULTS: During the study period, 162 HIV-infected patients with early syphilis received benzathine penicillin G and 237 patients received azithromycin. At 12 months follow-up, the serological response rate for penicillin and azithromycin groups was 61.1% and 56.5% (P = 0.41), respectively; respective response rate was 61.1% and 65.9% (P = 0.49) if we only included patients infected with T. pallidum not harbouring macrolide resistance in the azithromycin group. In multivariate analysis, RPR titres >=1:32 (OR 2.56; 95% CI 1.55-4.21) and prior syphilis (OR 0.54; 95% CI 0.35-0.81) were predictors of serological response. Most common adverse effects of azithromycin included diarrhoea (52.7%), nausea (22.4%), abdominal pain (18.6%), bloating (17.7%) and lassitude/somnolence (27.4%). CONCLUSIONS: In the setting of a low prevalence of macrolide-resistant T. pallidum, 2 g single-dose azithromycin achieved a similar serological response to benzathine penicillin G in HIV-infected patients with early syphilis. Major adverse effects of azithromycin were gastrointestinal symptoms and lassitude/somnolence. PMID- 26604242 TI - Description of an erm(B)-carrying Campylobacter coli isolate in Europe. PMID- 26604244 TI - beta Adrenergic Receptor Kinase C-Terminal Peptide Gene-Therapy Improves beta2 Adrenergic Receptor-Dependent Neoangiogenesis after Hindlimb Ischemia. AB - After hindlimb ischemia (HI), increased catecholamine levels within the ischemic muscle can cause dysregulation of beta2-adrenergic receptor (beta2AR) signaling, leading to reduced revascularization. Indeed, in vivo beta2AR overexpression via gene therapy enhances angiogenesis in a rat model of HI. G protein-coupled receptor kinase 2 (GRK2) is a key regulator of betaAR signaling, and beta adrenergic receptor kinase C-terminal peptide (betaARKct), a peptide inhibitor of GRK2, has been shown to prevent betaAR down-regulation and to protect cardiac myocytes and stem cells from ischemic injury through restoration of beta2AR protective signaling (i.e., protein kinase B/endothelial nitric oxide synthase). Herein, we tested the potential therapeutic effects of adenoviral-mediated betaARKct gene transfer in an experimental model of HI and its effects on betaAR signaling and on endothelial cell (EC) function in vitro. Accordingly, in this study, we surgically induced HI in rats by femoral artery resection (FAR). Fifteen days of ischemia resulted in significant betaAR down-regulation that was paralleled by an approximately 2-fold increase in GRK2 levels in the ischemic muscle. Importantly, in vivo gene transfer of the betaARKct in the hindlimb of rats at the time of FAR resulted in a marked improvement of hindlimb perfusion, with increased capillary and betaAR density in the ischemic muscle, compared with control groups. The effect of betaARKct expression was also assessed in vitro in cultured ECs. Interestingly, ECs expressing the betaARKct fenoterol, a beta2AR agonist, induced enhanced beta2AR proangiogenic signaling and increased EC function. Our results suggest that betaARKct gene therapy and subsequent GRK2 inhibition promotes angiogenesis in a model of HI by preventing ischemia-induced beta2AR down-regulation. PMID- 26604243 TI - Specific gyrA gene mutations predict poor treatment outcome in MDR-TB. AB - OBJECTIVES: Mutations in the gyrase genes cause fluoroquinolone resistance in Mycobacterium tuberculosis. However, the predictive value of these markers for clinical outcomes in patients with MDR-TB is unknown to date. The objective of this study was to determine molecular markers and breakpoints predicting second line treatment outcomes in M. tuberculosis patients treated with fourth generation fluoroquinolones. METHODS: We analysed treatment outcome data in relation to the gyrA and gyrB sequences and MICs of ofloxacin, gatifloxacin and moxifloxacin for pretreatment M. tuberculosis isolates from 181 MDR-TB patients in Bangladesh whose isolates were susceptible to injectable drugs. RESULTS: The gyrA 90Val, 94Gly and 94Ala mutations were most frequent, with the highest resistance levels for 94Gly mutants. Increased pretreatment resistance levels (>2 mg/L), related to specific mutations, were associated with lower cure percentages, with no cure in patients whose isolates were resistant to gatifloxacin at 4 mg/L. Any gyrA 94 mutation, except 94Ala, predicted a significantly lower proportion of cure compared with all other gyrA mutations taken together (all non-94 mutants + 94Ala) [OR = 4.3 (95% CI 1.4-13.0)]. The difference in treatment outcome was not explained by resistance to the other drugs. CONCLUSIONS: Our study suggests that gyrA mutations at position 94, other than Ala, predict high-level resistance to gatifloxacin and moxifloxacin, as well as poor treatment outcome, in MDR-TB patients in whom an injectable agent is still effective. PMID- 26604246 TI - Imaging Characteristics of Growing and Ruptured Vertebrobasilar Non-Saccular and Dolichoectatic Aneurysms. AB - BACKGROUND AND PURPOSE: Vertebrobasilar, nonsaccular, and dolichoectatic aneurysms generally have a poor natural history. We performed a study examining the natural history of vertebrobasilar, nonsaccular, and dolichoectatic aneurysms receiving serial imaging and studied imaging characteristics associated with growth and rupture. METHODS: We included all vertebrobasilar dolichoectatic, fusiform, and transitional aneurysms with serial imaging follow-up seen at our institution over a 15-year period. Two radiologists and a neurologist evaluated aneurysms for size, type, mural T1 signal, mural thrombus, daughter sac, mass effect, and tortuosity. Primary outcomes were aneurysm growth or rupture. Univariate analysis was performed with chi-squared tests for categorical variables and Student's t test or analysis of variance for continuous variables. Multivariate logistic regression analysis was performed to identify variables independently associated with aneurysm growth or rupture. RESULTS: One hundred and fifty-two patients with 542 patient-years (mean 3.6+/-3.5 years) of imaging follow-up were included. Aneurysms were fusiform in 45 cases (29.6%), dolichoectatic in 75 cases (49.3%), and transitional in 32 cases (21.1%). Thirty five aneurysms (23.0%) grew (growth rate=6.5%/year). Eight aneurysms (5.3%) ruptured (rupture rate=1.5%/year). Variables associated with growth and rupture on univariate analysis were size >10 mm (57.6% versus 16.0%, P<0.0001), mural T1 signal (39.7% versus 16.3%, P=0.001), daughter sac (56.3% versus 21.3%), and mural thrombus (45.5% versus 13.4%, P<0.0001). 26.7% of fusiform aneurysms, 9.3% of dolichoectatic aneurysms, and 59.4% of transitional aneurysms grew or ruptured (P<0.0001). The only variable independently associated with rupture was transitional morphology (P=0.003). CONCLUSIONS: Vertebrobasilar, nonsaccular, and dolichoectatic aneurysms are associated with a poor natural history with high growth and rupture rates. Further research is needed to determine the best treatments for this disease. PMID- 26604245 TI - Factors Influencing the Central Nervous System Distribution of a Novel Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitor GSK2126458: Implications for Overcoming Resistance with Combination Therapy for Melanoma Brain Metastases. AB - Small molecule inhibitors targeting the mitogen-activated protein kinase pathway (Braf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) have had success in extending survival for patients with metastatic melanoma. Unfortunately, resistance may occur via cross-activation of alternate signaling pathways. One approach to overcome resistance is to simultaneously target the phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway. Recent reports have shown that GSK2126458 [2,4-difluoro-N-(2-methoxy-5 (4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl) benzenesulfonamide], a dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor, can overcome acquired resistance to Braf and mitogen-activated protein kinase kinase inhibitors in vitro. These resistance mechanisms may be especially important in melanoma brain metastases because of limited drug delivery across the blood-brain barrier. The purpose of this study was to investigate factors that influence the brain distribution of GSK2126458 and to examine the efficacy of GSK2126458 in a novel patient-derived melanoma xenograft (PDX) model. Both in vitro and in vivo studies indicate that GSK2126458 is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), two dominant active efflux transporters in the blood-brain barrier. The steady-state brain distribution of GSK2126458 was 8-fold higher in the P-gp/Bcrp knockout mice compared with the wild type. We also observed that when simultaneously infused to steady state, GSK212658, dabrafenib, and trametinib, a rational combination to overcome mitogen-activated protein kinase inhibitor resistance, all had limited brain distribution. Coadministration of elacridar, a P-gp/Bcrp inhibitor, increased the brain distribution of GSK2126458 by approximately 7-fold in wild-type mice. In the PDX model, GSK2126458 showed efficacy in flank tumors but was ineffective in intracranial melanoma. These results show that P-gp and Bcrp are involved in limiting the brain distribution of GSK2126458 and provide a rationale for the lack of efficacy of GSK2126458 in the orthotopic PDX model. PMID- 26604248 TI - Large Volumes of Critically Hypoperfused Penumbral Tissue Do Not Preclude Good Outcomes After Complete Endovascular Reperfusion: Redefining Malignant Profile. AB - BACKGROUND AND PURPOSE: Acute ischemic stroke patients with large volumes of severe hypoperfusion (Tmax>10 s>100 mL) on magnetic resonance imaging have a higher likelihood of intracranial hemorrhage and poor outcomes after reperfusion. We aim to evaluate the impact of the extent of Tmax>10 s CTP lesions in patients undergoing successful treatment. METHODS: Retrospective database review of endovascular acute ischemic stroke treatment between September 2010 and March 2015 for patients with anterior circulation occlusions with baseline RAPID CTP and full reperfusion (mTICI 3). The primary outcome was the impact of the Tmax>10 s lesion spectrum on infarct growth. Secondary safety and efficacy outcomes included parenchymal hematomas and good clinical outcomes (90-day modified Rankin Scale score, 0-2). RESULTS: Of 684 treated patients, 113 patients fit the inclusion criteria. Tmax>10 s>100 mL patients (n=37) had significantly higher baseline National Institutes of Health Stroke Scale (20.7+/-3.8 versus 17.0+/ 5.9; P<0.01), more internal carotid artery terminus occlusions (29% versus 9%; P=0.02), and larger baseline (38.6+/-29.6 versus 11.7+/-15.8 mL; P<0.01) and final (60.7+/-60.0 versus 29.4+/-33.9 mL; P<0.01) infarct volumes when compared with patients without Tmax>10 s>100 mL (n=76); however, the 2 groups were otherwise well balanced. There were no significant differences in infarct growth (22.1+/-51.6 versus 17.8+/-32.4 mL; P=0.78), severe intracranial hemorrhage (PH2: 2% versus 4%; P=0.73), good outcomes (90-day mRS score, 0-2: 56% versus 59%; P=0.83), or 90-day mortality (16% versus 7%; P=0.28). On multivariate analysis, only baseline National Institutes of Health Stroke Scale (odds ratio, 1.19; 95% confidence interval, 1.06-1.34; P<0.01) and baseline infarct core volume (odds ratio, 1.05; 95% confidence interval, 1.02-1.08; P<0.01) were independently associated with Tmax>10 s>100 mL. There was no association between Tmax>10 s>100 mL with any PH, good outcome, or infarct growth. CONCLUSIONS: In the setting of limited baseline ischemic cores, large Tmax>10 s lesions on computed tomographic perfusion do not seem to be associated with a higher risk of parenchymal hematomas and do not preclude good outcomes in patients undergoing endovascular reperfusion with contemporary technology. PMID- 26604249 TI - Socioeconomic Conditions in Childhood, Adolescence, and Adulthood and the Risk of Ischemic Stroke. AB - BACKGROUND AND PURPOSE: The association between socioeconomic status in adulthood and the risk of stroke is well established; however, the independent effects of socioeconomic conditions in different life phases are less understood. METHODS: Within a population-based stroke registry, we performed a case-control study with 470 ischemic stroke patients (cases) aged 18 to 80 years and 809 age- and sex matched stroke-free controls, randomly selected from the population (study period October 2007 to April 2012). We assessed socioeconomic conditions in childhood, adolescence, and adulthood, and developed a socioeconomic risk score for each life period. RESULTS: Socioeconomic conditions were less favorable in cases regarding paternal profession, living conditions and estimated family income in childhood, school degree, and vocational training in adolescence, last profession, marital status and periods of unemployment in adulthood. Using tertiles of score values, low socioeconomic conditions during childhood (odds ratio 1.77; 95% confidence interval 1.20-2.60) and adulthood (odds ratio 1.74; 95% confidence interval 1.16-2.60) but not significantly during adolescence (odds ratio 1.64; 95% confidence interval 0.97-2.78) were associated with stroke risk after adjustment for risk factors and other life stages. Medical risk factors attenuated the effect of childhood conditions, and lifestyle factors reduced the effect of socioeconomic conditions in adolescence and adulthood. Unfavorable childhood socioeconomic conditions were particularly associated with large artery atherosclerotic stroke in adulthood (odds ratio 2.13; 95% confidence interval 1.24-3.67). CONCLUSIONS: This study supports the hypothesis that unfavorable childhood socioeconomic conditions are related to ischemic stroke risk, independent of established risk factors and socioeconomic status in adulthood, and fosters the idea that stroke prevention needs to begin early in life. PMID- 26604247 TI - Different Antiplatelet Strategies in Patients With New Ischemic Stroke While Taking Aspirin. AB - BACKGROUND AND PURPOSE: Selecting among different antiplatelet strategies when patients experience a new ischemic stroke while taking aspirin is a common clinical challenge, currently addressed by a paucity of data. METHODS: This study is an analysis of a prospective multicenter stroke registry database from 14 hospitals in South Korea. Patients with acute noncardioembolic stroke, who were taking aspirin for prevention of ischemic events at the time of onset of stroke, were enrolled. Study subjects were divided into 3 groups according to the subsequent antiplatelet therapy strategy pursued; maintaining aspirin monotherapy (MA group), switching aspirin to nonaspirin antiplatelet agents (SA group), and adding another antiplatelet agent to aspirin (AA group). The primary study end point was the composite of stroke (ischemic and hemorrhagic), myocardial infarction, and vascular death up to 1 year after stroke onset. RESULTS: A total of 1172 patients were analyzed for this study. Antiplatelet strategies pursued in study patients were MA group in 212 (18.1%), SA group in 246 (21.0%), and AA group in 714 (60.9%). The Cox proportional hazards regression analysis showed that, compared with the MA group, there was a reduction in the composite vascular event primary end point in the SA group (hazard ratio, 0.50; 95% confidence interval, 0.27-0.92; P=0.03) and in the AA group (hazard ratio, 0.40; 95% confidence interval, 0.24-0.66; P<0.001). CONCLUSIONS: This study showed that, compared with maintaining aspirin, switching to or adding alternative antiplatelet agents may be better in preventing subsequent vascular events in patients who experienced a new ischemic stroke while taking aspirin. PMID- 26604250 TI - D-4F Decreases White Matter Damage After Stroke in Mice. AB - BACKGROUND AND PURPOSE: Stroke-induced neuroinflammation and white matter damage are associated with neurological deficits. Whether D-4F, an apolipoprotein A-I mimetic peptide, treatment of stroke decreases neuroinflammation and white matter damage and improves functional outcome has not been investigated. METHODS: Adult male C57BL/6 mice were subjected to permanent middle cerebral artery occlusion (MCAo) and were orally administered saline as a vehicle control and different doses of D-4F (2, 4, 8, 16, or 32 mg/kg) starting at 2 h after MCAo and daily until euthanized at 7 days after MCAo. D-4F treatment did not alter the blood levels of high-density lipoprotein, total cholesterol, triglyceride, blood-brain barrier leakage, and infarction volume compared with control group. RESULTS: D-4F (16 mg/kg) treatment of stroke significantly improved functional outcome, increased the white matter density and the number of oligodendrocyte progenitor cells in the ischemic boundary zone of the ipsilateral striatum, and increased myelin basic protein, insulin-like growth factor-1 (IGF1), but decreased inflammatory factor Toll-like receptor-4 and tumor necrosis factor-alpha expression in the ischemic brain 7 days after MCAo (P<0.05, n=11/group). The neurite/axonal outgrowth in primary cultured neurons was significantly increased when treated with D-4F (100 ng/mL) and IGF1 (100 ng/mL) compared with the nontreatment control. Inhibition of IGF1 significantly attenuated D-4F or IGF1 treatment-induced axonal outgrowth. D-4F-treatment did not increase oligodendrocyte-progenitor cell proliferation but decreased oligodendrocyte progenitor cell death. CONCLUSIONS: D-4F treatment initiated 2 h after MCAo decreases neuroinflammation and white matter damage and improves functional outcome after stroke. D-4F-induced increase in IGF1 may contribute to D-4F induced neurite/axonal outgrowth after stroke. PMID- 26604251 TI - An International Standard Set of Patient-Centered Outcome Measures After Stroke. AB - BACKGROUND AND PURPOSE: Value-based health care aims to bring together patients and health systems to maximize the ratio of quality over cost. To enable assessment of healthcare value in stroke management, an international standard set of patient-centered stroke outcome measures was defined for use in a variety of healthcare settings. METHODS: A modified Delphi process was implemented with an international expert panel representing patients, advocates, and clinical specialists in stroke outcomes, stroke registers, global health, epidemiology, and rehabilitation to reach consensus on the preferred outcome measures, included populations, and baseline risk adjustment variables. RESULTS: Patients presenting to a hospital with ischemic stroke or intracerebral hemorrhage were selected as the target population for these recommendations, with the inclusion of transient ischemic attacks optional. Outcome categories recommended for assessment were survival and disease control, acute complications, and patient-reported outcomes. Patient-reported outcomes proposed for assessment at 90 days were pain, mood, feeding, selfcare, mobility, communication, cognitive functioning, social participation, ability to return to usual activities, and health-related quality of life, with mobility, feeding, selfcare, and communication also collected at discharge. One instrument was able to collect most patient-reported subdomains (9/16, 56%). Minimum data collection for risk adjustment included patient demographics, premorbid functioning, stroke type and severity, vascular and systemic risk factors, and specific treatment/care-related factors. CONCLUSIONS: A consensus stroke measure Standard Set was developed as a simple, pragmatic method to increase the value of stroke care. The set should be validated in practice when used for monitoring and comparisons across different care settings. PMID- 26604253 TI - Dynamic Angiographic Nature of Cerebral Mycotic Aneurysms in Patients With Infective Endocarditis. PMID- 26604252 TI - Role of Vascular Disease in Alzheimer-Like Progressive Cognitive Impairment. PMID- 26604254 TI - Role of Prestroke Vascular Pathology in Long-Term Prognosis After Stroke: The Rotterdam Study. AB - BACKGROUND AND PURPOSE: Mortality after stroke remains high for years, mostly because of cardiovascular causes. Given that cardiovascular pathology plays an important role in causing the initial stroke, such prestroke pathology might also influence the prognosis after stroke. Within the population-based Rotterdam Study, we examined the proportion of deaths after stroke that are attributable to pre-existent cardiovascular risk factors before stroke (the population attributable risk). METHODS: We examined 1237 patients with first-ever stroke and 4928 stroke-free participants (between 1990 and 2012), matched on age, sex, examination round, and stroke date (index date). Cardiovascular risk factors measured on ~4 years before index date were used as determinants. Participants were continuously followed up for mortality (~6 years) after the index date. We calculated separate and combined population attributable risk of hypertension, total cholesterol, high-density lipoprotein-cholesterol, body mass index, diabetes mellitus, smoking, transient ischemic attack, and atrial fibrillation. RESULTS: Nine hundred and nineteen patients with stroke and 2654 stroke-free participants died. The combined population attributable risk in patients with stroke was 27% (95% confidence interval, 14%-45%) and in stroke-free participants was 19% (95% confidence interval, 12%-29%). Population attributable risks of diabetes mellitus, smoking, and atrial fibrillation were higher in patients with stroke than in the reference group because of a higher prevalence of risk factors. In addition, people with atrial fibrillation and stroke had a higher hazard ratio for death than those with only atrial fibrillation. CONCLUSIONS: One quarter of deaths after stroke could theoretically be prevented with rigorous cardiovascular prevention and treatment, but this should preferably start before stroke occurrence. In addition, research into factors explaining the remaining deaths needs to be encouraged. PMID- 26604255 TI - Incidence of acute mountain sickness in UK Military Personnel on Mount Kenya. AB - BACKGROUND: Acute mountain sickness (AMS) is a common problem of trekkers to high altitude. The UK military train at high altitude through adventurous training (AT) or as exercising troops. The ascent of Point Lenana at 4985 m on Mount Kenya is frequently attempted on AT. This study sought to establish the incidence of AMS within this population, to aid future planning for military activities at altitude. METHODS: A voluntary questionnaire was distributed to all British Army Training Unit Kenya based expeditions attempting to ascend Mount Kenya during the period from February to April 2014. The questionnaire included twice daily Lake Louise and Borg (perceived exertion scale) self-scoring. All expeditions were planned around a 5-day schedule, which included reserve time for acclimatisation, illness and inclement weather. RESULTS: Data were collected on 47 participants, 70% of whom reached the summit of Point Lenana. 62% (29/47) self-reported AMS (defined as Lake Louise score (LLS) >=3) on at least one occasion during the ascent, and 34% (10/29) suffered severe AMS (LLS >=6). Those who attempted the climb within 2 weeks of arrival in Kenya had a higher incidence of AMS (12/15 (80%) vs 17/32 (53%), p=0.077). Participants recording a high Borg score were significantly more likely to develop AMS (16/18 vs 9/21, p=0.003). CONCLUSIONS: This represents the first informative dataset for Mount Kenya ascents and altitude. The incidence of AMS during AT on Mount Kenya using this ascent profile is high. Adapting the current ascent profile, planning the ascent after time in country and reducing perceived exertion during the trek may reduce the incidence of AMS. PMID- 26604256 TI - A Quantitative System-Scale Characterization of the Metabolism of Clostridium acetobutylicum. AB - Engineering industrial microorganisms for ambitious applications, for example, the production of second-generation biofuels such as butanol, is impeded by a lack of knowledge of primary metabolism and its regulation. A quantitative system scale analysis was applied to the biofuel-producing bacterium Clostridium acetobutylicum, a microorganism used for the industrial production of solvent. An improved genome-scale model, iCac967, was first developed based on thorough biochemical characterizations of 15 key metabolic enzymes and on extensive literature analysis to acquire accurate fluxomic data. In parallel, quantitative transcriptomic and proteomic analyses were performed to assess the number of mRNA molecules per cell for all genes under acidogenic, solventogenic, and alcohologenic steady-state conditions as well as the number of cytosolic protein molecules per cell for approximately 700 genes under at least one of the three steady-state conditions. A complete fluxomic, transcriptomic, and proteomic analysis applied to different metabolic states allowed us to better understand the regulation of primary metabolism. Moreover, this analysis enabled the functional characterization of numerous enzymes involved in primary metabolism, including (i) the enzymes involved in the two different butanol pathways and their cofactor specificities, (ii) the primary hydrogenase and its redox partner, (iii) the major butyryl coenzyme A (butyryl-CoA) dehydrogenase, and (iv) the major glyceraldehyde-3-phosphate dehydrogenase. This study provides important information for further metabolic engineering of C. acetobutylicum to develop a commercial process for the production of n-butanol. IMPORTANCE: Currently, there is a resurgence of interest in Clostridium acetobutylicum, the biocatalyst of the historical Weizmann process, to produce n-butanol for use both as a bulk chemical and as a renewable alternative transportation fuel. To develop a commercial process for the production of n-butanol via a metabolic engineering approach, it is necessary to better characterize both the primary metabolism of C. acetobutylicum and its regulation. Here, we apply a quantitative system-scale analysis to acidogenic, solventogenic, and alcohologenic steady-state C. acetobutylicum cells and report for the first time quantitative transcriptomic, proteomic, and fluxomic data. This approach allows for a better understanding of the regulation of primary metabolism and for the functional characterization of numerous enzymes involved in primary metabolism. PMID- 26604257 TI - Memory of Germinant Stimuli in Bacterial Spores. AB - Bacterial spores, despite being metabolically dormant, possess the remarkable capacity to detect nutrients and other molecules in their environment through a biochemical sensory apparatus that can trigger spore germination, allowing the return to vegetative growth within minutes of exposure of germinants. We demonstrate here that bacterial spores of multiple species retain memory of transient exposures to germinant stimuli that can result in altered responses to subsequent exposure. The magnitude and decay of these memory effects depend on the pulse duration as well as on the separation time, incubation temperature, and pH values between the pulses. Spores of Bacillus species germinate in response to nutrients that interact with germinant receptors (GRs) in the spore's inner membrane, with different nutrient types acting on different receptors. In our experiments, B. subtilis spores display memory when the first and second germinant pulses target different receptors, suggesting that some components of spore memory are downstream of GRs. Furthermore, nonnutrient germinants, which do not require GRs, exhibit memory either alone or in combination with nutrient germinants, and memory of nonnutrient stimulation is found to be more persistent than that induced by GR-dependent stimuli. Spores of B. cereus and Clostridium difficile also exhibit germination memory, suggesting that memory may be a general property of bacterial spores. These observations along with experiments involving strains with mutations in various germination proteins suggest a model in which memory is stored primarily in the metastable states of SpoVA proteins, which comprise a channel for release of dipicolinic acid, a major early event in spore germination. IMPORTANCE: Cellular memory is defined as a sustained response to a transient environmental stimulus, and yet its generation and storage have not been described in bacterial spores. We demonstrate here that bacterial spores of multiple species retain memory of transient exposures to germinant stimuli that can result in altered responses to subsequent exposure. Memory was induced by activation of germinant receptors (GRs) or by GR-independent germinants and was accessed by both GR-dependent and GR-independent germinants. Analysis of effects on memory of exposure to GR-dependent and GR-independent germinants as well as in spores lacking various germination proteins suggests a model in which memory is stored primarily in metastable states of SpoVA proteins which comprise a channel for release of spore dipicolinic acid. Spore memory can also significantly reduce the concentration of nutrient germinants necessary to trigger germination, and this may be used to respond to low levels of nutrient germinants. PMID- 26604258 TI - Evolutionary Selection on Barrier Activity: Bar1 Is an Aspartyl Protease with Novel Substrate Specificity. AB - Peptide-based pheromones are used throughout the fungal kingdom for coordinating sexual responses between mating partners. Here, we address the properties and function of Bar1, an aspartyl protease that acts as a "barrier" and antagonist to pheromone signaling in multiple species. Candida albicans Bar1 was purified and shown to exhibit preferential cleavage of native alpha pheromone over pheromones from related fungal species. This result establishes that protease substrate specificity coevolved along with changes in its pheromone target. Pheromone cleavage by Bar1 occurred between residues Thr-5 and Asn-6 in the middle of the tridecapeptide sequence. Surprisingly, proteolytic activity was independent of the amino acid residues present at the scissile bond and instead relied on residues at the C terminus of alpha pheromone. Unlike most aspartyl proteases, Bar1 also exhibited a near-neutral pH optimum and was resistant to the class-wide inhibitor pepstatin A. In addition, genetic analysis was performed on C. albicans BAR1 and demonstrated that the protease not only regulates endogenous pheromone signaling but also can limit interspecies pheromone signaling. We discuss these findings and propose that the unusual substrate specificity of Bar1 is a consequence of its coevolution with the alpha pheromone receptor Ste2 for their shared peptide target. IMPORTANCE: Pheromones are important for intraspecies communication across the tree of life. In the fungal kingdom, extracellular proteases play a key role in antagonizing pheromone signaling in multiple species. This study examines the properties and function of Candida albicans Bar1, an aspartyl protease that cleaves and thereby inactivates alpha pheromone. We demonstrate that Bar1 plays important roles in regulating both intra- and interspecies pheromone signaling. The fungal protease shows preferential activity on the endogenous pheromone, but, surprisingly, cleavage activity is dependent on amino acid residues distal to the scissile bond. We propose that the unusual substrate specificity of Bar1 is a direct result of coevolution with Ste2, the receptor for alpha pheromone, for recognition of the same peptide target. The novel specificity of Bar1 reveals the complex forces shaping the evolution of mating pathways in fungi and uncovers a protease with potentially important applications in the biotechnology industry. PMID- 26604260 TI - Cigarette smokers' classification of tobacco products. AB - INTRODUCTION: Cigarette consumption has declined in the USA. However, cigar consumption has increased. This may be due in part to some cigarette smokers switching to filtered cigars as a less expensive substitute for cigarettes. Additionally, some cigarette smokers may perceive and consume little filtered cigars as cigarettes. The purpose of this study was to determine how cigarette smokers classify tobacco products when presented with photographs of those products. METHODS: An online survey was conducted with a sample of 344 self identified cigarette smokers. Respondents were presented with pictures of various types of tobacco products, both with and without packaging, and then asked to categorise them as either a cigarette, little cigar, cigarillo, cigar or machine injected roll-your-own cigarette (RYO). Respondents were also asked about their tobacco use and purchasing behaviour. RESULTS: Overall, respondents had difficulty distinguishing between cigarettes, little cigars, cigarillos and RYO. When presented with images of the products without packaging, 93% of respondents identified RYO as a cigarette, while 42% identified a little cigar as a cigarette. Additionally, respondents stated that they would consider purchasing little cigars as substitutes for cigarettes because of the price advantage. CONCLUSIONS: The results of this survey suggest that when presented with photographs of tobacco products, large proportions of current smokers were unable to differentiate between cigarettes, little cigars, cigarillos, RYO and cigars. Findings have implications for existing public health efforts targeting cigarette smokers, and underscore the need to review current definitions of tobacco products and federal excise taxes on such products. PMID- 26604259 TI - Phylogenetic Distribution of CRISPR-Cas Systems in Antibiotic-Resistant Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is an antibiotic-refractory pathogen with a large genome and extensive genotypic diversity. Historically, P. aeruginosa has been a major model system for understanding the molecular mechanisms underlying type I clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR associated protein (CRISPR-Cas)-based bacterial immune system function. However, little information on the phylogenetic distribution and potential role of these CRISPR-Cas systems in molding the P. aeruginosa accessory genome and antibiotic resistance elements is known. Computational approaches were used to identify and characterize CRISPR-Cas systems within 672 genomes, and in the process, we identified a previously unreported and putatively mobile type I-C P. aeruginosa CRISPR-Cas system. Furthermore, genomes harboring noninhibited type I-F and I-E CRISPR-Cas systems were on average ~300 kb smaller than those without a CRISPR Cas system. In silico analysis demonstrated that the accessory genome (n = 22,036 genes) harbored the majority of identified CRISPR-Cas targets. We also assembled a global spacer library that aided the identification of difficult-to characterize mobile genetic elements within next-generation sequencing (NGS) data and allowed CRISPR typing of a majority of P. aeruginosa strains. In summary, our analysis demonstrated that CRISPR-Cas systems play an important role in shaping the accessory genomes of globally distributed P. aeruginosa isolates. IMPORTANCE: P. aeruginosa is both an antibiotic-refractory pathogen and an important model system for type I CRISPR-Cas bacterial immune systems. By combining the genome sequences of 672 newly and previously sequenced genomes, we were able to provide a global view of the phylogenetic distribution, conservation, and potential targets of these systems. This analysis identified a new and putatively mobile P. aeruginosa CRISPR-Cas subtype, characterized the diverse distribution of known CRISPR-inhibiting genes, and provided a potential new use for CRISPR spacer libraries in accessory genome analysis. Our data demonstrated the importance of CRISPR-Cas systems in modulating the accessory genomes of globally distributed strains while also providing substantial data for subsequent genomic and experimental studies in multiple fields. Understanding why certain genotypes of P. aeruginosa are clinically prevalent and adept at horizontally acquiring virulence and antibiotic resistance elements is of major clinical and economic importance. PMID- 26604261 TI - Global Profiling of Huntingtin-associated protein E (HYPE)-Mediated AMPylation through a Chemical Proteomic Approach. AB - AMPylation of mammalian small GTPases by bacterial virulence factors can be a key step in bacterial infection of host cells, and constitutes a potential drug target. This posttranslational modification also exists in eukaryotes, and AMP transferase activity was recently assigned to HYPE Filamentation induced by cyclic AMP domain containing protein (FICD) protein, which is conserved from Caenorhabditis elegans to humans. In contrast to bacterial AMP transferases, only a small number of HYPE substrates have been identified by immunoprecipitation and mass spectrometry approaches, and the full range of targets is yet to be determined in mammalian cells. We describe here the first example of global chemoproteomic screening and substrate validation for HYPE-mediated AMPylation in mammalian cell lysate. Through quantitative mass-spectrometry-based proteomics coupled with novel chemoproteomic tools providing MS/MS evidence of AMP modification, we identified a total of 25 AMPylated proteins, including the previously validated substrate endoplasmic reticulum (ER) chaperone BiP (HSPA5), and also novel substrates involved in pathways of gene expression, ATP biosynthesis, and maintenance of the cytoskeleton. This dataset represents the largest library of AMPylated human proteins reported to date and a foundation for substrate-specific investigations that can ultimately decipher the complex biological networks involved in eukaryotic AMPylation. PMID- 26604262 TI - HIV and the right not to know. AB - It is a tenet of the prevailing ethic in medicine that competent adults have the 'right to know' information necessary to make informed decisions about their healthcare. Whether there is a 'right not to know' unwanted information is more hotly debated. When deciding whether or not to override a competent adult's desire not to know his/her HIV result, a desire to respect patient autonomy can be seen to pull in both directions. We thus conclude that there is not a very strong presumption on the side of non-disclosure but rather the adult's interest in not knowing must be weighed against the potential harms and benefits of disclosure for both the individual and others. This does not, however, negate the fact that patients retain a right to refuse an HIV test and this is so even where issues of bodily integrity are not at stake. This implies that explicit consent should still be sought for HIV testing, at least where there is some possibility that the patient may refuse, or want more information, if given the chance. PMID- 26604264 TI - Immunosuppression in a Comparative Study of Feline Leukemia Virus Vaccines. PMID- 26604267 TI - ADHD in the United Kingdom: Regional and Socioeconomic Variations in Incidence Rates Amongst Children and Adolescents (2004-2013). AB - OBJECTIVE: To describe the incidence and distribution of ADHD within the United Kingdom, and to examine whether there was any association between ADHD incidence and socioeconomic deprivation. METHOD: The study used data from the Clinical Practice Research Datalink (CPRD). Patients diagnosed with ADHD before the age of 19 between January 1, 2004 and December 31, 2013 were stratified according to the region in which their general practice was based. Practice Index of Multiple Deprivation (IMD) score was used as a surrogate measure of patients' deprivation status. RESULTS: ADHD incidence was relatively stable between 2004 and 2013, but peaked in the last 2 years studied. Statistically significant ( p <= .05) differences in incidence were observed between U.K. regions. In almost every year studied, incidence rates were highest among the most deprived patients and lowest among the least deprived patients. CONCLUSION: In the United Kingdom, ADHD may be associated with socioeconomic deprivation. PMID- 26604265 TI - Reply to "Immunosuppression in a Comparative Study of Feline Leukemia Virus Vaccines". PMID- 26604268 TI - Prevalence, Clinicopathological Characteristics, and Outcome of Human Papillomavirus-Associated Oropharyngeal Cancer in Southern Chinese Patients. AB - BACKGROUND: Although the global incidence of human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing, there is little information on southern Chinese population available. METHODS: We analyzed 207 patients which constituted 63.5% of all newly diagnosed OPSCC in Hong Kong during a 5-year period from 2005 to 2009. RESULTS: We used E6/7 mRNA as a marker of oncogenic involvement and found 20.8% (43/207) of OPSCC and 29.0% (36/124) of tonsillar SCC was associated with HPV. HPV-16 was identified in all cases except one (HPV-18). Patients with HPV-associated OPSCCs were significantly younger than HPV-negative patients (mean age: 59.8 vs. 63.9 years, P = 0.05). Multivariate analysis showed that HPV-associated OPSCC was more likely to occur in nonsmokers (39.5% vs. 15.1%, OR: 2.89, P = 0.05), nondrinkers (52.5% vs. 25.6%, OR: 2.72, P = 0.04), originate from the palatine tonsils (83.7% vs. 53.7%, OR: 3.88, P = 0.01), present with an early primary tumor (T1/2; 79.1% vs. 47.6%, OR: 3.81, P = 0.004), and exhibit basaloid differentiation (33.3% vs. 7.3%, OR: 19.74, P = 0.006). HPV positivity was an independent predictor for better prognosis for both 5-year overall and 5-year disease-specific survivals (DSS; 63.0% vs. 29.7%, HR: 0.33, P < 0.001, and 87.8% vs. 42.6%, HR: 0.16, P < 0.001, respectively). CONCLUSION: The estimated age-standardized incidence of OPSCC in Hong Kong during the period 2005-2009 was 0.12/100,000/year. IMPACT: This study has provided the most comprehensive clinical and pathologic information to date about this newly recognized disease in southern Chinese. In view of the global trend, we should anticipate and prepare for an increase in HPV-related OPSCC in southern China. PMID- 26604269 TI - Circulating DNA and Survival in Solid Tumors. AB - BACKGROUND: The ability to undertake molecular analysis to inform on prognosis and predictors of response to therapy is limited by accessibility of tissue. Measurement of total circulating free DNA (cfDNA) or circulating tumor DNA (ctDNA) in peripheral blood may allow easier access to tumor material and help to predict clinical outcomes. METHODS: A systematic review of electronic databases identified publications exploring the association between cfDNA or ctDNA and overall survival (OS) in solid tumors. HRs for OS were extracted from multivariable analyses and included in a meta-analysis. Pooled HRs were computed and weighted using generic inverse variance and random-effect modeling. For studies not reporting multivariable analyses, univariable ORs were estimated from Kaplan-Meier curves for OS at 1 and 3 years. RESULTS: Thirty-nine studies comprising 4,052 patients were included in the analysis. Detection of ctDNA was associated with a significantly worse OS in multivariable analyses [HR, 2.70; 95% confidence interval (CI), 2.02-3.61; P < 0.001). Similar results were observed in the univariable analyses at 3 and 1 year (OR, 4.83; 95% CI, 3.20-7.28; P < 0.001).There was also a statistically significant association between high total cfDNA and worse OS for studies reporting multivariable and univariate data at 3 years (HR, 1.91; 95% CI, 1.59-2.29; P < 0.001 and OR, 2.82; 95% CI, 1.93-4.13; P < 0.001, respectively). CONCLUSIONS: High levels of total cfDNA and presence of ctDNA are associated with worse survival in solid tumors. IMPACT: Circulating DNA is associated with worse outcome in solid tumors. PMID- 26604270 TI - Collecting Fecal Samples for Microbiome Analyses in Epidemiology Studies. AB - BACKGROUND: The need to develop valid methods for sampling and analyzing fecal specimens for microbiome studies is increasingly important, especially for large population studies. METHODS: Some of the most important attributes of any sampling method are reproducibility, stability, and accuracy. We compared seven fecal sampling methods [no additive, RNAlater, 70% ethanol, EDTA, dry swab, and pre/post development fecal occult blood test (FOBT)] using 16S rRNA microbiome profiling in two laboratories. We evaluated nine commonly used microbiome metrics: abundance of three phyla, two alpha-diversities, and four beta diversities. We determined the technical reproducibility, stability at ambient temperature, and accuracy. RESULTS: Although microbiome profiles showed systematic biases according to sample method and time at ambient temperature, the highest source of variation was between individuals. All collection methods showed high reproducibility. FOBT and RNAlater resulted in the highest stability without freezing for 4 days. In comparison with no-additive samples, swab, FOBT, and 70% ethanol exhibited the greatest accuracy when immediately frozen. CONCLUSIONS: Overall, optimal stability and reproducibility were achieved using FOBT, making this a reasonable sample collection method for 16S analysis. IMPACT: Having standardized method of collecting and storing stable fecal samples will allow future investigations into the role of gut microbiota in chronic disease etiology in large population studies. PMID- 26604271 TI - MicroRNA Profiles of Barrett's Esophagus and Esophageal Adenocarcinoma: Differences in Glandular Non-native Epithelium. AB - BACKGROUND: The tissue specificity and robustness of miRNAs may aid risk prediction in individuals diagnosed with Barrett's esophagus. As an initial step, we assessed whether miRNAs can positively distinguish esophageal adenocarcinoma from the precursor metaplasia Barrett's esophagus. METHODS: In a case-control study of 150 esophageal adenocarcinomas frequency matched to 148 Barrett's esophagus cases, we quantitated expression of 800 human miRNAs in formalin-fixed paraffin-embedded tissue RNA using NanoString miRNA v2. We tested differences in detection by case group using the chi(2) test and differences in expression using the Wilcoxon rank-sum test. Bonferroni-corrected statistical significance threshold was set at P < 6.25E-05. Sensitivity and specificity were assessed for the most significant miRNAs using 5-fold cross-validation. RESULTS: We observed 46 distinct miRNAs significantly increased in esophageal adenocarcinoma compared with Barrett's esophagus, 35 of which remained when restricted to T1b and T2 malignancies. Three miRNAs (miR-663b, miR-421, and miR-502-5p) were detected in >80% esophageal adenocarcinoma, but <20% of Barrett's esophagus. Seven miRNAs (miR-4286, miR-630, miR-575, miR-494, miR-320e, miR-4488, and miR-4508) exhibited the most extreme differences in expression with >5-fold increases. Using 5-fold cross-validation, we repeated feature (miR) selection and case-control prediction and computed performance criteria. Each of the five folds selected the same top 10 miRNAs, which, together, provided 98% sensitivity and 95% specificity. CONCLUSION: This study provides evidence that tissue miRNA profiles can discriminate esophageal adenocarcinoma from Barrett's esophagus. This large analysis has identified miRNAs that merit further investigation in relation to pathogenesis and diagnosis of esophageal adenocarcinoma. IMPACT: These candidate miRNAs may provide a means for improved risk stratification and more cost effective surveillance. PMID- 26604272 TI - Systemic Biomarkers in 2-Phase Antibiotic Periodontal Treatment: A Randomized Clinical Trial. AB - Accumulating evidence suggests that periodontal infections may have an impact on systemic health. In patients with untreated periodontitis, very high values for several inflammatory markers in serum are expressed simultaneously. We investigated to what extent these peak values change after nonsurgical and surgical periodontal treatment, with adjunctive antibiotics administered during the first or the second treatment phase. In a single-center, randomized, placebo controlled, and double-masked clinical trial, 80 patients with chronic or aggressive periodontitis were randomized into 2 treatment groups: group A, receiving systemic amoxicillin and metronidazole during the first, nonsurgical phase of periodontal therapy (phase 1), and group B, receiving the antibiotics during the second, surgical phase (phase 2). Serum samples were obtained at baseline (BL), 3 mo after phase 1 (M3), and 6 and 12 mo after phase 2 (M6, M12). Samples were evaluated for 15 cytokines and 9 acute-phase proteins using the Bio Plex bead array multianalyte detection system. For each analyte, peak values were defined as greater than mean +2 SD of measurements found in 40 periodontally healthy persons. Sixty-six patients showed a peak value of at least 1 analyte at BL. At M12, the number of these patients was only 36 (P = 0.0002). This decrease was stronger in group A (BL: 35, M12: 19, P = 0.0009) than in group B (BL: 31, M12: 17, P = 0.14). Twenty patients displayed peak values of at least 4 biomarkers at BL. The nonsurgical therapy delivered in the first phase reduced most of these peaks (group A, BL: 9, M3: 4, P = 0.17; group B, BL: 11, M3: 2, P = 0.01), irrespective of adjunctive antibiotics. The reductions obtained at M3 were maintained until M12 in both groups. Initial, nonsurgical periodontal therapy reduced the incidence of peak levels of inflammatory markers. Antibiotics and further surgical therapy did not enhance the effect (Clinicaltrials.gov NCT02197260). PMID- 26604273 TI - The Temporal Pole Top-Down Modulates the Ventral Visual Stream During Social Cognition. AB - The temporal pole (TP) has been associated with diverse functions of social cognition and emotion processing. Although the underlying mechanism remains elusive, one possibility is that TP acts as domain-general hub integrating socioemotional information. To test this, 26 participants were presented with 60 empathy-evoking film clips during fMRI scanning. The film clips were preceded by a linguistic sad or neutral context and half of the clips were accompanied by sad music. In line with its hypothesized role, TP was involved in the processing of sad context and furthermore tracked participants' empathic concern. To examine the neuromodulatory impact of TP, we applied nonlinear dynamic causal modeling to a multisensory integration network from previous work consisting of superior temporal gyrus (STG), fusiform gyrus (FG), and amygdala, which was extended by an additional node in the TP. Bayesian model comparison revealed a gating of STG and TP on fusiform-amygdalar coupling and an increase of TP to FG connectivity during the integration of contextual information. Moreover, these backward projections were strengthened by emotional music. The findings indicate that during social cognition, TP integrates information from different modalities and top-down modulates lower-level perceptual areas in the ventral visual stream as a function of integration demands. PMID- 26604276 TI - Insulin's Role in Diabetes Management: After 90 Years, Still Considered the Essential "Black Dress". PMID- 26604277 TI - Pharmacokinetics and Pharmacodynamics of Biosimilar Insulins: Is Clamp Technology Fit for Purpose? PMID- 26604275 TI - Philip E. Cryer, MD: Seminal Contributions to the Understanding of Hypoglycemia and Glucose Counterregulation and the Discovery of HAAF (Cryer Syndrome). AB - Optimized glycemic control prevents and slows the progression of long-term complications in patients with type 1 and type 2 diabetes. In healthy individuals, a decrease in plasma glucose below the physiological range triggers defensive counterregulatory responses that restore euglycemia. Many individuals with diabetes harbor defects in their defenses against hypoglycemia, making iatrogenic hypoglycemia the Achilles heel of glycemic control. This Profile in Progress focuses on the seminal contributions of Philip E. Cryer, MD, to our understanding of hypoglycemia and glucose counterregulation, particularly his discovery of the syndrome of hypoglycemia-associated autonomic failure (HAAF). PMID- 26604278 TI - How to Accurately Establish Pharmacokinetics/Pharmacodynamics of Long-Acting Insulins in Humans: Relevance to Biosimilar Insulins. PMID- 26604279 TI - Technosphere Inhaled Insulin: Is Faster Better? PMID- 26604280 TI - Sodium-Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport: From Bench to Bedside. AB - Type 2 diabetes is a chronic disease with disabling micro- and macrovascular complications that lead to excessive morbidity and premature mortality. It affects hundreds of millions of people and imposes an undue economic burden on populations across the world. Although insulin resistance and insulin secretory defects play a major role in the pathogenesis of hyperglycemia, several other metabolic defects contribute to the initiation/worsening of the diabetic state. Prominent among these is increased renal glucose reabsorption, which is maladaptive in patients with diabetes. Instead of an increase in renal glucose excretion, which could ameliorate hyperglycemia, there is an increase in renal glucose reabsorption, which helps sustain hyperglycemia in patients with diabetes. The sodium-glucose cotransporter (SGLT) 2 inhibitors are novel antidiabetes agents that inhibit renal glucose reabsorption and promote glucosuria, thereby leading to reductions in plasma glucose concentrations. In this article, we review the long journey from the discovery of the glucosuric agent phlorizin in the bark of the apple tree through the animal and human studies that led to the development of the current generation of SGLT2 inhibitors. PMID- 26604283 TI - Comment on Weber et al. Type 1 Diabetes Is Associated With an Increased Risk of Fracture Across the Life Span: A Population-Based Cohort Study Using The Health Improvement Network (THIN). Diabetes Care 2015;38:1913-1920. PMID- 26604281 TI - Long-term Glycemic Variability and Risk of Adverse Outcomes: A Systematic Review and Meta-analysis. AB - OBJECTIVE: Glycemic variability is emerging as a measure of glycemic control, which may be a reliable predictor of complications. This systematic review and meta-analysis evaluates the association between HbA1c variability and micro- and macrovascular complications and mortality in type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: Medline and Embase were searched (2004-2015) for studies describing associations between HbA1c variability and adverse outcomes in patients with type 1 and type 2 diabetes. Data extraction was performed independently by two reviewers. Random-effects meta-analysis was performed with stratification according to the measure of HbA1c variability, method of analysis, and diabetes type. RESULTS: Seven studies evaluated HbA1c variability among patients with type 1 diabetes and showed an association of HbA1c variability with renal disease (risk ratio 1.56 [95% CI 1.08-2.25], two studies), cardiovascular events (1.98 [1.39-2.82]), and retinopathy (2.11 [1.54-2.89]). Thirteen studies evaluated HbA1c variability among patients with type 2 diabetes. Higher HbA1c variability was associated with higher risk of renal disease (1.34 [1.15-1.57], two studies), macrovascular events (1.21 [1.06-1.38]), ulceration/gangrene (1.50 [1.06-2.12]), cardiovascular disease (1.27 [1.15-1.40]), and mortality (1.34 [1.18-1.53]). Most studies were retrospective with lack of adjustment for potential confounders, and inconsistency existed in the definition of HbA1c variability. CONCLUSIONS: HbA1c variability was positively associated with micro- and macrovascular complications and mortality independently of the HbA1c level and might play a future role in clinical risk assessment. PMID- 26604284 TI - Response to Comment on Weber et al. Type 1 Diabetes is Associated With an Increased Risk of Fracture Across the Life Span: A Population-Based Cohort Study Using The Health Improvement Network (THIN). Diabetes Care 2015;38:1913-1920. PMID- 26604285 TI - Comment on Leese et al. Progression of Diabetes Retinal Status Within Community Screening Programs and Potential Implications for Screening Intervals. Diabetes Care 2015;38:488-494. PMID- 26604286 TI - Response to Comment on Leese et al. Progression of Diabetes Retinal Status Within Community Screening Programs and Potential Implications for Screening Intervals. Diabetes Care 2015;38:488-494. PMID- 26604287 TI - Comment on Anjana et al. Incidence of Diabetes and Prediabetes and Predictors of Progression Among Asian Indians: 10-Year Follow-up of the Chennai Urban Rural Epidemiology Study (CURES). Diabetes Care 2015;38:1441-1448. PMID- 26604288 TI - Response to Comment on Anjana et al. Incidence of Diabetes and Prediabetes and Predictors of Progression Among Asian Indians: 10-Year Follow-up of the Chennai Urban Rural Epidemiology Study (CURES). Diabetes Care 2015;38:1441-1448. PMID- 26604289 TI - Comment on Boyko and Jensen. Do We Know What Homeostatis Model Assessment Measures? If Not, Does It Matter? Diabetes Care 2007;30:2725-2728. PMID- 26604290 TI - Response to Comment on Boyko and Jensen. Do We Know What Homeostatis Model Assessment Measures? If Not, Does It Matter? Diabetes Care 2007;30:2725-2728. PMID- 26604291 TI - Comment on Xu et al. Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes. Diabetes Care 2015;38:1858-1867. PMID- 26604292 TI - Response to Comment on Xu et al. Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes. Diabetes Care 2015;38:1858 1867. PMID- 26604293 TI - Changes to student nurse financing in the UK: a good or a bad thing? PMID- 26604294 TI - A rare cause of virilisation. PMID- 26604295 TI - Outcome after video-assisted thoracoscopic surgery and open pulmonary lobectomy in patients with low VO2 max: a case-matched analysis from the ESTS database?. AB - OBJECTIVES: The aim was to verify the association of low VO2 max with postoperative morbidity and mortality after video-assisted thoracoscopic surgery (VATS) or open pulmonary lobectomy using the European Society of Thoracic Surgeons (ESTS) database. METHODS: A retrospective analysis of data collected from the ESTS database was conducted. A total of 1684 lobectomy patients with available VO2 max values were included (2007-14). Patients operated through VATS (281 patients) or thoracotomy (1403 patients) were separately analysed. Propensity score analyses were performed to match patients with high (>=15 ml/kg/min) and low VO2 max (<15 ml/kg/min) for each approach. The following variables were used to construct the score: age, body mass index, predicted postoperative forced expiratory volume in 1 s (%), coronary artery disease, American Society of Anaesthesiology grade and Eastern Cooperative Oncology Group performance score. Cardiopulmonary morbidity and 30-day mortality were compared between the matched groups. RESULTS: Mean VO2 max was 17.4 ml/kg/min. A total of 471 patients (28%) had low VO2 max. Overall postoperative cardiopulmonary morbidity and mortality rates were 30% (505 patients) and 4.1% (70 patients), respectively. Morbidity and mortality rates in low VO2 max patients were 33% (156 patients) and 6% (28 patients), respectively. After VATS, cardiopulmonary morbidity and mortality rates were 2-fold (13 of 72, 18% vs 143 of 399, 36%, P = 0.003) and 5-fold (1 of 72, 1.4% vs 27 of 399, 6.7%, P = 0.09) lower compared with thoracotomy. Matched comparison after thoracotomy (399 pairs): Mortality was significantly higher in patients with low VO2 max (27 patients, 6.7%) compared with those with high VO2 max (11 patients, 2.8%, P = 0.008). Complication rates were similar between the two groups (low VO2 max: 143 patients, 36% vs high VO2 max: 133 patients, 33%, respectively, P = 0.5). Matched comparison after vats (72 pairs): Morbidity and mortality rates of patients with low VO2 max were similar to those of patients with high VO2 max (morbidity: 13 patients, 18% vs 17 patients, 24%, P = 0.4; mortality: 1 patient, 1.4% vs 4 patients, 5.5%, P = 0.4). CONCLUSIONS: Low VO2 max was not associated with an increased surgical risk after VAT lobectomy, which challenges the traditional operability criteria when this technique is used. PMID- 26604296 TI - Hypothermic continuous machine perfusion enables preservation of energy charge and functional recovery of heart grafts in an ex vivo model of donation following circulatory death. AB - OBJECTIVES: Cardiac transplantation using hearts from donors after circulatory death (DCD) is critically limited by the unavoidable warm ischaemia and its related unpredictable graft function. Inasmuch as hypothermic machine perfusion (MP) has been shown to improve heart preservation, we hypothesized that MP could enable the use of DCD hearts for transplantation. METHODS: We recovered 16 pig hearts following anoxia-induced cardiac arrest and cardioplegia. Grafts were randomly assigned to two different groups of 4-h preservation using either static cold storage (CS) or MP (Modified LifePort(c) System, Organ Recovery Systems(c), Itasca, Il). After preservation, the grafts were reperfused ex vivo using the Langendorff method for 60 min. Energetic charge was quantified at baseline, post preservation and post-reperfusion by measuring lactate and high-energy phosphate levels. Left ventricular contractility parameters were assessed both in vivo prior to ischaemia and ex vivo during reperfusion. RESULTS: Following preservation, the hearts that were preserved using CS exhibited higher lactate levels (57.1 +/- 23.7 vs 21.4 +/- 12.2 umol/g; P < 0.001), increased adenosine monophosphate/adenosine triphosphate ratio (0.53 +/- 0.25 vs 0.11 +/- 0.11; P < 0.001) and lower phosphocreatine/creatine ratio (9.7 +/- 5.3 vs 25.2 +/- 11; P < 0.001) in comparison with the MP hearts. Coronary flow was similar in both groups during reperfusion (107 +/- 9 vs 125 +/- 9 ml/100 g/min heart; P = ns). Contractility decreased in the CS group, yet remained well preserved in the MP group. CONCLUSION: MP preservation of DCD hearts results in improved preservation of the energy and improved functional recovery of heart grafts compared with CS. PMID- 26604297 TI - In vitro investigation of a novel elastic vascular prosthesis for valve-sparing aortic root and ascending aorta replacement. AB - OBJECTIVES: Prosthetic replacement of the thoracic aorta with common Dacron prostheses impairs the aortic 'windkessel' and, in valve-sparing procedures, also aortic valve function. Elastic graft material may overcome these deficiencies. METHODS: Fresh porcine aortas including the root were set up in a mock circulation before and after replacement of the ascending part with a novel vascular prosthesis providing elastic behaviours. In a first series (n = 14), haemodynamics and leaflet motions of the aortic valve were investigated and also cyclic changes of aortic dimensions at different levels of the root. In a second series (n = 7), intravascular pressure and dimensions of the proximal descending aorta were measured and the corresponding wall tension was calculated. RESULTS: Haemodynamics of the aortic valve remain comparable after replacement. Though the novel prosthesis does not feature such high distensibility as the native aorta, the dynamic of the root was significantly increased compared with common Dacron prostheses at the commissural level, preserving 'windkessel' function. Thus, wall tension of the residual aorta remained unchanged; nevertheless, maximum pressure time differential dp/dt increased by 13%. CONCLUSIONS: The use of the novel elastic prosthesis for replacement of the ascending aorta seems to be beneficial, especially with regard to the preservation of the aortic windkessel. Further studies will be needed to clarify long-term utilization of the material in vivo. PMID- 26604298 TI - Hybrid DynaCT-guided electromagnetic navigational bronchoscopic biopsy?. AB - Electromagnetic navigational bronchoscopy-guided biopsy of small pulmonary nodules can be challenging. Navigational error of the system and movement of the biopsy tool during its deployment adversely affect biopsy success. Furthermore, conventional methods to confirm navigational success such as fluoroscopy and radial endobronchial ultrasound become less useful for the biopsy of small lesions. A hybrid operating theatre can provide unparalleled real-time imaging through DynaCT scan to guide and confirm successful navigation and biopsy of difficult-to-reach or small lesions. We describe our technique for DynaCT image guided electromagnetic navigational bronchoscopic biopsy of a small pulmonary nodule in the hybrid operating theatre. The advantages, disadvantages and special considerations in adopting this approach are discussed. PMID- 26604299 TI - ARMC5 mutations in a large French-Canadian family with cortisol-secreting beta adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia. AB - BACKGROUND: Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing's syndrome (CS) and its familial clustering has been described previously. Recent studies identified that ARMC5 mutations occur frequently in BMAH, but the relation between ARMC5 mutation and the expression of aberrant G protein-coupled receptor has not been examined in detail yet. METHODS: We studied a large French-Canadian family with BMAH and sub-clinical or overt CS. Screening was performed using the 1-mg dexamethasone suppression test (DST) in 28 family members. Screening for aberrant regulation of cortisol by various hormone receptors were examined in vivo in nine individuals. Sequencing of the coding regions of ARMC5 gene was carried out. RESULTS: Morning ambulating cortisol post 1 mg DST were >50 nmol/l in 5/8 members in generation II (57-68 years old), 9/22 in generation III (26-46 years old). Adrenal size was enlarged at different degrees. All affected patients increased cortisol following upright posture, insulin-induced hypoglycemia and/or isoproterenol infusion. beta-blockers led to the reduction of cortisol secretion in all patients with the exception of two who had adrenalectomies because of beta-blockers intolerance. We identified a heterozygous germline variant in the ARMC5 gene c.327_328insC, (p.Ala110Argfs*9) in nine individuals with clinical or subclinical CS, in four out of six individuals with abnormal suppression to dexamethasone at initial investigation and one out of six individuals with current normal clinical screening tests. CONCLUSIONS: Systematic screening of members of the same family with hereditary BMAH allows the diagnosis of unsuspected subclinical CS associated with early BMAH. The relation between the causative ARMC5 mutation and the reproducible pattern of aberrant beta-adrenergic and V1-vasopressin receptors identified in this family remains to be elucidated. PMID- 26604302 TI - News Feature: How online studies are transforming psychology research. PMID- 26604304 TI - Filling constraints for spin-orbit coupled insulators in symmorphic and nonsymmorphic crystals. AB - We determine conditions on the filling of electrons in a crystalline lattice to obtain the equivalent of a band insulator--a gapped insulator with neither symmetry breaking nor fractionalized excitations. We allow for strong interactions, which precludes a free particle description. Previous approaches that extend the Lieb-Schultz-Mattis argument invoked spin conservation in an essential way and cannot be applied to the physically interesting case of spin orbit coupled systems. Here we introduce two approaches: The first one is an entanglement-based scheme, and the second one studies the system on an appropriate flat "Bieberbach" manifold to obtain the filling conditions for all 230 space groups. These approaches assume only time reversal rather than spin rotation invariance. The results depend crucially on whether the crystal symmetry is symmorphic. Our results clarify when one may infer the existence of an exotic ground state based on the absence of order, and we point out applications to experimentally realized materials. Extensions to new situations involving purely spin models are also mentioned. PMID- 26604301 TI - Molecular architecture of the ribosome-bound Hepatitis C Virus internal ribosomal entry site RNA. AB - Internal ribosomal entry sites (IRESs) are structured cis-acting RNAs that drive an alternative, cap-independent translation initiation pathway. They are used by many viruses to hijack the translational machinery of the host cell. IRESs facilitate translation initiation by recruiting and actively manipulating the eukaryotic ribosome using only a subset of canonical initiation factor and IRES transacting factors. Here we present cryo-EM reconstructions of the ribosome 80S- and 40S-bound Hepatitis C Virus (HCV) IRES. The presence of four subpopulations for the 80S*HCV IRES complex reveals dynamic conformational modes of the complex. At a global resolution of 3.9 A for the most stable complex, a derived atomic model reveals a complex fold of the IRES RNA and molecular details of its interaction with the ribosome. The comparison of obtained structures explains how a modular architecture facilitates mRNA loading and tRNA binding to the P-site. This information provides the structural foundation for understanding the mechanism of HCV IRES RNA-driven translation initiation. PMID- 26604305 TI - Atomic-resolution structure of the CAP-Gly domain of dynactin on polymeric microtubules determined by magic angle spinning NMR spectroscopy. AB - Microtubules and their associated proteins perform a broad array of essential physiological functions, including mitosis, polarization and differentiation, cell migration, and vesicle and organelle transport. As such, they have been extensively studied at multiple levels of resolution (e.g., from structural biology to cell biology). Despite these efforts, there remain significant gaps in our knowledge concerning how microtubule-binding proteins bind to microtubules, how dynamics connect different conformational states, and how these interactions and dynamics affect cellular processes. Structures of microtubule-associated proteins assembled on polymeric microtubules are not known at atomic resolution. Here, we report a structure of the cytoskeleton-associated protein glycine-rich (CAP-Gly) domain of dynactin motor on polymeric microtubules, solved by magic angle spinning NMR spectroscopy. We present the intermolecular interface of CAP Gly with microtubules, derived by recording direct dipolar contacts between CAP Gly and tubulin using double rotational echo double resonance (dREDOR)-filtered experiments. Our results indicate that the structure adopted by CAP-Gly varies, particularly around its loop regions, permitting its interaction with multiple binding partners and with the microtubules. To our knowledge, this study reports the first atomic-resolution structure of a microtubule-associated protein on polymeric microtubules. Our approach lays the foundation for atomic-resolution structural analysis of other microtubule-associated motors. PMID- 26604307 TI - Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno PET imaging. AB - Signaling through the immune checkpoint programmed cell death protein-1 (PD-1) enables tumor progression by dampening antitumor immune responses. Therapeutic blockade of the signaling axis between PD-1 and its ligand programmed cell death ligand-1 (PD-L1) with monoclonal antibodies has shown remarkable clinical success in the treatment of cancer. However, antibodies have inherent limitations that can curtail their efficacy in this setting, including poor tissue/tumor penetrance and detrimental Fc-effector functions that deplete immune cells. To determine if PD-1:PD-L1-directed immunotherapy could be improved with smaller, nonantibody therapeutics, we used directed evolution by yeast-surface display to engineer the PD-1 ectodomain as a high-affinity (110 pM) competitive antagonist of PD-L1. In contrast to anti-PD-L1 monoclonal antibodies, high-affinity PD-1 demonstrated superior tumor penetration without inducing depletion of peripheral effector T cells. Consistent with these advantages, in syngeneic CT26 tumor models, high-affinity PD-1 was effective in treating both small (50 mm(3)) and large tumors (150 mm(3)), whereas the activity of anti-PD-L1 antibodies was completely abrogated against large tumors. Furthermore, we found that high affinity PD-1 could be radiolabeled and applied as a PET imaging tracer to efficiently distinguish between PD-L1-positive and PD-L1-negative tumors in living mice, providing an alternative to invasive biopsy and histological analysis. These results thus highlight the favorable pharmacology of small, nonantibody therapeutics for enhanced cancer immunotherapy and immune diagnostics. PMID- 26604306 TI - TRPC6 channel translocation into phagosomal membrane augments phagosomal function. AB - Defects in the innate immune system in the lung with attendant bacterial infections contribute to lung tissue damage, respiratory insufficiency, and ultimately death in the pathogenesis of cystic fibrosis (CF). Professional phagocytes, including alveolar macrophages (AMs), have specialized pathways that ensure efficient killing of pathogens in phagosomes. Phagosomal acidification facilitates the optimal functioning of degradative enzymes, ultimately contributing to bacterial killing. Generation of low organellar pH is primarily driven by the V-ATPases, proton pumps that use cytoplasmic ATP to load H(+) into the organelle. Critical to phagosomal acidification are various channels derived from the plasma membrane, including the anion channel cystic fibrosis transmembrane conductance regulator, which shunt the transmembrane potential generated by movement of protons. Here we show that the transient receptor potential canonical-6 (TRPC6) calcium-permeable channel in the AM also functions to shunt the transmembrane potential generated by proton pumping and is capable of restoring microbicidal function to compromised AMs in CF and enhancement of function in non-CF cells. TRPC6 channel activity is enhanced via translocation to the cell surface (and then ultimately to the phagosome during phagocytosis) in response to G-protein signaling activated by the small molecule (R)-roscovitine and its derivatives. These data show that enhancing vesicular insertion of the TRPC6 channel to the plasma membrane may represent a general mechanism for restoring phagosome activity in conditions, where it is lost or impaired. PMID- 26604308 TI - Correction for Rasmussen et al., Purkinje cell activity during classical conditioning with different conditional stimulus explains central tenet of Rescorla-Wagner model. PMID- 26604309 TI - Reply to Holliday and Boslough et al.: Synchroneity of widespread Bayesian modeled ages supports Younger Dryas impact hypothesis. PMID- 26604310 TI - Reply to Marchenko et al.: Flux analysis of GroEL-assisted protein folding/unfolding. PMID- 26604312 TI - David M. Raup, 1933-2015. PMID- 26604311 TI - PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density. AB - The postsynaptic density (PSD)-95 family of membrane-associated guanylate kinases (MAGUKs) are major scaffolding proteins at the PSD in glutamatergic excitatory synapses, where they maintain and modulate synaptic strength. How MAGUKs underlie synaptic strength at the molecular level is still not well understood. Here, we explore the structural and functional roles of MAGUKs at hippocampal excitatory synapses by simultaneous knocking down PSD-95, PSD-93, and synapse-associated protein (SAP)102 and combining electrophysiology and transmission electron microscopic (TEM) tomography imaging to analyze the resulting changes. Acute MAGUK knockdown greatly reduces synaptic transmission mediated by alpha-amino-3 hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) and N-methyl-d aspartate receptors (NMDARs). This knockdown leads to a significant rise in the number of silent synapses, diminishes the size of PSDs without changes in pre- or postsynaptic membrane, and depletes the number of membrane-associated PSD-95-like vertical filaments and transmembrane structures, identified as AMPARs and NMDARs by EM tomography. The differential distribution of these receptor-like structures and dependence of their abundance on PSD size matches that of AMPARs and NMDARs in the hippocampal synapses. The loss of these structures following MAGUK knockdown tracks the reduction in postsynaptic AMPAR and NMDAR transmission, confirming the structural identities of these two types of receptors. These results demonstrate that MAGUKs are required for anchoring both types of glutamate receptors at the PSD and are consistent with a structural model where MAGUKs, corresponding to membrane-associated vertical filaments, are the essential structural proteins that anchor and organize both types of glutamate receptors and govern the overall molecular organization of the PSD. PMID- 26604313 TI - DksA regulates RNA polymerase in Escherichia coli through a network of interactions in the secondary channel that includes Sequence Insertion 1. AB - Sensing and responding to nutritional status is a major challenge for microbial life. In Escherichia coli, the global response to amino acid starvation is orchestrated by guanosine-3',5'-bisdiphosphate and the transcription factor DksA. DksA alters transcription by binding to RNA polymerase and allosterically modulating its activity. Using genetic analysis, photo-cross-linking, and structural modeling, we show that DksA binds and acts upon RNA polymerase through prominent features of both the nucleotide-access secondary channel and the active site region. This work is, to our knowledge, the first demonstration of a molecular function for Sequence Insertion 1 in the beta subunit of RNA polymerase and significantly advances our understanding of how DksA binds to RNA polymerase and alters transcription. PMID- 26604314 TI - Unusual Mott transition in multiferroic PbCrO3. AB - The Mott insulator in correlated electron systems arises from classical Coulomb repulsion between carriers to provide a powerful force for electron localization. Turning such an insulator into a metal, the so-called Mott transition, is commonly achieved by "bandwidth" control or "band filling." However, both mechanisms deviate from the original concept of Mott, which attributes such a transition to the screening of Coulomb potential and associated lattice contraction. Here, we report a pressure-induced isostructural Mott transition in cubic perovskite PbCrO3. At the transition pressure of ~3 GPa, PbCrO3 exhibits significant collapse in both lattice volume and Coulomb potential. Concurrent with the collapse, it transforms from a hybrid multiferroic insulator to a metal. For the first time to our knowledge, these findings validate the scenario conceived by Mott. Close to the Mott criticality at ~300 K, fluctuations of the lattice and charge give rise to elastic anomalies and Laudau critical behaviors resembling the classic liquid-gas transition. The anomalously large lattice volume and Coulomb potential in the low-pressure insulating phase are largely associated with the ferroelectric distortion, which is substantially suppressed at high pressures, leading to the first-order phase transition without symmetry breaking. PMID- 26604315 TI - Association mapping reveals the role of purifying selection in the maintenance of genomic variation in gene expression. AB - The evolutionary forces that maintain genetic variation in quantitative traits within populations remain poorly understood. One hypothesis suggests that variation is under purifying selection, resulting in an excess of low-frequency variants and a negative correlation between minor allele frequency and selection coefficients. Here, we test these predictions using the genetic loci associated with total expression variation (eQTLs) and allele-specific expression variation (aseQTLs) mapped within a single population of the plant Capsella grandiflora. In addition to finding eQTLs and aseQTLs for a large fraction of genes, we show that alleles at these loci are rarer than expected and exhibit a negative correlation between phenotypic effect size and frequency. Overall, our results show that the distribution of frequencies and effect sizes of the loci responsible for local expression variation within a single outcrossing population are consistent with the effects of purifying selection. PMID- 26604316 TI - Incomplete Bayesian model rejects contradictory radiocarbon data for being contradictory. PMID- 26604317 TI - Problematic dating of claimed Younger Dryas boundary impact proxies. PMID- 26604318 TI - Strict experimental evidence that apo-chaperonin GroEL does not accelerate protein folding, although it does accelerate one of its steps. PMID- 26604319 TI - Cerebral cavernous malformations: radiological findings and implications for genetic testing. PMID- 26604320 TI - Inhibition of Wnt signalling and breast tumour growth by the multi-purpose drug suramin through suppression of heterotrimeric G proteins and Wnt endocytosis. AB - Overactivation of the Wnt signalling pathway underlies oncogenic transformation and proliferation in many cancers, including the triple-negative breast cancer (TNBC), the deadliest form of tumour in the breast, taking about a quarter of a million lives annually worldwide. No clinically approved targeted therapies attacking Wnt signalling currently exist. Repositioning of approved drugs is a promising approach in drug discovery. In the present study we show that a multi purpose drug suramin inhibits Wnt signalling and proliferation of TNBC cells in vitro and in mouse models, inhibiting a component in the upper levels of the pathway. Through a set of investigations we identify heterotrimeric G proteins and regulation of Wnt endocytosis as the likely target of suramin in this pathway. G protein-dependent endocytosis of plasma membrane-located components of the Wnt pathway was previously shown to be important for amplification of the signal in this cascade. Our data identify endocytic regulation within Wnt signalling as a promising target for anti-Wnt and anti-cancer drug discovery. Suramin, as the first example of such drug or its analogues might pave the way for the appearance of first-in-class targeted therapies against TNBC and other Wnt-dependent cancers. PMID- 26604321 TI - Evidence for a heritable contribution to neuroendocrine tumors of the small intestine. AB - Small intestinal neuroendocrine tumors (SI-NETs) are rare tumors arising from the enterochromaffin cells of the gut. Having a first-degree relative with a SI-NET has been shown to confer a substantial risk arising from shared environment and genetics. Heritable risk was examined using a computerized genealogy linked to historical statewide cancer data. A population-based analysis of the observed familial clustering of SI-NETs was performed to assess the genetic risk in distant relatives. A test for significant excess relatedness of 384 individuals with genealogy data and histologically confirmed SI-NETs was performed by comparing pairwise relatedness of cases to 1000 sets of matched controls. Overall significant excess pairwise relatedness was found for the 384 cases (P<0.001) and was still observed when closer than first cousin relationships were ignored (P=0.041). Relative risks (RRs) for SI-NETs were estimated as a ratio of observed to expected number of SI-NET cases among each relationship class. Siblings have a 13.4-fold (P<0.0001) and parents have a 6.5-fold (P=0.143) RR, suggesting both genetic and environmental influences. The risk extends out to third-degree relatives with a 2.3-fold RR (P=0.008). Metachronous cancers were also reported in 26% of the SI-NET cases demonstrating an increased RR of colon, bladder, non Hodgkin lymphoma, melanoma, and prostate cancers. Although SI-NETs are rare, relatives of these cases are at a significantly elevated risk of developing a SI NET due to heritable genetic factors. Definition of the genetic risk factors will be an important tool for earlier diagnosis and better outcomes for SI-NETs. PMID- 26604322 TI - Diagnostic technologies for circulating tumour cells and exosomes. AB - Circulating tumour cells (CTCs) and exosomes are promising circulating biomarkers. They exist in easily accessible blood and carry large diversity of molecular information. As such, they can be easily and repeatedly obtained for minimally invasive cancer diagnosis and monitoring. Because of their intrinsic differences in counts, size and molecular contents, CTCs and exosomes pose unique sets of technical challenges for clinical translation-CTCs are rare whereas exosomes are small. Novel technologies are underway to overcome these specific challenges to fully harness the clinical potential of these circulating biomarkers. Herein, we will overview the characteristics of CTCs and exosomes as valuable circulating biomarkers and their associated technical challenges for clinical adaptation. Specifically, we will describe emerging technologies that have been developed to address these technical obstacles and the unique clinical opportunities enabled by technological innovations. PMID- 26604324 TI - Television watching and risk of childhood obesity: a meta-analysis. AB - BACKGROUND: Over the last few decades, there has been a worldwide epidemic of childhood obesity. An important step in successful prevention in paediatrics is the identification of modifiable risk factors of childhood obesity. Many studies have evaluated the associations between television (TV) watching and childhood obesity but yielded inconsistent results. METHODS: To help elucidate the role of TV watching, PubMed and Embase databases were searched for published studies on associations between TV watching and childhood obesity. Random-effects models and dose-response meta-analyses were used to pool study results. RESULTS: Fourteen cross-sectional studies with 24 reports containing 106 169 subjects were included in the meta-analysis. Subgroup analyses were conducted by the available characteristics of studies and participants. The multivariable-adjusted overall OR of the childhood obesity for the highest vs. the lowest time of TV watching was 1.47 [95% confidence interval (95% CI): 1.33-1.62]. A linear dose-response relationship was also found for TV watching and childhood obesity (P < 0.001), and the risk increased by 13% for each 1 h/day increment in TV watching. Subgroup analysis showed a basically consistent result with the overall analysis. The association is observed in both boys and girls (for boys, OR 1.30, 95% CI 1.16 1.45; for girls, OR 1.26, 95% CI 1.11-1.41). CONCLUSIONS: our meta-analysis suggested that increased TV watching is associated with increased risk of childhood obesity. And restricting TV time and other sedentary behaviour of children may be an important public health strategy to prevent childhood obesity. PMID- 26604325 TI - Measures of discriminatory accuracy and categorizations in public health: a response to Allan Krasnik's editorial. PMID- 26604326 TI - BIX-01294 increases pig cloning efficiency by improving epigenetic reprogramming of somatic cell nuclei. AB - Accumulating evidence suggests that faulty epigenetic reprogramming leads to the abnormal development of cloned embryos and results in the low success rates observed in all mammals produced through somatic cell nuclear transfer (SCNT). The aberrant methylation status of H3K9me and H3K9me2 has been reported in cloned mouse embryos. To explore the role of H3K9me2 and H3K9me in the porcine somatic cell nuclear reprogramming, BIX-01294, known as a specific inhibitor of G9A (histone-lysine methyltransferase of H3K9), was used to treat the nuclear transferred (NT) oocytes for 14-16 h after activation. The results showed that the developmental competence of porcine SCNT embryos was significantly enhanced both in vitro (blastocyst rate 16.4% vs 23.2%, P<0.05) and in vivo (cloning rate 1.59% vs 2.96%) after 50 nm BIX-01294 treatment. BIX-01294 treatment significantly decreased the levels of H3K9me2 and H3K9me at the 2- and 4-cell stages, which are associated with embryo genetic activation, and increased the transcriptional expression of the pluripotency genes SOX2, NANOG and OCT4 in cloned blastocysts. Furthermore, the histone acetylation levels of H3K9, H4K8 and H4K12 in cloned embryos were decreased after BIX-01294 treatment. However, co treatment of activated NT oocytes with BIX-01294 and Scriptaid rescued donor nuclear chromatin from decreased histone acetylation of H4K8 that resulted from exposure to BIX-01294 only and consequently improved the preimplantation development of SCNT embryos (blastocyst formation rates of 23.7% vs 21.5%). These results indicated that treatment with BIX-01294 enhanced the developmental competence of porcine SCNT embryos through improvements in epigenetic reprogramming and gene expression. PMID- 26604323 TI - How, with whom and when: an overview of CD147-mediated regulatory networks influencing matrix metalloproteinase activity. AB - Matrix metalloproteinases (MMPs) comprise a family of 23 zinc-dependent enzymes involved in various pathologic and physiologic processes. In cancer, MMPs contribute to processes from tumour initiation to establishment of distant metastases. Complex signalling and protein transport networks regulate MMP synthesis, cell surface presentation and release. Earlier attempts to disrupt MMP activity in patients have proven to be intolerable and with underwhelming clinical efficacy; thus targeting ancillary proteins that regulate MMP activity may be a useful therapeutic approach. Extracellular matrix metalloproteinase inducer (EMMPRIN) was originally characterized as a factor present on lung cancer cells, which stimulated collagenase (MMP-1) production in fibroblasts. Subsequent studies demonstrated that EMMPRIN was identical with several other protein factors, including basigin (Bsg), all of which are now commonly termed CD147. CD147 modulates the synthesis and activity of soluble and membrane-bound [membrane-type MMPs (MT-MMPs)] in various contexts via homophilic/heterophilic cell interactions, vesicular shedding or cell-autonomous processes. CD147 also participates in inflammation, nutrient and drug transporter activity, microbial pathology and developmental processes. Despite the hundreds of manuscripts demonstrating CD147-mediated MMP regulation, the molecular underpinnings governing this process have not been fully elucidated. The present review summarizes our present knowledge of the complex regulatory systems influencing CD147 biology and provides a framework to understand how CD147 may influence MMP activity. PMID- 26604327 TI - Inspiratory Muscle Strength and Endurance in Children and Adolescents with Cystic Fibrosis. AB - BACKGROUND: Pulmonary changes that occur in cystic fibrosis may influence inspiratory muscle strength and endurance. We evaluated inspiratory muscle strength and endurance in children and adolescents with cystic fibrosis in comparison with healthy subjects. METHODS: This is a cross-sectional observational study with subjects with cystic fibrosis and paired healthy individuals, age 6-18 y. Spirometry, impulse oscillometry, plethysmography, manovacuometry, and a protocol of inspiratory muscle endurance were performed. RESULTS: Subjects with cystic fibrosis (n = 34) had higher maximum percent-of predicted inspiratory pressure (PImax) than healthy (n = 68) subjects (118.5 +/- 25.8% vs 105.8 +/- 18.0%) and no significant difference in endurance (60.9 +/- 13.3% vs 65.3 +/- 12.3%). When restricting the analysis to subjects without Pseudomonas aeruginosa colonization and with FEV1 > 80%, PImax values were significantly higher, and inspiratory muscle endurance was lower, in comparison with the control group. PImax correlated significantly with FVC (r = 0.44, P = .02) and FEV1 (r = 0.41, P = .02), whereas endurance correlated better with total airway resistance (r = 0.35, P = .045) and with central airway resistance (r = 0.48, P = .004). CONCLUSIONS: Children and adolescents with cystic fibrosis with no colonization by P. aeruginosa and normal lung function present increased inspiratory muscle strength and decreased endurance compared with healthy individuals, indicating that changes in the respiratory muscle function seem to be distinctly associated with pulmonary involvement. Strength was related to pulmonary function parameters, whereas endurance was associated with airway resistance. PMID- 26604328 TI - The Role of Mean Platelet Volume in Chronic Obstructive Pulmonary Disease Exacerbation. AB - BACKGROUND: Studies have supported the correlation between mean platelet volume and COPD. However, there are limited data on the relationship between COPD exacerbation and mean platelet volume. We aimed to evaluate the mean platelet volume trend in patients with COPD exacerbation. METHODS: A total of 81 subjects, 62 men and 19 women, who were admitted to the hospital because of exacerbation of COPD during 9 months, were enrolled in this prospective observational study. The levels of mean platelet volume, C-reactive protein, complete blood count, and percent-of-predicted FEV1 were measured in subjects at admission (exacerbation period) and after 3 months (stable period). Thirty-seven age- and sex-matched healthy individuals constituted the control group. RESULTS: Subjects in the exacerbation period had significantly higher levels of C-reactive protein (P = .001), white blood cell count (P = .01), and percentage of neutrophils (P = .01) and lower percent-of-predicted FEV1 than in the stable period (P = .02). Mean platelet volume levels were significantly decreased in the exacerbation period (P = .001). Considering a cut-off point of mean platelet volume levels <8.2 fL for indicating COPD exacerbation showed a sensitivity of 80% and a specificity of 76%. Also, mean platelet volume levels correlated significantly with increase of C-reactive protein level, white blood cell count, and neutrophil percentage in the exacerbation period (P = .01, P = .01, and P = .02, respectively). CONCLUSIONS: Mean platelet volume may be an inflammatory marker in exacerbation of COPD, and the measurement of mean platelet volume values may be useful for identifying patients who are at increased risk for exacerbations of illness. PMID- 26604330 TI - Evaluation of Oxidative Damage and Antioxidant Mechanisms in COPD, Lung Cancer, and Obstructive Sleep Apnea Syndrome. AB - BACKGROUND: Oxidative damage is a major contributing factor to carcinogenesis and obstructive disorders in lungs. Current evidence suggests that the inflammatory processes yield to oxidative mechanisms, which underlie COPD, lung cancer, and obstructive sleep apnea syndrome (OSAS). This study aimed to evaluate the oxidative damage in these diseases by evaluating the oxidative and antioxidant biomarkers. METHODS: Malondialdehyde, 8-oxo-7,8-dihydro-2'-deoxyguanosine, and coenzyme Q10 levels were evaluated in the blood samples of subjects with COPD, lung cancer, and OSAS by high-pressure liquid chromatography. RESULTS: A total of 111 participants (35 females, 76 males) with OSAS (n = 29), COPD (n = 26), and lung cancer (n = 28) and healthy controls (n = 28) were included in the study. The malondialdehyde and coenzyme Q10 levels were significantly higher in all 3 diseases when compared with controls (P < .01), whereas 8-oxo-7,8-dihydro-2' deoxyguanosine levels were only significantly higher than in healthy controls in subjects with lung cancer (P = .005). The highest levels of malondialdehyde and coenzyme Q10 were determined in subjects with OSAS and lung cancer, respectively. The highest 8-oxo-7,8-dihydro-2'-deoxyguanosine levels were also observed in subjects with lung cancer, but the differences of this biomarker with other diagnoses were not statistically significant (P = .56). CONCLUSION: Oxidative damage was observed in all 3 diagnoses, and, as a response to oxidative stress, antioxidant mechanisms were also active in these diseases. Malondialdehyde and 8 oxo-7,8-dihydro-2'-deoxyguanosine were found to be efficiently usable in the evaluation of oxidative damage in chronic respiratory diseases. (ClinicalTrials.gov registration NCT02406053.). PMID- 26604329 TI - Assessment of Factors Related to Auto-PEEP. AB - BACKGROUND: Previous physiological studies have identified factors that are involved in auto-PEEP generation. In our study, we examined how much auto-PEEP is generated from factors that are involved in its development. METHODS: One hundred eighty-six subjects undergoing controlled mechanical ventilation with persistent expiratory flow at the beginning of each inspiration were enrolled in the study. Volume-controlled continuous mandatory ventilation with PEEP of 0 cm H2O was applied while maintaining the ventilator setting as chosen by the attending physician. End-expiratory and end-inspiratory airway occlusion maneuvers were performed to calculate respiratory mechanics, and tidal flow limitation was assessed by a maneuver of manual compression of the abdomen. RESULTS: The variable with the strongest effect on auto-PEEP was flow limitation, which was associated with an increase of 2.4 cm H2O in auto-PEEP values. Moreover, auto PEEP values were directly related to resistance of the respiratory system and body mass index and inversely related to expiratory time/time constant. Variables that were associated with the breathing pattern (tidal volume, frequency minute ventilation, and expiratory time) did not show any relationship with auto-PEEP values. The risk of auto-PEEP >=5 cm H2O was increased by flow limitation (adjusted odds ratio 17; 95% CI: 6-56.2), expiratory time/time constant ratio <1.85 (12.6; 4.7-39.6), respiratory system resistance >15 cm H2O/L s (3; 1.3 6.9), age >65 y (2.8; 1.2-6.5), and body mass index >26 kg/m(2) (2.6; 1.1-6.1). CONCLUSIONS: Flow limitation, expiratory time/time constant, resistance of the respiratory system, and obesity are the most important variables that affect auto PEEP values. Frequency expiratory time, tidal volume, and minute ventilation were not independently associated with auto-PEEP. Therapeutic strategies aimed at reducing auto-PEEP and its adverse effects should be primarily oriented to the variables that mainly affect auto-PEEP values. PMID- 26604331 TI - Pulmonary Function Changes Over 1 Year After Lobectomy in Lung Cancer. AB - BACKGROUND: This study was conducted to measure the serial changes in pulmonary function over 12 months after lobectomy in subjects with lung cancer and to evaluate the actual recovery of pulmonary function in comparison with the predicted postoperative values. METHODS: Subjects who underwent lobectomy for primary lung cancer were included in this study. In the statistical analysis, we included data from 76 subjects (52 men and 24 women; mean age, 63.4 y) who completed perfusion scintigraphy 1 week before surgery and FEV1 and diffusion capacity of the lung for carbon monoxide (DLCO) assessments preoperatively and at 1, 6, and 12 months postoperatively. RESULTS: The actual percent-of-predicted FEV1 1 month postoperatively was 77.9% of the preoperative value, which was almost equal to the predicted postoperative value, and significantly increased to 84.3% by 6 months and 84.2% at 12 months. The actual percent-of-predicted DLCO 1 month postoperatively was 81.8% of the preoperative value, which was similar to the predicted postoperative value, and also significantly increased to 91.3% at 6 months and 96.5% at 12 months. However, the actual pulmonary function test results at 1 y in subjects with COPD or in those who underwent thoracotomy or received adjuvant chemotherapy were not different from the predicted postoperative values. CONCLUSIONS: Actual pulmonary function compared with predicted postoperative values improved over time over 1 y after lobectomy. However, this improvement was not observed in subjects with COPD or in those who underwent thoracotomy or received postoperative adjuvant chemotherapy. PMID- 26604332 TI - What we can learn from existing evidence about physical activity for juvenile idiopathic arthritis? PMID- 26604333 TI - Cardiovascular risk with NSAIDs in rheumatoid arthritis: an analysis using routinely collected data. PMID- 26604335 TI - Probiotics, prebiotics and synbiotics- a review. AB - The health benefits imparted by probiotics and prebiotics as well as synbiotics have been the subject of extensive research in the past few decades. These food supplements termed as functional foods have been demonstrated to alter, modify and reinstate the pre-existing intestinal flora. They also facilitate smooth functions of the intestinal environment. Most commonly used probiotic strains are: Bifidobacterium, Lactobacilli, S. boulardii, B. coagulans. Prebiotics like FOS, GOS, XOS, Inulin; fructans are the most commonly used fibers which when used together with probiotics are termed synbiotics and are able to improve the viability of the probiotics. Present review focuses on composition and roles of Probiotics, Prebiotics and Synbiotics in human health. Furthermore, additional health benefits like immune-modulation, cancer prevention, inflammatory bowel disease etc. are also discussed. Graphical abstractPictorial summary of health benefits imparted by probiotics, prebiotics and synbiotics. PMID- 26604336 TI - Flavor impacts of glycerol in the processing of yeast fermented beverages: a review. AB - Glycerol contributes to the beverage body and fullness. Moreover, it also influences the flavor intensity. As a major byproduct, glycerol not only serves critical roles in yeast osmoregulation and redox balancing, but also acts as the carbon competitor against ethanol in alcoholic fermentation. Therefore, increasing glycerol yield benefits both the flavor and ethanol reduction for the fermented beverages. Glycerol yield has been elevated either by fermentation optimization or by yeast genetic modification. The fermentation optimizations reached maximum 14 g/L glycerol through screening yeast strains and optimizing fermentation parameters. Meanwhile the yeast overexpressing GPD1 (encoding glycerol-3-phosphate dehydrogenase) produced up to 6 folds more glycerol for beer and wine. Except for glycerol improvement, the genetically modified yeasts accumulated dramatically undesirable compounds such as acetaldehyde, acetate and acetoin which are detrimental for beverage flavor. In comparison, the natural high glycerol producers showed strain-specific manner on the yeast-derived aroma compounds like volatile acids, fusel alcohols, esters, and aldehydes. Temperature, sugar concentration, nitrogen composition, oxygen and pH-value, which influence glycerol biosynthesis, also obtained various effects on the production of aromatic compounds. In the current review, we firstly deliberate the organoleptic contributions of glycerol for fermented beverages. Furthermore, glycerol optimization strategies are discussed regarding to the yield improvement, the genes expressions, the overall flavor impacts and the feasibilities in beverage applications. Lastly, for improving beverage flavor by glycerol optimization, a high-throughput platform is proposed to increase the screening capacity of yeast strains and parameters in the processing of fermented beverages. PMID- 26604334 TI - Advanced glycation End-products (AGEs): an emerging concern for processed food industries. AB - The global food industry is expected to increase more than US $ 7 trillion by 2014. This rise in processed food sector shows that more and more people are diverging towards modern processed foods. As modern diets are largely heat processed, they are more prone to contain high levels of advanced glycation end products (AGEs). AGEs are a group of complex and heterogeneous compounds which are known as brown and fluorescent cross-linking substances such as pentosidine, non-fluorescent cross-linking products such as methylglyoxal-lysine dimers (MOLD), or non-fluorescent, non-cross linking adducts such as carboxymethyllysine (CML) and pyrraline (a pyrrole aldehyde). The chemistry of the AGEs formation, absorption and bioavailability and their patho-biochemistry particularly in relation to different complications like diabetes and ageing discussed. The concept of AGEs receptor - RAGE is mentioned. AGEs contribute to a variety of microvascular and macrovascular complications through the formation of cross links between molecules in the basement membrane of the extracellular matrix and by engaging the receptor for advanced glycation end products (RAGE). Different methods of detection and quantification along with types of agents used for the treatment of AGEs are reviewed. Generally, ELISA or LC-MS methods are used for analysis of foods and body fluids, however lack of universally established method highlighted. The inhibitory effect of bioactive components on AGEs by trapping variety of chemical moieties discussed. The emerging evidence about the adverse effects of AGEs makes it necessary to investigate the different therapies to inhibit AGEs. PMID- 26604337 TI - In vitro meat production system: why and how? AB - Due to the nutritional importance and the sustained popularity of meat as a foodstuff, the livestock production sector has been expanding incessantly. This exponential growth of livestock meat sector poses a gigantic challenge to the sustainability of food production system. A new technological breakthrough is being contemplated to develop a substitute for livestock meat. The idea is to grow meat in a culture in the lab and manipulate its composition selectively. This paper aims to discuss the concept of In Vitro Meat production system, articulate the underlying technology and analyse the context of its implications, as proposed by several scientists and stakeholders. The challenges facing this emerging technology have also been discussed. PMID- 26604338 TI - Novel vinegar-derived product enriched with dietary fiber: effect on polyphenolic profile, volatile composition and sensory analysis. AB - Dietary fiber derived from citrus fruits was added to vinegar. Different sources and quantities of fiber and storage conditions have been scrutinized. Formulated vinegars were evaluated on the basis of their phenolic profile, volatile composition and sensory analysis. The addition of citrus fiber enhanced the phenolic and volatile profile of the resulted vinegars. Whereas lemon fiber contributed mostly to the enrichment of the polyphenolic composition, orange fiber was that which increased in a higher way the volatile composition of the vinegars. Moreover, the content of hydroxycinnamic acid derivatives and the majority of volatile compounds decreased as the dose of fiber increased. Furthermore, the judges preferred fiber-enriched vinegars, but in different quantities depending of the fiber source. This preference was mainly based on citric attribute, contributing several terpenes and ketones derived from them. The addition of citrus fiber to vinegar did not result in a marked storage dependence. PMID- 26604339 TI - Engineering and functional properties of biodegradable pellets developed from various agro-industrial wastes using extrusion technology. AB - Different agro-industrial wastes were mixed with different plasticizers and extruded to form the pellets to be used further for development of biodegradable molded pots. Bulk density and macro-porosity are the important engineering properties used to determine the functional characteristics of the biodegradable pellets viz., expansion volume, water solubility, product colour, flowability and compactness. Significant differences in the functional properties of pellets with varying bulk densities (loose and tapped) and macro-porosities (loose, tapped) were observed. The observed mean bulk density of biodegradable pellets made from different formulations ranged between 0.213 and 0.560 g/ml for loose fill conditions and 0.248 to 0.604 g/ml for tapped fill conditions. Biodegradable pellets bear a good compaction for both loose and tapped fill methods. The mean macro-porosity of biodegradable pellets ranged between 1.19 and 54.48 % for loose fill condition and 0.29 to 53.35 % for tapped fill condition. Hausner ratio (HR) for biodegradable pellets varied from 1.026 to 1.328, indicating a good flowability of biodegradable pellets. Pearson's correlation between engineering properties and functional properties of biodegradable pellets revealed that from engineering properties functional properties can be predicted. PMID- 26604340 TI - Recrystallization of starches by hydrothermal treatment: digestibility, structural, and physicochemical properties. AB - Gelatinized starches were recrystallized under hydrothermal treatment and their properties were characterized by X-ray diffractometry, solid-state (13)C cross polarization and magic-angle spinning nuclear magnetic resonance, differential scanning calorimetry, gel-permeation chromatography, high-performance anion exchange chromatography using pulsed amperomeric detection, high-performance size exclusion chromatography with attached multiangle laser light scattering and refractive index detectors, and digestibility analysis. Amylopectin molecules of hylon (V, VII) and water yam starch contained long side-chains with high proportion of fb1 and fb2. Under hydrothermal treatment, the double helix proportion and relative crystallinity significantly increased and reached maxima of water yam (48.7 and 28.2 %, respectively). Except water yam starch, X-ray diffraction pattern of all starches exhibited the evidence of type 2 amylose lipid complex. Besides, under DSC measurement, potato and hylon starches showed the endotherm of amylose-amylose interaction. The hydrothermal treatment caused the recrystallization resulting in the decrease of RDS, especially in case of hylon and water yam starch. HTT water yam contained highest SDS (48.3 %) and HTT hylon VII contained highest RS (44.5 %). The relationship between structure and digestibility was observed, in which, high amylose content and specific structures of amylopectin molecule were necessary for the production of RS and/or SDS of hydrothermally treated starches. PMID- 26604341 TI - Application of class-modelling techniques to infrared spectra for analysis of pork adulteration in beef jerkys. AB - The use of chemometrics to analyse infrared spectra to predict pork adulteration in the beef jerky (dendeng) was explored. In the first step, the analysis of pork in the beef jerky formulation was conducted by blending the beef jerky with pork at 5-80 % levels. Then, they were powdered and classified into training set and test set. The second step, the spectra of the two sets was recorded by Fourier Transform Infrared (FTIR) spectroscopy using atenuated total reflection (ATR) cell on the basis of spectral data at frequency region 4000-700 cm(-1). The spectra was categorised into four data sets, i.e. (a) spectra in the whole region as data set 1; (b) spectra in the fingerprint region (1500-600 cm(-1)) as data set 2; (c) spectra in the whole region with treatment as data set 3; and (d) spectra in the fingerprint region with treatment as data set 4. The third step, the chemometric analysis were employed using three class-modelling techniques (i.e. LDA, SIMCA, and SVM) toward the data sets. Finally, the best result of the models towards the data sets on the adulteration analysis of the samples were selected and the best model was compared with the ELISA method. From the chemometric results, the LDA model on the data set 1 was found to be the best model, since it could classify and predict 100 % accuracy of the sample tested. The LDA model was applied toward the real samples of the beef jerky marketed in Jember, and the results showed that the LDA model developed was in good agreement with the ELISA method. PMID- 26604342 TI - Properties and characteristics of nanocomposite films from tilapia skin gelatin incorporated with ethanolic extract from coconut husk. AB - Impacts of ethanolic extract from coconut husk (EECH) at 0-0.4 % (w/w, on protein basis) on properties of films from tilapia skin gelatin and gelatin/Cloisite Na(+) nanocomposite films were investigated. Young's Modulus, tensile strength and elongation at break of both films decreased with addition of EECH (P < 0.05). The lowest water vapour permeability (WVP) was obtained for gelatin film containing 0.05 % EECH (w/w) (P < 0.05). Nevertheless, the nanocomposite film showed the lowest WVP when incorporated with 0.4 % EECH (w/w) (P < 0.05). Generally, L*- value (lightness) decreased and a*- value (redness) of films increased (P < 0.05) with increasing levels of EECH, regardless of nanoclay incorporation. Transparency of both films generally decreased as the level of EECH increased (P < 0.05). Intercalated or exfoliated structure of nanocomposite films was revealed by wide angle X-ray diffraction (WAXD) analysis. Based on scanning electron microscopic (SEM) analysis, the rougher surface was found when EECH was added. EECH had varying impact on thermal stability of films as revealed by thermogravimetric (TGA) and differential scanning calorimetric (DSC) analyses. Thus, the incorporation of EECH determined the properties of both gelatin film and nanocomposite film in which the improved water vapour barrier property could be obtained. PMID- 26604343 TI - The changes in the volatile aldehydes formed during the deep-fat frying process. AB - Volatile aldehydes (VAs) formed during soybean oil (SBO) heating, wheat dough (WD) frying, and chicken breast meat (CBM) frying processes were comparatively investigated by solid-phase micro-extraction-gas chromatography-mass spectrometry (SPME-GC-MS). The results showed that relative amounts (RAs) of the most detected VAs were firstly increased to maximum values in oil samples collected at the second hour of the seventh day and the values were then decreased with the increase in the time of oil heating process (control). However, for food frying processes, the time needed for reaching maximum RAs of VAs was shorter and the values were decreased with the increase in frying time. Significant change in contents of the VAs was observed for oil samples fried with CBM due to the high contents of water, protein, and lipid content compared to oil samples fried with WD. Based on the obtained results, free radical reaction, particularly positional isomerization and cis-trans isomerization, was deduced to occur when WD or CBM was fried in SBO. The relatively high RAs of VAs formed during the deep-fat frying process presented certain invaluable measures for evaluating of frying oil and fried food quality and safety. PMID- 26604344 TI - Enzymatic hydrolysis of whey and casein protein- effect on functional, rheological, textural and sensory properties of breads. AB - Milk proteins were hydrolyzed by papain and their effect on the rheological, textural and sensory properties of bread were investigated. Water absorption capacity, emulsification capacity, foam volume, foam stability and solubility of Whey and casein protein concentrates and their hydrolysates were determined. The farinograph parameters of wheat flour and blends of wheat flour with casein and whey protein and their hydrolysates were determined to evaluate changes in water absorption capacity, dough development time, dough stability time and mixing tolerance index. The incorporation of WPC, casein and their hydrolysates up to the level of 5 % showed dough properties comparable to control. It was also found that 5 % level incorporation of milk proteins and their hydrolysates have no drastic effect on physical and sensory attributes of bread. The pasting properties showed significant decrease (p <= 0.05) when compared with wheat flour at all levels of addition of whey and casein protein concentrates and hydrolysates. Scanning electron microscopy of bread samples shows disruption in the well-defined protein - starch complex of wheat flour bread and the structure of gluten was weak as the concentration of whey protein increases in the wheat flour bread. PMID- 26604345 TI - Assessment of pectinase production by Bacillus mojavensis I4 using an economical substrate and its potential application in oil sesame extraction. AB - Carrot (Daucus carota) peels, local agricultural waste product, is rich in lignocellulolytic material, including pectin which can act as an inducer of pectinase production. Pectinolytic enzymes production by Bacillus mojavensis I4 was studied in liquid state fermentation using carrot peel as a substrate. Medium composition and culture conditions for the pectinase production by I4 were optimized using two statistical methods: Taguchi design was applied to find the key ingredients and conditions for the best yield of enzyme production and The Box-Behnken design was used to optimize the value of the four significant variables: carrot peels powder, NH4Cl, inoculum size and incubation time. The optimal conditions for higher production of pectinase were carrot peels powder 6.5 %, NH4Cl 0.3 %, inoculum level 3 % and cultivation time 32 h. Under these conditions, the pectinase experimental yield (64.8 U/ml) closely matched the yield predicted by the statistical model (63.55 U/ml) with R (2) = 0.963. The best pectinase activity was observed at the temperature of 60 degrees C and at pH 8.0. The enzyme retained more than 90 % of its activity after 24 h at pH ranging from 6.0 to 10.0. The enzyme preserved more than 85 % of its initial activity after 60 min of pre-incubation at 30-40 degrees C and more than 67 % at 50 degrees C. The extracellular juice of I4 was applied in the process of sesame seeds oil extraction. An improvement of 3 % on the oil yield was obtained. The findings demonstrated that the B. mojavensis I4 has a promising potential for future use in a wide range of industrial and biotechnological applications. PMID- 26604346 TI - Nettle (Urtica dioica L.) extracts as functional ingredients for production of chocolates with improved bioactive composition and sensory properties. AB - Pursuant to the tendencies of producing functional foods, attractive to a wide range of consumers, in this study chocolates enriched with freeze dried (FD) and concentrated (CE) nettle extracts were formulated, and their polyphenolic and antioxidant capacity stability evaluated during 12 months of storage. A simple aqueous extraction procedure of nettle was developed, and the defined extract evaluated for its cytotoxic and antioxidant/prooxidant activity on human colon cancer cell line (SW 480). An increase in total polyphenolic content, chlorogenic acid and flavonoid derivatives (originating from nettle extract) contents was achieved in enriched chocolates. Implementation of FD extract enabled higher increase of polyphenolic content in comparison to CE extract. During storage, fluctuations of polyphenolic content were observed, but the final bioactive parameters did not differ (or increased) from the initial ones. Nettle enriched chocolates exhibited more intense bitterness and astringency, while dark chocolates were preferred over milk and semisweet ones. PMID- 26604347 TI - Volatile phenols depletion in red wine using molecular imprinted polymers. AB - Wines can be modified by microorganisms during the ageing process, by producing off-flavours like volatile phenols (VP), leading to their deterioration, with great economic losses. The development of methods to recover wines affected by unwanted VP became an important target. Molecular imprinted polymers (MIPs) are synthetic materials with artificially-generated recognition sites for selective extraction of organic compounds from different matrices. In this work, two MIPs to remove unwanted VP from wines were developed and their effects were evaluated. Volatile compounds were determined by GC-FID and GC-IT/MS and phenolic compounds (non-coloured and anthocyanins) by HPLC-DAD. The treatment with MIP-4EG and MIP 4EP significantly reduced the content of 4-ethylguaiacol and 4-ethylphenol, respectively. Nevertheless, the changes observed in wine non-coloured and coloured phenolics and sensorial analysis indicate that their specificity and selectivity regarding off-flavours still needs to be improved. PMID- 26604348 TI - Status in physical properties of coloured rice varieties before and after inducing retro-gradation. AB - Three varieties of paddy in brown, red (non-waxy) and black (waxy) forms were de husked and milled before and after inducing retro-gradation and their physical properties were studied. Normalized grain weight, porosity of parboiled paddy (PP) and its de-husked rice (DR), were high compared to their respective native. True and bulk density were lowest for black variety, its DR, its raw and parboiled forms compared to other varieties of paddy. Angle of repose increased from raw paddy to PP whereas it decreased from raw DR to parboiled DR. Under similar conditions of milling of DR, raw and parboiled milled rice of black variety was the darkest. Raw husk showed higher EMC compared to husk of parboiled. Hardness followed the pattern: Raw: Paddy (~230-280 N) > DR (~120-260 N) > Milled rice (~110 N); for parboiled: DR (~270-480 N) > PP (~260-425 N) > Parboiled milled rice (~250-340 N). Cooking time was high for DR of parboiled ones and least for waxy raw milled rice. Results of this study will be helpful in understanding the quality of pigmented rice cultivars, design and fabrication of some of the equipments in rice processing industry. PMID- 26604349 TI - Development of multigrain premixes-its effect on rheological, textural and micro structural characteristics of dough and quality of biscuits. AB - Four different Multigrain Premixes (MGPs) namely MGP I, MGP II, MGP III, MGP IV were developed to select the best premix for preparation of biscuits based on nutritional value and biscuit quality. The MGPs were prepared using cereals (barley, sorghum, maize, oats), pulses (chickpea dhal, green gram, peas, soya flour), millets (pearl millet, finger millet) and wheat germ each at 20 % level. The MGPs developed had 22.91-27.84 % protein, 16.82-18.72 % dietary fiber and 3.11-3.46 % minerals. The wheat flour was replaced with MGPs separately at different levels of 10, 20, 30, 40 and 50 %. The incorporation of these MGPs significantly (p <= 0.05) decreased the water absorption (56.0-50.9 %), peak viscosity (273.67-154.92 RVU), biscuit spread ratio (10.28-8.15) and increased the pasting temperature (67.10-79.20 degrees C), dough hardness (311.66-460.26 N) and biscuit breaking strength (13.25-28.68 N). SEM studies showed that incorporation of MGP disrupted the protein matrix. Among the MGPs, MGP III was found to be more suitable even at the 40 % level for obtaining nutritious multigrain biscuits with higher protein, dietary fiber, and mineral content. PMID- 26604350 TI - Technological approach to reduce NaCl content of traditional smoked dry-cured hams: effect on quality properties and stability. AB - The modification of the salting procedure (from a three- to a two-salt coverage steps) and its effects on quality and stability properties has been investigated to reduce NaCl content of traditional dry-cured ham. The study was applied on green hams of small-S and large-L weight classes. Results evidenced that a two salt coverage steps salting could be applied to reduce significantly NaCl content of S-size hams and to reach the physico-chemical conditions required for microbial stability at the end of ripening. The final salt content of the products results (p < 0.05) to depend on salting procedure and initial weight of the hams, while limited differences on quality properties have been observed being the latter mainly associated to the pattern of the volatile compounds. In particular, aldehydes and hexanal content were lower in hams undergone to a 2 steps salting. Sensory analysis evidenced that the hams with reduced NaCl (2s-S and 2s-L) were less easy to chew, less salty and with a lower intensity of the smoky flavour in respect to the 3s- ones. The study confirmed the feasibility of salt content reduction of traditional dry-cured hams by modifying the salting process. However, the weight of the initial tights resulted a critical factor in affecting salting diffusion, salt content and water activity of the ripened products, their quality and stability properties. PMID- 26604351 TI - Influence of pin and hammer mill on grinding characteristics, thermal and antioxidant properties of coriander powder. AB - In present study, influence of grinding (hammer and pin mills) and moisture content (range: 6.4-13.6 % dry basis) on the quality traits of coriander powder were investigated. These include grinding parameters, colour parameters, specific heat, thermal conductivity, thermal diffusivity, glass transition temperature, essential oil, total phenolic content, total flavonoid content and DPPH scavenging (%) of coriander powder. For coriander seed, the geometric properties such as major, medium, minor dimensions, geometric mean diameter, arithmetic mean diameter, sphericity, surface area and volume of coriander seeds increased significantly with increasing moisture (6.4-13.6 % db). For coriander powder, the grinding parameters such as average particle size, volume surface mean diameter and volume mean diameter increased significantly with increasing moisture (6.4 13.6 % db). With the grinding method, the colour attributes of coriander powder such as L-value, a-value, b-value, hue angle and browning index varied significantly. It was observed that the specific heat followed second order polynomial relationship with temperature and moisture whereas thermal conductivity varied linearly with temperature and moisture content. The variation of glass transition temperature with moisture can be best represented in quadratic manner. Total flavonoid content (mg QE/g crude seed extract) and DPPH scavenging % activity of coriander powder is significantly affected by grinding methods. A lower value of specific heat was observed for hammer ground coriander powder as compared to pin mill ground coriander powder. The thermal conductivity of hammer mill ground coriander powder was higher as compared to pin mill ground coriander. It was observed that hammer mill yields more fine coriander powder in comparison to pin mill. The browning index was more in hammer mill ground coriander powder. PMID- 26604352 TI - Effects of polysaccharide-based edible coatings enriched with dietary fiber on quality attributes of fresh-cut apples. AB - Little information is available regarding the incorporation of dietary fiber into edible films and coatings. In this work, apple fiber and inulin were incorporated into polysaccharide-based (alginate, pectine and gellan gum) edible coating formulations and their effects on the quality attributes of fresh-cut apples were evaluated. Antioxidant properties, color, firmness, sensory quality and microbial growth of fresh-cut apple were studied during 16 days of storage at 4 degrees C. Results show that dietary fiber extracts incorporated to gellan gum, pectin and alginate-based coatings together with calcium chloride and ascorbic acid successfully maintained the firmness and color of coated fresh-cut apples in comparison with uncoated control samples, which presented severe texture softening and browning. The firmness of apple pieces coated with polysaccharide based coating formulations incorporating apple fiber doubled, and sometimes tripled, that of uncoated samples. Any of the assayed coatings exhibited a positive effect on the sensory properties of fresh-cut apples. The incorporation of apple fiber, together with the use of ascorbic acid, contributed to keep the antioxidant potential of the fruit at least during the first week of storage. Furthermore, gellan gum coatings had a marked effect in reducing mesophilic and psychrophilic counts on fresh-cut apples throughout storage regardless the addition of dietary fibers. The results achieved demonstrate the feasibility of the addition of dietary fiber to edible coating formulations for increasing the nutritional value of fresh-cut apples without compromising their fresh-like quality attributes. PMID- 26604353 TI - Impact of phytic acid on nutrient bioaccessibility and antioxidant properties of dehusked rice. AB - Whole grains consumption promotes health benefits, but demonstrates controversial impacts from phytic acid in meeting requirements of good health. Therefore, this study was aimed to determine the nutrient bioaccessibility and antioxidant properties of rice cultivars named "Adan" or "Bario" and deduce the nutritional impact of phytic acid. Majority of the dehusked rice in the collection showed an acceptable level of in-vitro starch digestibility and in-vitro protein digestibility, but were poor in antioxidant properties and bioaccessibility of minerals (Ca, Fe and Zn). The drawbacks identified in the rice cultivars were due to relatively high phytic acid content (2420.6 +/- 94.6 mg/100 g) and low phenolic content (152.39 +/- 18.84 MUg GAE/g). The relationship between phytic acid content and mineral bioaccessibility was strongest in calcium (r = 0.60), followed by iron (r = 0.40) and zinc (r = 0.27). Phytic acid content did not significantly correlate with in-vitro starch digestibility and in-vitro protein digestibility but showed a weak relationship with antioxidant properties. These suggest that phytic acid could significantly impair the mineral bioaccessibility of dehusked rice, and also act as an important antioxidant in non-pigmented rice. Bario rice cultivars offered dehusked rice with wide range of in-vitro digestibility of starch and protein, and also pigmented rice as a good source of antioxidants. However, there is a need to reduce phytic acid content in dehusked rice for improved mineral bioaccessibility among Bario rice cultivars. PMID- 26604354 TI - Optimization of continuous hydrothermal treatment for improving the dehulling of black gram (Vigna mungo L). AB - Black gram kernels with three initial moisture contents (10, 14 & 18 % w.b.) were steam treated in a continuous steaming unit at three inlet steam pressures (2, 3 & 4 kg/cm(2)) for three grain residence times (2, 4 & 6 min) in order to determine best treatment condition for maximizing the dhal yield while limiting the colour change in acceptable range. The dhal yield, dehulling loss and the colour difference (Delta E*) of the dehulled dhal were found to vary respectively, from 56.4 to 78.8 %, 30.8 to 8.6 % and 2.1 to 9.5 with increased severity of treatment. Optimization was done in order to obtain higher dhal yield while limiting the colour difference (Delta E*) within acceptable range i.e. 2.0 to 3.5 using response surface methodology. The best condition was obtained with the samples having 13.1 % initial moisture treated with 4 kg/cm(2) for about 6 min to achieve a dhal yield of 71.2 % and dehulling loss of 15.5 %. PMID- 26604355 TI - Bioactive constituents in liposomes incorporated in orange juice as new functional food: thermal stability, rheological and organoleptic properties. AB - Liposomes were developed with bioactive constituents (omega-3, omega-6, tocopherol) incorporated in acid food. They were made of soy phosphatidylcholine (SPC) allowing the encapsulation of antioxidant vitamin C (VC) and tocopherol. Stearic acid (SA) or calcium stearate (CaS) was added as a bilayer stabilizer. The structural and oxidative stability of the liposomes were studied considering the heat effect of pasteurization. Size was analyzed by light scattering; shape and structure were studied by optical and transmission electron microscopy, respectively. Membrane packing was studied with merocyanine 540. Surface charge and oxidative stability were analyzed by zeta potential and ORAC method, respectively. The liposomes showed significant stability in all of the parameters mentioned above and an important protective effect over thermolabile VC. To confirm their applicability in food, the rheological behavior and a sensory evaluation of liposomes with vitamin C and bioactive constituents were studied. The sensory evaluation of liposomes in orange juice was performed by the overall acceptability and triangular tests with 40 and 78 potential consumers, respectively. The incorporation of all liposomal formulation did not change the acceptability of orange juice. Noteworthy, SPC and SPC:SA systems had rheological behavior similar to a Newtonian fluid whereas that SPC:CaS presented a pseudoplastic one, both considered excellent for larger scale production. From all the obtained results, we can conclude that these liposomal formulations are suitable for food industry applications, incorporating bioactive constituents and generating functional orange juice that conserves its bioactivity after pasteurization. PMID- 26604356 TI - Optimization of pretreatments and process parameters for sorghum popping in microwave oven using response surface methodology. AB - Sorghum is a popular healthy snack food. Popped sorghum was prepared in a domestic microwave oven. A 3 factor 3 level Box and Behneken design was used to optimize the pretreatment conditions. Grains were preconditioned to 12-20 % moisture content by the addition of 0-2 % salt solutions. Oil was applied (0-10 % w/w) to the preconditioned grains. Optimization of the pretreatments was based on popping yield, volume expansion ratio, and sensory score. The optimized condition was found at 16.62 % (wb), 0.55 % salt and 10 % oil with popping yield of 82.228 %, volume expansion ratio of 14.564 and overall acceptability of 8.495. Further, the microwave process parameters were optimized using a 2 factor 3 level design having microwave power density ranging from 9 to 18 W/g and residence time ranging from 100 to 180 s. For the production of superior quality pop sorghum, the optimized microwave process parameters were microwave power density of 18 Wg( 1) and residence time of 140 s. PMID- 26604357 TI - Evaluation of antioxidant activity and nutritional composition of flavoured dehydrated soups packaged in different formats. Reducing the sodium content. AB - The antioxidant activity and nutritional composition of four dehydrated soups (vegetables, meat, chicken and fish) packaged in four formats - carton, plastic, and aluminium bags (the last with and without modified atmosphere) - were evaluated during 12 months' storage. The results showed that all four soups had a good or very good antioxidant capacity as tested by the lipid peroxidation, deoxyribose, and Trolox equivalent antioxidant capacity (TEAC) tests. Of interest from a nutritional point of view was the finding that the lipid fraction of all the soups was below 1 %. The sodium content of the four soups and their ingredients was also analysed. By modifying some of the ingredients, a 25 % reduction in the sodium content of the soups was obtained, permitting them to be labelled as "sodium reduced". The monosodium glutamate (MSG) content of the reformulated soups (lower sodium content) was below levels permitted by European legislation. PMID- 26604358 TI - Enhancing the functional properties and nutritional quality of ice cream with processed amla (Indian gooseberry). AB - Amla (Indian gooseberry) and its processed products are rich source of vitamin C, phenols, dietary fibre and antioxidants. In contrast, ice cream is a poor source of these phytochemicals and antioxidants; therefore, the present investigation was undertaken to enhance the functional properties and nutritional quality of ice cream with the incorporation of processed amla. Ice cream was prepared using amla shreds, pulp, preserve and candy at 5 to 20 % and powder at 0.5 to 2.0 % levels in ice cream mix prior to freezing. Inclusion of amla products at augmented levels resulted in significant changes in physico-chemical properties and phytochemical content of ice cream. The total solids decreased on addition of shreds and pulp and increased with preserve, candy and powder in ice cream at increasing levels. The functional constituents i.e. fibre, total phenols, tannins, ascorbic acid and antioxidant activity increased with greater level of inclusion. Incorporation of processed amla raised the melting resistance of ice cream and decreased the overrun. The samples with 5 % shreds and pulp, 10 % preserve and candy and 0.5 % powder were found to have highest overall acceptability scores. Inclusion of amla in all the forms i.e. shreds, pulp, preserve, candy and powder enhanced the functional properties and nutritional value of ice cream. PMID- 26604359 TI - Effect of pretreatments and modified atmosphere packaging on the shelf life and quality of fresh- cut green bell pepper. AB - Present study was aimed at understanding the effect of pretreatments and modified atmosphere packaging on the quality of fresh-cut green bell pepper (Capsicum annuum L.) during low temperature storage. Dip treatment of freshly cut green bell pepper pieces in 2 % calcium propionate followed by surface drying and subsequent packing in cryovac PD961 film which maintained an equilibrium modified atmosphere of 13-14 % O2 and 7 % CO2 helped to extend the marketability till 9 days storage at 8 degrees C. The microbiological quality was at the best level up to 6 days of storage, as evidenced by a surge in aerobic plate count, pectinolysers and pseudomonads on subsequent days. Head space volatile analysis of the produce at regular intervals showed a reduction in monoterpenoids and simultaneous increase of aldehydes and ketones, sesquiterpenoids, esters, furans and pyrazines during storage. Principal component analysis of the head space volatiles identified, cis - ocimene, 1,3,8-paramenthatriene, trans 3- caren 2-ol, bergamotene, 2-hexenal, ethyl 1- decanol, (E)-3- hexenol and heptane thiol as the markers of freshness in minimally processed green bell pepper. PMID- 26604360 TI - Ethanol extract of mango (Mangifera indica L.) peel inhibits alpha-amylase and alpha-glucosidase activities, and ameliorates diabetes related biochemical parameters in streptozotocin (STZ)-induced diabetic rats. AB - Peel is a major by-product during processing of mango fruit into pulp. Recent report indicates that the whole peel powder ameliorated diabetes. In the present study, ethanolic extract of mango peel was analysed for its bioactive compounds, evaluated for alpha-amylase and alpha-glucosidase inhibitory properties, oral glucose tolerance test, antioxidant properties, plasma insulin level and biochemical parameters related to diabetes. In addition to gallic and protocatechuic acids, the extract also had chlorogenic and ferulic acids, which were not reported earlier in mango peel extracts. The peel extract inhibited alpha-amylase and alpha-glucosidase activities, with IC50 values of 4.0 and 3.5 MUg/ml. Ethanolic extract of peel showed better glucose utilization in oral glucose tolerance test. Treatment of streptozotocin-induced diabetic rats with the extract decreased fasting blood glucose, fructosamine and glycated hemoglobin levels, and increased plasma insulin level. Peel extract treatment decreased malondialdehyde level, but increased the activities of antioxidant enzymes significantly in liver and kidney compared to diabetic rats. These beneficial effects were comparable to metformin, but better than gallic acid treated diabetic rats. The beneficial effects of peel extract may be through different mechanism like increased plasma insulin levels, decreased oxidative stress and inhibition of carbohydrate hydrolyzing enzyme activities by its bioactive compounds. Thus, results suggest that the peel extract can be a potential source of nutraceutical or can be used in functional foods and this is the first report on antidiabetic properties of mango peel extract. PMID- 26604361 TI - Antidiabetic and antioxidant activity of Stevia rebaudiana extracts (Var. Morita) and their incorporation into a potential functional bread. AB - In this study a new wheat bread was designed whose sugars were replaced with S. rebaudiana Bertoni aqueous extract. The impact of the S. rebaudiana Bertoni aqueous extract on nutritional and sensory quality, its ability to reduce sugar intake and its antioxidant properties were investigated. Functional bread with 50 % of sugars replaced with S. rebaudiana extract was compared with traditional wheat bread. The extract demonstrated alpha amylase (IC50 = 198.40 MUg/mL) glucosidase (596.77 MUg/mL) inhibition. The radical scavenging activity exhibited an IC50 value of 335.94 mg/mL. In comparison with the control, the bread with stevia extract was softer and had lower microbial growth during the shelf-life study. The sensory test showed that the substitution of 50 % stevia extract was more acceptable when comparing with all quality characteristics. Regarding the nutritional contribution, the content of dietary fiber and digestible carbohydrates in the bread with stevia extract was higher and lower respectively, so caloric intake was significantly reduced. The results showed that the biological properties of S. rebaudiana extract were retained after the bread making process and that the proposed bread is suitable as functional food in human nutrition. PMID- 26604362 TI - Effect of presoaking high hydrostatic pressure on the cooking properties of brown rice. AB - Effects of presoaking-high hydrostatic pressure (PHHP) on cooking time, hardness, gumminess, springiness, and microstructure of brown rice were evaluated. Compared with traditional soaking treatment, PHHP significantly shorten the cooking time of brown rice from 34 to 14 min. The hardness of brown rice treated by PHHP reduced remarkably, which is lower than that treated by soaking process and similar to that of white rice. The gumminess and springiness of brown rice dramatically decreased under pressure above 500 MPa. However, the water uptake capacity of brown rice treated by PHHP was not obviously affected, whose moisture contents were much lower than that of soaked samples. The analysis of thermal properties revealed that the enthalpy of brown rice was influenced by PHHP, and the denaturation of brown rice components generated. These results and microstructure analysis revealed that the structures of pericarp and aleurone layer of brown rice were damaged by PHHP, which allows water to be easily absorbed by the rice kernel during cooking process. PHHP treatment could be a potentially applicable pretreatment for improving cooking properties of brown rice. PMID- 26604363 TI - Anti- and pro-oxidative effect of fresh and freeze-dried vegetables during storage of mayonnaise. AB - Mayonnaise was supplemented with vegetables (5 % w/w) and the effect of storage time at 4 degrees C on the oxidative stability of the dispersed phase was investigated. Results indicated that mayonnaise is prone to lipid oxidation during storage under refrigerator conditions. The type of vegetable used for mayonnaise reformulation was critical in inhibiting oxidation and followed the order beetroot > carrot ~ onion with respect to antioxidant capacity. Broccoli induced a pro-oxidant effect and the rate of oxidation by the end of the storage period was 42 times higher compared with the control. The addition of beetroot, either fresh or freeze-dried, improved the oxidative stability of mayonnaise significantly. The process of freeze-drying affected adversely the ability of vegetables to decrease oil oxidation of the emulsions. This may reflect loss of important natural antioxidants during the drying procedure. PMID- 26604364 TI - Involvement of antioxidant activity of Lactobacillus plantarum on functional properties of olive phenolic compounds. AB - Eight lactic acid bacteria strains isolated from traditional fermented foods were investigated for their antioxidant activity against DPPH free radicals, beta carotene bleaching assay and linoleic acid test. L. plantarum LAB 1 at a dose of 8.2 10(9) CFU/ml showed the highest DPPH scavenging activity, with inhibition rate of 57.07 +/- 0.57 % and an antioxidant activity (TAA = 43.47 +/- 0.663 % and AAC = 172.65 +/- 5.57), which increase with cell concentrations. When L. plantarum LAB 1 was administered to oxidative enzymes, residual activities decreased significantly with cell concentrations. The use of L. plantarum LAB 1 on olives process, favours the increase of the antioxidant activity (24 %). HPLC results showed a significant increase of orthodiphenols (74 %). Viable cells of strain were implicated directly on minimum media growth with 500 mg/l of olive phenolic compounds. Results showed an increase in their antioxidant activity. CG SM analysis, identify the presence of compounds with higher antioxidant activity as vinyl phenol and hydroxytyrosol. PMID- 26604365 TI - Loss of lipid material during the dehulling of oilseeds with different structural characteristics. AB - The loss of lipid material by migration to the hull during the dehulling of oilseeds with different structural characteristics was evaluated. The samples selected -three sunflower hybrids and a safflower cultivar- were processed under optimal dehulling operating conditions and with two passes through a dehuller. From the SEM micrographs of the samples it was possible to observe structural differences which affect the mechanical properties of the pericarps and, consequently, the dehulling process. The black-hull sunflower hybrid exhibited residual hull percentages lightly above those recommended by the industry after one pass through the dehuller, therefore, this hybrid should not be further processed to avoid oil losses due to migration to the hull. On the other hand, the safflower cultivar and the high stearic high oleic sunflower hybrid and the traditional striped-hull sunflower require two passes through the dehuller, but this resulted in an oil loss due to migration to the hull of over 0.9 % per gram of grains processed. These results suggest the need to reach 'compromise' decisions based on economic impact studies in the face of the variables that originate simultaneously both positive and negative effects. PMID- 26604366 TI - Composition and antioxidant properties of wild mushrooms Boletus edulis and Xerocomus badius prepared for consumption. AB - Wild edible mushrooms Boletus edulis and Xerocomus badius were prepared for consumption by braising with 10 % canola oil (half of the batch was blanched prior to braising). Fresh X.badius had comparable to B.edulis amounts of proximate components and higher levels of most B-group vitamins and antioxidants. Analyzed mushrooms prepared for consumption fulfilled 7-14 % RDA of vitamin B1 for healthy adults and 15-35, 18-37 and 1 % RDA of B2, B3 and B3 respectively. Prepared for consumption mushrooms were rich in antioxidants containing in 100 g dry weight 164,601 mg total polyphenols, 19-87 mg total flavonoids, 22.1-27.4 mg L-ascorbic acid, 0.531-1.031 mg beta-carotene, 0.325-0.456 mg lycopene and 38.64 44.49 mg total tocopherols and presented high antioxidant activity against ABTS (4.9-36.5 mmol TE), against DPPH (7.8-21.3 mmol TE) and in FRAP assay (15.0-28.1 mmol Fe(2+)). Mushrooms prepared for consumption with blanching prior to culinary treatment showed lower antioxidant properties and vitamin content in comparison to mushrooms braised raw. PMID- 26604367 TI - Physicochemical characterization of white, yellow and purple maize flours and rheological characterization of their doughs. AB - White, yellow and purple maize flours were obtained after dried kernels milling with two different sieves (200 and 500 MUm). Hygroscopic characteristics, particle size distribution, colour and total starch and damaged starch (DS) of flours were determined. Maize flour doughs were obtained by mixing of flour and water in a laboratory kneader (Mixolab(r)) at constant dough consistency (1.10 +/ 0.07 Nm). Dough properties like water absorption (WA), development and stability times were determined. Rheological characterization was carried out at 30 degrees C by means of oscillatory frequency sweep (1-100 rad s(-1)) at 0.1 % strain and creep (50 Pa, 60 s) - recovery (0 Pa, 180 s) tests using a controlled stress rheometer. No significant differences were observed among water desorption isotherms of maize varieties and Halsey model was satisfactorily employed. Under the same milling conditions, white maize flours showed higher average particles size than purple and yellow maize flours. A model to predict flours colour involving colour parameters of the particle size fractions is proposed. Flours obtained with smaller particle size showed higher DS content and WA. For tested doughs, the mechanical spectra showed that elastic component was dominant over the viscous one. Damping factor varied slightly with angular frequency. Moduli values depended on average particle size and WA of dough. Creep-recovery data were satisfactorily fit with Burgers model. Instantaneous creep compliance varied with the same trend than elastic modulus. Viscoelastic creep compliance increased linearly with WA of the tested doughs and, at constant average flour particle size, increased with increasing DS. PMID- 26604368 TI - Serish inulin and wheat biopolymers interactions in model systems as a basis for understanding the impact of inulin on bread properties: a FTIR investigation. AB - In this study the interactions between Serish root inulin and the main biopolymer types of wheat flour namely gluten, starch and phospholipid, were investigated in different model systems using Fourier transform infrared (FTIR) spectroscopy to unravel the underlying physical mechanism by which inulin impacts dough and bread properties. Interactions of inulin with starch and phospholipid were not considerable compared to gluten, but it was also clear that the modes of these interactions varied with the type and the amount of additives used in model formulation. This study revealed that when inulin is added to gluten, water redistribution promotes partial dehydration of gluten and collapse of beta spirals into intermolecular beta-sheet structures; this trans-conformations might be due to physical reasons are believed to further impact the poor quality of bread containing added inulin. Upon performing Gaussian-Lorenzian curve fitting, it was observed that by adding of inulin to model systems, the relative contribution of characteristic peaks of beta-turn and intramolecular beta-sheet was progressively decreased whereas intermolecular beta-sheet and alpha-helix contents were increased. PMID- 26604369 TI - Application of ultrafiltration technique for the quality improvement of dahi. AB - Ultrafiltered milk (UF1 and UF2), ultrafiltrate retentate added milk (UF3 and UF4) and SMP added milk (UF0) were used for dahi preparation in the present study. Treatments were evaluated for rheological, textural and sensorial characteristics. Significant increase (p < 0.01) in values of firmness, stickiness, work of shear, work of adhesion and sensory scores, but significant decrease (p < 0.01) in whey syneresis values were observed with treatments UF1, UF2, UF3 and UF4 as compared to UF0. Principal component analysis (PCA) revealed that first four principal components (PC) explained 87.39 % relationship between samples and attributes. PC1 accounted for 48.34 % of data variance was characterized by protein content, firmness, work of shear, body & texture and opposed by total carbohydrates, stickiness, syneresis and work of adhesion. Total carbohydrates content (r = -0.982, P < 0.01), whey syneresis (r = -0.783, P < 0.01), stickiness (r = -0.729, P < 0.01) and work of adhesion (r = -0.684, P < 0.01) are negatively while body and texture (r = +0.600, P < 0.01), firmness (r = +0.574, P < 0.05) and work of shear (r = +0.538, P < 0.05) of dahi are highly positively correlated with protein content. PMID- 26604370 TI - Spatial variability of theaflavins and thearubigins fractions and their impact on black tea quality. AB - The spatial distribution of theaflavin and thearubigin fractions and their impact on black tea quality were investigated using multivariate and geostatistics techniques. Black tea samples were collected from tea gardens of six geographical regions of Assam and West Bengal, India. Total theaflavin (TF) and its four fractions of upper Assam, south bank and North Bank teas were higher than the other regions. Simple theaflavin showed highest significant correlation with tasters' quality. Low molecular weight thearubigins of south bank and North Bank were significantly higher than other regions. Total thearubigin (TR) and its fractions revealed significant positive correlation with tasters' organoleptic valuations. Tea tasters' parameters were significantly and positively correlated with each other. The semivariogram for quality parameters were best represented by gaussian models. The nugget/sill ratio indicated a strong/moderate spatial dependence of the studied parameters. Spatial variation of tea quality parameters may be used for quality assessment in the tea growing areas of India. PMID- 26604371 TI - Effect of garlic extract on physical, oxidative and microbial changes during refrigerated storage of restructured product from Thai pangas (pangasianodon hypophthalmus) surimi. AB - The effect of garlic's aqueous extract (GAE) during refrigerated storage of the restructured products from Pangasius (Pangasianodon hypophthalmus) was evaluated. Protein and lipid oxidation, protein pattern on SDS-PAGE, TPC as well as WHC, gelling properties, texture profiles and whiteness of the surimi gel was evaluated periodically during a refrigerated storage period of 20 days. Increase of water holding capacity in GAE added gels indicated stronger protein network formation, whereas, decrease of protein solubility suggested formation of protein aggregates during gelation process. Lipid oxidation decreased in treated samples but the rate of increase varied, depending upon the concentration of GAE. Protein carbonyl content increased during storage, but slow increase in treated samples. Gel strength in treated samples increased and accompanied by thickening of myofibrillar head chain. Hardness, adhesiveness and gumminess parameters affected most due to addition of GAE. Sensory analysis revealed that the RP with 1 % GAE preferred most and control was acceptable upto 12 days. PMID- 26604372 TI - Solubility of caffeine from green tea in supercritical CO2: a theoretical and empirical approach. AB - Decaffeination of fresh green tea was carried out with supercritical CO2 in the presence of ethanol as co-solvent. The solubility of caffeine in supercritical CO2 varied from 44.19 * 10(-6) to 149.55 * 10(-6) (mole fraction) over a pressure and temperature range of 15 to 35 MPa and 313 to 333 K, respectively. The maximum solubility of caffeine was obtained at 25 MPa and 323 K. Experimental solubility data were correlated with the theoretical equation of state models Peng-Robinson (PR), Soave Redlich-Kwong (SRK), and Redlich-Kwong (RK). The RK model had regressed experimental data with 15.52 % average absolute relative deviation (AARD). In contrast, Gordillo empirical model regressed the best to experimental data with only 0.96 % AARD. Under supercritical conditions, solubility of caffeine in tea matrix was lower than the solubility of pure caffeine. Further, solubility of caffeine in supercritical CO2 was compared with solubility of pure caffeine in conventional solvents and a maximum solubility 90 * 10(-3) mol fraction was obtained with chloroform. PMID- 26604373 TI - Rice phytochemicals concentrated by molecular distillation process and their use as co-surfactant in water dispersion. AB - This study investigated the effects of evaporating temperature during molecular distillation (MD) process employed to deodorizer distillate (DD) on the retention of rice phytochemicals in the unevaporated fraction (UMDs), which were then further used as co-surfactants in the fabrication of water-dispersible vesicles. The pilot-scale MD unit was operated at 120, 140 or 160 degrees C and 0.1 Pa to concentrate rice phytosterols from 1540.8 mg in 100 g DD to 3990.2-4904.8 mg in 100 g UMDs by evaporating out free fatty acids. Although gamma-oryzanol content was increased from 598.9 mg in 100 g DD to 870.0-1018.1 mg in 100 g UMDs when the temperature was raised to 160 degrees C, such high temperature decreased tocols from 2185.7 mg in 100 g DD to 850.5 mg in 100 g UMDs and antioxidant capacity of UMDs measured as 2,2-diphenyl-1-picrylhydrazyl scavenging capacity. The UMD obtained after distillation at 140 degrees C was used as co-surfactant with soy lecithin, sucrose palmitate or polyoxyethylene sorbitan monooleate (Tween 80) to fabricate vesicles in pH 7.0 phosphate buffered saline (PBS). This study showed potential use of the UMD as a source of rice phytochemicals and a co-surfactant when used with Tween80 in small vesicle fabrication. The fabricated Tween 80/UMD vesicles in PBS had the size range of 200-300 nm and were stable within a temperature range of 4 to 37 degrees C for 96 h. PMID- 26604374 TI - The effect of terebinth (Pistacia terebinthus L.) coffee addition on the chemical and physical characteristics, colour values, organic acid profiles, mineral compositions and sensory properties of ice creams. AB - The aim of this research was to evaluate the effect of terebinth (Pistacia terebinthus L.) coffee addition (0.5, 1 and 2 %) on the chemical and physical properties, colour values, organic acid profiles, mineral contents and sensory characteristics of ice creams. The total solids, fat, titratable acidity, viscosity, first dripping time and complete melting time values, a (*) and b (*) colour properties, citric, lactic, acetic and butyric acid levels and Ca, Cu, Mg, Fe, K, Zn and Na concentrations of ice creams showed an increase with the increment of terebinth coffee amount, while protein, pH, L (*), propionic acid and orotic acid values decreased. However, Al and malic acid were not detected in any of the samples. The overall acceptability scores of the sensory properties showed that the addition of 1 % terebinth coffee to the ice cream was more appreciated by the panellists. PMID- 26604375 TI - Effect of maize based composite flour noodles on functional, sensory, nutritional and storage quality. AB - To explore the feasibility of utilization of maize flour in noodle preparation, eight different combinations (T1 to T8) with varied amount of maize flour (MF), refined wheat flour (RWF), rice flour (RF), wheat gluten (WG), soya protein isolate (SPI), kansui (Sodium Carbonates), potato starch (PS) were extruded to standardize good quality noodles. Among various combinations tested, the combination T5 (50 %MF + 30 %RWF + 10 %SPI + 7 %RF + 3 %WG) was rated the best for appearance (8.3) colour (8.25) taste (8.5) elasticity (8.3) with an overall acceptability of 8.2 on a nine point hedonic rating sensory scale. There was no significant difference in normal noodle (NN) and Quality protein maize (QPM) noodle (QN) for T5 with respect to sensory characteristics when compared to control noodle (CN) prepared out of refined wheat flour. The cooked yield was more for maize based noodle (234 g NN and 220 g QN) with lower cooking loss of 7.80 and 7.76 respectively for NN & QN. The nutritional composition of maize noodles revealed that addition of 10 % soya protein isolate had increased the protein content of noodles to the tune of 16.6 and 12.7 % in QN and NN respectively. The soluble (3.18NN, 3.76QN) and insoluble fiber (21.67NN, 21.87QN) contents of both NN & QN was significantly more compared to CN (0.15 and 9.3 g).There was non- significant increase in moisture and peroxide values up to 3 months of storage with high overall acceptable sensory scores (4.0, 4.1, & 4.2 respectively for NN, QN and CN but beyond third month of storage the increase was significant. However the noodles were within the acceptable range up to 6 months of storage with an overall acceptability score of 3.0, 3.4 and 3.2 for NN, QN and CN respectively on a five point hedonic scale. PMID- 26604376 TI - Effect of the phytochemicals curcumin, cinnamaldehyde, thymol and carvacrol on the oxidative stability of corn and palm oils at frying temperatures. AB - Several active components naturally available in plants are strongly considered as good antioxidants to retard the lipid oxidation. Response surface methodology was used to investigate the effects of frying temperature (150-180 degrees C) and concentration of four plant-based active components (60-350 mg/kg oil); curcumin, cinnamaldehyde, thymol and carvacrol on oxidative stability of corn and palm oils. According to induction time values, the stability of oils drastically decreased with increasing temperature. Curcumin and cinnamaldehyde showed no significant effect (p > 0.05) on both oils. Carvacrol significantly increased induction times of corn and palm oils, but thymol was effective in palm oil only (p < 0.05). An actual frying experiment was carried out with only corn oil to confirm efficiency of carvacrol. The free fatty acid (%), peroxide value (meq/kg), para-anisidine, and total polar component values (%) of the fresh oil were 0.080, 2.55, 2.85, and 7.5, respectively. These values changed to 0.144, 1.47, 12.01, 10.0, respectively for the control oil; 0.138, 2.27, 11.49, 10.0 for BHT-added oil; 0.132, 1.42, 5.66, 9.5 for carvacrol-added oil after 30 frying cycles. Therefore, carvacrol could be considered as a good alternative to BHT for preservation of oils at frying temperatures. PMID- 26604377 TI - Effect of roasting conditions on the browning intensity and structural changes in jackfruit (Artocarpus hetrophyllus) seeds. AB - Central composite rotatable design (CCRD) was used to optimize the settings for the roasting conditions of jackfruit (Artocapus hetrophyllus) seed (JFS). The response variables studied were; color attributes L*, a*, and b*, browning intensity, and fracturability. The colors L*, a*, b* and browning intensity were well predicted by a second-order polynomial model. Fracturability was predicted by a first-order polynomial. The determination coefficients for colors L*, a*, b*, browning intensity, and fracturability were 0.81, 0.96, 0.93, 0.92, and 0.74 respectively. The fitted models were checked for adequacy using analysis of variance (ANOVA). The optimum roasting conditions were established at a temperature of 153.36 degrees C, 34.36 min, and pH of 6.34 with composite desirability value of 0.95. Micro-structural studies of both raw and roasted JFS at different roasting levels (i.e., low, medium, and high) were also investigated using scanning electron microscope (SEM). JFS starch granules fell in the B-type category with semi-oval to bell-shaped granules (5-9 MUm in diameter). In addition, Fourier Transform Infrared analysis was carried out on both raw and roasted JFS. The IR spectra was in the 4000-1000 cm(-1) region which is described by five main modes; O-H, C-H, C = O, (C-H) CH3, and C-O. PMID- 26604378 TI - In-vitro antioxidant and antibacterial properties of fermentatively and enzymatically prepared chicken liver protein hydrolysates. AB - Protein hydrolysates were prepared from chicken liver using fermentation and enzymatic hydrolysis. The lactic acid bacteria Pediococcus acidilactici NCIM5368 was employed in the fermentation process and a commercial protease (Alcalase(r) 2.5) was used in enzymatic hydrolysis. Chicken liver hydrolysates prepared by fermentation (FCLH) and enzymatic hydrolysis (ECLH) revealed appreciable amounts of protein [55.85 and 61.34 %; on dry weight basis, respectively]. Fermentation and enzymatic hydrolysis resulted in 14.3 and 26.12 % of degree of hydrolysis. Total antioxidant activity, reducing power, scavenging of superoxide, 2- diphenyl 1-picrylhydrazyl (DPPH) and 2, 2-azino-bis-3-ethyl-benzthiazoline-6-sulphonic acid (ABTS) radicals were determined for both FCLH & ECLH. FCLH & ECLH showed total antioxidant activity of 0.99 and 1.13 MUg AAE mg(-1) proteins, respectively; while, they scavenged 96.14 and 92.76 % of DPPH radicals respectively. FCLH showed higher ABTS radical scavenging activity (32.16 %) than ECLH (19.29 %). Superoxide anion scavenging activity of FCLH & ECLH were found to be 95.02 & 88.94 %, respectively. Residues obtained after both treatments also exhibited antioxidant activities. FCLH reported highest antagonistic activity against Listeria monocytogenes (30 mm); while, ECLH showed antibacterial activity only against Micrococcus luteus (12 mm). Both hydrolysates have the potential to be a protein rich ingredient for use in formulated foods and possible help in reduction of oxidative stress. PMID- 26604379 TI - Development of slow release formulations of beta-carotene employing amphiphilic polymers and their release kinetics study in water and different pH conditions. AB - beta-carotene, a potent antioxidant, has been encapsulated and slow release (SR) formulations were prepared using laboratory synthesized poly(ethylene glycols) (PEGs) based functionalized amphiphilic copolymers. Encapsulation efficiency and loading capacity of the developed formulations were determined which ranged from 22.60 to 28.08 % and 2.2 to 2.8 % respectively. The release kinetics of beta carotene from developed formulations in water revealed increased solubility and prolonged stability of beta-carotene. The formulations were further subjected to different pH conditions (viz., 1.8, 6.8 and 7.8) corresponding to human gastrointestinal tract to study the effect of pH on the release of beta-carotene. The diffusion exponent (n values) ranged from the 0.1540 to 0.2342 for developed formulation. The results showed that developed slow release formulations were unaffected by the highly acidic conditions referring to the gastric environment of human body. However, the release of beta-carotene was high at pH 7.8 and slightly higher at pH 6.8. PMID- 26604380 TI - A high correlation indicating for an evaluation of antioxidant activity and total phenolics content of various chilli varieties. AB - Use of dimethyl sulfoxide (DMSO) as a suitable extraction solvent under the optimum conditions of microwave assisted extraction (MAE) prior to total phenolics determination and antioxidant activity assay was conducted. The MAE method was done with 0.05 g sample in 10 mL DMSO at 500 W within 5 min. The effects of DMSO on various antioxidant activities using DPPH(.+), DMPD(.+), ABTS(.+) and FRAP, and Folin-Ciocalteu reagent were investigated. From the results, it is clearly demonstrated that the DMSO itself shows no effect on any of those antioxidant assays including total phenolics content. The DMSO extracts of 14 local chilli varieties gave their antioxidant activities in the following ranges: DPPH, 3.07-20.0; DMPD, 1.52-6.61; ABTS, 20.4-56.0; FRAP, 8.98-42.1 mg GA/g DW. Their total phenolics contents were found in the range of 53.7-200 mg GA/g DW. This study demonstrates that DMSO was found as the most suitable extraction solvent for antioxidants and phenolics from chilli. In addition, analysis of the data obtained among four antioxidant activity assays with respect to total phenolics shows a highly significant and positive regression coefficient (r > 0.92), indicating the total phenolics are primarily responsible for their antioxidant activity of the chilli extract. PMID- 26604381 TI - A comparative study of the capsaicinoid and phenolic contents and in vitro antioxidant activities of the peppers of the genus Capsicum: an application of chemometrics. AB - This paper presents a comparison of the contents of capsaicin, dihydrocapsaicin and total phenolics as well as of the antioxidant activities of six types of peppers of the genus Capsicum. The varieties were analyzed in terms of their in vitro antioxidant activity using ferric reducing antioxidant powder (FRAP), 1,1 diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis 3-ethylbenzothiazoline 6 sulfonate (ABTS(?+)) assays. The contents of phenolics and capsainoids as well as the antioxidant activities were higher in seeds than in pulps. The correlations (rho < 0.01) between the phenolic composition and the capsaicinoids levels were high (r = 0.98). Similarly high were also the correlations between the antioxidant activities and the contents of total phenolics and capsaicinoids. Data were analyzed using principal component analysis (PCA), hierarchical cluster analysis (HCA) and multiple linear regression (MLR). PCA explained 97.77 % of the total variance of the data, and their separation into three groups in a scatter plot was divised. Using HCA, three clusters were suggested. Cluster one, formed by pulps (bell pepper, orange habanero, cayenne, dedo de moca and red habanero), showed the lowest levels of the compounds quantified. Most seed samples were grouped in cluster two (bell pepper, cayenne, dedo de moca and malagueta) together with malagueta pulp. Cluster three was formed by orange and red habanero seeds, which showed the highest levels of all compounds analyzed. The MRL revealed that the values of capsaicinoids and total phenols are more adequate to predict the antioxidant activity measured by the FRAP assay. PMID- 26604382 TI - Exploring the heat-induced structural changes of beta-lactoglobulin -linoleic acid complex by fluorescence spectroscopy and molecular modeling techniques. AB - Linoleic acid (LA) is the precursor of bioactive oxidized linoleic acid metabolites and arachidonic acid, therefore is essential for human growth and plays an important role in good health in general. Because of the low water solubility and sensitivity to oxidation, new ways of LA delivery without compromising the sensory attributes of the enriched products are to be identified. The major whey protein, beta-lactoglobulin (beta-Lg), is a natural carrier for hydrophobic molecules. The thermal induced changes of the beta-Lg-LA complex were investigated in the temperature range from 25 to 85 degrees C using fluorescence spectroscopy techniques in combination with molecular modeling study and the results were compared with those obtained for beta-Lg. Experimental results indicated that, regardless of LA binding, the polypeptide chain rearrangements at temperatures higher than 75 degrees C lead to higher exposure of hydrophobic residues causing the increase of fluorescence intensity. Phase diagram indicated an all or none transition between two conformations. The LA surface involved in the interaction with beta-Lg was about 497 A(2), indicating a good affinity between those two components even at high temperatures. Results obtained in this study provide important details about heat-induced changes in the conformation of beta-Lg-LA complex. The thermal treatment at high temperature does not affect the LA binding and carrier functions of beta-Lg. PMID- 26604383 TI - Xanthan gum as a fat replacer in goshtaba-a traditional meat product of India: effects on quality and oxidative stability. AB - Goshtaba is a restructured meat product of Kashmiri wazwan prepared from meat emulsion with added fat (20 %), salt, spices and condiments and cooked in the curd. The present study was undertaken for the development of low fat goshtaba with the addition of xanthan gum as a fat replacer and was evaluated for proximate composition, pH, colour, lipid and protein oxidation, texture, microstructure and sensory properties. Low fat goshtaba formulations containing xanthan gum were higher in protein and moisture contents but, lower in fat content and pH value than the high fat control (p < 0.05). Colour evaluation revealed that high fat goshtaba had significantly higher L* value, but lower a* value than its low fat counterparts (p < 0.05). The significant decrease of TBARS values, protein carbonyls and loss of protein sulphydryl groups in low fat goshtaba formulations reflects the potential antioxidant activity of xanthan gum (p < 0.05). Hardness was significantly higher in high fat control but, cohesiveness, gumminess, and chewiness did not show any significant difference. Springiness increased with the increasing concentration of xanthan gum (0.5-1.5 %) and was higher in low fat product containing 1.5 % xanthan gum. SEM results indicate that xanthan gum lead to formation of an additional gel network which holds more water. Sensory evaluation revealed that goshtaba product with 0.5 % xanthan gum had quality characteristics that were similar to the control product containing 20 % fat. PMID- 26604384 TI - Effect of guar gum and xanthan gum on pasting and noodle-making properties of potato, corn and mung bean starches. AB - The effect of xanthan and guar-gum on pasting and noodle-making properties of potato, corn and mung bean starches was studied. Mung bean starch showed the highest amylose content (43.4 %) followed by potato (23.2 %) and corn starch (15.5 %). Potato starch showed the highest swelling power (19.0 g/g) and solubility index (17.5 %) and exhibited the highest paste viscosities. Addition of both gums improved peak viscosity, hot paste viscosity and final viscosity for mung and corn starches; while for potato starch, guar gum increased peak and final viscosities and decreased hot paste viscosity while xanthan gum increased hot paste and final viscosities and decreased peak viscosity. The noodles made from mung bean starch showed the most desirable characteristics in terms of the lowest-cooking loss and adhesiveness. The gums increased noodle cooking time and decreased cooking loss, firmness and cohesiveness. PMID- 26604385 TI - Effect of virgin coconut meal (VCM) on the rheological, micro-structure and baking properties of cake and batter. AB - Virgin coconut meal (VCM) cakes were prepared by replacing refined wheat flour (maida) (5 to 20 % level) to check its effect on chemical, textural and rheological attributes of cake. The addition of VCM significantly (p <= 0.05) increased redness (a*), yellowness (b*) while reduced lightness (L*) of cakes. The incorporation of VCM affects the hardness, adhesiveness gumminess and chewiness of cake. The effect of flour replacement with VCM increased the viscosity of batter which leads to increase in consistency index and lower the shearthining behavior. The viscoelastic behavior of cake batter in which elastic modulus (G') and viscous modulus (G") both were decreased with the increase in percentage of VCM. The differential scanning calorimetry (DSC) analysis revealed that the onset (To), end set (Tc) and enthalpy of gelatinization (DeltaH) increased with the increased level of VCM. PMID- 26604386 TI - Fourier transform infrared spectroscopy (FTIR) analysis, chlorophyll content and antioxidant properties of native and defatted foliage of green leafy vegetables. AB - FTIR analysis for five selected green leafy vegetables (GLVs) viz., Hibiscus cannabinus L., (kenaf), H. sabdariffa L., (roselle), Basella alba L., (vine spinach), B. rubra L. (malabar spinach) and Rumex vesicarius L., (sorrel) confirmed the presence of free alcohol, intermolecular bonded alcohol, intramolecular bonded alcohol, alkane, aromatic compounds, imine or oxime or ketone or alkene, phenol and amine stretching. The chlorophyll content was higher in native leaves of B. alba (2.96 g/kg) than defatted samples (1.11 g/kg). Total phenolic content (TPC) in H. sabdariffa native methanol extractives is more (17.6 g/kg) than defatted leaves (9.67 g/kg). Native B. rubra methanol extractives exhibited highest total flavonoid content (TFC) (21.59 g/kg), while that of R. vesicarius was lowest (3.21 g/kg). In general, antioxidant activities showed a significant reduction in retention of antioxidants in both native and defatted GLVs samples of ethanol and methanol extractives. Methanol extractives showed significantly stronger antioxidant activity probably due to greater solubility of phenolics and destruction of cellular components. PMID- 26604388 TI - Extension of the shelf life of guava by individual packaging with cling and shrink films. AB - Guava is a climacteric fruit so physico-chemical changes continuously occur after harvest till fruit become unfit for consumption and suffers from post harvest losses. The main objective of this work was to assess the effectiveness of individual film in form of Shrink and Cling wrap on shelf life of guava. Fruits were individually packed in polythene bags (LDPE) of 200 gauge thickness by Shrink and Cling wrapping and stored at 7 +/- 3 degrees C. Individual wrapping reduced the magnitude of changes during storage i.e., ripening process drastically as evident from lower total soluble solids, higher ascorbic acid, polyphenol content with lower polyphenol oxidase activity and physiological loss of weight (PLW) was less than 3.5 %. Film wrapping preserved freshness of wrapped fruits as they remained acceptable for whole storage time in contrast to control fruits which turned unacceptable by 15(th) day of storage. Control fruits showed significant compositional changes as well as in polyphenol content, ascorbic acid and reduced number of marketable fruits while Cling and Shrink wrapping enhanced the shelf life by 10 days. PMID- 26604387 TI - Optimization of ultrasound assisted extraction of anthocyanins from red cabbage using Taguchi design method. AB - There is a growing demand for developing suitable and more efficient extraction of active compounds from the plants and ultrasound is one of these novel methodologies. Moreover, the experimental set up to reach an appropriate condition for an optimum yield is demanding and time consuming. In the present study, Taguchi L9 orthogonal design was applied to optimize the process parameters (output power, time, temperature and pulse mode) for ultrasound assisted extraction of anthocyanins from red cabbage and the concluding yield of anthocyanin was measured by pH differential method. The statistical analysis revealed that the most important factors contributing to the extraction efficiency were time, temperature and power, respectively and the optimum condition was at 30 min, 15 degrees C and 100 W which could result the maximum anthocyanin yield of about 20.9 mg/L. The theoretical result was confirmed experimentally by carrying out the trials at the optimum condition and evaluating the actual yield. PMID- 26604389 TI - Advanced trends in controlling Helicobacter pylori infections using functional and therapeutically supplements in baby milk. AB - Helicobacter pylori is a common human pathogen infecting about 30 % of children and 60 % of adults worldwide. It is responsible for diseases such as gastritis, peptic ulcer and gastric cancer. H. pylori treatment based on antibiotics with proton pump inhibitor, but therapy failure is shown to be higher than 20 % and is essentially due to an increasing in prevalence of antibiotic-resistant bacteria, which has led to the search for alternative therapies. In this study, we discuss the usage of natural extracts mixture as alternative or complementary agents in controlling H. pylori infection so here, we focused on the plant extracts of (Cloves, Pepper, Cumin, Sage, Pomegranate peel, Ginger, Myrrh and Licorice). To that end, Phytochemical constituents detection like Tannins, Glycosides, Alkaloids, Flavonoids, Terpenoids, Saponins, Phenolic compounds, Reducing sugars, Volatile oils, Amino acids and Proteins was demonstrated. Each plant extract was examined individually or in combination for its antimicrobial activity against H. pylori. Out of the used extracts, four mixes were prepared and tested against H. pylori. The antibacterial activities of the four mixes, represented by the diameter of inhibition clear zone, recorded 21, 39, 23 and 28 mm. The most potent mix (mix2) was chosen and mixed with baby milk as a new combination for H. pylori infections treatment in babies. PMID- 26604390 TI - Effect of resistant starch and aging conditions on the physicochemical properties of frozen soy yogurt. AB - The present study investigated the effects of resistant starch concentration (0, 1, 2 %), aging time (2, 13, 24 h) and aging temperature (2, 4, 6 degrees C) on the physicochemical properties of frozen soy yogurt. The results showed that resistant starch increased viscosity because of its water binding properties. Resistant starch also increased foam stability, fat destabilization, and hardness, but it decreased overrun and meltdown rate. Viscosity, hardness and fat destabilization increased as aging time increased. An increase in aging temperature decreased viscosity, overrun, hardness and fat destabilization of frozen yoghurt, but increased the meltdown rate. PMID- 26604391 TI - Oxidative stability, chemical composition and organoleptic properties of seinat (Cucumis melo var. tibish) seed oil blends with peanut oil from China. AB - Seinat seed oil was blended with peanut oil for the enhancement of stability and chemical characteristics of the blend. The physicochemical properties (relative density, refractive index, free fatty acids, saponification value, iodine value and peroxide value) of seinat seed and peanut oil blends in ratios 95:5, 85:15, 30:70 and 50:50 proportions were evaluated, as well as oxidative stability index, deferential scanning calorimetric (DSC) characteristics and tocopherols content. Results of oil blend showed that there was no negative effect by the addition of seinat seed oil to peanut oil and also had decreased percentages of all saturated fatty acids except stearic acid, conversely, increased the levels of unsaturated fatty acids. As for the sensory evaluation, the panelist results showed that seinat seed oil blends had no significant differences (p < 0.05) in all attributes except the purity. The results indicated that the blending of seinat seed oil with peanut oil had also increased the stability and tocopherols content. As Sudan is the first producer of seinat oil, blending of seinat seed oil with traditional oil like quality, and may decrease the consumption of other expensive edible oils. PMID- 26604392 TI - Thermodynamic sorption of red cabbage extract (Brassica oleracea L. var. capitata L. f. rubra) encapsulated by spray drying. AB - Red cabbage aqueous extract acidified with 2 % citric acid was spray-dried using gum Arabic as encapsulating agent. The concentration of anthocyanin in the powder was 253.45 +/- 10.82 mg/100 g of dry basis and antioxidant activity of 4.6 +/- 0.2 mmol trolox/kg of dry basis. The sorption isotherms were determined at 15, 25 and 35 degrees C, and the GAB model was the one that best adjusted to the experimental data. The differential enthalpy and entropy for moisture levels up to 2 g of water/g of dry basis decreased to a minimum value of -4.36 kJ/mol and 0.019 kJ/molK respectively, and then increased in magnitude with the rise in moisture content to levels close to the free moisture with a spontaneous process, governed by the entropy. The spreading pressure increased with the rise in water activity for all temperatures, while net integral enthalpy and entropy decreased with the rise in moisture content reaching levels close to 10 kJ/mol and 0.025 kJ/molK, respectively. PMID- 26604393 TI - Effect of extruded wheat flour as a fat replacer on batter characteristics and cake quality. AB - The effects of three levels of fat replacement (1/3, 2/3, and 3/3) by extruded flour paste and the effects of the presence of emulsifier on layer cake batter characteristics and final cake quality were studied. Replacement of oil by extruded flour paste modified the batter density and microscopy, reducing the number of air bubbles and increasing their size, while emulsifier incorporation facilitated air entrapment in batter. Emulsifier addition also increased the elastic and viscous moduli of the batter, while oil reduction resulted in a less structured batter. Emulsifier incorporation leads to good quality cakes, minimizing the negative effect of oil reduction, maintaining the volume and reducing the hardness of cakes. Furthermore, consumer acceptability of the reduced fat cakes was improved by the addition of emulsifier. Thus, the results confirmed the positive effect of partial oil substitution (up to 2/3) by extruded flour paste on the quality of reduced fat cakes when emulsifier was incorporated. PMID- 26604394 TI - Antibacterial mechanism and activities of black pepper chloroform extract. AB - Black pepper extracts reportedly inhibit food spoilage and food pathogenic bacteria. This study explored the antimicrobial activity of black pepper chloroform extract (BPCE) against Escherichia coli and Staphylococcus aureus. The antibacterial mechanism of BPCE was elucidated by analyzing the cell morphology, respiratory metabolism, pyruvic acid content, and ATP levels of the target bacteria. Scanning electron micrographs showed that the bacterial cells were destroyed and that plasmolysis was induced. BPCE inhibited the tricarboxylic acid pathway of the bacteria. The extract significantly increased pyruvic acid concentration in bacterial solutions and reduced ATP level in bacterial cells. BPCE destroyed the permeability of the cell membrane, which consequently caused metabolic dysfunction, inhibited energy synthesis, and triggered cell death. PMID- 26604395 TI - Quality evaluation of yellow peach chips prepared by explosion puffing drying. AB - Nineteen evaluation indicators in 15 yellow peach chips prepared by explosion puffing drying were analyzed, including color, rehydration ratio, texture, and so on. The analysis methods of principle component analysis (PCA), analytic hierarchy process (AHP), K-means cluster (KC) and Discriminate analysis (DA) were used to analyze the comprehensive quality of the yellow peach chips. The dispersed coefficient of variation of the 19 evaluation indicators varied from 3.58 to 852.89 %, suggesting significant differences among yellow peach cultivars. The characteristic evaluation indicators, namely, reducing sugar content, out-put ratio, water content, a value and L value were analyzed by PCA, and their weights 0.0429, 0.1140, 0.4816, 1.1807 and 0.1807 were obtained by AHP. The levels in 15 cultivars effectively were classified by discrimination functions which obtained by KC and DA. The results suggested that three levels of comprehensive quality for yellow peach chips were divided, and the highest synthesis scores was observed in "senggelin" (11.1037), while the lowest synthesis value was found in "goldbaby" (-3.7600). PMID- 26604396 TI - Comparison between two different methods to obtain the proportions of myoglobin redox forms on fresh meat from reflectance measurements. AB - Two procedures based on reflectance (R) measurements to calculate the proportions of deoxymyoglobin (DMb), oxymyoglobin (OMb) and metmyoglobin (MMb) in meat are recommended by the American Meat Science Association (AMSA). One uses the K/S ratios (K and S are the absorption and scattering coefficients) and the other method (Krzywicki 1979) uses the reflex attenuance A = log (1/R). Both methods were compared in: a) synthetic sets of two pigment mixtures and b) 15 samples of beef Longissimus Lumborum measured after 24 h, 4 and 7 days of exposure to air. It was found that K/S and Krzywicki methods gave different values of pigment proportions. However both methods exhibited a high linear correlation (R(2) = 0.8733 in DMb, R(2) = 0.9771 in OMb and R(2) = 0.9390 in MMb, p < 0.0001). This makes them equivalent for statistical analysis based on differences in pigment proportions. PMID- 26604397 TI - Antioxidant activities of orange peel extract in ghee (butter oil) stored at different storage temperatures. AB - Antioxidant activities of butylatedhydroxyanisole (BHA) and orange peel powder extract in ghee stored at different storage temperatures (T1:6 +/- 2 degrees C; T2: 32 +/- 2 degrees C; T3:60 +/- 2 degrees C) were evaluated during storage period of 21 days. Peroxide value (PV), thiobarbituric acid (TBA), radical scavenging activity (RSA) and free fatty acids (FFA) of ghee samples were analyzed during the study. PV, TBA and FFA of ghee samples increased significantly while radical scavenging activity (RSA) of ghee samples decreased significantly at accelerated temperature (T3) as compared to the temperatures at T1 and T2. Effect of storage temperature on development of peroxides and TBA of ghee samples was significantly higher than the effect of treatment and storage period while treatment had more significant effect on the change in FFA and RSA as compared to storage temperature and storage period. Ghee incorporated with orange peel extract (OPE) showed stronger activity in quenching DPPH radicals and least development of PV, TBA and FFA than ghee incorporated with BHA and control. The study revealed that orange peel could be a good natural source of antioxidants which can be used in fat rich food products like ghee to retard oxidative deterioration. PMID- 26604398 TI - Effect of sequential bio-processing conditions on the content and composition of vitamin K2 and isoflavones in fermented soy food. AB - In the present research, effect of sequential addition of Bifidobacterium bifidum, Bacillus subtilis and Rhizopus oligosporus on content and composition of vitamin K2 and isoflavones in fermented soy foods have been investigated. Initially, soybeans were fermented with B. bifidum; then this fermented mass was re-fermented with co-culture of B. subtilis and R. oligosporus. The evolved sequence of microbes inoculation tended towards significantly (p < 0.5) higher enzymes levels (126.16 +/- 2.23 IU/mg lipase, 36.52 +/- 1.25 IU/mg phytase and 8.52 +/- 1.12 IU/mg beta-glucosidase); maximum menaquinone-7 production (9.3 +/- 1.27 MUg/g); and isoflavone content (84.64 +/- 1.97 % daidzein, 99.29 +/- 0.86 % genistein, 96.42 +/- 1.32 % glycitein) after 72 h of solid-state fermentation. The study showed that co-fermentation of soybean with different microbes in a particular sequence can enhance nutritional value batter than the mono-culture fermentation due to the positive correlation between enzymes (lipase, phytase, beta-glucosidase) levels, menaquinone-7 and soy isoflavones content. PMID- 26604399 TI - Thermal inactivation of Salmonella Enteritidis on chicken skin previously exposed to acidified Sodium chlorite or tri-sodium phosphate. AB - Thermal inactivation of normal and starved cells of Salmonella Enteritidis on chicken skin previously exposed to different concentrations of acidified sodium chlorite (ASC) or tri-sodium phosphate (TSP) was investigated. Inoculated skin was pretreated with different concentration of ASC or TSP, packaged in bags, and then immersed in a circulating water bath at 60 to 68 degrees C. The recovery medium was Hektoen enteric agar. D-values, determined by linear regression, for normal cells on chicken skin, were 2.79, 1.17 and 0.53 min whereas D-values for starved cells were 4.15, 1.83 and 0.66 at 60, 64 and 68 degrees C, respectively. z-values for normal cells were 3.54 and for starved cells were 2.29. Pretreatment of Salmonella Enteritidis cells with 0 to 200 ppm of ASC or 0 to 1.0 % TSP resulted in lower D-values at all temperatures. Sensory results indicated no significance differences for control and treatments. Thus, results of this study indicated that pretreatment of chicken skin with ASC or TSP increased sensitivity of Salmonella Enteritidis to heat without affecting organoleptic quality of chicken meat. PMID- 26604400 TI - Fructan distribution in banana cultivars and effect of ripening and processing on Nendran banana. AB - Many plants store fructan as reserve carbohydrate. Fructans naturally present in almost all plant foods, are also used as functional ingredients by the food industry to modify the texture and taste due to their properties as gelling agents, fat substitutes, soluble dietary fibers and low calorie sweeteners. Seven banana cultivars were analysed for fructans and Nendran banana was selected for the next set of experiments as it had the highest fructan content (1433.3 mg/100 g) among the cultivars studied. Low temperature ripening (16 degrees C) of Nendran banana resulted in higher fructan accumulation of these carbohydrates in cold conditions. Pectinase pre-treatment significantly increased yield of total fructans from 1.4/100 g to 6.5 g/100 g i.e., 370 %. Fructan composition was affected by processing, namely steaming and puree preparation in Nendran. The fructan composition data documented in this study will enable including banana, naturally high in fructans in the diet and will facilitate storage and processing for nutritional formulation for higher fructan consumption. PMID- 26604401 TI - Enzymatic process of rice bran: a stabilized functional food with nutraceuticals and nutrients. AB - Rice bran (RB), a byproduct of rice milling industry, is a rich source of nutraceuticals and nutrients. However its utility is limited due to the presence of lipase and lipoxygenase which initiates rancidity on milling. The aim of this investigation is to prevent oxidation of free fatty acids by enzymatic approach for its effective utilization. The enzymatic treatment comprised of alcalase treatment for complete inactivation of lipase along with reduction in lipoxygenase (LOX) activity and endoglucanase for improving the soluble fiber content. The enzyme treated rice bran was drum dried for further use. The nutraceutical molecules like gamma-oryzanol, alpha-tocopherol and polyphenols were retained in the range of 68 to 110 % and the total antioxidant activity was improved. By the action of endoglucanase the complex carbohydrate was converted into glucose (72.28 %), cellobiose (18.36 %) and cellotriose (9.36 %). The prebiotic effect of enzyme treated rice bran was evaluated by the action of lactobacillus which was measured through the release of the short chain free fatty acids (SCFAs) analyzed by HPLC. The SCFAs; acetic acid and propionic acid increased by 1.72 folds and 2.12 folds respectively. B-complex vitamins showed maximum retention with vitamins like B1 (66.3 %), B2 (68.3 %) and B3 (55.0 %) after enzyme treatment. At different humidity levels, storage studies showed no change in LOX activity and also retained ubiquinol-10 in reduced state in enzyme treated RB for a period of 3 months. A stabilized RB has been developed enriched with short chain prebiotics and antioxidant molecules. PMID- 26604402 TI - Bread enriched in lycopene and other bioactive compounds by addition of dry tomato waste. AB - The tomato processing industry generates high amounts of waste, mainly tomato skins and seeds, which create environmental problems. These residues are attractive sources of valuable bioactive components and pigments. A relatively simple recovery technology could consist of production of powders to be directly incorporated into foods. Tomato waste coming from a Romanian tomato processing unit were analyzed for the content of several bioactive compounds like ascorbic acid, beta-carotene, lycopene, total phenolics, mineral and trace elements. In addition, its antioxidant capacity was assayed. Results revealed that tomato waste (skins and seeds) could be successfully utilized as functional ingredient for the formulation of antioxidant rich functional foods. Dry tomato processing waste were used to supplement wheat flour at 6 and 10 % levels (w/w flour basis) and the effects on the bread's physicochemical, baking and sensorial characteristics were studied. The following changes were observed: increase in moisture content, titratable acidity and bread crumb elasticity, reduction in specific volume and bread crumb porosity. The addition of dry tomato waste at 6 % resulted in bread with good sensory characteristics and overall acceptability but as the amount of dry tomato waste increased to 10 %, bread was less acceptable. PMID- 26604403 TI - Lipase catalyzed interesterification of Amazonian pataua oil and palm stearin for preparation of specific-structured oils. AB - This study showed that enzymatic interesterification of Amazonian oils could be an important tool in order to produce new oils with physicochemical properties that improve the applications of these raw materials. Structured oils of Amazonian pataua oil and palm stearin using two lipases were produced in three different enzymatic systems: first, a crude lipase from the fungus Rhizopus sp (a microorganism isolated in our laboratory); second, a commercial lipase; and third, to check any synergistic effect, a mixture of both lipases (Rhizopus sp and commercial). The lipase from Rhizopus sp was specific in the incorporation of oleic acid at the sn-1,3 positions of the triacylglycerol, resulting in an oil richer in saturated fatty acid in the sn-2 position. This enzyme, produced by solid-state fermentation, even though crude, was fatty acid and positional specific and able to operate at low concentration (2.5 %, w/w). In the second enzyme system, the commercial lipase from Thermomyces lanuginosus was not specific in the tested conditions; there was no change in the distribution of saturated and unsaturated fatty acids in the three positions of the triacylglycerol profile, there was only a replacement by the type of fatty acid at the same position. In the third enzyme system, the mixture of both lipases shows no synergic effect. The structured oils retained the concentration of bioactive alpha- and gamma- tocopherol in the three enzyme systems. Triacylglycerol classes and Thermal behavior tests indicated the formation of more homogeneous triacylglycerols, especially the mono and di-unsaturated. PMID- 26604404 TI - Effects of alternative steeping methods on composition, antioxidant property and colour of green, black and oolong tea infusions. AB - Cold water steeping is reported to maximise tea health benefits, but requires long infusion time. In this work, the employment of a brief hot infusion step followed by ice addition was evaluated. The comparison of this innovative method with hot and cold steeping was investigated on green, black and oolong teas. Catechins, xanthines and gallic acid content, antioxidant power, total phenolics and colour analysis were evaluated. Hot infusion shown rapid extractive power, but relevant compound degradation. On the contrary, cold infusion extracted higher level of healthy molecules with slow kinetic. The innovative method achieved in short time similar properties of cold infusion in terms of antioxidant power. As for bioactive compounds, such as gallic acid and epigallocatechin gallate, highest values, about double than in hot infusion, were recorded for green and black teas. This steeping method may represent an alternative approach for industrial beverage preparation. PMID- 26604405 TI - Biochemical and microbial characterization of Ngari and Hentaak - traditional fermented fish products of India. AB - Ngari and hentaak are the two most preferred traditional salt-free fermented fish products of North-Eastern (NE) states of India. Chemical and microbial composition, antioxidative potential, fatty acid profile and electrophoretic pattern of protein in ngari and hentaak were studied. pH and total titratable acidity (TTA) of the products justified their stability at ambient temperature. Both ngari and hentaak showed higher contents of calcium (362.79 +/- 26.89, 472.11 +/- 62.7); sodium (199.66 +/- 24.92, 94.0 +/- 12.78); potassium (58.20 +/- 7.36, 75.74 +/- 6.62) and magnesium (16.056 +/- 3.89, 21.125 +/- 3.78) respectively. Iron, copper and zinc were found in lesser amount. DPPH (.) radical scavenging activity was close to 87 % in both the products and the ferric chloride reducing power assay was dose dependent in both the products. Both omega 3 and omega-6 fatty acids were found in ngari; whereas, only omega-3 fatty acids were observed in hentaak. Linoleic acid (11.68 %) and arachidonic acid (0.65 %) were the n-6 PUFA in ngari; while, in hentaak, it was only arachidonic acid (8.54 %). Apart from essential fatty acids, essential amino acids were also found in considerable quantity in both the products. Micrococcus sp. and Staphylococcus sp. were found to be the dominant bacterial genus in both the products; while Ngari also had lactic acid bacteria group. The nutritional properties afforded by these products justify their preference by the population. PMID- 26604406 TI - Relationship between galactomannan structure and physicochemical properties of films produced thereof. AB - In this work five sources of galactomannans, Adenanthera pavonina, Cyamopsis tetragonolobus, Caesalpinia pulcherrima, Ceratonia siliqua and Sophora japonica, presenting mannose/galactose ratios of 1.3, 1.7, 2.9, 3.4 and 5.6, respectively, were used to produce galactomannan-based films. These films were characterized in terms of: water vapour, oxygen and carbon dioxide permeabilities (WVP, O 2 P and CO 2 P); moisture content, water solubility, contact angle, elongation-at-break (EB), tensile strength (TS) and glass transition temperature (T g ). Results showed that films properties vary according to the galactomannan source (different galactose distribution) and their mannose/galactose ratio. Water affinity of mannan and galactose chains and the intermolecular interactions of mannose backbone should also be considered being factors that affect films' properties. This work has shown that knowing mannose/galactose ratio of galactomannans is possible to foresee galactomannan-based edible films properties. PMID- 26604407 TI - Antiproliferative, ACE-inhibitory and functional properties of protein hydrolysates from rohu (Labeo rohita) roe (egg) prepared by gastrointestinal proteases. AB - Previously, we have reported the chemical composition, molecular mass distribution and antioxidant activity of rohu roe protein hydrolysates. In the current study, antiproliferative, angiotensin-converting enzyme (ACE)-inhibitory activities and functional properties of protein hydrolysates from rohu (Labeo rohita) roe proteins, prepared by gastrointestinal proteases (pepsin and trypsin), were investigated. Antiproliferative activity was evaluated against human colon cancer cell line Caco-2. The results showed that the pepsin hydrolysate possessed dose dependent inhibitory effect on Caco-2 cell line. Pepsin and trypsin hydrolysates displayed ACE-inhibitory activity in vitro. The ACE-inhibitory activity of the hydrolysate generated by pepsin (47 +/- 1.7 %, at 1 mg/ml) is higher than that obtained by trypsin (36 +/- 3.2 %). Additionally, the undigested rohu roe proteins and its hydrolysates exhibited functional properties. Solubilities of the hydrolysates were above 81 +/- 9.2 % at all pH values tested. Pepsin and trypsin hydrolysates showed good foaming capacity (45 211 %) and emulsification activity (4-29 m(2)/g). The foaming abilities and emulsifying activity index (EAI) were affected by pH. The results suggest that protein hydrolysates from rohu roe could be useful in food industry for various applications. PMID- 26604408 TI - Flavouring compounds in Indian potato snacks. AB - Market for processed potato products is rising day by day. Flavour plays important role in decision making by consumers due to their preferences for better tasting food. In potato and potato products, glutamic acid, aspartic acid, guanosine 5'-monophosphate (GMP) and adenosine 5'-monophosphate (AMP) are the major umami compounds which contribute towards flavour. Therefore, umami 5' nucleotides (AMP+GMP) were estimated from local potato products available as common fried products in the Indian markets and processed potato products being sold by the retailers. The analysis was also carried in raw, microwaved and pressure cooked tubers of forty seven Indian potato cultivars. Umami 5' nucleotide content ranged from 2.63 (Aloo seekh) to 8.26 MUg/g FW (fried lachcha) in local potato products. In processed potato products, the content ranged from 2.72 MUg/g FW (Smiles) to 14.75 MUg/g FW (Aloo Bhujia). Along with aloo bhujia, umami 5' nucleotides were also high in dehydrated aloo lachcha (11.14 MUg/g FW) and dehydrated potato chips (10.13 MUg/g FW) and low in Smiles (2.72 MUg/g FW) and Potato Shortz (3.40 MUg/g FW). The study suggests that the potato products prepared solely from potato contained higher levels of umami 5' nucleotides compared to other products prepared by mixing potato with other cereals and vegetables. In Indian potato cultivars overall there was 14 % increase on microwave cooking and 31 % increase in flavouring compounds on pressure cooking. This type of study enabled in identifying better tasting cultivars for further product development and also to develop products with less addition of salt. PMID- 26604409 TI - Effect of the oriental and yellow mustard flours as natural preservative against aflatoxins B1, B2, G1 and G2 production in wheat tortillas. AB - Reduction of the AFs produced by Aspergillus parasiticus CECT 2681 in wheat tortillas by isothiocyanates (ITCs) from oriental and yellow mustard flours was evaluated in this study. Polyethylene plastic bags were introduced with wheat tortillas contaminated with A. parasiticus and treated with 0, 0.1, 0.5 or 0.1 g of either oriental or yellow mustard flour added with 2 ml of water. The wheat tortillas were stored at room temperature during 1 month. The quantification of the AFs produced was analyzed by liquid chromatography (LC) coupled to the mass spectrometry detection in tandem (MS/MS). Gaseous allyl isothiocyanate (AITC) from oriental mustard was more effective than p-hydroxybenzyl isothiocyanate (p HBITC) from yellow mustard to inhibit the production of AFs. More importantly, 1 g of AITC was able to reduce >90 % of AFs B1, B2, G1 and G2. p-HBITC is less stable and volatile than AITC, leading to a much lower AFs (average of 17.7 to 45.2 %). Further studies should investigate the use of active packaging using oriental mustard flour and water to reduce the production of AFs by Aspergillus species in bakery goods. PMID- 26604410 TI - Extraction, partial purification and determination of some biochemical properties of beta-glucosidase from Tea Leaves (Camellia sinensis L.). AB - This research was carried out to determine biochemical properties of beta glucosidase (beta-D-glucoside glucohydrolase, EC 3.2.1.21) isolated from Turkish tea leaves. Two protein peaks containing beta-glucosidase activity were recovered and characterized, which were denoted as isoenzyme A and isoenzyme B. Their pH optimum, thermal resistances, affinity towards p-nitrophenyl-beta-D glucopyranoside differed markedly. They both displayed maximal activity at pH 5.0. The effects of the inhibitors tested varied in a dose dependent manner. PMID- 26604411 TI - Quality changes of chicken meat jerky with different sweeteners during storage. AB - Chicken meat jerky with high sugar content is popular intermediate-moisture meat product in Asia. Different types of sugar, sucrose and mixed sugar (sucrose: fructose: sorbitol 70: 15: 15), were evaluated to improve the quality of product. Quality changes of chicken meat jerky stored in vacuum and aerobic (33 and 75 %relative humidity, %RH) conditions were studied for suitable condition to extend shelf-life of product. The samples were determined the physical and chemical characteristics, as well as sensory evaluation during storage at room temperature. The moisture content and water activity (aw) of samples stored in 33 %RH conditions was continuously diminished during storage that related to harder texture and unacceptable quality in sensory evaluation. All samples stored in vacuum and 75 %RH condition demonstrated the lower shear force value than that stored in 33%RH condition (p < 0.05). Samples stored in vacuum condition had the lowest lipid oxidation (p < 0.05.) which corresponding to the highest scores in less rancidity and overall acceptance attributes. All samples stored in vacuum condition also had the highest acceptability in all sensory attributes (taste, rancidity, color and overall acceptance) followed by 75 %RH storage condition (p < 0.05). Samples prepared with mixed sugar could improve color and retard rancidity in chicken jerky meat product. Sample prepared with mixed sugar kept in vacuum condition had the lowest lipid oxidation and highest sensory score in overall acceptance attributes along the extended storage. PMID- 26604412 TI - Sonication inhibited browning but decreased polyphenols contents and antioxidant activity of fresh apple (malus pumila mill, cv. Red Fuji) juice. AB - Enzyme browning is the main challenge in the preparation of fresh apple juice. The influence of sonication on browning, as well as polyphenols and antioxidant activity of fresh apple juice was investigated. It was found that ultrasound can inhibit the browning of fresh apple (Malus pumila Mill, cv. Red Fuji) juice, but decreased the contents of total phenolic content (TPC), total flavonoid content (TFC) and chlorogenic acid and reduced the antioxidant activity. On the whole, ultrasound technology cannot be used to the antibrowning of fresh apple (Malus pumila Mill, cv. Red Fuji) juice. PMID- 26604413 TI - Production, characterization and biological features of bacterial cellulose from scum obtained during preparation of sugarcane jaggery (gur). AB - Bacterial cellulose (BC) has been given an ample attention due to its high potential for many industrial applications. However, the high cost of production medium has hindered the commercialization of BC. Several efforts have been made to explore cheep, raw and waste sources for BC production. The current study aims at investigating the BC production from a waste source; the scum obtained during preparation of sugarcane jaggery or gur (JS). JS was five-fold diluted with distilled water and used as culturing medium without any additional nutrients. The production of BC was monitored till 10th days of cultivation both at static and shaking culturing conditions. A maximum of 2.51 g/L and 2.13 g/L BC was produced in shaking and static cultures, respectively, after 10 days. The structure features of BC were confirmed through FTIR, XRD and SEM analysis. The chemical structure and physical appearance strongly resembled the BC produced form synthetic media. It was noteworthy that the BC produced from JS showed higher mechanical and thermal properties. The cell adhesion and proliferation capabilities of produced BC were observed that depicted definite animal cell adhesion without any considerable cytotoxicity. Besides providing an economically feasible way for BC production, the high level of physico-mechanical and biological properties insured the importance in medical fields. PMID- 26604414 TI - Citrus peel extract incorporated ice cubes to protect the quality of common pandora: Fish storage in ice with citrus. AB - The objective of this study was to investigate the effects of ice with albedo and flavedo fragments of Citrus (Grapefruit (Citrus paradisi) and Bitter orange (Citrus aurantium L.)) extracts on the quality of common pandora (Pagellus erythrinus). Concentrated citrus extracts were diluted with distilled water (1/100 w/v) before making of ice. The ice cubes were spread on each layer of fishes and stored at 0 degrees C for 15 days. The pH value showed a regular increase in all samples. TVB-N levels of bitter orange treatment groups were recorded lower than the other groups reaching to 25.11 +/- 0.02 mg/100 g at the end of the storage. The TMA-N values of bitter orange treatment groups were lower than that of control and grapefruit treatment groups. In terms of TBARS value, alteration was observed in the control samples and this value significantly (p < 0.01) increased from 0.101 +/- 0.011 mg MA/kg to 0.495 +/- 0.083 mg MA/kg, while remained lower in the citrus extracts treatment groups at the end of storage since their antioxidant capacity. The oxidation was suppressed in citrus extracts treatment groups, especially in bitter orange flavedo treatment. The results showed the bitter orange albedo and bitter orange flavedo extracts in combination with ice storage have more effectiveness in controlling the biochemical indices in common pandora. PMID- 26604415 TI - Quality evaluation of little millet (Panicum miliare) incorporated functional bread. AB - The study was undertaken with the objective of formulating a fiber enriched functional bread by incorporating little millet flour (LMF). Wheat flour (WF) was replaced with LMF at various proportions (10, 30 and 50%) in the bread preparation. The developed breads were evaluated for physical, sensory and nutritional characteristics. The loaf volume, weight, height and specific volume were decreased significantly with increased levels of LMF. The wheat bread (control), 10 and 30 % percent incorporation of LMF did not show significance difference in the sensory scores. Control and bread with 30 % incorporation of LMF were evaluated further for nutritional characteristics. There was an increase in the percentage of micronutrients such as Iron (94%), Zinc (29%), Copper (70%), Phosphorus (28%) and also fiber (19%) which improved the nutritional value of the wheat bread when substituted with LMF. The incorporation of LMF at 30% level in bread can be considered as a functional and nutritional food choice for the management of diet related metabolic disorders. PMID- 26604416 TI - Effect of chemical modifications on thermal, rheological and morphological properties of yellow sorghum starch. AB - Starch isolated from yellow sorghum grains was subjected to chemical modifications like acetylation, hydroxypropylation and benzylation. Proximate compositions of these, such as crude protein, crude fat, moisture content and ash content were determined. The effects of modifications on thermal, rheological and morphological properties of yellow sorghum starch were investigated. Differential Scanning Calorimetry studies showed that the gelatinization temperature and enthalpy of modified yellow sorghum starches decreased when compared to that of native starch. The results showed that peak, hot pasting, final, breakdown and setback viscosities were significantly reduced except in hydroxypropylated starch that showed increase in breakdown and setback viscosities. Scanning electron microscopy pictures showed that the modified starch granules had disrupted surfaces compared to native starch granules; hydroxypropylated starch showed the presence of slight fragmentation and a distinct groove in their central core region. The extent of granule disruption was observed to be higher for hydroxypropylated starch than other modified starches. PMID- 26604417 TI - Kaulath, a new fungal fermented food from horse gram. AB - Horse gram (Macrotyloma uniflorum) is used in the traditional method for treatmentof several health complications. It is also known that fermentation of such substrates yields a number of compounds that enhance the overall activities against several disease states. Solid state fermentation of horse gram using Penicillium camemberti showed an inhibition of pancreatic lipase and alpha glucosidase activities. The fermented material, termed Kaulath, showed 60 % increase in fat content. A reduction in sodium and increased levels of potassium and calcium was observed in Kaulath. In addition, a higher free radical scavenging activity was noted in this product compared to unfermented horse gram. Anti-nutritional factors, such as phytic acid and trypsin inhibitors showed a reduction in Kaulath. Furthermore, Kaulath, upto 1 g per kg body weight, did not exhibit any mortality or toxic effects in experimental rats after 14 days of administration. The hematological and clinical parameters were within safe limits between the groups, supported by the histopathology of liver and kidney. These results indicate potential food use of Kaulath in diets and as functional ingredients in formulated foods. PMID- 26604418 TI - Hydration kinetics and physical properties of split chickpea as affected by soaking temperature and time. AB - In this study, some physical properties (principal dimensions, mean diameters, sphericity, area, density and electrical conductivity) of split chickpea were measured as function of soaking time (up to 360 min) and temperature (25-65 degrees C). Initially, the water absorption rate was high and then it showed a progressive decrease at all temperatures, whereas solid loss exhibited a power function of temperature (P < 0.05). The Peleg model was predicted well the kinetic of split chickpea soaking. No significant difference (P < 0.05) was observed in Peleg rate constant (K1) and Peleg capacity constant (K2) at all temperatures except for K1 at 25 degrees C. The discrepancy for K1 was in relation to permeability characteristics of split chickpea at temperature of 25 degrees C. As temperature increased from 25 to 65 degrees C, the K1 value decreased from 0.04620 to 0.00945 g h(-1), whereas the K2 value increased from 0.08597 to 0.11320 g(-1). Plot for K1 exhibited a slope changes around 45 degrees C corresponding to gelatinization temperature of split chickpeas. The effect of temperature and time on physical properties of split chickpea during soaking was monitored by regression equations. It was concluded that physical properties of split chickpea affected by its water absorption especially at higher temperatures. PMID- 26604419 TI - Antioxidant property and [Formula: see text]-glucosidase, [Formula: see text] amylase and lipase inhibiting activities of Flacourtia inermis fruits: characterization of malic acid as an inhibitor of the enzymes. AB - Flacourtia inermis Roxb. (Flacourtiaceae), is a moderate sized tree cultivated in Sri Lanka for its fruits known as Lovi. The current study was undertaken to study the biological activity of extracts of the fruits in an attempt to increase the value of the under exploited fruit crops. Fruits of F. inermis were found to be rich in phenolics and anthocyanins. Polyphenol content of the fruits was determined to be 1.28 g gallic acid equivalents per 100 g of fresh fruit and anthocyanin content was estimated as 108 mg cyanidin-3-glucoside equivalents per 100 g of fresh fruits. The EtOAc extract showed moderate antioxidant activity in the DPPH radical scavenging assay with IC50 value of 66.2 ppm. The EtOAc and MeOH extracts of the fruits also exhibited inhibitory activities toward alpha glucosidase, alpha-amylase and lipase enzymes with IC50values ranging from 549 to 710 ppm, 1021 to 1949 ppm and 1290 to 2096 ppm, respectively. The active principle for the enzyme inhibition was isolated through activity-guided fractionation and was characterized as (S)-malic acid. The results of this study indicate that F. inermis fruits have the potential to be used in health foods and in nutritional supplements. PMID- 26604420 TI - Effect of ball milling energy on rheological and thermal properties of amaranth flour. AB - Pearled amaranth grains obtained by abrasive milling were processed by planetary ball milling to produce amaranth flours. The influence of milling energy on rheological and thermal behavior of amaranth flour dispersions and stability during 24 h storage at 4 degrees C were investigated based on a factorial design. The rheological behavior of flour dispersions (4 % and 8 % w/v) was determined using a rotational viscometer, while gelatinization degree was determined by differential scanning calorimetry as a measure of structural changes.The power law model was found to be suitable in expressing the relationship between shear stress and shear rate. Flour dispersions showed a pseudoplastic behavior. However this character decreased with the storage being dependent on flour concentration and milling energy. A decrease of the consistency index and an increase of the flow behavior index were observed as a result of the increasing milling energy. Gelatinization enthalpy decrease showed the loss of crystalline structure due to ball milling. Amaranth flour dispersions presented increasing stability during storage. It was observed, that the stability changed with the concentration of amaranth flours.Thus, more stable dispersions were obtained as the flour concentration increased. The highly milled sample was the most stable sample during the storage. PMID- 26604421 TI - Effect of additives and steaming on quality of air dried noodles. AB - Texture is the most important property for consumer acceptance in cooked noodles. The air dried noodles are known to have higher cooking loss and cooking time, to that of instant fried noodles. But the fat content of instant fried noodles is more. In the present work attempts were made to optimize the moisture content so as to obtain a smooth dough for extruded noodle preparation and develop air dried noodles of low fat content with lesser cooking loss and cooking time. To meet the objectives, the effect of various additives and steaming treatment on cooking quality, sensory attributes, textural properties and microstructure of noodles were studied. Dough prepared by addition of 40 ml water to 100 g flour resulted into formation of a soft dough, leading to production of noodles of improved surface smoothness and maximum yield. The use of additives (5 g oil, 0.2 g guar gum, 2 g gluten and 1 ml of 1 % kansui solution for 100 g of flour) and steaming treatment showed significant effect on noodles quality, with respect to cooking characteristics, sensory attributes and textural properties. The microstructure images justified the positive correlation between the effects of ingredients with steaming and quality parameters of noodles. Air dried noodles with reduced cooking loss (~50 % reduction) with marginal reduction in cooking time was developed, which were having similar characteristics to that of instant fried noodles. Compared to the instant fried noodle, the prepared air dried noodle was having substantially reduced fat content (~70 % reduction). Thus the present study will be useful for guiding extrusion processes for production of air dried noodles having less cooking time and low fat content. PMID- 26604422 TI - Dielectric properties of cereals at frequencies useful for processes with microwave heating. AB - Dielectric properties of barley, corn (white and yellow), sorghum, and wheat at microwave frequencies for heating purpose were analyzed. Properties were determined at 915, 2450 and 5800 MHz with the free space transmission method in the cereals at 20, 30, 40, 50 and 60 degrees C. epsilon' and epsilon"of all the cereals decreased with increasing frequency. epsilon' slightly increased with temperature, while epsilon "remained practically constant for all the cereals in the temperature range from 20 to 60 degrees C. Penetration depth decreased with increasing frequency for all the samples, and increased with increasing temperature at 915 MHz, except for barley. These results are useful for further microwave heating applications for the studies on cereals. PMID- 26604423 TI - Effect of atmospheric pressure plasma jet on the foodborne pathogens attached to commercial food containers. AB - Bacterial biofilms are associated with numerous infections and problems in the health care and food industries. The aim of this study was to evaluate the bactericidal effect of an atmospheric pressure plasma (APP) jet on Escherichia coli O157:H7, Listeria monocytogenes, and Salmonella Typhimurium biofilm formation on collagen casing (CC), polypropylene (PP) and polyethylene terephthalate (PET), which are widely used food container materials. The samples were treated separately with the APP jet at a 50-W input power for 5 and 10 min, and nitrogen (6 l per minute) gas combined with oxygen (10 standard cubic centimeters per minute) was used to produce the APP. The APP jet reduced the number of bacterial cells in a time-dependent manner. All pathogens attached to CC, PP, and PET were reduced by 3-4 log CFU/cm(2) by the 10-min APP treatment. The developed APP jet was effectively reduced biofilms on CC, PP, and PET. PMID- 26604424 TI - GLOBALLY ADAPTIVE QUANTILE REGRESSION WITH ULTRA-HIGH DIMENSIONAL DATA. AB - Quantile regression has become a valuable tool to analyze heterogeneous covaraite response associations that are often encountered in practice. The development of quantile regression methodology for high dimensional covariates primarily focuses on examination of model sparsity at a single or multiple quantile levels, which are typically prespecified ad hoc by the users. The resulting models may be sensitive to the specific choices of the quantile levels, leading to difficulties in interpretation and erosion of confidence in the results. In this article, we propose a new penalization framework for quantile regression in the high dimensional setting. We employ adaptive L1 penalties, and more importantly, propose a uniform selector of the tuning parameter for a set of quantile levels to avoid some of the potential problems with model selection at individual quantile levels. Our proposed approach achieves consistent shrinkage of regression quantile estimates across a continuous range of quantiles levels, enhancing the flexibility and robustness of the existing penalized quantile regression methods. Our theoretical results include the oracle rate of uniform convergence and weak convergence of the parameter estimators. We also use numerical studies to confirm our theoretical findings and illustrate the practical utility of our proposal. PMID- 26604425 TI - Clustering High-Dimensional Landmark-based Two-dimensional Shape Data?. AB - An important goal in image analysis is to cluster and recognize objects of interest according to the shapes of their boundaries. Clustering such objects faces at least four major challenges including a curved shape space, a high dimensional feature space, a complex spatial correlation structure, and shape variation associated with some covariates (e.g., age or gender). The aim of this paper is to develop a penalized model-based clustering framework to cluster landmark-based planar shape data, while explicitly addressing these challenges. Specifically, a mixture of offset-normal shape factor analyzers (MOSFA) is proposed with mixing proportions defined through a regression model (e.g., logistic) and an offset-normal shape distribution in each component for data in the curved shape space. A latent factor analysis model is introduced to explicitly model the complex spatial correlation. A penalized likelihood approach with both adaptive pairwise fusion Lasso penalty function and L2 penalty function is used to automatically realize variable selection via thresholding and deliver a sparse solution. Our real data analysis has confirmed the excellent finite sample performance of MOSFA in revealing meaningful clusters in the corpus callosum shape data obtained from the Attention Deficit Hyperactivity Disorder 200 (ADHD-200) study. PMID- 26604426 TI - DNA Repair Gene Polymorphism and the Risk of Mitral Chordae Tendineae Rupture. AB - Polymorphisms in Lys939Gln XPC gene may diminish DNA repair capacity, eventually increasing the risk of carcinogenesis. The aim of the present study was to evaluate the significance of polymorphism Lys939Gln in XPC gene in patients with mitral chordae tendinea rupture (MCTR). Twenty-one patients with MCTR and thirty seven age and sex matched controls were enrolled in the study. Genotyping of XPC gene Lys939Gln polymorphism was carried out using polymerase chain reaction- (PCR ) restriction fragment length polymorphism (RFLP). The frequencies of the heterozygote genotype (Lys/Gln-AC) and homozygote genotype (Gln/Gln-CC) were significantly different in MCTR as compared to control group, respectively (52.4% versus 43.2%, p = 0.049; 38.15% versus 16.2%, p = 0.018). Homozygote variant (Gln/Gln) genotype was significantly associated with increased risk of MCTR (OR = 2.059; 95% CI: 1.097-3.863; p = 0.018). Heterozygote variant (Lys/Gln) genotype was also highly significantly associated with increased risk of MCTR (OR = 1.489; 95% CI: 1.041-2.129; p = 0.049). The variant allele C was found to be significantly associated with MCTR (OR = 1.481; 95% CI: 1.101-1.992; p = 0.011). This study has demonstrated the association of XPC gene Lys939Gln polymorphism with MCTR, which is significantly associated with increased risk of MCTR. PMID- 26604427 TI - Hybrid Invariance and Stability of a Feedback Linearizing Controller for Powered Prostheses. AB - The development of powered lower-limb prostheses has the potential to significantly improve amputees' quality of life. By applying advanced control schemes, such as hybrid zero dynamics (HZD), to prostheses, more intelligent prostheses could be designed. Originally developed to control bipedal robots, HZD based control specifies the motion of the actuated degrees of freedom using output functions to be zeroed, and the required torques are calculated using feedback linearization. Previous work showed that an HZD-like prosthesis controller can successfully control the stance period of gait. This paper shows that an HZD-based prosthesis controller can be used for the entire gait cycle and that feedback linearization can be performed using only information measured with on-board sensors. An analytic metric for orbital stability of a two-step periodic gait is developed. The results are illustrated in simulation. PMID- 26604429 TI - Rapid Exercise-Induced Mobilization of Dendritic Cells Is Potentially Mediated by a Flt3L- and MMP-9-Dependent Process in Multiple Sclerosis. AB - In healthy individuals, one exercise bout induces a substantial increase in the number of circulating leukocytes, while their function is transiently suppressed. The effect of one exercise bout in multiple sclerosis (MS) is less studied. Since recent evidence suggests a role of dendritic cells (DC) in the pathogenesis of MS, we investigated the effect of one combined endurance/resistance exercise bout on the number and function of DC in MS patients and healthy controls. Our results show a rapid increase in the number of DC in response to physical exercise in both MS patients and controls. Further investigation revealed that in particular DC expressing the migratory molecules CCR5 and CD62L were increased upon acute physical activity. This may be mediated by Flt3L- and MMP-9-dependent mobilization of DC, as demonstrated by increased circulating levels of Flt3L and MMP-9 following one exercise bout. Circulating DC display reduced TLR responsiveness after acute exercise, as evidenced by a less pronounced upregulation of activation markers, HLA-DR and CD86, on plasmacytoid DC and conventional DC, respectively. Our results indicate mobilization of DC, which may be less prone to drive inflammatory processes, following exercise. This may present a negative feedback mechanism for exercise-induced tissue damage and inflammation. PMID- 26604428 TI - MPNs as Inflammatory Diseases: The Evidence, Consequences, and Perspectives. AB - In recent years the evidence is increasing that chronic inflammation may be an important driving force for clonal evolution and disease progression in the Philadelphia-negative myeloproliferative neoplasms (MPNs), essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Abnormal expression and activity of a number of proinflammatory cytokines are associated with MPNs, in particular MF, in which immune dysregulation is pronounced as evidenced by dysregulation of several immune and inflammation genes. In addition, chronic inflammation has been suggested to contribute to the development of premature atherosclerosis and may drive the development of other cancers in MPNs, both nonhematologic and hematologic. The MPN population has a substantial inflammation-mediated comorbidity burden. This review describes the evidence for considering the MPNs as inflammatory diseases, A Human Inflammation Model of Cancer Development, and the role of cytokines in disease initiation and progression. The consequences of this model are discussed, including the increased risk of second cancers and other inflammation-mediated diseases, emphasizing the urgent need for rethinking our therapeutic approach. Early intervention with interferon-alpha2, which as monotherapy has been shown to be able to induce minimal residual disease, in combination with potent anti inflammatory agents such as JAK-inhibitors is foreseen as the most promising new treatment modality in the years to come. PMID- 26604430 TI - Genetic Polymorphisms of Multidrug Resistance Gene-1 (MDR1/ABCB1) and Glutathione S-Transferase Gene and the Risk of Inflammatory Bowel Disease among Moroccan Patients. AB - Inflammatory bowel diseases (IBD) are multifactorial disorders resulting from environmental and genetic factors. Polymorphisms in MDR1 and GSTs genes might explain individual differences in susceptibility to IBD. We carried out a case control study to examine the association of MDR1 (C1236T and C3435T), GSTT1, and GSTM1 polymorphisms with the risk of IBD. Subjects were genotyped using PCR-RFLP for MDR1 gene and multiplex PCR for GSTT1 and GSTM1. Meta-analysis was performed to test the association of variant allele carriage with IBD risk. We report that GSTT1 null genotype is significantly associated with the risk of CD (OR: 2.5, CI: 1.2-5, P = 0.013) and UC (OR: 3.5, CI: 1.5-8.5, P = 0.004) and can influence Crohn's disease behavior. The interaction between GSTT1 and GSTM1 genes showed that the combined null genotypes were associated with the risk of UC (OR: 3.1, CI: 1.1-9, P = 0.049). Furthermore, when compared to combined 1236CC/CT genotypes, the 1236TT genotype of MDR1 gene was associated with the risk of UC (OR: 3.7, CI: 1.3-10.7, P = 0.03). Meta-analysis demonstrated significantly higher frequencies of 3435T carriage in IBD patients. Our results show that GSTT1 null and MDR1 polymorphisms could play a role in susceptibility to IBD. PMID- 26604431 TI - The Anti-Inflammatory Effect of Human Telomerase-Derived Peptide on P. gingivalis Lipopolysaccharide-Induced Inflammatory Cytokine Production and Its Mechanism in Human Dental Pulp Cells. AB - Porphyromonas gingivalis is considered with inducing pulpal inflammation and has lipopolysaccharide (LPS) as an inflammatory stimulator. GV1001 peptide has anticancer and anti-inflammation activity due to inhibiting activation of signaling molecules after penetration into the various types of cells. Therefore, this study examined inhibitory effect of GV1001 on dental pulp cells (hDPCs) stimulated by P. gingivalis LPS. The intracellular distribution of GV1001 was analyzed by confocal microscopy. Real-time RT-PCR was performed to determine the expression levels of TNF-alpha and IL-6 cytokines. The role of signaling by MAP kinases (ERK and p38) was explored using Western blot analysis. The effect of GV1001 peptide on hDPCs viability was measured by MTT assay. GV1001 was predominantly located in hDPC cytoplasm. The peptide inhibited P. gingivalis LPS induced TNF-alpha and IL-6 production in hDPCs without significant cytotoxicity. Furthermore, GV1001 treatment markedly inhibited the phosphorylation of MAP kinases (ERK and p38) in LPS-stimulated hDPCs. GV1001 may prevent P. gingivalis LPS-induced inflammation of apical tissue. Also, these findings provide mechanistic insight into how GV1001 peptide causes anti-inflammatory actions in LPS-stimulated pulpitis without significantly affecting cell viability. PMID- 26604434 TI - How Should We Study Residential Recovery Homes? AB - PURPOSE: Persons with serious alcohol and drug problems who are attempting to maintain abstinence often lack an alcohol and drug free living environment that supports sustained recovery. Residential recovery homes, called "sober living houses" in California, are alcohol and drug-free living environments that offer long-term support for persons with addictive disorders. They do not offer formal treatment services but usually encourage or mandate attendance at self-help recovery groups such as Alcoholics Anonymous. APPROACH: This paper weighs the strengths and weaknesses of different research designs for studying residential recovery homes. Alternatives to randomized designs that are able to capture "real world" data that are readily generalized are described and understudied topics are identified. FINDINGS: A significant limitation of traditional randomized designs is they eliminate mutual selection processes between prospective residents and recovery home residents and staff. Naturalistic research designs have the advantage of including mutual selection processes and there are methods available for limiting self-selection bias. Qualitative methods should be used to identify factors that residents experience as helpful that can then be studied further. Innovative studies are needed to investigate how outcomes are affected by architectural characteristics of the houses and resident interactions with the surrounding community. PRACTICAL IMPLICATIONS: Use of the recommended strategies could lead to findings that are more informative, intuitively appealing, and interpretable. SOCIAL IMPLICATIONS: Recovery homes and similar programs will be more responsive to consumers. ORIGINALITY: This paper represents one of the first to review various options for studying recovery homes and to provide suggestions for new studies. PMID- 26604432 TI - Collagen Induced Arthritis in DBA/1J Mice Associates with Oxylipin Changes in Plasma. AB - Oxylipins play important roles in various biological processes and are considered as mediators of inflammation for a wide range of diseases such as rheumatoid arthritis (RA). The purpose of this research was to study differences in oxylipin levels between a widely used collagen induced arthritis (CIA) mice model and healthy control (Ctrl) mice. DBA/1J male mice (age: 6-7 weeks) were selected and randomly divided into two groups, namely, a CIA and a Ctrl group. The CIA mice were injected intraperitoneally (i.p.) with the joint cartilage component collagen type II (CII) and an adjuvant injection of lipopolysaccharide (LPS). Oxylipin metabolites were extracted from plasma for each individual sample using solid phase extraction (SPE) and were detected with high performance liquid chromatography/tandem mass spectrometry (HPLC-ESI-MS/MS), using dynamic multiple reaction monitoring (dMRM). Both univariate and multivariate statistical analyses were applied. The results in univariate Student's t-test revealed 10 significantly up- or downregulated oxylipins in CIA mice, which were supplemented by another 6 additional oxylipins, contributing to group clustering upon multivariate analysis. The dysregulation of these oxylipins revealed the presence of ROS-generated oxylipins and an increase of inflammation in CIA mice. The results also suggested that the collagen induced arthritis might associate with dysregulation of apoptosis, possibly inhibited by activated NF-kappaB because of insufficient PPAR-gamma ligands. PMID- 26604435 TI - Is there a need to make multiple guidelines for management? PMID- 26604433 TI - Sphingosine-1-Phosphate and Its Receptors: A Mutual Link between Blood Coagulation and Inflammation. AB - Sphingosine-1-phosphate (S1P) is a versatile lipid signaling molecule and key regulator in vascular inflammation. S1P is secreted by platelets, monocytes, and vascular endothelial and smooth muscle cells. It binds specifically to a family of G-protein-coupled receptors, S1P receptors 1 to 5, resulting in downstream signaling and numerous cellular effects. S1P modulates cell proliferation and migration, and mediates proinflammatory responses and apoptosis. In the vascular barrier, S1P regulates permeability and endothelial reactions and recruitment of monocytes and may modulate atherosclerosis. Only recently has S1P emerged as a critical mediator which directly links the coagulation factor system to vascular inflammation. The multifunctional proteases thrombin and FXa regulate local S1P availability and interact with S1P signaling at multiple levels in various vascular cell types. Differential expression patterns and intracellular signaling pathways of each receptor enable S1P to exert its widespread functions. Although a vast amount of information is available about the functions of S1P and its receptors in the regulation of physiological and pathophysiological conditions, S1P-mediated mechanisms in the vasculature remain to be elucidated. This review summarizes recent findings regarding the role of S1P and its receptors in vascular wall and blood cells, which link the coagulation system to inflammatory responses in the vasculature. PMID- 26604436 TI - Advances in nonmuscle invasive bladder cancer. PMID- 26604438 TI - Diagnostics techniques in nonmuscle invasive bladder cancer. AB - INTRODUCTION: Nonmuscle invasive bladder cancer (NMIBC) is the most common presentation of bladder cancer and is often treatable with endoscopic resection and intravesical therapies. Cystoscopy and urine cytology are the gold standard in diagnosis and surveillance but are limited by their sensitivity in some situations. We seek to provide an overview of recent additions to the diagnostic armamentarium for urologists treating this disease. METHODS: Articles were identified through a literature review of articles obtained through PubMed searches including the terms "bladder cancer" and various diagnostic techniques described in the article. RESULTS: A variety of urinary biomarkers are available to assist the diagnosis and management of patients with NMIBC. Many have improved sensitivity over urine cytology, but less specificity. There are certain situations in which this has proved valuable, but as yet these are not part of the standard guidelines for NMIBC. Fluorescence cystoscopy has level 1 evidence demonstrating increased rates of tumor detection and prolonged recurrence-free survival when utilized for transurethral resection. Other technologies seeking to enhance cystoscopy, such as narrow band imaging, confocal laser endomicroscopy, and optical coherence tomography are still under evaluation. CONCLUSIONS: A variety of urine biomarker and adjunctive endoscopic technologies have been developed to assist the management of NMIBC. While some, such as fluorescence cystoscopy, have demonstrated a definite benefit in this disease, others are still finding their place in the diagnosis and treatment of this disease. Future studies should shed light on how these can be incorporated to improve outcomes in NMIBC. PMID- 26604437 TI - Biomarkers for non-muscle invasive bladder cancer: Current tests and future promise. AB - The search continues for optimal markers that can be utilized to improve bladder cancer detection and to predict disease recurrence. Although no single marker has yet replaced the need to perform cystoscopy and urine cytology, many tests have been evaluated and are being developed. In the future, these promising markers may be incorporated into standard practice to address the challenge of screening in addition to long-term surveillance of patients who have or are at risk for developing bladder cancer. PMID- 26604439 TI - Non-muscle invasive bladder cancer risk stratification. AB - INTRODUCTION: Non-muscle invasive bladder cancer (NMIBC) comprises about 70% of all newly diagnosed bladder cancer, and includes tumors with stage Ta, T1 and carcinoma in situ (CIS.) Since, NMIBC patients with progression to muscle invasive disease tend to have worse prognosis than with patients with primary muscle-invasive disease, there is a need to significantly improve risk stratification and earlier definitive treatment for high-risk NMIBC. MATERIALS AND METHODS: A detailed Medline search was performed to identify all publications on the topic of prognostic factors and risk predictions for superficial bladder cancer/NMIBC. The manuscripts were reviewed to identify variables that could predict recurrence and progression. RESULTS: The most important prognostic factor for progression is grade of tumor. T category, tumor size, number of tumors, concurrent CIS, intravesical therapy, response to bacillus Calmette-Guerin at 3- or 6-month follow-up, prior recurrence rate, age, gender, lymphovascular invasion and depth of lamina propria invasion are other important clinical and pathological parameters to predict recurrence and progression in patients with NMIBC. The European Organization for Research and Treatment of Cancer (EORTC) and the Spanish Club UrologicoEspanol de Tratamiento Oncologico (CUETO) risk tables are the two best-established predictive models for recurrence and progression risk calculation, although they tend to overestimate risk and have poor discrimination for prognostic outcomes in external validation. Molecular biomarkers such as Ki-67, FGFR3 and p53 appear to be promising in predicting recurrence and progression but need further validation prior to using them in clinical practice. CONCLUSION: EORTC and CUETO risk tables are the two best established models to predict recurrence and progression in patients with NMIBC though they tend to overestimate risk and have poor discrimination for prognostic outcomes in external validation. Future research should focus on enhancing the predictive accuracy of risk assessment tools by incorporating additional prognostic factors such as depth of lamina propria invasion and molecular biomarkers after rigorous validation in multi-institutional cohorts. PMID- 26604440 TI - Intravesical chemotherapy in non-muscle-invasive bladder cancer. AB - Non-muscle-invasive bladder cancer (NMIBC) is characterized by a tendency for recurrence and capacity for progression. Intravesical instillation therapy has been employed in various clinical settings, which are summarized within this review. Several chemotherapeutic agents have shown clinical efficacy in reducing recurrence rates in the post-transurethral resection of bladder tumor (TURBT) setting, including mitomycin C (MMC), doxorubicin, and epirubicin. Mounting evidence also supports the use of intravesical MMC following nephroureterectomy to reduce later urothelial bladder recurrence. In the adjuvant setting, bacillus Calmette-Guerin (BCG) immunotherapy is an established first-line agent in the management of carcinoma in situ (CIS) and high-grade non muscle invasive urothelial carcinoma (UC). Among high and intermediate-risk patients (based on tumor grade, size, and focality) improvements in disease-free intervals have been seen with adjunctive administration of MMC prior to scheduled BCG dosing. Following failure of first-line intravesical therapy, gemcitabine and valrubicin have demonstrated modest activity, though valrubicin remains the only agent currently Food and Drug Administration (FDA)-approved for the treatment of BCG refractory CIS. Techniques to optimize intravesical chemotherapy delivery have also been explored including pharmacokinetic methods such as urinary alkalization and voluntary dehydration. Chemohyperthermia and electromotive instillation have been associated with improved freedom from recurrence intervals but may be associated with increased urinary toxicity. Improvements in therapeutic selection may be heralded by novel opportunities for genomic profiling and refinements in clinical risk stratification. PMID- 26604441 TI - Intravesical immunotherapy in nonmuscle invasive bladder cancer. AB - INTRODUCTION: Nonmuscle invasive urothelial cell carcinoma is the most frequent malignancy of the urinary bladder. The high recurrence rate (up to 80%) and risk of progression (up to 30%) reflect the need for long-term follow-up and sometimes multiple interventions. To reduce the rate of recurrences and tumor progression, intravesical immunotherapy, especially the use of Bacille Calmette-Guerin (BCG), represents the gold standard adjuvant treatment of high-risk nonmuscle invasive bladder cancer (NMIBC). This article reviews the role of BCG therapy and several promising new immunotherapeutic approaches such as mycobacterium phlei cell wall nucleic acid complex, interleukin-10 (IL-10) antibody, vaccine-based therapy, alpha-emitter therapy, and photodynamic therapy checkpoint inhibitors. METHODS: A systematic literature review was performed using the terms (immunotherapy, NMIBC, BCG, and intravesical) using PubMed and Cochrane databases. RESULTS: BCG represents the most common intravesical immunotherapeutic agent for the adjuvant treatment of high-risk NMIBC. Its use is associated with a significant reduction of recurrence and progression. Patients with NMIBC of intermediate and high-risk benefit the most from BCG therapy. To achieve maximal efficacy, an induction therapy followed by a maintenance schedule should be used. Full-dose BCG is recommended to obtain ideal antitumoral activity and there is no evidence of a reduction of side effects in patients treated with a reduced dose. There are multiple new approaches and agents in immunotherapy with potential and promising antineoplastic effects. CONCLUSIONS: The beneficial effect of BCG is well documented and established. To reduce the tumor specific mortality, it is essential to follow guideline-based treatment. In patients with BCG-failure, there are new promising alternatives other than BCG but BCG remains the gold standard at this stage. PMID- 26604442 TI - Treatment options in non-muscle-invasive bladder cancer after BCG failure. AB - Bladder cancer is the ninth-most prevalent cancer worldwide. Most patients with urothelial cell carcinoma of the bladder present with non-muscle-invasive disease and are treated with bacillus Calmette-Guerin (BCG) intravesical therapy. Many of these patients experience disease recurrence after BCG failure. Radical cystectomy is the recommended treatment for high-risk patients failing BCG. However, many patients are unfit for or unwilling to undergo this procedure. We searched the published literature on the treatment of non-muscle-invasive bladder cancer (NMIBC) after BCG failure. We review current evidence regarding intravesical therapy with gemcitabine, mitomycin combined with thermo chemotherapy, docetaxel, nab-paclitaxel, photodynamic therapy (PDT), BCG with interferon (IFN), and combination sequentially administered chemotherapy. PMID- 26604443 TI - Guideline-based management of non-muscle invasive bladder cancer. AB - INTRODUCTION: Non-muscle invasive bladder cancer (NMIBC) represents a broad spectrum of disease, the hallmarks of which include disease recurrence and progression. Clinicians have a number of surgical and therapeutic options at their disposal when treating this disease, and the underlying evidence continues to evolve. A number of professional organizations have invested in the development of clinical practice guidelines to guide patient management. MATERIALS AND METHODS: We review and summarize four major guidelines, the American Urological Association, the European Association of Urology, the International Consultation on Urological Disease and the National Comprehensive Cancer Network. RESULTS: Guideline panels differed in their composition, methodological approach and structure of recommendations. Despite this, many recommendations were similar between various panels, although differences are present in panel recommendations related to initial diagnosis and treatment, adjuvant therapy and disease surveillance. CONCLUSIONS: Guideline recommendations are similar at many decision points that clinicians face when managing NMIBC, although they are far from uniform. While future prospective, well-designed studies will hopefully clarify NMIBC management, urologists ultimately must rely on a combination of evidence-based recommendations, which they should seek to integrate with patients' values and preferences and the individual circumstances to provide the best possible patient care. PMID- 26604444 TI - A new classification of inferior vena cava thrombus in renal cell carcinoma could define the need for cardiopulmonary or venovenous bypass. AB - INTRODUCTION: Although the level of inferior vena cava (IVC) thrombus governs the type of surgical approach, there is no consistency in reporting the levels of IVC thrombus in the literature. This prospective study illustrates a simple three level classification based on the need for clamping hepatoduodenal ligament and venovenous or cardiopulmonary bypass. MATERIALS AND METHODS: Between January 2010 and June 2014, 30 patients of renal mass with renal vein and/or IVC thrombus were treated after classifying the IVC thrombus into three levels on the basis of need for clamping the hepatoduodenal ligament. After excluding renal vein thrombi, level I was described as thrombus located caudal to the hepatic vein. Level II included all retrohepatic, suprahepatic infradiaphragmatic or supradiaphragmatic thrombi reaching till the right atrium. Atrial thrombi were categorized as level III. Level I and II thrombi were managed without venovenous or cardiopulmonary bypass. Level III thrombus required cardiopulmonary bypass. RESULTS: Of 26 patients with thrombus, 13 had level I thrombus. Of eight cases with level II thrombus, three were retrohepatic, three were suprahepatic infradiaphragmatic and two were supradiaphragmatic. All were removed successfully. Of five patients with level III thrombus, three were operated with cardiopulmonary bypass while the remaining two patients were too sick to be taken up for surgery. The median hepatoduodenal ligament clamp time was 10 min. One patient with level II thrombus had transient liver enzyme elevation. CONCLUSION: Renal vein thrombus should not be categorized as level I thrombus. Level II thrombus, irrespective of its relation to the diaphragm, could be managed without venovenous or cardiopulmonary bypass. PMID- 26604445 TI - Can we predict the need for clean intermittent catheterization after orthotopic neobladder construction? AB - INTRODUCTION: We aimed to identify peri-operative and pathologic characteristics that may predict the need for clean intermittent catheterization (CIC) following radical cystectomy (RC) with orthotopic neobladder (ONB) in order to improve patient counseling on choice of urinary diversion. MATERIALS AND METHODS: Between July 2004 and February 2013, all patients who underwent RC with ONB were identified. Peri-operative clinical and pathological features were evaluated and correlated with patients reported need for CIC. The independent T-test was performed for continuous variables and Chi-square test was performed for categorical variables. Multivariate forward stepwise logistic regression analysis was used to identify variables that correlated with need for CIC after ONB. RESULTS: During the study period, 114 patients underwent RC with ONB creation. On univariate analysis, patients with higher body mass index, younger age, and non vaginal or non-nerve-sparing procedures were more likely to require catheterization for complete emptying. Multivariate analysis demonstrates that conservative surgery (nerve sparing in males or vaginal sparing in females) was associated with a significantly lower rate of requiring CIC (Odds Ratio [OR] 0.20, P < 0.01). Surprisingly, older age was also associated with a slightly lower, but statistically significant, rate of requiring CIC (OR 0.92,P < 0.01). CONCLUSIONS: When counseling patients regarding the different types of diversions after RC, the potential need for long-term CIC after ONB must be discussed. The clinical factors that appear to increase the need for CIC include non conservative RC (non-nerve sparing in males and non-vaginal sparing in females) and, to a certain degree, younger age. PMID- 26604446 TI - Trans-vaginal anterior vaginal wall prolapse repair using a customized tension free bell-shaped prolene mesh: A single-center experience with long-term functional analysis. AB - INTRODUCTION: The existing literature shows that mesh reinforcement improves the anatomical success rate of cystocele repair. We report the long-term results of a custom bell-shaped mesh with simultaneous urethral support for the repair of cystocele. MATERIALS AND METHODS: The present study was a single-center, single surgeon case series of 36 patients. Only patients with Pelvic Organ Prolapse Quantification system (POP-Q) stage 2 and above were included in the study. Patients having rectocele or uterine/vault prolapse were excluded. Body of the mesh was used for reinforcement of the cystocele repair and two limbs were left tension free in the retropubic space. Patients were followed 3 monthly for the first year and yearly thereafter. Recurrence was defined as cystocele >=stage 2 (Aa or Ba 0) any time after the first follow-up. RESULTS: Mean patient age was 58.5 +/- 6.2 years. The mean parity was 3.2 +/- 1.6. Of 36 patients, 11 (30.5%) of the patients were POPQ stage 2, 15 (41.7%) were stage 3 and 10 (27.7%) were stage 4 cystocele. The mean follow-up period was 53.4 months, with 32 patients reporting for follow-up till date (88.9%). There was no bladder injury, no mesh erosion or infection. No patient required CIC (clean intermittent catheterization) or had stress urinary incontinence post-operatively at 5 years of follow-up. CONCLUSION: The bell-shaped mesh is a simple, effective and safe procedure in the surgical management of cystocele with excellent long-term outcome. PMID- 26604447 TI - Severe forms of concealed penis without hypospadias: Surgical strategies. AB - INTRODUCTION: Concealed penis (CP) may vary in severity and includes megaprepuce (MP) as a variant. Many different surgical strategies have been described in order to maximize penile exposure and to deal with skin deficiency. We describe the strategies that we use to overcome technical problems in severe cases of CP. MATERIALS AND METHODS: Six consecutive cases of severe CP (including 3 with MP) were treated in a 2-year period between January 2011 and April 2013. These patients were treated using extensive degloving, removal of dysplastic dartos, Alexander's preputial flap, scrotal flaps and skin grafts. Three patients had been previously circumcised. Cases associated with hypospadias, obesity, disorders of sexual differentiation and micropenises were excluded. RESULTS: All six patients attained good results, with good exposure of the penis, ability to void standing with a well-directed flow and reasonable esthetic results. A technical algorithm for the treatment of primary or recurring cases of CP is proposed. CONCLUSION: Alexander' s distally based ventral preputial flap is a useful technical resource to treat MP cases. Free skin grafts and/or laterally based scrotal flaps may be used to cover the penis after release in severe cases of CP. PMID- 26604448 TI - Is frozen section analysis of the urethra at the time of radical cystectomy and orthotopic neobladder urinary diversion mandatory? AB - INTRODUCTION: This study was aimed at analyzing the need for routine use of frozen section analysis (FSA) before performing orthotopic neobladder (ONB) after radical cystectomy for carcinoma urinary bladder. MATERIALS AND METHODS: A total of 233 patients underwent radical cystectomy from January 2000 to June 2013. Of these, 151 (65.6%) patients were planned for ONB. In the initial 109 (72%) patients, FSA of urethral margin was performed, but, in the subsequent 42 (28%) patients, frozen section of urethral margin was not sent. Impact of hydroureteronephrosis, tumor size and location of tumor in relation to the bladder neck on the status of the urethral margin was analyzed. RESULTS: Only three of the 109 (2.7%) patients had a positive urethral margin. Two of them had ileal conduit and one, after negative re-resection, had ONB. Although none of the factors was found to be significant, all three patients with a positive urethral margin had growth at the bladder neck and died of cancer at a mean follow up of 29.33 +/- 18.3 months, without urethral recurrence. Among the negative FSA (106), two patients had recurrence in the penile urethra. The mean follow-up was 46.3 +/ 25.1 months. None of the patients without FSA (42) had urethral recurrence at the mean follow-up of 36 +/- 9.3 months. Of the 28 patients who had their growth located at the bladder neck, three had positive FSA, while none with growth away from the bladder neck had positive FSA. CONCLUSION: Routine FSA of the urethra before performing ONB can be avoided in those patients where the tumor does not reach the bladder neck. PMID- 26604450 TI - Solitary fibrous tumor mimicking prolapsed ureteral polyp. AB - Solitary fibrous tumor of the ureter is extremely rare. We describe a case where the polyp was prolapsing into the bladder mimicking a bladder tumor. PMID- 26604449 TI - Role of uroflowmetry with electromyography in the evaluation of children with lower urinary tract dysfunction. AB - INTRODUCTION: A conventional urodynamic study (UDS) is considered invasive while uroflowmetry is considered inadequate in the evaluation of children with lower urinary tract dysfunction. The aims of this study were to identify the role of uroflowmetry with electromyography (UFEMG) in this group. METHODS: A cohort of 121 children (age 5-12 years; M:F = 2:3) with symptoms of lower urinary tract dysfunction underwent a detailed voiding history and clinical assessment. Those with evidence of neurological abnormality, obstructive uropathy or active urinary tract infection were not included. They were prospectively studied using UFEMGfirst, followed by UDS on the same day. RESULTS: A total of 76 (63%) children had abnormality on UFEMG while only 12 (10%) had abnormality on UDS. UFEMG was significantly superior in picking up abnormality (P = 0.03). Three types of UFEMG abnormalities were identified: (1) dysfunctional voiding (prolonged staccato trace with active pelvic floor and normal voided volume: n = 42), (2) idiopathic detrusor overactivity (shortened trace with quiet pelvic floor and reduced voided volume: n = 16) and (3) detrusor underutilization disorder (prolonged flat trace with quiet pelvic floor and large voided volume: n = 18). CONCLUSIONS: UFEMG is ideal non-invasive test in children with lower urinary tract dysfunction. It helps in identifying the different patterns and the appropriate treatment modality. PMID- 26604451 TI - A rare cause of anuria: Bilateral synchronous isolated mid-ureteric tubercular lesions. AB - A young female presenting with right flank pain, fever, raised creatinine and bilateral hydronephrosis was treated with antibiotics elsewhere, with presumptive diagnosis of bilateral pyelonephritis. She had partial relief in symptoms and her creatinine level showed an improvement. Three months later during evaluation at our center she had anuria, hypertensive crisis and pulmonary edema which were managed with emergency bilateral percutaneous nephrostomies. Cross-sectional imaging and ureteroscopy suggested bilateral synchronous intramural mid-ureteric lesions as underlying pathology. Histopathology of the ureteric segments during laparotomy revealed caseating granulomas suggestive of tuberculosis. This clinical presentation has not been previously described in urinary tuberculosis. PMID- 26604452 TI - Solitary second metatarsal metastasis as the first site of distant spread in TCC urinary bladder: A case report. AB - Metastasis to the skeleton is uncommon in muscle-invasive carcinoma of the urinary bladder. When present, it most commonly involves the axial and proximal appendicular skeleton, and acrometastasis (metastasis to hand and foot) is very rare. We report a patient who developed a solitary metastatic lesion of the left metatarsal 2 weeks after radical cystectomy. The lack of suspicion and magnetic resonance imaging findings suggestive of inflammation led to a diagnosis of tubercular osteomyelitis and antitubercular therapy was started. The patient developed nodal metastasis and, because the foot lesion did not respond to treatment, fine needle aspiration cytology from it revealed poorly differentiated metastatic cancer. PMID- 26604453 TI - Urinary bladder leiomyosarcoma following radiotherapy in a patient with bilateral retinoblastoma: A case report. AB - Retinoblastoma patients have excellent survival following primary treatment by enucleation, radiotherapy or chemotherapy. Patients receiving chemotherapy or radiotherapy may develop second malignancies years later due to DNA damage or genetic mutations. Urinary bladder leiomyosarcoma is one among them and most such cases have been reported after chemotherapy. We report the third case occurring after isolated radiotherapy. PMID- 26604454 TI - Glandular diphallus with urethral duplication: Conventional technique for a rare congenital anomaly. AB - Diphallus is a rare anomaly and its association with urethral duplication is extremely rare. Numerous associated genitourinary and gastrointestinal anomalies have been reported with this condition. Challenges in the management are incorporation of the glans and the dominant urethra during reconstruction. We report the successful management of a case of glandular diphallus with complete urethral duplication retaining the dorsal urethra. PMID- 26604455 TI - Left retrocaval ureter without situs inversus or inferior venacava duplication. AB - Retrocaval ureter (pre-ureteral vena cava) is an uncommon congenital anomaly that causes ureteral obstruction by external compression. Although right retrocaval ureter is a common entity, left retrocaval ureter is extremely rare. A left retrocaval ureter is usually associated with situs inversus or duplicated inferior venacava (IVC). An isolated left retrocaval ureter with single left sided IVC is even rarer and only four cases have been reported in the literature. We present images of a case with isolated left retrocaval ureter with a single left-sided IVC without situs inversus. PMID- 26604456 TI - Re: Sharma G, Sharma A. Determining the angle and depth of puncture for fluoroscopy-guided percutaneous renal access in the prone position. Indian J Urol 2015;31:38-41. PMID- 26604457 TI - Re: Sharma G, Sharma A. Determining the angle and depth of puncture for fluoroscopy-guided percutaneous renal access in the prone position. Indian J Urol 2015;31:38.41. PMID- 26604458 TI - Authors' Reply. PMID- 26604460 TI - Osteoradionecrosis of the Jaws: Clinico-Therapeutic Management: A Literature Review and Update. AB - Osteoradionecrosis is one of the most serious oral complications of head and neck cancer treatment. It is a severe delayed radiation-induced injury, characterized by bone tissue necrosis and failure to heal for at least 3 months. In most cases osteoradionecrosis gradually progresses, becoming more extensive and painful that leads to infection and pathological fracture. The present paper provides a literature review and update on the risk factors underlying osteoradionecrosis, its clinical and diagnostic particulars, prevention and most widely accepted treatment options including the latest treatment modalities. Lastly, a new early management protocol is proposed based on the current clinical criteria relating to osteonecrosis secondary to treatment with bisphosphonates, together with the adoption of new therapies supported by increased levels of evidence. PMID- 26604459 TI - Management of Midline Facial Clefts. AB - Median or midline facial clefts are rare anomalies of developmental origin, etiology of whose occurrence is still unknown precisely. The most basic presentation of midline facial clefts is in the form of a Median cleft lip which is defined as any congenital vertical cleft through the centre of the upper lip. First described by Bechard in 1823, it is the most common amongst all atypical clefts reported. The incidence is about 1:10,00,000 births. This may occur as a sporadic event or as a part of an inherited sequence of anomalies. It arises embryologically from incomplete fusion of the medial nasal prominences. The authors present a series of eight cases with varying degrees of midline facial clefts. This review article aims to give a broad idea on the various classifications used for further understanding of midline facial clefts and a brief idea about the various surgical management techniques used in the repair of these facial clefts. PMID- 26604461 TI - Concomitant Association of Oral Submucous Fibrosis and Oral Squamous Cell Carcinoma and Incidence of Malignant Transformation of Oral Submucous Fibrosis in a Population of Central India: A Retrospective Study. AB - AIM: To evaluate the incidence of oral squamous cell carcinoma concomitant with oral sub mucous fibrosis in central India and to correlate precipitating factors associated with oral submucous fibrosis and oral squamous cell carcinoma. This paper also aims to study the incidence of oral squamous cell carcinoma arising secondary to untreated oral submucous fibrosis. MATERIALS AND METHODS: Two hundred and twenty five cases of oral squamous cell carcinoma and one hundred and nineteen cases of oral submucous fibrosis of various regions in oral cavity were included in the study. All the included cases were clinically and histopathologically diagnosed and retrospective data was retrieved. RESULT: In the present study of 119 patients of oral submucous fibrosis, 97.4 % were found to have betel nut chewing habit. Incidence of malignant transformation to oral squamous cell carcinoma in patients of untreated oral submucous fibrosis was found to be 4.2 % in the present study. The incidence of oral cancer concomitant with oral submucous fibrosis was found to be 25.77 %, which is statistically significant. CONCLUSION: From the present study, it is evident that the malignant potential of OSF is underestimated. However, considering the small sample size and the fact that the study was carried out in a small geographical area, further study with a larger sample size and longer duration of follow up on a multicentric basis may be required to reveal the actual malignant potential of the disease. PMID- 26604462 TI - Growth Factor Measurement and Histological Analysis in Platelet Rich Fibrin: A Pilot Study. AB - OBJECTIVE: The aim of this study was to compare growth factor amount contained in platelet rich fibrin (PRF) and compare with that in platelet rich plasma (PRP), and in whole blood. And also to investigate distribution of growth factors and cellular components in PRF. MATERIALS AND METHODS: PRF and PRP were obtained from the same sample of peripheral blood. Extraction of proteins were done with lysis buffer, accompanied by freeze and thaw procedures. Concentration of two representative growth factors in platelets: platelet derived growth factor (PDGF) and transforming growth factor beta (TGF-beta), were measured with enzyme-linked immunosorbent assay (ELISA). PRF was cut into three parts: (top, middle and bottom), and growth factor concentration was measured respectively. Paraffin embedded section of PRF was observed with Giemsa stain. Immuno-histochemical analysis with anti-PDGF and anti-TGF-beta antibodies was also conducted. RESULTS: The growth factor levels in PRF was higher than in peripheral blood and comparable to those in PRP. Growth factor levels in bottom part of PRF was much higher than in top and middle part. Microscopically, platelets and mono-nucleated cells were concentrated just above the yellow-red interface. Poly-nucleated cells were concentrated below the interface. CONCLUSION: The growth factors were surely concentrated in PRF. This result can support basis of good clinical outcomes. For effective application of PRF, the knowledge that growth factors and cells are not equally distributed in PRF should be utilized. PMID- 26604463 TI - Immunoexpression of Metallothionein in Oral Squamous Cell Carcinoma. AB - BACKGROUND AND OBJECTIVES: Metallothionein (MT) is a family of ubiquitous low molecular weight (7 kDa), intracellular (cytoplasmic/nuclear), cysteine rich proteins with high affinity for heavy metals, present in both normal cells and neoplastic cells. Increased expression of MT has been reported to be associated with poor prognosis in various tumours. The objectives of the present study were to compare the expression of MT in normal subjects and in patients with oral squamous cell carcinoma (OSCC), to correlate the expression of MT with respect to clinical staging of OSCC and to evaluate the expression of MT with respect to different histopathological grades of OSCC. METHODS: Thirty cases of OSCC were staged clinically and graded histopathologically. Immunohistochemical method was used to detect the expression of MT in OSCC. The scores obtained were documented and compared statistically. RESULTS: MT immunoreactivity was noticed in all cases of OSCC. A statistically significant difference was observed in immunoreactivity of MT between the normal and OSCC, and in different histopathological grades of OSCC (p = 0.00001*). However, no statistical significance was found in a number of immunopositive cells in different clinical stages of OSCC (p = 0.7573). CONCLUSION: The MT immunoexpression increased from low grade to high grade OSCC. Hence, increased expression of MT may be related to poor prognosis in patients with OSCC. PMID- 26604464 TI - Cranioplasty of Hemispherical Defects Using Calcium Phosphate Cements Along with Titanium Mesh: Our Experience. AB - INTRODUCTION: Cranial defects may arise due to trauma, infection, surgical ablation or errors in development. Restoration of such defects is important for esthetics, function and morale of the patient. Several materials are available. Each has its advantages and disadvantages. Search is on for an ideal material. Autogenous grafts remain the gold standard in reconstruction of such defects. However, the morbidity associated with their harvest, additional time required, the need for a second surgical site and the limited supply has led to the search for newer substitutes. Although many materials are available today including biologic and non biologic substitutes, there is still no consensus about the best material. In this article we describe our use of calcium phosphate cements for reconstruction of hemispherical cranial defects. MATERIALS AND METHODS: Cases requiring reconstruction of hemispherical cranial defects (more than 15 cm in any dimension) were selected for study. After exposing the defect under GA, titanium mesh was adapted to the defect for support. Then the calcium phosphate cement was prepared and injected on the mesh to establish good contour. The alloplastic insert in each patient was evaluated for: (a) Immediate post-operative complications (b) Restoration of contour and soft tissue support (c) New bone formation ascertained on HRCT at the end of 2 years. Patients were examined on postoperative first week, at 3 and at 6 months. High resolution computed tomography scans were taken at 2 years postop. There were two female and three male patients. RESULTS: There were no complications in the post operative period. The general condition of the patients improved post operatively. Even though the cements maintained their contour at 2 years, there were no signs of bone formation within the cement. CONCLUSION: Calcium phosphate cement is a good bone substitute for use in cranioplasty. In defects requiring mechanical strength, it should be supported by a titanium mesh. It retains the contour but is not replaced by bone even after 2 years. PMID- 26604465 TI - Ocular Injuries Associated with Midface Fractures: A 5 Year Survey. AB - AIM: The aim of this study is retrospective analysis of ocular injuries after maxillofacial trauma reporting to the Department of Oral and Maxillofacial Surgery at V.S. Dental College and Kempegowda Institute of Medical Sciences and Hospital, Bangalore. STUDY DESIGN: A retrospective analysis of ocular injuries following facial trauma from 2008 to 2013. RESULTS: Road traffic incident was the most common etiology (55.46 %). Zygomaticomaxillary complex fracture was the most common fracture associated with ocular injuries (67.22 %). Out of 119 patients, 5 had severe visual impairment and (0.84 %) had blindness. CONCLUSION: Maxillofacial trauma particularly that associated with Lefort II, Lefort III and Zygomatico maxillary complex fracture may lead to opthalmic injuries and even blindness. A thorough opthalmic examination should be carried out for every patient with maxillofacial trauma and suspected cases should be placed under closed observation so that immediate and active treatment can be taken if necessary. PMID- 26604466 TI - Giant Cell Lesions Associated with Primary Hyperparathyroidism. AB - AIMS AND OBJECTIVE: To evaluate the prevalence, clinical features, diagnostic laboratory values and treatment outcome of giant cell lesions (brown tumors) associated with primary hyperparathyroidism (PHPT) in oral and maxillofacial region. STUDY DESIGN: A 5 year retrospective data was analyzed wherein all histopathologically proven cases of giant cell lesions involving oral and maxillofacial region were evaluated. Out of these cases, those associated with PHPT were tabulated. Correlation was established with other concomitant clinical features and also with the laboratory values of altered serum calcium, phosphate, alkaline phosphate and parathormone. Follow up of these cases after the correction of PHPT was also noted. RESULT: Out of 85 cases of histopathologically proven giant cell lesions, five cases were associated with PHPT. There was involvement of maxilla and mandible in one case each. Only frontal bone was involved in two cases. Fifth case had multiple lytic lesions in maxilla and frontal bone. All patients consistently showed very high values of alkaline phosphate and parathormone. Hypercalcemia and hypophosphatemia was noted in four cases. All cases showed regression of the lytic lesion after parathyroidectomy obviating the need for surgical excision of the jaw lesions. CONCLUSION: Giant cell lesions (brown tumors) associated with PHPT in oral and maxillofacial region are rare clinical entities. The prevalence of PHPT associated giant cell lesions is 5.9 %. They are clinically, radiologically and histopathologically similar to any other peripheral or central giant cell tumor. Relevant history may alert the clinician and altered biochemical values may help in correlating the oral and maxillofacial findings with the underlying systemic disease. At times, the brown tumor maybe the only presenting sign leading to the diagnosis of PHPT. PMID- 26604467 TI - Diversified and Unusual Presentations of Neck Space Infections: Still a Big Concern for Physicians. AB - The aim of this clinical study was to find similarities; dissimilarities of neck space infections along with challenges faced by treating physician for their diversified clinical presentations and complications. Patients with neck space infections were compared for the purpose. The classic manifestations of these infections, such as high fever, systemic toxicity, and local signs were not present in all cases leading to dilemma in physician's decision making. They progress towards fatality very fast. Prompt recognition, diagnosis and management of such cases and complications are of paramount importance to reduce morbidity and mortality. In addition to broad spectrum antibiotic therapy along airway protection, surgical drainage is necessary in nearly all cases. Neck space infections still continue to be a well prevalent health problem in poor socioeconomic group in developing countries having significant morbidity as well as mortality. PMID- 26604469 TI - Comparison Between Physics and Conventional Forceps in Simple Dental Extraction. AB - BACKGROUND: Atraumatic dental extraction preserves bone, gingival architecture, and allows for the option of future or immediate dental implant placement. A number of tools and techniques have been proposed for minimally invasive tooth removal such as physics forceps. The biomechanical design of physics forceps decreases the incidence of root fracture, and maintains the buccal bone plate, which is essential for the proper healing of an immediately placed dental implant. PURPOSE: This study was conducted to evaluate the efficacy of physics forceps versus conventional forceps in simple dental extraction. PATIENTS AND METHODS: 200 adult patients seeking simple dental extraction were selected from the Outpatient Clinic in the Oral and Maxillofacial Surgery Department, Faculty of Dentistry, Mansoura University, Egypt. The selected patients were randomly allocated into two groups: group I: included 100 patients, in this group extraction was done using physics forceps, and group II: included 100 patients, in this group extraction was done using conventional forceps. RESULTS: In physics forceps group: crown fracture occurred in three cases (3 %), buccal bone fracture occurred in three cases (3 %), and root fracture occurred in 14 roots (8.5 %), while in conventional forceps group: crown fracture occurred in 10 cases (10 %), buccal bone fracture occurred in seven cases (7 %), and root fracture occurred in 27 roots (16.6 %). CONCLUSION: Physics forceps are innovative extraction instruments. By using them, it is possible to perform difficult extractions, with predictable results, and without need to reflect a flap. Using physics forceps decreases the incidence of crown, root, and buccal bone plate fractures, in comparison to the conventional forceps. PMID- 26604468 TI - Superolateral Dislocation of the Mandibular Condyle: A Series of Seven Cases. AB - INTRODUCTION: Anterior and anteromedial dislocations of the mandibular condyle are seen frequently in mandibular fractures. Less frequent are dislocations of the condylar head in the lateral, medial and posterior direction whereas superior dislocation into the middle cranial fossa is rare. We report a series of seven cases encountered over the years, which, incidentally, is the largest case series reported till date with lateral and superolateral dislocation of the condyle after a traumatic injury. MATERIALS AND METHOD: In all cases but one, the condyle was reduced by manual manipulation with the patient in general anaesthesia. In all cases but one there was simultaneous fracture in the mandibular symphyseal region. The associated fractures were reduced and fixed with bone plates and screws. RESULTS: Patients were generally free from any long term complications of injury or surgery except for facial nerve paresis of a transient nature in one case. CONCLUSION: To our knowledge, this clinical series presents the first reported case of superolateral dislocation which required open reduction. The etiology and mechanism of dislocation has been discussed along with a brief review of the literature. PMID- 26604470 TI - Mandibular Third Molar Position Influencing the Condylar and Angular Fracture Patterns. AB - PURPOSE: The aim of this study was to assess the influence of position of mandibular 3rd molar on angle and condylar fractures. MATERIALS AND METHODS: Panoramic radiographs were used to determine the mandibular fracture patterns based on the presence or absence of the third molar. RESULTS: Of the 64 patients with mandibular fractures, condyle and angle fractures were found to be 67 and 33 % respectively. The greatest percentage (75 %) of condylar fractures were associated with erupted third molar teeth, and 25 % had impacted teeth. Subcondylar region was found to be the most common site that predisposes to fracture. Moderate force lead to condylar fracture when third molar is erupted or absent and mild force showed angle fracture when third molar is impacted. Increased incidence of angle fracture was observed when tooth is in mesioangular and distoangular position. CONCLUSION: Impacted mandibular 3rd molar leads to an increased risk of angle fracture and decreased risk of condylar fracture especially when they are more deeply seated. PMID- 26604471 TI - Maxillofacial Surgeon as Fact Witness for Medico-Legal Cases: Indian Scenario. AB - An Oral and Maxillofacial surgeon at any time during the practice will encounter medicolegal cases (MLC). There are lacunae in the knowledge and understanding of the correct method of dealing with such cases. Many of the practitioners are apprehensive and anxious as they have to interact with individuals and systems outside the normal realm of practice. In today's arena, it is of utmost importance to be aware of legal system and law of the land. An OMF surgeon needs to have thorough understanding in recording and maintenance of the details of all MLCs and presenting the same in the court. Professional guidelines for expert witness are often not well recognised as those relating to the clinical practice. Surgeon has an obligation to conduct him/herself to highest ethical standards. This article provides insight into the details of registration of MLC, examination and recording of injuries, collecting medico-legal evidences and writing a medico legal report. Also discusses the court proceedings and possible questions that may be faced by the surgeon in the court. PMID- 26604472 TI - Bite Force Evaluation of Conventional Plating System Versus Locking Plating System for Mandibular Fracture. AB - AIMS AND OBJECTIVES: To compare and evaluate the variation in recorded bite forces in patients with mandibular fractures undergoing open reduction and rigid internal fixation using standard 2.0 versus 2.0 mm locking miniplates. MATERIALS AND METHODS: A prospective randomized study was conducted for the treatment of mandibular fractures. Twenty adult patients with 31 mandibular fractures requiring an open reduction and internal fixation were included in the study. The sample was divided into two groups depending upon whether the patients received 2.0 mm non-locking (standard) or 2.0 mm locking miniplates for rigid fixation respectively. Bite force was evaluated at 1st, 3rd and 6th week after the open reduction and rigid fixation using miniplates. RESULTS: A statistically significant difference was not found in the clinical parameters such as pain, swelling, infection, paresthesia, hardware failure, and mobility between the fracture segments. The results showed that amongst locking vs non-locking miniplates, the former showed a greater bite force enhancement when compared to baseline values(post-trauma).A comparison between 2nd day post-operative vs 6th week post-operative values showed a significant increase in bite force in Group 1 (non-locking) (p < 0.05) whereas the values Were highly significant (p < 0.001) in Group 2 (locking Plate). CONCLUSION: The findings were suggestive that the efficacy of locking miniplates plate in mandibular fracture was superior in terms of bearing the masticatory loads during osteosynthesis of the fracture. However, the clinical results were almost similar to those seen with non-locking miniplate osteosynthesis. PMID- 26604473 TI - Comparison of Management of Mandibular Angle Fractures by Three Approaches. AB - BACKGROUND AND OBJECTIVES: Various methods have been reported in the literature for treating mandibular angle fractures comparing extra oral, intra oral and transbuccal approaches for achieving the goals of restoration of anatomic form, maintenance of segment position and bony union. MATERIALS AND METHODS: This study was conducted to assess the simple and effective surgical approach in treating mandibular angle fractures and the outcome by means of three approaches i.e. intra oral, transbuccal and extra oral approaches. RESULTS/CONCLUSION: A total of 45 patients with mandibular angle fracture were divided into three groups. Group I-intra oral approach-15 patients, Group II-transbuccal with intraoral approach 15 patients, Group III-extra oral approach-15 patients. The results of our study found intraoral approach to be much better because it is simple, precise, duration is short, and post operative complications are less with minimal morbidity and pain. PMID- 26604475 TI - Facial Candidal Abscess in a Patient with Unknown Type 2 Diabetes Mellitus. AB - INTRODUCTION: Facial candidal abscess is an infection with a fungal cause which was presented in this case such a rarity. We report a rare case of facial abscess due to Candida species in a patient with unknown diabetes. MATERIALS AND METHODS: The patient presented with a longstanding firm swelling which occurred 2 weeks ago and did not show any improvement of healing process in spite of surgical and medical treatments. MRI examinations were conclusive and compatible with abscess, so she underwent surgical intervention. Facial candidal abscess was the final diagnosis. CONCLUSIONS: We concluded that, in persistent abscesses, invasive candidiasis should be considered in the differential diagnosis of bacterial infections as it generally affects individuals with diabetes or general defects in the immune system, or those who use widespread antibiotics and steroids. PMID- 26604474 TI - A Comparative Prospective Study of Two Different Treatment Sequences i.e. Bottom Up-Inside Out and Topdown-Outside in, in the Treatment of Panfacial Fractures. AB - PURPOSE: To compare the sequence bottom-up inside-out with top-down outside-in, in the treatment of pan facial fractures and to evaluate the outcome of these approaches. PATIENTS AND METHODS: The data from 11 patients with panfacial fracture are prospectively analysed. Five cases are treated with bottom-up approach and six patients with top-down approach. RESULTS: There were 11 male patients (six in top-down approach and five in bottom-up approach), ranging in age from 24 to 50 years. All injuries were result of RTA (n = 11, 100 %). Final treatment outcome was excellent in 3 (50 %), 1 (16 %) good and 2 (32 %) cases were fair in topdown approach, 3 (60 %) excellent and 2 (40 %) fair in bottom up approach with contingency coefficient value (P < .632) which was insignificant. There was no significant deviation from the two groups in the final treatment outcome. CONCLUSION: Within the limitation of low sample size we found that both bottom-up inside-out and top-down outside-in approaches have similar clinical outcomes. Hence it could be suggestive to start fixation of least disrupted (more stable) facial half as a guide for reconstruction of the remaining. Choice of the bottom-up inside-out or top-down outside-in sequence should be according to the pattern of fractures and preference of the surgeon. However, further controlled clinical trials, comparative studies with a larger sample size would be better to evaluate the final clinical outcome of individual techniques. PMID- 26604476 TI - Basal Cell Adenoma of Submandibular Salivary Gland: A Case Report and Literature Review. AB - BACKGROUND: Salivary gland tumours constitute about 3-4 % of all head and neck neoplasms. Approximately 80 % originate in the parotid gland and they are rarely present in the submandibular gland. Basal cell adenoma is a benign epithelial salivary gland tumour that appears to have unique histologic characteristics. The diagnosis of this entity must be established by histological study. CASE REPORT: The literature revealed only four reported cases of basal cell adenoma of submandibular salivary gland. This article presents a rarely occurring basal cell adenoma as a fifth reported case in submandibular salivary gland in a 23 year old female. DISCUSSION: A rare case of basal cell adenoma of submandibular salivary gland is reported with clinical features, diagnosis, histopathological features and treatment modalities. When there is involvement of submandibular gland with a tumour the histopathological confirmation is mandatory instead of relying on FNAC and it must be differentiated from pleomorphic adenoma, adenoid cystic carcinoma, adenocarcinoma due to its prognostic implications. CONCLUSION: Entities like basal cell adenoma can only be established by histopathological examination after excisional biopsy. The treatment done also affects the ultimate prognosis. As such the surgeon has to make his clinical decision based on many factors like history, clinical examination, histopathological examinations, radiological examination and immunohistochemistry study. No single criteria should be relied upon. We recommend to carry out genetic pattern study in a person with basal cell adenoma to rule out pathogenesis and establish a correct diagnosis of it for better understanding and prognosis. PMID- 26604478 TI - Successful Harvest of Free Fibula Flap in a Rare Anomalous Variant of the Peroneal Artery. AB - We present a case of successful harvest and anastomosis of a free fibula flap with 15 cm of bone where the peroneal artery was only 1.0 cm long and situated in the distal 1/3rd of the fibula. PMID- 26604477 TI - Peripheral Osteoma of the Body of Mandible: A Case Report. AB - Osteoma is a slow growing benign tumor consisting of well differentiated compact or cancellous bone that increases in size by continuous growth. It can be of a central, peripheral, or extraskeletal type. The peripheral type arises from the periosteum and is rarely seen in mandible. Although completely curable with adequate surgical treatment, osteomas precede the clinical radiographic evidence of colonic polyposis/Gardner's syndrome. Therefore they may be sensitive markers for the disease. Recurrence of peripheral osteoma after surgical excision is extremely rare. However it is appropriate to provide both clinical and radiographic follow up after surgical excision of peripheral osteoma. This article describes the case of a 45 year old male who presented with painless swelling of the right body of mandible and resultant cosmetic facial disfigurement and functional impairment. PMID- 26604479 TI - Vagus Nerve Paraganglioma: Radiological Features We Should Be Aware of. AB - INTRODUCTION: A rare case of vagal paraganglioma is reported. MATERIAL AND METHODS: The specific radiological features of this tumor are presented to the clinician in order to make presumptive diagnosis. CONCLUSION: By CT-scan and/or MRI it must be suspected when a hypervascular tumor in relation to the major cervical vessels displaces the internal and external carotid arteries forward, does not open the carotid bifurcation, and displaces the internal jugular vein backwards. PMID- 26604480 TI - From the Editor's desk. PMID- 26604481 TI - Brush off the brush biopsy. PMID- 26604482 TI - Cancer conundrum. PMID- 26604483 TI - Hyaline ring granuloma. PMID- 26604484 TI - The domino effect: Role of hypoxia in malignant transformation of oral submucous fibrosis. AB - INTRODUCTION: Oral submucous fibrosis (OSMF) is a precancerous condition predominantly seen in people of Asian descent. About 7-12% OSMF patients develop oral squamous cell carcinoma (OSCC). Morphological features of OSMF especially fibrosis suggests a possibility of the hypoxic environment in diseased tissues. Oral cancer usually develops from hyperplasia through dysplasia to carcinoma. Neovascularization and increased glycolysis, represent adaptations to a hypoxic microenvironment that are correlated with tumor invasion and metastasis. The adaptation of cells to hypoxia appears to be mediated via hypoxia inducible factor-1alpha (HIF-1alpha). HIF-1alpha is said to be associated with malignant transformation of epithelium in other sites. It appears that HIF-1alpha plays a significant role in both prostate and cervical carcinogenesis at early stages. We hypothesize that progression of OSMF and malignant transformation in the background of fibrosis mediates via HIF-1alpha either by up- or down-regulation of various such molecules. Therefore, the main objective of this study was to investigate the relationship between the expression of HIF-1alpha in OSMF, OSCC and OSCC with OSMF. AIM: To investigate the relationship between the expression of HIF-1alpha in OSMF, OSCC and OSCC with OSMF. MATERIALS AND METHODS: The study group consists of histopathologically diagnosed 20 cases of OSCC, oral submucous fibrosis and OSCC with OSMF each. The immunohistochemistry was carried out on neutral buffered formalin-fixed paraffin-embedded tissue sections by using the monoclonal antibody of HIF-1alpha. RESULTS: A rise in the expression of HIF 1alpha from OSMF to OSCC to OSCC with OSMF is observed. PMID- 26604485 TI - Immuno-reactivity of excised lymph nodes in neck dissections of squamous cell carcinomas of oral cavity. AB - BACKGROUND: Regional lymph nodes play an important role in acting as anatomic barriers to systemic dissemination of tumor cells. This reflects in the host immunologic response. Oral squamous cell carcinoma, is known to be associated with early deficiencies of cell-mediated immunity, the pathology of which is reflected in the histology of the regional lymph nodes. AIM: The goal of this study was to study the different immunity reactions in the lymph nodes and to correlate it with the histopathology of tumor proper. MATERIALS AND METHODS: Out of 40 head and neck dissections, 30 were male and 10 females within the age range of 21-72 years. According to Tumor Node Metastasis classification, there were 12 cases of stage II and stage III, respectively while 16 were of stage IV. A total of 372 nodes were histologically evaluated. The harvested lymph nodes were categorized into metastatic and non-metastatic nodes exhibiting four patterns as: Lymphocyte predominance pattern, germinal center predominance pattern, lymphocyte depleted pattern and unstimulated pattern. RESULTS: The predominant pattern of lymph node reactivity was of lymphocyte predominance (199 nodes) followed by germinal center predominance (117 nodes); lymphocyte depleted (17 nodes) and unstimulated node pattern (39 nodes). Twenty-seven nodes were positive for metastasis. A statistically significant relationship (P = 0.0019 and P = 0.0290, chi square, respectively) was observed between the number of nodes harvested and stage and level of lymph nodes. A brief follow-up period of 3 years was carried out. CONCLUSION: Further studies relating the immuno-morphologic assessment of the lymph nodes in conjunction with other factors may be helpful in assessing the metastases risk of the individual. PMID- 26604486 TI - Acetic acid as an adjunct vital stain in diagnosis of tobacco-associated oral lesions: A pilot study. AB - BACKGROUND: One of the most important risk factors for oral precancer and cancer in India is the use of tobacco. In chronic tobacco users, the mucosa may appear clinically healthy, however, changes are observed histologically. Screening of such tobacco users for an early diagnosis is, therefore, of paramount importance. Several adjunctive diagnostic modalities have been used in the past, but none has been conclusively validated as confirmative and cost-effective screening methodology. The aim of this study was to evaluate the use of 5% acetic acid as a vital staining agent in tobacco-associated oral lesions. MATERIALS AND METHODS: The study subjects were divided into two groups. Group I (n = 40) subjects with a history of chronic tobacco use and clinically apparent normal mucosa. Group II (n = 40) subjects suspected of having oral cancer, 5% acetic acid was applied to the mucosa/lesions, followed by incisional biopsy for confirmatory diagnosis. RESULTS: The sensitivity and specificity for Groups I and II were 97%, 50% and 95%, 60%, respectively. Positive predictive value (PPV) and negative predictive value (NPV) of Group I were 0.95 and 0.66. Group II showed PPV and NPV of 0.95 and 0.60. CONCLUSION: The results of this study suggest that acetic acid holds promise for future. Hence, further studies are needed to be undertaken on a large scale to assess its potential as a screening tool for high-risk individuals and oral cancer. PMID- 26604487 TI - Serum lipid profile in oral submucous fibrosis: A clinico pathological study. AB - BACKGROUND: Lipids play a key role in the maintenance of cell integrity. These are major cell membrane components essential for various biological functions, including cell growth and division of normal and malignant tissues. Abnormal changes have long been associated with alterations in lipid profile. AIM: The aim of this study was to evaluate the alterations in lipid profile in oral submucous fibrosis (OSMF) patients and to compare the levels with respect to the clinical staging and histological grading. MATERIALS AND METHODS: Fifty patients of OSMF, diagnosed clinically and histopathologically, were included as the study subjects. A group of 50 age and sex matched normal subjects without any oral pernicious habits were taken as controls. The serum lipid profile consisting of total cholesterol (TC), triglycerides (TGs), high density lipoprotein (HDL), very low density lipoprotein (VLDL) and low density lipoprotein (LDL) were analyzed using Erba Chem-5 Plus Analyzer. RESULTS: Serum TC, HDL and LDL levels were significantly decreased in OSMF patients as compared to controls. As the clinical stage progresses, the TC and HDL levels were gradually reduced. All the lipid profile parameters such as TC, TG, HDL, VLDL and LDL progressively reduced as the histological grade advanced. CONCLUSION: The results of the present study showed that there is an inverse relationship between lipid profile and the presence of OSMF. The decreased serum lipid profile may be considered as a useful indicator for initial changes occurring in the cells of potentially malignant disorders like OSMF. PMID- 26604488 TI - Efficacy of curcumin in the treatment for oral submucous fibrosis - A randomized clinical trial. AB - INTRODUCTION: Oral submucous fibrosis (OSF) is a chronic, insidious disease that is associated with significant functional morbidity and an increased risk for malignancy. Turmeric and its active ingredient "curcumin" are being studied upon as chemopreventive agents in various diseases. The present study aims to determine the efficacy of curcumin in the treatment of OSF. MATERIALS AND METHODS: Thirty clinically diagnosed OSF patients were divided into two groups, 15 patients in each group from the Outpatient Department. Test group patients were treated with Longvida (curcumin) lozenges and control group with Tenovate ointment (clobetasol propionate (0.05%). The treatment was given for 3 months duration and follow-up was done for 6 months. Both the groups were advised for physiotherapy exercises by mouth exercise device. The baseline and follow-up results were compared for IIO (interincisal distance on maximum mouth opening), Visual Analogue Scale (VAS) for normal food and VAS for spicy food. RESULTS: The test group showed 5.93 (+/-2.37) mm increase in mouth opening compared to 2.66 (+/-1.76) mm of the control group. In relation to VAS scale with spicy and normal food the average reduction was 64 (42-73) and 77 (70.5-82) as compared to 34 (14.5-64.5) and 64 (46-75.5) respectively in control group. The test group results achieved in the treatment span was sustained in the follow-up (P < 0.05) compared to control group which showed statistically significant (P < 0.05) relapse. CONCLUSION: It can be concluded that combination strategies for the management of OSF which include the stoppage of causative ill habits, appropriate medicinal and physiotherapy management is more efficient than single therapeutic modality. It is evident from the study that curcumin holds good promise in the treatment of OSF in future. PMID- 26604489 TI - Imaging and image management: A survey on current outlook and awareness in pathology practice. AB - BACKGROUND: Flexibility of digital photography enables it to be an integral part of pathology practice. An assessment of guidelines of imaging is essential for proper usage of photographs. OBJECTIVES: The purpose of the study was to assess awareness of oral pathologists about various aspects of medical photography. METHODS: Questionnaire based on the availability of facilities, usage, technical details and ethical issues of medical photography was sent to postgraduate students and teaching faculties of Oral Pathology in various localities in India. RESULTS: Photographs were taken mostly for the purposes of publication, medical documentation and education. Significant number of postgraduate students and faculties of Oral Pathology didn't receive any training or hadn't gone through any publications/books (P = 0.000) about medical photography. Consent for patient photography was taken by significant number of respondents (P = 0.000) but in a verbal form. Majority of people used image editing software, but 19.0% of faculties and 21.1% of postgraduate students were unaware of deleterious effect of image editing. Firm and sensible instructions concerning image storage, sharing and accessibility were not yet created. CONCLUSION: This survey drew attention towards lack of proper understanding about the technical details, medical protocols and ethical issues related to medical photography. These findings recommend implementation of basic training for medical photography and policy for image management for students and faculties in every health care institution. PMID- 26604490 TI - Comparison of salivary flow and candidal carriage in patients with oral submucous fibrosis. AB - BACKGROUND: Oral submucous fibrosis (OSMF) is a high-risk precancerous condition that predominantly affects Indians due to prevalent gutka chewing. Changes in the salivary flow rate and its effect on candidal carriage in patients suffering from OSMF have not been extensively explored. AIM: The aim of this study is to compare the salivary flow rate and salivary candidal carriage in OSMF patients and healthy individuals. MATERIALS AND METHODS: This pilot study included a total of 30 OSMF patients and 30 healthy individuals. Salivary flow was estimated using preweighed cotton rolls placed at the openings of major salivary duct for 5 min. The cotton rolls were then removed from the oral cavity and weighed again. The difference in weight was recorded. Salivary samples were collected by the oral rinse technique and cultured on Sabouraud agar medium. The cultured yeast colonies were identified based on Gram's staining, periodic acid-Schiff (PAS) and germ tube formation. RESULT: There was statistically significant (P < 0.001) decreased salivary flow rate in OSMF individuals as compared to the control. Salivary flow rates constantly reduced with different grades of OSMF patients, although candidal carriage was seen in grade II and grade III OSMF patients. CONCLUSION: A higher incidence of Candida was observed in OSMF patients when compared to the healthy individuals. The results of our study suggest that a higher candidal carriage in grade II and grade III OSMF patients could be related to decreased salivary flow rate. PMID- 26604491 TI - Assessment of ABO blood grouping and secretor status in the saliva of the patients with oral potentially malignant disorders. AB - BACKGROUND: Secretor status may possibly be one of the factors in the etiopathogenesis of oral precancerous lesions and subsequently cancer. Studies have shown the relationship between the pathogenesis of disease and secretor status. They have made known that secretor status is a possible factor influencing disease status. Studies have revealed the association between blood groups and specific diseases. AIMS: To assess any association of ABO blood grouping with oral potentially malignant disorders (OPMDs) and to examine whether there is any difference in the saliva secretor status in the patients with OPMDs and healthy controls. MATERIALS AND METHODS: The study consisted of 90 subjects, with 45 patients assigned to two groups (a) Patients with potentially malignant disorders and (b) healthy controls. ABO blood grouping was done and 1 ml of unstimulated saliva was collected in a sterile test tube. The Wiener agglutination test was performed to analyze the secretor status in both the groups. Chi-square test and odd ratio were used to assess the relationship between ABO blood group and OPMDs. Chi-square test was performed to assess the relationship between secretor status and OPMDs. Probability level was fixed at <0.05. RESULTS: The results demonstrated a statistically significant relation between OPMDs and secretor status (P = 0.00). Eighty-seven percent of patients with OPMDs were nonsecretors, while in the control group sixteen percent of them were nonsecretors. There was no statistically significant relationship between ABO blood groups and OPMDs (P > 0.05). CONCLUSIONS: The study confirms the inability to secrete blood group antigens in the saliva of patients with OPMDs which could be regarded as a host risk factor. Results could not propose a relationship between ABO blood group and OPMDs. PMID- 26604492 TI - Prevalence of human papillomavirus in oral lichen planus in an Iranian cohort. AB - CONTEXT: Oral lichen planus (OLP) is a chronic inflammatory mucocutaneous disease with female predominance with the potential for malignant transformation. Human papillomavirus (HPV) is associated with both malignant and benign disease in the head and neck region. AIMS: The present study assesses the prevalence of high risk HPV-16 and HPV-18 in tissue and saliva samples from an Iranian population diagnosed with OLP. SUBJECTS AND METHODS: Deoxyribonucleic acid was extracted and investigated using polymerase chain reaction from tissue and saliva samples of the same individuals from 40 OLP cases and saliva samples of 40 healthy controls. STATISTICAL ANALYSIS: The prevalence of data was compared using the Chi-square test and inter-group differences were analyzed using Fisher's exact test. RESULTS: OLP specimens were HPV-positive in 11 of 40 (27.5%) cases compared with three of 40 (7.5%) saliva specimens, representing a statistically significant difference (P = 0.0367). HPV-16 and HPV-18 were positive in eight of 40 (20%) OLP tissues and three of 40 (7.5%) saliva samples. Five of the 40 healthy saliva samples were positive for HPV-16. In the OLP patients with dysplasia, four of seven tissue samples were HPV-positive; threeof these four were HPV-16- positive in comparision with seven of 33 HPV-positive samples from OLP patients without dysplasia. CONCLUSIONS: Biopsies were more accurate than saliva analysis for evaluating HPV prevalence in OLP patients. HPV prevalence was higher in dysplastic than nondysplastic OLP lesions in this Iranian cohort. PMID- 26604493 TI - Habit-associated salivary pH changes in oral submucous fibrosis-A controlled cross-sectional study. AB - CONTEXT: Oral submucous fibrosis (OSF) is a multi-causal inflammatory reaction to the chemical or mechanical trauma caused due to exposure to arecanut containing products with or without tobacco (ANCP/T). Arecanut and additional components such as lime and chewing tobacco render ANCP/T highly alkaline. Fibrosing repair is a common reaction to an alkaline exposure in the skin. OSF may be related to the alkaline exposure by ANCP/T in a similar manner. AIMS: The study was aimed at establishing the relationship of habit-associated salivary pH changes and OSF. SETTINGS AND DESIGN: The study design was controlled cross-sectional. MATERIALS AND METHODS: Base line salivary pH (BLS pH), salivary pH after chewing the habitual ANCP/T substance, post chew salivary pH (PCSpH) for 2 min and salivary pH recovery time (SpHRT) were compared in 30 OSF patients and 30 sex-matched individuals with ANCP/T habits and apparently healthy oral mucosa. RESULTS: The group's mean BLSpH values were similar and within normal range and representative of the population level values. The average PCSpH was significantly higher (P ? 0.0001) than the average BLSpH in both groups. There was no significant difference (P = 0.09) between PCSpH of OSF patients and controls. OSF patients had a significantly longer (P = 0.0076) SpHRT than controls. Factors such as age, daily exposure, cumulative habit years, BLSpH and PCSpH, had varying effects on the groups. CONCLUSIONS: Chewing ANCP/T causes a significant rise in salivary pH of all individuals. SpHRT has a significant association with OSF. The effect of salivary changes in OSF patients differs with those in healthy controls. PMID- 26604494 TI - Palatal changes of reverse smokers in a rural coastal Andhra population with review of literature. AB - AIM: To investigate and record the palatal changes in individuals habituated to reverse chutta smoking in rural coastal Andhra population. MATERIALS AND METHODS: Sixty individuals out of whom 47 females and 13 males habituated to reverse smoking with no other tobacco and alcohol habits and no other systemic disturbances were selected. The palatal changes were recorded by six examiners. Database were searched for the following terms "reverse smokers," "nicotina palatini" and "palatal lesions." RESULTS: The mean and percentage prevalence of the each lesion recorded and agreed by six examiners among 60 subjects showed presence of 87.77% hyperpigmented areas, 64.44% depigmented areas, 51.66% excrescences, 32.22% potentially malignant lesions and 9.72% frank ulcerations. CONCLUSION: Reverse smoking is an endemic tobacco habit still practiced in the coastal rural Andhra Pradesh. It is a well-established and socially acceptable habit among adult females. The changes recorded clinically shows characteristic features that are unique among this population group. PMID- 26604495 TI - Periodic Acid Schiff-Diastase as a key in Exfoliative cytology in diabetics: A pilot study. AB - BACKGROUND: Diabetes mellitus is the fifth most common chronic condition and the sixth most frequent cause of death among the elderly. The objective of this research was to develop a new method for diabetes diagnosis by analysis of the glycogen content of the oral epithelial cells. MATERIALS AND METHODS: Ten control subjects and ten diabetic patients (study group) were taken, four oral smears for both control and study group from the buccal mucosa were taken and stained with hematoxylin and eosin stain, Papanicolaou (PAP) stain, periodic acid Schiff (PAS) stain and PAS-Diastase (PAS-D) stain. RESULTS: The results showed that in the diabetic group: (i) The epithelial cells stained with PAP stain exhibited figures of binucleation and occasional karyorrhexis, (ii) the epithelial cells treated with PAS-D showed that glycogen containing cells did not take up the stain as compared to the other cells. CONCLUSION: The results associated with clinical and histological observations suggest that diabetes mellitus can produce alterations of oral epithelial cells as well as in their glycogen content. PMID- 26604496 TI - Estimation of argyrophilic nucleolar organizer regions in different grades of oral submucous fibrosis. AB - CONTEXT: Assessment of potential for malignant transformation of oral submucous fibrosis (OSF) through clinical or light microscopic examination of hematoxylin and eosin stained tissue sections is not totally satisfactory. The search is for such a tissue marker that will differentiate those cases of OSF, which carry a higher risk for malignant transformation. During the past few years, numerous workers have validated the usefulness of enumerating argyrophilic nucleolar organizer regions (AgNORs) in predicting the malignant potential of lesions. The present study was carried out to validate the diagnostic potential of this marker. OBJECTIVES OF THE STUDY: Quantitative and qualitative assessment of AgNORs in different grades of OSF and to compare the count of AgNORs in different grades of OSF and normal mucosa. MATERIALS AND METHODS: AgNORs were investigated in tissue specimens from 90 patients diagnosed with different histopathological grades of OSF. AgNORs were identified in tissue specimens stained with silver nitrate, using light microscope. AgNORs were counted as small, large and total count to analyze them both quantitatively and qualitatively. STATISTICAL ANALYSIS USED: Results were subjected to statistical analysis for obtaining significance value (P value) by unpaired Student's t-test. RESULTS: The mean total count of AgNORs was 2.464 +/- 0.101, 4.358 +/- 0.108, 3.704 +/- 0.106 and 3.279 +/- 0.161 in normal mucosa, Grades I, II and III of OSF, respectively. A qualitative difference was observed in the presentation of AgNORs in different grades of OSF. Mean value of small nucleolar organizer regions (NORs) decreased while the mean of large NORs increased as the grade of OSF increased. CONCLUSIONS: The study findings suggest that AgNORs are increased in OSF and they can serve as a reliable tool adjunct to histopathological diagnosis. Their ease of demonstration and high specificity to cellular proliferation make them the best available histopathological marker in the arsenal of an oral pathologist. PMID- 26604497 TI - Grading of oral epithelial dysplasia: Points to ponder. AB - BACKGROUND: Over the years many grading systems have been put forward in an attempt to obtain objectivity in grading oral epithelial dysplasia (OED). However, despite these efforts variability remains unresolved. Our study aimed to evaluate the intra- and inter-observer variability in grading OED, using World Health Organization (WHO), Smith and Pindborg and Ljubljana grading systems and discuss the possible reasons for this variability if any. MATERIALS AND METHODS: Three oral pathologists graded 50 slides of OED independently twice at a time interval of 3 months. Variability was evaluated by multivariate kappa analysis. RESULTS: Intra-observer reproducibility ranged from moderate to good in WHO system, fair to moderate in Smith and Pindborg system and moderate to poor in Ljubljana grading system. Inter-observer agreement was found to be fair in WHO, poor in Smith and Pindborg system and poor to fair in Ljubljana grading systems. Intra-observer reproducibility of the dysplastic features in WHO system was good for all except the loss of polarity and basilar hyperplasia for first observer and enlarged nucleoli for the third observer. Inter-observer agreement was good for increased number of mitosis and nuclear hyperchromatism. Intra-observer reproducibility and inter-observer agreement were found to be best in the WHO grading system though variability within this system still existed. CONCLUSION: There is a need for an International body of pathologists to come to a consensus on a more definable grading system to resolve the issue of variability in grading dysplasia. PMID- 26604498 TI - An in vitro study of antifungal drug susceptibility of Candida species isolated from human immunodeficiency virus seropositive and human immunodeficiency virus seronegative individuals in Lucknow population Uttar Pradesh. AB - BACKGROUND: Candidiasis is the most common opportunistic infection in human immunodeficiency virus (HIV) seropositive patients, starting from asymptomatic colonization to pathogenic forms and gradual colonization of non-albicans in patients with advanced immunosuppression leads to resistance for azole group of antifungal drugs with high rate of morbidity and mortality. OBJECTIVES: To isolate the Candida species and determine of antifungal drug susceptibility against fluconazole, itraconazole, nystatin, amphotericin B, and clotrimazolein HIV seropositive and control individuals, with or without clinical oropharyngeal candidiasis (OPC). MATERIALS AND METHODS: Includes samples from faucial region of 70 subjects with and without clinical candidiasis in HIV seropositive and controls were aseptically inoculated onto Sabaraud's Dextrose Agar media and yeasts were identified for the specific species by Corn Meal Agar, sugar fermentation and heat tolerance tests. Antifungal drug susceptibility of the isolated species was done against above-mentioned drugs by E-test and disc diffusion method. RESULTS: The commonly isolated species in HIV seropositive and controls were Candida albicans, Candida glabrata and Candida tropicalis Candida guilliermondii and Candida dubliniensis isolated only in HIV seropositive patients. Susceptibility against selected antifungal drugs was observed more in HIV-negative individuals whereas susceptible dose-dependent and resistance were predominant in HIV-positive patients. CONCLUSION: Resistance is the major problem in the therapy of OPC, especially in HIV seropositive patients due to aggressive and prolonged use of antifungal agents, therefore, our study emphasizes the need for antifungal drug susceptibility testing whenever antifungal treatment is desired, especially in HIV-infected subjects. PMID- 26604501 TI - beta catenin in health: A review. AB - beta catenin belongs to the armadillo family of proteins. It plays a crucial role in developmental and homeostatic processes. Wnts are a family of 19 secreted glycoproteins that transduce multiple signaling cascades, including the canonical Wnt/beta catenin pathway, Wnt/Ca(2+) pathway and the Wnt/polarity pathway. This is a review on beta catenin, Wnt proteins and their secretion, the signaling pathway, the associated factors and the crucial role of beta catenin in odontogenesis. PMID- 26604499 TI - The wonderous chaperones: A highlight on therapeutics of cancer and potentially malignant disorders. AB - Diverse environmental and physiological factors are known to induce the transcription of a set of genes encoding special protective molecules known as "molecular chaperones" within our cells. Literature abounds in evidence regarding the varied roles; these "guides" can effectively perform in our system. Highly conserved through evolution, from the prokaryotes to the eukaryotes, these make perfect study tools for verifying their role in both the pathogenesis as well as the therapeutics of varied neurodegenerative, autoimmune and potentially malignant disorders and varied cancer states. We present a concise review of this ever dynamic molecule, highlighting the probable role in a potentially malignant disorder, oral lichen planus. PMID- 26604502 TI - Numb chin syndrome associated with metastatic invasive ductal carcinoma of breast. AB - Numb chin syndrome (NCS), also known as mental nerve neuropathy, is characterized by facial and oral numbness restricted to the distribution of the mental nerve. Although not a common neuropathy, the clinical importance of this syndrome is its frequent association with malignancies. A 56-year-old Indian female reported with a complaint of numbness on the left side of chin. She had undergone a radical mastectomy with axillary lymph node dissection for invasive ductal carcinoma of the right breast 4 years ago. Biopsy revealed tumor cells showing pleomorphic hyperchromatic nuclei arranged in cord and nests leading to a diagnosis of metastatic carcinoma of breast origin. Bone scan showed increased uptake in multiple areas in skull, left hemimandible, multiple vertebrae, multiple ribs on either sides, right clavicle both scapulae and sternum, both humeri, multiple pelvic bones and trochanteric region of left femur. The patient was referred to a tertiary cancer institute where she received palliative hormonal and chemotherapy, which helped with her pain and halted the progression of the metastatic disease for past 22 months. The present case depicts the importance of proper recognition of NCS as it may often be the only symptom of an underlying malignancy or the first evidence of dissemination from a primary site as evident in this case. PMID- 26604500 TI - Neural crest: The fourth germ layer. AB - The neural crest cells (NCCs), a transient group of cells that emerges from the dorsal aspect of the neural tube during early vertebrate development has been a fascinating group of cells because of its multipotency, long range migration through embryo and its capacity to generate a prodigious number of differentiated cell types. For these reasons, although derived from the ectoderm, the neural crest (NC) has been called the fourth germ layer. The non neural ectoderm, the neural plate and the underlying mesoderm are needed for the induction and formation of NC cells. Once formed, NC cells start migrating as a wave of cells, moving away from the neuroepithelium and quickly splitting into distinct streams. These migrating NCCs home in to different regions and give rise to plethora of tissues. Umpteen number of signaling molecules are essential for formation, epithelial mesenchymal transition, delamination, migration and localization of NCC. Authors believe that a clear understanding of steps and signals involved in NC formation, migration, etc., may help in understanding the pathogenesis behind cancer metastasis and many other diseases. Hence, we have taken this review to discuss the various aspects of the NC cells. PMID- 26604503 TI - Unusual cases of carcinoma of palatine tonsil. AB - We present two unusual cases of carcinoma of palatine tonsil in elderly patients. Both the cases were initially diagnosed as squamous cell carcinoma of the tonsil, second case, in addition, showed lung metastasis. On subsequent follow-up, the first case developed cutaneous metastasis in the right frontoparietal region while second case showed granulocytosis as paraneoplastic manifestation. The association of cutaneous metastasis and paraneoplastic granulocytosis with carcinoma of tonsil is rare. Cutaneous metastasis has been described only once in the literature while paraneoplastic granulocytosis is being reported for the first time. Both the conditions need long-term follow-up as they manifest at the extreme edges of the neoplastic process. PMID- 26604504 TI - Metastatic small cell carcinoma of the cervix to the oral cavity: A rare case report and an insight into pathogenesis of metastasis. AB - The oral cavity is an uncommon site for metastatic tumor cell colonization and is usually evidence of a widespread disease, with an incidence of about 1% of all oral cancers. The jawbones, particularly the mandible, are more frequently affected than the oral soft tissues (2:1). Small cell carcinoma (SCC) of the uterine cervix is a rare tumor characterized by a highly aggressive clinical course and poor prognosis. The purpose of this report is two-fold: To present a case of metastatic SCC of the uterine cervix to post extraction site in oral cavity, which is the first reported case in the literature, as per our knowledge and to analyze the possible mechanism of metastasis from the lower part of the abdomen to the post-extraction site and to gain additional knowledge in this phenomenon. PMID- 26604505 TI - Odontoameloblastoma: A case report. AB - Odontoameloblastoma (OA) is an extremely rare odontogenic tumor that contains an ameloblastomatous component together with odontoma-like elements. Till date, very few cases have fulfilled the criteria of the current World Health Organization classification of odontogenic tumors. It is characterized by slow, progressively growing lesion with growth pattern similar to solid multi-cystic ameloblastoma. The majority of the tumors are associated with unerupted teeth and commonly seen in males. It is usually asymptomatic and may occur in either maxilla or mandible, but shows a slight predilection for mandible. As this tumor is extremely rare, there exists controversy regarding its treatment. Here, we present a case of OA in 17-year-old female patient resembling a fibro-osseous lesion and a brief review of the related literature. PMID- 26604506 TI - Ill-fitting dentures as primary presentation of mantle cell lymphoma: A case report and literature review of the primary mantle cell lymphomas of the hard palate. AB - Mantle cell lymphoma (MCL) is a subtype of B-cell non-Hodgkin's lymphoma seen predominantly in males. Common extra-nodal sites of involvement of MCL are Waldeyer's ring, gastrointestinal tract, bone marrow and peripheral blood. The extra-nodal palatal localization of MCL is quite uncommon. MCL is seen in predominantly older patients, therefore undiagnosed MCL patients are likely to have total prosthesis. In this study, a case of MCL, initially presenting as palatal swelling was reported with relevant literature review and the possible role of dental professionals in the diagnosis of this rare entity was discussed. PMID- 26604507 TI - Hemangiopericytoma/solitaryfibrous tumor of mandible: A rare entity. PMID- 26604508 TI - Saliva in forensic odontology: A comprehensive update. AB - In recent years, saliva has attracted much interest among researchers especially in the field of forensic sciences. This complex body fluid is gaining popularity due to its ease of collection, safety in handling and its close relationship with plasma. Analysis of saliva for serological testing and cellular content has proved to be of wide use in crime detection, drug and alcohol abuse, hormone identification, cases of poisoning and animal bites. There is a need for forensic laboratories to automate the settings specific for saliva as routinely done for blood or urine in order to consider saliva as the primary investigating tool in the absence of other body fluids. This update is aimed at highlighting the many uses of saliva in the practice of forensic odontology. PMID- 26604509 TI - Oro-facial-digital syndrome type II with otolaryngological manifestations. AB - We present a case of oro-facial-digital syndrome type II (Mohr's syndrome) which is characterized by malformations of the oral cavity, face and digits. The facial and oral features include tongue nodules, cleft or high-arched palate, missing teeth, broad nose; cleft lip. The digital features include clinodactyly, polydactyly, syndactyly, brachydactyly and duplication of the hallux. PMID- 26604510 TI - Histopathological spectrum of polymorphous low-grade adenocarcinoma. AB - Polymorphous low-grade adenocarcinomas (PLGA) are distinctive salivary gland neoplasms, with an almost exclusive propensity to arise from the minor salivary glands. PLGA frequently manifests as an asymptomatic, slow-growing mass within the oral cavity, which must be separated from adenoid cystic carcinoma and benign mixed tumor for therapeutic and prognostic considerations. We report a case of a 67-year-old male, who presented with a long-standing mass in the palate. This lesion was diagnosed as PLGA based on histopathological findings, which was further confirmed by the immunohistochemical marker. PMID- 26604513 TI - Single rooted primary first molar with nonsyndromic hypodontia: A rare case report. AB - Dental anomalies of number, shape and size are the most common to dental literature, the most common being the agenesis and morphologic dental anomalies. However, very few cases have been reported regarding the presence of single root in primary molars. The purpose of this article was to present a rare case of single root in primary mandibular first molar associated with nonsyndromic hypodontia. PMID- 26604512 TI - Squamous cell carcinoma of the gingiva: A diagnostic enigma. AB - Oral squamous cell carcinoma (OSCC) is the most common epithelial malignant neoplasm affecting the oral cavity; early detection is an important criterion for achieving high cure rate. Occasionally, it may be misdiagnosed because of its variable and innocuous clinical appearance. Carcinomas of the gingiva are a unique subset of OSCC, constituting approximately 10% of OSCCs and can mimic a multitude of oral lesions especially those of inflammatory origin with benign features, often leading to delay in the diagnosis and hence delayed treatment. This article reports a rare case of gingival OSCC in a 62-year-old female patient mimicking an inflammatory gingival mass. PMID- 26604511 TI - Gorlin-Goltz Syndrome: Case report and literature review. AB - Gorlin-Goltz syndrome (GGS) is an infrequent multisystemic disease with an autosomal dominant trait, with complete penetrance and variable expressivity, though sporadic cases have been described. This article includes a case report and an extensive review of the GGS with regard to its history, incidence, etiology, features, investigations, diagnostic criteria, keratocystic odontogenic tumor and treatment modalities. PMID- 26604514 TI - A rare case of hybrid odontogenic tumor: Calcifying epithelial odontogenic tumor combined with ameloblastoma. AB - A hybrid odontogenic tumor comprising two distinct lesions is extremely rare. Nevertheless, such tumors have been reported in the literature for academic and research interest. However, it is still obscure whether they behave as a new entity or they solely present separate histopathologic patterns. Here, we present a true hybrid neoplasm of combined ameloblastoma and calcifying epithelial odontogenic tumor showing intermixed histopathologic patterns of both the tumors. PMID- 26604515 TI - Intraosseous calcifying epithelial odontogenic (Pindborg) tumor: A rare entity. AB - Calcifying epithelial odontogenic tumor (CEOT) is a locally aggressive, rare benign odontogenic neoplasm that accounts for <1% of all odontogenic tumors. It was first described by a Dutch pathologist Jens Jorgen Pindborg in 1955. It is most often located in the posterior mandible. The tumor usually appears between the second and sixth decade of life and has no gender predilection. It is slow growing neoplasm with a recurrence rate of 10-15% and with rare malignant transformation. Early diagnosis is essential to avoid oro-maxillofacial deformation and destruction. CEOT is rarely reported in India. We, herewith present a rare case of CEOT with unusual features associated with an impacted right third molar in the posterior mandible of 35 years male, with an emphasis on clinical, radiographic, histopathology and immunohistochemical features. PMID- 26604516 TI - Vascular changes in hard palate sialolipoma: Sialoangiolipoma or vascular malformation? AB - Palate sialolipomas are rare. Less than 10 cases located in the hard palate are reported to our knowledge. We report a case of hard palate sialolipoma, peculiar by the intratumor vascular patterns. A 67-year-old man presented with a 1.5 cm lesion of the oral hard palate. The lesion was surgically resected. On microscopy, the lesion, partly encapsulated, consisted of a proliferation of mature adipocytes containing normal minor salivary gland tissue and branching intratumoral vessels of varied size with irregularly thickened wall and papillary projections or tufts. The microscopic features of the tumor we report suggest that vascular malformation-like patterns may occur in sialolipomas of the hard palate. This morphological vascular peculiarity should be acknowledged since it may represent source of hemorrhage. PMID- 26604517 TI - Desmoplastic Fibroma-A Rare Case Report. AB - Desmoplastic fibroma (DF) is a benign intra-osseous neoplasm, that is, recognized as the intra-osseous counterpart of soft tissue fibromatosis in both gnathic and extra-gnathic sites. It has a propensity for locally aggressive behavior and local recurrence. An occurrence of intra-osseous lesion other than that of odontogenic origin is rare in the jaws. In this case report, we define the clinico-pathological and radiographic features of DF of the mandible in a 35-year old female, who presented to the Outpatient Department with a 3-year history of a slowly expanding painless mass in the left mandibular posterior region. Thus, we present a classic case of DF exhibiting characteristic features along with a review of the literature. PMID- 26604518 TI - Diffuse large B-cell lymphoma (extranodal) of maxillary buccal vestibule. AB - Lymphomas are the group of neoplasms originating from lymphoreticular system mainly from lymph nodes, among them up to 40% of non-Hodgkin's lymphomas present extra nodally. In oral cavity, lymphomas are least common and account for 3-5% of all malignancies, presenting mainly in older age groups with male predominance. According to Revised European-American Lymphoma classification, among B-cell and T-cell subtypes of non-Hodgkin's lymphomas, diffuse large B-cell lymphoma (DLBCL) is the most common, characterized by diffuse proliferation of large neoplastic B lymphoid cells. Here we present a case report of DLBCL affecting oral cavity involving left buccal vestibule and extending onto the palate, along with its clinical, histopathologic and immunohistochemical features. PMID- 26604519 TI - Infantile fibrosarcoma of ethmoid sinus, misdiagnosed as an adenoid in a 5-year old child. AB - Infantile fibrosarcoma of head and neck is rare and the presence of this tumor in ethmoid sinus is even more uncommon. To the best of our knowledge, <5 cases have been reported in the last 20 years in the English literature, so far, only one of which has been infantile type in a 15 months old girl. In this case report, we will explain our experience with a rare case of infantile fibrosarcoma originating from ethmoid sinus in a 5-year-old boy who presented with dyspnea and epistaxis. After biopsy, it was diagnosed as fibrosarcoma of sinus origin. PMID- 26604520 TI - Premature loss of primary teeth with gingival erythema: An alert to dentist. AB - Premature exfoliation of primary teeth is an important diagnostic event warranting urgent investigation. The majority of conditions presenting with early loss of teeth are serious and in some cases could be fatal. The most common causes of premature tooth loss are Papillion-Lefevre syndrome, Chediak-Higashi syndrome, hypophosphatasia, neutropenia, leukemia and in some cases Langerhans cell histiocytosis (LCH). LCH is a disorder of unknown cause, characterized by abnormal proliferation of histiocytes. The disease has a predilection for children, although LCH may occur in adults. Owing to the relative rarity of the condition, it remains a disease in which the diagnosis is often delayed or missed and in which many questions remain unanswered, ranging from etiology and pathogenesis to therapy. The purpose of the review is, therefore, to raise awareness of the disease and to highlight the clinical findings that should make the odontologist or primary caregiver suspect the diagnosis. PMID- 26604521 TI - What's new in emergencies, trauma and shock? Extraperitoneal pelvic pressure packing: Placing this procedure in context. PMID- 26604522 TI - Extra-peritoneal pressure packing without external pelvic fixation: A life-saving stand-alone surgical treatment. AB - PURPOSE: Traditional maneuvers aim to decrease retroperitoneal bleeding in hemodynamically unstable multi-trauma patients with unstable pelvic fractures, are reportedly successful in approximately only 50%. The life-saving effect of extra-peritoneal pressure packing (EPPP) is based on direct compression and control of both venous and arterial retroperitoneal bleeders. This study describes the safety and efficacy of emergent EPPP employment, as a stand-alone surgical treatment, that is, carried out without external pelvic fixation or emergent angiography. MATERIALS AND METHODS: A retrospective chart review of all hemodynamic unstable, multi-trauma patients with mechanically unstable pelvic fractures treated by the EPPP technique at our medical center between the years 2005 and 2011. Survival rates, clinical, and physiological outcomes were followed prospectively. RESULTS: Twenty-five of the 181 pelvic fracture patients had biomechanically unstable fractures that required surgical fixation. Fourteen of those 25 patients had deteriorating hemodynamic instability from massive pelvic bleeding which was resistant to resuscitation, and they underwent EPPP, as a stand-alone treatment. The procedure successfully achieved hemodynamic stability in all 14 patients and obviated the early mortality associated with massive pelvic bleeding. Three of these patients eventually succumbed to their multiple injuries. CONCLUSION: Implementation of EPPP improved all measured physiological outcome parameters and survival rates of hemodynamically unstable multi-trauma patients with unstable pelvic fractures in our trauma center. It provided the unique advantage of directly compressing the life-threatening retroperitoneal bleeders by applying direct pressure and causing a tamponade effect to stanch venous and arterial pelvic blood flow and obviate the early mortality associated with massive pelvic bleeding. PMID- 26604523 TI - Comparison of three supraglottic airway devices for airway rescue in the prone position: A manikin-based study. AB - BACKGROUND: Accidental extubation during surgery in prone position can be life threatening. Supraglottic airway devices (SAD) have been used successfully in such situations to rescue the airway. However, which SAD would be most appropriate in this setting has not been described in the literature. AIMS: The aim of our study was to determine the most appropriate SAD for securing airway in a prone position during accidental extubation. MATERIALS AND METHODS: In the study, Airway Trainer (Laerdal) manikin was used for studying insertion of three SADs; I-gel, Laryngeal Mask Airway ProSealTM (PLMA) and LMA ClassicTM (CLMA) in the prone position. Forty anesthesia resident doctors participated in this study. The time taken for insertion; ease of insertion and ventilation; bronchoscopic view; and insertion score were compared among the three groups. RESULTS: The time taken for I-gel insertion was significantly lesser (12.89 +/- 3.94 seconds) as compared to CLMA (17.07 +/- 3.5 seconds) and PLMA (25 + 4.78 seconds). Least resistance was encountered in the insertion of I-gel, while maximum resistance was experienced in PLMA group (22.5% vs. 90%). The maneuver required for optimal positioning was observed in 27.5% of PLMA insertion, 2.5% in CLMA while no maneuver was required in any of the I-gel insertion. Ease of ventilation was comparable in all three SADs. The bronchoscopic view and insertion score were significantly higher with I-gel as compared to CLMA and PLMA. CONCLUSION: All three SADs were successful as rescue devices during accidental extubation in the prone position. However, the ease of insertion was maximum with I-gel, followed by CLMA and PLMA. PMID- 26604524 TI - Frequency, causes and pattern of abdominal trauma: A 4-year descriptive analysis. AB - BACKGROUND: The incidence of abdominal trauma is still underreported from the Arab Middle-East. We aimed to evaluate the incidence, causes, clinical presentation, and outcome of the abdominal trauma patients in a newly established trauma center. MATERIALS AND METHODS: A retrospective analysis was conducted at the only level I trauma center in Qatar for the patients admitted with abdominal trauma (2008-2011). Patients demographics, mechanism of injury, pattern of organ injuries, associated extra-abdominal injuries, Injury Severity Score (ISS), Abbreviated Injury Scale, complications, length of Intensive Care Unit, and hospital stay, and mortality were reviewed. RESULTS: A total of 6888 trauma patients were admitted to the hospital, of which 1036 (15%) had abdominal trauma. The mean age was 30.6 +/- 13 years and the majority was males (93%). Road traffic accidents (61%) were the most frequent mechanism of injury followed by fall from height (25%) and fall of heavy object (7%). The mean ISS was 17.9 +/- 10. Liver (36%), spleen (32%) and kidney (18%) were most common injured organs. The common associated extra-abdominal injuries included chest (35%), musculoskeletal (32%), and head injury (24%). Wound infection (3.8%), pneumonia (3%), and urinary tract infection (1.4%) were the frequently observed complications. The overall mortality was 8.3% and late mortality was observed in 2.3% cases mainly due to severe head injury and sepsis. The predictors of mortality were head injury, ISS, need for blood transfusion, and serum lactate. CONCLUSION: Abdominal trauma is a frequent diagnosis in multiple trauma and the presence of extra-abdominal injuries and sepsis has a significant impact on the outcome. PMID- 26604525 TI - Effects of a hospital-wide introduction of a massive transfusion protocol on blood product ratio and blood product waste. AB - BACKGROUND: Massive transfusion protocols (MTPs) are increasingly used in the transfusion practice and are developed to provide the standardized and early delivery of blood products and procoagulant agents and to supply the transfusion of blood products in a well-balanced ratio. AIM: The aim of this study was to investigate the effect of a hospital-wide introduction of an MTP on blood product ratio and a waste of blood products. MATERIALS AND METHODS: Retrospective analysis was performed to compare the transfusion practice in massive bleeding patients before and after the introduction of an MTP and between the use of an MTP and transfusion off-protocol. Massive bleeding was defined as an administration of >=5 units of red blood cells (RBCs) within 12 h. RESULTS: Of 547 massively transfused patients, 192 patients were included in the pre-MTP period and 355 patients in the MTP period. The ratio of RBC to fresh frozen plasma (FFP) and the platelets transfused shifted significantly toward 1:1:1 in the MTP period (P = 0.012). This was mainly caused by a shift in RBC: FFP ratio (P = 0.014). An increase in the waste of blood products was observed, most notably FFPs (P = 0.026). Extending the storage time after thawing reduced the waste of FFPs from 11% to 4%. CONCLUSION: Hospital-wide introduction of an MTP is an adequate way to achieve a well-balanced transfusion ratio of 1:1:1. This comes at the cost of an increase in the waste of FFPs, which is lowered after extending the duration of storage time after thawing. PMID- 26604526 TI - The usefulness of brain natriuretic peptide level in diagnosis and prognosis of patients admitted to critical care unit with shortness of breath. AB - BACKGROUND: Brain Natriuretic Peptide (BNP) is a polypeptide secreted by the ventricles as a response to cardio-myocyte stretching. Due to its cardiac origin and correlation with volume overload it has been successfully used for a long time in diagnosing and prognosticating Cardiogenic Pulmonary Edema. MATERIALS AND METHODS: In this retrospective cohort study, an attempt was made to observe any correlation between admission BNP levels with APACHE II scores and length of ICU stay, in patients admitted with dyspnea to the ICU of a community based hospital. RESULTS/CONCLUSION: This study showed no significant correlation between length of stay in an ICU and admission BNP levels in dyspneic patients. Independent variables such as age and gender failed to show any coorelation either. PMID- 26604527 TI - Adverse events and outcomes of procedural sedation and analgesia in major trauma patients. AB - CONTEXT: Trauma patients requiring procedural sedation and analgesia (PSA) may have increased risk of adverse events (AEs) and poor outcomes. AIMS: To determine the incidence of AEs in adult major trauma patients who received PSA and to evaluate their postprocedural outcomes. SETTINGS AND DESIGN: Retrospective analysis of adult patients (age >16) who received PSA between 2006 and 2014 at a Canadian academic tertiary care center. MATERIALS AND METHODS: We compared the incidence of PSA-related AEs in trauma patients with nontrauma patients. Postprocedural outcomes including Intensive Care Unit admission, length of hospital stay, and mortality were compared between trauma patients who did or did not receive PSA. STATISTICAL ANALYSIS USED: Descriptive statistics and multivariable logistic regression. RESULTS: Overall, 4324 patients received PSA during their procedure, of which 101 were trauma patients (107 procedures). The majority (77%) of these 101 trauma patients were male, relatively healthy (78% with American Society of Anesthesiologists Physical Status [ASA-PS] 1), and most (85%) of the 107 procedures were orthopedic manipulations. PSA-related AEs were experienced by 45.5% of the trauma group and 45.9% of the nontrauma group. In the trauma group, the most common AEs were tachypnea (23%) and hypotension (20%). After controlling for age, gender, and ASA-PS, trauma patients were more likely than nontrauma patients to develop hypotension (odds ratio 1.79; 95% confidence interval 1.11-2.89). CONCLUSION: Although trauma patients were more likely than nontrauma patients to develop hypotension during PSA, their outcomes were not worse compared to trauma patients who did not have PSA. PMID- 26604530 TI - Trauma triggering thyrotoxic crisis with lactic acidosis. AB - Thyrotoxic crisis (TC) is defined as a life-threatening exacerbation of the hyperthyroid state that causes multiple autonomic and metabolic disturbances. It is considered to be an endocrine emergency that must be urgently diagnosed and treated. We describe a case of TC precipitated by trauma with a resultant lactic acidosis. The patient is a 24-year-old male with a history of hyperthyroidism who presented to the emergency department following a motor vehicle accident. The patient was initially tachycardic and hypertensive, however, was afebrile. Initial laboratory analysis showed an anion gap of 26, lactic acid 7.6, free T4 5.61 and thyroid stimulating hormone < 0.015. A diagnosis of TC was made, and he was treated with intravenous fluids, propranolol, and methimazole with improvement of tachycardia and lactic acidosis. We discuss the features of this case, which reviews the presentations of TC as well as its metabolic sequelae. PMID- 26604528 TI - Pediatric open globe injury: A review of the literature. AB - Open globe injury (OGI) is a severe form of eye trauma estimated at 2-3.8/100,000 in the United States. Most pediatric cases occur at home and are the result of sharp object penetration. The aim of this article is to review the epidemiology, diagnosis, management, and prognosis of this condition by conducting a systematic literature search with inclusion of all case series on pediatric OGI published between 1996 and 2015. Diagnosis of OGI is based on patient history and clinical examination supplemented with imaging, especially computed tomography when indicated. Few prospective studies exist for the management of OGI in pediatric patients, but adult recommendations are often followed with success. The main goals of surgical management are to repair the open globe and remove intraocular foreign bodies. Systemic antibiotics are recommended as medical prophylaxis against globe infection, or endophthalmitis. Other complications are similar to those seen in adults, with the added focus of amblyopia therapy in children. Severe vision decline is most likely due to traumatic cataracts. The ocular trauma score, a system devised to predict final visual acuity (VA) in adults, has proven to be of prognostic value in pediatric OGI as well. Factors indicating poor visual prognosis are young age, poor initial VA, posterior eye involvement, long wound length, globe rupture, lens involvement, vitreous hemorrhage, retinal detachment, and endophthalmitis. A thorough understanding of OGI and the key differences in epidemiology, diagnosis, management, and prognosis between adults and children is critical to timely prevention of posttraumatic vision loss early in life. PMID- 26604531 TI - A case of luftsichel sign for left upper lobe collapse. AB - The differential diagnosis of dyspnea in Emergency Department (ED) patients is broad and atelectasis is one of the differentials among these. We present a 29 year-old women presented to our ED for evaluation of shortness of breath. On her chest examination, air entry and breath sounds were diminished on the left side but normal on the right. A posteroanterior chest radiograph showed radioluscent area in the upper zone of the left lung, around the aortic arch and also hyperdens area neighbouring this, like covered by a veil. Luftsichel sign together with this hiperdensity were consistent with the diagnose of left lung upper lobe collapse. The Luftsichel sign represents the hyperexpanded superior segment of the left lower lobe interposed between the atelectatic left upper lobe and aortic arch. Patient was discharged to home with chest physiotherapy and breathing exercises together with analgesic prescreption. PMID- 26604529 TI - Comorbidity polypharmacy score and its clinical utility: A pragmatic practitioner's perspective. AB - Modern medical management of comorbid conditions has resulted in escalating use of multiple medications and the emergence of the twin phenomena of multimorbidity and polypharmacy. Current understanding of how the polypharmacy in conjunction with multimorbidity influences trauma outcomes is limited, although it is known that trauma patients are at increased risk for medication-related adverse events. The comorbidity-polypharmacy score (CPS) is a simple clinical tool that quantifies the overall severity of comorbidities using the polypharmacy as a surrogate for the "intensity" of treatment necessary to adequately control chronic medical conditions. Easy to calculate, CPS is derived by counting all known pre-injury comorbid conditions and medications. CPS has been independently associated with mortality, increased risk for complications, lower functional outcomes, readmissions, and longer hospital stays. In addition, CPS may help identify older trauma patients at risk of post-emergency department undertriage. The goal of this article was to review and refine the rationale for CPS and to provide an evidence-based outline of its potential clinical applications. PMID- 26604532 TI - Rudimentary horn pregnancy mimicking an acute abdomen in the emergency department. PMID- 26604533 TI - Transient paraplegia in an elderly due to lightning injury: An unusual cause. PMID- 26604534 TI - "The best is nothing": Non-operative management of hemodynamically stable grade V liver trauma. PMID- 26604535 TI - Physical trauma in epilepsy: Characteristics and implications in a Nigerian adolescent with severe generalized epilepsy. PMID- 26604536 TI - Successful use of high-dose insulin therapy in atenolol overdose refractory to conventional management. PMID- 26604537 TI - A case of tension pyothorax with septic shock. PMID- 26604538 TI - The outstanding diagnosis. PMID- 26604539 TI - Prevalence of Oral Habits among Eleven to Thirteen Years Old Children in Jaipur. AB - AIM: Oral habits that are prevalent well beyond the normal age frequently result in facial deformity and malocclusions. The aim of the present study was to know the prevalence of oral habits in 11 to 13 years old children of Jaipur city. METHODOLOGY: The study included 1,000 children of age 11 to 13 years, belonging to different government and private schools of Jaipur city who were screened for any deleterious habits at their school site. The statistical analysis was done using Chi-square test. RESULTS: The result showed that 18% children had a habit of tongue thrusting, 17% mouth breathing and 3% nail biting. Sex-wise prevalence showed 18% females had oral habits and 20% of male had oral habit. CONCLUSION: The distribution of children aged 11 to 13 years having oral habits was evaluated with tongue thrusting being most prevalent and exhibiting minimal sexual predilection. How to cite this article: Sharma S, Bansal A, Asopa K. Prevalence of Oral Habits among Eleven to Thirteen Years Old Children in Jaipur. Int J Clin Pediatr Dent 2015;8(3):208-210. PMID- 26604540 TI - Knowledge, Attitude and Practice toward Infant Oral Healthcare among the Pediatricians of Mysore: A Questionnaire Survey. AB - BACKGROUND: The aim of this study was to study the knowledge, attitude and practice of the pediatricians toward infant oral healthcare and the objective was to determine what can improve the knowledge, attitude and practice toward infant oral healthcare. MATERIALS AND METHODS: A systematic random survey of pediatricians in Mysore received a questionnaire pertaining to individual details, knowledge level and approach toward infant oral healthcare. RESULTS: Most of pediatricians acknowledged the importance of pediatric dentistry. Pediatricians agree that it is important to do dental examination before 1 year. The importance of initiating oral hygiene practice before the eruption of first tooth was not seen to be prevalent among the pediatricians. Most of them were less aware of the first dental visit including early childhood caries (ECC). All pediatricians agree that both medical and dental professionals together are responsible for infant oral healthcare. They should work together to appropriately educate and train themselves to be able to provide risk assessment and to provide preventive oral health services. How to cite this article: Indira MD, Dhull KS, Nandlal B. Knowledge, Attitude and Practice toward Infant Oral Healthcare among the Pediatricians of Mysore: A Questionnaire Survey. Int J Clin Pediatr Dent 2015;8(3):211-214. PMID- 26604541 TI - Surgical Derotation Technique: A Novel Approach in the Management of Rotated Immature Permanent Incisor. AB - Surgical derotation is a method of placing a rotated tooth in normal alignment in a dental arch; surgically, immediately and permanently. It is a potentially convenient and cost-effective treatment modality as compared to conventional orthodontic procedure for rotated maxillary incisor with open apex. Here is a presentation of a severely rotated maxillary left permanent central incisor in a nine and half years old girl, with a radiographic evidence of immature root apex which was surgically derotated, orthodontically retroclined and intruded to its normal position. Postsurgical clinical and radiographic evaluation was done for a period of one and half years to confirm the vitality and continued physiological root formation of the affected tooth. How to cite this article: Dutta B, Krishnapriya V, Sriram CH, Reddy MKR. Surgical Derotation Technique: A Novel Approach in the Management of Rotated Immature Permanent Incisor. Int J Clin Pediatr Dent 2015;8(3):220-223. PMID- 26604542 TI - Vestibular Extension along with Frenectomy in Management of Localized Gingival Recession in Pediatric Patient: A New Innovative Surgical Approach. AB - This paper reports case of pediatric localized gingival recession (LGR) in mandibular anterior region which was treated by using new innovative surgical approach, i.e. combination of frenectomy and vestibular extension. These interceptive surgeries not only gained sufficient width of attached gingival but also lower the attachment of labial frenum. How to cite this article: Jingarwar M, Pathak A, Bajwa NK, Kalaskar R. Vestibular Extension along with Frenectomy in Management of Localized Gingival Recession in Pediatric Patient: A New Innovative Surgical Approach. Int J Clin Pediatr Dent 2015;8(3):224-226. PMID- 26604543 TI - Management of Ectopically Erupting Maxillary Incisors: A Case Series. AB - Eruption disturbances related to the position include ectopic eruption and transpositions. The occurrence of ectopic eruption is most commonly associated with maxillary incisors. The normal eruption, position and morphology of these teeth are crucial to craniofacial development, facial esthetics as well as phonetics. It is essential that the clinicians have thorough knowledge of the eruption disturbances in order to make an appropriate, as well as timely intervention, as dictated by the complexity of the problem. How to cite this article: Suresh KS, Uma HL, Nagarathna J, Kumar P. Management of Ectopically Erupting Maxillary Incisors: A Case Series. Int J Clin Pediatr Dent 2015;8(3):227 233. PMID- 26604544 TI - Correction of a Severely Rotated Maxillary Incisor by Elastics in Mixed Dentition Complicated by a Mesiodens. AB - The aim of this case study was to report a potentially convenient approach instead of a conventional orthodontic procedure for correcting severe rotation of anterior tooth of an 11-year-old Indian boy, with a mixed dentition class I malocclusion. The child reported seeking treatment for severely rotated upper right central incisor with mesiodens and a single tooth crossbite. The supernumerary tooth was first extracted and bondable buttons were placed on the rotated tooth, an appliance composed of a removable plate with Adam's clasp with distal extension and a loop for engagement of elastics was delivered. Circumferential supracrestal fibrotomy was performed on the corrected derotated tooth. Then, Hawley's appliance with a z-spring and posterior bite plane was fabricated and placed for correction of crossbite. Thus, this removable appliance can be a simplified and a cost-effective treatment alternative for derotation of anterior tooth, especially during the mixed dentition period. How to cite this article: Sidiq M, Yousuf A, Bhat M, Sharma R, Bhargava N, Ganta S. Correction of a Severely Rotated Maxillary Incisor by Elastics in Mixed Dentition Complicated by a Mesiodens. Int J Clin Pediatr Dent 2015;8(3):234-238. PMID- 26604545 TI - Oral Manifestations and Dental Management of Epidermolysis Bullosa Simplex. AB - Epidermolysis bullosa (EB) is a group of hereditary chronic disorders, characterized by fragility of the skin and mucous membranes in response to minor mechanical trauma. The objective of this study was to report the case of a young girl diagnosed with epidermolysis bullosa simplex (EBS), transmitted by an autosomal dominant gene. Cutaneous findings included blisters and dystrophy following minimal friction. Recurrent blisters and vesicle formation on the hard palate were the main oral findings. In conclusion, publications concerning the oral and clinical manifestations of EBS are important for providing knowledge and an early multidisciplinary approach that prevents blister formation and improves these patients' quality of life, with the dentist playing an important role in oral health management. How to cite this article: Scheidt L, Sanabe ME, Diniz MB. Oral Manifestations and Dental Management of Epidermolysis Bullosa Simplex. Int J Clin Pediatr Dent 2015;8(3):239-241. PMID- 26604547 TI - Editorial. PMID- 26604546 TI - Permanent Maxillary Canine Agenesis: A Rare Case Report. AB - Congenitally missing teeth (CMT) are among one of the commonly known dental anomalies. The most frequently missing teeth in the permanent dentition, excluding the third molars, are mandibular second premolars and maxillary lateral incisors. Exclusive agenesis of both maxillary canines is an extremely rare occurrence and only a few cases have been reported. Previous studies showed that the prevalence of maxillary canine agenesis varies between 0.07 and 0.13%. In recent studies on Indian population, no cases of maxillary canine agenesis have been documented. This paper reports a case of non-syndromic bilateral agenesis of permanent maxillary canines, along with agenesis of both mandibular central incisors in a healthy 13-year-old Indian female patient; and a brief literature review on prevalence, etiology and treatment modalities of the condition. How to cite this article: Kambalimath HV, Jain S, Patil RU, Asokan A, Kambalimath D. Permanent Maxillary Canine Agenesis: A Rare Case Report. Int J Clin Pediatr Dent 2015; 8(3):242-246. PMID- 26604548 TI - Public perception of AYUSH. PMID- 26604549 TI - Comparative clinical evaluation of Boerhavia diffusa root extract with standard Enalapril treatment in Canine chronic renal failure. AB - BACKGROUND: Complementing herbal drugs with conservative modern treatment could improve renal condition in canine chronic renal failure (CRF). OBJECTIVE: In this study, clinical evaluation of Boerhavia diffusa root extract was carried out in CRF in dogs in comparison with standard enalapril. MATERIALS AND METHODS: A total of 20 dogs of mixed breeds suffering from CRF from 1 to 2 months were divided into two groups (n = 10) and treated as follows: Group I - Enalapril at 0.5 mg/kg p.o. once daily for 90 days + amoxicillin and cloxacillin at 25 mg/kg i.m. once daily for 1-week; Group II - B. diffusa root extract at 500 mg p.o per dog daily for 90 days. Both groups were maintained on a supportive fluid therapy. The data were analyzed using paired t-test and one-way ANOVA followed by Dunnett's post hoc test. RESULTS: CRF caused a significant (P < 0.05) increase in systolic and diastolic blood pressure, serum creatinine, urea nitrogen, sodium, potassium, phosphorus, urinary protein, alkaline phosphatase (ALP), and glutamyl transferase (GGT). A significant (P < 0.05) decrease in hemoglobin and total erythrocyte count (TEC) was also observed. Nephrosonography revealed indistinct corticomedullary junction, altered renal architecture, hyper-echoic cortex, medulla, and sunken kidneys. Both the treatments significantly (P < 0.05) reduced systolic and diastolic blood pressure by day 30. Serum Creatinine, urea nitrogen, phosphorus, urinary protein, ALP, and GGT showed significant (P < 0.05) reduction by day 60 in both the treatments. However, potassium levels were normalized only by B. diffusa root extract treatment by day 30. Both the treatments failed to show a significant improvement in nephrosonographic picture even after 90 days posttreatment. CONCLUSION: In conclusion, the efficacy of B. diffusa root extract was comparable to standard enalapril treatment of CRF in dogs. PMID- 26604550 TI - Anxiolytic and nootropic activity of Vetiveria zizanioides roots in mice. AB - BACKGROUND: Vetiveria zizanioides (VZ) (family: Poaceae), an aromatic plant commonly known as "Vetiver" has been used for various ailments. Concerning the various ailments being listed as the traditional uses of VZ, no mention about anxiety and memory was found. OBJECTIVE: The present study examined the anxiolytic and memory enhancing activity of ethanolic extract of V. zizanioides (EEVZ) dried roots in mice. MATERIALS AND METHODS: Activity of EEVZ was assessed using models of anxiety (elevated plus-maze [EPM], light/dark test, hole board test, marble-burying test) and learning and memory (EPM, passive shock avoidance paradigm). RESULTS: EEVZ at doses of 100, 200, and 300 mg/kg b.w. illustrated significant anxiolytic activity indicated by increase in time spent and number of entries in open arm, time spent in lightened area, number of head poking and number marble buried when compared to that of diazepam (1 mg/kg b.w.), a reference standard. The same treatment showed a significant decrease in transfer latency to reach open arm, shock-free zone, and number of mistakes when compared to that of scopolamine (0.3 mg/kg b.w.). EEVZ in all the doses (100, 200, and 300 mg/kg b.w.) significantly decreased mortality in sodium nitrite (250 mg/kg b.w.) induced hypoxia and also significantly increases contraction induced by acetylcholine on rat ileum preparation. CONCLUSION: The result emanated in the present investigation revealed EEVZ possesses significant anxiolytic and nootropic activity by possibly interplaying with neurotransmitters implicated in anxiety and learning and memory. PMID- 26604551 TI - Molecular approach to identify antidiabetic potential of Azadirachta indica. AB - BACKGROUND: Azadirachta indica (Neem) is a medicinal plant, used in Ayurveda for treating various diseases, one of which is diabetes mellitus. It is known to possess antiinflammatory, antipyretic, antimicrobial, antidiabetic and diverse pharmacological properties. However, the molecular mechanism underlying the effect of A. indica on insulin signal transduction and glucose homeostasis is obscure. OBJECTIVE: The aim was to study the effects of A. indica aqueous leaf extract on the expression of insulin signaling molecules and glucose oxidation in target tissue of high-fat and fructose-induced type-2 diabetic male rat. MATERIALS AND METHODS: The oral effective dose of A. indica leaf extract (400 mg/kg body weight [b.wt]) was given once daily for 30 days to high-fat diet induced diabetic rats. At the end of the experimental period, fasting blood glucose, oral glucose tolerance, serum lipid profile, and the levels of insulin signaling molecules, glycogen, glucose oxidation in gastrocnemius muscle were assessed. RESULTS: Diabetic rats showed impaired glucose tolerance and impairment in insulin signaling molecules (insulin receptor, insulin receptor substrate-1, phospho-IRS-1(Tyr632), phospho-IRS-1(Ser636), phospho-Akt(Ser473), and glucose transporter 4 [GLUT4] proteins), glycogen concentration and glucose oxidation. The treatment with A. indica leaf extract normalized the altered levels of blood glucose, serum insulin, lipid profile and insulin signaling molecules as well as GLUT4 proteins at 400 mg/kg b.wt dose. CONCLUSION: It is concluded from the present study that A. indica may play a significant role in the management of type-2 diabetes mellitus, by improving the insulin signaling molecules and glucose utilization in the skeletal muscle. PMID- 26604552 TI - Effect of Ferula assa-foetida oleo gum resin on spermatic parameters and testicular histopathology in male wistar rats. AB - BACKGROUND: In Ayurveda and traditional medicines of different countries such as Iran, America and Brazil, asafoetida has been used as an aphrodisiac agent. OBJECTIVE: The present study was aimed to evaluate the effectiveness of asafoetida on spermatic and testicular parameters in treated rats. MATERIALS AND METHODS: A total of 30 male Wistar rats divided equally to five groups (one control and four test groups receiving 25, 50,100 and 200 mg/kg asafoetida respectively). After 6 weeks, a small part of the cauda epididymis of each rat was dissected, and the spermatic parameters were evaluated for at least 200 spermatozoa of each animal. Testis of all rats was harvested for pathologic examination. The testosterone concentration of serum was also determined. Data were statistically assessed by one-way ANOVA and value of P < 0.05 was considered as the level of significance. RESULTS: This study indicated that the asafoetida significantly increased the number and viability of sperms (P < 0.05). Histological study showed that spermatogenesis process and numbers of Leydig cells were increased with increasing the dose, but the Leydig cells become vacuolated. Johnsen score in experimental groups was increased compared to control although this difference was not significant (P > 0.05). CONCLUSION: Asafoetida showed a positive effect on spermatic parameters although the histopathological effects on the testis were observed, particularly at high doses. PMID- 26604553 TI - Protective effect of Triphala Rasayana against paracetamol-induced hepato-renal toxicity in mice. AB - BACKGROUND: Paracetamol, a widely used analgesic and antipyretic, is known to cause liver and renal injury in humans when administered in higher and repeated doses that cause acute liver injury. Triphala is a well-known Ayurvedic Rasayana formulation that is prescribed for balancing of Vata, Pitta and Kapha. Traditionally, it is used for the treatment of liver and kidney diseases. OBJECTIVE: The present study was undertaken to examine the protective effect of Triphala extract against paracetamol-induced hepato-renal injury in Swiss albino mice. MATERIALS AND METHODS: Swiss albino mice (weight 20-25 g) were used in this study. The mice were divided into five groups of six animals each. The aqueous extract of Triphala was given orally at two different doses (100 and 300 mg/kg body weight) for seven consecutive days, followed by a single intraperitoneal injection of paracetamol (500 mg/kg body weight) to induce hepato-renal toxicity. Serum levels of liver enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, creatinine, urea and uric acid were measured as indices of liver and renal injury. All the statistical analyses were performed with the help of one-way analysis of variance (ANOVA) followed by Student-Newman-Keuls test as post hoc test. Results were considered statistically significant when P < 0.05. RESULTS: Pre-treatment with Triphala extract at 100 mg/kg and 300 mg/kg body weight exhibited a significant (P < 0.01) hepatoprotective activity. The protective effect of Triphala extract at 300 mg/kg body weight appears more effective than 100 mg/kg body weight. CONCLUSION: The present study gives an evidence of the protective role of Triphala extract against paracetamol-induced hepato-renal toxicity and validates its traditional claim in the Ayurveda system. PMID- 26604554 TI - Potential interaction of green tea extract with hydrochlorothiazide against doxorubicin-induced myocardial damage. AB - BACKGROUND: Treatment of ischemic hypertensive patients with hydrochlorothiazide can precipitate cardiac arrhythmias. Green tea, by virtue of its antioxidant potential, is responsible for cardio-protective activity. OBJECTIVE: The present study was under taken to evaluate the pharmacodynamic interaction of green tea extract with hydrochlorothiazide (HCTZ) against doxorubicin (DOX)-induced myocardial toxicity. MATERIALS AND METHODS: Rats were treated with high (500 mg/kg, p.o.) and low (100 mg/kg, p.o.) dose of green tea extract in alone and interactive groups for 28 days. Standard, high and low dose of interactive groups received hydrochlorothiazide (10 mg/kg, p.o.) for the last 7 days. Apart from normal controls, all other groups were subjected to DOX (3 mg/kg, i.p.) toxicity on Days 1, 7, 14, 21 and 28, and the effect of different treatments was evaluated by changes in electrocardiographic parameters, serum biomarkers and tissue antioxidant levels. Apart from that, lipid profile and histological studies were also carried out. RESULTS: Compared with the DOX control group, both high and low dose of green tea exhibited a significant decrease in serum biomarkers and increase in tissue antioxidant levels. Green tea treatment was also responsible for significant improvement in ECG parameter, lipid profile and histological score. Incorporation of high and low dose of green tea with HCTZ exhibited significant protection compared with the HCTZ alone treated group. CONCLUSION: The present findings clearly suggest that the green tea extract dose-dependently reduces DOX-induced myocardial toxicity. Green tea when combined with HCTZ can reduce the associated side-effects and exhibits myocardial protection. PMID- 26604555 TI - Spasmolytic effect of traditional herbal formulation on guinea pig ileum. AB - BACKGROUND: The herbal formulation consisting of Andrographis paniculata Nees., Cassia fistula L., Foeniculum vulgare Mill. and Cuminum cyminum L. is widely used by the local traditional practitioners in rural Northern Karnataka for spasmodic abdominal pain. OBJECTIVE: The present study was undertaken to evaluate safety and spasmolytic effect of poly-herbal formulation. MATERIALS AND METHODS: Acute toxicity studies were carried out in Swiss mice, as per the Organization for Economic Co-operation and Development (OECD) guidelines. The spasmolytic activity of the formulation was studied in isolated guinea pig ileum model using histamine and acetylcholine as agonists. The data were analyzed by one-way ANOVA, followed by Dunnetts post-hoc test and P <= 0.05 was considered as significant. RESULTS: The formulation did not show any adverse toxic effects and found to be safe. It also showed significant (P < 0.05) relaxation in different agonist like histamine and acetylcholine-induced contractions in guinea pig ileum. CONCLUSION: Antispasmodic activity of the herbal formulation can be attributed to its atropine-like activity. The present findings, therefore, support its utility in spasmodic abdominal pain. PMID- 26604556 TI - Critical analysis of India's National Mission on Medicinal Plants (NMMP) in providing access to quality botanical drugs to improve public health. AB - Drugs play an important role in improving health of the population. Medicinal plants help in addressing the health issues of a large section of the population especially the low and middle-income people. However, there are some concerns about the supply, efficacy and safety in using them. This study reviews India's major initiative toward medicinal plants namely, the National Mission on Medicinal Plants to meet medicinal plants challenges. The study analyzed the mission's probable shortcomings due to its design and operational details. This study used "content analysis" approach for analysis of mission's publicly available documents, viz. "Operational guidelines" and its two amendments. The study identified prevalent 28 shortcomings in the original document related to clarity of the document; accountability, transparency and stakeholders' representation. These challenges were partially addressed in two amendments, which indicate persistence of shortcomings in design and operational details. The mission can help in improving and strengthening the Ayurveda, Yoga, Unani, Siddha and Homeopathy program by addressing those shortcomings. PMID- 26604557 TI - Naturopathy curriculum: A step for health reform in Thailand. PMID- 26604558 TI - Are we engaged in reproducible research? PMID- 26604559 TI - Don't read too much into National Sample Survey Organization survey results. PMID- 26604560 TI - Integrative approach to health: Challenges and opportunities. PMID- 26604561 TI - The second international congress (sfec-2015) of society for ethnopharmacology, india. PMID- 26604562 TI - Raising the awareness of infant ora mutilation - myths and facts. PMID- 26604563 TI - The good, the bad and the ugly!! - Antibiotics. PMID- 26604564 TI - Association of Fc gamma-receptors IIa, IIIa, and IIIb genetic polymorphism with susceptibility to chronic periodontitis in South Indian population. AB - BACKGROUND AND OBJECTIVE: Fc gamma receptors (FcgammaRs) are the members of the immunoglobulin superfamily and may play a role in the pathogenesis of periodontitis. Genetic variation in these receptors and its link with various forms of periodontitis is being studied in different populations. The aim of the present study is to determine whether specific FcgammaRIIa, FcgammaRIIIa, and FcgammaRIIIb alleles and/or genotypes are associated with risk for susceptibility to generalized chronic periodontitis (GCP) in South Indian population. MATERIALS AND METHODS: The study population consisted of 120 South Indian subjects; 60 with GCP and 60 periodontally healthy. Deoxyribonucleic acid (DNA) was extracted from samples collected by scrapping buccal epithelium. FcgammaRIIa and FcgammaRIIIa genotyping were performed by polymerase chain reaction (PCR) amplification of DNA with allele-specific primers followed by allele-specific restriction digestion of the products. However, FcgammaRIIIb genotyping was done by allele-specific PCR. RESULTS: No significant difference in the distribution of FcgammaRIIa H/R and FcgammaRIIIa NA1/NA2 genotypes or their respective alleles was observed in GCP patients and healthy subjects. For FcgammaRIIIa F/V genetic polymorphism, the homozygous V/V genotype and V allele were significantly overrepresented in GCP patients while F/F genotype and F allele in controls. CONCLUSION: The present study demonstrates that FcgammaRIIIa V/V genotype, as well as V allele, could be a possible risk factor for chronic periodontitis in South Indian population. PMID- 26604565 TI - Correlation of dental pulp stones, carotid artery and renal calcifications using digital panoramic radiography and ultrasonography. AB - BACKGROUND: The human tissues continuously undergo modification as deposition of calcium (CA) salts either in an organized or disorganized pattern. The latter pattern usually occurs in the soft tissues such as in arteries, brain, kidneys, lungs, and dental pulp. The purpose of this study is to evaluate the presence of pulp calcification and carotid artery calcification (CDC) as a marker for renal calcification and altered serum biomarkers such as serum CA, phosphorus (P), and alkaline phosphatase (ALP). MATERIALS AND METHODS: Digital panoramic radiographs of 50 patients with the presence of pulp stones and suspected CAC were subjected to carotid artery and renal ultrasonography (USG) examination for the presence of vascular calcification and also to evaluate the alterations in serum CA, P, and ALP levels. Data were analyzed statistically using Chi-square test. RESULTS: Panoramic radiographs of 50 patients showed 88.28% of teeth with the presence of pulp stones stones and 91% carotid arteries with calcification. The sensitivity of panoramic radiograph was greater than that of USG (93.67%), but the specificity of USG was more than the panoramic radiograph (44.44%) in detecting CAC. The prevalence rate of renal calcification on USG was 92%. The statistical difference between the patients with or without alteration in serum Ca levels was not significant (chi(2) = 0.581 and P = 0.446). On comparison of serum P and ALP, the difference was found to be statistically significant. CONCLUSION: Presence of pulp stones and CAC's on panoramic radiograph have remarkably proved to establish the chances of renal artery calcification associated with alterations in serum CA levels. PMID- 26604566 TI - Estimation of salivary tumor necrosis factor-alpha in chronic and aggressive periodontitis patients. AB - INTRODUCTION: Periodontitis is a chronic bacterial infection characterized by persistent inflammation, connective tissue breakdown and alveolar bone destruction mediated by pro-inflammatory mediators. Tumor necrosis factor-alpha (TNF-alpha) is an important pro-inflammatory mediator that produced causes destruction of periodontal tissues. OBJECTIVE: The aim of the study is to estimate the salivary TNF-alpha in chronic and aggressive periodontitis and control participants and further correlate the levels with clinical parameter such as gingival index (GI), plaque index (PI), probing pocket depth (PPD) and clinical attachment loss. MATERIALS AND METHODS: The study population consisted of 75 subjects age ranging from 25 to 55 years attending the outpatient section of Department of Periodontics, Saveetha Dental College and Hospital. The study groups included Groups 1, 2, and 3 with participants with healthy periodontium (n = 25), generalized chronic periodontitis (n = 25) and generalized aggressive periodontitis (n = 25), respectively. Salivary samples from the participants were used to assess the TNF-alpha levels using enzyme-linked immunosorbent assay. RESULTS: GI and PI were found to be significantly higher in chronic and aggressive periodontitis compared to the controls. The mean TNF-alpha value in chronic periodontitis patients (12.92 +/- 17.21 pg/ml) was significantly higher than in control subjects (2.15 +/- 3.60 pg/ml). Whereas, in aggressive periodontitis patients the mean TNF-alpha (7.23 +/- 7.67) were not significantly different from chronic periodontitis or healthy subjects. Among periodontitis participants, aggressive periodontitis subjects exhibited a significant positive correlation between the salivary TNF-alpha and PPD. CONCLUSION: Salivary TNF alpha levels are significantly higher in chronic periodontitis than in healthy subjects, but there was no significant correlation with the clinical parameters. PMID- 26604567 TI - Estimation of serum, salivary immunoglobulin G, immunoglobulin A levels and total protein, hemoglobin in smokeless tobacco chewers and oral submucous fibrosis patients. AB - BACKGROUND: Oral submucous fibrosis (OSMF) is a debilitating, potentially cancerous oral condition. Although areca nut is the most important causative agent, it is also considered that the disease is immunologically mediated. AIM OF THE STUDY: To establish that autoimmunity and nutritional deficiency play a role in the etiopathogenesis of OSMF. OBJECTIVES OF THE STUDY: To show that serum immunoglobulin markers (immunoglobulin-G [IgG], immunoglobulin-A [IgA]) and nutritional parameters such as total serum protein (TSP), Hemoglobin (Hb) play a role in causing OSMF and also to correlate serum, salivary IgG, IgA levels in OSMF patients. SETTINGS AND DESIGN: A case-control study was done with 50 patients (25 patients who were provisionally diagnosed as OSMF - Group I, and 25 patients who were chronic smokeless tobacco chewers and who did not have any intraoral lesion - Group II). MATERIALS AND METHODS: Five milliliters of blood and saliva were collected from both the groups. Quantitative analysis of serum, and salivary IgG, IgA was done by turbidometric immunoassay. TSP and Hemoglobin (Hb) were estimated by spectrophotometry. STATISTICAL ANALYSIS: Results were analyzed by independent samples t-test and one-way analysis of variance (ANOVA). RESULTS: All patients of OSMF showed significant (P < 0.01) increase in serum IgG, IgA, and salivary IgG levels as compared to smokeless tobacco chewers. The salivary IgA levels showed a significant decrease in OSMF patients (P < 0.05). TSP and Hb levels showed significant (P < 0.01) decrease in OSMF patients as compared to smokeless tobacco chewers. CONCLUSION: The elevation of immunoglobulin levels supports the concept of autoimmunity. The decrease in TSP and Hb suggests that nutritional deficiency plays a defined role in the occurrence as well as a further progression of OSMF. PMID- 26604568 TI - Evaluation and comparison of the microhardness of enamel after bleaching with fluoride free and fluoride containing carbamide peroxide bleaching agents and post bleaching anticay application: An in vitro study. AB - AIMS AND OBJECTIVES: The purpose of the study was to evaluate and compare the microhardness of enamel after the application of anticay on bleached enamel with fluoride containing and fluoride free bleaching agent. MATERIALS AND METHODS: Twenty freshly extracted teeth decoronated and divided mesiodistally into two halves were randomly divided into five groups with 10 samples in each group. The enamel surface was treated as follows: Group 1 - no treatment, Group 2 - fluoride free bleaching agent, Group 3 - fluoride containing bleaching agent, and Group 4 fluoride free bleaching agent followed by anticay application. The samples were subjected to indentation to test the microhardness using Vicker's hardness analyzer. CONCLUSION: Enamel microhardness significantly increased in samples where anticay was used after the application of bleaching agent. PMID- 26604569 TI - Prevalence of gingival biotype and its relationship to clinical parameters. AB - INTRODUCTION: The dimensions of gingiva and different parts of the masticatory mucosa have a profound impact in periodontics as it governs the way; the gingival tissue reacts to various physical, chemical, or bacterial insults. The purpose of the following study was to assess the gingival thickness (GT) and correlate it to gender, presence of recession, and width of keratinized gingiva (WKG) in a subset of the Indian population. METHODS: A total of 400 subjects in the age range of 20 35 years (200 males and 200 females) were included in the study. Clinical parameters such as probing depth, recession depth, WKG, and GT were recorded for all the patients. RESULTS: The prevalence of thin biotype was 43.25%, and that of thick gingival biotype was 56.75%. The mean GT of central incisor, lateral incisor, and canine in Group I was 1.11 +/- 0.17, 1.01 +/- 0.16, and 0.82 +/- 0.17 mm, respectively. No significant association was observed between the gender and the presence of gingival recession to GT. The mean WKG of central incisor, lateral incisor, and canine in Group I was 4.38 +/- 1.18, 5.18 +/- 1.25, 4.16 +/- 1.16 mm, respectively. A positive correlation exists between WKG and the GT (P < 0.05). CONCLUSION: It was concluded that the prevalence of thick and thin gingival biotype is 56.75% versus 43.25%, respectively, and there is no significant relationship between age, gender, and the presence of recession to gingival biotype. A positive correlation exists between WKG and the GT. PMID- 26604570 TI - Role of oxidative stress in the pathogenesis of oral submucous fibrosis: A preliminary prospective study. AB - BACKGROUND: In the current scenario pathogenesis of majority of the diseases is deeply linked with the oxidative stress, irrespective of its etiology. Enumerable data suggests that reactive oxygen species play a key role in multistage carcinogenesis. Oral submucous fibrosis (OSMF) is considered as a potentially malignant disorder. Its increased incidence over recent years in the Indian subcontinent is a major health concern to oral physicians. However, the role of oxidative stress has not been widely investigated in OSMF. AIMS: Is to evaluate both antioxidant and oxidant status in OSMF and to compare with controls. SETTINGS AND DESIGN: Twenty patients and 20 controls of the same age group were enrolled in the study. SUBJECTS AND METHODS: Five milliliters of blood were collected from each individual and serum was separated. Malondialdehyde (MDA) estimation using thiobarbituric acid (TBA) method, and antioxidant activity (AOA) using principle of TBA reactive substances was done using this serum, with a calorimetric method. STATISTICAL ANALYSIS USED: Student's t-test and ANOVA test. RESULTS: The mean serum AOA status was seen to significantly decrease in OSMF patients, as compared to controls (P = 0.013). The increase in mean serum MDA level was highly significant in OSMF patients, as compared to controls (P < 0.001). CONCLUSION: The disparity between AOA and MDA levels in the patients clearly demonstrates the role of oxidative stress in the disease process. The results also suggest the use of antioxidants in the management of OSMF. PMID- 26604571 TI - Prevalence of aberrant dental morphological details in 6-10 year old school children in an Indian population. AB - BACKGROUND: Variations in the structure of teeth have always been a great curiosity to the dentist from the scientific and practical point of view. AIM: To evaluate the prevalence of a few aberrant morphological features namely, cusp of Carabelli in primary maxillary second molar and in permanent first molar, five cusp in primary maxillary second molar and permanent first molar, shoveling and double shoveling with respect to permanent maxillary central incisors, four cusped primary mandibular second molar and permanent first molar, six cusped primary mandibular second molar and permanent first molar and seven cusped primary mandibular second molar and permanent first molar in 6-10 year old children belonging to the East Bengaluru, a City in India. DESIGN: A cross sectional survey was conducted among 2111 children by two stage sampling method. Type III examination was performed. The findings were subjected to Chi-square test. RESULTS: 83.8% of the studied population had one or more of the variations checked for, as mentioned above. The variation most commonly seen was double shoveling (66.6%) followed by shoveling (65.7%). No significant results were observed in any trait with respect to gender. CONCLUSION: This study is the first of its kind, providing a baseline data of the prevalence of morphological details in the pediatric Indian population. PMID- 26604572 TI - Detection and measurement of oral malodor in chronic periodontitis patients and its correlation with levels of select oral anaerobes in subgingival plaque. AB - INTRODUCTION: Oral malodor is generally ascribable to oral microbial putrefaction generating malodorous volatile sulfur compounds. The aim of the present study is to correlate organoleptic recordings with a small handheld portable volatile sulfide monitor and periodontal clinical parameters and correlate the levels of halitosis causing bacteria in plaque between baseline, 1-week, and 1-month. MATERIALS AND METHODS: A total of 20 systemically healthy subjects with self reported halitosis were subjected to organoleptic examination and FitScan((r)). Subgingival plaque samples for anaerobic culturing were harvested followed by an assessment of plaque index (PI), gingival bleeding index (GBI), and pocket probing depth. Data derived were subjected to statistical analysis using Wilcoxon signed rank test and Spearman's rank test (P < 0.05). RESULTS: No correlation was seen between organoleptic measurements and portable volatile sulfide monitor at any time interval. There was a statistically significant (P < 0.05) correlation between the scores of PI, gingival index, GBI, and myeloproliferative disease with organoleptic readings at all-time intervals. Anaerobic culture has shown to identify Fusobacterium species, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia. However, no correlation could be established in between total microbial load with organoleptic and FitScan((r)) reading at any time interval (P < 0.05). CONCLUSION: Significant correlation could be established between organoleptic readings and periodontal parameters. PMID- 26604573 TI - Evaluation and comparison of the efficacy of low fluoridated and calcium phosphate-based dentifrice formulations when used with powered and manual toothbrush in children with autism. AB - BACKGROUND: Autism is a neurobiological disorder characterized by impaired social interaction, communication difficulties, and lacking manual dexterity. These limitations make the oral hygiene maintenance very difficult. AIM: The aim of this present study is to evaluate and compare the efficacy of low fluoridated and calcium phosphate-based dentifrice formulations when used with powered and manual toothbrush in children with autism. SETTING AND DESIGN: Sample comprised 22 children with autism who daily visited a day care and education center named ARUSHI - a center for children with special health care needs in Bhopal. METHODS: Children were divided into two groups (Group A and B) according to toothbrush used and further divided into subgroups (A1 and B1 [low fluoridated - Pediflor toothpaste] and A2 and B2 [calcium sucrose phosphate - Enafix toothpaste]). Oral hygiene instructions and brushing technique demonstration were given every day for a period of 1-month. Oral health status was evaluated before and after the study using simplified oral hygiene index (OHI-S) and its Miglani's modification for primary dentition, plaque index (PI), gingival index (GI), and decayed, missing, and filled teeth (DMFT)/deft index. The perception of parents regarding oral hygiene practices for their kids was also evaluated by an awareness and attitude questionnaire. STATISTICAL ANALYSIS: OHI-S, GI, PI, and DMFT/deft were statistically evaluated using Mann-Whitney U- test. RESULTS AND CONCLUSION: Mean value of OHI-S decreased significantly with powered toothbrush (0.035 [P < 0.05]) in both groups. However, PI decreased significantly for Enafix when used with powered toothbrush (0.042 [P < 0.05]). Perception of parents was seen to improve significantly after 1-month study (0.000 [P < 0.05]). PMID- 26604574 TI - Gorlin-Goltz syndrome: A case series of 5 patients in North Indian population with comparative analysis of literature. AB - OBJECTIVE: In Indian scenario, Gorlin-Goltz syndrome (nevoid basal cell carcinoma syndrome [NBCCS]) has been rarely reported. The clinical, radiological, and histopathological findings and major and minor criteria in five cases of NBCCS in North Indian population have been presented along with a discussion of the role of gene mutation analysis in early diagnosis of syndrome. MATERIALS AND METHODS: The diagnostic findings of Gorlin-Goltz syndrome in 5 patients were compared with other reports in Indian population and with reports of this syndrome in other parts of the world. RESULTS: The most common features seen were keratocystic odontogenic tumors (100%), calcifications of falx cerebri (60%), palmar-plantar pits (80%), rib anomalies (80%), macroencephaly (60%), ocular hypertelorism (80%), and frontal bossing (60%) in our series. Retained deciduous teeth seen in 80% patients whose association has not been previously reported has been presented. None of our patients had basal cell carcinoma, syndactyly or polydactyly, pectus deformity, bridging of sella turcica, pigmented nevi, or family history of this syndrome in contrast to such findings in other Indian patients. Medulloblastoma has not been reported in any Indian patient so far compared to this finding in other studies conducted worldwide. CONCLUSIONS: Combining the features of 48 patients in 38 cases of NBCCS being published in Indian literature with five cases of our series and on comparison with other studies in the world, a wide disparity in different ethnic groups and a wide variation in presentation of syndrome within the same population is suggested. PMID- 26604575 TI - Evaluation of arch width among Class I normal occlusion, Class II Division 1, Class II Division 2, and Class III malocclusion in Indian population. AB - OBJECTIVE: To test the hypothesis that there is no difference between Class I (CI) normal occlusion, Class II division 1 (CIId1) and CII division 2 (CIId2), and Class III (CIII) malocclusion with respect to arch widths, width of the maxillary and mandibular arches, gender dimorphism within groups, and gender comparisons. MATERIALS AND METHODS: Samples of 40 CI subjects, 40 CIId1 subjects, 40 CIId2 subjects, and 34 CIII subjects were studied. All subjects were Indians with no history of orthodontic treatment. An analysis of variance and Duncan's test statistically compared the groups and genders. RESULTS: CIId1 malocclusion showed the narrowest maxillary arch compared with the other types of malocclusions. CIII malocclusion showed largest mandibular arch than other types of malocclusions. Gender dimorphism is more commonly seen in CI normal occlusion than other types of malocclusions. Gender dimorphism is not observed in CIId1 group. Gender comparisons revealed arch width differences between different types of malocclusions more pronounced in males than in females. The maxillary/mandibular intermolar width difference is positive for CI normal occlusion and negative for CIId1, CIId2, and CIII malocclusions, which suggested, the presence of crossbite tendency in CII and CIII malocclusions. CONCLUSION: The hypothesis is rejected by the findings of this study. PMID- 26604576 TI - Prediction of canine and premolar size using the widths of various permanent teeth combinations: A cross-sectional study. AB - AIMS: To suggest the best predictor/s for determining the mesio-distal widths (MDWs) of canines (C) and premolars (Ps), and propose regression equation/s for hitherto unreported population. METHODS: Impressions of maxillary and mandibular arches were made for 201 children (100 boys and 101 girls; age range: 11-15 years) who met the inclusion criteria and poured with dental stone. The maximum MDWs of all the permanent teeth were measured using digital vernier caliper. Thirty-three possible combinations (patterns) of permanent maxillary and mandibular first molars, central and lateral incisors were framed and correlated with MDWs of C and Ps using Pearson correlation test. RESULTS: There were significant correlations between the considered patterns and MDWs of C and Ps, with difference noted between girls (range of r: 0.34-0.66) and boys (range of r: 0.28-0.77). Simple linear and multiple regression equations for boys, girls, and combined sample were determined to predict MDW of C and Ps in both the arches. CONCLUSIONS: The accuracy of prediction improved considerably with the inclusion of as many teeth as possible in the regression equations. The newly proposed equations based on the erupted teeth may be considered clinically useful for space analysis in the considered population. PMID- 26604577 TI - Importance of cephalographs in diagnosis of patients with sleep apnea. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is considered to be a potentially life threatening disorder, which is characterized by repeated collapse of the upper airway during sleep with cessation of breathing. The cephalometric method despite being a static, two-dimensional evaluation of dynamic three-dimensional structures of the head and neck is useful in diagnosing patients with OSA, as they have shown that significant differences exist between asymptomatic controls and patients with OSA. AIMS AND OBJECTIVES: This study is designed to compare and validate the craniofacial morphology in patients with OSA using lateral cephalometry in both upright and supine position. MATERIALS AND METHODS: Sixty subjects participated in the study of which 30 were patients with OSA diagnosed by questionnaire and 30 were healthy control group with age range of 25-45 years. RESULTS: The study group demonstrated an increased ANB, mandibular plane angles (GoGn-SN), lower anterior facial height which are statistically significant with a significant P < 0.05. Significant decrease in posterior airway space, increased soft palate length, tongue length, and thickness suggesting reduced airway space in supine posture. CONCLUSION: Evaluation of craniofacial morphology in OSA patients using lateral cephalometry helps in recognizing the morphological changes induced by altered sleep pattern and for appropriate treatment planning. PMID- 26604578 TI - C-deletion in exon 4 codon 63 of p53 gene as a molecular marker for oral squamous cell carcinoma: A preliminary study. AB - BACKGROUND: Exfoliated oral cancer cells in saliva samples from patients with oral squamous cell carcinoma (OSCC) can be used to determine the incidence and type of mutations of the p53 tumor suppressor gene. The purpose of this study was to identify C-deletion mutation in exon 4 codon 63 of p53 gene in the saliva of OSCC patients by polymerase chain reaction (PCR). MATERIALS AND METHODS: Saliva samples of 20 newly histopathologically diagnosed OSCC patients and 5 healthy volunteers were subjected to isolation of the total genomic DNA and PCR amplification for C-deletion on exon 4 of p53 gene. The resulting products were resolved by agarose gel electrophoresis, viewed and photographed on ultraviolet transilluminator. RESULTS: The relationship between the frequencies of genetic alterations was assessed by Chi-square test. Differences with values of P < 0.05 were statistically significant. CONCLUSION: The study concluded a 100% presence of C-deletion mutation in exon 4 codon 63 of p53 in the saliva of OSCC patients. This study suggests that detection of mutation in exon 4 codon 63 of p53 by PCR is a fast, reliable, accurate, and sensitive molecular method for OSCC diagnosis. PMID- 26604579 TI - Validation of dental impact on daily living questionnaire among tribal population of India. AB - BACKGROUND: Oral conditions are known to affect various aspects of quality of life. Similarly, the social consequence of the quality of life in the day to day living is also equally important. Several studies have quantified the social consequences of diseases through activity limitations in people's daily living. The instruments which cover a broad spectrum of life are proposed to be compared with the clinical oral hygiene status of people from different social classes. AIM: To assess the validity of dental impact on daily living (DIDL) questionnaire measuring subjective dental problems and their impact in the day to day life among tribes of Wayanad. STUDY DESIGN: Cross-sectional. MATERIALS AND METHODS: DIDL questionnaire developed by Leao and Sheiham was used. We recorded the clinical oral health status using decayed, missing, filled, simplified oral hygiene index, and community periodontal index indices, to correlate the subjective findings of dental impact tribe to obtain construct validity of the questionnaire. ANALYSIS: Descriptive statistics and Spearman's correlation using IBM SPSS software version 20. RESULTS: In the study population of 250 participants, the majority of the participants were from the age group between 36 and 50 years (40%) and females were in the majority (64%). The clinical status of the participants was poor in the majority while their perceived impact in their day to day living was found to be relatively satisfied. The study results show the DIDL tool had weak validity in relation to the clinical status with relevance to the social status of Indian tribal population. CONCLUSION: The study result shows that there was insignificant and weak validity between the DIDL tool and the oral health status among these tribes who were from a low social class. This might be because their priority in life which is different from what a person from high social class. So the dental problem is ignored at the level of individual depending on his/her priority and at the community level by the policy makers. PMID- 26604580 TI - Knowledge and awareness of informed consent among orthodontists and patients: A pilot study. AB - AIM: Despite fixed professional opinion of what might constitute optimal treatment, patients must be informed of the various treatment options available in orthodontics to manage their clinical problem. The purpose of this study was to compare and evaluate the knowledge and awareness among practicing orthodontists and patients with regard to informed consent in clinical practice and research. MATERIALS AND METHODS: Twenty-five orthodontists and 25 patients were enrolled in a questionnaire study which was descriptive and cross-sectional in the nature. The questionnaire focused on the following aspects; contents of informed consent, at what age and who can give consent. RESULTS: The study showed a majority of orthodontists (79.14%) were aware of knowledge regarding informed consent when compared to patients(35.14%). CONCLUSION: The overall result showed the huge gap that exists between orthodontists and patients and thus making it categorical for patients to be more involved in the decision-making process. PMID- 26604581 TI - Evaluation of anti-microbial activity of spore powder of Ganoderma lucidum on clinical isolates of Prevotella intermedia: A pilot study. AB - AIM: This study aimed at evaluating the anti-microbial activity of spore powder of Ganoderma lucidum on Prevotella intermedia isolated from subgingival plaque from chronic periodontitis patients. SETTINGS AND DESIGN: Written informed consent was obtained from each subject enrolled in the study. The Institutional Ethics Committee granted the ethical clearance for the study. MATERIALS AND METHODS: This study included 20 patients diagnosed with chronic periodontitis. Pooled subgingival plaque samples were collected using sterile curettes from the deepest sites of periodontal pockets. The collected samples were then transported in 1 mL of reduced transport fluid. The organisms were cultured and confirmed. These organisms were then used for minimum inhibitory concentration (MIC) procedure. STATISTICAL ANALYSIS: Mean of the MIC value obtained was calculated. RESULTS: Thirteen out of the 20 clinical samples were tested that showed sensitivity at various concentrations. Five samples showed sensitivity at all concentrations. Twelve samples showed sensitivity at 8 mcg/ml. Eleven samples showed sensitivity at 4 mcg/ml, 8 samples showed sensitivity at 2 mcg/ml, and 5 samples showed sensitivity even at 1 mcg/ml. Mean MIC value of G. lucidum spore powder for P. intermedia obtained was 3.62 mcg/ml. CONCLUSION: G. lucidum with its multipotential bioactivity could be used as an anti-microbial, in conjunction with conventional therapy in periodontal disease. PMID- 26604582 TI - Identifying risk groups for osteoporosis by digital panoramic radiography. AB - BACKGROUND: Osteoporosis is a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to bone fragility, and enhanced susceptibility to fractures. Dental radiographs, especially panoramic images, have been used to predict bone mineral density. A number of indices, (mandibular cortical index [MCI], mandibular cortical width [MCW], and panoramic mandibular index [PMI]) have been developed to assess and quantify the quality of mandibular bone mass and to observe the signs of resorption. OBJECTIVES: The objectives of the study were to assess mental index (MI), MCW index, and PMI with bone density in identifying risk group for osteoporosis and also to investigate influence of age and gender on MI, MCI, and PMI. MATERIALS AND METHODS: After obtaining consent, details regarding age, gender, systemic health status, and oral parafunctional habits were recorded in each patient. Then a digital panoramic radiograph was taken. The image thus obtained was subjected to calibrations and morphometric analysis using Digora version 2.7. The obtained values of indices were compared with the mean values of indices, to evaluate subjects whether they are prone to osteoporosis or not. The obtained information was subjected to statistical analysis for the significance of the parameters. RESULTS: Data analysis showed that calibration indices were highly significant in the assessment of risk group for osteoporosis than noncalibration index. The subjects at a higher risk for development of osteoporosis were old-aged adults with higher prevalence being reported in women compared to male subjects. CONCLUSION: In conclusion, our results suggest that higher percentage of subjects with undetected decreased bone mineral density may be identified based on trained general dental practitioners analyses of their panoramic radiographs using simple screening analytical calibration MI and MCI. PMID- 26604583 TI - Telescopic overdenture for oral rehabilitation of ectodermal dysplasia patient. AB - Reduced number of teeth with underdeveloped alveolar ridges poses a greatest prosthetic challenge in rehabilitation of ectodermal dysplasia patients (ED). Furthermore, surgical risks and financial constraints may preclude the implant supported prosthesis, the most desirable treatment option in an adult ED patient. Long edentulous span does not permit fixed dental prosthesis (FDP) as well. Telescopic denture by incorporating the best of both fixed and removable prosthesis can be a viable treatment alternative for ED patients with compromised dentition and limited finances. A 21-year-old young girl presented with chief complaint of esthetics and mastication due to missing upper and lower teeth. A provisional diagnosis of ED was made based on familial history, physical, and oral examination. This clinical report describes management of an adult ED patient by means of telescopic overdenture prosthesis in mandibular arch and FDP in maxillary arch which restored esthetics, function, and social confidence of the patient in a cost effective manner. PMID- 26604584 TI - Buccal mucosal hypertrophy secondary to open bite. AB - Timely and accurate diagnosis of a medical/dental condition is the first critical step to ensure appropriate treatment. Lack of astuteness in diagnosis may assume many forms. Each medical/dental practitioner is morally and legally bound to perform his or her duties to a specified standard of care. The cause of misdiagnosis may be hurriedness, lack of testing, or a simple mistake; failure to diagnose can constitute a breach of that duty, making the medical/dental provider liable for any resulting damages. The following case report highlights one such misdiagnosed case. PMID- 26604585 TI - Benign fibrous histiocytoma: A rare case involving jaw bone. AB - Benign fibrous histiocytoma (BFH) is a soft tissue neoplasm which occurs mostly on the skin of extremities. BFH rarely occurs in bone and may affect femur, tibia, and pelvic bone. Jaw bone involvement is very unusual with only 11 cases reported till date. This report describes a case of BFH occurring in a 30-year old female patient affecting left mandibular posterior region. Computed tomography revealed a well-defined expansile lytic lesion in the posterior mandible. Gross examination of the tumor revealed an admixture of fibroblasts and histiocytes in a fascicular and storiform pattern. Immunohistochemical staining was positive for CD68. PMID- 26604586 TI - Conservative management of dens evaginatus and attached supernumerary tooth/odontome in mandibular premolar with dual radiolucencies. AB - Recently, an innovative, nonsurgical regenerative endodontic treatment protocol "SealBio" was introduced to manage mature nonvital permanent teeth with periapical lesions. This paper explains the management of an unusual case of dens evaginatus and an attached supernumerary tooth/an odontome associated with two distinct radiolucencies in a mandibular premolar with "SealBio" technique and discusses the various hypotheses on the pathogenesis of unusual malformation and associated pericervical cyst-like radiolucency in the involved tooth. PMID- 26604587 TI - Management of residual mucogingival defect resulting from the excision of recurrent peripheral ossifying fibroma by periodontal plastic surgical procedure. AB - Peripheral ossifying fibroma (POF) is a local gingival reactive lesion, thought to be originating from the superficial periodontal ligament. It is found most often in the anterior maxilla with predilection for females and high recurrence rate. Clinically, the lesion is observed in gingiva or interdental papilla and manifested either as sessile or pedunculated mass which may appear ulcerated or erythematous or exhibit no color difference from the adjacent healthy gingival tissue. The present case report describes the diagnosis, treatment of POF, and immediate management of residual functional and cosmetic mucogingival defect which originated as a sequel of excisional biopsy of recurrent POF by utilizing modification of Grupe and Warren technique (modified laterally displaced flap). Clinical healing was uneventful at 2 weeks, and excellent coverage of residual mucogingival defect without any evidence of recession and or recurrence of POF was observed at surgical site 9 months postoperatively. PMID- 26604588 TI - Paracetamol induced Steven-Johnson syndrome: A rare case report. AB - In the contemporary era, use of drugs is the dominant paradigm of health care. The most quotidian drug used for fever and pain is paracetamol. Although adverse reactions to paracetamol in India are rare, at times they can cause life threatening situations. Stevens-Johnson syndrome (SJS) is one such potentially lethal adverse drug reaction. The most reported cases of analgesic-induced SJS were due to oxicams or propionic acid derivatives. There are very few detailed reports of SJS due to the use of paracetamol. We report a case of SJS, which occurred due to the use of paracetamol. The clinical features of this condition and multidisciplinary management of the patient are described in brief. PMID- 26604589 TI - Unusual presentation of oral amyloidosis. AB - Amyloidosis is a rare disease of difficult diagnosis that occurs due accumulation of amyloid substance localized or systemic. The oral cavity is an unusual site and can be related to both localized and systemic forms and for that reason a full investigation is necessary to determine the extent of the disease. This study reports a case of a 58-year-old melanoderm male patient referred to the Department of Oral and Maxillofacial Surgery with white plaques on the tongue and multiple nodules in the region of the buccal mucosa and labial commissure, with 6 months of evolution and painful symptoms. An incisional biopsy was performed on both sites and histological examination indicated the presence of eosinophilic amorphous material within the connective tissue, positive for crystal violet staining, consistent with amyloidosis. At the present time, there is no consensus on the management of local amyloidosis. Surgical treatment of localized forms is indicated in some cases to reduce the functional prejudice. Moreover, follow-up is mandatory, both to manage recurrences and to monitor the possible evolution of the disease to the systemic form. PMID- 26604590 TI - Leprous macrocheilia: A rare clinical presentation. AB - Oral leprosy, a granulomatous disease is classified under the term oro-facial granulomatosis which comprises a group of diseases characterized by noncaseating granulomas affecting the soft tissues of the oral and maxillofacial region. The most common clinical presentation of oro-facial granulomatous conditions is persistent swelling of one or both lips. Due to its rare incidence and clinical findings overlapping with other granulomatous conditions such as sarcoidosis, Crohn's disease, and cheilitis granulomatosa; it is practically difficult for a dental surgeon to easily diagnose this condition. This study presents a case of leprosy causing macrocheilia as the only clinical presentation and diagnosed initially as Miescher's cheilitis based on exclusion criteria. PMID- 26604591 TI - Cone-beam computed tomography exploration and surgical management of palatal, inverted, and impacted mesiodens. AB - Supernumerary teeth are extra teeth or toothlike structures which may have either erupted or unerupted in addition to the 20 deciduous teeth and the 32 permanent teeth. Mesiodens is one of these located in the midline between the two central incisors. Their presence may give rise to a variety of clinical problems. This paper describes a rare case of palatal placed, inverted and impacted mesiodens associated to two supernumerary teeth which were detected during a radiographic examination for delayed eruption of permanent central incisors in the case of a healthy 8-year-old girl monitored at the oral surgery service while discussing the usefulness of cone beam computed tomography for accurate diagnosis and management. PMID- 26604592 TI - Surgical augmentation of interdental papilla - A case series. AB - Formation of black triangles between teeth due to loss of interdental palpilla is one of the common problems encountered in routine clinical practice, as extreme importance is given to esthetics. This paper discusses two different surgical approaches in treating three cases with papillary loss in the first case the reconstruction of papilla was achieved by using a semilunar coronally repositioned papilla technique and in second and the third case reconstruction of the papilla was achieved by modification of Nodland's microsurgical technique. In all the three cases a free connective tissue graft was used to reconstruct the lost volume of interdental papilla. Complete reconstruction of the lost papilla was achieved in all the three cases 6 months postoperatively. PMID- 26604593 TI - Prevalence of carotid artery calcification in postmenopausal women and its correlation with atherogenic risk factors. AB - AIM: The aim of the present study was to determine the prevalence of carotid artery calcification (CAC) in postmenopausal females on panoramic radiographs and to study the correlation of CAC with possible risk factors such as hypertension, osteoporosis, and hypercholesterolemia, among others. MATERIALS AND METHODS: Totally, 1214 panoramic radiographs of postmenopausal females attending the Department of Oral Medicine and Radiology were examined for the presence of CAC. The subjects were also assessed for the presence of various risk factors and the possible correlation to CAC. Statistical analysis was done using Chi-square test, and P < 0.05 was considered to be statistically significant. RESULTS: Two hundred and seventy-eight postmenopausal females presented with CAC and a prevalence of 22.9%. These patients presented with a medical history that was laden with risk factors, of which hypertension (71.2%) was the most common risk factor. Hypertension, hypercholesterolemia, osteoporosis, and obesity were significantly (P < 0.05) related to the presence of CAC while age, diabetes, and smoking were not significantly (P > 0.05) related to CAC. CONCLUSION: The incidental finding of CAC on panoramic radiographs during the routine dental examination can provide life-saving information for the identification of postmenopausal females who are at a higher risk for stroke. Oral clinicians should, therefore, record a proper medical history of such patients to identify the atherogenic risk factors and refer such patients to the physician for careful evaluation and conformation of the disease. PMID- 26604594 TI - Efficacy of topical application of 0.03% tacrolimus eye ointment in the management of allergic conjunctivitis. AB - BACKGROUND: Allergic conjunctivitis is commonly observed eye diseases in Sikkim, India due to the abundance of seasonal pollens, environmental pollutants, and house dust. We evaluated the efficacy of topical 0.03% tacrolimus eye ointment in the management of simple allergic conjunctivitis. MATERIALS AND METHODS: A prospective observational study was designed consisting of 41 patients with refractory simple allergic conjunctivitis, whose condition responded very poorly to conventional anti-allergic eye drops (azelastine, olopatadine, chlorpheniramine maleate, sodium chromoglycate). Simple allergic conjunctivitis cases were diagnosed and followed up evaluating both subjective and objective findings (itching, photophobia, tearing, chemosis, conjunctival congestion, tarsal papilla, and eyelid edema). Existing ocular treatment was discontinued at enrolment and 0.03% tacrolimus ointment was applied into the conjunctival sac of the affected eyes twice daily for 4 weeks followed by a 2 weeks washout period. Patients were followed up at the end of 1(st) week, 4(th) week, and at 7(th) week (2 weeks washout period). RESULTS: Symptoms of simple allergic conjunctivitis (itching, tearing and photophobia) were significantly reduced at the end of 1(st) week. Signs such as conjunctival chemosis, congestion, tarsal papillae, and eyelid edema were effectively treated in all cases at the end of 1(st) week. At the end of 4(th) week, all cases were fully cured and none of the patient had any recurrences up to 7(th) week. Mean score at 1(st) day (9.6 +/- 3.27) was significantly (P < 0.0001) reduced by 7(th) day (1.35 +/- 1.19) of treatment. CONCLUSION: Topical application of tacrolimus ointment is an excellent alternative to anti-allergic and steroids eye drops for the treatment of simple allergic conjunctivitis as it significantly reduces recurrences. PMID- 26604595 TI - Comparative evaluation of the efficacy of curcumin gel with and without photo activation as an adjunct to scaling and root planing in the treatment of chronic periodontitis: A split mouth clinical and microbiological study. AB - AIMS AND OBJECTIVES: Harnessing Mother Nature's bountiful remedies for rejuvenation has been in vogue since time immemorial. Turmeric contains the polyphenol Curcumin in its rhizome. It produces reactive oxygen species (ROS) with visible light irradiation as photodynamic therapy (PDT) - which validates its use in the treatment of periodontitis. This study compares Curcumin and Curcumin PDT as an adjunct to conventional Scaling and Root Planing (SRP) with SRP alone in the treatment of patients with chronic periodontitis. MATERIALS AND METHODS: Sixty sites in fifteen untreated chronic periodontitis patients were randomly assigned in a split mouth design for one of the treatment modalities; 1) Scaling and root planing (SRP) alone, (2) SRP + Curcumin application for 5 min, (3) SRP + Curcumin application for 5 min + irradiation with blue light emitting diode of wavelength 470 nm for 5 min. (Curcumin PDT) on 0 day.(4) SRP + Curcumin PDT on "0", 7(th) and 21(st) day. The clinical parameters included plaque index (PI), bleeding on probing (BOP) measured by sulcus bleeding index (SBI), probing pocket depth (PPD), clinical attachment level (CAL) recorded at the baseline & 3(rd) month. The site with greatest probing pocket depth (PPD) was selected from each quadrant for bacterial sampling and culturing for Aggregatibacter actinomycetemcomitans (Aa) and other black pigment producing microorganisms (BPB) like Porphyromonas gingivalis & Prevotella intermedia. CONCLUSION: The present study showed that Curcumin photodynamic therapy is a valuable treatment modality adjunctive to conventional scaling and root planing over Curcumin application. Moreover, multiple adjunctive applications of photodynamic therapy are more beneficial than single application in reducing clinical & microbiological parameters. PMID- 26604596 TI - Dental caries status of inmates in central prison, Chennai, Tamil Nadu, India. AB - AIM: To understand the dental health among prison inmates, we assessed the dental caries status of central prison inmates in Chennai, India. MATERIALS AND METHODS: A total of 1060 inmates from three divisions of the central prison in Chennai were assessed by a single investigator for dental caries status based on World Health Organization specifications. RESULTS: Among the inmates, 58.2% of males and 54.2% of females had decayed teeth. About 4.1% of males and 2.9% of females had filled teeth. The mean decayed, missing, filled teeth index was 5.1 and 3.9 for female and male prisoners, respectively. The prevalence of dental caries was highest among inmates younger than 24 years age. CONCLUSION: Our study suggests that a high proportion of prison inmates was affected by dental caries, which necessitates the need for initiating oral health promotion activities among prison inmates. PMID- 26604597 TI - Cone-beam computed tomography evaluation of Pont's index predictability for Malay population in orthodontics. AB - INTRODUCTION: In orthodontic treatment, three-dimensional (3D) dental casts has a significant role in diagnosis and treatment planning. The aim of this study was to evaluate Pont's index predictability in orthodontics. MATERIALS AND METHODS: Premolar arch width, molar arch width and mesiodistal width of the maxillary incisors were measured three-dimensionally to assess shape of dental arches. The data source was cone beam computed tomography (CBCT) high volumetric data acquisitions from Malay ethnic background. Arch widths were measured and recorded from 53 subjects (32 male and 21 female with the mean age, 25.81), both the maxillary and mandibular arches, to obtain CBCT high volumetric data. All measurements were obtained through CBCT Planmeca Romexis TM Software 2.3.1.R (Helsinki, Finland). RESULTS: Pont's formula overestimated the upper and lower interpremolar distance, with mean differences of 8.35 +/- 3 mm and 12.02 +/- 3.20 mm, respectively. Furthermore, the formula overestimated the upper and lower intermolar distance, with mean differences of 7.87 +/- 3 mm and 16.14 +/- 5.86 mm, respectively. CONCLUSIONS: The results indicate that Pont's index is not practical for use with the Malaysian population since the index overestimated interpremolar and intermolar widths. This raises questions whether the index is a true predictor of arch width measurements. PMID- 26604598 TI - Attitude of Indian dental professionals toward scientific publications: A questionnaire based study. AB - BACKGROUND: Due to competitiveness and academic benefits, most dental professionals feel an urgent need to increase their publications. Hence, we explored the attitude of students and faculty members toward scientific publications through a questionnaire. MATERIALS AND METHODS: A questionnaire consisting of 13 questions was sent by e-mails and posting the printed copies to dental postgraduate (PG) students (second and third year) and faculty members (n = 500 each). The returned completed questionnaires were analyzed. RESULTS: About 37% of dental PG faculty and 35.6% PG students responded to the questionnaire, with overall response of 72.6%. Among the PG faculty, professors (P) had more scientific publications, followed by senior lecturers (SL) and readers (R). The publications as first or corresponding author were less among both faculty and PG students while co-authorship was more among PG students compared to faculty members. Awareness about the term "plagiarism" was overall high and relatively highest among R, followed by SL, P and PG students. The percentage of publications in fee charging journals was more among PG students than faculty members and self-funding for publication was observed in 86.4% of PG students and 94-100% among faculty members. CONCLUSION: About 72.6% of dental professionals were involved in publishing of their research work and the number of publications increased steadily with an increase in their academic experience. All the dental professionals concurred publications as the criteria for academic excellence. PMID- 26604600 TI - Role of abnormal Langerhans cells in oral epithelial dysplasia and oral squamous cell carcinoma: A pilot study. AB - BACKGROUND: The oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC), although initiated by tobacco carcinogens, their progression is due to inability of Langerhans cells (LCs) to detect these abnormal cells and promote lymphocytes to destroy these cells. We assessed and quantified the tumor associated LCs and inflammation in OED and OSCC to understand their role. MATERIALS AND METHODS: Fifty-five microscopic sections were assessed (27 OED and 28 OSCC). The LCs were detected using S-100 immunohistochemical marker. The number of tumor associated LCs were counted. The presence of abnormal appearing large cells and its relation to histopathologic grade and inflammation was assessed. RESULTS: Significant increase in the LC count was observed in OSCC when compared to dysplasia. Large, abnormal appearing cells were observed in dysplasia and carcinomas however, these were more pronounced in moderate dysplasia and poorly-differentiated carcinomas. The presence of these abnormal appearing cells was associated with decrease in lymphocytic infiltrate. CONCLUSION: The present study indicates more LC are recruited into the carcinoma. These accumulated nonfunctional LC in the tumor tissue are indicative of aggressive tumor with potential malignant transformation. PMID- 26604599 TI - Effect of misoprostol for cervical priming before gynecological procedures on nonpregnant premenopausal women. AB - BACKGROUND: Misoprostol is very effective in cervical ripening and is used for termination of pregnancy. A similar effect on the nonpregnant uterus will facilitate gynecological operations, and hence we assessed the effect of misoprostol on the nonpregnant uterus of premenopausal women. MATERIALS AND METHODS: In a prospective double-blinded randomized controlled trial, 280 women were randomly allocated into two groups (12 women did not complete the intervention). Study (A) and control (B) group received 400 MUg of misoprostol or 400 mg of metronidazole tablets (as a placebo) respectively in the posterior vaginal wall 6 h prior to gynecological procedures. RESULTS: The mean cervical dilatation was significantly higher (P < 0.0001) in misoprostol compared to placebo group (4.6 +/- 0.96 mm vs. 3.6 +/- 0.82 mm), benefit were also observed on secondary outcome measures which were need for further dilatation, time taken for further dilatation, ease of dilatation, subjective assessment of pain by visual analog scale. Only 3.61% patients complained of intolerable pain during dilatation in the study group while in control group 48.74% complained of intolerable pain and required anesthesia. Most common side effects of misoprostol were abdominal pain and mild vaginal bleeding. CONCLUSION: Misoprostol was effective in cervical ripening of nonpregnant premenopausal uterus to facilitate gynecological procedures. PMID- 26604601 TI - Variation in levels of anxiety to dental treatment among nonorphan and orphan children living under different systems. AB - BACKGROUND: It is essential to understand the factors influencing the level of anxiety to dental treatment among different children as it can influence seeking dental care. Here, we assessed the impact of parental loss on dental anxiety among 6-13-year-old children. MATERIALS AND METHODS: A total of 444 children within the age group 6-13 years were selected. Group 1 consisted of orphan children living in government-run orphanages, Group 2 consisted of orphan children taken care by a person with a motherly relationship, Group 3 consisted of abandoned children living in private organization and Group 4 consisted of children living with their parents. Dental anxiety was measured using children's fear survey schedule-dental subscale and modified faces version of modified child dental anxiety scale. RESULTS: The highest number of anxious children were observed in Group 4 and the difference in the anxiety levels among the four groups was found to be highly statistically significant. Children living in government-run orphanages had least dental anxiety. CONCLUSION: All the orphans may not have the same anxiety levels and the environment of upbringing the orphans plays a significant role in the development of the anxiety. PMID- 26604602 TI - Correlation of cytomorphological patterns and acid-fast Bacilli positivity in tuberculous lymphadenitis in a rural population of southern India. AB - BACKGROUND: One of the most common causes of lymphadenopathy in India is tuberculosis. It can be diagnosed by a minimally invasive procedure known as fine needle aspiration cytology (FNAC), and thereby unnecessary surgical interventions are avoided. AIM: This study was undertaken to evaluate cytomorphological patterns of tuberculous lymphadenitis including human immunodeficiency virus positive cases, to correlate the acid-fast Bacilli (AFB) positivity with cytomorphological patterns and also to find out overall AFB positivity. MATERIALS AND METHODS: In this study, a total of 212 cases of cytologically proven tuberculous lymphadenitis were retrieved and analyzed retrospectively between March 2012 and March 2015 for three different cytomorphological patterns (epithelioid granuloma without necrosis [pattern A], epithelioid granuloma with necrosis [pattern B], and necrosis without epithelioid granuloma [pattern C]) and bacillary loads on Ziehl-Neelsen stain (ZN) for AFB. RESULTS: Pattern A through C was observed in 40 (18.9%), 102 (48.1%), and 70 (33%) cases, respectively. AFB positivity was found in 2 (5%) cases of pattern A, 62 (60.8%) cases of pattern B, and 54 (77.1%) cases of pattern C. The highest percentage of AFB positivity (64.7%) was observed in aspirate containing purulent/pus and caseous/cheesy material. The overall AFB positivity was seen in 55.7% (118/212) cases. On grading of AFB positivity, Grade 1+ was observed in 29.7%, Grade 2+ was observed in 28.8%, and Grade 3+ was observed in 41.5% cases. CONCLUSION: FNAC is a sensitive, simple, convenient, safe, minimally invasive procedure to diagnose tuberculous lymphadenitis. Study of both cytomorphological patterns and ZN staining for AFB can improve the diagnostic yield. Regardless of the presence of granuloma, ZN stain must be employed whenever infective pathology is suspected. PMID- 26604603 TI - Morbidity profile and out of pocket health care expenditure among under five children of an urban area of Puducherry. AB - BACKGROUND: Information on out of pocket (OOP) health care expenditure is essential for health planning and devising strategies for Universal Health Coverage (UHC). AIMS AND OBJECTIVES: To describe morbidity profile, treatment preferences and OOP expenditure toward health care of under five children in an urban primary health center of Puducherry. MATERIALS AND METHODS: A cross sectional study was conducted in four Anganwadi centers selected randomly from a total of 13 centers in the urban service area of JIPMER, Puducherry. All mothers of under five children from selected centers were interviewed regarding sociodemographic details, treatment preferences, and expenditure incurred on illness of under five children by the family for a period of 15 days and 3 months (exclusive of past 15 days) preceding the day of interview. RESULTS: Among the 164 children studied, 23.8% and 30% reported illnesses in the past 15 days and 3 months, respectively. Most frequent illness reported was respiratory infections. Private facilities (60%) were the preferred sources for seeking health care. Median OOP expenditure in last 15 days was Rs. 375 and Rs. 450 for the past 3 months, amounting to 8% and 6.8% of the total family income, respectively. The majority of the health care expenditure was toward drugs (71%). No money was spent toward healthcare in government facilities. CONCLUSION: Almost all OOP health care expenditure was incurred when the illnesses were managed by private providers. Hence, strategies can be planned to include private providers under UHC. PMID- 26604604 TI - Hybrid approach to fabrication of hollow internally weighted mandibular denture: A case report. AB - Preservation of ridge dimensions is critical for denture success. For long the concept of an internally weighted denture, which suggested that gravity and the additional weight to the mandibular complete denture aids in prosthetic retention is widely accepted. However, excessive weight and pressure can accelerate bone resorption. Here, we describe a unique modification of internally weighted metal denture base for the resorbed mandibular ridge with an incorporated additional hollow section over the anterior knife-edge ridge. The weight provided retention and stability while the hollow portion prevented further resorption of the bone. PMID- 26604605 TI - Influence of female sex hormones on periodontium: A case series. AB - Dental plaque is the primary etiologic factor for the periodontal diseases. Although pathogenic bacteria in dental plaque are necessary for the incidence of periodontal disease, but a susceptible host is as important. The susceptibility of the host can be modified by various systemic factors with hormones level being one. The periodontium shows an exaggerated inflammatory response to plaque modified by female sex hormone during puberty, pregnancy, in women taking oral contraceptives and at the postmenopausal stage. This paper presents such few cases where periodontium is influenced by variation in sex steroid hormones of female during different phases of their life time and to discuss how much a same hormone at different age and stage shows an exaggerated gingival response to plaque. PMID- 26604606 TI - Sigmoid carcinoma localized in the sac of a right inguinoscrotal hernia. AB - The inguinoscrotal hernia with colonic malignancy in the sac presents rare but severe consequence. The most common side of this type of hernia is the left one while the most common part of the large bowel is the sigmoid colon. The clinical picture can be easily confused with simple inguinoscrotal hernia unless the clinician is alert to the presence of certain sinister symptoms and signs. We report an extremely rare case of a 91-year-old man presented with anemia who had a right inguinoscrotal hernia containing a sigmoid colon carcinoma. PMID- 26604607 TI - Asymptomatic extraperitoneal inguinoscrotal hernia involving ureter: A case presentation and review of the literature. AB - An inguinoscrotal hernia is a common disorder that usually contains intraperitoneal organs (small intestine, colon, appendix, ovaries). Extraperitoneal ureteral herniation into an inguinoscrotal hernia is a rare condition and often associated with congenital abnormalities or postoperative anatomic changes. A high index of suspicion is needed in order to avoid intraoperative ureteric injuries. We herein report the case of a ureteric herniation into an inguinoscrotal hernia incidentally found during a scheduled hernia repair. PMID- 26604608 TI - Preservative management of traumatized maxillary central incisor using fiber reinforced composite and mineral trioxide aggregate: Report of a case. AB - The myriads of technological advancements in dentistry in last two decades have led to a dramatic shift from conventional invasive procedures to more conservative biomimetic therapies. In this series, management of traumatic dental injuries has taken a big leap in that now it is possible to conserve many of these teeth which were otherwise doomed to extraction. Depending on the extent of injury, esthetic and functional requirements, traumatic dental injuries can be managed by a variety of clinical procedures including composite resin restorations, reattachment of fractured fragment, endodontic therapy with or without post and core or lastly extraction. Reattaching natural tooth structure offers an advantage over the others in that it is instant, provides superior esthetics, preserves the natural tooth structure and is best accepted by the patient. This paper describes the comprehensive management of traumatized maxillary central incisor involving pulp exposure while maintaining pulp vitality and natural appearance of a tooth. PMID- 26604609 TI - A report of nonunion at medial wedge high tibial osteotomy site and its management. AB - High tibial osteotomy (HTO) is an accepted treatment option for correcting deformities and reducing pain in the treatment of uni-compartment osteoarthritis of the knee. The principle is to redistribute the weight-bearing load. Medial open wedge HTO (MOWHTO) has gained popularity over lateral closed wedge osteotomy due to its decreased incidence of complications. MOWHTO surgical techniques have many variations in fixation techniques and in the use of bone grafts or bone substitute augmentation. In spite of the existing guidelines, there are no clear indications of grafting at the osteotomy site. Delayed union and nonunion although are possible complications, nonunion is especially rarely reported. Thus authors in this case report, like to point attention towards this under-reported complication and its management. PMID- 26604610 TI - Incidental finding of two rare developmental anomalies: Fusion and dilaceration: A case report and literature review. AB - A number of developmental anomalies of morphology are there. However, as compared to the more common oral diseases like caries or periodontal problems, they account for a relatively lower number. When present, they may pose various problems of esthetic, function, malocclusion, or possible disposition to other oral problems. Hence, though rare, their timely diagnosis is very vital in proper treatment planning to avoid unseen complications during extractions, endodontic or orthodontic treatment. The present case is of a patient reporting with two very rare developmental anomalies, that is, fusion and root dilaceration, in contralateral sides of the same patient. To the knowledge of the author, reportedly it is the first such case. The terminologies, etiology, and epidemiology of both these anomalies are also discussed. PMID- 26604611 TI - Erupted complex odontoma of the posterior maxilla: A rarity. AB - Complex odontomas, hamartomas of aborted tooth development, mainly occur in posterior part of the mandible and rarely erupt into the oral cavity. The spontaneous eruption may be associated with pain, inflammation of adjacent soft tissues or recurrent infection. The present case of complex odontoma is of particular interest due to its apparent eruption in the maxillary posterior segment, its association with agenesis of the second molar and impacted third molar; with the lesion being completely asymptomatic. PMID- 26604612 TI - Comparison of the effect of aspirin and heparin with or without intravenous immunoglobulin in treatment of recurrent abortion with unknown etiology: A clinical study. AB - INTRODUCTION AND OBJECTIVE: Abortion is the most common complication of pregnancy, defined as spontaneous expulsion of products of conception before 24 weeks of pregnancy or termination of pregnancy with a fetus weighing <500 g. The aim of this study was to compare the efficacy of intravenous immunoglobulin (IVIG) in combination regimens with aspirin and heparin versus aspirin and heparin combination alone in women with idiopathic recurrent abortion. MATERIALS AND METHODS: This randomized, clinical trial was performed at Imam Khomeini Hospital in Sari-Iran between March 2010 and March 2013. Sixty people were randomly allocated into two groups. The control group was treated by subcutaneous enoxaparin 40 mg daily up to 24 weeks associated with aspirin 80 mg daily up to 37 weeks of gestation. The intervention group received IVIG 200 mg/kg monthly up to 24 weeks of gestation with enoxaparin and aspirin for the same therapeutic period and the same dose as the control group. RESULTS: Three patients (10%) in the intervention group had abortion and 25 (90%) had live births with mean birth weight 3.5 +/- 0.9 kg. Four patients (13%) in the control group had abortions, and 28 (87%) had live births with birth weight 3.4 +/- 1.2 kg (P = 0.74). The difference was not statistically significant. CONCLUSIONS: It seems that employing the heparin and aspirin combination therapeutic regimen is appropriate for idiopathic abortions and avoids the high cost of IVIG use and its complications. PMID- 26604613 TI - A cytomorphometric analysis of oral mucosal changes in tobacco users. AB - AIM: Tobacco use is the major cause of oral cancer, which is the sixth most common form of malignancy globally. Even in the absence of clinical manifestations, early changes in the oral mucosa can be detected microscopically by exfoliative cytology. The present study aimed to study and compare the cellular changes in the oral mucosa of tobacco users using cytomorphometry. MATERIALS AND METHODS: A total of 80 subjects were included: 20 without any tobacco use habits, 20 tobacco chewers, 20 smokers, and 20 mishri users. Smears were collected from each subject, fixed, and stained using Papanicolaou stain. All slides were evaluated for nuclear and cytoplasmic changes using image analysis software. RESULTS: Statistically significant decrease in cytoplasmic area and an increase in nuclear area and nuclear-cytoplasmic ratio were observed in tobacco users. CONCLUSION: Tobacco in any form causes significant cellular changes, which could be the earliest indicators of developing malignant pathology. Exfoliative cytology can be used to detect such changes. PMID- 26604614 TI - Outbreak of gastroenteritis among medical students, Madhya Pradesh, Central India. AB - INTRODUCTION: Although diarrheal diseases with known etiologies are under regular surveillance by the integrated disease surveillance project in India, only limited food-borne outbreaks were subjected to systematic epidemiological investigation. We examined one incidence of a food-borne outbreak among medical students in Bhopal, India, to identifying the source and mode of transmission, and to implement appropriate preventive measures. MATERIALS AND METHODS: We constituted two teams. We did the line listing, filled the structured questionnaire and collected the biological samples. We did in-depth interviews of the case patients. We interviewed food handlers in mess. We randomly collected food and water samples. RESULTS: The study results identified 30 hosteller case patients for a total of 239 students (overall attack rate [AR]: 12.6%). In female students, the AR was 18.1% and in the male students it was 6.7%. The AR was highest in female hostel no. One compared to other female and male hostel (19.8% vs. 14.3%, 6.7%). We identified four different risk factors for the illness. DISCUSSION: As AR s are high compared to the general population. As the AR was high among the girls, the probable source of infection resides in the female hostel. PMID- 26604615 TI - Prevalence of reproductive tract infections and their determinants in married women residing in an urban slum of North-East Delhi, India. AB - BACKGROUND: Reproductive tract infections (RTIs) have adverse implications on the health of the women. Community-based studies in India have shown a high prevalence of RTIs but here is a lack of sizeable literature from urban slums and resettlement areas. AIMS AND OBJECTIVES: The objective was to document the prevalence and determinants of RTIs in married women (15-49 years) residing in an urban slum in Delhi, India. MATERIALS AND METHODS: The study was conducted in an urban resettlement colony of Gokulpuri in the North-East district of Delhi. Systematic random sampling method was adopted to choose the study subjects, that is, married and non-pregnant women in the reproductive age group (15-49 years) residing in the study area. Data were collected using a pretested semi-structured questionnaire, through the house to house visits. The diagnosis of RTIs was made as per the World Health Organization syndromic approach. Data were analyzed in SPSS version 16 (Chicago, IL, USA). RESULTS: A total of 802 women were interviewed. The mean age of study subjects was 30.79 +/- 7 years. A total of 352 (43.9%) women currently had symptoms of RTIs. The most frequently reported symptoms included abdominal pain (68.2%), back pain (69.6%), and vaginal discharge (59.3%). Older women (>=25 years) (odds ratio [OR] 2.2, 95% confidence interval [CI]; 1.4-3.5), those belonging to the lower socioeconomic status (OR 2.1, 95% CI; 1.5-2.9), those using cloth during menses (OR 2.6, 95% CI; 1.6-4.3), those having more than three pregnancies (OR 1.8, 95% CI; 1.2-2.6) and those using an intrauterine contraceptive device (OR 11.8, 95% CI; 4.3-32.0) had higher odds of having RTIs. CONCLUSIONS: A high case load was found based on the syndromic approach. Generating community awareness, ensuring proper menstrual hygiene, and improving the socioeconomic status would help in reducing the cases of RTI. PMID- 26604616 TI - Pleomorphism of argyrophilic nucleolar organizer regions in oral submucous fibrosis and oral squamous cell carcinoma. AB - BACKGROUND: Argyrophilic nucleolar organizer regions (AgNORs) is demonstrated to be useful in diagnostic pathology, mainly to distinguish benign lesions from their malignant counterparts. We aimed to correlate AgNORs pleomorphism with the severity of lesion in oral submucous fibrosis (OSMF) and oral squamous cell carcinoma (OSCC) using a retrospective study on 45 archival tissues. MATERIALS AND METHODS: Silver nitrate staining was performed on archival tissues consisting of 20 OSMF and 20 OSCC. Five biopsies from normal oral mucosa acted as a control. One hundred cells per slide were observed for AgNORs dots, which were classified as typical (spherical) and atypical (large, kidney-shaped and clustered). RESULTS: A positive and significant correlation was found between increased atypical shapes and increasing grades of OSMF and OSCC. CONCLUSIONS: AgNORs pleomorphism can be a reliable criterion to assess disease severity and progression in OSMF and OSCC. PMID- 26604617 TI - Study of molecular complexation of glycyrrhizic acid with chloramphenicol by electrospray ionization mass spectrometry. AB - CONTEXT: Glycyrrhizic acid (GA) is a triterpene glycoside representing the main active component of licorice root extract obtained from plants of the Glycyrrhiza glabra L. and widely used as a complex-forming agent for the synthesis of new transport forms of the well-known drugs. AIMS: For the first time, the complexation of GA with chloramphenicol antibiotic (ChlA) was investigated by electrospray ionization mass spectrometry (ESI MS). SUBJECTS AND METHODS: ESI MS was utilized in order to determine the composition and evaluate the stability of complexes of the GA and ChlA. The validation of the complex formation was confirmed by ultraviolet/visible and infrared (IR) spectroscopy. RESULTS: MS data confirmed the noncovalent interactions between chloramphenicol and GA. Formation of the host: guest complexes of GA and chloramphenicol with the ratio 1:1 and 2:1 were registered in the negative ion mode. Binding of GA and ChlA was accompanied by changes in absorbance and IR spectrum of ChlA indicating the complex formation of these compounds. CONCLUSIONS: The research results confirmed the considerable potential of ESI MS as a technique for simple and fast detection of formation of the complexes of GA and the well-known drugs. PMID- 26604618 TI - Assessment of microbial contamination on twice a day used toothbrush head after 1 month and 3 months: An in vitro study. AB - PURPOSE: The purpose of vitro study was to assessment of the bacterial contamination on daily twice-used toothbrushes in different conditions after 1 month and 3 months. MATERIALS AND METHODS: Forty children aged between 6 and 12 years were selected for this study. Toothbrushes and toothpaste were distributed among those children. Among those children, 20 children brushed their teeth for 1 month and 20 brushed their teeth for 3 months twice a day. Among those, 10 were kept in same brush box with a family member and 10 were kept in separate brush box after the use. Toothbrush from every child was recollected to investigate the contamination of microorganisms. Head of the toothbrushes transferred to a tube containing 10 ml of tryptone soy broth. This was followed by vortex mixing for 1 min to dislodge suspected adherent bacteria. The bacterial suspension was serially diluted to obtain dilution factors of up to 10(-3). 1 ml each of the dilution factors was obtained using a sterile pipette and plated on plate count agar. Petri dishes containing agar media were incubated and examined using a compound microscope. RESULTS: There was high mean difference between 1-month and 3 months, twice a day used toothbrush those kept with family members and those kept separate. CONCLUSIONS: Toothbrush should keep in a separate box. Moreover, toothbrush should to be change after 3-4 weeks. PMID- 26604619 TI - A prospective study evaluating utility of Mannheim peritonitis index in predicting prognosis of perforation peritonitis. AB - AIMS: We aimed to validate Mannheim peritonitis index (MPI) for prediction of outcome in patients with perforation peritonitis. MATERIALS AND METHODS: A prospective study involving 100 subjects operated for perforation peritonitis over the period of 2 years was designed. Postevaluation of predesigned performa, MPI score was calculated and analyzed for each patient with death being the main outcome measure. The MPI scores were divided into three categories; scores <15 (category 1), 16-25 (category 2), and >25 (category 3). RESULTS: Our study consisted of 82 males and 18 females (male:female ratio 4.56:1), with the mean patients age of 37.96 +/- 17.49 years. 47, 26, and 27 cases belonged to MPI score categories 1, 2, and 3, respectively. The most common origin of sepsis was ileal with small intestine dominating the source of perforation. When the individual parameters of MPI score were assessed against the mortality only, age >50 years (P = 0.015), organ failure (P = 0.0001), noncolonic origin of sepsis (P = 0.002), and generalized peritonitis (P = 0.0001) significantly associated with mortality. The sensitivity of MPI was 92% with a specificity of 78% in receiver operating characteristic curves. CONCLUSION: MPI is an effective tool for prediction of mortality in cases of perforation peritonitis. PMID- 26604620 TI - Comparative clinical efficacy evaluation of three gingival displacement systems. AB - AIM: We compared the clinical efficacy of three gingival displacement systems to accurately record intra-crevicular margins of tooth preparation. MATERIALS AND METHODS: One mechanical (magic foam cord) and two chemico-mechanical (expasyl paste and retraction cord impregnated with 15% aluminum chloride) gingival displacement systems were used. This study was conducted on the maxillary central incisors of 20 patients (20-60 years old) requiring full coverage restoration. All the three gingival displacement systems were tested in three sessions at an interval of 14 days in same order. The casts were sectioned and viewed under an optical microscope, followed by quantitative measurements of the width of the pre and postretracted sulci. RESULTS: All the three displacement systems produced highly significant horizontal gingival displacement. Retraction cord soaked in 15% aluminum chloride produced maximum displacement (0.74 mm), followed by expasyl paste (0.48 mm) whereas magic foam cord produced the least displacement (0.41 mm). CONCLUSIONS: Gingival displacement shown by each displacement system was found to be more than the accepted value necessary for elastomeric impression accuracy (0.2 mm) to record intra-crevicular margins of tooth preparation. PMID- 26604621 TI - Does audit improve diabetes care in a primary care setting? A management tool to address health system gaps. AB - INTRODUCTION: Diabetes mellitus is one of the emerging epidemics. Regular clinical and biochemical monitoring of patients, adherence to treatment and counseling are cornerstones for prevention of complications. Clinical audits as a process of improving quality of patient care and outcomes by reviewing care against specific criteria and then reviewing the change can help in optimizing care. OBJECTIVE: We aimed to audit the process of diabetes care using patient records and also to assess the effect of audit on process of care indicators among patients availing diabetes care from a rural health and training center in Puducherry, South India. MATERIALS AND METHODS: A record based study was conducted to audit diabetes care among patients attending noncommunicable disease clinic in a rural health center of South India. Monitoring of blood pressure (BP), blood glucose, lipid profile and renal function test were considered for auditing in accordance with standard guidelines. Clinical audit cycle (CAC), a simple management tool was applied and re-audit was done after 1-year. RESULTS: We reviewed 156 and 180 patients records during year-1 and year-2, respectively. In the audit year-1, out of 156 patients, 78 (50%), 70 (44.9%), 49 (31.4%) and 19 (12.2%) had got their BP, blood glucose, lipid profile and renal function tests done. Monitoring of blood glucose, BP, lipid profile and renal function improved significantly by 35%, 20.7%, 36.4% and 56.1% over 1-year. CONCLUSION: CAC improves process of diabetes care in a primary care setting with existing resources. PMID- 26604622 TI - Predebridement wound culture in open fractures does not predict postoperative wound infection: A pilot study. AB - BACKGROUND: There is confusion in the current literature regarding the value of obtaining predebridement wound cultures in the management of open fractures with several studies reporting contrasting results. We undertook a pilot study to determine the initial bacterial flora of open fractures in our environment and determine the correlation between subsequent wound infection if any, and the initial bacterial flora. MATERIALS AND METHODS: Initial/predebridement wound swabs were obtained for 32 patients with open fractures. Patients underwent a debridement of the open wound and preliminary stabilization of fracture in the operating room within 24 h. Postdebridement wound cultures were obtained at 48 h and repeated subsequently, if indicated, during the follow-up period. The antibiotic therapy was modified based on the culture reports. RESULTS: Initial wound swab culture showed bacterial contamination in 18 patients (56%); 14 patients (44%) developed an infection in the immediate postoperative period or during follow-up. Age, gender, co-morbid medical condition, delay in presentation, and grade of open fracture were not found to be predictors of postoperative infection. No patient had an infection with the same organism, which was present in the initial culture. CONCLUSION: The findings of this study suggest that the initial flora are not the infecting organisms in the open fracture wounds, and predebridement wound cultures have no value in predicting postdebridement wound infection. PMID- 26604623 TI - Water and sanitation hygiene knowledge, attitude, and practices among household members living in rural setting of India. AB - BACKGROUND: Rural population in developing countries face water, sanitation, and hygiene-related health issues. To objectively highlight these issues, we studied the knowledge, attitude, and practices-related to drinking water and sanitation facilities among the rural population of Chennai, India. MATERIALS AND METHODS: A cross-sectional study was designed involving individuals over 18 years of age living in Thandalam village, Chennai, India. Basic information about sociodemographic profile and existing drinking water and sanitation related knowledge, attitude, and practices was collected using a modified version of previously validated questionnaire and analyzed. RESULTS: Forty-five percent of the participants were not following any methods of water treatment and among them half of the participants felt that water available to them was clean and did not require any additional treatment. Twenty-five percent of the participants surveyed did not have access to toilets inside their household. CONCLUSION: There is a need for intervention to educate individuals about drinking water treatment methods, sanitation, and hand washing practices. PMID- 26604624 TI - Comparative analysis of detecting cervical lymph node metastasis with fine needle aspiration cytology. AB - OBJECTIVES: We correlated the results of cervical lymph node (LN) status by T tumor size, N-nodal metastasis, M-distant metastasis (TNM) staging, and fine needle aspiration cytology (FNAC) in oral cancer patients to assess the discrepancy index (DI) between nodal metastasis (N) and FNAC results of cervicofacial LNs. MATERIALS AND METHODS: A total of 63 patients (29 females and 34 males) aged from 30 to 85 years were included in our study. Cervical LN status through TNM staging and FNAC results were matched and DI was calculated. RESULTS: DI in case of nodal status was 64.10% and 43.47% for TNMN1 and N2, respectively, indicating that tendency for observation of positive result on FNAC increased from N1 to N2. CONCLUSION: Hence, we suggest that relying solely on clinical examination and routine diagnostic tests like FNAC may not be appropriate and additional diagnostic imaging modalities should be considered. PMID- 26604625 TI - Relation between glycosylated hemoglobin and lipid and thyroid hormone among patients with type 2 diabetes mellitus at King Abdulaziz Medical City, Riyadh. AB - BACKGROUND: The main objectives of this study were to: (1) Evaluate the levels of thyroid hormones and glycosylated hemoglobin (HbA1c) among patients, (2) correlate between thyroid hormones and HbA1c and different types of lipids and HbA1c among diabetic patients. MATERIALS AND METHODS: A retrospective chart review study was conducted at Department of Clinical Chemistry, King Abdulaziz Medical City (KAMC) in Riyadh, Saudi Arabia, during the period from August 2014 to December 2014, including 100 male and female patients diagnosed with diabetes mellitus (DM) type 2 and excluding patients with DM type 1. These patients were admitted to the hospital in 2013. Biochemical laboratory results were retrieved from biochemistry laboratory database while age and sex of patients were retrieved from patient files. Statistical analysis was performed using SPSS software conducting frequency analysis and correlation test. RESULTS: The result showed increased mean levels of HbA1c (8.4%) and normal level of thyroid stimulating hormone (TSH) (4.5 mlU/L) and T4 (14.1 pmol/L). The results also showed a weak positive correlation between HbA1c and TSH (r = 0.212, P = 0.034) and insignificant correlation with thyroxin T4 (r = -0.018, P = 0.855). There was a weak positive correlation between HbA1c and total cholesterol and low density lipoprotein (r = 0.258, P = 0.001), (r = 0.297, P = 0.003), respectively. CONCLUSION: It is concluded that increased blood glucose could trigger anterior pituitary gland to increase secretion of TSH, whereas there was no direct correlation between increased glycemic index and the rate of thyroxine secretion. Furthermore, it is concluded that there is an association between blood glucose and some lipid markers. PMID- 26604626 TI - Determination of the serum levels of troponin I and creatinine among Sudanese type 2 diabetes mellitus patients. AB - BACKGROUND: Diabetes mellitus (DM) is a significant risk factor for developing cardiac diseases. Hence, we compare the serum levels of cardiac troponin I (CTnI) among type 2 diabetic and healthy patients. We additionally correlated CTnI and creatinine levels with duration of disease. MATERIALS AND METHODS: A cross sectional study was conducted at Department of Clinical Chemistry, Sudan University of Sciences and Technology, Khartoum, Sudan, from February 2008 to February 2011. 200 patients diagnosed with DM type 2 from Jabir Abulizz Diabetes Centre in Khartoum state, Sudan, and 100 healthy volunteers were included in this study. Blood samples were collected from both groups, and the serum levels of CTnI, creatinine, fasting plasma glucose and glycosylated hemoglobin (HbA1c) levels were measured. RESULTS: Significant increase in serum levels of CTnI, glucose, HbA1c, and creatinine was observed in diabetic patients compared to healthy controls. In addition, the significant increase in CTnI and creatinine levels was observed among diabetic patients with ischemic heart disease or hypertension when compared with those without ischemic heart disease or hypertension. Further a strong positive correlation was observed between the duration of diabetes and the serum levels of CTnI and creatinine (r = 0.84, P > 0.01) and (r = 0.72, P > 0.01), respectively. CONCLUSION: The higher levels of CTnI and creatinine may be indicative of progressive cardiovascular disease and nephropathy among diabetic patients. PMID- 26604627 TI - Frequency distribution of sickle cell anemia, sickle cell trait and sickle/beta thalassemia among anemic patients in Saudi Arabia. AB - BACKGROUND: Notwithstanding, the growing incidence of sickle cell hemoglobinopathies (SCH) such as sickle cell anemia (SCA) or sickle cell disease, sickle/beta-thalassemia; the exact prevalence remains obscure in Saudi Arabia. Hence, this study is an attempt to determine the frequency of SCA and sickle cell trait (SCT) among all anemic patients with SCH treated at the King Abdul-Aziz Medical City (KAMC), Riyadh, Saudi Arabia. Furthermore, the hemoglobin (Hb) S and other Hb patterns (Hb AS and Hb F) were also estimated in SCA and SCT patients. MATERIALS AND METHODS: Results of Hb capillary electrophoresis performed on all patients with SCH from January 2011 to December 2013 were evaluated retrospectively. RESULTS: Of a total of 3332 patient data analyzed, 307 were anemic patients (58% males and 42% females) with SCH. The sickling test showed all the patients to be positive. Hb electrophoresis revealed the incidence of 96.7%, 3.3%, and 0% of the patients suffered from SCA, SCT and sickle/beta thalassemia, respectively. Patients with SCA had a higher level of Hb F and showed no crisis when compared with other SCA patients who had lower or no Hb F levels. CONCLUSION: SCA is relatively frequent among males (56.4%) than females out of all patients with SCH. The SCA incidence was more common (48.5%) among children, frequency of SCT among adult age group was 1.6%, while sickle/beta thalassemia was 0%. PMID- 26604628 TI - Assessment of microalbuminuria and albumin creatinine ratio in patients with type 2 diabetes mellitus. AB - AIM: We aimed to evaluate the levels of urine microalbumin, urine albumin creatinine ratio, plasma creatinine and glycosylated hemoglobin (HbA1c) among type 2 diabetic patients and assessed the correlation between microalbuminuria and plasma creatinine levels. MATERIALS AND METHODS: A retrospective chart review study was conducted at Department of Clinical Chemistry, King Abdulaziz Medical City in Riyadh, Saudi Arabia, during August to December 2014. The study included 100 male and female patients diagnosed with type 2 diabetes mellitus (DM) and excluding patients with type 1 DM. Medical history and biochemical laboratory data were obtained from medical records and from biochemistry laboratory database. RESULTS: Increase in mean level of plasma creatinine (138 MUmol/L), urine microalbuminuria (240 mg/L), albumin creatinine ratio (82) and HbA1c (8.7%) was observed among type 2 DM patients. Moderate positive correlation was observed between microalbuminuria and urine albumin creatinine ratio (r = 0.509 P = 0.0006) and between urine albumin creatinine ratio and plasma creatinine (r = 0.553 P = 0.017). CONCLUSION: We concluded that type 2 DM patients who are at risk of developing renal impairment must be regularly monitored for microalbuminuria, urine albumin creatinine ratio, and HbA1c levels. PMID- 26604629 TI - Periodontal status and oral health behavior in hospitalized patients with chronic obstructive pulmonary disease. AB - AIM: We evaluated the periodontal health status and oral health behavior among hospitalized patients with chronic obstructive pulmonary disease (COPD) to assess the association of COPD with dental health. MATERIALS AND METHODS: A group of 100 hospitalized patients with COPD and a group of 100 age, sex, and race-matched control patients were included in this study. Detailed case histories along with standardized measures of oral health including gingival index, plaque index (PI), and simplified oral hygiene index (OHI) were estimated and compared. Probing depths and clinical attachment levels (CALs) were recorded at four sites per tooth. C-reactive protein (CRP) levels in saliva and serum were also measured. RESULTS: The study subjects had similar demographics and distribution in either group. Patients with COPD had significantly lower brushing frequency, poor periodontal health (OHI and PI), greater gingival inflammation, and deeper pockets/CALs compared to controls. Further COPD patients had significantly higher serum and salivary CRP levels compared to control groups. CONCLUSIONS: Lower brushing frequency, poor oral health, and presence of destructive periodontal disease were observed among patients with COPD, which warrants promoting dental care and oral health knowledge as an integrated approach to treating COPD patients. PMID- 26604630 TI - Acetylcholinesterase activity as a neurotoxicity marker within the context of experimentally-simulated hyperprolinaemia: An in vitro approach. AB - Hyperprolinaemia is characterized by increased tissue accumulation of proline (Pro) and is known to exert serious cognitive and/or neuropsychiatric symptomatology as a direct result of Pro accumulation in the brain. The aim of this study was to explore a putative link between experimentally-simulated hyperprolinaemia and the activity of acetylcholinesterase (AChE); a crucial neurotoxicity marker. In vitro experiments were undertaken on purified eel derived AChE, as well as on adult mouse brain homogenates, in order to examine the effect of a spectrum of Pro concentrations (3, 30, 500, and 1000 MUM) on this marker. Our data showed that although Pro exerted a significant inhibitory effect on pure AChE activity, mouse brain-derived membrane-bound AChE activity was found either unaltered or significantly increased following incubation with Pro. The use of AChE activity as a neurotoxicity marker within the context of experimentally-simulated hyperprolinaemia should be considered with caution and in parallel with a number of other experimental parameters. PMID- 26604631 TI - Gallbladder carcinoma: Prognostic factors and therapeutic options. AB - The outcome of gallbladder carcinoma is poor, and the overall 5-year survival rate is less than 5%. In early-stage disease, a 5-year survival rate up to 75% can be achieved if stage-adjusted therapy is performed. There is wide geographic variability in the frequency of gallbladder carcinoma, which can only be explained by an interaction between genetic factors and their alteration. Gallstones and chronic cholecystitis are important risk factors in the formation of gallbladder malignancies. Factors such as chronic bacterial infection, primary sclerosing cholangitis, an anomalous junction of the pancreaticobiliary duct, and several types of gallbladder polyps are associated with a higher risk of gallbladder cancer. There is also an interesting correlation between risk factors and the histological type of cancer. However, despite theoretical risk factors, only a third of gallbladder carcinomas are recognized preoperatively. In most patients, the tumor is diagnosed by the pathologist after a routine cholecystectomy for a benign disease and is termed ''incidental or occult gallbladder carcinoma'' (IGBC). A cholecystectomy is performed frequently due to the minimal invasiveness of the laparoscopic technique. Therefore, the postoperative diagnosis of potentially curable early-stage disease is more frequent. A second radical re-resection to complete a radical cholecystectomy is required for several IGBCs. However, the literature and guidelines used in different countries differ regarding the radicality or T-stage criteria for performing a radical cholecystectomy. The NCCN guidelines and data from the German registry (GR), which records the largest number of incidental gallbladder carcinomas in Europe, indicate that carcinomas infiltrating the muscularis propria or beyond require radical surgery. According to GR data and current literature, a wedge resection with a combined dissection of the lymph nodes of the hepatoduodenal ligament is adequate for T1b and T2 carcinomas. The reason for a radical cholecystectomy after simple CE in a formally R0 situation is either occult invasion or hepatic spread with unknown lymphogenic dissemination. Unfortunately, there are diverse interpretations and practices regarding stage adjusted therapy for gallbladder carcinoma. The current data suggest that more radical therapy is warranted. PMID- 26604632 TI - Stage migration vs immunology: The lymph node count story in colon cancer. AB - Lymph node staging is of crucial importance for the therapy stratification and prognosis estimation in colon cancer. Beside the detection of metastases, the number of harvested lymph nodes itself has prognostic relevance in stage II/III cancers. A stage migration effect caused by missed lymph node metastases has been postulated as most likely explanation for that. In order to avoid false negative node staging reporting of at least 12 lymph nodes is recommended. However, this threshold is met only in a minority of cases in daily practice. Due to quality initiatives the situation has improved in the past. This, however, had no influence on staging in several studies. While the numbers of evaluated lymph nodes increased continuously during the last decades the rate of node positive cases remained relatively constant. This fact together with other indications raised doubts that understaging is indeed the correct explanation for the prognostic impact of lymph node harvest. Several authors assume that immune response could play a major role in this context influencing both the lymph node detectability and the tumor's behavior. Further studies addressing this issue are need. Based on the findings the recommendations concerning minimal lymph node numbers and adjuvant chemotherapy should be reconsidered. PMID- 26604634 TI - Recent aspects for disseminated carcinomatosis of the bone marrow associated with gastric cancer: What has been done for the past, and what will be needed in future? AB - Disseminated carcinomatosis of the bone marrow is characterized by widespread bone metastasis (bone marrow infiltration) from solid tumors with hematological disorders coexisted. This disease is frequently complicated with gastric cancer among solid tumors although its incidence is very rare. In recent years, technological innovations in diagnosis and treatment for cancer have remarkably improved, which made survival rates of various cancers prolonged. Prognosis of disseminated carcinomatosis of the bone marrow associated with gastric cancer, however, is still poor (less than a year), possibly because this disease has not been given attention due to low incidence. In this review, I summarize the results obtained for the past, and propose ways to improve the prognosis of this disease. PMID- 26604633 TI - Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer. AB - Irinotecan hydrochloride is a camptothecin derivative that exerts antitumor activity against a variety of tumors. SN-38 produced in the body by carboxylesterase is the active metabolite of irinotecan. After irinotecan was introduced for the treatment of metastatic colorectal cancer (CRC) at the end of the last century, survival has improved dramatically. Irinotecan is now combined with 5-fluorouracil, oxaliplatin and several molecularly-targeted anticancer drugs, resulting in the extension of overall survival to longer than 30 mo. Severe, occasionally life-threatening toxicity occurs sporadically, even in patients in relatively good condition who have a low risk of chemotherapy-induced toxicity, often causing the failure of irinotecan-based chemotherapy. Clinical pharmacological studies have revealed that such severe toxicity is related to exposure to SN-38 and genetic polymorphisms in UDP-glucuronosyltransferase 1A1 gene. The large inter- and intra-patient variability in systemic exposure to SN 38 is determined not only by genetic factors but also by physiological and environmental factors. This review first summarizes the roles of irinotecan in chemotherapy for metastatic CRC and then discusses the optimal dosing of irinotecan based on the aforementioned factors affecting systemic exposure to SN 38, with the ultimate goal of achieving personalized irinotecan-based chemotherapy. PMID- 26604635 TI - Targeting the PI3K/Akt signaling pathway in gastric carcinoma: A reality for personalized medicine? AB - Frequent activation of phosphatidylinositol-3 kinases (PI3K)/Akt/mTOR signaling pathway in gastric cancer (GC) is gaining immense popularity with identification of mutations and/or amplifications of PIK3CA gene or loss of function of PTEN, a tumor suppressor protein, to name a few; both playing a crucial role in regulating this pathway. These aberrations result in dysregulation of this pathway eventually leading to gastric oncogenesis, hence, there is a need for targeted therapy for more effective anticancer treatment. Several inhibitors are currently in either preclinical or clinical stages for treatment of solid tumors like GC. With so many inhibitors under development, further studies on predictive biomarkers are needed to measure the specificity of any therapeutic intervention. Herein, we review the common dysregulation of PI3K/Akt/mTOR pathway in GC and the various types of single or dual pathway inhibitors under development that might have a superior role in GC treatment. We also summarize the recent developments in identification of predictive biomarkers and propose use of predictive biomarkers to facilitate more personalized cancer therapy with effective PI3K/Akt/mTOR pathway inhibition. PMID- 26604636 TI - MicroRNA in inflammatory bowel disease: Translational research and clinical implication. AB - Idiopathic inflammatory bowel disease (IBD) predominantly includes ulcerative colitis and Crohn's disease. The pathogenesis of IBD is complex and not completely understood. MicroRNAs belong to a class of noncoding small RNAs that post-transcriptionally regulate gene expression. Unique microRNA expression profiles have been explored in IBD. In this review, we focus on the unique microRNA expression pattern in both tissue and peripheral blood from IBD patients and emphasize the potential diagnostic and therapeutic applications. The discovery of microRNAs has contributed to our understanding of IBD pathogenesis and might lead to clinical advance in new therapeutics. PMID- 26604637 TI - Th17 plasticity and its changes associated with inflammatory bowel disease. AB - CD4 T helper (Th) cell differentiation into distinct T cell subsets is critical to the normal function of the immune system. Until recently, the paradigm held that naive T cells differentiated into distinct subsets under the guidance of environmental cues (e.g., cytokines) and that once polarized, these cells were committed to a particular functional state. However, the existence of transdifferentiated T cell populations, which express signature transcription factors and cytokines associated with more than one Th subset, challenges the immutability of T helper subsets and suggests that plasticity is a feature of multifaceted immune responses. How this process impacts immune dysregulation in diseases such as inflammatory bowel diseases (IBD) and the machinery that underlies this process is far from fully understood. Interleukin (IL)-17 secreting helper T (Th17) cells have been heavily implicated in tissue-specific immune pathology including murine models of IBD, human Crohn's disease and ulcerative colitis. Plasticity within this subset is suggested by the existence of IL-17 secreting cells, which, can also secrete interferon-gamma, the signature cytokine for Th1 cells or, can co-express the anti-inflammatory transcription factor forkhead box p3, a signature transcription factor of regulatory T cells. In this review we mainly discuss evidence for Th17 plasticity, mechanisms, which govern it, and highlight the potential to therapeutically target this process in human IBD. PMID- 26604638 TI - Genetics of inflammatory bowel disease from multifactorial to monogenic forms. AB - Inflammatory bowel disease (IBD) is a group of chronic multifactorial disorders. According to a recent study, the number of IBD association loci is increased to 201, of which 37 and 27 loci contribute specifically to the development of Crohn's disease and ulcerative colitis respectively. Some IBD associated genes are involved in innate immunity, in the autophagy and in the inflammatory response such as NOD2, ATG16L1 and IL23R, while other are implicated in immune mediated disease (STAT3) and in susceptibility to mycobacterium infection (IL12B). In case of early onset of IBD (VEO-IBD) within the 6(th) year of age, the disease may be caused by mutations in genes responsible for severe monogenic disorders such as the primary immunodeficiency diseases. In this review we discuss how these monogenic disorders through different immune mechanisms can similarly be responsible of VEO-IBD phenotype. Moreover we would highlight how the identification of pathogenic genes by Next Generation Sequencing technologies can allow to obtain a rapid diagnosis and to apply specific therapies. PMID- 26604639 TI - Role of liver transplantation in human immunodeficiency virus positive patients. AB - End-stage liver disease (ESLD) is a leading cause of morbidity and mortality amongst human immunodeficiency virus (HIV)-positive individuals. Chronic hepatitis B and hepatitis C virus (HCV) infection, drug-induced hepatotoxicity related to combined anti-retro-viral therapy, alcohol related liver disease and non-alcohol related fatty liver disease appear to be the leading causes. It is therefore, anticipated that more HIV-positive patients with ESLD will present as potential transplant candidates. HIV infection is no longer a contraindication to liver transplantation. Key transplantation outcomes such as rejection and infection rates as well as medium term graft and patient survival match those seen in the non-HIV infected patients in the absence of co-existing HCV infection. HIV disease does not seem to be negatively impacted by transplantation. However, HIV-HCV co-infection transplant outcomes remain suboptimal due to recurrence. In this article, we review the key challenges faced by this patient cohort in the pre- and post-transplant period. PMID- 26604640 TI - Effect of rifaximin on gut microbiota composition in advanced liver disease and its complications. AB - Liver cirrhosis is a paradigm of intestinal dysbiosis. The qualitative and quantitative derangement of intestinal microbial community reported in cirrhotic patients seems to be strictly related with the impairment of liver function. A kind of gut microbial "fingerprint", characterized by the reduced ratio of "good" to "potentially pathogenic" bacteria has recently been outlined, and is associated with the increase in Model for End-Stage Liver Disease and Child Pugh scores. Moreover, in patients presenting with cirrhosis complications such as spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), and, portal hypertension intestinal microbiota modifications or the isolation of bacteria deriving from the gut are commonly reported. Rifaximin is a non-absorbable antibiotic used in the management of several gastrointestinal diseases. Beyond bactericidal/bacteriostatic, immune-modulating and anti-inflammatory activity, a little is known about its interaction with gut microbial environment. Rifaximin has been demonstrated to exert beneficial effects on cognitive function in patients with HE, and also to prevent the development of SBP, to reduce endotoxemia and to improve hemodynamics in cirrhotics. These results are linked to a shift in gut microbes functionality, triggering the production of favorable metabolites. The low incidence of drug-related adverse events due to the small amount of circulating drug makes rifaximin a relatively safe antibiotic for the modulation of gut microbiota in advanced liver disease. PMID- 26604642 TI - N-acetylcysteine modulates angiogenesis and vasodilation in stomach such as DNA damage in blood of portal hypertensive rats. AB - AIM: To evaluate the antioxidant effect of N-acetylcysteine (NAC) on the stomach of rats with portal hypertension. METHODS: Twenty-four male Wistar rats weighing +/- 250 g were divided into four experimental groups (n = 6 each): Sham-operated (SO), SO + NAC, partial portal vein ligation (PPVL), and PPVL + NAC. Treatment with NAC in a dose of 10 mg/kg (i.p.) diluted in 0.6 mL of saline solution was administered daily for 7 d starting 8 d after the surgery. Animals from the PPVL and SO group received saline solution (0.6 mL) for the same period of time as the PPVL + NAC and SO + NAC group. On the 15(th) day the animals were anesthetized and we evaluated portal pressure by cannulating mesenteric artery. After, we removed the stomach for further analysis. We performed immunohistochemical analysis for endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), and nitrotirosine (NTT) proteins in stomach. We also evaluated eNOS and VEGF by Western blot analysis and assessed DNA damage in blood samples by the comet assay. RESULTS: The portal hypertension group exhibited increases in portal pressure when compared to SO group (29.8 +/- 1.8 vs 12.0 +/- 0.3 mmHg) (P < 0.001). The same was observed when we compared the eNOS (56.8 +/- 3.7 vs 13.46 +/- 2.8 pixels) (P < 0.001), VEGF (34.9 +/- 4.7 vs 17.46 +/- 2.6 pixels) (P < 0.05), and NTT (39.01 +/- 4.0 vs 12.77 +/- 2.3 pixels) (P < 0.05) expression by immunohistochemistry of the PPVL animals with the SO group. The expression of eNOS (0.39 +/- 0.03 vs 0.25 +/- 0.03 a.MU) (P < 0.01) and VEGF (0.38 +/- 0.04 vs 0.26 +/- 0.04 a.MU) (P < 0.01) were also evaluated by Western blot analysis, and we observed an increase of both proteins on PPVL animals. We also evaluated the DNA damage by comet assay, and observed an increase on damage index and damage frequency on those animals. NAC decreased portal pressure values in PPVL + NAC animals (16.46 +/- 2 vs 29.8 +/- 1.8 mmHg) (P < 0.001) when compared to PPVL. The expression of eNOS (14.60 +/- 4.1 vs 56.8 +/- 3.7 pixels) (P < 0.001), VEGF (19.53 +/- 3.2 vs 34.9 +/- 4.7 pixels) (P < 0.05) and NTT (21.84 +/- 0.7 vs 39.01 +/- 4.0 pixels) (P < 0.05) evaluated by immunohistochemistry were also reduced in PPVL + NAC animals. Also, when evaluated by Western blot eNOS expression (0.32 +/- 0.03 vs 0.39 +/- 0.03 a.MU) (P < 0.05) and VEGF expression (0.31 +/- 0.09 vs 0.38 +/- 0.04 a.MU) (P < 0.01). Furthermore, NAC modulated DNA damage in PPVL + NAC animals. CONCLUSION: In view of these results, we believe NAC is able to protect the stomach from the alterations induced by the PPVL procedure. PMID- 26604641 TI - Stem cell-based regenerative opportunities for the liver: State of the art and beyond. AB - The existing mismatch between the great demand for liver transplants and the number of available donor organs highlights the urgent need for alternative therapeutic strategies in patients with acute or chronic liver failure. The rapidly growing knowledge on stem cell biology and the intrinsic repair processes of the liver has opened new avenues for using stem cells as a cell therapy platform in regenerative medicine for hepatic diseases. An impressive number of cell types have been investigated as sources of liver regeneration: adult and fetal liver hepatocytes, intrahepatic stem cell populations, annex stem cells, adult bone marrow-derived hematopoietic stem cells, endothelial progenitor cells, mesenchymal stromal cells, embryonic stem cells, and induced pluripotent stem cells. All these highly different cell types, used either as cell suspensions or, in combination with biomaterials as implantable liver tissue constructs, have generated great promise for liver regeneration. However, fundamental questions still need to be addressed and critical hurdles to be overcome before liver cell therapy emerges. In this review, we summarize the state-of-the-art in the field of stem cell-based therapies for the liver along with existing challenges and future perspectives towards a successful liver cell therapy that will ultimately deliver its demanding goals. PMID- 26604643 TI - Hepatitis C virus NS5A promotes insulin resistance through IRS-1 serine phosphorylation and increased gluconeogenesis. AB - AIM: To investigate the mechanisms of insulin resistance in human hepatoma cells expressing hepatitis C virus (HCV) nonstructural protein 5A (NS5A). METHODS: The human hepatoma cell lines, Huh7 and Huh7.5, were infected with HCV or transiently transfected with a vector expressing HCV NS5A. The effect of HCV NS5A on the status of the critical players involved in insulin signaling was analyzed using real-time quantitative polymerase chain reaction and Western blot assays. Data were analyzed using Graph Pad Prism version 5.0. RESULTS: To investigate the effect of insulin treatment on the players involved in insulin signaling pathway, we analyzed the status of insulin receptor substrate-1 (IRS-1) phosphorylation in HCV infected cells or Huh7.5 cells transfected with an HCV NS5A expression vector. Our results indicated that there was an increased phosphorylation of IRS 1 (Ser(307)) in HCV infected or NS5A transfected Huh7.5 cells compared to their respective controls. Furthermore, an increased phosphorylation of Akt (Ser(473)) was observed in HCV infected and NS5A transfected cells compared to their mock infected cells. In contrast, we observed decreased phosphorylation of Akt Thr308 phosphorylation in HCV NS5A transfected cells. These results suggest that Huh7.5 cells either infected with HCV or ectopically expressing HCV NS5A alone have the potential to induce insulin resistance by the phosphorylation of IRS-1 at serine residue (Ser(307)) followed by decreased phosphorylation of Akt Thr(308), Fox01 Ser(256) and GSK3beta Ser(9), the downstream players of the insulin signaling pathway. Furthermore, increased expression of PECK and glucose-6-phosphatase, the molecules involved in gluconeogenesis, in HCV NS5A transfected cells was observed. CONCLUSION: Taken together, our results suggest the role of HCV NS5A in the induction of insulin resistance by modulating various cellular targets involved in the insulin signaling pathway. PMID- 26604644 TI - Magnesium isoglycyrrhizinate inhibits inflammatory response through STAT3 pathway to protect remnant liver function. AB - AIM: To investigate the protective effect of magnesium isoglycyrrhizinate (MgIG) on excessive hepatectomy animal model and its possible mechanism. METHODS: We used the standard 90% hepatectomy model in Sprague-Dawley rats developed using the modified Emond's method, in which the left, middle, right upper, and right lower lobes of the liver were removed. Rats with 90% liver resection were divided into three groups, and were injected intraperitoneally with 3 mL saline (control group), 30 mg/kg (low-dose group) and 60 mg/kg (high-dose group) of MgIG, respectively. Animals were sacrificed at various time points and blood was drawn from the vena cava. Biochemical tests were performed with an automatic biochemical analyzer for the following items: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamyl endopeptidase, total bilirubin (TBil), direct bilirubin (DBil), total protein, albumin, blood glucose (Glu), hyper-sensitivity C-reactive protein, prothrombin time (PT), and thrombin time (TT). Postoperative survival time was observed hourly until death. Hepatocyte regeneration was analyzed by immunohistochemistry. Serum inflammatory cytokines (IL-1, IL-6, IL-10, and iNOS) was analyzed by ELISA. STAT3 protein and mRNA were analyzed by Western blot and quantitative reverse-transcription PCR, respectively. RESULTS: The high-dose group demonstrated a significantly prolonged survival time, compared with both the control and the low-dose groups (22.0 +/- 4.7 h vs 8.9 +/- 2.0 vs 10.3 +/- 3.3 h, P = 0.018). There were significant differences among the groups in ALT, Glu and PT levels starting from 6 h after surgery. The ALT levels were significantly lower in the MgIG treated groups than in the control group. Both Glu and PT levels were significantly higher in the MgIG treated groups than in the control group. At 12 h, ALT, AST, TBil, DBil and TT levels showed significant differences between the MgIG treated groups and the control group. No significant differences in hepatocyte regeneration were found. Compared to the control group, the high-dose group showed a significantly increase in serum inflammatory cytokines IL-1 and IL-10, and a decrease in IL-6. Both STAT3 protein and mRNA levels were significantly lower in the MgIG treated groups than in the control group at 6 h, 12 h, and 18 h after surgery. CONCLUSION: High-dose MgIG can extend survival time in rats after excessive hepatectomy. This hepatoprotective effect is mediated by inhibiting the inflammatory response through inhibition of the STAT3 pathway. PMID- 26604645 TI - Retinoic acid receptor alpha promotes autophagy to alleviate liver ischemia and reperfusion injury. AB - AIM: To study the role of autophagy and the relationship between retinoic acid receptor alpha (RARalpha) and autophagy in liver ischemia and reperfusion (IR) injury. METHODS: All-trans retinoic acid (ATRA) was administered to mice for two weeks before operation. Reverse transcription-polymerase chain reaction and Western blot were used to detect the expression levels of related factors. To demonstrate the role of RARalpha, LE540, a RARalpha inhibitor, was used to treat hepatocytes injured by H2O2 in vitro. RESULTS: ATRA pretreatment noticeably diminished levels of serum alanine aminotransferase and aspartate aminotransferase as well as the degree of histopathological changes. Apoptosis was also inhibited, whereas autophagy was promoted. In vitro, RARalpha was inhibited by LE540, which resulted in decreased autophagy and increased apoptosis. Similarly, the expression of Foxo3a and p-Akt was downregulated, but Foxo1 expression was upregulated. CONCLUSION: This research provides evidence that ATRA can protect the liver from IR injury by promoting autophagy, which is dependent on Foxo3/p-Akt/Foxo1 signaling. PMID- 26604646 TI - Proposal of an ultrasonographic classification for hepatic alveolar echinococcosis: Echinococcosis multilocularis Ulm classification-ultrasound. AB - AIM: To establish an ultrasonographic classification based on a large sample of patients with confirmed hepatic alveolar echinococcosis (AE). METHODS: Clinical data and ultrasonography (US) findings of 185 patients (100 males; 85 females; mean age at diagnosis: 51.4 +/- 17.6 years; mean age at time of US examination: 58.7 +/- 18.2 years) were retrospectively reviewed with respect to the US morphology of hepatic AE lesions. The sonomorphological findings were grouped according to a five-part classification scheme. RESULTS: Application of the new classification resulted in the following distribution of sonomorphological patterns among the patients examined: hailstorm (54.1%); pseudocystic (13.5%); ossification (13.0%); hemangioma-like (8.1%); and metastasis-like (6.5%). Only 4.9% of lesions could not be assigned to a sonomorphological pattern. CONCLUSION: The sonomorphological classification proposed in the present study facilitates the diagnosis, interpretation and comparison of hepatic alveolar echinococcosis in routine practice and in the context of scientific studies. PMID- 26604647 TI - Surgery in (pre)malignant celiac disease. AB - AIM: To report the outcome of surgery in patients with (pre)malignant conditions of celiac disease (CD) and the impact on survival. METHODS: A total of 40 patients with (pre)malignant conditions of CD, ulcerative jejunitis (n = 5) and enteropathy associated T-cell lymphoma (EATL) (n = 35), who underwent surgery between 2002 and 2013 were retrospectively evaluated. Data on indications, operative procedure, post-operative morbidity and mortality, adjuvant therapy and overall survival (OS) were collected. Eleven patients with EATL who underwent chemotherapy without resection were included as a control group for survival analysis. Patients were followed-up every three months during the first year and at 6-mo intervals thereafter. RESULTS: Mean age at resection was 62 years. The majority of patients (63%) underwent elective laparotomy. Functional stenosis (n = 13) and perforation (n = 12) were the major indications for surgery. In 70% of patients radical resection was performed. Early postoperative complications, mainly due to leakage or sepsis, occurred in 14/40 (35%) of patients. Eight patients required reoperation. More patients who underwent resection in the acute setting (n = 3, 20%) died compared to patients treated in the elective setting. With a median follow-up of 20 mo, seven patients (18%) required reoperation due to long-term complications. Significantly more patients who underwent acute surgery could not be treated with adjuvant chemotherapy. Patients who first underwent surgical resection showed significantly better OS than patients who received chemotherapy without resection. CONCLUSION: Although the complication rate is high, the preferred first step of treatment in (pre)malignant CD consists of local resection as early as possible to improve survival. PMID- 26604648 TI - Comparison of selected inflammation-based prognostic markers in relapsed or refractory metastatic colorectal cancer patients. AB - AIM: To investigate the impact of systemic inflammation-based prognostic markers on overall survival in relapsed/refractory metastatic colorectal cancer (mCRC) patients. METHODS: To investigate prognostic markers in mCRC patients, this study was performed with patients who have experienced relapsed/refractory mCRC with standard chemotherapy or were inapplicable to conventional treatment modality because of poor performance status, age, or comorbidity. We reviewed the medical records of 177 mCRC patients managed with Korean Medicine (KM) treatment modality using an anticancer agent of Rhus verniciflua Stokes extract from June 2006 to April 2013. The clinicopathologic characteristics, laboratory test, the systemic inflammation markers including the modified Glasgow prognostic score (mGPS), neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), lymphocyte monocyte ratio (LMR), and prognostic nutritional index (PNI) were analyzed. The overall survival of patients was calculated with the Kaplan-Meier method and the statistical significance was compared using with the log-rank test. To compare the impact of systemic inflammation based markers, the hazard ratio (HR) of mGPS, NLR, PLR, LMR, and PNI for overall survival were evaluated with the Cox proportional hazards regression. RESULTS: The majority of mCRC patients had relapsed/refractory to standard chemotherapy; 128 patients (72.3%) had undergone more than second line chemotherapy, and the median time from diagnosis of mCRC to initiation of KM was 9.4 mo. The median overall survival of enrolled patients was 8.3 mo. On univariate analyses, the inflammation markers of higher mGPS (P < 0.001), NLR >= 5 (P < 0.001), PLR > 300 (P = 0.004), LMR <= 3.4 (P < 0.001), and PNI <= 45.3 (P = 0.001) were significantly associated with decreased survival time. On stepwise multivariate proportional hazards model, mGPS at 2 vs 0 (HR = 3.212, 95%CI: 1.437-7.716, P = 0.004), and LMR <= 3.4 (HR = 1.658, 95%CI: 1.092 2.518, P = 0.018) as independent predictors associated with poor overall survival along with carbohydrate antigen 19-9 (HR = 1.482, 95%CI: 1.007-2.182, P = 0.046), AST >= 40 (HR = 2.377, 95%CI: 1.359-4.155, P = 0.002), and the treatment duration for KM less than 2.9 mo (HR = 1.718, 95%CI: 1.160-2.543, P = 0.007). CONCLUSION: These results indicate that the inflammatory markers, mGPS and LMR are independent prognostic factors for predicting overall survival in relapsed/refractory mCRC patients. PMID- 26604649 TI - Relationship between virological response and FIB-4 index in chronic hepatitis B patients with entecavir therapy. AB - AIM: To investigate whether long-term low-level hepatitis B virus (HBV) DNA influences dynamic changes of the FIB-4 index in chronic hepatitis B (CHB) patients receiving entecavir (ETV) therapy with partial virological responses. METHODS: We retrospectively analyzed 231 nucleos(t)ide (NA) naive CHB patients from our previous study (NCT01926288) who received continuous ETV or ETV maleate therapy for three years. The patients were divided into partial virological response (PVR) and complete virological response (CVR) groups according to serum HBV DNA levels at week 48. Seventy-six patients underwent biopsies at baseline and at 48 wk. The performance of the FIB-4 index and area under the receiver operating characteristic (AUROC) curve for predicting fibrosis were determined for the patients undergoing biopsy. The primary objective of the study was to compare the cumulative probabilities of virological responses between the two groups during the treatment period. The secondary outcome was to observe dynamic changes of the FIB-4 index between CVR patients and PVR patients. RESULTS: For hepatitis B e antigen (HBeAg)-positive patients (n = 178), the cumulative probability of achieving undetectable levels at week 144 was 95% and 69% for CVR and PVR patients, respectively (P < 0.001). In the Cox proportional hazards model, a lower pretreatment serum HBV DNA level was an independent factor predicting maintained viral suppression. The cumulative probability of achieving undetectable levels of HBV DNA for HBeAg-negative patients (n = 53) did not differ between the two groups. The FIB-4 index efficiently identified fibrosis, with an AUROC of 0.80 (95%CI: 0.69-0.89). For HBeAg-positive patients, the FIB-4 index was higher in CVR patients than in PVR patients at baseline (1.89 +/- 1.43 vs 1.18 +/- 0.69, P < 0.001). There was no significant difference in the reduction of the FIB-4 index between the CVR and PVR groups from weeks 48 to 144 (-0.11 +/- 0.47 vs -0.13 +/- 0.49, P = 0.71). At week 144, the FIB-4 index levels were similar between the two groups (1.24 +/- 0.87 vs 1.02 +/- 0.73, P = 0.06). After multivariate logistic regression analysis, a lower baseline serum HBV DNA level was associated with improvement of liver fibrosis. In HBeAg-negative patients, the FIB-4 index did not differ between the two groups. CONCLUSION: The cumulative probabilities of HBV DNA responses showed significant differences between CVR and PVR HBeAg-positive CHB patients undergoing entecavir treatment for 144 wk. However, long-term low-level HBV DNA did not deteriorate the FIB-4 index, which was used to evaluate liver fibrosis, at the end of three years. PMID- 26604650 TI - Re-re-treatment of hepatitis C virus: Eight patients who relapsed twice after direct-acting-antiviral drugs. AB - AIM: To determine risk factors associated with hepatitis C virus (HCV) treatment failure after direct acting antivirals in patients with complex treatment histories. METHODS: All HCV mono-infected patients who received treatment at our institution were queried. Analysis was restricted to patients who previously failed treatment with boceprevir (BOC) or telaprevir (TVR) and started simeprevir (SMV) and sofosbuvir (SOF) +/- ribavirin (RBV) between December 2013 and June 2014. Patients with human immunodeficiency virus (HIV)/HCV co-infection or patients who received a liver transplant in the past were excluded. Viral loads were recorded while on treatment and after treatment. Data collection continued until December, 31(st) 2014 when data analysis was initiated. Patients missing virologic outcomes data were not included in the analysis. Analysis of 35 patients who had virologic outcome data available resulted in eight patients who were viral load negative at the end of treatment with SMF/SOF but later relapsed. Data related to patient demographics, HCV infection, and treatment history was collected in order to identify risk factors shared among patients who failed treatment with SMF/SOF. RESULTS: Eight patients who were treated with the first generation HCV protease inhibitors BOC or TVR in combination with pegylated interferon (PEG) and RBV who failed this triple therapy were subsequently re treated with an off-label all-oral regimen of SMV and SOF for 12 wk, with RBV in seven cases. Treatment was initiated before the Food and Drug Administration approved a 24-wk SMV/SOF regimen for patients with liver cirrhosis. All eight patients had an end of treatment response, but later relapsed. Eight (100%) patients were male. Mean age was 56 (range, 49-64). Eight (100%) patients had previously failed PEG/RBV dual therapy at least once in addition to prior failure with triple therapy. Total number of times treated ranged from 3-6 (mean 3.8). Eight (100%) patients were male had liver cirrhosis as determined by Fibroscan or MRI. Seven (87.5%) patients had genotype 1a HCV. Seven (87.5%) patients had over 1 million IU/mL HCV RNA at the time of re-treatment. CONCLUSION: This study identifies factors associated with SMV/SOF treatment failure and provides evidence that twleve weeks of SMV/SOF/RBV is insufficient in cirrhotics with high titer genotype 1a HCV. PMID- 26604651 TI - Combined transjugular intrahepatic portosystemic shunt and other interventions for hepatocellular carcinoma with portal hypertension. AB - AIM: To evaluate combination transjugular intrahepatic portosystemic shunt (TIPS) and other interventions for hepatocellular carcinoma (HCC) and portal hypertension. METHODS: Two hundred and sixty-one patients with HCC and portal hypertension underwent TIPS combined with other interventional treatments (transarterial chemoembolization/transarterial embolization, radiofrequency ablation, hepatic arterio-portal fistulas embolization, and splenic artery embolization) from January 1997 to January 2010 at Beijing Shijitan Hospital. Two hundred and nine patients (121 male and 88 female, aged 25-69 years, mean 48.3 +/ 12.5 years) with complete clinical data were recruited. We evaluated the safety of the procedure (procedure-related death and serious complications), change of portal vein pressure before and after TIPS, symptom relief [e.g., ascites, hydrothorax, esophageal gastric-fundus variceal bleeding (EGVB)], cumulative rates of survival, and distributary channel restenosis. The characteristics of the patients surviving >= 5 and < 5 years were also analyzed. RESULTS: The portosystemic pressure was decreased from 29.0 +/- 4.1 mmHg before TIPS to 18.1 +/- 2.9 mmHg after TIPS (t = 69.32, P < 0.05). Portosystemic pressure was decreased and portal hypertension symptoms were ameliorated. During the 5 year follow-up, the total recurrence rate of resistant ascites or hydrothorax was 7.2% (15/209); 36.8% (77/209) for EGVB; and 39.2% (82/209) for hepatic encephalopathy. The cumulative rates of distributary channel restenosis at 1, 2, 3, 4, and 5 years were 17.2% (36/209), 29.7% (62/209), 36.8% (77/209), 45.5% (95/209) and 58.4% (122/209), respectively. No procedure-related deaths and serious complications (e.g., abdominal bleeding, hepatic failure, and distant metastasis) occurred. Moreover, Child-Pugh score, portal vein tumor thrombosis, lesion diameter, hepatic arterio-portal fistulas, HCC diagnosed before or after TIPS, stent type, hepatic encephalopathy, and type of other interventional treatments were related to 5 year survival after comparing patient characteristics. CONCLUSION: TIPS combined with other interventional treatments seems to be safe and efficacious in patients with HCC and portal hypertension. PMID- 26604652 TI - Epidural anesthesia improves pancreatic perfusion and decreases the severity of acute pancreatitis. AB - AIM: To study the safety of epidural anesthesia (EA), its effect on pancreatic perfusion and the outcome of patients with acute pancreatitis (AP). METHODS: From 2005 to August 2010, patients with predicted severe AP [Ranson score >= 2, C reactive protein > 100 or necrosis on computed tomography (CT)] were prospectively randomized to either a group receiving EA or a control group treated by patient controlled intravenous analgesia. Pain management was evaluated in the two groups every eight hours using the visual analog pain scale (VAS). Parameters for clinical severity such as length of hospital stay, use of antibiotics, admission to the intensive care unit, radiological/clinical complications and the need for surgical necrosectomy including biochemical data were recorded. A CT scan using a perfusion protocol was performed on admission and at 72 h to evaluate pancreatic blood flow. A significant variation in blood flow was defined as a 20% difference in pancreatic perfusion between admission and 72 h and was measured in the head, body and tail of the pancreas. RESULTS: We enrolled 35 patients. Thirteen were randomized to the EA group and 22 to the control group. There were no differences in demographic characteristics between the two groups. The Balthazar radiological severity score on admission was higher in the EA group than in the control group (mean score 4.15 +/- 2.54 vs 3.38 +/- 1.75, respectively, P = 0.347) and the median Ranson scores were 3.4 and 2.7 respectively (P = NS). The median duration of EA was 5.7 d, and no complications of the epidural procedure were reported. An improvement in perfusion of the pancreas was observed in 13/30 (43%) of measurements in the EA group vs 2/27 (7%) in the control group (P = 0.0025). Necrosectomy was performed in 1/13 patients in the EA group vs 4/22 patients in the control group (P = 0.63). The VAS improved during the first ten days in the EA group compared to the control group (0.2 vs 2.33, P = 0.034 at 10 d). Length of stay and mortality were not statistically different between the 2 groups (26 d vs 30 d, P = 0.65, and 0% for both respectively). CONCLUSION: Our study demonstrates that EA increases arterial perfusion of the pancreas and improves the clinical outcome of patients with AP. PMID- 26604653 TI - Sulforaphane-rich broccoli sprout extract improves hepatic abnormalities in male subjects. AB - AIM: To evaluate effects of dietary supplementation of sulforaphane (SF)-rich broccoli sprout (BS) extract on hepatic abnormalities in Japanese male participants. METHODS: In a randomized, placebo-controlled, double blind trial, male participants with fatty liver received either BS capsules containing glucoraphanin [GR; a precursor of SF (n = 24)] or placebo (n = 28) for 2 mo. Liver function markers, serum levels of aspartate and alanine aminotransferases (AST and ALT, respectively) and gamma-glutamyl transpeptidase (gamma-GTP) and an oxidative stress marker, urinary levels of 8-hydroxydeoxyguanosine (8-OHdG), were measured and compared in participants before and after the trial period. In an animal model, chronic liver failure was induced in Sprague-Dawley rats by successive intraperitoneal injection with N-nitrosodimethylamine (NDMA) for 4 wk. Concomitantly, rats received AIN-76 diets supplemented with or without BS extract. Thereafter, rats were sacrificed, and their sera and livers were collected to measure serum liver function markers and hepatic levels of thiobarbituric acid reactive substances (TBARS) levels and hepatic glutathione S transferase (GST) activity, a prototypical phase 2 antioxidant enzyme. RESULTS: Dietary supplementation with BS extract containing SF precursor GR for 2 mo significantly decreased serum levels of liver function markers, ALT [median (interquartile range), before: 54.0 (34.5-79.0) vs after supplementation: 48.5 (33.3-65.3) IU/L, P < 0.05] and gamma-GTP [before: 51.5 (40.8-91.3) vs after: 50.0 (37.8-85.3) IU/L, P < 0.05], as well as the alkali phosphatase activity. Placebo showed no significant effects on the markers. The urinary level of 8 OHdG, an established oxidative stress marker, was significantly reduced in participants who had received BS capsules but not the placebo [before: 6.66 (5.51 9.03) vs after: 5.49 (4.89-6.66) ng/mg-creatinine, P < 0.05]. The reduction of urinary 8-OHdG was significantly correlated with decreased levels of both ALT and gamma-GTP [?8-OHdG and ?ALT: Spearman r (r) 0.514 and P = 0.012, ?8-OHdG and ?gamma-GTP: r = 0.496 and P = 0.016]. Intake of BS extract prevented NDMA-induced chronic liver failure in rats, which was attributable to the suppression of the increase in TBARS through induction of hepatic phase 2 antioxidant enzymes including hepatic GST (86.6 +/- 95.2 vs 107.8 +/- 7.7 IU/g, P < 0.01). CONCLUSION: Dietary supplementation with BS extract containing the SF precursor GR is likely to be highly effective in improving liver function through reduction of oxidative stress. PMID- 26604654 TI - Self-expandable metal stents for malignant gastric outlet obstruction: A pooled analysis of prospective literature. AB - AIM: To provide an overview of the clinical outcomes of self-expandable metal stent (SEMS) placement for malignant gastric outlet obstruction (MGOO). METHODS: A systematic literature search was performed in PubMed of the literature published between January 2009 and March 2015. Only prospective studies that reported on the clinical success of stent placement for MGOO were included. The primary endpoint was clinical success, defined according to the definition used in the original article. Data were pooled and analyzed using descriptive statistics. Subgroup analyses were performed for partially covered SEMSs (PCSEMSs) and uncovered SEMSs (UCSEMSs) using Fisher's exact test. RESULTS: A total of 19 studies, including 1281 patients, were included in the final analysis. Gastric (42%) and pancreatic (37%) cancer were the main causes of MGOO. UCSEMSs were used in 76% of patients and PCSEMSs in 24%. The overall pooled technical success rate was 97.3% and the clinical success rate was 85.7%. Stent dysfunction occurred in 19.6% of patients, mainly caused by re-obstruction (12.6%) and stent migration (4.3%), and was comparable between PCSEMSs and UCSEMSs (21.2% vs 19.1%, respectively, P = 0.412). Re-obstruction was more common with UCSEMSs (14.9% vs 5.1%, P < 0.001) and stent migration was more frequent after PCSEMS placement (10.9% vs 2.2%, P < 0.001). The overall perforation rate was 1.2%. Bleeding was reported in 4.1% of patients, including major bleeding in 0.8%. The median stent patency ranged from 68 to 307 d in five studies. The median overall survival ranged from 49 to 183 d in 13 studies. CONCLUSION: The clinical outcomes in this large population showed that enteral stent placement was feasible, effective and safe. Therefore, stent placement is a valid treatment option for the palliation of MGOO. PMID- 26604655 TI - Cooperative laparoscopic endoscopic and hybrid laparoscopic surgery for upper gastrointestinal tumors: Current status. AB - AIM: To investigate the cooperative laparoscopic and endoscopic techniques used for the resection of upper gastrointestinal tumors. METHODS: A systematic research of the literature was performed in PubMed for English and French language articles about laparoscopic and endoscopic cooperative, combined, hybrid and rendezvous techniques. Only original studies using these techniques for the resection of early gastric cancer, benign tumors and gastrointestinal stromal tumors of the stomach and the duodenum were included. By excluding case series of less than 10 patients, 25 studies were identified. The study design, number of cases, tumor pathology size and location, the operative technique name, the endoscopy team and surgical team role, operative time, type of closure of visceral wall defect, blood loss, complications and length of hospital stay of these studies were evaluated. Additionally all cooperative techniques found were classified and are presented in a systematic approach. RESULTS: The studies identified were case series and retrospective cohort studies. A total of 706 patients were operated on with a cooperative technique. The tumors resected were only gastrointestinal stromal tumors (GIST) in 4 studies, GIST and various benign submucosal tumors in 22 studies, early gastric cancer (pT1a and pT1b) in 6 studies and early duodenal cancer in 1 study. There was important heterogeneity between the studies. The operative techniques identified were: laparoscopic assisted endoscopic resection, endoscopic assisted wedge resection, endoscopic assisted transgastric and intragastric surgery, laparoscopic endoscopic cooperative surgery (LECS), laparoscopic assisted endoscopic full thickness resection (LAEFR), clean non exposure technique and non-exposed endoscopic wall inversion surgery (NEWS). Each technique is illustrated with the roles of the endoscopic and laparoscopic teams; the indications, characteristics and short term results are described. CONCLUSION: Along with the traditional cooperative techniques, new procedures like LECS, LAEFR and NEWS hold great promise for the future of minimally invasive oncologic procedures. PMID- 26604656 TI - Intraductal papillary neoplasm of the bile ducts: A case report and literature review. AB - Intraductal papillary neoplasm of the bile duct (IPNB) is a rare bile duct neoplasm mostly found in far eastern nations where hepatolithiasis and clonorchiasis infections are endemic. In western countries, it is very rare and the etiology is unknown. In this article, we report the first IPNB patient we encountered in our clinic and a literature review. The patient is a 38-year-old female with a history of choledocholithiasis who presented with obstructive jaundice. She was found to have a papillary mass at the junction of the right hepatic duct and common hepatic duct with six masses in the liver parenchyma. The immunophenotypic and histologic features of the tumor are consistent with IPNB, gastric subtype. The patient had a partial hepatectomy and has been receiving palliative chemotherapy. In a search of PubMed database, we collected 354 IPNB patients reported in 22 articles. In these patients, 52.8% were from Japan and 27.7% were from western countries including the United States (11.0%). The age of the patients ranged from 35 to 80 years old with an average of 64.6. Male/female ratio was 1.5. Macroscopically, 57.5% of the tumors were in the left lobe and 29.5% were in the right lobe. The average size of the tumor were 4.2 cm at the time of diagnosis. Histologically, pancreato-biliary subtype accounted for 41.8%, intestinal 28.0%, gastric 13.5% and oncocytic 16%. An invasive component is most often present in the pancreato-biliary and gastric subtypes. Despite recent advanced technologies, diagnosis of IPNB is still challenging, especially in western countries due to its rarity. Defined clinico-pathologic features are in demand for the accurate diagnosis and proper treatment. PMID- 26604657 TI - Cholestasis, ascites and pancytopenia in an immunocompetent adult with severe cytomegalovirus hepatitis. AB - Human cytomegalovirus (CMV) is a herpesvirus, which establishes lifelong latency after primary infection and leads to severe disease in immunocompromised patients. However, CMV infection in immunocompetent patients is usually asymptomatic and severe organ damage is rarely reported. We report a case of severe CMV hepatitis in an immunocompetent patient presenting with cholestasis, portal hypertension-related ascites and pancytopenia. The patient was asymptomatic with normal liver function and negative CMV DNA after two weeks of antiviral therapy. This case is an example of a common infection with an uncommon presentation, and suggests that testing for CMV should be carried out, even in patients with normal immune status, presenting with severe liver damage or cholestasis. PMID- 26604658 TI - Hepatitis C eradication: A long way to go. AB - Hepatitis C virus (HCV) is a major global health problem with high morbidity and mortality. About 185 million people are living with HCV, of which 80% are living in low and middle income countries. With the development of new highly effective treatments for HCV, it is considered that the eradication of HCV may only be one step away. The major problem with new treatment options is its high price. The price of sofosbuvir-based treatment for one patient in the United States is US$85000-110000, while the actual production cost of a 12 wk direct-acting antiviral regimen is less than US$250. Another major hindrance in HCV eradication is the lack of quality management of blood transfusion screens. Due to the lack of HCV screening, 75% of people in the United States with HCV infection are unaware of their positive HCV status. The control of massive HCV pandemic will require a significant financial investment, political will, and support from medical, pharmaceutical, and civil organizations around the globe. PMID- 26604659 TI - Psychometrics of the Symptoms and Functioning Severity Scale for High-Risk Youth. AB - Youth in residential care have significant mental health needs which require regular progress monitoring; however, very few emotional or behavioral assessments have been examined with this unique, high-risk population. This study examined the psychometrics of the Symptom Functioning and Severity Scale, a brief 24-item measure designed to assess the emotional and behavioral status of youth. This study examined the SFSS ratings from 143 youth with a disruptive behavior diagnosis living in a group-home facility in the Midwest and 52 of their service providers. Overall, the findings suggest that the psychometrics of the SFSS, when rated by staff or youth were similar to the original outpatient clinical samples. More specifically, the Rasch analyses indicate that the SFSS items and the overall scale is performing adequately, and the confirmatory factor analyses replicated the two-factor structure for staff. However, the fit of the two-factor model was less compelling for youth ratings. In all, the brief SFSS seems a promising measure for assessing problem severity for youth in residential care. PMID- 26604660 TI - Molecular analysis of the CHST6 gene in Korean patients with macular corneal dystrophy: Identification of three novel mutations. AB - PURPOSE: To identify the underlying genetic defect in Korean patients with macular corneal dystrophy (MCD). METHODS: Genomic DNA was isolated from peripheral blood leukocytes of seven patients from six unrelated families with MCD (three men and four women). Polymerase chain reaction was performed for coding regions of the carbohydrate sulfotransferase (CHST6), gene followed by bidirectional sequencing. Targeted mutational analysis (exons 4, 11-12, 14) of the transforming growth factor, beta-induced (TGFBI) gene was performed for all patients. RESULTS: All seven patients were found to have compound heterozygous mutations in the CHST6 gene. In addition to six previously reported mutations, c.95C>A (p.Ser32*), c.521A>G (p.Lys174Arg), c.557C>G (p.Pro186Arg), c.613C>T (p.Arg205Trp), c.820G>A (p.Glu274Lys), and c.1072T>C (p.Tyr358His), three novel mutations were identified in this study, including two missense mutations, c.353C>T (p.Ser118Phe) and c.922C>T (p.His308Tyr), and one frameshift mutation, c.786delC (p.L264Cfs*117). Among the three novel mutations, only the c.353C>T mutation had been reported in the Exon Aggregation Consortium database at an extremely low frequency of 0.00005072. In addition, these three novel mutations were absent from controls in 1,000 genomes, dbSNP, and the TIARA genome database, which is a Korean personal genome database. The most frequent mutation was c.613C>T (p.Arg205Trp), revealed in four unrelated Korean families, which has not previously been reported in other populations. No mutations were detected in the TGFBI gene. DISCUSSION: This is the first report on genetic analysis of Korean MCD patients. Three novel and six previously reported disease-causing CHST6 mutations were identified, which expands the mutational spectrum of MCD. PMID- 26604661 TI - Effects of chondrocyte-derived extracellular matrix in a dry eye mouse model. AB - PURPOSE: The occurrence of repetitive dry eye is accompanied by inflammation. This study investigated the anti-inflammatory effects of chondrocyte-derived extracellular matrix (CDECM) on the cornea and conjunctiva in a dry eye mouse model. METHODS: Dry eyes were experimentally induced in 12- to 16-week-old NOD.B10.H2(b) mice (Control) via subcutaneous injections of scopolamine (muscarinic receptor blocker) and exposure to an air draft for 10 days (desiccation stress [DS] 10D group). Tear volume and corneal smoothness were measured at 3, 5, 7, and 10 days after the instillation of PBS (PBS group) or CDECM (CDECM group). The corneas and conjunctivas were sectioned and stained with hematoxylin and eosin (H&E) and periodic acid Schiff (PAS). The expression of inflammatory markers (i.e., tumor necrosis factor-alpha [TNF-alpha], matrix metalloproteinase-2 [MMP-2], MMP-9, intercellular adhesion molecule-1 [ICAM-1], and vascular cell adhesion molecule-1 [VCAM-1]) was detected by quantitative real time (qRT)-PCR and western blotting. All data were statistically processed using SPSS version 18.0. RESULTS: The instillation of CDECM after the removal of the DS increased tear production by up to 3.0-fold, and corneal smoothness improved to 80% compared to the PBS group (p<0.05). In the CDECM group, the detachment of the corneal epithelial cells was reduced by 73.3% compared to the PBS group, and the conjunctival goblet cell density was significantly recovered to the control levels (p<0.05). The expression of inflammatory factors was decreased in the cornea and conjunctiva of the CDECM group compared to the PBS group. CONCLUSIONS: These observations suggest that CDECM induced effective anti-inflammatory improvements in the cornea and conjunctiva in this experimental model of dry eye. PMID- 26604662 TI - Crosslinked chitosan-dextran sulfate nanoparticle for improved topical ocular drug delivery. AB - PURPOSE: To examine the benefits of chitosan-dextran sulfate nanoparticles (CDNs) as a topical ocular delivery system with lutein as a model drug. METHODS: CDNs were developed by polyelectrolyte complexation of positively charged chitosan (CS) and negatively charged dextran sulfate (DS). 1-Ethyl-3-(3 dimethylaminopropyl)-carbodiimide (EDC) and polyethylene glycol 400 (PEG400) were used as co-crosslinking and stabilizing agents, respectively. The influence of these on the properties of CDNs, including drug release and mucoadhesiveness, was examined. The chemical stability of lutein in CDNs (LCDNs) was also examined. RESULTS: Typically, LCDNs showed a spherical shape, possessing a mean size of ~400 nm with a narrow size distribution. The entrapment efficiency of lutein was in the range of 60%-76%. LCDNs possessing a positive surface charge (+46 mV) were found to be mucoadhesive. The release profile of LCDNs followed Higuchi's square root model, suggesting drug release by diffusion from the polymer matrix. Lutein in LCDNs showed increased chemical stability during storage compared to its solution form. CONCLUSIONS: These characteristics of CDNs make them suitable for drug delivery to the ocular surface. PMID- 26604663 TI - Transcriptome networks in the mouse retina: An exon level BXD RI database. AB - PURPOSE: Differences in gene expression provide diverse retina phenotypes and may also contribute to susceptibility to injury and disease. The present study defines the transcriptome of the retina in the BXD RI strain set, using the Affymetrix Mouse Gene 2.0 ST array to investigate all exons of traditional protein coding genes, non-coding RNAs, and microRNAs. These data are presented in a highly interactive database on the GeneNetwork website. METHODS: In the Normal Retina Database, the mRNA levels of the transcriptome from retinas was quantified using the Affymetrix Mouse Gene 2.0 ST array. This database consists of data from male and female mice. The data set includes a total of 52 BXD RI strains, the parental strains (C57BL/6J and DBA/2J), and a reciprocal cross. RESULTS: In combination with GeneNetwork, the Department of Defense (DoD) Congressionally Directed Medical Research Programs (CDMRP) Normal Retina Database provides a large resource for mapping, graphing, analyzing, and testing complex genetic networks. Protein-coding and non-coding RNAs can be used to map quantitative trait loci (QTLs) that contribute to expression differences among the BXD strains and to establish links between classical ocular phenotypes associated with differences in the genomic sequence. Using this resource, we extracted transcriptome signatures for retinal cells and defined genetic networks associated with the maintenance of the normal retina. Furthermore, we examined differentially expressed exons within a single gene. CONCLUSIONS: The high level of variation in mRNA levels found among the BXD RI strains makes it possible to identify expression networks that underline differences in retina structure and function. Ultimately, we will use this database to define changes that occur following blast injury to the retina. PMID- 26604664 TI - Using Disease-Associated Coding Sequence Variation to Investigate Functional Compensation by Human Paralogous Proteins. AB - Gene duplication enables the functional diversification in species. It is thought that duplicated genes may be able to compensate if the function of one of the gene copies is disrupted. This possibility is extensively debated with some studies reporting proteome-wide compensation, whereas others suggest functional compensation among only recent gene duplicates or no compensation at all. We report results from a systematic molecular evolutionary analysis to test the predictions of the functional compensation hypothesis. We contrasted the density of Mendelian disease-associated single nucleotide variants (dSNVs) in proteins with no discernable paralogs (singletons) with the dSNV density in proteins found in multigene families. Under the functional compensation hypothesis, we expected to find greater numbers of dSNVs in singletons due to the lack of any compensating partners. Our analyses produced an opposite pattern; paralogs have over 35% higher dSNV density than singletons. We found that these patterns are concordant with similar differences in the rates of amino acid evolution (ie, functional constraints), as the proteins with paralogs have evolved 33% slower than singletons. Our evolutionary constraint explanation is robust to differences in family sizes, ages (young vs. old duplicates), and degrees of amino acid sequence similarities among paralogs. Therefore, disease-associated human variation does not exhibit significant signals of functional compensation among paralogous proteins, but rather an evolutionary constraint hypothesis provides a better explanation for the observed patterns of disease-associated and neutral polymorphisms in the human genome. PMID- 26604666 TI - Health coaching for glaucoma care: a pilot study using mixed methods. AB - INTRODUCTION: Adherence to glaucoma medications is essential for successful treatment of the disease but is complex and difficult for many of our patients. Health coaching has been used successfully in the treatment of other chronic diseases. This pilot study explores the use of health coaching for glaucoma care. METHODS: A mixed methods study design was used to assess the health coaching intervention for glaucoma patients. The health coaching intervention consisted of four to six health coaching sessions with a certified health coach via telephone. Quantitative measures included demographic and health information, adherence to glaucoma medications (using the visual analog adherence scale and medication event monitoring system), and an exit survey rating the experience. Qualitative measures included a precoaching health questionnaire, notes made by the coach during the intervention, and an exit interview with the subjects at the end of the study. RESULTS: Four glaucoma patients participated in the study; all derived benefits from the health coaching. Study subjects demonstrated increased glaucoma drop adherence in response to the coaching intervention, in both visual analog scale and medication event monitoring system. Study subjects' qualitative feedback reflected a perceived improvement in both eye and general health self care. The subjects stated that they would recommend health coaching to friends or family members. CONCLUSION: Health coaching was helpful to the glaucoma patients in this study; it has the potential to improve glaucoma care and overall health. PMID- 26604668 TI - Lowered intraocular pressure in a glaucoma patient after intravitreal injection of ocriplasmin. AB - We report the case of a glaucoma patient who received a single intravitreal injection of 125 ug ocriplasmin for vitreomacular traction in the right eye. The patient had bilateral advanced glaucoma and had previously undergone an implantation of an Ahmed glaucoma valve in the right eye and trabeculectomy in both eyes. The patient was using three topical ophthalmic intraocular pressure (IOP)-lowering medications on the day of injection. Baseline uncorrected Snellen visual acuity was 20/80-1 and IOP was 19 mmHg. Resolution of vitreomacular traction was achieved 1 week after injection. IOP was transiently decreased, reaching a maximum reduction of 12 mmHg below baseline at 1 month after injection, when serous choroidal effusion was also present. IOP returned to baseline levels and choroidal effusion resolved at 2 months after injection of IOP-lowering medication. Vitrectomy with epiretinal membrane and internal limiting membrane peeling, endolaser photocoagulation, and fluid-gas exchange were performed in the right eye ~3.5 months after injection to treat persistent epiretinal membrane, and presumed tractional retinal detachment. Final visual acuity was 20/50+ and IOP was 18 mmHg at 16 weeks after surgery. To our knowledge, this is the first report of IOP reduction and serous choroidal effusion after ocriplasmin injection. PMID- 26604665 TI - Current Perspectives on the Beneficial Role of Ginkgo biloba in Neurological and Cerebrovascular Disorders. AB - Ginkgo biloba extract is an alternative medicine available as a standardized formulation, EGb 761((r)), which consists of ginkgolides, bilobalide, and flavonoids. The individual constituents have varying therapeutic mechanisms that contribute to the pharmacological activity of the extract as a whole. Recent studies show anxiolytic properties of ginkgolide A, migraine with aura treatment by ginkgolide B, a reduction in ischemia-induced glutamate excitotoxicity by bilobalide, and an alternative antihypertensive property of quercetin, among others. These findings have been observed in EGb 761 as well and have led to clinical investigation into its use as a therapeutic for conditions such as cognition, dementia, cardiovascular, and cerebrovascular diseases. This review explores the therapeutic mechanisms of the individual EGb 761 constituents to explain the pharmacology as a whole and its clinical application to cardiovascular and neurological disorders, in particular ischemic stroke. PMID- 26604667 TI - Advantages of diabetic tractional retinal detachment repair. AB - PURPOSE: To evaluate the outcomes and complications of patients with diabetic tractional retinal detachment (TRD) treated with pars plana vitrectomy (PPV). PATIENTS AND METHODS: We retrospectively studied a case series of 24 eyes of 21 patients at a single tertiary, university-affiliated medical center. A review was carried out on patients who underwent PPV for the management of TRD due to proliferative diabetic retinopathy from October 2011 to November 2013. Preoperative and final visual outcomes, intraoperative and postoperative complications, and medical background were evaluated. RESULTS: A 23 G instrumentation was used in 23 eyes (95.8%), and a 25 G instrumentation in one (4.2%). Mean postoperative follow-up time was 13.3 months (4-30 months). Visual acuity significantly improved from logarithm of the minimum angle of resolution (LogMAR) 1.48 to LogMAR 1.05 (P<0.05). Visual acuity improved by >=3 lines in 75% of patients. Intraoperative complications included iatrogenic retinal breaks in seven eyes (22.9%) and vitreal hemorrhage in nine eyes (37.5%). In two eyes, one sclerotomy was enlarged to 20 G (8.3%). Postoperative complications included reoperation in five eyes (20.8%) due to persistent subretinal fluid (n=3), vitreous hemorrhage (n=1), and dislocated intraocular lens (n=1). Thirteen patients (54.2%) had postoperative vitreous hemorrhage that cleared spontaneously, five patients (20.8%) required antiglaucoma medications for increased intraocular pressure, seven patients (29.2%) developed an epiretinal membrane, and two patients (8.3%) developed a macular hole. CONCLUSION: Patients with diabetic TRD can benefit from PPV surgery. Intraoperative and postoperative complications can be attributed to the complexity of this disease. PMID- 26604669 TI - Efficacy of vitrectomy and epiretinal membrane peeling in eyes with dry age related macular degeneration. AB - OBJECTIVE: To study the efficacy of epiretinal membrane (ERM) peeling in eyes with dry age-related macular degeneration (AMD). METHODS: We retrospectively analyzed patient charts on 17 eyes (16 patients) that underwent ERM peeling with a concurrent diagnosis of dry AMD. RESULTS: Eyes with concurrent dry AMD and with a good preoperative best-corrected visual acuity (BCVA) (better than or equal to 20/50) had a statistically significant mean BCVA improvement at 6 months after ERM peeling. There was a statistical increase in mean BCVA from 20/95 to 20/56 in dry AMD eyes, and no eyes showed worsening in BCVA at 6 months or at most recent follow-up. Five/seventeen (29.4%) eyes had cataract formation or progression. There were no other complications, reoperations, or reoccurrences. CONCLUSION: ERM peeling in eyes with dry AMD may show significant improvement, especially in eyes with good preoperative BCVA. The procedure is relatively safe with low complications and reoccurrences. PMID- 26604670 TI - Study of association of PAX6 polymorphisms with susceptibility to high myopia in a Japanese population. AB - PURPOSE: Many studies have investigated the relationship of paired box 6 (PAX6) gene polymorphisms with the risk of high myopia, but the results across studies remain inconsistent and ambiguous. In the present work, we investigated whether PAX6 polymorphisms are associated with high myopia in a Japanese population. METHODS: A total of 1,585 Japanese patients with high myopia (spherical equivalent [SE] <-9.00 diopters [D]) and 1,011 Japanese healthy controls (SE>= 1.00 D) were recruited. To compare genotype frequencies between cases and controls, we genotyped five single nucleotide polymorphisms in the PAX6 gene that are reportedly associated with high/extreme myopia: rs662702, rs3026393, rs644242, rs3026390, and rs667773. RESULTS: For rs662702, rs644242, and rs667773, odds ratios (ORs) for their risk alleles tended to increase with the progression of SE and axial length in the additive and recessive models. Of these, rs644242 had the highest OR (2.56) in patients with SE<-15 D in both eyes in the recessive model. On the other hand, for rs3026393 and rs3026390, the ORs for their risk alleles tended to increase according to the progression of SE and axial length in the dominant model. Of the two, rs3026393 had the highest OR (2.32) in patients with SE<-15 D in both eyes in the dominant model. However, no significant associations were identified in this study. CONCLUSION: We found that these PAX6 single nucleotide polymorphisms were associated with an increased risk of extreme myopia. Although the results, which are in agreement with some previous studies, did not reach statistical significance, PAX6 single nucleotide polymorphisms may be important risk factors for the development of extreme myopia. Further genetic studies with larger sample sizes and taking into account the degree of myopia are needed to clarify the contribution of PAX6 variants in myopia development. PMID- 26604671 TI - Scleral lens for keratoconus: technology update. AB - Scleral lenses are large diameter lenses which rest over the sclera, unlike the conventional contact lenses which rest on the cornea. These lenses are fitted to not touch the cornea and there is a space created between the cornea and the lens. These lenses are inserted in the eyes after filling with sterile isotonic fluid. Generally, scleral contact lenses are used for high irregular astigmatism as seen in various corneal ectatic diseases such as keratoconus, pellucid marginal degeneration, or/and as liquid bandage in ocular surface disorders. In this article, we review the new developments, that have taken place over the years, in the field of scleral contact lenses as regard to new designs, materials, manufacturing technologies, and fitting strategies particularly for keratoconus. PMID- 26604672 TI - Aloe vera gel facilitates re-epithelialization of corneal alkali burn in normal and diabetic rats. AB - PURPOSE: To investigate the efficacy of topical applied aloe vera (AV) and to facilitate the repair of the standardized alkaline corneal ulcer in normal and diabetic rats. MATERIALS AND METHODS: The corneal alkali-burn injury model was established unilaterally in Wistar rats by filter paper saturated with 0.01 M NaOH contacting the eyes for 45 seconds. Rats were divided into four groups: normal control (NC), normal AV (NAV), diabetic control (DC), and diabetic AV (DAV). NAV and DAV groups were treated with AV gel eye drops four times daily, and NC and DC groups were treated with normal saline for 3 days. Corneal epithelial wound closure and degree of edema were recorded using slit lamp and optical coherence tomography at 0, 24, 48, and 72 hours postwounding. Histological examination was conducted to evaluate the degree of inflammation and the healing effect. RESULTS: Corneal epithelial wound healing was better in the NAV group than in the NC group, and it was significantly higher in the DAV group than in the DC group (P<0.05). In comparison to the DC group, DAV treated with AV demonstrated a marked reduction in edema at 48 and 72 hours. Histologically, corneal re-epithelialization was complete and higher in DAV group than that in DC group; moreover, the inflammatory cells were increased in DC group than DAV group (P<0.05). CONCLUSION: This study demonstrated the efficacy of AV for enhanced corneal re-epithelialization, as well as reduced inflammatory response after alkali burn in rats; therefore, it could be useful as a therapy for diabetic keratopathy. PMID- 26604673 TI - Intravitreal ranibizumab as a primary or a combined treatment for severe retinopathy of prematurity. AB - PURPOSE: The aim of the study was to assess the outcomes of severe retinopathy of prematurity (ROP) in zone I or posterior zone II treated with intravitreal ranibizumab (IVR) as monotherapy or combined treatment with laser photocoagulation. METHODS: This is a retrospective study analyzing clinical records of the included patients. Patients were divided into two groups: group 1 included patients who received only IVR treatment; and group 2 was subdivided into group 2A - including patients with IVR as initial treatment and complementary laser photocoagulation if retinal neovascularization or plus disease did not regress, and group 2B - including patients with initial laser photocoagulation and IVR as rescue therapy. Favorable outcomes were regression of the retinal neovascularization and plus disease, meaning control of the disease. Unfavorable outcomes were progression to stages 4 and 5 of ROP. RESULTS: Fifty seven eyes were included in the study. Mean birth weight and gestational age were 1,281+/-254 g and 29.5+/-2.1 weeks, respectively. Group 1 comprised of 16 eyes, with favorable outcomes in 14 eyes (87.5%). Group 2 comprised of 41 eyes, with favorable outcomes in 29 eyes (70.7%), in a mean follow-up period of 12.8 months. CONCLUSION: IVR was effective to treat severe cases of ROP as a primary or a combined treatment. Forty-three of the 57 treated eyes (75.4%) achieved regression of ROP and favorable outcomes. PMID- 26604674 TI - Foveal structure during the induction phase of anti-vascular endothelial growth factor therapy for occult choroidal neovascularization in age-related macular degeneration. AB - PURPOSE: To evaluate the efficacy of monthly injections of aflibercept and ranibizumab on foveal structure after three months, for the treatment of occult choroidal neovascularization (CNV) in age-related macular degeneration (AMD). METHODS: We retrospectively studied 103 eyes with treatment-naive neovascular AMD with occult and no classic CNV. Seventy-four of 103 eyes were treated with ranibizumab (intravitreal ranibizumab injection [IVR] group); 29 eyes were treated with aflibercept (intravitreal aflibercept injection [IAI] group). The best-corrected visual acuity and the retinal and choroidal structure at the fovea were evaluated using optical coherence tomography. RESULTS: The total foveal thickness, the height of serous retinal detachments, and subfoveal choroidal thickness were compared with baseline, and the incidence of retinal pigment epithelial elevation significantly decreased in the IAI group compared with the IVR group. In contrast, the thickness of the sensory retina at the fovea significantly decreased in the IVR group when compared with the IAI group. The logarithm of the minimum angle of resolution (logMAR) best-corrected visual acuity improved more significantly in the IVR group (-0.085+/-0.164) than in the IAI group (-0.020+/-0.125) at 3 months (P=0.017). CONCLUSION: After intravitreal injection, aflibercept more rapidly reduced subretinal fluid and subfoveal choroidal thickness. In contrast, ranibizumab decreased the sensory retinal thickness compared with aflibercept. The responses of the retinal and choroidal tissue to these anti-VEGF agents may be different during the induction phase for eyes with occult CNV secondary to neovascular AMD. PMID- 26604676 TI - Letter to the editor: dexamethasone intravitreal implant in the treatment of diabetic macular edema. PMID- 26604675 TI - A prospective 3-year follow-up trial of implantation of two trabecular microbypass stents in open-angle glaucoma. AB - PURPOSE: To evaluate 3-year safety and intraocular pressure (IOP) following two trabecular microbypass stents in phakic and pseudophakic subjects with open-angle glaucoma (OAG) not controlled on preoperative medication. PATIENTS AND METHODS: In this prospective pilot study, phakic or pseudophakic subjects with OAG and IOP between 18 mmHg and 30 mmHg on one preoperative topical ocular hypotensive medication underwent medication washout. Thirty-nine qualified subjects with preoperative unmedicated IOP >=22 mmHg and <=38 mmHg received two stents. Postoperative examinations were scheduled at Day 1, Week 1, Months 1, 3, 6, and 12, and semiannually through Month 60. Ocular hypotensive medication was considered if postoperative IOP exceeded 21 mmHg. IOP, medication use, and safety were assessed at each visit. Subject follow-up through Month 36 was completed. RESULTS: Thirty-six eyes (92.3%; 95% confidence interval [CI] 79.1%, 98.4%) achieved the primary efficacy end point of Month 12 reduction in IOP >=20% from baseline (unmedicated IOP) without ocular hypotensive medication. Four subjects required medication during the Month 36 follow-up period. Mean IOP at 36 months for subjects not taking medication was 15.2 mmHg. At 36 months, subjects sustained mean IOP decrease of 9.1+/-2.7 mmHg (95% CI 8.0 mmHg, 10.14 mmHg), or 37% IOP reduction, from unmedicated baseline IOP. Compared to preoperative medicated IOP, subjects had mean reduction at Month 36 of 5.5+/-2.7 mmHg (95% CI 4.5 mmHg, 6.6 mmHg), or 26% reduction. Both measures of IOP reduction were highly significant (P<0.001). Other than one case of early postoperative hyphema that resolved at 1 week, no postoperative adverse events were attributed to stent implantation. CONCLUSION: In a pilot study, two trabecular microbypass stents to treat OAG subjects on one preoperative medication provided statistically significant, sustained, and safe reduction of IOP to <=15 mmHg without medication through 36 months. PMID- 26604677 TI - Endoilluminator-assisted Descemet membrane endothelial keratoplasty and endoilluminator-assisted pre-Descemet endothelial keratoplasty. PMID- 26604679 TI - Use of anti-TNFs for difficult-to-treat urticaria: response to Cooke et al. PMID- 26604678 TI - Management of orbital fractures: challenges and solutions. AB - Many specialists encounter and treat orbital fractures. The management of these fractures is often challenging due to the impact that they can have on vision. Acute treatment involves a thorough clinical examination and management of concomitant ocular injuries. The clinical and radiographic findings for each individual patient must then be analyzed for the need for surgical intervention. Deformity and vision impairment can occur from these injuries, and while surgery is intended to prevent these problems, it can also create them. Therefore, surgical approach and implant selection should be carefully considered. Accurate anatomic reconstruction requires complete assessment of fracture margins and proper implant contouring and positioning. The implementation of new technologies for implant shaping and intraoperative assessment of reconstruction will hopefully lead to improved patient outcomes. PMID- 26604680 TI - Drug usage analysis and health care resources consumption in naive patients with rheumatoid arthritis. AB - OBJECTIVES: The use of biologic agents has revolutionized the management of rheumatoid arthritis (RA) in the past 2 decades. These biologic agents directly target molecules and cells involved in the pathogenesis of RA. The purpose of this study was to assess the usage of biologic agents in terms of persistence to treatment, dose escalation, and consumption of health care resources (hospitalizations, drugs, and outpatients service) in the real clinical practice in naive patients with RA. METHODS: We conducted a real-world, retrospective, observational cohort study based on data obtained from administrative databases of three Local Health Units in Italy. The population included adults diagnosed with RA who had at least one prescription between January 1, 2009 and December 31, 2011, for a biologic that was approved for treatment of RA. The patients were followed for 12 months after enrollment. The clinical characteristics of the patients enrolled in this study were also investigated in the 1-year period before the index date. The main and secondary endpoints were evaluated only in biologic-naive patients without switches. The overall health care costs for patients were evaluated. RESULTS: A total of 594 patients met the study criteria (mean age 53.5+/-13.5, female:male ratio =3:1). Thirty-nine percent received etanercept, 25% adalimumab, 14% infliximab, 10% abatacept, 9% tocilizumab, and 3% golimumab. After 1 year of observation, patients showed similar use of other RA related medication. For the naive patients without switches, the persistence levels were: 78% for etanercept, 72% for tocilizumab, 71% for adalimumab, 69% for infliximab, and 64% for abatacept. For all agents, dose escalation was 21.4% for infliximab, 11.5% for adalimumab, 5.6% for abatacept, 4% for tocilizumab, and 3.8% for etanercept. The annual costs per treated patients were ?12,803 for adalimumab, ?11,924 for etanercept, ?11,830 for tocilizumab, ?11,201 for infliximab, and ?10,943 for abatacept. CONCLUSION: The role of biologic therapies in the treatment of RA continues to evolve; our study reflects real-world drug utilization data in adult patients with RA. These observations could be used by decision makers to support formulary decisions, although further research is needed using a larger sample to validate these results. PMID- 26604681 TI - Advanced basal cell carcinoma, the hedgehog pathway, and treatment options - role of smoothened inhibitors. AB - Cutaneous basal cell carcinoma (BCC) is the most common human cancer and its incidence is rising worldwide. Ultraviolet radiation exposure, including tanning bed use, as well as host factors play a role in its development. The majority of cases are treated and cured with local therapies including surgery. Yet, the health care costs of diagnosis and treatment of BCCs in the US is substantial. In the United States, the cost of nonmelanoma skin cancer care in the Medicare population is estimated to be US$426 million per year. While rare, locally advanced BCCs that can no longer be controlled with surgery and/or radiation, and metastatic BCCs do occur and can be associated with significant morbidity and mortality. Vismodegib (GDC-0449), a smoothened inhibitor targeted at the hedgehog pathway, is the first US Food and Drug Association (FDA)-approved agent in the treatment of locally advanced, unresectable, and metastatic BCCs. This class of agents appears to be changing the survival rates in advanced BCC patients, but appropriate patient selection and monitoring are important. Multidisciplinary assessments are essential for the optimal care and management of these patients. For some patients with locally advanced BCC, treatment with a hedgehog inhibitor may eliminate the need for an excessively disfiguring or morbid surgery. PMID- 26604682 TI - Efficacy of trabectedin in advanced soft tissue sarcoma: beyond lipo- and leiomyosarcoma. AB - OBJECTIVE: Trabectedin is effective in leiomyosarcoma and liposarcoma, especially the myxoid variant, related to the presence of the FUS-CHOP transcript. We evaluated the efficacy of trabectedin in specific subgroups of patients with soft tissue sarcomas (STS). METHODS: Seventy-two patients with advanced anthracycline pretreated STS, who received trabectedin at a dose of 1.5 mg/m(2) every 3 weeks by continuous 24-hour infusion, were retrospectively analyzed. Best response rate according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria and severe adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.02) were evaluated. Secondary endpoints included progression-free survival and overall survival (OS). RESULTS: Median age was 48 (range, 20-75) years, with a median Eastern Cooperative Oncology Group performance status of 0. The median number of previous chemotherapy regimens was 1 (range, 0-5). Median number of trabectedin cycles was 3 (range, 1-17). About 69/72 patients (95.8%) were evaluable for response: 9 patients (13%) achieved partial response and 26 (37.7%) stable disease. According to histotype, clinical benefit (partial response + stable disease) was reported in synovial sarcoma (n=5), retroperitoneal liposarcoma (n=10), myxoid liposarcoma (n=5), leiomyosarcoma (n=8), high-grade undifferentiated pleomorphic sarcoma (n=5), Ewing/peripheral primitive neuroectodermal tumor (n=1), and malignant peripheral nerve sheath tumor (n=1). Any grade AEs were noncumulative, reversible, and manageable. G3/G4 AEs included anemia (n=1, 1.4%), neutropenia (n=7, 9.6%), liver toxicity (n=6, 8.3%), and fatigue (n=2, 2.8%). With a median follow-up time of 11 (range, 2-23) months, median progression-free survival and OS of the entire cohort were 2.97 months and 16.5 months, respectively. CONCLUSION: Our experience confirms trabectedin as an effective therapeutic option for metastatic lipo- and leiomyosarcoma and suggests promise in synovial sarcomas and high-grade undifferentiated pleomorphic sarcoma. PMID- 26604683 TI - Curcuma purpurascens BI. rhizome accelerates rat excisional wound healing: involvement of Hsp70/Bax proteins, antioxidant defense, and angiogenesis activity. AB - PURPOSE: Curcuma purpurascens BI. is a member of Zingiberaceae family. The purpose of this study is to investigate the wound healing properties of hexane extract of C. purpurascens rhizome (HECP) against excisional wound healing in rats. MATERIALS AND METHODS: Twenty four rats were randomly divided into 4 groups: A) negative control (blank placebo, acacia gum), B) low dose of HECP, C) high dose of HECP, and D) positive control, with 6 rats in each group. Full thickness incisions (approximately 2.00 cm) were made on the neck area of each rat. Groups 1-4 were treated two-times a day for 20 days with blank placebo, HECP (100 mg/kg), HECP (200 mg/kg), and intrasite gel as a positive control, respectively. After 20 days, hematoxylin and eosin and Masson's trichrome stainings were employed to investigate the histopathological alterations. Protein expressions of Bax and Hsp70 were examined in the wound tissues using immunohistochemistry analysis. In addition, levels of enzymatic antioxidants and malondialdehyde representing lipid peroxidation were measured in wound tissue homogenates. RESULTS: Macroscopic evaluation of wounds showed conspicuous elevation in wound contraction after topical administration of HECP at both doses. Moreover, histopathological analysis revealed noteworthy reduction in the scar width correlated with the enhanced collagen content and fibroblast cells, accompanied by a reduction of inflammatory cells in the granulation tissues. At the molecular level, HECP facilitates wound-healing process by downregulating Bax and upregulating Hsp70 protein at the wound site. The formation of new blood vessel was observed in Masson's trichrome staining of wounds treated with HECP (100 and 200 mg/kg). In addition, HECP administration caused a significant surge in enzymatic antioxidant activities and a decline in lipid peroxidation. CONCLUSION: These findings suggested that HECP accelerated wound-healing process in rats via antioxidant activity, angiogenesis effect and anti-inflammatory responses involving Hsp70/Bax. PMID- 26604684 TI - Profile of pridopidine and its potential in the treatment of Huntington disease: the evidence to date. AB - Huntington disease (HD) is a chronic, genetic, neurodegenerative disease for which there is no cure. The main symptoms of HD are abnormal involuntary movements (chorea and dystonia), impaired voluntary movements (ie, incoordination and gait balance), progressive cognitive decline, and psychiatric disturbances. HD is caused by a CAG-repeat expanded mutation in the HTT gene, which encodes the huntingtin protein. The inherited mutation results in the production of an elongated polyQ mutant huntingtin protein (mHtt). The cellular functions of the Htt protein are not yet fully understood, but the functions of its mutant variant are thought to include alteration of gene transcription and energy production, and dysregulation of neurotransmitter metabolism, receptors, and growth factors. The phenylpiperidines pridopidine (4-[3-methanesulfonyl-phenyl]-1-propyl piperidine; formerly known as ACR16) and OSU6162 ([S]-[-]-3-[3-methane [sulfonyl phenyl]-1-propyl-piperidine) are members of a new class of pharmacologic agents known as "dopamine stabilizers". Recent clinical trials have highlighted the potential of pridopidine for symptomatic treatment of patients with HD. More recently, the analysis of HD models (ie, in vitro and in mice) highlighted previously unknown effects of pridopidine (increase in brain-derived neurotrophic factor, reduction in mHtt levels, and sigma-1 receptor binding and modulation). These additional functions of pridopidine suggest it might be a neuroprotective and disease-modifying drug. Data from ongoing clinical trials of pridopidine will help define its place in the treatment of HD. This commentary examines the available preclinical and clinical evidence regarding the use of pridopidine in HD. PMID- 26604685 TI - Prevalence of the rs7903146C>T polymorphism in TCF7L2 gene for prediction of type 2 diabetes risk among Iranians of different ethnicities. AB - BACKGROUND: Pharmacogenetics is the study of genetic polymorphisms affecting responses to drug therapy. The common rs7903146 (C>T) polymorphism of the TCF7L2 gene has recently been associated with type 2 diabetes (T2D). In this study, prevalence of the rs7903146 (C>T) polymorphism in the TCF7L2 gene for prediction of T2D risk was examined in an Iranian population of different ethnicities. METHODS: The prevalence of rs7903146 (C>T) and the predicted phenotypes, including extensive metabolizers, intermediate metabolizers, and poor metabolizers were investigated in blood samples of 300 unrelated healthy individuals in an Iranian population, including Fars, Turk, Lure, and Kurd, using polymerase chain reaction restriction fragment length polymorphism and direct genomic DNA sequencing. RESULTS: The homozygous wild-type (C/C), heterozygous (C/T), and homozygous (T/T) allelic frequencies of rs7903146 (C>T) in the TCF7L2 gene were 29% (extensive metabolizers), 66.34% (intermediate metabolizers), and 4.66% (poor metabolizers), respectively. The C/C, C/T, and T/T genotypic frequencies of the rs7903146 (C>T) allele were significantly different (P<0.01) among Iranians of different ethnicities. The frequency of the homozygous T/T variant of the rs7903146 (C>T) allele was significantly low in the Lure (P<0.01) and high in the Fars (P<0.001) ethnicities. Additionally, the frequency of the T/T variant of the rs7903146 (C>T) allele in the South of Iran was the highest (P<0.04), while the East of Iran had the lowest frequency (P<0.01). CONCLUSION: The prediction of rs7903146 (C>T) is required in drug research and routine treatment, where the information would be helpful for clinicians to optimize therapy and adverse drug reactions and predict drug response in individuals at risk of T2D. PMID- 26604686 TI - The relevance of piroxicam for the prevention and treatment of nonmelanoma skin cancer and its precursors. AB - Piroxicam (PXM), a nonsteroidal anti-inflammatory drug, is an enolic benzothiazine and a potent member of the oxicam series. The drug suppresses the synthesis of proinflammatory enzymes, such as cyclo-oxygenases-1 and -2 (COX-1 and 2), downregulates the production of prostaglandins (PGs) and tromboxanes, and inhibits polyamines production by blocking ornithine decarboxylase induction involved in nonmelanoma skin carcinogenesis. In addition, PXM is able to induce tumor cell apoptosis and suppresses metalloproteinase 2 activities. Skin carcinogenesis is a multistep process in which the accumulation of genetic events leads to a gradually dysplastic cellular expression, deregulation of cell growth, and carcinomatous progression. COX-1 upregulation plays a significant role in PG and vascular epidermal growth factor production supporting tumor growth. Increased level of PGs in premalignant and/or malignant cutaneous tumors is also favored by upregulation of COX-2 and downregulation of the tumor suppressor gene 15-hydroxy-prostaglandin dehydrogenase. Chemoprevention can be a hopeful approach to inhibit carcinoma occurrence before an invasive tumor develops. The chemopreventive effect of nonsteroidal anti-inflammatory drugs on nonmelanoma skin cancers has been established. In this study, we highlighted the different modalities of action of PXM on the pathogenesis of nonmelanoma skin cancer, analyzing and evaluating binding modes and energies between COX-1 or COX-2 and PXM by protein-ligand molecular docking. Our clinical experience about the local use of PXM on actinic keratoses and field cancerization is also reported, confirming its efficacy as target therapy. PMID- 26604687 TI - In silico approach for the discovery of new PPARgamma modulators among plant derived polyphenols. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a well characterized member of the PPAR family that is predominantly expressed in adipose tissue and plays a significant role in lipid metabolism, adipogenesis, glucose homeostasis, and insulin sensitization. Full agonists of synthetic thiazolidinediones (TZDs) have been therapeutically used in clinical practice to treat type 2 diabetes for many years. Although it can effectively lower blood glucose levels and improve insulin sensitivity, the administration of TZDs has been associated with severe side effects. Based on recent evidence obtained with plant-derived polyphenols, the present in silico study aimed at finding new selective human PPARgamma (hPPARgamma) modulators that are able to improve glucose homeostasis with reduced side effects compared with TZDs. Docking experiments have been used to select compounds with strong binding affinity (DeltaG values ranging from -10.0+/-0.9 to -11.4+/-0.9 kcal/mol) by docking against the binding site of several X-ray structures of hPPARgamma. These putative modulators present several molecular interactions with the binding site of the protein. Additionally, most of the selected compounds have favorable druggability and good ADMET properties. These results aim to pave the way for further bench-scale analysis for the discovery of new modulators of hPPARgamma that do not induce any side effects. PMID- 26604688 TI - Critical appraisal of Timothy grass pollen extract GRAZAX in the management of allergic rhinitis. AB - Allergic rhinitis is one of the most common diseases of adult and pediatric age, associated with grass pollen (GP) allergy in >50% cases, with a consistent impact on quality of life of affected patients. A grass allergen tablet, containing standardized extract derived from Timothy grass (Phleum pratense) pollen and ~15 MUg major allergen P. pratense (rPhl p 5), may be the future of allergen-specific immunotherapy (IT) for GP allergy. The aim of this review was to critically evaluate the role of Timothy GP extract IT for the management of allergic rhinitis. For this purpose, we have tried to analyze potential mechanisms of action at the basis of Timothy GP extract, we have reviewed efficacy studies to establish potential benefits and clinical response, and we have also evaluated safety and tolerability profiles and patient focus perspective, such as quality of life, satisfaction and acceptability, and compliance to this IT. PMID- 26604689 TI - PACE4 regulates apoptosis in human prostate cancer cells via endoplasmic reticulum stress and mitochondrial signaling pathways. AB - BACKGROUND: PACE4 is a proprotein convertase capable of processing numerous substrates involved in tumor growth, invasion, and metastasis. However, the precise role of PACE4 during prostate cancer cell apoptosis has not been reported. METHODS: In the present study, human prostate cancer cell lines DU145, LNCaP, and PC3 were transfected with PACE4 small interfering (si)RNA to investigate the underlying mechanisms of apoptosis. RESULTS: We revealed that PACE4 siRNA exhibited antitumor activity by inducing apoptosis, as determined by Cell Counting Kit-8 (CCK-8), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltet razolium bromide (MTT) assay, cell cycle analysis, Hoechst staining, caspase-3/7 activity, and western blot analysis. In addition, PACE4 siRNA significantly increased the ratio of Bax/Bcl-2, which led to the release of cytochrome c. Moreover, PACE4 siRNA also induced endoplasmic reticulum stress by increasing the expression of GRP78, GRP94, p-PERK, and p-eIF2alpha. The ratio of Bax/Bcl-2 and GRP78 were also increased in PACE4 gene knockdown prostate cancer cells compared with the control cells. CONCLUSION: These data demonstrate that PACE4 siRNA may exert its antitumor activity through mitochondrial and endoplasmic reticulum stress signaling pathways, indicating it may be a novel therapeutic target for prostate cancer. PMID- 26604690 TI - Efficacy and safety of ifosfamide-based chemotherapy for osteosarcoma: a meta analysis. AB - BACKGROUND: The efficacy of ifosfamide-based chemotherapy in the treatment of osteosarcoma has been investigated; however, results are inconsistent. Therefore, we reviewed the relevant studies and conducted a meta-analysis to assess the efficacy of ifosfamide-based chemotherapy in patients with osteosarcoma. METHODS: A systematic literature search on PubMed, Embase, and Web of Science databases was performed. Eligible studies were clinical trials of patients with osteosarcoma who received ifosfamide-based chemotherapy. Hazard ratios (HRs) were pooled to compare event-free survival (EFS) and overall survival (OS). Risk ratios (RRs) were pooled to compare good histologic response rates and adverse event incidence. Meta-analysis was performed using a fixed-effects model or a random-effects model according to heterogeneity. RESULTS: A total of seven randomized controlled trials were included in this meta-analysis. Pooled results showed that ifosfamide-based chemotherapy significantly improved EFS (HR=0.72, 95% confidence interval [CI]: 0.63, 0.82; P=0.000) and OS (HR=0.83, 95% CI: 0.70, 0.99; P=0.034); furthermore, this form of chemotherapy increased good histologic response rate (RR=1.27, 95% CI: 1.10, 1.46; P=0.001). In addition, patients in the ifosfamide group exhibited a significantly higher incidence of fever (RR=2.23, 95% CI: 1.42, 3.50; P=0.000) and required more frequent platelet transfusion (RR=1.92, 95% CI: 1.23, 3.01; P=0.004). CONCLUSION: This meta analysis confirmed that ifosfamide-based chemotherapy can significantly improve EFS and OS; this chemotherapy can also increase good histologic response rate in patients with osteosarcoma. However, evidence may be limited by potential biases and confounders. Thus, large-scale well-designed randomized controlled trials are needed to verify current findings. PMID- 26604691 TI - Bauhinia championii flavone inhibits apoptosis and autophagy via the PI3K/Akt pathway in myocardial ischemia/reperfusion injury in rats. AB - This study aimed to determine the effects of Bauhinia championii flavone (BCF) on myocardial ischemia/reperfusion injury (MI/RI) in rats and to explore potential mechanisms. The MI/RI model in rats was established by ligating the left anterior descending coronary artery for 30 minutes, then reperfusing for 3 hours. BCF at 20 mg/kg was given 20 minutes prior to ischemia via sublingual intravenous injection, with 24 MUg/kg phosphoinositide 3-kinase inhibitor (PI3K; wortmannin) as a control. The creatine kinase-MB and nitric oxide content were assessed by colorimetry. The levels of mitochondrial permeability transition pores and tumor necrosis factor alpha were determined by an enzyme-linked immunosorbent assay. Cardiomyocyte apoptosis was detected by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Additionally, the expression of PI3K, endothelial nitric oxide synthase, caspase-3, and Beclin1 was analyzed by fluorescence quantitative polymerase chain reaction and Western blotting, respectively. Akt and microtubule-associated protein 1 light chain 3-II protein levels were also evaluated. Pretreatment with BCF significantly decreased the levels of creatine kinase-MB, tumor necrosis factor alpha, and mitochondrial permeability transition pores, but increased the nitric oxide content. Furthermore, BCF inhibited apoptosis, downregulated caspase-3, Beclin1, and microtubule-associated protein 1 light chain 3-II, upregulated PI3K, and increased the protein levels of phosphorylated Akt and endothelial nitric oxide synthase. However, all of the previously mentioned effects of BCF were blocked when BCF was coadministered with wortmannin. In conclusion, these observations indicated that BCF has cardioprotective effects against MI/RI by reducing cell apoptosis and excessive autophagy, which might be related to the activation of the PI3K/Akt signaling pathway. PMID- 26604692 TI - Systematic review and meta-analysis: bezafibrate in patients with primary biliary cirrhosis [Erratum]. PMID- 26604693 TI - Tumor-induced VEGF-C overexpression in retroperitoneal lymph nodes in VX2 carcinoma-bearing rabbits. AB - OBJECTIVE: To establish the retroperitoneal lymph node (RLN) metastasis model of cervical carcinoma in rabbits and evaluate the relationship of vascular endothelial growth factor-C (VEGF-C) expression and the lymph node status. METHODS: Forty-eight rabbits were injected with VX2 cells or RPMI solution at muscular mucosae of the myometrium 0.5 cm away from the cervix. Animals were treated with or without cis-diamminedichloroplatinum(II) (cisplatin: DDP) and sacrificed on days 15, 21, and 27 post-VX2 or RPMI injections. Tumor mass and RLNs were examined histopathologically. Quantitative real-time PCR was used to examine the changes in VEGF-C mRNA expression. Levels of VEGF-C protein expression in tissues were determined using immunohistochemistry staining. RESULTS: Development of VX2 cervical carcinoma and the RLNs metastasis was confirmed with pathological examination. Significantly increased tumor volume was observed on days 15, 21, and 27 postinjection (P<0.05). The enlargement of RLNs was found on day 21. Expression of VEGF-C was significantly upregulated in peripheral white blood cells, tumor mass, and RLNs in an association with cancer progression. DDP resulted in a suppression of VEGF-C expression, whereas the influences on tumor mass and lymphatic metastasis were insignificant. CONCLUSION: Elevated VEGF-C expressions in peripheral white blood cells and RLNs are associated with tumor progression and lymphatic metastasis. DDP treatment inhibits VEGF-C expression and fails to protect against metastatic cervical cancer. PMID- 26604694 TI - Lentinus squarrosulus (Mont.) mycelium enhanced antioxidant status in rat model. AB - AIM: Lentinus squarrosulus is an edible wild mushroom commonly found in Asia. This species has several interesting features such as rapid mycelial growth, and hence has the potential to be used as food, functional food, and nutraceuticals. Our previous study shows that L. squarrosulus contains potent antioxidant compounds in vitro. This study aims to investigate the in vivo bioavailability of L. squarrosulus mycelium extract and its antioxidant effect on biomarkers of antioxidant defense and oxidative stress. METHODS: Water extract of mycelial biomass of L. squarrosulus was analyzed for in vivo antioxidant effects, including cupric-reducing antioxidant capacity (CUPRAC), glutathione peroxidase (GPx), xanthine oxidase (XO), advanced oxidation protein products (AOPPs), and lipid hydroperoxides (LHPs) at 0 and 28 days. GPx and XO were also analyzed in liver homogenates. Normal Sprague Dawley rats were treated with 250 and 500 mg/kg of extract for 28 days. RESULTS: The serum CUPRAC level increased after treatment with both concentrations, indicating that there was sufficient bioavailability of the extract which contributed to the total antioxidant capacity. GPx activity in both serum and liver was increased and this correlated with LHP level after treatment with 250 mg/kg of extract, but XO activity was significantly decreased after treatment with 500 mg/kg of the extract. Lack of difference between AOPP levels implied that there were no significant changes in oxidative damage of protein after treatment. CONCLUSION: This study clearly showed that L. squarrosulus mycelium antioxidant extract contains absorbable antioxidants that enter the circulating plasma and cause a significant acute increase in plasma antioxidant capacity. Thus, the water extract of L. squarrosulus mycelium, which can be obtained abundantly by liquid fermentation, may serve as an antioxidant ingredient in functional foods and nutraceuticals. PMID- 26604695 TI - Phytocompounds and modulatory effects of Anacardium microcarpum (cajui) on antibiotic drugs used in clinical infections. AB - BACKGROUND: The challenge of antibiotic resistance and the emergence of new infections have generated considerable interest in the exploration of natural products from plant origins as combination therapy. In this context, crude ethanolic extract (CEE), ethyl acetate fraction (EAF), and methanolic fraction (MF) from Anacardium microcarpum were tested alone or in combination with antibiotics (amikacin, gentamicin, ciprofloxacin, and imipenem) against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. METHODS: Antibiotic resistance-modifying activity was performed using the microdilution method by determining the minimal inhibitory concentration (MIC). In addition, phytochemical prospecting analyses of tested samples were carried out. RESULTS: Our results indicated that all the extracts showed low antibacterial activity against multidrug-resistant strains (MIC =512 MUg/mL). However, addition of CEE, EAF, and MF to the growth medium at the subinhibitory concentration (MIC/8=64 MUg/mL) significantly modulated amikacin- and gentamicin-resistant E. coli 06. CEE and EAF also demonstrated a significant (P<0.001) synergism with imipenem against S. aureus. In contrast, MF antagonized the antibacterial effect of ciprofloxacin and gentamicin against P. aeruginosa 03 and S. aureus 10, respectively. Qualitative phytochemical analysis of the extracts revealed the presence of secondary metabolites including phenols, flavonoids, xanthones, chalcones, and tannin pyrogallates. CONCLUSION: Taken together, our results suggest that A. microcarpum is a natural resource with resistance-modifying antibacterial activity that needs to be further investigated to overcome the present resistant-infection problem. PMID- 26604696 TI - Mechanisms underlying the perifocal neuroprotective effect of the Nrf2-ARE signaling pathway after intracranial hemorrhage. AB - BACKGROUND: It has been found that nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2-ARE) signaling pathway plays a role in antioxidative response, anti-inflammatory response, and neuron-protection in intracerebral hemorrhage (ICH). The aim of this study is to explore mechanisms underlying the perifocal neuroprotective effect of the Nrf2-ARE signaling pathway after ICH. METHODS: There were a total of 90 rats with basal ganglia hemorrhage, which were randomly divided into the following four groups: ICH (Sprague-Dawley rats with autologous femoral arterial blood injection into the basal ganglia), sulforaphane (SFN) (SFN was intraperitoneally administered into rats), retinoic acid (RA) (RA was intraperitoneally administered into rats), and dimethyl sulfoxide (the rats were treated with dimethyl sulfoxide). We observed the neurological score of the rats in the different groups, and collected brain tissues for immunofluorescence, Western blot, and reverse transcription polymerase chain reaction to detect expression of Nrf2, heme oxygenase (HO-1), nuclear factor-kappaB (NF-kappaB), and tumor necrosis factor-alpha (TNF-alpha). RESULTS: The results indicated that neurological dysfunction of rats was significantly improved in the SFN group, and the expressions of Nrf2 and HO-1 in tissues surrounding the hemorrhage were increased. Also, the level of NF-kappaB and TNF-alpha were reduced compared to the ICH group. The RA group exhibited more severe neurological dysfunction and lower levels of Nrf2 and HO-1 than the SFN and ICH groups. Compared to the ICH group, the NF-kappaB and TNF-alpha expression in the RA groups was increased. In conclusion, RA inhibits Nrf2 dissociation and translocation into nucleus, thereby suppressing the anti-inflammatory effect of Nrf2-ARE signaling pathway. The activation of Nrf2-ARE signaling pathway by SFN can elevate expression of antioxidant enzyme HO-1, reduce perifocal inflammatory response after ICH, and thus may play a neuroprotective role. CONCLUSION: The results suggest that Nrf2-ARE signaling pathway may serve as a new target for treatment of perifocal inflammatory injury caused by ICH. PMID- 26604697 TI - Protective effects of triptolide on retinal ganglion cells in a rat model of chronic glaucoma. AB - PURPOSE: To study the effects of triptolide, a Chinese herb extract, on retinal ganglion cells (RGCs) in a rat model of chronic glaucoma. METHODS: Eighty Wistar rats were randomly divided into triptolide group (n=40) and normal saline (NS) group (n=40). Angle photocoagulation was used to establish the model of glaucoma, with right eye as laser treated eye and left eye as control eye. Triptolide group received triptolide intraperitoneally daily, while NS group received NS. Intraocular pressure (IOP), anti-CD11b immunofluorescent stain in retina and optic nerve, RGCs count with Nissel stain and microglia count with anti-CD11b immunofluorescence stain in retina flat mounts, retinal tumor necrosis factor (TNF)-alpha mRNA detection by reverse transcription-polymerase chain reaction, and double immunofluorescent labeling with anti-TNF-alpha and anti-CD11b in retinal frozen section were performed. RESULTS: Mean IOP of the laser treated eyes significantly increased 3 weeks after photocoagulation (P<0.05), with no statistical difference between the two groups (P>0.05). RGCs survival in the laser treated eyes was significantly improved in the triptolide group than the NS group (P<0.05). Microglia count in superficial retina of the laser treated eyes was significantly less in the triptolide group (30.40+/-4.90) than the NS group (35.06+/-7.59) (P<0.05). TNF-alpha mRNA expression in the retina of the laser treated eyes in the triptolide group decreased by 60% compared with that in the NS group (P<0.01). The double immunofluorescent labeling showed that TNF-alpha was mainly distributed around the microglia. CONCLUSION: Triptolide improved RGCs survival in this rat model of chronic glaucoma, which did not depend on IOP decrease but might be exerted by inhibiting microglia activities and reducing TNF alpha secretion. PMID- 26604698 TI - DNAzyme-based probe for circulating microRNA detection in peripheral blood. AB - BACKGROUND: The recent discovery of microRNAs (miRNAs) and their extracellular presence suggest a potential role of these regulatory molecules in defining the metastatic potential of cancer cells and mediating the cancer-host communication. This study aims to improve the sensitivity of miRNA detection via DNAzyme-based method and enhance the selectivity by using the DNAzyme-based probe to reduce nonspecific amplification. METHODS: The miRNA probes were chemically synthesized with a phosphate at the 5' end and purified by polyacrylamide gel electrophoresis. Exosomal RNA from peripheral blood was isolated. Carboxylated magnetic microsphere beads (MBs) were functionalized with streptavidin (SA) according to a previously reported method with some modification. T capture probe coated SA-MBs (DNA-MBs) were also prepared. The fluorescent spectra were measured using a spectrofluorophotometer. RESULTS: We designed an incomplete DNAzyme probe with two stems and one bubble structure as a recognition element for the specific detection of miRNA with high sensitivity. The background effects were decreased with increase of the added of DNA-MBs and capturing times. Therefore, 20 minutes was selected as the optimal concentration in the current study. The fluorescence intensity increases as the hybridization time changed and reached a constant level at 40 minutes, and 1 MUM is the optimum signal probe concentration for self assembled DNA concatemers formation. In the presence of miRNA, the fluorescence of the solution increased with increasing miRNA concentration. There is no obvious fluorescence in the presence of 10 mM of other nontarget DNA. CONCLUSION: A simple, rapid method with high performance has been constructed based on identified circulating miRNA signatures using miRNA-induced DNAzyme. This assay is simple, inexpensive, and sensitive, enabling quantitative detection of as low as 10 fM miRNA. PMID- 26604699 TI - Alpinetin inhibits lung cancer progression and elevates sensitization drug resistant lung cancer cells to cis-diammined dichloridoplatium. AB - OBJECTIVE: Alpinetin is a novel flavonoid that has demonstrated potent antitumor activity in previous studies. However, the efficacy and mechanism of alpinetin in treating lung cancer have not been determined. METHODS: We evaluated the impact of different doses and durations of alpinetin treatment on the cell proliferation, the apoptosis of lung cancer cells, as well as the drug-resistant lung cancer cells. RESULTS: This study showed that the alpinetin inhibited the cell proliferation, enhanced the apoptosis, and inhibited the PI3K/Akt signaling in lung cancer cells. Moreover, alpinetin significantly increased the sensitivity of drug-resistant lung cancer cells to the chemotherapeutic effect of cis diammined dichloridoplatium. Taken together, this study demonstrated that alpinetin significantly suppressed the development of human lung cancer possibly by influencing mitochondria and the PI3K/Akt signaling pathway and sensitized drug-resistant lung cancer cells. CONCLUSION: Alpinetin may be used as a potential compound for combinatorial therapy or as a complement to other chemotherapeutic agents when multiple lines of treatments have failed to reduce lung cancer. PMID- 26604700 TI - Nanoethosomal transdermal delivery of vardenafil for treatment of erectile dysfunction: optimization, characterization, and in vivo evaluation. AB - Vesicular drug delivery systems have recently gained attention as a way of improving dosing accuracy for drugs with poor transdermal permeation. The current study focuses on utilization of the natural biocompatible vesicles to formulate vardenafil nanoethosomes (VRD-NE), for the enhancement of their transdermal permeation and bioavailability. Fifteen formulations were prepared by thin-layer evaporation technique according to Box-Behnken design to optimize formulation variables. The effects of lipid composition, sonication time, and ethanol concentration on particle size and encapsulation efficiency were studied. The diffusion of vardenafil (VRD) from the prepared nanoethosomes specified by the design was carried out using automated Franz diffusion cell apparatus. The optimized formula was investigated for in vivo pharmacokinetic parameters compared with oral VRD suspension. Confocal laser scanning microscopy images were used to confirm enhanced diffusion release of VRD in rat skin. The results showed that the optimized formula produced nanoethosomes with an average size of 128 nm and an entrapment efficiency of 76.23%. VRD-NE provided a significant improvement in permeation with an enhancement ratio of 3.05-fold for a film made with optimally formulated VRD-NE compared with a film made with VRD powder. The transdermal bioavailability of VRD from the nanoethosome film was approximately twofold higher than the oral bioavailability from an aqueous suspension. VRD-NE thus provide a promising transdermal drug delivery system. As a result, management of impotence for a longer duration could be achieved with a reduced dosage rate that improves patient tolerability and compliance for the treatment of erectile dysfunction. PMID- 26604701 TI - Efficacy and safety of a conversion from the original tacrolimus and mycophenolate mofetil to the generics Tacpan and Mowel after liver transplantation. AB - BACKGROUND: Expensive pharmaceuticals are a major reason for cost intensive health care systems. Long-term immunosuppressive therapy plays a relevant role after organ transplantation. Patents of original drugs have expired and cheaper products are available. Little data are available regarding efficacy and safety of generic immunosuppressive agents. METHODS: In this prospective study, 25 patients, who were clinically stable for a minimum of 2 years after liver transplantation, were converted from the original formulations of tacrolimus (TAC) and mycophenolate mofetil to the generics Tacpan (TAP) and Mowel (MOW). Patients were followed-up for 6 months. Results were compared retrospectively to 25 age- and sex-matched controls treated with the original brands. RESULTS: In the matched-pair analysis of TAC trough level/dose ratio, no significant difference was found between TAP/MOW and TAC/mycophenolate mofetil groups. No acute rejection occurred in either group. In total, 17 patients reported mild side effects in the TAP/MOW group. The most common side effects were gastrointestinal symptoms. Intra-individual analysis of costs revealed a considerable cost reduction in the TAP/MOW group (in median 25.03%; P<0.001). CONCLUSION: In summary, the use of the generics TAP/MOW is effective and seems to be safe and cost-efficient in stable liver-transplantation patients. PMID- 26604702 TI - Barriers to medication taking among Kuwaiti patients with type 2 diabetes: a qualitative study. AB - BACKGROUND: Nonadherence to medications among Kuwaitis with type 2 diabetes mellitus (T2DM) is believed to be a major barrier to appropriate management of the disease. Published studies of barriers to medication adherence in T2DM suggest a Western bias, which may not adequately describe the Kuwaiti experience. AIM: The purpose of this study was to explore barriers to medication adherence among Kuwaiti adults with T2DM. METHODS: Semi-structured interviews were conducted with 20 Kuwaiti patients with type 2 diabetes. The interviews were digitally recorded, transcribed, and analyzed using thematic analysis. RESULTS: Barriers to medication adherence were identified. Emerging themes were: 1) lack of education/awareness about diabetes/medications, 2) beliefs about medicines/diabetes, 3) spirituality and God-centered locus of control, 4) attitudes toward diabetes 5) perceptions of self-expertise with the disease and body awareness, 6) social stigma, 7) perceptions of social support, 8) impact of illness on patient's life, 9) perceptions of health care providers' attitudes toward patients, and 10) health system-related factors, such as access difficulties and inequalities of medication supply and services. CONCLUSION: Personal, sociocultural, religious, health care provider, and health care system related factors may impede medication adherence among Kuwaitis with type 2 diabetes. Interventions to improve care and therapeutic outcomes in this particular population must recognize and attempt to resolve these factors. PMID- 26604703 TI - A mixed-methods study of the implementation of medication adherence policy solutions: how do European countries compare? AB - OBJECTIVES: We describe a key informant study that invited national medicines policy leads for the European Union member states to self-assess the level of implementation of medicines adherence initiatives in their country and the adequacy of that implementation. Interviews with medicines policy leads enabled in-depth understanding of the variation in adherence support across nations and the ways in which different nations prioritize, plan, and implement medicines adherence systems and services. METHODS: Ten national policy leads (Bulgaria, Denmark, Estonia, Finland, Germany, Ireland, Latvia, Lithuania, Malta, and the Netherlands) completed a self-assessment survey, and seven (Estonia, Finland, Germany, Ireland, Lithuania, Malta, and the Netherlands) engaged in a follow-up interview. KEY FINDINGS: Policy leads varied in the level of implementation of medication adherence solutions that they reported in their nations; most initiatives were aimed directly at patients with few initiatives at government or health care commissioner levels of action. Policy leads reported insufficient implementation of medication adherence initiatives across all potential domains. Barriers to implementation included lack of resources, strategic planning, evidence to support action, the "hidden" nature of medication adherence within policy work, and dispersed responsibility for medication adherence as a policy and practice theme. CONCLUSION: This study has international significance and summarizes the emergent characteristics of nations with and without coordinated medication adherence activity. We highlight the importance of sharing good practice in policy formulation and implementation for medication adherence. PMID- 26604704 TI - What are the preferences of health care professionals in Germany regarding fully liquid, ready-to-use hexavalent pediatric vaccine versus hexavalent pediatric vaccine that needs reconstitution? AB - Diphtheria, tetanus and acellular pertussis (DTaP) based combined vaccines have led to significant reduction in incidence of several serious pediatric infectious diseases. A new, fully liquid combined hexavalent vaccine has been introduced and has been shown to reduce administration time. This fully liquid vaccine may also be simpler to administer and could reduce handling errors. The present study was designed to understand the value that health care providers (HCPs) place on aspects of injection devices for combined hexavalent vaccine programs in Germany. A discrete choice experiment (DCE) was designed to elicit the views of HCPs regarding hexavalent vaccines. The key attributes of injection devices were identified through a focused literature search and interviews with HCPs. Five key attributes, each with two or three levels were described which included: type of device, experience of this hexavalent vaccine on the German market, preparation time, probability of handling errors, and dosage errors. Physicians (n=150) and nurses (n=150) who administered hexavalent vaccines in Germany completed the survey. Choice data were analyzed using the conditional logit procedure. All attributes were significant and important independent influences on physicians' and nurses' choices. Reducing any "probability of dosage errors" was the most important attribute. Both physicians and nurses had a strong preference to reduce preparation time. All other things equal both groups also significantly preferred a fully liquid hexavalent vaccine. They also preferred vaccines that had been on the market for a few years compared to ones that had not (especially the physicians). Additional analyses explored participants' preferences in more detail through interaction terms. The DCE choice data provide useful insights into how HCPs view each aspect of the vaccination device. Overall, the HCPs preferred fully liquid vaccines. The survey also highlighted the importance of handling and dosage errors, reducing preparation time, and also experience of the HCPs with the use of a vaccine. The survey work included physicians and nurses and explored their views separately. PMID- 26604705 TI - A feasible method to improve adherence of Hawley retainer in adolescent orthodontic patients: a randomized controlled trial. AB - BACKGROUND: Retention is an important component of orthodontic treatment; however, poor compliance with retainer use is often encountered, especially in adolescents. The purpose of this study was to prove the hypothesis that verbal instructions combined with images showing the severe consequences of poor compliance can increase retainer use. METHODS: This study was a randomized controlled trial. The sample was recruited from Wenzhou, People's Republic of China, between February 2013 and May 2014, and 326 participants were randomized into three groups. Patients and parents in Group A (n=106) were given routine retainer wear instructions only; in Group B (n=111), images illustrating the severe consequences of poor compliance with Hawley retainer use were shown to patients, combined with routine instructions; and in Group C (n=109), images illustrating the severe consequences of poor compliance with Hawley retainer use were shown to patients and parents, combined with routine instructions. Three months after debonding, questionnaires were used to investigate daily wear time and the reasons for poor compliance. Differences in means between the groups were tested by one-way analysis of variance. RESULTS: The mean daily wear time in Group C (15.09+/-4.13 hours) was significantly greater than in Group A (12.37+/ 4.58 hours, P<0.01) or Group B (13.50+/-4.22 hours, P<0.05); the mean daily wear time in Group B was greater than in Group A, but was not significant (P=0.67). Reasons for nonusage were forgetting to wear the retainer (51%) and finding the retainer bothersome to frequently insert and remove (42%). CONCLUSION: Verbal instructions combined with images showing the severe consequences of poor compliance can increase retainer use. Parents play an important role in compliance with retainer use in adolescent patients. PMID- 26604706 TI - Who takes the medicine? Adherence to antiretroviral therapy in Southern Ethiopia. AB - BACKGROUND: Treatment adherence is critical for the success of antiretroviral therapy (ART) for people living with HIV. There is limited representative information on ART drug adherence and its associated factors from Southern Ethiopia. We aimed at estimating the level of adherence to ART among people living with HIV and factors associated with it in 20 randomly selected ART clinics of Southern Ethiopia. METHODS: In this cross-sectional study, we interviewed consecutive HIV patients on first-line antiretroviral regimen attending the clinics in June 2014 using a pretested and structured questionnaire. For measuring adherence, we used 4-day recall method based on "The AIDS Clinical Trial Group adherence assessment tool". Patients were classified as "Incomplete adherence" if they missed any of the doses in the last 4 days. Data were singly entered using EpiData and descriptive analysis, and unadjusted odds ratios were calculated using EpiDataStat software. Multivariate logistic regression analysis was performed using Stata v12.0. RESULTS: Of 974 patients interviewed, 539 (56%) were females, and mean age was 35 years. The proportion of patients with incomplete adherence was 13% (95% confidence interval: 11%-15%). In multivariate analysis, factors significantly associated with incomplete adherence included young age, being Protestant Christian, consuming alcohol, being single, and being a member of an HIV association. Psychosocial factors like stigma, depression, and satisfaction to care were not associated with incomplete adherence in the current context. CONCLUSION: The overall adherence to ART was good. However, there were certain subgroups with incomplete adherence who need special attention. The health care providers (especially counselors) need to be aware of these subgroups and tailor their counseling to improve adherence among these groups. Exploratory qualitative studies may help uncover the exact reasons for incomplete adherence. PMID- 26604707 TI - Variation in medication adherence across patient behavioral segments: a multi country study in hypertension. AB - OBJECTIVES: This study determines the following for a hypertensive patient population: 1) the prevalence of patient worldview clusters; 2) differences in medication adherence across these clusters; and 3) the adherence predictive power of the clusters relative to measures of patients' concerns over their medication's cost, side effects, and efficacy. METHODS: Members from patient panels in the UK, Germany, Italy, and Spain were invited to participate in an online survey that included the Medication Adherence Report Scale-5 (MARS-5) adherence instrument and a patient segmentation instrument developed by CoMac Analytics, Inc, based on a linguistic analysis of patient talk. Subjects were screened to have a diagnosis of hypertension and treatment with at least one antihypertensive agent. RESULTS: A total of 353 patients completed the online survey in August/September 2011 and were categorized against three different behavioral domains: 1) control orientation (n=176 respondents [50%] for I, internal; n=177 respondents [50%] for E, external); 2) emotion (n=100 respondents [28%] for P, positive; n=253 respondents [72%] for N, negative); and 3) agency or ability to act on choices (n=227 respondents [64%] for H, high agency; n=126 [36%] for L, low agency). Domains were grouped into eight different clusters with EPH and IPH being the most prevalent (88 respondents [25%] in each cluster). The prevalence of other behavior clusters ranged from 6% (22 respondents, INH) to 12% (41 respondents, IPL). The proportion of patients defined as perfectly adherent (scored 25 on MARS-5) varied sharply across the segments: 51% adherent (45 of 88 respondents) for the IPH vs 8% adherent (2 of 25 respondents) classified as INL. Side effects, being employed, and stopping medicine because the patient got better were all significant determinants of adherence in a probit regression model. CONCLUSION: By categorizing patients into worldview clusters, we identified wide differences in adherence that can be used to prioritize interventions and to customize adherence messages. Also, the predictive power of segments was greater than that for variables measuring concerns over cost, side effects, and efficacy. PMID- 26604708 TI - Associations of quality of life, pain, and self-reported arthritis with age, employment, bleed rate, and utilization of hemophilia treatment center and health care provider services: results in adults with hemophilia in the HERO study. AB - INTRODUCTION: Severe hemophilia and subsequent hemophilic arthropathy result in joint pain and impaired health-related quality of life (HRQoL). Assessment of HRQoL in persons with hemophilia (PWH), including underlying factors that drive HRQoL differences, is important in determining health care resource allocation and in making individualized clinical decisions. AIM: To examine potential associations between HRQoL, pain interference, and self-reported arthritis and age, employment, activity, bleed frequency, and hemophilia treatment center and health care professional utilization. METHODS: PWH (age >=18 years) from ten countries completed a 5-point Likert scale on pain interference over the previous 4 weeks, the EQ-5D-3L scale (mobility, usual activities, self-care, pain/discomfort, anxiety/depression) including a health-related visual analog scale (0-100, coded as an 11-point categorical response). RESULTS: Pain interference (extreme/a lot) was higher in PWH aged >40 years (31%) compared to those aged 31-40 years (27%) or <=30 years (21%). In an analysis of eight countries with home treatment, PWH who reported EQ-5D mobility issues were less likely to be employed (53% vs 79%, with no mobility issues). Median annual bleed frequency increased with worsening EQ-5D pain or discomfort. The percentage of PWH with inhibitors reporting visual analog scale scores of 80-90-100 was lower (20%) than those without inhibitors (34%). Median bleed frequency increased with pain. Globally, nurse and social worker involvement increased with disability and pain; physiotherapist utilization was moderate regardless of the extent of disability or pain. CONCLUSION: Increased disability and pain were associated with increased age, lower employment, higher reported bleed frequency, and lower HRQoL. PMID- 26604709 TI - Health state utility valuation in radioactive iodine-refractory differentiated thyroid cancer. AB - PURPOSE: The aim of this study was to elicit utilities for radioactive iodine refractory differentiated thyroid cancer (RR-DTC) and evaluate the impact of treatment response and toxicities on quality of life. PATIENTS AND METHODS: RR DTC health states were developed based on data from a previous qualitative study and iterative review by clinical experts. Following piloting, health states underwent valuation by 100 members of the UK public during time trade-off interviews. Mean utilities and descriptive distribution statistics were calculated, and a logistic regression analysis was conducted. RESULTS: The demographic characteristics of the study sample were generally reflective of the UK population. Clear differentiation in valuation between health states was observed. No response/stable disease had an adjusted utility value of 0.87, with a corresponding gain of +0.04 following a treatment response and a decline of 0.35 for disease progression. Adverse events were associated with utility decrements between -0.47 (grade III diarrhea) and -0.05 (grade I/II alopecia). CONCLUSION: The trade-off interviews derived utility weights show clear differentiation between RR-DTC health states in response to treatment. The values reported in this study are suitable for cost-effectiveness evaluations for new treatments in RR-DTC. PMID- 26604710 TI - How do patients with a Turkish background evaluate their medical care in Germany? An observational study in primary care. AB - BACKGROUND: Patients' evaluation of medical care is an essential dimension of quality of care and an important aspect of the feedback cycle for health care providers. The aim of this study was to document how patients with a Turkish background evaluate primary care in Germany and determine which aspects of care are associated with language abilities. METHODS: The study was based on an observational design. Patients with a Turkish background from German primary care practices completed the EUROPEP (European Project on Patient Evaluation of General Practice Care) questionnaire consisting of 23 items. Seventeen primary care practices were involved with either German (n=8) or Turkish (n=9) general practitioners (GPs). RESULTS: A convenience sample of 472 patients with a Turkish background from 17 practices participated in the study (response rate 39.9%). Practices with a German GP had a lower response rate (19.6%) than those with a Turkish GP (57.5%). Items evaluated the highest were "keeping data confidential" (73.4%) and "quick services for urgent health problems" (69.9%). Subgroup analysis showed lower evaluation scores from patients with good or excellent German language abilities. Patients who consulted a Turkish GP had higher evaluation scores. CONCLUSION: The evaluation from patients with a Turkish background living in Germany with either Turkish or German GPs showed lower scores than patients in other studies in Europe using EUROPEP. However, our results had higher evaluation scores than those of Turkish patients evaluating GPs in Turkey. Therefore, different explanation models for these findings should be explored in future studies. PMID- 26604711 TI - Simplicity, flexibility, and respect: preferences related to patient education in hardly reached people with type 2 diabetes. AB - Individuals with lower income and less education are two to four times more likely to develop diabetes than more advantaged individuals. In response to this, there is a need for developing health promotion activities targeting hardly reached populations. The aim of this study was to examine the perspectives of hardly reached people with type 2 diabetes on patient education, focusing on their wishes and needs regarding format and approach. Data were collected through qualitative interviews with nine individuals with type 2 diabetes with little or no education and characterized as hardly reached patients by health professionals. Interviews were transcribed verbatim and analyzed according to systematic text condensation. We identified four main categories of preferences for patient education: 1) flexibility related to start time, duration, and intensity; 2) simple and concrete education tools, with regard to design and extent; 3) being together, related to meeting people in a similar situation; and 4) respectful educators, related to constructive patient-educator relationships. Insights into the preferences of hardly reached people with diabetes can contribute to the development of appropriately tailored patient education for this patient group. PMID- 26604712 TI - Self-reported adherence to oral cancer therapy: relationships with symptom distress, depression, and personal characteristics. AB - BACKGROUND: Therapeutic cancer chemotherapy is most successful when complete dosing is achieved. Because many newer therapeutic agents are oral and self administered by the patient, adherence is a concern. The purpose of our analysis was to explore relationships between adherence, patient characteristics, and barriers to adherence. METHODS: This secondary analysis utilized self-reported data from a randomized trial of self-care management conducted at two cancer centers in the US. Symptom distress was measured using the 15-item Symptom Distress Scale (SDS-15) and depression with the Patient Health Questionnaire-9 (PHQ-9). Adherence to oral medication was self-reported using the 8-item Morisky Medication Adherence Scale (MMAS-8). Measures were collected via Web-based, study specific software ~8 weeks after treatment start date. Odds of low/medium adherence (score <8) were explored using univariate logistic regression. Given the number of factors and possible relationships among factors, a classification tree was built in lieu of a multivariable logistic regression model. RESULTS: Of the eligible participants enrolled, 77 were on oral therapy and 70 had an MMAS score. Forty-nine (70%) reported a high adherence score (=8). Higher odds of low/medium adherence were associated with greater symptom distress (P=0.09), more depression (P=0.05), chemotherapy vs hormonal oral medication (P=0.03), being female (P=0.02), and being randomized to the control group in the parent trial (P=0.09). Conversely, high adherence was associated with working (P=0.08), being married/partnered (P=0.004), and being older (P=0.02). Factors identified as significantly related to low/medium adherence from the univariate logistic regression analyses were supported by the classification tree results. CONCLUSION: Nonadherence to therapeutic oral medications in patients with cancer was associated with being unmarried/unpartnered, symptom distress, younger age, not working, and female sex. These findings may help to identify patients at risk for nonadherence and for whom supportive interventions to enhance adherence may be needed. PMID- 26604713 TI - Exploring older adults' perceptions of a patient-centered education manual for hip fracture recovery: "everything in one place". AB - PURPOSE: To describe older adults' perspectives on a new patient education manual for the recovery process after hip fracture. MATERIALS AND METHODS: The Fracture Recovery for Seniors at Home (FReSH) Start manual is an evidence-based manual for older adults with fall-related hip fracture. The manual aims to support the transition from hospital to home by facilitating self-management of the recovery process. We enrolled 31 community-dwelling older adults with previous fall related hip fracture and one family member. We collected data using a telephone based questionnaire with eight five-point Likert items and four semi-structured open-ended questions to explore participants' perceptions on the structure, content, and illustration of the manual. The questionnaire also asked participants to rate the overall utility (out of 10 points) and length of the manual. We used content analysis to describe main themes from responses to the open-ended interview questions. RESULTS: Participants' ratings for structure, content, and illustrations ranged from 4 to 5 (agree to highly agree), and the median usefulness rating was 9 (10th percentile: 7, 90th percentile: 10). Main themes from the content analysis included: ease of use and presentation; health literacy; illustration utility; health care team delivery; general impression, information support from hospital to home; emotional and decision-making support; and the novelty of the manual. CONCLUSION: The FReSH Start manual was perceived as comprehensive in content and acceptable for use with older adults post-fall related hip fracture. Participants expressed a need for delivery and explanation of the manual by a health care team member. PMID- 26604714 TI - "I wish they could be in my shoes": patients' insights into tertiary health care for type 2 diabetes mellitus. AB - BACKGROUND: Insightful accounts of patient experience within a health care system can be valuable for facilitating improvements in service delivery. OBJECTIVE: The aim of this study was to explore patients' perceptions and experiences regarding a tertiary hospital Diabetes and Endocrinology outpatient service for the management of type 2 diabetes mellitus (T2DM). METHOD: Nine patients participated in discovery interviews with an independent trained facilitator. Patients' stories were synthesized thematically using a constant comparative approach. RESULTS: Three major themes were identified from the patients' stories: 1) understanding T2DM and diabetes management with subthemes highlighting that specialist care is highly valued by patients who experience a significant burden of diabetes on daily life and who may have low health literacy and low self confidence; 2) relationships with practitioners were viewed critical and perceived lack of empathy impacted the effectiveness of care; and 3) impact of health care systems on service delivery with lack of continuity of care relating to the tertiary hospital model and limitations with appointment bookings negatively impacting on patient experience. DISCUSSION: The patients' stories suggest that the expectation of establishing a productive, ongoing relationship with practitioners is highly valued. Tertiary clinics for T2DM are well placed to incorporate novel technological approaches for monitoring and follow-up, which may overcome many of the perceived barriers of traditional service delivery. CONCLUSION: Investing in strategies that promote patient-practitioner relationships may enhance effectiveness of treatment for T2DM by meeting patient expectations of personalized care. Future changes in service delivery would benefit from incorporating patients as key stakeholders in service evaluation. PMID- 26604715 TI - Cellulose nanocrystals: synthesis, functional properties, and applications. AB - Cellulose nanocrystals are unique nanomaterials derived from the most abundant and almost inexhaustible natural polymer, cellulose. These nanomaterials have received significant interest due to their mechanical, optical, chemical, and rheological properties. Cellulose nanocrystals primarily obtained from naturally occurring cellulose fibers are biodegradable and renewable in nature and hence they serve as a sustainable and environmentally friendly material for most applications. These nanocrystals are basically hydrophilic in nature; however, they can be surface functionalized to meet various challenging requirements, such as the development of high-performance nanocomposites, using hydrophobic polymer matrices. Considering the ever-increasing interdisciplinary research being carried out on cellulose nanocrystals, this review aims to collate the knowledge available about the sources, chemical structure, and physical and chemical isolation procedures, as well as describes the mechanical, optical, and rheological properties, of cellulose nanocrystals. Innovative applications in diverse fields such as biomedical engineering, material sciences, electronics, catalysis, etc, wherein these cellulose nanocrystals can be used, are highlighted. PMID- 26604716 TI - Development and Application of a Genetic Algorithm for Variable Optimization and Predictive Modeling of Five-Year Mortality Using Questionnaire Data. AB - The problem of selecting important variables for predictive modeling of a specific outcome of interest using questionnaire data has rarely been addressed in clinical settings. In this study, we implemented a genetic algorithm (GA) technique to select optimal variables from questionnaire data for predicting a five-year mortality. We examined 123 questions (variables) answered by 5,444 individuals in the National Health and Nutrition Examination Survey. The GA iterations selected the top 24 variables, including questions related to stroke, emphysema, and general health problems requiring the use of special equipment, for use in predictive modeling by various parametric and nonparametric machine learning techniques. Using these top 24 variables, gradient boosting yielded the nominally highest performance (area under curve [AUC] = 0.7654), although there were other techniques with lower but not significantly different AUC. This study shows how GA in conjunction with various machine learning techniques could be used to examine questionnaire data to predict a binary outcome. PMID- 26604718 TI - Rates and factors associated with falls in older European Americans, Afro Caribbeans, African-Americans, and Hispanics. AB - PURPOSE: To evaluate rates and factors associated with older adult falls in different ethnic groups. PARTICIPANTS AND METHODS: Information on demographics, medical and falls history, and pain and physical activity levels was collected from 550 community-dwelling older adults (75+/-9 years old, 222 European Americans, 109 Afro-Caribbeans, 106 African-Americans, and 113 Hispanics). RESULTS: Taking medications for anxiety (risk ratio [RR] =1.4, 95% confidence interval [CI] =1.1-2.0), having incontinence (RR =1.4, 95% CI =1.1-1.8, P=0.013), back pain (RR =1.4, 95% CI =1.0-1.8), feet swelling (RR =1.3, 95% CI =1.1-1.7), and age >=75 years (RR =1.3, 95% CI =1.0-1.6) were associated with falls. The associations were stronger for Afro-Caribbeans, but they presented approximately 40% lower prevalence of falls than the other groups. CONCLUSION: Taking anxiety medication, incontinence, back pain, feet swelling, and age >=75 years were associated with falls, and Afro-Caribbeans presented lower prevalence of falls. These findings need to be taken into consideration in clinical interventions in aging. PMID- 26604717 TI - Cerebral small vessel disease and Alzheimer's disease. AB - Cerebral small vessel disease (CSVD) is a group of pathological processes with multifarious etiology and pathogenesis that are involved into the small arteries, arterioles, venules, and capillaries of the brain. CSVD mainly contains lacunar infarct or lacunar stroke, leukoaraiosis, Binswanger's disease, and cerebral microbleeds. CSVD is an important cerebral microvascular pathogenesis as it is the cause of 20% of strokes worldwide and the most common cause of cognitive impairment and dementia, including vascular dementia and Alzheimer's disease (AD). It has been well identified that CSVD contributes to the occurrence of AD. It seems that the treatment and prevention for cerebrovascular diseases with statins have such a role in the same function for AD. So far, there is no strong evidence-based medicine to support the idea, although increasing basic studies supported the fact that the treatment and prevention for cerebrovascular diseases will benefit AD. Furthermore, there is still lack of evidence in clinical application involved in specific drugs to benefit both AD and CSVD. PMID- 26604719 TI - Multicomponent physical exercise with simultaneous cognitive training to enhance dual-task walking of older adults: a secondary analysis of a 6-month randomized controlled trial with 1-year follow-up. AB - BACKGROUND: About one-third of people older than 65 years fall at least once a year. Physical exercise has been previously demonstrated to improve gait, enhance physical fitness, and prevent falls. Nonetheless, the addition of cognitive training components may potentially increase these effects, since cognitive impairment is related to gait irregularities and fall risk. We hypothesized that simultaneous cognitive-physical training would lead to greater improvements in dual-task (DT) gait compared to exclusive physical training. METHODS: Elderly persons older than 70 years and without cognitive impairment were randomly assigned to the following groups: 1) virtual reality video game dancing (DANCE), 2) treadmill walking with simultaneous verbal memory training (MEMORY), or 3) treadmill walking (PHYS). Each program was complemented with strength and balance exercises. Two 1-hour training sessions per week over 6 months were applied. Gait variables, functional fitness (Short Physical Performance Battery, 6-minute walk), and fall frequencies were assessed at baseline, after 3 months and 6 months, and at 1-year follow-up. Multiple regression analyses with planned comparisons were carried out. RESULTS: Eighty-nine participants were randomized to three groups initially; 71 completed the training and 47 were available at 1 year follow-up. DANCE/MEMORY showed a significant advantage compared to PHYS in DT costs of step time variability at fast walking (P=0.044). Training-specific gait adaptations were found on comparing DANCE and MEMORY: DANCE reduced step time at fast walking (P=0.007) and MEMORY reduced gait variability in DT and DT costs at preferred walking speed (both trend P=0.062). Global linear time effects showed improved gait (P<0.05), functional fitness (P<0.05), and reduced fall frequency (-77%, P<0.001). Only single-task fast walking, gait variability at preferred walking speed, and Short Physical Performance Battery were reduced at follow-up (all P<0.05 or trend). CONCLUSION: Long-term multicomponent cognitive physical and exclusive physical training programs demonstrated similar potential to counteract age-related decline in physical functioning. PMID- 26604720 TI - Efficacy and safety of stenting for elderly patients with severe and symptomatic carotid artery stenosis: a critical meta-analysis of randomized controlled trials. AB - OBJECTIVE: To investigate both short-term and long-term therapeutic efficacy and safety of carotid artery stenting (CAS) and carotid artery endarterectomy (CEA) for elderly patients with severe and symptomatic carotid artery stenosis. METHODS: PubMed, EMBASE, Cochrane Library, Clinical Trials Register Centers, and Google Scholar were comprehensively searched. After identifying relevant randomized controlled trials, methodological quality was assessed by using Cochrane tools of bias assessment. Meta-analysis was performed by RevMan software, and subgroup analyses according to different follow-up periods were also conducted. RESULTS: Sixteen articles of nine randomized controlled trials containing 6,984 patients were included. Compared with CEA, CAS was associated with high risks of stroke during periprocedural 30 days (risk ratio [RR]=1.47, 95% confidence interval [CI]: 1.15-1.88), 48 months (RR=1.37, 95% CI: 1.11-1.70), and >48 months (RR=1.76, 95% CI: 1.34-2.31). There was no significant difference in the aspects of death, disabling stroke, or death at any time between the groups. For other periprocedural complications, CAS decreased the risk of myocardial infarction (RR=0.44, 95% CI: 0.26-0.75), cranial nerve palsy (RR=0.09, 95% CI: 0.04-0.22) and hematoma (RR=0.31, 95% CI: 0.14-0.68) compared with CEA, while it increased the risk of bradycardia or hypotension (RR=8.45, 95% CI 2.91 24.58). CONCLUSION: Compared with CEA, CAS reduced hematoma, periprocedural myocardial infarction, and cranial nerve palsy, while it was associated with higher risks of both short-term and long-term nondisabling stroke. And they seemed to be equivalent in other outcome measures. As regards to its minimal invasion, it should be applied only in specific patients. PMID- 26604722 TI - A quantitative dynamic systems model of health-related quality of life among older adults. AB - Health-related quality of life (HRQOL) is a person-centered concept. The analysis of HRQOL is highly relevant in the aged population, which is generally suffering from health decline. Starting from a conceptual dynamic systems model that describes the development of HRQOL in individuals over time, this study aims to develop and test a quantitative dynamic systems model, in order to reveal the possible dynamic trends of HRQOL among older adults. The model is tested in different ways: first, with a calibration procedure to test whether the model produces theoretically plausible results, and second, with a preliminary validation procedure using empirical data of 194 older adults. This first validation tested the prediction that given a particular starting point (first empirical data point), the model will generate dynamic trajectories that lead to the observed endpoint (second empirical data point). The analyses reveal that the quantitative model produces theoretically plausible trajectories, thus providing support for the calibration procedure. Furthermore, the analyses of validation show a good fit between empirical and simulated data. In fact, no differences were found in the comparison between empirical and simulated final data for the same subgroup of participants, whereas the comparison between different subgroups of people resulted in significant differences. These data provide an initial basis of evidence for the dynamic nature of HRQOL during the aging process. Therefore, these data may give new theoretical and applied insights into the study of HRQOL and its development with time in the aging population. PMID- 26604721 TI - Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study. AB - BACKGROUND: The aim of this study was to investigate the ability of a glucosamine containing supplement to improve locomotor functions in subjects with knee pain. METHODS: A randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted for 16 weeks in 100 Japanese subjects (age, 51.8+/-0.8 years) with knee pain. Subjects were randomly assigned to one of the two supplements containing 1) 1,200 mg of glucosamine hydrochloride, 60 mg of chondroitin sulfate, 45 mg of type II collagen peptides, 90 mg of quercetin glycosides, 10 mg of imidazole peptides, and 5 MUg of vitamin D per day (GCQID group, n=50) or 2) a placebo (placebo group, n=50). Japanese Knee Osteoarthritis Measure, visual analog scale score, normal walking speed, and knee-extensor strength were measured to evaluate the effects of the supplement on knee-joint functions and locomotor functions. RESULTS: In subjects eligible for efficacy assessment, there was no significant group * time interaction, and there were improvements in knee-joint functions and locomotor functions in both groups, but there was no significant difference between the groups. In subjects with mild-to severe knee pain at baseline, knee-extensor strength at week 8 (104.6+/-5.0% body weight vs 92.3+/-5.5% body weight, P=0.030) and the change in normal walking speed at week 16 (0.11+/-0.03 m/s vs 0.05+/-0.02 m/s, P=0.038) were significantly greater in the GCQID group than in the placebo group. Further subgroup analysis based on Kellgren-Lawrence (K-L) grade showed that normal walking speed at week 16 (1.36+/-0.05 m/s vs 1.21+/-0.02 m/s, P<0.05) was significantly greater in the GCQID group than in the placebo group in subjects with K-L grade I. No adverse effect of treatment was identified in the safety assessment. CONCLUSION: In subjects with knee pain, GCQID supplementation was effective for relieving knee pain and improving locomotor functions. PMID- 26604723 TI - Consumer views about aging-in-place. AB - BACKGROUND: Supporting older people's choices to live safely and independently in the community (age-in-place) can maximize their quality of life and minimize unnecessary hospitalizations and residential care placement. Little is known of the views of older people about the aging-in-place process, and how they approach and prioritize the support they require to live in the community accommodation of their choice. PURPOSE: To explore and synthesize the experiences and perspectives of older people planning for and experiencing aging-in-place. METHODS: Two purposively sampled groups of community-dwelling people aged 65+ years were recruited for individual interviews or focus groups. The interviews were semistructured, audio-recorded, and transcribed. Themes were identified by three researchers working independently, then in consort, using a qualitative thematic analysis approach. RESULTS: Forty-two participants provided a range of insights about, and strategies for, aging-in-place. Thematic saturation was reached before the final interviews. We identified personal characteristics (resilience, adaptability, and independence) and key elements of successful aging-in-place, summarized in the acronym HIPFACTS: health, information, practical assistance, finance, activity (physical and mental), company (family, friends, neighbors, pets), transport, and safety. DISCUSSION: This paper presents rich, and rarely heard, older people's views about how they and their peers perceive, characterize, and address changes in their capacity to live independently and safely in the community. Participants identified relatively simple, low-cost, and effective supports to enable them to adapt to change, while retaining independence and resilience. The findings highlighted how successful aging-in place requires integrated, responsive, and accessible primary health and community services. PMID- 26604724 TI - Undertreatment of osteoporosis and the role of gastrointestinal events among elderly osteoporotic women with Medicare Part D drug coverage. AB - OBJECTIVES: To examine the rate of osteoporosis (OP) undertreatment and the association between gastrointestinal (GI) events and OP treatment initiation among elderly osteoporotic women with Medicare Part D drug coverage. METHODS: This retrospective cohort study utilized a 20% random sample of Medicare beneficiaries. Included were women >=66 years old with Medicare Part D drug coverage, newly diagnosed with OP in 2007-2008 (first diagnosis date as the index date), and with no prior OP treatment. GI event was defined as a diagnosis or procedure for a GI condition between OP diagnosis and treatment initiation or at the end of a 12-month follow-up, whichever occurred first. OP treatment initiation was defined as the use of any bisphosphonate (BIS) or non-BIS within 1 year postindex. Logistic regression, adjusted for patient characteristics, was used to model the association between 1) GI events and OP treatment initiation (treated versus nontreated); and 2) GI events and type of initial therapy (BIS versus non-BIS) among treated patients only. RESULTS: A total of 126,188 women met the inclusion criteria: 72.1% did not receive OP medication within 1 year of diagnosis and 27.9% had GI events. Patients with a GI event were 75.7% less likely to start OP treatment (odds ratio [OR]=0.243; P<0.001); among treated patients, patients with a GI event had 11.3% lower odds of starting with BIS versus non-BIS (OR=0.887; P<0.001). CONCLUSION: Among elderly women newly diagnosed with OP, only 28% initiated OP treatment. GI events were associated with a higher likelihood of not being treated and, among treated patients, a lower likelihood of being treated with BIS versus non-BIS. PMID- 26604725 TI - The effectiveness of a standardized rose hip powder, containing seeds and shells of Rosa canina, on cell longevity, skin wrinkles, moisture, and elasticity. AB - OBJECTIVE: To evaluate the effects of a rose hip powder (Hyben Vital((r))) made from seeds and shells on cell senescence, skin wrinkling, and aging. METHODS: A total of 34 healthy subjects, aged 35-65 years, with wrinkles on the face (crow's feet) were subjected to a randomized and double-blinded clinical study of the effects of the rose hip powder, as compared to astaxanthin, a well-known remedy against wrinkles. During the 8-week study, half of the participants ingested the standardized rose hip product, while the other half ingested astaxanthin. Objective measurements of facial wrinkles, skin moisture, and elasticity were made by using Visioscan, Corneometer, and Cutometer at the beginning of the study, after 4 weeks, and after 8 weeks. Evaluation of participant satisfaction of both supplements was assessed using questionnaires. In addition, the effect of the rose hip preparation on cell longevity was measured in terms of leakage of hemoglobin through red cell membranes (hemolytic index) in blood samples kept in a blood bank for 5 weeks. Significance of all values was attained with P<=0.05. RESULTS: In the double-blinded study, the rose hip group showed statistically significant improvements in crow's-feet wrinkles (P<0.05), skin moisture (P<0.05), and elasticity (P<0.05) after 8 weeks of treatment. A similar improvement was observed for astaxanthin, with P-values 0.05, 0.001, and 0.05. Likewise, both groups expressed equal satisfaction with the results obtained in their self-assessment. The rose hip powder further resulted in increased cell longevity of erythrocyte cells during storage for 5 weeks in a blood bank. CONCLUSION: Results suggest that intake of the standardized rose hip powder (Hyben Vital((r))) improves aging-induced skin conditions. The apparent stabilizing effects of the rose hip product on cell membranes of stored erythrocyte cells observed in this study may contribute to improve the cell longevity and obstructing skin aging. PMID- 26604726 TI - Social representation of "hearing loss": cross-cultural exploratory study in India, Iran, Portugal, and the UK. AB - BACKGROUND: Hearing loss is one of the most common chronic conditions in older adults. In audiology literature, several studies have examined the attitudes and behavior of people with hearing loss; however, not much is known about the manner in which society in general views and perceives hearing loss. This exploratory study was aimed at understanding the social representation of hearing loss (among the general public) in the countries of India, Iran, Portugal, and the UK. We also compared these social representations. MATERIALS AND METHODS: The study involved a cross-sectional design, and participants were recruited using the snowball sampling method. A total of 404 people from four countries participated in the study. Data were collected using a free-association task where participants were asked to produce up to five words or phrases that came to mind while thinking about hearing loss. In addition, they were also asked to indicate if each word they presented had positive, neutral, or negative associations in their view. Data were analyzed using various qualitative and quantitative methods. RESULTS: The most frequently occurring categories were: assessment and management; causes of hearing loss; communication difficulties; disability; hearing ability or disability; hearing instruments; negative mental state; the attitudes of others; and sound and acoustics of the environment. Some categories were reported with similar frequency in most countries (eg, causes of hearing loss, communication difficulties, and negative mental state), whereas others differed among countries. Participants in India reported significantly more positive and fewer negative associations when compared to participants from Iran, Portugal, and the UK. However, there was no statistical difference among neutral responses reported among these countries. Also, more differences were noted among these countries than similarities. CONCLUSION: These findings provide useful insights into the public perception of hearing loss that may prove useful in public education and counseling. PMID- 26604728 TI - Medicinal clays improve the endurance of loaded inspiratory muscles in COPD: a randomized clinical trial of nonpharmacological treatment. AB - BACKGROUND: Inspiratory resistive breathing (IRB) challenges affect respiratory muscle endurance in healthy individuals, which is considered to be an interleukin 6 (IL-6)-dependent mechanism. Whether nonpharmacological thermal therapies promote the endurance of loaded inspiratory muscles in chronic obstructive pulmonary disease (COPD) is unclear. The objectives of this study were to compare the effects of two thermal interventions on endurance time (ET) and plasma IL-6 concentration following an IRB challenge. METHODS: This study was a randomized, parallel-group, unblinded clinical trial in a single-center setting. Forty-two patients (aged 42-76 years) suffering from mild to severe COPD participated in this study. Both groups completed 12 sessions of the mud bath therapy (MBT) (n=22) or leisure thermal activity (LTA) (n=19) in a thermal spa center in Italy. Pre- and postintervention spirometry, maximum inspiratory pressure, and plasma mediators were obtained and ET and endurance oxygen expenditure (VO2Endur) were measured following IRB challenge at 40% of maximum inspiratory pressure. RESULTS: There was no difference in DeltaIL-6 between the intervention groups. But, IRB challenge increased cytokine IL-6 plasma levels systematically. The effect size was small. A statistically significant treatment by IRB challenge effect existed in ET, which significantly increased in the MBT group (P=0.003). In analysis of covariance treatment by IRB challenge analysis with LnVO2Endur as the dependent variable, DeltaIL-6 after intervention predicted LnVO2Endur in the MBT group, but not in the LTA group. Adverse events occurred in two individuals in the MBT group, but they were mainly transient. One patient in the LTA group dropped out. CONCLUSION: MBT model improves ET upon a moderate IRB challenge, indicating the occurrence of a training effect. The LnVO2Endur/DeltaIL-6 suggests a physiologic adaptive mechanism in respiratory muscles of COPD patients allocated to treatment. Both thermal interventions are safe. PMID- 26604727 TI - Causative factors for formation of toxic islet amyloid polypeptide oligomer in type 2 diabetes mellitus. AB - Human islet amyloid polypeptide (h-IAPP) is a peptide hormone that is synthesized and cosecreted with insulin from insulin-secreting pancreatic beta-cells. Recently, h-IAPP was proposed to be the main component responsible for the cytotoxic pancreatic amyloid deposits in patients with type 2 diabetes mellitus (T2DM). Since the causative factors of IAPP (or amylin) oligomer aggregation are not fully understood, this review will discuss the various forms of h-IAPP aggregation. Not all forms of IAPP aggregates trigger the destruction of beta cell function and loss of beta-cell mass; however, toxic oligomers do trigger these events. Once these toxic oligomers form under abnormal metabolic conditions in T2DM, they can lead to cell disruption by inducing cell membrane destabilization. In this review, the various factors that have been shown to induce toxic IAPP oligomer formation will be presented, as well as the potential mechanism of oligomer and fibril formation from pro-IAPPs. Initially, pro-IAPPs undergo enzymatic reactions to produce the IAPP monomers, which can then develop into oligomers and fibrils. By this mechanism, toxic oligomers could be generated by diverse pathway components. Thus, the interconnections between factors that influence amyloid aggregation (eg, absence of PC2 enzyme, deamidation, reduction of disulfide bonds, environmental factors in the cell, genetic mutations, copper metal ions, and heparin) will be presented. Hence, this review will aid in understanding the fundamental causative factors contributing to IAPP oligomer formation and support studies for investigating novel T2DM therapeutic approaches, such as the development of inhibitory agents for preventing oligomerization at the early stages of diabetic pathology. PMID- 26604729 TI - Health care and social care costs of pneumonia in Denmark: a register-based study of all citizens and patients with COPD in three municipalities. AB - BACKGROUND: Pneumonia is a frequent lung infection and a serious illness, which is often diagnosed among patients hospitalized with acute exacerbations of COPD. The aim of this study was to estimate the attributable costs due to pneumonia among patients hospitalized with pneumonia compared to a matched general population control group without pneumonia hospitalization. METHODS: This study includes citizens older than 18 years from three municipalities (n=142,344). Based on national registers and municipal data, the health and social care costs of pneumonia in the second half of 2013 are estimated and compared with propensity score-matched population controls. RESULTS: The average health care costs of 383 patients hospitalized with pneumonia in the second half of 2013 were US$34,561 per patient. Among pneumonia patients with COPD, the costs were US$35,022. The attributable costs of patients with pneumonia compared to the population control group for the 6-month period were US$24,155 per case. Overall, the attributable costs for the 383 pneumonia cases amounted to US$9.25 million. Subgroup analyses showed that costs increased with age. The attributable costs due to pneumonia were highest among the 18-59-year-old and the 70-79-year-old patients. This difference is likely to reflect an increased risk of mortality among the pneumonia patients. Men have higher costs than women in the pneumonia group. CONCLUSION: The costs of pneumonia are considerable. In three Danish municipalities, the attributable costs due to pneumonia were US$24,155 per case or US$64,992 per 1,000 inhabitants in the second half of 2013. Similar high health care and social care costs were found for pneumonia patients with COPD - the largest group having pneumonia episodes. The municipalities are responsible for 49% of the costs, while a closer focus on the prevention of pneumonia may be advisable, eg, starting with citizens having COPD. PMID- 26604730 TI - Long-term effects of gastrectomy in patients with spirometry-defined COPD and patients at risk of COPD: a case-control study. AB - OBJECTIVE: Comorbidities are characteristic of COPD. However, little is known about the secondary manifestations of COPD in the gastrointestinal tract. Therefore, we aimed to explore the long-term effects of gastrectomy in patients with spirometry-defined COPD or those at risk of COPD. PARTICIPANTS: Subjects included 87 patients either with COPD or at risk of COPD (symptomatic) who underwent gastrectomy between December 2003 and October 2013 (group A), and 174 patients either with COPD or at risk of COPD, matched by age (+/-5 years), sex, and forced expiratory volume in 1 second (FEV1) as percentage of predicted (FEV1% predicted) (+/-5%) (group B). METHODS: All patients underwent routine blood chemistry and pulmonary function tests, arterial blood gas analysis, 6-minute walk test (6MWT), high-resolution chest computed tomography scans, and nutritional assessments. RESULTS: The mean duration postgastrectomy was 18.3+/ 15.4 years. The mean FEV1 and FEV1% predicted were 2.07+/-0.76 L and 74.6+/ 24.5%, respectively. Univariate analysis indicated that group A patients had significantly lower body mass index, fat-free mass index, and serum hemoglobin and albumin concentration (all P=0.00), and walked a significantly shorter distance in the 6MWT (P<0.05). Multivariate linear regression analysis for the distance in the 6MWT indicated that increased residual volume (RV) to total lung capacity (TLC) as percentage of predicted (%RV/TLC) alone was an independent and significant predictor of reduced distances in the 6MWT. CONCLUSION: We concluded that nutritional insufficiency in patients with COPD (or those at risk of COPD) who previously underwent gastrectomy might lead to hyperinflation and consequently, decreased exercise capacity. PMID- 26604731 TI - Erdosteine reduces inflammation and time to first exacerbation postdischarge in hospitalized patients with AECOPD. AB - PURPOSE: Mucolytics can improve disease outcome in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The objectives of this study were to investigate the effects of erdosteine (ER), a mucolytic agent with antioxidant activity, on systemic inflammation, symptoms, recurrence of exacerbation, and time to first exacerbation postdischarge in hospitalized patients with AECOPD. PATIENTS AND METHODS: Patients admitted to hospital with AECOPD were randomized to receive either ER 900 mg daily (n=20) or a matching control (n=20). Treatment was continued for 10 days until discharge. Patients also received standard treatment with steroids, nebulized bronchodilators, and antibiotics as appropriate. Serum C-reactive protein levels, lung function, and breathlessness-cough-sputum scale were measured on hospital admission and thereafter at days 10 and 30 posttreatment. Recurrence of AECOPD-requiring antibiotics and/or oral steroids and time to first exacerbation in the 2 months (days 30 and 60) postdischarge were also assessed. RESULTS: Mean serum C-reactive protein levels were lower in both groups at days 10 and 30, compared with those on admission, with significantly lower levels in the ER group at day 10. Improvements in symptom score and forced expiratory volume in 1 second were greater in the ER than the control group, which reached statistical significance on day 10. ER was associated with a 39% lower risk of exacerbations and a significant delay in time to first exacerbation (log-rank test P=0.009 and 0.075 at days 30 and 60, respectively) compared with controls. CONCLUSION: Results confirm that the addition of ER (900 mg/d) to standard treatment improves outcomes in patients with AECOPD. ER significantly reduced airway inflammation, improved the symptoms of AECOPD, and prolonged time to first exacerbation. The authors suggest ER could be most beneficial in patients with recurring, prolonged, and/or severe exacerbations of COPD. PMID- 26604732 TI - The phenotype of concurrent chronic bronchitis and frequent exacerbations in patients with severe COPD attending Swedish secondary care units. AB - BACKGROUND: Chronic bronchitis and previous exacerbations are both well-known risk factors for new exacerbations, impaired health-related quality of life, and increased mortality in COPD. The aim of the study was to characterize the phenotype of concurrent chronic bronchitis and frequent exacerbation in severe COPD. METHODS: Information on patient characteristics, comorbidity, and exacerbations from the previous year (total number and number requiring hospitalization) was collected from 373 patients with stage III and IV COPD attending 27 secondary care respiratory units in Sweden. Logistic regression used chronic bronchitis and frequent exacerbations (>=2 exacerbations or >=1 hospitalized exacerbations in the previous year) as response variables. Stratification and interaction analyses examined effect modification by sex. RESULTS: Chronic bronchitis was associated with current smoking (adjusted odds ratio [OR] [95% CI], 2.75 [1.54-4.91]; P=0.001), frequent exacerbations (OR [95% CI], 1.93 [1.24-3.01]; P=0.004), and musculoskeletal symptoms (OR [95% CI], 1.74 [1.05-2.86]; P=0.031), while frequent exacerbations were associated with lung function (forced expiratory volume in 1 second as a percentage of predicted value [FEV1% pred]) (OR [95% CI] 0.96 [0.94-0.98]; P=0.001) and chronic bronchitis (OR [95% CI] 1.73 [1.11-2.68]; P=0.015). The phenotype with both chronic bronchitis and frequent exacerbations was associated with FEV1% pred (OR [95% CI] 0.95 [0.92 0.98]; P=0.002) and musculoskeletal symptoms (OR [95% CI] 2.55 [1.31-4.99]; P=0.006). The association of smoking with the phenotype of chronic bronchitis and exacerbations was stronger in women than in men (interaction, P=0.040). CONCLUSION: Musculoskeletal symptoms and low lung function are associated with the phenotype of combined chronic bronchitis and frequent exacerbations in severe COPD. In women, current smoking is of specific importance for this phenotype. This should be considered in clinical COPD care. PMID- 26604733 TI - The importance of inhaler devices: the choice of inhaler device may lead to suboptimal adherence in COPD patients. AB - OBJECTIVE: This study aims to identify factors associated with poor adherence to COPD treatment in patients receiving a fixed-dose combination (FDC) of inhaled corticosteroids and long-acting beta2-agonist (ICS/LABA), focusing on the importance of inhaler devices. METHODS: We conducted a retrospective and multicenter study based on a review of medical registries between 2007 and 2012 of COPD patients (n=1,263) treated with ICS/LABA FDC, whose medical devices were either dry powder inhalers (DPIs) or pressurized metered-dose inhalers (pMDI). Medication adherence included persistence outcomes through 18 months and medication possession ratios. Data on exacerbations, comorbidities, demographic characteristics, and health care resource utilization were also included as confounders of adherence. RESULTS: The analyses revealed that COPD patients whose medication was delivered through a DPI were less likely to have medication adherence compared to patients with pMDI, after adjusting for confounding factors, especially active ingredients. Younger groups of patients were less likely to be adherent compared to the oldest group. Smoker men were less likely to be adherent compared to women and non-smokers. Comorbidities decreased the probability of treatment adherence. Those patients that visited their doctor once a month were more likely to adhere to their medication regimen; however, suboptimal adherence was more likely to occur among those patients who visited more than three times per month their doctor. We also found that worsening of COPD is negatively associated with adherence. CONCLUSION: According to this study, inhaler devices influence patients' adherence to long-term COPD medication. We also found that DPIs delivering ICS/LABA FDC had a negative impact on adherence. Patients' clinic and socioeconomic characteristics were associated with adherence. PMID- 26604735 TI - Erratum: Pulmonary hemodynamic profile in chronic obstructive pulmonary disease [Corrigendum]. PMID- 26604734 TI - The efficacy and safety of triple inhaled treatment in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis using Bayesian methods. AB - PURPOSE: Although tiotropium (TIO) and inhaled corticosteroid (ICS)/long-acting beta-agonists are frequently prescribed together, the efficacy of "triple therapy" has not been scientifically demonstrated. We conducted a systematic review and meta-analysis using Bayesian methods to compare triple therapy and TIO monotherapy. METHODS: We searched the MEDLINE, EMBASE, and Cochrane Library databases for randomized controlled trials comparing the efficacy and safety of triple therapy and TIO monotherapy in patients with chronic obstructive pulmonary disease (COPD). We conducted a meta-analysis to compare the effectiveness and safety of triple therapy and TIO monotherapy using Bayesian random effects models. RESULTS: Seven trials were included, and the risk of bias in the majority of the studies was acceptable. There were no statistically significant differences in the incidence of death and acute exacerbation of disease in the triple therapy and TIO monotherapy groups. Triple therapy improved the prebronchodilator forced expiratory volume in 1 second (mean difference [MD], 63.68 mL; 95% credible interval [CrI], 45.29-82.73), and patients receiving triple therapy showed more improvement in St George Respiratory Questionnaire scores (MD, -3.11 points; 95% CrI, -6.00 to -0.80) than patients receiving TIO monotherapy. However, both of these differences were lower than the minimal clinically important difference (MCID). No excessive adverse effects were reported in triple therapy group. CONCLUSION: Triple therapy with TIO and ICSs/long-acting beta-agonists was only slightly more efficacious than TIO monotherapy in treating patients with COPD. Further investigations into the efficacy of new inhaled drugs are needed. PMID- 26604736 TI - Current care services provided for patients with COPD in the Eastern province in Saudi Arabia: a descriptive study. AB - BACKGROUND: COPD is a leading cause of morbidity and mortality worldwide. The prevalence rate of COPD in the general Saudi population is estimated to be 2.4% and 14.2% among smokers. Not much is known about current health care services for patients with COPD in Saudi Arabia. The objective of this study was to determine the current care services for patients with COPD provided by government hospitals in the Eastern province of Saudi Arabia. METHODS: A cross-sectional study was conducted in the Eastern province of Saudi Arabia. Directors of the Department of Internal Medicine from all 22 general government hospitals that are under the responsibility of the Ministry of Health or the Ministry of Higher Education in this region were asked to participate. Data were collected using a questionnaire. RESULTS: The study results indicated that there are limited hospital facilities for patients with COPD: no respiratory departments in any of the included hospitals, no spirometry in 77.3% of the hospitals, no intensive care units in 63.7% of the hospitals, and no pulmonary rehabilitation program in any of the hospitals. Among the included 22 hospitals, 24 respiratory physicians, 29 respiratory therapists, and three physiotherapists were involved in COPD care. CONCLUSION: In conclusion, current care services provided by government hospitals in the Eastern province of Saudi Arabia for patients with COPD do not meet international recommendations for COPD management. Increased awareness, knowledge, and implementation of COPD guidelines by health care providers will most probably improve COPD management in Saudi Arabia. In addition, the government could improve dissemination of information about COPD management through national programs and by offering specific education regarding respiratory diseases. PMID- 26604737 TI - Triple therapy with salmeterol/fluticasone propionate 50/250 plus tiotropium bromide improve lung function versus individual treatments in moderate-to-severe Japanese COPD patients: a randomized controlled trial - Evaluation of Airway sGaw after treatment with tripLE. AB - PURPOSE: Triple therapy using salmeterol/fluticasone propionate (FP) and tiotropium bromide is commonly used to treat chronic obstructive pulmonary disease (COPD), but sparse efficacy data exist in COPD patients with fewer symptoms and with a lower dose of inhaled corticosteroid in Japanese patients. The effects of of salmeterol/fluticasone propionate 50/250 MUg (SFC250) twice daily plus tiotropium 18 MUg (TIO) once daily and individual treatments on lung function were compared. PATIENTS AND METHODS: Fifty three Japanese COPD patients participated in this randomized, double-blind, double-dummy, Williams square design crossover study. Lung function was assessed by plethysmography and spirometry. RESULTS: The primary endpoint of postdose specific airway conductance area under the curve (AUC0-4h) on day 28 was significantly higher following SFC250 + TIO (0.854) compared with TIO (0.737, 15.8%) and SFC250 (0.663, 28.8%) alone. SFC250 + TIO significantly improved trough forced expiratory volume in 1 second from baseline versus TIO (0.161 L, P<0.001) and SFC250 (0.103 L, P=0.008). SFC250 + TIO significantly improved residual volume compared with TIO (P<0.001) and SFC250 (P=0.003) on day 28. Nonsignificant improvements were seen in trough inspiratory capacity, total lung capacity, and thoracic gas volume. There was no mean change seen in rescue medication. CONCLUSION: Triple therapy using SFC250 + TIO was well tolerated and gave a greater improvement in bronchodilation compared with TIO and SFC250 alone in Japanese patients with COPD. There was improvement in few symptoms, but no mean change was seen in patient-reported outcomes measured by rescue medication use. PMID- 26604738 TI - Comparative efficacy of long-acting muscarinic antagonist monotherapies in COPD: a systematic review and network meta-analysis. AB - BACKGROUND: Randomized, controlled trials comparing long-acting muscarinic antagonist (LAMA) efficacy in COPD are limited. This network meta-analysis (NMA) assessed the relative efficacy of tiotropium 18 ug once-daily (OD) and newer agents (aclidinium 400 ug twice-daily, glycopyrronium 50 ug OD, and umeclidinium 62.5 ug OD). METHODS: A systematic literature review identified randomized, controlled trials of adult COPD patients receiving LAMAs. A NMA within a Bayesian framework examined change from baseline in trough forced expiratory volume in 1 second (FEV1), transitional dyspnea index focal score, St George's Respiratory Questionnaire score, and rescue medication use. RESULTS: Twenty-four studies (n=21,311) compared LAMAs with placebo/each other. Aclidinium, glycopyrronium, tiotropium, and umeclidinium, respectively, demonstrated favorable results versus placebo, for change from baseline (95% credible interval) in 12-week trough FEV1 (primary endpoint: 101.40 mL [77.06-125.60]; 117.20 mL [104.50-129.90]; 114.10 mL [103.10-125.20]; 136.70 mL [104.20-169.20]); 24-week trough FEV1 (128.10 mL [84.10-172.00]; 135.80 mL [123.10-148.30]; 106.40 mL [95.45-117.30]; 115.00 mL [74.51-155.30]); 24-week St George's Respiratory Questionnaire score (-4.60 [ 6.76 to -2.54]; -3.14 [-3.83 to -2.45]; -2.43 [-2.92 to -1.93]; -4.69 [-7.05 to 2.31]); 24-week transitional dyspnea index score (1.00 [0.41-1.59]; 1.01 [0.79 1.22]; 0.82 [0.62-1.02]; 1.00 [0.49-1.51]); and 24-week rescue medication use (data not available; -0.41 puffs/day [-0.62 to -0.20]; -0.52 puffs/day [-0.74 to 0.30]; -0.30 puffs/day [-0.81 to 0.21]). For 12-week trough FEV1, differences in change from baseline (95% credible interval) were -12.8 mL (-39.39 to 13.93), aclidinium versus tiotropium; 3.08 mL (-7.58 to 13.69), glycopyrronium versus tiotropium; 22.58 mL (-11.58 to 56.97), umeclidinium versus tiotropium; 15.90 mL (-11.60 to 43.15), glycopyrronium versus aclidinium; 35.40 mL (-5.06 to 76.07), umeclidinium versus aclidinium; and 19.50 mL (-15.30 to 54.38), umeclidinium versus glycopyrronium. Limitations included inhaler-related factors and safety; longer-term outcomes were not considered. CONCLUSION: The new LAMAs studied had at least comparable efficacy to tiotropium, the established class standard. Choice should depend on physician's and patient's preference. PMID- 26604739 TI - Computed tomography measurement of pulmonary artery for diagnosis of COPD and its comorbidity pulmonary hypertension. AB - Computed tomography (CT) is widely used for evaluation of lung diseases. To evaluate the value of CT measurement of pulmonary artery for diagnosis of chronic obstructive pulmonary disease (COPD) and its comorbidity pulmonary hypertension (PH), we retrospectively reviewed the CT of 221 patients with COPD and 115 control patients without cardiovascular or lung disease. Patients with COPD were divided into PH (COPD-PH) and non-PH according to systolic pulmonary artery pressure. Main pulmonary artery (MPA), right pulmonary artery (RPA) and left pulmonary artery branches, and ascending aorta (AAo) and descending aorta (DAo) diameters were measured. Meanwhile, the ratios of MPA/AAo and MPA/DAo were calculated. MPA, RPA, and left pulmonary artery diameters were significantly larger in COPD than those in the controls, and this augment was more obvious in COPD-PH. AAo and DAo diameters did not vary obviously between groups, while MPA/AAo and MAP/DAo increased significantly in COPD and PH. MPA could be helpful for COPD diagnosis (MPA diameter >=27.5 mm, sensitivity 54%, and specificity 80%), and RPA could be applied for COPD-PH diagnosis (RPA diameter >=23.4 mm, sensitivity 67%, and specificity 76%). There was a marked correlation between MPA/DAo and systolic pulmonary artery pressure (r=0.594, P<0.001). Therefore, chest CT could be a simple and effective modality for diagnostic evaluation of COPD and its comorbidity, PH. PMID- 26604740 TI - FePt nanoparticles as a potential X-ray activated chemotherapy agent for HeLa cells. AB - Nanomaterials have an advantage in "personalized" therapy, which is the ultimate goal of tumor treatment. In order to investigate the potential ability of FePt nanoparticles (NPs) in the diagnosis and chemoradiotherapy treatment of malignant tumors, superparamagnetic, monodispersed FePt (~3 nm) alloy NPs were synthesized, using cysteamine as a capping agent. The NPs were characterized by means of X-ray diffraction; transmission electron microscopy, Physical Property Measurement System, and Fourier transform infrared spectroscopy. The cytotoxicity of FePt NPs on Vero cells was assessed using an MTT assay, and tumor cell proliferation inhibited by individual FePt NPs and FePt NPs combined with X-ray beams were also collected using MTT assays; HeLa human cancer cell lines were used as in vitro models. Further confirmation of the combined effect of FePt NPs and X-rays was verified using HeLa cells, after which, the cellular uptake of FePt NPs was captured by transmission electron microscopy. The results indicated that the growth of HeLa cells was significantly inhibited by FePt NPs in a concentration dependent manner, and the growth was significantly more inhibited by FePt NPs combined with a series of X-ray beam doses; the individual NPs did not display any remarkable cytotoxicity on Vero cells at a concentration <250 MUg/mL. Meanwhile, the FePt NPs showed negative/positive contrast enhancement for MRI/CT molecule imaging at the end of the study. Therefore, the combined results implied that FePt NPs might potentially serve as a promising nanoprobe for the integration of tumor diagnosis and chemoradiotherapy. PMID- 26604742 TI - Erratum: Cytotoxicity and physicochemical characterization of iron-manganese doped sulfated zirconia nanoparticles [Corrigendum]. PMID- 26604741 TI - The interaction of sterically stabilized magnetic nanoparticles with fresh human red blood cells. AB - Sterically stabilized superparamagnetic iron oxide nanoparticles (SPIONs) were incubated with fresh human erythrocytes (red blood cells [RBCs]) to explore their potential application as magnetic resonance imaging contrast agents. The chemical shift and linewidth of (133)Cs(+) resonances from inside and outside the RBCs in (133)Cs nuclear magnetic resonance spectra were monitored as a function of time. Thus, we investigated whether SPIONs of two different core sizes and with three different types of polymeric stabilizers entered metabolically active RBCs, consuming glucose at 37 degrees C. The SPIONs broadened the extracellular (133)Cs(+) nuclear magnetic resonance, and brought about a small change in its chemical shift to a higher frequency; while the intracellular resonance remained unchanged in both amplitude and chemical shift. This situation pertained over incubation times of up to 90 minutes. If the SPIONs had entered the RBCs, the intracellular resonance would have become broader and possibly even shifted. Therefore, we concluded that our SPIONs did not enter the RBCs. In addition, the T 2 relaxivity of the small and large particles was 368 and 953 mM(-1) s(-1), respectively (three and nine times that of the most effective commercially available samples). This suggests that these new SPIONs will provide a superior performance to any others reported thus far as magnetic resonance imaging contrast agents. PMID- 26604743 TI - Hierarchical micro/nanostructured titanium with balanced actions to bacterial and mammalian cells for dental implants. AB - A versatile strategy to endow dental implants with long-term antibacterial ability without compromising the cytocompatibility is highly desirable to combat implant-related infection. Silver nanoparticles (Ag NPs) have been utilized as a highly effective and broad-spectrum antibacterial agent for surface modification of biomedical devices. However, the high mobility and subsequent hazardous effects of the particles on mammalian cells may limit its practical applications. Thus, Ag NPs were immobilized on the surface of sand-blasted, large grit, and acid-etched (SLA) titanium by manipulating the atomic-scale heating effect of silver plasma immersion ion implantation. The silver plasma immersion ion implantation-treated SLA surface gave rise to both good antibacterial activity and excellent compatibility with mammalian cells. The antibacterial activity rendered by the immobilized Ag NPs was assessed using Fusobacterium nucleatum and Staphylococcus aureus, commonly suspected pathogens for peri-implant disease. The immobilized Ag NPs offered a good defense against multiple cycles of bacteria attack in both F. nucleatum and S. aureus, and the mechanism was independent of silver release. F. nucleatum showed a higher susceptibility to Ag NPs than S. aureus, which might be explained by the presence of different wall structures. Moreover, the immobilized Ag NPs had no apparent toxic influence on the viability, proliferation, and differentiation of rat bone marrow mesenchymal stem cells. These results demonstrated that good bactericidal activity could be obtained with very small quantities of immobilized Ag NPs, which were not detrimental to the mammalian cells involved in the osseointegration process, and promising for titanium-based dental implants with commercial SLA surfaces. PMID- 26604744 TI - Microarc-oxidized titanium surfaces functionalized with microRNA-21-loaded chitosan/hyaluronic acid nanoparticles promote the osteogenic differentiation of human bone marrow mesenchymal stem cells. AB - Dental implants have been widely used for the replacement of missing teeth in the clinic, but further improvements are needed to meet the clinical demands for faster and tighter osseointegration. In this study, we fabricated safe and biocompatible chitosan (CS)/hyaluronic acid (HA) nanoparticles to deliver microRNA-21 (miR-21) and thereby accelerate osteogenesis in human bone marrow mesenchymal stem cells (hBMMSCs). The CS/HA/miR-21 nanoparticles were cross linked with 0.2% gel solution onto microarc oxidation (MAO)-treated titanium (Ti) surfaces to fabricate the miR-21-functionalized MAO Ti surface, resulting in the development of a novel coating for reverse transfection. To characterize the CS/HA/miR-21 nanoparticles, their particle size, zeta potential, surface morphology, and gel retardation ability were sequentially investigated. Their biological effects, such as cell viability, cytotoxicity, and expression of osteogenic genes by hBMMSCs on the miR-21-functionalized MAO Ti surfaces, were evaluated. Finally, we explored appropriate CS/HA/miR-21 nanoparticles with a CS/HA ratio of 4:1 and N/P ratio 20:1 for transfection, which presented good spherical morphology, an average diameter of 160.4+/-10.75 nm, and a positive zeta potential. The miR-21-functionalized MAO Ti surfaces demonstrated cell viability, cytotoxicity, and cell spreading comparable to those exhibited by naked MAO Ti surfaces and led to significantly higher expression of osteogenic genes. This novel miR-21-functionalized Ti implant may be used in the clinic to allow more effective and robust osseointegration. PMID- 26604745 TI - Preclinical evaluation of a urokinase plasminogen activator receptor-targeted nanoprobe in rhesus monkeys. AB - PURPOSE: To translate a recombinant peptide containing the amino-terminal fragment (ATF) of urokinase plasminogen activator receptor-targeted magnetic iron oxide (IO) nanoparticles (uPAR-targeted human ATF-IONPs) into clinical applications, we conducted a pilot study to evaluate the toxicity and pharmacokinetics of this nanoparticle in normal rhesus monkeys. METHODS: We assessed the changes in the following: magnetic resonance imaging (MRI) signals from pretreatment stage to 14 days posttreatment, serum iron concentrations from 5 minutes posttreatment to 12 weeks posttreatment, routine blood examination and serum chemistry analysis results from pretreatment stage to 12 weeks after administration, and results of staining of the liver with Perls' Prussian Blue and hematoxylin-eosin at 24 hours and 3 months posttreatment in two rhesus monkeys following an intravenous administration of the targeted nanoparticles either with a polyethylene glycol (ATF-PEG-IONP) or without a PEG (ATF-IONP) coating. RESULTS: The levels of alkaline phosphatase, alanine transaminase, and direct bilirubin in the two monkeys increased immediately after the administration of the IONPs but returned to normal within 20 days and stayed within the normal reference range 3 months after the injection. The creatinine levels of the two monkeys stayed within the normal range during the study. In addition, red blood cells, white blood cells, hemoglobin level, and platelets remained normal during the 3 months of the study. CONCLUSION: All of the results suggest that a transient injury in terms of normal organ functions, but no microscopic necrotic lesions, was observed at a systemic delivery dose of 5 mg/kg of iron equivalent concentration in the acute phase, and that no chronic toxicity was found 3 months after the injection. Therefore, we conclude that uPAR-targeted IONPs have the potential to be used as receptor-targeted MRI contrasts as well as theranostic agents for the detection and treatment of human cancers in future studies. PMID- 26604746 TI - Biodegradable mesoporous calcium-magnesium silicate-polybutylene succinate scaffolds for osseous tissue engineering. AB - The structural features of bone engineering scaffolds are expected to exhibit osteoinductive behavior and promote cell adhesion, proliferation, and differentiation. In the present study, we employed synthesized ordered mesoporous calcium-magnesium silicate (om-CMS) and polybutylene succinate (PBSu) to develop a novel scaffold with potential applications in osseous tissue engineering. The characteristics, in vitro bioactivity of om-CMS/PBSu scaffold, as well as the cellular responses of MC3T3-E1 cells to the composite were investigated. Our results showed that the om-CMS/PBSu scaffold possesses a large surface area and highly ordered channel pores, resulting in improved degradation and biocompatibility compared to the PBSu scaffold. Moreover, the om-CMS/PBSu scaffold exhibited significantly higher bioactivity and induced apatite formation on its surface after immersion in the simulated body fluid. In addition, the om CMS/PBSu scaffold provided a high surface area for cell attachment and released Ca, Mg, and Si ions to stimulate osteoblast proliferation. The unique surface characteristics and higher biological efficacy of the om-CMS/PBSu scaffold suggest that it has great potential for being developed into a system that can be employed in osseous tissue engineering. PMID- 26604747 TI - Fluorescent graphene quantum dots as traceable, pH-sensitive drug delivery systems. AB - Graphene quantum dots (GQDs) were rationally fabricated as a traceable drug delivery system for the targeted, pH-sensitive delivery of a chemotherapeutic drug into cancer cells. The GQDs served as fluorescent carriers for a well-known anticancer drug, doxorubicin (Dox). The whole system has the capacity for simultaneous tracking of the carrier and of drug release. Dox release is triggered upon acidification of the intracellular vesicles, where the carriers are located after their uptake by cancer cells. Further functionalization of the loaded carriers with targeting moieties such as arginine-glycine-aspartic acid (RGD) peptides enhanced their uptake by cancer cells. DU-145 and PC-3 human prostate cancer cell lines were used to evaluate the anticancer ability of Dox loaded RGD-modified GQDs (Dox-RGD-GQDs). The results demonstrated the feasibility of using GQDs as traceable drug delivery systems with the ability for the pH triggered delivery of drugs into target cells. PMID- 26604748 TI - A novel nano-copper-bearing stainless steel with reduced Cu(2+) release only inducing transient foreign body reaction via affecting the activity of NF-kappaB and Caspase 3. AB - Foreign body reaction induced by biomaterials is a serious problem in clinical applications. Although 317L-Cu stainless steel (317L-Cu SS) is a new type of implant material with antibacterial ability and osteogenic property, the foreign body reaction level still needs to be assessed due to its Cu(2+) releasing property. For this purpose, two macrophage cell lines were selected to detect cellular proliferation, apoptosis, mobility, and the secretions of inflammatory cytokines with the influence of 317L-Cu SS. Our results indicated that 317L-Cu SS had no obvious effect on the proliferation and apoptosis of macrophages; however, it significantly increased cellular migration and TNF-alpha secretion. Then, C57 mice were used to assess foreign body reaction induced by 317L-Cu SS. We observed significantly enhanced recruitment of inflammatory cells (primarily macrophages) with increased TNF-alpha secretion and apoptosis level in tissues around the materials in the early stage of implantation. With tissue healing, both inflammation and apoptosis significantly decreased. Further, we discovered that NF-kappaB pathway and Caspase 3 played important roles in 317L-Cu SS induced inflammation and apoptosis. We concluded that 317L-Cu SS could briefly promote the inflammation and apoptosis of surrounding tissues by regulating the activity of NF-kappaB pathway and Caspase 3. All these discoveries demonstrated that 317L Cu SS has a great potential for clinical application. PMID- 26604749 TI - Anti-hyperglycemic activity of selenium nanoparticles in streptozotocin-induced diabetic rats. AB - The study was designed to investigate the anti-hyperglycemic activity of selenium nanoparticles (SeNPs) in streptozotocin-induced diabetic rats. Fifty-five mg/kg of streptozotocin was injected in rats to induce diabetes. Animals either treated with SeNPs alone or with insulin (6 U/kg) showed significantly decreased fasting blood glucose levels after 28 days of treatment. The serum insulin concentration in untreated diabetic animals was also enhanced by SeNPs. The results demonstrated that SeNPs could significantly decrease hepatic and renal function markers, total lipid, total cholesterol, triglyceride and low-density lipoprotein cholesterol levels, and glucose-6-phosphatase activity. At the same time, SeNPs increased malic enzyme, hexokinase and glucose-6-phosphate dehydrogenase activity, liver and kidney glycogen contents, and high-density lipoprotein cholesterol levels. In addition, SeNPs were able to prevent the histological injury in the hepatic and renal tissues of rats. However, insulin injection also exhibited a significant improvement in diabetic animals after 28 days of treatment. This study suggests that SeNPs can alleviate hyperglycemia and hyperlipidemia in streptozotocin-induced diabetic rats, possibly by eliciting insulin-mimetic activity. PMID- 26604752 TI - Review on lipegfilgrastim. PMID- 26604751 TI - Tumor-targeted and pH-controlled delivery of doxorubicin using gold nanorods for lung cancer therapy. AB - BACKGROUND: In lung cancer, the efficacy of conventional chemotherapy is limited due to poor drug accumulation in tumors and nonspecific cytotoxicity. Resolving these issues will increase therapeutic efficacy. METHODS: GNR-Dox-Tf-NPs (gold nanorod-doxorubicin-transferrin-nanoparticles) were prepared by different chemical approaches. The efficacy of these nanoparticles was carried out by cell viability in lung cancer and primary coronary artery smooth muscle cells. The receptor-mediated endocytosis studies were done with human transferrin and desferrioxamine preincubation. The GNR-Dox-Tf nanoparticles induced apoptosis, and DNA damage studies were done by Western blot, H2AX foci, and comet assay. RESULTS: We developed and tested a gold nanorod-based multifunctional nanoparticle system (GNR-Dox-Tf-NP) that carries Dox conjugated to a pH-sensitive linker and is targeted to the transferrin receptor overexpressed in human lung cancer (A549, HCC827) cells. GNR-Dox-Tf-NP underwent physicochemical characterization, specificity assays, tumor uptake studies, and hyperspectral imaging. Biological studies demonstrated that transferrin receptor-mediated uptake of the GNR-Dox-Tf-NP by A549 and HCC827 cells produced increased DNA damage, apoptosis, and cell killing compared with nontargeted GNR-Dox-NP. GNR-Dox Tf-NP-mediated cytotoxicity was greater (48% A549, 46% HCC827) than GNR-Dox-NP mediated cytotoxicity (36% A549, 39% HCC827). Further, GNR-Dox-Tf-NP markedly reduced cytotoxicity in normal human coronary artery smooth muscle cells compared with free Dox. CONCLUSION: Thus, GNR-Dox-Tf nanoparticles can selectively target and deliver Dox to lung tumor cells and alleviate free Dox-mediated toxicity to normal cells. PMID- 26604753 TI - Photosensitizer and peptide-conjugated PAMAM dendrimer for targeted in vivo photodynamic therapy. AB - Challenges in photodynamic therapy (PDT) include development of efficient near infrared-sensitive photosensitizers (5,10,15,20-tetrakis(4-hydroxyphenyl)-21H,23H porphine [PS]) and targeted delivery of PS to the tumor tissue. In this study, a dual functional dendrimer was synthesized for targeted PDT. For targeting, a poly(amidoamine) dendrimer (G4) was conjugated with a PS and a nitrilotriacetic acid (NTA) group. A peptide specific to human epidermal growth factor 2 was expressed in Escherichia coli with a His-tag and was specifically bound to the NTA group on the dendrimer. Reaction conditions were optimized to result in dendrimers with PS and the NTA at a fractional occupancy of 50% and 15%, respectively. The dendrimers were characterized by nuclear magnetic resonance, matrix-assisted laser desorption/ionization, absorbance, and fluorescence spectroscopy. Using PS fluorescence, cell uptake of these particles was confirmed by confocal microscopy and fluorescence-activated cell sorting. PS-dendrimers are more efficient than free PS in PDT-mediated cell death assays in HER2 positive cells, SK-OV-3. Similar effects were absent in HER2 negative cell line, MCF-7. Compared to free PS, the PS-dendrimers have shown significant tumor suppression in a xenograft animal tumor model. Conjugation of a PS with dendrimers and with a targeting agent has enhanced photodynamic therapeutic effects of the PS. PMID- 26604750 TI - Recent trends in the development of nanophytobioactive compounds and delivery systems for their possible role in reducing oxidative stress in Parkinson's disease models. AB - Oxidative stress plays a very critical role in neurodegenerative diseases, such as Parkinson's disease (PD), which is the second most common neurodegenerative disease among elderly people worldwide. Increasing evidence has suggested that phytobioactive compounds show enhanced benefits in cell and animal models of PD. Curcumin, resveratrol, ginsenosides, quercetin, and catechin are phyto-derived bioactive compounds with important roles in the prevention and treatment of PD. However, in vivo studies suggest that their concentrations are very low to cross blood-brain barrier thereby it limits bioavailability, stability, and dissolution at target sites in the brain. To overcome these problems, nanophytomedicine with the controlled size of 1-100 nm is used to maximize efficiency in the treatment of PD. Nanosizing of phytobioactive compounds enhances the permeability into the brain with maximized efficiency and stability. Several nanodelivery techniques, including solid lipid nanoparticles, nanostructured lipid carriers, nanoliposomes, and nanoniosomes can be used for controlled delivery of nanobioactive compounds to brain. Nanocompounds, such as ginsenosides (19.9 nm) synthesized using a nanoemulsion technique, showed enhanced bioavailability in the rat brain. Here, we discuss the most recent trends and applications in PD, including 1) the role of phytobioactive compounds in reducing oxidative stress and their bioavailability; 2) the role of nanotechnology in reducing oxidative stress during PD; 3) nanodelivery systems; and 4) various nanophytobioactive compounds and their role in PD. PMID- 26604755 TI - Visible-light-responsive ZnCuO nanoparticles: benign photodynamic killers of infectious protozoans. AB - Human beings suffer from several infectious agents such as viruses, bacteria, and protozoans. Recently, there has been a great interest in developing biocompatible nanostructures to deal with infectious agents. This study investigated benign ZnCuO nanostructures that were visible-light-responsive due to the resident copper in the lattice. The nanostructures were synthesized through a size controlled hot-injection process, which was adaptable to the surface ligation processes. The nanostructures were then characterized through transmission electron microscopy, X-ray diffraction, diffused reflectance spectroscopy, Rutherford backscattering, and photoluminescence analysis to measure crystallite nature, size, luminescence, composition, and band-gap analyses. Antiprotozoal efficiency of the current nanoparticles revealed the photodynamic killing of Leishmania protozoan, thus acting as efficient metal-based photosensitizers. The crystalline nanoparticles showed good biocompatibility when tested for macrophage toxicity and in hemolysis assays. The study opens a wide avenue for using toxic material in resident nontoxic forms as an effective antiprotozoal treatment. PMID- 26604754 TI - Enhanced bioavailability of nerve growth factor with phytantriol lipid-based crystalline nanoparticles in cochlea. AB - PURPOSE: Supplementation of exogenous nerve growth factor (NGF) into the cochlea of deafened animals rescues spiral ganglion cells from degeneration. However, a safe and potent delivery of therapeutic proteins, such as NGF, to spiral ganglion cells remains one of the greatest challenges. This study presents the development of self-assembled cubic lipid-based crystalline nanoparticles to enhance inner ear bioavailability of bioactive NGF via a round window membrane route. METHODS: A novel nanocarrier-entrapped NGF was developed based on phytantriol by a liquid precursor dilution, with Pluronic((r)) F127 and propylene glycol as the surfactant and solubilizer, respectively. Upon dilution of the liquid lipid precursors, monodispersed submicron-sized particles with a slight negative charge formed spontaneously. RESULTS: Biological activity of entrapped NGF was assessed using pheochromocytoma cells with NGF-loaded reservoirs to induce significant neuronal outgrowth, similar to that seen in free NGF-treated controls. Finally, a 3.28-fold increase in inner ear bioavailability was observed after administration of phytantriol lipid-based crystalline nanoparticles as compared to free drug, contributing to an enhanced drug permeability of the round window membrane. CONCLUSION: Data presented here demonstrate the potential of lipid-based crystalline nanoparticles to improve the outcomes of patients bearing cochlear implants. PMID- 26604756 TI - Aqueous extract of Rabdosia rubescens leaves: forming nanoparticles, targeting P selectin, and inhibiting thrombosis. AB - The hot water extract of Rabdosia rubescens was traditionally used as an antithrombotic medicine. To explore its antithrombotic utility and mechanism, we carried out a series of in vitro and in vivo assays in this study. In vitro platelet aggregation assay showed that the half maximal inhibitory concentration values of aqueous extract of R. rubescens leaves (AERL) inhibiting platelet aggregation induced by thrombin, arachidonic acid, adenosine diphosphate, and platelet-activating factor ranged from 0.12 mg/mL to 1.43 mg/mL. The minimal effective oral dose of AERL inhibiting the rats from forming thrombus was 25 mg/kg. Both in vitro and in vivo actions were correlated with AERL concentration dependently inhibiting sP-selectin release. In water, AERL formed nanoparticles, and their size depended on the concentration. Docking the five nucleotides, 21 phenolic acids, and four diterpenoids identified by high-performance liquid chromatography-photodiode array detector/(-)electrospray ionization-tandem mass spectrometry analysis into the active site of P-selectin, rosmarinic acid was predicted to be the antithrombotic ingredient of AERL. In flow cytometry analysis, 1 MUM of rosmarinic acid effectively inhibited sP-selectin release in arachidonic acid-activated platelets. In a rat model, 5 mg/kg of oral rosmarinic acid effectively inhibited thrombosis. PMID- 26604757 TI - Role of surface charge in determining the biological effects of CdSe/ZnS quantum dots. AB - The growing potential of quantum dots (QDs) in biomedical applications has provoked the urgent need to thoroughly address their interaction with biological systems. However, only limited studies have been performed to explore the effects of surface charge on the biological behaviors of QDs. In the present study, three commercially available QDs with different surface coatings were used to systematically evaluate the effects of surface charge on the cellular uptake, cytotoxicity, and in vivo biodistribution of QDs. Our results demonstrated that charged QDs entered both cancer cells and macrophages more efficiently than neutral ones, while negative QDs internalized mostly. Upon entry into cells, QDs were localized in different subcellular compartments (eg, cytoplasm and lysosomes) depending on the surface charge. Interestingly, inconsistent with the result of internalization, positive QDs but not negative QDs exhibited severe cytotoxicity, which was likely due to their disruption of cell membrane integrity, and production of reactive oxygen species. Biodistribution studies demonstrated that negative and neutral QDs preferentially distributed in the liver and the spleen, whereas positive QDs mainly deposited in the kidney with obvious uptake in the brain. In general, surface charge plays crucial roles in determining the biological interactions of QDs. PMID- 26604758 TI - Efficient gene delivery to human umbilical cord mesenchymal stem cells by cationized Porphyra yezoensis polysaccharide nanoparticles. AB - This study centered on an innovative application of Porphyra yezoensis polysaccharide (PPS) with cationic modification as a safe and efficient nonviral gene vector to deliver a plasmid encoding human Wnt3a (pWnt3a) into human umbilical cord mesenchymal stem cells (HUMSCs). After modification with branched low-molecular-weight (1,200 Da) polyethylenimine, the cationized PPS (CPPS) was combined with pWnt3a to form spherical nanoscale particles (CPPS-pWnt3a nanoparticles). Particle size and distribution indicated that the CPPS-pWnt3a nanoparticles at a CPPS:pWnt3a weight ratio of 40:1 might be a potential candidate for DNA plasmid transfection. A cytotoxicity assay demonstrated that the nanoparticles prepared at a CPPS:pWnt3a weight ratio of 40:1 were nontoxic to HUMSCs compared to those of Lipofectamine 2000 and polyethylenimine (25 kDa). These nanoparticles were further transfected to HUMSCs. Western blotting demonstrated that the nanoparticles (CPPS:pWnt3a weight ratio 40:1) had the greatest transfection efficiency in HUMSCs, which was significantly higher than that of Lipofectamine 2000; however, when the CPPS:pWnt3a weight ratio was increased to 80:1, the nanoparticle-treated group showed no obvious improvement in translation efficiency over Lipofectamine 2000. Therefore, CPPS, a novel cationic polysaccharide derived from P. yezoensis, could be developed into a safe, efficient, nonviral gene vector in a gene-delivery system. PMID- 26604759 TI - Osteoinductive peptide-functionalized nanofibers with highly ordered structure as biomimetic scaffolds for bone tissue engineering. AB - The construction of functional biomimetic scaffolds that recapitulate the topographical and biochemical features of bone tissue extracellular matrix is now of topical interest in bone tissue engineering. In this study, a novel surface functionalized electrospun polycaprolactone (PCL) nanofiber scaffold with highly ordered structure was developed to simulate the critical features of native bone tissue via a single step of catechol chemistry. Specially, under slightly alkaline aqueous solution, polydopamine (pDA) was coated on the surface of aligned PCL nanofibers after electrospinning, followed by covalent immobilization of bone morphogenetic protein-7-derived peptides onto the pDA-coated nanofiber surface. Contact angle measurement, Raman spectroscopy, and X-ray photoelectron spectroscopy confirmed the presence of pDA and peptides on PCL nanofiber surface. Our results demonstrated that surface modification with osteoinductive peptides could improve cytocompatibility of nanofibers in terms of cell adhesion, spreading, and proliferation. Most importantly, Alizarin Red S staining, quantitative real-time polymerase chain reaction, immunostaining, and Western blot revealed that human mesenchymal stem cells cultured on aligned nanofibers with osteoinductive peptides exhibited enhanced osteogenic differentiation potential than cells on randomly oriented nanofibers. Furthermore, the aligned nanofibers with osteoinductive peptides could direct osteogenic differentiation of human mesenchymal stem cells even in the absence of osteoinducting factors, suggesting superior osteogenic efficacy of biomimetic design that combines the advantages of osteoinductive peptide signal and highly ordered nanofibers on cell fate decision. The presented peptide-decorated bone-mimic nanofiber scaffolds hold a promising potential in the context of bone tissue engineering. PMID- 26604760 TI - Combination of PEI-Mn0.5Zn0.5Fe2O4 nanoparticles and pHsp 70-HSV-TK/GCV with magnet-induced heating for treatment of hepatoma. AB - BACKGROUND: To explore a new combination of thermal treatment and gene therapy for hepatoma, a heat-inducible herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy system was developed in which thermal energy generated by Mn0.5Zn0.5Fe2O4 nanoparticles (MZF-NPs) under an alternating magnetic field was used to activate gene expression. METHODS: First, a recombinant eukaryotic plasmid, pHsp 70-HSV-TK, was constructed as a target gene for therapy. This recombinant plasmid was used to transfect SMMC-7721 hepatoma cells and the gene expression was evaluated. Magnet-induced heating was then applied to cells to assess the antihepatoma effects of the polyethylenimine (PEI)-MZF-NPs/pHsp 70-HSV TK/GCV complex, in vitro and in vivo. RESULTS: The results showed that cells were successfully transfected with pHsp 70-HSV-TK and that expression levels of HSV-TK remained stable. Both in vitro and in vivo results indicated that the combination of gene therapy and heat treatment resulted in better therapeutic effects than heating-alone group. The rates of apoptosis and necrosis in the combined treatment group were 49.0% and 7.21%, respectively. The rate of inhibition of cell proliferation in the combined treatment group was significantly higher (87.5%) than that in the heating-alone group (65.8%; P<0.01). The tumor volume and mass inhibition rates of the combined treatment group were 91.3% and 87.91%, respectively, and were significantly higher than the corresponding rates of the heating-alone group (70.41% and 57.14%; P<0.01). The expression levels of Stat3 and Bcl-xL messenger RNA and p-Stat3 and Bcl-xL protein in the combined treatment group were significantly lower than those in the other groups (P<0.01). The expression levels of Bax messenger RNA and protein in the recombinant plasmid group were significantly higher than those in the other groups (P<0.01). CONCLUSION: It can therefore be concluded that the combined application of heat treatment and gene therapy has a synergistic and complementary effect and that PEI-MZF-NPs can simultaneously act both as a nonviral gene vector and a magnet induced source of heat, thereby representing a viable approach for the treatment of cancer. PMID- 26604761 TI - Effectiveness of a focused, brief psychoeducation program for parents of ADHD children: improvement of medication adherence and symptoms. AB - OBJECTIVE: To evaluate the efficacy of a psychoeducation program for parents of children with ADHD in enhancing adherence to pharmacological treatment and improving clinical symptoms. METHODS: We developed a psychoeducation program based on the theory of planned behavior (TPB). Eighty-nine children with ADHD were cluster randomly assigned for their families to receive 3 months of well structured psychoeducation (intervention group, n=44) or only general clinical counseling (control group, n=45). Parents in the intervention group were given an expert lecture (with slides and a parent manual), attended two expert-guided parent group sessions, and were invited to join a professional-guided online community. Measurement of parents' knowledge about ADHD, components of the TPB model, and child ADHD symptoms were taken before and after intervention. Medication adherence was assessed thoroughly at the end of the first and third months. Satisfaction with the psychoeducation program was assessed only in the intervention group. Two-independent-samples t-test, ANOVA, and chi-square test were employed to compare differences between groups. RESULTS: Compared to the control group, medication adherence in the intervention group was significantly higher after 1 and 3 months (97.7% intervention vs 75.6% control, P=0.002, and 86.4% intervention vs 53.3% control, P=0.001, respectively). Accordingly, the ADHD rating scale scores were lower in the intervention group than the control group after intervention (33.7+/-5.4 vs 45.1+/-7.9, P=0.008). Greater improvements in parents' knowledge about ADHD and many components of the TPB model were observed in the intervention group, especially increased intention to adhere to medication, compared to the control group (P<0.001). CONCLUSION: This psychoeducation program had a positive impact on both medication adherence and clinical symptoms of ADHD children. It could be considered as a potential beneficial supplement to clinical practice. PMID- 26604763 TI - Association study of sepiapterin reductase gene promoter polymorphisms with schizophrenia in a Han Chinese population. AB - Sepiapterin reductase participates in the biosynthesis of tetrahydrobiopterin, which plays very important roles in the pathogenesis of schizophrenia via dysregulation of neurotransmitter systems. Here, two single nucleotide polymorphisms (rs1876487 and rs2421095) in the promoter region of SPR were genotyped in 941 schizophrenic patients and 944 controls in a Han Chinese population using the SNaPshot technique. No significant differences were found in the distribution of alleles or genotypes of the two single nucleotide polymorphisms (SNPs) between schizophrenic patients and controls (all P>0.05). Likewise, no haplotype was found to be associated with schizophrenia. However, sex-stratified analysis revealed that the frequencies of the A allele of rs1876487 and the A-A (rs2421095-rs1876487) haplotype were all significantly different between schizophrenia and controls in females (P=0.040 and P=0.033, respectively), but not in males. Additionally, luciferase reporter gene assays revealed that the A-A haplotype had significantly higher SPR transcriptional activity compared with the A-C haplotype in SH-SY5Y cells. Our data indicate that the two SNPs do not influence the risk of schizophrenia when using the total sample, but the A allele of rs1876487 and the A-A haplotype may contribute to protective roles for schizophrenia in females. PMID- 26604762 TI - Association of EEG, MRI, and regional blood flow biomarkers is predictive of prodromal Alzheimer's disease. AB - BACKGROUND: Thinning in the temporoparietal cortex, hippocampal atrophy, and a lower regional blood perfusion is connected with prodromal stage of Alzheimer's disease (AD). Of note, an increase of electroencephalography (EEG) upper/low alpha frequency power ratio has also been associated with these major landmarks of prodromal AD. METHODS: Clinical and neuropsychological assessment, EEG recording, and high-resolution three-dimensional magnetic resonance imaging were done in 74 grown up subjects with mild cognitive impairment. This information was gathered and has been assessed 3 years postliminary. EEG recording and perfusion single-photon emission computed tomography assessment was done in 27 subjects. Alpha3/alpha2 frequency power ratio, including cortical thickness, was figured for every subject. Contrasts in cortical thickness among the groups were assessed. Pearson's r relationship coefficient was utilized to evaluate the quality of the relationship between cortical thinning, brain perfusion, and EEG markers. RESULTS: The higher alpha3/alpha2 frequency power ratio group corresponded with more prominent cortical decay and a lower perfusional rate in the temporoparietal cortex. In a subsequent meetup after 3 years, these patients had AD. CONCLUSION: High EEG upper/low alpha power ratio was connected with cortical diminishing and lower perfusion in the temporoparietal brain area. The increase in EEG upper/low alpha frequency power ratio could be helpful in recognizing people in danger of conversion to AD dementia and this may be quality information in connection with clinical assessment. PMID- 26604765 TI - The low level of understanding of depression among patients treated with antidepressants: a survey of 424 outpatients in Japan. AB - BACKGROUND: We used self-administered questionnaires to investigate the level of understanding of depression among outpatients who were administered antidepressants. METHODS: A total of 424 outpatients were enrolled in this study. We used an original self-administered questionnaire that consisted of eight categories: (A) depressive symptoms, (B) the course of depression, (C) the cause of depression, (D) the treatment plan, (E) the duration of taking antidepressants, (F) how to discontinue antidepressants, (G) the side effects of the antidepressants, and (H) psychotherapy. Each category consisted of the following two questions: "Have you received an explanation from the doctor in charge?" and "How much do you understand about it?" The level of understanding was rated on a scale of 0-10 (11 anchor points). The Quick Inventory of Depressive Symptomatology Japanese version, Global Assessment of Functioning, and Clinical Global Impression - Severity scale were administered, and clinical characteristics were investigated. RESULTS: The percentages of participants who received explanations were as follows: 61.8% for (A), 49.2% for (B), 50.8% for (C), 57.2% for (D), 46.3% for (E), 28.5% for (F), 50.6% for (G), and 36.1% for (H). The level of understanding in participants who received explanations from their physicians was significantly higher compared with patients who did not receive explanations for all evaluated categories. Patient age, age at disease onset, and Global Assessment of Functioning scores were significantly associated with more items compared with the other variables. CONCLUSION: Psychoeducation is not sufficiently performed. According to the study results, it is possible for patients to receive better psychoeducation and improve their clinical outcomes. PMID- 26604764 TI - Connectomics in psychiatric research: advances and applications. AB - Psychiatric disorders disturb higher cognitive functions and severely compromise human health. However, the pathophysiological mechanisms underlying psychiatric disorders are very complex, and understanding these mechanisms remains a great challenge. Currently, many psychiatric disorders are hypothesized to reflect "faulty wiring" or aberrant connectivity in the brains. Imaging connectomics is arising as a promising methodological framework for describing the structural and functional connectivity patterns of the human brain. Recently, alterations of brain networks in the connectome have been reported in various psychiatric disorders, and these alterations may provide biomarkers for disease diagnosis and prognosis for the evaluation of treatment efficacy. Here, we summarize the current achievements in both the structural and functional connectomes in several major psychiatric disorders (eg, schizophrenia, attention-deficit/hyperactivity disorder, and autism) based on multi-modal neuroimaging data. We highlight the current progress in the identification of these alterations and the hypotheses concerning the aberrant brain networks in individuals with psychiatric disorders and discuss the research questions that might contribute to a further mechanistic understanding of these disorders from a connectomic perspective. PMID- 26604766 TI - Reliability and validity of the Thai self-report version of the Yale-Brown Obsessive-Compulsive Scale-Second Edition. AB - PURPOSE: The self-report version of the Yale-Brown Obsessive-Compulsive Scale (Y BOCS) has been developed to overcome the limitations of the clinician administered version, which needs to be executed by trained personnel and is time consuming. The second edition of the Y-BOCS (Y-BOCS-II) was developed to address some limitations of the original version. However, there is no self-report version of the Y-BOCS-II at the moment. This study aimed to evaluate the psychometric properties of the developed Thai self-report version of the Yale Brown Obsessive-Compulsive Scale-Second Edition (Y-BOCS-II-SR-T). PATIENTS AND METHODS: Y-BOCS-II-SR-T was developed from the Thai version of the Yale-Brown Obsessive-Compulsive Scale-Second Edition (Y-BOCS-II-T). The Y-BOCS-II-SR-T, the Y-BOCS-II-T, the Thai version of the Florida Obsessive-Compulsive Inventory (FOCI T), the Hamilton Rating Scale for Depression (HAM-D), the nine-item Patient Health Questionnaire (PHQ-9), and the Pictorial Thai Quality of Life (PTQL) instrument were administered to 52 obsessive-compulsive disorder (OCD) patients. Internal consistency for the Y-BOCS-II-SR-T was calculated with Cronbach's alpha coefficient (alpha), and the factor analyses were completed. Pearson's correlation was used in determining convergent and divergent validity among the other measures. RESULTS: The mean score of the Y-BOCS-II-SR-T total score was 20.71+/-11.16. The internal consistencies of the Y-BOCS-II-SR-T total scores, the obsession subscale, and the compulsion subscale scores were excellent (alpha=0.94, alpha=0.90, and alpha=0.89, respectively). The correlation between each item and the Y-BOCS-II-SR-T total score showed strong correlation for all items. Confirmatory factor analysis with model modification showed adequate fit for obsession and compulsion factor models. The Y-BOCS-II-SR-T had strong correlation with the YBOCS-II-T and the FOCI-T (r s>0.90) and weaker correlation with the HAM-D, PHQ-9, and PTQL (r s<0.60), which implied good convergent and divergent validity. CONCLUSION: The Y-BOCS-II-SR-T is a psychometrically sound and valid measure for assessing obsessive-compulsive symptoms. PMID- 26604767 TI - Neurological soft signs might be endophenotype candidates for patients with deficit syndrome schizophrenia. AB - BACKGROUND: Schizophrenia is a chronic, disabling, disorder that affects approximately 1% of the population. The nature of schizophrenia is heterogeneous, and unsuccessful efforts to subtype this disorder have been made. Deficit syndrome schizophrenia (DS) is a clinical diagnosis that has not been placed in main diagnostic manuals. In this study, we aimed to investigate and compare neurological soft signs (NSS) in DS patients, non-deficit schizophrenia (NDS) patients, and healthy controls (HCs). We suggest that NSS might be an endophenotype candidate for DS patients. METHODS: Sixty-six patients with schizophrenia and 30 HCs were enrolled in accordance with our inclusion and exclusion criteria. The patients were sub-typed as DS (n=24) and NDS (n=42) according to the Schedule for the Deficit Syndrome. The three groups were compared in terms of sociodemographic and clinical variables and total scores and subscores on the Physical and Neurological Examination for Soft Signs (PANESS). Following the comparison, a regression analysis was performed for predictability of total PANESS score and its subscales in the diagnosis of DS and NDS. RESULTS: The groups were similar in terms of age, sex, and smoking status. The results of our study indicated that the total PANESS score was significantly higher in the DS group compared to the NDS and HC groups, and all PANESS subscales were significantly higher in the DS group than in the HC group. The diagnosis of DS was predicted significantly by total PANESS score (P<0.001, odds ratio =9.48, 95% confidence interval: 0.00-4.56); the synergy, graphesthesia, stereognosis, motor tasks, and ability to maintain posture subscales were found to be significant predictors. CONCLUSION: This study confirms that NSS were higher in patients with DS. In addition, we suggest that our results might support the notion of DS as a different and distinct type of schizophrenia. NSS might also be a promising candidate as an endophenotype for DS. However, large sampled, multicentric studies are needed to clarify the place of NSS as an endophenotype in DS. PMID- 26604768 TI - In vitro screening of major neurotransmitter systems possibly involved in the mechanism of action of antibodies to S100 protein in released-active form. AB - Experimentally and clinically, it was shown that released-active form of antibodies to S100 protein (RAF of Abs to S100) exerts a wide range of pharmacological activities: anxiolytic, antiasthenic, antiaggressive, stress protective, antihypoxic, antiischemic, neuroprotective, and nootropic. The purpose of this study was to determine the influence of RAF of Abs to S100 on major neurotransmitter systems (serotoninergic, GABAergic, dopaminergic, and on sigma receptors as well) which are possibly involved in its mechanism of pharmacological activity. Radioligand binding assays were used for assessment of the drug influence on ligand-receptor interaction. [(35)S]GTPgammaS binding assay, cyclic adenosine monophosphate HTRFTM, cellular dielectric spectroscopy assays, and assays based on measurement of intracellular concentration of Ca(2+) ions were used for assessment of agonist or antagonist properties of the drug toward receptors. RAF of Abs to S100 increased radioligand binding to 5-HT1F, 5 HT2B, 5-HT2Cedited, 5-HT3, and to D3 receptors by 142.0%, 131.9%, 149.3%, 120.7%, and 126.3%, respectively. Also, the drug significantly inhibited specific binding of radioligands to GABAB1A/B2 receptors by 25.8%, and to both native and recombinant human sigma1 receptors by 75.3% and 40.32%, respectively. In the functional assays, it was shown that the drug exerted antagonism at 5-HT1B, D3, and GABAB1A/B2 receptors inhibiting agonist-induced responses by 23.24%, 32.76%, and 30.2%, respectively. On the contrary, the drug exerted an agonist effect at 5 HT1A receptors enhancing receptor functional activity by 28.0%. The pharmacological profiling of RAF of Abs to S100 among 27 receptor provides evidence for drug-related modification of major neurotransmitter systems. PMID- 26604769 TI - Frequency and risk factor analysis of cognitive and anxiety-depressive disorders in patients with amyotrophic lateral sclerosis/motor neuron disease. AB - OBJECTIVES: To examine the frequency and risk factors of cognitive and anxiety depressive disorders in patients with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). METHODS: This was an observational study of 100 ALS/MND patients treated at our hospital outpatient and inpatient departments between January 2009 and April 2010 and 100 matched healthy controls. Subjects were surveyed using Mini Mental State Examination (MMSE), Zung Self-Rating Anxiety Scale (SAS), and Zung Self-Rating Depression Scale (SDS). Patient neurological status was graded by the ALS Functional Rating Scale (ALSFRS). Multivariate linear regression was used to identify factors associated with the MMSE, SAS, SDS, and ALSFRS scores. RESULTS: Patients had significantly lower MMSE scores than controls (P<0.05). MMSE score did not differ by sex or age (<50/>=50 years) (P>0.05). Patients with higher educational level (college and above), shorter disease course (<2 years), and lower ALSFRS score (<20) had significantly higher MMSE scores (all P<0.05). Multivariate analysis revealed that higher education, shorter disease course, and lower ALSFRS score were independent predictors of better cognitive function (higher MMSE score). Patients had significantly higher mean SAS and SDS total scores than controls (both P<0.05), indicating higher subjective anxiety and depression. Female patients, patients with higher education, and those with higher ALSFRS scores had significantly higher SAS and SDS scores (all P<0.05). Age, occupation, diagnostic classification, disease duration, and disease awareness did not influence SAS or SDS scores. Multivariate analysis indicated that lower education and lower ALSFRS were protective factors against anxiety and depression. CONCLUSION: The frequency of anxiety-depressive disorders was high among patients with ALS/MND. High educational level, short course of disease, and lower ALSFRS were associated with preserved cognitive function. Female sex, higher education, and lower ALSFRS score conferred a greater risk of anxiety and depression. Tailored pharmacotherapy and psychological interventions may help in reducing anxiety and depression in these patients. PMID- 26604770 TI - Early stages of pediatric bipolar disorder: retrospective analysis of a Czech inpatient sample. AB - BACKGROUND: Approximately 30%-60% of adults diagnosed with bipolar disorder (BD) report onset between the ages 15 and 19 years; however, a correct diagnosis is often delayed by several years. Therefore, investigations of the early features of BD are important for adequately understanding the prodromal stages of the illness. METHODS: A complete review of the medical records of 46 children and adolescents who were hospitalized for BD at two psychiatric teaching centers in Prague, Czech Republic was performed. Frequency of BD in all inpatients, age of symptom onset, phenomenology of mood episodes, lifetime psychiatric comorbidity, differences between very-early-onset (<13 years of age) and early-onset patients (13-18 years), and differences between the offspring of parents with and without BD were analyzed. RESULTS: The sample represents 0.83% of the total number of inpatients (n=5,483) admitted during the study period at both centers. BD often started with depression (56%), followed by hypomania (24%) and mixed episodes (20%). The average age during the first mood episode was 14.9 years (14.6 years for depression and 15.6 years for hypomania). Seven children (15%) experienced their first mood episode before age 13 years (very early onset). Traumatic events, first-degree relatives with mood disorders, and attention deficit hyperactivity disorder were significantly more frequent in the very-early-onset group vs the early-onset group (13-18 years) (P<=0.05). The offspring of bipolar parents were significantly younger at the onset of the first mood episode (13.2 vs 15.4 years; P=0.02) and when experiencing the first mania compared to the offspring of non-BD parents (14.3 vs 15.9 years; P=0.03). Anxiety disorders, substance abuse, specific learning disabilities, and attention deficit hyperactivity disorder were the most frequent lifetime comorbid conditions. CONCLUSION: Clinicians must be aware of the potential for childhood BD onset in patients who suffer from recurrent depression, who have first-degree relatives with BD, and who have experienced severe psychosocial stressors. PMID- 26604771 TI - Comparison between anterior cervical discectomy with fusion and anterior cervical corpectomy with fusion for the treatment of cervical spondylotic myelopathy: a meta-analysis. AB - BACKGROUND: Whether anterior cervical discectomy with fusion (ACDF) or anterior cervical corpectomy with fusion (ACCF) is superior in the treatment of cervical spondylotic myelopathy remains controversial. Therefore, we conducted a meta analysis to quantitatively compare the efficacy and safety of ACDF and ACCF in the treatment of cervical spondylotic myelopathy. METHODS: PubMed, Embase, Web of Science, SinoMed (Chinese BioMedical Literature Service System, People's Republic of China), and CNKI (China National Knowledge Infrastructure, People's Republic of China) were systematically searched to identify all available studies comparing efficacy and safety between patients receiving ACDF and ACCF. The weighted mean difference (WMD) was pooled to compare the Japanese Orthopaedic Association scores, visual analog scale scores, hospital stay, operation time, and blood loss. The risk ratio was pooled to compare the incidence of complications and fusion rate. Pooled estimates were calculated by using a fixed effects model or a random-effects model according to the heterogeneity among studies. RESULTS: Eighteen studies (17 observational studies and one randomized controlled trial) were included in this meta-analysis. Our results suggest that hospital stay (WMD =-1.33, 95% confidence interval [CI]: -2.29, -0.27; P=0.014), operation time (WMD =-26.9, 95% CI: -46.13, -7.67; P=0.006), blood loss (WMD = 119.36, 95% CI: -166.94, -71.77; P=0.000), and incidence of complications (risk ratio =0.51, 95% CI: 0.33, 0.80; P=0.003) in the ACDF group were significantly less than that in the ACCF group. However, other clinical outcomes, including post-Japanese Orthopaedic Association score (WMD =-0.27, 95% CI: -0.57, 0.03; P=0.075), visual analog scale score (WMD =0.03, 95% CI: -1.44, 1.50; P=0.970), and fusion rate (risk ratio =1.04, 95% CI: 0.99, 1.09; P=0.158), between the two groups were not significantly different. CONCLUSION: Evidence from the meta analysis of 18 studies demonstrated that surgical options of cervical spondylotic myelopathy using ACDF or ACCF seemed to have similar clinical outcomes. However, ACDF was found to be superior to ACCF in terms of hospital stay, operation time, blood loss, and incidence of complications. PMID- 26604773 TI - Type of dyslipidemia and achievement of the LDL-cholesterol goal in chronic kidney disease patients at the University Hospital. AB - BACKGROUND: Chronic kidney disease (CKD) has been defined as a coronary artery disease risk equivalent. Therefore, the current guideline has been recommended for CKD patients to reach and maintain a low-density lipoprotein-cholesterol (LDL C) goal of less than 100 mg/dL. However, the data regarding the achievement of LDL-C goal in these patients is lacking. OBJECTIVE: This study was conducted to evaluate the types of dyslipidemia affecting patients with CKD stages 3 and 4 and to determine whether these patients achieved LDL-C goal. METHODS: We performed a retrospective chart review of patients with CKD stage 3 or 4 and dyslipidemia who were followed-up at Siriraj Hospital between October 2011 and September 2012. RESULTS: In total, 150 patients with CKD stage 3 or 4 and dyslipidemia were recruited. The mean age was 72+/-10 years, and the body mass index was 25.6+/-4 kg/m(2); 60% had CKD stage 3 with an estimated glomerular filtration rate of 34+/ 12 mL/min/1.73 m(2), and 54% had type 2 diabetes. The percentage of patients with hypercholesterolemia was 78%, hypertriglyceridemia 54%, and low high-density lipoprotein-C 36%. Of these, 52% had mixed hyperlipidemia. Statin treatment was prescribed to 87% of the patients, of which only 31.3% achieved the LDL-C goal according to the National Cholesterol Education Program and the European Society of Cardiology/European Atherosclerosis Society recommendations. Patients who did not achieve the LDL-C goal had a higher cholesterol level at diagnosis and higher prevalence of type 2 diabetes and stroke than those who achieved it. CONCLUSION: Two-thirds of CKD patients with hyperlipidemia had mixed hyperlipidemia. Despite the high frequency of statin treatment, only one-third of patients with CKD achieved the LDL-C goal. Thus, a developmental plan for the management of dyslipidemia in patients with CKD should be implemented to increase their achievement of the LDL-C goal. PMID- 26604772 TI - Managing atrial fibrillation in the very elderly patient: challenges and solutions. AB - Atrial fibrillation (AF) is the most common arrhythmia affecting elderly patients. Management and treatment of AF in this rapidly growing population of older patients involve a comprehensive assessment that includes comorbidities, functional, and social status. The cornerstone in therapy of AF is thromboembolic protection. Anticoagulation therapy has evolved, using conventional or newer medications. Percutaneous left atrial appendage closure is a new invasive procedure evolving as an alternative to systematic anticoagulation therapy. Rate or rhythm control leads to relief in symptoms, fewer hospitalizations, and an improvement in quality of life. Invasive methods, such as catheter ablation, are the new frontier of treatment in maintaining an even sinus rhythm in this particular population. PMID- 26604774 TI - Effectiveness and tolerability of treatment intensification to basal-bolus therapy in patients with type 2 diabetes on previous basal insulin-supported oral therapy with insulin glargine or supplementary insulin therapy with insulin glulisine: the PARTNER observational study. AB - BACKGROUND: Due to the progressive nature of type 2 diabetes mellitus (T2DM), antidiabetic treatment needs to be continuously intensified to avoid long-term complications. In T2DM patients on either basal insulin-supported oral therapy (BOT) or supplementary insulin therapy (SIT) presenting with HbA1c values above individual targets for 3-6 months, therapy should be intensified. This study investigated effectiveness and tolerability of an intensification of BOT or SIT to a basal-bolus therapy (BBT) regimen in T2DM patients in daily clinical practice. METHODS: This noninterventional, 8-month, prospective, multicenter study evaluated parameters of glucose control, occurrence of adverse events (eg, hypoglycemia), and acceptance of devices in daily clinical practice routine after 12 and 24 weeks of intensifying insulin therapy to a BBT regimen starting from either preexisting BOT with insulin glargine (pre-BOT) or preexisting SIT with >=3 daily injections of insulin glulisine (pre-SIT). RESULTS: A total of 1,530 patients were documented in 258 German medical practices. A total of 1,301 patients were included in the full analysis set (55% male, 45% female; age median 64 years; body mass index median 30.8 kg/m(2); pre-BOT: n=1,072; pre-SIT: n=229), and 1,515 patients were evaluated for safety. After 12 weeks, HbA1c decreased versus baseline (pre-BOT 8.67%; pre-SIT 8.46%) to 7.73% and 7.66%, respectively (Delta mean -0.94% and -0.80%; P<0.0001). At week 24, HbA1c was further reduced to 7.38% and 7.30%, respectively (Delta mean -1.29% and -1.15%; P<0.0001), with a mean reduction of fasting blood glucose values in both treatment groups by more than 46 mg/dL. An HbA1c goal of <=6.5% was reached by 17.9% (pre-BOT) and 18.6% (pre-SIT), and an HbA1c <=7.0% by 46.1% (pre-BOT) and 43.0% (pre-SIT) of patients. During 24 weeks, severe as well as serious hypoglycemic events were rare (pre-BOT: n=5; pre-SIT: n=2; pretreated with both insulins: n=1). CONCLUSION: Intensifying glargine-based BOT or glulisine-based SIT to a BBT regimen in poorly controlled T2DM patients in daily routine care led to marked improvements of glycemic control and was well tolerated. PMID- 26604775 TI - Reversal of statin-induced memory dysfunction by co-enzyme Q10: a case report. AB - Statins are useful in the armamentarium of the clinician dealing with dyslipidemia, which increases cardiovascular morbi-mortality in hypertensive and diabetic patients among others. Dyslipidemia commonly exists as a comorbidity factor in the development of atherosclerotic cardiovascular disease. Use of statins is however associated with side effects which at times are so disabling as to interfere with activities of daily living. There are various ways of dealing with this, including use of more water-soluble varieties, intermittent dosing, or use of statin alternatives. Of late, use of co-enzyme Q10 has become acceptable for the muscle side effects. Only one report of any benefit on the rarely reported memory side effect was encountered by the author in the search of English medical literature. This is a report of a documented case of a Nigerian woman with history of statin intolerance in this case, memory dysfunction despite persisting dyslipidemia comorbidity. Her memory dysfunction side effect which interfered with activities of daily living and background muscle pain cleared when coenzyme Q10 was administered alongside low dose statin. Her lipid profile normalized and has remained normal. It is being recommended for use when statin side effects (muscle- and memory-related) impair quality of life and leave patient at dyslipidemia-induced cardiovascular morbi-mortality. PMID- 26604776 TI - Methodological Issues in Assessing the Impact of Prenatal Drug Exposure. AB - Prenatal drug exposure is a common public health concern that can result in perinatal complications, birth defects, and developmental disorders. The growing literature regarding the effects of prenatal exposure to specific drugs such as tobacco, alcohol, cocaine, and heroin is often conflicting and constantly changing. This review discusses several reasons why the effects of prenatal drug exposure are so difficult to determine, including variations in dose, timing, duration of exposure, polydrug use, unreliable measures of drug exposure, latent or "sleeper" effects, genetic factors, and socioenvironmental influences. In addition to providing research guidelines, this review also aims to help clinicians and policy makers to identify the strengths and weaknesses in studies investigating the effects of prenatal drug exposure. This knowledge may be used to make better informed decisions regarding the appropriate treatment for pregnant, drug-dependent women and their children. PMID- 26604777 TI - La(3+) Alters the Response Properties of Neurons in the Mouse Primary Somatosensory Cortex to Low-Temperature Noxious Stimulation of the Dental Pulp. AB - Although dental pain is a serious health issue with high incidence among the human population, its cellular and molecular mechanisms are still unclear. Transient receptor potential (TRP) channels are assumed to be involved in the generation of dental pain. However, most of the studies were conducted with molecular biological or histological methods. In vivo functional studies on the role of TRP channels in the mechanisms of dental pain are lacking. This study uses in vivo cellular electrophysiological and neuropharmacological method to directly disclose the effect of LaCl3, a broad spectrum TRP channel blocker, on the response properties of neurons in the mouse primary somatosensory cortex to low-temperature noxious stimulation of the dental pulp. It was found that LaCl3 suppresses the high-firing-rate responses of all nociceptive neurons to noxious low-temperature stimulation and also inhibits the spontaneous activities in some nonnociceptive neurons. The effect of LaCl3 is reversible. Furthermore, this effect is persistent and stable unless LaCl3 is washed out. Washout of LaCl3 quickly revitalized the responsiveness of neurons to low-temperature noxious stimulation. This study adds direct evidence for the hypothesis that TRP channels are involved in the generation of dental pain and sensation. Blockade of TRP channels may provide a novel therapeutic treatment for dental pain. PMID- 26604778 TI - Meeting the Challenge of Ebola Virus Disease in a Holistic Manner by Taking into Account Socioeconomic and Cultural Factors: The Experience of West Africa. AB - Even if an effective vaccine against Ebola virus disease (EVD) becomes available, the challenges posed by this disease are complex. Certain socioeconomic and cultural factors have been linked to recent outbreaks of EVD in West Africa. The outbreaks revealed widespread ignorance by laypersons of EVD etiology, mode of transmission, and personal protective measures that can be taken. Lack of trust in the authorities, virus infection during the preparation of "bushmeat" for human consumption, traditional funerary practices, and relatively free flow of goods and people between regions and across international borders may have facilitated the spread of EVD and hindered outbreak control efforts. Inadequacy in health systems of the most seriously affected countries, such as Guinea, Sierra Leone, and Liberia, is also an important factor. The objectives of this article are to argue that EVD should be evaluated in a systematic and holistic manner and that this can be done through the use of the modified Haddon Matrix. PMID- 26604779 TI - The Impact of Capsid Proteins on Virus Removal and Inactivation During Water Treatment Processes. AB - This study examined the effect of the amino acid composition of protein capsids on virus inactivation using ultraviolet (UV) irradiation and titanium dioxide photocatalysis, and physical removal via enhanced coagulation using ferric chloride. Although genomic damage is likely more extensive than protein damage for viruses treated using UV, proteins are still substantially degraded. All amino acids demonstrated significant correlations with UV susceptibility. The hydroxyl radicals produced during photocatalysis are considered nonspecific, but they likely cause greater overall damage to virus capsid proteins relative to the genome. Oxidizing chemicals, including hydroxyl radicals, preferentially degrade amino acids over nucleotides, and the amino acid tyrosine appears to strongly influence virus inactivation. Capsid composition did not correlate strongly to virus removal during physicochemical treatment, nor did virus size. Isoelectric point may play a role in virus removal, but additional factors are likely to contribute. PMID- 26604780 TI - A DNA vaccine encoding mutated HPV58 mE6E7-Fc-GPI fusion antigen and GM-CSF and B7.1. AB - BACKGROUND: Persistent infection with high-risk human papillomavirus (HPV) is a predominant cause of cervical cancer, and HPV58 is the third most common virus detected in the patients with cervical cancer in Asia. E6 and E7 are the viral oncogenes which are constitutively expressed in HPV-associated tumor cells and can be used as target antigens for related immunotherapy. In this study, we modified the HPV58 E6 and E7 oncogenes to eliminate their oncogenic potential and constructed a recombinant DNA vaccine that coexpresses the sig-HPV58 mE6E7-Fc-GPI fusion antigen in addition to granulocyte-macrophage colony-stimulating factor (GM-CSF) and B7.1 as molecular adjuvants (PVAX1-HPV58 mE6E7FcGB) for the treatment of HPV58 (+) cancer. METHODS: PVAX1-HPV58 mE6E7FcGB recombinant DNA vaccine was constructed to express a fusion protein containing a signal peptide, a modified HPV58 mE6E7 gene, and human IgG Fc and glycosylphosphatidylinositol (GPI)-anchoring sequences using the modified DNA vaccine vector PVAX1-IRES GM/B7.1 that coexpresses GM-CSF, and B7.1. C57BL/6 mice were challenged by HPV58 E6E7-expressing B16-HPV58 E6E7 cells, followed by immunization by PVAX1-HPV58 mE6E7FcGB vaccine on days 7, 14, 21 after tumor challenge. The cellular immune responses in immunized mice were assessed by measuring IFN-gamma production in splenocytes upon stimulation by HPV58 E6E7-GST protein and the lysis of B16-HPV58 E6E7 target cells by splenocytes after restimulation with HPV58 E6E7-GST protein. The antitumor efficacy was evaluated by monitoring the growth of the tumor. RESULTS: PVAX1-HPV58 mE6E7FcGB elicited varying levels of IFN-lsgdB58onn T-cell immune responses and lysis of target cell in mice in response to the recombinant antigen HPV58 E6E7-GST. Furthermore, the vaccine also induced antitumor responses in the HPV58 (+) B16-HPV58 E6E7 tumor challenge model as evidenced by delayed tumor development. CONCLUSION: The recombinant DNA vaccine PVAX1-HPV58 mE6E7FcGB efficiently generates cellular immunity and antitumor efficacy in immunized mice. These data provide a basis for the further study of this recombinant vaccine as a potential candidate vaccine. PMID- 26604781 TI - SKF95365 induces apoptosis and cell-cycle arrest by disturbing oncogenic Ca(2+) signaling in nasopharyngeal carcinoma cells. AB - BACKGROUND: Aberrant modulation of store-operated calcium ions (Ca(2+)) entry promotes the progression of human malignancies. Previously, we reported that the blockage of store-operated Ca(2+) entry inhibited epidermal growth factor (EGF) stimulated migration and distant metastasis in nasopharyngeal carcinoma (NPC) cells. However, the effects of pharmacological blocker on other Ca(2+) signaling regulated malignant characteristics in NPC cells remained poorly understood. METHODS: We examined the effects of SKF96365, an inhibitor of store-operated Ca(2+) channel, on EGF-launched Ca(2+) signaling in two NPC cell lines. We determined the effects of SKF96365 on cell proliferation, colony formation, apoptosis, and cell-cycle status in vitro. We further elucidated the antitumor activity of SKF96365 in xenograft-bearing mice. RESULTS: It was found that SKF96365 disturbed the thapsigargin (TG)-stimulated Ca(2+) release from endoplasmic reticulum and the subsequent Ca(2+) influx. SKF96365 alone stimulated Ca(2+) responses merely due to endoplasmic reticulum-released Ca(2+). SKF96365 promoted cell mortality, inhibited colony formation, and induced apoptosis and cell-cycle arrest, while blunting the EGF-evoked Ca(2+) signaling. Furthermore, we confirmed that SKF96365 reduced NPC xenograft growth while activating caspase 7-related apoptotic pathway. CONCLUSION: SKF96365 exerts multiple antitumor activities through the distraction on the oncogenic Ca(2+) signaling transduction in NPC cells. PMID- 26604782 TI - A high LDL-C to HDL-C ratio predicts poor prognosis for initially metastatic colorectal cancer patients with elevations in LDL-C. AB - Although lipid disequilibrium has been documented for several types of cancer including colorectal cancer (CRC), it remains unknown whether lipid parameters are associated with the outcome of metastatic CRC (mCRC) patients. Here, we retrospectively examined the lipid profiles of 453 mCRC patients and investigated whether any of the lipid parameters correlated with the outcome of mCRC patients. Pretreatment serum lipids, including triglyceride, cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), were collected in 453 initially mCRC patients. The LDL-C to HDL-C ratio (LHR) was calculated and divided into the first, second, and third tertiles. Univariate and multivariate analyses were performed to evaluate the impact of lipids on overall survival (OS) and progression-free survival (PFS). Nearly two-fifths of the patients (41.3%) exhibited elevations in LDL-C while most patients (88.3%) showed normal HDL-C levels. Decreased HDL-C (P=0.542) and increased LDL-C (P=0.023) were prognostic factors for poor OS, while triglyceride (P=0.542) and cholesterol (P=0.215) were not. Multivariate analysis revealed that LDL-C (P=0.031) was an independent prognostic factor. Triglyceride, cholesterol, HDL-C, and LDL-C did not correlate with PFS. Among patients with elevations in LDL-C levels, patients in the third tertile of the LHR had a markedly shorter median OS compared to those in the first or second tertile (P=0.012). Thus, increased LDL-C level is an independent prognostic factor for poor prognosis in mCRC patients, and a high LHR predicts poor prognosis for initially mCRC patients with elevations in LDL-C. PMID- 26604783 TI - Expression and prognostic value of GalNAc-T3 in patients with completely resected small (<=2 cm) peripheral lung adenocarcinoma after IASLC/ATS/ERS classification. AB - BACKGROUND: GalNAc-T3 catalyzes initial glycosylation of mucin-type O-linked protein involved in proliferation, adhesion, and migration of tumor cells. This study was performed to explore the relationships of the expression of GalNAc-T3 in small peripheral lung adenocarcinoma, especially as an indicator of prognosis. MATERIALS AND METHODS: A retrospective analysis of the patients with small peripheral lung lesions, including 106 adenocarcinoma and two precancerous lesions (atypical adenomatous hyperplasia and adenocarcinoma in situ) after complete surgical resection, was launched. Expression of GalNAc-T3 was examined using immunohistochemistry staining on primary tumor specimens, and the tumors were reclassified in light of the IASLC/ATS/ERS (International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society) adenocarcinoma classifications followed by grading and scoring. Moreover, reverse transcription polymerase chain reaction and Western blot were used to study the expression of GalNAc-T3 in vivo. RESULTS: The low expression of GalNAc-T3 was found in the cytoplasm of tumor cells in 56 of 108 patients (51.9%) and was associated with IASLC/ATS/ERS classification of high risk groups (P=0.007), high Sica score (P=0.036), poorly differentiated tumor (P=0.023), poor tumor-node metastasis (TNM) stage (P=0.007), pleural invasion (P=0.007), and vascular invasion (P<0.001) by Pearson's chi-squared test, but not with sex, age, smoking status, concentration of carcinoembryonic antigen, and lymph node metastasis. In logistic regression analysis, low GalNAc-T3 expression was only correlated with high-ranking TNM stage (odds ratio [OR] =8.975, 95% confidence interval [CI]: 1.797-44.661), vascular invasion (OR =5.668, 95% CI: 1.827-17.578), and the higher risk grade (low risk grade: OR =0.141, 95% CI: 0.027-0.719; moderate risk grade: OR =0.122, 95% CI: 0.017-40.871). The low expression of the GalNAc-T3 usually in adenocarcinoma cell lines was compared with normal bronchial epithelium cell line. Based on the univariate and multivariate analysis, poor TNM stage (P<0.001), pleural invasion (hazard ratio [HR]: 7.958, P=0.021), vascular invasion (HR: 2.403, P=0.040), and low GalNAc-T3 expression (HR: 3.317, P=0.016) were shown to be independently associated with an unfavorable prognosis. However, IASLC/ATS/ERS classification of risk groups and Sica score (P=0.034 and P=0.032, respectively) was correlated with overall survival on Kaplan-Meier method but not Cox regression model. CONCLUSION: GalNAc-T3 expression was correlated with the IASLC/ATS/ERS classification and also associated with prognosis of patients with completely resected small (<=2 cm) peripheral lung adenocarcinoma. PMID- 26604784 TI - Perineural invasion correlates with postoperative distant metastasis and poor overall survival in patients with PT1-3N0M0 esophageal squamous cell carcinoma. AB - The aim of this study was to determine the prognostic value of perineural invasion (PNI) in patients with PT1-3N0M0 esophageal squamous cell carcinoma (ESCC) who underwent curative resection. A total of 148 patients with PT1-3N0M0 ESCC, who underwent surgery in Zhejiang Cancer Hospital (Hangzhou, People's Republic of China), between 2006 and 2009, were evaluated in this retrospective study. The effects of PNI on distant metastasis-free survival (DMFS) and overall survival (OS) were assessed using Kaplan-Meier analysis. Independent prognostic factors were identified by multivariate Cox analysis. Positive PNI was identified in 25.0% of all the cases. The depth of invasion (PT stage) was closely associated with the PNI positivity (P<0.001). The 5-year DMFS rate and OS rate of the PNI-positive patients were significantly worse than those of the PNI-negative patients (DMFS: 37.2% vs 62.3%, P=0.009; OS: 31.3% vs 74.3%, P,0.001). Multivariate analysis indicated that the positivity of PNI was an independent prognostic factor for both DMFS (hazard ratio [HR] =2.35, P=0.039) and OS (HR =3.56, P=0.002). Our results suggest that PNI was a predictor of distant metastasis and independently associated with prognosis of patients with PT1-3N0M0 ESCC. PMID- 26604785 TI - MicroRNA-328 enhances cellular motility through posttranscriptional regulation of PTPRJ in human hepatocellular carcinoma. AB - OBJECTIVE: Interaction between microRNA (miR-328) and PTPRJ (protein tyrosine phosphatase, receptor type, J) has been reported to be responsible for miR-328 dependent increase in epithelial cancer cell proliferation. However, the role of miR-328 and PTPRJ in hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to investigate the clinical significance of miR-328 and/or PTPRJ expression in human HCC and determine their precise biological functions in this malignancy. METHODS: Expression levels of miR-328 and PTPRJ messenger RNA (mRNA) in 100 pairs of HCC and adjacent noncancerous tissues were detected using quantitative real-time reverse transcription polymerase chain reaction. The associations between miR-328 and/or PTPRJ expression and various clinicopathological features of HCC patients were further statistically assessed. Then, the functions of miR-328 and PTPRJ in migration and invasion of two human HCC cell lines were determined by transwell assays. RESULTS: miR-328 and PTPRJ mRNA expression levels were markedly upregulated and down-regulated in HCC tissues, respectively, compared to adjacent noncancerous tissues. Notably, the upregulation of miR-328 in HCC tissues was significantly correlated with the downregulation of PTPRJ mRNA in HCC tissues (r=-0.362, P=0.01). In addition, miR 328-high and/or PTPRJ-low expression were found to be closely correlated with high Edmondson-Steiner grading (all P<0.05) and advanced tumor-node-metastasis stage (all P<0.05). Moreover, the restoration of miR-328 dramatically promoted HCC cell migration and invasion by repressing PTPRJ expression. Interestingly, the loss of PTPRJ expression could significantly attenuate the inhibitory effects of knockdown miR-328 on the migration and invasion of HCC cells. CONCLUSION: These findings demonstrated that the dysregulation of miR-328 and PTPRJ may be associated with tumor progression of HCC patients. Functionally, miR-328 may serve as a crucial oncogene and be implicated in the motility of HCC cells at least in part by the suppression of PTPRJ. PMID- 26604786 TI - Treating patients with advanced rectal cancer and lateral pelvic lymph nodes with preoperative chemoradiotherapy based on pretreatment imaging. AB - Preoperative chemoradiotherapy (CRT) and lateral pelvic lymph node (LPLN) dissection (LPLD) based on pretreatment imaging are performed to improve oncological outcomes at our institution. However, the advantage of LPLD following preoperative CRT in advanced rectal cancer remains unclear. The objective of the present study was to assess the validity of this approach. Thirty-two patients with advanced rectal cancer were included in the study. All patients were treated with preoperative CRT and curative operation. Of these, 16 patients who were treated between August 2005 and June 2008 underwent LPLD on both sides (LPLD group). Sixteen patients who were treated between July 2008 and January 2013 underwent LPLD only on the side with suspected LPLN metastasis determined by pretreatment imaging; in cases without LPLN metastasis, only total mesorectal excision was performed (limited-LPLD group). The overall survival and relapse free survival between the LPLD and the limited-LPLD groups were compared. Preoperative CRT was able to lower clinical lymph node status in 50% of the cases. In addition, pathological lymph node status did not exceed the pretreatment clinical lymph node status stage in the LPLD group. There were no differences in the overall survival and relapse-free survival between the two groups (P=0.729 and P=0.874, respectively). We conclude that multi-imaging studies have a very low risk of overlooking pathologically positive LPLN metastases. Therefore, limited LPLD is a feasible strategy for patients with advanced rectal cancer and suspicious LPLN metastases based on pretreatment imaging. PMID- 26604787 TI - miR-122 inhibits metastasis and epithelial-mesenchymal transition of non-small cell lung cancer cells. AB - miR-122 may function as a novel tumor suppressor. Expression of miR-122 could suppress the proliferation of multi-kinds of human cancer cell lines. In this work, expression of miR-122 via adenoviral vector in non-small-cell lung cancer (NSCLC) cells reduces the number of invasion and migration cells. miR-122 attenuates the epithelial-mesenchymal transition process, which mediates cancer cells metastasis in NSCLC cells A549 and H460. The mechanisms data reveals that miR-122 would disrupt the epithelial-mesenchymal transition process by downregulating PI3K/AKT activation via reducing endogenous expression of insulin like growth factor 1 receptor. These data highlight the detailed roles and potential application of miR-122 in NSCLC cells. PMID- 26604788 TI - miR-132 can inhibit glioma cells invasion and migration by target MMP16 in vitro. AB - Gliomas are the most common malignant primary brain tumors, and new clinical biomarkers and therapeutic targets are imminently required. MicroRNAs (miRNAs) are a novel class of small non-coding RNAs (~22nt) involved in the regulation of various biological processes. Here, by using real-time polymerase chain reaction, miRNA-132 was found to be significantly deregulated in glioma tissues. Based on the prediction of the target genes of miR-132, we hypothesized that there is a significant association between miR-132 and matrix metalloproteinase (MMP) 16 (MT3-MMP), a protein of the MMP family. We showed that the up-expression of miR 132 inhibited cell migration and invasion in the human glioma cell lines A172, SHG44, and U87. Furthermore, the overexpression of miR-132 reduced the expression of MMP16 in A172, SHG44, and U87 cells. Taken together, our study suggested that miR-132 affects glioma cell migration and invasion by MMP16 and implicates miR 132 as a metastasis-inhibiting miRNA in gliomas. PMID- 26604789 TI - Percutaneous CT-guided microwave ablation as maintenance after first-line treatment for patients with advanced NSCLC. AB - BACKGROUND: Systemic therapy is recommended for advanced non-small-cell lung cancer (NSCLC). However, conventional first-line treatment has generated a plateau in response rate of 25% to 35%. Few studies have shown patients benefit from microwave ablation (MWA) in combination with radiotherapy and chemotherapy. This study aims to evaluate safety and efficacy of percutaneous computed tomography-guided MWA as maintenance after first-line treatment for patients with advanced NSCLC. METHODS: Patients with histologically verified NSCLC stage IIIB or IV between January 2010 and March 2014 were involved. After completion of first-line treatment with partial response or stable disease, 35 patients with 39 tumors underwent 39 MWA procedures. Complications, progression-free survival (PFS), overall survival (OS), and correlated predictors were analyzed. RESULTS: During a median follow-up of 17.7 months and 10.8 months after initial MWA, local efficacy was 87.2%, median MWA-related local control time was 10.6 months, and tumor size was the only predictor (P=0.002). Median MWA-related PFS, MWA-related OS, PFS, and OS were 5.4, 10.6, 11.8 and 17.7 months, respectively. Local efficacy was significantly correlated with MWA-related PFS (P=0.003), MWA-related OS (P=0.000), and OS (P=0.001). There were no procedure-specific deaths. Total incidence of major complications was 12.8%, including pneumothorax resolved by closed pleural drainage and pneumonia controlled by antibiotics in a short time. CONCLUSION: This study concluded two points, including: 1) patients benefited from MWA as maintenance both in local control and survival; 2) as maintenance MWA was superior to conventional maintenance therapy with improved survival and well tolerated complications. Therefore, MWA was a safe and effective maintenance after first-line treatment in patients with advanced NSCLC. PMID- 26604790 TI - Management experiences of primary angiosarcoma of breast: a retrospective study from single institute in the People's Republic of China. AB - BACKGROUND: Primary angiosarcoma of breast (PAOB) is a rare and highly aggressive malignancy. There is no general agreement on optimal treatments or prognostic factors for this orphan disease. The objective of this study was to investigate the clinicopathologic features and management experiences of PAOB. METHODS: We performed a retrospective review of medical and pathologic records of 17 consecutive patients diagnosed with PAOB between January 2000 and February 2014 at FuDan University Shanghai Cancer Center. We evaluated the clinical characteristics, multimodality treatments, and associated clinical outcomes. RESULTS: A total of 16 patients were included in this retrospective study (median age at PAOB presentation 33.5 years, range: 19-56 years). Palpable tumor with or without breast skin ecchymosis presented as the most common initial symptom. All patients underwent surgery with curative intent. Median disease-free survival and overall survival (OS) were 9 months and 13.6 months, respectively. One-year and 3 year disease-free survival rates were 43.8% and 6.3%, with OS rates of 93.8% and 78.1%, respectively. High histologic grade indicated poorer OS by univariate analysis (P=0.01). However, neither adjuvant chemotherapy nor radiotherapy contributed to clinical outcomes in our series. CONCLUSION: PAOB is considered as an infrequent breast neoplasm with aggressive characteristics. Histologic grade and early metastasis (within 12 months after diagnosis) are associated with poor prognosis. Regardless of grade, additional benefit was not observed with adjuvant therapy. PMID- 26604791 TI - miR-21 inhibits the effects of cyclooxygenase-2 inhibitor NS398 on apoptosis and invasion in gastric cancer cells. AB - OBJECTIVE: To investigate the role of miR-21 in cyclooxygenase-2 inhibitor NS398 induced apoptosis and invasion in gastric cancer (GC) cells. METHODS: AGS cells were treated with NS398 and transfected with miR-21. Quantitative real-time polymerase chain reaction was used to measure miR-21 mRNA expression. Apoptotic cells were assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and flow cytometric analysis. The protein expression of cleaved caspase-3, Bcl-2, Bax, Bak, and PTEN was detected by Western blot. The capacities for invasion and migration were measured by transwell and wound-healing assays, respectively. RESULTS: Treatment of AGS cells with NS398 induced apoptosis in a dose-dependent manner accompanied by significant downregulation of miR-21 mRNA expression. Upregulation of miR-21 expression by transfection of miR-21 mimics into AGS cells blocked NS398-induced apoptosis. Treatment of AGS cells with NS398 induced changes in Bcl-2 protein family members, showing an increase in the protein expression of Bax, Bak, and PTEN, with a concomitant decrease in the protein expression of Bcl-2. In cells transfected with miR-21 mimics, these changes were reversed. The decrease in cellular invasiveness and migration induced by NS398 was blocked by upregulation of miR-21. CONCLUSION: miR-21 mediates anticancer effects of NS398 in GC cells by regulating apoptosis-related proteins. miR-21 is one of the molecular targets of this specific cyclooxygenase 2 inhibitor in the prevention and treatment of GC. PMID- 26604792 TI - Use of taxane-containing induction chemotherapy in combination with concurrent chemoradiotherapy in Chinese patients with locally advanced nasopharyngeal carcinoma: a meta-analysis. AB - PURPOSE: Taxane-containing induction chemotherapy (IC) regimens in combination with concurrent chemoradiotherapy (CCRT) have been compared with non-taxane containing IC combined with CCRT in randomized controlled trials (RCTs) in Chinese patients with advanced nasopharyngeal carcinoma (NPC). This meta-analysis aimed to systematically evaluate their clinical efficacy and safety profiling in this ethnic population. METHODS: The electronic databases, PubMed, Embase, MEDLINE, and Chinese Biomedical Database, were searched for eligible studies. The outcomes included overall response rate (ORR), 1-year survival rate, and different types of adverse events. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. RESULTS: A total of 12 RCTs (representing 835 patients) were identified. The pooled analysis showed that taxane-containing regimens had a significant improvement in ORR for nasopharyngeal lesion (OR =4.57, 95% CI =1.14-18.30, P=0.032, z=2.15) but not in cervical lymph nodes (OR =1.23, 95% CI =0.65-2.36, P=0.532, z=0.64) and in 1-year survival rates (OR =1.19, 95% CI =0.10-14.82, P=0.893, z=0.13) compared with non taxane-containing regimens. Regarding the adverse events and toxicities, grade 3 4 leukopenia and neutropenia were significantly different between the two groups (P<0.001) in favor of the non-taxane-containing regimens, but grade 3-4 vomiting was significantly different between the two groups (P<0.005) in favor of the taxane-containing regimens. CONCLUSION: When combined with CCRT, taxane containing IC regimens may be more efficient for short-term local control in Chinese patients with locally advanced NPC than the non-taxane-containing IC regimens. Moreover, the major toxic effects, which were bone marrow suppression, could be tolerated by majority of patients. More long-term follow-up and high quality trials of NPC are needed to validate our findings. PMID- 26604793 TI - Assessing the potential value of long interspersed element-1 hypomethylation in colorectal cancer: evidence from retrospective studies. AB - BACKGROUND AND AIMS: Long interspersed element-1 (LINE-1) hypomethylation may play an important role in colorectal cancer (CRC). Studies were identified that investigated LINE-1 methylation levels in CRC compared with normal controls. METHODS: The random-effects model was used to estimate standardized mean difference with 95% confidence intervals according to the heterogeneity between the studies. We explored the relationship between LINE-1 hypomethylation and microsatellite instability (MSI) status, clinical features, and molecular features in CRC patients using a fixed-effects model. RESULTS: A total of 7396 CRC patients were included in the meta-analysis. LINE-1 methylation was significantly lower in CRC patients than in controls (P=0.000). Mean LINE-1 methylation was significantly lower in non-MSI-high than in MSI-high tumors (P=0.000). LINE-1 hypomethylation was found more frequently in patients with a family history compared with those without family history (P=0.002). Patients with left colon cancer had lower LINE-1 methylation than those with right colon cancer (P=0.001). LINE-1 methylation was not associated with body mass index or patient sex. LINE-1 hypomethylation was found in p21 lost tumors (P=0.000). LINE 1 methylation levels were not associated with KRAS or PIK3CA-mutation status. CONCLUSION: LINE-1 hypomethylation is a potential biomarker for risk of CRC and associated with various clinical and molecular features of CRC. PMID- 26604794 TI - Prognostic value of Bcl-2 expression in patients with non-small-cell lung cancer: a meta-analysis and systemic review. AB - OBJECTIVE: B-cell-lymphoma-2 (Bcl-2) is a proto-oncogene that plays an important role in the regulation of apoptosis and cell survival. However, there are much conflicting data in the literature concerning the association between Bcl-2 and prognosis in non-small-cell lung cancer (NSCLC). There is little in the way of meta-analysis focused on Bcl-2 and its effect on NSCLC prognosis. This study was performed to provide an assessment of whether expression levels of Bcl-2 are associated with prognosis in patients with NSCLC. MATERIALS AND METHODS: We searched PubMed, the Cochrane Library, and China National Knowledge Infrastructure for all eligible studies. The combined hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) in terms of overall survival were evaluated. RESULTS: Fifty published studies including 6,863 patients with lung cancer were included in this meta-analysis. Overall, Bcl-2 was expressed in 33% of the NSCLC tumors studied. Our analysis indicates that NSCLC patients with Bcl-2-positive expression have a better prognosis than those with Bcl-2-negative expression in both Asian and non-Asian study populations (HR 0.79, 95% CI 0.72 0.87, P<0.00001). However, Bcl-2-positive expression seems to have no significant impact on survival of stage I NSCLC patients. CONCLUSION: Our results indicated that Bcl-2 might be a useful prognostic marker for NSCLC generally. Larger clinical trials are needed to confirm the prognostic value of Bcl-2 in stage I NSCLC. PMID- 26604795 TI - Experience with combination of nimotuzumab and intensity-modulated radiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma. AB - AIM: To evaluate the efficacy and safety of using nimotuzumab in combination with intensity-modulated radiotherapy (IMRT) in the primary treatment of locoregionally advanced nasopharyngeal carcinoma. METHODS: Between December 2009 and December 2013, 38 newly diagnosed patients with stage III-IV nasopharyngeal carcinoma were treated with IMRT and nimotuzumab concomitantly. The distribution of disease was stage III in 20 (52.6%), stage IV A in 9 (23.7%), and stage IV B in 9 (23.7%). All the patients received at least two cycles of cisplatin-based neoadjuvant chemotherapy followed by nimotuzumab 200 mg/week concurrently with IMRT. Acute and late radiation-related toxicities were graded according to the Acute and Late Radiation Morbidity Scoring Criteria of Radiation Therapy Oncology Group. RESULTS: With a median follow-up of 39.7 months (range, 13.3-66.5 months), the estimated 3-year local recurrence-free survival, regional recurrence-free survival, distant metastasis-free survival, progression failure-free survival, and overall survival rates were 92.8%, 92.9%, 89.5%, 78.7%, and 87.5%, respectively. The median cycle for nimotuzumab addition was 6 weeks. Grade 3 radiation-induced mucositis accounted for 36.8% of treated people. No skin rash and infusion reaction were observed, distinctly from what is reported in cetuximab-treated patients. CONCLUSION: Nimotuzumab plus IMRT showed promising outcomes in terms of locoregional control and survival, without increasing the incidence of radiation-related toxicities for patients. PMID- 26604796 TI - Overexpression of miR-100 inhibits cell proliferation, migration, and chemosensitivity in human glioblastoma through FGFR3. AB - BACKGROUND: Glioblastoma multiforme is one of the most deadly forms of brain cancer. We investigated the regulatory effects of microRNA-100 (miR-100) on cell proliferation, migration, and chemosensitivity in human glioblastoma. METHODS: miR-100 expression was assessed by quantitative real-time polymerase chain reaction in both glioblastoma cells and human tumors. Lentiviruses of miR-100 mimics and inhibitors were transfected into U251 and T98G cells. The regulatory effects of either overexpressing or downregulating miR-100 on glioblastoma were evaluated by a viability assay, growth assay, migration assay, chemosensitivity assay, and an in vivo tumor transplantation assay. Expression of fibroblast growth factor receptor 3 (FGFR3), the bioinformatically predicted target of miR 100, was examined by Western blot in glioblastoma. FGFR3 was then ectopically overexpressed in U251 and T98G cells, and its effects on miR-100-mediated cancer regulation were evaluated by growth, migration, and chemosensitivity assays. RESULTS: MiR-100 was markedly downregulated in both glioblastoma cell lines and human tumors. Overexpressing miR-100 through lentiviral transfection in U251 and T98G cells significantly inhibited cancer growth (both in vitro and in vivo) and migration and increased chemosensitivity to cisplatin and 1, 3-bis (2 chloroethyl)-l-nitrosourea, whereas downregulation of miR-100 had no effects on development of cancer. FGFR3 was directly regulated by miR-100 in glioblastoma. Ectopically overexpressing FGFR3 was able to ameliorate the anticancer effects of upregulation of miR-100 on glioblastoma growth, migration, and chemosensitivity. CONCLUSION: MiR-100 was generally downregulated in glioblastoma. Overexpressing miR-100 had anticancer effects on glioblastoma, likely through regulation of FGFR3. The MiR-100/FGFR3 signaling pathway might be a biochemical target for treatment in patients with glioblastoma. PMID- 26604797 TI - Impact of lymphovascular invasion on recurrence and progression rates in patients with pT1 urothelial carcinoma of bladder after transurethral resection. AB - OBJECTIVE: To evaluate the clinical significance of lymphovascular invasion (LVI) on recurrence and progression rates in patients with pT1 urothelial carcinoma of bladder after transurethral resection. METHODS: This retrospective study was performed with 155 patients with newly diagnosed pT1 urothelial carcinoma of bladder who were treated with transurethral resection of bladder tumor at our institution from January 2006 to January 2010. The presence or absence of LVI was examined by pathologists. Chi-square test was performed to identify the correlations between LVI and other clinical and pathological features. Kaplan Meier method was used to estimate the recurrence-free survival (RFS) and progression-free survival curves and difference was determined by the log-rank test. Univariate and multivariate analyses were performed to determine the predictive factors through a Cox proportional hazards analysis model. RESULTS: LVI was detected in a total of 34 patients (21.9%). While LVI was associated with high-grade tumors (P<0.001) and intravesical therapy (P=0.009). Correlations with age (P=0.227), sex (P=0.376), tumor size (P=0.969), tumor multiplicity (P=0.196), carcinoma in situ (P=0.321), and smoking (P=0.438) were not statistically significant. There was a statistically significant tendency toward higher recurrence rate and shorter RFS time in LVI-positive patients. However, no statistically significant differences were observed in progression rate between the two groups. Moreover, multivariate Cox proportional hazards analysis revealed that LVI, tumor size, and smoking were independent prognostic predictors of recurrence. The hazard ratios (95% confidence interval) were 2.042 (1.113-3.746, P=0.021), 1.817 (1.014-3.256, P=0.045), and 2.079 (1.172-3.687, P=0.012), respectively. CONCLUSION: The presence of LVI in transurethral resection of bladder tumor specimens is significantly associated with higher recurrence rate and shorter RFS time in patients with newly diagnosed T1 urothelial carcinoma of the bladder. It is an independent prognostic predictor for disease recurrence. Thus, patients with LVI should be followed up closely. PMID- 26604798 TI - Novel prognostic genes of diffuse large B-cell lymphoma revealed by survival analysis of gene expression data. AB - OBJECTIVE: This study aimed to identify prognostic genes for diffuse large B-cell lymphoma (DLBCL), using bioinformatic methods. METHODS: Five gene expression data sets were downloaded from the Gene Expression Omnibus database. Significance analysis of microarrays algorithm was used to identify differentially expressed genes (DEGs) from two data sets. Functional enrichment analysis was performed for the DEGs with the Database for Annotation, Visualization and Integration Discovery (DAVID). Survival analysis was performed with the Kaplan-Meier method using function survfit from package survival of R for the other three data sets. Cox univariate regression analysis was used to further screen out prognostic genes. RESULTS: Thirty-one common DEGs were identified in the two data sets, mainly enriched in the regulation of lymphocyte activation, immune response, and interleukin-mediated signaling pathway. Combined with 47 DLBCL-related genes acquired by literature retrieval, a total of 78 potential prognostic genes were obtained. Cases from the other three data sets were used in hierarchical clustering, and the 78 genes could cluster them into several subtypes with significant differences in survival curves. Cox univariate regression analysis revealed 45, 33, and eleven prognostic genes in the three data sets, respectively. Five common prognostic genes were revealed, including LCP2, TNFRSF9, FUT8, IRF4, and TLE1, among which LCP2, FUT8, and TLE1 were novel prognostic genes. CONCLUSION: Five prognostic genes of DLBCL were identified in this study. They could not only be used for molecular subtyping of DLBCL but also be potential targets for treatment. PMID- 26604799 TI - Baseline blood immunological profiling differentiates between Her2-breast cancer molecular subtypes: implications for immunomediated mechanisms of treatment response. AB - PURPOSE: Breast cancer patients' response to treatment is highly dependent on the primary tumor molecular features, with triple-negative breast tumors having the worst prognosis of all subtypes. According to the molecular features, tumors stimulate the microenvironment to induce distinct immune responses, baseline immune activation being associated with higher likelihood of pathologic response. In this study, we investigated the deconvolution of the immunological status of triple-negative tumors in comparison with luminal tumors and the association with patients' clinicopathological characteristics. PATIENTS AND METHODS: Gene expression of 84 inflammatory molecules and their receptors were analyzed in 40 peripheral blood samples from patients with Her2- primary breast cancer tumors. We studied the association of triple-negative phenotype with age, clinical stage, tumor size, lymph nodes, and menopausal status. RESULTS: We observed that more patients with estrogen (ER)/progesterone (PR)-negative tumors had grade III, while more patients with ER/PR-positive tumors had grade II tumors. Gene expression analysis revealed a panel of 14 genes to have differential expression between the two groups: several interleukins: IL13, IL16, IL17C and IL17F, IL1A, IL3; interleukin receptors: IL10RB, IL5RA; chemokines: CXCL13 and CCL26; and cytokines: CSF2, IFNA2, OSM, TNSF13. CONCLUSION: The expression levels of these genes have been previously shown to be associated with reduced immunological status; indeed, the triple-negative breast cancer patients presented with lower counts of lymphocytes and eosinophils than the ER/PR-positive ones. These results contribute to a better understanding of the possible role of antitumor immune responses in mediating the clinical outcome. PMID- 26604801 TI - Parallel computing in genomic research: advances and applications. AB - Today's genomic experiments have to process the so-called "biological big data" that is now reaching the size of Terabytes and Petabytes. To process this huge amount of data, scientists may require weeks or months if they use their own workstations. Parallelism techniques and high-performance computing (HPC) environments can be applied for reducing the total processing time and to ease the management, treatment, and analyses of this data. However, running bioinformatics experiments in HPC environments such as clouds, grids, clusters, and graphics processing unit requires the expertise from scientists to integrate computational, biological, and mathematical techniques and technologies. Several solutions have already been proposed to allow scientists for processing their genomic experiments using HPC capabilities and parallelism techniques. This article brings a systematic review of literature that surveys the most recently published research involving genomics and parallel computing. Our objective is to gather the main characteristics, benefits, and challenges that can be considered by scientists when running their genomic experiments to benefit from parallelism techniques and HPC capabilities. PMID- 26604800 TI - Molecular dynamics simulations: advances and applications. AB - Molecular dynamics simulations have evolved into a mature technique that can be used effectively to understand macromolecular structure-to-function relationships. Present simulation times are close to biologically relevant ones. Information gathered about the dynamic properties of macromolecules is rich enough to shift the usual paradigm of structural bioinformatics from studying single structures to analyze conformational ensembles. Here, we describe the foundations of molecular dynamics and the improvements made in the direction of getting such ensemble. Specific application of the technique to three main issues (allosteric regulation, docking, and structure refinement) is discussed. PMID- 26604802 TI - Human adipose stem cell and ASC-derived cardiac progenitor cellular therapy improves outcomes in a murine model of myocardial infarction. AB - BACKGROUND: Adipose tissue is an abundant and potent source of adult stem cells for transplant therapy. In this study, we present our findings on the potential application of adipose-derived stem cells (ASCs) as well as induced cardiac-like progenitors (iCPs) derived from ASCs for the treatment of myocardial infarction. METHODS AND RESULTS: Human bone marrow (BM)-derived stem cells, ASCs, and iCPs generated from ASCs using three defined cardiac lineage transcription factors were assessed in an immune-compromised mouse myocardial infarction model. Analysis of iCP prior to transplant confirmed changes in gene and protein expression consistent with a cardiac phenotype. Endpoint analysis was performed 1 month posttransplant. Significantly increased endpoint fractional shortening, as well as reduction in the infarct area at risk, was observed in recipients of iCPs as compared to the other recipient cohorts. Both recipients of iCPs and ASCs presented higher myocardial capillary densities than either recipients of BM derived stem cells or the control cohort. Furthermore, mice receiving iCPs had a significantly higher cardiac retention of transplanted cells than all other groups. CONCLUSION: Overall, iCPs generated from ASCs outperform BM-derived stem cells and ASCs in facilitating recovery from induced myocardial infarction in mice. PMID- 26604803 TI - Managing nut-induced anaphylaxis: challenges and solutions. AB - The prevalence of peanut and tree nut allergy in the USA has increased, especially in the pediatric population. Nut allergy remains the leading cause of fatal anaphylactic reactions. Management of anaphylaxis includes not only treatment of symptoms during a reaction, but strict dietary avoidance and education on potential situations, which may place the patient at high risk for accidental exposure. Cross-reactivity between various nuts along with various cross-contamination sources should be discussed with all nut-allergic individuals. Exciting research continues to emerge on other potential treatments for patients allergic to nuts, including allergen immunotherapy. Results of such interventions have been encouraging, though further studies are needed regarding safety and long-term outcomes before these can be applied to clinical practice. PMID- 26604804 TI - The past, present, and future of monoclonal antibodies to IL-5 and eosinophilic asthma: a review. AB - Asthma is a heterogeneous syndrome that might be better described as a constellation of phenotypes or endotypes, each with distinct cellular and molecular mechanisms, rather than as a singular disease. One of these phenotypes is eosinophilic asthma. As the development of eosinophilic inflammation is categorically dependent on the biological activity of Interleukin (IL)-5, IL-5 antagonism became an obvious target for therapy in this phenotype. Early trials of monoclonal antibodies targeting the biological activity of IL-5, including reslizumab, mepolizumab, and benralizumab, were performed on asthmatics with no concern for evidence of eosinophilia. These trials were largely unsuccessful. However, during these trials, researchers recognized the need to quantify eosinophilia in asthma subjects in order to identify those asthmatics in whom these medications would be more likely to improve symptoms and lung function. Using biomarkers, such as sputum and blood eosinophilia, recent studies of these medications have shown improvements in blood and sputum eosinophilia, forced expiratory volume in 1 second, and quality of life assessments as well as reducing occurrences of exacerbations. Moving forward, better and less invasive biomarkers of eosinophilia are necessary to ensure that the correct patients are chosen to receive these medications to receive maximal benefit. PMID- 26604805 TI - Delamanid expanded access novel treatment of drug resistant tuberculosis. AB - Tuberculosis (TB) remains a global emergency and is one of the most common infectious disease causes of death in developing countries. Current treatment regimens for multi-drug resistant TB are associated with low treatment success rates, are toxic, and require long duration of treatment. The need for shorter and more effective treatment regimens is urgent. Delamanid (Deltyba, or formerly known as OPC-67683) is a new dihydro-imidazooxazole anti-TB drug active against resistant forms of pulmonary TB. Delamanid kills Mycobacterium tuberculosis by inhibiting the synthesis of mycolic acids required for cell wall synthesis. Whilst delamanid has been included in the WHO Model List of Essential Medicine by the World Health Organization Expert Committee on Selection and Use of Essential Medicines and in international guidance for the treatment of multi-drug resistant TB since April 2014, its access in countries with the greatest need, has proven challenging. This review provides an update on currently available clinical safety and efficacy data on delamanid and offers a discussion on research priorities and recommendations for expedited, expanded access. PMID- 26604806 TI - Laboratory-based nationwide surveillance of antimicrobial resistance in Ghana. AB - Global efforts are underway to combat antimicrobial resistance (AMR). A key target in this intervention is surveillance for local and national action. Data on AMR in Ghana are limited, and monitoring of AMR is nonexistent. We sought to generate baseline data on AMR, and to assess the readiness of Ghana in laboratory based surveillance. Biomedical scientists in laboratories across Ghana with capacity to perform bacteriological culture were selected and trained. In-house standard operating protocols were used to perform microbiological investigations on clinical specimens. Additional microbiological tests and data analyses were performed at a centralized laboratory. Surveillance data were stored and analyzed using WHONET program files. A total of 24 laboratories participated in the training, and 1,598 data sets were included in the final analysis. A majority of the bacterial species were isolated from outpatients (963 isolates; 60.3%). Urine (617 isolates; 38.6%) was the most common clinical specimen cultured, compared to blood (100 isolates; 6.3%). Ten of 18 laboratories performed blood culture. Bacteria isolated included Escherichia coli (27.5%), Pseudomonas spp. (14.0%), Staphylococcus aureus (11.5%), Streptococcus spp. (2.3%), and Salmonella enterica serovar Typhi (0.6%). Most of the isolates were multidrug-resistant, and over 80% of them were extended-spectrum beta-lactamases-producing. Minimum inhibitory concentration levels at 50% and at 90% for ciprofloxacin, ceftriaxone, and amikacin on selected multidrug-resistant bacteria species ranged between 2 ug/mL and >256 ug/mL. A range of clinical bacterial isolates were resistant to important commonly used antimicrobials in the country, necessitating an effective surveillance to continuously monitor AMR in Ghana. With local and international support, Ghana can participate in global AMR surveillance. PMID- 26604807 TI - Variation in hospital resource use and cost among surgical procedures using topical absorbable hemostats. AB - BACKGROUND: Adjunctive hemostats are used to assist with the control of intraoperative bleeding. The most common types are flowables, gelatins, thrombins, and oxidized regenerated celluloses (ORCs). In the US, Surgicel((r)) products are the only US Food and Drug Administration-approved ORCs. OBJECTIVE: To compare the outcomes of health care resource utilization (HRU) and costs associated with using ORCs compared to other adjunctive hemostats (OAHs are defined as flowables, gelatins, and topical thrombins) for surgical procedures in the US inpatient setting. PATIENTS AND METHODS: A retrospective, US-based cohort study was conducted using hospital inpatient discharges from the 2011-2012 calendar years in the Premier Healthcare Database. Patients with either an ORC or an OAH who underwent a cardiovascular procedure (valve surgery and/or coronary artery bypass graft surgery), carotid endarterectomy, cholecystectomy, or hysterectomy were included. Propensity score matching was used to create comparable groups of ORC and OAH patients. Clinical, economic, and HRU outcomes were compared. RESULTS: The propensity score matching created balanced patient cohorts for cardiovascular procedure (22,718 patients), carotid endarterectomy (10,890 patients), cholecystectomy (6,090 patients), and hysterectomy (9,348 patients). In all procedures, hemostatic agent costs were 28%-56% lower for ORCs, and mean hemostat units per discharge were 16%-41% lower for ORCs compared to OAHs. Length of stay and total procedure costs for patients treated with ORCs were lower for carotid endarterectomy patients (0.3 days and US$700) and for cholecystectomy patients (1 day and US$3,350) (all P<0.001). CONCLUSION: Costs and HRU for patients treated with ORCs were lower than or similar to patients treated with OAHs. Proper selection of the appropriate hemostatic agents has the potential to influence clinical outcomes and treatment costs. PMID- 26604808 TI - Specific cut-off points for waist circumference and waist-to-height ratio as predictors of cardiometabolic risk in Black subjects: a cross-sectional study in Benin and Haiti. AB - PURPOSE: Waist circumference (WC) and waist-to-height ratio (WHtR) are widely used as indicators of abdominal adiposity and the cut-off values have been validated primarily in Caucasians. In this study we identified the WC and WHtR cut-off points that best predicted cardiometabolic risk (CMR) in groups of African (Benin) and African ancestry (Haiti) Black subjects. METHODS: This cross sectional study included 452 apparently healthy subjects from Cotonou (Benin) and Port-au-Prince (Haiti), 217 women and 235 men from 25 to 60 years. CMR biomarkers were the metabolic syndrome components. Additional CMR biomarkers were a high atherogenicity index (total serum cholesterol/high density lipoprotein cholesterol >=4 in women and >=5 in men); insulin resistance set at the 75th percentile of the calculated Homeostasis Model Assessment index (HOMA-IR); and inflammation defined as high-sensitivity C-reactive protein (hsCRP) concentrations between 3 and 10 mg/L. WC and WHtR were tested as predictors of two out of the three most prevalent CMR biomarkers. Receiver operating characteristic (ROC) curves, Youden's index, and likelihood ratios were used to assess the performance of specific WC and WHtR cut-offs. RESULTS: High atherogenicity index (59.5%), high blood pressure (23.2%), and insulin resistance (25% by definition) were the most prevalent CMR biomarkers in the study groups. WC and WHtR were equally valid as predictors of CMR. Optimal WC cut-offs were 80 cm and 94 cm in men and women, respectively, which is exactly the reverse of the generic cut-offs. The standard 0.50 cut-off of WHtR appeared valid for men, but it had to be increased to 0.59 in women. CONCLUSION: CMR was widespread in these population groups. The present study suggests that in order to identify Africans with high CMR, WC thresholds will have to be increased in women and lowered in men. Data on larger samples are needed. PMID- 26604809 TI - Role of implants in the treatment of diabetic macular edema: focus on the dexamethasone intravitreal implant. AB - Diabetic macular edema (DME) is the leading cause of sight-threatening complication in diabetic patients, and several treatment modalities have been developed and evaluated to treat this pathology. Intravitreal agents, such as anti-vascular endothelial growth factors (anti-VEGF) or corticosteroids, have become more popular in recent years and are widely used for treating DME. Sustained release drugs appear to be mentioned more often nowadays for extending the period of intravitreal activity, and corticosteroids play a key role in inhibiting the inflammatory process in DME. A potent corticosteroid, dexamethasone (Ozurdex((r))), in the form of an intravitreal implant, has been approved for various ocular etiologies among which DME is also one. This review evaluates the role of implants in the treatment of DME, mainly focusing on the dexamethasone intravitreal implant. PMID- 26604810 TI - Birch pollen influence the severity of atopic eczema - prospective clinical cohort pilot study and ex vivo penetration study. AB - There is little clinical evidence for a correlation between the severity of atopic eczema (AE) and pollen exposition. To obtain more data, we performed a clinical cohort pilot study about the influence of pollen on AE between sensitized and nonsensitized subjects and an experimental study addressing the cutaneous penetration of pollen into the skin. Fifty-five patients were monitored during birch pollen season. To study the cutaneous penetration, grass pollen allergens were applied on excised skin and the uptake in CD1c-expressing dendritic cells was investigated. The correlation between environmental pollen load and severity of the Scoring Atopic Dermatitis (SCORAD) score and pruritus was observed, regardless of the status of sensitization. The sensitized group recovered significantly worse after the birch pollen season. Remarkably higher amounts of pollen allergens taken up by CD1c cells were detected in epidermal cells derived from skin explants with a disturbed epidermal barrier. These findings suggest an exacerbating role of pollen in AE utilizing the epidermal route. PMID- 26604811 TI - Profile of clindamycin phosphate 1.2%/benzoyl peroxide 3.75% aqueous gel for the treatment of acne vulgaris. AB - Acne vulgaris is a common and chronic skin disease, and is a frequent source of morbidity for affected patients. Treatment of acne vulgaris is often difficult due to the multifactorial nature of this disease. Combination therapy, such as that containing clindamycin and benzoyl peroxide, has become the standard of care. Several fixed formulations of clindamycin 1% and benzoyl peroxide of varying concentrations are available and have been used with considerable success. The major limitation is irritation and dryness from higher concentrations of benzoyl peroxide, and a combination providing optimal efficacy and tolerability has yet to be determined. Recently, a clindamycin and benzoyl peroxide 3.75% fixed combination formulation was developed. Studies have suggested that this formulation may be a safe and effective treatment regimen for patients with acne vulgaris. Here, we provide a brief review of acne pathogenesis, benzoyl peroxide and clindamycin, and profile a new Clindamycin-BP 3.75% fixed combination gel for the treatment of moderate-to-severe acne vulgaris. PMID- 26604812 TI - The use of pharmacogenetics in clinical practice for the treatment of individuals with HIV infection in Thailand. AB - OBJECTIVES: The objectives of this study were to describe the use of pharmacogenetics in clinical practice for the treatment of individuals with human immunodeficiency virus (HIV) infection and to determine the treatment outcomes of HIV-infected patients in whom pharmacogenetic testing was performed. METHODS: This study involves a retrospective collection of medical records of HIV-infected patients who attended Ramathibodi Hospital during January 2011 to November 2014 and in whom pharmacogenetic testing was performed. We reviewed patients' characteristics, reasons for pharmacogenomic testing, results of human leukocyte antigen-B* (HLA-B*) 5701, HLA-B*3505, HLA-B*4001, CYP2B6, and antiretroviral drug (ARV) levels, treatment planning after the physicians were informed the results, and outcome after changing the treatment. RESULTS: A total of 103 HIV-infected patients with a median age of 46 (range, 20-85) years were enrolled, and 68.9% of them were male. The reasons for pharmacogenomic testing were having adverse drug reactions besides rash (37.9%), screening before prescribing ARV (36.9%), choice of next ARV (19.4%), and confirmation of the cause of skin rash (5.8%). After the physicians knew the results, they adjusted the treatment plan including changing the regimens, changing the ARV dose for avoiding toxicity, and stopping ARV. Among 45 patients, side effects, such as dizziness from efavirenz or rash from abacavir, were improved in 96.4%. Among 27 patients, abnormal laboratory results, such as renal insufficiency from tenofovir or anemia from zidovudine, were improved and some returned to normal in 59.3%. HIV RNA was undetectable after treatment adjustment in 94.9%. CONCLUSION: The benefits of pharmacogenetic testing are either guiding the initial drug regimen or individualizing regimen, increasing efficacy, and simultaneously avoiding adverse drug reactions. Use of pharmacogenetic testing in HIV-infected Thai adults should be considered. PMID- 26604813 TI - Validation of Siriraj Stroke Score in southeast Nigeria. AB - The aim of the study is to validate the use of Siriraj Stroke Score (SSS) in the diagnosis of acute hemorrhagic and acute ischemic stroke in southeast Nigeria. This was a prospective study on validity of SSS in the diagnosis of stroke types in southeast Nigeria. Subjects diagnosed with stroke for whom brain computerized tomography (CT) scan was performed on admission were recruited during the study period. SSS was calculated for each subject, and the SSS diagnosis was compared with brain CT scan-based diagnosis. A total of 2,307 patients were admitted in the hospital medical wards during the study period, of whom 360 (15.6%) were stroke patients and of these, 113 (31.4%) adult subjects met the inclusion criteria. The mean age of the subjects was 66.5+/-2.6 years. The mean interval between ictus and presentation was 2.5+/-0.4 days. Ischemic stroke was confirmed by CT in 74 subjects; however, SSS predicted 60 (81.1%) of these subjects correctly (P<0.05). Hemorrhagic stroke was confirmed by CT in 39 subjects, and SSS predicted 36 (92.3%) of them correctly (P<0.05). In acute ischemic stroke, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of SSS were 92%, 94%, 97%, 86%, and 93%, respectively, while in patients with hemorrhagic stroke, the corresponding percentages were 94%, 92%, 86%, 97%, and 93%, respectively. SSS is not reliable enough to clinically differentiate stroke types in southeast Nigeria to warrant interventions like thrombolysis in acute ischemic stroke. PMID- 26604814 TI - Palmitoylethanolamide, a neutraceutical, in nerve compression syndromes: efficacy and safety in sciatic pain and carpal tunnel syndrome. AB - Palmitoylethanolamide (PEA) is an endogenous lipid modulator in animals and humans, and has been evaluated since the 1970s as an anti-inflammatory and analgesic drug in more than 30 clinical trials, in a total of ~6,000 patients. PEA is currently available worldwide as a nutraceutical in different formulations, with and without excipients. Here we describe the results of all clinical trials evaluating PEA's efficacy and safety in nerve compression syndromes: sciatic pain and pain due to carpal tunnel syndrome, and review preclinical evidence in nerve impingement models. Both the pharmacological studies as well as the clinical trials supported PEA's action as an analgesic compound. In total, eight clinical trials have been published in such entrapment syndromes, and 1,366 patients have been included in these trials. PEA proved to be effective and safe in nerve compression syndromes. In one pivotal, double blind, placebo controlled trial in 636 sciatic pain patients, the number needed to treat to reach 50% pain reduction compared to baseline was 1.5 after 3 weeks of treatment. Furthermore, no drug interactions or troublesome side effects have been described so far. Physicians are not always aware of PEA as a relevant and safe alternative to opioids and co-analgesics in the treatment of neuropathic pain. Especially since the often prescribed co-analgesic pregabaline has been proven to be ineffective in sciatic pain in a double blind enrichment trial, PEA should be considered as a new and safe treatment option for nerve compression syndromes. PMID- 26604816 TI - An integrated safety analysis of intravenous ibuprofen (Caldolor((r))) in adults. AB - Intravenous (IV) nonsteroidal anti-inflammatory drugs such as IV ibuprofen are increasingly used as a component of multimodal pain management in the inpatient and outpatient settings. The safety of IV ibuprofen as assessed in ten sponsored clinical studies is presented in this analysis. Overall, 1,752 adult patients have been included in safety and efficacy trials over 11 years; 1,220 of these patients have received IV ibuprofen and 532 received either placebo or comparator medication. The incidence of adverse events (AEs), serious AEs, and changes in vital signs and clinically significant laboratory parameters have been summarized and compared to patients receiving placebo or active comparator drug. Overall, IV ibuprofen has been well tolerated by hospitalized and outpatient patients when administered both prior to surgery and postoperatively as well as for nonsurgical pain or fever. The overall incidence of AEs is lower in patients receiving IV ibuprofen as compared to those receiving placebo in this integrated analysis. Specific analysis of hematological and renal effects showed no increased risk for patients receiving IV ibuprofen. A subset analysis of elderly patients suggests that no dose adjustment is needed in this higher risk population. This integrated safety analysis demonstrates that IV ibuprofen can be safely administered prior to surgery and continued in the postoperative period as a component of multimodal pain management. PMID- 26604815 TI - Spinal pain: current understanding, trends, and the future of care. AB - This commissioned review paper offers a summary of our current understanding of nonmalignant spinal pain, particularly persistent pain. Spinal pain can be a complex problem, requiring management that addresses both the physical and psychosocial components of the pain experience. We propose a model of care that includes the necessary components of care services that would address the multidimensional nature of spinal pain. Emerging care services that tailor care to the individual person with pain seems to achieve better outcomes and greater consumer satisfaction with care, while most likely containing costs. However, we recommend that any model of care and care framework should be developed on the basis of a multidisciplinary approach to care, with the scaffold being the principles of evidence-based practice. Importantly, we propose that any care services recommended in new models or frameworks be matched with available resources and services - this matching we promote as the fourth principle of evidence-based practice. Ongoing research will be necessary to offer insight into clinical outcomes of complex interventions, while practice-based research would uncover consumer needs and workforce capacity. This kind of research data is essential to inform health care policy and practice. PMID- 26604817 TI - Landmark-based versus ultrasound-guided ilioinguinal/iliohypogastric nerve blocks in the treatment of chronic postherniorrhaphy groin pain: a retrospective study. AB - BACKGROUND: Chronic postherniorrhaphy groin pain (CPGP) is a debilitating condition, which is often refractory to conservative medical management. To our knowledge, there have been no studies directly comparing landmarked-based and ultrasound-guided approaches in this population. OBJECTIVE: To compare the effectiveness of landmark-based and ultrasound-guided ilioinguinal/iliohypogastric nerve blocks in the treatment of CPGP. STUDY DESIGN: This is a retrospective chart review of patients who presented to our tertiary care pain medicine clinic with a diagnosis of CPGP. Inclusion criteria were the following: age >18 years, diagnosis of groin pain, and prior history of herniorrhaphy. Exclusion criteria included those who were seen for initial consultation but were lost to follow-up. Primary outcomes were 50% or greater reduction in pain on visual analog scale (VAS). Secondary outcomes were 30% or greater reduction in VAS pain score, changes in VAS pain scores, and reported complications. RESULTS: A total of 36 patients were included in the study. Of them, 20 patients underwent the landmark-based and 16 underwent the ultrasound guided techniques. There was no significant difference in baseline demographics. The average VAS score preinjection was 7.08 in the landmark-based and 7.0 in the ultrasound-guided groups (P=0.65). A total of 14 patients (70%) in the landmark based and eleven patients (79%) in the ultrasound-guided groups experienced at least a 50% reduction in VAS scores. There was no statistically significant difference between the two groups (P=1.0), and no complications were noted. We also did not find a significant difference in terms of number of patients with 30% or greater reduction (P=0.71) and changes in VAS pain scores (P=0.64). No complications were reported in either group. CONCLUSION: In our study, there was no statistically significant difference between the landmark-based and ultrasound guided groups in terms of a reduction in VAS pain scores, and no complications were noted in either group. PMID- 26604818 TI - Low-dose naloxone provides an abuse-deterrent effect to buprenorphine. AB - In developmental research, plasma buprenorphine concentrations comparable to a 2 mg buprenorphine-naloxone (BN) sublingual tablet have been achieved with a 0.75 mg dose of BN buccal film, a small, bioerodible polymer film for application to mucosal membranes. This was a randomized, double-blind, placebo-controlled, single-dose, four-period crossover study in opioid-dependent subjects with chronic pain receiving >100 mg oral morphine equivalents daily who experienced withdrawal following a naloxone challenge dose. The objective of the study was to determine if intravenous (IV) naloxone doses of 0.1 and 0.2 mg would produce a withdrawal response when coadministered with a 0.75 mg IV dose of buprenorphine. Fifteen subjects receiving 90-1,260 mg oral morphine equivalents per day enrolled and completed the study. Precipitated withdrawal occurred in 13% (2/15) of placebo-treated subjects and 47% (7/15) of buprenorphine-treated subjects. When combined with the 0.75 mg dose of buprenorphine, a 0.1 mg dose of naloxone increased the incidence of precipitated withdrawal to 60%, and a 0.2 mg dose of naloxone increased the incidence to 73%. By 15 minutes postdose, the mean change in Clinical Opioid Withdrawal Scale (COWS) score from predose was 3.0 for placebo, 6.9 for buprenorphine, 9.8 for BN 0.1 mg, and 12.4 for BN 0.2 mg. The mean COWS score with each active treatment was significantly greater than placebo (P<0.001), and the mean COWS score for each of the naloxone-containing treatments was significantly greater than for buprenorphine alone (P<0.001). Naloxone doses as low as 0.1 mg added an abuse-deterrent effect to a 0.75 mg IV dose of buprenorphine. PMID- 26604819 TI - Comparative evaluation of continuous intercostal nerve block or epidural analgesia on the rate of respiratory complications, intensive care unit, and hospital stay following traumatic rib fractures: a retrospective review. AB - BACKGROUND: Thoracic trauma accounts for 10%-15% of all trauma admissions. Rib fractures are the most common injury following blunt thoracic trauma. Epidural analgesia improves patient outcomes but is not without problems. The use of continuous intercostal nerve blockade (CINB) may offer superior pain control with fewer side effects. This study's objective was to compare the rate of pulmonary complications when traumatic rib fractures were treated with CINB vs epidurals. METHODS: A hospital trauma registry provided retrospective data from 2008 to 2013 for patients with 2 or more traumatic rib fractures. All subjects were admitted and were treated with either an epidural or a subcutaneously placed catheter for continuous intercostal nerve blockade. Our primary outcome was a composite of either pneumonia or respiratory failure. Secondary outcomes included total hospital days, total ICU days, and days on the ventilator. RESULTS: 12.5% (N=8) of the CINB group developed pneumonia or had respiratory failure compared to 16.3% (N=7) in the epidural group. No statistical difference (P=0.58) in the incidence of pneumonia or vent dependent respiratory failure was observed. There was a significant reduction (P=0.05) in hospital days from 9.72 (SD 9.98) in the epidural compared to 6.98 (SD 4.67) in the CINB group. The rest of our secondary outcomes showed no significant difference. CONCLUSION: This study did not show a difference in the rate of pneumonia or ventilator-dependent respiratory failure in the CINB vs epidural groups. It was not sufficiently powered. Our data supports a reduction in hospital days when CINB is used vs epidural. CINB may have advantages over epidurals such as fewer complications, fewer contraindications, and a shorter time to placement. Further studies are needed to confirm these statements. PMID- 26604820 TI - Hypofractionated whole breast radiotherapy: current perspectives. AB - Adjuvant radiotherapy (RT) is an important part of breast cancer management but the dose and fractionation schedules used are variable. A total of 50 Gy in 25 daily fractions delivered over 5 weeks is often considered the "standard" adjuvant RT prescription. Hypofractionated regimes such as 42.5 Gy in 16 daily fractions or 40 Gy in 15 daily fractions following breast-conserving surgery have proven to be equally effective and achieve similar or better cosmetic and normal tissue outcomes for both invasive and in situ diseases and when treating the regional nodes. Hypofractionation is more convenient for patients and less costly. However, certain patients at higher risk of RT late effects may benefit from a less intense, even more extended fractionation schedule. This review describes the indications for whole breast hypofractionated adjuvant RT for patients with breast cancer following breast-conserving surgery and proposes that hypofractionation should be the new "standard" for adjuvant breast cancer RT. PMID- 26604822 TI - Incidence, morbidity, mortality, and prevalence of diabetes in Denmark, 2000 2011: results from the Diabetes Impact Study 2013. AB - PURPOSE: As part of the Danish Diabetes Impact Study 2013, we present trends in the incidence, morbidity, mortality, and prevalence of diabetes in Denmark for the period 2000 through 2011. PATIENTS AND METHODS: The Danish National Diabetes Register was established in 2006 and is assumed to cover all patients with diabetes, alive as of the end of 1996, and all subsequent new cases. The present study is based on the content of the register as of July 3, 2013 (n=497,232 patients). Using the personal identification code assigned to all Danish inhabitants, all available supplementary information from the Danish National Patient Register and the Danish Civil Registration Service was used to define the date of diagnosis of diabetes and the first date of experiencing complications (grouped according to impact and severity). RESULTS: During the period of 2000 to 2011, the incidence rate of diabetes increased approximately 5% annually. During the same period, decreasing trends were observed for both the rates of progression in complications and of the complication-specific mortality. During the same period, the prevalence of diabetes doubled. CONCLUSION: The increasing prevalence of diabetes in Denmark is driven by increasing incidence combined with decreasing morbidity and mortality in the population of patients with diabetes. These mechanisms will be explored further as part of the Diabetes Impact Study 2013, together with investigations into the socioeconomic and health economic aspects of diabetes. PMID- 26604821 TI - Critical appraisal of rituximab in the maintenance treatment of advanced follicular lymphoma. AB - Rituximab is an IgG1, chimeric monoclonal antibody specifically designed to recognize the CD20 antigen expressed on the surface of normal and malignant B lymphocytes, from the B-cell precursor to the mature B-cells of the germinal center, and by most neoplasms derived from B-cells. After 2 decades of use, rituximab is firmly positioned in the treatment of follicular lymphoma (FL), both in the front line and in the relapsing disease, improving previous results by including it in classical chemotherapy regimens. However, the pharmacology of rituximab continues to generate controversial issues especially regarding the mechanisms of action in vivo. The contribution of rituximab as a maintenance treatment in FL has been significant progress in the management of this disease without an increase in side effects or a decrease in the quality of life of patients. With the widespread use of rituximab, there are new security alerts and side effects not previously detected in the pivotal trials that clinicians should learn to recognize and manage. In this article, we will review the pharmacokinetics and pharmacodynamics of rituximab, the management issues in the treatment of advanced FL focusing on maintenance rituximab, its long-term efficacy and safety profile, and its effect on the quality of life. PMID- 26604823 TI - Cross-sectional study on comorbidities and adverse events in patients with advanced and recurrent ovarian cancer in France. AB - PURPOSE: The purpose of this study was to evaluate the prevalence of comorbidities and adverse events (AEs), and determine the treatment patterns according to platinum-sensitivity status in patients with advanced (stage IIIB IV) or recurrent epithelial ovarian cancer (EOC). METHODS: A cross-sectional study was carried out in France with patients over 18 years, diagnosed with advanced (stage IIIB-IV) or recurrent EOC between 2009 and 2012. A total of 23 physicians (oncologists and gynecologists) participated, contributing 127 patients. Data were abstracted by participating physicians into a case report form. RESULTS: Of the 127 patients included, 92 (72.4%) had advanced EOC and 35 (27.6%) had recurrent EOC. A total of 73 comorbidities were reported in 44 patients (34.6%). Vascular (10.2%), metabolic (7.1%), respiratory (5.5%), and psychiatric disorders (5.5%) were the most common types of comorbidities reported. Prevalence of AEs was 74.8%, of which 12.6% were classified as serious. The most common AEs were anemia (16.5%), hematologic events (12.6%), taste change (11.8%), and headache (7.1%). Throughout the follow-up period, twelve patient deaths were reported (six due to disease progression). Of 35 patients with recurrent disease, 16 were highly platinum sensitive (recurrence >12 months after stopping platinum-based therapy), eleven were partially platinum sensitive (recurrence 6-12 months after stopping platinum-based therapy), seven were platinum resistant (recurrence within 6 months of stopping platinum-based therapy or progression while receiving second- or later-line platinum-based therapy), and one was platinum refractory (recurrence within 6 months from the start of first line platinum-based therapy). CONCLUSION: In this cross-sectional study of advanced and metastatic ovarian cancer patients, approximately one-third of patients were diagnosed with comorbidities, and approximately three-quarters were diagnosed with AEs (12.6% with severe AEs). PMID- 26604825 TI - Challenges facing effective implementation of co-trimoxazole prophylaxis in children born to HIV-infected mothers in the public health facilities. AB - BACKGROUND: If children born to HIV-infected mothers are not identified early, approximately 30% of them will die within the first year of life due to opportunistic infections. In order to prevent morbidity and mortality due to opportunistic infections in children, the World Health Organization recommends the use of prophylaxis using co-trimoxazole. However, the challenges affecting effective implementation of this policy in Tanzania have not been documented. AIM: In this study, we assessed the challenges facing the provision of co trimoxazole prophylaxis among children born to HIV-infected mothers in the public hospitals of Dar es Salaam, Tanzania. METHODOLOGY: Four hundred and ninety-eight infants' PMTCT (Prevention of Mother-to-Child Transmission of HIV) register books for the past 2 years were reviewed to obtain information regarding the provision of co-trimoxazole prophylaxis. One hundred and twenty-six health care workers were interviewed to identify success stories and challenges in the provision of co-trimoxazole prophylaxis in children. In addition, 321 parents and guardians of children born to HIV-infected mothers were interviewed in the health facilities. RESULTS: Approximately 80% of children were initiated with co-trimoxazole prophylaxis within 2 months after birth. Two hundred and ninety-one (58.4%) children started using co-trimoxazole within 4 weeks after birth. Majority (n=458, 91.8%) of the children were prescribed 120 mg of co-trimoxazole per day, whereas 39 (7.8%) received 240 mg per day. Only a small proportion (n=1, 0.2%) of children received 480 mg/day. Dose determination was based on the child's age rather than body weight. Parents and guardians reported that 42 (13.1%) children had missed one or more doses of co-trimoxazole during the course of prophylaxis. The majority of health care workers (89.7%) reported that co-trimoxazole is very effective for the prevention of opportunistic infections among children, but frequent shortage of co-trimoxazole in the health facilities was the main challenge. CONCLUSION: Most children who were initiated with co-trimoxazole prophylaxis did not experience significant opportunistic infections, and the drug was well tolerated. The major barrier for co-trimoxazole prophylaxis was due to frequent out-of-stocks of pediatric co-trimoxazole formulations in the health facilities. Dose determination was based on the age rather than the weight of children, thus creating potential for under- or over-dosing of children. PMID- 26604826 TI - Management of HIV/AIDS in older patients-drug/drug interactions and adherence to antiretroviral therapy. AB - Patients with human immunodeficiency virus (HIV) are living longer with their disease, as HIV has become a chronic illness managed with combination antiretroviral therapy (cART). This has led to an increasing number of patients greater than 50 years old living successfully with HIV. As the number of older adults with HIV has increased, there are special considerations for the management of HIV. Older adults with HIV must be monitored for drug side effects and toxicities. Their other non-HIV comorbidities should also be considered when choosing a cART regimen. Older adults with HIV have unique issues related to medication compliance. They are more likely than the younger HIV patients to have vision loss, cognitive impairment, and polypharmacy. They may have lower expectations of their overall health status. Depression and financial concerns, especially if they are on a fixed income, may also contribute to noncompliance in the aging HIV population. PMID- 26604824 TI - The Danish National Patient Registry: a review of content, data quality, and research potential. AB - BACKGROUND: The Danish National Patient Registry (DNPR) is one of the world's oldest nationwide hospital registries and is used extensively for research. Many studies have validated algorithms for identifying health events in the DNPR, but the reports are fragmented and no overview exists. OBJECTIVES: To review the content, data quality, and research potential of the DNPR. METHODS: We examined the setting, history, aims, content, and classification systems of the DNPR. We searched PubMed and the Danish Medical Journal to create a bibliography of validation studies. We included also studies that were referenced in retrieved papers or known to us beforehand. Methodological considerations related to DNPR data were reviewed. RESULTS: During 1977-2012, the DNPR registered 8,085,603 persons, accounting for 7,268,857 inpatient, 5,953,405 outpatient, and 5,097,300 emergency department contacts. The DNPR provides nationwide longitudinal registration of detailed administrative and clinical data. It has recorded information on all patients discharged from Danish nonpsychiatric hospitals since 1977 and on psychiatric inpatients and emergency department and outpatient specialty clinic contacts since 1995. For each patient contact, one primary and optional secondary diagnoses are recorded according to the International Classification of Diseases. The DNPR provides a data source to identify diseases, examinations, certain in-hospital medical treatments, and surgical procedures. Long-term temporal trends in hospitalization and treatment rates can be studied. The positive predictive values of diseases and treatments vary widely (<15% 100%). The DNPR data are linkable at the patient level with data from other Danish administrative registries, clinical registries, randomized controlled trials, population surveys, and epidemiologic field studies - enabling researchers to reconstruct individual life and health trajectories for an entire population. CONCLUSION: The DNPR is a valuable tool for epidemiological research. However, both its strengths and limitations must be considered when interpreting research results, and continuous validation of its clinical data is essential. PMID- 26604827 TI - Gene expression profiles and protein-protein interaction network analysis in AIDS patients with HIV-associated encephalitis and dementia. AB - Central nervous system dysfunction is an important cause of morbidity and mortality in patients with human immunodeficiency virus type 1 (HIV-1) infection and acquired immunodeficiency virus syndrome (AIDS). Patients with AIDS are usually affected by HIV-associated encephalitis (HIVE) with viral replication limited to cells of monocyte origin. To examine the molecular mechanisms underlying HIVE-induced dementia, the GSE4755 Affymetrix data were obtained from the Gene Expression Omnibus database and the differentially expressed genes (DEGs) between the samples from AIDS patients with and without apparent features of HIVE-induced dementia were identified. In addition, protein-protein interaction networks were constructed by mapping DEGs into protein-protein interaction data to identify the pathways that these DEGs are involved in. The results revealed that the expression of 1,528 DEGs is mainly involved in the immune response, regulation of cell proliferation, cellular response to inflammation, signal transduction, and viral replication cycle. Heat-shock protein alpha, class A member 1 (HSP90AA1), and fibronectin 1 were detected as hub nodes with degree values >130. In conclusion, the results indicate that HSP90A and fibronectin 1 play important roles in HIVE pathogenesis. PMID- 26604828 TI - Profile and birthing practices of Maranao traditional birth attendants. AB - This study determined the profile and birthing practices in both modern and traditional ways among Maranao traditional birth attendants (TBAs) in Lanao del Norte, Philippines. It employed a descriptive research design. The respondents were 50 Maranao TBAs selected through the snowball sampling technique. A questionnaire was developed by the researchers to identify the respondents' modern birthing practices utilizing the Essential Intrapartum and Newborn Care (EINC) Protocol. To determine their profile and traditional birthing practices, items from a previous study and the respondents' personal claims were adapted. This study shows that Maranao TBAs have less compliance to the EINC Protocol and they often practice the traditional birthing interventions, thus increasing the risk of complications to both mother and newborn. PMID- 26604829 TI - Hemostatic assessment, treatment strategies, and hematology consultation in massive postpartum hemorrhage: results of a quantitative survey of obstetrician gynecologists. AB - OBJECTIVE: To assess potential diagnostic and practice barriers to successful management of massive postpartum hemorrhage (PPH), emphasizing recognition and management of contributing coagulation disorders. STUDY DESIGN: A quantitative survey was conducted to assess practice patterns of US obstetrician-gynecologists in managing massive PPH, including assessment of coagulation. RESULTS: Nearly all (98%) of the 50 obstetrician-gynecologists participating in the survey reported having encountered at least one patient with "massive" PPH in the past 5 years. Approximately half (52%) reported having previously discovered an underlying bleeding disorder in a patient with PPH, with disseminated intravascular coagulation (88%, n=23/26) being identified more often than von Willebrand disease (73%, n=19/26). All reported having used methylergonovine and packed red blood cells in managing massive PPH, while 90% reported performing a hysterectomy. A drop in blood pressure and ongoing visible bleeding were the most commonly accepted indications for rechecking a "stat" complete blood count and coagulation studies, respectively, in patients with PPH; however, 4% of respondents reported that they would not routinely order coagulation studies. Forty-two percent reported having never consulted a hematologist for massive PPH. CONCLUSION: The survey findings highlight potential areas for improved practice in managing massive PPH, including earlier and more consistent assessment, monitoring of coagulation studies, and consultation with a hematologist. PMID- 26604830 TI - To what extent will women accept HPV self-sampling for cervical cancer screening? A qualitative study conducted in Switzerland. AB - OBJECTIVES: Human papillomavirus self-sampling (self-HPV) is regarded as an alternative to Pap smear testing for women who do not participate in cervical cancer screening. This qualitative study aimed to determine women's views on cervical cancer screening and the various obstacles to participation in screening, and to evaluate the perceived benefits and disadvantages of self-HPV. METHOD: Twenty-four focus groups were conducted in 2012, with a total of 125 participants aged between 24 and 67 years. They were recruited through different channels, including flyers and posters, personal contacts, and an ongoing clinical trial focused on the unscreened population. Interview transcripts have been coded with the ATLAS.ti CAQDAS. RESULTS: Fifty-seven participants regularly attended screening and 68 had not been screened in the past 3 years. While some participants considered self-HPV as an acceptable screening method, others expressed concerns. Benefits included access, reduced costs, and time-saving. Disadvantages included the fear of not performing the test correctly, hurting oneself, and the accuracy of the test. Participants expressed concern that self HPV would replace gynecological visits. CONCLUSION: Self-HPV is not likely to rapidly or substantially modify women's behaviors in regard to screening. While it may offer benefits in some specific situations, most women emphasized the advantages of regular gynecologist visits. PMID- 26604831 TI - History of cardiovascular events and cardiovascular risk factors among patients initiating strontium ranelate for treatment of osteoporosis. AB - PURPOSE: To estimate the proportion of osteoporosis patients in whom initiating strontium ranelate treatment, under new EMA guidelines, should be contraindicated because of a history of cardiovascular events or risk for cardiovascular events. MATERIALS AND METHODS: This was a retrospective analysis of medical and pharmacy claims using the Clinical Practice Research Datalink database. Patients were included if they had >=1 prescription of strontium from September 1, 2008 to August 31, 2013, were aged >=50 as of the index date (the date of the first ever strontium ranelate prescription), and had >=1 year of medical records pre-index. Cardiovascular events occurring any time pre-index were identified, which included ischemic heart disease, cerebrovascular disease, uncontrolled hypertension, and peripheral arterial disease. Cardiovascular risk factors assessed included 1) diabetes or hypertension any time pre-index; 2) hyperlipidemia in the 12 months pre-index; or 3) obesity in the 12 months pre index. RESULTS: A total of 7,474 patients were included: 90.4% were women, with an average age of 76.5 years, and 84.5% used osteoporosis therapy, either bisphosphonates or non-bisphosphonates, prior to strontium initiation. A total of 23.6% of patients experienced >=1 cardiovascular event prior to strontium initiation; the rate was lower among female patients than in male patients (22.4% vs 35.3%, P<0.01). A total of 45.9% had risk factors for cardiovascular events (without cardiovascular event history). CONCLUSION: More than one-fifth of osteoporosis patients in the UK who used strontium had a cardiovascular event history, and one-half had cardiovascular risk factors prior to strontium initiation. PMID- 26604832 TI - En-face optical coherence tomography angiography of neovascularization elsewhere in hemicentral retinal vein occlusion. AB - PURPOSE: To evaluate how the growth of neovascularization elsewhere (NVE) was delineated in an eye with hemicentral retinal vein occlusion (CRVO) using optical coherence tomography (OCT) angiography. PATIENTS AND METHODS: We examined a 64 year-old man diagnosed with hemi-CRVO. The area around the occluded vein was scanned using a spectral-domain OCT device (RTVue XR Avanti). Blood flow was detected using the split-spectrum amplitude-decorrelation angiography (SSADA) algorithm. Color fundus photography, fluorescein angiography (FA), and OCT angiography examinations were performed at the first visit and at 3 and 6 months postpresentation. RESULTS: At the first visit, FA revealed delayed retinal venous filling and extensive areas of capillary nonperfusion. The patient underwent a trial of intravitreal ranibizumab injection (0.5 mg/0.05 mL) for the treatment of macular edema. At 3 months postpresentation, there was no NVE around the occluded vein in the en-face SSADA image, but at 6 months, NVE appeared on the occluded veins. The en-face SSADA image showed the NVE structure in the fibrovascular membrane on the occluded vein more clearly than FA images. CONCLUSION: OCT angiography clearly visualized the sprouting of NVE in an eye with hemi-CRVO. New findings of the vascular structure of NVE in hemi-CRVO were revealed using the en face SSADA algorithm. PMID- 26604834 TI - Mediastinal vacuum phenomenon: atypical pneumomediastinum caused by gas replacement of diminished fat. AB - We report a case involving an 83-year-old man with interstitial lung disease who developed atypical pneumomediastinum caused by gas replacement of diminished fat. The patient presented with a complaint of worsening symptoms of respiratory difficulty since a diagnosis of chronic eosinophilic pneumonia 5 months back. He had been under observation with no particular treatment for 5 months. Computed tomography performed on admission revealed pneumomediastinum. When the current scan was compared with that obtained 5 months ago, it was evident that the fat surrounding the mediastinum had been replaced by gas density. There was no mediastinal enlargement, pneumothorax, or pneumopericardium. Because the patient was elderly, home oxygen therapy was initiated for the interstitial pneumonia with no steroid therapy. Computed tomography performed 10 months after discharge showed the reappearance of mediastinal fat and no evidence of gas density. This case is unique because the pneumomediastinum was distinct from spontaneous pneumomediastinum caused by alveolar air leaks and resembled the vacuum phenomenon caused by intervertebral disc degeneration. PMID- 26604833 TI - Giant malignant peripheral nerve sheath tumor of thigh in an adolescent with neurofibromatosis type 1: a case report. AB - Malignant peripheral nerve sheath tumors (MPNSTs) are rare sarcomas of children and adolescents, and they are aggressive tumors with a high rate of local recurrence. We present a 15-year-old boy with neurofibromatosis type 1 (NF1), who had a giant MPNST on the right thigh taking into account the available literature. Diagnosis of MPNST may be delayed in NF1 patients due to confusion with a neurofibroma and/or a plexiform neurofibroma. Malignancy should be considered, especially in cases with big masses, with heterogeneous involvement, or in the presence of cysts or necrotic nodules. The aim of surgical treatment is complete surgical excision. PMID- 26604835 TI - Anophthalmia and serious microphthalmia: a summary of the problems associated with antenatal diagnosis and therapeutic refunding in Sub-Saharan Africa. AB - Anophthalmia and serious microphthalmia are conditions characterized by the complete lack of the primary optic vesicle or the presence of the rudimentary eye like structure. These are rare prenatal conditions, yet diagnoses remain a challenge in Black African areas, raising a major concerns surrounding care after birth. This paper reports a case of anophthalmia and serious microphthalmia, the diagnosis of which was not possible despite many ultrasounds undergone by the mother during pregnancy. PMID- 26604836 TI - Magnetic resonance imaging investigation of the bone conduction implant - a pilot study at 1.5 Tesla. AB - PURPOSE: The objective of this pilot study was to investigate if an active bone conduction implant (BCI) used in an ongoing clinical study withstands magnetic resonance imaging (MRI) of 1.5 Tesla. In particular, the MRI effects on maximum power output (MPO), total harmonic distortion (THD), and demagnetization were investigated. Implant activation and image artifacts were also evaluated. METHODS AND MATERIALS: One implant was placed on the head of a test person at the position corresponding to the normal position of an implanted BCI and applied with a static pressure using a bandage and scanned in a 1.5 Tesla MRI camera. Scanning was performed both with and without the implant, in three orthogonal planes, and for one spin-echo and one gradient-echo pulse sequence. Implant functionality was verified in-between the scans using an audio processor programmed to generate a sequence of tones when attached to the implant. Objective verification was also carried out by measuring MPO and THD on a skull simulator as well as retention force, before and after MRI. RESULTS: It was found that the exposure of 1.5 Tesla MRI only had a minor effect on the MPO, ie, it decreased over all frequencies with an average of 1.1+/-2.1 dB. The THD remained unchanged above 300 Hz and was increased only at lower frequencies. The retention magnet was demagnetized by 5%. The maximum image artifacts reached a distance of 9 and 10 cm from the implant in the coronal plane for the spin-echo and the gradient-echo sequence, respectively. The test person reported no MRI induced sound from the implant. CONCLUSION: This pilot study indicates that the present BCI may withstand 1.5 Tesla MRI with only minor effects on its performance. No MRI induced sound was reported, but the head image was highly distorted near the implant. PMID- 26604837 TI - Treatment of sleep-disordered breathing with positive airway pressure devices: technology update. AB - Many types of positive airway pressure (PAP) devices are used to treat sleep disordered breathing including obstructive sleep apnea, central sleep apnea, and sleep-related hypoventilation. These include continuous PAP, autoadjusting CPAP, bilevel PAP, adaptive servoventilation, and volume-assured pressure support. Noninvasive PAP has significant leak by design, which these devices adjust for in different manners. Algorithms to provide pressure, detect events, and respond to events vary greatly between the types of devices, and vary among the same category between companies and different models by the same company. Many devices include features designed to improve effectiveness and patient comfort. Data collection systems can track compliance, pressure, leak, and efficacy. Understanding how each device works allows the clinician to better select the best device and settings for a given patient. This paper reviews PAP devices, including their algorithms, settings, and features. PMID- 26604838 TI - A critical appraisal of the clinical utility of proton therapy in oncology. AB - Proton therapy is an emerging technology for providing radiation therapy to cancer patients. The depth dose distribution of a proton beam makes it a preferable radiation modality as it reduces radiation to the healthy tissue outside the tumor, compared with conventional photon therapy. While theoretically beneficial, its clinical values are still being demonstrated from the increasing number of patients treated with proton therapy, from several dozen proton therapy centers around the world. High equipment and facility costs are often the major obstacle for its wider adoption. Because of the high cost and lack of definite clinical evidence of its superiority, proton therapy treatment faces criticism on its cost-effectiveness. Technological development is causing a gradual lowering of costs, and research and clinical studies are providing further evidence on its clinical utility. PMID- 26604839 TI - Measuring postural stability with an inertial sensor: validity and sensitivity. AB - INTRODUCTION/PURPOSE: To examine the concurrent validity, and sensitivity, of an inertial sensor for use in the assessment of postural sway. METHODS: This was a laboratory-based, repeated-measures design with ten healthy participants. Concurrent validity was tested between an inertial sensor, forceplate, and rigid body kinematics across three commonly used balance tests. Further, the inertial sensor measures were compared across eight commonly used tests of balance. Variables manipulated include stance position, surface condition, and eyes-open versus eyes-closed. RESULTS: The inertial sensor was correlated to both the forceplate-derived measures (r=0.793) and rigid-body kinematics (r=0.887). Significant differences between the balance tests were observed when tested with the inertial sensor. In general, there was a three-way interactions between the three balance factors (surface, stance, and vision) leading to pairwise comparisons between each balance test. The root-mean-square showed an increase across tasks of greater difficulty ranging from an average of 0.0368 with two legs, eyes-open to 0.911 when tested during tandem stance, eyes-closed tested on a foam pad. CONCLUSION: The new inertial sensor shows promise for use in the assessment of postural sway. Additionally, the inertial sensor appears sensitive to differences in balance tasks of varying degrees of difficulty when tested in a healthy sample of young adults. This inertial sensor may provide new opportunities for further research in the assessment of balance changes in the mild traumatic brain injury population. PMID- 26604840 TI - Investigation of the mechanical performance of Siemens linacs components during arc: gantry, MLC, and electronic portal imaging device. AB - BACKGROUND: In radiotherapy treatments, it is crucial to monitor the performance of linac components including gantry, collimation system, and electronic portal imaging device (EPID) during arc deliveries. In this study, a simple EPID-based measurement method is suggested in conjunction with an algorithm to investigate the stability of these systems at various gantry angles with the aim of evaluating machine-related errors in treatments. METHODS: The EPID sag, gantry sag, changes in source-to-detector distance (SDD), EPID and collimator skewness, EPID tilt, and the sag in leaf bank assembly due to linac rotation were separately investigated by acquisition of 37 EPID images of a simple phantom with five ball bearings at various gantry angles. A fast and robust software package was developed for automated analysis of image data. Three Siemens linacs were investigated. RESULTS: The average EPID sag was within 1 mm for all tested linacs. Two machines showed >1 mm gantry sag. Changes in the SDD values were within 7.5 mm. EPID skewness and tilt values were <1 degrees in all machines. The maximum sag in leaf bank assembly was <1 mm. CONCLUSION: The method and software developed in this study provide a simple tool for effective investigation of the behavior of Siemens linac components with gantry rotation. Such a comprehensive study has been performed for the first time on Siemens machines. PMID- 26604841 TI - Magnetic resonance imaging arthrography following type II superior labrum from anterior to posterior repair: interobserver and intraobserver reliability. AB - BACKGROUND: Arthroscopic repair of type II superior labrum from anterior to posterior (SLAP) lesions is a common surgical procedure. However, anatomic healing following repair has rarely been investigated. The intraobserver and interobserver reliability of magnetic resonance imaging arthrography (MRA) following type II SLAP repair has not previously been investigated. This is of particular interest due to recent reports of poor clinical results following type II SLAP lesion repair. PURPOSE: To evaluate the MRA findings following arthroscopic type II SLAP lesion repair and determine its intraobserver and interobserver reliability. STUDY DESIGN: Cohort study (diagnosis), Level of Evidence, 2. METHODS: Twenty-five patients with an isolated type II SLAP lesion (confirmed via diagnostic arthroscopy) underwent standard suture anchor-based repair. At a mean of 25.2 months post-operatively, patients underwent a standardized MRA protocol to investigate the integrity of the repair. MRAs were independently reviewed by two radiologists and a fellowship trained shoulder surgeon. The outcomes were classified as healed SLAP repair or re-torn SLAP repair. RESULTS: On average, 54% of MRAs were interpreted as healed SLAP repairs while 46% of MRAs were interpreted as having a re-torn SLAP repair. Overall, only 43% of the studies had 100% agreement across all interpretations. The intraobserver reliability ranged from 0.71 to 0.81 while the interobserver reliability between readers ranged from 0.13 to 0.44 (Table 1). CONCLUSION: The intraobserver agreement of MRA in the evaluation of type II SLAP repair was substantial to excellent. However, the interobserver agreement of MRA was poor to fair. As a result, the routine use of MRA in the evaluation of type II SLAP lesion repair should be utilized with caution. A global evaluation of the patient, including detailed history and physical examination, is paramount in determining the cause of failure and one should not rely on MRA alone. PMID- 26604842 TI - Anthropometric factors related to sprint and agility performance in young male soccer players. AB - OBJECTIVE: To investigate the relationship between anthropometrics and sprint and agility performance and describe the development of sprint (acceleration) and agility performance in 10- to 16-year-old male soccer players. METHODS: One hundred and thirty-two participants were divided into three age groups, 10-12 years (mean 10.8+/-0.50), 13-14 years (mean 13.9+/-0.50), and 15-16 years (mean 15.5+/-0.24), with assessment of 20 m sprint with 10 m split time and agility performance related to body height and body mass within groups. RESULTS: In the 10- to 12-year-olds, there were no significant correlations between height, weight, and the performance variables, except for body mass, which was correlated to 10-20 m sprint (r=0.30). In the 13- to 14-year-olds, body height was significantly correlated with 10 m sprint (r=0.50) and 20 m sprint (r=0.52), as well as 10-20 m sprint (r=0.50) and agility performance (r=0.28). In the 15- to 16-year-old group, body height was correlated to 20 m (r=0.38) and 10-20 m (r=0.45) sprint. Body mass was significantly correlated to 10 m spring (r=0.35) in the 13- to 14-year-olds, as well as 20 m (r=0.33) and 10-20 m (r=0.35) sprint in the 15- to 16-year-olds. CONCLUSION: Height and body mass were significantly correlated with sprint performance in 13- to 16-year-old male soccer players. However, the 10- to 12-year-olds showed no significant relationship between sprint performance and anthropometrics, except for a small correlation in 10-20 m sprint. This may be attributed to maturation, with large differences in body height and body mass due to different patterns in the growth spurt. The agility performance related to anthropometrics was insignificant apart from a moderate correlation in the 13- to 14-year-olds. PMID- 26604843 TI - Local inpatient units may increase patients' utilization of outpatient services: a comparative cohort-study in Nordland County, Norway. AB - OBJECTIVES: In the last few decades, there has been a restructuring of the psychiatric services in many countries. The complexity of these systems may represent a challenge to patients that suffer from serious psychiatric disorders. We examined whether local integration of inpatient and outpatient services in contrast to centralized institutions strengthened continuity of care. METHODS: Two different service-systems were compared. Service-utilization over a 4-year period for 690 inpatients was extracted from the patient registries. The results were controlled for demographic variables, model of service-system, central inpatient admission or local inpatient admission, diagnoses, and duration of inpatient stays. RESULTS: The majority of inpatients in the area with local integration of inpatient and outpatient services used both types of care. In the area that did not have beds locally, many patients that had been hospitalized did not receive outpatient follow-up. Predictors of inpatients' use of outpatient psychiatric care were: Model of service-system (centralized vs decentralized), a diagnosis of affective disorder, central inpatient admission only, and duration of inpatient stays. CONCLUSION: Psychiatric centers with local inpatient units may positively affect continuity of care for patients with severe psychiatric disorders, probably because of a high functional integration of inpatient and outpatient care. PMID- 26604844 TI - Preoperative psychological assessment of patients seeking weight-loss surgery: identifying challenges and solutions. AB - Preoperative psychosocial assessment is the standard of care for patients seeking weight-loss surgery (WLS). However, the assessment procedure varies widely by surgery site. Comprehensive assessments can provide a wealth of information that assists both the patient and the treatment team, anticipate and prepare for challenges associated with extensive behavioral and lifestyle changes that are required postsurgery. In this review, we provide an overview of the purpose of the preoperative psychosocial assessment and domains to be included. Challenges commonly identified in the assessment are discussed, including maladaptive eating behaviors, psychiatric comorbidities, and alcohol use. Potential solutions and approaches to these challenges are provided. Additionally, patient populations requiring special consideration are presented to include adolescents, those with cognitive vulnerabilities, and aging adults. PMID- 26604845 TI - The contributions of the European Medicines Agency and its pediatric committee to the fight against childhood leukemia. AB - BACKGROUND: Although the diagnosis of childhood leukemia is no longer a death sentence, too many patients still die, more with acute myeloid leukemia than with acute lymphoblastic leukemia. The European Union pediatric legislation was introduced to improve pharmaceutical treatment of children, but some question whether the European Medicines Agency (EMA) approach is helping children with leukemia. Some have even suggested that the decisions of EMA pediatric committee (PDCO) are counterproductive. This study was designed to investigate the impact of PDCO-issued pediatric investigation plans (PIPs) for leukemia drugs. METHODS: All PIPs listed under "oncology" were downloaded from the EMA website. Non leukemia decisions including misclassifications, waivers (no PIP), and solid tumors were discarded. The leukemia decisions were analyzed, compared to pediatric leukemia trials in the database http://www.clinicaltrials.gov, and discussed in the light of current literature. RESULTS: The PDCO leukemia decisions demand clinical trials in pediatric leukemia for all new adult drugs without prioritization. However, because leukemia in children is different and much rarer than in adults, these decisions have resulted in proposed studies that are scientifically and ethically questionable. They are also unnecessary, since once promising new compounds are approved for adults, more appropriate, prioritized pediatric leukemia trials are initiated worldwide without PDCO involvement. CONCLUSION: EMA/PDCO leukemia PIPs do little to advance the treatment of childhood leukemia. The unintended negative effects of the flawed EMA/PDCO's standardized requesting of non-prioritized testing of every new adult leukemia drug in children with relapsed or refractory disease expose these children to questionable trials, and could undermine public trust in pediatric clinical research. Institutions, investigators, and ethics committees/institutional review boards need to be skeptical of trials triggered by PDCO. New, better ways to facilitate drug development for pediatric leukemia are needed. PMID- 26604846 TI - Economic burden of Clostridium difficile in five hospitals of the Florence health care system in Italy. AB - INTRODUCTION: Despite the awareness about the increasing rates of Clostridium difficile infection (CDI) and the economic burden arising from its management (prolonged hospitalization, laboratory tests, visits, surgical treatment, environmental sanitation), few studies are available in Italy on the economic costs directly attributable to the CDI. The Florence health care system has designed a study with the aim of describing the costs attributable to the CDI and defines the incremental economic burden associated with the management of this complication. METHODS: We conducted a retrospective study in five hospitals of the Florence health care system. The enrolled population included all patients who were hospitalized during the year 2013 with a diagnosis of CDI. Of the 187 total cases reported in 2013, 69 patients were enrolled, for whom the main cause of hospitalization was directly attributable to CDI. RESULTS: We enrolled 69 patients (19 males and 50 females), with a mean age of 82.16 years (minimum 46 to maximum 98). The total number of hospitalization days observed was 886 (12.8 per patient on average). The data from this study show that the mean total incremental cost for a patient with CDI was ?3,270.52 per year. The hospital stay length is the most significant cost parameter, having the largest influence on the overall costs, with an impact of 87% on the total cost. The results confirm the costs for the management of CDI in five hospitals of the Florence health care system are in line with data from the international literature. CONCLUSION: The economic impact of CDI is most evident in the extension of the duration of hospitalization and emergency recurrences requiring new therapeutic options with the need to develop and implement new diagnostic and therapeutic algorithms in clinical practice. PMID- 26604847 TI - Consumer sleep monitors: is there a baby in the bathwater? AB - The rapid expansion of consumer sleep devices is outpacing the validation data necessary to assess the potential use of these devices in clinical and research settings. Common sleep monitoring devices utilize a variety of sensors to track movement as well as cardiac and respiratory physiology. The variety of sensors and user-specific factors offer the potential, at least theoretically, for clinically relevant information. We describe the current challenges for interpretation of consumer sleep monitoring data, since the devices are mainly used in non-medical contexts (consumer use) although medically-definable sleep disorders may commonly occur in this setting. A framework for addressing questions of how certain devices might be useful is offered. We suggest that multistage validation efforts are crucially needed, from the level of sensor data and algorithm output, to extrapolations beyond healthy adults and into other populations and real-world environments. PMID- 26604848 TI - Modified Small Incision Cataract Surgery and Intraocular Lens Implantation in HIV Patients. AB - AIM: To describe a surgical technique suitable for cataract surgery in regions with a high prevalence of HIV infection. METHODS: We reviewed the medical records of 20 consecutive AIDS patients with cataract who underwent modified small incision cataract surgery (mSICS) with posterior chamber lens implantation. Classic extracapsular cataract extraction (ECCE) was compared to mSICS. The number of potentially risky steps for contamination during surgery and duration of surgery were analyzed. A risky step was defined as any time when the surgeon had to use a sharp instrument. Student's paired t-test was carried out to compare continuous variables, and P-values <0.05 were considered statistically significant. RESULTS: Twenty patients were included in the study, 13 males (65%) and seven females (35%). The mean age was 46.3 +/- 13.6 years (range 22-70 years). The number of potentially risky steps for contamination was significantly higher in the classical ECCE than in mSICS (P < 0.001). The mean duration of cataract surgery with mSICS was significantly shorter as well (P < 0.001). CONCLUSION: Conversion to mSICS is essential in order to reduce accidental injuries during cataract surgery in sub-Saharan countries. Sharp instruments should be passed through a neutral zone to ensure that the surgeon and nurse do not touch the same instrument at the same time. PMID- 26604849 TI - Giant Left Ventricular Pseudoaneurysm and Myocardial Dissection as a Complication of Multiple Ventricular Tachycardia Ablations in a Patient with Cardiac Sarcoidosis. AB - Late development of left ventricular (LV) pseudoaneurysms after ventricular tachycardia (VT) catheter ablation is a rare phenomenon, and very few cases have been reported in the medical literature. We describe the case of a giant LV pseudoaneurysm as a late complication of multiple epicardial and endocardial VT ablations in a female in her 50s with known cardiac sarcoidosis. PMID- 26604850 TI - Cachexia Index in Advanced Non-Small-Cell Lung Cancer Patients. AB - INTRODUCTION: Cancer cachexia affects many advanced non-small-cell lung cancer (NSCLC) patients. Cachexia index (CXI) was developed to assess the degree of cachexia in these patients. METHODS: Patients with metastatic NSCLC diagnosed between January 1, 2000, and June 30, 2011, at our institution were retrospectively studied. Abdominal computed tomography scans done within 1 month of diagnosis were reviewed to estimate skeletal muscle area (SMA) and skeletal muscle index (SMI) at the L3 level. CXI was developed as follows: [Formula: see text] where SMI is the skeletal muscle index, Alb is the serum albumin, and NLR is the neutrophil-to-lymphocyte ratio. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Survival among various factors was calculated using the log-rank test. Multivariate Cox regression was used to perform survival analysis in order to estimate the effects of various factors. RESULTS: Patients were divided into two groups around the median into stage I cachexia (CXI >=35, n = 56) and stage II cachexia (CXI <35, n = 56). Groups did not differ in age, gender, ethnicity, or histology of cancer. Patients with stage II cachexia had significantly worse PFS (2.45 vs 5.43 months, P < 0.0001) and OS (3.45 vs 8.8 months, P = 0.0001) than those with stage I cachexia. On multivariate analysis adjusting for gender, race, and histology, patients with stage II cachexia were found to have worse PFS (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.27-2.95) and OS (HR 1.53, 95% CI 1.0009 2.34). CONCLUSION: The CXI is a novel index for estimating cachexia that also correlates with prognosis in both men and women with advanced NSCLC. PMID- 26604851 TI - High Aneuploidy Rates Observed in Embryos Derived from Donated Oocytes are Related to Male Aging and High Percentages of Sperm DNA Fragmentation. AB - CAPSULE: Male aging effects on aneuploidy rates in embryos. OBJECTIVE: Paternal age is associated with decreasing sperm quality; however, it is unknown if it influences chromosomal abnormalities in embryos. The objective of this study is to evaluate if the aneuploidy rates in embryos are affected by advanced paternal age. METHODS: A total of 286 embryos, obtained from 32 in vitro fertilization/intracytoplasmic sperm injection cycles with donated oocytes in conjunction with preimplantation genetic diagnosis, were allocated according to paternal age in three groups: Group A: <=39 years (n = 44 embryos); Group B: 40 49 years (n = 154 embryos); and Group C: >=50 years (n = 88 embryos). Fertilization rates, embryo quality at day 3, blastocyst development, and aneuploidy embryo rates were then compared. RESULTS: There was no difference in the seminal parameters (volume, concentration, and motility) in the studied groups. Fertilization rate, percentages of zygotes underwent cleavage, and good quality embryos on day 3 were similar between the three evaluated groups. The group of men >=50 years had significantly more sperm with damaged DNA, low blastocyst development rate, and higher aneuploidy rates in embryos compared to the other two evaluated groups (P < 0.05). CONCLUSIONS: Our findings suggest that advanced paternal age increases the aneuploidy rates in embryos from donated oocytes, which suggests that genetic screening is necessary in those egg donor cycles with sperm from patients >50 years old. PMID- 26604852 TI - Improving medical students' knowledge of genetic disease: a review of current and emerging pedagogical practices. AB - Genetics is an essential subject to be mastered by health professional students of all types. However, technological advances in genomics and recent pedagogical research have changed the way in which many medical training programs teach genetics to their students. These advances favor a more experience-based education focused primarily on developing student's critical thinking skills. In this review, we examine the current state of genetics education at both the preclinical and clinical levels and the ways in which medical and pedagogical research have guided reforms to current and emerging teaching practices in genetics. We discover exciting trends taking place in which genetics is integrated with other scientific disciplines both horizontally and vertically across medical curricula to emphasize training in scientific critical thinking skills among students via the evaluation of clinical evidence and consultation of online databases. These trends will produce future health professionals with the skills and confidence necessary to embrace the new tools of medical practice that have emerged from scientific advances in genetics, genomics, and bioinformatics. PMID- 26604853 TI - Time-motion studies of internal medicine residents' duty hours: a systematic review and meta-analysis. AB - BACKGROUND: Since the mid-1980s, medical residents' long duty hours have been under scrutiny as a factor affecting patient safety and the work environment for the residents. After several mandated changes in duty hours, it is important to understand how residents spend their time before proposing and implementing future changes. Time-motion methodology may provide reliable information on what residents do while on duty. PURPOSE: The purpose of this study is to review all available literature pertaining to time-motion studies of internal medicine residents while on a medicine service and to understand how much of their time is apportioned to various categories of tasks, and also to determine the effects of the Accreditation Council for Graduate Medical Education (ACGME)-mandated duty hour changes on resident workflow in North America. METHODS: Electronic bibliographic databases were searched for articles in English between 1941 and April 2013 reporting time-motion studies of internal medicine residents rotating through a general medicine service. RESULTS: Eight articles were included. Residents spent 41.8% of time in patient care activities, 18.1% communicating, 13.8% in educational activities, 19.7% in personal/other, and 6.6% in transit. North American data showed the following changes after the implementation of the ACGME 2003 duty hours standard: patient care activities from 41.8% to 40.8%, communication activities from 19.0% to 22.3%, educational activities from 17.7% to 11.6%, and personal/other activities from 21.5% to 17.1%. CONCLUSION: There was a paucity of time-motion data. There was great variability in the operational definitions of task categories reported in the studies. Implementation of the ACGME duty hour standards did not have a significant effect on the percentage of time spent in particular tasks. There are conflicting reports on how duty hour changes have affected patient safety. A low proportion of time spent in educational activities deserves further study and may point to a review of the educational models used. PMID- 26604854 TI - Cross-reactivity of the CEDIA buprenorphine assay in drugs-of-abuse screening: influence of dose and metabolites of opioids. AB - PURPOSE: The cloned enzyme donor immunoassay (CEDIA) for buprenorphine is applied for both urine drugs-of-abuse screening and compliance monitoring. Sensitivity, specificity, and optimal cutoff of this assay have differed between studies. This may indicate that cross-reactivity has to be taken into account during assay evaluation. We therefore investigated the performance of the CEDIA buprenorphine assay for use in our patient population and explored the impact of cross reactivity on assay accuracy. METHODS: The CEDIA buprenorphine assay and high performance liquid chromatography-tandem mass spectrometry were employed to analyze drugs-of-abuse in urine samples from a healthy drug-naive male volunteer after intake of two tablets of a prescription drug containing 400 mg paracetamol +30 mg codeine phosphate, and in urine samples (n=2,272) from drug-addicted patients. Receiver operating characteristic analyses were performed to express the diagnostic accuracy of the CEDIA buprenorphine assay. RESULTS: CEDIA buprenorphine was positive in one urine sample from the drug-naive person after intake of the prescription drug. Twenty-five (1.1%) of the patient urine samples were positive for buprenorphine by CEDIA, but negative by high-performance liquid chromatography-tandem mass spectrometry. Codeine, morphine, and their respective metabolites were prevalent in samples that were false positive for buprenorphine. The specificity of the CEDIA buprenorphine assay increased to 99.7% when the cutoff was increased from 5 ng/mL to 10 ng/mL. CONCLUSION: Intake of a therapeutic dose of codeine can yield a false-positive CEDIA buprenorphine result. Additive effects from metabolites of codeine contribute to cross reactivity in concentrations much lower than listed in the manufacturer's cross reactivity guide. Raising the cutoff from 5 ng/mL to 10 ng/mL increased the diagnostic accuracy. Clinicians should be informed about the risk of false positive results with the CEDIA buprenorphine assay. PMID- 26604855 TI - The prognostic influence of tumor infiltrating Foxp3(+)CD4(+), CD4(+) and CD8(+) T cells in resected non-small cell lung cancer. AB - BACKGROUND: Different subsets of tumor infiltrating T lymphocytes are believed to play essential role in the immune response to cancer cells. The data of these cells in NSCLC are relatively rare and controversial therefore we aimed to evaluate the infiltration patterns of Foxp3 + CD4+, CD4+ and CD8+ T cells in NSCLC and to analyze their relations to survival. METHODS: Lung tissue specimens from 80 newly diagnosed and untreated patients who underwent surgery for NSCLC (stages I-III), and 16 control group subjects, who underwent surgery due to recurrent spontaneous pneumothorax, were analyzed. Foxp3 + CD4+, CD4+ and CD8+ T cells in tumor stroma and islets were evaluated immunohistochemically. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS), version 20.0. RESULTS: Tumor infiltrating CD4+, CD8+ T cells were associated with neither overall survival nor disease-free survival. The presence of high tumor stroma infiltrating Foxp3 + CD4+ T cells was independently associated with improved NSCLC patients overall survival (P < 0.05). CONCLUSIONS: Our study demonstrated that tumor infiltrating Foxp3 + CD4+ T cells are associated with improved NSCLC patients' survival. In addition our findings highlight a tendency of high CD4+/CD8+ and CD8+/Foxp3 + CD4+ T cells ratio in prolonged NSCLC patients' survival. PMID- 26604856 TI - Predicting Crystallization Propensity of Proteins from Arabidopsis Thaliana. AB - BACKGROUND: Many studies have correlated characteristics of amino acids with crystallization propensity, as part of the effort to determine the factors that affect the propensity of protein crystallization. However, these characteristics are constant; that is, the encoded amino acid sequences have the same value for each type of amino acid. To overcome this inflexibility, three dynamic characteristics of amino acids and protein were introduced to analyze the crystallization propensity of proteins. Both logistic regression and neural network models were used to correlate each of two dynamic characteristics with the crystallization propensity of 301 proteins from Arabidopsis thaliana, and their results were compared with those obtained from each of 531 constant amino acid characteristics, which served as the benchmark. RESULTS: The neural network model was more powerful for predicting the crystallization propensity of proteins than the logistic regression model. Compared with the benchmark, the dynamic characteristics of amino acids provided good prediction results for the crystallization propensity, and the distribution probability gave the highest sensitivity. Using 90 % accuracy as a cutoff point, the predictable portion of A. thaliana portions was ranked, and the statistical analysis showed that the larger the predictable portion, the better the prediction. CONCLUSIONS: These results demonstrate that dynamic characteristics have a certain relationship with the crystallization propensity, and they could be helpful for the prediction of protein crystallization, which may provide a theoretical concept for certain proteins before conducting experimental crystallization. PMID- 26604857 TI - The Role of Nonlinear Gradients in Parallel Imaging: A k-Space Based Analysis. AB - Sequences that encode the spatial information of an object using nonlinear gradient fields are a new frontier in MRI, with potential to provide lower peripheral nerve stimulation, windowed fields of view, tailored spatially-varying resolution, curved slices that mirror physiological geometry, and, most importantly, very fast parallel imaging with multichannel coils. The acceleration for multichannel images is generally explained by the fact that curvilinear gradient isocontours better complement the azimuthal spatial encoding provided by typical receiver arrays. However, the details of this complementarity have been more difficult to specify. We present a simple and intuitive framework for describing the mechanics of image formation with nonlinear gradients, and we use this framework to review some the main classes of nonlinear encoding schemes. PMID- 26604858 TI - Simultaneously Detection of 50 Mutations at 20 Sites in the BRAF and RAS Genes by Multiplexed Single-Nucleotide Primer Extension Assay Using Fine-Needle Aspirates of Thyroid Nodules. AB - Fine-needle aspiration (FNA) is commonly used for primary evaluation of thyroid nodules. Twenty to 30 percent of thyroid nodules remain indeterminate after FNA evaluation. Studies show the BRAF p.V600E to be highly specific for papillary thyroid carcinoma (PTC), while RAS mutations carry up to 88 percent positive predictive value for malignancy. We developed a two-tube multiplexed PCR assay followed by single-nucleotide primer extension assay for simultaneous detection of 50 mutations in the BRAF (p.V600E, p.K601E/Q) and RAS genes (KRAS and NRAS codons 12, 13, 19, 61 and HRAS 61) using FNA smears of thyroid nodules. Forty-two FNAs and 27 paired formalin-fixed, paraffin-embedded (FFPE) tissues were tested. All BRAF p.V600E-positive FNA smears (five) carried a final diagnosis of PTC on resection. RAS mutations were found in benign as well as malignant lesions. Ninety-two percent concordance was observed between FNA and FFPE tissues. In conclusion, our assay is sensitive and reliable for simultaneous detection of multiple BRAF/RAS mutations in FNA smears of thyroid nodules. PMID- 26604859 TI - Bygiene: The New Paradigm of Bidirectional Hygiene. AB - The pervasive dogma surrounding the evolution of virulence - -namely, that a pathogen's virulence decreases over time to prevent threatening its host -- is an archaic assertion that is more appropriately cast as an optimization of virulence cost and benefit. However, the prevailing attitudes underlying practices of medical hygiene and sanitization remain entrenched in these passe ideas. This is true despite the emergence of evidence linking those practices to mounting virulence and antimicrobial resistance in the hospital. It is, therefore, our position that just as the microbe has sought an optimized balance in virulence, so should we seek such an optimized balance in vigilance, complementing warfare with restoration. We call this approach "bygiene," or bidirectional hygiene. PMID- 26604860 TI - Value of Organoids from Comparative Epithelia Models. AB - Organoids have tremendous therapeutic potential. They were recently defined as a collection of organ-specific cell types, which self-organize through cell sorting, develop from stem cells, and perform an organ specific function. The ability to study organoid development and growth in culture and manipulate their genetic makeup makes them particularly suitable for studying development, disease, and drug efficacy. Organoids show great promise in personalized medicine. From a single patient biopsy, investigators can make hundreds of organoids with the genetic landscape of the patient of origin. This genetic similarity makes organoids an ideal system in which to test drug efficacy. While many investigators assume human organoids are the ultimate model system, we believe that the generation of epithelial organoids of comparative model organisms has great potential. Many key transport discoveries were made using marine organisms. In this paper, we describe how deriving organoids from the spiny dogfish shark, zebrafish, and killifish can contribute to the fields of comparative biology and disease modeling with future prospects for personalized medicine. PMID- 26604861 TI - Combinatorial Versus Individual Gene Pharmacogenomic Testing in Mental Health: A Perspective on Context and Implications on Clinical Utility. AB - Pharmacogenomic testing in mental health has not yet reached its full potential. An important reason for this involves differentiating individual gene testing (IGT) from a combinatorial pharmacogenomic (CPGx) approach. With IGT, any given gene reveals specific information that may, in turn, pertain to a smaller number of medications. CPGx approaches attempt to encompass more complete genomic information by combining moderate risk alleles and synergistically viewing the results from the perspective of the medication. This manuscript will discuss IGT and CPGx approaches to psychiatric pharmacogenomics and review the clinical validity, clinical utility, and economic parameters of both. PMID- 26604862 TI - Taking Control of Castleman Disease: Leveraging Precision Medicine Technologies to Accelerate Rare Disease Research. AB - Castleman disease (CD) is a rare and heterogeneous disorder characterized by lymphadenopathy that may occur in a single lymph node (unicentric) or multiple lymph nodes (multicentric), the latter typically occurring secondary to excessive proinflammatory hypercytokinemia. While a cohort of multicentric Castleman disease (MCD) cases are caused by Human Herpes Virus-8 (HHV-8), the etiology of HHV-8 negative, idiopathic MCD (iMCD), remains unknown. Breakthroughs in "omics" technologies that have facilitated the development of precision medicine hold promise for elucidating disease pathogenesis and identifying novel therapies for iMCD. However, in order to leverage precision medicine approaches in rare diseases like CD, stakeholders need to overcome several challenges. To address these challenges, the Castleman Disease Collaborative Network (CDCN) was founded in 2012. In the past 3 years, the CDCN has worked to transform the understanding of the pathogenesis of CD, funded and initiated genomics and proteomics research, and united international experts in a collaborative effort to accelerate progress for CD patients. The CDCN's collaborative structure leverages the tools of precision medicine and serves as a model for both scientific discovery and advancing patient care. PMID- 26604865 TI - Personalized Medicine: How Studying Individual Differences Can Shed Light on Treating Thousands of Patients: An Interview with Richard Lifton, PhD. PMID- 26604863 TI - Tailoring the Treatment of Melanoma: Implications for Personalized Medicine. AB - Oncology has been revolutionized by the ability to selectively inhibit the growth of cancerous cells while ostensibly avoiding the disruption of proteins and pathways necessary for normal cellular function. This paradigm has triggered an explosion of targeted therapies for cancer, creating a burgeoning billion-dollar industry of small molecules and monoclonal antibodies [1]. Largely due to these new treatments, spending on cancer pharmaceuticals has surpassed $100 billion worldwide [2]. In particular, the treatment of melanoma, a deadly and fast spreading form of skin cancer, has been transformed by these new targeted therapies. In this mini-review, we summarize the progress made in the field of personalized treatment of melanoma, with an emphasis on targeted therapies. We then outline future directions for treatment, including novel cell-mediated therapies and new potential targets. PMID- 26604864 TI - PART of the WHOLE: A Case Study in Wellness-Oriented Personalized Medicine. AB - We describe the Wellness and Health Omics Linked to the Environment (WHOLE) personalized medicine profile for a 50-year-old Caucasian male living in Atlanta, Georgia. Based on the principle that genomic medicine will be most effective when presented in the context of an individual's clinical and lifestyle data, we propose the use of a "risk radar" that summarizes health risks in eight domains. Rather than providing overwhelming lists of potentially deleterious genetic variants, we argue that profiles should be palatable, actionable, reproducible, and teachable: the PART principle. Genetic risk scores for this individual are strikingly concordant for his height, body mass index (BMI), waist hip ration (WHR), and cholesterol, and blood transcriptome data agrees with and complements his complete blood counts. Despite enjoying currently good health, his risk radar highlights metabolic disease as his major health concern. PMID- 26604866 TI - Crowdfunding for Personalized Medicine Research. AB - Given the current funding situation of the National Institutes of Health, getting funding for rare disease research is extremely difficult. In light of the enormous potential for research in the rare diseases and the scarcity of research funding, we provide a case study of a novel successful crowdfunding approach at a non-profit organization called Rare Genomics Institute. We partner with biotechnology companies willing to donate their products, such as mouse models, gene editing software, and sequencing services, for which researchers can apply. First, we find that personal stories can be powerful tools to seek funding from sympathetic donors who do not have the same rational considerations of impact and profit. Second, for foundations facing funding restrictions, company donations can be a valuable tool in addition to crowdfunding. Third, rare disease research is particularly rewarding for scientists as they proceed to be pioneers in the field during their academic careers. Overall, by connecting donors, foundations, researchers, and patients, crowdfunding has become a powerful alternative funding mechanism for personalized medicine. PMID- 26604867 TI - Precision in Addiction Care: Does It Make a Difference? AB - This perspective article explores the possibilities of precision in addiction care -- even better individually fitted or tailor-made care -- and examines what changes we need to make in order to realize sensible progress in epidemiological key figures. The first part gives a short review on the development of addiction care and tries to answer the question of where we stand now and what has been achieved in addiction science through the development and evaluation of interventions in the past decades. Following this analysis, attention will be paid to what lies ahead. This second part focuses on the question of how addiction care can deal with the consequences of the emerging paradigm of personalized or precision medicine, which is based on the fundamental assumption that individual differences matter. Finally, some limitations and conditions as well as tasks and goals for progress are raised. In conclusion, it is argued that integration of addiction care in (mental) health care in the future is desirable. PMID- 26604868 TI - The Sociology of the Deceased Harvard Medical Unit at Boston City Hospital. AB - Many graduates of the Harvard Medical Unit (HMU) at Boston City Hospital, in either the clinical training/residency program or the research program at the Thorndike Memorial Laboratory, contributed in major ways to the HMU and constantly relived their HMU experiences. The HMU staff physicians, descending from founder and mentor physicians Francis W. Peabody, Soma Weiss, and George R. Minot, were dedicated to the teaching, development, and leadership of its clinical and research trainees, whose confidence and dedication to patient care as a result of their mentorship led many to lifelong achievements as clinicians, teachers, and mentors. Their experience also led to a lifelong love of the HMU (despite its loss), camaraderie, happiness, and intense friendships with their associates. PMID- 26604870 TI - Fall 2015 Introduction. PMID- 26604869 TI - Label-free mass spectrometric analysis reveals complex changes in the brain proteome from the mdx-4cv mouse model of Duchenne muscular dystrophy. AB - BACKGROUND: X-linked muscular dystrophy is a primary disease of the neuromuscular system. Primary abnormalities in the Dmd gene result in the absence of the full length isoform of the membrane cytoskeletal protein dystrophin. Besides progressive skeletal muscle wasting and cardio-respiratory complications, developmental cognitive deficits and behavioural abnormalities are clinical features of Duchenne muscular dystrophy. In order to better understand the mechanisms that underlie impaired brain functions in Duchenne patients, we have carried out a proteomic analysis of total brain extracts from the mdx-4cv mouse model of dystrophinopathy. RESULTS: The comparative proteomic profiling of the mdx-4cv brain revealed a significant increase in 39 proteins and a decrease in 7 proteins. Interesting brain tissue-associated proteins with an increased concentration in the mdx-4cv animal model were represented by the glial fibrillary acidic protein GFAP, the neuronal Ca(2+)-binding protein calretinin, annexin AnxA5, vimentin, the neuron-specific enzyme ubiquitin carboxyl-terminal hydrolase isozyme L1, the dendritic spine protein drebrin, the cytomatrix protein bassoon of the nerve terminal active zone, and the synapse-associated protein SAP97. Decreased proteins were identified as the nervous system-specific proteins syntaxin-1B and syntaxin-binding protein 1, as well as the plasma membrane Ca(2+) transporting ATPase PMCA2 that is mostly found in the brain cortex. The differential expression patterns of GFAP, vimentin, PMCA2 and AnxA5 were confirmed by immunoblotting. Increased GFAP levels were also verified by immunofluorescence microscopy. CONCLUSIONS: The large number of mass spectrometrically identified proteins with an altered abundance suggests complex changes in the mdx-4cv brain proteome. Increased levels of the glial fibrillary acidic protein, an intermediate filament component that is uniquely associated with astrocytes in the central nervous system, imply neurodegeneration-associated astrogliosis. The up-regulation of annexin and vimentin probably represent compensatory mechanisms involved in membrane repair and cytoskeletal stabilization in the absence of brain dystrophin. Differential alterations in the Ca(2+)-binding protein calretinin and the Ca(2+)-pumping protein PMCA2 suggest altered Ca(2+)-handling mechanisms in the Dp427-deficient brain. In addition, the proteomic findings demonstrated metabolic adaptations and functional changes in the central nervous system from the dystrophic phenotype. Candidate proteins can now be evaluated for their suitability as proteomic biomarkers and their potential in predictive, diagnostic, prognostic and/or therapy-monitoring approaches to treat brain abnormalities in dystrophinopathies. PMID- 26604871 TI - Enhancing Practice Efficiency and Patient Care by Sharing Electronic Health Records. AB - One primary function of community pharmacies is to dispense medications to patients. In doing so, pharmacists frequently communicate with physicians' offices to clarify prescription orders and obtain additional information to ensure the safe and accurate dispensing of medications. Such communication is often done by telephone or fax, which is inefficient for both the pharmacy and the physician's office. This problem was highlighted in a recent American Medical Association resolution defining certain pharmacy inquiries as "interference with the practice of medicine and unwarranted." As a result, many are seeking to understand how to balance the needs of the patient care process with the need for operational efficiency in the physician's office and pharmacy. This study presents one example of a health information technology-based solution involving shared access to an electronic health record (EHR), and describes a case in which a physician's office and a community pharmacy experimented with this model to promote practice efficiency while also providing enhanced access to clinical information in both directions. The rationale behind the process change, a brief description of how the new process came into existence, and a description of how information sharing can be helpful in related clinical situations are provided. Similar models that involve sharing of EHRs may create valuable opportunities for collaboration between physicians and pharmacists to enhance patient care and improve workflow efficiency. PMID- 26604872 TI - Clinicians' Knowledge and Perception of Telemedicine Technology. AB - INTRODUCTION: Telemedicine is an application of information and communication technology in the healthcare environment. This study aimed to compare knowledge and perceptions of telemedicine technology among different groups of clinicians. METHODS: This survey study was conducted in 2013. The potential participants included 532 clinicians who worked in two hospitals and three clinics in a northern province of Iran. Data were collected using a five-point Likert-scale questionnaire. The content validity of the questionnaire was checked, and the reliability was calculated using Cronbach's alpha coefficient (alpha = 0.73). RESULTS: The results showed that most of the clinicians (96.1 percent) had little knowledge about telemedicine. They perceived the advantages of telemedicine at a moderate level and its disadvantages at a low level. The knowledge of dentists about this technology was less than that of other groups, and as a result they were less positive about the advantages of telemedicine compared to nurses, general physicians, and specialists. CONCLUSION: The limited knowledge of clinicians about telemedicine seems to have influenced their perceptions of the technology. Therefore, providing healthcare professionals with more information about new technologies in healthcare, such as telemedicine, can help to gain a more realistic picture of their perceptions. PMID- 26604873 TI - Health Information Exchange Readiness for Demonstrating Return on Investment and Quality of Care. AB - OBJECTIVE: To study the extent to which community health information exchanges (HIEs) deliver and measure return on investment (ROI) and improvements in the quality of care. MATERIALS AND METHODS: We surveyed operational HIEs for their characteristics, information domains, impact on quality of care, and ROI. RESULTS: A 60 percent response rate was achieved. Two-thirds of respondents agreed that community HIEs demonstrated a positive ROI, while one-third had no opinion or disagreed. One-fourth or fewer respondents reported using various metrics to calculate ROI. Most respondents agreed that HIEs improve the quality of care, though several were not sure and were awaiting further evidence. Most respondents indicated that they did not deliver reports on quality measures (76 percent) and that data were not being used to measure quality performance of participating providers (73 percent). DISCUSSION: Respondents from most HIEs believe that the HIEs are demonstrating a positive ROI; however, a minority of them indicated they had used or will use specific metrics to calculate ROI. HIE representatives overwhelmingly reported that they believe the HIE activities improve the quality of healthcare delivered, but only a few are using data to evaluate provider performance or generate reports on quality measures. CONCLUSION: This study demonstrates the challenge faced by policy makers and healthcare organizations that are investing millions of dollars in HIEs that are believed to improve health outcomes and increase efficiency, but still need more time to develop the evidence to confirm that belief. Our study shows that calculating ROI for HIEs or their impact on quality of care remains a secondary priority for most HIEs. This finding raises serious questions for the sustained support of HIEs, both financially and as a policy lever, given the end of Health Information Technology for Economic and Clinical Health (HITECH) Act funding. PMID- 26604874 TI - Consumer Opinions of Health Information Exchange, e-Prescribing, and Personal Health Records. AB - BACKGROUND: Consumer satisfaction is a crucial component of health information technology (HIT) utilization, as high satisfaction is expected to increase HIT utilization among providers and to allow consumers to become full participants in their own healthcare management. OBJECTIVE: The primary objective of this pilot study was to identify consumer perspectives on health information technologies including health information exchange (HIE), e-prescribing (e-Rx), and personal health records (PHRs). METHODS: Eight focus groups were conducted in seven towns and cities across Nebraska in 2013. Each group consisted of 10-12 participants. Discussions were organized topically in the following categories: HIE, e-Rx, and PHR. The qualitative analysis consisted of immersion and crystallization to develop a coding scheme that included both preconceived and emergent themes. Common themes across focus groups were identified and compiled for each discussion category. RESULTS: The study had 67 participants, of which 18 (27 percent) were male. Focus group findings revealed both perceived barriers and benefits to the adoption of HIT. Common HIT concerns expressed across focus groups included privacy and security of medical information, decreases in quality of care, inconsistent provider participation, and the potential cost of implementation. Positive expectations regarding HIT included better accuracy and completeness of information, and improved communication and coordination between healthcare providers. Improvements in patient care were expected as a result of easy physician access to consolidated information across providers as well as the speed of sharing and availability of information in an emergency. In addition, participants were optimistic about patient empowerment and convenient access to and control of personal health data. CONCLUSION: Consumer concerns focused on privacy and security of the health information, as well as the cost of implementing the technologies and the possibility of an unintended negative impact on the quality of care. While negative perceptions present barriers for potential patient acceptance, benefits such as speed and convenience, patient oversight of health data, and safety improvements may counterbalance these concerns. PMID- 26604875 TI - Adoption and Barriers to Adoption of Electronic Health Records by Nurses in Three Governmental Hospitals in Eastern Province, Saudi Arabia. AB - Although electronic health records (EHRs) have been implemented in many hospitals and healthcare providers benefit from their effective and efficient data processing, their evaluation from nurses has received little attention. This project aimed to assess the adoption and barriers to the use of an EHR system by nurses at three governmental hospitals implementing the same EHR software and functionalities in Eastern Province, Saudi Arabia. The study was a cross sectional, paper-based questionnaire study. SPSS version 20 was used for data entry and analysis, and descriptive statistics were calculated. The study found underutilization of almost all functionalities among all hospitals and no utilization of any communication tools with patients. In addition, there were no instances of "allowing patients to use the Internet to access parts of their health records." The most frequently cited barrier among all hospitals was "loss of access to medical records transiently if computer crashes or power fails" (88.6 percent). This was followed by "lack of continuous training/ support from information technology staff in hospital" (85.9 percent), "additional time required for data entry" (84.9 percent), and "system hanging up problem" (83.8 percent). Complexity of technology (81.6 percent) and lack of system customizability (81.1 percent) were also frequently reported problems. The formation of an EHR committee to discuss problems with the system in Saudi hospitals is recommended. PMID- 26604876 TI - Physicians' and Nurses' Opinions about the Impact of a Computerized Provider Order Entry System on Their Workflow. AB - INTRODUCTION: In clinical practices, the use of information technology, especially computerized provider order entry (CPOE) systems, has been found to be an effective strategy to improve patient care. This study aimed to compare physicians' and nurses' views about the impact of CPOE on their workflow. METHODS: This case study was conducted in 2012. The potential participants included all physicians (n = 28) and nurses (n = 145) who worked in a teaching hospital. Data were collected using a five-point Likert-scale questionnaire and were analyzed using SPSS version 18.0. RESULTS: The results showed a significant difference between physicians' and nurses' views about the impact of the system on interorganizational workflow (p = .001) and working relationships between physicians and nurses (p = .017). CONCLUSION: Interorganizational workflow and working relationships between care providers are important issues that require more attention. Before a CPOE system is designed, it is necessary to identify workflow patterns and hidden structures to avoid compromising quality of care and patient safety. PMID- 26604877 TI - Neuroinflammation and comorbidities are frequently ignored factors in CNS pathology. AB - Virtually all drug interventions that have been successful pre-clinically in experimental stroke have failed to prove their efficacy in a clinical setting. This could be partly explained by the complexity and heterogeneity of human diseases as well as the associated co-morbidities which may render neuroprotective drugs less efficacious in clinical practice. One aspect of crucial importance in the physiopathology of stroke which is not completely understood is neuroinflammation. At the present time, it is becoming evident that subtle, but continuous neuroinflammation can provide the ground for disorders such as cerebral small vessel disease. Moreover, advanced aging and a number of highly prevalent risk factors such as obesity, hypertension, diabetes and atherosclerosis could act as "silent contributors" promoting a chronic proinflammatory state. This could aggravate the outcome of various pathological entities and can contribute to a number of subsequent post-stroke complications such as dementia, depression and neurodegeneration creating a pathological vicious cycle. Moreover, recent data suggests that the inflammatory process might be closely linked with multiple neurodegenerative pathways related to depression. In addition, pro-inflammatory cytokines could play a central role in the pathophysiology of both depression and dementia. PMID- 26604878 TI - Cell replacement therapy for central nervous system diseases. AB - The brain and spinal cord can not replace neurons or supporting glia that are lost through traumatic injury or disease. In pre-clinical studies, however, neural stem and progenitor cell transplants can promote functional recovery. Thus the central nervous system is repair competent but lacks endogenous stem cell resources. To make transplants clinically feasible, this field needs a source of histocompatible, ethically acceptable and non-tumorgenic cells. One strategy to generate patient-specific replacement cells is to reprogram autologous cells such as fibroblasts into pluripotent stem cells which can then be differentiated into the required cell grafts. However, the utility of pluripotent cell derived grafts is limited since they can retain founder cells with intrinsic neoplastic potential. A recent extension of this technology directly reprograms fibroblasts into the final graftable cells without an induced pluripotent stem cell intermediate, avoiding the pluripotent caveat. For both types of reprogramming the conversion efficiency is very low resulting in the need to amplify the cells in culture which can lead to chromosomal instability and neoplasia. Thus to make reprogramming biology clinically feasible, we must improve the efficiency. The ultimate source of replacement cells may reside in directly reprogramming accessible cells within the brain. PMID- 26604879 TI - Enhancing endogenous stem cells in the newborn via delayed umbilical cord clamping. AB - There is currently no consensus among clinicians and scientists over the appropriate or optimal timing for umbilical cord clamping. However, many clinical studies have suggested that delayed cord clamping is associated with various neonatal benefits including increased blood volume, reduced need for blood transfusion, increased cerebral oxygenation in pre-term infants, and decreased frequency of iron deficiency anemia in term infants. Human umbilical cord blood contains significant amounts of stem and progenitor cells and is currently used in the treatment of several life-threatening diseases. We propose that delayed cord clamping be encouraged as it enhances blood flow from the placenta to the neonate, which is accompanied by an increase supply of valuable stem and progenitor cells, as well as may improve blood oxygenation and increase blood volume, altogether reducing the infant's susceptibility to both neonatal and age related diseases. PMID- 26604881 TI - The choline pathway as a strategy to promote central nervous system (CNS) remyelination. PMID- 26604880 TI - PTEN inhibition and axon regeneration and neural repair. AB - The intrinsic growth ability of all the neurons declines during development although some may grow better than others. Numerous intracellular signaling proteins and transcription factors have been shown to regulate the intrinsic growth capacity in mature neurons. Among them, PI3 kinase/Akt pathway is important for controlling axon elongation. As a negative regulator of this pathway, the tumor suppressor phosphatase and tensin homolog (PTEN) appears critical to control the regenerative ability of young and adult neurons. This review will focus on recent research progress in axon regeneration and neural repair by PTEN inhibition and therapeutic potential of blocking this phosphatase for neurological disorders. Inhibition of PTEN by deletion in conditional knockout mice, knockdown by short-hairpin RNA, or blockade by pharmacological approaches, including administration of selective PTEN antagonist peptides, stimulates various degrees of axon regrowth in juvenile or adult rodents with central nervous system injuries. Importantly, post-injury PTEN suppression could enhance axonal growth and functional recovery in adult central nervous system after injury. PMID- 26604882 TI - Non-steroidal anti-inflammatory drugs (NSAIDs) and neuroprotection in the elderly: a view from the mitochondria. PMID- 26604883 TI - Neural correlates of the Heidelberg Music Therapy: indicators for the regeneration of auditory cortex in tinnitus patients? PMID- 26604885 TI - Can progesterone be a better alternative to dexamethasone for use in routine brain surgery? PMID- 26604884 TI - Neurochemical plasticity of Muller cells after retinal injury: overexpression of GAT-3 may potentiate excitotoxicity. PMID- 26604886 TI - Adipose-brain crosstalk: do adipokines have a role in neuroprotection? PMID- 26604887 TI - Shine bright: considerations on the use of fluorescent substrates in living monoaminergic neurons in vitro. PMID- 26604888 TI - The changes of oligodendrocytes induced by anesthesia during brain development. PMID- 26604889 TI - The roles of tubulin-folding cofactors in neuronal morphogenesis and disease. PMID- 26604890 TI - Epigallocatechin-3-gallate treatment to promote neuroprotection and functional recovery after nervous system injury. PMID- 26604891 TI - Repairing peripheral nerve injury using tissue engineering techniques. PMID- 26604892 TI - Olfactory ensheathing cells for spinal cord repair: crucial differences between subpopulations of the glia. PMID- 26604893 TI - From adaption to death: endoplasmic reticulum stress as a novel target of selective neurodegeneration? PMID- 26604894 TI - Tailoring of therapy for chronic inflammatory demyelinating polyneuropathy. PMID- 26604895 TI - Neuronal gene transcription modulates demyelination and remyelination in a mouse model of multiple sclerosis. PMID- 26604896 TI - Substance P and its tachykinin NK1 receptor: a novel neuroprotective target for Parkinson's disease. PMID- 26604897 TI - Application and implications of polyethylene glycol-fusion as a novel technology to repair injured spinal cords. PMID- 26604898 TI - In search for novel strategies towards neuroprotection and neuroregeneration: is PPARalpha a promising therapeutic target? PMID- 26604899 TI - Is hyperexcitability really guilty in amyotrophic lateral sclerosis? PMID- 26604900 TI - Subaxial cervical spine injury classification system: is it most appropriate for classifying cervical injury? PMID- 26604901 TI - Piroxicam-mediated modulatory action of 5-hydroxytryptamine serves as a "brake" on neuronal excitability in ischemic stroke. AB - Our previous studies indicated an increase in extracellular gamma-aminobutyric acid (GABA) in rodent's ischemic brain after Piroxicam administration, leading to alleviation of glutamate mediated excitotoxicity through activation of type A GABA receptor (GABAA). This study was to investigate if GABAA activation by Piroxicam affects extracellular 5-hydroxytryptamine or not. High performance liquid chromatography revealed that there was a significant decrease in extracellular 5-hydroxytryptamine release in ischemic cerebral cortex and striatum in Piroxicam pre-treated rat brains. This suggests a probable role of Piroxicam in reducing extracellular 5-hydroxytryptamine release in ischemic cerebral cortex and striatum possibly due to the GABAA activation by Piroxicam. PMID- 26604902 TI - Chitosan-collagen porous scaffold and bone marrow mesenchymal stem cell transplantation for ischemic stroke. AB - In this study, we successfully constructed a composite of bone marrow mesenchymal stem cells and a chitosan-collagen scaffold in vitro, transplanted either the composite or bone marrow mesenchymal stem cells alone into the ischemic area in animal models, and compared their effects. At 14 days after co-transplantation of bone marrow mesenchymal stem cells and the hitosan-collagen scaffold, neurological function recovered noticeably. Vascular endothelial growth factor expression and nestin-labeled neural precursor cells were detected in the ischemic area, surrounding tissue, hippocampal dentate gyrus and subventricular zone. Simultaneously, a high level of expression of glial fibrillary acidic protein and a low level of expression of neuron-specific enolase were visible in BrdU-labeled bone marrow mesenchymal stem cells. These findings suggest that transplantation of a composite of bone marrow mesenchymal stem cells and a chitosan-collagen scaffold has a neuroprotective effect following ischemic stroke. PMID- 26604903 TI - Overexpression of brain-derived neurotrophic factor in the hippocampus protects against post-stroke depression. AB - Post-stroke depression is associated with reduced expression of brain-derived neurotrophic factor (BDNF). In this study, we evaluated whether BDNF overexpression affects depression-like behavior in a rat model of post-stroke depression. The middle cerebral artery was occluded to produce a model of focal cerebral ischemia. These rats were then subjected to isolation-housing combined with chronic unpredictable mild stress to generate a model of post-stroke depression. A BDNF gene lentiviral vector was injected into the hippocampus. At 7 days after injection, western blot assay and real-time quantitative PCR revealed that BDNF expression in the hippocampus was increased in depressive rats injected with BDNF lentivirus compared with depressive rats injected with control vector. Furthermore, sucrose solution consumption was higher, and horizontal and vertical movement scores were increased in the open field test in these rats as well. These findings suggest that BDNF overexpression in the hippocampus of post-stroke depressive rats alleviates depression-like behaviors. PMID- 26604904 TI - Oxygen-glucose deprivation regulates BACE1 expression through induction of autophagy in Neuro-2a/APP695 cells. AB - Our previous findings have demonstrated that autophagy regulation can alleviate the decline of learning and memory by eliminating deposition of extracellular beta-amyloid peptide (Abeta) in the brain after stroke, but the exact mechanism is unclear. It is presumed that the regulation of beta-site APP-cleaving enzyme 1 (BACE1), the rate-limiting enzyme in metabolism of Abeta, would be a key site. Neuro-2a/amyloid precursor protein 695 (APP695) cell models of cerebral ischemia were established by oxygen-glucose deprivation to investigate the effects of Rapamycin (an autophagy inducer) or 3-methyladenine (an autophagy inhibitor) on the expression of BACE1. Either oxygen-glucose deprivation or Rapamycin down regulated the expression of BACE1 while 3-methyladenine up-regulated BACE1 expression. These results confirm that oxygen-glucose deprivation down-regulates BACE1 expression in Neuro-2a/APP695 cells through the introduction of autophagy. PMID- 26604905 TI - The role of Rho/Rho-kinase pathway and the neuroprotective effects of fasudil in chronic cerebral ischemia. AB - The Rho/Rho-kinase signaling pathway plays an important role in cerebral ischemia/reperfusion injury. However, very few studies have examined in detail the changes in the Rho/Rho-kinase signaling pathway in chronic cerebral ischemia. In this study, rat models of chronic cerebral ischemia were established by permanent bilateral common carotid artery occlusion and intragastrically administered 9 mg/kg fasudil, a powerful ROCK inhibitor, for 9 weeks. Morris water maze results showed that cognitive impairment progressively worsened as the cerebral ischemia proceeded. Immunohistochemistry, semi-quantitative RT-PCR and western blot analysis showed that the expression levels of Rho-kinase, its substrate myosin-binding subunit, and its related protein alpha smooth muscle actin, significantly increased after chronic cerebral ischemia. TUNEL staining showed that chronic cerebral ischemia could lead to an increase in neuronal apoptosis, as well as the expression level of caspase-3 in the frontal cortex of rats subjected to chronic cerebral ischemia. Fasudil treatment alleviated the cognitive impairment in rats with chronic cerebral ischemia, and decreased the expression level of Rho-kinase, myosin-binding subunit and alpha smooth muscle actin. Furthermore, fasudil could regulate cerebral injury by reducing cell apoptosis and decreasing caspase-3 expression in the frontal cortex. These findings demonstrate that fasudil can protect against cognitive impairment induced by chronic cerebral ischemia via the Rho/Rho-kinase signaling pathway and anti-apoptosis mechanism. PMID- 26604906 TI - Effects of total saponins of Panax notoginseng on immature neuroblasts in the adult olfactory bulb following global cerebral ischemia/reperfusion. AB - The main active components extracted from Panax notoginseng are total saponins. They have been shown to inhibit platelet aggregation, increase cerebral blood flow, improve neurological behavior, decrease infarct volume and promote proliferation and differentiation of neural stem cells in the hippocampus and lateral ventricles. However, there is a lack of studies on whether total saponins of Panax notoginseng have potential benefits on immature neuroblasts in the olfactory bulb following ischemia and reperfusion. This study established a rat model of global cerebral ischemia and reperfusion using four-vessel occlusion. Rats were administered total saponins of Panax notoginseng at 75 mg/kg intraperitoneally 30 minutes after ischemia then once a day, for either 7 or 14 days. Total saponins of Panax notoginseng enhanced the number of doublecortin (DCX)(+) neural progenitor cells and increased co-localization of DCX with neuronal nuclei and phosphorylated cAMP response element-binding/DCX(+) neural progenitor cells in the olfactory bulb at 7 and 14 days post ischemia. These findings indicate that following global brain ischemia/reperfusion, total saponins of Panax notoginseng promote differentiation of DCX(+) cells expressing immature neuroblasts in the olfactory bulb and the underlying mechanism is related to the activation of the signaling pathway of cyclic adenosine monophosphate response element binding protein. PMID- 26604907 TI - Lactulose enhances neuroplasticity to improve cognitive function in early hepatic encephalopathy. AB - Lactulose is known to improve cognitive function in patients with early hepatic encephalopathy; however, the underlying mechanism remains poorly understood. In the present study, we investigated the behavioral and neurochemical effects of lactulose in a rat model of early hepatic encephalopathy induced by carbon tetrachloride. Immunohistochemistry showed that lactulose treatment promoted neurogenesis and increased the number of neurons and astrocytes in the hippocampus. Moreover, lactulose-treated rats showed shorter escape latencies than model rats in the Morris water maze, indicating that lactulose improved the cognitive impairments caused by hepatic encephalopathy. The present findings suggest that lactulose effectively improves cognitive function by enhancing neuroplasticity in a rat model of early hepatic encephalopathy. PMID- 26604908 TI - Modification of tenascin-R expression following unilateral labyrinthectomy in rats indicates its possible role in neural plasticity of the vestibular neural circuit. AB - We have previously found that unilateral labyrinthectomy is accompanied by modification of hyaluronan and chondroitin sulfate proteoglycan staining in the lateral vestibular nucleus of rats and the time course of subsequent reorganization of extracellular matrix assembly correlates to the restoration of impaired vestibular function. The tenascin-R has repelling effect on pathfinding during axonal growth/regrowth, and thus inhibits neural circuit repair. By using immunohistochemical method, we studied the modification of tenascin-R expression in the superior, medial, lateral, and descending vestibular nuclei of the rat following unilateral labyrinthectomy. On postoperative day 1, tenascin-R reaction in the perineuronal nets disappeared on the side of labyrinthectomy in the superior, lateral, medial, and rostral part of the descending vestibular nuclei. On survival day 3, the staining intensity of tenascin-R reaction in perineuronal nets recovered on the operated side of the medial vestibular nucleus, whereas it was restored by the time of postoperative day 7 in the superior, lateral and rostral part of the descending vestibular nuclei. The staining intensity of tenascin-R reaction remained unchanged in the caudal part of the descending vestibular nucleus bilaterally. Regional differences in the modification of tenascin-R expression presented here may be associated with different roles of individual vestibular nuclei in the compensatory processes. The decreased expression of the tenascin-R may suggest the extracellular facilitation of plastic modifications in the vestibular neural circuit after lesion of the labyrinthine receptors. PMID- 26604909 TI - Cerebrospinal fluid from rats given hypoxic preconditioning protects neurons from oxygen-glucose deprivation-induced injury. AB - Hypoxic preconditioning activates endogenous mechanisms that protect against cerebral ischemic and hypoxic injury. To better understand these protective mechanisms, adult rats were housed in a hypoxic environment (8% O2/92% N2) for 3 hours, and then in a normal oxygen environment for 12 hours. Their cerebrospinal fluid was obtained to culture cortical neurons from newborn rats for 1 day, and then the neurons were exposed to oxygen-glucose deprivation for 1.5 hours. The cerebrospinal fluid from rats subjected to hypoxic preconditioning reduced oxygen glucose deprivation-induced injury, increased survival rate, upregulated Bcl-2 expression and downregulated Bax expression in the cultured cortical neurons, compared with control. These results indicate that cerebrospinal fluid from rats given hypoxic preconditioning protects against oxygen-glucose deprivation-induced injury by affecting apoptosis-related protein expression in neurons from newborn rats. PMID- 26604910 TI - Hyperbaric oxygen therapy combined with Schwann cell transplantation promotes spinal cord injury recovery. AB - Schwann cell transplantation and hyperbaric oxygen therapy each promote recovery from spinal cord injury, but it remains unclear whether their combination improves therapeutic results more than monotherapy. To investigate this, we used Schwann cell transplantation via the tail vein, hyperbaric oxygen therapy, or their combination, in rat models of spinal cord contusion injury. The combined treatment was more effective in improving hindlimb motor function than either treatment alone; injured spinal tissue showed a greater number of neurite-like structures in the injured spinal tissue, somatosensory and motor evoked potential latencies were notably shorter, and their amplitudes greater, after combination therapy than after monotherapy. These findings indicate that Schwann cell transplantation combined with hyperbaric oxygen therapy is more effective than either treatment alone in promoting the recovery of spinal cord in rats after injury. PMID- 26604911 TI - Transplantation of erythropoietin gene-modified neural stem cells improves the repair of injured spinal cord. AB - The protective effects of erythropoietin on spinal cord injury have not been well described. Here, the eukaryotic expression plasmid pcDNA3.1 human erythropoietin was transfected into rat neural stem cells cultured in vitro. A rat model of spinal cord injury was established using a free falling object. In the human erythropoietin-neural stem cells group, transfected neural stem cells were injected into the rat subarachnoid cavity, while the neural stem cells group was injected with non-transfected neural stem cells. Dulbecco's modified Eagle's medium/F12 medium was injected into the rats in the spinal cord injury group as a control. At 1-4 weeks post injury, the motor function in the rat lower limbs was best in the human erythropoietin-neural stem cells group, followed by the neural stem cells group, and lastly the spinal cord injury group. At 72 hours, compared with the spinal cord injury group, the apoptotic index and Caspase-3 gene and protein expressions were apparently decreased, and the bcl-2 gene and protein expressions were noticeably increased, in the tissues surrounding the injured region in the human erythropoietin-neural stem cells group. At 4 weeks, the cavities were clearly smaller and the motor and somatosensory evoked potential latencies were remarkably shorter in the human erythropoietin-neural stem cells group and neural stem cells group than those in the spinal cord injury group. These differences were particularly obvious in the human erythropoietin-neural stem cells group. More CM-Dil-positive cells and horseradish peroxidase-positive nerve fibers and larger amplitude motor and somatosensory evoked potentials were found in the human erythropoietin-neural stem cells group and neural stem cells group than in the spinal cord injury group. Again, these differences were particularly obvious in the human erythropoietin-neural stem cells group. These data indicate that transplantation of erythropoietin gene-modified neural stem cells into the subarachnoid cavity to help repair spinal cord injury and promote the recovery of spinal cord function better than neural stem cell transplantation alone. These findings may lead to significant improvements in the clinical treatment of spinal cord injuries. PMID- 26604912 TI - Polylactic-co-glycolic acid microspheres containing three neurotrophic factors promote sciatic nerve repair after injury. AB - A variety of neurotrophic factors have been shown to repair the damaged peripheral nerve. However, in clinical practice, nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor are all peptides or proteins that may be rapidly deactivated at the focal injury site; their local effective concentration time following a single medication cannot meet the required time for spinal axons to regenerate and cross the glial scar. In this study, we produced polymer sustained-release microspheres based on the polylactic-co glycolic acid copolymer; the microspheres at 300-MUm diameter contained nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor. Six microspheres were longitudinally implanted into the sciatic nerve at the anastomosis site, serving as the experimental group; while the sciatic nerve in the control group was subjected to the end-to-end anastomosis using 10/0 suture thread. At 6 weeks after implantation, the lower limb activity, weight of triceps surae muscle, sciatic nerve conduction velocity and the maximum amplitude were obviously better in the experimental group than in the control group. Compared with the control group, more regenerating nerve fibers were observed and distributed in a dense and ordered manner with thicker myelin sheaths in the experimental group. More angiogenesis was also visible. Experimental findings indicate that polylactic-co-glycolic acid composite microspheres containing nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor can promote the restoration of sciatic nerve in rats after injury. PMID- 26604913 TI - Repair of peripheral nerve defects with chemically extracted acellular nerve allografts loaded with neurotrophic factors-transfected bone marrow mesenchymal stem cells. AB - Chemically extracted acellular nerve allografts loaded with brain-derived neurotrophic factor-transfected or ciliary neurotrophic factor-transfected bone marrow mesenchymal stem cells have been shown to repair sciatic nerve injury better than chemically extracted acellular nerve allografts alone, or chemically extracted acellular nerve allografts loaded with bone marrow mesenchymal stem cells. We hypothesized that these allografts compounded with both brain-derived neurotrophic factor- and ciliary neurotrophic factor-transfected bone marrow mesenchymal stem cells may demonstrate even better effects in the repair of peripheral nerve injury. We cultured bone marrow mesenchymal stem cells expressing brain-derived neurotrophic factor and/or ciliary neurotrophic factor and used them to treat sciatic nerve injury in rats. We observed an increase in sciatic functional index, triceps wet weight recovery rate, myelin thickness, number of myelinated nerve fibers, amplitude of motor-evoked potentials and nerve conduction velocity, and a shortened latency of motor-evoked potentials when allografts loaded with both neurotrophic factors were used, compared with allografts loaded with just one factor. Thus, the combination of both brain derived neurotrophic factor and ciliary neurotrophic factor-transfected bone marrow mesenchymal stem cells can greatly improve nerve injury. PMID- 26604914 TI - Stem Cell Ophthalmology Treatment Study (SCOTS) for retinal and optic nerve diseases: a case report of improvement in relapsing auto-immune optic neuropathy. AB - We present the results from a patient with relapsing optic neuropathy treated within the Stem Cell Ophthalmology Treatment Study (SCOTS). SCOTS is an Institutional Review Board approved clinical trial and has become the largest ophthalmology stem cell study registered at the National Institutes of Health to date (www.clinicaltrials.gov Identifier NCT 01920867). SCOTS utilizes autologous bone marrow-derived stem cells (BMSCs) for treatment of retinal and optic nerve diseases. Pre-treatment and post-treatment comprehensive eye exams of a 54 year old female patient were performed both at the Florida Study Center, USA and at The Eye Center of Columbus, USA. As a consequence of a relapsing optic neuritis, the patient's previously normal visual acuity decreased to between 20/350 and 20/400 in the right eye and to 20/70 in the left eye. Significant visual field loss developed bilaterally. The patient underwent a right eye vitrectomy with injection of BMSCs into the optic nerve of the right eyeand retrobulbar, subtenon and intravitreal injection of BMSCs in the left eye. At 15 months after SCOTS treatment, the patient's visual acuity had improved to 20/150 in the right eye and 20/20 in the left eye. Bilateral visual fields improved markedly. Both macular thickness and fast retinal nerve fiber layer thickness were maximally improved at 3 and 6 months after SCOTS treatment. The patient also reduced her mycophenylate dose from 1,500 mg per day to 500 mg per day and required no steroid pulse therapy during the 15-month follow up. PMID- 26604915 TI - Optimal concentration and time window for proliferation and differentiation of neural stem cells from embryonic cerebral cortex: 5% oxygen preconditioning for 72 hours. AB - Hypoxia promotes proliferation and differentiation of neural stem cells from embryonic day 12 rat brain tissue, but the concentration and time of hypoxic preconditioning are controversial. To address this, we cultured neural stem cells isolated from embryonic day 14 rat cerebral cortex in 5% and 10% oxygen in vitro. MTT assay, neurosphere number, and immunofluorescent staining found that 5% or 10% oxygen preconditioning for 72 hours improved neural stem cell viability and proliferation. With prolonged hypoxic duration (120 hours), the proportion of apoptotic cells increased. Thus, 5% oxygen preconditioning for 72 hours promotes neural stem cell proliferation and neuronal differentiation. Our findings indicate that the optimal concentration and duration of hypoxic preconditioning for promoting proliferation and differentiation of neural stem cells from the cerebral cortex are 5% oxygen for 72 hours. PMID- 26604916 TI - Elastic modulus affects the growth and differentiation of neural stem cells. AB - It remains poorly understood if carrier hardness, elastic modulus, and contact area affect neural stem cell growth and differentiation. Tensile tests show that the elastic moduli of Tiansu and SMI silicone membranes are lower than that of an ordinary dish, while the elastic modulus of SMI silicone membrane is lower than that of Tiansu silicone membrane. Neural stem cells from the cerebral cortex of embryonic day 16 Sprague-Dawley rats were seeded onto ordinary dishes as well as Tiansu silicone membrane and SMI silicone membrane. Light microscopy showed that neural stem cells on all three carriers show improved adherence. After 7 days of differentiation, neuron specific enolase, glial fibrillary acidic protein, and myelin basic protein expression was detected by immunofluorescence. Moreover, flow cytometry revealed a higher rate of neural stem cell differentiation into astrocytes on Tiansu and SMI silicone membranes than on the ordinary dish, which was also higher on the SMI than the Tiansu silicone membrane. These findings confirm that all three cell carrier types have good biocompatibility, while SMI and Tiansu silicone membranes exhibit good mechanical homogenization. Thus, elastic modulus affects neural stem cell differentiation into various nerve cells. Within a certain range, a smaller elastic modulus results in a more obvious trend of cell differentiation into astrocytes. PMID- 26604917 TI - Is transcranial magnetic stimulation useful in posttraumatic disorders? PMID- 26604918 TI - Imaging Performance of Quantitative Transmission Ultrasound. AB - Quantitative Transmission Ultrasound (QTUS) is a tomographic transmission ultrasound modality that is capable of generating 3D speed-of-sound maps of objects in the field of view. It performs this measurement by propagating a plane wave through the medium from a transmitter on one side of a water tank to a high resolution receiver on the opposite side. This information is then used via inverse scattering to compute a speed map. In addition, the presence of reflection transducers allows the creation of a high resolution, spatially compounded reflection map that is natively coregistered to the speed map. A prototype QTUS system was evaluated for measurement and geometric accuracy as well as for the ability to correctly determine speed of sound. PMID- 26604919 TI - PPARalpha Is Required for PPARdelta Action in Regulation of Body Weight and Hepatic Steatosis in Mice. AB - Peroxisome proliferator activated receptors alpha (PPARalpha) and delta (PPARdelta) belong to the nuclear receptor superfamily. PPARalpha is a target of well established lipid-lowering drugs. PPARdelta (also known as PPARbeta/delta) has been investigated as a promising antidiabetic drug target; however, the evidence in the literature on PPARdelta effect on hepatic lipid metabolism is inconsistent. Mice conditionally expressing human PPARdelta demonstrated pronounced weight loss and promoted hepatic steatosis when treated with GW501516 (PPARdelta-agonist) when compared to wild type mice. This effect was completely absent in mice with either a dominant negative form of PPARdelta or deletion of the DNA binding domain of PPARdelta. This confirmed the absolute requirement for PPARdelta in the physiological actions of GW501516 and confirmed the potential utility against the human form of this receptor. Surprisingly the genetic deletion of PPARalpha also abrogated the effect of GW501516 in terms of both weight loss and hepatic lipid accumulation. Also the levels of the PPARalpha endogenous agonist 16:0/18:1-GPC were shown to be modulated by PPARdelta in wild type mice. Our results show that both PPARdelta and PPARalpha receptors are essential for GW501516-driven adipose tissue reduction and subsequently hepatic steatosis, with PPARalpha working downstream of PPARdelta. PMID- 26604920 TI - Effect of Narrow-Band Ultraviolet B Phototherapy and Methotrexate on MicroRNA (146a) Levels in Blood of Psoriatic Patients. AB - Background. Recently, some miRNAs have been proven to show aberrant expression in psoriasis and play a role in the pathogenesis of the disease. Objective. To find out whether NB-UVB or methotrexate treatment affects whole blood levels of human miRNA (146a) in patients with psoriasis and demonstrate its correlation with disease severity. Methods. Blood samples were obtained from healthy control and from psoriatic patients before and 12 weeks after treatment with NB-UVB, methotrexate. Quantification of human miRNA (146a) by Real Time PCR (RT-PCR). Results. Blood human miRNA (146a) levels were higher in patients with psoriasis than those in healthy controls (P = 0.001); it had no significant positive relation with PASI scores in patients (r = 0.2, P = 0.107). Real Time PCR showed that, after 12 weeks of treatment with NB-UVB phototherapy or treatment with methotrexate, there was significantly decreased level of miR146a (P = 0.001; P = 0.002, resp.). Conclusion. The expression of miRNA146a is increased in whole blood samples from psoriasis patients, so we can evaluate its possibility to work as a future therapeutic objective in the treatment of psoriasis. With these markers, it is able to screen therapeutics effect or changes to a further aggressive treatment for psoriasis. PMID- 26604921 TI - On the Role of the Blood Vessel Endothelial Microvilli in the Blood Flow in Small Capillaries. AB - Endothelial microvilli that protrude into the capillary lumen, although invisible in the optical microscopy, may play an important role in the blood flow control in the capillaries. Because of the plug effects, the width of the gap between the capillary wall and the blood cell is especially critical for the blood flow dynamics in capillaries, while microvilli located on the capillary wall can easily control the velocity of the blood flow. We report that microvilli in the capillaries of different vertebrate species have similar characteristics and density, suggesting similarities between the respective regulation mechanisms. A simplified physical model of the capillary effective diameter control by the microvilli is presented. PMID- 26604922 TI - Acute beta-N-Methylamino-L-alanine Toxicity in a Mouse Model. AB - The cyanobacterial neurotoxin beta-N-methylamino-L-alanine (BMAA) is considered to be an "excitotoxin," and its suggested mechanism of action is killing neurons. Long-term exposure to L-BMAA is believed to lead to neurodegenerative diseases including Parkinson's and Alzheimer's diseases and amyotrophic lateral sclerosis (Lou Gehrig's disease). Objectives of this study were to determine the presumptive median lethal dose (LD50), the Lowest-Observed-Adverse-Effect Level (LOAEL), and histopathologic lesions caused by the naturally occurring BMAA isomer, L-BMAA, in mice. Seventy NIH Swiss Outbred mice (35 male and 35 female) were used. Treatment group mice were injected intraperitoneally with 0.03, 0.3, 1, 2, and 3 mg/g body weight L-BMAA, respectively, and control mice were sham injected. The presumptive LD50 of L-BMAA was 3 mg/g BW and the LOAEL was 2 mg/g BW. There were no histopathologic lesions in brain, liver, heart, kidney, lung, or spleen in any of the mice during the 14-day study. L-BMAA was detected in brains and livers in all of treated mice but not in control mice. Males injected with 0.03 mg/g BW, 0.3 mg/g BW, and 3.0 mg/g BW L-BMAA showed consistently higher concentrations (P < 0.01) in brain and liver samples as compared to females in those respective groups. PMID- 26604923 TI - The Protective Effects of Nigella sativa and Its Constituents on Induced Neurotoxicity. AB - Nigella sativa (N. sativa) is an annual plant and widely used as medicinal plant throughout the world. The seeds of the plant have been used traditionally in various disorders and as a spice to ranges of Persian foods. N. sativa has therapeutic effects on tracheal responsiveness (TR) and lung inflammation on induced toxicity by Sulfur mustard. N. sativa has been widely used in treatment of various nervous system disorders such as Alzheimer disease, epilepsy, and neurotoxicity. Most of the therapeutic properties of this plant are due to the presence of some phenolic compounds especially thymoquinone (TQ), which is major bioactive component of the essential oil. The present review is an effort to provide a comprehensive study of the literature on scientific researches of pharmacological activities of the seeds of this plant on induced neurotoxicity. PMID- 26604924 TI - Galectin-3 and Cyclin D3 Immunohistochemistry and Tumor Dimensions Are Useful in Distinguishing Follicular Oncocytic Carcinomas from Oncocytic Adenomas of the Thyroid. AB - Aims. Oncocytic (Hurthle) follicular cell tumors (OTs) of the thyroid are both adenomas (OAs) and follicular carcinomas (OCs). The routine diagnosis of these tumors can be problematic even after an accurate sampling and histological examination. Beside preoperative evaluation due to the tumor's dimension several studies have been performed to find markers able to distinguish malignant from benign follicular tumors in the thyroid, with Galectin-3 being one of the most effective. Recently, some authors suggested cyclin D3 as adjunct to the diagnosis of the oncocytic lesions of the thyroid. Methods and Results. In this paper we assess the role of Galectin-3 and cyclin D3 in a well-selected group of follicular oncocytic tumors (14 OCs and 26 OAs). The diameter of each lesion was also evaluated. The combination of Galectin-3 and cyclin D3 has a good specificity (81%) and sensitivity (100%). Moreover, the maximum diameter (in cm) of OCs is greater than OAs (4.1 versus 2.3). Conclusions. We believe that the use of Galectin-3 and cyclin D3 in OTs of the thyroid can be a helpful panel in daily practice when histology is doubtful. PMID- 26604926 TI - Spectrophotometric Analysis of Caffeine. AB - The nature of caffeine reveals that it is a bitter white crystalline alkaloid. It is a common ingredient in a variety of drinks (soft and energy drinks) and is also used in combination with various medicines. In order to maintain the optimum level of caffeine, various spectrophotometric methods have been developed. The monitoring of caffeine is very important aspect because of its consumption in higher doses that can lead to various physiological disorders. This paper incorporates various spectrophotometric methods used in the analysis of caffeine in various environmental samples such as pharmaceuticals, soft and energy drinks, tea, and coffee. A range of spectrophotometric methodologies including chemometric techniques and derivatization of spectra have been used to analyse the caffeine. PMID- 26604925 TI - Association between Serum Soluble Klotho Levels and Mortality in Chronic Hemodialysis Patients. AB - Klotho is a single-pass transmembrane protein predominantly expressed in the kidney. The extracellular domain of Klotho is subject to ectodomain shedding and is released into the circulation as a soluble form. Soluble Klotho is also generated from alternative splicing of the Klotho gene. In mice, defects in Klotho expression lead to complex phenotypes resembling those observed in dialysis patients. However, the relationship between the level of serum soluble Klotho and overall survival in hemodialysis patients, who exhibit a state of Klotho deficiency, remains to be delineated. Here we prospectively followed a cohort of 63 patients with a mean duration of chronic hemodialysis of 6.7 +/- 5.4 years for a median of 65 months. Serum soluble Klotho was detectable in all patients (median 371 pg/mL, interquartile range 309-449). Patients with serum soluble Klotho levels below the lower quartile (<309 pg/mL) had significantly higher cardiovascular and all-cause mortality rates. Furthermore, the higher all cause mortality persisted even after adjustment for confounders (hazard ratio 4.14, confidence interval 1.29-13.48). We conclude that there may be a threshold for the serum soluble Klotho level associated with a higher risk of mortality. PMID- 26604927 TI - Validation of a HPLC/FLD Method for Quantification of Tocotrienols in Human Plasma. AB - Quantification of tocotrienols in human plasma is critical when the attention towards tocotrienols on its distinctive properties is arising. We aim to develop a simple and practical normal-phase high performance liquid chromatography method to quantify the amount of four tocotrienol homologues in human plasma. Using both the external and internal standards, tocotrienol homologues were quantified via a normal-phase high performance liquid chromatography with fluorescence detector maintained at the excitation wavelength of 295 nm and the emission wavelength of 325 nm. The four tocotrienol homologues were well separated within 30 minutes. A large interindividual variation between subjects was observed as the absorption of tocotrienols is dependent on food matrix and gut lipolysis. The accuracies of lower and upper limit of quantification ranged between 92% and 109% for intraday assays and 90% and 112% for interday assays. This method was successfully applied to quantify the total amount of four tocotrienol homologues in human plasma. PMID- 26604928 TI - In Vitro Evaluation of Antimicrobial Efficacy of Extracts Obtained from Raw and Fermented Wild Macrofungus, Lenzites quercina. AB - In recent time, there is a major concern about antibiotic resistance displayed by some pathogenic microorganisms and this had involved a continuous search for natural antimicrobial products. The phytochemistry as well as antimicrobial activity of extracts obtained from Lenzites quercina was investigated. The extracts and purified fractions were, respectively, tested against indicator organisms using agar well diffusion and disc diffusion methods. The quantity of phytochemicals found in the extracts of L. quercina ranged from 14.4 to 20.7 mg/g for alkaloids, 6.1 to 12.8 mg/g for steroids, 4.5 to 10.6 mg/g for saponins, 2.8 to 17.2 mg/g for terpenoids, and 0.41 to 17.1 mg/g for flavonoids. The gas chromatography mass spectrophotometry (GCMS) analysis of the extract reveals the presence of caprylic acid, stearic acid, tetradecanoic acid, methyl-11 octadecenoate, oleic acid, and 4-methyl-2-propyl-1-pentanol. Extracts of L. quercina and its purified fractions exhibited wider range of inhibition (4 mm to 26 mm) on Staphylococcus aureus (ATCC 29213), Pseudomonas aeruginosa (ATCC 27853), Escherichia coli (ATCC 35218), Methicillin Resistant Staphylococcus aureus (MRSA), Salmonella typhi, Bacillus cereus, Enterococcus faecalis, Candida albicans, and Aspergillus niger. The antimicrobial effects of L. quercina extracts indicate that this wild macrofungus contains significant amount of pharmacological agents, which could be extracted to curb the menace of antibiotic resistances by pathogenic organisms. PMID- 26604929 TI - Arthrogryposis Multiplex Congenita: Multiple Congenital Joint Contractures. AB - Arthrogryposis multiplex congenita (AMC) is a syndrome characterized by nonprogressive multiple congenital joint contractures. The etiology of disease is multifactorial; it is most commonly suspected from absent fetal movements and genetic defects. AMC affects mainly limbs; also it might present with other organs involvement. It is crucial that the diagnosis of AMC should be kept in mind by musculoskeletal physicians in newborns with multiple joint contractures and patients must begin rehabilitation in early stage after accurate diagnosis in terms of functional independence. We present the diagnosis, types, clinical features, and treatment approaches of this disease in our case with literature reviews. PMID- 26604930 TI - Association between Neurofibromatosis Type 1 and Breast Cancer: A Report of Two Cases with a Review of the Literature. AB - Neurofibromatosis type 1 (NF1) is one of the most common genetic diseases in humans and is associated with various benign and malignant tumors, including breast cancer. However, an increased risk of breast cancer in NF1 patients has not been widely recognized or accepted. Here, we report two cases of breast cancer in NF1 patients and review the literature on the association between NF1 and breast cancer. PMID- 26604931 TI - Multisystemic Side Effects of an Indispensable Old Drug: A Case Report of Chronic Lithium Use (A Patient with Multiple Side Effects of Lithium). AB - Presented here is a case of long-term lithium use, with multiple emerging lithium associated side effects. An 82-year-old woman was brought into the emergency department because of loss of consciousness. According to the physical examination and laboratory analyses, patient was diagnosed with lithium associated hypercalcemia, hyperparathyroidism, nephrogenic diabetes insipidus (NDI), symptomatic sinus bradycardia, and thyroid dysfunction. In the literature, there is a limited number of case reports with lithium induced multiple clinical conditions. Multiple clinical manifestations due to the side effects of chronic lithium use might be seen. Health care professionals should keep in mind that lithium-related side effects might trigger or exacerbate each other. To avoid toxicity, close follow-up and clinical supervision are important for the early diagnosis and treatment of these side effects, due to the narrow therapeutic index and obscure clinical signs and symptoms of toxicity. PMID- 26604932 TI - From the Editor-in-Chief. PMID- 26604934 TI - Generic brands in the prevention of fragility fractures. AB - Generic drugs are safe and effective, but their prescription in Italy is among the lowest in Europe (30% to 60-70% in other Countries). According to a recently published retrospective study, generics are not statistically different from their corresponding brand counterpart in the therapy of osteoporosis, a bone defects characterized by a decrease in bone mineral density, which can lead to an increased frailty and risk of fracture. Unfortunately there are a lot of problems in compliance with these drugs: it is only about 7.19% in the first year, despite their consumption is simple and effective in the prevention of fracture. Various studies made by GPs are highlighting many barriers in the path from the contact with the doctor to the purchase at the pharmacy: the idea GPs have of generics, the patients' perception of it, the big amount of drugs in the pharmacies and the advice that comes from the pharmacist. The published study, proving non inferiority of generics and lack of differences in mortality and access to specialists among those using generic and brand drugs, encourages to use those drugs that not only are safe and effective, but that are also good for the economical and financial balance of Italian sanitary system. PMID- 26604933 TI - Clodronate: new directions of use. AB - Clodronate is the father of bisphosphonates. For over three decades it has been subject of study in biological and clinical areas, proving to be an extremely interesting molecule from different points of view. It has been the first drug for osteoporosis that can be administered pulsatorily (once every 15 days or once a week). This, along with good tolerability, has been the first cause of its success, when there were no solid data in literature about its antifracture efficacy. There are three published studies that prove its antifracture effect: two by McCloskey published in 2004 and 2007 on BMR, and our study about fracture prevention in corticosteroids OP. In these studies a dose of 800 mg/day orally administered or 100 mg/week I.M. was used, and they are basically the same if you consider that clodronate absorption, orally administered, is on average 1.9%. However, a series of works where higher doses were used (1600 mg orally administered) with greater effectiveness on bone mass, especially in higher risk populations, lead us to consider the use of 200 mg i.m. formulation. First of all, we proved densitometric equivalence of 200 mg i.m./14 days and 100 mg i.m./week in a first study; then, in a second study, we proved a greater densitometric efficacy of 200 mg/week compared to 100 mg/week, clearer at femoral level, where the drug had not proven to prevent femoral fracture because of inadequate bone mass increase at that level. Moreover, as for ibandronate case, monthly dose was doubled compared to pivotal trial, in order to maximize the effects on femoral bone mass and therefore prevent femoral fractures. Consequently, on the basis of the risk envelope, whether it is identified according to BMD and the presence of one risk factor at least or more correctly identified through risk chart (FRAX or DeFRA), you can put forward a differential use of 100 mg i.m. and 200 mg i.m., weekly, "off-label" or every 14 days, adjusting doses in relation to fracture risk and painful symptoms gravity, as well as improving its ease of use and therefore assist compliance. Common experience and clinical and biological works have proved that clodronate has an analgesic effect that can be increased by doubling the doses. The analgesic effect is present not only with patients with fractures, but also with patients suffering from osteoarthritis or arthritis. Therefore, the drug would fit well in the therapeutic program of rheumatic patient, also because of its symptomatic effects. Clodronate at small doses (2 mg) could also have protective effects on cartilage (introduction of intra-articular formulation is expected) and at 10-100 fold higher doses it has certainly anti-inflammatory effects and more specifically antimacrophage and anticytokine effects (IL-1, IL-6, TNFalpha, PGE). These effects are amplified by putting clodronate in monolayer liposomes. This drug, therefore, has to be considered as adjuvant in arthritis therapy, whose origin can be linked to a strong osteoclastic activation caused by an increase of cytokines and the RANKL/OPG relationship. It is clear that clodronate can work on cytokine at first and on osteoclastic effector in the end. The drug has been used "off-label" for decades intravenously in complex regional pain syndrome (CRPS type 1) in relation to schemes that change according to different Authors and according to cumulative doses ranging from 3 to 5 g. The introduction on the market of the 200 mg i.m. formulation could allow to get more practical but equally effective schemes. For example, we used this scheme: 200 mg/day for 10 days and then 200 mg every other day for 20 days (cumulative dose of 4 g in a month). Said scheme can be repeated in the following months in particular cases. Results, as for efficacy and lack of relapses, show that clodronate is the leader drug for this syndrome. In recent years, relationship between costs and benefits has started to matter, especially after the creation of some algorithms, such as FRAX, that let us choose patients with a higher fracture risk in 10 years, and after pharmaceutic-economic models that let us calculate FRAX intervention threshold, on the basis of drug price and monitoring, antifracture efficacy, quality of life and how much a community can or wants to spend. In this respect, a sub-analysis of McCloskey's study on people over the age of 75, conducted on 3974 subjects, shows that clodronate is more efficient with patients with a higher fracture risk, calculated according to FRAX. Furthermore, another study by McCloskey revealed that, for a 100-pound/year drug (very similar to clodronate), 'cost effective' intervention threshold is about 7-10%. In conclusion, clodronate prevents fractures, decrease osteo-articular pain, is easy to handle, tolerable and had a great cost/benefit relationship. PMID- 26604935 TI - The natural approach to osteoporosis. AB - Osteoporosis is normally the result of a wrong life-style (diet, physical inactivity, smoke, dental hygiene, intestinal dysbiosis,...) and environmental toxicity which stimulate the chronic expression of inflammatory genes and alter the immuno-endocrine balance. A natural approch should face all the factors involved, leading the patients to become aware of their own responsability, and helping them with natural therapies, healthy food and life-style which support their body in the process of self-healing. PMID- 26604937 TI - Drugs for type 2 diabetes: role in the regulation of bone metabolism. AB - Until a few years ago, the possibility that glucose-lowering drugs affect glucose metabolism and fracture risk was not even considered. The increased incidence of fractures with thiazolidinediones in women was a causal finding. This phenomenon, which has been demonstrated by large-scale clinical trials, is associated with a reduction in bone density. Thiazolidinediones stimulate adipocyte differentiation, and inhibit osteoblast differentiation, from bone marrow stromal cells; other mechanisms could also be involved in the thiazolidinedione-induced reduction of bone density. Insulin has an anabolic effect on the bone, but it is nonetheless associated with an increased incidence of fractures in observational studies. Although this finding could be partly due to unaccounted confounders, it is likely that insulin-induced hypoglycemia, and consequent falls, produce a higher risk for fractures, at least in the elderly. Among older drugs, metformin and sulfonylureas do not appear to produce any beneficial or detrimental effects on the bone. Of newer agents, DPP4 inhibitors have been associated with a possible protective effect in earlier trials, but this result has not been confirmed in larger scale studies on patients with a higher level of comorbidities. Considering that the increase in active incretin levels determined by DPP4 inhibitors could theoretically improve bone density, further clinical studies are needed to assess more clearly the effect of this class of drugs. GLP 1 receptor agonists also increase bone density in experimental models, but human data are still insufficient to draw any conclusion. PMID- 26604938 TI - Pharmacological perspectives in sarcopenia: a potential role for renin angiotensin system blockers? AB - Sarcopenia represents a major health problem highly prevalent in elderly and age related chronic diseases. Current pharmacological strategies available to prevent and reverse sarcopenia are largely unsatisfactory thus raising the need to identify novel targets for pharmacological intervention and possibly more effective and safe drugs. This review highlights the current knowledge of the potential benefits of renin-angiotensin system blockade in sarcopenia and discuss the main mechanisms underlying the effects. PMID- 26604936 TI - Prevention and treatment of bone fragility in cancer patient. AB - It is well known that fractures increase the risk of morbidity and mortality. The various mechanisms responsible for bone loss in cancer patients may have a different impact depending on the characteristics of the clinical case and correlates with the therapies used, or caused by the therapies used against cancer. Some hormonal treatments cause hypogonadism, event which contributes to the progressive loss of bone mass. This is detectable in patients with breast cancer receiving determines that estrogen-deprivation and in men with prostate cancer with therapies that determine androgen deprivation. Chemotherapy treatments used in cancer patients have reduced bone mass. In addition, low bone mass is detectable in patients with lymphoma treated with corticosteroids or radiation or alkylating agents. In premenopausal patients suffering from breast cancer, treatment with cytotoxic therapy or ablation of ovarian function, can lead to an 8% reduction in bone mineral density at the spine and 4% in the femur. With a chemotherapy regimen in CMF, the reduction of BMD is 6.5%; this bone loss is not recovered after discontinuation of therapy. Tamoxifen given for five years reduces bone remodeling and cause a 32% increase in the risk of osteoporotic fractures when used in premenopausal. After menopause, tamoxifen has a protective effect on bone mass, with a reduced risk of new fractures. Aromatase inhibitors in post-menopausal women, depending on the formulation can cause different effects on the reduction of BMD and fracture risk. We have in fact steroids, exemestane and nonsteroidal, letrozole and anastrozole. Patients at increased risk of fragility fractures should undergo preventive therapies as soon as possible after tests performed for the study of bone health. They can be used DEXA and the FRAX algorithm, which can define a secondary osteoporosis. Prevention and treatment of the increased risk of osteoporotic fracture is to maintain adequate levels of calcium and vitamin D. Bisphosphonates and denosumab are used for the management of bone remodeling and bone loss induced by cancer treatments. Bisphosphonates also have anti-tumor effects per se, which are expressed in potentially prevent the development of bone metastases. In men with metastatic prostate cancer and which is induced androgen deprivation, it is usefully used denosumab 120 mg monthly or zoledronic acid 4 mg monthly. PMID- 26604939 TI - Vascular calcification and fracture risk. AB - Osteoporosis and cardiovascular diseases are public health problems. Fragility fractures are associated with high risk of cardiovascular event and patients with cardiovascular diseases have higher risk of fracture. Severe abdominal aortic calcification (AAC) is associated with higher cardiovascular mortality and morbidity. Severe AAC is associated with higher risk of fracture. In cross sectional studies severe AAC was associated with greater prevalence, higher number and greater severity of vertebral fractures after adjustment for confounders including bone mineral density (BMD). Prospective studies confirm the association between baseline AAC severity and prospectively assessed fracture risk in both sexes. Data on the link between AAC and BMD are discordant. Age, smoking, hypertension, diabetes mellitus, and low grade systemic inflammation are possible risk factors of severe AAC and fracture risk. However, in clinical studies, the link between AAC and fracture was significant after adjustment for these factors. Data on the association between calcification in other vascular beds and BMD are limited and discordant. PMID- 26604940 TI - New perspectives in echographic diagnosis of osteoporosis on hip and spine. AB - Currently, the accepted "gold standard" method for bone mineral density (BMD) measurement and osteoporosis diagnosis is dual-energy X-ray absorptiometry (DXA). However, actual DXA effectiveness is limited by several factors, including intrinsic accuracy uncertainties and possible errors in patient positioning and/or post-acquisition data analysis. DXA employment is also restricted by the typical issues related to ionizing radiation employment (high costs, need of dedicated structures and certified operators, unsuitability for population screenings). The only commercially-available alternative to DXA is represented by "quantitative ultrasound" (QUS) approaches, which are radiation-free, cheaper and portable, but they cannot be applied on the reference anatomical sites (lumbar spine and proximal femur). Therefore, their documented clinical usefulness is restricted to calcaneal applications on elderly patients (aged over 65 y), in combination with clinical risk factors and only for the identification of healthy subjects at low fracture risk. Literature-reported studies performed some QUS measurements on proximal femur, but their clinical translation is mostly hindered by intrinsic factors (e.g., device bulkiness). An innovative ultrasound methodology has been recently introduced, which performs a combined analysis of B mode images and corresponding "raw" radiofrequency signals acquired during an echographic scan of the target reference anatomical site, providing two novel parameters: Osteoporosis Score and Fragility Score, indicative of BMD level and bone strength, respectively. This article will provide a brief review of the available systems for osteoporosis diagnosis in clinical routine contexts, followed by a synthesis of the most promising research results on the latest ultrasound developments for early osteoporosis diagnosis and fracture prevention. PMID- 26604941 TI - Rare causes of osteoporosis. AB - Osteoporosis is a metabolic bone disease characterized by loss of bone mass and strength, resulting in increased risk of fractures. It is classically divided into primary (post-menopausal or senile), secondary and idiopathic forms. There are many rare diseases, that cause directly or indirectly osteoporosis. The identification and classification of most of these rare causes of osteoporosis is crucial for the specialists in endocrinology and not, in order to prevent this bone complication and to provide for an early therapy. Several pathogenic mechanisms are involved, including various aspects of bone metabolism such as: decreased bone formation, increased bone resorption, altered calcium, phosphorus and/or vitamin D homeostasis, and abnormal collagen synthesis. In this review, less common forms of primary and secondary osteoporosis are described, specifying, if applicable: genetic causes, epidemiology, clinical features, and pathogenic mechanisms causing osteoporosis. A greater awareness of all rare causes of osteoporosis could reduce the number of cases classified as idiopathic osteoporosis and allow the introduction of appropriate and timely treatments. PMID- 26604942 TI - Clinical manifestations and management of Gaucher disease. AB - Gaucher disease is a rare multi-systemic metabolic disorder caused by the inherited deficiency of the lysosomal enzyme beta-glucocerebrosidase, which leads to the accumulation of its normal substrate, glucocerebroside, in tissue macrophages with damage to haematological, visceral and bone systems. Anaemia, thrombocytopenia, enlargement of liver and/or spleen, skeletal abnormalities (osteopenia, lytic lesions, pathological fractures, chronic bone pain, bone crisis, bone infarcts, osteonecrosis and skeletal deformities) are typical manifestations of the most prevalent form of the disease, the so-called non neuronopathic type 1. However, severity and coexistence of different symptoms are highly variable. The determination of deficient beta-glucocerebrosidase activity in leukocytes or fibroblasts by enzymatic assay is the gold standard for the diagnosis of Gaucher disease. Comprehensive and reproducible evaluation and monitoring of all clinically relevant aspects are fundamental for the effective management of Gaucher disease patients. Enzyme replacement therapy has been shown to be effective in reducing glucocerebroside storage burden and diminishing the deleterious effects caused by its accumulation. Tailored treatment plan for each patient should be directed to symptom relief, general improvement of quality of life, and prevention of irreversible damage. PMID- 26604943 TI - Gaucher disease: the role of the specialist on metabolic bone diseases. AB - According to European legislation, a disease can be considered rare or "orphan" when it affects less than 1 subject of 2000 (1). Often these diseases affecting the pediatric age, are complex diseases and chronically debilitating and for this motive need the intervention of multidisciplinary skills specific. Among the rare disease as affecting the skeleton more than 400 are characterized by dysplastic changes of the skeleton (2). Alongside the disorders affecting the skeleton primitively, many systemic diseases can have a bone involvement. Among these, the Gaucher disease (GD), an heterogeneous lysosomal storage determined by hereditary enzyme deficiency of beta-glucosidase. Patients with this disease have skeletal disorders of varying severity (Erlenmeyer flask deformity, lytic lesions and osteonecrosis, pathological fractures) that affects both the bone marrow, both mineralized bone with progressive damage of the tissue. The bone disease is the most debilitating of GD and can have a significant impact on the quality of life of patients. Thorough evaluations by monitoring biochemical markers of bone turnover and instrumental, with a quantitative and qualitative evaluation of the bone, are of fundamental importance to intervene early so they can prevent complications irreversible. PMID- 26604944 TI - Clinical management of hypophosphatasia. AB - HPP is a rare disease that manifests in different ways across the life course. Accurate diagnosis depends upon the use of appropriate age-related normative data. A new therapy is undergoing clinical trials; the preliminary published data is encouraging, but the scope of clinical application remains to be determined. PMID- 26604945 TI - Periodontitis and bone metabolism. AB - Periodontitis is a plaque induced disease characterized by tissue destruction. The extent of the alveolar bone loss depends on the host response stimulated by bacterial infection. Recently researchers have focused on the role of the immune system, of RANK/RANKL/OPG pathway and of cytokines network. Another recent field of interest is osteoimmunology that try to explain the relationship between immune and bone cells in activating bone resorption. Advances in the understanding of the pathogenic mechanisms allowed a better understanding of the relationship with other diseases like osteoporosis and also to hypothesize new therapies based on modulation of host response (host modulatory therapy - HMT). The purpose of this mini-review is to briefly discuss these topics. PMID- 26604946 TI - Detecting low bone mineral density from dental radiographs: a mini-review. AB - Over a number of years researchers have reported associations between osteoporosis or low bone mineral density and signs that can be detected on dental radiographs, particularly in the width of the inferior mandibular cortex and the texture of the trabecular bone. As patients visit the dentist more regularly than they visit their doctor, there is the possibility that such signs could be used as a means of identifying individuals at risk of developing osteoporosis or suffering from consequent fracture. This paper reviews the historical background behind this research and the current status, including recent developments in automation of measurement using computer image analysis. PMID- 26604947 TI - Bone graft and mesenchimal stem cells: clinical observations and histological analysis. AB - Autologous bone, for its osteoconductive, osteoinductive and osteogenetic properties, has been considered to be the gold standard for maxillary sinus augmentation procedures. Autograft procedures bring also some disadvantages: sometimes the limited amount of available intraoral bone makes necessary to obtain bone from an extraoral site, and this carries an associated morbidity. To overcome this problem we started using homologous freeze-dried bone in maxillary sinus augmentation procedures. This bone is industrially processed with gamma irradiation to eliminate its disease transmission potential and it's considered safe, but this treatment also eliminates the osteoinductive and osteogenetic properties, making it just an inert scaffold for regeneration. Mesenchymal stem cells are successfully used in and orthopedic surgery for their amplification potential of healing mechanisms. We assumed that mesenchymal stem cells can restore the osteogenetic and osteoinductive properties in homologous bone grafts. The aim of this study was an histological evaluation of bone regeneration in maxillary sinus elevation using: 1) mesenchymal stem cells engineered freeze dried bone allografts; 2) freeze-dried bone allografts. Twenty patients (10M, 10F) with a mean age of 55.2 years affected by severe maxillary atrophy were treated with bilateral maxillary sinus floor elevation. For each patient were randomly assigned a "test" side and a "control" side, different from each other exclusively in the composition of the graft material. The "control" sides were composed by corticocancellous freeze-dried bone chips and the "test" sides were composed by corticocancellous freeze-dried bone chips engineered in a bone marrow mesenchymal stem cells concentrate. After three months bone biopsies were performed on the grafts and histological specimens were made in order to evaluate the healed bone from an histological point of view. Histologically all the specimens showed active remodelling signs and all the tissues were free of inflammatory cells. "Control" side specimens showed a substantial persistence of the grafted bone and, with the interposition of connective tissue, a considerable amount of newly formed bone. "Test" side specimens showed a much more represented cellular component compared to the "control" sides. The grafted bone trabeculae, when detectable, were completely imprisoned inside new formed bone, in direct contact with it and without interposition of connective tissue. Freeze-dried bone can be used successfully as graft material in the treatment of maxillary atrophy. The same bone engineered with stem cells showed a greater histological integration potential comparable with autografts histological morphology. Further studies are needed to confirm these hypotheses. PMID- 26604949 TI - Periodontal disease in Paget's disease of bone. AB - A 59-year-old man suffering from Paget's disease of bone and periodontal disease was examined in anticipation of bisphosphonate treatment. The previous therapy with clodronate resulted ineffective and markers of bone turnover were markedly elevated. Periodontal disease was correctly approached and treated with an excellent outcome. 5 mg zoledronate iv infusion induced a remarkable reduction of bone markers which persisted on time within the normal range. After zoledronate treatment no signs of osteonecrosis of the jaw (ONJ) were observed. A correct management of periodontal disease is mandatory in pagetic patients on bisphosphonate treatment. PMID- 26604948 TI - Danio rerio: the Janus of the bone from embryo to scale. AB - Danio rerio (zebrafish), like the Roman god Janus, is an old animal model which is recently emerged and looks to the future with an increasing scientific success. Unlike other traditional animal models, zebrafish represents a versatile way to approach the study of the skeleton. Transparency of the larval stage, genetic manipulability and unique anatomical structures (scales) makes zebrafish a powerful and versatile instrument to investigate the bone tissue in terms of structure and function. Like Janus, zebrafish offers two different faces, or better, two models in one animal: larval and adult stage. The embryo can be used to isolate new genes involved in osteogenesis by large-scale mutagenesis screenings. The behavior of bone cells and genes in osteogenesis can be investigate by using transgenic lines, vital dyes, mutants and traditional molecular biology techniques. The adult zebrafish represents an important resource to study the pathways related to the bone metabolism and turnover. In particular, the properties of the caudal fin allow to study mechanisms of bone regeneration and reparation whereas the elasmoid scale represents an unique tool to investigate the bone metabolism under physiological or pathological conditions. PMID- 26604950 TI - Primary hyperparathyroidism presenting with acute pancreatitis and asymptomatic bone involvement. AB - A 15-year-old female patient presented to the emergency room with vomiting and abdominal pain. She had two similar attacks in the previous three months both of them were diagnosed as pancreatitis in two different hospitals. On admission, her serum calcium and parathyroid hormone levels were very high. CT scan revealed left inferior parathyroid adenoma. Investigations to rule out possible multiple endocrine neoplasia were all negative. The patient was managed by intravenous fluids and furosemide to lower her serum calcium level. Then, left inferior parathyroidectomy was done. Postoperatively, the patient had hungry bone syndrome with severe hypocalcaemia and was managed by intravenous calcium infusion for five days in the intensive care unit. Later, she was kept on oral calcium and vitamin D supplementation. She became symptom-free and her serum calcium improved gradually. PMID- 26604951 TI - Bulbous epiphysis and popcorn calcification as related to growth plate differentiation in osteogenesis imperfecta. AB - BACKGROUND: Osteogenesis Imperfecta (OI) is an heritable systemic disorder of connective tissue due to different sequence variants in genes affecting both the synthesis of type I collagen and osteoblast function. Dominant and recessive inheritance is recognized. Approximately 90% of the OI cases are due to mutations in COL1A1/A2 genes. We clinically and radiologically describes an adult male with type III osteogenesis imperfecta who presents a rare bone dysplasia termed bulbous epiphyseal deformity in association with popcorn calcifications. Popcorn calcifications may occur with bulbous epiphyseal deformity or independently. METHODS: Molecular analysis was performed for COL1A1, COL1A2, LEPRE1 and WNT1 genes. RESULTS: An uncommon COL1A1 mutation was identified. Clinical and radiological exams confirmed a distinctive bulbous epiphyseal deformity with popcorn calcifications in distal femurs. We have identified four additional OI patients reported in current literature, whose X-rays show bulbous epiphyseal deformity related to mutations in CR-TAP, LEPRE1 and WNT1 genes. CONCLUSION: The mutation identified here had been previously described twice in OI patients and no previous correlation with bulbous epiphyseal deformity was described. The occurrence of this bone dysplasia focuses attention on alterations in normal growth plate differentiation and the subsequent effect on endochondral bone formation in OI. PMID- 26604954 TI - The use of platelet-rich fibrin (PRF) and PRF-mixed particulated autogenous bone graft in the treatment of bone defects: An experimental and histomorphometrical study. AB - BACKGROUND: Various materials and techniques have been developed to facilitate bone healing process and reduce its healing period. In recent studies, it is pointed out that, platelet-rich fibrin (PRF) which is derived autogenously from the own blood of the individuals, increase regeneration and accelerate the healing of the wound, due to the consisting various growing factors. The aim of the experimental study is to evaluate the efficiency of PRF and PRF/autogenous graft combination on bone healing in different time intervals. MATERIALS AND METHODS: A total of 24 skeletally mature New Zealand rabbits were used. Animals were divided randomly into two groups. Two bone defects with a diameter 3, 3 mm were created on the right and left tibia in all group animals. Only particulate autogeneous bone graft, only PRF, combination of PRF and autogeneous bone graft and empty bone cavity, were performed to all animals. The animals in the first experimental group were sacrificed after 30 days. The animals in the second experimental group were sacrificed after 60 days from the operation. Histomorphometrical and statistical analysis was performed. The data were analyzed using Tukey test (P < 0.05 for osteoblast number, P < 0.01 for osteoclast and new bone area values). RESULTS: Histomorphometrical analyzes showed that either PRF used alone or used in conjuction with autogenous bone graft, PRF accelerated the healing of the bone defects. There were statistically significant differences in osteoblast, osteoblast and new bone area values in PRF alone and autogenous graft with PRF than the other groups. CONCLUSION: Our preliminary result demonstrated that PRF increase new bone formation and has a positive effect on early bone healing. PMID- 26604953 TI - Outcomes of vital pulp therapy in permanent teeth with different medicaments based on review of the literature. AB - Vital pulp therapy (VPT) is a biologic and conservative treatment modality to preserve the vitality and function of the coronal or remaining radicular pulp tissue in vital permanent teeth. A search was conducted via the Cochrane database, PubMed, MEDLINE, and Ovid for any articles with the criteria for "pulp capping," or "pulp-capping materials" and "VPT outcomes" from 1978 to mid 2014. All articles were evaluated and the valid papers were selected. The outcomes of various VPT techniques, including indirect pulp treatment, direct pulp treatment, partial pulpotomy, and complete pulpotomy in vital permanent teeth were extracted. Although various studies have different research approach, most studies noted a favorable treatment outcome. Mineral trioxide aggregate (MTA) appears to be more effective than calcium hydroxide (Ca(OH)2) for maintaining long-term pulp vitality after indirect and direct pulp-capping. However, it seems that the success rate for partial pulpotomy and pulpotomy with Ca(OH)2 is similar to MTA. PMID- 26604952 TI - The antioxidant master glutathione and periodontal health. AB - Glutathione, considered to be the master antioxidant (AO), is the most-important redox regulator that controls inflammatory processes, and thus damage to the periodontium. Periodontitis patients have reduced total AO capacity in whole saliva, and lower concentrations of reduced glutathione (GSH) in serum and gingival crevicular fluid, and periodontal therapy restores the redox balance. Therapeutic considerations for the adjunctive use of glutathione in management of periodontitis, in limiting the tissue damage associated with oxidative stress, and enhancing wound healing cannot be underestimated, but need to be evaluated further through multi-centered randomized controlled trials. PMID- 26604955 TI - Viscosity of endodontic irrigants: Influence of temperature. AB - BACKGROUND: The aim of this study was to assess the influence of temperature on the viscosity of different endodontic irrigants. MATERIALS AND METHODS: The measurements of viscosity of 3% hydrogen peroxide, 0.9% sodium chloride, aqueous solution of 0.2% chlorhexidine (CHX) and 0.2% cetrimide, 5% sodium hypochlorite (NaOCl) and 17% ethylenediaminetetraacetic acid (EDTA) at different temperatures (22 degrees C, 30 degrees C, 40 degrees C, 50 degrees C and 60 degrees C) were obtained using Mohr balance and Ostwald viscometer. The Shapiro-Wilk test and Mann-Whitney U-tests were used for the statistical analysis. (alpha = 0.05). RESULTS: No significant differences were recorded at each temperature among 3% hydrogen peroxide, 0.9% sodium chloride and aqueous solution of 0.2% CHX and 0.2% cetrimide. 5% NaOCl and 17% EDTA showed the higher values. Viscosity statistically decreased with increasing temperature. CONCLUSION: Within the limitations of this study, 5% NaOCl and 17% EDTA are significantly viscous at room temperature and their viscosity reduces with elevating temperature. PMID- 26604956 TI - Three-dimensional accuracy of different impression techniques for dental implants. AB - BACKGROUND: Accurate impression making is an essential prerequisite for achieving a passive fit between the implant and the superstructure. The aim of this in vitro study was to compare the three-dimensional accuracy of open-tray and three closed-tray impression techniques. MATERIALS AND METHODS: Three acrylic resin mandibular master models with four parallel implants were used: Biohorizons (BIO), Straumann tissue-level (STL), and Straumann bone-level (SBL). Forty-two putty/wash polyvinyl siloxane impressions of the models were made using open-tray and closed-tray techniques. Closed-tray impressions were made using snap-on (STL model), transfer coping (TC) (BIO model) and TC plus plastic cap (TC-Cap) (SBL model). The impressions were poured with type IV stone, and the positional accuracy of the implant analog heads in each dimension (x, y and z axes), and the linear displacement (DeltaR) were evaluated using a coordinate measuring machine. Data were analyzed using ANOVA and post-hoc Tukey tests (alpha = 0.05). RESULTS: The DeltaR values of the snap-on technique were significantly lower than those of TC and TC-Cap techniques (P < 0.001). No significant differences were found between closed and open impression techniques for STL in Deltax, Deltay, Deltaz and DeltaR values (P = 0.444, P = 0.181, P = 0.835 and P = 0.911, respectively). CONCLUSION: Considering the limitations of this study, the snap-on implant-level impression technique resulted in more three-dimensional accuracy than TC and TC Cap, but it was similar to the open-tray technique. PMID- 26604957 TI - Effect of electrical spot welding on load deflection rate of orthodontic wires. AB - BACKGROUND: One of the methods used for joining metals together is welding, which can be carried out using different techniques such as electric spot welding. This study evaluated the effect of electric spot welding on the load deflection rate of stainless steel and chromium-cobalt orthodontic wires. MATERIALS AND METHODS: In this experimental-laboratory study, load deflection rate of 0.016 * 0.022 inch stainless steel and chromium cobalt wires were evaluated in five groups (n =18): group one: Stainless steel wires, group two: chromium-cobalt wires, group three: stainless steel wires welded to stainless steel wires, group four: Stainless steel wires welded to chromium-cobalt wires, group five: chromium-cobalt wire welded to chromium-cobalt wires. Afterward, the forces induced by the samples in 0.5 mm, 1 mm, 1.5 mm deflection were measured using a universal testing machine. Then mean force measured for each group was compared with other groups. The data were analyzed using repeated measure analysis of variance (ANOVA), one-way ANOVA, and paired t-test by the SPSS software. The significance level was set as 0.05. RESULTS: The Tukey test showed that there were significant differences between the load deflection rates of welded groups compared to control ones (P < 0.001). CONCLUSION: Considering the limitation of this study, the electric spot welding process performed on stainless steel and chromium-cobalt wires increased their load deflection rates. PMID- 26604958 TI - Correlation between cervical vertebral maturation and chronological age in a group of Iranian females. AB - BACKGROUND: Correlation between chronological age at different stages of cervical vertebral maturation (CVM) is important in clinical orthodontic practice. The objective of this study was to evaluate the correlation between CVM stage and chronological age in a group of Iranian female patients. MATERIALS AND METHODS: This study was conducted on 196 digital lateral cephalometry of female patients with the age ranged 9-14 years. The CVM stage was determined with two calibrated examiners, using the method developed by Baccetti and its correlation with mean chronological age was assessed by the Spearman rank-order. The intra and inter agreements were evaluated by weighted Kappa statistics in overall diagnosis of stages, in addition to determination of presence or absent of concavities at the lower border of second, third and fourth cervical vertebrae and the shapes of the third and fourth vertebrae. P < 0.05 was considered as significant. RESULTS: The correlation coefficient between CVM stages and chronological age was relatively low (r = 0.62). The least amount of inter-observer agreement was determined to be at the clinical decision of the shape of the fourth vertebra. CONCLUSION: Regarding the low reported correlation, the concomitant usage of other skeletal indicators seems necessary for precise determination of physiological age of the patients. PMID- 26604959 TI - Inflammatory markers in gingival crevicular fluid of periodontitis patients with type 2 diabetes mellitus according to glycemic control: A pilot study. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) and periodontitis are inflammatory conditions with a bidirectional association. This pilot study aimed to evaluate whether T2DM and glycemic control interfere in inflammatory markers profiles in gingival crevicular fluid (GCF) in periodontitis patients. MATERIALS AND METHODS: Fourteen diabetic periodontitis patients were enrolled in this study, seven with adequate glycemic control (glycated hemoglobin [HbA1c] <8.0%) (DMA + P) and seven with inadequate control (HbA1c >=8.0%) (DMI + P). Seven chronic periodontitis patients without diabetes formed the control group (P). GCF was obtained from diseased sites (probing depth >6 mm) of an entirely hemiarch, pooled and cytokines levels determined using multiplex beads immunoassay. Clinical periodontal parameters were analyzed by Mann-Whitney test and levels of cytokines by Kruskal-Wallis and Dunn's multiple comparison tests with confidence level of 95% (P < 0.05). RESULTS: Cytokines profile of GCF obtained from deep periodontal pockets presented high levels of inflammatory cytokines, and there were no statistical differences between levels of interleukin-6 (IL-6), IL-8 and tumor necrosis factor-alpha according to presence of diabetes or percentage of HbA1c among the groups, despite groups with T2DM and periodontitis exhibit higher levels of PD. CONCLUSION: Within the limitations of this study, inflammatory mediators in GCF are dependent to the local response and do not correlate with the diabetic status. PMID- 26604960 TI - Therapeutic effects of Zataria Multiflora essential oil on recurrent oral aphthous lesion. AB - BACKGROUND: Aphthous lesions are one of the most common diseases of the oral cavity. They can cause severe pain, and there is no definite treatment. The purpose of this study was to determine the efficacy of Zataria multiflora (ZM, a thyme-like plant) essential oil for the control and treatment of aphthous lesions. MATERIALS AND METHODS: This Triple blind clinical trial study was performed on 28 patients who were divided into two groups (eight men and six women in each group) and given ZM or placebo (control). The healing time, pain intensity, and aphthous zone diameter were recorded for each patient and followed for 6-month. Data were analyzed using Mann-Whitney and Friedman tests (P < 0.05). RESULTS: After 6-month of follow-up, 4 patients in the placebo group and 6 patients in the ZM group suffered from recurrent aphthous lesions. The average complete healing time and duration of burning sensation were significantly lower in the ZM group (P < 0.05). Significant difference was observed between the two groups with regard to the diameter of lesions and halo of the lesions (P < 0.05). CONCLUSION: Within the limitations of this study, ZM shortened the healing period compared to placebo. PMID- 26604961 TI - Effect of the use of snuff on the levels of interleukin-1 beta and interleukin-8 in the gingival crevicular fluid of periodontitis patients. AB - BACKGROUND: Use of smokeless tobacco in the form of moist snuff placed in the oral cavity is popular in rural India. The aim of the present cross-sectional study was to determine the effect of snuff on periodontitis by assessing interleukin (IL)-1 beta and IL-8 levels in gingival crevicular fluid. MATERIALS AND METHODS: A total of 60 subjects were selected for this study. 40 subjects presented with periodontitis, which included 20 snuff users (SP) and 20 nonsnuff users (NS). 20 periodontally healthy patients formed the controls (healthy control: HC). The clinical parameters recorded were gingival index (GI), plaque index, calculus index, bleeding on probing (BOP), probing depth (PD), recession (RC), and clinical attachment level (CAL). The IL-1 beta and IL-8 levels were assessed through enzyme-linked immunosorbent assay (Quantikine((r))). Analysis of variance (ANOVA), post-hoc Tukey's, Kruskal-Walli's ANOVA and Mann-Whitney test was used for comparison among groups and P > 0.05 was considered statistically significant. RESULTS: No significant difference was seen in levels of IL-1 beta and IL-8 between SP and NS groups (P = 0.16, 0.97). However, both the periodontitis groups (SP and NS) had increased IL-beta levels when compared to HC group (P = 0.01, 0.001). The snuff users showed significant increase in GI, BOP, RC, and CAL when compared with NS (P = 0.002, 0.001, 0.012, 0.002) whereas NS group had significant increase in PD (P = 0.003). CONCLUSION: Within the limitations of this study, use of snuff does not affect the host inflammatory response associated with periodontitis and leads to RC and increased CAL due to local irritant effect. PMID- 26604962 TI - Clinical evaluation of the effect of platelet rich plasma on the coronally advanced flap root coverage procedure. AB - BACKGROUND: Coronally advanced flap (CAF) has been shown to effectively treat gingival recession. Platelet rich plasma (PRP), containing autologous growth factors, has been shown to promote soft tissue healing. The aim of this clinical study was to determine whether the addition of an autologous PRP to a CAF when compared to a CAF alone would improve the clinical outcome for treatment of multiple gingival recessions. MATERIALS AND METHODS: Thirty patients with Miller's class I and class II buccal recession defect were randomly assigned to control (CAF alone) or test (CAF with PRP) groups. Recession depth (RD), recession width (RW), probing depth (PD), clinical attachment level (CAL), width of keratinized tissue, wound healing index, percentage of root coverage was assessed. Patients were followed at 2, 4, 12 and 16 weeks post-surgery. Statistical analysis for intra and inter group comparisons was done using Wilcoxon sign rank and Wilcoxon rank sum tests respectively. P < 0.05 denoted statistical significance. RESULTS: The differences between the test and control groups were not significant with respect to all the clinical variables. The RD at 16 weeks was significantly reduced from 2.88 +/- 0.69 to 0.76 +/- 0.24 mm in control group (P < 0.05) and from 2.95 +/- 0.43 to 0.76 +/- 0.35 mm in the test group (P < 0.05). The mean percentage of root coverage was 73.1 +/- 7.3 in the control group and 75.0 +/- 8.3 in test group (P < 0.05). The CAL gain was 3.17 +/ 0.84 mm within the control group and 3.17 +/- 0.79 mm within test group. CONCLUSION: Within the limitations of this study, PRP with CAF can provide an early healing of soft tissues, but does not provide clinically measurable improvement in the final therapeutics outcome in CAF. PMID- 26604963 TI - Improving oral health status of preschool children using motivational interviewing method. AB - BACKGROUND: Oral diseases are common chronic diseases that are affected by human health behavior. One-way to promote health behaviors can be achieved through education. The present study aims to assess the effect of an oral health education program using motivational interviewing (MI) method on oral health status of preschool children. MATERIALS AND METHODS: This study recruited 222 volunteer children and their parents from 10 elementary schools into a community trial. At baseline, plaque, gingival and decayed, missing, and filled teeth indexes were measured in the children. They were randomly allocated into test groups where they and their parents received oral health education using MI and the control group received traditional oral health education. The test group had recall and postal reminder during 6 months of the study, but there was no reminder for the control group. After 6 months, the same oral health indexes were measured. Data were analyzed using SPSS version 20 (SPSS Inc., Chicago, IL, USA) by t-test, Mann-Whitney and Wilcoxon signed ranks test. P < 0.05 was considered as significant. RESULTS: The results showed that after both oral health education programs, differences of plaque index (PI) (P = 0.000) and gingival index (P = 0.000) were significant between the two groups. The number of children with healthy gingiva and low PI were more frequent in the test group after intervention. CONCLUSION: Considering the limitations of this study, oral health status of children after education of parents using MI was observed, and it should be considered in oral health education programs. PMID- 26604964 TI - Systemic effects of fluoxetine on the amount of tooth movement, root resorption, and alveolar bone remodeling during orthodontic force application in rat. AB - BACKGROUND: Antidepressant drugs such as fluoxetine are of the most commonly used drugs among the public. These drugs may impact the regulation of bone cell functioning, and thus affect orthodontic tooth movement. The aim of this study was to determine the effect of fluoxetine on tooth movements during orthodontic treatment in rats. MATERIALS AND METHODS: In this study, 30 male rats were randomly assigned into two groups and injected with fluoxetine 10 mg/kg (experimental group) and normal saline (control group) for a period of 1-month intraperitoneally 5 times/week. Then, the rats were anesthetized and a nickel titanium closed-coil spring was placed between the left maxillary first molar and left maxillary central incisors of all samples, and then fluoxetine (experimental group) and normal saline (control group) were injected for another 3 weeks by the same method. After measuring tooth movements, rats were sacrificed, and histomorphometric analyses were conducted and the obtained data were statistically analyzed using independent t-test and the significance was set at 0.05. RESULTS: Following the fluoxetine injection, the mean amount of tooth movements in the experimental group was reduced compared to the control group, which was not statistically significant (P = 0.14). There was no significant difference between the two groups regarding bone apposition rate (P = 0.83), external root resorption rate (P = 0.1), and mean number of root resorption lacunae (P = 0.16). CONCLUSION: Within the limitations of this study, systemic use of fluoxetine may cause insignificant reduction of tooth movement rate in rats; however, this subject needs more evaluations. PMID- 26604965 TI - Management of external perforating root resorption by intentional replantation followed by Biodentine restoration. AB - Resorption of tooth structures can occur as a result of physiological, pathological, and idiopathic factors. Early diagnosis and appropriate treatment can prevent its serious complications. This case report presents surgical endodontic management of a trauma-induced perforating external root resorption, which was diagnosed with the help of cone beam computed tomography. Following root canal treatment, intentional replantation of the tooth was performed so as to expose the opening of the resorption defect to allow for complete debridement and closure. Eighteen months follow-up showed arrest of root resorption, and progressive healing of the defect. PMID- 26604966 TI - Giant sialoliths of Wharton duct: Report of two rare cases and review of literature. AB - Sialolithiasis is a common disease of the major salivary glands, characterized by the obstruction of a salivary gland or its excretory duct due to the formation of calcareous concretions. Sialoliths usually measure from 1 mm to <10 mm. They rarely measure more than 15 mm, and infrequently giant salivary gland calculi >15 mm have been reported in the literature. The submandibular gland and its duct appear to be the most susceptible sites for this disease. In this article, we report two unique cases, including a giant bilateral case, measuring 50 mm in length and 5 mm in width on the right side and one, 30 mm in length, and 5 mm in width on the left side; and another case, measuring 83 mm in length. The diagnostic and therapeutic approaches consisted of transocclusal radiography with the conservative transoral surgical technique in both cases. The follow-up showed the normal function of the relevant salivary glands. To the best of our knowledge and belief, similar cases have not been reported in the literature. PMID- 26604967 TI - Emergence of cancer stem cells in head and neck squamous cell carcinoma: A therapeutic insight with literature review: Retraction. AB - [This retracts the article on p. 239 in vol. 9, PMID: 23087725.]. PMID- 26604969 TI - Anti-Inflammatory Effect of Combination of Scutellariae Radix and Liriopis Tuber Water Extract. AB - Scutellariae Radix and Liriopis Tuber have been used to treat the inflammatory diseases in traditional Korean medicine and anti-inflammatory effect of each herb has been shown partially in several articles. However, the combined extract of these medicinal herbs (SL) has not been reported for its anti-inflammatory effects. In this study, we investigated the effects of SL on the creation of several proinflammatory mediators in RAW 264.7 cell mouse macrophages induced by Lipopolysaccharide (LPS). SL inhibited significantly the increase of NO, the release of intracellular calcium, the increase of interleukin-6 (IL-6), macrophage inflammatory proteins (MIP-1alpha, MIP-1beta, and MIP-2), and granulocyte colony-stimulating factor (G-CSF) in LPS-induced RAW 264.7 cell at the concentrations of 25, 50, and 100 MUg/mL, and SL inhibited significantly the increase of macrophage colony-stimulating factor (M-CSF) at the concentrations of 25 and 50 MUg/mL, and tumor necrosis factor (TNF) at the concentration of 25 MUg/mL. These results implicate that SL has anti-inflammatory effects by suppressing the production of various inflammatory mediators in macrophages. But SL did not inhibit significantly the increase of granulocyte macrophage colony stimulating factor (GM-CSF), leukemia inhibitory factor (LIF), and Regulated on Activation, Normal T cell Expressed and Secreted (RANTES); therefore, further study is demanded for the follow-up research to find out the possibility of SL as a preventive and therapeutic medicine for various inflammatory diseases. PMID- 26604968 TI - Fucoidans Disrupt Adherence of Helicobacter pylori to AGS Cells In Vitro. AB - Fucoidans are complex sulphated polysaccharides derived from abundant and edible marine algae. Helicobacter pylori is a stomach pathogen that persists in the hostile milieu of the human stomach unless treated with antibiotics. This study aims to provide preliminary data to determine, in vitro, if fucoidans can inhibit the growth of H. pylori and its ability to adhere to gastric epithelial cells (AGS). We analysed the activity of three different fucoidan preparations (Fucus A, Fucus B, and Undaria extracts). Bacterial growth was not arrested or inhibited by the fucoidan preparations supplemented into culture media. All fucoidans, when supplemented into tissue culture media at 1000 ug mL(-1), were toxic to AGS cells and reduced the viable cell count significantly. Fucoidan preparations at 100 ug mL(-1) were shown to significantly reduce the number of adherent H. pylori. These in vitro findings provide the basis for further studies on the clinical use of sulphated polysaccharides as complementary therapeutic agents. PMID- 26604970 TI - Beneficial Effects of Qili Qiangxin Capsule on Lung Structural Remodeling in Ischemic Heart Failure via TGF-beta1/Smad3 Pathway. AB - Qili qiangxin (QL) capsule is a traditional Chinese medicine that is widely used for the treatment of patients with chronic heart failure (CHF) of all etiologies, although the exact mechanisms of action remain unclear. CHF leads to pulmonary vascular remodelling and thickening of the alveolar-capillary barrier that may be important mechanisms in the poor clinical outcome in patients with end-stage heart failure. We examined whether QL could improve lung injury in ischemic CHF by reducing lung remodeling. Rats with myocardial infarct received QL (1.0 g/kg/day) for 4 weeks. Echocardiographic and morphometric measurements were obtained followed by echocardiography, histological staining, and immunohistochemical analysis of lung sections. CHF caused significant lung structural remodeling evidenced by collagen deposition and thickening of the alveolar septa after myocardial infarct that were greatly improved by QL. Lung weight increased after infarct with no evidence of pulmonary edema and was normalized by QL. QL also reduced lung transforming growth factor-beta1 (TGF beta1), p-Smad3, tumor necrosis factor-alpha (TNF-alpha), and Toll-like receptor 4 (TLR4) expression. Thus, QL reduces lung remodeling associated with CHF, mainly by suppressing the TGF-beta1/Smad3 signaling pathway. The mechanism may also involve inhibition of TLR4 intracellular signaling. PMID- 26604971 TI - Propolis Ethanol Extract Stimulates Cytokine and Chemokine Production through NF kappaB Activation in C2C12 Myoblasts. AB - Myoblast activation is a triggering event for muscle remodeling. We assessed the stimulatory effects of propolis, a beehive product, on myoblasts. After an 8 h treatment with 100 MUg/mL of Brazilian propolis ethanol extract, expression of various chemokines, including CCL-2 and CCL-5, and cytokines, such as IL-6, increased. This propolis-induced cytokine production appears to depend on NF kappaB activation, because the IKK inhibitor BMS-345541 repressed mRNA levels of CCL-2 by ~66%, CCL-5 by ~81%, and IL-6 by ~69% after propolis treatment. Supernatant from propolis-conditioned C2C12 cells upregulated RAW264 macrophage migration. The supernatant also stimulated RAW264 cells to produce angiogenic factors, including VEGF-A and MMP-12. Brazilian green propolis therefore causes myoblasts to secrete cytokines and chemokines, which might contribute to tissue remodeling of skeletal muscle. PMID- 26604972 TI - Protective Effects of Aqueous Extract of Luehea divaricata against Behavioral and Oxidative Changes Induced by 3-Nitropropionic Acid in Rats. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disease. Accordingly, 3-nitropropionic acid (3-NP) has been found to effectively produce HD-like symptoms. Luehea divaricata (L. divaricata), popularly known in Brazil as "acoita-cavalo," may act as a neuroprotective agent in vitro and in vivo. We evaluated the hypothesis that the aqueous extract of L. divaricata could prevent behavioral and oxidative alterations induced by 3-NP in rats. 25 adult Wistar male rats were divided into 5 groups: (1) control, (2) L. divaricata (1000 mg/kg), (3) 3-NP, (4) L. divaricata (500 mg/kg) + 3-NP, and (5) L. divaricata (1000 mg/kg) + 3-NP. Groups 2, 4, and 5 received L. divaricata via intragastric gavage daily for 10 days. Animals in groups 3, 4, and 5 received 20 mg/kg 3-NP daily from days 8-10. At day 10, parameters of locomotor activity and biochemical evaluations were performed. Indeed, rats treated with 3-NP showed decreased locomotor activity compared to controls. Additionally, 3-NP increased levels of reactive oxygen species and lipid peroxidation and decreased ratio of GSH/GSSG and acetylcholinesterase activity in cortex and/or striatum. Our results suggest that rats pretreated with L. divaricata prior to 3-NP treatment showed neuroprotective effects when compared to 3-NP treated controls, which may be due to its antioxidant properties. PMID- 26604975 TI - Human Immunodeficiency Virus-associated primary effusion lymphoma: An exceedingly rare entity in cerebrospinal fluid. AB - Primary effusion lymphoma (PEL) in patients with Human Immunodeficiency Virus (HIV) infection may involve pleural, pericardial, and peritoneal cavities. PEL involving the cerebrospinal fluid (CSF) is exceedingly rare, and to our knowledge has only been reported in two cases. We report another case of PEL diagnosed in CSF from a 61-year-old male with Acquired Immunodeficiency Syndrome that presented with neurological symptoms. Imaging studies of his brain showed leptomeningeal/periventricular enhancement, but no mass lesion. His CSF demonstrated human herpesvirus-8 positive pleomorphic lymphoplasmacytoid cells of null cell phenotype. This case highlights that albeit rare, PEL should be included in the differential diagnosis when large atypical cells are encountered in CSF of HIV-positive patients, even when such patients have no history of lymphoma. As in this case, ancillary studies are required to make an accurate diagnosis of PEL in CSF cytology. PMID- 26604973 TI - Characteristics of spinal microglia in aged and obese mice: potential contributions to impaired sensory behavior. AB - BACKGROUND: Both aging and obesity have been recognized widely as health conditions that profoundly affect individuals, families and the society. Aged and obese people often report altered pain responses while underlying mechanisms have not been fully elucidated. We aim to understand whether spinal microglia could potentially contribute to altered sensory behavior in aged and obese population. RESULTS: In this study, we monitored pain behavior in adult (6 months) and aged (17 months) mice fed with diet containing 10 % or 60 % Kcal fat. The group of young adult (3 months) mice was included as theoretical baseline control. Compared with lean adult animals, diet-induced-obese (DIO) adult, lean and DIO aged mice showed enhanced painful response to heat and cold stimuli, while exhibiting hyposensitivity to mechanical stimulation. The impact of aging and obesity on microglia properties was evidenced by an increased microglial cell density in the spinal cords, stereotypic morphological changes and polarization towards pro-inflammatory phenotype. Obesity strikingly exacerbated the effect of aging on spinal microglia. CONCLUSION: Aging/obesity altered microglia properties in the spinal cords, which can dysregulate neuron-microglia crosstalk and impair physiological pain signal transmission. The inflammatory functions of microglia have special relevance for understanding of abnormal pain behavior in aged/obese populations. PMID- 26604974 TI - Neo-epitopes emerging in the degenerative hippocampal granules of aged mice can be recognized by natural IgM auto-antibodies. AB - BACKGROUND: Degenerative granular structures appear progressively with age in the hippocampus of most mouse strains. We recently reported that these granules contain a neo-epitope that is recognised by IgM antibodies present as contaminants in many commercial antibodies obtained from mouse ascites and mouse or rabbit serum. We hypothesise that these anti-neo-epitope IgMs are in fact natural auto-antibodies that are generated spontaneously during the foetal stage without previous contact with external antigens and whose repertoire and reactivity pattern have been determined through evolution, being remarkably stable within species and even between species. FINDINGS: In the present work we found that mice from the ICR-CD1, BALB/C and SAMP8 strains have anti-neo-epitope IgM antibodies in their plasma at all ages tested and even when maintained under specific opportunistic pathogen-free conditions. Moreover, we determined that these anti-neo-epitope IgMs are also present in rabbit, goat and rat serum. We also found that, in each mouse that presented hippocampal granules, the anti-neo epitope IgMs contained in its plasma recognised the neo-epitopes in its own granules. CONCLUSIONS: This study led to the conclusion that anti-neo-epitope IgMs are widespread natural auto-antibodies contained in the plasma of mice and other species. The presence of these natural auto-antibodies not only explains why they are frequently found as contaminants in commercial antibodies, but also paves the way for a new approach to a treatment and diagnosis of pathological brain processes based on natural IgMs and neo-epitopes. PMID- 26604977 TI - The route of science: Labyrinths and algorithms - Inspirations by human papillomavirus testing and cervical cancer. PMID- 26604976 TI - The effectiveness of acetic acid wash protocol and the interpretation patterns of blood contaminated cervical cytology ThinPrep((r)) specimens. AB - BACKGROUND: ThinPrep((r)) (TP) cervical cytology, as a liquid-based method, has many benefits but also a relatively high unsatisfactory rate due to debris/lubricant contamination and the presence of blood. These contaminants clog the TP filter and prevent the deposition of adequate diagnostic cells on the slide. An acetic acid wash (AAW) protocol is often used to lyse red blood cells, before preparing the TP slides. DESIGN: From 23,291 TP cervical cytology specimens over a 4-month period, 2739 underwent AAW protocol due to initial unsatisfactory smear (UNS) with scant cellularity due to blood or being grossly bloody. Randomly selected 2739 cervical cytology specimens which did not undergo AAW from the same time period formed the control (non-AAW) group. Cytopathologic interpretations of AAW and non-AAW groups were compared using the Chi-square test. RESULTS: About 94.2% of the 2739 cases which underwent AAW were subsequently satisfactory for evaluation with interpretations of atypical squamous cells of undetermined significance (ASCUS) 4.9% (135), low-grade squamous intraepithelial lesions (LSIL) 3.7% (102), and high-grade squamous intraepithelial lesions (HSIL) 1% (28). From the 2739 control cases, 96.3% were satisfactory with ASCUS 5.5% (151), LSIL 5.1% (139), and HSIL 0.7% (19). The prevalence of ASCUS interpretations was similar (P = 0.33). Although there were 32% more HSIL interpretations in the AAW group (28 in AAW vs. 19 in non-AAW), the difference was statistically insignificant (P = 0.18). AAW category; however, had significantly fewer LSIL interpretations (P = 0.02). The percentage of UNS cases remained higher in the AAW group with statistical significance (P < 0.01). CONCLUSIONS: While AAW had a significantly higher percent of UNS interpretations, the protocol was effective in rescuing 94.2% of specimens which otherwise may have been reported unsatisfactory. This improved patient care by avoiding a repeat test. The prevalence of ASCUS and HSIL interpretations between AAW and non AAW groups were comparable. Though not statistically significant, HSIL interpretations were relatively higher in the AAW group. LSIL interpretations showed lower prevalence in AAW group. PMID- 26604978 TI - Bacterial metabolites directly modulate farnesoid X receptor activity. AB - BACKGROUND: The farnesoid X receptor (FXR), a ligand-activated transcription factor belonging to the adopted orphan receptor, plays an important role in maintaining health of the liver and intestine. In this study, we identified individual bacterial strains that directly modulated the activation of intestinal FXR. METHODS: The FXR stimulatory potential of 38 bacterial strains was determined using a stable FXR reporter system derived from intestinal epithelial cells (IEC). The induction of FXR target genes by screened FXR stimulatory bacteria was determined by real-time PCR. In addition, a high fat diet (HFD) induced obese mouse model was used to evaluate in vivo FXR stimulatory potential of bacterial metabolites screened in this study. RESULTS: A luciferase assay with the FXR reporter cell line demonstrated that the FXR-stimulatory activity of most bacterial cell samples was less than 2-fold. The culture supernatants of Bacteroides dorei and Eubacterium limosum induced FXR activity and selectively regulated FXR target expression in the FXR reporter system. Treatment with B. dorei-derived metabolites strongly induced ileal bile acid binding protein (IBABP) (8.4-fold) and organic solute transporter (OST) alpha (3.1-fold) compared with E. limosum-derived metabolites. Furthermore, administration of B. dorei derived metabolites showed significant reduction in body weight gain, and both two bacterial metabolites reduced liver weight in obese mice compared to PBS treated controls. Administration of each bacterial metabolites improved in serum levels of obesity-related metabolic biochemical markers such as ALT, AST, total cholesterol, and triglyceride. Furthermore, two bacterial metabolites enhanced the Fxr gene expression in the intestine and liver, and ileal Shp gene expression tended to be increased by treatment with the metabolites derived from B. dorei. CONCLUSIONS: B. dorei and E. limosum secreted the bioactive substances that directly stimulate FXR in the intestinal epithelial cells. Administration of these bacterial FXR-stimulatory metabolites improves the obesity phenotype including body weight gain, liver damage, lipid metabolism in DIO mice. PMID- 26604979 TI - Addressing viral resistance through vaccines. AB - Antimicrobial resistance is a serious healthcare concern affecting millions of people around the world. Antiviral resistance has been viewed as a lesser threat than antibiotic resistance, but it is important to consider approaches to address this growing issue. While vaccination is a logical strategy, and has been shown to be successful many times over, next generation viral vaccines with a specific goal of curbing antiviral resistance will need to clear several hurdles including vaccine design, evaluation and implementation. This article suggests that a new model of vaccination may need to be considered: rather than focusing on public health, this model would primarily target sectors of the population who are at high risk for complications from certain infections. PMID- 26604980 TI - Novel Method for Border Irregularity Assessment in Dermoscopic Color Images. AB - BACKGROUND: One of the most important lesion features predicting malignancy is border irregularity. Accurate assessment of irregular borders is clinically important due to significantly different occurrence in benign and malignant skin lesions. METHOD: In this research, we present a new approach for the detection of border irregularities, as one of the major parameters in a widely used diagnostic algorithm the ABCD rule of dermoscopy. The proposed work is focused on designing an efficient automatic algorithm containing the following steps: image enhancement, lesion segmentation, borderline calculation, and irregularities detection. The challenge lies in determining the exact borderline. For solving this problem we have implemented a new method based on lesion rotation and borderline division. RESULTS: The algorithm has been tested on 350 dermoscopic images and achieved accuracy of 92% indicating that the proposed computational approach captured most of the irregularities and provides reliable information for effective skin mole examination. Compared to the state of the art, we obtained improved classification results. CONCLUSIONS: The current study suggests that computer-aided system is a practical tool for dermoscopic image assessment and could be recommended for both research and clinical applications. The proposed algorithm can be applied in different fields of medical image analysis including, for example, CT and MRI images. PMID- 26604981 TI - Intra-abdominal hypertension; prevalence, incidence and outcomes in a low resource setting; a prospective observational study. AB - BACKGROUND: Intra-abdominal hypertension (IAH) is defined as a sustained elevation in intra-abdominal pressure (IAP) greater than or equal to 12 mmHg. IAH has been shown to cause organ derangements and dysfunction in the body. Objective screening of IAH is neither done early enough nor at all thus leading to significant morbidity and mortality among surgical patients. The epidemiology and outcome of IAH among surgical patients has not been documented in Uganda. The aim of this study was to determine the prevalence, incidence and outcome of intra abdominal hypertension among patients undergoing emergency laparotomy. METHODOLOGY: Prospective observational study, conducted from January to April 2015 among patients undergoing emergency laparotomy. Inclusion criteria was; age >7 yrs, scheduled for emergency laparotomy, able to lie supine. EXCLUSION CRITERIA: pregnant, failed urethral catheterization, known cardiac, renal and respiratory disorders. Consecutive sampling was used. IAP, blood pressure, heart rate, respiratory rate, Sp02, Serum creatinine, Serum urea, and Urine output were measured preoperatively and postoperatively at 0, 6, 24 and 48 h. IAH was defined as IAP > 12 mmHg on three consecutive readings 3 min apart. RESULTS: In total 192 patients were enrolled. Mean age +/- SD was 14.25 (+/-3.16) yrs in the paediatrics and 34.4(+/-13.72) yrs in the adults with male preponderance 65 and 80.7 % respectively. The prevalence of IAH was 25 % paediatrics and 17.4 % adults and the cumulative incidence after surgery was 20 % paediatrics and 21 % adults. In paediatrics, IAH was associated with mortality at 0 h postoperatively, RRR = 1:24, 95 % CI (1.371-560.178), p-value 0.048. In adults, the statistically significant outcomes associated with IAH were respiratory system dysfunction RRR1:2.783, p-value 0.023, 95 % CI (1.148-6.744) preoperatively and mortality RRR 1:2.933, p-value 0.034, 95 % CI (1.017-8.464) at 6 h, RRR 1:3.769, p-value 0.033, 95 % CI (1.113-12.760) at 24 h postoperatively. CONCLUSION: The prevalence and incidence of IAH in the paediatrics and adults group in our study population were high. IAH was associated with mortality in both adult and paediatrics groups and respiratory system dysfunction in adult group. This calls for objective monitoring of intraabdominal pressure in patients undergoing emergency laparotomy with the aim of reducing associated mortality. PMID- 26604982 TI - Massive hemothorax due to inferior phrenic artery injury after blunt trauma. AB - Injury to the inferior phrenic artery after blunt trauma is an extremely rare event, and it may occur under unanticipated conditions. This case report describes an injury to the left inferior phrenic artery caused by blunt trauma, which was complicated by massive hemothorax, and treated with transcatheter arterial embolization (TAE). An 81 year-old female hit by a car while walking at the traffic intersection was transferred to the emergency department, computed tomography scanning revealed active extravasations of the contrast medium within the retrocrural space and from branches of the internal iliac artery. The patient underwent repeated angiography, and active extravasation of contrast medium was observed between the retrocrural space and the right pleural space originating from the left inferior phrenic artery. The injured left inferior phrenic artery was successfully embolized with N-butyl cyanoacrylate, resulting in stabilization of the patient's clinical condition. Inferior phrenic artery injury should be recognized as a rare phenomenon and causative factor for hemothorax. TAE represents a safe and effective treatment for this complication and obviates the need for a thoracotomy. PMID- 26604983 TI - A behavioral science/behavioral medicine core curriculum proposal for Japanese undergraduate medical education. AB - Behavioral science and behavioral medicine have not been systematically taught to Japanese undergraduate medical students. A working group under the auspices of Japanese Society of Behavioral Medicine developed an outcome-oriented curriculum of behavioral science/behavioral medicine through three processes: identifying the curriculum contents, holding a joint symposium with related societies, and defining outcomes and proposing a learning module. The behavioral science/behavioral medicine core curriculum consists of 11 units of lectures and four units of practical study. The working group plans to improve the current core curriculum by devising formative assessment methods so that students can learn and acquire attitude as well as the skills and knowledge necessary for student-centered clinical practice. PMID- 26604984 TI - Erratum to: Do girls with depressive symptoms exhibit more physical aggression than boys? A cross sectional study in a national adolescent sample. AB - [This corrects the article DOI: 10.1186/s13034-015-0064-5.]. PMID- 26604985 TI - Neurological features of 14q24-q32 interstitial deletion: report of a new case. AB - BACKGROUND: Interstitial deletions of the long arm of chromosome 14 involving the 14q24-q32 region have been reported in less than 20 patients. Previous studies mainly attempted to delineate recognizable facial dysmorphisms; conversely, descriptions on neurological features are limited to the presence of cognitive and motor delay, but no better characterization exists. CASE PRESENTATION: In this paper we report on a patient with a de novo interstitial deletion of 5.5 Mb at 14q24.3-q31.1. The deletion encompasses 84 genes, including fourteen Mendelian genes. He presented with dysmorphic face, developmental delay, paroxysmal non epileptic events and, subsequently, epilepsy. CONCLUSIONS: The clinical and molecular evaluation of this patient and the review of the literature expand the phenotype of 14q23-q32 deletion syndrome to include paroxysmal non-epileptic events and infantile-onset focal seizures. PMID- 26604986 TI - CBP binding outside of promoters and enhancers in Drosophila melanogaster. AB - BACKGROUND: CREB-binding protein (CBP, also known as nejire) is a transcriptional co-activator that is conserved in metazoans. CBP plays an important role in embryonic development and cell differentiation and mutations in CBP can lead to various diseases in humans. In addition, CBP and the related p300 protein have successfully been used to predict enhancers in both humans and flies when they occur with monomethylation of histone H3 on lysine 4 (H3K4me1). RESULTS: Here, we compare CBP chromatin immunoprecipitation sequencing data from Drosophila S2 cells with modENCODE data and show that CBP is bound at genomic sites with a wide range of functions. As expected, we find that CBP is bound at active promoters and enhancers. In addition, we find that the strongest CBP sites in the genome are found at Polycomb response elements embedded in histone H3 lysine 27 trimethylated (H3K27me3) chromatin, where they correlate with binding of the Pho repressive complex. Interestingly, we find that CBP also binds to most insulators in the genome. At a subset of these, CBP may regulate insulating activity, measured as the ability to prevent repressive H3K27 methylation from spreading into adjacent chromatin. CONCLUSIONS: We conclude that CBP could be involved in a much wider range of functions than has previously been appreciated, including Polycomb repression and insulator activity. In addition, we discuss the possibility that a common role for CBP at all functional elements may be to regulate interactions between distant chromosomal regions and speculate that CBP is controlling higher order chromatin organization. PMID- 26604987 TI - Are clinical measures of foot posture and mobility associated with foot kinematics when walking? AB - BACKGROUND: There is uncertainty as to which foot posture measures are the most valid in terms of predicting kinematics of the foot. The aim of this study was to investigate the associations of clinical measures of static foot posture and mobility with foot kinematics during barefoot walking. METHOD: Foot posture and mobility were measured in 97 healthy adults (46 males, 51 females; mean age 24.4 +/- 6.2 years). Foot posture was assessed using the 6-item Foot Posture Index (FPI), Arch Index (AI), Normalised Navicular Height (NNHt) and Normalised Dorsal Arch Height (DAH). Foot mobility was evaluated using the Foot Mobility Magnitude (FMM) measure. Following this, a five-segment foot model was used to measure tri planar motion of the rearfoot, midfoot, medial forefoot, lateral forefoot and hallux. Peak and range of motion variables during load acceptance and midstance/propulsion phases of gait were extracted for all relative segment to segment motion calculations. Hierarchical regression analyses were conducted, adjusting for potential confounding variables. RESULTS: The degree of variance in peak and range of motion kinematic variables that was independently explained by foot posture measures was as follows: FPI 5 to 22 %, NNHt 6 to 20 %, AI 7 to 13 %, DAH 6 to 8 %, and FMM 8 %. The FPI was retained as a significant predictor across the most number of kinematic variables. However, the amount of variance explained by the FPI for individual kinematic variables did not exceed other measures. Overall, static foot posture measures were more strongly associated with kinematic variables than foot mobility measures and explained more variation in peak variables compared to range of motion variables. CONCLUSIONS: Foot posture measures can explain only a small amount of variation in foot kinematics. Static foot posture measures, and in particular the FPI, were more strongly associated with foot kinematics compared with foot mobility measures. These findings suggest that foot kinematics cannot be accurately inferred from clinical observations of foot posture alone. PMID- 26604988 TI - A Strategy for Minimizing Background Signal in Autoinductive Signal Amplification Reactions for Point-of-Need Assays. AB - Rapid point-of-need assays are used to detect abundant biomarkers. The development of in situ signal amplification reactions could extend these assays to screening and triaging of patients for trace levels of biomarkers, even in resource-limited settings. We, and others, have developed small molecule-based in situ signal amplification reactions that eventually may be useful in this context. Herein we describe a design strategy for minimizing background signal that may occur in the absence of the target analyte, thus moving this in situ signal amplification approach one step closer to practical applications. Specifically, we describe allylic ethers as privileged connectors for linking detection and propagating functionality in a small molecule signal amplification reagent. Allylic ethers minimize background reactions while still enabling controlled release of a propagating signal in order to continue the signal amplification reaction. This paper characterizes the ability of allylic ethers to provide an amplified response, and offers insight into additional design considerations that are needed before in situ small molecule-based signal amplification becomes a viable strategy for point-of-need diagnostics. PMID- 26604989 TI - Chemometric analysis of MALDI mass spectrometric images of three-dimensional cell culture systems. AB - As imaging mass spectrometry (IMS) has grown in popularity in recent years, the applications of this technique have become increasingly diverse. Currently there is a need for sophisticated data processing strategies that maximize the information gained from large IMS data sets. Traditional two-dimensional heat maps of single ions generated in IMS experiments lack analytical detail, yet manual analysis of multiple peaks across hundreds of pixels within an entire image is time-consuming, tedious and subjective. Here, various chemometric methods were used to analyze data sets obtained by matrix-assisted laser desorption/ionization (MALDI) IMS of multicellular spheroids. HT-29 colon carcinoma multicellular spheroids are an excellent in vitro model system that mimic the three dimensional morphology of tumors in vivo. These data are especially challenging to process because, while different microenvironments exist, the cells are clonal which can result in strong similarities in the mass spectral profiles within the image. In this proof-of-concept study, a combination of principal component analysis (PCA), clustering methods, and linear discriminant analysis was used to identify unique spectral features present in spatially heterogeneous locations within the image. Overall, the application of these exploratory data analysis tools allowed for the isolation and detection of proteomic changes within IMS data sets in an easy, rapid, and unsupervised manner. Furthermore, a simplified, non-mathematical theoretical introduction to the techniques is provided in addition to full command routines within the MATLAB programming environment, allowing others to easily utilize and adapt this approach. PMID- 26604990 TI - Multifunctional and Spatially Controlled Bioconjugation to Melt Coextruded Nanofibers. AB - Polymeric fibers have drawn recent interest for uses in biomedical technologies that span drug delivery, regenerative medicine, and wound-healing patches, amongst others. We have recently reported a new class of fibrous biomaterials fabricated using coextrusion and a photochemical modification procedure to introduce functional groups onto the fibers. In this report, we extend our methodology to control surface modification density, describe methods to synthesize multifunctional fibers, and provide methods to spatially control functional group modification. Several different functional fibers are reported for bioconjugation, including propargyl, alkene, alkoxyamine, and ketone modified fibers. The modification scheme allows for control over surface density and provides a handle for downstream functionalization with appropriate bioconjugation chemistries. Through the use of multiple orthogonal chemistries, fiber chemistry could be differentially controlled to append multiple modifications. Spatial control on the fiber surface was also realized, leading to reverse gradients of small molecule dyes. One application is demonstrated for pH responsive drug delivery of an anti-cancer therapeutics. Finally, the introduction of orthogonal chemical modifications onto these fibers allowed for modification with multiple cell-responsive peptides providing a substrate for osteoblast differentiation. PMID- 26604991 TI - mHealth Clinic Appointment PC Tablet: Implementation, Challenges and Solutions. AB - BACKGROUND: Patients requiring daily intravenous (IV) home parenteral nutrition (HPN) would benefit from in-home professional observation to improve self-care, to assess, detect and prevent serious complications. AIMS: The study aims are to assess the viability and utility of conducting mobile healthcare (mHealth) videoconference assessments with patients managing lifelong daily 12-hour IV nutrition infusions in their homes. The challenges and solutions to implementing mobile personal computer (PC) tablet based clinic appointments are described. METHODS: A wireless Apple iPad MiniTM mobile touch-screen tablet computer with 5 mega-pixel camera was loaned to patients. Each tablet had Polycom RealPresence software and a fourth generation (4G) mobile telecommunications data plan. These supported audio-visual mobile videoconferencing encrypted connections between health professionals in their offices and HPN patients and their family members in their homes. Patients' and professionals' evaluations of their mHealth clinic experiences are collected. RESULTS: Patients (mean age = 41.9, SD = 2.8 years) had been prescribed 12-hour home parenteral nutrition (HPN) infusions daily due short bowel disorders. Patients had been on HPN from 1 to 10 years (M=4, SD=3.6). Evaluation of clinic appointments revealed that 100% of the patients (n=45) and the professionals (n=6) indicated that they can clearly hear and easily see one another. The mHealth audio-visual interactions were highly rated by patients and family members. Professionals highly rated their ability to obtain a medical history and visual inspection of patients. Several challenges were identified and recommendations for resolutions are described. DISCUSSION: All patients and professionals highly rated the iPad mHealth clinic appointments for convenience and ease of communicating between homes and offices. An important challenge for all mHealth visits is the clinical professional's ability to make clinically accurate judgments about what they observed and heard from the patients. Following our solutions for obtaining clear visuals with the iPad can improve ability to make clinical assessments. PMID- 26604992 TI - Implementation of "social and communicative competencies" in medical education. The importance of curriculum, organisational and human resource development. AB - OBJECTIVE: With this article we want to support teachers and curriculum planners to be aware of and apply knowledge and recommendations of organisational (OD), curriculums (CD) and human resource development (HRD) ideas already in the planning phase of a project. Taking these into account can influence the process of change successfully and controlled during the introduction and establishment of curricula in the field of communication and social skills in medical education. APPROACH AND RESULTS: In the context of a multi-stage developmental process, a recommendation on CD for "Communicative and social competencies" was developed. The basis for it was made during two workshops of the GMA-committee "Communicative and social competencies" and supplemented by the available literature and the experience of communication experts. The "Undeloher Recommendation" (see attachment ) includes a compilation of recommendations and guiding questions, which is geared to the various phases of CD. Additionally, general approaches and recommendations of organisational and human resource development were integrated, which turned out to be particularly relevant in the process of CD. Thus, the "Undeloher recommendation" includes an orientation for each phase of the curriculum development process, the organisation and the staff in order to successfully implement a longitudinal curriculum. In addition to theoretical models the long-term discussion process and the personal experiences of a variety of curriculum planners and teachers have been integrated. CONCLUSION: The "Undeloher recommendation" can support the implementation processes of curricula in communication and social skills during development and realisation. Its application was reviewed in the context of workshops based on concrete examples. The participating teachers and curriculum planners assessed it to be very helpful. The recommendation goes beyond of what has been described in terms of content models in the CD so fare. In particular, the organisational and human resource development related aspects such as the formation of a steering committee and recommendations for the phase of sustainability. PMID- 26604993 TI - Virtual patients in continuing medical education and residency training: a pilot project for acceptance analysis in the framework of a residency revision course in pediatrics. AB - AIM: Virtual patients (VPs) are a one-of-a-kind e-learning resource, fostering clinical reasoning skills through clinical case examples. The combination with face-to-face teaching is important for their successful integration, which is referred to as "blended learning". So far little is known about the use of VPs in the field of continuing medical education and residency training. The pilot study presented here inquired the application of VPs in the framework of a pediatric residency revision course. METHODS: Around 200 participants of a pediatric nephology lecture ('nephrotic and nephritic syndrome in children') were offered two VPs as a wrap-up session at the revision course of the German Society for Pediatrics and Adolescent Medicine (DGKJ) 2009 in Heidelberg, Germany. Using a web-based survey form, different aspects were evaluated concerning the learning experiences with VPs, the combination with the lecture, and the use of VPs for residency training in general. RESULTS: N=40 evaluable survey forms were returned (approximately 21%). The return rate was impaired by a technical problem with the local Wi-Fi firewall. The participants perceived the work-up of the VPs as a worthwhile learning experience, with proper preparation for diagnosing and treating real patients with similar complaints. Case presentations, interactivity, and locally and timely independent repetitive practices were, in particular, pointed out. On being asked about the use of VPs in general for residency training, there was a distinct demand for more such offers. CONCLUSION: VPs may reasonably complement existing learning activities in residency training. PMID- 26604994 TI - Internationalizing Medical Education: The Special Track Curriculum 'Global Health' at Justus Liebig University Giessen. AB - Internationalizing higher education is considered to be a major goal for universities in Germany and many medical students aspire to include international experiences into their academic training. However, the exact meaning of "internationalizing" medical education is still poorly defined, just as is the possible pedagogic impact and effects. Against this background, this article presents the special track curriculum on global health (in German: Schwerpunktcurriculum Global Health, short: SPC) at Justus Liebig University Giessen, which was established in 2011 as a comprehensive teaching program to integrate international perspectives and activities systematically into the clinical years of the medical curriculum. The report of the structure, content, didactic principles and participants' evaluations of the SPC is embedded into a larger discussion of the pedagogic value of a broad and interdisciplinary perspective on "global health" in medical education, that explicitly includes attention for health inequities, social determinants of health and the cultural dimensions of medicine and health abroad and "at home" (e.g. in relation to migration). We conclude that if properly defined, the emerging field of "global health" represents a didactically meaningful approach for adding value to medical education through internationalizing the curriculum, especially in regard to themes that despite of their uncontested value are often rather weak within medical education. The concrete curricular structures, however, have always to be developed locally. The "SPC" at Giessen University Medical School is only one possible way of addressing these globally relevant issues in one particular local academic setting. PMID- 26604995 TI - Introduction of the HAM-Nat examination--applicants and students admitted to the Medical Faculty in 2012-2014. AB - BACKGROUND/AIM: In the 2012/13 winter semester, the Magdeburg Medical Faculty introduced a test of knowledge for the selection of applicants. The Hamburg Assessment Test for Medicine - Natural Sciences (HAM-Nat) comprises a multiple choice test with questions on the aspects of biology, physics, chemistry and mathematics relevant to medicine, which was specifically developed for the selection of medicine applicants. The aim is to study how the HAM-Nat influences student selection, the reasons why students decide to take the test as part of their application procedure and what expectations they have of their course of study. METHODS: The selection procedures applied at the university in 2011 (without HAM-Nat) and in 2012-2014 (with HAM-Nat) are compared. On the basis of the results of exploratory interviews, university entrants in winter semester 2013/2014 participated in a written survey on why they chose their subject and place of study and their expectations of their course of study. RESULTS: No problems were encountered in introducing the extended selection procedure that included the HAM-Nat Test. The HAM-Nat had a great influence on the selection decision. About 65% of the students admitted would not have obtained a place if the decision had been based exclusively on their Abitur grade [grade obtained in the German school-leaving examination]. On average, male applicants obtained better HAM-Nat results than female ones. The questionnaire was answered by 147 out of 191 university entrants (77%). In the case of applicants from Saxony Anhalt, the principle reasons for choosing the regional capital are its proximity, the social environment offered, good conditions for studying and the feel-good factor at the university. For the majority of applicants, however, particularly applicants from other federal states, the relatively good chances of admission in Magdeburg were the main reason. CONCLUSION: The Magdeburg Medical Faculty regards the HAM-Nat as a suitable tool for selecting applicants with outstanding knowledge of natural sciences and thus of increasing and harmonising levels of knowledge at the start of the course. Completion of the standard period of study and success in the 1st part of the German Medical Examination will be the subject of further observation of the students. The HAM-Nat, as a performance related selection procedure, is not suitable for giving active preference to natives of Saxony-Anhalt in the application procedure but their number has increased since it was introduced. Applicants primarily use the selection procedure tactically to obtain the university place they want to study medicine. Specifics relating to curricula and university profile and research areas are not critical to their choice. PMID- 26604996 TI - Use and future of wiki systems in veterinary education?--A survey of lecturers in German-speaking countries. AB - OBJECTIVES: Wiki systems are becoming increasingly important in university teaching. Not much is known about the opinion of lecturers of veterinary medicine regarding the active participation of students in teaching, their opinion on wiki systems and their motivation to use them in courses and to improve the quality of information. The objective of the present study was to evaluate how lecturers of veterinary medicine estimate learning management systems and the production of text or material by students in courses, if they rate wiki systems as an appropriate tool for teaching, if they would use wiki systems for their courses and if they are willing to improve the quality of information. METHODS: The data collection was carried out as an online survey using a five-point Likert scale. Lecturers of veterinary medicine in Germany, Austria and Switzerland were contacted (n=approx. 1700) out of which 139 completed (8.2%) the survey. RESULTS: Most lecturers use LMS and consider it to be suitable for providing course material. Half of all respondents indicated that they believe that students achieve greater learning success by developing their own learning material. In courses 23.0% of their students develop own materials. The majority of lecturers considered wiki systems as an appropriate and complementary tool for teaching (53.6%). A collection of wiki articles is seen as useful (56.6%), particularly when experts review the contents. One third of the lecturers would use wiki systems for the creation of material by students, but 82.5% have not yet used them in teaching. One third is willing to participate in the review of articles with regard to their quality. CONCLUSION: The results show that many lecturers are willing to use veterinary wiki systems and that they regard them useful for teaching. According to the opinion of the majority of lecturers, the creation of material by students can lead to greater learning success and wiki systems are suitable for this purpose. We are about to develop strategies to support the implementation of wiki systems into veterinary education and a peer review system supported by lecturers. In a further project the actual learning success provided by the active use of wiki-systems by students will be evaluated. PMID- 26604997 TI - The Questionnaire D-RECT German: Adaptation and testtheoretical properties of an instrument for evaluation of the learning climate in medical specialist training. AB - AIM: Boor et al developed and validated the questionnaire D-RECT (Dutch Residency Educational Climate Test ) to measure the clinical learning environment within the medical specialist training. In this study, a German version of this questionnaire (D-RECT German) is analyzed regarding testtheoretical properties. PROBLEM: Are the results of Boor et al replicable as a proof for validity of the questionnaire D-RECT? MATERIAL & METHODS: The study was performed as online survey using the questionnaire D-RECT German (50 items in 11 subscales). To determine item characteristics and internal consistency (Cronbach's alpha), item- and reliability analyses were performed. Furthermore, a confirmatory factor analysis was performed using a model for maximum-likelihood estimation to evaluate validity. RESULTS: This replication study on the psychometric properties of the D-RECT with 255 residents at 17 German hospitals revealed heterogeneous discriminatory power for all items and an internal consistency of Cronbach's alpha between 0.57 and 0.85. Within the confirmatory factor analysis, 6 items showed standardized regression coeffizients <0.5, two of them in the subscale "Attendings role". Furthermore, strong interdependencies (>0.7) were found between the subscales "Supervision", "Coaching" and "Attendings role". CONCLUSION: The present replication study with the D-RECT German showed structural differences with respect to factorial validity underpinning the need of further validation studies. PMID- 26604999 TI - Replication--The ugly duckling of science? PMID- 26605000 TI - Using Kepler for Tool Integration in Microarray Analysis Workflows. AB - Increasing numbers of genomic technologies are leading to massive amounts of genomic data, all of which requires complex analysis. More and more bioinformatics analysis tools are being developed by scientist to simplify these analyses. However, different pipelines have been developed using different software environments. This makes integrations of these diverse bioinformatics tools difficult. Kepler provides an open source environment to integrate these disparate packages. Using Kepler, we integrated several external tools including Bioconductor packages, AltAnalyze, a python-based open source tool, and R-based comparison tool to build an automated workflow to meta-analyze both online and local microarray data. The automated workflow connects the integrated tools seamlessly, delivers data flow between the tools smoothly, and hence improves efficiency and accuracy of complex data analyses. Our workflow exemplifies the usage of Kepler as a scientific workflow platform for bioinformatics pipelines. PMID- 26604998 TI - Desire and reality--teaching and assessing communicative competencies in undergraduate medical education in German-speaking Europe--a survey. AB - OBJECTIVES: Increasingly, communicative competencies are becoming a permanent feature of training and assessment in German-speaking medical schools (n=43; Germany, Austria, Switzerland - "D-A-CH"). In support of further curricular development of communicative competencies, the survey by the "Communicative and Social Competencies" (KusK) committee of the German Society for Medical Education (GMA) systematically appraises the scope of and form in which teaching and assessment take place. METHODS: The iterative online questionnaire, developed in cooperation with KusK, comprises 70 questions regarding instruction (n=14), assessment (n=48), local conditions (n=5), with three fields for further remarks. Per location, two to three individuals who were familiar with the respective institute's curriculum were invited to take part in the survey. RESULTS: Thirty nine medical schools (40 degree programmes) took part in the survey. Communicative competencies are taught in all of the programmes. Ten degree programmes have a longitudinal curriculum for communicative competencies; 25 programmes offer this in part. Sixteen of the 40 programmes use the Basler Consensus Statement for orientation. In over 80% of the degree programmes, communicative competencies are taught in the second and third year of studies. Almost all of the programmes work with simulated patients (n=38) and feedback (n=37). Exams are exclusively summative (n=11), exclusively formative (n=3), or both summative and formative (n=16) and usually take place in the fifth or sixth year of studies (n=22 and n=20). Apart from written examinations (n=15) and presentations (n=9), practical examinations are primarily administered (OSCE, n=31); WPA (n=8), usually with self-developed scales (OSCE, n=19). With regards to the examiners' training and the manner of results-reporting to the students, there is a high variance. CONCLUSIONS: Instruction in communicative competencies has been implemented at all 39 of the participating medical schools. For the most part, communicative competencies instruction in the D-A-C-H region takes place in small groups and is tested using the OSCE. The challenges for further curricular development lie in the expansion of feedback, the critical evaluation of appropriate assessment strategies, and in the quality assurance of exams. PMID- 26605002 TI - MODEL-BASED CLUSTERING OF LARGE NETWORKS. AB - We describe a network clustering framework, based on finite mixture models, that can be applied to discrete-valued networks with hundreds of thousands of nodes and billions of edge variables. Relative to other recent model-based clustering work for networks, we introduce a more flexible modeling framework, improve the variational-approximation estimation algorithm, discuss and implement standard error estimation via a parametric bootstrap approach, and apply these methods to much larger data sets than those seen elsewhere in the literature. The more flexible framework is achieved through introducing novel parameterizations of the model, giving varying degrees of parsimony, using exponential family models whose structure may be exploited in various theoretical and algorithmic ways. The algorithms are based on variational generalized EM algorithms, where the E-steps are augmented by a minorization-maximization (MM) idea. The bootstrapped standard error estimates are based on an efficient Monte Carlo network simulation idea. Last, we demonstrate the usefulness of the model-based clustering framework by applying it to a discrete-valued network with more than 131,000 nodes and 17 billion edge variables. PMID- 26605001 TI - Bioabsorbable polymers in cancer therapy: latest developments. AB - Cancer is a devastating disease, being responsible for 13 % of all deaths worldwide. One of the main challenges in treating cancer concerns the fact that anti-cancer drugs are not highly specific for the cancer cells and the "death" of healthy cells in the course of chemotherapy treatment is inevitable. In this sense, the use of drug delivery systems (DDS) can be seen as a powerful tool to minimize or overcome this very important issue. DDS can be designed to target specific tissues in order to mitigate side effects. Bioabsorbable polymers, due to their inherent characteristics, and because they can be synthesized in a variety of forms, are materials whose importance in the DDS for cancer therapy has risen significantly in the last years. This review intends to give an overview about the latest developments in the use of bioabsorbable polymers as DDS in cancer therapy, with special focus on nanoparticles, micelles, and implants. PMID- 26605003 TI - Weight Loss Intervention for Breast Cancer Survivors: A Systematic Review. AB - To determine the effectiveness of weight loss intervention for breast cancer survivors. From October 2012 until March 2013, Pubmed was searched for weight loss intervention trials that reported body weight or weight loss as a primary outcome. Fifteen of these studies are included in this review. Of the 15 studies included, 14 resulted in statistically significant weight loss and 10 obtained clinically meaningful weight loss of >=5 % from baseline. Evidence was provided of the feasibility of using several methods of weight loss intervention (telephone, in person, individual, group). Successful intervention used a comprehensive approach, with dietary, physical activity, and behavior modification components. Weight loss improved cardiovascular risk factors and markers of glucose homeostasis. However, there is insufficient evidence to identify the components of this intervention that led to successful weight loss, or to determine the weight loss necessary to affect biomarkers linked to breast cancer prognosis. The small number of randomized controlled trials shared several limitations, including small study sample sizes and lack of follow-up beyond 6 months. Intervention with longer follow-up revealed weight regain, showing the importance of considering strategies to promote long-term weight maintenance. Weight loss intervention for breast cancer survivors can lead to statistically significant and clinically meaningful weight loss, but the limited number of interventional studies, small sample sizes, and short duration of follow-up in many studies limit our ability to draw conclusions regarding the most efficacious weight-loss intervention after a breast cancer diagnosis. The findings to date are encouraging, but research on the effect of weight loss on breast cancer recurrence and mortality, and on prevention of weight gain for women newly diagnosed with breast cancer, is needed. PMID- 26605004 TI - Draft genome sequence of Janthinobacterium lividum strain MTR reveals its mechanism of capnophilic behavior. AB - Janthinobacterium lividum is a Gram-negative bacterium able to produce violacein, a pigment with antimicrobial and antitumor properties. Janthinobacterium lividum colonizes the skin of some amphibians and confers protection against fungal pathogens. The mechanisms underlying this association are not well understood. In order to identify the advantages for the bacterium to colonize amphibian skin we sequenced Janthinobacterium lividum strain MTR, a strain isolated from Cajon del Maipo, Chile. The strain has capnophilic behavior, with growth favored by high concentrations (5 %) of carbon dioxide. Its genome is 6,535,606 bp in size, with 5,362 coding sequences and a G + C content of 62.37 %. The presence of genes encoding for products that participate in the carbon fixation pathways (dark CAM pathways), and the entire set of genes encoding for the enzymes of the glyoxylate cycle may explain the capnophilic behavior and allow us to propose that the CO2 secreted by the skin of amphibians is the signal molecule that guides colonization by Janthinobacterium lividum. PMID- 26605005 TI - Complete genome sequence of bacteriophage P26218 infecting Rhodoferax sp. strain IMCC26218. AB - Bacteriophage P26218 is a virus that thrives in freshwater and infects Rhodoferax sp. strain IMCC26218, both of which were isolated from Soyang Lake, Korea. The bacterial host, IMCC26218, belongs to the genus Rhodoferax and is closely related to R. saidenbachensis, with 98.7 % 16S rRNA gene sequence similarity. Bacteriophage P26218 has an icosahedral head structure with a diameter of ~52 nm and short tail of ~9 nm, which is a typical morphology of the Podoviridae family. Its complete dsDNA genome was 36,315 bp with 56.7 % G + C content. This is the first genome sequence reported for a lytic phage of the genus Rhodoferax. PMID- 26605006 TI - Evidence Based Medicine and Medical Biotechnology. PMID- 26605007 TI - A Comprehensive Review of Clinical Trials on EGFR Inhibitors Such as Cetuximab and Panitumumab as Monotherapy and in Combination for Treatment of Metastatic Colorectal Cancer. AB - Metastatic colorectal cancer is the fourth most common cause of death due to cancer after those of lung, stomach, and liver. Anti epidermal growth factor receptor drugs as a targeting therapy seem to be good candidates for curing metastatic colorectal cancer. Two available anti epidermal growth factor receptor monoclonal antibodies are cetuximab and panitumumab which have been approved for metastatic colorectal cancer treatment. Through the available literature on NCBI and clinical trials, 31 clinical trials in which cetuximab or panitumumab as monotherapy or in combination with chemotherapy were used for the treatment of metastatic colorectal cancer patients in different line settings and 12 clinical trials in which bevacizumab was used for being compared with anti epidermal growth factor receptor monoclonal antibodies or chemotherapy were chosen for reviewing and comparing the results of overall survival, progression free survival and adverse effects. Cetuximab and panitumumab are well accepted for the treatment of mCRC patients at all stages in different line settings. Although cetuximab administration in metastatic colorectal cancer patients is mostly associated with better overall survival and panitumumab results in better progression free survival, to confirm the superiority of each of them in the treatment protocol of epidermal growth factor receptor monoclonal antibodies, more clinical trials with larger sample size are needed. Through current available data from clinical studies, it can be concluded that the best treatment outcome is achieved by a combination of anti epidermal growth factor receptor monoclonal antibodies with conventional chemotherapy. PMID- 26605008 TI - Preliminary Assessment of Various Additives on the Specific Reactivity of Anti- rHBsAg Monoclonal Antibodies. AB - BACKGROUND: Antibodies have a wide application in diagnosis and treatment. In order to maintain optimal stability of various functional parts of antibodies such as antigen binding sites, several approaches have been suggested. Using additives such as polysaccharides and polyols is one of the main methods in protecting antibodies against aggregation or degradation in the formulation. The aim of this study was to evaluate the protective effect of various additives on the specific reactivity of monoclonal antibodies (mAbs) against recombinant HBsAg (rHBsAg) epitopes. METHODS: To estimate the protective effect of different additives on the stability of antibody against conformational epitopes (S3 antibody) and linear epitopes (S7 and S11 antibodies) of rHBsAg, heat shock at 37 degrees C was performed in liquid and solid phases. Environmental factors were considered to be constant. The specific reactivity of antibodies was evaluated using ELISA method. The data were analyzed using SPSS software by Mann-Whitney nonparametric test with the confidence interval of 95%. RESULTS: Our results showed that 0.25 M sucrose, 0.04 M trehalose and 0.5% BSA had the most protective effect on maintaining the reactivity of mAbs (S3) against conformational epitopes of rHBsAg. Results obtained from S7 and S11 mAbs against linear characteristics showed minor differences. The most efficient protective additives were 0.04 M trehalose and 1 M sucrose. CONCLUSION: Nowadays, application of appropriate additives is important for increasing the stability of antibodies. It was concluded that sucrose, trehalose and BSA have considerable effects on the specific reactivity of anti rHBsAg mAbs during long storage. PMID- 26605009 TI - The Potential of Brittle Star Extracted Polysaccharide in Promoting Apoptosis via Intrinsic Signaling Pathway. AB - BACKGROUND: Anti-cancer potential of marine natural products such as polysaccharides represented therapeutic potential in oncological researches. In this study, total polysaccharide from brittle star [Ophiocoma erinaceus (O. erinaceus)] was extracted and chemopreventive efficacy of Persian Gulf brittle star polysaccharide was investigated in HeLa human cervical cancer cells. METHODS: To extract polysaccharide, dried brittle stars were ground and extracted mechanically. Then, detection of polysaccharide was performed by phenol sulfuric acid, Ultra Violet (UV)-sulfuric acid method and FTIR. The anti proliferative activity of isolated polysaccharide was examined by MTT assay and evaluation of cell death was done through morphological cell changes; Propodium Iodide staining, fluorescence microscopy and caspase-3, -9 enzymatic measurements. To assess its underlying mechanism, expression of Bax, Bcl-2 was evaluated. RESULTS: The polysaccharide detection methods demonstrated isolation of crude polysaccharide from Persian Gulf brittle star. The results revealed that O. erinaceus polysaccharide suppressed the proliferation of HeLa cells in a dose and time dependent manner. Morphological observation of DAPI and Acridine Orange/Propodium Iodide staining was documented by typical characteristics of apoptotic cell death. Flow cytometry analyses exhibited the accumulation of treated cells in sub-G1 region. Additionally, polysaccharide extracted induced intrinsic apoptosis via up-regulation of caspase-3, caspase-9 and Bax along with down-regulation of Bcl-2 in HeLa cells. CONCLUSION: Taken together, the apoptosis inducing effect of brittle star polysaccharide via intrinsic pathway confirmed the anti tumor potential of marine polysaccharide. Therefore, these findings proposed new insight into anti cancer properties of brittle star polysaccharide as a promising agent in cervical cancer treatment. PMID- 26605010 TI - Interferences in the Optimization of the MTT Assay for Viability Estimation of Proteus mirabilis. AB - BACKGROUND: The chromogenic assay based on MTT bioreduction was adapted to Proteus mirabilis viability estimations. We primarily intended to use the assay for the evaluation of novel antimicrobial compounds, including structures with possible permeabilizing activity. Therefore, the influence of basic permeabilizing agents like Triton X-100 and EDTA upon the MTT assay was studied. METHODS: 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) was used as a substrate for the whole-cell dehydrogenase activity estimations. The amount of formazan product was evaluated in the end-point reactions terminated with acidic isopropanol or in the continuous reactions run in the presence of low detergent concentrations. RESULTS: The generally established procedure of the end product dissolution with acidic isopropanol caused absorbance instability which strongly affected the results accuracy. The disadvantage was especially pronounced when the assay was conducted in Mueller Hinton Broth. PBS with 0.01% Triton X-100 used as the reaction medium allowed to omit the formazan dissolution step and follow the microbial MTT reduction in a continuous mode. It was observed that in Proteus mirabilis with a compromised outer membrane the assay score was artificially increased above the untreated control. CONCLUSION: The dependence of the assay results on the cell integrity might be a major drawback of the MTT assay application for the evaluation of novel antimicrobials against Gram-negative microorganisms. On the other hand, the MTT reduction could be conveniently used to assay the permeabilization degree in biotechnological protocols. PMID- 26605011 TI - Association of Transforming Growth Factor Alpha Polymorphisms with Nonsyndromic Cleft Lip and Palate in Iranian Population. AB - BACKGROUND: Cleft lip with or without cleft palate (CL/P) is one of the most common congenital anomalies and the etiology of orofacial clefts is multifactorial. Transforming growth factor alpha (TGFA) is expressed at the medial edge epithelium of fusing palatal shelves during craniofacial development. In this study, the association of two important TGFA gene polymorphisms, BamHI (rs11466297) and RsaI (rs3732248), with CL/P was evaluated in an Iranian population. METHODS: The frequencies of BamHI and RsaI variations were determined in 105 unrelated Iranian subjects with nonsyndromic CL/P and 218 control subjects using PCR and RFLP methods, and the results were compared with healthy controls. A p-value of <0.05 was considered statistically significant. RESULTS: The BamHI AC genotype was significantly higher (p=0.016) in the patients (12.4%) than the control group (5.0%). The BamHI C allele was significantly higher (p=0.001; OR=3.4, 95% CI: 1.6-7.4) in the cases (8.0%) compared with the control group (2.5%). CONCLUSION: Our study showed that there was an association between the TGFA BamHI variation and nonsyndromic CL/P in Iranian population. PMID- 26605012 TI - Association between Serum Paraoxonase 1 Activities (PONase/AREase) and L55M Polymorphism in Risk of Female Infertility. AB - BACKGROUND: The risk of developing female infertility has been associated with gene polymorphisms that decrease the activity of enzymes involved in systemic Oxidative Stress (OS). In this study, PON1 L55M polymorphism for association with susceptibility to infertility was investigated among Iranian female population. METHODS: Samples from 120 Iranian females [20 endometriosis; 30 Polycystic Ovary Syndrome (PCO); 70 controls] were analyzed and PCR-RFLP assay was used to determine the PON1 rs854560 (L55M) frequencies. The paraoxonase (PONase) and arilesterase (AREase) activities of PON1 enzyme were also assessed in order to investigate the association between serum PON1 activities, female infertility, and PON1 L55M polymorphism. RESULTS: The women with a MM genotype (p=0.021; OR=2.55) showed more possibilities of experiencing infertility than those with a LM genotype (p=0.039; OR=1.91). According to LSD test, endometriosis subjects had significantly lower paraoxonase enzyme activity compared to control group (p=0.0024; CI=95%). No significant difference was found in women with PCOS for both PONase and AREase activity in comparison with control group (p=0.469; CI=95%). Furthermore, PON1 activities were the highest in LL genotype followed by LM and then MM genotype (MM=50 years were more likely to undergo an abdominal flap compared to those <40. Conclusions. Our results indicate that sociodemographic factors affect the reconstructive procedure received. As we move forward into a new era of patient centered care, providing tailored treatment options to reconstruction patients will likely lead to higher satisfaction and better outcomes for those we serve. PMID- 26605083 TI - Associations between Wage System and Risk Factors for Musculoskeletal Disorders among Construction Workers. AB - Piece rate and performance based wage systems are common in the construction industry. Construction workers are known to have an increased risk of pain and musculoskeletal disorders (MSD). In this cross-sectional questionnaire study, we examined the association between wage system and (1) physical exertion, (2) time pressure, (3) pain, and (4) fatigue. The participants comprised 456 male Danish construction workers working on one of three different wage systems: group based performance wage, individually based performance wage, and time based wage system. The statistical analyses indicated differences between the wage systems in relation to physical exertion (etap = 0.05) and time pressure (etap = 0.03) but not to pain or fatigue. Workers on group based performance wage scored higher (i.e., worse) than workers on individual performance based wage and workers with an hourly/monthly wage. In conclusion, group performance based wage was associated with higher levels of physical exertion and time pressure. Accordingly, group performance based wage can be viewed as a factor that has the potential to complicate prevention of MSD among construction workers. Since performance based wage systems are common in many countries across the world, more attention should be paid to the health effects of these types of payment. PMID- 26605084 TI - Effects of Symptom Perception Interventions on Trigger Identification and Quality of Life in Children with Asthma. AB - BACKGROUND: Management of individual triggers is suboptimal in practice. In this project, we investigated the impact of symptom perception interventions on asthma trigger identification and self-reported asthma quality of life. METHODS: Children with asthma (n=227) participated in three asthma education sessions and then were randomized first to one of three home monitoring conditions (symptom monitoring and peak flow training with feedback, peak flow training without feedback, or no peak flow training) and then subsequently to one of three resistive load discrimination training conditions (signal detection training with feedback, signal detection training without feedback, or no training). Triggers were reported at enrollment, following home monitoring, and following discrimination training; quality of life was measured after home monitoring and after resistive load testing. RESULTS: Symptom perception interventions resulted in increases in reported triggers, which increased reliably as a function of home monitoring, and increased further in participants who completed discrimination training with feedback. Increases in the number of reported asthma triggers were associated with decreases in quality of life. DISCUSSION: Patients may benefit from strategies that make trigger-symptom contingencies clear. Complementary strategies are needed to address changes in the perceived burden of asthma which comes from awareness of new asthma triggers. PMID- 26605085 TI - Parenting Behavior in Mothers of Preschool Children with ASD: Development of a Self-Report Questionnaire. AB - Parents of young children with autism spectrum disorder (ASD) encounter many daily challenges and often experience much stress. However, little research exists about parenting behavior among these parents. With this study, we aim to address this gap. We examined the structure and internal consistency of a questionnaire intended to measure parenting behavior among mothers of young children with ASD. Furthermore, we compared parenting behavior among mothers of young children with and without ASD between two and six years old. Factor analyses resulted in a factor solution with seven subscales of parenting behavior. Two additional subscales especially relevant for parenting preschoolers with ASD were also considered. Analyses of covariance, controlling for gender and age, showed significantly higher scores for Discipline and Stimulating the Development in the control group in comparison with the ASD group. These findings suggest that mothers of preschoolers with ASD are still trying to find strategies to guide and stimulate their child's behavior and development effectively. PMID- 26605087 TI - Oral Antineoplastic Agents: Assessing the Delay in Care. AB - The study was undertaken to determine the length of time between when a prescription for an oral antineoplastic agent is written by the provider and when the medication is received by the patient and to identify risk factors that significantly increase time to medication receipt. First-time fill prescriptions for oral antineoplastic agents were identified. The date the prescription was written and received by the patient was determined. A retrospective review was completed to gather additional information, including prescribed medication, indication, insurance coverage, patient assistance program use, dispensing pharmacy, and prior authorization requirements. The data was analyzed through multivariate statistical analysis and used to identify risk factors that may significantly increase the time to medication receipt. A total of 58 patients were included in the study. A median of 8 days elapsed between when the medication was prescribed and when it was received by the patient. Medication prescribed, absence of a Risk Evaluation Mitigation Strategies (REMS) program, and insurance type are factors that increased time to medication receipt. An understanding of the median time involved, as well as factors affecting the time to delivery of prescriptions, will help healthcare providers better plan and prepare for the use of oral antineoplastic agents. PMID- 26605086 TI - About Face: Evaluating and Managing Tactile Impairment at the Time of Autism Diagnosis. AB - Evaluation for sensory impairment is a routine part of autism diagnosis. Sensory impairment of hearing, vision, or touch results in developmental delay and must be addressed before delay can resolve. Recent studies confirm that tactile impairment is present in autism and can be effectively treated with a tactile stimulation protocol. The research suggests a change in management at the time of autism diagnosis to include evaluation and treatment of tactile impairment. Here we validate screening and management tool for tactile impairment, the Autism Touch and Self-Regulation Checklist, in 404 typical and autistic preschool children. The tool assesses tactile impairment by location and severity. Autistic children were distinguished by mixed pain and numbness on multiple areas including the face and mouth (F = 412.1 (1,402);p < .000). Oral-facial tactile impairment interferes with the tactile stimulus to orienting. We hypothesized that oral-facial tactile impairment and difficulty orienting are predictive of ASD and that severity of tactile impairment is predictive of severity of ASD. Questions evaluating oral-facial and orienting responses correctly predicted 91% of the autism group. Severity of tactile impairment correctly predicted 81% of mild versus severe ASD. Results underscore the importance of evaluating and treating tactile impairment at the time of autism diagnosis. PMID- 26605088 TI - Influence of Abdominal Obesity on the Lipid-Lipoprotein Profile in Apoprotein E2/4 Carriers: The Effect of an Apparent Duality. AB - Background. Apolipoprotein (Apo) E plays a key role in the handling of lipoprotein particles with ApoE2 and ApoE4 frequently having opposite effects compared to ApoE3. Some individuals simultaneously carry both E2 and E4 alleles. The impact of the ApoE2/4 genotype on lipid concentrations and its consequences on health remain poorly documented. Objective. This study compared the lipid profile between ApoE2/4 carriers and other ApoE genotypes in relation to the waist circumference. Methods. Cholesterol, triglyceride (TG), and ApoB concentrations were measured among 2,680 Caucasians. Multivariate logistic regression models were used to estimate the contribution of ApoE2/4 to various dyslipidemic profiles associated with abdominal obesity. Results. In presence of abdominal obesity, the lipid profile was as deteriorated in ApoE2/4 carriers as in carriers of other ApoE genotypes. There was a more pronounced effect on TG rich lipoproteins, particularly in ApoE2/2 (a feature of type III dysbetalipoproteinemia), and non-high-density lipoprotein (HDL) cholesterol in ApoE4/4. Compared to ApoE2/2, ApoE2/4 carriers presented lower very-low-density lipoprotein (VLDL) cholesterol concentrations and VLDL-cholesterol/TG ratios, with or without obesity, and higher low-density lipoprotein (LDL) cholesterol concentrations. Conclusion. In presence of abdominal obesity, the influence of the ApoE2 allele could be less pronounced than that of ApoE4 among ApoE2/4 individuals. PMID- 26605089 TI - Race/Ethnicity, Primary Language, and Income Are Not Demographic Drivers of Mortality in Breast Cancer Patients at a Diverse Safety Net Academic Medical Center. AB - Objective. To examine the impact of patient demographics on mortality in breast cancer patients receiving care at a safety net academic medical center. Patients and Methods. 1128 patients were diagnosed with breast cancer at our institution between August 2004 and October 2011. Patient demographics were determined as follows: race/ethnicity, primary language, insurance type, age at diagnosis, marital status, income (determined by zip code), and AJCC tumor stage. Multivariate logistic regression analysis was performed to identify factors related to mortality at the end of follow-up in March 2012. Results. There was no significant difference in mortality by race/ethnicity, primary language, insurance type, or income in the multivariate adjusted model. An increased mortality was observed in patients who were single (OR = 2.36, CI = 1.28-4.37, p = 0.006), age > 70 years (OR = 3.88, CI = 1.13-11.48, p = 0.014), and AJCC stage IV (OR = 171.81, CI = 59.99-492.06, p < 0.0001). Conclusions. In this retrospective study, breast cancer patients who were single, presented at a later stage, or were older had increased incidence of mortality. Unlike other large scale studies, non-White race, non-English primary language, low income, or Medicaid insurance did not result in worse outcomes. PMID- 26605091 TI - Nosocomial Methemoglobinemia Resulting from Self-Administration of Benzocaine Spray. AB - Methemoglobinemia is life-threatening and bears pathognomonic signs difficult to diagnose in real time. Local anesthetics are widely used and are known for eliciting this condition. We report a case of methemoglobinemia secondary to self administered use of benzocaine spray. A 27-year-old woman was found to be in respiratory distress during postoperative recovery. After desaturation persisted, arterial blood gas yielded a methemoglobin level of 47%. The patient was successfully treated with intravenous methylene blue. Review of the events revealed self-administered doses of benzocaine spray to alleviate discomfort from a nasogastric tube. We review this case in detail in addition to discussing methemoglobinemia and its relevant biochemistry, pathophysiology, clinical presentation, and medical management. Given the recognized risk of methemoglobinemia associated with benzocaine use, we recommend its removal from the market in favor of safer alternatives. PMID- 26605090 TI - Alterations of the Ceramide Metabolism in the Peri-Infarct Cortex Are Independent of the Sphingomyelinase Pathway and Not Influenced by the Acid Sphingomyelinase Inhibitor Fluoxetine. AB - Ceramides induce important intracellular signaling pathways, modulating proliferation, migration, apoptosis, and inflammation. However, the relevance of the ceramide metabolism in the reconvalescence phase after stroke is unclear. Besides its well-known property as a selective serotonin reuptake inhibitor, fluoxetine has been reported to inhibit the acid sphingomyelinase (ASM), a key regulator of ceramide levels which derives ceramide from sphingomyelin. Furthermore, fluoxetine has shown therapeutic potential in a randomized controlled rehabilitation trial in stroke patients. Our aim was to investigate and modulate ceramide concentrations in the peri-infarct cortex, whose morphological and functional properties correlate with long-term functional outcome in stroke. We show that certain ceramide species are modulated after experimental stroke and that these changes do not result from alterations of ASM activity, but rather from nontranscriptional induction of the ceramide de novo pathway. Unexpectedly, although reducing lesion size, fluoxetine did not improve functional outcome in our model and had no significant influence on ASM activity or the concentration of ceramides. The ceramide metabolism could emerge as a potential therapeutic target in the reconvalescence phase after stroke, as its accumulation in the peri-infarct cortex potentially influences membrane functions as well as signaling events in the tissue essential for neurological recovery. PMID- 26605092 TI - Serratia marcescens: A Rare Cause of Recurrent Implantable Cardioverter Defibrillator Site Infection. AB - We present a unique case of a patient who experienced recurrent infections of his implantable cardioverter defibrillator (ICD) site with the bacterium Serratia marcescens. This report highlights the virulence of this bacterium, its resistance to antibiotic therapy, and its ability to remain latent for prolonged periods between episodes of sepsis. It also demonstrates the merits of reimplanting devices at different sites in the context of Serratia marcescens infection. PMID- 26605093 TI - Cardiac and Pulmonary Ultrasound for Diagnosing TRALI. AB - Unexpected acute respiratory failure after anesthesia is a diagnostic challenge: residual neuromuscular blockade, bronchial hyperresponsiveness, laryngospasm, atelectasis, aspiration pneumonitis, and other more uncommon causes should be taken into account at diagnosis. Lung ultrasound and echocardiography are diagnostic tools that would provide the differential diagnosis. We report a suspected case of a transfusion related acute lung injury (TRALI) following administration of platelets. The usefulness of lung and cardiac ultrasound is discussed to facilitate the challenging diagnosis of the acute early postoperative respiratory failure. PMID- 26605094 TI - A Case of Simultaneous Unilateral Anterior and Posterior Stafne Bone Defects. AB - Stafne bone defects (SBDs) are asymptomatic mandibular lingual bone depressions mainly caused by soft tissue inclusions. The most common form of SBDs is posterior; the anterior variant of SBD is relatively uncommon. Although posterior SBD is easily diagnosed by the unique location on radiography, anterior SBD is sometimes misdiagnosed and confused with other pathological entities owing to the location. We report herein a case of simultaneous unilateral anterior and posterior SBDs. In the present case, definitive diagnosis for the anterior mandibular cavity was unclear, as in reported cases. Surgical exploration was thus performed for the lesion in the anterior mandibular cavity. Pathologic examination of the removed tissue showed salivary gland with chronic inflammation. Postoperatively, no functional disturbance has been observed. Management of the posterior SBD was conservative, with radiographic follow-up. To the best of our knowledge, this represents the first report of simultaneous unilateral anterior and posterior SBDs. PMID- 26605095 TI - Vibrio alginolyticus Associated Chronic Myringitis Acquired in Mediterranean Waters of Turkey. AB - Vibrio alginolyticus was originally classified as biotype 2 of Vibrio parahaemolyticus. Most clinical isolates are recovered from superficial wounds or the external ear infections. V. alginolyticus is acknowledged to be nearly nonpathogenic in humans. The reason for presence of V. alginolyticus's virulence is uncertain. We describe a chronic myringitis case in a 47-year-old female due to V. alginolyticus. According to her anamnesis, it was detected that she had sea bathing history in Mugla Coast in Turkey. Pure isolation of V. alginolyticus was obtained from external auditory canal's culture. Investigation and antimicrobial susceptibility of the isolate were performed by the automatized BD Phoenix system and Kirby-Bauer disk diffusion method, respectively. The bacteria were sensitive to all antibiotics. This case was presented to pay attention to Vibrio alginolyticus infections. PMID- 26605096 TI - Enterococcus faecium Mediastinitis Complicated by Disseminated Candida parapsilosis Infection after Congenital Heart Surgery in a 4-Week-Old Baby. AB - Background. Cardiac surgery offers multiple treatment options for children with congenital heart defects. However, infectious complications still remain a major cause of morbidity and mortality in these patients. Mediastinitis is a detrimental complication in children undergoing cardiac surgery. The risk of mediastinitis after delayed sternal closure is up to 10%. Case Presentation. We report a case of Enterococcus faecium mediastinitis in a 4-week-old female baby on extracorporeal membrane oxygenation after Norwood procedure. Although repeated antibiotic irrigation, debridement, and aggressive antibiotic treatment were started early, the pulmonary situation deteriorated. Candida parapsilosis was isolated from bronchoalveolar lavage after pulmonary hemorrhage. Disseminated C. parapsilosis infection with pulmonary involvement was treated with liposomal amphotericin B. Subsequently, inflammatory markers increased again and eventually C. parapsilosis was isolated from the central venous catheter. Conclusion. Children undergoing delayed sternal closure have a higher risk of mediastinitis. Therefore, antibiotic prophylaxis, for example, for soft tissue infection seems justified. However, long-term antibiotic treatment is a risk factor for fungal superinfection. Antifungal treatment of disseminated C. parapsilosis infection may fail in PICU patients with nonbiological material in place due to capacity of this species to form biofilms on medical devices. Immediate removal of central venous catheters and other nonbiological material is life-saving in these patients. PMID- 26605097 TI - Central Pontine Myelinolysis with Minimal Hyponatremia in the Setting of AIDS. AB - Central pontine myelinolysis (CPM) is classically attributed to overly rapid correction of profound hyponatremia. However, there are case reports of this disease in the setting of normal serum sodium or minimal hyponatremia. These cases have been hypothesized to be secondary to other metabolic disturbances such as hyperglycemia or hypophosphatemia. Eunatremic CPM has also been described in patients with advanced acquired immune deficiency syndrome (AIDS). The mortality risk in this special population is significantly higher than those with hyponatremia-associated CPM, but the mechanisms are unclear. We discuss a case of a man with AIDS who developed CPM with minimal hyponatremia and no other metabolic disturbances. Common variables within this population, such as hypoalbuminemia and lymphoma, are discussed as potential factors contributing to the pathophysiology. Reporting these atypical cases is crucial to our understanding of how to prevent future cases. PMID- 26605098 TI - Prenatal Diagnosis of WAGR Syndrome. AB - Wilm's tumour, aniridia, genitourinary abnormalities, and mental retardation (WAGR) syndrome is a rare genetic disorder with an estimated prevalence of 1 in 500,000 to 1 million. It is a contiguous gene syndrome due to deletion at chromosome 11p13 in a region containing WT1 and PAX6 genes. Children with WAGR syndrome mostly present in the newborn/infancy period with sporadic aniridia. The genotypic defects in WAGR syndrome have been well established. However, antenatal ultrasonographic presentation of this syndrome has never been reported. Prenatal diagnosis of this condition is possible in some cases with careful ultrasound examination of classical and nonclassical manifestations of this syndrome. The key point for this rare diagnosis was the decision to perform chromosomal microarray analysis after antenatal diagnosis of absent corpus callosum and absent cavum septum pellucidum, as this finding mandates search for potentially associated genetic disorders. We report a case of WAGR syndrome diagnosed prenatally at 29-week gestation. The diagnosis of the anomaly was based on two- and three-dimensional ultrasound as well as fetal MRI scan and microarray analysis. The ultrasonographic findings included borderline ventriculomegaly, absent corpus callosum, and absent cavum septum pellucidum. Cytogenetic results from the amniotic fluid confirmed WAGR syndrome. Parental karyotype was normal, with no evidence of copy number change, deletion, or rearrangement of this region of chromosome 11. PMID- 26605099 TI - Short-Term Isoflavone Intervention in the Treatment of Severe Vasomotor Symptoms after Surgical Menopause: A Case Report and Literature Review. AB - Isoflavones are soy phytoestrogens that potentially exert various favorable effects in postmenopausal women, for example, alleviating vasomotor episodes, attenuating bone loss, and stimulating vaginal epithelial maturation. There has, however, been lack of consensus regarding those therapeutic effects. Most clinical studies of isoflavones have been conducted with women who had undergone natural menopause, but not those who had undergone surgical menopause. This study reports on a 51-year-old woman who presented with severe vasomotor episodes after undergoing a hysterectomy and a bilateral oophorectomy due to hypermenorrhea secondary to myoma uteri. She refused hormone therapy due to fear of adverse drug reactions so was treated with oral soy isoflavones (two capsules twice daily, equivalent to at least 100 mg daily dose) for 8 weeks. The number and severity of hot flushes and her menopause-specific quality of life dramatically improved from baseline values. The serum bone resorption marker (beta C-telopeptide) decreased markedly, while vaginal epithelial maturation improved slightly, suggesting the potential of isoflavones in attenuating bone loss and stimulating vaginal maturation. The intervention did not adversely affect the hormonal profile (FSH, LH, and estradiol) and liver or renal functions. Thus, isoflavones could be an option for women experiencing severe vasomotor episodes after surgical menopause. PMID- 26605100 TI - A Rare Case of Paclitaxel and/or Trastuzumab Induced Acute Hepatic Necrosis. AB - Paclitaxel induced mild derangement of liver functions including bilirubin, alkaline phosphatase, and AST has been infrequently noticed in clinical trials. Contrary to Paclitaxel, hepatocellular injury, hepatitis, and liver tenderness are common laboratory and clinical findings with Trastuzumab. However, hepatic failure/necrosis secondary to Paclitaxel or Trastuzumab has never been reported in literature. A 62-year-old lady, previously healthy, was treated with adjuvant therapy for left breast stage II, high grade invasive ductal carcinoma which was node negative, oestrogen receptor negative, progesterone receptor positive, and HER2 receptor positive. After modified radical mastectomy and axillary clearance, she finished four cycles of Doxorubicin/Cyclophosphamide chemotherapy and then commenced on Paclitaxel/Trastuzumab combination chemotherapy. Within twelve hours of first dose of Paclitaxel/Trastuzumab therapy, patient required hospital admission for acute onset respiratory failure. Patient died within 36 hours of therapy and autopsy was suggestive of acute hepatic necrosis without any other significant findings. Detailed investigations were not carried out as event was quick with rapid deterioration. There was no history of prior liver pathology/injury and preliminary investigations for major organ involvement were unremarkable. As per our knowledge, Paclitaxel and/or Trastuzumab induced acute hepatic necrosis has never been reported in literature before, hence difficult to predict. PMID- 26605101 TI - Aggressive Angiomyxoma of the Bladder Neck Requiring Local Excision and Mitrofanoff Formation. AB - Aggressive angiomyxoma is a rare mesenchymal tumour predominantly affecting the female pelvis and perineum but has also been described in males. This tumour can often present a diagnostic challenge and has a propensity for local recurrence after surgical excision. We present an unusual case of aggressive angiomyxoma arising from the bladder of a female patient which required local excision and Mitrofanoff formation. PMID- 26605102 TI - Knowledge and Practice of Clinicians regarding Syndromic Management of Sexually Transmitted Infections in Public Health Facilities of Gamo Gofa Zone, South Ethiopia. AB - Background. Sexually Transmitted Infections (STIs) are the leading causes of morbidity among young adults. This study assessed the knowledge and practice of clinicians regarding syndromic management of STIs in public health facilities of Gamo Gofa Zone, Southern Ethiopia. Methods. Facility based cross-sectional study with mixed methods of data collection was conducted in public health facilities of Gamo Gofa Zone. The study included 250 clinicians and 12 health facilities, 26 mystery clients were hired, and 120 STI patient cards were reviewed. Data was entered in EPI info version 7.0.1 and analyzed by SPSS version 20. Results. Of the participated clinicians, 32 (12.8%) were trained on syndromic management of STIs. Highest knowledge of clinicians was for urethral discharge (27.2%). Professional category of clinicians and type of health facility (AOR = 0.194; 95% CI = 0.092, 0.412) were determinants of urethral discharge knowledge. Of the cards reviewed, only in 8.3% of cards and 19.23% of mystery clients did the clinicians correctly follow the guideline. Conclusion. Knowledge and practice of clinicians regarding syndromic management of STIs in study area were poor. Efforts should be made to increase the knowledge of clinicians by providing training on syndromic management of STIs and supportive supervision should be regular. PMID- 26605104 TI - Assessment of Trace Metals Concentration in Tree Barks as Indicator of Atmospheric Pollution within Ibadan City, South-West, Nigeria. AB - Tree bark species were randomly collected from 65 sites having different anthropogenic activities, such as industrial, high traffic commercial, residential high and residential low traffic volume areas of Ibadan City, Nigeria. Levels of Cd, Cu, Pb, Zn, Co, and Cr of the dry-ashed bark samples were determined by AAS. The mean metal concentrations (mg kg(-1)) in samples from industrial zone were found as Pb: 3.67 +/- 1.97, Cd: 0.10 +/- 0.07, Zn: 30.96 +/- 32.05, Cu: 7.29 +/- 5.17, Co: 0.91 +/- 0.58, and Cr: 2.61 +/- 1.84. The trend of mean trace metal concentrations at high traffic commercial zone follows the order: Zn > Pb > Cu > Cr > Co > Cd. Residential high traffic and low traffic zones revealed the same trend as Cd < Co < Cr < Pb < Cu < Zn. Relatively strong positive correlation between the heavy metals at rho < 0.05, such as Zn versus Cu (r = 0.79) and Co versus Cu (r = 0.77), was observed. The results of the study suggest that tree bark samples could potentially serve as bioindicators for Cu, Pb, Zn, Cr, and possibly Co and Cd. Furthermore, interspecies variation of heavy metal concentrations in plants barks is recommended. PMID- 26605103 TI - Association between Community Ambulation Walking Patterns and Cognitive Function in Patients with Parkinson's Disease: Further Insights into Motor-Cognitive Links. AB - Background. Cognitive function is generally evaluated based on testing in the clinic, but this may not always reflect real-life function. We tested whether parameters derived from long-term, continuous monitoring of gait are associated with cognitive function in patients with Parkinson's disease (PD). Methods. 107 patients with PD (age: 64.9 +/- 9.3 yrs; UPDRS motor sum "off": 40.4 +/- 13.2; 25.23% women) wore a 3D accelerometer on their lower back for 3 days. Computerized measures of global cognitive function, executive function, attention, and nonverbal memory were assessed. Three-day acceleration derived measures included cadence, variability, bilateral coordination, and dynamic postural control. Associations between the acceleration derived measures and cognitive function were determined. Results. Linear regression showed associations between vertical gait variability and cadence and between global cognitive score, attention, and executive function (p <= 0.048). Dynamic postural control was associated with global cognitive score and attention (p <= 0.027). Nonverbal memory was not associated with the acceleration-derived measures. Conclusions. These findings suggest that metrics derived from a 3-day worn body fixed sensor reflect cognitive function, further supporting the idea that the gait pattern may be altered as cognition declines and that gait provides a window into cognitive function in patients with PD. PMID- 26605105 TI - Stability-Indicating HPLC Assay for Determination of Idebenone in Pharmaceutical Forms. AB - A stability-indicating method was validated for the determination in pharmaceutical forms of idebenone a coenzyme Q10-like compound. The assay was achieved by liquid chromatography analysis using a reversed-phase C18 column and a detector set at 480 nm. The optimized mobile phase consisted of isocratic flow rate at 1.0 mL/min for 3 min with methanol. The linearity of the assay was demonstrated in the range of 3.0 to 8.0 mg/mL with a correlation coefficient r (2) > 0.998. The limits of detection and quantification were 0.03 and 0.05 mg/mL, respectively. The intraday and interday precisions were less than 1.0%. Accuracy of the method ranged from 98.6 to 101.5% with RSD < 0.6%. Specificity of the assay showed no interference from tablets components and breakdown products formed by alkaline, acidic, oxidative, sunlight, and high temperature conditions. This method allows accurate and reliable determination of idebenone for drug stability assay in pharmaceutical studies. PMID- 26605106 TI - Biodegradation of PAHs by Burkholderia sp. VITRSB1 Isolated from Marine Sediments. AB - The polycyclic aromatic hydrocarbons (PAHs) pollution to the environment is a major threat to the living organisms, and hence the degradation of these PAHs is necessary. Studies on PAHs degrading bacteria have focussed on terrestrial microbes and the potential of marine derived microbes is undermined. Herein we report the isolation and characterization of PAHs degrading Burkholderia sp. from lagoon sediments collected at the Southern coast of India. The strain was Gram negative, rod-shaped, motile, and ~2-5 MUm in length. Based on the phylogenetic data the strain was identified as Burkholderia and designated as VITRSB1. Initial PAHs degradation ability of the strain was assessed using basal salt medium supplemented with diesel, kerosene, toluene, aniline, naphthalene, and phenol. The strain was found to be effectively degrading kerosene, diesel, toluene, and aniline even at higher concentration (1%). However, naphthalene and aniline were degraded only at lower concentration (0.1%) and phenol, camphor, and DAP inhibited the growth of the strain. Furthermore, the degraded end products of the PAHs were determined using FTIR. Notably, none of the end products were found to be toxic to the biosphere. Our results indicate that the isolated Burkholderia sp. could be a prospective candidate for the effective degradation of selective PAHs. PMID- 26605107 TI - Incidence and management of cerebrospinal fluid fistulas in 336 multilevel laminectomies with noninstrumented fusions. AB - BACKGROUND: The incidence (e.g., 3-27%) and the types of cerebrospinal fluid (CSF) fistulas occurring during multilevel lumbar laminectomy with noninstrumented spinal fusions varies. METHODS: From 2000 to 2015, we retrospectively evaluated the incidence/etiologies of CSF fistulas occurring for 336 patients undergoing average 4.7 laminectomies with average 1.4 level noninstrumented fusions over a 15 year period. The varied etiologies of CSF leaks included; ossification of the yellow ligament (OYL) extending through the dura, postoperative surgical scar, iatrogenic traumatic leak, epidural steroid injections (ESI), resection of synovial cysts, and the removal of intradural tumors. Techniques for primary repairs included combinations of; 7-0 Gore-Tex (Newark, Delaware, USA) sutures, micro-dural staples, muscle patch/other (e.g., bovine pericardial) grafts, fibrin sealants/glues (e.g., Tisseel; Baxter International Inc., Westlake Village, CA, USA), and Duragen (Integra LifeSciences, Hawthorne, NY, USA) including both the thin and suturable types. RESULTS: The etiologies of CSF fistulas in descending order included: Epidural spinal injections (ESI) (7 patients), synovial cysts (6 patients), OYL (5 patients), and equally for postoperative scar and intradural tumors (3 patients). CSF fistulas occurred in 24 (7.14%) of 336 patients; this frequency was reduced to 4.2% when ESI and intradural tumors were excluded. CONCLUSION: CSF fistulas occurred in 7.14% of 336 patients undergoing average 4.7 multilevel laminectomies with average 1.4 level noninstrumented fusions attributed to a lumbar stenosis with mild/moderate instability. The dural repair addressed seven prior ESI, six synovial cysts, five OYL, and operative scarring and intradural tumors (three apiece). Knowing the pathologies contributing to CSF fistulas should help the surgeon to better anticipate and treat these fistulas. PMID- 26605108 TI - Prophylactic inferior vena cava filter placement prior to lumbar surgery in morbidly obese patients: Two-case study and literature review. AB - BACKGROUND: Preoperative "prophylactic" placement of inferior vena cava (IVC) filters in morbidly obese patients (e.g., body mass index [BMI] >40 or BMI over 35 with hypertension/diabetes) undergoing multilevel decompressive lumbar laminectomies may reduce the risk of postoperative pulmonary embolism (PE), and death. METHODS: Two patients, ages 69 and 68, with morbid obesity (BMI's of 40.4 and 37.5 both with hypertension and diabetes), received prophylactic IVC filters prior to L1-S1 laminectomies. Intraoperatively and postoperatively, both received alternating compression stocking prophylaxis, and received subcutaneous heparin 5000 U q12 h 48 h after surgery until discharge; none developed deep venous thrombosis (DVT) or PE, and both filters were uneventfully removed within 3 postoperative months. RESULTS: The spinal surgical literature largely supports the placement of IVC filters for major risk factors; obesity (BMI >40), a history of DVT/PE, cancer, fusions, hypercoagulation syndromes, pulmonary/circulatory disorders, preoperative/postoperative immobility, staged procedures (five spinal levels), combined anterior-posterior surgery, iliocaval manipulation, age >80, and prolonged surgery (e.g., >261 min vs. >8 h). Although the safety and efficacy of prophylactic IVC filters for spine surgery in patients with morbidly obesity are well substantiated, those for bariatric patients are less clear. CONCLUSIONS: Prophylactic IVC filters were successfully placed/retrieved in 2 morbidly obese patients, ages 68 and 69, undergoing L1-S1 lumbar decompressions. Although the spine surgery literature documents the safety/efficacy of prophylactic IVC filters in patients with morbid obesity, the bariatric literature still has major concerns. PMID- 26605109 TI - Timing and prognosis of surgery for spinal epidural abscess: A review. AB - BACKGROUND: The nonsurgical versus surgical management of spinal epidural abscesses (SEAs) remains controversial. Even with the best preoperative screening for multiple risk factors, high nonoperative failure rates are attended by considerable morbidity (e.g., irreversible paralysis) and mortality. Therefore, the focus remains on early surgery. METHODS: Most papers promote early recognition of the clinical triad (e.g., fever [50%], spinal pain [92-100%], and neurological deficits [47%]) for SEA. They also identify SEA-related risk factors for choosing nonsurgical versus surgical approaches; advanced age (>65 or 80), diabetes (15-30%), cancer, intravenous drug abuse (25%), smoking (23%), elevated white blood cell count (>12.5), high C-reactive protein >115, positive blood cultures, magnetic resonance imaging/computed tomographic documented cord compression, and significant neurological deficits (e.g., 19-45%). RESULTS: Surgical options include: decompressions, open versus minimally invasive biopsy/culture/irrigation, or fusions. Up to 75% of SEA involve the thoracolumbar spine, and 50% are located ventrally. Wound cultures are positive in up to 78.8% of cases and are often (60%) correlated with positive blood cultures. The most typical offending organism is methicillin resistant Staphylococcus aureus, followed by methicillin sensitive S. aureus. Unfortunately, the failure rates for nonoperative treatment of SEA remain high (e.g., 41-42.5%), contributing to significant morbidity (22% risk of permanent paralysis), and mortality (3-25%). CONCLUSION: The vast majority of studies advocated early surgery to achieve better outcomes for treating SEA; this avoids high failure rates (41-42.5%) for nonoperative therapy, and limits morbidity/mortality rates. PMID- 26605110 TI - Neurofibromatosis type 1 and pregnancy: The transformation of a nodular to cystic neurofibroma in the cervical region. AB - BACKGROUND: The peripheral hallmarks of neurofibromatosis type 1 (NF1) are Cafe au lait and solid nodular neurofibromas. The morphological behavior of these lesions could be susceptible to modification during pregnancy. The present case report describes a case of cystic transformation of a nodular neurofibroma, with progressive growth and mass effect in the anterior cervical region, which was surgically resolved without any complications. CASE DESCRIPTION: A 33-year-old female patient with a known personal history of NF1, with annual control of the peripheral neurofibromas and cerebral and spinal magnetic resonance imaging follow-ups. Under genetic counseling, she decides to get pregnant following all the medical advises. Once the pregnancy is confirmed, she starts to notice the growth of one of them adjacent to the left cervical region. Such neurofibroma presented with the progressive gradual increase and in the last month, she presented dysphagia, dysphonia, and postural pain localized by the mass effect. Once the pregnancy concluded, the microsurgical approach was scheduled for resection of the lesion, where a cystic mass was found within the walls of the neurofibroma. The resection was uneventful. CONCLUSION: The transformation of a nodular to cystic neurofibroma during pregnancy is a very rare presentation, which may exacerbate the clinical symptomatology depending on the topography of the lesion due to the mass effect it may create. This condition may alert to the recommendations and vigilance in patients with NF1, who are pregnant or are planning on a future pregnancy. The neurosurgical resolution in this region is safe and beneficial. PMID- 26605112 TI - Preoperative prealbumin level as a risk factor for surgical site infection following elective spine surgery. AB - BACKGROUND: Nutritional status is a critical factor in patient outcomes in a variety of medical contexts. In the surgical fields, there is substantial evidence suggesting that clinical outcomes including infection risk and surgical efficacy may be affected by preoperative nutritional status. The purpose of this study is to evaluate preoperative serum prealbumin levels, the currently preferred serum biomarker of nutritional deficiency, in relation to the risk of developing a surgical site infection. METHODS: A retrospective case-control series was conducted comparing prospectively collected preadmission serum prealbumin levels to the risk for surgical site infection following elective spine surgery. The analysis was conducted under an approved institutional quality assurance protocol. Patients were identified by querying the department billing codes for deep wound washouts over a 3-year period. A cohort of 32 patients with preoperative prealbumin levels who underwent spine surgery complicated by postoperative deep tissue infection was identified. This was compared against a case-control cohort of 74 patients who underwent spine surgery and did not experience postoperative infection. Clinical variables included demographic information, body mass index, smoking, diabetes, steroid use, length of the procedure, and length of hospital stay. The data were analyzed using multivariate Cox regression. RESULTS: Two variables: Preoperative prealbumin < 20 and diabetes were both statistically significant predictors for the risk of developing a postoperative infection with hazard ratios of 2.12 (95% confidence interval [CI]: 1.03-4.37) and 2.22 (95% CI: 1.04-4.75), respectively. CONCLUSIONS: Our results reinforce the relationship between preoperative nutritional status and outcomes in elective spine surgery. The data indicate that preoperative prealbumin levels may be useful in risk stratification. Further study is needed to determine whether nutritional supplementation may reduce the risk of infection. PMID- 26605111 TI - Tracking patient-reported outcomes in spinal disorders. AB - BACKGROUND: Patient-reported outcome measures (PROMs) quantify health status from the patient's point of view. While the number of published outcomes studies grows each year, so too has the number of instruments being reported, leading to confusion on which instruments are appropriate to use for various spinal conditions. METHODS: A broad search was conducted to identify commonly used PROMs in patients undergoing spinal surgery. We searched PubMed for combinations of terms related to anatomic location and a measure of patient-reported outcome in the title or text. We supplemented the search using the "related articles" feature of PubMed and by manually searching the bibliographies of selected articles. RESULTS: Major categories of PROMs in spine surgery include health related quality-of-life, pain, and disease-specific disability, for which several different instrument options were identified and detailed. The minimal clinically important difference varies between instruments and differentiates statistical significance from clinical significance. In addition, the accurate estimation of costs has become a challenging but intrinsically linked variable to outcomes as increased attention is paid to the relative value of surgical interventions. CONCLUSION: While a number of PROMs are available for tracking outcomes in spine surgery, only a handful appear to be widely used. At least one instrument from each category should be measured pre- and post-operatively to quantify treatment effect. In addition, while the primary goal is to select the most appropriate instruments for the patient's condition, one should keep in mind sustainability of efforts with regard to patient and administrative burden. PMID- 26605113 TI - What are we waiting for? An argument for early surgery for spinal epidural abscesses. AB - BACKGROUND: In the article: Timing and prognosis of surgery for spinal epidural abscess (SEA): A review, Epstein raises one major point; it is imperative that spinal surgeons "take back decision-making" from our medical cohorts and reinstitute early surgery (<24 h) to better treat SEAs. METHODS: Spine surgeons recognize the clinical triad (e.g., fever [50%], spinal pain [92-100%], and neurological deficits [47%]) for establishing the diagnosis of an SEA. We also appreciate the multiple major risk factors for developing SEA; diabetes (15-30%), elevated white blood cell count (>12.5), high C-reactive protein (>115), positive blood cultures, radiographic cord compression, and significant neurological deficits (e.g., 19-45%). RESULTS: Recognizing these risk factors should prompt early open surgery (<24 h from the onset of a neurological deficit). Open surgery better defines the correct/multiple organisms present, and immediately provides adequate/thorough neurological decompression (with fusion if unstable). Although minimally invasive surgery may suffice in select cases, too often it provides insufficient biopsy/culture/irrigation/decompression. Most critically, nonsurgical options result in unacceptably high failure rates (e.g., 41-42.5-75% requiring delayed surgery), while risking permanent paralysis (up to 22%), and death (up to 25%). CONCLUSION: As spine surgeons, we need to "take back decision making" from our medical cohorts and advocate for early surgery to achieve better outcomes for our patients. Why should anyone accept the >41-42.5 to up to the 75% failure rate that accompanies the nonsurgical treatment of SEA, much less the >25% mortality rate? PMID- 26605114 TI - Commentary on the effect of steroid use in anterior cervical discectomy and fusion surgery; a randomized controlled trial by Shiveindra B. et al. Journal of Neurosurgery Spine 2015;23:137-43. AB - BACKGROUND: Steroids are often used in patients undergoing anterior cervical discectomy and fusion (ACDF) surgery to limit postoperative dysphagia. However, a major concern remains steroids' impact is on fusion. METHODS: In this prospective, randomized, double-blinded controlled study, the authors assessed the impact of steroids on swallowing/airway and fusion rates in 112 patients undergoing multilevel ACDF. The patients were randomly assigned to saline or dexamethasone groups prior to surgery; multiple other variables including different outcome analyses were also utilized over a 2-year postoperative period. The patients were followed for 1, 3, 6, 12, and 24 months postoperatively, and computed tomography (CT) studies were performed at 6, 12, and 24 postoperative months to establish fusion. RESULTS: The authors found no significant 2-year differences in the clinical parameters or surgical outcomes for patients undergoing ACDF with or without steroids. Steroids reduced dysphagia in the 1(st) postoperative month, produced a "trend" for reducing postoperative airway complications (e.g., intubation), and length of stay. Notably, CT-fusion rates with steroids were reduced at the 6(th) postoperative month but equalized by the 1(st) postoperative year. CONCLUSIONS: The authors concluded that dexamethasone administered at the time of ACDF surgery improved swallowing within the 1(st) postoperative month, reduced perioperative airway complications, reduced the length of stay, and reduced 6 month but not 12 month fusion rates. Although the findings regarding postoperative dysphagia are helpful, the performance of multiple 3D-CT scans postoperatively to document fusion would appear to subject these patients to excessive radiation exposure without sufficient clinical indications. PMID- 26605116 TI - Support patient search on pathology reports with interactive online learning based data extraction. AB - BACKGROUND: Structural reporting enables semantic understanding and prompt retrieval of clinical findings about patients. While synoptic pathology reporting provides templates for data entries, information in pathology reports remains primarily in narrative free text form. Extracting data of interest from narrative pathology reports could significantly improve the representation of the information and enable complex structured queries. However, manual extraction is tedious and error-prone, and automated tools are often constructed with a fixed training dataset and not easily adaptable. Our goal is to extract data from pathology reports to support advanced patient search with a highly adaptable semi automated data extraction system, which can adjust and self-improve by learning from a user's interaction with minimal human effort. METHODS: We have developed an online machine learning based information extraction system called IDEAL-X. With its graphical user interface, the system's data extraction engine automatically annotates values for users to review upon loading each report text. The system analyzes users' corrections regarding these annotations with online machine learning, and incrementally enhances and refines the learning model as reports are processed. The system also takes advantage of customized controlled vocabularies, which can be adaptively refined during the online learning process to further assist the data extraction. As the accuracy of automatic annotation improves overtime, the effort of human annotation is gradually reduced. After all reports are processed, a built-in query engine can be applied to conveniently define queries based on extracted structured data. RESULTS: We have evaluated the system with a dataset of anatomic pathology reports from 50 patients. Extracted data elements include demographical data, diagnosis, genetic marker, and procedure. The system achieves F-1 scores of around 95% for the majority of tests. CONCLUSIONS: Extracting data from pathology reports could enable more accurate knowledge to support biomedical research and clinical diagnosis. IDEAL-X provides a bridge that takes advantage of online machine learning based data extraction and the knowledge from human's feedback. By combining iterative online learning and adaptive controlled vocabularies, IDEAL-X can deliver highly adaptive and accurate data extraction to support patient search. PMID- 26605115 TI - Practical considerations in genomic decision support: The eMERGE experience. AB - BACKGROUND: Genomic medicine has the potential to improve care by tailoring treatments to the individual. There is consensus in the literature that pharmacogenomics (PGx) may be an ideal starting point for real-world implementation, due to the presence of well-characterized drug-gene interactions. Clinical Decision Support (CDS) is an ideal avenue by which to implement PGx at the bedside. Previous literature has established theoretical models for PGx CDS implementation and discussed a number of anticipated real-world challenges. However, work detailing actual PGx CDS implementation experiences has been limited. Anticipated challenges include data storage and management, system integration, physician acceptance, and more. METHODS: In this study, we analyzed the experiences of ten members of the Electronic Medical Records and Genomics (eMERGE) Network, and one affiliate, in their attempts to implement PGx CDS. We examined the resulting PGx CDS system characteristics and conducted a survey to understand the unanticipated implementation challenges sites encountered. RESULTS: Ten sites have successfully implemented at least one PGx CDS rule in the clinical setting. The majority of sites elected to create an Omic Ancillary System (OAS) to manage genetic and genomic data. All sites were able to adapt their existing CDS tools for PGx knowledge. The most common and impactful delays were not PGx-specific issues. Instead, they were general IT implementation problems, with top challenges including team coordination/communication and staffing. The challenges encountered caused a median total delay in system go live of approximately two months. CONCLUSIONS: These results suggest that barriers to PGx CDS implementations are generally surmountable. Moreover, PGx CDS implementation may not be any more difficult than other healthcare IT projects of similar scope, as the most significant delays encountered were not unique to genomic medicine. These are encouraging results for any institution considering implementing a PGx CDS tool, and for the advancement of genomic medicine. PMID- 26605117 TI - Working toward consensus among professionals in the identification of classical cervical cytomorphological characteristics in whole slide images. AB - INTRODUCTION: Cervical cancer is one of the most common causes of death in women worldwide.([1]) The introduction of cervical cytology in screening programs is an effective way for early detection and treatment of cervical precancerous lesions. Conventional screening of cervical cytology slides is still considered the current "gold standard" for the assessment of proficiency in becoming a cytotechnician, but diagnosis using digital whole slide images (WSI) may offer many advantages. MATERIALS AND METHODS: In this study, we have used a selection of WSI from thin-layer specimens of the most common cervical infections and (pre) neoplastic lesions, and hypothesized that weekly WSI based case-meetings would help to obtain optimal acceptance of the new digital workflow in daily pathology practice. A questionnaire, before and after the test period was used to study the effect of our approach. RESULTS: The participants clearly had to go through a learning curve to get accustomed to viewing WSI. In the beginning, there was a little self-confidence in recognizing classical cervical cytomorphological features in the WSI, and there were complaints about the speed of viewing and insufficient Z-resolution for cell groups. Adjusting the Z-stack settings resulted in better three-dimensional information due to better focusing options. Weekly meetings appeared to be instrumental in the implementation process, as participants had to select and present WSI from thematic cases themselves, and thereby, got used to viewing WSI. Some WSI were replaced by better ones until a final set of 45 representatives WSI remained. Eventually, the consensus was reached among all participants that cytomorphological features in WSI from thin layers cervical specimens could comparably be appreciated in WSI as by conventional microscopy. The selection of 45 WSI was now used to create a digital WSI based reference atlas to support further studies. CONCLUSION: We have obtained consensus between professionals that WSI from cervical cytology can be used to identify cytomorphological features, necessary for diagnosis. In addition, we observed that active participation of professionals had a positive effect on the overall acceptance of WSI and was important in the change management. PMID- 26605118 TI - Rapid evaluation of fresh ex vivo kidney tissue with full-field optical coherence tomography. AB - BACKGROUND: Full-field optical coherence tomography (FFOCT) is a real-time imaging technique that rapidly generates images reminiscent of histology without any tissue processing, warranting its exploration for evaluation of ex vivo kidney tissue. METHODS: Fresh tissue sections from tumor and adjacent nonneoplastic kidney (n = 25 nephrectomy specimens; clear cell renal cell carcinoma (CCRCC) = 12, papillary RCC (PRCC) = 4, chromophobe RCC (ChRCC) = 4, papillary urothelial carcinoma (PUC) = 1, angiomyolipoma (AML) = 2 and cystic nephroma = 2) were imaged with a commercial FFOCT device. Sections were submitted for routine histopathological diagnosis. RESULTS: Glomeruli, tubules, interstitium, and blood vessels were identified in nonneoplastic tissue. In tumor sections, the normal architecture was completely replaced by either sheets of cells/trabeculae or papillary structures. The former pattern was seen predominantly in CCRCC/ChRCC and the latter in PRCC/PUC (as confirmed on H&E). Although the cellular details were not very prominent at this resolution, we could identify unique cytoplasmic signatures in some kidney tumors. For example, the hyper-intense punctate signal in the cytoplasm of CRCC represents glycogen/lipid, large cells with abundant hyper-intense cytoplasm representing histiocytes in PRCC, and signal-void large polygonal cell representing adipocytes in AML. According to a blinded analysis was performed by an uropathologist, all nonneoplastic tissues were differentiated from neoplastic tissues. Further, all benign tumors were called benign and malignant were called malignant. A diagnostic accuracy of 80% was obtained in subtyping the tumors. CONCLUSION: The ability of FFOCT to reliably differentiate nonneoplastic from neoplastic tissue and identify some tumor types makes it a valuable tool for rapid evaluation of ex vivo kidney tissue e.g. for intraoperative margin assessment and kidney biopsy adequacy. Recently, higher resolution images were achieved using an experimental FFOCT setup. This setup has the potential to further increase the diagnostic accuracy of FFOCT. PMID- 26605119 TI - Cytopathology whole slide images and virtual microscopy adaptive tutorials: A software pilot. AB - BACKGROUND: The constant growth in the body of knowledge in medicine requires pathologists and pathology trainees to engage in continuing education. Providing them with equitable access to efficient and effective forms of education in pathology (especially in remote and rural settings) is important, but challenging. METHODS: We developed three pilot cytopathology virtual microscopy adaptive tutorials (VMATs) to explore a novel adaptive E-learning platform (AeLP) which can incorporate whole slide images for pathology education. We collected user feedback to further develop this educational material and to subsequently deploy randomized trials in both pathology specialist trainee and also medical student cohorts. Cytopathology whole slide images were first acquired then novel VMATs teaching cytopathology were created using the AeLP, an intelligent tutoring system developed by Smart Sparrow. The pilot was run for Australian pathologists and trainees through the education section of Royal College of Pathologists of Australasia website over a period of 9 months. Feedback on the usability, impact on learning and any technical issues was obtained using 5-point Likert scale items and open-ended feedback in online questionnaires. RESULTS: A total of 181 pathologists and pathology trainees anonymously attempted the three adaptive tutorials, a smaller proportion of whom went on to provide feedback at the end of each tutorial. VMATs were perceived as effective and efficient E-learning tools for pathology education. User feedback was positive. There were no significant technical issues. CONCLUSION: During this pilot, the user feedback on the educational content and interface and the lack of technical issues were helpful. Large scale trials of similar online cytopathology adaptive tutorials were planned for the future. PMID- 26605120 TI - Utility of telepathology as a consultation tool between an off-site surgical pathology suite and affiliated hospitals in the frozen section diagnosis of lung neoplasms. AB - BACKGROUND: Increasingly, as in our institution, operating rooms are located in hospitals and the pathology suite is located at a distant location because of off site consolidation of pathology services. Telepathology is a technology which bridges the gap between pathologists and offers a means to obtain a consultation remotely. We aimed to evaluate the utility of telepathology as a means to assist the pathologist at the time of intraoperative consultation of lung nodules when a subspecialty pathologist is not available to directly review the slide. METHODS: Cases of lung nodules suspicious for a neoplasm were included. Frozen sections were prepared in the usual manner. The pathologists on the intraoperative consultation service at two of our system hospitals notified the thoracic pathologist of each case after rendering a preliminary diagnosis. The consultation was performed utilizing a NikonTM Digital Sight camera and web-based Remote Medical TechnologiesTM software with live video streaming directed by the host pathologist. The thoracic pathologist rendered a diagnosis without knowledge of the preliminary interpretation then discussed the interpretation with the frozen section pathologist. The interpretations were compared with the final diagnosis rendered after sign-out. RESULTS: One hundred and three consecutive cases were included. The frozen section pathologist and a thoracic pathologist had concordant diagnoses in 93 cases (90.2%), discordant diagnoses in nine cases (8.7%), and one case in which both deferred. There was an agreement between the thoracic pathologist's diagnosis and the final diagnosis in 98% of total cases including 8/9 (88.9%) of the total discordant cases. In two cases, if the thoracic pathologist had not been consulted, the patient would have been undertreated. CONCLUSIONS: We have shown that telepathology is an excellent consultation tool in the frozen section diagnosis of lung nodules. PMID- 26605121 TI - Diagnostic performance on briefly presented digital pathology images. AB - BACKGROUND: Identifying new and more robust assessments of proficiency/expertise (finding new "biomarkers of expertise") in histopathology is desirable for many reasons. Advances in digital pathology permit new and innovative tests such as flash viewing tests and eye tracking and slide navigation analyses that would not be possible with a traditional microscope. The main purpose of this study was to examine the usefulness of time-restricted testing of expertise in histopathology using digital images. METHODS: 19 novices (undergraduate medical students), 18 intermediates (trainees), and 19 experts (consultants) were invited to give their opinion on 20 general histopathology cases after 1 s and 10 s viewing times. Differences in performance between groups were measured and the internal reliability of the test was calculated. RESULTS: There were highly significant differences in performance between the groups using the Fisher's least significant difference method for multiple comparisons. Differences between groups were consistently greater in the 10-s than the 1-s test. The Kuder Richardson 20 internal reliability coefficients were very high for both tests: 0.905 for the 1-s test and 0.926 for the 10-s test. Consultants had levels of diagnostic accuracy of 72% at 1 s and 83% at 10 s. CONCLUSIONS: Time-restricted tests using digital images have the potential to be extremely reliable tests of diagnostic proficiency in histopathology. A 10-s viewing test may be more reliable than a 1-s test. Over-reliance on "at a glance" diagnoses in histopathology is a potential source of medical error due to over-confidence bias and premature closure. PMID- 26605122 TI - Analysis of the impact of high-resolution monitors in digital pathology. PMID- 26605123 TI - Response to Rojo and Bueno: "Analysis of the impact of high resolution monitors in digital pathology". PMID- 26605124 TI - Inclusion probability for DNA mixtures is a subjective one-sided match statistic unrelated to identification information. AB - BACKGROUND: DNA mixtures of two or more people are a common type of forensic crime scene evidence. A match statistic that connects the evidence to a criminal defendant is usually needed for court. Jurors rely on this strength of match to help decide guilt or innocence. However, the reliability of unsophisticated match statistics for DNA mixtures has been questioned. MATERIALS AND METHODS: The most prevalent match statistic for DNA mixtures is the combined probability of inclusion (CPI), used by crime labs for over 15 years. When testing 13 short tandem repeat (STR) genetic loci, the CPI(-1) value is typically around a million, regardless of DNA mixture composition. However, actual identification information, as measured by a likelihood ratio (LR), spans a much broader range. This study examined probability of inclusion (PI) mixture statistics for 517 locus experiments drawn from 16 reported cases and compared them with LR locus information calculated independently on the same data. The log(PI(-1)) values were examined and compared with corresponding log(LR) values. RESULTS: The LR and CPI methods were compared in case examples of false inclusion, false exclusion, a homicide, and criminal justice outcomes. Statistical analysis of crime laboratory STR data shows that inclusion match statistics exhibit a truncated normal distribution having zero center, with little correlation to actual identification information. By the law of large numbers (LLN), CPI(-1) increases with the number of tested genetic loci, regardless of DNA mixture composition or match information. These statistical findings explain why CPI is relatively constant, with implications for DNA policy, criminal justice, cost of crime, and crime prevention. CONCLUSIONS: Forensic crime laboratories have generated CPI statistics on hundreds of thousands of DNA mixture evidence items. However, this commonly used match statistic behaves like a random generator of inclusionary values, following the LLN rather than measuring identification information. A quantitative CPI number adds little meaningful information beyond the analyst's initial qualitative assessment that a person's DNA is included in a mixture. Statistical methods for reporting on DNA mixture evidence should be scientifically validated before they are relied upon by criminal justice. PMID- 26605125 TI - Pineal Gland Lymphoma: Case Report and Literature Review. AB - A 65-year-old male presented to our institution with acute-onset headache. Imaging studies demonstrated a mass in the region of the pineal gland, with subsequent histopathology findings being consistent with large B cell lymphoma. The patient was treated with methotrexate, but ultimately did not survive. Primary central nervous system (CNS) lymphoma rarely involves the pineal gland, but should be considered in the differential diagnosis of pineal gland tumors in the appropriate clinical setting. PMID- 26605126 TI - Traumatic Brain Injury by a Closed Head Injury Device Induces Cerebral Blood Flow Changes and Microhemorrhages. AB - OBJECTIVES: Traumatic brain injury is a poly-pathology characterized by changes in the cerebral blood flow, inflammation, diffuse axonal, cellular, and vascular injuries. However, studies related to understanding the temporal changes in the cerebral blood flow following traumatic brain injury extending to sub-acute periods are limited. In addition, knowledge related to microhemorrhages, such as their detection, localization, and temporal progression, is important in the evaluation of traumatic brain injury. MATERIALS AND METHODS: Cerebral blood flow changes and microhemorrhages in male Sprague Dawley rats at 4 h, 24 h, 3 days, and 7 days were assessed following a closed head injury induced by the Marmarou impact acceleration device (2 m height, 450 g brass weight). Cerebral blood flow was measured by arterial spin labeling. Microhemorrhages were assessed by susceptibility-weighted imaging and Prussian blue histology. RESULTS: Traumatic brain injury rats showed reduced regional and global cerebral blood flow at 4 h and 7 days post-injury. Injured rats showed hemorrhagic lesions in the cortex, corpus callosum, hippocampus, and brainstem in susceptibility-weighted imaging. Injured rats also showed Prussian blue reaction products in both the white and gray matter regions up to 7 days after the injury. These lesions were observed in various areas of the cortex, corpus callosum, hippocampus, thalamus, and midbrain. CONCLUSIONS: These results suggest that changes in cerebral blood flow and hemorrhagic lesions can persist for sub-acute periods after the initial traumatic insult in an animal model. In addition, microhemorrhages otherwise not seen by susceptibility-weighted imaging are present in diverse regions of the brain. The combination of altered cerebral blood flow and microhemorrhages can potentially be a source of secondary injury changes following traumatic brain injury and may need to be taken into consideration in the long-term care of these cases. PMID- 26605127 TI - Ganglioglioma of the Spinal Cord. AB - Ganglioglioma is a rare tumor consisting of neoplastic glial and neuronal elements. It accounts for only 0.5% of all primary central nervous system (CNS) neoplasms. We report an unusual case of extensive intramedullary thoracic spinal cord ganglioglioma in a 14-month-old girl who underwent subtotal resection followed by adjuvant chemotherapy. The epidemiology, histopathologic features, imaging findings, treatment, and prognosis are subsequently reviewed. PMID- 26605128 TI - Periappendicular Abscess Presenting within an Inguinal Hernia. AB - The presence of the appendix within an inguinal hernia is a rare finding. We present the case of an elderly woman who developed appendicitis within an inguinal hernia, complicated by a supervening periappendicular abscess. She was successfully treated with a combination of antibiotics and percutaneous drainage. PMID- 26605129 TI - Incidental Cystic Lymphangioma of the Small Bowel Mesentery. AB - Lymphangiomas are benign lesions of mesenchymal origin. Although more commonly encountered in the head and neck, intra-abdominal lymphangiomas are a rare entity that typically present as multiloculated intra-abdominal cystic lesions that are often incidentally discovered on imaging. This case report discusses such a case. PMID- 26605132 TI - Superior performance of cone beam tomography in detecting a calcaneus fracture. AB - Cone beam computed tomography is a state-of-the-art imaging tool, initially developed for dental and maxillofacial application. With its high resolution and low radiation dose, cone beam tomography has been expanding its application fields, for example, to diagnosis of traumata and fractures in the head and neck area. In this study, we demonstrate superior and satisfactory performance of cone beam tomography for the imaging of a calcaneus fracture in comparison to conventional X-ray and computed tomography. PMID- 26605130 TI - Regulation of Cell Signaling and Function by Endothelial Caveolins: Implications in Disease. AB - Caveolae are cholesterol- and glycosphingolipid-rich omega-shaped invaginations of the plasma membrane that are very abundant in vascular endothelial cells and present in most cell types. Caveolins are the major coat protein components of caveolae. Multiple studies using knockout mouse, small interfering RNA, and cell permeable peptide delivery approaches have significantly enhanced our understanding of the role of endothelial caveolae and caveolin-1 in physiology and disease. Several postnatal pulmonary and cardiovascular pathologies have been reported in caveolin-1 knockout mice, many of which have been recently rescued by selective re-expression of caveolin-1 in endothelium of these mice. A large body of experimental evidence mostly using caveolin-1 knockout mice suggests that, depending on the disease model, endothelial caveolin-1 may play either a protective or a detrimental role. For instance, physiological or higher expression levels of caveolin-1 in endothelium might be beneficial in such diseases as pulmonary hypertension, cardiac hypertrophy, or ischemic injury. On the other hand, endothelial caveolin-1 might contribute to acute lung injury and inflammation, atherosclerosis or pathological angiogenesis associated with inflammatory bowel disease. Moreover, depending on the specific model, endothelial caveolin-1 may either promote or suppress tumor-induced angiogenesis. In addition to overwhelming evidence for the role of endothelial caveolin-1, more recent studies also suggest that endothelial caveolin-2 could possibly play a role in pulmonary disease. The purpose of this review is to focus on how caveolin 1 expressed in endothelial cells regulates endothelial cell signaling and function. The review places particular emphasis on relevance to disease, including but not limited to Pulmonary and cardiovascular disorders as well as cancer. In addition to caveolin-1, possible importance of the less-studied endothelial caveolin-2 in pulmonary diseases will be also discussed. PMID- 26605131 TI - Breast cancer brain metastases: the last frontier. AB - Breast cancer is a common cause of brain metastases, with metastases occurring in at least 10-16 % of patients. Longer survival of patients with metastatic breast cancer and the use of better imaging techniques are associated with an increased incidence of brain metastases. Unfortunately, patients who develop brain metastases tend to have poor prognosis with short overall survival. In addition, brain metastases are a major cause of morbidity, associated with progressive neurologic deficits that result in a reduced quality of life. Tumor subtypes play a key role in prognosis and treatment selection. Current therapies include surgery, whole-brain radiation therapy, stereotactic radiosurgery, chemotherapy and targeted therapies. However, the timing and appropriate use of these therapies is controversial and careful patient selection by using available prognostic tools is extremely important. This review will focus on current treatment options, novel therapies, future approaches and ongoing clinical trials for patients with breast cancer brain metastases. PMID- 26605133 TI - Reconstructive kidney surgery for organ-preserving therapy of renal tumors. AB - BACKGROUND: The objective of this study was to evaluate differences in various clinical endpoints in patients with reconstructive surgery by renal partial nephrectomy for tumors up to 4 cm compared to tumors larger than 4 cm. MATERIAL AND METHODS: A total of 170 partial renal resection patients that presented malignant tumors were included in the retrospective study. Data was analyzed retrospectively based on internal clinic files, as well as a questionnaire to enhance the follow-up clinical outcomes data obtained. The most important outcomes determined included post-operative renal function, intra- and post operative complications, local recurrence rate and total survival time. RESULTS: The local recurrence rate was 6.1% for tumors up to 4 cm in size, compared to 14.9% for tumors that were larger than 4 cm. Compared to results for partial resection of T1a tumors, results for partial resection of tumors larger than 4 cm are worse in terms of post-operative renal function (p=0.007), as well as in terms of a total complications rate (p=0.048). It is important to note that there was not only a higher risk of post-operative bleeding that required transfusions (p=0.012), but also a higher risk of a hypertensive episode during the post operative period reviewed (p=0.022). In addition, the total survival time for patients presenting tumors of up to 4 cm in size was significantly better (p=0.003). CONCLUSION: The results of our retrospective study of 170 patients that underwent partial renal resection after the diagnosis of malignant tumors, is that partial renal resection presents an oncologicaly safe surgical solution with low local recurrence rates. Additionally, partial resection in case of tumors that are larger than 4 cm showed worse post-operative renal function, a higher complications rate and a worse survival rate. PMID- 26605134 TI - A rare case of aortic sinuses of valsalva fistula to multiple cardiac chambers secondary to periannular aortic abscess formation from underlying Brucella endocarditis. AB - The concomitant presence of abnormal connection from three aortic valsalva sinuses to cardiac chambers is a rare complication of native aortic Brucella endocarditis. This case report presents a 37-year-old Iranian female patient who had native aortic valve Brucella endocarditis complicated by periannular abscess formation and subsequent perforation to multi-cardiac chambers associated with congestive heart failure and left bundle branch block. Multiple aorto-cavitary fistulas to right atrium, main pulmonary artery, and formation of a pocket over left atrial roof were detected by transthoracic echocardiogram (TTE). She had received a full course of antibiotics therapy in a local hospital and was referred to our center for further surgery. TTE not only detected multiple aorto cavitary fistulas but also revealed large vegetation in aortic and mitral valve leaflets and also small vegetation in the entrance of fistula to right atrium. However, the tricuspid valve was not involved in infective endocarditis. She underwent open cardiac surgery with double valve replacement with biologic valves and reconstruction of left sinus of valsalva fistula to supra left atrial pocket by pericardial patch repair. The two other fistulas to main pulmonary artery and right atrium were closed via related chambers. The post-operative course was complicated by renal failure and prolonged dependency to ventilator that was managed accordingly with peritoneal dialysis and tracheostomy. The patient was discharged on the 25(th) day after admission in relatively good condition. The TTE follow-up one year after discharge revealed mild paravalvular leakage in aortic valve position, but the function of mitral valve was normal and no residual fistulas were detected. PMID- 26605135 TI - Impact of a modified Broviac maintenance care bundle on bloodstream infections in paediatric cancer patients. AB - BACKGROUND: During intensive chemotherapy, bloodstream infection (BSI) represents an important complication in paediatric cancer patients. Most patients carry a long-term central venous access device (CVAD). Improved maintenance care of these vascular catheters may decrease the risk of BSI. METHODS: Intervention study (adapted CVAD prevention protocol) with two observation periods (P1: 09-2009 until 05-2011; P2: 09-2011 until 05-2013); prospective surveillance of all laboratory confirmed BSIs. In P2, ready to use sterile NaCl 0.9% syringes were used for CVAD flushing and octenidine/isopropanol for the disinfection of catheter hubs and 3-way stopcocks. RESULTS: During P1, 84 patients were included versus 81 patients during P2. There were no significant differences between the two patient populations in terms of median age, gender, underlying malignancy or disease status (first illness or relapse). Nearly all CVADs were Broviac catheters. The median duration from implantation to removal of the CVAD was 192 days (Inter-quartile-range (IQR); 110-288 days) in P1 and 191 days (IQR; 103-270 days) in P2. 28 BSI were diagnosed in 22 patients in P1 (26% of all patients experienced at least one BSI) and 15 BSI in 12 patients in P2 (15% of all patients). The corresponding results for incidence density (ID) were 0.44 (CI95 0.29-0.62) for P1 vs. 0.34 (0.19-0.53) BSI per 100 inpatient days for P2 and for incidence rate (IR) 7.76 (5.16-10.86) in P1 vs. 4.75 (2.66-7.43) BSI per 1,000 inpatient CVAD utilization days. In P1, 9 BSI were caused by CoNS vs. only 2 in P2 (IR 2.49; CI95 0.17-4.17 vs. 0.63; CI95 0.08-1.72). In P1 two BSI (7%) lead to early removal of the device. During P2 one CVAD was prematurely removed due to a Broviac-related BSI (6.7%). CONCLUSION: The preventive protocol investigated in this study led to a reduction of BSI in paediatric cancer patients. This result was clinically relevant but - due to insufficient power in a single centre observation - the difference did not reach statistical significance. The most pronounced trend in BSI reduction was observed for CoNS infections. Thus, improving maintenance care of the CVAD may result in lower CVAD-linked infection rates. The higher acquisition cost of the ready to use NaCl 0.9% flushing syringes and octenidine/propanol hub disinfection were probably balanced by cost savings in the intervention period. PMID- 26605136 TI - Murine erythroid 5-aminolevulinate synthase: Adenosyl-binding site Lys221 modulates substrate binding and catalysis. AB - 5-Aminolevulinate synthase (ALAS) catalyzes the initial step of mammalian heme biosynthesis, the condensation between glycine and succinyl-CoA to produce CoA, CO2, and 5-aminolevulinate. The crystal structure of Rhodobacter capsulatus ALAS indicates that the adenosyl moiety of succinyl-CoA is positioned in a mainly hydrophobic pocket, where the ribose group forms a putative hydrogen bond with Lys156. Loss-of-function mutations in the analogous lysine of human erythroid ALAS (ALAS2) cause X-linked sideroblastic anemia. To characterize the contribution of this residue toward catalysis, the equivalent lysine in murine ALAS2 was substituted with valine, eliminating the possibility of a hydrogen bond. The K221V substitution produced a 23-fold increase in the [Formula: see text] and a 97% decrease in [Formula: see text]. This reduction in the specificity constant does not stem from lower affinity toward succinyl-CoA, since the [Formula: see text] of K221V is lower than that of wild-type ALAS. For both enzymes, the [Formula: see text] value is significantly different from the [Formula: see text]. That K221V has stronger binding affinity for succinyl-CoA was further deduced from substrate protection studies, as K221V achieved maximal protection at lower succinyl-CoA concentration than wild-type ALAS. Moreover, it is the CoA, rather than the succinyl moiety, that facilitates binding of succinyl CoA to wild-type ALAS, as evident from identical [Formula: see text] and [Formula: see text] values. Transient kinetic analyses of the K221V-catalyzed reaction revealed that the mutation reduced the rates of quinonoid intermediate II formation and decay. Altogether, the results imply that the adenosyl-binding site Lys221 contributes to binding and orientation of succinyl-CoA for effective catalysis. PMID- 26605138 TI - Mobilizing action and inspiring change in quality of life of our patients. PMID- 26605137 TI - Sulfurtransferase and thioredoxin specifically interact as demonstrated by bimolecular fluorescence complementation analysis and biochemical tests. AB - Sulfurtransferases (Strs) and thioredoxins (Trxs) are members of large protein families. Trxs are disulfide reductases and play an important role in redox related cellular processes. They interact with a broad range of proteins. Strs catalyze the transfer of a sulfur atom from a suitable sulfur donor to nucleophilic sulfur acceptors in vitro, but the physiological roles of these enzymes are not well defined. Several studies in different organisms demonstrate protein-protein interactions of Strs with members of the Trx family. We are interested in investigating the specificity of the interaction between Str and Trx isoforms. In order to use the bimolecular fluorescence complementation (BiFC), several Str and Trx sequences from Arabidopsis thaliana were cloned into the pUC-SPYNE and pUC-SPYCE split-YFP vectors, respectively. Each couple of plasmids containing the sequences for the putative interaction partners were transformed into Arabidopsis protoplasts and screened using a confocal laser scanning microscope. Compartment- and partner-specific interactions could be observed in transformed protoplasts. Replacement of cysteine residues in the redox-active site of Trxs abolished the interaction signal. Therefore, the redox site is not only involved in the redox reaction but also responsible for the interaction with partner proteins. Biochemical assays support a specific interaction among Strs and certain Trxs. Based on the results obtained, the interaction of Strs and Trxs indicates a role of Strs in the maintenance of the cellular redox homeostasis. PMID- 26605139 TI - Salivary antioxidants of male athletes after aerobic exercise and garlic supplementation on: A randomized, double blind, placebo-controlled study. AB - PURPOSE: Production of reactive oxygen species and reactive nitrogen species is a natural biological event in metabolism. However, the presence of antioxidants can highly reduce the negative effect of free radicals. Thus, the efficiency of antioxidant system in the physiology of exercise is very important. DESIGN: Considering the known antioxidant capacity of garlic, the purpose of this study was to evaluate the effect on combining 14 days aerobic exercise till exhaustion with garlic extract supplementation on the antioxidant capacity of saliva. METHODS: Sixteen young men volunteered to participate in this randomized, double blind, placebo-controlled study and were randomly placed into two groups, placebo (Group I) and garlic extract (Group II). The participants performed exhaustive aerobic exercise on a treadmill before and after supplementation. Their unstimulated salivary samples were collected before, immediately after, and 1 h after the activity. The antioxidant activity in terms of peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT) was then measured in the collected samples using their specific substrates. RESULTS: A significant increase in salivary antioxidant activity of SOD, POD, and CAT was observed in saliva of the supplement group compared to the placebo group (P <= 0.05). CONCLUSION: The findings from this study suggest that increased activity of antioxidant enzymes could possibly decrease exercise-induced oxidative damage in male athletes. PMID- 26605140 TI - SATB2 gene variants in non-syndromic cleft lip with or without cleft palate in Indian population. AB - OBJECTIVES: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common craniofacial birth defects and little is known about its aetiology. Initial studies of cytogenetic analysis provided the clues for possible genes involved in the pathogenesis of NSCL/P. This approach led to the identification of SATB2 gene on 2q32-q33. The aim of this study was to determine the association between SATB2 mutations and NSCL/P. MATERIALS AND METHODS: The rs137853127, rs200074373 and rs1992950 mutations of the SATB2 gene were investigated in 173 patients with NSCL/P and 176 normal controls using Kbioscience KASPar chemistry, which is a competitive allele-specific PCR SNP genotyping system. RESULTS: The mutations in exon 6 (rs137853127 and rs200074373) were monomorphic, the intronic variant (rs1992950) was polymorphic and genotype distribution was in agreement with Hardy-Weinberg equilibrium. The rs1992950 genotype distribution is not statistically significant between NSCL/P and controls. CONCLUSION: Our findings suggest that the SATB2 gene variations do not contribute to the development of NSCL/P in the south Indian population. PMID- 26605141 TI - Expression of p63 in potentially malignant and malignant oral lesions. AB - BACKGROUND: p63, a member of p53 family, known to be expressed in embryonic tissues and basal regenerative layers of many epithelial tissues in the adult, is also expressed in various benign and malignant lesions of body including lesions of oral cavity. To evaluate the expression of p63 and compare the expression qualitatively and quantitatively in normal buccal mucosa, epithelial dysplasia, oral submucous fibrosis (OSMF), and oral squamous cell carcinoma (OSCC). METHODS: The study material consisted of 45 archival cases which were divided into Group I with 5 cases of normal buccal mucosa, Group II with 15 cases of epithelial dysplasia, and Group III with 10 cases of OSMF and 15 cases of OSCC. Immunohistochemical expression of p63 was assessed by using mean, standard deviation, and analysis of variance. RESULTS: Overexpression of p63 was seen in epithelial dysplasia, OSMF, and squamous cell carcinoma with an increased suprabasal expression in cases of epithelial dysplasia. The mean labeling index (LI) of p63 was found to be in increasing order from normal oral mucosa (33.75%), OSMF (57.37%), epithelial dysplasia (63.87%) to squamous cell carcinoma (69.76%). CONCLUSION: The results suggest a possible role of p63 in oral carcinogenesis, and an increased LI as well as increased suprabasal expression of this gene in dysplastic lesions may have a potential to be utilized as a marker for premalignancy. PMID- 26605142 TI - Stress on external hexagon and Morse taper implants submitted to immediate loading. AB - BACKGROUND/AIMS: This study aimed to evaluate the stress distribution around external hexagon (EH) and Morse taper (MT) implants with different prosthetic systems of immediate loading (distal bar (DB), casting technique (CT), and laser welding (LW)) by using photoelastic method. METHODS: Three infrastructures were manufactured on a model simulating an edentulous lower jaw. All models were composed by five implants (4.1 mm * 13.0 mm) simulating a conventional lower protocol. The samples were divided into six groups. G1: EH implants with DB and acrylic resin; G2: EH implants with titanium infrastructure CT; G3: EH implants with titanium infrastructure attached using LW; G4: MT implants with DB and acrylic resin; G5: MT implants with titanium infrastructure CT; G6: MT implants with titanium infrastructure attached using LW. After the infrastructures construction, the photoelastic models were manufactured and a loading of 4.9 N was applied in the cantilever. Five pre-determined points were analyzed by Fringes software. RESULTS: Data showed significant differences between the connection types (p < 0.0001), and there was no significant difference among the techniques used for infrastructure. CONCLUSION: The reduction of the stress levels was more influenced by MT connection (except for CT). Different bar types submitted to immediate loading not influenced stress concentration. PMID- 26605143 TI - Teeth movement in denture and implant-supported prosthesis influenced by microwave flask systems. AB - BACKGROUND/AIMS: This study evaluated the teeth movement in maxillary dentures and mandibular implantsupported prostheses processed by microwave flasks. METHODS: A model mounted on articulator was used to manufacture Co-Cr frameworks. Pins were placed for measurements on the incisal edge of upper and lower central incisors (I), buccal cusp of first upper and lower premolars (PM), and mesiobuccal cusps of upper and lower second molars (M). Distances I-I (incisor to incisor), PM-PM (premolar to premolar), M-M (molar to molar), RI-RM (right incisor to right molar), and LI-LM (left incisor to left molar) were measured before and after processing using a microscope (0.0005 mm). Vertical misfit between abutment and implant platform was evaluated for regions A (left distal implant), B (left median implant), C (medial implant), D (right median implant), and E (right distal implant) in predetermined labial and lingual sites. Prostheses were divided into groups G1 - conventional flask, and G2 - experimental HH flask. Acrylic resin was microwaved at 1400 W (30% for 3 min, 0% for 3 min, and 60% for 3 min). Horizontal teeth displacement and vertical misfit between abutment and implant platform were considered before and after procedures. Data were submitted to three-way ANOVA and Tukey's test (alpha = 0.05). RESULTS: Except for M-M distance, the teeth showed displacements without statistical difference for prosthesis and flask factors. There was no significant difference for vertical misfit values for both flasks. CONCLUSION: Diferente flasks did not cause significant changes in the teeth displacement, except for M M. Vertical misfit values were not influenced by the flasks. PMID- 26605144 TI - Analysis of micro-shear bond strength of self-etch adhesive systems with dentine: An in vitro study. AB - BACKGROUND: Success or failure of a composite restoration largely depends on its bonding to enamel/dentine. Several better adhesive systems have been developed during the last few years due to rapid advancement in the technology. Recent self etched adhesives have fewer clinical steps and are less technique sensitive. METHODS: Ninety extracted human permanent molars were collected, grounded and finished to prepare flat dentine-bonding surfaces on their occlusal surface. All specimens were divided into three groups (n = 30) on the basis of three adhesive systems Adper Easy Bond (AE), Beautibond (BB) and Xeno IV (XE). These adhesive systems were applied on prepared mid-dentine-bonding surface. A restorative resin was added with the help of a transparent tube of 2 mm height and 1.7 mm internal diameter and cured. Fifteen specimens in each group were loaded to failure in an Instron Universal Testing Machine after storage for 24 h at 37 degrees C to check micro-shear bond strength. Another fifteen specimens from each group were thermocycled 500 times at 5 degrees C and 55 degrees C with dwell time of 1 min in each bath followed by loading to failure. The data obtained was analyzed with SPSS version 21 at significance level of <05. RESULTS: After 24 h, micro-shear bond strength of BB was higher (26.04 MPa) than XE (23.69 MPa) and AE (21.50 MPa). After thermocycling, micro-shear bond strength decreased significantly in BB (P = .001) and XE (P = .03). CONCLUSION: The micro-shear bond strength of BB was highest among three groups, which decreased after thermocycling. PMID- 26605145 TI - Prevalence of and relationship between pulp and renal stones: A radiographic study. AB - AIM: The aim of the present study was to determine the prevalence of and the relationship between pulp and renal in affected patients and in healthy adults. MATERIALS AND METHODS: A total of 240 patients participated in the study. Group A consisted of 120 patients who had renal calculi and Group B had 120 randomly selected controls for the study. The periapical radiographs for all patients were evaluated for the presence or absence of the narrowing of dental pulp chambers and pulp canals. The radiographs were also evaluated to determine the presence or absence of pulp stones. The results were compared and analyzed using the Chi square test (p < 0.001). RESULTS: A total of 164 patients had pulp narrowing and 112 patients had pulp stones, which included 55 controls and 57 renal calculi patients. There was no statistical correlation between pulp narrowing and renal stones (p > 0.001) and also between pulp stones and renal stones (p > 0.001). CONCLUSION: However, there was no significant correlation between the presence of pulp stones and renal stones, and the incidental findings of pulp stones on periapical radiographs can provide useful information in the early diagnosis of the systemic calcifications. PMID- 26605146 TI - Do costochondral grafts have any growth potential in temporomandibular joint surgery? A systematic review. AB - PURPOSE OF THE STUDY: To assess the growth potential of costochondral graft in temporomandibular joint reconstruction in patients with temporomandibular ankylosis and hemifacial microsomia. METHOD: Systematic review after inclusion of articles fulfilling the following criteria: (1) only human studies; (2) patients of temporomandibular joint ankylosis and hemifacial microsomia; and (3) studies with minimum of five cases and with a minimum follow-up for a period of 5 years. The primary outcome measure was the percentage of patients with optimum growth of costochondral graft. Secondary outcomes were any abnormal growth and restoration of function. Delphi's criteria were used for assessing the quality of the included studies. RESULT: Only three studies satisfied all the inclusion criteria. A total of 96 costochondral grafts were placed in the included studies. Optimum growth was reported in 54 grafts, undergrowth in 1 graft, overgrowth in 7 grafts, lateral overgrowth in 1 graft and no growth in 1 graft. Graft resorption, reankylosis and sequestration were seen in 21, 8 and 3 cases, respectively. When the Delphi's criteria were applied to the case series for the assessment of quality, majority of the studies could be considered as satisfying at least 50% of the criteria. CONCLUSION: There are no randomised clinical trials and the only evidence is in the form of case series that is considered as the lowest level of evidence for any study. No inference can be interpreted regarding growth potential of costochondral graft. Thus, on the basis of available evidence, it can be concluded that use of costochondral graft for temporomandibular joint reconstruction lacks scientific evidence. PMID- 26605147 TI - Role of matrix metalloproteinases in dental caries, pulp and periapical inflammation: An overview. AB - Matrix metalloproteinases (MMPs) are a group of more than 25 secreted and membrane bound enzymes that represent class of enzymes responsible for degradation of pericellular substrates. They have been isolated from dentine, odontoblasts, pulp and periapical tissue. They play an important role in dentine matrix formation, modulating caries progression and secondary dentine formation. Earlier microbial proteolytic enzymes were believed to be responsible for degradation of dentine organic matrix, but lately the accumulated body of evidence suggests that MMPs have an important role in the process. During normal tissue modelling, differentiation during development, in modulating the cell behaviour, maintaining homeostasis and in numerous extracellular pathologic conditions, MMPs tends to be an equally important participant. Odontoblasts secrete some of the essential MMPs for both physiologic and pathologic conditions. MMPs also appear to be a participant in the process of reversible and irreversible pulpitis. Although they tend to have low expression and activity in adult tissues but at the onset of any destructive pathologic process, their production shoots up. They appear to have a significant presence during times of inflammation in the periapical region as well. We take a look at the various factors and evidence pointing towards the role of MMPs in the progression of caries, pulpal and periapical inflammation. PMID- 26605148 TI - Peripheral myxoma of the infratemporal region: An unusual case report. AB - Odontogenic myxoma (OM) is a rare locally invasive benign neoplasm, almost exclusively occurring in the jawbones, comprising 3-6% of all the odontogenic tumors. The mandible is more commonly involved than the maxilla. Intraoral soft tissue myxoma is an extremely rare lesion and only few reports are available in the literature. We present probably the first of its kind in literature a soft tissue OM occurring in an unusual location: the infratemporal fossa. PMID- 26605149 TI - Auto exposure control (AEC) modality in CBCT devices: Revisiting the reported parameters in current orthodontic literature. PMID- 26605150 TI - Associations between genetic variants in folate and drug metabolizing pathways and relapse risk in pediatric acute lymphoid leukemia on CCG-1952. AB - Genetic variation in drug detoxification pathways may influence outcomes in pediatric acute lymphoblastic leukemia (ALL). We evaluated relapse risk and 24 variants in 17 genes in 714 patients in CCG-1961. Three TPMT and 1 MTR variant were associated with increased risks of relapse (rs4712327, OR 3.3, 95%CI 1.2 8.6; rs2842947, OR 2.7, 95%CI 1.1-6.8; rs2842935, OR 2.5, 95%CI 1.1-5.0; rs10925235, OR 4.9, 95%CI 1.1-25.1). One variant in SLC19A1 showed a protective effect (rs4819128, OR 0.5, 95%CI 0.3-0.9). Our study provides data that relapse risk in pediatric ALL is associated with germline variations in TPMT, MTR and SLC19A1. PMID- 26605151 TI - The YPEL5-PPP1CB fusion transcript is detected in different hematological malignancies and in normal samples. AB - Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in Western adults. It was suggested that transcripts from a reciprocal trans-splicing event between YPEL5 and PPP1CB were present exclusively in CLL patients (more than 90%). Here we show that the YPEL5-PPP1CB fusion is not specific for CLL but is also detected in other hematological malignancies such as chronic myeloid leukemia, monoclonal B cell lymphocytosis or acute leukemia and also in normal samples. As such, it is unlikely that the YPEL5-PPP1CB fusion is a good drug target in CLL or a suitable target to monitor disease. PMID- 26605152 TI - Epidemiology of Carbapenem Resistance among Multi-drug Resistant Enterobacteriaceae in Uganda. AB - BACKGROUND: Multi-drug resistant (MDR) Enterobacteriaceae are on the increase worldwide and their spread has become a global challenge. Escalating the challenge is the possibility that many of these are Carbapenemase-producing Enterobacteriaceae (CPE). This further complicates patient management. The magnitude of MDR-CPE in many developed settings has been reported, however, there is paucity of data from resource limited settings. We evaluated the epidemiology of MDR-CPE of clinical origin in South Western Uganda. METHODS: From September 2013 to June 2014, all Enterobacteriaceae isolated from diverse specimens obtained from patients attending Mbarara Regional Referral Hospital, South western Uganda, were screened for MDR in a laboratory-based cross sectional study. Isolates found to be MDR were screened for carbapenem susceptibility/resistance phenotypically by Kirby Bauer disc diffusion method following CLSI guidelines and genetically using the multiplex real-time Polymerase Chain Reaction (RT-PCR). RESULTS: Of the 658 strains isolated, 183 (27.8%) were MDR and 68 (37.15%) of those MDR exhibited at least one form of carbapenem resistance with 23 (12.57%) and 56 (30.60%) isolates expressing phenotypic and genetic resistance, respectively. Eleven MDR-CPE (6.01%) isolates exhibited both phenotypic and genotypic resistance to carbapenems. Only blaVIM and blaOXA-48 genes were detected among the genetically resistant isolates. CONCLUSION: The high prevalence of MDR-CPE calls for aggressive infection control and prevention strategies, including reinforcement of hand hygiene, using contact precautions and early detection of CPE through use of targeted surveillance and molecular techniques in resource limited settings. PMID- 26605153 TI - Recombinant DNA technology: A revolutionizing outlook. PMID- 26605154 TI - Effect of Brahmyadi Churna (Brahmi, Shankhapushpi, Jatamansi, Jyotishmati, Vacha, Ashwagandha) and tablet Shilajatu in essential hypertension: An observational study. AB - Hypertension (HTN) is one among the fiery health problems of the present era. Since it does not cause symptoms usually for many years until a vital organ is damaged. The present study was carried out on 40 patients of essential HTN with Brahmyadi Churna and tablet Shilajatu for a period of 1 month with milk as Anupana. Observation was done before the treatment, 3 mid test assessments on 7(th), 14(th), and 21(st) day, posttest assessment was done on 30(th) day. Intervention revealed that 19 had marked improvement, 14 had moderate improvement, 5 had mild improvement, and no improvement was noticed in 2 individuals. Reduction in blood pressure was observed markedly with P < 0.000. PMID- 26605155 TI - Perception of Nigerian medical students on adverse drug reaction reporting. AB - Spontaneous reporting (SPR) and intensive monitoring are the conventional systems used for detecting, recording, and reporting adverse drug reactions (ADRs). Using spontaneous reporting a lot of successes has been made as existing ADRs were identified and new ones prevented through this methods. The aim of this appraisal was to evaluate the knowledge, attitude, and the practice of medical students with regards to ADRs reporting and to see if differences exist between the level of study and genders. The questionnaire was adopted, modified, and validated from previous studies. It comprised of 25 questions. It was administered year-IV and V medical students of Bayero University Kano, Nigeria. The data collected were coded and analyzed using the Statistical Package for the Social Sciences (SPSS) version 20, currently known as IBM SPSS Statistics. The response rate was 74%. Among the 108 participants, 80% got the definition of ADRs correct; 63% of them knew the precise functions of pharmacovigilance (PV). In addition, 82% strongly agreed that ADR reporting is health care workers responsibility; 82% also said PV should be taught in detail. Meanwhile, 99% have noticed patient experiencing ADRs; 67% said even mild ADRs should be reported. The outcome of this study showed good knowledge and attitude with respect to ADRs and PV among the medical students surveyed. Unfortunately, the practice of medical students was found to be unsatisfactory. There is a need to upgrade the students teaching the curriculum with respect to ADRs monitoring. PMID- 26605156 TI - Evaluation of the bioavailability of major withanolides of Withania somnifera using an in vitro absorption model system. AB - Withania somnifera (L.) Dunal, shows several pharmacological properties which are attributed mainly to the withanolides present in the root. The efficacy of medicinally active withanolides constituents depends on the absorption and transportation through the intestinal epithelium. We examined these characteristics by employing the Sino-Veda Madin-Darby canine kidney cells culture system, which under in vitro condition shows the absorption characteristics similar to the human intestinal epithelium. Thus, the aim of the present investigation was to assess the bioavailability of individual withanolides. Withanolides were diluted in Hank's buffered saline at a concentration of 2 MUg/ml were tested for permeability studies carried out for 1 h duration. Permeability was measured in terms of efflux pump (P eff) in cm/s. P eff values of withanolide A (WN A), withanone (WNN), 1,2-deoxywithastramonolide (1,2 DWM), withanolide B (WN B), withanoside IV-V (WS IV-V), and withaferin A were 4.05 * 10(-5), 2.06 * 10(-5), 1.97 * 10(-5), 1.80 * 10(-5), 3.19 * 10(-6), 3.03 * 10(-6) and 3.30 * 10(-7) respectively. In conclusion, the nonpolar and low molecular weight compounds (WN A, WNN, 1,2 DWM, and WN B) were highly permeable. As against this, the glycosylated and polar WS IV and WS V showed low permeability. Surprisingly and paradoxically, the highly biologically active withaferin A was completely impermeable, suggesting that further studies possibly using human epithelial colorectal adenocarcinoma (Caco-2) cells may be needed to delineate the absorption characteristics of withanolides, especially withaferin A. PMID- 26605157 TI - Effect of sorafenib on sperm count and sperm motility in male Swiss albino mice. AB - The issue of male germ line mutagenesis and the effects on developmental defects in the next generation has become increasingly high profile over recent years. Mutagenic substance affects germinal cells in the testis. Since the cells are undergoing different phases of cell division and maturation, it is an ideal system to study the effect of chemotherapeutic agents. There are lacunae in the literature on the effect of sorafenib on gonadal function. With background, a study was planned to evaluate the effects of sorafenib on sperm count and sperm motility in male Swiss albino mice. Male Swiss albino mice were used for the study. The animals were segregated into control, positive control (PC) and three treatment groups. PC received oral imatinib (100 mg/kg body weight) and treatment groups received 25, 50, and 100 mg/kg body weight of sorafenib orally for 7 consecutive days at intervals of 24 h between two administrations. The control group remained in the home cage for an equal duration of time to match their corresponding treatment groups. The animals were sacrificed at the end of 1(st), 2(nd), 4(th), 5(th), 7(th), and 10(th) weeks after the last exposure to drug, respectively. Sperm suspensions were prepared and introduced into a counting chamber. Total sperm count and motility were recorded. There was a significant decrease in sperm count and sperm motility by sorafenib which was comparable with the effect of PC imatinib. Sorafenib adversely affects sperm count and sperm motility which are reversible after discontinuation of treatment. PMID- 26605158 TI - In vitro antibiogram pattern of Staphylococcus aureus isolated from wound infection and molecular analysis of mecA gene and restriction sites in methicillin resistant Staphylococcus aureus. AB - Staphylococcus aureus is a common nosocomial pathogen with property to develop resistance to antimicrobial agents. But in the modern era, drug resistance had been developed by microbes due to its continuous usage of antibiotics. This study was carried out to evaluate antibiotic resistant pattern of methicillin resistant Staphylococcus aureus (MRSA) using molecular genotyping. In view of the present problem, the study has been conducted to detect the molecular genotyping of mecA gene from MRSA and confirmation of its restriction sites using EcoRI and BamHI. The pus samples were swabbed out, and clinical strains were isolated using standard microbiological procedures. Then the strains were subjected to in vitro antibiotic susceptibility assay and identified MRSA. Further molecular genotyping of mecA gene was determined by polymerase chain reaction technique. The percentage analysis was done. The clinical strains were isolated from the wound infected patients. A total of 60 samples were collected, of 60 samples, 40 (66.7%) were showed positive to strains of S. aureus. The in vitro antibiotic susceptibility assay was carried to find the drug sensitive and resistant patterns. Further methicillin resistant strains (35%) of S. aureus were screened and subjected to molecular genotyping of mecA gene and was confirmed by restriction digestion. Overall, 70% of plasmids show positive for the presence of mecA gene, although all strains have restriction sites. Hence, the present study revealed that the early detection of antibiotic resistant character using molecular genotyping will help the infected patient to cure short period and will reduce the development of multidrug resistance. PMID- 26605159 TI - Anti-urolithiatic activity of standardized extract of Biophytum sensitivum against zinc disc implantation induced urolithiasis in rats. AB - Biophytum sensitivum (L.) DC (family: Oxalidaceae) has been used in the Indian indigenous system of medicine, Ayurveda, for the treatment of various health aliments including renal calculi. The present study was undertaken to investigate the anti-urolithiatic activity of standardized methanolic extract of whole plant of B. sensitivum (MBS) in rats. Urolithiasis was induced by surgical implantations of zinc disc in the urinary bladders of rats. Upon postsurgical recovery, different doses of MBS (viz., 100, 200, and 400 mg/kg body weight) were administered to zinc disc-implanted rats for the period of 7 days by the oral route. Anti-urolithiatic activity was evaluated by measuring various dimensions of stones and estimating levels of various biomarkers in serum and urine samples. A significant decrease in urinary output was observed in the disc-implanted animals, which was prevented by the MBS treatment. Supplementation with MBS caused significant improvement in glomerular filtration rate and protein excretion. The elevated levels of serum creatinine, uric acid, and blood urea nitrogen were also prevented by the MBS treatment. The MBS treatment showed reduced formation of deposition around the implanted zinc disc. The higher dose of MBS (400 mg/kg) found more effective. These results indicate that the administration of MBS significantly prevents the growth of urinary stones. The possible mechanism underlying this effect is mediated collectively through diuretic, antioxidant and anti-inflammatory effects of the plant. The results concluded that the methanolic extract of whole plant of B. sensitivum possessed significant anti-urolithiatic activity. PMID- 26605160 TI - Nymphaea nouchali Burm. f. hydroalcoholic seed extract increases glucose consumption in 3T3-L1 adipocytes through activation of peroxisome proliferator activated receptor gamma and insulin sensitization. AB - Nymphaea nouchali Burm. f. (Family - Nymphaeaceae) is a well-known medicinal plant used in the Indian ayurvedic system of medicine for treating diabetes. The seeds especially have been prescribed for diabetes. The hydroalcoholic extract of N. nouchali seeds has been demonstrated to possess anti-hyperglycemic effects in diabetic rats, but the functional mechanism remains unknown. The nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARgamma) is noted to play an important role in glucose and lipid homeostasis. This study was hence focused in evaluating the effect of the extract on PPARgamma activation, adipocyte differentiation, and glucose consumption in 3T3-L1 cells. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), followed by adipogenesis assay using Oil Red O technique. Glucose consumption of preadipocytes and adipocytes in the presence of the extract was also determined. Real-time polymerase chain reaction was performed to identify the expression of genes involved in glucose consumption in the adipocytes. MTT assay confirmed the extract to be nontoxic, and Oil Red O staining confirmed enhanced adipocyte differentiation of 3T3-L1 cells in a dose-dependent manner. The extract also increased the expression of PPARgamma target gene, which in turn enhanced the expression of GLUT-4. The data, therefore, suggests that N. nouchali seed extract promotes adipocyte differentiation and glucose consumption by inducing PPARgamma activation, which in turn increases mRNA GLUT-4 expression and subsequently enhances insulin-responsiveness in insulin target tissues. PMID- 26605161 TI - A prospective study of incidence of medication-related problems in general medicine ward of a tertiary care hospital. AB - The study is aimed to assess the incidence of drug-related problems (DRPs) and provide pharmacist interventions for identified DRPs. A prospective, observational study was conducted among 189 patients with cardiovascular disease who were aged 18 years or older and admitted to the general medicine in-patient ward. During the 6 months study period, the incidence of DRPs was identified using Pharmaceutical Care Network Europe Foundation classification system version 6.2. A total of 189 patients were screened for DRPs. Among them, 130 patients have at least one DRP. A total of 416 DRPs were identified (on average, 2.2 DRPs per each patient). Of the 416 DRPs, 125 (30.04%) interventions were accepted, 7 (1.68%) interventions were not accepted, while remaining (68.26%) accepted but no action taken. The results of the study indicate that incidence of DRPs is substantial and pharmacist-led interventions resulted in resolution of DRPs. This represents the need for the active role of the clinical pharmacist in the developing countries like India. PMID- 26605162 TI - Detection of arecoline by simple high-performance thin-layer chromatographic method in Indian nontobacco pan masala. AB - Chewing the habit of blended pan masala containing areca nut with or without tobacco is a common practice in the Indian subcontinent. Arecoline, a pyridine alkaloid presence in areca nut alarmed for oral carcinogenesis and strictly prohibited in the western world. However, in India using blended pan masala is very popular among young and old individuals. In this context, we aimed to detect arecoline in Indian blended nontobacco pan masala sold in Kolkata using a simple densitometric high-performance thin-layer chromatographic (HPTLC) method and for alarming their use in common people. Eleven popularly Indian blended nontobacco pan masala were collected from the territory of Kolkata and isolated arecoline, following solvent extraction method derived for pyridine alkaloid. The quantitative analysis of arecoline was measured using automated software-based HPTLC instruments and validated the method according to International Conference on Harmonization guidelines. Arecoline was detected in all 11 blended nontobacco pan masala samples in a range of minimum 130 to maximum 415 MUg/g dry samples. Arecoline is hazardous carcinogenic compound, so the use of Indian blended nontobacco pan masala should be restricted. Further, the method was found suitable for routine quantitative analysis of arecoline in areca nut containing substances. PMID- 26605163 TI - The Elevation of Annals of Rehabilitation Medicine to the Status of an International Journal After Adopting an English-Only Policy. AB - OBJECTIVE: To use bibliometric analyses to determine whether Annals of Rehabilitation Medicine (hereafter also referred to as Annals) became an international journal after adopting an English-only policy in 2011. METHODS: Articles from the third issue of 2011 to the third issue of 2015 were analyzed according to the following parameters: whether the research was supported by funding, country of authorship, impact factor, total citations, the countries of researchers who cited Annals; the journals that cited Annals; and the Hirsch index. RESULTS: One hundred twenty-eight (34.2%) of the 374 original articles were supported by research funds. The main authors were from Korea (550/556, 98.9%), the USA (3), Iran (2), Japan (1), Turkey (1), and the United Kingdom (1). The manually calculated impact factors in 2013 and 2014 were 0.582 and 0.667, respectively. The total annual citations from years 2012 to 2015 were 15, 130, 252, and 189, respectively. The countries of residence of the main authors who cited Annals were the USA (146), Korea (89), and China (49). The journals that cited Annals most frequently were the Journal of Physical Therapy (34), Archives of Physical Medicine and Rehabilitation (15), and Frontiers in Human Neuroscience (13). The Hirsch index was 9. CONCLUSION: The above results demonstrate that the change of the language policy of Annals to English-only was successful in elevating the journal to the international level. The journal's aim of sharing up to-date knowledge dedicated to advancing the care of the disabled and enhancing their everyday abilities and quality of life has been satisfactorily realized. PMID- 26605164 TI - The Effect of Pulsed Radiofrequency Applied to the Peripheral Nerve in Chronic Constriction Injury Rat Model. AB - OBJECTIVE: To investigate the effect of pulsed radiofrequency (PRF) applied proximal to the injured peripheral nerve on the expression of tumor necrosis factor-alpha (TNF-alpha) in a neuropathic pain rat model. METHODS: Nineteen male Sprague-Dawley rats were used in the study. All rats underwent chronic constriction injury (CCI) procedure. After 7 days of CCI, withdrawal frequency of affected hind paw to mechanical stimuli and withdrawal latency of affected hind paw to heat stimulus were measured. They were randomly divided into two groups: group A, CCI group (n=9) and group B, CCI treated with PRF group (n=10). Rats of group B underwent PRF procedure on the sciatic nerve. Withdrawal frequency and withdrawal latency were measured at 12 hours, and 7 days after PRF. Immunohistochemistry and Western blot analysis were performed using a TNF-alpha antibody. RESULTS: Before PRF, withdrawal frequency and withdrawal latency were not different in both groups. After PRF, withdrawal frequency decreased and withdrawal latency prolonged over time in group B. There was significant interaction between time and group for each withdrawal frequency and withdrawal latency. Group B showed decreased TNF-alpha immunoreactivity of the spinal cord and sciatic nerve at 7 days. CONCLUSION: PRF applied proximal to the peripheral nerve injury is potentially helpful for the reduction of neuropathic pain by neuromodulation of inflammatory markers. PMID- 26605165 TI - Neuropsychological Outcomes of Preterm Birth in Children With No Major Neurodevelopmental Impairments in Early Life. AB - OBJECTIVES: To investigate cognition, social adaptive functioning, behavior, and emotional development in the preschool period and to determine the effects of the age of onset of walking on those developmental areas in children who were born preterm without major neurodevelopmental impairments (NDI) early in life. METHODS: Fifty-eight children who were born preterm without major NDI early in life participated in this study. The Korean versions of the Wechsler Preschool and Primary Scale of Intelligence or the Bayley Scales of Infant Development, the social maturity scale, the Korean version of the Child Behavior Checklist (CBCL), Conners' abbreviated parent/teacher rating scale, the Childhood Autism Rating Scale, and a speech developmental test were administered. The participants were divided into two groups: early walkers (group A) and late walkers (group B). RESULTS: The full-scale intelligence quotient (IQ) and performance IQ were significantly lower in group B than in group A, while the verbal IQ did not differ significantly between the groups. The children in group B had greater risks of cognitive deficits than did the children in group A, especially in performance skills. The social quotient (SQ) was significantly lower in group B than in group A (p<0.05). The rates of mild or significant deficits based on SQ and the CBCL did not differ significantly between the groups. Four children in group A and one child in group B had attention/hyperactivity problems. One child in group A had autistic behavior. Only one child in group B showed a significant speech developmental delay. CONCLUSIONS: Problems in cognition, social adaptive functioning, and emotional and behavioral development can occur in children without major NDI early in life. Late walkers had significantly lower scores in cognition and social adaptive functioning than did early walkers. PMID- 26605166 TI - Prevalence of and Risk Factors for Multidrug-Resistant Bacteria in Urine Cultures of Spinal Cord Injury Patients. AB - OBJECTIVE: To identify the prevalence of multidrug-resistant (MDR) bacteria and identify their specific risk factors in routine urine specimens of spinal cord injury (SCI) patients. METHODS: This study was designed in a retrospective manner, reviewing the medical records of SCI patients who were admitted to a specialized SCI unit between January 2001 and December 2013. Patients were investigated for age, gender, American Spinal Injury Association impairment scale, SCI level, duration after injury, bladder management method, and hospitalization history within four weeks prior to visiting our unit. The results of routine urine cultures including presence of MDR organisms were analyzed. RESULTS: Among the total 2,629 urine samples from the newly admitted SCI patients, significant bacteriuria was identified in 1,929 (73.4%), and MDR organisms were isolated in 29 (1.1%) cultures. There was an increasing trend of MDR organism prevalence from 2001 to 2013 (p<0.01). The isolation of MDR organisms in inpatients who were admitted for rehabilitation (1.3%) was significantly higher than it was among community-residing persons (0.2%) (p<0.05). By voiding method, patients who used a suprapubic indwelling catheter (3.3%) or a urethral indwelling catheter (2.6%) showed a higher rate of MDR organism isolation (p<0.05). CONCLUSION: There was an increasing trend of MDR organism isolation in SCI patients. Inpatients and persons who used indwelling catheters showed a higher risk of MDR organism isolation. PMID- 26605167 TI - Changes in Body Temperature in Incomplete Spinal Cord Injury by Digital Infrared Thermographic Imaging. AB - OBJECTIVE: To investigate changes in the core temperature and body surface temperature in patients with incomplete spinal cord injuries (SCI). In incomplete SCI, the temperature change is difficult to see compared with complete spinal cord injuries. The goal of this study was to better understand thermal regulation in patients with incomplete SCI. METHODS: Fifty-six SCI patients were enrolled, and the control group consisted of 20 healthy persons. The spinal cord injuries were classified according to International Standards for Neurological Classification of Spinal Cord Injury. The patients were classified into two groups: upper (neurological injury level T6 or above) and lower (neurological injury level T7 or below) SCIs. Body core temperature was measured using an oral thermometer, and body surface temperature was measured using digital infrared thermographic imaging. RESULTS: Twenty-nine patients had upper spinal cord injuries, 27 patients had lower SCIs, and 20 persons served as the normal healthy persons. Comparing the skin temperatures of the three groups, the temperatures at the lower abdomen, anterior thigh and anterior tibia in the patients with upper SCIs were lower than those of the normal healthy persons and the patients with lower SCIs. No significant temperature differences were observed between the normal healthy persons and the patients with lower SCIs. CONCLUSION: In our study, we found thermal dysregulation in patients with incomplete SCI. In particular, body surface temperature regulation was worse in upper SCIs than in lower injuries. Moreover, cord injury severity affected body surface temperature regulation in SCI patients. PMID- 26605168 TI - Reliability, Validity, and Responsiveness of the Korean Version of the Shoulder Disability Questionnaire and Shoulder Rating Questionnaire. AB - OBJECTIVE: To translate, adapt, and test the reliability, validity, and responsiveness of the Korean version of the Shoulder Disability Questionnaire (SDQ) and the Shoulder Rating Questionnaire (SRQ). METHODS: The international guideline for the adaptation of questionnaires was referenced for the translation and adaptation of the original SDQ and SRQ. Correlations of the SDQ-K and SRQ-K with the Shoulder Pain and Disability Index (SPADI) and the Numeric Rating Scale (NRS) were assessed to determine the reliability and validity of the questionnaires. To evaluate reliability, surveys were performed at baseline and a mean of 6 days later in 29 subjects who did not undergo any treatment for shoulder problems. To evaluate responsiveness, assessments were performed at baseline with 4-week intervals in 23 subjects with adhesive capsulitis who were administered triamcinolone injection into the glenohumeral joint. RESULTS: Fifty two subjects with shoulder-related problems were surveyed. Cronbach alpha for internal consistency was 0.82 for the summary SDQ-K and 0.75 for the summary SRQ K. The test-retest reliability of the SDQ-K, SRQ-K, and domains of the SRQ-K ranged from 0.84 to 0.95. The SDQ-K and SRQ-K summary scores correlated well with the SPADI and NRS summary scores. Generally, the effect sizes and standardized response means of the summary scores of the SDQ-K, SRQ-K, and domains of the SRQ K were large, reflecting their responsiveness to clinical changes after treatment. CONCLUSION: The reliability, validity, and responsiveness of the SDQ-K and SRQ-K were excellent. The SDQ-K and SRQ-K are feasible for Korean patients with shoulder pain or disability. PMID- 26605169 TI - Short-Term Effect of Percutaneous Bipolar Continuous Radiofrequency on Sacral Nerves in Patients Treated for Neurogenic Detrusor Overactivity After Spinal Cord Injury: A Randomized Controlled Feasibility Study. AB - OBJECTIVE: To investigate the short-term effects of bipolar radiofrequency applied to sacral nerves to treat neurogenic detrusor overactivity in patients with spinal cord injury. METHODS: Ten patients with spinal cord injury with neurogenic detrusor overactivity were recruited. These subjects were randomized to two groups: intervention (n=5) and control (n=5), members of which received conventional treatment. Voiding diary, International Consultation on Incontinence Questionnaire (ICIQ) and the urinary incontinence quality of life scale (IQOL) data were obtained and an urodynamic study (UDS) was performed before and after intervention. In the intervention group, percutaneous bipolar continuous radiofrequency (CRF) was performed on both the S2 and S3 nerves in each patient. RESULTS: In a comparison of daily frequency and number of urinary incontinence and ICIQ and IQOL scores at baseline and at 1 and 3 months after intervention, all variables achieved a significant effect for time (p<0.05). Regarding UDS parameters, pre/post intervention differences between baseline and 3-month post intervention for volume at maximal detrusor pressure during filling and reflex detrusor volume at first contraction were significantly different between the two groups (p<0.05). However, pre/post intervention differences in maximum cystometric capacity and maximum detrusor pressure during filling were not significant between the two groups (p>0.05). CONCLUSION: Percutaneous bipolar CRF applied to sacral nerves might be an effective therapy for neurogenic overactive bladder that reduces urinary incontinence and improves quality of life. PMID- 26605170 TI - Change in Musculoskeletal Pain in Patients With Work-Related Musculoskeletal Disorder After Tailored Rehabilitation Education: A One-Year Follow-Up Survey. AB - OBJECTIVE: To apply tailored rehabilitation education to video display terminal (VDT) workers with musculoskeletal pain and to assess changes in musculoskeletal pain after rehabilitation education. METHODS: A total of 8,828 VDT workers were screened for musculoskeletal disorders using a self-report questionnaire. Six hundred twenty-six VDT workers selected based on their questionnaires were enrolled in musculoskeletal rehabilitation education, which consisted of education on VDT syndrome and confirmed diseases, exercise therapy including self stretching and strengthening, and posture correction. One year later, a follow-up screening survey was performed on 316 VDT workers, and the results were compared with the previous data. RESULTS: Compared with the initial survey, pain intensity was significantly decreased in the neck area; pain duration and frequency were significantly decreased in the low back area; and pain duration, intensity, and frequency were significantly decreased in the shoulder and wrist after tailored rehabilitation education. In addition, pain duration, intensity, and frequency showed a greater significant decrease after tailored rehabilitation education in the mild pain group than in the severe pain group. CONCLUSIONS: This study found that work-related musculoskeletal pain was reduced after tailored rehabilitation education, especially in the shoulder, wrist, and low back. PMID- 26605171 TI - The Factors Associated With the Successful Outcomes of Percutaneous Disc Decompression in Patients With Lumbar Herniated Nucleus Pulposus. AB - OBJECTIVE: To determine clinical and radiological factors that predict the successful outcome of percutaneous disc decompression (PDD) in patients with lumbar herniated nucleus pulposus (HNP). METHODS: We retrospectively reviewed the clinical and radiological features of patients who underwent lumbar PDD from April 2009 to March 2013. Sixty-nine patients with lumbar HNP were studied. Clinical outcome was assessed by the visual analogue scale (VAS) and the Oswestry Disability Index (ODI). Multivariate logistic regression analysis was performed to assess relationship among clinical and radiological factors and the successful outcome of the PDD. RESULTS: The VAS and the ODI decreased significantly at 1 year follow-up (p<0.01). One year after PDD, the reduction of the VAS (DeltaVAS) was significantly greater in the patients with pain for <6 months (p=0.03) and subarticular HNP (p=0.015). The reduction of the ODI (DeltaODI) was significantly greater in the patients with high intensity zone (p=0.04). Multivariate logistic regression analysis revealed the following 5 factors that were associated with the successful outcome after PDD: pain duration for <6 months (odds ratio [OR]=14.036; p=0.006), positive straight leg raising test (OR=8.425, p=0.014), the extruded HNP (OR=0.106, p=0.04), the sequestrated HNP (OR=0.037, p=0.026), and the subarticular HNP (OR=10.876, p=0.012). CONCLUSION: PDD provided significant improvement of pain and disability of patients. The results of the analysis indicated that the duration of pain <6 months, positive straight leg raising test, the subarticular HNP, and the protruded HNP were predicting factors associated with the successful response of PDD in patients with lumbar HNP. PMID- 26605172 TI - Shoulder Manipulation After Distention Arthrography: Does Audible Cracking Affect Improvement in Adhesive Capsulitis? A Preliminary Study. AB - OBJECTIVE: To investigate whether an audible cracking sound during shoulder manipulation following distention arthrography is clinically significant in patients with adhesive capsulitis of the shoulder. METHODS: A total of 48 patients (31 women, 17 men) with primary adhesive capsulitis of the shoulder completed the study. All participants underwent C-arm-guided arthrographic distention of the glenohumeral joint with injections of a corticosteroid and normal saline. After distention, we performed flexion and abduction manipulation of the shoulder. The patients were grouped into sound and non-sound groups based on the presence or absence, respectively, of an audible cracking sound during manipulation. We assessed shoulder pain and disability based on a Numeric Rating Scale (NRS), the Shoulder Pain and Disability Index (SPADI), and passive range of motion (ROM) measurements (flexion, abduction, internal and external rotation) before the procedure and again at 3 weeks and at 6 weeks after the intervention. RESULTS: The patients were divided into two groups: 21 were included in the sound group and 27 in the non-sound group. In both groups, the results of the NRS, SPADI, and ROM assessments showed statistically significant improvements at both 3 and 6 weeks after the procedure. However, there were no significant differences between the two groups except with respect to external rotation at 6 weeks, at which time the sound group showed a significant improvement in external rotation when compared with the non-sound group (p<0.05). CONCLUSION: These findings showed that manipulation following distention arthrography was effective in decreasing pain and increasing shoulder range of motion. In addition, the presence of an audible cracking sound during manipulation, especially on external rotation, was associated with better shoulder range of motion. PMID- 26605173 TI - Relationship Between Grip and Pinch Strength and Activities of Daily Living in Stroke Patients. AB - OBJECTIVE: To investigate the relationship between grip and pinch strength and independence in activities of daily living (ADL) in stroke patients. METHODS: Medical records of 577 stroke patients from January 2010 to February 2013 were retrospectively reviewed. Patients' grip and pinch strength of both hemiplegic and non-hemiplegic hands and the Korean version of Modified Barthel Index (K-MBI) score were collected. These patients were divided into three groups: group A (onset duration: <=3 months), group B (onset duration: >3 months and <2 years), and group C (onset duration: >=2 years). The correlation between grip and pinch strength and the K-MBI score was analyzed. RESULTS: In group A (95 patients), the K-MBI score was significantly (p<0.05) correlated with the grip and pinch strength of both hands in patients with right hemiplegia. Significant (p<0.05) correlation between the K-MBI score and the grip and pinch strength of the hemiplegic hand was shown in patients with left hemiplegia. In group B (69 patients) and group C (73 patients), the K-MBI score was significantly (p<0.05) correlated with the grip and pinch strength of the hemiplegic hand. CONCLUSION: Stroke patients in subacute stage mainly performed activities of daily living using their dominant hand. However, independence in ADL was associated with the strength of the affected dominant hand. For stroke patients in chronic and late chronic stages, their hand power of the affected hand was associated with independence in ADL regardless whether the dominant hand was affected. PMID- 26605174 TI - Associations Between Prolonged Intubation and Developing Post-extubation Dysphagia and Aspiration Pneumonia in Non-neurologic Critically Ill Patients. AB - OBJECTIVE: To identify the associations between the duration of endotracheal intubation and developing post-extubational supraglottic and infraglottic aspiration (PEA) and subsequent aspiration pneumonia. METHODS: This was a retrospective observational study from January 2009 to November 2014 of all adult patients who had non-neurologic critical illness, required endotracheal intubation and were referred for videofluoroscopic swallowing study. Demographic information, intensive care unit (ICU) admission diagnosis, severity of critical illness, duration of endotracheal intubation, length of stay in ICU, presence of PEA and severity of dysphagia were reviewed. RESULTS: Seventy-four patients were enrolled and their PEA frequency was 59%. Patients with PEA had significantly longer endotracheal intubation durations than did those without (median [interquartile range]: 15 [9-21] vs. 10 [6-15] days; p=0.02). In multivariate logistic regression analysis, the endotracheal intubation duration was significantly associated with PEA (odds ratio, 1.09; 95% confidence interval [CI], 1.01-1.18; p=0.04). Spearman correlation analysis of intubation duration and dysphagia severity showed a positive linear association (r=0.282, p=0.02). The areas under the receiver operating characteristic curves (AUCs) of endotracheal intubation duration for developing PEA and aspiration pneumonia were 0.665 (95% CI, 0.542-0.788; p=0.02) and 0.727 (95% CI, 0.614-0.840; p=0.001), respectively. CONCLUSION: In non-neurologic critically ill patients, the duration of endotracheal intubation was independently associated with PEA development. Additionally, the duration was positively correlated with dysphagia severity and may be helpful for identifying patients who require a swallowing evaluation after extubation. PMID- 26605175 TI - The Effect of Oral Processing on the Viscosity of Thickened Drinks for Patients With Dysphagia. AB - OBJECTIVE: To determine whether a gum-containing thickener maintains its viscosity better during oral processing than a completely starch-based thickener. METHODS: Thirty-five healthy volunteers participated in a double-blind, cross over study. Artificial tap water was thickened to honey-like consistency (effective viscosity of 1,300+/-100 mPa.s at a shear rate of 50 per second at 20C) with a starch-based thickener (SB) or a gum-containing thickener (GC). Bolus viscosity was determined after standardized oral processing of the thickened water by the subjects for 10 and 20 seconds. Significant effects were determined by ANOVA analysis and pairwise comparisons. RESULTS: Both thickeners were susceptible to breakdown during oral processing. However, GC-thickened water retained its viscosity significantly better than SB-thickened water. CONCLUSION: The presence of gums has a protective effect on the starch hydrolysis by salivary amylase in thickened drinks, which may facilitate safer swallowing. PMID- 26605176 TI - Improved Dysphagia After Decannulation of Tracheostomy in Patients With Brain Injuries. AB - OBJECTIVE: To investigate improved dysphagia after the decannulation of a tracheostomy in patients with brain injuries. METHODS: The subjects of this study are patients with brain injuries who were admitted to the Department of Rehabilitation Medicine in Myongji Hospital and who underwent a decannulation between 2012 and 2014. A video fluoroscopic swallowing study (VFSS) was performed in order to investigate whether the patients' dysphagia had improved. We measured the following 5 parameters: laryngeal elevation, pharyngeal transit time, post swallow pharyngeal remnant, upper esophageal width, and semisolid aspiration. We analyzed the patients' results from VFSS performed one month before and one month after decannulation. All VFSS images were recorded using a camcorder running at 30 frames per second. An AutoCAD 2D screen was used to measure laryngeal elevation, post-swallow pharyngeal remnant, and upper esophageal width. RESULTS: In this study, a number of dysphagia symptoms improved after decannulation. Laryngeal elevation, pharyngeal transit time, and semisolid aspiration showed no statistically significant differences (p>0.05), however after decannulation, the post-swallow pharyngeal remnant (pre 37.41%+/-24.80%, post 21.02%+/-11.75%; p<0.001) and upper esophageal width (pre 3.57+/-1.93 mm, post 4.53+/-2.05 mm; p<0.001) showed statistically significant differences. CONCLUSION: When decannulation is performed on patients with brain injuries who do not require a ventilator and who are able to independently excrete sputum, improved esophageal dysphagia can be expected. PMID- 26605177 TI - The Association Between Serum Leptin Levels and Post-Stroke Depression: A Retrospective Clinical Study. AB - OBJECTIVE: To investigate the question of whether serum leptin levels might be associated with post-stroke depression. METHODS: We studied 130 patients who experienced a first episode of stroke of more than three months' duration, without any previous history of depression or speech disorders. Data were collected regarding the patient demographics, depressive mood (Diagnostic and Statistical Manual of Mental Disorders 4th edition [DSM-IV] criteria and Beck Depression Inventory) and serum leptin levels measured by an enzyme-linked immunosorbent assay (ELISA). In addition, the Korean version of Modified Barthel Index (K-MBI) and Korean version of Mini-Mental State Examination (K-MMSE) were used to assess the subjects' independence, in regard to the activities of daily living and cognition. A statistical analysis was performed to determine differences the serum leptin levels between patients with depression and those without depression, and to determine the difference in the MBI and K-MMSE scores between the groups separated according to the serum leptin levels. RESULTS: Higher serum leptin levels were observed in patients with depression, compared with those without depression (38.5 ng/mL [range, 25.1-59.2 ng/mL] vs. 8.2 ng/mL [range, 4.9-17.8 ng/mL]; p<0.01. The serum leptin level showed an association with depression (odds ratio, 1.21; 95% confidence interval, 1.01-1.45; p=0.021). The K-MMSE and K-MBI improvement scores were lower, with statistical significance, in the group with the highest leptin level (>30 mg/dL), compared to the other two groups. CONCLUSION: High serum leptin levels are associated with depression after stroke, and patients with elevated serum leptin levels were disadvantaged in regard to functional and cognitive outcomes. PMID- 26605178 TI - Effect of Repetitive Transcranial Magnetic Stimulation on Patients With Dysarthria After Subacute Stroke. AB - OBJECTIVE: To evaluate whether repetitive transcranial magnetic stimulation (rTMS) could improve dysarthria in stroke patients at the subacute stage. METHODS: This study was a prospective, randomized, double-blind controlled trial. Patients who had unilateral middle cerebral artery infarction were enrolled. In patients in the rTMS group, we found hot spots by searching for the evoked motor potential of the orbicularis oris on the non-affected side. We performed rTMS at a low frequency (1 Hz), 1,500 stimulations/day, 5 days a week for 2 weeks on the hotspots. We used the same protocol in the sham stimulation group patients as that in the rTMS group, except that the angle of the coil was perpendicular to the skull rather than tangential to it. The patients in both groups received speech therapy for 30 minutes, 5 days a week from a skilled speech therapist. The speech therapist measured the Urimal Test of Articulation and Phonology, alternative motion rates, sequential motion rates, and maximal phonation time before and after intervention sessions. RESULTS: Forty-two patients were enrolled in this study and 20 completed the study. Statistical analysis revealed significant improvements on the dysarthria scales in both groups. The sequential motion rate (SMR)-PeTeKe showed significantly greater improvement in the rTMS group patients than in the sham stimulation group. CONCLUSION: Patients in the rTMS group showed greater improvement in articulation than did patients in the sham rTMS group. Therefore, rTMS can have a synergistic effect with speech therapy in treating dysarthria after stroke. PMID- 26605179 TI - A Survey of Caregivers' Knowledge About Caring for Stroke Patients. AB - OBJECTIVE: To investigate how much formal caregivers know about caring for stroke patients, and whether they adequately provide it. METHODS: Formal caregivers, who worked for stroke patients at 8 hospitals (including 4 university hospitals, 2 rehabilitation hospitals, and 2 convalescent hospitals) participated in this study. The survey was based on a self-report questionnaire, with 6 categories containing a total of 48 questions about the specific care of stroke patients: the demographic characteristics of the caregivers, bed positioning, the provision of meals, position changes and transfers, the range of motion exercises, and caregiver training. RESULTS: A total of 217 caregivers were surveyed, and they were distributed as follows: 41% came from the university hospitals, 35% came from the rehabilitation hospitals, and 24% came from the convalescent hospitals. The percentages of correct answers were distributed as follows: 64.3% for bed positioning, 74.3% for providing meals, and 62.4% for position change and transfer. The total and subscale scores of the caregivers working at convalescent hospitals were significantly lower than those of the caregivers working at the other types of hospitals (p<0.05). Only 7.8% of the total participants received training on a regular basis. The caregivers obtained most of the information from caregiver associations (58.1%), and the majority of the caregivers (65.4%) were willing to receive training. CONCLUSION: About one third (33.8%) of caregivers did not have adequate knowledge of how to properly care for stroke patients; in fact, a significant number of caregivers demonstrated inappropriate and insufficient knowledge in several areas. It is assumed that the provision of regular training, by rehabilitation experts, will improve the professionalism and knowledge of the caregivers, and positively affect patient outcomes. PMID- 26605180 TI - Correlation Between Pain, Fear of Falling and Disability in Low Back Pain. AB - OBJECTIVE: To ascertain if there is a correlation between low back pain (LBP), fear of falling, and disability so that the patients with LBP are aware of the fact that other problems may occur with LBP. Hence, steps can be taken for decreasing the fear of falling and disability in order to improve the condition of patients. METHODS: A sample size of 100 patients with low back pain, with a range of ages from 40 to 73 years, participated in the study. The Falls Efficacy Scale was used to assess the fear of falling and the Oswestry Disability Index was used to assess the disability and pain in LBP individuals. RESULTS: The Pearson correlation analysis signifies the relationship between pain, fear of falling, and disability in LBP. CONCLUSION: First, LBP increases the fear of falling. Second, LBP can result in a person becoming disabled. Third, the fear of falling and disability are correlated with each other. PMID- 26605181 TI - Prolonged Motor Weakness With Syringomyelia in Japanese Encephalitis: A Case Study. AB - Japanese encephalitis (JE) shows characteristic brain lesions, including bilateral thalamus, midbrain, internal capsule, basal ganglia, and occasionally involves an anterior horn cell. We encountered a case of a 44-year-old man who initially presented with encephalitis, which was finally diagnosed as Japanese encephalomyelitis with syringomyelia. The patient showed severe motor weakness followed by delayed recovery of functional motor activities. Cervical magnetic resonance imaging showed syrinx formation at the C5 level suggesting myelitis, and abnormal electromyographic findings were noted. Clinicians should consider the possibility that the spinal cord may be involved; an example would be syringomyelia due to myelitis in a case of JE presenting with severe and prolonged motor weakness. PMID- 26605182 TI - Hypokalemia-Induced Rhabdomyolysis by Primary Aldosteronism Coexistent With Sporadic Inclusion Body Myositis. AB - We describes a patient with hypokalemia-induced rhabdomyolysis due to primary aldosteronism (PA), who suffered from slowly progressive muscle weakness after laparoscopic adrenalectomy, and was later diagnosed with coexisting sporadic inclusion body myositis (sIBM). A 54-year-old Asian male presented with severe muscle weakness of both lower extremities. Laboratory findings showed profound hypokalemia, and extreme elevation of the serum creatine phosphokinase levels, suggestive of hypokalemia-induced rhabdomyolysis. Further evaluation strongly suggested PA by an aldosterone-producing adenoma, which was successfully removed surgically. However, muscle weakness slowly progressed one year after the operation and a muscle biopsy demonstrated findings consistent with sIBM. This case is the first report of hypokalemia-induced rhabdomyolysis by PA coexistent with sIBM, to the best of our knowledge. PMID- 26605183 TI - Multiple Lower Extremity Mononeuropathies by Segmental Schwannomatosis: A Case Report. AB - Schwannoma is an encapsulated nerve sheath tumor that is distinct from neurofibromatosis. It is defined as the occurrence of multiple schwannomas without any bilateral vestibular schwannomas. A 46-year-old man with multiple schwannomas involving peripheral nerves of the ipsilateral lower extremity presented with neurologic symptoms. Electrodiagnostic studies revealed multiple mononeuropathies involving the left sciatic, common peroneal, tibial, femoral and superior gluteal nerves. Histologic findings confirmed the diagnosis of schwannoma. We reported this rare case of segmental schwannomatosis that presented with neurologic symptoms including motor weakness, which was confirmed as multiple mononeuropathies by electrodiagnostic studies. PMID- 26605184 TI - Isolated A1 Pulley Rupture of Left Fourth Finger in Kendo Players: Two Case Reports. AB - Annular pulley injury of fingers is usually observed in rock climbers who support their entire body weight with flexed fingers during climbing. But these lesions can also follow trivial trauma, such as lifting heavy objects with the fingertips, or during sports and recreational activities. The A2 and A4 pulleys are most usually involved and reported most frequently. However, traumatic A1 pulley rupture has not been reported yet, to the best of our knowledge. Kendo is a very vigorous martial art with frequent physical contact. Therefore, we reported two cases of repetitive microtraumatic left fourth finger A1 pulley rupture in Kendo players with results from physical examination and imaging studies, such as ultrasonography and magnetic resonance imaging, together with related literature. PMID- 26605185 TI - Type 2 Superior Labral Anterior to Posterior Lesion-Related Paralabral Cyst Causing Isolated Infraspinatus Paralysis: Two Case Reports. AB - Type 2 superior labral anterior to posterior (SLAP) lesion is a common cause of shoulder pain requiring surgical operation. SLAP tears are often associated with paralabral cysts, but they rarely cause nerve compression. However, we experienced two cases of type 2 SLAP-related paralabral cysts at the spinoglenoid notch which were confirmed as isolated nerve entrapment of the infraspinatus branch of the suprascapular nerve by electrodiagnostic assessment and magnetic resonance imaging. In these pathological conditions, comprehensive electrodiagnostic evaluation is warranted for confirmation of neuropathy, while surgical decompression of the paralabral cyst combined with SLAP repair is recommended. PMID- 26605186 TI - Preliminary investigation of a biological augmentation of rotator cuff repairs using a collagen implant: a 2-year MRI follow-up. AB - BACKGROUND: the inability to restore the normal tendon footprint and limit strains on the repair site are thought to contribute to re-tearing following rotator cuff repair. The purpose of this study was to use a collagen implant to augment rotator cuff repairs through the restoration of the native tendon footprint and the induction of new tissue to decrease overall tendon strain. METHODS: repairs of full-thickness rotator cuff lesions in 9 adult patients were augmented with a novel collagen implant placed over the bursal surface of the repair. Tendon thickness and footprint anatomy were evaluated using MRI at 3, 6, 12, and 24 months. Clinical results were assessed using standard outcome metrics. Mean follow-up for all patients was 25.8 months. RESULTS: the implant induced significant new tissue formation in all patients by 3 months. This tissue matured over time and became indistinguishable from the underlying tendon. At 24 months all repairs remained intact and normal footprint anatomy of the tendon was restored in all patients. All clinical scores improved significantly over time. CONCLUSION: the ability of a collagen implant to induce new host tissue formation and restore the normal footprint anatomy may represent a significant advancement in the biological augmentation and ultimate durability of rotator cuff repairs. PMID- 26605187 TI - Substantial creep in healing human Achilles tendons. A pilot study. AB - BACKGROUND: healing after rupture of the Achilles tendon can be described in terms of mechanical properties of the new-formed tissue, constituting the tendon callus. In previous human studies, the elastic modulus and the density remained almost constant during 3 months after mobilization started, and then improved up to one year. So far, time-dependent deformation of the healing human tendon has not been reported. METHODS: in a series of 16 patients, operated with Achilles tendon suture, we implanted tantalum beads into the tendon and measured the distance between them repeatedly during 3 min of constant loading, using an ordinary image intensifier. The patients unloaded their leg for 30 min before the test. To avoid bias, all images were investigated in a randomized and blinded order. RESULTS: total strain during 3 min of constant loading at 7 weeks post injury amounted to 5%, and at 19 weeks to 3%. About half of the strain, after the loading was applied, occurred during the second and third min. Considerable strain also occurred just before loading, when the patient was told that a load would be applied, but before this was actually done. CONCLUSION: the measurements were crude, and this study should be seen as a pilot. Still, visco-elastic properties seem to dominate the mechanical behavior the healing Achilles tendon from start of mobilization to 19 weeks, at least when tested after 30 min rest. This deserves further studies with more precise methods. PMID- 26605188 TI - Can Platelet rich plasma stimulate human ACL growth in culture? A preliminary experience. AB - INTRODUCTION: Platelet Rich Plasma (PRP) contains numerous growth factors; Platelet poor plasma (PPP) is plasma proteins without platelets, containing growth factors other than platelet derived. We planned to evaluate the effect of both autologous PRP & PPP on human ACL cell growth characteristics in culture conditions to see if one was better than the other. METHODS: ACL remnants were collected from eleven patients during ACL reconstruction surgery; PPP and PRP were prepared from blood of these patients. Cells were isolated, identified and cultured and were then divided into six groups. Groups A-D had Fetal Bovine Serum (FBS) added to them along with different concentrations of PRP and PPP. Groups E and F had 5% and 10% PRP respectively but lacked FBS. Cell viability was assayed by MTT and Annexin V assay, and DNA content was evaluated by propidium iodide staining and flow cytometry. RESULTS: analysis of cultured cells showed that addition of PRP (5 or 10%) increased the viability of ACL cells in 4 out of 11 and promoted cell proliferation in 8 of 11 donor samples; 10% PRP was more effective than 5% PRP. However, the difference in effectiveness of 10% PRP was not significantly better than 5% PRP. 5% PPP had no significant effect on cell viability, but it led to an increase in DNA content in 5 of 11. There was no statistically significant effect of either PRP or PPP in preventing cell death (depicted by apoptosis rate). CONCLUSION: PRP may have an enhancing effect on ACL cell viability and promotion of cell proliferation but the ideal concentration of PRP for these positive effects needs to be determined before it could be used in clinical settings for enhancing primary repair of torn ACL. Also larger, more controlled and better studies are needed to confirm its clinical utility. PMID- 26605189 TI - Percutaneous injections of Platelet rich plasma for treatment of intrasubstance meniscal lesions. AB - INTRODUCTION: management of intrasubstance meniscal lesions is still controversial. Intrasubstance meniscal lesions can lead to reduced sports activity and meniscal rupture. Physical therapy is often not satisfactory. Therefore new treatment methods are requested. Platelet Rich Plasma (PRP) has the ability to regenerate tissue; this was proved in several experimental studies. Whether percutaneous injections of PRP are effective in intrasubstance meniscal lesions is unknown. We hypothesize that percutaneous PRP injections lead to pain relief and halt of progression on MRI over 6 months in patients with grade 2 meniscal lesions. MATERIALS AND METHODS: ten recreational athletes with intrasubstance meniscal lesions (grade II according to Reicher) proven by MR Imaging (MRI) were treated by percutaneous injections of PRP in the affected meniscal area. Three sequential injections in seven day intervals were performed in every patient. All injections were performed with image converter. Follow-up MRI was done six months after last injection in every patient. Level of sports activity and amount of pain at athletic loads according to numeric rating scale (NRS-11) were noted in each patient before injections and at the time of follow up MRI after six months. The t-test was used to determine statistical differences. RESULTS: four of ten patients (40%) showed decrease of meniscal lesion in follow up MRI after six months. Nine of ten patients (90%) complained about short episodes of heavy pain after the injections with average NRS-Score of 7.9 at daily loads after the last injection. Six of ten patients (60%) showed Improvement of NRS-Score at final follow up. Average NRS-Score improved significantly (p=0.027) from 6.9 before injections to 4.5 six month after treatment. Six of ten patients (60%) reported increase of sports activity compared to the situation before injections. In four patients (40%) additional surgical treatment was necessary because of persistent knee pain or progression of meniscal lesion. CONCLUSIONS: percutaneous injections of PRP have the ability to achieve pain relief and halt of progression on MRI over 6 months in patients with grade 2 meniscal lesions. Therefore it could be considered as a treatment option in patients with persisting pain. LEVEL OF EVIDENCE: IV. PMID- 26605190 TI - Extracorporeal shock wave therapy vs cryoultrasound therapy in the treatment of chronic lateral epicondylitis. One year follow up study. AB - BACKGROUND: the purpose of this study is to compare the therapeutic effects of extracorporeal shock wave therapy (ESWT) to those of cryoultrasound (Cryo-US) therapy in chronic lateral epicondylitis during a 12-month period. METHODS: single-blinded, randomized, controlled study of 80 participants treated for chronic LE with 3 ESWT sessions at 48/72-hours intervals (n=40) or 12 Cryo-US therapy sessions (4 sessions per week) (n=40). VAS and satisfactory results, considered as the sum of excellent and good scores in the Roles and Maudsley score, were used as outcome measures at baseline and 3, 6 and 12 months post treatment. RESULTS: the results show statistically significant differences in VAS between the two groups at 6 (p<0.001) and 12 months (p<0.001) in favour of the ESWT Group. At 12 months, a difference of more than 2 points in the VAS between the two groups is demonstrated in favour of the ESWT Group. Considering satisfactory results, significant differences between the two groups are observed at 6 (p=0.003) and 12 months (p <0.001) in favour of the ESWT Group where patients achieve a satisfactory rate over 50%. CONCLUSIONS: ESWT has better clinical therapeutic results at 6- and 12-month follow-up as compared to Cryo-US therapy. LEVEL OF EVIDENCE: 1B. PMID- 26605191 TI - Knee stability, athletic performance and sport-specific tasks in non-professional soccer players after ACL reconstruction: comparing trans-tibial and antero-medial portal techniques. AB - BACKGROUND: a wrong position of bone tunnels, in particular on the femur, is one of the most frequent causes of a failed anterior cruciate ligament (ACL) reconstruction. Several studies demonstrated that drilling the femoral tunnel through the antero-medial portal (AMP) allows a more anatomical placement on the lateral femoral condyle and higher knee stability, compared to trans-tibial (TT) technique. The aim of this study was to retrospectively evaluate two groups of soccer players operated on for ACL reconstruction according to either one of these two techniques. METHODS: two groups of non-professional soccer players operated on for a single bundle ACL reconstruction with hamstrings autograft using either a TT (20 patients) or an AMP (23 patients) technique were retrospectively evaluated with KT-1000 arthrometer, manual pivot shift test, isokinetic test, the incremental treadmill-running test, athletic and sport specific tasks, and knee scores (IKDC, Lysholm and KOOS). RESULTS: the AMP group showed better results at pivot shift test and KOOS, but lower flexion angles at single leg squat test. There were no differences in all the other considered outcomes. CONCLUSIONS: the better rotational stability of the knee achieved in AMP group did not lead to significantly better clinical and functional results in our patients. LEVEL OF EVIDENCE III TREATMENT STUDY: Case-control study. PMID- 26605192 TI - Quantifying the problem of kneeling after a two incision bone tendon bone arthroscopic anterior cruciate ligament reconstruction. AB - INTRODUCTION: the aims of this study was to investigate the post-operative incidence of anterior knee pain and quantify the problem of kneeling in patients who have underwent anterior cruciate ligament (ACL) reconstruction with a bone tendon bone (BTB) graft. METHODS: prospective study of 71 male patients who participated in competitive sports and underwent BTB ACL reconstruction using a two incision approach between August 2008 and May 2011. The patella defect was packed with bone graft, and the peritenon was preserved and repaired. A questionnaire was used to evaluate pain and kneeling capability. All patients had pre and post operative Lysholm/Tegner scores, KT1000 evaluation and hop tests to assess knee stability and function. RESULTS: 71 patients were operated and had a follow up of 42 months, mean age 29.8. 22 patients had anterior knee pain on kneeling, paraesthesia of anterior knee was found in 23 patients. 65 patients were still able to kneel and 6 found they were unable. 36 were able to kneel for unrestricted periods, 9 for 5-15 minutes, 15 kneel for 1-5 minutes and 5 for >1 minute. Anterior knee pain was compared to kneeling time (P=0.001). Paraesthesia and kneeling time, (P=0.001). Anterior knee pain when compared with Lysholm score (P=0.540), hop test (P=0.277), and Lachman's (P=0.254). CONCLUSIONS: two incision BTB grafting of the patella and repair of the paritenon minimises the length of scar at the front of the knee. This reduces any palpable defects which could be causation factor for pain whilst kneeling. We have quantified kneeling and pain, thus aiding patients and surgeons in making the right decision for graft choice for ACL reconstruction. PMID- 26605194 TI - High volume image guided injections and structured rehabilitation in shoulder impingement syndrome: a retrospective study. AB - BACKGROUND: the aim was to establish the effect of a high volume-image guided injection and structured rehabilitation (HVIGI&SR) on both pain and function in shoulder impingement syndrome (SIS). METHODS: 44 participants treated between January 2008 and January 2012 with a >3 month history of recalcitrant ultrasound confirmed SIS were sent a retrospective questionnaire. All participants had received a HVIGI under ultrasound-guidance consisting of 20 mls of Marcaine with 50 mg of hydrocortisone, followed by a period of physiotherapist-led rehabilitation. The validated Shoulder Pain and Disability Index (SPADI) score was used to establish the change in the score between 1 week pre-injection and 3 weeks post-injection, along with an 11-point pain scale. RESULTS: 59% of participants responded. There was a clinically and statistically significant decrease in the SPADI score of 58.7 +/- 29.9 (p<0.01). 76% of participants had an improvement in their score of over 50% from their initial score. There was a clinically and statistically significant improvement in pain of 5.19 +/- 2.62 (p<0.01) on the numerical rating scale of pain. CONCLUSION: HVIGI&SR should be considered for short-term treatment of SIS as it showed a significant improvement in both pain and function. A prolonged period of physiotherapist-led rehabilitation can then be undertaken for long term benefits. PMID- 26605193 TI - Relationship of body mass status with running and jumping performances in young basketball players. AB - PURPOSE: the main purpose of this study was to examine the relationship of body mass (BM) status with running and jumping performances in young male basketball players. METHODS: basketball players (n=72, age 12.9+/-2.8 yrs), who were grouped into U-12 (9-12 yrs), U-15 (12-15 yrs) and U-18 (15-18 yrs), performed a battery of anthropometric, running and jumping tests. We examined differences among age groups, and between normal weight and overweight players. RESULTS: the results indicated significant and large differences among age groups in BM, height, body mass index (BMI), fat mass (FM), fat-free mass, speed, endurance, standing long jump, countermovement jump (CMJ), mean power in 30 s jumping test (Pmean) (p<0.001, eta(2)>=0.23) with older players presenting higher values. Within each age group, overweight players had higher BM, BMI, body fat percentage and FM (p<0.05) than their normal weight counterparts. Overweight players had worst performance in running (sprint and endurance) and jumping (CMJ and Pmean) in U 12, and worst endurance in U-18 (p<0.05, |d|>=0.82) than normal-weight players, whereas there was no difference in U-15. CONCLUSIONS: it was concluded that the relationship of BMI with running and jumping performances varied according to age. Based on these findings, trainers and coaches should focus on special intervention exercise and nutrition programs targeting optimal body mass especially in young basketball players, where the excess of body mass seemed to have the most detrimental effect on running and jumping performances. PMID- 26605195 TI - Sport injuries in enduro riders: a review of literature. AB - INTRODUCTION: enduro is an off road motorcycling event. It is a fast, exciting adventure sport with increasing numbers of participants and competitions. MATERIALS AND METHODS: we performed search of PubMed, Medline, CINAHL, and Embase databases using the following keywords 'Enduro injuries', 'off-road motorcycle injuries' and 'Enduro sport'. We identified four studies which described the physiological characteristic of enduro riders and the injury pattern sustained by these athletes. RESULTS: hands, wrists and forearms are the predominant areas of overuse in enduro riders. The extremities are the most injured parts in enduro. However, 98% of these injuries are mild to moderate with abbreviated injury scale grades 1 and 2. CONCLUSION: there is paucity of published data on enduro injuries. In depth understanding of the physiological aspect of enduro riders with close monitoring of injuries is needed to promote safety measures in enduro and to reduce risk factors of injury which in turn can help to make enduro a safe alternative to the other dangerous motorcycling sports. PMID- 26605196 TI - Active knee range of motion assessment in elite track and field athletes: normative values. AB - BACKGROUND: flexibility is an important physical characteristic in athletes in terms of performance and injury prevention. Active Range Of Motion (AROM) was assessed in elite Greek track and field athletes. METHODS: prospective cohort study was carried out. In the period 2000-2010, the AROM was measured bilaterally with the Active Knee Extension (AKE) test during an in-season period with a goniometer in 127 athletes. RESULTS: male runners and jumpers had a higher mean AROM than throwers, but this result was not statistically significant. Female jumpers had a higher mean AROM than both runners and throwers, but the difference was also not statistically significant. CONCLUSION: in athletes, mean posterior thigh muscle flexibility is likely to be between 72.3 degrees and 73.9 degrees . Posterior thigh muscle flexibility is associated with performance, the higher the AROM, the better performance is achieved athletes have generally high AROM, and this may be a result of their increased muscle flexibility. The normative values of posterior thigh flexibility may assist in better monitoring rehabilitation of the posterior thigh muscle injuries and be useful in pre-season screening of athletes' flexibility. PMID- 26605197 TI - Effect of different types of shoes on balance among soccer players. AB - BACKGROUND: in soccer, balance ability is important to reduce non-contact injuries. The effect of footwear on balance is poorly understood in this sport. Soccer boots and futsal trainers need to guarantee a good grip on compliant surfaces. Running shoes are designed to reduce friction on rigid su rfaces. The purpose of the present study was to investigate these types of shoes on balance ability. METHODS: twenty-four healthy male volunteers were recruited from amateur soccer teams. They were ask to perform the BESS (Balance Error Scoring System) test to measure the number of instability episodes in 6 conditions: double-leg, single-leg, and tandem stances on firm and foam surfaces. Anova with factor (several shoes) and Bonferroni were used to compare the means of two subtotal scores (firm and foam surface) and the final total score (BESS). RESULTS: the three shoe models led to greater stability than when the subject was barefoot (p=0.001). Only on the firm surface the soccer boots were statistically better than futsal trainers (p=0.009). CONCLUSIONS: the lack of stability while barefoot could be explained by the fact that with shoes there is a greater surface area, which produces a sensory filter that leads to posture modifications to improve stability. The greater stability, that was found in the three types of footwear, could be guaranteed by the design to reduce friction (for running shoes) and by the presence of studs (for soccer boots and futsal trainers). PMID- 26605199 TI - Enthesopathy of the pectoralis major tendon mimicking osteoid osteoma. A case report with an unfortunate series of events. AB - BACKGROUND: we present the case of an enthesopathy at the proximal humerus which was initially - due to the clinical history and a positive bone scintigraphy - regarded suspicious for metastatic breast cancer in a 50-year-old woman. CASE REPORT: after complementing radiographs and a magnetic resonance (MR) examination exhibiting a focally contrast enhancing juxtacortical osteolysis of the humerus, a metastasis seemed radiologically unlikely, but besides a traction-related periosteal reaction of the pectoralis major tendon an unusual osteoid osteoma could not unequivocally be ruled out. Although radiological follow-up was recommended the patient insisted on a surgical resection that was performed subsequently and confirmed an enthesopathy. Shortly after, she fractured her upper arm following minor trauma but is doing well after conservative treatment since then. CONCLUSION: enthesopathies presenting as unusual periosteal reactions can mimic primary and secondary bone tumors and should always be included in the differential diagnosis. PMID- 26605198 TI - Groin pain syndrome: an association of different pathologies and a case presentation. AB - BACKGROUND: groin pain affects all types of athletes, especially soccer players. Many diseases with different etiologies may cause groin pain. PURPOSE: offer a mini review of groin pain in soccer accompanied by the presentation of a case report highlighting the possible association of more clinical frameworks into the onset of groin pain syndrome, in order to recommend that clinical evaluations take into account possible associations between bone, muscle and tendon such as inguinal canal disease. CONCLUSION: the multifactorial etiology of groin pain syndrome needs to be examined with a comprehensive approach, with standardized clinical evaluation based on an imaging protocol in order to evaluate all possible diseases. STUDY DESIGN: Mini review- Case report (Level V). PMID- 26605200 TI - Sarcoidosis and Antiphospholipid Syndrome: A Systematic Review of Cases. AB - Association between sarcoidosis and antiphospholipid syndrome (APS) is rare with few reported cases. We sought to systematically review the published cases of APS with sarcoidosis to better characterize the demographics, clinical characteristics, treatment, and the outcome of this association. Systematic electronic search for case report, case series, and related articles published until May 2014 was carried out and relevant data were extracted and analyzed. Four cases of APS with sarcoidosis were identified exclusively in females. These cases were seen in the sixth decade of life. Pulmonary embolism and central retinal artery occlusion were the presenting thrombotic events. All the patients were treated with lifelong anticoagulation with warfarin. During the median follow-up period of 5.5 months, additional thrombotic events were not observed. Although rare, sarcoidosis may be associated with APS. Further reporting of the cases will help to better establish this association, elucidate pathogenesis, and define clinical characteristics and outcomes. PMID- 26605201 TI - Awareness and Performance of Iranian Nurses with Regard to Health Economics: A Cross-Sectional Study. AB - BACKGROUND: Health costs have risen everywhere, worldwide, and nurses play a pivotal role in cost savings and in contributing to the financial stability of hospitals. AIM: This study evaluated the awareness and performance of Iranian nursing staff, with regard to health economics. MATERIALS AND METHODS: A total of 175 nurses who worked in three teaching hospitals in Mashhad (Iran) were selected for this descriptive cross-sectional study, and data were gathered via a 27-item questionnaire. Statistical analysis was performed using one-way analysis of variance, multiple regression analysis, and Pearson's correlation coefficient. RESULTS: A total of 78% (n = 39) of nurses did not have a good awareness of health economics. The overall mean score for economic awareness was 5.9 +/- 2.1 (possible range, 0-16), and for economic performance was 26.6 +/- 4 (possible range, 0-44). There was a significant relationship between the economic awareness and performance of nurses, and nurses in higher positions had a greater awareness of health economics. CONCLUSIONS: Considering the inadequacy of the health economics awareness and performance of nurses, it is essential that efforts are made to enhance their knowledge and behavior with regard to economic issues and cost saving in all the fields of nursing, through the use of continuing education courses and workshops. PMID- 26605203 TI - Immunofluorescence Patterns in Selected Dermatoses, Including Blistering Skin Diseases Utilizing Multiple Fluorochromes. AB - BACKGROUND: Autoimmune vesiculobullous disorders represent a heterogeneous group of dermatoses whose diagnosis is made based on clinical history, histologic features, and immunopathologic features. The most commonly used techniques for the diagnosis of these diseases are direct and indirect immunofluorescence (DIF and IIF), including salt-split processing. NaCl split skin is used to determine the level of blister formation, and the localization of autoantibodies relative to the split. Classically, immunofluorescence has been performed with one fluorochrome in the diagnosis of autoimmune bullous skin diseases. AIMS: To compare DIF and IIF of the skin, using a single fluorochrome versus multiple fluorochromes. MATERIALS AND METHODS: We studied 20 autoimmune skin disease cases using fluorescein isothiocyanate (FITC) alone, in comparison to multiple fluorochromes (with or without DNA counterstaining). RESULTS: The use of multiple fluorochromes helped to simultaneously visualize reactivity in multiple skin areas, in contrast to using FITC alone. CONCLUSIONS: Using multiple fluorochromes allows simultaneous labeling of two or more antigens within the same cell/or tissue section, assists in colocalization of unknown antigens with known molecules, and helps in ruling out "background" staining. PMID- 26605202 TI - The Preventive Effects of Neural Stem Cells and Mesenchymal Stem Cells Intra ventricular Injection on Brain Stroke in Rats. AB - INTRODUCTION: Stroke is one of the most important causes of disability in developed countries and, unfortunately, there is no effective treatment for this major problem of central nervous system (CNS); cell therapy may be helpful to recover this disease. In some conditions such as cardiac surgeries and neurosurgeries, there are some possibilities of happening brain stroke. Inflammation of CNS plays an important role in stroke pathogenesis, in addition, apoptosis and neural death could be the other reasons of poor neurological out come after stroke. In this study, we examined the preventive effects of the neural stem cells (NSCs) and mesenchymal stem cells (MSCs) intra-ventricular injected on stroke in rats. AIM: The aim of this study was to investigate the preventive effects of neural and MSCs for stroke in rats. MATERIALS AND METHODS: The MSCs were isolated by flashing the femurs and tibias of the male rats with appropriate media. The NSCs were isolated from rat embryo ganglion eminence and they cultured NSCs media till the neurospheres formed. Both NSCs and MSCs were labeled with PKH26-GL. One day before stroke, the cells were injected into lateral ventricle stereotactically. RESULTS: During following for 28 days, the neurological scores indicated that there are better recoveries in the groups received stem cells and they had less lesion volume in their brain measured by hematoxylin and eosin staining. Furthermore, the activities of caspase-3 were lower in the stem cell received groups than control group and the florescent microscopy images showed that the stem cells migrated to various zones of the brains. CONCLUSION: Both NSCs and MSCs are capable of protecting the CNS against ischemia and they may be good ways to prevent brain stroke consequences situations. PMID- 26605204 TI - Demographic and Etiological Patterns of Gastric Outlet Obstruction in Kerala, South India. AB - BACKGROUND: In the modern era, the major cause of gastric outlet obstruction (GOO) is known to be a malignancy, especially in the developed world. Many books and articles do suggest that the benign causes continue to be the major cause of GOO in the developing world however, there is growing evidence proving the contrary. Males were (more commonly) affected females and individuals in their fifth and sixth decade have been the predominant age group in the majority of studies. There is a minimal data of GOO from South India. AIMS: A retrospective analysis of the endoscopic findings of patients presenting with features of GOO to determine the demographic and etiological patterns. MATERIALS AND METHODS: A retrospective study of the endoscopic findings of patients with GOO from January 2005 to January 2014 was done. The diagnosis of GOO was based on clinical presentation, and an inability during the upper endoscopy to enter the second portion of the duodenum as documented in the endoscopy registers. Patients who have already been diagnosed with malignancy prior to the endoscopy were excluded from the study; so were the patients with gastroparesis. RESULTS: A total of 342 patients with GOO underwent the endoscopy during the study period. The causes for benign obstruction were predominantly peptic ulcer disease. The major cause for malignant obstruction was carcinoma of stomach involving the distal stomach. The male to female ratio was 3.2:1. The patients with malignancy were older than patients with benign disorders. Most of the patients were in the sixth and seventh decade. The risk of malignancy was higher with increasing age, especially in women. A fourth of all carcinoma stomach presented with GOO. CONCLUSION: The study demonstrates that the cause for GOO in Kerala, South India is predominantly malignancy. The etiological and demographic patterns were similar to the studies conducted in the developed nations. PMID- 26605205 TI - Acute Liver Failure after Initiation of Rivaroxaban: A Case Report and Review of the Literature. AB - CONTEXT: Rivaroxaban is a direct factor Xa inhibitor approved for the prevention of thromboembolism. Drug induced liver injury has been increasingly reported with rivaroxaban recently, but actual liver failure has not been reported. CASE REPORT: We present a case report on the probable occurrence of acute liver failure with rivaroxaban therapy. An 89 year old woman with history of atrial fibrillation was hospitalized for biventricular congestive heart failure with passive congestion of liver, which responded to furosemide. She was discharged home on rivaroxaban for prevention of thrombo-embolism. Liver function tests upon discharge returned to almost normal range. One week later, she presented with abdominal pain and was found to have highly elevated liver enzymes, elevated bilirubin, and an abnormal coagulation profile. A day later, she developed hepatic encephalopathy, suggesting liver failure. CONCLUSION: Liver enzymes declined rapidly with the discontinuation of all of her medications, however patient died because of multi-organ failure. The causality assessment in this patient was "probable" with rivaroxaban. PMID- 26605206 TI - Arthroscopy Assisted Balloon Osteoplasty of a Tibia Plateau Depression Fracture: A Case Report. AB - CONTEXT: A clinical case of a tibia plateau fracture is presented which was treated with balloon osteoplasty and arthroscopy guidance. Balloon Tibioplasty has been shown to be a very useful method for the management of tibial plateau fractures. The use of calcium phosphate has been described in the literature for management and restoration of bone defects in tibial plateau fractures. CASE REPORT: A 45-years-old Caucasian woman was presented after a fall from a ladder. The patient sustained a lateral tibia plateau fracture which was classified as Shatzker type III (AO 41-B2) with posterolateral depression of the joint surface. Surgical treatment was applied using a minimal approach which included percutaneous reduction of the fracture under arthroscopy and fluoroscopy guidance. The bone defect was filled with calcium phosphate via injection. The clinical outcome at the 6, 12 and 24 weeks was excellent with full-range of motion of the knee joint. CONCLUSION: Arthroscopy assisted balloon osteoplasty seems to be a safe and effective method for the treatment of depressed tibia plateau fractures. Further study is needed for the proper evidence based use and application of this method. PMID- 26605207 TI - Hemophagocytic Lymphohistiocytosis: A Series of Five Clinical Cases in Adult Patients at a Single Institution with a Review of the Literature. AB - CONTEXT: Hemophagocytic Lymphohistiocytosis or the "Hemophagocytic Syndrome" is a spectrum of disorders of regulatory immunomodulatory pathways inciting phagocytosis of hematopoietic cells resulting in end-organ damage. The condition appears in both heritable and non-heritable forms from a multitude of possible environmental triggers, most notably infection. The condition often results in a fatal outcome without prompt diagnosis and treatment. Cases in children have been reported much more frequently and classically than in adult patients. CASE REPORT: In this case series we examined five such cases in adult patients that were found at our institution in a window as small at 2 years with more cases having presented since the time of this writing. In these cases, likely triggers were found ranging from infectious, drug-inducing and even underlying malignancy. The condition can be diagnosed by a set of laboratory and physical criteria (Hemophagocytic Lymphohistiocytosis -2004). Treatment ranges from immunosuppressive agents to chemotherapeutic approaches with variable success. CONCLUSION: Clinicians must maintain a higher index of suspicion in cases presenting with ominous symptomatology to ensure a prompt diagnosis and effective treatment of this potentially deadly condition. PMID- 26605208 TI - Managing the adverse events of intravesical bacillus Calmette-Guerin therapy. AB - This paper provides recommendations on the management of complications arising from intravesical treatment with bacillus Calmette-Guerin (BCG) for nonmuscle invasive bladder tumors. There is minimal recommendations currently available as randomized trials on the side effects of intravesical BCG are lacking and severe complications are usually described in case reports only. All physicians giving intravesical BCG should be aware of the possible complications that could arise and how to treat these. The incidence of bladder irritation, general malaise, and fever is very high, while severe complications remain rare. Approximately 8% of patients have to stop treatment because of these complications. BCG infections and reactions can occur anywhere in the body, and may happen straight away or even several months or years after BCG treatment, making early diagnosis difficult. Additionally, correct diagnosis is hampered by the uncertain appearance of BCG in tissue and body fluid. An essential step in the management complications arising from BCG is written information for both the family doctor and the patient on the possible adverse events and their management. Recent data demonstrated that none of the earlier advocated methods to prevent BCG toxicity are valid: lowering the dose, tuberculostatic drugs, or oxybutynin. Severe complications are treated with three or four tuberculostatics over 3-12 months, depending on the severity of the situation. Corticosteroids are an essential therapy in BCG septicemia. Nonsteroidal anti-inflammatory drugs and corticosteroids can manage efficiently the immunological complications. PMID- 26605209 TI - Peyronie's disease after urethral swab, an unusual complication: a case report. AB - Urethral swabs are still currently used as a diagnostic tool when urethritis or prostatitis are suspected. Urologists are certainly aware that Peyronie's disease may occur after traumatic urethral instrumentation (catheterization, urethrocystoscopy, etc), but onset of Peyronie's disease after urethral swab for diagnostic purposes has never been reported in the literature. This paper presents the case of a patient who developed Peyronie's disease after a clumsy urethral swab insertion. It is an unusual, and to date unreported, complication which we would like to call attention to. In the case of our patient, the swab had been inserted to a greater depth than normally required and strong pressure had also been applied. During the procedure, the patient experienced severe urethral and penile pain, which was followed by urethrorrhagia, and later penile curvature. The patient was treated conservatively with good results, partly because the disease was still in its active stage and not yet stable. In the light of what we report, when ordering a urethral swab, physicians should always recommend that it be performed at testing centers that follow accurate, rigorous standards. Patients should also be informed that the test they are to undergo consists of a swab being inserted into the urethra for a short distance, not more than 2-3 cm. PMID- 26605210 TI - Comparative investigation of two surgical techniques of orchiopexy in the post operative recurrence rate and testicular size in children in clinical trial study. AB - BACKGROUND: Cryptorchidism is a common problem which is prevalent in 3% of male infants. This study aimed to determine the effect of both trans fixation and Dartos pouch fixation methods on the postoperative recurrence rate and testicular changes. MATERIALS AND METHODS: In a clinical trial study, 70 children were randomly divided into two groups. In the first group, the correction of cryptorchidism was done by Dartos pouch without suture and in the second group; testis was sutured using common trans fixation. The size of testicles was measured before and 6 months after surgery, children were followed on postoperative complications, trauma to testicles and recurrence of disease in both groups. Data were analyzed using SPSS soft ware. RESULTS: The mean size of testicles was 87.16 +/- 20.6 mm(2) in the group with fixed testicle and 182.4 +/- 37.9 mm(2) in the group with not-fixed testicle before operation and the difference between the two groups was significant (P = 0.013). After surgery, the mean size of testicles was 90.8 +/- 19.9 mm(2) in the group with fixed testicle and 183.7 +/- 41.2 mm(2) in the group with not-fixed testicle and the difference between them was significant (P = 0.026). The average of changes in testicular size was 3.62 +/- 1.93 and 1.25 +/- 5.35 mm(2) in both fixed and not-fixed groups, respectively and changes in testicular size had no significant difference between the two groups. (P = 0.68). CONCLUSIONS: Type of fixation had no effect on the size of testes or relevance to the level of retraction. The above management protocol did very well in our hands, and we recommend it for application in the management of undescended testis. PMID- 26605211 TI - The relationship of GH and LEP gene polymorphisms with fat-tail measurements (fat tail dimensions) in fat-tailed Makooei breed of Iranian sheep. AB - BACKGROUND: The present study was designed to investigate the association of GH and LEP genes' single-nucleotide polymorphisms with fat-tail measurements (fat tail dimensions) in Makooei sheep. MATERIALS AND METHODS: DNA was extracted from whole blood samples collected from 100 sheep. Polymerase chain reaction (PCR) products were subjected to single-strand conformation polymorphism (SSCP) denaturation and polyacrylamide gel electrophoresis. Data were collected at the Makooei Sheep Breeding Station in Makoo (36 degrees , 35'S and 48 degrees , 22'E) of West Azerbaijan province. Climatically, this location has temperate summers and cold winters and receives a mean annual rainfall of about 400 mm. Ewes are raised in an annual breeding cycle starting in September. In general, the flock is managed under a semi-migratory system. RESULTS: In the tested Makooei sheep population, significant statistical results were found in all traits of fat-tail measurements for GH and LEP genes. Individuals with the G4, L4 genotype of GH and LEP genes had lower tail length (rump length), fat thickness (the thick rump), and tail width (rump width) when compared to those of individuals with other genotypes (P < 0.05). In addition, the results demonstrated that individuals with the G5, L5 genotype of GH and LEP genes had superiority of tail length (rump length) and fat thickness (the thick rump) compared to those individuals with other genotypes (P < 0.05). Individuals with the G2, L2 genotype of GH and LEP genes had superiority of tail width (rump width) compared individuals with other genotypes (P < 0.05). CONCLUSION: These results confirmed potential usefulness of GH and LEP genes in marker-assisted selection programs of sheep breeding. PMID- 26605212 TI - Evaluation of the prevalence of herpes simplex-1 infection in oral squamous cell carcinoma specimens in Alzahra and Kashani Hospitals with polymerase chain reaction method in 2012-2013. AB - BACKGROUND: Although tobacco, alcohol abuse are well-recognized risk factors for oral squamous cell carcinoma (OSCC), there is evidence to indicate that herpes simplex virus (HSV) may also play some inducing role. The purpose of this study was to investigate the presence of HSV in Iranian patients with OSCC using the polymerase chain reaction (PCR). MATERIALS AND METHODS: Biopsies of OSCC were obtained from 60 patients, 54 males and 6 females, aged between 36 and 80 years old. Paraffin-embedded, histologically confirmed specimens were analyzed for the presence of HSV DNA using PCR. RESULTS: Only three samples (5%) was positive, suggesting that HSV may not play an important role in this group of patients. CONCLUSIONS: The prevalence of HSV-1 positive sample in this study was 5%. It shows that HSV-1 has no important role in OSCC. PMID- 26605213 TI - Nucleus and cytoplasm segmentation in microscopic images using K-means clustering and region growing. AB - BACKGROUND: Segmentation of leukocytes acts as the foundation for all automated image-based hematological disease recognition systems. Most of the time, hematologists are interested in evaluation of white blood cells only. Digital image processing techniques can help them in their analysis and diagnosis. MATERIALS AND METHODS: The main objective of this paper is to detect leukocytes from a blood smear microscopic image and segment them into their two dominant elements, nucleus and cytoplasm. The segmentation is conducted using two stages of applying K-means clustering. First, the nuclei are segmented using K-means clustering. Then, a proposed method based on region growing is applied to separate the connected nuclei. Next, the nuclei are subtracted from the original image. Finally, the cytoplasm is segmented using the second stage of K-means clustering. RESULTS: The results indicate that the proposed method is able to extract the nucleus and cytoplasm regions accurately and works well even though there is no significant contrast between the components in the image. CONCLUSIONS: In this paper, a method based on K-means clustering and region growing is proposed in order to detect leukocytes from a blood smear microscopic image and segment its components, the nucleus and the cytoplasm. As region growing step of the algorithm relies on the information of edges, it will not able to separate the connected nuclei more accurately in poor edges and it requires at least a weak edge to exist between the nuclei. The nucleus and cytoplasm segments of a leukocyte can be used for feature extraction and classification which leads to automated leukemia detection. PMID- 26605214 TI - Design, formulation and evaluation of Aloe vera chewing gum. AB - BACKGROUND: Aloe vera has antioxidant, antiinflammatory, healing, antiseptic, anticancer and antidiabetic effects. The aim of the present study was to design and evaluate the formulation of Aloe vera chewing gum with an appropriate taste and quality with the indications for healing oral wounds, such as lichen planus, mouth sores caused by cancer chemotherapy and mouth abscesses as well as reducing mouth dryness caused by chemotherapy. MATERIALS AND METHODS: In Aloe vera powder, the carbohydrate content was determined according to mannose and phenolic compounds in terms of gallic acid. Aloe vera powder, sugar, liquid glucose, glycerin, sweeteners and different flavors were added to the soft gum bases. In Aloe vera chewing gum formulation, 10% of dried Aloe vera extract entered the gum base. Then the chewing gum was cut into pieces of suitable sizes. Weight uniformity, content uniformity, the organoleptic properties evaluation, releasing the active ingredient in the phosphate buffer (pH, 6.8) and taste evaluation were examined by Latin square method. RESULTS: One gram of Aloe vera powder contained 5.16 +/- 0.25 mg/g of phenolic compounds and 104.63 +/- 4.72 mg/g of carbohydrates. After making 16 Aloe vera chewing gum formulations, the F16 formulation was selected as the best formulation according to its physicochemical and organoleptic properties. In fact F16 formulation has suitable hardness, lack of adhesion to the tooth and appropriate size and taste; and after 30 min, it released more than 90% of its drug content. CONCLUSION: After assessments made, the F16 formulation with maltitol, aspartame and sugar sweeteners was selected as the best formulation. Among various flavors used, peppermint flavor which had the most acceptance between consumers was selected. PMID- 26605215 TI - Stability and biological activity evaluations of PEGylated human basic fibroblast growth factor. AB - BACKGROUND: Human basic fibroblast growth factor (hBFGF) is a heparin-binding growth factor and stimulates the proliferation of a wide variety of cells and tissues causing survival properties and its stability and biological activity improvements have received much attention. MATERIALS AND METHODS: In the present work, hBFGF produced by engineered Escherichia coli and purified by cation exchange and heparin affinity chromatography, was PEGylated under appropriate condition employing 10 kD polyethylene glycol. The PEGylated form was separated by size exclusion chromatography. Structural, biological activity, and stability evaluations were performed using Fourier transform infrared (FITR) spectroscopy, 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay and effect denaturing agent, respectively. RESULTS: FITR spectroscopy revealed that both PEGylated and native forms had the same structures. MTT assay showed that PEGyalated form had a 30% reduced biological activity. Fluorescence spectrophotometry indicated that the PEGylated form denatured at higher concentrations of guanidine HCl (1.2 M) compared with native, which denatured at 0.8 M guanidine HCl. CONCLUSIONS: PEGylation of hBFGF makes it more stable against denaturing agent but reduces its bioactivity up to 30%. PMID- 26605216 TI - Evaluation of estrogen receptor expression and its relationship with clinicopathologic findings in gastric cancer. AB - BACKGROUND: The presence of estrogen receptor alpha has been reported in the cell and tissue levels in gastric cancer; however, its impact on patients' survival remains unclear. The aim of this study was to investigate the expression of estrogen receptor in gastric carcinoma as well as its relationship with the clinicopathologic findings of the patients. MATERIALS AND METHODS: The study was performed on 100 endoscopic biopsies of gastric adenocarcinoma for estrogen receptor expression using an immunohistochemical method, and their relationship with the clinicopathologic findings of the patients, such as age, gender, tumor site, size, grade, depth of tumor invasion (T), and lymphatic status (N), were analyzed using independent sample t-test and Pearson Chi-square test. A P < 0.05 was considered significant in all analyses. RESULTS: Using an immunohistochemical method on endoscopic biopsies of 74 males and 26 females with the mean age of 63 years, estrogen receptor was found to be positive in 41% of patients. No significant difference was found between estrogen receptor expression and other clinicopathologic findings (P = 0.75). There was a significant difference between estrogen receptor (+) and estrogen receptor (-) groups in nodal involvement (P = 0.001). The estrogen receptor (+) patients had more number of lymph nodes involved. CONCLUSION: This study showed that lymph node involvement has a significant relationship with estrogen receptor expression. However, no significant relationship was found between estrogen receptor expression and other clinicopathologic findings such as age, gender, tumor site in stomach, tumor size, tumor grade, and T-stage. PMID- 26605217 TI - Silver nitrate versus tetracycline in pleurodesis for malignant pleural effusions; a prospective randomized trial. AB - BACKGROUND: In this study, we aimed to investigate the effectiveness of silver nitrate (SN) versus tetracycline in pleurodesis among patients with malignant pleural effusion (MPE). METHODS: In this prospective randomized clinical trial, patients with unilateral MPE candidate for pleurodesis were enrolled. The patients randomly allocated in two groups for receiving 20 mL 0.5% SN or 2.5 g tetracycline diluted in 30 cc normal saline and 0.1% lidocaine, through the chest tube. Patients were followed-up immediately (during 24 h) and 1-month after the procedure for evaluating recurrence of the pleural effusion using chest radiograph. They were clinically evaluated for chest pain and/or dyspnea and fever using a questionnaire that completed by the surgeon. The results were compared with two groups. RESULTS: During this trial, 50 patients with MPE candidate for pleurodesis were selected and randomized into two interventional groups (25 patients in each group). Immediate and late recurrence of pleural effusion after pleurodesis were similar in two groups (P > 0.05). All patients in tetracycline group had fever and chest pain, but in SN group fever and chest pain were reported in 3 (12%) and 12 (48%) of patients, respectively (P < 0.05). CONCLUSION: SN is at least as effective as tetracycline for MPE treatment. In addition, its side effects were lower than tetracycline. Other advantages of SN are its low cost, availability, and safety. For more accurate results, it is recommended to design further trials with larger sample size and with lower doses of both SN and tetracycline. PMID- 26605218 TI - Expression of ZFX gene correlated with the central features of the neoplastic phenotype in human brain tumors with distinct phenotypes. AB - BACKGROUND: The zinc finger transcription factor zinc finger protein, X-linked (ZFX) acts as an important director of self-renewal in several stem cell types. Moreover, ZFX expression abnormally increases in various cancers and relates to tumor grade. We performed this study, to examine its role in the pathogenesis of astrocytoma and meningioma. MATERIALS AND METHODS: We used real-time reverse transcription polymerase chain reaction method for evaluation of ZFX expression in 25 astrocytoma tumoral tissue and 25 meningioma tumoral tissues with different WHO grades. Furthermore, the association of gene expression with various clinic pathological characteristics was examined. RESULTS: We found that there is a significant association between gene expression and different tumor grades, the presence or absence of invasion, forming and nonforming of glomeruloid vessels, the age over or under 50 and the presence or absence of calcification in astrocytomas. This is the first report that shows that ZFX was directly correlated with the central features of the neoplastic phenotype, including the growth of cancer cells, angiogenesis, and invasion. CONCLUSION: Regarding all the above-mentioned studies, it is highly plausible that silencing the expression of ZFX gene in gliomas has a major role in the therapeutic interventions of the disease in future. PMID- 26605219 TI - Type 2 diabetes mellitus and renal stones. AB - BACKGROUND: The incidence of urinary stone disease has shown a steep rise in recent decades along with marked modifications in dietary habits and life- style. There has been an increased prevalence of urinary stone disease in patients with diabetes. We took up this study to determine the association of diabetes mellitus with kidney stones in patients undergoing surgical treatment. MATERIALS AND METHODS: Patients presenting with renal stones for surgical management formed the study group. Body mass index (BMI) was calculated by noting the weight and height of the patient. The extracted stone/stone fragments were analyzed to determine the chemical composition. Urinary pH was similarly noted in all. RESULTS: The mean BMI among the diabetics was 26.35 +/- 5.20 (range 17.75-35.60), whereas the mean BMI among the non-diabetics was 23.41 +/- 2.85 (range 17.71-31.62) (P < 0.0004). The incidence of uric acid calculi in the diabetics was significantly high (P < 0.03). The mean urinary pH among the diabetics was 5.61 +/- 0.36 and among the non-diabetics was 6.87 +/- 0.32, which was significantly lower (P < 0.000044). CONCLUSIONS: There is a strong association between type 2 diabetes and uric acid stone formation. There is also a strong association between diabetes mellitus, BMI, and also with lower urinary pH. PMID- 26605220 TI - Comparison of the effects of colloid preload, vasopressor administration and leg compression on hemodynamic changes during spinal anesthesia for lumbar disc surgery in knee-chest position. AB - BACKGROUND: Hypotension is a serious and the most common adverse effect of spinal anesthesia. Many studies have focused on prevention of hypotension due to spinal anesthesia. The aim of this study was to compare the efficacy of three different methods of using colloid, ephedrine and wrapping of extremities on the incidence of hypotension and bradycardia following spinal anesthesia in patients undergoing elective lumbar disc surgery in knee-chest position. MATERIALS AND METHODS: A total of 180, ASA (I-II), adult patients candidate of lumbar disc surgery in one or two levels who met the inclusion criteria were randomly allocated in one of three treatment groups of receiving Voluven (6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride injection), ephedrine and leg wrapping. After establishment of spinal anesthesia, patients were outsourced and knee-chest position was done. Heart rate and blood pressure of patients were recorded at different times till 60 min after spinal injection. Statistical analyses of data were performed with SPSS (version 20) and by considering groups, values of P < 0.05 were considered statistically significant. RESULTS: Mean systolic blood pressure (119.5 +/- 7.4 mmHg) and mean heart rate (71.7 +/- 6.7 b/min) were higher in a group receiving Voluven (P < 0.05). The Voluven group significantly experienced less nausea and vomiting in recovery room in comparing with other groups (P = 0.027). They also received significantly less ephedrine (P = 0.012) and ondansetron [12 (20%)] (P = 0.02). Furthermore, patients receiving elastic bandage had significantly more blood loss than the other groups (P = 0.013). CONCLUSION: Colloid therapy was the most effective method in keeping hemodynamic stability, prevention of decrease in systolic blood pressure and incidence of side effects during spinal anesthesia for lumbar disc surgery in knee-chest position. PMID- 26605221 TI - Evaluation of antimullerian hormone levels before and after laparoscopic management of endometriosis. AB - BACKGROUND: Serum antimullerian hormone (AMH) proposed to be a reliable marker of ovarian reserve; the aim of this study was to evaluate the influence and value of laparoscopic management in endometriosis as measured by serum AMH levels. MATERIALS AND METHODS: In this cross-sectional study, 33 infertile patients who referred to fertility - Infertility Center of Isfahan - with different stages of endometriosis managed by diagnostic operative laparoscopy and serum AMH levels were measured pre and one month postoperative laparoscopy. Main outcome measures were serum AMH levels in correlation with the type of infertility, stage of endometriosis, and type of surgery in infertile patients. RESULTS: 33 infertile patients enrolled in the study with mean age 28.9 +/- 5 years, and thus did not show a significant difference. Mean serum AMH levels was 4.23 +/- 3.75 ng/ml and 2.2 +/- 2.47 ng/ml, respectively, in primary and secondary infertility groups before and one month after laparoscopy, which shows a significant difference (P < 0.001). Median AMH level changes in Cauterization (0.67 +/- 0.76 ng/ml), endometrioma excision 2 +/- 0.6 ng/ml, both 2.18 +/- 0.81 ng/ml and shows no significant differences. Mean serum AMH levels were definitely decreased in minimal/mild and severe stage endometriosis before and 1 month after laparoscopy, (1.84 +/- 2.06 ng/ml and 2.18 +/- 3.45 ng/ml), respectively. Also serum AMH according to ovarian appearance and evolvement showed no significant differences after laparoscopy: (5.5 +/- 1.4 ng/ml and 2.76 +/- 0.96 ng/ml) and (3.37 +/- 2.2 ng/ml and 1.84 +/- 1.5 ng/ml). CONCLUSION: Serum AMH levels clearly decreased 1 month after operative laparoscopy. PMID- 26605222 TI - Dietary nutrient intake and antioxidant status in preeclamptic women. AB - BACKGROUND: Preeclampsia (PE) is the most common cause of maternal death in the world. Some studies showed that inadequate intake of foods rich in antioxidant leads to increase oxidative stress and adverting obstetrical outcomes. The aim of the present study was to investigate the relationship between antioxidant status and dietary nutrient intake in pregnant women with PE. MATERIALS AND METHODS: This cross-sectional study was conducted among 55 pregnant women with PE admitted in the Obstetrics and Gynecology department of Shahid Beheshti Hospital in Isfahan, Iran. The subjects were interviewed about demographic data and dietary intakes by using a 168-items semi-quantitative food frequency questionnaire (FFQ). The total antioxidant capacity (TAC) of this serum was measured by using a double-antibody sandwich enzyme-linked immune-sorbent assay (ELISA). Nonparametric correlation statistics were used to meet assumptions of normality and equal variances. RESULTS: Total antioxidant status was significantly higher in comparison with healthy pregnant women (which measured as pilot). Intake of vitamin E was below the dietary reference intakes, and was positively associated with serum TAC (r = 0.367, P = 0.003), but this correlation was significantly negative about dietary selenium. There wasn't any significant correlation between intake of vitamin C, beta-carotene, riboflavin, copper and serum TAC. CONCLUSION: Our findings showed that intake of vitamin E was positively associated with serum TAC. Little support was found on a relationship between dietary intakes of other micronutrients and serum TAC. Further research is required to explore the relationships between maternal nutrient intake and antioxidant status in women with PE. PMID- 26605223 TI - Fibrocalculous pancreatic diabetes in adult. AB - Fibrocalculous pancreatic diabetes has distinctive features like younger age at onset, presence of large intraductal calculi, aggressive course of the disease, and proneness for pancreatic cancer. Pancreatic calculi are the hallmark for the diagnosis. We report a 32-year-old male patient, a known case of diabetes since 2 years, presented with recurrent pain abdomen, malabsorption, and neuropathic symptoms. The diagnosis was established on the basis of clinical examination, biochemical and radiological investigations. He was prescribed two doses of premix insulin and pancreatic enzyme supplements for relief of abdominal pain and steatorrhea. PMID- 26605224 TI - Nocardial brain abscess in a patient with pulmonary alveolar proteinosis. AB - Brain abscesses caused by Nocardia are rare but have a very high mortality and specific requirements of antibiotic treatment. Nocardial brain abscesses are mainly found in patients with predisposing conditions such as pulmonary alveolar proteinosis (PAP), a disease associated with chronic exposure to silica dust. We present a case of multiple nocardial brain abscesses in a man with PAP probably due to long-term occupational exposure to silica dust. Conclusively, in patients presenting brain abscesses and a history of chronic exposure to silica dust, PAP and opportunistic nocardial infection should always be considered as possible diagnoses. PMID- 26605225 TI - Agreement between static magnetic resonance urography and diuretic renal scintigraphy in patients with ureteropelvic junction obstruction after pyeloplasty. AB - BACKGROUND: Ureteropelvic junction obstruction (UPJO) is the most common cause of hydronephrosis within childhood that usually treat by surgery. According to anatomical variations in different individuals, scheduling similar procedures for all patients is not suitable, and thus the best decision for an appropriate surgical technique should be considered separately for each patient. Regardless of the type of applied technique, creating a funnel-shape UPJ with a suitable size is a successful treatment. In this context, the assessment of a successful surgical treatment in a short-term follow-up means repairing revealed anatomical defects. The present study aimed to compare the diagnostic value of static magnetic resonance urography (MRU) and diuretic-based renalscintigraphy (DRS) in patients with UPJO after pyeloplasty. MATERIALS AND METHODS: A total of 30 consecutive patients with UPJO, who underwent unilateral pyeloplasty between 2012 and 2013 were assessed. All subjects underwent DRS and also MRU about 1-month after the former procedure. RESULTS: The Kendall's tau correlation showed a very strong correlation between results of MRU and diuretic renal scintigraphy (r = 0.932, P < 0.001). This strong correlation was also shown by Somers'd test (r = 0.932, P < 0.001) similarly. CONCLUSIONS: Our study shows a strong agreement between DRS and MRU to assess UPJO. MRU static fluid has a high accuracy for assessment of renal system anatomy. Due to the lack of dangerous consequences of contrast materials, MRU can be the best option instead of DRS. PMID- 26605226 TI - Risk factor assessment of stroke and its awareness among stroke survivors: A prospective study. AB - BACKGROUND: Stroke is the second most common cause of death and major cause of disability worldwide. The objective of this study is to identify the major risk factors and assess the awareness among the stroke survivors. MATERIALS AND METHODS: A prospective study was conducted at super specialty hospital, from December 2010 to July 2011. All the stroke patients of the age >25 years with either sex admitted in the hospital were included in the study. In order to assess the awareness among the stroke survivors, questionnaire established on the risk factors for stroke from the previously published studies. RESULTS: A total of 100 patients with stroke or cerebrovascular accident were included in the study. Of 100 patients, 73% patients had ischemic stroke and 26% patients had hemorrhagic stroke. The mean age of the patients was 50 years and the incidence of stroke was predominant in males 73%, followed by females 27. It was observed that 70% of patients were hypertensives, 28% were diabetics, 27% were alcoholics, and 24% of patients had a habit of smoking, followed by others. The knowledge of the risk factors for stroke in stroke survivors was also very low, and the knowledge was varied among the subjects according to their level of educational status. CONCLUSION: This study reveals that hypertension is the most common risk factor for stroke followed by diabetes, smoking, and dyslipidemia. The awareness of risk factor among stroke survivors was poor. PMID- 26605227 TI - Cytoprotective and antioxidant effects of human lactoferrin against H2O2-induced oxidative stress in human umbilical vein endothelial cells. AB - BACKGROUND: Lactoferrin (LF) is an iron-binding glycoprotein with antioxidant, anti-inflammatory and nitric oxide-dependent vasodilatory properties. In the present study, we investigated the protective and antioxidant effects of LF on H2O2-induced oxidative stress in human umbilical vein endothelial cells (HUVECs). MATERIALS AND METHODS: HUVECs were pretreated by (6.25-100 MUg/ml) LF for 24 h and then exposed to 0.5 mM H2O2 for 2 h. Cell viability was assessed by 3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The intra- and extra-cellular hydroperoxides concentration and ferric reducing antioxidant power (FRAP) were determined in pretreated cells. RESULTS: Pretreatment of HUVECs with LF at the concentrations of 25-100 MUg/ml significantly reduced the cytotoxicity of H2O2 in a concentration-dependent manner using MTT assay. LF pretreatment at different concentration ranges also decreased the hydroperoxides level and augmented the FRAP value in both intra-and extra-cellular assay. CONCLUSION: These findings revealed antioxidant and cytoprotective effects of LF against H2O2 induced oxidative stress in HUVECs. With regard to the beneficial vascular activity of LF, further investigations are suggested for understanding its clinical value in human endothelial dysfunction and prevention and/or treatment of CVDs. PMID- 26605228 TI - Pitfalls in molecular diagnosis of 21-hydroxylase deficiency in congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasia (CAH) is a putative error of metabolism with autosomal recessive heredity pattern. The main manifestations of classic form of CAH are salt-wasting, dehydration and simple virilization in both sexes and ambiguous genitalia in female gender. 21-hyroxylase (CYP21A2) impairment with prevalence value of 1 in 10,000-15,000 live births is the most common etiology of CAH. Because of consanguineous marriages, the frequency of the CAH in Iran is very high. A wide range of mutations diversity exists in CYP21A2 gene and a large number of these mutations derived from a highly homologous pseudogene, CYP21A1P, through gene conversion. In addition, new mutations such as small and large deletion and point mutations can also result in enzyme deficiency. Various methods for mutation detection were performed. The main obstacle in molecular diagnosis of CAH is amplification of pseudogene during polymerase chain reaction of CYP21A2. All attempts focus on discrimination of pseudogene from gene; that is why, there is the majority of mutations on pseudogene, and if we have contamination with the pseudogene, the result will be unreliable. Here, we discuss this methods and advantage and disadvantage of those. PMID- 26605229 TI - Effect of tubeless percutaneous nephrolithotomy on early renal function: Does it deteriorate? AB - BACKGROUND: The impact of standard percutaneous nephrolithotomy (PCNL) on short or long-term renal function has been evaluated in many studies. We evaluated the effect of tubeless PCNL on early renal function. MATERIALS AND METHODS: A total of 117 patients referring to our university center for PCNL were enrolled in the study if they were matched with the inclusion criteria. Serum creatinine and hemoglobin (Hb) levels were measured before PCNL and 6, 24, 48, and 72 h after the operation. Glomerular filtration rate (GFR) was calculated using Cockroft Gault formula. RESULTS: There were 79 (67.5%) men and 38 women (32.5%) with the mean age of 49.94 years ranging from 18 to 80 years in the study group. The mean creatinine level elevated in the first 48 h after PCNL but it started to reduce on the 3(rd) day (mean preoperative creatinine level: 1.32 +/- 0.18 mg/dL, mean creatinine level after 48 h: 1.59 +/- 0.24 mg/dL, creatinine level after 72 h: 1.42 +/- 0.21245 mg/dL) (P < 0.0001). GFR values had the same rise and fall pattern as serum creatinine level (mean preoperative GFR: 74.89 mL/min, mean GFR after 48 h: 64.04 mL/min, GFR after 72 h: 69.54 mL/min, P < 0.0001). PCNL also affected blood Hb level. The mean preoperative Hb level was 15.06 +/- 0.87 g/dL and it significantly decreased to 13.09 +/- 1.06 g/dL after the operation (P < 0.0005). CONCLUSIONS: Tubeless PCNL like standard PCNL decreases GFR in the very early postoperative days. It is recommended that factors that might have a negative impact on renal function during first few days after PCNL be avoided. PMID- 26605230 TI - Iranian-Islamic traditional medicine: An ancient comprehensive personalized medicine. AB - Personalized medicine (PM) is a novel term used for a medical model in which all diagnostic, prognostic, and therapeutic aspects of a disease are individualized for a patient using specific molecular testing. In Iranian-Islamic traditional medicine (IITM) an ancient paradigm for PM has been described which has been introduced in this paper. We reviewed the ancient resources of IITM and many valid recent studies on personalized medicine and described an ancient feature of personalized medicine in comparison with new ones. According to IITM scholars, every person has an individual temperament which is concluded of four basic humors combination. The individual temper is influenced by internal and external factors such as age, gender, ethnicity, season, and environment. This variability leads to different physical and mental behaviors toward a particular condition; so if we could identify the patient's temper, we would predict his/her health related behaviors rather than predisposition and prognosis to different diseases, and select the best treatment. This holistic viewpoint of IITM to the human health and disease justifies the variable phenotypes among similar illnesses; the fact around which more advanced high-tech researches are being developed to explore all specific molecular pathways. IITM offers an ancient comprehensive PM (APM) which is more available and inexpensive compared to the modern PM (MPM). Moreover, APM focuses more on fitness than illness in comparison to MPM. It seems more attention to APM introduced by IITM could help us to promote health community. Design studies using high-tech MPM techniques would likely lead to clarification of most molecular aspects of APM. PMID- 26605231 TI - Hippocampal volume and hippocampal angle (a more practical marker) in mild cognitive impairment: A case-control magnetic resonance imaging study. AB - BACKGROUND: Mild cognitive impairment (MCI) accompanies brain atrophy in neuroimaging investigations. The aim of this study was to compare MCI patients with the normal population for hippocampal volume (HV) and hippocampal angle (HA), and to assess the correlation between HV and HA. MATERIALS AND METHODS: In a case-control study on 2014, in Kashani Hospital (Isfahan, Iran), 20 MCI patients were compared with 20 normal controls for HV and HA. Subjects were diagnosed with MCI or normal control, based on neuropsychiatry interview, which was confirmed by neuropsychiatry unit cognitive assessment tool (NUCOG). All magnetic resonance imaging scans were processed using the Free-Surfer software package for HV assessment. The HA was measured on the most rostral slice in which the uncal sulcus could be identified on a coronal plane. The data were analyzed using multiple analysis of co-variance and Pearson correlation. RESULTS: The mean (standard deviation [SD]) score of NUCOG in control and case group were 91.05 (3.01) and 82.42 (3.57), respectively. Comparison of HV and HA scores in two groups, showed that mean (SD) HV and HA were not different between control and case groups, significantly, (P = 0.094 and P = 0.394, respectively). There was a negative correlation between the adjusted HV and the HA in case (r = -0.642, P = 0.004), and control groups (r = -0.654, P = 0.003). CONCLUSION: HV and HA were not different between MCI patients and normal controls; however, HA is correlated with HV negatively and may be used as an alternative factor because of more feasibility and availability in clinical settings in compared to HV. PMID- 26605232 TI - Maternal and neonatal morbidity and mortality rate in caesarean section and vaginal delivery. AB - BACKGROUND: The cesarean section is one of the most common procedures to prevent health-threatening risks to the mother and infant. Increasing rate of cesarean section attracted the attention of professionals and the overall objective of this study was to determine the frequency of maternal and neonatal morbidity and mortality rates in the two methods of delivery. MATERIALS AND METHODS: In a comparative cohort study, 300 cases undergoing caesarean section and 300 cases with vaginal delivery were selected in two main hospitals of Isfahan, Iran during 2013 and 2014. Demographic characteristics and factors related to mortality and morbidity of mothers and infants were studied. Mothers were also recruited 6 weeks after delivery to ask for complications. Mothers and infants mortality and morbidity were studied and analyzed by SPSS 22 software. RESULTS: Follow-up of deliveries up to 1-month after delivery suggested 2 cases of infant death (7%) in vaginal delivery group, while no case of infant death was reported in cesarean delivery group (P = 0.5). Incidence of fever was observed in first 10 days after delivery in 7 cases in the vaginal delivery group and 11 cases in the cesarean delivery group (2.3% vs. 3.7%, P = 0.4). CONCLUSION: Despite all the benefits of vaginal delivery compared with cesarean section, in many cases, especially in emergency cesarean section delivery can substantially reduce the maternal and neonatal mortality and morbidity. It is recommended to assess the complications of each method in all pregnant women about to give birth, and then decide on the method of delivery. PMID- 26605233 TI - Does working in hospital increases seroprevalence and carrier state against Bordetella pertussis? AB - BACKGROUND: Health care environments have been the setting for a number of pertussis outbreaks. Immunity after vaccination wanes overtime leading to a growing population of susceptible adolescents and adults. A number of pertussis outbreaks have occurred in hospitals resulting in transmission to health care workers (HCWs), and other patients. The aim of this study was to assess immunity status of a group of basic medical students and interns who worked in hospitals for about 4 years. MATERIALS AND METHODS: In a cross-sectional study, we measured the serum antibody titer of cases by enzyme-linked immunosorbent assay test. All 70 subjects have received pertussis vaccine in the routine childhood vaccination schedule. All cases were healthy and had no symptoms of any respiratory diseases. We also obtained a pharyngeal culture on Bordet-Gengou Agar for isolating Bordetella pertussis. RESULTS: The results of B. pertussis pharyngeal culture was positive for 5 (7.1%) cases and negative for 65 (92.9%). The IgM, IgA, and IgG serum antibody was positive in 1.4%, 7.1%, and 11.4% of cases, respectively. The mean age of cases had no significant effect on serum antibody titers (P = 0.23). CONCLUSIONS: This study showed that majority of cases do not have protective serum antibody against B. pertussis. Working in hospitals does not affect seroprevalence and carrier state of B. pertussis. Immunization schedules that include no booster doses are at increased risk of pertussis. Due to the importance of the transmission in health care settings, vaccination of HCWs is a priority. PMID- 26605234 TI - Interleukin-4 receptor alpha T1432C and A1652G polymorphisms are associated with risk of visceral leishmaniasis. AB - BACKGROUND: Immune responses play significant roles in protection against leishmaniasis. Polymorphisms within the interleukin 4 receptor alpha chain (IL 4Ralpha) gene affect the production of cytokines, which is important for the clearance of many pathogens. The aim of the current study was to identify the relationship between visceral leishmaniasis (VL) infection and polymorphisms at positions T1432C and A1652G of IL-4Ralpha in an Iranian population. MATERIALS AND METHODS: This cross-sectional study was performed during 2004-2012 and included three groups of participants: VL patients (Group 1, n = 124), seropositive healthy controls (Group 2, n = 101), and seronegative healthy controls (Group 3, n = 55). The IL-4Ralpha T1432C and A1652G polymorphisms were evaluated using a polymerase chain reaction-restriction fragment length polymorphism technique, and anti-Leishmania antibody titers were determined by using immunofluorescence technique. Alleles and genotypes were compared between groups of the study as well as Groups 1 and 2 based on the titer of antibodies. The validity of the data was analyzed using Hardy-Weinberg equilibrium and one-way analysis of variance, as well as chi (2) tests. RESULTS: The polymorphisms at IL-4Ralpha positions T1432C and A1652G were significantly associated with active VL infection. These results demonstrated that the IL-4Ralpha T1432C and A1652G polymorphisms were not associated with anti-Leishmania antibody production. CONCLUSION: Our results indicate that these IL-4Ralpha polymorphisms may be risk factors for the development of VL. PMID- 26605235 TI - Sleep apnea syndrome and restless legs syndrome in kidney transplant recipients. AB - BACKGROUND: This study was aimed to evaluate the prevalence of obstructive sleep apnea (OSA) and restless legs syndrome (RLS) in patients with end-stage renal disease (ESRD) after kidney transplantation. MATERIALS AND METHODS: Two hundred kidney transplant recipients were enrolled in this cross-sectional study. Data on age, gender, etiology of ESRD, history of previous kidney transplantation, serum creatinine, and the presence or absence of OSA and RLS were collected. Symptoms of RLS were identified using the RLS questionnaire which was completed by the patients. The Berlin questionnaire and polysomnography were used for diagnosing OSA. RESULTS: The mean age of the studied patients was 45.86 +/- 10.24 years. The prevalence of OSA was 26% (52 of 200 studied patients) and of RLS was 51.5% (103 of 200 studied patients). Majority of the patients with high-risk OSA were male and significantly older than the patients with low-risk OSA (P < 0.05). The prevalence of RLS was higher in patients with high-risk OSA and a higher level of creatinine compared to that in those with a low risk of OSA (P < 0.0001). Level of creatinine in patients with positive RLS was significantly higher than in those with negative RLS (P < 0.0001). OSA was observed in almost 42% of patients with positive RLS, compared to 9% of patients with negative RLS (P < 0.0001). CONCLUSION: In summary, our results indicate that the prevalence of OSA and RLS in kidney transplant recipients was higher than in the general population. Also, there was a significant association between OSA and RLS in these patients. PMID- 26605236 TI - Prophylactic use of intravenous ondansetron versus ketamine - midazolam combination for prevention of shivering during spinal anesthesia: A randomized double-blind placebo-controlled trial. AB - BACKGROUND: The aim of this study was to compare the efficacy intravenous (IV) ondansetron with ketamine plus midazolam for the prevention of shivering during spinal anesthesia (SA). MATERIALS AND METHODS: Ninety patients, aged 18-65 years, undergoing lower extremity orthopedic surgery were included in the present study. SA was performed in all patients with hyperbaric bupivacaine 15 mg. The patients were randomly allocated to receive normal saline (Group C), ondansetron 8 mg IV (Group O) or ketamine 0.25 mg/kg IV plus midazolam 37.5 MUg/kg IV (Group KM) immediately after SA. During surgery, shivering scores were recorded at 5 min intervals. The operating room temperature was maintained at 24 degrees C. RESULTS: The incidences of shivering were 18 (60%) in Group C, 6 (20%) in Group KM and 8 (26.6%) in Group O. The difference between Groups O and Group KM with Group C was statistically significant (P < 0.05). No significant difference was noted between Groups KM with Group O in this regard (P > 0.05). Peripheral and core temperature changes throughout surgery were not significantly different among three groups (P > 0.05). Incidence (%) of hallucination was not significantly different between the three groups (0, 3.3, 0 in Group O, Group KM, Group C respectively, P > 0.05). CONCLUSION: Prophylactic use of ondansetron 8 mg IV was comparable to ketamine 0.25 mg/kg IV plus midazolam 37.5 MUg/kg IV in preventing shivering during SA. PMID- 26605237 TI - Evaluation of the outcomes of corneal collagen cross-linking in progressive keratoconic eyes. AB - BACKGROUND: Corneal collagen cross-linking (CXL) is gaining popularity as a treatment in arresting the progression of keratoconus. It is a relatively new therapy using ultraviolet-A (UVA) with a photosensitizer to increase corneal stiffness. The purpose of this study was to evaluate visual, keratometric and topographic outcomes after corneal CXL in progressive keratoconic eyes. MATERIALS AND METHODS: In this prospective nonrandomized clinical study, 140 eyes of 110 patients with progressive keratoconus were treated by combined riboflavin/UVA CXL. Mean sphere, mean cylinder uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest refractive spherical equivalent, corneal topography, pachymetry, and endothelial cell morphology were examined preoperatively and 12-24 months postoperatively. RESULTS: The preoperative mean sphere was -3.33 +/- 3.13 diopter (D) and decreased to -3.09 +/ 3.09 D (P = 0.007). The preoperative mean cylinder was -4.05 +/- 2.29 D and changed to -3.79 +/- 2.23 D (P = 0.011). UDVA changed from 0.95 +/- 0.64 logarithm of the minimum angle of resolution (logMAR) to 0.85 +/- 0.59 logMAR (P = 0.003). Thirty-five eyes (25%) gained one or more lines of preoperative UDVA, 87 eyes (62.1%) did not change and 18 eyes (12.8%) lost one or more lines of the preoperative UDVA. CDVA in 80% of the patients remained stable (no lines lost). Statistical analysis of keratometry, pachymetry, and endothelial cell count did not show the significant difference after surgery. CONCLUSION: Our study showed improvement in visual and refractive results of the corneal CXL and confirmed that CXL is the safe and effective procedure. PMID- 26605238 TI - Changes of neural markers expression during late neurogenic differentiation of human adipose-derived stem cells. AB - BACKGROUND: Different studies have been done to obtain sufficient number of neural cells for treatment of neurodegenerative diseases, spinal cord, and traumatic brain injury because neural stem cells are limited in central nerves system. Recently, several studies have shown that adipose-derived stem cells (ADSCs) are the appropriate source of multipotent stem cells. Furthermore, these cells are found in large quantities. The aim of this study was an assessment of proliferation and potential of neurogenic differentiation of ADSCs with passing time. MATERIALS AND METHODS: Neurosphere formation was used for neural induction in isolated human ADSCs (hADSCs). The rate of proliferation was determined by 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and potential of neural differentiation of induced hADSCs was evaluated by immunocytochemical and real-time reverse transcription polymerase chain reaction analysis after 10 and 14 days post-induction. RESULTS: The rate of proliferation of induced hADSCs increased after 14 days while the expression of nestin, glial fibrillary acidic protein, and microtubule-associated protein 2 was decreased with passing time during neurogenic differentiation. CONCLUSION: These findings showed that the proliferation of induced cells increased with passing time, but in early neurogenic differentiation of hADSCs, neural expression was higher than late of differentiation. Thus, using of induced cells in early differentiation may be suggested for in vivo application. PMID- 26605239 TI - Absence of association between -286C>A>T polymorphism in the CRP gene and metabolic syndrome in Iranian pediatric. AB - BACKGROUND: As a common pathophysiological condition worldwide, metabolic syndrome (MetS) is a clustering of multiple risk factors implicating in the development of many chronic disorders. Of note, obesity-induced chronic, low grade inflammation is a major cause of insulin resistance and MetS. In the present study, we evaluated the association of rs3091244 variant of the C reactive protein (CRP) gene, a well-recognized systemic inflammatory marker, with MetS in Iranian children and adolescents. MATERIALS AND METHODS: Genotyping was performed by mismatched polymerase chain reaction-restriction fragment length polymorphism in 100 MetS and 100 normal individuals aged 9-19 years recruited in the central part of Iran in 2011. A t-test or one-way ANOVA with post-hoc multiple comparisons were used to analyze the differences between groups. Statistical significance was defined as P <= 0.05. Logistic regression used to evaluate the association between alleles of the CRP rs3091244 and increased MetS risk. RESULTS: There were no differences in the genotype frequencies or allele distribution for -286C>A>T CRP polymorphism between MetS and control groups. Logistic regression showed that only the T allele of the CRP rs3091244 and not any of the genotypes confers a borderline significant (P = 0.059) increased MetS risk compared to A allele with the odds ratio of 1.70 (0.98-2.96). CONCLUSIONS: This study suggests that in Iranian children and adolescents, -286C>A>T CRP polymorphism is not associated with the increased risk for MetS. PMID- 26605240 TI - The effect of add-on memantine on global function and quality of life in schizophrenia: A randomized, double-blind, controlled, clinical trial. AB - BACKGROUND: Schizophrenia severely influences function and quality of life. The benefit of newer antipsychotics in improving the quality of life in schizophrenia still remains controversial. The aim of the present study is to evaluate the effect of memantine on global function and quality of life in patients with schizophrenia. MATERIALS AND METHODS: This was a randomized controlled trial on inpatient cases of schizophrenia in Noor University Hospital, Isfahan, Iran. A number of 64 patients were selected through sequential sampling; patients were randomly allocated in intervention and placebo groups. The intervention group was treated with memantine plus previously administered, stabled-dose, atypical antipsychotic, while the control group received placebo plus previously administered, stabled-dose, atypical antipsychotic. Memantine administration was initiated at 5 mg daily; the dosage was increased at weekly intervals by 5 mg and finally up-titrated to 20 mg daily within 4 weeks. All patients were assessed by means of Global Assessment of Functioning (GAF) and quality of life scale (QLS) initially and every four weeks to the end of the 12(th) week. RESULTS: Analysis of baseline GAF and QLS scores showed no significant differences between the two groups (P = 0.081 and P = 0.225, respectively). GAF and QLS scores increased in both groups; but it was higher in the intervention group. The difference between the two groups was statistically significant. (P < 0.001 and P < 0.001, respectively) memantine was well tolerated, with no significant side effects. CONCLUSION: Add-on memantine was significantly effective in improving the global function of patients as well as their quality of life. PMID- 26605241 TI - Effects of cumin on nonalcoholic steatohepatitis: A double blind, randomised, controlled trial. AB - BACKGROUND: This study was designed to evaluate the effect of cumin on nonalcoholic steatohepatitis (NASH) in compare to placebo. MATERIALS AND METHODS: One hundred patients with histopathological diagnosis NASH in two groups of case and control received oral cumin capsule or placebo thrice daily for 6 months. Clinical and laboratory data were body mass index (BMI), serum triglyceride, serum total cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST), high-density lipoprotein (HDL), low-density lipoprotein (LDL), fasting blood sugar (FBS), steatosis grade, and side-effects and were measured at baseline and after treatment period using standard clinical chemistry techniques. The grade of steatosis was assessed by liver sonography in 3 stages (mild, moderate and severe). RESULTS: Of 100 eligible patients during follow-up 10/50 cases and 9/50 controls were excluded. At baseline and after treatment BMI, triglyceride, cholesterol, ALT, AST, HDL, LDL, and FBS were not statistically significant between groups (P >= 0.5). BMI, triglyceride, cholesterol, ALT, AST, LDL, and FBS after treatment decreased compare to baseline but were not statistically significant (P >= 0.5). The mean of changes in the level of BMI, triglyceride, cholesterol, ALT, LDL and FBS were not statistically significant (P >= 0.5). The mean of changes in AST and HDL between groups was significant (P < 0.05). The grade of steatosis before and after treatment between studied groups was not statistically significant (P >= 0.5). Side-effects were not statistically significant among the two groups. CONCLUSION: Findings show that there the effect of cumin in in the treatment of NASH was not significantly different in compare to placebo. PMID- 26605242 TI - The relation between serum Vitamin D levels and body antioxidant status in ischemic stroke patients: A case-control study. AB - BACKGROUND: Stroke is the second cause of death among elderly people. Oxidative stress plays an important role in brain damage after stroke. Currently, Vitamin D has been shown as an antioxidant. The aim of this study was to evaluate the status of Vitamin D, antioxidant enzymes, and the relation between them in ischemic stroke patients. MATERIALS AND METHODS: This case-control study was carried out on 36 patients with ischemic stroke patients and 36 matched subjects as controls. Intake of fruits and vegetables, exposure of sunlight, serum lipid profile, concentrations of serum 25-dihydroxy Vitamin D (25(OH) D), activities of serum superoxide dismutase, and glutathione peroxidase enzymes were determined. RESULTS: Severe Vitamin D deficiency was seen in 30% of the patients versus 11% of the controls (P < 0.05). Consumption of fruits and vegetables was lower in patients than that of controls (P < 0.05). Activities of antioxidant enzymes and intake of fruits were positively correlated in stroke patients (P = 0.02). The most potent predictors of stroke risk were hypertension, high levels of low density lipoprotein cholesterol (LDL-C) and history of cardiovascular disease (CVD) (odds ratios: 3.33, 3.15, and 3.14, respectively, P < 0.05 for all). There was no association between 25(OH) D levels with activities of serum antioxidant enzymes and lipid profile in the two groups. CONCLUSION: Ischemic stroke patients have higher prevalence of severe Vitamin D deficiency and lower intakes of fruits and vegetables. Intake of fruits was positive correlated to higher antioxidant enzymes levels. High levels of blood pressure, history of CVD, and high LDL-C levels are the strongest predictors of ischemic stroke. PMID- 26605243 TI - Potential health concerns of trace elements and mineral content in commonly consumed greenhouse vegetables in Isfahan, Iran. AB - BACKGROUND: This study aimed to investigate the potential health concerns of trace elements and mineral content of commonly consumed greenhouse vegetables in Isfahan, Iran. MATERIALS AND METHODS: Six kinds of greenhouse vegetables namely; Raphanus sativus (Radish), Cucumis sativus (Cucumber), Solanum lycopersicum (Tomato), green Capsicum annuum (Green bell pepper), yellow C. annuum (Yellow bell pepper), and red C. annuum (Red bell pepper) were collected from Isfahan greenhouses, between December 2012 and March 2013. The vegetables were analyzed in order to determine the concentrations of trace elements and trace minerals using instrumental neutron activation analysis (INAA). RESULTS: The results of INAA showed that the concentrations of aluminum, bromine, cobalt, rubidium and strontium of these vegetables were varied from 7.2 to 28.4 mg/kg, 0.6-11.7 mg/kg, 0.1-0.5 mg/kg, 4.2-8.4 mg/kg, and 12.0-141.0 mg/kg, respectively. The trace mineral concentrations of As, Cr, Cs, Sc, Th, and U in all of the samples were less than the defined tolerable upper intake level. CONCLUSION: The results of this study revealed that considering the measured trace elements and mineral content levels, Isfahan greenhouse vegetables do not impose any serious health harmful effects for individuals in the studied area due to their meal consumptions. PMID- 26605244 TI - Median and ulnar nerve injuries; what causes different repair outcomes? AB - BACKGROUND: Peripheral nerve injuries have significant effects on patients' life quality. To make patients' therapeutic expectations more realistic, prediction of repair outcome has significant importance. MATERIALS AND METHODS: Totally, 74 patients with 94 nerve injuries (44 median and 50 ulnar nerves) were evaluated and followed up for 5 years between 2008 and 2013 in two main university hospitals of Isfahan. Patients' age was 6-64 years. 24 nerves were excluded from the study and among the remaining; 53 nerves were repaired primarily and 17 nerves secondarily. 42 nerves were injured at a low-level, 17 nerves at intermediate and 11 at a high one. Medical Research Council Scale used for sensory and motor assessment. S3+ and S4 scores for sensory recovery and M4 and M5 scores for motor recovery were considered as favorable results. The follow-up time was between 8 and 24 months. RESULTS: There was no significant difference between favorable sensory outcomes of median and ulnar nerves. The difference between favorable motor outcomes of the median nerve was higher than ulnar nerve (P = 0.03, odds ratio = 2.9). More favorable results were seen in high-level injuries repair than low ones (P = 0.035), and also cases followed more than 18 months compared to less than 12 months (P = 0.041), respectively. The favorable outcomes for patients younger than 16 were more than 40 and older, however, their difference was not significant (P = 0.059). The difference between primary and secondary repair favorable outcomes was not significant (P = 0.37). CONCLUSION: In patients older than 40 or injured at a high-level, there is a high possibility of repetitive operations and reconstructive measures. The necessity for long-term follow-up and careful attentions during a postoperative period should be pointed to all patients. PMID- 26605245 TI - Tumor necrosis factor-alpha inhibits effects of aryl hydrocarbon receptor ligands on cell death in human lymphocytes. AB - BACKGROUND: Activation of aryl hydrocarbon receptor (AhR) leads to diverse outcome in various kinds of cells. AhR activation may induce apoptosis or prevent of apoptosis and cell death. Recent studies suggest that apoptosis effects of AhR can be modulated by inflammatory cytokine like tumor necrosis factor alpha (TNF alpha). In this study, we try to investigate the possible interaction of TNF alpha with the 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), a ligand of AhR, on peripheral lymphocytes. MATERIALS AND METHODS: Human peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood by discontinuous density gradient centrifugation on ficoll. Isolated PBMCs were divided into four groups: Control group, TNF-alpha administered group, TCDD administered group, co administered group with TCDD and TNF-alpha. Cells were maintained for a week in lymphocyte culture condition. Then, TNF-alpha was added to group 2 and 4. Finally, apoptosis and necrosis were analyzed in all samples using flowcytometry. RESULT: In group 4, the mean percent of necrosis and apoptosis in TCDD treatment groups was significantly larger than other groups; (P < 0.05). Furthermore, there was no significant difference between the mean percent of cell death in TNF-alpha administered group and TCDD administered group (P > 0.05). However, the mean percent of cell death in co-administered group with TCDD and TNF-alpha was significantly lower than other groups; (P < 0.05). CONCLUSION: TNF-alpha could significantly inhibit effects of TCDD on lymphocytes apoptosis. Combination effects of TNF-alpha and TCDD on lymphocyte increase cell survival. PMID- 26605246 TI - In silico design of fusion protein of FimH from uropathogenic Escherichia coli and MrpH from Proteus mirabilis against urinary tract infections. AB - BACKGROUND: Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) and Proteus mirabilis are the most important pathogens causing UTIs. The FimH from type 1 pili of UPEC and the MrpH from P. mirabilis play critical roles in the UTI process and have presented as ideal vaccine candidates against UTIs. There is no effective vaccine against UTI and the development of an ideal UTI vaccine is required. MATERIALS AND METHODS: In this study, we planned to design a novel fusion protein of FimH from UPEC and MrpH from P. mirabilis. For this purpose, we modeled fusion protein forms computationally using the Iterative Threading Assembly Refinement (I-TASSER) server and evaluated their interactions with toll-like receptor 4 (TLR4). The best fusion protein was constructed using overlap extension polymerase chain reaction (OE-PCR) and the biological activity of fusion was evaluated by the induction of interleukin-8 (IL-8) in the HT-29 cell line. RESULTS: Our study indicated that based on the Protein Structure Analysis (ProSA)-web and the docking results, MrpH.FimH showed better results than did FimH.MrpH, and it was selected for construction. The results of bioassay on the HT-29 showed that FimH and MrpH.FimH induced significantly higher IL-8 responses than untreated cells or MrpH alone in the cell line tested. CONCLUSIONS: In the present study, we designed and constructed the novel fusion protein MrpH.FimH from UPEC and P. mirabilis based on in silico methods. Our bioassay results indicate that the MrpH.FimH fusion protein is active and capable of inducing immune responses. PMID- 26605247 TI - 2,3,7,8-tetrachlorodibenzo-p-dioxin decrease expression of aryl hydrocarbon receptor in peripheral lymphocyte of beta-thalassemia major patients. AB - BACKGROUND: beta-thalassemia major is a hereditary disease with inefficient erythropoiesis. Level of inflammatory cytokine is elevated in these patients. In this study, we investigate the effect of aryl hydrocarbon receptor (AhR) ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), on the expression of inflammatory mediators in beta-thalassemia major patient's lymphocytes. MATERIALS AND METHODS: Peripheral blood mononuclear cells of patients and healthy participants was isolated and cultured in favor of lymphocytes increment. Based on the treatment, we divided the cell into four groups. The orders of group's treatments were no treatment, tumor necrosis factor-alpha (TNF-alpha) treatment, TNF-alpha and TCDD treatment, TCDD treatment in Group 1-4, respectively. After cell culture, we extracted the cells RNA and converted them to cDNA. Real-time polymerase chain reaction was performed to assessment relative expression of caspase-1, NLRP3, and AhR. We compared all patient groups with equal healthy (control) groups. RESULTS: Results showed that expression of caspase-1 in patients (Groups 1 and 2) was significantly lower than healthy individuals (P < 0.05). Although, no significant difference was found (Groups 1, 2, and control) in AhR gene expression (P > 0.05). Expression of AhR in other groups of patients (3 and 4) was significantly lower than control groups (P < 0.05). Expression of caspase-1 in Group 4 was significantly larger than the control group (P < 0.001). CONCLUSIONS: We show here that chronic inflammation decrease caspase-1 expression and exposure of human lymphocytes to TCDD promote caspase-1 expression. Furthermore, activation of AhR with TCDD decreases AhR expression in lymphocytes of beta-thalassemia major disease. PMID- 26605248 TI - Nanobiological studies on drug design using molecular mechanic method. AB - BACKGROUND: Influenza H1N1 is very important worldwide and point mutations that occur in the virus gene are a threat for the World Health Organization (WHO) and druggists, since they could make this virus resistant to the existing antibiotics. Influenza epidemics cause severe respiratory illness in 30 to 50 million people and kill 250,000 to 500,000 people worldwide every year. Nowadays, drug design is not done through trial and error because of its cost and waste of time; therefore bioinformatics studies is essential for designing drugs. MATERIALS AND METHODS: This paper, infolds a study on binding site of Neuraminidase (NA) enzyme, (that is very important in drug design) in 310K temperature and different dielectrics, for the best drug design. Information of NA enzyme was extracted from Protein Data Bank (PDB) and National Center for Biotechnology Information (NCBI) websites. The new sequences of N1 were downloaded from the NCBI influenza virus sequence database. Drug binding sites were assimilated and homologized modeling using Argus lab 4.0, HyperChem 6.0 and Chem. D3 softwares. Their stability was assessed in different dielectrics and temperatures. RESULT: Measurements of potential energy (Kcal/mol) of binding sites of NA in different dielectrics and 310K temperature revealed that at time step size = 0 pSec drug binding sites have maximum energy level and at time step size = 100 pSec have maximum stability and minimum energy. CONCLUSIONS: Drug binding sites are more dependent on dielectric constants rather than on temperature and the optimum dielectric constant is 39/78. PMID- 26605249 TI - Detection of ESBL- and AmpC-producing E. coli isolates from urinary tract infections. AB - BACKGROUND: Extended-spectrum beta-lactamases (ESBLs) and AmpC enzymes have been observed in virtually all species of the family Enterobacteriaceae. The beta lactamase producing bacteria cause many serious infections, including urinary tract infections. These enzymes are predominantly plasmid mediated. There are no recommended guidelines for detection of this resistance mechanism and there is a need to address this issue as much as the detection of ESBLs. This study was undertaken to characterize ESBL and AmpC producers among Escherichia coli by polymerase chain reaction (PCR), which were initially screened by phenotypic method. MATERIALS AND METHODS: A total of 90 isolates of E. coli were recovered from the urinary tract during a 7-month period, and were screened for ESBLs and AmpC production by disk diffusion test using cefoxitin (30 MUg) disks and confirmed by combined disk diffusion test using phenyl boronic acid. The presence of genes encoding CIT, FOX, and TEM was detected by PCR. RESULTS: On disk diffusion test, 59 of 90 isolates were resistant to third generation of cephalosporins; of these 37 (62.7%) and 3 (5%) were ESBL and AmpC producers, respectively. PCR showed that 29 (49.1%) and 3 (5%) were positive for blaT EM and bla CMY-2, respectively. CONCLUSION: ESBL- and AmpC-producing E. coli isolates cause significant resistance to cephalosporin. There is a need for a correct and reliable phenotypic test to identify AmpC beta-lactamases and to discriminate between AmpC and ESBL producers. This work showed that boronic acid can differentiate ESBL enzymes from AmpC enzymes. PMID- 26605250 TI - The Role of Peer Reviewing in the World of Open Access Publishing, Today and Tomorrow. PMID- 26605251 TI - Clinical and radiological results after coracoclavicular ligament reconstruction for type III acromioclavicular joint dislocation using three different techniques. A retrospective study. AB - PURPOSE: the purpose of this retrospective study was to present the outcomes of three different techniques for the treatment of type III acromioclavicular joint dislocations: arthroscopic TightRope (TR), arthroscopic GraftRope (GR), and open reconstruction of the coracoclavicular (CC) ligament using the Ligament Augmentation and Reconstruction System (LARS). METHODS: eighteen patients underwent clinical and radiological evaluations after a mean follow-up time of 43 months. The following clinical outcome measures were considered: the Disability of the Arm, Shoulder and Hand outcome measure (DASH), the Nottingham Clavicle Score (NCS), and the Constant score (CS). On X-rays, the CC distance was measured. RESULTS: the median DASH score at follow-up was 12.5 in the TR group, 5 in the GR group, and 4.2 in the LARS group. The median NCS value was 88 in the TR group, 88 in the GR group, and 91 in the LARS group. The median CS was 100 in the TR group, 95 in the GR group, and 94.5 in the LARS group. The mean CC distance was 10.3 mm in the TR group, 13.8 in the GR group, and 16.6 in the LARS group. CONCLUSIONS: all three techniques proved to be reliable in providing good clinical outcomes, although none of the studied techniques demonstrated reliability in maintaining anatomical reduction after surgery. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 26605252 TI - Analysis of complications of reverse total shoulder arthroplasty. AB - PURPOSE: the aim of this study was to analyze complications of reverse total shoulder arthroplasty (RTSA) used to treat different shoulder diseases. METHODS: from March 2000 to March 2013, 195 RTSA were implanted by the senior Author. The indications for reverse prosthesis surgery were secondary osteoarthritis (OA) in 49 cases, irreparable rotator cuff tear (RCT) in 48 cases, and complex humeral fractures in 75 cases, while 19 were patients requiring surgical revision for first prosthesis implant. We used different prostheses with different designs. RESULTS: the clinical and radiological results of all the patients were analyzed retrospectively at an average follow-up of 7 years. The cases were divided into four groups on the basis of the diagnosis and complications were classified as perioperative, postoperative, or late. The mean total Constant score improved from 28 to 69 points in the OA group; from 21 to 70.8 points in the irreparable RCT group, to 76.4 in the fracture group, and from 16.6 to 59.8 points in the revision group. Scapular notching was observed in 59 cases (30.2%). Thirty-three other complications (16.9%) were observed, namely: hematomas (n=3), instability of the humeral component (n=1), scapular spine fractures (n=2), ulnar nerve deficit (n=2), long thoracic nerve palsy (n=2), deep infections (n=2), periprosthetic fractures (n=6), glenoid fractures (n=2), implant loosening (n=2), anterior deltoid muscle deficiency (n=2) and periarticular heterotopic calcifications (n=9). CONCLUSIONS: the rates of complications, especially fractures, reported in the present study were lower than those reported in the current literature. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 26605253 TI - Treatment of cam-type femoroacetabular impingement. AB - PURPOSE: the aim of this study was to evaluate preliminary clinical and radiographic results of arthroscopic treatment of cam-type femoroacetabular impingement (FAI). METHODS: thirty-eight patients underwent hip arthroscopy for cam-type FAI between 2009 and 2012. Preoperative assessment was based on clinical examination, modified Harris Hip Score (mHHS) and radiographic examination with anteroposterior pelvis, frog-leg and Lequesne views. The patients' clinical conditions at follow-up were assessed using the mHHS administered as a telephone survey. Radiographic outcome measurements evaluated pre and postoperatively were the alpha angle and femoral head-neck offset. RESULTS: the patients were clinically evaluated at a mean follow-up of 36 months. Radiographic follow-up was performed at an average of 12.7 months. Thirty of the 38 patients (79%) were satisfied with the results of the arthroscopic procedure. A total of nine patients subsequently underwent a total hip replacement. All 30 patients who declared themselves satisfied recorded an mHHS increase; in particular, the mHHS increased from a mean of 52.9 preoperatively (range: 27.5-82.5) to a mean of 85.6 postoperatively (range: 45.1-100.1). Three significant differences between the two groups of patients (satisfied and not satisfied) were recorded: mean age, alpha angle and BMI were all significantly greater in the patients who were not satisfied with the treatment. CONCLUSIONS: a crucial aspect in order to obtain good clinical outcomes of arthroscopic treatment of cam-type impingement is correct selection of patients who are likely to benefit from this kind of surgery. Hip arthroscopy should be avoided in patients aged over 50 years with risk factors for early osteoarthritis (high BMI and a significantly increased alpha angle). LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 26605255 TI - Treatment of pincer-type femoroacetabular impingement. AB - Pincer femoroacetabular impingement (FAI) consists of pathological contact between the acetabular labrum and rim and the femoral head-neck junction. Manifold conditions underlie pincer FAI: anatomical abnormalities, malorientation of the acetabulum, torsional abnormalities of the neck and femoral shaft (these defects can be constitutional, post-traumatic or post-surgical), and involvement in sports characterized by repeated and sudden maximum joint excursions. In a high percentage of cases, pincer FAI is associated with cam FAI. The aims of surgical treatment of pincer FAI are to eliminate the cause of the contact and repair the joint damage; the surgery may be open or arthroscopic, performed with an articular or extra-articular approach. Recently, arthroscopic treatment of FAI had a rapid and widespread diffusion due to the advantages it offers compared with the open technique. Arthroscopic treatment can repair the joint damage and in some cases, characterized by minor deformity, compensate for extra-articular defects. The acetabular labrum must always be preserved and sutured; only in extreme cases can it be sacrificed. Post-operative mobilization must respect the healing time of the labral repair. PMID- 26605254 TI - Anatomic shoulder arthroplasty: an update on indications, technique, results and complication rates. AB - A shoulder replacement is indicated in patients affected by glenohumeral arthropathy with severely reduced range of motion, persistent pain, especially at night, and loss of strength. There is much discussion in the scientific community about the prosthetic options for these cases: hemiarthroplasty, anatomic total shoulder arthroplasty, and reverse total shoulder arthroplasty. We analyzed the indications for, results of, and complications associated with this kind of surgery, focusing on anatomic arthroplasty and on the concept of modularity. PMID- 26605256 TI - Medial unicondylar knee arthroplasty: technical pearls. AB - Unicondylar knee arthroplasty implantation is extremely demanding as the prosthesis needs to be integrated in the natural anatomy of the knee. It ensures the integrity of the natural knee kinematic. Some studies and registries data have shown lower success rate in comparison with total knee arthroplasty, and patient-related factors may have an impact on outcome. While, better results have been published by high volume centres. The indications for surgery should be reconsidered critically, even if medial osteoarthritis of the knee remains the most common. This article sets out the diagnostic, and surgical steps in order to fine tuning the unicompartmental replacement of the knee. PMID- 26605257 TI - Anterior cruciate ligament reconstruction with a novel porcine xenograft: the initial Italian experience. AB - At the current state of the art in anterior cruciate ligament (ACL) reconstruction, multiple techniques have been presented but none has given clearly defined and improved results. One of the main issues concerns the choice of graft. The concept of using xenograft tissue, defined as a graft tissue from one species and destined for implantation in an unlike species, was introduced in order to try to overcome the mechanical and biological concerns associated with synthetic materials and the safety and quality concerns and availability problems of allograft tissue. Xenograft tissue carries the risk of producing an immunological reaction. In order to try to overcome or attenuate the immune response against porcine xenograft tissue, the Z-Process(r) (Aperion Biologics Inc, San Antonio, Texas, USA) has been developed and used to produce the Z-Lig(r) family of devices for ACL reconstruction procedures. Z-Lig(r) is a tendon graft with or without bone blocks, sourced from animal tissue in a manner consistent with what has normally been sourced from human tissue, and processed to overcome anti-Gal-mediated rejection and to attenuate other immunological recognition in humans. All this while ensuring sterility, viral inactivation and preservation of mechanical proprieties appropriate for an ACL reconstruction device. The Z-Lig(r) device has been tested in skeletally mature monkeys and given interesting and promising results from the preclinical performance and safety profile point of view. On this basis, it was possible to proceed with the first clinical trial involving humans, which gave similar encouraging results. The Z-Lig(r) device has also been implanted in Italy at the Rizzoli Orthopaedic Institute in Bologna, as a part of international multicenter prospective randomized blinded controlled study aimed at comparing xenograft with allograft tissue. PMID- 26605258 TI - Irreducible posterolateral dislocation of the knee: a case report. AB - Irreducible posterolateral dislocations of the knee are rare lesions, generally caused by high-energy trauma inducing rotational stress and a posterior and lateral displacement of the tibia. In these conditions, the interposition of abundant soft tissue inside the enlarged medial joint space prevents spontaneous reduction or non-surgical treatment by manipulation of the dislocation. Surgical treatment is therefore compulsory. We report the clinical case of a woman who suffered a subluxation of the knee while jogging. The case we describe is of interest because it shows that even less severe knee dislocations, like this subluxation caused by a low-velocity sports trauma, may present in an irreducible form requiring open surgery. Clinical-instrumental monitoring did not reveal any signs of vascular or nerve injury. Owing to the irreducibility of the lesion we were obliged to perform open surgery in order to free the joint from the interposed muscle tissue and repair medial capsule-ligament lesions. Repair of the damaged cruciate ligaments was deferred to a second stage, but ultimately rendered necessary by the persistence of joint instability and the need to address the patient's functional needs. In the literature, different one- and two step surgical options, performed by arthroscopy or arthrotomy, are reported for such related problems. The Authors discuss these various options and examine and discuss their own decision taken during the surgical work-up of this case. PMID- 26605259 TI - Measles may be a Risk Factor for Malignant Brain Tumors. AB - BACKGROUND: A possible risk factor for brain tumor might be measles, since late neurologic sequelae are part of measles pathology. Subacute sclerosing panencephalitis, a devastating neurologic illness, is prone to develop years after measles infection. METHODS: Because measles damage to the brain might increase the risk of brain tumor, we examined the relationship of measles incidence in 1960 and brain tumor incidence in 50 US States and the District of Columbia, 2004-2007. Data on number of cases of measles by state in 1960 are from the Morbidity and Mortality Weekly Report. In 1960 measles was a childhood illness. We calculated measles incidence by obtaining the population of each state from the 1960 US Census and then age adjusting our results to the cumulative percent of the state population under age 21, since this would have been the measles-infected group. Data on the percentage white population by state are from the US Census (www.census.gov). Age-adjusted incidence (to the 2000 US standard population) of brain tumors is from the Central Brain Tumor Registry of the United States 2011 report. RESULTS: There was a significant correlation between 1960 measles incidence and incidence of malignant brain tumors in persons 20 and older in 2004-2007 (r=0.321, p=0.026). Because glioblastoma is more frequent in whites and males, multivariate linear regression was performed with tumor incidence as the dependent variable, measles incidence, percent white population, and sex ratio by state as independent variables. Measles incidence was significantly correlated with malignant brain tumor incidence (beta=0.361, p<0.001) and independent of the effect of race (beta=0.734, p<0.001) and sex ratio m/f (beta=-0.478, p<0.001). There was no correlation of measles incidence with brain tumor incidence in persons younger than 20. CONCLUSION: Inflammation is a critical component of tumor development. The inflammation of measles-induced subacute sclerosing panencephalitis, even subclinical cases, could well promote tumor formation, since many tumors arise from sites of infection, chronic irritation and inflammation. PMID- 26605260 TI - Treatment Strategy of Intracranial Hemangiopericytoma. AB - BACKGROUND: Recent studies suggest aggressive management combining a grossly total resection (GTR) with adjuvant radiotherapy (RT) as a treatment of choice for intracranial hemangiopericytoma (HPC). However, in these papers, the definitions of complete or GTR are equivocal. In the present study, we reviewed the relevant cases from our experience focused on the clinical efficacy of surgical grading of resection, and analyzed the optimal treatment strategies as well. METHODS: From January 1995 through December 2014, 17 patients treated for intracranial HPC were included in this study. We analyzed clinical presentation, radiologic appearance, pathologic diagnosis, extent of resection, and follow-up outcomes. RESULTS: A total of 26 operations were performed including 9 recurrent intracranial HPCs. Every tumor was single and had no evidence of metastasis. Most common area of tumor was parasagittal (8 patients, 47.1%), which is adjoined to superior sagittal sinus. For the initial operation, GTR was performed in 16 cases (61.5%), partial resection (PR) in 8 cases (30.8%), and an endoscopic biopsy in 2 patients (7.7%). In Simpson grading system, grade 1 was done in 2 patients (7.7%), grade 2 in 11 patients (42.3%) and grade 3 in 3 patients (11.5%). Postoperative RT was delivered in 16 patients (94.1%) regardless of the extent of resection. The median 57.57 Gy (range, 50-60 Gy) was delivered in median 33 fractions (range, 30-40). The extent of resection (conventional classification and Simpson grading system) and adjuvant RT were significantly associated with recurrence-free survival. CONCLUSION: Surgical resection of intracranial HPC, in an attempt to reach Simpson grade 1 removal, is necessary for better outcome. Adjuvant RT should be done as recommended before, to prevent recurrence, regardless of surgical resection and pathological diagnosis. PMID- 26605261 TI - Efficacy of Procarbazine, Lomustine, and Vincristine Chemotherapy for Recurrent Primary Central Nervous System Lymphomas. AB - BACKGROUND: Optimal treatment for recurrent primary central nervous system lymphomas (PCNSLs) has not been defined yet and there is no general consensus about the salvage chemotherapy after high-dose methotrexate (HD-MTX)-based chemotherapy. The purpose of the present study was to evaluate the efficacy and safety of procarbazine, lomustine, and vincristine (PCV) chemotherapy for recurrent PCNSLs. METHODS: We reviewed eight immunocompetent patients (five males/three females, mean age: 56 years) who received salvage PCV chemotherapy (procarbazine 60 mg/m(2), days 8 through 21: CCNU 110 mg/m(2), day 1: vincristine 2 mg, days 8 and 28) for recurrent PCNSL and two patients switched to PCV chemotherapy due to severe adverse effects of HD-MTX chemotherapy. Radiologic responses, survival, and adverse effects were analyzed. RESULTS: Of the eight recurrent PCNSLs, three patients (37.5%) showed radiologic complete response, one patient (12.5%) showed partial response, and four patients (50%) showed progressive disease after PCV chemotherapy. Median progression free survival (PFS) from the first administration of PCV to relapse or last follow-up was 7 months (range 5-32 months) and median overall survival was 8 months (range 2-41 months). The two patients who switched to PCV chemotherapy showed PFS of 9 and 5 months from the beginning of PCV to relapse. The common side effects were thrombocytopenia, neutropenia, and peripheral neuropathy. There were 4 grade III or IV myelo-suppression, but no fatal complications, including severe hemorrhage or infection, were observed. CONCLUSION: Salvage PCV chemotherapy has a moderate anti-lymphoma activity for recurrent PCNSLs after the HD-MTX-based chemotherapy with tolerable toxicity. PMID- 26605262 TI - Role of Craniofacial Resection for Malignant Tumors Involving the Anterior Skull Base: Surgical Experience in a Single Institution. AB - BACKGROUND: Craniofacial resection (CFR) has been regarded as a standard treatment for various tumors involving the anterior skull base. The purpose of this study was to evaluate the results of CFR for the patients with anterior skull base malignancies in our hospital. METHODS: We retrospectively analyzed 17 patients with anterior skull base malignancies treated with CFR between 2001 and 2012. Mean follow-up duration was 41 months (range, 2-103 months). RESULTS: Intracranial involvement was found in 11 patients (65%) and orbital extension in 6 patients (35%). Classical bifrontal craniotomy was combined with endoscopic endonasal approach in 14 patients and external approach in 3 patients. Vascularized flap was used for reconstruction of the anterior fossa floor in 16 patients (94%). The most common pathological type was squamous cell carcinoma (6 patients). Gross total resection was achieved in all cases. Postoperative complications developed in 4 patients (24%) and included local wound problem and brain abscess. One patient with liver cirrhosis died from unexpected varix bleeding after the operation. Although postoperative treatment, such as radiotherapy or chemotherapy, was performed in 14 patients, local recurrence was seen in 6 patients. The mean overall survival time after the operation was 69.0 months (95% confidence interval: 47.5-90.5 months) with a 1-, 2-, and 5-year survival rate of 82.3%, 76.5%, and 64.7%, respectively. Postoperative radiotherapy was found to be the powerful prognostic factor for favorable survival. CONCLUSION: Considering the higher local control rate and acceptable complication or mortality rate, CFR with adjuvant radiotherapy is a gold standard treatment option for malignant tumors involving anterior skull base, especially with extensive intracranial involvement. PMID- 26605263 TI - Analysis of Circulating Endostatin and Vascular Endothelial Growth Factor in Patients with Pituitary Adenoma Treated by Stereotactic Radiosurgery: A Preliminary Study. AB - BACKGROUND: The purpose of this study was to investigate plasma levels of endostatin and vascular endothelial growth factor (VEGF) in normal subjects and in patients with pituitary adenoma and to evaluate change in these levels following stereotactic radiosurgery (SRS) for pituitary adenoma. METHODS: Peripheral venous blood was collected from five patients with pituitary adenoma before SRS using Gamma Knife and at the 1 week and 1 month follow-up visits. Plasma endostatin and VEGF levels were measured using commercially available enzyme-linked immunosorbent assay kits. Peripheral blood samples were obtained from 10 healthy volunteers as controls. RESULTS: Mean baseline plasma endostatin level (105.3 ng/mL, range, 97.0-120.2 ng/mL) in patients with pituitary adenoma was higher than that of the healthy controls (86.6 ng/mL, range, 71.3-98.2 ng/mL) (p=0.001). Mean plasma VEGF level was 89.5 pg/mL (range, 24.1-171.8 pg/mL) in patients with pituitary adenoma at baseline and 29.3 pg/mL (range, 9.2-64.3 pg/mL) in the control group (p=0.050). Plasma endostatin level changed to 106.6 ng/mL 1 week after SRS and decreased to 95.9 ng/mL after 1 month. Plasma VEGF level following SRS decreased to 74.1 pg/mL after 1 week and 79.0 pg/mL after 1 month. There was a trend toward decreased plasma endostatin and VEGF concentrations 1 month after SRS compared to baseline levels (p=0.195, p=0.812, respectively). CONCLUSION: Plasma endostatin and VEGF levels in patients with pituitary adenoma were significantly elevated over controls at baseline, which decreased from baseline to 1 month after SRS for pituitary adenomas. PMID- 26605264 TI - Comparative Analysis of Efficacy and Safety of Multisession Radiosurgery to Single Dose Radiosurgery for Metastatic Brain Tumors. AB - BACKGROUND: The purpose of this study is to compare the efficacy and safety of multisession radiosurgery to those of single dose radiosurgery for metastatic brain tumors. METHODS: Between February 2008 and February 2012, 90 patients with 196 metastatic brain tumors were treated with cyberknife radiosurgery, and we reviewed these patients retrospectively. Among them, 57 patients underwent single dose radiosurgery, and 33 patients multisession radiosurgery. Tumors involving the eloquent area and large tumors (>5 cc) were treated with multisession radiosurgery. The median tumor volume and the median treatment dose of single dose radiosurgery were 2.05+/-0.72 cc and 19.76+/-1.54 Gy respectively, and in the case of multisession radiosurgery, 5.30+/-1.70 cc and 29.6+/-1.70 Gy respectively. The frequency of multisession dose was 3 to 5 times, on average 3.55 times, and 8.91 Gy were given per 1 session on average. RESULTS: The overall survival (OS) of multisession radiosurgery was 16.0 months, whereas that of single dose radiosurgery was 11.5 months. The radiologic tumor response rates were 90% in single dose radiosurgery and 95.4% in multisession radiosurgery, respectively. Over 6-month and 1-year periods, the OS rates of single dose radiosurgery were 71.4% and 44.9%, whereas those of multisession radiosurgery were 69.1% and 58.3%, respectively (p=0.83). Toxicities were seen in 18.1% in the single dose radiosurgery group versus 4% in the multisession radiosurgery group. The difference was significant (p<0.05). CONCLUSION: In this study, the multisession radiosurgery group, despite the location and size constraints, did not differ from the single dose radiosurgery group when comparing the survival and recurrence rates, but complications and toxicity were lower. Thus, multisession radiosurgery is thought to be beneficial for treatment of large tumors and tumors located in the eloquent area. PMID- 26605265 TI - Long-Term Results of Gamma Knife Radiosurgery for Intracranial Meningioma. AB - BACKGROUND: The predominant treatment modality for meningioma is surgical resection. However, gamma knife radiosurgery is also an important treatment modality for meningioma that is small or cannot be completely removed because of its location. In this study, we evaluated the effectiveness and long-term results of radiosurgical treatment for meningioma in our institution. METHODS: We studied 628 patients (130 men and 498 women) who underwent gamma knife radiosurgery for intracranial meningioma, which is radiologically diagnosed, from Jan 2008 to Nov 2012. We included patients with single lesion meningioma, and followed up after 6 months with imaging, and then at 24 months with a clinical examination. Patients with high-grade meningioma or multiple meningiomas were excluded. We analyzed each of the factors associated with progression free survival. The median patient's age was 56.8 years. Maximal dosage was 27.8 Gy and marginal dosage was 13.9 Gy. RESULTS: The overall tumor control rate was 95%. Twenty-eight patients (4.4%) showed evidence of tumor recurrence. Ninety-eight patients (15%) developed peritumoral edema (PTE) after gamma-knife surgery; two of them (2%) underwent surgical resections due to PTE. Nine patients had craniotomy and tumor removal after gamma knife surgery. CONCLUSION: Gamma knife surgery for intracranial meningioma has proven to be a safe and effective treatment tool with successful long-term outcomes. Gamma knife radiosurgery can be especially effective in cases of remnant meningioma after surgical resection or where PTE is not present. PMID- 26605266 TI - The Efficacy of Postoperative Chemotherapy for Patients with Metastatic Brain Tumors from Non-Small Cell Lung Cancer. AB - BACKGROUND: The purpose of this study is to evaluate the effect of postoperative chemotherapy on recurrence and survival in patients after resection of metastatic brain tumors from non-small cell lung cancers. METHODS: Patients who went through resection of a single metastatic brain tumor from non-small cell lung cancer from July 2001 to December 2012 were reviewed. Those selected were 77 patients who survived more than 3 months after surgery were selected. Among them, 44 patients received various postoperative systemic chemotherapies, 33 patients received postoperative adjuvant whole brain radiotherapy (WBRT). Local/distant recurrence rate, local/distant recurrence free survival, disease free survival (DFS), and overall survival were compared between the two groups. RESULTS: Among the 77 patients, there were 19 (24.7%) local recurrences. Local recurrence occurred in 7 (21.2%) of 33 patients in the adjuvant radiotherapy (RT) group and in 12 (27.3%) of the 44 patients in the chemotherapy group (p=0.542). Among the 77 patients, there were 34 (44.1%) distant recurrences. Distant recurrence occurred in 7 (21.2%) of the 33 patients in the adjuvant RT group and in 27 (61.4%) of the 44 patients in the chemotherapy group (p<0.0005). Patients' survival in terms of local recurrence free survival, distant recurrence free survival, DFS, and overall survival was not shown to be statistically different between the two groups before and after adjusting for covariates. CONCLUSION: There was no significant difference observed between postoperative adjuvant chemotherapy and adjuvant WBRT in terms of patients' survival. Postoperative chemotherapy is more feasible and may be an appropriate option for simultaneous control of both primary and metastatic lesions. PMID- 26605267 TI - Aneurysmal Bone Cyst of Sphenoid Bone and Clivus Misdiagnosed as Chordoma: A Case Report. AB - Aneurysmal bone cysts (ABCs) are benign and rapidly expanding bone destructive lesions of any bone. They are commonly localized in the metaphysis of long bones, whereas skull base ABCs are rare. We report a case of a 21-year-old man who had been misdiagnosed as chordoma and undergone surgery. However, histopathological examination revealed it to be an ABC. PMID- 26605268 TI - The Pterional-Transsylvian Approach for Tumor in the Temporal Horn: A Case Report. AB - A variety of surgical approaches to temporal horn tumors of the lateral ventricle have been described. Magnetic resonance imaging (MRI) and angiography are the preferred modalities for preoperative evaluation and provide important information for the choice of surgical approach. A 59-year-old man was referred to our hospital due to confusion and gait disturbance. On enhanced MRI, a homogeneous enhanced solitary mass was observed within the temporal horn of the left lateral ventricle with transependymal extension. The lesion was accompanied by increased hypervascular tumor blush on preoperative cerebral angiography. Subtotal removal of the temporal horn tumor was performed because the lesion was identified as lymphoma during surgery. The postoperative course was un-eventful. The patient was referred to the oncology department for conventional chemotherapy. Adjuvant chemotherapy improved the clinical outcome. The pterional transsylvian approach was beneficial for partial removal of the tumor and tissue diagnosis in this case. PMID- 26605269 TI - Multimodal Treatment of Skull Base Inflammatory Pseudotumor: Case Report. AB - lnflammatory pseudotumor (IPT) is a rare, non-neoplastic inflammatory process. It is most commonly occurs in the orbit, but extension into brain parenchyma is uncommon. In a confirmed case of IPT, most cases show good improvement with steroid theraphy. A 50-year-old man with progressive left-eye visual disturbance and mass lesion was admitted in a hospital. A left orbital mass biopsy revealed what was highly suspected as an inflammatory pseudotumor. Steroid pulse therapy with dexamethasone, radiation therapy, and chemotherapy with amphotericin B were performed, but they were not effective in improving the condition of the patient. Revision open surgery was then performed. A follow-up brain enhancement computerized tomography showed an enlarged mass volume and hydrocephalus with periventricular enhancement. As an additional procedure, ventriculoperitoneal shunt and tuberculosis medication were administered. About 2 weeks later, clinical symptoms and radiologic findings improved. We present a case of intra cranial IPT and discuss further treatment methods. PMID- 26605270 TI - Solitary Fibrous Tumor of Central Nervous System: A Case Report. AB - Solitary fibrous tumor (SFT) is a rare neoplasm of mesenchymal origin, especially in the central nervous system (CNS). Reported herein is a case of SFT of CNS in a 63-year-old female patient who had confused mentality, without other neurological deficit. The brain MRI showed an ovoid mass in the right frontal lobe. The tumor was surgically removed grossly and totally, and the pathologic diagnosis was SFT. At 55 months after the surgery, the tumor recurred at the primary site and at an adjacent area. A second operation was thus done, and the tumor was again surgically removed grossly and totally. The pathologic diagnosis was the same as the previous, but the Ki-67 index was elevated. Ten months later, two small recurring tumors in the right frontal skull base were found in the follow-up MRI. It was decided that radiation therapy be done, and MRI was done again 3 months later. In the follow-up MRI, the size of the recurring mass was found to have decreased, and the patient did not manifest any significant symptom. Follow-up will again be done 18 months after the second surgery. PMID- 26605271 TI - Remote Postoperative Epidural Hematoma after Brain Tumor Surgery. AB - A postoperative epidural hematoma (EDH) is a serious and embarrassing complication, which usually occurs at the site of operation after intracranial surgery. However, remote EDH is relatively rare. We report three cases of remote EDH after brain tumor surgery. All three cases seemed to have different causes of remote postoperative EDH; however, all patients were managed promptly and showed excellent outcomes. Although the exact mechanism of remote postoperative EDH is unknown, surgeons should be cautious of the speed of lowering intracranial pressure and implement basic procedures to prevent this hazardous complication of brain tumor surgery. PMID- 26605272 TI - Unusual Radiologic Finding of Intracranial Inflammatory Myofibroblastic Tumor Presenting a Cyst with Mural Nodule. AB - An intracranial cyst tumor with a mural nodule can be representative of some types of brain tumors, but is a rare presentation of intracranial inflammatory myofibroblastic tumor (IMT). Herein, we report the case of an intracranial IMT in a 48-year-old woman presenting with the extremely unusual radiologic findings of a cyst with a mural nodule. PMID- 26605273 TI - Remote Cerebellar Infarction after Supratentorial Craniotomy and Its Management: Two Case Reports. AB - The cerebellar infarction resulting from supratentorial craniotomy is uncommon event and its management has been controversial. After removal of space occupying lesion on right frontal area, two cases of remote cerebellar infarctions occurred. We reviewed each cases and the techniques to manage such complications are discussed. Early extraventricular catheter insertion and midline suboccipital craniectomy were effectively performed in obtunded patients from cerebellar infarction. PMID- 26605274 TI - Crush Cytology of Secretory Meningioma: A Case Report. AB - Secretory meningioma, a histologic subtype of meningioma of World Health Organization grade 1, is clinically significant because it is frequently accompanied by peritumoral brain edema. The patient was a 53-year-old woman suffering from dysarthria and motor weakness of the right arm. Enhanced magnetic resonance images showed an enhancing mass measuring 2.5 cm in size located in the right parietal convexity. Intraoperative squash cytology showed moderately cellular smears composed mainly of clusters of ovoid cells with scattered whorl formations. The cells had round nuclei and a moderate amount of eosinophilic cytoplasm with ill-defined cell borders. Neither atypia nor mitosis was observed. Some scattered round shaped eosinophilic refractile hyaline globules, measuring from 5 to 25 um, were observed, and a periglobular halo was occasionally observed. The diagnosis of secretory meningioma should be made as early as possible so that neurosurgeons can prevent postoperative aggravation of peritumoral edema. We emphasize that cytologic findings including eosinophilic, non-fibrillary cytoplasm with eosinophilic refractile hyaline globules are helpful in differentiating secretory meningioma from other subtypes of meningioma, primary and metastatic brain tumors. PMID- 26605275 TI - Primary Intraosseous Osteolytic Meningioma of the Skull Mimicking Scalp Mass: A Case Report and Review of Literature. AB - Primary extradural meningioma is about 1-2% of all meningiomas. Primary intraosseous meningioma is a rare form of intra-bone tumors that account for approximately 67% of extradural meningiomas. We report a primary intraosseous meningioma of a 69-year-old man who had headaches and a mass on right parietal scalp for the past few months. Remarkably, the brain tissue within the osteolytic cavity of the skull was normal in computed tomography and magnetic resonance images. Resection, duraplasty, and cranioplasty were performed. The patient's symptoms disappeared after surgery, and the histological diagnosis was an osseous meningothelial meningioma (World Health Organization grade I). PMID- 26605276 TI - A Case of Radiation-Induced Osteosarcoma after the Treatment of Pineoblastoma. AB - Radiation therapy has an important role in postoperative treatment of neoplasms originated from central nervous system, but may induce secondary malignancies like as sarcomas, gliomas, and meningiomas. The prognosis of radiation-induced osteosarcomas is known as poor, because they has aggressive nature invasive locally and intractable to multiple treatment strategies like as surgical resection, chemotherapy, and so on. We report a case of radiation-induced osteosarcoma developed from skull after 7 years of craniospinal radiotherapy for pineoblastoma. PMID- 26605277 TI - Systematic review of peri-operative nutritional support for patients undergoing hepatobiliary surgery. AB - BACKGROUND: Malnutrition is prevalent among peri-operative patients undergoing hepatobiliary surgery and is an important prognostic factor. Both hepatobiliary disease and surgical trauma significantly affects body's metabolism and environment. Therefore, it is very important for patients with liver diseases undergoing hepatobiliary surgery to receive essential nutritional support during peri-operative period. METHODS: We summarized our clinical experience and reviewed of related literature to find the way for implementing the appropriate nutritional strategy. RESULTS: We found after comprehensively evaluating nutrition status, function of liver and gastrointestinal tract, nutritional strategy would be selected correctly. In severe malnutrition, initiation of enteral nutrition (EN) and/or parenteral nutrition (PN) with essential or special formulae is often recommended. Especially nasojejunal feeding is indicated that early application can improve nutritional status and liver function, reduce complications and prolong survival. CONCLUSIONS: The reasonable peri-operative nutritional support therapy can improve the effect of surgical treatment and promote the patients' recovery. PMID- 26605278 TI - Accumulated myeloid-derived suppressor cells demonstrate distinct phenotypes and functions in two non-alcoholic steatohepatitis mouse models. AB - BACKGROUND: To examine the steady state of hepatic myeloid-derived suppressor cells (MDSCs) and the lipid accumulation and inflammation-related changes in these cells, we analyzed the presence and functions of hepatic MDSCs in the following two non-alcoholic steatohepatitis (NASH) mouse models. METHODS: Monosodium glutamate (MSG) model; MSG was subcutaneously injected into neonatal male C57BL/6J mice that were fed with normal diet up to 18 weeks of age. Methionine/choline-deficient diet (MCD) model; 16-week-old male C57BL/6J mice were fed with an MCD for 2 weeks. Those hepatic MDSCs were evaluated by flow cytometry and immunohistochemically. RESULTS: Both MSG and MCD mice exhibited greater numbers of hepatic lipid droplets than 18-week-old male control mice. Hepatocellular ballooning was obvious in MSG, whereas inflammatory cell infiltration were apparent in MCD mice. CD11b, CD115, and Gr-1-positive hepatic MDSCs were increased in both models but higher in MCD mice, and demonstrated higher expression of an M2 macrophage marker CD206 mean fluorescence intensity (MFI) in MSG compared to MCD mice. Degree of reactive oxygen species production was evaluated using the DCFDA MFI values, which were significantly elevated in hepatic MDSCs from MCD mice. MSG mouse livers demonstrated Gr-1 positive cell accumulation around lipid droplets, mimicking crown-like structures in adipose tissues. In contrast, hepatic Gr-1 positive cells were primarily located in inflammatory cell aggregates in MCD mice. CONCLUSIONS: These results suggest that hepatic fatty changes promote MDSC accumulation, and inflammatory changes induce phenotypic and functional alteration in hepatic MDSCs in NASH mouse models. PMID- 26605279 TI - Laparoscopic liver resection for hepatocellular carcinoma in cirrhotic patients: single center experience of 90 cases. AB - BACKGROUND: Hepatocellular carcinoma (HCC) with or without underlying liver disease can be treated by surgical resection. The aim of this study was to evaluate the feasibility, morbidity and mortality of a laparoscopic approach in cirrhotic patients with HCC. METHODS: From 2004 to September 2014, 90 patients underwent a laparoscopic liver resection (LLR) for HCC. Data were collected in a prospectively maintained database since 2001. Preoperative patient evaluation was based on a multidisciplinary team meeting assessment. RESULTS: Median age was 63 years; 67 (74.4%) patients were male. Median body mass index (BMI) was 26.7. Underlying liver disease was known in 68 patients: in 46 patients' hepatitis C virus (HCV)-related, in 15 patients to hepatitis B virus (HBV)-related, in 5 patients alcohol-related. Child-Pugh Score was of grade A in 85 patients and of grade B in 5 patients; 63 patients had a Model for End-stage Liver Disease (MELD) <10 and 27 patients MELD >10. A total of 18 left lateral sectionectomies, 1 left hepatectomy and 71 wedge resections or segmentectomies were performed. Conversion to laparotomy was necessary in 7 (7.7%) patients (five cases for bleeding and two cases for oncological reasons). In 90 patients, 98 HCC nodules were resected: 79 patients had one nodule, 8 patients had two nodules and 1 patient had three nodules. HCC nodules medium diameter was 29 mm (range, 4-100 mm) with median value of 25 mm. Tumor margins distance was 16 mm (range, 0-35 mm) with a median of 5 mm. Seventy nodules were located within the anterior sectors and 28 nodules within the posterior sectors. CONCLUSIONS: LLR for HCC can be performed with acceptable morbidity in patients with underlying liver disease. The use of laparoscopic surgery in cirrhotic patients may be proposed as the first-line treatment for HCC or as bridge treatment before liver transplantation. PMID- 26605280 TI - Pancreatic cancer and thromboembolic disease, 150 years after Trousseau. AB - The connection between pancreatic cancer and venous thrombosis has been discussed for almost 150 years. The exact pathophysiological mechanisms are still partly understood, but it is known that pancreatic cancer induces a prothrombotic and hypercoagulable state and genetic events involved in neoplastic transformation (e.g., KRAS, c-MET, p53), procoagulant factors [e.g., tissue factor (TF), platelet factor 4 (PF4), plasminogen activator inhibitor type 1 (PAI-1)], mucin production (e.g., through activation of P- and L-selectin) and pro-inflammatory factors [e.g., cytokines, cyclooxygenase-2 (COX-2)] may be implicated. Also pancreatitis, both acute and chronic, is associated with increased risk of venous thrombosis, but in this circumstance a direct inflammatory process may be more important. This article discusses the incidence, treatment and outcome of venous thromboembolism (VTE) complicating pancreatic disease, with special emphasis on new knowledge obtained during the last fifteen years. PMID- 26605282 TI - Laparoscopic first step approach in the two stage hepatectomy. AB - Resection is the gold standard therapeutic option for patients with colorectal liver metastases. However, only 20-30% of patients are resectable. In patients with a concomitant future liver remnant (FLR) less than 25-30%, a single stage resection is not feasible. The aim of this study is to evaluate the feasibility and the rates of morbidity and mortality of the laparoscopic approach in the first-step of two stage hepatectomy. From 2004 to March 2014, 73 patients underwent a two stage hepatectomy: of these, four underwent a totally laparoscopic first step [wedge left liver resection and right portal vein ligation (PVL)]. All the patients were male. Median age was 55 years. One patient underwent an atypical wedge resection of segment II-III and a laparoscopic PVL (LPVL), one patient had a first wedge resection of segment II and LPVL, and two patients underwent a wedge resection of segment III and LPVL. First step surgical mean time was 189 (range, 160-244) min, mean blood loss was 22 (range, 0-50) cc. No transfusion was required in this series. The results of our study demonstrate that the first step of hepatic resection and PVL is feasible with a laparoscopic approach in patients with bilobar liver metastases. PMID- 26605281 TI - The management of perioperative nutrition in patients with end stage liver disease undergoing liver transplantation. AB - Malnutrition is found in almost 100% of patients with end stage liver disease (ESLD) awaiting transplantation and malnutrition before transplantation leads to higher rates of post-transplant complications and worse graft survival outcomes. Reasons for protein energy malnutrition include several metabolic alterations such as inadequate intake, malabsorption, and overloaded expenditure. And also, stress from surgery, gastrointestinal reperfusion injury, immunosuppressive therapy and corticosteriods use lead to delayed bowl function recovery and disorder of nutrients absorption. In the pretransplant phase, nutritional goals include optimization of nutritional status and treatment of nutrition-related symptoms induced by hepatic decompensation. During the acute post-transplant phase, adequate nutrition is required to help support metabolic demands, replenish lost stores, prevent infection, arrive at a new immunologic balance, and promote overall recovery. In a word, it is extremely important to identify and correct nutritional deficiencies in this population and provide an adequate nutritional support during all phases of liver transplantation (LT). This study review focuses on prevalence, nutrition support, evaluation, and management of perioperative nutrition disorder in patients with ESLD undergoing LT. PMID- 26605283 TI - Serial insertion of bilateral uncovered metal stents for malignant hilar obstruction using an 8 Fr biliary system: a case series of 17 consecutive patients. AB - Controversy exists over the need for unilateral versus bilateral stent placement in patients with malignant obstruction at the biliary hilum. Placement of bilateral uncovered self-expanding metal stent (UCSEMS) at this location is technically challenging, and generally associated with lower rates of procedural success. Serial insertion of side-by-side UCSEMS may be especially difficult when simultaneous deployment is not possible using larger stent delivery catheters. In this single-center, retrospective case series of all patients who underwent bilateral placement of uncovered Wallflex(TM) biliary stents between July 2008 and July 2014, we evaluate the feasibility, technical success, and safety of patients undergoing serial insertion of bilateral UCSEMS using the 8 Fr Wallflex(TM) biliary system for malignant hilar obstruction. A total of 17 patients were included. Primary cholangiocarcinoma, Bismuth IV, was the most common diagnosis. Mean procedure time was 54.4 minutes. Overall procedural technical success was achieved in 17/17 patients. Stricture dilation was necessary prior to Wallflex(TM) insertion in 8/17 patients (47.1%). Transpapillary extension of two stents was performed in all patients. There were no cases of stent deployment malfunction, or inability to insert or deploy the 2(nd) stent. Nine of 17 patients (52.9%) required inpatient hospitalization following ERCP; the most common indications were abdominal pain and need for IV antibiotics. There was one case of ERCP-related cholangitis otherwise; there were no other major complications. Bilateral, serial insertion of UCSEMS using the 8 Fr Wallflex(TM) biliary system in malignant hilar obstruction is feasible with an excellent technical success profile. Using this device for side-by-side deployment of UCSEMS appears to be safe in the majority of patients. PMID- 26605285 TI - Endometrial stromal sarcoma presenting as large bleeding left upper quadrant mass. AB - Endometrial stromal sarcoma (ESS) represents only 0.2% of all uterine malignancies. Even fewer cases have been reported on patients presenting with symptomatic disease. We report the case of young lady presenting with a large bleeding abdominal mass. At the time of surgery, an en bloc excision of the mass with a partial pancreatectomy, splenectomy, transverse colectomy, left nephrectomy, left adrenalectomy and resection of the diaphragm was performed. The final pathology revealed a malignant spindle and epithelial cell neoplasm with features favoring a variant of ESS. ESS can present in an atypical fashion as an intra-abdominal mass; a multi-disciplinary treatment approach for patients with this disease is crucial. PMID- 26605284 TI - Hepatoid carcinoma of the pancreas combined with serous cystadenoma: a case report and review of the literature. AB - Pancreatic hepatoid carcinoma (HC) is an extremely uncommon neoplasm of pancreas that resembles hepatocellular carcinoma (HCC). We report a case of incidentally detected pancreatic HC combined with a serous microcystic cystadenoma, in a 47 year-old man, while he was being evaluated for renal calculi. Contrast enhanced computed tomography (CECT) of abdomen revealed a lesion with mild heterogeneous enhancement in the tail of pancreas and another proximal lesion having moderate enhancement, and a calculus in the neck of gallbladder. Serum chromogranin, carcinoembryonic antigen (CEA) and CA 19-9 levels were within normal limits. He underwent laparoscopic distal pancreatectomy with splenectomy and cholecystectomy. Pathologically the distal tumor was encapsulated and characterized by eosinophilic cytoplasm, vesicular nucleus with prominent nucleolus and intranuclear eosinophilic inclusions. The cells were arranged in trabecular pattern separated by sinusoids. Canalicular and intercellular bile plugs were seen. On immunohistochemistry tumor cells were positive for hepatocyte specific antigen and weakly positive for alpha fetoprotein (AFP). The proximal tumor showed features of serous microcystic adenoma. Based on these findings, the case was diagnosed as hepatoid tumor of pancreas combined with serous microcystic cystadenoma. Post operative AFP was 1.75 IU/mL. The patient is on follow up for the last eight months and there is no evidence of recurrence. PMID- 26605286 TI - Markedly elevated liver transaminases following pancreaticoduodenectomy: celiac artery thrombosis in disguise. PMID- 26605287 TI - Ankle metastasis as a sign of intrahepatic cholangiocellular carcinoma. PMID- 26605289 TI - Diagnosis of ligamentous and meniscal pathologies in patients with anterior cruciate ligament injury: comparison of magnetic resonance imaging and arthroscopic findings. AB - BACKGROUND: Magnetic resonance imaging (MRI) is routinely used to diagnose or support clinical diagnoses for meniscal or ligamentous injuries prior to offering patients arthroscopic treatment. However, the sensitivity of MRI for the detection of meniscal injury is not yet 100%. Sportsmen have occasionally returned to play with undiagnosed meniscal lesions on the basis of a normal MRI examination. This study was designed to assess the diagnostic parameters of MRI in patients with acute anterior cruciate ligament (ACL) injury. METHODS: MRI and arthroscopic findings of 320 patients with acute ACL injury were included in this retrospective review. Patients belonged to a single surgeon from a high volume tertiary healthcare institution. All patients had either a MRI or an arthroscopic diagnosis of an acute ACL injury of one knee or both. All patients underwent therapeutic arthroscopy by the senior author routinely as part of arthroscopy aided ACL reconstruction. Arthroscopic findings were the diagnostic reference based on which the positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity and concordance strength of association of MRI were calculated for ACL, posterior cruciate ligament (PCL), medial meniscus (MM) and lateral meniscus (LM) injuries. RESULTS: MRI was most accurate in diagnosing cruciate ligament injuries with a PPV approaching 100%. The PPV of MRI in diagnosing meniscal injuries was approximately 60%. MRI was almost 100% sensitive and specific in diagnosing ACL injuries and 82% sensitive and 100% specific in diagnosing PCL injuries. Conversely, MRI was 77% sensitive and 90% specific in diagnosing MM injuries; and 57% sensitive and 95% specific in diagnosing LM injuries. CONCLUSIONS: MRI remains the gold standard for diagnosing soft tissue injuries of the knee. However, there is a false positive rate ranging from 6% to 11% for meniscal tears. PMID- 26605290 TI - Extended leukocyte differential count and C-reactive protein in septic patients with liver impairment: diagnostic approach to evaluate sepsis in intensive care unit. AB - BACKGROUND: Sepsis is still a major cause of death in intensive care units (ICUs) worldwide. Patients with liver impairment express an imbalanced cytokine response which alters common sepsis biphasic nature. Cytokines measurement is expensive, often unavailable, whereas leukocytes (WBC) evaluation performed through hematology analyzers can provide a practical strategy for monitoring inflammatory response. METHODS: A total of 200 healthy subjects (HS) and 84 patients (18 with, 66 without liver impairment) admitted to ICU, were assessed for International Sepsis Definitions, Sequential Organ Failure Assessment (SOFA) and Model for End Stage Liver Disease (MELD) scores. We tested 1,022 peripheral blood samples using Sysmex XN-9000, estimating diagnostic accuracy of leukocyte differential count and nontraditional parameters through receiver operating characteristics (ROC) curves analysis compared to clinical classification. RESULTS: Median value of all leukocyte parameters was different in ICU patients compared to HS. Leukocytes, neutrophils (NE) and immature granulocytes (IGs) in sepsis and septic shock (SS) were higher than no sepsis (NS), with an area under the curve: 0.81, 0.82 and 0.78 respectively. Lymphocytes (LY) and monocytes (MO) were significantly associated with liver impairment. CONCLUSIONS: Diagnostic accuracy of all leukocyte parameters may provide valuable information for diagnosis and follow-up of sepsis in ICU patients, especially those with liver impairment. PMID- 26605288 TI - National consensus in China on diagnosis and treatment of patients with advanced breast cancer. AB - The recently available guidelines on the management of advanced breast cancer (ABC) organized by Chinese Anti-Cancer Association, Committee of Breast Cancer Society (CACA-CBCS) do not elucidate ABC in details. To instruct clinicians in treatment of ABC, a Chinese expert consensus meeting on diagnosis and treatment of ABC was held in June 2014 and a consensus is developed. The following consensus provides the level of evidence and supporting documents for each recommendation, and introduces research topics to be urgently addressed. Notably, the consensus on diagnosis and treatment of ABC in China is developed to be applied nationwide. In different areas, multidisciplinary treatment (MDT) tailored to the each patient and the disease itself should be applied based on the basic principles of modern oncology. PMID- 26605291 TI - Mucin1 expression in focal epidermal dysplasia of actinic keratosis. AB - BACKGROUND: Actinic keratoses (AKs) are generally considered as premalignant skin lesions that can progress into squamous cell carcinoma (SCC) in situ and invasive SCC. However, its progression to SCC is still matter of debate. A transmembrane glycoprotein that contributes to the progression of certain premalignant and malignant lesions is mucin1 (MUC1). Nevertheless, their functions in the skin lesions are not yet fully clear. Therefore, the aim of this study is to ascertain whether MUC1 is present in the focal epidermal dysplasia of AK. METHODS: Fourteen skin biopsies from patients diagnosed with AK were selected. They were classified according to the degree of dysplasia in keratinocyte intraepidermal neoplasia (KIN) I, KIN II, and KIN III. In five biopsies the three degrees were present, in two biopsies both KIN I and KIN II, in four biopsies only KIN I, and in three biopsies only KIN III. The presence of MUC1 was assessed by immunofluorescence staining using confocal laser scanning microscopy. RESULTS: Immunostaining revealed that MUC1 was present over the entire cell surface of only a few atypical basal keratinocytes confined to the lower third of the epidermis (KIN I). While in KIN II where atypical keratinocytes occupy the lower two thirds, MUC1 was localized at the apical surface of some atypical keratinocytes and over the entire cell surface of some of them. Interestingly, in KIN III where the atypical keratinocytes extend throughout the full thickness, MUC1 was localized at the apical surface and over the entire cell surface of many of these cells. Conversely, MUC1 expression was not detected in the epidermis of normal skin. CONCLUSIONS: Our findings suggest that the expression of MUC1 in AK would be induced by alteration of keratinocyte stratification and differentiation and associated to the degree of dysplasia rather than the thickness of the epidermis. PMID- 26605292 TI - Effectiveness of anisodamine for the treatment of critically ill patients with septic shock (ACIdoSIS study): study protocol for randomized controlled trial. AB - BACKGROUND: Septic shock is an important contributor of mortality in the intensive care unit (ICU). Although strenuous effort has been made to improve its outcome, the mortality rate is only marginally decreased. The present study aimed to investigate the effectiveness of anisodamine in the treatment of septic shock, in the hope that the drug will provide alternatives to the treatment of septic shock. METHODS: The study is a multi-center randomized controlled clinical trial. Study population will include critically ill patients with septic shock requiring vasopressor use. Blocked randomization was performed where anisodamine and control treatments were allocated at random in a ratio of 1:1 in blocks of sizes 2, 4, 6, 8, and 10 to 354 subjects. Interim analysis will be performed. The primary study end point is the hospital mortality, and other secondary study endpoints include ICU mortality, length of stay in ICU and hospital, organ failure free days. Adverse events including new onset psychosis, urinary retention, significant hypotension and tachycardia will be reported. DISCUSSION: The study will provide new insight into the treatment of septic shock and can help to reduce mortality rate of septic shock. TRIAL REGISTRATION: NCT02442440 (https://register.clinicaltrials.gov/). PMID- 26605294 TI - Biologic therapy and gene therapy in the multimodality treatment of malignant pleural mesothelioma. AB - The last years have witnessed an abrupt paradigm shift in cancer treatment owing to the discoveries concerning the relationships between the immune system and neoplastic cells. In the field of malignant mesothelioma, which, despite painstaking efforts, remains an incurable form of cancer, the researchers' attention has been seized by a variety of new biologic approaches, including both viral gene therapy and active immunotherapy. The former is meant to induce programmed cell death by introducing a specific gene in the target cell, this gene encoding a specific protein with anticancer activity. Active immunotherapy, on the other hand, tires to induce an active response of the immune system, whose surveillance may be easily dodged by cancer cells. In fact, this mechanism seems to play an important role in the development, growth and diffusion of malignant mesothelioma which easily manages to hinder the immune response. A thorough understanding of the relationships existing between mesothelioma and immune system is the basis for the success of those immune therapies, which are showing promising results in the preclinical setting, especially when combined with other approaches, such as cytoreductive surgery. PMID- 26605293 TI - The factor XIIa blocking antibody 3F7: a safe anticoagulant with anti inflammatory activities. AB - The plasma protein factor XII (FXII) is the initiating protease of the procoagulant and proinflammatory contact system. FXII activates both the bradykinin (BK) producing kallikrein-kinin system and the intrinsic pathway of coagulation. Contact with negatively charged surfaces induces auto-activation of zymogen FXII that results in activated FXII (FXIIa). Various in vivo activators of FXII have been identified including heparin, misfolded protein aggregates, nucleic acids and polyphosphate. Murine models have established a central role of FXII in arterial and venous thromboembolic diseases. Despite the central function of FXII in pathologic thrombosis, its deficiency does not impair hemostasis in animals or humans. The selective role of FXIIa in thrombosis, but not hemostasis, offers an exciting novel strategy for safe anticoagulation based on interference with FXIIa. We have generated the recombinant fully human FXIIa-blocking antibody 3F7, which abolished FXIIa enzymatic activity and prevented thrombosis in a cardiopulmonary bypass system in large animals, in the absence of increased therapy-associated bleeding. Furthermore, 3F7 also interfered with BK-driven edema in the severe swelling disorder hereditary angioedema (HAE) type III. Taken together, targeting FXIIa with 3F7 appears to be a promising approach to treat edema disorders and thrombosis. PMID- 26605295 TI - A specified therapeutic window for neuregulin-1 to regenerate neonatal heart muscle. PMID- 26605297 TI - T cell therapies-are T memory stem cells the answer? AB - T memory stem cells (TSCM) are the earliest developmental stage of memory T cells, displaying stem cell-like properties and exhibiting a gene profile between naive and central memory (CM) T cells. Their long-lifespan, robust proliferative potential and self-renewal capacity has generated much research and clinical interest particularly for therapeutic use. Here, we discuss recent findings published in Science Translational Medicine by Biasco and colleagues [2015 Feb 4;7(273):273ra13], which provided evidence for the persistence of TSCM in humans for up to 12 years after infusion of genetically modified lymphocytes, and we examine the implications for the development of novel immunotherapies using TSCM. PMID- 26605296 TI - Childhood cancer: an emerging public health issue in China. PMID- 26605298 TI - Role of skin homing T cells in acute dengue infection. PMID- 26605299 TI - Circulating tumor DNA: a resuscitative gold mine? PMID- 26605300 TI - A potential role of homeobox transcription factors in osteoarthritis. AB - When a healthy joint progressively becomes osteoarthritic, the structures of the affected cartilage, bone and synovia undergo an initial phase of rearrangement. The exact molecular and cellular events occurring in this early osteoarthritic transition phase still remain elusive. Homeobox (Hox) genes encode for transcription factors that typically regulate limb morphogenesis and skeletal formation during development. More recently they were shown to be required for tissue remodelling and homeostasis in adults and to be modulated in a variety of pathologies. Here we present and discuss the hypothesis that dysregulation of specific Hox genes is associated with the onset and development of osteoarthritis (OA). Discovering mechanisms modulating Hox gene expression could not only provide important information in understanding OA pathology and its initiation, but also help to identify biomarkers reflecting the state of early OA. This knowledge would allow anticipating the time window for clinical treatment of the affected cartilage and assist in the development of innovative strategies to restore joint homeostasis, e.g., by cell or gene therapy. PMID- 26605301 TI - HPV and beyond-looking out for biomarkers for distinguishing the good prognosis from the bad prognosis group in locally advanced and clinically high risk HNSCC. PMID- 26605303 TI - Gene replacement rescues severe muscle pathology and prolongs survival in myotubularin-deficient mice and dogs. PMID- 26605302 TI - Strategies for functional bioscaffold-based skeletal muscle reconstruction. AB - Tissue engineering and regenerative medicine-based strategies for the reconstruction of functional skeletal muscle tissue have included cellular and acellular approaches. The use of acellular biologic scaffold material as a treatment for volumetric muscle loss (VML) in five patients has recently been reported with a generally favorable outcome. Further studies are necessary for a better understanding of the mechanism(s) behind acellular bioscaffold-mediated skeletal muscle repair, and for combination cell-based/bioscaffold based approaches. The present overview highlights the current thinking on bioscaffold based remodeling including the associated mechanisms and the future of scaffold based skeletal muscle reconstruction. PMID- 26605304 TI - Reactive aldehydes: an initial path to develop precision medicine for pain control. AB - With the risks of opioid addiction, abuse, and overdose, there is a need to identify new molecular targets contributing to pain sensation in order to develop directed treatments for pain. One mechanism to treat pain is to target reactive aldehydes either by limiting production or by increasing metabolism. In response to a recent editorial in the Annals of Translational Medicine (ATM), we discuss how reactive aldehyde production can trigger pain and how the enzyme mitochondrial aldehyde dehydrogenase 2 (ALDH2) regulates inflammatory pain by reactive aldehyde metabolism. We also comment about the possible clinical impact caused by the inefficiency of reactive aldehyde metabolism for the ~540 million people with an ALDH2*2 variant. Further, we discuss how developing therapeutics specifically targeting ALDH2 may lead to the development of a pathway to potentially create precision medicine for pain control. PMID- 26605305 TI - Two cases of gastrointestinal stromal tumor of the small intestine with liver and bone metastasis. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. These tumors most commonly occur in the stomach (60%), jejunum and ileum (30%). Metastasis is characteristically the malignant behavior of the GISTs. GISTs most frequently metastasize to the liver and peritoneum, whereas bone and lung metastases are uncommon sites. Here, we described two cases of bone and liver metastases in patients with advanced GISTs. Both of them showed liver metastasis at disease presentation and bone metastasis in early time after the diagnosis. Bone metastases involved the lumber spine and right femur in first patient and L2 vertebral body in the second case. All of the lesions presented a lytic pattern. These cases are presented because of the rare incidence of bone metastasis to femur and vertebral bodies. More attention should be paid to the diagnosis of bone metastases from GISTs in clinical practice despite the shortage of available data on the sensitivity and specificity of bone scintigraphy and PET-CT. PMID- 26605306 TI - China experts consensus on icotinib for non-small cell lung cancer treatment (2015 version). PMID- 26605308 TI - Muscle pathology, limb strength, walking gait, respiratory function and neurological impairment establish disease progression in the p.N155K canine model of X-linked myotubular myopathy. AB - BACKGROUND: Loss-of-function mutations in the myotubularin (MTM1) gene cause X linked myotubular myopathy (XLMTM), a fatal, inherited pediatric disease that affects the entire skeletal musculature. Labrador retriever dogs carrying an MTM1 missense mutation exhibit strongly reduced synthesis of myotubularin, the founder member of a lipid phosphatase required for normal skeletal muscle function. The resulting canine phenotype resembles that of human patients with comparably severe mutations, and survival does not normally exceed 4 months. METHODS: We studied MTM1 mutant dogs (n=7) and their age-matched control littermates (n=6) between the ages of 10 and 25 weeks. Investigators blinded to the animal identities sequentially measured limb muscle pathology, fore- and hind limb strength, walking gait, respiratory function and neurological impairment. RESULTS: MTM1-mutant puppies display centrally-nucleated myofibers of reduced size and disrupted sarcotubular architecture progressing until the end of life, an average of 17 weeks. In-life measures of fore- and hind limb strength establish the rate at which XLMTM muscles weaken, and their corresponding decrease in gait velocity and stride length. Pulmonary function tests in affected dogs reveal a right-shifted relationship between peak inspiratory flow (PIF) and inspiratory time (TI); neurological assessments indicate that affected puppies as young as 10 weeks show early signs of neurological impairment (neurological severity score, NSS =8.6+/-0.9) with progressive decline (NSS =5.6+/-1.7 at 17 weeks-of-age). CONCLUSIONS: Our findings document the rate of disease progression in a large animal model of XLMTM and lay a foundation for preclinical studies. PMID- 26605309 TI - Radiographic grading of the patellofemoral joint is more accurate in skyline compared to lateral views. AB - BACKGROUND: The patellofemoral joint is perhaps the most commonly involved compartment in knee osteoarthritis (OA). Radiographic studies are routinely ordered and are seen as the first-line investigations for patellofemoral osteoarthritis (PFOA). The Kellgren-Lawrence (K&L) grading scale is often used to quantify the severity of radiographic OA. In this study, we aim to determine the correlation of the K&L grading scale on both the skyline and lateral views with arthroscopic visualization of articular cartilage damage. METHODS: All patients with clinical and radiographic features of PFOA who underwent knee arthroscopy by a single surgeon from 2006 to 2010 in our institution were reviewed. The study group consisted of 66 patients with PFOA. All patients had skyline and lateral radiographs of the knee taken before surgery. All patients had arthroscopic evidence of PFOA. Blinded investigators graded the radiographs according to the K&L grading scale. At arthroscopy, the patellofemoral joint was graded according to the Outerbridge classification. Correlation and statistical analysis of the radiographic and arthroscopic grade was carried out. RESULTS: The general trend shows that the higher the radiographic K&L grading, the greater the severity of articular cartilage degeneration on arthroscopy. However, an increasing K&L grade accounts for only 39.7% and 28.4% of the variation of severity of arthroscopically-determined articular cartilage degeneration on skyline and lateral views respectively. Interestingly, on both views, better correlation with arthroscopic findings was seen in early (K&L grades 1 and 2) PFOA. Skyline views were superior to lateral views in terms of specificity, PPV, NPV and accuracy in predicting early OA. CONCLUSIONS: Skyline radiographs are more accurate than lateral radiographs in prediction of severity of PFOA. PMID- 26605307 TI - The relevance of molecular biomarkers in cervical cancer patients treated with radiotherapy. AB - BACKGROUND: Radiotherapy (RT) plays an integral role in the combined-modality management of cervical cancer. Various molecular mechanisms have been implicated in the adaptive cellular response to RT. Identification of these molecular processes may permit the prediction of treatment outcome and enhanced radiation induced cancer cell killing through tailoring of the management approach, and/or the employment of selective inhibitors of these pathways. METHODS: PubMed was searched for studies presenting biomarkers of cervical cancer radioresistance validated in patient studies or in laboratory experimentation. RESULTS: Several biomarkers of cervical cancer radioresistance are validated by patient survival or recurrence data. These biomarkers fall into categories of biological function including hypoxia, cell proliferation, cell-cell adhesion, and evasion of apoptosis. Additional radioresistance biomarkers have been identified in exploratory experiments. CONCLUSIONS: Biomarkers of radioresistance in cervical cancer may allow molecular profiling of individual tumors, leading to tailored therapies and better prognostication and prediction of outcomes. PMID- 26605310 TI - Characterization of acute respiratory infections among 340 infants in Wuxi, Jiangsu Province. AB - BACKGROUND: To investigate the etiological and epidemiological features of acute respiratory infections among children in Wuxi, Jiangsu Province. METHODS: Nasopharyngeal swab specimens were collected from 340 pediatric patients from Wuxi Second People's Hospital from June 2012 to May 2014. Seven respiratory viruses including influenza virus A (FA), influenza virus B (FB), parainfluenza virus I (PIVI), parainfluenza virus II (PIVII), parainfluenza virus III (PIVIII), adenovirus (ADV), and respiratory syncytial virus (RSV) were detected using direct immunofluorescence method. Epidemiological analysis was performed in terms of gender, age, and seasonal distribution. RESULTS: Among these 340 patients, viral pathogens were detected in 116 cases (34.12%), with the leading three viruses being RSV (16.18%; 55/340), FB (5.29%; 18/340), and FA (5.00%; 17/340). The positive rate was not significantly different between male (36.32%; 73/201) and female (31.65%; 44/139) patients (P>0.05). The positive rate was highest in the 0-1-year-old group (48.48%; 32/66) and in winter (42.72%; 44/103). CONCLUSIONS: RSV is the most commonly detected respiratory virus in Wuxi. Infants aged 0-1 year should be a priority population during disease prevention and control. Respiratory infections among children are more common in winter. PMID- 26605314 TI - Wound dressings for primary and revision total joint arthroplasty. AB - BACKGROUND: Preventing post-surgical complications after total joint arthroplasty (TJA) is of great importance, and application of an appropriate wound dressing is necessary. Since no dressing encompasses all the parameters required for ideal wound healing, a comparison of the available dressing types can assist the surgeon to choose the best dressing after TJA. METHODS: Studies evaluating postoperative wound dressings after TJA were reviewed in order to assess the outcomes, complications and costs associated with dressing types. RESULTS: Traditional cotton dressings have a high ability to absorb exudate. However, they dry out sooner and there is a risk of pain and additional trauma during dressing changes. Although vapor permeable dressings allow transmission of moisture, but they have low absorptive capacity and require frequent changes even with moderately exudating wounds. On the other hand, hydrofiber and hydrocolloid dressings have high absorptive capacity and permeability, and can cope with exudate production. They are changed less often and have low blistering rates, which may reduce surgical site infection (SSI). Although the unit cost associated with advanced dressings is much higher than the traditional dressings, the decreased rate of periprosthetic joint infection (PJI) and the cost associated with treating PJI more than compensate for it. CONCLUSIONS: Choice of dressing type after TJA should depend upon permeability, absorptive capacity, documented rate of SSI and cost effectiveness with its use, apart from a surgeon's past clinical experience and familiarity. PMID- 26605313 TI - Immune checkpoint inhibitors: therapeutic advances in melanoma. AB - In recent years, new strategies for treating melanoma have been introduced, improving the outlook for this challenging disease. One of the most important advances has been the development of immunotherapy. The better understanding of the role of the immunological system in tumor control has paved the way for strategies to enhance the immune response against cancer cells. Monoclonal antibodies (mAbs) against the immune checkpoints cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have demonstrated high activity in melanoma and other tumors. Ipilimumab, an anti CTLA 4 antibody, was the first drug of this class that was approved. Although the response rate with ipilimumab is low (less than 20% of patients have objective responses), 20% of patients have long survival, with similar results in the first and second line settings. Nivolumab and pembrolizumab, both anti PD-1 inhibitors, have been approved for the treatment of melanoma, with response rates of 40% and a demonstrated survival advantage in phase III trials. This has marked a new era in the treatment of metastatic melanoma and much research is now ongoing with other drugs targeting checkpoint inhibitors. In addition, the agonist of activating molecules on T cells and their combinations are being investigated. Herein we review the clinical development of checkpoint inhibitors and their approval for treatment of metastatic melanoma. PMID- 26605312 TI - Other targeted drugs in melanoma. AB - Targeted therapy drugs are developed against specific molecular alterations on cancer cells. Because they are "targeted" to the tumor, these therapies are more effective and better tolerated than conventional therapies such as chemotherapy. In the last decade, great advances have been made in understanding of melanoma biology and identification of molecular mechanisms involved in malignant transformation of cells. The identification of oncogenic mutated kinases involved in this process provides an opportunity for development of new target therapies. The dependence of melanoma on BRAF-mutant kinase has provided an opportunity for development of mutation-specific inhibitors with high activity and excellent tolerance that are now being used in clinical practice. This marked a new era in the treatment of metastatic melanoma and much research is now ongoing to identify other "druggable" kinases and transduction signaling networking. It is expected that in the near future the spectrum of target drugs for melanoma treatment will increase. Herein, we review the most relevant potential novel drugs for melanoma treatment based on preclinical data and the results of early clinical trials. PMID- 26605315 TI - Minimally invasive thoracic surgery: new trends in Italy. AB - In Italy there exists quite a long and rich history in minimally invasive thoracic surgery. Pioneer Italian surgeons have been amongst those who first adopted video-assisted thoracic surgery (VATS) to perform procedures such as lobectomy and esophagectomy, respectively and quite many others have provided important contributions related to minimally invasive thoracic surgery and have proposed innovative ideas and creative technical refinements. According to a web search on recent studies published in Italy on minimally invasive thoracic surgery along the last 3 years, uniportal, nonintubated, and robotic VATS as well as VATS lobectomy have been found to represent the most frequently investigated issues. An ongoing active investigation in each of these sub-topics is contributing to a better definition of indications advantages and disadvantages of the various surgical strategies. In addition it is likely that combination strategies including adoption of uniportal and nonintubated approaches will lead to define novel ultra-minimally invasive treatment options. PMID- 26605311 TI - Melanoma: oncogenic drivers and the immune system. AB - Advances and in-depth understanding of the biology of melanoma over the past 30 years have contributed to a change in the consideration of melanoma as one of the most therapy-resistant malignancies. The finding that oncogenic BRAF mutations drive tumor growth in up to 50% of melanomas led to a molecular therapy revolution for unresectable and metastatic disease. Moving beyond BRAF, inactivation of immune regulatory checkpoints that limit T cell responses to melanoma has provided targets for cancer immunotherapy. In this review, we discuss the molecular biology of melanoma and we focus on the recent advances of molecularly targeted and immunotherapeutic approaches. PMID- 26605316 TI - A primer on medical education in the United States through the lens of a current resident physician. AB - Physician training and standards for medical licensure differ widely across the globe. The medical education process in the United States (US) typically involves a minimum of 11 years of formal training and multiple standardized examinations between graduating from secondary school and becoming an attending physician with full medical licensure. Students in the US traditionally enter a 4-year medical school after completing an undergraduate bachelor's degree, in contrast to most other countries where medical training begins after graduation from high school. Medical school seniors planning to practice medicine in the US must complete postgraduate clinical training, referred to as residency, within the specialty of their choosing. The duration of residency varies depending on specialty, typically lasting between 3 and 7 years. For subspecialty fields, additional clinical training is often required in the form of a fellowship. Many experts have called for changes in the medical education system to shorten medical training in the US, and reforms are ongoing in some institutions. However, physician education in the US generally remains a progression from undergraduate premedical coursework to 4 years of medical school, followed by residency training with an optional subspecialty fellowship. PMID- 26605317 TI - Membranous glomerulonephritis and cellular crescents induced by levamisole adulterated cocaine abuse: a case report. AB - Levamisole is illicitly employed as a cocaine adulterant. The consumption of levamisole-adulterated cocaine can provoke anti-neutrophil cytoplasmic antibody (ANCA)-associated syndromes. Patients carrying an HLAB27 allele are known to be at higher risk of developing agranulocytosis when treated with levamisole. Likewise, patients with ANCA-associated vasculitis (AAV) and internal organ involvement have typically been exposed to offending agents for prolonged periods of time, often on the order of years. Here, we report an unusual case of a patient in which kidney biopsy showed membranous glomerulonephritis with cellular crescents associated with levamisole-contaminated cocaine use. PMID- 26605319 TI - Therapeutic exercise in improving acute lung injury: a long distance to be covered. PMID- 26605318 TI - Raising the bar: optimizing combinations of targeted therapy and immunotherapy. PMID- 26605320 TI - Radiation therapy to the primary tumor in locally advanced prostate cancer is not "closing the barn door after the horse has bolted". PMID- 26605321 TI - Local infiltration anesthesia: does it really work? PMID- 26605322 TI - Ultrasound attacks Alzheimer's disease? PMID- 26605323 TI - Significance of microRNA-based biomarkers for pancreatic cancer. PMID- 26605324 TI - Adoptive T cell therapy for the treatment of viral infections. PMID- 26605325 TI - Dual Monitoring of Secretion and ATP Levels during Chondrogenesis Using Perfusion Culture-Combined Bioluminescence Monitoring System. AB - Skeletal pattern formation in limb development depends on prechondrogenic condensation which prefigures the cartilage template. However, although morphogens such as TGF-betas and BMPs have been known to play essential roles in skeletal patterning, how the morphogens induce prechondrogenic cells to aggregate and determine patterns of cartilage elements has remained unclear. Our previous study reported that ATP oscillations are induced during chondrogenesis. This result suggests the possibility that ATP oscillations lead to the oscillatory secretion of morphogens, due to the fact that secretion process requires ATP. To examine the correlation between ATP oscillations and secretion levels of morphogens, we have developed perfusion culture-combined bioluminescence monitoring system to simultaneously monitor intracellular ATP levels and secretion levels. Using this system, we found that secretory activity oscillates in phase with ATP oscillations and that secretion levels of TGF-beta1 and BMP2 oscillate during chondrogenesis. The oscillatory secretion of the morphogens would contribute to amplifying the fluctuation of the morphogens, underlie the spatial patterning of morphogens, and consequently lead to skeletal pattern formation. PMID- 26605327 TI - Corrigendum to "Sleep-Disordered Breathing in Patients with Heart Failure: New Trends in Therapy". PMID- 26605326 TI - Case Report Associated with Aspergillosis and Hepatitis E Virus Coinfection in Himalayan Griffons. AB - This study involved a death which occurred in four Himalayan griffons housed in Beijing zoo, China. Based on pathogen identification and the pathological changes observed, we did characterize the fungi and Hepatitis E virus (HEV) in four dead Himalayan griffons. Pathological changes were severe. Membranous-like material was observed on the surface of the internal organs. Spleen was necrotic. Focal lymphocyte infiltration in the liver and many sunflower-like fungi nodules were evident in the tissues, especially in the kidney. PCR was used to identify the pathogen. Based on the 18SrRNA genomic sequence of known fungi, the results confirmed that all four dead Himalayan griffons were infected with Aspergillus. At the same time the detection of HEV also showed positive results. To the best of our knowledge, this work appears to be the first report of concurrent presence of Aspergillosis and Hepatitis E virus in rare avian species. PMID- 26605328 TI - Association of the NOTCH4 Gene Polymorphism rs204993 with Schizophrenia in the Chinese Han Population. AB - NOTCH4 regulates signaling pathways associated with neuronal maturation, a process involved in the development and patterning of the central nervous system. The NOTCH4 gene has also been identified as a possible susceptibility gene for schizophrenia (SCZ). The objective of this study was to examine the relationship between NOTCH4 polymorphisms and SCZ in the Chinese Han population. The rs2071287 and rs204993 polymorphisms of the NOTCH4 gene were analyzed in 443 patients with SCZ and 628 controls of Han Chinese descent. Single SNP allele-, genotype-, and gender-specific associations were analyzed using different models (i.e., additive, dominant, and recessive models). This association study revealed that the rs204993 polymorphism is significantly associated with susceptibility for SCZ and that the AA genotype of rs204993 is associated with a higher risk for SCZ (P = 0.027; OR = 1.460; 95% CI, 1.043-2.054). Our data are consistent with those obtained in previous studies that suggested that rs204993 is associated with SCZ and that the AA genotype of rs204993 demonstrates a higher risk. Further large scale association analyses in Han Chinese populations are warranted. PMID- 26605329 TI - Geographic Variation of Chronic Kidney Disease Prevalence: Correlation with the Incidence of Renal Cell Carcinoma or Urothelial Carcinoma? AB - BACKGROUND: The aim of this study is to evaluate whether geographic variations in the prevalence of late-stage chronic kidney disease (CKD) exist and are associated with incidence rates of renal cell carcinoma (RCC), upper tract urothelial carcinoma (UTUC), or lower tract urothelial carcinoma (LTUC). METHODS: Prevalence rates of late-stage CKD for 366 townships (n > 30) in Taiwan were calculated for 1,518,241 and 1,645,151 subjects aged 40 years or older in years 2010 and 2009, respectively. Late-stage CKD prevalence in year 2010 was used as a training set and its age-adjusted standardized morbidity rates (ASMR) were divided into three groups as defined <1.76%, 1.76% <= ASMR < 2.64%, and >=2.64%, respectively. Year 2009, defined as the validation set, was used to validate the results. RESULTS: The ASMR of late-stage CKD in years 2010 and 2009 were 1.76%, and 2.09%, respectively. Geographic variations were observed, with notably higher rates of disease in areas of the central, southwestern mountainside, and southeastern seaboard. There were no significant differences among different combined risk groups of RCC, UTUC, and LTUC incidence. CONCLUSION: The substantial geographic variations in the prevalence of late-stage CKD exist, but are not correlated with RCC, UTUC, or LTUC incidence. PMID- 26605330 TI - Protective Effects of Paricalcitol on Peritoneal Remodeling during Peritoneal Dialysis. AB - Peritoneal dialysis (PD) is associated with structural and functional alterations of the peritoneal membrane, consisting of fibrosis, angiogenesis, and loss of ultrafiltration capacity. Vitamin D receptor activation (VDRA) plays an important role in mineral metabolism and inflammation, but also antiangiogenic and antifibrotic properties have been reported. Therefore, the effects of active vitamin D treatment on peritoneal function and remodeling were investigated. Rats were either kept naive to PDF exposure or daily exposed to 10 mL PDF and were treated for five or seven weeks with oral paricalcitol or vehicle control. Non PDF-exposed rats showed no peritoneal changes upon paricalcitol treatment. Paricalcitol reduced endogenous calcitriol but did not affect mineral homeostasis. However, upon PDF exposure, loss of ultrafiltration capacity ensued which was fully rescued by paricalcitol treatment. Furthermore, PD-induced ECM thickening was significantly reduced and omental PD-induced angiogenesis was less pronounced upon paricalcitol treatment. No effect of paricalcitol treatment on total amount of peritoneal cells, peritoneal leukocyte composition, and epithelial to mesenchymal transition (EMT) was observed. Our data indicates that oral VDRA reduces tissue remodeling during chronic experimental PD and prevents loss of ultrafiltration capacity. Therefore, VDRA is potentially relevant in the prevention of treatment technique failure in PD patients. PMID- 26605331 TI - Myopia Control with a Novel Peripheral Gradient Soft Lens and Orthokeratology: A 2-Year Clinical Trial. AB - OBJECTIVE: To evaluate the degree of axial elongation with soft radial refractive gradient (SRRG) contact lenses, orthokeratology (OK), and single vision (SV) spectacle lenses (control) during a period of 1 year before treatment and 2 years after treatment. METHODS: This was a prospective, longitudinal, nonrandomized study. The study groups consisted of 30, 29, and 41 children, respectively. The axial length (AL) was measured during 2 years after recruitment and lens fitting. RESULTS: The baseline refractive sphere was correlated significantly (Spearman's Rho (rho) correlation = 0.542; P < 0.0001) with the amount of myopia progression before baseline. After 2 years, the mean myopia progression values for the SRRG, OK, and SV groups were -0.56 +/- 0.51, -0.32 +/- 0.53, and -0.98 +/- 0.58 diopter, respectively. The results represent reductions in myopic progression of 43% and 67% for the SRRG and OK groups, respectively, compared to the SV group. The AL increased 27% and 38% less in the SRRG and OK groups, respectively compared with the SV group at the 2-year visit (P < 0.05). Axial elongation was not significantly different between SRRG and OK (P = 0.430). CONCLUSION: The SRRG lens significantly decreased AL elongation compared to the SV control group. The SRRG lens was similarly effective to OK in preventing myopia progression in myopic children and adolescent. PMID- 26605332 TI - Efficient Multicriteria Protein Structure Comparison on Modern Processor Architectures. AB - Fast increasing computational demand for all-to-all protein structures comparison (PSC) is a result of three confounding factors: rapidly expanding structural proteomics databases, high computational complexity of pairwise protein comparison algorithms, and the trend in the domain towards using multiple criteria for protein structures comparison (MCPSC) and combining results. We have developed a software framework that exploits many-core and multicore CPUs to implement efficient parallel MCPSC in modern processors based on three popular PSC methods, namely, TMalign, CE, and USM. We evaluate and compare the performance and efficiency of the two parallel MCPSC implementations using Intel's experimental many-core Single-Chip Cloud Computer (SCC) as well as Intel's Core i7 multicore processor. We show that the 48-core SCC is more efficient than the latest generation Core i7, achieving a speedup factor of 42 (efficiency of 0.9), making many-core processors an exciting emerging technology for large-scale structural proteomics. We compare and contrast the performance of the two processors on several datasets and also show that MCPSC outperforms its component methods in grouping related domains, achieving a high F-measure of 0.91 on the benchmark CK34 dataset. The software implementation for protein structure comparison using the three methods and combined MCPSC, along with the developed underlying rckskel algorithmic skeletons library, is available via GitHub. PMID- 26605333 TI - The Role of Focused Echocardiography in Pediatric Intensive Care: A Critical Appraisal. AB - Echocardiography is a key tool for hemodynamic assessment in Intensive Care Units (ICU). Focused echocardiography performed by nonspecialist physicians has a limited scope, and the most relevant parameters assessed by focused echocardiography in Pediatric ICU are left ventricular systolic function, fluid responsiveness, cardiac tamponade and pulmonary hypertension. Proper ability building of pediatric emergency care physicians and intensivists to perform focused echocardiography is feasible and provides improved care of severely ill children and thus should be encouraged. PMID- 26605334 TI - Healthy Aging and Compensation of Sentence Comprehension Auditory Deficits. AB - OBJECTIVES: To analyze the effect of aging on sentence auditory comprehension and to study the relationship between this language skill and cognitive functions (attention, working memory, and executive functions). METHODS: A total of 90 healthy subjects were divided into three groups: adults (50-59 years), young-old (60-69 years), and old-old (70-80 years). Subjects were assessed using the Revised Token Test. The measures used for performance analysis were number of correct answers (accuracy) and execution time of commands on the different subtests. RESULTS: Regarding accuracy, groups showed similar performance on the first blocks, but the young-old and old-old performed worse than adults on blocks 9 and 10. With respect to execution time, groups differed from block 2 (i.e., the groups differed for all blocks, except for block 1), with the worst performance observed in the old-old group, followed by that of the young-old group. Therefore, the elderly required more time to attain performance similar to that of adults, showing that time measurements are more sensitive for detecting the effects of age. Sentence comprehension ability is correlated with cognitive test performance, especially for global cognition and working memory tests. CONCLUSIONS: Healthy aging is characterized by the ability to compensate for difficulties in linguistic processing, which allows the elderly to maintain functional communication. PMID- 26605335 TI - Alteration of Regional Homogeneity within the Sensorimotor Network after Spinal Cord Decompression in Cervical Spondylotic Myelopathy: A Resting-State fMRI Study. AB - There is a lack of longitudinal research to evaluate the function of neurons' adaptive changes within the sensorimotor network (SMN) following recovery after cervical cord decompression. Regional homogeneity (ReHo) may provide information that is critical to fully understand CSM-related functional neural synchrony alterations. The purpose of this study was to assess the ReHo alterations of resting state-functional MRI (rs-fMRI) within pre- and postdecompression CSM and healthy controls (HC) and its correlations with clinical indices. Predecompression CSM demonstrated a significantly lower ReHo in the left primary sensory cortex and primary motor cortex (PostG/PreG) but enhanced ReHo in the right superior parietal lobule (SPL) compared with HC. In comparison with predecompression CSM, the postdecompression CSM showed increased ReHo in the left PostG/PreG but significantly lower ReHo in the right SPL compared with HC patients. Abnormal ReHo regions in pre- or postdecompression CSM showed no significant correlation with the Japanese Orthopaedic Association (JOA) scores, Neck Disability Index (NDI) scores, and disease duration (P > 0.05). This result demonstrated disrupted regional homogeneity within SMN in CSM. This adaptive change in the brain may favor the preservation of sensorimotor networks before and after cervical cord decompression and clinical symptoms independent of ReHo within SMN. PMID- 26605336 TI - Frontiers in Integrative Genomics and Translational Bioinformatics. PMID- 26605337 TI - An Effective Big Data Supervised Imbalanced Classification Approach for Ortholog Detection in Related Yeast Species. AB - Orthology detection requires more effective scaling algorithms. In this paper, a set of gene pair features based on similarity measures (alignment scores, sequence length, gene membership to conserved regions, and physicochemical profiles) are combined in a supervised pairwise ortholog detection approach to improve effectiveness considering low ortholog ratios in relation to the possible pairwise comparison between two genomes. In this scenario, big data supervised classifiers managing imbalance between ortholog and nonortholog pair classes allow for an effective scaling solution built from two genomes and extended to other genome pairs. The supervised approach was compared with RBH, RSD, and OMA algorithms by using the following yeast genome pairs: Saccharomyces cerevisiae Kluyveromyces lactis, Saccharomyces cerevisiae-Candida glabrata, and Saccharomyces cerevisiae-Schizosaccharomyces pombe as benchmark datasets. Because of the large amount of imbalanced data, the building and testing of the supervised model were only possible by using big data supervised classifiers managing imbalance. Evaluation metrics taking low ortholog ratios into account were applied. From the effectiveness perspective, MapReduce Random Oversampling combined with Spark SVM outperformed RBH, RSD, and OMA, probably because of the consideration of gene pair features beyond alignment similarities combined with the advances in big data supervised classification. PMID- 26605338 TI - Comparative Genomic Hybridization Analysis of Yersinia enterocolitica and Yersinia pseudotuberculosis Identifies Genetic Traits to Elucidate Their Different Ecologies. AB - Enteropathogenic Yersinia enterocolitica and Yersinia pseudotuberculosis are both etiological agents for intestinal infection known as yersiniosis, but their epidemiology and ecology bear many differences. Swine are the only known reservoir for Y. enterocolitica 4/O:3 strains, which are the most common cause of human disease, while Y. pseudotuberculosis has been isolated from a variety of sources, including vegetables and wild animals. Infections caused by Y. enterocolitica mainly originate from swine, but fresh produce has been the source for widespread Y. pseudotuberculosis outbreaks within recent decades. A comparative genomic hybridization analysis with a DNA microarray based on three Yersinia enterocolitica and four Yersinia pseudotuberculosis genomes was conducted to shed light on the genomic differences between enteropathogenic Yersinia. The hybridization results identified Y. pseudotuberculosis strains to carry operons linked with the uptake and utilization of substances not found in living animal tissues but present in soil, plants, and rotting flesh. Y. pseudotuberculosis also harbors a selection of type VI secretion systems targeting other bacteria and eukaryotic cells. These genetic traits are not found in Y. enterocolitica, and it appears that while Y. pseudotuberculosis has many tools beneficial for survival in varied environments, the Y. enterocolitica genome is more streamlined and adapted to their preferred animal reservoir. PMID- 26605339 TI - Renal Doppler Resistive Index as a Marker of Oxygen Supply and Demand Mismatch in Postoperative Cardiac Surgery Patients. AB - BACKGROUND AND OBJECTIVE: Renal Doppler resistive index (RDRI) is a noninvasive index considered to reflect renal vascular perfusion. The aim of this study was to identify the independent hemodynamic determinants of RDRI in mechanically ventilated patients after cardiac surgery. METHODS: RDRI was determined in 61 patients by color and pulse Doppler ultrasonography of the interlobar renal arteries. Intermittent thermodilution cardiac output measurements were obtained and blood samples taken from the tip of pulmonary artery catheter to measure hemodynamics and mixed venous oxygen saturation (SvO2). RESULTS: By univariate analysis, RDRI was significantly correlated with SvO2, oxygen extraction ratio, left ventricular stroke work index, and cardiac index, but not heart rate, central venous pressure, mean artery pressure, pulmonary capillary wedge pressure, systemic vascular resistance index, oxygen delivery index, oxygen consumption index, arterial lactate concentration, and age. However, by multivariate analysis RDRI was significantly correlated with SvO2 only. CONCLUSIONS: The present data suggests that, in mechanically ventilated patients after cardiac surgery, RDRI increases proportionally to the decrease in SvO2, thus reflecting an early vascular response to tissue hypoxia. PMID- 26605340 TI - The Preoperative CT-Scan Can Help to Predict Postoperative Complications after Pancreatoduodenectomy. AB - After pancreatoduodenectomy, complication rates are up to 40%. To predict the risk of developing postoperative pancreatic fistula or severe complications, various factors were evaluated. 110 consecutive patients undergoing pancreatoduodenectomy at our institute between January 2012 and September 2014 with complete CT scan were retrospectively identified. Pre-, per-, and postoperative patients and pathological information were gathered. The CT-scans were analysed for the diameter of the pancreatic duct, attenuation of the pancreas, and the visceral fat area. All data was statistically analysed for predicting POPF and severe complications by univariate and multivariate logistic regression analyses. The POPF rate was 18%. The VFA measured at umbilicus (OR 1.01; 95% CI = 1.00-1.02; P = 0.011) was an independent predictor for POPF. The severe complications rate was 33%. Independent predictors were BMI (OR 1.24; 95% CI = 1.10-1.42; P = 0.001), ASA class III (OR 17.10; 95% CI = 1.60-182.88; P = 0.019), and mean HU (OR 0.98; 95% CI = 0.96-1.00; P = 0.024). In conclusion, VFA measured at the umbilicus seems to be the best predictor for POPF. BMI, ASA III, and the mean HU of the pancreatic body are independent predictors for severe complications following PD. PMID- 26605341 TI - Breast Cancer Metabolism and Mitochondrial Activity: The Possibility of Chemoprevention with Metformin. AB - Metabolic reprogramming refers to the ability of cancer cells to alter their metabolism in order to support the increased energy request due to continuous growth, rapid proliferation, and other characteristics typical of neoplastic cells. It has long been believed that the increase of metabolic request was independent of the mitochondrial action but recently we know that mitochondrial activity together with metabolism plays a pivotal role in the regulation of the energy needed for tumor cell growth and proliferation. For these reasons the mitochondria pathways could be a new target for therapeutic and chemopreventive intervention. Metformin in particular is actually considered a promising agent against mitochondrial activity thanks to its ability to inhibit the mitochondrial complex I. PMID- 26605342 TI - Immune Checkpoint Modulation in Colorectal Cancer: What's New and What to Expect. AB - Colorectal cancer (CRC), as one of the most prevalent types of cancer worldwide, is still a leading cause of cancer related mortality. There is an urgent need for more efficient therapies in metastatic disease. Immunotherapy, a rapidly expanding field of oncology, is designed to boost the body's natural defenses to fight cancer. Of the many approaches currently under study to improve antitumor immune responses, immune checkpoint inhibition has thus far been proven to be the most effective. This review will outline the treatments that take advantage of our growing understanding of the role of the immune system in cancer, with a particular emphasis on immune checkpoint molecules, involved in CRC pathogenesis. PMID- 26605343 TI - A Humanized Anti-CD22-Onconase Antibody-Drug Conjugate Mediates Highly Potent Destruction of Targeted Tumor Cells. AB - Antibody-drug conjugates (ADCs) have evolved as a new class of potent cancer therapeutics. We here report on the development of ADCs with specificity for the B-cell lineage specific (surface) antigen CD22 being expressed in the majority of hematological malignancies. As targeting moiety a previously generated humanized anti-CD22 single-chain variable fragment (scFv) derivative from the monoclonal antibody RFB4 was reengineered into a humanized IgG1 antibody format (huRFB4). Onconase (ranpirnase), a clinically active pancreatic-type ribonuclease, was employed as cytotoxic payload moiety. Chemical conjugation via thiol-cleavable disulfide linkage retained full enzymatic activity and full binding affinity of the ADC. Development of sophisticated purification procedures using size exclusion and ion exchange chromatography allowed the separation of immunoconjugate species with stoichiometrically defined number of Onconase cargos. A minimum of two Onconase molecules per IgG was required for achieving significant in vitro cytotoxicity towards lymphoma and leukemia cell lines. Antibody-drug conjugates with an Onconase to antibody ratio of 3 : 1 exhibited an IC50 of 0.08 nM, corresponding to more than 18,400-fold increased cytotoxicity of the ADC when compared with unconjugated Onconase. These results justify further development of this ADC as a promising first-in-class compound for the treatment of CD22-positive malignancies. PMID- 26605344 TI - EPIPOX: Immunoinformatic Characterization of the Shared T-Cell Epitome between Variola Virus and Related Pathogenic Orthopoxviruses. AB - Concerns that variola viruses might be used as bioweapons have renewed the interest in developing new and safer smallpox vaccines. Variola virus genomes are now widely available, allowing computational characterization of the entire T cell epitome and the use of such information to develop safe and yet effective vaccines. To this end, we identified 124 proteins shared between various species of pathogenic orthopoxviruses including variola minor and major, monkeypox, cowpox, and vaccinia viruses, and we targeted them for T-cell epitope prediction. We recognized 8,106, and 8,483 unique class I and class II MHC-restricted T-cell epitopes that are shared by all mentioned orthopoxviruses. Subsequently, we developed an immunological resource, EPIPOX, upon the predicted T-cell epitome. EPIPOX is freely available online and it has been designed to facilitate reverse vaccinology. Thus, EPIPOX includes key epitope-focused protein annotations: time point expression, presence of leader and transmembrane signals, and known location on outer membrane structures of the infective viruses. These features can be used to select specific T-cell epitopes suitable for experimental validation restricted by single MHC alleles, as combinations thereof, or by MHC supertypes. PMID- 26605345 TI - Gene Expression Profile of Dendritic Cell-Tumor Cell Hybrids Determined by Microarrays and Its Implications for Cancer Immunotherapy. AB - BACKGROUND: Dendritic cell- (DC-) tumor fusion cells stimulate effective in vivo antitumor responses. However, therapeutic approaches are dependent upon the coadministration of exogenous 3rd signals. The purpose of this study was to determine the mechanisms for inadequate 3rd signaling by electrofused DC-tumor cell hybrids. METHODS: Murine melanoma cells were fused with DCs derived from C57BL/6 mice. Quantitative real-time PCR (qPCR) was used to determine relative changes in Th (T helper) 1 and Th2 cytokine gene expression. In addition, changes in gene expression of fusion cells were determined by microarray. Last, cytokine secretion by fusion cells upon inhibition of signaling pathways was analyzed by ELISA. RESULTS: qPCR analyses revealed that fusion cells exhibited a downregulation of Th1 associated cytokines IL-12 and IL-15 and an upregulation of the Th2 cytokine IL-4. Microarray studies further showed that the expression of chemokines, costimulatory molecules, and matrix-metalloproteinases was deregulated in fusion cells. Lastly, inhibitor studies demonstrate that inhibition of the PI3K/Akt/mTOR signaling pathway could restore the secretion of bioactive IL-12p70 by fusion cells. CONCLUSION: Our results suggest that combining fusion cell-based vaccination with administration of inhibitors of the PI3K/Akt/mTOR signaling pathway may enhance antitumor responses in patients. PMID- 26605346 TI - The Novel Functions of the PLC/PKC/PKD Signaling Axis in G Protein-Coupled Receptor-Mediated Chemotaxis of Neutrophils. AB - Chemotaxis, a directional cell migration guided by extracellular chemoattractant gradients, plays an essential role in the recruitment of neutrophils to sites of inflammation. Chemotaxis is mediated by the G protein-coupled receptor (GPCR) signaling pathway. Extracellular stimuli trigger activation of the PLC/PKC/PKD signaling axis, which controls several signaling pathways. Here, we concentrate on the novel functions of PLC/PKC/PKD signaling in GPCR-mediated chemotaxis of neutrophils. PMID- 26605348 TI - Eye and Vision (E & V): the critical link between eye and vision. PMID- 26605347 TI - The Protective Role of HLA-DRB1(*)13 in Autoimmune Diseases. AB - Autoimmune diseases (AIDs) are characterized by a multifactorial aetiology and a complex genetic background, with the MHC region playing a major role. We genotyped for HLA-DRB1 locus 1228 patients with AIDs-213 with Systemic Lupus Erythematosus (SLE), 166 with Psoriasis or Psoriatic Arthritis (Ps + PsA), 153 with Rheumatoid Arthritis (RA), 67 with Systemic Sclerosis (SSc), 536 with Multiple Sclerosis (MS), and 93 with Myasthenia Gravis (MG) and 282 unrelated controls. We confirmed previously established associations of HLA-DRB1(*)15 (OR = 2.17) and HLA-DRB1(*)03 (OR = 1.81) alleles with MS, HLA-DRB1(*)03 with SLE (OR = 2.49), HLA-DRB1(*)01 (OR = 1.79) and HLA-DRB1(*)04 (OR = 2.81) with RA, HLA DRB1(*)07 with Ps + PsA (OR = 1.79), HLA-DRB1(*)01 (OR = 2.28) and HLA-DRB1(*)08 (OR = 3.01) with SSc, and HLA-DRB1(*)03 with MG (OR = 2.98). We further observed a consistent negative association of HLA-DRB1(*)13 allele with SLE, Ps + PsA, RA, and SSc (18.3%, 19.3%, 16.3%, and 11.9%, resp., versus 29.8% in controls). HLA DRB1(*)13 frequency in the AIDs group was 20.0% (OR = 0.58). Although different alleles were associated with particular AIDs, the same allele, HLA-DRB1(*)13, was underrepresented in all of the six diseases analysed. This observation suggests that this allele may confer protection for AIDs, particularly for systemic and rheumatic disease. The protective effect of HLA-DRB1(*)13 could be explained by a more proficient antigen presentation by these molecules, favouring efficient clonal deletion during thymic selection. PMID- 26605349 TI - Surgical options for correction of refractive error following cataract surgery. AB - Refractive errors are frequently found following cataract surgery and refractive lens exchange. Accurate biometric analysis, selection and calculation of the adequate intraocular lens (IOL) and modern techniques for cataract surgery all contribute to achieving the goal of cataract surgery as a refractive procedure with no refractive error. However, in spite of all these advances, residual refractive error still occasionally occurs after cataract surgery and laser in situ keratomileusis (LASIK) can be considered the most accurate method for its correction. Lens-based procedures, such as IOL exchange or piggyback lens implantation are also possible alternatives especially in cases with extreme ametropia, corneal abnormalities, or in situations where excimer laser is unavailable. In our review, we have found that piggyback IOL is safer and more accurate than IOL exchange. Our aim is to provide a review of the recent literature regarding target refraction and residual refractive error in cataract surgery. PMID- 26605351 TI - Refractive surgery today: is there innovation or stagnation? PMID- 26605350 TI - Small incision lenticule extraction (SMILE) history, fundamentals of a new refractive surgery technique and clinical outcomes. AB - This review summarizes the current status of the small incision lenticule extraction (SMILE) procedure. Following the early work by Sekundo et al. and Shah et al., SMILE has become increasingly popular. The accuracy of the creation of the lenticule with the VisuMax femtosecond laser (Carl Zeiss Meditec) has been verified using very high-frequency (VHF) digital ultrasound and optical coherence tomography (OCT). Visual and refractive outcomes have been shown to be similar to those achieved with laser in situ keratomileusis (LASIK), notably in a large population reported by Hjortdal, Vestergaard et al. Safety in terms of the change in corrected distance visual acuity (CDVA) has also been shown to be similar to LASIK. It was expected that there would be less postoperative dry eye after SMILE compared to LASIK because the anterior stroma is disturbed only by the small incision, meaning that the anterior corneal nerves should be less affected. A number of studies have demonstrated a lower reduction and faster recovery of corneal sensation after SMILE than LASIK. Some studies have also used confocal microscopy to demonstrate a lower decrease in subbasal nerve fiber density after SMILE than LASIK. The potential biomechanical advantages of SMILE have been modeled by Reinstein et al. based on the non-linearity of tensile strength through the stroma. Studies have reported a similar change in Ocular Response Analyzer (Reichert) parameters after SMILE and LASIK, however, these have previously been shown to be unreliable as a representation of corneal biomechanics. Retreatment options after SMILE are discussed. Tissue addition applications of the SMILE procedure are also discussed including the potential for cryo-preservation of the lenticule for later reimplantation (Mohamed-Noriega, Angunawela, Lim et al.), and a new procedure referred to as endokeratophakia in which a myopic SMILE lenticule is implanted into a hyperopic patient (Pradhan et al.). Finally, studies reporting microdistortions in Bowman's layer and corneal wound healing responses are also described. PMID- 26605352 TI - Presbyopic correction on the cornea. AB - PURPOSE: The aim of this systematic review was to synthesize and appraise the evidence of the benefits of presbyopic correction on the cornea for visual function. SUMMARY: Comprehensive search was conducted in MEDLINE using keywords like "presbylasik", "presbyopic refractive surgery", "corneal pseudoaccommodation" and "corneal multifocality". We reviewed corrected and uncorrected visual acuities for distance and near (uncorrected distance visual acuity (UDVA), uncorrected near visual acuity (UNVA), corrected distance visual acuity (CDVA), distance corrected near visual acuity (DCNVA), corrected near visual acuity (CNVA)), along with the refractive outcomes in spherical equivalent (SE) and astigmatism comparing the differences observed between preoperative myopic and hyperopic patients, as well as among techniques. Thirty-one studies met the inclusion and quality criteria. Monovision provides excellent distance and near uncorrected acuities, but with a 17% retreatment and a 5% reversal rate. Initial multifocal ablations result in 12% loss of 2 or more lines of CDVA, and a 21% retreatment rate. Laser Blended Vision provides excellent UDVA, but with a 19% retreatment rate. Initial experiences with Supracor show moderate predictability and a 22% retreatment rate. Intracor results in 9% loss of 2 or more lines of CDVA. KAMRA provides excellent UDVA, with only a 1% retreatment rate, but a 6% reversal rate. Initial experiences with PresbyMAX provided excellent UNVA and DCNVA, showing excellent predictability and a 1% reversal rate. CONCLUSIONS: The findings have implications for clinicians and policymakers in the health-care industry and emphasize the need for additional trials examining this important and widely performed clinical procedure. PMID- 26605354 TI - Spontaneous exudative retinal detachment in a patient with sturge-weber syndrome after taking arginine, a supplement for erectile dysfunction. AB - BACKGROUND: Patients with Sturge-Weber syndrome can have ipsilateral diffuse or circumscribed choroidal hemangiomas. These hemangiomas have been seen to undergo spontaneous exudative or hemorrhagic retinal detachments. There is no definitive treatment for these types of retinal detachments, but radiotherapy, photodynamic therapy, oral propranolol, pegaptinib and bevacizumab have been used. CASE PRESENTATION: A 26-year-old male with Sturge-Weber Syndrome developed an exudative retinal detachment that occurred immediately after taking a supplement containing arginine. The patient was treated with intravitreal bevacizumab 1.25 mg in 0.05 ml solution. Resolution of the retinal detachment was seen after 4 treatments over a six-month period. CONCLUSIONS: Arginine and other medications that cause a release of nitric oxide may lead to intravascular leakage and exudative retinal detachments in patients who have a choroidal hemangioma. PMID- 26605355 TI - An overview of thyroid eye disease. AB - Thyroid eye disease (also known as Graves' ophthalmopathy) is a complex orbital inflammatory disease, which can be sight threatening, debilitating and disfiguring. This overview discusses the epidemiology, risk factors, pathogenesis, presentation, ophthalmic clinical features, investigations and treatment of thyroid eye disease. PMID- 26605353 TI - Practical issues concerning tear protein assays in dry eye. AB - Dry eye is a common clinical condition diagnosed by cumulative evidence of symptoms and signs. Many new treatments in dry eye are either expensive, invasive, have potential for side effects, or are not easily accessible. In severe dry eye, the ideal modality of treatment to begin with is often not clear as specific molecular disturbances are not evident from just examination of clinical manifestations. Assessing the effects of ongoing treatment is not straight forward since there is lack of agreement between clinical signs and symptoms. There is a need to have more objective methods of selecting treatment for dry eye and monitoring the effect of treatment. Recently, there are many new technologies applied to the discovery of tear biomarkers, for e.g., mass spectrometry based proteomics techniques and multiplex assays such as the bead based sandwich indirect immunofluorescent assays. Tear proteins assays have even been made available as point-of-care devices. This review focuses on the evidence for the involvements of tear proteins in dry eye, possible changes in tear concentrations with therapy and the strength of evidence regarding dry eye pathology. Much remains to be done in terms of developing office-based assays and ascertaining their reliability, but current evidence suggests that tear proteins have a role in the clinical practice of dry eye. PMID- 26605356 TI - Refractive lens exchange in modern practice: when and when not to do it? AB - Cataract surgery due to advances in small incision surgery evolved from a procedure concerned with the primary focus on the safe removal of cataractous lens to a procedure focused on the best possible postoperative refractive result. As the outcomes of cataract surgery became better, the use of lens surgery as a refractive modality in patients without cataracts has increased in interest and in popularity. Removal of the crystalline lens for refractive purposes or refractive lens exchange (RLE) presents several advantages over corneal refractive surgery. Patients with high degrees of myopia, hyperopia and astigmatism are still not good candidates for laser surgery. Moreover, presbyopia can currently only be corrected with monovision or reading spectacles. RLE supplemented with multifocal or accommodating intraocular lenses (IOLs) in combination with corneal astigmatic procedures might address all refractive errors including presbyopia, and eliminate the future need for cataract surgery. PMID- 26605357 TI - Fast segmentation of anterior segment optical coherence tomography images using graph cut. AB - BACKGROUND: Optical coherence tomography (OCT) is a non-invasive imaging system that can be used to obtain images of the anterior segment. Automatic segmentation of these images will enable them to be used to construct patient specific biomechanical models of the human eye. These models could be used to help with treatment planning and diagnosis of patients. METHODS: A novel graph cut technique using regional and shape terms was developed. It was evaluated by segmenting 39 OCT images of the anterior segment. The results of this were compared with manual segmentation and a previously reported level set segmentation technique. Three different comparison techniques were used: Dice's similarity coefficient (DSC), mean unsigned surface positioning error (MSPE), and 95% Hausdorff distance (HD). A paired t-test was used to compare the results of different segmentation techniques. RESULTS: When comparison with manual segmentation was performed, a mean DSC value of 0.943 +/- 0.020 was achieved, outperforming other previously published techniques. A substantial reduction in processing time was also achieved using this method. CONCLUSIONS: We have developed a new segmentation technique that is both fast and accurate. This has the potential to be used to aid diagnostics and treatment planning. PMID- 26605358 TI - Clinical outcomes with a new microincisional diffractive multifocal IOL. AB - BACKGROUND: To evaluate the refractive outcomes and the optical performance as well as the quality of life in patients implanted with a new diffractive multifocal intraocular lens (IOL). METHODS: Prospective, clinical study including 41 cases of patients who underwent cataract surgery and were divided in two groups: group 1, including 20 eyes implanted with the multifocal IOL SeeLens MF (Hanita Lenses, Israel); group 2, 21 eyes implanted with the Acrysof SA60AT IOL. Visual acuity, defocus curve, intraocular aberrations, contrast sensitivity function and quality of life were assessed during a follow up period of 6 months. RESULTS: Significant improvement was observed in the uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) in both groups (p < 0.02). The multifocal group showed better results in terms of uncorrected near visual acuity (UNVA) and distance-corrected near visual acuity (DCNVA) (p < 0.01). Comparison of both groups showed better visual acuities for the multifocal IOL group in defocus levels from -3.0 D to -1.50 D (p <= 0.01). At 6 months, there was a significant reduction of the internal higher order aberrations (p <= 0.04). A significant increase in scotopic contrast sensitivity was detected for 6 cycles/ degrees spatial frequency during follow up (p = 0.04), but no significant changes were observed for the rest of spatial frequencies (p >= 0.06). Visual Functioning Index (VF-14) questionnaire showed that patients reported high levels of satisfaction when performing daily tasks. CONCLUSIONS: The SeeLens MF IOL is able to successfully restore distance, near and intermediate visions after cataract surgery. It also provides functional intermediate vision with optimal intraocular optical quality. PMID- 26605359 TI - Effect of image registration on longitudinal analysis of retinal nerve fiber layer thickness of non-human primates using Optical Coherence Tomography (OCT). AB - BACKGROUND: In this paper we determined the benefits of image registration on estimating longitudinal retinal nerve fiber layer thickness (RNFLT) changes. METHODS: RNFLT maps around the optic nerve head (ONH) of healthy primate eyes were measured using Optical Coherence Tomography (OCT) weekly for 30 weeks. One automatic algorithm based on mutual information (MI) and the other semi-automatic algorithm based on log-polar transform cross-correlation using manually segmented blood vessels (LPCC_MSBV), were used to register retinal maps longitudinally. We compared the precision and recall between manually segmented image pairs for the two algorithms using a linear mixed effects model. RESULTS: We found that the precision calculated between manually segmented image pairs following registration by LPCC_MSBV algorithm is significantly better than the one following registration by MI algorithm (p < <0.0001). Trend of the all-rings and temporal, superior, nasal and inferior (TSNI) quadrants average of RNFLT over time in healthy primate eyes are not affected by registration. RNFLT of clock hours 1, 2, and 10 showed significant change over 30 weeks (p = 0.0058, 0.0054, and 0.0298 for clock hours 1, 2 and 10 respectively) without registration, but stayed constant over time with registration. CONCLUSIONS: The LPCC_MSBV provides better registration of RNFLT maps recorded on different dates than the automatic MI algorithm. Registration of RNFLT maps can improve clinical analysis of glaucoma progression. PMID- 26605360 TI - Centration axis in refractive surgery. AB - The human eye is an asymmetric optical system and the real cornea is not a rotationally symmetrical volume. Each optical element in the eye has its own optical and neural axes. Defining the optimum center for laser ablation is difficult with many available approaches. We explain the various centration approaches (based on these reference axes) in refractive surgery and review their clinical outcomes. The line-of-sight (LOS) (the line joining the entrance pupil center with the fixation point) is often the recommended reference axis for representing wavefront aberrations of the whole eye (derived from the definition of chief ray in geometrical optics); however pupil centration can be unstable and change with the pupil size. The corneal vertex (CV) represents a stable preferable morphologic reference which is the best approximate for alignment to the visual axis. However, the corneal light reflex can be considered as non constant, but dependent on the direction of gaze of the eye with respect to the light source. A compromise between the pupil and CV centered ablations is seen in the form of an asymmetric offset where the manifest refraction is referenced to the CV while the higher order aberrations are referenced to the pupil center. There is a need for a flexible choice of centration in excimer laser systems to design customized and non-customized treatments optimally. PMID- 26605362 TI - Excimer laser 6(th) generation: state of the art and refractive surgical outcomes. AB - After nearly three decades of innovation in excimer laser, today we are presented with a state of the art generation targeting minimally invasive refractive surgery with high speed laser, faster trackers, pupil monitoring systems and better customization profiles. These systems are capable of delivering better treatments with less induced postoperative high order aberrations. The results reported by many authors had confirmed the superiority in efficiency and safety profiles of this generation compared to previous generations. Still, current technology is facing major challenges in the correction of high hyperopic errors and in presbyopic treatments, with upgrades in ablation centration and thermal control needed, which will ensure better biomechanical results, as a step closer to perfection in refractive surgery. PMID- 26605361 TI - Polymodal roles of transient receptor potential channels in the control of ocular function. AB - Maintenance of intracellular Ca(2+) levels at orders of magnitude below those in the extracellular environment is a requisite for preserving cell viability. Membrane channels contribute to such control through modulating their time dependent opening and closing behaviour. Such regulation requires Ca(2+) to serve as a second messenger mediating receptor control of numerous life-sustaining responses. Transient receptor potential (TRP) channels signal transduce a wide variety of different sensory stimuli to induce responses modulating cellular function. These channels are non-selective cation channels with variable Ca(2+) selectivity having extensive sequence homology. They constitute a superfamily made up of 28 different members that are subdivided into 7 different subfamilies based on differences in sequence homology. Some of these TRP channel isotypes are expressed in the eye and localized to both neuronal and non-neuronal cell membranes. Their activation generates intracellular Ca(2+) transients and other downstream-linked signalling events that affect numerous responses required for visual function. As there is an association between changes in functional TRP expression in various ocular diseases, there are efforts underway to determine if these channels can be used as drug targets to reverse declines in ocular function. We review here our current knowledge about the expression, function and regulation of TRPs in different eye tissues in health and disease. Furthermore, some of the remaining hurdles are described to developing safe and efficacious TRP channel modulators for use in a clinical setting. PMID- 26605363 TI - Intraocular lens power calculation following laser refractive surgery. AB - Refractive outcomes following cataract surgery in patients that have previously undergone laser refractive surgery have traditionally been underwhelming. This is related to several key issues including the preoperative assessment (keratometry) and intraocular lens power calculations. Peer-reviewed literature is overwhelmed by the influx of methodology to manipulate the corneal or intraocular lens (IOL) powers following refractive surgery. This would suggest that the optimal derivative formula has yet been introduced. This review discusses the problems facing surgeons approaching IOL calculations in these post-refractive laser patients, the existing formulae and programs to address these concerns. Prior published outcomes will be reviewed. PMID- 26605364 TI - Femtosecond laser cataract surgery. AB - Femtosecond laser (FSL) cataract surgery is in its infancy but is rapidly gaining popularity due to the improved consistency and predictability for corneal incisions and anterior capsulorhexis. It enables subsequently less phacoemulsification energy and time to be employed, which has gains in terms of reduced corneal oedema. In addition, the FSL allows better circularity of the anterior capsulotomy, capsule overlap, intraocular lens (IOL) placement and centration of the IOL. These advantages have resulted in improved visual and refractive outcomes in the short term. Complication rates are low which reduce with surgeon experience. This review article focuses on the Alcon LenSx system. PMID- 26605366 TI - Predictability of refraction following immediate sequential bilateral cataract surgery (ISBCS) performed under general anaesthesia. AB - BACKGROUND: To evaluate the predictability of refraction following immediate sequential bilateral cataract surgery (ISBCS) performed under general anaesthesia. METHODS: This is a retrospective review of all ISBCS performed at Kantonsspital Winterthur, Switzerland, between April 2000 and September 2013. The case notes of 250 patients were reviewed. Patients having full refraction reported (110 patients/220 eyes) were included. 210 (95 %) eyes had a straight forward phacoemulsification with posterior chamber intraocular lens implantation, seven eyes had a planned extracapsular cataract extraction (ECCE); three eyes had an intracapsular cataract extraction. RESULTS: Both eyes of 110 patients (64 women, 46 men) with a mean age of 79.0 years, standard deviation (SD) +/-11.4 (range 26 to 97 years) were included. Median preoperative best corrected visual acuity (BCVA) was 0.5 LogMAR in the first eye, the interquartile range (IQR) was [0.4, 1.2]; 0.7 LogMAR in the second eye with IQR [0.4, 1.8]. At one month, the median BCVA was 0.2 LogMAR, IQR [0.1, 0.3] in the first eye, median BCVA was 0.1 LogMAR and IQR [0.0, 0.5] in the second eye. There were 3 eyes (3 %) that lost 3 lines or more in BCVA at one month (control vs. pre-operatively). In all three cases, poor visual acuity had been recorded pre-operatively (>1 LogMAR). Achieved refraction was within +/-1.0 D of the target in 83 % of eyes. There were only 5 % (n = 6) of cases where if delayed sequential bilateral extraction had been performed could potentially intraocular lens (IOL) choice have been adjusted, in four of these cases, target refraction was within +/-1.0 D in the second eye. CONCLUSIONS: ISBCS performed under general anaesthesia achieves target refraction in 83 % of eyes after consideration of complications, ocular co-morbidities and systemic restrictions. In the majority of cases where IOL power calculation could be considered, the achieved refraction of the second surgical eye was within +/ 1.0 D of intended refraction. This undermines the utility of IOL power adjustments in the second surgical eye. PMID- 26605367 TI - Efficacy, predictability and safety of small incision lenticule extraction (SMILE). AB - BACKGROUND: The purpose of this case series is to report the one-year outcomes of small incision lenticule extraction (SMILE) using the VisuMax(r) femtosecond laser. METHODS: Two hundred and six patients were recruited for this retrospective, single center study at TRSC International LASIK Center in Bangkok, Thailand. Patients underwent SMILE, whereby an intrastromal lenticule was cut using a femtosecond laser and then manually extracted without the need for flap creation. Outcome measures included refraction, visual acuity and contrast sensitivity evaluation. Patients were treated and followed for one year. RESULTS: SMILE for the correction of low to high myopia was performed on 347 eyes of 206 patients. The mean preoperative spherical equivalent was -4.96 +/- 1.88 diopters (D). On the first day following surgery, for eyes with a plano target refraction (99.14 % of all eyes), uncorrected distance visual acuity (UDVA) was 20/20 or better in 90 % of eyes. At the one week postoperative exam, the mean spherical equivalent was 0.01 +/- 0.36 D and UDVA was 20/20 or better in 84 % of eyes. After one year follow-up, no eyes showed loss of 2 or more lines of visual acuity and 31 % of eyes gained one or more lines. The photopic contrast sensitivity of SMILE treated eyes at 12 and 18 cycles per degree (cpd) improved from 1.59 and 0.94 preoperatively to 1.6 and 0.98, respectively, after one year. CONCLUSIONS: In this series, SMILE using the VisuMax(r) femtosecond laser demonstrated that after one year it is an effective, predictable and safe minimally invasive corneal refractive procedure. PMID- 26605365 TI - The evolution of corneal and refractive surgery with the femtosecond laser. AB - The use of femtosecond lasers has created an evolution in modern corneal and refractive surgery. With accuracy, safety, and repeatability, eye surgeons can utilize the femtosecond laser in almost all anterior refractive procedures; laser in situ keratomileusis (LASIK), small incision lenticule extraction (SMILE), penetrating keratoplasty (PKP), insertion of intracorneal ring segments, anterior and posterior lamellar keratoplasty (Deep anterior lamellar keratoplasty (DALK) and Descemet's stripping endothelial keratoplasty (DSEK)), insertion of corneal inlays and cataract surgery. As the technology matures, it will push surgical limits and open new avenues for ophthalmic intervention in areas not yet explored. As we witness the transition from femto-LASIK to femto-cataract surgery it becomes obvious that this innovation is here to stay. This article presents some of the most relevant advances of femtosecond lasers to modern corneal and refractive surgery. PMID- 26605368 TI - Corneal collagen cross-linking (CXL) in thin corneas. AB - Corneal collagen cross-linking (CXL) is a therapeutic procedure aiming at increasing the corneal stiffness in the keratoconus eyes by induction of cross links within the extracellular matrix. It is achieved by ultraviolet-A (370 nm) irradiation of the cornea after saturation with the photosensitizer riboflavin. In the conventional CXL protocol, a minimum de-epithelialized corneal thickness of 400 MUm is recommended to avoid potential irradiation damage to the corneal endothelium. In advanced keratoconus, however, stromal thickness is often lower than 400 MUm, which limits the application of CXL in that category. Efforts have been undertaken to modify the conventional CXL procedure to be applicable in thin corneas. The current review discusses different techniques employed to achieve this end and their results. The overall safety and efficacy of the modified CXL protocols are good, as most of them managed to halt the progression of keratectasia without postoperative complications. However, the evidence of safety and efficacy in the use of modified CXL protocols is still limited to few studies with few patients involved. Controlled studies with long-term follow-up are required to confirm the safety and efficacy of the modified protocols. PMID- 26605369 TI - Anti-glaucoma potential of Heliotropium indicum Linn in experimentally-induced glaucoma. AB - BACKGROUND: Heliotropium indicum is used as a traditional remedy for hypertension in Ghana. The aim of the study was to evaluate the anti-glaucoma potential of an aqueous whole plant extract of H. indicum to manage experimentally-induced glaucoma. METHODS: The percentage change in intraocular pressure (IOP), after inducing acute glaucoma (15 mLkg(-1) of 5 % dextrose, i.v.), in New Zealand White rabbits pretreated with Heliotropium indicum aqueous extract (HIE) (30-300 mgkg( 1)), acetazolamide (5 mgkg(-1)), and normal saline (10 mLkg(-1)) per os were measured. IOPs were also monitored in chronic glaucoma in rabbits (induced by 1 % prednisolone acetate drops, 12 hourly for 21 days) after treatments with the same doses of HIE, acetazolamide, and normal saline for 2 weeks. The anti-oxidant property of the extract was assessed by assaying for glutathione levels in the aqueous humour. Glutamate concentration in the vitreous humour was also determined using ELISA technique. Histopathological assessment of the ciliary bodies was made. RESULTS: The extract significantly reduced intraocular pressure (p <= 0.05-0.001) in acute and chronic glaucoma, preserved glutathione levels and glutamate concentration (p <= 0.01-0.001). Histological assessment of the ciliary body showed a decrease in inflammatory infiltration in the extract and acetazolamide-treated group compared with the normal saline-treated group. CONCLUSION: The aqueous whole plant extract of Heliotropium indicum has ocular hypotensive, anti-oxidant and possible neuro-protective effects, which therefore underscore its plausible utility as an anti-glaucoma drug with further investigation. PMID- 26605371 TI - Development and validation of a novel PCR-RFLP based method for the detection of 3 primary mitochondrial mutations in Leber's hereditary optic neuropathy patients. AB - BACKGROUND: Leber's Hereditary Optic Neuropathy (LHON; MIM 535000) is one of the most commonly inherited optic neuropathies and it results in significant visual morbidity among young adults with a peak age of onset between the ages of 15-30. The worldwide incidence of LHON is approximately 1 in 31,000. 95 % of LHON patients will have one of 3 primary mitochondrial mutations, G3460A (A52T of ND1), G11778A (R340H of ND4) and T14484C (M64V of ND6). There is incomplete penetrance and a marked gender bias in the development of visual morbidity with approximately 50 % of male carriers and 10 % of female carriers developing optic neuropathy. Visual recovery can occur but is dependent on the mutation present with the highest level of visual recovery seen in patients who have the T14484C mutation. The 3 primary mutations are typically identified by individual end point PCR-restriction fragment length polymorphism (RFLP) or individual targeted bi-directional Sanger sequencing reactions. The purpose of this study was to design a simple multiplex PCR-RFLP that could detect these 3 primary LHON mutations in one assay. METHODS: PCR primers were designed to incorporate a MaeIII restriction site in the presence of 3460A and 14484C mutations with the 11778A mutation naturally incorporating a MaeIII site. A multiplex PCR-RFLP assay was developed to detect the 3 common mutations in a single assay. Synthetic LHON controls based on the mitochondrial genome harbouring the 3 common mutations were synthesized and cloned into plasmids to act as reliable assay controls. DNA from previously tested patients and the synthetic LHON controls were subjected to the multiplex PCR-RFLP assay. The RFLP products were detected by agarose gel electrophoresis. RESULTS: The novel PCR-RFLP assay accurately detects the 3 primary mutations both in patient DNA and in synthesized DNA control samples with a simple visual mutation detection procedure. The synthesized DNA was demonstrated to be a robust control for the detection of LHON Mutations. CONCLUSION: In this paper, we describe a novel, robust and simple PCR-RFLP based method for the detection of mutations causing LHON, and report the generation of a series of LHON DNA controls suitable for all currently published assays. PMID- 26605372 TI - Identification of an adeno-associated virus binding epitope for AVB sepharose affinity resin. AB - Recent successes of adeno-associated virus (AAV)-based gene therapy have created a demand for large-scale AAV vector manufacturing and purification techniques for use in clinical trials and beyond. During the development of purification protocols for rh.10, hu.37, AAV8, rh.64R1, AAV3B, and AAV9 vectors, based on a widely used affinity resin, AVB sepharose (GE), we found that, under the same conditions, different serotypes have different affinities to the resin, with AAV3B binding the best and AAV9 the poorest. Further analysis revealed a surface exposed residue (amino acid number 665 in AAV8 VP1 numbering) differs between the high-affinity AAV serotypes (serine in AAV3B, rh.10, and hu.37) and the low affinity ones (asparagine in AAV8, rh.64R1, and AAV9). The residue locates within a surface-exposed, variable epitope flanked by highly conserved residues. The substitution of the epitope in AAV8, rh.64R1, and AAV9 with the corresponding epitope of AAV3B (SPAKFA) resulted in greatly increased affinity to AVB sepharose with no reduction in the vectors' in vitro potency. The presence of the newly identified AVB-binding epitope will be useful for affinity resin selection for the purification of novel AAV serotypes. It also suggests the possibility of vector engineering to yield a universal affinity chromatography purification method for multiple AAV serotypes. PMID- 26605373 TI - Generation of new peptide-Fc fusion proteins that mediate antibody-dependent cellular cytotoxicity against different types of cancer cells. AB - Antibody-dependent cellular cytotoxicity (ADCC), a key effector function for the clinical effectiveness of monoclonal antibodies, is triggered by the engagement of the antibody Fc domain with the Fcgamma receptors expressed by innate immune cells such as natural killer (NK) cells and macrophages. Here, we fused cancer cell-binding peptides to the Fc domain of human IgG1 to engineer novel peptide-Fc fusion proteins with ADCC activity. The designed fusion proteins were expressed in human embryonic kidney 293T cells, followed by purification and characterization by western blots. One of the engineered variants (WN-Fc), bound with high affinity to a wide range of solid tumor cell lines (e.g., colon, lung, prostate, skin, ovarian, and mammary tumors). Treatment of cancer cells with the engineered peptide-Fc fusions in the presence of effector NK cells potentially enhanced cytotoxicity, degranulation, and interferon-gamma production by NK cells when compared to cells treated with the Fc control. The presence of competing peptides inhibited NK cell activation. Furthermore, a bispecific peptide-Fc fusion protein activated NK cells against HER-1- and/or HER-2-expressing cancer cells. Collectively, the engineered peptide-Fc fusions constitute a new promising strategy to recruit and activate NK cells against tumor cells, a primary goal of cancer immunotherapy. PMID- 26605374 TI - Higher than expected frequencies of non-ovarian cancers within a large familial ovarian cancer registry. AB - Our objective was to determine whether the frequencies of non-ovarian cancers (NOC) within families in a large Familial Ovarian Cancer Registry (FOCR) are significantly different from the frequencies listed in the SEER database. The FOCR was established in 1981. Registry members are families with two or more first degree relatives who have a diagnosis of ovarian cancer, three or more cases of cancer on one side of the family with at least one being ovarian, at least one female with two or more primary cancers in which one is ovary, or a history of two or more cancers in the family with at least one being ovarian cancer diagnosed before the age of 45. The data was analyzed to find relative rates of 10 of the most common cancers found within the database, with the exception of ovarian and breast. These include bladder, CNS, cervical, colorectal, liver, lung, pancreas, prostate, stomach, and uterine. Cancers were further stratified by age at diagnosis, and compared to information in the SEER database. There are 2,671 pedigrees and a total of 50,454 individuals within the FOCR. There are 1,938 families with two or more relatives with ovarian cancer, accounting for 4,816 individuals with ovarian cancer. The total number of individuals with ovarian cancer is 5,421. Of these individuals with ovarian cancer, 2,249 have been verified with testing or physician correspondence. The frequencies of the NOCs within the registry were higher than that of the general population as described in the SEER database. In particular, the overall frequencies of cancers of the bladder, cervix, prostate, and uterus were higher within the FOCR at 2.3, 7.4, 25.2, and 11.9 per 1,000 respectively. Furthermore, diagnoses of both cervical and uterine cancers tended to occur at an earlier age within the FOCR. The overall frequencies of cancers of the bladder, cervix, prostate, and uterus are higher in the FOCR compared with a general population database. Future studies on segregation analysis and genome-wide linkage studies are warranted on families with NOC within the Familial Ovarian Cancer Registry. PMID- 26605375 TI - An Efficient Framework for Large Scale Multimedia Content Distribution in P2P Network: I2NC. AB - Network coding (NC) makes content distribution more effective and easier in P2P content distribution network and reduces the burden of the original seeder. It generalizes traditional network routing by allowing the intermediate nodes to generate new coded packet by combining the received packets. The randomization introduced by network coding makes all packets equally important and resolves the problem of locating the rarest block. Further, it reduces traffic in the network. In this paper, we analyze the performance of traditional network coding in P2P content distribution network by using a mathematical model and it is proved that traffic reduction has not been fully achieved in P2P network using traditional network coding. It happens due to the redundant transmission of noninnovative information block among the peers in the network. Hence, we propose a new framework, called I2NC (intelligent-peer selection and incremental-network coding), to eliminate the unnecessary flooding of noninnovative coded packets and thereby to improve the performance of network coding in P2P content distribution further. A comparative study and analysis of the proposed system is made through various related implementations and the results show that 10-15% of traffic reduced and improved the average and maximum download time by reducing original seeder's workload. PMID- 26605370 TI - Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. AB - Diabetic retinopathy (DR) is a leading cause of vision-loss globally. Of an estimated 285 million people with diabetes mellitus worldwide, approximately one third have signs of DR and of these, a further one third of DR is vision threatening DR, including diabetic macular edema (DME). The identification of established modifiable risk factors for DR such as hyperglycemia and hypertension has provided the basis for risk factor control in preventing onset and progression of DR. Additional research investigating novel risk factors has improved our understanding of multiple biological pathways involved in the pathogenesis of DR and DME, especially those involved in inflammation and oxidative stress. Variations in DR prevalence between populations have also sparked interest in genetic studies to identify loci associated with disease susceptibility. In this review, major trends in the prevalence, incidence, progression and regression of DR and DME are explored, and gaps in literature identified. Established and novel risk factors are also extensively reviewed with a focus on landmark studies and updates from the recent literature. PMID- 26605376 TI - Persea americana Glycolic Extract: In Vitro Study of Antimicrobial Activity against Candida albicans Biofilm and Cytotoxicity Evaluation. AB - This study evaluated the antifungal activity of Persea americana extract on Candida albicans biofilm and its cytotoxicity in macrophage culture (RAW 264.7). To determine the minimum inhibitory concentration (MIC), microdilution in broth (CLSI M27-S4 protocol) was performed. Thereafter, the concentrations of 12.5, 25, 50, 100, and 200 mg/mL (n = 10) with 5 min exposure were analyzed on mature biofilm in microplate wells for 48 h. Saline was used as control (n = 10). After treatment, biofilm cells were scraped off and dilutions were plated on Sabouraud dextrose agar. After incubation (37 degrees C/48 h), the values of colony forming units per milliliter (CFU/mL) were converted to log10 and analyzed (ANOVA and Tukey test, 5%). The cytotoxicity of the P. americana extract was evaluated on macrophages by MTT assay. The MIC of the extract was 6.25 mg/mL and with 12.5 mg/mL there was elimination of 100% of planktonic cultures. Regarding the biofilms, a significant reduction (P < 0.001) of the biofilm at concentrations of 50 (0.580 +/- 0.209 log10), 100 (0.998 +/- 0.508 log10), and 200 mg/mL (1.093 +/- 0.462 log10) was observed. The concentrations of 200 and 100 mg/mL were cytotoxic for macrophages, while the concentrations of 50, 25, and 12.5 mg/mL showed viability higher than 55%. PMID- 26605377 TI - Identifying User Interaction Patterns in E-Textbooks. AB - We introduce a new architecture for e-textbooks which contains two navigational aids: an index and a concept map. We report results from an evaluation in a university setting with 99 students. The interaction sequences of the users were captured during the user study. We found several clusters of user interaction types in our data. Three separate user types were identified based on the interaction sequences: passive user, term clicker, and concept map user. We also discovered that with the concept map interface users started to interact with the application significantly sooner than with the index interface. Overall, our findings suggest that analysis of interaction patterns allows deeper insights into the use of e-textbooks than is afforded by summative evaluation. PMID- 26605379 TI - Knowledge Discovery Using Big Data in Biomedical Systems. PMID- 26605381 TI - Guest Editors Introduction to the Special Section on Software and Databases. PMID- 26605380 TI - Guest Editorial for the 25th International Conference on Genome Informatics (GIW/ISCB-Asia 2014). PMID- 26605378 TI - Can we observe changes in mRNA "state"? Overview of methods to study mRNA interactions with regulatory proteins relevant in cancer related processes. AB - RNA binding proteins (RBP) regulate the editing, localization, stabilization, translation, and degradation of ribonucleic acids (RNA) through their interactions with specific cis-acting elements within target RNAs. Post transcriptional regulatory mechanisms are directly involved in the control of the immune response and stress response and their alterations play a crucial role in cancer related processes. In this review, we discuss mRNAs and RNA binding proteins relevant to tumorigenesis, current methodologies for detecting RNA interactions, and last, we describe a novel method to detect such interactions, which combines peptide modified, RNA imaging probes (FMTRIPs) with proximity ligation (PLA) and rolling circle amplification (RCA). This assay detects native RNA in a sequence specific and single RNA sensitive manner, and PLA allows for the quantification and localization of protein-mRNA interactions with single interaction sensitivity in situ. PMID- 26605382 TI - Selected Articles from the 2012 IEEE International Workshop on Genomic Signal Processing and Statistics (GENSIPS 2012). PMID- 26605383 TI - Reply: To PMID 25884579. PMID- 26605384 TI - Increase in reported malaria cases prompts clarification regarding diagnosis and treatment. In reply. PMID- 26605385 TI - TCBB Special Section on the Brazilian Symposium on Bioinformatics 2013. PMID- 26605386 TI - Glycemic control is an important consideration in diabetes care. In reply. PMID- 26605387 TI - IEEE/ACM Transactions on Computational Biology and Bioinformatics. Editorial from the Editor-in-Chief. PMID- 26605388 TI - Guest Editorial for the International Conference on Genome Informatics (GIW 2013). PMID- 26605389 TI - Guest Editorial for Special Section on BIBM 2013. PMID- 26605390 TI - Bing-Neel syndrome: a rare complication of Waldenstrom macroglobulinemia. PMID- 26605391 TI - Extreme dyserythropoiesis in the setting of acute erythroid leukemia. PMID- 26605392 TI - Guest Editors' Introduction: Selected Papers from ACM-BCB 2013. PMID- 26605393 TI - Guest Editorial for Special Section on BIOKDD2013. PMID- 26605394 TI - Guest Editorial for the 12th Asia Pacific Bioinformatics Conference. PMID- 26605395 TI - Guest Editor's Introduction: Special Section on the IEEE Pacific Visualization Symposium. PMID- 26605396 TI - Fracture risk and SSRIs for vasomotor symptoms. PMID- 26605397 TI - Cardiovascular disease remains number one killer for U.K. women. PMID- 26605398 TI - Guest Editors Introduction to the Special Section on Bioinformatics Research and Applications. PMID- 26605400 TI - This book highlights contemporary and emerging aspects of improving medical treatment modalities employing biomaterials or transplantation. Introduction. PMID- 26605399 TI - Guest Editorial: Pattern Recognition in Bioinformatics. PMID- 26605401 TI - Over the past decade, we have made great advances in the field of multiple sclerosis. Introduction. PMID- 26605402 TI - [T. Sanner & T.K. Grimsrud reply]. PMID- 26605403 TI - Response. PMID- 26605404 TI - This volume of Advances in Experimental Medicine and Biology holds the proceedings of the XVIIIth meeting. Introduction. PMID- 26605405 TI - Guest Editors' Introduction: Special Section on the ACM SIGGRAPH/Eurographics Symposium on Computer Animation (SCA). PMID- 26605406 TI - Free Energy-Based Conformational Search Algorithm Using the Movable Type Sampling Method. AB - In this article, we extend the movable type (MT) sampling method to molecular conformational searches (MT-CS) on the free energy surface of the molecule in question. Differing from traditional systematic and stochastic searching algorithms, this method uses Boltzmann energy information to facilitate the selection of the best conformations. The generated ensembles provided good coverage of the available conformational space including available crystal structures. Furthermore, our approach directly provides the solvation free energies and the relative gas and aqueous phase free energies for all generated conformers. The method is validated by a thorough analysis of thrombin ligands as well as against structures extracted from both the Protein Data Bank (PDB) and the Cambridge Structural Database (CSD). An in-depth comparison between OMEGA and MT-CS is presented to illustrate the differences between the two conformational searching strategies, i.e., energy-based versus free energy-based searching. These studies demonstrate that our MT-based ligand conformational search algorithm is a powerful approach to delineate the conformational ensembles of molecular species on free energy surfaces. PMID- 26605422 TI - Sunflower Polymers for Folate-Mediated Drug Delivery. AB - Polymeric delivery vehicles can improve the safety and efficacy of chemotherapy drugs by facilitating preferential tumor delivery. Polymer-drug conjugates are especially attractive carriers because additional formulation steps are not required during manufacturing, and drug release profiles can be altered based on linker choice. For clinical translation, these vehicles should also be reproducibly and controllably synthesized. Recently, we reported the development of a class of materials called "sunflower polymers," synthesized by controlled radical polymerization of hydrophilic "petals" from a cyclic multimacroinitiator "core". This synthesis strategy afforded control over the size of the polymer nanostructures based on their petal polymerization time. In this work, we demonstrate that particle size can be further tuned by varying the degree of polymerization of the cyclic core in addition to that of the petals. Additionally, we investigate the application of these materials for tumor targeted drug delivery. We demonstrate that folate-targeted, doxorubicin conjugated sunflower polymers undergo receptor-mediated uptake into cancer cells and pH-triggered drug release leading to cytotoxicity. These materials are attractive as drug carriers due to their discrete and small size, shielded drug cargo that can be triggered for release, and relative ease of synthesis. PMID- 26605423 TI - A biopsychosocial investigation of changes in self-concept on the Head Injury Semantic Differential Scale. AB - This study aimed to investigate the influence of the "good-old-days" bias, neuropsychological functioning and cued recall of life events on self-concept change. Forty seven adults with TBI (70% male, 1-5 years post-injury) and 47 matched controls rated their past and present self-concept on the Head Injury Semantic Differential Scale (HISD) III. TBI participants also completed a battery of neuropsychological tests. The matched control group of 47 were from a sample of 78 uninjured participants who were randomised to complete either the Social Readjustment Rating Scale-Revised (cued recall) or HISD (non-cued recall) first. Consistent with the good-old-days bias, participants with TBI rated their pre injury self-concept as more positive than their present self-concept and the present self-concept of controls (p < .05). More positive pre-injury self-concept ratings were related to lower estimated premorbid IQ and poorer verbal fluency and delayed memory (p < .05). For uninjured participants, cued recall, life events and event appraisals each accounted for unique variance in self-concept change (p < .01) after controlling for negative affect. The cued recall group rated their past self-concept as significantly more negative than the non-cued group (p < .01). Overall, the good-old-days bias, neuropsychological functioning and cued recall influenced reports of self-concept change by affecting retrospective ratings of past self-concept. Further research is needed to investigate the impact of contextual cues on self-concept change after TBI. PMID- 26605424 TI - Relative importance and interactions of furan precursors in sterilised, vegetable based food systems. AB - Mitigation strategies aimed at an intervention in the reaction pathways for furan formation (e.g., by adjusting precursor concentrations) might offer an additional route for furan reduction in sterilised, vegetable-based foods, without adverse effects on other food safety or quality attributes. As a first step towards product reformulation, the aim of the present study was to determine the relative importance and interactions of possible furan precursors in these types of foods. Based on an I-optimal experimental design, potato puree (naturally low in furan precursors) was spiked with known amounts of sugars, ascorbic acid, olive oil and beta-carotene, and subjected to a thermal sterilisation. Significant correlations were observed between furan concentrations after thermal treatment and starting concentrations of ascorbic acid and monosaccharides (i.e., fructose and glucose). Ascorbic acid had a clear furan-reducing effect as an antioxidant by protecting (polyunsaturated) fatty acids against oxidative degradation. Fructose and glucose were the main precursors, which can most probably be attributed to their high, but realistic, concentrations in the product. The contributions of fatty acids and beta-carotene were strongly dependent on redox interactions with other food constituents. In the same potato purees, only low concentrations (0-2 ng g(-1) puree) of 2-methylfuran were detected, indicating that the direct importance of the spiked food constituents as a precursor for methylfuran formation was rather small. Based on the results of this study, reducing the amount of monosaccharides or adjusting the redox conditions of the matrix are suggested as two possible approaches for furan mitigation on the product side. PMID- 26605425 TI - Adsorption of heavy metal from aqueous solution by dehydrated root powder of long root Eichhornia crassipes. AB - The root powder of long-root Eichhornia crassipes, as a new kind of biodegradable adsorbent, has been tested for aqueous adsorption of Pb, Zn, Cu, and Cd. From FT IR, we found that the absorption peaks of phosphorous compounds, carbonyl, and nitrogenous compounds displayed obvious changes before and after adsorption which illustrated that plant characteristics may play a role in binding with metals. Surface properties and morphology of the root powders have been characterized by means of SEM and BET. Energy spectrum analysis showed that the metals were adsorbed on root powders after adsorption. Then, optimum quantity of powder, pH values, and metal ion concentrations in single-system and multi-system were detected to discuss the characteristics and mechanisms of metal adsorption. Freundlich model and the second-order kinetics equation could well describe the adsorption of heavy metals in single-metal system. The adsorption of Pb, Zn, and Cd in the multi-metal system decreased with the concentration increased. At last, competitive adsorption of every two metals on root powder proved that Cu and Pb had suppressed the adsorption performance of Cd and Zn. PMID- 26605427 TI - Isometric muscle strength and mobility capacity in children with cerebral palsy. AB - PURPOSE: To determine the relationship between isometric leg muscle strength and mobility capacity in children with cerebral palsy (CP) compared to typically developing (TD) peers. METHOD: Participants were 62 children with CP (6-13 years), able to walk with (n = 10) or without (n = 52) walking aids, and 47 TD children. Isometric muscle strength of five muscle groups of the leg was measured using hand-held dynamometry. Mobility capacity was assessed with the 1-min walk, the 10-m walk, sit-to-stand, lateral-step-up and timed-stair tests. RESULTS: Isometric strength of children with CP was reduced to 36-82% of TD. When adjusted for age and height, the percentage of variance in mobility capacity that was explained by isometric strength of the leg muscles was 21-24% (walking speed), 25% (sit-to-stand), 28% (lateral-step-up) and 35% (timed-stair) in children with CP. Hip abductors and knee flexors had the largest contribution to the explained variance, while knee extensors showed the weakest correlation. Weak or no associations were found between strength and mobility capacity in TD children. CONCLUSION: Isometric strength, especially hip abductor and knee flexor strength, is moderately related to mobility capacity in children with CP, but not in TD children. To what extent training of these muscle groups will lead to better mobility capacity needs further study. Implications for Rehabilitation Strength training in children with cerebral palsy (CP) may be targeted more specifically at hip abductors and knee flexors. The moderate associations imply that large improvements in mobility capacity may not be expected when strength increases. PMID- 26605426 TI - Mutant characterization and in vivo conditional repression identify aromatic amino acid biosynthesis to be essential for Aspergillus fumigatus virulence. AB - Pathogenicity of the saprobe Aspergillus fumigatus strictly depends on nutrient acquisition during infection, as fungal growth determines colonisation and invasion of a susceptible host. Primary metabolism has to be considered as a valid target for antimycotic therapy, based on the fact that several fungal anabolic pathways are not conserved in higher eukaryotes. To test whether fungal proliferation during invasive aspergillosis relies on endogenous biosynthesis of aromatic amino acids, defined auxotrophic mutants of A. fumigatus were generated and assessed for their infectious capacities in neutropenic mice and found to be strongly attenuated in virulence. Moreover, essentiality of the complete biosynthetic pathway could be demonstrated, corroborated by conditional gene expression in infected animals and inhibitor studies. This brief report not only validates the aromatic amino acid biosynthesis pathway of A. fumigatus to be a promising antifungal target but furthermore demonstrates feasibility of conditional gene expression in a murine infection model of aspergillosis. PMID- 26605428 TI - Influence of patient, physician, and hospital characteristics on the receipt of guideline-concordant care for inflammatory breast cancer. AB - PURPOSE: Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer for which treatments vary, so we sought to identify factors that affect the receipt of guideline-concordant care. METHODS: Patients diagnosed with IBC in 2004 were identified from the Breast and Prostate Cancer Data Quality and Patterns of Care Study, containing information from cancer registries in seven states. Variation in guideline-concordant care for IBC, based on National Comprehensive Cancer Network (NCCN) guidelines, was assessed according to patient, physician, and hospital characteristics. RESULTS: Of the 107 IBC patients in the study without distant metastasis at the time of diagnosis, only 25.8% received treatment concordant with guidelines. Predictors of non concordance included patient age (>=70 years), non-white race, normal body mass index (BMI 18.5-25 kg/m(2)), patients with physicians graduating from medical school >15 years prior, and smaller hospital size (<200 beds). IBC patients survived longer if they received guideline-concordant treatment based on either 2003 (p=0.06) or 2013 (p=0.06) NCCN guidelines. CONCLUSIONS: Targeting factors associated with receipt of care that is not guideline-concordant may reduce survival disparities in IBC patients. Prompt referral for neoadjuvant chemotherapy and post-operative radiation therapy is also crucial. PMID- 26605430 TI - Contaminants of Emerging Concern: Mass Balance and Comparison of Wastewater Effluent and Upstream Sources in a Mixed-Use Watershed. AB - Understanding the sources, transport, and spatiotemporal variability of contaminants of emerging concern (CECs) is important for understanding risks and developing monitoring and mitigation strategies. This study used mass balances to compare wastewater treatment plant (WWTP) and upstream sources of 16 CECs to a mixed-use watershed in Minnesota, under different seasonal and hydrological conditions. Three distinct CEC groups emerged with respect to their source proportionality and instream behavior. Agricultural herbicides and daidzein inputs were primarily via upstream routes with the greatest loadings and concentrations during high flows. Trimethoprim, mecoprop, nonprescription pharmaceuticals, and personal care products entered the system via balanced/mixed pathways with peak loadings and concentrations in high flows. Carbaryl, 4 nonylphenol, and the remaining prescription pharmaceuticals entered the system via WWTP effluent with relatively stable loadings across sampling events. Mass balance analysis based on multiple sampling events and sites facilitated CEC source comparisons and may therefore prove to be a powerful tool for apportioning sources and exploring mitigation strategies. PMID- 26605429 TI - Adherence to World Cancer Research Fund/American Institute for Cancer Research recommendations and pancreatic cancer risk. AB - BACKGROUND: Pancreatic cancer is a leading cause of cancer death. A role of dietary factors in pancreatic carcinogenesis has been suggested. The World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) published 8 recommendations for cancer prevention. We evaluated the effect of adherence to the WCRF/AICR recommendations on pancreatic cancer risk. METHODS: We operationalized 7 of the 8 WCRF/AICR recommendations to generate a WCRF/AICR score. We examined the association of WCRF/AICR score with pancreatic cancer in data from an Italian case-control study of 326 incident cases and 652 controls. RESULTS: Adherence to WCRF/AICR recommendations was associated with a significantly decreased risk of pancreatic cancer. Using a WCRF/AICR score <3.5 as a reference, the adjusted odds ratio (OR) for a score 3.5-<4 was 0.80 (95% CI 0.49, 1.28), for a score 4-<5 0.54 (95% CI 0.35, 0.82), and for score 5 or more 0.41 (95% CI 0.24, 0.68; p-value for trend 0.0002). The OR for a continuous increment of one unit of the WCRF/AICR score was 0.72 (95% CI 0.60, 0.87). CONCLUSION: Adherence to the WCRF/AICR recommendations may reduce pancreatic cancer risk. PMID- 26605431 TI - Large pi-Conjugated Quinacridone Derivatives: Syntheses, Characterizations, Emission, and Charge Transport Properties. AB - Two 11-ring-fused quinacridone derivatives, TTQA and DCNTTQA, have been synthesized by ferric chloride mediated cyclization and Knoevenagel reaction. Replacement of the carbonyl groups (in TTQA) with dicyanoethylene groups (in DCNTTQA) not only red-shifted the emission to the near-infrared region but also led to a nonplanar skeleton that significantly improved the solubility of DCNTTQA. Moreover, dicyanoethylene groups rendered DCNTTQA low-lying HOMO and LUMO levels. DCNTTQA-based solution-processed field-effect transistors showed a hole mobility up to 0.217 cm(2) V(-1) s(-1). PMID- 26605432 TI - Oncological outcomes of robotic-assisted radical hysterectomy. AB - TFeasibility and favorable short term outcome with respect to complications has been already convincingly shown for robotic-assisted radical hysterectomy. With respect to oncological safety there are at present only few studies mainly retrospectively. However, these seem to confirm the data from classical laparoscopic surgery that oncological outcome is not impaired by minimal-invasive surgery. Since robotic-assisted radical hysterectomy is in fact technically supported laparoscopic radical hysterectomy it is reasonable to assume that results are at least equal compared to the classical laparoscopic approach. PMID- 26605434 TI - A Welcome to New Editorial Board Members. PMID- 26605433 TI - Etiology of fatal thoracic aortic injuries: Secondary data analysis. AB - OBJECTIVES: Motor vehicle crashes remain a leading cause of death in the United States (US). Thoracic aortic dissection due to blunt trauma remains a major injury mechanism, and up to 90% of these injuries result in death on the scene. The objective of this study is to understand the modern risk factors and etiology of fatal thoracic aortic injuries in the current US fleet. METHODS: Using a unique, linked, Fatality Analysis Reporting System (FARS) and Multiple Cause of Death (MCOD) database from 2000-2010, 144,169 drivers over 16 years of age who suffered fatal injuries were identified. The merged database provides an unparalleled fidelity for identifying thoracic aortic injuries due to motor vehicle accidents. Thoracic aortic injuries were defined by ICD-10 codes S250. Univariate and multivariate logistic regression models for presence of any thoracic aortic injuries were fitted. Age, gender, BMI weight categories, vehicle class, model year, crash type/direction, severity of crash damage, airbag deployment location, and seatbelt use, fatal injury codes, and location of injury were considered. Odds ratios (OR) and corresponding 95% confidence intervals (95%CI) are calculated. RESULTS: There were 2953 deaths (2.10%) related to thoracic aortic injuries that met the inclusion criteria. Nearside crashes were associated with an increased odds (OR = 1.42, 1.1-1.83), while rollover crashes (OR =.44,.29-.66) were associated with a reduced odds of fatal thoracic aortic injury. Using backward selection on the full multivariate model, the only significant model effects that remained were vehicle type, crash type, body region, and injury type. CONCLUSIONS: The increased prevalence of fatal thoracic aortic injury in nearside crashes, increasing age, and vehicle type provide some insight into the current US fleet. Important factors, including model year, had significantly lower levels of the injury in univariate analysis, demonstrating the effect of safety improvements in newer model vehicles. Further study of this fatal injury is warranted, including comparisons of those who survive the injury. PMID- 26605435 TI - Combined Veterinary-Human Medical Education: A Complete One Health Degree? PMID- 26605436 TI - LSU-SVM Shelter Medicine Program. PMID- 26605437 TI - Response to Letter to the Editor "LSU-SVM Shelter Medicine Program". PMID- 26605438 TI - Engineered Hybrid Nanoparticles for On-Demand Diagnostics and Therapeutics. AB - Together with the simultaneous development of nanomaterials and molecular biology, the bionano interface brings about various applications of hybrid nanoparticles in nanomedicine. The hybrid nanoparticles not only present properties of the individual components but also show synergistic effects for specialized applications. Thus, the development of advanced hybrid nanoparticles for targeted and on-demand diagnostics and therapeutics of diseases has rapidly become a hot research topic in nanomedicine. The research focus is to fabricate novel classes of programmable hybrid nanoparticles that are precisely engineered to maximize drug concentrations in diseased cells, leading to enhanced efficacy and reduced side effects of chemotherapy for the disease treatment. In particular, the hybrid nanoparticle platforms can simultaneously target diseased cells, enable the location to be imaged by optical methods, and release therapeutic drugs to the diseased cells by command. This Account specially discusses the rational fabrication of integrated hybrid nanoparticles and their applications in diagnostics and therapeutics. For diagnostics applications, hybrid nanoparticles can be utilized as imaging agents that enable detailed visualization at the molecular level. By the use of suitable targeting ligands incorporated on the nanoparticles, targeted optical imaging may be feasible with improved performance. Novel imaging techniques such as multiphoton excitation and photoacoustic imaging using near-infrared light have been developed using the intrinsic properties of particular nanoparticles. The use of longer-wavelength excitation sources allows deeper penetration into the human body for disease diagnostics and at the same time reduces the adverse effects on normal tissues. Furthermore, multimodal imaging techniques have been achieved by combining several types of components in nanoparticles, offering higher accuracy and better spatial views, with the aim of detecting life-threatening diseases before symptoms appear. For therapeutics applications, various nanoparticle-based treatment methods such as photodynamic therapy, drug delivery, and gene delivery have been developed. The intrinsic ability of organic nanoparticles to generate reactive oxygen species has been utilized for photodynamic therapy, and mesoporous silica nanoparticles have been widely used for drug loading and controlled delivery. Herein, the development of controlled-release systems that can specifically deliver drug molecules to target cells and release then upon triggering is highlighted. By control of the release of loaded drug molecules at precise sites (e.g., cancer cells or malignant tumors), side effects of the drugs are minimized. This approach provides better control and higher efficacy of drugs in the human body. Future personalized medicine is also feasible through gene delivery methods. Specific DNA/RNA-carrying nanoparticles are able to deliver them to target cells to obtain desired properties. This development may create an evolution in current medicine, leading to more personalized healthcare systems that can reduce the population screening process and also the duration of drug evaluation. Furthermore, nanoparticles can be incorporated with various components that can be used for simultaneous diagnostics and therapeutics. These multifunctional theranostic nanoparticles enable real-time monitoring of treatment process for more efficient therapy. PMID- 26605439 TI - Aging Oxidation Reactions on Atmospheric Black Carbon by OH Radicals. A Theoretical Modeling Study. AB - Aging processes of black carbon (BC) particles require knowledge of their chemical reactivities, which have impact on cloud condensation nuclei (CCN) activities, radiant properties and health problems related to air pollutions. In the present work, interactions between several OH radicals with BC (modeled with a coronene molecule) were calculated by using DFT and PM6 codes as described by Mysak et al. Water interaction with BC was also included. Results show that OH radical adsorption is preferred on border sites, independent of the theoretical method employed. Potential energy curves using DFT(TPSS-D3) approach for OH chemisorption showed small-energy barriers, as reported in previous work with PM6. A dipole moment has been created, and the hydrophobic coronene surface is transformed to hydrophilic after the first OH chemisorption. Several stages were found in the BC aging by OH radicals, thus (a) Hydroxylation of coronene by several OH radical would lead to H abstractions directly from the substrate. (b) Abstraction of H from adsorbed OH (at the border sites) drives a C-C bond breaking and the formation of carboxyl groups. (c) Hydrogen abstraction from carboxyl group produces decarboxylation (CO2 plus water) as experimentally obtained. Potential energy curves of one of the reactive path were calculated with the PM6 method. The formation of products was confirmed using DFT. Coronene interaction with O2 was also considered to have a realistic atmospheric environment. PMID- 26605440 TI - Caesarean Section Scar Ectopic Pregnancy. PMID- 26605441 TI - Standing on the Shoulders of Giants. PMID- 26605442 TI - Letter to the Editor: Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies. PMID- 26605443 TI - Letter to the Editor: In Response. PMID- 26605444 TI - Letter to the Editor: Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy: Executive Summary. PMID- 26605445 TI - Letter to the Editor: In Response. PMID- 26605446 TI - Is Preterm Premature Rupture of Membranes Latency Influenced by Single Versus Multiple Agent Antibiotic Prophylaxis in Group B Streptococcus Positive Women Delivering Preterm? AB - OBJECTIVE: To evaluate the influence of antibiotic regimen on the duration of latency (time from preterm pre-labour rupture of membranes [PPROM] to delivery) and significant infectious neonatal morbidity from rupture of membranes to delivery < 37 weeks' gestational age in women known to be group B Streptococcus (GBS) positive. METHODS: We obtained data from the Nova Scotia Atlee Perinatal Database. In a retrospective, cohort, population-based study, we included pregnancies complicated by PPROM but excluded pregnancies in this group requiring immediate delivery. The cohort was categorized by antibiotic regimen (single vs. multiple agents) and we compared latency and adverse neonatal outcomes according to antibiotic regimen used. Summary characteristics were compared using chi square analysis with significance < 0.05. Logistic regression was used to estimate adjusted odds ratios, 95% confidence intervals, and mean differences for all outcomes and to account for confounding variables. RESULTS: From 1988 to 2011, the potential study population was 119 158 pregnancies. In total, 3435 deliveries were identified to be PPROM (3%). Of these, 303 mother-baby pairs (9%) were known to be GBS positive by urine or swab culture. Adjusted comparisons of latency and neonatal sepsis showed no difference according to antibiotic regimen (P > 0.05). CONCLUSION: The 2013 SOGC guideline on GBS prophylaxis recommends antibiotic therapy in women with PPROM for both latency and prevention of GBS related neonatal sepsis. This clinically relevant evaluation in a select preterm group demonstrated that type of antibiotic regimen did not influence either latency with PPROM and GBS positive culture or rates of neonatal sepsis. Ongoing evaluation of serious neonatal outcomes is essential in view of this new recommendation. PMID- 26605447 TI - Alloimmune Red Blood Cell Antibodies: Prevalence and Pathogenicity in a Canadian Prenatal Population. AB - OBJECTIVE: The goals of this study were to determine the prevalence and relative frequencies of red blood cell antibodies in a Canadian prenatal population, and to evaluate the fetal and neonatal outcomes of affected pregnancies. METHODS: We conducted a retrospective review of pregnancies that screened positive for red cell antibodies between 2006 and 2010. The following antibodies were included: anti-D, -C, -c, -E, -e, -Fya, -Fyb, -Jka, and-Jkb. Cases of anti-Kell as the sole antibody were excluded. Fetal and neonatal outcome data were then collected and analyzed. RESULTS: The population prevalence of a positive antibody screen was 0.36%. Anti-E was the most frequent antibody at 48.5%, followed by anti-c and anti-Jka. Anti-D made up 6.8% of cases, but had significantly higher titres and was responsible for the majority of severely affected fetuses. Sixteen cases in our series experienced severe adverse fetal or neonatal outcomes. All severe outcomes occurred in cases that had a maximum titre of >= 8. CONCLUSION: Despite the decreasing incidence of anti-D alloimmunization, anti-D remains responsible for the majority of severe cases of hemolytic disease of the fetus and newborn. PMID- 26605448 TI - Smoking Cessation Strategies in Pregnancy. AB - Although pregnancy often motivates women to quit smoking, 20% to 25% will continue to smoke. Smoking is associated with adverse obstetric and neonatal outcomes such as placental abruption, stillbirth, preterm birth and sudden infant death syndrome, and it is therefore important to motivate women to quit during pregnancy. In this review, we explore the efficacy and evidence for safety of strategies for smoking cessation in pregnancy, including behavioural and pharmacologic therapies. The PubMed, Medline, EMBASE, and Cochrane databases (1990 to 2014) were accessed to identify relevant studies, using the search terms "smoking cessation," "pregnancy," "medicine, behavioural," "nicotine replacement products," "bupropion," and "varenicline." Studies were selected based on the levels of evidence presented by the Canadian Task Force on Preventative Health Care. Based on our review of the evidence, incentives combined with behavioural therapy appear to show the greatest promise for abstaining from smoking in the pregnant population. Nicotine replacement therapy administered in the form of gum may be better than using transdermal forms to avoid high levels of nicotine in the fetal circulation. One small trial demonstrated that bupropion is an effective aid for smoking cessation and that it does not appear to be associated with an increased risk of major congenital malformations. The currently available studies of varenicline in pregnancy are insufficient to provide evidence for the safety or efficacy of its use. PMID- 26605449 TI - Generalized Anxiety Disorder and Major Depressive Disorder in Pregnant and Postpartum Women: Maternal Quality of Life and Treatment Outcomes. AB - OBJECTIVES: Comorbid generalized anxiety disorder (GAD) and major depressive disorder (MDD) in perinatal women is often under-diagnosed, resulting in suboptimal treatment and leading to significant maternal dysfunction. We describe a prospective, longitudinal study of the course, treatment outcomes, and quality of life (QoL) in pregnant and postpartum women with MDD and anxiety disorders. METHODS: Two separate cohorts of women were recruited through the Reproductive Mental Health Program, Women's and Children's Hospital, Vancouver, British Columbia, for pharmacotherapy of depressed mood. One cohort was recruited during pregnancy and followed to one month postpartum; the other cohort was recruited postpartum and followed for 12 weeks. All women met the DSM-5 criteria for MDD and anxiety disorders. This non-lactating perinatal population completed measures of depression, anxiety, worry symptoms, and QoL at multiple study visits. Depressed women with GAD or excessive worry were compared to those without GAD in each cohort. RESULTS: Analysis revealed that despite the majority of women with MDD having remission of symptoms with treatment, those with postpartum GAD displayed a poorer quality of life, with persistent worry symptoms, and their illness was slower to remit. Pregnant depressed women with uncontrollable worry (a GAD indicator) showed a lower probability of achieving remission of symptoms with treatment than those without uncontrollable worry. CONCLUSION: All pregnant and postpartum women with GAD and MDD responded to pharmacotherapy, and the majority attained complete remission of MDD. However, their GAD symptoms persisted, and their QoL was compromised. Given the chronic debilitating course of concomitant MDD and GAD in the perinatal population, it is essential to focus on adjunctive therapies to aim for full recovery. PMID- 26605450 TI - An Evaluation Model for a Multidisciplinary Chronic Pelvic Pain Clinic: Application of the RE-AIM Framework. AB - OBJECTIVE: Chronic pelvic pain (CPP) is a prevalent, debilitating, and costly condition. Although national guidelines and empiric evidence support the use of a multidisciplinary model of care for such patients, such clinics are uncommon in Canada. The BC Women's Centre for Pelvic Pain and Endometriosis was created to respond to this need, and there is interest in this model of care's impact on the burden of disease in British Columbia. We sought to create an approach to its evaluation using the RE-AIM (Reach, Efficacy, Adoption, Implementation, Maintenance) evaluation framework to assess the impact of the care model and to guide clinical decision-making and policy. METHODS: The RE-AIM evaluation framework was applied to consider the different dimensions of impact of the BC Centre. The proposed measures, data sources, and data management strategies for this mixed-methods approach were identified. RESULTS: The five dimensions of impact were considered at individual and organizational levels, and corresponding indicators were proposed to enable integration into existing data infrastructure to facilitate collection and early program evaluation. CONCLUSION: The RE-AIM framework can be applied to the evaluation of a multidisciplinary chronic pelvic pain clinic. This will allow better assessment of the impact of innovative models of care for women with chronic pelvic pain. PMID- 26605452 TI - Splenic Artery Aneurysm in Pregnancy. AB - BACKGROUND: Splenic artery aneurysm (SAA), a rare condition chiefly affecting women, poses significant challenges for management when it occurs during pregnancy. Reports of successful management of SAA before rupture in pregnancy are limited, with several post-rupture cases reported. CASE: We describe the case of a woman with an SAA of 13 * 9 mm near the hilum of the spleen who subsequently became pregnant. Embolization of the splenic artery in the third trimester resulted in occlusion of the aneurysm but was followed three weeks later by a splenic abscess. The patient went on to deliver a healthy baby. CONCLUSION: This case illustrates the importance of maintaining awareness of SAA in pregnancy because the condition carries a high risk of rupture and hemorrhage with high rates of fetal and maternal mortality. PMID- 26605451 TI - Growth Hormone Supplementation in the Luteal Phase Before Microdose GnRH Agonist Flare Protocol for In Vitro Fertilization. AB - OBJECTIVE: Growth hormone (GH) acts in both early and late follicular development to stimulate the proliferation and differentiation of granulosa cells and to increase the production of estradiol in animal and human ovaries. Investigators have therefore explored GH supplementation to improve outcomes in women undergoing in vitro fertilization, with the greatest interest in women with diminished ovarian reserve. Recent meta-analyses indicate that GH supplementation can be beneficial for poor responders undergoing IVF. In most studies, GH has been given concomitantly with gonadotropins during the follicular phase; this may not be optimal, since follicular recruitment begins during the preceding luteal phase. We therefore wished to examine the effect of GH supplementation in the luteal phase before controlled ovarian stimulation (COH) with a microdose GnRH agonist flare (MDF) protocol in women undergoing in vitro fertilization. METHODS: We performed a retrospective matched case-control study of patients undergoing treatment at a private IVF facility between June 2012 and July 2013. Patients identified as poor responders to COH were offered adjuvant GH treatment as part of their ovarian stimulation regimen. The patients in the experimental group chose to take GH, 3.33 mg daily by subcutaneous injection for 14 days, before starting COH. All patients had an MDF stimulation protocol using 450 IU of follicle stimulating hormone (FSH) daily. RESULTS: A total of 42 women were included in the study. There were 14 women in the experimental group (GH) and 28 controls (C) matched for age, BMI, and day 3 FSH level. There was no difference between the groups in clinical pregnancy rate (GH = 29%, C = 32%, P = 0.99), number of mature oocytes retrieved (GH = 2.5, C = 5.0, P = 0.13), cycle cancellation rate (GH = 21%, C = 14%, P = 0.88), duration of COH (GH = 10.1, C = 10.1, P = 0.93), or mean peak estradiol level (GH = 4174 pmol/L, C = 5105 pmol/L, P = 0.44). CONCLUSION: The administration of growth hormone during the luteal phase before a microdose GnRH agonist flare protocol for in vitro fertilization did not improve outcomes in "poor responder" patients. PMID- 26605453 TI - A Prospective Cohort Study Using e-Learning Modules as a Supplemental Teaching Resource for Obstetrics and Gynaecology Clerkship Students. AB - OBJECTIVE: Increasing enrolment in medical schools in Canada has necessitated the development of distributed clinical learning sites to provide appropriate clinical experience. The Faculty of Medicine at Dalhousie University has clinical clerkship sites distributed across Nova Scotia, New Brunswick, and Prince Edward Island, with diverse educational exposures. This study was designed to examine the influence of online learning modules, developed to standardize learning across education sites during the clinical clerkship, on the acquisition of knowledge by medical students during their obstetrics and gynaecology clerkship rotation. METHODS: The third year medical school class was divided into two natural cohorts for the purposes of this study. Group 1 had their obstetrics and gynaecology rotation from September 2012 to March 2013 (n = 54), and Group 2 had their rotation from April to September 2013 (n = 60). All students were given the opportunity to complete an online formative examination before their summative multiple choice examination; only Group 2 students had access to six obstetrics and gynaecology e-learning modules, upon which the formative examination was based. RESULTS: Forty-seven students in Group 1 (87%) and 45 students in Group 2 (75%) completed the formative examination, with an overall participation rate of 81%. There was no difference in median scores between Group 1 (score 9, IQR 8 to 10) and Group 2 (score 9, IQR 8 to 11, P = 0.08). CONCLUSION: Having access to six e-learning modules did not improve the third year medical students' scores on a formative examination completed before their summative multiple choice examination. PMID- 26605454 TI - Teaching an Experienced Multidisciplinary Team About Postpartum Hemorrhage: Comparison of Two Different Methods. AB - OBJECTIVE: Morbidity from postpartum hemorrhage (PPH) affects 20% of pregnancies worldwide and remains a significant cause of maternal mortality. This study compared the impressions of experienced clinicians on the effect of two methods of educational interventions in a MoreOB training program designed to improve recognition and management of PPH. METHODS: Participants were exposed to a traditional didactic lecture and an interactive clinical intervention exercise incorporating video simulation of a PPH event with opportunities for feedback and discussion of how to proceed. They were then invited to respond to a questionnaire regarding their impressions of both methods. RESULTS: Of 150 participants, 110 completed the questionnaire. Respondents considered the interactive format to be more effective (55%) and enjoyable (72%) than the traditional didactic format. The majority (81%), however, still recommended a mixture of both interactive and didactic formats in future events, supported by a multidisciplinary drill. CONCLUSION: Clinical learners value interactivity and mutual reinforcement among varied learning exercises in their educational experiences. Future educational programs may consider incorporating similar methods in order to maximize participants' receptiveness. PMID- 26605455 TI - The Latest Thorn by Any Other Name: Germ-Line Nuclear Transfer in the Name of "Mitochondrial Replacement". PMID- 26605457 TI - Generalized Hartree-Fock Description of Molecular Dissociation. AB - An electronic structure method is said to be size-consistent if the energy of noninteracting fragments is the same when the fragments are treated in a supermolecule approach or are treated in isolation. Size consistency is often violated by Hartree-Fock when symmetries of the exact wave function are imposed on the Hartree-Fock determinant. Relaxing the requirement that the Hartree-Fock wave function be a spin eigenfunction leads to unrestricted Hartree-Fock, which is often (but not always) size-consistent. In this Perspective, we discuss the usually forgotten fact that imposing none of the exact symmetries in what is known as generalized Hartree-Fock allows Hartree-Fock to always be size consistent and allows size extensive correlated methods such as coupled cluster theory to also be size-consistent. Furthermore, with all symmetries broken, dissociation curves connect the molecule to the fragments better than with symmetries imposed, although the curves are not smooth and show derivative discontinuities akin to unphysical phase transitions. In many cases, correlated dissociation curves based on this generalized Hartree-Fock reference are discontinuous. PMID- 26605456 TI - Umbilical Cord Blood: Counselling, Collection, and Banking. AB - OBJECTIVE: To review current evidence regarding umbilical cord blood counselling, collection, and banking and to provide guidelines for Canadian health care professionals regarding patient education, informed consent, procedural aspects, and options for cord blood banking in Canada. OPTIONS: Selective or routine collection and banking of umbilical cord blood for future stem cell transplantation for autologous (self) or allogeneic (related or unrelated) treatment of malignant and non-malignant disorders in children and adults. Cord blood can be collected using in utero or ex utero techniques. OUTCOMES: Umbilical cord blood counselling, collection, and banking, education of health care professionals, indications for cord blood collection, short- and long-term risk and benefits, maternal and perinatal morbidity, parental satisfaction, and health care costs. EVIDENCE: Published literature was retrieved through searches of Medline and PubMed beginning in September 2013 using appropriate controlled MeSH vocabulary (fetal blood, pregnancy, transplantation, ethics) and key words (umbilical cord blood, banking, collection, pregnancy, transplantation, ethics, public, private). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date limits, but results were limited to English or French language materials. Searches were updated on a regular basis and incorporated in the guideline to September 2014. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, and national and international medical specialty societies. VALUES: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). BENEFITS, HARMS, AND COSTS: Umbilical cord blood is a readily available source of hematopoetic stem cells used with increasing frequency as an alternative to bone marrow or peripheral stem cell transplantation to treat malignant and non-malignant conditions in children and adults. There is minimal harm to the mother or newborn provided that priority is given to maternal/newborn safety during childbirth management. Recipients of umbilical cord stem cells may experience graft-versus-host disease, transfer of infection or genetic abnormalities, or therapeutic failure. The financial burden on the health system for public cord blood banking and on families for private cord blood banking is considerable. Recommendations 1. Health care professionals should be well-informed about cord blood collection and storage and about factors that influence the volume, quality, and ability to collect a cord blood unit. (III-A) 2. Health care professionals caring for women and families who choose private umbilical cord blood banking must disclose any financial interests or potential conflicts of interest. (III-A) 3. Pregnant women should be provided with unbiased information about umbilical cord blood banking options, including the benefits and limitations of public and private banks. (III-A) 4. Health care professionals should obtain consent from mothers for the collection of umbilical cord blood prior to the onset of active labour, ideally during the third trimester, with ample time to address any questions. (III-A) 5. Health care professionals must be trained in standardized procedures (ex utero and in utero techniques) for cord blood collection to ensure the sterility and quality of the collected unit. (II-2A) 6. Umbilical cord blood should be collected with the goal of maximizing the content of hematopoietic progenitors through the volume collected. The decision to bank the unit will depend upon specific measures of graft potency. (II-2A) 7. Umbilical cord blood collection must not adversely affect the health of the mother or newborn. Cord blood collection should not interfere with delayed cord clamping. (III-E) 8. Health care professionals should inform pregnant women and their partners of the benefits of delayed cord clamping and of its impact on cord blood collection and banking. (II-2A) 9. Cord blood units collected for public or private banking can be used for biomedical research, provided consent is obtained, when units cannot be banked or when consent for banking is withdrawn. (II-3B) 10. Mothers may be approached to donate cells for biomedical research. Informed consent for research using cord blood should ideally be obtained prior to the onset of active labour or elective Caesarean section following established research ethics guidelines. (II-2A). PMID- 26605458 TI - Bridging the Gap between Folding Simulations and Experiments: The Case of the Villin Headpiece. AB - The increasing accuracy of molecular dynamics force fields parameters and the increasing resolution of experimental results allow one to carefully compare and complement in silico data with experimental observations. Here, we study the human villin headpiece C-terminal helical subdomain (HP35) with the recent highly optimized Amber99SB*-ILDN force field and compare the results with recent high resolution triplet-triplet energy transfer (TTET) experiments. The correct reproduction of the main structural features reveals a good agreement between experimental data and simulations. PMID- 26605459 TI - Proton Wires via One-Dimensional Water Chains Adsorbed on Metallic Steps. AB - The process of proton transfer is here analyzed for one-dimensional water chains adsorbed on metallic steps. When the water chain contains a hydronium and a hydroxyl ion, two different mechanisms are possible, depending on the metal substrate. On coinage metals (Ag, Au), recombination is observed through a spontaneous Grotthuss mechanism. On more reactive surfaces (Pd and Pt), the hydronium ion is unstable and releases a proton that adsorbs onto the metal, leaving the negatively charged OH(-) unbalanced. In this case, the negative charge can be transferred along the wire with very low activation barriers. PMID- 26605460 TI - Testing a Variety of Electronic-Structure-Based Methods for the Relative Energies of 5-Formyluracil Crystals. AB - The lattice energies of the experimental and several hypothetical crystal structures of the RNA base uracil derivative 5-formyluracil are calculated with a range of methods, based either on the electronic structure of the molecule or the lattice. The explicit modeling of the polarization within the crystal in the model intermolecular potential and the inclusion of an empirical dispersion correction to the periodic density functional energy (DFT-D2) were the only methods able to calculate the energy balance between different conformations, hydrogen bonding, and pi-pi stacking possibilities sufficiently accurately to give the observed structure as the most stable. Even these two methods underestimated the density of the room temperature structure, showing the need for improvement in the modeling of organic crystal structures. PMID- 26605461 TI - Derivation of an Electron-Proton Correlation Functional for Multicomponent Density Functional Theory within the Nuclear-Electronic Orbital Approach. AB - Multicomponent density functional theory enables the quantum mechanical treatment of electrons and selected hydrogen nuclei. An electron-proton correlation functional is derived from the electron-proton pair density associated with a recently proposed ansatz for the explicitly correlated nuclear-electronic wave function. This ansatz allows the retention of all terms in the pair density, and the resulting functional is expected to scale properly and to be computationally efficient. Applications to model systems illustrate that it provides accurate nuclear densities. PMID- 26605462 TI - Photodynamics of All-trans Retinal Protonated Schiff Base in Bacteriorhodopsin and Methanol Solution. AB - Nonadiabatic ONIOM(CASSCF:AMBER) and CASSCF simulations elucidated different photodynamics of an all-trans retinal protonated Schiff base (RPSB) in bacteriorhodopsin and methanol as well as without an environment. The bR protein matrix holds RPSB tight via specific interactions and promotes bond-specific (along the C13?C14 bond), unidirectional, and ultrafast photoisomerization with a high quantum yield. In contrast, in methanol and for the twisted bare RPSB, photoisomerization is not bond-specific (mainly along the C11?C12 bond), is nonunidirectional, and is ineffective. Therefore, bR efficiently "catalyzes" photoisomerization and stores enough energy to promote the subsequent proton pumping and protein conformational changes. PMID- 26605463 TI - Efficient Sampling of a Dual-Resolution Ensemble by Means of Dragging. AB - A method to simulate a dual-resolution ensemble for molecular systems is introduced. The dual-resolution system is characterized by an atomistic Hamiltonian and coarse coordinates connected by linear springs to this atomistic system. A 'dragging' update scheme based on an idea of Neal (Neal, R. M. Taking Bigger Metropolis Steps by Dragging Fast Variables; Technical Report; University of Toronto: Toronto, Canada, October, 2004; http://arxiv.org/PS_cache/math/pdf/0502/0502099v1.pdf ) is proposed. It is theoretically proven that the scheme correctly samples the dual ensemble. As a proof-of-principle we show that in an one-dimensional barrier crossing simulation, the relaxation speeds up by a factor 80. In an asymmetric two dimensional barrier crossing problem, the speedup is a factor 20. The application to molecular simulations is discussed. PMID- 26605464 TI - Flow-Dependent Unfolding and Refolding of an RNA by Nonequilibrium Umbrella Sampling. AB - Nonequilibrium experiments of single biomolecules such as force-induced unfolding reveal details about a few degrees of freedom of a complex system. Molecular dynamics simulations can provide complementary information, but exploration of the space of possible configurations is often hindered by large barriers in phase space that separate metastable regions. To solve this problem, enhanced sampling methods have been developed that divide a phase space into regions and integrate trajectory segments in each region. These methods boost the probability of passage over barriers and facilitate parallelization since integration of the trajectory segments does not require communication, aside from their initialization and termination. Here, we present a parallel version of an enhanced sampling method suitable for systems driven far from equilibrium: nonequilibrium umbrella sampling (NEUS). We apply this method to a coarse-grained model of a 262-nucleotide RNA molecule that unfolds and refolds in an explicit flow field modeled with stochastic rotation dynamics. Using NEUS, we are able to observe extremely rare unfolding events that have mean first passage times as long as 45 s (1.1 * 10(15) dynamics steps). We examine the unfolding process for a range of flow rates of the medium, and we describe two competing pathways in which different intramolecular contacts are broken. PMID- 26605465 TI - Can DFT Accurately Predict Spin Densities? Analysis of Discrepancies in Iron Nitrosyl Complexes. AB - Iron nitrosyl complexes are a particularly challenging case for density functional theory. In particular, for the low-spin state, different exchange correlation functionals yield very different spin densities [ Conradie , J. ; Ghosh , A. J. Phys. Chem. B 2007 , 111 , 12621 - 12624 ]. Here, we investigate the origin of these differences in detail by analyzing the Kohn-Sham molecular orbitals. Furthermore, to decide which exchange-correlation functionals yield the most accurate spin densities, we make comparisons to CASSCF calculations. To ensure that the spin densities are converged with respect to the size of the active space, this comparison is performed for [Fe(NO)](2+) as a model system. We find that none of the investigated exchange-correlation functionals are able to reproduce the CASSCF spin densities accurately. PMID- 26605466 TI - Efficient and Accurate Methods for the Geometry Optimization of Water Clusters: Application of Analytic Gradients for the Two-Body:Many-Body QM:QM Fragmentation Method to (H2O)n, n = 3-10. AB - The structures of more than 70 low-lying water clusters ranging in size from (H2O)3 to (H2O)10 have been fully optimized with several different quantum mechanical electronic structure methods, including second-order Moller-Plesset perturbation theory (MP2) in conjunction with correlation consistent triple-zeta basis sets (aug-cc-pVTZ for O and cc-pVTZ for H, abbreviated haTZ). Optimized structures obtained with less demanding computational procedures were compared to the MP2/haTZ ones using both MP2/haTZ single point energies and the root-mean square (RMS) deviations of unweighted Cartesian coordinates. Based on these criteria, B3LYP/6-31+G(d,2p) substantially outperforms both HF/haTZ and MP2/6 31G*. B3LYP/6-31+G(d,2p) structures never deviate from the MP2/haTZ geometries by more than 0.44 kcal mol(-1) on the MP2/haTZ potential energy surface, whereas the errors associated with the HF/haTZ and MP2/6-31G* structures grow as large as 12.20 and 2.98 kcal mol(-1), respectively. The most accurate results, however, were obtained with the two-body:many-body QM:QM fragmentation method for weakly bound clusters, in which all one- and two-body interactions are calculated at the high-level, while a low-level calculation is performed on the entire cluster to capture the cooperative effects (nonadditivity). With the haTZ basis set, the MP2:HF two-body:many-body fragmentation method generates structures that deviate from the MP2/haTZ ones by 0.01 kcal mol(-1) on average and not by more than 0.03 kcal mol(-1). PMID- 26605467 TI - Stability of Hydrocarbons of the Polyhedrane Family: Convergence of ab Initio Calculations and Corresponding Assessment of DFT Main Approximations. AB - Highly accurate coupled-cluster (CC) calculations with large basis sets have been performed to study the binding energy of the (CH)12, (CH)16, (CH)20, and (CH)24 polyhedral hydrocarbons in two, cage-like and planar, forms. We also considered the effect of other minor contributions: core-correlation, relativistic corrections, and extrapolations to the limit of the full CC expansion. Thus, chemically accurate values could be obtained for these complicated systems. These nearly exact results are used to evaluate next the performance of main approximations (i.e., pure, hybrid, and double-hybrid methods) within density functional theory (DFT) in a systematic fashion. Some commonly used functionals, including the B3LYP model, are affected by large errors, and only those having reduced self-interaction error (SIE), which includes the last family of conjectured expressions (double hybrids), are able to achieve reasonable low deviations of 1-2 kcal/mol especially when an estimate for dispersion interactions is also added. PMID- 26605468 TI - Accuracy of Effective Core Potentials and Basis Sets for Density Functional Calculations, Including Relativistic Effects, As Illustrated by Calculations on Arsenic Compounds. AB - For molecules containing the fourth-period element arsenic, we test (i, ii) the accuracy of all-electron (AE) basis sets from the def2-xZVP and ma-xZVP series (where xZ is S, TZ, or QZ), (iii) the accuracy of the 6-311G series of AE basis sets with additional polarization and diffuse functions, and (iv) the performance of effective core potentials (ECPs). The first set of tests involves basis-set convergence studies with eleven density functionals for five cases: equilibrium dissociation energy (De) of As2, vertical ionization potential (VIP) of As2, IP of As, acid dissociation of H3AsO4, and De of FeAs. A second set of tests involves the same kinds of basis-set convergence studies for the VIP and De values of As3 and As4 clusters. Both relativistic and nonrelativistic calculations are considered, including in each case both AE calculations and calculations with ECPs. Convergence and accuracy are assessed by comparing to relativistic AE calculations with the cc-pV5Z-DK or ma-cc-pV5Z-DK basis and to nonrelativistic AE calculations with the cc-pV5Z or ma-cc-pV5Z basis. The primary objective of this study is to evaluate the abilities of ECPs with both their recommended basis sets and other basis sets to reproduce the results of all electron relativistic calculations. The performance of the def2 and ma series basis sets is consistent with their sizes, and quadruple-zeta basis sets are the best. The def2-TZVP basis set performs better than most of the 6-311G series basis sets, which are the most commonly used basis sets in the previous studies of arsenic compounds. However, relativistic def2-TZVP calculations are not recommended. The large-core ECPs, which are the only available ECPs for arsenic in the popular Gaussian program, have average errors of 9-12 kcal/mol for the arsenic systems studied; therefore, these ECPs are not recommended. The triple zeta small-core relativistic ECP (RECP) basis set cc-pVTZ-PP is found to have performance better than that of the def2-TZVP basis set, and it is highly recommended for arsenic-containing systems. The double-zeta RECP basis set ma-sc SVP is recommended for large arsenic systems for which the def2-TZVP and cc-pVTZ PP basis sets are unaffordable, if a basis-set error of ~2 kcal/mol can be tolerated. PMID- 26605469 TI - Natural Orbitals for Wave Function Based Correlated Calculations Using a Plane Wave Basis Set. AB - We demonstrate that natural orbitals allow for reducing the computational cost of wave function based correlated calculations, especially for atoms and molecules in a large box, when a plane wave basis set under periodic boundary conditions is used. The employed natural orbitals are evaluated on the level of second-order Moller-Plesset perturbation theory (MP2), which requires a computational effort that scales as [Formula: see text](N(5)), where N is a measure of the system size. Moreover, we find that a simple approximation reducing the scaling to [Formula: see text](N(4)) yields orbitals that allow for a similar reduction of the number of virtual orbitals. The MP2 natural orbitals are applied to coupled cluster singles and doubles (CCSD) as well as full configuration interaction Quantum Monte Carlo calculations of the H2 molecule to test our implementation. Finally, the atomization energies of the LiH molecule and solid are calculated on the level of MP2 and CCSD. PMID- 26605470 TI - Variational Monte Carlo Method with Dirichlet Boundary Conditions: Application to the Study of Confined Systems by Impenetrable Surfaces with Different Symmetries. AB - Variational Monte Carlo method is a powerful tool to determine approximate wave functions of atoms, molecules, and solids up to relatively large systems. In the present work, we extend the variational Monte Carlo approach to study confined systems. Important properties of the atoms, such as the spatial distribution of the electronic charge, the energy levels, or the filling of electronic shells, are modified under confinement. An expression of the energy very similar to the estimator used for free systems is derived. This opens the possibility to study confined systems with little changes in the solution of the corresponding free systems. This is illustrated by the study of helium atom in its ground state (1)S and the first (3)S excited state confined by spherical, cylindrical, and plane impenetrable surfaces. The average interelectronic distances are also calculated. They decrease in general when the confinement is stronger; however, it is seen that they present a minimum for excited states under confinement by open surfaces (cylindrical, planes) around the radii values corresponding to ionization. The ground (2)S and the first (2)P and (2)D excited states of the lithium atom are calculated under spherical constraints for different confinement radii. A crossing between the (2)S and (2)P states is observed around rc = 3 atomic units, illustrating the modification of the atomic energy level under confinement. Finally the carbon atom is studied in the spherical symmetry by using both variational and diffusion Monte Carlo methods. It is shown that the hybridized state sp(3) becomes lower in energy than the ground state (3)P due to a modification and a mixing of the atomic orbitals s, p under strong confinement. This result suggests a model, at least of pedagogical interest, to interpret the basic properties of carbon atom in chemistry. PMID- 26605471 TI - Intra- and Interatomic Spin Interactions by the Density Functional Theory plus U Approach: A Critical Assessment. AB - Accurate evaluation of the total energy difference between different spin states in molecular magnetic systems is currently a great challenge in theoretical chemistry. In this work we assess the performance of the density functional theory plus the Hubbard U (DFT+U) approach for the first-principles description of the high spin-low spin (HS-LS) splitting and the exchange coupling constant, corresponding to the intra- and interatomic spin interactions, respectively. The former is investigated using a set of mononuclear ion complexes with different HS LS splitting, including seven spin-crossover (SCO) compounds, while the latter is investigated in a series of binuclear copper complexes covering both ferromagnetic and antiferromagnetic interactions. We find that the DFT+U approach can reproduce experimental data as accurately as the hybrid functionals approach but with much lower computational efforts. We further analyze the effect of U in terms of spin density on magnetic centers, and we find that the main effect of the U correction can be attributed to the enhanced localization of magnetic orbitals. Even taking the uncertainty related to the determination of U into account, we think the DFT+U approach is an efficient and predictive first principles method for the SCO phenomenon and interatomic magnetic interactions. PMID- 26605472 TI - The Role of Anharmonicity in Hydrogen-Bonded Systems: The Case of Water Clusters. AB - The nature of vibrational anharmonicity has been examined for the case of small water clusters using second-order vibrational perturbation theory (VPT2) applied on second-order Moller-Plesset perturbation theory (MP2) potential energy surfaces. Using a training set of 16 water clusters (H2O)n=2-6,8,9 with a total of 723 vibrational modes, we determined scaling factors that map the harmonic frequencies onto anharmonic ones. The intermolecular modes were found to be substantially more anharmonic than intramolecular bending and stretching modes. Due to the varying levels of anharmonicity of the intermolecular and intramolecular modes, different frequency scaling factors for each region were necessary to achieve the highest accuracy. Furthermore, new scaling factors for zero-point vibrational energies (ZPVE) and vibrational corrections to the enthalpy (DeltaHvib) and the entropy (Svib) have been determined. All the scaling factors reported in this study are different from previous works in that they are intended for hydrogen-bonded systems, while others were built using experimental frequencies of covalently bonded systems. An application of our scaling factors to the vibrational frequencies of water dimer and thermodynamic functions of 11 larger water clusters highlights the importance of anharmonic effects in hydrogen bonded systems. PMID- 26605473 TI - Local MP2 with Density Fitting for Periodic Systems: A Parallel Implementation. AB - A parallel implementation is presented for the evaluation of local second-order Moller-Plesset perturbation theory (LMP2) energies in periodic, nonconducting crystalline systems with a density-fitting approximation of two-electron repulsion integrals. Peculiarities of the periodic case with respect to parallel LMP2 implementations in molecular codes, such as the use of translational and point symmetry, impose different strategies in order to achieve good parallel performance. The implementation is benchmarked on a few systems, representing a choice of the most interesting solid state quantum-chemistry problems where the MP2 approach can be decisive. Good parallel efficiency of the algorithms is demonstrated for up to 54 processors. Test systems include a metal organic framework (MOF-5) 3D crystalline structure with a triple-zeta-quality basis set: this is the largest calculation performed so far with 106 atoms, 532 correlated electrons, and 2884 atomic orbitals per unit cell. PMID- 26605474 TI - Diabatization Schemes for Generating Charge-Localized Electron-Proton Vibronic States in Proton-Coupled Electron Transfer Systems. AB - A scheme for the rigorous construction of charge-localized diabatic electron proton vibronic states for proton-coupled electron transfer (PCET) reactions is presented. The diabatic electronic states are calculated using an adiabatic-to diabatic transformation designed to ensure that the first-order nonadiabatic couplings with respect to a specified one-dimensional reaction coordinate vanish exactly. This scheme is applied to both symmetric and asymmetric PCET systems with several different one-dimensional reaction coordinates, including the hydrogen transfer coordinate, a normal mode coordinate, and the intrinsic reaction coordinate. This approach is also extended to describe the three dimensional motion of the transferring hydrogen. The diabatic electronic states exhibit relatively invariant charge distributions along the reaction coordinate and are in excellent agreement with the analogous states obtained from the generalized Mulliken-Hush and Boys localization methods. Furthermore, these diabatic electronic states are combined with the associated proton vibrational wave functions to generate charge-localized electron-proton vibronic states that describe one- or three-dimensional hydrogen motion. These electron-proton vibronic states can be used to calculate the vibronic couplings, rate constants, and kinetic isotope effects of PCET reactions. PMID- 26605475 TI - Accurate Interaction Energies for Problematic Dispersion-Bound Complexes: Homogeneous Dimers of NCCN, P2, and PCCP. AB - All intermolecular interactions involve London dispersion forces. The accurate treatment of dispersion is essential for the computation of realistic interaction potentials. In general, the most reliable method for computing intermolecular interactions is coupled-cluster singles and doubles with perturbative triples [CCSD(T)] in conjunction with a sufficiently flexible Gaussian atomic orbital basis set, a combination which is not routinely applicable due to its excessive computational demands (CPU time, memory, storage). Recently, many theoretical methods have been developed that attempt to account for dispersion in a more efficient manner. It is well-known that dispersion interactions are more difficult to compute in some systems than others; for example, pi-pi dispersion is notoriously difficult, while alkane-alkane dispersion is relatively simple to compute. In this work, numerous theoretical methods are tested for their ability to compute reliable interaction energies in particularly challenging systems, namely, the P2, PCCP, and NCCN dimers. Symmetry-adapted perturbation theory (SAPT) is applied to these dimers to demonstrate their sensitivity to the treatment of dispersion. Due to the small size of these systems, highly accurate CCSD(T) potential energy curves could be estimated at the complete basis set limit. Numerous theoretical methods are tested against the reliable CCSD(T) benchmarks. Methods using a treatment of dispersion that relies on time-dependent density functional theory (TDDFT) response functions are found to be the most reliable. PMID- 26605476 TI - Obtaining Good Performance With Triple-zeta-Type Basis Sets in Double-Hybrid Density Functional Theory Procedures. AB - A variety of combinations of B-LYP-based double-hybrid density functional theory (DHDFT) procedures and basis sets have been examined. A general observation is that the optimal combination of exchange contributions is in the proximity of 30% Becke 1988 (B88) exchange and 70% Hartree-Fock (HF) exchange, while for the correlation contributions, the use of independently optimized spin-component scaled Moller-Plesset second-order perturbation theory (SCS-MP2) parameters (MP2OS and MP2SS) is beneficial. The triple-zeta Dunning aug'-cc-pVTZ+d and Pople 6-311+G(3df,2p)+d basis sets are found to be cost-effective for DHDFT methods. As a result, we have formulated the DuT-D3 DHDFT procedure, which employs the aug' cc-pVTZ+d basis set and includes 30% B88 and 70% HF exchange energies, 59% LYP, 47% MP2OS, and 36% MP2SS correlation energies, and a D3 dispersion correction with the parameters s6 = 0.5, sr,6 = 1.569, and s8 = 0.35. Likewise, the PoT-D3 DHDFT procedure was formulated with the 6-311+G(3df,2p)+d basis set and has 32% B88 and 68% HF exchange energies, 63% LYP, 46% MP2OS, and 27% MP2SS correlation energies, and the D3 parameters s6 = 0.5, sr,6 = 1.569, and s8 = 0.30. Testing using the large E3 set of 740 energies demonstrates the robustness of these methods. Further comparisons show that the performance of these methods, particularly DuT-D3, compares favorably with the previously reported DSD-B-LYP and DSD-B-LYP-D3 methods used in conjunction with quadruple-zeta aug'-pc3+d and aug'-def2-QZVP basis sets but at lower computational expense. The previously reported omegaB97X-(LP)/6-311++G(3df,3pd) procedure also performs very well. Our findings highlight the cost-effectiveness of appropriate- and moderate-sized triple-zeta basis sets in the application of DHDFT procedures. PMID- 26605477 TI - Effects of Spin-Orbit Coupling on Covalent Bonding and the Jahn-Teller Effect Are Revealed with the Natural Language of Spinors. AB - The orbital-based natural language describing the complexity of chemistry ( Stowasser , R. ; Hoffmann , R. J. Am. Chem. Soc. 1999 , 121 , 3414 ) was extended by us recently to the definition of spin-orbit natural spinors ( Zeng , T. et al. J. Chem. Phys. 2011 , 134 , 214107 ). This novel method gives chemical insights into the role of spin-orbit coupling in covalent bonding and in the Jahn-Teller effect. The natural spinors are used to explain antibonding spin-orbit effects on TlH and Tl2: it is found that the spin-orbit induced charge transfer from the bonding to the nonbonding or antibonding orbitals has a large effect on the bond strength. The natural spinors are also used to explain the spin-orbit quenching of the Jahn-Teller effect in WF5: the spin-orbit interaction can stabilize the totally symmetric electron distribution so that the high-symmetry molecular structure becomes more stable than its distortions. A general discussion of the role of the spin-orbit coupling in covalent bonding and Jahn-Teller effect is given in terms of the competition between the rotational nature of the spin-orbit coupling and the directionality of the two effects. The natural spinors offer the advantage of providing a simple and clear pictorial explanation for the profound relativistic spin-dependent interactions in chemistry often appearing as a black box answer. PMID- 26605478 TI - First Step in the Reaction of Zerovalent Iron with Water. AB - Here we present a comprehensive quantum chemical study of the simplest model system for the reactions of nanoscale zerovalent iron, i.e., the gas-phase reaction of an iron atom with water, to identify a theoretical method that provides reasonably accurate geometries and thermochemical data for selected iron compounds along the reaction path (Fe, FeO, HFeOH, Fe(OH)2). The energies of selected stationary points on the ground electronic potential energy surface were systematically studied using HF and post-HF methods (MP2, MP3, MP4, CCSD, CCSD(T), CASSCF, MRCI) and selected DFT functionals (B3LYP, B97-1, BPW91, M06, M06-HF, M06-L, M06-2X and MPW1K) using various basis sets up to the complete basis set. Scalar relativistic effects were modeled using the Douglas-Kroll-Hess Hamiltonian up to the fourth order, and the effects of valence plus outer-core electronic correlation were also evaluated. The calculations showed that (i) dynamic electron correlation is crucial for accurate modeling of the reactions in question, (ii) the PES around the stationary points along the reaction path is rather flat, (iii) the single-point energies calculated at the CCSD(T)/CBS level are in reasonably good agreement with experimental measurements, (iv) it is difficult to interpret DFT energies in the absence of benchmarking against experimental data or results obtained at a level of theory that is known to accurately reproduce experimental results, (v) relativistic effects are relatively modest in this system but should be included if chemical accuracy is desired, and (vi) careful analysis of the multireference character of the system and potential spin contamination is important. The CCSD(T)-3s3p-DKH2/CBS method can be considered the gold standard for this reaction because calculations at this level are in good agreement with experimental atomic excitation energies and thermochemical data. The gas-phase activation energy of the reaction between Fe and H2O is 23.6 kcal/mol including the ZPVE correction (DeltaG(?)298K = 29.2 kcal/mol), and HFeOH is a stable intermediate lying -31.2 kcal/mol below the reactants (DeltaG298K = -25.4 kcal/mol). PMID- 26605479 TI - Quantum Corrections to Classical Molecular Dynamics Simulations of Water and Ice. AB - Classical simulations of simple water models reproduce many properties of the liquid and ice but overestimate the heat capacity by about 65% at ordinary temperatures and much more for low temperature ice. This is due to the fact that the atomic vibrations are quantum mechanical. The application of harmonic quantum corrections to the molecular motion results in good heat capacities for the liquid and for ice at low temperatures but a successively growing positive deviation from experimental results for ice above 200 K that reaches 15% just below melting. We suggest that this deviation is due to the lack of quantum corrections to the anharmonic motions. For the liquid, the anharmonicities are even larger but also softer and thus in less need of quantum correction. Therefore, harmonic quantum corrections to the classically calculated liquid heat capacities result in agreement with the experimental values. The classical model underestimates the heat of melting by 15%, while the application of quantum corrections produces fair agreement. On the other hand, the heat of vaporization is overestimated by 10% in the harmonically corrected classical model. PMID- 26605480 TI - Small Molecule Solvation Free Energy: Enhanced Conformational Sampling Using Expanded Ensemble Molecular Dynamics Simulation. AB - We present an efficient expanded ensemble molecular dynamics method to calculate the solvation free energy (or residual chemical potential) of small molecules with complex topologies. The methodology is validated by computing the solvation free energy of ibuprofen in water, methanol, and ethanol at 300 K and 1 bar and comparing to reference simulation results using Bennett's acceptance ratio method. Difficulties with ibuprofen using conventional molecular dynamics methods stem from an inadequate sampling of the carboxylic acid functional group, which, for the present study, is subject to free energy barriers of rotation of 14-20 kBT. While several advances have been made to overcome such weaknesses, we demonstrate how this shortcoming is easily overcome by using an expanded ensemble methodology to facilitate conformational sampling. Not only does the method enhance conformational sampling but it also boosts the rate of exploration of the configurational phase space and requires only a single simulation to calculate the solvation free energy. Agreement between the expanded ensemble and the reference calculations is good for all three solvents, with the reported uncertainties of the expanded ensemble being comparable to the uncertainties of the reference calculations, while requiring less simulation time; the reduced simulation time demonstrates the improved performance gained from the expanded ensemble method. PMID- 26605481 TI - Structural Stability of V-Amylose Helices in Water-DMSO Mixtures Analyzed by Molecular Dynamics. AB - Computational techniques have been employed to fundamentally understand the behavior of helically structured amylose in water/DMSO mixtures. Using a computationally generated amylose helix of 55 glucose residues, we have investigated the time-dependent behavior of intra- and intermolecular hydrogen bonds, particularly between O2 and O3 of adjacent glucose molecules and between O6 and neighboring O2 and O3 groups. The helix character was defined by the total number of residually existing hydrogen bonds. Our results parallel the experimental finding that increasing the percentage of DMSO results in increasing helical stability. It can be shown that O6-O2/O3 hydrogen bonds are preferentially lost when the helix starts to unfold to a finally resulting random coil structure. While water is small enough to interact with every hydroxyl group at the helix surface and finally penetrate the helix coil, DMSO can initially only form single hydrogen bonds to part of the OH groups of the amylose molecule, thereby allowing a longer conservation of intramolecular hydrogen bonds that are necessary to maintain the helix. However, given a long enough time for interaction, the helical structure of amylose is lost in water as well as in DMSO, yielding a random orientation of the glucose strand. PMID- 26605482 TI - Benchmarking Semiempirical Methods for Thermochemistry, Kinetics, and Noncovalent Interactions: OMx Methods Are Almost As Accurate and Robust As DFT-GGA Methods for Organic Molecules. AB - Semiempirical quantum mechanical (SQM) methods offer a fast approximate treatment of the electronic structure and the properties of large molecules. Careful benchmarks are required to establish their accuracy. Here, we report a validation of standard SQM methods using a subset of the comprehensive GMTKN24 database for general main group thermochemistry, kinetics, and noncovalent interactions, which has recently been introduced to evaluate density functional theory (DFT) methods ( J. Chem. Theory Comput. 2010 , 6 , 107 ). For all SQM methods considered presently, parameters are available for the elements H, C, N, and O, and consequently, we have extracted from the GMTKN24 database all species containing only these four elements (excluding multireference cases). The resulting GMTKN24 hcno database has 370 entries (derived from 593 energies) compared with 715 entries (derived from 1033 energies) in the original GMTKN24 database. The current benchmark covers established standard SQM methods (AM1, PM6), more recent approaches with orthogonalization corrections (OM1, OM2, OM3), and the self consistent-charge density functional tight binding method (SCC-DFTB). The results are compared against each other and against DFT results using standard functionals. We find that the OMx methods outperform AM1, PM6, and SCC-DFTB by a significant margin, with a substantial gain in accuracy especially for OM2 and OM3. These latter methods are quite accurate even in comparison with DFT, with an overall mean absolute deviation of 6.6 kcal/mol for PBE and 7.9 kcal/mol for OM3. The OMx methods are also remarkably robust with regard to the unusual bonding situations encountered in the "mindless" MB08-165 test set, for which all other SQM methods fail badly. PMID- 26605483 TI - Solvation Structure and Dynamics of Ni(2+)(aq) from First Principles. AB - The aqueous solution of Ni(2+) was investigated using first principles molecular dynamics (FPMD) simulation based on periodic density-functional theory (DFT) calculations. The experimental structural parameters of the Ni(aq) complex are reproduced well by the simulation. An exchange event of the water molecule in the first solvation shell is observed, supporting the proposed dissociative mechanism of exchange. The calculated dynamic characteristics of the surrounding water molecules indicate too slow translational diffusion in comparison to experimental results, in agreement with other FPMD studies employing a similar level of theory. We also find that the reorientational dynamics of water are an order of magnitude slower as compared to experimental data. On the other hand, the angular momentum dynamics are in better agreement with the experimental data than the previously reported results from MD simulations employing empirical force fields. The obtained MD trajectory can supply accurate structures for the calculation of magnetic properties. PMID- 26605484 TI - Hybrid Particle-Field Coarse-Grained Models for Biological Phospholipids. AB - In the framework of a recently developed scheme for a hybrid particle-field simulation technique where self-consistent field theory (SCF) and molecular dynamics (MD) are combined [ J. Chem. Phys. 2009 , 130 , 214106 ], specific coarse-grained models for phospholipids and water have been developed. We optimized the model parameters, which are necessary in evaluating the interactions between the particles and the density fields, so that the coarse grained model can reproduce the structural properties of the reference particle particle simulations. The development of these specific coarse-grained models suitable for hybrid particle-field simulations opens the way toward simulations of large-scale systems employing models with chemical specificity, especially for biological systems. PMID- 26605485 TI - Understanding RNA Flexibility Using Explicit Solvent Simulations: The Ribosomal and Group I Intron Reverse Kink-Turn Motifs. AB - Reverse kink-turn is a recurrent elbow-like RNA building block occurring in the ribosome and in the group I intron. Its sequence signature almost matches that of the conventional kink-turn. However, the reverse and conventional kink-turns have opposite directions of bending. The reverse kink-turn lacks basically any tertiary interaction between its stems. We report unrestrained, explicit solvent molecular dynamics simulations of ribosomal and intron reverse kink-turns (54 simulations with 7.4 MUs of data in total) with different variants (ff94, ff99, ff99bsc0, ff99chiOL, and ff99bsc0chiOL) of the Cornell et al. force field. We test several ion conditions and two water models. The simulations characterize the directional intrinsic flexibility of reverse kink-turns pertinent to their folded functional geometries. The reverse kink-turns are the most flexible RNA motifs studied so far by explicit solvent simulations which are capable at the present simulation time scale to spontaneously and reversibly sample a wide range of geometries from tightly kinked ones through flexible intermediates up to extended, unkinked structures. A possible biochemical role of the flexibility is discussed. Among the tested force fields, the latest chiOL variant is essential to obtaining stable trajectories while all force field versions lacking the chi correction are prone to a swift degradation toward senseless ladder-like structures of stems, characterized by high-anti glycosidic torsions. The type of explicit water model affects the simulations considerably more than concentration and the type of ions. PMID- 26605486 TI - Water Defect and Pore Formation in Atomistic and Coarse-Grained Lipid Membranes: Pushing the Limits of Coarse Graining. AB - Defects in lipid bilayers are important in a range of biological processes, including interactions between antimicrobial peptides and membranes, transport of polar molecules (including drugs) across membranes, and lipid flip-flop from one monolayer to the other. Passive lipid flip-flop and the translocation of polar molecules across lipid membranes occur on a slow time scale because of high energy intermediates involving water defects and pores in the membrane. Such defects are an interesting test case for coarse-grained models because of their relatively small characteristic size at the level of water molecules and the complex environment of water and polar head groups in a low-dielectric membrane interior. Here we compare coarse-grained simulations with the MARTINI model with the standard MARTINI water and two recently developed coarse-grained polarizable water models to atomistic simulations. Although in several cases the MARTINI model reproduces the correct free energies, there are structural differences between the atomistic and coarse-grained models. The polarizable water model improves the free energies but only moderately improves the structures. Atomistic test simulations in which water molecules are artificially tethered to each other in groups of four, the resolution of MARTINI, suggest that the limiting factor is not the size of the coarse-grained particles but rather the simple interaction potential and/or the entropy lost in coarse graining the system. By increasing the attractive interaction between the lipids' headgroup and water, we did observe pore formation but at the expense of the correct equilibrium properties of the bilayers. PMID- 26605487 TI - Conformational Analysis of Oligoarabinofuranosides: Overcoming Torsional Barriers with Umbrella Sampling. AB - In this report, the conformations of a series of mono- and oligoarabinofuranosides were probed through the use of umbrella sampling simulations with the AMBER force field and the GLYCAM carbohydrate parameter set. The rotamer population distribution about the exocyclic C4-C5 bonds and the puckering distributions of the rings obtained from these umbrella sampling simulations were found to be in excellent agreement with those obtained from conventional long MD simulations for small monosaccharide fragments. For larger systems, the conventional MD approach becomes impractical, and we propose the use of umbrella sampling to circumvent poor sampling of certain conformations. The same umbrella sampling simulations were used to calculate the distributions about the vicinal protons and ensemble-averaged vicinal proton-proton coupling constants ((3)JH,H). The distributions about the vicinal protons of a monomer, methyl-alpha-l-arabinofuranoside (1), were found to be very similar to those obtained from direct umbrella sampling simulations about the vicinal protons. We calculated (3)JH,H based on DFT-based Karplus-like relationships for l arabinofuranosides. The (3)JH,H values were found to be very similar to those obtained with the conventional MD simulations. For 1, the (3)JH,H values obtained with the DFT-based Karplus equations agree very well with experimental results; the agreement is, however, not as good for the larger oligomers. An approach to determine the experimental rotamer populations from the simulations is also discussed. PMID- 26605488 TI - RI-MP2 and MPWB1K Study of pi-Anion-pi' Complexes: MPWB1K Performance and Some Additivity Aspects. AB - Several sandwich complexes of hexafluorobenzene, trifluorobenzene, s-triazine, and trifluoro-s-triazine with halides, nitrate, and carbonate anions have been optimized at the RI-MP2/6-31++G** (full and frozen core), B3LYP/6-31++G**, and MPWB1K/6-31++G** levels of theory. All possible combinations of the pi-systems and anions (to generate the sandwich pi-anion-pi' complexes) have been computed and analyzed using the aforementioned levels of theory. This allows us to evaluate the reliability and the performance of the MPWB1K functional to compute the binding energies of the anion-pi complexes and to analyze the additivity of the interaction in pi-anion-pi' complexes where the aromatic rings are of different nature (pi-acidity). We have also explored the Cambridge Structural Database and several interesting X-ray structures that support the theoretical calculations that have been found. PMID- 26605489 TI - A Failure of DFT Is Not Necessarily a DFT Failure-Performance Dependencies on Model System Choices. AB - The claim that DFT does not provide an accurate description of a weak Ru-C interaction (J. Chem. Theory Comput.2007, 3, 665-670) is put into broader perspective. The mismatch between structures obtained from DFT (BP86) as well as DFT-D (BP86-D2) calculations of isolated molecules in the gas phase and geometries resulting from X-ray crystal structure determination is due to a dissatisfactory chemical model system. Intermolecular forces within the molecular surroundings of the crystal obtained from semiempirical lattice energy calculations emerge as likely candidates responsible for the incongruity of experimental results and computation. PMID- 26605490 TI - Ultrasensitive Detection of Single-Walled Carbon Nanotubes Using Surface Plasmon Resonance. AB - Because single-walled carbon nanotubes (SWNTs) are known to be a potentially dangerous material, inducing cancers and other diseases, any possible leakage of SWNTs through an aquatic medium such as drinking water will result in a major public threat. To solve this problem, for the present study, a highly sensitive, quantitative detection method of SWNTs in an aqueous solution was developed using surface plasmon resonance (SPR) spectroscopy. For a highly sensitive and specific detection, a strong affinity conjugation with biotin-streptavidin was adopted on an SPR sensing mechanism. During the pretreatment process, the SWNT surface was functionalized and hydrophilized using a thymine-chain based biotinylated single strand DNA linker (B-ssDNA) and bovine serum albumin (BSA). The pretreated SWNTs were captured on a sensing film, the surface of which was immobilized with streptavidin on biotinylated gold film. The captured SWNTs were measured in real time using SPR spectroscopy. Specific binding with SWNTs was verified through several validation experiments. The present method using an SPR sensor is capable of detecting SWNTs of as low as 100 fg/mL, which is the lowest level reported thus far for carbon-nanotube detection. In addition, the SPR sensor showed a linear characteristic within the range of 100 pg/mL to 200 ng/mL. These findings imply that the present SPR sensing method can detect an extremely low level of SWNTs in an aquatic environment with high sensitivity and high specificity, and thus any potential leakage of SWNTs into an aquatic environment can be precisely monitored within a couple of hours. PMID- 26605492 TI - Plasmonic Coupling Dynamics of Silver Nanoparticles in an Optical Trap. AB - We investigate binding and plasmonic coupling between optically trapped 80 nm silver spheres using a combination of spectroscopic sensing and 3D interferometric laser particle tracking on a 1 MUs time scale. We demonstrate that nanoparticle coupling can be either spontaneous or induced by another particle through confinement of diffusion. We reveal ultrafast entries and exits of nanoparticles inside the optical trap, fast particle rearrangements before binding, and dimer formation allowing new insights into nanoparticle self assembly. PMID- 26605491 TI - Micro- and Nanopatterned Topographical Cues for Regulating Macrophage Cell Shape and Phenotype. AB - Controlling the interactions between macrophages and biomaterials is critical for modulating the response to implants. While it has long been thought that biomaterial surface chemistry regulates the immune response, recent studies have suggested that material geometry may in fact dominate. Our previous work demonstrated that elongation of macrophages regulates their polarization toward a pro-healing phenotype. In this work, we elucidate how surface topology might be leveraged to alter macrophage cell morphology and polarization state. Using a deep etch technique, we fabricated titanium surfaces containing micro- and nanopatterned grooves, which have been previously shown to promote cell elongation. Morphology, phenotypic markers, and cytokine secretion of murine bone marrow derived macrophages on different groove widths were analyzed. The results suggest that micro- and nanopatterned grooves influenced macrophage elongation, which peaked on substrates with 400-500 nm wide grooves. Surface grooves did not affect inflammatory activation but drove macrophages toward an anti-inflammatory, pro-healing phenotype. While secretion of TNF-alpha remained low in macrophages across all conditions, macrophages secreted significantly higher levels of anti inflammatory cytokine, IL-10, on intermediate groove widths compared to cells on other Ti surfaces. Our findings highlight the potential of using surface topography to regulate macrophage function, and thus control the wound healing and tissue repair response to biomaterials. PMID- 26605493 TI - Halloysite Nanotube Coatings Suppress Leukocyte Spreading. AB - The nanoscale topography of adhesive surfaces is known to be an important factor governing cellular behavior. Previous work has shown that surface coatings composed of halloysite nanotubes enhance the adhesion, and therefore capture of, rare target cells such as circulating tumor cells. Here we demonstrate a unique feature of these coatings in their ability to reduce the adhesion of leukocytes and prevent leukocyte spreading. Surfaces were prepared with coatings of halloysite nanotubes and functionalized for leukocyte adhesion with E-selectin, and the dilution of nanotube concentration revealed a threshold concentration below which cell spreading became comparable to smooth surfaces. Evaluation of surface roughness characteristics determined that the average distance between discrete surface features correlated with adhesion metrics, with a separation distance of ~2 MUm identified as the critical threshold. Computational modeling of the interaction of leukocytes with halloysite nanotube-coated surfaces of varying concentrations demonstrates that the geometry of the cell surface and adhesive counter-surface produces a significantly diminished effective contact area compared to a leukocyte interacting with a smooth surface. PMID- 26605494 TI - Estimating the Prevalence of Sexual Function Problems: The Impact of Morbidity Criteria. AB - Establishing the clinical significance of symptoms of sexual dysfunction is challenging. To address this, the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) introduced two new morbidity criteria (duration and symptom severity) to the existing criteria of distress. This study sought to establish the impact of these three criteria on the population prevalence of sexual function problems. The data come from a national probability survey (Natsal-3) and are based on 11,509 male and female participants aged 16 74, reporting at least one sexual partner in the past year. The key outcomes were: proportion of individuals reporting proxy measures of DSM-5 problems, and the proportion of those meeting morbidity criteria. We found that among sexually active men, the prevalence of reporting one or more of four specific sexual problems was 38.2%, but 4.2% after applying the three morbidity criteria; corresponding figures for women reporting one or more of three specific sexual problems, were 22.8% and 3.6%. Just over a third of men and women reporting a problem meeting all three morbidity criteria had sought help in the last year. We conclude that the DSM-5 morbidity criteria impose a focus on clinically significant symptoms. PMID- 26605495 TI - The Importance of Quality of Life Assessment. PMID- 26605496 TI - Value of neutrophil to lymphocyte ratio as a biomarker in colorectal adenocarcinoma. PMID- 26605498 TI - Applicability of Smartphone-Based Screening Programs. PMID- 26605497 TI - Alteration of complex negative emotions induced by music in euthymic patients with bipolar disorder. AB - BACKGROUND: Research has shown bipolar disorder to be characterized by dysregulation of emotion processing, including biases in facial expression recognition that is most prevalent during depressive and manic states. Very few studies have examined induced emotions when patients are in a euthymic phase, and there has been no research on complex emotions. We therefore set out to test emotional hyperreactivity in response to musical excerpts inducing complex emotions in bipolar disorder during euthymia. METHODS: We recruited 21 patients with bipolar disorder (BD) in a euthymic phase and 21 matched healthy controls. Participants first rated their emotional reactivity on two validated self-report scales (ERS and MAThyS). They then rated their music-induced emotions on nine continuous scales. The targeted emotions were wonder, power, melancholy and tension. We used a specific generalized linear mixed model to analyze the behavioral data. RESULTS: We found that participants in the euthymic bipolar group experienced more intense complex negative emotions than controls when the musical excerpts induced wonder. Moreover, patients exhibited greater emotional reactivity in daily life (ERS). Finally, a greater experience of tension while listening to positive music seemed to be mediated by greater emotional reactivity and a deficit in executive functions. LIMITATIONS: The heterogeneity of the BD group in terms of clinical characteristics may have influenced the results. CONCLUSIONS: Euthymic patients with bipolar disorder exhibit more complex negative emotions than controls in response to positive music. PMID- 26605499 TI - Characterization of the glycoproteins of bat-derived influenza viruses. AB - Recently found bat-derived influenza viruses (BatIVs) have hemagglutinin (HA) and neuraminidase (NA) gene segments distinct from those of previously known influenza A viruses. However, pathogenicities of these BatIVs remain unknown since infectious virus strains have not been isolated yet. To gain insight into the biological properties of BatIVs, we generated vesicular stomatitis viruses (VSVs) pseudotyped with the BatIV HA and NA. We found that VSVs pseudotyped with BatIV HAs and NAs efficiently infected particular bat cell lines but not those derived from primates, and that proteolytic cleavage with a trypsin-like protease was necessary for HA-mediated virus entry. Treatment of the susceptible bat cells with some enzymes and inhibitors revealed that BatIV HAs might recognize some cellular glycoproteins as receptors rather than the sialic acids used for the other known influenza viruses. These data provide fundamental information on the mechanisms underlying the cellular entry and host restriction of BatIVs. PMID- 26605500 TI - Multi-Informant Assessment of ADHD Symptom-Related Impairments Among Children and Adolescents. AB - Existing methods of assessing attention-deficit/hyperactivity disorder (ADHD) are limited because they do not examine impairments in relation to symptoms of ADHD. This study investigated parent and teacher ratings of multiple domains of impairment, assessed in relation to the symptom dimensions of ADHD using the ADHD Rating Scale-5. Nationally representative samples of children rated by parents and teachers were recruited through commercial research firms. One sample included 2,079 parents who rated one of their children of age 5 to 17 years. The second sample included 1,070 teachers in grades K to 12 who rated 2 randomly selected students on their class rosters. Informants rated the extent to which each child displayed the 18 behaviors symptomatic of ADHD over the previous 6 months, as well as symptom-related impairments in the areas of family/teacher relationships, peer relationships, academics, behavior problems, homework, and self-esteem. Respondents were asked to complete the 6 impairment items after rating each of the Inattention and Hyperactivity/Impulsivity symptom items. For both informants a 6-factor model that combined impairment items across source of impairment was adequate and superior to a 2-factor structure based on source of impairment (i.e., impairment due to Inattention vs. Hyperactivity-Impulsivity). Impairment ratings were impacted by child demographic factors, but effect sizes were low. In contrast, impairment ratings were strongly related to ratings on the ADHD symptom dimensions. The study provides support for assessing 6 symptom related domains of impairment but does not support differentiating whether Inattention or Hyperactivity-Impulsivity is the source of impairment. PMID- 26605501 TI - Cost-Utility Analyses of Cataract Surgery in Advanced Age-Related Macular Degeneration. AB - PURPOSE: To explore the cost-utility of cataract surgery in patients with advanced age-related macular degeneration (AMD). METHODS: Patients who were diagnosed as having and treated for age-related cataract and with a history of advanced AMD at the Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, were included in the study. All of the participants underwent successful phacoemulsification with foldable posterior chamber intraocular lens implantation under retrobulbar anesthesia. Best corrected visual acuity (BCVA) and utility value elicited by time trade-off method from patients at 3-month postoperative time were compared with those before surgery. Quality-adjusted life years (QALYs) gained in a lifetime were calculated at a 3% annual discounted rate. Costs per QALY gained were calculated using the bootstrap method, and probabilities of being cost-effective were presented using a cost-effectiveness acceptability curve. Sensitivity analyses were performed to test the robustness of the results. RESULTS: Mean logarithm of the minimum angle of resolution BCVA in the operated eye increased from 1.37 +/- 0.5 (Snellen, 20/469) to 0.98 +/- 0.25 (Snellen, 20/191) (p < 0.001); BCVA in the weighted average from both eyes (=75% better eye + 25% worse eye) was changed from 1.13 +/- 0.22 (Snellen, 20/270) to 0.96 +/- 0.17 (Snellen, 20/182) (p < 0.001). Utility values from both patients and doctors increased significantly after surgery (p < 0.001 and p = 0.007). Patients gained 1.17 QALYs by cataract surgery in their lifetime. The cost per QALY was 8835 Chinese yuan (CNY) (1400 U.S. dollars [USD]). It is cost-effective at the threshold of 115,062 CNY (18,235 USD) per QALY in China recommended by the World Health Organization. The cost per QALY varied from 7045 CNY (1116 USD) to 94,178 CNY (14,925 USD) in sensitivity analyses. CONCLUSIONS: Visual acuity and quality of life assessed by utility value improved significantly after surgery. Cataract surgery was a cost-effective intervention for patients with coexistent AMD. PMID- 26605502 TI - Utility of histogram analysis of apparent diffusion coefficient maps obtained using 3.0T MRI for distinguishing uterine carcinosarcoma from endometrial carcinoma. AB - PURPOSE: We explored the role of histogram analysis of apparent diffusion coefficient (ADC) maps for discriminating uterine carcinosarcoma and endometrial carcinoma. MATERIALS AND METHODS: We retrospectively evaluated findings in 13 patients with uterine carcinosarcoma and 50 patients with endometrial carcinoma who underwent diffusion-weighted imaging (b = 0, 500, 1000 s/mm(2) ) at 3T with acquisition of corresponding ADC maps. We derived histogram data from regions of interest drawn on all slices of the ADC maps in which tumor was visualized, excluding areas of necrosis and hemorrhage in the tumor. We used the Mann-Whitney test to evaluate the capacity of histogram parameters (mean ADC value, 5th to 95th percentiles, skewness, kurtosis) to discriminate uterine carcinosarcoma and endometrial carcinoma and analyzed the receiver operating characteristic (ROC) curve to determine the optimum threshold value for each parameter and its corresponding sensitivity and specificity. RESULTS: Carcinosarcomas demonstrated significantly higher mean vales of ADC, 95th, 90th, 75th, 50th, 25th percentiles and kurtosis than endometrial carcinomas (P < 0.05). ROC curve analysis of the 75th percentile yielded the best area under the ROC curve (AUC; 0.904), sensitivity of 100%, and specificity of 78.0%, with a cutoff value of 1.034 * 10( 3) mm(2) /s. CONCLUSION: Histogram analysis of ADC maps might be helpful for discriminating uterine carcinosarcomas and endometrial carcinomas. J. Magn. Reson. Imaging 2016;43:1301-1307. PMID- 26605503 TI - In situ photo-assisted deposition and photocatalysis of ZnIn2S4/transition metal chalcogenides for enhanced degradation and hydrogen evolution under visible light. AB - The effective immobilization of a transition chalcogenide co-catalyst via an in situ aqueous photo-assisted deposition technique has shown great accessibility to complex ZnIn2S4 host hierarchical nanostructured materials with homogeneous distribution. The complementary photo-assisted deposition readily deposits finely dispersed co-catalyst particles and simultaneously generates photocatalytic hydrogen. Another added advantage is that the photo-assisted deposition of the co catalyst does not compromise the crystal structure or the integrity of the host photocatalyst, hence offering a better alternative to the doping technique. A systematic study of various transition metal chalcogenide co-catalysts and optimization of wt% MoS2, CuS and Ag2S loadings were demonstrated. Among them, the ZnIn2S4/MoS2 composite exhibits exceptional photocatalytic hydrogen production and stability as well as superior MO degradation under visible light irradiation. The present methodology is expected to be extendable to various transition metal oxides/chalcogenides since ionic derivatives exhibit high affinity to a variety of materials under photoirradiation. PMID- 26605504 TI - Temperature-Dependent Evolution of Poly(3-Hexylthiophene) Type-II Phase in a Blended Thin Film. AB - The structure of P3HT in P3HT:PCBM films is examined on a poly(3,4 ethylenedioxythiophene) polystyrene sulfonate ( PEDOT: PSS) substrate subjected to cryo-cooling to low temperature (-143 degrees C) followed by gradual heating to 50 degrees C. The behavior of these systems is examined in the absence and presence of an Al electrode on top of the P3HT:PCBM film. At temperatures below 10 degrees C, only the type-I phase of P3HT is observed. However, the type-II phase of P3HT starts to form near -10 degrees C, in both the presence and absence of the Al layer. In the system without an Al layer, the type-II phase disappears at 30 degrees C, but this phase persists to 50 degrees C in the presence of the Al layer. Concomitant with the formation of the type-II phase, a 1:3 ordered P3HT type-II (1/3,0,0) superlattice peak emerged. The type-II domains tend to form near the Al electrode layer and show a higher degree of alignment than the type-I crystals. PMID- 26605505 TI - Brief Report: Switch to Ritonavir-Boosted Atazanavir Plus Raltegravir in Virologically Suppressed Patients With HIV-1 Infection: A Randomized Pilot Study. AB - This open-label, multinational, pilot study randomized (1:2 ratio) adults with HIV-1 RNA <40 copies per milliliter and nucleos(t)ide-related safety/tolerability issues to switch to ritonavir-boosted atazanavir (ATV/r) plus tenofovir disoproxil fumarate/emtricitabine (n = 37) or the nucleos(t)ide reverse transcriptase inhibitor-sparing regimen of ATV/r plus raltegravir (RAL) (n = 72). At 24 weeks, 35/37 (94.6%) and 58/72 (80.6%) of patients, respectively, maintained virological suppression, the primary endpoint, and 1 (2.7%) and 7 (9.7%), respectively, experienced virological rebound. Corresponding 48-week proportions were 86.5%, 69.4%, 2.7%, and 12.5%, respectively. Adherence was lower and treatment discontinuation was higher with ATV/r+RAL. In conclusion, switching to ATV/r+RAL resulted in a higher virological rebound rate than switching to ATV/r plus tenofovir disoproxil fumarate/emtricitabine. PMID- 26605506 TI - Nutritional and Immunological Correlates of Memory and Neurocognitive Development Among HIV-Infected Children Living in Kayunga, Uganda. AB - OBJECTIVE: To identify the nutritional and immunological correlates of memory and neurocognitive development as measured by the Mullen Scales of Early Learning (MSEL) and by the Color Object Association Test (COAT) among children in Uganda. DESIGN: This analysis uses baseline data collected between 2008 and 2010 from 119 HIV-infected children aged 1-6 years, participating in a randomized controlled trial of an interventional parenting program in Kayunga, Uganda. METHODS: Peripheral blood draws were performed to determine immunological biomarkers. Unadjusted and adjusted linear regression models were used to relate MSEL and COAT scores to sociodemographic characteristics, weight-for-age Z scores (WAZs), antiretroviral therapy status, and immunological biomarkers. RESULTS: In the final analysis, 111 children were included. Lower levels of CD4 CD38 T cells (P = 0.04) were associated to higher immediate and total recall scores (P = 0.04). Higher levels of CD8 HLA-DR T cells were associated with higher total recall score (P = 0.04) of the COAT. Higher CD4 CD38 HLA-DR T cells levels were associated with higher gross motor scores of the MSEL (P = 0.02). WAZ was positively correlated to visual reception, fine motor, expressive language, and composite score of the MSEL. CONCLUSIONS: Overall, WAZ was a stronger predictor of neurocognitive outcomes assessed by the MSEL. CD4 CD38 T cells were more specifically associated with memory-related outcomes. Future research should include immunological markers and standardized neurocognitive tests to further understand this relationship. PMID- 26605507 TI - Efficacy and safety of live varicella zoster vaccine in diabetes: a randomized, double-blind, placebo-controlled trial. AB - AIMS: To elucidate varicella zoster virus (VZV)-specific cell-mediated immunity and humoral immunogenicity against live attenuated Oka varicella zoster vaccine concurrently vaccinated with 23-valent pneumococcal polysaccharide vaccine (PPSV23) in elderly people with diabetes mellitus. METHODS: This double-blind randomized controlled single-centre study of 60-70-year-old people with diabetes compared immunity and safety profiles 3 months after one dose of varicella zoster vaccine or placebo. PPSV23 was immunized simultaneously. Primary analysis evaluated cell-mediated immunity using the VZV skin test. Secondary analyses were a VZV interferon-gamma enzyme-linked immunospot (ELISPOT) assay and immunoadherence haemagglutination test. Adverse experiences were recorded using diary questionnaires. RESULTS: By intent-to-treat analysis, 27 participants with diabetes who had been administered the vaccine were compared with 27 participants who were given a placebo. Changes in skin test scores were 0.41 +/- 0.80 and 0.11 +/- 0.93 (P = 0.2155), and geometric mean fold rises of the ELISPOT counts were 1.2 [95% confidence interval (CI) 0.2, 7.9] and 1.2 (95% CI 0.2, 7.3) (P = 0.989) in the vaccine and placebo groups, respectively. The geometric mean titre did not increase 3 months after vaccination in either group. No vaccination-related severe adverse experience was reported and no participant developed herpes zoster. DISCUSSION: Our previous results demonstrated that varicella zoster vaccine safely enhanced VZV-specific immunity in elderly people with or without diabetes. The results of this study showed that varicella zoster vaccine can be used safely, but it cannot boost virus-specific immunity in elderly people with diabetes when administered with concurrent PPSV23. Alternative strategies are needed to prevent VZV-associated diseases in this population. PMID- 26605508 TI - The Brain Fights Back: New Approaches to Mitigating Cognitive Decline. PMID- 26605509 TI - Activation of specific neuronal networks leads to different seizure onset types. AB - OBJECTIVE: Ictal events occurring in temporal lobe epilepsy patients and in experimental models mimicking this neurological disorder can be classified, based on their onset pattern, into low-voltage, fast versus hypersynchronous onset seizures. It has been suggested that the low-voltage, fast onset pattern is mainly contributed by interneuronal (gamma-aminobutyric acidergic) signaling, whereas the hypersynchronous onset involves the activation of principal (glutamatergic) cells. METHODS: Here, we tested this hypothesis using the optogenetic control of parvalbumin-positive or somatostatin-positive interneurons and of calmodulin-dependent, protein kinase-positive, principal cells in the mouse entorhinal cortex in the in vitro 4-aminopyridine model of epileptiform synchronization. RESULTS: We found that during 4-aminopyridine application, both spontaneous seizure-like events and those induced by optogenetic activation of interneurons displayed low-voltage, fast onset patterns that were associated with a higher occurrence of ripples than of fast ripples. In contrast, seizures induced by the optogenetic activation of principal cells had a hypersynchronous onset pattern with fast ripple rates that were higher than those of ripples. INTERPRETATION: Our results firmly establish that under a similar experimental condition (ie, bath application of 4-aminopyridine), the initiation of low voltage, fast and of hypersynchronous onset seizures in the entorhinal cortex depends on the preponderant involvement of interneuronal and principal cell networks, respectively. PMID- 26605510 TI - IgG4-Related Sacroiliitis. PMID- 26605512 TI - State variation in HIV/AIDS health outcomes: the effect of spending on social services and public health. AB - OBJECTIVE: Despite considerable advances in the prevention and treatment of HIV/AIDS, the burden of new infections of HIV and AIDS varies substantially across the country. Previous studies have demonstrated associations between increased healthcare spending and better HIV/AIDS outcomes; however, less is known about the association between spending on social services and public health spending and HIV/AIDS outcomes. We sought to examine the association between state-level spending on social services and public health and HIV/AIDS case rates and AIDS deaths across the United States. DESIGN: We conducted a retrospective, longitudinal study of the 50 U.S. states over 2000-2009 using a dataset of HIV/AIDS case rates and AIDS deaths per 100 000 people matched with a unique dataset of state-level spending on social services and public health per person in poverty. METHODS: We estimated multivariable regression models for each HIV/AIDS outcome as a function of the social service and public health spending 1 and 5 years earlier in the state, adjusted for the log of state GDP per capita, regional and time fixed effects, Medicaid spending as % of GDP, and socio demographic, economic, and health resource factors. RESULTS: States with higher spending on social services and public health per person in poverty had significantly lower HIV and AIDS case rates and fewer AIDS deaths, both 1 and 5 years post expenditure (P <= 0.05). CONCLUSION: Our findings suggest that spending on social services and public health may provide a leverage point for state policymakers to reduce HIV/AIDS case rates and AIDS deaths in their state. PMID- 26605511 TI - Transforming growth factor-beta1-mediated cardiac fibrosis: potential role in HIV and HIV/antiretroviral therapy-linked cardiovascular disease. PMID- 26605513 TI - CD4+ and CD8+ T-cell kinetics in aviremic HIV-infected patients developing Hodgkin or non-Hodgkin lymphoma. AB - OBJECTIVE: The risk of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) is increased in HIV-infected individuals. We studied the kinetics of lymphocyte subsets in patients who subsequently developed HL or NHL while on virologically suppressive antiretroviral therapy (ART). DESIGN: Using a nested case-control design, cases of HIV+ HL or NHL were selected from two prospective clinical studies. Aviremia was defined as less than 200 HIV-RNA copies/ml for at least 6 months prior to lymphoma diagnosis. Each case was matched to three aviremic HIV+ controls without lymphoma. RESULTS: In the 81 cases (50 HL and 31 NHL), prediagnostic CD4 T cells and CD8 T cells displayed discordant kinetics compared with controls. Within the last and within the next-to-last year preceding HL diagnosis, mean CD4 T cells decreased by -168 and by -2 cells/MUl, compared with an increase of +44 and +73 cells/MUl in the controls, respectively. Mean CD8 T cells decreased by -352 and -115 cells/MUl, compared with nonsignificant changes of -29 and +/-0 cells/MUl in the controls, respectively. T-cell kinetics demonstrated a marked inter-individual variability. Kinetics of CD4 and CD8 T cells were also discordant between NHL cases and controls. CONCLUSION: This study on a large number of aviremic patients developing HL and NHL who were carefully matched with controls, gives insights to prediagnostic kinetics of immune parameters. The discordant kinetics of both CD4 and CD8 T cells are already seen 1-2 years prior to lymphoma diagnosis, are more pronounced during the last year and in patients developing HL but are also seen in NHL. PMID- 26605514 TI - A phase 1 randomized placebo-controlled safety and pharmacokinetic trial of a tenofovir disoproxil fumarate vaginal ring. AB - BACKGROUND: Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir (TFV), may be ideal for topical HIV preexposure prophylaxis because it has higher tissue and cell permeability than TFV; is not adversely impacted by seminal proteins; and its active metabolite, TFV-diphosphate (TFV-DP), has a long intracellular half-life. We engineered a TDF eluting polyurethane reservoir intravaginal ring (IVR) to provide near constant mucosal antiretroviral concentrations. METHODS: A first-in-human randomized placebo-controlled trial was conducted to assess the safety and pharmacokinetics of the TDF IVR in healthy, sexually abstinent women (15 TDF and 15 placebo). Drug concentrations were measured in cervicovaginal fluid (CVF) obtained by swab, cervical tissue, plasma, and dried blood spots (DBS) over 14 days of continuous ring use. RESULTS: There were 43 total, 23 reproductive tract, and eight product-related grade 1 adverse events. Steady state CVF TFV concentrations were achieved proximal (vagina, ectocervix) and distal (introitus) to the TDF IVR 1 day after ring insertion. Median tissue TFV DP concentrations 14 days after TDF IVR placement were 120 fmol/mg (interquartile range 90, 550). CVF collected from the cervix 1 week and 2 weeks after TDF IVR insertion provided significant protection against ex-vivo HIV challenge. Eleven of 14 (78%) participants had detectable TFV-DP DBS concentrations 14 days after TDF IVR placement, suggesting that DBS may provide a surrogate marker of adherence in future clinical trials. CONCLUSION: A TDF IVR is safe, well tolerated, and results in mucosal TFV concentrations that exceed those associated with HIV protection. The findings support further clinical evaluation of this TDF IVR. PMID- 26605515 TI - Complement component 3: a new paradigm in tuberculosis vaccine. AB - Vaccines are critical for the control of tuberculosis (TB) affecting humans and animals worldwide. First-generation vaccines protect from active TB but new vaccines are required to protect against pulmonary disease and infection. Recent advances in post-genomics technologies have allowed the characterization of host pathogen interactions to discover new protective antigens and mechanisms to develop more effective vaccines against TB. Studies in the wild boar model resulted in the identification of complement component 3 (C3) as a natural correlate of protection against TB. Oral immunization with heat-inactivated mycobacteria protected wild boar against TB and showed that C3 plays a central role in protection. These results point at C3 as a target to develop novel vaccine formulations for more effective protection against TB in humans and animals. PMID- 26605516 TI - Quality of anticoagulation and outcome of bleeding in cirrhosis. PMID- 26605517 TI - Severity of coronary atherosclerosis in patients with COPD. AB - BACKGROUND AND AIMS: Chronic obstructive pulmonary disease (COPD) has many comorbidities such as coronary artery disease (CAD) and stroke. Chronic low-grade systemic inflammation and oxidative stress play a significant role in CAD and COPD. We analysed that impact of COPD on intensity and severity of coronary artery lesions on the angiogram in the groups of patients with COPD according to the Global Initiative for Obstructive Lung Disease (GOLD) grades updated in 2015. METHODS: The study included 102 COPD patients and 80 randomly selected subjects without any pulmonary disease who underwent coronary angiography. According to the GOLD grade for COPD, patients were divided into four groups: A, B, C and D. The severity and extent of CAD were determined using the Gensini score. RESULTS: There were no significant between-group differences in age, body mass index, smoking history, plasma lipids levels, frequency of hypertension, diabetes and CAD. The mean Gensini score in patients with COPD was significantly higher than those without (respectively, 25.7 +/- 32.9 vs 17.5 +/- 24.8, P = 0.01). While Gensini score was the highest level in the patient group D (64.9 +/- 34.9), it was the lowest level in the patient group A (10.2 +/- 19.4, P = 0.0001). The Gensini scores increased in accordance with increases in the GOLD grades. We observed that COPD was independently predictive for Gensini score after a multi variate logistic regression analysis (odds ratio 1.374; 95% confidence interval 1.672-9.232; P = 0.001). CONCLUSION: Severity and intensity of coronary atherosclerosis increases in accordance with increases in the GOLD grades for COPD. PMID- 26605518 TI - Evolution of motion uncertainty in rectal cancer: implications for adaptive radiotherapy. AB - Reduction of motion uncertainty by applying adaptive radiotherapy strategies depends largely on the temporal behavior of this motion. To fully optimize adaptive strategies, insight into target motion is needed. The purpose of this study was to analyze stability and evolution in time of motion uncertainty of both the gross tumor volume (GTV) and clinical target volume (CTV) for patients with rectal cancer. We scanned 16 patients daily during one week, on a 1.5 T MRI scanner in treatment position, prior to each radiotherapy fraction. Single slice sagittal cine MRIs were made at the beginning, middle, and end of each scan session, for one minute at 2 Hz temporal resolution. GTV and CTV motion were determined by registering a delineated reference frame to time-points later in time. The 95th percentile of observed motion (dist95%) was taken as a measure of motion. The stability of motion in time was evaluated within each cine-MRI separately. The evolution of motion was investigated between the reference frame and the cine-MRIs of a single scan session and between the reference frame and the cine-MRIs of several days later in the course of treatment. This observed motion was then converted into a PTV-margin estimate. Within a one minute cine MRI scan, motion was found to be stable and small. Independent of the time-point within the scan session, the average dist95% remains below 3.6 mm and 2.3 mm for CTV and GTV, respectively 90% of the time. We found similar motion over time intervals from 18 min to 4 days. When reducing the time interval from 18 min to 1 min, a large reduction in motion uncertainty is observed. A reduction in motion uncertainty, and thus the PTV-margin estimate, of 71% and 75% for CTV and tumor was observed, respectively. Time intervals of 15 and 30 s yield no further reduction in motion uncertainty compared to a 1 min time interval. PMID- 26605519 TI - Clinical evaluation of a novel microfluidic device for epitope-independent enrichment of circulating tumour cells in patients with small cell lung cancer. AB - Circulating tumour cells (CTCs) have potential utility as minimally-invasive biomarkers to aid cancer treatment decision making. However, many current CTC technologies enrich CTCs using specific surface epitopes that do not necessarily reflect CTC heterogeneity. Here we evaluated the epitope-independent Parsortix system which enriches CTCs based on size and rigidity using both healthy normal volunteer blood samples spiked with tumour cells and blood samples from patients with small cell lung cancer (SCLC). Blood samples were maintained unfractionated at room temperature for up to 4 days followed by plasma removal for circulating free DNA (cfDNA) isolation and direct application of the remaining cell component to the Parsortix system. For tumour cells expressing the EpCAM cell surface marker the numbers of spiked cells retained using the Parsortix system and by EpCAM-positive selection using CellSearch(r) were not significantly different, whereas only the Parsortix system showed strong enrichment of cells with undetectable EpCAM expression. In a pilot clinical study we banked both enriched CTCs as well as plasma from SCLC patient blood samples. Upon retrieval of the banked Parsortix cellular samples we could detect cytokeratin positive CTCs in all 12 SCLC patients tested. Interestingly, processing parallel samples from the same patients by EpCAM enrichment using CellSearch(r) revealed only 83% (10/12) with cytokeratin positive CTCs indicating the Parsortix system is enriching for EpCAM negative SCLC CTCs. Our combined results indicate the Parsortix system is a valuable tool for combined cfDNA isolation and CTC enrichment that enables CTC analysis to be extended beyond dependence on surface epitopes. PMID- 26605520 TI - Developmental Trajectories of Impaired Community Functioning in Schizophrenia. AB - IMPORTANCE: Community functioning is a core component of the functional deficits in schizophrenia, yet little systematic research on the origins of these functional deficits has been performed. OBJECTIVES: To examine 3 key domains of community functioning--social activity, independent behavior, and functioning in school or work--before first hospitalization for schizophrenia and to determine whether these domains are familial. DESIGN, SETTING, AND PARTICIPANTS: In this population-based, prospective study that included a sibling-control comparison, data from the Israeli National Draft Board Registry were linked with data from the Israeli Psychiatric Hospitalization Case Registry. The merged file included data for all male adolescents who visited the draft board and were followed up for as much as 25.4 years from draft board assessment (through the end of 2010). The 3 functional domains for cases, their unaffected siblings, and controls were compared by time between assessment and time to hospitalization. Analyses were conducted from March 13, 2014, to October 19, 2014. MAIN OUTCOMES AND MEASURES: The trajectories and familiality of 3 key components of community functioning- social activity, independent behavior, and functioning in school or work--in the years preceding hospitalization for schizophrenia. RESULTS: Participants included 723,316 Israeli male adolescents who underwent a mandatory behavioral assessment to determine eligibility for military service. Linkage identified 3929 individuals hospitalized for schizophrenia. Data for 338,550 sibling pairs, 1659 hospitalized with schizophrenia, were similarly ascertained. Among those with schizophrenia, impairments in social activity (effect size [d], 0.55) and functioning in school or work (d = 0.37) were recognizable up to 15 years before hospitalization. Independent behavior seemed preserved until the few years before first admission. For social activity, differences between cases and controls were progressively greater for patients admitted closer to time of testing (F = 115.33, P < .001). Unaffected siblings had small impairments compared with controls in social activity (F = 28.25, P < .001) and functioning in school or work scales (F = 14.77, P < .001). Group familial (sibling) correlations were relatively high for social activity (r = 0.40; 95% CI, 0.39-0.41) and functioning in school or work (r = 0.50; 95% CI, 0.49-0.51) but nil for independent behavior (r = 0; 95% CI, -0.01 to -0.01). Impairments in siblings had no progressive increase and were unrelated to their affected sibling's time of illness onset (time trend: social activity: F = 5.463, P = .02; independent behavior: F = 0.908, P = .34; and functioning in school or work: F = 1.386, P = .24). CONCLUSIONS AND RELEVANCE: Various components of impaired community functioning in schizophrenia followed different developmental trajectories. Our results indicate that impairments in social activity and functioning in school or work are familial. PMID- 26605521 TI - Relativistic baryonic jets from an ultraluminous supersoft X-ray source. AB - The formation of relativistic jets by an accreting compact object is one of the fundamental mysteries of astrophysics. Although the theory is poorly understood, observations of relativistic jets from systems known as microquasars (compact binary stars) have led to a well established phenomenology. Relativistic jets are not expected to be produced by sources with soft or supersoft X-ray spectra, although two such systems are known to produce relatively low-velocity bipolar outflows. Here we report the optical spectra of an ultraluminous supersoft X-ray source (ULS) in the nearby galaxy M81 (M81 ULS-1; refs 9, 10). Unexpectedly, the spectra show blueshifted, broad Halpha emission lines, characteristic of baryonic jets with relativistic speeds. These time-variable emission lines have projected velocities of about 17 per cent of the speed of light, and seem to be similar to those from the prototype microquasar SS 433 (refs 11, 12). Such relativistic jets are not expected to be launched from white dwarfs, and an origin from a black hole or a neutron star is hard to reconcile with the persistence of M81 ULS-1's soft X-rays. Thus the unexpected presence of relativistic jets in a ULS challenges canonical theories of jet formation, but might be explained by a long speculated, supercritically accreting black hole with optically thick outflows. PMID- 26605522 TI - Structural biology: A transcriptional specialist resolved. PMID- 26605523 TI - Corrigendum: Human body epigenome maps reveal noncanonical DNA methylation variation. PMID- 26605525 TI - Corrigendum: NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells. PMID- 26605524 TI - Immune homeostasis enforced by co-localized effector and regulatory T cells. AB - FOXP3(+) regulatory T cells (Treg cells) prevent autoimmunity by limiting the effector activity of T cells that have escaped thymic negative selection or peripheral inactivation. Despite the information available about molecular factors mediating the suppressive function of Treg cells, the relevant cellular events in intact tissues remain largely unexplored, and whether Treg cells prevent activation of self-specific T cells or primarily limit damage from such cells has not been determined. Here we use multiplex, quantitative imaging in mice to show that, within secondary lymphoid tissues, highly suppressive Treg cells expressing phosphorylated STAT5 exist in discrete clusters with rare IL-2 positive T cells that are activated by self-antigens. This local IL-2 induction of STAT5 phosphorylation in Treg cells is part of a feedback circuit that limits further autoimmune responses. Inducible ablation of T cell receptor expression by Treg cells reduces their regulatory capacity and disrupts their localization in clusters, resulting in uncontrolled effector T cell responses. Our data thus reveal that autoreactive T cells are activated to cytokine production on a regular basis, with physically co-clustering T cell receptor-stimulated Treg cells responding in a negative feedback manner to suppress incipient autoimmunity and maintain immune homeostasis. PMID- 26605527 TI - Cell biology: Architecture of a protein entry gate. PMID- 26605526 TI - Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides. AB - Copy number variations have been frequently associated with developmental delay, intellectual disability and autism spectrum disorders. MECP2 duplication syndrome is one of the most common genomic rearrangements in males and is characterized by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections and early death. The broad range of deficits caused by methyl-CpG-binding protein 2 (MeCP2) overexpression poses a daunting challenge to traditional biochemical-pathway-based therapeutic approaches. Accordingly, we sought strategies that directly target MeCP2 and are amenable to translation into clinical therapy. The first question that we addressed was whether the neurological dysfunction is reversible after symptoms set in. Reversal of phenotypes in adult symptomatic mice has been demonstrated in some models of monogenic loss-of-function neurological disorders, including loss of MeCP2 in Rett syndrome, indicating that, at least in some cases, the neuroanatomy may remain sufficiently intact so that correction of the molecular dysfunction underlying these disorders can restore healthy physiology. Given the absence of neurodegeneration in MECP2 duplication syndrome, we propose that restoration of normal MeCP2 levels in MECP2 duplication adult mice would rescue their phenotype. By generating and characterizing a conditional Mecp2-overexpressing mouse model, here we show that correction of MeCP2 levels largely reverses the behavioural, molecular and electrophysiological deficits. We also reduced MeCP2 using an antisense oligonucleotide strategy, which has greater translational potential. Antisense oligonucleotides are small, modified nucleic acids that can selectively hybridize with messenger RNA transcribed from a target gene and silence it, and have been successfully used to correct deficits in different mouse models. We find that antisense oligonucleotide treatment induces a broad phenotypic rescue in adult symptomatic transgenic MECP2 duplication mice (MECP2-TG), and corrected MECP2 levels in lymphoblastoid cells from MECP2 duplication patients in a dose dependent manner. PMID- 26605528 TI - Corrigendum: Acute stress facilitates long-lasting changes in cholinergic gene expression. PMID- 26605530 TI - Erratum: Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. PMID- 26605529 TI - A mechanism for expansion of regulatory T-cell repertoire and its role in self tolerance. AB - T-cell receptor (TCR) signalling has a key role in determining T-cell fate. Precursor cells expressing TCRs within a certain low-affinity range for complexes of self-peptide and major histocompatibility complex (MHC) undergo positive selection and differentiate into naive T cells expressing a highly diverse self MHC-restricted TCR repertoire. In contrast, precursors displaying TCRs with a high affinity for 'self' are either eliminated through TCR-agonist-induced apoptosis (negative selection) or restrained by regulatory T (Treg) cells, whose differentiation and function are controlled by the X-chromosome-encoded transcription factor Foxp3 (reviewed in ref. 2). Foxp3 is expressed in a fraction of self-reactive T cells that escape negative selection in response to agonist driven TCR signals combined with interleukin 2 (IL-2) receptor signalling. In addition to Treg cells, TCR-agonist-driven selection results in the generation of several other specialized T-cell lineages such as natural killer T cells and innate mucosal-associated invariant T cells. Although the latter exhibit a restricted TCR repertoire, Treg cells display a highly diverse collection of TCRs. Here we explore in mice whether a specialized mechanism enables agonist driven selection of Treg cells with a diverse TCR repertoire, and the importance this holds for self-tolerance. We show that the intronic Foxp3 enhancer conserved noncoding sequence 3 (CNS3) acts as an epigenetic switch that confers a poised state to the Foxp3 promoter in precursor cells to make Treg cell lineage commitment responsive to a broad range of TCR stimuli, particularly to suboptimal ones. CNS3-dependent expansion of the TCR repertoire enables Treg cells to control self-reactive T cells effectively, especially when thymic negative selection is genetically impaired. Our findings highlight the complementary roles of these two main mechanisms of self-tolerance. PMID- 26605531 TI - Immunology: In the right place at the right time. PMID- 26605532 TI - Genome-wide detection of DNase I hypersensitive sites in single cells and FFPE tissue samples. AB - DNase I hypersensitive sites (DHSs) provide important information on the presence of transcriptional regulatory elements and the state of chromatin in mammalian cells. Conventional DNase sequencing (DNase-seq) for genome-wide DHSs profiling is limited by the requirement of millions of cells. Here we report an ultrasensitive strategy, called single-cell DNase sequencing (scDNase-seq) for detection of genome-wide DHSs in single cells. We show that DHS patterns at the single-cell level are highly reproducible among individual cells. Among different single cells, highly expressed gene promoters and enhancers associated with multiple active histone modifications display constitutive DHS whereas chromatin regions with fewer histone modifications exhibit high variation of DHS. Furthermore, the single-cell DHSs predict enhancers that regulate cell-specific gene expression programs and the cell-to-cell variations of DHS are predictive of gene expression. Finally, we apply scDNase-seq to pools of tumour cells and pools of normal cells, dissected from formalin-fixed paraffin-embedded tissue slides from patients with thyroid cancer, and detect thousands of tumour-specific DHSs. Many of these DHSs are associated with promoters and enhancers critically involved in cancer development. Analysis of the DHS sequences uncovers one mutation (chr18: 52417839G>C) in the tumour cells of a patient with follicular thyroid carcinoma, which affects the binding of the tumour suppressor protein p53 and correlates with decreased expression of its target gene TXNL1. In conclusion, scDNase-seq can reliably detect DHSs in single cells, greatly extending the range of applications of DHS analysis both for basic and for translational research, and may provide critical information for personalized medicine. PMID- 26605534 TI - Sensory Threshold Studies of Picrocrocin, the Major Bitter Compound of Saffron. AB - This study is part of a wider project on the bitter taste of saffron and its preparations. A deeper knowledge on the taste perception of picrocrocin is necessary in order to develop products that satisfy consumer senses and provide them with adequate amounts of saffron major constituents, also appreciated for bioactivity. A systematic approach on the bitterness of picrocrocin, the major responsible compound, was conducted. A panel was trained specifically for the determination of taste detection and recognition thresholds of picrocrocin, which were found to be 5.34 and 7.26 mg/L, respectively, using the Ascending Forced Choice of Limits methodology. The threshold values were examined in water in absence and presence of other saffron constituents and ethanol and were found to decrease when served hot (61 +/- 4 degrees C). Bitterness was enhanced in 40% (v/v) aqueous ethanol. In both aqueous and ethanol extracts, the presence of saffron volatiles improved bitterness perception. The usefulness of the study was tested in the case of commercial saffron based infusions. PMID- 26605533 TI - Molecular structures of unbound and transcribing RNA polymerase III. AB - Transcription of genes encoding small structured RNAs such as transfer RNAs, spliceosomal U6 small nuclear RNA and ribosomal 5S RNA is carried out by RNA polymerase III (Pol III), the largest yet structurally least characterized eukaryotic RNA polymerase. Here we present the cryo-electron microscopy structures of the Saccharomyces cerevisiae Pol III elongating complex at 3.9 A resolution and the apo Pol III enzyme in two different conformations at 4.6 and 4.7 A resolution, respectively, which allow the building of a 17-subunit atomic model of Pol III. The reconstructions reveal the precise orientation of the C82 C34-C31 heterotrimer in close proximity to the stalk. The C53-C37 heterodimer positions residues involved in transcription termination close to the non template DNA strand. In the apo Pol III structures, the stalk adopts different orientations coupled with closed and open conformations of the clamp. Our results provide novel insights into Pol III-specific transcription and the adaptation of Pol III towards its small transcriptional targets. PMID- 26605535 TI - Lateral Wedge Insoles for Reducing Biomechanical Risk Factors for Medial Knee Osteoarthritis Progression: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: Lateral wedge insoles are intended to reduce biomechanical risk factors of medial knee osteoarthritis (OA) progression, such as increased knee joint load; however, there has been no definitive consensus on this topic. The aim of this systematic review and meta-analysis was to establish the within subject effects of lateral wedge insoles on knee joint load in people with medial knee OA during walking. METHODS: Six databases were searched from inception until February 13, 2015. Included studies reported on the immediate biomechanical effects of lateral wedge insoles during walking in people with medial knee OA. Primary outcomes of interest relating to the biomechanical risk of disease progression were the first and second peak external knee adduction moment (EKAM) and knee adduction angular impulse (KAAI). Eligible studies were pooled using random-effects meta-analysis. RESULTS: Eighteen studies were included with a total of 534 participants. Lateral wedge insoles resulted in a small but statistically significant reduction in the first peak EKAM (standardized mean difference [SMD] -0.19; 95% confidence interval [95% CI] -0.23, -0.15) and second peak EKAM (SMD -0.25; 95% CI -0.32, -0.19) with a low level of heterogeneity (I(2) = 5% and 30%, respectively). There was a favorable but small reduction in the KAAI with lateral wedge insoles (SMD -0.14; 95% CI -0.21, -0.07, I(2) = 31%). Risk of methodologic bias scores (quality index) ranged from 8 to 13 out of 16. CONCLUSION: Lateral wedge insoles cause small reductions in the EKAM and KAAI during walking in people with medial knee OA. Current evidence demonstrates that lateral wedge insoles appear ineffective at attenuating structural changes in people with medial knee OA as a whole and may be better suited to targeted use in biomechanical phenotypes associated with larger reductions in knee load. PMID- 26605537 TI - Gluten Sensitivity. AB - Non-celiac gluten sensitivity (NCGS) is a syndrome characterized by intestinal and extraintestinal symptoms related to the ingestion of gluten-containing food in subjects who are not affected by either celiac disease (CD) or wheat allergy (WA). The prevalence of NCGS is not clearly defined yet. Indirect evidence suggests that NCGS is slightly more common than CD, the latter affecting around 1% of the general population. NCGS has been mostly described in adults, particularly in females in the age group of 30-50 years; however, pediatric case series have also been reported. Since NCGS may be transient, gluten tolerance needs to be reassessed over time in patients with NCGS. NCGS is characterized by symptoms that usually occur soon after gluten ingestion, disappear with gluten withdrawal, and relapse following gluten challenge within hours/days. The 'classical' presentation of NCGS is a combination of irritable bowel syndrome like symptoms, including abdominal pain, bloating, bowel habit abnormalities (either diarrhea or constipation), and systemic manifestations such as 'foggy mind', headache, fatigue, joint and muscle pain, leg or arm numbness, dermatitis (eczema or skin rash), depression, and anemia. In recent years, several studies explored the relationship between the ingestion of gluten-containing food and the appearance of neurological and psychiatric disorders/symptoms like ataxia, peripheral neuropathy, schizophrenia, autism, depression, anxiety, and hallucinations (so-called gluten psychosis). The diagnosis of NCGS should be considered in patients with persistent intestinal and/or extraintestinal complaints showing a normal result of the CD and WA serological markers on a gluten-containing diet, usually reporting worsening of symptoms after eating gluten-rich food. NCGS should not be an exclusion diagnosis only. Unfortunately, no biomarker is sensitive and specific enough for diagnostic purposes; therefore, the diagnosis of NCGS is currently based on establishing a clear-cut cause-effect relationship between the ingestion of gluten and the appearance of symptoms by a standardized double-blind, placebo-controlled gluten challenge. PMID- 26605536 TI - Nociceptive Sensitizers Are Regulated in Damaged Joint Tissues, Including Articular Cartilage, When Osteoarthritic Mice Display Pain Behavior. AB - OBJECTIVE: Pain is the most common symptom of osteoarthritis (OA), yet where it originates in the joint and how it is driven are unknown. The aim of this study was to identify pain-sensitizing molecules that are regulated in the joint when mice subjected to surgical joint destabilization develop OA-related pain behavior, the tissues in which these molecules are being regulated, and the factors that control their regulation. METHODS: Ten-week-old mice underwent sham surgery, partial meniscectomy, or surgical destabilization of the medial meniscus (DMM). Pain-related behavior as determined by a variety of methods (testing of responses to von Frey filaments, cold plate testing for cold sensitivity, analgesiometry, incapacitance testing, and forced flexion testing) was assessed weekly. Once pain-related behavior was established, RNA was extracted from either whole joints or microdissected tissue samples (articular cartilage, meniscus, and bone). Reverse transcription-polymerase chain reaction analysis was performed to analyze the expression of 54 genes known to regulate pain sensitization. Cartilage injury assays were performed using avulsed immature hips from wild-type or genetically modified mice or by explanting articular cartilage from porcine joints preinjected with pharmacologic inhibitors. Levels of nerve growth factor (NGF) protein were measured by enzyme-linked immunosorbent assay. RESULTS: Mice developed pain-related behavior 8 weeks after undergoing partial meniscectomy or 12 weeks after undergoing DMM. NGF, bradykinin receptors B1 and B2, tachykinin, and tachykinin receptor 1 were significantly regulated in the joints of mice displaying pain-related behavior. Little regulation of inflammatory cytokines, leukocyte activation markers, or chemokines was observed. When tissue samples from articular cartilage, meniscus, and bone were analyzed separately, NGF was consistently regulated in the articular cartilage. The other pain sensitizers were also largely regulated in the articular cartilage, although there were some differences between the 2 models. NGF and tachykinin were strongly regulated by simple mechanical injury of cartilage in vitro in a transforming growth factor beta-activated kinase 1-, fibroblast growth factor 2-, and Src kinase-dependent manner. CONCLUSION: Damaged joint tissues produce proalgesic molecules, including NGF, in murine OA. PMID- 26605538 TI - Schwann Cells Transplantation Improves Locomotor Recovery in Rat Models with Spinal Cord Injury: a Systematic Review and Meta-Analysis. AB - BACKGROUND/AIMS: Schwann cells (SCs) which were demonstrated to be responsible for axonal myelination and ensheathing are widely studied and commonly used for cell transplantation to treat spinal cord injury (SCI). We performed this meta analysis to summarize the effects of SCs versus controls for locomotor recovery in rat models of traumatic SCI. METHODS: Studies of the BBB scores after transplantation of SCs were searched out from Pubmed, Cochrane Library Medline databases and analyzed by Review Manager 5.2.5. RESULTS: Thirteen randomized controlled animal trials were selected with 283 rats enrolled. The studies were divided to different subgroups by different models of SCI, different cell doses for transplantation, different sources of SCs and different transplantation ways. The pooled results of this meta-analysis suggested that SCs transplantation cannot significantly improve the locomotor recovery at a short time after intervention (1 week after transplantation) in both impacted and hemi-sected SCI models. However, at a longer time after intervention (3, 5-7 and over 8 weeks after transplantation), significant improvement of BBB score emerged in SCs groups compared with control groups. Subgroup analyses revealed that SCs transplantation can significantly promote locomotor recovery regardless of in high or low doses of cells, from different sources (isolated from sciatic nerves or differentiated from bone marrow stromal cells(BMSCs)) and with or without scaffolding. CONCLUSION: SCs seem to demonstrate substantial beneficial effects on locomotor recovery in a widely-used animal models of SCI. PMID- 26605539 TI - West Nile Virus Seroprevalence in the Greek Population in 2013: A Nationwide Cross-Sectional Survey. AB - Cases of West Nile Virus (WNV) disease were recorded for three consecutive years in Greece following the year 2010 outbreak. A cross-sectional serologic survey was conducted to estimate the WNV seroprevalence and assess the ratio of infection to neuroinvasive disease. A stratified left-over sampling methodology was used including age and residence strata. A total of 3,962 serum samples was collected and tested for WNV Immunoglobulin G (IgG) antibodies by Enzyme-Linked Immunosorbent Assay (ELISA). All positive samples were further tested by Plaque Reduction Neutralization Test (PRNT) and WNV Immunoglobulin M (IgM) antibodies. WNV IgG antibodies were detected in 82 samples and 61 were also positive in PRNT representing a weighted seroprevalence of 2.1% (95% C.I.: 1.7-2.6) and 1.5% (95% C.I.: 1.2-2.0), respectively. Multivariable analysis showed that seroprevalence was associated with age and residence. The overall ratio of neuroinvasive disease to infected persons was estimated at 1:376 (95% C.I.: 1:421-1:338), while the elderly people had the highest ratio. This nationwide study provided valuable data regarding the epidemiology of WNV in Greece based on the fact that elderly people have higher risk of being both infected and having severe disease. PMID- 26605540 TI - Strengthening Community Networks for Vital Event Reporting: Community-Based Reporting of Vital Events in Rural Mali. AB - BACKGROUND: Like many developing countries, Mali has few sources of mortality data. High quality mortality estimates are available from household surveys, such as the demographic and health surveys (DHS), approximately every five years, making it difficult to track progress in reducing mortality. The Rapid Mortality Monitoring (RMM) project in Mali aimed to address this issue by testing a community-based approach to measuring under-five mortality on a yearly basis. METHODS AND FINDINGS: Seventy-eight community-based workers (relais) were identified in 20 villages comprising approximately 5,300 households. The relais reported pregnancies, births, and under-five deaths from July, 2012 to November, 2013. Data were double-entered, reconciled, cleaned, and analyzed monthly. In November-December 2013, we administered a full pregnancy history (FPH) to women of reproductive age in a census of the households in the project villages. We assessed the completeness of the counts of births and deaths, and the validity of under-five, infant, and neonatal mortality rates from the community-based method against the retrospective FPH for two rolling twelve-month periods. Monthly reporting by relais was high, with reports on pregnancies, births, and deaths consistently provided from all 78 relais catchment areas. Relais reported 1,660 live births and 276 under-five deaths from July, 2012 to November, 2013. The under-five mortality rate calculated from the relais data was similar to that estimated using the validation survey, where the overall ratios of the community based to FPH-based mortality rates for the reporting periods were 100.4 (95% CI: 80.4, 120.5) and 100.8 (95% CI: 79.5, 122.0). CONCLUSIONS: On a small scale, the community-based method in Mali produced estimates of annualized under-five mortality rates that were consistent with those obtained from a FPH. The community-based method should be considered for scale-up in Mali, with appropriate measures to ensure community engagement, data quality, and cross validation with comparable FPHs. PMID- 26605541 TI - Effect of Acetaminophen Alone and in Combination with Morphine and Tramadol on the Minimum Alveolar Concentration of Isoflurane in Rats. AB - BACKGROUND: It has been observed that acetaminophen potentiates the analgesic effect of morphine and tramadol in postoperative pain management. Its capacity as an analgesic drug or in combinations thereof to reduce the minimum alveolar concentration (MAC) of inhalational anesthetics represents an objective measure of this effect during general anesthesia. In this study, the effect of acetaminophen with and without morphine or tramadol was evaluated on the isoflurane MAC. METHODS: Forty-eight male Wistar rats were anesthetized with isoflurane in oxygen. MACISO was determined from alveolar gas samples at the time of tail clamping without the drug, after administering acetaminophen (300 mg/kg), morphine (3 mg/kg), tramadol (10 mg/kg), acetaminophen (300 mg/kg) + morphine (3 mg/kg), and acetaminophen (300 mg/kg) + tramadol (10 mg/kg). RESULTS: The control and acetaminophen groups did not present statistically significant differences (p = 0.98). The values determined for MACISO after treatment with acetaminophen + morphine, acetaminophen + tramadol, morphine, and tramadol were 0.98% +/- 0.04%, 0.99% +/- 0.009%, 0.97% +/- 0.02%, and 0.99% +/- 0.01%, respectively. CONCLUSIONS: The administration of acetaminophen did not reduce the MAC of isoflurane and did not potentiate the reduction in MACISO by morphine and tramadol in rats, and therefore does not present a sparing effect of morphine or tramadol in rats anesthetized with isoflurane. PMID- 26605543 TI - Correction: Integrin alpha5beta1 Function Is Regulated by XGIPC/kermit2 Mediated Endocytosis during Xenopus laevis Gastrulation. PMID- 26605542 TI - Expression Patterns and Potential Biological Roles of Dip2a. AB - Disconnected (disco)-interacting protein 2 homolog A is a member of the DIP2 protein family encoded by Dip2a gene. Dip2a expression pattern has never been systematically studied. Functions of Dip2a in embryonic development and adult are not known. To investigate Dip2a gene expression and function in embryo and adult, a Dip2a-LacZ mouse model was generated by insertion of beta-Gal cDNA after Dip2a promoter using CRISPR/Cas9 technology. Dip2a-LacZ mouse was designed to be a lacZ reporter mouse as well as a Dip2a knockout mouse. Heterozygous mice were used to study endogenous Dip2a expression and homozygotes to study DIP2A-associated structure and function. LacZ staining indicated that Dip2a is broadly expressed in neuronal, reproductive and vascular tissues, as well as in heart, kidney, liver and lung. Results demonstrate that Dip2a is expressed in ectoderm-derived tissues in developing embryos. Adult tissues showed rich staining in neurons, mesenchymal, endothelial, smooth muscle cells and cardiomyocytes by cell types. The expression pattern highly overlaps with FSTL1 and supports previous report that DIP2A to be potential receptor of FSTL1 and its protective roles of cardiomyocytes. Broad and intense embryonic and adult expression of Dip2a has implied their multiple structural and physiological roles. PMID- 26605544 TI - Event Networks and the Identification of Crime Pattern Motifs. AB - In this paper we demonstrate the use of network analysis to characterise patterns of clustering in spatio-temporal events. Such clustering is of both theoretical and practical importance in the study of crime, and forms the basis for a number of preventative strategies. However, existing analytical methods show only that clustering is present in data, while offering little insight into the nature of the patterns present. Here, we show how the classification of pairs of events as close in space and time can be used to define a network, thereby generalising previous approaches. The application of graph-theoretic techniques to these networks can then offer significantly deeper insight into the structure of the data than previously possible. In particular, we focus on the identification of network motifs, which have clear interpretation in terms of spatio-temporal behaviour. Statistical analysis is complicated by the nature of the underlying data, and we provide a method by which appropriate randomised graphs can be generated. Two datasets are used as case studies: maritime piracy at the global scale, and residential burglary in an urban area. In both cases, the same significant 3-vertex motif is found; this result suggests that incidents tend to occur not just in pairs, but in fact in larger groups within a restricted spatio temporal domain. In the 4-vertex case, different motifs are found to be significant in each case, suggesting that this technique is capable of discriminating between clustering patterns at a finer granularity than previously possible. PMID- 26605545 TI - Antepartum Antibiotic Treatment Increases Offspring Susceptibility to Experimental Colitis: A Role of the Gut Microbiota. AB - BACKGROUND AND AIMS: Postnatal maturation of the immune system is largely driven by exposure to microbes, and thus the nature of intestinal colonization may be associated with development of childhood diseases that may persist into adulthood. We investigated whether antepartum antibiotic (ATB) therapy can increase offspring susceptibility to experimental colitis through alteration of the gut microbiota. METHODS: Pregnant C57Bl/6 mice were treated with cefazolin at 160 mg/kg body weight or with saline starting six days before due date. At 7 weeks, fecal samples were collected from male offspring after which they received 4% dextran sulfate sodium (DSS) in drinking water for 5 days. Disease activity index, histology, colonic IL-6, IL-1beta and serum C-reactive protein (CRP) were determined. The V3-V4 region of colonic and fecal bacterial 16S rRNA was sequenced. Alpha-, beta-diversity and differences at the phylum and genus levels were determined, while functional pathways of classified bacteria were predicted. RESULTS: ATB influenced fecal bacterial composition and hence bacterial functional pathways before induction of colitis. After induction of colitis, ATB increased onset of clinical disease, histologic score, and colonic IL-6. In addition, ATB decreased fecal microbial richness, changed fecal and colon microbial composition, which was accompanied by a modification of microbial functional pathways. Also, several taxa were associated with ATB at lower taxonomical levels. CONCLUSIONS: The results support the hypothesis that antepartum antibiotics modulate offspring intestinal bacterial colonization and increase susceptibility to develop colonic inflammation in a murine model of colitis, and may guide future interventions to restore physiologic intestinal colonization in offspring born by antibiotic-exposed mothers. PMID- 26605546 TI - Toxicity Minimized Cryoprotectant Addition and Removal Procedures for Adherent Endothelial Cells. AB - Ice-free cryopreservation, known as vitrification, is an appealing approach for banking of adherent cells and tissues because it prevents dissociation and morphological damage that may result from ice crystal formation. However, current vitrification methods are often limited by the cytotoxicity of the concentrated cryoprotective agent (CPA) solutions that are required to suppress ice formation. Recently, we described a mathematical strategy for identifying minimally toxic CPA equilibration procedures based on the minimization of a toxicity cost function. Here we provide direct experimental support for the feasibility of these methods when applied to adherent endothelial cells. We first developed a concentration- and temperature-dependent toxicity cost function by exposing the cells to a range of glycerol concentrations at 21 degrees C and 37 degrees C, and fitting the resulting viability data to a first order cell death model. This cost function was then numerically minimized in our state constrained optimization routine to determine addition and removal procedures for 17 molal (mol/kg water) glycerol solutions. Using these predicted optimal procedures, we obtained 81% recovery after exposure to vitrification solutions, as well as successful vitrification with the relatively slow cooling and warming rates of 50 degrees C/min and 130 degrees C/min. In comparison, conventional multistep CPA equilibration procedures resulted in much lower cell yields of about 10%. Our results demonstrate the potential for rational design of minimally toxic vitrification procedures and pave the way for extension of our optimization approach to other adherent cell types as well as more complex systems such as tissues and organs. PMID- 26605547 TI - Programmed Cell Death Progresses Differentially in Epidermal and Mesophyll Cells of Lily Petals. AB - In the petals of some species of flowers, programmed cell death (PCD) begins earlier in mesophyll cells than in epidermal cells. However, PCD progression in each cell type has not been characterized in detail. We separately constructed a time course of biochemical signs and expression patterns of PCD-associated genes in epidermal and mesophyll cells in Lilium cv. Yelloween petals. Before visible signs of senescence could be observed, we found signs of PCD, including DNA degradation and decreased protein content in mesophyll cells only. In these cells, the total proteinase activity increased on the day after anthesis. Within 3 days after anthesis, the protein content decreased by 61.8%, and 22.8% of mesophyll cells was lost. A second peak of proteinase activity was observed on day 6, and the number of mesophyll cells decreased again from days 4 to 7. These biochemical and morphological results suggest that PCD progressed in steps during flower life in the mesophyll cells. PCD began in epidermal cells on day 5, in temporal synchrony with the time course of visible senescence. In the mesophyll cells, the KDEL-tailed cysteine proteinase (LoCYP) and S1/P1 nuclease (LoNUC) genes were upregulated before petal wilting, earlier than in epidermal cells. In contrast, relative to that in the mesophyll cells, the expression of the SAG12 cysteine proteinase homolog (LoSAG12) drastically increased in epidermal cells in the final stage of senescence. These results suggest that multiple PCD-associated genes differentially contribute to the time lag of PCD progression between epidermal and mesophyll cells of lily petals. PMID- 26605548 TI - Comparison of Multiparametric MRI Scoring Systems and the Impact on Cancer Detection in Patients Undergoing MR US Fusion Guided Prostate Biopsies. AB - INTRODUCTION: Multiple scoring systems have been proposed for prostate MRI reporting. We sought to review the clinical impact of the new Prostate Imaging Reporting and Data System v2 (PI-RADS) and compare those results to our proposed Simplified Qualitative System (SQS) score with respect to detection of prostate cancers and clinically significant prostate cancers. METHODS: All patients who underwent multiparametric prostate MRI (mpMRI) had their images interpreted using PI-RADS v1 and SQS score. PI-RADS v2 was calculated from prospectively collected data points. Patients with positive mpMRIs were then referred by their urologists for enrollment in an IRB-approved prospective phase III trial of mpMRI-Ultrasound (MR/TRUS) fusion biopsy of suspicious lesions. Standard 12-core biopsy was performed at the same setting. Clinical data were collected prospectively. RESULTS: 1060 patients were imaged using mpMRI at our institution during the study period. 341 participants were then referred to the trial. 312 participants underwent MR/TRUS fusion biopsy of 452 lesions and were included in the analysis. 202 participants had biopsy-proven cancer (64.7%) and 206 (45.6%) lesions were positive for cancer. Distribution of cancer detected at each score produced a Gaussian distribution for SQS while PI-RADS demonstrates a negatively skewed curve with 82.1% of cases being scored as a 4 or 5. Patient-level data demonstrated AUC of 0.702 (95% CI 0.65 to 0.73) for PI-RADS and 0.762 (95% CI 0.72 to 0.81) for SQS (p< 0.0001) with respect to the detection of prostate cancer. The analysis for clinically significant prostate cancer at a per lesion level resulted in an AUC of 0.725 (95% CI 0.69 to 0.76) and 0.829 (95% CI 0.79 to 0.87) for the PI-RADS and SQS score, respectively (p< 0.0001). CONCLUSIONS: mpMRI is a useful tool in the workup of patients at risk for prostate cancer, and serves as a platform to guide further evaluation with MR/TRUS fusion biopsy. SQS score provided a more normal distribution of scores and yielded a higher AUC than PI-RADS v2. However until our findings are validated, we recommend reporting of detailed sequence-specific findings. This will allow for prospectively collected data to be utilized in determining the impact of ongoing changes to these scoring systems as our understanding of mpMRI interpretation evolves. PMID- 26605549 TI - First Steps into the Wild - Exploration Behavior of European Bison after the First Reintroduction in Western Europe. AB - Biodiversity is rapidly declining globally. One strategy to help to conserve species is to breed species in captivity and release them into suitable habitats. The way that reintroduced animals explore new habitats and/or disperse from the release site is rarely studied in detail and represents key information for the success of reintroduction projects. The European bison (Bison bonasus L. 1758) was the largest surviving herbivore of the post-glacial megafauna in Europe before it became extinct in the wild, surviving only in captivity since 1919. We investigated the exploration behavior of a herd of European bison reintroduced into the Rothaargebirge, a commercial forest in low range mountain intensively used and densely populated by humans, in the first six months after release. We focused on three questions: (1) how did the European bison move and utilize the habitat on a daily basis, (2) how did the animals explore the new environment, and (3) did their habitat preferences change over time. The European bison dispersed away from their previous enclosure at an average rate of 539 m/month, with their areas of daily use ranging from 70 to 173 ha, their movement ranging from 3.6 km to 5.2 km per day, and their day-to-day use of areas ranged between 389 and 900 m. We could identify three major exploration bouts, when the animals entered and explored areas previously unknown to them. During the birthing phase, the European bison reduced daily walking distances, and the adult bull segregated from the herd for 58 days. Around rut, roaming behavior of the herd increased slightly. The animals preferred spruce forest, wind thrown areas and grassland, all of which are food abundant habitat types, and they avoided beech forest. Habitat preference differed slightly between phases of the study period, probably due to phenological cycles. After six months, the complete summer home range was 42.5 km2. Our study shows that a small free-ranging herd of European bison can live in an area intensively used by humans and describes in detail the initial roaming behavior and habitat utilization of the animals. PMID- 26605550 TI - Cannabis Liberalization and Adolescent Cannabis Use: A Cross-National Study in 38 Countries. AB - AIMS: To assess the associations between types of cannabis control policies at country level and prevalence of adolescent cannabis use. SETTING, PARTICIPANTS AND DESIGN: Multilevel logistic regressions were performed on 172,894 adolescents 15 year of age who participated in the 2001/2002, 2005/2006, or 2009/2010 cross sectional Health Behaviour in School-Aged Children (HBSC) survey in 38 European and North American countries. MEASURES: Self-reported cannabis use status was classified into ever use in life time, use in past year, and regular use. Country level cannabis control policies were categorized into a dichotomous measure (whether or not liberalized) as well as 4 detailed types (full prohibition, depenalization, decriminalization, and partial prohibition). Control variables included individual-level sociodemographic characteristics and country-level economic characteristics. FINDINGS: Considerable intra-class correlations (.15 .19) were found at country level. With respect to the dichotomized cannabis control policy, adolescents were more likely to ever use cannabis (odds ratio (OR) = 1.10, p = .001), use in past year (OR = 1.09, p = .007), and use regularly (OR = 1.26, p = .004). Although boys were substantially more likely to use cannabis, the correlation between cannabis liberalization and cannabis use was smaller in boys than in girls. With respect to detailed types of policies, depenalization was associated with higher odds of past-year use (OR = 1.14, p = .013) and regular use (OR = 1.23, p = .038), and partial prohibition was associated with higher odds of regular use (OR = 2.39, p = .016). The correlation between cannabis liberalization and regular use was only significant after the policy had been introduced for more than 5 years. CONCLUSIONS: Cannabis liberalization with depenalization and partial prohibition policies was associated with higher levels of regular cannabis use among adolescents. The correlations were heterogeneous between genders and between short- and long terms. PMID- 26605552 TI - Modeling Solvent Broadening on the Vibronic Spectra of a Series of Coumarin Dyes. From Implicit to Explicit Solvent Models. AB - We present a protocol to estimate the solvent-induced broadening of electronic spectra based on a model that explicitly takes into account the environment embedding the solute. Starting from a classical approximation of the solvent contribution to the spectrum, the broadening arises from the spread of the excitation energies due to the fluctuation of the solvent coordinates, and it is represented as a Gaussian line shape that convolutes the vibronic spectrum of the solute. The latter is computed in harmonic approximation at room temperature with a time-dependent approach. The proposed protocol for the computation of spectral broadening exploits molecular dynamics (MD) simulations performed on the solute solvent system, keeping the solute degrees of freedom frozen, followed by the computation of the excitation properties with a quantum mechanics/molecular mechanics (QM/MM) approach. The factors that might influence each step of the protocol are analyzed in detail, including the selection of the empirical force field (FF) adopted in the MD simulations and the QM/MM partition of the system to compute the excitation energies. The procedure is applied to a family of coumarin dyes, and the results are compared with experiments and with the predictions of a very recent work (Cerezo et al., Phys. Chem. Chem. Phys. 2015, 17, 11401-11411), where an implicit model was adopted for the solvent. The final spectra of the considered coumarins were obtained without including ad hoc phenomenological parameters and indicate that the broadenings computed with explicit and implicit models both follow the experimental trend, increasing as the polarity change from the initial to the final state increases. More in detail, the implicit model provides larger estimations of the broadening that are closer to the experimental evidence, while explicit models appear to better capture relative differences arising from different solvents or different solutes. Possible inaccuracies of the adopted FF that may lead to the observed underestimation are analyzed in detail. PMID- 26605553 TI - Early-Lanthanide(III) Acetonitrile-Solvento Adducts with Iodide and Noncoordinating Anions. AB - Dissolution of LnI3 (Ln = La, Ce) in acetonitrile (MeCN) results in the highly soluble solvates LnI3(MeCN)5 [Ln = La (1), Ce (2)] in good yield. The ionic complex [La(MeCN)9][LaI6] (4), containing a rare homoleptic La(3+) cation and anion, was also isolated as a minor product. Extending this chemistry to NdI3 results in the consistent formation of the complex ionic structure [Nd(MeCN)9]2[NdI5(MeCN)][NdI6][I] (3), which contains an unprecedented pentaiodide lanthanoid anion. Also described is the synthesis, isolation, and structural characterization of several homoleptic early-lanthanide MeCN solvates with noncoordinating anions, namely, [Ln(MeCN)9][AlCl4]3 [Ln = La (5), Ce (6), Nd (7)]. Notably, complex 6 is the first homoleptic cerium MeCN solvate reported to date. All reported complexes were structurally characterized by X-ray crystallography, as well as by IR spectroscopy and CHN elemental analysis. Complexes 1-3 were also characterized by thermogravimetric analysis coupled with mass spectrometry to further elucidate their bulk composition in the solid-state. PMID- 26605551 TI - Long-Acting Beta Agonists Enhance Allergic Airway Disease. AB - Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (beta2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related beta2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related beta2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6. PMID- 26605554 TI - Direct Amidation of N-Boc- and N-Cbz-Protected Amines via Rhodium-Catalyzed Coupling of Arylboroxines and Carbamates. AB - N-Boc- and N-Cbz-protected amines are directly converted into amides by a novel rhodium-catalyzed coupling of arylboroxines and carbamates, replacing the traditional two-step deprotection-condensation sequence. Both protected anilines and aliphatic amines are efficiently transformed into a wide variety of secondary benzamides, including sterically hindered and electron-deficient amides, as well as in the presence of acid-labile and reducible functional groups. PMID- 26605555 TI - Cell therapy for bone nonunion: a retrospective study. AB - AIM: The aim of this study was to report our experience in augmenting nonunion both with bone marrow mononuclear cells/mesenchymal stem cells (MSCs) and conventional surgical approaches; and for clinical applications, a simple, safe, and reproducible method to effectively treat bone mass loss disease. METHODS: A retrospective analysis was performed on stem cell-treated bone nonunion patients from October 1, 2007 to October 1, 2009. Nine patients were categorized into two groups: group 1 consists of 3 patients who received autologous bone marrow mononuclear cells transplantation; group 2 consists of 6 patients who received umbilical cord MSCs (hUC-MSCs) transplantation. All patients accepted conventional surgical treatment and X-ray supervised at 3, 6, and 12 months or so after transplantation, while T cells' subtype was analyzed. RESULTS: All patients were followed up for 36 months through recheck Out-patient Department and X-ray examination to observe the fracture healing. The mean time for clinical healing was comparable in both groups. The mean time of fracture lines blurred partly, continuous bone callus formation, marrow flow was 3.5M, 6.2M, and 9.1M, respectively, in the human umbilical cord mesenchymal stem cells (hUC-MSCs) treatment group. The compared healing times were 3.8 M, 7.1M and 10.6 months in autologous bone marrow mononuclear cells transplantation, respectively. The serum levels of CD4, CD56, and HLA-DR in hUC-MSCs graft group were negative, while the serum level of CD8 was 7.8% positive. Clearly, there was no significant difference in the percent of T subsets between the 2 groups of T cells' subtype. CONCLUSION: Our study showed that patients treated by allograft-augmentation had no complications, reduced treatment- dissatisfaction. The use of hUC-MSCs should be offered to suitable patients in the preoperative consultation as a valuable alternative for autologous grafting and larger clinical trials should be considered in the future. PMID- 26605556 TI - Lung cancer screening and management. AB - Deaths from lung cancer are greater than for any other type of malignancy. Many people present with advanced stage cancer at diagnosis and survival is limited. Low radiation dose CT (LDCT) screening appears to offer part of the solution to this. The US National Lung Screening Trial (NLST) showed a 20% reduction in cancer related mortality and a 6.7% reduction in all cause mortality in patients who had LDCT compared to chest X-ray. Lung Cancer screening is now being implemented in the US using the NLST screening criteria but many questions remain about the details of the methodology of screening and its cost effectiveness. Many of these questions are being answered by ongoing European trials that are reporting their findings. In this review we objectively analyse current research evidence and explore the issues that need to be resolved before implementation, including technical considerations, selection criteria and effective nodule management protocols. We discuss the potential barriers that will be faced when beginning a national screening programme and possible solutions to them. PMID- 26605557 TI - Electrum, the Gold-Silver Alloy, from the Bulk Scale to the Nanoscale: Synthesis, Properties, and Segregation Rules. AB - The alloy Au-Ag system is an important noble bimetallic phase, both historically (as "Electrum") and now especially in nanotechnology, as it is applied in catalysis and nanomedicine. To comprehend the structural characteristics and the thermodynamic stability of this alloy, a knowledge of its phase diagram is required that considers explicitly its size and shape (morphology) dependence. However, as the experimental determination remains quite challenging at the nanoscale, theoretical guidance can provide significant advantages. Using a regular solution model within a nanothermodynamic approach to evaluate the size effect on all the parameters (melting temperature, melting enthalpy, and interaction parameters in both phases), the nanophase diagram is predicted. Besides an overall shift downward, there is a "tilting" effect on the solidus liquidus curves for some particular shapes exposing the (100) and (110) facets (cube, rhombic dodecahedron, and cuboctahedron). The segregation calculation reveals the preferential presence of silver at the surface for all the polyhedral shapes considered, in excellent agreement with the latest transmission electron microscopy observations and energy dispersive spectroscopy analysis. By reviewing the nature of the surface segregated element of different bimetallic nanoalloys, two surface segregation rules, based on the melting temperatures and surface energies, are deduced. Finally, the optical properties of Au-Ag nanoparticles, calculated within the discrete dipole approximation, show the control that can be achieved in the tuning of the local surface plasmon resonance, depending of the alloy content, the chemical ordering, the morphology, the size of the nanoparticle, and the nature of the surrounding environment. PMID- 26605558 TI - The Canadian Incidence Study of Reported Child Abuse and Neglect: a partnership. AB - In the mid-1990s, Health Canada's Family Violence Prevention Unit commissioned a study to assess the possibility of collecting child maltreatment data from child welfare agencies across Canada. A Health Canada group responsible for maternal and child health surveillance built on the results of this study. This group consulted widely with provincial and territorial partners to build a surveillance system, resulting in a truly collaborative effort that led to the implementation of the Canadian Incidence Study of Reported Child Abuse and Neglect (CIS). This was a remarkable accomplishment considering the challenge of working with multiple partners, different legislative frameworks and the stigma that often accompanies the experience of child maltreatment. PMID- 26605559 TI - A review of recent analyses of the Canadian Incidence Study of Reported Child Abuse and Neglect (CIS). AB - INTRODUCTION: The objective of this analysis is to identify, assess the quality and summarize the findings of peer-reviewed articles that used data from the Canadian Incidence Study of Reported Child Abuse and Neglect (CIS) published since November 2011 and data from provincial oversamples of the CIS as well as to illustrate evolving uses of these datasets. METHODS: Articles were identified from the Public Health Agency of Canada's data request records tracking access to CIS data and publications produced from that data. At least two raters independently reviewed and appraised the quality of each article. RESULTS: A total of 32 articles were included. Common strengths of articles included clearly stated research aims, appropriate control variables and analyses, sufficient sample sizes, appropriate conclusions and relevance to practice or policy. Common problem areas of articles included unclear definitions for variables and inclusion criteria of cases. Articles frequently measured the associations between maltreatment, child, caregiver, household and agency/referral characteristics and investigative outcomes such as opening cases for ongoing services and placement. CONCLUSION: Articles using CIS data were rated positively on most quality indicators. Researchers have recently focussed on inadequately studied categories of maltreatment (exposure to intimate partner violence [IPV]), neglect and emotional maltreatment) and examined factors specific to First Nations children. Data from the CIS oversamples have been underutilized. The use of multivariate analysis techniques has increased. PMID- 26605560 TI - Correlates of joint child protection and police child sexual abuse investigations: results from the Canadian Incidence Study of Reported Child Abuse and Neglect-2008. AB - INTRODUCTION: Our study examines the frequency of joint investigations by child protection workers and the police in sexual abuse investigations compared to other maltreatment types and the association of child-, caregiver-, maltreatment- and investigation-related characteristics in joint investigations, focussing specifically on investigations involving sexual abuse. METHODS: We analyzed data from the Canadian Incidence Study of Reported Child Abuse and Neglect-2008 using logistic regression. RESULTS: The data suggest that sexual abuse (55%), and then physical abuse, neglect and emotional maltreatment, are most often co investigated. Substantiation of maltreatment, severity of maltreatment, placement in out-of-home care, child welfare court involvement and referral of a family member to specialized services was more likely when the police were involved in an investigation. CONCLUSION: This study adds to the limited information on correlates of joint child protection agency and police investigations. Further research is needed to determine the effectiveness of these joint investigations. PMID- 26605561 TI - Child maltreatment surveillance: enumeration, monitoring, evaluation and insight. AB - Application of epidemiologic surveillance to child abuse and neglect (CAN) presents specific challenges related to varying definitions and incident reporting. Definitions of abuse and neglect differ within and across countries, obscuring estimates of the true magnitude of the problem. Definitions also vary depending on the nature of the child protection system. Countries may lack legal or social systems with specific responsibility for responding to and recording reports of CAN, particularly countries where populations are remote or in flux (e.g. due to conflict). Underreporting of CAN results in underestimates of prevalence. Violence by caregivers toward children is often known only to the perpetrator, and depending on the developmental capacity of the child, the victim. Further, CAN cases may be reported to a wide variety of sentinels (e.g. educators, clergy, physicians, law enforcement, child welfare), or may not be reported to any official source at all. Social stigma and unintended consequences of reporting, as well as cultural and political barriers, also impact reporting both within communities and globally. PMID- 26605562 TI - The Nurse-Family Partnership: evidence-based public health in response to child maltreatment. AB - Too many Canadian children are exposed to child maltreatment-neglect, emotional maltreatment, exposure to intimate partner violence, and physical and sexual abuse. Retrospective data indicates that 32% of Canadian adults have experienced childhood abuse. There is evidence that child maltreatment is associated with a wide array of negative health consequences across the life span. These consequences expand across physical, mental, developmental and social domains to include suicide, substance abuse, anxiety, depression and physical health problems. Experts have asked for coordinated national leadership in protecting children from maltreatment. They also envision broadening the mandate for injury prevention to include not only physical injury but also emotional injury and harm. PMID- 26605563 TI - Vulnerability within families headed by teen and young adult mothers investigated by child welfare services in Canada. AB - INTRODUCTION: Young mothers' families are at increased risk of child maltreatment and other poor health and social outcomes. METHODS: Chi-square analyses of pooled child welfare services data from the Canadian Incidence Study of Reported Child Abuse and Neglect (CIS-2003; CIS-2008) were used to compare 284 teen mothers (18 years or younger) and 800 young mothers (19-21 years) and their families with 5752 families where the mother was 22 years or older. RESULTS: Twenty-six percent of young mothers were 18 years or younger. Most (68% of teen-mother families and 57% of families with a young adult mother) received social assistance as their main source of income compared with 36% of families with a mother aged 22 years or older. Teen and young adult mothers were more likely than those aged 22 or older to have childhood histories of out-of-home care (31% and 23% vs. 10%) and were more likely to have risk factors such as alcohol abuse (25% and 23% vs. 18%) and few social supports (46% and 41% vs. 37%). Secondary caregivers in families with young mothers also had more risk factors. Teen and young adult mother families were more likely to have their child placed out-of-home during the investigation (29% and 27% vs. 17%). All were equally likely to be victims of domestic violence and to have mental health issues. CONCLUSION: Within this sample of high-risk families, young mothers' families were more at risk than comparison families. Mothers' youth may be a useful criterion to identify families for targeted interventions. PMID- 26605564 TI - Adapting, piloting and evaluating complex public health interventions: lessons learned from the Nurse-Family Partnership in Canadian public health settings. AB - INTRODUCTION: The Nurse-Family Partnership (NFP) is a home-visit program for young and first-time, socially and economically disadvantaged mothers. Evidence from three United States randomized controlled trials (RCTs) on the effectiveness of this intervention at improving pregnancy outcomes, improving child health and development, and increasing maternal economic self-sufficiency is robust. However, the effectiveness of the NFP in Canada, with its different health and social care context, needs to be determined. The purpose of this article is to describe the complex process for moving the NFP from the research arena to full implementation in Canada. METHODS: This process of evaluation in Canada includes (1) adapting the intervention; (2) piloting the intervention in small-scale feasibility and acceptability studies; and (3) conducting an RCT and process evaluation through a study called the British Columbia Healthy Connections Project (BCHCP). This large-scale evaluation also creates an opportunity to expand the NFP evidence base by conducting an additional study to examine potential biological mechanisms linking intervention and behavioural outcomes in children. RESULTS: Adaptation of the NFP home-visit materials is a continuous process. A pilot project determined that it was feasible to enrol eligible women into the NFP. This pilot also determined that, in Canada, it was most appropriate for public health agencies to implement the NFP and for public health nurses to deliver the intervention. Finally, the pilot showed that this intensive home visit program was acceptable to clients, their family members and health care providers. Through the BCHCP, the next steps - the RCT and process evaluation - are currently underway. The BCHCP will also set the foundation for long-term evaluation of key public health outcomes in a highly vulnerable population of families. PMID- 26605565 TI - Health care and social service professionals' perceptions of a home-visit program for young, first-time mothers. AB - INTRODUCTION: Little is known about health care and social service professionals' perspective on the acceptability of long-term home-visit programs serving low income, first-time mothers. This study describes the experiences and perspectives of these community care providers involved with program referrals or service delivery to mothers who participated in the Nurse-Family Partnership (NFP), a targeted nurse home-visit program. METHODS: The study included two phases. Phase I was a secondary qualitative data analysis used to analyze a purposeful sample of 24 individual interviews of community care providers. This was part of a larger case study examining adaptations required to increase acceptability of the NFP in Hamilton, Ontario, Canada. In Phase II (n = 4), themes identified from Phase I were further explored through individual, semi-structured interviews with community health care and social service providers, giving qualitative description. RESULTS: Overall, the NFP was viewed as addressing an important service gap for first-time mothers. Providers suggested that frequent communication between the NFP and community agencies serving these mothers could help improve the referral process, avoid service duplication, and streamline the flow of service access. The findings can help determine key components required to enhance the success of integrating a home-visit program into an existing network of community services. CONCLUSION: The function of home-visit programs should not be viewed in isolation. Rather, their potential can be maximized when they collaborate and share information with other agencies to provide better services for first-time mothers. PMID- 26605567 TI - Improved Statistical Sampling and Accuracy with Accelerated Molecular Dynamics on Rotatable Torsions. AB - In enhanced sampling techniques, the precision of the reweighted ensemble properties is often decreased due to large variation in statistical weights and reduction in the effective sampling size. To abate this reweighting problem, here, we propose a general accelerated molecular dynamics (aMD) approach in which only the rotatable dihedrals are subjected to aMD (RaMD), unlike the typical implementation wherein all dihedrals are boosted (all-aMD). Nonrotatable and improper dihedrals are marginally important to conformational changes or the different rotameric states. Not accelerating them avoids the sharp increases in the potential energies due to small deviations from their minimum energy conformations and leads to improvement in the precision of RaMD. We present benchmark studies on two model dipeptides, Ace-Ala-Nme and Ace-Trp-Nme, simulated with normal MD, all-aMD, and RaMD. We carry out a systematic comparison between the performances of both forms of aMD using a theory that allows quantitative estimation of the effective number of sampled points and the associated uncertainty. Our results indicate that, for the same level of acceleration and simulation length, as used in all-aMD, RaMD results in significantly less loss in the effective sample size and, hence, increased accuracy in the sampling of phi psi space. RaMD yields an accuracy comparable to that of all-aMD, from simulation lengths 5 to 1000 times shorter, depending on the peptide and the acceleration level. Such improvement in speed and accuracy over all-aMD is highly remarkable, suggesting RaMD as a promising method for sampling larger biomolecules. PMID- 26605566 TI - Adapting and retesting evidence-based child maltreatment prevention programs: a case study in Canada. AB - This special issue of Health Promotion and Chronic Disease Prevention in Canada is timely, as child maltreatment is a significant public health problem; globally, the number affected is at least in the hundreds of millions. One quarter of adults report having been physically abused and over one-third emotionally abused as children; one in 5 women and one in 13 men report having been sexually abused. Recent national surveys of violence against children conducted in Africa and in other low- and middle-income countries reveal rates of childhood physical, sexual and emotional abuse even higher than the global rates. PMID- 26605568 TI - Excited States of Butadiene to Chemical Accuracy: Reconciling Theory and Experiment. PMID- 26605569 TI - Effects of Molecular Dynamics Thermostats on Descriptions of Chemical Nonequilibrium. AB - The performance of popular molecular dynamics (MD) thermostat algorithms in constant temperature simulations of equilibrium systems is well-known. This is not the case, however, in the context of nonequilibrium chemical systems, such as chemical reactions or nanoscale self-assembly processes. In this work, we investigate the effect of popular thermostat algorithms on the "natural" (i.e., Hamiltonian) dynamics of a nonequilibrium, chemically reacting system. By comparing constant-temperature quantum mechanical MD (QM/MD) simulations of carbon vapor condensation using velocity scaling, Berendsen, Andersen, Langevin, and Nose-Hoover chain thermostat algorithms with natural NVE simulations, we show that efficient temperature control and reliable reaction dynamics are mutually exclusive in such a system. This problem may be circumvented, however, by placing the reactive system in an inert He atmosphere, which is itself described using NVT MD. We demonstrate that both realistic temperature control and dynamics consistent with natural NVE dynamics can then be obtained simultaneously. In essence, the thermal energy created by the natural dynamics of the NVE subsystem is drained by the thermostat acting on the NVT atmosphere, without adversely affecting the dynamics of the reactive system itself. PMID- 26605570 TI - Bridging Static and Dynamical Descriptions of Chemical Reactions: An ab Initio Study of CO2 Interacting with Water Molecules. AB - Extracting reliable thermochemical parameters from molecular dynamics simulations of chemical reactions, although based on ab initio methods, is generally hampered by difficulties in reproducing the results and controlling the statistical errors. This is a serious drawback with respect to the quantum-chemical description based on potential energy surfaces. This work is an attempt to fill this gap. We apply molecular dynamics, based on density functional theory (DFT) and empowered by path metadynamics (MTD), to simulate the reaction of CO2 with (one, two, and three) water molecules in the gas phase. This study relies on a strategy that ensures a precise control of the accuracy of the reaction coordinates and of the reconstructed free-energy surface on this space, namely, on (i) fully reversible MTD simulations, (ii) a committor probability analysis for the diagnosis of the collective variables, and (iii) a cluster analysis for the characterization of the reconstructed free-energy surfaces. This robust procedure permits a meaningful comparison with more traditional calculations of the potential energy surfaces that we also perform within the same DFT computational scheme. This comparison shows in particular that the reactants and products of systems with only three water molecules can no longer be understood in terms of one structure but must be described as statistical configuration ensembles. Calculations carried out with different prescriptions for the exchange correlation functionals also allow us to establish their quantitative effect on the activation barriers for the formation and the dissociation of carbonic acid. Their decrease induced by the addition of one water molecule (catalytic effect) is found to be largely independent of the specific functional. PMID- 26605571 TI - Local Sampling in Steered Monte Carlo Simulations Decreases Dissipation and Enhances Free Energy Estimates via Nonequilibrium Work Theorems. AB - Configurational freezing (J. Chem. Theory Comput.2011, 7, 582) is a method devised for steered Monte Carlo simulations aimed at improving free energy estimates via nonequilibrium work theorems (see Jarzynski in Phys. Rev. Lett.1997, 78, 2690 and Crooks in J. Stat. Phys.1998, 90, 1481). The basic idea is to limit the sampling to particles located in the region of space where dissipation occurs, while leaving the other particles fixed. Therefore, the method is based on the reasonable assumption that dissipation is a local phenomenon in single-molecule nonequilibrium processes, a statement which holds for many processes including, for example, folding of biopolymers and protein ligand binding/unbinding. In this article, the configurational freezing approach, based on the sampling of particles located around hot-spot sites encompassing the high dissipation domain, is supplemented by the possibility of selecting such particles (for trial Monte Carlo moves) dependent on their distance from the hot spots. This is accomplished by exploiting an extension of the Owicki's preferential sampling (J. Am. Chem. Soc.1977, 99, 7413) in the original configurational freezing machinery. The combined strategy is shown to improve the accuracy of free energy estimates in physically sound cases: the calculation of the water to methane relative hydration free energy and the calculation of the potentials of mean force of two solvated methane molecules and two solvated benzene molecules along the direction connecting the centers of mass. PMID- 26605572 TI - Choice of Optimal Shift Parameter for the Intruder State Removal Techniques in Multireference Perturbation Theory. AB - An extensive critical evaluation of intruder state removal techniques (aka shift techniques) applicable to multireference perturbation theory (MRPT) shows that the magnitude of the shift parameter sigma does not influence the spectroscopic parameters of diatomics to a significant degree, provided that the shift is chosen to be sufficiently large. In such case, typical variation of spectroscopic parameters over a wide range of shift parameters is smaller than 0.005 A for equilibrium distances, 30 cm(-1) for harmonic vibrational frequencies, and 0.1 eV for dissociation energies. It is found that large values of sigma not only remove intruder states but they also bring the MRPT energies and properties closer to experimental values. The presented analysis allows us to determine optimal values of the shift parameters to be used in conjunction with various versions of MRPT; these values are recommended to replace the ad hoc values of sigma suggested in MRPT manuals in calculations for diatomics. Transferability of the optimal shift parameters to larger molecular systems and to other basis sets than aug-cc-pVTZ is anticipated but remains to be formally established. PMID- 26605573 TI - Error-Balanced Segmented Contracted Basis Sets of Double-zeta to Quadruple-zeta Valence Quality for the Lanthanides. AB - For lanthanides, segmented contracted Gaussian basis sets of double-zeta valence to quadruple-zeta valence quality are presented, with two different polarization sets for each level of quality. The bases are designed for use in connection with small-core Wood-Boring effective core potentials. A set of compounds representing most lanthanides in their common oxidation states is used to assess the quality. Parameters investigated were atomization energies, dipole moments, and structure parameters for Hartree-Fock, density functional, and correlated (Moller-Plesset) methods. So, the "def2" basis set series is extended to lanthanides with errors that are very similar to those previously obtained for the other elements with this type of basis set. Furthermore, for lanthanides, auxiliary bases for density fitting of Coulomb and Hartree-Fock exchange matrices are presented and tested. PMID- 26605574 TI - Dynamic Electron Correlation Effects on the Ground State Potential Energy Surface of a Retinal Chromophore Model. AB - The ground state potential energy surface of the retinal chromophore of visual pigments (e.g., bovine rhodopsin) features a low-lying conical intersection surrounded by regions with variable charge-transfer and diradical electronic structures. This implies that dynamic electron correlation may have a large effect on the shape of the force fields driving its reactivity. To investigate this effect, we focus on mapping the potential energy for three paths located along the ground state CASSCF potential energy surface of the penta-2,4 dieniminium cation taken as a minimal model of the retinal chromophore. The first path spans the bond length alternation coordinate and intercepts a conical intersection point. The other two are minimum energy paths along two distinct but kinetically competitive thermal isomerization coordinates. We show that the effect of introducing the missing dynamic electron correlation variationally (with MRCISD) and perturbatively (with the CASPT2, NEVPT2, and XMCQDPT2 methods) leads, invariably, to a stabilization of the regions with charge transfer character and to a significant reshaping of the reference CASSCF potential energy surface and suggesting a change in the dominating isomerization mechanism. The possible impact of such a correction on the photoisomerization of the retinal chromophore is discussed. PMID- 26605575 TI - Symmetric Nonlocal Weighted Density Approximations from the Exchange-Correlation Hole of the Uniform Electron Gas. AB - Nonlocal exchange-correlation energy functionals are constructed using the accurate model exchange-correlation hole for the uniform electron gas developed by Gori-Giorgi and Perdew. The exchange-correlation hole is constrained to be symmetric and normalized, so the resulting functionals can be viewed as symmetrized versions of the weighted density approximation; we call them two point weighted density approximations. Even without optimization of parameters or functional forms, the exchange-correlation energies for small molecules are competitive with those of the best generalized gradient approximation functionals. Two-point weighted density approximations seem to be an interesting new direction for functional development. A more general version of the conditions that define the energy for fractional electron number and fractional spin are presented. These "generalized flat-planes" conditions are closely linked to the normalization of the spin-resolved exchange-correlation hole at noninteger electron number. This and many other properties of the exact exchange-correlation functional can be imposed straightforwardly and directly in symmetrized weighted density approximation. PMID- 26605576 TI - Computing the Density Matrix in Electronic Structure Theory on Graphics Processing Units. AB - The self-consistent solution of a Schrodinger-like equation for the density matrix is a critical and computationally demanding step in quantum-based models of interatomic bonding. This step was tackled historically via the diagonalization of the Hamiltonian. We have investigated the performance and accuracy of the second-order spectral projection (SP2) algorithm for the computation of the density matrix via a recursive expansion of the Fermi operator in a series of generalized matrix-matrix multiplications. We demonstrate that owing to its simplicity, the SP2 algorithm [Niklasson, A. M. N. Phys. Rev. B2002, 66, 155115] is exceptionally well suited to implementation on graphics processing units (GPUs). The performance in double and single precision arithmetic of a hybrid GPU/central processing unit (CPU) and full GPU implementation of the SP2 algorithm exceed those of a CPU-only implementation of the SP2 algorithm and traditional matrix diagonalization when the dimensions of the matrices exceed about 2000 * 2000. Padding schemes for arrays allocated in the GPU memory that optimize the performance of the CUBLAS implementations of the level 3 BLAS DGEMM and SGEMM subroutines for generalized matrix-matrix multiplications are described in detail. The analysis of the relative performance of the hybrid CPU/GPU and full GPU implementations indicate that the transfer of arrays between the GPU and CPU constitutes only a small fraction of the total computation time. The errors measured in the self-consistent density matrices computed using the SP2 algorithm are generally smaller than those measured in matrices computed via diagonalization. Furthermore, the errors in the density matrices computed using the SP2 algorithm do not exhibit any dependence of system size, whereas the errors increase linearly with the number of orbitals when diagonalization is employed. PMID- 26605577 TI - Comparative Study of Single and Double Hybrid Density Functionals for the Prediction of 3d Transition Metal Thermochemistry. AB - The performance of 13 density functionals, including hybrid-GGA, hybrid-meta-GGA, and double-hybrid functionals, in combination with the correlation consistent basis sets, has been evaluated for the prediction of gas phase enthalpies of formation for a large set of 3d transition-metal-containing molecules with versatile bonding features. Of the methods studied, the hybrid B97-1 functional and the double hybrid functional mPW2-PLYP exhibit the best overall performance with mean absolute deviations (MAD) from experimental data of 7.2 and 7.3 kcal mol(-1), respectively. For single reference molecules, where dynamic correlation predominates, the results of the hybrid functionals B97-1, B98, and omegaB97X and the double hybrid functionals B2-PLYP, B2GP-PLYP, and mPW2-PLYP yield the smallest deviations from the experimental enthalpies of formation. For the prediction of thermodynamic properties of coordination complexes including metal carbonyls, B97-1 and mPW2-PLYP are the most promising functionals of those investigated. When the size of the molecule is considered, B97-1 and B98 outperform mPW2-PLYP for diatomics and triatomics, while mPW2-PLYP yields the lowest MAD for larger molecules. PMID- 26605578 TI - How Evenly Can Approximate Density Functionals Treat the Different Multiplicities and Ionization States of 4d Transition Metal Atoms? AB - The ability of density functional theory to predict the relative energies of different spin states, especially for systems containing transition metal atoms, is of great importance for many applications. Here, in order to sort out the key factors determining accuracy, we compare the predictions of 60 density functional approximations of 10 different types [local spin density approximation, generalized gradient approximation (GGA), nonseparable gradient approximation (NGA), global-hybrid GGA, range-separated hybrid GGA, range-separated hybrid GGA plus molecular mechanics, meta-GGA, meta-NGA, global-hybrid meta-GGA, and range separated hybrid meta-GGA] for their ability to represent the spin-flip transitions of all 4d transition metal atoms of groups 3-10 (Y through Pd) and their singly positive cations. We consider all 16 excitation energies connecting the ground states (of the neutral atoms and the cations) to their first excited states of different multiplicities, and we also consider all eight ionization potentials. We also test the Hartree-Fock method. All density functional and Hartree-Fock calculations are converged to a stable solution, in which the spatial symmetry is allowed to be completely broken to achieve the lowest possible energy solution. By analyzing the fractional subshell occupancies and spin contaminations, we are able to sort out the effects of s orbital vs d orbital bias and high-spin vs low-spin bias. A reliable functional should have little or no bias of either type rather than succeeding for a limited subset of cases by cancellation of errors. We find that the widely used correlations of spin splittings to percentage of Hartree-Fock exchange are not borne out by the data, and the correlation functionals also play a significant role. We eventually conclude that SOGGA11-X, B1LYP, B3V5LYP, and MPW3LYP are the most consistently reliable functionals for balanced treatments of 4d transition metal atoms and their cations. PMID- 26605579 TI - A Strategy to Determine Appropriate Active Orbitals and Accurate Magnetic Couplings in Organic Magnetic Systems. AB - This work addresses the following paradox observed in diradicalar conjugated hydrocarbons: while the natural orbitals occupation numbers clearly indicate only two open-shell orbitals, i.e. two unpaired electrons, the minimal CAS zero-order description fails to reproduce accurately the electronic structures of the lowest states (spin density distribution and singlet-triplet energy gap, i.e., magnetic coupling). We will focus on the question of the optimization of both magnetic and nonmagnetic orbitals for the determination of accurate magnetic interactions in organic compounds. It is analytically demonstrated (in the Appendix) and numerically shown from multireference configuration interaction calculations performed on a series of original organic ferro- and antiferromagnetic compounds that, (i) some double excitations must be considered to obtain reliable magnetic orbitals for the calculation of magnetic couplings, (ii) the account of these excitations results in a larger spatial extent of the magnetic orbitals on the surrounding ligands and hence better drives the interaction between several magnetic centers, and (iii) the reliability of the orbitals is a crucial ingredient for the determination of accurate magnetic couplings. A strategy which optimizes the orbitals at a reasonable computational cost is proposed. It relies on a CAS(2,2) zero-order description and provides orbitals of the same quality as the CAS(full valence pi)SCF orbitals. The values of the magnetic couplings computed using the difference dedicated configuration interaction on top of the CAS(2,2) references with the new orbital set are very close to those obtained at the much more computationally demanding CAS(full valence pi)PT2 level of treatment. PMID- 26605581 TI - Linear Response Theory and Electronic Transition Energies for a Fully Polarizable QM/Classical Hamiltonian. AB - A fully polarizable quantum/classical Hamiltonian including SCF (HF or DFT), fluctuating charge, and polarizable continuum regions is introduced and implemented for electronic energies of ground and excited states, using, in the latter case, a linear response formulation. After calibration and validation of the approach, preliminary results are presented for pyrimidine in aqueous solution and for retinal in a rhodopsin mimic. The results are consistent with more tested methodologies and pave the route toward fully consistent yet effective simulations of large systems of technological and/or biological interest in their natural environments. PMID- 26605580 TI - Taming the First-Row Diatomics: A Full Configuration Interaction Quantum Monte Carlo Study. AB - The initiator full configuration interaction quantum Monte Carlo (i-FCIQMC) method has recently been developed as a highly accurate stochastic electronic structure technique. It has been shown to calculate the exact basis-set ground state energy of small molecules, to within modest stochastic error bars, using tractable computational cost. Here, we use this technique to elucidate an often troublesome series of first-row diatomics consisting of Be2, C2, CN, CO, N2, NO, O2, and F2. Using i-FCIQMC, the dissociation energies of these molecules are obtained almost entirely to within chemical accuracy of experimental results. Furthermore, the i-FCIQMC calculations are performed in a relatively black-box manner, without any a priori knowledge or specification of the wave function. The size consistency of i-FCIQMC is also demonstrated with regards to these diatomics at their more multiconfigurational stretched geometries. The clear and simple i FCIQMC wave functions obtained for these systems are then compared and investigated to demonstrate the dynamic identification of the dominant determinants contributing to significant static correlation. The appearance and nature of such determinants is shown to provide insight into both the i-FCIQMC algorithm and the diatomics themselves. PMID- 26605582 TI - New Multithreaded Hybrid CPU/GPU Approach to Hartree-Fock. AB - In this article, a new multithreaded Hartree-Fock CPU/GPU method is presented which utilizes automatically generated code and modern C++ techniques to achieve a significant improvement in memory usage and computer time. In particular, the newly implemented Rys Quadrature and Fock Matrix algorithms, implemented as a stand-alone C++ library, with C and Fortran bindings, provides up to 40% improvement over the traditional Fortran Rys Quadrature. The C++ GPU HF code provides approximately a factor of 17.5 improvement over the corresponding C++ CPU code. PMID- 26605583 TI - Second-Order Moller-Plesset Perturbation Theory in the Condensed Phase: An Efficient and Massively Parallel Gaussian and Plane Waves Approach. AB - A novel algorithm, based on a hybrid Gaussian and plane waves (GPW) approach, is developed for the canonical second-order Moller-Plesset perturbation energy (MP2) of finite and extended systems. The key aspect of the method is that the electron repulsion integrals (ia|lambdasigma) are computed by direct integration between the products of Gaussian basis functions lambdasigma and the electrostatic potential arising from a given occupied-virtual pair density ia. The electrostatic potential is obtained in a plane waves basis set after solving the Poisson equation in Fourier space. In particular, for condensed phase systems, this scheme is highly efficient. Furthermore, our implementation has low memory requirements and displays excellent parallel scalability up to 100 000 processes. In this way, canonical MP2 calculations for condensed phase systems containing hundreds of atoms or more than 5000 basis functions can be performed within minutes, while systems up to 1000 atoms and 10 000 basis functions remain feasible. Solid LiH has been employed as a benchmark to study basis set and system size convergence. Lattice constants and cohesive energies of various molecular crystals have been studied with MP2 and double-hybrid functionals. PMID- 26605584 TI - Reliable Quantum Chemical Prediction of the Localized/Delocalized Character of Organic Mixed-Valence Radical Anions. From Continuum Solvent Models to Direct COSMO-RS. AB - A recently proposed quantum-chemical protocol for the description of the character of organic mixed-valence (MV) compounds, close from both sides to the localized/delocalized borderline, is evaluated and extended for a series of dinitroaryl radical anions 1-6. A combination of global hybrid functionals with exact-exchange admixtures of 35% (BLYP35) or 42% (BMK) with appropriate solvent modeling allows an essentially quantitative treatment of, for example, structural symmetry-breaking in Robin/Day class II systems, thermal electron transfer (ET) barriers, and intervalence charge-transfer (IV-CT) excitation energies, while covering also the delocalized class III cases. Global hybrid functionals with lower exact-exchange admixtures (e.g., B3LYP, M05, or M06) provide a too delocalized description, while functionals with higher exact-exchange admixtures (M05-2X, M06-2X) provide a too localized one. The B2PLYP double hybrid gives reasonable structures but far too small barriers in class II cases. The CAM-B3LYP range hybrid gives somewhat too high ET barriers and IV-CT energies, while the range hybrids omegaB97X and LC-BLYP clearly exhibit too much exact exchange. Continuum solvent models describe the situation well in most aprotic solvents studied. The transition of 1,4-dinitrobenzene anion 1 from a class III behavior in aprotic solvents to a class II behavior in alcohols is not recovered by continuum solvent models. In contrast, it is treated faithfully by the novel direct conductor-like screening model for real solvents (D-COSMO-RS). The D-COSMO RS approach, the TURBOMOLE implementation of which is reported, also describes accurately the increased ET barriers of class II systems 2 and 3 in alcohols as compared to aprotic solvents and can distinguish at least qualitatively between different aprotic solvents with identical or similar dielectric constants. The dominant role of the solvent environment for the ET character of these MV radical anions is emphasized, as in contrast to some previous computational suggestions essentially all of the present systems have delocalized class III character in the gas phase. The present approach allows accurate estimates from the gas phase to aprotic and protic solvent environments, without the need for explicit ab initio molecular dynamics simulations, and without artificial constraints. PMID- 26605585 TI - Accurate Spin-State Energetics of Transition Metal Complexes. 1. CCSD(T), CASPT2, and DFT Study of [M(NCH)6](2+) (M = Fe, Co). PMID- 26605586 TI - Asymptotic Expansion for Electrostatic Embedding Integrals in QM/MM Calculations. AB - In QM/MM studies with large MM regions, the calculation of electrostatic embedding integrals can become a computational bottleneck. To overcome this problem, an asymptotic expansion for nuclear attraction-type integrals is developed. As a result, the long-range interactions between the QM and MM atoms reduce to atom-centered multipole moment-like expansions. The algorithm uses a natural spatial division of the molecular structure. To further improve the computational performance, a cutoff radius for the multipole moment-like expansion is introduced. The new code was validated and benchmarked with deMon2k/CHARMM QM/MM calculations on an RNA polymerase II model with almost 350 000 atoms. It is shown that the computational time for the calculation of the embedding integrals in this system can be reduced below 200 s on a small parallel architecture (eight cores) without a loss of accuracy. PMID- 26605587 TI - Two-Component Relativistic Calculations of Electric-Field Gradients Using Exact Decoupling Methods: Spin-orbit and Picture-Change Effects. PMID- 26605588 TI - The Nature of Transannular Interactions in E4N4 and E8(2+) (E = S, Se). AB - The electronic structures of tetrachalcogen tetranitrides, E4N4, and octachalcogen dications, E8(2+), and the nature of their intramolecular E...E interactions (E = S, Se) was studied with high-level theoretical methods. The results reveal that the singlet ground states of both systems have a surprisingly large correlation contribution which functions to weaken and therefore lengthen the cross-ring E-E bond. The observed correlation effects are primarily static in E4N4, whereas in E8(2+) the dynamic part largely governs the total correlation contribution. The presented description of bonding is the first that gives an all inclusive picture of the origin of cross-ring interactions in E4N4 and E8(2+); not only does it succeed in reproducing all experimental structures but it also offers a solid explanation for the sporadic performance of different computational methods that has been reported in previous studies. Furthermore, the theoretical data demonstrate that E...E bonds in E4N4 and E8(2+) are unique and fundamentally different from, for example, dispersion that plays a major role in weak intermolecular chalcogen...chalcogen contacts. PMID- 26605589 TI - W1X-1 and W1X-2: W1-Quality Accuracy with an Order of Magnitude Reduction in Computational Cost. AB - We have examined a number of approaches for reducing the computational requirements of the W1w and W1-F12 procedures, while maintaining the accuracy. A key finding is that MP2/cc-pCVTZ provides a reliable means for the evaluation of core-correlation effects at a cost that is negligible in the context of W1-type procedures. This greatly reduces the overall computational cost, since calculations for core-correlation represent the most time-consuming steps for both W1w and W1-F12. For the evaluation of valence CCSD(T)/CBS, we find that truncation of the sets of diffuse functions leads to a significant savings in time, with only a minor deterioration in the performance. In order to eliminate the need to carry out CCSD calculations with a quadruple-zeta basis set, we have maintained the approach employed in W1-F12, namely the use of explicitly correlated procedures. Our resulting procedures are termed W1X-1 and W1X-2 (where the X refers to the eXplicitly correlated procedures). Of these, the W1X-1 protocol requires two CCSD-F12b plus two CCSD(T) calculations to obtain the valence CCSD(T)/CBS energy component, as with W1-F12. The W1X-2 procedure, on the other hand, requires only two CCSD(T)-F12b calculations for the evaluation of CCSD(T)/CBS and is therefore less expensive than W1X-1. Indeed, the W1X-2 protocol is an order of magnitude less computationally demanding than W1w and ~80% less costly than W1-F12. Extensive assessment of the W1X-1 and W1X-2 procedures shows that W1X-1 performs well and comparably to W1w and W1-F12 in virtually all cases. The W1X-2 method gives equivalently good results for most thermochemical properties, but the heats of formation of fluorocarbons and complexation energies of hydrogen fluoride clusters represent notable exceptions. PMID- 26605590 TI - Analytical First and Second Derivatives for a Fully Polarizable QM/Classical Hamiltonian. AB - In this work, we present the derivation and implementation of analytical first and second derivatives for a fully polarizable QM/MM/PCM energy functional. First derivatives with respect to both QM- and MM-described nuclear coordinates and electric perturbations are derived and implemented, and some preliminary application is shown. Analytical second derivatives with respect to nuclear and electric perturbations are then derived, and some numerical test is presented both for a solvated system and for a cromophore embedded in a biological matrix. PMID- 26605591 TI - Effects of Heterogeneity in Small pi-Type Dimers: Homogeneous and Mixed Dimers of Diacetylene and Cyanogen. AB - The homo- and heterogeneous dimers of diacetylene (H-C=C-C=C-H) and cyanogen (N=C C=N) were studied using ab initio electronic structure computations to probe the effects of heterogeneity on noncovalent interactions between systems with delocalized pi electron networks. Full geometry optimizations and harmonic vibrational frequencies were performed using the robust coupled-cluster with single and double and perturbative triple excitations (CCSD(T)) method with the triple-zeta plus 2 sets of polarization functions TZ2P(f,d)++ basis set. Seven basic configurations were examined for each dimer (cross, stacked, parallel slipped, parallel-tipped, linear, T-shaped and Y-shaped), but only four stationary points were identified on the potential energy surfaces (PESs) of the homogeneous cyanogen dimer and the mixed diacetylene/cyanogen dimer. Six previously characterized stationary points on the diacetylene dimer PES were re examined with the CCSD(T) method and the TZ2P(f,d)++ basis set for consistency. Second-order Moller-Plesset perturbation theory (MP2) and CCSD(T) complete basis set (CBS) limit interaction energies were estimated using the explicitly correlated MP2-F12 and CCSD(T)-F12 methods in conjunction with the VQZ-F12 basis set. On the cyanogen dimer PES, the C2v T-shaped structure is the only minimum, with an average electronic interaction energy, Eint, of -1.96 kcal mol(-1) at the CCSD(T) CBS limit. The Cs Y-shaped structure (in agreement with previous results) is the global minimum on the diacetylene dimer PES, having a mean CCSD(T) CBS limit Eint of -1.75 kcal mol(-1). Three low-lying minima have been identified on the diacetylene/cyanogen dimer PES, a Cinfinityv linear, a C2v cross, and a Cs parallel-slipped structure with average CCSD(T) CBS limit interaction energies of -2.00, -2.16, and -2.45 kcal mol(-1), respectively. PMID- 26605592 TI - Benchmark Calculations of Noncovalent Interactions of Halogenated Molecules. AB - We present a set of 40 noncovalent complexes of organic halides, halohydrides, and halogen molecules where the halogens participate in a variety of interaction types. The set, named X40, covers electrostatic interactions, London dispersion, hydrogen bonds, halogen bonding, halogen-pi interactions, and stacking of halogenated aromatic molecules. Interaction energies at equilibrium geometries were calculated using a composite CCSD(T)/CBS scheme where the CCSD(T) contribution is calculated using triple-zeta basis sets with diffuse functions on all atoms but hydrogen. For each complex, we also provide 10 points along the dissociation curve calculated at the CCSD(T)/CBS level. We use this accurate reference to assess the accuracy of selected post-HF methods. PMID- 26605593 TI - Exploring the Limits of Density Functional Approximations for Interaction Energies of Molecular Precursors to Organic Electronics. AB - Neutral and charged assemblies of pi-conjugated molecules span the field of organic electronics. Electronic structure computations can provide valuable information regarding the nature of the intermolecular interactions within molecular precursors to organic electronics. Here, we introduce a database of neutral (Pi29n) and radical (Orel26rad) dimer complexes that represent binding energies between organic functional units. The new benchmarks are used to test approximate electronic structure methods. Achieving accurate interaction energies for neutral complexes (Pi29n) is straightforward, so long as dispersion interactions are properly taken into account. However, pi-dimer radical cations (Orel26rad) are examples of highly challenging situations for density functional approximations. The role of dispersion corrections is crucial, yet simultaneously long-range corrected exchange schemes are necessary to provide the proper dimer dissociation behavior. Nevertheless, long-range corrected functionals seriously underestimate the binding energy of Orel26rad at equilibrium geometries. In fact, only omegaB97X-D, an empirical exchange-correlation functional fitted together with an empirical "classical" dispersion correction, leads to suitable results. Valuable alternatives are the more demanding MP2/6-31G*(0.25) level, as well as the most cost-effective combination involving a dispersion corrected long-range functional together with a smaller practical size basis set (e.g., LC-omegaPBEB95 dDsC/6-31G*). The Orel26rad test set should serve as an ideal benchmark for assessing the performance of improved schemes. PMID- 26605594 TI - First-Principles Modeling of Non-Covalent Interactions in Supramolecular Systems: The Role of Many-Body Effects. AB - Supramolecular host-guest systems play an important role for a wide range of applications in chemistry and biology. The prediction of the stability of host guest complexes represents a great challenge to first-principles calculations due to an interplay of a wide variety of covalent and noncovalent interactions in these systems. In particular, van der Waals (vdW) dispersion interactions frequently play a prominent role in determining the structure, stability, and function of supramolecular systems. On the basis of the widely used benchmark case of the buckyball catcher complex (C60@C60H28), we assess the feasibility of computing the binding energy of supramolecular host-guest complexes from first principles. Large-scale diffusion Monte Carlo (DMC) calculations are carried out to accurately determine the binding energy for the C60@C60H28 complex (26 +/- 2 kcal/mol). On the basis of the DMC reference, we assess the accuracy of widely used and efficient density-functional theory (DFT) methods with dispersion interactions. The inclusion of vdW dispersion interactions in DFT leads to a large stabilization of the C60@C60H28 complex. However, DFT methods including pairwise vdW interactions overestimate the stability of this complex by 9-17 kcal/mol compared to the DMC reference and the extrapolated experimental data. A significant part of this overestimation (9 kcal/mol) stems from the lack of dynamical dielectric screening effects in the description of the molecular polarizability in pairwise dispersion energy approaches. The remaining overstabilization arises from the isotropic treatment of atomic polarizability tensors and the lack of many-body dispersion interactions. A further assessment of a different supramolecular system - glycine anhydride interacting with an amide macrocycle - demonstrates that both the dynamical screening and the many body dispersion energy are complex contributions that are very sensitive to the underlying molecular geometry and type of bonding. We discuss the required improvements in theoretical methods for achieving "chemical accuracy" in the first-principles modeling of supramolecular systems. PMID- 26605595 TI - Characterization of the t-Butyl Radical and Its Elusive Anion. AB - The t-butyl radical and its anion are studied theoretically using state-of-the art quantum mechanical methods including coupled cluster theory with full single, double, and triple excitations (CCSDT) and CCSDT with perturbative quadruple excitations [CCSDT(Q)], in concert with large correlation-consistent cc-pVXZ and aug-cc-pVXZ (X = D, T, Q, 5) basis sets. The relative energies are extrapolated to the complete basis set limit (CBS). The lowest energy structure of the t-butyl radical has a nonplanar carbon backbone with overall C3v symmetry. Low-lying C3h and Cs symmetry transition states, for pyramidal inversion and methyl group rotation, respectively, between equivalent C3v minima are investigated. The barriers for these interconversions are both less than 1 kcal mol(-1), but the corresponding barriers on the anion potential energy surface are more pronounced. Using the focal point analysis technique, we obtain a value of -0.48 kcal mol(-1) for the t-butyl radical adiabatic electron affinity at the CCSDT(Q)/CBS level of theory, where the negative sign indicates that the formation of the t-butyl anion is adiabatically unfavorable. We show that the electron affinity, whose sign has been the subject of debate, is very sensitive to both the basis set and the correlation treatment, and previous experimental and theoretical estimates of its value bracket the value computed herein. Our results indicate that the t-butyl anion is classically metastable with a vertical detachment energy of over 10 kcal mol(-1) to reach the neutral potential energy surface. However, the inclusion of the zero-point vibrational effects seems to favor its nonexistence. PMID- 26605596 TI - Generalized Moller-Plesset Multiconfiguration Perturbation Theory Applied to an Open-Shell Antisymmetric Product of Strongly Orthogonal Geminals Reference Wave Function. AB - The antisymmetric product of strongly orthogonal geminals (APSG) method is a wave function theory that can effectively treat the static electron correlation. Recently, we proposed the open-shell APSG method using one-electron orbitals for open-shell parts. In this paper, we have extended the perturbation correction to the open-shell APSG calculations through Moller-Plesset-type multiconfiguration perturbation theory (MP-MCPT). Numerical applications demonstrate that the present open-shell MP-MCPT can reasonably reproduce the dissociation energies or equilibrium distances for open-shell systems. PMID- 26605597 TI - Analysis of Optical Activity in Terms of Bonds and Lone-Pairs: The Exceptionally Large Optical Rotation of Norbornenone. AB - Norbornenone, which has both a C?O and a C?C chromophore in a rigid bicyclic hydrocarbon framework, exhibits optical rotation (OR) an order of magnitude larger than that of similar molecules with only one of these chromophores (e.g., alpha-pinene). Its OR is also very sensitive to approximations in electronic structure calculations. The present study demonstrates a novel approach to interpret optical rotation using familiar concepts of chemical bonding, aided by first-principles calculations. A theoretical procedure is developed for analyzing the OR tensor components of a molecule in terms of individual bonds and lone pairs. The link between the chemist's bond and quantum mechanics is provided by localized molecular orbitals obtained from density functional theory (DFT) calculations. Delocalization of pi orbitals is shown to play a crucial role in the large OR of norbornenone, as hinted by the DFT delocalization error inherent in many standard functionals and confirmed by detailed analysis. The OR contributions generated by the double bond in alpha-pinene are even stronger than that of norbornenone. The isotropic average, observed in solution or in gas phase, is small as a result of cancellation of tensor components with opposite signs. The electronic coupling and delocalization of the C?C pi bond and the C?O oxygen pi lone pair in norbornenone selectively enhance one of the OR tensor components, resulting in the exceptionally large negative isotropic OR. PMID- 26605598 TI - Can the Closed-Shell DFT Methods Describe the Thermolysis of 1,2-Dioxetanone? AB - The chemiluminescent decomposition of 1,2-dioxetanone has in the past been studied by state-of-the-art multireference quantum chemical calculations, and a stepwise biradical mechanism was established. Recently, this decomposition has been reinvestigated, and a concerted mechanism has been proposed based on calculations performed at the closed-shell density functional theory (DFT) level of theory. In order to solve this apparent mechanistic contradiction, the present paper presents restricted and unrestricted DFT results obtained using functionals including different amounts of Hartree-Fock (HF) exchange, repeating and complementing the above-mentioned DFT calculations. The calculated results clearly indicate that the closed-shell DFT methods cannot correctly describe the thermolysis of 1,2-dioxetanone. It is found that unrestricted Kohn-Sham reaction energies and barriers are always lower than the ones obtained using a restricted formalism. Hence, from energy principles, the biradical mechanism is found to be prevailing in the understanding of the 1,2-dioxetanone thermolysis. PMID- 26605599 TI - Counterion Effects on the Denaturing Activity of Guanidinium Cation to Protein. AB - The denaturation of a three-alpha-helix bundle, the B domain of protein A, by guanidinium is studied by molecular dynamics simulations. The simulation results showed that in GdmCl solution, guanidinium cations accumulate around the protein surface, whereas chloride anions are expelled from the protein. In contrast, in GdmSCN solution, both cations and anions accumulate around the protein surface and the degree of Gdm(+) accumulation is higher than that in GdmCl, suggesting the cooperativity between the cations and anions in preferential binding. Moreover, the accumulation of guanidinium around the protein surface is not uniform, and it prefers to populate near residues with negatively charged or planar side chains. On the other hand, guanidinium participates in direct hydrogen bonding with backbone carbonyl groups. Meanwhile, guanidinium also promotes the hydrogen bonding of water to a backbone carbonyl group by changing the hydrogen bonding network within solvent. Therefore, the attack from both water and guanidinium breaks backbone hydrogen bonds and results in the destruction of secondary structures of the protein. The stronger accumulation of guanidinium and more hydrogen bonding from guanidinium in GdmSCN leads to the increase of its denaturing efficiency compared to GdmCl. In the latter solution, the ion pairing between Cl(-) and guanidinium limits the approach of guanidinium to protein and the hydrogen bonding between guanidinium and protein, and the main denaturing contributor is the hydrogen bonding from water. PMID- 26605600 TI - Improving Generalized Born Models by Exploiting Connections to Polarizable Continuum Models. II. Corrections for Salt Effects. AB - A previous analytical investigation of the generalized Born (GB) implicit solvation model is extended to solvents of nonzero ionic strength. The GB model with salt effects (GB-SE) is shown to resemble the Debye-Huckel-like screening model (DESMO), a polarizable continuum model (PCM) that we have recently developed for salty solutions. DESMO may be regarded either as a generalization of the conductor-like PCM (C-PCM) that extends C-PCM to electrolyte solutions or alternatively as a generalization of Debye-Huckel theory to arbitrary cavity shapes. The connection between GB-SE and DESMO suggests how the former can be modified to account for the exclusion of mobile ions from the cavity interior, an effect that is typically absent in GB-SE models. We propose two simple GB-SE models that are exact for a point charge in a spherical cavity and that introduce the ability to account, albeit approximately, for the finite size of the mobile ions. The accuracy of these new models is demonstrated by applications to both model systems and real proteins. These tests also demonstrate the accuracy of the DESMO approach, as compared to more sophisticated PCMs developed for electrolyte solutions. PMID- 26605601 TI - Enhancing Conformation and Protonation State Sampling of Hen Egg White Lysozyme Using pH Replica Exchange Molecular Dynamics. AB - We evaluate the efficiency of the pH replica exchange molecular dynamics (pH REMD) method proposed by Itoh et al. (Proteins2011, 79, 3420-3436) by using it to predict the pKa values of the titratable residues in hen egg white lysozyme (HEWL). pKa values predicted using pH-REMD converge significantly faster than those calculated using constant pH molecular dynamics (CpHMD). Furthermore, increasing the frequency between exchange attempts in pH-REMD simulations improves protonation and conformational state sampling. By enabling the simulation to sample both conformational and protonation states more rapidly, pH REMD simulations provide valuable insight into the pH-dependence of HEWL that the CpHMD simulations failed to capture. We present an efficient and highly scalable implementation of pH-REMD as an attractive enhancement to traditional CpHMD methods. PMID- 26605602 TI - Basis Set Recommendations for DFT Calculations of Gas-Phase Optical Rotation at Different Wavelengths. AB - Even for pure substances, the deduction of the absolute configuration is not always straightforward since there is no direct link between the magnitude and sign of the optical rotation and the absolute configuration. It would be very useful to use computations of the optical rotation to link experimentally measured optical rotations to an absolute configuration. Such electronic structure calculations of the optical rotation typically employ regular energy optimized basis sets from wave function theory, and especially the aug-cc-pVDZ basis set has been popular. Here, we have carried out extrapolation of the optical rotation to the basis set limits for nine small or medium sized molecules, using basis sets developed specifically for DFT and magnetic properties (aug-pcS-n series). We suggest that assignment of absolute configuration by comparisons between theoretical and experimental optical rotations may be improved by employing different wavelengths, and accordingly the optical rotation at two wavelengths (589.3 and 355.0 nm) has been investigated. Several fitting schemes were used to estimate the optical rotations at the basis set limit. It was found that use of the aug-cc-pVDZ basis set often leads to results that deviate significantly form the basis set limit results, especially at 355.0 nm but also at 589.3 nm. The double-zeta aug-pcS-1 basis set usually provides results which are closer to the limiting values. The basis set requirements are generally more severe at 355.0 nm, where also the aug-cc-pVTZ and 6-311++G(3fd,3dp) basis sets show significant deviations from the basis set limit results, while the aug-pcS-2 basis set always leads to results within an acceptable deviation. PMID- 26605603 TI - Accurate Theoretical Description of the (1)La and (1)Lb Excited States in Acenes Using the All Order Constricted Variational Density Functional Theory Method and the Local Density Approximation. AB - We present the results of calculations on the vertical singlet (1)La and (1)Lb excitation energies in acenes within time dependent density functional theory (TDDFT), second order constricted variational DFT (CV(2)-DFT), and all order constricted variational DFT (CV(infinity)-DFT) using the local density approximation LDA(VWN). For the linear acenes it is shown that the application of the Tamm-Dancoff (TD) approximation to TDDFT (TDDFT-TD) substantially improves the agreement with experiment compared to pure TDDFT. This improvement leads to the correct ordering of the (1)La and (1)Lb excitation energies in naphthalene. As TDDFT-TD is equivalent to the second order CV(2)-TD method one might hope for further improvements by going to all orders in CV(infinity)-TD. Indeed, for linear acenes the application of the CV(infinity)-TD method brings the agreement with experiment to within 0.1 eV for both types of excitations using the simple LDA functional. The CV(infinity)-TD method based on LDA is also shown to be accurate for 15 nonlinear acenes with root-mean-square deviations of 0.24 eV for (1)La and 0.17 eV for (1)Lb. PMID- 26605604 TI - Full Configuration Interaction Excitations of Ethene and Butadiene: Resolution of an Ancient Question. AB - We employ the recently developed full configuration interaction quantum Monte Carlo (FCIQMC) method to compute the pi -> pi* vertical excitation energies of ethene and all-trans butadiene. These excitations have been the subject of extensive theoretical studies, and their location with respect to the corresponding absorption band maximum is the source of a long lingering debate. Here, we reliably estimate the vertical excitations of ethene and butadiene by performing FCIQMC calculations for spaces as large as 10(18) and 10(29) Slater determinants, respectively. For ethene, we obtain a vertical excitation energy in the range 7.89-7.96 eV, depending on the particular equilibrium ground-state geometry employed, and definitely higher than the absorption maximum located at 7.66 eV. For the computationally more challenging case of butadiene, our calculations provide a robust estimate of about 6.3 eV for this excitation, that is, 0.4 eV higher than the corresponding absorption band maximum. Our FCIQMC excitation energies represent a reliable benchmarking reference for future calculations. PMID- 26605605 TI - A Configuration Interaction Picture for a Molecular Environment Using Localized Molecular Orbitals: The Excited States of Retinal Proteins. AB - Electronic excitations of chromophores in proteins and solutions are associated with the electronic response of the molecular environment. The underlying interactions are important origins of solvatochromism. We performed large-scale configuration interaction singles (CIS) calculations (up to 1000 atoms) for retinal chromophores in proteins and methanol solution, in which one-electron processes (polarization and charge-transfer effects of the environment) are included. The present approach also improved the electrostatic potential, as compared to that described by a molecular mechanics (MM) force field. The CIS results were combined with the symmetry adapted cluster (SAC)-CI result using our own N-layer integrated molecular orbital molecular mechanics (ONIOM) method. As compared to the MM description, the CIS reduces the calculated excitation energy by 0.1-0.3 eV and also improves the relative excitation energies among retinal proteins. We applied our localized molecular orbital (LMO) transformation scheme to analyze the CI wave functions. The result clarified the contributions of the amino acids. In bacteriorhodopsin, Tyr185 contributes intermolecular CT excitations. The radial distribution of amino acids' contributions to the CI wave function was also analyzed. The results of the analysis are useful not only for understanding the molecular interactions and the role of amino acids in color tuning, but also for providing insight into the structure of the excited-state wave function for the molecular environment. An excitation-energy decomposition analysis also supported the results of the excited-state wave functions. PMID- 26605606 TI - Toward a Unified Modeling of Environment and Bridge-Mediated Contributions to Electronic Energy Transfer: A Fully Polarizable QM/MM/PCM Approach. AB - Recent studies have unveiled the similar nature of solvent (screening) effects and bridge-mediated contributions to electronic energy transfer, both related to the bridge/solvent polarizability properties. Here, we exploit the similarity of such contributions to develop a fully polarizable mixed QM/discrete/continuum model aimed at studying electronic energy transfer processes in supramolecular systems. In the model, the definition of the three regions is completely flexible and allows us to explore the possibility to describe bridge-mediated contributions by using a polarizable MM description of the linker. In addition, we show that the classical MMPol description of the bridge can be complemented either with an analogous atomistic or with a continuum description of the solvent. Advantages and drawbacks of the model are finally presented and discussed with respect to the system under study. PMID- 26605607 TI - Time-Dependent Approach to Resonance Raman Spectra Including Duschinsky Rotation and Herzberg-Teller Effects: Formalism and Its Realistic Applications. AB - Efficient quantum dynamical and electronic structure approaches are presented to calculate resonance Raman spectroscopy (RRS) with inclusion of Herzberg-Teller (HT) contribution and mode-mixing (Duschinsky) effect. In the dynamical method, an analytical expression for RRS in the time domain is proposed to avoid summation over the large number of intermediate vibrational states. In the electronic structure calculations, the analytic energy-derivative approaches for the excited states within the time-dependent density functional theory (TDDFT), developed by us, are adopted to overcome the computational bottleneck of excited state gradient and Hessian calculations. In addition, an analytic calculation to the geometrical derivatives of the transition dipole moment, entering the HT term, is also adopted. The proposed approaches are implemented to calculate RR spectra of a few of conjugated systems, phenoxyl radical, 2-thiopyridone in water solution, and free-base porphyrin. The calculated RR spectra show the evident HT effect in those pi-conjugated systems, and their relative intensities are consistent with experimental measurements. PMID- 26605608 TI - Vibrationally Resolved Absorption and Emission Spectra of Dithiophene in the Gas Phase and in Solution by First-Principle Quantum Mechanical Calculations. AB - The absorption and emission spectra of dithiophene have been computed in different environments (gas phase, apolar, and polar solvents) and at different temperatures, including Duschinsky, temperature and solvent effects at full ab initio level, and considering the anharmonicity of the double well potential associated with the inter-ring torsional mode. The computed spectra are in very good agreement with the experimental ones, allowing for a complete assignment of the main vibrational features. Five different density functionals (BLYP, B3LYP, CAM-B3LYP, BHLYP, and PBE0) have been tested, and CAM-B3LYP and PBE0 are the most accurate. PMID- 26605609 TI - Absorption and Emission Spectra of Solvated Molecules with the EOM-CCSD-PCM Method. AB - The accurate calculation of transition energies and properties of isolated molecules is not enough for realistic simulations of their absorption and emission spectra in solution. In fact, the solvent influences the solute geometry, electronic structure, and response to external fields, and a proper description of the solvent effect is fundamental. However, the computational cost of including explicit solvent molecules around the solute becomes rather onerous when an accurate method such as the equation of motion coupled cluster singles and doubles (EOM-CCSD) is employed. The polarizable continuum model of solvation (PCM) may provide an efficient alternative to explicit models, since the sampling of solvent configurations is implicit and the solute-solvent mutual polarization is naturally accounted for. In this contribution, the absorption and emission spectra of molecules in solution are modeled through the EOM-CCSD-PCM method. The equilibrium solvation regime is employed for the geometry optimization of the solute molecule in the ground and excited states, while the nonequilibrium solvation regime is employed for vertical transitions. The theory, implementation, and prototypical applications of the method are presented. The numerical tests involve solvents that are particularly challenging for PCM: low polar and protic polar solvents. Nonetheless, the experimental trends are well reproduced, and the overall agreement with the measured data is remarkable. PMID- 26605610 TI - An Improved Isotropic Periodic Sum Method That Uses Linear Combinations of Basis Potentials. AB - Isotropic periodic sum (IPS) is a technique that calculates long-range interactions differently than conventional lattice sum methods. The difference between IPS and lattice sum methods lies in the shape and distribution of remote images for long-range interaction calculations. The images used in lattice sum calculations are identical to those generated from periodic boundary conditions and are discretely positioned at lattice points in space. The images for IPS calculations are "imaginary", which means they do not explicitly exist in a simulation system and are distributed isotropically and periodically around each particle. Two different versions of the original IPS method exist. The IPSn method is applied to calculations for point charges, whereas the IPSp method calculates polar molecules. However, both IPSn and IPSp have their advantages and disadvantages in simulating bulk water or water-vapor interfacial systems. In bulk water systems, the cutoff radius effect of IPSn strongly affects the configuration, whereas IPSp does not provide adequate estimations of water-vapor interfacial systems unless very long cutoff radii are used. To extend the applicability of the IPS technique, an improved IPS method, which has better accuracy in both homogeneous and heterogeneous systems has been developed and named the linear-combination-based isotropic periodic sum (LIPS) method. This improved IPS method uses linear combinations of basis potentials. We performed molecular dynamics (MD) simulations of bulk water and water-vapor interfacial systems to evaluate the accuracy of the LIPS method. For bulk water systems, the LIPS method has better accuracy than IPSn in estimating thermodynamic and configurational properties without the countercharge assumption, which is used for IPSp. For water-vapor interfacial systems, LIPS has better accuracy than IPSp and properly estimates thermodynamic and configurational properties. In conclusion, the LIPS method can successfully estimate homogeneous and heterogeneous systems of polar molecular systems with good accuracy. PMID- 26605611 TI - Atomistic Simulations of the ZnO(1210)/Water Interface: A Comparison between First-Principles, Tight-Binding, and Empirical Methods. AB - We investigate the adsorption behavior of water over the zinc oxide (1210) surface starting from single molecules up to bulk liquid by means of atomistic molecular dynamics simulations. We compare results obtained with density functional theory, density-functional tight binding, and a recently developed reactive force field. The methods perform comparably up to the level of a single monolayer of adsorbed water, predicting only small differences in adsorption energies and, as a consequence, adsorption geometries. These lie within the error bars of typical quantum mechanical calculations performed with different exchange correlation functionals. However, the discrepancies among the methods have a dramatic effect on the dissociation equilibria and the structuring of liquid water layers in contact with the surface. Especially the different treatment of electrostatic interactions via self-consistent atomic point charges appears to heavily influence the simulation outcomes. Critical comparisons with experimental studies and possibly ad hoc reparametrizations of the semiempirical functionals may thus be necessary to study phenomena such as dissolution or biomolecular adsorption at ZnO surfaces within statistically relevant time and size scales. PMID- 26605612 TI - Solvent Boundary Potentials for Hybrid QM/MM Computations Using Classical Drude Oscillators: A Fully Polarizable Model. AB - Accurate quantum mechanical/molecular mechanical (QM/MM) treatments should account for MM polarization and properly include long-range electrostatic interactions. We report on a development that covers both these aspects. Our approach combines the classical Drude oscillator (DO) model for the electronic polarizability of the MM atoms with the generalized solvent boundary Potential (GSBP) and the solvated macromolecule boundary potential (SMBP). These boundary potentials (BP) are designed to capture the long-range effects of the outer region of a large system on its interior. They employ a finite difference approximation to the Poisson-Boltzmann equation for computing electrostatic interactions and take into account outer-region bulk solvent through a polarizable dielectric continuum (PDC). This approach thus leads to fully polarizable three-layer QM/MM-DO/BP methods. As the mutual responses of each of the subsystems have to be taken into account, we propose efficient schemes to converge the polarization of each layer simultaneously. For molecular dynamics (MD) simulations using GSBP, this is achieved by considering the MM polarizable model as a dynamical degree of freedom, and hence contributions from the boundary potential can be evaluated for a frozen state of polarization at every time step. For geometry optimizations using SMBP, we propose a dual self-consistent field approach for relaxing the Drude oscillators to their ideal positions and converging the QM wave function with the proper boundary potential. The chosen coupling schemes are evaluated with a test system consisting of a glycine molecule in a water ball. Both boundary potentials are capable of properly reproducing the gradients at the inner-region atoms and the Drude oscillators. We show that the effect of the Drude oscillators must be included in all terms of the boundary potentials to obtain accurate results and that the use of a high dielectric constant for the PDC does not lead to a polarization catastrophe of the DO models. Optimum values for some key parameters are discussed. We also address the efficiency of these approaches compared to standard QM/MM-DO calculations without BP. In the SMBP case, computation times can be reduced by around 40% for each step of a geometry optimization, with some variation depending on the chosen QM method. In the GSBP case, the computational advantages of using the boundary potential increase with system size and with the number of MD steps. PMID- 26605614 TI - Carbon Nanotube Container: Complexes of C50H10 with Small Molecules. AB - The stability of complexes of a recently synthetized (Scott et al. J. Am. Chem. Soc.2011, 134, 107) opened nanocontainer C50H10 with several guest molecules, H2, N2, CO, HCN, H2O, CO2, CS2, H2S, C2H2, NH3, CH4, CH3CN, CH3OH, CH3CCH, 2-butyne, methyl halides, and with noble gas atoms, has been examined by means of symmetry adapted perturbation theory of intermolecular interactions, which fully incorporates all important energy components, including a difficult dispersion term. All complexes under scrutiny have been found stable for all studied guests at 0 K, but entropic effects cause many of them to dissociate into constituent molecules under standard conditions. The estimation of temperature at which the Gibbs free energy DeltaG = 0 revealed that the recently observed (Scott et al. J. Am. Chem. Soc.2011, 134, 107) complex CS2@C50H10 is the most stable at room temperature while the corresponding complexes with HCN and Xe guests should decompose at ca. 310 K and that with CO2 at room temperature (ca. 300 K). In agreement with the DeltaG estimation, molecular dynamics simulations performed in vacuum for the CS2@C50H10 complex predicted that the complex is stable but decomposes at ca. 350 K. The MD simulations in CHCl3 solution showed that the presence of solvent stabilizes the CS2@C50H10 complex in comparison to vacuum. Thus, for the complexes obtained in solution the CO2 gas responsible for the greenhouse effect could be stored in the C50H10 nanotube. PMID- 26605613 TI - Configurational Behavior and Conductance of Alkanedithiol Molecular Wires from Accelerated Dynamics Simulations. AB - An accelerated dynamics scheme is employed to sample the configurational space of a system consisting of an alkanedithiol molecule confined to the gap between a metal tip and a perfect metal surface. With this information and by means of nonequilibrium green functions techniques (NEGF), conductance calculations are performed. The present results show that even for this system, which is one of the most simple conceivable because of the perfectness of the surface, a complex behavior appears due to the occurrence of an unexpected tip-molecule-surface arrangement, where the insertion of one of the molecular ends into the tip surface gap generates configurations with strongly enhanced conductance. Estimates are also made for the time required to generate the molecular junction, indicating that it should depend on the tip-surface distance, thus opening the way to new experiments in this direction. PMID- 26605615 TI - Accurate Force Field Development for Modeling Conjugated Polymers. AB - The modeling of the conformational properties of conjugated polymers entails a unique challenge for classical force fields. Conjugation imposes strong constraints upon bond rotation. Planar configurations are favored, but the concomitantly shortened bond lengths result in moieties being brought into closer proximity than usual. The ensuing steric repulsions are particularly severe in the presence of side chains, straining angles, and stretching bonds to a degree infrequently found in nonconjugated systems. We herein demonstrate the resulting inaccuracies by comparing the LMP2-calculated inter-ring torsion potentials for a series of substituted stilbenes and bithiophenes to those calculated using standard classical force fields. We then implement adjustments to the OPLS-2005 force field in order to improve its ability to model such systems. Finally, we show the impact of these changes on the dihedral angle distributions, persistence lengths, and conjugation length distributions observed during molecular dynamics simulations of poly[2-methoxy-5-(2'-ethylhexyloxy)-p-phenylene vinylene] (MEH PPV) and poly 3-hexylthiophene (P3HT), two of the most widely used conjugated polymers. PMID- 26605616 TI - Multiscale Modeling Approach toward the Prediction of Viscoelastic Properties of Polymers. AB - We report a multiscale modeling approach to study static and dynamical properties of polymer melts at large time and length scales. We use a bottom-up approach consisting of deriving coarse-grained models from an atomistic description of the polymer melt. We use the iterative Boltzmann inversion (IBI) procedure and a pressure-correction function to map the thermodynamic conditions of the atomistic configurations. The coarse-grained models are incorporated in the dissipative particle dynamics (DPD) method. The thermodynamic, structural, and dynamical properties of the cis-1,4-polybutadiene melt are very well reproduced by the coarse-grained DPD models with a significative computational gain. We complete this study by addressing the challenging question of the investigation of the shear modulus evolution. As expected from experiments, the stress correlation functions show behaviors that are dependent on the molecular weights defining unentangled and weakly entangled polymer melts. PMID- 26605617 TI - Molecular Dynamics Simulations of Phosphatidylcholine Membranes: A Comparative Force Field Study. AB - Molecular dynamics simulations provide a route to studying the dynamics of lipid bilayers at atomistic or near atomistic resolution. Over the past 10 years or so, molecular dynamics simulations have become an established part of the biophysicist's tool kit for the study of model biological membranes. As simulation time scales move from tens to hundreds of nanoseconds and beyond, it is timely to re-evaluate the accuracy of simulation models. We describe a comparative analysis of five freely available force fields that are commonly used to model lipid bilayers. We focus our analysis on 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers. We show that some bilayer properties have a pronounced force field dependence, while others are less sensitive. In general, we find strengths and weaknesses, with respect to experimental data, in all of the force fields we have studied. We do, however, find some combinations of simulation and force field parameters that should be avoided when simulating DPPC and POPC membranes. We anticipate that the results presented for some of the membrane properties will guide future improvements for several force fields studied in this work. PMID- 26605618 TI - Molecular Dynamics Simulations of a Characteristic DPC Micelle in Water. AB - We present the first comparative molecular dynamics investigation for a dodecylphosphocholine (DPC) micelle performed in condensed phase using the CHARMM36, GROMOS53A6, GROMOS54A7, and GROMOS53A6/Berger force fields and a set of parameters developed anew. Our potential consists of newly derived RESP atomic charges, which are associated with the Amber99SB force field developed for proteins. This new potential is expressly designed for simulations of peptides and transmembrane proteins in a micellar environment. To validate this new ensemble, molecular dynamics simulations of a DPC micelle composed of 54 monomers were carried out in explicit water using a "self-assembling" approach. Characteristic micellar properties such as aggregation kinetic, volume, size, shape, surface area, internal structure, surfactant conformation, and hydration were thoroughly examined and compared with experiments. Derived RESP charge values combined with parameters taken from Amber99SB reproduce reasonably well important structural properties and experimental data compared to the other tested force fields. However, the headgroup and alkyl chain conformations or the micelle hydration simulated with the Amber99SB force field display some differences. In particular, we show that Amber99SB slightly overestimates the trans population of the alkyl Csp(3)-Csp(3)-Csp(3)-Csp(3) dihedral angle (i.e., CCCC) and reduces the flexibility of the DPC alkyl chain. In agreement with experiments and previously published studies, the DPC micelle shows a slightly ellipsoidal shape with a radius of gyration of ~17 A for the different potentials evaluated. The surface of contact between the DPC headgroup and water molecules represents between 70% and 80% of the total micelle surface independently of the force field considered. Finally, molecular dynamics simulations show that water molecules form various hydrogen-bond patterns with the surfactant headgroup, as noted previously for phospholipids with a phosphatidylcholine headgroup. PMID- 26605619 TI - Effects of Dispersion in Density Functional Based Quantum Mechanical/Molecular Mechanical Calculations on Cytochrome P450 Catalyzed Reactions. AB - Density functional theory (DFT) based quantum mechanical/molecular mechanical (QM/MM) calculations have provided valuable insight into the reactivity of the cytochrome P450 family of enzymes (P450s). A failure of commonly used DFT methods, such as B3LYP, is the neglect of dispersion interactions. An empirical dispersion correction has been shown to improve the accuracy of gas phase DFT calculations of P450s. The current work examines the effect of the dispersion correction in QM/MM calculations on P450s. The hydrogen abstraction from camphor, and hydrogen abstraction and C-O addition of cyclohexene and propene by P450cam have been modeled, along with the addition of benzene to Compound I in CYP2C9, at the B3LYP-D2/CHARMM27 level of theory. Single point energy calculations were also performed at the B3LYP-D3//B3LYP-D2/CHARMM27 level. The dispersion corrections lower activation energy barriers significantly (by ~5 kcal/mol), as seen for gas phase calculations, but has a small effect on optimized geometries.These effects are likely to be important in modeling reactions catalyzed by other enzymes also. Given the low computational cost of including such dispersion corrections, we recommend doing so in all B3LYP based QM/MM calculations. PMID- 26605620 TI - Predictions from an Ising-like Statistical Mechanical Model on the Dynamic and Thermodynamic Effects of Protein Surface Electrostatics. AB - Charged residues on the surface of a protein are known hot-spots for post translational modification, protein/ligand-binding, and tuning conformational stabilities. Recent experimental evidence points to the fact that surface electrostatics can also modulate thermodynamic barriers and hence folding mechanisms. To probe for this behavior across different proteins, we develop a novel version of the Wako-Saito-Munoz-Eaton (WSME) model in which we include an electrostatic potential term in the energy function while simplifying the treatment of solvation free energy. Both of the energy terms are obtained by quantitatively fitting the model to differential scanning calorimetry (DSC) experiments that carry critical information on the protein partition function. We characterize four sets of structural/functional homologues (HEWL/BLA, CspB, engrailed, alpha-spectrin) either by fitting the experimental data of a single domain in the homologous set and predicting the conformational behavior of the rest with the same set of parameters or by performing semiblind predictions. The model with the added electrostatic term is able to successfully reproduce the order of thermodynamic stabilities and relaxation rates of most of the homologues. In parallel, we predict diverse conformational features including a wide range of thermodynamic barriers (~9-40 kJ/mol), broad native ensembles in helical proteins, structured unfolded states and intermediates, rugged folding landscapes, and further provide an independent protein-specific estimate of the folding speed limit at 298 K (1/(7-300 MUs)). Our results are evidence that protein surface electrostatics can be tailored to not only engineer stabilities but also folding mechanisms and the ruggedness of the underlying landscape. PMID- 26605621 TI - Efficient Free Energy Calculation of Biomolecules from Diffusion-Biased Molecular Dynamics. AB - Recently proposed metadynamics techniques offer an effective means for improving sampling in simulations of complex systems, including polymers and biological macromolecules. One of the drawbacks of such methods has been the absence of well defined or effective convergence criteria. A solution to this problem is considered here in which an optimal ensemble is introduced to minimize the travel time across the entire order parameter range of interest. The usefulness of the proposed approach is illustrated in the context of two systems consisting of biological molecules dissolved in water. The results presented in this work indicate that the proposed method is considerably faster than other existing algorithms for the study of these systems, and that the corresponding free energy that emerges from the simulations converges to the exact result. PMID- 26605622 TI - The Catalytic Machinery of Rhomboid Proteases: Combined MD and QM Simulations. AB - Rhomboid proteases are a ubiquitous family of intramembrane serine proteases in prokaryotic and eukaryotic organisms that cleave membrane proteins in their transmembrane region. Their catalytic activity is centered at a His-Ser catalytic dyad. We applied molecular dynamics and quantum mechanics calculations in order to clarify the protonation state of the catalytic residues of E. coli GlpG rhomboid protease and how it is affected by the immersion of the enzyme in the membrane. We identified (Nepsilon)H150(dpr)_H254(dpr)_S201(pr) as the protonation (and H150 tautomeric) state of free GlpG in both lipid-solubilized and membrane environments. We used our MD-QM/SCRF(VS) computational protocol to rationalize and predict the trend of pKa change caused by the decrease of water exposure of the active site of GlpG due to ligand binding. The catalytic diad of lipid solubilized GlpG exists as an H254(+)_S201(-) ion pair at the Michaelis complex stage, with Ser201 ready for nucleophilic attack on the substrate. Therefore, deprotonation of S201 does not contribute to the activation barrier of covalent tetrahedral complex formation. In contrast, both catalytic residues, H254 and S201, are neutral in the Michaelis complex of GlpG in the membrane. Therefore, S201 deprotonation by H254 general base catalysis should contribute to the activation barrier of the covalent tetrahedral complex formation. PMID- 26605623 TI - Calculation of Free Energy Landscape in Multi-Dimensions with Hamiltonian Exchange Umbrella Sampling on Petascale Supercomputer. AB - An extremely scalable computational strategy is described for calculations of the potential of mean force (PMF) in multidimensions on massively distributed supercomputers. The approach involves coupling thousands of umbrella sampling (US) simulation windows distributed to cover the space of order parameters with a Hamiltonian molecular dynamics replica-exchange (H-REMD) algorithm to enhance the sampling of each simulation. In the present application, US/H-REMD is carried out in a two-dimensional (2D) space and exchanges are attempted alternatively along the two axes corresponding to the two order parameters. The US/H-REMD strategy is implemented on the basis of parallel/parallel multiple copy protocol at the MPI level, and therefore can fully exploit computing power of large-scale supercomputers. Here the novel technique is illustrated using the leadership supercomputer IBM Blue Gene/P with an application to a typical biomolecular calculation of general interest, namely the binding of calcium ions to the small protein Calbindin D9k. The free energy landscape associated with two order parameters, the distance between the ion and its binding pocket and the root-mean square deviation (rmsd) of the binding pocket relative the crystal structure, was calculated using the US/H-REMD method. The results are then used to estimate the absolute binding free energy of calcium ion to Calbindin D9k. The tests demonstrate that the 2D US/H-REMD scheme greatly accelerates the configurational sampling of the binding pocket, thereby improving the convergence of the potential of mean force calculation. PMID- 26605624 TI - GROMOS 53A6GLYC, an Improved GROMOS Force Field for Hexopyranose-Based Carbohydrates. AB - An improved parameter set for explicit-solvent simulations of carbohydrates (referred to as GROMOS 53A6GLYC) is presented, allowing proper description of the most stable conformation of all 16 possible aldohexopyranose-based monosaccharides. This set includes refinement of torsional potential parameters associated with the determination of hexopyranose rings conformation by fitting to their corresponding quantum-mechanical profiles. Other parameters, as the rules for third and excluded neighbors, are taken directly from the GROMOS 53A6 force field. Comparisons of the herein presented parameter set to our previous version (GROMOS 45A4), the GLYCAM06 force field, and available NMR data are presented in terms of ring puckering free energies, conformational distribution of the hydroxymethyl group, and glycosidic linkage geometries for 16 selected monosaccharides and eight disaccharides. The proposed parameter modifications have shown a significant improvement for the above-mentioned quantities over the two tested force fields, while retaining full compatibility with the GROMOS 53A6 and 54A7 parameter sets for other classes of biomolecules. PMID- 26605625 TI - Finding Conformational Transition Pathways from Discrete Molecular Dynamics Simulations. AB - We present a new method for estimating pathways for conformational transitions in macromolecules from the use of discrete molecular dynamics and biasing techniques based on a combination of essential dynamics and Maxwell-Demon sampling techniques. The method can work with high efficiency at different levels of resolution, including the atomistic one, and can help to define initial pathways for further exploration by means of more accurate atomistic molecular dynamics simulations. The method is implemented in a freely available Web-based application accessible at http://mmb.irbbarcelona.org/MDdMD . PMID- 26605626 TI - A Glycam-Based Force Field for Simulations of Lipopolysaccharide Membranes: Parametrization and Validation. AB - Lipopolysaccharides (LPS) comprise the outermost layer of the Gram-negative bacteria cell envelope. Packed onto a lipid layer, the outer membrane displays remarkable physical-chemical differences compared to cell membranes. The carbohydrate-rich region confers a membrane asymmetry that underlies many biological processes such as endotoxicity, antibiotic resistance, and cell adhesion. Furthermore, unlike membrane proteins from other sources, integral outer-membrane proteins do not consist of transmembrane alpha helices; instead they consist of antiparallel beta-barrels, which highlights the importance of the LPS membrane as a medium. In this work, we present an extension of the GLYCAM06 force field that has been specifically developed for LPS membranes using our Wolf2Pack program. This new set of parameters for lipopolysaccharide molecules expands the GLYCAM06 repertoire of monosaccharides to include phosphorylated N- and O-acetylglucosamine, 3-deoxy-d-manno-oct-2-ulosonic acid, l-glycero-D-manno heptose and its O-carbamoylated variant, and N-alanine-d-galactosamine. A total of 1 MUs of molecular dynamics simulations of the rough LPS membrane of Pseudomonas aeruginosa PA01 is used to showcase the added parameter set. The equilibration of the LPS membrane is shown to be significantly slower compared to phospholipid membranes, on the order of 500 ns. It is further shown that water molecules penetrate the hydrocarbon region up to the terminal methyl groups, much deeper than commonly observed for phospholipid bilayers, and in agreement with neutron diffraction measurements. A comparison of simulated structural, dynamical, and electrostatic properties against corresponding experimentally available data shows that the present parameter set reproduces well the overall structure and the permeability of LPS membranes in the liquid-crystalline phase. PMID- 26605627 TI - Coarse-Grained Simulations of Protein Backbone Dynamics. 1. Local Sterics Define the Dihedral Angles. AB - Here, we present a coarse-grained model targeted for implicit solvent simulations of unfolded or intrinsically disordered proteins. The hierarchical model with its nonspherical building blocks allows one to reproduce the local dynamics of the backbone with simple harmonic bonds and steric collisions between a small number of atoms at the correct off-center positions on the building blocks. Here in part 1, we also describe the implementation of the global shape of the protein chain and the extended local interactions that add a first secondary structure bias, which will subsequently be augmented by additional hydrophobic interactions, hydrogen bonds, and dipole dipole couplings along the backbone. Due to its hierarchical setup, the model has a near-atomistic resolution on the local scale and the overall numerical efficiency of a coarse-grained model such that even long protein chains can be simulated efficiently. PMID- 26605628 TI - GPU-Based Massive Parallel Kawasaki Kinetics in the Dynamic Monte Carlo Simulations of Lipid Nanodomains. AB - Multicomponent lipid membranes in the liquid phase exhibit dynamic lateral heterogeneities which play an important role in specific cell membrane functions. A GPU-based parallel algorithm for two-dimensional lattice Dynamic Monte Carlo simulations of nanodomain formation in binary lipid membranes was developed and tested. Speedups of up to 50-times over CPU-based calculations were achieved, and simulations employing lattices of up to 1800 * 1800 sites were performed. The existence of large nonregular lipid domains of sizes up to 160 nm was demonstrated. This reveals the necessity to employ lattices of at least ~900 * 900 sites to study the lateral lipid organization in complex lipid membranes. PMID- 26605629 TI - Binding Mechanism and Magnetic Properties of a Multifunctional Spin Label for Targeted EPR Imaging of Amyloid Proteins: Insight from Atomistic Simulations and First-Principles Calculations. AB - Electron paramagnetic resonance (EPR) imaging techniques provide a promising approach to detect amyloid structures which are of paramount importance in early stage diagnosis of conformational diseases. Here, we report a combined molecular dynamics and density functional theory/molecular mechanics computational scheme for evaluation of the binding mechanism between a multifunctional spin label and the target amyloid protein. In addition, we consider evaluation of EPR spin Hamiltonian parameters with the aim of providing a better microscopic understanding and interpretation of EPR spectroscopy. The results from molecular dynamics simulations suggest that the oligothiophene conjugate part of the spin label interacts with hydrophobic residues of the amyloid protein through hydrophobic attraction and that both the N-O bond length and the N-O out-of-plane tilt angle in the nitroxide group are slightly diminished after complexation with the protein. The translational and rotational motions of the protein-bound spin label are considerably slowed compared to those of the free spin label in aqueous solution, but interestingly, hydrogen bonds formed between the nitroxide oxygen group and the surrounding water molecules are hardly affected by the presence of the amyloid protein. First-principles calculations suggest that EPR spin Hamiltonian parameters including the nitroxide nitrogen hyperfine coupling tensor A(N) and electronic g tensor suffer noticeable changes upon complexation with the protein. The magnitude of the A(N) tensor is found to be closely related to the nitroxide N-O out-of-plane tilt angle, while the g tensor is affected by both the nitroxide N-O bond length as well as the interaction between the spin label and the amyloid protein. With this work we show that state-of-the-art simulation techniques represent a promising way of providing a detailed understanding of the microscopic mechanisms responsible for the formation and stability of a spin label complexed with amyloid structures as well as the magnetic properties of the free and protein-bound spin label. PMID- 26605630 TI - Local Fluctuations and Conformational Transitions in Proteins. AB - The intrinsic plasticity of protein residues, along with the occurrence of transitions between distinct residue conformations, plays a pivotal role in a variety of molecular recognition events in the cell. Analysis aimed at identifying both of these features has been limited so far to protein-complex structures. We present a computationally efficient tool (T-pad), which quantitatively analyzes protein residues' flexibility and detects backbone conformational transitions. T-pad is based on directional statistics of NMR structural ensembles or molecular dynamics trajectories. T-pad is here applied to human ubiquitin (hU), a paradigmatic cellular interactor. The calculated plasticity is compared to hU's Debye-Waller factors from the literature as well as those from experimental work carried out for this paper. T-pad is able to identify most of the key residues involved in hU's molecular recognition, also in the absence of its cellular partners. Indeed, T-pad identified as many as 90% of ubiquitin residues interacting with their cognate proteins. Hence, T-pad might be a useful tool for the investigation of interactions between proteins and their cellular partners at the genome-wide level. PMID- 26605631 TI - Hybrid Quantum and Classical Simulations of the Formate Dehydrogenase Catalyzed Hydride Transfer Reaction on an Accurate Semiempirical Potential Energy Surface. AB - Formate dehydrogenase (FDH) catalyzes the oxidation of formic acid to carbon dioxide using nicotinamide adenine dinucleotide (NAD(+)) as a cofactor. In the current work we present extensive benchmark calculations for several model reactions in the gas phase that are relevant to the FDH catalyzed hydride transfer. To this end we employ G4MP2 and CBS-QB3 ab initio calculations as well as density functional theory methods. Using these results we develop a specific reaction parameter (SRP) Hamiltonian based on the semiempirical AM1 method. The SRP semiempirical Hamiltonian is subsequently used in hybrid quantum mechanics/molecular mechanics simulations of the FDH catalyzed reaction in Pseudomonas sp. 101 (PseFDH). The classical potential of mean force (PMF) is computed as a function of structural progress coordinates during the course of the hydride transfer reaction: The antisymmetric reactive stretch, the donor acceptor distance, and an orbital rehybridization coordinate. The quantum PMF is computed using a centroid Feynman path-integral (PI) approach. Subsequently, kinetic isotope effects are computed using a mass-perturbation based PI method. Finally, the antisymmetric stretch vibrational frequency is computed for an azide ion in FDH and in aqueous solution. PMID- 26605632 TI - Multiscale Coarse-Graining via Normal Mode Analysis. AB - A multiscale coarse-graining method called the normal-mode analysis based fluctuation matching (NMA-FM) is developed for constructing coarse-grained models of biomolecular systems. In the framework of normal-mode analysis, an arbitrary fine-grained model can be systematically converted to a more coarse-grained model, while the crucial low-frequency motions of the fine-grained system are able to be reproduced in the coarse-grained modeling. The method relies on the technique of fluctuation matching that has been devised earlier for parametrizing heterogeneous elastic network models based on data from atomistic molecular dynamics simulations. The new approach is quite efficient since it avoids expensive atomistic molecular dynamics simulations and can start from already coarse-grained elastic network models. In the practical aspect, the method is suitable for conformational analyses of large biomacromolecules and calculations of mechanical properties of biomaterials, which is demonstrated by the studied systems including an amyloid dimer, lysozyme and adenylate kinase proteins, and the S2 subdomain of myosin. PMID- 26605633 TI - Lipid Bilayers: The Effect of Force Field on Ordering and Dynamics. AB - The sensitivity of the structure and dynamics of a fully hydrated pure bilayer of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) in molecular dynamics simulations to changes in force-field and simulation parameters has been assessed. Three related force fields (the Gromos 54A7 force field, a Gromos 53A6 derived parameter set and a variant of the Berger parameters) in combination with either particle-mesh Ewald (PME) or a reaction field (RF) were compared. Structural properties such as the area per lipid, carbon-deuterium order parameters, electron density profile and bilayer thicknesses, are reproduced by all the parameter sets within the uncertainty of the available experimental data. However, there are clear differences in the ordering of the glycerol backbone and choline headgroup, and the orientation of the headgroup dipole. In some cases, the degree of ordering was reminiscent of a liquid-ordered phase. It is also shown that, although the lateral diffusion of the lipids in the plane of the bilayer is often used to validate lipid force fields, because of the uncertainty in the experimental measurements and the fact that the lateral diffusion is dependent on the choice of the simulation conditions, it should not be employed as a measure of quality. Finally, the simulations show that the effect of small changes in force-field parameters on the structure and dynamics of a bilayer is more significant than the treatment of the long-range electrostatic interactions using RF or PME. Overall, the Gromos 54A7 best reproduced the range of experimental data examined. PMID- 26605634 TI - Toward the Quantum Chemical Calculation of NMR Chemical Shifts of Proteins. 3. Conformational Sampling and Explicit Solvents Model. AB - Fragment-based quantum chemical calculations are able to accurately calculate NMR chemical shifts even for very large molecules like proteins. But even with systematic optimization of the level of theory and basis sets as well as the use of implicit solvents models, some nuclei like polar protons and nitrogens suffer from poor predictions. Two properties of the real system, strongly influencing the experimental chemical shifts but almost always neglected in the calculations, will be discussed here in great detail: (1) conformational averaging and (2) interactions with first-shell solvent molecules. Classical molecular dynamics simulations in explicit water were carried out for obtaining a representative ensemble including the arrangement of neighboring solvent molecules, which was then subjected to quantum chemical calculations. We could demonstrate with the small test system N-methyl acetamide (NMA) that the calculated chemical shifts show immense variations of up to 6 ppm and 50 ppm for protons and nitrogens, respectively, depending on the snapshot taken from a classical molecular dynamics simulation. Applying the same approach to the HA2 domain of the influenza virus glycoprotein hemagglutinin, a 32-amino-acid-long polypeptide, and comparing averaged values to the experiment, chemical shifts of nonpolar protons and carbon atoms in proteins were calculated with unprecedented accuracy. Additionally, the mean absolute error could be reduced by a factor of 2.43 for polar protons, and reasonable correlations were obtained for nitrogen and carbonyl carbon in contrast to all other studies published so far. PMID- 26605635 TI - Computational Study of Absorption Spectra of the Photoconvertible Fluorescent Protein EosFP in Different Protonation States. AB - Absorption spectra of the green-to-red convertible fluorescent protein EosFP have been computed in a hybrid quantum mechanical/molecular mechanical (QM/MM) framework. The experimentally observed absorption maximum at ~390 nm is well reproduced by the protein with a neutral chromophore, and the anionic form is computed to absorb close to the experimentally determined maximum at ~500 nm. Absorption of a zwitterionic form is calculated to lie in the same spectral region; however, this species cannot be unambiguously assigned to the experimental spectra. Variation of the protonation states of residues surrounding the chromophore do not have significant impact on the positions of the absorption maxima. In particular, protonation of Glu212 leaves the calculated spectra largely unaffected. This is consistent with the spectra of the E212Q mutant, which differ from the wild-type spectra only in the intensities but not in the positions of the absorption bands. PMID- 26605636 TI - Thermodynamics of Decaalanine Stretching in Water Obtained by Adaptive Steered Molecular Dynamics Simulations. AB - The nonequilibrium stretching of decaalanine in vacuum using steered molecular dynamics and Jarzynski's relation led to the landmark determination of its potential of mean force by Park and Schulten (Chem. Phys. 2004). In so doing, the relative thermodynamics of the hydrogen-bond contacts and the entropy of the chain were quantified through the reversible work, the potential of mean force (PMF). A recently developed adaptive steered molecular dynamics algorithm (Ozer et al. J. Chem. Theory Comput. 2010) has now made it possible to determine the thermodynamics, PMF, of the stretching of decaalanine in a model solvent of TIP3P water molecules. The loss of internal hydrogen bonds and the formation of hydrogen bonds between the peptide and the solvent has also been tracked with the corresponding stabilization in the PMF. As in the vacuum, most of the thermodynamic penalty to unravel the chain in solvent occurs during the regime when the internal hydrogen bonds are broken. The formation of hydrogen bonds with the solvent provides a significant stabilization not seen in vacuum, reducing the total energy cost to unravel by nearly a factor of 2. PMID- 26605637 TI - Free-Energy Landscape of a Thrombin-Binding DNA Aptamer in Aqueous Environment. AB - Thrombin-binding aptamer (TBA-15) is a single-stranded 15-mer oligonucleotide that has a wide range of biomedical applications. In the presence of metal cations of proper sizes, this aptamer displays G-quadruplexes with a single cation enclosed at its central binding site when it is completely folded. To understand how this aptamer folds into its stable three-dimensional structure in the presence of K(+) ions, we carried out free-energy calculations using the state-of-art replica exchange molecular dynamics simulation (REMD) at the all atom level. The resulting free energy map revealed that TBA-15 follows a two state folding behavior with a substantially large folding barrier of 6 kcal/mol at ambient temperature. Our simulation showed that the intervening TGT-loop, which is located in the middle of the TBA-15 sequence, virtually remains intact regardless of folding and unfolding states. Furthermore, in the conserved TGT loop structure, the base-pair stacking of G8 and T9 induces the native-like base orientations of G6 and G10 pertaining to the upper G-quadrant. This stacking interaction enhances the loop stability and reduces its dynamic fluctuations. Interestingly, for the G-stem to fold into its native state, the aggregation of the G8 and T9 residues in the TGT-loop is a key step for initiating the folding event of the G-stem by capturing a bulky cation. PMID- 26605639 TI - Synchronously Achieving Plasmonic Bi Metal Deposition and I(-) Doping by Utilizing BiOIO3 as the Self-Sacrificing Template for High-Performance Multifunctional Applications. AB - Herein, we uncover simultaneously achieving plasmonic Bi metal deposition and I( ) doping by employing wide-band-gap BiOIO3 as the self-sacrificing template. It was synthesized via a facile NaBH4-assisted in situ reduction route under ambient conditions. The reducing extent as well as photocatalytic levels can be easily modulated by controlling the concentration of NaBH4 solution. It is interesting that the band gap of BiOIO3 can be continuously narrowed by the modification, and the photoresponse range is drastically extended to cover the whole visible region. Bi/I(-) codecorated BiOIO3 not only exhibits profoundly upgraded photoreactivity in comparison with pristine BiOIO3 but also shows universally strong photooxidation properties toward decomposition of multiple industrial contaminants and pharmaceutical, including phenol, 2,4-Dichlorophenol (2,4-DCP), bisphenol A (BPA), dye model Rhodamine (RhB), tetracycline hydrochloride, and gaseous NO under visible light (lambda >= 420 nm) or simulated solar light irradiation. It also outperforms the well-known and important photocatalysts C3N4, BiOBr, and Bi2WO6 for NO removal. The cooperative effects from Bi SPR and I(-) doping endow BiOIO3 with a narrowed band gap and highly boosted separation of charge carriers, thus responsible for the outstanding catalytic activity. The present study provides an absorbing candidate for practical environmental applications and also furthers our understanding of developing high-performance photocatalysts by manipulating manifold strategies in a facile way. PMID- 26605638 TI - Nanoparticle-Assisted Removal of Protein in Human Serum for Metabolomics Studies. AB - Among human body fluids, serum plays a key role for diagnostic tests and, increasingly, for metabolomics analysis. However, the high protein content of serum poses significant challenges for nuclear magnetic resonance (NMR)-based metabolomics studies because it can strongly interfere with metabolite signal detection and quantitation. Although several methods for protein removal have been proposed, including ultrafiltration and organic-solvent-induced protein precipitation, there is currently no standard operating procedure for the elimination of protein from human serum samples. Here, we introduce novel procedures for the removal of protein from serum by the addition of nanoparticles. It is demonstrated how serum protein can be efficiently, cost effectively, and environmentally friendly removed at physiological pH (pH 7.4) through attractive interactions with silica nanoparticles. It is further shown how serum can be processed with nanoparticles prior to ultrafiltration or organic solvent-induced protein precipitation for optimal protein removal. After examination of all of the procedures, the combination of nanoparticle treatment and ultrafiltration is found to have a minimal effect on the metabolite content, leading to remarkably clean homo- and heteronuclear NMR spectra of the serum metabolome that compare favorably to other methods for protein removal. PMID- 26605640 TI - Super-Resolution Optical Fluctuation Bio-Imaging with Dual-Color Carbon Nanodots. AB - Success in super-resolution imaging relies on a proper choice of fluorescent probes. Here, we suggest novel easily produced and biocompatible nanoparticles carbon nanodots-for super-resolution optical fluctuation bioimaging (SOFI). The particles revealed an intrinsic dual-color fluorescence, which corresponds to two subpopulations of particles of different electric charges. The neutral nanoparticles localize to cellular nuclei suggesting their potential use as an inexpensive, easily produced nucleus-specific label. The single particle study revealed that the carbon nanodots possess a unique hybrid combination of fluorescence properties exhibiting characteristics of both dye molecules and semiconductor nanocrystals. The results suggest that charge trapping and redistribution on the surface of the particles triggers their transitions between emissive and dark states. These findings open up new possibilities for the utilization of carbon nanodots in the various super-resolution microscopy methods based on stochastic optical switching. PMID- 26605641 TI - Molecular Medicine Commemorates the Achievements of the First 20 Years. PMID- 26605642 TI - Once Upon a Time: The Adaptive Immune Response in Atherosclerosis--a Fairy Tale No More. AB - Extensive research has been carried out to decipher the function of the adaptive immune response in atherosclerosis, with the expectation that it will pave the road for the design of immunomodulatory therapies that will prevent or reverse the progression of the disease. All this work has led to the concept that some T- and B-cell subsets are proatherogenic, whereas others are atheroprotective. In addition to the immune response occurring in the spleen and lymph nodes, it has been shown that lymphoid neo-genesis takes place in the adventitia of atherosclerotic vessels, leading to the formation of tertiary lymphoid organs where an adaptive immune response can be mounted. Whereas the mechanisms orchestrating the formation of these organs are becoming better understood, their impact on atherosclerosis progression remains unclear. Several potential therapeutic strategies against atherosclerosis, such as protective vaccination against atherosclerosis antigens or inhibiting the activation of proatherogenic B cells, have been proposed based on our improving knowledge of the role of the immune system in atherosclerosis. These strategies have shown success in preclinical studies, giving hope that they will lead to clinical applications. PMID- 26605643 TI - 25 Years On: A Retrospective on Migration Inhibitory Factor in Tumor Angiogenesis. AB - Twenty-five years ago marked the publication of the first report describing a functional contribution by the cytokine, macrophage migration inhibitory factor (MIF), to tumor-associated angiogenesis and growth. Since first appearing, this report has been cited 304 times (as of this writing), underscoring not only the importance of this landmark study but also the importance of MIF in tumor neovascularization. Perhaps more importantly, this first link between MIF and stromal cell-dependent tumor angiogenesis presaged the subsequent identification of MIF in mediating protumorigenic contributions to several solid tumor stromal cell types, including monocytes, macrophages, T lymphocytes, NK cells, fibroblasts, endothelial progenitors and mesenchymal stem cells. This retrospective review will broadly evaluate both past and present literature stemming from this initial publication, with an emphasis on cellular sources, cellular effectors, signal transduction mechanisms and the clinical importance of MIF-dependent tumor vascularization. PMID- 26605644 TI - Detection and Clinical Significance of Circulating Tumor Cells in Colorectal Cancer--20 Years of Progress. AB - Circulating tumor cells (CTC) may be defined as tumor- or metastasis-derived cells that are present in the bloodstream. The CTC pool in colorectal cancer (CRC) patients may include not only epithelial tumor cells, but also tumor cells undergoing epithelial-mesenchymal transition (EMT) and tumor stem cells. A significant number of patients diagnosed with early stage CRC subsequently relapse with recurrent or metastatic disease despite undergoing "curative" resection of their primary tumor. This suggests that an occult metastatic disease process was already underway, with viable tumor cells being shed from the primary tumor site, at least some of which have proliferative and metastatic potential and the ability to survive in the bloodstream. Such tumor cells are considered to be responsible for disease relapse in these patients. Their detection in peripheral blood at the time of diagnosis or after resection of the primary tumor may identify those early-stage patients who are at risk of developing recurrent or metastatic disease and who would benefit from adjuvant therapy. CTC may also be a useful adjunct to radiological assessment of tumor response to therapy. Over the last 20 years many approaches have been developed for the isolation and characterization of CTC. However, none of these methods can be considered the gold standard for detection of the entire pool of CTC. Recently our group has developed novel unbiased inertial microfluidics to enrich for CTC, followed by identification of CTC by imaging flow cytometry. Here, we provide a review of progress on CTC detection and clinical significance over the last 20 years. PMID- 26605645 TI - Fibrocytes at 20 Years. PMID- 26605646 TI - Advanced Glycation End Products: A Molecular Target for Vascular Complications in Diabetes. AB - A nonenzymatic reaction between reducing sugars and amino groups of proteins, lipids and nucleic acids contributes to the aging of macromolecules and subsequently alters their structural integrity and function. This process has been known to progress at an accelerated rate under hyperglycemic and/or oxidative stress conditions. Over a course of days to weeks, early glycation products undergo further reactions such as rearrangements and dehydration to become irreversibly cross-linked, fluorescent and senescent macroprotein derivatives termed advanced glycation end products (AGEs). There is a growing body of evidence indicating that interaction of AGEs with their receptor (RAGE) elicits oxidative stress generation and as a result evokes proliferative, inflammatory, thrombotic and fibrotic reactions in a variety of cells. This evidence supports AGEs' involvement in diabetes- and aging-associated disorders such as diabetic vascular complications, cancer, Alzheimer's disease and osteoporosis. Therefore, inhibition of AGE formation could be a novel molecular target for organ protection in diabetes. This report summarizes the pathophysiological role of AGEs in vascular complications in diabetes and discusses the potential clinical utility of measurement of serum levels of AGEs for evaluating organ damage in diabetes. PMID- 26605648 TI - High Mobility Group Box Protein 1 (HMGB1): The Prototypical Endogenous Danger Molecule. AB - High mobility group box protein 1 (HMGB1) is an evolutionary ancient nuclear protein that exerts divergent biological tasks inside and outside of cells. The functions of HMGB1 depend on location, binding partners and redox states of the molecule. In the nucleus, HMGB1 organizes DNA and nucleosomes and regulates gene transcription. Upon cell activation or injury, nuclear HMGB1 can translocate to the cytoplasm, where it is involved in inflammasome activation and pyroptosis, as well as regulation of the autophagy/apoptosis balance. When actively secreted or passively released into the extracellular milieu, HMGB1 has cytokine, chemokine, neuroimmune and metabolic activities. Thus, HMGB1 plays multiple roles in the pathogenesis of inflammatory diseases and mediates immune responses that range from inflammation and bacterial killing to tissue repair. HMGB1 has been associated with divergent clinical conditions such as sepsis, rheumatoid arthritis and atherosclerosis. HMGB1 initiates and perpetuates immune responses during infectious and sterile inflammation, as the archetypical alarmin and damage-associated molecular pattern (DAMP) molecule. We here describe advances in the understanding of HMGB1 biology with focus on recent findings of its mission as a DAMP in danger sensing and as a therapeutic target in inflammatory diseases. PMID- 26605666 TI - Mycobacterium tuberculosis PPE68 and Rv2626c genes contribute to the host cell necrosis and bacterial escape from macrophages. AB - Alveolar macrophages are the main line of innate immune response against M. tuberculosis (Mtb) infection. However, these cells serve as the major intracellular niche for Mtb enhancing its survival, replication and, later on, cell-to-cell spread. Mtb-associated cytotoxicity of macrophages has been well documented, but limited information exists about mechanisms by which the pathogen induces cell necrosis. To identify virulence factors involved in the induction of necrosis, we screened 5,000 transposon mutants of Mtb for clones that failed to promote the host cell necrosis in a similar manner as the wild-type bacterium. Five Mtb mutants were identified as potential candidates inducing significantly lower levels of THP-1 cell damage in contrast to the H37Rv wild-type infection. Reduced levels of the cell damage by necrosis deficient mutants (NDMs) were also associated with delayed damage of mitochondrial membrane permeability when compared with the wild-type infection over time. Two knockout mutants of the Rv3873 gene, encoding a cell wall PPE68 protein of RD1 region, were identified out of 5 NDMs. Further investigation lead to the observation that PPE68 protein interacts and exports several unknown or known surface/secreted proteins, among them Rv2626c is associated with the host cell necrosis. When the Rv2626c gene is deleted from the genome of Mtb, the bacterium displays significantly less necrosis in THP-1 cells and, conversely, the overexpression of Rv2626c promotes the host cell necrosis at early time points of infections in contrast to the wild type strain. PMID- 26605647 TI - Twenty Years of Presenilins--Important Proteins in Health and Disease. AB - Alzheimer's disease (AD) is characterized by progressive decline in cognitive functions associated with depositions of aggregated proteins in the form of extracellular plaques and neurofibrillary tangles in the brain. Extracellular plaques contain characteristic fibrils of amyloid beta peptides (Abeta); tangles consist of paired helical filaments of the microtubuli-associated protein tau. Although AD manifests predominantly at ages above 65 years, rare cases show a much earlier onset of disease symptoms with very similar neuropathological characteristics. In 1995, two homologous genes were identified, in which mutations are associated with dominantly inherited familial forms of early onset AD. The genes therefore were dubbed presenilins (PS) and encode polytopic transmembrane proteins. At this time the role of these proteins in the pathogenesis of AD and their biological function in general were completely unknown. However, individuals carrying PS mutations showed alterations in the composition of different length variants of Abeta peptides in blood and cerebrospinal fluid, which indicated the potential involvement of presenilins in the metabolism of Abeta. After 20 years of intense research, the roles of presenilins in Abeta generation as well as important functions in biological processes have been identified. Presenilins represent the catalytic components of protease complexes that directly cleave the amyloid precursor protein (APP) but also many other proteins with important physiological functions. Here, the progress in presenilin research from basic characterization of their cellular functions to the targeting in clinical trials for AD therapy, and potential future directions, will be discussed. PMID- 26605667 TI - First Evidence of the Liposome-Mediated Deintercalation of Anticancer Drug Doxorubicin from the Drug-DNA Complex: A Spectroscopic Approach. AB - Biocompatible liposomes were used for the first time to study the deintercalation process of a prominent anticancer drug, doxorubicin (DOX), from doxorubicin intercalated DNA (DOX-DNA complex) under controlled experimental conditions. The study revealed that anionic liposomes (DMPG liposomes) appeared to be the most effective to bring in the highest percentage of drug release while cationic liposomes (DOTAP liposomes) scored the lowest percentage of release. The drug release was primarily attributed to the electrostatic interaction between liposomes and drug molecules. Apart from this interaction, changes in the hydrophobicity of the medium upon addition of liposomes to the DNA-drug solution accompanied by lipoplex formation between DNA and liposomes were also attributed to the observed deintercalation. The CD and the time-resolved rotational relaxation studies confirmed that lipoplex formation took place between liposomes and DNA owing to electrostatic interaction. The confocal study revealed that in the postrelease period, DOX binds with liposomes. The reason behind the binding is electrostatic interaction as well as the unique bilayer structure of liposomes which helps it to act as a "hydrophobic sink" for DOX. The study overall highlighted a novel strategy for deintercalation of drug using biocompatible liposomes, as the release of the drug can be controlled over a period of time by varying the concentration and composition of the liposomes. PMID- 26605668 TI - Evaluation of Corneal Thickness and Volume Parameters of Subclinical Keratoconus Using a Pentacam Scheimflug System. AB - PURPOSE: To evaluate the efficacy of corneal thickness and volume parameters measured with the Pentacam Scheimflug system in discriminating subclinical keratoconus corneas and normal corneas. METHODS: This study included 19 patients (19 eyes) with subclinical keratoconus and 29 patients (29 eyes) with myopic astigmatism as the control group. Corneas were evaluated using a Pentacam Scheimflug system (2002 model, Oculus, Berkshire, UK). We evaluated corneal thickness and volume parameters, including central corneal thickness (CCT), minimum corneal thickness (MCT), depressed corneal thickness (DCT), maximum progression index (MaxPI), average progression index (AvPI), minimum progression index (MinPI), and corneal volume values for the 3.0 mm (CV3), 5.0 mm (CV5), and 7.0 mm (CV7) central circles. Receiver operating characteristic (ROC) curves were used to compare the sensitivity and the specificity of the parameters. Partial least squares (PLS) analysis was used to construct models with corneal thickness and volume parameters for early diagnosis. RESULTS: There were significant differences in all parameters (p < 0.001), except CV3 and CV5, between subclinical keratoconus and normal corneas. The diagnostic accuracy for all parameters was high, with an area-under-the-curve (AUC) of approximately 1. The optimal cutoff values for DCT, MinPI, AvPI, and MaxPI were 5.5, 0.95, 1.05, and 1.45 for subclinical keratoconus, respectively. The PLS model for subclinical keratoconus fit well to the CCT, MCT, MaxPI, AvPI, MinPI, CV3, and CV7 data. CONCLUSION: Thickness and volume parameters measured by the Pentacam Scheimflug system effectively discriminate subclinical keratoconus corneas from normal corneas. PMID- 26605669 TI - The relationship between neuropsychological assessment, numeracy, and functional status in older adults with type 1 diabetes. AB - While data are accumulating on the association between neuropsychological performance and real-world endpoints, less is known about the association with medical self-management skills. The self-management of type 1 diabetes (T1D) is often complex, and mismanagement can result in hypoglycaemia and hyperglycaemia and associated morbidity and mortality. The T1D Exchange conducted a case-control study evaluating factors associated with severe hypoglycaemia in older adults (>= 60 years old) with longstanding T1D (>= 20 years). A battery of neuropsychological and functional assessments was administered, including measures of diabetes-specific self-management skill (diabetes numeracy) and instrumental activities of daily living (IADL). After adjusting for confounding variables, diabetes numeracy was related to memory and complex speeded attention; while IADL were associated with simple processing speed, executive functioning, complex speeded attention and dominant hand dexterity. The severity of overall cognitive deficit was uniquely associated with both diabetes numeracy and IADL, when controlling for age, education, frailty and depression. This study demonstrates that the cognitive deficits in older adults with T1D have functional implications for both diabetes management and IADL. Further research is needed to determine specific interventions to maximise diabetes self-management in older adults with declining cognition. PMID- 26605670 TI - Fumonisins B1 and B2 in the corn-milling process and corn-based products, and evaluation of estimated daily intake. AB - The distribution of fumonisins (FBs: FB1 and FB2) in the corn-milling process and in corn-based products, as well as daily intake estimates for the Brazilian population were evaluated. Among corn fractions samples, corn meal had the highest mean concentration of FB1 (1305 ug kg(-1)) and FB2 (651 ug kg(-1)) and a distribution factors of 452% and 256% in relation to corn grain, respectively. On the other hand, the distribution factor of FB1 and FB2 in corn flour was found to be 144% and 88% respectively, which demonstrates that fumonisins in this fraction were reduced compared with corn grain. As a result, almost half the corn meal samples (47%) would be non-compliant with future Brazilian regulation (2017) for fumonisins. However, corn-based products, such as corn flakes and popcorn, were in compliance with the regulation. The average probable daily intake and maximum probable daily intake of fumonisins estimated for the Santa Catarina state (Brazil) population were below the provisional maximum tolerable daily intake of 2 ug kg(-1) body weight day(-1) for all corn samples. Despite this, the adoption of practices to control the occurrence of fumonisins should be applied to the corn-milling fractions that may contain a higher concentration of this toxin, such as corn meal, often used for animal feed in Brazil. PMID- 26605671 TI - Inequities in access to rehabilitation: exploring how acute stroke unit clinicians decide who to refer to rehabilitation. AB - PURPOSE: Less than half of the patients with stroke in Australian hospitals are assessed by rehabilitation specialists. We sought to explore how clinicians working in acute stroke units (ASUs) determine which patients to refer to rehabilitation services. METHOD: Qualitative descriptive study. Team meetings were observed and medical records were reviewed over four weeks at two ASUs. Focus groups were conducted with staff from eight ASUs in two states of Australia. RESULTS: Rehabilitation was mentioned in team meetings for 50/64 patients (78%) during the observation period. Rehabilitation referrals were organised for 47 patients (94%) for whom rehabilitation was discussed (74% of the sample); and for no patients when rehabilitation was not discussed. Factors identified that influenced whether referrals were organised included the anticipated discharge destination; severity of stroke; staff expectations of the patient's recovery; and if there was advocacy by families about rehabilitation. Clinicians tended to refer the patients they considered would be accepted by the rehabilitation service. Staff at two ASUs expressed concern that referring all patients with stroke-related deficits to rehabilitation would be unfavourable with rehabilitation providers. CONCLUSIONS: Decisions made by ASU staff regarding who to refer to stroke rehabilitation are often not solely based on patients' rehabilitation requirements. Implications for Rehabilitation Not all patients on acute stroke units (ASUs) who may have benefited from rehabilitation were offered rehabilitation referrals. Criteria for rehabilitation referrals need to be made explicit and discussed openly with consumers, ASU clinicians and rehabilitation specialists. A change in rehabilitation assessment practices is required to provide data regarding the unmet rehabilitation needs of patients with stroke. New models of rehabilitation service delivery or increased rehabilitation services may be required to meet the rehabilitation needs of all patients with stroke. PMID- 26605672 TI - Intracellular transport and cell surface delivery of the neural cell adhesion molecule (NCAM). AB - The neural cell adhesion molecule (NCAM) regulates differentiation and functioning of neurons by accumulating at the cell surface where it mediates the interactions of neurons with the extracellular environment. NCAM also induces a number of intracellular signaling cascades, which coordinate interactions at the cell surface with intracellular processes including changes in gene expression, transport and cytoskeleton remodeling. Since NCAM functions at the cell surface, its transport and delivery to the cell surface play a critical role. Here, we review recent advances in our understanding of the molecular mechanisms of the intracellular transport and cell surface delivery of NCAM. We also discuss the data suggesting a possibility of cross talk between activation of NCAM at the cell surface and the intracellular transport and cell surface delivery of NCAM. PMID- 26605673 TI - Adolescent Substance Use Following a Deadly U.S. Tornado Outbreak: A Population Based Study of 2,000 Families. AB - : Despite conceptual links between disaster exposure and substance use, few studies have examined prevalence and risk factors for adolescent substance use and abuse in large, population-based samples affected by a recent natural disaster. We addressed this gap using a novel address-based sampling methodology to interview adolescents and parents who were affected by the 4th deadliest tornado outbreak in U.S. HISTORY: Postdisaster interviews were conducted with 2,000 adolescent-parent dyads living within a 5-mile radius of the spring 2011 U.S. tornadoes. In addition to descriptive analyses to estimate prevalence, hierarchical linear and logistic regression analyses were used to examine a range of protective and risk factors for substance use and abuse. Approximately 3% reported substance abuse since the tornado. Greater number of prior traumatic events and older age emerged as consistent risk factors across tobacco and alcohol use and substance abuse since the tornado. Tornado incident characteristics, namely, greater loss of services and resources after the tornado and posttraumatic stress disorder since the tornado, were associated with greater alcohol consumption. Service loss increased risk for binge drinking, whereas, for substance abuse, posttraumatic stress disorder increased risk and parent presence during the tornado decreased risk. Greater family tornado exposure was associated with a greater number of cigarettes smoked in female but not male teen participants. Both trauma and non-trauma-related factors are relevant to postdisaster substance abuse among adolescents. Future research should examine the role of broader ecological systems in heightening or curtailing substance use risk for adolescents following disaster exposure. PMID- 26605674 TI - Aldosterone and right ventricular dysfunction: more data to be collected with prospective cohort studies. PMID- 26605675 TI - Is the specific effect of receiving oxaliplatin, or merely the nonspecific effect of having suffered cancer, the cause of Takotsubo syndrome? PMID- 26605676 TI - Glasgow prognostic score in heart failure, how can we use it? PMID- 26605677 TI - Letter in reply: Glasgow Prognostic Score in heart failure, how can we use it? PMID- 26605678 TI - Kisspeptin as a therapeutic target in reproduction. AB - INTRODUCTION: Kisspeptins are a family of neuropeptides whose identification has become one of the biggest discoveries in reproductive endocrinology during the past decade. Kisspeptins act upstream of GnRH as high-level mediators of the reproductive axis. AREAS COVERED: The authors performed a search of all publications on kisspeptin since its discovery in 1996. A full appraisal of the expanding literature concerning kisspeptin is beyond the scope of this review. This article therefore aims to cover the principle human studies outlining kisspeptin action in human physiology and to discuss the key findings, describing kisspeptin's potential as a therapeutic target in human reproduction. EXPERT OPINION: The identification of the kisspeptin signaling pathway has greatly advanced the study of reproductive endocrinology. Building on a large body of animal data, a growing number of human studies have shown that exogenous kisspeptin can stimulate physiological gonadotropin responses in both healthy subjects and those with disorders of reproduction. There is an increasing appreciation that kisspeptin may act as a signal transmitter between metabolic status and reproductive function. Future work is likely to involve investigation of novel kisspeptin analogs and further exploration of role of neurokinin B and dynorphin on the kisspeptin-GnRH axis. PMID- 26605679 TI - Assessing the radiation-induced second cancer risk in proton therapy for pediatric brain tumors: the impact of employing a patient-specific aperture in pencil beam scanning. AB - The purpose of this study was to compare the radiation-induced second cancer risks for in-field and out-of-field organs and tissues for pencil beam scanning (PBS) and passive scattering proton therapy (PPT) and assess the impact of adding patient-specific apertures to sharpen the penumbra in pencil beam scanning for pediatric brain tumor patients. Five proton therapy plans were created for each of three pediatric patients using PPT as well as PBS with two spot sizes (average sigma of ~17 mm and ~8 mm at isocenter) and choice of patient-specific apertures. The lifetime attributable second malignancy risks for both in-field and out-of field tissues and organs were compared among five delivery techniques. The risk for in-field tissues was calculated using the organ equivalent dose, which is determined by the dose volume histogram. For out-of-field organs, the organ specific dose equivalent from secondary neutrons was calculated using Monte Carlo and anthropomorphic pediatric phantoms. We find that either for small spot size PBS or for large spot size PBS, a patient-specific aperture reduces the in-field cancer risk to values lower than that for PPT. The reduction for large spot sizes (on average 43%) is larger than for small spot sizes (on average 21%). For out-of field organs, the risk varies only marginally by employing a patient-specific aperture (on average from -2% to 16% with increasing distance from the tumor), but is still one to two orders of magnitude lower than that for PPT. In conclusion, when pencil beam spot sizes are large, the addition of apertures to sharpen the penumbra decreases the in-field radiation-induced secondary cancer risk. There is a slight increase in out-of-field cancer risk as a result of neutron scatter from the aperture, but this risk is by far outweighed by the in field risk benefit from using an aperture with a large PBS spot size. In general, the risk for developing a second malignancy in out-of-field organs for PBS remains much lower compared to PPT even if apertures are being applied. PMID- 26605680 TI - Does IV Iron Induce Plasma Oxidative Stress in Critically Ill Patients? A Comparison With Healthy Volunteers. AB - OBJECTIVE: To compare the oxidative stress induced by IV iron infusion in critically ill patients and in healthy volunteers. DESIGN: Multicenter, interventional study. SETTING: Two ICUs and one clinical research center. SUBJECTS: Anemic critically ill patients treated with IV iron and healthy volunteers. INTERVENTIONS: IV infusion of 100 mg of iron sucrose. MEASUREMENTS AND MAIN RESULTS: Thirty-eight anemic patients (hemoglobin, median [interquartile range] = 8.4 g/dL [7.7-9.2]) (men, 25 [66%]; aged 68 yr [48-77]; Simplified Acute Physiology Score II, 48.5 [39-59]) and 39 healthy volunteers (men, 18 [46%]; aged 42.1 yr [29-50]) were included. Blood samples were drawn before (H0) and 2, 6, and 24 hours (H2, H6, and H24) after a 60-minute iron infusion for the determination of nontransferrin bound iron, markers of lipid peroxidation-8alpha isoprostanes, protein oxidation-advanced oxidized protein product, and glutathione reduced/oxidized. Iron infusion had no effect on hemodynamic parameter in patients and volunteers. At baseline, patients had much higher interleukin-6, C-reactive protein, and hepcidin levels. 8alpha-isoprostanes was also higher in patients at baseline (8.5 pmol/L [6.5-12.9] vs 4.6 pmol/L [3.5 5.5]), but the area under the curve above baseline from H0 to H6 was not different (p = 0.38). Neither was it for advanced oxidized protein product and nontransferrin bound iron. The area under the curve above baseline from H0 to H6 (glutathione reduced/oxidized) was lower in volunteers (p = 0.009). Eight patients had a second set of dosages (after the fourth iron infusion), showing higher increase in 8alpha-isoprostanes. CONCLUSIONS: In our observation, IV iron infusion does not induce more nontransferrin bound iron, lipid, or protein oxidation in patients compared with volunteers, despite higher inflammation, oxidative stress, and hepcidin levels and lower antioxidant at baseline. In contrary, iron induces a greater decrease in antioxidant, compatible with higher oxidative stress in volunteers than in critically ill patients. PMID- 26605681 TI - Establishment of a highly metastatic buccal squamous cell carcinoma cell line from a Sprague-Dawley Rat. AB - OBJECTIVES: The incidence of buccal squamous cell carcinoma (buccal SCC) is considered to be the second highest out of all oral cancers, but the unsatisfactory in vivo tumorigenicity and metastatic potential of the widely used cell lines have greatly delayed studies on the mechanisms of tumor progression. This study aimed to establish a highly metastatic buccal SCC cell line, which may serve a useful tool in buccal SCC research. MATERIALS AND METHODS: Buccal SCC was induced by 4-nitroquinoline-1-oxide (4NQO) in Sprague-Dawley rats. The cancer samples were collected, and the tumor cells were purified in vitro. A highly aggressive cell line termed "Rca-B" was established by an invasion assay. Its proliferative ability, cell cycle distribution, baseline level of apoptosis, carcinogenicity and metastatic behavior in nude mice were investigated. RESULTS: To date, Rca-B cells have been stably cultured in vitro for more than 180 passages. These cells were polygonal or spindle-shaped, grew adhesively, and exhibited a stable epithelial phenotype as characterized by positive expression of cytokeratin. The population doubling time was 25.09 h. Cells in S-phase of the cell cycle accounted for 31.17% of the total number of cells, and the baseline level of apoptosis was 8.52%. The in vitro migration and invasion assays revealed highly aggressive features of Rca-B cells. In addition, the rate of xenograft formation was 100%, and the incidence of experimental lung metastasis was 81.8% in immunodeficient nude mice. CONCLUSION: The Rca-B cell line was established as a highly metastatic rat buccal SCC cell line, and its in-depth characterization, which includes malignant behaviors, allows for a wealth of functional studies on the molecular mechanisms of buccal SCC progression and targeted therapy. PMID- 26605682 TI - Impact of glycemic control on oral health status in type 2 diabetes individuals and its association with salivary and plasma levels of chromogranin A. AB - OBJECTIVE: To evaluate the effect of glycemic control status in type 2 diabetes mellitus (T2DM) individuals on clinical oral health indicators and to compare the concentrations of plasma and salivary chromogranin A (CHGA) among nondiabetic subjects and T2DM patients, exploring their associations. DESIGN: In this cross sectional study, 32 patients with controlled T2DM, 31 with poorly controlled T2DM and 37 nondiabetic subjects underwent a clinical and periodontal examination. CHGA concentrations were determined in saliva and plasma with ELISA. RESULTS: Poorly controlled T2DM group exhibited significantly higher mean buffering capacity, plaque index and bleeding on probing than other groups (P<0.05). No difference was found to DMFT (decayed, missed and filled teeth) index between groups. Sites with clinical attachment loss (CAL) of 4 and 5-6mm were significantly higher in both diabetic groups compared to control group (P<0.05). Poorly controlled T2DM group had significantly higher sites with CAL >= 7 mm than other groups (P=0.001). Significantly higher plasma and salivary CHGA levels were found in T2DM groups (P<0.05). In both diabetic groups, probing depths 5-6mm and CAL 5-6mm were associated with higher salivary CHGA concentration (P<0.05). CONCLUSIONS: The findings revealed that T2DM patients were more prone to periodontal tissue damage than to caries risk. The results also provide some evidence that the degree of attachment loss deteriorates significantly with poor glycemic control in T2DM (CAL >= 7 mm). Moreover, the results suggest that high concentrations of salivary CHGA are associated with worse periodontal parameters and T2DM, and this could be related to the pathogenesis of both diseases. PMID- 26605683 TI - New Insights into the Parasitoid Parvilucifera sinerae Life Cycle: The Development and Kinetics of Infection of a Bloom-forming Dinoflagellate Host. AB - Parvilucifera sinerae is a parasitoid of dinoflagellates, the major phytoplankton group responsible for harmful algal bloom events. Here we provide a detailed description of both the life cycle of P. sinerae, based on optical, confocal, and transmission electron microscopy observations, and its infection kinetics and dynamics. P. sinerae completes its life cycle in 3-4 days. The zoospore encounters and penetrates the host cell within 24h after its addition to the host culture. Inside the host, the parasitoid develops a trophocyte, which constitutes the longest stage of its life cycle. The trophocyte replicates and divides by schizogony to form hundreds of new zoospores contained within a sporangium. Under laboratory conditions, P. sinerae has a short generation time, a high rate of asexual reproduction, and is highly prevalent (up to 80%) in the Alexandrium minutum population. Prevalence was shown to depend on both the parasitoid inoculum size and host density, which increase the encounter probability rate. The parasitoid infection parameters described in this study are the first reported for the genus Parvilucifera. They show that P. sinerae is well-adapted to its dinoflagellate hosts and may be an important factor in the termination of A. minutum blooms in the natural environment. PMID- 26605684 TI - Genome size diversity in angiosperms and its influence on gene space. AB - Genome size varies c. 2400-fold in angiosperms (flowering plants), although the range of genome size is skewed towards small genomes, with a mean genome size of 1C=5.7Gb. One of the most crucial factors governing genome size in angiosperms is the relative amount and activity of repetitive elements. Recently, there have been new insights into how these repeats, previously discarded as 'junk' DNA, can have a significant impact on gene space (i.e. the part of the genome comprising all the genes and gene-related DNA). Here we review these new findings and explore in what ways genome size itself plays a role in influencing how repeats impact genome dynamics and gene space, including gene expression. PMID- 26605685 TI - Genomic insights into the distribution, genetic diversity and evolution of polyketide synthases and nonribosomal peptide synthetases. AB - Polyketides and nonribosomal peptides are important secondary metabolites that exhibit enormous structural diversity, have many pharmaceutical applications, and include a number of clinically important drugs. These complex metabolites are most commonly synthesized on enzymatic assembly lines of polyketide synthases and nonribosomal peptide synthetases. Genome-mining studies making use of the recent explosion in the number of genome sequences have demonstrated unexpected enzymatic diversity and greatly expanded the known distribution of these enzyme systems across the three domains of life. The wealth of data now available suggests that genome-mining efforts will uncover new natural products, novel biosynthetic mechanisms, and shed light on the origin and evolution of these important enzymes. PMID- 26605686 TI - Characterization of corrosion scale formed on stainless steel delivery pipe for reclaimed water treatment. AB - To reveal corrosion behavior of stainless steel delivery pipe used in reclaimed water treatment, this research focused on the morphological, mineralogical and chemical characteristics of stainless steel corrosion scale and corroded passive film. Corrosion scale and coupon samples were taken from a type 304 pipe delivering reclaimed water to a clear well in service for more than 12 years. Stainless steel corrosion scales and four representative pipe coupons were investigated using mineralogy and material science research methods. The results showed corrosion scale was predominantly composed of goethite, lepidocrocite, hematite, magnetite, ferrous oxide, siderite, chrome green and chromite, the same as that of corroded pipe coupons. Hence, corrosion scale can be identified as podiform chromite deposit. The loss of chromium in passive film is a critical phenomenon when stainless steel passive film is damaged by localized corrosion. This may provide key insights toward improving a better comprehension of the formation of stainless steel corrosion scale and the process of localized corrosion. The localized corrosion behavior of stainless steel is directly connected with reclaimed water quality parameters such as residual chlorine, DO, Cl(-) and SO4(2-). In particular, when a certain amount of residual chlorine in reclaimed water is present as an oxidant, ferric iron is the main chemical state of iron minerals. PMID- 26605687 TI - Concomitant nitrates enhance clopidogrel response during dual anti-platelet therapy. AB - BACKGROUND: Despite advances in modern anti-platelet strategies, clopidogrel still remains the cornerstone of dual anti-platelet therapy (DAPT) in patients undergoing percutaneous coronary interventions (PCI). There is some inconclusive evidence that response after clopidogrel may be impacted by concomitant medications, potentially affecting clinical outcomes. Sustained released nitrates (SRN) are commonly used together with clopidogrel in post-PCI setting for mild vasodilatation and nitric oxide-induced platelet inhibition. METHODS: We prospectively enrolled 458 patients (64.5 +/- 9.6 years old, and 73.4% males) following PCI undergoing DAPT with clopidogrel and aspirin. Platelet reactivity was assessed by the VerifyNowTM P2Y12 assay at the maintenance outpatient setting. RESULTS: Concomitant SRN (n=266) significantly (p=0.008) enhanced platelet inhibition after DAPT (251.6 +/- 80.9PRU) when compared (232.1 +/- 73.5PRU) to the SRN-free (n=192) patients. Multivariate logistic regression analysis with the cut-off value of 253 PRU for defining heightened platelet reactivity confirmed independent correlation of more potent platelet inhibition during DAPT and use of SRN (Relative risk=1.675; Odds ratio [1.059-2.648]; p=0.027). In contrast, statins, calcium-channel blockers, beta blockers, angiotensin receptor blockers, ACE-inhibitors, diuretics, and anti-diabetic agents did not significantly impact platelet inhibition following DAPT. CONCLUSION: The synergic ability of SRN to enhance response during DAPT may have important clinical implications with regard to better cardiovascular protection, but extra bleeding risks, requiring further confirmation in a large randomized study. PMID- 26605688 TI - REal-LIfe Evidence of stroke prevention in patients with atrial Fibrillation--The RELIEF study. PMID- 26605689 TI - Role of (99m)Tc-DPD scintigraphy on discrimination of familial cardiac amyloidosis. PMID- 26605690 TI - Effects of EPAP on exercise tolerance in COPD patients with dynamic hyperinflation and suspected abnormal left ventricular filling pressure by echocardiography. PMID- 26605691 TI - Retinal Arterial Tortuosity in Moyamoya Disease. PMID- 26605692 TI - Abnormal carbene-silicon halide complexes. AB - Reaction of the anionic N-heterocyclic dicarbene (NHDC), [:C{[N(2,6 Pr(i)2C6H3)]2CHCLi}]n (1), with SiCl4 gives the trichlorosilyl-substituted (at the C4 carbon) N-heterocyclic carbene complex (7). Abnormal carbene-SiCl4 complex (8) may be conveniently synthesized by combining 7 with HCl.NEt3. In addition, 7 may react with CH2Cl2 in warm hexane, giving the abnormal carbene-complexed SiCl3(+) cation (9). The nature of the bonding in 9 was probed with complementary DFT computations. PMID- 26605693 TI - Disseminated Red Violaceous Papulonodular Lesions. PMID- 26605695 TI - Surrogates for Survival or Other End Points in Oncology. PMID- 26605694 TI - The effect of normal aging and age-related macular degeneration on perceptual learning. AB - We investigated whether perceptual learning could be used to improve peripheral word identification speed. The relationship between the magnitude of learning and age was established in normal participants to determine whether perceptual learning effects are age invariant. We then investigated whether training could lead to improvements in patients with age-related macular degeneration (AMD). Twenty-eight participants with normal vision and five participants with AMD trained on a word identification task. They were required to identify three letter words, presented 10 degrees from fixation. To standardize crowding across each of the letters that made up the word, words were flanked laterally by randomly chosen letters. Word identification performance was measured psychophysically using a staircase procedure. Significant improvements in peripheral word identification speed were demonstrated following training (71% +/ 18%). Initial task performance was correlated with age, with older participants having poorer performance. However, older adults learned more rapidly such that, following training, they reached the same level of performance as their younger counterparts. As a function of number of trials completed, patients with AMD learned at an equivalent rate as age-matched participants with normal vision. Improvements in word identification speed were maintained at least 6 months after training. We have demonstrated that temporal aspects of word recognition can be improved in peripheral vision with training across a range of ages and these learned improvements are relatively enduring. However, training targeted at other bottlenecks to peripheral reading ability, such as visual crowding, may need to be incorporated to optimize this approach. PMID- 26605696 TI - Accurate Estimation of the Entropy of Rotation-Translation Probability Distributions. AB - The estimation of rotational and translational entropies in the context of ligand binding has been the subject of long-time investigations. The high dimensionality (six) of the problem and the limited amount of sampling often prevent the required resolution to provide accurate estimates by the histogram method. Recently, the nearest-neighbor distance method has been applied to the problem, but the solutions provided either address rotation and translation separately, therefore lacking correlations, or use a heuristic approach. Here we address rotational-translational entropy estimation in the context of nearest-neighbor based entropy estimation, solve the problem numerically, and provide an exact and an approximate method to estimate the full rotational-translational entropy. PMID- 26605697 TI - Iridium-Catalyzed Intramolecular Asymmetric Allylic Dearomatization Reaction of Pyridines, Pyrazines, Quinolines, and Isoquinolines. AB - The first Ir-catalyzed intramolecular asymmetric allylic dearomatization reaction of pyridines, pyrazines, quinolines, and isoquinolines has been developed. Enabled by in situ formed chiral Ir-catalyst, the dearomatized products were isolated in high levels of yield (up to 99% yield) and enantioselectivity (up to 99% ee). It is worth noting that the Me-THQphos ligand is much more efficient than other tested ligands for the dearomatization of pyrazines and certain quinolines. Mechanistic studies of the dearomatization reaction were carried out, and the results suggest the feasibility of an alternative process which features the formation of a quinolinium as the key intermediate. The mechanistic findings render this reaction a yet unknown type in the chemistry of Reissert-type reactions. In addition, the utility of this method was showcased by a large-scale reaction and formal synthesis of (+)-gephyrotoxin. PMID- 26605698 TI - Submolecular Imaging by Noncontact Atomic Force Microscopy with an Oxygen Atom Rigidly Connected to a Metallic Probe. AB - In scanning probe microscopy, the imaging characteristics in the various interaction channels crucially depend on the chemical termination of the probe tip. Here we analyze the contrast signatures of an oxygen-terminated copper tip with a tetrahedral configuration of the covalently bound terminal O atom. Supported by first-principles calculations we show how this tip termination can be identified by contrast analysis in noncontact atomic force and scanning tunneling microscopy (NC-AFM, STM) on a partially oxidized Cu(110) surface. After controlled tip functionalization by soft indentations of only a few angstroms in an oxide nanodomain, we demonstrate that this tip allows imaging an organic molecule adsorbed on Cu(110) by constant-height NC-AFM in the repulsive force regime, revealing its internal bond structure. In established tip functionalization approaches where, for example, CO or Xe is deliberately picked up from a surface, these probe particles are only weakly bound to the metallic tip, leading to lateral deflections during scanning. Therefore, the contrast mechanism is subject to image distortions, artifacts, and related controversies. In contrast, our simulations for the O-terminated Cu tip show that lateral deflections of the terminating O atom are negligible. This allows a detailed discussion of the fundamental imaging mechanisms in high-resolution NC-AFM experiments. With its structural rigidity, its chemically passivated state, and a high electron density at the apex, we identify the main characteristics of the O terminated Cu tip, making it a highly attractive complementary probe for the characterization of organic nanostructures on surfaces. PMID- 26605699 TI - Organoheterotrophic Bacterial Abundance Associates with Zinc Removal in Lignocellulose-Based Sulfate-Reducing Systems. AB - Syntrophic relationships between fermentative and sulfate-reducing bacteria are essential to lignocellulose-based systems applied to the passive remediation of mining-influenced waters. In this study, seven pilot-scale sulfate-reducing bioreactor columns containing varying ratios of alfalfa hay, pine woodchips, and sawdust were analyzed over ~500 days to investigate the influence of substrate composition on zinc removal and microbial community structure. Columns amended with >10% alfalfa removed significantly more sulfate and zinc than did wood-based columns. Enumeration of sulfate reducers by functional signatures (dsrA) and their putative identification from 16S rRNA genes did not reveal significant correlations with zinc removal, suggesting limitations in this directed approach. In contrast, a strong indicator of zinc removal was discerned in comparing the relative abundance of core microorganisms shared by all reactors (>80% of total community), many of which had little direct involvement in metal or sulfate respiration. The relative abundance of Desulfosporosinus, the dominant putative sulfate reducer within these reactors, correlated to representatives of this core microbiome. A subset of these clades, including Treponema, Weissella, and Anaerolinea, was associated with alfalfa and zinc removal, and the inverse was found for a second subset whose abundance was associated with wood-based columns, including Ruminococcus, Dysgonomonas, and Azospira. The construction of a putative metabolic flowchart delineated syntrophic interactions supporting sulfate reduction and suggests that the production of and competition for secondary fermentation byproducts, such as lactate scavenging, influence bacterial community composition and reactor efficacy. PMID- 26605701 TI - Palladium-Catalyzed C-2 C-H Heteroarylation of Chiral Oxazolines: Diverse Synthesis of Chiral Oxazoline Ligands. AB - A direct, efficient, and practical protocol to install a chiral oxazoline unit onto aryl/heteroaryl rings via palladium-catalyzed C-H functionalization of 2 positions of oxazolines with a variety of halides using dppe as the ligand has been developed. Various chiral oxazoline ligands could be synthesized, even in a 10-g scale process. This protocol is a good supplement to traditional methods and for diverse synthesis of chiral oxazoline ligands. PMID- 26605700 TI - Synthesis and Photophysical Study of a [NiFe] Hydrogenase Biomimetic Compound Covalently Linked to a Re-diimine Photosensitizer. AB - The synthesis, photophysics, and photochemistry of a linked dyad ([Re]-[NiFe2]) containing an analogue ([NiFe2]) of the active site of [NiFe] hydrogenase, covalently bound to a Re-diimine photosensitizer ([Re]), are described. Following excitation, the mechanisms of electron transfer involving the [Re] and [NiFe2] centers and the resulting decomposition were investigated. Excitation of the [Re] center results in the population of a diimine-based metal-to-ligand charge transfer excited state. Reductive quenching by NEt3 produces the radically reduced form of [Re], [Re](-) (kq = 1.4 +/- 0.1 * 10(7) M(-1) s(-1)). Once formed, [Re](-) reduces the [NiFe2] center to [NiFe2](-), and this reduction was followed using time-resolved infrared spectroscopy. The concentration dependence of the electron transfer rate constants suggests that both inter- and intramolecular electron transfer pathways are involved, and the rate constants for these processes have been estimated (kinter = 5.9 +/- 0.7 * 10(8) M(-1) s( 1), kintra = 1.5 +/- 0.1 * 10(5) s(-1)). For the analogous bimolecular system, only intermolecular electron transfer could be observed (kinter = 3.8 +/- 0.5 * 10(9) M(-1) s(-1)). Fourier transform infrared spectroscopic studies confirms that decomposition of the dyad occurs upon prolonged photolysis, and this appears to be a major factor for the low activity of the system toward H2 production in acidic conditions. PMID- 26605702 TI - Helicobacter pylori infection in children with portal hypertensive gastropathy. AB - BACKGROUND: Data about the association of Helicobacter pylori (H. pylori) and portal hypertensive gastropathy (PHG) are scarce in children. The present study aimed to fill the knowledge gap in this area. METHODS: The prevalence of H. pylori infection was studied in a group of infants and children with PHG using rapid urease test and histological demonstration of H. pylori in gastric mucosal biopsy obtained by upper gastrointestinal endoscopy. The results were compared to a control group who underwent endoscopy for other indications mainly hematemesis and/or dyspepsia. RESULTS: H. pylori was equally prevalent in both groups (~60%). Children with PHG were significantly stunted in height, had significantly lower hemoglobin, platelets and serum iron. Severe PHG was associated with higher grade of esophageal varices. Within the group with PHG, H. pylori infection was associated with lower hemoglobin, serum iron and serum ferritin. Moderate to severe PHG was more associated with H. pylori infection. CONCLUSIONS: H. pylori infection was not more commonly associated with PHG, however, it might contribute to the severity of PHG. The synergistic effect of PHG and H. pylori infection might contribute to the retarded growth and iron deficiency status noted in this group. PMID- 26605703 TI - Allergen immunotherapy and respiratory infections in children: an encouraging experience. AB - BACKGROUND: Allergic inflammation may promote respiratory infections (RI). House dust mite (HDM) sensitization is common in childhood. Allergen immunotherapy may cure allergy as it restores a physiological immune and clinical tolerance toward the causal allergen and exerts anti-inflammatory activity. This study retrospectively investigated whether 3 year high-dose HDM-sublingual immunotherapy (SLIT) could affect respiratory infections in children with allergic rhinitis. METHODS: Globally, 33 HDM allergic children (18 males, mean age 9.3 years) were subdivided in 2 groups: 20 treated with symptomatic drugs alone (group 1) and 13 by high-dose SLIT, titrated in mcg of major allergens (group 2) for 3 years. RESULTS: SLIT-treated children had significantly (P=0.01) less RI episodes (3.6) than symptomatically-treated children (5.4). In addition, SLIT-treated children had less fever (P<0.01) and took fewer medications, such as antibiotics (P<0.05) and fever-reducers (P<0.01), than symptomatically-treated children. CONCLUSIONS: This preliminary study suggests that high-dose 3-year SLIT might lessen RI in allergic children. PMID- 26605704 TI - Erratum, Vol. 12, August 20 Release. AB - [This corrects the article DOI: 10.5888/pcd12.140529.]. In the article "Tobacco Use Screening and Counseling During Hospital Outpatient Visits Among US Adults, 2005-2010," the caption for Figure 2 was incorrectly phrased by the author. The original caption read as follows: "Percentage of cessation assistance (counseling, or medications, or both) ordered or provided during hospital outpatient visits by adults aged >=18 years, National Hospital Ambulatory Medical Care Survey, United States 2005-2010." The correct caption is as follows: "Percentage of cessation assistance (counseling, or medications, or both) ordered or provided during hospital outpatient visits by current tobacco users aged >=18 years, National Hospital Ambulatory Medical Care Survey, United States 2005 2010." The change was made to our website on November 10, 2015, and can be accessed at http://www.cdc.gov/pcd/issues/2015/14_0529.htm. We regret any confusion this error may have caused. PMID- 26605705 TI - Pet Dogs and Children's Health: Opportunities for Chronic Disease Prevention? AB - INTRODUCTION: Positive associations between having a pet dog and adult health outcomes have been documented; however, little evidence exists regarding the benefits of pet dogs for young children. This study investigates the hypothesis that pet dogs are positively associated with healthy weight and mental health among children. METHODS: This cross-sectional study accrued a consecutive sample of children over 18 months in a pediatric primary care setting. The study enrolled 643 children (mean age, 6.7 years); 96% were white, 45% were female, 56% were privately insured, and 58% had pet dogs in the home. Before an annual visit, parents of children aged 4 to 10 years completed the DartScreen, a comprehensive Web-based health risk screener administered using an electronic tablet. The screener domains were child body mass index (BMI), physical activity, screen time, mental health, and pet-related questions. RESULTS: Children with and children without pet dogs did not differ in BMI (P = .80), screen time of 2 hours or less (P = 0.99), or physical activity (P = .07). A lower percentage of children with dogs (12%) met the clinical cut-off value of Screen for Child Anxiety and Related Disorders (SCARED-5) of 3 or more, compared with children without dogs (21%, P = .002). The mean SCARED-5 score was lower among children with dogs (1.13) compared with children without dogs (1.40; P = .01). This relationship was retained in multivariate analysis after controlling for several covariates. CONCLUSIONS: Having a pet dog in the home was associated with a decreased probability of childhood anxiety. Future studies need to establish whether this relationship is causal and, if so, how pet dogs alleviate childhood anxiety. PMID- 26605706 TI - Association Between Food Insecurity and Serious Psychological Distress Among Hispanic Adults Living in Poverty. AB - INTRODUCTION: Food insecurity has been associated with negative health outcomes, but the relationship between psychological distress and food insecurity among ethnic minorities has not been extensively examined in the literature. The goal of this study was to evaluate whether low food security and very low food security were significantly associated with past month serious psychological distress (SPD) among Hispanic adults living in poverty. METHODS: We studied 10,966 Hispanic respondents to the California Health Interview Survey for 2007, 2009, and 2011-2012 whose income was below 200% of the federal poverty level. The relationship between food insecurity and SPD was evaluated by using survey weighted univariate and logistic regression analyses. RESULTS: Nearly 30% of the study population had low food security and 13% had very low food security. Low food security and very low food security were associated with 1.99 and 4.43 odds of past month SPD, respectively, and perceived low neighborhood safety was related to 1.47 odds of past month SPD. CONCLUSIONS: We found that food insecurity was prevalent among Hispanic people living in poverty and was significantly associated with past month SPD. These results demonstrate the need for further targeted public health efforts, such as community gardens led by promotores, faith-based initiatives, and initiatives to reduce barriers to participation in food-assistance programs. PMID- 26605707 TI - Wellness Coaching for People With Prediabetes: A Randomized Encouragement Trial to Evaluate Outreach Methods at Kaiser Permanente, Northern California, 2013. AB - INTRODUCTION: Health coaching can improve lifestyle behaviors known to prevent or manage chronic conditions. Little is known about effective ways to encourage health and wellness coaching among people who might benefit. The purpose of this randomized encouragement trial was to assess the relative success of 3 outreach methods (secured email message, telephone message, and mailed letter) on the use of wellness coaching by people with prediabetes. METHODS: A total of 14,584 Kaiser Permanente Northern California (KPNC) patients with diagnosed prediabetes (fasting plasma glucose, 110-125mg/dL) were randomly assigned to be contacted via 1 of 4 intervention arms from January through May 2013. The uptake rate (making an appointment at the Wellness Coaching Center [WCC]) was assessed, and the association between uptake rate and patient characteristics was examined via multivariable logistic regression. RESULTS: The overall uptake rate across intervention arms was 1.9%. Secured email message had the highest uptake rate (3.0%), followed by letters and telephone messages (P < .05 for all pairwise comparisons). No participants in the usual-care arm (ie, no outreach) made an appointment with the WCC. For each year of increased age, the estimated odds of the uptake increased by 1.02 (odds ratio [OR] = 1.02; 95% CI, 1.01-1.04). Women were nearly twice as likely to make an appointment at the WCC as men (OR = 1.87; 95% CI, 1.40-2.51). CONCLUSION: Our results suggest that the WCC can recruit and encourage KPNC members with prediabetes to participate in the WCC. Future research should focus on increasing participation rates in health coaching among patients who may benefit. PMID- 26605709 TI - Recommendation to Reduce Patients' Blood Pressure and Cholesterol Medication Costs. PMID- 26605708 TI - Reducing Medication Costs to Prevent Cardiovascular Disease: A Community Guide Systematic Review. AB - INTRODUCTION: Hypertension and hyperlipidemia are major cardiovascular disease risk factors. To modify them, patients often need to adopt healthier lifestyles and adhere to prescribed medications. However, patients' adherence to recommended treatments has been suboptimal. Reducing out-of-pocket costs (ROPC) to patients may improve medication adherence and consequently improve health outcomes. This Community Guide systematic review examined the effectiveness of ROPC for medications prescribed for patients with hypertension and hyperlipidemia. METHODS: We assessed effectiveness and economics of ROPC for medications to treat hypertension, hyperlipidemia, or both. Per Community Guide review methods, reviewers identified, evaluated, and summarized available evidence published from January 1980 through July 2015. RESULTS: Eighteen studies were included in the analysis. ROPC interventions resulted in increased medication adherence for patients taking blood pressure and cholesterol medications by a median of 3.0 percentage points; proportion achieving 80% adherence to medication increased by 5.1 percentage points. Blood pressure and cholesterol outcomes also improved. Nine studies were included in the economic review, with a median intervention cost of $172 per person per year and a median change in health care cost of -$127 per person per year. CONCLUSION: ROPC for medications to treat hypertension and hyperlipidemia is effective in increasing medication adherence, and, thus, improving blood pressure and cholesterol outcomes. Most ROPC interventions are implemented in combination with evidence-based health care interventions such as team-based care with medication counseling. An overall conclusion about the economics of the intervention could not be reached with the small body of inconsistent cost-benefit evidence. PMID- 26605711 TI - Introducing the ELF Topological Analysis in the Field of Quasirelativistic Quantum Calculations. AB - We present an original formulation of the electron localization function (ELF) in the field of relativistic two-component DFT calculations. Using I2 and At2 species as a test set, we show that the ELF analysis is suitable to evaluate the spin-orbit effects on the electronic structure. Beyond these examples, this approach opens up new opportunities for the bonding analysis of large molecular systems involving heavy and superheavy elements. PMID- 26605710 TI - A Randomized Controlled Trial Translating the Diabetes Prevention Program to a University Worksite, Ohio, 2012-2014. AB - INTRODUCTION: Working adults spend much time at the workplace, an ideal setting for wellness programs targeting weight loss and disease prevention. Few randomized trials have evaluated the efficacy of worksite diabetes prevention programs. This study evaluated the efficacy of a worksite lifestyle intervention on metabolic and behavioral risk factors compared with usual care. METHODS: A pretest-posttest control group design with 3-month follow-up was used. Participants with prediabetes were recruited from a university worksite and randomized to receive a 16-week lifestyle intervention (n = 35) or usual care (n = 34). Participants were evaluated at baseline, postintervention, and 3-month follow-up. Dietary intake was measured by a food frequency questionnaire and level of physical activity by accelerometers. Repeated measures analysis of variance compared the change in outcomes between and within groups. RESULTS: Mean (standard error [SE]) weight loss was greater in the intervention (-5.5% [0.6%]) than in the control (-0.4% [0.5%]) group (P < .001) postintervention and was sustained at 3-month follow-up (P < .001). Mean (SE) reductions in fasting glucose were greater in the intervention (-8.6 [1.6] mg/dL) than in the control ( 3.7 [1.6] mg/dL) group (P = .02) postintervention; both groups had significant glucose reductions at 3-month follow-up (P < .001). In the intervention group, the intake of total energy and the percentage of energy from all fats, saturated fats, and trans fats decreased, and the intake of dietary fiber increased (all P < .01) postintervention. CONCLUSION: The worksite intervention improved metabolic and behavioral risk factors among employees with prediabetes. The long-term impact on diabetes prevention and program sustainability warrant further investigation. PMID- 26605712 TI - Which Density Functional Is the Best in Computing C-H Activation Energies by Pincer Complexes of Late Platinum Group Metals? AB - Using the recently proposed corrective LCCSD(T) method as a reference, we systematically assess the widely used approximate density functionals to reproduce C-H bond activation barriers by pincer complexes of the late platinum group transition metals (TMs) (TM = Rh, Pd, Ir, Pt). The pincer ligands explored here cover a wide range of PNP, PCP, POCOP, NCN, and SCS types. Interestingly, B3LYP is found to be the most accurate functional, followed by several others previously identified as well-performing functionals, like B2GP-PLYP, B2-PLYP, and PBE0. However, all tested functionals were found to exhibit the following uniform trends: (1) the DFT barriers for reactions of group 9 TM (Rh and Ir) pincer complexes show higher accuracy compared with those for group 10 TM (Pd and Pt) reactions; (2) within the same group, 5d TM pincer complexes have higher accuracy than 4d TM ones. Consequently, the barriers for C-H activation by Pd(II) pincer complexes were found to be the least accurate among the four TMs in almost all functionals tested here. The DFT empirical dispersion correction (DFT-D3) is shown to have a very small effect on barrier height. This study has some implications for other sigma-bond activations like H-H, C-C, and C-halogen bonds by late platinum group pincer complexes. PMID- 26605713 TI - Parametric Study of ReaxFF Simulation Parameters for Molecular Dynamics Modeling of Reactive Carbon Gases. AB - The development of innovative carbon-based materials can be greatly facilitated by molecular modeling techniques. Although the Reax Force Field (ReaxFF) can be used to simulate the chemical behavior of carbon-based systems, the simulation settings required for accurate predictions have not been fully explored. Using the ReaxFF, molecular dynamics (MD) simulations are used to simulate the chemical behavior of pure carbon and hydrocarbon reactive gases that are involved in the formation of carbon structures such as graphite, buckyballs, amorphous carbon, and carbon nanotubes. It is determined that the maximum simulation time step that can be used in MD simulations with the ReaxFF is dependent on the simulated temperature and selected parameter set, as are the predicted reaction rates. It is also determined that different carbon-based reactive gases react at different rates, and that the predicted equilibrium structures are generally the same for the different ReaxFF parameter sets, except in the case of the predicted formation of large graphitic structures with the Chenoweth parameter set under specific conditions. PMID- 26605714 TI - Modified Anderson Method for Accelerating 3D-RISM Calculations Using Graphics Processing Unit. AB - A fast algorithm is proposed to solve the three-dimensional reference interaction site model (3D-RISM) theory on a graphics processing unit (GPU). 3D-RISM theory is a powerful tool for investigating biomolecular processes in solution; however, such calculations are often both memory-intensive and time-consuming. We sought to accelerate these calculations using GPUs, but to work around the problem of limited memory size in GPUs, we modified the less memory-intensive "Anderson method" to give faster convergence to 3D-RISM calculations. Using this method on a Tesla C2070 GPU, we reduced the total computational time by a factor of 8, 1.4 times by the modified Andersen method and 5.7 times by GPU, compared to calculations on an Intel Xeon machine (eight cores, 3.33 GHz) with the conventional method. PMID- 26605715 TI - Two Dimensional Epitaxial Water Adlayer on Mica with Graphene Coating: An ab Initio Molecular Dynamics Study. AB - Motivated by a recent atomic-force-microscopy (AFM) study of water adlayers on mica by Heath and co-workers (Graphene Visualizes the First Water Adlayers on Mica at Ambient Conditions. Science2010, 329, 1188), we performed an ab initio molecular dynamics study of structural and dynamic properties of monolayer, bilayer, and trilayer water adlayers on the muscovite mica (001) surface with and without a graphene coating. We find that in the first epitaxial water adlayer, water molecules that form strong hydrogen bonds with the oxygen on the mica surface show little motions, thereby solid-like, while those "bridging" water molecules on top of the first water adlayer exhibit "itinerant" behavior, thereby liquid-like. Overall, the Born-Oppenheim molecular dynamics (BOMD) simulations (based on the BLYP-D functional) show that the first water adlayer on mica exhibits a unique hybrid solid-liquid-like behavior with a very low diffusion coefficient at ambient conditions. In particular, no dangling hydrogen bonds are found in the first water adlayer on mica. Moreover, the bilayer and trilayer water adlayers show slightly higher structural stability than the first water adlayer. A graphene coating on the water adlayer further enhances stability of the water adlayers. Most importantly, the bilayer water adlayer on mica with the graphene coating becomes fully solid-like, the structure of which is the same as the bilayer slice of ice-Ih with a thickness of 7.4 A, consistent with the AFM measurement. PMID- 26605716 TI - Application of Local Second-Order Moller-Plesset Perturbation Theory to the Study of Structures in Solution. AB - In this work, we discuss the use of local second order Moller-Plesset perturbation theory (LMP2) in combination with the COSMO continuum solvation model for obtaining optimized geometries of molecules in solution. Density fitting approximations, which reduce the computational cost relative to the basis set size, are also applied. We present results for small molecular systems, which show the same pattern observed in gas phase calculations. LMP2 results are found to be in excellent agreement with the canonical method. The only difference noticed is a slight increase in the average bond lengths, which is linked to the implicit reduction of basis set superposition effects (BSSE). Applications in the geometry optimization of an arginine model interacting with anions in solution as well as to the conformers of oligo-beta-peptides are discussed. PMID- 26605717 TI - Natural Spinors Reveal How the Spin-Orbit Coupling Affects the Jahn-Teller Distortions in the Hexafluorotungstate(V) Anion. AB - We investigate the Jahn-Teller distortions in the hexafluorotungstate(V) anion (WF6(-)) by applying the recently developed concept of natural spinors (spin orbitals) and show that they are a very powerful tool providing simple and clear pictorial explanation for the spin-orbit effect in determining the structure of the anion. The calculations are performed at the levels of spin-orbit configuration interaction and multiconfigurational quasi-degenerate perturbation theory. The hexafluorotungstate(V) anion represents a very rare example of spin orbit coupling enhancing the Jahn-Teller distortion, and the natural spinor analysis gives a clear interpretation of this enhancement. Advantages of using the natural spinors are explored and explained in detail in this case study. PMID- 26605718 TI - GPU Linear Algebra Libraries and GPGPU Programming for Accelerating MOPAC Semiempirical Quantum Chemistry Calculations. AB - In this study, we present some modifications in the semiempirical quantum chemistry MOPAC2009 code that accelerate single-point energy calculations (1SCF) of medium-size (up to 2500 atoms) molecular systems using GPU coprocessors and multithreaded shared-memory CPUs. Our modifications consisted of using a combination of highly optimized linear algebra libraries for both CPU (LAPACK and BLAS from Intel MKL) and GPU (MAGMA and CUBLAS) to hasten time-consuming parts of MOPAC such as the pseudodiagonalization, full diagonalization, and density matrix assembling. We have shown that it is possible to obtain large speedups just by using CPU serial linear algebra libraries in the MOPAC code. As a special case, we show a speedup of up to 14 times for a methanol simulation box containing 2400 atoms and 4800 basis functions, with even greater gains in performance when using multithreaded CPUs (2.1 times in relation to the single-threaded CPU code using linear algebra libraries) and GPUs (3.8 times). This degree of acceleration opens new perspectives for modeling larger structures which appear in inorganic chemistry (such as zeolites and MOFs), biochemistry (such as polysaccharides, small proteins, and DNA fragments), and materials science (such as nanotubes and fullerenes). In addition, we believe that this parallel (GPU-GPU) MOPAC code will make it feasible to use semiempirical methods in lengthy molecular simulations using both hybrid QM/MM and QM/QM potentials. PMID- 26605719 TI - DFT and Proton Transfer Reactions: A Benchmark Study on Structure and Kinetics. AB - A significant number of different exchange correlation functionals, ranging from generalized gradient approximations to double hybrids, has been tested on a difficult playground represented by proton transfer reactions. In order to have a complete picture of their performances, both energetics and structural features have been compared and the obtained ranking compared with those issued from the standard test for kinetics (i.e., the DBH24/08 set). Among all of the functionals, the omegaB97X, BMK, B1LYP, and PBE0-DH approaches are those providing a good error balance on all four trials. Beyond these figures, the obtained results allow for some general considerations, such as those on the role of Hartree-Fock exchange in reaction barriers or the relation between structure and energetics. PMID- 26605720 TI - On the Electronic and Geometric Structures of FeO2(-/0) and the Assignment of the Anion Photoelectron Spectrum. AB - The photoelectron spectrum of FeO2(-) has been assigned by performing geometry optimizations at the CASPT2 and RCCSD(T) levels of computation. All relevant states are found to possess floppy C2v geometrical structures as the Renner Teller splittings of the linear states are extremely small and the corresponding energy barriers for the OFeO bond angle inversions are calculated in the range of a few hundred wavenumbers. In this sense, the description of the electronic structure in terms of the Dinfinityh point group is acceptable, and the experimentally proposed linear structure for FeO2(-) is theoretically confirmed. High accuracy single-point multireference RASPT2 and single-reference RCCSD(T) calculations support a (2)Deltag as the ground state of the anion, even though the energy differences between the (4)Pig and (6)Sigmag(+) states are smaller than 0.2 eV. After this identification of the doublet ground state, the photoelectron spectra of FeO2(-) could be assigned in all aspects. The (2)Deltag >(3)Deltag ionization appears to be at the origin of the X band at 2.36 eV, while the A band at 3.31 eV should be ascribed to the (2)Deltag->(3)Sigmag(+) ionization. This assignment is substantiated by Franck-Condon factors for which BP86 optimized geometries and harmonic vibrational frequencies were employed. Indeed, no pronounced vibrational progression should be observed since both bands involve electron detachments out of nonbonding mainly 3d iron molecular orbitals. PMID- 26605721 TI - Energy Densities in the Strong-Interaction Limit of Density Functional Theory. AB - We discuss energy densities in the strong-interaction limit of density functional theory, deriving an exact expression within the definition (gauge) of the electrostatic potential of the exchange-correlation hole. Exact results for small atoms and small model quantum dots (Hooke's atoms) are compared with available approximations defined in the same gauge. The idea of a local interpolation along the adiabatic connection is discussed, comparing the energy densities of the Kohn Sham, the physical, and the strong-interacting systems. We also use our results to analyze the local version of the Lieb-Oxford bound, widely used in the construction of approximate exchange-correlation functionals. PMID- 26605722 TI - Efficient Sparse Matrix Algorithm to Speed Up the Calculation of the Ladder Term in Coupled Cluster Programs. AB - A new algorithm is presented for the calculation of the ladder-type term of the coupled cluster singles and doubles (CCSD) equations using two-electron integrals in atomic orbital (AO) basis. The method is based on an orbital grouping scheme, which results in an optimal partitioning of the AO integral matrix into sparse and dense blocks allowing efficient matrix multiplication. Carefully chosen numerical tests have been performed to analyze the performance of all aspects of the new algorithm. It is shown that the suggested scheme allows an efficient utilization of modern highly parallel architectures and devices in CCSD calculations. Details of the implementation in the development version of CFOUR quantum chemical program package are also presented. PMID- 26605723 TI - How Accurate Can a Local Coupled Cluster Approach Be in Computing the Activation Energies of Late-Transition-Metal-Catalyzed Reactions with Au, Pt, and Ir? AB - To improve the accuracy of local coupled cluster (LCC) methods in computing activation energies, we propose herein a new computational scheme. Its applications to various types of late-transition-metal-catalyzed reactions involving Au, Pt, and Ir indicate that the new corrective approach for LCC methods can downsize the mean unsigned deviation and maximum deviation, from the CCSD(T)/CBS reference, to about 0.3 and 0.9 kcal/mol. Using this method, we also calibrated the performance of popular density functionals, with respect to the same test set of reactions. It is concluded that the best functional is the general-purpose double hybrid functional B2GP-PLYP. Other well-performing functionals include the "kinetic" functionals M06-2X and BMK, which have a large percentage of HF exchange, and general-purpose functionals like PBE0 and wB97X. Comparatively, general-purpose functionals like PBE0 and TPSSh perform much better than the tested "kinetic" functionals for Pt-/Ir-catalyzed reactions, while the opposite is true for Au-catalyzed reactions. In contrast, wB97X performs more uniformly in these two classes of reactions. These findings hint that even within the scope of late transition metals, different types of reactions may require different types of optimal DFT methods. Empirical dispersion correction of DFT was found to have a small or no effect on the studied reactions barriers. PMID- 26605724 TI - Determination of Barrier Heights for Proton Exchange in Small Water, Ammonia, and Hydrogen Fluoride Clusters with G4(MP2)-Type, MPn, and SCS-MPn Procedures-A Caveat. AB - Calculation of accurate water-water interaction energies is of fundamental importance in computational modeling of many biological and chemical phenomena. We have obtained benchmark barrier heights for proton-exchange reactions and complexation energies in water clusters (H2O)n (n = 1-6) by means of the high level W1-F12 procedure. We find that lower-cost composite procedures (e.g., G4(MP2) and G4(MP2)-6X), as well as MP2 and SCS-MP2, exhibit surprisingly poor performance for the barrier heights of reactions involving multiple proton exchanges. Moreover, the performance significantly deteriorates with increasing size of the clusters. Similar observations apply to complexation energies in water clusters, and to barrier heights for proton exchange in ammonia and hydrogen fluoride clusters. We propose a modified version of G4(MP2)-6X (denoted G4(MP2)-6X+) that includes sp- and d-diffuse functions in the CCSD(T) term, which gives excellent proton-exchange barrier heights at a computational cost only slightly greater than that of standard G4(MP2). G4(MP2)-6X+ also leads to a substantial improvement over G4(MP2) and G4(MP2)-6X for the calculation of electron affinities. PMID- 26605725 TI - Trust Region Minimization of Orbital Localization Functions. AB - The trust region method has been applied to the minimization of localization functions, and it is shown that both local occupied and local virtual Hartree Fock (HF) orbitals can be obtained. Because step sizes are size extensive in the trust region method, large steps may be required when the method is applied to large molecular systems. For an exponential parametrization of the localization function only small steps are allowed, and the standard trust radius update therefore has been replaced by a scheme where the direction of the step is determined using a conservative estimate of the trust radius and the length of the step is determined from a line search along the obtained direction. Numerical results for large molecular systems have shown that large steps can then safely be taken, and a robust and nearly monotonic convergence is obtained. PMID- 26605726 TI - Magnetic Exchange Couplings from Semilocal Functionals Evaluated Nonself Consistently on Hybrid Densities: Insights on Relative Importance of Exchange, Correlation, and Delocalization. AB - Semilocal functionals generally yield poor magnetic exchange couplings for transition-metal complexes, typically overpredicting in magnitude the experimental values. Here we show that semilocal functionals evaluated nonself consistently on densities from hybrid functionals can yield magnetic exchange couplings that are greatly improved with respect to their self-consistent semilocal values. Furthermore, when semilocal functionals are evaluated nonself consistently on densities from a "half-and-half" hybrid, their errors with respect to experimental values can actually be lower than those from self consistent calculations with standard hybrid functionals such as PBEh or TPSSh. This illustrates that despite their notoriously poor performance for exchange couplings, for many systems semilocal functionals are capable of delivering accurate relative energies for magnetic states provided that their electron delocalization error is corrected. However, while self-consistent calculations with hybrids uniformly improve results for all complexes, evaluating nonself consistently with semilocal functionals does not give a balanced improvement for both ferro- and antiferromagnetically coupled complexes, indicating that there is more at play with the overestimation problem than simply the delocalization error. Additionally, we show that for some systems the conventional wisdom of choice of exchange functional mattering more than correlation does not hold. This combined with results from the nonself-consistent calculations provide insight on clarifying the relative roles of exchange, correlation, and delocalization in calculating magnetic exchange coupling parameters in Kohn-Sham Density Functional Theory. PMID- 26605727 TI - Heats of Formation for CrO, CrO2, and CrO3: An Extreme Challenge for Black-Box Composite Procedures. AB - In the present study, we use composite methods, denoted CM(5)Lambda and CM5, with post-CCSD(T) terms up to CCSDTQ(5)Lambda and CCSDTQ5, respectively, to evaluate the atomization energies for CrO, CrO2, and CrO3. The heats of formation (DeltaHf,298) based on our best estimated atomization energies are 198.3 +/- 5 kJ mol(-1) (CrO), -81.3 +/- 5 kJ mol(-1) (CrO2), and -286.8 +/- 20 kJ mol(-1) (CrO3). Standard G4-type composite methods yield atomization energies that are adequate for CrO, less good for CrO2, and least good for CrO3. CrO3 is highly multireference in character, and therefore, a "black box" approach of using a single-reference RHF wave function is inadequate, even for "high-level" G4-type methods. We find that, for CrO3, there is a very large difference in the G4 atomization energies depending on whether an RHF or a UHF reference is used, which is mainly associated with large differences in the MP4 components. In general, we propose that a large R-versus-U difference is likely to be an indication of potential problems in the theoretical treatment. Going beyond G4 to a more rigorous UCCSD(T)-based composite scheme [termed U-CM(3:[DZ,TZ]) in the present study], we again find a large difference (but significantly smaller than that for G4) between the CrO3 atomization energies based on RHF or UHF references. Intriguingly, the use of Brueckner orbitals as reference orbitals in all components, as in the corresponding Brueckner Doubles (BD) procedure [B CM(3:[DZ,TZ])], produces results for CrO3 that are independent of whether RHF or UHF orbitals are used as the starting point. PMID- 26605728 TI - Physical Nature of Substituent Effects in XH/pi Interactions. AB - XH/pi interactions (e.g.: CH/pi, OH/pi, etc.) are ubiquitous in chemical and biochemical contexts. Although there have been many studies of substituent effects in XH/pi interactions, there have been only limited systematic studies covering a broad range of substituents. We provide a comprehensive and systematic study aimed at unraveling the nature of aryl substituent effects on model BH/pi, CH/pi, NH/pi, OH/pi, and F/pi interactions (e.g.: BH3...C6H5Y, CH4...C6H5Y, etc.) based on estimated CCSD(T)/aug-cc-pVTZ interaction energies as well as symmetry adapted perturbation theory (SAPT) results. We show that the impact of substituents on XH/pi interactions depends strongly on the identity of the XH group, and the strength of these effects increases with increasing polarization of the XH bond. Overall, the results are in accord with previous work and follow expected trends from basic physical principles. That is, electrostatic effects dominate the substituent effects for the polar XH/pi interactions (NH/pi, OH/pi, and FH/pi), while dispersion effects are more important for the nonpolar BH/pi and CH/pi interactions. The electrostatic component of these interactions is shown to correlate well with Hammett constants (sigmam), while accounting for the dispersion component requires consideration of molar refractivities (MR) and interaction distances concurrently. The correlation of the dispersion component of these interactions with MR values alone is rather weak. PMID- 26605729 TI - Prediction of Reaction Barriers and Thermochemical Properties with Explicitly Correlated Coupled-Cluster Methods: A Basis Set Assessment. AB - We assessed the performance of our perturbative explicitly correlated coupled cluster method, CCSD(T)F12, for accurate prediction of chemical reactivity. The reference data included reaction barrier heights, electronic reaction energies, atomization energies, and enthalpies of formation from the following sources: (1) the DBH24/08 database of 22 reaction barriers (Truhlar et al.), (2) the HJO12 set of isogyric reaction energies (Helgaker et al.), and (3) a HEAT set of atomization energies and heats of formation (Stanton et al.). We performed two types of analyses targeting the two distinct uses of explicitly correlated CCSD(T) models: as a replacement for basis-set-extrapolated CCSD(T) in highly accurate composite methods like HEAT and as a distinct model chemistry for standalone applications. Hence, we analyzed in detail (1) the basis set error of each component of the CCSD(T)F12 contribution to the chemical energy difference in question and (2) the total error of the CCSD(T)F12 model chemistry relative to the benchmark values. Two basis set families were utilized in the calculations: the standard aug-cc-p(C)VXZ-F12 (X = D, T, Q) basis sets for the conventional correlation methods and the cc-p(C)VXZ-F12 (X = D, T, Q) basis sets of Peterson and co-workers that are specifically designed for explicitly correlated methods. Our conclusion is that the performance of the two families for CCSD correlation contributions (which are the only components affected by the explicitly correlated terms in our formation) are nearly identical with triple- and quadruple-zeta quality basis sets, with some differences at the double-zeta level. Chemical accuracy (~4.18 kJ/mol) for reaction barrier heights, electronic reaction energies, atomization energies, and enthalpies of formation is attained on average with the aug-cc-pVDZ, aug-cc-pVTZ, cc-pCVTZ-F12/aug-cc-pCVTZ, and cc pCVDZ-F12 basis sets, respectively, at the CCSD(T)F12 level of theory. The corresponding mean unsigned errors are 1.72 kJ/mol, 1.5 kJ/mol, ~2 kJ/mol, and 2.17 kJ/mol, and the corresponding maximum unsigned errors are 4.44 kJ/mol, 3.6 kJ/mol, ~5 kJ/mol, and 5.75 kJ/mol. PMID- 26605730 TI - Quantum Chemical Benchmarking, Validation, and Prediction of Acidity Constants for Substituted Pyridinium Ions and Pyridinyl Radicals. AB - Sensibly modeling (photo)electrocatalytic reactions involving proton and electron transfer with computational quantum chemistry requires accurate descriptions of protonated, deprotonated, and radical species in solution. Procedures to do this are generally nontrivial, especially in cases that involve radical anions that are unstable in the gas phase. Recently, pyridinium and the corresponding reduced neutral radical have been postulated as key catalysts in the reduction of CO2 to methanol. To assess practical methodologies to describe the acid/base chemistry of these species, we employed density functional theory (DFT) in tandem with implicit solvation models to calculate acidity constants for 22 substituted pyridinium cations and their corresponding pyridinyl radicals in water solvent. We first benchmarked our calculations against experimental pyridinium deprotonation energies in both gas and aqueous phases. DFT with hybrid exchange correlation functionals provide chemical accuracy for gas-phase data and allow absolute prediction of experimental pKas with unsigned errors under 1 pKa unit. The accuracy of this economical pKa calculation approach was further verified by benchmarking against highly accurate (but very expensive) CCSD(T)-F12 calculations. We compare the relative importance and sensitivity of these energies to selection of solvation model, solvation energy definitions, implicit solvation cavity definition, basis sets, electron densities, model geometries, and mixed implicit/explicit models. After determining the most accurate model to reproduce experimentally-known pKas from first principles, we apply the same approach to predict pKas for radical pyridinyl species that have been proposed relevant under electrochemical conditions. This work provides considerable insight into the pitfalls using continuum solvation models, particularly when used for radical species. PMID- 26605731 TI - Ab Initio Parametrized Force Field for the Flexible Metal-Organic Framework MIL 53(Al). AB - A force field is proposed for the flexible metal-organic framework MIL-53(Al), which is calibrated using density functional theory calculations on nonperiodic clusters. The force field has three main contributions: an electrostatic term based on atomic charges derived with a modified Hirshfeld-I method, a van der Waals (vdW) term with parameters taken from the MM3 model, and a valence force field whose parameters were estimated with a new methodology that uses the gradients and Hessian matrix elements retrieved from nonperiodic cluster calculations. The new force field predicts geometries and cell parameters that compare well with the experimental values both for the large and narrow pore phases. The energy profile along the breathing mode of the empty material reveals the existence of two minima, which confirms the intrinsic bistable behavior of the MIL-53. Even without the stimulus of external guest molecules, the material may transform from the large pore (lp) to the narrow pore (np) phase [Liu et al. J. Am. Chem. Soc.2008, 120, 11813]. The relative stability of the two phases critically depends on the vdW parameters, and the MM3 dispersion interaction has the tendency to overstabilize the np phase. PMID- 26605732 TI - A Novel Approach for Deriving Force Field Torsion Angle Parameters Accounting for Conformation-Dependent Solvation Effects. AB - A procedure for deriving force field torsion parameters including certain previously neglected solvation effects is suggested. In contrast to the conventional in vacuo approaches, the dihedral parameters are obtained from the difference between the quantum-mechanical self-consistent reaction field and Poisson-Boltzmann continuum solvation models. An analysis of the solvation contributions shows that two major effects neglected when torsion parameters are derived in vacuo are (i) conformation-dependent solute polarization and (ii) solvation of conformation-dependent charge distribution. Using the glycosidic torsion as an example, we demonstrate that the corresponding correction for the torsion potential is substantial and important. Our approach avoids double counting of solvation effects and provides parameters that may be used in combination with any of the widely used nonpolarizable discrete solvent models, such as TIPnP or SPC/E, or with continuum solvent models. Differences between our model and the previously suggested solvation models are discussed. Improvements were demonstrated for the latest AMBER RNA chiOL3 parameters derived with inclusion of solvent effects in a previous publication (Zgarbova et al. J. Chem. Theory Comput.2011, 7, 2886). The described procedure may help to provide consistently better force field parameters than the currently used parametrization approaches. PMID- 26605733 TI - On the Numerical Accuracy of Ewald, Smooth Particle Mesh Ewald, and Staggered Mesh Ewald Methods for Correlated Molecular Systems. AB - In this work, we develop the accurate error estimates for three state-of-art algorithms of long-range electrostatic interaction in inhomogeneous and correlated molecular systems. They are the Ewald summation, the smooth particle mesh Ewald (SPME) and the staggered mesh Ewald methods. Two branches of force computation, namely the ik- and analytical differentiation, are considered. All the estimates are developed by proposing a more general framework: if the error force is of pairwise form, then the root-mean-square force error is composed of three additive parts, the homogeneity error, the inhomogeneity error and the correlation error. Computationally scalable estimates (estimating the errors at the cost O(N log N)) are developed for all the considered algorithms. The effectiveness of the proposed estimates and the important role of the correlation error are carefully checked and demonstrated by example systems. PMID- 26605734 TI - PERI-CC2: A Polarizable Embedded RI-CC2 Method. AB - We present a combination of the polarizable embedding (PE) method with the resolution-of-the-identity implementation of the approximate coupled-cluster singles and doubles method CC2. The new approach, termed PERI-CC2, allows one to study excited state phenomena of large solvated molecular systems with an accurate correlated wave function method. Central to the PE approach is the advanced description of the environmental electrostatic potential and inclusion of polarization, and the quintessence of RI-CC2 is efficient access to excited state properties while retaining the accuracy associated with CC theory. To maintain efficiency, an approximate truncated CC2 density is introduced to calculate the PE contributions. Explicitly, we derive the central equations and outline an implementation of polarizable embedding for the RI-CC2 approach. The new method is tested against previous PE-CC2 and PE-CCSD results for solvatochromic shifts, demonstrating how the important effects of polarization are incorporated well with PERI-CC2 but with a dramatically reduced overall computational cost. A follow-up investigation of the solvatochromic shift of uracil in aqueous solution further illustrates the potential of PERI-CC2. We discuss the need to explicitly incorporate several water molecules into the region treated by quantum mechanics in order to obtain a reliable and accurate description of the physical effects when specific solute/solvent interactions as, e.g., hydrogen-bonds are involved. PMID- 26605735 TI - Linear-Response and Real-Time Time-Dependent Density Functional Theory Studies of Core-Level Near-Edge X-Ray Absorption. AB - We discuss our implementation and application of time-dependent density functional theory (TDDFT) to core-level near-edge absorption spectroscopy, using both linear-response (LR) and real-time (RT) approaches. We briefly describe our restricted excitation window TDDFT (REW-TDDFT) approach for core excitations, which has also been reported by other groups. This is followed by a detailed discussion of real-time TDDFT techniques tailored to core excitations, including obtaining spectral information through delta-function excitation, postprocessing time-dependent signals, and resonant excitation through quasi-monochromatic excitation. We present results for the oxygen K-edge of water and carbon monoxide; the carbon K-edge of carbon monoxide; the ruthenium L3-edge for the hexaamminerutheium(III) ion, including scalar relativistic corrections via the zeroth order regular approximation (ZORA); and the carbon and fluorine K-edges for a series of fluorobenzenes. In all cases, the calculated spectra are found to be in reasonable agreement with experimental results, requiring only a uniform shift ranging from -4 eV to +19 eV, i.e., on the order of a few percent of the excitation energy. Real-time TDDFT visualization of excited state charge densities is used to visually examine the nature of each excitation, which gives insight into the effects of atoms bound to the absorbing center. PMID- 26605736 TI - Structural Substituent Effect in the Excitation Energy of a Chromophore: Quantitative Determination and Application to S-Nitrosothiols. AB - A methodology for the prediction of excitation energies for substituted chromophores on the basis of ground state structures has been developed. The formalism introduces the concept of "structural substituent excitation energy effect" for the rational prediction and quantification of the substituent effect in the excitation energy of a chromophore to an excited electronic state. This effect quantifies exclusively the excitation energy variation due to the structural changes of the chromophore induced by the substituent. Therefore, excitation bathochromic and hypsochromic shifts of substituted chromophores can be predicted on the basis of known ground and excited potential energy surfaces of a reference unsubstituted chromophore, together with the ground state minimum energy structure of the substituted chromophore. This formalism can be applied if the chemical substitution does not affect the nature of the electronic excitation, where the substituent effect can be understood as a force acting on the chromophore and provoking a structural change on it. The developed formalism provides a useful tool for quantitative and qualitative determination of the excitation energy of substituted chromophores and also for the analysis and determination of the structural changes affecting this energy. The proposed methodology has been applied to the prediction of the excitation energy to the first bright state of several S-nitrosothiols using the potential energy surfaces of methyl-S-nitrosothiol as a reference unsubstituted chromophore. PMID- 26605737 TI - On the Computation of Adiabatic Energies in Aza-Boron-Dipyrromethene Dyes. AB - We have simulated the optical properties of Aza-Boron-dipyrromethene (Aza-BODIPY) dyes and, more precisely, the 0-0 energies as well as the shape of both absorption and fluorescence bands, thanks to the computation of vibronic couplings. To this end, time-dependent density functional theory (TD-DFT) calculations have been carried out with a systematic account of both vibrational and solvent effects. In a first step, we assessed different atomic basis sets, a panel of global and range-separated hybrid functionals as well as different solvent models (linear-response, corrected linear-response, and state-specific). In this way, we have defined an accurate yet efficient protocol for these dyes. In a second stage, several simulations have been carried out to investigate acidochromic and complexation effects, as well as the impact of side groups on the topology of the optical bands. In each case, theory is able to accurately reproduce experimental results and the proposed protocol is consequently useful to design new dyes featuring improved properties. PMID- 26605738 TI - MMPBSA.py: An Efficient Program for End-State Free Energy Calculations. AB - MM-PBSA is a post-processing end-state method to calculate free energies of molecules in solution. MMPBSA.py is a program written in Python for streamlining end-state free energy calculations using ensembles derived from molecular dynamics (MD) or Monte Carlo (MC) simulations. Several implicit solvation models are available with MMPBSA.py, including the Poisson-Boltzmann Model, the Generalized Born Model, and the Reference Interaction Site Model. Vibrational frequencies may be calculated using normal mode or quasi-harmonic analysis to approximate the solute entropy. Specific interactions can also be dissected using free energy decomposition or alanine scanning. A parallel implementation significantly speeds up the calculation by dividing frames evenly across available processors. MMPBSA.py is an efficient, user-friendly program with the flexibility to accommodate the needs of users performing end-state free energy calculations. The source code can be downloaded at http://ambermd.org/ with AmberTools, released under the GNU General Public License. PMID- 26605739 TI - First-Principles Calculation of the Intrinsic Aqueous Solubility of Crystalline Druglike Molecules. AB - We demonstrate that the intrinsic aqueous solubility of crystalline druglike molecules can be estimated with reasonable accuracy from sublimation free energies calculated using crystal lattice simulations and hydration free energies calculated using the 3D Reference Interaction Site Model (3D-RISM) of the Integral Equation Theory of Molecular Liquids (IET). The solubilities of 25 crystalline druglike molecules taken from different chemical classes are predicted by the model with a correlation coefficient of R = 0.85 and a root mean square error (RMSE) equal to 1.45 log10S units, which is significantly more accurate than results obtained using implicit continuum solvent models. The method is not directly parametrized against experimental solubility data, and it offers a full computational characterization of the thermodynamics of transfer of the drug molecule from crystal phase to gas phase to dilute aqueous solution. PMID- 26605740 TI - First-Principles Predictions of Thermoelectric Figure of Merit for Organic Materials: Deformation Potential Approximation. AB - We propose a combined computational scheme to predict the thermoelectric properties of organic semiconductors, taking alpha-form phthalocyanine crystals H2Pc, CuPc, NiPc, and TiOPc as examples. This completely parameter-free approach combines first-principles band structure calculations, Boltzmann transport theory, deformation potential theory for electron-phonon coupling, and nonequilibrium molecular dynamics for heat transport. We abandon the constant relaxation time approximation commonly practiced in the literature. Instead, we calculate it from first principles with the deformation potential approximation. The obtained Seebeck coefficients are in good agreement with experimental results, validating our treatment for relaxation time. From the calculated thermoelectric figure of merit (ZT) value, we show that phthalocyanine crystals could be excellent thermoelectric materials when n-doped, with the highest ZT value of 2.5 in NiPc at a doping level of -1.5 * 10(20) cm(-3). PMID- 26605741 TI - Interactions and Ordering of Ionic Liquids at a Metal Surface. AB - An atomistic force field for ionic liquids interacting with a metal surface is built on the basis of quantum methods. Density functional calculations of alkylammonium cations and alkylsulfonate anions interacting with a cluster of iron atoms were performed, at a series of distances and orientations, using the M06 functional that represents noncovalent interactions. A site-site potential function was then adjusted to the BSSE-corrected DFT interaction energies. Finally, the polarization of the metal by the ions was taken into account using induced dipoles to reproduce the interaction energy between charges and a conductor surface. When combined with a molecular force field for the ionic liquid and a suitable potential for metals, our model allows the computer simulation of heterogeneous systems containing metal surfaces or nanoparticles in the presence of ionic liquids. Our aim is to study tribological systems with ionic lubricants. We report molecular dynamics results on the structure of the interfacial layer of several alkylammonium alkylsulfonate ionic liquids at a flat iron surface, including analyses of the positional and orientational ordering of the ions near the surface, and charge density profiles. Both anions and cations are found in the first ordered layer of ions near the surface, with the oxygen atoms of the sulfonyl groups interacting more strongly with the metal. The interfacial layer is essentially one ion thick, except for very short chain ionic liquids in which a second layer is observed. The effects of different lengths of the nonpolar alkyl side chains on the cation and the anion are different: whereas butyl chains on the sulfonate anions tend to be directed away from the surface, those on ammonium cations lie more parallel to the surface. PMID- 26605742 TI - 3D-RISM-Dock: A New Fragment-Based Drug Design Protocol. AB - We explore a new approach in the rational design of specificity in molecular recognition of small molecules based on statistical-mechanical integral equation theory of molecular liquids in the form of the three-dimensional reference interaction site model with the Kovalenko-Hirata closure (3D-RISM-KH). The numerically stable iterative solution of conventional 3D-RISM equations includes the fragmental decomposition of flexible ligands, which are treated as distinct species in solvent mixtures of arbitrary complexity. The computed density functions for solution (including ligand) molecules are obtained as a set of discrete spatial grids that uniquely describe the continuous solvent-site distribution around the protein solute. Potentials of mean force derived from these distributions define the scoring function interfaced with the AutoDock program for an automated ranking of docked conformations. As a case study in terms of solvent composition, we analyze cooperative interactions encountered in the binding of a flexible thiamine molecule to the prion protein at near physiological conditions. The predicted location and residency times of computed binding modes are in excellent agreement with the available experimental data. PMID- 26605743 TI - Reaction Dynamics of ATP Hydrolysis in Actin Determined by ab Initio Molecular Dynamics Simulations. AB - Energy released by the hydrolysis of the high-energy phosphate bond of nucleoside triphosphate (NTP) cofactors is the driving force behind most biological processes. To understand how this energy is used to induce differences in protein structure and function, we examine the transfer of vibrational energy into the nucleotide-bound actin active site immediately after reaction activation. To this end, we perform Born-Oppenheimer molecular dynamics simulations of the active site at the level of density functional theory (DFT) starting at the calculated transition state (TS) structure. Similarly to the mechanism determined in many nucleotide-bound protein systems, the Os-Pgamma bond is first elongated. Then, nucleophilic attack of the lytic water on Pgamma occurs. Subsequently, protons are transferred in a cycle formed by water molecules, a protein residue, Asp154, and the gamma-phosphate group, resulting in the formation of H2PO4(-). To investigate the possible creation of excited vibrational states in the products, power spectra of bond-length autocorrelation functions for relevant bonds within the active site are compared for simulations that start at the TS, at reactants, and at reaction end products. The hydroxyl bond formed in the final proton transfer to the phosphate molecule is observed to exhibit relatively high kinetic energies and large oscillations during reaction. It is also likely that some of the energy released by the reaction is captured by the low-energy stretching vibrations of the phosphoryl bonds of orthophosphate, which oscillate with large amplitudes in nonequilibrium simulations of end products. PMID- 26605744 TI - Coarse-Grained Structure-Based Model for RNA-Protein Complexes Developed by Fluctuation Matching. AB - RNA and RNA-protein complexes have recently been intensively studied in experiments, but the corresponding molecular simulation work is much less abundant, primarily due to its large system size and the long time scale involved. Here, to overcome these bottlenecks, we develop a coarse-grained (CG) structure-based simulation model for RNA and RNA-protein complexes and test it for several molecular systems. The CG model for RNA contains three particles per nucleotide, each for phosphate, sugar, and a base. Focusing on RNA molecules that fold to well-defined native structures, we employed a structure-based potential, which is similar to the Go-like potential successfully used in CG modeling of proteins. In addition, we tested three means to approximate electrostatic interactions. Many parameters involved in the CG potential were determined via a multiscale method: We matched the native fluctuation of the CG model with that by all-atom simulations for 16 RNA molecules and 10 RNA-protein complexes, from which we derived a generic set of CG parameters. We show that the derived parameters can reproduce native fluctuations well for four RNA and two RNA protein complexes. For tRNA, the native fluctuation in solution includes large amplitude motions that reach conformations nearly corresponding to the hybrid state P/E and EF-Tu-bound state A/T seen in the complexes with ribosome. Finally, large-amplitude modes of ribosome are briefly described. PMID- 26605745 TI - MM-ISMSA: An Ultrafast and Accurate Scoring Function for Protein-Protein Docking. AB - An ultrafast and accurate scoring function for protein-protein docking is presented. It includes (1) a molecular mechanics (MM) part based on a 12-6 Lennard-Jones potential; (2) an electrostatic component based on an implicit solvent model (ISM) with individual desolvation penalties for each partner in the protein-protein complex plus a hydrogen bonding term; and (3) a surface area (SA) contribution to account for the loss of water contacts upon protein-protein complex formation. The accuracy and performance of the scoring function, termed MM-ISMSA, have been assessed by (1) comparing the total binding energies, the electrostatic term, and its components (charge-charge and individual desolvation energies), as well as the per residue contributions, to results obtained with well-established methods such as APBSA or MM-PB(GB)SA for a set of 1242 decoy protein-protein complexes and (2) testing its ability to recognize the docking solution closest to the experimental structure as that providing the most favorable total binding energy. For this purpose, a test set consisting of 15 protein-protein complexes with known 3D structure mixed with 10 decoys for each complex was used. The correlation between the values afforded by MM-ISMSA and those from the other methods is quite remarkable (r(2) ~ 0.9), and only 0.2-5.0 s (depending on the number of residues) are spent on a single calculation including an all vs all pairwise energy decomposition. On the other hand, MM-ISMSA correctly identifies the best docking solution as that closest to the experimental structure in 80% of the cases. Finally, MM-ISMSA can process molecular dynamics trajectories and reports the results as averaged values with their standard deviations. MM-ISMSA has been implemented as a plugin to the widely used molecular graphics program PyMOL, although it can also be executed in command-line mode. MM-ISMSA is distributed free of charge to nonprofit organizations. PMID- 26605746 TI - Regularizing Binding Energy Distributions and the Hydration Free Energy of Protein Cytochrome C from All-Atom Simulations. AB - By introducing an external field to temper short-range protein water interactions, we regularize the statistical problem of calculating the hydration free energy, MU(ex), of the protein cytochrome C using the potential distribution theorem. Using this approach, we calculate the nonelectrostatic (dispersion) and electrostatic contributions to MU(ex). The nonelectrostatic contribution interpreted within an accessible surface area approach leads to a surface energy parameter that is about twice the value based on the hydration of small alkanes: at the size scale of the protein, hydrophobic hydration is more stronger relative to small alkanes. The electrostatic contribution does not obey linear response behavior. Further, depending on the choice of the protein dielectric constant, continuum dielectric calculations of the electrostatic contribution differ from the all-atom result by between 6%-12% (in a net value of about -2000 kcal/mol). We conclude by indicating potential applications of the present physically transparent approach toward illuminating the role of water, ions, and osmolytes in protein solution thermodynamics, including in protein folding and aggregation. PMID- 26605747 TI - Free Energy Guided Sampling. PMID- 26605748 TI - Mitochondrial DNA Depletion in Respiratory Chain-Deficient Parkinson Disease Neurons. AB - OBJECTIVE: To determine the extent of respiratory chain abnormalities and investigate the contribution of mtDNA to the loss of respiratory chain complexes (CI-IV) in the substantia nigra (SN) of idiopathic Parkinson disease (IPD) patients at the single-neuron level. METHODS: Multiple-label immunofluorescence was applied to postmortem sections of 10 IPD patients and 10 controls to quantify the abundance of CI-IV subunits (NDUFB8 or NDUFA13, SDHA, UQCRC2, and COXI) and mitochondrial transcription factors (TFAM and TFB2M) relative to mitochondrial mass (porin and GRP75) in dopaminergic neurons. To assess the involvement of mtDNA in respiratory chain deficiency in IPD, SN neurons, isolated with laser capture microdissection, were assayed for mtDNA deletions, copy number, and presence of transcription/replication-associated 7S DNA employing a triplex real time polymerase chain reaction (PCR) assay. RESULTS: Whereas mitochondrial mass was unchanged in single SN neurons from IPD patients, we observed a significant reduction in the abundances of CI and II subunits. At the single-cell level, CI and II deficiencies were correlated in patients. The CI deficiency concomitantly occurred with low abundances of the mtDNA transcription factors TFAM and TFB2M, which also initiate transcription-primed mtDNA replication. Consistent with this, real-time PCR analysis revealed fewer transcription/replication-associated mtDNA molecules and an overall reduction in mtDNA copy number in patients. This effect was more pronounced in single IPD neurons with severe CI deficiency. INTERPRETATION: Respiratory chain dysfunction in IPD neurons not only involves CI, but also extends to CII. These deficiencies are possibly a consequence of the interplay between nDNA and mtDNA-encoded factors mechanistically connected via TFAM. PMID- 26605749 TI - A description of a technique for ultrasound-guided lumbar plexus catheter in dogs: cadaveric study. AB - OBJECTIVE: To describe an ultrasound-guided approach for lumbar plexus catheter placement in dogs. STUDY DESIGN: Prospective experimental cadaveric study. ANIMALS: Eleven thawed canine cadavers (13 +/- 2 kg). MATERIAL AND METHODS: A technique to place a catheter in the psoas compartment at the level of the lumbar plexus under ultrasound guidance was described. Ultrasonographic landmarks for the placement of a lumbar plexus catheter were identified as the body of the sixth lumbar vertebrae, the psoas muscle and the femoral nerve. All catheters were placed by the principal investigator using epidural sets with an 18-G Tuohy needle. The procedure was carried out twice in each cadaver, with the aim of placing a catheter at the point of the left and right lumbar plexuses. A total volume of 0.4 mL kg(-1) of 1% methylene blue solution was injected into the psoas compartment after which the catheter was removed. After performing the injection in four cadavers, the technique was modified, altering the angle of needle placement and length of catheter insertion. Staining of the femoral and obturator nerves was assessed. Success was recorded if both nerves were stained over a length >1 cm. The spreading of the dye into the abdomen or to the nerve roots was also recorded. RESULTS: The success rate after the first four cadavers was four out of eight, and dye was found in the abdomen of two of the cadavers. When the modified technique was used in the subsequent seven cadavers, the success rate was 12 out of 14, and no dye was found in the abdomens. CONCLUSIONS AND CLINICAL RELEVANCE: This technique has shown a high percentage of success and low rate of complications. The only complication investigated in this study was the spread to the abdomen or epidural space. To establish safety, clinical studies will be needed. PMID- 26605750 TI - Cochlear, auditory brainstem responses in Type 1 diabetes: relationship with metabolic variables and diabetic complications. AB - AIMS: Few studies have analysed the presence of hearing abnormalities in diabetes. We assessed the presence of subclinical auditory alterations and their possible association with early vascular and neurological dysfunction in young adults with Type 1 diabetes of long duration. METHODS: Thirty-one patients with Type 1 diabetes (mean age 33 +/- 2.3 years, disease duration 25.7 +/- 4.2 years) and 10 healthy controls underwent pure tone audiometry (PTA), distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) analyses. Associations with metabolic variables and chronic complications were explored. RESULTS: Compared with healthy controls, patients with diabetes had significantly higher mean hearing thresholds, although still within the normoacusic range. DPOAE intensities at medium frequencies (2.8-4 kHz) were significantly lower in patients with diabetes. In ABR, in addition to waves I, III and V, we observed the appearance of a visible wave IV in patients with diabetes compared with controls (prevalence 61% vs. 10%, P < 0.05), and its appearance was related to a prolonged I-V interval (4.40 +/- 0.62 ms vs. 4.19 +/- 0.58 ms, P < 0.05). Diastolic blood pressure was higher in people with abnormal DPOAE (P < 0.05), whereas systolic blood pressure correlated with wave V and interpeak I-V interval latencies. A trend towards an association between evidence of wave IV and the presence of somatic neuropathy or abnormal cardiovascular autonomic tests was observed. CONCLUSIONS: Young adults with long-term Type 1 diabetes have subclinical abnormalities in qualitative auditory perception, despite normal hearing thresholds, which might reflect neuropathic and/or vascular alterations. PMID- 26605751 TI - Development, Optimization, and Evaluation of a Duplex Droplet Digital PCR Assay To Quantify the T-nos/hmg Copy Number Ratio in Genetically Modified Maize. AB - Certified reference materials (CRMs) are required to guarantee the reliability of analytical measurements. The CRMs available in the field of genetically modified organisms (GMOs) are characterized using real-time polymerase chain reaction (qPCR). This technology has limited application, because of its dependence on a calibrant. The objective of this study was to obtain a method with higher metrological quality, to characterize the CRMs for their contents of T-nos/hmg copy number ratio in maize. A duplex droplet digital PCR (ddPCR) assay was developed and optimized by a central composite design. The developed method achieved an absolute limit of detection (LOD) of 11 cP T-nos, a relative LOD of 0.034%, a limit of quantification (LOQ) of 23 cP (relative LOQ of 0.08%), and a dynamic range of 0.08%-100% T-nos/hmg ratio. The specificity and applicability of the assay were established for the analysis of low T-nos concentrations (0.9%) in several corn varieties. The convenience of DNA digestion to reduce measurement bias in the case of multiple-copy binding was confirmed through an enzymatic restriction assay. Given its overall performance, this method can be used to characterize CRM candidates for their contents of T-nos/hmg ratio. PMID- 26605753 TI - Identification of Drivers of Liking for Bar-Type Snacks Based on Individual Consumer Preference. AB - Understanding consumer hedonic responses on food products are of greatest interests in global food industry. A global partial least square regression (GPLSR) had been well accepted method for understanding consumer preferences. Recently, individual partial least square regression (IPLSR) was accepted as an alternative method of predicting consumer preferences on given food product, because it utilizes the individual differences on product acceptability. To improve the understanding of what constitutes bar-type snack preference, the relationship between sensory attributes and consumer overall liking for 12 bar type snacks was determined. Sensory attributes that drive consumer product likings were analyzed using averaged-consumer data by GPLSR. To facilitate the interpretation of individual consumer liking, a dummy matrix for the significant weighted regression coefficients of each consumer derived from IPLSR was created. From the application of GPLSR and IPLSR, current study revealed that chocolate and cereal-flavored bars were preferred over fruit-flavored bars. Attributes connected to chocolate flavor positively influenced consumer overall likings on the global and individual consumer levels. Textural attributes affected liking only on the individual level. To fully capture the importance of sensory attributes on consumer preference, the use of GPLSR in conjunction with IPLSR is recommended. PMID- 26605752 TI - Use of Low-Literacy Decision Aid to Enhance Knowledge and Reduce Decisional Conflict Among a Diverse Population of Adults With Rheumatoid Arthritis: Results of a Pilot Study. AB - OBJECTIVE: Despite innovations in treatment of rheumatoid arthritis (RA), adherence is poor and disparities persist. Shared decision making (SDM) promotes patient engagement and enhances adherence; however, few tools support SDM in RA. Our objective was to pilot a low-literacy medication guide and decision aid to facilitate patient-clinician conversations about RA medications. METHODS: RA patients were consecutively enrolled into 1 of 3 arms: 1) control; patients received existing medication guide prior to clinic visit, 2) adapted guide prior to visit, and 3) adapted guide prior to plus decision aid during visit. Outcomes were collected immediately postvisit, at 1-week, and at 3- and 6-month interviews. Eligible adults had to have failed at least 1 disease-modifying antirheumatic drug and fulfill 1 of the following: age >65 years, immigrant, non English speaker, less than high school education, limited health literacy, and racial/ethnic minority. Primary outcomes were knowledge of RA medications, decisional conflict, and acceptability of interventions. RESULTS: The majority of 166 patients were immigrants (66%), non-English speakers (54%), and had limited health literacy (71%). Adequate RA knowledge postvisit in arm 3 was higher (78%) than arm 1 (53%; adjusted odds ratio 2.7, 95% confidence interval 1.2, 6.1). Among patients with a medication change, there was lower (better) mean decisional conflict in arms 2 and 3 (P = 0.03). There were no significant differences in acceptability. CONCLUSION: A low-literacy medication guide and decision aid was acceptable, improved knowledge, and reduced decisional conflict among vulnerable RA patients. Enhancing knowledge and patient engagement with decision support tools may lead to medication choices better aligned with RA patients' values and preferences. PMID- 26605754 TI - Additional transbronchial needle aspiration through a guide sheath for peripheral pulmonary lesions that cannot be detected by radial EBUS. AB - BACKGROUND: Endobronchial ultrasound with a guide sheath (EBUS-GS) has resulted to better diagnostic outcome for peripheral pulmonary lesions (PPLs), although the yield is not satisfactory for lesions that cannot be located by EBUS. We aimed to evaluate whether the addition of a new technique, transbronchial needle aspiration through a guide sheath (GS-TBNA), can increase the yield for these cases. METHODS: This was a retrospective review of cases that were not located by EBUS during EBUS-GS for PPL diagnosis. From September 2012 to August 2014, 67 PPLs had 'invisible' EBUS-GS location prior to transbronchial sampling. The patients were divided into two groups according to the use of additional GS-TBNA: GS-TBNA group (n=22) and non-GS-TBNA group (n=45). Diagnostic yields were compared and multivariate analysis was performed to determine the factors associated with increased diagnostic yield. RESULTS: The diagnostic yield was significantly higher in the GS-TBNA group than in the non-GS-TBNA group (54.5% vs 17.8%, P<0.01). The complication rate was not significantly different between the GS-TBNA group and the non-GS-TBNA group (0% vs 4.4%, P=1.0). Multivariate analysis showed that only performing GS-TBNA was significantly associated with increased diagnostic yield (odds ratio 3.99, P=0.03). CONCLUSION: GS-TBNA is a safe technique for PPL diagnosis and may be useful when the EBUS probe cannot reach the lesion. PMID- 26605755 TI - Importance of lymphovascular invasion and invasive front on survival in floor of mouth cancer. AB - BACKGROUND: The floor of mouth (FOM) is a common site of oral squamous cell carcinoma (SCC). The purpose of this study was to investigate pathological predictors of survival in FOM SCC. METHODS: We conducted a retrospective study of 54 consecutive patients undergoing surgery for FOM SCC. Pathological parameters were extracted from histological reports with original pathology slides re reviewed by 2 pathologists for missing data. RESULTS: On univariate analysis, depth of invasion >10 mm (p = .009), lymphovascular invasion (LVI; p < .001), noncohesive invasive front (p = .006), perineural invasion (PNI; p = .003), and nodal metastases (p = .02) were significant predictors of overall survival. On multivariate analysis, LVI (p = .009) and invasive front (p < .001) remained significant. Postoperative radiotherapy improved survival in patients with LVI, PNI, and nodal metastases, and was just outside significance for noncohesive invasive front (p = .06). CONCLUSION: LVI is an adverse prognosticator in FOM SCC and indicates postoperative radiotherapy. Further study is required to investigate the importance of invasive front. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1528-E1534, 2016. PMID- 26605756 TI - T2 * relaxation time in Achilles tendinosis and controls and its correlation with clinical score. AB - PURPOSE: To investigate if the T2 * of Achilles tendons can discriminate between chronic Achilles tendinosis and healthy controls; to correlate with clinical score; to evaluate its short-term repeatability; and to estimate minimal detectable change. MATERIALS AND METHODS: Twenty patients, with chronic mid portion Achilles tendinosis, and 10 controls without history of Achilles tendon symptoms, were examined with a 3T MR scanner with a 3D flash ultrashort time to echo sequence with five different echo times. The sequence was run twice to test repeatability. The tendon border was delineated on axial slices at three different levels in the calculated T2 * maps. The clinical severity of Achilles tendinosis was measured by a VISA-A questionnaire. RESULTS: There was a significant difference in mean T2 * between symptomatic and control tendons (P < 0.001). In patients with unilateral symptoms no significant difference in T2 * was found between symptomatic and contralateral asymptomatic tendons (P = 0.19). There was no significant correlation between clinical severity and T2 * (r = 0.28, P = 0.22). The short-term repeatability of T2 * showed a coefficient of variation of 18%, a least significant change of 50%, and the intraclass correlation coefficient had an average consistency of 0.99. CONCLUSION: T2 * may help to differentiate between chronic Achilles tendinosis and healthy controls but was not associated with the clinical score. However, and notably, the reproducibility of the method was low and the number of patients was small. J. Magn. Reson. Imaging 2016;43:1417-1422. PMID- 26605757 TI - The rs2294918 E434K variant modulates patatin-like phospholipase domain containing 3 expression and liver damage. AB - The patatin-like phosholipase domain-containing 3 (PNPLA3) rs738409 polymorphism (I148M) is a major determinant of hepatic fat and predisposes to the full spectrum of liver damage in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate whether additional PNPLA3 coding variants contribute to NAFLD susceptibility, first in individuals with contrasting phenotypes (with early-onset NAFLD vs. very low aminotransferases) and then in a large validation cohort. Rare PNPLA3 variants were not detected by sequencing coding regions and intron-exon boundaries either in 142 patients with early-onset NAFLD nor in 100 healthy individuals with alanine aminotransferase <22/20 IU/mL. Besides rs738409 I148M, the rs2294918 G>A polymorphism (E434K sequence variant) was over represented in NAFLD (adjusted P = 0.01). In 1,447 subjects with and without NAFLD, the 148M-434E (P < 0.0001), but not the 148M-434K, haplotype (P > 0.9), was associated with histological NAFLD and steatohepatitis. Both the I148M (P = 0.0002) and E434K variants (P = 0.044) were associated with serum ALT levels, by interacting with each other, in that the 434K hampered the association with liver damage of the 148M allele (P = 0.006). The E434K variant did not affect PNPLA3 enzymatic activity, but carriers of the rs2294918 A allele (434K) displayed lower hepatic PNPLA3 messenger RNA and protein levels (P < 0.05). CONCLUSIONS: Rare loss-of-function PNPLA3 variants were not detected in early-onset NAFLD. However, PNPLA3 rs2294918 E434K decreased PNPLA3 expression, lessening the effect of the I148M variant on the predisposition to steatosis and liver damage. This suggests that the PNPLA3 I148M variant has a codominant negative effect on triglycerides mobilization from lipid droplets, mediated by inhibition of other lipases. PMID- 26605759 TI - Insight into Metalized Interfaces in Nano Devices by Surface Analytical Techniques. AB - Connections between metals and heterogeneous solid state materials form buried interfaces. These ubiquitous structures play an essential role in determining the performances of many nano- and microdevices. However, the information about the chemistry, structure, and properties of these real interfaces is intrinsically difficult to extract by traditional techniques. Therefore, approaches to efficiently discovering metalized interfaces are in high demand. Here, we demonstrate the transformation of nanoscale metal/oxide interface problems into surface problems through a novel metal-hydrogenation detaching method. We applied this technique to study the thickness dependence in Pb(Zr,Ti)O3 (PZT) ferroelectric thin films, a long-standing interface problem in a model metal/insulator device, and this allowed comprehensive surface analytical techniques to be adapted. A nonstoichiometric interfacial layer of 4.1 nm thick with low mass density, low permittivity, and weak ferroelectricity was quantified at the Pt/PZT interface and attributed to the preferential diffusions among the compositional elements. Targeted interface engineering by Pb rebalance led to a substantial recovery of ferroelectric properties. Our results therefore pave the way to a better understanding of metallized interface in ferroelectric and dielectric nanodevices. We hope that more useful information about metalized interfaces of other solid materials could, analogously, be accessed by surface analytical techniques. PMID- 26605760 TI - Encapsulated Silver Nanoparticles Can Be Directly Converted to Silver Nanoshell in the Gas Phase. AB - We report, for the first time, that an encapsulated silver nanoparticle can be directly converted to a silver nanoshell through a nanoscale localized oxidation and reduction process in the gas phase. Silver can be etched when exposed to a mixture of NH3/O2 gases through a mechanism analogous to the formation of aqueous Tollens' reagent, in which a soluble silver-ammonia complex was formed. Starting with Ag@resorcinol-formaldehyde (RF) resin core-shell nanoparticles, we demonstrate that RF-core@Ag-shell nanoparticles can be prepared successfully when the etching rate and RF thickness were well controlled. Due to the strong surface plasmon resonance (SPR) coupling effect among neighboring silver nanoparticles, the RF@Ag nanoparticle showed great SPR and SERS performance. This process provides a general route to the conversion of Ag-core to Ag-shell nanostructures and might be extended to other systems. PMID- 26605761 TI - Ovarian cancer: beyond resistance. PMID- 26605758 TI - Endochondral Growth Defect and Deployment of Transient Chondrocyte Behaviors Underlie Osteoarthritis Onset in a Natural Murine Model. AB - OBJECTIVE: To explore whether aberrant transient chondrocyte behaviors occur in the joints of STR/Ort mice (which spontaneously develop osteoarthritis [OA]) and whether they are attributable to an endochondral growth defect. METHODS: Knee joints from STR/Ort mice with advanced OA and age-matched CBA (control) mice were examined by Affymetrix microarray profiling, multiplex polymerase chain reaction (PCR) analysis, and immunohistochemical labeling of endochondral markers, including sclerostin and MEPE. The endochondral phenotype of STR/Ort mice was analyzed by histologic examination, micro-computed tomography, and ex vivo organ culture. A novel protocol for quantifying bony bridges across the murine epiphysis (growth plate fusion) using synchrotron x-ray computed microtomography was developed and applied. RESULTS: Meta-analysis of transcription profiles showed significant elevation in functions linked with endochondral ossification in STR/Ort mice (compared to CBA mice; P < 0.05). Consistent with this, immunolabeling revealed increased matrix metalloproteinase 13 (MMP-13) and type X collagen expression in STR/Ort mouse joints, and multiplex quantitative reverse transcriptase-PCR showed differential expression of known mineralization regulators, suggesting an inherent chondrocyte defect. Support for the notion of an endochondral defect included accelerated growth, increased zone of growth plate proliferative chondrocytes (P < 0.05), and widespread type X collagen/MMP 13 labeling beyond the expected hypertrophic zone distribution. OA development involved concomitant focal suppression of sclerostin/MEPE in STR/Ort mice. Our novel synchrotron radiation microtomography method showed increased numbers (P < 0.001) and mean areal growth plate bridge densities (P < 0.01) in young and aged STR/Ort mice compared to age-matched CBA mice. CONCLUSION: Taken together, our data support the notion of an inherent endochondral defect that is linked to growth dynamics and subject to regulation by the MEPE/sclerostin axis and may represent an underlying mechanism of pathologic ossification in OA. PMID- 26605762 TI - The problem with platinum. PMID- 26605763 TI - Including the Patient Voice in Aesthetic Rhinoplasty Outcomes: A New Patient Reported Outcome Tool for Rhinoplasty. PMID- 26605779 TI - New insights into the host cell necrosis in tuberculosis. PMID- 26605780 TI - MicroRNA-145 Suppresses Osteosarcoma Metastasis via Targeting MMP16. AB - BACKGROUND: Metastasis is a leading cause of mortality for osteosarcoma (OS) patients, and its molecular pathological mechanisms remain to be elucidated. Previous studies have suggested a significant role of microRNAs (miRNAs) in the control of cancel cell migration and invasion. METHODS: Real-time PCR was used to screen the differentially expressed miRNAs between OS with or without metastasis, and miR-145 underexpression was observed in metastatic OS. Luciferase assay was performed to validate the target gene. RESULTS: Further, we identified three genes, MMP16, ADAM17 and metadherin, as possible targets of miR-145. We identified MMP16 as a target gene of miR-145 and ruled out ADAM17 and metadherin as targets in OS using a dual luciferase reporter system. Subsequently, we determined and compared the expression level of MMP16 in human OS samples and showed that the mRNA and protein levels of MMP16 were significantly up-regulated in primary OS with metastasis compared with those without metastasis. We also altered miR-145 expression by transfecting OS cells with miR-145 mimics or inhibitors. MMP16 expression was similarly downregulated in the cells transfected with miR-145 mimics or MMP16-specific siRNA, and the invasive and migratory capability of those cells was significantly suppressed compared with negative controls. MMP16 expression was consistently significantly upregulated in the cells transfected with miR-145 inhibitors, and the invasive and migratory capability of those cells was significantly promoted compared with negative controls. Conclcusion: Our results suggest that miR-145 functions as a tumor metastasis suppressor gene by down-regulating MMP16 and may be a potential target in osteosarcoma treatment. PMID- 26605781 TI - The continuum of HIV care in Catalonia. AB - The objective was to produce a cascade of care for Catalonia to gain a public health perspective on the overall quality of HIV services and allow comparison with other countries. It was constructed using the Integrated Epidemiological Surveillance System of HIV in Catalonia and data from the PISCIS Cohort. Estimates of the number of people living with HIV in Catalonia are modelled using Spectrum Projection Package 2011 (UNAIDS/WHO). Totals for each stage in the cascade are obtained by applying to the preceding stage a proportion estimated from available surveillance and cohort data. Undiagnosed HIV was estimated from the European literature. The proportions retained in care, on ART and virally suppressed were derived from the PISCIS cohort. Programmatic data on ART consumption was used to validate estimates. By the end of 2011 there were about 33,000 people living with HIV in Catalonia, 71% of which had been both diagnosed and linked to care. We estimate that 61% of all HIV infected persons were retained in care, 56% were on ART and 48% were virally suppressed. These figures data are comparable, although slightly lower, than that of France or the UK. The Cascade of HIV Care in Catalonia is similar to other western European countries such as France and the UK. Direct estimates of the undiagnosed HIV population and linkage to care are desirable but the contribution of cohort data to the cascade highlights their continued importance in HIV surveillance and design of evidence based health strategies. PMID- 26605782 TI - Inhibition of Pathogenic Mutant SOD1 Aggregation in Cultured Motor Neuronal Cells by Prevention of Its SUMOylation on Lysine 75. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective death of motor neurons. Mutations in the SOD1 gene encoding the superoxide dismutase 1 are present in 15% of familial ALS cases and in 2% of sporadic cases. These mutations are associated with the formation of SOD1-positive aggregates. The mechanisms of aggregation remain unknown, but posttranslational modifications of SOD1 may be involved. Here, we report that NSC 34 motor neuronal cells expressing mutant SOD1 contained aggregates positive for small ubiquitin modifier-1 (SUMO-1), and in parallel a reduced level of free SUMO 1. CLEM (correlative light and electron microscopy) analysis showed nonorganized cytosolic aggregates for all mutations tested (SOD1A4V, SOD1V31A, and SOD1G93C). We next show that preventing the SUMOylation of mutant SOD1 by the substitution of lysine 75, the SUMOylation site of SOD1, significantly reduces the number of motor neuronal cells with aggregates. These results support the need for further research on the SUMOylation pathways, which may be a potential therapeutic target in ALS. PMID- 26605783 TI - Microbiome and Gluten. AB - Celiac disease (CD) is a frequent chronic inflammatory enteropathy caused by gluten in genetically predisposed individuals that carry disease susceptibility genes (HLA-DQ2/8). These genes are present in about 30-40% of the general population, but only a small percentage of carriers develops CD. Gluten is the key environmental trigger of CD, but its intake does not fully explain disease onset; indeed, an increased number of cases experience gluten intolerance in late adulthood after many years of gluten exposure. Consequently, additional environmental factors seem to be involved in CD. Epidemiological studies indicate that common perinatal and early postnatal factors influence both CD risk and intestinal microbiota structure. Prospective studies in healthy infants at risk of developing CD also reveal that the HLA-DQ genotype, in conjunction with other environmental factors, influences the microbiota composition. Furthermore, CD patients have imbalances in the intestinal microbiota (dysbiosis), which are not fully normalized despite their adherence to a gluten-free diet. Therefore, it is hypothesized that the disease can promote dysbiosis that aggravates CD pathogenesis, and dysbiosis, in turn, can initiate and sustain inflammation through the expansion of proinflammatory pathobionts and decline of anti inflammatory mutualistic bacteria. Studies in experimental models are also contributing to understand the role of intestinal bacteria and its interactions with a predisposed genotype in promoting CD. Advances in this area could aid in the development of microbiome-informed intervention strategies that optimize the partnership between the gut microbiota and host immunity for improving CD management. PMID- 26605784 TI - Melatonin releasing PLGA micro/nanoparticles and their effect on osteosarcoma cells. AB - Melatonin loaded poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles and microparticles in the diameter of ~200 nm and 3.5 MUm, respectively, were prepared by emulsion-diffusion-evaporation method. Melatonin entrapment into the particles was significantly improved with the addition of 0.2% (w/v) melatonin into the aqueous phase and encapsulation efficiencies were found as 14 and 27% for nanoparticles and microparticles, respectively. At the end of 40 days, ~70% of melatonin was released from both of particles, with high burst release. Both blank and melatonin loaded PLGA nanoparticles caused toxic effect on the MG-63 cells due to their uptake by the cells. However, when 0.05 mg microparticle that is carrying ~1.7 MUg melatonin was added to the cm(2) of culture, inhibitory effect of melatonin on the cells were obviously observed. The results would provide an expectation about the usage of melatonin as an adjunct to the routine chemotherapy of osteosarcoma by encapsulating it into a polymeric carrier system. PMID- 26605785 TI - Exploring the relationship between posttraumatic growth, cognitive processing, psychological distress, and social constraints in a sample of breast cancer patients. AB - Posttraumatic growth (the perception of positive life changes after an encounter with a trauma) often occurs among breast cancer patients and can be influenced by certain demographic, medical, and psychosocial parameters. Social constraints on disclosure (the deprivation of the opportunity to express feelings and thoughts regarding the trauma) and the cognitive processing of the disease seem to be involved in the development of posttraumatic growth. Through the present study the authors aim to: investigate the levels of posttraumatic growth in a sample of 202 women with breast cancer in Greece, explore the relationships between posttraumatic growth and particular demographic, medical, and psychosocial variables according to a proposed model, and test the role of social constraints in the relationship between automatic and deliberate cognitive processing of the trauma. The results showed that posttraumatic growth was evident in the majority of the sample and was associated inversely with age at diagnosis (beta = -0.174, p < .05) and psychological distress (beta = -0.394, p = .001), directly with time since diagnosis (beta = 0.181, p < .05), and indirectly with intrusions and psychological distress, through reflective rumination (beta = 0.323, p = .001). Social constraints were found to moderate the relationship between intrusions and reflective rumination. Implications of the results and suggestions for future research and practice are outlined. PMID- 26605786 TI - Temporal generalization gradients following an interdimensional discrimination protocol. AB - We investigated the effects of interdimensional discrimination training in the temporal generalization gradient. In a matching-to-sample task, pigeons learned to choose key S after a T-s houselight sample and key NS in the absence of the houselight sample. For one group of pigeons, T = 20 s; for another, T = 10 s. Subsequently, houselight duration was varied to obtain temporal generalization gradients. Results showed that (a) proportion S increased as houselight duration ranged from 0 s to T s and then remained high for houselight durations longer than T; (b) the gradients were well described by negative-exponential functions; (c) these non-flat gradients were present from the beginning of testing, and; (d) the average gradients obtained with T = 20 s and T = 10 s overlapped when plotted in relative time. We conclude that temporal control does not require explicit discrimination training along the temporal dimension, and that temporal generalization gradients obtained with an interdimensional protocol show the scalar property of timing. We discuss how these findings challenge current models of timing. PMID- 26605787 TI - Serosurvey of Smooth Brucella, Leptospira spp. and Toxoplasma gondii in Free Ranging Jaguars (Panthera onca) and Domestic Animals from Brazil. AB - This study investigated the exposure of jaguar populations and domestic animals to smooth Brucella, Leptospira spp. and Toxoplasma gondii in the Cerrado, Pantanal and Amazon biomes of Brazil. Between February 2000 and January 2010, serum samples from 31 jaguars (Panthera onca), 1,245 cattle (Bos taurus), 168 domestic dogs (Canis lupus familiaris) and 29 domestic cats (Felis catus) were collected and analysed by rose bengal test for smooth Brucella, microscopic agglutination test for Leptospira spp. and modified agglutination test for T. gondii. Cattle populations from all sites (9.88%) were exposed to smooth Brucella, but only one jaguar from Cerrado was exposed to this agent. Jaguars captured in the Cerrado (60.0%) and in the Pantanal (45.5%) were seropositive for different serovars of Leptospira spp., cattle (72.18%) and domestic dogs (13.1%) from the three sites and one domestic cat from Pantanal were also seropositive for the agent. The most prevalent serotype of Leptospira spp. identified in jaguars from the Cerrado (Grippotyphosa) and the Pantanal (Pomona) biomes were distinct from those found in the domestic animals sampled. Jaguars (100%), domestic dogs (38.28%) and domestic cats (82.76%) from the three areas were exposed to T. gondii. Our results show that brucellosis and leptospirosis could have been transmitted to jaguars by domestic animals; and jaguars probably play an important role in the maintenance of T. gondii in nature. PMID- 26605789 TI - Facial Recognition in a Group-Living Cichlid Fish. AB - The theoretical underpinnings of the mechanisms of sociality, e.g. territoriality, hierarchy, and reciprocity, are based on assumptions of individual recognition. While behavioural evidence suggests individual recognition is widespread, the cues that animals use to recognise individuals are established in only a handful of systems. Here, we use digital models to demonstrate that facial features are the visual cue used for individual recognition in the social fish Neolamprologus pulcher. Focal fish were exposed to digital images showing four different combinations of familiar and unfamiliar face and body colorations. Focal fish attended to digital models with unfamiliar faces longer and from a further distance to the model than to models with familiar faces. These results strongly suggest that fish can distinguish individuals accurately using facial colour patterns. Our observations also suggest that fish are able to rapidly (<= 0.5 sec) discriminate between familiar and unfamiliar individuals, a speed of recognition comparable to primates including humans. PMID- 26605788 TI - Chronic Microdose Lithium Treatment Prevented Memory Loss and Neurohistopathological Changes in a Transgenic Mouse Model of Alzheimer's Disease. AB - The use of lithium is well established in bipolar disorders and the benefits are being demonstrated in neurodegenerative disorders. Recently, our group showed that treatment with microdose lithium stabilized the cognitive deficits observed in Alzheimer's disease (AD) patients. In order to verify the lithium microdose potential in preventing the disease development, the aim of this work was to verify the effects of chronic treatment with microdose lithium given before and after the appearance of symptoms in a mouse model of a disease similar to AD. Transgenic mice (Cg-Tg(PDGFB-APPSwInd)20Lms/2J) and their non-transgenic litter mate genetic controls were treated with lithium carbonate (0.25mg/Kg/day in drinking water) for 16 or 8 months starting at two and ten months of age, respectively [corrected]. Similar groups were treated with water. At the end of treatments, both lithium treated transgenic groups and non-transgenic mice showed no memory disruption, different from what was observed in the water treated transgenic group. Transgenic mice treated with lithium since two months of age showed decreased number of senile plaques, no neuronal loss in cortex and hippocampus and increased BDNF density in cortex, when compared to non-treated transgenic mice. It is suitable to conclude that these data support the use of microdose lithium in the prevention and treatment of Alzheimer's disease, once the neurohistopathological characteristics of the disease were modified and the memory of transgenic animals was maintained. PMID- 26605790 TI - Spectrophotometric determination of low levels arsenic species in beverages after ion-pairing vortex-assisted cloud-point extraction with acridine red. AB - A new, low-cost, micellar-sensitive and selective spectrophotometric method was developed for the determination of inorganic arsenic (As) species in beverage samples. Vortex-assisted cloud-point extraction (VA-CPE) was used for the efficient pre-concentration of As(V) in the selected samples. The method is based on selective and sensitive ion-pairing of As(V) with acridine red (ARH(+)) in the presence of pyrogallol and sequential extraction into the micellar phase of Triton X-45 at pH 6.0. Under the optimised conditions, the calibration curve was highly linear in the range of 0.8-280 ug l(-1) for As(V). The limits of detection and quantification of the method were 0.25 and 0.83 ug l(-1), respectively. The method was successfully applied to the determination of trace As in the pre treated and digested samples under microwave and ultrasonic power. As(V) and total As levels in the samples were spectrophotometrically determined after pre concentration with VA-CPE at 494 nm before and after oxidation with acidic KMnO4. The As(III) levels were calculated from the difference between As(V) and total As levels. The accuracy of the method was demonstrated by analysis of two certified reference materials (CRMs) where the measured values for As were statistically within the 95% confidence limit for the certified values. PMID- 26605791 TI - Quantitation of 5-Methyltetrahydrofolic Acid in Dried Blood Spots and Dried Plasma Spots by Stable Isotope Dilution Assays. AB - Because of minimal data available on folate analysis in dried matrix spots (DMSs), we combined the advantages of stable isotope dilution assays followed by LC-MS/MS analysis with DMS sampling to develop a reliable method for the quantitation of plasma 5-methyltetrahydrofolic acid in dried blood spots (DBSs) and dried plasma spots (DPSs) as well as for the quantitation of whole blood 5 methyltetrahydrofolic acid in DBSs. We focused on two diagnostically conclusive parameters exhibited by the plasma and whole blood 5-methyltetrahydrofolic acid levels that reflect both temporary and long-term folate status. The method is performed using the [2H4]-labeled isotopologue of the vitamin as the internal standard, and three steps are required for the extraction procedure. Elution of the punched out matrix spots was performed using stabilization buffer including Triton X-100 in a standardized ultrasonication treatment followed by enzymatic digestion (whole blood only) and solid-phase extraction with SAX cartridges. This method is sensitive enough to quantify 27 nmol/L whole blood 5 methyltetrahydrofolic acid in DBSs and 6.3 and 4.4 nmol/L plasma 5 methyltetrahydrofolic acid in DBSs and DPSs, respectively. The unprecedented accurate quantification of plasma 5-methyltetrahydrofolic acid in DBSs was achieved by thermal treatment prior to ultrasonication, inhibiting plasma conjugase activity. Mass screenings are more feasible and easier to facilitate for this method in terms of sample collection and storage compared with conventional clinical sampling for the assessment of folate status. PMID- 26605792 TI - Associations between Medical Conditions and Breast Cancer Risk in Asians: A Nationwide Population-Based Study in Taiwan. AB - BACKGROUND: The breast cancer incidence in Asia is rising. To explore whether the etiology of breast cancer is different from the known risk factors from studies in Western countries, we conducted a nested case-control study using data from the Taiwan National Health Insurance Research Database (NHIRD). METHODS: All medical conditions based on the first three digits of the ICD-9 and a list of medical conditions based on literature review were retrieved for each case and control. The odds ratios (OR) and 95% confidence intervals (CI) of the associations between medical conditions and breast cancer risks were estimated using conditional logistic regression and adjusted for occupation, number of breast cancer screening, and the average number of outpatient visits prior the diagnosis. The associations were also estimated for younger (<50 years old) and older subjects separately. RESULTS: The analyses included 4,884 breast cancer cases and 19,536 age-matched controls. Prior breast diseases (OR, 95% CI: 2.47, 2.26-2.71), obesity (1.43, 1.04-1.96), endometriosis (1.44, 1.15-1.80), uterine leiomyoma (1.20, 1.03-1.40), hypertensive diseases (1.14, 1.05-1.25), and disorders in lipid metabolism (1.13, 1.04-1.24) were associated with increased breast cancer risk. No heterogeneity was observed between age groups (<50 and >=50 years old). CONCLUSIONS: In addition to benign breast diseases, obesity, endometriosis, uterine leiomyoma, hypertensive diseases, and disorders of lipid metabolism were associated with a subsequent breast cancer risk. IMPACTS: Our results suggest that estrogen related factors may play an important role in breast cancer risks in the Taiwanese female population. PMID- 26605793 TI - A Pyrosequencing Investigation of Differences in the Feline Subgingival Microbiota in Health, Gingivitis and Mild Periodontitis. AB - Periodontitis is the most frequently diagnosed health problem in cats yet little is known about the bacterial species important for the disease. The objective of this study was to identify bacterial species associated with health, gingivitis or mild periodontitis (<25% attachment loss) in feline plaque. Knowledge of these species is a first step in understanding the potential for improving oral health of cats via dietary interventions that alter the proportions of influential species. Subgingival plaque samples were collected from 92 cats with healthy gingiva, gingivitis or mild periodontitis. Pyrosequencing of the V1-V3 region of the 16S rDNA from these plaque samples generated more than one million reads and identified a total of 267 operational taxonomic units after bioinformatic and statistical analysis. Porphyromonas was the most abundant genus in all gingival health categories, particularly in health along with Moraxella and Fusobacteria. The Peptostreptococcaceae were the most abundant family in gingivitis and mild periodontitis. Logistic regression analysis identified species from various genera that were significantly associated with health, gingivitis or mild periodontitis. The species identified were very similar to those observed in canine plaque in the corresponding health and disease states. Such similarities were not observed between cat and human at the bacterial species level but with disease progression similarities did emerge at the phylum level. This suggests that interventions targeted at human pathogenic species will not be effective for use in cats but there is more potential for commonalities in interventions for cats and dogs. PMID- 26605794 TI - Structural and Functional Analysis of the ApolipoproteinA-I A164S Variant. AB - Apolipoprotein A-I (apoA-I) is the main protein involved in the formation of high density lipoprotein (HDL), it is the principal mediator of the reverse cholesterol transfer (RCT) pathway and provides cardio-protection. In addition to functional wild-type apoA-I, several variants have been shown to associate with hereditary amyloidosis. In this study we have performed biophysical and biochemical analyses of the structure and functional properties of the A164S variant of apoA-I (1:500 in the Danish general population), which is the first known mutation of apoA-I that leads to an increased risk of ischaemic heart disease (IHD), myocardial infarction and mortality without associated low HDL cholesterol levels. Despite the fact that epidemiologically IHD is associated with low plasma levels of HDL, the A164S mutation is linked to normal plasma levels of lipids, HDL and apoA-I, suggesting impaired functionality of this variant. Using biophysical techniques (e.g., circular dichroism spectroscopy and electron microscopy) to determine secondary structure, stability and pro amyloidogenic property of the lipid free A164S apoA-I variant, our observations suggest similarity in structural properties between apoA-I WT and apoA-I A164S. However, the A164S apoA-I variant exhibits lower binding affinity to lipids but forms similar sized HDL particles to those produced by WT. PMID- 26605795 TI - The Influence of Depression on Cognitive Control: Disambiguating Approach and Avoidance Tendencies. AB - Dysfunctions of approach and avoidance motivation play an important role in depression, which in turn may affect cognitive control, i.e., the ability to regulate thoughts and action to achieve internal goals. We use a novel experimental paradigm, i.e. a computer simulated driving-task, to study the impact of depression on cognitive control by measuring approach and avoidance actions in continuous time. In this task, 39 subjects with minimal to severe depression symptoms were instructed to use a joystick to move a virtual car as quickly as possible to a target point without crossing a stop-sign or crashing into a wall. We recorded their continuous actions on a joystick and found that depression 1) leads to further stopping distance to task target; and 2) increases the magnitude of late deceleration (avoidance) but not early acceleration (approach), which was only observed in the stop-sign condition. Taken together, these results are consistent with the hypothesis that depressed individuals have greater avoidance motivation near stopping target, but are minimally affected by approach motivation. PMID- 26605796 TI - Dual Action of Lysophosphatidate-Functionalised Titanium: Interactions with Human (MG63) Osteoblasts and Methicillin Resistant Staphylococcus aureus. AB - Titanium (Ti) is a widely used material for surgical implants; total joint replacements (TJRs), screws and plates for fixing bones and dental implants are forged from Ti. Whilst Ti integrates well into host tissue approximately 10% of TJRs will fail in the lifetime of the patient through a process known as aseptic loosening. These failures necessitate revision arthroplasties which are more complicated and costly than the initial procedure. Finding ways of enhancing early (osseo)integration of TJRs is therefore highly desirable and continues to represent a research priority in current biomaterial design. One way of realising improvements in implant quality is to coat the Ti surface with small biological agents known to support human osteoblast formation and maturation at Ti surfaces. Lysophosphatidic acid (LPA) and certain LPA analogues offer potential solutions as Ti coatings in reducing aseptic loosening. Herein we present evidence for the successful bio-functionalisation of Ti using LPA. This modified Ti surface heightened the maturation of human osteoblasts, as supported by increased expression of alkaline phosphatase. These functionalised surfaces also deterred the attachment and growth of Staphylococcus aureus, a bacterium often associated with implant failures through sepsis. Collectively we provide evidence for the fabrication of a dual-action Ti surface finish, a highly desirable feature towards the development of next-generation implantable devices. PMID- 26605797 TI - Automated Classification and Cluster Visualization of Genotypes Derived from High Resolution Melt Curves. AB - INTRODUCTION: High Resolution Melting (HRM) following PCR has been used to identify DNA genotypes. Fluorescent dyes bounded to double strand DNA lose their fluorescence with increasing temperature, yielding different signatures for different genotypes. Recent software tools have been made available to aid in the distinction of different genotypes, but they are not fully automated, used only for research purposes, or require some level of interaction or confirmation from an analyst. MATERIALS AND METHODS: We describe a fully automated machine learning software algorithm that classifies unknown genotypes. Dynamic melt curves are transformed to multidimensional clusters of points whereby a training set is used to establish the distribution of genotype clusters. Subsequently, probabilistic and statistical methods were used to classify the genotypes of unknown DNA samples on 4 different assays (40 VKORC1, CYP2C9*2, CYP2C9*3 samples in triplicate, and 49 MTHFR c.665C>T samples in triplicate) run on the Roche LC480. Melt curves of each of the triplicates were genotyped separately. RESULTS: Automated genotyping called 100% of VKORC1, CYP2C9*3 and MTHFR c.665C>T samples correctly. 97.5% of CYP2C9*2 melt curves were genotyped correctly with the remaining 2.5% given a no call due to the inability to decipher 3 melt curves in close proximity as either homozygous mutant or wild-type with greater than 99.5% posterior probability. CONCLUSIONS: We demonstrate the ability to fully automate DNA genotyping from HRM curves systematically and accurately without requiring any user interpretation or interaction with the data. Visualization of genotype clusters and quantification of the expected misclassification rate is also available to provide feedback to assay scientists and engineers as changes are made to the assay or instrument. PMID- 26605798 TI - The Selective Myosin II Inhibitor Blebbistatin Reversibly Eliminates Gastrovascular Flow and Stolon Tip Pulsations in the Colonial Hydroid Podocoryna carnea. AB - Blebbistatin reversibly disrupted both stolon tip pulsations and gastrovascular flow in the colonial hydroid Podocoryna carnea. Epithelial longitudinal muscles of polyps were unaffected by blebbistatin, as polyps contracted when challenged with a pulse of KCl. Latrunculin B, which sequesters G actin preventing F actin assembly, caused stolons to retract, exposing focal adhesions where the tip epithelial cells adhere to the substratum. These results are consistent with earlier suggestions that non-muscle myosin II provides the motive force for stolon tip pulsations and further suggest that tip oscillations are functionally coupled to hydrorhizal axial muscle contraction. PMID- 26605799 TI - Eggshell Porosity Provides Insight on Evolution of Nesting in Dinosaurs. AB - Knowledge about the types of nests built by dinosaurs can provide insight into the evolution of nesting and reproductive behaviors among archosaurs. However, the low preservation potential of their nesting materials and nesting structures means that most information can only be gleaned indirectly through comparison with extant archosaurs. Two general nest types are recognized among living archosaurs: 1) covered nests, in which eggs are incubated while fully covered by nesting material (as in crocodylians and megapodes), and 2) open nests, in which eggs are exposed in the nest and brooded (as in most birds). Previously, dinosaur nest types had been inferred by estimating the water vapor conductance (i.e., diffusive capacity) of their eggs, based on the premise that high conductance corresponds to covered nests and low conductance to open nests. However, a lack of statistical rigor and inconsistencies in this method render its application problematic and its validity questionable. As an alternative we propose a statistically rigorous approach to infer nest type based on large datasets of eggshell porosity and egg mass compiled for over 120 extant archosaur species and 29 archosaur extinct taxa/ootaxa. The presence of a strong correlation between eggshell porosity and nest type among extant archosaurs indicates that eggshell porosity can be used as a proxy for nest type, and thus discriminant analyses can help predict nest type in extinct taxa. Our results suggest that: 1) covered nests are likely the primitive condition for dinosaurs (and probably archosaurs), and 2) open nests first evolved among non-avian theropods more derived than Lourinhanosaurus and were likely widespread in non-avian maniraptorans, well before the appearance of birds. Although taphonomic evidence suggests that basal open nesters (i.e., oviraptorosaurs and troodontids) were potentially the first dinosaurs to brood their clutches, they still partially buried their eggs in sediment. Open nests with fully exposed eggs only became widespread among Euornithes. A potential co-evolution of open nests and brooding behavior among maniraptorans may have freed theropods from the ground-based restrictions inherent to covered nests and allowed the exploitation of alternate nesting locations. These changes in nesting styles and behaviors thus may have played a role in the evolutionary success of maniraptorans (including birds). PMID- 26605800 TI - Task-Shifting and Quality of HIV Testing Services: Experiences from a National Reference Hospital in Zambia. AB - BACKGROUND: With new testing technologies, task-shifting and rapid scale-up of HIV testing services in high HIV prevalence countries, assuring quality of HIV testing is paramount. This study aimed to explore various cadres of providers' experiences in providing HIV testing services and their understanding of elements that impact on quality of service in Zambia. METHODS: Sixteen in-depth interviews and two focus group discussions were conducted with HIV testing service providers including lay counselors, nurses and laboratory personnel at purposively selected HIV testing sites at a national reference hospital in Lusaka. Qualitative content analysis was adopted for data analysis. RESULTS: Lay counselors and nurses reported confidentiality and privacy to be greatly compromised due to limited space in both in- and out-patient settings. Difficulties in upholding consent were reported in provider-initiated testing in in-patient settings. The providers identified non-adherence to testing procedures, high workload and inadequate training and supervision as key elements impacting on quality of testing. Difficulties related to testing varied by sub-groups of providers: lay counselors, in finger pricking and obtaining adequate volumes of specimen; non laboratory providers in general, in interpreting invalid, false-negative and false-positive results. The providers had been participating in a recently established national HIV quality assurance program, i.e. proficiency testing, but rarely received site supervisory visits. CONCLUSION: Task-shifting coupled with policy shifts in service provision has seriously challenged HIV testing quality, protection of confidentiality and the process of informed consent. Ways to better protect confidentiality and informed consent need careful attention. Training, supervision and quality assurance need strengthening tailored to the needs of the different cadres of providers. PMID- 26605801 TI - Transparency and the Supreme Court--Can Employers Refuse to Disclose How Much They Pay for Health Care? PMID- 26605802 TI - Composite biopolymer scaffolds shape muscle nucleus: Insights and perspectives from Drosophila. AB - Contractile muscle fibers produce enormous intrinsic forces during contraction/relaxation waves. These forces are directly applied to their cytoplasmic organelles including mitochondria, sarcoplasmic reticulum, and multiple nuclei. Data from our analysis of Drosophila larval somatic muscle fibers suggest that an intricate network of organized microtubules (MT) intermingled with Spectrin-Repeat-Containing Proteins (SRCPs) are major structural elements that protect muscle organelles and maintain their structure and position during muscle contraction. Whereas the perinuclear MT network provides structural rigidity to the myonucleus, the SRCPs Nesprin and Spectraplakin form semiflexible filamentous biopolymer networks, providing nuclei with the elasticity required to resist the contractile cytoplasmic forces produced by the muscle. Spectrin repeats are domains found in numerous structural proteins, which are able to unfold under tension and are subject to mechanical stresses in the cell. This unique composite scaffold combines rigidity and resilience in order to neutralize the oscillating cellular forces occurring during muscle contraction/relaxation waves and thereby protect myonuclei. We suggest that the elastic properties of SRCPs are critical for nuclear protection and proper function in muscle fibers. PMID- 26605803 TI - Impact of Fitness Characteristics on Tennis Performance in Elite Junior Tennis Players. AB - The impact of fitness characteristics on tennis performance in adolescent players is not clearly understood. Therefore, the aim of the present study was to test whether physical characteristics are related to players' competitive level (i.e., national youth ranking). A secondary aim was to compare adolescent tennis players by performance level (i.e., regional selected players and the national team). A total of 902 male and female junior players (aged, 11-16 years) in Germany were evaluated using a physical testing battery: grip strength; countermovement jump; 10 and 20-m sprint; tennis-specific sprint; overhead, forehand, and backhand medicine ball throws (MBT); serve velocity and tennis-specific endurance test (hit and turn tennis test). Results showed that serve velocity (r = -0.43 to 0.64 for female subjects [?]; r = -0.33 to 0.49 for male subjects [?]) and upper-body power (e.g., MBT r = -0.26 to -0.49 ?; r = -0.20 to -0.49 ?) were the most correlated predictors of tennis performance (i.e., national youth ranking) in both female and male tennis players. Moreover, national selected players showed better performance levels than their regional counterparts, mainly in the most predictive physical characteristics (i.e., serve velocity: effect size [ES], 0.78 1.04 ?; ES 0.92-1.02 ?, MBT: ES, 0.66-0.88 ?; ES, 0.67-1.04 ?) and specific endurance (ES, 0.05-0.95 ?; ES, 0.31-0.73 ?). The present findings underline the importance of certain physical attributes, especially serve velocity and strength and power-related variables (upper body), and suggest the need to include these parameters in the area of training, physical testing, and talent identification of young tennis players. PMID- 26605806 TI - Preparing for Combat Readiness for the Fight: Physical Performance Profile of Female U.S. Marines. AB - Females have been restricted from serving in direct combat arms' positions for decades. One reason for the exclusion derives from the perceived physical demands of these positions. As a result, many current efforts are directed toward defining the physical demands of combat arms' positions. The purpose of this study was to develop a physical performance and body composition profile of females who could overcome the physical demands of combat tasks that rely primarily on upper body strength. This study is based on an analysis of archival data from 2 separate samples of active-duty female Marines (n = 802), who had been recruited to participate in heavy lifting tasks. These tasks included lifting a heavy machine gun (HMG) lift (cohort 1, n = 423) and Clean and Press lifts (29.5-52.3 kg) (cohort 2, n = 379). To develop the physical performance profile, data from annual physical fitness tests were collected, which included run times, ammunition can lift, 804. Seven-meter (880-yard) movement to contact, and the maneuver under fire. In cohort 1, 65 females (~15%; n = 423 females) successfully completed HMG; in cohort 2, 33 females (~9%; n = 379 females) successfully completed another strength task, a Clean and Press of 52.3 kg. In both samples, female Marines who were successful on these tasks also outperformed their unsuccessful counterparts on the annual physical fitness tests. In addition, larger females typically outperformed their smaller counterparts. Females seeking assignment to closed combat arms' positions would thus be well served by targeting upper body strength, while maintaining overall physical fitness. PMID- 26605807 TI - Longer Interset Rest Periods Enhance Muscle Strength and Hypertrophy in Resistance-Trained Men. AB - Schoenfeld, BJ, Pope, ZK, Benik, FM, Hester, GM, Sellers, J, Nooner, JL, Schnaiter, JA, Bond-Williams, KE, Carter, AS, Ross, CL, Just, BL, Henselmans, M, and Krieger, JW. Longer interset rest periods enhance muscle strength and hypertrophy in resistance-trained men. J Strength Cond Res 30(7): 1805-1812, 2016 The purpose of this study was to investigate the effects of short rest intervals normally associated with hypertrophy-type training versus long rest intervals traditionally used in strength-type training on muscular adaptations in a cohort of young, experienced lifters. Twenty-one young resistance-trained men were randomly assigned to either a group that performed a resistance training (RT) program with 1-minute rest intervals (SHORT) or a group that employed 3-minute rest intervals (LONG). All other RT variables were held constant. The study period lasted 8 weeks with subjects performing 3 total body workouts a week comprised 3 sets of 8-12 repetition maximum (RM) of 7 different exercises per session. Testing was performed prestudy and poststudy for muscle strength (1RM bench press and back squat), muscle endurance (50% 1RM bench press to failure), and muscle thickness of the elbow flexors, triceps brachii, and quadriceps femoris by ultrasound imaging. Maximal strength was significantly greater for both 1RM squat and bench press for LONG compared to SHORT. Muscle thickness was significantly greater for LONG compared to SHORT in the anterior thigh, and a trend for greater increases was noted in the triceps brachii (p = 0.06) as well. Both groups saw significant increases in local upper body muscle endurance with no significant differences noted between groups. This study provides evidence that longer rest periods promote greater increases in muscle strength and hypertrophy in young resistance-trained men. PMID- 26605808 TI - Seasonal Training Load Distribution of Professional Futsal Players: Effects on Physical Fitness, Muscle Damage and Hormonal Status. AB - The aims of the present study were to describe the training load (TL) distribution of a professional futsal team and verify its subsequent effects on physical performance, muscle damage, and hormonal status. Twelve male professional futsal players (24.3 +/- 4.7 years old; 75.5 +/- 7.7 kg; and 173.4 +/- 4.5 cm) participated in this study. A training program of 22 weeks (6 weeks of pre-season and 16 weeks of in-season) was analyzed. The session rating of perceived exertion method was used to monitor TLs. Physical tests (PTs; countermovement jump (CMJ), 5- and 20-m sprint, T-test, and multistage 20-m shuttle-run tests) were performed 4 times throughout the season (PT1-PT4). Blood sample (BS) collection (Creatine kinase [CK], testosterone, and cortisol) was performed in 7 occasions (BS1-BS7). TLs were higher in pre-season compared to in season (p < 0.001). Countermovement jumps (CMJs) and 5- and 20-m performances were better in PT3 (CMJ: 0/23/77, 5-m: 0/3/97, and 20-m: 0/1/99) and PT4 (CMJ: 0/8/92, 5- and 20-m: 0/0/100) than in PT1; T-test performance and V[Combining Dot Above]O2max was better in all moments compared with those of PT1 (0/0/100). Higher CK concentration (p = 0.03) and testosterone to cortisol (T:C) ratio values (p = 0.02) were detected in BS2 vs. BS1. An increase in C (p = 0.007) and a decrease in T:C ratio (p = 0.003) was observed from BS4 to BS5. The training program demonstrated higher TLs during the periods with low incidence of matches, emphasis on endurance and strength training during pre-season, speed and power training throughout in-season. This TL organization provides sufficient stimulus for appropriate physical fitness development in professional futsal players, without causing negative disturbances. PMID- 26605809 TI - The Effects of 120 Minutes of Simulated Match Play on Indices of Acid-Base Balance in Professional Academy Soccer Players. AB - This study investigated the changes in indices of acid-base balance during 120 minutes of simulated soccer match play that included a 30 minute extra-time (ET) period. Eight English Premier League academy soccer players participated in a simulated soccer match that required varying intensities of intermittent exercise including 15-m sprints and soccer dribbling throughout. Blood samples were obtained before (i.e., baseline and pre-exercise) and throughout exercise (i.e., 15, 30, 45, 60, 75, 90, 105, and 120 minutes), and at half time. Sprint speeds over 15 m reduced in ET compared to the first half (-0.39 +/- 0.37 m.s, -7 +/- 6%, p = 0.021) but not the second half (-0.18 +/- 0.25 m.s, -3 +/- 4%, p = 0.086). At 105 minutes, blood lactate concentrations reduced compared with that in the opening 30 minutes (-0.9 to -1.2 mmol.L, p <= 0.05). Blood pH (-0.03 to 0.04 units), base excess (-0.95 to -1.48 mmol.L), and bicarbonate concentrations (-0.9 +/- 0.8 mmol.L) were depressed at 120 minutes compared with those at 105 minutes, baseline and half time (all p <= 0.05). There were no significant correlations between changes in acid-base balance and sprint speed (all p > 0.05). Although the perturbations in acid-base balance during ET were statistically significant, the decreases in blood pH, lactate, base excess, and bicarbonate concentrations may not represent metabolic acidosis or impairments in buffering capacity that are likely to explain reduced physical performance. Further research is warranted to investigate mechanisms of fatigue during ET and to develop interventions that attenuate decrements in performance. PMID- 26605810 TI - Influence of Lower Extremity Muscle Size and Quality on Stair-Climb Performance in Career Firefighters. AB - The purpose of this study was to examine the influence of lower extremity muscular size and quality on stair-climb performance (SCP) in career firefighters. Forty-six male career firefighters (age = 37.0 +/- 7.2 years; stature = 180.2 +/- 6.9 cm; body mass = 108.0 +/- 19.8 kg) volunteered for this study. Panoramic ultrasound images of the vastus lateralis and rectus femoris were obtained to determine cross-sectional area (CSA) and echo intensity (EI) of each muscle. The CSA of each muscle was then summed together and normalized to body mass (CSA/BM [QCSA]). Additionally, EI was averaged across both muscles (QEI). Participants then performed a timed and weighted SCP assessment where they ascended and descended 26 stairs 4 times as quickly as possible while wearing a weighted vest (22.73 kg) to simulate the weight of their self-contained breathing apparatus and turnout gear. Bivariate correlations and stepwise regression analyses were used to examine the relationships among variables and the relative contributions of QCSA and QEI to SCP. Partial correlations were used to examine the relationship between QCSA and SCP and QEI and SCP while controlling for age and body mass index (BMI). The results indicated that QCSA and QEI were significantly related to SCP before (r = -0.492, p = 0.001; r = 0.363, p = 0.013, respectively) and after accounting for age and BMI (r = -0.324, p = 0.032; r = 0.413, p = 0.005, respectively). Both QCSA and QEI contributed significantly to the prediction of SCP (r = 0.560, p < 0.001). These findings indicate that lower extremity muscle size and quality are important contributors to critical firefighting tasks, which have been shown to be improved with resistance training. PMID- 26605811 TI - Sleeping Toward Behavioral Regulation: Relations Between Sleep and Externalizing Symptoms in Toddlers and Preschoolers. AB - The aim of this study was to investigate the concurrent and longitudinal relations between sleep and externalizing symptoms among young children. Sixty four families (mostly Caucasian; 36 boys) were met twice, when children were 2 (T1) and 4 years of age (T2). At T1, children wore an actigraph monitor for a 72 hr period, and both mothers and fathers completed the Child Behavior Checklist. At T2, both parents as well as the daycare educator filled the Child Behavior Checklist. At T1, longer sleep duration and higher sleep efficiency were associated with fewer externalizing symptoms as assessed by mothers. Results also indicated that higher sleep efficiency at T1 was related to fewer parent-reported externalizing symptoms at T2 (while controlling for prior externalizing symptoms). Relations between sleep efficiency at T1 and externalizing symptoms as assessed by mothers at T1 and by fathers at T2 were moderated by child sex, such that links were significant among boys only. Results pertaining to educators' reports were inconclusive. The current study highlights the importance of rapidly treating sleep difficulties, which are associated with persistent behavioral maladjustment, perhaps especially for boys. PMID- 26605812 TI - Association Between Particulate Air Pollution and QT Interval Duration in an Elderly Cohort. AB - BACKGROUND: Short-term fine particulate matter (PM2.5) exposure has been linked with increased QT interval duration, a marker of ventricular repolarization and a risk factor for cardiac arrhythmia and sudden death, in several studies. Only one previous study evaluated whether long-term PM exposure is related to the QT interval. We aim to evaluate whether subchronic and long-term exposure to PM2.5 at home is linked with QT duration in an elderly cohort. METHODS: We measured heart-rate corrected QT interval duration among 404 participants from the Greater Boston area between 2003 and 2011. We modeled residential PM2.5 exposures using a hybrid satellite- and land use-based model. We evaluated associations between moving averages of short-term (1-2 days), subchronic (3-28 days), and long-term (1 year) pollutant exposures and corrected QT duration using linear mixed models. We also evaluated effect modification by oxidative stress genetic score using separated regression models and interaction terms. RESULTS: We observed positive associations between subchronic and long-term PM2.5 exposure and corrected QT duration, with the strongest results for longer-term exposures. For example, a one standard deviation increase in 1-year PM2.5 was associated with a 6.3 ms increase in corrected QT (95% confidence interval: 1.8, 11). We observed somewhat greater effects among subjects with higher (8.5 ms) rather than lower (3.1 ms) oxidative stress allelic profiles (P interaction = 0.25). CONCLUSIONS: PM2.5 was associated with increased corrected QT duration in an elderly cohort. While most previous studies focused on short-term air pollution exposures, our results suggest that longer-term exposures are associated with cardiac repolarization. PMID- 26605813 TI - Physician's Prescribing Preference as an Instrumental Variable: Exploring Assumptions Using Survey Data. AB - BACKGROUND: Physician's prescribing preference is increasingly used as an instrumental variable in studies of therapeutic effects. However, differences in prescribing patterns among physicians may reflect differences in preferences or in case-mix. Furthermore, there is debate regarding the possible assumptions for point estimation using physician's preference as an instrument. METHODS: A survey was sent to general practitioners (GPs) in The Netherlands, the United Kingdom, New Zealand, Ireland, Switzerland, and Germany, asking whether they would prescribe levothyroxine to eight fictitious patients with subclinical hypothyroidism. We investigated (1) whether variation in physician's preference was observable and to what extent it was explained by characteristics of GPs and their patient populations and (2) whether the data were compatible with deterministic and stochastic monotonicity assumptions. RESULTS: Levothyroxine prescriptions varied substantially among the 526 responding GPs. Between-GP variance in levothyroxine prescriptions (logit scale) was 9.9 (95% confidence interval: 8.0, 12) in the initial mixed effects logistic model, 8.3 (6.7, 10) after adding a fixed effect for country and 8.2 (6.6, 10) after adding GP characteristics. The occurring prescription patterns falsified the deterministic monotonicity assumption. All cases in all countries were more likely to receive levothyroxine if a different case of the same GP received levothyroxine, which is compatible with the stochastic monotonicity assumption. The data were incompatible with this assumption for a different definition of the instrument. CONCLUSIONS: Our study supports the existence of physician's preference as a determinant in treatment decisions. Deterministic monotonicity will generally not be plausible for physician's preference as an instrument. Depending on the definition of the instrument, stochastic monotonicity may be plausible. PMID- 26605816 TI - Certification and Recertification. PMID- 26605817 TI - Strategic Planning: Building for the Future. PMID- 26605815 TI - Particulate Air Pollution and Clinical Cardiovascular Disease Risk Factors. AB - BACKGROUND: Long-term exposure to ambient particulate matter (PM) air pollution is associated with increased cardiovascular disease (CVD); however, the impact of PM on clinical risk factors for CVD in healthy subjects is unclear. We examined the relationship of PM with levels of circulating lipids and blood pressure in the Third National Health and Nutrition Examination Survey (NHANES III), a large nationally representative US survey. METHODS: This study was based on 11,623 adult participants of NHANES III (1988-1994; median age 41.0). Serum lipids and blood pressure were measured during the NHANES III examination. Average exposure for 1988-1994 to particulate matter <10 MUm in aerodynamic diameter (PM10) at the residences of participants was estimated based on measurements from US Environmental Protection Agency monitors. Multivariate linear regression was used to estimate the associations of PM10 with lipids and blood pressure. RESULTS: An interquartile range width increase in PM10 exposure (11.1 MUg/m) in the study population was associated with 2.42% greater serum triglycerides (95% confidence interval: 1.09, 3.76); multivariate adjusted means of triglycerides according to increasing quartiles of PM10 were 137.6, 142.5, 142.6, and 148.9 mg/dl, respectively. An interquartile range width increase in PM10 was associated with 1.43% greater total cholesterol (95% confidence interval: 1.21, 1.66). These relationships with triglycerides and total cholesterol did not differ by age or region. Associations of PM10 with blood pressure were modest. CONCLUSIONS: Findings from this large, diverse study indicate that greater long-term PM10 exposure is associated with elevated serum triglycerides and total cholesterol, potentially mediating air pollution-related effects on CVD. PMID- 26605814 TI - A Method to Estimate the Size and Characteristics of HIV-positive Populations Using an Individual-based Stochastic Simulation Model. AB - It is important not only to collect epidemiologic data on HIV but to also fully utilize such information to understand the epidemic over time and to help inform and monitor the impact of policies and interventions. We describe and apply a novel method to estimate the size and characteristics of HIV-positive populations. The method was applied to data on men who have sex with men living in the UK and to a pseudo dataset to assess performance for different data availability. The individual-based simulation model was calibrated using an approximate Bayesian computation-based approach. In 2013, 48,310 (90% plausibility range: 39,900-45,560) men who have sex with men were estimated to be living with HIV in the UK, of whom 10,400 (6,160-17,350) were undiagnosed. There were an estimated 3,210 (1,730-5,350) infections per year on average between 2010 and 2013. Sixty-two percent of the total HIV-positive population are thought to have viral load <500 copies/ml. In the pseudo-epidemic example, HIV estimates have narrower plausibility ranges and are closer to the true number, the greater the data availability to calibrate the model. We demonstrate that our method can be applied to settings with less data, however plausibility ranges for estimates will be wider to reflect greater uncertainty of the data used to fit the model. PMID- 26605818 TI - Letter from the President of PSNCB. PMID- 26605819 TI - Working Out the Woes: An Analysis of the Impact of Exercise on Depression. AB - The purpose of this review is to examine existing research to determine whether exercise has a significant effect on improving emotional well-being and symptoms of depression. At any given time, it is estimated that greater than 15% of Americans are plagued by a depressive mood disorder. Plastic surgical nurses will encounter individuals with symptoms of depression who seek elective plastic surgical and cosmetic procedures. With a broad spectrum of symptoms and presentations, both practitioners and those suffering may have difficulty identifying depression. Even after being identified, it can be quite challenging to effectively treat depressive mood disorders. The integration of exercise into the plan of care not only helps tackle one's mental health condition but also benefits any physical health concerns. The plastic surgical nurse can advocate for evidence-based practices and educate the plastic surgical patient on the benefits of physical exercise. Additional research is needed to determine the most effective amount and types of exercise to be used in clinical settings. PMID- 26605821 TI - Cutaneous Melanoma: A Population Health Problem. AB - Cutaneous melanoma (CM), generally referred to as melanoma, has been identified as an overall population health problem. Examination of evidence-based research revealed a strong correlation between CM and tanning bed usage, specifically by young females. For these reasons, a preliminary research question/hypothesis was structured that proposed examining different geographical locations, and whether the relationship between melanoma and tanning bed exposure by young females would be affected. Epidemiologic principles will be utilized to provide guidelines and tools for comprehensively examining this health issue and how it might affect morbidity and mortality within the populations where occurrences are identified. Furthermore, to understand some of the contributing factors of this disease, melanoma was discussed in terms of person, place, time, and how tanning bed exposure may significantly heighten CM as a potentially fatal health problem. PMID- 26605822 TI - Correction of Tear Trough Deformity With a Cohesive Polydensified Matrix Hyaluronic Acid: A Case Series. AB - The tear trough or infraorbital hollow is a challenging area to treat, and only a few fillers are suitable for this delicate area. We report on a European case series of six subjects with mild to severe tear troughs who received treatment with cohesive polydensified matrix (CPM(r)) technology hyaluronic acid gel (Belotero(r) Balance). The product was injected as small depots (up to ten small boli 0.2 mL maximum each per side) at the supraperiosteal level along or below the orbital rim. Follow-up visits took place at 1, 3, 6, and 9 months after injection for independent evaluation of the clinical effect using the Merz Aesthetics ScaleTM for infraorbital hollows and the Global Aesthetic Improvement Scale. Adverse events were also recorded. Mean hollowness scores were considerably improved compared with baseline in all subjects. In all women, the improvements remained throughout the 9-month study, with none reverting to their baseline score. Subjects' satisfaction with treatment was very high throughout the study, and all women stated that they would repeat treatment with the same product. The CPM hyaluronic acid gel was well tolerated. CPM hyaluronic acid gel is a safe and effective treatment for the tear trough area. PMID- 26605823 TI - Compassion Fatigue: Strategies for Minimizing Impact on Aesthetic Medical Providers. AB - Compassion fatigue is emotional, physical, and spiritual exhaustion from witnessing and absorbing the problems of others. Aesthetic providers are prone to becoming victims of compassion fatigue because of the stress of meeting the often overwhelming needs of patients. This article discusses what is known about compassion fatigue, what differentiates it from burnout, and how to recognize and combat it. PMID- 26605824 TI - The Role of the Plastic Surgery Nurse in the Management of Infantile Hemangioma Using Propranolol Therapy. PMID- 26605825 TI - Update on the Management of Rosacea. AB - Refining diagnostic criteria has identified key characteristics differentiating rosacea, a chronic skin disorder, from other common cutaneous inflammatory conditions. The current classification system developed by the National Rosacea Society Expert Committee consists of erythematotelangiectatic, papulopustular, phymatous, and ocular subtypes. Each subtype stands as a unique entity among a spectrum, with characteristic symptoms and physical findings, along with an intricate pathophysiology. The main treatment modalities for rosacea include topical, systemic, laser, and light therapies. Topical brimonidine tartrate gel and calcineurin inhibitors are at the forefront of topical therapies, alone or in combination with traditional therapies such as topical metronidazole or azelaic acid and oral tetracyclines or isotretinoin. Vascular laser and intense pulsed light therapies are beneficial for the erythema and telangiectasia, as well as the symptoms (itching, burning, pain, stinging, swelling) of rosacea. Injectable botulinum toxin, topical ivermectin, and microsecond long-pulsed neodymium yttrium aluminum garnet laser are emerging therapies that may prove to be extremely beneficial in the future. Once a debilitating disorder, rosacea has become a well known and manageable entity in the setting of numerous emerging therapeutic options. Herein, we describe the treatments currently available and give our opinions regarding emerging and combination therapies. PMID- 26605826 TI - In Vitro Parallel Evaluation of Antibacterial Activity and Cytotoxicity of Commercially Available Silver-Containing Wound Dressings. AB - PURPOSE: This study evaluated the in vitro antibacterial activity and cytotoxicity of various commercially available silver-containing dressings (Ag dressing). METHODS: Biohesive Ag (hydrocolloid, silver sulfadiazine), Aquacel(r) Ag (nonwoven fabric, ionic silver [Ag]), AlgisiteTM Ag (nonwoven fabric, Ag), Mepilex(r) Ag (foam, silver sulfate), and PolyMem(r) Ag (foam, nanocrystalline silver) were tested for characteristics of Ag release, antibacterial activity, and cytotoxicity. The release of Ag was investigated in cell culture medium at immersion periods of 6, 24, and 48 hours. The antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa were accessed by a disc diffusion test. The cytotoxicity was evaluated using V79 cells, by an extraction method. RESULTS: The cytotoxicity was not a monotonic function of the antibacterial activity among the Ag dressings and could not be simply explained by Ag-release properties. Biohesive Ag was regarded as a slow-release Ag dressing, showing the lowest cytotoxicity, while the antibacterial activity was classified as "strong" or "significant" against the two species of bacteria. Aquacel Ag and Algisite Ag showed higher antibacterial activity and cytotoxic effects, which were supported by the higher Ag release. Mepilex Ag showed the highest release of Ag, and the cytotoxicity was the highest among the Ag dressings. However, the antibacterial activity was classified as "significant" or "no activity" for P. aeruginosa and S. aureus, respectively. PolyMem Ag showed the lowest Ag release, and the antibacterial activity classified as "significant" or "no activity" for S. aureus and P. aeruginosa, respectively, whereas the cytotoxicity was similar to those of Aquacel Ag and Algisite Ag. CONCLUSION: The efficacy and adverse effects of the Ag dressings revealed differences that should be considered by clinicians during wound management. PMID- 26605828 TI - Somatostatin analogues in functioning gastroenteropancreatic neuroendocrine tumours: literature review, clinical recommendations and schedules. AB - OBJECTIVE: Neuroendocrine tumours (NETs) represent a heterogeneous group of neoplasms, which include functioning and non-functioning forms. Somatostatin analogues (SSAs) play a key role in the management of these tumours. Herein, we aimed at reviewing the current evidence about the role of SSAs in the treatment of gastro-entero-pancreatic (GEP)-NETs. MATERIAL AND METHODS: An extensive bibliographical search was performed in PubMed using the following keywords: gastro-entero-pancreatic neuroendocrine tumours, somatostatin analogues, octreotide, lanreotide, in order to identify all the pertinent English-written articles published between 1990 and 2015. RESULTS: SSAs have shown to help the symptomatic and biochemical improvement of patients with NETs and to exhibit a good safety profile. Recent studies have also reported a role for SSAs in tumour growth control, although the results are less impressive and the underlying mechanisms are not fully understood. CONCLUSIONS: SSAs are well known as a symptomatic and, to lesser extent, anti-proliferative treatment in GEP-NETs. However, some issues, including optimal dosage, benefits and adverse events of combination with other molecules, and the role of new analogues, remain to be elucidated in further randomised studies. PMID- 26605829 TI - Obsessive-compulsive symptoms and attentional bias: An eye-tracking methodology. AB - BACKGROUND AND OBJECTIVES: Cognitive models suggest that attentional biases are integral in the maintenance of obsessive-compulsive symptoms (OCS). Such biases have been established experimentally in anxiety disorders; however, the evidence is unclear in Obsessive Compulsive disorder (OCD). In the present study, an eye tracking methodology was employed to explore attentional biases in relation to OCS. METHODS: A convenience sample of 85 community volunteers was assessed on OCS using the Yale-Brown Obsessive Compulsive Scale-self report. Participants completed an eye-tracking paradigm where they were exposed to OCD, Aversive and Neutral visual stimuli. Indices of attentional bias were derived from the eye tracking data. RESULTS: Simple linear regressions were performed with OCS severity as the predictor and eye-tracking measures of the different attentional biases for each of the three stimuli types were the criterion variables. Findings revealed that OCS severity moderately predicted greater frequency and duration of fixations on OCD stimuli, which reflect the maintenance attentional bias. No significant results were found in support of other biases. LIMITATIONS: Interpretations based on a non-clinical sample limit the generalisability of the conclusions, although use of such samples in OCD research has been found to be comparable to clinical populations. Future research would include both clinical and sub-clinical participants. CONCLUSIONS: Results provide some support for the theory of maintained attention in OCD attentional biases, as opposed to vigilance theory. Individuals with greater OCS do not orient to OCD stimuli any faster than individuals with lower OCS, but once a threat is identified, these individuals allocate more attention to OCS-relevant stimuli.. PMID- 26605827 TI - Comparison of analytical and numerical approaches for CT-based aberration correction in transcranial passive acoustic imaging. AB - Computed tomography (CT)-based aberration corrections are employed in transcranial ultrasound both for therapy and imaging. In this study, analytical and numerical approaches for calculating aberration corrections based on CT data were compared, with a particular focus on their application to transcranial passive imaging. Two models were investigated: a three-dimensional full-wave numerical model (Connor and Hynynen 2004 IEEE Trans. Biomed. Eng. 51 1693-706) based on the Westervelt equation, and an analytical method (Clement and Hynynen 2002 Ultrasound Med. Biol. 28 617-24) similar to that currently employed by commercial brain therapy systems. Trans-skull time delay corrections calculated from each model were applied to data acquired by a sparse hemispherical (30 cm diameter) receiver array (128 piezoceramic discs: 2.5 mm diameter, 612 kHz center frequency) passively listening through ex vivo human skullcaps (n = 4) to emissions from a narrow-band, fixed source emitter (1 mm diameter, 516 kHz center frequency). Measurements were taken at various locations within the cranial cavity by moving the source around the field using a three-axis positioning system. Images generated through passive beamforming using CT-based skull corrections were compared with those obtained through an invasive source-based approach, as well as images formed without skull corrections, using the main lobe volume, positional shift, peak sidelobe ratio, and image signal-to-noise ratio as metrics for image quality. For each CT-based model, corrections achieved by allowing for heterogeneous skull acoustical parameters in simulation outperformed the corresponding case where homogeneous parameters were assumed. Of the CT-based methods investigated, the full-wave model provided the best imaging results at the cost of computational complexity. These results highlight the importance of accurately modeling trans-skull propagation when calculating CT-based aberration corrections. Although presented in an imaging context, our results may also be applicable to the problem of transmit focusing through the skull. PMID- 26605830 TI - Seawater intrusion mapping using electrical resistivity tomography and hydrochemical data. An application in the coastal area of eastern Thermaikos Gulf, Greece. AB - The aim of this study was to determine the extent and geometrical characteristics of seawater intrusion in the coastal aquifer of the eastern Thermaikos Gulf, Greece. Hydrochemical data and geoelectrical measurements were combined and supplemented to determine the hydrochemical regime of the study site in regard to seawater phenomena. Chemical analysis of groundwater was performed in 126 boreholes and fifteen electrical resistivity tomographies (ERT) were measured, whereas in two sites the ERT measurements were repeated following the wet season. The Cl(-) concentrations recorded reached 2240 mg/L indicating seawater intrusion which was also verified by ionic ratios. The ionic ratios were overlapped and a seawater intrusion map (SWIM) was produced. A significant part of the coastal aquifer (up to 150 km(2)) is influenced by seawater intrusion. The areas with the most intensive salinization are located between Nea Kallikratia-Epanomi and Aggelochori-Peraia. According to the ERTs, in the influenced areas the salinization of the aquifer exceeds 1 km toward the mainland and its depth reaches 200 m. In the area surrounding Thessaloniki airport, the ERTs revealed salinization of the upper aquifer to depths of up to 40 m, whereas the lower aquifer is uninfluenced. This abnormal distribution of seawater intrusion demonstrates the value of geoelectrical methods in the study of seawater intrusion especially in areas with limited available hydrochemical data. PMID- 26605831 TI - A new approach to estimate fugitive methane emissions from coal mining in China. AB - Developing a more accurate greenhouse gas (GHG) emissions inventory draws too much attention. Because of its resource endowment and technical status, China has made coal-related GHG emissions a big part of its inventory. Lacking a stoichiometric carbon conversion coefficient and influenced by geological conditions and mining technologies, previous efforts to estimate fugitive methane emissions from coal mining in China has led to disagreeing results. This paper proposes a new calculation methodology to determine fugitive methane emissions from coal mining based on the domestic analysis of gas geology, gas emission features, and the merits and demerits of existing estimation methods. This new approach involves four main parameters: in-situ original gas content, gas remaining post-desorption, raw coal production, and mining influence coefficient. The case studies in Huaibei-Huainan Coalfield and Jincheng Coalfield show that the new method obtains the smallest error, +9.59% and 7.01% respectively compared with other methods, Tier 1 and Tier 2 (with two samples) in this study, which resulted in +140.34%, +138.90%, and -18.67%, in Huaibei-Huainan Coalfield, while +64.36%, +47.07%, and -14.91% in Jincheng Coalfield. Compared with the predominantly used methods, this new one possesses the characteristics of not only being a comparably more simple process and lower uncertainty than the "emission factor method" (IPCC recommended Tier 1 and Tier 2), but also having easier data accessibility, similar uncertainty, and additional post-mining emissions compared to the "absolute gas emission method" (IPCC recommended Tier 3). Therefore, methane emissions dissipated from most of the producing coal mines worldwide could be more accurately and more easily estimated. PMID- 26605832 TI - Fractionation and analysis of veterinary antibiotics and their related degradation products in agricultural soils and drainage waters following swine manure amendment. AB - The fate of antimicrobial active compound residues in the environment, and especially antibiotics used in swine husbandry are of particular interest for their potential toxicity and contribution to antibiotic resistance. The presence of relatively high concentrations of bioactive compounds has been reported in agricultural areas but few information is available on their degradation products. Veterinary antibiotics reach terrestrial environments through many routes, including application of swine manure to soils. The objectives of this project were first, to develop an analytical method able to quantify and identify veterinary antibiotics and their degradation products in manure, soil and water samples; and second, to study the distribution of these target compounds in soils and drainage waters. A brief evaluation of their potential toxicity in the environment was also made. In order to achieve these objectives, liquid chromatography coupled to high-resolution mass spectrometry was used for its ability to quantify contaminants with sensitivity and selectivity, and its capacity to identify degradation products. Samples of manure, soil and water came from a long-term experimental site where swine manure containing veterinary antibiotics has been applied for many years. In this study, tetracycline antibiotics were found at several hundred MUg L(-1) in the swine manure slurry used for fertilization, several hundred of ng L(-1) in drainage waters and several ng g(-1) in soils, while degradation products were sometimes found at concentrations higher than the parent compounds. PMID- 26605833 TI - Advection and dispersion heat transport mechanisms in the quantification of shallow geothermal resources and associated environmental impacts. AB - Borehole Heat Exchangers (BHEs) are increasingly being used to exploit shallow geothermal energy. This paper presents a new methodology to provide a response to the need for a regional quantification of the geothermal potential that can be extracted by BHEs and the associated environmental impacts. A set of analytical solutions facilitates accurate calculation of the heat exchange of BHEs with the ground and its environmental impacts. For the first time, advection and dispersion heat transport mechanisms and the temporal evolution from the start of operation of the BHE are taken into account in the regional estimation of shallow geothermal resources. This methodology is integrated in a GIS environment, which facilitates the management of input and output data at a regional scale. An example of the methodology's application is presented for Barcelona, in Spain. As a result of the application, it is possible to show the strengths and improvements of this methodology in the development of potential maps of low temperature geothermal energy as well as maps of environmental impacts. The minimum and maximum energy potential values for the study site are 50 and 1800 W/m(2) for a drilled depth of 100 m, proportionally to Darcy velocity. Regarding to thermal impacts, the higher the groundwater velocity and the energy potential, the higher the size of the thermal plume after 6 months of exploitation, whose length ranges from 10 to 27 m long. A sensitivity analysis was carried out in the calculation of heat exchange rate and its impacts for different scenarios and for a wide range of Darcy velocities. The results of this analysis lead to the conclusion that the consideration of dispersion effects and temporal evolution of the exploitation prevent significant differences up to a factor 2.5 in the heat exchange rate accuracy and up to several orders of magnitude in the impacts generated. PMID- 26605834 TI - Validating maps from single particle electron cryomicroscopy. AB - Progress in single particle cryo-EM, most recently due to the introduction of direct detector devices, has made the high-resolution structure determination of biological assemblies smaller than 500kDa more routine, but has also increased attention on the need for tools to demonstrate the validity of single particle maps. Although map validation is a continuing subject of research, some consensus has been reached on procedures that reduce model bias and over-fitting during map refinement as well as specific tests that demonstrate map validity. Tilt-pair analysis may be used as a method for demonstrating the consistency at low resolution of a map with image data. For higher-resolution maps, new procedures for more robust resolution assessment and for validating the refinement of atomic coordinate models into single particle maps have been developed. PMID- 26605835 TI - BCR and co-receptor crosstalk facilitate the positive selection of self-reactive transitional B cells. AB - The establishment of a diverse B cell repertoire requires fine-tuning of antigen receptor selection during development in order to permit sufficient diversity while reducing the potential for autoimmunity. In this review, we highlight recent studies demonstrating the central role of the B cell antigen receptor (BCR), in coordination with other key pro-survival signals mediated by CD40, BAFF R, TACI and/or TLRs, in regulating both negative and positive selection of autoreactive B cells. In particular, we show how altered antigen or co stimulatory signaling can facilitate positive selection of transitional B cells with self-reactive BCRs, ultimately leading to their entry into the mature, naive B cell compartment. We propose a model wherein altered receptor signals (due to inherited genetic changes) leads: first, to enhanced positive selection of autoreactive cells into the naive B cell repertoire; subsequently, to an increased probability of pathogenic germinal center responses in individuals with a broad range of autoimmune disorders. PMID- 26605837 TI - A template for a planar tetracoordinate heavier group 14 atom: a global study of C2Si2X(q) (X = C, Si, Ge, Sn, Pb; q = +1, 0, -1). AB - Through a global isomeric study, we computationally identified the first structural template C2Si2X that could encompass a planar tetracoordinate X for all the heavier group 14 elements X in the 0, +1 or -1 charge state. We thus significantly expanded the traditional 16/17/18ve rules to 19/20/21ve for ptX. PMID- 26605838 TI - Online Reviews of Physicians: Valuable Feedback, Valuable Advertising. PMID- 26605840 TI - Manual tracking enhances smooth pursuit eye movements. AB - Previous studies have reported that concurrent manual tracking enhances smooth pursuit eye movements only when tracking a self-driven or a predictable moving target. Here, we used a control-theoretic approach to examine whether concurrent manual tracking enhances smooth pursuit of an unpredictable moving target. In the eye-hand tracking condition, participants used their eyes to track a Gaussian target that moved randomly along a horizontal axis. In the meantime, they used their dominant hand to move a mouse to control the horizontal movement of a Gaussian cursor to vertically align it with the target. In the eye-alone tracking condition, the target and cursor positions recorded in the eye-hand tracking condition were replayed, and participants only performed eye tracking of the target. Catch-up saccades were identified and removed from the recorded eye movements, allowing for a frequency-response analysis of the smooth pursuit response to unpredictable target motion. We found that the overall smooth pursuit gain was higher and the number of catch-up saccades made was less when eye tracking was accompanied by manual tracking than when not. We conclude that concurrent manual tracking enhances smooth pursuit. This enhancement is a fundamental property of eye-hand coordination that occurs regardless of the predictability of the target motion. PMID- 26605841 TI - The effect of blur on cortical responses to global form and motion. AB - Global form and motion sensitivity undergo long development in childhood with motion sensitivity rather than form being impaired in a number of childhood disorders and both impaired in adult clinical populations. This suggests extended development and vulnerability of extrastriate cortical areas associated with global processing. However, in some developmental and clinical populations, it remains unclear to what extent impairments might reflect deficits at earlier stages of visual processing, such as reduced visual acuity and contrast sensitivity. To address this, we investigated the impact of degraded spatial vision on cortical global form and motion processing in healthy adults. Loss of high spatial frequencies was simulated using a diffuser to blur the stimuli. Participants completed behavioral and EEG tests of global form and motion perception under three levels of blur. For the behavioral tests, participants' form and motion coherence thresholds were measured using a two-alternative, forced-choice procedure. Steady-state visual evoked potentials were used to measure cortical responses to changes in the coherence of global form and motion stimuli. Both global form and global motion perception were impaired with increasing blur as measured by elevated behavioral thresholds and reduced cortical responses. However, form thresholds showed greater impairment in both behavioral and EEG measures than motion thresholds at the highest levels of blur. The results suggest that high spatial frequencies play an important role in the perception of both global form and motion but are especially significant for global form. Overall, the results reveal complex interactions between low-level factors and global visual processing, highlighting the importance of taking these factors into account when investigating extrastriate function in low vision populations. PMID- 26605842 TI - Perceived temporal asynchrony between sinusoidally modulated luminance and depth. AB - Simultaneously presented visual events lead to temporally asynchronous percepts. This has led some researchers to conclude that the asynchronous experience is a manifestation of differences in neural processing time for different visual attributes. Others, however, have suggested that the asynchronous experience is due to differences in temporal markers for changes of different visual attributes. Here, two sets of bars were presented, one to each eye. Either the bars were moving or their luminance was gradually changing. Bars moved horizontally in counterphase at low frequencies along short trajectories and were presented stereoscopically, such that the horizontal movements were perceived as back-and-forth motion on a sagittal plane, or monocularly to a dominant eye, preserving a perception of the horizontal movements on a frontal plane. In a control condition, bars were stationary and their luminance was modulated. The changes in stimulus speed or luminance occurred sinusoidally. When asked to adjust the phase of one stimulus to the other to achieve synchronous perception, participants showed a constant phase offset at the lowest frequencies used. Given the absence of abrupt transitions and the presence of similar gradual turning points in our stimuli to control for attentional effects, it can be concluded that asynchronous percepts in multimodal stimuli may at least in part be a manifestation of difference in neural processing time of visual attributes rather than solely a difference in the temporal markers (transitions versus turning points). PMID- 26605843 TI - Cue-invariant shape recognition in rats as tested with second-order contours. AB - Nonhuman primates are the main animal model to investigate high-level properties of human cortical vision. For one property, transformation-invariant object recognition, recent studies have revealed interesting and unknown capabilities in rats. Here we report on the ability of rats to rely upon second-order cues that are important to structure the incoming visual images into figure and background. Rats performed a visual shape discrimination task in which the shapes were not only defined by first-order luminance information but also by a variety of second order cues such as a change in texture properties. Once the rats were acquainted with a first set of second-order stimuli, they showed a surprising degree of generalization towards new second-order stimuli. The limits of these capabilities were tested in various ways, and the ability to extract the shapes broke down only in extreme cases where no local cues were available to solve the task. These results demonstrate how rats are able to make choices based on fairly complex strategies when necessary. PMID- 26605844 TI - Facilitation of contrast detection by flankers without perceived orientation. AB - To extract meaningful structure from noisy input signals, the human visual processing system uses elementary structures, such as contours, to extract more complex informative structures. The first step in contour processing involves identifying local orientation. The phenomenon of collinear facilitation is important for understanding how orientation detection is implemented; at the fovea, a stripe near the contrast threshold (target) is easier to detect when it is collinearly flanked by stripes with the same orientation (flankers). This facilitation requires collinear alignment and presumably reflects cortical mechanisms in the early visual cortex. Strong collinear orientation signals are said to help in detecting a feeble signal and in establishing a smooth conscious linkage of orientations. However, contrary to this notion, we show here that relatively small but significant facilitation occurs even when the flankers have no perceived orientation. One such case involves concentric flankers that have unbiased luminance energies in all orientations. When collinearly surrounding an oriented target, these flankers facilitated detection of the target. In another case, oriented flankers that were made invisible through interocular suppression and that were monocularly surrounding an oriented target yielded collinear facilitation even though the flankers themselves were completely masked by random patterns presented to the other eye. These findings indicate that automatic, preconscious processing of orientation information at some early stage can improve the visibility of local linear elements. They also indicate the usefulness of latent visual information in detecting orientation and constructing our visual world. PMID- 26605845 TI - Templates for rejection can specify semantic properties of nontargets in natural scenes. AB - In contrast to standard search templates that specify a target object's expected features, templates for rejection (TFR) may specify features of nontargets, biasing attention away from irrelevant objects. Little is known about TFR, and virtually nothing is known about their role in guiding search across natural scenes. In such scenes, targets and nontargets may not be easily distinguished on the basis of their visual features; it has been claimed that standard search templates may therefore specify target objects' semantic features to guide attention. Here, we ask whether TFR can do so. Noting a limitation of previous procedures used to study standard search templates, we trialed an alternative method to examine semantic templates for nontarget exclusion in natural scene search. We found that when nontargets belonged unpredictably to either of two physically distinct categories, search was less efficient than when targets belonged to one known category. This two-category cost, attributed to inefficient application of search templates, was absent for two physically dissimilar but semantically related categories. Adding a training phase to highlight semantic distinctiveness of two object categories reinstated the two-category cost, precluding stimulus-based accounts of the effect. These patterns were not observed for one-image displays or when observers searched for object categories rather than ignoring them, demonstrating their specificity to TFR, the inadequacy of search-and-destroy models to account for them, and likely basis in attentional guidance. TFR can specify semantic information to guide attention away from nontargets. PMID- 26605846 TI - There is no attentional global effect: Attentional shifts are independent of the saccade endpoint. AB - Many studies have found a strong coupling between selective attention and eye movements. The premotor theory of attention suggests that saccade preparation is directly responsible for such attentional shifts. While it has already been shown that the attentional shift is not directly coupled to the final stages of motor execution, it is currently unknown to what aspect of the earlier stages of saccade preparation the attentional shift is coupled. An important step in this preparation process is resolving the landing point when multiple elements compete for the saccade. Here we ask how such a competition influences the presaccadic attentional locus and whether the presaccadic shift of attention is coupled to the saccade landing position or the possible saccade goals. To this end, we adopt a global effect paradigm where a target is accompanied by a salient distractor resulting in the majority of eye movements landing in between target and distractor. To determine the allocation of attention, participants are presented with a discrimination task shortly before the execution of the saccade. Despite a strong global effect obtained for saccade endpoints, we find little evidence for attentional facilitation at the location between target and distractor, but strong attentional facilitation at the location of the target and distractor. We argue that attention is coupled to active oculomotor programs, but not part of the resolution of these programs towards the execution of the saccade. PMID- 26605847 TI - Visual orientation processing in autism spectrum disorder: No sign of enhanced early cortical function. AB - It has been suggested that enhanced perceptual processing underlies some of the social difficulties associated with autism spectrum disorder (ASD). While a variety of visual tasks have been reported in which individuals with ASD outperform neurotypical individuals in control groups, the precise origin of such effects within the visual pathway remains unclear. It has recently been established that visual acuity is intact yet unremarkable in ASD. This suggests that the earliest levels of retinal processing are an unlikely candidate as the source of differences. The next potential levels for divergent visual processing are those involved in processing simple aspects of visual stimuli, such as orientation and spatial frequency, considered to be functions of early visual cortex. Here we focused on the basic processing of orientation. In three experiments, we assessed three basic aspects of orientation processing discrimination, veridical perception, and detection-in participants with ASD in comparison to age-, gender-, and IQ-matched adults without ASD. Each experiment allowed for both qualitative and quantitative comparisons between the two groups. These provided a dense array of data indicating that participants with ASD perceive orientation of low-level stimuli in a qualitatively (as well as quantitatively) similar manner to participants without ASD in control groups, with no evidence of superior processing in detection, precision, or accuracy aspects of orientation perception. These results suggest that the source for altered perceptual abilities should be sought elsewhere, possibly in specific subgroups of people with ASD, other aspects of low-level vision such as spatial frequency, or subsequent levels of visual processing. PMID- 26605848 TI - Role of form information in motion pooling and segmentation. AB - Traditional theories of visual perception have focused on either form or motion processing, implying a functional separation. However, increasing evidence indicates that these features interact at early stages of visual processing. The current study examined a well-known form-motion interaction, where a shape translates along a circular path behind opaque apertures, giving the impression of either independently translating lines (segmentation) or a globally coherent, translating shape. The purpose was to systemically examine how low-level motion information and form information interact to determine which percept is reported. To this end, we used a stimulus with boundaries comprising multiple, spatially separated Gabor patches with three to eight sides. Results showed that shapes with four or fewer sides appeared to move in a segmented manner, whereas those with more sides were integrated as a solid shape. The separation between directions, rather than the total number of sides, causes this switch between integrated or segmented percepts. We conclude that the change between integration and segmentation depends on whether local motion directions can be independently resolved. We also reconcile previous results on the influence of shape closure on motion integration: Shapes that form open contours cause segmentation, but with no corresponding enhanced sensitivity for shapes forming closed contours. Overall, our results suggest that the resolution of the local motion signal determines whether motion segmentation or integration is perceived with only a small overall influence of form. PMID- 26605849 TI - Spectral sensitivity measurements reveal partial success in restoring missing rod function with gene therapy. AB - Restored rod visual function after gene therapy can be established unequivocally by demonstrating that, after dark adaptation, spectral sensitivity has the shape characteristic of rods and that this shape collapses to a cone-like shape before rods have recovered after an intense bleach. We used these tests to assess retinal function in eight young adults and children with early-onset severe retinal dystrophy from Phase II of a clinical gene-therapy trial for RPE65 deficiency that involved the subretinal delivery of a recombinant adeno associated viral vector carrying RPE65. We found substantial improvements in rod sensitivity in two participants: dark-adapted spectral sensitivity was rod-like after treatment and was cone-like before rods had recovered after a bleach. After 40 min of dark adaptation, one participant showed up to 1,000-fold sensitivity improvements 4 months after treatment and the second up to 100-fold improvements 6 months after treatment. The dark-adapted spectral sensitivities of the other six participants remained cone-like and showed little improvement in sensitivity. PMID- 26605850 TI - Chromatic contrast in luminance-defined images affects performance and neural activity during a shape classification task. AB - Models of object recognition generally emphasize the importance of luminance defined shape. However, it is still not fully understood how color signals combine with luminance signals to affect object-related form processing. This electroencephalographic study aimed to examine the contribution of chromatic contrast by assessing its effects on the time course of shape-related processing. Participants classified Gaborized images of object shapes, nonobject shapes, and patches of pseudorandomly scattered Gabors. Stimuli excited (a) the luminance (L+M) channel alone, (b) luminance and L-M channels, or (c) luminance, L-M, and S (L+M) channels and were presented either at mean discrimination threshold or at twice this mean threshold. As expected, classification accuracy was comparable at threshold, as were the attributes of the early, perceptual first negative (N1) component of the event-related potential (ERP). Differences emerged at suprathreshold: Objects defined by the full combination of channels were associated with the poorest performance and the lowest N1 amplitude. Shape sensitivity was not consistently observed in the N1 but was more evident in the late positive potential (LPP), a cognitive ERP component. Both the N1 and the LPP were affected by the amount and type of contrast in the image. While the effects of luminance and L-M contrast were similar, affecting the ERP selectively during the N1 and LPP period, S-(L+M) contrast elicited a sustained shift in amplitude. Our results demonstrate, for the first time using a combination of behavioral as well as early and late electrophysiological effects, that shape classification is determined by both the chromatic and the luminance content of the image. PMID- 26605851 TI - Tubular optical microcavities of indefinite medium for sensitive liquid refractometers. AB - Optical microcavities enable circulated light to intensively interact with a detecting liquid, thus promising high sensitivity in fluidic refractometers. Based on Mie scattering theory, we propose a tubular metamaterial device for liquid sensing, which utilizes anisotropic metamaterials with hyperbolic dispersion called indefinite media (IM). Besides traditional whispering gallery modes (WGMs), such tubular cavities can support surface plasmon polariton (SPP) WGMs, enabling high sensitivity liquid detection. Three configurations of such metamaterial tubes for sensing are discussed: tube-in-liquid, hollow-tube-in liquid and liquid-in-tube; these are analyzed using numerical formulas and compared with dielectric and metal materials. Compared with traditional dielectric media (DM), the IM tubular cavity exhibits a higher sensitivity (S), which is close to that of a metal tubular cavity. However, compared with metal media, such an IM cavity can achieve higher quality (Q) factors similar to the DM tubular cavity. Therefore, the IM tubular cavity can offer the highest figures of merit (QS) for the sensing performance among the three types of materials. Our results suggest a novel tubular optofluidic device based on metamaterials, which could be useful for liquid refractometers. PMID- 26605852 TI - Pelvis Plus Prostate Radiation Therapy and the Risk of Death in Men With Newly Diagnosed Node-Positive Prostate Cancer. PMID- 26605836 TI - Association of Baseline Visual Acuity and Retinal Thickness With 1-Year Efficacy of Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema. AB - IMPORTANCE: Comparisons of the relative effect of 3 anti-vascular endothelial growth factor agents to treat diabetic macular edema warrant further assessment. OBJECTIVE: To provide additional outcomes from a randomized trial evaluating 3 anti-vascular endothelial growth factor agents for diabetic macular edema within subgroups based on baseline visual acuity (VA) and central subfield thickness (CST) as evaluated on optical coherence tomography. DESIGN, SETTING, AND PARTICIPANTS: Post hoc exploratory analyses were conducted of randomized trial data on 660 adults with diabetic macular edema and decreased VA (Snellen equivalent, approximately 20/32 to 20/320). The original study was conducted between August 22, 2012, and August 28, 2013. Analysis was conducted from January 7 to June 2, 2015. INTERVENTIONS: Repeated 0.05-mL intravitreous injections of 2.0 mg of aflibercept (224 eyes), 1.25 mg of bevacizumab (218 eyes), or 0.3 mg of ranibizumab (218 eyes) as needed per protocol. MAIN OUTCOMES AND MEASURES: One year VA and CST outcomes within prespecified subgroups based on both baseline VA and CST thresholds, defined as worse (20/50 or worse) or better (20/32 to 20/40) VA and thicker (>=400 um) or thinner (250 to 399 um) CST. RESULTS: In the subgroup with worse baseline VA (n = 305), irrespective of baseline CST, aflibercept showed greater improvement than bevacizumab or ranibizumab for several VA outcomes. In the subgroup with better VA and thinner CST at baseline (61-73 eyes across 3 treatment groups), VA outcomes showed little difference between groups; mean change was +7.2, +8.4, and +7.6 letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively. However, in the subgroup with better VA and thicker CST at baseline (31-43 eyes), there was a suggestion of worse VA outcomes in the bevacizumab group; mean change from baseline to 1 year was +9.5, +5.4, and +9.5 letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively, and VA letter score was greater than 84 (approximately 20/20) in 21 of 33 (64%), 7 of 31 (23%), and 21 of 43 (49%) eyes, respectively. The adjusted differences and 95% CIs were 39% (17% to 60%) for aflibercept vs bevacizumab, 25% (5% to 46%) for ranibizumab vs bevacizumab, and 13% (-8% to 35%) for aflibercept vs ranibizumab. CONCLUSIONS AND RELEVANCE: These post hoc secondary findings suggest that for eyes with better initial VA and thicker CST, some VA outcomes may be worse in the bevacizumab group than in the aflibercept and ranibizumab groups. Given the exploratory nature of these analyses and the small sample size within subgroups, caution is suggested when using the data to guide treatment considerations for patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01627249. PMID- 26605853 TI - Long-Time Dynamics through Parallel Trajectory Splicing. AB - Simulating the atomistic evolution of materials over long time scales is a longstanding challenge, especially for complex systems where the distribution of barrier heights is very heterogeneous. Such systems are difficult to investigate using conventional long-time scale techniques, and the fact that they tend to remain trapped in small regions of configuration space for extended periods of time strongly limits the physical insights gained from short simulations. We introduce a novel simulation technique, Parallel Trajectory Splicing (ParSplice), that aims at addressing this problem through the timewise parallelization of long trajectories. The computational efficiency of ParSplice stems from a speculation strategy whereby predictions of the future evolution of the system are leveraged to increase the amount of work that can be concurrently performed at any one time, hence improving the scalability of the method. ParSplice is also able to accurately account for, and potentially reuse, a substantial fraction of the computational work invested in the simulation. We validate the method on a simple Ag surface system and demonstrate substantial increases in efficiency compared to previous methods. We then demonstrate the power of ParSplice through the study of topology changes in Ag42Cu13 core-shell nanoparticles. PMID- 26605854 TI - Viridicatumtoxins: Expanding on a Rare Tetracycline Antibiotic Scaffold. AB - Viridicatumtoxins, which belong to a rare class of fungal tetracycline-like mycotoxins, were subjected to comprehensive spectroscopic and chemical analysis, leading to reassignment/assignment of absolute configurations and characterization of a remarkably acid-stable antibiotic scaffold. Structure activity relationship studies revealed exceptional growth inhibitory activity against vancomycin-resistant Enterococci (IC50 40 nM), >270-fold more potent than the commercial antibiotic oxytetracycline. PMID- 26605855 TI - Redox- and pH-Responsive Orthogonal Supramolecular Self-Assembly: An Ensemble Displaying Molecular Switching Characteristics. AB - Two heteroditopic monomers, namely a thiopropyl-functionalized tetrathiafulvalene annulated calix[4]pyrrole (SPr-TTF-C[4]P 1) and phenyl C61 butyric acid (PCBA 2), have been used to assemble a chemically and electrochemically responsive supramolecular ensemble. Addition of an organic base initiates self-assembly of the monomers via a molecular switching event. This results in the formation of materials that may be disaggregated via the addition of an organic acid or electrolysis. PMID- 26605856 TI - Identification of New and Distinctive Exposures from Little Cigars. AB - Little cigar mainstream smoke is less well-characterized than cigarette mainstream smoke in terms of chemical composition. This study compared four popular little cigar products against four popular cigarette products to determine compounds that are either unique to or more abundant in little cigars. These compounds are categorized as new or distinctive exposures, respectively. Total particulate matter samples collected from machine-generated mainstream smoke were extracted with methylene chloride, and the extracts were analyzed using two-dimensional gas chromatography-time-of-flight mass spectrometry. The data were evaluated using novel data-processing algorithms that account for characteristics specific to the selected analytical technique and variability associated with replicate sample analyses. Among more than 25 000 components detected across the complete data set, ambrox was confirmed as a new exposure, and 3-methylbutanenitrile and 4-methylimidazole were confirmed as distinctive exposures. Concentrations of these compounds for the little cigar mainstream smoke were estimated at approximately 0.4, 0.7, and 12 MUg/rod, respectively. In achieving these results, this study has demonstrated the capability of a powerful analytical approach to identify previously uncharacterized tobacco-related exposures from little cigars. The same approach could also be applied to other samples to characterize constituents associated with tobacco product classes or specific tobacco products of interest. Such analyses are critical in identifying tobacco-related exposures that may affect public health. PMID- 26605857 TI - Chemotaxis Increases the Residence Time of Bacteria in Granular Media Containing Distributed Contaminant Sources. AB - The use of chemotactic bacteria in bioremediation has the potential to increase access to, and the biotransformation of, contaminant mass within the subsurface. This laboratory-scale study aimed to understand and quantify the influence of chemotaxis on the residence times of pollutant-degrading bacteria within homogeneous treatment zones. Focus was placed on a continuous-flow sand-packed column in which a uniform distribution of naphthalene crystals created distributed sources of dissolved-phase contaminant. A 10 mL pulse of Pseudomonas putida G7, which is chemotactic to naphthalene, and Pseudomonas putida G7 Y1, a nonchemotactic mutant strain, were simultaneously introduced into the sand-packed column at equal concentrations. Breakthrough curves obtained from experiments conducted with and without naphthalene were used to quantify the effect of chemotaxis on transport parameters. In the presence of the chemoattractant, longitudinal dispersion of PpG7 increased by a factor of 3, and percent recovery decreased by 43%. In contrast, PpG7 Y1 transport was not influenced by the presence of naphthalene. The results imply that pore-scale chemotaxis responses are evident at an interstitial velocity of 1.8 m/day, which is within the range of typical groundwater flow. Within the context of bioremediation, chemotaxis may work to enhance bacterial residence times in zones of contamination, thereby improving treatment. PMID- 26605858 TI - Molecular Dynamics Simulation of the Aggregation Patterns in Aqueous Solutions of Bile Salts at Physiological Conditions. AB - Classical molecular dynamics simulations are employed to monitor the aggregation behavior of six bile salts (nonconjugated and glycine- and taurine-conjugated sodium cholate and sodium deoxycholate) with concentration of 10 mM in aqueous solution in the presence of 120 mM NaCl. There are 150 ns trajectories generated to characterize the systems. The largest stable aggregates are analyzed to determine their shape, size, and stabilizing forces. It is found that the aggregation is a hierarchical process and that its kinetics depends both on the number of hydroxyl groups in the steroid part of the molecules and on the type of conjugation. The micelles of all salts are similar in shape-deformed spheres or ellipsoids, which are stabilized by hydrophobic forces, acting between the steroid rings. The differences in the aggregation kinetics of the various conjugates are rationalized by the affinity for hydrogen bond formation for the glycine-modified salts or by the longer time needed to achieve optimum packing for the tauro derivatives. Evidence is provided for the hypothesis from the literature that the entirely hydrophobic core of all aggregates and the enhanced dynamics of the molecules therein should be among the prerequisites for their pronounced solubilization capacity for hydrophobic substances in vivo. PMID- 26605859 TI - Effect of Isovalent Substitution on the Structure and Properties of the Zintl Phase Solid Solution Eu7Cd4Sb8-xAsx (2 <= x <= 5). AB - A novel Zintl phase structure type, Eu7Cd4Sb8-xAsx (x = 2, 3, 4, and 5), with the general formula Eu7Cd4Pn8 (Pn = mixed occupancy Sb and As), was synthesized by molten tin flux reaction. Its structure was determined using single-crystal X-ray diffraction methods. This structure type is only preserved for 2 <= x <= 5 under our experimental conditions, and efforts to synthesize samples with x < 2 or x > 5 resulted in other structure types. The mixed occupancy Sb and As can be thought of as a pseudoatom whose ideal size, in this range of Sb/As ratios, fits the structure. The title phase crystallizes in the I-centered monoclinic space group I2/m (No. 12, Z = 4) with unit cell parameters ranging as follows: a = 19.7116(17)-19.4546(13) A, b = 4.6751(4)-4.6149(3) A, c = 24.157(2)-23.871(15) A, and beta = 95.8798(1)-96.016(5) degrees , depending on the Sb/As ratio. The structure can be described as parallel double pentagonal tubes resulting from Cd Pn and Pn-Pn bonding. These double pentagons are formed through corner sharing of the Cd-centered CdPn4 tetrahedra and a Pn-Pn interaction from two adjacent CdPn4 tetrahedra. This structure type is closely related to the Sr11Cd6Sb12 structure type as both share the same bonding features of Pn-Pn bonding and double pentagonal tubes. Electron microprobe analysis confirms the composition of these new Zintl solid solution phases. The As exhibits preferential substitution on specific sites, and site specificity trends are supported by lowest energy models from theoretical calculations. Theoretical calculations also predict that Sb-rich compounds should be metallic or semimetallic and that they should become more insulating as As content increases. Members of the solid-solution order ferromagnetically between 5 and 6 K and exhibit relatively low electrical resistivity between 50 and 300 K, ranging from ~0.57 to ~26 mOmega.cm, increasing with increasing As content. PMID- 26605860 TI - Uncaging Alcohols Using UV or Visible Light Photoinduced Electron Transfer to 9 Phenyl-9-tritylone Ethers. AB - The clean and efficient photorelease of primary and secondary alcohols is reported from the deprotection of a new photoremovable protecting group, the 9 phenyltritylone (PTO) group. Deprotection is initiated by 350 nm excitation of the PTO chromophore in the presence of triethylamine or using 447 nm light in the presence of a visible light absorbing photocatalyst and triethylamine. Laser flash photolysis results are reported in support of a proposed deprotection mechanism for the release of alcohols on a ca. 20 MUs time scale. PMID- 26605863 TI - A framework for screening sites at risk from contaminants of emerging concern. AB - Trace levels of a variety of currently unregulated organic chemicals have been detected in treated wastewater effluents and surface waters that receive treated effluents. Many of these chemicals of emerging concern (CECs) originate from pharmaceuticals and personal care products that are used widely and that frequently are transported "down the drain" to a wastewater treatment plant (WWTP). Actual effects of CECs on aquatic life have been difficult to document, although biological effects consistent with effects of some CECs have been noted. There is a critical need to find appropriate ways to screen wastewater sites that have the greatest potential of CEC risk to biota. Building on the work of several researchers, the authors present a screening framework, as well as examples based on the framework, designed to identify high-risk versus lower-risk sites that are influenced by WWTP effluent. It is hoped that this framework can help researchers, utilities, and the larger water resource community focus efforts toward improving CEC risk determinations and management of these risks. PMID- 26605861 TI - Lower Levels of Antiretroviral Therapy Enrollment Among Men with HIV Compared with Women - 12 Countries, 2002-2013. AB - Equitable access to antiretroviral therapy (ART) for men and women with human immunodeficiency virus (HIV) infection is a principle endorsed by most countries and funding bodies, including the U.S. President's Emergency Plan for AIDS (acquired immunodeficiency syndrome) Relief (PEPFAR) (1). To evaluate gender equity in ART access among adults (defined for this report as persons aged >=15 years), 765,087 adult ART patient medical records from 12 countries in five geographic regions* were analyzed to estimate the ratio of women to men among new ART enrollees for each calendar year during 2002-2013. This annual ratio was compared with estimates from the Joint United Nations Programme on HIV/AIDS (UNAIDS)(?) of the ratio of HIV-infected adult women to men in the general population. In all 10 African countries and Haiti, the most recent estimates of the ratio of adult women to men among new ART enrollees significantly exceeded the UNAIDS estimates for the female-to-male ratio among HIV-infected adults by 23%-83%. In six African countries and Haiti, the ratio of women to men among new adult ART enrollees increased more sharply over time than the estimated UNAIDS female-to-male ratio among adults with HIV in the general population. Increased ART coverage among men is needed to decrease their morbidity and mortality and to reduce HIV incidence among their sexual partners. Reaching more men with HIV testing and linkage-to-care services and adoption of test-and-treat ART eligibility guidelines (i.e., regular testing of adults, and offering treatment to all infected persons with ART, regardless of CD4 cell test results) could reduce gender inequity in ART coverage. PMID- 26605864 TI - In Response: An academic perspective on the release of oil sands process-affected water. PMID- 26605865 TI - The Challenge: Safe release and reintegration of oil sands process-affected water. PMID- 26605866 TI - In Response: A provincial government perspective on the release of oil sands process-affected water. PMID- 26605867 TI - In Summary. PMID- 26605868 TI - A Framework for Web-Based Interprofessional Education for Midwifery and Medical Students. AB - Scheduling interprofessional team-based activities for health sciences students who are geographically dispersed, with divergent and often competing schedules, can be challenging. The use of Web-based technologies such as 3-dimensional (3D) virtual learning environments in interprofessional education is a relatively new phenomenon, which offers promise in helping students come together in online teams when face-to-face encounters are not possible. The purpose of this article is to present the experience of a nurse-midwifery education program in a Southeastern US university in delivering Web-based interprofessional education for nurse-midwifery and third-year medical students utilizing the Virtual Community Clinic Learning Environment (VCCLE). The VCCLE is a 3D, Web-based, asynchronous, immersive clinic environment into which students enter to meet and interact with instructor-controlled virtual patient and virtual preceptor avatars and then move through a classic diagnostic sequence in arriving at a plan of care for women throughout the lifespan. By participating in the problem-based management of virtual patients within the VCCLE, students learn both clinical competencies and competencies for interprofessional collaborative practice, as described by the Interprofessional Education Collaborative Core Competencies for Interprofessional Collaborative Practice. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health. PMID- 26605869 TI - Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with Type 2 diabetes. AB - AIMS: Metformin is the most widely used oral anti-diabetes agent and has considerable benefits over other therapies, yet 20-30% of people develop gastrointestinal side effects, and 5% are unable to tolerate metformin due to the severity of these side effects. The mechanism for gastrointestinal side effects and their considerable inter-individual variability is unclear. We have recently shown the association between organic cation transporter 1 (OCT1) variants and severe intolerance to metformin in people with Type 2 diabetes. The aim of this study was to explore the association of OCT1 reduced-function polymorphisms with common metformin-induced gastrointestinal side effects in Type 2 diabetes. METHODS: This prospective observational cohort study included 92 patients with newly diagnosed Type 2 diabetes, incident users of metformin. Patients were genotyped for two common loss-of-function variants in the OCT1 gene (SLC22A1): R61C (rs12208357) and M420del (rs72552763). The association of OCT1 reduced function alleles with gastrointestinal side effects was analysed using logistic regression. RESULTS: Forty-three patients (47%) experienced gastrointestinal adverse effects in the first 6 months of metformin treatment. Interestingly, the number of OCT1 reduced-function alleles was significantly associated with over two-fold higher odds of the common metformin-induced gastrointestinal side effects (odds ratio = 2.31, 95% confidence interval 1.07-5.01, P = 0.034). CONCLUSIONS: In conclusion, we showed for the first time the association between OCT1 variants and common metformin-induced gastrointestinal side effects. These results confirm recent findings related to the role of OCT1 in severe metformin intolerance, and suggest that high inter-individual variability in mild/moderate and severe gastrointestinal intolerance share a common underlying mechanism. These data could contribute to more personalized and safer metformin treatment. PMID- 26605870 TI - Using Marital Status and Continuous Marital Satisfaction Ratings to Predict Depressive Symptoms in Married and Unmarried Women With Systemic Sclerosis: A Canadian Scleroderma Research Group Study. AB - OBJECTIVE: Married persons have, on average, better mental health than nonmarried persons. Among married persons, marital satisfaction is associated with better mental health. Studies on mental health in married and nonmarried persons that consider marital satisfaction have categorized patients as satisfied versus unsatisfied, which reduces statistical power and does not generate clinically useful information on mental health across the satisfaction spectrum. Our objective was to demonstrate a novel regression approach to evaluate mental health in women with systemic sclerosis (SSc), comparing married and unmarried women, accounting for continuously measured marital satisfaction. METHODS: Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) and marital satisfaction with the Dyadic Adjustment Scale-7. A single multiple linear regression model was used to predict CES-D scores from marital status and, among married women, continuously measured marital satisfaction, controlling for demographic and clinical characteristics. RESULTS: Of 725 women, 494 (68%) were married or living as married. On average, married women had mean CES-D scores that were 2.0 points (0.19 SDs) lower than unmarried women (P = 0.013). Among married women, a 1.0 SD increase in marital satisfaction was associated with a 2.2 point (0.21 SDs) decrease in CES-D scores (P < 0.001). Married women whose marital satisfaction scores were below the 19th percentile had greater predicted depressive symptoms than unmarried women. Married women's predicted CES-D scores ranged from 6.7 points lower to 6.9 points higher than those of unmarried women, depending on marital satisfaction. CONCLUSION: Comparisons of mental health in married and unmarried patients with rheumatic diseases should include continuously measured marital satisfaction. PMID- 26605871 TI - Serum Cripto-1 is a novel biomarker for non-small cell lung cancer diagnosis and prognosis. AB - INTRODUCTION: Cripto-1 (CR-1) is highly expressed in several different types of human tumors. However, the clinical significance of CR-1 expression in serum specimens from non-small cell lung cancer (NSCLC) patients has not yet been determined. OBJECTIVES: The aim of this study was to explore the diagnostic and prognostic value of serum CR-1 levels in patients with NSCLC. METHODS: Serum specimens from 592 NSCLC patients, 180 benign lung disease patients and 240 healthy controls were collected. The concentrations of CR-1 were measured by sandwich enzyme-linked immunosorbent assay. RESULTS: Patients with NSCLC had higher serum CR-1 levels than the controls (P < 0.01) and patients with benign lung diseases (P < 0.01). When a cutoff point of 1.8 ng/mL was selected (diagnostic specificity 95%), the diagnostic sensitivity for NSCLC is 56.8%. About 37.5% of carcinoembryonic antigen (CEA)-negative lung cancer patients were CR-1 positive at 95% specificity. In patients with stage I/II lung cancer, use of these two markers in combination results in almost 21% increase in sensitivity, at 95% specificity, compared with CEA alone. Uni-variate analysis revealed that NSCLC patients with positive CR-1 had a shorter overall survival (OS) and progression-free survival (PFS) than those with negative CR-1 [hazard ratio (HR) of 2.93, P = 0.005; HR of 2.12, P = 0.005]. Cox multi-variate analysis indicated that CR-1 was an independent prognostic indicator of PFS and OS (HR of 1.91, P = 0.006; HR of 1.82, P = 0.007). Kaplan-Meier survival curves further confirmed that patients with negative CR-1 had longer PFS and OS (P = 0.026 and P = 0.011, respectively). CONCLUSIONS: In conclusion, measurement of serum CR-1 is a useful diagnostic and prognostic marker for NSCLC patients. PMID- 26605872 TI - Impact of xerostomia on dysphagia after chemotherapy-intensity-modulated radiotherapy for oropharyngeal cancer: Prospective longitudinal study. AB - BACKGROUND: The purpose of this study was to assess how xerostomia affects dysphagia. METHODS: Prospective longitudinal studies of 93 patients with oropharyngeal cancer treated with definitive chemotherapy-intensity-modulated radiotherapy (IMRT). Observer-rated dysphagia (ORD), patient-reported dysphagia (PRD), and patient-reported xerostomia (PRX) assessment of the swallowing mechanics by videofluoroscopy (videofluoroscopy score), and salivary flow rates, were prospectively assessed from pretherapy through 2 years. RESULTS: ORD grades >=2 were rare and therefore not modeled. Of patients with no/mild videofluoroscopy abnormalities, a substantial proportion had PRD that peaked 3 months posttherapy and subsequently improved. Through 2 years, highly significant correlations were observed between PRX and PRD scores for all patients, including those with no/mild videofluoroscopy abnormalities. Both PRX and videofluoroscopy scores were highly significantly associated with PRD. On multivariate analysis, PRX score was a stronger predictor of PRD than the videofluoroscopy score. CONCLUSION: Xerostomia contributes significantly to PRD. Efforts to further decrease xerostomia, in addition to sparing parotid glands, may translate into improvements in PRD. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1605-E1612, 2016. PMID- 26605873 TI - Viscoelastic shear properties of in vivo thigh muscles measured by MR elastography. AB - PURPOSE: To measure the viscoelastic properties of passive thigh muscles using multifrequency magnetic resonance elastography (MMRE) and rheological models. MATERIALS AND METHODS: Four muscles in five volunteers underwent MMRE tests set up inside a 1.5T magnetic resonance imaging (MRI) scanner. Compression excitation was generated with a driver attached around the thigh, and waves were generated at 70, 90, and 110 Hz. In vivo experimental viscoelastic parameters (G(omega) = G' + i G") were extracted from the wavelength and attenuation measurements along a local profile in the direction of the wave's displacement. The data-processing method was validated on a phantom using MMRE and RheoSpectris tests. The complex modulus (G(omega)) related to elasticity (MU) and viscosity (eta) was then determined using four rheological models. RESULTS: Zener was the best-fit model (chi ~0.35 kPa) for the rheological parameters of all muscles. Similar behaviors for the elastic components for each muscle were found for the Zener and springpot models. The gracilis muscle showed higher elastic values (about 2 kPa) in both models compared to other muscles. The alpha-values for each muscle was equivalent to the ratio G"/G' at 90 Hz. CONCLUSION: MMRE tests associated with data processing demonstrated that the complex shear modulus G(omega) of passive muscles could be analyzed using two rheological models. The viscoelastic data can be used as a reference for future assessment of muscular dysfunction. J. Magn. Reson. Imaging 2015. J. Magn. Reson. Imaging 2016;43:1423-1433. PMID- 26605874 TI - Reply. PMID- 26605875 TI - Bcl-3 in CD4+ T Cell-Mediated Rheumatoid Arthritis Pathogenesis: Comment on the Article by Meguro et al. PMID- 26605876 TI - Two-Dimensional Rectangular and Honeycomb Lattices of NbN: Emergence of Piezoelectric and Photocatalytic Properties at Nanoscale. AB - Using first-principles calculations, we predict that monolayered honeycomb and rectangular two-dimensional (2D) lattice forms of NbN are metastable and naturally derivable from different orientations of its rocksalt structure. While the rectangular form is shown to retain the metallic and superconducting (SC) properties of the bulk, spectacularly contrasting properties emerge in the honeycomb form of NbN: it exhibits (a) semiconducting electronic structure suitable for valleytronics and photocatalysis of water splitting, (b) piezoelectricity with a spontaneous polarization originating from a rare sd(2) sp(2) type hybridization, and (c) a wide gap in its phonon spectrum making it suitable for use in hot carrier solar cells. Our work demonstrates how low coordination numbers and associated strong bonding stabilize 2D nanoforms of covalently bonded solids and introduce novel functionalities of technological importance. PMID- 26605877 TI - Transcriptional architecture of the human brain. PMID- 26605878 TI - Does the hippocampus preplay memories? PMID- 26605879 TI - Thalamus controls recurrent cortical dynamics. PMID- 26605880 TI - Backward reasoning the formation rules. PMID- 26605883 TI - Corrigendum: Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. PMID- 26605884 TI - Erratum: Hippocampal-neocortical functional reorganization underlies children's cognitive development. PMID- 26605885 TI - Corrigendum: Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. PMID- 26605881 TI - The PsychENCODE project. PMID- 26605882 TI - Dendritic integration: 60 years of progress. AB - Understanding how individual neurons integrate the thousands of synaptic inputs they receive is critical to understanding how the brain works. Modeling studies in silico and experimental work in vitro, dating back more than half a century, have revealed that neurons can perform a variety of different passive and active forms of synaptic integration on their inputs. But how are synaptic inputs integrated in the intact brain? With the development of new techniques, this question has recently received substantial attention, with new findings suggesting that many of the forms of synaptic integration observed in vitro also occur in vivo, including in awake animals. Here we review six decades of progress, which collectively highlights the complex ways that single neurons integrate their inputs, emphasizing the critical role of dendrites in information processing in the brain. PMID- 26605886 TI - Corrigendum: The dorsal posterior insula subserves a fundamental role in human pain. PMID- 26605887 TI - Erratum: Optogenetics and the future of neuroscience. PMID- 26605888 TI - Corrigendum: Regulating anxiety with extrasynaptic inhibition. PMID- 26605905 TI - Prenatal exposure to endocrine disrupting chemicals and birth weight-A prospective cohort study. AB - Prenatal exposure to endocrine disrupting chemicals may affect fetal development through disruption of hormonal actions and epigenetic modifications, potentially predisposing individuals to later on-set health risks, such as obesity. The objective of this study was to determine associations between biological exposure markers of various endocrine disrupting chemicals and birth weight in a newly established, prospective mother-child cohort in the Netherlands. Birth weight (n = 91) was obtained from birth records, and exposure to dichlorodiphenyldichloroethylene (DDE), three di-2-ethylhexyl phthalate (DEHP) metabolites, polychlorinated biphenyl-153, perfluorooctanesulfonic acid (PFOS), and perfluorooctanoic acid (PFOA) was determined in cord plasma. For DDE, exposure was also measured in breast milk. Linear regression analysis was used to determine associations between compounds and birth weight, which were stratified for gender and adjusted for a priori defined covariates. Increased exposure to DDE was associated with lower birth weight in boys (>95.89 ng L-1, -325.9 g, 95% CI -634.26 to -17.56), whereas in girls a tendency towards a higher birth weight was observed. Lower birth weights for boys were also observed for high exposure to MECPP, and to a certain extent also for PFOA. MEHHP and PFOS exposure on the other hand were associated with higher birth weights in boys. In girls no effects were observed for these compounds. It can be concluded that prenatal exposure to DDE, perfluorinated alkyl acids, and phthalates was associated with changes in birth weight in this population. Associations were gender specific, and appeared to be non-linear. Since the population was relatively small, results should be interpreted with caution. PMID- 26605889 TI - Development and Psychometric Evaluation of the FACE-Q Scales for Patients Undergoing Rhinoplasty. AB - IMPORTANCE: Rhinoplasty continues to rank among the most popular cosmetic surgical treatments. Measuring what the nose looks like has typically involved the use of observer-reported or physician-reported outcome measures (eg, photographs). While objective outcomes are important, facial appearance is subjective, and asking patients what they think about the appearance of their nose is of paramount importance. The patient perspective can be measured using patient-reported outcome instruments. OBJECTIVE: To describe the development and psychometric evaluation of the FACE-Q scales and adverse effects checklist designed to measure rhinoplasty outcomes. DESIGN, SETTING, AND PARTICIPANTS: A questionnaire was completed by patients recruited between July 13, 2010, and March 1, 2015. Psychometric methods were used to select the most clinically sensitive items for inclusion in item-reduced scales as well as to examine reliability, validity, and ability to detect clinical change. The setting was plastic surgery clinics in the United States, England, and Canada. Participants were preoperative and postoperative patients 18 years or older undergoing rhinoplasty. MAIN OUTCOMES AND MEASURES: Responses and validation measures of the FACE-Q scales and adverse effects checklist. RESULTS: In total, 158 of 169 patients invited to participate in the study were enrolled (response rate, 93.5%). The most common adverse effect was the skin of the nose looking thick or swollen. Rasch measurement theory analysis led to the refinement of a 10-item Satisfaction With Nose Scale and a 5-item Satisfaction With Nostrils Scale. The person separation index and Cronbach alpha were 0.91 and 0.96, respectively, for the Satisfaction With Nose Scale and 0.89 and 0.96, respectively, for the Satisfaction With Nostrils Scale. All items had ordered thresholds and good item fit. Satisfaction with the nose and nostrils was incrementally lower in participants bothered by specific adverse effects (eg, the skin of the nose looking thick or swollen). Patient satisfaction on the Satisfaction With Nose Scale and the Satisfaction With Nostrils Scale and on 3 additional FACE-Q scales (ie, Satisfaction With Facial Appearance Scale, Psychological Function Scale, and Social Function Scale) was higher after surgery than before surgery (P < .001 for all, independent samples t test). Twenty-three participants who provided preoperative and postoperative data reported improvement on all 5 scales (P <= .003 for all). The effect sizes ranged from 0.6 to 2.3. Significant individual level change was reported by most participants for the Satisfaction With Nose Scale, Satisfaction With Nostrils Scale, Satisfaction With Facial Appearance Scale, and Social Function Scale. CONCLUSIONS AND RELEVANCE: A FACE-Q scales rhinoplasty module can be used in clinical practice, research, and quality improvement to incorporate the patient perspective in outcome assessments. LEVEL OF EVIDENCE: NA. PMID- 26605906 TI - Combination Treatment of Murine Colon Cancer with Doxorubicin and Redox Nanoparticles. AB - Conventional chemotherapeutic drugs such as doxorubicin (DOX) are associated with severe adverse effects such as cardiac, hepatic, and gastrointestinal (GI) toxicities. Excessive production of reactive oxygen species (ROS) was reported to be one of the main mechanisms underlying these severe adverse effects. Recently, we have developed 2 types of novel redox nanoparticles (RNPs) including pH sensitive redox nanoparticle (RNP(N)) and pH-insensitive redox nanoparticle (RNP(O)), which effectively scavenge overproduced ROS in inflamed and cancerous tissues. In this study, we investigated the effects of these RNPs on DOX-induced adverse effects during cancer chemotherapy. The DOX-induced body weight loss was significantly attenuated in the mice treated with RNPs, particularly pH insensitive RNP(O). We also found that cardiac ROS levels in the DOX-treated mice were dramatically decreased by treatment with RNPs, resulting in the reversal of cardiac damage, as confirmed by both plasma cardiac biomarkers and histological analysis. It was interesting to notice that, during cotreatment with DOX and RNPs, the DOX uptake was significantly enhanced in the cancer cells, but not in healthy aortic endothelial cells in vitro. Treatment with RNPs also improved anticancer efficacy of DOX in the colitis-associated colon cancer model mice in vivo. On the basis of these results, a combination of the novel antioxidative nanotherapeutics (RNPs) with conventional anticancer drugs seems to be a robust strategy for well-tolerated anticancer therapy. PMID- 26605907 TI - Commentary on failure in HIV research. PMID- 26605908 TI - Comparison between Fondaparinux and Low-Molecular-Weight Heparin in Patients with Acute Coronary Syndrome: A Meta-Analysis. AB - OBJECTIVE: A number of studies have evaluated the efficacy and safety of fondaparinux versus low-molecular-weight heparin (LMWH) in patients with acute coronary syndrome (ACS), but the findings were not consistent across these studies. METHODS: Electronic databases and article references were searched for studies that assessed fondaparinux versus LMWH in ACS patients. RESULTS: Six studies met the inclusion criteria. There was a lower risk of major adverse cardiac events (MACE) with fondaparinux-based regimens both in randomized controlled trials (RCT; risk ratio, RR: 0.91, p = 0.04) and observational studies (RR: 0.85, p < 0.0001). Mortality decreased in fondaparinux-treated patients in RCT (RR: 0.84, p = 0.02), but not in observational studies (RR: 1.44, p = 0.64). For the analysis of myocardial infarction (MI), recurrent ischemia and stroke, none of the studies showed significant results. In addition, fondaparinux lowered the risk of major bleeding in RCT (RR: 0.62, p < 0.0001) and observational studies (RR: 0.65, p < 0.0001). The net clinical outcome also favored fondaparinux over LMWH in RCT (RR: 0.82, p < 0.0001) and observational studies (RR: 0.84, p < 0.0001). CONCLUSIONS: Among ACS patients, a fondaparinux-based regimen presented advantages regarding MACE and major bleeding, and a net clinical benefit compared with LMWH, although the benefit is minimal regarding MACE. For death, MI, recurrent ischemia and stroke, fondaparinux has not shown significant benefits. PMID- 26605909 TI - Efficacy of the cat deafening method: Co-administration of ethacrynic acid and kanamycin. AB - OBJECTIVE: This study was designed to determine if hearing status monitoring during intravenous infusion of EA reduces individual variability and to evaluate the correlation between EA dose and Bwt. MATERIALS AND METHODS: Twenty-five cats with the mean age of 24 +/- 3.7 weeks (range = 20.6-28.3) and a mean weight of 3.21 +/- 0.84 kg (range = 1.9-5.1) were administered a subcutaneous injection of KM (300 mg/kg) followed by an intravenous infusion of EA (1 mg/min). Click-evoked auditory brainstem responses (ABRs) were recorded to monitor hearing during the infusion. When ABR thresholds exceeded a 90 dB sound pressure level, the infusion of EA was terminated. Histopathology forapex, middle, and base sections of the cochlea were examined after 6 months. RESULTS: The dose of EA was optimized for deafening through simultaneous ABR measurements. Bwt was positively correlated with EA dose (mg) (p < 0.001, R(2) = 0.548), which was different from a study previously reported. Cochlear histopathology assessments revealed an absence of organ of Corti in the majority of cochleae. CONCLUSION: Co-administration of kanamycin (KM) and ethacrynic acid (EA) was an easy and effective method for deafening procedures in adult animals. Body weight (Bwt) was positively correlated with EA dose (mg) and an optimal EA dose can be calculated. PMID- 26605910 TI - Mental health problems and acculturative issues among married immigrant women in Korea: A qualitative study. AB - Through this research the author explored immigrant women's mental health problems with the goal of deepening understanding to develop a framework for preventing mental disorders and improving their mental health. A qualitative research design was used to examine the women's lived experiences. The data were collected from February 2014 to October 2014. Twenty women were recruited from multicultural community service centers. Inclusion criteria were the ability to communicate and the absence of acute physical or psychological problems; participants were excluded if they were under 18 years old or separated. Individual in-depth interviews were conducted with participants regarding their experiences of living in Korean society. The data were analyzed using the grounded theory approach. A conceptual framework-Embracing Cultural Conflict Model-was constructed based on the personal-family-community context as well as the paradigm of the immigrant woman using eleven concepts. The conceptual framework suggests that multicultural programs and services should take into account a historical understanding of Korean society and family, address problem solving strategies including improving mental health literacy, build support from both the Korean family and family of origin, and offer multicultural activities to satisfy homeland-related cultural needs. PMID- 26605911 TI - Shared Molecular Mechanisms in Alzheimer's Disease and Amyotrophic Lateral Sclerosis: Neurofilament-Dependent Transport of sAPP, FUS, TDP-43 and SOD1, with Endoplasmic Reticulum-Like Tubules. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS), a debilitating neurodegenerative disorder of the motor neurons, leads to the disorganization of the neurofilament (NF) cytoskeleton and - ultimately - the deterioration of the neuromuscular junction. Some familial cases of ALS are caused by mutated FUS, TDP-43 or SOD1; it is thought that the mutated proteins inflict pathology either by gain or loss of function. The proper function of the neuromuscular junction requires sAPP, a soluble proteolytic fragment of the amyloid-beta precursor protein (APP) - a transmembrane protein implicated in the pathology of Alzheimer's disease (AD). Whether sAPP, FUS, TDP-43 and SOD1 are mechanistically linked in a common pathway deregulated in both AD and ALS is not known. SUMMARY: We show that sAPP, TDP-43, FUS and SOD1 are transported to neurite terminals by a mechanism that involves endoplasmic reticulum (ER)-like tubules and requires peripherin NFs. The transport of these proteins, and the translocation of the ER protein reticulon 4 (Rtn4) into neurites was studied in CAD cells, a brainstem-derived neuronal cell line highly relevant to AD and ALS. We show that a significant fraction of sAPP is generated in the soma and accumulates in a juxtanuclear ER subdomain. In neurites, sAPP localizes to Rtn4-positive ER-like tubules that extend from the soma into the growth cone and colocalizes with peripherin NFs. Knocking down peripherin disrupts the NF network and diminishes the accumulation of sAPP, TDP 43, FUS, SOD1 and Rtn4 at terminals. KEY MESSAGES: We propose that the impediment of a common, ER-mediated mechanism of transport of sAPP, TDP-43, FUS and SOD1, caused by a disrupted NF network, could be part of the mechanisms leading to AD and ALS. PMID- 26605912 TI - Multicentric Cancer Detected at Breast MR Imaging and Not at Mammography: Important or Not? AB - PURPOSE: To review the magnetic resonance (MR) imaging and pathologic features of multicentric cancer detected only at MR imaging and to evaluate its potential biologic value. MATERIALS AND METHODS: This retrospective study was institutional review board approved and HIPAA compliant; informed consent was waived. A review of records from 2001 to 2011 yielded 2021 patients with newly diagnosed breast cancer who underwent biopsy after preoperative MR imaging, 285 (14%) of whom had additional cancer detected at MR imaging that was occult at mammography. In 73 patients (3.6%), MR imaging identified 87 cancers in different quadrants than the known index cancer, constituting the basis of this report. In 62 of 73 patients (85%; 95% confidence interval [CI]: 75, 92), one additional cancer was found, and in 11 of 73 (15%; 95% CI: 8, 25), multiple additional cancers were found. A chi(2) test with adjustment for multiple lesions was used to examine whether MR imaging and pathologic features differ between the index lesion and additional multicentric lesions seen only at MR imaging. RESULTS: Known index cancers were more likely to be invasive than MR imaging-detected multicentric cancers (88% vs 76%, P = .023). Ductal carcinoma in situ (21 of 87 lesions [24%]; 95% CI: 15, 36) represented a minority of additional MR imaging-detected multicentric cancers. Overall, the size of MR imaging-detected multicentric invasive cancers (median, 0.6 cm; range, 0.1-6.3 cm) was smaller than that of the index cancer (median, 1.2 cm; range, 0.05-7.0 cm; P = .023), although 17 of 73 (23%) (95% CI: 14, 35) patients had larger MR imaging-detected multicentric cancers than the known index lesion, and 18 of 73 (25%) (95% CI: 15, 36) had MR imaging-detected multicentric cancers larger than 1 cm. MR imaging-detected multicentric cancers and index cancers differed in histologic characteristics, invasiveness, and grade in 27 of 73 (37%) patients (95% CI: 26, 49). In four of 73 (5%) patients (95% CI: 2, 13), MR imaging-detected multicentric cancers were potentially more biologically relevant because of the presence of unsuspected invasion or a higher grade. CONCLUSION: Multicentric cancer detected only at MR imaging was invasive in 66 of 87 patients (76%), larger than 1 cm in 18 of 73 patients (25%), larger than the known index cancer in 17 of 73 patients (23%), and more biologically important in four of 73 women (5%). An unsuspected additional multicentric cancer seen only at MR imaging is likely clinically relevant disease. PMID- 26605913 TI - Primary Prevention of Celiac Disease: Environmental Factors with a Focus on Early Nutrition. AB - Celiac disease (CD) is a common autoimmune disorder caused by ingestion of gluten. When diagnosed, it should be treated with a lifelong, strict gluten-free diet. Early infant feeding practices have been suggested as a means of preventing CD. In the last few decades, observational data have suggested that breastfeeding, especially at the time of introducing gluten into the infant's diet, as well as the time and mode of gluten first being given to a child could prevent or delay the occurrence of CD. As a result, recommendations advised that it is prudent to avoid both early (<4 months) and late (>7 months) introduction of gluten, and to introduce gluten gradually while the infant is still being breastfed, as this may reduce the risk of celiac disease, type 1 diabetes mellitus, and wheat allergy. Recently, the results of two large randomized trials have shown that breastfeeding in general, breastfeeding during gluten introduction, and early or delayed gluten introduction do not influence the total risk of CD in genetically predisposed individuals. Introducing gluten at 4 versus 6 months in very small amounts, or at 6 versus 12 months, resulted in similar rates of CD in these children. Thus, early feeding practices seem to have no impact on the risk of developing CD during childhood. In children without the genetic predisposition, the age and mode of gluten introduction do not influence the risk anyway. PMID- 26605914 TI - Hairy cell-like leukemia in a 9-year-old Friesian mare. PMID- 26605915 TI - What Do Eye Gaze Metrics Tell Us about Motor Imagery? AB - Many of the brain structures involved in performing real movements also have increased activity during imagined movements or during motor observation, and this could be the neural substrate underlying the effects of motor imagery in motor learning or motor rehabilitation. In the absence of any objective physiological method of measurement, it is currently impossible to be sure that the patient is indeed performing the task as instructed. Eye gaze recording during a motor imagery task could be a possible way to "spy" on the activity an individual is really engaged in. The aim of the present study was to compare the pattern of eye movement metrics during motor observation, visual and kinesthetic motor imagery (VI, KI), target fixation, and mental calculation. Twenty-two healthy subjects (16 females and 6 males), were required to perform tests in five conditions using imagery in the Box and Block Test tasks following the procedure described by Liepert et al. Eye movements were analysed by a non-invasive oculometric measure (SMI RED250 system). Two parameters describing gaze pattern were calculated: the index of ocular mobility (saccade duration over saccade + fixation duration) and the number of midline crossings (i.e. the number of times the subjects gaze crossed the midline of the screen when performing the different tasks). Both parameters were significantly different between visual imagery and kinesthesic imagery, visual imagery and mental calculation, and visual imagery and target fixation. For the first time we were able to show that eye movement patterns are different during VI and KI tasks. Our results suggest gaze metric parameters could be used as an objective unobtrusive approach to assess engagement in a motor imagery task. Further studies should define how oculomotor parameters could be used as an indicator of the rehabilitation task a patient is engaged in. PMID- 26605917 TI - Characterizing a Foraging Hotspot for Short-Finned Pilot Whales and Blainville's Beaked Whales Located off the West Side of Hawai'i Island by Using Tagging and Oceanographic Data. AB - Satellite tagging data for short-finned pilot whales (Globicephala macrorhynchus) and Blainville's beaked whales (Mesoplodon densirostris) were used to identify core insular foraging regions off the Kona (west) Coast of Hawai'i Island. Ship based active acoustic surveys and oceanographic model output were used in generalized additive models (GAMs) and mixed models to characterize the oceanography of these regions and to examine relationships between whale density and the environment. The regions of highest density for pilot whales and Blainville's beaked whales were located between the 1000 and 2500 m isobaths and the 250 and 2000 m isobaths, respectively. Both species were associated with slope waters, but given the topography of the area, the horizontal distribution of beaked whales was narrower and located in shallower waters than that of pilot whales. The key oceanographic parameters characterizing the foraging regions were bathymetry, temperature at depth, and a high density of midwater micronekton scattering at 70 kHz in 400-650 m depths that likely represent the island associated deep mesopelagic boundary community and serve as prey for the prey of the whales. Thus, our results suggest that off the Kona Coast, and potentially around other main Hawaiian Islands, the deep mesopelagic boundary community is key to a food web that supports insular cetacean populations. PMID- 26605916 TI - Use of Tethered Enzymes as a Platform Technology for Rapid Analyte Detection. AB - BACKGROUND: Rapid diagnosis for time-sensitive illnesses such as stroke, cardiac arrest, and septic shock is essential for successful treatment. Much attention has therefore focused on new strategies for rapid and objective diagnosis, such as Point-of-Care Tests (PoCT) for blood biomarkers. Here we use a biomimicry based approach to demonstrate a new diagnostic platform, based on enzymes tethered to nanoparticles (NPs). As proof of principle, we use oriented immobilization of pyruvate kinase (PK) and luciferase (Luc) on silica NPs to achieve rapid and sensitive detection of neuron-specific enolase (NSE), a clinically relevant biomarker for multiple diseases ranging from acute brain injuries to lung cancer. We hypothesize that an approach capitalizing on the speed and catalytic nature of enzymatic reactions would enable fast and sensitive biomarker detection, suitable for PoCT devices. METHODS AND FINDINGS: We performed in-vitro, animal model, and human subject studies. First, the efficiency of coupled enzyme activities when tethered to NPs versus when in solution was tested, demonstrating a highly sensitive and rapid detection of physiological and pathological concentrations of NSE. Next, in rat stroke models the enzyme-based assay was able in minutes to show a statistically significant increase in NSE levels in samples taken 1 hour before and 0, 1, 3 and 6 hours after occlusion of the distal middle cerebral artery. Finally, using the tethered enzyme assay for detection of NSE in samples from 20 geriatric human patients, we show that our data match well (r = 0.815) with the current gold standard for biomarker detection, ELISA-with a major difference being that we achieve detection in 10 minutes as opposed to the several hours required for traditional ELISA. CONCLUSIONS: Oriented enzyme immobilization conferred more efficient coupled activity, and thus higher assay sensitivity, than non-tethered enzymes. Together, our findings provide proof of concept for using oriented immobilization of active enzymes on NPs as the basis for a highly rapid and sensitive biomarker detection platform. This addresses a key challenge in developing a PoCT platform for time sensitive and difficult to diagnose pathologies. PMID- 26605918 TI - Abiotic Stresses Downregulate Key Genes Involved in Nitrogen Uptake and Assimilation in Brassica juncea L. AB - Abiotic stresses such as salinity, drought and extreme temperatures affect nitrogen (N) uptake and assimilation in plants. However, little is known about the regulation of N pathway genes at transcriptional level under abiotic stress conditions in Brassica juncea. In the present work, genes encoding nitrate transporters (NRT), ammonium transporters (AMT), nitrate reductase (NR), nitrite reductase (NiR), glutamine synthetase (GS), glutamate synthase (GOGAT), glutamate dehydrogenase (GDH), asparagines synthetase (ASN) were cloned from Brassica juncea L. var. Varuna. The deduced protein sequences were analyzed to predict their subcellular localization, which confirmed localization of all the proteins in their respective cellular organelles. The protein sequences were also subjected to conserved domain identification, which confirmed presence of characteristic domains in all the proteins, indicating their putative functions. Moreover, expression of these genes was studied after 1h and 24h of salt (150 mM NaCl), osmotic (250 mM Mannitol), cold (4 degrees C) and heat (42 degrees C) stresses. Most of the genes encoding nitrate transporters and enzymes responsible for N assimilation and remobilization were found to be downregulated under abiotic stresses. The expression of BjAMT1.2, BjAMT2, BjGS1.1, BjGDH1 and BjASN2 was downregulated after 1hr, while expression of BjNRT1.1, BjNRT2.1, BjNiR1, BjAMT2, BjGDH1 and BjASN2 was downregulated after 24h of all the stress treatments. However, expression of BjNRT1.1, BjNRT1.5 and BjGDH2 was upregulated after 1h of all stress treatments, while no gene was found to be upregulated after 24h of stress treatments, commonly. These observations indicate that expression of most of the genes is adversely affected under abiotic stress conditions, particularly under prolonged stress exposure (24h), which may be one of the reasons of reduction in plant growth and development under abiotic stresses. PMID- 26605919 TI - Visualized Exploratory Spatiotemporal Analysis of Hand-Foot-Mouth Disease in Southern China. AB - OBJECTIVES: In epidemiological research, major studies have focused on theoretical models; however, few methods of visual analysis have been used to display the patterns of disease distribution. DESIGN: For this study, a method combining the space-time cube (STC) with space-time scan statistics (STSS) was used to analyze the pattern of incidence of hand-foot-mouth disease (HFMD) in Guangdong Province from May 2008 to March 2009. In this research, STC was used to display the spatiotemporal pattern of incidence of HFMD, and STSS were used to detect the local aggregations of the disease. SETTING: The hand-foot-mouth disease data were obtained from Guangdong Province from May 2008 to March 2009, with a total of 68,130 cases. RESULTS: The STC analysis revealed a differential pattern of HFMD incidence among different months and cities and also showed that the population density and average precipitation are correlated with the incidence of HFMD. The STSS analysis revealed that the most likely aggregation includes the Shenzhen, Foshan and Dongguan populations, which are the most developed regions in Guangdong Province. CONCLUSION: Both STC and STSS are efficient tools for the exploratory data analysis of disease transmission. STC clearly displays the spatiotemporal patterns of disease. Using the maximum likelihood ratio, the STSS model precisely locates the most likely aggregation. PMID- 26605920 TI - Monitoring Change in Child Mortality through Household Surveys. AB - BACKGROUND: Most low- and middle-income countries lack fully functional civil registration systems. Measures of under-five mortality are typically derived from periodic household surveys collecting detailed information from women on births and child deaths. However, such surveys are expensive and are not appropriate for monitoring short-term changes in child mortality. We explored and tested the validity of two new analysis methods for less-expensive summary histories of births and child deaths for such monitoring in five African countries. METHODS AND FINDINGS: The first method we explored uses individual-level survey data on births and child deaths to impute full birth histories from an earlier survey onto summary histories from a more recent survey. The second method uses cohort changes between two surveys in the average number of children born and the number of children dead by single year of age to estimate under-five mortality for the inter-survey period. The first method produces acceptable annual estimates of under-five mortality for two out of six applications to available data sets; the second method produced an acceptable estimate in only one of five applications, though none of the applications used ideal data sets. CONCLUSIONS: The methods we tested were not able to produce consistently good quality estimates of annual under-five mortality from summary birth history data. The key problem we identified was not with the methods themselves, but with the underlying quality of the summary birth histories. If summary birth histories are to be included in general household surveys, considerable emphasis must be placed on quality control. PMID- 26605922 TI - Management of severe osteoporosis. AB - INTRODUCTION: Severe osteoporosis represents a disease of high mortality and morbidity. Recognition of what constitutes and causes severe osteoporosis and aggressive intervention with pharmacological agents with evidence to reduce fracture risk are outlined in this review. AREAS COVERED: This review is a blend of evidence obtained from literature searches from PubMed and The National Library of Medicine (USA), clinical experience and the author's opinions. The review covers the recognition of what constitutes severe osteoporosis, and provides up-to-date references on this sub-set of high risk patients. EXPERT OPINION: Severe osteoporosis can be classified by using measurements of bone densitometry, identification of prevalent fractures, and, knowledge of what additional risk factors contribute to high fracture risk. Once recognized, the potential consequences of severe osteoporosis can be mitigated by appropriate selection of pharmacological therapies and modalities to reduce the risk for falling. PMID- 26605921 TI - Inducible Knock-Down of the Mineralocorticoid Receptor in Mice Disturbs Regulation of the Renin-Angiotensin-Aldosterone System and Attenuates Heart Failure Induced by Pressure Overload. AB - Mineralocorticoid receptor (MR) inactivation in mice results in early postnatal lethality. Therefore we generated mice in which MR expression can be silenced during adulthood by administration of doxycycline (Dox). Using a lentiviral approach, we obtained two lines of transgenic mice harboring a construct that allows for regulatable MR inactivation by RNAi and concomitant expression of eGFP. MR mRNA levels in heart and kidney of inducible MR knock-down mice were unaltered in the absence of Dox, confirming the tightness of the system. In contrast, two weeks after Dox administration MR expression was significantly diminished in a variety of tissues. In the kidney, this resulted in lower mRNA levels of selected target genes, which was accompanied by strongly increased serum aldosterone and plasma renin levels as well as by elevated sodium excretion. In the healthy heart, gene expression and the amount of collagen were unchanged despite MR levels being significantly reduced. After transverse aortic constriction, however, cardiac hypertrophy and progressive heart failure were attenuated by MR silencing, fibrosis was unaffected and mRNA levels of a subset of genes reduced. Taken together, we believe that this mouse model is a useful tool to investigate the role of the MR in pathophysiological processes. PMID- 26605923 TI - Predator Presence and Vegetation Density Affect Capture Rates and Detectability of Litoria aurea Tadpoles: Wide-Ranging Implications for a Common Survey Technique. AB - Trapping is a common sampling technique used to estimate fundamental population metrics of animal species such as abundance, survival and distribution. However, capture success for any trapping method can be heavily influenced by individuals' behavioural plasticity, which in turn affects the accuracy of any population estimates derived from the data. Funnel trapping is one of the most common methods for sampling aquatic vertebrates, although, apart from fish studies, almost nothing is known about the effects of behavioural plasticity on trapping success. We used a full factorial experiment to investigate the effects that two common environmental parameters (predator presence and vegetation density) have on the trapping success of tadpoles. We estimated that the odds of tadpoles being captured in traps was 4.3 times higher when predators were absent compared to present and 2.1 times higher when vegetation density was high compared to low, using odds ratios based on fitted model means. The odds of tadpoles being detected in traps were also 2.9 times higher in predator-free environments. These results indicate that common environmental factors can trigger behavioural plasticity in tadpoles that biases trapping success. We issue a warning to researchers and surveyors that trapping biases may be commonplace when conducting surveys such as these, and urge caution in interpreting data without consideration of important environmental factors present in the study system. Left unconsidered, trapping biases in capture success have the potential to lead to incorrect interpretations of data sets, and misdirection of limited resources for managing species. PMID- 26605924 TI - Phenotypic and Functional Properties of Human Steady State CD14+ and CD1a+ Antigen Presenting Cells and Epidermal Langerhans Cells. AB - Cutaneous antigen presenting cells (APCs) are critical for the induction and regulation of skin immune responses. The human skin contains phenotypically and functionally distinct APCs subsets that are present at two separated locations. While CD1ahigh LCs form a dense network in the epidermis, the CD14+ and CD1a+ APCs reside in the dermal compartment. A better understanding of the biology of human skin APC subsets is necessary for the improvement of vaccine strategies that use the skin as administration route. In particular, progress in the characterization of uptake and activatory receptors will certainly improve APC targeting strategies in vaccination. Here we performed a detailed analysis of the expression and function of glycan-binding and pattern-recognition receptors in skin APC subsets. The results demonstrate that under steady state conditions human CD1a+ dermal dendritic cells (DCs) were phenotypically most mature as measured by the expression of CD83 and CD86, whereas the CD14+ cells showed a higher expression of the CLRs DC-SIGN, mannose receptor and DCIR and had potent antigen uptake capacity. Furthermore, steady state LCs showed superior antigen cross-presentation as compared to the dermal APC subsets. Our results also demonstrate that the TLR3 ligand polyribosinic-polyribocytidylic acid (pI:C) was the most potent stimulator of cytokine production by both LCs and dDCs. These studies warrant further exploration of human CD1a+ dDCs and LCs as target cells for cancer vaccination to induce anti-tumor immune responses. PMID- 26605925 TI - Preventing and Treating Narcotic Addiction--Century of Federal Drug Control. PMID- 26605926 TI - Intensity of Chronic Pain--The Wrong Metric? PMID- 26605927 TI - Nourishment. PMID- 26605929 TI - Treatment of Tuberculosis. PMID- 26605930 TI - IMAGES IN CLINICAL MEDICINE. Acrokeratosis Paraneoplastica. PMID- 26605928 TI - A Randomized Trial of Progesterone in Women with Recurrent Miscarriages. AB - BACKGROUND: Progesterone is essential for the maintenance of pregnancy. However, whether progesterone supplementation in the first trimester of pregnancy would increase the rate of live births among women with a history of unexplained recurrent miscarriages is uncertain. METHODS: We conducted a multicenter, double blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twice-daily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation. RESULTS: A total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, -4.0 to 9.0). There were no significant between-group differences in the rate of adverse events. CONCLUSIONS: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages. (Funded by the United Kingdom National Institute of Health Research; PROMISE Current Controlled Trials number, ISRCTN92644181.). PMID- 26605931 TI - CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 37-2015. A 76-Year-Old Man with Fevers, Leukopenia, and Pulmonary Infiltrates. PMID- 26605932 TI - Cardiovascular Risk and Sodium-Glucose Cotransporter 2 Inhibition in Type 2 Diabetes. PMID- 26605933 TI - Resolvin Infectious Inflammation by Targeting the Host Response. PMID- 26605934 TI - Cavity Shave Margins in Breast Cancer. PMID- 26605935 TI - Cavity Shave Margins in Breast Cancer. PMID- 26605936 TI - Cavity Shave Margins in Breast Cancer. PMID- 26605937 TI - Cavity Shave Margins in Breast Cancer. PMID- 26605939 TI - Palliative Care. PMID- 26605940 TI - Palliative Care. PMID- 26605941 TI - Hypoplastic Metatarsals--Beyond Cosmesis. PMID- 26605942 TI - VIDEOS IN CLINICAL MEDICINE. Insertion of an Intracranial-Pressure Monitor. PMID- 26605943 TI - IMAGES IN CLINICAL MEDICINE. Amaurosis Fugax Caused by a Branch Retinal Artery Embolus. PMID- 26605944 TI - Protective Effects of Lactobacillus plantarum CCFM8246 against Copper Toxicity in Mice. AB - Lactobacillus plantarum CCFM8246, which has a relatively strong copper binding capacity and tolerance to copper ions, was obtained by screening from 16 lactic acid bacteria in vitro. The selected strain was then applied to a mouse model to evaluate its protective function against copper intoxication in vivo. The experimental mice were divided into an intervention group and a therapy group; mice in the intervention group received co-administration of CCFM8246 and a copper ion solution by gavage, while mice in the therapy group were treated with CCFM8246 after 4 weeks of copper exposure. In both two groups, mice treated with copper alone and that treated with neither CCFM8246 nor copper served as positive and negative controls, respectively. At the end of the experimental period, the copper content in feces and tissues, the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, and oxidation stress indices in liver and kidney tissue were determined. Learning and memory ability was evaluated by Morris water maze experiments. The results indicated that treatment with CCFM8246 significantly increased the copper content in feces to promote copper excretion, reduce the accumulation of copper in tissues, reverse oxidative stress induced by copper exposure, recover the ALT and AST in serum and improve the spatial memory of mice. PMID- 26605945 TI - SPO73 and SPO71 Function Cooperatively in Prospore Membrane Elongation During Sporulation in Saccharomyces cerevisiae. AB - In the yeast Saccharomyces cerevisiae, cells undergoing sporulation form prospore membranes to surround their meiotic nuclei. The prospore membranes ultimately become the plasma membranes of the new cells. The putative phospholipase Spo1 and the tandem Pleckstrin Homology domain protein Spo71 have previously been shown to be required for prospore membrane development, along with the constitutively expressed Vps13 involved in vacuolar sorting. Here, we utilize genetic analysis, and find that SPO73 is required for proper prospore membrane shape and, like SPO71, is necessary for prospore membrane elongation. Additionally, similar to SPO71, loss of SPO73 partially suppresses spo1Delta. Spo73 localizes to prospore membranes and complexes with Spo71. We also find that phosphatidylserine localizes to the prospore membrane. Our results suggest a model where SPO71 and SPO73 act in opposition to SPO1 to form and elongate prospore membranes, while VPS13 plays a distinct role in prospore membrane development. PMID- 26605946 TI - Detection of Endogenous Iron Reduction during Hepatocarcinogenesis at Susceptibility-Weighted MR Imaging: Value for Characterization of Hepatocellular Carcinoma and Dysplastic Nodule in Cirrhotic Liver. AB - OBJECTIVE: To investigate the value of susceptibility-weighted imaging (SWI) for characterization of hepatocellular carcinoma (HCC) and dysplastic nodule (DN). MATERIALS AND METHODS: Sixty-eight cirrhotic patients with 89 hepatocellular nodules underwent SWI. The radiological features of hepatocellular nodules on SWI were classified into three types: type A (iso- or hypointensity, and background liver siderosis), type B (hyperintensity, and background liver siderosis), or type C (hyperintensity, and no background liver siderosis). Intranodular and background liver iron content was quantified and correlated with SWI pattern. Prussian blue staining was performed to quantify intranodular and background liver iron content. RESULTS: Type A pattern (n = 12) contained 11 (91.7%) DNs and 1 (8.3%) HCC, Type B pattern (n = 66) comprised 1 (1.5%) DN and 65 (98.5%) HCCs (including 12 DN-HCCs and 53 overt HCCs), and type C pattern (n = 11) was exclusively seen in HCCs. The iron scores of DN-HCCs and overt HCCs were significantly lower than those of background livers [(0.091+/-0.30) VS (2.18+/ 0.87), P = 0.000; (0.11+/-0.41) VS (2.16+/-0.97), P = 0.000; respectively]. There was no significant difference between iron scores of DNs and those of background livers [(1.92+/-0.29) VS (2.17+/-039), P = 0.191]. For lesion-based and patient based analysis of HCCs (DN-HCCs and overt HCCs), type B pattern showed a sensitivity, specificity, accuracy, positive predicative value (PPV), and negative predicative value (NPV) of 84.4% and 84.4%, 91.7% and 75%, 85.4% and 83.8%, 98.5% and 98.2%, 47.8% and 23.1%, respectively. CONCLUSION: SWI can provide valuable information for characterization of HCC and DN based on endogenous iron reduction during hepatocarcinogenesis. PMID- 26605947 TI - Social Constructions of Stigmatizing Discourse Around Type 2 Diabetes Diagnoses in Appalachian Kentucky. AB - Type 2 diabetes is a growing problem among Appalachian Kentucky residents. Several issues contribute to diabetes disparities in the region, including lack of access to health care and geographic isolation. Previous studies also indicate that social stigma may be associated with type 2 diabetes. We used 28 semistructured interviews to explore how stigma is socially constructed across health status (diagnosed/undiagnosed). Perceived severity of the disease is high, yet the etiology of diabetes is not well understood. Thus, onset is perceived to occur "out of the blue," and a positive diagnosis is perceived as having life threatening consequences. Diagnosed participants, who had learned more about the disease's etiology, prevention, and management, expressed intrapersonal stigma. In interpersonal situations, the visible indicators of a diabetes diagnosis (i.e., physical weight, insulin injection), rather than diagnosis status, tended to evoke stigmatizing interactions. These findings form the foundation for our recommendations for prevention messages in the region. PMID- 26605949 TI - Foreword. PMID- 26605948 TI - Impact of Pre-Analytical Variables on Cancer Targeted Gene Sequencing Efficiency. AB - Tumor specimens are often preserved as formalin-fixed paraffin-embedded (FFPE) tissue blocks, the most common clinical source for DNA sequencing. Herein, we evaluated the effect of pre-sequencing parameters to guide proper sample selection for targeted gene sequencing. Data from 113 FFPE lung tumor specimens were collected, and targeted gene sequencing was performed. Libraries were constructed using custom probes and were paired-end sequenced on a next generation sequencing platform. A PCR-based quality control (QC) assay was utilized to determine DNA quality, and a ratio was generated in comparison to control DNA. We observed that FFPE storage time, PCR/QC ratio, and DNA input in the library preparation were significantly correlated to most parameters of sequencing efficiency including depth of coverage, alignment rate, insert size, and read quality. A combined score using the three parameters was generated and proved highly accurate to predict sequencing metrics. We also showed wide read count variability within the genome, with worse coverage in regions of low GC content like in KRAS. Sample quality and GC content had independent effects on sequencing depth, and the worst results were observed in regions of low GC content in samples with poor quality. Our data confirm that FFPE samples are a reliable source for targeted gene sequencing in cancer, provided adequate sample quality controls are exercised. Tissue quality should be routinely assessed for pre-analytical factors, and sequencing depth may be limited in genomic regions of low GC content if suboptimal samples are utilized. PMID- 26605950 TI - Korean Immigrant Motherhood: Child-Rearing and Child Weight. AB - Health problems among immigrant children may persist not only throughout childhood but also into adulthood. The purpose of this study was to elicit information about Korean immigrant mothers' experiences with parenting, immigration, and raising their children in the United States. Four focus group interviews were conducted in the Chicago metropolitan area. Content analysis showed that Korean immigrant mothers practice intensive parenting and worry about it. They described the strategies they use to raise healthy children. Culturally appropriate intervention programs are needed to reduce stress, encourage a healthy lifestyle, and link this to the health of their children. PMID- 26605951 TI - Duration of US Residence Is Associated With Overweight Risk in Filipino Immigrants Living in New York Metro Area. AB - We examined the association between years living in the United States and overweight risk among a community sample of Filipino adult immigrants living in the New York metropolitan area. We found a significant and adverse association between years living in the United States and overweight risk. Compared with Filipinos who lived in the United States less than 5 years, those who lived in the United States 10 years or longer had a higher overweight risk; this association was present only among Filipinos who migrated to New York metropolitan area at 30 years of age or younger. Studies on causal mechanisms explaining this pattern are needed. PMID- 26605952 TI - An Exploratory Study of Internal Migration and Substance Use Among an Indigenous Community in Southern Mexico. AB - The primary aim of this study was to explore the association between internal migration experience within Mexico and lifetime substance use among a sample of 442 indigenous persons from Yucatan, Mexico. Adjusting for potential confounding, correlates of lifetime substance use were assessed among participants with and without internal migration experience. Internal migration to a tourist destination was independently associated with higher odds (adjusted odds ratio: 2.1; 95% confidence interval: 1.3-3.4) of reporting lifetime substance use. Findings suggest that environmental contexts of internal migration may be of importance in shaping vulnerability to substance use. PMID- 26605953 TI - Mental Health and Sociocultural Determinants in an Asian Indian Community. AB - In a US population of adult male and female Sikh immigrant participants (N = 350), we explored sociocultural factors related to depression, giving participants a choice between English or Punjabi surveys. Language preference pointed to a subgroup with higher levels of depression and lower satisfaction with life. Underreporting of depression suggests a general reluctance to discuss depression. While multiple sociocultural variables were associated with depression bivariably, multivariate analysis identified negative religious coping and anxiety as unique predictors of depression. Community interventions should tap into the protective close-knit social fabric of this community as an opportunity to change the stigma of mental health. PMID- 26605954 TI - Development of the Stress of Immigration Survey: A Field Test Among Mexican Immigrant Women. AB - The Stress of Immigration Survey (SOIS) is a screening tool used to assess immigration-related stress. The mixed methods approach included concept development, pretesting, field testing, and psychometric evaluation in a sample of 131 low-income women of Mexican descent. The 21-item SOIS screens for stress related to language, immigrant status, work issues, yearning for family and home country, and cultural dissonance. Mean scores ranged from 3.6 to 4.4 (a scale of 1-5, higher is more stress). Cronbach alpha values were more than 0.80 for all subscales. The SOIS may be a useful screening tool for detecting high levels of immigration-related stress in low-income Mexican immigrant women. PMID- 26605955 TI - Community Health Worker Perspectives on Recruitment and Retention of Recent Immigrant Women in a Randomized Clinical Trial. AB - This study explores the recruitment and retention strategies used by community health workers who enrolled Korean Americans in a church-based, randomized trial to promote mammogram and Papanicolaou tests and retained them for 6 months. We conducted 4 focus groups with 23 community health workers. Data were analyzed using a thematic analysis. Themes were identified in relation to recruitment: personal networks, formal networks at churches, building on trust and respect, and facilitating a nonthreatening environment. Themes were identified for retention: trust and peer support. Qualified, well-trained community health workers can recruit and retain hard-to-reach immigrant women in a randomized trial by using multiple culturally sensitive strategies. PMID- 26605956 TI - Access to and Use of Health Care Services Among Latinos in East Los Angeles and Boyle Heights. AB - This study examined differences in access, utilization, and barriers to health care by nativity, language spoken at home, and insurance status in East Los Angeles and Boyle Heights, California. Data from household interviews of neighborhood residents conducted as part of a corner store intervention project were used. Binary and multinomial logistic regression models were fitted. Results showed that uninsured and foreign-born individuals were differentially affected by lack of access to and utilization of health care. While the Affordable Care Act may ameliorate some disparities, the impact will be limited because of the exclusion of key groups, like the undocumented, from benefits. PMID- 26605957 TI - Quality assurance in MRI breast screening: comparing signal-to-noise ratio in dynamic contrast-enhanced imaging protocols. AB - MRI has been extensively used in breast cancer staging, management and high risk screening. Detection sensitivity is paramount in breast screening, but variations of signal-to-noise ratio (SNR) as a function of position are often overlooked. We propose and demonstrate practical methods to assess spatial SNR variations in dynamic contrast-enhanced (DCE) breast examinations and apply those methods to different protocols and systems. Four different protocols in three different MRI systems (1.5 and 3.0 T) with receiver coils of different design were employed on oil-filled test objects with and without uniformity filters. Twenty 3D datasets were acquired with each protocol; each dataset was acquired in under 60 s, thus complying with current breast DCE guidelines. In addition to the standard SNR calculated on a pixel-by-pixel basis, we propose other regional indices considering the mean and standard deviation of the signal over a small sub-region centred on each pixel. These regional indices include effects of the spatial variation of coil sensitivity and other structured artefacts. The proposed regional SNR indices demonstrate spatial variations in SNR as well as the presence of artefacts and sensitivity variations, which are otherwise difficult to quantify and might be overlooked in a clinical setting. Spatial variations in SNR depend on protocol choice and hardware characteristics. The use of uniformity filters was shown to lead to a rise of SNR values, altering the noise distribution. Correlation between noise in adjacent pixels was associated with data truncation along the phase encoding direction. Methods to characterise spatial SNR variations using regional information were demonstrated, with implications for quality assurance in breast screening and multi-centre trials. PMID- 26605958 TI - Dementia with Lewy bodies: The emerging role of primary care. AB - INTRODUCTION: Dementia with Lewy bodies (DLB) is an under recognized but frequent subtype of dementia. Misdiagnosis and delays in referral from primary care are common when compared to other forms of dementia. CASE: We present a case of a 63 year-old man who was eventually diagnosed with DLB three and a half years after his initial presentation. DISCUSSION: Core features of DLB such as hallucinations, Parkinsonism and fluctuating levels of cognition need to be recognized in primary care as being part of the DLB phenotype. DLB is a complex and debilitating neurodegenerative disorder often requiring multidisciplinary support to enable affected individuals to live well in the community. Carers of DLB patients often develop higher levels of subjective burden compared to carers of patients with other forms of dementia; this needs to be recognized and managed appropriately. There is limited research into the role of primary care physicians in DLB. Efforts should be made to reduce delays in identification. CONCLUSION: Primary care has an important role in identifying those who are at risk for DLB and in referring these patients timely to the appropriate specialist. Adequate management of these patients in the community might reduce the burden associated with the DLB phenotype. PMID- 26605959 TI - Promotion of Well-being During Treatment for Childhood Cancer: A Literature Review of Art Interventions as a Coping Strategy. AB - BACKGROUND: Scientific literature suggests that art interventions can assist children with cancer cope with physical and psychosocial difficulties associated with cancer treatment. Little is known about how the making of tangible visual art can be helpful and which proposed therapeutic mechanisms are clinically important. OBJECTIVE: The purpose of this literature review is to assess and synthesize the research evidence regarding the role of art therapy/art-making interventions for promoting the well-being of children with cancer undergoing treatment. METHODS: A search of electronic databases (MEDLINE [PubMed], CINAHL, PsycINFO) and EBM Reviews including Cochrane Database of Systematic Reviews (OVID) and manual review of references in articles accessed were undertaken. Inclusion criteria were as follows: research studies of any design; children with cancer undergoing treatment (2-21 years old), and art therapy/art-making intervention. Data extraction and quality appraisal were undertaken. Data were analyzed with an author-developed review sheet and synthesized into a table. RESULTS: Six articles reporting 6 studies met the inclusion criteria. Studies were based on qualitative (n = 3) and mixed quantitative/qualitative (n = 3) methodologies. Three outcome categories emerged that outline potential therapeutic roles of art interventions. CONCLUSIONS: Though sparse and developmental in nature, the existing evidence suggests that art interventions may potentially promote the well-being of children undergoing cancer treatment by reducing anxiety, fear, and pain and promoting collaborative behaviors; enhancing communication with the treatment team; and counteracting the disruption of selfhood that cancer treatment evokes. IMPLICATIONS FOR PRACTICE: Further and higher-quality research is warranted before routinely integrating standardized art interventions into the treatment protocols for children with cancer. PMID- 26605961 TI - Universality in eye movements and reading: A trilingual investigation. AB - Universality in language has been a core issue in the fields of linguistics and psycholinguistics for many years (e.g., Chomsky, 1965). Recently, Frost (2012) has argued that establishing universals of process is critical to the development of meaningful, theoretically motivated, cross-linguistic models of reading. In contrast, other researchers argue that there is no such thing as universals of reading (e.g., Coltheart & Crain, 2012). Reading is a complex, visually mediated psychological process, and eye movements are the behavioural means by which we encode the visual information required for linguistic processing. To investigate universality of representation and process across languages we examined eye movement behaviour during reading of very comparable stimuli in three languages, Chinese, English and Finnish. These languages differ in numerous respects (character based vs. alphabetic, visual density, informational density, word spacing, orthographic depth, agglutination, etc.). We used linear mixed modelling techniques to identify variables that captured common variance across languages. Despite fundamental visual and linguistic differences in the orthographies, statistical models of reading behaviour were strikingly similar in a number of respects, and thus, we argue that their composition might reflect universality of representation and process in reading. PMID- 26605960 TI - Language lateralization of hearing native signers: A functional transcranial Doppler sonography (fTCD) study of speech and sign production. AB - Neuroimaging studies suggest greater involvement of the left parietal lobe in sign language compared to speech production. This stronger activation might be linked to the specific demands of sign encoding and proprioceptive monitoring. In Experiment 1 we investigate hemispheric lateralization during sign and speech generation in hearing native users of English and British Sign Language (BSL). Participants exhibited stronger lateralization during BSL than English production. In Experiment 2 we investigated whether this increased lateralization index could be due exclusively to the higher motoric demands of sign production. Sign naive participants performed a phonological fluency task in English and a non-sign repetition task. Participants were left lateralized in the phonological fluency task but there was no consistent pattern of lateralization for the non sign repetition in these hearing non-signers. The current data demonstrate stronger left hemisphere lateralization for producing signs than speech, which was not primarily driven by motoric articulatory demands. PMID- 26605962 TI - Young children show representational flexibility when interpreting drawings. AB - Drawings can be ambiguous and represent more than one entity. In three experiments, we examine whether young children show representational flexibility by allowing one picture to be called by a second name. We also evaluate the hypothesis that children who are representationally flexible see the artist's intention as binding, rather than changeable. In Experiment 1, an artist declared what she intended to draw (e.g. a balloon) but then produced an ambiguous drawing. Children were asked whether the drawings could be interpreted differently (e.g. 'could this be a lollipop?') in the presence of a perceptually similar or dissimilar distractor (e.g., lollipop or snake). Six-year-olds accepted two labels for drawings in both conditions, but four-year-olds only did so in the dissimilar condition. Experiment 2 probed each possible interpretation more deeply by asking property questions (e.g., 'does it float?, does it taste good?'). Preschoolers who understood that the ambiguous drawing could be given two interpretations nevertheless mostly endorsed only properties associated with the prior intent. Experiment 3 provided converging evidence that 4-year-olds were representationally flexible using a paradigm that did not rely upon modal questioning. Taken together, our results indicate that even 4-year-olds understand that pictures may denote more than one referent, they still think of the symbol as consistent with the artist's original intention. PMID- 26605964 TI - Functional polymorphisms in the IL6 gene promoter and the risk of urinary bladder cancer in India. AB - BACKGROUND: Interleukin-6 is a multifunctional cytokine, which plays a key role in tumor proliferation and differentiation. Variations in its gene (IL6) sequence may affect the risk of developing various cancers, including urinary bladder cancer. The present study was done to find the association of functional polymorphisms in the IL6 promoter with urinary bladder cancer. MATERIALS AND METHODS: Single nucleotide polymorphisms were genotyped in histologically confirmed 232 cases of urinary bladder cancer and 250 healthy controls. The controls subjects were matched to the cases by age, sex, and ethnicity. Genotyping of the polymorphisms (-174G>C; -572G>C, -596A>G) was undertaken by direct DNA sequencing. The level of association between the genotypes and urinary bladder cancer risk was estimated by odds ratios and 95% confidence intervals generated by applying the chi-square test. Linkage disequilibrium (LD) between SNPs and haplotype analysis were performed using Haploview software. RESULT: Significantly higher number of smokers (p=0.047), tobacco chewers (p=<0.001) and those with non-vegetarian food habits (p=0.016) were seen in the case group. The distribution of genotypes at -174G>C locus differed significantly between cases and controls and the variant genotypes GC+CC were significantly rarer in the cases (p=0.00073; OR=0.52 95% CI 0.35-0.75). Variant genotypes (GC+CC) were more common in grade I than grade III tumors (p=0.032), further suggesting a protective effect. No LD was found between the SNPs; however, the frequency of haplotype AGC was significantly lesser in the cases than controls (p=0.0103), suggesting a protective effect. Genotype distribution at the other two loci ( 572G>C and -596A>G) did not show association with bladder cancer. CONCLUSIONS: IL6 (-174G>C) substitution confers significant protection against the risk of urinary bladder cancer in the study population, while other substitutions in this gene (-572G>C and -596A>G) do not affect the risk. In general, there is a lack of studies on the cytokine gene polymorphisms in urinary bladder cancer. PMID- 26605965 TI - Metabolic adaptation of tissues to stress releases metabolites influencing innate immunity. AB - Recent developments have demonstrated that metabolic rewiring imposed by adaptation of tissues to stress leads to the release of various metabolites which directly or indirectly impact innate immune responses and inflammation. Some metabolites can behave as second messengers and leave local cues in tissues. Immune cells which infiltrate stressed tissues reorient their metabolism to cope with these microenvironmental cues while preserving their effector functions in tissues. PMID- 26605963 TI - Comprehension priming as rational expectation for repetition: Evidence from syntactic processing. AB - Why do comprehenders process repeated stimuli more rapidly than novel stimuli? We consider an adaptive explanation for why such facilitation may be beneficial: priming is a consequence of expectation for repetition due to rational adaptation to the environment. If occurrences of a stimulus cluster in time, given one occurrence it is rational to expect a second occurrence closely following. Leveraging such knowledge may be particularly useful in online processing of language, where pervasive clustering may help comprehenders negotiate the considerable challenge of continual expectation update at multiple levels of linguistic structure and environmental variability. We test this account in the domain of structural priming in syntax, making use of the sentential complement direct object (SC-DO) ambiguity. We first show that sentences containing SC continuations cluster in natural language, motivating an expectation for repetition of this structure. Second, we show that comprehenders are indeed sensitive to the syntactic clustering properties of their current environment. In a series of between-groups self-paced reading studies, we find that participants who are exposed to clusters of SC sentences subsequently process repetitions of SC structure more rapidly than participants who are exposed to the same number of SCs spaced in time, and attribute the difference to the learned degree of expectation for repetition. We model this behavior through Bayesian belief update, showing that (the optimal degree of) sensitivity to clustering properties of syntactic structures is indeed learnable through experience. Comprehension priming effects are thus consistent with rational expectation for repetition based on adaptation to the linguistic environment. PMID- 26605966 TI - Effects of bandwidth feedback on the automatization of an arm movement sequence. AB - We examined the effects of a bandwidth feedback manipulation on motor learning. Effects on movement accuracy, as well as on movement consistency, have been addressed in earlier studies. We have additionally investigated the effects on motor automatization. Because providing error feedback is believed to induce attentional control processes, we suppose that a bandwidth method should facilitate motor automatization. Participants (N=48) were assigned to four groups: one control group and three intervention groups. Participants of the intervention groups practiced an arm movement sequence with 760 trials. The BW0 Group practiced with 100% frequency of feedback. For the BW10-Group, feedback was provided when the errors were larger than 10 degrees . The YokedBW10-Group participants were matched to the feedback schedule of research twins from the BW10-Group. All groups performed pre-tests and retention tests with a secondary task paradigm to test for automaticity. The BW10-Group indicated a higher degree of automatization compared with the BW0-Group, which did not exhibit a change in automaticity. The comparison of the YokedBW10-Group, which also exhibited automatization, and the BW10-Group leads to the proposal that reduction of quantitative feedback frequency and additional positive feedback are responsible for the bandwidth effect. Differences in movement accuracy and consistency were not evident. PMID- 26605967 TI - Automated Ptosis Measurements From Facial Photographs. AB - IMPORTANCE: Measurements of the margin reflex distances 1 and 2 are crucial for the surgical planning of ptosis repair and blepharoplasty. Facial photographs annotated with automated measurements of eyelid position could provide objective, accurate, and reproducible documentation of these features. OBJECTIVES: To describe a software algorithm for determining the margin reflex distances 1 and 2 from facial photographs and to evaluate its agreement with manual measurements of the margin reflex distances 1 and 2. DESIGN, SETTING, AND PARTICIPANTS: Observational study at a single-surgeon oculoplastic private practice among 55 eyes of 28 adult volunteers. The study dates were July 30, 2014, to September 12, 2014. The dates of our analysis were October 12, 2014, to June 18, 2015. MAIN OUTCOMES AND MEASURES: Agreement between manual and automated measurements of the margin reflex distances 1 and 2. RESULTS: Among 55 eyes of 28 participants, automated margin reflex distance 1 measurements were strongly correlated with manual measurements (r = 0.97; 95% CI, r = 0.95 to r = 0.98; P < .001). The bias of automated margin reflex distance 1 measurements was 0.03 mm (95% CI, -0.06 to 0.12 mm), with 95% confidence limits of -0.66 and 0.71 mm. Automated margin reflex distance 2 measurements were strongly correlated with manual measurements (r = 0.96; 95% CI, r = 0.93 to r = 0.98; P < .001). The bias of automated margin reflex distance 2 measurements was 0.13 mm (95% CI, 0.03-0.22 mm), with 95% confidence limits of -0.54 and 0.80 mm. CONCLUSIONS AND RELEVANCE: Automated ptosis measurements produced by our software algorithm compare favorably with manually performed clinical measurements. An automated, photography-based system could provide an archival and highly reproducible means for obtaining the margin reflex distances 1 and 2 and other facial morphometric data. PMID- 26605968 TI - The development and implementation of a theory-informed, integrated mother-child intervention in rural Uganda. AB - RATIONALE: A randomised cluster effectiveness trial of a parenting intervention in rural Uganda found benefits to child development among children 12-36 months, relevant parenting practices related to stimulation, hygiene and diet, and prevented the worsening of mothers' depressive symptoms. An examination of underlying implementation processes allows researchers and program developers to determine whether the program was implemented as intended and highlight barriers and facilitators that may influence replication and scale-up. OBJECTIVES: The objectives of this study were to describe and critically examine (a) perceived barriers and facilitators related to implementation processes of intervention content, training and supervision and delivery from the perspectives of delivery agents and supervisors; (b) perceived barriers and facilitators related to enactment of practices from the perspective of intervention mothers participating in the parenting program; and c) whether the program was implemented as intended. METHODS: Semi-structured interviews were conducted at midline with peer delivery agents (n = 12) and intervention mothers (n = 31) and at endline with supervisors (n = 4). Content analysis was used to analyze qualitative data in terms of barriers and facilitators of intervention content, training and supervision, delivery and enactment. Additionally, mothers' recall and enactment of practices were coded and analyzed statistically. Monitoring of group sessions and home visits were examined to reveal whether the program was implemented as intended. RESULTS: Among the program's five key messages, 'love and respect' targeting maternal psychological well-being was the most practiced by mothers, easiest to implement by delivery agents, and mothers reported the most internal facilitators for this message. A detailed manual and structured monitoring forms were perceived to facilitate training, intervention delivery, and supervision. Interactive and active strategies based on social-cognitive learning theory were reported as facilitators to intervention delivery. Only program attendance, but not barriers, facilitators or message recall, was significantly positively related to message enactment. Monitoring of group sessions and home visits showed that the program was largely implemented as intended. CONCLUSIONS: This implementation assessment revealed a number of important barriers and facilitators from the perspectives of delivery agents, supervisors and program participants. The methods and results are useful to examining and informing the content, delivery, and scaling up of the current program as well as future mother child interventions in LMIC settings. PMID- 26605969 TI - Associations between parental hearing impairment and children's mental health: Results from the Nord-Trondelag Health Study. AB - BACKGROUND: Some previous studies indicate that parental hearing loss may have negative consequences in the parent-child relationship. However, most of these studies are qualitative or have apparent methodological shortcomings. OBJECTIVE: This study is the first of its kind conducted in a large population-based sample with audiometrically measured hearing loss aimed at investigating the extent to which parental hearing loss affects adolescents' mental health. METHODS: Questionnaires were administered to the adult (>19 years) and adolescent (age 13 19 years) population of Nord-Trondelag county, Norway (1995-97), which collected information on mental and somatic health, including hearing loss. For adults participating in the study, pure tone audiometry tests were also administered. In total, 4047 fathers and 4785 mothers with self-reported hearing loss data were identified. The corresponding numbers with measured hearing loss data included 4079 fathers and 4861 mothers. The associations between the degrees of self reported or measured parental hearing loss and the mental health of their adolescent, measured by Hopkins Symptom Check List (SCL) 5, were estimated using generalized estimating equations. After adjusting for several covariates, the mental health symptoms of adolescents were compared by parental hearing loss (i.e., with versus without hearing loss). RESULTS: Adolescents whose mothers had severe measured or self-reported hearing loss had significantly worse mental health than their counterparts whose mothers did not have a hearing loss. No corresponding effects were found in the adolescents whose mothers had only a slight/moderate hearing loss, neither measured nor self-reported. Paternal slight/moderate self-reported hearing loss was associated with a small significant reduction of mental health in the adolescents, although attenuated when adjusting for paternal distress. No significant effects were detected in the adolescents whose fathers had measured hearing loss. CONCLUSION: Severe maternal hearing loss is associated with significantly increased adolescent distress. PMID- 26605970 TI - How shall we examine and learn about public-private partnerships (PPPs) in the health sector? Realist evaluation of PPPs in Hong Kong. AB - The World Health Organization advocates the goal of universal coverage of health systems to ensure that everyone can avail the services they need and are protected from the associated financial risks. Governments are increasingly engaging and interacting with the private sector in initiatives collectively referred to as public-private partnerships (PPPs) to enhance the capacity of health systems to meet this objective. Understanding the values that motivate partners and demonstrating commitment for building relationships were found to be key lessons in building effective PPPs; however there, remain many research gaps. This study focusses on the practice of PPPs at the inter-organisational (meso) level and interpersonal (micro) level in Hong Kong Special Administrative Region (HKSAR). The influence of the structural components of different PPPs on stakeholder interpretation and actions, as well as the eventual outcomes of the PPPs, is examined, in terms of a realist evaluation, which applies a context mechanism-outcome configuration as the research methodology. Seven key factors initiating commitment in a partnership, critical for sustainable PPPs, were identified as follows: (1) building of trust; (2) clearly defined objectives and roles; (3) time commitment; (4) transparency and candid information, particularly in relation to risk and benefit; (5) contract flexibility; (6) technical assistance or financial incentive behind procedural arrangements; and (7) the awareness and acceptability of structural changes related to responsibility and decisions (power and authority). PMID- 26605971 TI - Smallest molecular chalcogenidometalate anions of the heaviest metals: syntheses, structures, and their interconversion. AB - The syntheses of the first molecular meta-selenidomercurate(ii), ortho telluridothallate(iii) and a hydrate of an ortho-selenidoplubate(iv) are presented alongside an improved and facile synthesis of the selenidobismuthate(iii) with almost quantitative yields. By means of quantum chemical calculations, the energetics of the interconversions of small metalate anions is discussed and the existence of the heaviest homologues of [NO2](-), [NO3](-), [PO4](2-) and [CO3](2-) are predicted. PMID- 26605972 TI - Changes in Sex and Ethnic Diversity in Dermatology Residents Over Multiple Decades. PMID- 26605974 TI - Contrast-enhanced harmonic endoscopic ultrasonography for differential diagnosis of pancreatic cysts. AB - BACKGROUND AND STUDY AIM: Comparison of fundamental B-mode endoscopic ultrasonography (FB-EUS) and contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) in the differential diagnosis of pancreatic cysts according to presence of mural nodules. PATIENTS AND METHODS: Between April 2007 and April 2012, FB-EUS and CH-EUS data were prospectively collected from 581 consecutive patients with pancreatic cysts, and were retrospectively analyzed from 70 with subsequent cyst resection. Presence and height of mural nodules as detected on FB-EUS and CH-EUS were evaluated, and thence accuracies of both methods for diagnosing mucinous versus nonmucinous and malignant versus benign cysts. RESULTS: On pathological examination 48 cysts were mucinous and 22 were nonmucinous; 30 cysts were malignant (high grade dysplasia or invasive carcinoma) and 40 were benign. If presence of a mural nodule was considered to indicate a mucinous cyst, FB-EUS and CH-EUS accuracies did not differ significantly (respectively: sensitivity 85 % vs. 79 %; specificity 46 % vs. 96 %; accuracy 73 % vs. 84 %, P = 0.057). If presence of mural nodule was considered to indicate malignancy, CH-EUS was significantly more accurate than FB-EUS (respectively: sensitivity 97 % vs. 97 %; specificity 75 % vs. 40 %; accuracy 84 % vs. 64 %, P = 0.0001). For diagnosing malignancy by evaluating mural nodule height, the area under the receiver operating characteristic (AUROC) was 0.84 and 0.93 for FB-EUS and CH-EUS, respectively (P = 0.028). Presence of a mural nodule of height >= 4 mm on CH-EUS was a sign of malignancy (false-positive fraction 0.2; true-positive fraction 0.93; odds ratio 56.0). CONCLUSIONS: CH-EUS is more accurate than FB-EUS for diagnosing malignant pancreatic cysts. PMID- 26605975 TI - First UHF Implementation of the Incremental Scheme for Open-Shell Systems. AB - The incremental scheme makes it possible to compute CCSD(T) correlation energies to high accuracy for large systems. We present the first extension of this fully automated black-box approach to open-shell systems using an Unrestricted Hartree Fock (UHF) wave function, extending the efficient domain-specific basis set approach to handle open-shell references. We test our approach on a set of organic and metal organic structures and molecular clusters and demonstrate standard deviations from canonical CCSD(T) values of only 1.35 kJ/mol using a triple zeta basis set. We find that the incremental scheme is significantly more cost-effective than the canonical implementation even for relatively small systems and that the ease of parallelization makes it possible to perform high level calculations on large systems in a few hours on inexpensive computers. We show that the approximations that make our approach widely applicable are significantly smaller than both the basis set incompleteness error and the intrinsic error of the CCSD(T) method, and we further demonstrate that incremental energies can be reliably used in extrapolation schemes to obtain near complete basis set limit CCSD(T) reaction energies for large systems. PMID- 26605976 TI - Dose Escalation in Stage III Non-Small-Cell Lung Cancer: Patients Agree With the Clinical Results. PMID- 26605977 TI - An Enantioselective Approach to 4-O-Protected-2-cyclopentene-l,4-diol Derivatives via a Rhodium-Catalyzed Redox-Isomerization Reaction. AB - Kinetic resolution of a series of cyclopentene-1,4-diol derivatives has been successfully achieved with enantiomeric excess up to 99.4% and a kf/ks ratio of 55 by a rhodium-catalyzed redox-isomerization reaction in a noncoordinating solvent. PMID- 26605978 TI - The Nucleation and Growth Mechanism of Thiolate-Protected Au Nanoclusters. AB - The understanding of the evolution mechanism of thiolate-protected Au nanoclusters from the homoleptic Au(I)-SR clusters to core-stacked ones is crucial for the synthesis of novel thiolated Au clusters. In this work, the global search for a series of "intermediate" Aum(SR)n clusters with m and n ranging from 5 to 12 was implemented by combining basin hopping algorithm, genetic algorithm, and density functional theory (DFT) calculations. Most of Aum(SR)n clusters possess the core-shell structure. Specifically, some typical topologies, such as tetrahedral Au4, triangular bipyramid Au5, octahedral Au6, and vertex-shared Au7, are found to be dominant within the inner core of various clusters. Along with the increase in the number of gold atoms and thiolates, the preliminary nucleation and growth processes of both inner-core and staple-motif protecting units are grouped into three kinds of size evolution routes, i.e., core growth, core dissolution, and staple-motif growth, respectively. Some metastable isomers may also play an important role in the evolution of clusters. The core structures in the lowest-lying isomers and some metastable isomers are similar to the intact or part of the cores found in experimentally detected species. Both the lowest-lying and metastable intermediate clusters may serve as the building block for the further growth. These results rationalize the preliminary nucleation in the "reduction growth" stage, shedding light on the size-evolution mechanism of RS-AuNPs. PMID- 26605979 TI - Unimolecular Chemically Modified DNA Fluorescent Probe for One-Step Quantitative Measurement of the Activity of Human Apurinic/Apyrimidinic Endonuclease 1 in Biological Samples. AB - A novel DNA structure containing a 3' internal-loop modified abasic site has been constructed which enables effective differentiation between apurinic/apyrimidinic endonuclease (APE1) and nonspecific endonuclease (DNase I). When this unique substrate structure is employed, a double-loop frayed-end chimeric fluorescent probe is successfully developed for quantitative measurement of the activity of APE1 in biological samples without the need of additional cleanup or preconcentration steps. The method is simple and rapid and has a single-step with a linear working range between 0.1 and 5.0 U/mL and a lower limit of detection of 0.1 U/mL. It holds great potential in real-time monitoring of the variation of intracellular and extracellular APE1, which will be very useful for further understanding of the DNA repair pathways in different organisms. PMID- 26605981 TI - Iron and Carbon Dynamics during Aging and Reductive Transformation of Biogenic Ferrihydrite. AB - Natural organic matter is often associated with Fe(III) oxyhydroxides, and may be stabilized as a result of coprecipitation or sorption to their surfaces. However, the significance of this association in relation to Fe and C dynamics and biogeochemical cycling, and the mechanisms responsible for organic matter stabilization as a result of interaction with minerals under various environmental conditions (e.g., pH, Eh, etc.) are not entirely understood. The preservation of mineral-bound OM may be affected by OM structure and mineral identity, and bond types between OM and minerals may be central to influencing the stability, transformation and composition of both organic and mineral components under changing environmental conditions. Here we use bulk and submicron-scale spectroscopic synchrotron methods to examine the in situ transformation of OM-bearing, biogenic ferrihydrite stalks (Gallionella ferruginea-like), which formed following injection of oxygenated groundwater into a saturated alluvial aquifer at the Rifle, CO field site. A progression from oxidizing to reducing conditions during an eight-month period triggered the aging and reductive transformation of Gallionella-like ferrihydrite stalks to Fe (hydroxy)carbonates and Fe sulfides, as well as alteration of the composition and amount of OM. Spectromicroscopic measurements showed a gradual decrease in reduced carbon forms (aromatic/alkene, aliphatic C), a relative increase in amide/carboxyl functional groups and a significant increase in carbonate in the stalk structures, and the appearance of organic globules not associated with stalk structures. Biogenic stalks lost ~30% of their initial organic carbon content. Conversely, a significant increase in bulk organic matter accompanied these transformations. The character of bulk OM changed in parallel with mineralogical transformations, showing an increase in aliphatic, aromatic and amide functional groups. These changes likely occurred as a result of an increase in microbial activity, or biomass production under anoxic conditions. By the end of this experiment, a substantial fraction of organic matter remained in identifiable Fe containing stalks, but carbon was also present in additional pools, for example, organic matter globules and iron carbonate minerals. PMID- 26605982 TI - Quantitative Structure-Activity Relationship for High Affinity 5-HT1A Receptor Ligands Based on Norm Indexes. AB - Arylpiperazine derivatives are promising 5-hydroxytryptamine (5-HT) receptor ligands which can inhibit serotonin reuptake effectively. In this work, some norm index descriptors were proposed and further utilized to develop a model for predicting 5-HT1A receptor affinity (pKi) of 88 arylpiperazine derivatives. Results showed that this new model could provide satisfactory predictions with the square of the correction coefficient (R(2)) of 0.8891 and the squared correlation coefficient of cross-validation (Q(2)) of 0.8082, respectively. In addition, the applicability domain of this model was validated by using the leverage approach and results which suggested potential large scale for further utilization of this model. The results of statistical values and validation tests demonstrated that our proposed norm index based model could be successfully applied for predicting the affinity 5-HT1A receptor ligands of arylpiperazine derivatives. PMID- 26605983 TI - Dinuclear Zinc Salen Catalysts for the Ring Opening Copolymerization of Epoxides and Carbon Dioxide or Anhydrides. AB - A series of four dizinc complexes coordinated by salen or salan ligands, derived from ortho-vanillin and bearing (+/-)-trans-1,2-diaminocyclohexane (L1) or 2,2 dimethyl-1,3-propanediamine (L2) backbones, is reported. The complexes are characterized using a combination of X-ray crystallography, multinuclear NMR, DOSY, and MALDI-TOF spectroscopies, and elemental analysis. The stability of the dinuclear complexes depends on the ligand structure, with the most stable complexes having imine substituents. The complexes are tested as catalysts for the ring-opening copolymerization (ROCOP) of CO2/cyclohexene oxide (CHO) and phthalic anhydride (PA)/CHO. All complexes are active, and the structure/activity relationships reveal that the complex having both L2 and imine substituents displays the highest activity. In the ROCOP of CO2/CHO its activity is equivalent to other metal salen catalysts (TOF = 44 h(-1) at a catalyst loading of 0.1 mol %, 30 bar of CO2, and 80 degrees C), while for the ROCOP of PA/CHO, its activity is slightly higher than other metal salen catalysts (TOF = 198 h(-1) at a catalyst loading of 1 mol % and 100 degrees C). Poly(ester-block-carbonate) polymers are also afforded using the most active catalyst by the one-pot terpolymerization of PA/CHO/CO2. PMID- 26605980 TI - Protein Sulfenylation: A Novel Readout of Environmental Oxidant Stress. AB - Oxidative stress is a commonly cited mechanism of toxicity of environmental agents. Ubiquitous environmental chemicals such as the diesel exhaust component 1,2-naphthoquinone (1,2-NQ) induce oxidative stress by redox cycling, which generates hydrogen peroxide (H2O2). Cysteinyl thiolate residues on regulatory proteins are subjected to oxidative modification by H2O2 in physiological contexts and are also toxicological targets of oxidant stress induced by environmental contaminants. We investigated whether exposure to environmentally relevant concentrations of 1,2-NQ can induce H2O2-dependent oxidation of cysteinyl thiols in regulatory proteins as a readout of oxidant stress in human airway epithelial cells. BEAS-2B cells were exposed to 0-1000 MUM 1,2-NQ for 0-30 min, and levels of H2O2 were measured by ratiometric spectrofluorometry of HyPer. H2O2-dependent protein sulfenylation was measured using immunohistochemistry, immunoblotting, and isotopic mass spectrometry. Catalase overexpression was used to investigate the relationship between H2O2 generation and protein sulfenylation in cells exposed to 1,2-NQ. Multiple experimental approaches showed that exposure to 1,2-NQ at concentrations as low as 3 MUM induces H2O2-dependent protein sulfenylation in BEAS-2B cells. Moreover, the time of onset and duration of 1,2 NQ-induced sulfenylation of the regulatory proteins GAPDH and PTP1B showed significant differences. Oxidative modification of regulatory cysteinyl thiols in human lung cells exposed to relevant concentrations of an ambient air contaminant represents a novel marker of oxidative environmental stress. PMID- 26605984 TI - What is the Shape of an Air Bubble on a Liquid Surface? AB - We have calculated the equilibrium shape of the axially symmetric meniscus along which a spherical bubble contacts a flat liquid surface by analytically integrating the Young-Laplace equation in the presence of gravity, in the limit of large Bond numbers. This method has the advantage that it provides semianalytical expressions for key geometrical properties of the bubble in terms of the Bond number. Results are in good overall agreement with experimental data and are consistent with fully numerical (Surface Evolver) calculations. In particular, we are able to describe how the bubble shape changes from hemispherical, with a flat, shallow bottom, to lenticular, with a deeper, curved bottom, as the Bond number is decreased. PMID- 26605985 TI - Ligand-Controlled Diastereoselective 1,3-Dipolar Cycloadditions of Azomethine Ylides with Methacrylonitrile. AB - Copper-catalyzed reactions of glycine ester arylimines and methacrylonitrile provide selective access to either the endo or exo pyrrolidine cycloadducts. DFT calculations have elucidated the origins of ligand-controlled diastereoselectivity. PMID- 26605986 TI - Scale-up of HIV Viral Load Monitoring--Seven Sub-Saharan African Countries. AB - To achieve global targets for universal treatment set forth by the Joint United Nations Programme on human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) (UNAIDS), viral load monitoring for HIV-infected persons receiving antiretroviral therapy (ART) must become the standard of care in low- and middle-income countries (LMIC) (1). CDC and other U.S. government agencies, as part of the President's Emergency Plan for AIDS Relief, are supporting multiple countries in sub-Saharan Africa to change from the use of CD4 cell counts for monitoring of clinical response to ART to the use of viral load monitoring, which is the standard of care in developed countries. Viral load monitoring is the preferred method for immunologic monitoring because it enables earlier and more accurate detection of treatment failure before immunologic decline. This report highlights the initial successes and challenges of viral load monitoring in seven countries that have chosen to scale up viral load testing as a national monitoring strategy for patients on ART in response to World Health Organization (WHO) recommendations. Countries initiating viral load scale-up in 2014 observed increases in coverage after scale-up, and countries initiating in 2015 are anticipating similar trends. However, in six of the seven countries, viral load testing coverage in 2015 remained below target levels. Inefficient specimen transport, need for training, delays in procurement and distribution, and limited financial resources to support scale-up hindered progress. Country commitment and effective partnerships are essential to address the financial, operational, technical, and policy challenges of the rising demand for viral load monitoring. PMID- 26605987 TI - Two new species of Aristocleidus (Monogenea) from the gills of the Mexican mojarra Eugerres mexicanus (Perciformes, Gerreidae) from southwestern Mexico. AB - Aristocleidus mexicanus n. sp. and Aristocleidus lacantuni n. sp. are described from the gills of the Mexican mojarra Eugerres mexicanus (Gerreidae, Perciformes) from the Rio Lacantun basin, Chiapas State, Mexico. These new species differ from previously described congeneric species in the characteristics of several structures, including: (a) ventral anchors, with differences in length (i.e. 46 50 um in A. mexicanus vs. 38-43 um, 34-37 um, and 26-33 um in Aristocleidus hastatus Mueller, 1936, Aristocleidus sp. of Mendoza-Franco, Violante-Gonzalez & Roche 2009, and Aristocleidus lamothei Kritsky & Mendoza-Franco, 2008, respectively) and shape (i.e. slightly angular union of elongate arcing shaft and point in A. mexicanus vs. point and shaft united at a conspicuous angular bend in A. hastatus and Aristocleidus sp., and evenly curved shaft and point in A. lamothei); (b) male copulatory organ, i.e. a coiled tube with less than one ring in A. mexicanus and A. lacantuni (vs. a coiled tube of about 11/2 in Aristocleidus sp.); (c) distal end of the accessory piece (ornate in A. mexicanus vs. distally flattened and trifid in A. hastatus and A. lamothei, respectively); (d) vaginal tube (moderately long in A. mexicanus vs. short in A. lamothei and looping in Aristocleidus sp.); and (e) ventral bar (anteromedial process with terminal horn-like ornamentation in A. lacantuni vs. ornamentation absent in the other species). This study reports for the first time species of Aristocleidus from freshwater environments in Mexico. PMID- 26605988 TI - Baicalin Alleviates Silica-Induced Lung Inflammation and Fibrosis by Inhibiting the Th17 Response in C57BL/6 Mice. AB - Silicosis is an inflammatory and fibrotic lung disease caused by inhalation of silica. Th17 cells play a key role in causing silica-induced lung inflammation and fibrosis. Baicalin, a compound isolated from the Chinese herb Huangqin, could suppress the differentiation of Th17 cells and alleviate inflammation. However, there are very few reports of the immunoregulatory mechanisms of baicalin in experimental silica-induced lung inflammation and fibrosis. In our study, mice were exposed to silica by intratracheal instillation, and in this way we established an experimental silicosis model. To elucidate the effects and mechanisms of baicalin in silica-induced inflammation and fibrosis, we used baicalin to treat the developed mouse model of silicosis. Treatment with baicalin attenuated the accumulation of inflammatory cells and led to milder pathological inflammatory and fibrotic changes in lung tissues. Baicalin affected the immunological balance between Th17 and Treg responses. Therefore, baicalin caused a decrease in Th17 cells by stimulating Treg cells and by inhibiting IL-6 and IL 23. We further demonstrated that silica-induced Th1 and Th2 immune responses were both inhibited by increased Treg activation, which was promoted by baicalin. Our findings confirmed the potential functions of baicalin in inhibiting the Th17 response and reducing silica-induced inflammation and fibrosis. PMID- 26605989 TI - Disparity between state fish consumption advisory systems for methylmercury and US Environmental Protection Agency recommendations: A case study of the south central United States. AB - Fish consumption advisories are used to inform citizens in the United States about noncommercial game fish with hazardous levels of methylmercury (MeHg). The US Environmental Protection Agency (USEPA) suggests issuing a fish consumption advisory when concentrations of MeHg in fish exceed a human health screening value of 300 ng/g. However, states have authority to develop their own systems for issuing fish consumption advisories for MeHg. Five states in the south central United States (Arkansas, Louisiana, Mississippi, Oklahoma, and Texas) issue advisories for the general human population when concentrations of MeHg exceed 700 ng/g to 1000 ng/g. The objective of the present study was to estimate the increase in fish consumption advisories that would occur if these states followed USEPA recommendations. The authors used the National Descriptive Model of Mercury in Fish to estimate the mercury concentrations in 5 size categories of largemouth bass-equivalent fish at 766 lentic and lotic sites within the 5 states. The authors found that states in this region have not issued site specific fish consumption advisories for most of the water bodies that would have such advisories if USEPA recommendations were followed. One outcome of the present study may be to stimulate discussion between scientists and policy makers at the federal and state levels about appropriate screening values to protect the public from the health hazards of consuming MeHg-contaminated game fish. PMID- 26605990 TI - The Clinical Learning Dyad Model: An Innovation in Midwifery Education. AB - There is a national shortage of women's health and primary care providers in the United States, including certified nurse-midwives and certified midwives. This shortage is directly related to how many students can be trained within the existing system. The current model of midwifery clinical training is based on apprenticeship, with one-on-one interaction between a student and preceptor. Thus, the number of newly trained midwifery providers is limited by the number of available and willing preceptors. The clinical learning dyad model (CLDM), which pairs 2 beginning midwifery students with one preceptor in a busy practice, addresses this problem. In addition, this model brings in a senior midwife student as a near-peer mentor when the students are first oriented into outpatient clinical practice. The model began as a pilot project to improve the quality of training and increase available student spots in clinical education. This article discusses the origins of the model, the specifics of its design, and the results of a midterm and one-year postintervention survey. Students and preceptors involved in this model identified several advantages to the program, including increased student accountability, enhanced socialization into the profession, improved learning, and reduced teaching burden on preceptors. An additional benefit of the CLDM is that students form a learning community and collaborate with preceptors to care for women in busy clinical settings. Challenges of the model will also be discussed. Further research is needed to evaluate the effectiveness of the CLDM. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health. PMID- 26605991 TI - Efficacy and safety of linagliptin as add-on therapy to basal insulin and metformin in people with Type 2 diabetes. AB - AIM: To evaluate the efficacy and safety of linagliptin in people with Type 2 diabetes inadequately controlled on basal insulin and metformin. METHODS: This was a post hoc subanalysis of participants who received basal insulin and metformin in a global phase III study that randomized participants (1:1) to receive linagliptin 5 mg once daily or placebo for >=52 weeks as add-on therapy to basal insulin alone or in combination with metformin and/or pioglitazone. During the first 24 weeks, the background dose of basal insulin remained stable; thereafter, adjustments based on glucose concentrations were recommended. The primary endpoint of the subanalysis was the change from baseline in HbA1c after 24 weeks. The safety analysis incorporated data up to a maximum of 110 weeks. RESULTS: A total of 950 participants receiving background insulin and metformin were included in this subanalysis (linagliptin and placebo, both n = 475). At week 24, the placebo-corrected adjusted mean (+/-se) change from baseline in HbA1c with linagliptin was -7 (+/-1) mmol/mol [-0.7 (+/-0.1) %; 95% CI -0.8, 0.6; P < 0.0001]. The overall frequency of drug-related adverse events (linagliptin, 18.9%; placebo, 21.9%) and investigator-reported hypoglycaemia (linagliptin, 30.7%; placebo, 31.6%) were similar in both groups at the end of treatment. The frequency of severe hypoglycaemia was low (linagliptin, 1.7%; placebo, 0.8%). No meaningful changes in mean (+/-sd) body weight were noted in either group [week 52: linagliptin, -0.5 (+/-3.2) kg; placebo, 0.0 (+/-3.1) kg]. CONCLUSIONS: Linagliptin added to basal insulin and metformin improved glycaemic control, without increasing the risk of hypoglycaemia or body weight gain. PMID- 26605992 TI - Examining Changes in Central and Peripheral Pain as Mediates of Fatigue Improvement: Results From the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. AB - OBJECTIVE: Following anti-tumor necrosis factor (anti-TNF) therapy, improvements in rheumatoid arthritis (RA) fatigue are driven by reductions in pain. However, therapies may modify both central and peripheral pain. This study sought to examine the hypothesis that reductions in fatigue after anti-TNF therapy reflect changes in central, not peripheral, pain mechanisms. METHODS: Data came from patients with severe baseline fatigue (Short Form 36 health survey [SF-36] vitality scale <=12.5; n = 2,652), recruited to the British Society for Rheumatology Biologics Register for RA for commencing anti-TNF therapies between October 2000 and November 2008. Data of interest comprised change over 6 months in fatigue, pain (SF-36 bodily pain scale), and disease activity constituents (Disease Activity Score in 28 joints, erythrocyte sedimentation rate [ESR], global health, swollen joints, and tender joints). Principal components factor analysis with varimax rotation determined latent variables of symptom change; variables were accepted provided they had eigenvalues >=1. RESULTS: Six factors were identified, of which 2 met acceptance criteria (eigenvalues of 2.39 and 1.14, respectively). Following rotation, loadings indicated that factor 1 comprised markers of peripheral inflammation: change in ESR, swollen joints, tender joints, and global health. This distinct loading led to factor 1 being labeled peripheral inflammation. Conversely, factor 2 comprised change in pain, fatigue, and global health and an absence of peripheral inflammation markers and was therefore labeled central inflammation. CONCLUSION: Following anti-TNF therapies, reductions in fatigue and pain appear to reflect improvements in central, rather than peripheral, inflammation. Therefore, for those seeking to treat fatigue via pain mechanisms, improvements may be maximized by the application of treatment modalities that effectively target central mechanisms. PMID- 26605993 TI - Bacterial Ecology of Fermented Cucumber Rising pH Spoilage as Determined by Nonculture-Based Methods. AB - Fermented cucumber spoilage (FCS) characterized by rising pH and the appearance of manure- and cheese-like aromas is a challenge of significant economical impact for the pickling industry. Previous culture-based studies identified the yeasts Pichia manshurica and Issatchenkia occidentalis, 4 Gram-positive bacteria, Lactobacillus buchneri, Lactobacillus parrafaraginis, Clostridium sp., and Propionibacterium and 1 Gram-negative genus, Pectinatus, as relevant in various stages of FCS given their ability to metabolize lactic acid. It was the objective of this study to augment the current knowledge of FCS using culture-independent methods to microbiologically characterize commercial spoilage samples. Ion Torrent data and 16S rRNA cloning library analyses of samples collected from commercial fermentation tanks confirmed the presence of L. rapi and L. buchneri and revealed the presence of additional species involved in the development of FCS such as Lactobacillus namurensis, Lactobacillus acetotolerans, Lactobacillus panis, Acetobacter peroxydans, Acetobacter aceti, and Acetobacter pasteurianus at pH below 3.4. The culture-independent analyses also revealed the presence of species of Veillonella and Dialister in spoilage samples with pH above 4.0 and confirmed the presence of Pectinatus spp. during lactic acid degradation at the higher pH. Acetobacter spp. were successfully isolated from commercial samples collected from tanks subjected to air purging by plating on Mannitol Yeast Peptone agar. In contrast, Lactobacillus spp. were primarily identified in samples of FCS collected from tanks not subjected to air purging for more than 4 mo. Thus, it is speculated that oxygen availability may be a determining factor in the initiation of spoilage and the leading microbiota. PMID- 26605994 TI - Analysis of the relationship between health status and mortality in hypercapnic patients with noninvasive ventilation. AB - BACKGROUND: Health status and mortality are important outcomes in patients with advanced pulmonary diseases receiving noninvasive ventilation (NIV). However, their relationship has not been thoroughly investigated. METHODS: The present study prospectively recruited 56 stable outpatients treated with NIV for chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease and/or pulmonary tuberculosis sequelae. At baseline, health status was measured by the Medical Outcomes Study 36-item short form, a generic questionnaire; the St. George's Respiratory Questionnaire (SGRQ), a respiratory-specific questionnaire; and two respiratory failure-specific questionnaires, the Maugeri Respiratory Failure questionnaire and the Severe Respiratory Insufficiency (SRI) questionnaire. Arterial blood gas, pulmonary function, dyspnea and psychological status were also measured. RESULTS: In cross-sectional comparisons of the four health status questionnaires, the SGRQ and SRI questionnaire had lower floor and ceiling effects. During the 3-year follow-up, 16 patients (29%) died. Health status shown by the SGRQ and SRI was significantly predictive of mortality, independently of the physiological measures of low body mass index (BMI), hypercapnia, and low pulmonary function. Stepwise multivariate analyses indicated that the SRI summary score was the most significant predictor of mortality (P = 0.0006) followed by BMI (P = 0.012). CONCLUSION: There was a significant relationship between health status and 3-year mortality in patients with NIV, independently of under-nutrition, hypercapnia and low pulmonary function. Health status measurement is important not only to comprehensively evaluate disease severity in relation to its close association with mortality, but also to elucidate factors that improve the survival of patients with advanced respiratory diseases. PMID- 26605996 TI - Bone mineralization-dependent craniosynostosis and craniofacial shape abnormalities in the mouse model of infantile hypophosphatasia. AB - BACKGROUND: Inactivating mutations in tissue-nonspecific alkaline phosphatase (TNAP) cause hypophosphatasia (HPP), which is commonly characterized by decreased bone mineralization. Infants and mice with HPP can also develop craniosynostosis and craniofacial shape abnormalities, although the mechanism by which TNAP deficiency causes these craniofacial defects is not yet known. Manifestations of HPP are heterogeneous in severity, and evidence from the literature suggests that much of this variability is mutation dependent. Here, we performed a comprehensive analysis of craniosynostosis and craniofacial shape variation in the Alpl(-/-) mouse model of murine HPP as an initial step toward better understanding penetrance of the HPP craniofacial phenotype. RESULTS: Despite similar deficiencies in alkaline phosphatase, Alpl(-/-) mice develop craniosynostosis and a brachycephalic/acrocephalic craniofacial shape of variable penetrance. Only those Alpl(-/-) mice with a severe bone hypomineralization defect develop craniosynostosis and an abnormal craniofacial shape. CONCLUSIONS: These results indicate that variability of the HPP phenotype is not entirely dependent upon the type of genetic mutation and level of residual alkaline phosphatase activity. Additionally, despite a severity continuum of the bone hypomineralization phenotype, craniofacial skeletal shape abnormalities and craniosynostosis occur only in the context of severely diminished bone mineralization in the Alpl(-/-) mouse model of HPP. PMID- 26605995 TI - Intrinsic membrane properties determine hippocampal differential firing pattern in vivo in anesthetized rats. AB - The hippocampus plays a key role in learning and memory. Previous studies suggested that the main types of principal neurons, dentate gyrus granule cells (GCs), CA3 pyramidal neurons, and CA1 pyramidal neurons, differ in their activity pattern, with sparse firing in GCs and more frequent firing in CA3 and CA1 pyramidal neurons. It has been assumed but never shown that such different activity may be caused by differential synaptic excitation. To test this hypothesis, we performed high-resolution whole-cell patch-clamp recordings in anesthetized rats in vivo. In contrast to previous in vitro data, both CA3 and CA1 pyramidal neurons fired action potentials spontaneously, with a frequency of ~3-6 Hz, whereas GCs were silent. Furthermore, both CA3 and CA1 cells primarily fired in bursts. To determine the underlying mechanisms, we quantitatively assessed the frequency of spontaneous excitatory synaptic input, the passive membrane properties, and the active membrane characteristics. Surprisingly, GCs showed comparable synaptic excitation to CA3 and CA1 cells and the highest ratio of excitation versus hyperpolarizing inhibition. Thus, differential synaptic excitation is not responsible for differences in firing. Moreover, the three types of hippocampal neurons markedly differed in their passive properties. While GCs showed the most negative membrane potential, CA3 pyramidal neurons had the highest input resistance and the slowest membrane time constant. The three types of neurons also differed in the active membrane characteristics. GCs showed the highest action potential threshold, but displayed the largest gain of the input output curves. In conclusion, our results reveal that differential firing of the three main types of hippocampal principal neurons in vivo is not primarily caused by differences in the characteristics of the synaptic input, but by the distinct properties of synaptic integration and input-output transformation. PMID- 26605997 TI - Comparing in vivo biodistribution with radiolabeling and Franz cell permeation assay to validate the efficacy of both methodologies in the evaluation of nanoemulsions: a safety approach. AB - The Franz cells permeation assay has been performed for over 25 years. However, the advent of nanotechnology created a whole new world, especially with regard to topical products. In this new global scenario an increasing number of nanostructure-based delivery systems (NDSs) have emerged and a global warning relating to the safety of these NDSs is arising. This work studied the efficacy of the Franz cells assay, comparing it with the radiolabeling biodistribution test. For this purpose a formulation of sunscreen based on an NDS was developed and characterized. The results demonstrated both that the NDS did not present in vitro cytotoxicity and that the radiolabeling biodistribution test is more precise for the evaluation of NDS cosmetics than the Franz cells assay, since it detected the permeation of the NDS at a picogram order. Due to this fact, and considering all the concerns related to NDSs and nanoparticles in general, more precise methods must be used in order to guarantee the safe use of these new classes of products. PMID- 26605998 TI - Copper Silicate Hydrate Hollow Spheres Constructed by Nanotubes Encapsulated in Reduced Graphene Oxide as Long-Life Lithium-Ion Battery Anode. AB - Hierarchical copper silicate hydrate hollow spheres-reduced graphene oxide (RGO) composite is successfully fabricated by a facile hydrothermal method using silica as in situ sacrificing template. The electrochemical performance of the composite as lithium-ion battery anode was studied for the first time. Benefiting from the synergistic effect of the hierarchical hollow structure and conductive RGO matrix, the composite exhibits excellent long-life performance and rate capability. A capacity of 890 mAh/g is achieved after 200 cycles at 200 mA/g and a capacity of 429 mAh/g is retained after 800 cycles at 1000 mA/g. The results indicate that the strategy of combining hierarchical hollow structures with conductive RGO holds the potential in addressing the volume expansion issue of high capacity anode materials. PMID- 26605999 TI - Reply. PMID- 26606001 TI - Ultrafast Room-Temperature Single Photon Emission from Quantum Dots Coupled to Plasmonic Nanocavities. AB - Efficient and bright single photon sources at room temperature are critical components for quantum information systems such as quantum key distribution, quantum state teleportation, and quantum computation. However, the intrinsic radiative lifetime of quantum emitters is typically ~10 ns, which severely limits the maximum single photon emission rate and thus entanglement rates. Here, we demonstrate the regime of ultrafast spontaneous emission (~10 ps) from a single quantum emitter coupled to a plasmonic nanocavity at room temperature. The nanocavity integrated with a single colloidal semiconductor quantum dot produces a 540-fold decrease in the emission lifetime and a simultaneous 1900-fold increase in the total emission intensity. At the same time, the nanocavity acts as a highly efficient optical antenna directing the emission into a single lobe normal to the surface. This plasmonic platform is a versatile geometry into which a variety of other quantum emitters, such as crystal color centers, can be integrated for directional, room-temperature single photon emission rates exceeding 80 GHz. PMID- 26606000 TI - Down-regulation of the cyclin-dependent kinase inhibitor p57 is mediated by Jab1/Csn5 in hepatocarcinogenesis. AB - Down-regulation of p57 (KIP2) cyclin-dependent kinase inhibitors accelerates the growth and invasion of hepatocellular carcinoma (HCC), suggesting that p57 may play an important role in liver carcinogenesis. However, the mechanism or oncogenic signal leading to p57 down-regulation in HCC remains to be determined. Herein, we demonstrated that Jab1/Csn5 expression is negatively correlated with p57 levels in HCC tissues. Kaplan-Meier analysis of tumor samples revealed that high Jab1/Csn5 expression with concurrent low p57 expression is associated with poor overall survival. The inverse pattern of Jab1 and p57 expression was also observed during carcinogenesis in a chemically induced rat HCC model. We also found that mechanistically, Jab1-mediated p57 proteolysis in HCC cells is dependent on 26S-proteasome inhibitors. We further demonstrated that direct physical interaction between Jab1 and p57 triggers p57 down-regulation, independently of Skp2 and Akt pathways, in HCC cells. These data suggest that Jab1 is an important upstream negative regulator of p57 and that aberrant expression of Jab1 in HCC could lead to a significant decrease in p57 levels and contribute to tumor cell growth. Furthermore, restoration of p57 levels induced by loss of Jab1 inhibited tumor cell growth and further increased cell apoptosis in HCC cells. Moreover, silencing Jab1 expression further enhanced the antitumor effects of cisplatin-induced apoptosis in HCC cells. CONCLUSION: Jab1-p57 pathway confers resistance to chemotherapy and may represent a potential target for investigational therapy in HCC. PMID- 26606002 TI - Reconstruction of Full-Thickness Scalp Defects Using a Dermal Regeneration Template. AB - IMPORTANCE: Large full-thickness scalp defects pose a reconstructive problem and commonly require microvascular free flap reconstruction. OBJECTIVE: To describe a novel and effective reconstructive technique for full-thickness scalp defects that can be performed quickly without general anesthesia or free flap reconstruction. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of 10 patients at a single medical center who underwent surgical resection of a cutaneous lesion. Reconstruction of the large scalp defects included application of Integra bilayer wound matrix followed by delayed split-thickness skin grafting from January 1, 2008, to December 31, 2014. Patients ranged in age from 50 to 87 (mean, 71.5) years; 8 (80%) were men. Mean duration of follow-up was 481.1 days (range, 41-1199 days). MAIN OUTCOMES AND MEASURES: Skin graft viability and adherence to underlying tissue (take) and postoperative complications. RESULTS: The 10 patients in this study had excellent skin graft and wound closure outcomes. Nine patients showed a 100% initial take of the skin graft to the defect site. Only 1 patient showed a 95% to 100% initial take. Adequate coverage of the wound bed was achieved with acceptable cosmetic results. Two patients underwent postoperative intensity-modulated radiotherapy. One of these patients experienced radiotherapy-induced wound breakdown 31/2 months after completion of therapy, which resolved completely after more than 6 months. CONCLUSIONS AND RELEVANCE: This novel technique for reconstruction of large full-thickness scalp defects has low morbidity and can be performed on an outpatient basis with minimal wound care. The technique provides the surgeon with an alternative to other reconstructive options, including microvascular free tissue transfer, for repair of large full-thickness scalp defects. The procedure has excellent results and can be performed under sedation and local anesthesia, which avoids the risks associated with general anesthesia. LEVEL OF EVIDENCE: 4. PMID- 26606003 TI - Effect of High-Volume Injectate in Lumbar Transforaminal Epidural Steroid Injections: A Randomized, Active Control Trial. AB - BACKGROUND: There have been many studies proving the effectiveness of lumbar transforaminal epidural steroid injections (TFESIs) for the treatment of radicular pain. Dexamethasone has been suggested as an alternative to particulate steroids. However, no controlled trials have investigated the effect of different injected volumes for a same dose of dexamethasone. OBJECTIVE: To compare the effects of a high-volume injectate with those of a low-volume injectate using the same dose of dexamethasone for 2 groups in lumbar TFESI. STUDY DESIGN: A prospective, randomized, active control trial. SETTING: The outpatient clinic of a single academic medical center. METHODS: A total of 66 patients were randomized to receive lumbar transforaminal epidural dexamethasone injections with either a low-volume injectate (3 mL, N = 30) or a high-volume injectate (8 mL, N = 32). The primary outcome measures for this study were the incidence of the patients achieving meaningful pain relief and a reduction on the Visual Analogue Scale (VAS, range 0-100) at 4 weeks after the procedure. The definition of "meaningful pain relief" was >= 50% from baseline. The secondary outcomes included the Roland Morris Disability Questionnaire (RMDQ, range 0-24) score and adverse effects. The outcomes were assessed 4 weeks after the procedure. RESULTS: Four weeks after the procedure, in the DL8 group, the incidence of achieving meaningful pain relief was higher compared with DL3 group (19, 59.4% vs. 9, 30%, P = 0.024). Both groups demonstrated a significant improvement in their VAS and RMDQ scores (P < 0.05). The VAS of the high-volume injectate group (DL8) was significantly lower than that of the low-volume injectate group (DL3) (33.3 +/- 25 vs. 46.3 +/- 25, P = 0.036). There was no significant difference in the RMDQ score between the 2 groups. LIMITATIONS: We enrolled a small number of patients and did not check the long-term outcomes. CONCLUSIONS: Injectate at a volume of 8 mL was more effective than injectate at a volume of 3 mL for radicular pain in a lumbar transforaminal steroid injection, although both of the injectates contained the same dose of dexamethasone. PMID- 26606004 TI - Acupuncture-Analgesia Following a Single Treatment Session in Chronic Whiplash is Unrelated to Autonomic Nervous System Changes: A Randomized Cross-over Trial. AB - BACKGROUND: An acupuncture treatment can reduce pain sensitivity in patients with chronic whiplash associated disorders (WAD). But it has been hypothesized that many of the experimental results in acupuncture research could be interpreted as stress-induced analgesia. OBJECTIVE: The present study aimed at examining whether acupuncture has an effect on the autonomic nervous system response in patients with chronic WAD and if this response is related to the pain inhibition after an acupuncture session. STUDY DESIGN: Randomized crossover trial with blinded assessor. SETTING: Two private practices. METHODS: Thirty-nine patients with chronic WAD received 2 treatment sessions of identical duration, with acupuncture and relaxation therapy randomly crossed over in the 2 visits. The primary outcome measurement was the registration of autonomic nervous system parameters (heart rate, skin conductance, and heart rate variability parameters) during the administration of experimental pain. Endogenous analgesia was the secondary outcome. RESULTS: Following one acupuncture treatment session, there was a significant change for 2 parameters: the heart rate was slightly reduced and the skin conductance was raised. Comparing the effects of acupuncture and relaxation, no differences were found with respect to the change in any of the autonomic parameters. Further, the reduction in pain sensitivity in response to acupuncture treatment was unrelated to any of the changes in autonomic measurements. LIMITATIONS: The results were observed after only one session of acupuncture. CONCLUSION: In patients with chronic WAD, in response to a single treatment session, no acupuncture specific effects on the autonomic response to pain assessment were present and the analgesia after one session of acupuncture is not caused by stress-induced analgesia but is more likely the result of an acupuncture specific reaction. PMID- 26606005 TI - Predictive Factors Associated with Success and Failure for Radiofrequency Thermocoagulation in Patients with Trigeminal Neuralgia. AB - BACKGROUND: Radiofrequency thermocoagulation (RFT) has been widely used to manage trigeminal neuralgia (TN) refractory to oral medication. Careful selection of patients for managing TN with RFT can decrease morbidity and improve treatment efficacy. OBJECTIVES: The goal of this study was to determine clinical variables related to the treatment outcome in patients with TN undergoing RFT. STUDY DESIGN: Retrospective analysis. SETTING: University hospital in Korea. METHODS: Demographic and clinical data were garnered by billing records for patients with TN who received RFT by one pain physician between January 2005 and August 2014. A successful outcome was pre-defined as at least 50% pain relief on a 0-10 NRS pain score for longer than 6 months after RFT. Variables evaluated for their association with outcome included age, gender, baseline pain score, etiology, type of pain, co-existing psychopathology, and history of previous intervention. RESULTS: Among 90 patients who underwent RFT for managing TN, 75 patients (83.3%) reported a successful outcome (> 50% pain relief at 6 months after RFT procedure). Pain characteristics was the most significant predictor associated with successful outcomes of RFT in both univariate and multivariate logistic analysis; odds ratio of provoked paroxysmal pain was 131.516 and mixed type of pain was 20.602 in multivariate analysis. LIMITATIONS: Prospective studies are recommended to confirm our findings and ascertain which additional variables can be taken into account to improve the likelihood of a successful outcome for RFT in patients with TN. CONCLUSION: A provoked paroxysmal pain or mixed pain condition was associated with a positive outcome for RFT in patients with TN. In addition, bilateral TN, high baseline NRS pain score, or co-morbid psychiatric condition was related with negative outcomes in univariate analysis. Pain clinicians should consider these findings when selecting patients for managing TN to increase the efficacy of RFT. CLINICAL TRIAL REGISTRATION: IRB No. 1403-118 569. PMID- 26606006 TI - National Perioperative Outcomes for Intrathecal Pump, Spinal Cord Stimulator, and Peripheral Nerve Stimulator Procedures. AB - BACKGROUND: There is abundant literature on the long-term complications of intrathecal pumps (ITP), spinal cord stimulators (SCS), and peripheral nerve stimulators (PNS) used in the treatment of chronic pain. There is less information, however, on the perioperative complications of these procedures. OBJECTIVE: Exploration of the perioperative outcomes of implantable pain devices. STUDY DESIGN: Observational study. SETTING: University hospitals, community hospitals, specialty hospitals, attached surgery centers, and freestanding surgery centers METHODS: Data were obtained from the National Anesthesia Clinical Outcomes Registry (NACOR) of the Anesthesia Quality Institute (AQI). Information was collected on patient demographics, procedure information, anesthetic administered, diagnosis linked to the procedure, and perioperative outcomes. RESULTS: The search yielded 12,611 ITP, 19,276 SCS, and 15,184 PNS cases from 2010 to 2014. In this sample, the majority of procedures were performed at community hospitals, not university medical centers. The most common diagnosis cited for an ITP was an implant complication (n = 2,570), followed by spasticity, and non-malignant back pain. For SCS, the most common diagnoses were lower back pain (n = 5,515) or radiculopathy (n = 2,398). For PNS, by far the most common diagnosis related to urinary dysfunction (n = 8,745), with painful bladder syndrome a small minority (n = 133). General anesthetics were more often performed for ITP than for SCS and PNS procedures (60.6% vs. 31.8% and 32.2%, respectively). Hemodynamic instability was a common outcome (13.9% for ITP procedures); other common outcomes for all the procedures included case delays, inadequate pain control, and extended PACU stays. LIMITATIONS: Despite the large sample size in this study, not all medical centers transmit their outcome data to NACOR. Furthermore, some institutions do not report clinical outcomes for every case to NACOR, making the sample size of assessing complications smaller and potentially more biased. Finally, procedures identified in the NACOR database using CPT may be similar but not identical and therefore potentially influence outcomes. CONCLUSIONS: Databases such as NACOR can provide rich information on ITP, SCS, and PNS for physicians performing these procedures. In this sample, ITP procedures, performed on the patients with the most severe cormobidities and often-requiring general anesthesia, were the most likely to be associated with hemodynamic instability, inadequate pain control, and extended PACU stays. Complications relating to the ITP are also the most common reason for an operation. These findings underscore the importance of proper patient selection for ITP and other implantable pain devices, in particular for patients with malignant pain or multiple co-morbidities. To identify the root causes of complications, additional information is needed on the procedure performed (e.g., an implant vs a revision), the surgical technique used, and the device implanted, as well as on specific patient comorbidities. Such information will likely become more available as resources like NACOR expand and as electronic medical record systems and coding become more integrated. PMID- 26606008 TI - New Levels of Vertebral Compression Fractures after Percutaneous Kyphoplasty: Retrospective Analysis of Styles and Risk Factors. AB - BACKGROUND: The causes of subsequent vertebral fractures after kyphoplasty are debated. It is reported that most new vertebral fractures after kyphoplasty develop in adjacent vertebrae. OBJECTIVES: We explored whether kyphoplasty increases the incidence of adjacent vertebral fractures and identified risk factors for new vertebral compression fractures (VCFs) after kyphoplasty. STUDY DESIGN: Retrospective study. SETTING: Inpatient population of a single center. METHODS: We studied 356 patients treated with kyphoplasty from January 2008 to March 2012. Among those patients, there were 35 new VCFs after kyphoplasty. Subsequently, these patients were divided into 2 groups: an "adjacent fracture" group and a "nonadjacent fracture" group. In addition, all patients treated with kyphoplasty were further assigned to either a "new fracture" group or a "no fracture" group. RESULTS: The occurrence of new VCFs in the "nonadjacent fracture" group was significantly higher than that in the "adjacent fracture" group. The average bone mineral density (BMD) of the spine was -3.95 in the "new fracture" group and -2.86 in the "no fracture" group. The risk of new vertebral fracture increased as the bone mineral density decreased (P < 0.05). The morbidity of women was significantly higher in the "new fracture" group (94.29%) than in the "no fracture" group (77.88%) (P = 0.025). LIMITATIONS: Retrospective study at a single center. CONCLUSION: New VCFs after kyphoplasty occurred most often in nonadjacent vertebrae. VCFs after kyphoplasty were common in patients with low bone mineral density and in women, suggesting that osteoporosis is an underlying mechanism. INSTITUTIONAL REVIEW: This study was approved by the institutional review board. PMID- 26606007 TI - The Incidence and Risk Factors for Lumbar or Sciatic Scoliosis in Lumbar Disc Herniation and the Outcomes after Percutaneous Endoscopic Discectomy. AB - BACKGROUND: Some patients with lumbar herniated intervertebral disc disease (HIVD) suffer from both pain and lateral shift or trunk list. In addition to pain, patients have concerns regarding whether trunk list is reversible. Surgical treatment is performed when pain is intractable to conservative management, but a reversal of trunk list is an incidental outcome. Percutaneous lumbar endoscopic discectomy (PELD) is one of the surgical treatment options for lumbar HIVD, but no results concerning its effect on trunk list have been reported. OBJECTIVES: The objectives of the present study were to determine the incidence of, and risk factors for, trunk list scoliosis or lateral shift and to report the outcomes of trunk list after PELD. STUDY DESIGN: Retrospective case study. IRB No. H 1111-025 384 SETTING; University medical Center, Seoul, Korea. METHODS: We selected 164 patients who were less than 60 years old, complained of unilateral leg pain, and underwent PELD. We measured the maximum trunk shift from the central sacral vertical line (CSVL-max) on preoperative whole spine radiographs and classified trunk list as CSVL-max >= 10 mm. CSVL-max was measured on serial radiographs taken at one, 3, 6, and 12 months postoperatively in patients with trunk list. RESULTS: Twenty-nine patients (17.9%) had trunk list (M:F=10:19; mean age, 37.1 +/- 11.24 years). Female gender (OR 4.28; 95% CI, 1.49-12.3) and HIVD at L4-5 (OR 5.6; 95% CI, 1.8-16.7) were risk factors for trunk list. Trunk list was normalized (CSVL-max < 10 mm) in 15 (52%) patients after PELD, and the median time for normalization was 3-6 months. Prognostic factors for the recovery of trunk list were not identified. LIMITATIONS: Selection bias should be considered in interpreting these results. CONCLUSION: Trunk list, scoliosis or lateral shift, was observed in 18% of the patients at the time of surgery. Female gender and L4-5 disc herniation were risk factors for trunk list. Trunk list was reversible in more than 50% of patients within 6 months of PELD. PMID- 26606009 TI - Combined Ablation and Radiation Therapy of Spinal Metastases: A Novel Multimodality Treatment Approach. AB - BACKGROUND: Radiation therapy (RT) is the current gold standard for palliation of painful vertebral metastases. However, other percutaneous modalities such as radiofrequency ablation (RFA), cryoablation, and vertebral augmentation have also been shown to be effective in alleviating symptoms. Combined RT and ablation may be more effective than either therapy alone in palliating painful metastatic disease to the spine. OBJECTIVE: To evaluate the safety and efficacy of combined ablation, either RFA or cryoablation, and RT in the treatment of spinal metastases. STUDY DESIGN: Retrospective study. SETTING: This is a retrospective study at a single institution. METHODS: Medical records of all patients who underwent ablation of spine lesions at a single institution between March 2012 and June 2014 were reviewed; patients treated with both RT and either RFA or cryoablation concurrently were identified. Pain scores before and after RFA were measured with the numerical rating scale (NRS) (0-10 point scale) and compared. Procedural complications, changes in general activity level, and pain medication usage after ablation were also recorded. When available, follow-up imaging was evaluated for evidence of residual or recurrent disease. RESULTS: Twenty-one patients with 36 spine metastases were treated with RT and percutaneous ablation concurrently; either RFA (21/22) or cryoablation (1/22). One patient received 2 separate RFA treatments. Overall, mean worst pain score (8.0, SD = 2.3) significantly decreased at both one week (4.3, SD = 3.1; P < .02) and 4 weeks (2.9, SD = 3.3; P < .0003). Temporary post-procedural radicular pain occurred after one RFA treatment (4.5%; 1/22). Seven patients had radiation resistant tumors (renal cell, melanoma, or sarcoma). Post-procedural imaging (median 6 months; range 2-27 months) showed stable treated disease in 12/13 treatments at 3 months and 10/10 at 6 months. LIMITATIONS: The therapeutic effect of vertebral augmentation versus percutaneous ablation cannot be separated in this retrospective study. Radiation treatment protocols were variable and included both stereotactic body and conventional RT which may have different safety and efficacy profiles. CONCLUSION: Percutaneous ablation and concurrent RT is safe and effective in palliating painful spinal metastases and can be effective in those who have radiation resistant tumor histology. PMID- 26606010 TI - Anatomic Evaluation of the Sacroiliac Joint: A Radiographic Study with Implications for Procedures. AB - BACKGROUND: Sacroiliac joint (SI) pain is increasingly being recognized as a source of low back pain. Injections and percutaneous type procedures are performed to treat symptomatic joints. However, there are limited studies available assessing the anatomy of the SI joint in vivo among patients with pain. OBJECTIVES: The purpose of this study was to provide more precise information on the dimensions and orientation of the SI joint using a new technique for the radiographic evaluation of this joint. STUDY DESIGN: Observational study. SETTING: Emergency department METHODS: Three dimensional computed tomographic (CT) reconstructions of the pelvis were formatted from 100 SI joints in 50 patients who had clinically indicated abdominal/pelvic scans. These images were manipulated to evaluate the SI joint in multiple planes and measure its dimensions, area, and relationship to anatomic landmarks such as the anterior superior iliac spine (ASIS) and posterior superior iliac spine (PSIS). RESULTS: Of the 50 patients, 23 were men and 27 women. Their mean age was 47.6 years (+/- 18.1). The SI joint consists of a superior limb which measures 39.7 mm (+/- 4.8) in length, and an inferior limb which measures 54.3 mm (+/- 5.1), oriented at an angle of 100.1 degrees (+/- 8.1) to one another. The mean area of the joint was 1276.8 mm2 (+/- 189.8). The horizontal distance from the ASIS to the front of the superior SI joint is 75.4 mm (+/- 8.4). The horizontal distance from the PSIS to the back of the superior SI joint is 43.9 mm (+/- 5.6). The joint stretches 7.5 mm (+/- 5.9) cephalad and 38.1 mm (+/- 6.4) caudal to the PSIS, and 35.4 mm (+/- 8.8) cephalad and 10.2 mm (+/- 11.4) caudal to the ASIS. LIMITATIONS: CT scans were performed with patients lying supine, while most SI joint procedures are performed with a patient prone. However it is doubtful that the bony anatomic landmarks would change appreciable in this largely immobile joint. These patients were seen in the emergency department for a variety of conditions related to abdominal and pelvic pain, and not exclusively for SI joint pain. CONCLUSIONS: Treatment of the SI joint by surgeons and interventionalists is hampered by the limited number of anatomic studies in the literature. Our study presents the SI joint as a 2-limbed structure, sitting from slightly above the level of the PSIS rostrally to slightly below the level of the ASIS caudally. Palpation of these landmarks may assist in directing physicians to the joint. To begin an interventional pain procedure, with a patient lying prone, this data supports tilting the x-ray image intensifier 10 degrees caudal past the vertical anteroposterior (AP) view for optimal approach of the SI joint's inferior limb. The needle entry should be about 44.1 mm (1.75 inches) caudal to the PSIS. The image intensifier should have a 12 degree left lateral oblique view for injection of the right SI joint, and a 12 degree right lateral oblique view for the left SI joint. PMID- 26606011 TI - Factors Associated with Increased Risk for Clinical Insomnia in Patients with Chronic Neck Pain. AB - BACKGROUND: Insomnia is highly prevalent among people with chronic pain conditions. Because insomnia has been shown to worsen pain, mood, and physical functioning, it could negatively impact the clinical outcomes of patients with chronic pain. OBJECTIVE: To determine the risk factors associated with clinical insomnia in chronic neck pain (CNP) patients. STUDY DESIGN: Retrospective analysis. SETTING: Outpatient department for interventional pain management at a university hospital. METHODS: Data from 218 CNP patients were analyzed in this study. The Insomnia Severity Index (ISI) was used to determine the presence of clinical insomnia (ISI score >= 15). Patient demographics and pain-related factors were evaluated with logistic regression analysis to identify risk factors of clinical insomnia in CNP. RESULTS: In total, 53.7% of patients reported mild to severe insomnia after neck pain development; 22.9% of patients met the criteria for clinically significant insomnia (ISI score >= 15). In multivariate analysis, high pain intensity, the presence of comorbid musculoskeletal pain, and a high level of depression were strongly associated with clinical insomnia in patients with CNP. Among these factors, a greater level of depression was the strongest predictor of clinical insomnia, with the highest odds ratio of 3.689 (95% CI 1.570-8.667). LIMITATIONS: This study was conducted in a single clinical setting including a selected study population with a homogeneous racial background. The ISI does not include several sleep-related variables, the roles of which are unknown in determining insomnia severity. CONCLUSIONS: Insomnia should be addressed as an indispensable part of pain management in CNP patients with these risk factors, especially depression. CLINICAL TRIAL: This study is a retrospective analysis. IRB No: 4-2014-0801. PMID- 26606012 TI - Coxib's Safety in Patients with Inflammatory Bowel Diseases: A Meta-analysis. AB - BACKGROUND: Patients with inflammatory bowel diseases (IBD) frequently have extraintestinal manifestations including arthritis, sacroiliitis, and ankylosing spondylitis. While the treatment of these rheumatological conditions with traditional non-steroidal anti-inflammatory drugs (NSAIDs) has been reported to lead to frequent IBD exacerbation, the safety of cyclooxygenase-2 (COX-2) inhibitors (Coxibs) remains unclear. OBJECTIVES: Our aim is to carry out a meta analysis to verify if Coxibs, employed to treat rheumatological manifestations, are associated with an increased risk of exacerbation of IBD compared to placebo. STUDY DESIGN AND SETTING: A MEDLINE, SCOPUS, ISI-Web of Knowledge, and EMBASE search of all studies published in English from 1965 to April 15, 2015, was conducted. Articles on the safety of Coxibs in patients with IBD were identified using the terms "Coxibs or cyclooxygenase-2 inhibitors or COX-2 inhibitors AND inflammatory bowel disease." METHODS: The criteria of exclusion of the studies were NSAIDs administration within 2 weeks before starting Coxibs. For the "proportion" meta-analysis, the studies had to report the proportion of patients that had to discontinue the Coxibs therapy due to an exacerbation of IBD; for the "relative risk" meta-analysis, the studies had to be prospective with a comparison between patients taking Coxibs and patients taking placebo. Two authors independently reviewed titles and abstracts of references retrieved from the literature search and selected potentially relevant studies. Differences in opinion were resolved by discussion until consensus was reached. If an agreement failed to be reached, a third author was consulted. The quality of each study was assessed on a 5-point scale adapted from studies by the Quebec Task Force on Whiplash-Associated disorders and Jadad. RESULTS: The search identified 72 publications of which 7 studies reported the proportion of patients with IBD that had to stop the Coxibs therapy because of a worsening of the activity of IBD. The pooled proportion of flare up of IBD in patients that received Coxibs was 14.4% (95% CI: 6.7-24.4%). There was no statistically significant difference between patients that assumed Coxibs and those that assumed placebo (total fixed effect relative risk = 0.86, 95% CI: 0.39-1.88, P = 0.7). LIMITATIONS: A proportion of patients received maintenance therapy with azathioprine or 6-mercaptopurine and these co-interventions could have protected against a Coxib-induced flare; furthermore, the duration of Coxib assumption in the prospective studies is shorter compared to that of the medical practice. Three of the studies included in our meta-analysis had an insufficient quality but due to the higher number of recruited patients, the studies with a better quality had a higher weight in the final result. Moreover, to assess the relative risk of flare up of IBD only randomized controlled trials have been used in the second meta-analysis. CONCLUSIONS: This meta-analysis showed that Coxibs are safe in most patients with IBD. Controlled trials of Coxibs compared with NSAIDs would be useful, at least in patients suffering from rheumatic pain refractory to standard treatment. PMID- 26606013 TI - Co-Administration of Pioglitazone Improves Fluoxetine's Antinociceptive, Neuroprotective, and Antidepressant Effects in Chronic Constriction Injury in Rats. AB - BACKGROUND: Chronic pain may be associated with diabetes mellitus and/or depression. Use of therapies that target both comorbidities is encouraged. OBJECTIVE: This study was designed to investigate the potential antinociceptive, neuroprotective, and antidepressant effects of combinations of pioglitazone or metformin with fluoxetine in chronic constriction injury (CCI) in rats. STUDY DESIGN: Experimental trial in rats. SETTING: University lab in in Saudi Arabia. METHODS: Two sets of experiments were performed. In each one, 9 groups of rats (n = 8) were used: sham, CCI, and 7 CCI-treated groups. Treatments were given orally starting on day 7 post-surgery as follows (mg/kg/day): fluoxetine (10, 20, and 40), pioglitazone (20), metformin (50), fluoxetine (20) +' pioglitazone, and fluoxetine (20) +' metformin. In the first set, on day 14 post-surgery mechanical allodynia, thermal hyperalgesia, and serum cytokines were measured. Moreover, immunoreactivity of glial fibrillary acidic protein (GFAP, a marker for astrocytic activation) in the spinal cord was assessed and histopathological changes in the ipsilateral sciatic nerve were examined. In the second set, on days 14 and 21 post-surgery the forced swimming test was done. RESULTS: In the first set, all treatments significantly decreased mechanical allodynia while all treatments except F10 and F20 significantly decreased thermal hyperalgesia compared to the CCI group. The F20+'M group showed the highest decreases, however still significantly lower than those of the sham group. The treatments didn't impair motor function in the rotarod test. All treatments significantly decreased serum levels of tumor necrosis factor- alpha, interleukin-6, and monocyte chemoattractant protein-1 while increasing the level of interleukin-10. The CCI induced marked increase of GFAP immunoexpression has been reduced to moderate with fluoxetine (40) and pioglitazone, and to mild with metformin and the combination groups. The CCI-induced changes in sciatic nerve were less in fluoxetine (40), pioglitazone, and metformin groups, and least in the combination groups. In the second set, the immobility duration was significantly reduced by F20, F40, P, F20+'P, and F20+'M compared to the CCI group. The F20+'P group showed the highest decrease, however still significantly lower than that of the sham group. The treatments didn't affect locomotor activity in the open field test. LIMITATIONS: Measuring the cytokines levels only in blood and not in the spinal cord and sciatic nerve and measuring the outcome measures in the first set of experiments at only one time-point. CONCLUSIONS: Co-administration of pioglitazone or metformin with low-dose fluoxetine improved mechanical allodynia, thermal hyperalgesia, and neurohistopathological changes while co-administration of pioglitazone, but not metformin, improved the depressive-like behavior in the peripheral nerve injury model of neuropathic pain in rats. Extrapolation of the current results to clinical reality could be beneficial for pain patients with diabetes and/or depression, however this needs further confirmatory studies. PMID- 26606014 TI - Invasive Management for Pediatric Complex Regional Pain Syndrome: Literature Review of Evidence. AB - BACKGROUND: Complex regional pain syndrome (CRPS) is a multifactorial condition with complex pathogenesis characterized by spontaneous or stimulus-induced pain that is disproportionate to the inciting event. It is also commonly accompanied by a myriad of autonomic and motor disturbances in highly variable combinations. This condition has been underreported in children until recently. Consequently, the management of CRPS in the pediatric population presents an even greater challenge than in adults, partly because there is a lack of clinical data concerning the efficacy of the diverse treatment methods available, and partly because successful treatment of CRPS involves a multidisciplinary approach. There is a variety of invasive methods to the treatment of CRPS, but scarce pediatric focused trials have been published to date. OBJECTIVE: To examine and analyze the data currently existing for the invasive management of CRPS in children. It further suggests a management algorithm based in the evidence reviewed and our team experience. STUDY DESIGN: A comprehensive review of invasive management for pediatric CRPS. SETTING: Academic hospital in Spain. METHODS: A comprehensive review of all the evidence published to date was conducted. Four databases (PubMed, Medline, Web of Science, Embase, and Cochrane databases) were searched for articles published from 1980 to 2014. The eligibility criteria were any paper published in English or Spanish where a non-conventional approach was used to manage pediatric CRPS. Two independent reviewers extracted the data. RESULTS: Many case series have reported the use of interventional management with positive results; however, there is not a single randomized control trial to date comparing the conservative and the invasive management in children. The largest series of pediatric cases showed that between 29% to 35% of children with CRPS needed interventional measures to manage this condition successfully. Sympathetic blocks and spinal drug infusion emerge as the most reported techniques; the spinal infusion of drugs together with the spinal cord stimulation being the most successfully employed. Based upon the available evidence with regard to effect and complications, we recommend an algorithm for the management of pediatric CRPS. LIMITATIONS: The limitations of this study include the paucity of literature, lack of randomized trials, and lack of quality evidence. CONCLUSIONS: Invasive techniques have been used to treat CRPS over the last few decades; however, the evidence for their use is still very weak. Invasive management should be contemplated only when high-standard conservative management has failed to work. PMID- 26606015 TI - Manual Therapy for Hip Osteoarthritis: A Systematic Review and Meta-analysis. AB - BACKGROUND: Hip osteoarthritis (HOA) is one of the major causes of disability in seniors and is costly to society. Manual therapy is one therapeutic approach to treating HOA. OBJECTIVES: To assess the effect of manual therapy compared to the placebo or wait-list/no treatment or a minimal intervention control for HOA at post-treatment and short-, intermediate- and long-term follow-ups. STUDY DESIGN: A systematic review and meta-analysis of randomized controlled trials (RCTs). SETTING: Hospital outpatient clinic in China. METHODS: We searched PubMed, EMBASE, the Cochrane Library, CINAHL, ISI web of knowledge, and Chinese databases from the inception to October 2014 without language restrictions. References of systematic reviews and other related reviews, files in our department, and conference proceedings as grey literature were also screened by hand. RCTs compared manual therapy to the placebo, wait-list/no treatment or a minimal intervention control with an appropriate and precise description of randomization. Two reviewers independently conducted the search results identification, data extraction, and methodological quality assessment. We calculated the risk difference (RD) for dichotomous data and the mean difference (MD) or standardized mean difference (SMD) for continuous data in a fixed or random effect model. OUTCOME MEASURES: The primary outcomes were self-reported pain in the past week and physical function. The secondary outcomes were the quality of life, global perceived effect, patients' satisfaction, cost, and adverse events. RESULTS: Six studies involving 515 HOA patients were included. Five of the 6 studies ranked as high quality in the methodological assessment. Immediately post-treatment, there was low-quality evidence that manual therapy could not statistically significantly relieve pain (SMD: -0.07 [95%CI -0.38 to 0.24]); for physical function, a moderate quality of evidence showed that manual therapy could not improve the physical function significantly (SMD: 0.14 [95%CI 0.08 to 0.37]). We still found low-quality evidence that manual therapy did not benefit the patients in the global perceived effect (RD: 0.12 [95%CI -0.12 to 0.36]), and in terms of quality of life. In addition, the risks of patients in the manual therapy group was 0.13 times higher than that in the controls (RD: 0.13 [95%CI -0.05 to 0.31]) in the low-quality evidence studies. We could not find any evidence that manual therapy benefits the patients at short-, intermediate- or long-term follow-up. There were no studies reporting patients' satisfaction or cost. LIMITATIONS: The limitations of this systematic review include the paucity of literature and inevitable heterogeneity between included studies. CONCLUSION: This review did not suggest there was enough evidence for manual therapy for the management of HOA. However, we are not confident in making such a conclusion due to the limitations listed above. PMID- 26606016 TI - Percutaneous Kyphoplasty for Kummell Disease with Severe Spinal Canal Stenosis. AB - BACKGROUND: Percutaneous kyphoplasty (PKP) has been proven as an effective, minimally invasive procedure for the treatment of Kummell's disease in the early stages. However, a risk of cement leakage and further neurological damage remains during and after PKP, especially in chronic osteoporotic stage III Kummell's disease with severe spinal canal stenosis. OBJECTIVE: To evaluate the feasibility and efficacy of PKP for the treatment of chronic osteoporotic stage III Kummell's disease with severe spinal canal stenosis. STUDY DESIGN: A retrospective evaluation of postoperative radiographs. SETTING: Pain management clinic. METHODS: A retrospective study was performed on 9 patients with 11 levels managed with PKP for chronic osteoporotic stage III Kummell's disease with severe spinal canal stenosis. Clinical and radiological outcomes were assessed. RESULTS: Substantial pain relief was attained in all the patients. Both visual analogue scale (VAS) and Oswestry Disability Index (ODI) scores improved significantly from pre- to post-operation (P < 0.05), and remained unchanged at every follow up. No neurological deterioration was found. Postoperatively, the anterior and midline vertebral body heights were significantly corrected (P < 0.05), and were sustained at the final follow-up. Similar results were seen in the correction of kyphotic angle. Neither cement leakage into the spinal canal nor further dislodging of the posterior vertebral fragments occurred. Two cases experienced subsequent fractures with one having a second PKP and the other being treated conservatively. LIMITATIONS: Retrospective study of 9 cases with 11 levels due partly to the rarity of the disorder. CONCLUSIONS: PKP is an effective, minimally invasive procedure for the treatment of chronic osteoporotic stage III Kummell's disease with severe spinal stenosis, leading to a significant relief of symptoms and improvement of functional status. INSTITUTIONAL REVIEW: This study was approved by the Institutional Review Board. PMID- 26606017 TI - High Frequency Repetitive Transcranial Magnetic Stimulation Therapy For Chronic Neuropathic Pain: A Meta-analysis. AB - BACKGROUND: Increasing evidence supports an analgesic effect of repetitive transcranial magnetic stimulation (rTMS) for neuropathic pain (NP). However, the optimal parameters of rTMS (stimulation frequency and treatment sessions) for achieving long-term analgesic effects remain unknown. This study analyzed the current findings in the literature. OBJECTIVE: The aim of this study was to assess the optimal parameters of rTMS for NP, including the rTMS sessions needed for inducing acute as well as long-term analgesic effects. STUDY DESIGN: A meta analysis of the analgesic effect of high frequency rTMS (HF- rTMS) for neuropathic patients. SETTING: This meta-analysis examined all studies involving the analgesic efficacy of HF-rTMS for NP. METHODS: PubMed, Embase, and the Cochrane library were searched for clinical studies of rTMS treatment on NP published before December 31, 2014. Crude standardized mean differences (SMD) with 95% confidence interval (CI) were calculated for pain intensity after different treatment sessions (from 1 to 10) and follow-up of one or 2 months after rTMS treatment using random effect models. RESULTS: Twenty-five studies (including 32 trials and 589 patients) were selected for the meta-analysis according to the inclusion and exclusion criteria. All 3 HF-rTMS treatments (5, 10, and 20 Hz) produced pain reduction, while there were no differences between them, with the maximal pain reduction found after one and 5 sessions of rTMS treatment. Further, this significant analgesic effect remained forone month after 5 sessions of rTMS treatment. LIMITATIONS: There are limitations of this meta analysis. For example, the long-term analgesic effects of different HF-rTMS and low frequency (LF) rTMS sessions, including the single session of rTMS on different NP of varying origins have yet not been evaluated; the full degree of pain relief is still unclear for many rTMS studies. CONCLUSIONS: HF-rTMS stimulation on primary motor cortex is effective in relieving pain in NP patients. Although 5 sessions of rTMS treatment produced a maximal analgesic effect and may be maintained for at least one month, further large-scale and well controlled trials are needed to determine if this enhanced effect is specific to certain types of NP such as post-stroke related central NP. PMID- 26606018 TI - ANVCFV Score System: Assessment for Probability of New Vertebral Compression Fractures after Percutaneous Vertebroplasty in Patients with Vertebral Compression Fractures. AB - BACKGROUND: Percutaneous vertebroplasty (PVP) is widely used for the treatment of painful vertebral compression fractures (VCFs). However, new VCFs occur frequently after PVP. OBJECTIVES: We aim to establish an objective risk score system to assess the possibility of new vertebral fractures in patients with VCFs undergoing PVP. STUDY DESIGN: This study was a retrospective study, and it was approved by the Institutional Review Board of our 2 institutions. SETTING: This study consists of patients from 2 large academic centers. METHODS: Patients with VCFs who underwent their first PVP and met the inclusion criteria between January 2007 and December 2013 at Hospital A (training cohort) and Hospital B (validation cohort) were included. In the training cohort, the independent risk factors for new VCFs after PVP were identified by multivariate stepwise backward Cox regression analysis from the risk factors selected by univariate analysis and Harrell's C-statistics and used to develop the score system (assessment for new VCFs after PVP [ANVCFV]) to predict the probability of new VCFs. RESULTS: In total, 397 patients (training cohort: n = 241; validation cohort: n = 156) were included in this study. In the training cohort, the ANVCFV score was developed based on 5 independent risk factors for the new VCFs after PVP, including lower computed tomography (CT) values, pre-existing old VCFs, intradiscal cement leakage, more than one vertebra treated, and superior or inferior marginal cement distribution in the vertebra. The patients were divided into 2 groups by the ANVCFV score of -1.5 to 8.5 vs. > 8.5 points in the probability of new VCFs (median fracture-free time: 1846 vs. 732 days; P < 0.001) in the training cohort. The accuracy of this score system was 77.4% for the training cohort and 85.3% for the validation cohort. LIMITATIONS: The main limitations of this study are that it is a retrospective study and that there is a significant difference of the treated vertebrae of PVP per session between the 2 cohorts. CONCLUSION: Patients who underwent their first PVP with an ANVCFV score > 8.5 points may exhibit an increased chance of suffering from new VCFs. PMID- 26606019 TI - Validation of a Simplified Chinese Version of the Pain Catastrophizing Scale and an Exploration of the Factors Predicting Catastrophizing in Pain Clinic Patients. AB - BACKGROUND: Chronic pain is very common worldwide and can lead to disability, depression and absence from work. Catastrophizing has been proven to affect individuals' belief systems and coping strategies, and it is an essential risk factor for chronic pain. The pain catastrophizing scale (PCS) has been developed for the assessment of catastrophizing. However, a Chinese version of this scale is not available, and physicians are therefore unable to determine which patients are prone to catastrophizing. Additionally, the risk factors for catastrophizing are unknown. OBJECTIVE: We aimed to cross-culturally adapt and validate the PCS for simplified Chinese (SC-PCS) and explore the risk factors for catastrophizing in patients from a pain clinic. STUDY DESIGN: We utilized a prospective, nonrandomized, cross-sectional, descriptive survey design. A second analysis of test-retest reliability was performed in a longitudinal, observational study. SETTING: A convenience sample was recruited from a pain clinic in a tertiary hospital. METHODS: This study was performed in 3 stages. In the first stage, the PCS was translated and culturally adapted to create a Chinese version; in the second stage, the measurement properties of the SC-PCS were tested, including the content validity, construct validity and reliability; and in the third stage, factors affecting catastrophizing in a pain clinic setting were explored. The adaptation was performed using a forward-backward method, and content validity was analyzed by examining the response trend (Z-skewness and item-total correlation). Construct validity was analyzed by assessing structural validity (confirmatory factor analysis [CFA] and exploratory factor analysis [EFA]) and a priori hypothesis testing. Reliability was analyzed by internal consistency (Cronbach's alpha) and test-retest reliability (intraclass correlation coefficient [ICC]). Risk factors for catastrophizing were analyzed by multivariate linear regression. RESULTS: A total of 153 patients were included, with a response rate of 96%; no items were excluded from the SC-PCS. Both CFA and EFA confirmed a 3-factor structure, and 9/10 of the hypotheses were verified for construct validity. Excellent reliability was acquired with a Cronbach's alpha of 0.91, and an ICC of 0.94 was determined. Risk factors for catastrophizing included college education (beta = 0.47), pain duration (beta = 0.40), female (beta = 0.31), freelancer status (beta = 0.31), and retired status (beta = 0.19). LIMITATIONS: The recruited patients experienced severe pain or long-duration pain in a pain clinic setting. This may limit the applicability of the SC-PCS to patients with low or moderate pain levels. CONCLUSION: The PCS has been linguistically translated into simplified Chinese and culturally adapted for a Chinese population with remarkable clinical acceptance, good construct validity, and excellent internal consistency and test-retest reliability. Education, pain duration, marital status, gender, income, and use of pain medications are important factors affecting catastrophizing. PMID- 26606020 TI - Extracellular Signal-Regulated Kinase 5 in the Cerebrospinal Fluid-Contacting Nucleus Contributes to Neuropathic Pain in Rats. AB - BACKGROUND: The activation of mitogen-activated protein kinases (MAPKs) have been observed in synaptic plasticity processes of learning and memory in neuropathic pain. Cerebrospinal fluid-contacting nucleus (CSF-CN) has been identified with the onset and persistence of neuropathic pain. However, whether extracellular signal-regulated protein kinase 5 (ERK5), a member of MAPKs, in CSF-CN participates in neuropathic pain has not been studied yet. OBJECTIVE: The aim of the present study was to identify the role of ERK5 in CSF-CN on the formation and development of neuropathic pain, and to investigate its possible mechanism. STUDY DESIGN: Controlled animal study. SETTING: University laboratory. METHODS: After a chronic constriction injury (CCI) model was produced, BIX02188 was dissolved in 1% DMSO and injected into the lateral ventricles LV in a volume of 3 MUl with different doses (0.1 MUg, 1 MUg, 10 MUg). Mechanical allodynia and thermal hypersensitivity behavioral test, immunofluorescence, and western blot technique were used in this research. RESULT: Following CCI, mechanical allodynia and thermal hypersensitivity were developed within a day, peaked at 14 days, and persisted for 21 days. ERK5 was remarkably activated by CCI in CSF-CN. Moreover, selective inhibiting of p-ERK5 expression in CSF-CN by BIX02188 could significantly relieve CCI-induced mechanical allodynia and thermal hypersensitivity, accompanying with the decreased phosphorylation of cAMP response-element binding protein (CREB) in CSF-CN. LIMITATIONS: More underlying mechanism(s) of the role of ERK5 in CSF-CN on the formation and development of neuropathic pain will be needed to explore in future research. CONCLUSION: These findings suggest activation of ERK5 in CSF-CN might contribute to the onset and development of neuropathic pain and its role might be partly accomplished by p CREB. PMID- 26606021 TI - Rat Model of Trigeminal Neuralgia Using Cobra Venom Mimics the Electron Microscopy, Behavioral, and Anticonvulsant Drug Responses Seen in Patients. AB - BACKGROUND: A new animal model of trigeminal neuralgia produced by injecting cobra venom into the infraorbital nerve (ION) trunk in rats had been developed. We tested and extended the model by observing the ultrastructural alterations of neurons and ameliorative effect of pregabalin in cobra venom-induced pain behaviors of rats. OBJECTIVES: The goal of this study was to prove the feasibility of the cobra venom-induced model of trigeminal neuralgia and to demonstrate the demyelination change of ION and medulla oblongata is the major pathological change of trigeminal neuralgia. STUDY DESIGN: An experimental study. SETTING: Department of Anesthesiology, Pain Medicine, and Critical Care Medicine, Aviation General Hospital of China Medical University. METHODS: Experiments were carried out on male Sprague-Dawley rats. Video recordings were taken after the cobra venom injection and pregabalin administration. Ultrastructural alterations of ION and medulla oblongata were observed at the electron microscopic level. We also observed alteration in pain behaviors by analysis of video recordings. RESULTS: Compared to the preoperative and sham-operated group rats, experimental group rats exhibited significant changes in exploratory, resting, face-grooming, and head-shake behaviors on 3, 7, 14 days after operation (P < 0.01). The demyelination changes of ION and medulla oblongata were evident after administration of cobra venom to the ION. Compared to the pre-treated (no pregabalin administration) and control group rats, pregabalin group rats showed profound changes in exploratory, resting, face-grooming, and head-shake behaviors throughout the 14 day study period after treatment with drugs (P < 0.01). LIMITATIONS: Ultrastructural alterations of ION and medulla oblongata were not examined after the treatment with pregabalin. CONCLUSIONS: Video recordings of free behaviors and pregabalin application prove the feasibility of the rat model of trigeminal neuralgia. The results of electron micrographs are consistent with a previous study in humans showing that the demyelination change of axons is the major pathological change of trigeminal neuralgia. The central demyelination alterations may explain why the mechanical threshold was found to be decreased on the non-operated side of experimental animals. PMID- 26606022 TI - Experimental Evaluation of Percutaneous Lumbar Laser Disc Decompression Using a 1414 nm Nd:YAG Laser. AB - BACKGROUND: Laser ablation under an epiduroscopic view allows for the vaporization of a small amount of the nucleus pulposus, causing a reduction in intradiscal pressure and relief of radicular pain. Currently, Ho:YAG and Nd:YAG lasers are commonly used for spinal diseases. However, the use of the Nd:YAG laser for intra-spinal procedures can be limited because of thermal injury and low efficacy. OBJECTIVE: To investigate the efficacy and safety of epiduroscopic laser ablation using a 1414 nm Nd:YAG laser, we examined that laser ablation was able to penetrate nucleus pulposus without heating surrounding tissues and without mechanical damage to surrounding tissue. STUDY DESIGN: Our experiment involved live and cadaveric animal studies and a human cadaveric study. SETTING: University in Korea. METHODS: Two live pigs, 3 porcine cadavers, and 2 human cadavers were used. For the in vitro study, intradiscal and epidural pressure and temperature were compared in vertebral columns obtained from 3 porcine cadavers before and after laser ablation. For the in vivo study, 2 pigs were used to simulate percutaneous epiduroscopic laser ablation. They were observed for behavioral changes and neurological deficits for one month after the laser ablation procedure. Two human cadavers were used for placing the laser fiber and epiduroscope in the correct target site through the sacral hiatus. Histological analysis was also performed to observe any damage around the ablated lesion. RESULTS: Both intradiscal and epidural pressure were markedly reduced immediately after laser ablation as compared with the pre-ablative state. The amount of the pressure decrease in the intradiscal space was significantly greater than that in the epidural space (45.8 +/- 15.0 psi vs. 30.0 +/- 9.6 psi, P = 0.000). The temperature beneath the ipsilateral spinal nerve, which was the nearest site to the laser probe, never exceeded 40 degrees C. Histology revealed no evidence of thermal damage to surrounding structures, including the spinal nerves, end plates, and vertebrae, after laser ablation. All live pigs showed normal behavior without any sign of pain. In the human cadaveric study, there was no case of targeting failure or dural laceration. The mean time to reach the target region was less than 5 minutes. LIMITATIONS: The pressure measurements were performed on cadavers and not in vivo. Cadaver models cannot account for intradiscal pressure changes that occur during live muscle contraction and different positions, which may affect results. Moreover, although we controlled temperatures with heat baths, vascular and cerebrospinal fluid circulations were not simulated. Those circulations may change the temperature results in vivo. CONCLUSIONS: The 1414 nm Nd:YAG laser can be used effectively and safely under the guidance of a spinal epiduroscope in an in vivo porcine model and in a human cadaveric model. STUDY APPROVAL: Approval for the current study was granted by the Institutional Review Board of our institute (approval number: 1-2014-0049). PMID- 26606023 TI - Effect of Augmentation Material Stiffness on Adjacent Vertebrae after Osteoporotic Vertebroplasty Using Finite Element Analysis with Different Loading Methods. AB - BACKGROUND: Vertebroplasty is an effective treatment for osteoporotic vertebral fractures, which are one of the most common fractures associated with osteoporosis. However, clinical observation has shown that the risk of adjacent vertebral body fractures may increase after vertebroplasty. The mechanism underlying adjacent vertebral body fracture after vertebroplasty is not clear; excessive stiffness resulting from polymethyl methacrylate has been suspected as an important mechanism. OBJECTIVES: The aim of our study was to compare the effects of bone cement stiffness on adjacent vertebrae after osteoporotic vertebroplasty under load-controlled versus displacement-controlled conditions. STUDY DESIGN: An experimental computer study using a finite element analysis. SETTING: Medical research institute, university hospital, Korean. METHODS: A three-dimensional digital anatomic model of L1/2 bone structure was reconstructed from human computed tomographic images. The reconstructed three-dimensional geometry was processed for finite element analysis such as meshing elements and applying material properties. Two boundary conditions, load-controlled and displacement-controlled methods, were applied to each of 5 deformation modes: compression, flexion, extension, lateral bending, and torsion. RESULTS: The adjacent L1 vertebra, irrespective of augmentation, revealed nearly similar maximum von Mises stresses under the load-controlled condition. However, for the displacement-controlled condition, the maximum von Mises stresses in the cortical bone and inferior endplate of the adjacent L1 vertebra increased significantly after cement augmentation. This increase was more significant than that with stiffer bone cement under all modes, except the torsion mode. LIMITATIONS: The finite element model was simplified, excluding muscular forces and incorporating a large volume of bone cement, to more clearly demonstrate effects of bone cement stiffness on adjacent vertebrae after vertebroplasty. CONCLUSION: Excessive stiffness of augmented bone cement increases the risk of adjacent vertebral fractures after vertebroplasty in an osteoporotic finite element model. This result was most prominently observed using the displacement-controlled method. PMID- 26606024 TI - Ultrasound-Guided Injection of the Adductor Longus and Pectineus in a Cadaver Model. AB - BACKGROUND: The close anatomic and functional relationship between the proximal parts of the adductor longus and pectineus muscles produce considerable overlap in symptoms and signs in the inguinal region. To our knowledge, there have been no publications of ultrasound (US)-guided injection techniques into the 2 muscles. OBJECTIVE: This study sought to describe US-guided injection techniques in the proximal part of the adductor longus and pectineus muscles and to validate whether these techniques deliver injections appropriately to their target muscles in unembalmed cadavers. STUDY DESIGN: Cadaveric study. METHODS: A preliminary trial with 2 unembalmed cadavers provided information on the target sonographic structures of proximal adductor longus and pectineus muscles. Bilateral US-guided intramuscular injections in the proximal adductor longus and pectineus were performed using the remaining 5 unembalmed male cadavers. To avoid confusion of dye location, we did not inject into both the adductor longus and pectineus muscle in the same side. After injections, each specimen was dissected to evaluate the accuracy of injection. RESULTS: Ten injections (5 for the adductor longus muscle and 5 for the pectineus muscle) were performed targeting the proximal parts of muscles in 5 cadaveric specimens. All injections were successful and blue dye was injected accurately at the target area within the adductor longus and the pectineus muscles. No other muscles were injected unintentionally. There were no accidental penetrations and/or injuries at adjacent neurovascular structures as well. LIMITATION: Despite successful injection of the proximal parts of adductor longus and pectineus, this study did not verify the usefulness of this technique in clinical practice. CONCLUSIONS: The results of this study may play a role in the diagnosis and management of patients presenting with chronic pelvic pain syndrome and sports hernia. PMID- 26606025 TI - How Much Is Too Much? Are Opioids Always the Answer to Pain? PMID- 26606026 TI - Hypodermis Tension Loop: A New Preventative Measure for Lead Migration in the Morbidly Obese. AB - Electrode migration/displacement is reported to be the most common complication of spinal cord stimulator (SCS) implantation, with the literature reporting incidences from 13.2% to 22.6%. There have been numerous publications describing techniques preventing lead migration, with most involving tying leads to skin and fascia for trial and permanent leads, respectively. However, few have addressed how to prevent migration in the case of hypermobile tissue seen in the morbidly obese. We describe the creation of subcutaneous tension loops to prevent lead migration. PMID- 26606027 TI - Carbamazepine Withdrawal-induced Hyperalgesia in Chronic Neuropathic Pain. AB - Combined pharmacological treatments are the most used approach for neuropathic pain. Carbamazepine, an antiepileptic agent, is generally used as a third-line treatment for neuropathic pain and can be considered an option only when patients have not responded to the first- and second-line medications. In the case presented herein, a patient with neuropathic pain was treated using a combined pharmacological regimen. The patient's pain deteriorated, despite increasing the doses of opioids, when carbamazepine was discontinued, potentially because carbamazepine withdrawal disrupted the balance that was achieved by the multifaceted pharmacological regimen, thus inducing hyperalgesia. Interestingly, when carbamazepine was prescribed again, the patient's pain was successfully managed. Animal research has reported that carbamazepine can potentiate the analgesic effectiveness of morphine in rodent models of neuropathic pain and postoperative pain. This clinical case demonstrates that carbamazepine may have a synergistic effect on the analgesic effectiveness of morphine and may inhibit or postpone opioid-induced hyperalgesia. We postulate that a probable mechanism of action of carbamazepine may involve -aminobutyric acid-ergic potentiation and the interruption of glutamatergic function via N-methyl-D-aspartate receptors. Further research is warranted to clarify the analgesic action of carbamazepine and its potential use for the prevention of opioid-induced hyperalgesia in chronic neuropathic pain patients. PMID- 26606028 TI - Human Serum Modifies Aggregation Properties of Commonly Used Epidural Steroids. AB - BACKGROUND: Case reports of catastrophic neurological sequelae during ESIs have questioned the safety of this procedure. A proposed mechanism is particulate steroid embolization resulting in neuralischemia. Previous reports have described steroid clumping in common epidural injection mixtures. We demonstrate that physiologic medium can also modify aggregation. OBJECTIVE: To inspect and compare aggregative properties of steroid preparations with and without human serum. SETTING: Academic tertiary care center. HYPOTHESIS: Particulate steroids display different aggregation characteristics in serum compared to non-physiologic solutions. DESIGN: Solutions were inspected under light microscopy: betamethasone sodium phosphate/betamethasone acetate, methylprednisolone, and dexamethasone were each mixed in lidocaine 1%, bupivacaine 0.5%, or sterile water in a 1:1 ratio. All preparations were inspected under light microscopy with 100x and 400x magnifications by a pathologist blinded to our expectations and hypothesis. Five random viewing fields were selected within each slide and the number of aggregates per field and the number of particles per aggregate was evaluated. RESULTS: The addition of serum had a significant effect on steroid particle aggregation and number of particles per aggregate. LIMITATIONS: This study was limited by sample size as only 2 sets of human serum samples were tested with each preparation against one non-serum control. Additionally, as steroid preparations were evaluated under light microscopy, the ex vivo setting must be considered in the interpretation of results. Finally, mixing preparations with human serum as opposed to whole blood was necessary to allow for improved visibility on light microscopy despite the fact that whole blood may be necessary to more closely emulate in vivo coagulation setting. CONCLUSIONS: Overall, the presence of serum resulted in fewer large steroid particle aggregates when compared to non-serum control samples. Amongst particulate steroids, betamethasone with bupivacaine 0.5% demonstrated the fewest and smallest particle aggregates, suggesting that preparation may reduce the risk of embolic infarction. Methylprednisolone formed significantly larger particles in bupivicaine 0.5% with serum compared to non-serum controls. PMID- 26606029 TI - Pelvic Neuralgias by Neuro-Vascular Entrapment: Anatomical Findings in a Series of 97 Consecutive Patients Treated by Laparoscopic Nerve Decompression. AB - BACKGROUND: Some patients have pelvic, pudendal, or low lumbar pain radiating into the legs that is worse while sitting but differs from pudendal neuralgia. The purpose of this study was to present a new clinical entity of neuropathic pelvic pain by pelvic neuro-vascular entrapment. OBJECTIVES: To report about the locations of predilection for pelvic neurovascular entrapment. STUDY DESIGN: Prospective cohort pre- and post-intervention. SETTING: University referral unit specializing in advanced gynecological surgery and neuropelveology. METHODS: Patients, Intervention: In a prospective study, 97 patients presenting with intractable pelvic neuropathic pain (pudendal pain, gluteal pain, vulvodynia, coccygodynia, and sciatic pain) underwent laparoscopic exploration with decompression of compressed pelvic somatic nerves. The population included 76 (78.3%) women and 21 men. Indication for laparoscopic exploration of pelvic nerves suspected to be involved in pain has been indicated after neuropelveological work up, pelvic neuro-magnetic resonance imaging (MRI) and Doppler-sonography. Pain evolution was recorded over 2 years after the procedure. MEASUREMENTS AND MAIN RESULTS: Three entities were isolated: pudendal neuralgie by compression at the less sciatic notch, sacral radiculopathy at S2-4 by compression at the infracardinal level of the sacral plexus, and sciatica L5-S1/2 by compression at the greater sciatic notch. Pain was worse sitting (98%), during menstrual bleeding in women, and during Valsalva maneuver, but the pain did not wake the patients up at night and was not accompanied by neurologic dysfunctions. A decrease in VAS scores (> 50%) at 2 years follow-up was observed in 86 patients (88.6%). CONCLUSIONS: Neuro-vascular entrapment is a pathophysiologic phenomenon implicated in several pelvic neuropathies. The most common are L5-S1 sciatica, pudendal neuralgia, and sacral radiculopathy. After intraoperative confirmation, laparoscopic exploration of the entire sacral plexus is essential to diagnose conflict. Laparoscopic decompression is a treatment of choice, based on the separation of the offending vessel from the nerves. Those procedures are safe, with a high success rate; the neuropelveological approach is essential in order to obtain good treatment results. The laparoscopic approach gives the possibility of reducing morbidity and improving results by providing wider insight into the operating field with smaller intraoperative injury. PMID- 26606030 TI - Spontaneous Iliopsoas Haematoma Presenting with Groin Pain under Warfarin Therapy. PMID- 26606036 TI - Effects of in vivo exposure to polyfluorinated dibenzo-p-dioxins on organo somatic indices and ethoxyresorufin-O-deethylase activity in mice (Mus musculus). AB - In this study, five different congeners of polyfluorinated dibenzo-P-dioxins (PFDDs) (1,8-di-FDD, 1,3,8-tri-FDD, 1,3,6,8-tetra-FDD, 2,3,7,8-tetra-FDD and 1,2,3,4,5,6,7,8-octa-FDD), representing different numbers and positions of fluorine substituents of all 75 PFDD congeners, were synthesized and purified to evaluate their potential environmental impact on living organisms. Their toxicity was evaluated by determining the impact on the organo-somatic indices (OSI) and ethoxyresorufin-O-deethylase (EROD) activity in mice (Mus musculus) after intragastric administration with different doses (0.5-100 MUg/kg body weight) for 3 days. The results showed that these PFDDs significantly inhibited the growth and changed the OSI in mouse tissues. Notably, hepatic EROD activity was markedly induced in mice after exposure to these PFDDs, probably indicating a high affinity of binding to the aryl hydrocarbon receptor. Overall, these findings provided some preliminary but alarming toxicity data of PFDDs, and filled information gaps in the toxicological databases for living organisms. PMID- 26606031 TI - Efficacy of Epidural Injections in Managing Chronic Spinal Pain: A Best Evidence Synthesis. AB - BACKGROUND: Epidural injections have been used since 1901 in managing low back pain and sciatica. Spinal pain, disability, health, and economic impact continue to increase, despite numerous modalities of interventions available in managing chronic spinal pain. Thus far, systematic reviews performed to assess the efficacy of epidural injections in managing chronic spinal pain have yielded conflicting results. OBJECTIVE: To evaluate and update the clinical utility of the efficacy of epidural injections in managing chronic spinal pain. STUDY DESIGN: A systematic review of randomized controlled trials of epidural injections in managing chronic spinal pain. METHODS: In this systematic review, randomized trials with a placebo control or an active-control design were included. The outcome measures were pain relief and functional status improvement. The quality of each individual article was assessed by Cochrane review criteria, as well as the Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB). Best evidence synthesis was conducted based on the qualitative level of evidence (Level I to V). Data sources included relevant literature identified through searches of PubMed for a period starting in 1966 through August 2015; Cochrane reviews; and manual searches of the bibliographies of known primary and review articles. RESULTS: A total of 52 trials met inclusion criteria. Meta-analysis was not feasible. The evidence in managing lumbar disc herniation or radiculitis is Level II for long-term improvement either with caudal, interlaminar, or transforaminal epidural injections with no significant difference among the approaches. The evidence is Level II for long-term management of cervical disc herniation with interlaminar epidural injections. The evidence is Level II to III in managing thoracic disc herniation with an interlaminar approach. The evidence is Level II for caudal and lumbar interlaminar epidural injections with Level III evidence for lumbar transforaminal epidural injections for lumbar spinal stenosis. The evidence is Level II for cervical spinal stenosis management with an interlaminar approach. The evidence is Level II for axial or discogenic pain without facet arthropathy or disc herniation treated with caudal or lumbar interlaminar injections in the lumbar region; whereas it is Level II in the cervical region treated with cervical interlaminar epidural injections. The evidence for post lumbar surgery syndrome is Level II with caudal epidural injections and for post cervical surgery syndrome it is Level II with cervical interlaminar epidural injections. LIMITATIONS: Even though this is a large systematic review with inclusion of a large number of randomized controlled trials, the paucity of high quality randomized trials literature continues to confound the evidence. CONCLUSION: This systematic review, with an assessment of the quality of manuscripts and outcome parameters, shows the efficacy of epidural injections in managing a multitude of chronic spinal conditions. PMID- 26606037 TI - Variations in bacterial communities during foliar litter decomposition in the winter and growing seasons in an alpine forest of the eastern Tibetan Plateau. AB - Bacterial communities are the primary engineers during litter decomposition and related material cycling, and they can be strongly controlled by seasonal changes in temperature and other environmental factors. However, limited information is available on changes in the bacterial community from winter to the growing season as litter decomposition proceeds in cold climates. Here, we investigated the abundance and structure of bacterial communities using real-time quantitative PCR and denaturing gradient gel electrophoresis (DGGE) during a 2-year field study of the decomposition of litter of 4 species in the winter and growing seasons of an alpine forest of the eastern Tibetan Plateau. The abundance of the bacterial 16S rRNA gene was relatively high during decomposition of cypress and birch litter in the first winter, but for the other litters 16S rRNA abundance during both winters was significantly lower than during the following growing season. A large number of bands were observed on the DGGE gels, and their intensities and number from the winter samples were lower than those from the growing season during the 2-year decomposition experiment. Eighty-nine sequences from the bands of bacteria that had been cut from the DGGE gels were affiliated with 10 distinct classes of bacteria and an unknown group. A redundancy analysis indicated that the moisture, mass loss, and elemental content (e.g., C, N, and P) of the litter significantly affected the bacterial communities. Collectively, the results suggest that uneven seasonal changes in climate regulate bacterial communities and other decomposers, thus affecting their contribution to litter decomposition processes in the alpine forest. PMID- 26606038 TI - Predictive modeling of structured electronic health records for adverse drug event detection. AB - BACKGROUND: The digitization of healthcare data, resulting from the increasingly widespread adoption of electronic health records, has greatly facilitated its analysis by computational methods and thereby enabled large-scale secondary use thereof. This can be exploited to support public health activities such as pharmacovigilance, wherein the safety of drugs is monitored to inform regulatory decisions about sustained use. To that end, electronic health records have emerged as a potentially valuable data source, providing access to longitudinal observations of patient treatment and drug use. A nascent line of research concerns predictive modeling of healthcare data for the automatic detection of adverse drug events, which presents its own set of challenges: it is not yet clear how to represent the heterogeneous data types in a manner conducive to learning high-performing machine learning models. METHODS: Datasets from an electronic health record database are used for learning predictive models with the purpose of detecting adverse drug events. The use and representation of two data types, as well as their combination, are studied: clinical codes, describing prescribed drugs and assigned diagnoses, and measurements. Feature selection is conducted on the various types of data to reduce dimensionality and sparsity, while allowing for an in-depth feature analysis of the usefulness of each data type and representation. RESULTS: Within each data type, combining multiple representations yields better predictive performance compared to using any single representation. The use of clinical codes for adverse drug event detection significantly outperforms the use of measurements; however, there is no significant difference over datasets between using only clinical codes and their combination with measurements. For certain adverse drug events, the combination does, however, outperform using only clinical codes. Feature selection leads to increased predictive performance for both data types, in isolation and combined. CONCLUSIONS: We have demonstrated how machine learning can be applied to electronic health records for the purpose of detecting adverse drug events and proposed solutions to some of the challenges this presents, including how to represent the various data types. Overall, clinical codes are more useful than measurements and, in specific cases, it is beneficial to combine the two. PMID- 26606039 TI - Risk Factors for Femoral Head Deformity in the Early Stage of Legg-Calve-Perthes Disease: MR Contrast Enhancement and Diffusion Indexes. AB - PURPOSE: To determine whether changes in diffusion and/or contrast enhancement are of prognostic value in the early stage of Legg-Calve-Perthes disease (LCPD). MATERIALS AND METHODS: This study was approved by the institutional review board, and written informed consent was obtained from patient parents. Diffusion and contrast agent-enhanced magnetic resonance (MR) imaging studies were performed in 46 children (37 boys and nine girls; mean age, 7.5 years [age range, 3.3-11.9 years]) with unilateral LCPD at the early stage before development of extensive femoral head deformity. The degree of contrast enhancement was measured on the contrast-enhanced MR images, and the apparent diffusion coefficient (ADC) value was measured on the ADC map at various regions of interest in the proximal femur. The association of the MR imaging parameters that compared the affected side with the contralateral normal side with the femoral head deformity index value above 0.3 at 2 years was investigated. RESULTS: Increased diffusion in the metaphysis (P = .003) and decreased contrast enhancement in the central epiphysis (P = .034) were the significant prognostic indicators of subsequent femoral head deformation. ADC in the metaphysis 45% higher and a contrast enhancement in the central epiphysis 37% lower than those of the contralateral normal side are associated with a nonfavorable prognosis. For diffusion MR imaging, sensitivity was 83% (15 of 18), specificity was 86% (24 of 28), positive predictive value was 79% (15 of 19), negative predictive value was 89% (24 of 27), and accuracy was 85% (39 of 46). For contrast-enhanced MR imaging, sensitivity was 78% (14 of 18), specificity was 64% (18 of 28), positive predictive value was 58% (14 of 24), negative predictive value was 82% (18 of 22), and accuracy was 70% (32 of 46). CONCLUSION: Diffusion and contrast-enhanced MR imaging are potentially useful to assess risk of later development of femoral head deformity. PMID- 26606040 TI - Molecular Imaging and Precision Medicine. PMID- 26606041 TI - Production of sugarcane bagasse-based activated carbon for formaldehyde gas removal from potted plants exposure chamber. AB - Agricultural wastes such as rice straw, sugar beet, and sugarcane bagasse have become a critical environmental issue due to growing agriculture demand. This study aimed to investigate the valorization possibility of sugarcane bagasse waste for activated carbon preparation. It also aimed to fully characterize the prepared activated carbon (BET surface area) via scanning electron microscope (SEM) and in terms of surface functional groups to give a basic understanding of its structure and to study the adsorption capacity of the sugarcane bagasse-based activated carbon using aqueous methylene blue (MB). The second main objective was to evaluate the performance of sugarcane bagasse-based activated carbon for indoor volatile organic compounds removal using the formaldehyde gas (HCHO) as reference model in two potted plants chambers. The first chamber was labeled the polluted chamber (containing formaldehyde gas without activated carbon) and the second was taken as the treated chamber (containing formaldehyde gas with activated carbon). The results indicated that the sugarcane bagasse-based activated carbon has a moderate BET surface area (557 m2/g) with total mesoporous volume and microporous volume of 0.310 and 0.273 cm3/g, respectively. The prepared activated carbon had remarkable adsorption capacity for MB. Formaldehyde removal rate was then found to be more than 67% in the treated chamber with the sugarcane bagasse-based activated carbon. The plants' responses for this application as dry weight, chlorophyll contents, and protein concentration were also investigated. IMPLICATIONS: Preparation of activated carbon from sugarcane bagasse (SCBAC) is a promising approach to produce cheap and efficient adsorbent for gas pollutants removal. It may be also a solution for the agricultural wastes problems in big cities, particularly in Egypt. MB adsorption tests suggest that the SCBAC have high adsorption capacity. Formaldehyde gas removal in the plant chambers indicates that the SCBAC have potential to recover volatile gases. The results confirmed that the activated carbon produced from sugarcane bagasse waste raw materials can be used as an applicable adsorbent for treating a variety of gas pollutants from the indoor environment. PMID- 26606044 TI - Levodopa-Induced Motor and Dopamine Receptor Changes in Caenorhabditis elegans Overexpressing Human Alpha-Synuclein. AB - BACKGROUND: Levodopa-induced dyskinesia (LID) is a disabling complication of levodopa therapy in Parkinson's disease (PD) with no effective treatments. Fluctuations in levels of levodopa constitute a key risk factor of LID. There is a pressing need for the development of a simple animal model of LID. Several genetic and toxin-based models of PD in Caenorhabditis elegans have been described, which have advanced our understanding of PD pathophysiology. We aimed to study levodopa-induced changes in a Parkinson's disease model of C. elegans expressing human alpha-synuclein. METHODS: We exposed the alpha-synuclein C. elegans to levodopa in continuous and alternating fashions. Automated behavioral analysis was then used to quantify changes in motor activity. Confocal microscopy was used next to quantify changes in dopamine receptor distribution and expression in motor neurons of live C. elegans. RESULTS: Chronic exposure to levodopa led to hyperactivity of the alpha-synuclein C. elegans without meaningful increase in motor activity. There was also an increase in peripheral clustering and expression of dopamine receptors in motor neurons. Both of these changes were significantly higher with alternating, compared to continuous, exposure to levodopa. CONCLUSIONS: This is the first report of changes in motor and dopamine receptors induced by levodopa in C. elegans overexpressing human alpha-synuclein. We propose that these phenotypes represent a simple animal model of LID in C. elegans. Such a model holds the promise of enabling high-throughput screenings for potential therapeutic targets and drug candidates. PMID- 26606046 TI - Dynamic Trk and G Protein Signalings Regulate Dopaminergic Neurodifferentiation in Human Trophoblast Stem Cells. AB - Understanding the mechanisms in the generation of neural stem cells from pluripotent stem cells is a fundamental step towards successful management of neurodegenerative diseases in translational medicine. Albeit all-trans retinoic acid (RA) has been associated with axon outgrowth and nerve regeneration, the maintenance of differentiated neurons, the association with degenerative disease like Parkinson's disease, and its regulatory molecular mechanism from pluripotent stem cells to neural stem cells remain fragmented. We have previously reported that RA is capable of differentiation of human trophoblast stem cells to dopamine (DA) committed progenitor cells. Intracranial implantation of such neural progenitor cells into the 6-OHDA-lesioned substantia nigra pars compacta successfully regenerates dopaminergic neurons and integrity of the nigrostriatal pathway, ameliorating the behavioral deficits in the Parkinson's disease rat model. Here, we demonstrated a dynamic molecular network in systematic analysis by addressing spatiotemporal molecular expression, intracellular protein-protein interaction and inhibition, imaging study, and genetic expression to explore the regulatory mechanisms of RA induction in the differentiation of human trophoblast stem cells to DA committed progenitor cells. We focused on the tyrosine receptor kinase (Trk), G proteins, canonical Wnt2B/beta-catenin, genomic and non-genomic RA signaling transductions with Tyrosine hydroxylase (TH) gene expression as the differentiation endpoint. We found that at the early stage, integration of TrkA and G protein signalings aims for axonogenesis and morphogenesis, involving the novel RXRalpha/Galphaq/11 and RARbeta/Gbeta signaling pathways. While at the later stage, five distinct signaling pathways together with epigenetic histone modifications emerged to regulate expression of TH, a precursor of dopamine. RA induction generated DA committed progenitor cells in one day. Our results provided substantial mechanistic evidence that human trophoblast stem cell derived neural stem cells can potentially be used for neurobiological study, drug discovery, and as an alternative source of cell-based therapy in neurodegenerative diseases like Parkinson's disease. PMID- 26606048 TI - Tolerance of Organ Transplant Recipients to Physical Activity during a High Altitude Expedition: Climbing Mount Kilimanjaro. AB - BACKGROUND: It is generally unknown to what extent organ transplant recipients can be physically challenged. During an expedition to Mount Kilimanjaro, the tolerance for strenuous physical activity and high-altitude of organ transplant recipients after various types of transplantation was compared to non transplanted controls. METHODS: Twelve organ transplant recipients were selected to participate (2 heart-, 2 lung-, 2 kidney-, 4 liver-, 1 allogeneic stem cell- and 1 small bowel-transplantation). Controls comprised the members of the medical team and accompanying family members (n = 14). During the climb, cardiopulmonary parameters and symptoms of acute mountain sickness were recorded twice daily. Capillary blood analyses were performed three times during the climb and once following return. RESULTS: Eleven of the transplant participants and all controls began the final ascent from 4700 meters and reached over 5000 meters. Eight transplant participants (73%) and thirteen controls (93%) reached the summit (5895m). Cardiopulmonary parameters and altitude sickness scores demonstrated no differences between transplant participants and controls. Signs of hyperventilation were more pronounced in transplant participants and adaptation to high-altitude was less effective, which was related to a decreased renal function. This resulted in reduced metabolic compensation. CONCLUSION: Overall, tolerance to strenuous physical activity and feasibility of a high-altitude expedition in carefully selected organ transplant recipients is comparable to non transplanted controls. PMID- 26606047 TI - Effects of Persistent Atrial Fibrillation-Induced Electrical Remodeling on Atrial Electro-Mechanics - Insights from a 3D Model of the Human Atria. AB - AIMS: Atrial stunning, a loss of atrial mechanical contraction, can occur following a successful cardioversion. It is hypothesized that persistent atrial fibrillation-induced electrical remodeling (AFER) on atrial electrophysiology may be responsible for such impaired atrial mechanics. This simulation study aimed to investigate the effects of AFER on atrial electro-mechanics. METHODS AND RESULTS: A 3D electromechanical model of the human atria was developed to investigate the effects of AFER on atrial electro-mechanics. Simulations were carried out in 3 conditions for 4 states: (i) the control condition, representing the normal tissue (state 1) and the tissue 2-3 months after cardioversion (state 2) when the atrial tissue recovers its electrophysiological properties after completion of reverse electrophysiological remodelling; (ii) AFER-SR condition for AF-remodeled tissue with normal sinus rhythm (SR) (state 3); and (iii) AFER-AF condition for AF-remodeled tissue with re-entrant excitation waves (state 4). Our results indicate that at the cellular level, AFER (states 3 & 4) abbreviated action potentials and reduced the Ca2+ content in the sarcoplasmic reticulum, resulting in a reduced amplitude of the intracellular Ca2+ transient leading to decreased cell active force and cell shortening as compared to the control condition (states 1 & 2). Consequently at the whole organ level, atrial contraction in AFER SR condition (state 3) was dramatically reduced. In the AFER-AF condition (state 4) atrial contraction was almost abolished. CONCLUSIONS: This study provides novel insights into understanding atrial electro-mechanics illustrating that AFER impairs atrial contraction due to reduced intracellular Ca2+ transients. PMID- 26606049 TI - Treating patients with cancer and acute venous thromboembolism. AB - INTRODUCTION: Cancer and venous thromboembolism (VTE) are closely related, with a high risk of VTE associated with cancer and a strong impact of VTE on cancer prognosis. The management and treatment of cancer-associated VTE are particularly challenging and, in many cases, are not guided by a high level of evidence. AREAS COVERED: In this review, we present the best therapeutic approach to acute deep vein thrombosis (DVT) and pulmonary embolism (PE) and to some controversial issues, such as home treatment, optimal duration of anticoagulation, management of VTE recurrence during anticoagulant treatment, and of unsuspected PE. Then, the available evidence on other cancer-related VTE manifestations is presented, such as catheter-related thrombosis and splanchnic vein thrombosis. EXPERT OPINION: While solid evidence exists on the advantage of low molecular weight heparin (LMWH) over vitamin K antagonists (VKAs) during the first 3 to 6 months after acute DVT and/or PE, several issues have not been sufficiently investigated yet. These include the role of LMWH beyond the first 3 to 6 months, whether it is still more effective than VKA and if its intensity could be safely reduced, the strategies to identifying accurate predictors of VTE recurrence and the role of direct oral anticoagulants. PMID- 26606050 TI - The Influence of Prolonged Acetylsalicylic Acid Supplementation-Induced Gastritis on the Neurochemistry of the Sympathetic Neurons Supplying Prepyloric Region of the Porcine Stomach. AB - This experiment was designed to establish the localization and neurochemical phenotyping of sympathetic neurons supplying prepyloric area of the porcine stomach in a physiological state and during acetylsalicylic acid (ASA) induced gastritis. In order to localize the sympathetic perikarya the stomachs of both control and acetylsalicylic acid treated (ASA group) animals were injected with neuronal retrograde tracer Fast Blue (FB). Seven days post FB injection, animals were divided into a control and ASA supplementation group. The ASA group was given 100 mg/kg of b.w. ASA orally for 21 days. On the 28th day all pigs were euthanized with gradual overdose of anesthetic. Then fourteen-micrometer-thick cryostat sections were processed for routine double-labeling immunofluorescence, using primary antisera directed towards tyrosine hydroxylase (TH), dopamine beta hydroxylase (DbetaH), neuropeptide Y (NPY), galanin (GAL), neuronal nitric oxide synthase (nNOS), leu 5-enkephalin (LENK), cocaine- and amphetamine- regulated transcript peptide (CART), calcitonin gene-related peptide (CGRP), substance P (SP) and vasoactive intestinal peptide (VIP). The data obtained in this study indicate that postganglionic sympathetic nerve fibers supplying prepyloric area of the porcine stomach originate from the coeliac-cranial mesenteric ganglion complex (CCMG). In control animals, the FB-labelled neurons expressed TH (94.85 +/- 1.01%), DbetaH (97.10 +/- 0.97%), NPY (46.88 +/- 2.53%) and GAL (8.40 +/- 0.53%). In ASA group, TH- and DbetaH- positive nerve cells were reduced (85.78 +/ 2.65% and 88.82 +/- 1.63% respectively). Moreover, ASA- induced gastritis resulted in increased expression of NPY (76.59 +/- 3.02%) and GAL (26.45 +/- 2.75%) as well as the novo-synthesis of nNOS (6.13 +/- 1.11%) and LENK (4.77 +/- 0.42%) in traced CCMG neurons. Additionally, a network of CART-, CGRP-, SP-, VIP , LENK-, nNOS- immunoreactive (IR) nerve fibers encircling the FB-positive perikarya were observed in both intact and ASA-treated animals. The results of this study indicate involvement of these neuropeptides in the development or presumably counteraction of gastric inflammation. PMID- 26606051 TI - In Depth Characterization of Repetitive DNA in 23 Plant Genomes Reveals Sources of Genome Size Variation in the Legume Tribe Fabeae. AB - The differential accumulation and elimination of repetitive DNA are key drivers of genome size variation in flowering plants, yet there have been few studies which have analysed how different types of repeats in related species contribute to genome size evolution within a phylogenetic context. This question is addressed here by conducting large-scale comparative analysis of repeats in 23 species from four genera of the monophyletic legume tribe Fabeae, representing a 7.6-fold variation in genome size. Phylogenetic analysis and genome size reconstruction revealed that this diversity arose from genome size expansions and contractions in different lineages during the evolution of Fabeae. Employing a combination of low-pass genome sequencing with novel bioinformatic approaches resulted in identification and quantification of repeats making up 55-83% of the investigated genomes. In turn, this enabled an analysis of how each major repeat type contributed to the genome size variation encountered. Differential accumulation of repetitive DNA was found to account for 85% of the genome size differences between the species, and most (57%) of this variation was found to be driven by a single lineage of Ty3/gypsy LTR-retrotransposons, the Ogre elements. Although the amounts of several other lineages of LTR-retrotransposons and the total amount of satellite DNA were also positively correlated with genome size, their contributions to genome size variation were much smaller (up to 6%). Repeat analysis within a phylogenetic framework also revealed profound differences in the extent of sequence conservation between different repeat types across Fabeae. In addition to these findings, the study has provided a proof of concept for the approach combining recent developments in sequencing and bioinformatics to perform comparative analyses of repetitive DNAs in a large number of non-model species without the need to assemble their genomes. PMID- 26606053 TI - Corrigendum. AB - Following publication of the Systematic Review by Cyril Atkinson-Clement, Jasmin Sadat & Serge Pinto titled "Behavioral treatments for speech in Parkinson's disease: meta-analyses and review of the literature", which appeared in the June 2015 issue of Neurodegenerative Disease Management (5[3], 233-248 [2015]; www.futuremedicine.com/doi/full/10.2217/nmt.15.16), it has come to our attention that Tables 2 and 3 were presented incorrectly. The corrected tables appear below. PMID- 26606052 TI - The Induction Effect of Am80 and TSA on ESC Differentiation via Regulation of Stra8 in Chicken. AB - Stra8 encodes stimulated by retinoic acid gene 8, a protein that is important for initiation of meiosis in mammals and birds. This study was aimed at identifying the active control area of chicken STRA8 gene core promoter, to screen optimum inducers of the STRA8 gene, thus to enhance the differentiation of embryonic stem cells (ESCs) into spermatogonial stem cells. Fragments of chicken STRA8 gene promoter were cloned into fluorescent reporter plasmids and transfected into DF-1 cells. Then Dual-Luciferase(r) Reporter Assay System was used to identify the activity of the STRA8 gene under different inducers. Our studies showed that the promoter fragment -1055 bp to +54 bp of Suqin chicken Stra8 revealed the strongest activity. The dual-luciferase(r) reporter showed that Tamibarotene (Am80) and TrichostatinA (TSA) could significantly enhance STRA8 transcription. The in vitro inductive culture of chicken ESCs demonstrated that spermatogonial stem cells (SSC)-like cells appeared and Integrinbeta1 protein was expressed on day 10, indicating that Am80 and TSA can promote ESCs differentiation into SSCs via regulation of Stra8. PMID- 26606054 TI - An Atherogenic Paigen-Diet Aggravates Nephropathy in Type 2 Diabetic OLETF Rats. AB - Diabetic nephropathy develops in association with hyperglycemia, is aggravated by atherogenic factors such as dyslipidemia, and is sometimes initiated before obvious hyperglycemia is seen. However, the precise mechanisms of progression are still unclear. In this study, we investigated the influence of an atherogenic Paigen diet (PD) on the progression of nephropathy in spontaneous type 2 diabetic OLETF rats. Feeding PD to male OLETF rats for 12 weeks caused an extensive increase in excretion of urinary albumin and markers of tubular injury such as KIM-1 and L-FABP, accompanied by mesangial expansion and tubular atrophy. PD significantly increased plasma total cholesterol concentration, which correlates well with increases in urine albumin excretion and mesangial expansion. Conversely, PD did not change plasma glucose and free fatty acid concentrations. PD enhanced renal levels of mRNA for inflammatory molecules such as KIM-1, MCP-1, TLR4 and TNF-alpha and promoted macrophage infiltration and lipid accumulation in the tubulointerstitium and glomeruli in OLETF rats. Intriguingly, PD had little effect on urine albumin excretion and renal morphology in normal control LETO rats. This model may be useful in studying the complex mechanisms that aggravate diabetic nephropathy in an atherogenic environment. PMID- 26606055 TI - Functional Cross-Talking between Differentially Expressed and Alternatively Spliced Genes in Human Liver Cancer Cells Treated with Berberine. AB - Berberine has been identified with anti-proliferative effects on various cancer cells. Many researchers have been trying to elucidate the anti-cancer mechanisms of berberine based on differentially expressed genes. However, differentially alternative splicing genes induced by berberine might also contribute to its pharmacological actions and have not been reported yet. Moreover, the potential functional cross-talking between the two sets of genes deserves further exploration. In this study, RNA-seq technology was used to detect the differentially expressed genes and differentially alternative spliced genes in BEL-7402 cancer cells induced by berberine. Functional enrichment analysis indicated that these genes were mainly enriched in the p53 and cell cycle signalling pathway. In addition, it was statistically proven that the two sets of genes were locally co-enriched along chromosomes, closely connected to each other based on protein-protein interaction and functionally similar on Gene Ontology tree. These results suggested that the two sets of genes regulated by berberine might be functionally cross-talked and jointly contribute to its cell cycle arresting effect. It has provided new clues for further researches on the pharmacological mechanisms of berberine as well as the other botanical drugs. PMID- 26606056 TI - Assessment of the Mutagenicity of Sediments from Yangtze River Estuary Using Salmonella Typhimurium/Microsome Assay. AB - Sediments in estuaries are of important environmental concern because they may act as pollution sinks and sources to the overlying water body. These sediments can be accumulated by benthic organisms. This study assessed the mutagenic potential of sediment extracts from the Yangtze River estuary by using the Ames fluctuation assay with the Salmonella typhimurium his (-) strain TA98 (frameshift mutagen indicator) and TA100 (baseshift mutagen indicator). Most of the sediment samples were mutagenic to the strain TA98, regardless of the presence or absence of exogenous metabolic activation (S9 induction by beta naphthoflavone/phenobarbital). However, none of the samples were mutagenic to the strain TA100. Thus, the mutagenicity pattern was mainly frameshift mutation, and the responsible toxicants were both direct (without S9 mix) and indirect (with S9 mix) mutagens. The mutagenicity of the sediment extracts increased when S9 was added. Chemical analysis showed a poor correlation between the content of priority polycyclic aromatic hydrocarbons and the detected mutagenicity in each sample. The concept of effect-directed analysis was used to analyze possible compounds responsible for the detected mutagenic effects. With regard to the mutagenicity of sediment fractions, non-polar compounds as well as weakly and moderately polar compounds played a main role. Further investigations should be conducted to identify the responsible components. PMID- 26606057 TI - Advanced HIV Disease at Enrolment in HIV Care: Trends and Associated Factors over a Ten Year Period in Cambodia. AB - BACKGROUND: Early HIV diagnosis and enrolment in care is needed to achieve early antiretroviral treatment (ART) initiation. Studies on HIV disease stage at enrolment in care from Asian countries are limited. We evaluated trends in and factors associated with late HIV disease presentation over a ten-year period in the largest ART center in Cambodia. METHODS: We conducted a retrospective analysis of program data including all ARV-naive adults (> 18 years old) enrolling into HIV care from March 2003-December 2013 in a non-governmental hospital in Phnom Penh, Cambodia. We calculated the proportion presenting with advanced stage HIV disease (WHO clinical stage IV or CD4 cell count <100 cells/MUL) and the probability of ART initiation by six months after enrolment. Factors associated with late presentation were determined using multivariate logistic regression. RESULTS: From 2003-2013, a total of 5642 HIV-infected patients enrolled in HIV care. The proportion of late presenters decreased from 67% in 2003 to 44% in 2009 and 41% in 2013; a temporary increase to 52% occurred in 2011 coinciding with logistical/budgetary constraints at the national program level. Median CD4 counts increased from 32 cells/MUL (IQR 11-127) in 2003 to 239 cells/MUL (IQR 63-291) in 2013. Older age and male sex were associated with late presentation across the ten-year period. The probability of ART initiation by six months after enrolment increased from 22.6% in 2003-2006 to 79.9% in 2011-2013. CONCLUSION: Although a gradual improvement was observed over time, a large proportion of patients still enroll late, particularly older or male patients. Interventions to achieve early HIV testing and efficient linkage to care are warranted. PMID- 26606058 TI - Conflict and Stress in Hospital Nursing: Improving Communicative Responses to Enduring Professional Challenges. AB - Nurses function as central figures of health teams, coordinating direct care and communication between team members, patients, and their families. The importance of nurses to health care cannot be understated, but neither can the environmental struggles nurses routinely encounter in their jobs. Organizational communication and nursing scholarship show conflict and stress as two visible and ongoing challenges. This case study aims to (a) explore the ways conflict communication and communicative stress are experienced and endure in nursing and (b) understand how nurses discursively (mis)manage conflict and stress. Open-ended survey comments from nurses (N = 135) employed at a large teaching and research hospital were qualitatively analyzed. Weick's model of organizing, specifically his notion of communication cycles, emerged as a conceptual lens helpful for understanding cyclical conflict and stress. Results show that exclusionary communication, specifically nonparticipatory and unsupportive messages, contribute to nurse conflict and stress. Nurses tend to (mis)manage conflict and stress using respectful and disrespectful discourse. These communication patterns can facilitate or prohibit positive change. Metaphorically, nurse communicative conflict and stress can be depicted as fire. Relationships can go up in flames due to out-of-control fires in the form of destructive conflict. However, conflict and stress, like fire, can be harnessed for positive ends such as organizational decision making and innovation. Findings suggest conveying respect may help nurses manage and even avoid flames of conflict and stress. Solutions are offered to mitigate the effects of conflict and stress while developing respectful organizational cultures. PMID- 26606060 TI - Possible Influences of Spark Discharges on Cardiac Pacemakers. AB - Exposure to spark discharges may occur beneath high voltage transmission lines when contact is initiated with a conductive object (such as a motor vehicle) with the spark discharge mediated by the ambient electric field from the line. The objective of this study was to assess whether such exposures could interfere with the normal functioning of implanted cardiac pacemakers (PMs). The experiment consisted of PMs implanted in a human-sized phantom and then exposed to spark discharge through an upper extremity. A circuit was designed that produced spark discharges between two spherical electrodes fed to the phantom's left hand. The circuit was set to deliver a single discharge per half cycle (every 10 ms) about 10 MUs in duration with a peak current of 1.2-1.3 A, thus simulating conditions under a 400-kV power line operating at 50 Hz. Of 29 PMs acquired, all were tested in unipolar configuration and 20 in bipolar configuration with exposure consisting of 2 min of continuous exposure (one unit was exposed for 1 min). No interference was observed in bipolar configuration. One unit in unipolar configuration incorrectly identified ventricular extra systoles (more than 400 beats min(-1)) for 2 s. The use of unipolar configuration in new implants is extremely rare, thus further minimizing the risk of interference with the passage of time. Replication of this study and, if safety for human subjects can be assured, future testing of human subjects is also advisable. PMID- 26606059 TI - M2 Polarization of Human Macrophages Favors Survival of the Intracellular Pathogen Chlamydia pneumoniae. AB - Intracellular pathogens have developed various strategies to escape immunity to enable their survival in host cells, and many bacterial pathogens preferentially reside inside macrophages, using diverse mechanisms to penetrate their defenses and to exploit their high degree of metabolic diversity and plasticity. Here, we characterized the interactions of the intracellular pathogen Chlamydia pneumoniae with polarized human macrophages. Primary human monocytes were pre-differentiated with granulocyte macrophage colony-stimulating factor or macrophage colony stimulating factor for 7 days to yield M1-like and M2-like macrophages, which were further treated with interferon-gamma and lipopolysaccharide or with interleukin-4 for 48 h to obtain fully polarized M1 and M2 macrophages. M1 and M2 cells exhibited distinct morphology with round or spindle-shaped appearance for M1 and M2, respectively, distinct surface marker profiles, as well as different cytokine and chemokine secretion. Macrophage polarization did not influence uptake of C. pneumoniae, since comparable copy numbers of chlamydial DNA were detected in M1 and M2 at 6 h post infection, but an increase in chlamydial DNA over time indicating proliferation was only observed in M2. Accordingly, 72+/-5% of M2 vs. 48+/-7% of M1 stained positive for chlamydial lipopolysaccharide, with large perinuclear inclusions in M2 and less clearly bordered inclusions for M1. Viable C. pneumoniae was present in lysates from M2, but not from M1 macrophages. The ability of M1 to restrict chlamydial replication was not observed in M1-like macrophages, since chlamydial load showed an equal increase over time for M1-like and M2-like macrophages. Our findings support the importance of macrophage polarization for the control of intracellular infection, and show that M2 are the preferred survival niche for C. pneumoniae. M1 did not allow for chlamydial proliferation, but failed to completely eliminate chlamydial infection, giving further evidence for the ability of C. pneumoniae to evade cellular defense and to persist in human macrophages. PMID- 26606061 TI - Strontium-90 Biokinetics from Simulated Wound Intakes in Non-human Primates Compared with Combined Model Predictions from National Council on Radiation Protection and Measurements Report 156 and International Commission on Radiological Protection Publication 67. AB - This study had a goal to evaluate the predictive capabilities of the National Council on Radiation Protection and Measurements (NCRP) wound model coupled to the International Commission on Radiological Protection (ICRP) systemic model for 90Sr-contaminated wounds using non-human primate data. Studies were conducted on 13 macaque (Macaca mulatta) monkeys, each receiving one-time intramuscular injections of 90Sr solution. Urine and feces samples were collected up to 28 d post-injection and analyzed for 90Sr activity. Integrated Modules for Bioassay Analysis (IMBA) software was configured with default NCRP and ICRP model transfer coefficients to calculate predicted 90Sr intake via the wound based on the radioactivity measured in bioassay samples. The default parameters of the combined models produced adequate fits of the bioassay data, but maximum likelihood predictions of intake were overestimated by a factor of 1.0 to 2.9 when bioassay data were used as predictors. Skeletal retention was also over predicted, suggesting an underestimation of the excretion fraction. Bayesian statistics and Monte Carlo sampling were applied using IMBA to vary the default parameters, producing updated transfer coefficients for individual monkeys that improved model fit and predicted intake and skeletal retention. The geometric means of the optimized transfer rates for the 11 cases were computed, and these optimized sample population parameters were tested on two independent monkey cases and on the 11 monkeys from which the optimized parameters were derived. The optimized model parameters did not improve the model fit in most cases, and the predicted skeletal activity produced improvements in three of the 11 cases. The optimized parameters improved the predicted intake in all cases but still over predicted the intake by an average of 50%. The results suggest that the modified transfer rates were not always an improvement over the default NCRP and ICRP model values. PMID- 26606062 TI - Validation of the Cytokinesis-block Micronucleus Assay Using Imaging Flow Cytometry for High Throughput Radiation Biodosimetry. AB - The cytokinesis-block micronucleus assay can be employed in triage radiation biodosimetry to determine the dose of radiation to an exposed individual by quantifying the frequency of micronuclei in binucleated lymphocyte cells. Partially automated analysis of the assay has been applied to traditional microscope-based methods, and most recently, the assay has been adapted to an automated imaging flow cytometry method. This method is able to automatically score a larger number of binucleated cells than are typically scored by microscopy. Whole blood samples were irradiated, divided into 2 mL and 200 MUL aliquots, cultured for 48 h and 72 h, and processed to generate calibration curves from 0-4 Gy. To validate the method for use in radiation biodosimetry, nine separate whole blood samples were then irradiated to known doses, blinded, and processed. Results indicate that dose estimations can be determined to within +/-0.5 Gy of the delivered dose after only 48 h of culture time with an initial blood volume of 200 MUL. By performing the cytokinesis-block micronucleus assay using imaging flow cytometry, a significant reduction in the culture time and volume requirements is possible, which greatly increases the applicability of the assay in high throughput triage radiation biodosimetry. PMID- 26606063 TI - Radiation Monitoring for the Masses. AB - In response to the Fukushima-Daiichi incident, many commercial vendors have produced applications and equipment targeted at the average member of the public in order to enable them to make radiation measurements themselves at little to no cost. The authors have evaluated a small selection of these items in order to validate their performance when exposed to a calibrated 137Cs dose rate irradiator. The products fall into two primary categories: the first using the CMOS from the camera on ubiquitous smartphones and the second using an accessory that performs the radiation measurement. Presented here are the performance data of a selection and recommendations on how to interpret the produced values. PMID- 26606064 TI - Characterization of MOSFET Dosimeter Angular Response Using a Spherical Phantom for Fluoroscopic Dosimetry. AB - Metal-Oxide Semiconductor Field-Effect Transistor (MOSFET) dosimeters, placed in anthropomorphic phantoms, are a standard method for organ dosimetry in medical x ray imaging applications. However, many x-ray applications, particularly fluoroscopy procedures, use variable projection angles. During dosimetry, the MOSFET detector active area may not always be perpendicular to the x-ray beam. The goal of this study was to characterize the dosimeter's angular response in the fluoroscopic irradiation involved in pediatric cardiac catheterization procedures, during which a considerable amount of fluoroscopic x-ray irradiation is often applied from various projection angles. A biological x-ray irradiator was used to simulate the beam quality of a biplane fluoroscopy imaging system. A custom-designed acrylic spherical scatter phantom was fabricated to measure dosimeter response (in mV) in two rotational axes, axial (psi) and normal-to axial (theta), in 30 degrees increments, as well as four common oblique angles used in cardiac catheterization: a) 90 degrees Left Anterior Oblique (LAO); b) 70 degrees LAO/ 20 degrees Cranial; c) 20 degrees LAO/ 15 degrees Cranial; and d) 30 degrees Right Anterior Oblique (RAO). All results were normalized to the angle where the dosimeter epoxy is perpendicular to the beam or the Posterior Anterior projection angle in the clinical setup. The relative response in the axial rotation was isotropic (within +/- 10% deviation); that in the normal-to axial rotation was isotropic in all angles except the psi = 270 degrees angle, where the relative response was 83 +/- 9%. No significant deviation in detector response was observed in the four common oblique angles, with their relative responses being: a) 102 +/- 3%; b) 90 +/- 3%; c) 92 +/- 3%; and d) 95 +/- 3%, respectively. These angular correction factors will be used in future dosimetry studies for fluoroscopy. The spherical phantom may be useful for other applications, as it allows the measurement of dosimeter response in virtually all angles in the 3-dimensional spherical coordinates. PMID- 26606065 TI - Effect of Very Low Dose Fast Neutrons on the DNA of Rats' Peripheral Blood Mononuclear Cells and Leukocytes. AB - The effect of very low dose fast neutrons on the chromatin and DNA of rats' peripheral blood mononuclear cells (PBMC) and leukocytes has been studied in the present work using Fourier transform infrared (FTIR) and single-cell gel electrophoresis (comet assay). Fourteen female Wistar rats were used; seven were irradiated with neutrons of 0.9 cGy (Am-Be, 0.02 cGy h(-1)), and seven others were used as control. Second derivative and curve fitting were used to analyze the FTIR spectra. In addition, hierarchical cluster analysis (HCA) was used to classify the group spectra. Meanwhile, the tail moment and percentage of DNA in the tail were used as indicators to sense the breaking and the level of damage in DNA. The analysis of FTIR spectra of the PBMC of the irradiated group revealed a marked increase in the area of phosphodiesters of nucleic acids and the area ratios of RNA/DNA and phosphodiesters/carbohydrates. A sharp significant increase and decrease in the areas of RNA and DNA ribose were recorded, respectively. In the irradiated group, leukocytes with different tail lengths were observed. The distributions of tail moments and the percentage of DNA in the tail of irradiated groups were heterogeneous. The mean value of the percentages of DNA in the tail at 0.5 h post-irradiation represented low-level damage in the DNA. Therefore, one can conclude that very low dose fast neutrons might cause changes in the DNA of PBMC at the submolecular level. It could cause low-level damage, double-strand break, and chromatin fragmentation of DNA of leukocytes. PMID- 26606066 TI - Plutonium-DTPA Model Application with USTUR Case 0269. AB - A plutonium-DTPA (Pu-DTPA) biokinetic model was introduced that had originated from the study of a plutonium-contaminated wound. This work evaluated the extension of the Pu-DTPA model to United States Transuranium and Uranium Registry (USTUR) Case 0269 involving an acute inhalation of a plutonium nitrate aerosol. Chelation was administered intermittently for the first 7 mo as Ca-EDTA, mostly through intravenous injection, with Ca-DTPA treatments administered approximately 2.5 y post intake. Urine and fecal bioassays were collected following intake for several years. Tissues were collected and analyzed for plutonium content approximately 38 y post intake. This work employed the Pu-DTPA model for predicting the urine and fecal bioassay and final tissue quantity at autopsy. The Pu-DTPA model was integrated with two separate plutonium systemic models (i.e., ICRP Publication 67 and its proposed modification). This work illustrated that the Pu-DTPA model was useful for predicting urine and fecal bioassay, including final tissue quantity, 38 y post intake. PMID- 26606067 TI - Activity Concentrations and Dose Assessment of Gamma Emitting Radionuclides in Canned Tuna and Sardines Produced after the Fukushima Nuclear Accident. AB - The aim of the present work was to investigate the radioactivity concentrations of gamma emitting radionuclides in canned tuna and sardines that were produced after the Fukushima nuclear accident and to assess the resulting radiation doses to the public. Fifty-eight brands of canned tuna and sardines consumed in the Middle East and produced from different parts of the world were analyzed using a germanium detector. Cesium-137 (137Cs) was not detected above the minimum detectable activity in any of the samples. Natural radionuclides 40K, 226Ra and 228Ra were detected with wide activity concentration ranges and with average values of (in Bq kg(-1) wet weight): 68 +/- 36, 0.31 +/- 0.45, 0.34 +/- 0.25, respectively, in tuna samples and with averages of 129 +/- 67, 0.20 +/- 0.33, 0.60 +/- 0.31 in sardine samples. The results of the activity concentrations of 40K and 226Ra showed some regional dependence. Tuna samples produced in Europe have almost twice the concentration of 40K and half the concentration of 226Ra as compared to samples produced in either East or South Asia and North America. Moreover, sardine samples produced in North Africa and Europe have almost twice the concentrations of 40K and 226Ra as those produced in East or South Asia and North America. Dose assessment due to ingestion of canned seafood was also performed, and the committed effective dose was found to be well within the worldwide average. PMID- 26606068 TI - Reliability of Questionnaire Data in the Distant Past: Relevance for Radiation Exposure Assessment. AB - Interviews with questionnaires are often employed to provide information that may be used for exposure assessment, although the reliability of such information is largely unknown. In this work, the consistency of individual behavior and dietary data collected by means of personal interviews during two study screenings was evaluated. Data were collected for a cohort of about 11,000 persons exposed to 131I in childhood and adolescence shortly after the Chernobyl accident. The best recollection was found for residential history, milk consumption patterns, and, to a lesser degree, stable iodine administration, while reproducibility of responses about consumption of milk products and leafy vegetables was poor. Consistency of information reported during the personal interviews by the study subjects younger than 10 y at the time of the accident was somewhat lower than for the subjects aged 10-18 y. The authors found slightly better reproducibility of responses for female study subjects than for male subjects and when the time span between two interviews was shorter. In the majority of instances, the best consistency in responses was observed when the mother was interviewed during both screenings rather than the subject. Information that was collected during two personal interviews was used to calculate two sets of thyroid doses due to 131I intakes. This study shows that, because dose-related measurements are available for all study subjects, the quality of individual behavior and dietary data has, in general, a small influence on the results of the retrospective dose assessment. For studies in which dose-related measurements are not available for all study subjects and only modeling is used for dose reconstruction, high quality individual behavior and dietary data for the study subjects are required to provide realistic and reliable dose estimates. PMID- 26606072 TI - Conversion to Once-Daily Tacrolimus Results in Increased p38MAPK Phosphorylation in T Lymphocytes of Kidney Transplant Recipients. AB - BACKGROUND: The once-daily formulation of tacrolimus (TAC(OD)) has been developed to overcome adherence problems. Conversion from the twice-daily TAC (TAC(BID)) formulation to TAC(OD) on a 1:1 basis, however, often leads to a decrease of TAC predose concentrations, which averages ~15%. Switching between the two TAC formulations may thus influence drug efficacy and necessitates therapeutic drug monitoring. As an additional tool in transplantation diagnostics, phospho specific flow cytometry was used to study the biological effects of conversion on p38MAPK phosphorylation, a kinase involved in T-lymphocyte activation. METHODS: Stable renal transplant recipients (n = 12), at least 1 year after their transplantation, were converted from TAC(BID) to TAC(OD) on 1:1 mg for mg base. Comedication consisted of mycophenolate mofetil (n = 10) and prednisolone (n = 3). TAC whole-blood predose concentrations were determined by immunoassay before and 3 months after conversion. P38MAPK phosphorylation was measured in T lymphocytes by whole-blood phospho-specific flow cytometry. RESULTS: Three months after conversion, no significant decreases in TAC predose concentrations (C0) were found (P = 0.54), whereas p38MAPK phosphorylation increased with 11.4% (P < 0.05) in CD4 and with 15.6% (P < 0.05) in CD8 T lymphocytes. The TAC C0 during treatment with TAC(BID) correlated inversely with p38MAPK phosphorylation in T lymphocytes (rs = -0.638; P < 0.05). CONCLUSIONS: These results suggest that the measurement of p38MAPK phosphorylation status in T lymphocytes is a sensitive method to determine the biological effects of TAC before and after conversion from TAC(BID) to TAC(OD). This method could be a more sensitive tool for therapeutic drug monitoring of TAC. PMID- 26606073 TI - A Tale of Two Features: Perception of Cantonese Lexical Tone and English Lexical Stress in Cantonese-English Bilinguals. AB - This study investigated the similarities and differences in perception of Cantonese tones and English stress patterns by Cantonese-English bilingual children, adults, and English monolingual adults. All three groups were asked to discriminate pairs of syllables that minimally differed in either Cantonese tone or in English stress. Bilingual children's performance on tone perception was comparable to their performance on stress perception. By contrast, bilingual adults' performance on tone perception was lower than their performance on stress perception, and there was a similar pattern in English monolingual adults. Bilingual adults tended to perform better than English monolingual adults on both the tone and stress perception tests. A significant correlation between tone perception and stress perception performance was found in bilingual children but not in bilingual adults. All three groups showed lower accuracy in the high rising-low rising contrast than any of the other 14 Cantonese tone contrasts. The acoustic analyses revealed that average F0, F0 onset, and F0 major slope were the critical acoustic correlates of Cantonese tones, whereas multiple acoustic correlates were salient in English stress, including average F0, spectral balance, duration and intensity. We argue that participants' difficulty in perceiving high rising-low rising contrasts originated from the contrasts' similarities in F0 onset and average F0; indeed the difference between their major slopes was the only cue with which to distinguish them. Acoustic-perceptual correlation analyses showed that although the average F0 and F0 onset were associated with tone perception performance in all three groups, F0 major slope was only associated with tone perception in the bilingual adult group. These results support a dynamic interactive account of suprasegmental speech perception by emphasizing the positive prosodic transfer between Cantonese tone and English stress, and the role that level of bilingual language experience and age play in shaping suprasegmental speech perception. PMID- 26606075 TI - Bone marrow mononuclear cells enhance anti-inflammatory effects of pravastatin against isoproterenol-induced myocardial infarction in rats. AB - The current study investigated the combinatorial effect of pravastatin (PRAV) and bone marrow mononuclear cells (BM-MNC) on acute myocardial infarction (AMI) induced experimentally in rats. After induction of MI, rats were given oral PRAV (20 mg/kg/day) for 28 days or a bolus intravenous injection (via lateral vein) of a total of 14 * 10(6) autologous BM-MNC or a combination of both. Serum brain natriuretic peptide (BNP) and histologic changes in cardiac tissues were assessed. Cardiac contents of lipid peroxides, superoxide dismutase (SOD) and inflammatory biomarkers including tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta as well as vascular endothelial growth factor (VEGF) and nitric oxide (NO) were also measured. Combined PRAV and BM-MNC treatment significantly suppressed serum BNP. Cardiac cell apoptosis and inflammatory cell infiltration in heart tissue decreased significantly in both the PRAV and the PRAV + BM-MNC groups. Cardiac lipid peroxides along with TNFalpha and IL-1beta levels were significantly reduced in both the PRAV and PRAV + BM-MNC hosts with an increase in SOD levels. However, the combined treatment increased cardiac NO levels and did not modify cardiac VEGF levels. The current results indicated that administration of BM-MNC improved the therapeutic efficacy of PRAV treatment by improving the morphology of infarcted hearts as well as decreasing inflammation in a host, but did not do so by inducing therapeutic angiogenesis. PMID- 26606076 TI - Update on immunotherapy for the treatment of asthma. AB - PURPOSE OF REVIEW: Despite that specific immunotherapy can boast being more than a century old, there is still skepticism about its real effectiveness, and therefore it is still used too little in clinical practice. The purpose of this review was to analyze the most recent articles in the literature to highlight scientific evidence for the proper use of allergen immunotherapy (AIT). RECENT FINDINGS: In the near future, the concept of medicine for trials will have to be revised and in certain cases abandoned in favor of a personalized medicine, able to use a drug more targeted for the individual patient and not for the disease. SUMMARY: For AIT, it will become increasingly important to use products designed properly, standardized and with a well documented effectiveness in clinical studies. We must overcome the disputes of subcutaneous immunotherapy versus sublingual immunotherapy, arrive at the concept of personalized medicine regarding AIT, framing in different phenotypes of asthma patients to use the optimal preparation for each particular patient. PMID- 26606074 TI - Protective Effects of Dietary Supplementation with a Combination of Nutrients in a Transgenic Mouse Model of Alzheimer's Disease. AB - OBJECTIVE: This study investigated the effects of intervention with a combination of nutrients in the amyloid precursor protein-presenilin (APP-PSN) C57BL/6J double transgenic mouse model of Alzheimer's disease (AD). METHODS: A total of 72 2-month-old APP-PSN mice were randomly assigned to three groups. The model group (MG) was fed regular, unsupplemented chow, while the low- and high-dose treatment groups (LG and HG, respectively) were given a combination of nutrients that included phosphatidylserine, blueberry extracts, docosahexaenoic acid, and eicosapentaenoic acid as part of their diet. An additional 24 wild-type littermates that were fed unsupplemented chow served as the negative control group (NG). After 3 and 7 months of treatment, the cognitive performance was assessed with the Morris water maze and the shuttle box escape/avoidance task, and the biochemical parameters and oxidative stress were evaluated in both the blood and brain. RESULTS: An improvement in antioxidant capacity was observed in the treatment groups relative to the MG at 3 months, while superior behavioral test results were observed in the mice of the HG and NG groups. In the MG, pycnosis was detected in neuronal nuclei, and a loss of neurons was observed in the cerebral cortex and the hippocampus. At 7 months, the beta-amyloid1-42 peptide accumulation was significantly elevated in the MG but was markedly lower in the mice fed the nutrient combination. The antioxidant capacity and behavioral test scores were also higher in these mice. CONCLUSIONS: Early intervention with a combination of nutrients should be considered as a strategy for preventing cognitive decline and other symptoms associated with AD. PMID- 26606077 TI - Diagnostic challenges of adult asthma. AB - PURPOSE OF REVIEW: Bronchial asthma is a common disorder that affects about 300 million people worldwide. Its signs and symptoms however, can be present in other pulmonary and/or airway diseases and therefore a careful workup of patients with respiratory symptoms that might be due to asthma is required to a) keep a broad differential diagnosis, especially in cases that do not respond well to standard antiasthmatic therapy and b) attempt to subphenotype patients within the syndrome of asthma to diagnose e.g. precipitating factors, inflammatory subtypes and comorbidities. RECENT FINDINGS: The syndrome of asthma contains a number of different phenotypes that offer the possibility of personalized medicine based on the respective asthma phenotype. There are attempts to combine asthma and COPD in newly postulated overlap syndromes which this review discourages to do but instead, based on new and old information concerning asthma phenotyping, suggests to rule in comorbidities and rule out a number of other diseases that can mimick asthma clinically. SUMMARY: Bronchial asthma, although one of the most common respiratory diseases, can be mimicked by a number of other pulmonary and airway diseases, and especially patients with so called severe or treatment refractory asthma should receive a detailed diagnostic workup with a rather broad differential diagnosis. PMID- 26606078 TI - Smoking asthma phenotype: diagnostic and management challenges. AB - PURPOSE OF REVIEW: The prevalence of active smoking in adults with asthma is similar to the general population. Smoking asthma is associated with poorer disease control, impaired response to corticosteroid therapy, accelerated decline in lung function, and increased rate of healthcare utilization. Current asthma guidelines do not provide specific treatment advice for smoking asthmatic patients. There is an urgent need for better understanding of the underlying mechanisms and effective treatment for smoking asthmatic patients. RECENT FINDINGS: An association between both active and passive smoking and adult-onset asthma is supported by many studies.The asthma-COPD overlap syndrome (ACOS) has recently gained particular interest and smoking asthmatic patients should be evaluated for ACOS.Treatment regimens for smoking asthma include higher doses of inhaled corticosteroids (ICS), extrafine particle ICS formulations, antileukotrienes, and combinations of these options.Asthma is associated with increased risk of cardiovascular comorbidities whereas smoking is an additional strong independent risk factor for pulmonary and cardiovascular diseases. Tobacco smoking and not asthma per se seems to be the reason of poor prognosis, especially with regard to lung cancer, cardiovascular diseases, and mortality in asthmatic patients. SUMMARY: Smoking asthma represents a common challenge to the clinician both in terms of diagnosis and management. These aspects have not been thoroughly evaluated and deserve further investigation. PMID- 26606079 TI - Emerging role of long-acting anticholinergics in children with asthma. AB - PURPOSE OF REVIEW: Although the use of inhaled anticholinergics in obstructive airway disease has been established for several years, the clinical experience using these medications in treating patients with asthma is limited. Only few studies so far have included pediatric patients with asthma, but these studies demonstrate relevant therapeutic effects. This review will explore the pharmacological effects of inhaled anticholinergics, provide an overview about current adult and pediatric asthma studies using tiotropium, and describe future research needs. RECENT FINDINGS: In a phase II study with tiotropium as add-on to maintenance treatment to inhaled corticosteroids (ICSs) in moderate persistent adolescent with asthma, significant improvement of peak and trough forced expiratory volume in 1 s (FEV1) with a good safety profile could be demonstrated. A pediatric phase II study in symptomatic patients with asthma aged 6-11with comparable study design also demonstrated significant improvement of peak FEV1 with no serious adverse events. However, both studies could not document a significant clinical improvement analyzed by standardized scores. SUMMARY: Tiotropium might become an add-on treatment option in symptomatic pediatric and adolescent patients with asthma despite adequate therapy with ICS and long-acting beta2-agonist (LABA) or as an alternative to LABA in patients with safety concerns related to LABA. For a better assessment of the clinical effect, long term studies are needed. PMID- 26606081 TI - Production of polyhydroxyalkanoate (PHA) by Ralstonia eutropha JMP 134 with volatile fatty acids from palm oil mill effluent as precursors. AB - The highest volatile fatty acids (VFAs) concentration from palm oil mill effluent (POME) treated by anaerobic fermentation was achieved for a 1-day process when the main acids used were acetic, propionic and butyric acids. Polyhydroxyalkanoate (PHA) production with VFAs from POME as precursors in the fed-batch mode has advantages over batch mode, both in terms of its productivity and 3HV (3-hydroxyvalerate) composition in the produced polymer. With the fed batch, the productivity increased to 343% and contained more 3HV than those of the batch. The structures of the PHA were identified by different methods and they supported each other; the resulting products consisted of functional groups of 3HB (3-hydroxybutyrate) and 3HV. PMID- 26606082 TI - Dissolved organic nitrogen (DON) during batch denitrification of low concentrations of nitrate using suspended and attached biomass. AB - The occurrence and removal of dissolved organic nitrogen (DON) is an issue of increasing importance for the reclamation of treated wastewater. Effluent DON may act as a precursor of disinfection by-products during wastewater disinfection and may contribute to eutrophication of receiving surface waters. The aim of this study was to understand the effect of the post-denitrification process on final effluent DON (organic nitrogen filtered by 0.45 MUm pore size) concentration to further gain knowledge on how to optimize denitrifying filtration, in order to reach the required discharge standards. To evaluate DON variation, denitrification batch experiments were carried out with suspended and attached biomass under different shear conditions. For both conditions, with suspended and attached biomass, DON concentration did not increase or decrease during the denitrification process with addition of an external carbon source. Moreover, the increase of shear rate did not affect the DON concentration. Apparently, there is no direct link between DON evolution and the denitrification process itself. PMID- 26606083 TI - Thermochemical pretreatment of lignocellulose residues: assessment of the effect on operational conditions and their interactions on the characteristics of leachable fraction. AB - Annually, large amounts of agricultural residues are produced in Chile, which can be turned into a good opportunity to diversify the energy matrix. These residues have a slow hydrolysis stage during anaerobic digestion; therefore, the application of a pretreatment seems to be an alternative to improve the process. This work focused on applying a thermochemical pretreatment with NaOH on two lignocellulosic residues. The experiments were performed according to a 2(4) factorial design. The factors studied in a 2(4) factorial design were: temperature (60 and 120 degrees C), pretreatment time (10 and 30 minutes), NaOH dose (2 and 4%), and residue size (<1 and 1-3 mm for wheat straw; 1-5 and 5-10 mm for corn stover). The analyzed response variables were the solubilization of organic matter, and the biodegradability of the lignocellulose hydrolysate. The statistical analysis of the data allowed the identification of the experimental conditions that maximized solubilization of organic matter and biodegradability. The main results showed that more aggressive experimental conditions could increase the breaking down of the structure; in addition, the time of pretreatment was not significant. Conversely, the less aggressive experimental conditions, regarding regent dosage and downsizing, favored the release of biodegradable organic matter. The main conclusion of this study was the identification of the operational conditions of the thermochemical pretreatment that promote maximum biogas production, which was caused due to the solubilization of a large amount of organic matter, but not because of the increase in biodegradability of the released organic matter. PMID- 26606084 TI - Evaluating the performance of water purification in a vegetated groundwater recharge basin maintained by short-term pulsed infiltration events. AB - Infiltration of surface water constitutes an important pillar in artificial groundwater recharge. However, insufficient transformation of organic carbon and nutrients, as well as clogging of sediments often cause major problems. The attenuation efficiency of dissolved organic carbon (DOC), nutrients and pathogens versus the risk of bioclogging for intermittent recharge were studied in an infiltration basin covered with different kinds of macrovegetation. The quality and concentration of organic carbon, major nutrients, as well as bacterial biomass, activity and diversity in the surface water, the porewater, and the sediment matrix were monitored over one recharge period. Additionally, the numbers of viral particles and Escherichia coli were assessed. Our study showed a fast establishment of high microbial activity. DOC and nutrients have sustainably been reduced within 1.2 m of sediment passage. Numbers of E. coli, which were high in the topmost centimetres of sediment porewater, dropped below the detection limit. Reed cover was found to be advantageous over bushes and trees, since it supported higher microbial activities along with a good infiltration and purification performance. Short-term infiltration periods of several days followed by a break of similar time were found suitable for providing high recharge rates, and good water purification without the risk of bioclogging. PMID- 26606085 TI - A new approach to implementing decentralized wastewater treatment concepts. AB - Planners and decision-makers in the wastewater sector are often confronted with the problem of identifying adequate development strategies and most suitable finance schemes for decentralized wastewater infrastructure. This paper research has focused on providing an approach in support of such decision-making. It is based on basic principles that stand for an integrated perspective towards sustainable wastewater management. We operationalize these principles by means of a geographic information system (GIS)-based approach 'Assessment of Local Lowest Cost Wastewater Solutions'--ALLOWS. The main product of ALLOWS is the identification of cost-effective local wastewater management solutions for any given demographic and physical context. By using universally available input data the tool allows decision-makers to compare different wastewater solutions for any given wastewater situation. This paper introduces the ALLOWS-GIS tool. Its application and functionality are illustrated by assessing different wastewater solutions for two neighboring communities in rural Jordan. PMID- 26606086 TI - Simultaneous removal of ammonium and nitrate by HDTMA-modified zeolite. AB - In this study, surfactant (hexadecyltrimethylammonium, HDTMA) modified zeolite (clinoptilolite) (SMZ) was used for simultaneous removal of ammonium and nitrate in wastewater, and the sorption properties of SMZ were determined. Results showed that natural clinoptilolite had good affinity for ammonium, but low sorption ability for nitrate, and the ammonium sorption process was well described by the pseudo-second order kinetic model. The SMZ had a significant enhancement on nitrate sorption and could simultaneously remove ammonium and nitrate at specific conditions, with removal efficiency up to 93.6% and 81.8%, respectively. The sorption process fitted well with the Langmuir isotherm. Orthogonal experiments showed that ammonium concentration was the most important factor for ammonium sorption on SMZ. However, surfactant loading was the major factor for nitrate sorption. Meanwhile, phosphate did not interfere with nitrate removal. Semi empirical quantum mechanics molecular simulation indicated that electrostatic attraction existed between HDTMA and nitrate. Results of this study demonstrated that SMZs may have great potential for removing cations and anions simultaneously in the aquatic environment. PMID- 26606087 TI - Fe and Mn removal from mining drainage using goaf filling materials obtained from coal mining process. AB - Coal gangue, sandy soil and clay (mass ratio 45:4:1) as goaf filling materials acquired from coal mining processes were applied to remove Fe and Mn effectively from mining drainage. The results of an adsorption kinetic study showed that the Fe adsorption equation was y=21.454y+8.4712, R2=0.9924 and the Mn adsorption equation was y=7.5409x+0.905, R2=0.9957. Meanwhile, the goaf filling materials had low desorption capacity (Fe 6.765 MUg/g, Mn 1.52 MUg/g) and desorption ratio (Fe 8.98%, Mn 11.04%). Experiments demonstrated that Fe and Mn from mining drainage could be removed stably at a flow rate of 1.2 L/min, Fe inlet concentration of less than 40 mg/L, Mn inlet concentration of less than 2 mg/L and neutral or alkaline conditions. During a procedure of continuous experiments, the effluent quality could meet the requirement of the 'Code for Engineering Design of Sewage Regeneration-GB503352-2002'. A real-application project using goaf filling materials to treat mining drainage in Shendong coal mine showed that the average cost per ton of mining drainage was about 0.55 RMB, which could bring about considerable economic benefit for coal mining enterprises. PMID- 26606088 TI - Start-up of membrane bioreactor and hybrid moving bed biofilm reactor-membrane bioreactor: kinetic study. AB - A hybrid moving bed biofilm reactor-membrane bioreactor (hybrid MBBR-MBR) system was studied as an alternative solution to conventional activated sludge processes and membrane bioreactors. This paper shows the results obtained from three laboratory-scale wastewater treatment plants working in parallel in the start-up and steady states. The first wastewater treatment plant was a MBR, the second one was a hybrid MBBR-MBR system containing carriers both in anoxic and aerobic zones of the bioreactor (hybrid MBBR-MBRa), and the last one was a hybrid MBBR-MBR system which contained carriers only in the aerobic zone (hybrid MBBR-MBRb). The reactors operated with a hydraulic retention time of 30.40 h. A kinetic study for characterizing heterotrophic biomass was carried out and organic matter and nutrients removals were evaluated. The heterotrophic biomass of the hybrid MBBR MBRb showed the best kinetic performance in the steady state, with yield coefficient for heterotrophic biomass=0.30246 mg volatile suspended solids per mg chemical oxygen demand, maximum specific growth rate for heterotrophic biomass=0.00308 h(-1) and half-saturation coefficient for organic matter=3.54908 mg O2 L(-1). The removal of organic matter was supported by the kinetic study of heterotrophic biomass. PMID- 26606089 TI - Evaluation of treated sewage reuse potential and membrane-based water reuse technology for the Bangkok Metropolitan area. AB - Only 3.4% of total water use in the Bangkok Metropolitan area is reused treated sewage. This study anticipates that further treated-sewage reuse in industrial sectors, commercial buildings and public parks, in addition to present in-plant and street cleaning purposes, would increase total water reuse to about 10%. New water reuse technologies using membrane bioreactor (MBR) and microfiltration (MF) as tertiary treatment were implemented to assess their potential for their application in the Bangkok Metropolitan area. The MBR was applied to the treatment of raw sewage in a central treatment plant of the Bangkok Metropolitan area. The MF membrane was used for polishing the effluent of the treatment plant. The results show the quality of treated water from MBR and tertiary MF treatment could meet stringent water reuse quality standard in terms of biochemical oxygen demand, suspended solids and biological parameters. Constant permeate flux of the membrane was achieved over long-term operation, during which inorganic fouling was observed. This is due to the fact that incoming sewage contains a considerable amount of inorganic constituents contributed from storm water and street inlet in the combined sewerage systems. The total cost of the MBR for sewage treatment and production of reuse water is estimated to be about USD1.10/m3. PMID- 26606091 TI - Quantification and characterization of greywater from schools. AB - Survey of schools of different education levels (primary, intermediate and secondary) in Kuwait showed an average greywater generation rate of 7.3 L/p/d and varied in the range of 2.9-16 l/p/d, reflecting the school level of education (i.e. student age). The highest rates were observed for primary schools while the lowest rates were observed in secondary schools where students are more mature and use the water more wisely. The greywater characteristics indicated waste with low chemical oxygen demand (COD) and 5-day biochemical oxygen demand (BOD5) values but relatively high solids, conductivity, and sodium content due to excessive use of hand soap. Total coliform values ranged between 89 and 352 most probable number (MPN)/mL with an average of 196 MPN/mL while no fecal coliform values were detected. Greywater collected from schools is classified as light greywater and contains much lower levels of organic matter and nutrients compared to residential greywater and domestic wastewater. It is suitable for non-potable reuse after minimal treatment since microbial contamination may pose a serious threat to health if greywater comes into contact with humans. It also provides a good opportunity for reuse in toilet flushing since it can be easily collected from wash sinks and fountains, as major sources, and recycled. PMID- 26606090 TI - Potential applications of next generation DNA sequencing of 16S rRNA gene amplicons in microbial water quality monitoring. AB - The applicability of next generation DNA sequencing (NGS) methods for water quality assessment has so far not been broadly investigated. This study set out to evaluate the potential of an NGS-based approach in a complex catchment with importance for drinking water abstraction. In this multi-compartment investigation, total bacterial communities in water, faeces, soil, and sediment samples were investigated by 454 pyrosequencing of bacterial 16S rRNA gene amplicons to assess the capabilities of this NGS method for (i) the development and evaluation of environmental molecular diagnostics, (ii) direct screening of the bulk bacterial communities, and (iii) the detection of faecal pollution in water. Results indicate that NGS methods can highlight potential target populations for diagnostics and will prove useful for the evaluation of existing and the development of novel DNA-based detection methods in the field of water microbiology. The used approach allowed unveiling of dominant bacterial populations but failed to detect populations with low abundances such as faecal indicators in surface waters. In combination with metadata, NGS data will also allow the identification of drivers of bacterial community composition during water treatment and distribution, highlighting the power of this approach for monitoring of bacterial regrowth and contamination in technical systems. PMID- 26606092 TI - Kinetics of organic matter and ammonia removal in horizontal reed beds treating wastewater in Nepal. AB - In Nepal, both horizontal bed and vertical bed subsurface flow constructed wetlands have been used for wastewater treatment. However, these units were designed based on the empirical findings from other countries. The rational design criteria developed so far has some limitations as the performance of the units is sensitive to the behaviour of the microorganisms, climatic conditions and other attributes pertaining to the local contexts. Secondly, only limited numbers of studies have been carried out to assess the performance of these systems leading to the development of rationale design criteria. Considering these facts, the major objectives of the study were set to: (1) evaluate the performance of the subsurface flow reed bed system in terms of organic matter and ammonia removal; (2) estimate the reaction rate constant and effective specific surface area; (3) assess the relationship between performance and age of the system; and (4) investigate the dynamic behaviour of the reaction rate constant. The study was carried on three full-scale domestic wastewater treatment units and one pilot-scale ranging the age of horizontal beds from 1 to 5 years. PMID- 26606094 TI - Fouling and long-term durability of an integrated forward osmosis and membrane distillation system. AB - An integrated forward osmosis (FO) and membrane distillation (MD) system has great potential for sustainable wastewater reuse. However, the fouling and long term durability of the system remains largely unknown. This study investigates the fouling behaviour and efficiency of cleaning procedures of FO and MD membranes used for treating domestic wastewater. Results showed that a significant decline in flux of both FO and MD membranes were observed during treatment of wastewater with organic foulants. However, shear force generated by the increased cross-flow physically removed the loosely attached foulants from the FO membrane surface and resulted in 86-88% recovery of flux by cleaning with tap water. For the MD membrane, almost no flux recovery was achieved due to adsorption of organic foulants on the hydrophobic membrane surface, thus indicating significant irreversible fouling/wetting, which may not be effectively cleaned even with chemical reagents. Long-term (10 d) tests showed consistent performance of the FO membrane by rejecting the contaminants. However, organic foulants reduced the hydrophobicity of the MD membrane, caused wetting problems and allowed contaminants to pass through. The results demonstrate that combination of the FO and MD processes can effectively reduce irreversible membrane fouling and solve the wetting problem of the MD membrane. PMID- 26606093 TI - Enhanced removal of nitrate from water using nZVI@MWCNTs composite: synthesis, kinetics and mechanism of reduction. AB - Herein, multi-wall carbon nanotubes (MWCNTs) were used as the carrier of nano zero valent iron (nZVI) particles to fabricate a composite known as nZVI@MWCNTs. The composite was then characterized and applied in the nitrate removal process in a batch system under anoxic conditions. The influential parameters such as pH, various concentrations of nitrate and composite were investigated within 240 min of the reaction. The mechanism, kinetics and end-products of nitrate reduction were also evaluated. Results revealed that the removal nitrate percentage for nZVI@MWCNTs composite was higher than that of nZVI and MWCNTs alone. Experimental data from nitrate reduction were fitted to the Langmuir-Hinshelwood kinetic model. The values of observed rate constant (kobs) decreased with increasing the initial concentration of nitrate. Our experiments proved that the nitrate removal efficiency was favorable once both high amounts of nZVI@MWCNTs and low concentrations of nitrate were applied. The predominant end-products of the nitrate reduction were ammonium (84%) and nitrogen gas (15%). Our findings also revealed that ZVI@MWCNTs is potentially a good composite for removal/reduction of nitrate from aqueous solutions. PMID- 26606095 TI - Investigating the permeability of fractured rock masses and the origin of water in a mine tunnel in Shandong Province, China. AB - The coastal Sanshandao mine is threatened by the overlying Quaternary water and seawater. Following an introduction to the geology and hydrogeological conditions in the mine area, a detailed hydrogeological survey and sampling were conducted and hydrochemical and stable isotopic (delta2H and delta18O) tests on various waters were carried out to characterize the origin of water in the mine tunnels. Investigation and statistical analysis indicated that the northwest-trending fractures with large dip angles and long trace lengths are well developed in the northeast compared with those in the southwest of the mine. The permeability coefficients of the rock masses are in the range 4.19*10(-8)-2.25*10(-5) m/s, indicating that the fractured rock masses have generally low permeability. The seepage water had higher values of EC, total dissolved solids, and concentrations of most elements than the seawater and saline groundwater. Besides, the isotope composition of the waters indicated that the seepage water was more isotopically enriched than seawater but less than brine. The proportions of the three different sources were calculated based on hydrochemical and isotopic analyses. Overall, the mine water was composed of 72% seawater, 14.8% brine, and 13.2% atmospheric precipitation, respectively. Therefore, some preventive measures are essential to avoid the probability of seawater inrush. PMID- 26606096 TI - Effects of thermal hydrolysis temperature on physical characteristics of municipal sludge. AB - Effects of thermal hydrolysis temperature on the physical properties of municipal sludge was further studied by a series of experiments. There was a decrease in bound water content with an increase in hydrolysis temperature, while there was an increase in pH at temperatures below 120 degrees C, and a decrease at temperatures exceeding 120 degrees C. An analysis of settleability, centrifugation and vacuum filtration of the treated sludge indicated that the threshold temperature was 120 degrees C, which was the same as the temperature for the bound water content and particle size. In addition, raw sludge with a solids content of 100 g/L, exhibited significant non-Newtonian fluid characteristics. At thermal hydrolysis temperatures exceeding 120 degrees C, non Newtonian fluid characteristics including liquid and solid characteristics were significantly weakened. The consistency index (k) decreased from 5.90 Pa.s to 0.068 Pa.s, while the flow index (n) increased from 0.31 to 0.74, suggesting that thermal hydrolysis sludge was much closer to Newtonian fluids compared to raw sludge. Modification of bound water content, particle size and viscosity with hydrolysis temperature, revealed the nature of improved dewaterability by thermal hydrolysis. The fractal dimension of the sludge floc increased from 2.74 to 2.90, meaning that the floc became more compact after thermal hydrolysis. PMID- 26606097 TI - The effect of material and flushing water type on urine scale formation. AB - One of the important challenges with current sanitation practices is pipe blockage in urinals caused by urine scale formation. Urinal material and flushing water type are the two most important factors affecting scale formation. This paper examines the scale formation process on different materials which are commonly used in urinal manufacturing and exposed to different urine-based aqua cultures. This study shows that urine scale formation is the greatest for carbon steel material, and the least for PVC. Additionally, material exposure to the urine-rainwater mixture resulted in the smallest amount of scale formation. Based on these results, two new methods for improving sanitation practices are proposed: (1) using PVC as production material for urinals and pipelines; and (2) using rainwater for flushing systems. PMID- 26606098 TI - A downflow hanging sponge (DHS) reactor for faecal coliform removal from an upflow anaerobic sludge blanket (UASB) effluent. AB - This research was conducted to study the faecal coliforms removal capacity of downflow hanging sponge (DHS) reactors as a post-treatment for an upflow anaerobic sludge blanket (UASB) reactor. Three long-term continuous laboratory scale DHS reactors, i.e. a reactor with cube type sponges without recirculation, a similar one with recirculation and a reactor with curtain type sponges, were studied. The porosities of the applied medium were 91%, 87% and 47% respectively. The organic loading rates were 0.86 kgCOD m(-3) d(-1), 0.53 kgCOD m(-3) d(-1) and 0.24 kgCOD m(-3) d(-1) correspondingly at hydraulic loading rates of 1.92 m3 m( 2) d(-1), 2.97 m3 m(-2) d(-1) and 1.32 m3 m(-2) d(-1), respectively (COD: chemical oxygen demand). The corresponding averages for faecal coliform removal were 99.997%, 99.919% and 92.121% respectively. The 1989 WHO guidelines standards, in terms of faecal coliform content for unrestricted irrigation (category A), was achieved with the effluent of the cube type DHS (G1) without recirculation. Restricted irrigation, category B and C, is assigned to the effluent of the cube type with recirculation and the curtain type, respectively. Particularly for organic compounds, the effluent of evaluated DHS reactors complies with USEPA standards for irrigation of so called non-food crops like pasture for milking animals, fodder, fibre, and seed crops. PMID- 26606099 TI - Influence of micelle properties on micellar-enhanced ultrafiltration for chromium recovery. AB - An investigation of micelle properties on the recovery of chromium for micellar enhanced ultrafiltration (MEUF) process was conducted using cationic surfactant of cetyltrimethylammonium bromide (CTAB). The relationship between degree of ionization, micellar sizes and chromium removal were determined in this study. The results showed that the complete ionization for CTA+ and Br- was observed for CTAB lower than 0.72 mM and aggregation initiated at concentration of CTAB higher than 0.72 mM to yield attraction of counterion. The micellar sizes increased with increase in concentration of CTAB (higher than 4.02 mM) to generate micron-sized micelles. The distribution of micellar sizes was used to estimate the molecular weight cutoff of membrane used in the MEUF process. As chromium was added into aqueous CTAB solution, the chromate was dominant and bound on the micellar surface instead of Br-. Moreover, the presence of micelle formed a gel-layer to slightly shrink the membrane pore, therefore, UF membrane of 30k Da molecular weight cutoff (pore size~7.9 nm) was selected in the MEUF process to achieve the removal efficiency of Cr(VI) higher than 95%. PMID- 26606100 TI - The role of a hybrid phytosystem in landscape water purification and herbicides removal. AB - The performance of a hybrid phytosystem in landscape water purification and herbicides removal was investigated. The phytosystem operating in an arboretum is located in the Minhang Campus of Shanghai Jiao Tong University, China. The phytosystem is composed of two purification stages: sedimentation Stage 1 without external air supply; and Stage 2 with an external air supply. Stage 2 is also vegetated with three major kinds of plants, namely Pontederia cordata L., Typha latifolia L. and Cyperus alternifolius L. The system's hydraulic loading rate (HLR) was maintained at 1.632 m/day between December 2013 and November 2014. Sedimentation, filtration and adsorption by filter media, combined microbial processes in the rhizosphere (nitrification-denitrification) and plant uptake of the pollutants were all responsible for water purification in the phytosystem. The biological and physical parameters analyzed were total dissolved nitrogen (TDN), nitrate (NO3-N), nitrite (NO2-N), ammonia (NH3-N), total dissolved phosphorus (TDP), dissolved organic carbon (DOC), turbidity, chlorophyll-a and algal cells number. Highest removal efficiencies for TDN, TDP, turbidity, DOC, chlorophyll-a and algal cells were 56.9%, 73.3%, 92.4%, 29.9%, 94.3% and 91.0%, respectively. When the phytosystem was considered for herbicides removal, removal efficiencies of more than 25% were noted for all the herbicides. PMID- 26606101 TI - Polyaniline/reduced graphene oxide/Fe3O4 nano-composite for aqueous Hg(II) removal. AB - To ease the adsorbent recovery and to increase the adsorption capacity of polyaniline (PANI), aniline was polymerized in the presence of a solvothermally prepared nano-composite of reduced graphene oxide and Fe3O4 (RGO/Fe3O4). The polyaniline was formed along the RGO/Fe3O4 composite in transmission electron microscope (TEM). The thus formed PANI/RGO/Fe3O4 adsorbent was tested and applied in removing Hg(II) in aqueous solution. The initial adsorption rate as well as the adsorption capacity increases with the incorporation of RGO/Fe3O4. The magnetic separation of PANI/RGO/Fe3O4 was easy, and its regeneration can be carried out at the optimal pH of 2. Test results proved the competence of the prepared adsorbent in pollution remediation applications for safer water quality and environmental protection. PMID- 26606102 TI - Cellular automata-based modelling and simulation of biofilm structure on multi core computers. AB - The article presents a mathematical model of biofilm growth for aerobic biodegradation of a toxic carbonaceous substrate. Modelling of biofilm growth has fundamental significance in numerous processes of biotechnology and mathematical modelling of bioreactors. The process following double-substrate kinetics with substrate inhibition proceeding in a biofilm has not been modelled so far by means of cellular automata. Each process in the model proposed, i.e. diffusion of substrates, uptake of substrates, growth and decay of microorganisms and biofilm detachment, is simulated in a discrete manner. It was shown that for flat biofilm of constant thickness, the results of the presented model agree with those of a continuous model. The primary outcome of the study was to propose a mathematical model of biofilm growth; however a considerable amount of focus was also placed on the development of efficient algorithms for its solution. Two parallel algorithms were created, differing in the way computations are distributed. Computer programs were created using OpenMP Application Programming Interface for C++ programming language. Simulations of biofilm growth were performed on three high-performance computers. Speed-up coefficients of computer programs were compared. Both algorithms enabled a significant reduction of computation time. It is important, inter alia, in modelling and simulation of bioreactor dynamics. PMID- 26606103 TI - Adsorption experiment of toxic micro-pollutants derived from automobiles using red soil. AB - In some countries, non-point source pollution derived from a city's economic activities tends to be a barrier to the improvement of water quality. Roadway runoff is known to contain toxic micro-pollutants such as polycyclic aromatic hydrocarbons (PAHs). Conversely, red soil is known to adsorb some organic matter. In this study, artificial roadway runoff water containing toxic micro-pollutants was made using roadway dust collected from a highway, and used for both batch type tests and soil column tests with red soil in order to understand adsorption ability of the red soil on such toxic micro-pollutants, especially PAHs. In the batch-type tests, PAHs could be removed by approximately 40% when the contact time was 90 minutes. In the soil column tests, PAHs were removed by more than 80% while suspended solids were removed by more than 90%. Notably, PAHs with a high molecular weight were removed more readily in the tests than PAHs with a low molecular weight. PMID- 26606104 TI - Recovery of Cu(II) by chemical reduction using sodium dithionite: effect of pH and ligands. AB - Wastewaters containing Cu(II) and ligands are ubiquitous in various industrial sectors, and efficacy of copper removal processes, especially precipitation, is greatly compromised by ligands. Chemical reduction, being commonly employed for production of metal nanoparticles, is also effective for metal removal. Adjustment of pH and addition of ligands are important to control the particle size in metallic nanoparticle production. Exploiting the fact that ligands and metals coexist in many wastewaters, chemical reduction was employed to treat ligand-containing wastewater in this study. The experimental result shows that depending on pH, type of ligands, and copper:ligand molar ratio, copper could be removed by either the reduction or precipitation mechanism. Almost complete copper removal could be achieved by the reduction mechanism under optimal condition for solutions containing either EDTA (ethylenediaminetetraacetic acid) or citrate ligands. For solutions containing ammonia, depending on pH and Cu:ammonia molar ratio, copper was removed by both precipitation and reduction mechanisms. At pH of 9.0, formation of nano-sized particles, which readily pass through a 0.45 MUm filter used for sample pretreatment before residual copper analysis, results in the lowest copper removal efficiency. Both cuprous oxide and metallic copper are identified in the solids produced, and the possible explanations are provided. PMID- 26606105 TI - Photocatalysis assisted by peroxymonosulfate and persulfate for benzotriazole degradation: effect of pH on sulfate and hydroxyl radicals. AB - Recently, notable attempts have been devoted to removing emerging pollutants from water resources. Benzotriazole (BTA) as an emerging pollutant has widely been detected in the aquatic environment and water resources. In the current work, peroxymonosulfate (PMS) and persulfate (PS) were added to a TiO2/UV system for BTA degradation, as electron acceptors to overcome recombination of hole and electron. Additions of PMS and PS to the photocatalysis process considerably increased removal efficiency. The rate constants of UV/TiO2/PMS, UV/TiO2/PS and UV/TiO2 were 0.0217 min(-1), 0.0152 min(-1) and 0.0052 min(-1) respectively. The results showed that pH significantly affected the UV/TiO2/PMS system while it marginally affected UV/TiO2/PS. Scavenging experiments using alcohols indicated that in acidic pH, the dominant oxidant was sulfate radical in both systems. The contribution of hydroxyl radical in BTA degradation was boosted at alkaline and neutral conditions especially in the UV/TiO2/PMS system. Moreover, other scavenging experiments implied that reaction of radicals occurred at both the catalyst surface and in solution. The mineralization results showed that PMS and PS significantly increased chemical oxygen demand and total organic carbon removal efficiencies. In general, presence of PMS in the photocatalysis process had a better performance compared to PS in terms of BTA removal and mineralization. PMID- 26606106 TI - Clear regression of harvested intertidal mollusks. A 20-year (1994-2014) comparative study. AB - Intertidal mollusks are subjected to an intense environmental pressure, from human-induced stressors, mainly harvesting, to competition for food and space with other species. Here we used mollusk shell size as a measure of size distribution and reproductive potential of intertidal limpets. Two species of exploited limpets (Patella candei crenata and Patella aspera) were monitored throughout the littoral of Tenerife (Canary Islands, NE Atlantic Ocean), an overpopulated island with a high coastal pressure. The exploitation of these two limpet species is controlled by regional legislation, with seasonal closures and limits of harvest for professional (10 kg) and recreational harvesters (3-5 kg). A long-term comparison (1994-2014) of limpet size has been conducted as a surrogate of the state of conservation of these two limpets. Both species showed populations dominated largely by small-sized individuals (<30 mm) and a lack of large adults (>60 mm). The proximity to coastal settlements was not a factor to explain limpet assemblage structure. The temporal (1994-2014) comparative study showed a sharp decrease in the mean size of both limpet species (7 mm in P. aspera and 5 mm in P. candei crenata). These results might be indicative of overharvesting of both species in Tenerife. The conservation of the two studied species needs to be accomplished by the strict fulfillment of current protective strategies, as well as the creation of marine protected areas where intertidal harvesting is totally banned all over the year. PMID- 26606107 TI - Different carbon sources affect PCB accumulation by marine bivalves. AB - Pampean creeks were evaluated in the present study as potential land-based sources of PCB marine contamination. Different carbon and nitrogen sources from such creeks were analysed as boosters of PCB bioaccumulation by the filter feeder bivalve Brachidontes rodriguezii and grazer limpet Siphonaria lessoni. Carbon of different source than marine and anthropogenic nitrogen assimilated by organisms were estimated through their C and N isotopic composition. PCB concentration in surface sediments and mollusc samples ranged from 2.68 to 6.46 ng g(-1) (wet weight) and from 1074 to 4583 ng g(-1) lipid, respectively, reflecting a punctual source of PCB contamination related to a landfill area. Thus, despite the low flow of creeks, they should not be underestimated as contamination vectors to the marine environment. On the other hand, mussels PCB bioaccumulation was related with the carbon source uptake which highlights the importance to consider this factor when studying PCB distribution in organisms of coastal systems. PMID- 26606108 TI - Determination of mesalazine, a low bioavailability olsalazine metabolite in human plasma by UHPLC-MS/MS: Application to a pharmacokinetic study. AB - Olsalazine sodium, salicylate derivative (prodrug) is effectively bioconverted to mesalazine (5-aminosalicylic acid; 5-ASA), which has an anti-inflammatory activity in ulcerative colitis. In this article, a novel highly sensitive and selective method was developed and validated to determine mesalazine in human plasma using a derivatization technique to enhance the signal intensity by using ultra- high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) with an electrospray ionization interface. The sample preparation consisted of a derivatization with propionyl anhydride followed by liquid liquid extraction (LLE) to remove the interference and minimize the matrix effect of human plasma. The multiple reaction monitoring (MRM) mode of the negative ion was performed and the transitions of m/z 208.1->107.0 and m/z 211.1->110.1 were used to measure the derivative of mesalazine and mesalazine-d3. The chromatographic separation was achieved using kinetex XB-C18 (100*4.6mm 2.6MU) analytical column with 0.1% formic acid in water and acetonitrile as mobile phase with a gradient elution. Nominal retention times of mesalazine and IS were 3.08 and 3.07min, respectively. Absolute recovery was found to be between 82-95% for analyte and about 78% for IS. The standard curves was linear (r(2)>0.995) in the concentration range 0.10 to 12.0ng/mL with lower limit of quantification (LLOQ) in human plasma was 0.10ng/mL. The average intra-day/inter-day precision values (%CV) were in the range from 0.6-2.9 % and 1.3-3.8 %, respectively, while the average accuracy value was 103.8-107.2%. This method has been successfully applied to the human pharmacokinetics of olsalazine sodium 250mg capsules following single oral administration. PMID- 26606109 TI - Purification of glycocalicin from human plasma. AB - Glycocalicin (GC) is a large extracellular proteolytic fragment of glycoprotein Ib, a membrane platelet component playing an essential role in the physiological processes of platelet adhesion and aggregation. GC contains the binding sites for thrombin and von Willebrand factor. GC circulates normally in vivo in significant concentrations and the plasma level of this protein reflects a complex function of factors including platelet count or platelet turnover. It can therefore serve as a good indicator for many diseases like hypoplastic thrombocytopenia and idiopathic thrombocytopenic purpura. For this reason, several purification assays have been previously described. In this work, we describe a novel analytical method for GC purification from human platelets based on preparative HPLC gel filtration followed by immuno-affinity chromatography on NHS activated column conjugated with specific antibody. Pure GC was obtained from tiny amount of starting material. Our protocol of GC purification is simple, fast and provides a pure end product. PMID- 26606111 TI - Exploring the acid-catalyzed substitution mechanism of [Fe4S4Cl4](2-). AB - Kinetic studies on the acid-catalyzed substitution reactions of the teminal chloro-ligands in [Fe4S4Cl4](2-) by PhS(-) in the presence of the acids NHR3(+) (R = Me, Pr(n) or Bu(n)) are reported. Although these acids have very similar pKas (17.6-18.4) the reactions show a variety of different kinetics, some of which are inconsistent with a mechanism involving simple protonation of the cluster followed by substitution of a terminal ligand. The observed behaviour is more consistent with the recently proposed mechanism in which Fe-(MU3-SH) bond elongation/cleavage occurs upon protonation of a MU3-S, and suggests that both the acidity and bulk of the acid is important in the protonation step. Other studies have determined the activation parameters (DeltaH(?) and DeltaS(?)) for both the protonation and substitution steps of the acid-catalyzed substitution reactions of [Fe4S4X4](2-) (X = Cl or SEt). A significantly negative DeltaS(?) is observed for the substitution steps of both clusters indicating associative pathways. This is inconsistent with earlier interpretation of the kinetics of these reactions (based exclusively on the dependence of the rate on the concentration of nucleophile) and indicates that there is no dissociative substitution mechanism and the pathway associated with a zero order dependence on the concentration of PhS(-) involves associative substitution with the solvent (MeCN) being the nucleophile. PMID- 26606110 TI - Clinical Validation of a Smartphone-Based Adapter for Optic Disc Imaging in Kenya. AB - IMPORTANCE: Visualization and interpretation of the optic nerve and retina are essential parts of most physical examinations. OBJECTIVE: To design and validate a smartphone-based retinal adapter enabling image capture and remote grading of the retina. DESIGN, SETTING, AND PARTICIPANTS: This validation study compared the grading of optic nerves from smartphone images with those of a digital retinal camera. Both image sets were independently graded at Moorfields Eye Hospital Reading Centre. Nested within the 6-year follow-up (January 7, 2013, to March 12, 2014) of the Nakuru Eye Disease Cohort in Kenya, 1460 adults (2920 eyes) 55 years and older were recruited consecutively from the study. A subset of 100 optic disc images from both methods were further used to validate a grading app for the optic nerves. Data analysis was performed April 7 to April 12, 2015. MAIN OUTCOMES AND MEASURES: Vertical cup-disc ratio for each test was compared in terms of agreement (Bland-Altman and weighted kappa) and test-retest variability. RESULTS: A total of 2152 optic nerve images were available from both methods (also 371 from the reference camera but not the smartphone, 170 from the smartphone but not the reference camera, and 227 from neither the reference camera nor the smartphone). Bland-Altman analysis revealed a mean difference of 0.02 (95% CI, -0.21 to 0.17) and a weighted kappa coefficient of 0.69 (excellent agreement). The grades of an experienced retinal photographer were compared with those of a lay photographer (no health care experience before the study), and no observable difference in image acquisition quality was found. CONCLUSIONS AND RELEVANCE: Nonclinical photographers using the low-cost smartphone adapter were able to acquire optic nerve images at a standard that enabled independent remote grading of the images comparable to those acquired using a desktop retinal camera operated by an ophthalmic assistant. The potential for task shifting and the detection of avoidable causes of blindness in the most at-risk communities makes this an attractive public health intervention. PMID- 26606112 TI - Complete Remission of Squamous Cell Carcinoma After Treatment With Panitumumab in a Patient With Cetuximab-Induced Anaphylaxis. PMID- 26606114 TI - Consensus on the Existence of Functional Erythropoietin Receptors on Cancer Cells. PMID- 26606116 TI - [Robot assisted endometrial cancer staging - evaluation the first 100 operations and comparing the first andthe last 30 operations]. AB - OBJECTIVE: To describe and evaluate our experience with robotically assisted laparoscopic staging of endometrial cancer in first hundred cases as compared with the first and last 30 cases of patients staged by this method. DESIGN: Comparative retrospective study. SETTING: Department of Obstetrics and Gynaecology, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Czech Republic. Institute of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Czech Republic. METHODS: The robotic centre at the Faculty Hospital in Olomouc was opened in August 2009 which enabled to perform robotically assisted laparoscopic staging of endometrial cancer. Retrospectively we evaluated the first hundred patients with the early stage of endometrial cancer who underwent hysterectomy, bilateral salpingo-oophorectomy, and pelvic/paraaortic lymphadenectomy using four-armed da Vinci S HD surgical robotic system. In the second stage of the evaluation we compared the first and the last 30 cases operated by the above mentioned minimally invasive approach. All cases were performed by two surgeons (P.R., D.P.), within the same institution in the course of learning this technique. Age, body mass index (BMI), clinical stage of disease, length of operation, nodal yield, blood loss, the pre operative and post-operative hemoglobin concentration difference and operating complications were documented and compared. RESULTS: The first hundred patients were operated by the above mentioned minimally invasive method between September 2009 nad June 2014. All patients were between 33 and 85 years of age. The average age of the entire group of patients was 65 years of age, the average BMI reached 31.0 (ranging from 18.0 to 49.0), the operating times median was 206 minutes. The estimated median of blood loss was 100 ml. The conversion of robotic surgery to a laparotomy was recordedin 6 cases. When comparing the first and the last30 operated patients there was observed a statistically significant increase in BMI in the group of the last30 operations (29.5 vs. 33.0, p = 0.004) and there was a decrease in the number of conversions from 4 to 1.In particular, however, there was a statistically significant increase in the total number of the obtained lymph nodes in the group of the last 30 vs. the first30 patients (27 vs. 17), and the increase in the number of removed pelvic lymph nodes (21 vs. 17) and the paraaortic nodes (4 vs. 0). CONCLUSION: The robotically assisted laparoscopic staging is one of several possible surgical approaches in the treatment of patients with endometrial cancer and it can be performed adequately in this way. According to the results from our patients group it is a surgical modality with significantly low blood loss, safe even for patients with high BMI and age. The increasing erudition of the surgeon is linked to the shortening of the operating time, reducing the number of conversions and the higher yield of lymph nodes and a reduction in blood loss which was reflected in particular in the comparison of the pre-operative and post-operative hemoglobin difference. PMID- 26606117 TI - [Diaphragmatic surgery in advanced ovarian cancer therapy]. AB - OBJECTIVE: Advanced ovarian cancer is a lethal disease. More than 75% of women with ovarian cancer are diagnosed in advanced stage FIGO IIIC-IV. The combination of surgical cytoreduction without residual tumor, and chemotherapy is the only way to prolong overall survival of women with advanced ovarian cancer. DESIGN: Systematic review. SUBJECT AND METHODS: Current literature review. CONCLUSION: Due to frequent involvement of the diaphragm in women with advanced ovarian cancer and the effort of optimal debulking is the inclusion of diaphragmatic surgery necessary for so affected women. Diaphragmatic surgery increases the rates of optimal cytoreduction, improves survival of women with advanced ovarian cancer and has acceptable morbidity rate. PMID- 26606115 TI - VDJtools: Unifying Post-analysis of T Cell Receptor Repertoires. AB - Despite the growing number of immune repertoire sequencing studies, the field still lacks software for analysis and comprehension of this high-dimensional data. Here we report VDJtools, a complementary software suite that solves a wide range of T cell receptor (TCR) repertoires post-analysis tasks, provides a detailed tabular output and publication-ready graphics, and is built on top of a flexible API. Using TCR datasets for a large cohort of unrelated healthy donors, twins, and multiple sclerosis patients we demonstrate that VDJtools greatly facilitates the analysis and leads to sound biological conclusions. VDJtools software and documentation are available at https://github.com/mikessh/vdjtools. PMID- 26606118 TI - [Radical fertility preserving surgery of gynaecological malignancies - five-year old file]. AB - OBJECTIVE: Analysis of radical fertility preserving surgery, oncogynaecological treatment including their pregnancy effort. DESIGN: Prospective study. SETTING: Department of Obstetrics and Gynaecology, Masaryk University and Faculty Hospital Brno. METHODS: The group of 13 patients in age fifteen to thirty-six, who underwent radical fertility preserving surgery of oncogynecological tumors (cervix, ovarium), 9 patients with ovarian cancer and 4 patients with carcinoma of cervix. RESULTS: Histology showed seven times ovarial epithelial carcinoma, twice nonepithelial ovarial carcinoma, twice spinocelular cervical carcinoma, one adenosquamous and one lymfoepithelioma like carcinoma. We reported lymphocele as the most often postoperative complication by five patients with ovarial carcinoma, lymphoedema of lower limbs in one case and one of them complicated by bilateral hydronephrosis. After surgery procedures of cervical carcinoma, there was a stenosis of cervical canal with postoperative correction. In one case there was provided vaginal revision of cervix followed by embolisation of uterine arteries because of heavy bleeding in early postoperative period. After two years follow up, there are 12 patients in remission. There were four patients with fertlity plan, two with ovarial carcinoma, two with cervical carcinoma. The first group describes two pregnancies - one misscariage and one spontaneus labour in the date of delivery. There were 4 pregnancies in two patients wit cervical carcinoma. One patient has an intrapartal cesarean section because of scarring of the cervix after the operation. Next patients has two labours in due date, three labours in 34-37th week of pregnancy and one misscariage in 23 week of pregnancy. One patient has ovarial cancer during pregnancy, so the radical fertility preserving surgery was done after delivery. CONCLUSION: Methods and procedures of surgery with fertility preserving goals in our oncogynecological centre are in concordance with actual knowledge of medicine and respect oncological safety of patients with malignancies, who currently wish for fertility preserving treatment. Presented group of patients is relatively small, but results of oncological treatment and fertility plan demonstrate right-fulness of this treatment. PMID- 26606119 TI - [Efficacy of surgical treatment of stress urinary incontinence with mini-invasive single incision sling]. AB - OBJECTIVE: The purpose of this study is to evaluate the surgical treatment of stress urinary incontinence by the single incision sling Ophira (Promedon). DESIGN: Prospective observational study. SETTING: Department of Obstetrics and Gynaecology, Masaryk University and University Hospital Brno, Brno. METHODS: Patients with confirmed urodynamic stress urinary incontinence (SUI) were included in the study. Patients with urgent urinary incontinence or mixed incontinence with predominance of urgent folder, patients with insufficiency of internal sphincter of the urethra and pelvic organ prolapse, as well as after previous surgical treatment, patients with pelvic organ prolapse or with other serious pathology of organs of small pelvis were excluded. All patients included in the study received single incision sling (SIS) Ophira (Promedon). The length of the surgery and blood loss and complication was observed. Postoperative observation one year after the treatment was set and evaluated objective and subjective parameters of SUI. RESULTS: In the study were 138 patients examined, total of 45 (34.8%) were included. Postoperative observation completed 44 (97.7%) patients. Mean age was 62.3 years. The mean follow-up was 12.9 months, when 40 patients (90.9%) had a negative cough standardized test (CST). Total of 41 patients (93.1%) evaluated the operation as a major improvement by using a questionnaire Patient Global Impression of Improvement (PGI-I). Quality of life scores were evaluated by International Consultation on Incontinence Questionnaire - Short Form (ICIQ-SF). Before the surgery ranged from 14.8 +/- 2.5 points, after the surgery 3.3 +/- 2.0 which is an improvement of 11.5 +/- 3.1 points. There weren't serious perioperative and postoperative complications. CONCLUSION: Our results are comparable with literary data and are correlated with other studies evaluating the effectiveness of other types of SIS. The method seems to be safe and efficient enough. Observing the group of patients will be continued in order to assess the short- and long-term results. PMID- 26606120 TI - [Correlation of subjective and objective assessment of vaginal prolapse surgery - secondary analysis of randomized controlled study in patients with pelvic floor injury treated with vaginal mesh or with sacrospinous ligament fixation]. AB - OBJECTIVE: We had provided secondary analysis of our randomized controlled study comparing vaginal mesh with sacrospinous fixation for vaginal prolapse. We correlated data from subjective and objective assessment. Secondly we had provided correlations results of subjective and objective assessment between patient with anatomical failure and those without. The aim of this analysis was to provide correlation between objective and subjective outcome measures. DESIGN: Subanalysis of randomized controlled study. SETTING: Obstetric Gynecology Department, First Faculty of Medicine of Charles University and General University Hospital in Prague. METHODS: This is secondary analysis of single center randomized controlled study comparing two standard procedures for vaginal prolapse after hysterectomy in patients with levator avulsion injury. We had analyzed pre- and postoperative subjective POPDI score (Pelvic Organ Prolapse Distress Inventory) and correlated this score with most prolapsed portion of vaginal wall. We had compared all vaginal compartments using POPQ (Pelvic Organ Prolapse Quantification): anterior wall with point Ba, apical with point C, and posterior with point Bp. Subsequently we compared subjective POPDI score in group of patients with anatomical failure and those without. RESULTS: We had included in randomized study 70 women. Mean preoperative POPDI score was 65.25 (3.57-200). We didnt found any correlation between subjective score and objective assessment in preoperative data: POPDI vs. Ba (p = 0.75) POPDI vs. C (p = 0.57) a POPDI vs. Bp (p = 0.22) and no correlation in postoperative assessment. Postoperative POPDI score decreased to 26.1, but there was no difference in POPDI score in woman with anatomical failure and no failure - 17.4 vs. 23.3 (p = 0.64)CONCLUSION: Secondary analysis of randomized controlled study had shown that objective and subjective assessment have poor correlation. We didnt found any correlation between degree of prolapse and intensity of complains. The large inter-individual variability in symptoms and low sensitivity of subjective assessment to detect difference makes subjective assessment as an inappropriate tool as a primary outcome measure of pelvic floor surgery. PMID- 26606121 TI - [Mental changes in women due to the use of hormonal contraception]. AB - The study investigates physical, mental and sexual changes in women at the beginning of use or after discontinuation of a combined hormonal contraception. Thirty women were interviewed at least 3 months and at most 2 years after the start of use or discontinuation of combined hormonal contraception. Semi structured interviews were supplemented by 16-symptom rating scale on which women assessed the results of an imaginary study of side effects of hormonal contraception. Both methods identically demonstrated pronounced effect of combined hormonal contraception on decline in sexual desire and painful menstruation. No clear difference was found in psychical symptoms, although qualitative analysis indicated possible changes. PMID- 26606122 TI - [Histological types of uterine fibroids in reproductive age and postmenopausal women]. AB - OBJECTIVE: To review the incidence of histologic variants of uterine fibroids of patients in reproductive age and postmenopause. Analysis of potential relations between histological fibroids variants and hormonal activity of the patient. DESIGN: Retrospective analysis. SETTING: Department of Obstetrics and Gynecology, Masaryk University and University Hospital Brno. MATERIAL AND METHODS: Retrospective analysis of 2,397 women who underwent myomectomy or hysterectomy at the Department of Obstetrics and Gynecology, Masaryk University and University Hospital Brno in years 2008-2014. According to input criteria - age of patients between 18-65 years, ultrasound confirmed uterine fibroid. Exclusion criteria was irregular menstrual cycle, hormonal therapy in history or hysterectomy performed for tumors of the small pelvis or for cancer of the uterus or cervix.Group A consisted of 235 patients with regular menstrual cycles, between ages 18-40. Myomectomy was chosen for these patients.Group B consisted of 433 postmenopausal patients between ages 50-65. Laparoscopic and abdominal hysterectomy was performed to these patients. RESULTS: A statistically significant difference was observed in the occurrence of epithelioid type of leiomyoma between women age groups 18-40 and 50-65. In the group of postmenopausal women four malignant forms of leiomyoma were recorded, which were not statistically relevant. CONCLUSION: After evaluating statistical analysis it was found, that there is a statistically significant difference in epithelioid type of uterine leiomyoma. Four patients were detected malignant variant of leiomyoma - leiomyosarcoma in the group of postmenopausal women. PMID- 26606123 TI - Delivery modes and the neonatal outcomes of low birth-weight neonates in a Brazilian reference health center. AB - OBJECTIVE: This study compared the neonatal results of low weight neonates born by cesarean and vaginal delivery. DESIGN: A retrospective cohort study. SETTING: Maternity of Hospital - Irmandade Santa Casa de Misericordia de Sao Paulo, Brazil. METHODS: The analysis included the neonates born alive, of unique pregnancy, <2000 g from October 1999 to July 2013. To obtain the information about the neonatal period, as well as their Apgar score in the 1st and 5th min of life, a search in the database of a neonatal intensive care unit was performed. RESULTS: In total, 830 neonates were included as per the study criteria. Of these, 519 (62.5%) were born by cesarean delivery and 311 (37.5%) by vaginal delivery. There was a statistically significant difference in the incidence of neonatal complications, with better results in the neonates born by vaginal delivery, except for the group with neonates <1500 g. In this group, there was a higher incidence of intracranial hemorrhage and death before discharge from the hospital. There was also a higher incidence of respiratory distress syndrome and intraventricular hemorrhage in neonates born by vaginal delivery, in all weight groups. Comparing the Apgar scores, there was a statistically significant difference between the delivery modes, with better results observed in the ones born by vaginal delivery. However, the opposite was observed in the group with neonates <1000 g. CONCLUSION: There was no indication of cesarean delivery benefits in neonates 1000-2000 g. However, the opposite was observed when the neonates were <1000 g. PMID- 26606124 TI - [Robotic sacrocolpopexy - two case reports and literature overview]. AB - OBJECTIVE: To describe first two cases of robotic sacrocolpopexy in the Czech Republic. DESIGN: Two case reports with literature overview. SETTING: Department of Obstetrics and Gynaecology, Faculty of Medicine and Dentistry, Palacky University in Olomouc. CASE REPORT: Robotic sacrocolpopexy was performed in two patients of the age 36 and 59 at the department of obstetrics and gynecology in Olomouc in 2009. We describe vaginal prolapse treatment in one case, and supracervical hysterectomy with cervicosacropexy in the other. These two cases are compared with literature overview, including long-term follow-up. CONCLUSION: Robotic sacrocolpopexy encompasses all advantages of minimally invasive surgery. Our results, as well as published data show very good long term results of vaginal prolapse treatment using this approach. PMID- 26606125 TI - [Heterotopic pregnancy after spontaneous conception]. AB - DESIGN: Case report. SETTING: Departement of Obstetrics and Gyneacology, Silesian Hospital in Opava. METHODS: Case interpretation. CONCLUSION: Heterotopic pregnancy after spontaneous conception is diagnosed with a rare, often difficult to ascertain, however, the increasing incidence has justified its place in the differential diagnosis of acute abdominal not only for women enrolled in the program of assisted reproduction. PMID- 26606126 TI - [Caesarean scar pregnancy - case report]. AB - OBJECTIVE: The aim of this article is to bring attention to possible occurrence of rare ectopic gravidity located in hysterotomy after previous caesarean section. DESIGN: Case report. SETTING: Department of Obstetrics and Gynaecology, Masaryk Municipal Hospital Jilemnice. CASE REPORT: We report a case of 36 years old patient with caesarean scar pregnancy primary solved by hysteroscopic resection, secondary due to severe bleeding solved by laparotomic excision. CONCLUSION: Taking into consideration growing number of caesarean section it is necessary to count with more frequent occurrence of caesarean scar pregnancy. Early diagnosis is important for successful treatment and thus for preservation of patient's fertility. PMID- 26606127 TI - London Dispersion Decisively Contributes to the Thermodynamic Stability of Bulky NHC-Coordinated Main Group Compounds. AB - We evaluated the dispersion stabilization of a series of seemingly reactive main group compounds coordinated to bulky N-heterocyclic carbene ligands. We computed the thermochemistry of hypothetical isodesmic exchange reactions of these ligands with their unsubstituted parent systems employing the B3LYP/6-311G(d,p) level of theory with and without dispersion corrections. The energy difference between these two approaches gave dispersion corrections of 30 kcal mol(-1) and more. We therefore conclude that London dispersion contributes critically to the thermodynamic stabilities of these compounds. As such, these core-shell structures undergo reactions of the reactive core as long as the dispersion stabilization is conserved. PMID- 26606128 TI - Smart Nonaqueous Foams from Lipid-Based Oleogel. AB - Oil foams are composed of gas bubbles dispersed in an oil phase. These systems are scarcely studied despite their great potential in diverse fields such as the food and cosmetic industries. Contrary to aqueous foams, the production of oil foams is difficult to achieve due to the inefficiency of surfactant adsorption at oil-air interfaces. Herein, we report a simple way to produce oil foams from oleogels, whose liquid phase is a mixture of sunflower oil and fatty alcohols. The temperature at which the oleogel formed was found to depend on both fatty alcohol chain length and concentration. The air bubbles in the oleogel foam were stabilized by fatty alcohol crystals. Below the melting temperature of the crystals, oleogel foams were stable for months. Upon heating, these ultrastable foams collapsed within a few minutes due to the melting of the crystal particles. The transition between crystal formation and melting was reversible, leading to thermoresponsive nonaqueous foams. The reversible switching between ultrastable and unstable foam depended solely on the temperature of the system. We demonstrate that these oleogel foams can be made to be photoresponsive by using internal heat sources such as carbon black particles, which can absorb UV light and dissipate the absorbed energy as heat. This simple approach for the formulation of responsive oil foams could be easily extended to other oleogel systems and could find a broad range of applications due to the availability of the components in large quantities and at low cost. PMID- 26606129 TI - Dapsone as Second-Line Treatment for Cutaneous Lupus Erythematosus? A Retrospective Analysis of 34 Patients and a Review of the Literature. AB - BACKGROUND: A variety of therapeutic options have been reported for cutaneous lupus erythematosus (CLE); one of these is dapsone. However, no high priority has been given to this drug. OBJECTIVE: To determine whether dapsone is an effective and safe treatment alternative in patients with LE. METHODS: We reviewed the literature and analyzed retrospectively 34 CLE patients who were treated with dapsone as monotherapy or combined with antimalarials. We assessed the course of the disease under treatment, response, concomitant treatment and side effects. RESULTS: Six patients went into remission, 14 patients improved, and in 6 patients disease remained constant during the observation period. Dapsone was discontinued in 9 patients: in 4 due to reversible side effects and in 5 patients due to poor efficacy. CONCLUSION: Our data confirm that dapsone with/without antimalarials is effective in more than 50% of patients with CLE and could be used as second-line therapy for CLE. PMID- 26606131 TI - Analysis of Genetic Damage in Lymphocytes of Former Uranium Processing Workers. AB - The frequency of cells containing micronuclei (MN) and the presence of centromeres in these MN were analyzed in lymphocytes of 98 men from Southern Bohemia. Forty-six of them had worked at the uranium processing plant 'MAPE Mydlovary' which was closed in 1991, and 52 men were controls from the same area. FISH using human pan-centromeric chromosome paint was employed to detect centromere-positive (CEN+) and -negative (CEN-) MN. A total of 1,000 binucleated cells (BNC) per participant were analyzed after cytochalasin B treatment. All BNC with MN (CEN+ or CEN-) were recorded. No differences were found between formerly exposed workers and the control group, neither in the total frequency of cells with MN per 1,000 BNC (mean levels +/- SD, 9.1 +/- 3.1 and 9.8 +/- 2.5, respectively) nor in the percentage of CEN- MN, which were equal (50 +/- 18 and 49 +/- 17, respectively). Also, there was no difference between individuals living in the 3 villages closest to the uranium processing plant and those living further away. Considering the fact that effective doses of the workers at MAPE Mydlovary were overall similar to those of former uranium miners in whom higher frequencies of CEN- MN have been found more than 10 years after they had finished working underground, these results are somewhat surprising. A more detailed analysis of the exposures indicates that uranium miners received a greater percentage of their effective dose from the inhalation of radon and its daughters, whereas uranium processing workers received it from the incorporation of long-lived radioactive nuclides such as uranium. If, as has been suggested before, the higher level of DNA damage in miners is due to induced genomic instability, then this phenomenon may be related to radon exposure rather than exposure to uranium. PMID- 26606130 TI - AF710B, a Novel M1/sigma1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer's Disease. AB - We previously developed orthosteric M1 muscarinic agonists (e.g. AF102B, AF267B and AF292), which act as cognitive enhancers and potential disease modifiers. We now report on a novel compound, AF710B, a highly potent and selective allosteric M1 muscarinic and sigma1 receptor agonist. AF710B exhibits an allosteric agonistic profile on the M1 muscarinic receptor; very low concentrations of AF710B significantly potentiated the binding and efficacy of carbachol on M1 receptors and their downstream effects (p-ERK1/2, p-CREB). AF710B (1-30 ug/kg, p.o.) was a potent and safe cognitive enhancer in rats treated with the M1 antagonist trihexyphenidyl (passive avoidance impairment). These effects of AF710B involve sigma1 receptor activation. In agreement with its antiamnesic properties, AF710B (at 30 nM), via activation of M1 and a possible involvement of sigma1 receptors, rescued mushroom synapse loss in PS1-KI and APP-KI neuronal cultures, while AF267B (1 uM) was less potent in PS1-KI and ineffective in APP-KI models, respectively. In female 3xTg-AD mice, AF710B (10 ug/kg, i.p./daily/2 months) (i) mitigated cognitive impairments in the Morris water maze; (ii) decreased BACE1, GSK3beta activity, p25/CDK5, neuroinflammation, soluble and insoluble Abeta40, Abeta42, plaques and tau pathologies. AF710B differs from conventional sigma1 and M1 muscarinic (orthosteric, allosteric or bitopic) agonists. These results highlight AF710B as a potential treatment for Alzheimer's disease (e.g. improving cognitive deficits, synaptic loss, amyloid and tau pathologies, and neuroinflammation) with a superior profile over a plethora of other therapeutic strategies. PMID- 26606132 TI - Assessing Low Redox Stability of Myoglobin Relative to Rapid Hemin Loss from Hemoglobin. AB - Bovine myoglobin (Mb) auto-oxidized 11-fold faster at pH 5.7 compared to bovine hemoglobin (Hb). Replacement of Ser(F7) in bovine Mb with positively charged or large apolar residues decreased auto-oxidation rates (2- to 4-fold) in comparison with wild-type Mb (P < 0.05). However, the same substitutions increased hemin loss rate (15- to 28-fold), indicating that hydrogen bonding between Ser(F7) and the heme-7-propionate is critical for stabilizing protoporphyrin in the globin. The anchoring of Ser(F7) to the heme-7-propionate in the proximal pocket of Mb is suggested to expose the distal pocket to solvent molecules that accelerate auto oxidation. The rate of hemin loss from metHb at pH 5.7 was 68-fold faster compared to metMb. The ability of Ser(F7) and His(FG3) in Mb to form stabilizing contacts with the heme-7-propionate maintains hemin within the globin whereas Leu(F7) and Leu(FG3) of Hb cannot form stabilizing contacts which results in low hemin affinity. MetHb promoted lipid oxidation more effectively in washed muscle at pH 5.7 compared to metMb (P < 0.05). The greater ability of bovine metHb to promote lipid oxidation is likely due to its enhanced rate of hemin dissociation compared to bovine metMb. PMID- 26606133 TI - Roemerine Improves the Survival Rate of Septicemic BALB/c Mice by Increasing the Cell Membrane Permeability of Staphylococcus aureus. AB - Staphylococcus aureus is one of the most frequently occurring hospital- and community-associated pathogenic bacteria featuring high morbidity and mortality. The occurrence of methicillin-resistant S. aureus (MRSA) has increased persistently over the years. Therefore, developing novel anti-MRSA drugs to circumvent drug resistance of S. aureus is highly important. Roemerine, an aporphine alkaloid, has previously been reported to exhibit antibacterial activity. The present study aimed to investigate whether roemerine can maintain these activities against S.aureus in vivo and further explore the underlying mechanism. We found that roemerine is effective in vitro against four S. aureus strains as well as in vivo against MRSA insepticemic BALB/c mice. Furthermore, roemerine was found to increase cell membrane permeability in a concentration dependent manner. These findings suggest that roemerine may be developed as a promising compound for treating S. aureus, especially methicillin-resistant strains of these bacteria. PMID- 26606134 TI - p,p'-DDE Induces Gonadal Intersex in Japanese Medaka (Oryzias latipes) at Environmentally Relevant Concentrations: Comparison with o,p'-DDT. AB - Previous studies have reported high body burdens of dichlorodiphenyltrichloroethane (DDT) and its metabolites in wild fishes worldwide. This study evaluated the adverse effects of 1,1-dichloro-2,2-bis (p chlorophenyl)-ethylene (p,p'-DDE) and o,p'-DDT on gonadal development and reproduction by exposing transgenic Japanese medaka (Oryzias latipes) from hatch for 100 days. While both p,p'-DDE and o,p'-DDT induced intersex in male medaka, the lowest observable effective concentration (LOEC) of o,p'-DDT was 57.7 ng/g ww, about 5-fold lower than that (272 ng/g ww) of p,p'-DDE. Since LOECs of both chemicals were comparable to the body concentrations in wild fish, DDT contamination would likely contribute to the occurrence of intersex observed in wild fish. Exposure to o,p'-DDT resulted in much higher expression of vitellogenin in liver of males than p,p'-DDE, accordant with the higher potency of o,p'-DDT than p,p'-DDE to induce intersex. This phenomenon could be partly explained by the significantly elevated levels of 17beta-estradiol in plasma of males exposed to o,p'-DDT, in addition to its estrogenic activity via the estrogen receptor. Significantly lower fertilization (p = 0.006) and hatchability (p = 0.019) were observed in the 13 intersex males. This study for the first time demonstrated the induction of intersex and reproductive effects of p,p'-DDE and o,p'-DDT at environmentally relevant concentrations. PMID- 26606135 TI - Comparison of the Prognostic Utility of the Diverse Molecular Data among lncRNA, DNA Methylation, microRNA, and mRNA across Five Human Cancers. AB - INTRODUCTION: Advances in high-throughput technologies have generated diverse informative molecular markers for cancer outcome prediction. Long non-coding RNA (lncRNA) and DNA methylation as new classes of promising markers are emerging as key molecules in human cancers; however, the prognostic utility of such diverse molecular data remains to be explored. MATERIALS AND METHODS: We proposed a computational pipeline (IDFO) to predict patient survival by identifying prognosis-related biomarkers using multi-type molecular data (mRNA, microRNA, DNA methylation, and lncRNA) from 3198 samples of five cancer types. We assessed the predictive performance of both single molecular data and integrated multi-type molecular data in patient survival stratification, and compared their relative importance in each type of cancer, respectively. Survival analysis using multivariate Cox regression was performed to investigate the impact of the IDFO identified markers and traditional variables on clinical outcome. RESULTS: Using the IDFO approach, we obtained good predictive performance of the molecular datasets (bootstrap accuracy: 0.71-0.97) in five cancer types. Impressively, lncRNA was identified as the best prognostic predictor in the validated cohorts of four cancer types, followed by DNA methylation, mRNA, and then microRNA. We found the incorporating of multi-type molecular data showed similar predictive power to single-type molecular data, but with the exception of the lncRNA + DNA methylation combinations in two cancers. Survival analysis of proportional hazard models confirmed a high robustness for lncRNA and DNA methylation as prognosis factors independent of traditional clinical variables. CONCLUSION: Our study provides insight into systematically understanding the prognostic performance of diverse molecular data in both single and aggregate patterns, which may have specific reference to subsequent related studies. PMID- 26606136 TI - Novel Alleles of gon-2, a C. elegans Ortholog of Mammalian TRPM6 and TRPM7, Obtained by Genetic Reversion Screens. AB - TRP (Transient Receptor Potential) cation channels of the TRPM subfamily have been found to be critically important for the regulation of Mg2+ homeostasis in both protostomes (e.g., the nematode, C. elegans, and the insect, D. melanogaster) and deuterostomes (e.g., humans). Although significant progress has been made toward understanding how the activities of these channels are regulated, there are still major gaps in our understanding of the potential regulatory roles of extensive, evolutionarily conserved, regions of these proteins. The C. elegans genes, gon-2, gtl-1 and gtl-2, encode paralogous TRP cation channel proteins that are similar in sequence and function to human TRPM6 and TRPM7. We isolated fourteen revertants of the missense mutant, gon-2(q338), and these mutations affect nine different residues within GON-2. Since eight of the nine affected residues are situated within regions that have high similarity to human TRPM1,3,6 and 7, these mutations identify sections of these channels that are potentially critical for channel regulation. We also isolated a single mutant allele of gon-2 during a screen for revertants of the Mg2+-hypersensitive phenotype of gtl-2(-) mutants. This allele of gon-2 converts a serine to phenylalanine within the highly conserved TRP domain, and is antimorphic against both gon-2(+) and gtl-1(+). Interestingly, others have reported that mutation of the corresponding residue in TRPM7 to glutamate results in deregulated channel activity. PMID- 26606137 TI - Knowledge and Beliefs of Breast Self-Examination and Breast Cancer among Market Women in Ibadan, South West, Nigeria. AB - BACKGROUND: In most resource constrained settings like Nigeria, breast self examination self-breast examination (BSE) is culturally acceptable, religious friendly and attracts no cost. Women's knowledge and beliefs about breast cancer and its management may contribute significantly to medical help-seeking behaviours. This study aimed to assess knowledge and beliefs of BSE among market women. METHODS: A descriptive cross-sectional study was conducted among 603 market women in Ibadan, Nigeria. Data was collected using semi-structured interviews and analyzed using descriptive and analytic statistical methods. RESULTS: The mean age of the respondents was 34.6+/-9.3 years with 40% of the women aged between 30-39years. The proportion of married women was 339 (68.5%) with 425 (70.8%) respondents reporting that they do not know how to perform BSE. However, 372 (61.7%) women strongly agreed that BSE is a method of screening for breast cancer. Highest proportion 219 (36.3%) reported that the best time for a woman to perform BSE was 'anytime'. Most of the respondents believed breast cancer is a dangerous disease that kills fast and requires a lot of money for treatment. CONCLUSION: More efforts are needed in creating awareness and advocacy campaigns in the grassroots in order to detect early breast cancer and enhance prevention strategies that would reduce the burden of breast cancer in Nigeria. PMID- 26606138 TI - Correction: A genetically defined asymmetry underlies the inhibitory control of flexor-extensor locomotor movements. PMID- 26606139 TI - Correction: Brief Parenteral Nutrition Accelerates Weight Gain, Head Growth Even in Healthy VLBWs. PMID- 26606140 TI - Picrajavanicins A-G, Quassinoids from Picrasma javanica Collected in Myanmar. AB - Seven new tetracyclic quassinoids, picrajavanicins A-G (1-7), along with three known analogues, were isolated from a CHCl3-soluble extract of the bark of Picrasma javanica collected in Myanmar. The structures of these compounds were elucidated using spectroscopic techniques, including 1D and 2D NMR. The absolute configuration at C-2 of 2 was determined to be S by the modified Mosher method. All the isolates were tested for their antiproliferative activities against a small panel of five human cancer cell lines. However, none of the isolated compounds exhibited inhibitory activity against any of the cancer cells used (IC50 values >10 MUM). PMID- 26606141 TI - Strong Confinement Effects on Homocrystallization by Stereocomplex Crystals in Electrospun Polylactide Fibers. AB - In asymmetric poly(l-lactide)/poly(d-lactide) (PLLA/PDLA) blends, the pre existing stereocomplex crystals can impose confinement effects on homocrystallization of uncomplexed PLLA among them. However, confinement effects are very weak in the blend films because of relatively large PLLA domains distributed in the skeleton of stereocomplex crystals. As a comparison, in the electrospun blend fibers, fine distribution of uncomplexed PLLA results in strong confinement effects. This is manifested by the significant decrease in the crystallization temperature and melting point. Even so, confinement effects have little influence on the crystal form, and PLLA alpha-crystals prevail in the electrospun blend fibers after melt crystallization. Finally, confinement effects in the electrospun blend fibers depend on annealing temperatures and almost disappear when the samples are annealed above the melting point of stereocomplex crystals. PMID- 26606142 TI - Chiral Platinum(II) Complexes Featuring Phosphine and Chloroquine Ligands as Cytotoxic and Monofunctional DNA-Binding Agents. AB - Chiral molecules in nature are involved in many biological events; their selectivity and specificity make them of great interest for understanding the behavior of bioactive molecules, by providing information about the chiral discrimination. Inspired by these conformational properties, we present the design and synthesis of novel chiral platinum(II) complexes featuring phosphine and chloroquine ligands with the general formula [PtCl(P)2(CQ)]PF6 (where (P)2 = triphenylphosphine (PPh3) (5), 1,3-bis(diphenylphosphine)propane (dppp) (6), 1,4 bis(diphenylphosphine)butane (dppb) (7), 1,1'-bis(diphenylphosphine)ferrocene (dppf) (8), and CQ = chloroquine] and their precursors of the type [PtCl2(P)2] are described. The complexes were characterized by elemental analysis, absorption spectroscopy in the infrared and ultraviolet-visible (UV-vis) regions, multinuclear ((1)H, (13)C, (31)P, (15)N, and (195)Pt) NMR spectroscopy, cyclic voltammetry, and mass spectrometry (in the case of chloroquine complexes). The interactions of the new platinum-chloroquine complexes with both albumin (BSA), using fluorescence spectroscopy, and DNA, by four widely reported methods were also evaluated. These experiments showed that these Pt-CQ complexes interact strongly with DNA and have high affinities for BSA, in contrast to CQ and CQDP (chloroquine diphosphate), which interact weakly with these biomolecules. Additional assays were performed in order to investigate the cytotoxicity of the platinum complexes against two healthy cell lines (mouse fibroblasts (L929) and the Chinese hamster lung (V79-4)) and four tumor cell lines (human breast (MDA-MB 231 and MCF-7), human lung (A549), and human prostate (DU-145)). The results suggest that the Pt-CQ complexes are generally more cytotoxic than the free CQ, showing that they are promising as anticancer drugs. PMID- 26606143 TI - Generalised Sandpile Dynamics on Artificial and Real-World Directed Networks. AB - The main finding of this paper is a novel avalanche-size exponent tau ~ 1.87 when the generalised sandpile dynamics evolves on the real-world Japanese inter-firm network. The topology of this network is non-layered and directed, displaying the typical bow tie structure found in real-world directed networks, with cycles and triangles. We show that one can move from a strictly layered regular lattice to a more fluid structure of the inter-firm network in a few simple steps. Relaxing the regular lattice structure by introducing an interlayer distribution for the interactions, forces the scaling exponent of the avalanche-size probability density function tau out of the two-dimensional directed sandpile universality class tau = 4/3, into the mean field universality class tau = 3/2. Numerical investigation shows that these two classes are the only that exist on the directed sandpile, regardless of the underlying topology, as long as it is strictly layered. Randomly adding a small proportion of links connecting non adjacent layers in an otherwise layered network takes the system out of the mean field regime to produce non-trivial avalanche-size probability density function. Although these do not display proper scaling, they closely reproduce the behaviour observed on the Japanese inter-firm network. PMID- 26606144 TI - Technical-Induced Hemolysis in Patients with Respiratory Failure Supported with Veno-Venous ECMO - Prevalence and Risk Factors. AB - The aim of the study was to explore the prevalence and risk factors for technical induced hemolysis in adults supported with veno-venous extracorporeal membrane oxygenation (vvECMO) and to analyze the effect of hemolytic episodes on outcome. This was a retrospective, single-center study that included 318 adult patients (Regensburg ECMO Registry, 2009-2014) with acute respiratory failure treated with different modern miniaturized ECMO systems. Free plasma hemoglobin (fHb) was used as indicator for hemolysis. Throughout a cumulative support duration of 4,142 days on ECMO only 1.7% of the fHb levels were above a critical value of 500 mg/l. A grave rise in fHb indicated pumphead thrombosis (n = 8), while acute oxygenator thrombosis (n = 15) did not affect fHb. Replacement of the pumphead normalized fHb within two days. Neither pump or cannula type nor duration on the first system was associated with hemolysis. Multiple trauma, need for kidney replacement therapy, increased daily red blood cell transfusion requirements, and high blood flow (3.0-4.5 L/min) through small-sized cannulas significantly resulted in augmented blood cell trauma. Survivors were characterized by lower peak levels of fHb [90 (60, 142) mg/l] in comparison to non-survivors [148 (91, 256) mg/l, p<=0.001]. In conclusion, marked hemolysis is not common in vvECMO with modern devices. Clinically obvious hemolysis often is caused by pumphead thrombosis. High flow velocity through small cannulas may also cause technical induced hemolysis. In patients who developed lung failure due to trauma, fHb was elevated independantly of ECMO. In our cohort, the occurance of hemolysis was associated with increased mortality. PMID- 26606145 TI - Spatio-Temporal Regulation of Rac1 Mobility by Actin Islands. AB - Rho GTPases play important roles in many aspects of cell migration, including polarity establishment and organizing actin cytoskeleton. In particular, the Rho GTPase Rac1 has been associated with the generation of protrusions at leading edge of migrating cells. Previously we showed the mobility of Rac1 molecules is not uniform throughout a migrating cell (Hinde E et. al. PNAS 2013). Specifically, the closer a Rac1 molecule is to the leading edge, the slower the molecule diffuses. Because actin-bound Rac1 diffuses slower than unbound Rac1, we hypothesized that regions of high actin concentration, called "actin islands", act as diffusive traps and are responsible for the non-uniform diffusion observed in vivo. Here, in silico model simulations demonstrate that equally spaced actin islands can regulate the time scale for Rac1 diffusion in a manner consistent with data from live-cell imaging experiments. Additionally, we find this mechanism is robust; different patterns of Rac1 mobility can be achieved by changing the actin islands' positions or their affinity for Rac1. PMID- 26606146 TI - Occurrence of ESBL-Producing Escherichia coli in Livestock and Farm Workers in Mecklenburg-Western Pomerania, Germany. AB - In recent years, extended-spectrum beta-lactamases (ESBL) producing bacteria have been found in livestock, mainly as asymptomatic colonizers. The zoonotic risk for people working in close contact to animal husbandry has still not been completely assessed. Therefore, we investigated the prevalence of ESBL-producing Escherichia spp. in livestock animals and workers to determine the potential risk for an animal-human cross-transmission.In Mecklenburg-Western Pomerania, northeast Germany, inguinal swabs of 73 individuals with livestock contact from 23 different farms were tested for ESBL-producing Escherichia spp. Two pooled fecal samples per farm of animal origin from 34 different farms (17 pig farms, 11 cattle farms, 6 poultry farms) as well as cloacal swabs of 10 randomly selected broilers or turkeys were taken at each poultry farm. For identification, selective chromogenic agar was used after an enrichment step. Phenotypically ESBL producing isolates (n = 99) were tested for CTX-M, OXA, SHV and TEM using PCR, and isolates were further characterized using multilocus sequence typing (MLST). In total, 61 diverse isolates from different sources and/or different MLST/PCR results were acquired. Five farm workers (three from cattle farms and two from pig farms) harbored ESBL-producing E. coli. All human isolates harbored the CTX-M beta-lactamase; TEM and OXA beta-lactamases were additionally detected in two, resp. one, isolates. ESBL-producing Escherichia spp. were found in fecal samples at pig (15/17), cattle (6/11) and poultry farms (3/6). In total, 70.6% (24/36) of the tested farms were ESBL positive. Furthermore, 9 out of 60 cloacal swabs turned out to be ESBL positive. All isolated ESBL-producing bacteria from animal sources were E. coli, except for one E. hermanii isolate. CTX-M was the most prevalent beta-lactamase at cattle and pig farms, while SHV predominated in poultry. One human isolate shared an identical MLST sequence type (ST) 3891 and CTX-M allele to the isolate found in the cattle fecal sample from the same farm, indicating a zoonotic transfer. Two other pairs of human-pig and human-cattle E. coli isolates encoded the same ESBL genes but did not share the same MLST ST, which may indicate horizontal resistance gene transfer. In summary, the study shows the high prevalence of ESBL-producing E.coli in livestock in Mecklenburg- Western Pomerania and provides the risk of transfer between livestock and farm workers. PMID- 26606147 TI - Physiological Costs of Repetitive Courtship Displays in Cockroaches Handicap Locomotor Performance. AB - Courtship displays are typically thought to have evolved via female choice, whereby females select mates based on the characteristics of a display that is expected to honestly reflect some aspect of the male's quality. Honesty is typically enforced by mechanistic costs and constraints that limit the level at which a display can be performed. It is becoming increasingly apparent that these costs may be energetic costs involved in the production of dynamic, often repetitive displays. A female attending to such a display may thus be assessing the physical fitness of a male as an index of his quality. Such assessment would provide information on his current physical quality as well as his ability to carry out other demanding activities, qualities with which a choosy female should want to provision her offspring. In the current study we use courtship interactions in the Cuban burrowing cockroach, Byrsotria fumigata to directly test whether courtship is associated with a signaler's performance capacity. Males that had produced courtship displays achieved significantly lower speeds and distances in locomotor trials than non-courting control males. We also found that females mated more readily with males that produced a more vigorous display. Thus, males of this species have developed a strategy where they produce a demanding courtship display, while females choose males based on their ability to produce this display. Courtship displays in many taxa often involve dynamic repetitive actions and as such, signals of stamina in courtship may be more widespread than previously thought. PMID- 26606148 TI - Vital Signs: Estimated Percentages and Numbers of Adults with Indications for Preexposure Prophylaxis to Prevent HIV Acquisition--United States, 2015. AB - BACKGROUND: In 2014, approximately 40,000 persons in the United States received a diagnosis of human immunodeficiency virus (HIV) infection. Preexposure prophylaxis (PrEP) with daily oral antiretroviral medication is a new, highly effective intervention that could reduce the number of new HIV infections. METHODS: CDC analyzed nationally representative data to estimate the percentages and numbers of persons in the United States, by transmission risk group, with indications for PrEP consistent with the 2014 U.S. Public Health Service's PrEP clinical practice guideline. RESULTS: Approximately 24.7% of sexually active adult men who have sex with men (MSM) (492,000 [95% confidence interval {CI} = 212,000-772,000]), 18.5% of persons who inject drugs (115,000 [CI = 45,000 185,000]), and 0.4% of heterosexually active adults (624,000 [CI = 404,000 846,000]), had substantial risks for acquiring HIV consistent with PrEP indications. CONCLUSIONS: Based on current guidelines, many MSM, persons who inject drugs, and heterosexually active adults have indications for PrEP. A higher percentage of MSM and persons who inject drugs have indications for PrEP than heterosexually active adults, consistent with distribution of new HIV diagnoses across these populations. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Clinical organizations, health departments, and community-based organizations should raise awareness of PrEP among persons with substantial risk for acquiring HIV infection and their health care providers. These data can be used to inform scale-up and evaluation of PrEP coverage. Increasing delivery of PrEP and other highly effective HIV prevention services could lower the number of new HIV infections occurring in the United States each year. PMID- 26606149 TI - The relationship of benthic community metrics to pyrethroids, metals, and sediment characteristics in Cache Slough, California. AB - A bioassessment multiple stressor study was conducted at 12 sites in Cache Slough, California during the Spring and Fall of 2012, 2013 and 2014. Specific study goals were to: (1) collect and identify benthic macroinvertebrates and develop a suite of benthic metrics; (2) measure total organic carbon (TOC), grain size, bulk metals, simultaneously extracted metals (SEM) and acid volatile sulfides (AVS), and 8 pyrethroids in sediment; (3) measure basic water quality parameters; and, (4) use univariate and stepwise multiple regressions and canonical correlation analysis to determine the relationship between various benthic metrics (i.e., taxa richness, abundance) and TOC, grain size, metals (bulk metals and SEM/AVS) and pyrethroids using the 3-year database. Five benthic metrics showed statistically significant relationships with environmental variables. Taxonomic Richness, a metric that decreases with stress, tended to be greater in less organic-rich, coarser sediments and the apparent relationships with toxicants such as pyrethroids or metals were diminished when these conditions are taken into account. The % Amphipod metric, which has a variable response to environmental stressors, showed a direct relationship with arsenic, an inverse relationship with chromium and an inverse relationship with % silt. The % Corbicula metric, which has a variable response to environmental stressors, was directly correlated with cypermethrin and nickel. Therefore, it appears that Corbicula tends to be associated with more contaminated sediments in Cache Slough. The metric % Collectors/Filterers & Collectors/Gatherers, a metric that increases in stressed environments, was reported to increase in sediments with higher arsenic concentrations. This relationship makes ecological sense because this metric should increase with an increase in arsenic concentrations. The benthic metric Abundance, a metric that decreases with stress, was reported to be inversely correlated with % TOC and % silt. The abundance of benthic communities increases in coarser, less organic rich sediments. In general, relatively few statistically significant relationships were observed between the various combinations of benthic metrics and environmental variables. Benthic communities in Cache Slough appear to be more closely associated with sediment characteristics and with metals concentrations than with the pyrethroid concentrations. PMID- 26606150 TI - Digital laser printing of metal/metal-oxide nano-composites with tunable electrical properties. AB - We study the electrical properties of aluminum structures printed by the laser forward transfer of molten, femtoliter droplets in air. The resulting printed material is an aluminum/aluminum-oxide nano-composite. By controlling the printing conditions, and thereby the droplet volume, its jetting velocity and duration, it is possible to tune the electrical resistivity to a large extent. The material resistivity depends on the degree of oxidation which takes place during jetting and on the formation of electrical contact points as molten droplets impact the substrate. Evidence for these processes is provided by FIB cross sections of printed structures. PMID- 26606151 TI - Prevention of Hand Osteoarthritis by Hemiparesis. PMID- 26606152 TI - Sirolimus for the treatment of noninfectious uveitis. AB - INTRODUCTION: Noninfectious posterior uveitis (NIPU) remains a significant burden of legal blindness. Because of its immune mediated and chronic recurrent nature, common therapy includes (systemic) corticosteroids and immune modulatory agents. Most treatments bear the risk of significant adverse effects. Therefore efforts are made to administer therapeutic agents directly into the vitreous cavity. The purpose of this article is to identify the role of intravitreally applied sirolimus as a recently approved therapeutic option in NIPU. AREAS COVERED: A MEDLINE database search was conducted through August 2015 using the terms: intravitreal injection, pharmacology, sirolimus, treatment and uveitis. To provide ongoing and future perspectives in treatment options, also clinical trials as registered at ClinicalTrials.gov were included. Sirolimus (Opsiria) was in licensed from SANTEN in 2015 and approved in Phase III registration trials in the US, Europe and other countries for NIPU. Current information results mainly from registration and Phase III trials. EXPERT OPINION: Intravitreal sirolimus appears to be an interesting option in the treatment algorithms of NIPU because of its highly targeted molecular effects, nonsteroidal nature and good safety profile. It has the advantage to avoid systemic side effects, but this has to be balanced against the fact that treatment covers one eye only and bears the risks of any intraocular procedure. Nevertheless a careful evaluation of this agent has to be made, as current experience is almost exclusively based on registration trials and long-term effects still have to be explored. PMID- 26606153 TI - Sensing and Sensibility: Single-Islet-based Quality Control Assay of Cryopreserved Pancreatic Islets with Functionalized Hydrogel Microcapsules. AB - Despite decades of research and clinical studies of islet transplantations, finding simple yet reliable islet quality assays that correlate accurately with in vivo potency is still a major challenge, especially for real-time and single islet-based quality assessment. Herein, proof-of-concept studies of a cryopreserved microcapsule-based quality control assays are presented for single islets. Individual rat pancreatic islets and fluorescent oxygen-sensitive dye (FOSD) are encapsulated in alginate hydrogel microcapsules via a microfluidic device. To test the susceptibility of the microcapsules and the FOSD to cryopreservation, the islet microcapsules containing FOSD are cryopreserved and the islet functionalities (adenosine triphosphate, static insulin release measurement, and oxygen consumption rate) are assessed after freezing and thawing steps. The cryopreserved islet capsules with FOSD remain functional after encapsulation and freezing/thawing procedures, validating a simple yet reliable individual-islet-based quality control method for the entire islet processing procedure prior to transplantation. This work also demonstrates that the functionality of cryopreserved islets can be improved by introducing trehalose into the routinely used cryoprotectant dimethyl sulfoxide. The functionalized alginate hydrogel microcapsules with embedded FOSD and optimized cryopreservation protocol presented in this work serve as a versatile islet quality assay and offer tremendous promise for tackling existing challenges in islet transplantation procedures. PMID- 26606154 TI - Resource seasonality and reproduction predict fission-fusion dynamics in black and-white ruffed lemurs (Varecia variegata). AB - Ruffed lemurs (genus Varecia) are often described as having a flexible social organization, such that both cohesive (low fission-fusion dynamics) and fluid (high fission-fusion dynamics) grouping patterns have been observed. In ruffed lemur communities with high fission-fusion dynamics, group members vary in their temporal and spatial dispersion throughout a communally defended territory. These patterns have been likened to those observed in several haplorrhine species that exhibit the most fluid types of fission-fusion social organization (e.g., Pan and Ateles). To substantiate and further refine these claims, we describe the fission fusion dynamics of a black-and-white ruffed lemur (Varecia variegata) community at Mangevo, an undisturbed primary rainforest site in Ranomafana National Park, Madagascar. We collected instantaneous group scan samples from August 2007 December 2008 (4,044 observation hours) to study and characterize patterns of subgroup size, composition, cohesion, and social association. In 16 consecutive months, we never found all members of the community together. In fact, individuals spent nearly half of their time alone. Subgroups were small, cohesive, and typically of mixed-sex composition. Mixed-sex subgroups were significantly larger, less cohesive, and more common than either male-only or female-only subgroups. Subgroup dynamics were related to shifts in climate, phenology of preferred fruit species, and female reproductive state. On average, association indices were low. Males and females were equally gregarious; however, adult male-male associations were significantly weaker than any other association type. Results presented herein document striking differences in fission-fusion dynamics between black-and-white ruffed lemurs and haplorrhines, while also demonstrating many broad-scale similarities to haplorrhine taxa that possess the most fluid fission-fusion societies. PMID- 26606155 TI - Clinical characteristics and outcomes of patients with community-acquired, health care-associated and hospital-acquired empyema. AB - BACKGROUND AND AIMS: Patients with pneumonia, a common cause of empyema, are stratified based on their risk factors, and the treatment of empyema might benefit from this risk stratification. METHODS: The etiology, bacteriologic profile and outcome of patients diagnosed with empyema in Shinko Hospital between May 2005 and October 2013 were retrospectively studied. The patients were stratified according to whether they had community-acquired empyema (CAE), health care-associated empyema (HCAE) or hospital-acquired empyema (HAE). RESULTS: The study included 81 patients, 25 CAE, 40 HCAE and 16 HAE. The comorbidity rate was highest among HAE patients (100%), followed by 95% of HCAE and 72% of CAE patients (P = 0.005). The rates of cancer and central nervous system (CNS) disease were higher in patients with HCAE and HAE than in patients with CAE (P = 0.030, P = 0.018, respectively). Pleural fluid cultures were positive in 58/81 patients. Streptococcus species were the most common organisms cultured from CAE (12/15) and HCAE patients (17/30), but not from HAE patients (3/13). Anaerobic organisms were cultured from 3 CAE, 5 HCAE and 3 HAE patients. Methicillin resistant Staphylococcus aureus and Pseudomonas aeruginosa were only cultured from HCAE and HAE patients. The mortality rates were higher in HCAE (18%) and HAE (50%) than in CAE (4%) patients (log-rank test: P = 0.0012). CONCLUSIONS: Half of patients with empyema were HCAE patients, who had comorbidities, bacteriological profile and outcome different from CAE patients. The patient with HCAE should be differentiated from CAE patient, and the stratification of patients based on risk factors may be useful for treatment strategy. PMID- 26606156 TI - Synthesis of a Chiral Crystal Form of MOF-5, CMOF-5, by Chiral Induction. AB - Chiral variants of the prototypal metal-organic framework MOF-5, Lambda-CMOF-5 and Delta-CMOF-5, have been synthesized by preparing MOF-5 in the presence of L proline or D-proline, respectively. CMOF-5 crystallizes in chiral space group P213 instead of Fm3m as exhibited by MOF-5. The phase purity of CMOF-5 was validated by single-crystal and powder X-ray diffraction, infrared spectroscopy, thermogravimetric analysis, N2 adsorption, microanalysis, and solid-state vibrational circular dichroism. CMOF-5 undergoes a reversible single crystal-to single crystal phase change to MOF-5 when immersed in a variety of organic solvents, although N-methyl-2-pyrrolidone (NMP) does not induce loss of chirality. Indeed, MOF-5 undergoes chiral induction when immersed in NMP, affording racemic CMOF-5. PMID- 26606157 TI - Family Health Climate and Adolescents' Physical Activity and Healthy Eating: A Cross-Sectional Study with Mother-Father-Adolescent Triads. AB - INTRODUCTION: The importance of the family environment for children's and adolescents' health behavior has been demonstrated, the underlying mechanisms of this influence remain unclear. Therefore, the aim of the study was to investigate the relationship between family environmental and individual determinants. It was hypothesized that the Family Health Climate (FHC) is associated with adolescents' physical activity and dietary behavior and that intrinsic motivation mediates this association. METHODS: Cross-sectional data were collected from 198 families (mother, father, and child) using questionnaires. Perceptions of FHC of mothers, fathers, and their children were assessed using the FHC-scales for physical activity (FHC-PA) and nutrition (FHC-NU). The adolescents also rated their intrinsic motivation for exercise and healthy eating, their physical activity and consumption of healthful food. A structural equation model was analyzed and a bootstrapping procedure was used to test direct and indirect effects. RESULTS: The FHC-PA was related to the amount of weekly physical activity and the FHC-NU to the consumption of fruit, vegetables and salad. These effects were mediated by adolescents' intrinsic motivation; the indirect effects were significant for both behaviors. DISCUSSION: These results emphasize the importance of the FHC in shaping adolescents' physical activity and dietary behavior. Individual motivational factors are potential mediators of family and parental influences. Considering family-level variables and their interaction with individual factors contributes to the understanding of adolescents' health behavior. PMID- 26606158 TI - [Health behavior from the gender perspective--The concept of "doing genders" and the perspective of intersectionality as an explanation]. AB - Unfortunately, the wrong institution was specified, the correct one is: Karl Franzens-University Graz, coordinator for Gender Studies,Women's Studies and Gender Equality. You can find the corrected post here:10.1055 / s-0035-1562984. Please excuse the mistake. PMID- 26606159 TI - Teaching Labor Support: An Interprofessional Simulation. AB - Support for women during labor encompasses the continuous presence of a person who provides psychosocial, emotional, and physical support. Providing labor support to women in the intrapartum setting is a core midwifery competency and a clinical skill that midwifery students are expected to master. Instruction on labor support is a common objective in midwifery education intrapartum courses and skills labs, yet there is no standard for teaching this skill to midwifery students. Thus, in order to accomplish this objective, we created an interprofessional simulation on labor support that involves the use of a standardized patient, a written scenario, an interprofessional team of nursing and midwifery students, faculty observations, and a reflective debrief. The goals of the labor support simulation are to allow midwifery students the opportunity to practice intrapartum labor support techniques and interprofessional communication prior to entering the clinical setting. A postsimulation structured debrief allows for student learning and reflection. This article describes the design, planning, and implementation of this unique simulation experience. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health. PMID- 26606160 TI - Endemic Burkitt Lymphoma: Long-term Outcome in 87 Patients Who Presented With Paraplegia in Cameroon. AB - The reported long-term outcome of endemic Burkitt lymphoma (eBL) patients who present with paraplegia is largely unknown. Records of BL patients treated with comparable short-interval cyclophosphamide chemotherapy schedules between 2004 and 2014 at three Baptist mission hospitals in Cameroon were reviewed. Survivors were followed up and examined at home or in hospital. Eighty-seven of 948 (9.2%) patients had paraplegia at diagnosis. The survival rate in eBL patients with paraplegia at diagnosis was 33% (n = 29) after follow-up of between 2 and 96 (median 40) months. Seven patients (24%) had neurological sequelae and needed rehabilitation. There was no relationship between the duration of symptoms (<2, 2 4, >4 weeks) and the survival rate or the risk to have neurological sequelae. The survival rate and risk for sequelae were similar in patients with confirmed St. Jude stage III and IV diseases. PMID- 26606161 TI - Reduced Contact Cognitive-Behavioral Interventions for Adult Depression: A Review. AB - Depression is a highly prevalent and debilitating mental health condition. Evidence suggests that there is a widening gap between the demand for and availability of effective treatments. As such, there is a vast need for the development and dissemination of accessible and affordable treatments for depression. In the past decade, there has been a proliferation of reduced client therapist contact protocols for depression. In this article, the authors review and compare the efficacy of reduced contact cognitive-behavioral interventions for adult depression across two degrees of therapist-client contact (i.e., no therapist-client contact versus minimal therapist-client contact interventions). The authors also discuss the methodological and theoretical limitations of this research base. The present review suggests that a) reduced contact interventions for depression can be effective in remediating the symptoms of depression; b) the effect sizes of some reduced contact protocols may approximate those reported in traditional protocols involving significantly greater client-therapist contact; and c) protocols which employ some form of client-therapist contact, on average, generate higher effect sizes than those that are purely self-help in nature. A discussion of the theoretical and applied implications of such findings, as well as areas in need of further research, is provided. PMID- 26606162 TI - Bisphenol S alters embryonic viability, development, gallbladder size, and messenger RNA expression in chicken embryos exposed via egg injection. AB - Amid concerns about the toxicological effects and environmental prevalence of bisphenol A (BPA), efforts to find suitable, safer replacement alternatives are essential. Bisphenol S (BPS) is a potential chemical substitute for BPA; however, few studies are available confirming that it has a more desirable ecotoxicological profile. In the present study, BPS was injected into the air cell of unincubated, fertilized chicken embryos at 6 concentrations ranging from 0 MUg/g to 207 MUg/g egg to determine effects on pipping success, development, hepatic messenger ribonucleic acid (mRNA) expression, thyroid hormone levels, and circulating bile acid concentrations. Concentrations of BPS increased in a dose dependent manner in whole-embryo homogenates, and exposure to the highest dose, 207 MUg/g, resulted in decreased pipping success (estimated median lethal dose = 279 MUg/g; 95% confidence interval = 161-486 MUg/g). Exposure to BPS also reduced growth metrics including embryo mass and tarsus length, whereas the most pronounced phenotypic effect was the concentration-dependent, significant increase in gallbladder size at concentrations >=52.8 MUg/g. These adverse phenotypic outcomes were associated with the modulation of gene targets from a chicken ToxChip polymerase chain reaction array, which are involved with xenobiotic metabolism, lipid homeostasis, bile acid synthesis, and the thyroid hormone pathway. Expression levels of 2 estrogen-responsive genes, apolipoprotein II and vitellogenin, were too low at the sampling time point assessed (i.e., pipping embryos) to quantify changes, and no effects were observed on circulating free thyroxine or bile acid concentrations. The present study provides novel, whole-animal toxicological data for a BPA replacement alternative that is not well characterized. Environ Toxicol Chem 2016;35:1541-1549. (c) 2015 SETAC. PMID- 26606163 TI - The Feasibility of Buccal Fat Pad Flap in Oral Reconstruction Based on Clinical Experience in a Governmental Hospital, Alexandria, Egypt. AB - OBJECTIVE: The purpose of this study was to evaluate the pedicled buccal fat pad flap for its applicability in the reconstruction of surgically created oral defects. We highlighted the technique of flap harvesting, its different applications, and limitations. DESIGN: Prospective analysis of patients with intraoral defects repaired by the buccal fat pad flap. SETTING: Institutional center. PATIENTS/PARTICIPANTS: Twenty-nine patients with surgical defects of the palate, maxilla, upper gingiva, buccal mucosa, lower gingiva, retromolar region, oral floor, and temporomandibular joint. INTERVENTIONS: Pedicled buccal fat pad flap for treatment of small to medium-sized intraoral defects. OUTCOME MEASURES: Patients had repair using a pedicled buccal fat pad flap between 2012 and 2014. Patients' photographs and clinical records were collected. The technique of flap harvesting, its advantages, and its drawbacks are described in this study. RESULTS: Patients were followed up over a mean period of 13.7 months to check flap viability, competent repair, and donor site function and aesthetics. Complete epithelialization was observed within 4 to 6 weeks postoperatively according to the extent of the defect. All patients showed uneventful healing without complications. CONCLUSIONS: Buccal fat pad flap proved to be feasible for the reconstruction of surgically induced proximal small to medium-sized defects and can be extended to the palate, mandible, mouth angle, and temporomandibular joint region. Further research using preoperative computed tomography or magnetic resonance imaging for evaluation of the size of the buccal fat pad is needed when reconstructing large distal defects. PMID- 26606164 TI - Running per se stimulates the dendritic arbor of newborn dentate granule cells in mouse hippocampus in a duration-dependent manner. AB - Laboratory rodents provided chronic unlimited access to running wheels display increased neurogenesis in the hippocampal dentate gyrus. In addition, recent studies indicate that such an access to wheels stimulates dendritic arborization in newly formed neurons. However, (i) the presence of the running wheel in the housing environment might also bear intrinsic influences on the number and shape of new neurons and (ii) the dendritic arborization of new neurons might be insensitive to moderate daily running activity (i.e., several hours). In keeping with these uncertainties, we have examined neurogenesis and dendritic arborization in newly formed granular cells in adult C57Bl/6N male mice housed for 3 weeks under standard conditions, with a locked wheel, with a running wheel set free 3 h/day, or with a running wheel set permanently free. The results indicate that the presence of a blocked wheel in the home cage increased cell proliferation, but not the number of new neurons while running increased in a duration-dependent manner the number of newborn neurons, as assessed by DCX labeling. Morphological analyses of the dendritic tree of newborn neurons, as identified by BrdU-DCX co-staining, revealed that although the presence of the wheel stimulated their dendritic architecture, the amplitude of this effect was lower than that elicited by running activity, and was found to be running duration-dependent. PMID- 26606165 TI - A Large Liver Mass With Acute Hemorrhage. PMID- 26606166 TI - Effects of early and late treatment with soy isoflavones in the mammary gland of ovariectomized rats. AB - INTRODUCTION: Soy isoflavones have been shown to be an alternative to hormone therapy at menopause, without causing side-effects such as breast cancer. However, the effects of early and late treatment with isoflavones on the mammary gland remain controversial. OBJECTIVE: To investigate the effects of early and late treatment with soy isoflavones on the mammary gland of ovariectomized rats. METHODS: Thirty 3-month-old rats were ovariectomized and divided equally into groups: Control, treated with vehicle solution; or with 150 mg/kg/body weight of isoflavones by gavage; or subcutaneously treated with 10 MUg/kg/body weight with 17beta-estradiol. Treatments started 3 days (early treatment) or 30 days (late treatment) after ovariectomy and lasted for 30 consecutive days. Thereafter, the animals were euthanized and the mammary glands were removed and processed for paraffin embedding. Sections were stained with hematoxylin and eosin for histomorphometry or subjected to immunohistochemical detection of Ki-67 and VEGF A. RESULTS: The ductal, lobular and total epithelial fractions were similar between controls and the early/late isoflavone groups, but they were significantly higher in the groups treated with estradiol. In both epithelial and stromal regions, the immunoreactivity of VEGF-A and the percentage of Ki-67 positive cells were significantly higher in the groups treated with estradiol, while they were similar in the early/late isoflavone groups and control groups. CONCLUSION: Our results indicate that early and late treatment with soy isoflavones at the dose of 150 mg/kg/body weight does not show proliferative and angiogenic effects on the mammary gland of ovariectomized rats. PMID- 26606167 TI - Rapid identification of slow healing wounds. AB - Chronic nonhealing wounds have a prevalence of 2% in the United States, and cost an estimated $50 billion annually. Accurate stratification of wounds for risk of slow healing may help guide treatment and referral decisions. We have applied modern machine learning methods and feature engineering to develop a predictive model for delayed wound healing that uses information collected during routine care in outpatient wound care centers. Patient and wound data was collected at 68 outpatient wound care centers operated by Healogics Inc. in 26 states between 2009 and 2013. The dataset included basic demographic information on 59,953 patients, as well as both quantitative and categorical information on 180,696 wounds. Wounds were split into training and test sets by randomly assigning patients to training and test sets. Wounds were considered delayed with respect to healing time if they took more than 15 weeks to heal after presentation at a wound care center. Eleven percent of wounds in this dataset met this criterion. Prognostic models were developed on training data available in the first week of care to predict delayed healing wounds. A held out subset of the training set was used for model selection, and the final model was evaluated on the test set to evaluate discriminative power and calibration. The model achieved an area under the curve of 0.842 (95% confidence interval 0.834-0.847) for the delayed healing outcome and a Brier reliability score of 0.00018. Early, accurate prediction of delayed healing wounds can improve patient care by allowing clinicians to increase the aggressiveness of intervention in patients most at risk. PMID- 26606168 TI - Cough event classification by pretrained deep neural network. AB - BACKGROUND: Cough is an essential symptom in respiratory diseases. In the measurement of cough severity, an accurate and objective cough monitor is expected by respiratory disease society. This paper aims to introduce a better performed algorithm, pretrained deep neural network (DNN), to the cough classification problem, which is a key step in the cough monitor. METHOD: The deep neural network models are built from two steps, pretrain and fine-tuning, followed by a Hidden Markov Model (HMM) decoder to capture tamporal information of the audio signals. By unsupervised pretraining a deep belief network, a good initialization for a deep neural network is learned. Then the fine-tuning step is a back propogation tuning the neural network so that it can predict the observation probability associated with each HMM states, where the HMM states are originally achieved by force-alignment with a Gaussian Mixture Model Hidden Markov Model (GMM-HMM) on the training samples. Three cough HMMs and one noncough HMM are employed to model coughs and noncoughs respectively. The final decision is made based on viterbi decoding algorihtm that generates the most likely HMM sequence for each sample. A sample is labeled as cough if a cough HMM is found in the sequence. RESULTS: The experiments were conducted on a dataset that was collected from 22 patients with respiratory diseases. Patient dependent (PD) and patient independent (PI) experimental settings were used to evaluate the models. Five criteria, sensitivity, specificity, F1, macro average and micro average are shown to depict different aspects of the models. From overall evaluation criteria, the DNN based methods are superior to traditional GMM-HMM based method on F1 and micro average with maximal 14% and 11% error reduction in PD and 7% and 10% in PI, meanwhile keep similar performances on macro average. They also surpass GMM-HMM model on specificity with maximal 14% error reduction on both PD and PI. CONCLUSIONS: In this paper, we tried pretrained deep neural network in cough classification problem. Our results showed that comparing with the conventional GMM-HMM framework, the HMM-DNN could get better overall performance on cough classification task. PMID- 26606170 TI - Linguistic Stereotyping in Older Adults' Perceptions of Health Care Aides. AB - The cultural and linguistic diversity of the U.S. health care provider workforce is expanding. Diversity among health care personnel such as paraprofessional health care assistants (HCAs)-many of whom are immigrants-means that intimate, high-stakes cross-cultural and cross-linguistic contact characterizes many health interactions. In particular, nonmainstream HCAs may face negative patient expectations because of patients' language stereotypes. In other contexts, reverse linguistic stereotyping has been shown to result in negative speaker evaluations and even reduced listening comprehension quite independently of the actual language performance of the speaker. The present study extends the language and attitude paradigm to older adults' perceptions of HCAs. Listeners heard the identical speaker of Standard American English as they watched interactions between an HCA and an older patient. Ethnolinguistic identities either an Anglo native speaker of English or a Mexican nonnative speaker-were ascribed to HCAs by means of fabricated personnel files. Dependent variables included measures of perceived HCA language proficiency, personal characteristics, and professional competence, as well as listeners' comprehension of a health message delivered by the putative HCA. For most of these outcomes, moderate effect sizes were found such that the HCA with an ascribed Anglo identity-relative to the Mexican guise-was judged more proficient in English, socially superior, interpersonally more attractive, more dynamic, and a more satisfactory home health aide. No difference in listening comprehension emerged, but the Anglo guise tended to engender a more compliant listening mind set. Results of this study can inform both provider-directed and patient-directed efforts to improve health care services for members of all linguistic and cultural groups. PMID- 26606169 TI - Mechanism of Action of Two Flavone Isomers Targeting Cancer Cells with Varying Cell Differentiation Status. AB - Apoptosis can be triggered in two different ways, through the intrinsic or the extrinsic pathway. The intrinsic pathway is mediated by the mitochondria via the release of cytochrome C while the extrinsic pathway is prompted by death receptor signals and bypasses the mitochondria. These two pathways are closely related to cell proliferation and survival signaling cascades, which thereby constitute possible targets for cancer therapy. In previous studies we introduced two plant derived isomeric flavonoids, flavone A and flavone B which induce apoptosis in highly tumorigenic cancer cells of the breast, colon, pancreas, and the prostate. Flavone A displayed potent cytotoxic activity against more differentiated carcinomas of the colon (CaCo-2) and the pancreas (Panc28), whereas flavone B cytotoxic action is observed on poorly differentiated carcinomas of the colon (HCT 116) and pancreas (MIA PaCa). Apoptosis is induced by flavone A in better differentiated colon cancer CaCo-2 and pancreatic cancer Panc 28 cells via the intrinsic pathway by the inhibition of the activated forms of extracellular signal-regulated kinase (ERK) and pS6, and subsequent loss of phosphorylation of Bcl-2 associated death promoter (BAD) protein, while apoptosis is triggered by flavone B in poorly differentiated colon cancer HCT 116 and MIA PaCa pancreatic cancer cells through the extrinsic pathway with the concomitant upregulation of the phosphorylated forms of ERK and c-JUN at serine 73. These changes in protein levels ultimately lead to activation of apoptosis, without the involvement of AKT. PMID- 26606171 TI - Theoretical and Experimental Investigation of Thermodynamics and Kinetics of Thiol-Michael Addition Reactions: A Case Study of Reversible Fluorescent Probes for Glutathione Imaging in Single Cells. AB - Density functional theory (DFT) was applied to study the thermodynamics and kinetics of reversible thiol-Michael addition reactions. M06-2X/6-31G(d) with the SMD solvation model can reliably predict the Gibbs free energy changes (DeltaG) of thiol-Michael addition reactions with an error of less than 1 kcal.mol(-1) compared with the experimental benchmarks. Taking advantage of this computational model, the first reversible reaction-based fluorescent probe was developed that can monitor the changes in glutathione levels in single living cells. PMID- 26606173 TI - Case Scenario: Perioperative Management of a Young Woman with Fontan Repair for Major Gynecologic Surgery. AB - Effective treatment for many congenital heart diseases diagnosed before birth has become available since the last three decades. Continuous improvements in surgical knowledge and techniques have allowed patients born with severe heart defects to survive through adulthood. However, palliative surgery often implies profound modifications of classical circulatory physiology, which must be taken into account particularly when general anesthesia is needed for major noncardiac surgery. Among the palliative surgeries, Fontan repair is an intervention aiming at excluding the right heart chambers with a total cavopulmonary conduit, which directs blood flow from both inferior and superior vena cavae directly to the right pulmonary artery. In such condition, patients are very sensitive to both preload reduction and pulmonary vascular resistances increase, so that a careful monitoring during anesthesia is required. Unfortunately, standard monitoring with a pulmonary artery catheter is not possible because of altered anatomy of right sections. In this case scenario, the authors report the perioperative management of a young woman who underwent major gynecologic surgery, who was managed using a transpulmonary thermodilution technique that was deemed more accurate than noncalibrated pulse-contour method and also able to provide more information regarding preload status. The authors adopted an integrated approach merging together hemodynamic and functional data (ScvO2 and venoarterial CO2 difference) to assess the appropriateness of hemodynamic management. The authors describe also pathophysiologic changes during such condition and also potential drawbacks of chosen technique. PMID- 26606172 TI - Why the recent ACIP recommendations regarding conjugate pneumococcal vaccine in adults may be irrelevant. AB - The Advisory Committee on Immunization Practices of the US Centers for Disease Control (ACIP) has recently recommended the 13-valent protein-conjugate pneumococcal vaccine (PCV13) for routine use in adults age 18-65 who have immunocompromising conditions as well as in all adults over the age of 65. By comparison to 23-valent pneumococcal polysaccharide vaccine (PPSV23), antibody responses to PCV13 are similar or modestly better one month after vaccination. The implication that PCV13 will provide more persistent immunity has been disproven; 12 months later, recipients of PPSV23 or PCV13 have identical anti pneumococcal activity. The theoretical concept that a protein-based vaccine will be followed by a booster effect when pure polysaccharide antigens are administered is based on remarkably little evidence. The strongest objection to the current recommendations is that, since PCVs stimulate mucosal antibodies, the widespread use of these PCVs has led to a near-disappearance of vaccine serotypes from the population. This phenomenon has been amply documented for PCV7, and PCV13 is well on its way to doing the same. Thus, as US physicians are convincing their adult patients to receive 2 "pneumonia shots" instead of one, the use of PCV13 in the USA is rapidly becoming irrelevant. PMID- 26606174 TI - Arterial Line Placement: Safety First. PMID- 26606175 TI - Acetazolamide-Induced Nephrolithiasis in Idiopathic Intracranial Hypertension Patients. AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) is a neurological disorder characterized by elevated intracranial pressure of unknown cause. Acetazolamide is widely used as the initial treatment option; however, previously published evidence suggests that this drug may also increase the risk of nephrolithiasis. The purpose of this study was to examine daily acetazolamide use and its relationship to nephrolithiasis and compare clinical presentation of IIH between those with and without nephrolithiasis. METHODS: We conducted a case-control study using patient data collected by the Intracranial Hypertension Registry. A total of 670 patients were identified as potential study participants, 19 meeting the case definition of developing a stone during acetazolamide treatment for IIH. From the remaining pool of eligible participants, 40 controls were randomly selected. Two-sampled t tests, Fisher exact testing, and exact logistic regression were used to examine differences between cases and controls and to ascertain associations with IIH clinical features and mean daily acetazolamide dosage. RESULTS: Among all eligible patients, 19 (2.8%) developed a stone during acetazolamide treatment for IIH. Among these patients, 17 (89.5%) developed a stone within 1.5 years of initial acetazolamide treatment. Daily acetazolamide use was not significantly related to stone development (odds ratio = 0.95; 95% confidence intervals: 0.86-1.05). Additionally, the relationship between the clinical presentation of IIH at the time of diagnosis (signs and symptoms) and stone development did not reach statistical significance (P > 0.05). CONCLUSIONS: Our results demonstrate that: 1) stone formation during acetazolamide treatment is a relatively infrequent occurrence within the IIH population; 2) among patients who develop a stone, formation is likely to occur within the first year and half; 3) there is no evidence to support the association between acetazolamide daily dosage and stone development; and 4) no unique IIH disease features at the time of diagnosis are associated with stone development. Treatment with acetazolamide should be administered to IIH patients with caution and closely monitored for stone development especially within the first year and a half of treatment. PMID- 26606177 TI - Cytogenetics and Molecular Genetics of Prostate Cancer: A Comprehensive Update. AB - Prostate cancer (PCa) is the one of the most commonly diagnosed cancers in males living in the United States, and approximately 222,800 men will contract PCa in 2015. Recent molecular studies have found novel genetic associations with PCa and genetic changes of potential clinical relevance in cancer detection and treatment. Single nucleotide polymorphism (SNP) arrays have revealed unique SNPs connected with patient ethnicity and other medical conditions, as well as uncovered new information on genes such as KLK3, which produces prostate specific antigen (PSA) and promotes PCa metastasis. Identification of embryonic stem cell gene predictors serve as more accurate indicators when used with clinical parameters (e.g., PSA levels, biopsy Gleason score, clinical stage) in determining the risk of developing prostate cancer and survival times than clinical parameters alone. Studies utilizing exome sequencing have linked mutations in specific genes with PCa progression. In this review, we summarize the most recent and significant molecular and cytogenetic PCa literature, and discuss directions for future research focused on improving diagnostic utility and supplanting PSA testing. PMID- 26606176 TI - Discovering the truth about life after discharge: Long-term trauma-related mortality. AB - BACKGROUND: Outcome after traumatic injury has typically been limited to the determination at time of discharge or brief follow-up. This study investigates the natural history of long-term survival after trauma. METHODS: All highest level activation patients prospectively enrolled in an ongoing cohort study from 2005 to 2012 were selected. To allow for long-term follow-up, patients had to be enrolled at least 1 year before the latest available data from the National Death Index (NDI, 2013). Time and cause of mortality was determined based on death certificates. Survival status was determined by the latest date of either care in our institution or NDI query. Kaplan-Meier curves were created stratified for Injury Severity Score (ISS). Survival was compared with estimated actuarial survival based on age, sex, and race. RESULTS: A total of 908 highest-level activation patients (median ISS, 18) were followed up for a median 1.7 years (interquartile range 1.0-2.9; maximum, 9.8 years). Survival data were available on 99.8%. Overall survival was 73% (663 of 908). For those with at least 2-year follow-up, survival was only 62% (317 of 509). Severity of injury predicted long term survival (p < 0.0001) with those having ISS of 25 or greater with the poorest outcome (57% survival at 5 years). For all ISS groups, survival was worse than predicted actuarial survival (p < 0.001). When excluding early deaths (<=30 days), observed survival was still significantly lower than estimated actuarial survival (p < 0.002). Eighteen percent (44 of 245 deaths) of all deaths occurred after 30 days. Among late deaths, 53% occurred between 31 days and 1 year after trauma. Trauma-related mortality was the leading cause of postdischarge death, accounting for 43% of the late deaths. CONCLUSION: Postdischarge deaths represent a significant percentage of total trauma-related mortality. Despite having "survived" to leave the hospital, long-term survival was worse than predicted actuarial survival, suggesting that the mortality from injury does not end at "successful" hospital discharge. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 26606178 TI - The Nature of Iron Deposits Differs between Symptomatic and Asymptomatic Carotid Atherosclerotic Plaques. AB - Iron within atherosclerotic plaque has been implicated as a catalyst of oxidative stress that causes progression of plaque, and plaque rupture. Iron is believed to accumulate within plaque by incorporation of erythrocytes following plaque rupture and hemorrhage. There is only indirect evidence to support this hypothesis. Plaque specimens were obtained from ten symptomatic and fifteen asymptomatic patients undergoing carotid endarterectomy at a single institution. Plaques were sectioned for study using synchrotron radiation induced X-ray fluorescence the study the distribution of zinc, calcium and iron. Histologic staining was carried out with Prussian Blue, and immunohistochemical staining was done to localize macrophages with CD68. Data were compared against patient clinical variables. Ten symptomatic (15 +/- 10 days between index symptoms and surgery) and fifteen asymptomatic carotid plaques were studied. Zinc and calcium co-localized in mineralized areas of symptomatic and asymptomatic plaque. Iron was identified away from zinc and calcium in both symptomatic and asymptomatic plaques. Within the symptomatic plaques, iron was found within the thrombus associated with plaque rupture and hemorrhage. It did not stain with Prussian Blue, but was found in association with CD68 positive macrophages. In symptomatic plaques, the abundance of iron showed an association with the source patient's LDL cholesterol (R2 = 0.39, Significance F = 0.05). Iron in asymptomatic plaque was present as hemosiderin/ferritin that stained positive with Prussian Blue, and was observed in association with CD68 positive macrophages. Iron in acutely symptomatic plaques is found within thrombus, in the presence of macrophages. The abundance of iron in symptomatic plaques is associated with the source patient's LDL cholesterol. Within asymptomatic plaques, iron is found in association with macrophages, as hemosiderin/ferritin. PMID- 26606179 TI - Response of two rice cultivars differing in their sensitivity towards arsenic, differs in their expression of glutaredoxin and glutathione S transferase genes and antioxidant usage. AB - Embodied study investigates the role of GRX and associated antioxidant enzymes in the detoxification mechanism between arsenic (As) sensitive (Usar-3) and tolerant cultivar (Pant Dhan 11) of Oryza sativa against As(III) and As(V), under GSH enriched, and GSH deprived conditions. The overall growth and physiological parameters in sensitive cultivar were lower than the tolerant cultivar, against various treatments of As(III) and As(V). The As accumulation in sensitive cv. against both As(III) and As(V) was lower than the corresponding treatments in tolerant cv. However, the As translocation against As(V) was lower (35% and 64%, resp.) than that of As(III), in both the cultivars. In sensitive cv. translocation of Zn and Cu was influenced by both As(V) and As(III) whereas, in tolerant cv. the translocation of Cu, Mn and Zn was influenced only by As(III). Translocation of Fe was negatively influenced by translocation of As in sensitive cv. and positively in tolerant cv. Strong correlation between H2O2, SOD, GRX, GR, GST and GSH/GSSG in sensitive cv. and between DHAR, APX, MDHAR and AsA in tolerant cv. demonstrates the underlying preference of GSH as electron donor for detoxification of H2O2 in sensitive cv. and AsA in tolerant cv. Higher expression of the four GRX and two GST genes in the sensitive cv. than tolerant cv, suggests that under As stress, GRX are synthesized more in the sensitive cv. than tolerant cv. Also, the expression of four GRX genes were higher against As(V) than As(III). The higher As accumulation in the tolerant cv. is due to lower GST expression, is attributed to the absence of thiolation and sequestration of As in roots, the translocation of As to shoots is higher. PMID- 26606180 TI - Seasonal changes of basic erythrocyte-metric parameters in Pelophylaxridibundus (Amphibia: Ranidae) from anthropogenically polluted biotopes in Southern Bulgaria and their role as bioindicators. AB - The purpose of this research work is to present data that show the seasonal changes (spring-summer-autumn) of basic erythrocyte-metric parameters (EL: Erythrocyte length, EW: Erythrocyte width, EL/EW, ES: Erythrocyte size; NL: Nucleus length, NW: Nucleus width, NL/NW; NS: Nucleus size, NS/ES: Nucleus cytoplasmic ratio) in Pelophylax ridibundus populations from three biotopes located on two rivers in Southern Bulgaria (less disrupted biotope, with domestic sewage pollution and heavy metal pollution). Differences of high statistical significance were found among the different populations. Within the population living in conditions of domestic sewage pollution, for the entire period of the investigation the erythrocytes and their nuclei had an elliptical shape (a slight elongation of ellipses in autumn) and the biggest sizes (EL, EW, ES, NL and NS were constantly higher than the less disrupted biotope), NS/ES, became significantly smaller in autumn. Throughout the period of investigation, the values of all nine cellular and nuclear parameters were statistically significantly the lowest in the population from the biotope with heavy metal pollution. The parameters: EL, EW, NL, NW and ES became significantly lower, progressively and statistically, during seasonal transitions. Cells and nuclei grew ovular in shape in comparison to the populations from the other two biotopes (this process was most pronounced in autumn) and NS/ES numbers were significantly decreased in summer and autumn. PMID- 26606181 TI - Evaluation of adsorption properties of sulphurised activated carbon for the effective and economically viable removal of Zn(II) from aqueous solutions. AB - The prospective application of sulphurised activated carbon (SAC) as an ecofriendly and cost-effective adsorbent for Zinc(II) removal from aqueous phase is evaluated, with an emphasis on kinetic and isotherm aspects. SAC was prepared from sugarcane bagasse pith obtained from local juice shops in Sree Bhadrakali Devi Temple located at Ooruttukala, Neyyattinkara, Trivandrum, India during annual festive seasons. Activated carbon modified with sulphur containing ligands was opted as the adsorbent to leverage on the affinity of Zn(II) for sulphur. We report batch-adsorption experiments for parameter optimisations aiming at maximum removal of Zn(II) from liquid-phase using SAC. Adsorption of Zn(II) onto SAC was maximum at pH 6.5. For initial concentrations of 25 and 100mgL(-1), maximum of 12.3mgg(-1) (98.2%) and 23.7mgg(-1) (94.8%) of Zn(II) was adsorbed onto SAC at pH 6.5. Kinetic and equilibrium data were best described by pseudo-second-order and Langmuir models, respectively. A maximum adsorption capacity of 147mgg(-1) was obtained for the adsorption of Zn(II) onto SAC from aqueous solutions. The reusability of the spent adsorbent was also determined. PMID- 26606182 TI - Current status, key challenges and its solutions in the design and development of graphene based ORR catalysts for the microbial fuel cell applications. AB - Microbial fuel cells (MFC) are considered as the futuristic energy device that generates electricity from the catalytic degradation of biodegradable organic wastes using microbes, which exist in waste water. In MFCs, oxygen serves as a cathodic electron acceptor and oxygen reduction kinetics played a significant role in the determination of overall efficiency. A wide range of strategies have been developed for the preparation and substantial modification of oxygen reduction reaction (ORR) catalysts to improve the maximum volumetric power density of MFCs, in which the efforts on graphene based ORR catalysts are highly imperative. Although numerous research endeavors have been achieved in relation with the graphene based ORR catalysts applicable for MFCs, still their collective summary has not been developed, which hinders the acquirement of adequate knowledge on tuning the specific properties of said catalysts. The intension of this review is to outline the significant role of ORR catalysts, factors influencing the ORR activity, strategies behind the modifications of ORR catalysts and update the research efforts devoted on graphene based ORR catalysts. This review can be considered as a pertinent guide to understand the design and developmental strategies of competent graphene based ORR catalysts, which are not only applicable for MFCs but also for number of electrochemical applications. PMID- 26606183 TI - Veterinary drugs in the environment and their toxicity to plants. AB - Veterinary drugs used for treatment and prevention of diseases in animals represent important source of environmental pollution due to intensive agri- and aquaculture production. The drugs can reach environment through the treatment processes, inappropriate disposal of used containers, unused medicine or livestock feed, and manufacturing processes. Wide scale of veterinary pharmaceuticals e.g. antibiotics, antiparasitic and antifungal drugs, hormones, anti-inflammatory drugs, anaesthetics, sedatives etc. enter the environment and may affect non-target organisms including plants. This review characterizes the commonly used drugs in veterinary practice, outlines their behaviour in the environment and summarizes available information about their toxic effect on plants. Significant influence of many antibiotics and hormones on plant developmental and physiological processes have been proved. However, potential phytotoxicity of other veterinary drugs has been studied rarely, although knowledge of phytotoxicity of veterinary drugs may help predict their influence on biodiversity and improve phytoremediation strategies. Moreover, additional topics such as long term effect of low doses of drugs and their metabolites, behaviour of mixture of veterinary drugs and other chemicals in ecosystems should be more thoroughly investigated to obtain complex information on the impact of veterinary drugs in the environment. PMID- 26606185 TI - Formation and occurrence of new polar iodinated disinfection byproducts in drinking water. AB - During drinking water disinfection, iodinated disinfection byproducts (I-DBPs) can be generated through reactions between iodide, disinfectants, and natural organic matter. Drinking water I-DBPs have been increasingly attracting attention as emerging organic pollutants as a result of their significantly higher toxicity and growth inhibition than their chloro- and bromo-analogues. In this study, by adopting ultra performance liquid chromatography/electrospray ionization-triple quadrupole mass spectrometry precursor ion scan, multiple reaction monitoring, and product ion scan analyses, 11 new polar I-DBPs with confirmed structures and eight new polar I-DBPs with proposed structures were detected in simulated drinking water samples. Chloramination of simulated raw waters containing natural organic matter with higher aromaticity produced higher levels of new phenolic I DBPs. Formation of new polar I-DBPs and total organic iodine (TOI) was most favored in chloramination, followed by chlorine dioxide treatment, and relatively minor in chlorination. Lower pH in chloramination substantially enhanced the formation of new polar I-DBPs and TOI. NH2Cl and dissolved organic nitrogen could be important nitrogen sources and precursors for formation of the two new nitrogenous phenolic I-DBPs. Notably, in tap water samples collected from nine major cities located in the Yangtze River Delta region of China, seven of the 11 new polar I-DBPs with confirmed structures were detected at levels from 0.11 to 28 ng/L, and the two new nitrogenous phenolic I-DBPs were ubiquitous with concentrations from 0.12 to 24 ng/L, likely due to the relatively high dissolved organic nitrogen levels in regional source waters. PMID- 26606184 TI - Perturbations in polar lipids, starvation survival and reproduction following exposure to unsaturated fatty acids or environmental toxicants in Daphnia magna. AB - Acclimating to toxicant stress is energy expensive. In laboratory toxicology tests dietary conditions are ideal, but not in natural environments where nutrient resources vary in quality and quantity. We compared the effects of additional lipid resources, docosahexaenoic acid (n-3; DHA) or linoleic acid (n 6; LA), or the effects of the toxicants, atrazine or triclosan on post-treatment starvation survival, reproduction, and lipid profiles. Chemical exposure prior to starvation had chemical-specific effects as DHA showed moderately beneficial effects on starvation survival and all of the other chemicals showed adverse effects on either survival or reproduction. Surprisingly, pre-exposure to triclosan inhibits adult maturation and in turn completely blocks reproduction during the starvation phase. The two HR96 activators tested, atrazine and LA adversely reduce post-reproduction survival 70% during starvation and in turn show poor fecundity. DHA and LA show distinctly different lipid profiles as DHA primarily increases the percentage of large (>37 carbon) phosphatidylcholine (PC) species and LA primarily increases the percentage of smaller (<37 carbon) PC species. The toxicants atrazine and triclosan moderately perturb a large number of different phospholipids including several phosphatidylethanolamine species. Some of these polar lipid species may be biomarkers for diets rich in specific fatty acids or toxicant classes. Overall our data demonstrates that toxicants can perturb lipid utilization and storage in daphnids in a chemical specific manner, and different chemicals can produce distinct polar lipid profiles. In summary, biological effects caused by fatty acids and toxicants are associated with changes in the production and use of lipids. PMID- 26606186 TI - Concentrations of neonicotinoid insecticides in honey, pollen and honey bees (Apis mellifera L.) in central Saskatchewan, Canada. AB - Neonicotinoid insecticides (NIs) and their transformation products were detected in honey, pollen and honey bees, (Apis mellifera) from hives located within 30 km of the City of Saskatoon, Saskatchewan, Canada. Clothianidin and thiamethoxam were the most frequently detected NIs, found in 68 and 75% of honey samples at mean concentrations of 8.2 and 17.2 ng g(-1) wet mass, (wm), respectively. Clothianidin was also found in >50% of samples of bees and pollen. Concentrations of clothianidin in bees exceed the LD50 in 2 of 28 samples, while for other NIs concentrations were typically 10-100-fold less than the oral LD50. Imidaclorpid was detected in ~30% of samples of honey, but only 5% of pollen and concentrations were PFOA > PFHpA. Sorption isotherm data were well fitted by the Freundlich model with the sorption capacity (Kf) of PFOS, PFOA and PFHpA being 4.45, 2.42 and 1.66 respectively. This suggests that the hydrophilic head group on PFAAs, i.e. sulfonate vs carboxylic, has a strong influence on their sorption. Comparison between PFOA and PFHpA revealed that hydrophobicity could also play a role in the sorption of PFAAs on GAC when the fluorocarbon chain length is different. Analyses using Attenuated Total Reflection (ATR)-Fourier Transform Infrared (FTIR) spectroscopy suggested possible formation of a negative charge-assisted H-bond between PFAAs and the functionalities on GAC surfaces, including non-aromatic ketones, sulfides, and halogenated hydrocarbons. PMID- 26606189 TI - Catalytic decomposition of gaseous 1,2-dichlorobenzene over CuOx/TiO2 and CuOx/TiO2-CNTs catalysts: Mechanism and PCDD/Fs formation. AB - Gaseous 1,2-dichlorobenzene (1,2-DCBz) was catalytically decomposed in a fixed bed catalytic reactor using composite copper-based titanium oxide (CuOx/TiO2) catalysts with different copper ratios. Carbon nanotubes (CNTs) were introduced to produce novel CuOx/TiO2-CNTs catalysts by the sol-gel method. The catalytic performances of CuOx/TiO2 and CuOx/TiO2-CNTs on 1,2-DCBz oxidative destruction under different temperatures (150-350 degrees C) were experimentally examined and the correlation between catalyst structure and catalytic activity was characterized and the role of oxygen in catalytic reaction was discussed. Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) generation during 1,2-DCBz catalytic oxidation by CuOx/TiO2-CNTs composite catalyst was also examined. Results indicate that the 1,2-DCBz destruction/removal efficiencies of CuOx (4 wt%)/TiO2 catalyst at 150 degrees C and 350 degrees C with a GHSV of 3400 h(-1) are 59% and 94% respectively and low-temperature (150 degrees C) catalytic activity of CuOx/TiO2 on 1,2-DCBz oxidation can be improved from 59 to 77% when CNTs are introduced. Furthermore, oxygen either in catalyst or from reaction atmosphere is indispensible in reaction. The former is offered to activate and oxidize the 1,2-DCBz adsorbed on catalyst, thus can be generally consumed during reaction and the oxygen content in catalyst is observed lost from 39.9 to 35.0 wt% after reacting under inert atmosphere; the latter may replenish the vacancy in catalyst created by the consumed oxygen thus extends the catalyst life and raises the destruction/removal efficiency. The introduction of CNTs also increases the Cu(2+)/Cu(+) ratio, chemisorbed oxygen concentration and surface lattice oxygen binding energy which are closely related with catalytic activity. PCDD/Fs is confirmed to be formed when 1,2-DCBz catalytically oxidized by CuOx/TiO2-CNTs composite catalyst with sufficient oxygen (21%), proper temperature (350 degrees C) and high concentration of 1,2-DCBz feed (120 ppm). PMID- 26606190 TI - Effects of aging on the fraction distribution and bioavailability of selenium in three different soils. AB - Aging refers to the processes by which the mobility and bioavailability of metals in soil decline with time. Although long-term aging is a key process that needs to be considered in risk assessment of metals, few investigations has been attempted to determine whether and how residence time influences the selenium (Se) fractions and bioavailability in soil. In this study, the fractions of Se in soils was evaluated, and bioavailability were assessed by measuring Se concentration in pak choi (Brassica chinensis L.). Results showed that the change of soil available Se in all tested soils divided into two phases: rapid decrease at the initial time (42 d) and slow decline thereafter. The second-order equation could describe the decrease processes of available Se in tested soils during the entire incubation time (R(2) > 0.99), while parabolic diffusion equation had less goodness of fit. Those results indicated that Se aging was controlled not only by diffusion process but also by other processes such as nucleation/precipitation, adsorption/desorption with soil component, occlusion by organic matter and reduction reaction. Soil available Se fractions tended to transform to more stable fractions during aging. The changes of Se concentration in pak choi were consistent with the variation in soil available Se content. In addition, 21 d could be reference for the time of Se aging reaching stabilization in krasnozems and fluvo-aquic soil, and 30 d for black soil. Results could provide theoretical basis to formulate environmental quality criterion and choose the equilibrium time before implementing a pot experiment in Se-spiked soils. PMID- 26606191 TI - Evaluation of Stain Penetration by Beverages in Demineralized Enamel Treated With Resin Infiltration. AB - PURPOSE: To evaluate stain penetration by different beverages in artificially demineralized human teeth treated with resin infiltration. METHODS AND MATERIALS: Sixty extracted human permanent molars were demineralized, treated with resin infiltration (Icon), and immersed in four different beverages (coffee, grape juice, iced tea, and distilled water; N=15) for four weeks. After aging, teeth in the distilled water group were stained with 2% methylene blue for 24 hours. All teeth were sectioned, and stain penetration was evaluated under light microscopy. Chi-square test, independent and paired sample t-test, analysis of variance with the Fisher least significant difference post hoc test, and the Kruskal-Wallis test were used to analyze the results (p<0.05). RESULTS: Resin infiltration treated surfaces (Icon surfaces) had statistically significant fewer samples with presence of stain penetration compared to untreated surfaces (control surfaces) (p<0.001). There was also a significant decrease in depth of stain penetration in Icon surfaces compared to the control surfaces (p<0.001). Among tested beverage groups, iced tea showed significantly greater depth of stain penetration (0.134+/ 0.029 mm), followed by grape juice (0.118+/-0.047 mm), methylene blue (0.022+/ 0.019 mm), and coffee (0.008+/-0.017 mm; p<0.001). CONCLUSION: Both Icon and control surfaces exhibit stain penetration by different beverages (iced tea, grape juice, and coffee). However, resin-infiltrated enamel surfaces allow significantly less depth of stain penetration compared to untreated surfaces. The iced tea group presents greatest depth of stain penetration, followed by grape juice, methylene blue, and coffee. PMID- 26606192 TI - Efficacy and tolerability of add-on Lacosamide treatment in adults with Lennox Gastaut syndrome: An observational study. AB - PURPOSE: To evaluate the efficacy, safety, and tolerability of lacosamide in adults with LGS in the clinical setting. METHOD: The present report is a retrospective, open-label treatment study carried out from June 2013 to December 2014 at the National Institute of Colombia. Lacosamide was introduced as add-on therapy. All caregivers were instructed to initiate lacosamide at low doses (25 50 mg) and gradually increasing it every 2 weeks. The efficacy was evaluated based on the reduction in the rate of each countable type of seizure. We also evaluated the retention rate for lacosamide as the number of days with lacosamide during follow-up. The tolerability was evaluated base on account the adverse events. RESULTS: We found that lacosamide only improves the seizure rate in three out of 19 patients with LGS, in two of them by more than 50%. The highest seizure reduction rate was observed in the focal and tonic-clonic seizures. The most commonly reported adverse events were worsening of seizures, aggressiveness and irritability. Nine patients (47.4%) showed worsening of their behavior during the treatment with lacosamide. CONCLUSION: Lacosamide can exacerbate both, the tonic and astatic seizures, and the encephalopathy associated with this epileptic syndrome. However, it is interesting to consider the likelihood of suppression of generalized tonic-clonic and focal seizures. That is why; lacosamide could be an option after carefully balancing risks and benefits in each individual case. PMID- 26606193 TI - A Child With a Bulging Hyperemic Tympanic Membrane. Complications of otitis media. PMID- 26606194 TI - A lead-porphyrin metal-organic framework: gas adsorption properties and electrocatalytic activity for water oxidation. AB - A 3D non-interpenetrating porous metal-organic framework [Pb2(H2TCPP)].4DMF.H2O (Pb-TCPP) (H6TCPP = 5,10,15,20-tetra(carboxyphenyl)porphyrin) was synthesized by employment of a robust porphyrin ligand. Pb-TCPP exhibits a one-dimensional channel possessing fairly good capability of gas sorption for N2, H2, Ar, and CO2 gases, and also features selectivity for CO2 over CH4 at 298 K. Furthermore, Pb TCPP shows electrocatalytic activity for water oxidation in alkaline solution. It is the first 3D porous Pb-MOF that exhibits both gas adsorption properties and electrocatalytic activity for an oxygen evolution reaction (OER). PMID- 26606195 TI - Application of acid-activated Bauxsol for wastewater treatment with high phosphate concentration: Characterization, adsorption optimization, and desorption behaviors. AB - Acid-activated Bauxsol was applied to treat wastewater with high phosphate concentration in a batch adsorption system in this paper. The effect of acid activation on the change of Bauxsol structure was systematically investigated. The mineralogical inhomogeneity and intensity of Bauxsol decreased after acid activation, and FeCl3.2H2O and Al(OH)3 became the dominant phases of acid activated Bauxsol adsorption. Moreover, the BET surface area and total pore volume of Bauxsol increased after acid activation. Interaction of initial solution pH and adsorption temperature on phosphate adsorption onto acid activated Bauxsol was investigated by using response surface methodology with central composite design. The maximum phosphate adsorption capacity of 192.94 mg g(-1) was achieved with an initial solution pH of 4.19 and an adsorption temperature of 52.18 degrees C, which increased by 7.61 times compared with that of Bauxsol (22.40 mg g(-1)), and was higher than other adsorbents. Furthermore, the desorption studies demonstrated that the acid-activated Bauxsol was successfully regenerated with 0.5 mol L(-1) HCl solution. The adsorption capacity and desorption efficiency of acid-activated Bauxsol maintained at 80.48% and 93.02% in the fifth adsorption-desorption cycle, respectively, suggesting that the acid-activated Bauxsol could be repeatedly used in wastewater treatment with high phosphate concentration. PMID- 26606196 TI - In-situ infiltration performance of different permeable pavements in a employee used parking lot--A four-year study. AB - Permeable pavements are being adopted as a green solution in many parts of the world to manage urban stormwater quantity and quality. This paper reports on the measured in-situ infiltration performance over a four-year period since construction and use of three permeable parking sections (permeable pavers, permeable concrete and permeable asphalt) of an employee car parking lot. There was only a marginal decline in infiltration rates of all three pavements after one year of use. However, between years two to four, the infiltration rates declined significantly due to clogging of pores either by dry deposition of particles and/or shear stress of vehicles driving and degrading the permeable surfaces; during the last two years, a greater decline was also observed in driving areas of the parking lots compared to parking slots, where minimal wear and tear are expected. Maintenance strategies were employed to reclaim some of the lost infiltration rate of the permeable pavements to limited success. Despite this decline, the infiltration rates were still four to five times higher than average rainstorm intensity in the region. Thus, these permeable pavement parking lots may have significant ecological importance due to their ability to infiltrate rainwater quickly, reduce the runoff in the catchment area, and also dampen runoff peak flows that could otherwise enter the collection system for treatment in a combined sewer area. PMID- 26606197 TI - Changes in Retail Prices of Prescription Dermatologic Drugs From 2009 to 2015. AB - IMPORTANCE: Physicians from many specialties as well as primary care prescribe dermatologic medications; as insurance formularies become increasingly restrictive and more patients are covered with high-deductible insurance plans, many patients are forced to pay high retail prices to obtain their medications. OBJECTIVES: To determine the changes in the prices of commonly prescribed dermatologic medications since 2009 and to identify trends in price increases for different classes of drugs. DESIGN, SETTING, AND PARTICIPANTS: Four national chain pharmacies received surveys requesting price data on commonly prescribed dermatologic drugs in 2009, 2011, 2014, and 2015. The initial survey requested information on 72 brand-name drugs. Subsequent surveys increased to eventually include 120 additional brand-name drugs and their generic alternatives when available. Owing to the frequency of prescription, diseases treated, or unusual price increases, 19 brand-name drugs surveyed in all 4 years were selected for final price trend analysis, which was conducted from August 1 to 15, 2015. MAIN OUTCOMES AND MEASURES: Retail prices of topical and systemic drugs for the treatment of various dermatologic conditions. RESULTS: Prices of surveyed brand name drugs increased rapidly between 2009 and 2015. Of the 19 brand-name drugs analyzed, the retail prices of 7 drugs more than quadrupled during the study period. Among these 19 drugs, the mean price increase was 401% during the 6-year survey period, with the majority of the price increases occurring after 2011. Prices of topical antineoplastic drugs had the greatest mean absolute and percentage increase ($10,926.58 [1240%]). Prices of drugs in the antiinfective class had the smallest mean absolute increase ($333.99); prices of psoriasis medications had the smallest mean percentage increase (180%). Prices of acne and rosacea medications increased a mean of 195%, and prices of topical corticosteroids increased a mean of 290% during the study period. Selected generic drugs surveyed in 2011 and 2014 also increased a mean of 279% during the 3-year period. CONCLUSIONS AND RELEVANCE: The price of prescription dermatologic drugs rose considerably from 2009 to 2015, with the vast majority of price increases occurring after 2011. Percent increases for multiple, frequently prescribed medications greatly outpaced inflation, national health expenditure growth, and increases in reimbursements for physician services. PMID- 26606199 TI - Regulators of Glucose Metabolism in CD4+ and CD8+ T Cells. AB - Much like cancer cells, activated T cells undergo various metabolic changes that allow them to grow and proliferate rapidly. By adopting aerobic glycolysis upon activation, T cells effectively prioritize efficiency in biosynthesis over energy generation. There are distinct differences in the way CD4+ and CD8+ T cells process activation signals. CD8+ effector T cells are less dependent on Glut1 and oxygen levels compared to their CD4+ counterparts. Similarly the downstream signaling by TCR also differs in both effector T cell types. Recent studies have explored PI3K/Akt, mTORC, HIF1alpha, p70S6K and Bcl-6 signaling in depth providing definition of the crucial roles of these regulators in glucose metabolism. These new insights may allow improved therapeutic manipulation against inflammatory conditions that are associated with dysfunctional T-cell metabolism such as autoimmune disorders, metabolic syndrome, HIV, and cancers. PMID- 26606201 TI - Clinical Characteristics of Hepatocellular Carcinoma in 19 cats from a Single Institution (1980-2013). AB - Clinical features of feline hepatocellular carcinoma (HCA) have been poorly characterized. In this retrospective study, we describe the signalment, clinical features, clinicopathologic parameters, imaging characteristics, hepatic mass size and lobe distribution, concurrent disorders, and survival in 19 cats with HCA. HCA is a rare neoplasm in elderly cats often associated with weight loss, hyporexia, and increased hepatic transaminase activities. Concurrent disorders (e.g., hyperthyroidism, inflammatory bowel disease, cholangiohepatitis, copper associated hepatopathy) often confounded interpretation of clinical and clinicopathologic findings; 42% of HCA were incidentally identified. Although an abdominal mass was palpated in only 21% of cats, many cats had masses identified on ultrasonographic imaging with 47% having lesions >4 cm. Tumors were nearly equally distributed between right and left liver lobes, and two cats had HCA in multiple liver lobes. Median survival of eight cats diagnosed antemortem was 1.7 (0.6 to 6.5) yr. Median survival of six cats undergoing HCA surgical resection was 2.4 (1.0 to 6.5) yr with two cats still alive at time of manuscript submission. Following surgical resection, one cat treated with carboplatin survived 4 yr. Two cats with HCA diagnosed antemortem without surgical resection survived for 0.6 and 1 yr. PMID- 26606202 TI - Evaluating Sucralfate as a Phosphate Binder in Normal Cats and Cats with Chronic Kidney Disease. AB - Control of hyperphosphatemia is an important part of the management of chronic kidney disease (CKD). The purpose of this study was to determine the efficacy of sucralfate as a phosphate binder in normal cats and normophosphatemic CKD cats. A 500 mg sucralfate slurry was administered orally q 8 hr for 2 wk, and serum phosphorus, urine fractional excretion of phosphorus, and fecal phosphorus concentrations were measured. In normal cats treated with sucralfate, significant changes in serum phosphorus concentration or urinary excretion of phosphorus were not detected, and vomiting occurred after 14.7% of administrations. Of the five normophosphatemic cats with CKD treated with sucralfate, three experienced clinical decompensation, including vomiting, anorexia, constipation, and increased azotemia. Administration of sucralfate did not result in significant changes in fecal phosphorus concentration in these cats. The effects of sucralfate administration on serum phosphorus concentration and urinary excretion of phosphorus in CKD cats was difficult to determine because of dehydration and worsening azotemia associated with decompensation. Due to side effects and the apparent lack of efficacy of the medication, the study was discontinued. This study was unable to confirm efficacy of this sucralfate formulation as a phosphate binder, and side effects were problematic during the study. PMID- 26606200 TI - Quality of Life Analysis of a Radiation Dose-Escalation Study of Patients With Non-Small-Cell Lung Cancer: A Secondary Analysis of the Radiation Therapy Oncology Group 0617 Randomized Clinical Trial. AB - IMPORTANCE: A recent randomized radiation dose-escalation trial in unresectable stage III non-small-cell lung cancer (NSCLC) (Radiation Therapy Oncology Group [RTOG] 0617) showed a lower survival rate in the high-dose radiation therapy (RT) arm (74 Gy) than in the low-dose arm (60 Gy) with concurrent chemotherapy. OBJECTIVE: The primary QOL hypothesis predicted a clinically meaningful decline in quality of life (QOL) via the Functional Assessment of Cancer Therapy (FACT) Lung Cancer Subscale (LCS) in the high-dose RT arm at 3 months. DESIGN, SETTING, AND PATIENTS: The RTOG 0617 trial was a randomized phase 3 study (conducted from November 2007 to November 2011) in stage III NSCLC using a 2 * 2 factorial design and stratified by histology, positron emission tomography staging, performance status, and irradiation technique (3-dimensional conformal RT [3D-CRT] vs intensity-modulated RT [IMRT]). A total of 185 institutions in the United States and Canada took part. Of 424 eligible patients with stage III NSCLC randomized, 360 (85%) consented to QOL evaluation, of whom 313 (88%) completed baseline QOL assessments. INTERVENTION: Treatment with 74-Gy vs 60-Gy RT with concurrent and consolidation carboplatin/paclitaxel with or without cetuximab. MAIN OUTCOMES AND MEASURES: The QOL data were collected prospectively via FACT Trial Outcome Index (FACT-TOI), calculated as the sum of the following measures: Physical Well Being (PWB), Functional Well Being (FWB), and the LCS. Data are presented at baseline and 3 and 12 months via minimal clinically meaningful changes of 2 points or more for PWB, FWB, and LCS or 5 points or more for TOI. RESULTS: Of the 313 patients who completed baseline QOL assessments, 219 patients (70%) completed the 3-month QOL assessments, and 137 of the living patients (57%) completed the 12-month assessment. Patient demographics and baseline QOL scores were comparable between the 74-Gy and 60-Gy arms. Significantly more patients in the 74-Gy arm than in the 60-Gy arm had clinically meaningful decline in FACT-LCS at 3 months (45% vs 30%; P = .02). At 12 months, fewer patients who received IMRT (vs 3D-CRT) had clinically meaningful decline in FACT-LCS (21% vs 46%; P = .003). Baseline FACT TOI was associated with overall survival in multivariate analysis. CONCLUSIONS AND RELEVANCE: Despite few differences in clinician-reported toxic effects between treatment arms, QOL analysis demonstrated a clinically meaningful decline in QOL in the 74-Gy arm at 3 months, confirming the primary QOL hypothesis. Baseline QOL was an independent prognostic factor for survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00533949. PMID- 26606203 TI - Cyniclomyces guttulatus Infection in Dogs: 19 Cases (2006-2013). AB - Cyniclomyces guttulatus, a gastrointestinal yeast of rabbits, is considered an uncommon, nonpathogenic, "pass through" organism and possible opportunistic pathogen in dogs that consume rabbit feces. This retrospective study aimed to characterize the presenting complaint, clinical findings, location of organisms, and final diagnosis of dogs in which yeast morphologically consistent with C. guttulatus were identified at a veterinary teaching hospital from 2006-2013. The prevalence of C. guttulatus infection in a general population of dogs from a regional animal shelter was also determined. Nineteen dogs were retrospectively identified as diagnosed with C. guttulatus infection. Among these, 79% presented with a chief complaint and/or clinical signs consistent with gastrointestinal tract disease. The most common clinical sign was chronic diarrhea. The majority of dogs had C. guttulatus identified cytologically within samples obtained from the gastrointestinal tract; however, four dogs had C. guttulatus identified in non-gastrointestinal tract samples, including a nasal biopsy (one dog) and urine (three dogs). C. guttulatus was not identified in any of 105 shelter dogs evaluated, suggesting low prevalence of C. guttulatus in our region. These findings suggest that additional studies to determine if C. guttulatus is a potential cause or consequence of gastrointestinal illness in dogs may be warranted. PMID- 26606204 TI - Postoperative Analgesia Provided by Liposomal Hydromorphone in Client-Owned Dogs Undergoing Limb Amputation. AB - The analgesic efficacy of liposomal hydromorphone (LE-hydro) was tested in dogs undergoing limb amputation. The positive controls (n = 10) received subcutaneous (SQ) hydromorphone (0.2 mg/kg) and 1.5 mL of blank liposomes before surgery; fentanyl continuous rate infusion (CRI), 5-10 MUg/kg/hr IV, during and for 24 hr after surgery; and a fentanyl patch at extubation. The negative controls (n = 7) received SQ hydromorphone (0.2 mg/kg) and 1.5 mLs of blank liposomes SQ before surgery, fentanyl CRI (5-10 MUg/kg/hr IV) during surgery but stopped at extubation, and a fentanyl patch at extubation. The test group (n = 11) received 3 mg/kg of LE-hydro and 1.5 mL of saline SQ before surgery, 1.5 mL of saline SQ, and a saline CRI during surgery. All groups received a bupivacaine block in the limb prior to amputation and carprofen prior to surgery. Treatment failures, pain scores, opioid side effects, heart rate, respiratory rate, temperature, and client-reported pain and side effects were evaluated. There were three treatment failures in the positive control (3/10) and test groups (3/11). Negative controls had seven treatment failures (7/7). Side effects for all three groups were within expected limits. LE-hydro provides postoperative analgesia equivalent to fentanyl CRI in dogs undergoing limb amputation. PMID- 26606205 TI - Nutritional Considerations for Dogs and Cats with Liver Disease. AB - The goals of nutritional management of liver disease in the dog and cat are directed at treating the clinical manifestations as opposed to treating the underlying cause. Specifically, the clinician strives to avoid overwhelming the remaining metabolic capacities of the damaged liver while providing sufficient nutrients for regeneration. A brief overview of liver diseases and associated clinical signs encountered in the dog and cat and a review of specific nutrients are discussed as well as amounts and sources of nutrients recommended to meet nutritional goals in the diseased liver. PMID- 26606206 TI - Peripheral Nerve Sheath Tumor of the Vagus Nerve in a Dog. AB - A peripheral nerve sheath tumor was diagnosed in a female, neutered Labrador retriever with a 6 mo history of coughing, retching, ptyalism, and left-sided Horner's syndrome. Computed tomography scan of the neck revealed a mass lesion between the carotid artery and esophagus in the mid-cervical region. Exploratory surgery was performed and an 18 cm section of thickened vagus nerve was excised. Histopathological findings and immunochemistry staining confirmed a malignant peripheral nerve sheath tumor. The tumor showed microscopic signs of malignancy, but there were no macroscopic signs of local extension or distant metastasis. This report documents a peripheral nerve sheath tumor of rare origin in dogs. PMID- 26606207 TI - Hypernatremia in a Cat with Toxoplasma-Induced Panencephalitis. AB - A 12 yr old female neutered Carthusian crossbreed cat was presented due to progressive neurological signs. Clinical signs included dehydration, stupor, and anisocoria. Laboratory examination revealed severe hypernatremia, azotemia, hyperglobulinemia, and an erythrocytosis. Clinical signs and hypernatremia suggested an intracranial process. Imaging studies revealed a loss of structure in the cerebrum, hypothalamus, and pituitary gland. Due to a poor prognosis, the cat was euthanatized. Histopathological examination revealed a subacute granulomatous and necrotizing panencephalitis with Toxoplasma-typical protozoa. The Toxoplasma-induced dysfunction of the hypothalamus and pituitary gland led to diabetes insipidus, which was, in combination with insufficient water intake, the most likely cause for the hypernatremia. PMID- 26606208 TI - Urinary Incontinence in Juvenile Female Soft-Coated Wheaten Terriers: Hospital Prevalence and Anatomic Urogenital Anomalies. AB - Urinary incontinence in juvenile female dogs is often associated with urogenital anatomic anomalies. Study objectives include: (1) determine hospital prevalence of urinary incontinence in juvenile female soft-coated wheaten terriers (SCWTs) compared to other affected dogs; (2) characterize anatomic anomalies affecting urinary incontinent juvenile female SCWTs utilizing uroendoscopy; and (3) compare incidence of ectopic ureters, paramesonephric remnants, and short urethras in juvenile female urinary incontinent SCWTs to other juvenile female dogs with urinary incontinence. We hypothesize juvenile SCWTs have an increased prevalence of urinary incontinence and an increased incidence of ectopic ureters, paramesonephric remnants, and short urethras compared to non-SCWTs with urinary incontinence within our hospital population. Medical records of female dogs 6 mo of age and younger with clinical signs of urinary incontinence and video uroendoscopic evaluation presenting to The Ohio State University Veterinary Medical Center from January 2000 to December 2011 were reviewed. Twelve juvenile SCWTs and 107 juvenile non-SCWTs met the inclusion criteria. Juvenile SCWTs were found to have an increased hospital prevalence of urinary incontinence compared to other affected breeds. Observed anomalies in SCWTs include: ectopic ureters, shortened urethras, paramesonephric remnants, and bifid vaginas. This information will help guide veterinarians in recognizing a breed-related disorder of the lower urogenital tract in SCWTs. PMID- 26606209 TI - Successful Treatment of Demodex gatoi with 10% Imidacloprid/1% Moxidectin. AB - Demodex gatoi is a transmissible, short-bodied mite found in the stratum corneum of cats. It is known to cause moderate to intense pruritus, often manifested as self-induced alopecia and excoriations. 10% imidacloprid/1% moxidectin (a) is a monthly, topical solution indicated for the treatment and/or prevention of fleas, heartworms, intestinal parasites, and ear mites. A household of cats was presented for pruritus that ranged from mild to severe in 8 of the 13 felines. The most common clinical signs included miliary-type papular dermatitis and focal areas of erythema associated with alopecia. Multiple skin scrapings of each animal revealed Demodex gatoi mites in only two cats. Weekly topical administration of 10% imidacloprid/1% moxidectin was used on all cats in the household for a total of ten doses. Skin scrapings following treatment were negative, and all cats in the house improved. Based on the successful treatment of this small number of cats, weekly application of 10% imidacloprid/1% moxidectin should be considered for the clinical resolution of cats affected by D. gatoi. PMID- 26606210 TI - Rotational and Axial Pattern Flaps in a Cat for Wound Reconstruction Secondary to Urethral Rupture. AB - A 3 yr old intact male domestic shorthair cat was presented with urine extravasation from urethral rupture. Extensive skin necrosis developed in the perineal region and left hind limb that necessitated delayed primary wound closure with a caudal superficial epigastric axial pattern flap, scrotal and preputial rotational skin flaps, and perineal urethrostomy. PMID- 26606211 TI - Canine Sialolithiasis: Two Case Reports with Breed, Gender, and Age Distribution of 29 Cases (1964-2010). AB - This study was conducted to investigate the clinical data of two cases of canine sialolithiasis and to analyze 29 cases identified in the Veterinary Medical Database by year of admission, breed, gender, and age. Medical records from the University of Missouri Veterinary Medical Teaching Hospital were reviewed and two dogs diagnosed with sialolithiasis (calcium oxalate) were identified between 1990 and 2010. The two dogs had cervical or pharyngeal sialocele and were successfully treated by sialolith removal and concurrent sialoadenectomy. Signalments of dogs with sialolithiasis between 1964 and 2010 were collected from the Veterinary Medical Database and evaluated. Several breeds of dogs were represented and the 10 to <15 yr old age group was shown to have significant association with sialolithiasis. Sialolithiasis is a rare veterinary condition. In this study, older dogs were at higher risk. In dogs, concurrent sialocele was common and good outcome could be expected after surgical removal of sialoliths with concurrent sialoadenectomy. PMID- 26606212 TI - The Diagnosis and Surgical Management of Intracardiac Quill Foreign Body in a Dog. AB - A dog was referred to Alta Vista Animal Hospital with a porcupine quill penetrating the right ventricle. The presenting complaint was tachypnea and dyspnea secondary to bilateral pneumothorax. Computed tomography revealed bilateral pneumothorax without evidence of quills. A median sternotomy was performed and the quill was removed. The dog recovered uneventfully. Quill injuries are common in dogs; however, intracardiac quill migration is rare. Dogs without evidence of severe cardiac injury secondary to intracardiac foreign bodies may have a good prognosis. PMID- 26606213 TI - Information-Guided Noise Reduction in Forward-Backward Semiclassical Dynamics. AB - Information-guided noise reduction (IGNoR) [Chem. Phys. Lett. 2004, 400, 446], a procedure for reducing the statistical error in Monte Carlo integration of oscillatory functions, is generalized to cases where both the prototype function and remaining integrand are complex-valued. The method is applied to the forward backward semiclassical dynamics approximation of time correlation functions. Illustrative calculations of velocity autocorrelation functions in supercritical argon and liquid neon are presented. PMID- 26606214 TI - Convergent Partially Augmented Basis Sets for Post-Hartree-Fock Calculations of Molecular Properties and Reaction Barrier Heights. AB - We present sets of convergent, partially augmented basis set levels corresponding to subsets of the augmented "aug-cc-pV(n+d)Z" basis sets of Dunning and co workers. We show that for many molecular properties a basis set fully augmented with diffuse functions is computationally expensive and almost always unnecessary. On the other hand, unaugmented cc-pV(n+d)Z basis sets are insufficient for many properties that require diffuse functions. Therefore, we propose using intermediate basis sets. We developed an efficient strategy for partial augmentation, and in this article, we test it and validate it. Sequentially deleting diffuse basis functions from the "aug" basis sets yields the "jul", "jun", "may", "apr", etc. basis sets. Tests of these basis sets for Moller-Plesset second-order perturbation theory (MP2) show the advantages of using these partially augmented basis sets and allow us to recommend which basis sets offer the best accuracy for a given number of basis functions for calculations on large systems. Similar truncations in the diffuse space can be performed for the aug-cc-pVxZ, aug-cc-pCVxZ, etc. basis sets. PMID- 26606215 TI - Correcting Systematic Errors in DFT Spin-Splitting Energetics for Transition Metal Complexes. AB - Spin-splittings of 57 octahedral first-row transition metal complexes calculated with B3LYP are compared with a database of experimental spectra collected from the literature. A variety of transition metal centers in various oxidation states and multiplicities along with a number of different coordinating ligands are considered. Environmental effects have been included to enable reasonable quantitative comparison with experiment. The manifold of states is studied using initial guesses constructed from ligand field theory. A localized orbital correction (LOC) model, referred to as DBLOC-DFT (d-block localized orbital corrected density functional theory), systematically corrects B3LYP calculations using five parameters. The final results are a considerable improvement over conventional DFT, bringing the mean unsigned error (MUE) from 10.14 kcal/mol with a standard deviation of 4.56 to 1.98 kcal/mol with a standard deviation of 1.62. Depending on the relative multiplicities of the ground and excited states, it is shown that B3LYP*, which has 15% exact nonlocal exchange, can lead to larger errors with respect to experiment than B3LYP. Application to 7 complexes from Swart et al. [ J. Phys. Chem. A 2004 , 108 , 5479. ] and 14 small-gap spin crossover complexes, from the literature, shows the DBLOC model provides good agreement with a variety of experimental data. PMID- 26606216 TI - Revisiting the Atomic Natural Orbital Approach for Basis Sets: Robust Systematic Basis Sets for Explicitly Correlated and Conventional Correlated ab initio Methods? AB - The performance of several families of basis sets for correlated wave function calculations on molecules is studied. The widely used correlation-consistent basis set family cc-pVXZ (n = D, T, Q, 5) is compared to a systematic series of atomic natural orbital basis sets (ano-pVXZ). These basis sets are built from the cc-pV6Z primitives in atomic multireference average coupled pair functional (MR ACPF) calculations. Segmented basis sets optimized for self-consistent field calculations (def2-SVP, def2-TZVPP, and def2-QZVPP as well as "pc-n", n = 1, 2, 3) were also tested. Reference Hartree-Fock energies are determined with the uncontracted aug-cc-pV6Z basis set for a set of 21 small molecules built from H, B, C, N, O, and F. Reference coupled cluster CCSD(T) correlation energies were determined from extrapolation at the cc-pV5Z/cc-pV6Z level. It is found that the ano-pVXZ basis sets outperform the other basis sets. The error in the SCF energies compared to cc-pVXZ basis sets is reduced by about a factor of 3 at each cardinal number. In addition, the ano-pVXZ consistently recovers more correlation energy than their competitors at each cardinal number. The ability of the four families of basis sets to extrapolate SCF and correlation energies to the basis set limit has been investigated. A conclusion by Truhlar is confirmed that the optimum exponent for correlation energy extrapolations at the DZ/TZ level is ~2.4. All TZ/QZ basis set pairs lead to an optimum exponent close to the expected value of 3. The SCF energy extrapolation proposed by Petersson and co-workers is found to be effective. At the DZ/TZ level, errors in total energies of less than 2 mEh are found for the test set, while at the TZ/QZ level one obtains the total energies within ~0.3 mEh of the basis set limit. For extrapolation, the "cc" and "ano" bases are found to be similarly successful. Extrapolation results were compared to explicitly correlated calculations with dedicated basis sets (cc-pVXZ F12) as well as the ano-pVXZ bases. It is found that the ano-pVXZ+ basis sets perform as well as the cc-pVXZ-F12 family (both are of comparable size); additional improvement should be possible by reoptimizing the ANO basis sets for explicitly correlated calculations. The error of the extrapolated energies is about 2-3 times smaller than what was found in the explicitly correlated calculations. However, the error in the explicitly correlated calculations is more systematic, and hence the same conclusion may not hold for the computation of energy differences. PMID- 26606217 TI - Modeling Charge Resonance in Cationic Molecular Clusters: Combining DFT-Tight Binding with Configuration Interaction. AB - In order to investigate charge resonance situations in molecular complexes, Wu et al. (J. Chem. Phys. 2007, 127, 164119) recently proposed a configuration interaction method with a valence bond-like multiconfigurational basis obtained from constrained DFT calculations. We adapt this method to the Self-Consistent Charge Density-Functional-based Tight Binding (SCC-DFTB) approach and provide expressions for the gradients of the energy with respect to the nuclear coordinates. It is shown that the method corrects the wrong SCC-DFTB behavior of the potential energy surface in the dissociation regions. This scheme is applied to determine the structural and stability properties of positively charged molecular dimers with full structural optimization, namely, the benzene dimer cation and the water dimer cation. The method yields binding energies in good agreement with experimental data and high-level reference calculations. PMID- 26606218 TI - Comparative Study on the Performance of Hybrid DFT Functionals in Highly Correlated Oxides: The Case of CeO2 and Ce2O3. AB - The outstanding catalytic properties of cerium oxides rely on the easy Ce(3+) <-> Ce(4+) redox conversion, which however constitutes a challenge in density functional based theoretical chemistry due to the strongly correlated nature of the 4f electrons present in the reduced materials. In this work, we report an analysis of the performance of five exchange-correlation functionals (HH, HHLYP, PBE0, B3LYP, and B1-WC) implemented in the CRYSTAL06 code to describe three properties of ceria: crystal structure, band gaps, and reaction energies of the CeO2 -> Ce2O3 process. All five functionals give values for cell parameters that are in fairly good agreement with experiment, although the PBE0 hybrid functional is found to be the most accurate. Band gaps, 2p-4f-5d in the case of CeO2 and 4f 5d in the case of Ce2O3, are found to be, in general, overestimated and drop off when the amount of Hartree-Fock exchange in the exchange-correlation functional decreases. In contrast, the reaction energies are found to be underestimated, and increase when the amount of HF exchange lowers. Overall, at its standard formulation, the B1-WC functional seems to be the best choice as it provides good band gaps and reaction energies, and very reasonable crystal parameters. PMID- 26606219 TI - Designing a Scalable Fault Tolerance Model for High Performance Computational Chemistry: A Case Study with Coupled Cluster Perturbative Triples. AB - In the past couple of decades, the massive computational power provided by the most modern supercomputers has resulted in simulation of higher-order computational chemistry methods, previously considered intractable. As the system sizes continue to increase, the computational chemistry domain continues to escalate this trend using parallel computing with programming models such as Message Passing Interface (MPI) and Partitioned Global Address Space (PGAS) programming models such as Global Arrays. The ever increasing scale of these supercomputers comes at a cost of reduced Mean Time Between Failures (MTBF), currently on the order of days and projected to be on the order of hours for upcoming extreme scale systems. While traditional disk-based check pointing methods are ubiquitous for storing intermediate solutions, they suffer from high overhead of writing and recovering from checkpoints. In practice, checkpointing itself often brings the system down. Clearly, methods beyond checkpointing are imperative to handling the aggravating issue of reducing MTBF. In this paper, we address this challenge by designing and implementing an efficient fault tolerant version of the Coupled Cluster (CC) method with NWChem, using in-memory data redundancy. We present the challenges associated with our design, including an efficient data storage model, maintenance of at least one consistent data copy, and the recovery process. Our performance evaluation without faults shows that the current design exhibits a small overhead. In the presence of a simulated fault, the proposed design incurs negligible overhead in comparison to the state of the art implementation without faults. PMID- 26606220 TI - Weak Molecular Interactions Studied with Parallel Implementations of the Local Pair Natural Orbital Coupled Pair and Coupled Cluster Methods. AB - A parallel implementation of the recently developed local pair natural orbital coupled electron pair approximation (LPNO-CEPA/n, n = Version 1, 2, or 3) and the corresponding LPNO coupled cluster method with single- and double excitations (LPNO-CCSD) is described. A detailed analysis alongside pseudocode is presented for the most important computational steps. The scaling with respect to the number of processors is reasonable and speedups of about 10 with 14 processors have been found in benchmark calculations (wall-clock time). The most important factor limiting the efficiency of the scaling with respect to the number of processors is probably the limited bandwidth of the presently prevailing multicore machines. The parallel LPNO methods were applied to study weak intermolecular interactions. Initially, the well-established S22 set of molecules was studied. The mean absolute error resulting from the use of the LPNO-CEPA/1 method relative to the most recent CCSD(T) reference data is found to be 0.24 kcal/mol. Thus, LPNO-CEPA/1 holds great promise for the efficient ab initio treatment of weak intermolecular interactions. In order to demonstrate the applicability of the methods to real systems, a two-dimensional potential energy surface for a trimer of 2,4-dihydroxy-3-acetyl-6-methyl acetophenone [C11H12O4] (81 atoms, 1296 basis functions, 133 single points) has been calculated with the LPNO-CEPA/1 method. In this system, a clear distinction can be made between hydrogen bonding and pi-pi interactions. The global minimum on the PES obtained from the calculations agrees excellently with the experimentally determined crystal structure. By contrast, popular density functional methods show no discernible minimum. PMID- 26606221 TI - Assessment of the Performance of DFT and DFT-D Methods for Describing Distance Dependence of Hydrogen-Bonded Interactions. AB - Noncovalent interactions such as hydrogen bonds, van der Waals forces, and pi-pi interactions play important roles influencing the structure, stability, and dynamic properties of biomolecules including DNA and RNA base pairs. In an effort to better understand the fundamental physics of hydrogen bonding (H-bonding), we investigate the distance dependence of interaction energies in the prototype bimolecular complexes of formic acid, formamide, and formamidine. Potential energy curves along the H-bonding dissociation coordinate are examined both by establishing reference CCSD(T) interaction energies extrapolated to the complete basis set limit and by assessing the performance of the density functional methods B3LYP, PBE, PBE0, B970, PB86, M05-2X, and M06-2X and empirical dispersion corrected methods B3LYP-D3, PBE-D3, PBE0-D3, B970-D2, BP86-D3, and omegaB97X-D, with basis sets 6-311++G(3df,3pd), aug-cc-pVDZ, and aug-cc-pVTZ. Although H bonding interactions are dominated by electrostatics, it is necessary to properly account for dispersion interactions to obtain accurate energetics. In order to quantitatively probe the nature of hydrogen bonding interactions as a function of distance, we decompose the interaction energy curves into physically meaningful components with symmetry-adapted perturbation theory (SAPT). The SAPT results confirm that the contribution of dispersion and induction are significant at and near equilibrium, although electrostatics dominate. Among the DFT/DFT-D techniques, the best overall results are obtained utilizing counterpoise corrected omegaB97X-D with the aug-cc-pVDZ basis set. PMID- 26606222 TI - Nature of the Carbon-Sulfur Bond in the Species H-CS-OH. AB - A QTAIM (Quantum-Theory-Atoms-in-Molecules) and ELF (electron localization function) topological analysis of the bonding in the recently reported molecule HCSX, X = OH reveals that the central carbon-sulfur bond is highly tunable, from having triple character at one limit to being almost a single bond at the other depending on the nature of the group X. PMID- 26606223 TI - Valence Excited States in Large Molecules via Local Multireference Singles and Doubles Configuration Interaction. AB - We demonstrate that valence excited states in large molecules can be treated using local multireference singles and doubles configuration interaction (LMRSDCI). The interior eigenvalues corresponding to the excited states of interest are transformed and shifted to the extrema of the spectrum by way of oblique projections and a matrix shift within a modified Davidson diagonalization scheme. In this way, the approximate wave function associated with the excited state of interest can be isolated independently of the lower lying roots, and residual minimization is used for final convergence to the target eigenstate. We find that vertical excitation energies calculated using LMRSDCI are mostly within 0.2 eV of nonlocal MRSDCI values. PMID- 26606224 TI - G4(MP2)-6X: A Cost-Effective Improvement to G4(MP2). AB - G4(MP2)-6X is developed as a composite procedure with a cost comparable to that of G4(MP2) but performance approaching that of G4. The new procedure is a variant of G4(MP2) that employs BMK/6-31+G(2df,p) geometries and has six additional scaling factors for the correlation energy components. The scaling factors and HLC parameters are optimized using the new E2 set of 526 energies, representing thermochemical properties, reaction energies and barriers, and weak interactions. G4(MP2)-6X achieves a mean absolute deviation (MAD) from benchmark values of 3.64 kJ mol(-1) for the E2 set, compared with 4.42 kJ mol(-1) for G4(MP2). For the E0 set of 148 energies, G4(MP2)-6X gives an MAD of 3.43 kJ mol(-1), compared with 3.22 kJ mol(-1) for G4 and 4.03 kJ mol(-1) for G4(MP2). The new G4(MP2)-6X procedure thus uses extra parametrization to provide a G4-type performance without incurring G4-type computational costs. PMID- 26606225 TI - Bonding Conundrums in the C2 Molecule: A Valence Bond Study. AB - The ab initio VB study for the electronic structure of the C2 molecule in the ground state is presented in this work. VB calculations involving 78 chemically relevant VB structures can predict the bonding energy of C2 quite well. Sequentially, a VBCIS calculation provides spectroscopic parameters that are very close to full CI calculated values in the same basis set. Furthermore, the analysis of the bonding scheme shows that a triply bonded structure is the major one in terms of weights, and the lowest in energy at the equilibrium distance. The second structure in terms of weights is an ethylene-like structure, displaying a sigma + pi double bond. The structure with two suspended pi bonds but no sigma bond contributes only marginally to the ground state. This ordering of weights for the VB structures describing the C2 molecule is shown to be consistent with the shape of the molecular orbitals and with the multireference character of the ground state. With the triply bonded bonding scheme, the natures of the pi and sigma bonds are investigated, and then the corresponding "in situ" bond strengths are estimated. The contribution of the covalent-ionic resonance energy to pi and sigma bonding is revealed and discussed. PMID- 26606226 TI - Substantial Dissociation Energies for the Recently Synthesized NC-Ag-NH3 and Br Ag-NH3 Molecules and Their Isovalent Family Members M(CN)XY3 and M(Br)XY3 (M = Cu, Ag, Au; X = N, P; Y = H, F). AB - Chippindale et al. have recently synthesized the unique molecules (NC)Ag(NH3) and BrAg(NH3) and shown the heavy atom skeletal structures to be linear. Here, a theoretical study is reported of 12 members each of the two isovalent series of molecules. For (NC)Ag(NH3) and BrAg(NH3), the theoretical structures agree well with those determined by X-ray crystallography. Structures for the 22 yet unknown compounds should be similarly reliable. The dissociation energies for a loss of NH3 from the two known compounds are significant (34 and 31 kcal/mol), confirming their viability. For the other systems, the ligand dissociation energies are highly variable, ranging from 9 kcal/mol (BrAg-NF3) to 44 kcal/mol (BrAu-PH3). The bond dissociation energies for the different metals follow the irregular order Au > Cu > Ag. For the XY3 ligands, the dissociation energies follow the order NH3 > PH3 > PF3 > NF3, except for the BrAu-XY3 complexes. Electronic structure insights are gained via Natural Bond Orbital (NBO) analyses. PMID- 26606227 TI - Role of Cation Polarization in holo- and hemi-Directed [Pb(H2O)n](2+) Complexes and Development of a Pb(2+) Polarizable Force Field. AB - Reduced Variational Space (RVS) calculations are reported that afford insight into the energetic origins of the hemi- and holo-directing behavior of [Pb(H2O)n](2+) complexes. It is shown that the distribution of ligands around the Pb(2+) center arises from a delicate balance between the first-order Coulomb plus exchange-repulsion energy that favors holo-directionality, and the second-order charge transfer plus polarization term that favors hemi-directionality. It is additionally demonstrated that the pseudopotential/basis set combination used to study such complexes should be carefully selected, as artifacts can arise when using large-core pseudopotentials. Finally, based on these findings, we introduce a new SIBFA force field parametrization for Pb(2+). Results yield close agreement with ab initio complexation energies in a series of [Pb(H2O)n](2+) complexes and successfully encapsulate the hemi- and holo-directing properties. SIBFA thus appears to be the first classical force field to be able to model the holo-/hemi directed transition within Pb complexes, avoiding the need for explicit wave function treatment and consequently providing the opportunity to deal with large leaded systems of biological interest. PMID- 26606228 TI - Accurate Vibrational Frequencies of Borane and Its Isotopologues. AB - Vibrational transitions of borane and its isotopologues ((11)BH3, (11)BD3, (10)BH3, and (10)BD3) have been obtained from state-specific vibrational configuration interaction calculations. Explicitly correlated coupled-cluster calculations, CCSD(T)-F12a, with additional corrections for high-order terms of the coupled-cluster expansion, i.e., CCSDT(Q), were used to determine multidimensional potential energy surfaces. Additional contributions due to core valence interactions, scalar relativistic effects, and such arising from the diagonal Born-Oppenheimer correction were accounted for in the one-dimensional terms within the expansion of the potential energy surface. From these, anharmonic vibrational spectra were obtained, which are in excellent agreement with experimental data. Mean absolute deviations from gas phase measurements were found to be in the sub-wavenumber regime. PMID- 26606229 TI - Multiconfigurational Second-Order Perturbation Theory Restricted Active Space (RASPT2) Method for Electronic Excited States: A Benchmark Study. AB - The recently developed second-order perturbation theory restricted active space (RASPT2) method has been benchmarked versus the well-established complete active space (CASPT2) approach. Vertical excitation energies for valence and Rydberg excited states of different groups of organic (polyenes, acenes, heterocycles, azabenzenes, nucleobases, and free base porphin) and inorganic (nickel atom and copper tetrachloride dianion) molecules have been computed at the RASPT2 and multistate (MS) RASPT2 levels using different reference spaces and compared with CASPT2, CCSD, and experimental data in order to set the accuracy of the approach, which extends the applicability of multiconfigurational perturbation theory to much larger and complex systems than previously. Relevant aspects in multiconfigurational excited state quantum chemistry such as the valence-Rydberg mixing problem in organic molecules or the double d-shell effect for first-row transition metals have also been addressed. PMID- 26606230 TI - DFT Calculations of Isotropic Hyperfine Coupling Constants of Nitrogen Aromatic Radicals: The Challenge of Nitroxide Radicals. AB - The performance of DFT methodology to predict with accuracy the isotropic hyperfine coupling constants (hfccs) of aromatic radicals containing (14)N nucleus is investigated by an extensive study in which 165 hfccs, belonging to 38 radical species, are obtained from calculations with B3LYP and PBE0 functionals combined with 6-31G*, N07D, TZVP, and EPR-III basis sets, and are compared to the reported experimental data. The results indicate that the selection of the basis set is of fundamental importance in the calculation of (14)N hfccs, whereas there is not so great an influence on the accurate computation of that parameter for (1)H nuclei. The values of the calculated (14)N coupling constants of aromatic nitroxide radicals using DFT methodology are noticeably lower than the experimental ones. A very simple relation to predict these hfccs with high accuracy is proposed on the basis of the present results, as an interesting alternative to the highly computationally demanding integrated approaches so far used. PMID- 26606231 TI - Oscillator Strengths in ONIOM Excited State Calculations. AB - We compute oscillator strengths with the ONIOM (Our own N-layer Integrated molecular Orbital molecular Mechanics) hybrid method between ground and valence excited states and compare the results with the high level of theory equation of motion coupled cluster singles and doubles (EOM-CCSD). This work follows our previous studies in which we validated the ability of ONIOM to compute accurate transition energies compared to EOM-CCSD. We test various levels of theory and molecular systems, as well as the effect of the link atom bond length. Our results show that oscillator strengths can be accurately computed with ONIOM, provided that a sensible choice of the partitioning and of the low level method is made. Being able to calculate both the transition energy and the oscillator strength, ONIOM represents a promising approach to completely characterize valence excited states of molecules that are too large to be studied with a conventional high-accuracy method. PMID- 26606232 TI - A Replica Exchange Molecular Dynamics Simulation of a Single Polyethylene Chain: Temperature Dependence of Structural Properties and Chain Conformational Study at the Equilibrium Melting Temperature. AB - The conformational properties of a finite length polyethylene chain were explored over a wide range of temperatures using a replica exchange molecular dynamics simulation providing high quality simulation data representative for the equilibrium behavior of the chain molecule. The radial distribution function (RDF) and the structure factor S(q) of the chain as a function of temperature are analyzed in detail. The different characteristic peaks in the RDF and S(q) were assigned to specific distances in the chain and structural changes occurring with the temperature. In S(q), a peak characteristic for the order in the solid state was found and used to determine the equilibrium melting temperature. A detailed scaling analysis of the structure factor covering the full q range was performed according to the work of Hammouda. In the Theta region, a quantitative analysis of the full structure factor was done using the equivalent Kuhn chain, which enabled us to assign the Theta region of our chain and to demonstrate, in our particular case, the failure of the Gaussian chain approach. The chain conformational properties at the equilibrium melting temperature are discussed using conformational distribution functions, using the largest principal component of the radius of gyration and shape parameters as order parameters. We demonstrate that for the system studied here, the Landau free energy expression based on this conformational distribution information leads to erroneous conclusions concerning the thermodynamic transition behavior. Finally, we focus on the instantaneous conformational properties at the equilibrium melting temperature and give a detailed analysis of the conformational shapes using different shape parameters and a simulation snapshot. We show that the chain does not only take the lamellar rod-like and globular conformational shapes, typical of the solid and liquid states, but can also explore many other conformational states, including the toroidal conformational state. It is the first demonstration that a flexible molecule like PE can also take a toroidal conformational state, which is normally linked to stiffer chains. PMID- 26606233 TI - TMSmesh: A Robust Method for Molecular Surface Mesh Generation Using a Trace Technique. AB - Qualified, stable, and efficient molecular surface meshing appears to be necessitated by recent developments for realistic mathematical modeling and numerical simulation of biomolecules, especially in implicit solvent modeling (e.g., see a review in B. Z. Lu et al. Commun. Comput. Phys. 2008, 3, 973-1009). In this paper, we present a new method: tracing molecular surface for meshing (TMSmesh) the Gaussian surface of biomolecules. The method computes the surface points by solving a nonlinear equation directly, polygonizes by connecting surface points through a trace technique, and finally outputs a triangulated mesh. TMSmesh has a linear complexity with respect to the number of atoms and is shown to be capable of handling molecules consisting of more than one million atoms, which is usually difficult for the existing methods for surface generation used in molecular visualization and geometry analysis. Moreover, the meshes generated by TMSmesh are successfully tested in boundary element solutions of the Poisson-Boltzmann equation, which directly gives rise to a route to simulate electrostatic solvation of large-scale molecular systems. The binary version of TMSmesh and a set of representative PQR benchmark molecules are downloadable at our Web page http://lsec.cc.ac.cn/~lubz/Meshing.html . PMID- 26606234 TI - The Importance of Going beyond Coulombic Potential in Embedding Calculations for Molecular Properties: The Case of Iso-G for Biliverdin in Protein-Like Environment. AB - The importance of the nonelectrostatic component of the embedding potential is investigated by comparing the complexation induced shifts of the iso-g obtained in embedding calculations to its supermolecular counterparts. The analyses are made in view of such multilevel simulations, for which supermolecular strategy is either impractical or impossible, such as the planned simulations for the whole enzyme ferredoxin oxidoreductase. For the biliverdin radical surrounded by a few amino acids, it is shown that the embedding potential comprising only Coulomb terms fails to reproduce even qualitatively the shifts evaluated from supermolecular calculations. The nonelectrostatic component of the exact embedding potential is a bifunctional of two electron densities [Wesolowski and Warshel, J. Phys. Chem. 1993, 97, 8050; Wesolowski, Phys. Rev. A 2008, 77, 012504]. Therefore we analyze in detail both the quality of the approximant for the bifunctional and the importance of the choice of the electron densities at which it is evaluated in practical calculations. PMID- 26606235 TI - Harmonic Vibrational Analysis in Delocalized Internal Coordinates. AB - It is shown that a principal component analysis of a large set of internal coordinates can be used to define a nonredundant set of delocalized internal coordinates suitable for the calculation of harmonic vibrational normal modes. The selection of internal coordinates and the principal component analysis provide large degrees of freedom in extracting a nonredundant set of coordinates, and thus influence how the vibrational normal modes are described. It is shown that long-range coordinates may be especially suitable for describing low frequency global deformation modes in proteins. PMID- 26606236 TI - Improved Replica Exchange Method for Native-State Protein Sampling. AB - We present a new replica exchange method, designed for optimal native state protein sampling in explicit solvent, called replica exchange with flexible tempering (REFT). The method was built upon the recently introduced replica exchange with solute tempering (REST). The potential function is adapted to direct the conformational search toward interdomain movements and the flexible portions of the protein. We demonstrate the improved sampling efficiency of REFT compared to the original REST for the bacteriophage T4 lysozyme. PMID- 26606237 TI - Long-Range Electrostatic Effects in QM/MM Studies of Enzymatic Reactions: Application of the Solvated Macromolecule Boundary Potential. AB - Long-range electrostatic interactions are important in simulations of enzymatic reactions. They can be divided into the effects due to bulk solvent and those due to the electrostatic potential of the outer macromolecule. We study and quantify the importance of these two effects for two test systems by application of the solvated macromolecule boundary potential (SMBP) [J. Chem. Theory Comput. 2009, 5, 3114-3128]. We validate the accuracy of the SMBP for these test systems and present a transferable protocol for determination of optimal SMBP parameters as well as recommended default values for these parameters. Two enzymatic reactions with different characteristics are studied: the intramolecular Claisen rearrangement in chorismate mutase that is associated with little charge transfer and the hydroxylation reaction in p-hydroxybenzoate hydroxylase that corresponds to a formal "OH(+)" transfer and thus involves significant charge transfer. It is found that the effects of the electrostatic potential of the outer macromolecule and of bulk solvent are only important in the latter case, where their neglect causes deviations in the computed barriers on the order of 1-2 kcal/mol, respectively. Even larger deviations on the order of several kilocalories per mole are observed for the reaction energies in p-hydroxybenzoate hydroxylase if the electrostatic potential of the outer macromolecule is neglected. PMID- 26606238 TI - Characterizing Drug Release from Nonfouling Polyampholyte Hydrogels. AB - Controlled delivery of bioactive signaling molecules and drugs is essential for the development of the next generation of tissue regeneration scaffolds. However, these molecules must be delivered from a nonfouling platform, so that the therapeutic role is not masked by the naturally occurring foreign body response. Therefore, the purpose of this study is to characterize the release profiles of three pseudodrug molecules from a nonfouling polyampholyte hydrogel to gain insight into the potential for this platform to serve as a tissue regeneration scaffold. Hydrogels composed of equimolar concentrations of [2 (acryloyloxy)ethyl] trimethylammonium chloride (TMA) and 2-carboxyethyl acrylate (CAA) monomers were synthesized in the presence of caffeine, methylene blue, or metanil yellow. Then the release of these three molecules was tracked as a function of the hydrogel cross-linker density, the solution pH, and the solution ionic strength. The results suggest that the release of the neutral caffeine molecule is dictated by diffusion alone, while the release of the two charged pseudodrug molecules are controlled by their interactions with the charged regions of the TMA and CAA monomer subunits. These interactions are clearly impacted by solution pH and ionic strength leading to clear changes in the rate of release and extent of release for metanil yellow and methylene blue. Additionally, an enzyme-linked immunosorbent assay was used to confirm that the TMA:CAA hydrogels retain their nonfouling characteristics following the release of the pseudodrug molecules. When these results are combined with the literature related to TMA:CAA hydrogels, it is concluded that this system represents a promising multifunctional platform for both short-term and long-term delivery of bioactive molecules for tissue regeneration. PMID- 26606239 TI - Reputation Effects in Public and Private Interactions. AB - We study the evolution of cooperation in a model of indirect reciprocity where people interact in public and private situations. Public interactions have a high chance to be observed by others and always affect reputation. Private interactions have a lower chance to be observed and only occasionally affect reputation. We explore all second order social norms and study conditions for evolutionary stability of action rules. We observe the competition between "honest" and "hypocritical" strategies. The former cooperate both in public and in private. The later cooperate in public, where many others are watching, but try to get away with defection in private situations. The hypocritical idea is that in private situations it does not pay-off to cooperate, because there is a good chance that nobody will notice it. We find simple and intuitive conditions for the evolution of honest strategies. PMID- 26606240 TI - Barrier function of the nasal mucosa in health and type-2 biased airway diseases. AB - The mucosal lining of the upper airways represents the outer surface of the body to the ambient air and its contents and is prepared for it as the first line of defense. Apart from the well-described physical barrier and the mucociliary clearance, a variety of systems, including the airway microbiome, antimicrobial proteins, damage-associated molecular patterns, innate lymphoid cells, epithelial derived cytokines and chemokines, and finally the adaptive immune system, as well as eosinophils as newly appreciated defense cells form different levels of protection against and response to any possible intruder. Of interest especially for allergic airway disease, mucosal germs might not just elicit a classical Th1/Th17-biased inflammatory response, but may directly induce a type-2 mucosal inflammation. Innovative therapeutic interventions may be possible at different levels also; however, whether modulations of the innate or adaptive immune responses will finally be more successful, and how the correction of the adaptive immune response might impact on the innate side, will be determined in the near future. PMID- 26606241 TI - Dermoscopy of Nodular Hidradenoma, a Great Masquerader: A Morphological Study of 28 Cases. AB - BACKGROUND: Nodular hidradenoma is an uncommon, benign, adnexal neoplasm of apocrine origin which is a clinical simulator of other tumours. OBJECTIVE: The aim of this study was to evaluate the morphological findings of a large series of nodular hidradenomas under dermoscopic observation. METHODS: Dermoscopic examination of 28 cases of nodular hidradenomas was performed to evaluate specific dermoscopic criteria and patterns. RESULTS: The most frequently occurring dermoscopic features were: (1) in 96.4% of cases, a homogeneous area that covered the lesion partially or totally, the colour of which was pinkish in 46.4% of cases, bluish in 28.6%, red-blue in 14.3%, and brownish in 10.7%; (2) white structures were found in 89.3% of cases; (3) in 82.1% of cases, vascular structures were also observed, especially arborising telangiectasias (39.3%) and polymorphous atypical vessels (28.6%). CONCLUSION: Nodular hidradenomas represent a dermoscopic pitfall, being difficult to differentiate clinically and dermoscopically from basal cell carcinomas and melanomas. PMID- 26606242 TI - Silver Accumulation in the Green Microalga Coccomyxa actinabiotis: Toxicity, in Situ Speciation, and Localization Investigated Using Synchrotron XAS, XRD, and TEM. AB - Microalgae are good candidates for toxic metal remediation biotechnologies. This study explores the cellular processes implemented by the green microalga Coccomyxa actinabiotis to take up and cope with silver over the concentration range of 10(-7) to 10(-2) M Ag(+). Understanding these processes enables us to assess the potential of this microalga for applications for bioremediation. Silver in situ speciation and localization were investigated using X-ray absorption spectroscopy, X-ray diffraction, and transmission electron microscopy. Silver toxicity was evaluated by monitoring microalgal growth and photochemical parameters. Different accumulation mechanisms were brought out depending on silver concentration. At low micromolar concentration, microalgae fixed all silver initially present in solution, trapping it inside the cells into the cytosol, mainly as unreduced Ag(I) bound with molecules containing sulfur. Silver was efficiently detoxified. When concentration increased, silver spread throughout the cell and particularly entered the chloroplast, where it damaged the photosystem. Most silver was reduced to Ag(0) and aggregated to form crystalline silver nanoparticles of face-centered cubic structure with a mean size of 10 nm. An additional minor interaction of silver with molecules containing sulfur indicated the concomitant existence of the mechanism observed at low concentration or nanoparticle capping. Nanoparticles were observed in chloroplasts, in mitochondria, on the plasma membrane, on cytosolic membrane structures, and in vacuoles. Above 10(-4) M Ag(+), damages were irreversible, and photosynthesis and growth were definitely inhibited. However, high silver amounts remained confined inside microalgae, showing their potential for the bioremediation of contaminated water. PMID- 26606243 TI - Increased Mammalian Target of Rapamycin Signaling Contributes to the Accumulation of Protein Oxidative Damage in a Mouse Model of Down's Syndrome. AB - BACKGROUND: Neurodegenerative diseases are characterized by increased levels of oxidative stress and an altered mammalian target of rapamycin (mTOR)/autophagy axis; however, the mutual relationship between these two events is controversial. Previous studies in Down's syndrome (DS) and Alzheimer's disease (AD) suggested that the accumulation of protein oxidative damage results from the increased free radical production, mainly related to metabolic alterations, mitochondrial degeneration and amyloid-beta deposition, and aberrant activity of protein degradative systems. SUMMARY: This study analyzed mTOR signaling in Ts65Dn mice, a model of DS, at 6 and 12 months of age compared with euploid mice showing the early aberrant hyperphosphorylation of mTOR coupled with the reduction of autophagosome formation. Moreover, the evaluation of protein oxidation shows an increase in protein nitration and protein-bound 4-hydroxynonenal in 12-month-old Ts65Dn mice suggesting the potential involvement of altered autophagy in the buildup of protein oxidative damage. In addition, data obtained on cell culture support the protective role of autophagy in reducing protein oxidation. KEY MESSAGES: Overall, this study provides further evidence for the role of mTOR hyperactivation and reduced autophagy in the accumulation of protein oxidative damage during DS and AD pathologies. PMID- 26606244 TI - Prognostic Impact of the ABCC11/MRP8 Polymorphism in Adjuvant Oral Chemotherapy with S-1 for Non-Small Cell Lung Cancer. AB - BACKGROUND: Postoperative 1-year administration of S-1, an oral derivative of 5 fluorouracil (5-FU), was shown to be feasible in lung cancer. The 5-year survival rates of postoperative patients treated with S-1 adjuvant chemotherapy and the prognostic impact of clinicopathological factors were examined. METHODS: The data of 50 patients with curatively resected pathological stage IB to IIIA non-small cell lung cancer, who were treated with S-1 postoperatively, were analyzed. The prognostic impacts of 22 clinicopathological factors including expressions of the 5-FU pathway enzymes were evaluated. A single-nucleotide polymorphism (SNP), i.e. 538G>A (rs17822931), of ABCC11/MRP8, which encodes a 5-FU excretion enzyme that is known as an earwax type determinant, was also evaluated. RESULTS: The 5-year overall and relapse-free survival rates were 72.5 and 67.5%, respectively. A performance status >= 1, lymphatic vessel invasion, blood vessel invasion, and the A/A type of SNP538, which is responsible for the dry earwax type, were significantly associated with shorter relapse-free survivals. In 34 patients who showed a relative performance of 70% or more for chemotherapy, multivariate survival analysis indicated significant hazard ratios only for the A/A type of SNP538 (p = 0.007). CONCLUSIONS: S-1 has sufficient power as adjuvant chemotherapy. However, its effect might be small in the dry earwax type patient group in an adjuvant setting. PMID- 26606245 TI - Organometallic Half-Sandwich Dichloridoruthenium(II) Complexes with 7-Azaindoles: Synthesis, Characterization and Elucidation of Their Anticancer Inactivity against A2780 Cell Line. AB - A series of organometallic half-sandwich dichloridoruthenium(II) complexes of the general formula [Ru(eta6-p-cym)(naza)Cl2] (1-8; p-cym = p-cymene; naza = 7 azaindole or its derivatives) was synthesised and fully characterized by elemental analysis, mass spectrometry, and infrared and multinuclear NMR spectroscopy. A single-crystal X-ray structural analysis of [Ru(eta6-p cym)(2Me4Claza)Cl2] (6) revealed a typical piano-stool geometry with an N7 coordination mode of 2-methyl-4-chloro-7-azaindole (2Me4Claza). The complexes have been found to be inactive against human ovarian cancer cell line A2780 up to the highest applied concentration (IC50 > 50.0 MUM). An inactivity of the complexes is caused by their instability in water-containing solvents connected with a release of the naza N-donor ligand, as proved by the detailed 1H NMR, mass spectrometry and fluorescence experiments. PMID- 26606246 TI - Giffonins J-P, Highly Hydroxylated Cyclized Diarylheptanoids from the Leaves of Corylus avellana Cultivar "Tonda di Giffoni". AB - Two new diaryl ether heptanoids, giffonins J and K (1 and 2), along with five new diarylheptanoids, giffonins L-P (3-7), were isolated from a methanol extract of the leaves of Corylus avellana cultivar "Tonda di Giffoni". These compounds were identified as highly hydroxylated cyclized diarylheptanoids by 1D- and 2D-NMR experiments. The relative configurations of giffonins J-P (1-7) were established by a combined QM (quantum mechanical)/NMR approach, comparing the experimental (13)C/(1)H NMR chemical shift data and the related predicted values. The cytotoxic activities of giffonins J-P (1-7) were evaluated against the human osteosarcoma U2Os and SAOs cell lines. PMID- 26606247 TI - White Matter Changes Associated with Resting Sympathetic Tone in Frontotemporal Dementia vs. Alzheimer's Disease. AB - BACKGROUND: Resting sympathetic tone, a measure of physiological arousal, is decreased in patients with apathy and inertia, such as those with behavioral variant frontotemporal dementia (bvFTD) and other frontally-predominant disorders. OBJECTIVE: To identify the neuroanatomical correlates of skin conductance levels (SCLs), an index of resting sympathetic tone and apathy, among patients with bvFTD, where SCLs is decreased, compared to those with Alzheimer's disease (AD), where it is not. METHODS: This study analyzed bvFTD (n = 14) patients and a comparison group with early-onset AD (n = 19). We compared their resting SCLs with gray matter and white matter regions of interest and white matter measures of fiber integrity on magnetic resonance imaging and diffusion tensor imaging. RESULTS: As expected, bvFTD patients, compared to AD patients, had lower SCLs, which correlated with an apathy measure, and more gray matter loss and abnormalities of fiber integrity (fractional anisotropy and mean diffusivity) in frontal-anterior temporal regions. After controlling for group membership, the SCLs were significantly correlated with white matter volumes in the cingulum and inferior parietal region in the right hemisphere. CONCLUSION: Among dementia patients, SCLs, and resting sympathetic tone, may correlate with quantity of white matter, rather than with gray matter or with white matter fiber integrity. Loss of white matter volumes, especially involving a right frontoparietal network, may reflect chronic loss of cortical axons that mediate frontal control of resting sympathetic tone, changes that could contribute to the apathy and inertia of bvFTD and related disorders. PMID- 26606248 TI - Human GAPDH Is a Target of Aspirin's Primary Metabolite Salicylic Acid and Its Derivatives. AB - The plant hormone salicylic acid (SA) controls several physiological processes and is a key regulator of multiple levels of plant immunity. To decipher the mechanisms through which SA's multiple physiological effects are mediated, particularly in immunity, two high-throughput screens were developed to identify SA-binding proteins (SABPs). Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH) from plants (Arabidopsis thaliana) was identified in these screens. Similar screens and subsequent analyses using SA analogs, in conjunction with either a photoaffinity labeling technique or surface plasmon resonance-based technology, established that human GAPDH (HsGAPDH) also binds SA. In addition to its central role in glycolysis, HsGAPDH participates in several pathological processes, including viral replication and neuronal cell death. The anti-Parkinson's drug deprenyl has been shown to suppress nuclear translocation of HsGAPDH, an early step in cell death and the resulting cell death induced by the DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine. Here, we demonstrate that SA, which is the primary metabolite of aspirin (acetyl SA) and is likely responsible for many of its pharmacological effects, also suppresses nuclear translocation of HsGAPDH and cell death. Analysis of two synthetic SA derivatives and two classes of compounds from the Chinese medicinal herb Glycyrrhiza foetida (licorice), glycyrrhizin and the SA-derivatives amorfrutins, revealed that they not only appear to bind HsGAPDH more tightly than SA, but also exhibit a greater ability to suppress translocation of HsGAPDH to the nucleus and cell death. PMID- 26606249 TI - Delay in Diagnosis of Testicular Cancer; A Need for Awareness Programs. AB - BACKGROUND AIM: To gain insight into patient and doctor delay in testicular cancer (TC) and factors associated with delay. MATERIALS AND METHODS: Sixty of the 66 eligible men; median age 26 (range 17-45) years, diagnosed with TC at the University Medical Center Groningen completed a questionnaire on patients' delay: interval from symptom onset to first consultation with a general practitioner (GP) and doctors' delay: interval between GP and specialist visit. RESULTS: Median patient reported delay was 30 (range 1-365) days. Patient delay and TC tumor stage were associated (p = .01). Lower educated men and men embarrassed about their scrotal change reported longer patient delay (r = -.25, r = .79 respectively). Age, marital status, TC awareness, warning signals, nor perceived limitations were associated with patient delay. Median patient reported time from GP to specialist (doctors' delay) was 7 (range 0-240) days. Referral time and disease stage were associated (p = .04). Six patients never reported a scrotal change. Of the 54 patients reporting a testicular change, 29 (54%) patients were initially 'misdiagnosed', leading to a median doctors' delay of 14 (1-240) days, which was longer (p< .001) than in the 25 (46%) patients whose GP suspected TC (median doctors' delay 1(0-7 days). CONCLUSIONS: High variation in patients' and doctors' delay was found. Most important risk variables for longer patient delay were embarrassment and lower education. Most important risk variable in GP's was 'misdiagnosis'. TC awareness programs for men and physicians are required to decrease delay in the diagnosis of TC and improve disease free survival. PMID- 26606250 TI - The Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5): Development and Initial Psychometric Evaluation. AB - The Posttraumatic Stress Disorder Checklist (PCL) is a widely used DSM correspondent self-report measure of PTSD symptoms. The PCL was recently revised to reflect DSM-5 changes to the PTSD criteria. In this article, the authors describe the development and initial psychometric evaluation of the PCL for DSM-5 (PCL-5). Psychometric properties of the PCL-5 were examined in 2 studies involving trauma-exposed college students. In Study 1 (N = 278), PCL-5 scores exhibited strong internal consistency (alpha = .94), test-retest reliability (r = .82), and convergent (rs = .74 to .85) and discriminant (rs = .31 to .60) validity. In addition, confirmatory factor analyses indicated adequate fit with the DSM-5 4-factor model, chi2 (164) = 455.83, p < .001, standardized root mean square residual (SRMR) = .07, root mean squared error of approximation (RMSEA) = .08, comparative fit index (CFI) = .86, and Tucker-Lewis index (TLI) = .84, and superior fit with recently proposed 6-factor, chi2 (164) = 318.37, p < .001, SRMR = .05, RMSEA = .06, CFI = .92, and TLI = .90, and 7-factor, chi2 (164) = 291.32, p < .001, SRMR = .05, RMSEA = .06, CFI = .93, and TLI = .91, models. In Study 2 (N = 558), PCL-5 scores demonstrated similarly strong reliability and validity. Overall, results indicate that the PCL-5 is a psychometrically sound measure of PTSD symptoms. Implications for use of the PCL-5 in a variety of assessment contexts are discussed. PMID- 26606251 TI - Phase Transition during Heating of Nanostructured Ultrahigh Molecular Weight Polyethylene Membranes. AB - Ultrahigh molecular weight polyethylene (UHMW-PE) membranes were prepared using biaxial melt-drawing and subsequent melt-shrinking. Electron microscopy observations indicate that the former membrane has more extended-chain crystals (ECCs), whereas the latter is mainly composed of folded-chain crystals (FCCs). Corresponding double-melting endotherms are recorded on differential scanning calorimetry (DSC) measurements. Detailed assignments of such double-melting components are performed using in situ X-ray measurements during heating. Wide- and small-angle X-ray diffraction and scattering (WAXD/SAXS) images were simultaneously recorded at SPring-8. Changes in WAXD images indicate that the orthorhombic reflection peak begins to decrease at 130 degrees C, followed by the appearance of the hexagonal reflection peak beyond 145 degrees C for both membranes, but the latter melt-shrunk membrane exhibits weaker hexagonal reflection intensity. Simultaneous SAXS results indicate that FCCs rapidly disappear at 135 degrees C for the melt-shrunk membrane, resulting in a sharper endotherm. In contrast, residual ECCs restrict the melting of FCCs for the melt drawn membrane, resulting in a broader endotherm of FCC melting spread to a slightly higher temperature position. PMID- 26606252 TI - Dual-Stage Consumable-Free Thermal Modulator for the Hyphenation of Thermal Analysis, Gas Chromatography, and Mass Spectrometry. AB - The design of the so-called "Peltier modulator" is presented. It is a new dual stage consumable-free thermal modulator for thermal analysis-gas chromatography mass spectrometry (TA-GC-MS). It requires only electrical power for operation as it facilitates thermo-electric coolers instead of cryogenics for trapping and resistive on-column heating for reinjection. Trapping and desorption temperatures as well as modulation cycles are freely adjustable. The stationary phase for the trapping region can be selected to suit the specific application, since common fused silica capillary is used. The Peltier modulator's performance is demonstrated with a broad range of different standard substances and with heavy crude oil as a complex real life sample. Successful modulation from n-pentane to pyrene (boiling points = 36/394 degrees C) is presented. The produced peaks show the narrowest bandwidths ever reported for a consumable-free thermal modulator, i.e., 12.8 +/- 1.2 ms for n-pentadecane. The Peltier modulator is rugged, cost effective, requires low maintenance, and decreases security issues significantly, compared to commercial available solutions using liquid N2/CO2. PMID- 26606253 TI - Synthesis, Structure, and Bonding for Bis(permethylpentalene)diiron. AB - The synthesis of the first homoleptic double metallocene complex of iron, Fe2Pn*2 (Pn* = permethylpentalene, C8Me6) is described. The structural and electronic properties of Fe2Pn*2 have been characterized by NMR and EPR spectroscopy, single crystal X-ray diffraction, magnetic measurements, cyclic voltammetry, and DFT calculations. Fe2Pn*2 adopts a Ci symmetry in the solid state with a Fe-Fe distance of 2.3175(9) A, slightly lower than the sum of radii in metallic iron. Magnetic measurements in solution, and of the solid phase between 60 and 300 K, indicate that Fe2Pn*2 is a triplet (S = 1) paramagnet, with effective magnetic moments (MUeff) of 3.4 and 3.48 MUB, respectively. DFT calculations indicate the origin of this high magnetic moment is likely to be unquenched orbital angular momentum contributions from two SOMOs which have metal d character. Cyclic voltammetry studies demonstrate that Fe2Pn*2 can access four charge states (-1, 0, +1, +2). PMID- 26606254 TI - Comprehensive Survey of miRNA-mRNA Interactions Reveals That Ccr7 and Cd247 (CD3 zeta) are Posttranscriptionally Controlled in Pancreas Infiltrating T Lymphocytes of Non-Obese Diabetic (NOD) Mice. AB - In autoimmune type 1 diabetes mellitus (T1D), auto-reactive clones of CD4+ and CD8+ T lymphocytes in the periphery evolve into pancreas-infiltrating T lymphocytes (PILs), which destroy insulin-producing beta-cells through inflammatory insulitis. Previously, we demonstrated that, during the development of T1D in non-obese diabetic (NOD) mice, a set of immune/inflammatory reactivity genes were differentially expressed in T lymphocytes. However, the posttranscriptional control involving miRNA interactions that occur during the evolution of thymocytes into PILs remains unknown. In this study, we postulated that miRNAs are differentially expressed during this period and that these miRNAs can interact with mRNAs involved in auto-reactivity during the progression of insulitis. To test this hypothesis, we used NOD mice to perform, for the first time, a comprehensive survey of miRNA and mRNA expression as thymocytes mature into peripheral CD3+ T lymphocytes and, subsequently, into PILs. Reconstruction of miRNA-mRNA interaction networks for target prediction revealed the participation of a large set of miRNAs that regulate mRNA targets related to apoptosis, cell adhesion, cellular regulation, cellular component organization, cellular processes, development and the immune system, among others. The interactions between miR-202-3p and the Ccr7 chemokine receptor mRNA or Cd247 (Cd3 zeta chain) mRNA found in PILs are highlighted because these interactions can contribute to a better understanding of how the lack of immune homeostasis and the emergence of autoimmunity (e.g., T1D) can be associated with the decreased activity of Ccr7 or Cd247, as previously observed in NOD mice. We demonstrate that these mRNAs are controlled at the posttranscriptional level in PILs. PMID- 26606256 TI - Preparation of activated carbons from peach stone by H4P2O7 activation and its application for the removal of Acid Red 18 and dye containing wastewater. AB - The present study consists of the preparation of activated carbon from peach stone (PSAC) by H4P2O7 activation and its detailed characterization. The influence of different activants and various operational conditions including; soaking time, activation time, and activation temperature during PSAC preparation were systematically investigated. The chemical properties and morphology of prepared activated carbon was characterized by various analytical techniques (FTIR, SEM and EDX). TG-DTA analysis showed that the pore development of PSAC was significant at temperatures > 450 degrees C. The prepared PSAC were utilized for the rapid removal and adsorption of Acid Red 18 (AR18) from aqueous solution that follows pseudo-second-order kinetics. The Langmuir isotherm model corresponded well with equilibrium data than the others, implying that the adsorption of AR18 onto prepared PSAC from the aqueous solutions proceeds by a monolayer formation. Thermodynamic investigations showed that the adsorption process is an exothermic and spontaneous process. During reusability studies, PSAC showed complete removal of AR18 upto seventh cycle increasing its practical applicability. Finally the prepared PSAC showed the best adsorptive capacity as compared to commercial AC for dye removal from actual industrial wastewater. This confers the possibility of applying PSAC economically viable option for the treatment of industrial wastewaters containing dye pollutants using suitable reactor. PMID- 26606255 TI - Entrainment of Human Alpha Oscillations Selectively Enhances Visual Conjunction Search. AB - The functional role of the alpha-rhythm which dominates the human electroencephalogram (EEG) is unclear. It has been related to visual processing, attentional selection and object coherence, respectively. Here we tested the interaction of alpha oscillations of the human brain with visual search tasks that differed in their attentional demands (pre-attentive vs. attentive) and also in the necessity to establish object coherence (conjunction vs. single feature). Between pre- and post-assessment elderly subjects received 20 min/d of repetitive transcranial alternating current stimulation (tACS) over the occipital cortex adjusted to their individual alpha frequency over five consecutive days. Compared to sham the entrained alpha oscillations led to a selective, set size independent improvement in the conjunction search task performance but not in the easy or in the hard feature search task. These findings suggest that cortical alpha oscillations play a specific role in establishing object coherence through suppression of distracting objects. PMID- 26606257 TI - Vital Signs: Increased Medicaid Prescriptions for Preexposure Prophylaxis Against HIV infection--New York, 2012-2015. AB - BACKGROUND: Approximately 3,000 incident cases of human immunodeficiency virus (HIV) infection occur in New York state each year. Daily HIV preexposure prophylaxis (PrEP) with the oral antiretroviral medication Truvada is a key component of New York's plan to end HIV/acquired immunodeficiency syndrome (AIDS) as an epidemic in the state by 2020. METHODS: Prescription data from the New York state Medicaid program from July 2012 through June 2015 were analyzed with an algorithm using medication and diagnoses codes to identify continuous use of Truvada for >30 days, after excluding use for postexposure prophylaxis or treatment of HIV or chronic hepatitis B infection. RESULTS: During July 2012-June 2013, a total of 259 persons filled prescriptions for PrEP in the Medicaid program. During July 2013-June 2014, a total of 303 persons filled prescriptions for PrEP. During July 2014-June 2015, a total of 1,330 persons filled prescriptions for PrEP, a substantial increase over the previous 12 months. Across all periods studied, 1,708 Medicaid recipients filled at least one prescription for PrEP, most of whom were New York City (NYC) residents, male, aged <50 years, and, for those with available data on race, white. CONCLUSIONS: PrEP use by Medicaid-insured persons increased substantially in the years following statewide efforts to increase knowledge of PrEP among potential prescribers and candidates for PrEP. Other jurisdictions can follow New York state's example by taking similar steps to remove the financial and knowledge barriers experienced by both potential users and prescribers of PrEP. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Although both state and local health department efforts contribute to the availability and use of PrEP, their collaboration enhances the successful implementation of strategies to increase PrEP use. In addition, the decision by the state Medicaid agency to cover PrEP recognizes the long-term benefits of preventing HIV infections. PMID- 26606258 TI - Enhanced thermoelectric transport in modulation-doped GaN/AlGaN core/shell nanowires. AB - The thermoelectric properties of unintentionally n-doped core GaN/AlGaN core/shell N-face nanowires are reported. We found that the temperature dependence of the electrical conductivity is consistent with thermally activated carriers with two distinctive donor energies. The Seebeck coefficient of GaN/AlGaN nanowires is more than twice as large as that for the GaN nanowires alone. However, an outer layer of GaN deposited onto the GaN/AlGaN core/shell nanowires decreases the Seebeck coefficient at room temperature, while the temperature dependence of the electrical conductivity remains the same. We attribute these observations to the formation of an electron gas channel within the heavily-doped GaN core of the GaN/AlGaN nanowires. The room-temperature thermoelectric power factor for the GaN/AlGaN nanowires can be four times higher than the GaN nanowires. Selective doping in bandgap engineered core/shell nanowires is proposed for enhancing the thermoelectric power. PMID- 26606259 TI - Circulating microRNAs in nonalcoholic fatty liver disease. AB - Liver biopsy is currently recognized as the most accurate method for diagnosing and staging nonalcoholic fatty liver disease (NAFLD). However, this procedure is typically performed when disease has progressed to clinically significant stages, thereby limiting early diagnosis of patients who are at high risk for development of liver- and cardiovascular-related morbidity and mortality. Recently, microRNAs (miRNAs), short, noncoding RNAs that regulate gene expression, have been associated with histological features of NAFLD and are readily detected in the circulation. As such, miRNAs are emerging as potentially useful noninvasive markers with which to follow the progression of NAFLD. In this article, we present the evidence linking circulating miRNAs with NAFLD and discuss the potential value of circulating miRNA profiles in the development of improved methods for NAFLD diagnosis and clinical monitoring of disease progression. PMID- 26606260 TI - Impaired Porphyromonas gingivalis-Induced Tumor Necrosis Factor Production by Dendritic Cells Typifies Patients With Rheumatoid Arthritis. AB - OBJECTIVE: The prevalence of periodontitis is increased in patients with rheumatoid arthritis (RA), and the severity of periodontitis can affect the level of arthritis. Porphyromonas gingivalis is one of the main bacteria involved in periodontitis. Our aim was to determine if there are differences in the innate immune response against P gingivalis between healthy controls and RA patients. METHODS: Monocyte-derived dendritic cells (DCs) from healthy controls, RA patients, and patients with psoriatic arthritis (PsA) were stimulated with P gingivalis, a range of other bacteria, and Toll-like receptor agonists. Cytokine production was determined, and blocking studies were performed to determine which receptors were involved in differential recognition of P gingivalis. Effects on T cell cytokines were also determined in cultures of peripheral blood mononuclear cells (PBMCs). RESULTS: Upon stimulation with P gingivalis, RA patient DCs produced less tumor necrosis factor as compared to healthy control DCs, which was not observed in PsA patients or upon stimulation with other bacteria. In addition, P gingivalis-mediated activation of RA patient PBMCs showed a clear reduction of interferon-gamma production. Among the various possible underlying mechanisms investigated, only blockade of CR3 abolished the difference between RA patients and healthy controls, suggesting the involvement of CR3 in this process. CONCLUSION: Immune cells from RA patients display a reduced response to P gingivalis, which has functional consequences for the immune response. This may result in prolonged survival of P gingivalis, possibly driving autoantibody formation and a self-perpetuating loop of chronic inflammation. The possible role of CR3 in this process warrants further investigation. PMID- 26606261 TI - MicroRNA Profiling Implies New Markers of Gemcitabine Chemoresistance in Mutant p53 Pancreatic Ductal Adenocarcinoma. AB - BACKGROUND: No reliable predictors of susceptibility to gemcitabine chemotherapy exist in pancreatic ductal adenocarcinoma (PDAC). MicroRNAs (miR) are epigenetic gene regulators with tumorsuppressive or oncogenic roles in various carcinomas. This study assesses chemoresistant PDAC for its specific miR expression pattern. METHODS: Gemcitabine-resistant variants of two mutant p53 human PDAC cell lines were established. Survival rates were analyzed by cytotoxicity and apoptosis assays. Expression of 1733 human miRs was investigated by microarray and validated by qRT-PCR. After in-silico analysis of specific target genes and proteins of dysregulated miRs, expression of MRP-1, Bcl-2, mutant p53, and CDK1 was quantified by Western blot. RESULTS: Both established PDAC clones showed a significant resistance to gemcitabine (p<0.02) with low apoptosis rate (p<0.001) vs. parental cells. MiR-screening revealed significantly upregulated (miR-21, miR 99a, miR-100, miR-125b, miR-138, miR-210) and downregulated miRs (miR-31*, miR 330, miR-378) in chemoresistant PDAC (p<0.05). Bioinformatic analysis suggested involvement of these miRs in pathways controlling cell death and cycle. MRP-1 (p<0.02) and Bcl-2 (p<0.003) were significantly overexpressed in both resistant cell clones and mutant p53 (p = 0.023) in one clone. CONCLUSION: Consistent miR expression profiles, in part regulated by mutant TP53 gene, were identified in gemcitabine-resistant PDAC with significant MRP-1 and Bcl-2 overexpression. These results provide a basis for further elucidation of chemoresistance mechanisms and therapeutic approaches to overcome chemoresistance in PDAC. PMID- 26606262 TI - Exploring the Potential of Starch/Polycaprolactone Aligned Magnetic Responsive Scaffolds for Tendon Regeneration. AB - The application of magnetic nanoparticles (MNPs) in tissue engineering (TE) approaches opens several new research possibilities in this field, enabling a new generation of multifunctional constructs for tissue regeneration. This study describes the development of sophisticated magnetic polymer scaffolds with aligned structural features aimed at applications in tendon tissue engineering (TTE). Tissue engineering magnetic scaffolds are prepared by incorporating iron oxide MNPs into a 3D structure of aligned SPCL (starch and polycaprolactone) fibers fabricated by rapid prototyping (RP) technology. The 3D architecture, composition, and magnetic properties are characterized. Furthermore, the effect of an externally applied magnetic field is investigated on the tenogenic differentiation of adipose stem cells (ASCs) cultured onto the developed magnetic scaffolds, demonstrating that ASCs undergo tenogenic differentiation synthesizing a Tenascin C and Collagen type I rich matrix under magneto-stimulation conditions. Finally, the developed magnetic scaffolds were implanted in an ectopic rat model, evidencing good biocompatibility and integration within the surrounding tissues. Together, these results suggest that the effect of the magnetic aligned scaffolds structure combined with magnetic stimulation has a significant potential to impact the field of tendon tissue engineering toward the development of more efficient regeneration therapies. PMID- 26606263 TI - The haemodynamic effects of intravenous paracetamol (acetaminophen) in healthy volunteers: a double-blind, randomized, triple crossover trial. AB - AIM: The haemodynamic effects of intravenous paracetamol have not been systematically investigated. We compared the physiological effects of intravenous mannitol-containing paracetamol, and an equivalent dosage of mannitol, and normal saline 0.9% in healthy volunteers. METHODS: We performed a blinded, triple crossover, randomized trial of 24 adult healthy volunteers. Participants received i.v. paracetamol (1 g paracetamol +3.91 g mannitol 100 ml(-1) ), i.v. mannitol (3.91 g mannitol 100 ml(-1) ) and i.v. normal saline (100 ml). Composite primary end points were changes in mean arterial pressure (MAP), systolic blood pressure (SBP) and diastolic blood pressure (DBP) measured pre-infusion, during a 15 min infusion period and over a 45 min observation period. Systemic vascular resistance index (SVRI) and cardiac index were measured at the same time points. RESULTS: Infusion of paracetamol induced a transient yet significant decrease in blood pressures from pre-infusion values (MAP -1.85 mmHg, 95% CI -2.6, -1.1, SBP 0.54 mmHg, 95% CI -1.7, 0.6 and DBP -1.92 mmHg, 95% CI -2.6, -1.2, P < 0.0001), associated with a transient reduction in SVRI and an increase in cardiac index. Changes were observed, but to a lesser extent with normal saline (MAP -0.15 mmHg, SBP +1.44 mmHg, DBP --0.73 mmHg, P < 0.0001), but not with mannitol (MAP +1.47 mmHg, SBP +4.03 mmHg, DBP +0.48 mmHg, P < 0.0001). CONCLUSIONS: I.v. paracetamol caused a transient decrease in blood pressure immediately after infusion. These effects were not seen with mannitol or normal saline. The physiological mechanism was consistent with vasodilatation. This study provides plausible physiological data in a healthy volunteer setting, supporting transient changes in haemodynamic variables with i.v. paracetamol and justifies controlled studies in the peri operative and critical care setting. PMID- 26606264 TI - The Menace of Schistosomiasis in Nigeria: Knowledge, Attitude, and Practices Regarding Schistosomiasis among Rural Communities in Kano State. AB - BACKGROUND: Schistosomiasis is one of the most common neglected tropical diseases, especially in the developing countries in Africa, Asia and South America, with Nigeria having the greatest number of cases of schistosomiasis worldwide. This community-based study aims to evaluate the knowledge, attitude and practices (KAP) regarding schistosomiasis among rural Hausa communities in Kano State, Nigeria. METHODS: A cross-sectional study was carried out among 551 participants from Hausa communities in five local government areas in Kano State, North Central Nigeria. Demographic, socioeconomic and environmental information as well as KAP data were collected using a pre-tested questionnaire. Moreover, faecal and urine samples were collected and examined for the presence of Schistosoma mansoni and S. haematobium eggs respectively. RESULTS: The overall prevalence of schistosomiasis was 17.8%, with 8.9% and 8.3% infected with S. mansoni and S. haematobium respectively, and 0.5% had co-infection of both species. Moreover, 74.5% of the participants had prior knowledge about schistosomiasis with 67.0% of them how it is transmitted and 63.8% having no idea about the preventive measures. Three-quarters of the respondents considered schistosomiasis a serious disease while their practices to prevent infections were still inadequate, with only 34.7% of them seeking treatment from clinics/hospitals. Significant associations between the KAP and age, gender, education and employment status were reported. Multiple logistic regression analysis revealed that age, gender, history of infection and educational level of the respondents were the most important factors significantly associated with the KAP on schistosomiasis among this population. CONCLUSIONS: Schistosomiasis is still prevalent among Hausa communities in Nigeria and participants' knowledge about the disease was poor. Mass drug administration, community mobilization and health education regarding the cause, transmission and prevention of schistosomiasis and education about good personal and sanitary hygiene practices should be considered in order to significantly reduce the prevalence and morbidity of infection within these communities. PMID- 26606266 TI - Heteropoly Acid/Nitrogen Functionalized Onion-like Carbon Hybrid Catalyst for Ester Hydrolysis Reactions. AB - A novel heteropoly acid (HPA)/nitrogen functionalized onion-like carbon (NOLC) hybrid catalyst was synthesized through supramolecular (electrostatic and hydrogen bond) interactions between the two components. The chemical structure and acid strength of the HPA/NOLC hybrid have been fully characterized by thermogravimetric analysis, IR spectroscopy, X-ray photoelectron spectroscopy, NH3 temperature-programmed desorption and acid-base titration measurements. The proposed method for the fabrication of the HPA/NOLC hybrid catalyst is a universal strategy for different types of HPAs to meet various requirements of acidic or redox catalysis. The hydrophobic environment of NOLC effectively prevents the deactivation of HPA in an aqueous system, and the combination of uniformly dispersed HPA clusters and the synergistic effect between NOLC and HPA significantly promotes its activity in ester hydrolysis reactions, which is higher than that of bare PWA as homogeneous catalyst. The kinetics of the hydrolysis reactions indicate that the aggregation status of the catalyst particles has great influence on the apparent activity. PMID- 26606265 TI - LEMONS - A Tool for the Identification of Splice Junctions in Transcriptomes of Organisms Lacking Reference Genomes. AB - RNA-seq is becoming a preferred tool for genomics studies of model and non-model organisms. However, DNA-based analysis of organisms lacking sequenced genomes cannot rely on RNA-seq data alone to isolate most genes of interest, as DNA codes both exons and introns. With this in mind, we designed a novel tool, LEMONS, that exploits the evolutionary conservation of both exon/intron boundary positions and splice junction recognition signals to produce high throughput splice-junction predictions in the absence of a reference genome. When tested on multiple annotated vertebrate mRNA data, LEMONS accurately identified 87% (average) of the splice-junctions. LEMONS was then applied to our updated Mediterranean chameleon transcriptome, which lacks a reference genome, and predicted a total of 90,820 exon-exon junctions. We experimentally verified these splice-junction predictions by amplifying and sequencing twenty randomly selected genes from chameleon DNA templates. Exons and introns were detected in 19 of 20 of the positions predicted by LEMONS. To the best of our knowledge, LEMONS is currently the only experimentally verified tool that can accurately predict splice-junctions in organisms that lack a reference genome. PMID- 26606267 TI - Temperature and Loading-Dependent Diffusion of Light Hydrocarbons in ZIF-8 as Predicted Through Fully Flexible Molecular Simulations. AB - Accurate and efficient predictions of hydrocarbon diffusivities in zeolitic imidazolate frameworks (ZIFs) are challenging, due to the small pore size of materials such as ZIF-8 and the wide range of diffusion time scales of hydrocarbon molecules in ZIFs. Here we have computationally measured the hopping rates of 15 different molecules (kinetic diameters of 2.66-5.10 A) in ZIF-8 via dynamically corrected transition state theory (dcTST). Umbrella sampling combined with the one-dimensional weighted histogram analysis method (WHAM) was used to calculate the diffusion free energy barriers. Both the umbrella sampling and dynamical correction calculations included ZIF-8 flexibility, which is found to be critical in accurately describing molecular diffusion in this material. Comparison of the computed diffusivities to extant experimental results shows remarkable agreement within an order of magnitude for all the molecules. The dcTST method was also applied to study the effect of hydrocarbon loadings. Self and transport diffusion coefficients of methane, ethane, ethylene, propane, propylene, n-butane, and 1-butene in ZIF-8 are reported over a temperature range of 0-150 degrees C and loadings from infinite dilution to liquid-like loadings. PMID- 26606268 TI - A Meta-Analysis of Sutureless or Rapid-Deployment Aortic Valve Replacement. AB - Objective To summarize the safety of sutureless or rapid-deployment aortic valve replacement (AVR), we performed a systematic review and meta-analysis of single arm studies. Methods MEDLINE and EMBASE were searched through December 2014. Studies considered for inclusion met the following criteria: the design was a single-arm study enrolling >=50 participants; the study population consisted of patients undergoing sutureless/rapid-deployment AVR; and main outcomes included early (in-hospital or 30-day) mortality and/or overall survival. Results Of 250 potentially relevant articles screened initially, 11 eligible studies enrolling a total of 2,066 patients were identified and included. The Enable, Intuity, and Perceval bioprostheses were used in three, two, and six studies, respectively. Mean age of patients was 77.6 years, and 56.9% of patients were women. Mean logistic European System for Cardiac Operative Risk Evaluation I and II were 10.5 and 7.4%, respectively. Aortic cross-clamp times in overall patients, patients undergoing isolated AVR, those undergoing AVR with any concomitant procedures, and those undergoing AVR with coronary artery bypass grafting were 44.7, 41.9, 56.2, and 51.3 minutes, respectively. Arithmetic mean of early mortality was 2.6%, and fixed-effects combined early mortality was 3.2% (95% confidence interval, 2.5-4.2%). Arithmetic mean of 1-year survival was 89.7%, and fixed effects combined 1-year mortality was 10.4% (9.0-12.1%). Conclusion Sutureless/rapid-deployment AVR is feasible and safe with approximate 3 and 10% of early and 1-year mortality, respectively. Large-size randomized controlled trials, however, are needed to determine whether sutureless/rapid-deployment AVR improves mortality compared with conventional AVR. PMID- 26606269 TI - Engaging a Nursing Workforce in Evidence-Based Practice: Introduction of a Nursing Clinical Effectiveness Committee. AB - This column shares the best evidence-based strategies and innovative ideas on how to facilitate the learning of EBP principles and processes by clinicians as well as nursing and interprofessional students. Guidelines for submission are available at http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1741-6787. PMID- 26606270 TI - Variability of Objectively Measured Sedentary Behavior. AB - INTRODUCTION: The primary purpose of this study was to evaluate variability of sedentary behavior (SB) throughout a 7-d measurement period and to determine if <7 d of SB measurement would be comparable with the typical 7-d measurement period. METHODS: Retrospective data from Ball State University's Clinical Exercise Physiology Laboratory on 293 participants (99 men, 55 +/- 14 yr, body mass index = 29 +/- 5 kg.m(-2); 194 women, 51 +/- 12 yr, body mass index = 27 +/- 7 kg.m(-2)) with seven consecutive days of data collected with ActiGraph accelerometers were analyzed (ActiGraph, Fort Walton Beach, FL). Time spent in SB (either <100 counts per minute or <150 counts per minute) and breaks in SB were compared between days and by sex using a two-way repeated-measures ANOVA. Stepwise regression was performed to determine if <7 d of SB measurement were comparable with the 7-d method, using an adjusted R2 of >=0.9 as a criterion for equivalence. RESULTS: There were no differences in daily time spent in SB between the 7 d for all participants. However, there was a significant interaction between sex and days, with women spending less time in SB on both Saturdays and Sundays than men when using the 100 counts per minute cut-point. Stepwise regression showed using any 4 d would be comparable with a 7-d measurement (R2 > 0.90). CONCLUSIONS: When assessed over a 7-d measurement period, SB appears to be very stable from day to day, although there may be some small differences in time spent in SB and breaks in SB between men and women, particularly on weekend days. The stepwise regression analysis suggests that a measurement period as short as 4 d could provide comparable data (91% of variance) with a 1-wk assessment. Shorter assessment periods would reduce both researcher and subject burden in data collection. PMID- 26606271 TI - Fructose Coingestion Does Not Accelerate Postexercise Muscle Glycogen Repletion. AB - BACKGROUND: Postexercise muscle glycogen repletion is largely determined by the systemic availability of exogenous carbohydrate provided. PURPOSE: This study aimed to assess the effect of the combined ingestion of fructose and glucose on postexercise muscle glycogen repletion when optimal amounts of carbohydrate are ingested. METHODS: Fourteen male cyclists (age: 28 +/- 6 yr; Wmax: 4.8 +/- 0.4 W.kg-1) were studied on three different occasions. Each test day started with a glycogen-depleting exercise session. This was followed by a 5-h recovery period, during which subjects ingested 1.5 g.kg-1.h-1 glucose (GLU), 1.2 g.kg-1.h-1 glucose + 0.3 g.kg-1.h-1 fructose (GLU + FRU), or 0.9 g.kg-1.h-1 glucose + 0.6 g.kg-1.h-1 sucrose (GLU + SUC). Blood samples and gastrointestinal distress questionnaires were collected frequently, and muscle biopsy samples were taken at 0, 120, and 300 min after cessation of exercise to measure muscle glycogen content. RESULTS: Plasma glucose responses did not differ between treatments (ANOVA, P = 0.096), but plasma insulin and lactate concentrations were elevated during GLU + FRU and GLU + SUC when compared with GLU (P < 0.01). Muscle glycogen content immediately after exercise averaged 207 +/- 112, 219 +/- 107, and 236 +/- 118 mmol.kg-1 dry weight in the GLU, GLU + FRU, and GLU + SUC treatments, respectively (P = 0.362). Carbohydrate ingestion increased muscle glycogen concentrations during 5 h of postexercise recovery to 261 +/- 98, 289 +/- 130, and 315 +/- 103 mmol.kg-1 dry weight in the GLU, GLU + FRU, and GLU + SUC treatments, respectively (P < 0.001), with no differences between treatments (time * treatment, P = 0.757). CONCLUSIONS: Combined ingestion of glucose plus fructose does not further accelerate postexercise muscle glycogen repletion in trained cyclists when ample carbohydrate is ingested. Combined ingestion of glucose (polymers) plus fructose or sucrose reduces gastrointestinal complaints when ingesting large amounts of carbohydrate. PMID- 26606272 TI - Longitudinal Relationship between Cardiorespiratory Fitness and Academic Achievement. AB - PURPOSE: The aim of this study was to examine the prospective associations between cardiorespiratory fitness (CRF) and academic achievement in the youth. METHODS: The sample included 1286 fifth-, sixth-, and seventh-grade students, age 11 to 14 yr (Mage = 11.3 +/- 1.1), from 14 schools followed for 3 yr. Academic achievement was assessed using the students' marks at baseline and at follow-up 3 yr apart, in Portuguese, mathematics, foreign language (English), and science. CRF was assessed by the Progressive Aerobic Cardiovascular Endurance Run test from the Fitnessgram battery. Students were classified as fit-fit, unfit-fit, fit unfit, and unfit-unfit according to the Progressive Aerobic Cardiovascular Endurance Run test results at baseline and follow-up. Ordinal regression analyses were performed to examine associations between CRF and academic achievement. RESULTS: Being persistently fit (fit-fit), compared with those classified unfit unfit, increased the odds of having high levels of academic achievement in Portuguese (odds ratio (OR) = 3.49; 95% CI, 1.97-6.20; P < 0.001) and foreign language (OR = 2.41; 95% CI, 1.39-4.14; P < 0.01) at follow-up. Students that improved their CRF and became fit (unfit-fit) had also higher odds of achieving better marks than those persistently unfit-unfit in Portuguese (OR = 2.52; 95% CI, 1.42-4.45; P < 0.01) and foreign language (OR = 2.13; 95% CI, 1.23-3.67; P < 0.01). CONCLUSION: Consistently high and improvements in cardiorespiratory fitness are prospectively associated with better academic achievement especially in mother tongue and foreign language. PMID- 26606273 TI - Sensory Enhancing Insoles Modify Gait during Inclined Treadmill Walking with Load. AB - INTRODUCTION: Inclined walking while carrying a loaded backpack induces fatigue, which may destabilize gait and lead to injury. Stochastic resonance (SR) technology has been used to stabilize spatiotemporal gait characteristics of elderly individuals but has not been tested on healthy recreational athletes. Herein, we determined if sustained vigorous walking on an inclined surface while carrying a load destabilizes gait and if SR has a further effect. METHODS: Participants were fitted with a backpack weighing 30% of their body weight and asked to walk at a constant self-selected pace while their feet were tracked using an optical motion capture system. Their shoes were fitted with SR insoles that were set at 90% of the participant's sensory threshold. The treadmill incline was increased every 5 min until volitional exhaustion after which the treadmill was returned to a level grade. SR stimulation was turned ON and OFF in a pairwise random fashion throughout the protocol. Spatiotemporal gait characteristics were calculated when SR was ON and OFF for the BASELINE period, the MAX perceived exertion period, and the POST period. RESULTS: Vigorous activity increases variability in the rhythmic stepping (stride time and stride length) and balance control (double support time and stride width) mechanisms of gait. Overall, SR increased stride width variability by 9% before, during, and after a fatiguing exercise. CONCLUSION: The increased stride time and stride length variability may compromise the stability of gait during and after vigorous walking. However, participants may compensate by increasing double support time and stride width variability to maintain their stability under these adverse conditions. Furthermore, applying SR resulted in an additional increase of stride width variability and may potentially improve balance before, during, and after adverse walking conditions. PMID- 26606274 TI - Test-retest Reproducibility of the Assessment of Motor and Process Skills in Children with Unilateral Cerebral Palsy. AB - AIMS: To examine test-retest reproducibility of the Assessment of Motor and Process Skills (AMPS) in children aged 8-16 years with unilateral cerebral palsy (UCP). METHODS: Thirty children with mild to moderate UCP (mean age = 11y 7m, SD 2y 4m; males = 18; Manual Ability Classification System level I = 10, II = 20; Gross Motor Function Classification System level I = 9, II = 21) enrolled in a large randomized controlled trial were recruited via consecutive series sampling. Children carried out two AMPS tasks over two consecutive days according to standardized AMPS administration procedures. The standard error of measurement (SEM), smallest detectable change (SDC), 95% limits of agreement using the Bland Altman method, and intraclass correlation coefficients (ICC; 2,1) were calculated. RESULTS: The SDC was 0.23 logits for the AMPS motor scale and 0.30 logits for the AMPS process scale. Test-retest reliability was excellent for both the AMPS motor scale (ICC = 0.93) and the AMPS process scale (ICC = 0.86). Intra rater reliability (n = 10) was excellent for AMPS motor scale (ICC = 0.96) and AMPS process scale (ICC = 0.98). CONCLUSIONS: The AMPS can be used by therapists with 8- to 16-year-old children with UCP as an outcome measure with changes in scores reflecting real changes in performance or capacity. PMID- 26606275 TI - Thoracic Hemisection in Rats Results in Initial Recovery Followed by a Late Decrement in Locomotor Movements, with Changes in Coordination Correlated with Serotonergic Innervation of the Ventral Horn. AB - Lateral thoracic hemisection of the rodent spinal cord is a popular model of spinal cord injury, in which the effects of various treatments, designed to encourage locomotor recovery, are tested. Nevertheless, there are still inconsistencies in the literature concerning the details of spontaneous locomotor recovery after such lesions, and there is a lack of data concerning the quality of locomotion over a long time span after the lesion. In this study, we aimed to address some of these issues. In our experiments, locomotor recovery was assessed using EMG and CatWalk recordings and analysis. Our results showed that after hemisection there was paralysis in both hindlimbs, followed by a substantial recovery of locomotor movements, but even at the peak of recovery, which occurred about 4 weeks after the lesion, some deficits of locomotion remained present. The parameters that were abnormal included abduction, interlimb coordination and speed of locomotion. Locomotor performance was stable for several weeks, but about 3-4 months after hemisection secondary locomotor impairment was observed with changes in parameters, such as speed of locomotion, interlimb coordination, base of hindlimb support, hindlimb abduction and relative foot print distance. Histological analysis of serotonergic innervation at the lumbar ventral horn below hemisection revealed a limited restoration of serotonergic fibers on the ipsilateral side of the spinal cord, while on the contralateral side of the spinal cord it returned to normal. In addition, the length of these fibers on both sides of the spinal cord correlated with inter- and intralimb coordination. In contrast to data reported in the literature, our results show there is not full locomotor recovery after spinal cord hemisection. Secondary deterioration of certain locomotor functions occurs with time in hemisected rats, and locomotor recovery appears partly associated with reinnervation of spinal circuitry by serotonergic fibers. PMID- 26606276 TI - Exposure to the lampricide 3-trifluoromethyl-4-nitrophenol results in increased expression of carbohydrate transporters in Saccharomyces cerevisiae. AB - The lampricide 3-trifluoromethyl-4-nitrophenol (TFM) is used to control sea lamprey (Petromyzon marinus) populations in freshwater lakes. Although TFM can have sublethal and lethal effects, little is known about gene expression changes with TFM exposure. Microarray analysis was used to determine differential gene expression over 4 h of exposure in Saccharomyces cerevisiae. Among the most significantly up-regulated genes were regulators of carbohydrate transport, including HXT1, HXT3, HXT4, IMA5, MIG2, and YKR075C. Environ Toxicol Chem 2016;35:1727-1732. (c) 2015 SETAC. PMID- 26606277 TI - Perceptual-Speech, Nasometric, and Cephalometric Results After Modified V-Y Palatoplasties With or Without Mucosal Graft. AB - OBJECTIVE: Although the goal of cleft palate (CP) repair is to achieve normal speech, no standard procedure ensures that patients' speech will be at the same level as speech in children without CP. In this study, postoperative speech outcomes following primary CP repair combined with or without a mucosal graft was analyzed in comparison with that of control subjects without CP. PARTICIPANTS: Eighty-two patients who underwent modified V-Y palatoplasty with a mucosal graft on the nasal side for symmetrical muscular reconstruction during 2006-2012 (MG group) and 109 patients who previously underwent modified V-Y palatoplasty without a mucosal graft (non-MG group) were enrolled in this study. Speech data on 37 Japanese subjects without CP were used as a control. MAIN OUTCOME MEASURES: Perceptual rating of resonance and nasal emission and nasometry were carried out for all participants. Furthermore, cephalometric analyses were performed to assess postoperative velopharyngeal morphology and velar movement. RESULTS: Normal resonance was achieved at a significantly higher rate (90.3% of patients) in the MG group than in the non-MG group (68.8%) (P < .01). The mean nasalance scores in the MG group were significantly lower (P < .01) and were almost at the same level as in controls. Cephalometric analyses revealed a greater velar length and velar elevation angle during phonation in the MG group (P < .01 and P < .05, respectively). CONCLUSIONS: Modified V-Y palatoplasty combined with a mucosal graft on the nasal side of the velum for symmetrical muscular reconstruction facilitates speech outcomes for children with cleft palate that are comparable with those for peers without CP. PMID- 26606278 TI - In vivo measurements of limbic glutamate and GABA concentrations in epileptic patients during affective and cognitive tasks: A microdialysis study. AB - Limbic system structures such as the amygdala (AMG) and the hippocampus (HIPP) are involved in affective and cognitive processing. However, because of the limitations in noninvasive technology, absolute concentrations of the neurotransmitters underlying limbic system engagement are not known. Here, we report changes in the concentrations of the neurotransmitters glutamate (Glu) and gamma-aminobutyric acid (GABA) in the HIPP and the AMG of patients with nonlesional temporal lobe epilepsy undergoing surgery for intracranial subdural and depth electrode implantation. We utilized an in-vivo microdialysis technique while subjects were engaged in cognitive tasks with or without emotional content. The performance of an emotion learning task (EmoLearn) was associated with a significant increase in the concentration of glutamate in the HIPP when images with high valence content were processed, as compared to its concentration while processing images with low valence. In addition, significantly decreased levels of glutamate were found in the AMG when images with predominantly low valence content were processed, as compared to its concentration at baseline. The processing of face stimuli with anger/fear content (FaceMatch task) was accompanied with significantly decreased concentrations of GABA in the AMG and HIPP compared to its levels at the baseline. The processing of shapes on the other hand was accompanied with a significantly decreased concentration of the glutamate in the AMG as well as in the HIPP compared to the baseline. Finally, the performance of a nondeclarative memory task (weather prediction task-WPT) was associated with relatively large and opposite changes in the GABA levels compared to the baseline in the AMG (decrease) and the HIPP (increase). These data are relevant for showing an involvement of the amygdala and the hippocampus in emotional processing and provide additional neurochemical clues towards a more refined model of the functional circuitry of the human limbic system. PMID- 26606279 TI - The High Stakes of Postoperative Clostridium difficile Infection. PMID- 26606280 TI - Cellular events during scar-free skin regeneration in the spiny mouse, Acomys. AB - In contrast to the lab mouse, Mus musculus, several species of spiny mouse, Acomys, can regenerate epidermis, dermis, hairs, sebaceous glands with smooth muscle erector pili muscles and skeletal muscle of the panniculus carnonsus after full thickness skin wounding. Here, we have compared the responses of these scarring and nonscarring organisms concentrating on the immune cells and wound cytokines, cell proliferation, and the collagenous components of the wound bed and scar. The blood of Acomys is very neutropenic but there are greater numbers of mast cells in the Acomys wound than the Mus wound. Most importantly there are no F4/80 macrophages in the Acomys wound and many proinflammatory cytokines are either absent or in very low levels which we suggest may be primarily responsible for the excellent regenerative properties of the skin of this species. There is little difference in cell proliferation in the two species either in the epidermis or mesenchymal tissues but the cell density and matrix composition of the wound is very different. In Mus there are 8 collagens which are up-regulated at least 5-fold in the wound creating a strongly trichrome-positive matrix whereas in Acomys there are very few collagens present and the matrix shows only light trichrome staining. The major component of the Mus matrix is collagen XII which is up-regulated between 10 and 30-fold after wounding. These results suggest that in the Acomys wound the absence of many cytokines resulting in the lack of macrophages is responsible for the failure to up-regulate fibrotic collagens, a situation which permits a regenerative response within the skin rather than the generation of a scar. PMID- 26606281 TI - EHR based Genetic Testing Knowledge Base (iGTKB) Development. AB - BACKGROUND: The gap between a large growing number of genetic tests and a suboptimal clinical workflow of incorporating these tests into regular clinical practice poses barriers to effective reliance on advanced genetic technologies to improve quality of healthcare. A promising solution to fill this gap is to develop an intelligent genetic test recommendation system that not only can provide a comprehensive view of genetic tests as education resources, but also can recommend the most appropriate genetic tests to patients based on clinical evidence. In this study, we developed an EHR based Genetic Testing Knowledge Base for Individualized Medicine (iGTKB). METHODS: We extracted genetic testing information and patient medical records from EHR systems at Mayo Clinic. Clinical features have been semi-automatically annotated from the clinical notes by applying a Natural Language Processing (NLP) tool, MedTagger suite. To prioritize clinical features for each genetic test, we compared odds ratio across four population groups. Genetic tests, genetic disorders and clinical features with their odds ratios have been applied to establish iGTKB, which is to be integrated into the Genetic Testing Ontology (GTO). RESULTS: Overall, there are five genetic tests operated with sample size greater than 100 in 2013 at Mayo Clinic. A total of 1,450 patients who was tested by one of the five genetic tests have been selected. We assembled 243 clinical features from the Human Phenotype Ontology (HPO) for these five genetic tests. There are 60 clinical features with at least one mention in clinical notes of patients taking the test. Twenty-eight clinical features with high odds ratio (greater than 1) have been selected as dominant features and deposited into iGTKB with their associated information about genetic tests and genetic disorders. CONCLUSIONS: In this study, we developed an EHR based genetic testing knowledge base, iGTKB. iGTKB will be integrated into the GTO by providing relevant clinical evidence, and ultimately to support development of genetic testing recommendation system, iGenetics. PMID- 26606283 TI - Synthesis and Activity of 6"-Deoxy-6"-thio-alpha-GalCer and Peptide Conjugates. AB - A major challenge in the development of highly defined synthetic vaccines is the codelivery of vaccine components (i.e., antigen and adjuvant) to secondary lymphoid tissue to induce optimal immune responses. This problem can be addressed by synthesizing vaccines that comprise peptide antigens covalently attached to glycolipid adjuvants through biologically cleavable linkers. Toward this, a strategy utilizing previously unreported 6"-deoxy-6"-thio analogues of alpha GalCer that can undergo chemoselective conjugation with peptide antigens is described. Administration of these conjugate vaccines leads to enhanced priming of antigen specific T cells. This simple vaccine design is broadly applicable to multiple disease indications such as cancer and infectious disease. PMID- 26606282 TI - A Comparative Analysis of Gene Expression Profiles during Skin Regeneration in Mus and Acomys. AB - The African spiny mouse (Acomys spp.) can heal full thickness excisional skin wounds in a scar-free manner with regeneration of all dermal components including hair and associated structures. Comparing Acomys scar-free healing from Mus scarring identifies gene expression differences that discriminate these processes. We have performed an extensive comparison of gene expression profiles in response to 8mm full-thickness excisional wounds at days 3, 5, 7 and 14 post wounding between Acomys and Mus to characterize differences in wound healing, and identify mechanisms involved in scar-free healing. We also identify similarities with scar-free healing observed in fetal wounds. While wounding in Mus elicits a strong inflammatory response, wounding in Acomys produces a moderated immune response and little to no increase in expression for most cytokines and chemokines assayed. We also identified differences in the ECM profiles of the Acomys wounds, which appear to have a collagen profile more similar to fetal wounds, with larger increases in expression of collagen types III and V. In contrast, Mus wounds have very high levels of collagen XII. This data suggests that an overall lack of induction of cytokines and chemokines, coupled with an ECM profile more similar to fetal wounds, may underlie scar-free wound healing in Acomys skin. These data identify candidate genes for further testing in order to elucidate the causal mechanisms of scar-free healing. PMID- 26606284 TI - Interrelationships Among Three Avoidant Coping Styles and Their Relationship to Trauma, Peritraumatic Distress, and Posttraumatic Stress Disorder. AB - Research suggests the existence of distinct avoidant coping mechanisms after trauma: peritraumatic dissociation, secondary alexithymia, and experiential avoidance. Within the Emotional Processing Model (Foa and Kozak, Psychol Bull. 99:20-35, 1986), research suggests that each of these avoidant coping mechanisms comes into play at a different phase of traumatic stress development. The present study sought to confirm if these three avoidant coping mechanisms are different constructs and how they relate to each other and the experience of trauma, peritraumatic distress, and posttraumatic stress disorder (PTSD). A total of 227 participants with a trauma history completed measures on trauma experience, peritraumatic distress, peritraumatic dissociation, secondary alexithymia, experiential avoidance, and PTSD. Structural equation modeling confirmed that peritraumatic dissociation, secondary alexithymia, and experiential avoidance influence different phases of the development of traumatic stress problems. These results also confirm that the Emotional Process Model provides a good context for understanding the interrelationships among the avoidant coping mechanisms. PMID- 26606285 TI - Analysis of Bone Repair and Inflammatory Process Caused by Simvastatin Combined With PLGA+HA+betaTCP Scaffold. AB - PURPOSE: This study evaluated the tissue and inflammatory responses to the use of simvastatin and poly(lactic-co-glycolic acid) + hydroxyapatite + beta-tricalcium phosphate (PLGA+HA+betaTCP) scaffold for bone repair. MATERIALS AND METHODS: Two defects of 5 mm in diameter were made in the calvaria of rats, which were shared into the following 6 groups: naive, sham, vehicle, PLGA+HA+betaTCP scaffold, simvastatin (4 mg/mL), and simvastatin with the scaffold. Tissue samples were collected at 1, 7, 15, 30, and 60 days after surgery. Inflammation was evaluated by interleukin-1 beta and tumor necrosis factor alpha quantification and by a hemogram, whereas bone repair was evaluated using densitometry and scanning electron microscopy. Data were statistically analyzed using ANOVA followed by post hoc tests (P < 0.05). RESULTS: There was an increased cytokine expression in the scaffold and simvastatin groups (P < 0.001 and P < 0.05, respectively) 1 day after surgery but no alterations on the hemogram were observed. It was found on bone tissue samples that 60 days after surgery all groups presented similar densitometry values and morphology characteristics, despite the occurrence of bone formation delay in the simvastatin group (P < 0.01). CONCLUSION: The use of simvastatin and PLGA+HA+betaTCP scaffold, associated or not, did not lead to improvement in bone repair. PMID- 26606286 TI - Bone Regenerative Efficacy of Limited-Dose Escherichia Coli-Derived rhBMP-2 With Biphasic Calcium Phosphate Carrier in Rabbit Calvarial Defect Model. AB - PURPOSE: The aim of this study was to characterize the healing in rabbit calvarial bone defects after delivery of limited-dose (1.5 MUg) Escherichia coli derived recombinant human bone morphogenetic protein-2 (ErhBMP-2), and evaluate biphasic calcium phosphate (BCP) as a carrier. MATERIALS AND METHODS: Four 8-mm diameter circular calvarial bone defects were made in 16 rabbits and filled with one of the following: (1) nothing, (2) BCP alone, (3) ErhBMP-2-loaded absorbable collagen sponge (ACS), or (4) ErhBMP-2-loaded BCP. The animals were allowed to heal for either 2 or 8 weeks and were evaluated in clinical, microcomputed tomographic, histological, and histomorphometric analyses. RESULTS: Microcomputed tomography revealed extensive new bone formation in both of the limited-dose ErhBMP-2-loaded groups. However, bony collapse of the upper defect borders was found in the ErhBMP-2-loaded ACS group. Histomorphometric examination revealed significantly greater new bone formation at 8 weeks than at 2 weeks in all 4 groups (P < 0.05). Both new bone formation and the size of the augmented area differed significantly between the ErhBMP-2-loaded BCP group (6.88 +/- 0.74 and 19.62 +/- 0.77) and the ErhBMP-2-loaded ACS group (3.04 +/- 0.27 and 5.41 +/- 0.43) at 8 weeks of healing. CONCLUSION: ErhBMP-2 promotes bone regeneration in rabbit calvarial defects, even at a limited dose (1.5 MUg). The results of this study suggest that BCP is the more efficient carrier for this protein than ACS. PMID- 26606287 TI - Synthesis, crystal structure, DNA and protein binding studies of novel binuclear Pd(II) complex of 6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde-4(N,N) dimethylthiosemicarbazone. AB - A novel binuclear palladium(II) complex [(AsPh3)2ClPd(L)PdCl] (LPd2) has been synthesized by reacting 2-oxo-1,2-dihydroquinoline-3-carbaldehyde-4(N,N) dimethylthiosemicarbazone (HL) with [PdCl2(AsPh3)2], and the molecular structure was confirmed by single crystal X-ray diffraction studies. The DNA interactions of the free ligand and of the complex have been evaluated by absorption and ethidium bromide (EB) competitive studies which revealed that the complex could interact with calf thymus DNA (CT-DNA) through intercalation. In addition, the interactions with bovine serum albumin (BSA) were also studied showing that the new binuclear palladium complex had a strong binding affinity with BSA. PMID- 26606288 TI - Uncovering novel 3-hydroxy-4-pyridinone metal ion complexes with potential anti inflammatory properties. AB - Ligands of the 3-hydroxy-4-pyridinone (3,4-HPO) type, with one (Hmpp) or two methyl groups (Hdmpp), have been reported to possess biomedical, chemical and analytical applications. In this first screening study aiming to uncover new promising agents to mitigate the oxidative damage highly present in several metabolic disorders, such as diabetes mellitus, we assessed the potential of twelve 3,4-HPO metal ion complexes to modulate oxidative burst in human neutrophils. Metal ion 3,4-HPO complexes of Ni, Fe, V, Co, Cu and Zn were synthesized and tested up to 15MUM. Among all the compounds, [Cu(mpp)2] and [Cu(dmpp)2] exhibited the highest scavenging capacity against superoxide radical (O2(-)) (IC50=0.36+/-0.07 and 0.30+/-0.06MUM, respectively) and against hypochlorous acid (HOCl) (IC50=0.6+/-0.3 and 0.4+/-0.1MUM, respectively). In the particular case of O2(-), [Fe(mpp)3] and [Fe(dmpp)3] (both at 15MUM) presented 35% and 22% of inhibition, respectively, while all the other compounds were neither able to scavenge O2(-) nor stimulate its production. Regarding the scavenging capacity against hydrogen peroxide (H2O2), all the compounds showed low efficiency (from 6-39%). Finally, with exception of [VO(mpp)2] and [VO(dmpp)2], all compounds exhibited scavenging activity against HOCl (39-81%) and the most efficient compounds were Cu(II) and Zn(II) complexes. Thus, these preliminary results uncover promising new metal ion complexes, inhibitors of neutrophil's oxidative burst, with potential anti-inflammatory properties, which may be seen as an useful strategy for further studies in the treatment of a number of diseases where oxidative damage is a serious issue. PMID- 26606289 TI - Water soluble heterometallic potassium-dioxidovanadium(V) complexes as potential antiproliferative agents. AB - Two water soluble heterometallic potassium-dioxidovanadium polymers, [KVO2(L1)]n (1) and [KVO2(L2)(H2O)]n (2) [H2L1= (2,3-dihydroxybenzylidene)-2 hydroxybenzohydrazide and H2L2=(2,3-dihydroxybenzylidene)benzohydrazide], have been synthesized and characterized by IR, NMR, elemental analysis and single crystal X-ray diffraction. The antiproliferative potentials of 1 and 2 were examined towards human colorectal carcinoma (HCT116), and lung (A549) and breast (MCF7) adenocarcinoma cell lines. 1 exhibits a high cytotoxic activity against colorectal carcinoma cells (HCT116), with IC50 lower than those for cisplatin. PMID- 26606290 TI - Specific binding modes of Cu(I) and Ag(I) with neurotoxic domain of the human prion protein. AB - Prion diseases are neurodegenerative disorders associated with a conformational change of the normal cellular isoform of the prion protein (PrP(C)) to an abnormal scrapie isoform (PrP(Sc)). human prion protein (hPrP(C)) is able to bind up to six Cu(II) ions. Four of them are distributed in the octarepeat domain, containing four tandem-repetitions of the sequence PHGGGWGQ. Immediately outside the octarepeat domain, in so called PrP amyloidogenic region, two additional and independent Cu(II) binding sites, encompassing His96 and His111 residues, respectively, are present. Considering the potential involvement of PrP in cellular redox homeostasis, investigations on Cu(I)-PrP interaction might be also biologically relevant. Interestingly, the amyloidogenic fragment of PrP contains a -M(X)nM- motif, known to act as Cu(I) binding site in different proteins. In order to shed more light on this issue, copper(I) and silver(I) interactions with model peptides derived from that region were analyzed. The results of our studies reveal that both metal ions are anchored to two thioether sulfurs of Met109 and Met112, respectively. Subsequent metal interaction and coordination to His96 and His111 imidazoles are primarily found for Cu(I) at physiological pH. Metal binding was also investigated in the presence of negatively charged micelles formed by the anionic surfactant, sodium dodecyl sulfate (SDS). Our results strongly support that metal binding mode strongly depends on the protein backbone structure. In particular we show that alpha-helix structuring of the amyloid PrP domain influences both the metal coordination sphere and the binding affinity. PMID- 26606291 TI - Pd(2+)-mediated base pairing in oligonucleotides. AB - Two short glycol nucleic acid (GNA) oligonucleotides, having either a terminal or an intrachain nucleobase replaced by the pyridine-2,6-dicarboxamide chelate of Pd(2+), have been synthesized and their hybridization properties studied by melting temperature measurements. In the termini of a double-stranded oligonucleotide, the Pd(2+) chelates provided dramatic stabilization of the duplex relative to its metal-free counterpart, in all likelihood owing to formation of Pd(2+)-mediated base pairs between pyridine-2,6-dicarboxamide and the opposing nucleobase. In contrast, no stabilization was observed when the Pd(2+) chelate was placed in the middle of the chain. Furthermore, the results could not be reproduced by adding a Pd(2+) salt in situ to the dilute oligonucleotide solutions but the palladated oligonucleotides had to be synthesized and purified prior to the hybridization studies. This behavior, presumably attributable to the relatively slow ligand-exchange reactions of Pd(2+), differs greatly from what is usually observed with more labile metal ions. The present results offer an explanation for the failure of previous attempts to incorporate Pd(2+)-mediated base pairs into oligonucleotides. PMID- 26606292 TI - Cytochrome unfolding pathways from computational analysis of crystal structures. AB - We have developed a model to study the role of geometrical factors in influencing the early stages of unfolding in three cytochromes: cyt c', cyt c-b562 and cyt c. Each stage in unfolding is quantified by the spatial extension lambdai of n residue segments, and by their angular extension . Similarities and differences between and among the three cytochromes in the unfolding of helical and non-helical regions can be determined by analyzing the data for each signature separately. Definite conclusions can be drawn when spatial and angular changes are considered in tandem. To facilitate comparisons, we present graphical portraits of the three cytochromes at the same stage of unfolding, and in relation to their native state structures. We also display specific segments at different stages of unfolding to illustrate differences in stability of defined domains thereby allowing us to make specific predictions on the unfolding of corresponding internal and terminal helices in cyt c' and cyt c-b562. Our work accords with an earlier experimental report on the presence and persistence of a hydrophobic core in cyt c. PMID- 26606293 TI - Transepithelial Corneal Cross-Linking With Vitamin E-Enhanced Riboflavin Solution and Abbreviated, Low-Dose UV-A: 24-Month Clinical Outcomes. AB - PURPOSE: To report the clinical outcomes with 24-month follow-up of transepithelial cross-linking using a combination of a D-alpha-tocopheryl polyethylene-glycol 1000 succinate (vitamin E-TPGS)-enhanced riboflavin solution and abbreviated low fluence UV-A treatment. METHODS: In a nonrandomized clinical trial, 25 corneas of 19 patients with topographically proven, progressive, mild to moderate keratoconus over the previous 6 months were cross-linked, and all patients were examined at 1, 3, 6, 12, and 24 months. The treatments were performed using a patented solution of riboflavin and vitamin E-TPGS, topically applied for 15 minutes, followed by two 5-minute UV-A treatments with separate doses both at fluence below 3 mW/cm(2) that were based on preoperative central pachymetry. RESULTS: During the 6-month pretreatment observation, the average Kmax increased by +1.99 +/- 0.29 D (diopter). Postoperatively, the average Kmax decreased, changing by -0.55 +/- 0.94 D, by -0.88 +/- 1.02 D and by -1.01 +/- 1.22 D at 6, 12, and 24 months. Postoperatively, Kmax decreased in 19, 20, and 20 of the 25 eyes at 6 months, 12 months, and 24 months, respectively. Refractive cylinder was decreased by 3 months postoperatively and afterward, changing by 1.35 +/- 0.69 D at 24 months. Best spectacle-corrected visual acuity (BSCVA) improved at 6, 12, and 24 months, including an improvement of -0.19 +/- 0.13 logarithm of the minimum angle of resolution units at 24 months. There was no reduction in endothelial cell count. No corneal abrasions occurred, and no bandage contact lenses or prescription analgesics were used during postoperative recovery. CONCLUSIONS: Transepithelial cross-linking using the riboflavin-vitamin E solution and brief, low-dose, pachymetry-dependent UV-A treatment safely stopped keratoconus progression. PMID- 26606294 TI - Effect of Intravitreal Injection of Methotrexate on Human Corneal Endothelial Cells. AB - PURPOSE: To evaluate the toxic effect of intravitreal methotrexate on human corneal endothelium. METHODS: In this prospective noncomparative interventional case series, intravitreal injection of 400 MUg methotrexate was performed in eyes with persistent diabetic macular edema. Corneal endothelial cell analyses and central corneal thickness measurements were performed before and 1, 3, and 6 months after injections, using noncontact specular microscopy. RESULTS: Twenty one eyes of 18 patients with a mean age of 60.5 +/- 6.8 years were evaluated. No statistically significant difference was found in endothelial cell density, coefficient of variation, average cell area, hexagonality, and central corneal thickness measurements before and after injections (P = 0.70, 0.39, 0.43, 0.64, and 0.67, respectively). CONCLUSIONS: In this 6-month follow-up study, intravitreal injection of 400 MUg methotrexate had no significant effect on corneal endothelial cell measurements performed by specular microscopy. PMID- 26606295 TI - Corneal Surface and Superficial Cells as Viewed by Scanning Electron Microscopy and Impression Cytology Sampling. AB - PURPOSE: To objectively compare sizes of corneal epithelial surface cells visualized by scanning electron microscopy (SEM) or collected by impression cytology (IC). METHODS: Corneas of recent postmortem sheep eyes were either glutaraldehyde fixed for SEM or IC samples taken, glutaraldehyde fixed, and then stained with Giemsa. The corneal epithelial surface was examined at *200, with the borders of all cells marked and dimensions and areas measured. For SEM, the cells were classified as having light, medium, or dark electron reflex and by the number of cell sides. RESULTS: SEM revealed a mosaic of polygonal features with different electron reflexes according to the density of cell surface microplicae. The cell area and longest dimension were predictably dependent on the number of cell sides. Compared with the overall average cell area of 1598 MUm(2) (range 200 3900 MUm(2)), the dark reflex cells were predominantly the largest, with an average area of 2435 MUm(2) and having the average longest dimension of 59.9 MUm(2). Cells collected by IC had a range of areas from 1150 to 4800 MUm(2) but were predominantly large and had an average area of 2802 MUm(2) with the average cell longest dimension averaging 64.4 MUm(2). IC-sampled cells had nucleocytoplasmic ratio values consistent with their having a squamous phenotype. CONCLUSIONS: Cells sampled by IC from the corneal epithelial surface are predominantly those that are enlarged (and flattened out) in preparation for desquamation, a feature also attributed to the dark reflex cells seen in SEM. PMID- 26606296 TI - Role of the Mannose Receptor During Aspergillus fumigatus Infection and Interaction With Dectin-1 in Corneal Epithelial Cells. AB - PURPOSE: To investigate the expression and function of the mannose receptor (MR) and to explore its interaction with dectin-1 in human corneal epithelial cells (HCECs) exposed to Aspergillus fumigatus. METHODS: HCECs were stimulated with A. fumigatus for 0, 4, 8, 12, 16, and 24 hours. MR expression was tested by the polymerase chain reaction, Western blot, and immunohistochemistry. HCECs were pretreated with 2 MUg/mL MR-blocking antibody. The expressions of p38, phosphorylated p38 (p-p38), and the downstream cytokines (TNF-alpha and IL-1beta) and dectin-1 were tested by the polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay. HCECs were pretreated with dectin-1 agonists (curdlan, 100 MUg/mL) and inhibitors (laminarin, 10 MUg/mL), and the expression of the MR was tested. RESULTS: MR expression was upregulated after stimulation with A. fumigatus. MR mRNA and protein levels began to rise at 8 and 16 hours, respectively. Stronger immunostaining of the MR was observed in fungal-infected corneal epithelium than in normal corneal epithelium. Aspergillus fumigatus increased the production of TNF-alpha (11-fold, 4-fold of the control), IL-1beta (4.7-fold, 3-fold of the control), p-p38 (2.1-fold of the control), and dectin-1 (2.3-fold, 2-fold of the control) in mRNA and protein levels. The MR antibody significantly suppressed the expression of TNF-alpha (28%, 50% reduction), IL 1beta (38%, 42% reduction), p-p38 (38% reduction), and dectin-1 (48%, 47% reduction). Curdlan increased the production of the MR (1.5-fold, 1.9-fold of the control), whereas laminarin decreased the expression of the MR (50%, 60% reduction) induced by A. fumigatus. CONCLUSIONS: HCECs express the MR, and A. fumigatus infection can increase MR expression. A. fumigatus induces the expression of inflammatory cytokines through the MR and p38 MAPK pathway. The expression of dectin-1 and the MR had mutual influence. PMID- 26606297 TI - Corneal Tattooing and Anterior Stromal Puncture for Treating Symptomatic Bullous Keratopathy. AB - PURPOSE: To investigate the efficacy of corneal tattooing, through anterior stromal puncture (ASP), for managing painful bullous keratopathy (BK). METHODS: This retrospective, case-controlled, consecutive case series study was performed at a university-based referral clinic. Patients with painful BK who underwent corneal tattooing with Chinese ink between 2007 and 2013 were included in analyses. Patients diagnosed with symptomatic BK who only underwent ASP during the same period were included as a control group. RESULTS: A total of 40 patients (27 men, 13 women) with a mean age of 57.5 +/- 15.3 years were included in analyses. The clinical diagnosis was pseudophakic BK in 5 subjects (12.5%), failed graft in 11 subjects (27.5%), BK secondary to perforating corneal injury repair in 19 subjects (47.5%), and end-stage glaucoma in 5 subjects (12.5%). Subjects were followed for a mean period of 26.4 +/- 7.5 months (range: 6-55 months). Recurrent bullae formation occurred in 3 of 31 patients (9.68%) who had undergone corneal tattooing and in all 9 patients (100%) who had undergone ASP (P < 0.001). CONCLUSIONS: Corneal tattooing with Chinese ink is a simple, effective outpatient procedure for treating painful BK in eyes with no visual potential. PMID- 26606298 TI - Follicular Lymphoma Presenting Solely as Chronic Follicular Conjunctivitis. AB - PURPOSE: Conjunctival lymphoma rarely can have atypical clinical presentations. The authors report a case of conjunctival follicular lymphoma that presented solely as bilateral chronic follicular conjunctivitis. This case underscores that the pathological characteristics of conjunctival follicles can only be determined by histopathologic examination. METHODS: The patient underwent conjunctival scraping and biopsy after clinical history and examination failed to reveal the etiology of his chronic, symptomatic, follicular conjunctivitis. RESULTS: Histopathologic and immunohistochemical testing disclosed a bilateral low-grade conjunctival follicular lymphoma. The patient was treated with radiation therapy and remained in remission clinically 6 months after the treatment. CONCLUSIONS: Although rare, conjunctival lymphoma should be included in the differential diagnosis of chronic follicular conjunctivitis. This case is unique and further supports the notion that tissue biopsy may be needed for chronic, symptomatic conjunctivitis of unknown etiology. PMID- 26606299 TI - Overestimation of Corneal Endothelial Cell Density in Smaller Frame Sizes in In Vivo Confocal Microscopy. AB - PURPOSE: To evaluate the effect of frame size on the calculated corneal endothelial cell density (CECD) in images of laser scanning in vivo confocal microscopy (IVCM). METHODS: Forty-nine corneal endothelial images acquired by laser scanning IVCM (Heidelberg Retina Tomograph 3 with Rostock Corneal Module) with different endothelial cell densities were analyzed. In each image (160,000 MUm), the CECD was calculated using the fixed-frame method by counting cells in the following frame sizes: 80,000 MUm, 40,000 MUm, 20,000 MUm, 10,000 MUm, 5000 MUm, and 2500 MUm. The calculated CECD was then compared with that of the variable-frame method as the reference value. RESULTS: There was no significant difference in the calculated CECD between the variable-frame method (2004 +/- 832 cells/mm), and the fixed-frame method using a 40,000-MUm frame (2023 +/- 810 cells/mm). On the other hand, the calculated CECD showed significant overestimations in frame sizes of 20,000 MUm (2066 +/- 820 cells/mm), 10,000 MUm (2156 +/- 785 cells/mm), 5000 MUm (2352 +/- 783 cells/mm), and 2500 MUm (2715 +/- 754 cells/mm), with P < 0.001 in all. This resulted in overestimations of 4.8 +/- 9.8%, 11.9 +/- 16.2%, 24.9 +/- 23.1%, and 49.1 +/- 38.8% for these frame sizes, respectively. Images with lower CECD demonstrated higher overestimations of cell density in smaller frame sizes. CONCLUSIONS: In laser scanning IVCM images, there is significant overestimation of CECD if the cells are counted in frames smaller than 25% of the image. Similar frame sizes should be used when monitoring CECD over time. PMID- 26606300 TI - Nice Ink. PMID- 26606301 TI - EEG MU rhythm in virtual reality reveals that motor coding of visual objects in peripersonal space is task dependent. AB - Previous fMRI studies have shown that the visual perception of manipulable objects spontaneously involves the sensorimotor system, especially when the objects are located in peripersonal space. However, it has also been suggested that the motor coding of manipulable objects perceived in peripersonal space depends on an anticipation to interact with them. The present study aims at clarifying this issue by analyzing healthy adults' EEG activity on the centro parietal region while perceptually judging intrinsic (prototypical or distorted shape) or extrinsic (reachable or not reachable location) properties of visual objects. In both the object identification and reachability judgment tasks, time frequency decomposition of EEG signals was performed across the first 1000 ms following object presentation for trials on which no post-stimulus response was required (90% of the trials). Event-Related-(De)Synchronization (ERD/S) of MU rhythm was computed using the 150 ms pre-stimulus period as baseline. In the reachability judgment task, EEG analysis showed a desynchronization of MU rhythm starting 300 ms after object presentation, but only when the objects were presented with a prototypical shape in peripersonal space. For those objects, desynchronization of MU rhythm diminished progressively from peripersonal to extrapersonal space. By contrast, no such gradient was observed in the object identification task. On the whole, these data indicate that motor coding of visual objects expressed in the MU rhythm depends on an object's shape and location in space, but also on the goal of the perceptual task. PMID- 26606302 TI - Cytotechnologist Performance for Screening Hurthle Cell Atypia in Indeterminate Thyroid Fine-Needle Aspirates. AB - OBJECTIVES: We have previously shown that specimens diagnosed as containing Hurthle cells have a 12% chance of being malignant if they are classified as atypia of undetermined significance (AUS-HC). The identification of Hurthle cells by cytotechnologists (CTs) during screening can improve cytopathologist efficiency and may prevent diagnostic errors due to the oversights of focal findings. Here, we examine the performance of our institutional CTs when screening for Hurthle cell atypia in thyroid fine-needle aspiration (FNA) specimens. STUDY DESIGN: Information on 8,814 thyroid cytopathology specimens was retrieved for a 10-year period. Specimens were screened by 1 of 11 CTs. A subsample of cases was categorized either as AUS-HC or suspicious for Hurthle cell neoplasm. RESULTS: AUS-HC screening diagnoses were more likely to be downgraded to benign but less likely to be upgraded compared to AUS diagnoses with nuclear or microfollicular atypia. AUS-HC represents almost all papillary thyroid carcinoma (PTC) screening diagnoses downgraded to the AUS category, which suggests that even low levels of Hurthle cell atypia can result in PTC being included in the differential diagnosis. CONCLUSION: Overall, there are few major discrepancies between CT and pathologist diagnoses for specimens containing Hurthle cell atypia. PMID- 26606303 TI - Machine Learning: How Much Does It Tell about Protein Folding Rates? AB - The prediction of protein folding rates is a necessary step towards understanding the principles of protein folding. Due to the increasing amount of experimental data, numerous protein folding models and predictors of protein folding rates have been developed in the last decade. The problem has also attracted the attention of scientists from computational fields, which led to the publication of several machine learning-based models to predict the rate of protein folding. Some of them claim to predict the logarithm of protein folding rate with an accuracy greater than 90%. However, there are reasons to believe that such claims are exaggerated due to large fluctuations and overfitting of the estimates. When we confronted three selected published models with new data, we found a much lower predictive power than reported in the original publications. Overly optimistic predictive powers appear from violations of the basic principles of machine-learning. We highlight common misconceptions in the studies claiming excessive predictive power and propose to use learning curves as a safeguard against those mistakes. As an example, we show that the current amount of experimental data is insufficient to build a linear predictor of logarithms of folding rates based on protein amino acid composition. PMID- 26606304 TI - A valveless rotary microfluidic device for multiplex point mutation identification based on ligation-rolling circle amplification. AB - Genetic variations such as single nucleotide polymorphism (SNP) and point mutations are important biomarkers to monitor disease prognosis and diagnosis. In this study, we developed a novel rotary microfluidic device which can perform multiplex SNP typing on the mutation sites of TP53 genes. The microdevice consists of three glass layers: a channel wafer, a Ti/Pt electrode-patterned resistance temperature detector (RTD) wafer, and a rotary plate in which twelve reaction chambers were fabricated. A series of sample injection, ligation-rolling circle amplification (L-RCA) reaction, and fluorescence detection of the resultant amplicons could be executed by rotating the top rotary plate, identifying five mutation points related with cancer prognosis. The use of the rotary plate eliminates the necessity of microvalves and micropumps to control the microfluidic flow in the channel, simplifying the chip design and chip operation for multiplex SNP detection. The proposed microdevice provides an advanced genetic analysis platform in terms of multiplexity, simplicity, and portability in the fields of biomedical diagnostics. PMID- 26606305 TI - Folic acid-conjugated fluorescent polymer for up-regulation folate receptor expression study via targeted imaging of tumor cells. AB - Thoroughly investigation of folate receptor (FR) expression related to targeting drug delivery in tumor cells has been intensively pursued in recent years. Herein, a simple and versatile strategy for determination of FR expression based on targeted imaging of tumor cells with fluorescent nano-conjugates was developed. The fluorescent nano-conjugates were composed of poly 2-vinyl-4,4 dimethyl azlactone (PVDMA) as the linker, folic acid as the targeting unit and amino-Rhodamine B as the fluorescent ligand. Owing to possessing dimethyl azlactone groups in polymer framework, PVDMA could easily reacted with amines or alcohols, and form water soluble materials. Fluorescent imaging studies indicated that the prepared nano-conjugates could specifically target tumor cells and monitor the over expressing of FR. Moreover, the FR expression up-regulation in HeLa cells through medicines regulation has been further explored. This new protocol opens an effective way through synthesis and design of novel fluorescent nano-conjugates for FR expression investigation in tumor cells via targeted imaging, showing great potential in drug delivery mechanism study and cancer therapy. PMID- 26606306 TI - A label-free kissing complexes-induced fluorescence aptasensor using DNA templated silver nanoclusters as a signal transducer. AB - Riboswitches are complex folded RNA domains that serve as receptors for specific metabolites which identified in prokaryotes. They are comprised of a biosensor that includes the binding site for a small ligand and they respond to association with this ligand by undergoing a conformational change. In the present study, we report on the integration of silver nanoclusters (AgNCs) and riboswitches for the development of a kissing complexes-induced aptasensor (KCIA). We specifically apply the tunable riboswitches properties of this strategy to demonstrate the multiplexes analysis of adenosine and adenosine deaminase (ADA). This strategy allows for simple tethering of the specific oligonucleotides stabilizing the AgNCs to the nucleic acid probes. This is a new concept for aptasensors, and opens an opportunity for design of more novel biosensors based on the kissing complexes-induced strategy. PMID- 26606307 TI - Differential detection of a surrogate biological threat agent (Bacillus globigii) with a portable surface plasmon resonance biosensor. AB - New methods and technology are needed to quickly and accurately detect potential biological warfare agents, such as Bacillus anthracis, causal agent of anthrax in humans and animals. Here, we report the detection of a simulant of B. anthracis (B. globigii) alone and in a mixture with a different species of Bacillus to test non-specific interference using a portable surface plasmon resonance (SPR) biosensor (SPIRIT 4.0, Seattle Sensor Systems). Both direct capture and antibody amplification were used to determine the limit of detection for spores of B. globigii, and to detect spores of B. globigii in a mixed sample containing another Bacillus spp. Spores of B. globigii were detected by anti-B. globigii (anti-Bg) coated sensors by direct capture at a concentration of 10(7)spores/mL, and with a secondary antibody amplification at a concentration of 10(5)spores/mL. Spores of B. globigii were differentially detected in a 1:1 mixture with B. pumilus spores from equal concentrations (10(7)spores/mL) with a secondary antibody amplification. To our knowledge, this is the first report of the differential detection of B. globigii with SPR in a mixed sample containing at least one additional Bacillus spp., highlighting the potential for SPR to detect any target bacterium in a mixed sample of closely related species. With the availability of portable instrumentation to accurately detect biological warfare agents such as B. anthracis, emergency responders can implement protocols in a timely fashion, limiting the amount of exposed individuals. PMID- 26606308 TI - Cubic Cu2O nanoframes with a unique edge-truncated structure and a good electrocatalytic activity for immunosensor application. AB - In this work, an ultrasensitive sandwich-type electrochemical immunosensor was developed for the quantitative detection of prostate specific antigen (PSA). Gold nanoparticles decorated 3-aminopropyltriethoxysilane functionalized graphene sheets (Au@APTES-GS) with a large specific surface area, good biocompatibility and superior electron transfer ability were employed as the matrix. In addition, cubic Cu2O nanoframes with hollow edges were employed as the label for the first time. Scanning electron microscope (SEM) images were used to confirm the nanostructure of Au@APTES-GS and Cu2O. Using square wave voltammetry (SWV) to monitor the electrocatalytic process, the signal amplification mechanism of the matrix and the label were explored successfully. Here we find that the unique edge-truncated structure of Cu2O nanoframes can load with a larger amount of redox mediators, ferrocenecarboxylic acid (Fc-COOH), offering a higher electrochemical signal response. Apart from that, Cu2O nanoframes have a good electrocatalytic activity towards the Fc-COOH and hydrogen peroxide (H2O2), making a contribution to further enhance the sensitivity of the fabricated immunosensor. Under optimal conditions, the proposed immunosensor achieved an ultrasensitive and specific detection of PSA, and displayed acceptable reproducibility, selectivity and stability. This work may provide an effective method for the clinical monitoring of tumor markers and demonstrate the potential application promising of nanoframes in the fabrication of immunosensors. PMID- 26606309 TI - Dual-recognition detection of Staphylococcus aureus using vancomycin functionalized magnetic beads as concentration carriers. AB - Vancomycin, which has a strong antibacterial effect to Gram-positive bacteria, was adopted as one molecular recognition agent for bacterial detection. Magnetic beads (MBs) were functionalized with this antibiotic to effectively concentrate Staphylococcus aureus (S. aureus). In addition, alkaline phosphatase (ALP)-tagged rabbit immunoglobulin G (ALP-IgG) was used as the second recognition agent to improve the specificity based on the binding between the Fc region of rabbit IgG and protein A in the cell wall of S. aureus. MBs-concentrated sandwich complex of vancomycin/S. aureus/ALP-IgG was formed with a one-step incubation protocol. Then ALP chemiluminescent reaction was triggered by injecting substrate solution to quantitate S. aureus. Based on the sandwich molecular recognition mechanism and MBs concentration, an ultrasensitive, specific and rapid method was developed for S. aureus detection. The linear range for S. aureus detection was 12-1.2 * 10(6)CFU mL(-1), with a very low detection limit of 3.3 CFU mL(-1). The whole detection process could be completed in 75 min. Other Gram-positive bacteria and Gram-negative bacteria, including Escherichia coli, Salmonella, Pseudomonas aeruginosa, Micrococcus luteus, Bacillus cereus and Bacillus subtilis, showed negligible interference to S. aureus detection. This method was successfully used to quantitate S. aureus in lake water, milk, human urine and human saliva with acceptable recoveries ranging from 70.0% to 116.7%. PMID- 26606310 TI - A reusable electrochemical immunosensor fabricated using a temperature-responsive polymer for cancer biomarker proteins. AB - In the present study, we describe a reusable electrochemical immunosensor for the repeated detection of cancer biomarkers using a single platform. The integration of a temperature-responsive polymer on the electrode surface enables easy manipulation of the biological sensing interface (i.e., addition of biotin, streptavidin, and antibody), thus allowing for temperature-induced regeneration and disruption of the interface architecture of the electrode surface. Using our immunosensor, we demonstrate sequential amperometric detection of three tumor markers: CA125, CEA, and PSA. Interestingly, greatly amplified signals are achieved by immersing the immunosensor in a solution of horseradish peroxidase (HRP) and antibody-labeled nanoparticles, resulting in a linear range of 0.0064 to 256 U/mL, 1 pg/mL to 100 ng/mL, and 10 pg/mL to 10 ng/mL with a detection limit of 0.007 U/mL, 0.7 pg/mL, and 0.9 pg/mL for CA125, CEA, and PSA, respectively. By alternating temperature, the immunosensor adsorbs and desorbs the biological elements without damage. Our proposed methodology can be expanded to measure other relevant biological species by repeated detection and thus has enormous potential for industrial and clinical applications. PMID- 26606311 TI - Quantitative, single-step dual measurement of hemoglobin A1c and total hemoglobin in human whole blood using a gold sandwich immunochromatographic assay for personalized medicine. AB - We describe a gold nanoparticle-based sandwich immunoassay for the dual detection and measurement of hemoglobin A1c (HbA1c) and total hemoglobin in the whole blood (without pretreatment) in a single step for personalized medicine. The optimized antibody-functionalized gold nanoparticles immunoreact simultaneously with HbA1c and total hemoglobin to form a sandwich at distinctive test lines to transduce visible signals. The applicability of this method as a personal management tool was demonstrated by establishing a calibration curve to relate % HbA1c, a useful value for type 2 diabetes management, to the signal ratio of captured HbA1c to all other forms of hemoglobin. The platform showed excellent selectivity (100%) toward HbA1c at distinctive test lines when challenged with HbA0, glycated HbA0 and HbA2. The reproducibility of the measurement was good (6.02%) owing to the dual measurement of HbA1c and total hemoglobin. A blood sample stability test revealed that the quantitative measurement of % HbA1c was consistent and no false positive results were detected. Also, this method distinguished the blood sample with elevated HbF from the normal samples and the variants. The findings of this study highlight the potential of a lateral flow immunosensor as a simple, inexpensive, consistent, and convenient strategy for the dual measurement of HbA1c and total Hb to provide useful % HbA1c values for better on-site diabetes care. PMID- 26606312 TI - Erratum. PMID- 26606314 TI - PEER REVIEW - 2015. PMID- 26606317 TI - The K-complex as a special reactive sleep slow wave - A theoretical update. AB - We aimed to integrate new data about K-complex (KC) physiology and relate KC to other low-frequency waves observed in slow wave sleep. KC can be considered a 'prototype' of reactive sleep slow waves. Similarly to slow waves, KCs feature up and down-states, they are subject to homeostatic regulation but they are also associated with sensory activation. As a part of the continuum of reactive sleep slow waves, the study of the KC may offer a better understanding of how slow waves are activated by the sensory system. KCs appear to have a special place among sleep slow waves and in the newly established framework of input-related NREM sleep regulation. It is a key element highlighting how the brain may choose to maintain sleep in response to a sensory input when facing the question "to wake or not to wake". PMID- 26606318 TI - Screening and assessment for obstructive sleep apnea in primary care. AB - Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder and contributes to increased morbidity and compromised cardiovascular outcomes. Sleep disorders are common but rarely reported and addressed by primary health providers. An American Academy of Sleep Medicine task force (2015) released quality measures for the care of adult patients with OSA; the first outcome is improved detection and categorization of OSA symptoms and severity to promote assessment and diagnosis of the disorder. This state of the science integrative review aimed to evaluate the screening and assessment for OSA in primary care settings including the psychometric properties of OSA screening measures. Studies that met inclusion criteria were fourteen non-experimental and three experimental designs. OSA screening measurements (Berlin questionnaire, Epworth sleepiness scale, STOP Bang) with extensive validation studies were examined. Conclusions are that the current practice model of screening and assessment for OSA in primary care is fragmented and ineffective. Primary care providers encounter patients with OSA symptoms but do not routinely screen, assess, or refer to a sleep specialist. More psychometric research is needed for the OSA screening measurements in primary care. The results of these studies can be translated into practice to increase detection of OSA. PMID- 26606319 TI - The effects of light therapy on sleep problems: A systematic review and meta analysis. AB - Although bright light therapy seems a promising treatment for sleep problems, research shows inconclusive results. This meta-analysis is the first to systematically review the effect of light therapy on sleep problems in general and on specific types of sleep problems in particular (circadian rhythm sleep disorders, insomnia, sleep problems related to Alzheimer's disease and dementia). Fifty-three studies with a total of 1154 participants were included. Overall effects and effects on separate circadian and sleep outcomes were examined. We calculated Hedges' g effect sizes and we investigated the effects of twelve moderators (design-related, treatment-related, participant-related). Light therapy was found effective in the treatment of sleep problems in general (g = 0.39), and for circadian rhythm sleep disorders (g = 0.41), insomnia (g = 0.47), and sleep problems related to Alzheimer's disease/dementia (g = 0.30) specifically. For circadian rhythm sleep disorders, effects were smaller for randomised controlled trials. For insomnia, we found larger effects for studies using a higher light intensity, and for sleep problems related to Alzheimer's disease/dementia larger effects were found for studies with more female participants. There was indication of publication bias. To conclude, light therapy is effective for sleep problems in general, particularly for circadian outcomes and insomnia symptoms. However, most effect sizes are small to medium. PMID- 26606320 TI - Atomistic simulation of hydrophobin HFBII conformation in aqueous and fluorous media and at the water/vacuum interface. AB - Hydrophobins are proteins of interest for numerous applications thanks to their unique conformational and surface properties and their ability to self-assemble at interfaces. Here we report fully atomistic molecular mechanics and molecular dynamics results together with circular dichroism experimental data, aimed to study the conformational properties of the hydrophobin HFBII in a fluorinated solvent in comparison with a water solution and/or at an aqueous/vacuum interface. Both the atomistic simulations and the circular dichroism data show the remarkable structural stability of HFBII at all scales in all these environments, with no significant structural change, although a small cavity is formed in the fluorinated solvent. The combination of theoretical calculations and circular dichroism data can describe in detail the protein conformation and flexibility in different solvents and/or at an interface, and constitutes a first step towards the study of their self-assembly. PMID- 26606321 TI - Maxillomandibular Advancement for Treatment of Obstructive Sleep Apnea: A Meta analysis. AB - IMPORTANCE: Maxillomandibular advancement (MMA) is an invasive yet effective surgical option for obstructive sleep apnea (OSA) that achieves enlargement of the upper airway by physically expanding the facial skeletal framework. OBJECTIVE: To identify criteria associated with surgical outcomes of MMA using aggregated individual patient data from multiple studies. DATA SOURCES: The Cochrane Library, Scopus, Web of Science, and MEDLINE from June 1, 2014, to March 16, 2015, using the Medical Subject Heading keywords maxillomandibular advancement, orthognathic surgery, maxillary osteotomy, mandibular advancement, sleep apnea, surgical, surgery, sleep apnea syndrome, and obstructive sleep apnea. STUDY SELECTION: Inclusion criteria consisted of studies in all languages of (1) adult patients who underwent MMA as treatment for OSA; (2) report of preoperative and postoperative quantitative outcomes for the apnea-hypopnea index (AHI) and/or respiratory disturbance index (RDI); and (3) report of individual patient data. Studies of patients who underwent adjunctive procedures at the time of MMA (including tonsillectomy, uvulopalatopharyngoplasty, and partial glossectomy) were excluded. DATA EXTRACTION: Three coauthors systematically reviewed the articles and updated the review through March 16, 2015. The PRISMA statement was followed. Data were pooled using a random-effects model and analyzed from July 1, 2014, to September 23, 2015. MAIN OUTCOMES AND MEASURES: The primary outcomes were changes in the AHI and RDI after MMA for each patient. Secondary outcomes included surgical success, defined as the percentage of patients with more than 50% reduction of the AHI to fewer than 20 events/h, and OSA cure, defined as a post-MMA AHI of fewer than 5 events/h. RESULTS: Forty-five studies with individual data from 518 unique patients/interventions were included. Among patients for whom data were available, 197 of 268 (73.5%) had undergone prior surgery for OSA. Mean (SD) postoperative changes in the AHI and RDI after MMA were -47.8 (25.0) and -44.4 (33.0), respectively; mean (SE) reductions of AHI and RDI outcomes were 80.1% (1.8%) and 64.6% (4.0%), respectively; and 512 of 518 patients (98.8%) showed improvement. Significant improvements were also seen in the mean (SD) postoperative oxygen saturation nadir (70.1% [15.6%] to 87.0% [5.2%]; P < .001) and Epworth Sleepiness Scale score (13.5 [5.2] to 3.2 [3.2]; P < .001). Rates of surgical success and cure were 389 (85.5%) and 175 (38.5%), respectively, among 455 patients with AHI data and 44 (64.7%) and 13 (19.1%), respectively, among 68 patients with RDI data. Preoperative AHI of fewer than 60 events/h was the factor most strongly associated with the highest incidence of surgical cure. Nevertheless, patients with a preoperative AHI of more than 60 events/h experienced large and substantial net improvements despite modest surgical cure rates. CONCLUSIONS AND RELEVANCE: Maxillomandibular advancement is an effective treatment for OSA. Most patients with high residual AHI and RDI after other unsuccessful surgical procedures for OSA are likely to benefit from MMA. PMID- 26606322 TI - Adsorption of pharmaceuticals onto activated carbon fiber cloths - Modeling and extrapolation of adsorption isotherms at very low concentrations. AB - Activated carbon fiber cloths (ACFC) have shown promising results when applied to water treatment, especially for removing organic micropollutants such as pharmaceutical compounds. Nevertheless, further investigations are required, especially considering trace concentrations, which are found in current water treatment. Until now, most studies have been carried out at relatively high concentrations (mg L(-1)), since the experimental and analytical methodologies are more difficult and more expensive when dealing with lower concentrations (ng L(-1)). Therefore, the objective of this study was to validate an extrapolation procedure from high to low concentrations, for four compounds (Carbamazepine, Diclofenac, Caffeine and Acetaminophen). For this purpose, the reliability of the usual adsorption isotherm models, when extrapolated from high (mg L(-1)) to low concentrations (ng L(-1)), was assessed as well as the influence of numerous error functions. Some isotherm models (Freundlich, Toth) and error functions (RSS, ARE) show weaknesses to be used as an adsorption isotherms at low concentrations. However, from these results, the pairing of the Langmuir Freundlich isotherm model with Marquardt's percent standard of deviation was evidenced as the best combination model, enabling the extrapolation of adsorption capacities by orders of magnitude. PMID- 26606323 TI - The effect of ISO 14001 on environmental performance: Resolving equivocal findings. PMID- 26606324 TI - Selective colorimetric detection of Cr(iii) and Cr(vi) using gallic acid capped gold nanoparticles. AB - A colorimetric assay is proposed for the selective detection of Cr(iii) and Cr(vi) via the aggregation-induced color change of gallic acid capped gold nanoparticles (GA-AuNPs). The AuNPs are characterized using UV-vis spectroscopy, transmission electron microscopy (TEM), dynamic light scattering (DLS) and Fourier-transform infrared spectrometry (FT-IR). To detect Cr(iii) and Cr(vi) coexisting in a sample, citrate and thiosulfate were applied to mask Cr(vi) for the detection of Cr(iii), and ethylenediaminetetraacetic acid disodium salt (EDTA) was applied to mask Cr(iii) for the detection of Cr(vi). At optimized experimental conditions, the selectivity of these AuNPs-based detection systems is excellent for Cr(iii) and/or Cr(vi) compared with other types of metal ions. The limit of detections (LODs) of a mixture of Cr(iii) and Cr(vi), Cr(iii) and Cr(vi) by eye vision are 1.5, 1.5 and 2 MUM, respectively, and those by UV-vis spectroscopy are 0.05, 0.1 and 0.1 MUM, respectively. The minimum detectable concentrations for Cr(iii) or Cr(vi) are all below the guideline value set by the US Environmental Protection Agency (EPA). The applicability of the AuNPs-based colorimetric sensor is also validated by the detection of Cr(iii) and Cr(vi) in electroplating wastewater and real water samples with high recoveries. PMID- 26606325 TI - Enhanced production of 3-hydroxypropionic acid from glucose via malonyl-CoA pathway by engineered Escherichia coli. AB - In this study, production of 3-HP via malonyl-CoA was investigated by using metabolically engineered Escherichia coli carrying heterogeneous acetyl-CoA carboxylase (Acc) from Corynebacterium glutamicum and codon-optimized malonyl-CoA reductase (MCR) from Chloroflexus aurantiacus. Three engineered E. coli strains with different host-vector systems were constructed and investigated. The results indicated that the combination of E. coli BL21(DE3) and pET28a was the most efficient host-vector system for 3-HP production, and the highest concentration of 3-HP attained in shake flask cultivation reached 1.80g/L by the strain BE-MDA with induction at 0.25mM IPTG and 25 degrees C, and supplementation of NaHCO3 and biotin. In fed-batch fermentation performed in a 5-L reactor, the concentration of 3-HP achieved 10.08g/L in 36h. PMID- 26606326 TI - Evaluation of Dermatology Practice Online Reviews: Lessons From Qualitative Analysis. AB - IMPORTANCE: Patient satisfaction is an increasingly important component of health care quality measures. Online reviews of physicians represent a promising platform for capturing patient perspectives of care. OBJECTIVE: To identify qualitative themes associated with patient reviews of dermatologic care on consumer reporting websites. DESIGN, SETTING, AND PARTICIPANTS: A qualitative analysis was conducted of patient-generated reviews of dermatology practices on 2 consumer review platforms. Yelp is an online consumer portal for users to review their experience with local businesses; ZocDoc is an online patient-scheduling portal that provides opportunity for patients to write reviews of physician practices. A total of 518 reviews from 45 dermatology practices on Yelp and 4921 reviews from 45 dermatology providers on ZocDoc were collected from 3 geographically diverse cities: Philadelphia, Pennsylvania; Houston, Texas; and Seattle, Washington. The study was conducted from January 15 to July 15, 2015. MAIN OUTCOMES AND MEASURES: Reviews were separated into high-scoring and low scoring groups. An inductive qualitative method was used to code and identify key themes associated with positive and negative patient experiences. Analysis was completed upon reaching thematic saturation. RESULTS: Reported as mean (95% CI), the overall Yelp score for the 45 selected practices was 3.46 of 5 stars (3.17 3.75) and overall ZocDoc score for the 45 selected practices was 4.72 of 5 stars (4.47-4.80). The proportion of individual reviews giving a score of 5.0 was significantly higher on ZocDoc (3986 [81.0%]) than on Yelp (229 [44.2%]) (P < .001). Qualitative themes centered on characteristics of the physician and the practice. Themes that emerged from the high-scoring and low-scoring reviews were similar in content but opposite in valence. Physician-specific themes included temperament, knowledge and competency, physical examination, communication abilities, and mindfulness of cost. Practice-specific themes included scheduling, staff temperament, office cleanliness, waiting room, and insurance. Patients appreciated physicians who are kind, respectful, and thorough with the physical examination; empathetic about the emotional difficulty of skin disease; and cognizant of cost. Negative experiences were frequently affected by considerations outside of the physician-patient interaction, such as curt interactions with staff, difficulty with scheduling, practice cleanliness, and insurance problems. Patients reported relying on consumer websites to identify dermatology providers. CONCLUSIONS AND RELEVANCE: Online consumer review websites are designed to facilitate instantaneous and public communication among patients. These platforms provide elaborate and timely data for dermatologists to garner insight into their patients' experiences. The themes identified in this study are consistent with past satisfaction studies and may aid dermatologists in optimizing the patient care experience. PMID- 26606327 TI - Synthesis and cation-binding studies of gold(I) complexes bearing oligoether isocyanide ligands with ester and amide as linkers. AB - A series of dinuclear gold(I) isocyanide complexes of bis(alkynyl)calix[4]arene was designed and synthesized, and their photophysical and cation recognition properties were studied. Complex 1, [{calix[4]arene-(OCH2CONH-C6H4C=C)2}{Au(CN C6H4O(CH2CH2O)2CH3)}2], was found to show a high selectivity towards Al(3+) in CH2Cl2-MeCN (1 : 1 v/v). Upon addition of Al(3+), drastic changes in the electronic absorption, emission and (1)H NMR spectra were observed. These changes have been attributed to the formation of Au(I)Au(i) interactions induced by the high binding affinity of the amide site for the Al(3+) ion, instead of the high binding affinity expected of the oligoether site for alkali and alkaline earth metal ions. Further studies with the control complex, [{calix[4]arene-(OOC C6H4C=C)2}{Au(CN-C6H4O(CH2CH2O)2CH3)}2] (4), indicated that the amide carbonyl oxygen in the flexible pendants is crucial for the binding of Al(3+). PMID- 26606328 TI - STAT1 and IRF8 in Vascular Inflammation and Cardiovascular Disease: Diagnostic and Therapeutic Potential. AB - Inflammation importantly contributes to the pathophysiology of Cardiovascular Disease (CVD). Signal Transducer and Activator of Transcription (STAT)1 operates at the frontier of innate and adaptive immunity and its involvement in CVD has been widely appreciated. A unique role of STAT1 in cross-talk between the pro inflammatory cytokine IFNgamma and TLR4 activators (TLR4-A) has been uncovered in immune as well as vascular cells increasing inflammation. Interferon Regulatory Factor (IRF)8 whose expression was initially identified in immune cells, controls development and differentiation in close connection with PU.1. In addition, as a STAT1-target, IRF8 accounts for "immune cell-specific" STAT1-dependent functions of IFNgamma and LPS. Novel studies prove that also in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), STAT1 and IRF8 orchestrate a transcriptional platform for cross-talk between IFNgamma and TLR4-A, which leads to amplified pro-atherogenic responses in the vasculature. In addition to its known immune cell functions, this points to a novel "inflammation-dependent" role of IRF8 in vascular cells. In this review we present a summary of these findings and postulate STAT1- and IRF8-target genes as promising markers of vascular inflammation, and STAT1 and IRF8 as potential targets for the development of new immunosuppressive and anti-inflammatory agents for the treatment of CVD. PMID- 26606330 TI - The combined use of corticotomy and clear aligners: A case report. AB - OBJECTIVE: To describe an orthodontic treatment that combines an esthetic approach (clear aligners) with surgery (alveolar corticotomy). MATERIALS AND METHODS: A patient with moderate dental crowding and Class I skeletal and molar relationships was selected. Orthodontic records of the patient were taken. Periodontal indexes, oral health-related quality of life (OHRQoL), and treatment time were evaluated. After we reflected a full-thickness flap beyond the teeth apices, the cortical bone was exposed on the buccal aspect and a modified corticotomy procedure was performed. Interproximal corticotomy cuts were extended through the entire thickness of the cortical layer, just barely penetrating into medullary bone. Orthodontic force was applied on the teeth immediately after surgery. RESULTS: Total treatment time was 2 months. Periodontal indexes were improved after correction of crowding. A deterioration of OHRQoL was limited to 3 days following surgery. CONCLUSION: This case report may encourage the use, limited to selected cases, of corticotomy associated with clear aligners to treat moderate crowding. PMID- 26606331 TI - Changes in salivary periodontal pathogens after orthodontic treatment: An in vivo prospective study. AB - OBJECTIVE: To analyze the initial changes in salivary levels of periodontal pathogens after orthodontic treatment with fixed appliances. MATERIALS AND METHODS: The subjects consisted of 54 adult patients. The Simplified Oral Hygiene Index, Plaque Index, and Gingival Index were measured as periodontal parameters. Both the plaque and gingival indexes were obtained from the central and lateral incisors and first molars of both arches. Whole saliva and periodontal parameters were obtained at the following four time points: immediately before debonding (T1), 1 week after debonding (T2), 5 weeks after debonding (T3), and 13 weeks after debonding (T4). Repeated measures analysis of variance was used to determine salivary bacterial levels and periodontal parameters among the four time points after quantifying salivary levels of Aggregatibacter actinomycetemcomitans (Aa), Fusobacterium nucleatum (Fn), Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), Tannerella forsythia (Tf), and total bacteria using the real-time polymerase chain reaction. RESULTS: All periodontal parameters were significantly decreased immediately after debonding (T2). The salivary levels of total bacteria and Pg were decreased at T3, while Pi and Tf levels were decreased at T4. However, the amount of Aa and Fn remained at similar levels in saliva during the experimental period. Interestingly, Aa and Fn were present in saliva at higher levels than were Pg, Pi, and Tf. CONCLUSION: The higher salivary levels of Aa and Fn after debonding suggests that the risk of periodontal problems cannot be completely eliminated by the removal of fixed orthodontic appliances during the initial retention period, despite improved oral hygiene. PMID- 26606329 TI - Failure-Free Survival and Radiotherapy in Patients With Newly Diagnosed Nonmetastatic Prostate Cancer: Data From Patients in the Control Arm of the STAMPEDE Trial. AB - IMPORTANCE: The natural history of patients with newly diagnosed high-risk nonmetastatic (M0) prostate cancer receiving hormone therapy (HT) either alone or with standard-of-care radiotherapy (RT) is not well documented. Furthermore, no clinical trial has assessed the role of RT in patients with node-positive (N+) M0 disease. The STAMPEDE Trial includes such individuals, allowing an exploratory multivariate analysis of the impact of radical RT. OBJECTIVE: To describe survival and the impact on failure-free survival of RT by nodal involvement in these patients. DESIGN, SETTING, AND PARTICIPANTS: Cohort study using data collected for patients allocated to the control arm (standard-of-care only) of the STAMPEDE Trial between October 5, 2005, and May 1, 2014. Outcomes are presented as hazard ratios (HRs) with 95% CIs derived from adjusted Cox models; survival estimates are reported at 2 and 5 years. Participants were high-risk, hormone-naive patients with newly diagnosed M0 prostate cancer starting long-term HT for the first time. Radiotherapy is encouraged in this group, but mandated for patients with node-negative (N0) M0 disease only since November 2011. EXPOSURES: Long-term HT either alone or with RT, as per local standard. Planned RT use was recorded at entry. MAIN OUTCOMES AND MEASURES: Failure-free survival (FFS) and overall survival. RESULTS: A total of 721 men with newly diagnosed M0 disease were included: median age at entry, 66 (interquartile range [IQR], 61-72) years, median (IQR) prostate-specific antigen level of 43 (18-88) ng/mL. There were 40 deaths (31 owing to prostate cancer) with 17 months' median follow-up. Two-year survival was 96% (95% CI, 93%-97%) and 2-year FFS, 77% (95% CI, 73%-81%). Median (IQR) FFS was 63 (26 to not reached) months. Time to FFS was worse in patients with N+ disease (HR, 2.02 [95% CI, 1.46-2.81]) than in those with N0 disease. Failure-free survival outcomes favored planned use of RT for patients with both N0M0 (HR, 0.33 [95% CI, 0.18-0.61]) and N+M0 disease (HR, 0.48 [95% CI, 0.29 0.79]). CONCLUSIONS AND RELEVANCE: Survival for men entering the cohort with high risk M0 disease was higher than anticipated at study inception. These nonrandomized data were consistent with previous trials that support routine use of RT with HT in patients with N0M0 disease. Additionally, the data suggest that the benefits of RT extend to men with N+M0 disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00268476; ISRCTN78818544. PMID- 26606332 TI - Computational Studies of the Luciferase Light-Emitting Product: Oxyluciferin. AB - Firefly luciferase is the most studied bioluminescence system, and its catalyzed reactions have been relatively well characterized. However, the color tuning mechanism that leads to firefly multicolor bioluminescence is still unknown, nor is consensual which is the yellow-green and red emitters. Computational studies have been essential in the study of oxyluciferin (OxyLH2) chemi- and bioluminescence and are responsible for most of our knowledge of this natural phenomenon. The objective of this manuscript is the analysis of the benefits and the conclusions derived from the theoretical studies of the light emitter, OxyLH2, and its applications on bioluminescence research. PMID- 26606333 TI - Molecular Dynamics Simulations Predict a Favorable and Unique Mode of Interaction between Lithium (Li(+)) Ions and Hydrophobic Molecules in Aqueous Solution. AB - We report the results of molecular dynamics simulations of the interaction thermodynamics of group I cations with hydrophobic molecules in water using a variety of nonpolarizable force fields. Surprisingly, we find that the Li(+) ion is predicted to form thermodynamically favorable interactions with methane and neopentane using a new mode of recognition that is intermediate between a direct contact and a solvent-separated complex. Further simulations show that this favorable interaction is only predicted by ion parameter sets that correctly reproduce Li(+)'s experimental hydration number. PMID- 26606334 TI - Can Electron-Rich pi Systems Bind Anions? AB - In general, anion-pi interactions exist between anions and aromatics with a positive quadrupole moment. The interaction between anions and aromatics with a negative quadrupole moment is expected to be unstable due to Coulombic repulsion. However, here we investigated the cases of aromatics with a negative quadrupole moment such as electron-rich alkyl/alkenyl/alkynyl-substituted benzenes and triphenylene, which interact with halides. Favorable binding was demonstrated with coupled cluster theory with singles, doubles, and perturbative triples excitations [CCSD(T)] at the complete basis set (CBS) limit. Stability increases with chain length, unsaturation, and halogenation. Energy decomposition analysis based on symmetry adapted perturbation theory (SAPT) shows that electrostatic repulsion is overcome by induction effects arising from the alkyl substituents. PMID- 26606335 TI - Resolutions of the Coulomb Operator: IV. The Spherical Bessel Quasi-Resolution. PMID- 26606336 TI - Coupled Cluster in Condensed Phase. Part I: Static Quantum Chemical Calculations of Hydrogen Fluoride Clusters. AB - A multiscale approach with roots in electronic structure calculations relies on the good description of intermolecular forces. In this study we lay the foundations for a condensed phase treatment based on the electronic structure of hydrogen fluoride on a very high level of theory. This investigation comprises cluster calculations in a static quantum chemical approach employing density functional theory, second order Moller-Plesset perturbation theory (MP2) and the coupled cluster singles, doubles with perturbative triples method in combination with several basis sets as well as at the complete basis set limit. The clusters we considered are up to 12 monomer units large and consist of ring and chain structures. We find a good agreement of the intramolecular distance obtained from the MP2 approach and the largest basis set. The binding energy of the hydrogen fluoride dimer calculated from coupled cluster at the basis set limit agrees excellently with experiment, whereas the calculated frequencies at all levels agree reasonably well with different experimental values. Large cooperative effects are observed for the ring structures as compared to the chain clusters. The energy per monomer unit indicates the most stable structures to be the ring clusters. PMID- 26606337 TI - Coupled Cluster in Condensed Phase. Part II: Liquid Hydrogen Fluoride from Quantum Cluster Equilibrium Theory. AB - Treating the bulk phase with high-level ab initio methods, such as coupled cluster, is a nontrivial task because of the computational costs of these electronic structure methods. In this part of our hydrogen fluoride study we make use of the quantum cluster equilibrium method, which employs electronic structure input of small clusters and combines it with simple statistical mechanics in order to describe condensed phase phenomena. If no parameter adjustment is applied, then the lower quantum chemical methods, such as density functional theory in conjunction with the generalized gradient approximation, provide wrong results in accordance with the description of the strength of the interaction in the clusters. While density functional theory describes the liquid phase too dense due to overbinding of the clusters, the coupled cluster method and the perturbation theory at the complete basis set limit agree well with experimental observations. If we allow the two parameters in the quantum cluster equilibrium method to vary, then these are able to compensate the overbinding, thereby leading to very good agreement with experiment. Correlated methods in combination with small basis sets giving rise to too weakly bound clusters cannot reach this accuracy even if the parameters are flexible. Only at the complete basis set limit, the performance of the correlated methods is again excellent. PMID- 26606338 TI - Effect of Triples to Dipole Moments in Fock-Space Multireference Coupled Cluster Method. AB - In this paper, we present the new implementation of partial triples for the dipole moment of doublet radicals in Lagrangian formulation of Fock-space multireference coupled cluster (Lambda-FSMRCC) response method. We have implemented a specific scheme of noniterative triples, in addition to singles and doubles schemes, which accounts for the effects appearing at least at the third order in dipole moments. The method is applied to the ground states of OH, OOH, HCOO, CN, CH, and PO radicals. PMID- 26606339 TI - Linear Scaling Constrained Density Functional Theory in CONQUEST. AB - The constrained density functional theory (cDFT) formalism is implemented in the linear scaling density functional theory (DFT) code CONQUEST. This will enable the simulation of electron-transfer processes in large biologically and technologically relevant systems. The Becke weight population scheme is chosen to define the constraint, as it enables force components to be calculated both analytically and efficiently in a linear scaling code. It is demonstrated that the imposition of a constraint is not affected by the truncation of the density matrix. Demonstration calculations are performed on charge-separated excited states in small biphenyl molecules, and cDFT is found to produce accurate energy and geometry changes for this system. The capability of the method is shown in calculations on poly phenylene-vinylene oligomers and a hydrated DNA 10-mer. PMID- 26606340 TI - DFT and Ab Initio Study of Iron-Oxo Porphyrins: May They Have a Low-Lying Iron(V) Oxo Electromer? AB - The energetics of various electromeric states for two heme complexes with an iron oxo (FeO(3+)) group, FeO(P)(+) and FeO(P)Cl (P = porphin), have been investigated, employing DFT and correlated ab initio methods (CASPT2, RASPT2). Our interest focused in particular on tri- and pentaradicaloid iron(IV)-oxo porphyrin radical states as well as iron(V)-oxo states. Surprisingly, the iron(V) oxo ground state is predicted for both models in vacuo. However, the presence of a polarizable medium, such as a solvent or a protein environment, favors the iron(IV)-oxo porphyrin radical cation, which is predicted to be the actual ground state of FeO(P)Cl under such conditions. Nonetheless, the iron(V)-oxo electromer is still expected to lie only a few kcal/mol above the ground state-a conclusion coming from both CASPT2 and RASPT2 calculations with a very large active space and further supported by a calibration with respect to coupled cluster CCSD(T) calculations for a simplified small model. The DFT results turn out to be strongly functional-dependent and thereby inconclusive. The widely used B3LYP functional-although correctly predicting the iron(IV)-oxo porphyrin radical ground state for FeO(P)Cl-seems to place the iron(V)-oxo states much too high in energy, as compared to the present CASPT2, RASPT2, and CCSD(T) results. PMID- 26606341 TI - Projected Coupled Cluster Amplitudes from a Different Basis Set As Initial Guess. AB - Many model chemistry schemes require a sequence of high level calculations, often at the coupled cluster (CC) level, with increasingly larger basis sets. The CC equations are solved iteratively, and the rate of convergence strongly depends on the quality of the initial guess. Here, we propose a strategy to define a better guess from a previous CC calculation with a different basis set by employing the concept of corresponding orbitals. (1, 2) Only the part of the converged amplitudes from the previous calculation that has a large correspondence to the space spanned by the new basis set is projected and used as a new starting point. The computational time for the projection is negligible and significantly reduces the number of cycles necessary for convergence in comparison to the standard guess based on the first order wave function. Numerical results are presented for ground and excited state calculations with the CC singles and doubles (CCSD) and the equation of motion CCSD (EOM-CCSD) methods with the restricted and unrestricted Hartree-Fock (HF) reference functions. However, this approach is more general and can be applied to any truncation of the cluster expansion and reference function. PMID- 26606342 TI - Benchmark Full Configuration Interaction Calculations on the Lowest-Energy (2)P and (4)P States of the Three-Electron Harmonium Atom. AB - Full configuration interaction calculations carried out in conjunction with careful optimization of basis sets and judicious extrapolation schemes for 12 values of the confinement strength omega ranging from 0.1 to 1000.0 provide benchmark energies for the (2)P ground state and the (4)P first excited state of the three-electron harmonium atom, allowing for numerical verification of the recently obtained second-order energy coefficients and confirming the few available results of Monte Carlo studies. The final energy values, obtained by correcting the extrapolated data for residual errors in the low-order energy coefficients, possess accuracy of ca. 20 MUHartree for the doublet state and ca. 10 MUHartree for the quartet one, making them suitable for calibration and testing of approximate electron correlation methods of quantum chemistry. The energy limits for individual angular momenta ranging from 1 to 4 are also available, facilitating comparisons with results of calculations involving finite basis sets. An example of application involving the BLYP and B3LYP functionals is provided. PMID- 26606343 TI - Distributed Multipoles and Energies of Flexible Molecules. AB - In this work we show that energies and distributed multipoles, up to and including rank two, can be accurately determined via a modified Shepard interpolation of ab initio data for small molecules. The molecules considered here are the amino aldehydes, Gly and Ala, which may be typical smaller fragment molecules in certain molecular energy-based fragmentation schemes. The method is general and should be suitable for applications also involving crystal structure prediction, modeling molecular clusters, and Monte Carlo or molecular/reaction dynamics simulations. The configuration space covered by the interpolation includes that sampled by the Gly and Ala peptides in protein crystal structures, i.e., 12 dimensions for Gly: 3 torsion angles (phi, psi, omega), 5 bond lengths, and 4 bond angles and 15 dimensions for Ala: 4 torsion angles, 6 bond lengths, and 5 bond angles. In this work we also describe a new method of importance, sampling the relevant configuration spaces, and show that it is possible to interpolate "axis free" multipoles. PMID- 26606344 TI - Dynamic Precision for Electron Repulsion Integral Evaluation on Graphical Processing Units (GPUs). AB - It has recently been demonstrated that novel streaming architectures found in consumer video gaming hardware such as graphical processing units (GPUs) are well suited to a broad range of computations including electronic structure theory (quantum chemistry). Although recent GPUs have developed robust support for double precision arithmetic, they continue to provide 2-8* more hardware units for single precision. In order to maximize performance on GPU architectures, we present a technique of dynamically selecting double or single precision evaluation for electron repulsion integrals (ERIs) in Hartree-Fock and density functional self-consistent field (SCF) calculations. We show that precision error can be effectively controlled by evaluating only the largest integrals in double precision. By dynamically scaling the precision cutoff over the course of the SCF procedure, we arrive at a scheme that minimizes the number of double precision integral evaluations for any desired accuracy. This dynamic precision scheme is shown to be effective for an array of molecules ranging in size from 20 to nearly 2000 atoms. PMID- 26606345 TI - The Nature of the Idealized Triple Bonds Between Principal Elements and the sigma Origins of Trans-Bent Geometries-A Valence Bond Study. AB - We describe herein a valence bond (VB) study of 27 triply bonded molecules of the general type X=Y, where X and Y are main element atoms/fragments from groups 13 15 in the periodic table. The following conclusions were derived from the computational data: (a) Single pi-bond and double pi-bond energies for the entire set correlate with the "molecular electronegativity", which is the sum of the X and Y electronegativites for X=Y. The correlation with the molecular electronegativity establishes a simple rule of periodicity: pi-bonding strength generally increases from left to right in a period and decreases down a column in the periodic table. (b) The sigma frame invariably prefers trans bending, while pi-bonding gets destabilized and opposes the trans distortion. In HC=CH, the pi bonding destabilization overrides the propensity of the sigma frame to distort, while in the higher row molecules, the sigma frame wins out and establishes trans bent molecules with 2(1)/2 bonds, in accord with recent experimental evidence based on solid state (29)Si NMR of the Sekiguchi compound. Thus, in the trans bent molecules "less bonds pay more". (c) All of the pi bonds show significant bonding contributions from the resonance energy due to covalent-ionic mixing. This quantity is shown to correlate linearly with the corresponding "molecular electronegativity" and to reflect the mechanism required to satisfy the equilibrium condition for the bond. The pi bonds for molecules possessing high molecular electronegativity are charge-shift bonds, wherein bonding is dominated by the resonance energy of the covalent and ionic forms, rather than by either form by itself. PMID- 26606346 TI - H2-Binding by Neutral and Multiply Charged Titaniums: Hydrogen Storage Capacity of Titanium Mono- and Dications. AB - Given that transition metal-hydrogen systems have been studied as a predecessor for hydrogen storage materials, we have investigated the neutral and multiply charged titanium-H2 systems (Ti-H2, Ti(+)-H2, Ti(2+)-H2, Ti(3+)-H2, and Ti(4+) H2) using density functional theory (DFT) and high-level ab initio calculations, including coupled cluster theory with single, double, and perturbatively triple excitations [CCSD(T)]. These systems show different types of hydrogenation depending on their charged state. The neutral Ti-H2 system shows dihydride structure with covalent interaction where the Ti-H distance is 1.76 A, while H2 is dissociated into two neigboring hydride ions by withdrawing electrons from Ti. The charged Ti(+)-H2, Ti(2+)-H2, and Ti(3+)-H2 systems show dihydrogen structures with noncovalent interaction, where the Ti(+)-H, Ti(2+)-H, and Ti(3+)-H distances are 2.00, 2.14, and 2.12 A, respectively. The main binding energies in these systems arise from the hydrogen polarizability driven interaction by the positive charge of Ti(n+) (n = 1-3). Among Ti(n+)-H2 (n = 1-3) the Ti(+)-H2 has the shortest distance against our common expectation, while Ti(2+)-H2 has the longest distance. The Ti(+)-H2 distance is the shortest because of the d-sigma* molecular orbital (MO) interaction which is not present in Ti(2+)-H2 and Ti(3+)-H2. The Ti(4+) ion does not bind H2. In this regard, we have investigated the maximal hydrogen binding capacity by Ti complexes. The coordination of titanium mono- and dications complexed with dihydrogen (H2) [Ti(+)(H2)n and Ti(2+)(H2)m] is studied along with their structures, binding energies, electronic properties, and spectra. The titanium monocations of the quartet ground state have up to the hexacoordinaton, while titanium dications of the triplet ground state have up to the octacoordination at very low temperatures. At room temperature, the monocations favor penta- to hexacoordination, while the dications favor hexacoordination. This information would be useful for the design of hydrogen storage devices of Ti complexes, such as Ti-decorated/dispersed polymer-graphene hybrid materials. PMID- 26606347 TI - Electronic Structure and Effectively Unpaired Electron Density Topology in closo Boranes: Nonclassical Three-Center Two-Electron Bonding. AB - This article provides a detailed study of the structure and bonding in closo borane cluster compounds X2B3H3 (X = BH(-), P, SiH, CH, N), with particular emphasis on the description of the electron distribution using the topology of the quantum many-body effectively unpaired density. The close relationship observed between the critical points of this quantity and the localization of the electron cloud allows us to characterize the nonclassical bonding patterns of these systems. The obtained results confirm the suitability of the local rule to detect three-center two-electron bonds, which was conjectured in our previous study on boron hydrides. PMID- 26606348 TI - Accurate Conformational Energy Differences of Carbohydrates: A Complete Basis Set Extrapolation. AB - Correlated ab initio wave function calculations have been performed, using nonrelativistic frozen core MP2 complete basis set extrapolation model chemistry. The calculations have been made for three test sets of gas-phase saccharide conformations to provide reference values for their relative energies. The remaining correlation effects are estimated from frozen core coupled-cluster singles and doubles [CCSD(T)] calculations. The test sets consist of 15 conformers of alpha- and beta-d-allopyranose, 15 of 3,6-anhydro-4-O-methyl-d galactitol, and four of beta-d-glucopyranose. For each set, conformational energies varied by about 7 kcal/mol. These benchmark quality relative conformational energies are used to re-evaluate the performance of the best density functional methods for conformational analyses of saccharides. Our results show that the B3PW91 and PBE0 relative energies are systematically better than the B3LYP and M05-2X results. Overall, the functionals based on the exact constraints perform better for the relative energies of monosaccharide conformers than the empirically fitted functionals. PMID- 26606349 TI - Parallel Implementation of the Four-Component Relativistic Quasidegenerate Perturbation Theory with General Multiconfigurational Reference Functions. AB - A new, efficient parallel algorithm for four-component relativistic generalized multiconfigurational quasidegenerate perturbation theory (GMC-QDPT) introducing Kramers symmetry is implemented. Because it utilizes the independence of the terms in the matrix element computations, this algorithm both speeds up the calculation and reduces the computational resources required for each node. In addition, the amount of memory for two-electron integrals is reduced to three eigths by Kramers restriction. The algorithm is applied to the d-d excitation energies of the platinum halide complexes, [PtCl4](2-), [PtBr4](2-), and [PtCl6](2-) and to the 6p-7s and 6p-7p excitation energies of the radon atom. It is shown to provide high parallelization efficiency and accurate excitation energies that agree well with experimental data. PMID- 26606350 TI - Concerted or Stepwise Mechanism? CASPT2 and LC-TDDFT Study of the Excited-State Double Proton Transfer in the 7-Azaindole Dimer. AB - Excited-state double proton transfer (ESDPT) in the 7-azaindole dimer is investigated using the complete active space second-order perturbation theory (CASPT2) method and the long-range corrected time-dependent density functional theory (LC-TDDFT) method. These methods are employed for geometry optimizations as well as single-point energy calculations of the excited-state potential energy profiles along the reaction paths. It is shown that three main reaction routes involving double proton transfer exist. In the first route, the ESDPT reaction takes place in the locally excited state through a single transition state following the concerted mechanism in which each proton-transfer process occurs simultaneously without forming any stable zwitterionic intermediate. The concerted ESDPT reaction is found to proceed asynchronously in Cs symmetry rather than synchronously in C2h symmetry. In the second and third routes, on the other hand, the ESDPT reaction takes place following the stepwise mechanism in which each proton-transfer process occurs sequentially forming a neutral intermediate in the charge-transfer state. The calculated energy profiles of the three routes exhibit a lower barrier in the first route than in the other routes, suggesting that the ESDPT in the gas phase is likely to follow the asynchronous concerted mechanism at the lowest excitation energy. PMID- 26606351 TI - New Interaction Parameters for Oxygen Compounds in the GROMOS Force Field: Improved Pure-Liquid and Solvation Properties for Alcohols, Ethers, Aldehydes, Ketones, Carboxylic Acids, and Esters. AB - A new parameter set (53A6OXY) is developed for the GROMOS force field, that combines reoptimized parameters for the oxygen-containing chemical functions (alcohols, ethers, aldehydes, ketones, carboxylic acids, and esters) with the current biomolecular force field version (53A6) for all other functions. In the context of oxygen-containing functions, the 53A6OXY parameter set is obtained by optimization of simulated pure-liquid properties, namely the density rholiq and enthalpy of vaporization DeltaHvap, as well as solvation properties, namely the free energies of solvation in water DeltaGwat and in cyclohexane DeltaGche, against experimental data for 10 selected organic compounds, and further tested for 25 other compounds. The simultaneous refinement of atomic charges and Lennard Jones interaction parameters against the four mentioned types of properties provides a single parameter set for the simulation of both liquid and biomolecular systems. Small changes in the covalent parameters controlling the geometry of the oxygen-containing chemical functions are also undertaken. The new 53A6OXY force-field parameters reproduce the mentioned experimental data within root-mean-square deviations of 22.4 kg m(-3) (rholiq), 3.1 kJ mol(-1) (DeltaHvap), 3.0 kJ mol(-1) (DeltaGwat), and 1.7 kJ mol(-1) (DeltaGche) for the 35 compounds considered. PMID- 26606352 TI - An Analysis of the Validity of Markov State Models for Emulating the Dynamics of Classical Molecular Systems and Ensembles. AB - Markov state models parametrized using molecular simulation data are powerful tools for the investigation of conformational changes in biomolecules and in recent years have gained increasing popularity. However, a Markov state model is an approximation to the true dynamics of the complete system. We show how Markov state models are derived from the generalized Liouville equation identifying the assumptions and approximations involved and review the mathematical properties of transition matrices. Using two model systems, a two-bit flipping model consisting of only four states, and molecular dynamics simulations of liquid butane, we subsequently assess the influence of the assumptions, for example, of the marginal degrees of freedom, used in the derivation on the validity of the Markov state model. PMID- 26606353 TI - Atomic Velocity Projection Method: A New Analysis Method for Vibrational Spectra in Terms of Internal Coordinates for a Better Understanding of Zeolite Nanogrowth. AB - An efficient protocol is presented to identify signals in vibrational spectra of silica oligomers based on theoretical molecular dynamics (MD) simulations. The method is based on the projection of the atomic velocity vectors on the tangential directions of the trajectories belonging to a predefined set of internal coordinates. In this way only contributions of atomic motions along these internal coordinates are taken into consideration. The new methodology is applied to the spectra of oligomers and rings, which play an important role in zeolite synthesis. A suitable selection of the relevant internal coordinates makes the protocol very efficient but relies on intuition and theoretical insight. The simulation data necessary to compute vibrational spectra of relevant silica species are obtained through MD using proper force fields. The new methodology-the so-called velocity projection method-makes a detailed analysis of vibrational spectra possible by establishing a one-to-one correspondence between a spectral signal and a proper internal coordinate. It offers valuable perspectives in understanding the elementary steps in silica organization during zeolite nanogrowth. The so-called velocity projection method is generally applicable on data obtained from all types of MD and is a highly valuable alternative to normal-mode analysis which has its limitations due to the presence of many local minima on the potential energy surface. In this work the method is exclusively applied to inelastic neutron scattering, but extension to the infrared power spectrum is apparent. PMID- 26606354 TI - Spectroscopic Properties of Azobenzene-Based pH Indicator Dyes: A Quantum Chemical and Experimental Study. AB - The UV-visible absorption spectra of six new optical sensors based on acidochromic azobenzenes have been measured and assigned with the help of quantum chemical calculations. The investigated compounds are able to monitor the pH in the range from pH 3-10. Using the hybrid density functional PBE0 and including solvent effects with a polarized continuum model, the agreement between the experimental and theoretical UV/vis spectra of the dyes in their neutral and anionic forms is very good. The spectroscopic pipi* states, responsible for the optical properties of the sensors, are described within an accuracy of 0.1 eV. Similar accuracy is demonstrated in the npi* states. The pipi* states can be assigned as a charge transfer from the aromatic pi orbital localized in the azo phenol moiety to the antibonding pi* of the azo group. Under basic conditions, the spectrum is bathochromically shifted and more intense than in acid media. Upon substitution in the phenyl moiety, red- or blue-shifts of the UV-visible bands are observed depending on whether the substituent is electron-donor or withdrawing, respectively. These effects are stronger at high pH values and can be rationalized in terms of the stabilization and/or destabilization of the involved frontier orbitals. PMID- 26606355 TI - A Computational Study (TDDFT and RICC2) of the Electronic Spectra of Pyranoanthocyanins in the Gas Phase and Solution. AB - The conformational structures and UV-vis absorption electronic spectra of a class of derived anthocyanin molecules (pyranoanthocyanins) have been investigated mainly by means of density functional (DFT) and time-dependent DFT methods. Pyranoanthocyanins are natural pigments present in aged wines and absorb at shorter wavelengths (around 500 nm) than the parent anthocyanin compounds, giving an orange-brown colored solution. The investigated molecules are derived from the reaction of glycosylated malvidin, peonidin, and petunidin with enolizable molecules (acetaldehyde and pyruvic acid) and vinyl derivatives. During wine storage, the concentration of pyranoanthocyanins increases with time, and analytical measurements (e.g., UV-vis spectroscopy) can characterize aged wines by color analysis. The prediction of absorption electronic spectra from TDDFT results, with the inclusion of water bulk solvation effects through the conductor like polarizable continuum model, gives an absolute mean deviation from experimental absorption maxima of 0.1 eV and a good reproduction of the spectra line shape over the visible range of the spectrum. TDDFT calculated excitation energies agree with those obtained from ab initio multireference coupled cluster with the resolution of identity approximation (RICC2) methods, calculated at DFT gas-phase geometries. PMID- 26606356 TI - Assessment of TD-DFT and CC2 Methods for the Calculation of Resonance Raman Intensities: Application to o-Nitrophenol. AB - The resonance Raman (RR) intensities of o-nitrophenol (oNP) were investigated theoretically with the aim of assessing the accuracy of excited state gradients calculated with DFT and CC2 approaches. It is found that the B3LYP and B2PLYP exchange-correlation (XC) functionals provide the best estimate of the ground state properties, while the other considered approaches present significantly less accurate vibrational frequencies and normal coordinates. Then, it is demonstrated that the use of the B3LYP force field for the ground state properties, in association with XC functionals including a large amount of HF exchange (M06-2X) or including long-range corrections (CAM-B3LYP and omegaB97X) for the excited state gradient calculations, provides the most accurate RR spectra. Moreover, it is found that the RR intensities calculated with the best XC functionals show comparable accuracy to the results obtained with CC2 calculations. Finally, it is seen that the accuracy of the excited state gradients does not correlate with the accuracy of the excitation energies and oscillator strengths, for which XC functionals with a lesser amount of HF exchange (B3LYP, M06, and HSE06) provide more accurate results in the case of oNP. This indicates that the assessment of excited state gradients via the calculation of RR intensities, can provide additional information about the performance of quantum chemistry approaches in predicting excited state properties. PMID- 26606357 TI - Normal Mode Analysis in Zeolites: Toward an Efficient Calculation of Adsorption Entropies. AB - An efficient procedure for normal-mode analysis of extended systems, such as zeolites, is developed and illustrated for the physisorption and chemisorption of n-octane and isobutene in H-ZSM-22 and H-FAU using periodic DFT calculations employing the Vienna Ab Initio Simulation Package. Physisorption and chemisorption entropies resulting from partial Hessian vibrational analysis (PHVA) differ at most 10 J mol(-1) K(-1) from those resulting from full Hessian vibrational analysis, even for PHVA schemes in which only a very limited number of atoms are considered free. To acquire a well-conditioned Hessian, much tighter optimization criteria than commonly used for electronic energy calculations in zeolites are required, i.e., at least an energy cutoff of 400 eV, maximum force of 0.02 eV/A, and self-consistent field loop convergence criteria of 10(-8) eV. For loosely bonded complexes the mobile adsorbate method is applied, in which frequency contributions originating from translational or rotational motions of the adsorbate are removed from the total partition function and replaced by free translational and/or rotational contributions. The frequencies corresponding with these translational and rotational modes can be selected unambiguously based on a mobile block Hessian-PHVA calculation, allowing the prediction of physisorption entropies within an accuracy of 10-15 J mol(-1) K(-1) as compared to experimental values. The approach presented in this study is useful for studies on other extended catalytic systems. PMID- 26606358 TI - First Principles-Based Calculations of Free Energy of Binding: Application to Ligand Binding in a Self-Assembling Superstructure. AB - The accurate prediction of ligand binding affinities to a protein remains a desirable goal of computational biochemistry. Many available methods use molecular mechanics (MM) to describe the system, however, MM force fields cannot fully describe the complex interactions involved in binding, specifically electron transfer and polarization. First principles approaches can fully account for these interactions, and with the development of linear-scaling first principles programs, it is now viable to apply first principles calculations to systems containing tens of thousands of atoms. In this paper, a quantum mechanical Poisson-Boltzmann surface area approach is applied to a model of a protein-ligand binding cavity, the "tennis ball" dimer. Results obtained from this approach demonstrate considerable improvement over conventional molecular mechanics Poisson-Boltzmann surface area due to the more accurate description of the interactions in the system. For the first principles calculations in this study, the linear-scaling density functional theory program ONETEP is used, allowing the approach to be applied to receptor-ligand complexes of pharmaceutical interest that typically include thousands of atoms. PMID- 26606359 TI - Wavelet Transform for Spectroscopic Analysis: Application to Diols in Water. AB - Wavelet transform has been used to correlate spectroscopic and structural properties from trajectories obtained by ab initio molecular dynamics simulations. This method has been applied to hydrogen bond dynamics of glycols in heavy water solutions, showing how the stretching frequency of the intramolecular O-H bond changes with the intermolecular hydrogen-bond distance. The resulting wavelet spectrograms have been interpreted according to H-bond strength and stability. PMID- 26606360 TI - A Stochastic Search for the Structures of Small Germanium Clusters and Their Anions: Enhanced Stability by Spherical Aromaticity of the Ge10 and Ge12(2-) Systems. AB - Investigations on germanium clusters in the neutral, anionic, and dianion states Gen(x) (n = 2-12 and x = 0, -1, -2) are performed using quantum chemical calculations with the B3LYP functional and the coupled-cluster singles and doubles [CCSD(T)] methods, in conjunction with the 6-311+G(d) basis set. An improved stochastic method is implemented for searching the low-lying isomers of clusters. Comparison of our results with previous reports on germanium clusters shows the efficiency of the search method. The Ge8 system is presented in detail. The anionic clusters Gen(-/2-) are studied theoretically and systematically for the first time, and their energetics are in good agreement with available experiments. The clusters Ge10, Ge10(2-), and Ge12(2-) are, in their ground state, characterized by large highest occupied molecular orbital-lowest unoccupied molecular orbital gaps, high vertical and adiabatic detachment energies, and substantial average binding energies. The enhanced stability of these magic clusters can consistently be rationalized using the jellium electron shell model and the spherical aromatic character. PMID- 26606361 TI - Molecular Dynamics Simulation Study of Chlorophyll a in Different Organic Solvents. AB - Herein, we present a new model of chlorophyll a for molecular dynamics simulations based on the optimized potentials for liquid simulations force field. The new model was used to study the structural and dynamic properties of the molecule in three different solvents: water, methanol, and benzene. The results of the simulations show that structural and dynamic properties of the chlorin ring are similar in both methanol and benzene. In methanol and water, the magnesium in the chlorin ring binds the oxygen of the solvent molecules with residence times of 2566 and 1300 ps, respectively. In both methanol and benzene, the phytol tail shows a worm-like chain distribution with a larger persistence length for the molecule in benzene. On the contrary, chlorophyll a in water adopts a more compact structure with the phytol chain folded onto the chlorin ring. This conformation is consistent with the expected conformation of the aggregates of chlorophyll a in aqueous environments. Finally, the rotational time constants obtained with our model from the simulations in methanol (125 ps) and benzene (192 ps) are in good agreement with the value extrapolated from the experimental data. PMID- 26606362 TI - Polarizable Atomic Multipole X-Ray Refinement: Particle Mesh Ewald Electrostatics for Macromolecular Crystals. AB - Refinement of macromolecular models from X-ray crystallography experiments benefits from prior chemical knowledge at all resolutions. As the quality of the prior chemical knowledge from quantum or classical molecular physics improves, in principle so will resulting structural models. Due to limitations in computer performance and electrostatic algorithms, commonly used macromolecules X-ray crystallography refinement protocols have had limited support for rigorous molecular physics in the past. For example, electrostatics is often neglected in favor of nonbonded interactions based on a purely repulsive van der Waals potential. In this work we present advanced algorithms for desktop workstations that open the door to X-ray refinement of even the most challenging macromolecular data sets using state-of-the-art classical molecular physics. First we describe theory for particle mesh Ewald (PME) summation that consistently handles the symmetry of all 230 space groups, replicates of the unit cell such that the minimum image convention can be used with a real space cutoff of any size and the combination of space group symmetry with replicates. An implementation of symmetry accelerated PME for the polarizable atomic multipole optimized energetics for biomolecular applications (AMOEBA) force field is presented. Relative to a single CPU core performing calculations on a P1 unit cell, our AMOEBA engine called Force Field X (FFX) accelerates energy evaluations by more than a factor of 24 on an 8-core workstation with a Tesla GPU coprocessor for 30 structures that contain 240 000 atoms on average in the unit cell. The benefit of AMOEBA electrostatics evaluated with PME for macromolecular X-ray crystallography refinement is demonstrated via rerefinement of 10 crystallographic data sets that range in resolution from 1.7 to 4.5 A. Beginning from structures obtained by local optimization without electrostatics, further optimization using AMOEBA with PME electrostatics improved agreement of the model with the data (Rfree was lowered by 0.5%), improved geometric features such as favorable (phi, psi) backbone conformations, and lowered the average potential energy per residue by over 10 kcal/mol. Furthermore, the MolProbity structure validation tool indicates that the geometry of these rerefined structures is consistent with X-ray crystallographic data collected up to 2.2 A, which is 0.9 A better than the actual mean quality (3.1 A). We conclude that polarizable AMOEBA assisted X-ray refinement offers advantages to methods that neglect electrostatics and is now efficient enough for routine use. PMID- 26606363 TI - From Coarse Grained to Atomistic: A Serial Multiscale Approach to Membrane Protein Simulations. AB - Coarse-grained molecular dynamics provides a means for simulating the assembly and the interactions of membrane protein/lipid complexes at a reduced level of representation, allowing longer and larger simulations. We describe a fragment based protocol for converting membrane simulation systems, comprising a membrane protein embedded in a phospholipid bilayer, from coarse-grained to atomistic resolution, for further refinement and analysis via atomistic simulations. Overall, this provides a method for generating an accurate and well equilibrated membrane protein/lipid complex. We exemplify the protocol using the acid sensing/amiloride-sensitive ion channel protein (ASIC) channel protein, a trimeric integral membrane protein. The method is further evaluated using a test set of 10 different membrane proteins of differing size and complexity. Simulations are assessed in terms of protein conformational drift, lipid/protein interactions, and lipid dynamics. PMID- 26606364 TI - The Catalytic Mechanism of RNA Polymerase II. AB - Eukaryotic RNA polymerase II (RNAP II) transcribes the DNA into mRNA. The presence of two metal ions (usually Mg(2+)) and conserved aspartate residues in the active sites of all nucleic acid polymerases led to the adoption of a universal catalytic mechanism, known as the "two metal ion catalysis". In this scheme, it is assumed that the coordination shell of Mg(2+) (geometry, number, and identity of the ligands) is basically the same for all of the enzymes, despite the significant differences in sequence and structure commonly found in multisubunit RNA polymerases versus single-subunit RNA polymerases and DNA polymerases. Here, we have studied the catalytic mechanism of RNAP II and found very interesting variations to the postulated mechanism. We have used an array of techniques that included thermodynamic integration free energy calculations and electronic structure calculations with pure DFT as well as hybrid DFT/semiempirical methods to understand this important mechanism. We have studied four different catalytic pathways in total, resulting from different combinations of proton donors/acceptors for the two proton transfers experimentally detected (deprotonation of the 3' hydroxyl of the terminal nucleotide (HORNA) and protonation of pyrophosphate). The obtained data unambiguously show that the catalytic mechanism involves the deprotonation of HORNA by a hydroxide ion coming from the bulk solvent, the protonation of pyrophosphate by the active site His1085, and the nucleophilic attack to the substrate by O(-)RNA. The overall barrier is 9.9 kcal/mol. This mechanism differs from those proposed in the identity of the general acid. The deprotonation of the HORNA and the transition state for the nucleophilic attack are similar to some (but not all) of the family members. PMID- 26606365 TI - Efficient Explicit-Solvent Molecular Dynamics Simulations of Molecular Association Kinetics: Methane/Methane, Na(+)/Cl(-), Methane/Benzene, and K(+)/18 Crown-6 Ether. AB - Atomically detailed views of molecular recognition events are of great interest to a variety of research areas in biology and chemistry. Here, we apply the weighted ensemble path sampling approach to improve the efficiency of explicit solvent molecular dynamics (MD) simulations in sampling molecular association events between two methane molecules, Na(+) and Cl(-) ions, methane and benzene, and the K(+) ion and 18-crown-6 ether. Relative to brute force simulation, we obtain efficiency gains of at least 300 and 1100-fold for the most challenging system, K(+)/18-crown-6 ether, in terms of sampling the association rate constant k and distribution of times required to traverse transition paths, respectively. Our results indicate that weighted ensemble sampling is likely to allow for even greater efficiencies for more complex systems with higher barriers to molecular association. PMID- 26606366 TI - RNA Conformational Sampling: II. Arbitrary Length Multinucleotide Loop Closure. AB - In this paper, we describe how the inverse kinematic solution to the loop closure problem may be generalized to reclose a RNA segment of arbitrary length containing any number of nucleotides without disturbing the atomic positions of the rest of the molecule. This generalization is made possible by representing the boundary conditions of the closure in terms of a set of virtual coordinates called RETO, allowing the inverse kinematics to be reduced from the original six variable/six-constraint problem to a four-variable/four-constraint problem. Based on this generalized closure solution, a new Monte Carlo algorithm has been formulated and implemented in a fully atomistic RNA simulation capable of moving loops of arbitrary lengths using torsion angle updates exclusively. Combined with other conventional Monte Carlo moves, this new algorithm is able to sample large scale RNA chain conformations much more efficiently. The utility of this new class of Monte Carlo moves in generating large-loop conformational rearrangements is demonstrated in the simulated unfolding of the full-length hammerhead ribozyme with a bound substrate. PMID- 26606367 TI - Optimizing Protein-Solvent Force Fields to Reproduce Intrinsic Conformational Preferences of Model Peptides. AB - While most force field efforts in biomolecular simulation have focused on the parametrization of the protein, relatively little attention has been paid to the quality of the accompanying solvent model. These considerations are especially relevant for simulations of intrinsically disordered peptides and proteins, for which energy differences between conformations are small and interactions with water are enhanced. In this work, we investigate the accuracy of the AMBER ff99SB force field when combined with the standard TIP3P model or the more recent TIP4P Ew water model, to generate conformational ensembles for disordered trialanine (Ala3), triglycine (Gly3), and trivaline (Val3) peptides. We find that the TIP4P Ew water model yields significantly better agreement with experimentally measured scalar couplings-and therefore more accurate conformational ensembles-for both Ala3 and Gly3. For Val3, however, we find that the TIP3P and TIP4P-Ew ensembles are equivalent in their performance. To further improve the protein-water force field combination and obtain more accurate intrinsic conformational preferences, we derive a straightforward perturbation to the phi' backbone dihedral potential that shifts the beta-PPII equilibrium. We find that the revised phi' backbone dihedral potential yields improved conformational ensembles for a variety of small peptides and maintains the stability of the globular ubiquitin protein in TIP4P-Ew water. PMID- 26606368 TI - Electron Localization Function at the Correlated Level: A Natural Orbital Formulation. PMID- 26606369 TI - Electron Processing at 50 eV of Terphenylthiol Self-Assembled Monolayers: Contributions of Primary and Secondary Electrons. AB - Aromatic self-assembled monolayers (SAMs) can serve as platforms for development of supramolecular assemblies driven by surface templates. For many applications, electron processing is used to locally reinforce the layer. To achieve better control of the irradiation step, chemical transformations induced by electron impact at 50 eV of terphenylthiol SAMs are studied, with these SAMs serving as model aromatic SAMs. High-resolution electron energy loss spectroscopy (HREELS) and electron-stimulated desorption (ESD) of neutral fragment measurements are combined to investigate electron-induced chemical transformation of the layer. The decrease of the CH stretching HREELS signature is mainly attributed to dehydrogenation, without a noticeable hybridization change of the hydrogenated carbon centers. Its evolution as a function of the irradiation dose gives an estimate of the effective hydrogen content loss cross-section, sigma = 2.7-4.7 * 10(-17) cm(2). Electron impact ionization is the major primary mechanism involved, with the impact electronic excitation contributing only marginally. Therefore, special attention is given to the contribution of the low-energy secondary electrons to the induced chemistry. The effective cross-section related to dissociative secondary electron attachment at 6 eV is estimated to be 1 order of magnitude smaller. The 1 eV electrons do not induce significant chemical modification for a 2.5 mC cm(-2) dose, excluding their contribution. PMID- 26606370 TI - Fluorine-Doped Tin Oxide Nanocrystal/Reduced Graphene Oxide Composites as Lithium Ion Battery Anode Material with High Capacity and Cycling Stability. AB - Tin oxide (SnO2) is a kind of anode material with high theoretical capacity. However, the volume expansion and fast capability fading during cycling have prevented its practical application in lithium ion batteries. Herein, we report that the nanocomposite of fluorine-doped tin oxide (FTO) and reduced graphene oxide (RGO) is an ideal anode material with high capacity, high rate capability, and high stability. The FTO conductive nanocrystals were successfully anchored on RGO nanosheets from an FTO nanocrystals colloid and RGO suspension by hydrothermal treatment. As the anode material, the FTO/RGO composite showed high structural stability during the lithiation and delithiation processes. The conductive FTO nanocrystals favor the formation of stable and thin solid electrolyte interface films. Significantly, the FTO/RGO composite retains a discharge capacity as high as 1439 mAhg(-1) after 200 cycles at a current density of 100 mAg(-1). Moreover, its rate capacity displays 1148 mAhg(-1) at a current density of 1000 mAg(-1). PMID- 26606371 TI - Barrel-shaped ClpP Proteases Display Attenuated Cleavage Specificities. AB - ClpP is a self-compartmentalizing protease with crucial roles in bacterial and mitochondrial protein quality control. Although the ClpP homocomplex is composed of 14 equivalent active sites, it degrades a multitude of substrates to small peptides, demonstrating its capability to carry out diverse cleavage reactions. Here, we show that ClpP proteases from E. coli, S. aureus, and human mitochondria exhibit preferences for certain amino acids in the P1, P2, and P3 positions using a tailored fluorogenic substrate library. However, this high specificity is not retained during proteolysis of endogenous substrates as shown by mass spectrometric analysis of peptides produced in ClpXP-mediated degradation reactions. Our data suggest a mechanism that implicates the barrel-shaped architecture of ClpP not only in shielding the active sites to prevent uncontrolled proteolysis but also in providing high local substrate concentrations to enable efficient proteolytic processing. Furthermore, we introduce customized fluorogenic substrates with unnatural amino acids that greatly surpass the sensitivity of previously used tools. We used these to profile the activity of cancer-patient- and Perrault-syndrome-derived ClpP mutant proteins. PMID- 26606372 TI - Rethinking Stability of Silver Sulfide Nanoparticles (Ag2S-NPs) in the Aquatic Environment: Photoinduced Transformation of Ag2S-NPs in the Presence of Fe(III). AB - The stability of engineered nanomaterials in a natural aquatic environment has drawn much attention over the past few years. Silver sulfide nanoparticles (Ag2S NPs) are generally assumed to be stable in a natural environment as a result of their physicochemical property; however, it may vary depending upon environmental conditions. Here, we investigated whether and how the environmentally relevant factors including light irradiation, solution pH, inorganic salts, dissolved organic matter (DOM), and dissolved oxygen (DO) individually and in combination influenced the stability of Ag2S-NPs in an aquatic environment. We presented for the first time that transformation of Ag2S-NPs can indeed occur in the aqueous system with an environmentally relevant concentration of Fe(3+) under simulated solar irradiation and natural sunlight within a short time (96 h), along with significant changes in morphology and dissolution. The photoinduced transformation of Ag2S-NPs in the presence of Fe(3+) can be dramatically influenced by solution pH, Ca(2+)/Na(+), Cl(-)/SO4(2-), DOM, and DO. Moreover, Ag2S-NP dissolution increased within 28 h, followed rapid decline in the next 68 h, which may be a result of the reconstitution of small Ag2S-NPs. Taken together, this work is of importance to comprehensively evaluate the stability of Ag2S-NPs in an aquatic environment, improving our understanding of their potential risks to human and environmental health. PMID- 26606373 TI - IL-17A increases TNF-alpha-induced COX-2 protein stability and augments PGE2 secretion from airway smooth muscle cells: impact on beta2 -adrenergic receptor desensitization. AB - BACKGROUND: IL-17A plays an important role in respiratory disease and is a known regulator of pulmonary inflammation and immunity. Recent studies have linked IL 17A with exacerbation in asthma and COPD. We have shown that the enzyme cyclooxygenase-2 (COX-2) and its prostanoid products, prostaglandin E2 (PGE2 ) in particular, are key contributors in in vitro models of infectious exacerbation; however, the impact of IL-17A was not known. METHODS AND RESULTS: We address this herein and show that IL-17A induces a robust and sustained upregulation of COX-2 protein and PGE2 secretion from airway smooth muscle (ASM) cells. COX-2 can be regulated at transcriptional, post-transcriptional and/or post-translational levels. We have elucidated the underlying molecular mechanisms responsible for the sustained upregulation of TNF-alpha-induced COX-2 by IL-17A in ASM cells and show that is not via increased COX-2 gene expression. Instead, TNF-alpha-induced COX-2 upregulation is subject to regulation by the proteasome, and IL-17A acts to increase TNF-alpha-induced COX-2 protein stability as confirmed by cycloheximide chase experiments. In this way, IL-17A acts to amplify the COX-2-mediated effects of TNF-alpha and greatly enhances PGE2 secretion from ASM cells. CONCLUSION: As PGE2 is a multifunctional prostanoid with diverse roles in respiratory disease, our studies demonstrate a novel function for IL-17A in airway inflammation by showing for the first time that IL-17A impacts on the COX-2/PGE2 pathway, molecules known to contribute to disease exacerbation. PMID- 26606375 TI - New-Onset Paroxysmal Atrial Fibrillation Diagnosis in Ischemic Stroke Patients. AB - INTRODUCTION: The aims of this study are to describe the incidence of paroxysmal atrial fibrillation (pAF) in patients with ischemic stroke (IS) or transient ischemic attack (TIA), and to create a risk prediction model, using immediately available clinical data associated with new pAF diagnosis. METHODS: We analyzed data from the BASICMAR stroke register, with 5 inclusion criteria: (1) diagnosis of IS/TIA; (2) no history of AF or structural cardiopathy; (3) stroke unit (SU) monitoring after normal electrocardiogram in the emergency room; (4) complete etiologic study; and (5) 3-month follow-up. We investigated clinical predictors of pAF detection; we analyzed newly diagnosed pAF according to 4 cardiac monitoring screening methods and created a pAF-risk prediction model. RESULTS: The final cohort included 1,240 patients. pAF was diagnosed in 139 patients (11.2%), the majority at the SU (54.7%). Multivariate predictors of new-pAF diagnosis during 3-month follow-up after ischemic event were age 75 years, female gender, history of congestive heart failure, and initial National Institute of Health Stroke Scale 15, with a predicted AF risk of 64%. CONCLUSIONS: This risk prediction model can be helpful to estimate the risk of an underlying pAF within 3 months after suffering an IS/TIA, contributing to increased AF detection efforts, thereby starting the correct secondary prevention treatment. PMID- 26606374 TI - Towards a Molecular Understanding of the Link between Imatinib Resistance and Kinase Conformational Dynamics. AB - Due to its inhibition of the Abl kinase domain in the BCR-ABL fusion protein, imatinib is strikingly effective in the initial stage of chronic myeloid leukemia with more than 90% of the patients showing complete remission. However, as in the case of most targeted anti-cancer therapies, the emergence of drug resistance is a serious concern. Several drug-resistant mutations affecting the catalytic domain of Abl and other tyrosine kinases are now known. But, despite their importance and the adverse effect that they have on the prognosis of the cancer patients harboring them, the molecular mechanism of these mutations is still debated. Here by using long molecular dynamics simulations and large-scale free energy calculations complemented by in vitro mutagenesis and microcalorimetry experiments, we model the effect of several widespread drug-resistant mutations of Abl. By comparing the conformational free energy landscape of the mutants with those of the wild-type tyrosine kinases we clarify their mode of action. It involves significant and complex changes in the inactive-to-active dynamics and entropy/enthalpy balance of two functional elements: the activation-loop and the conserved DFG motif. What is more the T315I gatekeeper mutant has a significant impact on the binding mechanism itself and on the binding kinetics. PMID- 26606376 TI - Metal-free melem/g-C3N4 hybrid photocatalysts for water treatment. AB - In this study, graphitic carbon nitride was engineered to produce metal-free melem/g-C3N4 hybrid photocatalysts through a hydrothermal technique. It was revealed that the hydrothermal treatment of g-C3N4 could produce a hybrid structure of "thorn ball" liked melem on g-C3N4 layer at a high temperature, and was able to modify the photoelectronic properties of g-C3N4. The spectroscopic measurements implied that a melem/g-C3N4 hybrid has better light absorption and lower electron/hole recombination than pristine g-C3N4. Therefore, the melem/g C3N4 photocatalysts can decompose methylene blue solution under artificial sunlight with a higher rate and also present good stability. PMID- 26606377 TI - Plasmon coupling between silver nanoparticles: Transition from the classical to the quantum regime. AB - We explore plasmon coupling between silver nanoparticles (AgNPs) as two AgNPs approach each other within a subnanometer distance. We prepare AgNP dimers with two 21-nm AgNPs separated by alkanedithiol linkers in high yield. Changing the length of the alkanedithiol linkers enables us to control the interparticle distance down to the subnanometer level on the molecular scale. We observe that the longitudinal plasmon coupling band, which is sensitive to the interaction between AgNPs, gradually redshifts as the interparticle distance decreases. This observation is fully consistent with the classical electromagnetic model. The redshift of the plasmon coupling, however, undergoes a drastic change when the interparticle distance reaches ~1nm. The longitudinal plasmon coupling band vanishes and a new intense band appears at a shorter wavelength. This band redshifts as the nanogap further narrows, but crosses over to a blueshift at ~0.7nm. A comparison of our observation with finite-difference time-domain simulations reveals that this band arises from quantum effects. Controlled assembly of AgNP dimers in combination with simulations allows us to observe the transition of the plasmon coupling from the classical to the quantum regime at the ensemble level. PMID- 26606378 TI - PVP-b-PEO block copolymers for stable aqueous and ethanolic graphene dispersions. AB - The ability to disperse pristine (unfunctionalized) graphene is important for various applications, coating, nanocomposites, and energy related systems. Herein we report that amphiphilic copolymers of poly(4-vinyl pyridine)-block poly(ethylene oxide) (PVP-b-PEO) are able to disperse graphene with high concentrations about 2.6mg/mL via sonication and centrifugation. Ethanolic and aqueous highly-ordered pyrolytic graphite (HOPG) dispersions with block copolymers were prepared and they were compared with the dispersions stabilized by P-123 Pluronic(r) (P123) and poly(styrene)-block-poly(ethylene oxide) (PS-b PEO) synthesized. Transmission electron microscopy, scanning electron microscopy, atomic force microscopy, X-ray diffraction, Raman and UV-visible spectroscopic studies confirmed that PVP-b-PEO block copolymers are better stabilizers for HOPG graphene than P123 and PS-b-PEO. X-ray photoelectron spectroscopy and force distance (F-d) curve analyses revealed that the nitrogen of vinyl pyridine plays a vital role in better attractive interaction with surface of graphene sheet. Thermogravimetric analysis showed that larger amount of PVP-b-PEO was adsorbed onto graphene with longer poly(4-vinyl pyridine) (PVP) block length and in aqueous medium, respectively, and which was consistent with electrical conductivity decreases. This study presents the dispersion efficiency of graphene using PVP-b-PEO varies substantially depending on the lengths of their hydrophobic (PVP) domains. PMID- 26606379 TI - Chronic Kidney Disease and Functional Outcomes 6 Months after Ischemic Stroke: A Prospective Multicenter Study. AB - BACKGROUND: The aim of this study was to investigate whether chronic kidney disease (CKD) predicts the outcome of the Functional Independence Measure (FIM) and the Korean version of the modified Barthel Index (K-MBI) 6 months after stroke with adjustment for age, gender, education, smoking, drinking, obesity, hypertension, diabetes mellitus, dyslipidemia, the FIM or K-MBI at discharge and the National Institutes of Health Stroke Scale (NIHSS) score 7 days post stroke. METHODS: This study is an interim report of the Korean Stroke Cohort for Functioning and Rehabilitation. The sample included 2,037 ischemic stroke patients aged 18 years or older. The FIM and K-MBI scores were assessed at discharge and at 6 months after the onset of stroke. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. CKD was defined as an eGFR <60 ml/min/1.73 m2. RESULTS: Overall, the mean age was 65.5 (+/-12.4) years. The proportion of men was 62.6%. The proportion of CKD cases was 12.7%. The means of the 6-month FIM and K-MBI were 109.8 (+/-27.9) and 87.0 (+/-26.4), respectively. In multiple linear regressions, the 6-month FIM after stroke was significantly associated with CKD (-2.85, p < 0.05), age (-0.29, p < 0.01), the FIM at discharge (0.46, p < 0.01) and the 7-day NIHSS score (-1.71, p < 0.01). Additionally, the post stroke 6-month K-MBI was significantly associated with CKD (-2.88, p < 0.01), age (-0.27, p < 0.01), the K-MBI at discharge (0.46, p < 0.01) and the 7-day NIHSS score (-1.55, p < 0.01). CONCLUSIONS: This nationwide hospital-based cohort study showed that CKD might predict poor 6-month FIM and K-MBI scores in ischemic stroke patients. PMID- 26606380 TI - Conformational Analysis of the Host-Defense Peptides Pseudhymenochirin-1Pb and 2Pa and Design of Analogues with Insulin-Releasing Activities and Reduced Toxicities. AB - Pseudhymenochirin-1Pb (Ps-1Pb; IKIPSFFRNILKKVGKEAVSLIAGALKQS) and pseudhymenochirin-2Pa (Ps-2Pa; GIFPIFAKLLGKVIKVASSLISKGRTE) are amphibian peptides with broad spectrum antimicrobial activities and cytotoxicity against mammalian cells. In the membrane-mimetic solvent 50% (v/v) trifluoroethanol-H2O, both peptides adopt a well-defined alpha-helical conformation that extends over almost all the sequence and incorporates a flexible bend. Both peptides significantly (p < 0.05) stimulate the rate of release of insulin from BRIN-BD11 clonal beta-cells at concentrations >= 0.1 nM but produce loss of integrity of the plasma membrane at concentrations >= 1 MUM. Increasing cationicity by the substitution Glu(17) -> l-Lys in Ps-1Pb and Glu(27) -> l-Lys in Ps-2Pa generates analogues with increased cytotoxicity and reduced insulin-releasing potency. In contrast, the analogues [R8r]Ps-1Pb and [K8k,K19k]Ps-2Pa, incorporating d-amino acid residues to destabilize the alpha-helical domains, retain potent insulin releasing activity but are nontoxic to BRIN-BD11 cells at concentrations of 3 MUM. [R8r]Ps-1Pb produces a significant increase in insulin release rate at 0.3 nM and [K8k,K19k]Ps-2Pa at 0.01 nM. Both analogues show low hemolytic activity (IC50 > 100 MUM) but retain broad-spectrum antimicrobial activity and remain cytotoxic to a range of human tumor cell lines, albeit with lower potency than the naturally occurring peptides. These analogues show potential for development into agents for type 2 diabetes therapy. PMID- 26606381 TI - A Phase II Study of S-1 for Previously Untreated Elderly Patients with Advanced Non-Small Cell Lung Cancer. AB - BACKGROUND: S-1, a novel oral fluoropyrimidine, is active in the treatment of non small cell lung cancer (NSCLC). However, data on S-1 for elderly patients with NSCLC are insufficient. METHODS: Eligibility criteria were no prior chemotherapy, stage IIIB or IV NSCLC, performance status 0-1, age >70 years, and adequate hematological, hepatic, and renal functions. Patients received S-1 (40 mg/m(2) twice a day) for 28 consecutive days. This schedule was repeated every 6 weeks. The primary end point was the tumor response rate. RESULTS: Thirty-two patients were enrolled and 31 patients were evaluable for response. The patients' median age was 80 years (range: 71-88). The response rate was 22.6% (95% CI: 11-38). Neutropenia, anemia, thrombocytopenia, febrile neutropenia, and diarrhea of grade >= 3 occurred in 6, 6, 10, 3, and 3%, respectively. CONCLUSIONS: In elderly patients with previously untreated advanced NSCLC, S-1 appears to be well tolerated and demonstrates encouraging activity. PMID- 26606382 TI - What Triggers a Diagnosis of HIV Infection in the Tokyo Metropolitan Area? Implications for Preventing the Spread of HIV Infection in Japan. AB - BACKGROUND: Japan has not succeeded in reducing the annual number of new HIV infected patients, although the prevalence of HIV infection is low (0.02%). METHODS: A single-center observational study was conducted at the largest HIV clinic in Tokyo, which treats 15% of the total patients in Japan, to determine the reasons for having diagnostic tests in newly infected individuals. HIV infected patients who visited our clinic for the first time between 2011 and 2014 were analyzed. RESULTS: The 598 study patients comprised one-third of the total reported number of new patients in Tokyo during the study period. 76% were Japanese MSM. The reasons for being tested which led to the diagnosis was voluntary testing in 32%, existing diseases in 53% (AIDS-defining diseases in 22%, sexually transmitted infections (STI) in 8%, diseases other than AIDS or STIs in 23%) and routine pre-surgery or on admission screening in 15%. 52% and 74% of the study patients and patients presented with AIDS, respectively, had never been tested. The median CD4 count in patients with history of previous testing (315/MUL) was significantly higher than that of patients who had never been tested (203/MUL, p<0.001). CONCLUSIONS: Only 32% of the newly HIV diagnosed patients were diagnosed because of voluntary testing, and 53% were diagnosed due to presence of other diseases. These results remain unchanged from our previous report 10 years earlier (2000-2004) on newly diagnosed patients at the same clinic. HIV testing has not been widely used by newly diagnosed patients in the Tokyo metropolitan area. PMID- 26606383 TI - Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases. AB - This review provides the reader with the up-to-date evidence-based basis for prescribing exercise as medicine in the treatment of 26 different diseases: psychiatric diseases (depression, anxiety, stress, schizophrenia); neurological diseases (dementia, Parkinson's disease, multiple sclerosis); metabolic diseases (obesity, hyperlipidemia, metabolic syndrome, polycystic ovarian syndrome, type 2 diabetes, type 1 diabetes); cardiovascular diseases (hypertension, coronary heart disease, heart failure, cerebral apoplexy, and claudication intermittent); pulmonary diseases (chronic obstructive pulmonary disease, asthma, cystic fibrosis); musculo-skeletal disorders (osteoarthritis, osteoporosis, back pain, rheumatoid arthritis); and cancer. The effect of exercise therapy on disease pathogenesis and symptoms are given and the possible mechanisms of action are discussed. We have interpreted the scientific literature and for each disease, we provide the reader with our best advice regarding the optimal type and dose for prescription of exercise. PMID- 26606384 TI - Dynamics in Supercooled Secondary Amide Mixtures: Dielectric and Hydrogen Bond Specific Spectroscopies. AB - Alkylacetamide-based model peptides display an intense Debye-type dielectric relaxation. In order to explore the extent to which this feature has to be regarded analogous to that in other supramolecular liquids, notably the monohydroxy alcohols, we applied broadband dielectric, time-dependent solvation, and near-infrared spectroscopies as well as shear rheology and various nuclear magnetic resonance techniques to mixtures of N-methylacetamide (NMA) or N ethylacetamide (NEA) with N-methylformamide. Compared in the modulus format, dielectric relaxation, solvation dynamics, and mechanical response indicate a common global and local dynamics. The present spin-relaxation measurements reflect motional processes which are significantly faster than the dominant Debye dielectric response, and a similar conclusion is drawn from measurements of the shear viscosity. The NH overtone stretching vibrations reveal a temperature dependent hydrogen-bond equilibrium that changes its characteristics near temperatures of 325 K. Finally, dielectric low-temperature data recorded for (NEA)0.4(NMF)0.6 mixed with 2-picoline indicate the existence of a critical concentration akin to the situation in various monohydroxy alcohol mixtures. PMID- 26606385 TI - Global Profiling and Novel Structure Discovery Using Multiple Neutral Loss/Precursor Ion Scanning Combined with Substructure Recognition and Statistical Analysis (MNPSS): Characterization of Terpene-Conjugated Curcuminoids in Curcuma longa as a Case Study. AB - To fully understand the chemical diversity of an herbal medicine is challenging. In this work, we describe a new approach to globally profile and discover novel compounds from an herbal extract using multiple neutral loss/precursor ion scanning combined with substructure recognition and statistical analysis. Turmeric (the rhizomes of Curcuma longa L.) was used as an example. This approach consists of three steps: (i) multiple neutral loss/precursor ion scanning to obtain substructure information; (ii) targeted identification of new compounds by extracted ion current and substructure recognition; and (iii) untargeted identification using total ion current and multivariate statistical analysis to discover novel structures. Using this approach, 846 terpecurcumins (terpene conjugated curcuminoids) were discovered from turmeric, including a number of potentially novel compounds. Furthermore, two unprecedented compounds (terpecurcumins X and Y) were purified, and their structures were identified by NMR spectroscopy. This study extended the application of mass spectrometry to global profiling of natural products in herbal medicines and could help chemists to rapidly discover novel compounds from a complex matrix. PMID- 26606386 TI - Cumulative (Dis)Advantage and the Matthew Effect in Life-Course Analysis. AB - To foster a deeper understanding of the mechanisms behind inequality in society, it is crucial to work with well-defined concepts associated with such mechanisms. The aim of this paper is to define cumulative (dis)advantage and the Matthew effect. We argue that cumulative (dis)advantage is an intra-individual micro level phenomenon, that the Matthew effect is an inter-individual macro-level phenomenon and that an appropriate measure of the Matthew effect focuses on the mechanism or dynamic process that generates inequality. The Matthew mechanism is, therefore, a better name for the phenomenon, where we provide a novel measure of the mechanism, including a proof-of-principle analysis using disposable personal income data. Finally, because socio-economic theory should be able to explain cumulative (dis)advantage and the Matthew mechanism when they are detected in data, we discuss the types of models that may explain the phenomena. We argue that interactions-based models in the literature traditions of analytical sociology and statistical mechanics serve this purpose. PMID- 26606387 TI - Stereospecific Rhodium-Catalyzed Allylic Substitution with Alkenyl Cyanohydrin Pronucleophiles: Construction of Acyclic Quaternary Substituted alpha,beta Unsaturated Ketones. AB - A highly regio- and stereospecific rhodium-catalyzed allylic alkylation of tertiary allylic carbonates with alkenyl cyanohydrin pronucleophiles is described. This protocol offers a fundamentally novel approach toward the synthesis of acyclic quaternary-substituted alpha,beta-unsaturated ketones and thereby provides a new cross-coupling strategy for target directed synthesis. A particularly attractive feature with this process is the ability to directly couple di-, tri- and tetrasubstituted alkenyl cyanohydrin pronucleophiles to prepare the corresponding alpha,beta-unsaturated ketone derivatives in a highly selective manner. Additionally, the chemoselective 1,4-reduction of the enone products provides rapid access to acyclic enantiomerically enriched alpha,alpha' dialkyl-substituted ketones, which are challenging motifs to prepare using conventional enolate alkylation. PMID- 26606388 TI - Trust-Enhanced Cloud Service Selection Model Based on QoS Analysis. AB - Cloud computing technology plays a very important role in many areas, such as in the construction and development of the smart city. Meanwhile, numerous cloud services appear on the cloud-based platform. Therefore how to how to select trustworthy cloud services remains a significant problem in such platforms, and extensively investigated owing to the ever-growing needs of users. However, trust relationship in social network has not been taken into account in existing methods of cloud service selection and recommendation. In this paper, we propose a cloud service selection model based on the trust-enhanced similarity. Firstly, the direct, indirect, and hybrid trust degrees are measured based on the interaction frequencies among users. Secondly, we estimate the overall similarity by combining the experience usability measured based on Jaccard's Coefficient and the numerical distance computed by Pearson Correlation Coefficient. Then through using the trust degree to modify the basic similarity, we obtain a trust-enhanced similarity. Finally, we utilize the trust-enhanced similarity to find similar trusted neighbors and predict the missing QoS values as the basis of cloud service selection and recommendation. The experimental results show that our approach is able to obtain optimal results via adjusting parameters and exhibits high effectiveness. The cloud services ranking by our model also have better QoS properties than other methods in the comparison experiments. PMID- 26606389 TI - Do Healthy Monarchs Migrate Farther? Tracking Natal Origins of Parasitized vs. Uninfected Monarch Butterflies Overwintering in Mexico. AB - Long-distance migration can lower parasite prevalence if strenuous journeys remove infected animals from wild populations. We examined wild monarch butterflies (Danaus plexippus) to investigate the potential costs of the protozoan Ophryocystis elektroscirrha on migratory success. We collected monarchs from two wintering sites in central Mexico to compare infection status with hydrogen isotope (delta2H) measurements as an indicator of latitude of origin at the start of fall migration. On average, uninfected monarchs had lower delta2H values than parasitized butterflies, indicating that uninfected butterflies originated from more northerly latitudes and travelled farther distances to reach Mexico. Within the infected class, monarchs with higher quantitative spore loads originated from more southerly latitudes, indicating that heavily infected monarchs originating from farther north are less likely to reach Mexico. We ruled out the alternative explanation that lower latitudes give rise to more infected monarchs prior to the onset of migration using citizen science data to examine regional differences in parasite prevalence during the summer breeding season. We also found a positive association between monarch wing area and estimated distance flown. Collectively, these results emphasize that seasonal migrations can help lower infection levels in wild animal populations. Our findings, combined with recent declines in the numbers of migratory monarchs wintering in Mexico and observations of sedentary (winter breeding) monarch populations in the southern U.S., suggest that shifts from migratory to sedentary behavior will likely lead to greater infection prevalence for North American monarchs. PMID- 26606390 TI - Removal of selected NSAIDs (nonsteroidal anti-inflammatory drugs) in aqueous samples by Octolig(r). AB - The possibility of removing representative nonsteroidal anti-inflammatory drugs (NSAIDs) from water was tested using Octolig(r), a commercially available material with polyethylenediimine moieties covalently attached to high-surface area silica gel. The effectiveness of removal should depend on selected NSAIDs having appropriate anionic functional groups. NSAIDs selected had aromatic carboxylic groups: diclofenac, fenoprofen, indomethacin, ketoprofen, mefenamic acid, naproxen, and sulindac. These substances in deionized (DI) water were removed by passage over Octolig columns with removal values approaching 90% at environmental pH values, e.g., ca pH 6. Fenoprofen, however, was only removed to an extent of 80% in DI water and 62% in well water, presumably a result of competition with bicarbonate ions. PMID- 26606392 TI - Enhancing and quenching luminescence with gold nanoparticle films: the influence of substrate on the luminescent properties. AB - Gold nanoparticle (AuNP) films were sputtered over glass and aluminum substrates to enhance optically stimulated luminescence (OSL), a luminescent technique employed for radiation detection, from x-ray irradiated NaCl nanocrystals. The AuNP films deposited over glass led to enhanced-OSL emission, whereas the AuNP films deposited on aluminum substrates quenched the OSL emission. The enhanced OSL intensity is proportional to the optical density of the film's plasmon resonance band at the stimulation wavelength. For the case of the AuNP/aluminum films, the luminescence quenching diminishes, and OSL intensity partially recovers upon increasing the distance between the AuNPs and the aluminum substrates, and between the luminescent nanocrystals and the AuNP films. These results suggest that plasmonic interactions between the emitter nanocrystals, the localized surface plasmons (LSP) of the AuNPs, and the substrate are responsible for the OSL enhancement and quenching. In this sense, the substrate dictates whether LSP relaxation occurs by radiative or non-radiative transisitions, leading to enhanced or quenched OSL, respectively. Therefore, besides showing that AuNP films can enhance and/or tune the sensitivity of luminescent radiation detectors, and demonstrating OSL as a new technique to investigate mechanisms of plasmon-enhanced luminescence, these results bring insights on how substrates strongly modify the optical properties of AuNP films. PMID- 26606394 TI - Clinical management of dilated cardiomyopathy: current knowledge and future perspectives. AB - Dilated cardiomyopathy (DCM) is a primary heart muscle disease characterized by a progressive dilation and dysfunction of either the left or both ventricles. The management of DCM is currently challenging for clinicians. The persistent lack of knowledge about the etiology and pathophysiology of this disease continues to determine important fields of uncertainty in managing this condition. Molecular cardiology and genetics currently represent the most crucial horizon of increasing knowledge. Understanding the mechanisms underlying the disease allows clinicians to treat this disease more effectively and to further improve outcomes of DCM patients through advancements in etiologic characterization, prognostic stratification and individualized therapy. Left ventricular reverse remodeling predicts a lower rate of major cardiac adverse events independently from other factors. Optimized medical treatment and device implantation are pivotal in inducing left ventricular reverse remodeling. Newly identified targets, such as angiotensin-neprilysin inhibition, phosphodiesterase inhibition and calcium sensitizing are important in improving prognosis in patients affected by DCM. PMID- 26606393 TI - Bullying and Victimization in Overweight and Obese Outpatient Children and Adolescents: An Italian Multicentric Study. AB - OBJECTIVE: Being overweight or obese is one of the most common reasons that children and adolescents are teased at school. We carried out a study in order to investigate: i) the relation between weight status and school bullying and ii) the relation between weight status categories and types of victimization and bullying in an outpatient sample of Italian children and adolescents with different degrees of overweight from minimal overweight up to severe obesity. PARTICIPANTS/METHODS: Nine-hundred-forty-seven outpatient children and adolescents (age range 6.0-14.0 years) were recruited in 14 hospitals distributed over the country of Italy. The participants were classified as normal-weight (N = 129), overweight (N = 126), moderately obese (N = 568), and severely obese (N = 124). The nature and extent of verbal, physical and relational bullying and victimization were assessed with an adapted version of the revised Olweus bully victim questionnaire. Each participant was coded as bully, victim, bully-victim, or not involved. RESULTS: Normal-weight and overweight participants were less involved in bullying than obese participants; severely obese males were more involved in the double role of bully and victim. Severely obese children and adolescents suffered not only from verbal victimization but also from physical victimization and exclusion from group activities. Weight status categories were not directly related to bullying behaviour; however severely obese males perpetrated more bullying behaviour compared to severely obese females. CONCLUSIONS: Obesity and bullying among children and adolescents are of ongoing concern worldwide and may be closely related. Common strategies of intervention are needed to cope with these two social health challenges. PMID- 26606395 TI - Transcriptome Analysis Revealed Highly Expressed Genes Encoding Secondary Metabolite Pathways and Small Cysteine-Rich Proteins in the Sclerotium of Lignosus rhinocerotis. AB - Lignosus rhinocerotis (Cooke) Ryvarden (tiger milk mushroom) has long been known for its nutritional and medicinal benefits among the local communities in Southeast Asia. However, the molecular and genetic basis of its medicinal and nutraceutical properties at transcriptional level have not been investigated. In this study, the transcriptome of L. rhinocerotis sclerotium, the part with medicinal value, was analyzed using high-throughput Illumina HiSeqTM platform with good sequencing quality and alignment results. A total of 3,673, 117, and 59,649 events of alternative splicing, novel transcripts, and SNP variation were found to enrich its current genome database. A large number of transcripts were expressed and involved in the processing of gene information and carbohydrate metabolism. A few highly expressed genes encoding the cysteine-rich cerato platanin, hydrophobins, and sugar-binding lectins were identified and their possible roles in L. rhinocerotis were discussed. Genes encoding enzymes involved in the biosynthesis of glucans, six gene clusters encoding four terpene synthases and one each of non-ribosomal peptide synthetase and polyketide synthase, and 109 transcribed cytochrome P450 sequences were also identified in the transcriptome. The data from this study forms a valuable foundation for future research in the exploitation of this mushroom in pharmacological and industrial applications. PMID- 26606396 TI - Diagnosis of Giant Cell Arteritis in an Asymptomatic Patient. PMID- 26606397 TI - Neuropathy Target Esterase Is Degraded by the Ubiquitin-Proteasome Pathway with ARA54 as the Ubiquitin Ligase. AB - Neuropathy target esterase (NTE) is an endoplasmic reticulum membrane-associated phospholipase B, which is essential for embryonic and nervous system development. However, the regulation of NTE at the protein level had not been thoroughly investigated. Our previous study showed that NTE was degraded not only by the macroautophagy-lysosome pathway but also by the ubiquitin-proteasome pathway. Here we further reveal that androgen receptor-associated protein 54 (ARA54) regulated the ubiquitin-proteasome degradation of NTE. We find that deletion of the regulatory domain of NTE, which possesses a putative destruction box and thus is essential for its degradation by the proteasome, prevented its degradation by the proteasome. In addition, we demonstrate that ARA54, which has a RING finger domain and E3 ligase activity, interacts directly with NTE. Overexpression of ARA54 downregulates the protein level of NTE, and knockdown of ARA54 inhibits the degradation of NTE. The mutation in the RING domain of ARA54 blocks the degradation of NTE by ARA54, which indicates that the RING domain is essential for ARA54's E3 activity. These findings suggest that ARA54 acts as the ubiquitin ligase to regulate the ubiquitin-proteasome degradation of NTE. PMID- 26606399 TI - The phylogenetic distribution, anatomy and histology of the post-cloacal bones and adnexa of geckos. AB - Post-cloacal bones of gekkotans may be present as a single (medial) pair, two pairs (medial and lateral), or may be lacking. We, herein, demonstrate that the presence of a single medial pair is the ancestral condition for the Gekkota, that the lateral pair is of sporadic occurrence within and between families, except for the Eublepharidae where it is universal, and that absence is also of sporadic occurrence except for the Sphaerodactylidae where it is the ancestral condition. Adult male Tokay geckos (Gekko gecko) possess only the medial pair of bones, and these exhibit a regionally-specific expression of woven, fibrolamellar, and lamellar bone, and an enclosed medullary cavity. Females and small juvenile males lack bony elements but exhibit a conspicuous band of dense connective tissue located about the anterior and lateral margins of the cloacal sacs. As males grow and attain sexual maturity, the medial post-cloacal bones condense in this band of dense connective tissue, and are thus shown to be dermal ossifications, similar to osteoderms but with muscular associations (although this is also known for crocodylians). Based upon ontogenetic data we set forth a scenario to explain the loss of the medial post-cloacal bones in various lineages. Differential staining of the cloacal sacs failed to reveal any specialized glandular structures. Investigation of the post-cloacal spurs shows them to be associated with cellular connective tissue of a type similar to that found in the vicinity of the medial post-cloacal bones. This suggests that the lateral post-cloacal bones may also be dermal bones, but histological evidence is needed to corroborate this. PMID- 26606398 TI - Association of Triple Therapy With Improvement in Cholesterol Profiles Over Two Year Followup in the Treatment of Early Aggressive Rheumatoid Arthritis Trial. AB - OBJECTIVE: To evaluate long-term changes in cholesterol levels in patients with early rheumatoid arthritis (RA) who were randomized to begin treatment with methotrexate (MTX) monotherapy, MTX plus etanercept, or triple therapy (MTX plus sulfasalazine plus hydroxychloroquine) in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial. METHODS: Levels of total cholesterol, low density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were analyzed in 416 patients participating in the TEAR trial, during 102 weeks of followup. Associations of cholesterol changes with disease activity and drug treatment were evaluated using repeated-measures analysis with mixed effect linear models to model within-subject covariance over time. RESULTS: Mixed effect models controlling for traditional cardiovascular (CV) risk factors, TEAR treatment, and baseline prednisone and statin use demonstrated significant inverse associations of RA disease activity with changes in cholesterol over time. Decreases in the 28-joint Disease Activity Score, the C-reactive protein level, or the erythrocyte sedimentation rate were associated with increases in levels of HDL cholesterol, LDL cholesterol, and total cholesterol in all treatment groups (P < 0.001-0.035). Triple therapy was strongly associated with higher levels of HDL cholesterol, lower levels of LDL cholesterol, and higher ratios of total cholesterol:HDL cholesterol (P < 0.001 for all) compared to MTX monotherapy or MTX plus etanercept therapy over the 2-year followup. CONCLUSION: Decreases in RA disease activity over long-term followup were associated with increases in cholesterol levels in patients with early RA treated with either biologic or nonbiologic therapies. The use of triple therapy during 2 years of followup was associated with higher HDL cholesterol levels, lower LDL cholesterol levels, and lower total cholesterol:HDL cholesterol ratios compared to those observed in patients who received MTX monotherapy or MTX plus etanercept combination therapy. Additional studies are needed to assess the effects of these cholesterol changes on CV events in patients with RA. PMID- 26606400 TI - Temperature-Responsive Chiral (A)6B Supramolecular Cages Based on Conformational Preferences. AB - Two chiral (A)6B-typed supramolecular cages were constructed from hydrogen-bonded C6 -symmetric zinc porphyrin hexamers and chiral C3-symmetric pyridyl hexadentates with a core of 1,3,5-triphenylbenzene. Circular dichroism and molecular simulations revealed that the symmetry of the supramolecular cages switched from pseudo-C3v to C3 with the rotational confinement of the biphenyl backbones at low temperatures, which generated conformationally chiral transfer and amplification. This unique phenomenon suggests a new strategy to develop smart materials with high sensitivity and excellent reversibility. PMID- 26606401 TI - Immuno-Northern Blotting: Detection of RNA Modifications by Using Antibodies against Modified Nucleosides. AB - The biological roles of RNA modifications are still largely not understood. Thus, developing a method for detecting RNA modifications is important for further clarification. We developed a method for detecting RNA modifications called immuno-northern blotting (INB) analysis and herein introduce its various capabilities. This method involves the separation of RNAs using either polyacrylamide or agarose gel electrophoresis, followed by transfer onto a nylon membrane and subsequent immunoblotting using antibodies against modified nucleosides for the detection of specific modifications. We confirmed that INB with the antibodies for 1-methyladenosine (m1A), N6-methyladenosine (m6A), pseudouridine, and 5-methylcytidine (m5C) showed different modifications in a variety of RNAs from various species and organelles. INB with the anti-m5C antibody revealed that the antibody cross-reacted with another modification on DNA, suggesting the application of this method for characterization of the antibody for modified nucleosides. Additionally, using INB with the antibody for m1A, which is a highly specific modification in eukaryotic tRNA, we detected tRNA derived fragments known as tiRNAs under the cellular stress response, suggesting the application for tracking target RNA containing specific modifications. INB with the anti-m6A antibody confirmed the demethylation of m6A by the specific demethylases fat mass and obesity-associated protein (FTO) and ALKBH5, suggesting its application for quantifying target modifications in separated RNAs. Furthermore, INB demonstrated that the knockdown of FTO and ALKBH5 increased the m6A modification in small RNAs as well as in mRNA. The INB method has high specificity, sensitivity, and quantitative capability, and it can be employed with conventional experimental apparatus. Therefore, this method would be useful for research on RNA modifications and metabolism. PMID- 26606402 TI - Functional Restoration for Chronic Pain Patients in the Military: Early Results of the San Antonio Military Medical Center Functional Restoration Program. PMID- 26606403 TI - Posttraumatic Stress Disorder: Five Vicious Cycles that Inhibit Effective Treatment. AB - Despite a wide range of studies and medical progress, it seems that we are far from significantly mitigating the problem of posttraumatic stress disorder (PTSD). The problem has major social and behavioral components. Developing innovative and effective policies requires a broad scope of analysis and consideration of the highly interconnected social, behavioral, and medical variables. In this article, we take a systems approach and offer an illustrative causal loop diagram which includes individual and social dynamics. Based on the map, we discuss 5 major barriers for effective interventions in PTSD. These barriers work as vicious cycles in the system, reduce effectiveness and therefore value of PTSD treatment. We also discuss policy implications of this perspective. PMID- 26606404 TI - Reliability of a Novel Return to Duty Screening Tool for Military Clinicians. AB - PURPOSE/HYPOTHESIS: Lower extremity and low back injuries represent a significant financial burden on the military healthcare system. Subsequent injuries often occur during the recuperation period or in the period directly after physical therapy ends when the patient returns to full duty. Medical providers have relatively few objective tools with which to determine if someone is ready for return to duty (RTD). The purpose of this study is to assess interrater and test retest reliability of a novel gender-neutral RTD screening tool that requires minimal training, equipment, and time. SUBJECTS: This study included 34 active duty military participants (male=22, female=12, age=28.5 +/- 5.9). 23 subjects (male=14, female=9, age=28.7 +/- 6.3) returned for follow-up testing within one week. MATERIALS/METHODS: After answering a medical questionnaire, all participants completed the RTD screening tool consisting of: (1) modified anterior reach, (2) modified deep squat, (3) modified trunk stability push-up, (4) modified hip abduction test, (5) forward step-down under low-light conditions, (6) modified Feagin hop test, and (7) perceived risk of future injury. Each individual event was qualitatively scored from 0 to 2 or 3. The composite score ranged from 0 to 16 with higher scores indicating better performance. RESULTS: For the primary rater, the mean score was 11.26 +/- 2.35 during the first trial session and 12.43 +/- 1.47 during the second trial session. For the secondary rater, the mean score during the first trial session was 11.38 +/- 2.51 and 12.61 +/- 1.73 during the second session. There was good interrater reliability for the composite score (intraclass correlation coefficient [ICC] (2,1)=0.88 (0.78, 0.94)). The test-retest reliability was moderate (ICC (3,1)=0.57, (0.21, 0.79)). The chance-corrected agreement was acceptable for all individual events except the modified hip abduction test. There were no significant differences between male and female composite scores. CONCLUSIONS: This novel RTD screening tool showed good overall interrater reliability, suggesting that entry-level clinicians trained on the grading requirements are able to reliably administer the tool. In addition, the screen showed gender-neutrality with no significant differences between men and women. However, the RTD screening tool had only moderate test-retest reliability, suggesting the possible presence of a learning effect. The modified hip abduction test demonstrated poor chance-corrected agreement. Future research should consider including a longer practice session to ameliorate any possible learning effect and to modify the hip abduction test to improve reliability. CLINICAL RELEVANCE: This study has demonstrated that a novel RTD screening tool can reliably be administered to an active duty population to assist clinicians in making RTD decisions. However, at this time, it cannot be determined if a certain composite or individual event score will indicate increased risk for injury. PMID- 26606406 TI - US Military Drawdowns 1970-1999: Army Medical Department and Military Health System Responses. PMID- 26606405 TI - Incremental Effects of Telephone Call Center and Healthcare Utilization Database Use to Improve Follow-up Rate in the Prevention of Low Back Pain in the Military Trial. AB - BACKGROUND: Studies that have relied exclusively on web-based surveys to secure follow-up have yielded inadequate follow-up rates, resulting in the need to explore whether supplementing with other methods results in incremental improvements. The primary purpose of this study was to determine the effectiveness of each follow up strategy that was used to collect the follow up data in our ongoing Prevention of Low Back Pain in the Military (POLM) trial. METHODS: This study represents a secondary analysis of the POLM trial. Twenty companies of Soldiers (N=4,325) were cluster randomized to complete one of four exercise programs. Since web-based response rates were lower than anticipated, a telephone call center was established to contact Soldiers who had not responded to the web-based survey. A military healthcare utilization database (M2) was also used to capture additional follow-up. Descriptive statistics and pairwise comparisons were performed to determine the incremental benefits of supplementing the primary web-based follow-up strategy in our ongoing POLM trial and determine whether differences existed in demographic characteristics, pain intensity, and low back pain incidence based on follow-up strategy. RESULTS: Of the 4,325 Soldiers who were enrolled, 632 (14.6%) subjects completed the monthly web-based survey only; 571 (13.2%) responded only to the telephone call; and 233 (5.4%) responded to both the web-based and telephone survey. Adding the telephone call center contributed 804 unique contributions to follow-up, increasing the overall follow-up to 33.2% (n=1,436) and resulting in a net 18.6% increase in follow-up rate. Querying the M2 database yielded follow-up data for an additional 2,788 Soldiers, increasing the follow-up rate by 64.5%. This rate, combined with the web-based and telephone strategies, resulted in an overall follow-up rate of 97.7%. Compared to the web-based survey, those who responded to the telephone call center tended to be younger, white, have a lower income, more likely to smoke, more likely to exercise regularly, and less likely to have low back pain (all with P<.05). CONCLUSIONS: The results of this study can inform the design of future clinical trials by establishing the benefit of supplementing a web-based survey with a telephone call center to secure additional follow-up. PMID- 26606407 TI - Using Evidence to Increase Compliance with Therapeutic Stretching for Chronic Low Back Pain. AB - PURPOSE: In June 2012, a team of nurses at the Army's Landstuhl Regional Medical Center was tasked to generate an evidence-based practice recommendation for patients experiencing chronic low back pain (CLBP). METHODOLOGY: Based on 14 articles, the evidence (a) validated the use of therapeutic stretching for control of CLBP, (b) identified specific modalities to increase patient adherence, and (c) supported military relevance. The team developed a questionnaire to assess previous experience with stretching exercises and preferred learning methods. Based on the responses from 32 patients, the initial goals included an increase in patient reported compliance within 3 months and a decrease in reported pain within 6 months. Long-terms goals targeted a 90% patient compliance in daily stretching regimen and a continued decrease in pain within 1 year. RESULTS: At 3 months, a 96% compliance rate was reported for patients returning for follow-up appointments; however, the average reported pain level did not decrease. IMPLICATIONS: Similar clinics could benefit from methods/tools used in this project, especially where lack of compliance becomes a deterrent to quality of care. PMID- 26606408 TI - Paralysis as a Presenting Symptom of Hyperthyroidism in an Active Duty Soldier. AB - Thyrotoxic periodic paralysis (TPP) is an endocrine disorder presenting with proximal motor weakness, typically greatest in the lower extremities, hypokalemia, and signs or laboratory findings consistent with hyperthyroidism. The incidence of TPP is highest in Asian males. This is a case report of a 30 year-old male active duty Soldier who presented to the emergency department complaining of several recent episodes of lower extremity paralysis. The patient underwent a workup which included serum and cerebrospinal fluid studies, and was found to be hypokalemic and hyperthyroid. Following consultation with neurology, the patient was admitted to the medicine service and treated for thyrotoxic periodic paralysis with potassium replacement and treatment of his hyperthyroidism. Since achieving a euthyroid state, he has had no recurrences of TPP. This disease should be considered in patients presenting with symmetric motor weakness and hypokalemia, whether or not symptoms of hyperthyroidism are elicited during the review of systems. PMID- 26606409 TI - A Field-Expedient Method for Direct Detection of Enterotoxigenic E Coli and Shigella from Stool. AB - We describe a field-expedient analytic system that fills a unique and critical public health role and potentially provides a valuable aid in diagnostics. Dual fluorigenic, hydrolysis probe (TaqMan), PCR assays for detection of causative agents of enterotoxigenic Escherichia coli (ETEC) disease and shigellosis/bacillary dysentery were prepared in a thermal-stable, hydrolytic enzyme resistant format. The assays were packaged as a kit for use with a portable, ruggedized, qRT-PCR thermocycler. The analytical limit of detection of each q RT-PCR: ETEC-STIa, ETEC-STIb, and ETEC-LT assay was 30 colony forming units (CFU) and Shigella/enteroinvasive E coli assay was 3 CFU. During field evaluation, testing was conducted using a blind-panel of 138 stored stool samples previously obtained from enterotoxigenic E coli disease (n=91) and shigellosis (n=47) patients. Sample processing and analyses were completed in 3 days. Test results of the qRT-PCR assays showed promise as aid in pathogen identification when compared to culture, digoxigenin-labeled probe (ETEC), and serotyping (Shigella) the qRT-PCR. The sensitivity of each of the 4 qRT-PCR assays was 100% and specificity was ETEC-STIa (92.4%), ETEC-STIb (92.6%), ETEC-LT (79.6%), and Shigella/enteroinvasive E coli (81.6%). Sequencing of qRT-PCR amplicon indicated that the sensitivity and specificity of each qRT-PCR assay exceeded the comparator methods. The system shows promise as a rapid method for direct detection of ETEC and Shigella from stool and is applicable for use in clinical diagnostics and biosurveillance as an extension of temporary field laboratories or as a part of fixed reference laboratory facilities. PMID- 26606410 TI - Data Analytics Under Deployed Conditions: A Case Study. AB - Like their colleagues in fixed facilities, healthcare planners operating in a combat environment face the problem of transforming data into actionable information. Not all data is useful for decision-making and not all data comes neatly packaged. In this case study, the authors present an effort to collect and analyze data about forward surgical team utilization. The article shares the variety of data collected and the process of analysis, and concludes with a recommended process for data analysis in the field. PMID- 26606411 TI - Implementation of TeamSTEPPS at a Level-1 Military Trauma Center: The San Antonio Military Medical Center Experience. AB - CONTEXT: When a health care system deals with complex trauma patients while simultaneously serving as an educational platform, teamwork and clear communication are imperative. While there are numerous tools and resources available to address the concerns surrounding patient safety, Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) emphasizes a team approach to improve communication among all caregivers and is specifically designed to improve patient safety through improved communication. This article reports the interim results of implementation of TeamSTEPPS in the operating room environment at the most complex and busiest tertiary military trauma center in the Department of Defense in the midst of the longest period of continuous combat operations in US history. METHODS: Data were collected from December 2013 through March 2014 on the number of total cases performed by month, number of debrief surveys submitted for those months, and associated percentage of surveys completed based on case category. RESULTS: The overall compliance rate for the TeamSTEPPS process (from the pre-op brief to the debrief survey completion) was 75.1%. Responses showed a decrease in concerns in all areas during the period of observation. Equipment-related complaints decreased by 48%; instrument-related issues decreased by 29.9%; supply issues decreased by 53.3%; personnel issues decreased by 90.5%; case scheduling issues decreased by 35.7%; and preference card issues decreased by 72.1%. CONCLUSIONS: Our results demonstrate that TeamSTEPPS can be successfully implemented in an integrated level-1 trauma center in the midst of combat casualty care with a greater than 75% overall compliance with TeamSTEPPS briefs. Further study on the sustainability of these results and the effect on operating room safety, productivity, and efficiency is necessary. PMID- 26606412 TI - Integration and Coordination of Governmental, Nongovernmental, and Host Nation Preventive Medicine Assets During Medical Stability Operations. PMID- 26606413 TI - A Review of Supplementary Medical Aspects of Post-Cold War UN Peacekeeping Operations: Trends, Lessons Learned, Courses of Action, and Recommendations. AB - Post-Cold War United Nations Peace Keeping Operations (UN PKOs) have been increasingly involved in dangerous areas with ill-defined boundaries, harsh and remote geographies, simmering internecine armed conflict, and disregard on the part of some local parties for peacekeepers' security and role. In the interest of force protection and optimizing operations, a key component of UN PKOs is healthcare and medical treatment. The expectation is that UN PKO medical support will adjust to the general intent and structure of UN PKOs. To do so requires effective policies and planning informed by a review of all medical aspects of UN PKO operations, including those considered supplementary, that is, less crucial but contributing nonetheless. Medical aspects considered paramount and key to UN PKOs have received relatively thorough treatment elsewhere. The intent of this article is to report on ancillary and supplemental medical aspects practical to post-Cold War UN PKO operations assembled through an iterative inquiry of open source articles. Recommendations are made about possible courses of action in terms of addressing trends found in such medical aspects of PKOs and relevance of US/NATO/European Union models and research. PMID- 26606414 TI - Nursing in the 8th Evacuation Hospital, 1942-1945. AB - This article describes the experiences of Army nurses in the University of Virginia sponsored 8th Evacuation Hospital during World War II. In addition, it examines gender and role differences within the Army Medical Department, and how nurses' contributions helped shape the profession. This research used traditional historical methods of inquiry to include both primary and secondary sources of information. Primary sources include newspaper clippings, letters, citations, and photographs from the archival collections of the 8th Evacuation Hospital located in the University of Virginia Historical Collections and Services, Charlottesville, VA, and journal articles from that period. Secondary sources consisted of bibliographical and historical texts. Evidence suggests that advances in the chain-of-evacuation, antibiotics, dissemination of blood products, and nurses' expanded roles all contributed to increased survival of the wounded. Nurses' performance garnered an enduring respect from combatants who received care, as well as the medical officers and enlisted personnel with whom they worked on a daily basis. Collaboration, mutual respect, and coordinated teamwork were critical for mission success. Army nurses demonstrated that they had the mettle to go into a war zone and perform in an exemplary manner. PMID- 26606415 TI - Leveraging Health Information Technology to Improve Quality in Federal Healthcare. AB - PURPOSE: Healthcare delivery in America is extremely complex because it is comprised of a fragmented and nonsystematic mix of stakeholders, components, and processes. Within the US healthcare structure, the federal healthcare system is poised to lead American medicine in leveraging health information technology to improve the quality of healthcare. We posit that through developing, adopting, and refining health information technology, the federal healthcare system has the potential to transform federal healthcare quality by managing the complexities associated with healthcare delivery. Although federal mandates have spurred the widespread use of electronic health records, other beneficial technologies have yet to be adopted in federal healthcare settings. The use of health information technology is fundamental in providing the highest quality, safest healthcare possible. In addition, health information technology is valuable in achieving the Agency for Healthcare Research and Quality's implementation goals. METHODS: We conducted a comprehensive literature search using the Google Scholar, PubMed, and Cochrane databases to identify an initial list of articles. Through a thorough review of the titles and abstracts, we identified 42 articles as having relevance to health information technology and quality. Through our exclusion criteria of currency of the article, citation frequency, applicability to the federal health system, and quality of research supporting conclusions, we refined the list to 11 references from which we performed our analysis. RESULTS: The literature shows that the use of computerized physician order entry has significantly increased accurate medication dosage and decreased medication errors. The use of clinical decision support systems have significantly increased physician adherence to guidelines, although there is little evidence that indicates any significant correlation to patient outcomes. Research shows that interoperability and usability are continuing challenges for implementation. COMMENT: The Veterans Administration is the only entity within the federal health system that has published research on the use of health information technology to improve quality. The federal healthcare system has existing systems in place with computerized physician order entry systems and clinical decision support systems, but these should be advanced. CONCLUSION: Particular focus and attention should be placed on data mining capabilities, integrating the electronic health record across all aspects of care, using the electronic health record to improve quality at the point of care, and developing interoperable and usable health information technology. PMID- 26606416 TI - Measurement of microvesicle levels in human blood using flow cytometry. AB - Microvesicles are fragments of cells released when the cells are activated, injured, or apoptotic. Analysis of microvesicle levels in blood has the potential to shed new light on the pathophysiology of many diseases. Flow cytometry is currently the only method that can simultaneously separate true lipid microvesicles from other microparticles in blood, determine the cell of origin and other microvesicle characteristics, and handle large numbers of clinical samples with a reasonable effort, but expanded use of flow cytometric measurement of microvesicle levels as a clinical and research tool requires improved, standardized assays. The goal of this review is to aid investigators in applying current best practices to microvesicle measurements. First pre-analytical factors are evaluated and data summarized for anticoagulant effects, sample transport and centrifugation. Next flow cytometer optimization is reviewed including interference from background in buffers and reagents, accurate microvesicle counting, swarm interference, and other types of coincidence errors, size calibration, and detection limits using light scattering, impedance and fluorescence. Finally current progress on method standardization is discussed and a summary of current best practices provided. (c) 2016 Clinical Cytometry Society. PMID- 26606417 TI - Antidepressants and Gastric Cancer: A Nationwide Population-Based Nested Case Control Study. AB - BACKGROUND: To our knowledge, no epidemiological study has reported on whether an association between antidepressant exposure and gastric cancer exists. Herein, we aim to investigate the possible association between antidepressant exposure and gastric cancer incidence. METHODS: Using a nested case-control design, we identified 26289 cases with gastric cancer and 127984 controls from Taiwan's National Health Insurance Research Database (NHIRD). The data were analyzed using a conditional logistic regression model adjusting for possible confounding variables. RESULTS: We found antidepressant use did not increase the risk of gastric cancer. The lack of an association between antidepressant prescription and elevated gastric cancer incidence was apparent for across selective serotonin reuptake inhibitors (SSRIs), tricyclic agents (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), reversible inhibitors of monoamine oxidase A (RIMA), trazodone, mirtazapine and bupropion. There were slightly decreased gastric cancer risks of SSRIs use (?28 DDD group, adjusted OR = 0.87; 95% CI = 0.78 0.96). Sensitive analysis showed SSRIs, TCAs, and SNRIs did not increase gastric cancer risks significantly even in the group with peptic ulcer history. CONCLUSIONS: An association between antidepressant exposure and gastric cancer was not apparent in this analysis. PMID- 26606418 TI - Increased BOLD activation in the left parahippocampal cortex after 1 year of medical school: an association with cumulative verbal memory learning. AB - Although several studies have shown left-right hippocampus asymmetry during learning, it is unclear whether such asymmetry also exists for the parahippocampal cortex, a structure within the limbic system that is also involved in memory and learning. Using a common mental navigation task known to activate the bilateral parahippocampal cortex, this study aimed at determining how BOLD activation in these two areas changes after 1 year of medical school, a program characterized by intensive verbal learning. Fifteen first-year medical students participated in this study and underwent two sessions of functional MRI, at a 1-year interval. In the first session, we observed marginal differences between left and right parahippocampal cortex activity. However, 1 year later, left parahippocampal activation significantly increased (+4.7%), whereas the right remained stable. These results bring new information as to how intensive learning can modify regional metabolism in the human brain and how the left parahippocampal region is particularly important for cumulative verbal memory. PMID- 26606419 TI - Understanding Engagement in Home-Based Interactive Computer Play: Perspectives of Children With Unilateral Cerebral Palsy and Their Caregivers. AB - AIMS: This study aimed to understand engagement of children in a home-based computer program, "Move it to improve it" (MitiiTM), designed to enhance motor, cognitive and visual perceptual skills. METHODS: Participants were 10 children with unilateral cerebral palsy involved in the 20-week MitiiTM program (mean age = 11 years; 5 males) and their caregivers. Semi-structured interviews were audio recorded, transcribed verbatim and analyzed independently by two researchers. Themes were identified using an inductive approach to identify themes, and mapped against an engagement framework. (King et al., 2014 ). RESULTS: Key themes were: (1) Child/family characteristics: children's interest captured through novelty and technology, motivation declines as novelty wears off, children require "finely tuned" programs, strong family support facilitates engagement, and children develop confidence and ownership; (2) Intervention characteristics: increased therapy frequency with reduced caregiver involvement, MitiiTM "becomes therapy" and competes with other interests; convenience within family routine, lack of real-time feedback and technical issues, and therapist guidance is essential; and (3) Service provider characteristics: initial and ongoing therapist input, family-friendly therapy approach, and tailored strategies to sustain engagement. CONCLUSIONS: Therapists should be cognisant of factors that may impact on children's engagement in home-based computer programs and devise individual strategies with families to support sustained engagement. PMID- 26606420 TI - Genome Analysis of Staphylococcus agnetis, an Agent of Lameness in Broiler Chickens. AB - Lameness in broiler chickens is a significant animal welfare and financial issue. Lameness can be enhanced by rearing young broilers on wire flooring. We have identified Staphylococcus agnetis as significantly involved in bacterial chondronecrosis with osteomyelitis (BCO) in proximal tibia and femorae, leading to lameness in broiler chickens in the wire floor system. Administration of S. agnetis in water induces lameness. Previously reported in some cases of cattle mastitis, this is the first report of this poorly described pathogen in chickens. We used long and short read next generation sequencing to assemble single finished contigs for the genome and a large plasmid from the chicken pathogen. Comparison of the S. agnetis genome to those of other pathogenic Staphylococci shows that S.agnetis contains a distinct repertoire of virulence determinants. Additionally, the S. agnetis genome has several regions that differ substantially from the genomes of other pathogenic Staphylococci. Comparison of our finished genome to a recent draft genome for a cattle mastitis isolate suggests that future investigations focus on the evolutionary epidemiology of this emerging pathogen of domestic animals. PMID- 26606421 TI - Pre-diabetes tsunami: incidence rates and risk factors of pre-diabetes and its different phenotypes over 9 years of follow-up. AB - AIMS: To investigate the incidence of pre-diabetes and its different phenotypes and the related risk factors during 9 years of follow-up. METHODS: A total of 5879 people (2597 men and 3282 women) aged >= 20 years, free of diabetes and pre diabetes, took part in the study. Multivariable Cox proportional hazard models were used to evaluate hazard ratios (HR) and 95% confidence intervals (CI) for all potential risk factors. RESULTS: Overall, 853 men and 902 women developed pre diabetes. Incidence rates of pre-diabetes were 46.1 per 1000 person-years in men and 36.8 per 1000 person-years in women, while isolated impaired fasting glucose had the highest incidence rate among all pre-diabetes phenotypes. In both sexes, age, family history of diabetes, fasting plasma glucose and 2-hour post-challenge plasma glucose were related to incident pre-diabetes. Among women, waist-to height ratio [HR: 1.02 (1.00-1.03)] and being divorced/widowed compared with married [HR: 0.67 (0.52-0.87)] were significant predictors of pre-diabetes; whereas among men, community-based intervention [HR: 0.79 (0.68-0.90)], higher level of education and being single [HR: 0.77 (0.6-0.97)] were protective against progression to pre-diabetes. Moreover, hip circumference among women [HR: 0.95 (0.93-0.98)] and current smoking among men [HR: 1.69 (1.15-2.48)] were related to incident combined impaired fasting glucose and impaired glucose tolerance. CONCLUSION: More than 4% of the Iranian population develop pre-diabetes each year, emphasizing the important role of socio-economic factors (marital status, education and smoking habits) and community-based intervention in progression to impaired glucose regulations. Thus, emergent intervention is necessary to halt the tsunami of pre-diabetes among the Iranian population. PMID- 26606422 TI - Mild Thyroid Hormone Insufficiency During Development Compromises Activity Dependent Neuroplasticity in the Hippocampus of Adult Male Rats. AB - Severe thyroid hormone (TH) deficiency during critical phases of brain development results in irreversible neurological and cognitive impairments. The mechanisms accounting for this are likely multifactorial, and are not fully understood. Here we pursue the possibility that one important element is that TH affects basal and activity-dependent neurotrophin expression in brain regions important for neural processing. Graded exposure to propylthiouracil (PTU) during development produced dose-dependent reductions in mRNA expression of nerve growth factor (Ngf) in whole hippocampus of neonates. These changes in basal expression persisted to adulthood despite the return to euthyroid conditions in blood. In contrast to small PTU-induced reductions in basal expression of several genes, developmental PTU treatment dramatically reduced the activity-dependent expression of neurotrophins and related genes (Bdnft, Bdnfiv, Arc, and Klf9) in adulthood and was accompanied by deficits in hippocampal-based learning. These data demonstrate that mild TH insufficiency during development not only reduces expression of important neurotrophins that persists into adulthood but also severely restricts the activity-dependent induction of these genes. Considering the importance of these neurotrophins for sculpting the structural and functional synaptic architecture in the developing and the mature brain, it is likely that TH-mediated deficits in these plasticity mechanisms contribute to the cognitive deficiencies that accompany developmental TH compromise. PMID- 26606424 TI - Survey of the Deficits in Surgeons' Knowledge of Contralateral Prophylactic Mastectomy. PMID- 26606423 TI - Cholinergic neuronal lesions in the medial septum and vertical limb of the diagonal bands of Broca induce contextual fear memory generalization and impair acquisition of fear extinction. AB - Previous research has shown that the ventral medial prefrontal cortex (vmPFC) and hippocampus (Hipp) are critical for extinction memory. Basal forebrain (BF) cholinergic input to the vmPFC and Hipp is critical for neural function in these substrates, which suggests BF cholinergic neurons may be critical for extinction memory. In order to test this hypothesis, we applied cholinergic lesions to different regions of the BF and observed the effects these lesions had on extinction memory. Complete BF cholinergic lesions induced contextual fear memory generalization, and this generalized fear was resistant to extinction. Animals with complete BF cholinergic lesions could not acquire cued fear extinction. Restricted cholinergic lesions in the medial septum and vertical diagonal bands of Broca (MS/vDBB) mimicked the effects that BF cholinergic lesions had on contextual fear memory generalization and acquisition of fear extinction. Cholinergic lesions in the horizontal diagonal band of Broca and nucleus basalis (hDBB/NBM) induced a small deficit in extinction of generalized contextual fear memory with no accompanying deficits in cued fear extinction. The results of this study reveal that MS/vDBB cholinergic neurons are critical for inhibition and extinction of generalized contextual fear memory, and via this process, may be critical for acquisition of cued fear extinction. Further studies delineating neural circuits and mechanisms through which MS/vDBB cholinergic neurons facilitate these emotional memory processes are needed. (c) 2015 Wiley Periodicals, Inc. PMID- 26606425 TI - Evaluation of Mercury Contamination in Fungi Boletus Species from Latosols, Lateritic Red Earths, and Red and Yellow Earths in the Circum-Pacific Mercuriferous Belt of Southwestern China. AB - For the first time, highly elevated levels of mercury (Hg) have been documented for several species of the edible Fungi genus Boletus growing in latosols, lateritic red earths, and red and yellow earths from the Yunnan province of China. Analysis of Hg concentrations in the genus suggests that geogenic Hg is the dominant source of Hg in the fungi, whereas anthropogenic sources accumulate largely in the organic layer of the forest soil horizon. Among the 21 species studied from 32 locations across Yunnan and 2 places in Sichuan Province, the Hg was found at elevated level in all samples from Yunnan but not in the samples from Sichuan, which is located outside the mercuriferous belt. Particularly abundant in Hg were the caps of fruiting bodies of Boletus aereus (up to 13 mg kg 1 dry matter), Boletus bicolor (up to 5.5 mg kg-1 dry matter), Boletus edulis (up to 22 mg kg-1 dry matter), Boletus luridus (up to 11 mg kg-1 dry matter), Boletus magnificus (up to 13 mg kg-1 dry matter), Boletus obscureumbrinus (up to 9.4 mg kg-1 dry matter), Boletus purpureus (up to 16 mg kg-1 dry matter), Boletus sinicus (up to 6.8 mg kg-1 dry matter), Boletus speciosus (up to 4.9mg kg-1 dry matter), Boletus tomentipes (up to 13 mg kg-1 dry matter), and Boletus umbriniporus (up to 4.9 mg kg-1 dry matter). Soil samples of the 0-10 cm topsoil layer from the widely distributed locations had mercury levels ranging between 0.034 to 3.4 mg kg-1 dry matter. In Yunnan, both the soil parent rock and fruiting bodies of Boletus spp. were enriched in Hg, whereas the same species from Sichuan, located outside the mercuriferous belt, had low Hg concentrations, suggesting that the Hg in the Yunnan samples is mainly from geogenic sources rather than anthropogenic sources. However, the contribution of anthropogenically derived Hg sequestered within soils of Yunnan has not been quantified, so more future research is required. Our results suggest that high rates of consumption of Boletus spp. from Yunnan can deliver relatively high doses of Hg to consumers, but that rates can differ widely because of large variability in mercury concentrations between species and locations. PMID- 26606427 TI - Proceedings of the 5th Meeting of the Core Outcome Measures in Effectiveness Trials (COMET) Initiative. PMID- 26606426 TI - Differential binding of ppGpp and pppGpp to E. coli RNA polymerase: photo labeling and mass spectral studies. AB - (p)ppGpp, a secondary messenger, is induced under stress and shows pleiotropic response. It binds to RNA polymerase and regulates transcription in Escherichia coli. More than 25 years have passed since the first discovery was made on the direct interaction of ppGpp with E. coli RNA polymerase. Several lines of evidence suggest different modes of ppGpp binding to the enzyme. Earlier cross linking experiments suggested that the beta-subunit of RNA polymerase is the preferred site for ppGpp, whereas recent crystallographic studies pinpoint the interface of beta'/omega-subunits as the site of action. With an aim to validate the binding domain and to follow whether tetra- and pentaphosphate guanosines have different location on RNA polymerase, this work was initiated. RNA polymerase was photo-labeled with 8-azido-ppGpp/8-azido-pppGpp, and the product was digested with trypsin and subjected to mass spectrometry analysis. We observed three new peptides in the trypsin digest of the RNA polymerase labeled with 8-azido-ppGpp, of which two peptides correspond to the same pocket on beta' subunit as predicted by X-ray structural analysis, whereas the third peptide was mapped on the beta-subunit. In the case of 8-azido-pppGpp-labeled RNA polymerase, we have found only one cross-linked peptide from the beta'-subunit. However, we were unable to identify any binding site of pppGpp on the beta-subunit. Interestingly, we observed that pppGpp at high concentration competes out ppGpp bound to RNA polymerase more efficiently, whereas ppGpp cannot titrate out pppGpp. The competition between tetraphosphate guanosine and pentaphosphate guanosine for E. coli RNA polymerase was followed by gel-based assay as well as by a new method known as DRaCALA assay. PMID- 26606428 TI - Body Image in Dyadic and Solitary Sexual Desire: The Role of Encoding Style and Distracting Thoughts. AB - This study explored the link between body image and desire to engage in sexual activity (dyadic and solitary desire) in adult women living in a long-term couple relationship. Moreover, it considered two psychological factors that may underlie such a link: the occurrence of body-related distracting thoughts during sexual activity and encoding style (i.e., the tendency to rely on preexisting internal schemata versus external information at encoding). A total of 53 women (29 to 47 years old) in heterosexual relationships completed questionnaires assessing sexual desire (dyadic, solitary), body image, body-related distracting thoughts during sexual activity, and encoding style. Results showed that poor body image was associated with low dyadic and solitary sexual desire. Body-related distracting thoughts during sexual activity mediated the link between body image and solitary (but not dyadic) sexual desire. Finally, the mediation of body related distracting thoughts between body image and solitary sexual desire was moderated by encoding style. A negative body image promoted the occurrence of body-related distracting thoughts during sexual activity, especially in internal encoders. Our study highlights the importance of body image, distracting thoughts, and encoding style in women's solitary sexuality and suggests possible factors that may reduce the impact of those body-related factors in dyadic sexual desire. PMID- 26606429 TI - Ligation of Intersphincteric Fistula Tract vs Ligation of the Intersphincteric Fistula Tract Plus a Bioprosthetic Anal Fistula Plug Procedure in Patients With Transsphincteric Anal Fistula: Early Results of a Multicenter Prospective Randomized Trial. AB - OBJECTIVE: The purpose of this study was to compare the ligation of intersphincteric fistula tract (LIFT) with an additional plug (LIFT-plug) in the treatment of transsphincteric anal fistula. SUMMARY BACKGROUND DATA: Both LIFT and LIFT-plug are recently reported effective alternatives of transsphincteric anal fistula. METHODS: This multicenter prospective randomized study (NCT01478139) was conducted at 5 university hospitals throughout China. A total of 235 patients were randomly assigned to undergo LIFT (118 patients) or LIFT plug (117 patients) between March 2011 and April 2013. The primary outcome measured was primary healing rate at 6 months postoperatively and healing time. Secondary outcomes included recurrence rate, postoperative pain, and incontinence rate. RESULTS: The LIFT procedure showed shorter operative time than the LIFT plug procedure (26.7 min vs 28.5 min, P = 0.03). Median healing time was 22 days in LIFT-plug group vs 30 days in LIFT group (P < 0.001). The difference in visual analog scale scores across all time points was not statistically significant between the groups (P = 0.13). The primary healing rate was higher in LIFT-plug group than in LIFT group [94.0% (95% confidence interval 89.7%-98.3%) vs 83.9% (95% confidence interval 77.2%-90.6%), P < 0.001]. There were no reported incontinence and recurrence within the follow-up period of 6 months. CONCLUSIONS: In patients with transsphincteric anal fistulas, both LIFT-plug and LIFT are simple, safe, and effective procedures. LIFT-plug has the advantage of a higher healing rate, less healing time, and a lower early postoperative pain score. PMID- 26606431 TI - Clean, fast and preserving normal anatomy: "the Helsinki revolution" in microneurosurgery. AB - After the senior author took chairmanship in Helsinki University Hospital in, he led the department into making neurosurgical operations much faster, safer and workflow more efficient, and at the same time maintaining high surgical quality and results. The aim was to describe the philosophies and style of Helsinki Microneurosurgery. The philosophies of Helsinki Neurosurgery are categorized into two concepts: The operation room TEAM concept and the main principle "Simple, clean, fast and respecting the normal anatomy". The way to be efficient is to find good methods based on logic, reason and experience. Specific and systematic procedures before the microneurosurgery followed by high quality skills under the microscope are of utmost importance. Moreover, intraoperatively, neuroanesthesia has to provide good surgical conditions. Today, Helsinki University Central hospital Department of Neurosurgery has an annual workflow 3500 neurosurgical operations. We believe that microneurosurgical treatment remains to be important for years ahead, and neurosurgeons of great hearts, minds and skills are welcomed all over the world. PMID- 26606430 TI - Pseudomonas aeruginosa in Dairy Goats: Genotypic and Phenotypic Comparison of Intramammary and Environmental Isolates. AB - Following the identification of a case of severe clinical mastitis in a Saanen dairy goat (goat A), an average of 26 lactating goats in the herd was monitored over a period of 11 months. Milk microbiological analysis revealed the presence of Pseudomonas aeruginosa in 7 of the goats. Among these 7 does, only goat A showed clinical signs of mastitis. The 7 P. aeruginosa isolates from the goat milk and 26 P. aeruginosa isolates from environmental samples were clustered by RAPD-PCR and PFGE analyses in 3 genotypes (G1, G2, G3) and 4 clusters (A, B, C, D), respectively. PFGE clusters A and B correlated with the G1 genotype and included the 7 milk isolates. Although it was not possible to identify the infection source, these results strongly suggest a spreading of the infection from goat A. Clusters C and D overlapped with genotypes G2 and G3, respectively, and included only environmental isolates. The outcome of the antimicrobial susceptibility test performed on the isolates revealed 2 main patterns of multiple resistance to beta-lactam antibiotics and macrolides. Virulence related phenotypes were analyzed, such as swarming and swimming motility, production of biofilm and production of secreted virulence factors. The isolates had distinct phenotypic profiles, corresponding to genotypes G1, G2 and G3. Overall, correlation analysis showed a strong correlation between sampling source, RAPD genotype, PFGE clusters, and phenotypic clusters. The comparison of the levels of virulence related phenotypes did not indicate a higher pathogenic potential in the milk isolates as compared to the environmental isolates. PMID- 26606432 TI - Prevention of ischemic complications during aneurysm surgery. AB - Ischemic complications during aneurysm surgery are a frequent cause of postoperative infarctions and new neurological deficits. In this article, we discuss imaging and neurophysiological tools that may help the surgeon to detect intraoperative ischemia. The strength of intraoperative digital subtraction angiography (DSA) is the full view of the arterial and venous vessel. DSA is the gold standard in complex and giant aneurysms, but due to certain disadvantages, it cannot be considered standard of care. Microvascular Doppler sonography is probably the fastest diagnostic tool and can quickly aid diagnosis of large vessel occlusions. Intraoperative indocyanine green videoangiography is the best tool to assess flow in perforating and larger arteries, as well as occlusion of the aneurysm sac. Intraoperative neurophysiological monitoring with somatosensory and motor evoked potentials indirectly measures blood flow by recording neuronal function. It covers all causes of intraoperative ischemia, provided that ischemia occurs in the brain areas under surveillance. However, every method has advantages and disadvantages. No single method is superior to the others in every aspect. Therefore, it is very important for the neurosurgeon to know the strengths and weaknesses of each tool in order to have them available, to know how to use them for each individual situation, and to be ready to apply them within the time window for reversible cerebral ischemia. PMID- 26606433 TI - A review and update on the current and emerging clinical trials for the acute management of cervical spine and spinal cord injuries - Part III. AB - INTRODUCTION: Spinal cord injury (SCI) is a debilitating disease with an average annual incidence of 29.5 persons per million worldwide. Hence, it is critical to refine and bolster evidence to inform standards of care and improve outcomes. EVIDENCE ACQUISITION: In 2013 the American Association of Neurological Surgeons and the Congress of Neurological Surgeons released updated management guidelines for acute cervical spine injuries and SCI; here, we explore cervical SCI treatment trials since the 2013 publication. Of 56 studies published in the Cochrane Library Central Register of Controlled Trials, 19 met inclusion criterion of acute cervical spine injury and are summarized across 4 subcategories: diagnosis, surgical stabilization, scopes/instrumentation, and therapeutic outcomes. EVIDENCE SYNTHESIS: We confirm the utility of computed tomography for diagnosis, and improved outcomes associated with early (<24 hours) decompressive surgery. We describe advances in laryngoscopy and intubation under various SCI indications. We explore the benefits of continuous positive airway pressure protocols for reducing respiratory insufficiency, and patient education standards for transfer and mobility success. We report on ongoing randomized controlled trials (RCT) for surgical and therapeutic approaches for subpopulations of interest, including incomplete cord lesion, canal stenosis, and riluzole pharmacotherapy. We recommend a large, multicenter, prospective confirmatory RCT to assess the impact of timing of surgery versus conservative management in an effort to generate Class I evidence on the topic. CONCLUSIONS: Such a study should utilize shared, common variables as outlined by the National Institutes of Health SCI Common Data Elements to enable international collaboration and data pooling for robust, reproducible analyses. PMID- 26606434 TI - Mechanism of Action, Efficacy, and Adverse Events of Calcium Antagonists in Hypertrophic Scars and Keloids: A Systematic Review. AB - BACKGROUND: Pathological scars often cause major cosmetic and functional consequences, which make effective treatment important. Intralesional therapies are widely used, with corticosteroid injection considered to be first choice. An emerging and promising treatment option is the calcium antagonist verapamil. OBJECTIVE: To provide a comprehensive evidence-based review of current evidence on mechanism of action, efficacy, and adverse events of calcium antagonists in treatment of hypertrophic scars and keloids. METHODS AND MATERIALS: A Cochrane Library and PubMed search was performed for the literature pertaining to treatment with calcium antagonists in pathological scars. Articles were categorized into two groups: mechanism of action or efficacy and adverse events. RESULTS: Six in vitro studies were included in the first subgroup. Calcium antagonists have been found to reduce extra cellular matrix production, induce procollagenase synthesis, and inhibit interleukin-6, vascular endothelial growth factor, and proliferation of fibroblasts. Eight studies with a median level of evidence of 3.5 (range: 2-4) were included in the second category. A good efficacy with no major side effects was reported for calcium antagonists. CONCLUSION: Important methodological shortcomings of the available literature were identified. Interesting results have been reported, but further large scale, high-quality studies are needed to optimally evaluate efficacy of treatment with calcium antagonists. PMID- 26606435 TI - HYC-24L Demonstrates Greater Effectiveness With Less Pain Than CPM-22.5 for Treatment of Perioral Lines in a Randomized Controlled Trial. AB - OBJECTIVE: This trial compares the effectiveness and safety of HYC-24L (Juvederm Ultra XC; Allergan plc, Dublin, Ireland) (24 mg/mL of hyaluronic acid, 0.3% lidocaine) and CPM-22.5 (Belotero Balance; Merz Aesthetics, Raleigh, NC) (22.5 mg/mL of hyaluronic acid) for the treatment of perioral lines. MATERIALS AND METHODS: Men and women aged 35 years or older with moderate-to-severe perioral lines were recruited for this randomized controlled, rater-blinded, 2-arm trial. The primary endpoint was a comparison of rater-assessed responder rates by the validated 4-point Perioral Lines Severity Scale at Month 6; responders were those who showed a >=1 point improvement. A secondary endpoint was subject-assessed change in perioral lines measured by the Global Assessment of Change Scale. RESULTS: A total of 136 subjects received treatment and 132 completed the trial (mean age: 58 +/- 8 years). Total volume injected was 1.18 mL (HYC-24L) and 1.32 mL (CPM-22.5). At Month 6, a significantly greater proportion of HYC-24L subjects responded to treatment (87%) than CPM-22.5 subjects (72%) (p < .04). At all time points, HYC-24L subjects reported significantly greater improvement in their perioral lines than CPM-22.5 subjects, with the greatest difference at Month 6. No unexpected adverse events occurred. CONCLUSION: HYC-24L subjects showed a higher response rate and a greater improvement in their perioral lines than CPM 22.5 subjects for up to 6 months. PMID- 26606436 TI - High Patient Satisfaction of a Hyaluronic Acid Filler Producing Enduring Full Facial Volume Restoration: An 18-Month Open Multicenter Study. AB - BACKGROUND: Volume restoration is an essential part of facial rejuvenation. OBJECTIVE: To assess long-term full-facial volume restoration using HAEL Volume Lidocaine hyaluronic acid filler. METHODS: An 18-month open study in 60 subjects with at least Grade 2 on the 4-point volume loss scale (VLS) for full face and at least 2 indications affected among chin, temporal areas, jawline, cheeks, cheekbones, and nasolabial folds (NLF). Performance was assessed by VLS, Lemperle rating scale (LRS), investigator Global Aesthetic Improvement Scale (GAIS), and 3 dimensional (3D) imaging. RESULTS: Most subjects (71.6%) had 3 or 4 indications injected, most commonly cheekbones (96.7%) and NLF (93.3%). At 18 months, at least a 1-grade improvement in VLS was observed for full face (68.3% of subjects), chin (77.8%), temporal areas (73.7%), cheeks (66.6%), cheekbones (58.6%), jawline (43.1%), and NLF (71.4%; LRS). For all indications, more than 60% of the volume gained at 3 weeks was sustained at 18 months based on 3D digital imaging. At 18 months, 95.0% of subjects had improved full-face GAIS and all subjects were satisfied with their aesthetic outcome. One subject (1.6%) had treatment-related adverse events. CONCLUSION: Full-facial volume restoration was well sustained over 18 months with high patient satisfaction and good tolerability. PMID- 26606437 TI - Pan-Facial Volumization: The New Face of Youth. PMID- 26606438 TI - The Food and Drug Administration Safety Communication on Unintentional Injection of Soft-Tissue Filler Into Facial Blood Vessels: Important Points and Perspectives. PMID- 26606439 TI - Commentary on Eruptive Keratoacanthomas After Photodynamic Therapy. PMID- 26606440 TI - Seeing Is Believing: Images of Wound Healing for Patient Education. PMID- 26606441 TI - Commentary for Treatment of Thin Linear Scars on the Scalp. PMID- 26606442 TI - Early in vivo discrimination of vulnerable atherosclerotic plaques that disrupt: A serial MRI study. AB - BACKGROUND AND AIMS: MRI has been validated as a suitable imaging modality for in vivo, non-invasive detection of atherosclerosis and has provided quantitative predictors of high-risk plaque. Here, we apply serial MRI to monitor the natural progression of plaques over a 3-month period in a rabbit model of atherothrombosis to determine differences over time between plaques that ultimately disrupt to form a luminal mural thrombus and plaques that remain stable. METHODS: Atherosclerotic plaques were induced in 12 male New Zealand White (NZW) rabbits by aortic endothelial injury and a 1% cholesterol diet. The rabbits were imaged 5 times: at baseline, 1, 2, and 3 months, and 48hr after pharmacological triggering for plaque disruption. RESULTS: Starting at 2 months, plaques that disrupted after triggering exhibited a higher remodeling ratio (RR, 1.05 +/- 0.11 vs 0.97 +/- 0.10, p = 0.0002) and a larger vessel wall area (VWA, 6.99 +/- 1.54 mm(2) vs 6.30 +/- 1.37 mm(2), p = 0.0072) than the stable non disrupted plaques. The same trends were observed at 3 months: plaques that disrupted had a higher RR (1.04 +/- 0.02 vs 0.99 +/- 0.01, p = 0.0209), VWA (8.19 +/- 2.69 mm(2) vs 6.81 +/- 1.60 mm(2), p = 0.0001), and increased gadolinium uptake (75.51 +/- 13.77% for disrupted vs 31.02 +/- 6.45% for non-disrupted, p = 0.0022). CONCLUSIONS: MR images of plaques that disrupted revealed larger VWAs, RRs, and increased gadolinium uptake at 2 months and continued progression of these vulnerable features between 2 and 3 months. Non-disrupted plaques had an independent history without these hallmarks of vulnerability. Our results show that MRI can provide early detection of plaques at a higher-risk for luminal thrombosis. PMID- 26606443 TI - Is it all about load? PMID- 26606445 TI - Polydopamine-based coordination nanocomplex for T1/T2 dual mode magnetic resonance imaging-guided chemo-photothermal synergistic therapy. AB - Despite the progress in the design and synthesis of theranostic agents, limitations on efficiency and safety offer significant room for improvement in these agents. Inspired by the natural binding ability of polydopamine nanospheres (PDAs) with iron ion, a simple and versatile synthesis strategy is developed to prepare biodegradable coordination polymer (CP) encapsulated PDAs nanocomplex (PDAs@CPx, x = 3, 6, 9). We found that the PDAs@CP3 can serve as a T1/T2 dual mode contrast agent (DMCA) for magnetic resonance imaging (MRI), which possesses high longitudinal (r1 = 7.524 mM(-1) s(-1)) and transverse (r2 = 45.92 mM(-1) s( 1)) relaxivities. In this system, benefitting from the high photothermal conversion efficiency derived from PDAs, DOX loaded PDAs@CP3 nanocomplex is able to not only destroy the tumor directly by heat, but also stimulate the chemotherapy by enabling NIR-responsive on demand delivery of DOX. To the best of our knowledge, this is the first example exploring the potential of PDAs@CPx nanocomplex for T1/T2 dual mode MRI-guided chemo-photothermal synergistic therapy. This work extends the currently available theranostic agents, and opens up new avenues to rationally design the high-performance T1/T2 DMCA. PMID- 26606446 TI - Tissue engineered pre-vascularized buccal mucosa equivalents utilizing a primary triculture of epithelial cells, endothelial cells and fibroblasts. AB - Artificial generated buccal mucosa equivalents are a promising approach for the reconstruction of urethral defects. Limiting in this approach is a poor blood vessel supply after transplantation, resulting in increased morbidity and necrosis. We generated a pre-vascularized buccal mucosa equivalent in a tri culture of primary buccal epithelial cells, fibroblasts and microvascular endothelial cells, using a native collagen membrane as a scaffold. A successful pre-vascularization and dense formation of capillary-like structures at superficial areas was demonstrated. The lumen size of pre-formed blood vessels corresponded to the capillary size in vivo (10-30 MUm). Comparing native with a highly cross-linked collagen membrane we found a distinct higher formation of capillary-like structures on the native membrane, apparently caused by higher secretion of angiogenic factors such as PDGF, IL-8 and angiopoietin by the cells. These capillary-like structures became functional blood vessels through anastomosis with the host vasculature after implantation in nude mice. This in vitro method should result in an accelerated blood supply to the biomaterial with cells after transplantation and increase the succes rates of the implant material. PMID- 26606444 TI - Poly(ethylene glycol) hydrogels with cell cleavable groups for autonomous cell delivery. AB - Cell-responsive hydrogels hold tremendous potential as cell delivery devices in regenerative medicine. In this study, we developed a hydrogel-based cell delivery vehicle, in which the encapsulated cell cargo control its own release from the vehicle in a protease-independent manner. Specifically, we have synthesized a modified poly(ethylene glycol) (PEG) hydrogel that undergoes degradation responding to cell-secreted molecules by incorporating disulfide moieties onto the backbone of the hydrogel precursor. Our results show the disulfide-modified PEG hydrogels disintegrate seamlessly into solution in presence of cells without any external stimuli. The rate of hydrogel degradation, which ranges from hours to months, is found to be dependent upon the type of encapsulated cells, cell number, and fraction of disulfide moieties present in the hydrogel backbone. The differentiation potential of human mesenchymal stem cells released from the hydrogels is maintained in vitro. The in vivo analysis of these cell-laden hydrogels, through a dorsal window chamber and intramuscular implantation, demonstrated autonomous release of cells to the host environment. The hydrogel mediated implantation of cells resulted in higher cell retention within the host tissue when compared to that without a biomaterial support. Biomaterials that function as a shield to protect cell cargos and assist their delivery in response to signals from the encapsulated cells could have a wide utility in cell transplantation and could improve the therapeutic outcomes of cell-based therapies. PMID- 26606447 TI - DNA-AuNP networks on cell membranes as a protective barrier to inhibit viral attachment, entry and budding. AB - Viral infections have caused numerous diseases and deaths worldwide. Due to the emergence of new viruses and frequent virus variation, conventional antiviral strategies that directly target viral or cellular proteins are limited because of the specificity, drug resistance and rapid clearance from the human body. Therefore, developing safe and potent antiviral agents with activity against viral infection at multiple points in the viral life cycle remains a major challenge. In this report, we propose a new modality to inhibit viral infection by fabricating DNA conjugated gold nanoparticle (DNA-AuNP) networks on cell membranes as a protective barrier. The DNA-AuNPs networks were found, via a plaque formation assay and viral titers, to have potent antiviral ability and protect host cells from human respiratory syncytial virus (RSV). Confocal immunofluorescence image analysis showed 80 +/- 3.8% of viral attachment, 91.1 +/ 0.9% of viral entry and 87.9 +/- 2.8% of viral budding were inhibited by the DNA AuNP networks, which were further confirmed by real-time fluorescence imaging of the RSV infection process. The antiviral activity of the networks may be attributed to steric effects, the disruption of membrane glycoproteins and limited fusion of cell membrane bilayers, all of which play important roles in viral infection. Therefore, our results suggest that the DNA-AuNP networks have not only prophylactic effects to inhibit virus attachment and entry, but also therapeutic effects to inhibit viral budding and cell-to-cell spread. More importantly, this proof-of-principle study provides a pathway for the development of a universal, broad-spectrum antiviral therapy. PMID- 26606448 TI - A highly tumor-specific light-triggerable drug carrier responds to hypoxic tumor conditions for effective tumor treatment. AB - Light-triggered drug delivery is among the most investigated stimulus-response strategies and has been widely explored in cancer treatment. However, the limited specificity of light-triggered drug delivery reduces the therapeutic efficacy and causes considerable undesirable side effects. In this work, we demonstrate a highly tumor-specific light-triggerable drug carrier (H-LTDC) induced by a combination of internal (i.e., tumor hypoxia) and external stimuli (i.e., light). The doxorubicin (DOX)-loaded H-LTDC was self-assembled from type-1-reactive oxygen species (ROStype1)-mediated degradable chondroitin sulfate (CS) conjugated with a photosensitizer (PS), Pheophorbide-a, which has a spherical shape and a uniform size distribution. Under hypoxic conditions, ROSType1 was mainly generated due to the electron-rich sulfate groups in the polysaccharide backbone. The ROStype1 generated by H-LTDC allowed laser-triggered drug release at low oxygen concentrations. From the in vitro cytotoxicity tests with colon cancer cells (HCT-116), under laser irradiation, DOX-loaded H-LTDCs showed higher toxicity under hypoxic conditions than that under normoxic conditions. In vivo and ex vivo biodistribution studies demonstrated that H-LTDCs selectively accumulated in the tumor tissues. As a result, drug-loaded H-LTDCs exhibited high anti-tumor activity in vivo. Overall, we believe that this approach could represent a promising platform for the treatment of tumor and hypoxia-associated diseases without undesirable side effects. PMID- 26606449 TI - A histological analysis of human median and ulnar nerves following implantation of Utah slanted electrode arrays. AB - For decades, epineurial electrodes have been used in clinical therapies involving the stimulation of peripheral nerves. However, next generation peripheral nerve interfaces for applications such as neuroprosthetics would benefit from an increased ability to selectively stimulate and record from nerve tissue. This increased selectivity may require the use of more invasive devices, such as the Utah Slanted Electrode Array (USEA). Previous research with USEAs has described the histological response to the implantation of these devices in cats and rats; however, no such data has been presented in humans. Therefore, we describe here the degree of penetration and foreign body reaction to USEAs after a four-week implantation period in human median and ulnar nerves. We found that current array designs penetrate a relatively small percentage of the available endoneurial tissue in these large nerves. When electrode tips were located within the endoneurial tissue, labels for axons and myelin were found in close proximity to electrodes. Consistent with other reports, we found activated macrophages attached to explanted devices, as well as within the tissue surrounding the implantation site. Despite this inflammatory response, devices were able to successfully record single- or multi-unit action potentials and elicit sensory percepts. However, modifying device design to allow for greater nerve penetration, as well as mitigating the inflammatory response to such devices, would likely increase device performance and should be investigated in future research. PMID- 26606450 TI - Hitchhiking nanoparticles: Reversible coupling of lipid-based nanoparticles to cytotoxic T lymphocytes. AB - Following intravenous injection of anti-cancer nanomedicines, many barriers need to be overcome en route to the tumor. Cell-mediated delivery of nanoparticles (NPs) is promising in terms of overcoming several of these barriers based on the tumoritropic migratory properties of particular cell types. This guided transport aims to enhance the NP accumulation in the tumor and moreover enhance the infiltration of regions that are typically inaccessible for free NPs. Within this study, cytotoxic CD8(+) T cells were selected as carriers based on both their ability to migrate to the tumor and their intrinsic cytolytic activity against tumor cells. Many anti-cancer nanomedicines require tumor cell internalization to mediate cytosolic drug delivery and enhance the anti-cancer effect. This proof-of concept therefore reports on the reversible attachment of liposomes to the surface of cytotoxic T lymphocytes via a reduction sensitive coupling. The activation status of the T cells and the liposome composition are shown to strongly influence the loading efficiency. Loading the cells with liposomes does not compromise T cell functionalities like proliferation and cytolytic function. Additionally, the triggered liposome release is demonstrated upon the addition of glutathione. Based on this optimization using liposomes as model NPs, a small interfering RNA (siRNA)-loaded NP was developed that can be coupled to the surface of CD8(+) T cells. PMID- 26606452 TI - Risk Factors Associated with Parasitic Infection Among Municipality Solid-Waste Workers in an Egyptian Community. AB - Solid-waste management is associated with several health hazards, particularly parasitic infection. The objective of the study was to determine the association between risk factors and the occurrence of intestinal parasitic infections (potentially pathogenic) among municipal waste collectors in Alexandria, Egypt. A cross-sectional survey was conducted in the main municipality company in Alexandria. A total of 346 municipality solid-waste workers (MSWWs) was interviewed using an in-depth questionnaire. The type of parasitic infections among waste handlers was determined using formol-ether concentration and modified Ziehl-Neelsen technique. About half of the workers were infected with parasites. The profile of parasitic infection revealed 12 parasitic species. These were comprised of the following helminths: Schistosoma mansoni (13.3%), Enterobius vermicularis (1.7%), Ascaris lumbricoides (1.4%), and Hymenolepis nana ova (0.6%). Among protozoa were pathogenic Entamoeba histolytica (3.2%), Giardia intestinalis (2.9%), nonpathogenic protozoa such as Entamoeba coli (1.7%), and potentially pathogenic or opportunistic ones as Cryptosporidium (23.4%), Microsporidia (20.25%), Cyclospora (2.0%), Blastocystis hominis (1.7%), and Cystoisospora belli (1.2%). About 1.4% of MSWWs have pediculosis and phthiriasis in their scalp and eyelashes respectively. Risk factors for infection were associated with direct exposure to solid fecal waste (odds ratio [OR] = 1.8, confidence interval [CI] = 1.1-3.0) and occupational activities that allowed for direct exposure to solid fecal waste (OR = 2.3, CI = 1.4-4.0). Logistic regression model has revealed that educational level and residence were the factors that contribute to parasitic infection among MSWWs (P < 0.05). MSWWs are at high risk of acquiring parasitic infections. Data of the present study highlighted the need for greater biomonitoring of MSWWs and the improvement of environmental conditions and health care in such marginalized communities to prevent parasitic infection and associated morbidities. PMID- 26606451 TI - Effect of prevascularization on in vivo vascularization of poly(propylene fumarate)/fibrin scaffolds. AB - The importance of vascularization in the field of bone tissue engineering has been established by previous studies. The present work proposes a novel poly(propylene fumarate) (PPF)/fibrin composite scaffold for the development of vascularized neobone tissue. The effect of prevascularization (i.e., in vitro pre culture prior to implantation) with human mesenchymal stem cells (hMSCs) and human umbilical vein endothelial cells (HUVECs) on in vivo vascularization of scaffolds was determined. Five conditions were studied: no pre-culture (NP), 1 week pre-culture (1P), 2 week pre-culture (2P), 3 week pre-culture (3P), and scaffolds without cells (control, C). Scaffolds were implanted subcutaneously in a severe combined immunodeficiency (SCID) mouse model for 9 days. During in vitro studies, CD31 staining showed a significant increase in vascular network area over 3 weeks of culture. Vascular density was significantly higher in vivo when comparing the NP and 3P groups. Immunohistochemical staining of human CD-31 expression indicated spreading of vascular networks with increasing pre-culture time. These vascular networks were perfused with mouse blood indicated by perfused lectin staining in human CD-31 positive vessels. Our results demonstrate that in vitro prevascularization supports in vivo vascularization in PPF/fibrin scaffolds. PMID- 26606453 TI - Mineral Metabolites, Angiotensin II Inhibition and Outcomes in Advanced Chronic Kidney Disease. AB - BACKGROUND: Evidence suggests that the renin-angiotensin-aldosterone system (RAAS) interacts with the vitamin D-fibroblast growth factor 23-Klotho axis. We investigated whether circulating mineral metabolism markers modify outcomes in response to RAAS inhibition in subjects with advanced chronic kidney disease (CKD). METHODS: In this retrospective cohort study, we analyzed the association of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) use with all-cause mortality and dialysis initiation among 1,753 subjects (1,099 CKD, estimated glomerular filtration rate 18 +/- 6 ml/min/1.73 m(2) and 654 end-stage renal disease [ESRD]) from the Homocysteine in Kidney and End Stage Renal Disease (HOST) study. A propensity score analysis accounted for indication bias and Cox regression models adjusted for mineral metabolism markers. RESULTS: Mean follow-up was 3.2 years; 714 (41%) subjects died and 615 (56%) initiated dialysis. In adjusted analyses, all subjects treated with ACEI/ARB had a significantly lower hazard of death (hazards ratio (HR) 0.81, 95% CI 0.70-0.95, p = 0.007). Those with CKD not on dialysis and treated with ACEI/ARB trended toward a lower hazard of dialysis initiation (HR 0.86, 95% CI 0.73-1.01, p = 0.06). The association with mortality did not differ by level of mineral metabolism marker (p for interaction >0.16); however, the relationship with dialysis initiation differed according to the median serum phosphorus level (p for interaction <0.001). CONCLUSIONS: RAAS inhibition was associated with decreased all-cause mortality independent of disordered mineral metabolism among mostly male HOST subjects with advanced CKD and ESRD. However, among those with CKD not requiring dialysis, the renoprotection associated with RAAS inhibition was attenuated by higher serum phosphorus levels. Further studies are needed to confirm this association. PMID- 26606454 TI - Characterization of Leukemia-Inducing Genes Using a Proto-Oncogene/Homeobox Gene Retroviral Human cDNA Library in a Mouse In Vivo Model. AB - The purpose of this research is to develop a method to screen a large number of potential driver mutations of acute myeloid leukemia (AML) using a retroviral cDNA library and murine bone marrow transduction-transplantation system. As a proof-of-concept, murine bone marrow (BM) cells were transduced with a retroviral cDNA library encoding well-characterized oncogenes and homeobox genes, and the virus-transduced cells were transplanted into lethally irradiated mice. The proto oncogenes responsible for leukemia initiation were identified by PCR amplification of cDNA inserts from genomic DNA isolated from leukemic cells. In an initial screen of ten leukemic mice, the MYC proto-oncogene was detected in all the leukemic mice. Of ten leukemic mice, 3 (30%) had MYC as the only transgene, and seven mice (70%) had additional proto-oncogene inserts. We repeated the same experiment after removing MYC-related genes from the library to characterize additional leukemia-inducing gene combinations. Our second screen using the MYC-deleted proto-oncogene library confirmed MEIS1and the HOX family as cooperating oncogenes in leukemia pathogenesis. The model system we introduced in this study will be valuable in functionally screening novel combinations of genes for leukemogenic potential in vivo, and the system will help in the discovery of new targets for leukemia therapy. PMID- 26606456 TI - The building blocks of a 'Liveable Neighbourhood': Identifying the key performance indicators for walking of an operational planning policy in Perth, Western Australia. AB - Planning policy makers are requesting clearer guidance on the key design features required to build neighbourhoods that promote active living. Using a backwards stepwise elimination procedure (logistic regression with generalised estimating equations adjusting for demographic characteristics, self-selection factors, stage of construction and scale of development) this study identified specific design features (n=16) from an operational planning policy ("Liveable Neighbourhoods") that showed the strongest associations with walking behaviours (measured using the Neighbourhood Physical Activity Questionnaire). The interacting effects of design features on walking behaviours were also investigated. The urban design features identified were grouped into the "building blocks of a Liveable Neighbourhood", reflecting the scale, importance and sequencing of the design and implementation phases required to create walkable, pedestrian friendly developments. PMID- 26606455 TI - Impact of neighborhoods and body size on survival after breast cancer diagnosis. AB - With data from the Neighborhoods and Breast Cancer Study, we examined the associations between body size, social and built environments, and survival following breast cancer diagnosis among 4347 women in the San Francisco Bay Area. Lower neighborhood socioeconomic status and greater neighborhood crowding were associated with higher waist-to-hip ratio (WHR). After mutual adjustment, WHR, but not neighborhood characteristics, was positively associated with overall mortality and marginally with breast cancer-specific mortality. Our findings suggest that WHR is an important modifiable prognostic factor for breast cancer survivors. Future WHR interventions should account for neighborhood characteristics that may influence WHR. PMID- 26606458 TI - Population-based prediction of subject-specific prostate deformation for MR-to ultrasound image registration. AB - Statistical shape models of soft-tissue organ motion provide a useful means of imposing physical constraints on the displacements allowed during non-rigid image registration, and can be especially useful when registering sparse and/or noisy image data. In this paper, we describe a method for generating a subject-specific statistical shape model that captures prostate deformation for a new subject given independent population data on organ shape and deformation obtained from magnetic resonance (MR) images and biomechanical modelling of tissue deformation due to transrectal ultrasound (TRUS) probe pressure. The characteristics of the models generated using this method are compared with corresponding models based on training data generated directly from subject-specific biomechanical simulations using a leave-one-out cross validation. The accuracy of registering MR and TRUS images of the prostate using the new prostate models was then estimated and compared with published results obtained in our earlier research. No statistically significant difference was found between the specificity and generalisation ability of prostate shape models generated using the two approaches. Furthermore, no statistically significant difference was found between the landmark-based target registration errors (TREs) following registration using different models, with a median (95th percentile) TRE of 2.40 (6.19) mm versus 2.42 (7.15) mm using models generated with the new method versus a model built directly from patient-specific biomechanical simulation data, respectively (N = 800; 8 patient datasets; 100 registrations per patient). We conclude that the proposed method provides a computationally efficient and clinically practical alternative to existing complex methods for modelling and predicting subject-specific prostate deformation, such as biomechanical simulations, for new subjects. The method may also prove useful for generating shape models for other organs, for example, where only limited shape training data from dynamic imaging is available. PMID- 26606457 TI - Sparse Reconstruction Challenge for diffusion MRI: Validation on a physical phantom to determine which acquisition scheme and analysis method to use? AB - Diffusion magnetic resonance imaging (dMRI) is the modality of choice for investigating in-vivo white matter connectivity and neural tissue architecture of the brain. The diffusion-weighted signal in dMRI reflects the diffusivity of water molecules in brain tissue and can be utilized to produce image-based biomarkers for clinical research. Due to the constraints on scanning time, a limited number of measurements can be acquired within a clinically feasible scan time. In order to reconstruct the dMRI signal from a discrete set of measurements, a large number of algorithms have been proposed in recent years in conjunction with varying sampling schemes, i.e., with varying b-values and gradient directions. Thus, it is imperative to compare the performance of these reconstruction methods on a single data set to provide appropriate guidelines to neuroscientists on making an informed decision while designing their acquisition protocols. For this purpose, the SPArse Reconstruction Challenge (SPARC) was held along with the workshop on Computational Diffusion MRI (at MICCAI 2014) to validate the performance of multiple reconstruction methods using data acquired from a physical phantom. A total of 16 reconstruction algorithms (9 teams) participated in this community challenge. The goal was to reconstruct single b value and/or multiple b-value data from a sparse set of measurements. In particular, the aim was to determine an appropriate acquisition protocol (in terms of the number of measurements, b-values) and the analysis method to use for a neuroimaging study. The challenge did not delve on the accuracy of these methods in estimating model specific measures such as fractional anisotropy (FA) or mean diffusivity, but on the accuracy of these methods to fit the data. This paper presents several quantitative results pertaining to each reconstruction algorithm. The conclusions in this paper provide a valuable guideline for choosing a suitable algorithm and the corresponding data-sampling scheme for clinical neuroscience applications. PMID- 26606459 TI - Effect of Gene Expression Classifier Molecular Testing on the Surgical Decision Making Process for Patients With Thyroid Nodules. AB - IMPORTANCE: Commercial molecular testing, such as the gene expression classifier (GEC), is now being used in the work up of cytologically indeterminate thyroid nodules. While this test may be helpful in ruling out malignancy in a thyroid nodule, its effect on surgical decision making has yet to be fully defined. OBJECTIVE: We aimed to determine the effect and outcome of GEC test results on the decision-making process for patients with thyroid nodules presenting for surgical consultation. DESIGN, SETTING, AND PARTICIPANTS: A surgical management algorithm was developed that incorporated individual Bethesda System for Reporting Thyroid Cytopathology classifications, in addition to clinical, laboratory, and radiological findings. We then retrospectively applied this algorithm to 273 consecutive patients with thyroid nodules and GEC test results who had presented for surgical consultation between February 1, 2012, and December 31, 2014. INTERVENTIONS: GEC testing. MAIN OUTCOMES AND MEASURES: Changes in management were recorded to identify the effect of GEC testing on the surgical decision-making process. An alteration in management of 20% of cases was considered significant. RESULTS: Of the 273 consecutive patients assessed by the GEC, mean (SD) age was 50.8 (14.7) years, 204 (74.7%) were female, and the mean (SD) nodule size was 2.4 (1.3) cm. Test results were suspicious for 233 (85.3%); benign for 31 (11.4%); and indeterminate for 8 (2.9%). The GEC test was also positive for medullary thyroid cancer for 1 patient (0.4%). The GEC test was correctly used as a rule-out test in only 127 patients (46.5%) with indeterminate nodules who lacked a clinical indication for surgery. The clinical management plan of only 23 (8.4%) patients was altered as a result of GEC test results, and of these 23 patients who proceeded to surgery, 16 patients (72.7%) were found to be inappropriately overtreated relative to postoperative histopathology analysis. We found that GEC testing did not affect the surgical decision-making process in 250 (91.6%) of our patients. In 146 cases, the use of GEC testing was not clinically indicated, and the test was being overused in patients for whom the results would not change surgical management. The positive predictive value of the GEC test for cytologically indeterminate nodules was 42.1%, and the negative predictive value was 83.3%. CONCLUSIONS AND RELEVANCE: The GEC testing did not significantly affect the surgical decision-making process. Gene expression classifier testing is often used incorrectly and is overused in patients for whom the results would not change management. The GEC test demonstrated a lower than expected negative predictive value, and there was evidence of overtreatment among patients whose treatment was altered based on this test. PMID- 26606461 TI - Single molecule microscopy and spectroscopy: concluding remarks. AB - Chemistry is all about molecules: control, synthesis, interaction and reaction of molecules. All too easily on a blackboard, one draws molecules, their structures and dynamics, to create an insightful picture. The dream is to see these molecules in reality. This is exactly what "Single Molecule Detection" provides: a look at molecules in action at ambient conditions; a breakthrough technology in chemistry, physics and biology. Within the realms of the Royal Society of Chemistry, the Faraday Discussion on "Single Molecule Microscopy and Spectroscopy" was a very appropriate topic for presentation, deliberation and debate. Undoubtedly, the Faraday Discussions have a splendid reputation in stimulating scientific debates along the traditions set by Michael Faraday. Interestingly, back in the 1830's, Faraday himself pursued an experiment that led to the idea that atoms in a compound were joined by an electrical component. He placed two opposite electrodes in a solution of water containing a dissolved compound, and observed that one of the elements of the compound accumulated on one electrode, while the other was deposited on the opposite electrode. Although Faraday was deeply opposed to atomism, he had to recognize that electrical forces were responsible for the joining of atoms. Probably a direct view on the atoms or molecules in his experiment would have convinced him. As such, Michael Faraday might have liked the gathering at Burlington House in September 2015 (). Surely, with the questioning eyes of his bust on the 1st floor corridor, the non-believer Michael Faraday has incited each passer-by to enter into discussion and search for deeper answers at the level of single molecules. In these concluding remarks, highlights of the presented papers and discussions are summarized, complemented by a conclusion on future perspectives. PMID- 26606460 TI - Large area magnetic micropallet arrays for cell colony sorting. AB - A new micropallet array platform for adherent cell colony sorting has been developed. The platform consisted of thousands of square plastic pallets, 270 MUm by 270 MUm on each side, large enough to hold a single colony of cells. Each pallet included a magnetic core, allowing them to be collected with a magnet after being released using a microscope mounted laser system. The micropallets were patterned from 1002F epoxy resist and were fabricated on translucent, gold coated microscope slides. The gold layer was used as seed for electroplating the ferromagnetic cores within every individual pallet. The gold layer also facilitated the release of each micropallet during laser release. This array allows for individual observation, sorting and collection of isolated cell colonies for biological cell colony research. In addition to consistent release and recovery of individual colonies, we demonstrated stable biocompatibility and minimal loss in imaging quality compared to previously developed micropallet arrays. PMID- 26606462 TI - Acclimation of a marine microbial consortium for efficient Mn(II) oxidation and manganese containing particle production. AB - Sediment contamination with metals is a widespread concern in the marine environment. Manganese oxidizing bacteria (MOB) are extensively distributed in various environments, but a marine microbial community containing MOB is rarely reported. In this study, a consortium of marine metal-contaminated sediments was acclimated using Mn(II). The shift in community structure was determined through high-throughput sequencing. In addition, the consortium resisted several harsh conditions, such as toxic metals (1mM Cu(II) and Fe(III)), and exhibited high Mn(II) oxidation capacities even the Mn(II) concentration was up to 5mM. Meanwhile, biogenic Mn containing particles were characterized by scanning electron microscope (SEM), X-ray powder diffraction (XRD), and N2 adsorption/desorption. Dye removal performance of the Mn containing particles was assayed using methylene blue, and 20.8 mg g(-1) adsorption capacity was obtained. Overall, this study revealed several new genera associated with Mn(II) oxidation and rare biogenic Na3MnPO4CO3. Results suggested the complexity of natural microbe-mediated Mn transformation. PMID- 26606463 TI - Strain mapping of semiconductor specimens with nm-scale resolution in a transmission electron microscope. AB - The last few years have seen a great deal of progress in the development of transmission electron microscopy based techniques for strain mapping. New techniques have appeared such as dark field electron holography and nanobeam diffraction and better known ones such as geometrical phase analysis have been improved by using aberration corrected ultra-stable modern electron microscopes. In this paper we apply dark field electron holography, the geometrical phase analysis of high angle annular dark field scanning transmission electron microscopy images, nanobeam diffraction and precession diffraction, all performed at the state-of-the-art to five different types of semiconductor samples. These include a simple calibration structure comprising 10-nm-thick SiGe layers to benchmark the techniques. A SiGe recessed source and drain device has been examined in order to test their capabilities on 2D structures. Devices that have been strained using a nitride stressor have been examined to test the sensitivity of the different techniques when applied to systems containing low values of deformation. To test the techniques on modern semiconductors, an electrically tested device grown on a SOI wafer has been examined. Finally a GaN/AlN superlattice was tested in order to assess the different methods of measuring deformation on specimens that do not have a perfect crystalline structure. The different deformation mapping techniques have been compared to one another and the strengths and weaknesses of each are discussed. PMID- 26606464 TI - Human Migration and Leishmaniasis-On the Move. PMID- 26606465 TI - Molecular dynamics simulation study of various zeolitic imidazolate framework structures. AB - We report the results of a series of molecular dynamics simulations on a number of zinc zeolitic imidazolate framework (ZIF) structures together with some lattice dynamics calculations on ZIF-4, providing information about the flexibilities of these structures. The simulations have used a force field we developed based on ab initio calculations of clusters of ligands and metal cations. We have shown that there are instabilities of the structures of some ZIF structures at low temperatures and high pressures. A rigidity analysis based on the Rigid Unit Mode model shows considerable degree of network flexibility, including a significant elastic flexibility. PMID- 26606466 TI - Anti-Infectious Human Vaccination in Historical Perspective. AB - A brief history of vaccination is presented since the Jenner's observation, through the first golden age of vaccinology (from Pasteur's era to 1938), the second golden age (from 1940 to 1970), until the current period. In the first golden age, live, such as Bacille Calmette Guerin (BCG), and yellow fever, inactivated, such as typhoid, cholera, plague, and influenza, and subunit vaccines, such as tetanus and diphtheria toxoids, have been developed. In the second golden age, the cell culture technology enabled polio, measles, mumps, and rubella vaccines be developed. In the era of modern vaccines, in addition to the conjugate polysaccharide, hepatitis A, oral typhoid, and varicella vaccines, the advent of molecular biology enabled to develop hepatitis B, acellular pertussis, papillomavirus, and rotavirus recombinant vaccines. Great successes have been achieved in the fight against infectious diseases, including the smallpox global eradication, the nearly disappearance of polio, the control of tetanus, diphtheria, measles, rubella, yellow fever, and rabies. However, much work should still be done for improving old vaccines, such as BCG, anthrax, smallpox, plague, or for developing effective vaccines against old or emerging infectious threats, such as human-immunodeficiency-virus, malaria, hepatitis C, dengue, respiratory syncytial-virus, cytomegalovirus, multiresistant bacteria, Clostridium difficile, Ebola virus. In addition to search for innovative and effective vaccines and global infant coverage, even risk categories should adequately be protected. Despite patients under immunosuppressive therapy are globally increasing, their vaccine coverage is lower than recommended, even in developed and affluent countries. PMID- 26606467 TI - Radiation Therapy for Hodgkin Lymphoma--Can It Be Administered More Safely if Necessary? PMID- 26606468 TI - Behavior Trees for Evolutionary Robotics. AB - Evolutionary Robotics allows robots with limited sensors and processing to tackle complex tasks by means of sensory-motor coordination. In this article we show the first application of the Behavior Tree framework on a real robotic platform using the evolutionary robotics methodology. This framework is used to improve the intelligibility of the emergent robotic behavior over that of the traditional neural network formulation. As a result, the behavior is easier to comprehend and manually adapt when crossing the reality gap from simulation to reality. This functionality is shown by performing real-world flight tests with the 20-g DelFly Explorer flapping wing micro air vehicle equipped with a 4-g onboard stereo vision system. The experiments show that the DelFly can fully autonomously search for and fly through a window with only its onboard sensors and processing. The success rate of the optimized behavior in simulation is 88%, and the corresponding real-world performance is 54% after user adaptation. Although this leaves room for improvement, it is higher than the 46% success rate from a tuned user-defined controller. PMID- 26606469 TI - Evolutionary Growth of Genome Representations on Artificial Cellular Organisms with Indirect Encodings. AB - Evolutionary design targets systems of continuously increasing complexity. Thus, indirect developmental mappings are often a necessity. Varying the amount of genotype information changes the cardinality of the mapping, which in turn affects the developmental process. An open question is how to find the genotype size and representation in which a developmental solution would fit. A restricted pool of genes may not be large enough to encode a solution or may need complex heuristics to find a realistic size. On the other hand, using the whole set of possible regulatory combinations may be intractable. In nature, the genomes of biological organisms are not fixed in size; they slowly evolve and acquire new genes by random gene duplications. Such incremental growth of genome information can be beneficial also in the artificial domain. For an evolutionary and developmental (evo-devo) system based on cellular automata, we investigate an incremental evolutionary growth of genomes without any a priori knowledge on the necessary genotype size. Evolution starts with simple solutions in a low dimensional space and incrementally increases the genotype complexity by means of gene duplication, allowing the evolution of scalable genomes that are able to adapt genetic information content while compactness and efficiency are retained. The results are consistent when the target phenotypic complexity, the geometry size, and the number of cell states are scaled up. PMID- 26606470 TI - Spectroscopic and Structural Studies of a Surface Active Porphyrin in Solution and in Langmuir-Blodgett Films. AB - Controlling aggregation of the dual sensitizer-emitter (S-E) zinc tetraphenylporphyrin (ZnTPP) is an important consideration in solid state noncoherent photon upconversion (NCPU) applications. The Langmuir-Blodgett (LB) technique is a facile means of preparing ordered assemblies in thin films to study distance-dependent energy transfer processes in S-E systems and was used in this report to control the aggregation of a functionalized ZnTPP on solid substrates. This was achieved by synthetic addition of a short polar tail to one of the pendant phenyl rings in ZnTPP in order to make it surface active. The surface active ZnTPP derivative formed rigid films at the air-water interface and exhibited mean molecular areas consistent with approximately vertically oriented molecules under appropriate film compression. A red shift in the UV-vis spectra as well as unquenched fluorescence emission of the LB films indicated formation of well-ordered aggregates. However, NCPU, present in the solution phase, was not observed in the LB films, suggesting that NCPU from ZnTPP as a dual S-E required not just a controlled aggregation but a specific orientation of the molecules with respect to each other. PMID- 26606471 TI - Filled Pentagons and Electron Counting Rule for Boron Fullerenes. AB - We have revisited the general constructing schemes for a large family of stable hollow boron fullerenes with 80 + 8n (n = 0, 2, 3, ...) atoms. In contrast to the hollow pentagon boron fullerenes with 12 hollow pentagons, the stable boron fullerenes constitute 12 filled pentagons and 12 additional hollow hexagons, which are more stable than the empty pentagon boron fullerenes including the "magic" B80 buckyball. On the basis of results from first-principles density functional calculations, an empirical rule for filled pentagons is proposed along with a revised electron counting scheme to account for the improved stability and the associated electronic bonding feature. PMID- 26606472 TI - Mechanism of Nitric Oxide Oxidation Reaction (2NO + O2 -> 2NO2) Revisited. AB - The reaction between molecular oxygen and two nitric oxide(II) molecules is studied with high-level ab initio wave function methods, including geometry optimizations with coupled cluster (CCSD(T,full)/cc-pCVTZ) and complete active space with second order perturbation theory levels (CASPT2/cc-pVDZ). The energy at the critical points was refined by calculations at the CCSD(T,full)/aug-cc pCVTZ level. The controversies found in the previous theoretical studies are critically discussed and resolved. The best estimate of the activation energy is 6.47 kJ/mol. PMID- 26606473 TI - Replica Temperatures for Uniform Exchange and Efficient Roundtrip Times in Explicit Solvent Parallel Tempering Simulations. AB - The efficiency of parallel tempering simulations is greatly influenced by the distribution of replica temperatures. In explicit solvent biomolecular simulations, where the total energy is dominated by the solvent, specific heat is usually assumed to be constant. From this, it follows that a geometric distribution of temperatures is optimal. We observe that for commonly used water models (TIP3P, SPC/E) under constant volume conditions and in the range of temperatures normally used, the specific heat is not a constant, consistent with experimental observations. Using this fact, we derive an improved temperature distribution which substantially reduces the round-trip times, especially when working with a small number of replicas. PMID- 26606474 TI - Generalized Normal Coordinates for the Vibrational Analysis of Molecular Dynamics Simulations. AB - The computation of vibrational spectra via molecular dynamics (MD) simulations has made lively progress in recent years. In particular, infrared spectra are accessible employing ab initio MD, for which only the total dipole moment has to be computed "on the fly" from the electronic structure along the trajectory. The analysis of such spectra in terms of the normal modes of intramolecular motion, however, still poses a challenge to theory. Here, we present an algorithm to extract such normal modes from MD trajectories by combining several ideas available in the literature. The algorithm allows one to compute both the normal modes and their vibrational bands without having to rely on an equipartition assumption, which hampered previous methods. Our analysis is based on a tensorial definition of the vibrational density of states, which spans both the frequency resolved cross- and auto-correlations of the molecular degrees of freedom. Generalized normal coordinates are introduced as orthonormal transforms of mass weighted coordinates, which minimize their mutual cross-correlations. The generalized normal coordinates and their associated normal modes are iteratively constructed by a minimization scheme based on the Jacobi diagonalization. Furthermore, the analysis furnishes mode local temperatures, which provide not only a measure for the convergence of the computed intensities but also permits one to correct these intensities a posteriori toward the ensemble limit. As a first non-trivial test application we analyze the infrared spectrum of isoprene based on ab initio MD, which is an important building block of various dye molecules in molecular biology. PMID- 26606475 TI - Reactive Molecular Dynamics Simulation of Fullerene Combustion Synthesis: ReaxFF vs DFTB Potentials. AB - The dynamic fullerene self-assembly process during benzene combustion was studied using classical Reactive Force Field (ReaxFF) nonequilibrium molecular dynamics (MD) simulations. In order to drive the combustion process, the hydrogen to carbon (H/C) ratio was gradually reduced during the course of the MD simulations. Target temperatures of 2500 and 3000 K were maintained by using a Berendsen thermostat. Simulation conditions and hydrogen removal strategies were chosen to match closely a previous quantum chemical MD (QM/MD) study based on the density functional tight-binding (DFTB) potential ( Saha et al. ACS Nano 2009 , 3 , 2241 ) to allow a comparison between the two different potentials. Twenty trajectories were computed at each target temperature, and hydrocarbon cluster size, CxHy composition, average carbon cluster curvature, carbon hybridization type, and ring count statistics were recorded as a function of time. Similarly as in the QM/MD simulations, only giant fullerene cages in the range from 155 to 212 carbon atoms self-assembled, and no C60 cages were observed. The most notable difference concerned the time required for completing cage self-assembly: Depending on temperature, it takes between 50 and 150 ps in DFTB/MD simulations but never less than 100 ps and frequently several 100s ps in ReaxFF/MD simulations. In the present system, the computational cost of ReaxFF/MD is about 1 order of magnitude lower than that of the corresponding DFTB/MD. Overall, the ReaxFF/MD simulations method paints a qualitatively similar picture of fullerene formation in benzene combustion when compared to direct MD simulations based on the DFTB potential. PMID- 26606476 TI - A Hirshfeld Partitioning of the MP2 Correlation Energy: Method and Its Application to the Benzene Dimers. AB - In this work a method is presented for the partitioning of MP2 correlation energies through a grid-space partitioning using the iterative Hirshfeld weight function. The correlation energies are partitioned into mono- and diatomic contributions using two alternative schemes, which allow different levels of parallelization. The method is tested on a set of 24 molecules containing various atoms, leading to the conclusion that, while the numerical results of the two schemes slightly differ, the chemical information contained in them is similar. The method is subsequently applied to the analysis of the interaction energy of three benzene dimers. PMID- 26606477 TI - The Accuracy of Density Functional Theory in the Description of Cation-pi and pi Hydrogen Bond Interactions. AB - Cation-pi and pi-hydrogen bond interactions are ubiquitous in protein folding, molecular recognition, and ligand-receptor associations. As such systems are routinely studied at the DFT level, it becomes essential to understand the underlying accuracy of the plethora of density functionals currently available for the description of these interactions. For that purpose, we carried out theoretical calculations on two small model systems (benzene-Na(+) and benzene H2O) that represent a paradigm for those intermolecular interactions and systematically tested 46 density functionals against the results of high-level post-HF methods, ranging from MP2 to extrapolated CCSD(T)/CBS. A total of 13 basis sets were also tested to examine the convergence of the interaction energy with basis set size. The convergence was surprisingly fast, with deviations below 0.2 kcal/mol for double-zeta polarized basis sets with diffuse functions. Concerning functional benchmarking, the Truhlar group functionals were particularly well suited for the description of the pi-hydrogen bond interactions. In the case of cation-pi interactions, there was not a clear correlation between accuracy and functional sophistication. Despite the large number of functionals predicting interaction energies within chemical accuracy (five for pi-hydrogen bond and 20 for cation-pi interactions), not a single functional has shown chemical accuracy in both cases. Moreover, if we calculate the average error for these two interactions, only two density functionals resulted in an average error below 1.0 kcal/mol (M06 and HCTH, with average errors of 0.6 and 0.8 kcal/mol). The obtained results serve as a guide for future computer simulations on this kind of system. PMID- 26606478 TI - Ab Initio Modeling of Donor-Acceptor Interactions and Charge-Transfer Excitations in Molecular Complexes: The Case of Terthiophene-Tetracyanoquinodimethane. AB - This work presents a thorough quantum chemical study of the terthiophene tetracyanoquinodimethane complex as a model for pi-pi donor-acceptor systems. Dispersion-corrected hybrid (B3LYP-D) and double hybrid (B2PLYP-D), hybrid meta (M06-2X and M06-HF), and recently proposed long-range corrected (LC-wPBE, CAM B3LYP, and wB97X-D) functionals have been chosen to deal with pi-pi intermolecular interactions and charge-transfer excitations in a balanced way. These properties are exhaustively compared to those computed with high-level ab initio SCS-MP2 and CASPT2 methods. The wB97X-D functional exhibits the best performance. It provides reliable intermolecular distances and interaction energies and predicts a small charge transfer from the donor to the acceptor in the ground state. In addition, wB97X-D is also able to yield an accurate description of the charge-transfer excitations in comparison to benchmark CASPT2 calculations. PMID- 26606479 TI - Definitive Benchmark Study of Ring Current Effects on Amide Proton Chemical Shifts. AB - The ring current effect on chemical shifts of amide protons (DeltadeltaRC) is computed at the B3LYP/6-311++G(d,p)//B3LYP/aug-cc-pVTZ level of theory for 932 geometries of dimers of N-methylacetamide and aromatic amino acid side chains extracted from 21 different proteins. These DeltadeltaRC values are scaled by 1.074, based on MP2/cc-pVQZ//B3LYP/aug-cc-pVTZ chemical shift calculations on four representative formamide/benzene dimers, and are judged to be accurate to within 0.1 ppm based on CCSD(T)/CBS//B3LYP/aug-cc-pVTZ calculations on formamide. The 932 scaled DeltadeltaRC values are used to benchmark three empirical ring current models, including the Haigh-Mallion model used in the SPARTA, SHIFTX, and SHIFTS chemical shift prediction codes. Though the RMSDs for these three models are below 0.1 ppm, deviations up to 0.29 ppm are found, but these can be decreased to below 0.1 ppm by changing a single parameter. The simple point dipole model is found to perform just as well as the more complicated Haigh Mallion and Johnson-Bovey models. PMID- 26606480 TI - A Simple Algorithm for Determining Orthogonal, Self-Consistent Excited-State Wave Functions for a State-Specific Hamiltonian: Application to the Optical Spectrum of the Aqueous Electron. AB - We recently introduced a mixed quantum/classical model for the hydrated electron that includes electron/water polarization in a self-consistent fashion, using a polarizable force field for the water molecules [ J. Chem. Phys. 2010 , 133 , 154506 ]. Calculation of the electronic absorption spectrum for this model is not straightforward, owing to the state-specific nature of the Hamiltonian, the high density of electronic states, and the large solvent polarization response upon electronic excitation. Together, these properties make it difficult or impossible to converge the polarizable solvent dipoles self-consistently for each excited state wave function. Here, we overcome this problem by means of an extended Lagrangian procedure for performing constrained annealing in the space of electronic variables. By construction, this algorithm affords self-consistent, mutually orthogonal solutions for any state-specific Hamiltonian, and we illustrate this approach by computing the optical spectrum of our polarizable model for the aqueous electron. The spectrum thus obtained affords better agreement with experiment than previous, perturbative calculations of solvent dipole relaxation. Strengths, weaknesses, and possible generalizations of this procedure are discussed. PMID- 26606481 TI - Theoretical Thermochemistry for Organic Molecules: Development of the Generalized Connectivity-Based Hierarchy. AB - A generalized, unique thermochemical hierarchy applicable for all closed shell organic molecules is developed in this paper. In this chemically intuitive, structure-based approach, the connectivity of the atoms in an organic molecule is used to construct our hierarchy called "connectivity-based hierarchy" (CBH). The hierarchy has several rungs and ascending up the hierarchy increasingly balances the reaction energy. It requires no prior knowledge of the types of molecules and hybridizations for the appropriate balancing of the bond types and the bonding environments of the atoms. The rungs can be generated by an automated computer program for any closed shell organic molecule, and the first three rungs generate the simplest reactions for the widely used isodesmic, hypohomodesmotic, and hyperhomodesmotic schemes. The generated reaction schemes are unique for each rung and are derived in a simpler manner than previous approaches, avoiding potential errors. This work also suggests that for closed shell organic molecules, the previously well-studied homodesmotic scheme does not have a fundamental structure-based origin. In a preliminary application of CBH, density functional theory has been used to calculate accurate enthalpies of formation for a test set of 20 organic molecules. The performance of the hierarchy suggests that it will be useful to predict accurate thermodynamic properties of larger organic molecules. PMID- 26606482 TI - Extraordinary Difference in Reactivity of Ozone (OOO) and Sulfur Dioxide (OSO): A Theoretical Study. AB - Ozone and sulfur dioxide are valence isoelectronic yet show very different reactivity. While ozone is one of the most reactive 1,3-dipoles, SO2 does not react in this way at all. The activation energies of dipolar cycloadditions of sulfur dioxide with either ethylene or acetylene are predicted here by B3LYP, M06 2X, CBS-QB3, and CCSD(T) to be much higher than reactions of ozone. The dipolar cycloaddition of ozone is very exothermic, while that of than sulfur dioxide is endothermic. The prohibitive barriers in the case of SO2 arise from large distortion energies as well as unfavorable interaction energies in the transition states. This arises in part from the HOMO-LUMO gap of sulfur dioxide, which is larger than that of ozone. Valence bond calculations also show that while ozone has a high degree of diradical character, SO2 does not, and is better characterized as a dritterion. PMID- 26606483 TI - The Remarkable Nb2(CO)12 with Seven-Coordinate Niobium: Decarbonylation to Nb2(CO)11 and Nb2(CO)10. AB - The dissociation of Nb2(CO)12 into two Nb(CO)6 units is predicted to require ~13 kcal/mol so that Nb2(CO)12 rather than Nb(CO)6 is the anticipated initial oxidation product of the known Nb(CO)6(-) anion. This differs from the corresponding vanadium carbonyl chemistry where V(CO)6 rather than V2(CO)12 is found experimentally to be the oxidation product of V(CO)6(-). The lowest energy Nb2(CO)12 structure consists of two Nb(CO)6 fragments joined by a Nb-Nb bond of ~3.4 A length so that each niobium atom is heptacoordinate, counting the metal metal bond. These niobium coordination polyhedra can be approximated by capped octahedra. Among unsaturated binuclear niobium carbonyls the lowest energy Nb2(CO)11 structure has a formal four-electron donor bridging eta(2)-MU-CO group and a formal Nb-Nb single bond rather than only two-electron donor carbonyl groups and a formal Nb?Nb double bond. The Nb2(CO)11 structures with formal Nb?Nb double bonds and exclusively two-electron donor carbonyl groups lie more than 13 kcal/mol above this low-energy Nb2(CO)10(eta(2)-MU-CO) structure. However, Nb2(CO)11 is predicted to be thermodynamically disfavored, owing to disproportionation into Nb2(CO)12 + Nb2(CO)10, a slightly exothermic process by ~4 kcal/mol. The Nb2(CO)10 structures with formal Nb=Nb triple bonds and all two electron donor carbonyl groups appear to be particularly favorable, as suggested by high CO dissociation energies and viability toward disproportionation. Such structures are isolobal with Cp2Mo2(CO)4, which was the first stable metal carbonyl to be discovered with a short metal-metal distance, corresponding to a formal triple bond. Considerably higher energy Nb2(CO)10 structures (by more than 20 kcal/mol) have two four-electron donor bridging carbonyl groups and long niobium-niobium distances. Such structures can be considered to consist of a bidentate Nb(CO)6 "ligand" coordinating to a Nb(CO)4 unit through the two eta(2) MU-CO groups. PMID- 26606484 TI - A New Efficient Method for Generating Conformations of Unfolded Proteins with Diverse Main-Chain Dihedral-Angle Distributions. AB - A new method for generating polypeptide-chain conformations has been developed for studying structural characteristics of unfolded proteins. It enables us to generate a large number of conformations very rapidly by avoiding atomic collisions efficiently with the use of main-chain dihedral-angle distributions derived from a crystal-structure database of proteins. In addition, combining main-chain dihedral-angle distributions for the amino acid residues incorporated in different secondary structures, we can obtain diverse conformational ensembles with different structural features. Structural characteristics of proteins denatured in high-concentration denaturant solution were analyzed by comparing predictions from this method with results from solution X-ray scattering (SXS) measurement. Analysis of the dependence of the mean square radius (Rsq) of protein on the number of residues and the shape of its Kratky profile has confirmed that the highly denaturing solvent serves as a good solvent in accordance with previous reports. It was also found that, in order for a conformational ensemble to reproduce experimental data, the percentage in which main-chain dihedral angles are found in the alpha region must be in the range of 20-40%. It agrees with studies on the (3)JHNalpha coupling constant using the multidimensional NMR method. These results confirm that our method for generating diverse conformations of polypeptide chains is very useful to the conformational analysis of unfolded protein, because it enables us to analyze comprehensively both of the local structural features obtained from NMR and the global ones obtained from SXS. PMID- 26606485 TI - Coarse-Grain Model for Glucose, Cellobiose, and Cellotetraose in Water. AB - We present a coarse-grain (CG) simulation model for aqueous solutions of beta-d glucose, cellobiose, and cellotetraose, based on atomistic simulation data for each system. In the model, three spherical beads are used to represent glucose, and a single bead is used to represent water. For glucose, the force field is calculated using force matching by minimizing the sum of the square differences between forces calculated from atomistic and CG simulations. For cellobiose and cellotetraose, we use a hybrid method where the nonbonded interactions are obtained using force matching and the bonded interactions are obtained using Boltzmann inversion. We demonstrate excellent agreement in the structural properties between the atomistic simulations and the CG simulations. This model represents the first step in developing a CG force field for cellulose, as it is of significant interest to study cellulose behavior at much longer time and length scales relative to atomistic simulations. PMID- 26606486 TI - High-Performance Solution of Hierarchical Equations of Motion for Studying Energy Transfer in Light-Harvesting Complexes. AB - Excitonic models of light-harvesting complexes, where the vibrational degrees of freedom are treated as a bath, are commonly used to describe the motion of the electronic excitation through a molecule. Recent experiments point toward the possibility of memory effects in this process and require one to consider time nonlocal propagation techniques. The hierarchical equations of motion (HEOM) were proposed by Ishizaki and Fleming to describe the site-dependent reorganization dynamics of protein environments ( J. Chem. Phys. 2009 , 130 , 234111 ), which plays a significant role in photosynthetic electronic energy transfer. HEOM are often used as a reference for other approximate methods but have been implemented only for small systems due to their adverse computational scaling with the system size. Here, we show that HEOM are also solvable for larger systems, since the underlying algorithm is ideally suited for the usage of graphics processing units (GPU). The tremendous reduction in computational time due to the GPU allows us to perform a systematic study of the energy-transfer efficiency in the Fenna Matthews-Olson (FMO) light-harvesting complex at physiological temperature under full consideration of memory effects. We find that approximative methods differ qualitatively and quantitatively from the HEOM results and discuss the importance of finite temperature to achieving high energy-transfer efficiencies. PMID- 26606487 TI - Calculation of Hyperfine Tensors and Paramagnetic NMR Shifts Using the Relativistic Zeroth-Order Regular Approximation and Density Functional Theory. AB - Density functional theory (DFT) calculations of molecular hyperfine tensors were implemented as a second derivative property within the two-component relativistic zeroth-order regular approximation (ZORA). Hyperfine coupling constants were computed for systems ranging from light atomic radicals to molecules with heavy d and f block elements. For comparison, computations were also performed with a ZORA first-order derivative approach. In each set of computations, Slater-type basis sets have been used. The implementation allows for nonhybrid and hybrid DFT calculations and incorporates a Gaussian finite nucleus model. A comparison of results calculated with the PBE nonhybrid and the PBE0 hybrid functional is provided. Comparisons with differing basis sets and incorporation of finite nucleus corrections are discussed. The second derivative method is applied to calculations of paramagnetic NMR ligand chemical shifts of three Ru(III) complexes. The results are consistent with those calculated using a first-order derivative method, and the results are consistent for different functionals used. A comparison of two different methods of calculating pseudo-contact shifts, one using the full hyperfine tensor and one assuming a point-charge paramagnetic center, is made for the Ru(III) complexes. PMID- 26606488 TI - Surface Hopping Excited-State Dynamics Study of the Photoisomerization of a Light Driven Fluorene Molecular Rotary Motor. AB - We report a theoretical study of the photoisomerization step in the operating cycle of a prototypical fluorene-based molecular rotary motor (1). The potential energy surfaces of the ground electronic state (S0) and the first singlet excited state (S1) are explored by semiempirical quantum-chemical calculations using the orthogonalization-corrected OM2 Hamiltonian in combination with a multireference configuration interaction (MRCI) treatment. The OM2/MRCI results for the S0 and S1 minima of the relevant 1-P and 1-M isomers and for the corresponding S0 transition state are in good agreement with higher-level calculations, both with regard to geometries and energetics. The S1 surface is characterized at the OM2/MRCI level by locating two S0-S1 minimum-energy conical intersections and nearby points on the intersection seam and by computing energy profiles for pathways toward these MECIs. Semiclassical Tully-type trajectory surface hopping (TSH) simulations with on-the-fly OM2/MRCI calculations are carried out to study the excited-state dynamics after photoexcitation to the S1 state. Fast relaxation to the ground state is observed through the conical intersection regions, predominantly through the lowest-energy one with a strongly twisted central C?C double bond and pyramidalized central carbon atom. The excited-state lifetimes for the direct and inverse photoisomerization reactions (1.40 and 1.79 ps) and the photostationary state ratio (2.7:1) from the TSH-OM2 simulations are in good agreement with the available experimental data (ca. 1.7 ps and 3:1). Excited state lifetimes, photostationary state ratio, and dynamical details of the TSH OM2 simulations also agree with classical molecular dynamics simulations using a reparametrized optimized potentials for liquid simulations (OPLS) all-atom force field with ad-hoc surface hops at predefined conical intersection points. The latter approach allows for a more extensive statistical sampling. PMID- 26606489 TI - Role of Many-Body Effects in Describing Low-Lying Excited States of pi-Conjugated Chromophores: High-Level Equation-of-Motion Coupled-Cluster Studies of Fused Porphyrin Systems. AB - The unusual photophysical properties of the pi-conjugated chromophores make them potential building blocks of various molecular devices. In particular, significant narrowing of the HOMO-LUMO gaps can be observed as an effect of functionalization chromophores with polycyclic aromatic hydrocarbons (PAHs). In this paper we present equation-of-motion coupled cluster (EOMCC) calculations for vertical excitation energies of several functionalized forms of porphyrins. The results for free-base porphyrin (FBP) clearly demonstrate significant differences between functionalization of FBP with one- (anthracene) and two-dimensional (coronene) structures. We also compare the EOMCC results with the experimentally available results for anthracene fused zinc-porphyrin. The impact of various types of correlation effects is illustrated on several benchmark models, where the comparison with the experiment is possible. In particular, we demonstrate that for all excited states considered in this paper, all of them being dominated by single excitations, the inclusion of triply excited configurations is crucial for attaining qualitative agreement with experiment. We also demonstrate the parallel performance of the most computationally intensive part of the completely renormalized EOMCCSD(T) approach (CR-EOMCCSD(T)) across 120 000 cores. PMID- 26606490 TI - Solvation Effects on Electronic Transitions: Exploring the Performance of Advanced Solvent Potentials in Polarizable Embedding Calculations. AB - The polarizable embedding (PE) approach, which combines quantum mechanics (QM) and molecular mechanics (MM), is applied to predict solvatochromic effects on excitation energies of several representative molecules in aqueous, methanol, acetonitrile, and carbon tetrachloride solutions. Good agreement with experimental results for excitation energies and for solvatochromic shifts is demonstrated on the basis of either density functional theory or coupled cluster methods. Solvent-dependent trends are fully reproduced in this diverse set of solvents. Furthermore, it is shown that the inclusion of higher order multipole moments and anisotropic polarizabilities in the electrostatic embedding potentials leads to a faster convergence with respect to a full QM treatment (within about 0.1 eV of estimated full QM treatments). It is thereby illustrated that the use of advanced solvent potentials can provide higher accuracy compared to various simpler approaches for the prediction of solvent shifts and do so in a computationally competitive manner. PMID- 26606491 TI - Calibration of the DFT/GGA+U Method for Determination of Reduction Energies for Transition and Rare Earth Metal Oxides of Ti, V, Mo, and Ce. AB - GGA+U calculation were performed for oxides of Ti, V, Mo, and Ce with the objective of establishing the best value of the parameter Ueff to use in order to match the calculated reduction and oxidation energies of each oxide with experimental values. In each case, the reaction involved the hydrogen reduction of an oxide to its next lower oxide and the formation of water. Our calculations show that the optimal value of Ueff required to match calculated and experimental values of the reaction energy are significantly different from those reported in the literature based on matching lattice parameters or electronic properties and that the use of these values of Ueff can result in errors in the calculated redox energies of over 100 kJ/mol. We also found that, when an element exhibits more than two oxidation states, the energy of redox reactions between different pairs of these states are described by slightly different values of Ueff. PMID- 26606492 TI - Theoretical Investigations on the Photoinduced Phase Transition Mechanism of Tetrathiafulvalene-p-chloranil. AB - The photoinduced phase transition (PIPT) mechanism of tetrathiafulvalene-p chloranil (TTF-CA) molecular crystal was theoretically investigated using the long-range corrected time-dependent density functional theory (LC-TDDFT) combined with a local response dispersion (LRD) method, which enables us to quantitatively reproduce charge transfer (CT) excitations of van der Waals clusters. By calculating the excitation spectrum and potential energy surface, we found that the PIPT of TTF-CA crystal may proceed through the angle change of the molecular planes. We also found that the CT excitation of one TTF-CA pair helps other neighboring TTF-CA pairs to become excited. Consequently, we theoretically proposed the initial structural change in the neutral-to-ionic PIPT of TTF-CA crystal, which is consistent with experiments. PMID- 26606493 TI - A Comparative Study for Molecular Dynamics Simulations of Liquid Benzene. AB - The classical equilibrium and nonequilibrium molecular dynamics simulations for liquid benzene, the prototypical aromatic pi-pi interaction system, are performed using a variety of molecular force fields, OPT-FF, AMBER 03, general AMBER force field (GAFF), OPLS-AA, OPLS-CS, CHARMM27, GROMOS 53A5, and GROMOS 53A6. The simulated results of the molecular structure and thermodynamic properties of liquid benzene are compared with the experimental data available in the literature, accounting for the superiority of each force field in the descriptions of the pi-pi interaction system. The OPLS-AA force field is recommended to be the best one, which reproduces quite well the properties examined in this work, while the others fail in predicting either the local structure or the thermodynamic properties. Such distinct discrepancies for the above force fields are discussed within the scheme of the pairwise interaction construction of the standard force field, which will stimulate searching for a force field with generally good quality not only in terms of microstructure descriptions but also in the predictions of the thermodynamic properties of the liquids. PMID- 26606494 TI - Quantum Mechanical Origins of the Iczkowski-Margrave Model of Chemical Potential. AB - Charge flow in materials at the atomistic level is controlled through chemical potential equalization among its constituents. Consequently employing this concept in a simulation requires some model of chemical potential. Current atomistic models of chemical potential, such as the Iczkowski-Margrave (IM) model, are built largely on heuristic arguments and depend linearly on the net charge of each constituent. To gain new insight into the IM model, a many electron model Hamiltonian is constructed at the atomistic level that is commensurate with the IM model, as opposed to one designed at the one-electron level. For a three-state, two-fragment system, the essential electronegativity and the chemical hardness energies are recovered. However, the model Hamiltonian imparts new charge dependencies not found in the IM model. Decidedly nonlinear, transitional or hopping contributions in those new dependencies are shown to be critical to regulating charge flow. Other modifications to the IM model are illustrated with simple two- and three-fragment systems, involving as many as five states, that act as paradigms for general materials models. Including more than three states in the three-fragment example introduces local bonding refinements to the Mulliken electronegativity and chemical hardness. PMID- 26606495 TI - Self-Consistent-Charge Density-Functional Tight-Binding Parameters for Cd-X (X = S, Se, Te) Compounds and Their Interaction with H, O, C, and N. AB - Parameters for CdX, SeX, and TeX (X = H, C, N, O, S, Se, Te, and Cd) have been generated within the self-consistent-charge density-functional tight-binding (SCC DFTB) framework. The approach has been tested against ab initio density functional theory calculations for the relevant bulk phases, surfaces, nanowires, and small molecular systems. The SCC-DFTB approach reproduces structural, electronic, and energetic properties very well, demonstrating that the developed parameters are fully transferable among different chemical environments. PMID- 26606496 TI - Improved Treatment of Ligands and Coupling Effects in Empirical Calculation and Rationalization of pKa Values. AB - The new empirical rules for protein pKa predictions implemented in the PROPKA3.0 software package (Olsson et al. J. Chem. Theory Comput.2010, 7, 525-537) have been extended to the prediction of pKa shifts of active site residues and ionizable ligand groups in protein-ligand complexes. We present new algorithms that allow pKa shifts due to inductive (i.e., covalently coupled) intraligand interactions, as well as noncovalently coupled interligand interactions in multiligand complexes, to be included in the prediction. The number of different ligand chemical groups that are automatically recognized has been increased to 18, and the general implementation has been changed so that new functional groups can be added easily by the user, aided by a new and more general protonation scheme. Except for a few cases, the new algorithms in PROPKA3.1 are found to yield results similar to or better than those obtained with PROPKA2.0 (Bas et al. Proteins: Struct., Funct., Bioinf.2008, 73, 765-783). Finally, we present a novel algorithm that identifies noncovalently coupled ionizable groups, where pKa prediction may be especially difficult. This is a general improvement to PROPKA and is applied to proteins with and without ligands. PMID- 26606497 TI - A Direct Comparison of the MM-GB/SA Scoring Procedure and Free-Energy Perturbation Calculations Using Carbonic Anhydrase as a Test Case: Strengths and Pitfalls of Each Approach. AB - MM-GB/SA scoring and free energy perturbation (FEP) calculations have emerged as reliable methodologies to understand structural and energetic relationships to binding. In spite of successful applications to elucidate the structure-activity relationships for few pairs of ligands, the reality is that the performance of FEP calculations has rarely been tested for more than a handful of compounds. In this work, a series of 13 benzene sulfonamide inhibitors of carbonic anhydrase with binding free energies determined by isothermal titration calorimetry was selected as a test case. R(2) values of 0.70, 0.71, and 0.49 with the experiment were obtained with MM-GB/SA and FEP simulations run with MCPRO+ and Desmond, respectively. All methods work well, but the results obtained with Desmond are inferior to MM-GB/SA and MCPRO+. The main contrast between the methods is the level of sampling, ranging from full to restricted flexibility to single conformation for the complexes in Desmond, MCPRO+, and MM-GB/SA, respectively. The current and historical results obtained with MM-GB/SA qualify this approach as a more attractive alternative for rank-ordering; it can achieve equivalent or superior predictive accuracy and handle more structurally dissimilar ligands at a fraction of the computational cost of the rigorous free-energy methods. As for the large theoretical dynamic range for the binding energies, that seems to be a direct result of the degree of sampling in the simulations since MCPRO+ as well as MM-GB/SA are plagued by this. Van't Hoff analysis for selected pairs of ligands suggests that the wider scoring spread is not only affected by missing entropic contributions due to restricted sampling but also exaggerated enthalpic separation between the weak and potent compounds caused by diminished shielding of electrostatic interactions, thermal effects, and protein relaxation/strain. PMID- 26606498 TI - Addressing Methionine in Molecular Design through Directed Sulfur-Halogen Bonds. AB - Halogen bonds are directional interactions involving an electron donor as binding partner. Employing quantum chemical calculations, we explore how they can be used in molecular design to address the sulfur atom in a methionine residue in a previously neglected, directed manner. We characterize energetics and directionality of these halogen bonds and elucidate their spatial variability in suboptimal geometries that are expected to occur in protein-ligand complexes featuring a multitude of concomitant interactions. We derive simple rules allowing medicinal chemists and chemical biologists to easily determine preferred areas of interaction within a binding site and to exploit them for scaffold decoration and design. Our work shows that sulfur-halogen bonds may be used to expand the patentable medicinal chemistry space. We demonstrate their potential to increase binding affinities and suggest that they can significantly contribute to inducing and tuning subtype selectivities. PMID- 26606499 TI - Using the Wimley-White Hydrophobicity Scale as a Direct Quantitative Test of Force Fields: The MARTINI Coarse-Grained Model. AB - The partitioning of proteins and peptides at the membrane/water interface is a key step in many processes, including the action of antimicrobial peptides, cell penetrating peptides, and toxins, as well as signaling. To develop a computational model that can be used to accurately represent such systems, the underlying model must be able to quantitatively represent the partitioning preferences of amino acids in the lipid membrane. The MARTINI model provides a consistent set of parameters for building coarse-grained models of systems involving lipids and proteins. Even though MARTINI is parametrized to reproduce the partitioning behavior of small molecules, its ability to reproduce partitioning preferences of amino acids at lipid/water interfaces has never been tested. In this study, we measured the partitioning free energies of side chains of amino acids using alchemical simulations and umbrella sampling. The pentapeptides of sequence Ac-WLXLL were simulated at the POPC/water and cyclohexane/water interfaces using MARTINI, and the computed free energies were compared with the Wimley-White hydrophobicity scale. The free energy values obtained using the free energy perturbation, thermodynamic integration, and umbrella sampling methods were compared to gain insight into the most efficient method and the degree of sampling required to obtain statistically accurate free energies for use with atomistic force fields in future work. With the standard MARTINI water model, the amino acids D, E, K, and R were found to be significantly too favorable in hydrophobic environments, whereas with the polarizable water model, the amino acids D, E, K, and R were found to give correct free energies of partitioning. The amino acids P and F showed significant deviations from the experimental values. This model system will be used in future improvements to the MARTINI model. PMID- 26606500 TI - Performance of Density Functional Theory and Moller-Plesset Second-Order Perturbation Theory for Structural Parameters in Complexes of Ru. AB - We assess the performance of density functional theory (DFT) and Moller-Plesset second-order perturbation theory (MP2) for predicting structural parameters in Ru complexes, in particular, a Ru(IV) allyl dicationic complex with the formula [Ru(eta(5)-Cp*)(eta(3)-CH2CHCHC6H5)(NCCH3)2](2+) and the molecules RuO4 and Ru(C2O4)2(H2O)2(-), where Cp* denotes C5Me5 and Me denotes methyl. The density functionals studied are B3LYP, B3PW91, M05, M06, M06-L, MOHLYP, MPW3LYP, PBE0, PW6B95, SOGGA, tauHCTHhyb, omegaB97X, and omegaB97X-D, in combination with three different basis sets, namely, LANL2DZ, def2-SVP, and def2-TZVP. The theoretically computed Ru-C distances corresponding to the phenylallyl complex are especially well predicted by the SOGGA (pure DFT) and omegaB97X-D (DFT plus an empirical molecular mechanics term) methods. This contrasts with an article in this Journal [ Calhorda , M. J. , Pregosin , P. S. , and Veiros , L. F. J. Chem. Theory Comput. 2007 , 3 , 665 - 670 ] in which it was found that DFT cannot account for these Ru-C distances. Averaging over four Ru-C distances in the allyl complex and three unique Ru-O distances in RuO4 and Ru(C2O4)2(H2O)2(-), the SOGGA and omegaB97X-D methods have both a smaller mean unsigned error than MP2 and the same maximum error. The M06, PW6B95, PBE0, M06-L, and omegaB97X density functionals also have a smaller or the same mean unsigned error as MP2. PMID- 26606501 TI - Correction to Application of Molecular Dynamics Simulations in Molecular Property Prediction. 1. Density and Heat of Vaporization. PMID- 26606502 TI - Antiferroelectric Thin-Film Capacitors with High Energy-Storage Densities, Low Energy Losses, and Fast Discharge Times. AB - We demonstrate a capacitor with high energy densities, low energy losses, fast discharge times, and high temperature stabilities, based on Pb(0.97)Y(0.02)[(Zr(0.6)Sn(0.4))(0.925)Ti(0.075)]O3 (PYZST) antiferroelectric thin-films. PYZST thin-films exhibited a high recoverable energy density of U(reco) = 21.0 J/cm(3) with a high energy-storage efficiency of eta = 91.9% under an electric field of 1300 kV/cm, providing faster microsecond discharge times than those of commercial polypropylene capacitors. Moreover, PYZST thin-films exhibited high temperature stabilities with regard to their energy-storage properties over temperatures ranging from room temperature to 100 degrees C and also exhibited strong charge-discharge fatigue endurance up to 1 * 10(7) cycles. PMID- 26606503 TI - Structure and Function of Transient Encounters of Redox Proteins. AB - Many biomolecular interactions proceed via lowly populated, transient intermediates. Believed to facilitate formation of a productive complex, these short-lived species are inaccessible to conventional biophysical and structural techniques and, until recently, could only be studied by theoretical simulations. Recent development of experimental approaches sensitive to the presence of minor species--in particular paramagnetic relaxation enhancement (PRE) NMR spectroscopy -has enabled direct visualization and detailed characterization of such lowly populated states. Collectively referred to as an encounter complex, the binding intermediates are particularly important in transient protein interactions, such as those orchestrating signaling cascades or energy-generating electron transfer (ET) chains. Here I discuss encounter complexes of redox proteins mediating biological ET reactions, which are essential for many vital cellular activities including oxidative phosphorylation and photosynthesis. In particular, this Account focuses on the complex of cytochrome c (Cc) and cytochrome c peroxidase (CcP), which is a paradigm of biomolecular ET and an attractive system for studying protein binding and enzymatic catalysis. The Cc-CcP complex formation proceeds via an encounter state, consisting of multiple protein-protein orientations sampled in the search of the dominant, functionally active bound form and exhibiting a broad spatial distribution, in striking agreement with earlier theoretical simulations. At low ionic strength, CcP binds another Cc molecule to form a weak ternary complex, initially inferred from kinetics experiments and postulated to account for the measured ET activity. Despite strenuous efforts, the ternary complex could not be observed directly and remained eagerly sought for the past two decades. Very recently, we have solved its structure in solution and shown that it consists of two binding forms: the dominant, ET-inactive geometry and an ensemble of lowly populated species with short separations between Cc and CcP cofactors, which summarily account for the measured ET rate. Unlike most protein complexes, which require accurate alignment of the binding surfaces in a single, well-defined orientation to carry out their function, redox proteins can form multiple productive complexes. As fast ET will occur any time the redox centers of the binding partners are close enough to ensure efficient electron tunneling across the interface, many protein-protein orientations are expected to be ET active. The present analysis confirms that the low-occupancy states can support the functional ET activity and contribute to the stability of redox protein complexes. As illustrated here, boundaries between the dominant and the encounter forms become blurred for many dynamic ET systems, which are more aptly described by ensembles of functionally and structurally heterogeneous bound forms. PMID- 26606504 TI - Investigating the Use Of Portable Air Pollution Sensors to Capture the Spatial Variability Of Traffic-Related Air Pollution. AB - Advances in microsensor technologies for air pollution monitoring encourage a growing use of portable sensors. This study aims at testing their performance in the development of exposure surfaces for nitrogen dioxide (NO2) and ozone (O3). In Montreal, Canada, a data-collection campaign was conducted across three seasons in 2014 for 76 sites spanning the range of land uses and built environments of the city; each site was visited from 6 to 12 times, for 20 min, using NO2 and O3 sensors manufactured by Aeroqual. Land-use regression models were developed, achieving R(2) values of 0.86 for NO2 and 0.92 for O3 when adjusted for regional meteorology to control for the fact that all of the locations were not monitored at the same time. A total of two exposure surfaces were then developed for NO2 and O3 as averages over spring, summer, and fall. Validation against the fixed-station data and previous campaigns suggests that Aeroqual sensors tend to overestimate the highest NO2 and O3 concentrations, thus increasing the range of values across the city. However, the sensors suggest a good performance with respect to capturing the spatial variability in NO2 and O3 and are very convenient to use, having great potential for capturing temporal variability. PMID- 26606505 TI - First evidence of occupational asthma to argan powder in a cosmetic factory. AB - BACKGROUND: Argan is used worldwide in numerous cosmetic products, as this fruit is supposed to have many beneficial properties on health. New cases of allergy can be expected with the growing use of argan. We investigated all workers (9) employed by a cosmetic factory and exposed to argan powder to identify possible allergies related to exposure to argan powder. METHODS: Patients were investigated in the occupational disease department and, according to their symptoms, underwent pulmonary function testing, methacholine challenge, specific inhalation challenge to argan powder, skin prick tests, and immunoblotting analysis. RESULTS: We report three cases of occupational asthma to argan powder and a probable case of rhinitis. Fifteen argan proteins were recognized by the patients' IgE. Identification of proteins, cross-reactions to nuts, and ELISA inhibition tests suggested that some argan allergens can cross-react in vitro with hazelnut allergens, including 11S globulin and vicilin. CONCLUSION: High level exposure to argan powder should be considered to be a potential cause of IgE-mediated allergy, and workers handling argan powder should be carefully investigated. PMID- 26606506 TI - Effectiveness of Emission Controls to Reduce the Atmospheric Concentrations of Mercury. AB - Coal-fired power plants in the United States are required to reduce their emissions of mercury (Hg) into the atmosphere to lower the exposure of Hg to humans. The effectiveness of power-plant emission controls on the atmospheric concentrations of Hg in the United States is largely unknown because there are few long-term high-quality atmospheric Hg data sets. Here, we present the atmospheric concentrations of Hg and sulfur dioxide (SO2) measured from 2006 to 2015 at a relatively pristine location in western Maryland that is several (>50 km) kilometers downwind of power plants in Ohio, Pennsylvania, and West Virginia. Annual average atmospheric concentrations of gaseous oxidized mercury (GOM), SO2, fine particulate mercury (PBM2.5), and gaseous elemental mercury (GEM) declined by 75%, 75%, 43%, and 13%, respectively, and were strongly correlated with power plant Hg emissions from the upwind states. These results provide compelling evidence that reductions in Hg emissions from power plants in the United States had their intended impact to reduce regional Hg pollution. PMID- 26606507 TI - Peers as clinicians: Examining the impact of Stay Play Talk on social communication in young preschoolers with autism. AB - BACKGROUND: Peer Mediated Interventions (PMIs) can be incorporated into integrated early childhood and preschool settings to address socialization impairments observed in children with ASD (Katz & Girolametto, 2013). However, research examining specific PMI strategies with young preschoolers remains limited. OBJECTIVE: The current study examines the efficacy of the Stay, Play, Talk PMI (English, Shafer, Goldstein, & Kaczmerek, 1997) on the social communication skills of young preschool children diagnosed with an Autism Spectrum Disorder (ASD). METHOD: Each of 3 typically developing children (ages 3 5 years) was paired with a child with an ASD (ages 3-4 years). Typically developing peers were taught to Stay with their friend, Play with their friend, and Talk to their friend. The child dyads played together during two, 20-min weekly sessions for 6-8 weeks. A multiple baseline design across participants was implemented to measure the impact of the Stay Play Talk strategies on social initiations and responses characterized by non-coordinated gestures, gestures, and words. Simulation Modeling Analysis was also conducted to confirm visual analysis. RESULTS: All 3 typical peer buddies and all 3 target children with ASD demonstrated increases in the frequency of their responses, reaching levels that greatly exceeded baseline levels. Further, social reciprocations increased among each dyad above baseline. Social initiations remained variable across dyads. Gains were not maintained two months post intervention. CONCLUSION: Results of this study corroborated previous findings that support the usefulness of PMIs to improve social communication of young children with ASD (Chan et al., 2009) and suggest an economical, naturally occurring approach to improve social communication during early childhood. LEARNING OUTCOMES: Readers will gain knowledge regarding the social communication profile of children with ASD and how this profile can negatively impact language development and peer relationships. In addition, readers will be able to identify the basic components of the Stay Play Talk intervention. Finally, this paper will explain the impacts of the Stay Play Talk intervention on the social communication skills of young children with ASD. PMID- 26606508 TI - Absolute Configurations of Zingiberenols Isolated from Ginger (Zingiber officinale) Rhizomes. AB - Two stereoisomeric zingiberenols in ginger were identified as (3R,6R,7S)-1,10 bisaboladien-3-ol (2) and (3S,6R,7S)-1,10-bisaboladien-3-ol (5). Absolute configurations were assigned by utilizing 1,10-bisaboladien-3-ol stereoisomers and two gas-chromatography columns: a 25 m Hydrodex-beta-6TBDM and 60 m DB-5MS. The C-6 and C-7 absolute configurations in both zingiberenols match those of zingiberene present abundantly in ginger rhizomes. Interestingly, zingiberenol 2 has recently been identified as a male-produced sex pheromone of the rice stink bug, Oebalus poecilus, thus indicating that ginger plants may be a potential source of the sex pheromone of this bug. PMID- 26606509 TI - Impact of the Neglected Tropical Diseases on Human Development in the Organisation of Islamic Cooperation Nations. PMID- 26606510 TI - Novel Nonsense Mutation in the NLRP7 Gene Associated with Recurrent Hydatidiform Mole. AB - AIM: This study aimed to clarify the genetic and epigenetic features of recurrent hydatidiform mole (RHM) in Japanese patients. METHODS: Four Japanese isolated RHM cases were analyzed using whole-exome sequencing. Villi from RHMs were collected by laser microdissection for genotyping and DNA methylation assay of differentially methylated regions (DMRs). Single nucleotide polymorphisms of PEG3 and H19 DMRs were used to confirm the parental origin of the variants. RESULTS: A novel homozygous nonsense mutation in NLRP7 (c.584G>A; p.W195X) was identified in 1 patient. Genotyping of one of her molar tissue revealed that it was biparental but not androgenetic in origin. Despite the fact that the RHM is biparental, maternally methylated DMRs of PEG3, SNRPN and PEG10 showed complete loss of DNA methylation. A paternally methylated DMR of H19 retained normal methylation. CONCLUSIONS: This is the first Japanese case of RHM with a novel homozygous nonsense NLRP7 mutation and a specific loss of maternal DNA methylation of DMRs. Notably, the mutation was identified in an isolated case of an ethnic background that has not previously been studied in this context. Our data underscore the involvement of NLRP7 in RHM pathophysiology and confirm that DNA methylation of specific regions is critical. PMID- 26606511 TI - Transplantation of kidneys from uncontrolled donation after circulatory determination of death: comparison with brain death donors with or without extended criteria and impact of normothermic regional perfusion. AB - The aim of this study was to compare the outcomes of kidney transplants from uncontrolled DCD (uDCD) with kidney transplants from extended (ECD) and standard criteria donors (SCD). In this multicenter study, we included recipients from uDCD (n = 50), and from ECD (n = 57) and SCD (n = 102) who could be eligible for a uDCD program. We compared patient and graft survival, and kidney function between groups. To address the impact of preservation procedures in uDCD, we compared in situ cold perfusion (ICP) with normothermic regional perfusion (NRP). Patient and graft survival rates were similar between the uDCD and ECD groups, but were lower than the SCD group (P < 0.01). Although delayed graft function (DGF) was more frequent in the uDCD group (66%) than in the ECD (40%) and SCD (27%) groups (P = 0.08 and P < 0.001), graft function was comparable between the uDCD and ECD groups at 3 months onwards post-transplantation. The use of NRP in the uDCD group (n = 19) was associated with a lower risk of DGF, and with a better graft function at 2 years post-transplantation, compared to ICP-uDCD (n = 31) and ECD. In conclusion, the use of uDCD kidneys was associated with post transplantation results comparable to those of ECD kidneys. NRP preservation may improve the results of uDCD transplantation. PMID- 26606513 TI - Effects of Shapes of Solute Molecules on Diffusion: A Study of Dependences on Solute Size, Solvent, and Temperature. AB - Diffusivities of basically linear, planar, and spherical solutes at infinite dilution in various solvents are studied to unravel the effects of solute shapes on diffusion. On the basis of the relationship between the reciprocal of diffusivity and the molecular volume of solute molecules with similar shape in a given solvent at constant temperature, the diffusivities of solutes of equal molecular volume but different shapes are evaluated and the effects due to different shapes of two equal-sized solute molecules on diffusion are determined. It is found that the effects are dependent on the size of the solute pairs studied. Evidence of the dependence of the solute-shape effects on solvent properties is also demonstrated and discussed. Here, some new diffusion data of aromatic compounds in methanol at different temperatures are reported. The result for methanol in this study indicates that the effects of solute shape on diffusivity are only weakly dependent on temperature. PMID- 26606512 TI - Familial Aggregation and Co-Aggregation of Essential Tremor and Parkinson's Disease. AB - BACKGROUND: Current data suggest that the 2 common tremor disorders, essential tremor (ET) and Parkinson's disease (PD), may be associated with one another. Familial aggregation studies allow one to further explore their relatedness. METHODS: Probands with ET (n = 110), PD (n = 130) or both ET and PD (n = 27) and control probands (n = 177) reported whether they had relatives with these diseases or with non-specific tremor. RESULTS: A greater proportion of ET probands than control probands reported relatives with ET (30.0 vs. 2.8%, p < 0.001), non-specific tremor (38.2 vs. 13.6%, p < 0.001) and both ET and PD in different relatives (6.4 vs. 0.6%, p = 0.004). A greater proportion of PD probands than control probands reported relatives with PD (20.0 vs. 8.5%, p = 0.003), ET (11.5 vs. 2.8%, p = 0.002) and both ET and PD in different relatives (6.9 vs. 0.6%, p = 0.002). CONCLUSIONS: This study provides evidence for the aggregation of ET in ET families and PD in PD families, and the familial co aggregation of ET and PD. PMID- 26606514 TI - Impact of Sample Matrix on Accuracy of Peptide Quantification: Assessment of Calibrator and Internal Standard Selection and Method Validation. AB - Protein quantification based on peptides using LC-MS/MS has emerged as a promising method to measure biomarkers, protein drugs, and endogenous proteins. However, the best practices for selection, optimization, and validation of the quantification peptides are not well established, and the influence of different matrices on protein digestion, peptide stability, and MS detection has not been systematically addressed. The aim of this study was to determine how biological matrices affect digestion, detection, and stability of peptides. The microsomal retinol dehydrogenase (RDH11) and cytosolic soluble aldehyde dehydrogenases (ALDH1As) involved in the synthesis of retinoic acid (RA) were chosen as model proteins. Considerable differences in the digestion efficiency, sensitivity, and matrix effects between peptides were observed regardless of the target protein's subcellular localization. The precision and accuracy of the quantification of RDH11 and ALDH1A were affected by the choice of calibration and internal standards. The final method using recombinant protein calibrators and stable isotope labeled (SIL) peptide internal standards was validated for human liver. The results demonstrate that different sample matrices have peptide, time, and matrix specific effects on protein digestion and absolute quantification. PMID- 26606515 TI - First Detection of OXA-10 Extended-Spectrum Beta-Lactamases and the Occurrence of mexR and nfxB in Clinical Isolates of Pseudomonas aeruginosa from Nigeria. AB - BACKGROUND: The characterization of beta-lactamase production in Pseudomonasaeruginosa is rarely reported in Nigeria. The objective of this study was to investigate the occurrence and characterize the different beta-lactamases as well as mechanisms of fluoroquinolones resistance among P. aeruginosa isolated from various clinical sources from Nigeria. MATERIALS AND METHOD: Isolates were investigated using PCR, RFLP and sequencing for the detection of various beta lactamases and efflux pump regulator genes. RESULT: The prevalence of OXA-10, AmpC, CTX-M and SHV in P. aeruginosa was 80, 70, 5 and 5%, respectively. The coexistence of blaOXA-10 with blaAmpC, blaSHV and blaCTX-M was reported in 40, 5 and 5% of isolates, respectively. The efflux pump regulator genes mexR and nfxB were both amplified in 45% of the OXA-10-positive isolates. CONCLUSION: This is the first report of the characterization of OXA-10 extended-spectrum beta lactamases and occurrence of mexR and nfxB efflux regulator genes in clinical isolates of P. aeruginosa in Nigeria. PMID- 26606516 TI - Lesion Location-Based Prediction of Visual Field Improvement after Cerebral Infarction. AB - BACKGROUND: Although the prognosis of ischemic stroke is highly dependent on the lesion location, it has rarely been quantitatively utilized. We investigated the usefulness of regional extent of ischemic lesion (rEIL) predicting the improvement of visual field defect (VFD) in patients with posterior cerebral artery infarction. METHODS: The rEILs were measured in each individual cortex after transforming the lesions to a standard atlas. Significant improvement of VFD was tentatively defined as 20% improvement at 3 months after stroke. The performances of clinical and imaging variables predicting significant improvement were measured by support vector machine. The maximum performance of variables predicting the significant improvement was compared between subgroups of variables (clinical, baseline severity and lesion volume) and the effect of adding rEIL to those subgroups of variables was evaluated. RESULTS: A total of 35 patients were enrolled in this study. Left PCA infarct, MR-time from onset, rEILs in the lingual, calcarine, and cuneus cortices were good prognostic indicators of hemi-VFD (performance for predicting the significant improvement: 72.8+/-11.8%, 66.1+/-11.2%, respectively). A combination of the rEILs of each cortical subregions demonstrated a better predictive performance for hemi-VFD (83.8+/ 9.5%) compared to a combination of clinical variables (72.8+/-11.8; p<0.001), baseline severity (63.0+/-11.9%; p<0.001), or lesion volume (62.6+/-12.7%; p<0.001). Adding a rEIL to other variables improved the prognostic prediction for hemi-VFD (74.4+/-11.6% to 91.3+/-7.7%; p<0.001). CONCLUSIONS: An estimation of rEIL provides useful information regarding the ischemic lesion location. rEIL accurately predicts the significant improvement of VFD and enhances the prediction power when combined with other variables. PMID- 26606517 TI - Research Resource: The Dexamethasone Transcriptome in Hypothalamic Embryonic Neural Stem Cells. AB - Exposure to excess glucocorticoids during fetal development has long-lasting physiological and behavioral consequences, although the mechanisms are poorly understood. The impact of prenatal glucocorticoids exposure on stress responses in juvenile and adult offspring implicates the developing hypothalamus as a target of adverse prenatal glucocorticoid action. Therefore, primary cultures of hypothalamic neural-progenitor/stem cells (NPSCs) derived from mouse embryos (embryonic day 14.5) were used to identify the glucocorticoid transcriptome in both males and females. NPSCs were treated with vehicle or the synthetic glucocorticoid dexamethasone (dex; 100nM) for 4 hours and total RNA analyzed using RNA-Sequencing. Bioinformatic analysis demonstrated that primary hypothalamic NPSC cultures expressed relatively high levels of a number of genes regulating stem cell proliferation and hypothalamic progenitor function. Interesting, although these cells express glucocorticoid receptors (GRs), only low levels of sex-steroid receptors are expressed, which suggested that sex specific differentially regulated genes identified are mediated by genetic and not hormonal influences. We also identified known or novel GR-target coding and noncoding genes that are either regulated equivalently in male and female NPSCs or differential responsiveness in one sex. Using gene ontology analysis, the top functional network identified was cell proliferation and using bromodeoxyuridine (BrdU) incorporation observed a reduction in proliferation of hypothalamic NPSCs after dexamethasone treatment. Our studies provide the first characterization and description of glucocorticoid-regulated pathways in male and female embryonically derived hypothalamic NPSCs and identified GR-target genes during hypothalamic development. These findings may provide insight into potential mechanisms responsible for the long-term consequences of fetal glucocorticoid exposure in adulthood. PMID- 26606518 TI - How Robust Is Your Project? From Local Failures to Global Catastrophes: A Complex Networks Approach to Project Systemic Risk. AB - Current societal requirements necessitate the effective delivery of complex projects that can do more while using less. Yet, recent large-scale project failures suggest that our ability to successfully deliver them is still at its infancy. Such failures can be seen to arise through various failure mechanisms; this work focuses on one such mechanism. Specifically, it examines the likelihood of a project sustaining a large-scale catastrophe, as triggered by single task failure and delivered via a cascading process. To do so, an analytical model was developed and tested on an empirical dataset by the means of numerical simulation. This paper makes three main contributions. First, it provides a methodology to identify the tasks most capable of impacting a project. In doing so, it is noted that a significant number of tasks induce no cascades, while a handful are capable of triggering surprisingly large ones. Secondly, it illustrates that crude task characteristics cannot aid in identifying them, highlighting the complexity of the underlying process and the utility of this approach. Thirdly, it draws parallels with systems encountered within the natural sciences by noting the emergence of self-organised criticality, commonly found within natural systems. These findings strengthen the need to account for structural intricacies of a project's underlying task precedence structure as they can provide the conditions upon which large-scale catastrophes materialise. PMID- 26606519 TI - Optimization of the aqueous synthesis of Cu2S quantum dots with different surface ligands. AB - Surface functionalization of quantum dots (QDs) is one of the most important aspects of designing and preparing the desired QDs for intended optical and biomedical applications. In this paper, we synthesized aqueous-phase Cu2S quantum dots coating by three different stabilizers, i.e. mercaptoacetic acid, mercaptopropionic acid and glutathione (GSH). Different stabilizers can influence the coordination modes between Cu(+) on the surface of Cu2S and S(2-) of the ligand. The Cu2S QDs were characterized by UV-vis spectroscopy, energy dispersive spectrometry, transmission electron microscopy, Fourier transform infrared spectroscopy, x-ray diffraction and Raman spectra. Then, we performed a systematic study to evaluate the colloidal stability and in vitro toxicity of the formulations of Cu2S QDs with different stabilizers. Our results show that Cu2S QDs modified with different stabilizers have distinct functional groups on their surface and these groups make Cu2S produce different vibrations according to Raman spectra. The Cu2S-GSH exhibit the best colloidal stability in all pH buffer solutions and the lowest toxicity compare to the other two stabilizers. These properties make the Cu2S-GSH quantum dots a candidate for bioapplications in the future. PMID- 26606521 TI - Merging Children's Oncology Group Data with an External Administrative Database Using Indirect Patient Identifiers: A Report from the Children's Oncology Group. AB - PURPOSE: Clinical trials data from National Cancer Institute (NCI)-funded cooperative oncology group trials could be enhanced by merging with external data sources. Merging without direct patient identifiers would provide additional patient privacy protections. We sought to develop and validate a matching algorithm that uses only indirect patient identifiers. METHODS: We merged the data from two Phase III Children's Oncology Group (COG) trials for de novo acute myeloid leukemia (AML) with the Pediatric Health Information Systems (PHIS). We developed a stepwise matching algorithm that used indirect identifiers including treatment site, gender, birth year, birth month, enrollment year and enrollment month. Results from the stepwise algorithm were compared against the direct merge method that used date of birth, treatment site, and gender. The indirect merge algorithm was developed on AAML0531 and validated on AAML1031. RESULTS: Of 415 patients enrolled on the AAML0531 trial at PHIS centers, we successfully matched 378 (91.1%) patients using the indirect stepwise algorithm. Comparison to the direct merge result suggested that 362 (95.7%) matches identified by the indirect merge algorithm were concordant with the direct merge result. When validating the indirect stepwise algorithm using the AAML1031 trial, we successfully matched 157 out of 165 patients (95.2%) and 150 (95.5%) of the indirectly merged matches were concordant with the directly merged matches. CONCLUSIONS: These data demonstrate that patients enrolled on COG clinical trials can be successfully merged with PHIS administrative data using a stepwise algorithm based on indirect patient identifiers. The merged data sets can be used as a platform for comparative effectiveness and cost effectiveness studies. PMID- 26606522 TI - Polymorphisms in Fibronectin Binding Proteins A and B among Staphylococcus aureus Bloodstream Isolates Are Not Associated with Arthroplasty Infection. AB - BACKGROUND: Nonsynonymous single nucleotide polymorphisms (SNPs) in fibronectin binding protein A (fnbA) of Staphylococcus aureus are associated with cardiac device infections. However, the role of fnbA SNPs in S. aureus arthroplasty infection is unknown. METHODS: Bloodstream S. aureus isolates from a derivation cohort of patients at a single U.S. medical center with S. aureus bacteremia (SAB) and prosthetic hip or knee arthroplasties that were infected (PJI, n = 27) or uninfected (PJU, n = 43) underwent sequencing of fnbA and fnbB. A validation cohort of S. aureus bloodstream PJI (n = 12) and PJU (n = 58) isolates from Germany also underwent fnbA and fnbB sequencing. RESULTS: Overall, none of the individual fnbA or fnbB SNPs were significantly associated with the PJI or PJU clinical groups within the derivation cohort. Similarly, none of the individual fnbA or fnbB SNPs were associated with PJI or PJU when the analysis was restricted to patients with either early SAB (i.e., bacteremia occurring <1 year after placement or manipulation of prostheses) or late SAB (i.e., bacteremia >1 year after placement or manipulation of prostheses). CONCLUSIONS: In contrast to cardiac device infections, there is no association between nonsynonymous SNPs in fnbA or fnbB of bloodstream S. aureus isolates and arthroplasty infection. These results suggest that initial steps leading to S. aureus infection of cardiovascular and orthopedic prostheses may arise by distinct processes. PMID- 26606523 TI - Can the sum of pooled data from observational studies better evaluate outcome measures for therapies in coronary artery disease? AB - Randomized control trials (RCTs) are considered the gold standard in the hierarchy of evidence based medicine. Guidelines and recommendations for clinical practice are based on the strength of evidence in this hierarchical tree. This article looks at the weakness of RCTs and variance between large pooled observational data and trial results for some of the historical trials in coronary artery disease. Observational studies can supplement data from resource intensive RCTs. Guidelines for reporting and analysis however need to be rigorous. It further discusses alternate systems of hierarchies as basis for recommendations. PMID- 26606524 TI - Rheumatoid Factor and Disease Activity Are Independent Predictors of Lymphoma in Primary Sjogren's Syndrome. AB - OBJECTIVE: To define parameters predictive of lymphoma development in patients with primary Sjogren's syndrome (SS). METHODS: A multicenter case-control survey was performed to identify predictors of lymphoma. Cases were patients who developed lymphoma after diagnosis of primary SS and were mainly recruited through the Club Rhumatismes et Inflammation network. For each case, 2 controls (matched for disease duration and age) were randomly selected among patients with primary SS and without lymphoma. Cases and controls were compared using univariate analysis and then using multivariate analysis to identify independent predictors of lymphoma. RESULTS: One hundred one patients with primary SS and lymphoma were included. Eighty-seven patients were women (86.1%), and the mean +/ SD age at lymphoma diagnosis was 57.4 +/- 12.6 years. The most frequent histologic type was B cell non-Hodgkin's lymphoma (NHL) in 99 of 101 patients, with marginal-zone lymphoma in 76 of the 99 patients (76.8%) including 58 (58.6%) with lymphoma of the mucosa-associated lymphoid tissue type. Lymphomas were most frequently located in the salivary glands (43 patients). A specific treatment was initiated at diagnosis in 87 patients with B cell NHL, and 61 patients (61.6%) achieved complete sustained remission after the first line of treatment. In the multivariate analysis, salivary gland enlargement, the presence of rheumatoid factor (RF), low C4, cryoglobulinemia, lymphopenia, and disease activity according to the European League Against Rheumatism Sjogren's Syndrome Disease Activity Index (excluding the lymphoma domain) were found to be predictors of lymphoma. No previous treatment for primary SS was associated with any effect on lymphoma occurrence. CONCLUSION: In addition to previously known factors predictive of lymphoma occurrence, the independent roles of RF and disease activity were demonstrated in this case-control study of primary SS-associated lymphoma. Our findings highlight the roles of chronic antigenic stimulation and disease activity in the development of this severe complication. PMID- 26606525 TI - MEDI-551 Treatment Effectively Depletes B Cells and Reduces Serum Titers of Autoantibodies in Mice Transgenic for Sle1 and Human CD19. AB - OBJECTIVE: To evaluate treatment with MEDI-551, a humanized anti-human CD19 monoclonal antibody, in a model of autoimmunity involving mice transgenic (Tg) for Sle1 and human CD19 (hCD19). METHODS: Sle1.hCD19-Tg mice were given either a single intravenous dose of MEDI-551 or repeated doses of MEDI-551 biweekly for up to 12 weeks. The numbers of B cells in the blood, spleen, and bone marrow were determined by flow cytometry assay. In the spleen and bone marrow, the number of IgM- and IgG-specific antibody-secreting cells (ASCs) and the number of ASCs specific for anti-double-stranded DNA (anti-dsDNA) were determined by enzyme linked immunospot assay. Serum autoantibody and total immunoglobulin levels were determined by enzyme-linked immunosorbent assay, and levels of inflammatory proteins were tested using a multianalyte profiling platform. RESULTS: MEDI-551 treatment of Sle1.hCD19-Tg mice resulted in effective and sustained B cell depletion throughout the duration of the experiment. The frequency of IgM and IgG ASCs in the spleen was reduced by >=90%, whereas in the bone marrow, the total ASC frequency was not changed. Levels of autoantibodies specific for dsDNA as well as antihistone and antinuclear antibodies were each reduced by 40-80%, but total serum immunoglobulin levels were largely unchanged at the end of 12 weeks of treatment. CONCLUSION: These findings highlight the ability of MEDI-551 to deplete B cells and ASCs in autoimmune Sle1.hCD19-Tg mice. MEDI-551 treatment resulted in a robust reduction of autoantibodies but had minimal effect on total serum immunoglobulins. Thus, the novel ability of MEDI-551 to remove a broad range of B cells as well as to lower most disease-driving autoantibodies in an autoimmune disease mouse model warrants continued research. Several clinical studies to explore the safety and activity of MEDI-551 in autoantibody-associated autoimmune diseases are ongoing. PMID- 26606526 TI - Diurnal Emotional States Impact the Sleep Course. AB - BACKGROUND: Diurnal emotional experiences seem to affect several characteristics of sleep architecture. However, this influence remains unclear, especially for positive emotions. In addition, electrodermal activity (EDA), a sympathetic robust indicator of emotional arousal, differs depending on the sleep stage. The present research has a double aim: to identify the specific effects of pre-sleep emotional states on the architecture of the subsequent sleep period; to relate such states to the sympathetic activation during the same sleep period. METHODS: Twelve healthy volunteers (20.1 +/- 1.0 yo.) participated in the experiment and each one slept 9 nights at the laboratory, divided into 3 sessions, one per week. Each session was organized over three nights. A reference night, allowing baseline pre-sleep and sleep recordings, preceded an experimental night before which participants watched a negative, neutral, or positive movie. The third and last night was devoted to analyzing the potential recovery or persistence of emotional effects induced before the experimental night. Standard polysomnography and EDA were recorded during all the nights. RESULTS: Firstly, we found that experimental pre-sleep emotional induction increased the Rapid Eye Movement (REM) sleep rate following both negative and positive movies. While this increase was spread over the whole night for positive induction, it was limited to the second half of the sleep period for negative induction. Secondly, the valence of the pre sleep movie also impacted the sympathetic activation during Non-REM stage 3 sleep, which increased after negative induction and decreased after positive induction. CONCLUSION: Pre-sleep controlled emotional states impacted the subsequent REM sleep rate and modulated the sympathetic activity during the sleep period. The outcomes of this study offer interesting perspectives related to the effect of diurnal emotional influences on sleep regulation and open new avenues for potential practices designed to alleviate sleep disturbances. PMID- 26606527 TI - Effects of trematode parasitism on the shell morphology of snails from flow and nonflow environments. AB - The primary function of the gastropod shell is protection. However, shells that function well in one environment may be maladaptive in another. Upon infection, the snail shell protects internal parasites and it is to the parasite's advantage to optimize, or not interfere with, shell functionality. However, parasites, particularly trematodes, are often pathogenic and it is not clear if parasitism will induce environment-dependent or -independent changes to gastropod shells. We conducted a field study and a complementary laboratory experiment to examine the effects of trematode parasitism on shell characteristics (shape, size, and crush resistance) of Physa acuta snails in flow and nonflow environments using geometric morphometrics and crush assays. Field results indicate wetland (nonflow) snails had large, crush resistant shells with narrow apertures and tall spires. In contrast, stream (flow) snails had small, weak shells with wide apertures and short spires. Parasitism had no apparent effect on the crush resistance of wetland snails but significantly reduced the crush resistance of stream snails. Parasitism had no significant effect on overall shell shape in stream or wetland snails. Similar to the results of our field study, nonflow tank snails had significantly more crush resistant shells than flow tank snails. Additionally, the shapes of flow and nonflow tank snails significantly differed where nonflow tank snails resembled wetland snails and flow tank snails resembled stream snails. For laboratory snails, parasitism reduced crush resistance regardless of flow/nonflow treatment. Our results demonstrate that habitat and/or flow treatment was the primary factor affecting P. acuta shell morphology and that trematode parasitism played a secondary role. PMID- 26606529 TI - Dose- and time-dependent benefits of iPad technology in an undergraduate human anatomy course. AB - This study examined the impact of iPad integration on performance in an undergraduate gross anatomy course. Two out of six course sections were assigned to one of the following conditions: control (no iPad, n = 61); limited access (laboratory iPads, n = 58); and unlimited access (personal iPads, n = 47). Student knowledge was assessed over time during the semester with two practical examinations in laboratory and four multiple choice/essay examinations in lecture. The same PowerPoint presentations and examinations were utilized for all conditions. Mixed ANOVA analysis identified an interaction effect between time and condition for both laboratory (F2,153 = 16.12; P < 0.05) and lecture (F6,462 = 5.47; P < 0.05) performance. Between laboratory examinations, student performance was lower by 4.2% and higher by 3.0% in control and unlimited access conditions, respectively. Unlimited access students scored higher than control and limited access (82.8 +/- 2.2 vs 71.5 +/- 2.6 and 74.3 +/- 1.7%; P < 0.05) and higher than control students (78.7 +/- 2.1 vs 70.6 +/- 2.0%; P < 0.05) on the third and fourth lecture examination, respectively. Postsemester surveys completed by experimental students (89.5% response rate) indicated that a greater percentage of unlimited vs limited access students agreed that laboratory (84.8 vs 56.3%, P < 0.05) and lecture (58.7 vs 14.6%, P < 0.05) performance was enhanced with the iPad. Results suggest that if students are given the opportunity to overcome the technology learning curve, tablet devices and relevant applications can be useful tools in human anatomy courses. Anat Sci Educ 9: 367-377. (c) 2015 American Association of Anatomists. PMID- 26606528 TI - Use of a High-Density Protein Microarray to Identify Autoantibodies in Subjects with Type 2 Diabetes Mellitus and an HLA Background Associated with Reduced Insulin Secretion. AB - New biomarkers for type 2 diabetes mellitus (T2DM) may aid diagnosis, drug development or clinical treatment. Evidence is increasing for the adaptive immune system's role in T2DM and suggests the presence of unidentified autoantibodies. While high-density protein microarrays have emerged as a useful technology to identify possible novel autoantigens in autoimmune diseases, its application in T2DM has lagged. In Pima Indians, the HLA haplotype (HLA-DRB1*02) is protective against T2DM and, when studied when they have normal glucose tolerance, subjects with this HLA haplotype have higher insulin secretion compared to those without the protective haplotype. Possible autoantibody biomarkers were identified using microarrays containing 9480 proteins in plasma from Pima Indians with T2DM without the protective haplotype (n = 7) compared with those with normal glucose regulation (NGR) with the protective haplotype (n = 11). A subsequent validation phase involving 45 cases and 45 controls, matched by age, sex and specimen storage time, evaluated 77 proteins. Eleven autoantigens had higher antibody signals among T2DM subjects with the lower insulin-secretion HLA background compared with NGR subjects with the higher insulin-secretion HLA background (p<0.05, adjusted for multiple comparisons). PPARG2 and UBE2M had lowest p-values (adjusted p = 0.023) while PPARG2 and RGS17 had highest case-to-control antibody signal ratios (1.7). A multi-protein classifier involving the 11 autoantigens had sensitivity, specificity, and area under the receiver operating characteristics curve of 0.73, 0.80, and 0.83 (95% CI 0.74-0.91, p = 3.4x10-8), respectively. This study identified 11 novel autoantigens which were associated with T2DM and an HLA background associated with reduced insulin secretion. While further studies are needed to distinguish whether these antibodies are associated with insulin secretion via the HLA background, T2DM more broadly, or a combination of the two, this study may aid the search for autoantibody biomarkers by narrowing the list of protein targets. PMID- 26606530 TI - Genome-Wide Identification of SSR and SNP Markers Based on Whole-Genome Re Sequencing of a Thailand Wild Sacred Lotus (Nelumbo nucifera). AB - Genomic resources such as single nucleotide polymorphism (SNPs), insertions and deletions (InDels) and SSRs (simple sequence repeats) are essential for crop improvement and better utilization in genetic breeding. However, the resources for the sacred lotus (Nelumbo nucifera Gaertn.) are still limited. In the present study, to dissect large-scale genomic molecular marker resources for sacred lotus, we re-sequenced a Thailand sacred lotus cultivar 'Chiang Mai wild lotus' and compared with the reported lotus genome 'Middle lake wild lotus'. A total of 3,180,059 SNPs, 328, 251 InDels and 14,191 SVs were found between the two genomes. The functional impact analyses of these SNPs indicated that they may be involved in metabolic processes, binding, catalytic activity, etc. Mining the genome sequences for SSRs showed that 191,657 SSRs were identified with a frequency of one SSR per 4.23 kb and 103,656 SSR primer pairs were designed. Furthermore, 14, 502 EST-SSRs were also indentified using the available RNA-seq data in the NCBI. A subset of 150 SSRs (genomic and EST-SSRs) was randomly selected for validation and genetic diversity analysis. The genotypes could be easily distinguished using these SSR markers and the 'Chiang Mai wild lotus' was obviously differentiated from the other Chinese accessions. This study provides considerable amounts of genomic resources and markers for the quantitative trait locus (QTL) identification and molecular selection of the species, which could have a potential role in various applications in sacred lotus breeding. PMID- 26606531 TI - Diagnostic and Prognostic Value of the Cerebrospinal Fluid Concentration of Immunoglobulin Free Light Chains in Clinically Isolated Syndrome with Conversion to Multiple Sclerosis. AB - BACKGROUND AND OBJECTIVE: In this study, we evaluated the diagnostic and prognostic significance of cerebrospinal fluid free light chains (CSF FLC) at the time of clinically isolated syndrome (CIS). METHODS: We compared FLC-parameters at the moment of CIS in patients with conversion to multiple sclerosis (MS) after 2 years (CIS-MS), patients who remained stable both clinically and radiologically after 2 years (CIS-nonMS), patients with non-inflammatory neurologic diseases (NIND) as a comparison group and patients with other inflammatory neurologic diseases (IND) with intrathecal oligoclonal bands (OCB) synthesis. ROC-analysis was conducted to define FLC-assay characteristics and cut-off values. We also compared FLC-concentrations in CIS patients to determine their OCB-status. A correlation analysis was performed between FLC-concentrations and the expanded disability scale score (EDSS), annualized relapse rate (ARR) and MRI-activity (i.e., number of new and gadolinium-enhancing (Gd+) lesions) in patients. RESULTS: The levels of kappa-FLC (k-FLCCSF) and lambda-FLC (lambda-FLCCSF) as well as kappa- and lambda-quotients (Q-k and Q-lambda) were elevated in CIS-MS compared to the CIS-nonMS and NIND groups. These levels did not differ significantly when compared with the IND group. We identified several patients with high k-FLCCSF and lambda-FLCCSF in OCB-negative CIS and IND groups. The level of k-FLCCSF production was significantly higher in OCB-positive patients in the CIS-MS group compared to the CIS-nonMS group. The concentrations of k-FLCCSF and Q-k in the CIS-MS group showed significant correlation with the level of EDSS after 2 years (k-FLC: r = 0.4477,p = 0.0016; Q-k: r = 0.4621, p = 0.0016). lambda FLCCSF and Q-lambda inversely correlated with the number of Gd+ lesions (CSF lambda-FLC: r = -0.3698, p = 0.0223; Q-lambda: r = -0.4527, p = 0.0056). CONCLUSION: The concentration of CSF FLC predicts conversion to MS within 2 years following CIS. OCB-positive patients with an early conversion have a higher concentration of CSF-FLC. We have also shown a prognostic significance of k FLCCSF for future EDSS-progression. PMID- 26606532 TI - Ultrathin Polyimide Membrane as Cell Carrier for Subretinal Transplantation of Human Embryonic Stem Cell Derived Retinal Pigment Epithelium. AB - In this study, we investigated the suitability of ultrathin and porous polyimide (PI) membrane as a carrier for subretinal transplantation of human embryonic stem cell (hESC) -derived retinal pigment epithelial (RPE) cells in rabbits. The in vivo effects of hESC-RPE cells were analyzed by subretinal suspension injection into Royal College of Surgeons (RCS) rats. Rat eyes were analyzed with electroretinography (ERG) and histology. After analyzing the surface and permeability properties of PI, subretinal PI membrane transplantations with and without hESC-RPE were performed in rabbits. The rabbits were followed for three months and eyes analyzed with fundus photography, ERG, optical coherence tomography (OCT), and histology. Animals were immunosuppressed with cyclosporine the entire follow-up time. In dystrophic RCS rats, ERG and outer nuclear layer (ONL) thickness showed some rescue after hESC-RPE injection. Cells positive for human antigen were found in clusters under the retina 41 days post-injection but not anymore after 105 days. In rabbits, OCT showed good placement of the PI. However, there was loss of pigmentation on the hESC-RPE-PI over time. In the eyes with PI alone, no obvious signs of inflammation or retinal atrophy were observed. In the presence of hESC-RPE, mononuclear cell infiltration and retinal atrophy were observed around the membranes. The porous ultrathin PI membrane was well tolerated in the subretinal space and is a promising scaffold for RPE transplantation. However, the rejection of the transplanted cells seems to be a major problem and the given immunosuppression was insufficient for reduction of xenograft induced inflammation. PMID- 26606533 TI - Thyroid surgery for Graves' disease and Graves' ophthalmopathy. AB - BACKGROUND: Graves' disease is an autoimmune disease caused by the production of auto-antibodies against the thyroid-stimulating hormone receptor, which stimulates follicular cell production of thyroid hormone. It is the commonest cause of hyperthyroidism and may cause considerable morbidity with increased risk of cardiovascular and respiratory adverse events. Five per cent of people with Graves' disease develop moderate to severe Graves' ophthalmopathy. Thyroid surgery for Graves' disease commonly falls into one of three categories: 1) total thyroidectomy, which aims to achieve complete macroscopic removal of thyroid tissue; 2) bilateral subtotal thyroidectomy, in which bilateral thyroid remnants are left; and 3) unilateral total and contralateral subtotal thyroidectomy, or the Dunhill procedure. Recent American Thyroid Association guidelines on treatment of Graves' hyperthyroidism emphasised the role of surgery as one of the first-line treatments. Total thyroidectomy removes target tissue for the thyroid stimulating hormone receptor antibody. It controls hyperthyroidism at the cost of lifelong thyroxine replacement. Subtotal thyroidectomy leaves a thyroid remnant and may be less likely to lead to complications, however a higher rate of recurrent hyperthyroidism is expected and revision surgery would be challenging. The choice of the thyroidectomy technique is currently largely a matter of surgeon preference, and a systematic review of the evidence base is required to determine which option offers the best outcomes for patients. OBJECTIVES: To assess the optimal surgical technique for Graves' disease and Graves' ophthalmopathy. SEARCH METHODS: We searched the Cochrane Library, MEDLINE and PubMed, EMBASE, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The date of the last search was June 2015 for all databases. We did not apply any language restrictions. SELECTION CRITERIA: Only randomised controlled trials (RCTs) involving participants with a diagnosis of Graves' disease based on clinical features and biochemical findings of hyperthyroidism were eligible for inclusion. Trials had to directly compare at least two surgical techniques of thyroidectomy. There was no age limit to study inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and cross-checked the data for analysis, evaluation of risk of bias and establishment of 'Summary of findings' tables using the GRADE instrument. The senior review authors reviewed the data and reconciled disagreements. MAIN RESULTS: We included five RCTs with a total of 886 participants; 172 were randomised to total thyroidectomy, 383 were randomised to bilateral subtotal thyroidectomy, 309 were randomised to the Dunhill procedure and 22 were randomised to either bilateral subtotal thyroidectomy or the Dunhill procedure. Follow-up ranged between six months and six years. One trial had three comparison arms. All five trials were conducted in university hospitals or tertiary referral centres for thyroid disease. All thyroidectomies were performed by experienced surgeons. The overall quality of the evidence ranged from low to moderate. In all trials, blinding procedures were insufficiently described. Outcome assessment for objective outcomes was blinded in one trial. Surgeons were not blinded in any of the trials. One trial blinded participants. Attrition bias was a substantial problem in one trial, with 35% losses to follow-up. In one trial the analysis was not carried out on an intention-to-treat basis.Total thyroidectomy was more effective than subtotal thyroidectomy techniques (both bilateral subtotal thyroidectomy and the Dunhill procedure) at preventing recurrent hyperthyroidism in 0/150 versus 11/200 participants (OR 0.14 (95% CI 0.04 to 0.46); P = 0.001; 2 trials; moderate quality evidence). Total thyroidectomy was also more effective than bilateral subtotal thyroidectomy at preventing recurrent hyperthyroidism in 0/150 versus 10/150 participants (odds ratio (OR) 0.13 (95% confidence interval (CI) 0.04 to 0.44); P = 0.001; 2 trials; moderate quality evidence). Compared to bilateral subtotal thyroidectomy, the Dunhill procedure was more likely to prevent recurrent hyperthyroidism in 20/283 versus 8/309 participants (OR 2.73 (95% CI 1.28 to 5.85); P = 0.01; 3 trials; low quality evidence). Total thyroidectomy compared with subtotal thyroidectomy conferred a greater risk of permanent hypocalcaemia/hypoparathyroidism in 8/172 versus 3/221 participants (OR 4.79 (95% CI 1.36 to 16.83); P = 0.01; 3 trials; low quality evidence). Effects of the various surgical techniques on permanent recurrent laryngeal nerve palsy and regression of Graves' ophthalmopathy were neutral. One death was reported in one study in year three of follow-up. No study investigated health-related quality of life or socioeconomic effects. AUTHORS' CONCLUSIONS: Total thyroidectomy is more effective than subtotal thyroidectomy (both bilateral subtotal thyroidectomy and the Dunhill procedure) at preventing recurrent hyperthyroidism in Graves' disease. The type of surgery performed does not affect regression of Graves' ophthalmopathy. There was some evidence that total thyroidectomy compared with subtotal thyroidectomy conferred a greater risk of permanent hypocalcaemia/hypoparathyroidism, which however, was not seen in comparison with bilateral subtotal thyroidectomy. Permanent recurrent laryngeal nerve palsy did not seem to be affected by type of thyroidectomy. Health-related quality of life as a patient-important outcome measure should form a core determinant of any future trial on the effects of thyroid surgery for Graves' disease. PMID- 26606534 TI - Gaze Following Is Modulated by Expectations Regarding Others' Action Goals. AB - Humans attend to social cues in order to understand and predict others' behavior. Facial expressions and gaze direction provide valuable information to infer others' mental states and intentions. The present study examined the mechanism of gaze following in the context of participants' expectations about successive action steps of an observed actor. We embedded a gaze-cueing manipulation within an action scenario consisting of a sequence of naturalistic photographs. Gaze induced orienting of attention (gaze following) was analyzed with respect to whether the gaze behavior of the observed actor was in line or not with the action-related expectations of participants (i.e., whether the actor gazed at an object that was congruent or incongruent with an overarching action goal). In Experiment 1, participants followed the gaze of the observed agent, though the gaze-cueing effect was larger when the actor looked at an action-congruent object relative to an incongruent object. Experiment 2 examined whether the pattern of effects observed in Experiment 1 was due to covert, rather than overt, attentional orienting, by requiring participants to maintain eye fixation throughout the sequence of critical photographs (corroborated by monitoring eye movements). The essential pattern of results of Experiment 1 was replicated, with the gaze-cueing effect being completely eliminated when the observed agent gazed at an action-incongruent object. Thus, our findings show that covert gaze following can be modulated by expectations that humans hold regarding successive steps of the action performed by an observed agent. PMID- 26606535 TI - THYROID-STIMULATING HORMONE LEVELS ARE INVERSELY ASSOCIATED WITH SERUM TOTAL BILE ACID LEVELS: A CROSS-SECTIONAL STUDY. AB - OBJECTIVE: Bile acids (BAs) synthesized from cholesterol play a critical role in eliminating excess cholesterol to maintain cholesterol homeostasis. BAs are also signaling molecules that are involved in the regulation of lipid, glucose, and energy metabolism. Thyroid-stimulating hormone (TSH) has been found to decrease liver BA synthesis via a sterol regulatory element-binding protein 2/hepatocyte nuclear factor 4 alpha/cholesterol 7alpha-hydroxylase (SREBP-2/HNF-4alpha/CYP7A1) pathway in vivo and in vitro. However, the relationship between serum TSH and total BA levels in humans is still unclear. METHODS: This was a single-center cross-sectional study of 339 subclinical hypothyroidism (SCH) patients and an equal number of controls matched by age and sex from 11,000 subjects. RESULTS: Serum total BA levels significantly decreased (3.11 +/- 2.05 vs. 5.87 +/- 2.39, P<.01), while total cholesterol (TC) levels increased (5.02 +/- 0.65 vs. 4.88 +/- 0.63, P<.01) in subclinical hypothyroidism (SCH) patients compared to control subjects. Serum TSH and BA levels were significantly and negatively correlated in subclinical hypothyroid patients who were also hypercholesterolemic (rs = -0.189, P = .004). Each 1 MUIU/mL increase in TSH level was associated with a decrease in log-transformed values of total BAs (logTBAs) by 0.182 after controlling for confounding factors relevant to BA metabolism. The relationship between TSH and serum total BAs was more significant in subjects younger than 65 years. CONCLUSION: Our results suggested that TSH is correlated with the total BA level in SCH patients independent of thyroid hormone, which suggests a potential physiological role of TSH and the importance of maintaining normal range TSH in SCH patients. PMID- 26606537 TI - Well-being Programs for Physicians and the Role of the "Doctors' Mess". PMID- 26606536 TI - Comparative Characterization of Vibrio cholerae O1 from Five Sub-Saharan African Countries Using Various Phenotypic and Genotypic Techniques. AB - We used standardized methodologies to characterize Vibrio cholerae O1 isolates from Guinea, Democratic Republic of the Congo (DRC), Togo, Cote d'Ivoire and Mozambique. We investigated 257 human isolates collected in 2010 to 2013. DRC isolates serotyped O1 Inaba, while isolates from other countries serotyped O1 Ogawa. All isolates were biotype El Tor and positive for cholera toxin. All isolates showed multidrug resistance but lacked ciprofloxacin resistance. Antimicrobial susceptibility profiles of isolates varied between countries. In particular, the susceptibility profile of isolates from Mozambique (East-Africa) included resistance to ceftriaxone and was distinctly different to the susceptibility profiles of isolates from countries located in West- and Central Africa. Molecular subtyping of isolates using pulsed-field gel electrophoresis (PFGE) analysis showed a complex relationship among isolates. Some PFGE patterns were unique to particular countries and clustered by country; while other PFGE patterns were shared by isolates from multiple countries, indicating that the same genetic lineage is present in multiple countries. Our data add to a better understanding of cholera epidemiology in Africa. PMID- 26606538 TI - Neuroticism and Men's Sexual Coercion as Reported by Both Partners in a Community Sample of Couples. AB - Compared with other forms of intimate partner violence, very little is known about sexual coercion (SC) and its correlates in intact couples from the general population. Among potential dispositional risk factors for SC, neuroticism has been related to various aspects of couple functioning, including psychological and physical partner abuse. Based on theoretical and empirical evidence, we suggest the existence of two maladaptive profiles on the neuroticism dimension and examine the curvilinear association between neuroticism and men's SC. A total of 299 adult couples completed measures of neuroticism and SC perpetrated by the male partner. Descriptive analyses indicated that SC translated mainly into insistence or partner pressure to engage the other in unwanted sexual activities. Results confirmed the hypothesis that both lower and higher levels of men's neuroticism predict higher levels of men's perpetrated SC, while low to moderate levels of neuroticism predict lower levels of men's SC. These findings contribute to the empirical literature on SC in community samples of couples and bear significant clinical implications for the evaluation and treatment of couples experiencing these negative sexual experiences. PMID- 26606539 TI - Editorial. PMID- 26606541 TI - How Do Females With PTSD and Substance Abuse View 12-Step Groups? An Empirical Study of Attitudes and Attendance Patterns. AB - BACKGROUND: Self-help groups are beneficial for many people with addiction, predominantly through 12-step models. Yet obstacles to attendance also occur. OBJECTIVES: We explored attendance patterns and attitudes toward self-help groups by 165 outpatient females with co-occurring posttraumatic stress disorder (PTSD) and substance use disorder (SUD), the first study of its kind. METHODS: Cross sectional self-report data compared adults versus adolescents, and those currently attending self-help versus not attending. We also explored attendance in relation to perceptions of the PTSD/SUD relationship and symptom severity. RESULTS: Adults reported higher attendance at self-help than adolescents, both lifetime and currently. Among current attendees, adults also attended more weekly groups than adolescents. Yet only a minority of both age cohorts attended any self-help in the past week. Adults perceived a stronger relationship between PTSD and SUD than adolescents, but both age groups gave low ratings to the fact that self-help groups do not address PTSD. That item also had low ratings by both those currently attending and not attending self-help. Analysis of those not currently attending identified additional negative attitudes toward self-help (spirituality, addiction as a life-long illness, sayings, and the fellowship). Symptom severity was not associated with attendance, but may reflect a floor effect. Finally, a surprising finding was that all-female groups were not preferred by any subsample. Conclusions/Importance. Creative solutions are needed to address obstacles to self-help among this population. Addressing trauma and PTSD, not just SUD, was valued by females we surveyed, and may be more helpful than all-female groups per se. PMID- 26606542 TI - Effects of a polysaccharide nanogel-crosslinked membrane on wound healing. AB - INTRODUCTION: Wound-dressing materials that promote wound healing while protecting wounds from infections are advantageous for clinical applications. Hence, we developed a cholesterol-bearing pullulan (CHP) nanogel that stimulated wound healing; however, it was mechanically weak and difficult to handle. Thus, the purpose of this study was to examine precisely the effects of a mechanically reinforced nanogel-crosslinked (NanoClik) membrane on wound healing. MATERIALS AND METHODS: NanoClik was prepared by mixing a thiol-terminated polyethylene glycol solution and an acryloyl group-modified CHP nanogel solution. A thin silicone sheet membrane, which was combined with NanoClik, was prepared. The NanoClick membranes and both positive and negative control membranes (collagen combined with silicone membrane and silicone membrane alone, respectively) were tested in vivo using a dorsal skin defect rat model. The rate and extent of wound healing was compared between groups after 7 and 14 days of implantation. RESULTS: In the NanoClik membrane group, the wound area was significantly reduced and neoepithelialization was promoted, compared with that observed in the other groups. In addition, extension and accumulation of collagen fibers were evident in the NanoClik membrane group. CONCLUSION: The NanoClik membrane is a strong candidate for use as an effective and safe wound-dressing material. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 544-550, 2017. PMID- 26606540 TI - Body Mass Index Genetic Risk Score and Endometrial Cancer Risk. AB - Genome-wide association studies (GWAS) have identified common variants that predispose individuals to a higher body mass index (BMI), an independent risk factor for endometrial cancer. Composite genotype risk scores (GRS) based on the joint effect of published BMI risk loci were used to explore whether endometrial cancer shares a genetic background with obesity. Genotype and risk factor data were available on 3,376 endometrial cancer case and 3,867 control participants of European ancestry from the Epidemiology of Endometrial Cancer Consortium GWAS. A BMI GRS was calculated by summing the number of BMI risk alleles at 97 independent loci. For exploratory analyses, additional GRSs were based on subsets of risk loci within putative etiologic BMI pathways. The BMI GRS was statistically significantly associated with endometrial cancer risk (P = 0.002). For every 10 BMI risk alleles a woman had a 13% increased endometrial cancer risk (95% CI: 4%, 22%). However, after adjusting for BMI, the BMI GRS was no longer associated with risk (per 10 BMI risk alleles OR = 0.99, 95% CI: 0.91, 1.07; P = 0.78). Heterogeneity by BMI did not reach statistical significance (P = 0.06), and no effect modification was noted by age, GWAS Stage, study design or between studies (P>=0.58). In exploratory analyses, the GRS defined by variants at loci containing monogenic obesity syndrome genes was associated with reduced endometrial cancer risk independent of BMI (per BMI risk allele OR = 0.92, 95% CI: 0.88, 0.96; P = 2.1 x 10-5). Possessing a large number of BMI risk alleles does not increase endometrial cancer risk above that conferred by excess body weight among women of European descent. Thus, the GRS based on all current established BMI loci does not provide added value independent of BMI. Future studies are required to validate the unexpected observed relation between monogenic obesity syndrome genetic variants and endometrial cancer risk. PMID- 26606543 TI - Digital blood glucose monitoring could provide new objective assessments of blood glucose control in women with gestational diabetes. PMID- 26606544 TI - Chlamydiacae: Polymorphic membrane proteins make the difference. PMID- 26606545 TI - Portable lysis apparatus for rapid single-step DNA extraction of Bacillus subtilis. AB - AIMS: To demonstrate and characterize a portable lysis apparatus for rapid single step bacterial DNA extraction. METHODS AND RESULTS: Our portable lysis apparatus employed a novel design consisting of an annular piezo-element with perforated diaphragm. Using Bacillus subtilis as target bacteria, our portable lysis apparatus was able to achieve a normalized percent lysis as high as 66% within 30 s. This is comparable to that by microprobe ultrasonication and almost 7 times higher than that by conventional bead beating. The effect from adding glass beads was predictable. However, the results from the addition of sodium dodecyl sulphate (SDS) were counter-intuitive because a further increase from 0.5 to 1% concentration reduced the lysis performance. The portable lysis apparatus is also at least 1.5-5 times more power efficient than microprobe ultrasonication. CONCLUSIONS: Our portable lysis apparatus is capable of rapidly extracting bacterial DNA and is more power efficient than microprobe ultrasonication. The addition of glass beads or SDS concentration (up to 0.5%) improves its performance. SIGNIFICANCE AND IMPACT OF THE STUDY: The portable lysis apparatus provides a standalone, rapid, low cost and power efficient way of obtaining genomic constituents prior to a variety of bioassays used in the field of environmental, biomedical and other applied microbiology. PMID- 26606546 TI - Endovascular techniques and devices for the treatment of intracranial aneurysms: a review of neurointerventional outcomes. AB - Endovascular technology for the treatment of intracranial aneurysms continues to evolve at a rapid pace. In addition to coil embolization, balloon and stent assisted coiling have been employed for the endovascular treatment of wide-necked or otherwise morphologically challenging intracranial aneurysms, and each technique confers unique advantages. Flow-diverting stents may also be used as a primary treatment modality for complex aneurysms and have a number of benefits and limitations. This article provides a review of the evidence supporting the use of newer coiling techniques and materials, as well as adjunctive technologies such as balloon-assisted and stent-assisted coiling, for the treatment of unruptured and ruptured intracranial aneurysms. PMID- 26606547 TI - Retractorless surgery for intracranial aneurysms. AB - Microsurgical clipping of intracranial aneurysms often requires access to the subarachnoid space deep in the brain. In the past, fixed retractors have been used to maintain the surgical corridor. However, studies have shown that fixed retraction leads to brain injuries. Here we present strategies to replace conventional fixed retractor blades with dynamic retraction so that the brain is no longer under constant pressure. We show that dynamic retraction without fixed retractors, when combined with optimal patient position and neuroprotective anesthetics, can provide the surgeon with adequate visualization of aneurysms and excellent surgical outcomes. PMID- 26606548 TI - Signal Increase on Unenhanced T1-Weighted Images in the Rat Brain After Repeated, Extended Doses of Gadolinium-Based Contrast Agents: Comparison of Linear and Macrocyclic Agents. AB - OBJECTIVES: In this prospective preclinical study, we evaluated T1-weighted signal intensity in the deep cerebellar nuclei (CN) and globus pallidus (GP) up to 24 days after repeated administration of linear and macrocyclic gadolinium based contrast agents (GBCAs) using homologous imaging and evaluation methods as in the recently published retrospective clinical studies. In a second part of the study, cerebrospinal fluid (CSF) spaces were evaluated for contrast enhancement by fluid-attenuated magnetic resonance imaging (MRI). MATERIALS AND METHODS: Sixty adult male Wistar-Han rats were randomly divided into a control and 5 GBCA groups (n = 10 per group). The administered GBCAs were gadodiamide, gadopentetate dimeglumine, and gadobenate dimeglumine (linear GBCAs) as well as gadobutrol and gadoterate meglumine (macrocyclic GBCAs) and saline (control). Over a period of 2 weeks, the animals received 10 intravenous injections at a dose of 2.5 mmol Gd/kg body weight, each on 5 consecutive days per week. Before GBCA administration, as well as 3 and 24 days after the last injection, a whole-brain MRI was performed using a standard T1-weighted 3-dimensional turbo spin echo sequence on a clinical 1.5 T scanner. The ratios of signal intensities in deep CN to pons (CN/Po) and GP to thalamus (GP/Th) were determined. For the evaluation of the CSF spaces, 18 additional rats were randomly divided into 6 groups (n = 3 per group) that received the same GBCAs as in the first part of the study. After MR cisternography for anatomical reference, a fluid-attenuated inversion recovery sequence was performed before and 1 minute after intravenous injection of a dose of 1 mmol Gd/kg body weight GBCA or saline. RESULTS: A significantly increased signal intensity ratio of CN/Po was observed 3 and 24 days after the last injection of gadodiamide and gadobenate dimeglumine. No significant changes were observed between the 2 time points. Gadopentetate dimeglumine injection led to a moderately elevated but statistically not significant CN/Po signal intensity ratio. No increased CN/Po signal intensity ratios were determined in the MRI scans of rats that received macrocyclic GBCAs gadobutrol and gadoterate meglumine or saline. The ratio of signal intensity in GP/Th was not elevated in any group injected with GBCAs or saline. Enhanced signal intensities of CSF spaces were observed in the postcontrast fluid-attenuated inversion recovery images of all animals receiving GBCAs but not for saline. CONCLUSIONS: In this animal study in rats, increased signal intensity in the CN was found up to 24 days after multiple, extended doses of linear GBCAs. However, in contrast to clinical reports, the signal enhancement in the GP was not reproduced, demonstrating the limitations of this animal experiment. The elevated signal intensities remained persistent over the entire observation period. In contrast, no changes of signal intensities in either the CN or the GP were observed for macrocyclic GBCAs. However, all GBCAs investigated were able to pass the blood-CSF barrier in rats to a certain, not yet quantified extent. PMID- 26606549 TI - Linear Gadolinium-Based Contrast Agents Are Associated With Brain Gadolinium Retention in Healthy Rats. AB - OBJECTIVES: The aim of this study was to evaluate Gd retention in the deep cerebellar nuclei (DCN) of linear gadolinium-based contrast agents (GBCAs) compared with a macrocyclic contrast agent. MATERIALS AND METHODS: The brain tissue retention of Gd of 3 linear GBCAs (gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide) and a macrocyclic GBCA (gadoterate meglumine) was compared in healthy rats (n = 8 per group) that received 20 intravenous injections of 0.6 mmol Gd/kg (4 injections per week for 5 weeks). An additional control group with saline was included. T1-weighted magnetic resonance imaging was performed before injection and once a week during the 5 weeks of injections and for another 4 additional weeks after contrast period. Total gadolinium concentration was measured with inductively coupled plasma mass spectrometry. Blinded qualitative and quantitative evaluations of the T1 signal intensity in DCN were performed, as well as a statistical analysis on quantitative data. RESULTS: At completion of the injection period, all the linear contrast agents (gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide) induced a significant increase in signal intensity in DCN, unlike the macrocyclic GBCA (gadoterate meglumine) or saline. The T1 hypersignal enhancement kinetic was fast for gadodiamide. Total Gd concentrations for the 3 linear GBCAs groups at week 10 were significantly higher in the cerebellum (1.21 +/- 0.48, 1.67 +/- 0.17, and 3.75 +/- 0.18 nmol/g for gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide, respectively) than with the gadoterate meglumine (0.27 +/- 0.16 nmol/g, P < 0.05) and saline (0.09 +/- 0.12 nmol/g, P < 0.05). No significant difference was observed between the macrocyclic agent and saline. CONCLUSIONS: Repeated administrations of the linear GBCAs gadodiamide, gadobenate dimeglumine, and gadopentetate dimeglumine to healthy rats were associated with progressive and significant T1 signal hyperintensity in the DCN, along with Gd deposition in the cerebellum. This is in contrast with the macrocyclic GBCA gadoterate meglumine for which no effect was observed. PMID- 26606550 TI - Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Quantitative Lung Perfusion Imaging Using the Dual-Bolus Approach: Comparison of 3 Contrast Agents and Recommendation of Feasible Doses. AB - OBJECTIVE: The aims of this study were to compare 3 contrast agents and to define feasible doses for quantitative lung perfusion imaging using the dual-bolus approach in dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). MATERIALS AND METHODS: Ten healthy volunteers (6 males, 4 females; mean age, 23.5 years) underwent DCE-MRI at 1.5 T using a 3D FLASH sequence. After a prebolus, 3 doses of gadopentetate dimeglumine (Gd-DTPA), gadofosveset, and gadobenate dimeglumine (Gd-BOPTA) were evaluated. Dose regimes were as follows: Gd-DTPA: 3.0 mL, 6.0 mL, and 12.0 mL with 1.5 mL prebolus; gadofosveset: 1.5 mL, 3.0 mL, and 6.0 mL with 0.8 mL prebolus; and Gd-BOPTA: 1.5 mL, 3.0 mL, and 6.0 mL with 0.8 mL prebolus. Pulmonary blood flow (PBF), pulmonary distribution volume, and mean transit time were assessed for each bolus. Region of interest measurements were used to determine the arterial input function (AIF) in the pulmonary trunk and signal intensities in lung parenchyma. Two radiologists independently rated the subjective image quality of the quantitative perfusion maps based on a 4-point Likert scale. RESULTS: Dose-dependent signal saturation effects were observed for all 3 contrast agents concerning AIF and parenchyma measurements. Signal yields were comparable using Gd-BOPTA (AIF, 214.49 arbitrary units [AU]; parenchyma, 41.7 AU) and Gd-DTPA (207.43 AU; 36.3 AU). Gadofosveset showed significantly lower signal yield (165.74 AU; 25.2 AU; p < 0.008). Highest signal increase was observed for Gd-DTPA. Using Gd-DTPA, mean PBF values for the 3 doses (3 mL, 6 mL, 12 mL) in mL/min per milliliter lung volume were 2.9 +/- 1.5, 2.4 +/- 1.1, and 1.6 +/- 1.0. For the 3 doses of gadofosveset (1.5 mL, 3 mL, 6 mL) mean PBF results were 3.1 +/- 1.1, 1.9 +/- 0.7, and 1.2 +/- 0.6. Last, mean PBF values for Gd-BOPTA (1.5 mL, 3 mL, 6 mL) were 3.4 +/- 1.7, 2.8 +/- 1.3, and 2.0 +/- 0.8. Measurements provided consistent values for all perfusion parameters (PBF, pulmonary distribution volume, mean transit time) when compared with reference literature. Contrast dose volume and the applied contrast agent had no relevant effects on the image quality scores. CONCLUSIONS: The dual-bolus approach using a 3D FLASH sequence is a feasible tool for quantitative lung perfusion imaging. Small boluses of 3 mL for Gd-DTPA, 1.5 mL for Gd-BOPTA, and 1.5 mL for gadofosveset provide sufficient signal yield for quantitative parenchyma measurements. Using higher boluses falsely lower perfusion values have to be considered due to signal saturation effects. Although gadofosveset yielded the lowest signal, the generated quantitative perfusion maps were of diagnostic quality. PMID- 26606551 TI - Compressed Sensing 3-Dimensional Time-of-Flight Magnetic Resonance Angiography for Cerebral Aneurysms: Optimization and Evaluation. AB - OBJECTIVES: The aims of this study were to optimize parameters for Nesterov algorithm (NESTA) in reconstruction of 3-dimensional time-of-flight (TOF) magnetic resonance angiography (MRA) at 3 T by performing an exhaustive search and to validate the performance of compressed sensing (CS) by applying it to data from cerebral aneurysms and evaluating diagnostic quality. MATERIALS AND METHODS: Three-dimensional TOF-MRA was obtained using a 3 T MR system with a 32-channel head coil for both healthy volunteers and 10 patients (11 aneurysms). No undersampling was applied for imaging parameters, including parallel imaging or other partial Fourier sampling. In the first step, the experimental setup was for healthy subjects to optimize CS parameters of NESTA and the undersampling mask pattern, so 24,696 different reconstruction conditions were surveyed for sampling rates of 8.0X and 5.0X. Mean square error (MSE) was calculated for each image reconstructed with the undersampling pattern and CS parameter sets. Evaluation was by normalized MSE, edge sharpness for MRA reconstructed using fully sampled data (MRA-full), zero-filled MRA (ZF-MRA) with Poisson disk undersampling mask, and CS-MRA (5.0X and 8.0X) with iterations of 5, 10, 15, 20, 25, 30, 35, 40, 45, and 50. CS-MRA (5.0X and 8.0X) with 5, 10, and 50 iterations of the sampling pattern and CS parameter set with the lowest MSE were visually inspected by 2 neuroradiologists to check the diagnostic quality. RESULTS: The sampling pattern and CS parameter set with the lowest MSE were identical for both CS-MRA 5.0X and CS-MRA 8.0X. At the initial 5 to 15 iterations, MSE of both sampling rates greatly decreased from that of ZF-MRA. For subsequent iterations, the decrease in MSE was relatively small. For CS-MRA, sharpness greatly increased from that of ZF MRA within the initial 5 to 15 iterations, followed by slight increases with further iterations. Two neuroradiologists graded most aneurysms as excellent, with the exception of 1 to 4 aneurysms recognized as good by 1 observer in CS-MRA (8.0X). CONCLUSIONS: Optimization of NESTA in the reconstruction of 3-dimensional TOF-MRA was conducted, and the parameters and undersampling mask with the lowest MSE were determined. Caliber measurement should be performed with CS (5.0X) with 25 or 30 iterations. Most cerebral aneurysms were sufficiently recognized using CS-MRA (5.0X) or CS-MRA (8.0X) with 10 iterations. PMID- 26606552 TI - High Atomic Number Contrast Media Offer Potential for Radiation Dose Reduction in Contrast-Enhanced Computed Tomography. AB - OBJECTIVES: Spectral optimization of x-ray computed tomography (CT) has led to substantial radiation dose reduction in contrast-enhanced CT studies using standard iodinated contrast media. The purpose of this study was to analyze the potential for further dose reduction using high-atomic-number elements such as hafnium and tungsten. As in previous studies, spectra were determined for which the patient dose necessary to provide a given contrast-to-noise ratio (CNR) is minimized. MATERIALS AND METHODS: We used 2 different quasi-anthropomorphic phantoms representing the liver cross-section of a normal adult and an obese adult patient with the lateral widths of 360 and 460 mm and anterior-posterior heights of 200 and 300 mm, respectively. We simulated and measured on 2 different scanners with x-ray spectra from 80 to 140 kV and from 70 to 150 kV, respectively. We determined the contrast for iodine-, hafnium-, and tungsten based contrast media, the noise, and 3-dimensional dose distributions at all available tube voltages by measurements and by simulations. The dose-weighted CNR was determined as optimization parameter. RESULTS: Simulations and measurements were in good agreement regarding their dependence on energy for all parameters investigated. Hafnium provided the best performance for normal and for obese patient phantoms, indicating a dose reduction potential of 30% for normal and 50% for obese patients at 120 kV compared with iodine; this advantage increased further with higher kV values. Dose-weighted CNR values for tungsten were always slightly below the hafnium results. Iodine proved to be the superior choice at voltage values of 80 kV and below. DISCUSSION: Hafnium and tungsten both seem to be candidates for contrast-medium-enhanced CT of normal and obese adult patients with strongly reduced radiation dose at unimpaired image quality. Computed tomography examinations of obese patients will decrease in dose for higher kV values. PMID- 26606554 TI - Conference programme. PMID- 26606553 TI - Dissociable contributions of amygdala and hippocampus to emotion and memory in patients with Alzheimer's disease. AB - The amygdala and the hippocampus are associated with emotional processing and declarative memory, respectively. Studies have shown that patients with bilateral hippocampal damage caused by anoxia/ischemia, and patients with probable Alzheimer's disease (AD), can experience emotions for prolonged periods of time, even when they cannot remember what caused the emotion in the first place (Feinstein et al. (2010) Proc Natl Acad Sci USA 107:7674-7679; Guzman-Velez et al. (2014) Cogn Behav Neurol 27:117-129). This study aimed to investigate, for the first time, the roles of the amygdala and hippocampus in the dissociation between feelings of emotion and declarative memory for emotion-inducing events in patients with AD. Individuals with probable AD (N = 12) and age-matched healthy comparisons participants (HCP; N = 12) completed a high-resolution (0.44 * 0.44 * 0.80 mm) T2-weighted structural MR scan of the medial temporal lobe. Each of these individuals also completed two separate emotion induction procedures (sadness and happiness) using film clips. We collected real-time emotion ratings at baseline and multiple times postinduction, and administered a test of declarative memory shortly after each induction. Consistent with previous research, hippocampal volume was significantly smaller in patients with AD compared with HCP, and was positively correlated with memory for the film clips. Sustained feelings of emotion and amygdala volume did not significantly differ between patients with AD and HCP. Follow-up analyses showed a significant negative correlation between amygdala volume and sustained sadness, and a significant positive correlation between amygdala volume and sustained happiness. Our findings suggest that the amygdala is important for regulating and sustaining an emotion independent of hippocampal function and declarative memory for the emotion-inducing event. (c) 2015 Wiley Periodicals, Inc. PMID- 26606555 TI - Day 1. Free Communications - Physical Activity for Health. PMID- 26606556 TI - Day 2. Posters - Psychology. PMID- 26606559 TI - Day 1. Free Communications - Psychology (Session 2). PMID- 26606557 TI - Day 2. Posters - Sport and Performance. PMID- 26606560 TI - Day 1. Free Communications - Sport and Performance. PMID- 26606561 TI - Day 1. Posters - Biomechanics and Motor Behaviour. PMID- 26606562 TI - Day 1. Posters - Physical Activity for Health. PMID- 26606563 TI - Day 1. Posters - Physiology and Nutrition. PMID- 26606564 TI - Day 1. Posters - Psychology. PMID- 26606566 TI - Day 1. Free Communications - Physiology and Nutrition. PMID- 26606565 TI - Day 1. Posters - Sport and Performance. PMID- 26606567 TI - Day 1. Posters - Teaching and Learning. PMID- 26606569 TI - Day 2. Free Communications - Physical Activity for Health. PMID- 26606568 TI - Day 2. Free Communications - Biomechanics and Motor Behaviour. PMID- 26606570 TI - Day 2. Free Communications - Physiology and Nutrition. PMID- 26606571 TI - Day 2. Free Communications - Psychology. PMID- 26606572 TI - Day 2. Free Communications - Sport and Performance. PMID- 26606574 TI - Day 2. Posters - Biomechanics and Motor Behaviour. PMID- 26606573 TI - Day 2. Posters - The British Association of Sport and Exercise Sciences Expert Statements. PMID- 26606576 TI - Day 1. Free Communications - Psychology (Session 1). PMID- 26606575 TI - Day 2. Posters - Physical Activity for Health. PMID- 26606577 TI - Day 2. Posters - Physiology and Nutrition. PMID- 26606578 TI - Detection of Salmonella enterica in pigs at slaughter and comparison with human isolates in Italy. AB - In 2013-2014, 201 pigs belonging to 67 batches were tested for Salmonella in their mesenteric lymph nodes (MLN) in one abattoir of Northern Italy. For each batch, faecal material was collected at lairage by swabbing the pen floor for approximately 1600 cm(2). The aim of this study was to investigate the prevalence of Salmonella in MLN of pigs at slaughter, to assess Salmonella contamination at lairage and to evaluate the effect of lairage duration on its prevalence. Serotyping, XbaI PFGE typing and antimicrobial testing of the isolates were performed. Pig and human Salmonella isolates of the same region of Italy were compared to evaluate possible correlations. Salmonella enterica was isolated from 19.9% of the MLN and 49.3% of the environmental faecal samples. Nine different serovars were identified among 75 S. enterica isolates. In MLN Salmonella Derby was the most common (52.5%), followed by S. enterica 4,[5],12:i:- (17.5%) and Salmonella Rissen (10.0%). In faecal samples S. Derby was prevalent (51.4%), followed by S. enterica 4,[5], 12:i:- (20.0%) and Salmonella Brandenburg (14.3%). Lairage holding varied between 1 and >= 12 h (median value: 2.5h). In pigs held for 1-3h, 14.1% were positive for Salmonella in MLN but the prevalence reached 31.8% when they were held for >= 12 h. The contamination of MLN was statistically different (p=0.0045) between the two groups, thus confirming the role of long lasting lairage in Salmonella contamination of pigs. XbaI PFGE typing detected 36 PFGE types. Twenty-three PFGE types were identified among the 40 MLN isolates and 22 PFGE types among the 35 faecal isolates. A total of 11 PFGE types were shared between the MLN of pigs and the lairage environment. Among S. Derby, 6 shared PFGE types between MLN and faeces were found and among S. enterica 4,[5],12:i:- one PFGE type was common between MLN and the faecal samples. Shared profiles between human and swine isolates of S. Derby, S. enterica 4,[5],12:i:-, S. Rissen, Salmonella Manhattan, S. Brandenburg, Salmonella Livingstone, Salmonella London and Salmonella Muenchen were identified. Among S. Derby and S. enterica 4,[5],12:i:- isolates found in pigs, 6/15 profiles (40.0%) and 8/10 (80.0%) were shared with human isolates. High resistance rates to streptomycin (97.3%), sulphonamide compounds (84.0%) and tetracycline (56.0%) were observed. No resistance was detected to ertapenem and meropenem. High proportions of isolates showed intermediate sensitivity to ciprofloxacin (85.3%) and cefotaxime (66.7%). High sensitivity rates were found to chloramphenicol (96.0%) and trimethoprim/sulfamethoxazole (81.3%). PMID- 26606579 TI - Complete Healing of a Laboratory-Confirmed Buruli Ulcer Lesion after Receiving Only Herbal Household Remedies. PMID- 26606580 TI - Synthesis of Boron-Doped Polycyclic Aromatic Hydrocarbons by Tandem Intramolecular Electrophilic Arene Borylation. AB - Tandem intramolecular electrophilic arene borylation was developed to facilitate access to B-doped polycyclic aromatic hydrocarbons (PAHs). DFT calculations revealed that electrophilic arene borylation occurred via a four-membered ring transition state, in which C-B and H-Br bonds formed in a concerted manner. An organic light-emitting diode employing the B-doped PAH as an emitter and a B doped PAH-based field-effect transistor were successfully fabricated, demonstrating the potential of B-doped PAHs in materials science. PMID- 26606581 TI - [Collaborative somatic care for patients with severe mental illness]. AB - Patients with severe mental illness have an accumulation of risk factors for physical diseases like cardiovascular diseases, metabolic syndrome, diabetes mellitus and COPD. These patients receive suboptimal care in the Netherlands. A major barrier to optimal care is the lack of collaboration between mental health professionals and general practitioners. An improvement could be made if all medical professionals actively supported these high-risk patients in taking adequate care of their health needs. This improvement can only be made if general practitioners and mental health professionals collaborate in a timely and structured manner. PMID- 26606582 TI - [An odour of disease and decay: the nose as a diagnostic instrument]. AB - Infectious diseases and cancer change a patient's metabolism and hence the metabolic compounds produced. The composition of volatile organic compounds (VOCs) in exhaled breath or urine or stool samples can therefore be characteristic of a particular disease. In recent years many studies have been conducted into the training of animals, including dogs, to recognise diseases by smell. Besides trained animals, electronic noses (e-noses) are also being developed. These devices can identify disease-specific odour profiles in VOCs. Although the results of research in the field of scent diagnosis are promising, the medical community remains largely sceptical. We discuss applications of scent detection as a diagnostic tool in modern medicine. PMID- 26606583 TI - [Digital necrosis after local anaesthesia with epinephrine]. AB - BACKGROUND: To date, there is a lack of consensus concerning the application of local anaesthetics with epinephrine in fingers, due to the alleged risk of ischaemic complications. CASE DESCRIPTION: We present the case of a 70-year old woman, with a medical history of diabetes mellitus and an ischemic cerebral infarct, who underwent operative trigger finger release under local anaesthetics with 1% lidocaine-epinephrine (1:100,000) solution. A few hours later, she developed persisting numbness and ischemic symptoms of the digits. Initial antithrombotic treatment with nadroparin did not resolve the issue, but vasodilatory treatment with nifedipine improved symptoms. Nevertheless, digital necrosis developed in the affected fingers several weeks later. Post-operatively, severe atherosclerosis was diagnosed in the affected hand. CONCLUSION: The use of local anaesthesia in conjunction with epinephrine for surgery on digits does offer advantages, but caution is warranted for patients with risk factors predisposing for local circulatory insufficiency. Timely vasodilatory treatment with phentolamine is the preferred option for patients who develop acute ischaemia following local anaesthesia with epinephrine. PMID- 26606584 TI - [Thrombus in a patent foramen ovale]. AB - BACKGROUND: A "thrombus in transit" is a relatively rare diagnosis involving a thrombus in a patent foramen ovale. Patent foramen ovale occurs in about 25% of the population. A thrombus in transit may lead to paradoxical arterial emboli in the cerebral circulatory system and the extremities, as well as other locations. CASE DESCRIPTION: A 60-year-old male patient with severe pneumonia sepsis appeared to have a thrombus in the right atrium, extending into the left atrium through a patent foramen ovale. The patient was treated with therapeutic anticoagulants. Cerebral embolization occurred despite this, with extensive cerebral ischaemia. The patient ultimately died from multiple organ failure. CONCLUSION: A thrombus in transit may be treated with heparins, thrombolysis or by surgical removal of the thrombus. The optimum treatment must be decided for each individual patient. The mortality rate of this condition is high (16-36%). PMID- 26606585 TI - [A patient with a painful swelling and a foot drop]. AB - A 72-year old patient presented himself at the outpatient clinic with a painful swelling on the dorsum of the left foot and a foot drop. The diagnosis was a complete rupture of the tibialis anterior tendon. PMID- 26606586 TI - [The Dietary Guidelines 2015 of the Health Council of the Netherlands--a commentary]. AB - The latest dietary guidelines recommend increased consumption of vegetables, fruits and nuts; weekly consumption of beans and fish; zero intake of alcohol; reduced meat and salt consumption; water, milk or yoghurt, filtered coffee, and 3 5 daily cups of tea rather than soft drinks and fruit juice; and replacing butter with vegetable oils and soft margarine. The glycemic index is considered not useful. The totality of the guidelines can lower blood pressure substantially. Effects on LDL cholesterol may be limited because the guidelines ignore the saturated fat content of foods, and treat all dairy products as equal. Interpretation of the effects of foods in terms of their constituent parts is mostly dismissed; this is a worrisome development in an otherwise valuable report. PMID- 26606587 TI - Rapid Diagnosis of Soybean Seedling Blight Caused by Rhizoctonia solani and Soybean Charcoal Rot Caused by Macrophomina phaseolina Using LAMP Assays. AB - A new method of direct detection of pathogenic fungi in infected soybean tissues has been reported here. The method rapidly diagnoses soybean seedling blight caused by Rhizoctonia solani and soybean charcoal rot caused by Macrophomina phaseolina, and features loop-mediated isothermal amplification (LAMP). The primers were designed and screened using internal transcribed spacers (ITS) as target DNAs of both pathogens. An ITS-Rs-LAMP assay for R. solani and an ITS-Mp LAMP assay for M. phaseolina that can detect the pathogen in diseased soybean tissues in the field have been developed. Both LAMP assays efficiently amplified the target genes over 60 min at 62 degrees C. A yellow-green color (visible to the naked eye) or intense green fluorescence (visible under ultraviolet light) was only observed in the presence of R. solani or M. phaseolina after addition of SYBR Green I. The detection limit of the ITS-Rs-LAMP assay was 10 pg MUl-1 of genomic DNA; and that of the ITS-Mp-LAMP assay was 100 pg MUl-1 of genomic DNA. Using the two assays described here, we successfully and rapidly diagnosed suspect diseased soybean samples collected in the field from Jiangsu and Anhui provinces. PMID- 26606588 TI - Correction: Enhancing carrier generation in TiO2 by a synergistic effect between plasmon resonance in Ag nanoparticles and optical interference. AB - Correction for 'Enhancing carrier generation in TiO2 by a synergistic effect between plasmon resonance in Ag nanoparticles and optical interference' by Giuseppe Cacciato et al., Nanoscale, 2015, 7, 13468-13476. PMID- 26606589 TI - Surgical and Audiometric Outcomes for Repair of Congenital Aural Atresia and Hypoplasia. AB - IMPORTANCE: Surgical repair of congenital aural atresia and hypoplasia (CAAH) is technically challenging. Long-term surgical and audiologic outcomes of atresiaplasty are incompletely understood. OBJECTIVES: To review the surgical outcomes for CAAH and analyze the hearing results. DESIGN, SETTING, AND PARTICIPANTS: A retrospective medical record review of CAAH outcomes was performed during an 11-year period from January 1, 2004, through December 31, 2014. The data analysis was undertaken from December 1, 2014, through January 31, 2015. The mean clinic follow-up time was 3.9 years, and the mean audiologic follow-time was 2.8 years. The study included 98 patients aged 5 to 66 years (mean age, 16.6 years) with CAAH who underwent a total of 104 operations. INTERVENTIONS: Surgical repair of CAAH. MAIN OUTCOMES AND MEASURES: Preoperative and postoperative pure-tone averages (PTAs), speech reception thresholds (SRTs), air-bone gaps (ABGs), and interaural PTA and SRT differences were compared. Factors that affect hearing outcomes were analyzed. The complication rates were reviewed and compared with results from similar studies. RESULTS: In the 98 patients with CAAH, the mean improvement in ABGs and SRTs was 26.7 and 25.9 dB, respectively, resulting in a postoperative ABG of 30 dB or less in 4 of 5 cases. The mean postoperative PTAs and SRTs were 36.9 and 34.3 dB, respectively. Patients with a functional native ossicular chain (36 of 104 [34.6%]) had significantly superior audiometric outcomes when compared with patients in whom a reconstruction prosthesis was required during primary or revision operations. Audiometric results from hypoplasia surgery were not significantly different from those of atresia surgery; results in patients with craniofacial syndromes were similarly not significantly different from those in patients with sporadic CAAH. We report a low incidence of meatal stenosis. CONCLUSIONS AND RELEVANCE: The mean hearing outcomes for this group compared favorably with other series. The need for ossicular chain reconstruction was associated with poorer audiometric outcomes. The safety profile and the demonstrated hearing improvement of CAAH surgery suggest that it remains a favorable option for patients. PMID- 26606590 TI - Amorphous Ultrathin SnO2 Films by Atomic Layer Deposition on Graphene Network as Highly Stable Anodes for Lithium-Ion Batteries. AB - Amorphous SnO2 (a-SnO2) thin films were conformally coated onto the surface of reduced graphene oxide (G) using atomic layer deposition (ALD). The electrochemical characteristics of the a-SnO2/G nanocomposites were then determined using cyclic voltammetry and galvanostatic charge/discharge curves. Because the SnO2 ALD films were ultrathin and amorphous, the impact of the large volume expansion of SnO2 upon cycling was greatly reduced. With as few as five formation cycles best reported in the literature, a-SnO2/G nanocomposites reached stable capacities of 800 mAh g(-1) at 100 mA g(-1) and 450 mAh g(-1) at 1000 mA g(-1). The capacity from a-SnO2 is higher than the bulk theoretical values. The extra capacity is attributed to additional interfacial charge storage resulting from the high surface area of the a-SnO2/G nanocomposites. These results demonstrate that metal oxide ALD on high surface area conducting carbon substrates can be used to fabricate high power and high capacity electrode materials for lithium-ion batteries. PMID- 26606591 TI - The Effect of Abeta1-42 Oligomers on APP Processing and Abeta1-40 Generation in Cultured U-373 Astrocytes. AB - BACKGROUND: Amyloid-beta (Abeta) peptides are a family of proteins that are considered to be a principal aspect of Alzheimer's disease (AD), the most common cause of senile dementia affecting elderly individuals. These peptides result from the proteolytic processing of amyloid precursor protein (APP) by sequential cleavage mediated via beta- and x03B3;-secretases. Evidence suggests that an overproduction and/or a lack of degradation may increase brain Abeta levels which, in turn, contribute to neuronal loss and development of AD. OBJECTIVES: In this study, we seek to determine what effect Abeta has on APP processing in cultured astrocytes. METHODS: Using the human astrocytoma cell line U-373, we investigated the effects induced by oligomeric Abeta1-42 treatment on the cellular levels/expression of APP and its products, C-terminal fragments alphaCTF and betaCTF, and Abeta1-40. In conjunction with these experiments, we examined the relative levels and activity of beta- and x03B3;-secretases in Abeta-treated astrocytes. RESULTS: We report here that Abeta1-42 treatment of astrocytes increased the expression of APP and its cleaved products including Abeta1-40 in a time-dependent manner. CONCLUSIONS: These results suggest that activated astrocytes can contribute to the development of AD by enhancing levels and processing of APP leading to an increased production/secretion of Abeta-related peptides. PMID- 26606592 TI - A Dynamic Model of pH-Induced Protein G'e Higher Order Structure Changes derived from Mass Spectrometric Analyses. AB - To obtain insight into pH change-driven molecular dynamics, we studied the higher order structure changes of protein G'e at the molecular and amino acid residue levels in solution by using nanoESI- and IM-mass spectrometry, CD spectroscopy, and protein chemical modification reactions (protein footprinting). We found a dramatic change of the overall tertiary structure of protein G'e when the pH was changed from neutral to acidic, whereas its secondary structure features remained nearly invariable. Limited proteolysis and surface-topology mapping of protein G'e by fast photochemical oxidation of proteins (FPOP) under neutral and acidic conditions reveal areas where higher order conformational changes occur on the amino-acid residue level. Under neutral solution conditions, lower oxidation occurs for residues of the first linker region, whereas greater oxidative modifications occur for amino-acid residues of the IgG-binding domains I and II. We propose a dynamic model of pH-induced structural changes in which protein G'e at neutral pH adopts an overall tight conformation with all four domains packed in a firm assembly, whereas at acidic pH, the three IgG-binding domains form an elongated alignment, and the N-terminal, His-tag-carrying domain unfolds. At the same time the individual IgG-binding domains themselves seem to adopt a more compacted fold. As the secondary structure features are nearly unchanged at either pH, interchange between both conformations is highly reversible, explaining the high reconditioning power of protein G'e-based affinity chromatography columns. PMID- 26606593 TI - Effect of Frozen Human Epidermis Storage Duration and Cryoprotectant on Barrier Function Using Two Model Compounds. AB - Skin is commonly stored frozen and then thawed prior to use for in vitro permeation experiments. Does frozen storage of skin alter its barrier property? Numerous studies have found contradictory answers to this question. In this study, the steady-state flux and lag time of diethyl phthalate (DEP) were measured for fresh human skin and skin frozen at -85 degrees C for 1, 2, 3, 6, 9, 12, and 18 months with 10% glycerol as a cryoprotective agent. No significant differences in steady-state flux were found between fresh and previously frozen samples (p = 0.6). For lag time, a significant (p = 0.002) difference was found among all groups, but comparisons with fresh skin were not significant. Does glycerol have a cryoprotective effect? The steady-state flux and lag time of DEP and caffeine were measured through human skin stored at -85 degrees C for up to 12 months with and without 10% glycerol. No significant differences in steady state flux or lag time were found between samples stored with or without glycerol for either DEP or caffeine (p >= 0.17). These findings support the use of frozen skin to measure the passive permeation of chemicals in studies unconcerned with viability and metabolism. PMID- 26606594 TI - Thin film composite nanofiltration membranes fabricated from quaternized poly(ether ether ketone) with crosslinkable moiety using a benign solvent. AB - Thin film composite nanofiltration membranes were fabricated through dip-coating and in situ cross-linking of quaternized poly(ether ether ketone) containing a certain amount of tertiary amine groups (QAPEEKs) on polyacrylonitrile (PAN) support. The effects of the variables in membrane formation such as the coating polymer concentration, the curing temperature, and the cross-linking agent types on resultant membrane were studied and the membrane properties such as the barrier layer chemical structure, the surface element composition and morphology were investigated. The obtained performance of uncross-linked and cross-linked QAPEEK-70 thin film composites in nanofiltration test was compared. The results indicated that the cross-linking improved the composite membranes' performance. For instance, the membrane cross-linked by bisphenol A diglycidyl ether (BPADGE) named M-C-BPADGE exhibited a MgCl2 rejection of 97.8%, a water flux of 11.8Lm( 2)h(-1), a MWCO of 800Da and corresponding pore size of 0.69nm, while for its uncross-linked membrane named M-U, a MgCl2 rejection of 91.2%, a water flux of 13.5Lm(-2)h(-1), a MWCO with 960Da and a pore size of 0.77nm were found. Furthermore, the M-C-BPADGE membrane exhibited selectivities of 16.0 for separation of mixed Mg(2+) and Na(+) cations, much larger than selectivity of 5.2 obtained for M-U, suggesting that the cross-linked membranes are promising in cation separation. PMID- 26606596 TI - Silver complexation by metallacryptates. AB - We report the first complete characterization of metallycryptates encapsulating Ag(I) cations: carboxylato ligands derived from l-proline and l-alanine chelate and bridge six Cu(II) centres arranged in a slightly distorted octahedral fashion. Eight oxygen atoms of these ligands are disposed in square-prismatic geometry and coordinate the monovalent cation. Two alternative metallacryptates based on alanine have been identified which differ with respect to aggregation: a solid in which pairs of encapsulating sites are formed competes with an infinite chain of M(I) coordinating sites. In contrast, the individual encrypting moieties are arranged as overall neutral and isolated molecular species in the proline based metallacryptate. This proline derivative can accomodate Ag(I) and Na(I) cations and form a solid solution. Susceptibility measurements confirm ferromagnetic interactions between the Cu(II) within the hexanuclear proline cryptate and thus underline the similarity between solids accommodating Na(I) and Ag(I). Spectroscopic results suggest that these metallacryptates hardly dissociate in methanol solution. PMID- 26606595 TI - The Sialic Acid Binding Protein, Hsa, in Streptococcus gordonii DL1 also Mediates Intergeneric Coaggregation with Veillonella Species. AB - Dental biofilm development involves initial colonization of the tooth's surface by pioneer colonizers, followed by cell-cell coaggregation between the pioneer and later colonizers. Streptococcus gordonii is one of the pioneer colonizers. In addition to its role in oral biofilm development, S. gordonii also is a pathogen in infective endocarditis in susceptible humans. A surface adhesin, Hsa, has been shown to play a critical role in colonization of S. gordonii on the heart tissue; however, its role in oral biofilm development has not been reported. In this study we demonstrate that Hsa is essential for coaggregation between S. gordonii and Veillonella sp., which are bridging species connecting the pioneer colonizers to the late colonizers. Interestingly, the same domains shown to be required for Hsa binding to sialic acid on the human cell surface are also required for coaggregation with Veillonella sp. However, sialic acid appeared not to be required for this intergeneric coaggregation. This result suggests that although the same domains of Hsa are involved in binding to eukaryotic as well as Veillonella cells, the binding mechanism is different. The gene expression pattern of hsa was also studied and shown not to be induced by coaggregation with Veillonella sp. PMID- 26606597 TI - Multiple Roles of MicroRNA-100 in Human Cancer and its Therapeutic Potential. AB - MicroRNAs (miRNAs) are a recently discovered class of endogenous, small (about 22 nucleotides) non-coding RNAs, which play important roles in cancer development and progression. Emerging evidence shows that microRNAs exert their regulatory effects by directly binding to the 3'- untranslated regions (UTRs) of their target genes. MicroRNA-100 (miR-100) is aberrantly expressed and functions in many human cancers by regulating multiple cell processes, such as cell cycle, proliferation, differentiation, migration, invasion and apoptosis, via post transcriptionally regulating various target genes. A better understanding of the molecular mechanisms involved in miR-100-mediated tumor progression will provide an opportunity for exploring novel miR-100-based targeted therapies for human cancers. This review aims to summarize the recently published literature on the roles of miR-100 in regulating tumorigenesis, and explore its potential clinical applications for cancer diagnosis, prognosis and clinical treatment. PMID- 26606598 TI - Deciphering the Genetic Complexity of Schizophrenia. PMID- 26606599 TI - Do Surrogates of Injury Severity Influence the Occurrence of Heterotopic Ossification in Fractures of the Acetabulum? AB - OBJECTIVES: To determine the relationship between injury severity surrogates and other patient factors with the development and severity of heterotopic ossification (HO) following open reduction internal fixation of acetabular fractures treated with a posterior approach. DESIGN: Retrospective review. SETTING: Academic level 1 trauma center. PARTICIPANTS: Two hundred forty-one patients who were treated through a posterior approach with a minimum of 6-month radiographic follow-up were identified from an acetabular fracture database. INTERVENTION: None. MAIN OUTCOME MEASURES: The occurrence and severity (Brooker Grade III/IV) of HO 6 months postsurgery. RESULTS: Length of stay (LOS) in the intensive care unit (ICU), non-ICU LOS >10 days, and HO prophylaxis with external radiation beam therapy (XRT) were significantly associated with the development of HO in a multivariate model [ICU LOS: 1-2 days, odds ratio (OR) = 4.33, 95% confidence interval (CI): 1.03-18.25; 3-6 days, OR = 4.1, 95% CI, 1.27-13.27; >6 days, OR = 11.7, 95% CI, 3.24-42.22; non-ICU LOS >10 days (vs. 0-6 days): OR = 7.6, 95% CI, 2.6-22.25; XRT HO prophylaxis: OR = 0.29, 95% CI, 0.10-0.85]. Other variables evaluated in multivariate modeling not significantly associated with development and severity of HO included age, gender, mechanism of injury, injury severity score, presence of neurologic injury, Letournel fracture type, occurrence of hip dislocation, interval from injury to surgery, operative time, and estimated blood loss. CONCLUSIONS: Surrogates of injury severity, including days in the ICU and non-ICU hospital LOS >10 days, were associated with the development of HO in our cohort of acetabular fracture patients. Prophylaxis with XRT was significantly protective against the development of HO, and the ability to provide prophylaxis is very likely related to the severity of injury. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 26606600 TI - Is There an Impact of Concomitant Injuries and Timing of Fixation of Major Fractures on Fracture Healing? A Focused Review of Clinical and Experimental Evidence. AB - OBJECTIVE: This review aims to summarize current knowledge regarding the underlying patho-mechanisms of delayed fracture healing in polytraumatized patients. DATA SOURCES AND STUDY SELECTION: The following search terms were used: "fracture", "hemorrhage," "chest trauma," "inflammation," "inflammatory response," "fracture healing," "delayed healing," "nonunion," "fracture stabilisation," "intramedullary nailing," "external fixation," "early total care," and "damage control." Medline, Embase, and Cochrane Library were searched for studies published between January 1, 1990 through March 30, 2014. Of 1322 publications, 68 were included in the current summary. CONCLUSION: Concomitant injuries and the strategy for fracture stabilization seem to affect bone metabolism and fracture healing. Among the relevant patho-mechanisms, interactions between the local and systemic inflammatory response seem to play a role. However, the consequences of fracture fixation strategies in case of severe concomitant injuries on local inflammation and bone healing remain unknown. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26606601 TI - Reverse Medial Hemisoleus Flaps for Coverage of Distal Third Leg Wounds: A Technical Trick. AB - Traditionally, free tissue transfer has been used to cover wounds of the distal third of the leg. Advances in flap anatomy, elevation, and surgical techniques have allowed the use of pedicled flaps to avoid the use of free tissue transfer in certain situations. The authors describe a technique for using a reversed medial hemisoleus flap to provide soft tissue coverage for wounds of the medial distal leg. In the senior authors experience, the use of this flap has achieved wound coverage in 100% of patients with smaller wounds (<=50 cm) of the medial leg. PMID- 26606602 TI - Is the Axillary Nerve at Risk During a Deltoid-Splitting Approach for Proximal Humerus Fractures? AB - OBJECTIVES: The strain placed across the axillary nerve during the deltoid splitting approach could correlate with microtrauma and place the patient at risk of a neuropraxia or more permanent injury. The purposes of this study were to evaluate the change in length and strain exhibited by the axillary nerve during the deltoid-splitting approach and to determine the presence of any microscopic structural damage. METHODS: The axillary nerve was identified through a lateral deltoid-splitting approach in 10 fresh-frozen cadaver specimens. Two suture tags were placed near the lateral margins of the incision. The initial distance between the 2 tags was measured and the distance at each retractor click of a Kolbel retractor until full expansion (6 clicks). The retractor was then released for a 1-minute break at 30, 60, 90, and 120 minutes. The strain at each interval was calculated as change in length divided by the initial distance. The section of nerve in the field of exposure was excised for histologic analysis. RESULTS: The location of the axillary nerve was 6.32 cm (range, 5.20-7.6 cm) from the anterolateral aspect of the acromion. The mean final increase in length was 8.42 mm (range, 6.43-12.26 mm). The strain increased to a final mean of 51% (range, 28%-99%). Histologic analysis confirmed disruption of the myelin sheaths and axonal retraction. CONCLUSIONS: This study demonstrated a progressive, irreversible increase in axillary nerve length and strain, resulting in microscopic damage to the neuronal structure during a deltoid-splitting approach. Prolonged soft tissue retraction can place the axillary nerve at substantial risk for injury. PMID- 26606603 TI - Peroneal Tendon Instability in Intra-Articular Calcaneus Fractures: A Retrospective Comparative Study and a New Surgical Technique. AB - OBJECTIVE: To compare the prevalence of peroneal tendon instability as determined by intraoperative evaluation versus preoperative computed tomography (CT) scans, and to identify specific risk factors that correlate with tendon instability. DESIGN: Retrospective comparative study. SETTING: Level 1 trauma hospital. PATIENTS: Patients with operatively treated intra-articular calcaneus fractures managed between January 1, 2002 and December 31, 2012 were reviewed for evidence of peroneal tendon instability. Of 254 fractures, 155 intra-articular calcaneus fractures met inclusion criteria and were available for final analysis. INTERVENTION: Operative notes were reviewed to confirm intraoperative testing for superior peroneal retinaculum (SPR) integrity and peroneal tendon stability. Preoperative CT scan and plain radiographs were evaluated for presence of peroneal tendon dislocation, fibular fracture or "fleck" sign, excessive lateral wall displacement, and/or calcaneal fracture-dislocation. MAIN OUTCOME MEASURES: Peroneal tendon stability was determined with intraoperative assessment of the intact SPR and its confluence with the peroneal tendon sheath. The incidence of peroneal tendon instability on intraoperative assessment was compared with preoperatively identified tendon dislocation on CT scan. Prevalence of peroneal tendon dislocation was determined using each diagnostic method. Risk factors for tendon instability were identified using a multivariate regression model. RESULTS: There was significantly higher prevalence of peroneal tendon instability as determined by preoperative imaging (30%; n = 47/155) compared with intraoperative retinaculum testing (11.6%; n = 18/155) (P < 0.001). Intraoperative tendon instability was significantly associated with increased fracture classification severity, fibular fracture/"fleck" sign, and fracture dislocation. CONCLUSIONS: Intraoperative evaluation of the SPR should be used in conjunction with preoperative imaging for diagnosis of peroneal instability in the setting of operatively treated, intra-articular calcaneus fractures. LEVEL OF EVIDENCE: Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26606604 TI - Biometric approach in selecting plants for phytoaccumulation of uranium. AB - This paper promotes the biometric classification system of plant cultivars, unique characteristics, in terms of the uranium (U) uptake, primarily in the function of the application for phytoremediation. It is known that the degree of adoption of U depends on the plant species and its morphological and physiological properties, but it is less known what impact have plants cultivars, sorts, and hybrids. Therefore, we investigated the U adoption in four cultivars of three plant species (corn, sunflower and soy bean). "Vegetation experiments were carried out in a plastic-house filled with soil (0.66 mgU) and with tailing (15.3 mgU kg(-1)) from closed uranium mine Gabrovnica-Kalna southeast of Serbia". Principal Component Analysis (PCA), Cluster Analysis (CA) and analysis of variance (ANOVA) were used for assessing the effect of different substrates cultivars, plant species and plant organs (root or shoot) on U uptake. Obtained results showed that a difference in U uptake by three investigated plant species depends not only of the type of substrate types and plant organs but also of their cultivars. Biometrics techniques provide a good opportunity for a better understanding the behavior of plants and obtaining much more useful information from the original data. PMID- 26606605 TI - Asynchronous hatching provides females with a means for increasing male care but incurs a cost by reducing offspring fitness. AB - In species with biparental care, sexual conflict occurs because the benefit of care depends on the total amount of care provided by the two parents while the cost of care depends on each parent's own contribution. Asynchronous hatching may play a role in mediating the resolution of this conflict over parental care. The sexual conflict hypothesis for the evolution of asynchronous hatching suggests that females adjust hatching patterns in order to increase male parental effort relative to female effort. We tested this hypothesis in the burying beetle Nicrophorus vespilloides by setting up experimental broods with three different hatching patterns: synchronous, asynchronous and highly asynchronous broods. As predicted, we found that males provided care for longer in asynchronous broods whereas the opposite was true of females. However, we did not find any benefit to females of reducing their duration of care in terms of increased lifespan or reduced mass loss during breeding. We found substantial negative effects of hatching asynchrony on offspring fitness as larval mass was lower and fewer larvae survived to dispersal in highly asynchronous broods compared to synchronous or asynchronous broods. Our results suggest that, even though females can increase male parental effort by hatching their broods more asynchronously, females pay a substantial cost from doing so in terms of reducing offspring growth and survival. Thus, females should be under selection to produce a hatching pattern that provides the best possible trade-off between the benefits of increased male parental effort and the costs due to reduced offspring fitness. PMID- 26606607 TI - Finding Reaction Pathways of Type A + B -> X: Toward Systematic Prediction of Reaction Mechanisms. AB - In these five decades, many useful tools have been developed for exploring quantum chemical potential energy surfaces. The success in theoretical studies of chemical reaction mechanisms has been greatly supported by these tools. However, systematic prediction of reaction mechanisms starting only from given reactants and catalysts is still very difficult. Toward this goal, we describe the artificial force induced reaction (AFIR) method for automatically finding reaction paths of type A + B -> X (+ Y). By imposing an artificial force to given reactants and catalysts, the method can find the reactive sites very efficiently. Further pressing by the artificial force provides approximate transition states and product structures, which can be easily reoptimized to the corresponding true ones. This procedure can be executed very efficiently just by minimizing a single function called the AFIR function. All important reaction paths can be found by repeating this cycle starting from many initial orientations. We also discuss perspectives of automated reaction path search methods toward the above goal. PMID- 26606606 TI - What Would Jaws Do? The Tyranny of Film and the Relationship between Gaze and Higher-Level Narrative Film Comprehension. AB - What is the relationship between film viewers' eye movements and their film comprehension? Typical Hollywood movies induce strong attentional synchrony-most viewers look at the same things at the same time. Thus, we asked whether film viewers' eye movements would differ based on their understanding-the mental model hypothesis-or whether any such differences would be overwhelmed by viewers' attentional synchrony-the tyranny of film hypothesis. To investigate this question, we manipulated the presence/absence of prior film context and measured resulting differences in film comprehension and eye movements. Viewers watched a 12-second James Bond movie clip, ending just as a critical predictive inference should be drawn that Bond's nemesis, "Jaws," would fall from the sky onto a circus tent. The No-context condition saw only the 12-second clip, but the Context condition also saw the preceding 2.5 minutes of the movie before seeing the critical 12-second portion. Importantly, the Context condition viewers were more likely to draw the critical inference and were more likely to perceive coherence across the entire 6 shot sequence (as shown by event segmentation), indicating greater comprehension. Viewers' eye movements showed strong attentional synchrony in both conditions as compared to a chance level baseline, but smaller differences between conditions. Specifically, the Context condition viewers showed slightly, but significantly, greater attentional synchrony and lower cognitive load (as shown by fixation probability) during the critical first circus tent shot. Thus, overall, the results were more consistent with the tyranny of film hypothesis than the mental model hypothesis. These results suggest the need for a theory that encompasses processes from the perception to the comprehension of film. PMID- 26606608 TI - Early Experiences with Computational Quantum Chemistry. AB - A description is given of the progress in computational quantum chemistry in the early 1960s, the time of the early mainframe computers. In particular, the first calculation of the barrier to internal rotation in ethane and the first molecular application of perturbed self-consistent-field equations are described with the accompanying developments, trials, and tribulations. PMID- 26606609 TI - Free Energy Profiles along Consensus Normal Modes Provide Insight into HIV-1 Protease Flap Opening. AB - Describing biological macromolecular energetics from computer simulations can pose major challenges, and often necessitates enhanced conformational sampling. We describe the calculation of conformational free-energy profiles along carefully chosen collective coordinates: "consensus" normal modes, developed recently as robust alternatives to conventional normal modes. In an application to the HIV-1 protease, we obtain efficient sampling of significant flap opening movements governing inhibitor binding from relatively short simulations, in close correspondence with experimental results. PMID- 26606610 TI - Resolutions of the Coulomb Operator: V. The Long-Range Ewald Operator. AB - We show that the long-range Ewald operator can be resolved as erf(omegar12)/r12 = ?k phik*(r1) phik(r2), where phik is proportional to the product of a spherical Bessel function and a spherical harmonic. We demonstrate the use of this new resolution by calculating the long-range Coulomb energy of the nanodiamond crystallite C84H64 and the long-range exchange energy of the graphene C96H24. The resolution appears particularly effective for long-range exchange calculations. PMID- 26606611 TI - Path Integral Computation of Quantum Free Energy Differences Due to Alchemical Transformations Involving Mass and Potential. AB - Thermodynamic integration, perturbation theory, and lambda-dynamics methods were applied to path integral molecular dynamics calculations to investigate free energy differences due to "alchemical" transformations. Several estimators were formulated to compute free energy differences in solvable model systems undergoing changes in mass and/or potential. Linear and nonlinear alchemical interpolations were used for the thermodynamic integration. We find improved convergence for the virial estimators, as well as for the thermodynamic integration over nonlinear interpolation paths. Numerical results for the perturbative treatment of changes in mass and electric field strength in model systems are presented. We used thermodynamic integration in ab initio path integral molecular dynamics to compute the quantum free energy difference of the isotope transformation in the Zundel cation. The performance of different free energy methods is discussed. PMID- 26606613 TI - Assessing Excited State Methods by Adiabatic Excitation Energies. AB - We compile a 109-membered benchmark set of adiabatic excitation energies (AEEs) from high-resolution gas-phase experiments. Our data set includes a variety of organic chromophores with up to 46 atoms, radicals, and inorganic transition metal compounds. Many of the 91 molecules in our set are relevant to atmospheric chemistry, photovoltaics, photochemistry, and biology. The set samples valence, Rydberg, and ionic states of various spin multiplicities. As opposed to vertical excitation energies, AEEs are rigorously defined by energy differences of vibronic states, directly observable, and insensitive to errors in equilibrium structures. We supply optimized ground state and excited state structures, which allows fast and convenient evaluation of AEEs with two single-point energy calculations per system. We apply our benchmark set to assess the performance of time-dependent density functional theory using common semilocal functionals and the configuration interaction singles method. Hybrid functionals such as B3LYP and PBE0 yield the best results, with mean absolute errors around 0.3 eV. We also investigate basis set convergence and correlations between different methods and between the magnitude of the excited state relaxation energy and the AEE error. A smaller, 15-membered subset of AEEs is introduced and used to assess the correlated wave function methods CC2 and ADC(2). These methods improve upon hybrid TDDFT for systems with single-reference ground states but perform less well for radicals and small-gap transition metal compounds. None of the investigated methods reaches "chemical accuracy" of 0.05 eV in AEEs. PMID- 26606612 TI - Are Peptides Good Two-State Folders? AB - The folding kinetics of proteins is frequently single-exponential, as basins of folded and unfolded conformations are well separated by a high barrier. However, for relatively short peptides, a two-state character of folding is rather the exception than the rule. In this work, we use a Zwanzig-type model of protein conformational dynamics to study the dependence of folding kinetics on the protein chain length, M. The analysis is focused on the gap in the eigenvalue spectrum of the rate matrix that describes the protein's conformational dynamics. When there is a large gap between the two smallest in magnitude nonzero eigenvalues, the corresponding relaxation times have qualitatively different physical interpretations. The longest of these two times characterizes the interbasin equilibration (i.e., folding), whereas the second time characterizes the intrabasin relaxation. We derive approximate analytical solutions for the two eigenvalues that show how they depend on M. From these solutions, we infer that there is a large gap between the two, and thus, the kinetics is essentially single-exponential when M is large enough such that 2(M+1) is much larger than M(2). PMID- 26606614 TI - Determining the Numerical Stability of Quantum Chemistry Algorithms. AB - We present a simple, broadly applicable method for determining the numerical properties of quantum chemistry algorithms. The method deliberately introduces random numerical noise into computations, which is of the same order of magnitude as the floating point precision. Accordingly, repeated runs of an algorithm give slightly different results, which can be analyzed statistically to obtain precise estimates of its numerical stability. This noise is produced by automatic code injection into regular compiler output, so that no substantial programming effort is required, only a recompilation of the affected program sections. The method is applied to investigate: (i) the numerical stability of the three-center Obara Saika integral evaluation scheme for high angular momenta, (ii) if coupled cluster perturbative triples can be evaluated with single precision arithmetic, (iii) how to implement the density fitting approximation in Moller-Plesset perturbation theory (MP2) most accurately, and (iv) which parts of density fitted MP2 can be safely evaluated with single precision arithmetic. In the integral case, we find a numerical instability in an equation that is used in almost all integral programs. Due to the results of (ii) and (iv), we conjecture that single precision arithmetic can be applied whenever a calculation is done in an orthogonal basis set and excessively long linear sums are avoided. PMID- 26606615 TI - Aurophilic Interactions from Wave Function, Symmetry-Adapted Perturbation Theory, and Rangehybrid Approaches. AB - The aurophilic interaction is examined in three model systems Au2((3)Sigmag(+)), (AuH)2, and (HAuPH3)2 which contain interactions of pairs of the Au centers in the oxidation state (I). Several methods are employed ranging from wave function theory-based (WFT) approaches to symmetry-adapted perturbation theory (SAPT) and range-separated hybrid (RSH) density functional theory (DFT) methods. The most promising and accurate approach consists of a combination of the DFT and WFT approaches in the RSH framework. In this combination the short-range DFT handles the slow convergence of the correlation cusp, whereas the long-range WFT is best suited for the long-range correlation. Of the three tested RSH DFT methods, the one which uses a short-range exchange functional based on the Ernzerhof-Perdew exchange hole model with a range-separation parameter of 0.4 bohr(-1) seems to be the best candidate for treatment of gold. In combination with the long-range coupled cluster singles, doubles, and noniterative triples [CCSD(T)] treatment it places the strength of aurophilic bonding in (HAuPH3)2 at 5.7 kcal/mol at R = 3.09 A. This value is somewhat larger than our best purely WFT result based on CCSD(T), 4.95 kcal/mol (R = 3.1 A), and considerably smaller than the Hartree Fock+dispersion value of 7.4 kcal/mol (R = 2.9 A). The 5.7 kcal/mol estimate fits reasonably well within the prediction of the empirical relationship proposed by Schwerdtfeger et al. (J. Am. Chem. Soc.1998, 120, 6587). A direct computation of dispersion energy, including exchange corrections, results in values of ca. -9 kcal/mol for Au2((3)Sigmag(+)) and (AuH)2 and -13 kcal/mol for (HAuPH3)2 at the distance of a typical aurophilic bond, R = 3.0 A. PMID- 26606616 TI - Charge-Transfer-Like pi->pi* Excitations in Time-Dependent Density Functional Theory: A Conundrum and Its Solution. AB - We address the conundrum posed by the well-known failure of time-dependent DFT (TDDFT) with conventional functionals for "charge-transfer-like" excitations in oligoacenes. We show that this failure is due to a small spatial overlap in orbitals obtained from the underlying single-electron orbitals by means of a unitary transformation. We further show that, as in true charge-transfer excitations, this necessarily results in failure of linear-response TDDFT with standard functionals. Range-separated hybrid functionals have been previously shown to mitigate such errors but at the cost of an empirically adjusted range separation parameter. Here, we explain why this approach should succeed where conventional functionals fail. Furthermore, we show that optimal tuning of a range-separated hybrid functional, so as to enforce the DFT version of Koopmans' theorem, restores the predictive power of TDDFT even for such difficult cases, without any external reference data and without any adjustable parameters. We demonstrate the success of this approach on the oligoacene series and on related hydrocarbons. This resolves a long-standing question in TDDFT and extends the scope of molecules and systems to which TDDFT can be applied in a predictive manner. PMID- 26606617 TI - Spin-Restriction in Explicitly Correlated Coupled Cluster Theory: The Z-Averaged CCSD(2)R12 Approach. AB - R12 methods have now been established to improve both the efficiency and accuracy of wave function-based theories. While closed-shell and spin-orbital methodologies for coupled cluster theory are well-studied, R12 corrections based on an open-shell, spin-restricted formalism have not been well developed. We present an efficient spin-restricted R12 method based on the symmetric exchange or Z-averaged approach that reduces the number of variational parameters. The current formalism reduces spin contamination relative to unrestricted methods but remains rigorously size consistent in contrast to other spin-adapted formulations. The theory is derived entirely in spin-orbital quantities, but Z averaged symmetries are exploited to minimize the computational work in the residual equations. R12 corrections are formulated in a perturbative manner and are therefore obtained with little extra cost relative to the standard coupled cluster problem. R12 results with only a triple-zeta basis are competitive with conventional aug-cc-pV5Z and aug-cc-pV6Z results, demonstrating the utility of the method in thermochemical problems for high-spin open-shell systems. PMID- 26606618 TI - Generalized Gradient Approximations of the Noninteracting Kinetic Energy from the Semiclassical Atom Theory: Rationalization of the Accuracy of the Frozen Density Embedding Theory for Nonbonded Interactions. AB - We present a new class of noninteracting kinetic energy (KE) functionals, derived from the semiclassical-atom theory. These functionals are constructed using the link between exchange and kinetic energies and employ a generalized gradient approximation (GGA) for the enhancement factor, namely, the Perdew-Burke Ernzerhof (PBE) one. Two of them, named APBEK and revAPBEK, recover in the slowly varying density limit the modified second-order gradient (MGE2) expansion of the KE, which is valid for a neutral atom with a large number of electrons. APBEK contains no empirical parameters, while revAPBEK has one empirical parameter derived from exchange energies, which leads to a higher degree of nonlocality. The other two functionals, APBEKint and revAPBEKint, modify the APBEK and revAPBEK enhancement factors, respectively, to recover the second-order gradient expansion (GE2) of the homogeneous electron gas. We first benchmarked the total KE of atoms/ions and jellium spheres/surfaces: we found that functionals based on the MGE2 are as accurate as the current state-of-the-art KE functionals, containing several empirical parameters. Then, we verified the accuracy of these new functionals in the context of the frozen density embedding (FDE) theory. We benchmarked 20 systems with nonbonded interactions, and we considered embedding errors in the energy and density. We found that all of the PBE-like functionals give accurate and similar embedded densities, but the revAPBEK and revAPBEKint functionals have a significant superior accuracy for the embedded energy, outperforming the current state-of-the-art GGA approaches. While the revAPBEK functional is more accurate than revAPBEKint, APBEKint is better than APBEK. To rationalize this performance, we introduce the reduced-gradient decomposition of the nonadditive kinetic energy, and we discuss how systems with different interactions can be described with the same functional form. PMID- 26606619 TI - Comparison of Methods to Obtain Force-Field Parameters for Metal Sites. AB - We have critically examined and compared various ways to obtain standard harmonic molecular mechanics (MM) force-field parameters for metal sites in proteins, using the 12 most common Zn(2+) sites as test cases. We show that the parametrization of metal sites is hard to treat with automatic methods. The choice of method is a compromise between speed and accuracy and therefore depends on the intended use of the parameters. If the metal site is not of central interest in the investigation, for example, a structural metal far from the active site, a simple and fast parametrization is normally enough, using either a nonbonded model with restraints or a bonded parametrization based on the method of Seminario. On the other hand, if the metal site is of central interest in the investigation, a more accurate method is needed to give quantitative results, for example, the method by Norrby and Liljefors. The former methods are semiautomatic and can be performed in seconds, once a quantum mechanical (QM) geometry optimization and frequency calculation has been performed, whereas the latter method typically takes several days and requires significant human intervention. All approaches require a careful selection of the atom types used. For a nonbonded model, standard atom types can be used, whereas for a bonded model, it is normally wise to use special atom types for each metal ligand. For accurate results, new atom types for all atoms in the metal site can be used. Atomic charges should also be considered. Typically, QM restrained electrostatic potential charges are accurate and easy to obtain once the QM calculation is performed, and they allow for charge transfer within the complex. For negatively charged complexes, it should be checked that hydrogen atoms of the ligands get proper charges. Finally, water ligands pose severe problems for bonded models in force fields that ignore nonbonded interactions for atoms separated by two bonds. Complexes with a single water ligand can normally be accurately treated with a bonded potential, once it is ensured that the water H atoms have nonzero Lennard Jones parameters. However, for metal sites with several water molecules, a nonbonded model with restraints (taken from the QM calculations) is more stable. PMID- 26606620 TI - Block Covariance Overlap Method and Convergence in Molecular Dynamics Simulation. AB - Molecular dynamics (MD) is a powerful tool for understanding the fluctuations of biomolecular systems. It is, however, subject to statistical errors in its sampling of the underlying distribution of states. One must understand these errors in order to draw meaningful conclusions from the simulation. This is becoming ever more critical as MD simulations of even larger systems are attempted. We present here a new method for determining the extent of convergence that relies on measures of the fluctuation space sampled by the simulation without any a priori knowledge of states or partitioning of the configuration space. This method reveals long correlation times, even for simple systems, and suggests caution when interpreting macromolecular simulations. We also compare this method with previous efforts to characterize the sampling of MD simulation. PMID- 26606621 TI - Benchmarking the Approximate Second-Order Coupled-Cluster Method on Biochromophores. AB - Extensive benchmarking calculations are presented to assess the accuracy of commonly used quantum chemical methods in studying excited state properties of biochromophores. The first few excited states of 12 common model chromophores of photoactive yellow protein, green fluorescent protein, and rhodopsin have been studied using approximate second-order coupled-cluster (CC2) and linear-response time-dependent density functional theory (TDDFT) calculations. The study comprises investigations of basis-set dependences on CC2 excitation energies as well as comparisons of the CC2 results with excitation energies obtained at other computational levels and with experimental data. The basis-set study shows that the accuracy of the two lowest excitation energies is generally sufficient when triple-zeta basis sets augmented with polarization functions are employed, whereas the third and higher excited states were found to require diffuse basis functions in the basis set. Augmenting the basis set with diffuse functions contributes less than 0.15 eV to the excitation energies of low-lying excited states, except for some of the studied anionic states and for Rydberg states. Calculations at the TDDFT level using the B3LYP functional show the necessity of stabilizing anions with point charges or counterions when aiming at reliable electronic excitation spectra. The two lowest excitation energies of the green fluorescent protein and rhodopsin chromophores calculated at the CC2 level agree within 0.15 eV with experimental excitation energies, whereas the B3LYP values are somewhat less accurate, with a maximum deviation of 0.27 eV. The computed excitation energies for the photoactive yellow protein chromophore models deviate from available experimental values by 0.3-0.4 eV and 0.1-0.5 eV, at the CC2 and B3LYP levels of theory, respectively. PMID- 26606622 TI - The Application of Constricted Variational Density Functional Theory to Excitations Involving Electron Transitions from Occupied Lone-Pair Orbitals to Virtual pi* Orbitals. AB - We have applied the constricted variational density functional method (CV(n)-DFT) to n -> pi* transitions in which an electron is moved from an occupied lone-pair orbital n to a virtual pi* orbital. A total of 34 transitions involving 16 different compounds were considered using the local density approximation (LDA), Becke, three-parameter, Lee-Yang-Parr (B3LYP), and BHLYP functionals. The DFT based results were compared to the "best estimates" (BE) from high-level ab initio calculations. With energy terms included to second order in the variational parameters (CV(2)-DFT), our theory is equivalent to the adiabatic version of time-dependent density functional theory (DFT). We find that calculated excitation energies for CV(2)-DFT using LDA and BHLYP differ substantially from BE with root-mean-square-deviations (rmsd) of 0.86 and 0.69 eV, respectively, whereas B3LYP affords an excellent fit with BE at rmsd = 0.18 eV. Resorting next to CV(infinity)-DFT, where energy terms to all orders in the variational parameters are included, results in all three functionals in too high excitation energies with rmsd = 1.69, 1.14, and 0.93 eV for LDA, B3LYP, and BHLYP, respectively. Adding in orbital relaxation considerably improves the results with rmsd = 0.54, 0.30, and 0.48 eV for LDA, B3LYP, and BHLYP, respectively. It is concluded that CV(infinity)-DFT with orbital relaxation is a robust method for which the accuracy is less functionally dependent than that of CV(2)-DFT or adiabatic TDDFT. PMID- 26606623 TI - Critical Examination of Explicitly Time-Dependent Density Functional Theory for Coherent Control of Dipole Switching. AB - We compare the performance of explicitly time-dependent density functional theory (DFT) with time-dependent configuration interaction (TDCI) to achieve the control task of a population inversion in LiCN. We assume that if a given pulse achieves the control task when used in TDCI, then there should be a pulse with similar frequency and intensity that achieves the task in time-dependent DFT (TDDFT). The present investigation indicates that this is not the case, if standard functionals are used in the adiabatic approximation. PMID- 26606624 TI - A Qualitative Index of Spatial Extent in Charge-Transfer Excitations. AB - With the aim of defining the spatial extent associated to an electronic transition, of particular relevance in the case of charge-transfer (CT) excitations, a new index, evaluated only from the computed density for the ground and excited state, is here derived and tested on a family of molecules that can be considered as prototypes of push-pull chromophores.The index (DCT) allows to define the spatial extent associated to a given transition as well as the associated fraction of electron transferred. By definition of centroids of charges associated to the density increase and depletion zones upon excitation, a qualitative and easy to visualize measure of the spatial extent of the donor and the acceptor moieties within a given molecular system is also given. Finally, an index (t) allowing to define the presence eventually pathologic CT transitions for time-dependent density functional theory treatment in conjunction with standard generalized gradient approximation or hybrid functional, that is through space CT, is disclosed. PMID- 26606625 TI - Ab Initio Trajectory Study on Triplet Ketene Photodissociation via Statistical Sampling of the Crossing Seam. AB - Triplet ketene exhibits a steplike structure in the experimentally observed dissociation rate, but its mechanism is still unclear despite many theoretical efforts. A previous surface-hopping simulation at the CASSCF level suggests that nonadiabatic transition from the S0 to T1 states creates the T1 species in a highly nonstatistical manner, which raises the question of whether the use of statistical rate theory is valid in itself for the T1 state. Here, we study this problem by performing ab initio trajectory simulation at the multireference second-order Moller-Plesset perturbation (MRMP) level of theory. Since the MRMP theory is too expensive for such a trajectory calculation, we first construct dual-level potential energy surfaces (PESs) for the S0 and T1 states by calibrating the PESs at the B3LYP level with a limited set of MRMP energies. We then introduce the assumption of vibrational equilibrium on the S0 surface and characterize the S0 -> T1 crossing points using the conditional microcanonical distribution on the S0/T1 seam surface. The latter distribution is obtained by running a constrained trajectory on the seam surface by use of an efficient SHAKE like method. Subsequently, we propagate a number of T1 trajectories from the seam surface to obtain the dissociation rate. The result shows that (i) the S0 -> T1 crossing points are localized mainly in the T1 reactant region; (ii) the lifetime on the T1 surface is about 30 ps at the MRMP level, which is 2 orders of magnitude greater than the previous estimate obtained from the surface-hopping simulation at the CASSCF level (~100 fs); and (iii) the calculated T1 dissociation rate agrees reasonably well with classical transition state theory. These results suggest that the T1 dissociation is rather statistical, given that the T1 trajectories are initiated from the conditional microcanonical distribution on the seam surface. PMID- 26606626 TI - Searching for Computational Strategies to Accurately Predict pKas of Large Phenolic Derivatives. AB - Twenty-two reaction schemes have been tested, within the cluster-continuum model including up to seven explicit water molecules. They have been used in conjunction with nine different methods, within the density functional theory and with second-order Moller-Plesset. The quality of the pKa predictions was found to be strongly dependent on the chosen scheme, while only moderately influenced by the method of calculation. We recommend the E1 reaction scheme [HA + OH(-) (3H2O) <-> A(-) (H2O) + 3H2O], since it yields mean unsigned errors (MUE) lower than 1 unit of pKa for most of the tested functionals. The best pKa values obtained from this reaction scheme are those involving calculations with PBE0 (MUE = 0.77), TPSS (MUE = 0.82), BHandHLYP (MUE = 0.82), and B3LYP (MUE = 0.86) functionals. This scheme has the additional advantage, compared to the proton exchange method, which also gives very small values of MUE, of being experiment independent. It should be kept in mind, however, that these recommendations are valid within the cluster-continuum model, using the polarizable continuum model in conjunction with the united atom Hartree-Fock cavity and the strategy based on thermodynamic cycles. Changes in any of these aspects of the used methodology may lead to different outcomes. PMID- 26606627 TI - A Solvent-Free Coarse Grain Model for Crystalline and Amorphous Cellulose Fibrils. AB - Understanding biomass structure and dynamics on a range of time and length scales is important for the development of cellulosic biofuels. Here, to enable length and time scale extension, we develop a coarse grain (CG) model for molecular dynamics (MD) simulations of cellulose. For this purpose, we use distribution functions from fully atomistic MD simulations as target observables. A single bead per monomer level coarse graining is found to be sufficient to successfully reproduce structural features of crystalline cellulose. Without the use of constraints the CG crystalline fibril is found to remain stable over the maximum simulation length explored in this study (>1 MUs). We also extend the CG representation to model fully amorphous cellulose fibrils. This is done by using an atomistic MD simulation of fully solvated individual cellulose chains as a target for developing the corresponding fully amorphous CG force field. Fibril structures with different degrees of crystallinity are obtained using force fields derived using a parameter coupling the crystalline and amorphous potentials. The method provides an accurate and constraint-free approach to derive CG models for cellulose with a wide range of crystallinity, suitable for incorporation into large-scale models of lignocellulosic biomass. PMID- 26606628 TI - Toward Quantitative Structure-Property Relationships for Charge Transfer Rates of Polycyclic Aromatic Hydrocarbons. AB - Quantitative structure-property relationships (QSPRs) have been developed and assessed for predicting the reorganization energy of polycyclic aromatic hydrocarbons (PAHs). Preliminary QSPR models, based on a combination of molecular signature and electronic eigenvalue difference descriptors, have been trained using more than 200 PAHs. Monte Carlo cross-validation systematically improves the performance of the models through progressive reduction of the training set and selection of best performing training subsets. The final biased QSPR model yields correlation coefficients q(2) and r(2) of 0.7 and 0.8, respectively, and an estimated error in predicting reorganization energy of +/-0.014 eV. PMID- 26606629 TI - Prediction of Charge Mobility in Amorphous Organic Materials through the Application of Hopping Theory. AB - The application of hopping theory to predict charge (hole) mobility in amorphous organic molecular materials is studied in detail. Application is made to amorphous cells of N,N'-diphenyl-N,N'-bis-(3-methylphenylene)-1,1'-diphenyl-4,4' diamine (TPD), 1,1-bis-(4,4'-diethylaminophenyl)-4,4-diphenyl-1,3,butadinene (DEPB), N4,N4'-di(biphenyl-3-yl)-N4,N4'-diphenylbiphenyl-4,4'-diamine (mBPD), N1,N4-di(naphthalen-1-yl)-N1,N4-diphenylbenzene-1,4-diamine (NNP), and N,N' bis[9,9-dimethyl-2-fluorenyl]-N,N'-diphenyl-9,9-dimethylfluorene-2,7-diamine (pFFA). Detailed analysis of the computation of each of the parameters in the equations for hopping rate is presented, including studies of their convergence with respect to various numerical approximations. Based on these convergence studies, the most robust methodology is then applied to investigate the dependence of mobility on such parameters as the monomer reorganization energy, the monomer-monomer coupling, and the material density. The results give insight into what will be required to improve the accuracy of predictions of mobility in amorphous organic materials, and what factors should be controlled to develop materials with higher (or lower) charge (hole) mobility. PMID- 26606630 TI - Improved Prediction of Properties of pi-Conjugated Oligomers with Range-Separated Hybrid Density Functionals. AB - Range-separated hybrid functionals along with global hybrids and pure density functionals have been employed to calculate geometries, ionization energies (IP)s, electron affinities (EA)s, and excitation energies of neutral and oxidized polyenes, thiophene, and furan oligomers. Long-range correction with 100% HF exchange solves the problem of density functional theory with incorrect chain length dependence of IPs and energy gaps. There is a possibility of overcorrection, if the short-range part of the functional with no or low HF exchange is too small. The wB97XD functional with 22% of HF exchange in the short range and a range-separation parameter of 0.2 seems to be just right for conjugated systems at all chain lengths. The wB97XD functional additionally produces negative orbital energies in very good agreement with IPs and EAs. With correct orbital energies, band gaps correspond to transport gaps (Et) and not to optical gaps (Eg). Et is much larger than Eg in the gas phase, but the difference is significantly smaller in the solid state. The accuracy of the negative orbital energies is good down to about 30 eV so that valence and innervalence PE spectra can be modeled. wB97XD is therefore suitable for calculating band structures of conjugated polymers employing orbital energies. PMID- 26606631 TI - Distinct Morphologies for Amyloid Beta Protein Monomer: Abeta1-40, Abeta1-42, and Abeta1-40(D23N). AB - Numerous experimental studies indicate that amyloid beta protein (Abeta) oligomers as small as dimers trigger Alzheimer's disease. Precise solution conformation of Abeta monomer is missing since it is highly dynamic and aggregation prone. Such a knowledge is however crucial to design drugs inhibiting oligomers and fibril formation. Here, we determine the equilibrium structures of the Abeta1-40, Abeta1-42, and Abeta1-40(D23N) monomers using an accurate coarse grained force field coupled to Hamiltonian-temperature replica exchange molecular dynamics simulations. We observe that even if these three alloforms are mostly disordered at the monomeric level, in agreement with experiments and previous simulations on Abeta1-40 and Abeta1-42, striking morphological differences exist. For instance, Abeta1-42 and Abeta1-40(D23N) have higher beta-strand propensities at the C-terminal, residues 30-42, than Abeta1-40. The D23N mutation enhances the conformational freedom of the residues 22-29 and the propensity for turns and beta-strands in the other regions. It also changes the network of contacts; the N terminal (residues 1-16) becoming more independent from the rest of the protein, leading to a less compact morphology than the wild-type sequence. These structural properties could explain in part why the kinetics and the final amyloid products vary so extensively between the Abeta1-40 and the Abeta1 40(D23N) peptides. PMID- 26606632 TI - Structural Instability of the Active Site of T1 Lipase Induced by Replacement of Na(+) with Water Complexed with the Phenylalanine Aromatic Ring. AB - The crystallographic analysis of T1 lipase suggested an interaction between Na(+) and the aromatic ring of Phe16 in the active site. However, experimental approaches could not dismiss the possible presence of water instead of Na(+). Our previous molecular dynamics (MD) simulations suggested that the significantly large enthalpy gain of the Na(+)-pi interaction was required to preserve the catalytic core structure of T1 lipase. In this study, to examine the effects of water, we performed further MD simulations of T1 lipase involving the water-pi interaction, instead of the Na(+)-pi interaction, exploiting various force fields, such as ff99, ff02, and an accurate potential field to describe the water pi interaction, which was generated using our recently developed scheme (referred to as the grid-based energy representation). The analyses revealed that the water pi complex was unstable in the catalytic core of T1 lipase even when the accurate potential of the water-pi complex represented by the grid-based energy function was employed in the MD simulations and led to the disruption of the coordinated structure. In contrast, the catalytic core structure of T1 lipase involving the Na(+)-pi complex was significantly stable in the 10 ns MD simulation using the grid-based energy representation of the Na(+)-pi interaction. Thus, the possible presence of water may be excluded, and our previous proposal concerning the functional role of the structural element involving the Na(+)-pi interaction in the catalytic site of T1 lipase has unambiguously been confirmed. Further, the strong coordination of Na(+) and Nepsilon of His358 was also shown to be substantial to preserve the core structure of the catalytic site. PMID- 26606633 TI - The Ethidium-UA/AU Intercalation Site: Effect of Model Fragmentation and Backbone Charge State. AB - We report a systematic analysis of the intermolecular interactions of cationic ethidium intercalated into a UA/AU step of RNA for a single conformation based on crystallographic coordinates. Interaction energies at the MP2/6-31G** level were partitioned into electrostatic, exchange, delocalization, and correlation components. Various pairwise interaction models built from chemically intuitive fragments reproduce within a few percent values obtained when treating the intercalation site as a whole. Gas phase results are very sensitive to the charge state of the two phosphate groups, with the electrostatic term nearly tripling when the counterions are removed. But this is largely compensated by solvation, an effect represented here within the polarizable continuum model. In a few cases, more diffuse and larger basis sets as well as QCISD(T) corrections were applied in an effort to estimate plausible ethidium-nucleobase electron correlation effects. PMID- 26606634 TI - Hybrid QM/MM Calculations on the First Redox Step of the Catalytic Cycle of Bovine Glutathione Peroxidase GPX1. AB - The first reaction step of the redox cycle of bovine erythrocyte glutathione peroxidase from class 1 (GPX1) was investigated using hybrid quantum mechanics/molecular mechanics (QM/MM) calculations using the ONIOM methodology. The reduction of hydrogen peroxide by the active-site selenocysteine in selenolate form assisted by the Arg177 residue was modeled based on a proposal from previous molecular dynamics simulations and pKa calculations (J. Chem. TheoryComput. 2010, 6, 1670-1681). The redox reaction is predicted as a concerted SN2 nucleophilic substitution with a concomitant proton transfer from Arg177 onto leaving hydroxide ion upon reduction of hydrogen peroxide. The height of the reaction barrier was predicted in range of 6-11 kcal mol(-1), consistent with an experimental rate constant of ca. 10(7) M(-1) s(-1). The proposed GPX1-Se(-) Arg177H(+) mechanism for GPX1 is compared with the GPX3-SeH-Gln83 one proposed for human glutathione peroxidase from class 3 (GPX3) and with the solvent assisted proton exchange mechanism proposed for GPX-like organic selenols. The structural and energetic parameters predicted by various density functional theory methods (B3LYP, MPW1PW91, MPW1K, BB1K, M05-2X, M06-2X, and M06) are also discussed. PMID- 26606635 TI - Continuous Constant pH Molecular Dynamics in Explicit Solvent with pH-Based Replica Exchange. AB - A computational tool that offers accurate pKa values and atomically detailed knowledge of protonation-coupled conformational dynamics is valuable for elucidating mechanisms of energy transduction processes in biology, such as enzyme catalysis and electron transfer as well as proton and drug transport. Toward this goal we present a new technique of embedding continuous constant pH molecular dynamics within an explicit-solvent representation. In this technique we make use of the efficiency of the generalized-Born (GB) implicit-solvent model for estimating the free energy of protein solvation while propagating conformational dynamics using the more accurate explicit-solvent model. Also, we employ a pH-based replica exchange scheme to significantly enhance both protonation and conformational state sampling. Benchmark data of five proteins including HP36, NTL9, BBL, HEWL, and SNase yield an average absolute deviation of 0.53 and a root mean squared deviation of 0.74 from experimental data. This level of accuracy is obtained with 1 ns simulations per replica. Detailed analysis reveals that explicit-solvent sampling provides increased accuracy relative to the previous GB-based method by preserving the native structure, providing a more realistic description of conformational flexibility of the hydrophobic cluster, and correctly modeling solvent mediated ion-pair interactions. Thus, we anticipate that the new technique will emerge as a practical tool to capture ionization equilibria while enabling an intimate view of ionization coupled conformational dynamics that is difficult to delineate with experimental techniques alone. PMID- 26606636 TI - Microsolvation Effect on the Twist of beta-sheets. AB - Under certain circumstances beta-sheets prefer to be twisted instead of flat. To get insight into the reasons of such preference, bare and microsolvated parallel and antiparallel two-strand polyalanine beta-sheets are investigated using density functional theory. Full geometry optimizations show that microsolvation increases interstrand twisting and promotes a flat to twist transition. It is found that the latter behavior is connected to compressive strain resulting from microsolvation. Residues in flat beta-sheets adjust the sense of its local intrastrand twist, which leads to the appearance of interstrand twist, to release strain and to favor water-water hydrogen bonding. The predicted microsolvation effect is corroborated analyzing the geometry of residues forming beta-sheet motifs in protein crystals. PMID- 26606637 TI - Entropy Calculations of Single Molecules by Combining the Rigid-Rotor and Harmonic-Oscillator Approximations with Conformational Entropy Estimations from Molecular Dynamics Simulations. AB - As shown by previous theoretical and computational work, absolute entropies of small molecules that populate different conformers can be predicted accurately on the basis of the partitioning of the intramolecular entropy into vibrational and conformational contributions. Herein, we further elaborate on this idea and propose a protocol for entropy calculations of single molecules that combines the rigid rotor harmonic oscillator (RRHO) entropies with the direct sampling of the molecular conformational space by means of classical molecular dynamics simulations. In this approach, the conformational states are characterized by discretizing the time evolution of internal rotations about single bonds, and subsequently, the mutual information expansion (MIE) is used to approach the full conformational entropy from the converged probability density functions of the individual torsion angles, pairs of torsions, triads, and so on. This RRHO&MIE protocol could have broad applicability, as suggested by our test calculations on systems ranging from hydrocarbon molecules in the gas phase to a polypeptide molecule in aqueous solution. For the hydrocarbon molecules, the ability of the RRHO&MIE protocol to predict absolute entropies is assessed by carefully comparing theoretical and experimental values in the gas phase. For the rest of the test systems, we analyze the advantages and limitations of the RRHO&MIE approach in order to capture high order correlation effects and yield converged conformational entropies within a reasonable simulation time. Altogether, our results suggest that the RRHO&MIE strategy could be useful for estimating absolute and/or relative entropies of single molecules either in the gas phase or in solution. PMID- 26606638 TI - Automated Repulsive Parametrization for the DFTB Method. AB - The density-functional-based tight-binding method is an efficient scheme for quantum mechanical atomistic simulations. While the most relevant part of the chemical energies is calculated within a DFT-like scheme, a fitted correction function-the repulsive energy-is used to achieve results as close to ab initio counterparts as possible. We have developed an automatic parametrization scheme to ease the process of the repulsive energy fitting, offering a more systematic and much faster alternative to the traditional fitting process. The quality of the resulting repulsives can be tuned by selecting and weighting the fit systems and the important physical properties (energy, force, Hessian) of them. Besides driving DFT calculators in the fitting process automatically, the flexibility of our scheme also allows the usage of external data (e.g., molecular dynamics trajectories or experimental data) as a reference. Results with several elements show that our procedure is able to produce parameter sets comparable to handmade ones, yet requiring far less human effort and time. PMID- 26606639 TI - Fully Numerical All-Electron Solutions of the Optimized Effective Potential Equation for Diatomic Molecules. PMID- 26606641 TI - Mechanism of Action of Probiotic Bacteria on Intestinal and Systemic Immunities and Antigen-Presenting Cells. AB - Immunomodulation has been shown to be one of the major functions of probiotic bacteria. This review is presented to provide detailed information on the immunomodulatory properties of probiotics in various animal models and clinical practices. Probiotics can regulate helper T (Th) responses and release of cytokines in a strain-specific manner. For example, Lactobacillus rhamnosus GG can induce beneficial Th1 immunomodulatory effect in infants with cow's milk allergy and relieve intestinal inflammation in atopic children by promoting IL-10 generation. Mechanism of action of probiotics on antigen-presenting cells at gastrointestinal tract is also postulated in this review. Probiotic bacterial cells and their soluble factors may activate dendritic cells, macrophages, and to certain extent monocytes via toll-like-receptor recognition and may further provoke specific Th responses. They are speculated to elicit immunomodulatory effects on intestinal and systemic immunities. PMID- 26606642 TI - Human Metabolite Lamotrigine-N(2)-glucuronide Is the Principal Source of Lamotrigine-Derived Compounds in Wastewater Treatment Plants and Surface Water. AB - Wastewater and surface water samples, extracted with four solid-phase extraction cartridges of different chemistries, were suspect-screened for the anticonvulsant lamotrigine (LMG), its metabolites, and related compounds. LMG, three human metabolites, and a LMG synthetic impurity (OXO-LMG) were detected. Preliminary results showed significantly higher concentrations of OXO-LMG in wastewater effluent, suggesting its formation in the wastewater treatment plants (WWTPs). However, biodegradation experiments with activated sludge demonstrated that LMG is resistant to degradation and that its human metabolite lamotrigine-N(2) glucuronide (LMG-N2-G) is the actual source of OXO-LMG in WWTPs. In batch reactors, LMG-N2-G was transformed, following pseudo-first-order kinetics to OXO LMG and LMG, but kinetic experiments suggested an incomplete mass balance. A fragment ion search applied to batch-reactor and environmental samples revealed another transformation product (TP), formed by LMG-N2-G oxidation, which was identified by high-resolution mass spectrometry. Accounting for all TPs detected, a total mass balance at two concentration levels in batch reactors was closed at 86% and 102%, respectively. In three WWTPs, the total mass balance of LMG-N2-G ranged from 71 to 102%. Finally, LMG-N2-G and its TPs were detected in surface water samples with median concentration ranges of 23-139 ng L(-1). The results of this study suggest that glucuronides of pharmaceuticals might also be sources of yet undiscovered, but environmentally relevant, transformation products. PMID- 26606640 TI - Residential Road Traffic Noise and High Depressive Symptoms after Five Years of Follow-up: Results from the Heinz Nixdorf Recall Study. AB - BACKGROUND: Traffic noise affects a large number of people, particularly in urbanized areas. Noise causes stress and annoyance, but less is known about the relationship between noise and depression. OBJECTIVE: We investigated the association of residential road traffic noise with depressive symptoms using 5 year follow-up data from a German population-based study. METHODS: We analyzed data from 3,300 participants in the Heinz Nixdorf Recall study who were between 45 and 75 years old and were without depressive symptoms at baseline (2000-2003). Depressive symptoms were defined based on the Center for Epidemiologic Studies Depression scale (CES-D) 15-item questionnaire (total score >= 17) and antidepressant medication intake. Road traffic noise was modeled according to European Parliament/Council Directive 2002/49/EC. High noise exposure was defined as annual mean 24-hr noise levels > 55 A-weighted decibels [dB(A)]. Poisson regression with robust variance was used to estimate relative risks (RRs) a) adjusting for the potential confounders age, sex, socioeconomic status (SES), neighborhood-level SES, and traffic proximity; b) additionally adjusting for body mass index and smoking; and c) additionally adjusting for the potential confounders/intermediates comorbidities and insomnia. RESULTS: Overall, 35.7% of the participants were exposed to high residential road traffic noise levels. At follow-up (mean = 5.1 years after baseline), 302 participants were classified as having high depressive symptoms, corresponding to an adjusted RR of 1.29 (95% CI: 1.03, 1.62; Model 1) for exposure to > 55 versus <= 55 dB(A). Adjustment for potential confounders/intermediates did not substantially alter the results. Associations were stronger among those who reported insomnia at baseline (RR = 1.62; 95% CI: 1.10, 2.59 vs. RR = 1.21; 95% CI: 0.94, 1.57) and appeared to be limited to those with <= 13 years of education (RR = 1.43; 95% CI: 1.10, 1.85 vs. 0.92; 95% CI: 0.56, 1.53 for > 13 years). CONCLUSION: Our results suggest that exposure to residential road traffic noise increases the risk of depressive symptoms. CITATION: Orban E, McDonald K, Sutcliffe R, Hoffmann B, Fuks KB, Dragano N, Viehmann A, Erbel R, Jockel KH, Pundt N, Moebus S. 2016. Residential road traffic noise and high depressive symptoms after five years of follow-up: results from the Heinz Nixdorf Recall Study. Environ Health Perspect 124:578-585; http://dx.doi.org/10.1289/ehp.1409400. PMID- 26606643 TI - Correction to Organic Carbon Burial in Lakes and Reservoirs of the Conterminous United States. PMID- 26606644 TI - Thermal Stability of Goethite-Bound Natural Organic Matter Is Impacted by Carbon Loading. AB - Dissolved natural organic matter (NOM) sorption at mineral surfaces can significantly affect the persistence of organic carbon in soils and sediments. Consequently, determining the mechanisms that stabilize sorbed NOM is crucial for predicting the persistence of carbon in nature. This study determined the effects of loadings and pH on the thermal stability of NOM associated with synthetic goethite (alpha-FeOOH) particle surfaces, as a proxy for NOM-mineral interactions taking place in nature. NOM thermal stability was investigated using temperature programmed desorption (TPD) in the 30-700 degrees C range to collect vibration spectra of thermally decomposing goethite-NOM assemblages, and to concomitantly analyze evolved gases using mass spectrometry. Results showed that NOM thermal stability, indicated by the range of temperatures in which CO2 evolved during thermal decomposition, was greatest in unbound NOM and lowest when NOM was bound to goethite. NOM thermal stability was also loading dependent. It decreased when loadings were in increased the 0.01 to 0.42 mg C m(-2) range, where the upper value corresponds to a Langmuirian adsorption maximum. Concomitant Fourier transform infrared (FTIR) spectroscopy measurement showed that these lowered stabilities could be ascribed to direct NOM-goethite interactions that dominated the NOM binding environment. Mineral surface interactions at larger loadings involved, on the contrary, a smaller fraction of the sorbed NOM, thus increasing thermal stability toward that of its unbound counterpart. This study thus identifies a sorption threshold below which NOM sorption to goethite decreases NOM thermal stability, and above which no strong effects are manifested. This should likely influence the fate of organic carbon exposed to thermal gradients in natural environments. PMID- 26606645 TI - Arsenic cardiotoxicity: An overview. AB - Arsenic, a naturally ubiquitous element, is found in foods and environment. Cardiac dysfunction is one of the major causes of morbidity and mortality in the world. Arsenic exposure is associated with various cardiopathologic effects including ischemia, arrhythmia and heart failure. Possible mechanisms of arsenic cardiotoxicity include oxidative stress, DNA fragmentation, apoptosis and functional changes of ion channels. Several evidences have shown that mitochondrial disruption, caspase activation, MAPK signaling and p53 are the pathways for arsenic induced apoptosis. Arsenic trioxide is an effective and potent antitumor agent used in patients with acute promyelocytic leukemia and produces dramatic remissions. As2O3 administration has major limitations such as T wave changes, QT prolongation and sudden death in humans. In this review, we discuss the underlying pathobiology of arsenic cardiotoxicity and provide information about cardiac health effects associated with some medicinal plants in arsenic toxicity. PMID- 26606646 TI - Evaluation of different smoking habits during music festivals through wastewater analysis. AB - Wastewater analysis is a powerful method that can provide useful information about the abuse of legal and illicit drugs. The aim of our study was to determine nicotine consumption during four different music festivals and to find a connection between smoking and preferences for specific music styles using wastewater analysis. The amount of the nicotine metabolite cotinine was monitored in wastewater at the influent of three waste water treatment plants WWTPs in the Czech Republic and Slovakia, where the festivals took place. Urinary bio-markers of nicotine utilization were analyzed by LC-HRMS. More than 80,000 festival participants were monitored during our study from June to September 2014. A significant increase of nicotine consumption was observed in wastewaters during music festivals. The nicotine ingestion level was back-calculated and expressed as mass of pure drug consumed per day and per 1000 inhabitants for selected cities of both countries. The highest differences between typical levels of cotinine in wastewaters and the levels during music festivals were detected in Piestany: 4 g/L/1000 inhabitants during non-festival days compared to 8 g/L/1000 inhabitants during the Topfest pop-rock festival and 6g/L/1000 inhabitants during the Grape dance festival. No significant increase of the amounts of cotinine in wastewater was recorded for the Country and Folk festivals. PMID- 26606647 TI - Antibacterial Activity of Geminized Amphiphilic Cationic Homopolymers. AB - The current study is aimed at investigating the effect of cationic charge density and hydrophobicity on the antibacterial and hemolytic activities. Two kinds of cationic surfmers, containing single or double hydrophobic tails (octyl chains or benzyl groups), and the corresponding homopolymers were synthesized. The antimicrobial activity of these candidate antibacterials was studied by microbial growth inhibition assays against Escherichia coli, and hemolysis activity was carried out using human red blood cells. It was interestingly found that the homopolymers were much more effective in antibacterial property than their corresponding monomers. Furthermore, the geminized homopolymers had significantly higher antibacterial activity than that of their counterparts but with single amphiphilic side chains in each repeated unit. Geminized homopolymers, with high positive charge density and moderate hydrophobicity (such as benzyl groups), combine both advantages of efficient antibacterial property and prominently high selectivity. To further explain the antibacterial performance of the novel polymer series, the molecular interaction mechanism is proposed according to experimental data which shows that these specimens are likely to kill microbes by disrupting bacterial membranes, leading them unlikely to induce resistance. PMID- 26606648 TI - Innovative New Drugs for Serious Nonlethal Diseases: The Cost to Develop and the Cost to Buy. PMID- 26606649 TI - Adaptive radiation of Darwin's finches revisited using whole genome sequencing. AB - We recently used genome sequencing to study the evolutionary history of the Darwin's finches. A prominent feature of our data was that different polymorphic sites in the genome tended to indicate different genetic relationships among these closely related species. Such patterns are expected in recently diverged genomes as a result of incomplete lineage sorting. However, we uncovered conclusive evidence that these patterns have also been influenced by interspecies hybridisation, a process that has likely played an important role in the radiation of Darwin's finches. A major discovery was that segregation of two haplotypes at the ALX1 locus underlies variation in beak shape among the Darwin's finches, and that differences between the two haplotypes in a 240 kb region in blunt and pointed beaked birds involve both coding and regulatory changes. As we review herein, the evolution of such adaptive haplotypes comprising multiple causal changes appears to be an important mechanism contributing to the evolution of biodiversity. PMID- 26606650 TI - Location-dependent sensing of nitric oxide and calcium ions in living rat kidney using an amperometric/potentiometric dual microsensor. AB - In this paper, we report the fabrication of a dual microsensor for sensing nitric oxide (NO) and calcium ions (Ca(2+)) and its application for simultaneous NO/Ca(2+) measurements in living rat kidney tissue. NO and Ca(2+) have very important physiological functions and are both intricately involved in many biological processes. The dual NO/Ca(2+) sensor is prepared based on a dual recessed electrode possessing Pt (diameter, 25 MUm) and Ag (diameter, 76 MUm) microdisks. The Pt disk surface (WE1) is electrodeposited with porous Pt black and then coated with fluorinated xerogel; and used for amperometric sensing of NO. The Ag disk surface (WE2) is chloridated to AgCl, followed by silanization and then Ca(2+) selective membrane loading; and used for potentiometric sensing of Ca(2+). The dual sensor exhibits high sensitivity of WE1 to NO (40.8 +/- 6.5 pA MUM(-1), n = 10) and reliable Nerntian response of WE2 to Ca(2+) changes (25.7 +/- 0.5 mV pCa(-1), n = 10) with excellent selectivity to only NO and Ca(2+) over common interferents and reliable stability (up to ~4 h tissue experiment). The prepared sensor is employed for real-time monitoring of the dynamic changes of NO and Ca(2+) levels of a rat kidney, which is induced by the administration of 10 mM l-N(G)-nitroarginine methyl ester (l-NAME, a NO synthase inhibitor). Due to the small sensor dimension, location-dependent analyses of NO and Ca(2+) are carried out at two different regions of a kidney (renal medulla and cortex). Higher NO and Ca(2+) levels are observed at the medulla than at the cortex. This study verifies the feasibility for real-time monitoring of intimately connected Ca(2+) and endogenous NO production; and also for localized concentration assessments of both NO and Ca(2+). PMID- 26606651 TI - Coherently Strained Si-SixGe1-x Core-Shell Nanowire Heterostructures. AB - Coherently strained Si-SixGe1-x core-shell nanowire heterostructures are expected to possess a positive shell-to-core conduction band offset, allowing for quantum confinement of electrons in the Si core. We report the growth of epitaxial, coherently strained Si-SixGe1-x core-shell heterostructures through the vapor liquid-solid mechanism for the Si core, followed in situ by the epitaxial SixGe1 x shell growth using ultrahigh vacuum chemical vapor deposition. The Raman spectra of individual nanowires reveal peaks associated with the Si-Si optical phonon mode in the Si core and the Si-Si, Si-Ge, and Ge-Ge vibrational modes of the SixGe1-x shell. The core Si-Si mode displays a clear red-shift compared to unstrained, bare Si nanowires thanks to the lattice mismatch-induced tensile strain, in agreement with calculated values using a finite-element continuum elasticity model combined with lattice dynamic theory. N-type field-effect transistors using Si-SixGe1-x core-shell nanowires as channel are demonstrated. PMID- 26606653 TI - Prospective regularization design in prior-image-based reconstruction. AB - Prior-image-based reconstruction (PIBR) methods leveraging patient-specific anatomical information from previous imaging studies and/or sequences have demonstrated dramatic improvements in dose utilization and image quality for low fidelity data. However, a proper balance of information from the prior images and information from the measurements is required (e.g. through careful tuning of regularization parameters). Inappropriate selection of reconstruction parameters can lead to detrimental effects including false structures and failure to improve image quality. Traditional methods based on heuristics are subject to error and sub-optimal solutions, while exhaustive searches require a large number of computationally intensive image reconstructions. In this work, we propose a novel method that prospectively estimates the optimal amount of prior image information for accurate admission of specific anatomical changes in PIBR without performing full image reconstructions. This method leverages an analytical approximation to the implicitly defined PIBR estimator, and introduces a predictive performance metric leveraging this analytical form and knowledge of a particular presumed anatomical change whose accurate reconstruction is sought. Additionally, since model-based PIBR approaches tend to be space-variant, a spatially varying prior image strength map is proposed to optimally admit changes everywhere in the image (eliminating the need to know change locations a priori). Studies were conducted in both an ellipse phantom and a realistic thorax phantom emulating a lung nodule surveillance scenario. The proposed method demonstrated accurate estimation of the optimal prior image strength while achieving a substantial computational speedup (about a factor of 20) compared to traditional exhaustive search. Moreover, the use of the proposed prior strength map in PIBR demonstrated accurate reconstruction of anatomical changes without foreknowledge of change locations in phantoms where the optimal parameters vary spatially by an order of magnitude or more. In a series of studies designed to explore potential unknowns associated with accurate PIBR, optimal prior image strength was found to vary with attenuation differences associated with anatomical change but exhibited only small variations as a function of the shape and size of the change. The results suggest that, given a target change attenuation, prospective patient-, change-, and data-specific customization of the prior image strength can be performed to ensure reliable reconstruction of specific anatomical changes. PMID- 26606654 TI - Life expectancy and health expenditure evolution in Eastern Europe-DiD and DEA analysis. AB - BACKGROUND: Exploration of long-term health expenditure and longevity trends across three major sub-regions of Eastern Europe since 1989. METHODS: 24 countries were classified as EU 2004, CIS, or SEE. European Health for All Database (HFA-DB) 1989-2012 data were processed using difference-in-difference (DiD) and data envelopment analysis (DEA). RESULTS: The strongest expenditure growth was recorded in EU 2004 followed by SEE and the CIS. A surprisingly similar longevity increase was present in SEE and EU 2004. In 1989, countries that joined EU in 2004 were relatively inefficient in the number of life-years gained yet had a lower life expectancy than the SEE region and was only slightly higher than the CIS region (DEA). By 2012 the revenue spent was roughly linear to additional life-year expectancies. CONCLUSION: EU 2004 members were the best performers in terms of balanced longevity increase followed by health expenditure growth. The SEE economies' longevity gains were lagging slightly behind at a far lower cost. An extrapolated CIS expenditure to longevity increase ratio has the fastest-growing long-term promise. PMID- 26606652 TI - Genome-Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. We undertook the present work to perform the first genome-wide association study on individuals from the Americas who are enriched for Native American heritage. METHODS: We analyzed 3,710 individuals from the US and 4 countries of Latin America who were diagnosed as having SLE, and healthy controls. Samples were genotyped with HumanOmni1 BeadChip. Data on out-of-study controls genotyped with HumanOmni2.5 were also included. Statistical analyses were performed using SNPtest and SNPGWA. Data were adjusted for genomic control and false discovery rate. Imputation was performed using Impute2 and, for classic HLA alleles, HiBag. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: The IRF5-TNPO3 region showed the strongest association and largest OR for SLE (rs10488631: genomic control-adjusted P [Pgcadj ] = 2.61 * 10(-29), OR 2.12 [95% CI 1.88-2.39]), followed by HLA class II on the DQA2-DQB1 loci (rs9275572: Pgcadj = 1.11 * 10(-16), OR 1.62 [95% CI 1.46 1.80] and rs9271366: Pgcadj = 6.46 * 10(-12), OR 2.06 [95% CI 1.71-2.50]). Other known SLE loci found to be associated in this population were ITGAM, STAT4, TNIP1, NCF2, and IRAK1. We identified a novel locus on 10q24.33 (rs4917385: Pgcadj = 1.39 * 10(-8)) with an expression quantitative trait locus (eQTL) effect (Peqtl = 8.0 * 10(-37) at USMG5/miR1307), and several new suggestive loci. SLE risk loci previously identified in Europeans and Asians were corroborated. Local ancestry estimation showed that the HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection against development of SLE. CONCLUSION: Our results demonstrate that studying admixed populations provides new insights in the delineation of the genetic architecture that underlies autoimmune and complex diseases. PMID- 26606655 TI - Human Injury Criteria for Underwater Blasts. AB - Underwater blasts propagate further and injure more readily than equivalent air blasts. Development of effective personal protection and countermeasures, however, requires knowledge of the currently unknown human tolerance to underwater blast. Current guidelines for prevention of underwater blast injury are not based on any organized injury risk assessment, human data or experimental data. The goal of this study was to derive injury risk assessments for underwater blast using well-characterized human underwater blast exposures in the open literature. The human injury dataset was compiled using 34 case reports on underwater blast exposure to 475 personnel, dating as early as 1916. Using severity ratings, computational reconstructions of the blasts, and survival information from a final set of 262 human exposures, injury risk models were developed for both injury severity and risk of fatality as functions of blast impulse and blast peak overpressure. Based on these human data, we found that the 50% risk of fatality from underwater blast occurred at 302+/-16 kPa-ms impulse. Conservatively, there is a 20% risk of pulmonary injury at a kilometer from a 20 kg charge. From a clinical point of view, this new injury risk model emphasizes the large distances possible for potential pulmonary and gut injuries in water compared with air. This risk value is the first impulse-based fatality risk calculated from human data. The large-scale inconsistency between the blast exposures in the case reports and the guidelines available in the literature prior to this study further underscored the need for this new guideline derived from the unique dataset of actual injuries in this study. PMID- 26606656 TI - The Impact of the Latest Danian Event on Planktic Foraminiferal Faunas at ODP Site 1210 (Shatsky Rise, Pacific Ocean). AB - The marine ecosystem has been severely disturbed by several transient paleoenvironmental events (<200 kyr duration) during the early Paleogene, of which the Paleocene-Eocene Thermal Maximum (PETM, ~56 Ma) was the most prominent. Over the last decade a number of similar events of Paleocene and Eocene age have been discovered. However, relatively little attention has been paid to pre-PETM events, such as the "Latest Danian Event" ("LDE", ~62.18 Ma), specifically from an open ocean perspective. Here we present new foraminiferal isotope (delta13C, delta18O) and faunal data from Ocean Drilling Program (ODP) Site 1210 at Shatsky Rise (Pacific Ocean) in order to reconstruct the prevailing paleoceanographic conditions. The studied five-meter-thick succession covers ~900 kyr and includes the 200-kyr-lasting LDE. All groups surface dwelling, subsurface dwelling and benthic foraminifera show a negative delta13C excursion of >0.60/00, similar in magnitude to the one previously reported from neighboring Site 1209 for benthic foraminifera. delta18O-inferred warming by 1.6 to 2.8 degrees C (0.4-0.70/00 delta18O measured on benthic and planktic foraminiferal tests) of the entire water column accompanies the negative delta13C excursion. A well stratified upper ocean directly before and during the LDE is proposed based on the stable isotope gradients between surface and subsurface dwellers. The gradient is less well developed, but still enhanced after the event. Isotope data are supplemented by comprehensive planktic foraminiferal faunal analyses revealing a dominance of Morozovella species together with Parasubbotina species. Subsurface-dwelling Parasubbotina shows high abundances during the LDE tracing changes in the strength of the isotope gradients and, thus, may indicate optimal living conditions within a well stratified surface ocean for this taxon. In addition, distinct faunal changes are reported like the disappearance of Praemurica species right at the base of the LDE and the continuous replacement of M. praeangulata with M. angulata across the LDE. PMID- 26606657 TI - Skin nerve misfolded alpha-synuclein in pure autonomic failure and Parkinson disease. AB - OBJECTIVE: To characterize the expression in skin nerves of native (n-syn) and misfolded phosphorylated (p-syn) alpha-synucleins in pure autonomic failure (PAF) and idiopathic Parkinson disease (IPD). The specific aims were to (1) define the importance of n-syn and p-syn as disease biomarkers and (2) ascertain differences in abnormal synuclein skin nerve deposits. METHODS: We studied 30 patients, including 16 well-characterized IPD patients and 14 patients fulfilling PAF diagnostic criteria, and 15 age-matched controls. Subjects underwent skin biopsy from proximal (ie, cervical) and distal (ie, thigh and leg) sites to study small nerve fiber and intraneural n-syn and p-syn. RESULTS: PAF and IPD showed length dependent somatic and autonomic small fiber loss, more severely expressed in patients with higher p-syn load. n-syn was similarly expressed in both groups of patients and controls. By contrast, p-syn was not evident in any skin sample of controls but was found in all PAF and IPD patients, although with different skin innervation. In addition, abnormal alpha-synuclein deposits were found in all analyzed skin samples in PAF but in only 49% of samples with a higher positivity rate at the proximal site in IPD. INTERPRETATION: (1) Intraneural p-syn was a reliable in vivo marker of PAF and IPD; (2) neuritic p-syn inclusions differed in PAF and IPD, suggesting a different underlying pathogenesis; (3) when searching for abnormal p-syn deposits in skin nerves, the site of analysis is irrelevant in PAF but it is critical in IPD. PMID- 26606658 TI - Adeno-associated Vector Toxicity-To Be or Not to Be? PMID- 26606661 TI - Gene Editing and Germ-line Intervention: The Need for Novel Responses to Novel Technologies. PMID- 26606662 TI - Corrigendum to "Disruption of KATP Channel Expression in Skeletal Muscle by Targeted Oligonucleotide Delivery Promotes Activity-linked Thermogenesis". PMID- 26606663 TI - Erratum to "A HER2-specific Modified Fc Fragment (Fcab) Induces Antitumor Effects Through Degradation of HER2 and Apoptosis". PMID- 26606664 TI - Brief Report: First Identification of Intrafamilial Recurrence of Blau Syndrome due to Gonosomal NOD2 Mosaicism. AB - OBJECTIVE: Blau syndrome is characterized by noncaseating granulomatous arthritis, dermatitis, and uveitis, and results from gain-of-function NOD2 mutations. This study was undertaken to identify the genetic cause of the disease in a family with 3 members with Blau syndrome. METHODS: We studied a family with 3 affected members across 2 consecutive generations. The children's symptoms started early (at 6 and 7 months of age) and included polyarthritis, dermatitis, uveitis, and fever. In contrast, the father's symptoms started later (at 22 years of age) and included noncaseating granulomatous dermatitis and uveitis. We analyzed the NOD2 gene in all patients by both the Sanger method of DNA sequencing and amplicon-based deep sequencing using an Ion Torrent PGM platform. RESULTS: Sanger chromatograms revealed the heterozygous c.1001G>A transition in both children, which resulted in the p.Arg334Gln mutation that causes Blau syndrome. In contrast, the father's chromatograms revealed a small peak of adenine at the c.1001 position, suggesting the presence of a somatic NOD2 mutation. To evaluate this hypothesis, we performed amplicon-based deep sequencing using DNA from different tissues, which confirmed a variable degree (0.9-12.9%) of somatic NOD2 mosaicism. The previous detection of the NOD2 mutation in his daughters strongly suggests the presence of gonosomal (somatic plus gonadal) NOD2 mosaicism in the father. Comparative analyses with Blau syndrome patients carrying the germline p.Arg334Gln NOD2 mutation revealed late onset of the disease, a mild inflammatory phenotype, and an absence of complications in patients with NOD2 mosaicism. CONCLUSION: This is the first description of gonosomal NOD2 mosaicism as the cause of intrafamilial recurrence of Blau syndrome. Our findings also indicate that Blau syndrome includes more diverse and milder phenotypes than previously described. PMID- 26606665 TI - A 21-Month-Old Male With Refusal to Walk, Rash, and Weight Loss. PMID- 26606666 TI - LipidBuilder: A Framework To Build Realistic Models for Biological Membranes. AB - The physical and chemical characterization of biological membranes is of fundamental importance for understanding the functional role of lipid bilayers in shaping cells and organelles, steering vesicle trafficking and promoting membrane protein signaling. Molecular dynamics simulations stand as a powerful tool to probe the properties of membranes at atomistic level. However, the biological membrane is highly complex, and closely mimicking its physiological constitution in silico is not a straightforward task. Here, we present LipidBuilder, a framework for creating and storing models of biologically relevant phospholipid species with acyl tails of heterogeneous composition. LipidBuilder also enables the assembly of these database-stored lipids into realistic bilayers featuring asymmetric distribution on layer leaflets and concentration of given membrane constituents as defined, for example, by lipidomics experiments. The ability of LipidBuilder to assemble robust membrane models was validated by simulating membranes of homogeneous lipid composition for which experimental data are available. Furthermore, taking advantage of the extensive lipid headgroup repertoire, we assembled models of membranes of heterogeneous nature as naturally found in viral (phage PRD1), bacterial (Salmonella enterica, Laurinavicius , S. ; Kakela , R. ; Somerharju , P. ; Bamford , D. H. ; Virology 2004 , 322 , 328 - 336 ) and plant (Chlorella kessleri, Rezanka , T. ; Podojil , M. ; J. Chromatogr. 1989 , 463 , 397 - 408 ) organisms. These realistic membrane models were built using a near-exact lipid composition revealed from analytical chemistry experiments. We suggest LipidBuilder as a useful tool to model biological membranes of near-biological complexity, and as a robust complement to the current efforts to characterize the biophysical properties of biological membrane using molecular simulation. PMID- 26606667 TI - Disclosure of Financial Conflicts of Interests in Interventions to Improve Child Psychosocial Health: A Cross-Sectional Study. AB - Academic journals increasingly request a full disclosure of financial conflict of interest (CoI). The Committee for Publication Ethics provides editors with guidance about the course of action in the case of suspected non-disclosure. No prior study has examined the extent to which journal articles on psychosocial interventions disclose CoI, and how journal editors process requests to examine suspected undisclosed CoI. Four internationally disseminated psychosocial interventions were examined. 136 articles related to an intervention, co-authored by intervention developers and published in health sciences journals were retrieved as requiring a CoI statement. Two editors refused consent to be included in the study. COI disclosures and editor responses were coded for 134 articles. Overall, 92/134 (71%) of all articles were found to have absent, incomplete or partly misleading CoI disclosures. Disclosure rates for the four programs varied significantly between 11% and 73%. Journal editors were contacted about 92 published articles with no CoI disclosure or a disclosure that was considered problematic. In 65/92 (71%) of all cases the editors published an 'erratum' or 'corrigendum'. In 16 of these cases the journal had mishandled a submitted disclosure. The most frequent reason for non-publication of an erratum was that the journal had no disclosure policy at the time of the publication (16 cases). Consumers of research on psychosocial interventions published in peer reviewed journals cannot currently assume that CoI disclosures are adequate and complete. More efforts are needed to achieve transparency. PMID- 26606668 TI - Safety and Efficacy of Gamma Knife Radiosurgery for the Management of Koos Grade 4 Vestibular Schwannomas. AB - BACKGROUND: Gamma Knife radiosurgery (GKRS) is commonly used in treating small vestibular schwannomas; however, its use for larger vestibular schwannomas is still controversial. OBJECTIVE: To assess the long-term safety and efficacy of treating eligible Koos grade 4 vestibular schwannomas with GKRS. METHODS: We conducted a single-center, retrospective evaluation of patient undergoing GKRS for Koos grade 4 vestibular schwannomas. We evaluated clinical, imaging, and treatment characteristics and assessed treatment outcome. Inclusion criteria were tumor size of >=4 cm and follow-up of at least 6 months. Patients with neurofibromatosis type 2 were excluded. Primary outcomes measured were tumor control rate, hearing and facial function preservation rate, and complications. All possible factors were analyzed to assess clinical significance. RESULTS: Sixty-eight patients met inclusion criteria. Median follow-up was 47 months (range, 6-125 months). Baseline hearing was serviceable in 60%. Median tumor volume at radiosurgery was 7.4 cm (range, 4-19 cm). The median marginal dose used was 12 Gy at the 50% isodose line. Actuarial tumor control rates were 95% and 92% at 2 and 10 years, respectively. Actuarial serviceable hearing preservation rates were 89% and 49% at 2 and 5 years, respectively. Facial nerve preservation was 100%. Clinical complications included balance disturbance (11%), facial pain (10%), facial numbness (5%), and tinnitus (10%). Most complications were mild and transient. Hydrocephalus occurred in 3 patients, requiring ventriculoperitoneal shunt insertion. Larger tumor size was significantly associated with persisting symptoms post-treatment. CONCLUSION: Patients with Koos grade 4 vestibular schwannomas and minimal symptoms can be treated safely and effectively with GKRS. PMID- 26606669 TI - The Relationship Between Serum Neuron-Specific Enolase Levels and Severity of Bleeding and Functional Outcomes in Patients With Nontraumatic Subarachnoid Hemorrhage. AB - BACKGROUND: The value of neuron-specific enolase (NSE) in predicting clinical outcomes has been investigated in a variety of neurological disorders. OBJECTIVE: To investigate the associations of serum NSE with severity of bleeding and functional outcomes in patients with subarachnoid hemorrhage (SAH). METHODS: We retrospectively reviewed the records of patients with SAH from June 2008 to June 2012. The severity of SAH bleeding at admission was measured radiographically with the Fisher scale and clinically with the Glasgow Coma Scale, Hunt and Hess grade, and World Federation of Neurologic Surgeons scale. Outcomes were assessed with the modified Rankin Scale at discharge. RESULTS: We identified 309 patients with nontraumatic SAH, and 71 had NSE testing. Median age was 54 years (range, 23 87 years), and 44% were male. In multivariable analysis, increased NSE was associated with a poorer Hunt and Hess grade (P = .003), World Federation of Neurologic Surgeons scale score (P < .001), and Glasgow Coma Scale score (P = .003) and worse outcomes (modified Rankin Scale at discharge; P = .001). There was no significant association between NSE level and Fisher grade (P = .81) in multivariable analysis. CONCLUSION: We found a significant association between higher NSE levels and poorer clinical presentations and worse outcomes. Although it is still early for any relevant clinical conclusions, our results suggest that NSE holds promise as a tool for screening patients at increased risk of poor outcomes after SAH. PMID- 26606671 TI - Complication-Effectiveness Analysis for Brain Arteriovenous Malformation Surgery: A Prospective Cohort Study. AB - BACKGROUND: Intervention for brain arteriovenous malformations (bAVMs) should aim at treatment that is safe and effective. OBJECTIVE: To analyze a prospective database to derive the probability of neurological deficit and adjust this risk for effectively treated bAVMs (complication-effectiveness analysis [CEA]). METHODS: First, we calculated the percentage of surgical complications leading to a modified Rankin Scale >1 at 12 months after surgery for each Spetzler-Ponce class (SPC). Second, we performed a sensitivity analysis of these results by including bAVMs not undergoing surgery, to correct for bias. Third, we established the long-term cumulative incidence of freedom from recurrence from Kaplan-Meier analysis. Finally, we combined the results to calculate the risk of surgery per effective treatment in a complication-effectiveness analysis. RESULTS: Seven hundred seventy-nine patients underwent 641 microsurgical resections. Complications of surgery leading to a modified Rankin Scale >1 at 12 months occurred in 1.4% (95% confidence interval [CI]: 0.5-3.3), 20% (95% CI: 15 26), and 41% (95% CI: 30-52) of SPC A, SPC B, and SPC C, respectively. The cumulative 9-year freedom from recurrence was 97% for SPC A and 92% for other bAVMs. The 9-year CEA risk was 1.4% (credible range: 0.5%-3.4%) for SPC A, 22% to 24% (credible range: 16%-31%) for SPC B, and 45% to 63% (credible range: 33%-73%) for SPC C bAVM. CONCLUSION: CEA presents the treatment outcome in the context of efficacy and provides a basis for comparing outcomes from techniques with different times to elimination of the bAVM. ABBREVIATIONS: bAVM, brain arteriovenous malformationCEA, complication-effectiveness analysisCI, confidence intervalCTA, computerized tomographic angiographyDSA, digital subtraction angiographyMRA, magnetic resonance angiographymRS, modified Rankin ScaleSMG, Spetzler-Martin gradeSPC, Spetzler-Ponce class. PMID- 26606670 TI - Rare Variants in Cardiomyopathy Genes Associated With Stress-Induced Cardiomyopathy. AB - BACKGROUND: Stress-induced cardiomyopathy (SIC) is a poorly understood condition associated with periods of emotional and physical stress. The clinical approaches for management of SIC are supportive and reactive to patient symptoms. OBJECTIVE: To utilize next-generation exome sequencing to define genetic variation associated with, and potentially responsible for, this disease. METHODS: We performed exome sequencing of 7 white female patients with SIC. Filtering of the identified variants was performed to limit our investigation to those sequences that passed quality control criteria, were rare or novel, were determined algorithmically to have high impact on the associated protein, and were within regions of high species conservation. All variants were verified by using Sanger sequencing. RESULTS: Exome-sequencing analysis revealed that each patient carried predicted deleterious variants affecting known cardiomyopathy genes. In each case, the identified variant was either not previously found in public human genome data or was previously annotated in a database of clinical variants associated with cardiac dysfunction. CONCLUSION: Patients with SIC harbor deleterious mutations in established cardiomyopathy genes at a level higher than healthy controls. We hypothesize that patients at highest risk for SIC likely live in a compensated state of cardiac dysfunction that manifests clinically only after the myocardium is stressed. In short, we propose that SIC is another example of an occult cardiomyopathy with a distinct physiological trigger and suggest that alternative clinical approaches to these patients may be warranted. ABBREVIATIONS: CADD, Combined Annotation Dependent DepletionFPKM, fragments per kilobase pair of exon per million fragments mappedNHLBI GO ESP, National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing ProjectPCR, polymerase chain reactionSIC, stress-induced cardiomyopathy. PMID- 26606672 TI - OmpW of Caulobacter crescentus Functions as an Outer Membrane Channel for Cations. AB - Caulobacter crescentus is an oligotrophic bacterium that lives in dilute organic environments such as soil and freshwater. This bacterium represents an interesting model for cellular differentiation and regulation because daughter cells after division have different forms: one is motile while the other is non motile and can adhere to surfaces. Interestingly, the known genome of C. crescentus does not contain genes predicted to code for outer membrane porins of the OmpF/C general diffusion type present in enteric bacteria or those coding for specific porins selective for classes of substrates. Instead, genes coding for 67 TonB-dependent outer membrane receptors have been identified, suggesting that active transport of specific nutrients may be the norm. Here, we report that high channel-forming activity was observed with crude outer membrane extracts of C. crescentus in lipid bilayer experiments, indicating that the outer membrane of C. crescentus contained an ion-permeable channel with a single-channel conductance of about 120 pS in 1M KCl. The channel-forming protein with an apparent molecular mass of about 20 kDa was purified to homogeneity. Partial protein sequencing of the protein indicated it was a member of the OmpW family of outer membrane proteins from Gram-negative bacteria. This channel was not observed in reconstitution experiments with crude outer membrane extracts of an OmpW deficient C. crescentus mutant. Biophysical analysis of the C. crescentus OmpW suggested that it has features that are special for general diffusion porins of Gram-negative outer membranes because it was not a wide aqueous channel. Furthermore, OmpW of C. crescentus seems to be different to known OmpW porins and has a preference for ions, in particular cations. A putative model for OmpW of C. crescentus was built on the basis of the known 3D-structures of OmpW of Escherichia coli and OprG of Pseudomonas aeruginosa using homology modeling. A comparison of the two known structures with the model of OmpW of C. crescentus suggested that it has a more hydrophilic interior and possibly a larger diameter. PMID- 26606673 TI - The contribution of mass spectrometry-based proteomics to understanding epigenetics. AB - Chromatin is a macromolecular complex composed of DNA and histones that regulate gene expression and nuclear architecture. The concerted action of DNA methylation, histone post-translational modifications and chromatin-associated proteins control the epigenetic regulation of the genome, ultimately determining cell fate and the transcriptional outputs of differentiated cells. Deregulation of this complex machinery leads to disease states, and exploiting epigenetic drugs is becoming increasingly attractive for therapeutic intervention. Mass spectrometry (MS)-based proteomics emerged as a powerful tool complementary to genomic approaches for epigenetic research, allowing the unbiased and comprehensive analysis of histone post-translational modifications and the characterization of chromatin constituents and chromatin-associated proteins. Furthermore, MS holds great promise for epigenetic biomarker discovery and represents a useful tool for deconvolution of epigenetic drug targets. Here, we will provide an overview of the applications of MS-based proteomics in various areas of chromatin biology. PMID- 26606674 TI - Characterisation of the Candida albicans Phosphopantetheinyl Transferase Ppt2 as a Potential Antifungal Drug Target. AB - Antifungal drugs acting via new mechanisms of action are urgently needed to combat the increasing numbers of severe fungal infections caused by pathogens such as Candida albicans. The phosphopantetheinyl transferase of Aspergillus fumigatus, encoded by the essential gene pptB, has previously been identified as a potential antifungal target. This study investigated the function of its orthologue in C. albicans, PPT2/C1_09480W by placing one allele under the control of the regulatable MET3 promoter, and deleting the remaining allele. The phenotypes of this conditional null mutant showed that, as in A. fumigatus, the gene PPT2 is essential for growth in C. albicans, thus fulfilling one aspect of an efficient antifungal target. The catalytic activity of Ppt2 as a phosphopantetheinyl transferase and the acyl carrier protein Acp1 as a substrate were demonstrated in a fluorescence transfer assay, using recombinant Ppt2 and Acp1 produced and purified from E.coli. A fluorescence polarisation assay amenable to high-throughput screening was also developed. Therefore we have identified Ppt2 as a broad-spectrum novel antifungal target and developed tools to identify inhibitors as potentially new antifungal compounds. PMID- 26606675 TI - Analysis of Morbidity and Mortality Outcomes in Postoperative Clostridium difficile Infection in the Veterans Health Administration. AB - IMPORTANCE: This study analyzes and reports Clostridium difficile infection (CDI) rates, risk factors, and associations with postoperative outcomes in the Veterans Health Administration (VHA). OBJECTIVE: To report 30-day postoperative CDI rates and outcomes and identify associated risks by surgical procedures and preoperative patient demographics in a large integrated health care system. DESIGN, SETTING, AND PARTICIPANTS: In a retrospective observational study conducted from September 2014 to April 2015, the Veterans Affairs Surgical Quality Improvement Program database and the Decision Support System pharmacy database were linked to analyze the association of postoperative CDI with patients' demographics, preoperative comorbidities, operative characteristics, and preoperative medications. The Veterans Affairs Surgical Quality Improvement Program assessments from October 1, 2009, to September 30, 2013, were investigated. The study was conducted at 134 VHA surgery programs, and the study population represents 12 surgical specialties: general, gynecological, neurosurgical, oral, orthopedics, otolaryngologic, plastic, podiatric, thoracic, transplant, urologic, and peripheral vascular. MAIN OUTCOMES AND MEASURES: Thirty day postoperative CDI rates, risk factors of CDI, and association of CDI with postoperative morbidity and mortality. RESULTS: Among 468,386 surgical procedures, the postoperative CDI rate was 0.4% per year and varied by the VHA Surgery Program (0.0% to 1.4%) and surgical specialty (0.0% to 2.4%). Thirty-day CDI rates were higher in emergency procedures, procedures with greater complexity and higher relative value units, and those with a contaminated/infected wound classification. Patients with postoperative CDI were significantly older, more frequently hospitalized after surgery (59.9% vs 15.4%), had longer preoperative hospital stays (9.1 days vs 1.9 days), and had received 3 or more classes of antibiotics (1.5% vs 0.3% for a single antibiotic class) (all P < .001). Patients with CDI had higher rates of other postoperative morbidity (86.0% vs 7.1%), 30 day mortality (5.3% vs 1.0%), and longer postoperative hospital stays (17.9 days vs 3.6 days). Independent risk factors for CDI included commonly identified patient factors (albumin, functional class, and weight loss), procedural characteristics (complexity, relative value units, emergency, and wound classification), surgical program complexity, the number of preoperative antibiotic classes, and length of preoperative hospital stay. CONCLUSIONS AND RELEVANCE: The number and class of antibiotics administered after surgery, preoperative length of stay, procedural characteristics, surgical program complexity, and patient comorbidities are associated with postoperative CDI in the VHA. PMID- 26606676 TI - Amelioration of Hyperglycemia with a Sodium-Glucose Cotransporter 2 Inhibitor Prevents Macrophage-Driven Atherosclerosis through Macrophage Foam Cell Formation Suppression in Type 1 and Type 2 Diabetic Mice. AB - Direct associations between hyperglycemia and atherosclerosis remain unclear. We investigated the association between the amelioration of glycemia by sodium glucose cotransporter 2 inhibitors (SGLT2is) and macrophage-driven atherosclerosis in diabetic mice. We administered dapagliflozin or ipragliflozin (1.0 mg/kg/day) for 4-weeks to apolipoprotein E-null (Apoe-/-) mice, streptozotocin-induced diabetic Apoe-/- mice, and diabetic db/db mice. We then determined aortic atherosclerosis, oxidized low-density lipoprotein (LDL)-induced foam cell formation, and related gene expression in exudate peritoneal macrophages. Dapagliflozin substantially decreased glycated hemoglobin (HbA1c) and glucose tolerance without affecting body weight, blood pressure, plasma insulin, and lipids in diabetic Apoe-/- mice. Aortic atherosclerotic lesions, atheromatous plaque size, and macrophage infiltration in the aortic root increased in diabetic Apoe-/- mice; dapagliflozin attenuated these changes by 33%, 27%, and 20%, respectively. Atherosclerotic lesions or foam cell formation highly correlated with HbA1c. Dapagliflozin did not affect atherosclerosis or plasma parameters in non-diabetic Apoe-/- mice. In db/db mice, foam cell formation increased by 4-fold compared with C57/BL6 mice, whereas ipragliflozin decreased it by 31%. Foam cell formation exhibited a strong correlation with HbA1c. Gene expression of lectin-like ox-LDL receptor-1 and acyl-coenzyme A:cholesterol acyltransferase 1 was upregulated, whereas that of ATP-binding cassette transporter A1 was downregulated in the peritoneal macrophages of both types of diabetic mice. SGLT2i normalized these gene expressions. Our study is the first to demonstrate that SGLT2i exerts anti-atherogenic effects by pure glucose lowering independent of insulin action in diabetic mice through suppressing macrophage foam cell formation, suggesting that foam cell formation is highly sensitive to glycemia ex vivo. PMID- 26606678 TI - Momentary Desire for Sexual Intercourse and Momentary Emotional Intimacy Associated With Perceived Relationship Quality and Physical Intimacy in Heterosexual Emerging Adult Couples. AB - Sexual desire and emotional intimacy are central to relationships, yet little is known about how these feelings vary within and between partners or relate to dyad functioning. We explored magnitude and stability of momentary sexual desire and emotional intimacy in relation to quality and functioning of heterosexual relationships. After reporting perceived relationship quality and physical intimacy enjoyment, members of 18 emerging adult heterosexual couples reported momentary partner-specific sexual desire and emotional intimacy several times a day for two weeks (2,224 reports). Mean and mean squared successive difference (MSSD) characterized magnitude and stability, respectively, of the momentary states. Regression models of relationship outcomes examined influence of the male versus female partner having greater or more stable desire and intimacy. Sexual desire and emotional intimacy magnitude and stability were associated with relationship quality and physical intimacy enjoyment differently for men versus women. Gender-specific differences between partners also predicted relationship outcomes. Men particularly perceived higher relationship quality and enjoyed physical intimacy more when they had higher and more stable sexual desire and their female partners had more stable emotional intimacy. Partner differences in momentary sexual desire and emotional intimacy may contribute to understanding quality and functioning of heterosexual relationships. PMID- 26606677 TI - Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK Dependent Manner in Chronic Lymphocytic Leukemia B-Cells. AB - CDK (cyclin-dependent kinase) inhibitors have shown remarkable activity in CLL, where its efficacy has been linked to inhibition of the transcriptional CDKs (7 and 9) and deregulation of RNA polymerase and short-lived pro-survival proteins such as MCL1. Furthermore, ER (endoplasmic reticulum) stress has been implicated in CDK inhibition in CLL. Here we conducted a pre-clinical study of a novel orally active kinase inhibitor P1446A in CLL B-cells. P1446A inhibited CDKs at nanomolar concentrations and induced rapid apoptosis of CLL cells in vitro, irrespective of chromosomal abnormalities or IGHV mutational status. Apoptosis preceded inactivation of RNA polymerase, and was accompanied by phosphorylation of stress kinases JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase). Pharmacologic inhibitors of JNK/p38 MAPK conferred protection from P1446A-mediated apoptosis. Treatment with P1446A led to a dramatic induction of NOXA in a JNK-dependent manner, and sensitized CLL cells to ABT-737, a BH3 mimetic. We observed concurrent activation of apoptosis stress-inducing kinase 1 (ASK1) and its interaction with inositol-requiring enzyme 1 (IRE1) and tumor necrosis factor receptor-associated factor 2 (TRAF2) in CLL cells treated with P1446A, providing insights into upstream regulation of JNK in this setting. Consistent with previous reports on limited functionality of ER stress mechanism in CLL cells, treatment with P1446A failed to induce an extensive unfolded protein response. This study provides rationale for additional investigations of P1446A in CLL. PMID- 26606679 TI - Exposure to Polybrominated Diphenyl Ethers (PBDEs) and Hypothyroidism in Canadian Women. AB - CONTEXT: Polybrominated diphenyl ethers (PBDEs) are used as flame retardants in a wide range of products, resulting in widespread human exposure. Epidemiological studies in some populations reported exposure to PBDEs and thyroid hormone levels but little epidemiological data are available among women from the general population. OBJECTIVE: The objective of the study was to examine the association of PBDEs with hypothyroidism. DESIGN AND SETTING: This was a cross-sectional analysis of the 2007-2009 Canadian Health Measures Survey. PARTICIPANTS: A total of 745 women representative of Canadian women aged 30-79 years participated in the study. Main Outcome and Methods: We estimated the prevalence ratios (PRs) for hypothyroidism in relation to plasma concentrations of BDE-47, -99, -100, and 153 and their sum (SigmaPBDEs). Women were identified as cases if they reported a doctor-diagnosed thyroid condition and underwent thyroid hormone replacement therapy (n = 90). RESULTS: Higher plasma levels of brominated diphenyl ether (BDE)-47 and -100 and SigmaPBDEs were associated with an increased prevalence of hypothyroidism. The PR for a 10-fold increase in SigmaPBDEs was 1.7 (95% confidence interval [CI] 1.0, 3.0). Associations were consistently higher among women aged 30-50 years than among those 51-79 years for SigmaPBDEs and the other PBDE congeners, although the interaction was significant only for BDE-100. For instance, in the younger age group, women with detectable levels of BDE-100 had a PR of 3.8 (95% CI 1.2, 12.3) compared with women with undetectable levels; the corresponding PR in the older age group was 1.2 (95% CI 0.6, 2.3). No association was observed for BDE-99 and -153. CONCLUSION: Plasma PBDE levels were associated with an increased prevalence of hypothyroidism in Canadian women aged 30-50 years. Although the cross-sectional design of the study limits inferences of causality, these findings have important implications, given the key role of thyroid hormones in several biological mechanisms during reproductive age. PMID- 26606680 TI - Clinical and Steroidogenic Characteristics of Aldosterone-Producing Adenomas With ATPase or CACNA1D Gene Mutations. AB - OBJECT: This comparative study clarified the clinical characteristics and in vitro steroidogenic activities of aldosterone-producing adenomas (APAs) harboring ATPase or CACNA1D gene mutations. DESIGN AND PATIENTS: Genetic testing was performed on 159 unilateral APAs. Somatic ATPase and CACNA1D gene mutations were analyzed in 42 APA tissues without KCNJ5 gene mutations. RESULTS: ATP1A1, ATP2B3, and CACNA1D mutations were detected in one, four, and four patients, respectively. Compared with patients without KCNJ5, ATPase, or CACNA1D mutations (wild type), ATPase mutations tended to have more severe hyperaldosteronism and smaller tumors; those with CACNA1D mutations had clinical characteristics and tumor sizes similar to those with wild-type genes. APAs with ATPase mutations were composed mainly of compact eosinophilic tumor cells, whereas CACNA1D mutations resulted in predominantly clear tumor cells. Aldosterone production in APA cells with ATP2B3 mutations were more responsive to dibutyryl cAMP, whereas those with CACNA1D mutations were more responsive to adrenocorticotropic hormone than the wild-type cells. CONCLUSION: APAs with ATPase mutations demonstrated a potentially severe primary aldosteronism phenotype, whereas those with CACNA1D mutations displayed characteristics similar to wild-type APAs. The status of stimulated aldosterone production was also different according to the cell types, suggesting that the regulatory effects of adrenocorticotropic hormone on aldosterone synthesis could possibly vary according to the intracellular signaling involved in hormone production. PMID- 26606683 TI - Can slight glucose intolerance during pregnancy predict future maternal atherosclerotic morbidity? AB - AIM: o examine the association between glucose level during pregnancy and the subsequent development of long-term maternal atherosclerotic morbidity. METHODS: A retrospective case-control study was conducted. The study included all women who had at least one glucose measurement during their pregnancies. Cases were all women who delivered between the years 2000-2012 and subsequently developed atherosclerotic morbidity (n = 815). Controls were randomly matched by age and year of delivery (n = 6065). The atherosclerotic morbidity group was further divided by severity: major events (cardiovascular, cerebrovascular disease, chronic renal failure), minor events (hypertension, diabetes mellitus and hyperlipidaemia without target organ damage or complications) and cardiac evaluation tests (such as coronary angiography without records of atherosclerosis, cardiac scan and stress test). The mean follow-up duration for the study group was 74 months. Cox proportional hazards model was used to control for confounders. RESULTS: A significant linear association was found between glucose levels during pregnancy and long-term maternal atherosclerotic morbidity. Among the cases with severe atherosclerotic morbidity, the proportion of women with a high glucose level (> 5.5 mmol/l) was the highest, whereas in controls it was the lowest (P < 0.001). In a Cox proportional hazard model, adjusted for atherosclerotic confounders such as gestational diabetes, pre-eclampsia and obesity, a glucose level of > 5.5 mmol/l was noted as an independent risk factor for hospitalizations later in non-pregnant life (hazard ratio = 1.3, 95% confidence interval 1.1-1.5, P < 0.003). CONCLUSION: A high glucose level during pregnancy, even if within the range of slight glucose intolerance, may serve as a marker for future maternal atherosclerotic morbidity. Further long-term studies are needed to confirm our findings. PMID- 26606681 TI - Physique and Performance of Young Wheelchair Basketball Players in Relation with Classification. AB - The relationships among physical characteristics, performance, and functional ability classification of younger wheelchair basketball players have been barely investigated to date. The purpose of this work was to assess anthropometry, body composition, and performance in sport-specific field tests in a national sample of Italian younger wheelchair basketball players as well as to evaluate the association of these variables with the players' functional ability classification and game-related statistics. Several anthropometric measurements were obtained for 52 out of 91 eligible players nationwide. Performance was assessed in seven sport-specific field tests (5m sprint, 20m sprint with ball, suicide, maximal pass, pass for accuracy, spot shot and lay-ups) and game-related statistics (free-throw points scored per match, two- and three-point field-goals scored per match, and their sum). Association between variables, and predictivity was assessed by correlation and regression analysis, respectively. Players were grouped into four Classes of increasing functional ability (A-D). One-way ANOVA with Bonferroni's correction for multiple comparisons was used to assess differences between Classes. Sitting height and functional ability Class especially correlated with performance outcomes, but wheelchair basketball experience and skinfolds did not. Game-related statistics and sport-specific field-test scores all showed significant correlation with each other. Upper arm circumference and/or maximal pass and lay-ups test scores were able to explain 42 to 59% of variance in game-related statistics (P<0.001). A clear difference in performance was only found for functional ability Class A and D. CONCLUSION: In younger wheelchair basketball players, sitting height positively contributes to performance. The maximal pass and lay-ups test should be carefully considered in younger wheelchair basketball training plans. Functional ability Class reflects to a limited extent the actual differences in performance. PMID- 26606682 TI - A Versatile Strategy for Production of Membrane Proteins with Diverse Topologies: Application to Investigation of Bacterial Homologues of Human Divalent Metal Ion and Nucleoside Transporters. AB - Membrane proteins play key roles in many biological processes, from acquisition of nutrients to neurotransmission, and are targets for more than 50% of current therapeutic drugs. However, their investigation is hampered by difficulties in their production and purification on a scale suitable for structural studies. In particular, the nature and location of affinity tags introduced for the purification of recombinant membrane proteins can greatly influence their expression levels by affecting their membrane insertion. The extent of such effects typically depends on the transmembrane topologies of the proteins, which for proteins of unknown structure are usually uncertain. For example, attachment of oligohistidine tags to the periplasmic termini of membrane proteins often interferes with folding and drastically impairs expression in Escherichia coli. To circumvent this problem we have employed a novel strategy to enable the rapid production of constructs bearing a range of different affinity tags compatible with either cytoplasmic or periplasmic attachment. Tags include conventional oligohistidine tags compatible with cytoplasmic attachment and, for attachment to proteins with a periplasmic terminus, either tandem Strep-tag II sequences or oligohistidine tags fused to maltose binding protein and a signal sequence. Inclusion of cleavage sites for TEV or HRV-3C protease enables tag removal prior to crystallisation trials or a second step of purification. Together with the use of bioinformatic approaches to identify members of membrane protein families with topologies favourable to cytoplasmic tagging, this has enabled us to express and purify multiple bacterial membrane transporters. To illustrate this strategy, we describe here its use to purify bacterial homologues of human membrane proteins from the Nramp and ZIP families of divalent metal cation transporters and from the concentrative nucleoside transporter family. The proteins are expressed in E. coli in a correctly folded, functional state and can be purified in amounts suitable for structural investigations. PMID- 26606684 TI - Adverse Effects of Wheat Gluten. AB - Man began to consume cereals approximately 10,000 years ago when hunter-gatherers settled in the fertile golden crescent in the Middle East. Gluten has been an integral part of the Western type of diet ever since, and wheat consumption is also common in the Middle East, parts of India and China as well as Australia and Africa. In fact, the food supply in the world heavily depends on the availability of cereal-based food products, with wheat being one of the largest crops in the world. Part of this is due to the unique properties of wheat gluten, which has a high nutritional value and is crucial for the preparation of high-quality dough. In the last 10 years, however, wheat and gluten have received much negative attention. Many believe that it is inherently bad for our health and try to avoid consumption of gluten-containing cereals; a gluten-low lifestyle so to speak. This is fueled by a series of popular publications like Wheat Belly; Lose the Wheat, Lose the Weight, and Find Your Path Back to Health. However, in reality, there is only one condition where gluten is definitively the culprit: celiac disease (CD), affecting approximately 1% of the population in the Western world. Here, I describe the complexity of the cereals from which gluten is derived, the special properties of gluten which make it so widely used in the food industry, the basis for its toxicity in CD patients and the potential for the development of safe gluten and alternatives to the gluten-free diet. PMID- 26606686 TI - In response to "Obstructive sleep apnea and adverse outcomes in surgical and nonsurgical patients on the wards". PMID- 26606685 TI - Differentiation of Human Protein-Induced Pluripotent Stem Cells toward a Retinal Pigment Epithelial Cell Fate. AB - Compared with many induced pluripotent stem cell (iPSC) lines generated using retrovirus and other non-integrating methods, the utilization of human protein induced iPSC (piPSC) lines may provide a safer alternative for the generation of retinal pigment epithelial (RPE) cells for transplantation in retinal degenerative diseases. Here we assess the ability of piPSCs to differentiate into RPE cells, and to perform native RPE cell behavior. piPSCs were seeded in 6-well low-attachment plates to allow embryoid body formation, and then analyzed for pluripotent stem cell markers NANOG, SSEA4 and TRA-1-60 by immunofluorescence. Following colony formation, piPSCs were assessed for confirmation of RPE cell differentiation by staining for zonula occludens (ZO-1), bestrophin, microphthalmia-associated transcription factor (MITF) and retinal pigment epithelium specific protein-65 (RPE65). To evaluate piPSC-RPE cell phagocytic ability, adult bovine photoreceptor rod outer segments (ROS) were fed to piPSC RPE cells, which were analyzed by fluorescent microscopy and flow cytometry. Undifferentiated piPSCs expressed all pluripotent markers assessed and formed embryoid body aggregates after 7 days. Differentiated piPSC-RPE cells expressed ZO-1, bestrophin, MITF and RPE65, typical RPE cell markers. Flow cytometry revealed robust ingestion of fluorescently-labeled ROS by piPSC-RPE cells, which was over four-times greater than that of undifferentiated piPSCs and comparable to that of an immortalized RPE cell line. Phagocytosis activity by piPSC-RPE cells was significantly reduced after the addition of anti-integrin alphaVbeta5. In conclusion, piPSCs can be differentiated toward an RPE cell fate, expressing RPE cell markers and resembling native RPE cells in behavior. These results demonstrate that piPSCs can be differentiated into RPE-like cells using a method that has an increased safety profile, a critical consideration for the development of better treatments for retinal degenerative diseases such as age related macular degeneration (AMD). PMID- 26606687 TI - Anti-infective assessment of Senecio smithioides (Asteraceae) and isolation of 9 oxoeuryopsin, a furanoeremophilane-type sesquiterpene with antiplasmodial activity. AB - The search for anti-infective activity in the antipyretic plant Senecio smithioides was conducted. Petroleum ether (PE), dichloromethane (CH2Cl2), ethyl acetate (EtOAc) and hydroethanolic (96% EtOH) extracts, and compounds 9 oxoeuryopsin (1), epoxydecompostin (2) and senecionine (3) were obtained from the aerial parts. All extracts and 1 were tested against chloroquine-resistant strain of Plasmodium falciparum (ref. chloroquine), Trypanosoma cruzi (ref. nifurtimox), Leishmania braziliensis, Leishmania amazonensis and Leishmania donovani (ref. pentamidine), Staphylococcus aureus and Escherichia coli (ref. gentamicin) and, Neurospora crassa and Candida albicans (ref. ketoconazole). The PE extract exhibited the strongest in vitro activity against Plasmodium falciparum IC50 < 1.0 MUg/mL. 1 was established as a potent antiplasmodial compound with an IC50 = 1.2 MUg/mL, 5.2 MUM. Other antiparasitic activities were recorded for all extracts and 1. Antibacterial and antifungal activity was negligible. PMID- 26606689 TI - Linoleic acid salt with ultrapure soft water as an antibacterial combination against dermato-pathogenic Staphylococcus spp. AB - AIMS: Skin colonization of Staphylococcus spp. critically affects the severity of dermatitis in humans and animals. We examined different types of fatty acid salts for their antibacterial activity against Staphylococcus spp. when used in ultrapure soft water (UPSW). We also evaluated their therapeutic effect on a spontaneous canine model of dermatitis. METHODS AND RESULTS: UPSW, in which Ca(++) and Mg(++) were replaced with Na(+) , was generated using a water softener with cation-exchange resin. Staphylococcus aureus (Staph. aureus), Staphylococcus intermedius (Staph. intermedius), and Staphylococcus pseudintermedius (Staph. pseudintermedius) were incubated with various fatty acid salts in distilled water (DW) or UPSW and the number of bacteria was counted. Among the fatty acids, oleic acid salt and linoleic acid (LA) salt reduced the number of these bacteria. Also, UPSW enhanced the antibacterial effect of LA on Staph. spp. In spontaneously developed itchy dermatitis in companion dogs, shampoo treatment with liquid soap containing 10% LA in UPSW improved skin conditions. CONCLUSIONS: LA salt showed antibacterial activity against Staph. spp. Treatment with soap containing LA with UPSW reduced clinical conditions in dogs with dermatitis. SIGNIFICANCE AND IMPACT OF THE STUDY: Because colonization of Staph. spp. on the skin exacerbates dermatitis, the use of LA-containing soap in UPSW may reduce unpleasant clinical symptoms of the skin. PMID- 26606690 TI - Uniportal VATS lobectomy. AB - Uniportal Video-Assisted Thoracic Surgery (uniportal VATS) lobectomy represents the last evolution of minimally invasive techniques for the surgical treatment of lung cancer. Uniportal VATS was developed from two-ports approach, with two main advantages: only one intercostal space is damaged and the direct view to the target tissue. Improvements in camera systems, instruments and stapler technology have facilitated this development. The operative technique is well defined for the different lobectomies and for the mediastinal lymphadenectomy. The parallel instrumentation achieved during the single port approach mimics the inside maneuvers performed during open surgery, together with the direct view facilitates the dissection and division of the hilar structures and the fissure. This makes possible the direct transition from open surgery to uniportal VATS. Uniportal VATS is feasible and reproducible. This is why its use is spreading in many centers in Spain, Europe and Asia, with good results. Training at centers with major experience or in wetlabs, and the proper patient selection are the best recommendations for the learning curve. In our center, as we gain experience with the approach, we performed advanced cases with similar results to the initial stages. Segmentectomies, bronchovascular reconstructions and selected cases that need chest wall resection were also carried out by uniportal VATS. The last advance is the uniportal VATS lobectomy in non-intubated patients with spontaneous breathing, the less invasive surgical approach in combination with a less invasive anesthetic management. PMID- 26606688 TI - Brucella discriminates between mouse dendritic cell subsets upon in vitro infection. AB - Brucella is a Gram-negative bacterium responsible for brucellosis, a worldwide re emerging zoonosis. Brucella has been shown to infect and replicate within Granulocyte macrophage colony-stimulating factor (GMCSF) in vitro grown bone marrow-derived dendritic cells (BMDC). In this cell model, Brucella can efficiently control BMDC maturation. However, it has been shown that Brucella infection in vivo induces spleen dendritic cells (DC) migration and maturation. As DCs form a complex network composed by several subpopulations, differences observed may be due to different interactions between Brucella and DC subsets. Here, we compare Brucella interaction with several in vitro BMDC models. The present study shows that Brucella is capable of replicating in all the BMDC models tested with a high infection rate at early time points in GMCSF-IL15 DCs and Flt3l DCs. GMCSF-IL15 DCs and Flt3l DCs are more activated than the other studied DC models and consequently intracellular bacteria are not efficiently targeted to the ER replicative niche. Interestingly, GMCSF-DC and GMCSF-Flt3l DC response to infection is comparable. However, the key difference between these 2 models concerns IL10 secretion by GMCSF DCs observed at 48 h post-infection. IL10 secretion can explain the weak secretion of IL12p70 and TNFalpha in the GMCSF-DC model and the low level of maturation observed when compared to GMCSF-IL15 DCs and Flt3l DCs. These models provide good tools to understand how Brucella induce DC maturation in vivo and may lead to new therapeutic design using DCs as cellular vaccines capable of enhancing immune response against pathogens. PMID- 26606691 TI - Extended video-assisted thoracic surgery (VATS) lobectomy. AB - VATS lobectomy was first performed more than twenty years ago. Early experience with the procedure led to the enumeration of contraindications, many of which have been circumvented by increasing familiarity with the approach and equipment changes. These previous contraindications to VATS lobectomy (pleural symphasis, chest wall involvement, sleeve resections, etc.) we define as extended lobectomy. This article reviews the literature and discusses some technical points to facilitate the completion of these operations. PMID- 26606695 TI - Para-Selective Halogenation of Nitrosoarenes with Copper(II) Halides. AB - The para-selective direct bromination and chlorination of nitrosoarenes with copper(II) bromide and chloride is reported. Under mild reaction conditions, a range of halogenated arylnitroso compounds are obtained in moderate to good yields with high regioselectivity. Additionally, the versatility of the method is demonstrated by the development of a one-pot procedure to obtain the corresponding para-halogenated aniline- and nitrobenzene derivatives. PMID- 26606693 TI - Pulmonary Artery Abnormalities in Ex-smokers with and without Airflow Obstruction. AB - Pulmonary vascular disease is a common complication of chronic obstructive pulmonary disease (COPD), and an important risk factor for COPD exacerbations and death. We explored the relationship between pulmonary artery volumes measured using thoracic computed tomography (CT) and lung structure-function measured using spirometry, CT and magnetic resonance imaging (MRI) in 124 ex-smokers with (n = 68) and without (n = 56) airflow obstruction, and a control group of 35 never-smokers. We observed significantly greater main (p = .01), right (p = .001) and total (p = .003) pulmonary artery volumes in ex-smokers with airflow obstruction as compared to ex-smokers without airflow obstruction. There were also significantly greater pulmonary artery volumes in both ex-smoker subgroups, compared to the never-smoker subgroup (p = .008). For all participants, there were significant correlations for pulmonary artery volumes with the ratio of the forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC), the diffusing capacity of the lung for carbon monoxide (DLCO%pred), airway count, MRI ventilation defect percent and MRI apparent diffusion coefficients. In ex smokers, ventilation defect percent was significantly correlated with right (r = 0.27, p = .02) and total (r = 0.25, p = .03) pulmonary artery volumes. Multivariate zero-inflated Poisson regression analysis showed that FEV1%pred (p = .004), DLCO%pred (p = .03), the six minute walk distance (p = .04) and total pulmonary artery volume (p = .03) were significant predictors of acute exacerbations of COPD, while the number of previous exacerbations was not. In conclusion, pulmonary artery enlargement measured using thoracic CT was observed even in ex-smokers without airflow obstruction and was predictive of COPD exacerbations in ex-smokers with airflow obstruction. PMID- 26606692 TI - Quantitative analysis of tibial subchondral bone: Texture analysis outperforms conventional trabecular microarchitecture analysis. AB - BACKGROUND: The aim of this study was to compare two different methods of quantitative assessment of tibial subchondral bone in osteoarthritis (OA): statistical texture analysis (sTA) and trabecular microarchitecture analysis (tMA). METHODS: Asymptomatic controls aged 20-30 (n = 10), patients aged 40-50 with chronic knee pain but without established OA (n = 10) and patients aged 55 85 with advanced OA scheduled for knee replacement (n = 10) underwent knee MR imaging at 3 Tesla with a three-dimensional gradient echo sequence to allow sTA and tMA. tMA and sTA features were calculated using region of interest creation in the medial (MT) and lateral (LT) tibial subchondral bone. Features were compared between groups using one-way analysis of variance. The two most discriminating tMA and sTA features were used to construct exploratory discriminant functions to assess the ability of the two methods to classify participants. RESULTS: No tMA features were significantly different between groups at either MT or LT. 17/20 and 11/20 sTA features were significantly different between groups at the MT/LT, respectively (P < 0.001). Discriminant functions created using tMA features classified 12/30 participants correctly (40% accuracy; 95% confidence interval [CI], 22-58%) based on MT data and 9/30 correctly (30%,; 95% CI, 14-46) based on LT data. Discriminant functions using sTA features classified 16/30 participants correctly (53%; 95% CI, 35-71) based on MT data and 14/30 correctly (47%; 95% CI, 29-65) based on LT data. CONCLUSION: sTA features showed more significant differences between the three study groups and improved classification accuracy compared with tMA features. PMID- 26606696 TI - An Unusual Complication of a Gellhorn Pessary. PMID- 26606697 TI - JOGC and FIGO 2015. PMID- 26606698 TI - Maternity Care in Russia: Issues, Achievements, and Potential. AB - In this review, we provide basic facts about maternity care services within the health care system in Russia. We give a short overview of such key aspects as the demographic situation, reproductive behaviour, regulatory framework for providing health care for women and children, maternal and perinatal mortality, and the availability of medical personnel. In 2012, Russia began registration of births in accordance with the WHO recommendations (births with weight >= 500 g at >= 22 weeks' gestation). Introduction of this new registration system increased the completeness and quality of the collected information and expanded possibilities for future international comparative assessments. A three-level system of specialized medical care has been introduced in Russia for women and newborns during pregnancy, childbirth, and the postpartum period. In 2014, the system included 1942 state (public) maternity hospitals providing 20 obstetric beds per 10 000 women aged 15 to 49 years. More than 100 perinatal centres (level III) are currently functioning in the country, with 32 new perinatal centres planned to open by 2016. The total number of obstetrician-gynaecologists in Russia is approximately 44 000, providing a ratio of 5.7 specialists per 10 000 women. The total number of midwives is 62 000, providing a ratio of 8.1 midwives per 10 000 women. In recent years we have succeeded in optimizing the maternity care system by increasing its accessibility and quality. This was achieved through qualitative and quantitative progress in the training of neonatologists, the development of intensive care technologies and neonatal critical care, capacity building of medical-genetic services and counselling, prenatal diagnosis, and the standardization of health care with data collection. PMID- 26606699 TI - Sexual and Reproductive Health at 2015 and Beyond: A Global Perspective. AB - The International Conference on Population and Development and Millennium Development Goals propelled reproductive health into priorities for international development through declarations, statements, and frameworks. However, key indicators demonstrate that progress in both service provision and clinical outcomes has not been optimal, especially for certain disadvantaged groups. With the Sustainable Development Goals, efforts over the next two decades will focus on access to and quality of health services. Advocacy for mobilizing resources will be complemented by accountability, especially monitoring and evaluation, for utilization of these resources during the life cycle. Stakeholders should emphasize national commitments, with broad partnerships, to ensure long-term sustainability. PMID- 26606700 TI - A New Approach to Teaching Obstetric Anaesthesia in Low-Resource Areas. AB - Maternal mortality is high in many low- and middle-income countries. Unsafe anaesthesia contributes to this, especially for women requiring Caesarean section. Anaesthesia providers with limited skills and poor resources are often faced with complicated obstetric patients. A new course called SAFE-OB teaches a systematic approach to anticipating, preparing for, and dealing with obstetric anaesthetic emergencies. The course has now been taught in many African, Asian, and Latin countries. Initial follow-up suggests improvement in skills and knowledge, and effective translation of these to the workplace. Efforts are made to make the course locally owned and sustainable. We feel that SAFE-OB is an effective method of improving obstetric anaesthesia care. PMID- 26606701 TI - Developing a Global Maternal Nutrition Guideline. PMID- 26606702 TI - Preeclampsia: Reflections on How to Counsel About Preventing Recurrence. AB - Preeclampsia is one of the most challenging diseases of pregnancy, with unclear etiology, no specific marker for prediction, and no precise treatment besides delivery of the placenta. Many risk factors have been identified, and diagnostic and management tools have improved in recent years. However, this disease remains one of the leading causes of maternal morbidity and mortality worldwide, especially in under-resourced settings. A history of previous preeclampsia is a known risk factor for a new event in a future pregnancy, with recurrence rates varying from less than 10% to 65%, depending on the population or methodology considered. A recent review that performed an individual participant data meta analysis on the recurrence of hypertensive disorders of pregnancy in over 99 000 women showed an overall recurrence rate of 20.7%; when specifically considering preeclampsia, it was 13.8%, with milder disease upon recurrence. Prevention of recurrent preeclampsia has been attempted by changes in lifestyle, dietary supplementation, antihypertensive drugs, antithrombotic agents, and others, with much uncertainty about benefit. It is always challenging to treat and counsel a woman with a previous history of preeclampsia; this review will be based on hypothetical clinical cases, using common scenarios in obstetrical practice to consider the available evidence on how to counsel each woman during pre conception and prenatal consultations. PMID- 26606703 TI - Women's Health and Surgical Care: Moving From Maternal Health to Comprehensive Surgical Systems. PMID- 26606704 TI - MicroResearch in East Africa: Opportunities for Addressing Gender Inequity. PMID- 26606705 TI - Traditional Rituals and Customs for Pregnant Women in Selected Villages in Southwest Uganda. PMID- 26606706 TI - Prevalence of Ethanol Use Among Pregnant Women in Southwestern Uganda. PMID- 26606707 TI - Knowledge, Attitudes, and Practices about Regular, Voluntary Non-remunerated Blood Donation in Peri-urban and Rural Communities in Mbarara District, South Western Uganda, and its Impact on Maternal Health. PMID- 26606708 TI - Transforming Maternal and Neonatal Outcomes in Tertiary Hospitals in Ghana: An Integrated Approach for Systems Change. AB - OBJECTIVE: In Ghana, regional referral facilities by design receive a disproportionate number of high-risk obstetric and neonatal cases and therefore have mortality rates higher than the national average. High volumes and case complexity result in these facilities experiencing unique clinical, operational, and leadership challenges. In order to improve outcomes in these settings, an integrated approach to strengthen the overall system is needed. METHODS: Clinical skills strengthening, quality improvement training, and leadership skill building have all been used to improve maternal and neonatal outcomes with some degree of success. We present here a customized model tailored to the particular context of tertiary referral hospitals that develops these three skills simultaneously, so that the complex interaction between clinical conditions, resource constraints, and organizational issues that affect the lives of mothers and babies can be considered together. This model uses local data to identify the drivers of poor maternal and neonatal outcomes and creates an integrated training package to focus on approaches to addressing these drivers. Based on this training, quality improvement projects are introduced to change the appropriate clinical or operational processes, or to strengthen organizational leadership. RESULTS: In testing in one of the largest referral hospitals in Ghana, the model has been well received and has improved performance in several cross-cutting areas affecting the quality of maternal and neonatal care, such as triage, patient flow, and NICU hand hygiene. CONCLUSION: An integrated approach to systems strengthening in referral hospitals holds much promise for improving outcomes for mothers with high-risk pregnancies and babies in Ghana and in other low-resource settings. PMID- 26606709 TI - Maternal Death Surveillance and Response in East and Southern Africa. AB - Maternal death surveillance and response (MDSR) is one of several low cost, high impact strategies to reduce maternal mortality. This initiative is supported in eastern and southern Africa by the United Nations Population Fund (UNFPA) and other partners. Currently, South Africa is the leading country in the institutionalization of MDSR through the Confidential Enquiry into Maternal Deaths (CEMD). With the support of UNFPA and other partners, at least 15 countries in the region have introduced MDSR into maternal and newborn health care programs. The report from the knowledge-sharing meeting and the findings of the evaluation of the South African MDSR show that MDSR is still not at an optimal level in most countries in sub-Saharan Africa, despite the efforts of national authorities and support from a number of development partners. Additional work is required on the part of national authorities, communities, and development organizations, and the challenges being faced were highlighted at the knowledge-sharing meeting. PMID- 26606710 TI - Vaginal Birth After Caesarean Section in Low Resource Settings: The Clinical and Ethical Dilemma. AB - Vaginal birth after Caesarean section (VBAC) has long been practised in low resource settings using unconventional methods. This not only poses danger to the woman and her baby, but could also have serious legal and ethical implications. The adoption of this practice has been informed by observational studies with many deficiencies; this is so despite other studies from settings in which the standard of care is much better that show that elective repeat Caesarean section (ERCS) may actually be safer than VBAC. This raises questions about whether we should insist on a dangerous practice when there are safer alternatives. We highlight some of the challenges faced in making this decision, and discuss why the fear of ERCS may not be justified after all in low resource settings. Since a reduction in rates of Caesarean section may not be applicable in these regions, because their rates are already low, the emphasis should instead be on adequate birth spacing and safer primary operative delivery. PMID- 26606711 TI - Global Women's Health Education in Canadian Obstetrics and Gynaecology Residency Programs: A Survey of Program Directors and Senior Residents. AB - OBJECTIVE: To become culturally competent practitioners with the ability to care and advocate for vulnerable populations, residents must be educated in global health priorities. In the field of obstetrics and gynaecology, there is minimal information about global women's health (GWH) education and interest within residency programs. We wished to determine within obstetrics and gynaecology residency programs across Canada: (1) current GWH teaching and support, (2) the importance of GWH to residents and program directors, and (3) the level of interest in a national postgraduate GWH curriculum. METHODS: We conducted an online survey across Canada of obstetrics and gynaecology residency program directors and senior obstetrics and gynaecology residents. RESULTS: Of 297 residents, 101 (34.0%) responded to the survey and 76 (26%) completed the full survey. Eleven of 16 program directors (68.8%) responded and 10/16 (62.5%) provided complete responses. Four of 11 programs (36.4%) had a GWH curriculum, 2/11 (18.2%) had a GWH budget, and 4/11 (36.4%) had a GWH chairperson. Nine of 10 program directors (90%) and 68/79 residents (86.1%) felt that an understanding of GWH issues is important for all Canadian obstetrics and gynaecology trainees. Only 1/10 program directors (10%) and 11/79 residents (13.9%) felt that their program offered sufficient education in these issues. Of residents in programs with a GWH curriculum, 12/19 (63.2%) felt that residents in their program who did not undertake an international elective would still learn about GWH, versus only 9/50 residents (18.0%) in programs without a curriculum (P < 0.001). CONCLUSION: Obstetrics and gynaecology residents and program directors feel that GWH education is important for all trainees and is currently insufficient. There is a high level of interest in a national postgraduate GWH educational module. PMID- 26606713 TI - Using Health Extension Workers for Monitoring Child Mortality in Real-Time: Validation against Household Survey Data in Rural Ethiopia. AB - BACKGROUND: Ethiopia has scaled up its community-based programs over the past decade by training and deploying health extension workers (HEWs) in rural communities throughout the country. Consequently, child mortality has declined substantially, placing Ethiopia among the few countries that have achieved the United Nations' fourth Millennium Development Goal. As Ethiopia continues its efforts, results must be assessed regularly to provide timely feedback for improvement and to generate further support for programs. More specifically the expansion of HEWs at the community level provides a unique opportunity to build a system for real-time monitoring of births and deaths, linked to a civil registration and vital statistics system that Ethiopia is also developing. We tested the accuracy and completeness of births and deaths reported by trained HEWs for monitoring child mortality over 15 -month periods. METHODS AND FINDINGS: HEWs were trained in 93 randomly selected rural kebeles in Jimma and West Hararghe zones of the Oromia region to report births and deaths over a 15-month period from January, 2012 to March, 2013. Completeness of number of births and deaths, age distribution of deaths, and accuracy of resulting under-five, infant, and neonatal mortality rates were assessed against data from a large household survey with full birth history from women aged 15-49. Although, in general HEWs, were able to accurately report events that they identified, the completeness of number of births and deaths reported over twelve-month periods was very low and variable across the two zones. Compared to household survey estimates, HEWs reported only about 30% of births and 21% of under-five deaths occurring in their communities over a twelve-month period. The under-five mortality rate was under estimated by around 30%, infant mortality rate by 23% and neonatal mortality by 17%. HEWs reported disproportionately higher number of deaths among the very young infants than among the older children. CONCLUSION: Birth and death data reported by HEWs are not complete enough to support the monitoring of changes in childhood mortality. HEWs can significantly contribute to the success of a CRVS in Ethiopia, but cannot be relied upon as the sole source for identification of vital events. Further studies are needed to understand how to increase the level of completeness. PMID- 26606714 TI - Is retrieval the key? Metamemory judgment and testing as learning strategies. AB - Re-reading is the most common learning strategy, albeit not a very efficient one. Testing is highly efficient, but not perceived by students as a learning strategy. Prospective judgment-of-learning (JOL) reflect the learner's impression of subsequently being able to retrieve the ongoing learning in a cued-recall task. Estimating JOL involves attempting to retrieve the information, as in testing. The few studies that have explored the potential mnemonic benefit of JOL have yielded contradictory results. Our aim was to compare JOL and testing with re-study and to examine the impact of these strategies according to the relative difficulty of the material (cue-target association strength) in two experiments. After a first encoding phase, participants re-studied, provided JOL, or took a test. Forty-eight hours later, they participated in a final cued-recall test, during which their confidence level judgments were collected. The main result was that delayed JOL behaved in the same way as testing, and both yielded better performances than re-study when material was of moderate difficulty. The easy or very difficult material revealed no differences between these strategies. JOL is proposed as an alternative to testing when faced with difficult material. PMID- 26606712 TI - Canadian Contraception Consensus (Part 1 of 4). AB - OBJECTIVE: To provide guidelines for health care providers on the use of contraceptive methods to prevent pregnancy and on the promotion of healthy sexuality. OUTCOMES: Guidance for Canadian practitioners on overall effectiveness, mechanism of action, indications, contraindications, non contraceptive benefits, side effects and risks, and initiation of cited contraceptive methods; family planning in the context of sexual health and general well-being; contraceptive counselling methods; and access to, and availability of, cited contraceptive methods in Canada. EVIDENCE: Published literature was retrieved through searches of Medline and The Cochrane Database from January 1994 to January 2015 using appropriate controlled vocabulary (e.g., contraception, sexuality, sexual health) and key words (e.g., contraception, family planning, hormonal contraception, emergency contraception). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from January 1994 to January 2015. Searches were updated on a regular basis and incorporated in the guideline to June 2015. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The quality of the evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). Chapter 1: Contraception in Canada Summary Statements 1. Canadian women spend a significant portion of their lives at risk of an unintended pregnancy. (II-2) 2. Effective contraceptive methods are underutilized in Canada, particularly among vulnerable populations. (II-2) 3. Long-acting reversible contraceptive methods, including contraceptive implants and intrauterine contraception (copper-releasing and levonorgestrel-releasing devices/systems), are the most effective reversible contraceptive methods and have the highest continuation rates. (II-1) 4. Canada currently does not collect reliable data to determine the use of contraceptive methods, abortion rates, and the prevalence of unintended pregnancy among reproductive-age women. (II-2) 5. A universal subsidy for contraceptive methods as provided by many of Canada's peer nations and a few Canadian provinces may produce health system cost-savings. (II-2) 6. Health Canada approval processes for contraceptives have been less efficient than those of other drug approval agencies and Health Canada processes for other classes of pharmaceuticals. (II-2) 7. It is feasible and safe for contraceptives and family planning services to be provided by appropriately trained allied health professionals such as midwives, registered nurses, nurse practitioners, and pharmacists. (II-2) Recommendations 1. Contraceptive counselling should include a discussion of typical use failure rates and the importance of using the contraceptive method consistently and correctly in order to avoid pregnancy. (II 2A) 2. Women seeking contraception should be counselled on the wide range of effective methods of contraception available, including long-acting reversible contraceptive methods (LARCs). LARCs are the most effective methods of reversible contraception, have high continuation rates, and should be considered when presenting contraceptive options to any woman of reproductive age. (II-2A) 3. Family planning counselling should include counselling on the decline of fertility associated with increasing female age. (III-A) 4. Health policy supporting a universal contraception subsidy and strategies to promote the uptake of highly effective methods as cost-saving measures that improve health and health equity should be considered by Canadian health decision makers. (III-B) 5. Canadian health jurisdictions should consider expanding the scope of practice of other trained professionals such as nurses, nurse practitioners, midwives, and pharmacists and promoting task-sharing in family planning. (II-2B) 6. The Canadian Community Health Survey should include adequate reproductive health indicators in order for health care providers and policy makers to make appropriate decisions regarding reproductive health policies and services in Canada. (III-B) 7. Health Canada processes and policies should be reviewed to ensure a wide range of modern contraceptive methods are available to Canadian women. (III-B) Chapter 2: Contraceptive Care and Access Summary Statements 8. Although there are many contraceptive options in Canada, only a narrow range of contraceptive methods are commonly used by those of reproductive age. (II-3) 9. Condom use decreases with longer relationship tenure and when the sexual partner is considered to be the main partner, likely due to a lower perceived risk of sexually transmitted infection in that relationship. Condom use may also decrease markedly as an unintended consequence when an effective non-barrier method, such as hormonal contraception or intrauterine contraception, is initiated. (II-3) 10. Family planning counselling provides a natural segue into screening for concerns about sexual function or intimate partner violence. (III) 11. Well-informed and well-motivated individuals who have developed skills to practise safer sex behaviours are more likely to use contraceptive and safer sex methods effectively and consistently. (II-2) Recommendations 8. Comprehensive family planning services, including abortion services, should be accessible to all Canadians regardless of geographic location. These services should be confidential, non judgemental, and respectful of individuals' privacy and cultural contexts. (III A) 9. A contraceptive visit should include history taking, screening for contraindications, dispensing or prescribing a method of contraception, and exploring contraceptive choice and adherence in the broader context of the individual's sexual behaviour, reproductive health risk, social circumstances, and relevant belief systems. (III-B) 10. Health care providers should provide practical information on the wide range of contraceptive options and their potential non-contraceptive benefits and assist women and their partners in determining the best user-method fit. (III-B) 11. Health care providers should assist women and men in developing the skills necessary to negotiate the use of contraception and the correct and consistent use of a chosen method. (III-B) 12. Contraceptive care should include discussion and management of the risk of sexually transmitted infection, including appropriate recommendations for condom use and dual protection, STI screening, post-exposure prophylaxis, and Hepatitis B and human papillomavirus vaccination. (III-B) 13. Health care providers should emphasize the use of condoms not only for protection against sexually transmitted infection, but also as a back-up method when adherence to a hormonal contraceptive may be suboptimal. (I-A) 14. Health care providers should be aware of current media controversies in reproductive health and acquire relevant evidence-based information that can be briefly and directly communicated to their patients. (III-B) 15. Referral resources for intimate partner violence, sexually transmitted infections, sexual dysfunction, induced abortion services, and child protection services should be available to help clinicians provide contraceptive care in the broader context of women's health. (III-B) Chapter 3: Emergency Contraception Summary Statements 12. The copper intrauterine device is the most effective method of emergency contraception. (II-2) 13. A copper intrauterine device can be used for emergency contraception up to 7 days after unprotected intercourse provided that pregnancy has been ruled out and there are no other contraindications to its insertion. (II-2) 14. Levonorgestrel emergency contraception is effective up to 5 days (120 hours) after intercourse; its effectiveness decreases as the time between unprotected intercourse and ingestion increases. (II-2) 15. Ulipristal acetate for emergency contraception is more effective than levonorgestrel emergency contraception up to 5 days after unprotected intercourse. This difference in effectiveness is more pronounced as the time from unprotected intercourse increases, especially after 72 hours. (I) 16. Hormonal emergency contraception (levonorgestrel emergency contraception and ulipristal acetate for emergency contraception) is not effective if taken on the day of ovulation or after ovulation. (II-2) 17. Levonorgestrel emergency contraception may be less effective in women with a body mass index > 25 kg/m2 and ulipristal acetate for emergency contraception may be less effective in women with a body mass index > 35 kg/m2. However, hormonal emergency contraception may still retain some effectiveness regardless of a woman's body weight or body mass index. (II-2) 18. Hormonal emergency contraception is associated with higher failure rates when women continue to have subsequent unprotected intercourse. (II 2) 19. Hormonal contraception can be initiated the day of or the day following the use of levonorgestrel emergency contraception, with back-up contraception used for the first 7 days. (III) 20. Hormonal contraception can be initiated 5 days following the use of ulipristal acetate for emergency contraception, with back-up contraception used for the first 14 days. (III) Recommendations 16. All emergency contraception should be initiated as soon as possible after unprotected intercourse. (II-2A) 17. Women should be informed that the copper intrauterine device (IUD) is the most effective method of emergency contraception and can be used by any woman with no contraindications to IUD use. (II-3A) 18. PMID- 26606715 TI - Understanding Quality Measures in Otolaryngology-Head and Neck Surgery. AB - As health care reimbursements based on pay-for-performance models become more common, there is an unprecedented demand for ways to measure health care quality and demonstrate value. Performance measures, a type of quality measure, are unique tools in a health care delivery system that allow objective monitoring of adherence to specific goals and tracking of outcomes. We sought to provide information on the development of quality measures in otolaryngology-head and neck surgery, as well as the goals of performance measurement at a national level and for our specialty. The historical development, various types, and approach to creating effective performance measures are discussed. The primary methods of developing performance measures (using clinical practice guidelines, clinical registries, and alternative methods) are also discussed. Performance measures are an important tool that can aid otolaryngologists in achieving effective, efficient, equitable, timely, safe, and patient-centered care as outlined by the Institute of Medicine. PMID- 26606716 TI - An electrically controlled drug delivery system based on conducting poly(3,4 ethylenedioxypyrrole) matrix. AB - As numerous therapeutic agents are not well tolerated when administrated systemically, localized and controlled delivery can help to decrease their toxicity by applying an optimized drug concentration at extended exposure time. Among different types of drug delivery systems, conjugated polymers are considered as promising materials due to their biocompatibility, electrical conductivity and ability to undergo controllable redox reactions. In this work poly(3,4-ethylenedioxypyrrole), PEDOP, matrix is described for the first time as a reservoir of a model drug, ibuprofen (IBU). Drug immobilization process is performed in situ, during the electrochemical polymerization of 10 mM EDOP in the presence of 5-50 mM IBU. The loading efficiency of polymer matrix is dependent on IBU concentration and reaches 25.0+/-1.3 MUg/cm2. The analysis of PEDOP-IBU chemical structure based on Raman spectroscopy, energy dispersive spectroscopy and surface morphology data provided by scanning electron microscopy shows that IBU is accumulated in the structure of matrix and evidently influences its morphology. IBU is then released in a controlled way under the influence of applied potential (-0.7 V vs. Ag/AgCl). It is demonstrated that the judicious choice of the synthesis conditions leads to a tailored loading efficiency of PEDOP matrix and to a tunable drug release. PMID- 26606717 TI - Meta-analysis of the changes in correlations between depression instruments used in longitudinal studies. AB - BACKGROUND: Correlations between instruments measuring the same construct reflect their concurrent validity. Little is known about changes in correlations between such instruments employed in studies with repeated assessment. The aim of this meta-analysis was to examine the changes in correlations between depression instruments in the course of longitudinal studies. METHODS: A literature search was conducted using MEDLINE and PsycINFO for the period from 1960 to 2013. The total number of collected articles was 3723, of which 61 were included. Three meta-analyses were performed for the changes in correlations between each pair of the three depression scales: Hamilton Rating Scale for Depression (HAMD), Montgomery-Asberg Depression Rating Scale (MADRS) and Beck Depression Inventory (BDI). The effect size in these meta-analyses was obtained by the z transformation of correlation coefficients. RESULTS: Correlations between depression scales increased over time in 52 studies. Significant changes in correlation coefficients were found for correlations between HAMD and BDI (p<0.001) and for correlations between HAMD and MADRS (p<0.001). An increase in correlations between the scales was associated with a decrease in depression scores and increase in their variability. LIMITATIONS: Univariable and multivariable meta-regression models were not obtained in all three meta-analyses because of the lack of data. CONCLUSIONS: A finding that correlations between depression instruments tended to increase over time has significant implications for assessment of the concurrent validity of these instruments. In longitudinal designs it is important to estimate correlations between depression scales over time because different thresholds for scale correlations indicate acceptable concurrent validity at different times. PMID- 26606718 TI - Executive function impairments in depression and bipolar disorder: association with functional impairment and quality of life. AB - BACKGROUND: The neuropsychological correlates of major depressive (MDD) and bipolar disorder (BD), and their association with quality of life (QOL) and functioning, have not been sufficiently studied in the literature. The present study aimed to compare executive functions, attention, processing speed, QOL and disability between patients with BD type I, BD type II, MDD and healthy controls. METHOD: 205 participants (n=37 BDI, 81% female; n=35 BDII, 80% female; n=45 MDD, 69% female; n=89C, 46% female) aged between 18 and 67 years were administered an extensive neurocognitive battery consisting of widely used standardized measures such as the Trail Making Test, the Stroop Color-Word Test and a modified version of the Wisconsin Card Sorting Task. Z-scores were compared between groups by ANCOVA. The prevalence of impairments on each measure (Z-score<1.5) was compared between groups using chi-square tests. The associations between cognition, quality of life and functioning were evaluated through correlational analysis. RESULTS: Patients with MDD showed poor selective and sustained attention, and exhibited impairments in timed tasks, suggesting low efficiency of executive processing. Patients with BDI displayed more widespread cognitive impairment than the remaining groups, and performed worse than subjects with MDD on measures of sustained attention and inhibitory control. Decision-making ability and attentional control were able to distinguish between patients with BDI and BDII. QOL and disability were most impaired in patients with BDI, and more closely associated with cognitive impairment than in the remaining groups. LIMITATIONS: No control of pharmacological variables, clinical or demographic characteristics. CONCLUSIONS: Our results provide important information regarding the nature and severity of the cognitive alterations associated with different mood disorders, and may contribute to the diagnosis, rehabilitation and treatment of these conditions. PMID- 26606719 TI - Assessing the Effectiveness of Case-Based Collaborative Learning via Randomized Controlled Trial. AB - PURPOSE: Case-based collaborative learning (CBCL) is a novel small-group approach that borrows from team-based learning principles and incorporates elements of problem-based learning (PBL) and case-based learning. CBCL includes a preclass readiness assurance process and case-based in-class activities in which students respond to focused, open-ended questions individually, discuss their answers in groups of 4, and then reach consensus in larger groups of 16. This study introduces CBCL and assesses its effectiveness in one course at Harvard Medical School. METHOD: In a 2013 randomized controlled trial, 64 medical and dental student volunteers were assigned randomly to one of four 8-person PBL tutorial groups (control; n = 32) or one of two 16-person CBCL tutorial groups (experimental condition; n = 32) as part of a required first-year physiology course. Outcomes for the PBL and CBCL groups were compared using final exam scores, student responses to a postcourse survey, and behavioral coding of portions of video-recorded class sessions. RESULTS: Overall, the course final exam scores for CBCL and PBL students were not significantly different. However, CBCL students whose mean exam performance in prior courses was below the participant median scored significantly higher than their PBL counterparts on the physiology course final exam. The most common adjectives students used to describe CBCL were "engaging," "fun," and "thought-provoking." Coding of observed behaviors indicated that individual affect was significantly higher in the CBCL groups than in the PBL groups. CONCLUSIONS: CBCL is a viable, engaging, active learning method. It may particularly benefit students with lower academic performance. PMID- 26606720 TI - Measuring the Impact of Longitudinal Faculty Development: A Study of Academic Achievement. AB - PURPOSE: Although faculty development programs in medical education have increased over the past two decades, there is a lack of rigorous program evaluation. The aim of this study was to determine quantifiable outcomes of Harvard Medical School's (HMS's) Fellowship in Medical Education and evaluate attainment of its goals. METHOD: In 2005 and 2009 the authors collected curricula vitae (CVs) and conducted within-subject analysis of 42 fellowship graduates and also conducted comparison analysis between 12 academic year 2005 fellows and 12 faculty who did not participate in the program. The authors identified 10 metrics of academic advancement. CV analysis for the 42 graduates started 2 years prior to fellowship enrollment and continued for 2-year intervals until June 2009 (10 years of data collection). CV analysis for the comparison group was from 2003 to 2009. The authors also analyzed association between gender and academic outcomes. RESULTS: Fellowship graduates demonstrated significant changes in 4 of 10 academic metrics by the end of the fellowship year: academic promotion, educational leadership, education committees, and education funding. Two metrics educational leadership and committees-showed increased outcomes two years post fellowship, with a positive trend for promotions. Fellowship graduates significantly outpaced the comparison group in 6 of 10 metrics. Women did significantly more committee work, secured more education funding, and were promoted more often than men. CONCLUSIONS: Findings indicate that the HMS Fellowship in Medical Education meets programmatic goals and produces positive, measurable academic outcomes. Standardized evaluation metrics of longitudinal faculty development programs would aid cross-institutional comparisons. PMID- 26606721 TI - Opportunities to Create New General Surgery Residency Programs to Alleviate the Shortage of General Surgeons. AB - PURPOSE: To estimate the capacity for supporting new general surgery residency programs among U.S. hospitals that currently do not have such programs. METHOD: The authors compiled 2011 American Hospital Association data regarding the characteristics of hospitals with and without a general surgery residency program and 2012 Accreditation Council for Graduate Medical Education data regarding existing general surgery residencies. They performed an ordinary least squares regression to model the number of residents who could be trained at existing programs on the basis of residency program-level variables. They identified candidate hospitals on the basis of a priori defined criteria for new general surgery residency programs and an out-of-sample prediction of resident capacity among the candidate hospitals. RESULTS: The authors found that 153 hospitals in 39 states could support a general surgery residency program. The characteristics of these hospitals closely resembled the characteristics of hospitals with existing programs. They identified 435 new residency positions: 40 hospitals could support 2 residents per year, 99 hospitals could support 3 residents, 12 hospitals could support 4 residents, and 2 hospitals could support 5 residents. Accounting for progressive specialization, new residency programs could add 287 additional general surgeons to the workforce annually (after an initial five- to seven-year lead time). CONCLUSIONS: By creating new general surgery residency programs, hospitals could increase the number of general surgeons entering the workforce each year by 25%. A challenge to achieving this growth remains finding new funding mechanisms within and outside Medicare. Such changes are needed to mitigate projected workforce shortages. PMID- 26606722 TI - Pregnancy and Parental Leave During Graduate Medical Education. AB - PURPOSE: To understand the pregnancy, childbirth, and parental leave plans and experiences of trainees in multiple graduate medical education (GME) programs at a single institution. METHOD: In 2013, the authors developed and deployed a voluntary, Internet-based survey of trainees in 269 residency and fellowship programs across the three sites of the Mayo School of Graduate Medical Education. The survey assessed pregnancy-related issues, including use of relevant institutional policies, changes in work due to pregnancy, and activities during pregnancy and parental leave. The authors analyzed the responses to make comparisons across groups. RESULTS: Forty-two percent (644/1,516) of trainees responded. Less than half (264; 41%) had children, and 46 (7%) were currently pregnant (themselves or their partners). Among parents, 24 (of 73; 33%) women and 28 (of 81; 35%) men planned to have another child during their current training program, and 13 (18%) women and 14 (17%) men planned to do so during their next training program. Among nonparents, 40 (of 135; 30%) women and 36 (of 111; 32%) men planned pregnancies during their current training program, and 25 (19%) women and 14 (13%) men planned pregnancies during their next training program. Of respondents eligible for parental leave, 81 (of 83; 98%) women and 89 (of 101; 88%) men had used it. CONCLUSIONS: Approximately 40% of respondents planned to have children during their GME training; most will require family leave and institutional support. GME programs should pursue policies and practices to minimize the effects of these leaves on their workforce. PMID- 26606723 TI - Creating the Exceptional Patient Experience in One Academic Health System. AB - Whether patient satisfaction scores can act as a catalyst for improving health care is highly debated. Some argue that pursuing patient satisfaction is overemphasized and potentially at odds with providing good care because it leads providers to overtest and overtreat patients and to bend to unreasonable patient demands, all to improve their ratings. Others cite studies showing that high patient satisfaction scores correlate with improved health outcomes. Ideally, assessing patient satisfaction metrics will encourage empathy, communication, trust, and shared decision making in the health care delivery process. From the patient's perspective, sharing such metrics motivates physicians to provide patient-centered care and meets their need for easily accessible information about their providers. In this article, the authors describe a seven-year initiative, which began in 2008, to change the culture of the University of Utah Health Care system to deliver a consistently exceptional patient experience. Five factors affected the health system's ability to provide such care: (1) a lack of good decision-making processes, (2) a lack of accountability, (3) the wrong attitude, (4) a lack of patient focus, and (5) mission conflict. Working groups designed initiatives at all levels of the health system to address these issues. What began as a patient satisfaction initiative evolved into a model for physician engagement, values-based employment practices, enhanced professionalism and communication, reduced variability in performance, and improved alignment of the mission and vision across hospital and faculty group practice teams. PMID- 26606724 TI - Direct and indirect effects of maltreatment typologies on suicidality in a representative Northern Irish sample: Psychopathology only partially mediates the relationship. AB - There has been a rise in suicide rates among men who grew up during the 1970's in Northern Ireland (NI). Conflict exposures (CEs) have been linked with suicide ideation but not attempts. Civil conflict has also been linked with aggressive parenting which is associated with the development of aggressive drives, psychopathology and suicidality. This study investigated (1) cohort specific associations between latent classes (LCs) of maltreatment and (2) associations between LCs, CEs, psychopathology and suicidality. Data were from NI Study of Health and Stress (N = 1986). Maltreatment and suicidality were queried using validated measures. Psychiatric assessments were based on DSM-IV criteria. Logistic regression, latent class analysis, chi square tests and mediation analyses were conducted. Two at risk LCs were identified, entitled "family violence exposure" (FVE, 10.4%; Male, 55.4%) and "family violence and sexual abuse exposure" (FVSAE, 1.2%; Female, 90.5%). Both were more likely to have experienced CEs (FVE = 71%; FVSAE = 77.5%) than the low risk class. The FVE were more likely to be male; aged 35-49 and to suffer from a mental disorder. The FVSAE class all endorsed rape, were more likely to be separated and to suffer from a mental disorder. CEs uniquely predicted ideation but not enactment. Psychopathology partially mediated the relationship between LCs and suicidality. FVE and FVSAE directly increased the odds of enactment. These findings are original and highly pertinent and they should be used to inform any strategy for addressing the cohort specific and trauma related rise in suicide rates in NI. PMID- 26606727 TI - Synthesis and magnetism of epsilon-Fe3N submicrorods for magnetic resonance imaging. AB - Fe3N submicrorods with desirable magnetic properties were prepared from a designed metal-organic framework precursor via a modified ethanediamine nitridation route. Magnetic resonance imaging using the Fe3N submicrorods was investigated carefully, confirming the Fe3N submicrorod could be acceptable as a significant contrast agent for its outstanding concentration dependent signal and high r2 relaxivity. Besides, the excellent saturation magnetization and homogeneous dispersity also developed the Fe3N application range. PMID- 26606726 TI - Correction: Intraspecies Variability Affects Heterotypic Biofilms of Porphyromonas gingivalis and Prevotella intermedia: Evidences of Strain Dependence Biofilm Modulation by Physical Contact and by Released Soluble Factors. PMID- 26606725 TI - Novelty, conditioning and attentional bias to sexual rewards. AB - The Internet provides a large source of novel and rewarding stimuli, particularly with respect to sexually explicit materials. Novelty-seeking and cue-conditioning are fundamental processes underlying preference and approach behaviors implicated in disorders of addiction. Here we examine these processes in individuals with compulsive sexual behaviors (CSB), hypothesizing a greater preference for sexual novelty and stimuli conditioned to sexual rewards relative to healthy volunteers. Twenty-two CSB males and forty age-matched male volunteers were tested in two separate behavioral tasks focusing on preferences for novelty and conditioned stimuli. Twenty subjects from each group were also assessed in a third conditioning and extinction task using functional magnetic resonance imaging. CSB was associated with enhanced novelty preference for sexual, as compared to control images, and a generalized preference for cues conditioned to sexual and monetary versus neutral outcomes compared to healthy volunteers. CSB individuals also had greater dorsal cingulate habituation to repeated sexual versus monetary images with the degree of habituation correlating with enhanced preference for sexual novelty. Approach behaviors to sexually conditioned cues dissociable from novelty preference were associated with an early attentional bias to sexual images. This study shows that CSB individuals have a dysfunctional enhanced preference for sexual novelty possibly mediated by greater cingulate habituation along with a generalized enhancement of conditioning to rewards. We further emphasize a dissociable role for cue-conditioning and novelty preference on the early attentional bias for sexual cues. These findings have wider relevance as the Internet provides a broad range of novel and potentially rewarding stimuli. PMID- 26606728 TI - Role of Hyperketonemia in Inducing Oxidative Stress and Cellular Damage in Cultured Hepatocytes and Type 1 Diabetic Rat Liver. AB - BACKGROUND/AIMS: Type 1 diabetic (T1D) patients have a higher incidence of liver disease. T1D patients frequently experience elevated plasma ketone levels along with hyperglycemia. However, no study has examined whether hyperketonemia per se has any role in excess liver damage in T1D. This study investigates the hypothesis that hyperketonemia can induce oxidative stress and cellular dysfunction. METHODS: STZ treated diabetic rats, FL83B hepatocytes, and GCLC knocked down (GSH deficient) hepatocytes were used. RESULTS: The blood levels of ALT and AST, biomarkers of liver damage, and ketones were elevated in T1D rats. An increase in NOX4 and ROS along with a reduction in GSH and GCLC levels was observed in T1D rat livers in comparison to those seen in non-diabetic control or type 2 diabetic rats. MCP-1 and ICAM-1 were also elevated in T1D rat livers and ketone treated hepatocytes. Macrophage markers CCR2 and CD11A that interact with MCP-1, and ICAM-1 respectively, were also elevated in the T1D liver, indicating macrophage infiltration. Additionally, activated macrophages increased hepatocyte damage with ketone treatment, which was similar to that seen in GCLC knockdown hepatocytes without ketones. CONCLUSION: Hyperketonemia per se can induce macrophage mediated damage to hepatocytes and the liver, caused by GSH depletion and oxidative stress up regulation in T1D. PMID- 26606729 TI - Structural Brain Connectivity as a Genetic Marker for Schizophrenia. AB - IMPORTANCE: Schizophrenia is accompanied by a loss of integrity of white matter connections that compose the structural brain network, which is believed to diminish the efficiency of information transfer among brain regions. However, it is unclear to what extent these abnormalities are influenced by the genetic liability for developing the disease. OBJECTIVE: To determine whether white matter integrity is associated with the genetic liability for developing schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: In 70 individual twins discordant for schizophrenia and 130 matched individual healthy control twins, structural equation modeling was applied to quantify unique contributions of genetic and environmental factors on brain connectivity and disease liability. The data for this study were collected from October 1, 2008, to September 30, 2013. The data analysis was performed between November 1, 2013, and March 30, 2015. MAIN OUTCOME MEASURES: Structural connectivity and network efficiency were assessed through diffusion-weighted imaging, measuring fractional anisotropy (FA) and streamlines. RESULTS: The sample included 30 monozygotic twins matched to 72 control participants and 40 dizygotic twins matched to 58 control participants. Lower global FA was significantly correlated with increased schizophrenia liability (phenotypic correlation, -0.25; 95% CI, -0.38 to -0.10; P = .001), with 83.4% explained by common genes. In total, 8.1% of genetic variation in global FA was shared with genetic variance in schizophrenia liability. Local reductions in network connectivity (as defined by FA-weighted local efficiency) of frontal, striatal, and thalamic regions encompassed 85.7% of genetically affected areas. Multivariate genetic modeling revealed that global FA contributed independently of other genetic markers, such as white matter volume and cortical thickness, to schizophrenia liability. CONCLUSIONS AND RELEVANCE: Global reductions in white matter integrity in schizophrenia are largely explained by the genetic risk of developing the disease. Network analysis revealed that genetic liability for schizophrenia is primarily associated with reductions in connectivity of frontal and subcortical regions, indicating a loss of integrity along the white matter fibers in these regions. The reported reductions in white matter integrity likely represent a separate and novel genetic vulnerability marker for schizophrenia. PMID- 26606730 TI - Spider Web DNA: A New Spin on Noninvasive Genetics of Predator and Prey. AB - Noninvasive genetic sampling enables biomonitoring without the need to directly observe or disturb target organisms. This paper describes a novel and promising source of noninvasive spider and insect DNA from spider webs. Using black widow spiders (Latrodectus spp.) fed with house crickets (Acheta domesticus), we successfully extracted, amplified, and sequenced mitochondrial DNA from spider web samples that identified both spider and prey to species. Detectability of spider DNA did not differ between assays with amplicon sizes from 135 to 497 base pairs. Spider and prey DNA remained detectable at least 88 days after living organisms were no longer present on the web. Spider web DNA as a proof-of-concept may open doors to other practical applications in conservation research, pest management, biogeography studies, and biodiversity assessments. PMID- 26606731 TI - Evidence of gene orthology and trans-species polymorphism, but not of parallel evolution, despite high levels of concerted evolution in the major histocompatibility complex of flamingo species. AB - The major histocompatibility complex (MHC) is a cornerstone in the study of adaptive genetic diversity. Intriguingly, highly polymorphic MHC sequences are often not more similar within species than between closely related species. Divergent selection of gene duplicates, balancing selection maintaining trans species polymorphism (TSP) that predate speciation and parallel evolution of species sharing similar selection pressures can all lead to higher sequence similarity between species. In contrast, high rates of concerted evolution increase sequence similarity of duplicated loci within species. Assessing these evolutionary models remains difficult as relatedness and ecological similarities are often confounded. As sympatric species of flamingos are more distantly related than allopatric species, flamingos represent an ideal model to disentangle these evolutionary models. We characterized MHC Class I exon 3, Class IIB exon 2 and exon 3 of the six extant flamingo species. We found up to six MHC Class I loci and two MHC Class IIB loci. As all six species shared the same number of MHC Class IIB loci, duplication appears to predate flamingo speciation. However, the high rate of concerted evolution has prevented the divergence of duplicated loci. We found high sequence similarity between all species regardless of codon position. The latter is consistent with balancing selection maintaining TSP, as under this mechanism amino acid sites under pathogen-mediated selection should be characterized by fewer synonymous codons (due to their common ancestry) than under parallel evolution. Overall, balancing selection maintaining TSP appears to result in high MHC similarity between species regardless of species relatedness and geographical distribution. PMID- 26606732 TI - A new turn on coumarin-based fluorescence probe for Ga(3+) detection in aqueous solution. AB - The probe CT was synthesized and investigated as a novel label-free chemosensor for Ga(3+) detection in water. Probe CT showed remarkable selectivity and sensitivity for Ga(3+) in Tris-HCl aqueous buffer solution (pH7.0). The chemosensor responded rapidly to Ga(3+) with a 1:1 stoichiometry. Meanwhile, the unapparent changes of fluorescence lifetime decays suggest the turn-on process of probe CT by Ga(3+) which appears to be a static mechanism. PMID- 26606733 TI - Quantitative multi-slice computed tomography assessment of the mitral valvular complex for transcatheter mitral valve interventions part 1: systematic measurement methodology and inter-observer variability. AB - AIMS: Transcatheter mitral valve replacement (TMVR) is an emerging technology with the potential to treat patients with severe mitral regurgitation at excessive risk for surgical mitral valve surgery. Multimodality imaging of the mitral valvular complex and surrounding structures will be an important component for patient selection for TMVR. Our aim was to describe and evaluate a systematic multi-slice computed tomography (MSCT) image analysis methodology that provides measurements relevant for transcatheter mitral valve replacement. METHODS AND RESULTS: A systematic step-by-step measurement methodology is described for structures of the mitral valvular complex including: the mitral valve annulus, left ventricle, left atrium, papillary muscles and left ventricular outflow tract. To evaluate reproducibility, two observers applied this methodology to a retrospective series of 49 cardiac MSCT scans in patients with heart failure and significant mitral regurgitation. For each of 25 geometrical metrics, we evaluated inter-observer difference and intra-class correlation. The inter observer difference was below 10% and the intra-class correlation was above 0.81 for measurements of critical importance in the sizing of TMVR devices: the mitral valve annulus diameters, area, perimeter, the inter-trigone distance, and the aorto-mitral angle. CONCLUSIONS: MSCT can provide measurements that are important for patient selection and sizing of TMVR devices. These measurements have excellent inter-observer reproducibility in patients with functional mitral regurgitation. PMID- 26606734 TI - Quantitative multi-slice computed tomography assessment of the mitral valvular complex for transcatheter mitral valve interventions part 2: geometrical measurements in patients with functional mitral regurgitation. AB - AIMS: Transcatheter mitral valve replacement (TMVR) is an emerging technology with the potential to treat patients with mitral regurgitation at excessive risk for mitral valve surgery. Geometrical measurements of the mitral valvular complex may have implications for the design of TMVR devices and for patient selection. This study sought to quantify the dynamic geometry of the mitral valvular complex in patients with significant functional mitral regurgitation (FMR) using multi slice computed tomography (MSCT). METHODS AND RESULTS: MSCT images were acquired in 32 patients with symptomatic, significant FMR. Two independent observers analysed image sets using a dedicated software package and a standard measurement methodology. In patients with FMR, the mean mitral annulus intercommissural and aorto-mural diameters were, respectively, 41.5+/-5.2 mm and 38.7+/-5.9 mm in systole, and were 41.5+/-4.4 mm and 40.0+/-4.7 mm in diastole. In patients without MR, the diameters were, respectively, 33.6+/-5.1 mm and 28.8+/-8.0 mm in systole, and 36.2+/-4.5 mm and 31.6+/-7.9 mm in diastole. The obstacle-free zone below the mitral annulus averaged more than 20.0 mm and varied by less than 1 mm between systole and diastole, which is not statistically significant. The aorto mitral angle was 129.7+/-10.5 degrees in systole and 131.0+/-9.4 degrees in diastole. CONCLUSIONS: The mitral annulus is larger in dimension, more circular, and less dynamic in patients with FMR. The obstacle-free zone below the mitral annulus is relatively constant during the cardiac cycle. Measurements of the mitral valvular apparatus vary considerably between patients, which suggests that tridimensional imaging will play an important role in the sizing of TMVR devices. PMID- 26606735 TI - Long-term ticagrelor monotherapy versus standard dual antiplatelet therapy followed by aspirin monotherapy in patients undergoing biolimus-eluting stent implantation: rationale and design of the GLOBAL LEADERS trial. AB - AIMS: The GLOBAL LEADERS trial is a superiority study in patients undergoing percutaneous coronary intervention, with a uniform use of Biolimus A9-eluting stents (BES) and bivalirudin. GLOBAL LEADERS was designed to assess whether a 24 month antithrombotic regimen with ticagrelor and one month of acetylsalicylic acid (ASA), compared to conventional dual antiplatelet therapy (DAPT), improves outcomes. METHODS AND RESULTS: Patients (n >16,000) are randomised (1:1 ratio) to ticagrelor 90 mg twice daily for 24 months plus ASA <=100 mg for one month versus DAPT with either ticagrelor (acute coronary syndrome) or clopidogrel (stable coronary artery disease) for 12 months plus ASA <=100 mg for 24 months. The primary outcome is a composite of all-cause mortality or non-fatal, new Q-wave myocardial infarction at 24 months. The key safety endpoint is investigator reported class 3 or 5 bleeding according to the Bleeding Academic Research Consortium (BARC) definitions. Sensitivity analysis will be carried out to explore potential differences in outcome across geographic regions and according to specific angiographic and clinical risk estimates. CONCLUSIONS: The GLOBAL LEADERS trial aims to assess the role of ticagrelor as a single antiplatelet agent after a short course of DAPT for the long-term prevention of cardiac adverse events, across a wide spectrum of patients, following BES implantation. PMID- 26606736 TI - A novel extracellular glycosidase activity from Rhodotorula mucilaginosa: its application potential in wine aroma enhancement. AB - The aim of the work was to evaluate the application potential of a glycosidase extract of one indigenous non-Saccharomyces strain in wine aroma enhancement. The isolate was selected from a local winemaking region in China for its high beta glucosidase level and was identified as Rhodotorula mucilaginosa. The tolerance of the glycosidase extract to the typical winemaking conditions was assessed using the activity of its beta-glucosidase. After that, the hydrolysis capacity of R. mucilaginosa glycosidase for liberation of grape aroma glycosides was characterized in comparison to commercial enzyme preparations. Results of this work revealed that glycosidase extract from R. mucilaginosa proved to be active in the presence of 0-20% (w/v) glucose, 0-20% (v/v) ethanol and at pH 3.0-5.0. In the hydrolysis of aroma precursors, enzymes obtained from different origins possessed various levels of specificity and activity, showing high origin dependence (alpha = 0.05). Compared to commercial enzymes, the indigenous R. mucilaginosa glycosidase extract presented better catalytic preference for the 'fruity and floral' glycosides of benzenic compounds and C13 -norisoprenoids, but less sensitivity to the glycosides of C6 compounds and volatile phenols. SIGNIFICANCE AND IMPACT OF THE STUDY: This work presents a novel extracellular glycosidase preparation from an indigenous Rhodotorula mucilaginosa strain selected from a local winemaking region in China. This enzyme extract exhibits strong tolerance towards winemaking conditions. It shows hydrolysis specificity for glycosides of benzenic compounds and C13 -norisoprenoids, proving a potential candidate for improving floral and fruity aroma characteristics of wine. PMID- 26606737 TI - The Characteristics and Function of Bacterial Lipopolysaccharides and Their Endotoxic Potential in Humans. AB - Cross-talk between enteral microbiota and human host is essential for the development and maintenance of the human gastrointestinal and systemic immune systems. The presence of lipopolysaccharides (LPS) lysed from the cell membrane of Gram-negative bacteria in the gut lumen is thought to promote the development of a balanced gut immune response whilst the entry of the same LPS into systemic circulation may lead to a deleterious pro-inflammatory systemic immune response. Recent data suggest that chronically low levels of circulating LPS may be associated with the development of metabolic diseases such as insulin resistance, type 2 diabetes, atherosclerosis and cardiovascular disease. This review focuses on the cross-talk between enteral commensal bacteria and the human immune system via LPS. We explain the structural characterisation of the LPS molecule and its function in the bacteria. We then examine how LPS is recognised by various elements of the human immune system and the signalling pathways that are activated by the structure of the LPS molecule and the effect of various concentrations. Further, we discuss the sequelae of this signalling in the gut associated and systemic immune systems i.e. the neutralisation of LPS and the development of tolerance to LPS. PMID- 26606738 TI - Drilling Deeper for Treatment Choices in Diabetic Macular Edema. PMID- 26606739 TI - Serum protein biomarkers relevant to hepatocellular carcinoma and their detection. AB - Hepatocellular carcinoma (HCC) is one of the most recurrent and lethal cancers worldwide. The low survival rate of this particular strain of carcinoma is largely due to the late stages at which it is diagnosed. Tumorigenesis of hepatocellular carcinoma is most frequently detected through ultrasonography, magnetic resonance imaging and computerized tomography scans, however, these methods are poor for detection of early tumor development. This review presents alternative hepatocellular carcinoma detection techniques through the use of protein and enzyme/isozyme biomarkers. The detection methods used to determine the serum levels of alpha-fetoprotein (AFP), glypican-3 (GPC3), Golgi protein 73 (GP73), alpha-L-fucosidase (AFU), des-gamma-carboxyprothrombin (DCP), gamma glutamyl transferase (GGT) and squamous cell carcinoma antigen (SCCA) are presented and each marker's respective validity in the diagnosis of hepatocellular carcinoma is evaluated. PMID- 26606740 TI - Serum Levels of Tryptase Suggest That Mast Cells Might Have an Antiinflammatory Role in Rheumatoid Arthritis: Comment on the Article by Rivellese et al. PMID- 26606741 TI - Free fatty acid as an outcome predictor of atrial fibrillation-associated stroke. AB - OBJECTIVE: We investigated whether baseline plasma free fatty acid (FFA) concentration is associated with any (ischemic/hemorrhagic) stroke, ischemic stroke/systemic embolism (ISSE), or ischemic stroke among stroke survivors with atrial fibrillation (A-fib). Moreover, we compared the outcome predictability of FFA with previously adopted models, including the CHADS2 and CHA2 DS2 -VASc scoring systems. METHODS: We analyzed data from 279 stroke patients with A-fib and investigated the association between plasma FFA concentration and outcomes using Cox regression models with competing risk analyses. RESULTS: Median follow up period was 17.5 months. During the study period, any stroke, ISSE, and ischemic stroke occurred in 22, 21, and 17 patients, respectively. The cumulative risk for any stroke, ISSE, and ischemic stroke were 5.1%, 4.7%, and 4.2% at the end of the first year and 14.8%, 12.1%, and 10.8% at the end of the third year, respectively. After adjusting covariates (model 1), baseline FFA concentration was associated with recurrence of any stroke (hazard ratio [HR] = 1.774, 95% confidence interval [CI] = 1.124-2.801, per 1mEq/l increment of FFA). FFA showed a trend association with ISSE (HR = 1.569, 95% CI = 0.950-2.592) and ischemic stroke (HR = 1.630, 95% CI = 0.967-2.746). In adjusted models including CHADS2 or CHA2 DS2 -VASc score as a covariate, (models 2 and 3) FFA was still shown to be an independent predictor of any stroke and ischemic stroke. There was a significant or trend association between FFA and ISSE. INTERPRETATION: FFA may be a potential biomarker that predicts outcome events in stroke with A-fib along with the CHADS2 and CHA2 DS2 -VASc scoring systems. PMID- 26606742 TI - Brief Report: Patterns and Secular Trends in Use of Immunomodulatory Agents During Pregnancy in Women With Rheumatic Conditions. AB - OBJECTIVE: To describe patterns and secular trends in the use of immunomodulatory agents in pregnant women with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS). METHODS: We identified a cohort of women with SLE, RA, PsA, or AS enrolled in public (Medicaid, 2001-2010) or private (Optum Clinformatics, 2004-2012) health insurance, and we included women filling prescriptions for immunomodulatory agents (including steroids, nonbiologic disease-modifying agents, and biologic agents) in the 3-month period immediately prior to their pregnancies. The proportion of women continuing or discontinuing individual agents during pregnancy was reported. Annual prescription fill rates, estimated after accounting for patient characteristics and random variability from year to year in mixed-effects regression models, were used to conduct time trends analysis. RESULTS: We included 2,645 women being treated with immunomodulatory agents prior to pregnancy. More women with PsA or AS stopped filling prescriptions for immunomodulatory agents during pregnancy (61%) than women with SLE (26%) or women with RA (34.5%). From the first to the third trimester, the proportions of women filling prescriptions for immunomodulatory agents decreased across all indications. Overall, steroids and hydroxychloroquine were the most frequently used agents in pregnancy (48.4% and 27.1%, respectively). The rates (reported per 100 deliveries in our cohort) for steroid prescription fills during pregnancy decreased significantly from 54.4 in 2001 to 42.4 in 2012, while rates for biologic agents increased from 5.1 in 2001 to 16.6 in 2012 (P < 0.001 for both trends). CONCLUSION: Steroids and hydroxychloroquine remain the most widely prescribed treatment options in pregnancy, but the use of biologic agents is becoming increasingly common. PMID- 26606743 TI - Genome-Wide Identification, Phylogenetic and Expression Analyses of the Ubiquitin Conjugating Enzyme Gene Family in Maize. AB - BACKGROUND: Ubiquitination is a post-translation modification where ubiquitin is attached to a substrate. Ubiquitin-conjugating enzymes (E2s) play a major role in the ubiquitin transfer pathway, as well as a variety of functions in plant biological processes. To date, no genome-wide characterization of this gene family has been conducted in maize (Zea mays). METHODOLOGY/PRINCIPAL FINDINGS: In the present study, a total of 75 putative ZmUBC genes have been identified and located in the maize genome. Phylogenetic analysis revealed that ZmUBC proteins could be divided into 15 subfamilies, which include 13 ubiquitin-conjugating enzymes (ZmE2s) and two independent ubiquitin-conjugating enzyme variant (UEV) groups. The predicted ZmUBC genes were distributed across 10 chromosomes at different densities. In addition, analysis of exon-intron junctions and sequence motifs in each candidate gene has revealed high levels of conservation within and between phylogenetic groups. Tissue expression analysis indicated that most ZmUBC genes were expressed in at least one of the tissues, indicating that these are involved in various physiological and developmental processes in maize. Moreover, expression profile analyses of ZmUBC genes under different stress treatments (4 degrees C, 20% PEG6000, and 200 mM NaCl) and various expression patterns indicated that these may play crucial roles in the response of plants to stress. CONCLUSIONS: Genome-wide identification, chromosome organization, gene structure, evolutionary and expression analyses of ZmUBC genes have facilitated in the characterization of this gene family, as well as determined its potential involvement in growth, development, and stress responses. This study provides valuable information for better understanding the classification and putative functions of the UBC-encoding genes of maize. PMID- 26606744 TI - Effects of Reductions in Body Mass Index on the Future Osteoarthritis Burden in Canada: A Population-Based Microsimulation Study. AB - OBJECTIVE: Osteoarthritis (OA) is the most common joint disease and a major cause of disability. Incidence and prevalence of OA are expected to increase due to population aging and increased levels of obesity. The purpose of this study was to project the effect of hypothetical interventions that change the distribution of body mass index (BMI) on OA burden in Canada. METHODS: We used a microsimulation computer model of OA based on the Population Health Model platform. The model used demographic predictions for Canada and population data from an administrative database in British Columbia and national Canadian surveys. RESULTS: Under the base-case scenario, between 2010 and 2030, OA prevalence is expected to increase from 11.5% to 15.6% in men and 16.3% to 21.1% in women. In scenarios assuming, on average, a 0.3-, 0.5-, or 1-unit drop in BMI per year, OA prevalence in 2030 would reach 14.9%, 14.6%, and 14.2% in men and 20.3%, 19.7%, and 18.5%, in women, respectively. Under these scenarios, the proportion of new cases prevented would be 9.5%, 13.2%, and 16.7%, respectively, in men, and 9.1%, 15.2%, and 25.0% in women. Targeting only those people ages >=50 years for weight reduction would achieve approximately 70% of the impact of a full population strategy. Targeting only the obese (BMI >=30) would likely result in a larger benefit for men than women. CONCLUSION: Due to the aging of the population, OA will remain a major and growing health issue in Canada over the next 2 decades, regardless of the course of the obesity epidemic. PMID- 26606745 TI - Implications of Sponge Biodiversity Patterns for the Management of a Marine Reserve in Northern Australia. AB - Marine reserves are becoming progressively more important as anthropogenic impacts continue to increase, but we have little baseline information for most marine environments. In this study, we focus on the Oceanic Shoals Commonwealth Marine Reserve (CMR) in northern Australia, particularly the carbonate banks and terraces of the Sahul Shelf and Van Diemen Rise which have been designated a Key Ecological Feature (KEF). We use a species-level inventory compiled from three marine surveys to the CMR to address several questions relevant to marine management: 1) Are carbonate banks and other raised geomorphic features associated with biodiversity hotspots? 2) Can environmental (depth, substrate hardness, slope) or biogeographic (east vs west) variables help explain local and regional differences in community structure? 3) Do sponge communities differ among individual raised geomorphic features? Approximately 750 sponge specimens were collected in the Oceanic Shoals CMR and assigned to 348 species, of which only 18% included taxonomically described species. Between eastern and western areas of the CMR, there was no difference between sponge species richness or assemblages on raised geomorphic features. Among individual raised geomorphic features, sponge assemblages were significantly different, but species richness was not. Species richness showed no linear relationships with measured environmental factors, but sponge assemblages were weakly associated with several environmental variables including mean depth and mean backscatter (east and west) and mean slope (east only). These patterns of sponge diversity are applied to support the future management and monitoring of this region, particularly noting the importance of spatial scale in biodiversity assessments and associated management strategies. PMID- 26606747 TI - Palliative Care Interventions for Surgical Patients: A Systematic Review. AB - IMPORTANCE: Inpatient palliative care improves symptom management and patient satisfaction with care and reduces hospital costs in seriously ill patients. However, the role of palliative care in the treatment of patients undergoing surgery (surgical patients) remains poorly defined. OBJECTIVE: To characterize the content, design, and results of interventions to improve access to palliative care or the quality of palliative care for surgical patients. EVIDENCE REVIEW: This systematic review was conducted according to PRIMSA guidelines. Articles were identified through searches of PubMed, PsycINFO, EMBASE, and CINAHL as well as manual review of references. Eligible articles included experimental, quasi experimental, and observational studies published in English from January 1, 1994, through October 31, 2014, in which patient outcomes of palliative care interventions for adult surgical patients were reported. Data on the study setting, design, intervention, participants, and results were extracted from the final study set and analyzed from December 22, 2014, to February 7, 2015. FINDINGS: A total of 3838 abstracts were identified and screened by 2 reviewers, 77 articles were reviewed in full text, and 25 articles (22 unique interventions involving 8575 unique patients) met the study criteria. Interrater agreement was good (kappa = 0.78). Nine single-institution retrospective cohort studies, 7 single-institution prospective cohort studies, 7 single-institution randomized clinical studies, and 2 multicenter randomized clinical studies were included. Nineteen of the 23 single-site studies were performed at academic hospitals. Given the heterogeneity of study methods and measures, meta-analysis was not possible. Preoperative decision-making interventions were associated with decreased mortality in 4 studies. Three studies reported improved quality of communication; 4, improved symptom management; and 7, decreased use of health care resources and decreased cost. However, many studies were small, performed in academic settings, and methodologically flawed and did not measure clinically meaningful outcomes. CONCLUSIONS AND RELEVANCE: The sparse evidence regarding interventions to introduce or improve palliative care for surgical patients is further limited by methodologic flaws. Rigorous evaluations of standardized palliative care interventions measuring meaningful patient outcomes are needed. PMID- 26606746 TI - A pooled analysis of post-diagnosis lifestyle factors in association with late estrogen-receptor-positive breast cancer prognosis. AB - Lifestyle factors have been well studied in relation to breast cancer prognosis overall; however, associations of lifestyle and late outcomes (>5 years after diagnosis) have been much less studied, and no studies have focused on estrogen receptor-positive (ER+) breast cancer survivors, who may have high risk of late recurrence and mortality. We utilized a large prospective pooling study to evaluate the associations of lifestyle factors with late recurrence and all-cause mortality among 6,295 5-year ER+ Stage I-III breast cancer survivors. Pooled and harmonized data were available on clinical factors and lifestyle factors (pre- to post-diagnosis weight change, body mass index (BMI) (kg/m(2)), recreational physical activity, alcohol intake and smoking history), measured on average 2.1 years after diagnosis. Updated information for weight only was available. Study heterogeneity was evaluated by the Q-statistic. Multivariable Cox regression models were stratified by study. Adjusting for clinical factors and potential confounders, >= 10% weight gain and obesity (BMI, 30-34.99 and >= 35) were associated with increased risk of late recurrence (hazard ratios (95% confidence intervals): 1.24 (1.00-1.53), 1.40 (1.05-1.86) and 1.41 (1.02-1.93), respectively). Daily alcohol intake was associated with late recurrence, 1.28 (1.01-1.62). Physical activity was inversely associated with late all-cause mortality (0.81 (0.71-0.93) and 0.71 (0.61-0.82) for 4.9 to <17.4 and >= 17.4 metabolic equivalent-hr/week). A U-shaped association was observed for late all cause mortality and BMI using updated weight (1.42 (1.15-1.74) and 1.40 (1.09 1.81), <21.5 and >= 35, respectively). Smoking was associated with increased risk of late outcomes. In this large prospective pooling project, modifiable lifestyle factors were associated with late outcomes among long-term ER+ breast cancer survivors. PMID- 26606748 TI - Novel Humoral Prognostic Markers in Small-Cell Lung Carcinoma: A Prospective Study. AB - PURPOSE: Favourable small cell lung carcinoma (SCLC) survival outcomes have been reported in patients with paraneoplastic neurological disorders (PNDs) associated with neuronal antibodies (Neur-Abs), but the presence of a PND might have expedited diagnosis. Our aim was to establish whether neuronal antibodies, independent of clinical neurological features, correlate with SCLC survival. EXPERIMENTAL DESIGN: 262 consecutive SCLC patients were examined: of these, 24 with neurological disease were excluded from this study. The remaining 238 were tested for a broad array of Neur-Abs at the time of cancer diagnosis; survival time was established from follow-up clinical data. RESULTS: Median survival of the non-PND cohort (n = 238) was 9.5 months. 103 patients (43%) had one or more antigen-defined Neur-Abs. We found significantly longer median survival in 23 patients (10%) with HuD/anti-neuronal nuclear antibody type 1 (ANNA-1, 13.0 months P = 0.037), but not with any of the other antigen-defined antibodies, including the PND-related SOX2 (n = 56, 24%). An additional 28 patients (12%) had uncharacterised anti-neuronal nuclear antibodies (ANNA-U); their median survival time was longer still (15.0 months, P = 0.0048), contrasting with the survival time in patients with non-neuronal anti-nuclear antibodies (detected using HEp-2 cells, n = 23 (10%), 9.25 months). In multivariate analyses, both ANNA-1 and ANNA U independently reduced the mortality hazard by a ratio of 0.532 (P = 0.01) and 0.430 (P<0.001) respectively. CONCLUSIONS: ANNAs, including the newly described ANNA-U, may be key components of the SCLC immunome and have a potential role in predicting SCLC survival; screening for them could add prognostic value that is similar in magnitude to that of limited staging at diagnosis. PMID- 26606749 TI - Placebo Trends across the Border: US versus Canada. AB - BACKGROUND: Physicians around the world report to using placebos in a variety of situations and with varying degrees of frequency. Inconsistent methodologies, however, complicate interpretation and prevent direct comparisons across studies. While US- and Canada-based physicians share similar professional standards, Canada harbours a less-litigious universal healthcare model with no formal placebo-related policy-factors that may impact how physicians view and use placebos. METHODS: To compare American and Canadian data, we circulated an online survey to academic physicians practicing in Canada, collected anonymous responses, and extracted those of internists and rheumatologists for comparison to US data obtained through parallel methodologies. RESULTS: Whereas our data show overall concordance across the border-from definitions to ethical limitations and therapeutic potential-differences between American- and Canadian based placebo practices merit acknowledgement. For example, compared to 45%-80% among US-based respondents, only 23+/-7% of Canada-based respondents reported using placebos in clinical practice. However, 79+/-7% of Canada-respondents-a figure comparable to US data-professed to prescribing at least one form of treatment without proven or expected efficacy. Placebo interventions including unwarranted vitamins and herbal supplements (impure placebos) as well as sugar pills and saline injections (pure placebos) appear more common in Canada, where more doctors described placebos as "placebos" (rather than "medications") and used them as a "diagnostic" tool (rather than a means of placating patient demands for treatment). INTERPRETATION: Cross-border variation in the use of clinical placebos appears minor despite substantial differences in health care delivery system, malpractice climate, and placebo-related policy. The prevalence of impure placebos in both Canadian and US clinics raises ethical and practical questions currently unaddressed by policy and warranting investigation. PMID- 26606750 TI - Hepatic Interferon-lambda3 (IFNL3) Gene Expression Reveals Not to Be Attenuated in Non-Favorable IFNL3 rs4803217 or IFNL4 rs368234815 Minor Allele Carriers in Chronic Hepatitis C. AB - Genetic polymorphisms in the region of the interferon-lambda genes (IFNL) associate with clearance of hepatitis C virus (HCV) infection. One of these polymorphisms, IFNL4 rs368234815, determines loss or gain of function of the IFNL4 gene by frameshift variation. The very same and a second one, IFNL3 rs4803217, are supposed to impact the expression of IFNL3: while IFNL4 rs368234815 is suggested to modulate IFNL3 transcription, IFNL3 rs4803217 is thought to alter IFNL3 mRNA stability. The latter process is believed to be partially driven by an HCV-induced ectopic expression of myosin heavy chain genes 7B and 7 and their co-expressed microRNAs mir499 and mir208B. These ideas are evidenced by functional investigations on peripheral blood mononuclear and hepatoma cells in culture. Our study aimed at exploring IFNL3 gene expression in clinical samples, i.e., in ex vivo derived liver tissue from patients with chronic hepatitis C (n = 57) and various other diseases (n = 56). By applying an assay designed to specifically quantify IFNL3 and discriminating paralogous IFNL2 transcripts, IFNL3 mRNA expression was not found to differ significantly between chronic hepatitis C and control samples. Among patients with chronic HCV infection, moreover, IFNL3 rs4803217 or IFNL4 rs368234815 minor alleles did not associate with reduced IFNL3 gene expression. Finally, myosin heavy chain genes 7B and 7 and corresponding microRNAs mir499 and mir208B were not found activated in liver in chronic HCV infection. Of note, detectability of MYH7 mRNA related to the procedure of liver biopsy sampling, as tissue obtained by direct punctation of the liver during laparoscopic inspection was less likely to contain MYH7 transcripts than samples acquired by percutaneous punctation. In conclusion, data on ex vivo derived liver tissue samples argue against an attenuating impact of IFNL3 rs4803217 or IFNL4 rs368234815 minor alleles on hepatic IFNL3 gene expression in vivo. PMID- 26606751 TI - Role of Structural Dynamics at the Receptor G Protein Interface for Signal Transduction. AB - GPCRs catalyze GDP/GTP exchange in the alpha-subunit of heterotrimeric G proteins (Galphabetagamma) through displacement of the Galpha C-terminal alpha5 helix, which directly connects the interface of the active receptor (R*) to the nucleotide binding pocket of G. Hydrogen-deuterium exchange mass spectrometry and kinetic analysis of R* catalysed G protein activation have suggested that displacement of alpha5 starts from an intermediate GDP bound complex (R**GGDP). To elucidate the structural basis of receptor-catalysed displacement of alpha5, we modelled the structure of R**GGDP. A flexible docking protocol yielded an intermediate R**GGDP complex, with a similar overall arrangement as in the X-ray structure of the nucleotide free complex (R**Gempty), however with the alpha5 C terminus (GalphaCT) forming different polar contacts with R*. Starting molecular dynamics simulations of GalphaCT bound to R* in the intermediate position, we observe a screw-like motion, which restores the specific interactions of alpha5 with R* in R**Gempty. The observed rotation of alpha5 by 60 degrees is in line with experimental data. Reformation of hydrogen bonds, water expulsion and formation of hydrophobic interactions are driving forces of the alpha5 displacement. We conclude that the identified interactions between R* and G protein define a structural framework in which the alpha5 displacement promotes direct transmission of the signal from R* to the GDP binding pocket. PMID- 26606752 TI - Source Memory for Mental Imagery: Influences of the Stimuli's Ease of Imagery. AB - The present study investigated how ease of imagery influences source monitoring accuracy. Two experiments were conducted in order to examine how ease of imagery influences the probability of source confusions of perceived and imagined completions of natural symmetric shapes. The stimuli consisted of binary pictures of natural objects, namely symmetric pictures of birds, butterflies, insects, and leaves. The ease of imagery (indicating the similarity of the sources) and the discriminability (indicating the similarity of the items) of each stimulus were estimated in a pretest and included as predictors of the memory performance for these stimuli. It was found that confusion of the sources becomes more likely when the imagery process was relatively easy. However, if the different processes of source monitoring-item memory, source memory and guessing biases-are disentangled, both experiments support the assumption that the effect of decreased source memory for easily imagined stimuli is due to decision processes and misinformation at retrieval rather than encoding processes and memory retention. The data were modeled with a Bayesian hierarchical implementation of the one high threshold source monitoring model. PMID- 26606753 TI - Recessive mutations in the cancer gene Ataxia Telangiectasia Mutated (ATM), at a locus previously associated with metformin response, cause dysglycaemia and insulin resistance. AB - AIM: To investigate glucose and insulin metabolism in participants with ataxia telangiectasia in the absence of a diagnosis of diabetes. METHODS: A standard oral glucose tolerance test was performed in participants with ataxia telangiectasia (n = 10) and in a control cohort (n = 10). Serial glucose and insulin measurements were taken to permit cohort comparisons of glucose-insulin homeostasis and indices of insulin secretion and sensitivity. RESULTS: During the oral glucose tolerance test, the 2-h glucose (6.75 vs 4.93 mmol/l; P = 0.029), insulin concentrations (285.6 vs 148.5 pmol/l; P = 0.043), incremental area under the curve for glucose (314 vs 161 mmol/l/min; P = 0.036) and incremental area under the curve for insulin (37,720 vs 18,080 pmol/l/min; P = 0.03) were higher in participants with ataxia telangiectasia than in the controls. There were no significant differences between groups in fasting glucose, insulin concentrations or insulinogenic index measurement (0.94 vs 0.95; P = 0.95). The Matsuda index, reflecting whole-body insulin sensitivity, was lower in participants with ataxia telangiectasia (5.96 vs 11.03; P = 0.019) than in control subjects. CONCLUSIONS: Mutations in Ataxia Telangiectasia Mutated (ATM) that cause ataxia telangiectasia are associated with elevated glycaemia and low insulin sensitivity in participants without diabetes. This indicates a role of ATM in glucose and insulin metabolic pathways. PMID- 26606754 TI - Urinary Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) * Insulin-Like Growth Factor-Binding Protein 7 (IGFBP7) Predicts Adverse Outcome in Pediatric Acute Kidney Injury. AB - BACKGROUND: The G1 cell cycle inhibitors tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been identified as promising biomarkers for the prediction of adverse outcomes including renal replacement therapy (RRT) and mortality in critically ill adult patients who develop acute kidney injury (AKI). However, the prognostic value of urinary TIMP-2 and IGFBP7 in neonatal and pediatric AKI for adverse outcome has not been investigated yet. METHODS: The product of the urinary concentration of TIMP-2 and IGFBP7 ([TIMP-2]*[IGFBP7]) was assessed by a commercially available immunoassay (NephroCheckTM) in a prospective cohort study in 133 subjects aged 0 18 years including 46 patients with established AKI according to pRIFLE criteria, 27 patients without AKI (non-AKI group I) and 60 apparently healthy neonates and children (non-AKI group II). AKI etiologies were: dehydration/hypovolemia (n = 7), hemodynamic instability (n = 7), perinatal asphyxia (n = 9), septic shock (n = 7), typical hemolytic-uremic syndrome (HUS; n = 5), interstitial nephritis (n = 5), vasculitis (n = 4), nephrotoxic injury (n = 1) and renal vein thrombosis (n = 1). RESULTS: When AKI patients were classified into pRIFLE criteria, 6/46 (13%) patients fulfilled the criteria for the category "Risk", 13/46 (28%) for "Injury", 26/46 (57%) for "Failure" and 1/46 (2%) for "Loss". Patients in the "Failure" stage had a median 3.7-fold higher urinary [TIMP-2]*[IGFBP7] compared to non-AKI subjects (P<0.001). When analyzed for AKI etiology, highest [TIMP 2]*[IGFBP7] values were found in patients with septic shock (P<0.001 vs. non-AKI I+II). Receiver operating characteristic (ROC) curve analyses in the AKI group revealed good performance of [TIMP-2]*[IGFBP7] in predicting 30-day (area under the curve (AUC) 0.79; 95% CI, 0.61-0.97) and 3-month mortality (AUC 0.84; 95% CI, 0.67-0.99) and moderate performance in predicting RRT (AUC 0.67; 95% CI, 0.50 0.84). CONCLUSIONS: This study shows that urinary [TIMP-2]*[IGFBP7] has a good diagnostic performance in predicting adverse outcomes in neonatal and pediatric AKI of heterogeneous etiology. PMID- 26606756 TI - In reference to "Obstructive sleep apnea and adverse outcomes in surgical and nonsurgical patients on the wards". PMID- 26606755 TI - Seroepidemiologic Survey of Potential Pathogens in Obligate and Facultative Scavenging Avian Species in California. AB - Throughout the world, populations of scavenger birds are declining rapidly with some populations already on the brink of extinction. Much of the current research into the factors contributing to these declines has focused on exposure to drug residues, lead, and other toxins. Despite increased monitoring of these declining populations, little is known about infectious diseases affecting scavenger bird species. To assess potential infectious disease risks to both obligate and facultative scavenger bird species, we performed a serosurvey for eleven potential pathogens in three species of scavenging birds in California: the California condor (Gymnogyps californianus), turkey vulture (Cathartes aura) and golden eagle (Aquila chrysaetos). California condors were seropositive for avian adenovirus, infectious bronchitis virus, Mycoplasma gallisepticum, avian paramyxovirus-2, West Nile virus (WNV) and Toxoplasma gondii. Golden eagles were seropositive for avian adenovirus, Chlamydophila psittaci and Toxoplasma gondii, and turkey vultures were seropositive for avian adenovirus, Chlamydophila psittaci, avian paramyxovirus-1, Toxoplasma gondii and WNV. Risk factor analyses indicated that rearing site and original release location were significantly associated with a positive serologic titer to WNV among free-flying condors. This study provides preliminary baseline data on infectious disease exposure in these populations for aiding in early disease detection and provides potentially critical information for conservation of the endangered California condor as it continues to expand its range and encounter new infectious disease threats. PMID- 26606757 TI - Retrospective review of intravenous pentamidine for Pneumocystis pneumonia prophylaxis in allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at risk of numerous opportunistic infections. Pneumocystis jirovecii pneumonia (PJP) is a potentially life-threatening infection that can develop in immunocompromised individuals. Current prophylaxis for PJP includes trimethoprim-sulfamethoxazole (TMP-SMX), dapsone, atovaquone, or inhaled pentamidine (PEN), often with varying breakthrough rates. The use of intravenous (IV) PEN for PJP prophylaxis has been evaluated in pediatric patients. METHODS: A single-institution retrospective review of electronic medical records was conducted for patients who underwent allo-HSCT between January 2001 and May 2013 and who had received at least 1 dose of IV PEN for PJP prophylaxis. Data collected included patient demographics, diagnosis, previous chemotherapy, pre-transplant conditioning regimen, other medications, microbiology test results, and clinical outcomes. RESULTS: A total of 113 patients were included in the study. The median number of PEN doses administered per patient was 3 (range 1-23). IV PEN was primary PJP prophylaxis in 74 of the patients (65%) and second-line prophylaxis in 39 (35%) post transplant, with the majority switching from oral TMP-SMX. Side effects of IV PEN administration were minimal. No patients who received IV PEN prophylaxis developed PJP infection. No case of PJP was seen in patients who received other agents for PJP prophylaxis. CONCLUSION: This retrospective study showed that IV PEN is very effective and well-tolerated prophylaxis for PJP; IV PEN can be considered a favorable alternative for PJP in situations where other agents might be contraindicated. Our findings provide strong support for prospective studies of IV PEN for PJP prophylaxis in adult HSCT recipients. PMID- 26606758 TI - Automated detection of white matter and cortical lesions in early stages of multiple sclerosis. AB - PURPOSE: To develop a method to automatically detect multiple sclerosis (MS) lesions, located both in white matter (WM) and in the cortex, in patients with low disability and early disease stage. MATERIALS AND METHODS: We developed a lesion detection method, based on the k-nearest neighbor (k-NN) technique, to detect lesions as small as 0.0036 mL. This method uses the image intensity information from up to four different 3D magnetic resonance imaging (MRI) sequences (magnetization-prepared rapid gradient-echo, MPRAGE; magnetization prepared two inversion-contrast rapid gradient-echo, MP2RAGE; 3D fluid-attenuated inversion recovery, FLAIR; and 3D double-inversion recovery, DIR), acquired on a 3T scanner. To these intensity features we added the information obtained by the spatial coordinates and tissue prior probabilities provided by the International Consortium for Brain Mapping (ICBM). Quantitative assessment was done in 39 early stage MS patients with a "leave-one-out" cross-validation. RESULTS: The best lesion detection rate (DR) performance in WM was obtained using MP2RAGE, FLAIR, and DIR intensities (77% for lesions >=0.0036 mL; 85% for lesions >=0.005 mL). Similar results were obtained excluding the DIR intensity as well as when using only MPRAGE and FLAIR (DR = 75%, P = 0.5720). However, the combination of FLAIR with DIR and MP2RAGE appeared to be the best for detecting cortical lesions (DR = 62%), compared to the other combination of sequences (P < 0.001). CONCLUSION: For WM lesion detection, similar results were observed when only conventional clinical sequences (FLAIR, MPRAGE) were used compared to a combination of conventional and "advanced" sequences (MP2RAGE, DIR). Cortical lesion detection increased significantly when "advanced" sequences were used. J. Magn. Reson. Imaging 2015. J. Magn. Reson. Imaging 2016;43:1445-1454. PMID- 26606760 TI - Methods in Cell Biology. Sorting and Recycling Endosomes. Preface. PMID- 26606759 TI - Immune Responses in Acute and Convalescent Patients with Mild, Moderate and Severe Disease during the 2009 Influenza Pandemic in Norway. AB - Increased understanding of immune responses influencing clinical severity during pandemic influenza infection is important for improved treatment and vaccine development. In this study we recruited 46 adult patients during the 2009 influenza pandemic and characterized humoral and cellular immune responses. Those included were either acute hospitalized or convalescent patients with different disease severities (mild, moderate or severe). In general, protective antibody responses increased with enhanced disease severity. In the acute patients, we found higher levels of TNF-alpha single-producing CD4+T-cells in the severely ill as compared to patients with moderate disease. Stimulation of peripheral blood mononuclear cells (PBMC) from a subset of acute patients with peptide T-cell epitopes showed significantly lower frequencies of influenza specific CD8+ compared with CD4+ IFN-gamma T-cells in acute patients. Both T-cell subsets were predominantly directed against the envelope antigens (HA and NA). However, in the convalescent patients we found high levels of both CD4+ and CD8+ T-cells directed against conserved core antigens (NP, PA, PB, and M). The results indicate that the antigen targets recognized by the T-cell subsets may vary according to the phase of infection. The apparent low levels of cross-reactive CD8+ T-cells recognizing internal antigens in acute hospitalized patients suggest an important role for this T-cell subset in protective immunity against influenza. PMID- 26606761 TI - Chris Marshall (1949-2015). PMID- 26606763 TI - Information in Health. Foreword. PMID- 26606762 TI - Medicare Program; Comprehensive Care for Joint Replacement Payment Model for Acute Care Hospitals Furnishing Lower Extremity Joint Replacement Services. Final rule. AB - This final rule implements a new Medicare Part A and B payment model under section 1115A of the Social Security Act, called the Comprehensive Care for Joint Replacement (CJR) model, in which acute care hospitals in certain selected geographic areas will receive retrospective bundled payments for episodes of care for lower extremity joint replacement (LEJR) or reattachment of a lower extremity. All related care within 90 days of hospital discharge from the joint replacement procedure will be included in the episode of care. We believe this model will further our goals in improving the efficiency and quality of care for Medicare beneficiaries with these common medical procedures. PMID- 26606764 TI - [IS PATIENT INFORMATION AN ILLUSION?]. AB - Although the idea is widespread today in the medical community that patients are fully informed, since this is now guaranteed by law, we should ask whether this information is always provided, and indeed truly encouraged. To answer this question, the reflection is based on data collected during two anthropological research projects, one on the information provided to people with serious diseases in the hospital environment and the other on information relating to medicines in the context of self-medication. This research reveals that the obligation to inform to which health professionals are bound is thwarted by the reality of information on the ground--which arises from cultural and social mechanisms--and that, despite declarations of faith in patient education, health information provision remains limited. PMID- 26606765 TI - [INFORMATION, A FUNDAMENTAL PATIENT RIGHT?]. AB - Although expressed before the "Lambert" case, which has led us to think about refusal and assent in the context of internal rights, conventional rights--and in the context of the patient's bed!--these simple remarks present the patient's right to medical information as a so-called fundamental right. But it can only be understood with a view to a treatment or other medical act; otherwise it has no reason to be and is only an academic exercise, however exciting, but not much use by itself. What if we reversed the terms of the problem: the right of the doctor to information? (The beautiful thesis of Ph. Gaston, Paris 8, 2 December 2014). PMID- 26606766 TI - [THE LACK OF PATIENT INFORMATION SANCTIONED BY JUDGMENT THE 9TH OF FEBRUARY 2012]. AB - Patient's right to information was explicitly recognised by law No. 2002-303 the 4th of March 2002, relating to patients' rights and to the quality of the health care system. This humanism duty is acknowledged to the article L.llll-2 of the Public Health Code. It guarantees the personal self-determination, as well as the dignity of the human person. It establishes a balance in the relation between the professional care and the patient, by allowing this one to have the adequate level of information to be completely associated with the decisions affecting his body integrity. Before the 3rd of June 2010 decision, the damage compensation was founded by the notion of loss of opportunity to avoid the realisation of the risk. Since then, it appears that the compensation of information deficiency constitutes an autonomous prejudice resulting from the non-compliance with the right to be informed and to consent to a physical injury. However, in the light of the 9'" of February 2012 judgment, it is necessary to consider if for the First Civil Chamber of the Final Court of Appeal, the failure to comply with the obligation of information causes a repairable damage for human dignity respect. PMID- 26606767 TI - [THE REMNANTS OF THE POWERS OF THE PHYSICIAN CONCERNING MEDICAL INFORMATION]. AB - The aim of the reporting obligation laid down by the law on the physician is to allow the patient to express their free and informed consent to health care and to be more concerned about their own health. However, the legislator has left particularly extensive pieces of power, making information a tool to. secure the misfit of medical conference. Furthermore, in practice the physician holds significant influential power on the patient's decision, sometimes unconscious, often controlled, and which the works of sociologists have highlighted. PMID- 26606768 TI - [INFORMATION ABOUT DRUGS]. AB - The disastrous nature of communication has a harmful effect on patients' confidence and consequences on the observance of their treatment. On the other hand, the European debate on the proposed directive on informing the public 'about drugs, although it has been somewhat slow, has clearly shown what is at stake and the complexity of the issue. PMID- 26606769 TI - [INFORMATION ON DRUGS]. AB - Drugs not being just a product like any other, prescribers, providers and patients must have access to the information relating the characteristics of such medicinal products. This information must be complete, objective and scientifically rigorous. It must be adapted to the use of the drug and be fully understandable. It should help in prescribing, expedite dispensing, and help the patient adhere to treatment. Thus, according to the recipient, the information will be different. It is the role of the pharmacist and the physician to use it for patient education. The information given must be objective. Medication guidelines published by HAS (Haute Autorite de Sante/National Health Agency) and Inserts given with the drugs should be considered the most reliable. Information can also be found in major scientific publication journals, in independent papers produced by groups of doctors and pharmacists, or in treatment guidelines. One must be very reserved about such information found on certain "Internet" sites. PMID- 26606770 TI - [HEALTH INSTITUTIONS: WHAT ABOUT RANKINGS, INDICATORS AND PERIODIC EVALUATIONS AVAILABLE TO THE "BIG" AUDIENCE?]. AB - This publication is a focus on what is proposed for the classification, evaluation of our health institutions. The Healthcare professionals and patients are usually interested to know the best... and avoid the worst. Some publications do not hesitate to publish blacklists of institutions. In France, the information provided by the minor and the great media and official accreditation agencies, do not concern the quality of service or the service provided to patients. This explains the low impact of the press in the choice of a health facility. Health is a unique and complex product/The request for information is mostly focused on the quality of care with respect to a specific treatment and improving the quality of life after this treatment. A more coordinated management of administrative information and better communication on improving the quality of life after admission would be more useful and relevant, when the choice is still possible between several health facilities. Medicine is an art, not an exact science. Many other terms and measures are needed to avoid any mercantile influences or manipulation of the public... It will take a few years to bring them together! PMID- 26606771 TI - [INFORMATION ABOUT HOSPITALS AND THE ORGANISATION OF THE HEALTHCARE SYSTEM: EVALUATION OR CLASSIFICATION? THE USERS' POINT OF VIEW]. AB - Until recently users felt that the French healthcare system was the best in the world and consequently all of the actors, structures and organisations were of a similar level of excellence and competence. Patients were often directed by their general practitioner or by the opinion of their friends and family. This feeling of homogenity of the quality of the hospitals or healthcare professionals has disappeared. Nowadays users want to have information which is useful for them and allows them to find their way in an organisation of healthcare that is very complex, and therefore a source of inequality. This informaion may come from institutional sites, league tables in newspapers or Internet sites. But, if it is to be useful, this information must be accessible and understandable by all, both in form and content. This is not always the case. It is in the interest of the healthcare system to be as transparent as possible, so it must resolutely go in this direction. PMID- 26606772 TI - Monitoring the Trends of Change. PMID- 26606773 TI - A nurse's bond knows no bounds. PMID- 26606774 TI - Marilyn Bagwell Leadership Development Grant Allows SNA to Fund Remote Area Clinics Service Project and Further Involvement in NSNA. PMID- 26606775 TI - Looking back--how NSNA responded to Katrina disaster call for help. PMID- 26606776 TI - Nursing in the 21st Century: Find Opportunities to Practice in Interprofessional Healthcare Teams. PMID- 26606777 TI - WHAT DOES THE FUTURE HOLD FOR HEALTHCARE DELIVERY? OPPORTUNITIES FOR EMERGING NURSE LEADERS. PMID- 26606778 TI - Expanding Horizons: Nurses Building a Culture of Health in America. PMID- 26606779 TI - Social Media in Nursing. PMID- 26606780 TI - SOME INDICATORS OF HEALTH CARE STATUS IN CROATIA. AB - The article presents the basic principles of health care, health care measures and strategic objectives of these measures in Croatia. The health of the population does not depend solely on the activities of the health care system but also on various demographic indicators. Our success in implementing health care depends largely on the structure of health facilities and health workers. The Croatian health system in late 2013 had permanently employed 74,489 workers. Out of these, 77% were health care workers. Most health care workers had only secondary school education (37.7%); physicians represented 17.4% of the workforce. On assessing the health of the population, certain health indicators are of utmost importance. The leading cause of deaths were circulatory diseases (in 2012, 24,988 persons died, 585.5/100,000). Neoplasms were the cause of death in 13,940 persons (326.6/100,000), then injuries and poisoning (69.1/100,000), diseases of the gastrointestinal system (53.1/100,000), and respiratory diseases (50.4/100,000). Data are presented on the basis of diseases reported from several national registries (cancer, psychoactive drug abuse, the disabled, diabetes, and suicides). The importance of vaccination for the control of infectious diseases in Croatia is especially emphasized, as well as the experience and excellent results achieved in this area. The epidemiological situation in Croatia in terms of infectious diseases can be assessed as favorable. This is due to the general living conditions, which contributed to the entire health system, making Croatia equal to other developed countries of Europe and throughout the world. PMID- 26606781 TI - [CHARACTERISTICS AND INCIDENCE OF HEAD AND NECK SKIN MALIGNANT NEOPLASMS IN THE POPULATION OF THE OSIJEK-BARANYA COUNTY 2004-2012]. AB - The aim of this study was to investigate the incidence and characteristics of malignant neoplasms of the skin of the head and neck region in the Osijek-Baranya County during the 2004-2012 period according to gender, age, place of residence, place of work, occupation, type and location of the neoplasm, and phenotypic characteristics of patients. SUBJECTS: The study included all subjects with the diagnosis confirmed by histopathology finding and residents of the Osijek-Baranya County. The study included a total of 2952 persons, 1487 (50.4%) male and 1465 (49.6%) female, yielding an approximate annual incidence of 104/100,000. Mean age was 72 years. Respondents were mostly from rural areas (n = 1952, 66.2%). There were 2137 (72.4%) of respondents mostly working outdoors, mainly farmers (n = 907, 42.4%) and construction workers (n = 889, 41.6%). RESULTS: According to the type of neoplasm, the basal cell type was most common with 2160 (73.2%) patients. Ninety-three (3.1 %) patients had malignant melanoma. According to localization, face was the most common site of malignant neoplasms with 839 (28.7%) and nose with 643 (22.0%) patients. Squamous cell carcinoma was significantly more common in men (n = 341, 56.6%) as compared with women (n = 262, (43.4%; p = 0.005). Subjects with malignant melanoma were significantly younger, with median age of 67 years. There were no significant differences according to the type of malignant neoplasms and place of residence, place of business, and occupation with regard to working outdoors or indoors. According to localization, significantly more squamous cell malignancies were found on the ears and lips (p = 0.039 and p < 0.001, respectively), malignant melanomas on the neck, head and eyes (p = 0.004, p < 0.001 and p = 0.026, respectively), and basal cell neoplasms on the nose (p = 0.002). There were no significant differences in the type and frequency of malignant neoplasms according to hair and eye color. CONCLUSION: It is obvious that the disease occurs after a decades-long incubation period and the cumulative effect of exposure to risk factors, with direct sun exposure, seems to have a significant role. Additional research is needed. PMID- 26606782 TI - [PROGNOSTIC ROLE OF NF-kappaB EXPRESSION IN DIFFUSE LARGE B-CELL LYMPHOMA SUBGROUPS]. AB - OBJECTIVE: Diffuse large B-cell lymphoma (DLBCL) with germinal center B-cell (GCB) phenotype has better prognosis than activated mature B-cell (ABC) phenotype or type 3 subgroup. Previous studies have reported on a major role of the nuclear factor-kappaB (NF-kappaB) in ABC and type 3 phenotypes, whereas GCB phenotype is characterized by frequent REL amplifications. METHODS: In 99 patients diagnosed with DLBCL, the presence of CD10, BCL6 and MUM1 was analyzed by immunohistochemical method to divide them into the GCB, ABC and type 3 subgroups. Then, NF-kappaB expression was analyzed in the nucleus and cytoplasm. Nuclear NF kappaB expression was detected in 22 (22%) cases from all DLBCL subgroups. NF kappaB expression in the cytoplasm was recorded in 77 (77%) cases from all DLBCL subgroups and this finding was significant. RESULTS: Results on the presence of CD10, BCL6 and MUM1 and the presence of NF-xB in the nucleus were not significant. Analysis of nuclear NF-kappaB accumulation is not associated with any of the clinical parameters including age, sex, stage of disease, therapy administered and IPP. According to Hans et al., patients with NF-kappaB expressed in the cytoplasm have significantly poorer survival irrespective of the subgroup than patients without cytoplasmic NF-kappaB, and these results are significant. Patients with GCB phenotype and negative nuclear NF-kappaB expression have better survival than those with GCB phenotype and positive nuclear NF-kappaB expression, and these results are also significant. Patients having received chemotherapy according to the R-CHOP schedule and with positive nuclear NF-kappaB expression have better survival; however, these results are not significant. DISCUSSION AND CONCLUSION: These data suggest that nuclear and cytoplasmic NF-kappaB expression may be a prognostic factor in DLBCL, thus explaining the stratified risk observed in patients in combination with GCB/non-GCB phenotype. Our study showed the NF kappaB activity to be crucial in all DLBCL subgroups, thus potentially representing a promising molecular target for future therapies. PMID- 26606783 TI - [THE ROLE OF STABILIZATION SPLINT IN THE TREATMENT OF TEMPOROMANDIBULAR DISORDERS]. AB - Stabilization splint is the treatment of choice for pain control in temporomandibular disorder (TMD) patients, even though its mechanism of action is still unknown. The aim of this systematic review is to provide a critical overview of the effectiveness of stabilization splint therapy on the basis of currently available literature data. The available Medline database was searched and 24 studies published since the 1995s have been consequently included in this review. The selection criteria were randomized controlled trials and clinical trials comparing splint therapy to either no treatment or another active treatment (physiotherapy, relaxation and drugs). Studies were grouped according to treatment type. Based on the currently best evidence available, it appears that stabilization splint has similar efficacy in controlling TMD symptoms as other active treatments (physiotherapy, relaxation and drugs). Stabilization splint therapy may be beneficial in reducing pain at rest and on palpation when compared with non-occluding splint. During a short period, education was slightly more effective than occlusal splint in treating spontaneous muscle pain. These two treatments did not have significantly different effects on pain-free mouth opening and pain during chewing. This review has shown evidence that most TMD patients are helped by incorporation of a stabilization splint. There is not enough data on the long-term efficacy and effectiveness of this widely used therapeutic tool. In the future, there is a need for well-conducted randomized controlled trials paying attention to adequate sample size, blind outcome assessment, duration of follow up, and using standardized methods for measuring treatment outcomes. PMID- 26606784 TI - [DENTIST AND EARLY DETECTION OF ORAL CARCINOMA]. AB - Oral cancer is one of the ten cancers with the worst prognosis. Higher mortality rate is due to the fact that the majority of cases are diagnosed at an advanced stage. Early stage of the disease causes no discomfort and symptoms start to present in later stages. Oral cancer can be detected in its earliest stage by simple examination of oral mucosa. Oral mucosa can be easily examined during routine dental examination. The examination itself is noninvasive, takes no more than one minute, does not require any special equipment, and poses no discomfort to the patient. Apart from better knowledge about the physiological and pathological characteristics of oral mucosa, dentist is in an ideal position to perform oral mucosa examinations every day, since he/she regularly sees the patient oral cavity. In Croatia, between 300 and 400 new cases of oral carcinoma per year are diagnosed at the sites that are visible during routine dental examination. Since oral cancer in its early stage does not cause any symptoms, dentists should be sensitized/motivated to perform mucosal as well as dental examinations in all patients irrespective of the patient's lack of complaint. PMID- 26606785 TI - [LOW BACK PAIN AT NEW WORKING AMBIENT IN ERA OF NEW ECONOMY: A SYSTEMATIC REVIEW ABOUT OCCUPATIONAL RISK FACTORS]. AB - Low back pain is the second most common symptom-related reason for physician visits and the first reason of working disability. Low back pain is a ubiquitous complaint, with particularly high prevalence among people in their working years (67%). For many individuals, episodes of back pain are self-limited and resolve without specific therapy. For others, however, back pain is recurrent or chronic, causing significant pain that interferes with employment and quality of life. Many occupations have been anecdotally linked to certain low back pain syndrome. However, the relationship between the work environment and the patient's symptoms, though clearly perceived by the patient to be causative, may be less certain. The injury model of an occupational disorder proposes that specific work activities are the cause of the patient's pain. The injury model for low back pain; implicating a causal connection with specific work activities, is complex and controversial. Determining whether a patient's low back pain is a consequence of his or her occupational activity, and how best to treat symptoms to maximize functionality and potential for a return to full employment capacity, can be challenging. In this systematic review which included patients/employees with low back pain, the following databases were searched: Pub Med, Embase, Medline and Web of science. The role of occupational mechanical exposure e.g. lifting as a risk factors for low back surgery has been debated for several decades. Diagnostic uncertainty exists even for those with back symptoms and well described findings on scan, as these findings are common even in subjects without back pain, and may be unrelated to the symptoms. As an example, herniated disks can be identified in significant numbers of CT or MRI low back studies in subjects with no back pain. In further analysis, lifestyle factors and occupational psychosocial exposures will be addressed. Many physicians, including those practicing in primary care settings where back pain is most often seen, lack training and confidence in addressing workplace issues. Occupational factors that have a significant influence on the development of low back pain disorders are not only mechanical and postural order but also organisational, social and psychological. Organisational changes and physical and psychological job demands should not be overestimated as causal factors. In the early phase of a work disability more emphasis should be laid however on appropriate information and medication and, in case of persistant impairment, active treatment (after 3 weeks or relapse). There is some evidence that catastrophizing as a stress coping strategy might lead to delayed recovery. Long-term work (sick) absence can be estimated through evaluation and observation of LBP risks and characteristics of the each individual case. An early return at workplace and to activities of daily life is urgent. To reduce LBS and its consequences, employers need to adopt a multifaced approach: concentrate on improving physical conditions as well as the psychosocial and environmental aspects of working environment. In cases at risk for chronification and/or with obstacles to reintegration at work an interdisciplinary work-oriented rehabilitation and occupational rehabilitation interventions (occupational reintegration) should be provided. PMID- 26606786 TI - [ASSOCIATION OF PSORIASIS WITH OTHER DISEASES]. AB - Psoriasis is a chronic relapsing autoimmune disease with a multigenetic predisposition, which occurs in about 2% of patients in Croatia and shows variable occurrence in the world. Psoriasis can be associated with various diseases, including autoimmune diseases (pemphigus, pemphigoid, vitiligo), and slightly less with allergic diseases (atopic dermatitis, asthma, urticaria, allergic contact dermatitis). According to clinical manifestations, psoriasis appears as plaque psoriasis, erythrodermic form and pustular psoriasis. Provocative factors that encourage psoriasis are infections, endogenous factors, hypocalcemia, psychogenic factors and medications. Psoriasis may worsen other dermatoses such as contact dermatitis, inflammatory dermatoses and skin cancer, and the association of psoriasis with internal diseases is quite common (HIV, Crohn's disease, liver lesions, vascular diseases, amyloidosis and gout). Today, psoriasis is considered as a systemic inflammatory disease that can also affect the joints. Atypical localization of psoriasis, as well as resistant cases of psoriasis and other papulosquamous and eczematoid dermatoses require detailed work-up and confirming of diagnosis because of the possibility of the existence of other diseases. This paper discusses the association of psoriasis with rheumatic and other internal diseases. PMID- 26606788 TI - [Reduction in variability of individual colonization programs in black-headed gulls (Larus ridibundus) leads to reproductive success diminishing]. AB - The problem of adaptive significance of territorial antagonism in colonial birds is addressed. Many of these birds are characterized, along with high tolerance to each other and tendency to aggregate, by intensive and variable territorial demonstrations. Here we consider the effects of territorial behavior on the viability of a breeding colony. We observed breeding of black-headed gull in two colonies formed under the impact of a short-term temperature fall in 2008, which resulted in the 7-day shift in timing of egg laying. Compared with the colonies at the same places, one in 2007 and one in 2009, in 2008 the number of nests and their density were rather smaller, whereas the duration of settling, the nest density increase and the average size of breeding territories have not changed. Average body weight of adult birds during incubation was stable through all the years. However, correlations, typical for 2007 and 2009 (negative between female mass and date of.clutch starting, and positive between masses of parents), were absent, suggesting that assortative mating by body mass and territory size was not the case in 2008. Average clutch, egg, and hatchling sizes were smaller in 2008 while mortality due to aerial predators was higher than in normal years. In 2007 and 2009, birds who started egg laying in the first 5 days after the first egg appeared in the colony (settlers) were larger than others (so-called followers) and produced larger offspring. These differences were not observed in 2008. According to our data, after the impact of cold weather, some birds abandoned their nesting sites, others were sick but mostly behaved as settlers and formed underpopulated and sparse colonies. We assume that the formation of a viable colony requires interaction of highly territorial 'pioneers' and a certain number of less competitive individuals. Withdrawal of the latter results into a general reproductive failure of the colony. Thus, the pattern of colony forma- tion as in the black-headed gull turns natural selection towards maintenance of the variety of individual programs of territorial competition. PMID- 26606789 TI - [The evolutionary role of predatory mammals and mechanisms of its realization]. AB - Considered are the interactions within food chains that allow to refine the mechanisms of selective prey taking, which is important for better understanding of the evolutionary role of predation. By use of greyhounds, the hunting by wild canids is modelled for the purpose of repeated reproduction of searching for, chasing, and taking off the prey. It is found out that parameters of chasing (i.e., speed, distance, duration) are important for hunting but not determinative. There can be a high actual selectivity determined by prey conditions and, at the same time, low success of chasing. The mechanisms of recognition of potential prey availability or unavailability are analyzed. The data are presented that indicate that superficial microflora can be considered as a common marker of various, deviations in the state of a prey. Unlike stabilizing selection, which preserves separate traits, selection by predation stabilizes the phenotype as a whole. PMID- 26606790 TI - [On the relation between encounter rate and population density: Are classical models of population dynamics justified?]. AB - A stochastic model of migrations on a lattice and with discrete time is considered. It is assumed that space is homogenous with respect to its properties and during one time step every individual (independently of local population numbers) can migrate to nearest nodes of lattice with equal probabilities. It is also assumed that population size remains constant during certain time interval of computer experiments. The following variants of estimation of encounter rate between individuals are considered: when for the fixed time moments every individual in every node of lattice interacts with all other individuals in the node; when individuals can stay in nodes independently, or can be involved in groups in two, three or four individuals. For each variant of interactions between individuals, average value (with respect to space and time) is computed for various values of population size. The samples obtained were compared with respective functions of classic models of isolated population dynamics: Verhulst model, Gompertz model, Svirezhev model, and theta-logistic model. Parameters of functions were calculated with least square method. Analyses of deviations were performed using Kolmogorov-Smirnov test, Lilliefors test, Shapiro-Wilk test, and other statistical tests. It is shown that from traditional point of view there are no correspondence between the encounter rate and functions describing effects of self-regulatory mechanisms on population dynamics. Best fitting of samples was obtained with Verhulst and theta-logistic models when using the dataset resulted from the situation when every individual in the node interacts with all other individuals. PMID- 26606791 TI - [The role of chemoreception in forming of Daphnia longispina sustainable population (the simulation experiments)]. AB - Individual-based mathematical models may be considered a promising tool for studying the patterns of aquatic animals population development under conditions of exposure to various environmental factors including those ones that are difficult to measure directly. To test the hypotheses on the role of chemoreception in vital activity of aquatic invertebrates, we used the previously designed individual-based simulation model of a mass pelagic species, Daphnia longispina, population. The model describes a population as an ordered list of individuals with specific set of traits. For each individual, its energetic traits are calculated, also the probabilities of outcomes from different life situations are assigned or calculated. Included in the model are responses of adult individuals to two types of chemical signals: 1) diurnal vertical migrations from surface to hypolimnion when detecting fish cairomones; 2) active search for mature females by adult males via pheromones, effects of which grow stronger with water temperature raising. By comparison with previous versions of the model, introduction of these responses allowed to reproduce seasonal dynamics of the model population most closely to real dynamics of the prototype population. Consecutive, and then joint switching off of the ability to detect chemical signals made it possible to obtain a quantitative estimate of their role in population dynamics optimization and to determine limiting levels of predators, both vertebrate and invertebrate, pressure on organisms lacking the ability to use chemotaxis. In particular, it was found out that, in the model population, the size of water flea spring generation is determined by the amount of overwintered dormant eggs which increases as a result of active search for mature females due to chemoreception. The size of summer-autumn generation is practically independent of initial numbers and is determined by living conditions during the season, first of all by the factor of consumption by predators. Chemoreception helps adult water fleas in avoiding to be eaten, which turns out to be effective in maintaining high abundance even at considerable pressure by predatory fishes. When a water flea population is deprived of the ability to response to chemical signals (for example, when there is no hypolimnion or shelters among vegetation), predation press increasing above some threshold, which depends on duration of embryonic development, leads to population instability and its decreasing in numbers till the total extinction. The model allowed to obtain a quantitative estimate of the role of chemoreception in forming of water flea population dynamics. In the present version of the model, annual production of the population is shown to raise 1.5 times due to chemoreception. In the absence of chemoreception, water flea population fails to use environmental resources in full measure and come up to production rates observed in nature. PMID- 26606792 TI - [Coral reefs in the face of ecological threats of XXI century]. AB - To date, more than a quarter of tropical coral reefs of the World Ocean are believed to be totally de- stroyed. Given the present rates of reefs degradation, this value may be doubled in the nearest 30 years. For the essential part of coastal community, the destruction of coral ecosystems implies the loss of the major food sources, natural protection from storms, and significant (if not the only) revenue from exploi- tation of reefs especially in tourism industry. Finally, the disappearance of low-laying coral islands may threat the local communities by deprivation of living space. Global negative effects include temperature anomalies of sea surface waters and an increase of atmospheric CO2 concentration leading to ocean acidification. Local negative effects are related to in- crease of sedimentation and eutrophication, cyclone and storm passes, coral diseases, chemical pollution, mechanical destruction of corals by humans, anthropogenic depletion of functional groups of fish and invertebrates. An entire set of responses of coral ecosystems to stressful factors on the levels of both separate taxa and ecosystem is discussed. An analysis of published data suggests that with high probability the tropical coral communities will come to collapse stage by the middle of the current century at more than 50% of the area of their biogeographic range, especially in the regions of dense human population. At the most optimistic scenario, complex effect of reviewed negative factors will result in coral ecosystems main- taining in some areas. However, after global transformations, these ecosystems will be dominated by the most resistant taxa, mainly massive and encrusting forms of long-lived species with low growth rates and high competitive ability. Among such taxa, Poritidae demonstrates the highest adaptive capability. At the most pessimistic scenario, scleractinian communities will be replaced by alternative communities of macroalgae and non-calcareous anthozoans. PMID- 26606794 TI - [The Principle of Genome Complementarity in the Enhancement of Plant Adaptive Capacities]. AB - In the present work, the potential for the enhancement of the adaptive capacity of microbe-plant systems (MPSs) through the integration of the symbiosis partners' genomes is considered on the example of different types of symbiotic relationships. The accumulated data on the genetic control of interactions for both the plant and microbe, which are discussed in the paper with respect to signaling genes, suggest that it is the complementarity of genetic determinants that underlies the successful formation of MPSs. A eukaryotic genome with limited information content, which is stable throughout a generation, is complemented by a virtually unlimited prokaryotic metagenome. The microsymbiont's ability to adapt to different living conditions is based on the restructuring of the accessory genome by different mechanisms, which are likely to be activated under the influence of plants, although the details of such a regulation remain unknown. Features of the genetic control of the interaction, particularly its universal character for different symbionts, allow us to formulate a principle of genome-complementarity with respect to interacting organisms and consider it an important factor, an adaptation that enhances the abilities of M PSs for their sustainable development in natural ecosystems and for high plant productivity in agrocenoses. PMID- 26606796 TI - [Genealogical Analysis of the Use of Aegilops (Aegilops L.) Genetic Material in Wheat (Triticum Aestivum L.)]. AB - A genealogical analysis of accessions in the global gene pool of the wheat database GRIS4.0 showed that the use of the genetic material of Aegilops in wheat breeding began about half a century ago. During this time, more than 1350 varieties and 9000 lines, the pedigree of which contains Aegilops species, were created in different regions of the world. The spatial and temporal dynamics of the distribution of wheat varieties containing the genetic material of Aegilops was investigated. Analysis of the data showed that most commercial varieties with a pedigree including Ae. tauschii and/or Ae. umbellulata were created and grown in North America. More than 70% of the varieties were produced with Ae. ventricosa, which is common in western and central Europe. A gradual increase in the proportion of varieties with Aegilops genetic material was recorded from 1962 to 2011. The percentage of varieties created with the involvement of Ae. umbellulata increased from 1-5% in the 1960s to 25-29% in the 2000s. Those created with Ae. tauschii increased from 0% to 14-18%, and those created with Ae. ventricosa increased from 1% to 34-37%. The increases in the number of these varieties indicates that the resistance genes from Aegilops species retain their effectiveness. Genealogical analysis of the varieties in which resistance genes from Aegilops were postulated revealed that varieties or lines that were sources of identified genes were often absent in the pedigree. This may be due to an incorrect pedigree record or errors in the identification of resistance genes by phytopathological testing and/or the use of molecular markers, or confusion in nurseries. Preliminary analysis of pedigrees provides an opportunity to reveal discrepancies between the pedigree and postulated genes. PMID- 26606795 TI - [Analysis of Phenotypic Manifestation of peanut Gene Expression Suppression by RNAi in Drosophila Oogenesis]. AB - The peanut gene functions in Drosophila melanogaster oogenesis were studied. It was demonstrated that the suppression of peanut expression by RNA interference in the ovary follicular cells results in the violation of oocyte polarization, anomalous cytokinesis in the chorion cells, and violation of the chromatin condensation in follicular cells. No oogenesis violations were observed in females with decreased peanut gene expression or an absence of the Pnut protein in the ovary generative cells. However, embryos produced by such females had a decreased survival rate caused by two death peaks. PMID- 26606797 TI - [Genetic Polymorphism of Durum Wheat (Triticum durum Desf.) Accessions of Azerbaijan]. AB - The genetic diversity of 110 durum wheat genotypes of Azerbaijan was evaluated by ISSR markers. A total of 107 fragments were determined, ranging from 9 to 18 per locus. ISSR primers have revealed a high level of polymorphism (average 82%) among different durum wheat varieties and botanical varieties. The ISSR markers used in the study were quite informative and made it possible to distinguish all durum wheat accessions from each other. Cluster analysis based on ISSR data classified the accessions into 11 major groups. No linkage was observed between the collection site and genetic structure of the samples. On the other hand, a few accessions were detected as unique genotypes and tended to form separate clusters. The estimated gene diversity value was high, both within the whole collection and within the different groups of botanical varieties. PMID- 26606798 TI - [Genetic Differentiation of Balkhash Perch Perca schrenki Kessler, 1874 from Lake Balkhash and Alakol Lake System of Kazakhstan]. AB - The genetic differentiation of two populations of Balkhash perch Perca schrenki Kessler, 1874 was examined. The study included (1) the population of Lake Balkhash and the Ili River delta, where this species is protected and it is prohibited to catch them and (2) the population of Alakol Lake system, where it is the main commercial species and forms two morphotypes--pelagic and coastal. Analysis of the mitochondrial DNA COI gene and. six microsatellite loci revealed genetic differentiation at the population level, while no statistically significant differences were found at the morphotype level. The results of this study make it possible with high probability to determine the belonging of caught fish to either the commercial (Alakol Lake system) or protected (Lake Balkhash) population. PMID- 26606799 TI - [On the Population Genetic Portrait of Kaluga, Acipenser dauricus Georgi, 1775 Analysis of Sequence Variation in the Mitochondrial DNA Control Region]. AB - The variability of the mtDNA D-loop was examined in kaluga endemic to the Amur River, which is classified as critically endangered by the IUCN Red List of Threatened species. Sequencing of the D-loop fragment (819 bp) in 122 kaluga specimens collected in Lower Amur revealed 27 unique genotypes. The sample was characterized by a relatively low level of haplotypic (0.927) and nucleotide (0.0044) diversity. No considerable deviations from the neutral mutation model of DNA polymorphism were observed. Overall, the mismatch distribution patterns and the results of testing of simple demographic models (sudden demographic expansion and exponential population growth) pointed to a past increase in the number of kaluga sturgeons. According to the Bayesian skyline, the kaluga population doubled over the last two to three thousand years. The number of mature females in the modern kaluga population and the assessment of their long-term effective population size (Nef) are roughly at the same level (about three thousand individuals), which confirms the validity of assigning kaluga to the category of species on the brink of extinction. PMID- 26606800 TI - [Variation and Distribution of the Eelpout Species of the Genus Zoarces (Pisces: Zoarcidae) of the Sea of Okhotsk]. AB - Complex molecular genetic, karyological, and comparative morphological analyses of eelpouts of the genus Zoarces from the Sea of Okhotsk were carried out. Genetic heterogeneity of Z. elongatus and the existence of a considerably diverged form probably deserving of species status was discovered. The eelpouts caught near Shantar Islands were identified as Z. fedorovi and Z. andriashevi. The new data point to a wider distribution of these species, from Western Kamchatka to the Shantar Islands. PMID- 26606801 TI - [Spatial Genetic Structure of the Crested Auklet (Aethia cristatella Pallas, 1769) Colony as Inferred from Data on the Mitochondrial DNA Control Region and Microsatellite Loci]. AB - The effect of philopatry on the formation of the intrapopulation structure in the crested auklet colony of the Talan Island, Taui Bay of the Sea of Okhotsk, was examined. The nucleotide sequences of the mitochondrial DNA control region fragment (408 bp) and five microsatellite loci (Apy03, Apy04, Apy06, Apy07, Apy10) in individuals from two study plots of the colony were examined. A high genetic diversity (h = 0.999 +/- 0.003) and the absence of intrapopulation genetic differentiation was observed at both types of markers. Thus, despite the high level of nest-area fidelity in breeding adults, no genetic isolation was revealed for crested auklets from different parts of the Talan Island colony. PMID- 26606803 TI - GENETIC DIVERSITY, PARENTAGE VERIFICATION AND GENETIC BOTTLENECKS EVALUATION IN IRANIAN TURKMEN HORSE BREED. AB - The present study was undertaken to genetically evaluate Turkmen horses for genetic diversity and to evaluate whether they have experienced any recent genetic bottlenecks. A total of 565 individuals from Turkmen horses were characterized for within breed diversity using 12 microsatellite markers. The estimated mean allelic diversity was (9.42 +/- 1.78) per locus, with a total of 131 alleles in genotyped samples. A high level of genetic variability within this breed was observed in terms of high values of effective number of alleles (4.70 +/- 1.36), observed heterozygosity (0.757 +/- 0.19), expected Nei's heterozygosity (0.765 +/- 0.13), and polymorphism information content (0.776 +/- 0.17). The estimated cumulative probability of exclusion of wrongly named parents (PE) was high, with an average value of 99.96% that indicates the effectiveness of applied markers in resolving of parentage typing in Turkmen horse population. The paternity testing results did not show any misidentification and all selected animals were qualified based on genotypic information using a likelihood-based method. Low values of Wright's fixation index, F(IS) (0.012) indicated low levels of inbreeding. A significant heterozygote excess on the basis of different models, as revealed from Sign and Wilcoxon sign rank test suggested that Turkmen horse population is not in mutation-drift equilibrium. But, the Mode-shift indicator test showed a normal 'L' shaped distribution for allelic class and proportion of alleles, thus indicating the absence of bottleneck events in the recent past history of this breed. Further research work should be carrying out to clarify the cause of discrepancy observed forbottleneck results in this breed. In conclusion, despite unplanned breeding in Turkmen horse population, this breed still has sufficient genetic variability and could provide a valuable source of genetic material that may use for meeting the demands of future breeding programs. PMID- 26606802 TI - [Mitochondrial DNA Polymorphism in Different Populations of Spangled Orloff Chickens]. AB - For the first time, the genetic diversity of the Spangled Orloff chickens was studied by analyzing the polymorphism of the hypervariable region in the D-loop of mitochondrial DNA (mtDNA). Samples for the analysis were collected at the farms ofthe All-Russia Poultry Research and Technological Institute (VNITIP), the All-Russia Institute of Farm Animal Genetics and Breeding (VNIIGRZh), and the Moscow Zoo. The D-loop partial sequences (between nucleotide positions 57 and 523) were determined according to the reference sequence of Gallus gallus spadiceus mtDNA, NC_007235 in 39 individuals obtained from these populations (GenBank Accession Nos. KM391754-KM391792). In the analyzed mtDNA fragment, a total of 20 polymorphic sites localized between positions 167 and 368, as well as at position 446, were described in Spangled Orloff chickens. One polymorphic site at position 221 (haplogroup E, haplotype ORL-2) was unique. All of the identified nucleotide changes were transition-type substitutions. Overall, based on the analysis of poly- morphic sites in the hypervariable fragment of the D-loop of Spangled Orloff chicken mtDNA, we found seven haplotypes belonging to four haplogroups (A, B, C, and E). Haplogroup E (haplotypes ORL-1, ORL-2, and ORL-3) was present in the majority of the studied individual, with the frequencies of 0.77 in the total sample and 0.47 in the VNIIGRZh farm population. Haplogroups A (haplotypes ORL-4 and ORL-7), B (ORL-6), and C (ORL-5) were found only in samples from the VNIIGRZh farm. The studied mtDNA region revealed a lower level of polymorphism in the VNITIP and Moscow Zoo populations, which only had the ORL-1 and ORL-3 haplotypes belonging to Haplogroup E, respectively. Our data suggested that the studied Spangled Orloff chicken populations differed in the composition and frequencies of mtDNA haplogroups and haplotypes. PMID- 26606804 TI - [SMN1 Gene Point Mutations in Type I-IV Proximal Spinal Muscular Atrophy Patients with a Single Copy of SMN1]. AB - Type I-IV proximal spinal muscular atrophy (SMA) is one of the most common autosomal-recessive diseas- es, which are characterized in the majority of cases by a severely disabling course. Proximal SMA results from mutations in the telomeric copy of SMN-SMN1 gene. Major SMN1 gene mutation types are deletions in the exons 7 and/or 8, which were revealed to be in the homozygous state in 95% of patients. Deletions in the in- dicated exons of SMN1 gene were revealed in a compound-heterozygous state in combination with intragenic point mutations in the remainder 5% of proximal SMA cases. In the present study, we conducted an analysis of point mutations in eight patients with type I-III proximal SMA phenotype, which had a deletion in 7-8- exons of SMN1 gene in the heterozygous state. We revealed seven different mutations, two of which (c.824G > C (p.Gly275A1a) and c.825-2A > T) are described here for the first time. In addition, mutation c.824G > C (p.Gly275A1a) was observed twice in the examined sample. In seven cases a heterozygous carrier of point mutations was one of the parents of the affected children (in six cases, the father; in one case, the mother). Only one mutation, c.43C > T (p.Gln15X), emerged de novo in a genital cell of the child's father. PMID- 26606805 TI - [dFOXO Transcription Factor Regulates Juvenile Hormone Metabolism in Drosophila melanogaster Females]. AB - dFOXO transcription factor is a component of the insulin/insulin-like growth factor signaling pathway in Drosophila. Juvenile hormone negatively regulates dFOXO gene expression. In the present work, the effect of hypomorphic dFOXO mutation on juvenile hormone metabolism under normal and stressing conditions and on D. melanogaster female resistance to thermal stress was studied. It was demonstrated that dFOXO mutation in D. melanogaster females induces (1) an increase in the level of juvenile hormone degradation and in the intensity of the response of the juvenile hormone metabolism system to thermal stress and (2) a decrease in thermal stress resistance. These parameters are indicators of the level of juvenile hormone synthesis and indicate its decrease in females with decreased dFOXO expression. Thus, the presence of feedback in the regulation of dFOXO gene expression by juvenile hormone was established for the first time. PMID- 26606806 TI - [MtDNA Polymorphism of Lake Baikal Epischura--A Key Endemic Species of the Plankton Community]. AB - The population structure of Epischura baicalensis Sars (Copepoda, Calanoida), one of the key endemic species of the plankton community of Lake Baikal was studied. An analysis of mitochondrial DNA polymorphism revealed no genetic differences between Epischura sampled in the different basins of the lake or in the winter spring/summer generations. Baikal Epischura is represented by a single panmictic population with a high level of mtDNA haplotype diversity. PMID- 26606807 TI - What's wrong with Dr. Oz? PMID- 26606808 TI - Tax Resolution and Bankruptcy for Professionals. PMID- 26606809 TI - To Roth or Not to Roth, That is the Question. PMID- 26606810 TI - Protecting Our Profession Through Telemedicine. PMID- 26606811 TI - Missouri Physicians Share Medical Expertise with the Country of Georgia through A Call to Serve International (ACTS-I). PMID- 26606812 TI - The Good and the Bad. PMID- 26606813 TI - Discoveries the Forefront of BioMedical Research. PMID- 26606814 TI - New Developments in Radiation Oncology. PMID- 26606815 TI - Proton Therapy. An Update on the S. Lee Kling Proton Therapy Center at Barnes Jewish Hospital and Washington University. PMID- 26606816 TI - World's First Application of MR-Guidance for Radiotherapy. AB - Radiotherapy localization is the process by which patient treatments are aligned on a daily basis. Localization has hiistorically been accomplished using 2 dimensional x-ray images, or cone-beam CT- imaging which permits excellent visualization of bony anatomy, but suboptimal soft-tissue imaging. The Department of Radiation Oncology at Washington University recently implemented the world's first MR-Image Guided Radiation Therapy program (MR-IGRT), which utilizes a O.35T MR scanner integrated with three 6"Co heads for treatment delivery. A high resolution volumetric MR image is acquired for each patient at the time of daily treatment setup, which allows localization based on soft-tissue anatomy, and modification to the treatment plan when required while the patient is on the treatment table. Herein, we review principles of radiotherapy localization, describe implementation of the world's first MR-IGRT program, and present future directions where MR-IGRT may be applied for patient treatments. PMID- 26606817 TI - Lung Stereotactic Body Radiation Therapy. AB - Lung stereotactic body radiation therapy (SBRT) is a novel and effective modality for treatment of early stage non-sail cell lung cancer (NSCLC), with expanding indications in locally advanced and metastatic disease. Herein, we will review current treatment recommendations for early stage NSCLC, detail treatment planning of SBRT, and discuss future directions. PMID- 26606818 TI - Intracavitary Brachytherapy for Gynecologic Malignancies: Applications and Innovations. AB - While surgical management is a common approach for gynecologic malignancies; often disease is locally advanced such that surgery is precluded or surgical pathology reveals disease extent that mandates adjuvant treatment. Gynecologic brachytherapy is an important tool for both definitive and adjuvant treatment of cervical and endometrial cancers. Brachytherapy enables high radiation doses to a target with rapid fall-off to protect adjacent normal structures. This paper aims to detail the usage of brachytherapy in gynecologic cancers with a focus on advances in technique. PMID- 26606819 TI - Imaging Advances in Stereotactic Radiosurgery. AB - Novel functional and metabolic MRI imaging provides the ability to analyze tumor tissue properties including tumor vasculature, vascular permeability, tumor cellularity, hypoxia, and tumor proliferation. Stereotactic radiosurgery involves the delivery of a very precise, focal dose of radiation to a target. Recent advances in MR imaging have the potential to improve accuracy for target volume delineation and to potentially improve outcome. Novel MR imaging techniques may also be used in subsequent post-treatment follow-up to distinguish between tumor recurrences versus non-neoplastic treatment-related changes. In this paper, we address multiparametric MR imaging and cerebral angiography as tools to reduce toxicity. PMID- 26606820 TI - Accelerated Partial Breast Irradiation: A Safe, Effective, and Convenient Early Breast Cancer Treatment Option. AB - Accelerated partial breast irradiation (APBI) is an excellent treatment option for many women with early stage breast cancer. Patient selection criteria include age over 40, status post lumpectomy, breast cancer (invasive or in situ disease) measuring <3 cm, negative margins (at least 2 mm), negative lymph nodes, and no lymphovascular space invasion. APBI is effective, well tolerated, and convenient. Women with early stage breast cancer and theii caregivers should be aware of this potential treatment option. PMID- 26606821 TI - The Evolution of Axillary Staging in Breast Cancer. AB - Breast cancer treatment has a long, fascinating history. Multimodality therapy utilizes surgery, systemic therapy and radiation. The role of surgical axillary staging in breast cancer continues to evolve. Secondary to randomized, controlled trials, sentinel lymph node biopsy is the standard for surgical staging in patients with a clinically negative axilla. Traditionally, when sentinel nodes revealed metastases, a complete axillary lymph node dissection was performed. Recently however, the value of complete axillary dissection is being challenged. PMID- 26606822 TI - Blood Conservation Strategies and Liver Transplantation Transfusion-Free Techniques Derived from Jehovah's Witness Surgical Cohorts. AB - Red blood cell and component transfusions are a frequent and widely accepted accompaniment of surgical procedures. Although the risk of specific disease transmission via allogeneic blood transfusions (ABT) is very low, the occurrence of transfusion related immune modulation (TRIM) still remains a ubiquitous concern. Recent studies have shown that ABT are linked to increased morbidity and mortality across various specialties, with negative outcomes directly correlated to number of transfusions. Blood conservation methods are therefore necessary to reduce ABT. Acute normo-volemic hemodilution (ANH) along with pre-operative blood augmentation and intraoperative cell salvage are blood conservation techniques utilized in tertiary and even quaternary (transplantation) surgery in Jehovah's Witnesses with excellent outcomes. The many hematologic complications such as anemia, thrombocytopenia and coagulopathies that occur with liver transplantation present a significant barrier when trying to avoid ABT. Despite this, living donor liver transplantation (LDLT) has been successfully performed in a transfusion-free environment, providing valuable insight into the possibilities of limiting ABT and its associated risks in all patients. PMID- 26606823 TI - [Role of Hormones in Perinatal and Early Postnatal Development: Possible Contribution to Programming/Imprinting Phenomena]. AB - In parallel to formulating the paradigm of developmental origins of health and disease (DOHaD), the search began on mechanisms of programming/imprinting in ontogeny. Some recent evidence has revealed the important role of glucocorticoids in such mechanisms. However, in the last decades numerous data have been accumulated on participation of other hormones in developmental bioregulation. In present article we analyse these data, as referred to melatonin, but also to neuroactive steroids, somatolactogens and related peptides: insulin-like growth factor of type I (IGF-I) and oxytocin, i.e. peptide regulators related to growth and lactation respectively. Special attention was devoted to the evidence of glucocorticoid interactions with some of these hormones. PMID- 26606824 TI - [Biological Age as a Method for Systematic Assessment of Ontogenetic Changes in the State of an Organism]. AB - Aging is a common feature of living and nonliving systems as a disturbance of the structure of the system accumulating with age. The only cause of aging of a living system, which is capable of renewal, is the insufficiency of renewal. The latter manifests itself as two global mechanisms of aging: the genetically determined nonrenewal of a number of structures that can only die with age (stochastic aging) and the regulatory reduction in the rate of self-renewal of living structures. The regulatory reduction in cellular self-renewal (cell growth and division) is most important. At the same chronological age, the degree of aging of the organism in general, as well as individual organs, cells, and systems of the organism, may be different, reflecting the concept of biological age (BA)--an indicator of the level of development, changes, or deterioration of a structure or function of an element of the organism, a functional system, or the organism as a whole. It is expressed in units oftime by relating the values of biomarkers defining the processes of aging with the standard average statistical dependences of changes in these biomarkers with the chronological age. The concept of BA is directly related to the concept of viability of the organism, which is determined by the sum (integral) of viabilities of its parts (in practice, the residual functional resource). For quantitative characterization of aging in general, the index of integrated biological age is used. To give a detailed characterization, the partial biological ages are used, which reflect the aging of different systems of the organism, as well as a number of indices reflecting its functional and psychological possibilities. The contribution of pathological processes to BA is also taken into account. In addition, the amount of retained adaptive reserves in the physical and nervous and mental aspects, the risk factors, and the factors of longevity should be determined. For this purpose, it is necessary to take into account the family history (hereditary factors) and the individual history (acquired factors). The use ofthe BA determination method by doctors in clinical practice stimulates the development of preventive medicine, which is important to improve both the individual health and the quality of life. The BA determination method is also the main tool for testing the effectiveness of tools and methods of geroprophylaxis. PMID- 26606825 TI - [Activity of Enzymes Involved in the Energy and Carbohydrate Metabolism and the Level of Some Molecular-Genetic Characteristics in Young Salmons (Salmo salar L.) with Different Age and Weight]. AB - In order to investigate the metabolic regulation in Atlantic salmon fries (Salmo salar L.) during their growth, development, and in the course of size divergence, age-related changes in the activity of enzymes involved in the energy and carbohydrate metabolism, including myosin heavy chain isoform expression, RNA/DNA ratio in the white muscles and liver of specimens at ages of 0+; 1+, and 2+, as well as correlations of these characteristics with the body weight of fish specimens were analyzed. Multidirectional changes in the activity of enzymes taking part in aerobic and anaerobic energy metabolism, as well as a decrease in the protein synthesis with age, were revealed. There was a positive correlation between the activities of cytochrome oxidase, lactate dehydrogenase, aldolase, and myosin gene expression in the muscles, cytochrome oxidase activity, glucose-6 phosphate dehydrogenase, and glycerol-3-phosphate dehydrogenase in the liver with the body weight of salmon specimens within the age groups. PMID- 26606826 TI - [Development of Arbuscular Mycorrhiza in Highly Responsive and Mycotrophic Host Plant-Black Medick (Medicago lupulina L.)]. AB - The main phases of arbuscular mycorrhiza (AM) development were analyzed in black medick (Medicago lupulina) with Glomus intraradices. Methods of light and transmission electron microscopy were used to investigate AM. The first mycorrhization was identified on the seventh day after sowing. M. lupulina with AM-fungus Glomus intraradices formed Arum type of AM. Roots of black medick at fruiting stage (on the 88th day) were characterized by the development of forceful mycelium. The thickness of mycelium was comparable with the vascular system of root central cylinder. The development of vesicules into intraradical spores was shown. Micelium, arbuscules, and vesicules developed in close vicinity to the division zone of root tip. This might be evidence of an active symbiotic interaction between partners. All stages of fungal development and breeding, including intraradical spores (in inter-cellular matrix of root cortex), were identified in the roots of black medick, which indicated an active utilization of host plant nutrient substrates by the mycosymbiont. Plant cell cytoplasm extension was identified around young arbuscular branches but not for intracellular hyphae. The presence of active symbiosis was confirmed by increased accumulation of phosphorus in M. lupulina root tissues under conditions of G. intraradices inoculation and low phosphorus level in the soil. Thus, black medick cultivar-population can be characterized as an ecologically obligate mycotrophic plant under conditions of low level of available phosphorus in the soil. Specific features of AM development in intensively mycotrophic black medick, starting from the stage of the first true leaf until host plant fruiting, were evaluated. The obtained plant-microbe system is a perspective model object for further ultracytological and molecular genetic studies of the mechanisms controlling arbuscular mycorrhiza symbiotic efficiency, including selection and investigation of new symbiotic plant mutants. PMID- 26606827 TI - [Somatic Embryogenesis in Pinus pumila and Productivity of Embryogenic Lines during Long-Term Cultivation In Vitro]. AB - Zygotic embryos and megagametophytes of Pinus pumila for cultivation in vitro were transferred in 1/2 LV medium supplemented with growth regulators 2,4 dichlorophenoxyacetic acid (2,4-D) and benzylaminopurine (6-BAP) to induce somatic embryogenesis. Four stably proliferating cell lines from two genotypes were derived. The cell lines differed in the number of globular somatic embryos and the weight of embryogenic calli. Cells of these lines were multiplied as a result of somatic polyembryogenesis via cleavage. In the nutrient medium for maturation, mature somatic embryos were obtained. However, somatic embryos of not all embryogenic cell lines reached maturation. In this study, plantlets were obtained in an in vitro culture for the first time. PMID- 26606828 TI - [Cytological State of Gonads and Level of Thyroid and Sex Steroid Hormones in Black Sea Trout Salmo trutta labrax Pall]. AB - Cytological state of the gonads and hormonal state of hatchery Black Sea trout before differentiation into resident and anadromous forms (parr) at an age of 15 months have been examined. It has been shown that the hormonal changes associated with the choice of life strategy in the Black Sea trout females and males are pronounced to different degrees. As compared with the resident and anadromous individuals; the female parr display a low rate of oogenesis and similar hormonal status, while characteristic of the male parr are an intermediate rate of spermatogenesis, a low level of thyroid hormones and estradiol, and a medium testosterone level. As has been found, the undifferentiated Black Sea trout individuals predominantly develop into the resident form. PMID- 26606829 TI - [Ontogenetic Mechanisms of Explosive Morphological Divergence in the Lake Tana (Ethiopia) Species Flock of Large African Barbs (Labeobarbus; Cyprinidae; Teleostei)]. AB - Species flock of Lake Tana (Ethiopia) large African barbs (Labeobarbus; Cyprinidae; Teleostei) was studied as a model system for investigating ontogenetic mechanisms of the explosive morphological divergence often accompanying sympatric speciation in bony fishes. Comparative morphological analysis carried out with the use ofgeometric morphometric techniques revealed quantitative differences in the head shapes of species under study. Comparative analysis of skull development revealed significant interspecies differences in the temporal characteristics of craniogenesis in these species. These two lines of evidence suggest that heterochronies in craniogenesis underlie divergence in the head shapes of adult Tana barbs. This prediction was verified via experimental changes of temporal characteristics of craniogenesis in L. intermedius, a putative ancestor for the Lake Tana species flock. For this aim, timing and rate of skull development were changed by artificial manipulation of thyroid hormone levels. In sum, it was shown that it is heterochronies that underlie an explosive morphological divergence of the Lake Tana barbs species flock. Our findings together with those reported in the literature suggest variability in the activity of the hypothalamic-pituitary-thyroid axis to contribute to these heterochronies. PMID- 26606830 TI - [Vladimir Igorevich Mitrofanov]. PMID- 26606831 TI - [Ol'ga Mikhailovna Ivanova-Kazas]. PMID- 26606832 TI - Significant changes to the mental health landscape--some good, some not so good. PMID- 26606833 TI - Patients with first episode psychosis benefit from immediate referral to high risk services. PMID- 26606834 TI - Use of police cells as 'place of safety' down by a third. PMID- 26606835 TI - There is a crisis in mental health support for children and young people. PMID- 26606836 TI - Going back to nature. PMID- 26606837 TI - FACING UP TO MENTAL HEALTH PROBLEMS. PMID- 26606838 TI - The big switch from DLA to PIP commences in October. PMID- 26606839 TI - Outside the box. PMID- 26606840 TI - The bigger picture. PMID- 26606841 TI - The Choices Method--helping people take control of their mental health. . PMID- 26606842 TI - Legal eye. PMID- 26606843 TI - Genetic research into depression could lead to better ways of managing the condition in the future. PMID- 26606844 TI - Animal instincts. PMID- 26606845 TI - Network. PMID- 26606846 TI - Less talk, more action. PMID- 26606847 TI - ON THE BALL. PMID- 26606848 TI - On the record. PMID- 26606850 TI - Demonstration of leapfrogging for implementing nonlinear model predictive control on a heat exchanger. AB - This work reveals the applicability of a relatively new optimization technique, Leapfrogging, for both nonlinear regression modeling and a methodology for nonlinear model-predictive control. Both are relatively simple, yet effective. The application on a nonlinear, pilot-scale, shell-and-tube heat exchanger reveals practicability of the techniques. PMID- 26606851 TI - Adaptive robust maximum power point tracking control for perturbed photovoltaic systems with output voltage estimation. AB - The problem of maximum power point tracking (MPPT) in photovoltaic (PV) systems, despite the model uncertainties and the variations in environmental circumstances, is addressed. Introducing a mathematical description, an adaptive sliding mode control (ASMC) algorithm is first developed. Unlike many previous investigations, the output voltage is not required to be sensed and the upper bound of system uncertainties and the variations of irradiance and temperature are not required to be known. Estimating the output voltage by an update law, an adaptive-based Hinfinity tracking algorithm is then developed for the case the perturbations are energy-bounded. The stability analysis is presented for the proposed tracking control schemes, based on the Lyapunov stability theorem. From a comparison viewpoint, some numerical and experimental studies are also presented and discussed. PMID- 26606849 TI - High-Frequency Stimulation at the Subthalamic Nucleus Suppresses Excessive Self Grooming in Autism-Like Mouse Models. AB - Approximately one quarter of individuals with an autism spectrum disorder (ASD) display self-injurious behavior (SIB) ranging from head banging to self-directed biting and punching. Sometimes, these behaviors are extreme and unresponsive to pharmacological and behavioral therapies. We have found electroconvulsive therapy (ECT) can produce life-changing results, with more than 90% suppression of SIB frequency. However, these patients typically require frequent maintenance ECT (mECT), as often as every 5 days, to sustain the improvement gained during the acute course. Long-term consequences of such frequent mECT started as early as childhood in some cases are unknown. Accordingly, there is a need for alternative forms of chronic stimulation for these patients. To explore the feasibility of deep brain stimulation (DBS) for intractable SIB seen in some patients with an ASD, we utilized two genetically distinct mouse models demonstrating excessive self-grooming, namely the Viaat-Mecp2(-/y) and Shank3B(-/-) lines, and administered high-frequency stimulation (HFS) via implanted electrodes at the subthalamic nucleus (STN-HFS). We found that STN-HFS significantly suppressed excessive self-grooming in both genetic lines. Suppression occurs both acutely when stimulation is switched on, and persists for several days after HFS is stopped. This effect was not explained by a change in locomotor activity, which was unaffected by STN-HFS. Likewise, social interaction deficits were not corrected by STN-HFS. Our data show STN-HFS suppresses excessive self-grooming in two autism-like mouse models, raising the possibility DBS might be used to treat intractable SIB associated with ASDs. Further studies are required to explore the circuitry engaged by STN-HFS, as well as other potential stimulation sites. Such studies might also yield clues about pathways, which could be modulated by non invasive stimulatory techniques. PMID- 26606852 TI - RTDS implementation of an improved sliding mode based inverter controller for PV system. AB - This paper proposes a novel approach for testing dynamics and control aspects of a large scale photovoltaic (PV) system in real time along with resolving design hindrances of controller parameters using Real Time Digital Simulator (RTDS). In general, the harmonic profile of a fast controller has wide distribution due to the large bandwidth of the controller. The major contribution of this paper is that the proposed control strategy gives an improved voltage harmonic profile and distribute it more around the switching frequency along with fast transient response; filter design, thus, becomes easier. The implementation of a control strategy with high bandwidth in small time steps of Real Time Digital Simulator (RTDS) is not straight forward. This paper shows a good methodology for the practitioners to implement such control scheme in RTDS. As a part of the industrial process, the controller parameters are optimized using particle swarm optimization (PSO) technique to improve the low voltage ride through (LVRT) performance under network disturbance. The response surface methodology (RSM) is well adapted to build analytical models for recovery time (Rt), maximum percentage overshoot (MPOS), settling time (Ts), and steady state error (Ess) of the voltage profile immediate after inverter under disturbance. A systematic approach of controller parameter optimization is detailed. The transient performance of the PSO based optimization method applied to the proposed sliding mode controlled PV inverter is compared with the results from genetic algorithm (GA) based optimization technique. The reported real time implementation challenges and controller optimization procedure are applicable to other control applications in the field of renewable and distributed generation systems. PMID- 26606853 TI - Cognitive requirements of cumulative culture: teaching is useful but not essential. AB - The cumulative nature of human culture is unique in the animal kingdom. Progressive improvements in tools and technologies have facilitated humanity's spread across the globe and shaped human evolution, but the cognitive mechanisms enabling cultural change remain unclear. Here we show that, contrary to theoretical predictions, cumulative improvements in tools are not dependent on specialised, high-fidelity social learning mechanisms. Participants were tasked with building a basket to carry as much rice as possible using a set of everyday materials and divided into treatment groups with differing opportunities to learn asocially, imitate, receive teaching or emulate by examining baskets made by previous chain members. Teaching chains produced more robust baskets, but neither teaching nor imitation were strictly necessary for cumulative improvements; emulation chains generated equivalent increases in efficacy despite exhibiting relatively low copying fidelity. People used social information strategically, choosing different materials to make their baskets if the previous basket in the chain performed poorly. Together, these results suggest that cumulative culture does not rest on high-fidelity social learning mechanisms alone. Instead, the roots of human cultural prowess may lie in the interplay of strategic social learning with other cognitive traits including the ability to reverse engineer artefacts through causal reasoning. PMID- 26606854 TI - PLGA carriers for inhalation: where do we stand, where are we headed? PMID- 26606856 TI - Development of novel mucoadhesive hyaluronic acid derivate as lubricant for the treatment of dry eye syndrome. AB - BACKGROUND: Dry eye - a disease affecting between 4 and 34% of the population worldwide. Stressful conditions to ocular surface, contact lenses as well as systemic disease cause dry eye. Novel synthesized hyaluronic acid derivate was evaluated in terms of its potential as mucoadhesive and lubricant. Results & methodology: Hyaluronic acid was chemically modified with cysteine ethyl ester (hyaluronic acid-cysteine ethyl ester). Mucoadhesion, disintegration and water uptake capacity, moreover, safety as the hen's egg test for mucous membrane compatibility were evaluated. According to the results, hyaluronic acid-cysteine ethyl ester achieved 3.81-fold increased swelling capacity, 30.5-fold more improvement mucoadhesive properties and 9.72-fold higher stability of hyaluronic acid, which was achieved due to the chemical modification. SUMMARY: Thus, the promising results underpin further exploitation of this versatile polysaccharide for treating dry eye syndrome. PMID- 26606855 TI - Combining hard and soft magnetism into a single core-shell nanoparticle to achieve both hyperthermia and image contrast. AB - BACKGROUND: A biocompatible core/shell structured magnetic nanoparticles (MNPs) was developed to mediate simultaneous cancer therapy and imaging. METHODS & RESULTS: A 22-nm MNP was first synthesized via magnetically coupling hard (FePt) and soft (Fe3O4) materials to produce high relative energy transfer. Colloidal stability of the FePt@Fe3O4 MNPs was achieved through surface modification with silane-polyethylene glycol (PEG). Intravenous administration of PEG-MNPs into tumor-bearing mice resulted in a sustained particle accumulation in the tumor region, and the tumor burden of treated mice was a third that of the mice in control groups 2 weeks after a local hyperthermia treatment. In vivo magnetic resonance imaging exhibited enhanced T2 contrast in the tumor region. CONCLUSION: This work has demonstrated the feasibility of cancer theranostics with PEG-MNPs. PMID- 26606857 TI - Vitamin D receptor knockout mice exhibit elongated intestinal microvilli and increased ezrin expression. AB - In addition to its principle function as a calcium regulator, vitamin D can affect cell and tissue morphology. The intestine is an important target tissue of vitamin D, as it must ensure the efficient transport of nutrients across the epithelium while excluding the passage of harmful molecules and bacteria into the organism. These functions require a highly organized morphology, which may be modified by vitamin D deficiency. To elucidate the role of vitamin D in gut morphology and barrier function, we compared the enterocyte microstructures, gut permeability, and cytoskeletal and cell junction protein expression in vitamin D receptor (VDR) knockout (KO) and wild-type (WT) mice. We found that the duodenal epithelial cells in the VDR-KO mice had longer microvilli (+19%) than those of the WT mice (P < .05). Interestingly, microvilli elongation in the VDR-KO mice was associated with higher messenger RNA and protein expression of ezrin, which is involved in the regulation of microvillus morphogenesis. Intestinal tight junction width and permeability were assessed by measuring the fluorescein isothiocyanate dextran concentrations in plasma; the concentrations were comparable between the 2 groups of mice. We further observed a decrease in the messenger RNA and protein expression of the calcium-transporting tight junction protein claudin-2 in the VDR-KO mice compared with the WT mice (P < .05). In conclusion, the mice lacking VDR had longer enterocyte microvilli, likely as a result of increased ezrin expression. However, the morphology of the tight junctions and the intestinal permeability for large molecules were not affected. PMID- 26606858 TI - Porphyrins Containing a Triphenylamine Donor and up to Eight Alkoxy Chains for Dye-Sensitized Solar Cells: A High Efficiency of 10.9%. AB - Porphyrins are promising DSSC sensitizers due to their structural similarity to chlorophylls as well as their tunable strong absorption. Herein, a novel D-pi-A porphyrin dye XW14 containing a strongly electron-donating triphenylamine moiety as the electron donor was designed and synthesized. To avoid undesirably decreased Voc caused by dye aggregation effect, two methoxy or hexyloxy chains were introduced to the para positions of the triphenylamine moiety to afford XW15 and XW16, respectively. To further extend the absorption to a longer wavelength, a benzothiadiazole unit was introduced as an auxiliary acceptor to furnish XW17. Compared with XW14, the introduction of additional methoxy or hexyloxy groups in XW15 and XW16 red-shift the onset wavelengths from 760 to 780 and 790 nm, respectively. More impressively, XW17 has a more extended pi-conjugation framework, and thus, it exhibits a much broader IPCE spectrum with an extremely red-shifted onset wavelength of 830 nm, resulting in the highest Jsc (18.79 mA cm(-2)). On the other hand, the hexyloxy chains are favorable for suppressing the dye aggregation effect, and thus XW16 shows the highest Voc of 734 mV. As a result, XW16 and XW17 demonstrate photovoltaic efficiencies of 9.1 and 9.5%, respectively, higher than those of XW14 (8.6%) and XW15 (8.7%), and obviously higher than that of 7.94% for our previously reported dye, XW4. On the basis of optimized porphyrin dye XW17, we used a nonporphyrin dye with a high Voc and strong absorption around 500 nm (WS-5) as the cosensitizer to improve the Voc from 700 to 748 mV, with synergistical Jsc enhancement from 18.79 to 20.30 mA cm( 2). Thus, the efficiency was dramatically enhanced to 10.9%, which is among the highest efficiencies obtained for the DSSCs based on traditional iodine electrolyte. In addition, the DSSCs based on XW17 + WS-5 exhibit good photostability, which is beneficial for practical applications. PMID- 26606859 TI - GSK-3beta mediates dexamethasone-induced pancreatic beta cell apoptosis. AB - AIMS: Glucocorticoids, such as dexamethasone, are widely used anti-inflammatory drugs. Their use is frequently associated with the development of steroid- associated diabetes. Pancreatic beta-cell dysfunction has been suggested to be one of the main causes of steroid-associated diabetes. However, the mechanism is not fully understood. Glycogen synthase kinase-3beta (GSK-3beta) is a multifunctional serine/threonine kinase and plays an important role in energy metabolism, cell growth and apoptosis. Therefore, the contribution of GSK-3beta in dexamethasone-induced pancreatic beta-cell apoptosis was determined in the present study. MAIN METHODS: The effect of dexamethasone treatment on rat pancreatic beta-cell line (INS-1) apoptosis (determined by TUNEL and Flow Cytometry), generation of reactive oxidative stress (ROS), and the phosphorylation status of GSK-3beta was determined. The inhibitory effect of GSK 3beta inhibitor-lithium chloride (LiCl) on dexamethasone-induced beta-cell apoptosis was also evaluated. KEY FINDINGS: Dexamethasone (0.1 MUM) treatment induced INS-1 apoptosis, which was associated with increased GSK-3beta activation and increased NOX4-derived ROS generation. Pretreatment of INS-1 with LiCl inhibited dexamethasone induced ROS generation and INS-1 apoptosis. SIGNIFICANCE: This study provides a new mechanism of Dex induced pancreatic beta cell apoptosis and may serve as a new therapeutic option for treating GC induced diabetes. PMID- 26606860 TI - Baicalein alleviates doxorubicin-induced cardiotoxicity via suppression of myocardial oxidative stress and apoptosis in mice. AB - AIMS: Doxorubicin is a widely used anthracycline derivative anticancer drug. Unfortunately, the clinical use of doxorubicin has the serious drawback of cardiotoxicity. In this study, we investigated whether baicalein, a bioflavonoid, can prevent doxorubicin-induced cardiotoxicity in vivo and we delineated the possible underlying mechanisms. MAIN METHODS: Male BALB/c mice were treated with either intraperitoneal doxorubicin (15 mg/kg divided into three equal doses for 15 days) and/or oral baicalein (25 and 50 mg/kg for 15 days). Serum markers of cardiac injury, histology of heart, parameters related to myocardial oxidative stress, apoptosis and inflammation were investigated. KEY FINDINGS: Treatment with baicalein reduced doxorubicin-induced elevation of serum creatine kinase-MB isoenzyme (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and ameliorated the histopathological damage. Baicalein restored the doxorubicin-induced decrease in both enzymatic and non-enzymatic myocardial antioxidants and increased the myocardial expression of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1). Further studies showed that baicalein could inverse the Bax/Bcl-2 ratio, suppress doxorubicin-induced p53, cleaved caspase-3 and PARP expression and prevented doxorubicin-induced DNA damage. Baicalein treatment also interferes with doxorubicin-induced myocardial NF-kappaB signaling through inhibition of IkappaBalpha phosphorylation and nuclear translocation of p65 subunit. Doxorubicin elevated iNOS and nitrites levels were also significantly decreased in baicalein treated mice. However, we did not find any significant change (p>0.05) in the myocardial TNF-alpha and IL-6 levels in control and treated animals. SIGNIFICANCE: Our finding suggests that baicalein might be a promising molecule for the prevention of doxorubicin-induced cardiotoxicity. PMID- 26606861 TI - Multiple Dirac Points and Hydrogenation-Induced Magnetism of Germanene Layer on Al (111) Surface. AB - A continuous germanene layer grown on the Al (111) surface has recently been achieved in experiment. In this work, we investigate its structural, electronic, and hydrogenation-induced properties through first-principles calculations. We find that despite having a different lattice structure from its free-standing form, germanene on Al (111) still possesses Dirac points at high-symmetry K and K' points. More importantly, there exist another three pairs of Dirac points on the K(K')-M high-symmetry lines, which have highly anisotropic dispersions due to the reduced symmetry. These massless Dirac Fermions become massive when spin orbit coupling is included. Hydrogenation of the germanene layer strongly affects its structural and electronic properties. Particularly, when not fully hydrogenated, ferromagnetism can be induced due to unpaired local orbitals from the unsaturated Ge atoms. Remarkably, we discover that the one-side semihydrogenated germanene turns out to be a two-dimensional half-semimetal, representing a novel state of matter that is simultaneously a half-metal and a semimetal. PMID- 26606862 TI - Highlights from the latest articles in nanomaterial-based therapies for targeting cancer stem cells. PMID- 26606864 TI - The Moderating Role of Purging Behaviour in the Relationship Between Sexual/Physical Abuse and Nonsuicidal Self-Injury in Eating Disorder Patients. AB - This study sought to examine predictors of nonsuicidal self-injury (NSSI) in eating disorder patients and to evaluate the moderating role of purging behaviours in the relationship between a theorised predictor (i.e. sexual/physical abuse) and NSSI. Participants in this study were 177 female patients with eating disorders (age range = 14-38 years) who completed semistructured interviews assessing eating disorder symptoms and eating disorder related risk factors (e.g. history of sexual and physical abuse, history of NSSI and feelings of fatness). Results revealed that 65 participants (36.7%) reported lifetime engagement in NSSI, and 48 participants (27.1%) reported a history of sexual/physical abuse. Early onset of eating problems, lower BMI, feeling fat, a history of sexual/physical abuse and the presence of purging behaviours were all positively associated with the lifetime occurrence of NSSI. The relationship between sexual/physical abuse before eating disorder onset and lifetime NSSI was moderated by the presence of purging behaviours, such that the relationship was stronger in the absence of purging. These findings are consistent with the notion that purging and NSSI may serve similar functions in eating disorder patients (e.g. emotion regulation), such that the presence of purging may attenuate the strength of the association between sexual/physical abuse history (which is also associated with elevated NSSI risk) and engagement in NSSI behaviours. PMID- 26606865 TI - Introducing a realistic and reusable quinsy simulator. AB - BACKGROUND: An increasing number of inexperienced doctors are rotating through otolaryngology departments and providing care to ENT patients. Numerous acute ENT conditions require basic surgical or technical intervention; hence, effective and efficient simulation induction training has become paramount in providing a safe yet valuable educational environment for the junior clinician. Whilst simulation has developed over the years for numerous ENT skills, to date there has not been a realistic and easily reproducible model for teaching the skills to manage one of the most common ENT emergencies, a peritonsillar abscess or 'quinsy'. METHOD: We have adapted the Laryngotech trainer, a well-established ENT simulation tool, to present a readily accessible, reusable and realistic simulation model. CONCLUSION: The model provides safe training for the drainage of quinsy. PMID- 26606863 TI - Neuropathic Ocular Pain due to Dry Eye is Associated with Multiple Comorbid Chronic Pain Syndromes. AB - Recent data show that dry eye (DE) susceptibility and other chronic pain syndromes (CPS) such as chronic widespread pain, irritable bowel syndrome, and pelvic pain, might share common heritable factors. Previously, we showed that DE patients described more severe symptoms and tended to report features of neuropathic ocular pain (NOP). We hypothesized that patients with a greater number of CPS would have a different DE phenotype compared with those with fewer CPS. We recruited a cohort of 154 DE patients from the Miami Veterans Affairs Hospital and defined high and low CPS groups using cluster analysis. In addition to worse nonocular pain complaints and higher post-traumatic stress disorder and depression scores (P < .01), we found that the high CPS group reported more severe neuropathic type DE symptoms compared with the low CPS group, including worse ocular pain assessed via 3 different pain scales (P < .05), with similar objective corneal DE signs. To our knowledge, this was the first study to show that DE patients who manifest a greater number of comorbid CPS reported more severe DE symptoms and features of NOP. These findings provided further evidence that NOP might represent a central pain disorder, and that shared mechanistic factors might underlie vulnerability to some forms of DE and other comorbid CPS. PERSPECTIVE: DE patients reported more frequent CPS (high CPS group) and reported worse DE symptoms and ocular and nonocular pain scores. The high CPS group reported symptoms of NOP that share causal genetic factors with comorbid CPS. These results imply that an NOP evaluation and treatment should be considered for DE patients. PMID- 26606866 TI - The local effect of octreotide on mechanical pain sensitivity is more sensitive in DA rats than DA.1U rats. AB - A recent study by the authors indicated that major histocompatibility complex (MHC) genes are associated with the differences in basal pain sensitivity and in formalin model between Dark-Agouti (DA) and novel congenic DA.1U rats, which have the same genetic background as DA rats except for the u alleles of MHC. The objective of the present study is to investigate whether there is a difference in the pristane-induced arthritis (PIA) model and local analgesic effect of octreotide (OCT) between DA and DA.1U rats. The hindpaw mechanical withdrawal threshold (MWT) and heat withdrawal latency (HWL) were observed. The C unit firings of the tibial nerve evoked by non-noxious and noxious toe movements were recorded by electrophysiological methods in normal and PIA models in DA and DA.1U rats before and after local OCT administration. The expression of somatostatin receptor 2A (SSTR2A) was observed by immunohistochemistry. The results demonstrate that DA rats have a higher mechanical sensitivity than DA.1U rats after PIA. Local OCT administration significantly elevated MWT in DA rats under normal and PIA sate, but not in DA.1U rats. The electrophysiological experiments showed OCT significantly attenuated the firings of C units evoked by non-noxious and noxious stimulation in DA rats more than those in DA.1U rats both in normal and PIA states. In addition, the expression of SSTR2A in the dorsal horn of the spinal cord was significantly higher in DA than in DA.1U rats. All of the findings suggest a higher local analgesic effect of OCT in DA rats than DA.1U rats, which might be associated with the MHC genes. PMID- 26606868 TI - Characteristics of Optic Disc Rotation in Myopic Eyes. AB - PURPOSE: To investigate the characteristics of optic disc rotation and ocular parameters affecting optic disc rotation in healthy myopic eyes. DESIGN: Cross sectional, comparative study. PARTICIPANTS: A total of 220 participants with healthy myopic eyes. METHODS: Spherical equivalent (SE) refractive error, axial length, central corneal thickness, and intraocular pressure (IOP) were evaluated. Optic disc tilt ratio, degree of optic disc rotation, and area of beta-zone parapapillary atrophy (PPA) were measured. Optic nerve head (ONH) parameters and thickness of the peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell-inner plexiform layer (mGCIPL) were measured using Cirrus optical coherence tomography (Carl Zeiss Meditec Inc., Dublin, CA). Subjects were divided into 2 groups, group 1 with superior rotation and group 2 with inferior rotation of the optic disc, and various parameters were compared. Linear regression analysis was performed to evaluate the relationships between the degree of optic disc rotation and several parameters. MAIN OUTCOME MEASURES: Degree of optic disc rotation. RESULTS: Among 220 eyes, 147 showed superior rotation of the optic disc and 73 showed inferior rotation. The mean tilt ratio and rotation degree were 1.16 and -19.51 degrees , respectively, in group 1 and 1.20 and 28.93 degrees , respectively, in group 2, showing significant differences between the groups (P = 0.028 and P = 0.035, respectively). There were also significant between-group differences in IOP (15.59 vs. 16.34 mmHg), SE refractive error (-4.05 vs. -5.66 diopters [D]), axial length (25.51 vs. 26.26 mm), and area of beta-zone PPA (0.32 vs. 0.70 mm(2)). Overall, a multivariate linear regression analysis showed that IOP, axial length, and area of beta-zone PPA were significant parameters related to the degree of optic disc rotation (P = 0.011, P = 0.043, and P = 0.030, respectively). Group 2 showed thinner pRNFL and mGCIPL thickness in general compared with group 1. CONCLUSIONS: In healthy myopic eyes, superior rotation of the optic disc was more prevalent than inferior rotation. As the optic disc rotates inferiorly, there was a significant positive correlation with IOP, axial length, and area of the beta-zone PPA. Conversely, a significant negative correlation with pRNFL and mGCIPL thickness was observed. PMID- 26606867 TI - Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results. AB - PURPOSE: Leber hereditary optic neuropathy (LHON) is a disorder characterized by severe and rapidly progressive visual loss when caused by a mutation in the mitochondrial gene encoding NADH:ubiquinone oxidoreductase subunit 4 (ND4). We have initiated a gene therapy trial to determine the safety and tolerability of escalated doses of an adeno-associated virus vector (AAV) expressing a normal ND4 complementary DNA in patients with a G to A mutation at nucleotide 11778 of the mitochondrial genome. DESIGN: In this prospective open-label trial (NCT02161380), the study drug (self-complementary AAV [scAAV]2(Y444,500,730F)-P1ND4v2) was intravitreally injected unilaterally into the eyes of 5 blind participants with G11778A LHON. Four participants with visual loss for more than 12 months were treated. The fifth participant had visual loss for less than 12 months. The first 3 participants were treated at the low dose of vector (5 * 10(9) vg), and the fourth participant was treated at the medium dose (2.46 * 10(10) vg). The fifth participant with visual loss for less than 12 months received the low dose. Treated participants were followed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations. PARTICIPANTS: Five legally blind patients with G11778A LHON. MAIN OUTCOME MEASURES: Loss of visual acuity. RESULTS: Visual acuity as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart remained unchanged from baseline to 3 months in the first 3 participants. For 2 participants with 90-day follow-up, acuity increased from hand movements to 7 letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. No one lost vision, and no serious adverse events were observed. Minor adverse events included a transient increase of intraocular pressure (IOP), exposure keratitis, subconjunctival hemorrhage, a sore throat, and a transient increase in neutralizing antibodies (NAbs) against AAV2 in 1 participant. All blood samples were negative for vector DNA. CONCLUSIONS: No serious safety problems were observed in the first 5 participants enrolled in this phase I trial of virus-based gene transfer in this mitochondrial disorder. Additional study follow-up of these and additional participants planned for the next 4 years is needed to confirm these preliminary observations. PMID- 26606869 TI - Rapid differentiation of Ralstonia solanacearum avirulent and virulent strains by cell fractioning of an isolate using high performance liquid chromatography. AB - Ralstonia solanacearum is one of the most destructive plant bacterial pathogens worldwide. The population dynamics and genetic stability are important issues, especially when an avirulent strain is used for biocontrol. In this study, we developed a rapid method to differentiate the virulent and avirulent strains of R. solanacearum and to predict the biocontrol efficiency of an avirulent strain using high performance liquid chromatography (HPLC). Three chromatographic peaks P1, P2 and P3 were observed on the HPLC spectra among 68 avirulent and 28 virulent R. solanacearum strains. Based on the HPLC peaks, 96 strains total were assigned to three categories. For avirulent strains, the intense peak is P1, while for virulent strains, P3 is the majority. Based on the HLPC spectra of R. solanacearum strains, a chromatography titer index (CTI) was established as CTIi = Si/(S1+S2+S3) * 100% (i represents an individual HPLC peak; S1, S2 and S3 represent peak areas of P1, P2 and P3, respectively). The avirulent strains had high values of CTI1 ranging from 63.6 to 100.0%, while the virulent strains displayed high values of CTI3 ranging from 90.2 to 100.0%. Biological inoculation studies of 68 avirulent strains revealed that the biocontrol efficacy was the best when CTI1 = 100%. The purity and genetic stability of R. solanacearum strains were confirmed in the P1 fraction of avirulent strain FJAT-1957 and P3 fraction of virulent strain FJAT-1925 after 30 generations of consecutive subculture. These results confirmed that fractioning by HPLC and their deduced CTI can be used for rapid and efficient evaluation and prediction of an isolate of R. solanacearum. To the best of our knowledge, this is the first report that HPLC fractioning can be used for rapid differentiation of virulent and avirulent strains of R. solanacearum. PMID- 26606870 TI - Persistent occurrence of serogroup Y/sequence type (ST)-23 complex invasive meningococcal disease among patients aged five to 14 years, Italy, 2007 to 2013. AB - In Italy, the incidence of invasive meningococcal disease (IMD) has remained stable since 2007 (around 0.3 cases/100,000 inhabitants). However, as reported for other European countries, an increase of serogroup Y Neisseria meningitidis has been observed. In this study we report IMD cases from 2007 to 2013 in Italy and investigate the clinical and epidemiological features of cases affected by serogroup Y. Molecular characteristics of serogroup Y strains are also described. During the study period, the proportion of IMD cases due to serogroup Y increased, ranging from 2% in 2007 to 17% in 2013 (odds ratio (OR): 8.8), whereby the five to 14 years age group was mostly affected (p < 0.001). Overall 81 serogroup Y IMD cases were identified, with a median age of 18 years, ranging from three months to 84 years. Of the 81 respective patient samples, 56 were further subject to molecular typing. The sequence type (ST)-23 complex (clonal complex (cc)23) was predominant among serogroup Y meningococci (54/56 samples), and included nine different STs. Presumably, ST-23 was the founding genotype, with all the other STs presenting as single-locus variants. All cc23 isolates analysed harboured mutations in the lpxL1 gene; however, no associations among lpxL1 mutations, ST and age group were identified. Overall, these findings generate scientific evidence for the use of the quadrivalent meningococcal conjugate vaccine in the five to 14 years age group. PMID- 26606871 TI - Two-Year Trajectory of Fall Risk in People With Parkinson Disease: A Latent Class Analysis. AB - OBJECTIVE: To examine fall risk trajectories occurring naturally in a sample of individuals with early to middle stage Parkinson disease (PD). DESIGN: Latent class analysis, specifically growth mixture modeling (GMM), of longitudinal fall risk trajectories. SETTING: Assessments were conducted at 1 of 4 universities. PARTICIPANTS: Community-dwelling participants with PD of a longitudinal cohort study who attended at least 2 of 5 assessments over a 2-year follow-up period (N=230). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Fall risk trajectory (low, medium, or high risk) and stability of fall risk trajectory (stable or fluctuating). Fall risk was determined at 6 monthly intervals using a simple clinical tool based on fall history, freezing of gait, and gait speed. RESULTS: The GMM optimally grouped participants into 3 fall risk trajectories that closely mirrored baseline fall risk status (P=.001). The high fall risk trajectory was most common (42.6%) and included participants with longer and more severe disease and with higher postural instability and gait disability (PIGD) scores than the low and medium fall risk trajectories (P<.001). Fluctuating fall risk (posterior probability <0.8 of belonging to any trajectory) was found in only 22.6% of the sample, most commonly among individuals who were transitioning to PIGD predominance. CONCLUSIONS: Regardless of their baseline characteristics, most participants had clear and stable fall risk trajectories over 2 years. Further investigation is required to determine whether interventions to improve gait and balance may improve fall risk trajectories in people with PD. PMID- 26606872 TI - Effectiveness of Neuromuscular Electrical Stimulation on Patients With Dysphagia With Medullary Infarction. AB - OBJECTIVE: To evaluate and compare the effects of neuromuscular electrical stimulation (NMES) acting on the sensory input or motor muscle in treating patients with dysphagia with medullary infarction. DESIGN: Prospective randomized controlled study. SETTING: Department of physical medicine and rehabilitation. PARTICIPANTS: Patients with dysphagia with medullary infarction (N=82). INTERVENTIONS: Participants were randomized over 3 intervention groups: traditional swallowing therapy, sensory approach combined with traditional swallowing therapy, and motor approach combined with traditional swallowing therapy. Electrical stimulation sessions were for 20 minutes, twice a day, for 5d/wk, over a 4-week period. MAIN OUTCOME MEASURES: Swallowing function was evaluated by the water swallow test and Standardized Swallowing Assessment, oral intake was evaluated by the Functional Oral Intake Scale, quality of life was evaluated by the Swallowing-Related Quality of Life (SWAL-QOL) Scale, and cognition was evaluated by the Mini-Mental State Examination (MMSE). RESULTS: There were no statistically significant differences between the groups in age, sex, duration, MMSE score, or severity of the swallowing disorder (P>.05). All groups showed improved swallowing function (P<=.01); the sensory approach combined with traditional swallowing therapy group showed significantly greater improvement than the other 2 groups, and the motor approach combined with traditional swallowing therapy group showed greater improvement than the traditional swallowing therapy group (P<.05). SWAL-QOL Scale scores increased more significantly in the sensory approach combined with traditional swallowing therapy and motor approach combined with traditional swallowing therapy groups than in the traditional swallowing therapy group, and the sensory approach combined with traditional swallowing therapy and motor approach combined with traditional swallowing therapy groups showed statistically significant differences (P=.04). CONCLUSIONS: NMES that targets either sensory input or motor muscle coupled with traditional therapy is conducive to recovery from dysphagia and improves quality of life for patients with dysphagia with medullary infarction. A sensory approach appears to be better than a motor approach. PMID- 26606873 TI - Masked hypertension and its associated cardiovascular risk in young individuals: the African-PREDICT study. AB - Hypertension prevalence is increasing globally, yet little is known about the occurrence of masked hypertension (MHT) in young, sub-Saharan African adults, and how it relates to elevated cardiovascular risk. The African-PREDICT study (recruitment based on normotensive clinic blood pressure (BP)) determined the frequency of MHT and its relationship with arterial stiffness and biochemical markers of inflammation and endothelial activation. We included men and women (n=352), 20-30 years, screened for normotensive clinic BP (54% white, 40% men). Clinic BP, ambulatory blood pressure monitoring (ABPM), central systolic pressure, aortic pulse wave velocity (aPWV), augmentation index, anthropometry, physical activity and biochemical markers of cardiovascular risk were assessed (lipids, glucose, insulin, markers of endothelial activation and inflammation). Eighteen percent of the study population had MHT (60% white, 68% men). Those with MHT had increased adiposity, clinic-, ABPM- (24-h, day and night) and central-BP (within normal ranges), heart rate, aPWV and biochemical markers of cardiovascular risk, compared with normotensives (all P<0.05). Using multivariable adjusted odds ratios, we found that MHT was associated with increased likelihood for higher aPWV (odds ratio (OR)=1.567, P=0.010), insulin (OR=1.499, P=0.049), monocyte chemoattractant protein-1 (OR=1.499, P=0.026), vascular cellular adhesion molecule (OR=1.409, P=0.042) and C-reactive protein (OR=1.440, P=0.044). In a young adult (supposedly healthy) cohort, the occurrence of MHT is alarming, especially since MHT further demonstrated elevated cardiovascular risk via increased adiposity, arterial stiffness, endothelial activation and inflammation. Detection of MHT is crucial to increase awareness of elevated cardiovascular risk, and to ensure the required lifestyle and/or pharmaceutical interventions. PMID- 26606874 TI - Dynamic prediction model and risk assessment chart for cardiovascular disease based on on-treatment blood pressure and baseline risk factors. AB - For patients with hypertension, an individual risk prediction tool for cardiovascular disease based on on-treatment blood pressure is needed and would be useful. The objective of this study was to establish a 3-year risk prediction model for cardiovascular disease based on data from 13 052 patients with no history of cardiovascular disease in the Olmesartan Mega study to determine the relationship between Cardiovascular Endpoints and Blood Pressure Goal Achievement study. To develop dynamic prediction models including on-treatment blood pressure, a Cox proportional hazard model using the sliding landmarking method with three landmark points (6, 12 and 18 months from baseline) was used. The prediction model included blood pressure (<130/85 mm Hg, ?130/85 to <140/90 mm Hg, ?140/90 to <160/100 mm Hg and ?160/100 mm Hg) as a time-dependent covariate and well-known baseline risk factors (sex, age, smoking, family history of coronary artery disease and diabetes) as covariates. The 3-year risk assessment chart was constructed using the combination of all risk factors in the prediction model, and six different colors were displayed on each chart corresponding to the predicted probability of cardiovascular disease. Judging from the chart, if an elderly man with diabetes and other risk factors had a blood pressure of <130/85 mm Hg at 6 months, the risk of cardiovascular disease would be 8.0%, whereas the risk would be 8.6% if he had a blood pressure of ?130/85 to <140/90 mm Hg. The risk assessment chart developed from the large-scale observational study data would help physicians to more easily assess the cardiovascular disease risk for hypertensive patients on antihypertensive treatments. PMID- 26606875 TI - Comparison of eplerenone and spironolactone for the treatment of primary aldosteronism. AB - The mineralocorticoid receptor (MR) is expressed in the kidneys and in adipose tissue, and primary aldosteronism (PA) is associated with metabolic syndrome. This study assessed the effects of MR blockade by eplerenone (EPL) and spironolactone (SPL) on blood pressure (BP) and metabolic factors in patients with PA. Fifty-four patients with PA were treated with one of two MRAs, EPL (25 100 mg daily, n=27) or SPL (12.5-100 mg daily, n=27) for 12 months. Visceral (VAT) and subcutaneous adipose tissue were quantified using CT and FatScan imaging analysis software. Body mass index, homeostasis model assessment-insulin resistance (HOMA-IR), serum creatinine, potassium and lipids, urinary albumin excretion (UAE) and plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were measured before and after treatment. EPL and SPL decreased BP and increased serum potassium levels to similar degrees. PAC and PRA did not differ between the two groups. Although treatment with the MRAs did not change HOMA-IR or serum lipids, they significantly decreased UAE and VAT (P<0.05). These results suggest that EPL and SPL are effective and safe for the treatment of PA. The long-term metabolic and renal effects of these MRAs should be further investigated. PMID- 26606876 TI - Impaired response of regulator of Galphaq signaling-2 mRNA to angiotensin II and hypertensive renal injury in Dahl salt-sensitive rats. AB - Dahl salt-sensitive (Dahl S) rats are prone to salt-dependent hypertension with severe organ damage, including stroke, cardiac failure and renal insufficiency. The mechanism for this susceptibility to kidney injury has not been elucidated. The present study proposed that an upregulation of intracellular signaling of angiotensin II (Ang-II) is responsible for the susceptibility to hypertensive kidney injury in Dahl S rats. Spontaneously hypertensive rats exhibited higher systolic blood pressure (SBP) and lower kidney damage than Dahl S rats fed a high salt diet for 2 weeks. Ang-II infusion for 4 weeks significantly increased SBP in Dahl S and Dahl salt-resistant (Dahl R) rats fed a low-salt diet. The increase in SBP in Dahl S rats was associated with significant kidney injury with greater glomerular sclerosis (P<0.001). The expression of regulatory protein of Galphaq signaling-2 (RGS2) mRNA in the aortic walls in response to Ang-II infusion was lower in Dahl S than Dahl R rats (P<0.05). Ang-II significantly increased RGS2 mRNA in the aorta in Dahl R rats, but the response was apparently blunted in Dahl S rats. These results suggest that Dahl S rats exhibit a blunted RGS2 response to Ang-II, and this blunted response may be partially responsible for the susceptibility to renal injury in Dahl S rats. PMID- 26606878 TI - [Limited application of the three drug-mixed anesthesia for bronchoalveolar lavage fluid sampling]. PMID- 26606877 TI - The impact of tetrahydrobiopterin administration on endothelial function before and after smoking cessation in chronic smokers. AB - Cardiovascular disease mortality is reduced following smoking cessation but the reversibility of specific atherogenic risk factors such as endothelial dysfunction is less established. We assessed brachial artery flow-mediated dilation (FMD) in 57 chronic smokers and 15 healthy controls, alone and after oral tetrahydrobiopterin (BH4) administration, to assess the extent to which reduced bioactivity of BH4, a cofactor for the endothelial nitric oxide synthase enzyme (eNOS), contributes to smoking-associated reductions in FMD. Thirty-four smokers then ceased cigarette and nicotine use for 1 week, after which FMD (+/ BH4 administration) was repeated. Brachial artery FMD was calculated as the peak dilatory response observed relative to baseline (%FMD). Endothelium-independent dilation was assessed by measuring the dilatory response to sublingual nitroglycerin (%NTG). Chronic smokers exhibited reduced %FMD relative to controls: (5.6+/-3.0% vs. 8.1+/-3.7%; P<0.01) and %NTG was not different between groups (P=0.22). BH4 administration improved FMD in both groups (P=0.03) independent of smoking status (P=0.78) such that FMD was still lower in smokers relative to controls (6.6+/-3.3% vs. 9.8+/-3.2%; P<0.01). With smoking cessation, FMD increased significantly (from 5.0+/-2.9 to 7.8+/-3.2%;P<0.01); %NTG was not different (P=0.57) and BH4 administration did not further improve FMD (P=0.33). These findings suggest that the blunted FMD observed in chronic smokers, likely due at least in part to reduced BH4 bioactivity and eNOS uncoupling, can be restored with smoking cessation. Post-cessation BH4 administration does not further improve endothelial function in chronic smokers, unlike the effect observed in nonsmokers, indicating a longer-term impact of chronic smoking on vascular function that is not acutely reversible. PMID- 26606879 TI - Fermentation of bioactive solid lipid nanoparticles by human gut microflora. AB - Solid lipid nanoparticles (SLNs) can be used for oral delivery of phenolic compounds in order to protect them from the harsh conditions of digestion and improve their bioavailability in the intestinal epithelium. Recently, the production and characterization of SLNs loaded with rosmarinic acid (RA) and herbal extracts was performed for future use as functional food ingredients. Diet components have been shown to have a huge impact on gut microbiota viability and metabolic activity. Hence, SLNs loaded with RA, sage and savoury extracts have been evaluated for their effect on intestinal microbiota growth and the metabolic products generated. Fermentations in anaerobic batch cultures using volunteer human faeces were performed during 24 h. Dynamic bacterial population changes were analysed using PCR-real time, as well as the generation of fatty acids and the quantification of phenolic compounds by analytical methods. Solid lipid nanoparticles released phenolic compounds at non-inhibitory bacterial growth concentrations. Released herbal extract phenolic compounds showed a beneficial effect on gut microbiota growth (e.g. bifidogenic effects) and were used as substrates. Acetate, formate, lactate and butyrate were produced in higher concentrations. The released phenolic compounds also induced PUFA and trans fatty acids metabolic activity, the production of saturated fatty acids, as well of potential beneficial conjugated linoleic acid isomers. Solid lipid nanoparticles modulate gut microbiota and metabolic activities. PMID- 26606880 TI - Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST. AB - Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. The vast majority of GISTs are driven by oncogenic activation of KIT, PDGFRA or, less commonly, BRAF. Loss of succinate dehydrogenase complex activity has been identified in subsets of KIT/PDGFRA/BRAF mutation negative tumours, yet a significant fraction of GISTs are devoid of any of such alterations. To address the pathobiology of these 'quadruple-negative' GISTs, we sought to explore the possible involvement of fusion genes. To this end we performed transcriptome sequencing on five KIT/PDGFRA/BRAF-mutation negative, SDH-proficient tumours. Intriguingly, the analysis unveiled the presence of an ETV6-NTRK3 gene fusion. The screening by FISH of 26 additional cases, including KIT/PDGFRA-mutated GISTs, failed to detect other ETV6 rearrangements beside the index case. This was a 'quadruple-negative' GIST located in the rectum, an uncommon primary site for GIST development (~4% of all GISTs). The fusion transcript identified encompasses exon 4 of ETV6 and exon 14 of NTRK3 and therefore differs from the canonical ETV6-NTRK3 chimera of infantile fibrosarcomas. However, it retains the ability to induce IRS1 phosphorylation, activate the IGF1R downstream signalling pathway and to be targeted by IGF1R and ALK inhibitors. Thus, the ETV6-NTRK3 fusion might identify a subset of GISTs with peculiar clinicopathological characteristics which could be eligible for such therapies. Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 26606881 TI - Scandinavian multicenter study on the safety and feasibility of the associating liver partition and portal vein ligation for staged hepatectomy procedure. AB - BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has emerged as an additional tool to increase the size of the future liver remnant (FLR) in the settings of advanced tumor burden in the liver. Initial reports have indicated high feasibility but also high mortality and morbidity. The aim of this study was to assess the initial experience with ALPPS in Scandinavia regarding feasibility, morbidity, and mortality. MATERIALS AND METHODS: We conducted a retrospective analysis of all patients who underwent ALPPS since its introduction at 3 Scandinavian hepatobiliary centers. RESULTS: Thirty-six patients were identified, 21 male and 15 female. Median age was 67 years (22-83). Colorectal liver metastases (n = 25) were the most common indication for ALPPS followed by hepatocellular carcinoma (n = 4), cholangiocarcinoma (n = 4), and other (n = 3). Median growth of the FLR between the operations was 67% (-17 to 238) in 6 (5-13) days. All patients completed the second operation, and 71% of the resections were R0. Although the total percentage of patients with complication(s) was 92%, only 4 patients (11%) had a grade 3b complication according to the Clavien-Dindo classification, and no other severe complications were noted. There was no in-hospital mortality, but 1 (2.8%) patient died within 90 days of operation. CONCLUSION: ALPPS is a highly feasible method to stimulate FLR growth in patients with colorectal liver metastases as well as primary hepatobiliary malignancies. The treatment can be carried out with relative safety. PMID- 26606882 TI - A network meta-analysis comparing perioperative outcomes of interventions aiming to decrease ischemia reperfusion injury during elective liver resection. AB - OBJECTIVE: This study sought to compare the perioperative outcomes of interventions aiming to decrease ischemia-reperfusion (IR) injury during elective liver resection. METHOD: A comprehensive literature search was performed to identify randomized controlled trials. A Bayesian network meta-analysis was performed using the Markov chain Monte Carlo method in WinBUGS following the guidelines of the National Institute for Health and Clinical Excellence Decision Support Unit. Odds ratios for binary outcomes and mean differences for continuous outcomes were calculated using a fixed effect model or a random effects model according to model fit. RESULTS: Forty-four trials with 2,457 patients having undergone liver resection were included and were divided into 8 classes of interventions aimed at decreasing IR injury and a control group, which was hepatectomy alone. There was no difference between the different interventions in mortality, quantity of blood transfusion, and durations of stay in an intensive therapy unit between any pairwise comparisons. Patients treated with ischemic preconditioning, cardiovascular modulators, and miscellaneous interventions had significantly fewer serious adverse events compared with patients undergoing liver resection alone. Ischemic preconditioning patients had significantly fewer transfusion proportions and shorter operative time than patients treated with steroids. Ischemic preconditioning had significantly less operative blood loss compared with all other interventions, and a lesser duration of hospital stay than hepatectomy alone. Sensitivity analysis showed that the drugs sevoflurane (a volatile anesthetic), verapamil (a calcium channel blocker), and gabexate mesilate (a thrombin inhibitor) produced fewer serious adverse events compared with hepatectomy alone. CONCLUSION: Ischemic preconditioning resulted in multiple beneficial clinical endpoints and further RCTs seem to be needed to confirm its clinical benefits. PMID- 26606884 TI - Mental illness stigma, secrecy and suicidal ideation. AB - AIMS: Whether the public stigma associated with mental illness negatively affects an individual, largely depends on whether the person has been labelled 'mentally ill'. For labelled individuals concealing mental illness is a common strategy to cope with mental illness stigma, despite secrecy's potential negative consequences. In addition, initial evidence points to a link between stigma and suicidality, but quantitative data from community samples are lacking. METHODS: Based on previous literature about mental illness stigma and suicidality, as well as about the potential influence of labelling processes and secrecy, a theory driven model linking perceived mental illness stigma and suicidal ideation by a mediation of secrecy and hopelessness was established. This model was tested separately among labelled and unlabelled persons using data derived from a Swiss cross-sectional population-based study. A large community sample of people with elevated psychiatric symptoms was examined by interviews and self-report, collecting information on perceived stigma, secrecy, hopelessness and suicidal ideation. Participants who had ever used mental health services were considered as labelled 'mentally ill'. A descriptive analysis, stratified logistic regression models and a path analysis testing a three-path mediation effect were conducted. RESULTS: While no significant differences between labelled and unlabelled participants were observed regarding perceived stigma and secrecy, labelled individuals reported significantly higher frequencies of suicidal ideation and feelings of hopelessness. More perceived stigma was associated with suicidal ideation among labelled, but not among unlabelled individuals. In the path analysis, this link was mediated by increased secrecy and hopelessness. CONCLUSIONS: Results from this study indicate that among persons labelled 'mentally ill', mental illness stigma is a contributor to suicidal ideation. One explanation for this association is the relation perceived stigma has with secrecy, which introduces negative emotional consequences. If our findings are replicated, they would suggest that programmes empowering people in treatment for mental illness to cope with anticipated and experienced discrimination as well as interventions to reduce public stigma within society could improve suicide prevention. PMID- 26606883 TI - Microfluidic Bioprinting of Heterogeneous 3D Tissue Constructs Using Low Viscosity Bioink. AB - A novel bioink and a dispensing technique for 3D tissue-engineering applications are presented. The technique incorporates a coaxial extrusion needle using a low viscosity cell-laden bioink to produce highly defined 3D biostructures. The extrusion system is then coupled to a microfluidic device to control the bioink arrangement deposition, demonstrating the versatility of the bioprinting technique. This low-viscosity cell-responsive bioink promotes cell migration and alignment within each fiber organizing the encapsulated cells. PMID- 26606885 TI - The role of acoustic signaling for spacing and group coordination in a nocturnal, pair-living primate, the western woolly lemur (Avahi occidentalis). AB - OBJECTIVES: How social groups govern their distribution in time and space is a central question in socioecology. The aim of this study is to explore the role of acoustic signaling for spacing and cohesiveness in a nocturnal, cohesive, pair living strepsirrhine. MATERIAL AND METHODS: The study was conducted in northwestern Madagascar. Six pairs of Avahi occidentalis were radio-collared and home range usage, vocalizations and call-associated behavior recorded using GPS based focal animal sampling. Home range size was analyzed using ArcView GIS 3.3. Calls were characterized by a multiparametric sound analysis. RESULTS: Three frequently used, acoustically distinct call types were identified: the avahee call, the whistle call, and the growling call, the latter is a soft; the two others are loud calls. Call types are given by both sexes and convey individually specific signatures. Call types are used primarily in the locomotion context in the non-core-area of home ranges. The least common avahee call is responded by the avahee call from farther away. The more common whistle call, given when partners become visually isolated, and the growling call emitted at close distances, were answered by the whistle and the growling call. Results suggest a spacing function for the avahee call and group coordination functions for the other call types. DISCUSSION: Our study provides first empirical evidence for a nocturnal, cohesive pair-living strepsirrhine that vocal signaling represents an important mechanism for spacing, group coordination and decision making. Findings contribute to a better understanding of the evolutionary roots of primate vocal communication. PMID- 26606886 TI - The structure of a food product assortment modulates the effect of providing choice on food intake. AB - Several authors showed that providing choice may increase food liking and food intake. However, the impact of choice may be modulated by assortment's characteristics, such as the number of alternatives or their dissimilarity. The present study compared the impact of choice on food liking and intake under the two following conditions: (1) when choosing a product to consume from among similar products versus dissimilar products; and (2) when choosing a product to consume from among pleasant products versus unpleasant products. Two experiments were carried out using the same design: the "apple puree" experiment (n = 80), where the volunteers choose from among similar products (apple purees varying in texture) and the "dessert" experiment (n = 80), where the volunteers choose from among dissimilar products (fruit dessert, dairy dessert, custard, pudding). During the first session, participants rated their liking for 12 products (apples purees or desserts). Then the participants were divided into a "pleasant" group (n = 40) in which volunteers were assigned three pleasant products, and an "unpleasant" group (n = 40) in which volunteers were assigned three unpleasant products. Finally, all of the volunteers participated in a choice session - volunteers were presented with their three assigned products and asked to choose one of the products, and a no-choice session - volunteers were served with one product that was randomly selected from among their three assigned products. Providing choice led to an increase in food liking in both experiments and an increase in food intake only for the desserts, namely only when the volunteers chose the product to consume from among "not too similar" alternatives. No effect of assortment's pleasantness was observed. PMID- 26606888 TI - Eosinophilic esophagitis strongly linked to chronic rhinosinusitis. AB - OBJECTIVES/HYPOTHESIS: To determine the relative risk of having eosinophilic esophagitis (EoE) coexist with chronic rhinosinusitis (CRS) in probands and their families using the Utah Population Database (UPDB). METHODS: This retrospective observational cohort study with population-based matched controls utilized the UPDB, a genealogical database linked to medical records. It was used to identify CRS and EoE patients diagnosed at any age between 2008 and 2012. The familial risks of an EoE diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 530.13) in CRS probands, and vice versa, and their first- through fifth-degree relatives and spouses were calculated using logistic regression models in comparison to controls randomly selected from the Utah population and individually matched 6:1 on sex and birth year. RESULTS: Probands with CRS demonstrated a 3.4-fold increased risk of having EoE themselves (P < 10(-15) ). First-degree relatives (parents, siblings, and children) of CRS probands had a 1.5-fold increased risk of having EoE (P < 10(-4) ), whereas more distant relatives did not show a significant increased risk. Spouses of probands had a 1.4-fold increased risk of having EoE (P = 0.055). Conversely, risk estimates of having CRS in EoE probands were consistent. CONCLUSION: We observed an increased risk of comorbid EoE in patients with CRS and their families. An association between CRS and EoE as comorbid conditions suggests that a familial component is contributing to the etiology of both diseases. Further analyses regarding the pathophysiology of the development of CRS in these specific patients will lead to a better understanding of both disease processes and may help target therapy. LEVEL OF EVIDENCE: 3b. Laryngoscope, 126:1279-1283, 2016. PMID- 26606887 TI - The impact of sugar sweetened beverage intake on hunger and satiety in minority adolescents. AB - Limited research has examined the effects of habitual SSB consumption on hunger/fullness ratings and gut hormones. This study hypothesized that high versus low intakes of habitual SSBs would result in greater hunger, decreased fullness, and a blunted gut hormone response, however the high versus low fiber group would exhibit decreased hunger and increased fullness. This was a randomized crossover feeding trial with 47 African American and Hispanic adolescents. The experiment included three 24-hour recalls to assess habitual dietary intake. During the test meal phase, subjects were served breakfast and lunch. During the ad libitum meal phase, subjects were fed an ad libitum dinner. During the test meal phase, blood was drawn every 30 minutes for 3 hours. During the ad libitum meal phase, hunger and fullness visual analogue scales were completed. For this analysis, subjects were grouped into the following habitual SSB categories: low SSB (<=1 SSB serv/day), medium SSB (>1 - <2 serv/day), and high SSB (>=2 serv/day). Fiber categories were created based on quartiles of intake. Mixed modeling was used to explore how SSB and fiber categories predicted ghrelin/PYY values and hunger/fullness ratings across time within and between test meals. The following a priori covariates included: sex, ethnicity, age, and obesity status. The low SSB group had higher fullness ratings over the ad libitum meal compared to the high SSB group (beta =-0.49, CI=(-0.89, -0.08), p=0.02) and higher ghrelin concentrations than the medium and high SSB group over the test meal phase (beta =-1.86, CI=(-2.81, -0.92), p<0.01). Habitual SSB intake appears to play a key role in moderating fullness responses possibly via ghrelin. PMID- 26606889 TI - Safety and efficiency of microwave ablation for recurrent and persistent secondary hyperparathyroidism after parathyroidectomy: A retrospective pilot study. AB - BACKGROUND: Recurrent and persistent secondary hyperparathyroidism (SHPT) nodules have an incidence of 10-70% after surgery. The treatment of recurrent and persistent SHPT nodules is a challenge, and surgical resection of difficult-to reach or post-operative adhesions often fails. PURPOSE: The aim of this research was to study the safety and effectiveness of microwave ablation (MWA) for recurrent and persistent SHPT. MATERIALS AND METHODS: This was a retrospective study of 11 patients enrolled with a total of 16 nodules, and MWA was employed to manage SHPT. The laboratory test results, including the intact parathyroid hormone (iPTH), serum calcium, phosphorus and alkaline phosphatase (ALP) levels, improvement of SHPT-related symptoms after ablation, and complications during and after MWA were recorded and analysed. RESULTS: After ablation the value of iPTH was markedly decreased from 1570 +/- 1765 pg/mL to 287 +/- 239 pg/mL 1 day after MWA (p < 0.05). The levels of serum calcium and phosphorus decreased from 2.51 +/ 0.23 mmol/L to 2.06 +/- 0.27 mmol/L (p < 0.001) and 1.80 +/- 0.43 mmol/L to 1.48 +/- 0.32 mmol/L (p < 0.05), respectively, 1 day after MWA. There was no significant difference in the ALP value before and after MWA (p > 0.05). The clinical symptoms, including ostalgia, pruritus, disability, and restless legs, improved after MWA. Minor complications and side effects encountered during or after MWA include haematoma (1/11, 9%), transient hoarseness (2/11, 18.2%), hypocalcemia (6/11, 54.5%). No major complication occurred. CONCLUSION: MWA may be safe and effective to manage recurrent and persistent SHPT nodules; a definite conclusion needs to expand the sample size with a longer follow-up time. PMID- 26606890 TI - Observation of strongly enhanced photoluminescence from inverted cone-shaped silicon nanostructures. [corrected]. AB - Silicon nanowires (SiNWs) attached to a wafer substrate are converted to inversely tapered silicon nanocones (SiNCs). After excitation with visible light, individual SiNCs show a 200-fold enhanced integral band-to-band luminescence as compared to a straight SiNW reference. Furthermore, the reverse taper is responsible for multifold emission peaks in addition to the relatively broad near infrared (NIR) luminescence spectrum. A thorough numerical mode analysis reveals that unlike a SiNW the inverted SiNC sustains a multitude of leaky whispering gallery modes. The modes are unique to this geometry and they are characterized by a relatively high quality factor (Q ~ 1300) and a low mode volume (0.2 < (lambda/n eff)(3) < 4). In addition they show a vertical out coupling of the optically excited NIR luminescence with a numerical aperture as low as 0.22. Estimated Purcell factors Fp ? Q/Vm of these modes can explain the enhanced luminescence in individual emission peaks as compared to the SiNW reference. Investigating the relation between the SiNC geometry and the mode formation leads to simple design rules that permit to control the number and wavelength of the hosted modes and therefore the luminescent emission peaks. PMID- 26606891 TI - Antimicrobial peptide LL-37 attenuates infection of hepatitis C virus. AB - AIM: Although recent studies indicate that supplementation with vitamin D (VD) potentiates a sustained viral response by interferon-based therapy to chronic hepatitis C, detailed mechanisms are not fully defined. The production of cathelicidin, an antimicrobial peptide, has been demonstrated to be part of the VD-dependent antimicrobial pathway in innate immunity. Cathelicidin is known to directly kill or inhibit the growth of microbial pathogens including mycobacteria and viruses. METHODS: We used a hepatitis C virus (HCV) cell culture system to clarify the anti-HCV effects of the human cathelicidin, LL-37. HuH-7 cells were administrated with LL-37 and infected with cell culture-generated HCV (HCVcc). HCV propagation was estimated by measuring the level of HCV core antigen (Ag). RESULTS: Treatment with LL-37 resulted in decreased intra- and extracellular levels of HCV core Ag, suggesting inhibition of HCV propagation. To assess the effects of LL-37 on HCV replication, JFH-1 subgenomic replicon RNA-transfected cells were treated with LL-37. However, inhibition of HCV replication was not detected by this assay. To clarify the effects on HCV infection, we treated HCVcc with LL-37 and removed the antimicrobial peptide prior to use of the virus in infection. This exposure of HCVcc to LL-37 diminished the infectivity titers in a dose-dependent fashion. Iodixanol density gradient analysis revealed that the peak fraction of infectivity titer was eliminated by LL-37 treatment. CONCLUSION: The VD-associated antimicrobial peptide LL-37 attenuated the infectivity of HCV. This anti-HCV effect of LL-37 may explain the contribution of VD to the improved efficacy of interferon-based therapy. PMID- 26606892 TI - Teacher and pupil perspectives on the use of Virtual Field Trips as physically active lessons. AB - BACKGROUND: Virtual Field Trips (VFTs) are emerging physically active lessons that combine curriculum content with globe-based movement using interactive whiteboards. No research has yet examined the acceptability of these sessions by target users. This study aimed to (1) assess current physically active lesson teaching practices, (2) assess teacher attitudes towards VFTs and (3) investigate pupil perceptions of VFTs. METHODS: Data was collected from teaching staff interviews (n = 12) and three elementary school pupil focus groups (k = 3, n = 18), with all participants provided with a sample VFT session. Thematic analysis was used to analyse data. RESULTS: Teachers described VFTs as a flexible teaching tool, allowing inclusive learning across abilities and a range of taught subjects. They stressed a packed curriculum may make delivering VFT sessions problematic and warned that some teachers may be resistant to their use of technology. Pupils enjoyed the ability to move in the classroom and the ability to share a new teaching experience with their peers. CONCLUSIONS: This work suggests positive attitudes towards VFTs as novel, physically active lessons and identifies potential teacher concerns for consideration in forthcoming intervention planning. Future experimental work will assess if these attitudes persist during longitudinal exposure to VFTs. PMID- 26606893 TI - UV-photoexcitation and ultrafast dynamics of HCFC-132b (CF2 ClCH2 Cl). AB - The UV-induced photochemistry of HCFC-132b (CF2 ClCH2 Cl) was investigated by computing excited-state properties with time-dependent density functional theory (TDDFT), multiconfigurational second-order perturbation theory (CASPT2), and coupled cluster with singles, doubles, and perturbative triples (CCSD(T)). Excited states calculated with TDDFT show good agreement with CASPT2 and CCSD(T) results, correctly predicting the main excited-states properties. Simulations of ultrafast nonadiabatic dynamics in the gas phase were performed, taking into account 25 electronic states at TDDFT level starting in two different spectral windows (8.5 +/- 0.25 and 10.0 +/- 0.25 eV). Experimental data measured at 123.6 nm (10 eV) is in very good agreement with our simulations. The excited-state lifetimes are 106 and 191 fs for the 8.5 and 10.0 eV spectral windows, respectively. Internal conversion to the ground state occurred through several different reaction pathways with different products, where 2Cl, C-Cl bond breakage, and HCl are the main photochemical pathways in the low-excitation region, representing 95% of all processes. On the other hand, HCl, HF, and C-Cl bond breakage are the main reaction pathways in the higher excitation region, with 77% of the total yield. (c) 2015 Wiley Periodicals, Inc. PMID- 26606894 TI - Chirality transfer from graphene quantum dots. AB - Chiral graphene quantum dots were prepared by acidic exfoliation and oxidation of graphite, dialysis, and esterification with enantiomerically pure (R) or (S)-2 phenyl-1-propanol. Circular dichroism studies support the formation of supramolecular aggregates with pyrene molecules, where a transfer of chirality occurs from the chiral graphene quantum dots to the pyrene. PMID- 26606895 TI - Co5In(BTC)4[B2O4(OH)]2: the first MOF material constructed by borate polyanions and carboxylate mixed ligands. AB - A novel heterometallic organic-inorganic hybrid MOF material, Co5In(BTC)4[B2O4(OH)]2, has been synthesized under ionothermal conditions. Its structure is characterized as a 3D open framework constructed by the Co2.5In0.5[B2O4(OH)] cluster and the 1,3,5-benzenetricarboxylate ligand. Furthermore, its fluorescent and adsorption properties have also been studied. PMID- 26606896 TI - The marker C-reactive protein is helpful in monitoring the integrity of anastomosis: plasma calprotectin. AB - BACKGROUND: Despite improved surgical techniques and materials, anastomotic leakage is a big problem for surgeons. The most frequently used laboratory parameters is leukocyte (white blood cell) and C-reactive protein (CRP). Availability of plasma calprotectin with CRP to detect anastomotic leakage was studied. METHODS: In this prospective study of 41 (male/female 18/23) patients in the anastomosis group, 30 (male/female 20/10) patients were included in the control group. The anastomosis groups viewed in preoperatively day and postoperatively 1st, 3rd, and 5th day of CRP, white blood cell, and plasma calprotectin values. RESULTS: Anastomosis group with complications and without complications were studied. Statistically significant similarities between plasma calprotectin and CRP levels in the postoperative period were observed. CONCLUSION: Plasma calprotectin in monitoring the integrity of the anastomosis can be used with a marker CRP. PMID- 26606897 TI - Analytical characterization of four new ortho-methoxybenzylated amphetamine-type designer drugs. AB - In a seizure of German custom authorities four N-(ortho-methoxybenzyl)amines with amphetamine partial structure were obtained as pure compounds: N-(ortho methoxybenzyl)-3,4-dimethoxyamphetamine (3,4-DMA-NBOMe (1)), N-(ortho methoxybenzyl)-4-ethylamphetamine (4-EA-NBOMe (2)), N-(ortho-methoxybenzyl)-4 methylmethamphetamine (4-MMA-NBOMe (3)), and N-(ortho-methoxybenzyl)-5-(2 aminopropyl)benzofuran (5-APB-NBOMe (4)). The compounds have been detected in Germany for the first time and no analytical data had been previously published. Mass spectrometric (MS), infrared (IR) spectroscopic, and nuclear magnetic resonance (NMR) spectroscopic data are presented. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26606898 TI - Enhancing Localized Evaporation through Separated Light Absorbing Centers and Scattering Centers. AB - This report investigates the enhancement of localized evaporation via separated light absorbing particles (plasmonic absorbers) and scattering particles (polystyrene nanoparticles). Evaporation has been considered as one of the most important phase-change processes in modern industries. To improve the efficiency of evaporation, one of the most feasible methods is to localize heat at the top water layer rather than heating the bulk water. In this work, the mixture of purely light absorptive plasmonic nanostructures such as gold nanoparticles and purely scattering particles (polystyrene nanoparticles) are employed to confine the incident light at the top of the solution and convert light to heat. Different concentrations of both the light absorbing centers and the light scattering centers were evaluated and the evaporation performance can be largely enhanced with the balance between absorbing centers and scattering centers. The findings in this study not only provide a new way to improve evaporation efficiency in plasmonic particle-based solution, but also shed lights on the design of new solar-driven localized evaporation systems. PMID- 26606899 TI - Impact of Implementing the 2013 ACC/AHA Cholesterol Guidelines on Vascular Events in a Statewide Community-Based Practice Registry. AB - Electronic health record data were analyzed to estimate the number of statin eligible adults with the 2013 American College of Cardiology/American Heart Association cholesterol guidelines not taking statin therapy and the impact of recommended statin therapy on 10-year atherosclerotic cardiovascular disease (ASCVD10 ) events. Adults aged 21 to 80 years in an outpatient network with >=1 clinic visit(s) from January 2011 to June 2014 with data to calculate ASCVD10 were eligible. Moderate-intensity statin therapy was assumed to lower low-density lipoprotein cholesterol by 30% and high-intensity therapy was assumed to reduce low-density lipoprotein cholesterol by 50%. ASCVD events were assumed to decline 22% for each 39 mg/dL decline in low-density lipoprotein cholesterol. Among 411,768 adults, 260,434 (63.2%) were not taking statins and 103,478 (39.7%) were eligible for a statin, including 79,069 (76.4%) patients with hypertension. Estimated ASCVD10 events were 18,781 without and 13,328 with statin therapy, a 29.0% relative and 5.3% absolute risk reduction with a number needed to treat of 19. The 2013 cholesterol guidelines are a relatively efficient approach to reducing ASCVD in untreated, statin-eligible adults who often have concomitant hypertension. PMID- 26606900 TI - Sex-Related Differences in Rat Choroid Plexus and Cerebrospinal Fluid: A cDNA Microarray and Proteomic Analysis. AB - The choroid plexus (CP) epithelium is a unique structure in the brain that forms an interface between the peripheral blood and the cerebrospinal fluid (CSF), which is mostly produced by the CP itself. Because the CP transcriptome is regulated by the sex hormone background, the present study compared gene/protein expression profiles in the CP and CSF from male and female rats aiming to better understand sex-related differences in CP functions and brain physiology. We used data previously obtained by cDNA microarrays to compare the CP transcriptome between male and female rats, and complemented these data with the proteomic analysis of the CSF of castrated and sham-operated males and females. Microarray analysis showed that 17 128 and 17 002 genes are expressed in the male and female CP, which allowed the functional annotation of 141 and 134 pathways, respectively. Among the most expressed genes, canonical pathways associated with mitochondrial dysfunctions and oxidative phosphorylation were the most prominent, whereas the most relevant molecular and cellular functions annotated were protein synthesis, cellular growth and proliferation, cell death and survival, molecular transport, and protein trafficking. No significant differences were found between males and females regarding these pathways. Seminal functions of the CP differentially regulated between sexes were circadian rhythm signalling, as well as several canonical pathways related to stem cell differentiation, metabolism and the barrier function of the CP. The proteomic analysis identified five down regulated proteins in the CSF samples from male rats compared to females and seven proteins exhibiting marked variation in the CSF of gonadectomised males compared to sham animals, whereas no differences were found between sham and ovariectomised females. These data clearly show sex-related differences in CP gene expression and CSF protein composition that may impact upon neurological diseases. PMID- 26606901 TI - Nucleoside phosphorylation by the mineral schreibersite. AB - Phosphorylation of the nucleosides adenosine and uridine by the simple mixing and mild heating of aqueous solutions of the organic compounds with synthetic analogs of the meteoritic mineral schreibersite, (Fe,Ni)3P under slightly basic conditions (pH ~9) is reported. These results suggest a potential role for meteoritic phosphorus in the origin and development of early life. PMID- 26606902 TI - Luminescence turn-on/off sensing of biological iron by carbon dots in transferrin. AB - Iron is a key nutrient as well as a potential toxin for almost all living organisms. In mammalian cells, serum transferrin (Tf) is responsible for iron transport and its iron overload/deficiency causes various diseases. Therefore, closely regulated iron homeostasis is extremely essential for cellular metabolism. In the present article we report the pH-dependent luminescence turn on/off sensing of bound Fe(3+) ions of serum Tf by carbon dots (CDs) with the help of photoluminescence (PL) spectroscopy, FTIR spectroscopy, dynamic light scattering (DLS), circular dichroism (CD) and PL imaging techniques. At physiological pH (7.4), the intrinsic luminescence of CDs gets quenched in the presence of Tf as a consequence of ground-state association, which is driven by favorable electrostatic interactions between negatively charged CDs (-25.45 +/- 1.23 mV) and positively charged Fe(3+) ions of Tf. The estimated detection limit of Tf by CDs at physiological pH is found to be 1.82 MUM (signal-to-noise ratio of 3), which is much lower than the in vivo plasma concentration of Tf (~ 25-35 MUM). Various thermodynamic parameters have been evaluated by using the van't Hoff equation. Importantly, the secondary structure of Tf remains unaltered upon association with CDs. However, at pH 3.5, no such luminescence quenching of CDs has been observed in the presence of Tf due to the lack of ground-state interactions between positively charged (+17.63 +/- 0.84 mV) CDs and Tf. Furthermore, the results from UV-Vis and far-UV CD measurements revealed a significant conformational change of Tf at pH 3.5 relative to pH 7.4, which triggers the subsequent release of bound iron from Tf. PL microscopy of individual CD revealed significant luminescence quenching at the single particle level, which further supports the non-emissive ground-state complexation at pH 7.4. Our present results show that these chemically synthesized water-dispersed CDs have the ability to selectively sense the bound iron from released iron of Tf without any conformational perturbation and hence they can be used as potential biological iron sensors as well as luminescent markers for the detection of iron deficiency/overload in biological macromolecules. PMID- 26606904 TI - Substrate tolerant direct block copolymer nanolithography. AB - Block copolymer (BC) self-assembly constitutes a powerful platform for nanolithography. However, there is a need for a general approach to BC lithography that critically considers all the steps from substrate preparation to the final pattern transfer. We present a procedure that significantly simplifies the main stream BC lithography process, showing a broad substrate tolerance and allowing for efficient pattern transfer over wafer scale. PDMS-rich poly(styrene b-dimethylsiloxane) (PS-b-PDMS) copolymers are directly applied on substrates including polymers, silicon and graphene. A single oxygen plasma treatment enables formation of the oxidized PDMS hard mask, PS block removal and polymer or graphene substrate patterning. PMID- 26606903 TI - Trienamine catalyzed asymmetric synthesis and biological investigation of a cytochalasin B-inspired compound collection. AB - Due to their enhanced metabolic needs many cancers need a sufficient supply of glucose, and novel inhibitors of glucose import are in high demand. Cytochalasin B (CB) is a potent natural glucose import inhibitor which also impairs the actin cytoskeleton leading to undesired toxicity. With a view to identifying selective glucose import inhibitors we have developed an enantioselective trienamine catalyzed synthesis of a CB-inspired compound collection. Biological analysis revealed that indeed actin impairment can be distinguished from glucose import inhibition and led to the identification of the first selective glucose import inhibitor based on the basic structural architecture of cytochalasin B. PMID- 26606905 TI - High-methionine diets accelerate atherosclerosis by HHcy-mediated FABP4 gene demethylation pathway via DNMT1 in ApoE(-/-) mice. AB - Homocysteine (Hcy) is an independent risk factor for atherosclerosis, but the underlying molecular mechanisms are not known. We investigated the effects of Hcy on fatty acid-binding protein 4 (FABP4), and tested our hypothesis that Hcy induced atherosclerosis is mediated by increased FABP4 expression and decreased methylation. The FABP4 expression and DNA methylation was assessed in the aorta of ApoE(-/-) mice fed high-methionine diet for 20weeks. Over-expression of FABP4 enhanced accumulation of total cholesterol and cholesterol ester in foam cells. The up-regulation of DNA methyltransferase 1 (DNMT1) promoted the methylation process and decreased FABP4 expression. These data suggest that FABP4 plays a key role in Hcy-mediated disturbance of lipid metabolism and that DNMT1 may be a novel therapeutic target in Hcy-related atherosclerosis. PMID- 26606906 TI - Targeting cholesterol with beta-cyclodextrin sensitizes cancer cells for apoptosis. AB - We found that targeting cholesterol with beta-cyclodextrin (bCD) and its derivatives disrupted signal transduction between PI3K and AKT, attenuating AKT pro-survival signals. In their absence, 2-deoxyglucose (2DG) caused anti apoptotic protein Mcll to dissociate from pro-apoptotic Bak at mitochondria. Normally Bak is sequestered by its inhibitory associations with Mcll and Bcl-xL, and only when Bak is released from both, is it free to form oligomers through which cytochrome c can escape into the cytosol. Thus an addition of a bcl-2 antagonist dissociates Bak from Bcl-xL, triggering cytochrome c release and inducing apoptosis. 2DG-bCD can also sensitize type II cancer cells for TRAIL mediated apoptosis. PMID- 26606907 TI - Down-regulation of 5S rRNA by miR-150 and miR-383 enhances c-Myc-rpL11 interaction and inhibits proliferation of esophageal squamous carcinoma cells. AB - 5S rRNA plays an important part in ribosome biology and is over-expression in multiple cancers. In this study, we found that 5S rRNA is a direct target of miR 150 and miR-383 in esophageal squamous cell carcinoma (ESCC). Overexpression of miR-150 and miR-383 inhibited ESCC cell proliferation in vitro and in vivo. Moreover, 5S rRNA silencing by miR-150 and miR-383 might intensify rpL11-c-Myc interaction, which attenuated role of c-Myc as an oncogenic transcriptional factor and dysregulation of multiple c-Myc target genes. Taken together, our results highlight the involvement of miRNAs in ribosomal regulation during tumorigenesis. PMID- 26606908 TI - Unusual effects of crowders on heme retention in myoglobin. AB - Myoglobin (Mb) undergoes pronounced heme loss under denaturing conditions wherein the proximal histidine gets protonated. Our data show that macromolecular crowding agents (both synthetic and protein based) can appreciably influence the extent of heme retention in Mb. Interestingly, glucose and sucrose, the monomeric constituents of dextran and ficoll-based crowders were much more effective in preventing heme dissociation of Mb, albeit, at much higher concentrations. The protein crowders BSA and lysozyme show very interesting results with BSA bringing about the maximum heme retention amongst all the crowding agents used while lysozyme induced heme dissociation even in the native state of Mb. The stark difference that these protein crowders exhibit when interacting with the heme protein is a testament to the varied interaction potentials that a test protein might be exposed to in the physiological (crowded) milieu. PMID- 26606909 TI - Central and peripheral fatigue following non-exhaustive and exhaustive exercise of disparate metabolic demands. AB - The development of fatigue after non-exhaustive and exhaustive exercise eliciting differing metabolic demands is poorly understood. Sixteen active males completed five cycling trials. The first trial established the lactate threshold (LT) and maximal oxygen uptake (VO2max ). Two of the remaining trials were completed at a severe intensity (halfway between LT and VO2max , SI) and two at a moderate intensity (90% LT, MI). Each trial involved two non-exhaustive bouts matched for work between intensities before cycling to exhaustion. Responses to stimulation of the femoral nerve and motor cortex were determined after each bout to determine peripheral and central fatigue. Corticospinal excitability, cortical silent period (cSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) were also assessed. Non-exhaustive cycling induced greater peripheral and central fatigue in the SI compared with the MI (P < 0.05). At exhaustion, there was no difference between intensities; however, peripheral fatigue tended to be greater in the SI vs MI (-31% vs -17%, respectively, P = 0.051). Exhaustive cycling increased SICI (24%, P < 0.001) and reduced the cSP (-14%, P < 0.001) in the SI, whereas ICF was reduced in the MI ( 16%, P < 0.001). These findings demonstrate exercise-induced metabolic stress accelerates the development of peripheral and central fatigue, and differentially influences intracortical excitability. PMID- 26606911 TI - Consequences of on-line dialysis on polyelectrolyte molar masses determined by size-exclusion chromatography with light scattering detection. AB - Size-exclusion chromatography with light scattering detection experiments conducted on poly(acrylic acid) neutralized to different degrees or using hydroxides with different counterions suggest that the same counterion and degree of neutralization is observed at the detector, irrespective of salt concentration, degree of neutralization and counterion at the time of injection. This strongly supports that during the chromatographic experiment the counterions of the polyelectrolyte are exchanged with those of the eluent, resulting in an effective dialysis of the polyelectrolyte solution during the size-exclusion chromatography experiment. Consequently, the refractive index increment determined by a refractive index detector equals the refractive index increment obtained after excessive dialysis against the pure eluent. Therefore, the species detected and characterized by light scattering coupled to size-exclusion chromatography are not identical to the species injected into the chromatographic system. Despite this structural change during the chromatographic experiments, the correct molar mass for the injected species is obtained by size-exclusion chromatography with light scattering detection. PMID- 26606910 TI - Management of poor-risk metastatic renal cell carcinoma: current approaches, the role of temsirolimus and future directions. AB - Targeted therapies have substantially improved outcomes in metastatic renal cell carcinoma (mRCC). As expected, poor-risk patients have the worst outcomes. Temsirolimus is currently the only agent licensed for treatment of poor-risk mRCC patients. It is associated with meaningful improvements in survival and quality of life, highlighting the importance of correctly stratifying risk in mRCC patients so they receive optimal treatment. Currently, data for other targeted therapies in poor-risk patients are relatively sparse. Optimizing outcomes in these patients is the subject of ongoing research, including studies of biomarkers and studies to elucidate the role of nephrectomy and neoadjuvant targeted therapy in poor-risk mRCC patients. The impacts of novel combinations including temsirolimus have also been explored to further improve outcomes. PMID- 26606912 TI - European Association for the Study of Diabetes 51st Annual Meeting. PMID- 26606913 TI - Ventricular Twisting and Dyssynchrony in Children with Single Left Ventricle Using Three-Dimensional Speckle Tracking Imaging after the Fontan Operation. AB - BACKGROUND: The importance of left ventricular (LV) twisting has been recognized in various types of heart disease, but no studies have investigated twisting of functional single ventricle using echocardiography. This study aimed to evaluate LV twisting and dyssynchrony of children with single left ventricle (SLV) after the Fontan operation and explore the relationship between twisting motion and ventricular contractility using three-dimensional speckle tracking imaging (3DSTI). METHODS: Thirty-five children with SLV and 35 healthy children (controls) were enrolled. The patients were divided into wide and narrow QRS groups according to the QRS interval. Atrioventricular valve inflow velocity and tissue Doppler imaging velocity were obtained, and the Tei index was calculated. Apical rotation, basal rotation, twist, torsion, time to peak apical rotation, time to peak basal rotation, time to peak twist, apical-basal rotation delay, and the systolic dyssynchrony index (SDI) were measured by 3DSTI. RESULTS: Patients with SLV had significantly lower apical rotation (2.50 +/- 2.25 degrees vs. 4.85 +/- 2.68 degrees , P < 0.001), basal rotation (-3.46 +/- 3.11 degrees vs. -7.76 +/- 2.11 degrees , P < 0.001), twist (5.15 +/- 4.75 degrees vs. 12.19 +/- 3.65 degrees , P < 0.001), and torsion (1.04 +/- 0.99 degrees /cm vs. 2.37 +/- 0.77 degrees /cm, P < 0.001) compared to controls. Time to peak basal rotation, apical basal rotation delay, and time to peak twist were significantly longer in patients. Apical rotation was significantly lower in the wide QRS group but similar in the narrow QRS group as compared to controls. Time to peak twist and apical-basal delay were significantly longer in the wide QRS group in contrast to the similar time in the narrow QRS group compared with controls. Among these twisting parameters, twist and torsion were most significantly correlated with left ventricular ejection fraction (LVEF), the Tei index, and SDI. Twist and age were significantly correlated. CONCLUSION: Twisting is reduced in children with SLV after the Fontan operation. Torsion is a good indicator of LV global function because of good reproducibility and its lack of association with age. PMID- 26606914 TI - Cognitive Impairment and Risk Factors in Elderly People Living in Fluorosis Areas in China. AB - Residents living in fluorosis areas generally experienced long-term exposure to excessive fluoride in drinking water. The adverse effects of high fluoride levels on the nervous system have been studied; however, the effect of fluoride exposure on cognitive functions of elderly people in fluorosis areas is rarely reported. This study was aimed to find out the potential risk factors of cognitive impairment among elderly people who lived in fluorosis areas of China. A total of 511 subjects, aged 60 years or above, were investigated in fluorosis areas of Heilongjiang Province, Inner Mongolia Autonomous Region, Qinghai Province, and Xinjiang Uygur Autonomous Region. The Mini-Mental State Examination (MMSE) was used to examine cognitive functions of the study subjects. Based on the MMSE scores, the study subjects were divided into normal group and cognitive impairment group that consisted of mild, moderate, and severe groups. Multivariable logistic regression showed that a higher risk of cognitive impairment was associated with increased age and decreased education levels. Multiple linear regression analysis revealed that MMSE scores were negatively associated with serum homocysteine (Hcy) levels. However, both urinary fluoride and serum Hcy levels in the normal group were not the lowest among the four groups. Spearman's correlation analysis showed that urinary fluoride levels were positively correlated with serum Hcy (r s = 0.209, P < 0.01). Our study suggests that people with cognitive impairment in fluorosis areas have elevated serum Hcy levels, which was positively correlated with urinary fluoride concentrations. A certain low dose of fluoride intake may play a potential protective rather than harmful role in cognitive functions; however, high fluoride exposure is a potential risk factor for cognitive impairment. PMID- 26606915 TI - Toxic Risk Assessment of Arsenic in Males Through Drinking Water in Tharparkar Region of Sindh, Pakistan. AB - Humans are exposed to arsenic (As) through air, drinking water, and food. The arsenic (As) hazardous quotient was calculated on the basis of its concentration in drinking water of different origin and scalp hair of male subjects (n = 313), residents of different exposed and non-exposed areas of Sindh, Pakistan. The total As was determined in water and scalp hair samples, while As species were determined in water samples by advance extraction methodologies. The total As concentrations in drinking water of less-exposed (LE) and high-exposed (HE) areas was found to be 2.63 to 4.46 and 52 to 235, fold higher than the permissible limit, respectively, than recommended by World Health Organization (2004) for drinking water. While the levels of As in drinking water of non-exposed (NE) areas was within the permissible limit. The resulted data indicated that the dominant species was As(+5) in groundwater samples. The levels of As in scalp hair samples of male subjects of two age groups (18-30 and 31-50 years), belonging to NE, LE, and HE areas, ranged from 0.26 to 0.69, 0.58 to 1.34, and 15.6 to 60.9 MUg/g, respectively. A significant correlation between As levels in drinking water and scalp hair was observed in HE area (r = 0.86-0.90, p < 0.001) as compared to those subjects belonging to LE area. A toxicity risk assessment was calculated as hazard quotient (HQ), which indicates that the study subjects of HE area have significantly higher values of HQ than LE. The population of As exposed areas is at high risk of non-carcinogenic and carcinogenesis effects. PMID- 26606916 TI - Erratum to: Selective Embolization of Systemic Collaterals for the Treatment of Recurrent Hemoptysis Secondary to Unilateral Absence of Pulmonary Artery in a Child. PMID- 26606917 TI - Patient Evaluation and Preparation in Vascular and Interventional Radiology: What Every Interventional Radiologist Should Know (Part 2: Patient Preparation and Medications). AB - Performing an interventional procedure imposes a commitment on interventional radiologists to conduct the initial patient assessment, determine the best course of therapy, and provide long-term care. Patient care before and after an interventional procedure, identification, and management of early and delayed complications of various procedures are equal in importance to the procedure itself. In this second part, we complete the comprehensive, methodical review of pre-procedural care and patient preparation before vascular and interventional radiology procedures. PMID- 26606918 TI - Improvement and efficient display of Bacillus thuringiensis toxins on M13 phages and ribosomes. AB - Bacillus thuringiensis (Bt) produces insecticidal proteins that have been used worldwide in the control of insect-pests in crops and vectors of human diseases. However, different insect species are poorly controlled by the available Bt toxins or have evolved resistance to these toxins. Evolution of Bt toxicity could provide novel toxins to control insect pests. To this aim, efficient display systems to select toxins with increased binding to insect membranes or midgut proteins involved in toxicity are likely to be helpful. Here we describe two display systems, phage display and ribosome display, that allow the efficient display of two non-structurally related Bt toxins, Cry1Ac and Cyt1Aa. Improved display of Cry1Ac and Cyt1Aa on M13 phages was achieved by changing the commonly used peptide leader sequence of the coat pIII-fusion protein, that relies on the Sec translocation pathway, for a peptide leader sequence that relies on the signal recognition particle pathway (SRP) and by using a modified M13 helper phage (Phaberge) that has an amber mutation in its pIII genomic sequence and preferentially assembles using the pIII-fusion protein. Also, both Cry1Ac and Cyt1Aa were efficiently displayed on ribosomes, which could allow the construction of large libraries of variants. Furthermore, Cry1Ac or Cyt1Aa displayed on M13 phages or ribosomes were specifically selected from a mixture of both toxins depending on which antigen was immobilized for binding selection. These improved systems may allow the selection of Cry toxin variants with improved insecticidal activities that could counter insect resistances. PMID- 26606919 TI - Discovery of a mcl-PHA with unexpected biotechnical properties: the marine environment of French Polynesia as a source for PHA-producing bacteria. AB - A library of microorganisms originating from various marine environments in French Polynesia was screened for polyhydroxyalkanoate producing bacteria. No significant connection was found between the geo-ecological source of bacteria and their ability to produce polyhydroxyalkanoate. A bacterial strain designated as Enterobacter FAK 1384 was isolated from a shark jaw. When grown on coprah oil, this bacterium produces a PHA constituting of 62 mol % 3-hydroxydecanoate and lower amount of 12 mol % 3-hydroxydodecenoate and of 7.6 mol % 3 hydroxydodecanoate. These interesting properties make this mcl-PHA a good candidate for further exploitations in many industrial sectors, as in film and coating manufacturing, as well as for biomedical applications. PMID- 26606920 TI - Duck enteritis virus UL54 is an IE protein primarily located in the nucleus. AB - BACKGROUND: The UL54 protein of Duck Enteritis Virus (DEV) is a homolog of herpes simplex virus-1 (HSV-1) immediate-early infectious cell protein 27 (ICP27), a multifunctional protein essential for viral infection. Nonetheless, there is little information on the UL54 protein of DEV. METHODS: The UL54 gene was cloned into the pPAL7 vector, and the recombinant protein, expressed in the E. coli Rosetta, was used to produce a specific antibody. Using this antibody, Western blotting and indirect immunofluorescence analysis (IFA) were used to analyze the expression level and intracellular localization, respectively, of UL54 in DEV infected cells at different times. Real-time quantitative reverse transcription PCR (RT-PCR) and the pharmacological inhibition test were utilized to ascertain the kinetic class of the UL54 gene. RESULTS: UL54 was expressed as a fusion protein of approximately 66.0 kDa using the prokaryotic expression system, and this protein was used to generate the specific anti-UL54 antibody. The UL54 protein was initially diffusely distributed throughout the cytoplasmic region; then, after 2 h, it gradually distributed into the nucleus, peaking at 24 h, and complete localization to the nucleus was observed thereafter. The UL54 transcript was detected as early as 0.5 h, and peak expression was observed at 24 h. The UL54 gene was insensitive to the DNA polymerase inhibitor Ganciclovir (GCV) and the protein synthesis inhibitor Cycloheximide (CHX), both of which confirmed that UL54 was an immediate early gene. CONCLUSIONS: The DEV UL54 gene was expressed in a prokaryotic expression system and characterized for expression level, intracellular localization and gene kinetic class. We propose that these results will provide the foundation for further functional analyses of this gene. PMID- 26606921 TI - Mortality differences and inequalities within and between 'protected characteristics' groups, in a Scottish Cohort 1991-2009. AB - BACKGROUND: Little is known about the interaction between socio-economic status and 'protected characteristics' in Scotland. This study aimed to examine whether differences in mortality were moderated by interactions with social class or deprivation. The practical value was to pinpoint population groups for priority action on health inequality reduction and health improvement rather than a sole focus on the most deprived socioeconomic groups. METHODS: We used data from the Scottish Longitudinal Study which captures a 5.3 % sample of Scotland and links the censuses of 1991, 2001 and 2011. Hazard ratios for mortality were estimated for those protected characteristics with sufficient deaths using Cox proportional hazards models and through the calculation of European age-standardised mortality rates. Inequality was measured by calculating the Relative Index of Inequality (RII). RESULTS: The Asian population had a polarised distribution across deprivation deciles and was more likely to be in social class I and II. Those reporting disablement were more likely to live in deprived areas, as were those raised Roman Catholic, whilst those raised as Church of Scotland or as 'other Christian' were less likely to. Those aged 35-54 years were the least likely to live in deprived areas and were most likely to be in social class I and II. Males had higher mortality than females, and disabled people had higher mortality than non-disabled people, across all deprivation deciles and social classes. Asian males and females had generally lower mortality hazards than majority ethnic ('White') males and females although the estimates for Asian males and females were imprecise in some social classes and deprivation deciles. Males and females who reported their raised religion as Roman Catholic or reported 'No religion' had generally higher mortality than other groups, although the estimates for 'Other religion' and 'Other Christian' were less precise.Using both the area deprivation and social class distributions for the whole population, relative mortality inequalities were usually greater amongst those who did not report being disabled, Asians and females aged 35-44 years, males by age, and people aged <75 years. The RIIs for the raised religious groups were generally similar or too imprecise to comment on differences. CONCLUSIONS: Mortality in Scotland is higher in the majority population, disabled people, males, those reporting being raised as Roman Catholics or with 'no religion' and lower in Asians, females and other religious groups. Relative inequalities in mortality were lower in disabled than nondisabled people, the majority population, females, and greatest in young adults. From the perspective of intersectionality theory, our results clearly demonstrate the importance of representing multiple identities in research on health inequalities. PMID- 26606922 TI - Protocol-developing meta-ethnography reporting guidelines (eMERGe). AB - BACKGROUND: Designing and implementing high-quality health care services and interventions requires robustly synthesised evidence. Syntheses of qualitative research studies can provide evidence of patients' experiences of health conditions; intervention feasibility, appropriateness and acceptability to patients; and advance understanding of health care issues. The unique, interpretive, theory-based meta-ethnography synthesis approach is suited to conveying patients' views and developing theory to inform service design and delivery. However, meta-ethnography reporting is often poor quality, which discourages trust in, and use of, meta-ethnography findings. Users of evidence syntheses require reports that clearly articulate analytical processes and findings. Tailored research reporting guidelines can raise reporting standards but none exists for meta-ethnography. This study aims to create an evidence-based meta-ethnography reporting guideline articulating the methodological standards and depth of reporting required to improve reporting quality. METHODS/DESIGN: The mixed-methods design of this National Institute of Health Research-funded study (http://www.stir.ac.uk/emerge/) follows good practice in research reporting guideline development comprising: (1) a methodological systematic review (PROSPERO registration: CRD42015024709) to identify recommendations and guidance in conducting/reporting meta-ethnography; (2) a review and audit of published meta-ethnographies to identify good practice principles and develop standards in conduct/reporting; (3) an online workshop and Delphi studies to agree guideline content with 45 international qualitative synthesis experts and 45 other stakeholders including patients; (4) development and wide dissemination of the guideline and its accompanying detailed explanatory document, a report template for National Institute of Health Research commissioned meta-ethnographies, and training materials on guideline use. DISCUSSION: Meta-ethnography, devised in the field of education, is now used widely in other disciplines. Methodological advances relevant to meta-ethnography conduct exist. The extent of discipline specific adaptations of meta-ethnography and the fit of any adaptions with the underpinning philosophy of meta-ethnography require investigation. Well-reported meta-ethnography findings could inform clinical decision-making. A bespoke meta ethnography reporting guideline is needed to improve reporting quality, but to be effective potential users must know it exists, trust it and use it. Therefore, a rigorous study has been designed to develop and promote a guideline. By raising reporting quality, the guideline will maximise the likelihood that high-quality meta-ethnographies will contribute robust evidence to improve health care and patient outcomes. PMID- 26606923 TI - Genome-wide identification of rubber tree (Hevea brasiliensis Muell. Arg.) aquaporin genes and their response to ethephon stimulation in the laticifer, a rubber-producing tissue. AB - BACKGROUND: Natural rubber, an important industrial raw material, is specifically synthesized in laticifers located inside the rubber tree (Hevea brasiliensis Muell. Arg.) trunk. Due to the absence of plasmodesmata, the laticifer water balance is mediated by aquaporins (AQPs). However, to date, the characterization of H. brasiliensis AQPs (HbAQPs) is still in its infancy. RESULTS: In this study, 51 full-length AQP genes were identified from the rubber tree genome. The phylogenetic analysis assigned these AQPs to five subfamilies, including 15 plasma membrane intrinsic proteins (PIPs), 17 tonoplast intrinsic proteins (TIPs), 9 NOD26-like intrinsic proteins (NIPs), 4 small basic intrinsic proteins (SIPs) and 6 X intrinsic proteins (XIPs). Functional prediction based on the analysis of the aromatic/arginine (ar/R) selectivity filter, Froger's positions and specificity-determining positions (SDPs) showed a remarkable difference in substrate specificity among subfamilies. Homology analysis supported the expression of 44 HbAQP genes in at least one of the examined tissues. Furthermore, deep sequencing of the laticifer transcriptome in the form of latex revealed a key role of several PIP subfamily members in the laticifer water balance, and qRT-PCR analysis showed diverse expression patterns of laticifer expressed HbAQP genes upon ethephon treatment, a widely-used practice for the stimulation of latex yield. CONCLUSIONS: This study provides an important genetic resource of HbAQP genes, which will be useful to improve the water use efficiency and latex yield of Hevea. PMID- 26606924 TI - [Preoperative imaging/operation planning for liver surgery]. AB - The currently established standard for planning liver surgery is multistage contrast media-enhanced multidetector computed tomography (CM-CT), which as a rule enables an appropriate resection planning, e.g. a precise identification and localization of primary and secondary liver tumors as well as the anatomical relation to extrahepatic and/or intrahepatic vascular and biliary structures. Furthermore, CM-CT enables the measurement of tumor volume, total liver volume and residual liver volume after resection. Under the condition of normal liver function a residual liver volume of 25 % is nowadays considered sufficient and safe. Recent studies in patients with liver metastases of colorectal cancer showed a clear staging advantage of contrast media-enhanced magnetic resonance imaging (CM-MRI) versus CM-CT. In addition, most recent data showed that the use of liver-specific MRI contrast media further increases the sensitivity and specificity of detection of liver metastases. This imaging technology seems to lead closer to the ideal "one stop shopping" diagnostic tool in preoperative planning of liver resection. PMID- 26606925 TI - Allele mining and enhanced genetic recombination for rice breeding. AB - Traditional rice varieties harbour a large store of genetic diversity with potential to accelerate rice improvement. For a long time, this diversity maintained in the International Rice Genebank has not been fully used because of a lack of genome information. The publication of the first reference genome of Nipponbare by the International Rice Genome Sequencing Project (IRGSP) marked the beginning of a systematic exploration and use of rice diversity for genetic research and breeding. Since then, the Nipponbare genome has served as the reference for the assembly of many additional genomes. The recently completed 3000 Rice Genomes Project together with the public database (SNP-Seek) provides a new genomic and data resource that enables the identification of useful accessions for breeding. Using disease resistance traits as case studies, we demonstrated the power of allele mining in the 3,000 genomes for extracting accessions from the GeneBank for targeted phenotyping. Although potentially useful landraces can now be identified, their use in breeding is often hindered by unfavourable linkages. Efficient breeding designs are much needed to transfer the useful diversity to breeding. Multi-parent Advanced Generation InterCross (MAGIC) is a breeding design to produce highly recombined populations. The MAGIC approach can be used to generate pre-breeding populations with increased genotypic diversity and reduced linkage drag. Allele mining combined with a multi parent breeding design can help convert useful diversity into breeding-ready genetic resources. PMID- 26606926 TI - Evaluation of transabdominal ultrasound after oral administration of an echoic cellulose-based gastric ultrasound contrast agent for gastric cancer. AB - BACKGROUND: With the remarkable improvements in ultrasound equipment, transabdominal ultrasound after oral administration of an echoic cellulose-based gastric ultrasound contrast agent (TUS-OCCA) has recently been suggested to be effective in initial screening of gastric cancer. The aim of this study was to evaluate the diagnostic value of TUS-OCCA for gastric cancer. METHODS: Consecutive patients with gastric cancers who underwent resection in our hospital were enrolled. Before the lesion was resected, TUS-OCCA examination was performed by a skilled examiner who was blinded to the site, size, and endoscopy diagnosis of the lesion. TUS-OCCA findings were compared with those of endoscopy and pathological diagnoses as the gold standard. RESULTS: There were a total of 288 consecutive patients enrolled in the study, including 228 with advanced gastric cancers (T2-T4 stage), 50 with early gastric cancer (26 with stage T1b and 24 with stage T1a), and 10 with high-grade intraepithelial neoplasia. TUS-OCCA had a detection rate of 100% (228/228) for advanced gastric cancers, 77% (20/26) for stage T1b, 67% (16/24) for stage T1a, and 60% (6/10) for high-grade intraepithelial neoplasia. The majority of patients with undetectable neoplasms using TUS-OCCA were obese (body mass index, 28.7-31.8 kg/m(2)). The overall accuracy of TUS-OCCA in determining the T stage of gastric cancer was 77.3% (62.5% for T1a, 70% for T1b, 71.1% for T2, 85.2% for T3, and 73.3% for T4). CONCLUSIONS: These findings indicate that TUS-OCCA achieved a high detection rate for gastric cancers and was useful in assessing the degree of gastric cancer invasion. PMID- 26606927 TI - Phenotype plasticity rather than repopulation from CD90/CK14+ cancer stem cells leads to cisplatin resistance of urothelial carcinoma cell lines. AB - BACKGROUND: Tumour heterogeneity and resistance to systemic treatment in urothelial carcinoma (UC) may arise from cancer stem cells (CSC). A recent model describes cellular differentiation states within UC based on corresponding expression of surface markers (CD) and cytokeratins (CK) with CD90 and CK14 positive cells representing the least differentiated and most tumourigenic population. Based on the fact that this population is postulated to constitute CSCs and the origin of cisplatin resistance, we enriched urothelial carcinoma cell lines (UCCs) for CD90 and studied the tumour-initiating potential of these separated cells in vitro. METHODS: Magnetic- and fluorescence-activated- cell sorting were used for separation of CD90(+) and CD90(-) UCCs. Distribution of cell surface markers CD90, CD44, and CD49f and cytokeratins CK14, CK5, and CK20 as well as the effects of short- and long-term treatment with cisplatin were assessed in vitro and measured by qRT-PCR, immunocytochemistry, reporter assay and flow cytometry in 11 UCCs. RESULTS: We observed cell populations with surface markers according to those reported in tumour xenografts. However, expression of cytokeratins did not concord regularly with that of the surface markers. In particular, expression of CD90 and CK14 diverged during enrichment of CD90(+) cells by immunomagnetic sorting or following cisplatin treatment. Enriched CD90(+) cells did not exhibit CSC-like characteristics like enhanced clonogenicity and cisplatin resistance. Moreover, selection of cisplatin resistant sublines by long-term drug treatment did not result in enrichment of CD90(+) cells. Rather, these sublines displayed significant phenotypic plasticity expressing EMT markers, an altered pattern of CKs, and WNT-pathway target genes. CONCLUSIONS: Our findings indicate that the correspondence between CD surface markers and cytokeratins reported in xenografts is not maintained in commonly used UCCs and that CD90 may not be a stable marker of CSC in UC. Moreover, UCCs cells are capable of substantial phenotypic plasticity that may significantly contribute to the emergence of cisplatin resistance. PMID- 26606928 TI - Developing a biostatistical support system in a resource-restricted academic institution in Africa: making it happen. AB - BACKGROUND: In order to address and support biostatistics for health research, the Health Sciences Research Office of the University of the Witwatersrand sought to introduce training in biomedical statistics to sustain research and postgraduate education. The experiences encountered in setting up such statistical support in a limited resource, developing country are discussed here. METHODS: Two cross-sectional surveys (a) statistical needs assessment (2009) and (b) feedback (2010-11) on the statistical support through biostatistics courses and consultations were conducted. These surveys were supplemented with information such as graduations, research publication output and costs of setting up the support. RESULTS: Seventy-three percent of respondents favoured short courses with "hands-on" practice. Eighty-nine percent agreed that these courses should be run and coordinated by the Health Sciences Research Office instead of the departments. There was use of varied statistical packages requiring one package for standardised support. The numbers of postgraduate students attending short courses in statistics increased from 2010 to 2012 as did the numbers attending statistical consultations. Graduations and publication outputs increased over this period of time although this may not be directly linked solely to the biostatistical support system introduced. CONCLUSIONS: There is a distinct need for biostatistics training in developing countries and the process described in this study could be replicated in any health sciences institution, especially in a resource-restricted environment. PMID- 26606929 TI - Expression of genes involved in the salicylic acid pathway in type h1 thioredoxin transiently silenced pepper plants during a begomovirus compatible interaction. AB - The type-h thioredoxins (TRXs) play a fundamental role in oxidative stress tolerance and defense responses against pathogens. In pepper plants, type-h TRXs participate in the defense mechanism against Cucumber mosaic virus. The goal of this study was to analyze the role of the CaTRXh1-cicy gene in pepper plants during compatible interaction with a DNA virus, the Euphorbia mosaic virus Yucatan Peninsula (EuMV-YP). The effects of a transient silencing of the CaTRXh1 cicy gene in pepper plants were evaluated by observing the accumulation of viral DNA and the visible symptoms of pepper plants under different treatments. The accumulation of salicylic acid (SA) and the relative expression of the defense genes NPR1 and PR10 were also evaluated. Results showed that viral DNA accumulation was higher in transiently CaTRXh1-cicy silenced plants that were also infected with EuMV-YP. Symptoms in these plants were more severe compared to the non-silenced plants infected with EuMV-YP. The SA levels in the EuMV-YP infected plants were rapidly induced at 1 h post infection (hpi) in comparison to the non-silenced plants inoculated with EuMV-YP. Additionally, in pepper plants infected with EuMV-YP, the expression of NPR1 decreased by up to 41 and 58 % at 28 days post infection (dpi) compared to the non-silenced pepper plants infected with only EuMV-YP and healthy non-inoculated pepper plants, respectively. PR10 gene expression decreased by up to 70 % at 28 dpi. Overall, the results indicate that the CaTRXh1-cicy gene participates in defense mechanisms during the compatible interaction of pepper plants with the EuMV-YP DNA virus. PMID- 26606930 TI - Whole-transcriptome analysis of mouse adipose tissue in response to short-term caloric restriction. AB - Caloric restriction (CR) has been shown to extend the lifespan of many species by improving cellular function and organismal health. Additionally, fat reduction by CR may play an important role in lengthening lifespan and preventing severe age related diseases. Interestingly, CR induced the greatest transcriptome change in the epididymal fat of mice in our study. In this transcriptome analysis, we identified and categorized 446 genes that correlated with CR level. We observed down-regulation of several signaling pathways, including insulin/insulin-like growth factor 1 (insulin/IGF-1), epidermal growth factor (EGF), transforming growth factor beta (TGF-beta), and canonical wingless-type mouse mammary tumor virus integration site (Wnt). Many genes related to structural features, including extracellular matrix structure, cell adhesion, and the cytoskeleton, were down-regulated, with a strong correlation to the degree of CR. Furthermore, genes related to the cell cycle and adipogenesis were down-regulated. These biological processes are well-identified targets of insulin/IGF-1, EGF, TGF-beta, and Wnt signaling. In contrast, genes involved in specific metabolic processes, including the tricarboxylic acid cycle and the electron transport chain were up regulated. We performed in silico analysis of the promoter sequences of CR responsive genes and identified two associated transcription factors, Paired-like homeodomain 2 (Pitx2) and Paired box gene 6 (Pax6). Our results suggest that strict regulation of signaling pathways is critical for creating the optimal energy homeostasis to extend lifespan. PMID- 26606932 TI - Plant species affect colonization patterns and metabolic activity of associated endophytes during phytoremediation of crude oil-contaminated soil. AB - Plants coupled with endophytic bacteria hold great potential for the remediation of polluted environment. The colonization patterns and activity of inoculated endophytes in rhizosphere and endosphere of host plant are among the primary factors that may influence the phytoremediation process. However, these colonization patterns and metabolic activity of the inoculated endophytes are in turn controlled by none other than the host plant itself. The present study aims to determine such an interaction specifically for plant-endophyte systems remediating crude oil-contaminated soil. A consortium (AP) of two oil-degrading endophytic bacteria (Acinetobacter sp. strain BRSI56 and Pseudomonas aeruginosa strain BRRI54) was inoculated to two grasses, Brachiaria mutica and Leptochloa fusca, vegetated in crude oil-contaminated soil. Colonization patterns and metabolic activity of the endophytes were monitored in the rhizosphere and endosphere of the plants. Bacterial augmentation enhanced plant growth and crude oil degradation. Maximum crude oil degradation (78%) was achieved with B. mutica plants inoculated with AP consortium. This degradation was significantly higher than those treatments, where plants and bacteria were used individually or L. fusca and endophytes were used in combination. Moreover, colonization and metabolic activity of the endophytes were higher in the rhizosphere and endosphere of B. mutica than L. fusca. The plant species affected not only colonization pattern and biofilm formation of the inoculated bacteria in the rhizosphere and endosphere of the host plant but also affected the expression of alkane hydroxylase gene, alkB. Hence, the investigation revealed that plant species can affect colonization patterns and metabolic activity of inoculated endophytic bacteria and ultimately the phytoremediation process. PMID- 26606931 TI - Is signet-ring cell carcinoma a specific entity among gastric cancers? AB - BACKGROUND: The prognosis and chemoresistance of signet-ring cell (SRC) gastric adenocarcinoma have been reported and debated, and the utility of perioperative chemotherapy for such a tumor has been questioned . This study was performed to assess the impact of the SRC type on survival following resection of gastric adenocarcinoma, and to assess whether the prognostic factors (including perioperative chemotherapy) for non-SRC adenocarcinoma differed from those for SRC adenocarcinoma. METHODS: 1799 cases of adenocarcinoma that were consecutively treated from 1997 to 2010 in 19 French centers by subtotal or total gastrectomy were included in a retrospective study. A D2 lymphadenectomy was performed for antropyloric tumors, and a modified D2 for upper tumors. SRC adenocarcinoma was diagnosed based on the presence of isolated carcinoma cells containing mucin. RESULTS: A total gastrectomy was performed in 979 (54.4 %) patients. SRC adenocarcinoma was diagnosed in 899 (50 %) patients. Patients with an SRC tumor were more frequently female, younger, and malnourished, had lower ASA scores, and had larger tumors than non-SRC patients. Median survival in patients with non-SRC carcinoma was 51 months, as compared to 26 months in patients with SRC carcinoma (p < 0.001). At multivariate analysis, SRC type remained an independent adverse prognostic factor (HR = 1.182). Factors that were prognostic in the SRC subgroup but not in the non-SRC subgroup were age >60 years, linitis, and involvement of adjacent organs. In contrast to non-SRC tumors, pre- and postoperative chemotherapy did not significantly impact on survival following resection of SRC adenocarcinoma. CONCLUSION: In comparison to non-SRC adenocarcinoma, the SRC type has a worse prognosis, different prognostic factors, and is only poorly sensitive to perioperative chemotherapy. Non-SRC and SRC adenocarcinomas should be considered different entities in future therapeutic trials. PMID- 26606933 TI - An extra-virgin olive oil rich in polyphenolic compounds has antioxidant effects in meat-type broiler chickens. AB - The aim of this study was to extend the knowledge on the antioxidant effect of extra-virgin olive oil (EVOO) in the liver of broiler chickens not subjected to any form of insult. A total of 120 male broiler chickens (Hubbard strain) were divided into three groups and fed ad libitum with three isoenergetic diets from hatching until slaughter age (49 days) on a completely randomized design. The dietary treatments consisted of 2.5% added oil or fat from three sources as follows: diet containing sunflower oil (SFO); diet containing lard (LRD), and diet containing extra-virgin olive oil (EVOO). The activity of the main antioxidative enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GS-Px) and glutathione S-transferase (GST), and lipid peroxidation as thiobarbituric acid-reactive substances (TBARS) content, was measured in the liver of chickens. The susceptibility to undergo lipid peroxidation was assessed by exposing liver homogenate to 30 degrees C or to an ascorbate/iron mixture as pro-oxidant system. Dietary oil or fat type improved significantly (P < 0.05) the body weight and gain as well as feed efficiency in birds fed EVOO compared to those fed with the other treatments. Supplementing EVOO in the diet significantly (P < 0.05) reduced lipid peroxidation by increasing antioxidant defense system. These findings, besides adding more results on the antioxidant effect of extra virgin olive oil on liver of other experimental model other than rats and humans, could be significant for animal welfare, with consequent benefits for both producers and consumers. PMID- 26606934 TI - Interaction of arsenic species with tropical river aquatic humic substances enriched with aluminum and iron. AB - The mobility and bioavailability of arsenic (As) are strongly controlled by adsorption/precipitation processes involving metal oxides. However, the organic matter present in the environment, in combination with these oxides, can also play an important role in the cycle of arsenic. This work concerns the interaction between As and two samples of aquatic humic substances (AHS) from tropical rivers. The AHS were extracted as proposed by IHSS, and were characterized by (13)C NMR. The experiments were conducted with the AHS in natura and enriched with metal cations, with different concentrations of As, and complexation capacity was evaluated at three different pH levels (5.0, 7.0, and 9.0). The AHS samples showed similar chemical compositions. The results suggested that there was no interaction between As(III) and AHS in natura or enriched with Al. Low concentrations of As(V) were bound to AHS in natura. For As(III), the complexation capacity of the AHS enriched with Fe was approximately 48 MUmol per g of C, while the values for As(V) were in the range 69-80 MUmol per grams of C. Fluorescence spectra showed that changes in Eh affected the complexation reactions of As(V) species with AHS. PMID- 26606935 TI - The potential of residues of furfural and biogas as calcareous soil amendments for corn seed production. AB - Intensive corn seed production in Northwest of China produced large amounts of furfural residues, which represents higher treatment cost and environmental issue. The broad calcareous soils in the Northwest of China exhibit low organic matter content and high pH, which led to lower fertility and lower productivity. Recycling furfural residues as soil organic and nutrient amendment might be a promising agricultural practice to calcareous soils. A 3-year field study was conducted to evaluate the effects of furfural as a soil amendment on corn seed production on calcareous soil with compared to biogas residues. Soil physical chemical properties, soil enzyme activities, and soil heavy metal concentrations were assessed in the last year after the last application. Corn yield was determined in each year. Furfural residue amendments significantly decreased soil pH and soil bulk density. Furfural residues combined with commercial fertilizers resulted in the greater cumulative on soil organic matter, total phosphorus, available phosphorus, available potassium, and cation exchange capacity than that of biogas residue. Simultaneously, urease, invertase, catalase, and alkaline phosphatase increased even at the higher furfural application rates. Maize seed yield increased even with lower furfural residue application rates. Furfural residues resulted in lower Zn concentration and higher Cd concentration than that of biogas residues. Amendment of furfural residues led to higher soil electrical conductivity (EC) than that of biogas residues. The addition of furfural residues to maize seed production may be considered to be a good strategy for recycling the waste, converting it into a potential resource as organic amendment in arid and semi-arid calcareous soils, and may help to reduce the use of mineral chemical fertilizers in these soils. However, the impact of its application on soil health needs to be established in long-term basis. PMID- 26606936 TI - Occurrence, compositional distribution, and toxicity assessment of pyrethroid insecticides in sediments from the fluvial systems of Chaohu Lake, Eastern China. AB - Surface sediment-associated synthetic pyrethroid insecticides (SPs) are known to pose high risks to the benthic organisms in Chaohu Lake, a shallow lake of Eastern China. However, the pollution status of the lake's tributaries and estuaries is still unknown. The present study was conducted to investigate the occurrence, compositional distribution, and toxicity of 12 currently used SPs in the surface sediments from four important tributaries, as well as in the sediment cores at their estuaries, using GC-MS for quantification. All SPs selected were detectable, with cypermethrin, es/fenvalerate, and permethrin dominant in both surface and core sediments, suggesting that these compounds were extensively applied. Urban samples contained the highest summed concentrations of the 12 SPs analyzed (Sigma12SP) in both surface and core sediments compared with rural samples, suggesting that urban areas near aquatic environments posed high risks for SPs. The mean concentration of Sigma12SP in surface sediments of each river was generally higher than that found in core sediments from its corresponding estuary, perhaps implying recent increases in SP usage. Surface sediments were significantly dominated by cypermethrin and permethrin, whereas core sediments were dominated by permethrin and es/fenvalerate. The compositional distributions demonstrated a spatial variation for surface sediments because urban sediments generally contained greater percentages of permethrin and cypermethrin, but rural sediments had significant levels of es/fenvalerate and cypermethrin. In all sediment cores, the percentage of permethrin gradually increased, whereas es/fenvalerate tended to decrease, from the bottom sediments to the top, indicating that the former represented fresh input, whereas the latter represented historical residue. Most urban samples would be expected to be highly toxic to benthic organisms due to the residue of SPs based on a calculation of toxic units (TUs) using toxicity data of the amphipod Hyalella azteca. However, low TU values were found for the samples from rural areas. These results indicate that the bottom sediments were exposed to high risk largely by the residual SPs from urban areas. The summed TUs were mostly attributable to cypermethrin, followed by lambda-cyhalothrin and es/fenvalerate. Despite permethrin contributing ~28.7 % of the Sigma12SP concentration, it only represented 6.34 % of the summed TUs. Therefore, our results suggest that high levels of urbanization can increase the accumulation of SPs in aquatic environments. PMID- 26606938 TI - A data-driven approach for quality assessment of radiologic interpretations. AB - Given the increasing emphasis on delivering high-quality, cost-efficient healthcare, improved methodologies are needed to measure the accuracy and utility of ordered diagnostic examinations in achieving the appropriate diagnosis. Here, we present a data-driven approach for performing automated quality assessment of radiologic interpretations using other clinical information (e.g., pathology) as a reference standard for individual radiologists, subspecialty sections, imaging modalities, and entire departments. Downstream diagnostic conclusions from the electronic medical record are utilized as "truth" to which upstream diagnoses generated by radiology are compared. The described system automatically extracts and compares patient medical data to characterize concordance between clinical sources. Initial results are presented in the context of breast imaging, matching 18 101 radiologic interpretations with 301 pathology diagnoses and achieving a precision and recall of 84% and 92%, respectively. The presented data-driven method highlights the challenges of integrating multiple data sources and the application of information extraction tools to facilitate healthcare quality improvement. PMID- 26606937 TI - Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors. AB - Adenosine can induce hypothermia, as previously demonstrated for adenosine A1 receptor (A1AR) agonists. Here we use the potent, specific A3AR agonists MRS5698, MRS5841, and MRS5980 to show that adenosine also induces hypothermia via the A3AR. The hypothermic effect of A3AR agonists is independent of A1AR activation, as the effect was fully intact in mice lacking A1AR but abolished in mice lacking A3AR. A3AR agonist-induced hypothermia was attenuated by mast cell granule depletion, demonstrating that the A3AR hypothermia is mediated, at least in part, via mast cells. Central agonist dosing had no clear hypothermic effect, whereas peripheral dosing of a non-brain-penetrant agonist caused hypothermia, suggesting that peripheral A3AR-expressing cells drive the hypothermia. Mast cells release histamine, and blocking central histamine H1 (but not H2 or H4) receptors prevented the hypothermia. The hypothermia was preceded by hypometabolism and mice with hypothermia preferred a cooler environmental temperature, demonstrating that the hypothermic state is a coordinated physiologic response with a reduced body temperature set point. Importantly, hypothermia is not required for the analgesic effects of A3AR agonists, which occur with lower agonist doses. These results support a mechanistic model for hypothermia in which A3AR agonists act on peripheral mast cells, causing histamine release, which stimulates central histamine H1 receptors to induce hypothermia. This mechanism suggests that A3AR agonists will probably not be useful for clinical induction of hypothermia. PMID- 26606939 TI - Acute coronary syndromes: what about older patients with frailty and multiple comorbidities? PMID- 26606942 TI - ECTRIMS 2015 Committees. PMID- 26606945 TI - Refugee crisis demands European Union-wide surveillance! PMID- 26606940 TI - Long-range coupling between the extracellular gates and the intracellular ATP binding domains of multidrug resistance protein pumps and cystic fibrosis transmembrane conductance regulator channels. AB - The ABCC transporter subfamily includes pumps, the long and short multidrug resistance proteins (MRPs), and an ATP-gated anion channel, the cystic fibrosis transmembrane conductance regulator (CFTR). We show that despite their thermodynamic differences, these ABCC transporter subtypes use broadly similar mechanisms to couple their extracellular gates to the ATP occupancies of their cytosolic nucleotide binding domains. A conserved extracellular phenylalanine at this gate was a prime location for producing gain of function (GOF) mutants of a long MRP in yeast (Ycf1p cadmium transporter), a short yeast MRP (Yor1p oligomycin exporter), and human CFTR channels. Extracellular gate mutations rescued ATP binding mutants of the yeast MRPs and CFTR by increasing ATP sensitivity. Control ATPase-defective MRP mutants could not be rescued by this mechanism. A CFTR double mutant with an extracellular gate mutation plus a cytosolic GOF mutation was highly active (single-channel open probability >0.3) in the absence of ATP and protein kinase A, each normally required for CFTR activity. We conclude that all 3 ABCC transporter subtypes use similar mechanisms to couple their extracellular gates to ATP occupancy, and highly active CFTR channels that bypass defects in ATP binding or phosphorylation can be produced. PMID- 26606947 TI - Mathematical and numerical comparisons of five single-population growth models. AB - We investigate the properties of five mathematical models used to represent the growth of a single population. By imposing a common set of (normalizing) initial conditions, we are able to calculate and explicitly compare the time intervals required to reach specific values of population levels. Based on these results, we conclude that one must be careful when applying these models to interpret the dynamics of single-population growth. An additional implication is that they provide evidence that such caution should also be extended to the incorporation of these models into the formulation of interacting, multi-population models, which are used, for example, to study the spread of disease. PMID- 26606946 TI - Indicators of the need for insulin treatment and the effect of treatment for gestational diabetes on pregnancy outcomes in Japan. AB - This study assessed indicators of the need for insulin therapy and the effect of treatment on pregnancy outcomes in Japanese patients with gestational diabetes mellitus (GDM). All patients diagnosed with GDM were hospitalized for three days. Plasma glucose profiles in patients under strict dietary management and the characteristics of GDM patients with high daily glucose levels were investigated. Patients who failed to achieve glycemic targets were treated with insulin. Indicators of the need for insulin treatment were investigated. Pregnancy outcomes in patients prescribed dietary management and patients prescribed insulin treatment were compared. The study included 112 patients with GDM. GDM patients with high daily glucose levels in the hospital exhibited significantly higher 1-h and 2-h plasma glucose levels in oral glucose tolerance tests (OGTTs) at diagnosis. In our hospital, 102 GDM patients with singleton pregnancies were followed until delivery; 32 (31.3%) were treated with insulin. Univariate analysis identified significant associations of insulin requirement with family history of diabetes and with 1-h and 2-h OGTT values at diagnosis. Multivariate analysis showed that the 1-h OGTT plasma glucose level at diagnosis was an independent predictor of the need for insulin. In perinatal outcomes, insulin treatment was associated with low birth weight. PMID- 26606948 TI - The footprint of TGF-beta in airway remodeling of the mustard lung. AB - Mustard lung is a major pulmonary complication in individuals exposed to sulfur mustard (SM) gas during the Iran-Iraq war. It shares common pathological and clinical features with some chronic inflammatory lung disorders, particularly chronic obstructive pulmonary disease (COPD). Airway remodeling, which is one of the main causes of lung dysfunction and the dominant phenomenon of chronic pulmonary diseases, is seen in the mustard lung. Among all mediators involved in the remodeling process, the transforming growth factor (TGF)-beta plays a pivotal role in lung fibrosis and consequently in the airway remodeling. Regarding the high levels of this mediator detected in mustard lung patients, in the present study, we have discussed the possible roles of TGF-beta in airway remodeling (including epithelial layer damage, subepithelial fibrosis and angiogenesis). Finally, based on TGF-beta targeting, we have reviewed new airway remodeling therapeutic approaches. PMID- 26606949 TI - Nanosensors for early cancer detection and for therapeutic drug monitoring. AB - The use of nanotechnology for drug delivery in cancer therapy has raised high expectations. Additionally, the use of nanomaterials in sensors to extract and detect tumor specific biomarkers, circulating tumor cells, or extracellular vesicles shed by the tumor holds the promise to detect cancer much earlier and hence improve long-term survival of the patients. Moreover, the monitoring of the anticancer drug concentration, which has a narrow therapeutic window, will allow for a personalized dosing of the drug and will lead to improved therapeutic outcome and life quality of the patient. This review will provide an overview on the use of nanosensors for the early diagnosis of cancer and for the therapeutic drug monitoring, giving some examples. We envision nanosensors to make significant improvements in the cancer management as easy-to-use point-of-care devices for a broad population of users. PMID- 26606950 TI - Vibronic and Coherent Effects on Interfacial Electron Transfer Dynamics. AB - This Letter examines fundamental issues for electron transfer (ET) dynamics, such as adiabatic versus nonadiabatic effects during interfacial ET, the influence of vibrational degrees of freedom on the electronic dynamics, the occurrence of electronic coherences and the ensuing dephasing effects. The interplay of these mechanisms during the ultrafast ET is discussed. A theoretical method for the quantum dynamics of electrons in flexible molecular systems is used to study such issues on the interfacial ET from the perylene chromophore to the TiO2 semiconductor surface. By analyzing the Fourier transform of the survival probability curves, it is possible to discern the oscillating features that are caused by electronic coherences and vibronic effects. The vibronic degrees of freedom are treated within the atomistic level of description and their effects identified on the charge transfer dynamics. The insights revealed are general and thus can be useful for the analysis of other ET phenomena. PMID- 26606951 TI - Hypertension: SPRINTing towards a new target for blood-pressure control. PMID- 26606953 TI - Anticoagulation therapy: Antidote to factor Xa inhibitors. PMID- 26606954 TI - Antiplatelet therapy: Clopidogrel plus aspirin reduces migrane attacks after ASD closure. PMID- 26606955 TI - Vascular disease: Combination therapy for PAD. PMID- 26606959 TI - Heart failure: Nitrates reduce activity levels in HFpEF. PMID- 26606960 TI - Cardiac resuscitation: Continuous chest compressions do not improve outcomes. PMID- 26606963 TI - Device therapy: Newly designed leadless pacemaker. PMID- 26606964 TI - The effect of ultralow-dose antibiotics exposure on soil nitrate and N2O flux. AB - Exposure to sub-inhibitory concentrations of antibiotics has been shown to alter the metabolic activity of micro-organisms, but the impact on soil denitrification and N2O production has rarely been reported. In this study, incubation and column transport experiments were conducted on soils exposed to as many as four antibiotics in the ng . kg(-1) range (several orders of magnitude below typical exposure rates) to evaluate the impact of ultralow dose exposure on net nitrate losses and soil N2O flux over time. Under anaerobic incubation conditions, three antibiotics produced statistically significant dose response curves in which denitrification was stimulated at some doses and inhibited at others. Sulfamethoxazole in particular had a stimulatory effect at ultralow doses, an effect also evidenced by a near 17% increase in nitrate removal during column transport. Narasin also showed evidence of stimulating denitrification in anaerobic soils within 3 days of exposure, which is concurrent to a statistically significant increase in N2O flux measured over moist soils exposed to similar doses. The observation that even ultralow levels of residual antibiotics may significantly alter the biogeochemical cycle of nitrogen in soil raises a number of concerns pertaining to agriculture, management of nitrogen pollution, and climate change, and warrants additional investigations. PMID- 26606965 TI - Is all cancer therapy immunotherapy? AB - Researchers must renew efforts to decipher how standard chemotherapies enhance the effects of targeted immunotherapeutic agents (Muller et al., this issue). PMID- 26606966 TI - Unmet needs: Research helps regulators do their jobs. AB - A plethora of innovative new medical products along with the need to apply modern technologies to medical-product evaluation has spurred seminal opportunities in regulatory sciences. Here, we provide eight examples of regulatory science research for diverse products. Opportunities abound, particularly in data science and precision health. PMID- 26606967 TI - Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade. AB - Targeted drug delivery with antibody-drug conjugates such as the HER2-directed ado-trastuzumab emtansine (T-DM1) has emerged as a powerful strategy for cancer therapy. We show that T-DM1 is particularly effective in eliciting antitumor immunity in patients with early breast cancer (WSG-ADAPT trial) and in a HER2 expressing orthotopic tumor model. In the latter, despite primary resistance to immunotherapy, combined treatment with T-DM1 and anti-CTLA-4/PD-1 (cytotoxic T lymphocyte-associated protein-4/programmed cell death protein-1) was curative because it triggered innate and adaptive immunity. Tumor rejection was accompanied by massive T cell infiltration, TH1 (T helper 1) cell polarization, and, notably, a substantial increase in regulatory T cells. Depletion of regulatory T cells resulted in inflammation and tissue damage, implying their essential role in protecting the host during therapy. This study provides insights into the mechanisms of T-DM1's therapeutic activity and a rationale for potential therapeutic combination strategies with immunotherapy. PMID- 26606968 TI - Type 1 diabetes immunotherapy using polyclonal regulatory T cells. AB - Type 1 diabetes (T1D) is an autoimmune disease that occurs in genetically susceptible individuals. Regulatory T cells (Tregs) have been shown to be defective in the autoimmune disease setting. Thus, efforts to repair or replace Tregs in T1D may reverse autoimmunity and protect the remaining insulin-producing beta cells. On the basis of this premise, a robust technique has been developed to isolate and expand Tregs from patients with T1D. The expanded Tregs retained their T cell receptor diversity and demonstrated enhanced functional activity. We report on a phase 1 trial to assess safety of Treg adoptive immunotherapy in T1D. Fourteen adult subjects with T1D, in four dosing cohorts, received ex vivo expanded autologous CD4(+)CD127(lo/-)CD25(+) polyclonal Tregs (0.05 * 10(8) to 26 * 10(8) cells). A subset of the adoptively transferred Tregs was long-lived, with up to 25% of the peak level remaining in the circulation at 1 year after transfer. Immune studies showed transient increases in Tregs in recipients and retained a broad Treg FOXP3(+)CD4(+)CD25(hi)CD127(lo) phenotype long-term. There were no infusion reactions or cell therapy-related high-grade adverse events. C peptide levels persisted out to 2+ years after transfer in several individuals. These results support the development of a phase 2 trial to test efficacy of the Treg therapy. PMID- 26606969 TI - Neutrophil-derived microvesicles enter cartilage and protect the joint in inflammatory arthritis. AB - Microvesicles (MVs) are emerging as a new mechanism of intercellular communication by transferring cellular lipid and protein components to target cells, yet their function in disease is only now being explored. We found that neutrophil-derived MVs were increased in concentration in synovial fluid from rheumatoid arthritis patients compared to paired plasma. Synovial MVs overexpressed the proresolving, anti-inflammatory protein annexin A1 (AnxA1). Mice deficient in TMEM16F, a lipid scramblase required for microvesiculation, exhibited exacerbated cartilage damage when subjected to inflammatory arthritis. To determine the function of MVs in inflammatory arthritis, toward the possibility of MV-based therapeutics, we examined the role of immune cell-derived MVs in rodent models and in human primary chondrocytes. In vitro, exogenous neutrophil-derived AnxA1(+) MVs activated anabolic gene expression in chondrocytes, leading to extracellular matrix accumulation and cartilage protection through the reduction in stress-adaptive homeostatic mediators interleukin-8 and prostaglandin E2. In vivo, intra-articular injection of AnxA1(+) MV lessened cartilage degradation caused by inflammatory arthritis. Arthritic mice receiving adoptive transfer of whole neutrophils displayed abundant MVs within cartilage matrix and revealed that MVs, but not neutrophils themselves, can penetrate cartilage. Mechanistic studies support a model whereby MV-associated AnxA1 interacts with its receptor FPR2 (formyl peptide receptor 2)/ALX, increasing transforming growth factor-beta production by chondrocytes, ultimately leading to cartilage protection. We envisage that MVs, either directly or loaded with therapeutics, can be harnessed as a unique therapeutic strategy for protection in diseases associated with cartilage degeneration. PMID- 26606970 TI - Transcriptome analysis of GVHD reveals aurora kinase A as a targetable pathway for disease prevention. AB - Graft-versus-host disease (GVHD) is the most common complication of hematopoietic stem cell transplant (HCT). However, our understanding of the molecular pathways that cause this disease remains incomplete, leading to inadequate treatment strategies. To address this, we measured the gene expression profile of nonhuman primate (NHP) T cells during acute GVHD. Utilizing microarray technology, we measured the expression profiles of CD3(+) T cells from five cohorts: allogeneic transplant recipients receiving (i) no immunoprophylaxis (No Rx), (ii) sirolimus monotherapy (Siro), (iii) tacrolimus-methotrexate (Tac-Mtx), as well as (iv) autologous transplant recipients (Auto) and (v) healthy controls (HC). This comparison allowed us to identify transcriptomic signatures specific for alloreactive T cells and determine the impact of both mTOR (mechanistic target of rapamycin) and calcineurin inhibition on GVHD. We found that the transcriptional profile of unprophylaxed GVHD was characterized by significant perturbation of pathways regulating T cell proliferation, effector function, and cytokine synthesis. Within these pathways, we discovered potentially druggable targets not previously implicated in GVHD, prominently including aurora kinase A (AURKA). Utilizing a murine GVHD model, we demonstrated that pharmacologic inhibition of AURKA could improve survival. Moreover, we found enrichment of AURKA transcripts both in allo-proliferating T cells and in sorted T cells from patients with clinical GVHD. These data provide a comprehensive elucidation of the T cell transcriptome in primate acute GVHD and suggest that AURKA should be considered a target for preventing GVHD, which, given the many available AURKA inhibitors in clinical development, could be quickly deployed for the prevention of GVHD. PMID- 26606971 TI - Validity of tools used for surveying physicians about their interactions with pharmaceutical company: a systematic review. AB - BACKGROUND: There is evidence that physicians' prescription behavior is negatively affected by the extent of their interactions with pharmaceutical companies. In order to develop and implement policies and interventions for better management of interactions, we need to understand physicians' perspectives on this issue. Surveys addressing physicians' interactions with pharmaceutical companies need to use validated tools to ensure the validity of their findings. OBJECTIVE: To assess the validity of tools used in surveys of physicians about the extent and nature of their interactions with pharmaceutical companies, and about their knowledge, beliefs and attitudes towards such interactions; and to identify those tools that have been formally validated. METHODS: We developed a search strategy with the assistance of a medical librarian. We electronically searched MEDLINE and EMBASE databases in September 2015. Teams of two reviewers conducted data selection and data abstraction. They identified eligible studies in one table and then abstracted the relevant data from the studies with validated tools in another table. Tables were piloted and standardized. RESULTS: We identified one validated questionnaire out of the 11 assessing the nature and extent of the interaction, and three validated questionnaires out of the 47 assessing knowledge, beliefs and attitudes of physicians toward the interaction. None of these validated questionnaires were used in more than one survey. CONCLUSION: The available supporting evidence of the issue of physicians' interaction with pharmaceutical company is of low quality. There is a need for research to develop and validate tools to survey physicians about their interactions with pharmaceutical companies. PMID- 26606972 TI - Development and application of loop-mediated isothermal amplification for detecting the highly benzimidazole-resistant isolates in Sclerotinia sclerotiorum. AB - Resistance of benzimidazole fungicides is related to the point mutation of the beta-tubulin gene in Sclerotinia sclerotiorum. The point mutation at codon 198 (GAG -> GCG, E198A) occurs in more than 90% of field resistant populations in China. Traditional detection methods of benzimidazole-resistant mutants of S. sclerotiorum are time-consuming, tedious and inefficient. To establish a suitable and rapid detection of benzimidazole-resistant mutants of S. sclerotiorum, an efficient and simple method with high specificity was developed based on loop mediated isothermal amplification (LAMP). Eight sets of LAMP primers were designed and four sets were optimized to specially distinguish benzimidazole resistant mutants of S. sclerotiorum. With the optimal LAMP primers, the concentration of LAMP components was optimized and the reaction conditions were set as 60-64 degrees C for 60 min. This method had a good specificity, sensitivity, stability and repeatability. In the 1491 sclerotia, 614 (41.18%) were positive by LAMP, and 629 (42.19%) positive by MIC. Therefore, the LAMP assay is more feasible to detect benzimidazole-resistant mutants of S. sclerotiorum than traditional detection methods. PMID- 26606973 TI - Decreased Diversity of the Oral Microbiota of Patients with Hepatitis B Virus Induced Chronic Liver Disease: A Pilot Project. AB - Increasing evidence suggests that altered gut microbiota is implicated in the pathogenesis of hepatitis B virus-induced chronic liver disease (HBV-CLD). However, the structure and composition of the oral microbiota of patients with HBV-CLD remains unclear. High-throughput pyrosequencing showed that decreased oral bacterial diversity was found in patients with HBV-CLD. The Firmicutes/Bacteroidetes ratio was increased significantly, which indicated that dysbiosis of the oral microbiota participated in the process of HBV-CLD development. However, the changing patterns of the oral microbiota in patients with HBV-induced liver cirrhosis (LC) were almost similar to patients with chronic hepatitis B (CHB). HBV infection resulted in an increase in potential H2S and CH3SH-producing phylotypes such as Fusobacterium, Filifactor, Eubacterium, Parvimonas and Treponema, which might contribute to the increased oral malodor. These key oral-derived phylotypes might invade into the gut as opportunistic pathogens and contribute to altering the composition of the gut microbiota. This study provided important clues that dysbiosis of the oral microbiota might be involved in the development of HBV-CLD. Greater understanding of the relationships between the dysbiosis of oral microbiota and the development of HBV CLD might facilitate the development of non-invasive differential diagnostic procedures and targeted treatments of HBV-CLD patients harbouring specific oral phylotypes. PMID- 26606974 TI - Clonal expansion under the microscope: studying lymphocyte activation and differentiation using live-cell imaging. AB - Clonal expansion of lymphocytes is a hallmark of vertebrate adaptive immunity. A small number of precursor cells that recognize a specific antigen proliferate into expanded clones, differentiate and acquire various effector and memory phenotypes, which promote effective immune responses. Recent studies establish a large degree of heterogeneity in the level of expansion and in cell state between and within expanding clones. Studying these processes in vivo, while providing insightful information on the level of heterogeneity, is challenging due to the complex microenvironment and the inability to continuously track individual cells over extended periods of time. Live cell imaging of ex vivo cultures within micro fabricated arrays provides an attractive methodology for studying clonal expansion. These experiments facilitate continuous acquisition of a large number of parameters on cell number, proliferation, death and differentiation state, with single-cell resolution on thousands of expanding clones that grow within controlled environments. Such data can reveal stochastic and instructive mechanisms that contribute to observed heterogeneity and elucidate the sequential order of differentiation events. Intercellular interactions can also be studied within these arrays by following responses of a controlled number of interacting cells, all trapped within the same microwell. Here we describe implementations of live-cell imaging within microwell arrays for studies of lymphocyte clonal expansion, portray insights already gained from these experiments and outline directions for future research. These tools, together with in vivo experiments tracking single-cell responses, will expand our understanding of adaptive immunity and the ways by which it can be manipulated. PMID- 26606975 TI - Defining an additivity framework for mixture research in inducible whole-cell biosensors. AB - A novel additivity framework for mixture effect modelling in the context of whole cell inducible biosensors has been mathematically developed and implemented in R. The proposed method is a multivariate extension of the effective dose (EDp) concept. Specifically, the extension accounts for differential maximal effects among analytes and response inhibition beyond the maximum permissive concentrations. This allows a multivariate extension of Loewe additivity, enabling direct application in a biphasic dose-response framework. The proposed additivity definition was validated, and its applicability illustrated by studying the response of the cyanobacterial biosensor Synechococcus elongatus PCC 7942 pBG2120 to binary mixtures of Zn, Cu, Cd, Ag, Co and Hg. The novel method allowed by the first time to model complete dose-response profiles of an inducible whole cell biosensor to mixtures. In addition, the approach also allowed identification and quantification of departures from additivity (interactions) among analytes. The biosensor was found to respond in a near additive way to heavy metal mixtures except when Hg, Co and Ag were present, in which case strong interactions occurred. The method is a useful contribution for the whole cell biosensors discipline and related areas allowing to perform appropriate assessment of mixture effects in non-monotonic dose-response frameworks. PMID- 26606976 TI - Defining near-surface groundwater flow regimes in the semi-arid glaciated plains of North America. AB - The dominant transport mechanisms controlling the migration of contaminants in geologic media are advection and molecular diffusion. To date, defining which transport mechanism dominates in saturated, non-lithified sediments has been difficult. Here, we illustrate the value of using detailed profiles of the conservative stable isotope values of water (delta(2)H and delta(18)O) to identify the dominant processes of contaminant transport (i.e. diffusion- or advection-dominated transport) in near-surface, non-lithified, saturated sediments of the Interior Plains of North America (IPNA). The approach presented uses detailed delta(18)O analyses of glacial till, glaciolacustrine clay, and fluvial sand core samples taken to depths of 11-50 m below ground at 22 sites across the IPNA to show whether transport in the fractured and oxidized sediments is dominated by advection or diffusion. Diffusion is by far the dominant transport mechanism in fine-textured lacustrine and glacial till sediments, but lateral advection dominates transport in sand-rich sediments and some oxidized, fine-textured lacustrine and glacial till sediments. The approach presented has a number of applications, including identifying dominant transport mechanisms in geomedia and potential protective barriers for underlying aquifers or surface waters, constraining groundwater transport models, and selecting optimum locations for monitoring wells. These findings should be applicable to most glaciated regions of the world that are composed of similar hydrogeologic units (i.e. low K clay till layers overlain by higher K coarse-textured aquifers or weathered clay till layers) and may also be applicable to non-glaciated regions exhibiting similar hydrogeologic characteristics. PMID- 26606978 TI - Information will be the key to successful implementation. AB - Making Fair Choices on the Path to Universal Health Coverage [UHC; World Health Organization (WHO), 2014] is to be welcomed because tackling the relationship between cost-effectiveness and fairness has been given too little attention in policy-making. The consensus that universal coverage is a good thing quickly disperses as the concept is translated into working national policies and local delivery processes. As Weale (2014) and Rumbold and Wilson (2014) point out, seeking practical solutions can lead to the re-exploration of previous givens and result in unexpected ethical and philosophical consequences. While the basic premise underlying the discussion on the ethics of resource concurs with the view that equity is always at odds with efficiency, this is not inevitable as the authors of the report point out in their analysis - a view more fully explored by Culyer (2006). The present report is a welcome attempt to reconcile, as countries progress to UHC, ethical norms with the reality of setting priorities, involving what to pay for and under what circumstances. PMID- 26606977 TI - Utility of transcervical management of Zenker's diverticulum. AB - OBJECTIVE: To evaluate our results in treating Zenker's diverticulum via the transcervical approach, and to compare our experiences with a recent systematic review of both open and endoscopic approaches to the pharyngeal pouch. METHOD: An audit yielded 41 consecutive cases of Zenker's diverticulum treated between 2003 and 2013. RESULTS: All 41 patients underwent transcervical cricopharyngeal myotomy; 29 sacs also required 'inversion'. The median and mean length of hospital stay was 1 night and 2.5 nights respectively. The recurrence rate was 2.4 per cent and the complication rate was 9.8 per cent. CONCLUSION: When compared to reported endoscopic techniques, transcervical cricopharyngeal myotomy (with or without inversion) in our unit resulted in: shorter hospital stay, a comparable complication rate and fewer recurrences. PMID- 26606979 TI - The path from nowhere? PMID- 26606980 TI - Environmental health and justice and the right to research: institutional review board denials of community-based chemical biomonitoring of breast milk. AB - Recently, conflicts and challenges have emerged regarding environmental justice and research ethics for some indigenous communities. Alaska Community Action on Toxics (ACAT) responded to community requests for breast milk biomonitoring and conceived the Breast Milk Pilot Study (BMPS). Despite having community support and federal and private funding, the BMPS remains incomplete due to repeated disapprovals by the Alaska Area IRB (Institutional Review Board). In this commentary, we explore the consequences of years of IRB denials, in terms of health inequalities, environmental justice, and research ethics. We highlight the greater significance of this story with respect to research in Alaska Native communities, biomonitoring, and global toxics regulation. We offer suggestions to community-based researchers conducting biomonitoring projects on how to engage with IRBs in order to cultivate reflective, context-based research ethics that better consider the needs and concerns of communities. PMID- 26606981 TI - Evidence that HIV-1 restriction factor SAMHD1 facilitates differentiation of myeloid THP-1 cells. AB - BACKGROUND: SAMHD1 counteracts HIV-1 or HIV-2/SIVsmm that lacks Vpx by depleting the intracellular pool of nucleotides in myeloid cells and CD4+ quiescent T cells, thereby inhibiting the synthesis of retroviral DNA by reverse transcriptase. Depletion of nucleotides has been shown to underline the establishment of quiescence in certain cellular systems. These observations led us to investigate whether SAMHD1 could control the transition between proliferation and quiescence using the THP-1 cell model. FINDINGS: The entry of dividing THP-1 myeloid cells into a non-dividing differentiated state was monitored after addition of phorbol-12-myristate-13-acetate (PMA), an inducer of differentiation. Under PMA treatment, cells overexpressing SAMHD1 display stronger and faster adhesion to their support, compared to cells expressing a catalytically inactive form of SAMHD1, or cells depleted of SAMHD1, which appear less differentiated. After PMA removal, cells overexpressing SAMHD1 maintain low levels of cyclin A, in contrast to other cell lines. Interestingly, SAMHD1 overexpression slightly increases cell adhesion even in the absence of the differentiation inducer PMA. Finally, we found that levels of SAMHD1 are reduced in proliferating primary CD4+ T cells after T cell receptor activation, suggesting that SAMHD1 may also be involved in the transition from a quiescent state to a dividing state in primary T cells. CONCLUSIONS: Altogether, we provide evidence that SAMHD1 may facilitate some aspects of THP-1 cell differentiation. Restriction of HIV-1 by SAMHD1 may rely upon its ability to modify cell cycle parameters, in addition to the direct inhibition of reverse transcription. PMID- 26606982 TI - Albumin treatment regimen for type 1 hepatorenal syndrome: a dose-response meta analysis. AB - BACKGROUND: Recommended treatment for type 1 hepatorenal syndrome consists of albumin and vasoconstrictor. The optimal albumin dose remains poorly characterized. This meta-analysis aimed to determine the impact of albumin dose on treatment outcomes. METHODS: Clinical studies of type 1 hepatorenal syndrome treatment with albumin and vasoconstrictor were sought. Search terms included: hepatorenal syndrome; albumin; vasoconstrictor; terlipressin; midodrine; octreotide; noradrenaline; and norepinephrine. A meta-analysis was performed of hepatorenal syndrome reversal and survival in relation to albumin dose. RESULTS: Nineteen clinical studies with 574 total patients were included, comprising 8 randomized controlled trials, 8 prospective studies and 3 retrospective studies. The pooled percentage of patients achieving hepatorenal syndrome reversal was 49.5% (95% confidence interval, 40.0-59.1%). Increments of 100 g in cumulative albumin dose were accompanied by significantly increased survival (hazard ratio, 1.15; 95% confidence interval, 1.02-1.31; p = 0.023). A non-significant increase of similar magnitude in hepatorenal syndrome reversal was also observed (odds ratio, 1.15; 95% confidence interval, 0.97-1.37; p = 0.10). Expected survival rates at 30 days among patients receiving cumulative albumin doses of 200, 400 and 600 g were 43.2% (95% confidence interval, 36.4-51.3%), 51.4% (95% confidence interval, 46.3-57.1%) and 59.0% (95% confidence interval, 51.9-67.2), respectively. Neither survival nor hepatorenal syndrome reversal was significantly affected by vasoconstrictor dose or type, treatment duration, age, baseline serum creatinine, bilirubin or albumin, baseline mean arterial pressure, or study design, size or time period. CONCLUSIONS: This meta-analysis suggests a dose-response relationship between infused albumin and survival in patients with type 1 hepatorenal syndrome. The meta-analysis provides the best current evidence on the potential role of albumin dose selection in improving outcomes of treatment for type 1 HRS and furnishes guidance for the design of future dose ranging studies. PMID- 26606983 TI - Regulatory network reconstruction reveals genes with prognostic value for chronic lymphocytic leukemia. AB - BACKGROUND: The clinical course of chronic lymphocytic leukemia (CLL) is highly variable; some patients follow an indolent course, but others progress to a more advanced stage. The mutational status of rearranged immunoglobulin heavy chain variable (IGVH) genes in CLL is a feature that is widely recognized for dividing patients into groups that are related to their prognoses. However, the regulatory programs associated with the IGVH statuses are poorly understood, and markers that can precisely predict survival outcomes have yet to be identified. METHODS: In this study, (i) we reconstructed gene regulatory networks in CLL by applying an information-theoretic approach to the expression profiles of 5 cohorts. (ii) We applied master regulator analysis (MRA) to these networks to identify transcription factors (TFs) that regulate an IGVH mutational status signature. The IGVH mutational status signature was developed by searching for differentially expressed genes between the IGVH mutational statuses in numerous CLL cohorts. (iii) To evaluate the biological implication of the inferred regulators, prognostic values were determined using time to treatment (TTT) and overall survival (OS) in two different cohorts. RESULTS: A robust IGVH expression signature was obtained, and various TFs emerged as regulators of the signature in most of the reconstructed networks. The TF targets expression profiles exhibited significant differences with respect to survival, which allowed the definition of a reduced profile with a high value for OS. TCF7 and its targets stood out for their roles in progression. CONCLUSION: TFs and their targets, which were obtained merely from inferred regulatory associations, have prognostic implications and reflect a regulatory context for prognosis. PMID- 26606984 TI - A disorder of surfactant metabolism without identified genetic mutations. AB - BACKGROUND: Surfactant metabolism disorders may result in diffuse lung disease in children. CASE PRESENTATION: We report a 3-years-old boy with dry cough, progressive hypoxemia, dyspnea and bilateral ground glass opacities at chest high resolution computed tomography (HRCT) who had no variants in genes encoding surfactant proteins or transcription factors. Lung histology strongly suggested an abnormality of surfactant protein. A 7-month course of pulse intravenous high dose methylprednisolone plus oral hydroxychloroquine and azithromycin led to gradual weaning from oxygen and oral steroids, and to improvement of cough and dyspnea. Over the follow-up period, hydroxychloroquine and azithromycin were not withdrawn as cough and dyspnea re-appeared at each attempt and disappeared at re start. At 6 years of age chest HRCT still appeared unchanged, but clinical symptoms or signs were absent. CONCLUSIONS: In children suspected of inborn errors of pulmonary surfactant metabolism who do not have a recognized genetic mutation, lung biopsy with consistent histology may help physicians to address the definitive diagnosis. PMID- 26606985 TI - Optical and material analysis of opacified hydrophilic intraocular lenses after explantation: a laboratory study. AB - BACKGROUND: The opacification of hydrophilic intraocular lenses (IOLs) is a very rare complication in terms of absolute numbers. We report on the analyses of opacified Euromaxx ALI313Y and ALI313 IOLs (Argonoptics, Germany) using light and scanning electron microscopy, X-ray spectroscopy and optical bench analysis. METHODS: Opacified Euromaxx ALI313Y and ALI313 IOLs were explanted after patients presented with a decrease in visual acuity. The explants were sent to our laboratory and examined using light and scanning electron microscopy. The composition of the deposits was analysed using X-ray spectroscopy. The optical quality of the intraocular lens (IOL) was assessed using the OptiSpheric IOL PRO optical bench (Trioptics GmbH Wedel, Germany). Modulation transfer function (MTF) was measured at all spatial frequencies and United States Air Force (USAF) 1951 resolution target pictures were documented. RESULTS: Macroscopically, the entire optic was opacified in all IOLs. Light and scanning electron microscopy revealed numerous fine, granular, crystalline-like deposits, which were always distributed in a line parallel to the anterior and posterior surfaces of the IOLs. X-ray spectroscopy could prove the deposits consisted of Calcium and Phosphate. Measurements in the optical bench showed deterioration of MTF values at all spatial frequencies and the USAF target pictures demonstrated a significant reduction of brightness as well as resolution with the opacified IOLs. CONCLUSIONS: The calcification of hydrophilic IOLs only occurs rarely. The exact chemical composition of the deposits can be assessed by means of X-ray spectroscopy. Optical quality analysis of the explanted Euromaxx ALI313Y and ALI313 IOLs showed significant reduction of MTF values, which was confirmed by USAF target pictures. PMID- 26606986 TI - Rough set theory based prognostic classification models for hospice referral. AB - BACKGROUND: This paper explores and evaluates the application of classical and dominance-based rough set theory (RST) for the development of data-driven prognostic classification models for hospice referral. In this work, rough set based models are compared with other data-driven methods with respect to two factors related to clinical credibility: accuracy and accessibility. Accessibility refers to the ability of the model to provide traceable, interpretable results and use data that is relevant and simple to collect. METHODS: We utilize retrospective data from 9,103 terminally ill patients to demonstrate the design and implementation RST- based models to identify potential hospice candidates. The classical rough set approach (CRSA) provides methods for knowledge acquisition, founded on the relational indiscernibility of objects in a decision table, to describe required conditions for membership in a concept class. On the other hand, the dominance-based rough set approach (DRSA) analyzes information based on the monotonic relationships between condition attributes values and their assignment to the decision class. CRSA decision rules for six month patient survival classification were induced using the MODLEM algorithm. Dominance-based decision rules were extracted using the VC-DomLEM rule induction algorithm. RESULTS: The RST-based classifiers are compared with other predictive and rule based decision modeling techniques, namely logistic regression, support vector machines, random forests and C4.5. The RST-based classifiers demonstrate average AUC of 69.74 % with MODLEM and 71.73 % with VC-DomLEM, while the compared methods achieve average AUC of 74.21 % for logistic regression, 73.52 % for support vector machines, 74.59 % for random forests, and 70.88 % for C4.5. CONCLUSIONS: This paper contributes to the growing body of research in RST-based prognostic models. RST and its extensions posses features that enhance the accessibility of clinical decision support models. While the non-rule-based methods-logistic regression, support vector machines and random forests-were found to achieve higher AUC, the performance differential may be outweighed by the benefits of the rule-based methods, particularly in the case of VC-DomLEM. Developing prognostic models for hospice referrals is a challenging problem resulting in substandard performance for all of the evaluated classification methods. PMID- 26606987 TI - Operative treatment of intraarticular calcaneal fractures: Anatomical and functional outcome of three different operative techniques. AB - INTRODUCTION: Management of the intraarticular calcaneal fracture is a challenge. The optimal method of treatment remains controversial. This study evaluates the anatomical and functional postoperative outcomes of displaced intraarticular calcaneal fractures that have been treated using three different techniques of ORIF. PATIENTS AND METHODS: Between 2004 and 2011 we treated 143 patients with calcaneal fractures, 40 of these patients (28%) were treated conservatively. This is a retrospective study of the remaining 103 patients (72%) who were operated on consecutively, mainly by one surgeon (NG). Calcaneal fractures were classified according to the Sanders classification. Three types of osteosynthesis were used: standard anatomical plate (SP), locking anatomical plate (LCP) and standard anatomical plate with autologous bone graft (SP+ABG). Clinical outcome was assessed one year after the operation: anatomical reduction was evaluated according to the analysis of Bohler's angle at final follow-up, and functional assessment was conducted using the Maryland Foot Score (MFS). RESULTS: The fractures were classified as follows: 35 (34%) Sanders type II, 47 (45.6%) Sanders type III and 21 (20.4%) Sanders type IV. The SP was used in 67 (65%) fractures, LCP in 16 (15.5%) and SP+ABH in 20 (19.4%). The correlation test showed a weak association between the Sanders fracture type and the operation technique (Pearson correlation coefficient r=0.26). The non-parametric tests showed that the fracture type did not significantly influence the postoperative Bohler's angle outcome (p=0.132), or the type of operation (p=0.664). Excellent or good reduction of the posterior calcaneal facet was achieved in all operated fractures. One year after the operation, the distribution of Bohler's angle was normal with a mean 31.9 degrees (SD 4.84) in all three groups. There was no significant difference in the functional postoperative outcome in terms of MFS in the three groups (p=0.601), but the Sanders fracture type had significant influence on the functional postoperative outcome in terms of MFS (p=0.001). CONCLUSION: In the representative sample of 103 operatively treated intraarticular calcaneal fractures, anatomical and functional postoperative efficacy outcomes appeared to be similar in all three treatment groups. High grade displaced intraarticular calcaneal fractures (Sanders IV) had worse functional results irrespective of the type of operation. The optimal method for management of intraarticular calcaneal fracture is operative, using the standard anatomic calcaneal plate. Autologous bone grafting is not required. Large sample comparative studies are still needed. PMID- 26606988 TI - Elastic nailing of tibia shaft fractures in young children up to 10 years of age. AB - INTRODUCTION: Although tibia shaft fractures in children usually have satisfactory results after closed reduction and casting, there are several surgical indications, including associated fractures and soft tissue injuries such as open fractures. Titanium elastic nails (TENs) are often used for pediatric tibia fractures, and have the advantage of preserving the open physis. However, complications such as delayed union or nonunion are not uncommon in older children or open fractures. In the present study, we evaluated children up to 10 years of age with closed or open tibial shaft fractures treated with elastic nailing technique. METHODS: A total of 16 tibia shaft fractures treated by elastic nailing from 2001 to 2013 were reviewed. The mean patient age at operation was 7 years (range: 5-10 years). Thirteen of 16 cases were open fractures (grade I: 4, grade II: 6, grade IIIA: 3 cases); the other cases had associated fractures that necessitated operative treatments. Closed, antegrade intramedullary nailing was used to insert two nails through the proximal tibial metaphysis. All patients were followed up for at least one year after the injury. Outcomes were evaluated using modified Flynn's criteria, including union, alignment, leg length discrepancies, and complications. RESULTS: All fractures achieved union a mean of 16.1 weeks after surgery (range: 11-26 weeks). No patient reported knee pain or experienced any loss of knee or ankle motion. There was a case of superficial infection in a patient with grade III open fracture. Three patients reported soft tissue discomfort due to prominent TEN tips at the proximal insertion site, which required cutting the tip before union or removing the nail after union. At the last follow-up, there were no angular or rotational deformities over 10 degrees in either the sagittal or coronal planes. With the exception of one case with an overgrowth of 15 mm, no patient showed shortening or overgrowth exceeding 10mm. Among final outcomes, 15 were excellent and 1 was satisfactory. SUMMARY: Even with open fractures or soft tissue injuries, elastic nailing can achieve satisfactory results in young children, with minimal complications of delayed bone healing, or infection. PMID- 26606989 TI - Driver's education may reduce annual incidence and severity of moped and scooter accidents. A population-based study. AB - BACKGROUND AND AIMS: In our previous study, the annual number of adolescents treated at Helsinki Children's Hospital and Toolo Trauma Centre for injuries from moped and scooter accidents increased five-fold between 2002 and 2007. In June 2011, the requirements for a moped/scooter license changed to include driver's education and a vehicle handling evaluation. The aim of this retrospective study was to assess the influence of legislative changes on moped and scooter related serious injuries in adolescents. PATIENTS AND METHODS: Data from 520 patients (age 15-16) treated for trauma from moped and scooter accidents at our institutions between January 2008 and December 2013 were included. Case numbers were compared with population data from national databases. Overall incidence, trauma mechanism, injury profile, and proportion of patients requiring hospital admission were calculated for time periods before and after the law amendment. RESULTS: After the law change in 2011, the annual incidence of moped/scooter injuries among 15-year-olds in our area decreased from 0.8% in 2011 to 0.3% in 2013 (p<0.001), and estimated incidence of injuries per new moped/scooter license declined from 1.8% in 2011 to 1.0% in 2013 (p=0.001). Simultaneously, proportions of patients injured in collisions, diagnosed with multiple trauma or requiring in patient care reduced. CONCLUSIONS: A change in moped/scooter license requirements may have a causal relationship with both reduced number and severity of moped/scooter related injuries in adolescents. PMID- 26606990 TI - Regional bone loss following femoral neck fracture: A comparison between cemented and cementless hemiarthroplasty. AB - The aim of this prospective, randomised study was to measure and evaluate regional bone mineral changes and clinical results following the use of cemented and cementless hemiarthroplasty (HA) for treatment of femoral neck fracture in elderly patients. The study comprised 60 patients, 30 with cemented HA (group A) and 30 with cementless HA (group B). All patients underwent osteodensitometry of the contralateral hip, lumbar spine and bilateral distal femur. Dual-energy x-ray absorptiometry (DEXA) was scheduled at 1 month, 6 months and 1 year after surgery. Harris Hip Score (HHS) was used for functional assessment. Overall mortality rate was 20.3% within 1 year after surgery. There were no significant differences in morbidity, mortality and hospital stay between the two groups of patients. The implantation of cemented prosthesis took statistically significantly longer than that of cementless prosthesis (79.03+/-3.59 vs 68.02+/ 5.97min; p=0.00). Functional score in patients treated with cemented HA was significantly higher compared with those with cementless HA. There was a trend of less intensive reduction of bone mineral density (BMD) in regions of interest of the lumbar spine and ipsilateral distal femur in patients with cemented HA (group A), whereas bone loss was less pronounced for the contralateral hip and distal femur in patients treated with cementless HA (group B). Management of displaced femoral neck fractures in elderly patients with cemented and cementless HA provides a comparable outcome with regard to morbidity and mortality; however, functional outcome of patients treated with cementless HA tends to be lower. There is less intensive BMD reduction in lumbar spine and ipsilateral distal femur in patients treated with cemented HA, whereas BMD reduction in patients treated with cementless HA is more likely to be less intensive in contralateral hip and distal femur. PMID- 26606991 TI - The influence of race and hospital environment on the care of patients with cervical spine fractures. AB - BACKGROUND: The influence of non-white race on outcomes following orthopedic injury has been described in the past. The impact of such factors on hospital processes and quality of care after spinal trauma is less well understood. STUDY DESIGN: A cohort control study using the Massachusetts Statewide Inpatient Dataset (2003-2010) was used as the study design. PURPOSE: This study aimed to determine whether (1) hospital processes and quality of care associated with the treatment of cervical spine fractures was significantly altered by non-white race and (2) whether findings were different among those treated at academic medical centers (AMCs). SAMPLE: The study comprised 10,841 patients. OUTCOMES: Surgical rate, postoperative morbidity, mortality, and length of stay (LOS) were the outcome measures. METHODS: Baseline differences between cohorts were evaluated using chi-square or Wilcoxon rank sum tests. Logistic and negative binomial regression techniques were used to adjust for confounders, including whether a surgical intervention was performed. Subset analyses were performed to evaluate whether findings were different for individuals treated at AMCs. RESULTS: The rate of surgical intervention was not significantly different between non-whites and whites (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.82-1.04). LOS (regression coefficient [RC] 0.18, 95% CI 0.13-0.23), mortality (OR 1.49, 95% CI 1.20-1.85), and complications (OR 1.17, 95% CI 1.02-1.33) were significantly increased among non-white patients. These findings were largely preserved among those treated at AMCs. CONCLUSIONS: Our results reinforce the fact that efforts at universal access to care may be insufficient to reduce differences in care among minority patients following cervical trauma. Future mixed-methods research is necessary to more effectively evaluate the etiologies behind health-care disparities associated with race in different health-care environments. LEVEL OF EVIDENCE: The level of evidence is Level III, prognostic study. PMID- 26606992 TI - A diet enriched with Mugil cephalus processed roes modulates the tissue lipid profile in healthy rats: a biochemical and chemometric assessment. AB - The effect of a diet enriched with mullet bottarga on the lipid profile (total lipids, total cholesterol, unsaturated fatty acids, alpha-tocopherol, and hydroperoxides) of plasma, liver, kidney, brain, and perirenal adipose tissues of healthy rats was investigated. Rats fed a 10% bottarga enriched-diet for 5 days showed body weights and tissue total lipid and cholesterol levels similar to those of animals fed control diet. Univariate and multivariate results showed that bottarga enriched-diet modified the fatty acid profile in all tissues, except brain. Significant increases of n-3 PUFA, particularly EPA, were observed together with a 20:4 n-6 decrease in plasma, liver, and kidney. Perirenal adipose tissue showed a fat accumulation that reflected the diet composition. The overall data suggest that mullet bottarga may be considered as a natural bioavailable source of n-3 PUFA and qualify it as a traditional food product with functional properties and a potential functional ingredient for preparation of n-3 PUFA enriched foods. PMID- 26606993 TI - Interactions of two cytotoxic organoruthenium(II) complexes with G-quadruplex. AB - Two previously isolated cytotoxic complexes [(eta(6)-p-cymene)Ru(kappa(2) CF3COCHCOC5H3O)L](n+) (L=Cl (1); n=0, pta (2) (pta=1,3,5-triaza-7 phosphaadamantane); n=1) were investigated for their selectivity and ability to interact with DNA G-quadruplex adopted by d[G3ATG3ACACAG4ACG3] (3) whose topology exhibits diagonal, edge-type and double-chain reversal loops. Structural changes were followed using high-resolution NMR techniques in the presence of 1 and 2. Results showed weak interaction between the organoruthenium complexes and G quadruplex. Moreover, no significant changes in thermal stability were confirmed by a UV-melting assay for both 1 and 2. These findings emphasize that anticancer activity of Ru(II) complexes may not be correlated with binding to nucleic acid like G-quadruplex. PMID- 26606994 TI - Observer design for a class of nonlinear piecewise systems. Application to an epidemic model with treatment. AB - Susceptible Exposed Infectious and Recovered epidemic model endowed with a treatment function (SEIR-T model) is a well-known model used to reproduce the behavior of an epidemic, where the susceptible population and the exposed population need to be estimated to predict and control the propagation of a contagious disease. This paper focuses on the nonlinear observer design for a class of nonlinear piecewise systems including SEIR-T models. For this purpose, two changes of coordinates are provided to transform the considered systems into an extended nonlinear observer normal form, on which a high gain observer can be applied. Then, the proposed method is applied to a SEIR-T model. Finally, simulation results are given to show its efficiency. PMID- 26606995 TI - Histiocytic and Nonhistiocytic Glomerular Lesions: Foam Cells and Their Mimickers. AB - Numerous histiocytes are sometimes noted in glomeruli, giving rise to a foamy appearing glomerulus. Foamy-appearing glomeruli may also be noted in conditions that do not contain numerous histiocytes. These disease entities are rare, have different underlying causes and pathophysiology, and can cause a diagnostic dilemma. We have observed this histiocytic/foamy glomerular change on the kidney biopsy specimen in 5 different disease entities: crystal-storing histiocytosis, histiocytic glomerulopathy associated with macrophage-activating syndrome, thrombotic microangiopathy, lecithin-cholesterol acyltransferase deficiency, and lipoprotein glomerulopathy. We describe and compare the kidney biopsy findings of these histiocytic and foamy-appearing entities. It is important to recognize the kidney biopsy findings of these rare conditions to correctly evaluate and identify the cause and manage these patients. PMID- 26606996 TI - Molecularly Defined Circuitry Reveals Input-Output Segregation in Deep Layers of the Medial Entorhinal Cortex. AB - Deep layers of the medial entorhinal cortex are considered to relay signals from the hippocampus to other brain structures, but pathways for routing of signals to and from the deep layers are not well established. Delineating these pathways is important for a circuit level understanding of spatial cognition and memory. We find that neurons in layers 5a and 5b have distinct molecular identities, defined by the transcription factors Etv1 and Ctip2, and divergent targets, with extensive intratelencephalic projections originating in layer 5a, but not 5b. This segregation of outputs is mirrored by the organization of glutamatergic input from stellate cells in layer 2 and from the hippocampus, with both preferentially targeting layer 5b over 5a. Our results suggest a molecular and anatomical organization of input-output computations in deep layers of the MEC, reveal precise translaminar microcircuitry, and identify molecularly defined pathways for spatial signals to influence computation in deep layers. PMID- 26606997 TI - A Comprehensive Optogenetic Pharmacology Toolkit for In Vivo Control of GABA(A) Receptors and Synaptic Inhibition. AB - Exogenously expressed opsins are valuable tools for optogenetic control of neurons in circuits. A deeper understanding of neural function can be gained by bringing control to endogenous neurotransmitter receptors that mediate synaptic transmission. Here we introduce a comprehensive optogenetic toolkit for controlling GABA(A) receptor-mediated inhibition in the brain. We developed a series of photoswitch ligands and the complementary genetically modified GABA(A) receptor subunits. By conjugating the two components, we generated light sensitive versions of the entire GABA(A) receptor family. We validated these light-sensitive receptors for applications across a broad range of spatial scales, from subcellular receptor mapping to in vivo photo-control of visual responses in the cerebral cortex. Finally, we generated a knockin mouse in which the "photoswitch-ready" version of a GABA(A) receptor subunit genomically replaces its wild-type counterpart, ensuring normal receptor expression. This optogenetic pharmacology toolkit allows scalable interrogation of endogenous GABA(A) receptor function with high spatial, temporal, and biochemical precision. PMID- 26606999 TI - Synaptic Integration of Adult-Born Hippocampal Neurons Is Locally Controlled by Astrocytes. AB - Adult neurogenesis is regulated by the neurogenic niche, through mechanisms that remain poorly defined. Here, we investigated whether niche-constituting astrocytes influence the maturation of adult-born hippocampal neurons using two independent transgenic approaches to block vesicular release from astrocytes. In these models, adult-born neurons but not mature neurons showed reduced glutamatergic synaptic input and dendritic spine density that was accompanied with lower functional integration and cell survival. By taking advantage of the mosaic expression of transgenes in astrocytes, we found that spine density was reduced exclusively in segments intersecting blocked astrocytes, revealing an extrinsic, local control of spine formation. Defects in NMDA receptor (NMDAR) mediated synaptic transmission and dendrite maturation were partially restored by exogenous D-serine, whose extracellular level was decreased in transgenic models. Together, these results reveal a critical role for adult astrocytes in local dendritic spine maturation, which is necessary for the NMDAR-dependent functional integration of newborn neurons. PMID- 26606998 TI - Genetic and Stress-Induced Loss of NG2 Glia Triggers Emergence of Depressive-like Behaviors through Reduced Secretion of FGF2. AB - NG2-expressing glia (NG2 glia) are a uniformly distributed and mitotically active pool of cells in the central nervous system (CNS). In addition to serving as progenitors of myelinating oligodendrocytes, NG2 glia might also fulfill physiological roles in CNS homeostasis, although the mechanistic nature of such roles remains unclear. Here, we report that ablation of NG2 glia in the prefrontal cortex (PFC) of the adult brain causes deficits in excitatory glutamatergic neurotransmission and astrocytic extracellular glutamate uptake and induces depressive-like behaviors in mice. We show in parallel that chronic social stress causes NG2 glia density to decrease in areas critical to Major Depressive Disorder (MDD) pathophysiology at the time of symptom emergence in stress-susceptible mice. Finally, we demonstrate that loss of NG2 glial secretion of fibroblast growth factor 2 (FGF2) suffices to induce the same behavioral deficits. Our findings outline a pathway and role for NG2 glia in CNS homeostasis and mood disorders. PMID- 26607000 TI - VAMP4 Is an Essential Cargo Molecule for Activity-Dependent Bulk Endocytosis. AB - The accurate formation of synaptic vesicles (SVs) and incorporation of their protein cargo during endocytosis is critical for the maintenance of neurotransmission. During intense neuronal activity, a transient and acute accumulation of SV cargo occurs at the plasma membrane. Activity-dependent bulk endocytosis (ADBE) is the dominant SV endocytosis mode under these conditions; however, it is currently unknown how ADBE mediates cargo retrieval. We examined the retrieval of different SV cargo molecules during intense stimulation using a series of genetically encoded pH-sensitive reporters in neuronal cultures. The retrieval of only one reporter, VAMP4-pHluorin, was perturbed by inhibiting ADBE. This selective recovery was confirmed by the enrichment of endogenous VAMP4 in purified bulk endosomes formed by ADBE. VAMP4 was also essential for ADBE, with a cytoplasmic di-leucine motif being critical for this role. Therefore, VAMP4 is the first identified ADBE cargo and is essential for this endocytosis mode to proceed. PMID- 26607001 TI - Lamination Speeds the Functional Development of Visual Circuits. AB - A common feature of the brain is the arrangement of synapses in layers. To examine the significance of this organizational feature, we studied the functional development of direction-selective (DS) circuits in the tectum of astray mutant zebrafish in which lamination of retinal ganglion cell (RGC) axons is lost. We show that although never laminar, the tuning of DS-RGC axons targeting the mutant tectum is normal. Analysis of mutant tectal neurons at late developmental stages reveals that directional tuning is indistinguishable from wild-type larvae. Furthermore, we show that structural plasticity of tectal dendrites and RGC axons compensates for the loss of lamination, establishing connectivity between DS-RGCs and their normal tectal targets. However, tectal direction selectivity is severely perturbed at earlier developmental stages. Thus, the formation of synaptic laminae is ultimately dispensable for the correct wiring of direction-selective tectal circuits, but it is crucial for the rapid assembly of these networks. PMID- 26607002 TI - Some Conceptual and Operational Considerations when Measuring 'Resilience': A Response to Hodgson et al. PMID- 26607003 TI - Ecologists Should Care about Insurance, too. PMID- 26607004 TI - Doxorubicin-transferrin conjugate triggers pro-oxidative disorders in solid tumor cells. AB - The formation of reactive oxygen species (ROS) is a widely accepted mechanism of doxorubicin (DOX) toxicity toward cancer cells. However, little is known about the potential of new systems, designed for more efficient and targeted doxorubicin delivery (i.e. protein conjugates, polymeric micelles, liposomes, monoclonal antibodies), to induce oxidative stress (OS) in tumors and hematological malignancies. Therefore, the objective of our study was to determine the relation between the toxicity of doxorubicin-transferring (DOX-TRF) conjugate and its capability to generate oxidative/nitrosative stress in solid tumor cells. Our research proves that DOX-TRF conjugate displays higher cytotoxicity towards lung adenocarcinoma epithelial (A549) and hepatocellular carcinoma (HepG2) cell lines than the reference free drug (DOX) and induces more extensive OS, characterized by a significant decrease in the total cellular antioxidant capacity, glutathione level and amount of -SH groups and an increase in hydroperoxide content. The intracellular redox imbalance was accompanied by changes in the transcription of genes encoding key antioxidant enzymes engaged in the sustaining of cellular redox homeostasis: superoxide dismutase (SOD), catalase (CAT), glutathione transferase (GST) and glutathione peroxidase (GP). PMID- 26607005 TI - Is it all in the hinge? A kryptoracemate and three of its alternative racemic polymorphs of an aminonitrile. AB - Four polymorphs of 2-(perfluorophenyl)-2-(phenylamino)acetonitrile have been crystallized and structurally analyzed: in addition to three racemic crystals, a rare kryptoracemate has been obtained. The central single bonds allow for conformational flexibility: the kryptoracemate as well as two of the remaining polymorphs contain several independent molecules with different conformation. In contrast to these uncommon packing modes, the fourth phase is unexceptional and crystallizes with a single molecule in the asymmetric unit. Individual crystallization batches may contain several crystal forms concomitantly. PMID- 26607006 TI - Mechanism of conformational coupling in SecA: Key role of hydrogen-bonding networks and water interactions. AB - SecA uses the energy yielded by the binding and hydrolysis of adenosine triphosphate (ATP) to push secretory pre-proteins across the plasma membrane in bacteria. Hydrolysis of ATP occurs at the nucleotide-binding site, which contains the conserved carboxylate groups of the DEAD-box helicases. Although crystal structures provide valuable snapshots of SecA along its reaction cycle, the mechanism that ensures conformational coupling between the nucleotide-binding site and the other domains of SecA remains unclear. The observation that SecA contains numerous hydrogen-bonding groups raises important questions about the role of hydrogen-bonding networks and hydrogen-bond dynamics in long-distance conformational couplings. To address these questions, we explored the molecular dynamics of SecA from three different organisms, with and without bound nucleotide, in water. By computing two-dimensional hydrogen-bonding maps we identify networks of hydrogen bonds that connect the nucleotide-binding site to remote regions of the protein, and sites in the protein that respond to specific perturbations. We find that the nucleotide-binding site of ADP-bound SecA has a preferred geometry whereby the first two carboxylates of the DEAD motif bridge via hydrogen-bonding water. Simulations of a mutant with perturbed ATP hydrolysis highlight the water-bridged geometry as a key structural element of the reaction path. PMID- 26607007 TI - Alteration of lipid membrane structure and dynamics by diacylglycerols with unsaturated chains. AB - Diacylglycerols (DAGs) with unsaturated acyl chains play many important roles in biomembranes, such as a second messenger and activator for protein kinase C. In this study, three DAGs of distinctly different chain unsaturations (i.e. di16:0DAG (DPG), 16:0-18:1DAG (POG), and di18:1DAG (DOG)) are studied using atomistic MD simulation to compare their roles in the structure and dynamics of 16:0-18:1phosphatidylcholine (POPC) membranes. All three DAGs are able to produce the so-called 'condensing effect' in POPC membranes: decreasing area-per-lipid, and increasing acyl chain order and bilayer thickness. Our visual and quantitative analyses clearly show that DAG with unsaturated chains induce larger spacing between POPC headgroups, compared with DAG with saturated chains; this particular effect has long been hypothesized to be crucial for activating enzymes and receptors in cell membranes. DAGs with unsaturated chains are also located closer to the bilayer/aqueous interface than DPG and are more effective in slowing down lateral diffusion of molecules. We show that DAG molecules seek the "umbrella coverage" from neighboring phospholipid headgroups - similar to cholesterol. Unlike cholesterol, DAGs also hide their chains from water by laterally inserting their chains into the surrounding. Thus, acyl chains of DAG are more spread and disordered than those of PC due to the insertion. By calculating the potential of mean force (PMF) for POPC in POPC/DAG bilayers, we found that all three DAGs can significantly increase the free energy barrier for POPC to flip-flop, but only DAGs with unsaturated chains can additionally increase the free energy of POPC desorption. PMID- 26607008 TI - Tryptophan-containing lipopeptide antibiotics derived from polymyxin B with activity against Gram positive and Gram negative bacteria. AB - Resistance to all known antibiotics is a growing concern worldwide, and has renewed the interest in antimicrobial peptides, a structurally diverse class of amphipathic molecules that essentially act on the bacterial membrane. Propelled by the antimicrobial potential of this compound class, we have designed three new lipopeptides derived from polymyxin B, sp-34, sp-96 and sp-100, with potent antimicrobial activity against both Gram positive and Gram negative bacteria. The three peptides bind with high affinity to lipopolysaccharide as demonstrated by monolayer penetration and dansyl-displacement. The interaction with the cytoplasmic membrane has been elucidated by biophysical experiments with model membranes of POPG or POPE/POPG (6:4), mimicking the Gram positive and Gram negative bacterial membrane. Trp-based fluorescence experiments including steady state, quenching, anisotropy and FRET, reveal selectivity for anionic phospholipids and deep insertion into the membrane. All three lipopeptides induce membrane fusion and leakage from anionic vesicles, a process that is favored by the presence of POPE. The molecules bind to zwitterionic POPC vesicles, a model of the eukaryotic membrane, but in a different way, with lower affinity, less penetration into the bilayer and no fusion or permeabilization of the membrane. Results in model membranes are consistent with flow cytometry experiments in Escherichia coli and Staphylococcus aureus using a membrane potential sensitive dye (bis-oxonol) and a nucleic acid dye (propidium iodide), suggesting that the mechanism of action is based on membrane binding and collapse of membrane integrity by depolarization and permeabilization. PMID- 26607009 TI - Functional activity of L-carnitine transporters in human airway epithelial cells. AB - Carnitine plays a physiologically important role in the beta-oxidation of fatty acids, facilitating the transport of long-chain fatty acids across the inner mitochondrial membrane. Distribution of carnitine within the body tissues is mainly performed by novel organic cation transporter (OCTN) family, including the isoforms OCTN1 (SLC22A4) and OCTN2 (SLC22A5) expressed in human. We performed here a characterization of carnitine transport in human airway epithelial cells A549, Calu-3, NCl-H441, and BEAS-2B, by means of an integrated approach combining data of mRNA/protein expression with the kinetic and inhibition analyses of L [(3)H]carnitine transport. Carnitine uptake was strictly Na(+)-dependent in all cell models. In A549 and BEAS-2B cells, carnitine uptake was mediated by one high affinity component (Km<2 MUM) identifiable with OCTN2. In both these cell models, indeed, carnitine uptake was maximally inhibited by betaine and strongly reduced by SLC22A5/OCTN2 silencing. Conversely, Calu-3 and NCl-H441 exhibited both a high (Km~20 MUM) and a low affinity (Km>1 mM) transport component. While the high affinity component is identifiable with OCTN2, the low affinity uptake is mediated by ATB(0,+), a Na(+), and Cl(-)-coupled transport system for neutral and cationic amino acids, as demonstrated by the inhibition by leucine and arginine, as well as by SLC6A14/ATB(0,+) silencing. The presence of this transporter leads to a massive accumulation of carnitine inside the cells and may be of peculiar relevance in pathologic conditions of carnitine deficiency, such as those associated to OCTN2 defects. PMID- 26607010 TI - 17beta-estradiol (E2) in membranes: Orientation and dynamic properties. AB - Non-genomic membrane effects of estrogens are of great interest because of the diverse biological activities they may elicit. To further our understanding of the molecular features of the interaction between estrogenic hormones and membrane bilayers, we have determined the preferred orientation, location, and dynamic properties of 17beta-estradiol (E2) in two different phospholipid membrane environments using (2)H-NMR and 2D (1)H-(13)C HSQC in conjunction with molecular dynamics simulations. Unequivocal spectral assignments to specific (2)H labels were made possible by synthesizing six selectively deuterated E2 molecules. The data allow us to conclude that the E2 molecule adopts a nearly "horizontal" orientation in the membrane bilayer with its long axis essentially perpendicular to the lipid acyl-chains. All four rings of the E2 molecule are located near the membrane interface, allowing both the E2 3-OH and the 17beta-OH groups to engage in hydrogen bonding and electrostatic interactions with polar phospholipid groups. The findings augment our knowledge of the molecular interactions between E2 and membrane bilayer and highlight the asymmetric nature of the dynamic motions of the rigid E2 molecule in a membrane environment. PMID- 26607011 TI - Giant MACPF/CDC pore forming toxins: A class of their own. AB - Pore Forming Toxins (PFTs) represent a key mechanism for permitting the passage of proteins and small molecules across the lipid membrane. These proteins are typically produced as soluble monomers that self-assemble into ring-like oligomeric structures on the membrane surface. Following such assembly PFTs undergo a remarkable conformational change to insert into the lipid membrane. While many different protein families have independently evolved such ability, members of the Membrane Attack Complex PerForin/Cholesterol Dependent Cytolysin (MACPF/CDC) superfamily form distinctive giant beta-barrel pores comprised of up to 50 monomers and up to 300A in diameter. In this review we focus on recent advances in understanding the structure of these giant MACPF/CDC pores as well as the underlying molecular mechanisms leading to their formation. Commonalities and evolved variations of the pore forming mechanism across the superfamily are discussed. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale. PMID- 26607012 TI - Nuclear Overhauser effect as a probe of molecular structure, dynamics and order of axially reorienting molecules in membranes. AB - The location, orientation, order and dynamics of cholesterol in model membranes have been well characterized, therefore cholesterol is an ideal molecule for developing new methods for studying structured molecules undergoing rapid axially symmetric reorientation. The use of (13)C filtering via short contact cross polarization transfer to (1)H allows the recovery of the weak cholesterol (1)H magic angle spinning NMR signals from beneath the strong phospholipid background in bicelles composed of chain perdeuterated dimyristoyl phosphatidylcholine/dicaproyl phosphatidylcholine/[3,4-(13)C]-cholesterol. Measurements of the nuclear Overhauser enhancement for (1)H nuclei located in the first ring of cholesterol are interpreted in terms of a simple two motion model consisting of axial reorientation, with a correlation time tau?, and a slower reorientation of the diffusion axis relative to the bilayer normal, with correlation time tau?. This approach can be extended to other molecules which undergo rapid axial reorientation such as small membrane associated peptides. PMID- 26607013 TI - The protein corona of circulating PEGylated liposomes. AB - Following systemic administration, liposomes are covered by a 'corona' of proteins, and preserving the surface functionality is challenging. Coating the liposome surface with polyethylene glycol (PEG) is the most widely used anti opsonization strategy, but it cannot fully preclude protein adsorption. To date, protein binding has been studied following in vitro incubation to predict the fate of liposomes in vivo, while dynamic incubation mimicking in vivo conditions remains largely unexplored. The main aim of this investigation was to determine whether shear stress, produced by physiologically relevant dynamic flow, could influence the liposome-protein corona. The corona of circulating PEGylated liposome was thoroughly compared with that formed by incubation in vitro. Systematic comparison in terms of size, surface charge and quantitative composition was made by dynamic light scattering, microelectrophoresis and nano liquid chromatography tandem mass spectrometry (nanoLC-MS/MS). Size of coronas formed under static vs. dynamic incubation did not appreciably differ from each other. On the other side, the corona of circulating liposomes was more negatively charged than its static counterpart. Of note, the variety of protein species in the corona formed in a dynamic flow was significantly wider. Collectively, these results demonstrated that the corona of circulating PEGylated liposomes can be considerably different from that formed in a static fluid. This seems to be a key factor to predict the biological activity of a liposomal formulation in a physiological environment. PMID- 26607016 TI - Insulin antibodies in patients with type 2 diabetic receiving recombinant human insulin injection: A report of 12 cases. AB - We report 12 cases of patients with type 2 diabetic receiving recombinant human insulin injection, who had uncontrolled hyperglycemia or frequent episodes of hypoglycemia, high levels of serum insulin and positive insulin antibodies. The clinical characteristics and insulin antibodies pharmacokinetics parameters were analyzed. After administration of glucocorticoids, changing insulin formulations or discontinuing the insulin and switching to oral antidiabetic agents, the level of insulin antibodies decreased and the plasma glucose restored. Thus, we recommend to identify the presence of high insulin antibodies in patients with type 2 diabetes who experience unexplained high plasma glucose or frequent reoccurrence of hypoglycemia. PMID- 26607017 TI - Low circulating ghrelin levels in women with polycystic ovary syndrome: a systematic review and meta-analysis. AB - Although numerous, human subject studies evaluating the relationship between circulating ghrelin levels and polycystic ovary syndrome (PCOS) risk have yielded inconsistent findings. We aimed to quantitatively assess the association by summarizing all available evidence from human subject studies. The PubMed and Web of Science databases were searched up to February 2015 for eligible studies. Studies were eligible if they reported circulating ghrelin levels in women with PCOS and healthy women controls. A fixed or random-effects model was used to pool risk estimations. Twenty studies including 894 PCOS patients and 574 controls were included in the meta-analysis. The studies had fair methodological quality. The pooling analysis of all available studies revealed that ghrelin levels were significantly lower in PCOS patients than in controls, with standardized mean difference of -0.40 (95% CI: -0.73, -0.08). The significant association persisted in many subgroup strata. However, the heterogeneity across studies was considerable and not eliminated in subgroup analyses. Meta-regression analysis further suggested that the heterogeneity might be relevant to variability in study location, PCOS relevant factors like HOMA-IR ratio, as well as other factors not assessed. In conclusion, our meta-analysis suggested that ghrelin levels were significantly lower in PCOS patients than in controls. Further studies with large sample sizes are warranted to replicate our findings. PMID- 26607018 TI - Epidemiological investigation and case-control study: a Legionnaires' disease outbreak associated with cooling towers in Warstein, Germany, August-September 2013. AB - Between 1 August and 6 September 2013, an outbreak of Legionnaires' disease (LD) with 159 suspected cases occurred in Warstein, North Rhine-Westphalia, Germany. The outbreak consisted of 78 laboratory-confirmed cases of LD, including one fatality, with a case fatality rate of 1%. Legionella pneumophila, serogroup 1, subtype Knoxville, sequence type 345, was identified as the epidemic strain. A case-control study was conducted to identify possible sources of infection. In univariable analysis, cases were almost five times more likely to smoke than controls (odds ratio (OR): 4.81; 95% confidence interval (CI): 2.33-9.93; p < 0.0001). Furthermore, cases were twice as likely to live within a 3 km distance from one identified infection source as controls (OR: 2.14; 95% CI: 1.09-4.20; p < 0.027). This is the largest outbreak of LD in Germany to date. Due to a series of uncommon events, this outbreak was most likely caused by multiple sources involving industrial cooling towers. Quick epidemiological assessment, source tracing and shutting down of potential sources as well as rapid laboratory testing and early treatment are necessary to reduce morbidity and mortality. Maintenance of cooling towers must be carried out according to specification to prevent similar LD outbreaks in the future. PMID- 26607019 TI - Multidimensional nanofibrous scaffolds of poly(lactide-co-caprolactone) and poly(ethyl oxazoline) with improved features for cardiac tissue engineering. AB - AIM: The aim of the study is to develop scaffolds that mimic native tissue properties for effective regeneration of the myocardium, which is affected by the gradual thinning of left ventricular tissue after an infarction. MATERIALS & METHODS: Heterogenous nanofibrous scaffolds made of poly(lactide-co-caprolactone) and poly(ethyl oxazoline) were characterized for physico-chemical properties. The biocompatibility of the scaffolds was evaluated by studying the adhesion, proliferation and differentiation of H9c2 cells. RESULTS: The scaffolds mimic the cardiac extracellular matrix and showed enhanced tensile strength, improved cell compatibility along with the expression of cardiac marker proteins. CONCLUSION: Our experimental data confirmed the importance of native tissue architecture and mechanical strength for improved cell response in cardiac tissue engineering. PMID- 26607020 TI - Thiazole derivative-modified upconversion nanoparticles for Hg(2+) detection in living cells. AB - Mercury ion (Hg(2+)) is an extremely toxic ion, which will accumulate in human bodies and cause severe nervous system damage. Therefore, the sensitive and efficient monitoring of Hg(2+) in human bodies is of great importance. Upconversion nanoparticle (UCNPs) based nano probes exhibit no autofluorescence, deep penetration depth and chemical stability in biological samples, as well as a large anti-stokes shift. In this study, we have developed thiazole-derivative functionalized UCNPs, and employed an upconversion emission intensity ratio of 540 nm to 803 nm (I540/I803) as a ratiometric signal to detect Hg(2+) in living cells showing excellent photo stability and high selectivity. Our nano probe was characterized using transmission electron microscopy (TEM) and powder X-ray diffraction (PXRD). The low cytotoxicity of our probe was confirmed by an MTT assay and the UCL test in HeLa cells was carried out by confocal microscopy. Our results demonstrated that organic-dye-functionalized UCNPs should be a good strategy for detecting toxic metal ions when studying cellular biosystems. PMID- 26607021 TI - Sperm deoxyribonucleic acid fragmentation assessment in normozoospermic male partners of couples with unexplained recurrent pregnancy loss: a prospective study. AB - OBJECTIVE: To determine whether sperm DNA integrity in normozoospermic male partners plays a role in idiopathic recurrent pregnancy loss (RPL). DESIGN: Prospective, cohort study. SETTING: Academic tertiary care center. PATIENT(S): Group I: 26 male partners of women with unexplained RPL. Group II: 31 normozoospermic males with proven fertility. INTERVENTION(S): Semen samples were collected by masturbation after 48-72 hours of abstinence. After liquefaction at room temperature, semen analysis was performed according to World Health Organization standards. Only samples with >20 * 10(6) spermatozoa/mL with at least 50% progressive sperm motility and 30 % normal morphology were selected for the study. DNA fragmentation of the sperm was assessed with TUNEL assay followed by flow cytometric analysis. MAIN OUTCOME MEASURE(S): Sperm DNA fragmentation in both groups. RESULT(S): Mean DNA fragmentation (mean +/- SD) was significantly more in men with RPL (36.8 +/- 5) compared with controls (9.4 +/- 2.7). CONCLUSION(S): Sperm DNA fragmentation may play a role in unexplained RPL despite normal semen analysis parameters. PMID- 26607022 TI - Effects of growth differentiation factor 8 on steroidogenesis in human granulosa lutein cells. AB - OBJECTIVE: To investigate the biological role of growth differentiation factor 8 (GDF8) in the regulation of steroidogenesis in human granulosa-lutein (hGL) cells. DESIGN: Experimental study. SETTING: Academic medical center. PATIENT(S): In vitro fertilization patients who provided hGL cells. INTERVENTION(S): Cultured hGL cells treated with recombinant human GDF8 for 24 hours. MAIN OUTCOME MEASURE(S): Expression of steroidogenic enzymes and steroid production in primary cultures of hGL cells used to investigate the effects of GDF8 via specific mRNA and protein levels examined using real time-quantitative polymerase chain reaction and Western blot analysis, respectively, and levels of estradiol and progesterone measured by enzyme immunoassays. RESULT(S): Extracts were prepared from cultured hGL cells after exposure to GDF8. The levels of cytochrome P450 aromatase (aromatase), the FSH receptor, and estradiol were increased, whereas steroidogenic acute regulatory protein (StAR), luteinizing hormone (LH) receptor, and progesterone levels were decreased after treatment with GDF8. In addition, follicle-stimulating hormone (FSH) stimulated the production of aromatase/estradiol, and LH induced the production of StAR/progesterone. Furthermore, pretreatment with GDF8 for 24 hours enhanced the effects of FSH on aromatase/estradiol induction, whereas GDF8 suppressed the effects of LH on StAR/progesterone stimulation. CONCLUSION(S): In human granulosa cells, GDF8 may play an important role in the modulation of cellular responsiveness to gonadotropins and in the regulation of ovarian steroid production, most likely as a luteinization inhibitor. PMID- 26607026 TI - Spread Films of Human Serum Albumin at the Air-Water Interface: Optimization, Morphology, and Durability. AB - It has been known for almost one hundred years that a lower surface tension can be achieved at the air-water interface by spreading protein from a concentrated solution than by adsorption from an equivalent total bulk concentration. Nevertheless, the factors that control this nonequilibrium process have not been fully understood. In the present work, we apply ellipsometry, neutron reflectometry, X-ray reflectometry, and Brewster angle microscopy to elaborate the surface loading of human serum albumin in terms of both the macroscopic film morphology and the spreading dynamics. We show that the dominant contribution to the surface loading mechanism is the Marangoni spreading of protein from the bulk of the droplets rather than the direct transfer of their surface films. The films can be spread on a dilute subphase if the concentration of the spreading solution is sufficient; if not, dissolution of the protein occurs, and only a textured adsorbed layer slowly forms. The morphology of the spread protein films comprises an extended network with regions of less textured material or gaps. Further, mechanical cycling of the surface area of the spread films anneals the network into a membrane that approach constant compressibility and has increased durability. Our work provides a new perspective on an old problem in colloid and interface science. The scope for optimization of the surface loading mechanism in a range of systems leading to its exploitation in deposition-based technologies in the future is discussed. PMID- 26607023 TI - Implementation of the findings of a national enquiry into the misdiagnosis of miscarriage in the Republic of Ireland: impact on quality of clinical care. AB - OBJECTIVE: To describe the findings of a national inquiry into cases of misdiagnosis of miscarriage in the Republic of Ireland and to report the results of implementation of the findings of the inquiry, including investment in new equipment and training, new national guidelines, and rigorous annual audit of early pregnancy units. DESIGN: Narrative description of the inquiry and its findings and results of a subsequent audit. SETTING: Not applicable. PATIENT(S): Women with problems of bleeding and/or pain in early pregnancy who were erroneously diagnosed as having a nonviable intrauterine pregnancy. INTERVENTION(S): After two cases of misdiagnosis of miscarriage that were widely reported in the Republic of Ireland in June 2010, a Miscarriage Misdiagnosis Review Team was commissioned by the Irish Health Service Executive (HSE) to undertake a national review of other possible cases of misdiagnosis of miscarriage. The Review Team made a series of recommendations that were subsequently implemented in full. The results of the implementation of the findings of the Review Team have been the subject of three annual audits across the country. MAIN OUTCOME MEASURE(S): The main outcome measure was the occurrence of misdiagnosis of miscarriage in the Republic of Ireland before and after implementation of the findings of the Review Team. RESULT(S): Twenty-four confirmed cases of misdiagnosis of miscarriage were identified, mostly occurring between 2005 and 2010. Analysis led to a series of recommendations by the Review Team, which were implemented in full by the HSE. Over ? 3 million was provided to fund implementation; 26 high-quality gynecological ultrasound machines were purchased to reequip 19 units involved in provision of care to women with suspected miscarriage. There was further allocation of resources for new equipment and improvement in the management and staffing of early pregnancy units across Ireland, with each center now having a dedicated and properly staffed Early Pregnancy Assessment Unit. A national training program in the management of early pregnancy problems has been implemented, along with regular national meetings to discuss early pregnancy problems. National clinical guidelines on the diagnosis and management of miscarriage for implementation have been distributed to all hospitals. CONCLUSION(S): No cases of miscarriage misdiagnosis were identified in any of the three annual audits, suggesting that implementation of the findings of the review has been successful. We believe that this is the first report of national change in practice leading to improvement in clinical outcomes in the management of suspected miscarriage. PMID- 26607027 TI - h-BN nanosheets as simple and effective additives to largely enhance the activity of Au/TiO2 plasmonic photocatalysts. AB - The activity of Au nanoparticle-loaded P25 TiO2 (Au/P25) plasmonic photocatalysts, evaluated by the oxidative decomposition of formic acid in water under visible light irradiation, was enhanced up to 3 times by simply mixing Au/P25 with photocatalytically inactive h-BN nanosheets as a result of electron transfer from photoexcited Au/TiO2 to the h-BN nanosheets and retardation of the charge recombination. PMID- 26607028 TI - Interleukin 1 receptor type 2 gene polymorphism is associated with reduced risk of preterm birth. AB - OBJECTIVE: Interleukin 1 receptor type 2 (IL1R2) regulates the inflammatory pathway that results in preterm delivery. We aim to investigate the impact of IL1R2 gene polymorphisms on the risk of preterm delivery. METHOD: A total of 664 women with spontaneous preterm and term deliveries were genotyped for IL1R2 gene polymorphisms (rs2072476A/G, rs2071008G/T, rs2072474C/T) using Sequenom MassARRAY platform. RESULTS: Ethnic-specific analysis revealed a significant association between the G allele of IL1R2 rs2072476 polymorphism and reduced risk of PTB in the Indian ethnic subgroup (OR: 3.7, 95% CI: 1.3-11.3, p = 0.017). The odds of G allele occurring among Indian women with term delivery (>37 weeks) was three times higher than those with preterm delivery (<37 weeks). Genotype analysis showed a significant association between the GG genotype of IL1R2 rs2072476 polymorphism and term delivery in the Indian women. CONCLUSION: This study shows disparity in the occurrence of preterm birth due to the differences in the genotype of the women. Particularly, Indian women with the minor allele of IL1R2 rs2072476 polymorphisms were more likely to deliver at term (>37 weeks). These findings suggest the possible influence of maternal IL1R2 gene polymorphism on the risk of preterm delivery. PMID- 26607029 TI - Percutaneous Transcatheter Mitral Valve Replacement: Patient-specific Three dimensional Computer-based Heart Model and Prototyping. AB - Mitral regurgitation is the most prevalent valvular heart disease worldwide. Despite the widespread availability of curative surgical intervention, a considerable proportion of patients with severe mitral regurgitation are not referred for treatment, largely due to the presence of left ventricular dysfunction, advanced age, and comorbid illnesses. Transcatheter mitral valve replacement is a promising therapeutic alternative to traditional surgical valve replacement. The complex anatomical and pathophysiological nature of the mitral valvular complex, however, presents significant challenges to the successful design and implementation of novel transcatheter mitral replacement devices. Patient-specific 3-dimensional computer-based models enable accurate assessment of the mitral valve anatomy and preprocedural simulations for transcatheter therapies. Such information may help refine the design features of novel transcatheter mitral devices and enhance procedural planning. Herein, we describe a novel medical image-based processing tool that facilitates accurate, noninvasive assessment of the mitral valvular complex, by creating precise three dimensional heart models. The 3-dimensional computer reconstructions are then converted to a physical model using 3-dimensional printing technology, thereby enabling patient-specific assessment of the interaction between device and patient. It may provide new opportunities for a better understanding of the mitral anatomy-pathophysiology-device interaction, which is of critical importance for the advancement of transcatheter mitral valve replacement. PMID- 26607031 TI - Polarization Spectroscopy of Defect-Based Single Photon Sources in ZnO. AB - Point defects in wide bandgap semiconductors are promising candidates for future applications that necessitate quantum light sources. Recently, defect-based single photon sources have been observed in ZnO that are very bright and remain photoactive from 4.5 K to room temperature. Despite several investigations, the structure and electronic states of these emitters remain unknown. In this work, we establish a procedure to distinguish a Z dipole from an XY dipole when studying quantum emitters that are randomly oriented. Our cryogenic and room temperature polarization measurements collectively establish that these unidentified ZnO quantum emitters have a Z dipole. We show that the associated absorption and emission dipoles are parallel within experimental uncertainty for all 32 individuals studied. Additionally, we apply group theory and find that, assuming the defect symmetry belongs to a point group relevant to the ZnO wurtzite lattice, the ground and excited states are orbital singlets. These results are a significant step in identifying the structure and electronic states of defect-based single photon sources in ZnO. PMID- 26607030 TI - Impact of Variations in Kidney Function on Nonvitamin K Oral Anticoagulant Dosing in Patients With Atrial Fibrillation and Recent Acute Heart Failure. AB - INTRODUCTION AND OBJECTIVES: Renal impairment and fluctuations in renal function are common in patients recently hospitalized for acute heart failure and in those with atrial fibrillation. The aim of the present study was to evaluate the hypothetical need for dosage adjustment (based on fluctuations in kidney function) of dabigatran, rivaroxaban and apixaban during the first 6 months after hospital discharge in patients with concomitant atrial fibrillation and heart failure. METHODS: An observational study was conducted in 162 patients with nonvalvular atrial fibrillation after hospitalization for acute decompensated heart failure who underwent creatinine determinations during follow-up. The hypothetical recommended dosage of dabigatran, rivaroxaban and apixaban according to renal function was determined at discharge. Variations in serum creatinine and creatinine clearance and consequent changes in the recommended dosage of these drugs were identified during 6 months of follow-up. RESULTS: Among the overall study population, 44% of patients would have needed dabigatran dosage adjustment during follow-up, 35% would have needed rivaroxaban adjustment, and 29% would have needed apixaban dosage adjustment. A higher proportion of patients with creatinine clearance < 60 mL/min or with advanced age (>= 75 years) would have needed dosage adjustment during follow-up. CONCLUSIONS: The need for dosage adjustment of nonvitamin K oral anticoagulants during follow-up is frequent in patients with atrial fibrillation after acute decompensated heart failure, especially among older patients and those with renal impairment. Further studies are needed to clarify the clinical importance of these needs for drug dosing adjustment and the ideal renal function monitoring regime in heart failure and other subgroups of patients with atrial fibrillation. PMID- 26607033 TI - Onset of frequent dust storms in northern China at ~AD 1100. AB - Dust storms in northern China strongly affect the living and health of people there and the dusts could travel a full circle of the globe in a short time. Historically, more frequent dust storms occurred during cool periods, particularly the Little Ice Age (LIA), generally attributed to the strengthened Siberian High. However, limited by chronological uncertainties in proxy records, this mechanism may not fully reveal the causes of dust storm frequency changes. Here we present a late Holocene dust record from the Qaidam Basin, where hydrological changes were previously reconstructed, and examine dust records from northern China, including the ones from historical documents. The records, being broadly consistent, indicate the onset of frequent dust storms at ~AD 1100. Further, peaked dust storm events occurred at episodes of high total solar irradiance or warm-dry conditions in source regions, superimposed on the high background of frequent dust storms within the cool LIA period. We thus suggest that besides strong wind activities, the centennial-scale dust storm events over the last 1000 years appear to be linked to the increased availability of dust source. With the anticipated global warming and deteriorating vegetation coverage, frequent occurrence of dust storms in northern China would be expected to persist. PMID- 26607032 TI - Parity and Risk of Coronary Heart Disease in Middle-aged and Older Chinese Women. AB - Pregnancy leads to physiological changes in lipid, glucose levels, and weight, which may increase the risk of coronary heart disease (CHD) in later life. The purpose of this study was to examine whether parity is associated with CHD in middle-aged and older Chinese women. A total of 20,207 women aged 37 to 94 years from Dongfeng-Tongji Cohort who completed the questionnaire, were medically examined and provided blood samples, were included in our analysis. CHD cases were determined by self-report of physician diagnosis through face-to-face interviews. Logistic regression models were used to estimate the association between parity and CHD. The rate of CHD was 15.8%. Parity had a positive association with CHD without adjustment of covariates. After controlling for the potential confounders, increasing risk of coronary heart disease was observed in women who had two (OR, 1.65; 95% CI, 1.41-1.93), three (OR, 1.76; 95% CI, 1.44 2.16), and four or more live births (OR, 1.71; 95% CI, 1.33-2.20) compared with women with just one live birth. High parity was significantly associated with increasing risk of CHD in Chinese women. This suggests that multiparity may be a risk factor for CHD among Chinese women. PMID- 26607035 TI - Stereotype or grammar? The representation of gender when two-year-old and three year-old French-speaking toddlers listen to role nouns. AB - Using a preferential looking paradigm, the current study examined the role that grammatical gender plays when preschool French-speaking toddlers process role nouns in the masculine form (e.g., chanteurs masculine 'singers'). While being auditorily prompted with "Look at the 'a role noun'!", two- and three-year-olds were presented with two pictures of two characters ('boy-boy' versus 'girl-boy') with attributes of the given role noun (e.g., singers with microphone and music notes). All role nouns were presented in the masculine plural form, which, despite its use to refer to mixed-gender groups, can be interpreted as referring to men. We expected toddlers to be biased by stereotypes, yet when non stereotypical role nouns were presented, toddlers were not influenced by grammatical gender, but by their own sex (even more so for three-year-old toddlers). The absence of sensitivity to grammatical cues for either age group is discussed in terms of the developmental awareness of grammatical gender. PMID- 26607034 TI - Impact of a wastewater treatment plant on microbial community composition and function in a hyporheic zone of a eutrophic river. AB - The impact of the installation of a technologically advanced wastewater treatment plant (WWTP) on the benthic microbial community of a vinyl chloride (VC) impacted eutrophic river was examined two years before, and three and four years after installation of the WWTP. Reduced dissolved organic carbon and increased dissolved oxygen concentrations in surface water and reduced total organic carbon and total nitrogen content in the sediment were recorded in the post-WWTP samples. Pyrosequencing of bacterial 16S rRNA gene fragments in sediment cores showed reduced relative abundance of heterotrophs and fermenters such as Chloroflexi and Firmicutes in more oxic and nutrient poor post-WWTP sediments. Similarly, quantitative PCR analysis showed 1-3 orders of magnitude reduction in phylogenetic and functional genes of sulphate reducers, denitrifiers, ammonium oxidizers, methanogens and VC-respiring Dehalococcoides mccartyi. In contrast, members of Proteobacteria adapted to nutrient-poor conditions were enriched in post-WWTP samples. This transition in the trophic state of the hyporheic sediments reduced but did not abolish the VC respiration potential in the post WWTP sediments as an important hyporheic sediment function. Our results highlight effective nutrient load reduction and parallel microbial ecological state restoration of a human-stressed urban river as a result of installation of a WWTP. PMID- 26607036 TI - Intra- and inter-nucleosomal interactions of the histone H4 tail revealed with a human nucleosome core particle with genetically-incorporated H4 tetra acetylation. AB - Post-translational modifications (PTMs) of histones, such as lysine acetylation of the N-terminal tails, play crucial roles in controlling gene expression. Due to the difficulty in reconstituting site-specifically acetylated nucleosomes with crystallization quality, structural analyses of histone acetylation are currently performed using synthesized tail peptides. Through engineering of the genetic code, translation termination, and cell-free protein synthesis, we reconstituted human H4-mono- to tetra-acetylated nucleosome core particles (NCPs), and solved the crystal structures of the H4-K5/K8/K12/K16-tetra-acetylated NCP and unmodified NCP at 2.4 A and 2.2 A resolutions, respectively. The structure of the H4-tetra-acetylated NCP resembled that of the unmodified NCP, and the DNA wrapped the histone octamer as precisely as in the unmodified NCP. However, the B-factors were significantly increased for the peripheral DNAs near the N-terminal tail of the intra- or inter-nucleosomal H4. In contrast, the B-factors were negligibly affected by the H4 tetra-acetylation in histone core residues, including those composing the acidic patch, and at H4-R23, which interacts with the acidic patch of the neighboring NCP. The present study revealed that the H4 tetra-acetylation impairs NCP self-association by changing the interactions of the H4 tail with DNA, and is the first demonstration of crystallization quality NCPs reconstituted with genuine PTMs. PMID- 26607037 TI - U-shaped association of body mass index in early adulthood with unintentional mortality from injuries: a cohort study of Swedish men with 35 years of follow up. AB - OBJECTIVES: To investigate the dose-response association between body mass index (BMI) in young adulthood and the risk of mortality caused by unintentional injuries. METHODS: We performed a cohort study including 7 43 398 men identified by linkage of the Multigeneration Register and the Military Service Conscription Register. Cox regression models were used to examine crude and adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) of the relationships between BMI at age 18-20 years and the risk of death from all unintentional injuries as well as from specific unintentional injuries. We then estimated the population attributable fractions (PAFs)-the proportion of unintentional deaths that was attributable to underweight, overweight and obesity in this population-based cohort. RESULTS: During 35.9 years of follow-up, 6461 deaths occurred from unintentional injuries, including 3064 deaths from road injury, 978 from poisoning, 503 from falls, 243 from fire and 348 from drowning. Underweight subjects had a higher risk of mortality in all unintentional injuries (HR, 1.05; 95% CI, 1.03-1.10) and mortality in burns (HR, 1.65; 95% CI, 1.13-2.40) compared with BMI between 18.5 and 22.5 kg m(-2) (reference group). BMI >25 kg m(-2) was associated with increased risk of death from all unintentional injuries (HR, 1.36; 95% CI, 1.12-1.65) and road accidents (HR, 1.50; 95% CI, 1.14-1.97). Estimates of PAF suggested that 4.4% of the mortality in Swedish men caused by unintentional injuries could have been avoided if BMI values were kept between 18.5 and 22.5 kg m(-2). CONCLUSIONS: A U-shaped association was observed between BMI and risk of unintentional death. Both underweight and overweight were associated with increased mortality risk for all unintentional injuries and for subtype causes. Our study suggests that BMI might be a significant target for preventive interventions on deaths caused by unintentional injuries. PMID- 26607038 TI - Telomere length increase after weight loss induced by bariatric surgery: results from a 10 year prospective study. AB - BACKGROUND/OBJECTIVES: Obesity contributes to telomere attrition. Studies focusing on short-term effects of weight loss have been unable to identify protection of telomere length. This study investigates long-term effects of pronounced weight loss induced by bariatric surgery on telomere length. SUBJECTS/METHODS: One hundred forty-two patients were recruited in a prospective, controlled intervention study, follow-up investigations were done after 10.46+/ 1.48 years. A control group of normal weight participants was recruited and followed from 1995 to 2005 in the Bruneck Study. A total of 110 participants from each study was matched by age and sex to compare changes in telomere length. Quantitative PCR was used to determine telomere length. RESULTS: Telomere length increased significantly by 0.024+/-0.14 (P=0.047) in 142 bariatric patients within 10 years after surgery. The increase was different from telomere attrition in an age- and sex-matched cohort population of the Bruneck Study (-0.057+/-0.18; beta=0.08; P=0.003). Significant changes in telomere length disappeared after adjusting for baseline body mass index (BMI) because of general differences in BMI and telomere length between the two study populations (beta=0.07; P=0.06). Age was proportional to telomere length in matched bariatric patients (r=0.188; P=0.049) but inversely correlated with telomere length in participants of the Bruneck Study (r=-0.197; P=0.039). There was no association between percent BMI/excess weight loss and telomere attrition in bariatric patients. Baseline telomere length in bariatric patients was inversely associated with baseline plasma cholesterol and triglyceride concentrations. Telomere shortening was associated with lower high-density lipoprotein cholesterol and higher fasting glucose concentration at baseline in bariatric patients. CONCLUSIONS: Increases in relative telomere length were found after bariatric surgery in the long term, presumably due to amelioration of metabolic traits. This may overrule the influence of age and baseline telomere length and facilitate telomere protection in patients experiencing pronounced weight loss. PMID- 26607039 TI - Bringing obesity to light: Rev-erbalpha, a central player in light-induced adipogenesis in the zebrafish? AB - BACKGROUND: Recent studies have led to an expansion of potential factors capable of stimulating obesity. Increasing evidence indicates that environmental factors, including disturbance of circadian rhythms, also contribute to its etiology. OBJECTIVES: To determine the effects of altered circadian rhythms on adipogenesis and to better understand how circadian and adipogenic regulatory pathways are linked, zebrafish larvae were exposed to various light/dark cycles or hypercaloric feeding (HCF). METHODS: Clock and adipogenic gene expression was quantitative real time PCR. Adipogenesis was characterized using coherent anti Stokes Raman scattering microscopy (CARS) and whole-mount lipid composition was analyzed by gas chromatography. The clock protein Rev-erbalpha and the adipogenesis-regulating protein Ppargamma were localized by immunohistochemistry. RESULTS: Zebrafish larvae exposed to continuous light (LL) had a sevenfold higher prevalence of adipocytes compared with control fish under a 14 h light and 10 h dark cycle. It was also significantly higher compared with that in HCF larvae with control light/dark cycle, which showed a 5.5-fold increase compared with control animals. Although total fatty acid content was unaffected, adipocyte lipid composition was altered in LL zebrafish. In contrast, shifting the onset and duration of the light periods did not affect adipogenesis or total fatty acid content. Gene expression analysis revealed effects of LL and HCF on circadian cyclicity, with increased expression of the clock gene period2 and altered circadian rev-erbalpha expression in LL larvae. Immunostaining revealed for the first time that Rev-erbalpha and Ppargamma colocalize in adipocytes, which together with the gene expression analysis suggests interplay between Rev erbalpha and Ppar isoforms. CONCLUSIONS: The amount of light, but not shifted light/dark cycles, affected adipogenesis and lipid composition, possibly due to increased period2 expression, which, in turn, enhances Rev-erbalpha-regulated gene expression. As the pparbetadelta promoter includes three Rev-erbalpha binding sites, we hypothesize that pparbetadelta may be a direct target that ultimately activates Ppargamma. PMID- 26607041 TI - Primary sclerosing cholangitis associated with CREST (calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly and telangiectasia) in an elderly woman: a case report. AB - INTRODUCTION: CREST (calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly, and telangiectasia) syndrome comprising calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia and primary sclerosing cholangitis are both chronic fibrotic diseases but the association between them is extremely rare. While primary sclerosing cholangitis has been associated with diffuse cutaneous scleroderma, the association with limited cutaneous scleroderma or CREST has not been previously reported in the literature. This case report illustrates the association between CREST and primary sclerosing cholangitis. CASE PRESENTATION: We report the case of an 84 year-old Asian woman with a long history of CREST who was admitted with abdominal pain, fatigue and progressive derangement of her liver enzymes. This was initially thought to be secondary to her bosentan therapy for pulmonary hypertension but it persisted despite bosentan being ceased. Primary sclerosing cholangitis was subsequently diagnosed on magnetic resonance cholangiopancreatography and she was referred to a hepatologist for treatment. CONCLUSIONS: This case highlights the need to consider primary sclerosing cholangitis in patients with CREST who present with abdominal symptoms and deranged liver enzymes when other causes have been excluded. Relevant differential diagnoses for this presentation, which can be difficult to exclude, include immunoglobulin G4-associated cholangitis and antimitochondrial antibody negative primary biliary cirrhosis. It is of particular significance to rheumatologists and gastroenterologists but has broader relevance to all medical specialists involved in the care of patients with CREST. PMID- 26607040 TI - A short-term transition from a high-fat diet to a normal-fat diet before pregnancy exacerbates female mouse offspring obesity. AB - BACKGROUND/OBJECTIVES: Recent findings have highlighted the detrimental influence of maternal overnutrition and obesity on fetal development and early life development. However, there are no evidence-based guidelines regarding the optimal strategy for dietary intervention before pregnancy. SUBJECTS/METHODS: We used a murine model to study whether switching from a high-fat (HF) diet to a normal-fat (NF) diet (H1N group) 1 week before pregnancy could lead to in utero reprogramming of female offspring obesity; comparator groups were offspring given a consistent maternal HF group or NF group until weaning. After weaning, all female offspring were given the HF diet for either 9 or 12 weeks before being killed humanely. RESULTS: H1N treatment did not result in maternal weight loss before pregnancy. NF offsprings were neither obese nor glucose intolerant during the entire experimental period. H1N offsprings were most obese after the 12-week postweaning HF diet and displayed glucose intolerance earlier than HF offsprings. Our mechanistic study showed reduced adipocyte insulin receptor substrate 1 (IRS1) and hepatic IRS2 expression and increased adipocyte p-Ser(636/639) and p Ser(612) of H1N or HF offspring compared with that in the NF offspring. Among all groups, the H1N offspring had lowest level of IRS1 and the highest levels of p Ser(636/639) and p-Ser(612) in gonadal adipocyte. In addition, the H1N offspring further reduced the expression of Glut4 and Glut2, vs those of the HF offspring, which was lower compared with the NF offspring. There were also enhanced expression of genes inhibiting glycogenesis and decreased hepatic glycogen in H1N vs HF or NF offspring. Furthermore, we showed extremely higher expression of lipogenesis and adipogenesis genes in gonadal adipocytes of H1N offspring compared with all other groups. CONCLUSIONS: Our results suggest that a transition from an HF diet to an NF diet shortly before pregnancy, without resulting in maternal weight loss, is not necessarily beneficial and may have deleterious effects on offspring. PMID- 26607042 TI - Current Methods to Assess Human Cutaneous Blood Flow: An Updated Focus on Laser Based-Techniques. AB - Several noninvasive techniques have been developed using laser light interaction in the skin to explore the skin's microcirculation. Combined with laser Doppler or LSCI, reactivity tests are used to explore skin endothelial and neurovascular function in humans, including PORH, LTH, PIV, and iontophoresis of vasodilators. Recent advances in our comprehension of the physiological pathways underlying these reactivity tests have been possible through topical or intradermal delivery of drugs that produce elevated local concentrations. Skin microvascular function has also been proposed as a prognostic biomarker or for evaluating the effect of drugs. Comprehension of the physiological pathways, together with recent technological improvements in microcirculation imaging, has provided reliable and reproducible tools to study skin microcirculation. PMID- 26607043 TI - Opioids in chronic obstructive pulmonary disease: the whole picture using all available evidence. PMID- 26607044 TI - New Mutations Associated with Rasopathies in a Central European Population and Genotype-Phenotype Correlations. AB - We performed the genetic analysis of Rasopathy syndromes in patients from Central European by direct sequencing followed by next generation sequencing of genes associated with Rasopathies. All 51 patients harboured the typical features of Rasopathy syndromes. Thirty-five mutations were identified in the examined patients (22 in PTPN11, two in SOS1, one in RIT1, one in SHOC2, two in HRAS, three in BRAF, two in MAP2K1 and two in the NF1 gene). Two of them (p.Gly392Glu in the BRAF gene and p.Gln164Lys in the MAP2K1 gene) were novel with a potentially pathogenic effect on the structure of these proteins. Statistically significant differences in the presence of pulmonary stenosis (63.64% vs. 23.81%, P = 0.013897) and cryptorchidism (76.47% vs. 30%, P = 0.040224) were identified as the result of comparison of the prevalence of phenotypic features in patients with the phenotype of Noonan syndrome and mutation in the PTPN11 gene, with the prevalence of the same features in patients without PTPN11 mutation. Cryptorchidism as a statistically significant feature in our patients with PTPN11 mutation was not reported as significant in other European countries (Germany, Italy and Greece). The majority of mutations were clustered in exons 3 (45.45%), 8 (22.73%), and 13 (22.73%) of the PTPN11 gene. PMID- 26607045 TI - Safety and efficacy of cryolipolysis for non-invasive reduction of submental fat. AB - BACKGROUND AND OBJECTIVES: Cryolipolysis has previously received FDA clearance for fat reduction in the abdomen, flanks, and thighs. There is also interest in small volume fat reduction for areas such as the chin, knees, and axilla. This article reports the results of a cryolipolysis pivotal IDE study for reduction of submental fullness. STUDY DESIGN/MATERIAL AND METHODS: A prototype small volume vacuum applicator (CoolMini applicator, CoolSculpting System, ZELTIQ Aesthetics) was used to treat 60 subjects in the submental area. At each treatment visit, a single treatment cycle was delivered at -10 degrees C for 60 minutes, the same temperature and duration used in current commercially-available cryolipolysis vacuum applicators. At the investigator's discretion, an optional second treatment was delivered 6 weeks after the initial treatment. The primary efficacy endpoint was 80% correct identification of baseline photographs by independent physician review. The primary safety endpoint was monitoring incidence of device- and/or procedure-related serious adverse events. Secondary endpoints included assessment of fat layer thickness by ultrasound and subject satisfaction surveys administered 12 weeks after final cryolipolysis treatment. RESULTS: Independent photo review from 3 blinded physicians found 91% correct identification of baseline clinical photographs. Ultrasound data indicated mean fat layer reduction of 2.0 mm. Patient questionnaires revealed 83% of subjects were satisfied, 80% would recommend submental cryolipolysis to a friend, 77% reported visible fat reduction, 77% felt that their appearance improved following the treatment, and 76% found the procedure to be comfortable. No device- or procedure-related serious adverse events were reported. CONCLUSION: The results of this clinical evaluation of 60 patients treated in a pivotal IDE study demonstrate that submental fat can be reduced safely and effectively with a small volume cryolipolysis applicator. Patient surveys revealed that submental cryolipolysis was well-tolerated, produced visible improvement in the neck contour, and generated high patient satisfaction. These study results led to FDA clearance of cryolipolysis for submental fat treatment. PMID- 26607047 TI - The Redin SCORE: useful, but not for all. PMID- 26607048 TI - Proteome and pathway effects of chronic haloperidol treatment in mouse hippocampus. AB - Proteomic exploration of the effects of psychotropic drugs on specific brain areas in rodents has the potential to uncover novel molecular networks and pathways affected by psychotropic medications, and may inform etiologic hypotheses on mental disorders. Haloperidol, a widely used first-generation antipsychotic, has been shown to produce structural and functional changes of the hippocampus, a brain region also implicated in the neuropathology of disorders such as schizophrenia and bipolar disorder. Seven adult male C57BL/6 mice were injected daily intraperitoneally with 0.5 mg/kg of haloperidol, for 28 days. A control group of six animals was injected with vehicle only (saline). Protein levels of postmortem hippocampus homogenate were determined using label-free LC/MS/MS. In the treatment group, 216 differentially expressed hippocampal proteins were identified as compared to controls. Ingenuity pathway analysis implicated oxidative phosphorylation and mitochondrial function as top canonical pathways, and local networks involved in tubulin-mediated cytoskeleton dynamics, clathrin-mediated endocytosis, and extracellular signal-regulated kinase and c Jun N-terminal kinase signaling. The findings of this study could stimulate further research into the cellular mechanisms associated with haloperidol treatment and the pathophysiology of psychotic disorders, assisting treatment biomarker discovery. All MS data have been deposited in the ProteomeXchange with identifier PXD002250 (http://proteomecentral.proteomexchange.org/dataset/PXD002250). PMID- 26607049 TI - Early Detection of Subclinical Uremic Cardiomyopathy Using Two-Dimensional Speckle Tracking Echocardiography. AB - BACKGROUND: Overhydration has a deleterious effect on cardio myocytes. This study was designated to evaluate left ventricular (LV) systolic and diastolic dysfunction in patients with various stages of chronic kidney disease (CKD) using conventional, tissue Doppler and two-dimensional speckle tracking echocardiography (2DSTE). METHODS: Forty controls and 90 CKD patients, aged 49.3 +/- 14 years old, were enrolled in the study. Patients were divided into 3 groups depending on their glomerular filtration rate. Group 1 (>=60 mL/min per 1.73 m(2) ), group 2 (<=60 mL/min per 1.73 m(2) ), and group 3 (<=60 mL/min per 1.73 m(2) and on regular dialysis for at least 12 months). Pulsed-Doppler and tissue Doppler studies were used to estimate LV filling pressure E/E'. Using 2DSTE, circumferential, radial, and longitudinal functions of the LV have been measured. RESULTS: LV longitudinal systolic strain, early, and late diastolic strain rates were significantly reduced in CKD patients (-16.9 +/- 3.8%, 1.6 +/- 0.5%, and 1.3 +/- 0.4% in CKD vs. -22.5 +/- 0.6%, 2.3 +/- 0.2%, and 1.9 +/- 0.1% in controls, P < 0.001 for all), and no difference was observed in terms of the circumferential LV functions (-22.4 +/- 1.7 vs. -22.5 +/- 1.4, P = 0.567). Severity of the kidney dysfunction appears to parallel with the rise of E/E' significantly (P < 0.001). CONCLUSION: In CKD, although the longitudinal and radial systolic functions were reduced, LV ejection fraction may remain within normal limits due to the preservation of the circumferential functions. Early detection of uremic cardiomyopathy might provide useful information for the risk stratification and decide the proper dialysis therapy in these patients. PMID- 26607046 TI - The consequences of fetal growth restriction on brain structure and neurodevelopmental outcome. AB - Fetal growth restriction (FGR) is a significant complication of pregnancy describing a fetus that does not grow to full potential due to pathological compromise. FGR affects 3-9% of pregnancies in high-income countries, and is a leading cause of perinatal mortality and morbidity. Placental insufficiency is the principal cause of FGR, resulting in chronic fetal hypoxia. This hypoxia induces a fetal adaptive response of cardiac output redistribution to favour vital organs, including the brain, and is in consequence called brain sparing. Despite this, it is now apparent that brain sparing does not ensure normal brain development in growth-restricted fetuses. In this review we have brought together available evidence from human and experimental animal studies to describe the complex changes in brain structure and function that occur as a consequence of FGR. In both humans and animals, neurodevelopmental outcomes are influenced by the timing of the onset of FGR, the severity of FGR, and gestational age at delivery. FGR is broadly associated with reduced total brain volume and altered cortical volume and structure, decreased total number of cells and myelination deficits. Brain connectivity is also impaired, evidenced by neuronal migration deficits, reduced dendritic processes, and less efficient networks with decreased long-range connections. Subsequent to these structural alterations, short- and long-term functional consequences have been described in school children who had FGR, most commonly including problems in motor skills, cognition, memory and neuropsychological dysfunctions. PMID- 26607050 TI - Pre-binding prior to full engagement improves loading conditions for front-row players in contested Rugby Union scrums. AB - We investigated the effect of a "PreBind" engagement protocol on the biomechanics of contested Rugby Union scrummaging at different playing levels. "PreBind" requires front-row props to take a bind on opposing players prior to the engagement, and to maintain the bind throughout the scrum duration. Twenty-seven teams from five different playing levels performed live scrums under realistic conditions. Video analysis, pressures sensors, and inertial measurement units measured biomechanical outcomes as teams scrummaged following different engagement protocols: the CTPE (referee calls "crouch-touch-pause-engage"), the CTS ("crouch-touch-set"), and the PreBind ("crouch-bind-set") variants. PreBind reduced the set-up distance between the packs (-27%) and the speed at which they came into contact by more than 20%. The peak biomechanical stresses acting on front rows during the engagement phase were decreased in PreBind by 14-25% with respect to CTPE and CTS, without reducing the capability to generate force in the subsequent sustained push. No relevant main effects were recorded for playing level due to within-group variability and there were no interaction effects between playing level and engagement protocol. Pre-binding reduced many mechanical quantities that have been indicated as possible factors for chronic and acute injury, and may lead to safer engagement conditions without affecting subsequent performance. PMID- 26607051 TI - Interventricular Septum and Posterior Wall Thickness Are Associated With Higher Systolic Blood Pressure. AB - Elevated blood pressure (BP) is a known factor that affects the structure of the left ventricle. The association between left ventricular hypertrophy (LVH) and BP in normotensive individuals is poorly understood. All individuals who underwent routine echocardiography and BP measurements as aircrew candidates for the Israeli Air Force in the years 2006 to 2012 were identified. Participants with normal values were included. Associations between echocardiographic characteristics and BP were studied. A total of 2386 participants were included. Mean systolic BP was 125.31+/-11.18 mm Hg and mean diastolic BP was 68.69+/-9.02 mm Hg. Interventricular septal (IVS) thickness was positively correlated with systolic BP (P<.001, correlation coefficient 0.121) and significantly inversely correlated with heart rate and hematocrit level (P<.001 for both). Men with evidence of IVS or posterior wall thickening on echocardiography, even within the normal range, may require a closer follow-up of BP. PMID- 26607052 TI - Control of the Metal-Insulator Transition at Complex Oxide Heterointerfaces through Visible Light. AB - The coupling of the localized surface plasmon resonance of Au nanoparticles is utilized to deliver a visible-light stimulus to control conduction at the LaAlO3 /SrTiO3 interface. A giant photoresponse and the controllable metal-insulator transition are characterized at this heterointerface. This study paves a new route to optical control of the functionality at the heterointerfaces. PMID- 26607053 TI - Neural Substrate Essential for Suppression of Vasopressin Secretion and Excretion of a Water Load. AB - Suppression of vasopressin secretion to very low levels is essential for the excretion of excess water. To investigate a role for the preoptic brain region in the suppression of vasopressin secretion and the excretion of a water load, lesions were made in the vicinity of the lamina terminalis in ewes (LTX-sheep) and responses to water-loading or reduction of cerebrospinal fluid NaCl by i.c.v. isotonic mannitol solution were investigated. In normal conscious sheep, intraruminal water-loading resulted in the urine flow rate increasing and urine osmolality decreasing within 1 h, such that renal free water clearance (CH 2O ) increased from -1.02 +/- 0.16 ml/min (mean +/- SEM) to a maximum of +4.99 +/- 0.62 ml/min at 2.5 h after water-loading (P < 0.05, n = 6). Plasma vasopressin levels fell from 0.88 +/- 0.17 pg/ml to undetectable levels (< 0.4 pg/ml, n = 4). In LTX-sheep (n = 6), CH 2O did not change significantly after water-loading ( 1.78 +/- 0.13 to -2.03 +/- 0.49 ml/min at 2.5 h after water-loading). Plasma vasopressin levels were inappropriately elevated in water-loaded LTX-sheep (n = 3). Intracerebroventricular mannitol (1 ml/h for 2 h) resulted in a water diuresis and increase in CH 2O (-1.16 +/- 0.12 to +2.81 +/- 0.58 ml/min, P < 0.05) after 2 h in normal sheep, and plasma vasopressin levels fell significantly from to 0.88 +/- 0.23 pg/ml to < 0.4 pg/ml (P < 0.05, n = 6). However, in LTX sheep, there was no change in CH 2O (-1.31 +/- 0.14 to -1.35 +/- 0.12 ml/min) or the plasma vasopressin concentration (1.47 +/- 0.18 to 1.60 +/- 0.44 pg/ml, not significant) with i.c.v. mannitol. The results suggest that an inhibitory pathway from the vicinity of the median preoptic nucleus to the supraoptic and hypothalamic paraventricular nuclei plays an important role in the suppression of vasopressin secretion and the excretion of excess water. PMID- 26607054 TI - Mitogenome assembly from genomic multiplex libraries: comparison of strategies and novel mitogenomes for five species of frogs. AB - Next-generation sequencing continues to revolutionize biodiversity studies by generating unprecedented amounts of DNA sequence data for comparative genomic analysis. However, these data are produced as millions or billions of short reads of variable quality that cannot be directly applied in comparative analyses, creating a demand for methods to facilitate assembly. We optimized an in silico strategy to efficiently reconstruct high-quality mitochondrial genomes directly from genomic reads. We tested this strategy using sequences from five species of frogs: Hylodes meridionalis (Hylodidae), Hyloxalus yasuni (Dendrobatidae), Pristimantis fenestratus (Craugastoridae), and Melanophryniscus simplex and Rhinella sp. (Bufonidae). These are the first mitogenomes published for these species, the genera Hylodes, Hyloxalus, Pristimantis, Melanophryniscus and Rhinella, and the families Craugastoridae and Hylodidae. Sequences were generated using only half of one lane of a standard Illumina HiqSeq 2000 flow cell, resulting in fewer than eight million reads. We analysed the reads of Hylodes meridionalis using three different assembly strategies: (1) reference-based (using bowtie2); (2) de novo (using abyss, soapdenovo2 and velvet); and (3) baiting and iterative mapping (using mira and mitobim). Mitogenomes were assembled exclusively with strategy 3, which we employed to assemble the remaining mitogenomes. Annotations were performed with mitos and confirmed by comparison with published amphibian mitochondria. In most cases, we recovered all 13 coding genes, 22 tRNAs, and two ribosomal subunit genes, with minor gene rearrangements. Our results show that few raw reads can be sufficient to generate high-quality scaffolds, making any Illumina machine run using genomic multiplex libraries a potential source of data for organelle assemblies as by-catch. PMID- 26607055 TI - Coronary thrombosis and marijuana smoking: a case report and narrative review of the literature. AB - We encountered evidence of myocardial infarction due to coronary thrombosis in an autopsy of an occasional marijuana smoker. These findings prompted us to perform a narrative review of the literature to determine when post-mortem toxicological tests may support a temporal relationship between marijuana smoking and cardiovascular disease. Toxicological examination showed the presence of Delta-9 tetrahydrocannabinol, its main metabolite and cannabinol in blood and urine. Quali-quantitative analysis revealed that Delta-9-tetrahydrocannabinol was taken within 2 h of the onset of cardiovascular symptoms, according to circumstantial data. Post-mortem toxicological results must take into account the degradation and post-mortem redistribution of analytes. However, for any inference about the specific cardiovascular triggering effect of Delta-9-tetrahydrocannabinol intake, we maintain that cannabinoid analysis in blood samples must be considered an essential requirement to estimate the time of last intake and avoid incomplete documentation. The literature, combined with the present case report, highlights an association between marijuana use and negative cardiovascular events, although few authors have supported their conclusions with toxicological results. Thus, additional research is needed. PMID- 26607056 TI - Feasibility of a single-stage tracheostomy decannulation protocol with endoscopy in adult patients. AB - OBJECTIVES/HYPOTHESIS: Gradual decrease in tube size and tube capping are considered the standard of care for tracheostomy decannulation. Both of these actions result in increased airway resistance. Immediate decannulation may offer a more tolerable approach. OBJECTIVE: To assess the feasibility of immediate tracheostomy decannulation compared with the traditional decannulation methods. METHODS: This study is a single institute, case-control retrospective study of patients between the years 2009 to 2014. The study group included all patients who underwent immediate decannulation, whereas the control group comprised patients who underwent traditional staged decannulation. An immediate decannulation protocol included admission to the intensive care unit, a comprehensive evaluation, decannulation, 24 hours of monitoring, and observation until discharge. RESULTS: Twenty-nine patients were included in the study group and 20 in the control group. No significant statistical difference was found between the two groups in the patients' medical history and tracheostomy data, except for the Acute Physiology and Chronic Health Evaluation II score and duration of the deflated cuff, which were significantly higher in the control group. A significant difference was found in the complication rate between the groups. In the staged decannulation group, four patients failed decannulation and required reinsertion of the tracheostomy cannula, whereas there were no such failures in the immediate decannulation group. Hospitalization duration after decannulation of the study group patients was significantly shorter than that of the control group. CONCLUSION: Immediate decannulation may offer a safe alternative for weaning from tracheostomy. It may also reduce the duration of the weaning process and hospitalization. LEVEL OF EVIDENCE: 3b Laryngoscope, 126:2057 2062, 2016. PMID- 26607057 TI - First identification of an IMI-1 carbapenemase-producing colistin-resistant Enterobacter cloacae in China. AB - BACKGROUND: Carbapenem resistance among the Enterobacteriaceae is a serious healthcare challenge. bla IMI is a carbapenemase gene mediating resistance to carbapenems but has not been commonly found. A bla IMI-carrying Enterobacter cloacae, which was also resistant to colistin, is reported here. FINDINGS: E. cloacae strain WCHECl-1060 was recovered from a blood sample of a leukemia patient, who was not previously exposed to colistin. Strain WCHECl-1060 belongs to a new sequence type, ST410, and was resistant to carbapenems and colistin but was susceptible to third-generation cephalosporins. A new allelic variant of bla IMI-1, which has two silent mutations compared to the original bla IMI-1 variant, was found in strain WCHECl-1060. Conjugation and transformation experiments failed to transfer bla IMI-1, suggesting a likely chromosome origin. CONCLUSIONS: To our knowledge, this is the first report of an IMI-1 carbapenemase-producing colistin-resistant E. cloacae in China. Microbiological laboratories should be aware of the unusual carbapenem-resistant but third-generation cephalosporin susceptible profiles of these IMI-producing isolates. The trend of colistin resistance among the Enterobacteriaceae should be also monitored. PMID- 26607058 TI - Clinical characteristics and STK11 gene mutations in Chinese children with Peutz Jeghers syndrome. AB - BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disease characterized by gastrointestinal hamartomatous polyps and mucocutaneous melanin spots. Germline mutation of the serine/threonine kinase 11 (STK11) gene are responsible for PJS. In this study, we investigated the clinical characteristics and molecular basis of the disease in Chinese children with PJS. METHODS: Thirteen children diagnosed with PJS in our hospital were enrolled in this study from 2011 to 2015, and their clinical data on polyp characteristics, intussusceptions events, family histories, etc. were described. Genomic DNA was extracted from whole-blood samples from each subject, and the entire coding sequence of the STK11 gene was amplified by polymerase chain reaction and analyzed by direct sequencing. RESULTS: The median age at the onset of symptoms was 2 years and 4 months. To date, these children have undergone 40 endoscopy screenings, 17 laparotomies and 9 intussusceptions. Polyps were found in the stomach, duodenum, small bowel, colon and rectum, with large polyps found in 7 children. Mutations were found in eleven children, including seven novel mutations (c.481het_dupA, c.943_944het_delCCinsG, c.397het_delG, c.862 + 1G > G/A, c.348_349het_delGT, and c.803_804het_delGGinsC and c.121_139de l19insTT) and four previously reported mutations (c.658C > C/T, c.890G > G/A, c.1062 C > C/G, and c.290 + 1G > G/A). One PJS patient did not have any STK11 mutations. CONCLUSIONS: The polyps caused significant clinical consequences in children with PJS, and mutations of the STK11 gene are generally the cause of PJS in Chinese children. This study expands the spectrum of known STK11 gene mutations. PMID- 26607059 TI - Non-pharmacological nurse-led interventions to manage anxiety in patients with advanced cancer: A systematic literature review. AB - BACKGROUND: Anxiety is a common symptom in patients with advanced cancer. Although pharmacological and psychosocial interventions are recommended, it remains unclear which role nurses can play in supporting patients with anxiety. OBJECTIVE: The objective was to provide an inventory of non-pharmacological nurse led interventions and evaluate the effectiveness in managing anxiety in advanced cancer patients. DESIGN: A systematic literature review was performed from xx-xx xxxx until March 2013. Four databases (MEDLINE, CINAHL, PsycINFO and Cochrane) were searched using predefined search terms without date limits. Randomized controlled trials, focusing on non-pharmacological nurse-led interventions in the management of anxiety in patients with advanced cancer were identified. Due to the heterogeneity of the included studies, results are presented in a descriptive way. RESULTS: A total of seven studies were included. The interventions were categorized into patient education, telemonitoring, psychotherapy, complementary care or a combination of these. Two studies showed significant improvements in anxiety levels in patients who received a psychoeducational intervention and in those who participated in a telemonitoring program. However, both studies were judged with a high risk of bias due to attrition, the randomization process and the lack of blinding which was not described. A complementary care intervention, a focused narrative interview and a telemonitoring program identified improvement in anxiety after each time the intervention was provided. However, no significant differences between intervention and control group were found. CONCLUSION: Although there is no firm evidence due to the high risk of bias, two studies showed that nurses could play a meaningful role in the management of anxiety with regard to early recognition and even in a specific set of psychotherapeutic interventions. Obviously, interventions should be adapted to the underlying cause of anxiety. However, the results of this systematic literature review show a limited degree of evidence to realize this goal. Future research should focus on the interpretation of the findings in order to understand why certain interventions are effective. Furthermore, clarification of which nurse competencies are needed to perform these interventions successfully must be defined. Nevertheless, this systematic literature review encourages nurses to take a key role in the management of anxiety and shows that it is worthwhile to investigate the difference that can be made by nurses in supporting advanced cancer patients with anxiety. PMID- 26607060 TI - Prevalence, type and concentration of human enterovirus and parechovirus in cerebrospinal fluid samples of pediatric patients over a 10-year period: a retrospective study. AB - BACKGROUND: Human enterovirus (EV) and parechovirus (HPeV) are significant causes of encephalitis and meningitis in children. The aim of this study was to determine the prevalence, type and viral RNA concentration of EV and HPeV in cerebrospinal fluid (CSF) samples in an unselected cohort of patients <18 years admitted to Bonn university hospital from 1998 to 2008. METHODS: A total of 327 CSF samples from 327 patients were retrospectively tested by real-time reverse transcriptase PCR (RT-PCR) for EV and HPeV, and by real-time PCR for cytomegalovirus (CMV), herpes simplex virus 1/2 (HSV), and varizella zoster-virus (VZV). Samples had been submitted for routine virological work-up due to suspected meningitis or encephalitis and had been stored at -20 degrees C hereafter. Positive samples for EV and HPeV were sequenced within the gene encoding the VP1 region (EV), the VP2 and the VP3/VP1 junction region (HPeV). RESULTS: The overall prevalence was 4.3 % (14/327) for EV, 0.6 % (2/327) for HPeV, and 0.3 % (1/327) for HSV and VZV, respectively. CMV was not detected in this cohort. In children less than 3 months of age the prevalence was 7.7 % (2/26) for EV and 7.7 % (2/26) for HPeV, respectively. Frequency of EV detection ranged from 0 to 12 % per year and highest rates were observed from June to September. All typed EV belonged to species B. Both HPeV infections were detected in the fall of 2008 and were typed as HPeV genotype 3. Viral RNA concentrations were highest in patients with HPeV infection, followed by echovirus 30 and other EV. In total, 86 % (12/14) of EV infections presented as aseptic meningitis, whereas both HPeV infections presented as severe sepsis-like illness. CONCLUSIONS: EV and HPeV were equally prevalent in children <3 months of age. Beyond the detection of EV and HPeV, the determination of viral RNA concentration and typing of EV and HPeV might prove beneficial for patient management and public health. PMID- 26607061 TI - Effects of infant massage on jaundiced neonates undergoing phototherapy. AB - BACKGROUND: Infant massage is a natural way for caregivers to improve health, sleep patterns, and reduce colic. We aimed to investigate the effects of infant massage on neonates with jaundice who are also receiving phototherapy. METHODS: Full-term neonates with jaundice, admitted for phototherapy at a regional teaching hospital, were randomly allocated to either a control group or a massage group. The medical information for each neonate, including total feeding amount, body weight, defecation frequency, and bilirubin level, was collected and compared between two groups. RESULTS: A total of 56 patients were enrolled in the study. This included 29 neonates in the control group and 27 in the experimental group. On the third day, the massage group showed significantly higher defecation frequency (p = 0.045) and significantly lower bilirubin levels (p = 0.03) compared with the control group. No significant differences related to feeding amount or body weight were observed between the two groups. CONCLUSION: Infant massage could help to reduce bilirubin levels and increase defecation frequency in neonates receiving phototherapy for jaundice. PMID- 26607062 TI - 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. PMID- 26607063 TI - Intermittent left cervical vagal nerve stimulation damages the stellate ganglia and reduces the ventricular rate during sustained atrial fibrillation in ambulatory dogs. AB - BACKGROUND: The effects of intermittent open-loop vagal nerve stimulation (VNS) on the ventricular rate (VR) during atrial fibrillation (AF) remain unclear. OBJECTIVE: The purpose of this study was to test the hypothesis that VNS damages the stellate ganglion (SG) and improves VR control during persistent AF. METHODS: We performed left cervical VNS in ambulatory dogs while recording the left SG nerve activity (SGNA) and vagal nerve activity. Tyrosine hydroxylase (TH) staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to assess neuronal cell death in the SG. RESULTS: We induced persistent AF by atrial pacing in 6 dogs, followed by intermittent VNS with short ON-time (14 seconds) and long OFF-time (66 seconds). The integrated SGNA and VR during AF were 4.84 mV.s (95% confidence interval [CI] 3.08-6.60 mV.s) and 142 beats/min (95% CI 116-168 beats/min), respectively. During AF, VNS reduced the integrated SGNA and VR, respectively, to 3.74 mV.s (95% CI 2.27-5.20 mV.s; P = .021) and 115 beats/min (95% CI 96-134 beats/min; P = .016) during 66-second OFF time and to 4.07 mV.s (95% CI 2.42-5.72 mV.s; P = .037) and 114 beats/min (95% CI 83-146 beats/min; P = .039) during 3-minute OFF-time. VNS increased the frequencies of prolonged (>3 seconds) pauses during AF. TH staining showed large confluent areas of damage in the left SG, characterized by pyknotic nuclei, reduced TH staining, increased percentage of TH-negative ganglion cells, and positive TUNEL staining. Occasional TUNEL-positive ganglion cells were also observed in the right SG. CONCLUSION: VNS damaged the SG, leading to reduced SGNA and better rate control during persistent AF. PMID- 26607064 TI - Impact of SNPs on methylation readouts by Illumina Infinium HumanMethylation450 BeadChip Array: implications for comparative population studies. AB - BACKGROUND: Infinium HumanMethylation 450 BeadChip Arrays by Illumina (Illumina HM450K) are among the most popular CpG microarray platforms widely used in biological and medical research. Several recent studies highlighted the potentially confounding impact of the genomic variation on the results of methylation studies performed using Illumina's Infinium methylation probes. However, the complexity of SNPs impact on the methylation level measurements (beta values) has not been comprehensively described. RESULTS: In our comparative study of European and Asian populations performed using Illumina HM450K, we found that the majority of Infinium probes, which differentiated two examined groups, had SNPs in their target sequence. Characteristic tri-modal or bi-modal patterns of beta values distribution among individual samples were observed for CpGs with SNPs in the first and second position, respectively. To better understand how SNPs affect methylation readouts, we investigated their impact in the context of SNP position and type, and of the Illumina probe type (Infinium I or II). CONCLUSIONS: Our study clearly demonstrates that SNP variation existing in the genome, if not accounted for, may lead to false interpretation of the methylation signal differences suggested by some of the Illumina Infinium probes. In addition, it provides important practical clues for discriminating between differences due to the methylation status and to the genomic polymorphisms, based on the inspection of methylation readouts in individual samples. This approach is of special importance when Illumina Infinium assay is used for any comparative population studies, whether related to cancer, disease, ethnicity where SNP frequencies differentiate the studied groups. PMID- 26607065 TI - Men report good mental health 20 to 23 years after in vitro fertilisation treatment. AB - BACKGROUND: Infertility and infertility treatment are known to have negative short-term psychological consequences for men and women, with more long-term consequences for women. The long-term wellbeing and mental health of men who have experienced in vitro fertilisation (IVF) treatment has not been extensively described in the literature. Therefore, the aim of this study was to analyse the mental health of men 20 to 23 years after IVF treatment. METHOD: The Symptom Checklist 90 tool was used to assess the self-perceived mental health of men who were part of a couple that underwent IVF treatment at Linkoping University Hospital, Sweden, 20 to 23 years earlier. We enrolled 292 out of the 490 men who took part in the hospital's IVF programme from 1986 to 1989 and compared them to an aged-matched control group. In addition, the men who had remained childless were compared to those who had fathered biological children and those who had adopted children. RESULTS: The overall mental health of the men who had received IVF was good. We found that 54% of the men had fathered their own biological children, 21% were childless and the remainder were part of a couple that had gone on to adopt. The childless men displayed more mental health problems than the other men in the study, as did men who were unemployed, single or divorced. CONCLUSION: This study carried out 20 to 23 years after IVF treatment showed that the majority of the men who took part were in good mental health. Those who remained childless faced an increased risk of negative psychological symptoms and men who were single showed more symptoms of depression and anxiety disorders. PMID- 26607066 TI - Thai health care provider knowledge of neonatal male circumcision in reducing transmission of HIV and other STIs. AB - BACKGROUND: Male circumcision (MC) reduces the risk of female-to-male transmission of HIV and other sexually transmitted infections (STIs). MC has not been practiced as a disease prevention measure in Thailand probably because of low recognition of its benefits among stakeholders. Neonatal male circumcision (NMC) is simpler, safer and cheaper than adult MC. This study aimed to assess Thai health care provider knowledge of benefits implementing NMC in Thailand. METHODS: Multi-stage sampling identified 16 government hospitals to represent various hospital sizes and regions of the country. Researchers administered a fixed choice questionnaire, developed by the research team based on a previous study, to physician administrators, practicing physicians, and nurses whose jobs involved NMC clinical procedures or oversight. The participants reviewed printed educational materials on the benefits of NMC during questionnaire completion. Data were analyzed using descriptive statistics, chi square tests, odds ratios, and logistic regression. RESULTS: One hundred thirty-three individuals participated in this quantitative study. Only 38% of the participants agreed that NMC reduced the risk of sexual transmission of HIV while 65% indicated that they knew that NMC prevented STIs. Most participants recognized the benefits of NMC on hygiene (96%) as well as cancer prevention (74%). Major concerns raised were potential trauma to the child, child rights and safety of NMC. After reviewing written information about the benefits of NMC, 59% of the participants agreed that NMC should be offered in their hospital. Physicians and nurses who had previous experience with circumcising patients of all ages were more reluctant to have NMC performed in their hospital. CONCLUSIONS: A clear policy advocating NMC, thorough preparation of health facilities, and staff training are needed before NMC could be used in Thailand as prevention strategy for HIV and other STIs. PMID- 26607067 TI - Discrimination of Japanese monosyllables in patients with high-frequency hearing loss. AB - OBJECTIVE: To analyze the difficulty of discriminating Japanese nonsense monosyllables in each of several grades of high-frequency hearing loss and to evaluate the limitations of amplification. METHODS: We collected retrospective data on the discrimination of Japanese nonsense monosyllables by patients with three grades of high-frequency hearing loss who fulfilled or nearly fulfilled the Japanese criteria for EAS. Discrimination of the twenty monosyllables included in the 67-S speech audiometric test, which is approved by the Japan Audiological Society, was evaluated under quiet conditions. RESULTS: One hundred and five ears of ninety-one adults with high-frequency hearing loss were tested. We classified the ears according to hearing threshold at 1000 Hz; Group 1: <45 dB; Group 2: >=45 dB and <70 dB; Group 3: >=70 dB. Under the best conditions, the best speech discrimination scores were 72.3 +/- 18.6% (mean +/- SD, N=11), 56.9 +/- 19.9% (N=57) and 38.1 +/- 22.6% (N=37) in Group 1, Group 2 and Group 3, respectively. For most of the monosyllables, discrimination score declined gradually as high frequency hearing loss became more severe. The high incidence in the Japanese language of [k], an easy consonant to distinguish, may be an advantage for patients with high-frequency hearing loss who use hearing aids. By employing a new confusion matrix that displays consonants and the following vowels separately, we were able to reveal the interactions of those two components. We observed that discrimination of preceding nasal consonants and that of the following vowels were not independent in patients with high-frequency hearing loss. CONCLUSION: Our classification based on threshold at 1000 Hz was useful to predict the effectiveness and limitations of amplification in high-frequency hearing loss. Threshold at 1000 Hz can be an index enabling us to refine the indications of EAS for native Japanese speakers to maximize its effectiveness against high-frequency hearing loss. PMID- 26607068 TI - [Dual role of daphnetin in suppressing HMGB1 release and HMGB1-induced inflammation in murine macrophage RAW264.7 cells and human monocytic THP-1 cells in vitro]. AB - OBJECTIVE: To investigate the dual role of daphnetin in suppressing high mobility group box-1 protein (HMGB1) release and blocking HMGB1-induced inflammatory response. METHODS: Murine macrophage RAW264.7 cells were cultured in the presence of daphnetin, lipopolysaccharide (LPS), or both. HMGB1 release from the cells was determined using ELISA, and phosphorylations of JAK1/2 and of STAT1 were detected by Western blotting. Human monocytic THP-1 cells exposed to daphnetin, rhHMGB1, or both were examined for NO production using a NO detection kit, for the release of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and prostaglandin E2 (PGE2) using ELISA, and for expressions of iNOS, COX-2 and phosphorylated p38, ERK, and JNK with Western blotting. RESULTS: Daphnetin dose dependently reduced the release of HMGB1 in RAW264.7 cells and suppressed rhHMGB1 induced iNOS and COX-2 expressions and release of TNF-alpha, IL-6, PGE2, and NO in THP-1 cells. Western blotting revealed that daphnetin significantly down regulated the phosphorylations of JAK-STAT1 pathway in LPS-stimulated RAW264.7 cells but did not suppress the phosphorylations of MAPKs signaling pathway induced by rhHMGB1 in THP-1 cells. CONCLUSION: Daphnetin can reduce the release of HMGB1 and suppress HMGB1-induced inflammatory response. In RAW264.7 cells, daphnetin inhibited LPS induced HMGB1 release is at least partly mediated by suppressing JAK-STAT1 signaling pathway activation. PMID- 26607069 TI - [Effect of stable DNA methyltransferase 3bknockdown on proliferation and apoptosis in bladder cancer cells in vitro]. AB - OBJECTIVE: To investigate the effect of stable knockdown of DNA methyltransferase 3b (DNMT3b) on the proliferation and apoptosis of bladder cancer cells. METHODS: Lentivirus expressing DNMT3b siRNA or the negative control siRNA was infected in human bladder cancer BIU-87 cells. MTT assay and flow cytometry were used to detect cell proliferation and apoptosis, respectively. The inhibitory effect of DNMT3b knockdown on xenograft tumors in nude mice was observed. Real-time PCR and Western blotting were carried out to investigate the expression level of cell apoptosis related genes. Methylation specific PCR was used to examine the methylation in the promoter region of the cell apoptosis related genes. RESULTS: The results of real-time PCR and Western blotting showed that DNMT3b mRNA and protein level were stably knocked down in BIU-87 cells. Stable DNMT3b knockdown suppressed BIU-87 cell growth and the tumor formation ability of the cells in nude mice. DNMT3b knockdown promoted the apoptosis of BIU-87 cells, increased the mRNA and protein expression of the cell growth and apoptosis related genes including DAPK, Bax and RASSF1A, and significantly decreased the methylation of these genes. CONCLUSION: Stable DNMT3b knockdown can affect the methylation of the cell growth and apoptosis related genes to regulate their expression, which might be a possible mechanism for suppressed cell growth and enhanced apoptosis of BIU-87 cells. PMID- 26607070 TI - [Quantification and size distribution of 24-hour urinary extracellular vesicles from healthy adults]. AB - OBJECTIVE: To analyze the quantity and size distribution of 24-hour urinary extracellular vesicles (uEVs) from healthy adults. METHODS: The 24-hour uEVs from 9 healthy adults were isolated by hydrostatic filtration dialysis (HFD). The effectiveness of uEVs enrichment was evaluated using Western blotting and transmission electron microscopy (TEM). The quantity and size distribution of the uEVs was analyzed with BCA protein quantification, TEM, and nanoparticle tracking analysis (NTA). RESULTS: uEVs with different sizes and morphologies were observed under TEM. Western blotting confirmed the expression of TSG101 in all the uEV fractions from the 9 donors, ranging from 132.50 to 760.70 ng/mL. NTA results showed that the number of 24-hour uEVs amount ranged from 3.56 * 1012 particles to 5.12 * 1012 particles, with a CV of 14.23%. The proportion of the vesicles with a diameter <40 nm was 0.04%-0.69% with a number range of (1.80-26.49)* 109 particles; the proportion of vesicles with a diameter of 40-100 nm (which is consistent with the size of exosomes)was 22.07%-42.08% with a number range of (1.00-1.77)* 1012 particles. The proportion of vesicles with a diameter of 100 1000 nm (consistent with the size of microvesicles) was 57.88%-77.85% with a number range of (2.09-3.86)* 1012 particles. CONCLUSION: The established HFD method allows efficient and convenient isolation of uEVs from a large amount of urine samples. The 24-hour uEVs from healthy adults show narrow differences between individuals and thus can be an ideal source of samples for relevant studies. PMID- 26607071 TI - [Value of C-reactive protein level on transplantation day in predicting early post-transplant infections and outcomes of allogeneic hematopoietic stem cell transplantation]. AB - OBJECTIVE: To investigate the value of C-reactive protein (CRP) on transplantation day in predicting early post-transplant infections and outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: We retrospectively analyzed the clinical data of 78 recipients undergoing allo-HSCT. The clinical reference value of CRP on transplantation day was determined, and its sensitivity and specificity for diagnosing bacteremia was analyzed using receiver-operating characteristic curve (ROC). The incidence of transplant related complications, overall survival, and relapse rate of the patients were analyzed with respect to the CRP level. RESULTS: The clinical reference value of CRP for diagnosing bacteremia was 23.3 mg/L (AUC=0.735 [95% CI: 0.623-0.848], P=0.001), which had a diagnostic sensitivity and specificity of 0.793 and 0.592, respectively. Compared with the patients with low CRP levels, the patients with high CRP levels tended to have delayed neutrophil reconstitution and platelet engraftment by 0.71 days (P=0.237) and 4.09 days (P=0.048), respectively, and had a significantly higher incidence of bacteremia (17.1% vs 53.5%, P=0.001) and CMV viremia (37.1% vs 72.1%, P=0.003) within 100 days following the transplantation; the incidences of EBV viremia, pulmonary invasive fungal infection, or acute graft versus host disease (aGVHD) showed no significant difference between the two groups (41.9% vs 22.9%, P=0.094; 14.0% vs 5.7%, P=0.285; 51.2% vs 45.7, P=0.656, respectively). During the follow-up for a median of 318 (7-773) days in high-CRP group and for 299 (78-747) days in low-CRP group, the high-CRP group showed a significantly lower 2-year overall survival than the low-CRP group (42.5% vs 78.4%, P=0.022), and tended to have a higher 2-year cumulative relapse rate (52.3% vs 19.8%, P=0.235). Logistic multivariate analysis identified a high CRP level on transplantation day as the independent risk factor for post transplant bacteremia within 100 days (OR=5.090 [95% CI: 1.115 -23.229], P=0.036). CONCLUSION: A high CRP level on transplantation day can be indicative of a high risk of early post-transplant bacteremia and CMV viremia and also a poor prognosis following allo-HSCT. PMID- 26607072 TI - [Effect of HMGB1 on proliferation of human nasopharyngeal carcinoma cell line C666-1 in vitro]. AB - OBJECTIVE: To observe the effect of high-mobility group box-1 protein (HMGB1) on the proliferation of human nasopharyngeal carcinoma cell line C666-1 and explore the possible underlying mechanisms. METHODS: Cultured C666-1 cells were treated with a siRNA targeting HMGB1 gene. The changes in the cell proliferation were detected by CCK8 analysis, the cell cycle distribution was assayed with flow cytometry, and the expressions of cyclin D1, CDK6 and related pathway proteins were detected with Western blotting. The effect of a HMGB1 plasmid carrying the reporter gene GFP on the proliferation of C666-1 cells was tested with CCK8 and EDU analysis. RESULTS: Compared with the control cells, the cells transfected with the siRNA targeting HMGB1 showed obviously suppressed cell proliferation (P<0.001), cell cycle arrest in G1 phase (P<0.001), and down-regulated expressions of cyclin D1, CDK6, STAT3 and P-STAT3. Overexpression of HMGB1 in cells transfected with the HMGB1 plasmid showed a significantly increased ratio of S phase cells (P<0.05) and obviously enhanced cell proliferation (P<0.001). CONCLUSION: HMGB1 can promote the proliferation of human nasopharyngeal carcinoma cell line C666-1 by up- regulating cyclin D1 and CDK6 via the STAT3 signaling pathway. PMID- 26607073 TI - [Construction of enterohemorrhagic Escherichia coli O157:H7 strains with espF gene deletion and complementation]. AB - OBJECTIVE: To construct enterohemorrhagic Escherichia coli (EHEC) O157:H7 strains with delection espF gene and its nucleotide fragment and with espF gene complementation. METHODS: A pair of homologous arm primers was designed to amplify the gene fragment of kanamycin resistance, which was transformed into EHEC O157:H7 EDL933w strain via the PKD46 plasmid by electroporation. The replacement of the espF gene by kanamycin resistance gene through the PKD46 mediated red recombination system was confirmed by PCR and sequencing. The entire coding region of espF along with its nucleotide fragment was amplified by PCR and cloned into pBAD33 plasmid, which was transformed into a mutant strain to construct the strain with espF complementation. RT-PCR was used to verify the transcription of espF and its nucleotide fragment in the complemented mutant strain. RESULTS AND CONCLUSION: We established EHEC O157:H7 EDL933w strains with espF gene deletion and with espF gene complementation. Both espF and its nucleotide fragment were transcribed in the complemented mutant strain. The two strains provide a basis for further study of the regulatory mechanism of espF. PMID- 26607074 TI - [Estrogen decreases vascular damage induced by chronic hypoperfusion through upregulating VEGF expression]. AB - OBJECTIVE: To evaluate the effect of physiological dose 17-beta-estrodiol (E2) replacement therapy on vascular dementia caused by cerebral chronic hypoperfusion. METHODS: The rats with bilateral common carotid artery occlusion (BCCAO) received E2 treatment starting from 3 days or 3 months after the operation. IgG leakage into the brain parenchyma and the changes of microvascular ultrastructure following BCCAO were examined using immunohistochemistry and electron microscopy, respectively; Western blotting was used to detect the expression of vascular endothelial growth factor (VEGF) protein. RESULTS: Compared with the sham-operated groups, the rats at 3 days and 3 months after BCCAO showed extensive vascular damages surrounded by IgG immunoreactivity in both the cortical and hippocampal CA1 regions. Stronger IgG immunoreactivity in the hippocampal CA1 region was observed at 3 days after BCCAO than at 3 months, but no significant IgG leakage was found in rats with continuous E2 treatment. Electron microscopy revealed severe edema around the blood vessels, mild vascular dilation, and endothelial cell damages at both 3 days and 3 months after BCCAO. E2 treatment markedly reduced the microvascular ultrastructural damages. Western blot analysis showed a significant increase in VEGF expression in the CA1 region at 6 h and 1 day after BCCAO followed by an obvious reduction till reaching the lowest level at 3 days; VEGF expression remained low even at 3 months after BCCAO and was significantly increased by E2 treatment. CONCLUSIONS: Vascular structural damage occurs early after BCCAO and can last for 3 months. E2 replacement therapy at physiological doses can reduce the incidence of BCCAO-induced vascular dementia by up-regulating VEGF expression. PMID- 26607075 TI - [Differential expressions of microRNAs and their predicted targets in liver transplant recipients with long-term stable survival]. AB - OBJECTIVE: To determine whether the miRNA expression profile in peripheral blood mononuclear cells (PBMCs) differs between liver transplant recipients with long term stable survival and those with acute rejection. METHODS: Twenty-nine liver transplant recipients with long-term stable survival (STA) group, 10 recipients with acute rejection (RJ group), and 17 healthy subjects (control group) were recruited for genome-wide microarray analysis of miRNA expressions in the PBMCs. The differentially expressed miRNAs among the 3 groups were validated by real time PCR, and the targets of these miRNAs were predicted. RESULTS: Compared with the RJ group, the STA group showed down-regulation of 13 miRNAs in the PBMCs. Of these down-regulated miRNAs, miRNA-18b, miRNA-340 and miRNA-106b were validated by real-time PCR, and the latter two miRNAs were predicted to target the TGF-beta pathway. CONCLUSIONS: The differentially expressed miRNAs in liver transplant recipients with long-term stable survival, namely miRNA-18b, miRNA-340 and miRNA 106b, can be potential clinical biomarkers to predict the outcomes of liver transplantation. PMID- 26607076 TI - [Effect of RbAp48 knockdown on migration and invasion of human cervical cancer cell line MS751 in vitro]. AB - OBJECTIVE: To investigate the effect of RbAp48 knockdown on the migration and invasion of human cervical cancer cells and explore the mechanism. METHODS: A small interference RNA (siRNA) was used to knock down the expression of RbAp48 in MS751 cells. The changes in cell migration and invasion were evaluated using wound healing assay and Transwell assay, respectively, and the expressions of RbAp48, vimentin, N-cadherin, E-cadherin, Snail, Twist, MMP-2 and TIMP-2 were determined with Western blotting. RESULTS: After siRNA-mediated RbAp48 knockdown, MS751 cells showed a significantly reduced expression of RbAp48 with significantly suppressed cell migration and invasion (P<0.01). RbAp48 knockdown induced obvious down-regulation of the expressions of interstitial cell phenotype proteins vimentin, N-cadherin, and MMP-2 and up-regulation of epithelial cell phenotype proteins E-cadherin and TIMP-2, suggesting the inhibition of epithelial mesenchymal transition of the cells. The expressions of Snail and Twist were significantly down-regulated in the cells following RbAp48 knockdown. CONCLUSION: Knockdown of RbAp48 can significantly inhibit epithelial-mesenchymal transition and suppress the migration and invasion of cervical cancer cell line MS751, the mechanism of which may involve the down-regulation of Snail and Twist expressions. PMID- 26607077 TI - [Transglycosylation of neolignans by enzymatic synthesis and evaluation of their antitumor activity]. AB - OBJECTIVE: To improve the water solubility and biological activity of neoligans (magnolol and honokiol) and test the antitumor activity of the modified compounds. METHODS: The glycosylated products of magnolol and honokiol were obtained by enzymatic synthesis using a UDP-glycosyltransferase (YjiC) from Bacillus. The products were characterized by high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS), and nuclear magnetic resonance (NMR) analysis. MTT assay was used to detect the growth inhibition of 4 human cancer cell lines induced by the compounds. RESULTS: We obtained two glucosides of neolignans (magnolol and honokiol) for the first time by enzymatic synthesis using a UDP-glycosyltransferase. Based on the spectroscopic data, the glucosides were identified as magnolol-2- O-beta-D glucopyranoside (1) and honokiol-4'-O-beta-D-glucopyranoside (2). Compounds 1-4 exhibited moderate anti-proliferative activities against the 4 human cancer cell lines, with IC50 values ranging from 9.41 to 111.21 umol/L. CONCLUSION: The glycoslated products show enhanced water solubility and drug sensitivity against SMMC7721 cells, suggesting their value as potential therapeutic drugs. PMID- 26607078 TI - [Cloning of human CD45 gene and its expression in Hela cells]. AB - OBJECTIVE: To clone human CD45 gene PTPRC and establish Hela cells overexpressing recombinant human CD45 protein. METHODS: The intact cDNA encoding human CD45 amplified using RT-PCR from the total RNA extracted from peripheral blood mononuclear cells (PBMCs) of a healthy donor was cloned into pMD-18T vector. The CD45 cDNA fragment amplified from the pMD-18T-CD45 by PCR was inserted to the coding region of the PcDNA3.1-3xflag vector, and the resultant recombinant expression vector PcDNA3.1-3xflag-CD45 was transfected into Hela cells. The expression of CD45 in Hela cells was detected by flow cytometry and Western blotting, and the phosphastase activity of CD45 was quantified using an alkaline phosphatase assay kit. RESULTS: The cDNA fragment of about 3 900 bp was amplified from human PBMCs and cloned into pMD-18T vector. The recombinant expression vector PcDNA3.1-3xflag-CD45 was constructed, whose restriction maps and sequence were consistent with those expected. The expression of CD45 in transfected Hela cells was detected by flow cytometry and Western blotting, and the expressed recombinant CD45 protein in Hela cells showed a phosphastase activity. CONCLUSION: The cDNA of human CD45 was successfully cloned and effectively expressed in Hela cells, which provides a basis for further exploration of the functions of CD45. PMID- 26607079 TI - [Robust low-dose CT myocardial perfusion deconvolution via high-dimension total variation regularization]. AB - OBJECTIVE: To develop a computed tomography myocardial perfusion (CT-MP) deconvolution algorithm by incorporating high-dimension total variation (HDTV) regularization. METHODS: A perfusion deconvolution model was formulated for the low-dose CT-MPI data, followed by HDTV regularization to regularize the consistency of the solution by fusing the spatial correlation of the vascular structure and the temporal continuation of the blood flow signal. RESULTS: Both qualitative and quantitative studies were conducted using XCAT and pig myocardial perfusion data to evaluate the present algorithm. The experimental results showed that this algorithm achieved hemodynamic parameter maps with better performances than the existing methods in terms of streak-artifacts suppression, noise resolution tradeoff, and diagnosis structure preservation. CONCLUSION: The proposed algorithm can achieve high-quality hemodynamic parameter maps in low dose CT-MPI. PMID- 26607080 TI - [Expressions of WWOX and CD133 in colorectal cancer and their clinical significance]. AB - OBJECTIVE: To investigate the expressions of WWOX and CD133 in colorectal cancer (CRC) and their relationship with the clinicopathologic characteristics of CRC. METHODS: The expressions of WWOX and CD133 proteins were examined by immunohistochemistry in 174 specimens of CRC tissues and 80 normal colorectal mucosa tissues. RESULTS: The positivity rates of WWOX and CD133 proteins were 41.4% and 53.4% in CRC tissues, respectively, significantly different from the rates in normal colorectal mucosa tissues (87.5% and 5.0%, respectively; P<0.05). WWOX and CD133 protein expressions were signi- ficantly correlated with the histological grades of the tumors, depth of invasion, lymph node metastasis, and Duke's stages (P<0.05). Spearman analysis showed a negative relationship between the WWOX expression and CD133 expression (P<0.05). Kaplan-Meier survival analysis showed that the overall survival time of CRC patients with a positive expression of WWOX was longer than that of patients with a negative expression of WWOX; the overall survival time of patients with a positive expression of CD133 was shorter than that of the negative patients (P<0.05). COX regression analysis identified positive expressions of WWOX and CD133 protein and Duke's stage as the independent prognostic factors of CRC. CONCLUSION: Abnormal expressions of WWOX and CD133 might be involved in the initiation, development, invasion, and metastasis of CRC. A combined detection of WWOX and CD133 can help in predicting the progression and prognosis of CRC. PMID- 26607082 TI - [Propensity score matching in SPSS]. AB - OBJECTIVE: To realize propensity score matching in PS Matching module of SPSS and interpret the analysis results. METHODS: The R software and plug-in that could link with the corresponding versions of SPSS and propensity score matching package were installed. A PS matching module was added in the SPSS interface, and its use was demonstrated with test data. RESULTS: Score estimation and nearest neighbor matching was achieved with the PS matching module, and the results of qualitative and quantitative statistical description and evaluation were presented in the form of a graph matching. CONCLUSION: Propensity score matching can be accomplished conveniently using SPSS software. PMID- 26607081 TI - [Effect of edaravone on oxidative stress and myocardial fibrosis induced by isoproterenol in rats]. AB - OBJECTIVE: To investigate the effect of edaravone on oxidative stress and myocardial fibrosis induced by isoproterenol in rats. METHODS: Fifty male SD rats were randomly divided into 5 groups, including a control group, a myocardial fibrosis model (established by injections of isopropyl adrenaline for 10 days) group, and 3 edaravone groups with edaravone treatment at low, medium, or high doses for 14 days. After the treatments, the rats were examined for the degree of myocardial fibrosis, left ventricular mass index (LVMI), collagen volume fraction (CVF), and myocardial contents of collagen I (Col I), collage III (Col III), hydroxyproline (Hyp), superoxide dismutase (SOD), malondialdehyde (MDA), and nitric oxide (NO); The expression of transforming growth factor-beta1 (TGF-beta1) in the myocardial tissues was examined by immunofluorescence assay and Western blotting. RESULTS: Compared with the control rats, the rat models of myocardial fibrosis showed significantly increased CVF and LVMI (P=0.000), which were lowered by edaravone treatments in a dose-dependent manner (P<0.05). The myocardial contents of Col I, Col III and Hyp also increased in the model group (P=0.000) and were lowered dose-dependently by edaravone; the contents of MDA was higher (P=0.000) and SOD and NO were lower in the model group (P=0.000), and edaravone treatments obviously increased SOD and NO contents (P<0.05). The model rats showed significantly increased myocardial expression of TGF-beta1 (P=0.000), which was markedly lowered by edaravone treatments (P=0.000). The myocardial content of MDA was positively correlated while SOD and NO were negatively with LVMI, CVF, Col I, Col III and Hyp; TGF-beta1 was positively correlated with LVMI, CVF, Col I, Col III, Hyp and MDA but negatively with SOD and NO. CONCLUSION: Edaravone can relieve oxidative stress and inhibit TGF-beta1 activation to ameliorate myocardial fibrosis in rats. PMID- 26607083 TI - [Effect of arginine vasopressin on alveolar fluid clearance in rats with acute lung injury]. AB - OBJECTIVE: To investigate the effect of arginine vasopressin (AVP) on alveolar fluid clearance (AFC) in acute lung injury (ALI). METHODS: Forty-eight healthy adult Sprague-Dawley rats were randomly divided into control group, ALI model group and AVP treatment group. The pathological changes in the lungs, lung water content, alveolar permeability and AFC were observed, and the expressions of alveolar epithelial sodium channel (ENaC) and Na+, K+-ATPase were measured. RESULTS: Compared with those in the model group, the rats treated with AVP showed significantly decreased alveolar permeability (0.27 +/- 0.15 vs 0.59 +/- 0.19) and lung water content (5.01 +/- 1.59 vs 8.67 +/- 1.79) (P<0.05) and increased AFC (23.56 +/- 4.51 vs 8.28 +/- 3.57) and of alpha-ENaC expressions (1.296 +/- 0.322 vs 0.349 +/- 0.141) and alpha1-Na+, K+-ATPase (1.421 +/- 0.389 vs 0.338 +/- 0.186) (P<0.05). CONCLUSION: AVP can promote AFC in with ALI possibly by up regulation of alpha-ENaC, alpha1-Na+, and K+-ATPase. PMID- 26607084 TI - [Serum 1, 5-anhydroglucose alcohol: a serum indicator for estimating acute blood sugar fluctuation in patients with fulminant type 1 diabetes]. AB - OBJECTIVE: To test the feasibility of using 1,5-anhydroglucose alcohol (1,5-AG) as a diagnostic indicator of fulminant type 1 diabetes (FT1DM). METHODS: Fifteen patients with newly diagnosed FT1DM and 52 with type 2 diabetes (T2DM) were examined for serum biochemistry, glycosylated hemoglobin (HbAlc), and serum 1, 5 AG level. RESULTS: The patients with FT1DM and T2DM showed significantly different fasting levels of blood glucose (FBG), fructosamine (FMN), creatinine (Cr), urea, HbAlc and serum 1,5-AG (P<0.05). In FT1DM patients, serum 1,5-AG was found to inversely correlate with FBG (r=-0.646, P=0.032) and FMN (r=-0.680, P=0.021), and in T2DM patients, serum 1,5-AG was inversely correlated with FBG (r=-0.407, P=0.001), FMN (r=-0.314, P=0.01) and HbAlc (r=-0.576, P<0.01). Receiver-operating characteristic (ROC) curve analysis showed an area under the curve of serum 1,5-AG of 0.804 with a cutoff value of 67.95, a sensitivity of 82.9% and a specificity of 60% for FT1DM diagnosis. CONCLUSION: Serum 1, 5-AG can reflect acute blood glucose fluctuation in FT1DM patients and is useful for differential diagnosis of FT1DM when combined with evaluations of the clinical characteristics of the patients and other related indicators. PMID- 26607085 TI - [Combined detection of thyroid transcription factor 1 and napsin A in pleural fluid cell blocks facilitates cytopathologic diagnosis of pulmonary adenocarcinoma]. AB - OBJECTIVE: To investigate the value of detecting thyroid transcription factor 1 (TTF-1) and Noval aspartic proteinase of pepsin family A (napsin A) in pleural fluid cell blocks in cytopathologic diagnosis of pulmonary adenocarcinoma. METHODS: Conventional cell smears of pleural effusions were obtained from 48 patients with a history of lung adenocarcinoma for cytological analysis. The cell blocks were prepared using the cytological specimens and examined with immunohistochemistry for TTF-1 and napsin A. The rates of a positive diagnosis of pulmonary adenocarcinoma were compared between the two methods, and the diagnositic value of TTF-1 and napsin A in pleural fluid cell blocks was evaluated. RESULTS: Immuno- histochemistry of the cell block sections yielded a significantly higher positive rate of diagnosis than cytological analysis of conventional cell smear (84.44% vs 55.56%, P<0.05). Most of the pleural fluid cell blocks showed positive expressions of TTF-1 (36/38, 94.74%) and napsin A (30/38, 78.95%), and none of samples showed TTF-1 or napsin A expression in the mesothelial cells (P<0.05). The combination detection of TTF-1 and napsin A in pleural fluid cell blocks had a high diagnosis value with a diagnostic sensitivity of 97.37% and a specificity of 100% for pulmonary adenocarcinoma. CONCLUSIONS: The combined detection of TTF-1 and napsin A in pleural fluid cell blocks facilitates cytopathologic diagnosis of pulmonary adenocarcinoma. PMID- 26607086 TI - [Euphorbia fischeriana extract reactivates latent HIV through nuclear factor kappaB pathway]. AB - OBJECTIVE: To investigate the effect of Euphorbia fischeriana extract on latent HIV reactivation and the pathway involved in this process and discuss the value of Euphorbia fischeriana extract in eliminating HIV. METHODS: Fresh tissues of Euphorbia fischeriana root were crushed into powder after quick freezing with liquid nitrogen and extracted with acetone followed by a three-day vacuum freeze drying for dehydration of the extract. The extract (EFE) was separated using RP C18 column with high-performance liquid chromatography (HPLC) and identified with mass spectrometry (MS). The activity of reactivated latent HIV was analyzed by fluorescence-activated cell sorting in a J-Lat 10.6 cell model treated with EFE (50 ug/mL) for 24 h, using TNF-alpha (10 ng/mL) as the positive control. The effect of a NF-kappaB pathway inhibitor (Bay 11-7082) on EFE activity was tested. The changes in P65 expression in the cell nuclei within 2 h and HIV protein p24 expression within 24 h were analyzed by Western blotting in cells treated with EFE. RESULTS: EFE was obtained by one-step acetone extraction, and the concentration of prostratin in the extract was around 0.53 mmol/L. About 50% of the cells showed HIV reactivation after treatment with 50 ug/mL EFE for 24 h accompanied by a significantly increased p24 expression. The activity of EFE in reactivating latent HIV was inhibited by Bay 11-7082 in a concentration-dependent manner, and p65 accumulation was detected in the cell nuclei within 2 h. CONCLUSION: EFE we obtained contains the active compounds of prostratin and its analogues and shows a strong capacity to reactivate latent HIV through classical NF-kappaB pathway. PMID- 26607087 TI - [miR-181c inhibits glycolysis by targeting hexokinase 2 in cancer-associated fibroblasts]. AB - OBJECTIVE: To investigate the role of miR-181c in glycolysis of cancer-associated fibroblasts (CAFs) and explore the mechanism. METHODS: Human lung CAFs and normal fibroblasts (NFs), isolated from fresh human lung adenocarcinoma tissue specimens by primary culture of tissue explants, were transfected with a miR -181c mimics, a miR-181c inhibitor, a siRNA siRNA-HK2 or the vector HK2-vector via Lipofectamine(TM) 2000. Quantitative real-time PCR was used to analyze the changes in miR-125b expression in the transfected cells; hexokinase-2 (HK2) protein expression in the cells was detected using Western blotting, and the cellular glucose uptake was assessed with 2-NBDG. Lactate production in the cells was examined and expression of HK2 mRNA was detected with dual luciferase reporter gene assay. RESULTS: No obvious difference was found in the cell morphology between CAFs and NFs. Compared with the NFs, the CAFs showed obviously increased glucose uptake, lactate production and HK2 protein expression with decreased expressions of the miR-181 family (P<0.05). Transfection with the miR 181 inhibito- rsignificantly increased glucose uptake, lactate production and HK2 protein expression in the NFs. In CAFs, transfection with the miR-181 mimics caused significantly lowered glucose uptake, lactate production and HK2 protein expression of. Knockdown of endogenous HK2 by siRNA abolished miR-181 mimics mediated decrease of glucose uptake and lactate production in CAFs, while transfection with miR-181 mimics suppressed HK2 overexpression-induced enhancement of glucose uptake and lactate production in NFs. CONCLUSION: Transfection with miR-181 mimics can suppress glycolysis in CAFs by inhibiting HK2 expression. PMID- 26607088 TI - [Expression of microRNA-100 and its correlation with drug resistance in human ovarian cancer SKOV3/DDP cells]. AB - OBJECTIVE: To investigate the expression of microRNA-100(miR-100) and the relationship with cisplatin resistance in human ovarian epithelial cancer SKOV3/DDP cells. METHODS: The SKOV3/DDP cells were transfected with the mimics or inhibitor of miR-100 or negative control RNA (NC) or inhibitor negative control RNA (inhibitor NC) by lipofectamine 2000. The experiment was divided into six groups: SKOV3 group, SKOV3/DDP group, miR-100 mimices group, NC group, miR-100 inhibitor group and inhibitor NC group. The expression of miR-100 and the cisplatin IC50 were measured by real-time PCR and CCK8 assay respectively. RESULTS: (1)The cisplatin resistance index of SKOV3/DDP was 2.23; (2)The express level of miR-100 in SKOV3/DDP cells was significantly lower than that in SKOV3 cells (P<0.001); (3)After transfected with miR-100 mimics, SKOV3/DDP cells showed that the level of miR-100 was 38.29 times higher than that in the NC group(P<0.01). The cisplatin IC50 of miR-100 mimices group was significantly lower than that in the NC group (P<0.001); (4) After transfected with miR-100 inhibitor, the level of miR-100 0f SKOV3/DDP was decreased by 97.7%. The cisplatin IC50 of miR-100 inhibitor group was significantly increased as compared with that in the inhibitor NC group (P<0.001). CONCLUSION: The expression of miR 100 is downregulated in SKOV3/DDP cells. Overexpressing miR-100 may effectively increase the sensitivity to cisplatin of human ovarian epithelial cancer SKOV3/DDP cells and may reverse cisplatin-resistance of EOC (epithelial ovarian cancer). PMID- 26607089 TI - [Detection of rifampicin concentration in cerebrospinal fluid by online enrichment and restricted-access media coupled with high-performance liquid chromatography]. AB - OBJECTIVE: To establish a method for detecting rifampicin in human cerebrospinal fluid (CSF) with restricted access media coupled with high-performance liquid chromatography that allows online direct sample injection and enrichment. METHODS: We used the column of restricted access media as the pre-treatment column and a C18 column as the analytical column. The mobile phase of pre treatment column was water-methanol (95:5,V/V) and the flow rate was 1 mL/min; the mobile phase of the analytical column was methanol-acetonitrile-10 mmol/L ammonuium acetate (volume ratio of 60:5:35). The detection wavelength was 254 nm and the column temperature was set at 25 degrees celsius;. RESULTS: For an injection volume of 100 uL, the peak area of rifampicin was 5.33 times that for an injection volume of 20 uL, and the limit of detection was effectively improved. The calibration curve showed an excellent linear relationship (r=0.9997) between rifampicin concentrations and peak areas within the concentration range of 0.25 to 8 ug/mL in CSF. The limits of detection and quantification was 0.07 ug/mL and 0.25 ug/mL, respecetively, with intra-day and inter-day assay precisions and relative standard deviation (RSD%) all below 5%. The recoveries of rifampicin at 3 blank spiked levels (low, medium, and high) ranged from 87.69% to 102.11%. In patients taking oral rifampicin at the dose of 10 mg/kg, the average rifampicin concentration was 0.29 in the CSF at 2 h after medication. CONCLUSION: The method we established is simple and fast for detecting rifampicin in CSF and allows direct online injection and enrichment with good detection precisions and accuracies. PMID- 26607090 TI - [Effects of tumor necrosis factor-alpha on release of MMP-3, MMP-9, and interleukin-17 in mouse bone marrow-derived mast cells in vitro]. AB - OBJECTIVE: To investigate the effect of tumor necrosis factor-alpha (TNF-alpha) on the release of matrix metalloproteinase-3 (MMP-3), MMP-9, and interleukin-17 (IL-17) in cultured mouse bone marrow-derived mast cells (BMMCs) in vitro. METHODS: Primarily cultured mouse BMMCs at 8 weeks were exposed PBS (control) or TNF-alpha at the concentrations of 2, 10, or 50 ng/mL for 12 or 24 h. Real-time PCR was performed to detect the mRNA expressions of MMP-3, MMP-9, and IL-17 in the exposed cells. RESULTS: A 12-hour exposure of the BMMCs to TNF-alpha caused significantly increased expressions of MMP-3, MMP-9, and IL-17 in a concentration dependent manner (P<0.05). Prolonged exposures of the cells to 2 and 10 TNF-alpha for 24 h further increased MMP-3, MMP-9, and IL-17 mRNA expressions, but exposure to 50 ng/mL TNF-alpha for 24 h increased only MMP-3 and MMP-9 expressions but not IL-17 mRNA expression. CONCLUSIONS: TNF-alpha treatment of primarily cultured BMMCs can significantly increase the cellular expressions of MMP-3, MMP-9, and IL 17 mRNA in a time- and dose-dependent manner. PMID- 26607091 TI - [Comparison of Bayesian interim analysis and classical interim analysis in group sequential design]. AB - OBJECTIVE: To explore the differences between the Bayesian interim analysis and the classical interim analysis. METHODS: To compare the means of two independent samples between control and treatment, superior hypothesis test was established. In line with the data requirements for group sequential design, Type Iota error of Bayesian interim analysis based on various prior distributions, Power, Average Sample Size and Average Stage were estimated in the interim analysis. RESULTS: In the Pocock and O' Brien & Fleming designs, the Type Iota errors in the Bayesian interim analysis based on the skeptical prior distribution and the handicap prior distribution were controlled at around 0.05. When the powers of these two classical designs were both 80%, Bayesian powers of the skeptical prior distribution and the handicap prior distribution were markedly lower. The powers of the non-informative prior distribution and the enthusiastic prior distribution were distinctly higher than 80%. CONCLUSION: In the Bayesian interim analysis based on the skeptical prior distribution and the handicap Prior distribution, the Type Iota errors can be well controlled. Bayesian interim analyses using these two prior distributions, compared with the analysis adopting the O' Brien & Fleming method, can markedly increase the possibility of ending the clinical trials ahead of time. The Bayesian interim analyses based on these two distributions do not have practical value for group sequential design of the Pocock method. PMID- 26607092 TI - [Suppression of Kiss-1 gene inhibits HCT116 human colorectal carcinoma cell migration in vitro via nuclear factor-kappaB signaling pathway]. AB - OBJECTIVE: To investigate the effect of Kiss-1 gene suppression on the metastatic capacity of HCT116 human colorectal carcinoma cells in vitro and the involvement of nuclear factor-kappaB (NF-kappaB) signaling pathway. METHODS: A recombinant lentiviral vector of Kiss-1 gene pGC-LV-Kiss-1-EGFP or the empty vector was transfected in HCT116 cells. Cell Counting Kit-8 (CCK8) and Transwell chamber assay were used to detect the changes in cell proliferation, invasion and migration ability after the transfection. Western blotting was used to detect the expression of I-kappaB, the inhibitive protein of NF-kappaB signal pathway, and the expression of the downstream effector MMP-9 before and after transfection. RESULTS: In cells over-expressing Kiss-1, I-kappaB expression increased and MMP-9 expression decreased significantly compared to those in the blank control and vector-transfected cells (P<0.05). Kiss-1 gene over-expression resulted in significant inhibition of HCT116 cell proliferation, invasion, and migration as compared to the control cells (P<0.05). CONCLUSION: Lentivirus-mediated Kiss-1 gene over-expression can inhibit the proliferation, invasion, and migration of HCT116 cells via the NF-B signaling pathway. PMID- 26607093 TI - [Effect of spvB/spvC gene on Salmonella virulence and the host immune function]. AB - OBJEVTIVE: To study the effect of spvB/spvC gene on Salmonella virulence and the Host immune. METHODS: STM.211, STM.211-Delta;spvB, STM.211-Delta;spvC, STM.211 Delta;spvB.spvC and PBS were infected with 0.2 mL 10(5) CFU corresponding strain respectively by intraperitoneal. We observed the mental status, movement, diarrhea, weight, pelage changed hair of the infected mouse. Then the level of IL 10, IL-12, IFN-gamma were detected by ELISA. Finally, we observe the pathological changes of liver and spleen with the general view and the microscope. RESULTS: Infection symptoms of STM.211, STM.211-Delta;spvB and STM.211-Delta;spvC were significantly worse than PBS group, but there was no significant difference between STM.211-spvB.spvC group and PBS group. The secretion of IFN-gamma and IL 12 of STM.211, STM.211-Delta;spvB, STM.211-Delta;spvC group were significantly lower than those in the STM.211-Delta;spvB.spvC group (P<0.05), but IL-10 secretion was significantly higher than STM.211-Delta;spvB.spvC group (P<0.05). There were no statistical significance among the STM.211, STM.211-Delta;SpvB, STM.211-Delta;spvC groups (P>0.05). CONCLUSIONS: Salmonella virulence can be affected obviously by spvB combined with spvC gene, but not by spvB or spvC. spvB/spvC gene can inhibit the TH1 cytokines (IFN-gamma and IL-12) secretion but promote the TH2 cytokines (IL-10) expression, leading immune response trend to TH2 shift. It shows that spvB/spvC gene can help the bacteria evade the host immune defenses, leading to aggravation of infection. PMID- 26607094 TI - [Effect of biofeedback in regulation of masseter muscle myoelectric activities]. AB - OBJECTIVE: To investigate the effect of the biofeedback in regulating the myoelectric activities of the masseter muscles. METHODS: Twenty orthodontic patients aged from 10 to 14 years with Angle Class II malocclusion, retrusive mandible, and an ANB angle > 6 degrees were enrolled in this study. The muscular activities of the anterior temporal muscle and the masseter muscle were evaluated before, during, and after biofeedback treatment by assessing the average integrated electromyogram and temporal/masseter (T/M) ratio in the clenching status. RESULTS: The patients' myoelectric activities of the anterior temporal muscle was significantly increased after biofeedback treatment (P<0.05). The patients' T/M ratio in the clenching status was increased after the treatment (1.76 +/- 1.46 before treatment, 4.71 +/- 4.03 immediately after treatment, and 2.57 +/- 2.07 at 1 day after treatment; t=4.86, P<0.05). CONCLUSION: Biofeedback treatment can regulate the activities of the anterior temporal and masseter muscles and increase the T/M ratio in the clenching status. PMID- 26607095 TI - [Early serological diagnosis of invasive aspergillosis in renal transplant recipients]. AB - OBJECTIVE: To evaluate the clinical value of serum 1,3-beta-D-glucan (BG) and galactomannan (GM) detection for early diagnosis of invasive aspergillosis (IA) in patients after renal transplantation. METHODS: Blood samples collected from 69 renal transplant recipients were divided into diagnosis group, clinical diagnosis group, suspected diagnosis group, and non-infected group for detection of serum BG and GM. RESULTS: The mean serum levels of BG in the diagnosis group, clinical diagnosis group, and suspected diagnosis group were significantly higher than that in non-infected group (P<0.05). The sensitivity, specificity, and positive and negative predictive values of BG was 69.49%, 70%, 93.18% and 35.71% for IA diagnosis, respectively. The serum levels of GM in the 3 diagnosis groups were also significantly higher than that in the non-infected group (P<0.05) with the sensitivity, specificity, and positive and negative predictive values of 84.75%, 90%, 96.15% and 52.63% for IA diagnosis, respectively. CONCLUSION: Increased serum BG and GM levels can serve as the evidence for early diagnosis of IA with a high diagnostic sensitivity and specificity in renal transplant recipients. PMID- 26607096 TI - [Application of precision medicine in the field of surgery]. AB - Precision medicine, based on personalized medicine, is to provide personalized and precise treatment. The emergence of 3D printing technique as well as genome sequencing provides an effective way to realize precise and personalized treatment. The application of 3D printing technique in the field of surgery is listed as following: optimize operation plan to achieve precise and personalized surgery; design personalized navigation template; personalized prosthesis production; design of personalized tissue and organ. With the development of tissue engineering, new material technology and genome sequencing and the improvement in related polices and regulations, precision medicine will step on a higher level in the field of surgery. This review introduces the application of precision medicine in the field of surgery. PMID- 26607097 TI - Role of relaxin-3/RXFP3 system in stress-induced binge-like eating in female rats. AB - Binge eating is frequently stimulated by stress. The neuropeptide relaxin-3 (RLN3) and its native receptor RXFP3 are implicated in stress and appetitive behaviors. We investigated the dynamics of the central RLN3/RXFP3 system in a newly established model of stress-induced binge eating. Female Sprague-Dawley rats were subjected to unpredictable intermittent 1-h access to 10% sucrose. When sucrose intake stabilized, rats were assessed for consistency of higher or lower sucrose intake in response to three unpredictable episodes of foot-shock stress; and assigned as binge-like eating prone (BEP) or binge-like eating resistant (BER). BEP rats displayed elevated consumption of sucrose under non-stressful conditions (30% > BER) and an additional marked increase in sucrose intake (60% > BER) in response to stress. Conversely, sucrose intake in BER rats was unaltered by stress. Chow intake was similar in both phenotypes on 'non-stress' days, but was significantly reduced by stress in BER, but not BEP, rats. After stress, BEP, but not BER, rats displayed a significant increase in RLN3 mRNA levels in the nucleus incertus. In addition, in response to stress, BEP, but not BER, rats had increased RXFP3 mRNA levels in the paraventricular and supraoptic nuclei of the hypothalamus. Intracerebroventricular administration of a selective RXFP3 antagonist, R3(B1-22)R, blocked the stress-induced increase in sucrose intake in BEP rats and had no effect on sucrose intake in BER rats. These results provide important evidence for a role of the central RLN3/RXFP3 system in the regulation of stress-induced binge eating in rats, and have therapeutic implications for eating disorders. PMID- 26607098 TI - The effect of Medicaid adult vision coverage on the likelihood of appropriate correction of distance vision: Evidence from the National Health and Nutrition Examination Survey. AB - BACKGROUND: Medicaid is the main public health insurance program for individuals with low income in the United States. Some state Medicaid programs cover preventive eye care services and vision correction, while others cover emergency eye care only. Similar to other optional benefits, states may add and drop adult vision benefits over time. RESEARCH OBJECTIVE: This article examines whether providing adult vision benefits is associated with an increase in the percentage of low-income individuals with appropriately corrected distance vision as measured during an eye exam. METHODOLOGY: We estimate the effect of Medicaid vision coverage on the likelihood of having appropriately corrected distance vision using examination data from the 2001-2008 National Health and Nutrition Examination Survey. We compare vision outcomes for Medicaid beneficiaries (n = 712) and other low income adults not enrolled in Medicaid (n = 4786) before and after changes to state vision coverage policies. FINDINGS: Between 29 and 33 states provided Medicaid adult vision benefits during 2001-2008, depending on the year. Our findings imply that Medicaid adult vision coverage is associated with a significant increase in the percentage of Medicaid beneficiaries with appropriately corrected distance vision of up to 10 percentage points. CONCLUSION: Providing vision coverage to adults on Medicaid significantly increases the likelihood of appropriate correction of distance vision. Further research on the impact of vision coverage on related functional outcomes and the effects of Medicaid coverage of other services may be appropriate. PMID- 26607099 TI - [Complications of untreated chronic blepharitis]. PMID- 26607100 TI - [Proptosis in a child secondary to an isolated orbital hydatid cyst]. PMID- 26607101 TI - [High myopic patients: A survey of their history, feelings, beliefs and needs]. AB - BACKGROUND AND OBJECTIVES: High myopia (HM), which affects 0.9 to 3.1% of the population, is a major cause of vision loss. The purpose of this investigation was to study and evaluate the impact of their high myopia on the daily lives of patients and to better understand their expectations in order to better meet their needs. MATERIALS AND METHODS: The survey was conducted between February 19 and March 21, 2014. To be eligible, patients had to have myopia of at least -8 diopters and be over 40 years of age, with or without myopic complications. Patients' degree of myopia was defined as the optical prescription of their worse eye. The 123 patients included were interviewed by phone using a questionnaire developed and validated by a scientific committee composed of experts and members of the patients' Association against myopic maculopathy (AMAM). The phone interview, semi-structured, lasted 20 minutes. RESULTS: On average, myopia was 11.7 diopters. Women accounted for 71% of the population, 89% of patients were under 65 years and were mostly professionals (65%). Over half of the subjects reported myopic complications; 5% of patients had choroidal neovascularization (CNV). Only 29% had been informed of the risk of CNV or maculopathy. HM was a handicap in sports for 64% of patients, in leisure activities for 51%, and in professional activities for more than a quarter (28%). Only 56% of HM patients reported living perfectly well with their condition. CONCLUSIONS: This survey is the first study on the daily life of people with HM aiming to analyze their social and emotional environment. It shows that HM has a profound impact on the daily lives of patients and may affect social life and professional activity. Most myopic patients possess incomplete or unclear information about the nature and risk of myopic complications. They expressed the desire to be better informed about their condition earlier, before the onset of complications. PMID- 26607102 TI - Predictors for symptom re-exacerbation after targeted stepwise drug discontinuation in first-episode schizophrenia: Results of the first-episode study within the German research network on schizophrenia. AB - BACKGROUND: After a first episode in schizophrenia guidelines recommend antipsychotic maintenance treatment (MT) for at least 1year. Recent RCTs on subsequent targeted intermittent treatment (IT) after stepwise drug discontinuation yielded noticeably higher relapse rates than during MT also in first-episode patients. Nevertheless, about 50% of patients remain stable under IT. Given the potential adverse effects of antipsychotics and the preference of many patients to discontinue drugs, valid predictors for the feasibility of IT are urgently needed to support decision making. METHODS: Based on a one-year RCT phase comparing MT with IT in first-episode patients after 1year of MT, conducted within the German Research Network on Schizophrenia (GRNS), predictors for deterioration under IT in 19 feasible patients were identified by logistic regression analysis. RESULTS: Deterioration occurred in 10 patients (52.6%). Univariate analyses indicated a lower PANSS positive score after acute treatment as well as after one year of MT as significant predictors; in multivariate logistic regression, in addition to the lower PANSS positive score after acute treatment, reaching enduring remission and having had a deterioration both during MT evolved as significant predictors and indicate a higher risk for deterioration. CONCLUSIONS: Although limited by the small sample size, our findings suggest that patients who show a favorable response and full and enduring symptom remission during antipsychotic treatment, as well as those with marked deterioration despite MT should rather be recommended to remain on treatment because they are at higher risk for symptom re-exacerbation after (stepwise) drug discontinuation. PMID- 26607103 TI - Mortality in schizophrenia and bipolar disorder: Clinical and serological predictors. AB - Persons with schizophrenia and with bipolar disorder have a reduced life expectancy due largely to death from natural causes. The reasons for this increased mortality have not been completely defined. We prospectively assessed a cohort of persons with schizophrenia and one with bipolar disorder with a clinical evaluation and a blood sample from which immune and infectious disease markers were measured. Mortality was determined with data from the National Death Index following a period of up to 14years. We examined the role of demographic, clinical, and serological factors on mortality in bivariate and multivariate models. A total of 43/710 (6.1%) persons with schizophrenia and 12/406 (3.0%) with bipolar disorder died of natural causes. In the schizophrenia group, mortality was predicted by the following variables in a multivariate model: cigarette smoking (RR=6.93, 95% CI 1.59, 30.1, p=0.0099); autoimmune disorder (RR=8.08, 95% CI 2.50, 26.1, p=0.00047); gastrointestinal disorder (GI) (RR=3.53, 95% CI 1.43, 8.69 p=0.0061); and reduced maternal education (RR=0.84, 95% CI 0.72, 0.97), p=0.018. The combination of smoking and an autoimmune disorder yielded an unadjusted relative risk of 18.1 for mortality, and the combination of smoking and a GI disorder an unadjusted relative risk of 9.45, compared with individuals with neither risk factor. In the bipolar disorder group, significant bivariate predictors of mortality included lower cognitive score (RR=0.95, p=.0085) and the presence of type 1 or 2 diabetes (RR=3.90, p=.026). Given the extraordinary high risk of death due to smoking in schizophrenia, smoking cessation remains an urgent priority. PMID- 26607105 TI - Zero-frequency and slow elastic modes in phononic monolayer granular membranes. AB - We theoretically study the dispersion properties of elastic waves in hexagonal and honeycomb monolayer granular membranes with either out-of-plane or in-plane particle motion. The particles interact predominantly via normal and transverse contact rigidities. When rotational degrees of freedom are taken into account, the bending and torsional rigidities of the intergrain contacts can control some of the phononic modes. The existence of zero-frequency modes, zero-group-velocity modes and their transformation into slow propagating phononic modes due to weak bending and torsional intergrain interactions are investigated. We also study the formation and manipulation of Dirac cones and multiple degenerated modes. This could motivate variety of potential applications in elastic waves control by manipulating the contact rigidities in granular phononic crystals. PMID- 26607104 TI - Acute restraint stress induces specific changes in nitric oxide production and inflammatory markers in the rat hippocampus and striatum. AB - Chronic mild stress has been shown to cause hippocampal neuronal nitric oxide synthase (NOS) overexpression and the resultant nitric oxide (NO) production has been implicated in the etiology of depression. However, the extent of nitrosative changes including NOS enzymatic activity and the overall output of NO production in regions of the brain like the hippocampus and striatum following acute stress has not been characterized. In this study, outbred male Wistar rats aged 6-7 weeks were randomly allocated into 0 (control), 60, 120, or 240 min stress groups and neural regions were cryodissected for measurement of constitutive and inducible NOS enzymatic activity, nitrosative status, and relative gene expression of neuronal and inducible NOS. Hippocampal constitutive NOS activity increased initially but was superseded by the inducible isoform as stress duration was prolonged. Interestingly, hippocampal neuronal NOS and interleukin 1beta mRNA expression was downregulated, while the inducible NOS isoform was upregulated in conjunction with other inflammatory markers. This pro-inflammatory phenotype within the hippocampus was further confirmed with an increase in the glucocorticoid-antagonizing macrophage migration inhibitory factor, Mif, and the glial surveillance marker, Ciita. This indicates that despite high levels of glucocorticoids, acute stress sensitizes a neuroinflammatory response within the hippocampus involving both pro-inflammatory cytokines and inducible NOS while concurrently modulating the immunophenotype of glia. Furthermore, there was a delayed increase in striatal inducible NOS expression while no change was found in other pro-inflammatory mediators. This suggests that short term stress induces a generalized increase in inducible NOS signaling that coincides with regionally specific increased markers of adaptive immunity and inflammation within the brain. PMID- 26607106 TI - Genotoxicity assessment of propyl thiosulfinate oxide, an organosulfur compound from Allium extract, intended to food active packaging. AB - Essential oils from onion (Allium cepa L.), garlic (Allium sativum L.), and their main components, such as propyl thiosulfinate oxide (PTSO) are being intended for active packaging with the purpose of maintaining and extending food product quality and shelf life. The present work aims to assess for the first time the potential mutagenicity/genotoxicity of PTSO (0-50 uM) using the following battery of genotoxicity tests: (1) the bacterial reverse-mutation assay in Salmonella typhimurium (Ames test, OECD 471); (2) the micronucleus test (OECD 487) (MN) and (3) the mouse lymphoma thymidine-kinase assay (OECD 476) (MLA) on L5178YTk(+/-), cells; and (4) the comet assay (with and without Endo III and FPG enzymes) on Caco-2 cells. The results revealed that PTSO was not mutagenic in the Ames test, however it was mutagenic in the MLA assay after 24 h of treatment (2.5-20 uM). The parent compound did not induce MN on mammalian cells; however, its metabolites (in the presence S9) produced positive results (from 15 uM). Data from the comet assay indicated that PTSO did not induce DNA breaks or oxidative DNA damage. Further in vivo genotoxicity tests are needed to confirm its safety before it is used as active additive in food packaging. PMID- 26607107 TI - Dietary exposure of acrylamide from the fifth Chinese Total Diet Study. AB - The levels of acrylamide in 240 food composite samples from the 5th Chinese Total Diet Study (TDS) were measured using an LC-MS/MS method and the exposure estimates for the general population were evaluated. The samples were collected from 20 provinces in China, covering about two thirds of the Chinese population. Acrylamide was detected in 40.0% of composite samples with the concentrations ranged from 0.8 to 211.8 MUg/kg. The average dietary intakes from the 5th Chinese TDS were 0.319 MUg kg(-1) bw day(-1) and an increase with about 70% was observed from the 3rd Chinese TDS in 2000 to the 5th Chinese TDS between 2009 and 2012. The main food group contributors to acrylamide exposure were vegetables (35.2%), cereals (34.3%) and potatoes (15.7%). Based on the benchmark dose lower confidence limit at 10% risk (BMDL10) of 0.31 mg kg(-1) bw day(-1) for the induction of mammary tumors in rats and 0.18 mg kg(-1) bw day(-1) for Harderian gland tumors in mice, the margins of exposure (MOEs) were 973 and 565 for Chinese general population, respectively. These MOEs indicate a human health concern. PMID- 26607108 TI - Some patterns of metallic nanoparticles' combined subchronic toxicity as exemplified by a combination of nickel and manganese oxide nanoparticles. AB - Stable suspensions of NiO and/or Mn3O4 nanoparticles with a mean diameter of 16.7 +/- 8.2 nm and 18.4 +/- 5.4 nm, respectively, prepared by laser ablation of 99.99% pure metals in de-ionized water were repeatedly injected IP to rats at a dose of 0.50 mg or 0.25 mg 3 times a week up to 18 injections, either separately or in different combinations. Many functional indices as well as histological features of the liver, spleen, kidneys and brain were evaluated for signs of toxicity. The accumulation of Ni and Mn in these organs was measured with the help of AES and EPR methods. Both metallic nanoparticles proved adversely bio active, but those of Mn3O4 were found to be more noxious in most of the non specific toxicity manifestations. Moreover, they induced a more marked damaging effect in the neurons of the caudate nucleus and hippocampus which may be considered an experimental correlate of manganese-induced parkinsonism. Mathematical analysis based on the Response Surface Methodology (RSM) revealed a diversity of combined toxicity types depending not only on particular effects these types are assessed for but on their level as well. The prognostic power of the RSM model proved satisfactory. PMID- 26607109 TI - Extended HSR/CARD domain mediates AIRE binding to DNA. AB - Autoimmune regulator (AIRE) activates the transcription of many genes in an unusual promiscuous and stochastic manner. The mechanism by which AIRE binds to the chromatin and DNA is not fully understood, and the regulatory elements that AIRE target genes possess are not delineated. In the current study, we demonstrate that AIRE activates the expression of transiently transfected luciferase reporters that lack defined promoter regions, as well as intron and poly(A) signal sequences. Our protein-DNA interaction experiments with mutated AIRE reveal that the intact homogeneously staining region/caspase recruitment domain (HSR/CARD) and amino acids R113 and K114 are key elements involved in AIRE binding to DNA. PMID- 26607110 TI - miR-4458 suppresses glycolysis and lactate production by directly targeting hexokinase2 in colon cancer cells. AB - miR-4458, a new tumor-suppressor, was reported to down-regulated in human hepatocellular carcinoma. The expression status, roles and inhibitory mechanisms of miR-4458 in other tumors still need to be clarified. The aim of this study is to investigate the effects of miR-4458 and to elucidate the potential mechanism in colon cancer cells. Using bioinformatic databases, we predicted that hexokinase2 (HK2), a rate-limiting enzyme in the glycolytic pathway, was a target of miR-4458, so the effects of miR-4458 on glycolysis and lactate production was assessed in colon cancer cells. We found that miR-4458 was down-regulated and HK2 was up-regulated in colon cancer cells. Overexpression of miR-4458 inhibited proliferation, glycolysis, and lactate production under both normoxic and hypoxic conditions. Luciferase activity assays showed that HK2 was a direct target of miR 4458. Moreover, knockdown of HK2 by specific RNAi also suppressed proliferation, glycolysis, and lactate production under both normoxic and hypoxic conditions. In conclusion, our findings suggested that miR-4458 inhibited the progression of colon cancer cells by inhibition of glycolysis and lactate production via directly targeting HK2 mRNA. PMID- 26607111 TI - Degradation by Cullin 3 and effect on WNK kinases suggest a role of KLHL2 in the pathogenesis of Familial Hyperkalemic Hypertension. AB - Mutations in WNK1 and WNK4, and in components of the Cullin-Ring Ligase system, kelch-like 3 (KLHL3) and Cullin 3 (CUL3), can cause the rare hereditary disease, Familial Hyperkalemic Hypertension (FHHt). The disease is characterized by overactivity of the renal sodium chloride cotransporter (NCC), which is phosphorylated and activated by the WNK-stimulated Ste20-type kinases, SPAK and OSR1. WNK kinases themselves can be targeted for ubiquitination and degradataion by the CUL3-KLHL3 E3 ubiquitin ligase complex. It is unclear, however, why there are significant differences in phenotypic severity among FHHt patients with mutations in different genes. It was reported that kelch-like 2 (KLHL2), a homolog of KLHL3, can also target WNK kinases for ubiquitation and degradation, and may play a special role in the systemic vasculature. Our recent study revealed the disease mutant CUL3 exhibits enhanced degradation of its adaptor protein KLHL3, potentially resulting in accumulation of WNK kinases secondarily. To investigate if KLHL2 plays a role in FHHt, we studied the effect of wild type and FHHt mutant CUL3 on degradation of KLHL2 and WNK kinase proteins in HEK293 cells. Although CUL3 facilitates KLHL2 degradation, the disease mutant CUL3 is more active in this regard. KLHL2 facilitated the degradation of wild type but not disease mutant WNK4 protein. These results suggest that KLHL2 likely plays a role in the pathogenesis of FHHt, and aggravates the phenotype caused by mutations in CUL3 and WNK4. PMID- 26607112 TI - CXCR7 suppression modulates microglial chemotaxis to ameliorate experimentally induced autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is the prototypical inflammatory demyelinating disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE), widely used as an animal model of MS, classically manifests as an ascending paralysis that is characterized by extensive infiltration of the CNS by inflammatory cells. Although several studies uncover the significant role of microglia in the development of EAE, the cellular mechanisms of microglia that govern EAE pathogenesis remain unknown. In the current study, we report that CXCR7 expression is dynamic regulated in activated microglia during CNS autoimmunity and positively correlates with the clinical severity of EAE. In addition, microglial chemotaxis is mediated by CXCR7 during CNS autoimmunity, signaling through extracellular signal-regulated kinase (ERK)1/2 activation, whereas p38 mitogen-activated protein kinase (MAPK) and (c-Jun N-terminal kinase) JNK are not involved. Most importantly, CXCR7 neutralizing treatment ameliorates the clinical severity of EAE along with ERK1/2 phosphorylation reduction. Collectively, our data demonstrate that CXCR7 suppression modulates microglial chemotaxis to ameliorate EAE. PMID- 26607113 TI - H3S10 phosphorylation-mediated transcriptional regulation by Aurora kinase A. AB - Histone H3S10 phosphorylation has been known as a cell cycle-specific marker and has a role in transcriptional activation. Various kinases phosphorylate H3S10 in different species, however, the role of the mitotic serine/threonine protein kinase Aurora A (AURKA) is largely unknown. Here we present evidence that AURKA phosphorylates H3S10 and activates target gene transcription. We show that down regulation of AURKA level during leukemia cell differentiation results in decreased H3S10 phosphorylation level. We further show that AURKA is recruited to target gene promoters and activates transcription via H3S10 phosphorylation. Furthermore, this recruitment can be disrupted by the AURKA inhibitor Alisertib and results in H3K9-me2 recruitment by G9a. PMID- 26607114 TI - Tuberculosis reaches new milestones, good and bad. PMID- 26607115 TI - Innovative Medicines Initiative and antibiotic resistance. PMID- 26607117 TI - Corrections. PMID- 26607118 TI - Corrections. PMID- 26607119 TI - How many patients with anti-JEV IgM in cerebrospinal fluid really have Japanese encephalitis? PMID- 26607120 TI - HIV and hepatitis C virus co-infection in Kenya. PMID- 26607121 TI - Schistosomiasis in Corsica and the pivotal role of travellers. PMID- 26607122 TI - Hepatitis C virus genotype 1 NS5A variants in Japanese patients. PMID- 26607123 TI - Mission Indradhanush and the counterfeit drug trade in India. PMID- 26607124 TI - Cholera and blame in Haiti. PMID- 26607125 TI - Honouring pioneers of treatments for malaria and nematode infections. PMID- 26607126 TI - Highlights from IDWeek 2015. PMID- 26607127 TI - Phage therapy for severe infections tested in the first multicentre trial. PMID- 26607131 TI - Miliary tuberculosis characterised by lipomembranous fat necrosis. PMID- 26607132 TI - Abdominal cocoon syndrome caused by Mycobacterium bovis from consumption of unpasteurised cow's milk. PMID- 26607130 TI - Extensively drug-resistant tuberculosis in a young child after travel to India. AB - Extensively drug-resistant (XDR) tuberculosis is becoming increasingly prevalent worldwide, but little is known about XDR tuberculosis in young children. In this Grand Round we describe a 2-year-old child from the USA who developed pneumonia after a 3 month visit to India. Symptoms resolved with empirical first-line tuberculosis treatment; however, a XDR strain of Mycobacterium tuberculosis grew in culture. In the absence of clinical or microbiological markers, low-radiation exposure pulmonary CT imaging was used to monitor treatment response, and guide an individualised drug regimen. Management was complicated by delays in diagnosis, uncertainties about drug selection, and a scarcity of child-friendly formulations. Treatment has been successful so far, and the child is in remission. This report of XDR tuberculosis in a young child in the USA highlights the risks of acquiring drug-resistant tuberculosis overseas, and the unique challenges in management of tuberculosis in this susceptible population. PMID- 26607133 TI - Plasma atrial natriuretic peptide and N-terminal pro B-type natriuretic peptide concentrations in dogs with right-sided congestive heart failure. AB - The clinical utility of plasma natriuretic peptide concentrations in dogs with right-sided congestive heart failure (CHF) remains unclear. We investigated whether plasma levels of atrial natriuretic peptide (ANP) and N-terminal pro B type natriuretic peptide (NT-proBNP) are useful for assessing the congestive signs of right-sided heart failure in dogs. This retrospective study enrolled 16 healthy dogs and 51 untreated dogs with presence (n=28) or absence (n=23) of right-sided CHF. Medical records of physical examinations, thoracic radiography and echocardiography were reviewed. The plasma concentration of canine ANP was measured with a chemiluminescent enzyme immunoassay. Plasma NT-proBNP concentrations were determined using an enzyme immunoassay. Plasma ANP and NT proBNP concentrations in dogs with right-sided CHF were significantly higher than in healthy controls and those without right-sided CHF. The plasma NT-proBNP concentration >3,003 pmol/l used to identify right-sided CHF had a sensitivity of 88.5% and specificity of 90.3%. An area under the ROC curve (AUC) was 0.93. The AUC for NT-proBNP was significantly higher than the AUCs for the cardiothoracic ratio, vertebral heart score, ratio of right ventricular end-diastolic internal diameter to body surface area, tricuspid late diastolic flow and ratio of the velocities of tricuspid early to late diastolic flow. These results suggest that plasma ANP and NT-proBNP concentrations increase markedly in dogs with right sided CHF. Particularly, NT-proBNP is simple and helpful biomarkers to assess the right-sided CHF. PMID- 26607134 TI - Effect of onion extract on corneal haze suppression after air assisted lamellar keratectomy. AB - This study evaluated the effect of onion extract on corneal haze suppression after applying the air assisted lamellar keratectomy. The air assisted lamellar keratectomy was performed on 24 canine eyes. They were treated with an artificial tear (group C), prednisolone acetate (group P), onion extract (group O) and TGF beta1 (group T) three times per day from 7 to 28 days after the surgery. Corneal haze occurred on the all eyes and was observed beginning 7 days after the surgery. The haze was significantly decreased in groups P and O from day 14 compared with the group C using the clinical (group P; P=0.021, group O; P=0.037) and objective evaluation method (group P; P=0.021, group O; P=0.039). In contrast, it was significantly increased in group T from day 14 compared with group C based on the clinical (P=0.002) and objective evaluation method (P<0.001). Subsequently, these eyes were enucleated after euthanasia, and immunohistochemistry with alpha-SMA antibodies was done. The total green intensity for alpha-SMA was significantly more expressed in group T and significantly less expressed in groups P and O than in group C. Onion extract could have potential as a therapeutic in preventing corneal haze development by suppressing the differentiation of fibroblasts into myofibroblasts. PMID- 26607136 TI - Role of exosite binding modulators in the inhibition of Fxa by TFPI. AB - Tissue factor pathway inhibitor (TFPI) down-regulates the extrinsic coagulation pathway by inhibiting FXa and FVIIa. Both TFPI and FXa interact with several plasma proteins (e. g. prothrombin, FV/FVa, protein S) and non-proteinaceous compounds (e. g. phospholipids, heparin). It was our aim to investigate effects of ligands that bind to FXa and TFPI on FXa inhibition by full-length TFPI (designated TFPI) and truncated TFPI (TFPI1-150). Inhibition of FXa by TFPI and TFPI1-150 and effects of phospholipids, heparin, prothrombin, FV, FVa, and protein S thereon was quantified from progress curves of conversion of the FXa specific chromogenic substrate CS11-(65). Low concentrations negatively charged phospholipids (~10 uM) already maximally stimulated (up to 5- to 6-fold) FXa inhibition by TFPI. Unfractionated heparin at concentrations (0.2-1 U/ml) enhanced FXa inhibition by TFPI ~8-fold, but impaired inhibition at concentrations > 1 U/ml. Physiological protein S and FV concentrations both enhanced FXa inhibition by TFPI 2- to 3-fold. In contrast, thrombin-activated FV (FVa) impaired the ability of TFPI to inhibit FXa. FXa inhibition by TFPI1-150 was not affected by FV, FVa, protein S, phospholipids and heparin. TFPI potently inhibited FXa-catalysed prothrombin activation in the absence of FVa, but hardly inhibited prothrombin activation in the presence of thrombin-activated FVa. In conclusion, physiological concentrations TFPI (0.25-0.5 nM TFPI) inhibit FXa with a t1/2 between 3-15 minutes. Direct FXa inhibition by TFPI is modulated by physiological concentrations prothrombin, FV, FVa, protein S, phospholipids and heparin indicating the importance of these modulators for the in vivo anticoagulant activity of TFPI. PMID- 26607137 TI - Engineered porphyrin loaded core-shell nanoparticles for selective sonodynamic anticancer treatment. AB - AIM: Porphyrin-loaded core-shell nanoparticles have been engineered for use as in vivo sonosensitizing systems, radio-tracers or magnetic resonance (MR) imaging agents, which may be suitable for the selective treatment of solid tumors and imaging analyses. MATERIALS & METHODS: Polymethyl methacrylate nanoparticles (PMMANPs) have been either loaded with meso-tetrakis (4-sulphonatophenyl) porphyrin (TPPS) for sonodynamic anticancer treatment, with (64)Cu-TPPS for positron emission tomography biodistribution studies or with Mn(III)-TPPS for MR tumor accumulation evaluation. RESULTS: PMMANPs are easily functionalized with negatively charged molecules and show favorable biodistribution. In vivo TPPS PMMANPs have demonstrated shock wave responsiveness in a Mat B III syngeneic rat breast cancer model as measured by MR analyses of pre- and post-treatment tumor volumes. CONCLUSION: TPPS-PMMANPs are a multimodal system which can efficiently induce in vivo sonodynamic anticancer activity. PMID- 26607138 TI - Unexpected multiple activated steps in the excited state decay of some bis(phenylethynyl)-fluorenes and -anthracenes. AB - The temperature effect on the photophysical parameters of four acetylene derivatives [bis(phenylethynyl)-anthracenes and -fluorenes with substituents of different electron acceptor efficiencies] has been investigated by absorption and emission spectroscopy, using stationary and pulsed (ns/fs resolution) techniques. The nature of the central nucleus (anthracene or fluorene) and the peripheral electron-withdrawing group (nitro or formyl) strongly affect the deactivation of the excited states of these push-pull molecules. In some cases the study evidenced an interesting role of two activated steps in the deactivation of the excited singlet state, namely an activated inter-system crossing to an upper triplet state of n,pi* nature (previously hypothesized on the basis of TD-DFT calculations) and a sort of activated internal conversion, discussed also on the basis of maximum entropy method analysis of the fluorescence decay data. Nicely, an efficient ISC was found for the fluorene-derivatives where small energy gaps between S1 (pi,pi*) and Tn (n,pi*) states had been calculated while no activated ISC was evidenced in the case of anthryl-derivatives where higher S1-Tn energy gaps are expected. A peculiar temperature effect for a fluorene-derivative was pointed out and also explained on the basis of quantum-mechanical calculations at the DFT level taking into account the solvation effects by means of the conductor like polarizable continuum model CPCM. The presence of dual emission, at first evidenced by a shoulder in the emission spectrum of the fluorene-derivative featuring a peripheral formyl group in dichloromethane at low temperatures, was nicely confirmed by femtosecond up-conversion measurements at room temperature. PMID- 26607139 TI - SPECT of Transplanted Islets of Langerhans by Dopamine 2 Receptor Targeting in a Rat Model. AB - Pancreatic islet transplantation can be a more permanent treatment for type 1 diabetes compared to daily insulin administration. Quantitative and longitudinal noninvasive imaging of viable transplanted islets might help to further improve this novel therapy. Since islets express dopamine 2 (D2) receptors, they could be visualized by targeting this receptor. Therefore, the D2 receptor antagonist based tracer [(125/123)I][IBZM] was selected to visualize transplanted islets in a rat model. BZM was radioiodinated, and the labeling was optimized for position 3 of the aromatic ring. [(125)I]-3-IBZM was characterized in vitro using INS-1 cells and isolated islets. Subsequently, 1,000 islets were transplanted in the calf muscle of WAG/Rij rats and SPECT/CT images were acquired 6 weeks after transplantation. Finally, the graft containing muscle was dissected and analyzed immunohistochemically. Oxidative radioiodination resulted in 3 IBZM isomers with different receptor affinities. The use of 0.6 mg/mL chloramine-T hydrate resulted in high yield formation of predominantly [(125)I]-3-IBZM, the isomer harboring the highest receptor affinity. The tracer showed D2 receptor mediated binding to isolated islets in vitro. The transplant could be visualized by SPECT 6 weeks after transplantation. The transplants could be localized in the calf muscle and showed insulin and glucagon expression, indicating targeting of viable and functional islets in the transplant. Radioiodination was optimized to produce high yields of [(125)I]-3-IBZM, the isomer showing optimal D2R binding. Furthermore, [(123)I]IBZM specifically targets the D2 receptors on transplanted islets. In conclusion, this tracer shows potential for noninvasive in vivo detection of islets grafted in the muscle by D2 receptor targeting. PMID- 26607135 TI - Sub-Saharan African migrants living with HIV acquired after migration, France, ANRS PARCOURS study, 2012 to 2013. AB - We estimated the proportion of migrants from sub-Saharan Africa who acquired human immunodeficiency virus (HIV) while living in France. Life-event and clinical information was collected in 2012 and 2013 from a random sample of HIV infected outpatients born in sub-Saharan Africa and living in the Paris region. We assumed HIV infection in France if at least one of the following was fulfilled: (i) HIV diagnosis at least 11 years after arrival in France, (ii) at least one negative HIV test in France, (iii) sexual debut after arrival in France. Otherwise, time of HIV infection was based on statistical modelling of first CD4(+) T-cell count; infection in France was assumed if more than 50% (median scenario) or more than 95% (conservative scenario) of modelled infection times occurred after migration. We estimated that 49% of 898 HIV-infected adults born in sub-Saharan Africa (95% confidence interval (CI): 45-53) in the median and 35% (95% CI: 31-39) in the conservative scenario acquired HIV while living in France. This proportion was higher in men than women (44% (95% CI: 37-51) vs 30% (95% CI: 25-35); conservative scenario) and increased with length of stay in France. These high proportions highlight the need for improved HIV policies targeting migrants. PMID- 26607147 TI - Comparison of congenital pulmonary airway malformation volume ratios calculated by ultrasound and magnetic resonance imaging. AB - OBJECTIVE: To compare congenital pulmonary airway malformation (CPAM) volume to head circumference ratios (CVRs) determined by different imaging modalities and calculation techniques. METHODS: Fetal thoracic lesion images by ultrasound (US) and magnetic resonance imaging (MRI) were retrospectively reviewed and the CVRs were calculated. The CVR(US) was determined by the standard method. The CVR(MRI) was calculated from T2-weighted sequences (HASTE/SSH-TSE) in two ways, dimensional measurements analogous to US technique (MRI-D) and by using a MRI software calculated volume (MRI-V). CVR values between methods were compared using Wilcoxon matched-pairs signed-rank testing, Bland-Altman analyses, and Spearman correlations. RESULTS: Appropriate images were available to compare CVR(US) to CVR(MRI-D) for 20 patients and CVR(US) to CVR(MRI-V) for 18 patients. There were no significant differences in CVR values between modalities. By Bland Altman analyses, the CVR measurements were largely within the limits of agreement: 18 of 20 for CVR(MRI-D) and 17 of 18 for CVR(MRI-V), with a slight bias towards larger measurements by MRI. CONCLUSIONS: Though values varied between modalities for individual patients, there was no systematic difference in CVRs determined by US or MRI. Fetal prognostic category for CPAMs did not change based on MRI in any patient in this series. PMID- 26607148 TI - Proposed three-dimensional model of the orbit and relevance to orbital fracture repair. AB - PURPOSE: To describe the relationship of the orbital rim and depth in Far Eastern skulls by anatomical study, using morphometry to yield an octagonal three dimensional model of the orbit. METHODS: Forty-one orbits of 21 Far Eastern skulls from the Department of Anatomy of St George's, University of London were included in this study. A morphometric study was conducted, measuring between eight reproducible orbital rim landmarks to yield perimeters, and from these landmarks to the optic canal to yield orbital depth. Orbital height and width were also recorded. Results were statistically analysed to look for evidence of gender variation or laterality before comparison with those from other ethnicities. The authors then present a method for three-dimensional description of the orbit. RESULTS: 67 % of orbits were male. Orbital height and width were significantly greater in males (34.6 +/- 2.0 and 39.4 +/- 1.7, vs. 32.5 +/- 2.3 and 37.2 +/- 2.4 mm). Orbital perimeter tended towards being larger in males (126.3 vs. 122.2 mm, p = 0.05), as was the angle between medial and lateral walls (50.1 degrees +/- 2.0 degrees , vs. 47.9 degrees +/- 3.0 degrees ). CONCLUSION: This study has proposed a new method for describing the orbit using three dimensional measurements, yielding clinically useful morphometric data. These results and model have applications in surgical navigation of the orbit, repair of fractures, and prediction of post-traumatic or surgical enophthalmos. PMID- 26607149 TI - Assessing the prevalence and clinical relevance of positive abdominal and pelvic CT findings in senior patients presenting to the emergency department. AB - The purpose of our study was to retrospectively evaluate the prevalence and clinical relevance of positive abdominal and pelvic CT findings for patients 65 years of age and older, when compared with all other scanned adult Emergency Department (ED) patients, at a single tertiary care hospital. Our hypothesis was that there is an increased prevalence and clinical relevance of positive abdominal/pelvic CT findings in senior patients. A research ethics board-approved retrospective review of all adult patients who underwent an emergency CT of the abdomen and pelvis for acute nontraumatic abdominal and/or pelvic signs and symptoms was performed. Two thousand one hundred two patients between October 1, 2011, and September 30, 2013, were reviewed. Six hundred thirty-one patients were included in the <65 group (298 men and 333 women; mean age 46, age range 18-64), and 462 were included in the >65 group (209 men and 253 women; mean age 77.6, age range 65-99). Overall, there were more positive CT findings for patients <65 (389 positive cases, 61.6 %) compared with the >65 group (257 positive cases, 55.6 %), which was a statistically significant difference (p < 0.03). Moreover, with the exception of complicated appendicitis cases, which were more common in the >65 group, there were no statistically significant differences in the clinical/surgical relevance of the positive CT findings between the two groups. The findings of our retrospective study therefore refute our hypothesis that there is an increased prevalence of positive abdominal CT findings in patients >65. This may be related to ED physicians at our institution being more hesitant to order CT examinations for the younger population, presumably due to radiation concerns. However, older patients in our series were more likely to present with complicated appendicitis, and a lower threshold for ordering CT examinations of the abdomen and pelvis in this patient population should therefore be considered. PMID- 26607151 TI - Pure Progressive Ataxia and Palatal Tremor (PAPT) Associated with a New Polymerase Gamma (POLG) Mutation. AB - Progressive ataxia with palatal tremor (PAPT) is a syndrome caused by cerebellar and brainstem lesions involving the dentato-rubro-olivary tract and associated with hypertrophic olivary degeneration. Etiologies include acquired posterior fossa lesions (e.g. tumors, superficial siderosis, and inflammatory diseases) and genetic disorders, such as glial fibrillary acidic protein (GFAP) and polymerase gamma (POLG) mutations. We describe the case of a 52-year-old man who developed pure progressive ataxia and palatal tremor. Genetic analysis has shown that he is compound heterozygote for a known pathogenic (W748S) and a novel POLG variant (I1185N). Patients with POLG recessive mutations usually manifest a more complex clinical picture, including polyneuropathy and epilepsy; our case emphasizes the need to consider a genetic origin in a seemingly sporadic and pure PAPT. PMID- 26607150 TI - Deletion of the GluRdelta2 Receptor in the Hotfoot Mouse Mutant Causes Granule Cell Loss, Delayed Purkinje Cell Death, and Reductions in Purkinje Cell Dendritic Tree Area. AB - Recent studies have found that in the cerebellum, the delta2 glutamate receptor (GluRdelta2) plays a key role in regulating the differentiation of parallel fiber Purkinje synapses and mediating key physiological functions in the granule cell Purkinje cell circuit. In the hotfoot mutant or GluRdelta2 knockout mice, the absence of GluRdelta2 expression results in impaired motor-related tasks, ataxia, and disruption of long-term depression at parallel fiber-Purkinje cell synapses. The goal of this study was to determine the long-term consequences of deletion of GluRdelta2 expression in the hotfoot mutant (GluRdelta2 ho/ho ) on Purkinje and granule cell survival and Purkinje cell dendritic differentiation. Quantitative estimates of Purkinje and granule cell numbers in 3-, 12-, and 20-month-old hotfoot mutants and wild-type controls showed that Purkinje cell numbers are within control values at 3 and 12 months in the hotfoot mutant but reduced by 20 % at 20 months compared with controls. In contrast, the number of granule cells is significantly reduced from 3 months onwards in GluRdelta2 ho/ho mutant mice compared to wild-type controls. Although the overall structure of Purkinje cell dendrites does not appear to be altered, there is a significant 27 % reduction in the cross-sectional area of Purkinje cell dendritic trees in the 20-month-old GluRdelta2 ho/ho mutants. The interpretation of the results is that the GluRdelta2 receptor plays an important role in the long-term organization of the granule-Purkinje cell circuit through its involvement in the regulation of parallel fiber-Purkinje cell synaptogenesis and in the normal functioning of this critical cerebellar circuit. PMID- 26607153 TI - Insulin sensitizes FGF21 in glucose and lipid metabolisms via activating common AKT pathway. AB - Previous studies reveal that fibroblast growth factor 21 (FGF21) sensitizes insulin to achieve a synergy in regulating glucose metabolism. Here, we report that insulin sensitizes FGF21 in regulating both glucose and lipid metabolisms. db/db diabetic mice were subcutaneously administrated once a day for 6 weeks. Effective dose of insulin (1 U) could control blood glucose level of the db/db mice for maximum of 2 h, increased the body weight of the db/db mice and did not improve serum lipid parameters. In contrast, effective dose of FGF21 (0.5 mg/kg) could maintain blood glucose of the db/db mice at normal level for at least 24 h, repressed the weight gain of the mice and significantly improved lipid parameters. Ineffective doses of FGF21 (0.125 mg/kg) and insulin had no effect on blood glucose level of the db/db mice after 24 h administration, body weight or lipid parameters. However, combination of the two ineffective doses could maintain blood glucose level of the db/db mice for at least 24 h, suppressed weight gain and significantly improved lipid parameters. These results suggest that insulin sensitizes FGF21 in regulating both glucose and lipid metabolism. The results aimed to study the molecular basis of FGF21 sensitization indicates that combination of the two ineffective doses increased the mRNA expression of glut1, glut4, beta-Klotho, sirt1, pgc-1alpha, ucp-1 and AKT phosphorylation, decreased fasn. The results demonstrate that insulin sensitizes FGF21 through elevating the phosphorylation of common gene Akt and amplifying FGF21 downstream signaling, including increasing expression of glut1 sirt1, pgc-1alpha, ucp-1, and decreasing fasn expression. In summary, we reports herein for the first time that insulin sensitizes FGF21 to achieve a synergy in regulating glucose and lipid metabolism. Along with previous studies, we conclude that the synergistic effect between FGF21 and insulin is realized through mutual sensitization. PMID- 26607154 TI - Acid deposition in the Athabasca Oil Sands Region: a policy perspective. AB - Industrial emissions of sulphur (S) and nitrogen (N) to the atmosphere associated with the oil sands industry in north-eastern Alberta are of interest as they represent the largest localized source in Canada (with potential for future growth) and the region features acid-sensitive upland terrain. Existing emission management policy for the Regional Municipality of Wood Buffalo, where the industry is located, is based on a time-to-effect approach that relies on dynamic model simulations of temporal changes in chemistry and features highly protective chemical criteria. In practice, the policy is difficult to implement and it is unlikely that a scientifically defensible estimate of acidification risk can be put forward due to the limitations primarily associated with issues of scale, chemical endpoint designation (selection of chemical limit for ecosystem protection from acidification) and data availability. A more implementable approach would use a steady-state critical load (CL) assessment approach to identify at-risk areas. The CL assessment would consider areas of elevated acid deposition associated with oil sands emissions rather than targeted political jurisdictions. Dynamic models should only be (strategically) used where acidification risk is identified via CL analysis, in order to characterize the potential for acidification-induced changes that can be detrimental to sensitive biota within the lifespan of the industry. PMID- 26607152 TI - Aggressive tumor growth and clinical evolution in a patient with X-linked acro gigantism syndrome. AB - X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 * 23.9 * 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 * 58.1 * 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome. PMID- 26607155 TI - [A software tool for pure-tone audiometry: Classification of audiograms for inclusion of patients in clinical trials. German version]. AB - OBJECTIVE: Selecting subjects for clinical trials on hearing loss therapies relies on the patient meeting the audiological inclusion criteria. In studies on the treatment of idiopathic sudden sensorineural hearing loss, the patient's acute audiogram is usually compared with a previous audiogram, the audiogram of the non-affected ear, or a normal audiogram according to an ISO standard. Generally, many more patients are screened than actually fulfill the particular inclusion criteria. The inclusion criteria often require a calculation of pure tone averages, selection of the most affected frequencies, and calculation of hearing loss differences. MATERIALS AND METHODS: A software tool was developed to simplify and accelerate this inclusion procedure for investigators to estimate the possible recruitment rate during the planning phase of a clinical trial and during the actual study. This tool is Microsoft Excel-based and easy to modify to meet the particular inclusion criteria of a specific clinical trial. The tool was retrospectively evaluated on 100 patients with acute hearing loss comparing the times for classifying automatically and manually. The study sample comprised 100 patients with idiopathic sudden sensorineural hearing loss. RESULTS AND CONCLUSION: The age- and sex-related normative audiogram was calculated automatically by the tool and the hearing impairment was graded. The estimated recruitment rate of our sample was quickly calculated. Information about meeting the inclusion criteria was provided instantaneously. A significant reduction of 30% in the time required for classifying (30 s per patient) was observed. PMID- 26607156 TI - A software tool for pure-tone audiometry. Classification of audiograms for inclusion of patients in clinical trials. English version. AB - OBJECTIVE: Selecting subjects for clinical trials on hearing loss therapies relies on the patient meeting the audiological inclusion criteria. In studies on the treatment of idiopathic sudden sensorineural hearing loss, the patient's acute audiogram is usually compared with a previous audiogram, the audiogram of the non-affected ear, or a normal audiogram according to an ISO standard. Generally, many more patients are screened than actually fulfill the particular inclusion criteria. The inclusion criteria often require a calculation of pure tone averages, selection of the most affected frequencies, and calculation of hearing loss differences. MATERIALS AND METHODS: A software tool was developed to simplify and accelerate this inclusion procedure for investigators to estimate the possible recruitment rate during the planning phase of a clinical trial and during the actual study. This tool is Microsoft Excel-based and easy to modify to meet the particular inclusion criteria of a specific clinical trial. The tool was retrospectively evaluated on 100 patients with acute hearing loss comparing the times for classifying automatically and manually. The study sample comprised 100 patients with idiopathic sudden sensorineural hearing loss. RESULTS AND CONCLUSION: The age- and sex-related normative audiogram was calculated automatically by the tool and the hearing impairment was graded. The estimated recruitment rate of our sample was quickly calculated. Information about meeting the inclusion criteria was provided instantaneously. A significant reduction of 30 % in the time required for classifying (30 s per patient) was observed. PMID- 26607157 TI - Sex-specific differences in risk factors for sarcopenia amongst community dwelling older adults. AB - With considerable variation including potential sex-specific differential rate of skeletal muscle loss, identifying modifiable factors for sarcopenia will be pivotal to guide targeted interventions. This study seeks to identify clinical and biological correlates of sarcopenia in community-dwelling older adults, with emphasis on the role of anabolic and catabolic stimuli, and special reference to gender specificity. In this cross-sectional study involving 200 community dwelling and functionally independent older adults aged >=50 years, sarcopenia was defined using the Asian Working Group for Sarcopenia criteria. Comorbidities, cognitive and functional performance, physical activity and nutritional status were routinely assessed. Biochemical parameters included haematological indices, lipid panel, vitamin D level, anabolic hormones [insulin-like growth factor-1 (IGF-1), free testosterone (males only)] and catabolic markers [inflammatory markers (interleukin-6, C-reactive protein) and myostatin]. Multiple logistic regression was performed to identify independent predictors for sarcopenia. Age was associated with sarcopenia in both genders. Malnutrition conferred significantly higher odds for sarcopenia in women (OR = 5.71, 95% CI 1.13 28.84.44, p = 0.035) while higher but acceptable range serum triglyceride was protective in men (OR = 0.05, 95% CI 0.00-0.52, p = 0.012). Higher serum myostatin independently associated with higher odds for sarcopenia in men (OR = 1.11, 95% CI 1.00-1.24, p = 0.041). Serum IGF-1 was significantly lower amongst female sarcopenic subjects, with demonstrable trend for protective effect against sarcopenia in multiple regression models, such that each 1 ng/ml increase in IGF 1 was associated with 1% decline in odds of sarcopenia in women (p = 0.095). Our findings support differential pathophysiological mechanisms for sarcopenia that, if corroborated, may have clinical utility in guiding sex-specific targeted interventions for community-dwelling older adults. PMID- 26607158 TI - A Comparative Study Between Modified Starch and Xanthan Gum Thickeners in Post Stroke Oropharyngeal Dysphagia. AB - Thickeners are used in post-stroke oropharyngeal dysphagia (OD) as a compensatory therapeutic strategy against aspirations. To compare the therapeutic effects of modified starch (MS) and xanthan gum (XG) thickeners on swallow safety and efficacy in chronic post-stroke OD patients using clinical and videofluoroscopic (VFS) assessment. Patients were studied by clinical assessment (volume-viscosity swallow test, V-VST) and VFS using 3 volumes (5, 10, 20 mL) and 3 viscosities (liquid, nectar and spoon thick), comparing MS and XG. We studied 122 patients (46MS, 76XG). (A) V-VST showed that both thickeners similarly improved safety of swallow. Prevalence of safe swallowing significantly increased with enhanced viscosity (P < 0.001 vs liquid), MS: 47.83 % at liquid, 84.93 % at nectar and 92.96 % at spoon thick; XG: 55.31 % at liquid, 77.78 % at nectar and 97.84 % at spoon thick. Patients on MS reported higher prevalence of pharyngeal residue at spoon-thick viscosities. (B) VFS: increasing bolus viscosity with either thickener increased prevalence of safe swallows (P < 0.001 vs liquid), MS: 30.25 % liquid, 61.07 % nectar and 92.64 % spoon thick; XG: 29.12 % liquid, 71.30 % nectar and 89.91 % spoon thick. Penetration-aspiration scale score was significantly reduced with increased viscosity with both thickeners. MS increased oral and pharyngeal residues at nectar and spoon-thick viscosities but XG did not. Timing of airway protection mechanisms and bolus velocity were not affected by either thickener. Increasing bolus viscosity with MS and XG thickeners strongly and similarly improved safety of swallow in chronic post-stroke OD by a compensatory mechanism; in contrast only MS thickeners increased oropharyngeal residue. PMID- 26607159 TI - Systematic Review: Non-Instrumental Swallowing and Feeding Assessments in Pediatrics. AB - There is a high incidence of parental reporting of abnormal swallowing and feeding function and the negative impacts thereof on children. As such there is a need for well validated assessments in the area of pediatric swallowing and feeding. While instrumental assessments are well validated, there is limited information available to guide the selection and use of non-instrumental assessments for swallowing and feeding function. The aim of this study was to identify and report on non-instrumental assessments available to clinicians for pediatric swallowing and/or feeding function in order to support clinical decision making. A systematic literature search was performed by two independent reviewers using Medline and Embase databases, to find non-instrumental assessments for pediatric swallowing and feeding function. Published assessments were also included in the study by searching well-known publishers and relevant feeding and swallowing textbooks. Assessments were summarized and evaluated according to respondent type, target populations, assessment design, domains of assessment and scoring. Thirty assessments were included in the final review. All assessments had either caregiver or clinician respondents. There was high variability in target populations, assessment designs and areas of assessment. Twenty-four of the 30 assessments did not provide instruction for scoring or interpreting scores. There is high variability among the many assessments available to clinicians in the area of feeding and swallowing function in pediatrics. There appears to be limited information available on the validity and reliability of these assessments. Thus, most assessments need to be used with caution. Further research is needed to evaluate the psychometric properties of the assessments. PMID- 26607160 TI - The Effect of the Cervical Orthosis on Swallowing Physiology and Cervical Spine Motion During Swallowing. AB - Cervical orthosis is used to immobilize the neck in various disorders such as trauma and post-operation. However, it is still uncertain how cervical orthosis restricts the degree of movement of the cervical spine during swallowing and how they affect swallowing physiology. The purpose of this study was to evaluate these issues using the Philadelphia((r)) Collar. We conducted videofluorography of swallowing in 39 healthy subjects (23 men, 16 women; mean age of 34.3 years) with and without cervical orthosis. To compare the two conditions regarding the cervical spine motion, we determined the angular and positional changes of the occipital bone (C0) and each cervical vertebra (C1-C7) from the oral phase to the pharyngeal phase. Similarly, to compare swallowing physiology, we assessed the start and end times and the durations of soft palate elevation, rapid hyoid anterosuperior movement, epiglottis inversion, closure of the laryngeal vestibule, and pharyngoesophageal segment (PES) opening. Finally, we compared the transit times of contrast agent in the two conditions. The respective extensions of C1, C2, and C3 were 0.31 degrees , 0.07 degrees , and 0.05 degrees (mean) with cervical orthosis, and the respective flexions of C1, C2, and C3 were 0.98 degrees , 1.42 degrees , and 0.85 degrees (mean) without. These results suggested that cervical orthosis restricted the flexion of C1-C3. Analysis of swallowing physiology revealed that the average durations of hyoid anterosuperior elevation, epiglottic inversion, and PES opening were prolonged by 0.09, 0.19, and 0.05 s, respectively. In conclusion, the cervical orthosis restricted the movement of the cervical spine during swallowing and changed swallowing physiology. PMID- 26607161 TI - M. tuberculosis T Cell Epitope Analysis Reveals Paucity of Antigenic Variation and Identifies Rare Variable TB Antigens. AB - Pathogens that evade adaptive immunity typically exhibit antigenic variation. By contrast, it appears that although the chronic human tuberculosis (TB)-causing pathogen Mycobacterium tuberculosis needs to counter host T cell responses, its T cell epitopes are hyperconserved. Here we present an extensive analysis of the T cell epitopes of M. tuberculosis. We combined population genomics with experimental immunology to determine the number and identity of T cell epitope sequence variants in 216 phylogenetically diverse strains of M. tuberculosis. Antigen conservation is indeed a hallmark of M. tuberculosis. However, our analysis revealed a set of seven variable antigens that were immunogenic in subjects with active TB. These findings suggest that M. tuberculosis uses mechanisms other than antigenic variation to evade T cells. T cell epitopes that exhibit sequence variation may not be subject to the same evasion mechanisms, and hence vaccines that include such variable epitopes may be more efficacious. PMID- 26607162 TI - Malaria Sporozoites Traverse Host Cells within Transient Vacuoles. AB - Plasmodium sporozoites are deposited in the host skin by Anopheles mosquitoes. The parasites migrate from the dermis to the liver, where they invade hepatocytes through a moving junction (MJ) to form a replicative parasitophorous vacuole (PV). Malaria sporozoites need to traverse cells during progression through host tissues, a process requiring parasite perforin-like protein 1 (PLP1). We find that sporozoites traverse cells inside transient vacuoles that precede PV formation. Sporozoites initially invade cells inside transient vacuoles by an active MJ-independent process that does not require vacuole membrane remodeling or release of parasite secretory organelles typically involved in invasion. Sporozoites use pH sensing and PLP1 to exit these vacuoles and avoid degradation by host lysosomes. Next, parasites enter the MJ-dependent PV, which has a different membrane composition, precluding lysosome fusion. The malaria parasite has thus evolved different strategies to evade host cell defense and establish an intracellular niche for replication. PMID- 26607163 TI - A review of blinatumomab, a novel immunotherapy. AB - Blinatumomab is a novel bispecific CD19-directed CD3 T-cell engager recently approved for the treatment of relapsed or refractory Ph-negative acute lymphoblastic leukemia in adults. The drug was approved after a phase II trial in adults with relapsed/refractory disease demonstrated complete remission or hematologic complete remission in 43% of patients within two treatment cycles, of which 40% went on to receive an allogeneic hematopoietic stem cell transplant. In a long-term survival analysis of patients with minimal residual disease after chemotherapy, hematologic relapse-free survival was estimated at 61% at a median of 33 months after blinatumomab. Nine patients underwent hematopoietic stem cell transplant, and six patients remained in complete remission without hematopoietic stem cell transplant or further therapy. Limited data in relapsed pediatric acute lymphoblastic leukemia are reviewed. Blinatumomab carries boxed warnings for neurotoxicity and cytokine release syndrome, which may be serious and lead to treatment interruption and discontinuation. Clinical controversies with blinatumomab include use in patients with Ph-positive acute lymphoblastic leukemia, dosing in underweight adults, and the optimal management of cytokine release syndrome. Oncology pharmacists must be aware of detailed preparation and administration procedures required for safe use of blinatumomab. Clinical trials are ongoing in the first-line setting for patients with Ph-negative acute lymphoblastic leukemia, in Ph-positive acute lymphoblastic leukemia, and other B cell malignancies. PMID- 26607164 TI - John Tooke: The hunt for brown trout. PMID- 26607165 TI - A sudden cardiac asystole and cardiopulmonary resuscitation of trigeminocardiac reflex during retrosigmoid approach surgery. PMID- 26607166 TI - Comment on: Hemidystonia caused by frontal cortical infarction. PMID- 26607167 TI - Distinct compositions of free-living, particle-associated and benthic communities of the Roseobacter group in the North Sea. AB - The Roseobacter group is one of the predominant lineages in the marine environment. While most investigations focus on pelagic roseobacters, the distribution and metabolic potential of benthic representatives is less understood. In this study, the diversity of the Roseobacter group was characterized in sediment and water samples along the German/Scandinavian North Sea coast by 16S rRNA gene analysis and cultivation-based methods. Molecular analysis indicated an increasing diversity between communities of the Roseobacter group from the sea surface to the seafloor and revealed distinct compositions of free-living and attached fractions. Culture media containing dimethyl sulfide (DMS), dimethyl sulfonium propionate (DMSP) or dimethyl sulfoxide (DMSO) stimulated growth of roseobacters showing highest most probable numbers (MPN) in DMSO-containing dilutions of surface sediments (2.1 * 10(7) roseobacters cm(-3)). Twenty roseobacters (12 from sediments) were isolated from DMSP- and DMS containing cultures. Sequences of the isolates represented 0.04% of all Bacteria and 4.7% of all roseobacters in the pyrosequencing dataset from sediments. Growth experiments with the isolate Shimia sp. SK013 indicated that benthic roseobacters are able to switch between aerobic and anaerobic utilization of organic sulfur compounds. This response to changing redox conditions might be an adaptation to specific environmental conditions on particles and in sediments. PMID- 26607168 TI - Weak Van der Waals Stacking, Wide-Range Band Gap, and Raman Study on Ultrathin Layers of Metal Phosphorus Trichalcogenides. AB - 2D semiconducting metal phosphorus trichalcogenides, particularly the bulk crystals of MPS3 (M = Fe, Mn, Ni, Cd and Zn) sulfides and MPSe3 (M = Fe and Mn) selenides, have been synthesized, crystallized and exfoliated into monolayers. The Raman spectra of monolayer FePS3 and 3-layer FePSe3 show the strong intralayer vibrations and structural stability of the atomically thin layers under ambient condition. The band gaps can be adjusted by element choices in the range of 1.3-3.5 eV. The wide-range band gaps suggest their optoelectronic applications in a broad wavelength range. The calculated cleavage energies of MPS3 are smaller than that of graphite. Therefore, the monolayers used for building of heterostructures by van der Waals stacking could be considered as the candidates for artificial 2D materials with unusual ferroelectric and magnetic properties. PMID- 26607169 TI - High-Performance Wrap-Gated InGaAs Nanowire Field-Effect Transistors with Sputtered Dielectrics. AB - Although wrap-gated nanowire field-effect-transistors (NWFETs) have been explored as an ideal electronic device geometry for low-power and high-frequency applications, further performance enhancement and practical implementation are still suffering from electron scattering on nanowire surface/interface traps between the nanowire channel and gate dielectric as well as the complicated device fabrication scheme. Here, we report the development of high-performance wrap-gated InGaAs NWFETs using conventional sputtered Al2O3 layers as gate dielectrics, instead of the typically employed atomic layer deposited counterparts. Importantly, the surface chemical passivation of NW channels performed right before the dielectric deposition is found to significantly alleviate plasma induced defect traps on the NW channel. Utilizing this passivation, the wrap-gated device exhibits superior electrical performances: a high ION/IOFF ratio of ~ 2 * 10(6), an extremely low sub-threshold slope of 80 mV/decade and a peak field-effect electron mobility of ~ 1600 cm(2)/(Vs) at VDS = 0.1 V at room temperature, in which these values are even better than the ones of state-of-the-art NWFETs reported so far. By combining sputtering and pre deposition chemical passivation to achieve high-quality gate dielectrics for wrap gated NWFETs, the superior gate coupling and electrical performances have been achieved, confirming the effectiveness of our hybrid approach for future advanced electronic devices. PMID- 26607170 TI - Morphogens: How to grow wings. PMID- 26607171 TI - A rice tonoplastic calcium exchanger, OsCCX2 mediates Ca2+/cation transport in yeast. AB - In plant cell, cations gradient in cellular compartments is maintained by synergistic action of various exchangers, pumps and channels. The Arabidopsis exchanger family members (AtCCX3 and AtCCX5) were previously studied and belong to CaCA (calcium cation exchangers) superfamily while none of the rice CCXs has been functionally characterized for their cation transport activities till date. Rice genome encode four CCXs and only OsCCX2 transcript showed differential expression under abiotic stresses and Ca(2+) starvation conditions. The OsCCX2 localized to tonoplast and suppresses the Ca(2+) sensitivity of K667 (low affinity Ca(2+) uptake deficient) yeast mutant under excess CaCl2 conditions. In contrast to AtCCXs, OsCCX2 expressing K667 yeast cells show tolerance towards excess Na(+), Li(+), Fe(2+), Zn(2+) and Co(2+) and suggest its ability to transport both mono as well as divalent cations in yeast. Additionally, in contrast to previously characterized AtCCXs, OsCCX2 is unable to complement yeast trk1trk2 double mutant suggesting inability to transport K(+) in yeast system. These finding suggest that OsCCX2 having distinct metal transport properties than previously characterized plant CCXs. OsCCX2 can be used as potential candidate for enhancing the abiotic stress tolerance in plants as well as for phytoremediation of heavy metal polluted soil. PMID- 26607173 TI - Reproducibility of a continuous ramp lower body negative pressure protocol for simulating hemorrhage. AB - Central hypovolemia elicited by application of lower body negative pressure (LBNP) has been used extensively to simulate hemorrhage in human subjects. Traditional LBNP protocols incorporate progressive steps in pressure held for specific time intervals. The aim of this study was to assess the reproducibility of applying continuous LBNP at a constant rate until presyncope to replicate actual bleeding. During two trials (>=4 weeks intervening), LBNP was applied at a rate of 3 mmHg/min in 18 healthy human subjects (12M; 6F) until the onset of presyncopal symptoms. Heart rate (HR), mean arterial pressure (MAP), stroke volume (SV), total peripheral resistance (TPR), mean middle and posterior cerebral artery velocities (MCAv, PCAv), and cerebral oxygen saturation (ScO2) were measured continuously. Time to presyncope (TTPS) and hemodynamic responses were compared between the two trials. TTPS (1649 +/- 98 sec vs. 1690 +/- 88 sec; P = 0.47 [t-test]; r = 0.77) and the subsequent magnitude of central hypovolemia (%Delta SV -54 +/- 4% vs. -53 +/- 4%; P = 0.55) were similar between trials. There were no statistically distinguishable differences at either baseline (P >= 0.17) or presyncope between trials for HR, MAP, TPR, mean MCAv, mean PCAv, or ScO2 (P >= 0.19). The rate of change from baseline to presyncope for all hemodynamic responses was also similar between trials (P >= 0.12). Continuous LBNP applied at a rate of 3 mmHg/min was reproducible in healthy human subjects, eliciting similar reductions in central blood volume and subsequent reflex hemodynamic responses. PMID- 26607172 TI - Electrophysiological properties of myocytes isolated from the mouse atrioventricular node: L-type ICa, IKr, If, and Na-Ca exchange. AB - The atrioventricular node (AVN) is a key component of the cardiac pacemaker conduction system. This study investigated the electrophysiology of cells isolated from the AVN region of adult mouse hearts, and compared murine ionic current magnitude with that of cells from the more extensively studied rabbit AVN. Whole-cell patch-clamp recordings of ionic currents, and perforated-patch recordings of action potentials (APs), were made at 35-37 degrees C. Hyperpolarizing voltage commands from -40 mV elicited a Ba(2+)-sensitive inward rectifier current that was small at diastolic potentials. Some cells (Type 1; 33.4 +/- 2.2 pF; n = 19) lacked the pacemaker current, If, whilst others (Type 2; 34.2 +/- 1.5 pF; n = 21) exhibited a clear If, which was larger than in rabbit AVN cells. On depolarization from -40 mV L-type Ca(2+) current, IC a,L, was elicited with a half maximal activation voltage (V0.5) of -7.6 +/- 1.2 mV (n = 24). IC a,L density was smaller than in rabbit AVN cells. Rapid delayed rectifier (IK r) tail currents sensitive to E-4031 (5 MUmol/L) were observed on repolarization to -40 mV, with an activation V0.5 of -10.7 +/- 4.7 mV (n = 8). The IK r magnitude was similar in mouse and rabbit AVN. Under Na-Ca exchange selective conditions, mouse AVN cells exhibited 5 mmol/L Ni-sensitive exchange current that was inwardly directed negative to the holding potential (-40 mV). Spontaneous APs (5.2 +/- 0.5 sec(-1); n = 6) exhibited an upstroke velocity of 37.7 +/- 16.2 V/s and ceased following inhibition of sarcoplasmic reticulum Ca(2+) release by 1 MUmol/L ryanodine, implicating intracellular Ca(2+) cycling in murine AVN cell electrogenesis. PMID- 26607174 TI - Challenging Regeneration to Transform Medicine. AB - The aging population in the U.S. and other developed countries has led to a large increase in the number of patients suffering from degenerative diseases. Transplantation surgery has been a successful therapeutic option for certain patients; however, the availability of suitable donor organs and tissues significantly limits the number of patients who can benefit from this approach. Regenerative medicine has witnessed numerous recent and spectacular advances, making the repair or replacement of dysfunctional organs and tissues an achievable goal. Public-private partnerships and government policies and incentives would further catalyze the development of universally available donor tissues, resulting in broad medical and economic benefits. This article describes a Regenerative Medicine Grand Challenge that the Alliance for Regenerative Medicine recently shared with the White House's Office of Science and Technology Policy in response to a White House call to action in scientific disciplines suggesting that the development of "universal donor tissues" should be designated as a Regenerative Medicine Grand Challenge. Such a designation would raise national awareness of the potential of regenerative medicine to address the unmet needs of many diseases and would stimulate the scientific partnerships and investments in technology needed to expedite this goal. Here we outline key policy changes and technological challenges that must be addressed to achieve the promise of a major breakthrough in the treatment of degenerative disease. A nationalized effort and commitment to develop universal donor tissues could realize this goal within 10 years and along the way result in significant innovation in manufacturing technologies. SIGNIFICANCE: Regenerative therapies, in which dysfunctional or degenerating cells, tissues, or organs are repaired or replaced, have the potential to cure chronic degenerative diseases. Such treatments are limited by a shortage of donor organs and tissues and the need for immune suppression to prevent rejection. This article proposes a 21st Century Grand Challenge that would address this significant medical need by coordinating a national effort to convene the multidisciplinary expertise needed to manufacture functional and engraftable cells, tissues, or organs that could be made available to any patient without significant risk of rejection-so-called universal donor tissues. PMID- 26607176 TI - Fitting Proportional Odds Model to Case-Control data with Incorporating Hardy Weinberg Equilibrium. AB - Genetic association studies have been proved to be an efficient tool to reveal the aetiology of many human complex diseases and traits. When the phenotype is binary, the logistic regression model is commonly employed to evaluate the association strength of the genetic variants predispose to human diseases because the maximum likelihood estimator of the odds ratio based on case-control data is equivalent to that from the same model by taking the data as being arisen prospectively. This equivalence does not hold for the proportional odds model and using it to analyze the case-control data directly often results in a substantial bias. Through putting a parameter of the minor allele frequency in the modified likelihood function under the condition that the Hardy-Weinberg equilibrium law holds within controls, a consistent estimator is obtained. On the basis of it, we construct a score test statistic to test whether the genetic variant is associated with the diseases. Simulation studies show that the proposed estimator has smaller mean squared error than the existing methods when the genetic effect size is away from zero and the proposed test statistic has a good control of type I error rate and is more powerful than the existing procedures. Application to 45 single nucleotide polymorphisms located in the region of TRAF1-C5 genes for the association with four-level anticyclic citrullinated protein antibody from Genetic Analysis Workshop 16 further demonstrates its performance. PMID- 26607175 TI - Human Periodontal Stem Cells Release Specialized Proresolving Mediators and Carry Immunomodulatory and Prohealing Properties Regulated by Lipoxins. AB - Unresolved inflammation and tissue destruction are underlying mechanisms of periodontitis, which is linked to dysregulated polymorphonuclear neutrophil (PMN) functions. Lipoxin A4 (LXA4) is a specialized proresolving lipid mediator (SPM) that dampens excessive inflammation, promotes resolution, and protects from leukocyte-mediated tissue damage. Human periodontal ligament stem cells (hPDLSCs) represent key players during tissue regeneration and may contribute to resolution of inflammation; thus, they may represent a promising tool in regenerative dentistry. In the present study, we investigated the actions of hPDLSCs on PMN apoptosis and antimicrobial functions, and determined the impact of LXA4 on hPDLSCs. hPDLSCs significantly reduced apoptosis and stimulated microbicidal activity of human PMNs, via both cell-cell interactions and paracrine mechanisms. Lipid mediator metabololipidomics analysis demonstrated that hPDLSCs biosynthesize SPMs, including resolvin D1, D2, D5, and D6; protectin D1; maresins; and LXB4; as well as prostaglandins D2, E2, and F2alpha. LXA4 significantly enhanced proliferation, migration, and wound healing capacity of hPDLSCs through the activation of its cognate receptor ALX/FPR2, expressed on hPDLSCs. Together, these results demonstrate that hPDLSCs modulate PMN functions, and provide the first evidence that stem cells generate SPM and that the LXA4 ALX/FPR2 axis regulates regenerative functions of hPDLSCs by a novel receptor mediated mechanism. SIGNIFICANCE: These findings uncovered unappreciated features of stem cells from the periodontal ligament, supporting the notion that these cells may act as master regulators of pathophysiological events through the release of mediators that promote the resolution of inflammation and bacterial killing. The study also demonstrated that it is possible to modulate important functions of periodontal stem cells using lipoxin A4, a potent endogenous stop signal of inflammation. Thus, this study revealed an unappreciated anti inflammatory proregenerative circuit that may be exploited to combat periodontal pathologies using resident stem cells. Moreover, the data may represent a more general template to explain the immunomodulatory functions of stem cells. PMID- 26607177 TI - A Case Study of Symptomatic Retroclival Ecchordosis Physaliphora: CT and MR Imaging. PMID- 26607178 TI - Smilax glabra Roxb targets Akt(p-Thr308) and inhibits Akt-mediated signaling pathways in SGC7901 cells. AB - BACKGROUND: Smilax glabra Roxb (SGR) as a novel anti-tumor agent has been paid attention in several types of cancer cells. However, the effect of SGR on SGC7901 cells has not been investigated. PURPOSE: We investigate the effect and potential mechanisms of SGR on SGC7901 cells in this study. METHODS: Three kinds of gastric cancer cell lines (BGC823, SGC7901 and MKN45) and one kind of human embryonic kidney cell line (HEK293) were exposed to varying concentrations of SRG. Then, we observed the effect of SRG on these cell lines and the changes on proliferation, invasion and apoptosis. Finally, we detected the signaling pathway in which SGR may involve. RESULTS: SGR effectively suppressed the proliferation of SGC7901 cell lines by inhibiting the phosphorylation of Akt (Thr308). Moreover, we found SGR could significantly induce SGC7901 cell lines apoptosis by inhibiting Akt(p Thr308)/Bad pathway and inhibit its migration and invasion partly by inhibiting Akt(p-Thr308)/MMPs pathway. DISCUSSION: SGR could effectively suppress the proliferation and invasion of SGC7901 cell lines by inhibiting the phosphorylation of Akt (Thr308) and its downstream relative pathways. CONCLUSION: SGR could effectively suppress the phosphorylation of Akt (Thr308) and then inhibit the proliferation and invasion of SGC7901 cell and enhance its apoptosis through Akt-mediated signaling pathways. PMID- 26607181 TI - Broadening the phenotypic spectrum of pathogenic LARP7 variants: two cases with intellectual disability, variable growth retardation and distinct facial features. AB - In 2012 Alazami et al. described a novel syndromic cause of primordial dwarfism with distinct facial features and severe intellectual disability. A homozygous frameshift mutation in LARP7, a chaperone of the noncoding RNA 7SK, was discovered in patients from a single consanguineous Saudi family. To date, only one additional patient has recently been described. To further delineate the phenotype associated with LARP7 mutations, we report two additional cases originating from the Netherlands and Saudi Arabia. The patients presented with intellectual disability, distinct facial features and variable short stature. We describe their clinical features and compare them with the previously reported patients. Both cases were identified by diagnostic whole-exome sequencing, which detected two homozygous pathogenic LARP7 variants: c.1091_1094delCGGT in the Dutch case and c.1045_1051dupAAGGATA in the Saudi Arabian case. Both variants are leading to frameshifts with introduction of premature stop codons, suggesting that loss of function is likely the disease mechanism. This study is an independent confirmation of the syndrome due to LARP7 depletion. Our cases broaden the associated clinical features of the syndrome and contribute to the delineation of the phenotypic spectrum of LARP7 mutations. PMID- 26607179 TI - Harpin Hpa1 Interacts with Aquaporin PIP1;4 to Promote the Substrate Transport and Photosynthesis in Arabidopsis. AB - Harpin proteins produced by plant-pathogenic Gram-negative bacteria are the venerable player in regulating bacterial virulence and inducing plant growth and defenses. A major gap in these effects is plant sensing linked to cellular responses, and plant sensor for harpin Hpa1 from rice bacterial blight pathogen points to plasma membrane intrinsic protein (PIP). Here we show that Arabidopsis AtPIP1;4 is a plasma membrane sensor of Hpa1 and plays a dual role in plasma membrane permeability of CO2 and H2O. In particular, AtPIP1;4 mediates CO2 transport with a substantial contribute to photosynthesis and further increases this function upon interacting with Hpa1 at the plasma membrane. As a result, leaf photosynthesis rates are increased and the plant growth is enhanced in contrast to the normal process without Hpa1-AtPIP1;4 interaction. Our findings demonstrate the first case that plant sensing of a bacterial harpin protein is connected with photosynthetic physiology to regulate plant growth. PMID- 26607180 TI - Coevolution of genes and languages and high levels of population structure among the highland populations of Daghestan. AB - As a result of the combination of great linguistic and cultural diversity, the highland populations of Daghestan present an excellent opportunity to test the hypothesis of language-gene coevolution at a fine geographic scale. However, previous genetic studies generally have been restricted to uniparental markers and have not included many of the key populations of the region. To improve our understanding of the genetic structure of Daghestani populations and to investigate possible correlations between genetic and linguistic variation, we analyzed ~550,000 autosomal single nucleotide polymorphisms, phylogenetically informative Y chromosome markers and mtDNA haplotypes in 21 ethnic Daghestani groups. We found high levels of population structure in Daghestan consistent with the hypothesis of long-term isolation among populations of the highland Caucasus. Highland Daghestani populations exhibit extremely high levels of between population diversity for all genetic systems tested, leading to some of the highest FST values observed for any region of the world. In addition, we find a significant positive correlation between gene and language diversity, suggesting that these two aspects of human diversity have coevolved as a result of historical patterns of social interaction among highland farmers at the community level. Finally, our data are consistent with the hypothesis that most Daghestanian-speaking groups descend from a common ancestral population (~6000 6500 years ago) that spread to the Caucasus by demic diffusion followed by population fragmentation and low levels of gene flow. PMID- 26607182 TI - Merkel Cell Carcinoma Presenting as Subcutaneous Breast Masses: An Uncommon Presentation of a Rare Neuroendocrine Neoplasm. PMID- 26607184 TI - Pelvic Actinomyces israelii abscess: a differential diagnosis of a pelvic mass. AB - A 52-year-old woman was admitted to our district general hospital, with a rapidly growing, increasingly tender mass in the right iliac fossa, difficulty mobilising with a fixed flexion deformity of the right hip and 15 kg weight loss in 5 months. Her 8-month long surgical history for investigation of a pelvic mass stemmed from the removal of an intrauterine device. It included radiological and surgical investigations. We report the second case in the literature, of a patient presenting with abdominal wall abscess, psoas abscess and hydronephrosis as a long-term complication of Actinomyces israelii infection of the ipsilateral ovary with a favourable outcome having excluded ovarian malignancy. PMID- 26607185 TI - Guillain-Barre syndrome as first presentation of systemic lupus erythematosus: a rare manifestation complicated by IVIg-induced splenic infarct. AB - A 44-year-old woman presented with progressively worsening neurological symptoms of 1 week duration. Physical examination revealed absent reflexes of the lower extremities and proximal muscle weakness, bilaterally. Cerebrospinal fluid analysis and electrophysiological studies were consistent with the diagnosis of Guillain-Barre syndrome (GBS) and the patient was started on intravenous immunoglobulin infusion. Along with positive neurological findings, rheumatological work up revealed elevated antinuclear antibody titres, positive double-stranded DNA and anti-Smith antibodies. These results, in conjunction with positive clinical findings, confirmed an underlying diagnosis of systemic lupus erythematosus (SLE). The patient's hospital course was complicated by an episode of severe left upper quadrant abdominal pain, fever, tachycardia and elevated inflammatory markers. CT scan of the abdomen revealed a splenic infarct following completion of IVIg infusion, making this a contributor to thrombus formation in the setting of an already thrombophilic state, and a rare complication of an approved method of treatment. PMID- 26607186 TI - DADS neuropathy associated with anti-TNF-alpha therapy. AB - A 52-year-old man with idiopathic Parkinson's disease and severe rheumatoid arthritis presented with a 1-year history of progressively worsening limb paraesthesia. Examination showed sensory loss in a glove and stocking distribution, absent reflexes and unsteady tandem gait. Nerve conduction studies suggested an acquired peripheral neuropathy with distal demyelination, which together with the clinical phenotype-was consistent with a Distal Acquired Demyelinating Symmetric (DADS) neuropathy pattern. This was attributed to therapy with adalimumab, an antitumor necrosis factor (TNF)-alpha agent, which the patient had been taking for 2 years for rheumatoid arthritis. One month after discontinuing adalimumab, the limb paraesthesia had resolved completely and the patient had a normal tandem gait. Demyelinating disorders may rarely occur as complications of anti-TNF-alpha agents and therefore have implications for pretreatment counselling and ongoing monitoring. DADS neuropathy is a subtype of chronic inflammatory demyelinating polyradiculoneuropathy, which responds poorly to standard therapy and has not previously been described with anti-TNF-alpha therapy. PMID- 26607187 TI - Successful treatment of recurrent rectal prolapse using three Thiersch sutures in children. AB - Many techniques are described to manage recurrent rectal prolapse in children, including repeated Thiersch stitch, phenol injections, Delorme and Altemeier procedures, and rectopexy. We describe a case of successful treatment of rectal prolapse by placing three Thiersch sutures circumferentially along the anal canal -a simple and novel modification of a well-known procedure. An 8-year-old boy with full-thickness rectal prolapse was treated with laxatives to no avail. He was subsequently treated with phenol-in-almond-oil injection and insertion of a 1/0PDS Thiersch suture. The effects were temporary with recurrence 3 months later. A further phenol-in-almond-oil injection was given and a 1/0PDS Thiersch suture placed, and the patient was discharged on laxatives. Recurrence occurred again at 3 months. This was treated with three circumferential Thiersch sutures along the anal canal--one Prolene 2/0 and two 1/0PDS. There has been no recurrence at follow-up. Placement of three sequential Thiersch sutures along the rectum is effective in treating recurrent rectal prolapse and a good alternative to major rectopexy. PMID- 26607188 TI - Amoebiasis masquerading as inflammatory bowel disease. AB - A 60-year-old Japanese man presented with bloody diarrhoea. He stated that he had been diagnosed with ulcerative colitis (UC) 3 years prior, but discontinued follow-up care as treatment was ineffective. One year later, he came to our hospital with anorexia and weight loss. The abdomen was soft and flat without tenderness. Laboratory tests were unremarkable; faecal culture and Clostridium difficile toxin were negative. Findings and biopsy from a subsequent colonoscopy reconfirmed his diagnosis of UC. Neither mesalazine, which was initially prescribed, nor additional treatments improved his symptoms. Repeat colonoscopy, performed 5 months later, demonstrated similar findings in the same area. Although the pathology remained consistent with UC, multiple treatment failures suggested ongoing occult infection. Additional testing revealed positive Entamoeba histolytica antibody. 14 days of metronidazole dramatically improved his symptoms. He has remained asymptomatic after 2 years. PMID- 26607189 TI - A young woman with a jejuno-jejunal intussusception. AB - A 27-year-old woman presented at the emergency department, with pain in the epigastric region. Because physical examination, blood results, urine tests and an X-ray of the thorax showed no abnormalities, she was discharged. Twelve hours later, she presented again at the emergency department, with intense abdominal pain. The blood results, an X-ray and ultrasound of the abdomen were now aberrant. A CT of the abdomen showed an extensive intussusception. During an emergency laparotomy, the intussusception of the proximal jejunum was confirmed. Owing to gangrene of the proximal jejunum, a resection was inevitable. A polyp in the resected part of the jejunum was the lead point of the intussusception. This case report shows the challenges of diagnosing an 'intussusception' and gives a short overview of this condition in adults. PMID- 26607183 TI - Cutaneous T-cell lymphoma: 2016 update on diagnosis, risk-stratification, and management. AB - DISEASE OVERVIEW: Cutaneous T-cell lymphomas are a heterogenous group of T-cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sezary Syndrome (SS). DIAGNOSIS: The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY: TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk adapted," multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral, or blood involvement are generally approached with biologic response modifiers or histone deacetylase inhibitors before escalating therapy to include systemic, single-agent chemotherapy. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients. PMID- 26607190 TI - Use of ticagrelor in human pregnancy, the first experience. AB - Ticagrelor was daily administered throughout pregnancy to a 37-year-old pregnant woman until 36 weeks of gestation. The patient, with Behcet disease, suffered from a non-ST elevation myocardial infarction 4 months before conception, possibly related to hypertension and tobacco abuse. Pregnancy and postpartum periods were uneventful. She delivered a healthy but small-for-gestational-age term neonate. PMID- 26607191 TI - The unexpected finding of a splenic infarction in a patient with infectious mononucleosis due to Epstein-Barr virus. AB - The authors present a case of a 24-year-old man with infectious mononucleosis (IM) due to Epstein-Barr virus (EBV). Among his symptoms, he reported abdominal pain in the upper left quadrant. An abdominal ultrasound and CT revealed an extensive splenic infarction. During the acute stage of this disease, the thrombophilic screening revealed reduced free protein S and elevated factor VIII, with normalisation on re-evaluation 6 weeks later. Splenic infarction is a very rare complication of IM due to EBV but should be considered in patients presenting abdominal pain. A hypercoagulability state should be investigated. To our knowledge, this is the first described case of a splenic infarction in a patient with IM due to EBV associated with a transient reduction of protein S and elevation of factor VIII. Thus, this work promotes the importance of including these factors in the thrombophilic screening conducted during the investigation of similar cases. PMID- 26607192 TI - Continuous use of enzalutamide in a patient who developed enzalutamide-induced thrombocytopenia. AB - Drug-induced thrombocytopenia (DIT) is known to be caused by many drugs. In daily clinical practice, it is not uncommon to observe cases of thrombocytopenia related to enzalutamide. We report the case of a 69-year-old patient with metastatic castration-resistant prostate cancer (CRPC) who was started on enzalutamide at a dose of 160 mg/day. Two weeks after starting enzalutamide, asymptomatic thrombocytopenia (platelet count 14,000/uL) occurred. Enzalutamide was withdrawn and the patient received platelet transfusions. The platelet count recovered immediately. Because the prostate-specific antigen (PSA) level had started to fall during treatment with enzalutamide, the patient was restarted on enzalutamide, but at a dose of 80 mg/day. He has continued to use enzalutamide without developing thrombocytopenia and the PSA level has kept falling. This case suggests that it is possible to again use enzalutamide in patients who have developed enzalutamide-induced thrombocytopenia. PMID- 26607193 TI - Bilateral total hip replacement in arthrogryposis multiplex congenita. AB - The authors present a case of bilateral total hip replacements (THRs) in a 56 year-old patient with arthrogryposis multiplex congenita (AMC). The considerations for the perioperative period and the outcome are discussed. Preoperative planning included an anaesthetic review and availability of fiberoptic intubation due to poor mouth opening. Perioperatively, contractures can make positioning and exposure difficult but in this case a standard posterior approach was taken. Particular attention was given to soft tissue balancing given the theoretical risk of dislocation. There were no perioperative complications. Postoperatively there has been improvement in pain and hip scores but the patient has failed to return to work. Objective improvements in range of motion (ROM) have not been made. This experience suggests THR is a safe and effective treatment for osteoarthritic hip pain in patients with AMC but patients should be informed that ROM is unlikely to improve. PMID- 26607194 TI - Fulminant antenatal pulmonary oedema in a woman with hypertension and superimposed preeclampsia. AB - An asymptomatic 40-year-old para 1 black African woman with pre-existing hypertension and a booking blood pressure of 120/80 mm Hg, was admitted with superimposed preeclampsia diagnosed because of worsening hypertension and significant proteinuria at 27+5 weeks gestation. Antenatally, her blood pressure was controlled with labetalol, and blood tests including serum creatinine were within normal limits for pregnancy. Three days later, the patient developed severe hypertension despite treatment, and reported sudden onset severe shortness of breath; oxygen saturations on air dropped to 93%. Auscultation revealed widespread crepitations leading to a working diagnosis of pulmonary oedema. Despite appropriate management, respiratory function continued to deteriorate and she required intubation, ventilation and emergency caesarean section under general anaesthesia. A live male infant was delivered floppy and was intubated and resuscitated. He awaits discharge home on oxygen. The mother's pulmonary oedema resolved postpartum. Echocardiogram showed left ventricular hypertrophy but normal left ventricular function and the patient's hypertension is being controlled on medication. PMID- 26607195 TI - Response to IV immunoglobulin in a case of osmotic demyelination syndrome. PMID- 26607196 TI - Unexpected cause of recurrent epistaxis. PMID- 26607197 TI - Successful removal of uterine leiomyosarcoma tumour thrombus propagating to the right atrium. AB - Although intravenous leiomyomatosis is widely documented, intravenous extension of leiomyosarcoma into the inferior vena cava (IVC) and subsequently into the right atrium is extremely rare. Less than five such cases have been reported in the literature worldwide. Uterine leiomyosarcoma is an aggressive smooth muscle tumour occurring with an incidence of 1% in all female genital tract cancers and comprises about 3-7% of uterine cancers. It carries a generally poor prognosis with 5-year survival rates ranging from 18.8% to 65% across all stages. We report a case of primary uterine leiomyosarcoma with intravascular tumour propagation extending to the renal vein, IVC and right atrium of the heart, which was successfully resected in a one stage operation by a multidisciplinary team. This case demonstrates the importance of preoperative radiological staging and multidisciplinary planning. PMID- 26607198 TI - A role for risperidone in the treatment of communication disorder and comorbid mental health problems? AB - This case report describes the co-occurrence of a psychiatric disorder with a specific communication disorder in a teenage girl who presented to youth mental health services in crisis, posing a significant risk of harm to herself and others. Description of this case would be of interest to practitioners in youth mental health in relation to the assessment and treatment of young people with similar difficulties. We present the case of a 17-year-old girl previously admitted to an inpatient adolescent unit. Her diagnosis was reformulated 4 months into her second admission to include a specific communication disorder with both receptive and expressive difficulties, evident from her pragmatic use of language. She was started on risperidone in month eight; following this, a significant improvement was seen and the patient was discharged a month later. Prior to the start of risperidone, a referral had been made to low secure adolescent services for further assessment and advice on management, due to the patient's challenging presentation and poor engagement with treatment. PMID- 26607199 TI - Thymic carcinoma presenting as atypical chest pain. AB - A 58-year-old woman with a 2-month history of atypical chest pain was referred to the chest pain clinic by the general practitioner. Exercise stress test was positive and subsequent coronary angiogram revealed significant triple vessel disease with left ventricular impairment requiring a coronary artery bypass graft (CABG). The patient had a chest X-ray as part of the preoperative work up. Chest X-ray revealed a large anterior mediastinal mass. Subsequent thorax CT revealed a 7.2 cm anterior mediastinal mass. CT-guided biopsy of the mass revealed the diagnosis of a poorly differentiated thymic basaloid carcinoma. The patient was successfully treated with concomitant surgery involving complete resection of the mass and a CABG procedure. PMID- 26607200 TI - Cold subcutaneous abscesses as the first manifestation of disseminated coccidioidomycosis in an immunocompromised host. AB - Coccidioidomycosis is an endemic fungal infection in the southwestern USA and northern Mexico. It is caused by Coccidioides immitis and C. posadasii. This infection occurs due to the inhalation of airborne arthroconidia, causing a mild pulmonary infection, but most cases are asymptomatic. Disseminated coccidioidomycosis (DC) is a rare entity occurring in less than 1% of all cases, usually in immunocompromised patients, and it carries high risks of morbidity and mortality. The skin is one of the most frequently affected organs and in some cases cutaneous lesions may be the first or only sign of infection. A wide spectrum of clinical lesions may develop, including cold abscess. In immunocompromised hosts, DC represents a diagnostic and therapeutic challenge. Treatment is based on antifungal drugs, such as amphotericin B and azoles, administered for long periods of time and under close follow up to monitor the treatment response and to detect relapse. In the following case report, we present a 35-year-old male patient with systemic lupus erythematosus under immunosuppressive therapy who presented with cold subcutaneous abscesses as the first sign of DC. PMID- 26607201 TI - Use of rivaroxaban in an elderly patient with intermediate-low early mortality risk due to pulmonary embolism: a case report. AB - INTRODUCTION: Pulmonary embolism remains one of the leading causes of cardiovascular mortality. The standard treatment for pulmonary embolism is anticoagulant therapy using low molecular weight heparin, fondaparinux and a vitamin K antagonist, but a recent clinical trial showed that rivaroxaban, an oral factor Xa inhibitor, was as effective as standard therapy for the initial and long-term treatment of pulmonary embolism and had less bleeding complications. CASE PRESENTATION: The present report describes the case of an 80 year-old white man with an intermediate to low early mortality risk of pulmonary embolism. He was successfully treated with rivaroxaban (administered orally as monotherapy), demonstrating rapid benefit without any adverse events. CONCLUSION: Rivaroxaban, particularly in the acute phase of pulmonary embolism, may be considered an effective and safe therapeutic choice even in elderly patients, a population less represented in clinical trials. PMID- 26607202 TI - Platelet endothelial cell adhesion molecule-1 (PECAM1) plays a critical role in the maintenance of human vascular endothelial barrier function. AB - Cardiovascular endothelial barrier dysfunction is associated with a number of cardiovascular diseases. This study aims to investigate the role of platelet endothelial cell adhesion molecule-1 (PECAM1) in the maintenance of the vascular endothelial barrier integrate. Human umbilical vein endothelial cells (HUVECs) were cultured into monolayers using as an in vitro model to assess the endothelial barrier function. Knockdown of the gene of PECAM1 markedly reduced the transendothelial resistance and increased the permeability of the HUVEC monolayers. From the wild HUVECs, we detected a complex of PECAM1, claudin1, occluding and endothelial cell selective adhesion molecule (ESAM); such a complex was not detected in the PECAM1-deficient HUVECs. Knockdown of either claudin1, or occludin, or ESAM, did not affect the formation of the tight junction (TJ) complex. Exposure to recombinant interleukin (IL)-13 inhibited the expression of PECAM1 and down-regulated the HUVEC monolayer barrier function. PECAM1 plays an important role in the formation of TJ complex. PMID- 26607204 TI - Combined MSC-Secreted Factors and Neural Stem Cell Transplantation Promote Functional Recovery of PD Rats. AB - Stem cell transplantation has enormous potential for the treatment of neurodegenerative disorders like Parkinson's disease (PD). Mesenchymal stem cells (MSCs) have attracted much attention because they can secrete a wide variety of cellular factors that promote cell growth. In this study, we prepared a conditioned medium (CM) using lyophilized MSC culture medium that contained the secretome of MSCs and applied this CM to the culture of neural stem cells (CM NSCs) for the transplantation of PD model rats. Quantitative real-time PCR, Western blot, and immunocytochemistry were used to identify cell differentiation and expression of dopaminergic neuron-specific genes in vitro. Behavioral tests including rotational behavior and MWM training tests were also performed to assess the recovery. Our results indicated that combined treatment of CM and neural stem cell transplantation can significantly reduce apomorphine-induced rotational asymmetry and improve spatial learning ability. The CM-NSCs were able to differentiate into dopaminergic neurons in the ventral tegmental area (VTA) and medial forebrain bundle (MFB), and migrated around the lesion site. They showed a higher activity than untreated NSCs in cell survival, migration, and behavior improvement in the dopa-deficit rat model. These findings suggest that the neural stem cells treated with conditioned medium possess a great potential as a graft candidate for the treatment of Parkinson's disease. PMID- 26607203 TI - How environment and self-motion combine in neural representations of space. AB - Estimates of location or orientation can be constructed solely from sensory information representing environmental cues. In unfamiliar or sensory-poor environments, these estimates can also be maintained and updated by integrating self-motion information. However, the accumulation of error dictates that updated representations of heading direction and location become progressively less reliable over time, and must be corrected by environmental sensory inputs when available. Anatomical, electrophysiological and behavioural evidence indicates that angular and translational path integration contributes to the firing of head direction cells and grid cells. We discuss how sensory inputs may be combined with self-motion information in the firing patterns of these cells. For head direction cells, direct projections from egocentric sensory representations of distal cues can help to correct cumulative errors. Grid cells may benefit from sensory inputs via boundary vector cells and place cells. However, the allocentric code of boundary vector cells and place cells requires consistent head-direction information in order to translate the sensory signal of egocentric boundary distance into allocentric boundary vector cell firing, suggesting that the different spatial representations found in and around the hippocampal formation are interdependent. We conclude that, rather than representing pure path integration, the firing of head-direction cells and grid cells reflects the interface between self-motion and environmental sensory information. Together with place cells and boundary vector cells they can support a coherent unitary representation of space based on both environmental sensory inputs and path integration signals. PMID- 26607205 TI - Posterior reversible encephalopathy syndrome after kidney transplantation in pediatric recipients: Two cases. AB - PRES is a neuro-clinical and radiological syndrome that can result as a consequence of several different conditions including hypertension, fluid overload, and immunosuppressive treatment. Herein, we report two children who received kidney and combined liver-kidney transplantation as treatment for renal hypodysplasia associated with bilateral vesico-ureteral reflux and methylmalonic acidemia, respectively. Early after surgery (seven and 10 days), both patients presented with hypertension and seizures. The patients' immunosuppressive regimen included steroid and calcineurin inhibitors (tacrolimus and cyclosporine, respectively) and basiliximab and one with anti-IL2 receptor. In both cases, the imaging strongly supported the diagnosis of PRES. In details, the CT scan showed hypodensities in the posterior areas of the brain, and brain MRI demonstrated parieto-occipital alterations indicative of vasogenic edema. Treatment with calcineurin inhibitors was temporally discontinued and restarted at lower dosage; arterial hypertension was treated with Ca-channel blockers. Both children fully recovered without any neurological sequels. In conclusion, in children undergoing solid organ transplantation, who develop neurological symptoms PRES, should be carefully considered in the differential diagnosis and once the diagnosis is ruled in, we recommend strict arterial blood pressure control and adjustment or withholding of calcineurin inhibitor therapy should be considered based upon blood levels. PMID- 26607206 TI - Underrepresentation of active histone modification marks in evolutionarily young genes. AB - It is known that evolutionarily new genes can rapidly evolve essential roles in fundamental biological processes. Nevertheless, the underlying molecular mechanism of how they acquire their novel transcriptional pattern is less characterized except for the role of cis-regulatory evolution. Epigenetic modification offers an alternative possibility. Here, we examined how histone modifications have changed among different gene age groups in Drosophila melanogaster by integrative analyses of an updated new gene dataset and published epigenomic data. We found a robust pattern across various datasets where both the coverage and intensity of active histone modifications, histone 3 lysine 4 trimethylation and lysine 36 trimethylation, increased with evolutionary age. Such a temporal correlation is negative and much weaker for the repressive histone mark, lysine 9 trimethylation, which is expected given its major association with heterochromatin. By further comparison with neighboring old genes, the depletion of active marks of new genes could be only partially explained by the local epigenetic context. All these data are consistent with the observation that older genes bear relatively higher expression levels and suggest that the evolution of histone modifications could be implicated in transcriptional evolution after gene birth. PMID- 26607207 TI - Melatonin inhibits paraquat-induced cell death in bovine preimplantation embryos. AB - Preimplantation embryos are sensitive to oxidative stress-induced damage that can be caused by reactive oxygen species (ROS) originating from normal embryonic metabolism and/or the external surroundings. Paraquat (PQ), a commonly used pesticide and potent ROS generator, can induce embryotoxicity. The present study aimed to investigate the effects of melatonin on PQ-induced damage during embryonic development in bovine preimplantation embryos. PQ treatment significantly reduced the ability of bovine embryos to develop to the blastocyst stage, and the addition of melatonin markedly reversed the developmental failure caused by PQ (20.9% versus 14.3%). Apoptotic assay showed that melatonin pretreatment did not change the total cell number in blastocysts, but the incidence of apoptotic nuclei and the release of cytochrome c were significantly decreased. Using real-time quantitative polymerase chain reaction analysis, we found that melatonin pre-incubation significantly altered the expression levels of genes associated with redox signaling, particularly by attenuating the transcript level of Txnip and reinforcing the expression of Trx. Furthermore, melatonin pretreatment significantly reduced the expression of the pro-apoptotic caspase-3 and Bax, while the expression of the anti-apoptotic Bcl-2 and XIAP was unaffected. Western blot analysis showed that melatonin protected bovine embryos from PQ-induced damage in a p38-dependent manner, but extracellular signal regulated kinase (ERK) and c-JUN N-terminal kinase (JNK) did not appear to be involved. Together, these results identify an underlying mechanism by which melatonin enhances the developmental potential of bovine preimplantation embryos under oxidative stress conditions. PMID- 26607208 TI - Nociceptin/orphanin FQ up-regulates P2X3 receptors in primary cultures of neonatal rat trigeminal ganglion neurons. AB - Recent evidence indicates a nociceptive role of the nociceptin/orphanin FQ-opioid receptor-like receptor (N/OFQ-ORL1) system in craniofacial pain; however, the mechanisms of such an effect remain unclear. We investigated whether the action of N/OFQ involves the modulation of P2X3 , a pain-transducing ionotropic receptor. Double-labeled immunohistochemical staining was used to determine the co-localization of ORL1 and P2X3 receptors in the trigeminal ganglia (TG) of neonatal Sprague-Dawley rats. The effect of N/OFQ (at a concentration ranging from 1 pM to 10 nM) on the expression of P2X3 receptors was detected by RT-PCR, western blotting, and immunocytochemical staining. We found that ORL1 receptors were co-localized with P2X3 receptors and that the application of N/OFQ could up regulate, in a concentration-dependent manner, the expression of P2X3 receptor mRNA and P2X3 receptor protein in TG neurons. Immunocytochemical staining also revealed enhanced P2X3 immunoreactivity beneath the neuronal membrane and an increased percentage of P2X3 -positive neurons after treatment with N/OFQ. Those effects were completely blocked by a specific ORL1 antagonist, UFP-101. Our results suggest that the activation of ORL1 receptors by N/OFQ can potentiate P2X3 receptors in primary cultures of neonatal trigeminal neurons, which may be a mechanism for the nociceptive role of N/OFQ in the modulation of craniofacial pain. Our findings may also have implications in treating craniofacial pain. PMID- 26607209 TI - Translation and psychometric properties of the Swedish version of the Index of Dental Anxiety and Fear (IDAF-4C+). AB - Dental anxiety (DA) is a common condition, with significant medical, psychological, and social consequences. High-quality psychometric tools for the assessment of dental anxiety are necessary for clinical and research purposes. The aim of this study was to adapt the Index of Dental Anxiety and Fear (IDAF 4C(+) ) to the Swedish language and to explore the psychometric properties of the translated version. The study included a clinical sample (n = 414; 17-91 yr of age) and a non-clinical sample (n = 51; 19-47 yr of age). The scales used were the IDAF-4C(+) , the Single-Question Assessment of Dental Anxiety (SQDA), the Dental Fear Survey (DFS), and the Internal Health Locus of Control (IHLOC). The Swedish IDAF anxiety module showed a clear, one-dimensional structure, good internal consistency (Cronbach's alpha = 0.95), and adequate validity, as evidenced by strong correlations with the other DA measures (SQDA and DFS) and weak correlations with the IHLOC. In addition, the IDAF phobia module and the IDAF stimulus module were strongly correlated with the other DA measures. To conclude, the study shows promising findings for the reliability and validity of the Swedish translation of the IDAF-4C(+) , as a useful measure of dental anxiety in research and clinical practice. PMID- 26607211 TI - Efficacy of selected food-safe compounds to prevent infestation of the ham mite, Tyrophagus putrescentiae (Schrank) (Acarina: Acaridae), on southern dry-cured hams. AB - BACKGROUND: Tyrophagus putrescentiae (Schrank) is a serious mite pest of dried meats and cheeses. Infestations of T. putrescentiae are controlled with the fumigant methyl bromide, which is an ozone-depleting substance and is currently being banned in most countries. Effective alternatives to methyl bromide are needed. The objective of this research was to use laboratory assays to investigate the effectiveness of food-safe compounds for preventing infestation of T. putrescentiae on dry-cured hams. RESULTS: Ham pieces dipped in solutions of either propylene glycol (1,2-propanediol), lard, ethoxyquin or butylated hydroxytoluene prevented or significantly reduced mite population growth. Behavioral assays revealed that more mites oriented to the untreated control ham cubes, and more eggs were laid on these untreated ham cubes, compared with cubes treated with various dips. Our results also indicated that a combination of carrageenan + propylene glycol alginate + 40% propylene glycol was effective in reducing mite numbers on whole aging hams compared with untreated whole hams. CONCLUSIONS: Several food-safe compounds can prevent infestation of T. putrescentiae on dry-cured hams and may represent alternatives for managing this pest. (c) 2015 Society of Chemical Industry. PMID- 26607212 TI - Vaccine Engineering with Dual-Functional Mineral Shell: A Promising Strategy to Overcome Preexisting Immunity. AB - Dual-functional biomineral-vaccine core-shell nanohybrids are obtained using recombinant adenovirus serotype 5 (rAd5) as templates, which efficiently masks the neutralizing epitope of vaccines and preserve their original immunogenicity. The versatile vaccine hybrid can evade the preexisting anti-Ad5 immunity, leading to boosted multifunctional antigen-specific cytokine-secreting T cell responses and presenting promising applications of vaccine-material hybrid for the rational design of vaccines. PMID- 26607213 TI - New insights into relationships between active and dormant organisms, phylogenetic diversity and ecosystem productivity. AB - Marine microbes make up a key part of ocean food webs and drive ocean chemistry through a range of metabolic processes. A fundamental question in ecology is whether the diversity of organisms in a community shapes the ecological functions of that community. While there is substantial evidence to support a positive link between diversity and ecological productivity for macro-organisms in terrestrial environments, this relationship has not previously been verified for marine microbial communities. One factor complicating the understanding of this relationship is that many marine microbes are dormant and are easily dispersed by ocean currents, making it difficult to ensure that the organisms found in a given environmental sample accurately reflect processes occurring in that environment. Another complication is that, due to microbes great range of genotypic and phenotypic variability, communities with distantly related species may have greater range of metabolic functions than communities have the same richness and evenness, but in which the species present are more closely related to each other. In this issue of Molecular Ecology, Galand et al. (2015) provide compelling evidence that the most metabolically active communities are those in which the nondormant portion of the microbial community has the highest phylogenetic diversity. They also illustrate that focusing on the active portion of the community allows for detection of temporal patterns in community structure that would not be otherwise evident. The authors' point out that the presence of many dormant organisms that do not contribute to ecosystem functioning is a feature that makes microbial ecosystems fundamentally different from macro ecosystems and that this difference needs to be accounted for in microbial ecology theory. PMID- 26607214 TI - Reproductive clonality in protozoan pathogens--truth or artifact? A comment on Ramirez and Llewellyn. AB - The predominant clonal evolution (PCE) model of micropathogens proposed by us has been challenged by a recent paper in Molecular Ecology. We review the main tenets of our model and show that the criticisms raised by the paper's authors are based on papers that are either misunderstood or misquoted. We argue that the PCE model and its recent developments (in particular the 'Russian doll model' dealing with micro-clonal evolution) are supported in most cases when adequate data are available. PMID- 26607215 TI - Response to Tibayrenc and Ayala: Reproductive clonality in protozoan pathogens- truth or artefact? AB - Tibayrenc and Ayala raised several interesting objections to an opinion piece we recently published in Molecular Ecology (Ramirez & Llewellyn 2014). Our piece examined the value of an alternative perspective to their theory of predominant clonal evolution (PCE) on the prevalence and importance of genetic exchange in parasitic protozoa. In particular, our aim was to establish whether population genetic signatures of clonality in parasites were representative of true biological/evolutionary processes or artefacts of inadequate tools and inappropriate or inadequate sampling. We address Tibayrenc and Ayala's criticisms and make a detailed response. In doing so, we deny the consensus that Tibayrenc and Ayala claim around their views and dismiss much of the language which Tibayrenc and Ayala have introduced to this debate as either arbitrary or inaccurate. We strongly reject accusations that we misunderstood and misquoted the work of others. We do not think the PCE provides a useful framework for understanding existing parasite population structures. Furthermore, on the eve of the population genomic era, we strongly urge Tibayrenc and Ayala to wait for the forthcoming wealth of high-resolution data before considering whether it is appropriate to refine or re-iterate their PCE hypothesis. PMID- 26607217 TI - Accounting for genotype uncertainty in the estimation of allele frequencies in autopolyploids. AB - Despite the increasing opportunity to collect large-scale data sets for population genomic analyses, the use of high-throughput sequencing to study populations of polyploids has seen little application. This is due in large part to problems associated with determining allele copy number in the genotypes of polyploid individuals (allelic dosage uncertainty-ADU), which complicates the calculation of important quantities such as allele frequencies. Here, we describe a statistical model to estimate biallelic SNP frequencies in a population of autopolyploids using high-throughput sequencing data in the form of read counts. We bridge the gap from data collection (using restriction enzyme based techniques [e.g. GBS, RADseq]) to allele frequency estimation in a unified inferential framework using a hierarchical Bayesian model to sum over genotype uncertainty. Simulated data sets were generated under various conditions for tetraploid, hexaploid and octoploid populations to evaluate the model's performance and to help guide the collection of empirical data. We also provide an implementation of our model in the R package polyfreqs and demonstrate its use with two example analyses that investigate (i) levels of expected and observed heterozygosity and (ii) model adequacy. Our simulations show that the number of individuals sampled from a population has a greater impact on estimation error than sequencing coverage. The example analyses also show that our model and software can be used to make inferences beyond the estimation of allele frequencies for autopolyploids by providing assessments of model adequacy and estimates of heterozygosity. PMID- 26607216 TI - A metagenetic approach to determine the diversity and distribution of cyst nematodes at the level of the country, the field and the individual. AB - Distinct populations of the potato cyst nematode (PCN) Globodera pallida exist in the UK that differ in their ability to overcome various sources of resistance. An efficient method for distinguishing between populations would enable pathogen informed cultivar choice in the field. Science and Advice for Scottish Agriculture (SASA) annually undertake national DNA diagnostic tests to determine the presence of PCN in potato seed and ware land by extracting DNA from soil floats. These DNA samples provide a unique resource for monitoring the distribution of PCN and further interrogation of the diversity within species. We identify a region of mitochondrial DNA descriptive of three main groups of G. pallida present in the UK and adopt a metagenetic approach to the sequencing and analysis of all SASA samples simultaneously. Using this approach, we describe the distribution of G. pallida mitotypes across Scotland with field-scale resolution. Most fields contain a single mitotype, one-fifth contain a mix of mitotypes, and less than 3% contain all three mitotypes. Within mixed fields, we were able to quantify the relative abundance of each mitotype across an order of magnitude. Local areas within mixed fields are dominated by certain mitotypes and indicate towards a complex underlying 'pathoscape'. Finally, we assess mitotype distribution at the level of the individual cyst and provide evidence of 'hybrids'. This study provides a method for accurate, quantitative and high throughput typing of up to one thousand fields simultaneously, while revealing novel insights into the national genetic variability of an economically important plant parasite. PMID- 26607218 TI - Black market products confiscated in Norway 2011-2014 compared to analytical findings in urine samples. AB - Doping agents are widely and illicitly distributed through the Internet. Analysis of these preparations is useful in order to monitor the availability of prohibited substances on the market, and more importantly to predict which substances are expected to be found in urine samples collected from athletes and to aid clinical and forensic investigations. Based on a close collaboration with the Norwegian police and the Norwegian custom authorities, the Norwegian Doping Control Laboratory has performed analyses of confiscated material suspected of containing doping agents. The analyses were performed using gas chromatography (GC) and liquid chromatography (LC) combined with mass spectrometry (MS). The majority (67%) of the analyzed black market products contained anabolic- androgenic steroids (AAS) as expected, whereas peptide- and protein-based doping substances were identified in 28% of the preparations. The Norwegian Doping Control Laboratory receives samples collected from recreational and elite athletes in addition to samples collected in clinical and forensic investigations. The findings in the seized material reflected the findings in the urine samples analyzed regarding the anabolic steroids. Thus, analyzing material seized in Norway may give a good indication of doping agents available on the local market. PMID- 26607219 TI - Neck recurrence and mortality in esthesioneuroblastoma: Implications for management of the N0 neck. AB - OBJECTIVES/HYPOTHESIS: To review the literature on neck recurrence in esthesioneuroblastoma. STUDY DESIGN: PubMed database. METHODS: A PubMed database search was performed using keywords "esthesioneuroblastoma," "olfactory neuroblastoma," and "esthesioneuroblastoma neck metastasis." Articles written in English with greater than 10 subjects that had data regarding the association of neck recurrence and mortality and/or the association of neck recurrence with Kadish stage were included for analysis. RESULTS: Thirteen studies met inclusion criteria with information regarding the association of neck recurrence and mortality, and 15 studies had data associating neck recurrence and Kadish stage. The neck recurrence rate was 14.1% in studies analyzing mortality. Among those patients who developed regional metastases, mortality was 60%. Of patients without regional recurrence, the mortality rate from disease was 26% (P < 0.0001) and overall mortality was 32% (P < 0.0001). The rate of neck recurrence within each Kadish stage was 0%, 11%, 21%, and 18% for Kadish stages A, B, C, and D, respectively. The trend toward an increased incidence of neck recurrence from stage A to stage D is statistically significant, with P value 0.003. CONCLUSION: The rate of neck recurrence in esthesioneuroblastoma is close to 15%. There is a strong association of recurrence with Kadish stage B and C. Mortality from disease in patients with recurrence in cervical lymph nodes is significant when compared to those who never develop neck disease. Prospective studies are needed to evaluate a potential role for elective neck dissection versus elective neck radiation for patients with esthesioneuroblastoma. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:1373-1379, 2016. PMID- 26607220 TI - Endothelialization of over- and undersized flow-diverter stents at covered vessel side branches: An in vivo and in silico study. AB - Although flow-diverting devices are promising treatment options for intracranial aneurysms, jailed side branches might occlude leading to insufficient blood supply. Especially differences in the local stent strut compression may have a drastic influence on subsequent endothelialization. To investigate the outcome of different treatment scenarios, over- and undersized stent deployments were realized experimentally and computationally. Two Pipeline Embolization Devices were placed in the right common carotid artery of large white swine, crossing the right ascending pharyngeal artery. DSA and PC-MRI measurements were acquired pre- and post-stenting and after three months. To evaluate the stent strut endothelialization and the corresponding ostium patency, the swine were sacrificed and scanning electron microscopy measurements were carried out. A more detailed analysis of the near-stent hemodynamics was enabled by a realistic virtual stenting in combination with highly resolved Computational Fluid Dynamics simulations using case-specific boundary conditions. The oversizing resulted in an elongated stent deployment with more open stent pores, while for the undersized case a shorter deployment with more condensed pores was present. In consequence, the side branch of the first case remained patent after three months and the latter almost fully occluded. The virtual investigation confirmed the experimental findings by identifying differences between the individual velocities as well as stent shear stresses at the distal part of the ostia. The choice of flow-diverting device and the subsequent deployment strategy strongly influences the patency of jailed side branches. Therefore, careful treatment planning is required, to guarantee sufficient blood supply in the brain territories supplied those branches. PMID- 26607221 TI - Nerve-Sparing Superior Hypogastric Plexus Para-Aortic Lymphadenectomy: Clinical Implications and Feasibility. PMID- 26607222 TI - The P2X7 receptor regulates cell survival, migration and invasion of pancreatic ductal adenocarcinoma cells. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is presently one of the cancers with the worst survival rates and least effective treatments. Moreover, total deaths due to PDAC are predicted to increase in the next 15 years. Therefore, novel insights into basic mechanism of PDAC development and therapies are needed. PDAC is characterized by a complex microenvironment, in which cancer and stromal cells release different molecules, such as ATP. ATP can be transported and/or exocytosed from active cancer cells and released from dying cells in the necrotic core of the cancer. We hypothesized that one of the ATP receptors, the P2X7 receptor (P2X7R) could be an important player in PDAC behaviour. METHODS: We determined the expression (real time PCR and Western blot) and localization (immunofluorescence) of P2X7R in human PDAC cell lines (AsPC-1, BxPC-3, Capan-1, MiaPaCa-2, Panc-1) and a "normal" human pancreatic duct epithelial cell line (HPDE). The function of P2X7R in proliferation (BrdU assay), migration (wound assay) and invasion (Boyden chamber with matrigel) was characterized. Furthermore, we studied P2X7R-dependent pore formation (YoPro-1 assay) and cell death (caspase and annexin V / propidium iodide assays). RESULTS: We found higher expression of P2X7R protein in PDAC compared to HPDE cells. P2X7R had notable disparate effects on PDAC survival. Firstly, high concentrations of ATP or the specific P2X7R agonist, BzATP, had cytotoxic effects in all cell lines, and cell death was mediated by necrosis. Moreover, the P2X7R-pore antagonist, A438079, prevented ATP-induced pore formation and cell death. Second, in basal conditions and with low concentrations of ATP/BzATP, the P2X7R allosteric inhibitor AZ10606120 reduced proliferation in all PDAC cell lines. P2X7R also affected other key characteristics of cancer cell behavior. AZ10606120 reduced cell migration and invasion in PDAC cell lines compared to that of untreated/vehicle-treated control cells, and stimulation with sub-millimolar concentrations of ATP or BzATP substantially increased cell invasion. CONCLUSIONS: PDAC cell lines overexpress P2X7R and the receptor plays crucial roles in cell survival, migration and invasion. Therefore, we propose that drugs targeting P2X7R could be exploited in therapy of pancreatic cancer. PMID- 26607223 TI - The impact of sphingosine kinase inhibitor-loaded nanoparticles on bioelectrical and biomechanical properties of cancer cells. AB - Cancer progression and physiological changes within the cells are accompanied by alterations in the biophysical properties. Therefore, the cell biophysical properties can serve as promising markers for cancer detection and physiological activities. To aid in the investigation of the biophysical markers of cells, a microfluidic chip has been developed which consists of a constriction channel and embedded microelectrodes. Single-cell impedance magnitudes at four frequencies and entry and travel times are measured simultaneously during their transit through the constriction channel. This microchip provides a high-throughput, label-free, automated assay to identify biophysical signatures of malignant cells and monitor the therapeutic efficacy of drugs. Here, we monitored the dynamic cellular biophysical properties in response to sphingosine kinase inhibitors (SphKIs), and compared the effectiveness of drug delivery using poly lactic-co glycolic acid (PLGA) nanoparticles (NPs) loaded with SphKIs versus conventional delivery. Cells treated with SphKIs showed significantly higher impedance magnitudes at all four frequencies. The bioelectrical parameters extracted using a model also revealed that the highly aggressive breast cells treated with SphKIs shifted electrically towards that of a less malignant phenotype; SphKI-treated cells exhibited an increase in cell-channel interface resistance and a significant decrease in specific membrane capacitance. Furthermore, SphKI-treated cells became slightly more deformable as measured by a decrease in their channel entry and travel times. We observed no significant difference in the bioelectrical changes produced by SphKI delivered conventionally or with NPs. However, NPs-packaged delivery of SphKI decreased the cell deformability. In summary, this study showed that while the bioelectrical properties of the cells were dominantly affected by SphKIs, the biomechanical properties were mainly changed by the NPs. PMID- 26607224 TI - Detection of HPV DNA in paraffin-embedded cervical samples: a comparison of four genotyping methods. AB - BACKGROUND: Identification of human papillomavirus (HPV) DNA in cervical tissue is important for understanding cervical carcinogenesis and for evaluating cervical cancer prevention approaches. However, HPV genotyping using formalin fixed, paraffin-embedded (FFPE) tissues is technically challenging. We evaluated the performance of four commonly used genotyping methods on FFPE cervical specimens conducted in different laboratories and compared to genotyping results from cytological samples. METHODS: We included 60 pairs of exfoliated-cell and FFPE specimens from women with histologically confirmed cervical intraepithelial lesions grade 2 or 3. Cytology specimens were genotyped using the Linear Array assay. Four expert laboratories processed tissue specimens using different preparation methods and then genotyped the resultant sample preparations using four different HPV genotyping methods: SPF10-PCR DEIA LiPA25 (version 1), Inno LiPA, Linear Array and the Onclarity assay. Percentage agreement, kappa statistics and McNemar's chi-square were calculated for each comparison of different methods and specimen types. RESULTS: Overall agreement with respect to carcinogenic HPV status for FFPE samples between different methods was: 81.7, 86.7 and 91.7% for Onclarity versus Inno-LiPA, Linear Array and SPF-LiPA25, respectively; 81.7 and 85.0% for Linear Array versus Inno-LiPA and SPF-LiPA25, respectively; and 86.7% for SPF-LiPA25 versus Inno-LiPA. Type-specific agreement was >88.3% for all pair-wise comparisons. Comparisons with cytology specimens resulted in overall agreements from 80 to 95% depending on the method and type specific agreement was >90% for most comparisons. CONCLUSIONS: Our data demonstrate that the four genotyping methods run by expert laboratories reliably detect HPV DNA in FFPE specimens with some variation in genotype-specific detection. PMID- 26607225 TI - Genetic determinants of Nef-mediated CD4 and HLA class I down-regulation differences between HIV-1 subtypes B and C. AB - BACKGROUND: HIV-1 subtype C Nef sequences have a significantly lower ability overall to down-regulate CD4 and HLA-I than subtype B Nef sequences. Here we investigated whether Nef amino acids differing in frequency between HIV-1 subtypes B and C explain lower CD4 and HLA-I down-regulation ability of subtype C. FINDINGS: Subtype-specific mutations were introduced into representative subtype B and C Nef sequences and the CD4 and HLA-I down-regulation ability of these mutants was measured by flow cytometry in a CD4+ T cell line. Subtype C consensus 20I and subtype B consensus 20M reduced and increased HLA-I down regulation respectively, and the S88G immune escape mutation (which is significantly more frequent in subtype C than subtype B) reduced CD4 and HLA-I down-regulation. CONCLUSIONS: Our data suggest that these subtype-specific differences may partly contribute to inter-subtype functional differences, and identification of an immune escape mutation - S88G - that impairs Nef function is of relevance to vaccine design. PMID- 26607226 TI - Improvement of prognostic performance in severely injured patients by integrated clinico-transcriptomics: a translational approach. AB - INTRODUCTION: Severe trauma triggers a systemic inflammatory response that contributes to secondary complications, such as nosocomial infections, sepsis or multi-organ failure. The present study was aimed to identify markers predicting complications and an adverse outcome of severely injured patients by an integrated clinico-transcriptomic approach. METHODS: In a prospective study, RNA samples from circulating leukocytes from severely injured patients (injury severity score >= 17 points; n = 104) admitted to a Level I Trauma Center were analyzed for dynamic changes in gene expression over a period of 21 days by quantitative RT-PCR. Transcriptomic candidates were selected based on whole genome screening of a representative discovery set (n = 10 patients) or known mechanisms of the immune response, including mediators of inflammation (IL-8, IL 10, TNF-alpha, MIF, C5, CD59, SPHK1), danger signaling (HMGB1, TLR2, CD14, IL-33, IL-1RL1), and components of the heme degradation pathway (HP, CD163, HMOX1, BLVRA, BLVRB). Clinical markers comprised standard physiological and laboratory parameters and scoring systems routinely determined in trauma patients. RESULTS: Leukocytes, thrombocytes and the expression of sphingosine kinase-1 (SPHK1), complement C5, and haptoglobin (HP) have been identified as markers with the best performance. Leukocytes showed a biphasic course with peaks on day 0 and day 11 after trauma, and patients with sepsis exhibited significantly higher leukocyte levels. Thrombocyte numbers showed a typical profile with initial thrombopenia and robust thrombocytosis in week 3 after trauma, ranging 2- to 3-fold above the upper normal value. 'Relative thrombocytopenia' was associated with multi-organ dysfunction, the development of sepsis, and mortality, the latter of which could be predicted within 3 days prior to the time point of death. SPHK1 expression at the day of admission indicated mortality with excellent performance. C5 expression on day 1 after trauma correlated with an increased risk for the development of nosocomial infections during the later course, while HP was found to be a marker for the development of sepsis. CONCLUSIONS: The combination of clinical and transcriptomic markers improves the prognostic performance and may represent a useful tool for individual risk stratification in trauma patients. PMID- 26607227 TI - Longitudinal DRG-based survey of all-cause and pneumococcal pneumonia and meningitis for inpatients in France (2005-2010). AB - OBJECTIVE: This population-based retrospective study quantified the burden of all cause and pneumococcal pneumonia and meningitis in the Rhone-Alpes region of France from 2005 to 2010, when the 7-valent pneumococcal conjugate vaccine uptake increased from 50 to>90% in children. PATIENTS AND METHODS: Hospital admission data was obtained from the French Diagnosis Related Groups program database (French acronym PMSI). Patients were residents of the Rhone-Alpes region hospitalized for the diseases of interest during 2005-2010. Hospitalization and in-hospital mortality rates were calculated by age, sex, and year on the basis of the Rhone-Alpes region population. Hospitalization and in-hospital mortality rates were compared using Chi(2) tests with statistical significance adjusted for multiple comparisons. RESULTS: The highest hospitalization rates by age group were: all-cause pneumonia, oldest group (>65 years); all-cause and pneumococcal meningitis, youngest group (0-4 years), and pneumococcal pneumonia, youngest and oldest groups. Hospitalization rates significantly decreased for all-cause pneumonia (5-19 years: -12.71%) and all-cause meningitis (20-49 years: -29.22%). Pneumococcal disease rates did not significantly change in any age group. Mortality rates from all-cause pneumonia and meningitis were highest in the oldest age groups. CONCLUSIONS: The burden of all-cause and pneumococcal pneumonia and meningitis remains substantial. Significant changes (decreases) between 2005 and 2010 in hospitalization rates were limited and varied among age groups, most likely because this study began 2 years after PCV7 was first introduced in France for children at broadly-defined high risk. Further research is needed on the relationship between serotype epidemiology and clinical patterns of disease. PMID- 26607228 TI - [Septic shock and Tissierella praeacuta]. PMID- 26607229 TI - Pediatric bacterial meningitis in French Guiana. AB - OBJECTIVE: Controlling vaccine-preventable infectious diseases is a public health priority in French Guiana but there is currently no epidemiological data on pediatric bacterial meningitis in this overseas department. Our aim was to describe data related to pediatric bacterial meningitis in French Guiana and compare it with that of metropolitan France. METHODS: We conducted a multicenter retrospective study from 2000 to 2010 to describe the clinical picture, biological data, epidemiology, and outcome of pediatric bacterial meningitis case patients in French Guiana. RESULTS: The median age of bacterial meningitis patients was 6months [0-15] and the sex ratio 1.06. We observed a total of 60 bacterial meningitis case patients. Most presented with pneumococcal meningitis (24 patients; 40%); 11 with Haemophilus influenzae type b meningitis (23%), five with group B streptococcal meningitis (8.5%), and five others (8.5%) with staphylococcal meningitis (three patients presented with coagulase-negative staphylococci and two with Staphylococcus aureus). Only one patient presented with group B meningococcal meningitis, an 18-month-old infant. We recorded 14 deaths (overall case fatality: 23%); eight were due to Streptococcus pneumoniae (case fatality: 33%). The overall sequelae rate was 28%. It was 32% for patients presenting with pneumococcal meningitis. We observed that 38% of children who had never been vaccinated were infected by a vaccine-preventable bacterium. We observed many differences in the distribution of the bacteria and in the patients' prognosis when comparing the French Guiana data with that of metropolitan France. CONCLUSION: Improving vaccination coverage would decrease the incidence of H. influenzae meningitis. PMID- 26607230 TI - [Severe sepsis and pulmonary abscess with bacteremia due to Elizabethkingia miricola]. PMID- 26607231 TI - Development and validation of a mixed-tissue oligonucleotide DNA microarray for Atlantic bluefin tuna, Thunnus thynnus (Linnaeus, 1758). AB - BACKGROUND: The largest of the tuna species, Atlantic bluefin tuna (Thunnus thynnus), inhabits the North Atlantic Ocean and the Mediterranean Sea and is considered to be an endangered species, largely a consequence of overfishing. T. thynnus aquaculture, referred to as fattening or farming, is a capture based activity dependent on yearly renewal from the wild. Thus, the development of aquaculture practices independent of wild resources can provide an important contribution towards ensuring security and sustainability of this species in the longer-term. The development of such practices is today greatly assisted by large scale transcriptomic studies. RESULTS: We have used pyrosequencing technology to sequence a mixed-tissue normalised cDNA library, derived from adult T. thynnus. A total of 976,904 raw sequence reads were assembled into 33,105 unique transcripts having a mean length of 893 bases and an N50 of 870. Of these, 33.4% showed similarity to known proteins or gene transcripts and 86.6% of them were matched to the congeneric Pacific bluefin tuna (Thunnus orientalis) genome, compared to 70.3% for the more distantly related Nile tilapia (Oreochromis niloticus) genome. Transcript sequences were used to develop a novel 15 K Agilent oligonucleotide DNA microarray for T. thynnus and comparative tissue gene expression profiles were inferred for gill, heart, liver, ovaries and testes. Functional contrasts were strongest between gills and ovaries. Gills were particularly associated with immune system, signal transduction and cell communication, while ovaries displayed signatures of glycan biosynthesis, nucleotide metabolism, transcription, translation, replication and repair. CONCLUSIONS: Sequence data generated from a novel mixed-tissue T. thynnus cDNA library provide an important transcriptomic resource that can be further employed for study of various aspects of T. thynnus ecology and genomics, with strong applications in aquaculture. Tissue-specific gene expression profiles inferred through the use of novel oligo microarray can serve in the design of new and more focused transcriptomic studies for future research of tuna physiology and assessment of the welfare in a production environment. PMID- 26607232 TI - Physical exercise at the workplace prevents deterioration of work ability among healthcare workers: cluster randomized controlled trial. AB - BACKGROUND: Imbalance between individual resources and work demands can lead to musculoskeletal disorders and reduced work ability. The purpose of this study was to investigate the effect of workplace- versus home-based physical exercise on work ability among healthcare workers. METHODS: Two hundred female healthcare workers (Age: 42.0, BMI: 24.1, work ability index [WAI]: 43.1) from 18 departments at three Danish hospitals participated (Copenhagen, Denmark, Aug 2013 Jan 2014). Participants were randomly allocated at the cluster level to 10 weeks of: 1) workplace physical exercise (WORK) performed during working hours for 5x10 min per week and up to 5 group-based coaching sessions on motivation for regular physical exercise, or 2) home-based physical exercise (HOME) performed during leisure time for 5x10 min per week. Both groups received ergonomic counseling on patient handling and use of lifting aides. The main outcome measure was the change from baseline to 10-week follow-up in WAI. RESULTS: Significant group by time interaction was observed for WAI (p < 0.05). WAI at follow-up was 1.1 (0.3 to 1.8) higher in WORK compared with HOME corresponding to a small effect size (Cohens'd = 0.24). Within-group changes indicated that between-group differences were mainly caused by a reduction in WAI in HOME. Of the seven items of WAI, item 2 (work ability in relation to the demands of the job) and item 5 (sickness absence during the past year) were improved in WORK compared with HOME (P < 0.05). CONCLUSIONS: Performing physical exercise together with colleagues at the workplace prevents deterioration of work ability among female healthcare workers. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01921764 . Registered 10 August 2013. PMID- 26607233 TI - Impact of Scientific Versus Emotional Wording of Patient Questions on Doctor Patient Communication in an Internet Forum: A Randomized Controlled Experiment with Medical Students. AB - BACKGROUND: Medical expert forums on the Internet play an increasing role in patient counseling. Therefore, it is important to understand how doctor-patient communication is influenced in such forums both by features of the patients or advice seekers, as expressed in their forum queries, and by characteristics of the medical experts involved. OBJECTIVE: In this experimental study, we aimed to examine in what way (1) the particular wording of patient queries and (2) medical experts' therapeutic health concepts (for example, beliefs around adhering to a distinctly scientific understanding of diagnosis and treatment and a clear focus on evidence-based medicine) impact communication behavior of the medical experts in an Internet forum. METHODS: Advanced medical students (in their ninth semester of medical training) were recruited as participants. Participation in the online forum was part of a communication training embedded in a gynecology course. We first measured their biomedical therapeutic health concept (hereinafter called "biomedical concept"). Then they participated in an online forum where they answered fictitious patient queries about mammography screening that either included scientific or emotional wording in a between-group design. We analyzed participants' replies with regard to the following dimensions: their use of scientific or emotional wording, the amount of communicated information, and their attempt to build a positive doctor-patient relationship. RESULTS: This study was carried out with 117 medical students (73 women, 41 men, 3 did not indicate their sex). We found evidence that both the wording of patient queries and the participants' biomedical concept influenced participants' response behavior. They answered emotional patient queries in a more emotional way (mean 0.92, SD 1.02) than scientific patient queries (mean 0.26, SD 0.55; t74=3.48, P<.001, d=0.81). We also found a significant interaction effect between participants' use of scientific or emotional wording and type of patient query (F2,74=10.29, P<.01, partial eta(2)=0.12) indicating that participants used scientific wording independently of the type of patient query, whereas they used emotional wording particularly when replying to emotional patient queries. In addition, the more pronounced the medical experts' biomedical concept was, the more scientifically (adjusted beta=.20; F1,75=2.95, P=.045) and the less emotionally (adjusted beta=-.22; F1,74=3.66, P=.03) they replied to patient queries. Finally, we found that participants' biomedical concept predicted their engagement in relationship building (adjusted beta=-.26): The more pronounced their biomedical concept was, the less they attempted to build a positive doctor patient relationship (F1,74=5.39, P=.02). CONCLUSIONS: Communication training for medical experts could aim to address this issue of recognizing patients' communication styles and needs in certain situations in order to teach medical experts how to take those aspects adequately into account. In addition, communication training should also make medical experts aware of their individual therapeutic health concepts and the consequential implications in communication situations. PMID- 26607234 TI - The impact of a mental work on food preferences, eating behavior traits and satiety efficiency. AB - Sedentary lifestyles, which are partly due to the type of labor being performed, have contributed to the increased prevalence of obesity. In general, labor in a modern context solicits mental work, which has been shown to promote overeating and altered satiety efficiency. The aim of this study was to evaluate the impact of knowledge-based work on food preferences, eating behaviors traits and appetite sensations. The relationship between these effects and the morphological profile was also assessed. A cross-over experimental design was used in this study for which 35 healthy adults (22 men and 13 women (mean age: 24+/-3years)), were recruited. The participants were randomly assigned the one of the two following conditions: mental work (reading a document and writing a summary of 350 words with the use of a computer) or control (rest in seated position). Each condition lasted 45min, and was followed by a standardized ad libitum buffet-type meal. Measurements included anthropometric variables, ad libitum food intake, appetite sensations before and after each condition, and satiety quotient, a marker of satiety efficiency in response to the meal. Eating behavior traits were also evaluated using the Three-Factor Eating Questionnaire (TFEQ). Eating behaviors (restriction, disinhibition) were not associated with the energy intake in both conditions and in both genders. Women appeared to have a higher energy intake after the mental work condition (p<0.05), which was accompanied by an increased carbohydrate intake (p<0.05). Moreover, participants with the highest waist circumference had lower satiety efficiency (r=0.43, p<0.05) in response to mental work. These results suggest that increased energy intake in response to knowledge based work is associated with food preference and an altered satiety efficiency in women and individuals with higher waist circumference. PMID- 26607235 TI - Cardiac rehabilitation in Canada and Arab countries: comparing availability and program characteristics. AB - BACKGROUND: Despite the high burden of cardiovascular diseases in Arab countries, little is known about cardiac rehabilitation (CR) delivery. This study assessed availability, and CR program characteristics in the Arab World, compared to Canada. METHODS: A questionnaire incorporating items from 4 national / regional published CR program surveys was created for this cross-sectional study. The survey was emailed to all Arab CR program contacts that were identified through published studies, conference abstracts, a snowball sampling strategy, and other key informants from the 22 Arab countries. An online survey link was also emailed to all contacts in the Canadian Association of Cardiovascular Prevention and Rehabilitation directory. Descriptive statistics were used to describe all closed ended items in the survey. All open-ended responses were coded using an interpretive-descriptive approach. RESULTS: Eight programs were identified in Arab countries, of which 5 (62.5 %) participated; 128 programs were identified in Canada, of which 39 (30.5%) participated. There was consistency in core components delivered in Arab countries and Canada; however, Arab programs more often delivered women-only classes. Lack of human resources was perceived as the greatest barrier to CR provision in all settings, with space also a barrier in Arab settings, and financial resources in Canada. The median number of patients served per program was 300 for Canada vs. 200 for Arab countries. CONCLUSION: Availability of CR programs in Arab countries is incredibly limited, despite the fact that most responses stemmed from high-income countries. Where available, CR programs in Arab countries appear to be delivered in a manner consistent with Canada. PMID- 26607236 TI - Manual cleaning of hospital mattresses: an observational study comparing high- and low-resource settings. AB - BACKGROUND: Hospital-associated infections (HAIs) are more frequently encountered in low- than in high-resource settings. There is a need to identify and implement feasible and sustainable approaches to strengthen HAI prevention in low-resource settings. AIM: To evaluate the biological contamination of routinely cleaned mattresses in both high- and low-resource settings. METHODS: In this two-stage observational study, routine manual bed cleaning was evaluated at two university hospitals using adenosine triphosphate (ATP). Standardized training of cleaning personnel was achieved in both high- and low-resource settings. Qualitative analysis of the cleaning process was performed to identify predictors of cleaning outcome in low-resource settings. FINDINGS: Mattresses in low-resource settings were highly contaminated prior to cleaning. Cleaning significantly reduced biological contamination of mattresses in low-resource settings (P < 0.0001). After training, the contamination observed after cleaning in both the high- and low-resource settings seemed comparable. Cleaning with appropriate type of cleaning materials reduced the contamination of mattresses adequately. Predictors for mattresses that remained contaminated in a low-resource setting included: type of product used, type of ward, training, and the level of contamination prior to cleaning. CONCLUSION: In low-resource settings mattresses were highly contaminated as noted by ATP levels. Routine manual cleaning by trained staff can be as effective in a low-resource setting as in a high-resource setting. We recommend a multi-modal cleaning strategy that consists of training of domestic services staff, availability of adequate time to clean beds between patients, and application of the correct type of cleaning products. PMID- 26607237 TI - Noninferiority is almost certain with lenient noninferiority margins. PMID- 26607238 TI - Noninferiority is (too) common in noninferiority trials. PMID- 26607239 TI - Kinetics, thermodynamics and mechanistic studies of carbofuran removal using biochars from tea waste and rice husks. AB - This study reports the thermodynamic application and non-linear kinetic models in order to postulate the mechanisms and compare the carbofuran adsorption behavior onto rice husk and tea waste derived biochars. Locally available rice husk and infused tea waste biochars were produced at 700 degrees C. Biochars were characterized by using proximate, ultimate and surface characterization methods. Batch experiments were conducted at 25, 35, and 45 degrees C for a series of carbofuran solutions ranging from 5 to 100 mg L(-1) with a biochar dose of 1 g L( 1) at pH 5.0 with acetate buffer. Molar O/C ratios indicated that rice husk biochar (RHBC700) is more hydrophilic than tea waste biochar (TWBC700). Negative DeltaG (Gibbs free energy change) values indicated the feasibility of carbofuran adsorption on biochar. Increasing DeltaG values with the rise in temperature indicated high favorability at higher temperatures for both RHBC and TWBC. Enthalpy values suggested the involvement of physisorption type interactions. Kinetic data modeling exhibited contribution of both physisorption, via pore diffusion, pi*-pi electron donor-acceptor interaction, H-bonding, and van der Waals dispersion forces and chemisorption via chemical bonding with phenolic, and amine groups. Equilibrium adsorption capacities of RHBC and TWBC determined by pseudo second order kinetic model were 25.2 and 10.2 mg g(-1), respectively. PMID- 26607240 TI - Principles and equations for measuring and interpreting protein stability: From monomer to tetramer. AB - The ability to measure the thermodynamic stability of proteins with precision is important for both academic and applied research. Such measurements rely on mathematical models of the protein denaturation profile, i.e. the relation between a global protein signal, corresponding to the folding states in equilibrium, and the variable value of a denaturing agent, either heat or a chemical molecule, e.g. urea or guanidinium hydrochloride. In turn, such models rely on a handful of physical laws: the laws of mass action and conservation, the law that relates the protein signal and concentration, and the one that relates stability and denaturant value. So far, equations have been derived mainly for the denaturation profiles of homomeric proteins. Here, we review the underlying basic physical laws and show in detail how to derive model equations for the unfolding equilibria of homomeric or heteromeric proteins up to trimers and potentially tetramers, with or without folding intermediates, and give full demonstrations. We show that such equations cannot be derived for pentamers or higher oligomers except in special degenerate cases. We expand the method to signals that do not correspond to extensive protein properties. We review and expand methods for uncovering hidden intermediates of unfolding. Finally, we review methods for comparing and interpreting the thermodynamic parameters that derive from stability measurements for cognate wild-type and mutant proteins. This work should provide a robust theoretical basis for measuring the stability of complex proteins. PMID- 26607241 TI - Crystal structure of phosphoglucomutase from Leishmania major at 3.5 A resolution. AB - The crystal structure of phosphoglucomutase (LmPGM) from the parasite Leishmania major has been solved at 3.5 A resolution. Although the active form of the enzyme is monomeric in solution, four molecules (A, B, C, D) were found in the asymmetric unit, of which the pairs (A,D) and (B,C) were of identical inter subunit geometry. The parasitic enzyme constituted of four domains exhibited the canonical 'heart' shape of the protein, with domains I to III having a conserved alpha|beta core, while the fourth (IV) domain being structurally distinct from the rest. Conformational variability of the IVth domain, postulated to be responsible for the catalytic function of the enzyme has been studied by normal mode analysis (NMA) and the conformational features responsible for domain movement in the 'hinge region' analyzed in detail. Although the active site of phosphoglucomutase is highly conserved from parasite to human, initial calculations show that a ligand binding pocket could exist near the hinge region, which is unique to the parasite. The enzymatic parameters of LmPGM have been determined and compared with other PGMs from orthologous species in addition to elucidating its mechanism of action by docking the substrate, intermediate onto the active site. PMID- 26607242 TI - Impact of gastrointestinal lipolysis on oral lipid-based formulations and bioavailability of lipophilic drugs. AB - Oil-in-water emulsions are common vehicles for lipids as nutrients and for the delivery of poorly water-soluble drugs. Enhancing oral bioavailability of these drugs using lipid-based formulations (LBF) or self-emulsifying drug delivery systems is one of the current challenges in pharmaceutical industry. Many of the compounds found in LBF (acylglycerols, surfactants with esterified fatty acids, ...) are however potential substrates for digestive enzymes. Their digestion (or lipolysis) in the gastrointestinal (GI) tract is critical for drug dissolution and absorption: it can be beneficial (drug solubilization/dispersion) or deleterous (drug precipitation) depending on the drug-LBF association. A better understanding of the fate of LBF in the GI tract is therefore required to engineer efficient lipid-based drug delivery systems. In vitro models for testing simultaneously LBF digestion and drug dispersion are in development to predict drug solubilization and bioavailability, select the best drug-LBF association and obtain better in vitro-in vivo correlations. So far, research in this area has focused on LBF lipolysis under intestinal conditions because the small intestine is the main target for drug delivery and absorption, as well as the main site of digestion by pancreatic enzymes. Lipolysis however starts within the stomach through the action of gastric lipase, the first enzyme involved in fat digestion in humans. In vitro digestion experiments show that most LBFs are submitted to gastric lipolysis, and therefore, both intragastric and intestinal digestions are critical for the fate of LBF and drug solubility. PMID- 26607243 TI - Early differences in metabolic flexibility between obesity-resistant and obesity prone mice. AB - Decreased metabolic flexibility, i.e. a compromised ability to adjust fuel oxidation to fuel availability supports development of adverse consequences of obesity. The aims of this study were (i) to learn whether obesity-resistant A/J and obesity-prone C57BL/6J mice differ in their metabolic flexibility right after weaning; and (ii) to characterize possible differences in control of glucose homeostasis in these animals using glucose tolerance tests (GTT). A/J and C57BL/6J mice of both genders were maintained at 20 degrees C and weaned to standard low-fat diet at 30 days of age. During the first day after weaning, using several separate animal cohorts, (i) GTT was performed using 1 or 3 mg glucose/g body weight (BW), while glucose was administered either orally (OGTT) or intraperitoneally (IPGTT) at 20 degrees C; and (ii) indirect calorimetry (INCA) was performed, either in a combination with oral gavage of 1 or 7.5 mg glucose/g BW, or during a fasting/re-feeding transition. INCA was conducted either at 20 degrees C or 34 degrees C. Results of both OGTT and IPGTT using 1 mg glucose/g BW at 20 degrees C, and INCA using 7.5 mg glucose/g BW at 34 degrees C, indicated higher glucose tolerance and higher metabolic flexibility to glucose, respectively, and lower fasting glycemia in A/J mice as compared with C57BL/6J mice. Thus, control of whole body glucose metabolism between A/J and C57BL/6J mice represents a phenotypic feature differentiating between the strains right after weaning. PMID- 26607244 TI - Enhanced muscular oxygen extraction in athletes exaggerates hypoxemia during exercise in hypoxia. AB - High rate of muscular oxygen utilization facilitates the development of hypoxemia during exercise at altitude. Because endurance training stimulates oxygen extraction capacity, we investigated whether endurance athletes are at higher risk to developing hypoxemia and thereby acute mountain sickness symptoms during exercise at simulated high altitude. Elite athletes (ATL; n = 8) and fit controls (CON; n = 7) cycled for 20 min at 100 W (EX100W), as well as performed an incremental maximal oxygen consumption test (EXMAX) in normobaric hypoxia (0.107 inspired O2 fraction) or normoxia (0.209 inspired O2 fraction). Cardiorespiratory responses, arterial Po2 (PaO2), and oxygenation status in m. vastus lateralis [tissue oxygenation index (TOIM)] and frontal cortex (TOIC) by near-infrared spectroscopy, were measured. Muscle O2 uptake rate was estimated from change in oxyhemoglobin concentration during a 10-min arterial occlusion in m. gastrocnemius. Maximal oxygen consumption in normoxia was 70 +/- 2 ml.min(-1.)kg( 1) in ATL vs. 43 +/- 2 ml.min(-1.)kg(-1) in CON, and in hypoxia decreased more in ATL (-41%) than in CON (-25%, P < 0.05). Both in normoxia at PaO2 of ~95 Torr, and in hypoxia at PaO2 of ~35 Torr, muscle O2 uptake was twofold higher in ATL than in CON (0.12 vs. 0.06 ml.min(-1).100 g(-1); P < 0.05). During EX100W in hypoxia, PaO2 dropped to lower (P < 0.05) values in ATL (27.6 +/- 0.7 Torr) than in CON (33.5 +/- 1.0 Torr). During EXMAX, but not during EX100W, TOIM was ~15% lower in ATL than in CON (P < 0.05). TOIC was similar between the groups at any time. This study shows that maintenance of high muscular oxygen extraction rate at very low circulating PaO2 stimulates the development of hypoxemia during submaximal exercise in hypoxia in endurance-trained individuals. This effect may predispose to premature development of acute mountain sickness symptoms during exercise at altitude. PMID- 26607245 TI - Exercise training normalizes renal blood flow responses to acute hypoxia in experimental heart failure: role of the alpha1-adrenergic receptor. AB - Recent data suggest that exercise training (ExT) is beneficial in chronic heart failure (CHF) because it improves autonomic and peripheral vascular function. In this study, we hypothesized that ExT in the CHF state ameliorates the renal vasoconstrictor responses to hypoxia and that this beneficial effect is mediated by changes in alpha1-adrenergic receptor activation. CHF was induced in rabbits. Renal blood flow (RBF) and renal vascular conductance (RVC) responses to 6 min of 5% isocapnic hypoxia were assessed in the conscious state in sedentary (SED) and ExT rabbits with CHF with and without alpha1-adrenergic blockade. alpha1 adrenergic receptor expression in the kidney cortex was also evaluated. A significant decline in baseline RBF and RVC and an exaggerated renal vasoconstriction during acute hypoxia occurred in CHF-SED rabbits compared with the prepaced state (P < 0.05). ExT diminished the decline in baseline RBF and RVC and restored changes during hypoxia to those of the prepaced state. alpha1 adrenergic blockade partially prevented the decline in RBF and RVC in CHF-SED rabbits and eliminated the differences in hypoxia responses between SED and ExT animals. Unilateral renal denervation (DnX) blocked the hypoxia-induced renal vasoconstriction in CHF-SED rabbits. alpha1-adrenergic protein in the renal cortex of animals with CHF was increased in SED animals and normalized after ExT. These data provide evidence that the acute decline in RBF during hypoxia is caused entirely by the renal nerves but is only partially mediated by alpha1 adrenergic receptors. Nonetheless, alpha1-adrenergic receptors play an important role in the beneficial effects of ExT in the kidney. PMID- 26607246 TI - Prostaglandin E2/cyclooxygenase pathway in human skeletal muscle: influence of muscle fiber type and age. AB - Prostaglandin E2 (PGE2) produced by the cyclooxygenase (COX) pathway regulates skeletal muscle protein turnover and exercise training adaptations. The purpose of this study was twofold: 1) define the PGE2/COX pathway enzymes and receptors in human skeletal muscle, with a focus on type I and II muscle fibers; and 2) examine the influence of aging on this pathway. Muscle biopsies were obtained from the soleus (primarily type I fibers) and vastus lateralis (proportionally more type II fibers than soleus) of young men and women (n = 8; 26 +/- 2 yr), and from the vastus lateralis of young (n = 8; 25 +/- 1 yr) and old (n = 12; 79 +/- 2 yr) men and women. PGE2/COX pathway proteins [COX enzymes (COX-1 and COX-2), PGE2 synthases (cPGES, mPGES-1, and mPGES-2), and PGE2 receptors (EP1, EP2, EP3, and EP4)] were quantified via Western blot. COX-1, cPGES, mPGES-2, and all four PGE2 receptors were detected in all skeletal muscle samples examined. COX-1 (P < 0.1) and mPGES-2 were ~20% higher, while EP3 was 99% higher and EP4 57% lower in soleus compared with vastus lateralis (P < 0.05). Aging did not change the level of skeletal muscle COX-1, while cPGES increased 45% and EP1 (P < 0.1), EP3, and EP4 decreased ~33% (P < 0.05). In summary, PGE2 production capacity and receptor levels are different in human skeletal muscles with markedly different type I and II muscle fiber composition. In aging skeletal muscle, PGE2 production capacity is elevated and receptor levels are downregulated. These findings have implications for understanding the regulation of skeletal muscle adaptations to exercise and aging by the PGE2/COX pathway and related inhibitors. PMID- 26607247 TI - Energetics of vertical kilometer foot races; is steeper cheaper? AB - Vertical kilometer foot races consist of a 1,000-m elevation gain in <5,000 m of overall distance, and the inclines of the fastest courses are ~30 degrees . Previous uphill locomotion studies have focused on much shallower angles. We aimed to quantify the metabolic costs of walking and running on very steep angles and to biomechanically distinguish walking from running. Fifteen runners (10 male, 5 female, 32.9 +/- 7.5 yr, 1.75 +/- 0.09 m, 64.3 +/- 9.1 kg) walked and ran for 5 min at seven different angles (9.4, 15.8, 20.4, 24.8, 30.0, 35.0, and 39.2 degrees ) all at a fixed vertical velocity (0.35 m/s). We measured the metabolic rates and calculated the vertical costs of walking (Cwvert) and running (Crvert). Using video analysis, we determined stride frequency, stride length, and duty factor (fraction of stride that each foot is in ground contact). At all angles other than 9.4 degrees , Cwvert was cheaper than Crvert (average -8.45 +/- 1.05%; P < 0.001). Further, broad minima for both Cwvert and Crvert existed between 20.4 and 35.0 degrees (average Cwvert 44.17 +/- 0.41 J.kg(-1).m(-1) and average Crvert 48.46 +/- 0.35 J.kg(-1).m(-1)). At all angles and speeds tested, both walking and running involved having at least one foot on the ground at all times. However, in walking, stride frequency and stride length were ~28% slower and longer, respectively, than in running. In conclusion, we found that there is a range of angles for which energy expenditure is minimized. At the vertical velocity tested, on inclines steeper than 15.8 degrees , athletes can reduce their energy expenditure by walking rather than running. PMID- 26607248 TI - Brain and behavioral effects of swallowing carbonated water on the human pharyngeal motor system. AB - Chemical stimulation of the swallowing network with carbonation and citric acid has been investigated, showing potential benefits on swallowing of dysphagic patients. Despite this, the underlying mechanisms for these effects are not fully understood. Here we investigated the effects of 5 ml liquid bolus swallows of carbonated, citric acid, and still water on a swallowing reaction-time tasks paradigm in 16 healthy adults (8 male, mean age 33 +/- 3.7 yr, protocol 1). We then investigated the net effects of "sensory bolus interventions" (40 repeated swallows every 15 s) of the three different liquid boluses on corticobulbar excitability, as examined with single-pulse transcranial magnetic stimulation (TMS) in 16 participants (8 female, mean age 33 +/- 3.7 yr, protocol 2). The findings showed that a larger number of correctly timed swallows (within a predetermined time window) was accomplished mainly with carbonated liquids (z = 2.04, P = 0.04 vs. still water, protocol 1). Both carbonated and citric acid liquid interventions with 40 swallows increased corticobulbar excitability of the stronger pharyngeal projection, suggesting a similar modulatory pathway for the effects on swallowing. However, carbonation showed superiority (P = 0.04, F = 4.75, 2-way ANOVA), with the changes lasting up to 60 min following the intervention. These results hold significance for future further and in-depth physiological investigations of the differences between different stimuli on swallowing neural network. PMID- 26607251 TI - BDNF levels are increased by aminoindan and rasagiline in a double lesion model of Parkinson's disease. AB - The anti-Parkinsonian drug rasagiline is a selective, irreversible inhibitor of monoamine oxidase and is used in the treatment of Parkinson's disease (PD). Its postulated neuroprotective effects may be attributed to MAO inhibition, or to its propargylamine moiety. The major metabolite of rasagiline, aminoindan, has shown promising neuroprotective properties in vitro but there is a paucity of studies investigating in vivo effects of this compound. Therefore, we examined neuroprotective effects of rasagiline and its metabolite aminoindan in a double lesion model of PD. Male Fisher 344 rats received i.p. injections of the noradrenergic neurotoxin DSP-4 and intra-striatal stereotaxic microinjections of the dopamine neurotoxin 6-OHDA. Saline, rasagiline or aminoindan (3mg/kg/day s.c.) were delivered via Alzet minipumps for 4 weeks. Rats were then tested for spontaneous locomotion and a novel object recognition task. Following behavioral testing, brain tissue was processed for ELISA measurements of growth factors and immunohistochemistry. Double-lesioned rats treated with rasagiline or aminoindan had reduced behavioral deficits, both in motor and cognitive tasks compared to saline-treated double-lesioned rats. BDNF levels were significantly increased in the hippocampus and striatum of the rasagiline- and aminoindan-lesioned groups compared to the saline-treated lesioned group. Double-lesioned rats treated with rasagiline or aminoindan exhibited a sparing in the mitochondrial marker Hsp60, suggesting mitochondrial involvement in neuroprotection. Tyrosine hydroxylase (TH) immunohistochemistry revealed a sparing of TH-immunoreactive terminals in double-lesioned rats treated with rasagiline or aminoindan in the striatum, hippocampus, and substantia nigra. These data provide evidence of neuroprotection by aminoindan and rasagiline via their ability to enhance BDNF levels. PMID- 26607249 TI - Effects of sodium nitrite supplementation on vascular function and related small metabolite signatures in middle-aged and older adults. AB - Insufficient nitric oxide (NO) bioavailability plays an important role in endothelial dysfunction and arterial stiffening with aging. Supplementation with sodium nitrite, a precursor of NO, ameliorates age-related vascular endothelial dysfunction and arterial stiffness in mice, but effects on humans, including the metabolic pathways altered, are unknown. The purpose of this study was to determine the safety, feasibility, and efficacy of oral sodium nitrite supplementation for improving vascular function in middle-aged and older adults and to identify related circulating metabolites. Ten weeks of sodium nitrite (80 or 160 mg/day, capsules, TheraVasc; randomized, placebo control, double blind) increased plasma nitrite acutely (5- to 15-fold, P < 0.001 vs. placebo) and chronically (P < 0.10) and was well tolerated without symptomatic hypotension or clinically relevant elevations in blood methemoglobin. Endothelial function, measured by brachial artery flow-mediated dilation, increased 45-60% vs. baseline (P < 0.10) without changes in body mass or blood lipids. Measures of carotid artery elasticity (ultrasound and applanation tonometry) improved (decreased beta stiffness index, increased cross-sectional compliance, P < 0.05) without changes in brachial or carotid artery blood pressure. Aortic pulse wave velocity was unchanged. Nitrite-induced changes in vascular measures were significantly related to 11 plasma metabolites identified by untargeted analysis. Baseline abundance of multiple metabolites, including glycerophospholipids and fatty acyls, predicted vascular changes with nitrite. This study provides evidence that sodium nitrite supplementation is well tolerated, increases plasma nitrite concentrations, improves endothelial function, and lessens carotid artery stiffening in middle-aged and older adults, perhaps by altering multiple metabolic pathways, thereby warranting a larger clinical trial. PMID- 26607252 TI - Lingo-1 shRNA and Notch signaling inhibitor DAPT promote differentiation of neural stem/progenitor cells into neurons. AB - Determination of the exogenous factors that regulate differentiation of neural stem/progenitor cells into neurons, oligodendrocytes and astrocytes is an important step in the clinical therapy of spinal cord injury (SCI). The Notch pathway inhibits the differentiation of neural stem/progenitor cells and Lingo-1 is a strong negative regulator for myelination and axon growth. While Lingo-1 shRNA and N-[N-(3, 5-difluorophenacetyl)-1-alanyl]-S-Phenylglycinet-butylester (DAPT), a Notch pathway inhibitor, have been used separately to help repair SCI, the results have been unsatisfactory. Here we investigated and elucidated the preliminary mechanism for the effect of Lingo-1 shRNA and DAPT on neural stem/progenitor cells differentiation. We found that neural stem/progenitor cells from E14 rat embryos expressed Nestin, Sox-2 and Lingo-1, and we optimized the transduction of neural stem/progenitor cells using lentiviral vectors encoding Lingo-1 shRNA. The addition of DAPT decreased the expression of Notch intracellular domain (NICD) as well as the downstream genes Hes1 and Hes5. Expression of NeuN, CNPase and GFAP in DAPT treated cells and expression of NeuN in Lingo-1 shRNA treated cells confirmed differentiation of neural stem/progenitor cells into neurons, oligodendrocytes and astrocytes. These results revealed that while Lingo-1 shRNA and Notch signaling inhibitor DAPT both promoted differentiation of neural stem cells into neurons, only DAPT was capable of driving neural stem/progenitor cells differentiation into oligodendrocytes and astrocytes. Since we were able to show that both Lingo-1 shRNA and DAPT could drive neural stem/progenitor cells differentiation, our data might aid the development of more effective SCI therapies using Lingo-1 shRNA and DAPT. PMID- 26607254 TI - Habitat odor can alleviate innate stress responses in mice. AB - Predatory odors, which can induce innate fear and stress responses in prey species, are frequently used in the development of animal models for several psychiatric diseases including post-traumatic stress disorder (PTSD) following a life-threatening event. We have previously shown that odors can be divided into at least three types; odors that act as (1) innate stressors, (2) as innate relaxants, or (3) have no innate effects on stress responses. Here, we attempted to verify whether an artificial odor, which had no innate effect on predatory odor-induced stress, could alleviate stress if experienced in early life as a habitat odor. In the current study, we demonstrated that the innate responses were changed to counteract stress following a postnatal experience. Moreover, we suggest that inhibitory circuits involved in stress-related neuronal networks and the concentrations of norepinephrine in the hippocampus may be crucial in alleviating stress induced by the predatory odor. Overall, these findings may be important for understanding the mechanisms involved in differential odor responses and also for the development of pharmacotherapeutic interventions that can alleviate stress in illnesses like PTSD. PMID- 26607253 TI - Sex differences in the locus coeruleus-norepinephrine system and its regulation by stress. AB - Women are more likely than men to suffer from post-traumatic stress disorder (PTSD) and major depression. In addition to their sex bias, these disorders share stress as an etiological factor and hyperarousal as a symptom. Thus, sex differences in brain arousal systems and their regulation by stress could help explain increased vulnerability to these disorders in women. Here we review preclinical studies that have identified sex differences in the locus coeruleus (LC)-norepinephrine (NE) arousal system. First, we detail how structural sex differences in the LC can bias females towards increased arousal in response to emotional events. Second, we highlight studies demonstrating that estrogen can increase NE in LC target regions by enhancing the capacity for NE synthesis, while reducing NE degradation, potentially increasing arousal in females. Third, we review data revealing how sex differences in the stress receptor, corticotropin releasing factor 1 (CRF1), can increase LC neuronal sensitivity to CRF in females compared to males. This effect could translate into hyperarousal in women under conditions of CRF hypersecretion that occur in PTSD and depression. The implications of these sex differences for the treatment of stress related psychiatric disorders are discussed. Moreover, the value of using information regarding biological sex differences to aid in the development of novel pharmacotherapies to better treat men and women with PTSD and depression is also highlighted. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID- 26607255 TI - Evidence for a specialized role of the locus coeruleus noradrenergic system in cortical circuitries and behavioral operations. AB - The brainstem nucleus locus coeruleus (LC) innervates the entire central nervous system and is the primary source of norepinephrine (NE) to the neocortex. While classically considered a homogenous modulator of forebrain activity by virtue of highly widespread and divergent axons, recent behavioral and pharmacological evidence suggest this nucleus may execute distinct operations within functionally distinct terminal fields. Summarized in this review are the anatomical and physiological properties of the nucleus within a historical context that led to the interpretation of the nucleus as a homogeneous entity with uniform and simultaneous actions throughout its terminal fields. Also included are findings from several laboratories which point to a more nuanced model of LC/NE function that parallels that seen in other forebrain-projecting monoaminergic nuclei. Such compartmentalized models of the nucleus promote the idea that specific LC circuits are involved in discrete behavioral operations, and therefore, by identifying the networks that are engaged by LC, the substrates for these behaviors can be identified and manipulated. Perturbations in the functional anatomy and physiology of this system may be related to neuropsychiatric conditions associated with dysregulation of the LC-noradrenergic system such as attention deficit hyperactivity disorder. Recent findings regarding the organization and operation of the LC/NE system collectively challenge the classical view of the nucleus as a relatively homogenous modulator of forebrain activity and provide the basis for a renewed scientific interest in this region of the brain. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID- 26607258 TI - Anemia Is a Risk Factor for Acute Kidney Injury and Long-Term Mortality in Critically Ill Patients. AB - Acute kidney injury (AKI) is a major health concern, because AKI is related with an increase in morbidity and mortality. Anemia is related to AKI in several clinical settings. However, the relationship between anemia and AKI and the effect of anemia on long-term mortality are unresolved in critically ill patients. A total of 2,145 patients admitted to the intensive care unit were retrospectively analyzed. We calculated a threshold value of hemoglobin associated with an increased risk of AKI and used this value to define anemia. The odds ratios (ORs) and hazard ratios for AKI and all-cause mortality were calculated after adjusting for multiple covariates. The OR of AKI increased depending on the decrease in hemoglobin level and the ideal threshold point of hemoglobin linked to increasing AKI risk was 10.5 g/dL. We categorized patients into anemia (< 10.5 g/dL) and non-anemia (>= 10.5 g/dL) groups. The risk of AKI was higher in the anemia group than the non-anemia group and this trend remained significant irrespective of the AKI development time (early vs. late) or duration (< 3 days vs. >= 3 days). Both anemia and AKI increased the 10-year mortality risk and this risk prediction was significantly separated by the presence of anemia and AKI. Furthermore, the risk prediction remained consistent irrespective of the AKI severity (i.e., recovery, stage, or duration of AKI). Based on these, we urge clinicians to monitor anemia and AKI in critically ill patients. PMID- 26607257 TI - Pharmacological Characterization of the Edema Caused by Vitalius dubius (Theraphosidae, Mygalomorphae) Spider Venom in Rats. AB - Bites by tarantulas (Theraphosidae, Mygalomorphae) in humans can result in mild clinical manifestations such as local pain, erythema, and edema. Vitalius dubius is a medium-sized, nonaggressive theraphosid found in southeastern Brazil. In this work, we investigated the mediators involved in the plasma extravasation caused by V. dubius venom in rats. The venom caused dose-dependent (0.1-100 MUg/site) edema in rat dorsal skin. This edema was significantly inhibited by ((S)1-{2-[3(3-4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)piperidine-3 yl]ethyl}-4-phenyl-1-azoniabicyclo[2.2.2]octone, chloride) (SR140333, a neurokinin NK1 receptor antagonist), indomethacin [a nonselective cyclooxygenase (COX) inhibitor], cyproheptadine (a serotonin 5-hydroxytryptamine1/2 and histamine H1 receptor antagonist), and N(omega)-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor). In contrast, mepyramine (a histamine H1 receptor antagonist), D-Arg-[Hyp(3),Thi(5),D-Tic(7),Oic(8)-]-BK (JE 049, a bradykinin B2 receptor antagonist), and ((S)-N-methyl-N-[4-(4-acetylamino-4 phenylpiperidino)-2-(3,4-di-chlorophenyl)butyl]benzamide) (SR48968, a neurokinin NK2 receptor antagonist) had no effect on the venom-induced increase in vascular permeability. In rat hind paws, the venom-induced edema was attenuated by ketoprofen (a nonselective COX inhibitor) administered 15 minutes postvenom. Preincubation of venom with commercial antiarachnid antivenom attenuated the venom-induced edema. These results suggest that the enhanced vascular permeability evoked by V. dubius venom involves serotonin, COX products, neurokinin NK1 receptors, and nitric oxide formation. The attenuation of hind paw edema by ketoprofen suggests that COX inhibitors could be useful in treating the local inflammatory response to bites by these spiders. PMID- 26607259 TI - Identification of polymorphic variants associated with erlotinib-related skin toxicity in advanced non-small cell lung cancer patients by DMET microarray analysis. AB - PURPOSE: Erlotinib is a targeted agent commonly used in advanced non-small cell lung cancer (aNSCLC). However, drug-related skin toxicity often may affect the quality of life of cancer patients and lead to treatment discontinuation. Genetic polymorphisms in drug transporters and metabolizing enzymes play a major role in the interindividual variability in terms of efficacy and toxicity of erlotinib treatment. The aim of our study was to identify genetic determinants in adsorption, distribution, metabolism, and excretion genes influencing skin rash (SR) by the novel drug-metabolizing enzyme and transporter (DMET) microarray Affymetrix platform in aNSCLC patients. METHODS: In a retrospective study, 34 erlotinib-treated aNSCLC patients were genotyped by DMET Plus chip: 23 patients experienced SR (cases), while 11 patients did not (controls). Peripheral blood DNA was genotyped. Genotype association was analyzed by Fisher's exact test, and the toxicity-associated gene sets underwent Ingenuity Pathway Analysis (IPA). RESULTS: Seven SNPs in six genes (CYP27B1, MAT1A1, CHST1, CYP4B1, ADH6, and SLC22A1) were associated with the occurrence of SR or with a protective effect. Specifically, the rs8176345 in CYP27B1 gene was significantly correlated with SR (p = 0.0003, OR 55.55, 95% CI 2.7036-1141.1707). The IPA on SR-related genes highlighted the role of a variety of canonical pathways including 1,25 dihydroxyvitamin D3 biosynthesis, S-adenosyl-L-methionine biosynthesis, and methionine degradation I (to homocysteine) in SR development. CONCLUSION: Although exploratory, this study indicates rs8176345 in CYP27B1 gene as significantly correlated with erlotinib-induced SR in aNSCLC patients probably through a mechanism mediated by vitamin D3 and inflammation at skin level. PMID- 26607260 TI - Flow of foam through a convergent channel. AB - We study experimentally the flow of a foam confined as a bubble monolayer between two plates through a convergent channel. We quantify the velocity, the distribution and orientation of plastic events, and the elastic stress, using image analysis. We use two different soap solutions: a sodium dodecyl sulfate (SDS) solution, with a negligible wall friction between the bubbles and the confining plates, and a mixture containing a fatty acid, giving a large wall friction. We show that for SDS solutions, the velocity profile obeys a self similar form which results from the superposition of plastic events, and the elastic deformation is uniform. For the other solution, the velocity field differs and the elastic deformation increases towards the exit of the channel. We discuss and quantify the role of wall friction on the velocity profile, the elastic deformation, and the rate of plastic events. PMID- 26607261 TI - Size-dependent effects of layered double hydroxide nanoparticles on cellular functions of mouse embryonic stem cells. AB - AIM: Layered double hydroxide nanoparticles (LDH NPs) are promising for stem cell research and applications. In this study, we investigated the size-dependent interactions of LDH NPs with mouse embryonic stem cells (mESCs). MATERIALS & METHODS: LDH NPs with diameters of 100 and 50 nm were synthesized and characterized. mESCs were cultured to undergo spontaneous differentiation. After incubation with LDH NPs, cytotoxicity, cellular uptake, pluripotency, differentiation and epithelial-mesenchymal transition process of mESCs were assessed. RESULTS: LDH NPs with the size of 50 nm induced higher cellular uptake and more outstandingly inhibited spontaneous differentiation and epithelial mesenchymal transition process. CONCLUSION: Our research demonstrated the size dependent effects of LDH NPs on controlling fate and cellular functions of mESCs. PMID- 26607256 TI - Regulation of neurological and neuropsychiatric phenotypes by locus coeruleus derived galanin. AB - Decades of research confirm that noradrenergic locus coeruleus (LC) neurons are essential for arousal, attention, motivation, and stress responses. While most studies on LC transmission focused unsurprisingly on norepinephrine (NE), adrenergic signaling cannot account for all the consequences of LC activation. Galanin coexists with NE in the vast majority of LC neurons, yet the precise function of this neuropeptide has proved to be surprisingly elusive given our solid understanding of the LC system. To elucidate the contribution of galanin to LC physiology, here we briefly summarize the nature of stimuli that drive LC activity from a neuroanatomical perspective. We go on to describe the LC pathways in which galanin most likely exerts its effects on behavior, with a focus on addiction, depression, epilepsy, stress, and Alzheimer's disease. We propose a model in which LC-derived galanin has two distinct functions: as a neuromodulator, primarily acting via the galanin 1 receptor (GAL1), and as a trophic factor, primarily acting via galanin receptor 2 (GAL2). Finally, we discuss how the recent advances in neuropeptide detection, optogenetics and chemical genetics, and galanin receptor pharmacology can be harnessed to identify the roles of LC-derived galanin definitively. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID- 26607262 TI - Intensive care unit surveillance of influenza infection in France: the 2009/10 pandemic and the three subsequent seasons. AB - During the 2009/10 pandemic, a national surveillance system for severe influenza cases was set up in France. We present results from the system's first four years. All severe influenza cases admitted to intensive care units (ICU) were reported to the Institut de Veille Sanitaire using a standardised form: data on demographics, immunisation and virological status, risk factors, severity (e.g. acute respiratory distress syndrome (ARDS) onset, mechanical ventilation, extracorporeal life support) and outcome. Multivariate analysis was performed to identify factors associated with ARDS and death. The number of confirmed influenza cases varied from 1,210 in 2009/10 to 321 in 2011/12. Most ICU patients were infected with A(H1N1)pdm09, except during the 2011/12 winter season when A(H3N2)-related infections predominated. Patients' characteristics varied according to the predominant strain. Based on multivariate analysis, risk factors associated with death were age >= 65 years, patients with any of the usual recommended indications for vaccination and clinical severity. ARDS occurred more frequently in patients who were middle-aged (36-55 years), pregnant, obese, or infected with A(H1N1)pdm09. Female sex and influenza vaccination were protective. These data confirm the persistent virulence of A(H1N1)pdm09 after the pandemic and the heterogeneity of influenza seasons, and reinforce the need for surveillance of severe influenza cases. PMID- 26607263 TI - pH-Sensitive self-assembling nanoparticles for tumor near-infrared fluorescence imaging and chemo-photodynamic combination therapy. AB - The development of visual tumor theranostic nanoparticles has become a great challenge. In this study, d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) was conjugated to acid-sensitive cis-aconitic anhydride-modified doxorubicin (CAD) to obtain pH-sensitive anti-tumor prodrug nanoparticles (TCAD NPs) via self-assembling. Subsequently, the photosensitizer chlorin e6 (Ce6) was loaded into the resulting prodrug nanoparticles to prepare a novel tumor near infrared fluorescence imaging and chemo-photodynamic combination therapy system (TCAD@Ce6 NPs). An accelerated release of doxorubicin (DOX) and chlorin e6 (Ce6) from the TCAD@Ce6 NPs could be achieved due to the hydrolysis of the acid sensitive amide linker under mild acidic conditions (pH = 5.5). An in vitro experiment showed that A549 lung cancer cells exhibited a significantly higher uptake of DOX and Ce6 by using our delivery system than the free form of DOX and Ce6. An in vivo experiment showed that TCAD@Ce6 NPs displayed better tumor targeting gathering through the enhanced permeability and retention (EPR) effect than free Ce6, thus improving fluorescence imaging. Moreover, the chemo photodynamic combination therapy of TCAD@Ce6 NPs combined with near-infrared laser irradiation was confirmed to be capable of inducing high apoptosis and necrosis of tumor cells (A549) in vitro and to display a significantly higher tumor growth suppression in the A549 lung cancer-bearing mice model. Furthermore, compared with exclusive chemotreatment (DOX) or photodynamic treatment (Ce6), our system showed enhanced therapeutic effects both in vitro and in vivo. In conclusion, the high performance TCAD@Ce6 NPs can be used as a promising NIR fluorescence imaging and highly effective chemo-photodynamic system for theranostics of lung cancer, etc. in the near future. PMID- 26607265 TI - Construction of recombinant Mip-FlaA dominant epitope vaccine against Legionella pneumophila and evaluation of the immunogenicity and protective immunity. AB - Legionnaires' disease, a kind of systemic disease with pneumonia as the main manifestation, is caused by Legionella pneumophila (L. pneumophila). In order to prevent the disease, we optimized Mip and FlaA, the virulence factors of L. pneumophila, to design recombinant Mip-FlaA dominant epitope vaccine against the pathogen. Firstly, the coding sequences of mip and flaA were optimized by DNAStar software and Expasy protein analysis system, and then, the tertiary structure and function of recombinant Mip-FlaA were predicted by PHYRE2 Protein Fold Recognition Server. After that, the optimized mip, flaA and mip-flaA were cloned, expressed and purified, and the proteins were used as dominant epitope vaccines to immunize BABL/c mice. Moreover, the IgG titers, histological changes in lung and the level of TNF-alpha, IFN-gamma, IL-6 and IL-1beta were detected to reflect the immunogenicity and protective immunity of the vaccines. The results of SDS PAGE and Western blot proved the recombinant Mip-FlaA was successfully expressed. ELISA results of IgG titers and these cytokines showed Mip-FlaA group was capable to induce the strongest immune response, compared to PBS, Mip and FlaA groups. In addition, histopathology analysis demonstrated the mice immunized with Mip-FlaA showed better immune protection. Therefore, the work indicated that the above described biological tools were useful in optimization of epitope vaccine. Antigenic characterization and immune protection of recombinant Mip-FlaA would be of great value in understanding the immunopathogenesis of the disease and in developing possible vaccine against the pathogen. PMID- 26607266 TI - Cluster of late preterm and term neonates with necrotizing enterocolitis symptomatology: descriptive and case-control study. AB - OBJECTIVE: To investigate a necrotizing enterocolitis (NEC) cluster of late preterm and term neonates (gestational age >=34 weeks). METHODS: We conducted a descriptive and a case-control study. Medical records of neonates with modified Bell stage >= IB NEC and matched controls were reviewed, in addition to microbiological and environmental investigation. Study variables included maternal/delivery and neonatal factors, medications, procedures and feeding practices. Univariable/multivariable logistic regression analyses were performed for all and for stage >= II cases. RESULTS: Out of 1841 late preterm and term neonates, 10 stage IB and 10 stage >= II [mean(SD) birthweight 2529.3 (493.04) g, gestational age 36.96 (1.48) weeks] presented with NEC symptomatology at mean 4.6 (range 2-8) days. Nearly all (19/20) resulted from high-risk pregnancies and received postpartum intermediate care. All were exclusively or partly formula fed. Most (14/20) were born by cesarean delivery. Eight underwent surgery, with no fatality. Intermediate care (p = 0.006), transient tachypnea (p = 0.049), not receiving breast milk (p = 0.019) and in addition intrauterine growth restriction (IUGR) (p = 0.017) for stage >= II cases were independently associated with NEC. CONCLUSIONS: Late preterm and term neonates in need of intermediate care, with IUGR and transient tachypnea were susceptible to NEC; feeding with breast milk was an important protective factor. PMID- 26607264 TI - Tumor MICA status predicts the efficacy of immunotherapy with cytokine-induced killer cells for patients with gastric cancer. AB - In this study, we determine the relationship between the expression of major histocompatibility complex class I chain-related gene A (MICA) in gastric cancer tumors after D2 gastrectomy and the clinical outcome of a CIK-containing adjuvant therapy. Ninety-five consecutive patients with gastric cancer after D2 gastrectomy who received adjuvant chemotherapy combined with CIK cell therapy were enrolled. The MICA expression of their tumors was determined by immunohistochemistry (IHC). High expression of MICA protein was documented by IHC in 38 of 95 tumor samples (40.0 %). The MICA status was significantly associated with the age and stage, p = 0.008 and 0.023, respectively. Analysis of NKG2D on in vitro expanded CIK cells showed that the percentages of NKG2D+ in CD3+/CD56+, CD3-/CD56+, and CD3+/CD8+ cells populations were 97.2 +/- 1.4, 97.9 +/- 1.8, and 95.6 +/- 2.1 %, respectively. For patient with high MICA-expressing tumors, the median DFS and OS were longer than for the patients with tumors with low expression of MICA; 46.0 versus 41.0 months (p = 0.027), and 48.0 versus 42.0 months (p = 0.031), respectively. In a multivariate analysis, stage and MICA expression were independent prognostic factors for DFS and OS. Our findings show that adjuvant chemotherapy plus CIK therapy treatment is a promising modality for treating gastric cancer patients after D2 gastrectomy. Especially, those who have tumors with high expression of MICA were more likely to benefit from such a treatment strategy. Subsequent studies in clinical trial cohorts will be required to confirm the clinical utility of these markers. PMID- 26607270 TI - Interaction of nucleobases with silicon doped and defective silicon doped graphene and optical properties. AB - The interaction of nucleobases (NBs) with the surface of silicon doped graphene (SiGr) and defective silicon doped graphene (dSiGr) has been studied using electronic structure methods. A systematic comparison of the calculated interaction energies (adsorption strength) of NBs with the surface of SiGr and dSiGr with those of pristine graphene (Gr) has also been made. The doping of graphene with silicon increases the adsorption strength of NBs. The introduction of defects in SiGr further enhances the strength of interaction with NBs. The appreciable stability of complexes (SiGr-NBs and dSiGr-NBs) arises due to the partial electrostatic and covalent (Si...O(N)) interaction in addition to pi-pi stacking. The interaction energy increases with the size of graphene models. The strong interaction between dSiGr-NBs and concomitant charge transfer causes significant changes in the electronic structure of dSiGr in contrast to Gr and SiGr. Further, the calculated optical properties of all the model systems using time dependent density functional theory (TD-DFT) reveal that absorption spectra of SiGr and dSiGr undergo appreciable changes after adsorption of NBs. Thus, the significant variations in the HOMO-LUMO gap and absorption spectra of dSiGr after interaction with the NBs can be exploited for possible applications in the sensing of DNA nucleobases. PMID- 26607269 TI - Upregulation of Dickkopf1 by oscillatory shear stress accelerates atherogenesis. AB - Numerous clinical studies have highlighted the pivotal role Dickkopf (DKK) 1 plays in atherosclerosis, but the underlying mechanisms remain unknown. The present study was designed to explore the contribution of DKK1 to the development of atherosclerosis under oscillatory shear stress. Oscillatory shear stress applied to endothelial cells induced DKK1 expression, which peaked at 6 h. siRNA knockdown or silencing DKK1 by lentiviral gene delivery counteracted the increased monocyte adhesion and impaired endothelial tight junction induced by oscillatory shear stress, thereby attenuating atherogenesis in ApoE-/- mice. As well, activation of endothelial proteinase-activated receptor 1 (PAR1) and its downstream transcription factor, cAMP response element-binding protein (CREB), was critical to the increased expression of DKK1 under oscillatory shear stress. We provide evidence that DKK1 contributes to the development of atherosclerosis under conditions of oscillatory shear stress. A better understanding of the role played by DKK1 in atherogenesis may provide clinicians with opportunities to prevent atherosclerosis. KEY MESSAGE: Disturbed oscillatory flow increases DKK1 expression. DKK1 knockdown attenuates OSS-induced monocyte adhesion and endothelial impairment. Genetic silencing of DKK1 limits atherogenesis in ApoE-/- mice. Activation of the PAR1/CREB pathway contributes to the upregulation of DKK1 via OSS. DKK1 is a promising candidate with respect to the treatment of atherosclerosis. PMID- 26607271 TI - Delayed Access to Involuntary Mental Health Examinations. AB - Delayed access to involuntary mental health examination for people who receive care in emergency departments (EDs) was examined, and factors that influenced delayed access were explored. A retrospective review of records for the 12 months prior to data collection was conducted to address the study questions. The health services utilization model served as the conceptual framework for this study. Societal, system, and individual factors were considered in examining access to involuntary emergency mental health examination by adult ED patients. Records of 170 people who sought care in EDs and who required involuntary mental health examinations at two hospitals in Florida served as the sources for study data. The mean duration of delay was 14.9 h. The determinants that were significantly associated with longer delays were being male, increased age, and intoxication. The findings can inform the allocation of resources to increase opportunities for positive long-term outcomes following involuntary care. PMID- 26607272 TI - Short Communication: HIV-1 Infection Suppresses Circulating Viral Restriction microRNAs. AB - MicroRNAs (miRNAs) participate in host innate immunity against HIV-1 infection. We examined the impact of HIV-1 infection on viral restriction miRNAs in plasma of HIV-1-infected subjects. HIV-1-infected subjects had significantly lower plasma levels of HIV-1 restriction miRNAs (miRs-29a, -29b, -125b, -223, -198, and -382) than control subjects. Further in vitro studies showed that HIV-1 infection of macrophages suppressed production of the extracellular miRs-29b, -125b, and 223. These data demonstrate the compelling evidence that HIV-1 infection impairs host innate immunity by inhibiting antiviral miRNAs, which provide a possible mechanism for HIV-1 persistence in the host. PMID- 26607274 TI - Did the late spring frost in 2007 and 2011 affect tree-ring width and earlywood vessel size in Pedunculate oak (Quercus robur) in northern Poland? AB - Trees are sensitive to extreme weather and environmental conditions. This sensitivity is visible in tree-ring widths and cell structure. In our study, we hypothesized that the sudden frost noted at the beginning of May in both 2007 and 2011 affected cambial activity and, consequently, the number and size of vessels in the tree rings. It was decided to test this hypothesis after damage to leaves was observed. The applied response function model did not show any significant relationships between spring temperature and growth. However, this method uses average values for long periods and sometimes misses the short-term effects. This is why we decided to study each ring separately, comparing them with rings unaffected by the late frost. Our study showed that the short-term effect of sudden frost in late spring did not affect tree rings and selected cell parameters. The most likely reasons for this are (i) cambial activity producing the earlywood vessels before the occurrence of the observed leaf damage, (ii) the forest micro-climate protecting the trees from the harsh frost and (iii) the temperature decline being too short-lived an event to affect the oaks. On the other hand, the visible damage may be occasional and not affect cambium activity and tree vitality at all. We conclude that oak is well-adapted to this phenomenon. PMID- 26607275 TI - Balneotherapy in rheumatoid arthritis-a systematic review. AB - Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent inflammation of synovial joints with pain, often leading to joint destruction and disability, and despite intensive research, the cause of RA remains unknown. Balneotherapy-also called mineral baths or spa therapy-uses different types of mineral water compositions like sulphur, radon, carbon dioxin, etc. The role of balneotherapy is on debate; Sukenik wrote that the sulphur mineral water has special proprieties to rheumatologic diseases, including in the course of active inflammatory phases in RA. The aim of this review is to summarize the available evidence on the effects of balneotherapy on patients with rheumatoid arthritis. We have made a systematic search of the articles published from 1980 to 2014 on this topic in PubMed, Scopus, CRD, PEDro, Web of Science and Embase databases. We have followed the method set by the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). These that have compared balneotherapy with other therapeutic modalities or with no intervention were considered. The inclusion criteria of these papers were randomized control trial (RCT); languages: English, French, Spanish, Italian and Portuguese; evaluation of efficacy (analysis of outcomes); use of natural mineral water baths; and participants with RA. A total of eight articles documenting RCTs were found and included for full review and critical appraisal involving a total of 496 patients. The studies selected highlighted an important improvement and statistically significant in several clinical parameters, in spite of their heterogeneity between the various studies. One study emphasized an important improvement on functional capacity up to 6 months of follow-up (FU). Some of the studies (std.) reveal an improvement on morning stiffness (5 std.), number of active joints (3 std.), Ritchie index (2 std.) and activities of daily living (2 std.) up to 3 months of FU. Three studies reveal the improvement on handgrip strength up to 1 month of FU. About pain (VAS), the three studies which evaluated this parameter were inconclusive about real significant improvement. Our tables summarize the published papers about this topic. Different authors emphasize the same problems: methodologies differing from study to study, treatment modalities, outcomes and their analysis. On the one hand, it is particularly difficult to have homogeneity on this population in all the parameters (patient's clinical heterogeneity, diverse clinical course of the disease, variety of the drugs), and on the other hand, natural mineral water composition is always unique with potential specific biological effects. This comprehensive review has revealed that there are very few published studies about the use of natural mineral water in RA. International multicentre studies, using the same methodologies, could be achieved by carrying the scientific arguments to support our clinical practice. PMID- 26607276 TI - Prevalence of left atrial thrombus in patients with non-valvular atrial fibrillation. A systematic review and meta-analysis of the literature. AB - We performed a meta-analysis about the prevalence of left atrial thrombus (LAT) in patients with atrial fibrillation (AF) undergoing trans-esophageal echocardiography (TEE). Studies reporting on LAT presence in AF patients were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases and the pooled LAT prevalence was evaluated as weighted mean prevalence (WMP). Seventy-two studies (20,516 AF patients) showed a LAT WMP of 9.8 % (95 %CI: 7.6 %-12.5 %). LAT presence was associated with a higher age (mean difference: 2.56, 95 %CI: 1.49-3.62), and higher prevalence of female gender (OR: 1.35, 95 %CI: 1.04-1.75), hypertension (OR: 1.78, 95 %CI: 1.38-2.30), diabetes mellitus (OR: 1.86, 95 %CI: 1.33-2.59) and chronic heart failure (OR: 3.67, 95 %CI: 2.40-5.60). Overall, LAT patients exhibited a higher CHADS2-score (mean difference 0.88, 95 %CI: 0.68-1.07) and a higher risk of stroke/systemic embolism (OR: 3.53, 95 %CI: 2.24-5.56) compared with those without LAT. A meta-regression showed an inverse association between LAT prevalence and the presence of anticoagulation (Z-value: -7.3, p< 0.001). Indeed, studies in which 100 % of patients received oral anticoagulation reported a 3.4 % WMP of LAT (95 %CI: 1.3 % 8.7 %), whereas studies in which 0 % of patients received anticoagulation showed a LAT WMP of 7.4 % (95 %CI: 2.3 %-21.5 %). Our data suggest that LAT is present in ?10 % of AF patients, and is associated with a 3.5-fold increased risk of stroke/systemic embolism. Interestingly, LAT is also reported in some of patients receiving anticoagulation. The implementation of the screening of LAT in AF patients before cardioversion/ablation could be useful for the prevention of vascular events. PMID- 26607277 TI - Vitamin D for hypertension: should we continue the search? PMID- 26607273 TI - Contaminant-induced oxidative stress in fish: a mechanistic approach. AB - The presence of reactive oxygen species (ROS) in living organisms was described more than 60 years ago and virtually immediately it was suggested that ROS were involved in various pathological processes and aging. The state when ROS generation exceeds elimination leading to an increased steady-state ROS level has been called "oxidative stress." Although ROS association with many pathological states in animals is well established, the question of ROS responsibility for the development of these states is still open. Fish represent the largest group of vertebrates and they inhabit a broad range of ecosystems where they are subjected to many different aquatic contaminants. In many cases, the deleterious effects of contaminants have been connected to induction of oxidative stress. Therefore, deciphering of molecular mechanisms leading to such contaminant effects and organisms' response may let prevent or minimize deleterious impacts of oxidative stress. This review describes general aspects of ROS homeostasis, in particular highlighting its basic aspects, modification of cellular constituents, operation of defense systems and ROS-based signaling with an emphasis on fish systems. A brief introduction to oxidative stress theory is accompanied by the description of a recently developed classification system for oxidative stress based on its intensity and time course. Specific information on contaminant-induced oxidative stress in fish is covered in sections devoted to such pollutants as metal ions (particularly iron, copper, chromium, mercury, arsenic, nickel, etc.), pesticides (insecticides, herbicides, and fungicides) and oil with accompanying pollutants. In the last section, certain problems and perspectives in studies of oxidative stress in fish are described. PMID- 26607278 TI - Author's reply to Valentine, Ninan, and Dalal and colleagues. PMID- 26607279 TI - Evaluating Best Practices in Raman Spectral Analysis for Uranium Speciation and Relative Abundance in Aqueous Solutions. AB - Raman spectroscopy is emerging as a powerful tool for identifying hexavalent uranium speciation in situ; however, there is no straightforward protocol for identifying uranyl species in solution. Herein, uranyl samples are evaluated using Raman spectroscopy, and speciation is monitored at various solution pH values and anion compositions. Spectral quality is evaluated using two Raman excitation wavelengths (532 and 785 nm) as these are critical for maximizing signal-to-noise and minimizing background from fluorescent uranyl species. The Raman vibrational frequency of uranyl shifts according to the identity of the coordinating ions within the equatorial plane and/or solution pH; therefore, spectral barcode analysis and rigorous peak fitting methods are developed that allow accurate and routine uranium species identification. All in all, this user's guide is expected to provide a user-friendly, straightforward approach for uranium species identification using Raman spectroscopy. PMID- 26607280 TI - Fibulin-4 deficiency increases TGF-beta signalling in aortic smooth muscle cells due to elevated TGF-beta2 levels. AB - Fibulins are extracellular matrix proteins associated with elastic fibres. Homozygous Fibulin-4 mutations lead to life-threatening abnormalities such as aortic aneurysms. Aortic aneurysms in Fibulin-4 mutant mice were associated with upregulation of TGF-beta signalling. How Fibulin-4 deficiency leads to deregulation of the TGF-beta pathway is largely unknown. Isolated aortic smooth muscle cells (SMCs) from Fibulin-4 deficient mice showed reduced growth, which could be reversed by treatment with TGF-beta neutralizing antibodies. In Fibulin 4 deficient SMCs increased TGF-beta signalling was detected using a transcriptional reporter assay and by increased SMAD2 phosphorylation. Next, we investigated if the increased activity was due to increased levels of the three TGF-beta isoforms. These data revealed slightly increased TGF-beta1 and markedly increased TGF-beta2 levels. Significantly increased TGF-beta2 levels were also detectable in plasma from homozygous Fibulin-4(R/R) mice, not in wild type mice. TGF-beta2 levels were reduced after losartan treatment, an angiotensin-II type-1 receptor blocker, known to prevent aortic aneurysm formation. In conclusion, we have shown increased TGF-beta signalling in isolated SMCs from Fibulin-4 deficient mouse aortas, not only caused by increased levels of TGF-beta1, but especially TGF-beta2. These data provide new insights in the molecular interaction between Fibulin-4 and TGF-beta pathway regulation in the pathogenesis of aortic aneurysms. PMID- 26607281 TI - Subglottic Squamous Cell Carcinoma: A Population-Based Study of 889 Cases. AB - OBJECTIVE: Subglottic squamous cell carcinoma (SCCa) is a rare malignancy representing <5% of all laryngeal cancers. Patients often present with late-stage disease, and survival outcomes are reportedly worse than those for SCCa in other regions of the larynx. STUDY DESIGN: Analysis of a population-based tumor registry. SETTING: Academic medical center. SUBJECTS AND METHODS: The US National Cancer Institute's Surveillance, Epidemiology, and End Results database was queried for cases of subglottic SCCa from 1973 to 2011 (889 cases). Resulting data were analyzed, including patient demographics, therapeutic measures, and survival outcomes. RESULTS: Subglottic SCCa most frequently occurred in the fifth to seventh decade of life, with a mean age at diagnosis of 65.7 +/- 11.3 years. There was a strong male predilection, with a male:female ratio of 3.83:1. Most patients were stage III and IV (64.4%) per the American Joint Committee on Cancer. The most common treatment modality was a combination of radiotherapy and surgery (38.8%), followed by radiotherapy alone (33.9%), and surgery alone (17.0%). Overall 5-year disease-specific survival rate was 53.7%. When stratified by treatment modality, 5-year disease-specific survival was 62.4% for surgery alone, 56.7% for radiotherapy alone, and 55.1% for surgery with adjuvant radiotherapy (P = .3892). CONCLUSION: This study represents the largest cohort of subglottic SCCa. It shows a strong predilection for men in the US population. Surgery with adjuvant radiotherapy was the most commonly employed treatment modality. No statistically significant differences were observed in 5-year DSS by treatment modality. PMID- 26607282 TI - Reoperative Parathyroidectomy: Overly Descended Superior Adenoma. AB - OBJECTIVES: To identify the importance of the ectopic, overly descended superior parathyroid adenoma variant and its prevalence in primary and reoperative parathyroid surgery and the implications for successful initial parathyroidectomy. STUDY DESIGN: Case series with planned data collection. SETTING: Tertiary endocrine surgery practice in an academic medical center. SUBJECTS AND METHODS: An analysis was undertaken of 561 consecutive patients undergoing parathyroid surgery in a tertiary endocrine surgery practice from March 2004 to April 2013. There were 270 patients who had curative primary or reoperative surgery for single-gland parathyroid adenomas during this time. Clinical records, imaging studies, operative reports, and pathology findings were evaluated, and cases from a subset of patients who had an ectopic, overly descended superior parathyroid adenoma were further analyzed. The prevalence of this entity in primary and revision surgeries was calculated. RESULTS: Among the 270 patients with single-gland parathyroid adenomas, there were 251 primary operations and 19 reoperative procedures referred from outside institutions. An ectopic, overly descended superior parathyroid adenoma was present in 23 (9.2%) primary cases and 4 (21.1%) reoperative cases. CONCLUSION: An overly descended superior parathyroid adenoma is frequently encountered during primary parathyroid surgery. It is more than twice as common in reoperative parathyroidectomy, reflecting the propensity to be missed at the first exploration. Recognition and proper treatment of this entity at the initial operation will reduce the need for revision surgery. PMID- 26607283 TI - Neural repair: Redirecting regeneration. PMID- 26607284 TI - Synaptic physiology: Dual role for dopamine. PMID- 26607285 TI - Effect of sonic stimulation on Bacillus endospore germination. AB - This study investigates the effect of sonic stimulation on Bacillus endospore germination. Germinating endospores in a microtiter plate were exposed to audible sound wave generated by an array of piezoelectric transducers. In situ germination kinetics was measured by terbium-dipicolinate fluorescence assay, optical density measurement and phase contrast microscopy. Fluorescence results revealed that sonic stimulation (5 kHz at 90 dB) promoted the germination speed by 43.7% +/- 11.3% and final germination level by 61.7% +/- 11.9% of Bacillus atrophaeus. This acoustic energy absorbed by endospores is postulated to change membrane permeability and increase enzyme activities; thereby, expediting the germination process. This also raises the likelihood of dormant endospores undergoing germination because of a rapid release of unidentified chemical mediators for quorum sensing. On the other hand, acoustic effect was not observed in B. subtilis endospores. This may be attributed to the different spore aspect ratio, 1.43 +/- 0.05 for B. atrophaeus and 2.02 +/- 0.08 for B. subtilis, which results in a difference in specific absorption rates towards audible sound waves. Our results demonstrate the modulation of endospore germination by an external field to shed light on germination mechanism and cell-wave interaction. PMID- 26607286 TI - FgNoxR, a regulatory subunit of NADPH oxidases, is required for female fertility and pathogenicity in Fusarium graminearum. AB - Fusarium graminearum is a filamentous fungal pathogen that causes wheat Fusarium head blight. In this study, we identified FgNoxR, a regulatory subunit of NADPH oxidases (Nox) in F. graminearum, and found that it plays an important role in the pathogenicity of F. graminearum. FgNoxR is localized on punctate structures throughout the cytoplasm in aerial hyphae while these structures tend to accumulate at or near the plasma membrane, septa and hyphal tips in germinated conidia. Deletion of the FgNOXR gene results in reduced conidiation and germination. Importantly, sexual development is totally abolished in the FgNOXR deletion mutant. In addition, the disease lesion of FgNOXR deletion mutant is limited to the inoculated spikelets of wheat heads. Finally, FgNoxR interacts with FgRac1 and FgNoxA, and all three proteins are required for female fertility. Taken together, our data indicate that FgNoxR contributes to conidiation, sexual reproduction and pathogenesis in F. graminearum. PMID- 26607288 TI - Aroma improvement by repeated freeze-thaw treatment during Tuber melanosporum fermentation. AB - The aroma attributes of sulfurous, mushroom and earthy are the most important characteristics of the aroma of Tuber melanosporum. However, these three aroma attributes are absent in the T. melanosporum fermentation system. To improve the quality of the aroma, repeated freeze-thaw treatment (RFTT) was adopted to affect the interplay of volatile organic compounds (VOCs). Using RFTT, not only was the score on the hedonic scale of the aroma increased from the "liked slightly" to the "liked moderately" grade, but the aroma attributes of sulfurous, mushroom and earthy could also be smelled in the T. melanosporum fermentation system for the first time. A total of 29 VOCs were identified, and 9 compounds were identified as the key discriminative volatiles affected by RFTT. Amino acid analysis revealed that methionine, valine, serine, phenylalanine, isoleucine and threonine were the key substrates associated with the biosynthesis of the 9 key discriminative VOCs. This study noted that amino acid metabolism played an important role in the regulation of the aroma of the T. melanosporum fermentation system. PMID- 26607289 TI - Is Passive Syntax Semantically Constrained? Evidence From Adult Grammaticality Judgment and Comprehension Studies. AB - To explain the phenomenon that certain English verbs resist passivization (e.g., *L5 was cost by the book), Pinker (1989) proposed a semantic constraint on the passive in the adult grammar: The greater the extent to which a verb denotes an action where a patient is affected or acted upon, the greater the extent to which it is compatible with the passive. However, a number of comprehension and production priming studies have cast doubt upon this claim, finding no difference between highly affecting agent-patient/theme-experiencer passives (e.g., Wendy was kicked/frightened by Bob) and non-actional experiencer theme passives (e.g., Wendy was heard by Bob). The present study provides evidence that a semantic constraint is psychologically real, and is readily observed when more fine grained independent and dependent measures are used (i.e., participant ratings of verb semantics, graded grammaticality judgments, and reaction time in a forced choice picture-matching comprehension task). We conclude that a semantic constraint on the passive must be incorporated into accounts of the adult grammar. PMID- 26607290 TI - Anterior cervical corpectomy and fusion for blastomycosis causing destruction of C6 vertebra: a case report. AB - INTRODUCTION: We describe a patient who had cervical spine osteomyelitis caused by Blastomyces dermatitidis that resulted in cord compression and cervical spine instability. CASE PRESENTATION: A 25-year-old Hispanic woman presented with fever, sweats, neck pain, and an enlarging neck mass with purulent discharge after sustaining a C6 vertebral body fracture. Magnetic resonance imaging confirmed C6 vertebral osteomyelitis, demonstrated by vertebral body destruction, cervical spine instability, prevertebral abscess, and spinal cord compression. She underwent C6 anterior cervical corpectomy and fusion, with fungal cultures confirming Blastomyces dermatitidis. CONCLUSIONS: Anterior cervical corpectomy and fusion successful debrided, decompressed, and restored cervical spine stability in a patient with vertebral osteomyelitis caused by Blastomyces dermatitidis. The patient was subsequently treated with a 1-year course of itraconazole and had no recurrence of infection 4 years postoperatively. PMID- 26607291 TI - High Rates of Undiagnosed Psychological Distress Exist in a Referral Population for Spinal Cord Stimulation in the Management of Chronic Pain. AB - BACKGROUND: Neuropathic pain affects various dimensions of patient health including physical, psychological, and socioeconomic. The spectrum of psychological dysfunction that accompanies this pain phenotype is unknown, as well as differences based on the etiology of the pain among patients referred for spinal cord stimulation (SCS). METHODS: We prospectively assessed SCS referral patients with neuropathic pain for features of psychological distress, either mood or anxiety. Demographic data included age, gender, diagnosis, marital status, and educational level. Screening tools were applied for neuropathic pain (Douleur Neuropathic Quatre and Leeds Assessment of Neuropathic Symptoms and Signs) and psychological distress (Beck Depression Inventory [BDI] and Beck Anxiety Inventory [BAI]). Descriptive statistics defined disease prevalence, compared by gender and diagnosis. Logistic regression correlated pain intensity with severity of psychopathology. RESULTS: Among 150 patients with suitable neuropathic pain diagnoses and no treatable structural pathology, 57% were women, median age was 54 years, and 35% and 42% admitted to routine smoking and alcohol use, respectively. The most common diagnoses were complex regional pain syndrome (46%) and failed back surgery syndrome (38%). Depression symptoms were screened positive by BDI in 63% of patients, and anxiety symptoms were screened positive by BAI in 23% of patients. Pain intensity correlated with BDI scores (p < 0.02) but not BAI scores (p = 0.43). CONCLUSION: The high frequency of depressive and anxiety symptoms screened by the Beck scores in this cohort is an order of magnitude higher than seen in the general population. That many of these cases are undiagnosed should motivate clinicians from primary care providers, comprehensive pain specialists, and surgeons to screen SCS patients for such psychopathology. This represents an opportunity to enhance overall pain management as well as success with invasive neuromodulation strategies. PMID- 26607287 TI - Are There Deleterious Cardiac Effects of Acute and Chronic Endurance Exercise? AB - Multiple epidemiological studies document that habitual physical activity reduces the risk of atherosclerotic cardiovascular disease (ASCVD), and most demonstrate progressively lower rates of ASCVD with progressively more physical activity. Few studies have included individuals performing high-intensity, lifelong endurance exercise, however, and recent reports suggest that prodigious amounts of exercise may increase markers for, and even the incidence of, cardiovascular disease. This review examines the evidence that extremes of endurance exercise may increase cardiovascular disease risk by reviewing the causes and incidence of exercise related cardiac events, and the acute effects of exercise on cardiovascular function, the effect of exercise on cardiac biomarkers, including "myocardial" creatine kinase, cardiac troponins, and cardiac natriuretic peptides. This review also examines the effect of exercise on coronary atherosclerosis and calcification, the frequency of atrial fibrillation in aging athletes, and the possibility that exercise may be deleterious in individuals genetically predisposed to such cardiac abnormalities as long QT syndrome, right ventricular cardiomyopathy, and hypertrophic cardiomyopathy. This review is to our knowledge unique because it addresses all known potentially adverse cardiovascular effects of endurance exercise. The best evidence remains that physical activity and exercise training benefit the population, but it is possible that prolonged exercise and exercise training can adversely affect cardiac function in some individuals. This hypothesis warrants further examination. PMID- 26607292 TI - Sway-dependent changes in standing ankle stiffness caused by muscle thixotropy. AB - KEY POINTS: The passive stiffness of the calf muscles contributes to standing balance, although the properties of muscle tissue are highly labile. We investigated the effect of sway history upon intrinsic ankle stiffness and demonstrated reductions in stiffness of up to 43% during conditions of increased baseline sway. This sway dependence was most apparent when using low amplitude stiffness-measuring perturbations, and the short-range stiffness component was smaller during periods of high sway. These characteristics are consistent with the thixotropic properties of the calf muscles causing the observed changes in ankle stiffness. Periods of increased sway impair the passive stabilization of standing, demanding more active neural control of balance. Quiet standing is achieved through a combination of active and passive mechanisms, consisting of neural control and intrinsic mechanical stiffness of the ankle joint, respectively. The mechanical stiffness is partly determined by the calf muscles. However, the viscoelastic properties of muscle are highly labile, exhibiting a strong dependence on movement history. By measuring the effect of sway history upon ankle stiffness, the present study determines whether this lability has consequences for the passive stabilization of human standing. Ten subjects stood quietly on a rotating platform whose axis was collinear with the ankle joint. Ankle sway was increased by slowly tilting this platform in a random fashion, or decreased by fixing the body to a board. Ankle stiffness was measured by using the same platform to simultaneously apply small, brief perturbations (<0.6 deg; 140 ms) at the same time as the resulting torque response was recorded. The results show that increasing sway reduces ankle stiffness by up to 43% compared to the body-fixed condition. Normal quiet stance was associated with intermediate values. The effect was most apparent when using smaller perturbation amplitudes to measure stiffness (0.1 vs. 0.6 deg). Furthermore, torque responses exhibited a biphasic pattern, consisting of an initial steep rise followed by a shallower increase. This transition occurred earlier during increased levels of ankle sway. These results are consistent with a movement-dependent change in passive ankle stiffness caused by thixotropic properties of the calf muscle. The consequence is to place increased reliance upon active neural control during times when increased sway renders ankle stiffness low. PMID- 26607294 TI - Renin angiotensinogen system gene polymorphisms and essential hypertension among people of West African descent: a systematic review. AB - This systematic review investigates the high level of hypertension found among urban dwellers in West Africa and in the West African Diaspora in the Americas in relation to variants within the genes encoding the renin angiotensinogen system. For comparison, the results from the Caucasian populations are reviewed as well. Through a PubMed search, 1252 articles were identified and 28 eligible articles assessed in detail of which 13 included a Caucasian population. The results suggest that among the people of West African descent and among the people of Caucasian descent, hypertension is partly related to a number of single nucleotide polymorphisms (SNPs) and haplotypes in the renin gene, the angiotensinogen gene, the angiotensinogen I-converting enzyme gene and the angiotensinogen II type 1 receptor gene. Concordance between these two populations was found for some SNPs. However, for others, it was found that the SNPs associating with hypertension and the disease allele frequencies differed between these populations. Understanding the importance of these variants in a modern life setting may assist our understanding of the increased risk of developing hypertension among West Africans. Because of inconsistency in the results, low statistical power and methodological differences between studies, these results can only be taken as indicative of an association. PMID- 26607295 TI - Serum carboxymethyl-lysine, a dominant advanced glycation end product, is increased in women with gestational diabetes mellitus. AB - AIMS: The objective of the study was to measure one of the circulating Advanced Glycation End Products (AGEs) - Nepsilon-(carboxymethyl)lysine (CML) - in a case control study (n = 307) of pregnant women with gestational diabetes mellitus (GDM) and physiological pregnancies and to ascertain the factors contributing to CML levels and the potential relevance of CML for selected perinatal and postpartum outcomes. METHODS: All subjects underwent oGTT between 24th and 30th week of gestation and GDM was diagnosed according to WHO criteria. CML was determined by ELISA using commercial kit. RESULTS: Unadjusted and plasma protein adjusted CML levels were significantly higher in women with GDM compared to healthy controls (P = 0.00043 and P = 1x10(-5), respectively, Mann-Whitney). CML was significantly inversely correlated with both pre- and mid-gestational BMI, however, differences between GDM and control group remained significant even after adjustment for BMI. CML levels correlated with 1-h and 2-h post-load glycaemia during oGTT. CONCLUSION: In conclusion, we found statistically significantly higher protein- and BMI-normalised CML levels measured during 24 30th week of gestation in women with GDM compared to healthy pregnant controls. Further studies are warranted to comprehensively asses the spectrum of AGEs in GDM and their relevance to future metabolic health of mother and offspring. PMID- 26607293 TI - Identification of potential inhibitors based on compound proposal contest: Tyrosine-protein kinase Yes as a target. AB - A search of broader range of chemical space is important for drug discovery. Different methods of computer-aided drug discovery (CADD) are known to propose compounds in different chemical spaces as hit molecules for the same target protein. This study aimed at using multiple CADD methods through open innovation to achieve a level of hit molecule diversity that is not achievable with any particular single method. We held a compound proposal contest, in which multiple research groups participated and predicted inhibitors of tyrosine-protein kinase Yes. This showed whether collective knowledge based on individual approaches helped to obtain hit compounds from a broad range of chemical space and whether the contest-based approach was effective. PMID- 26607296 TI - Expression profiles of somatostatin, dopamine, and estrogen receptors in pituitary adenomas determined by means of synthetic multilocus calibrators. AB - AIMS: Pituitary adenomas (PA) are non-invasive benign tumors with a high autopsy prevalence. They are classified according to the type of hormone secreted (prolactin, growth hormone, adrenocorticotropin, thyrotropin, folitropin, or luteinizing hormone). Clinically non-functioning adenomas (CNFA) lacking the typical hypersecretion of hormones make up a significant portion of PA. The aim of the study was to determine the complete expression profiles of somatostatin receptors (SSTR1-SSTR5), dopamine receptors type 2 (D2R), and estrogen receptors (ER1) in various types of PA. METHODS: Adenoma specimens were obtained from 206 patients during transsphenoidal resection. For quantitative analysis, reverse transcription and consequent real-time PCR with synthetic multilocus calibrators (SMC) were used. The obtained data were normalized to the number of transcripts of the beta-glucuronidase gene. RESULTS: The use of SMC enabled the alignment of individual calibration functions for all the receptors. No relationships between the expression of the receptors and the tumor size, site of extension, gender or age at diagnosis were significant. In growth hormone-secreting adenomas, D2R and SSTR2 transcripts were extensively expressed, followed by ER1, SSTR5, SSTR3, and SSTR1. In patients with macroprolactinomas, transsphenoidal resection was indicated because dopamine agonists did not normalize prolactin levels. D2R, ER1 and SSTR1 transcripts were significantly transcribed. Corticotroph adenomas showed high levels of D2R and ER1 transcripts and lower amounts of SSTR2 and SSTR1 transcripts. SSTR5 transcripts were very low. Subjects with CNFA dominantly expressed D2R and ER1, followed by SSTR2 and SSTR3 mRNA. CONCLUSION: We evaluated SSTR1-SSTR5, D2R, and ER1 expressions in a large group of pituitary adenomas and we found that determining their individual expression profiles could help when choosing the optimal postoperative treatment. PMID- 26607297 TI - Alogliptin for the treatment of type 2 diabetes: a drug safety evaluation. AB - INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors such as alogliptin are becoming more widely established as treatment options for patients with type 2 diabetes (T2DM) because of their ability to improve glycemic control without increasing the risk of hypoglycemia or weight gain. New therapies with improved safety profiles are needed, especially because of the chronic and progressive nature of T2DM. AREAS COVERED: In this article, the overall safety and tolerability of alogliptin are evaluated based upon a review of the literature. In particular, adverse events (AEs) that have been of interest for the DPP-4 class of drugs, such as the risk of major cardiovascular (CV) events and acute pancreatitis, will be investigated in detail. EXPERT OPINION: Alogliptin is generally well-tolerated in a broad range of patient populations including different ethnic groups and the elderly. In the pivotal EXAMINE clinical trial, alogliptin was found not to be associated with an increased risk of major CV events or acute pancreatitis/pancreatic cancer. PMID- 26607298 TI - Melatonin suppression of aerobic glycolysis (Warburg effect), survival signalling and metastasis in human leiomyosarcoma. AB - Leiomyosarcoma (LMS) represents a highly malignant, rare soft tissue sarcoma with high rates of morbidity and mortality. Previously, we demonstrated that tissue isolated human LMS xenografts perfused in situ are highly sensitive to the direct anticancer effects of physiological nocturnal blood levels of melatonin which inhibited tumour cell proliferative activity, linoleic acid (LA) uptake and metabolism to 13-hydroxyoctadecadienoic acid (13-HODE). Here, we show the effects of low pharmacological blood concentrations of melatonin following oral ingestion of a melatonin supplement by healthy adult human female subjects on tumour proliferative activity, aerobic glycolysis (Warburg effect) and LA metabolic signalling in tissue-isolated LMS xenografts perfused in situ with this blood. Melatonin markedly suppressed aerobic glycolysis and induced a complete inhibition of tumour LA uptake, 13-HODE release, as well as significant reductions in tumour cAMP levels, DNA content and [(3) H]-thymidine incorporation into DNA. Furthermore, melatonin completely suppressed the phospho-activation of ERK 1/2, AKT, GSK3beta and NF-kB (p65). The addition of S20928, a nonselective melatonin antagonist, reversed these melatonin inhibitory effects. Moreover, in in vitro cell culture studies, physiological concentrations of melatonin repressed cell proliferation and cell invasion. These results demonstrate that nocturnal melatonin directly inhibited tumour growth and invasion of human LMS via suppression of the Warburg effect, LA uptake and other related signalling mechanisms. An understanding of these novel signalling pathway(s) and their association with aerobic glycolysis and LA metabolism in human LMS may lead to new circadian-based therapies for the prevention and treatment of LMS and potentially other mesenchymally derived solid tumours. PMID- 26607299 TI - Meta-analysis of genome-wide association from genomic prediction models. AB - Genome-wide association (GWA) studies based on GBLUP models are a common practice in animal breeding. However, effect sizes of GWA tests are small, requiring larger sample sizes to enhance power of detection of rare variants. Because of difficulties in increasing sample size in animal populations, one alternative is to implement a meta-analysis (MA), combining information and results from independent GWA studies. Although this methodology has been used widely in human genetics, implementation in animal breeding has been limited. Thus, we present methods to implement a MA of GWA, describing the proper approach to compute weights derived from multiple genomic evaluations based on animal-centric GBLUP models. Application to real datasets shows that MA increases power of detection of associations in comparison with population-level GWA, allowing for population structure and heterogeneity of variance components across populations to be accounted for. Another advantage of MA is that it does not require access to genotype data that is required for a joint analysis. Scripts related to the implementation of this approach, which consider the strength of association as well as the sign, are distributed and thus account for heterogeneity in association phase between QTL and SNPs. Thus, MA of GWA is an attractive alternative to summarizing results from multiple genomic studies, avoiding restrictions with genotype data sharing, definition of fixed effects and different scales of measurement of evaluated traits. PMID- 26607301 TI - Desire for greater clarity when defining 'cognitive remediation' in reviews of treatment efficacy for schizophrenia. PMID- 26607300 TI - Device-Associated Infection Rates in 20 Cities of India, Data Summary for 2004 2013: Findings of the International Nosocomial Infection Control Consortium. AB - OBJECTIVE: To report the International Nosocomial Infection Control Consortium surveillance data from 40 hospitals (20 cities) in India 2004-2013. METHODS: Surveillance using US National Healthcare Safety Network's criteria and definitions, and International Nosocomial Infection Control Consortium methodology. RESULTS: We collected data from 236,700 ICU patients for 970,713 bed days Pooled device-associated healthcare-associated infection rates for adult and pediatric ICUs were 5.1 central line-associated bloodstream infections (CLABSIs)/1,000 central line-days, 9.4 cases of ventilator-associated pneumonia (VAPs)/1,000 mechanical ventilator-days, and 2.1 catheter-associated urinary tract infections/1,000 urinary catheter-days In neonatal ICUs (NICUs) pooled rates were 36.2 CLABSIs/1,000 central line-days and 1.9 VAPs/1,000 mechanical ventilator-days Extra length of stay in adult and pediatric ICUs was 9.5 for CLABSI, 9.1 for VAP, and 10.0 for catheter-associated urinary tract infections. Extra length of stay in NICUs was 14.7 for CLABSI and 38.7 for VAP Crude extra mortality was 16.3% for CLABSI, 22.7% for VAP, and 6.6% for catheter-associated urinary tract infections in adult and pediatric ICUs, and 1.2% for CLABSI and 8.3% for VAP in NICUs Pooled device use ratios were 0.21 for mechanical ventilator, 0.39 for central line, and 0.53 for urinary catheter in adult and pediatric ICUs; and 0.07 for mechanical ventilator and 0.06 for central line in NICUs. CONCLUSIONS: Despite a lower device use ratio in our ICUs, our device associated healthcare-associated infection rates are higher than National Healthcare Safety Network, but lower than International Nosocomial Infection Control Consortium Report. PMID- 26607302 TI - Decreased long- and short-range functional connectivity at rest in drug-naive major depressive disorder. AB - BACKGROUND: Abnormal functional connectivity has been observed in major depressive disorder. Anatomical distance may affect functional connectivity in patients with major depressive disorder. However, whether and how anatomical distance affects functional connectivity at rest remains unclear in drug-naive patients with major depressive disorder. METHODS: Forty-four patients with major depressive disorder, as well as 44 age-, sex- and education-matched healthy controls, underwent resting-state functional magnetic resonance imaging scanning. Regional functional connectivity strength was calculated for each voxel in the whole brain, which was further divided into short- and long-range functional connectivity strength. RESULTS: The patients showed decreased long-range positive functional connectivity strength in the right inferior parietal lobule, as well as decreased short-range positive functional connectivity strength in the right insula and right superior temporal gyrus relative to those of the controls. No significant correlations existed between abnormal functional connectivity strength and the clinical variables of the patients. CONCLUSION: The findings revealed that anatomical distance decreases long- and short-range functional connectivity strength in patients with major depressive disorder, which may underlie the neurobiology of major depressive disorder. PMID- 26607303 TI - The mental health of fire-fighters: An examination of the impact of repeated trauma exposure. AB - OBJECTIVE: Emergency workers, such as fire-fighters, are routinely exposed to potentially traumatic events. While a number of studies have examined the occurrence of post-traumatic stress disorder, the role of multiple traumas on other mental health sequelae, such as depression and alcohol misuse, among emergency workers remains unclear. This study aimed to assess the prevalence of post-traumatic stress disorder, depression and alcohol misuse in a sample of current and retired fire-fighters and examine their relationship with cumulative trauma exposure. METHOD: A cross-sectional survey was completed by current (n = 488) and retired (n = 265) fire-fighters from Fire and Rescue New South Wales, Australia. Demographic and occupational information was collected, including the number of fatal incidents fire-fighters reported attending across years of service. Validated, self-report measures were used to determine probable caseness for post-traumatic stress disorder, depression and heavy drinking. RESULTS: Among current fire-fighters, rates of post-traumatic stress disorder and depression were 8% and 5%, respectively, while 4% reported consumption of more than 42 alcoholic drinks per week. Retired fire-fighters reported significantly greater levels of symptomatology, with the prevalence estimates of post-traumatic stress disorder at 18% (p = 0.001), depression at 18% (p < 0.001) and heavy drinking at 7%. There was a significant positive linear relationship between the number of fatal incidents attended and rates of post-traumatic stress disorder, depression and heavy drinking. CONCLUSION: Fire-fighters suffer from high rates of mental disorders, with rates of post-traumatic stress disorder, depression and heavy drinking continuing to rise in a linear manner with each additional trauma exposure. The level of psychiatric morbidity among retired fire-fighters appears to be particularly high. Our findings have important implications for the ongoing debates surrounding the detection of mental disorders in high-risk occupations and for policy considerations around the welfare of current and retired emergency workers. PMID- 26607304 TI - Human milk sharing practices in the U.S. AB - The primary objective of this study is to describe human milk sharing practices in the U.S. Specifically, we examine milk sharing social networks, donor compensation, the prevalence of anonymous milk sharing interactions, recipients' concerns about specific milk sharing risks, and lay screening behaviors. Data on human milk sharing practices were collected via an online survey September 2013 March 2014. Chi-square analyses were used to test the association between risk perception and screening practices. A total of 867 (661 donors, 206 recipients) respondents were included in the analyses. Most (96.1%) reported sharing milk face-to-face. Only 10% of respondents reported giving or receiving milk through a non-profit human milk bank, respectively. There were no reports of anonymous purchases of human milk. A small proportion of recipients (4.0%) reported that their infant had a serious medical condition. Screening of prospective donors was common (90.7%) but varied with social relationship and familiarity. Likewise, concern about specific milk sharing risks was varied, and risk perception was significantly associated (P-values = 0.01 or less) with donor screening for all risk variables except diet. Understanding lay perceptions of milk sharing risk and risk reduction strategies that parents are using is an essential first step in developing public health interventions and clinical practices that promote infant safety. PMID- 26607305 TI - Rotational Angiography Based Three-Dimensional Left Atrial Reconstruction: A New Approach for Transseptal Puncture. AB - AIM: Rotational angiography is a well-known method for the three-dimensional (3 D) reconstruction of left atrium and pulmonary veins during left-sided atrial arrhythmia ablation procedures. In our study, we aimed to review our experience in transseptal puncture (TSP) using 3-D rotational angiography. METHODS: We included a total of 271 patients who underwent atrial fibrillation ablation using cryoballoon. Rotational angiography was performed to get the three-dimensional left atrial and pulmonary vein reconstructions using cardiac C-arm computed tomography. The image reconstruction was made using the DynaCT Cardiac software (Siemens, Erlangen, Germany). RESULTS: The mean age of the study population was 61 +/- 10 years. The indications for left atrial arrhythmia ablation were paroxysmal AF in 140 patients (52%) and persistent AF patients in 131 (48%) patients. The success rate of TSP using only rotational guidance was (264/271 patients, 97.4%). In the remaining seven patients, transesophageal guidance was used after the initial attempt due to thick interatrial septum in five patients and difficult TSP due to abnormal anatomy and mild pericardial effusion in the remaining two patients. Mean fluoroscopy dosage of the rotational angiography was 4896.4 +/- 825.3 MUGym(2). The mean time beginning from femoral vein puncture to TSP was 12.3 +/- 5.5 min. CONCLUSION: TSP guided by rotational angiography is a safe and effective method. Our results indicate that integration of rotational angiographic images into the real-time fluoroscopy can guide the TSP during the procedure. PMID- 26607306 TI - Genomic signature of successful colonization of Eurasia by the allopolyploid shepherd's purse (Capsella bursa-pastoris). AB - Polyploidization is a dominant feature of flowering plant evolution. However, detailed genomic analyses of the interpopulation diversification of polyploids following genome duplication are still in their infancy, mainly because of methodological limits, both in terms of sequencing and computational analyses. The shepherd's purse (Capsella bursa-pastoris) is one of the most common weed species in the world. It is highly self-fertilizing, and recent genomic data indicate that it is an allopolyploid, resulting from hybridization between the ancestors of the diploid species Capsella grandiflora and Capsella orientalis. Here, we investigated the genomic diversity of C. bursa-pastoris, its population structure and demographic history, following allopolyploidization in Eurasia. To that end, we genotyped 261 C. bursa-pastoris accessions spread across Europe, the Middle East and Asia, using genotyping-by-sequencing, leading to a total of 4274 SNPs after quality control. Bayesian clustering analyses revealed three distinct genetic clusters in Eurasia: one cluster grouping samples from Western Europe and Southeastern Siberia, the second one centred on Eastern Asia and the third one in the Middle East. Approximate Bayesian computation (ABC) supported the hypothesis that C. bursa-pastoris underwent a typical colonization history involving low gene flow among colonizing populations, likely starting from the Middle East towards Europe and followed by successive human-mediated expansions into Eastern Asia. Altogether, these findings bring new insights into the recent multistage colonization history of the allotetraploid C. bursa-pastoris and highlight ABC and genotyping-by-sequencing data as promising but still challenging tools to infer demographic histories of selfing allopolyploids. PMID- 26607307 TI - Evaluation of renal functions in pediatric liver transplantation. AB - AKI is an important complication after LT. As our LT series contains a quite high number of children with ALF unlike published studies, we aimed to determine pre LT and long-term renal functions in children both with ALF and with CLD. Demographic and disease-related data of 134 transplanted children were evaluated retrospectively. Pre-LT and follow-up GFR and pediatric RIFLE scores were determined. Mean pre-LT GFR was not dependent on the disease presentation or severity of chronic disease. While there was an initial decline until first week of post-LT in CLD children, an increase was observed in ALF. Neither mean GFR nor the pRIFLE on follow-up was different with respect to the type of LT or disease presentation. Mean GFR at first and sixth months were lower in children on cyclosporine compared to tacrolimus (p = 0.001 and p = 0.002, respectively). In conclusion, GFR-time curve was different in children with or without ALF. Type of LT, and severity of the CLD were not risk factors for CKD in any time, but younger age at LT, CLD, and cyclosporine usage were at sixth months of follow-up. PMID- 26607308 TI - In Vivo-Expressed Proteins of Virulent Leptospira interrogans Serovar Autumnalis N2 Elicit Strong IgM Responses of Value in Conclusive Diagnosis. AB - Leptospirosis is a serious zoonosis that is underdiagnosed because of limited access to laboratory facilities in Southeast Asia, Central and South America, and Oceania. Timely diagnosis of locally distributed serovars of high virulence is crucial for successful care and outbreak management. Using pooled patient sera, an expression gene library of a virulent Leptospira interrogans serovar Autumnalis strain N2 isolated in South India was screened. The identified genes were characterized, and the purified recombinant proteins were used as antigens in IgM enzyme-linked immunosorbent assay (ELISA) either singly or in combination. Sera (n = 118) from cases of acute leptospirosis along with sera (n = 58) from healthy subjects were tested for reactivity with the identified proteins in an ELISA designed to detect specific IgM responses. We have identified nine immunoreactive proteins, ArgC, RecA, GlpF, FliD, TrmD, RplS, RnhB, Lp28.6, and Lrr44.9, which were found to be highly conserved among pathogenic leptospires. Apparently, the proteins ArgC, RecA, GlpF, FliD, TrmD, and Lrr44.9 are expressed during natural infection of the host and undetectable in in vitro cultures. Among all the recombinant proteins used as antigens in IgM ELISA, ArgC had the highest sensitivity and specificity, 89.8% and 95.5%, respectively, for the conclusive diagnosis of leptospirosis. The use of ArgC and RecA in combination for IgM ELISA increased the sensitivity and specificity to 95.7% and 94.9%, respectively. ArgC and RecA thus elicited specific IgM responses and were therefore effective in laboratory confirmation of Leptospira infection. PMID- 26607310 TI - Apoptotic activity and gene responses in Drosophila melanogaster S2 cells, induced by azadirachtin A. AB - BACKGROUND: Azadirachtin has been used as an antifeedant and growth disruption agent for many insect species. Previous investigations have reported the apoptotic effects of azadirachtin on some insect cells, but the molecular mechanisms are still not clear. This study investigated the underlying molecular mechanisms for the apoptotic effects induced by azadirachtin on Drosophila melanogaster S2 cells in vitro. RESULTS: The results of the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay demonstrated that azadirachtin exhibited significant cytotoxicity to S2 cells in a time- and dose dependent manner. The changes in cellular morphology and the DNA fragmentation demonstrated that azadirachtin induced remarkable apoptosis of S2 cells. Expression levels of 276 genes were found to be significantly changed in S2 cells after exposure to azadirachtin, as detected by Drosophila genome array. Among these genes, calmodulin (CaM) was the most highly upregulated gene. Azadirachtin was further demonstrated to trigger intracellular Ca(2+) release in S2 cells. The genes related to the apoptosis pathway, determined from chip data, were validated by the real-time quantitative polymerase chain reaction method. CONCLUSION: The results showed that azadirachtin-mediated intracellular Ca(2+) release was the primary event that triggered apoptosis in Drosophila S2 cells through both pathways of the Ca(2+) -CaM and EcR/Usp signalling cascade. (c) 2015 Society of Chemical Industry. PMID- 26607309 TI - Evaluation of a Fiber-Modified Adenovirus Vector Vaccine against Foot-and-Mouth Disease in Cattle. AB - Novel vaccination approaches against foot-and-mouth disease (FMD) include the use of replication-defective human adenovirus type 5 (Ad5) vectors that contain the capsid-encoding regions of FMD virus (FMDV). Ad5 containing serotype A24 capsid sequences (Ad5.A24) has proved to be effective as a vaccine against FMD in livestock species. However, Ad5-vectored FMDV serotype O1 Campos vaccine (Ad5.O1C.2B) provides only partial protection of cattle against homologous challenge. It has been reported that a fiber-modified Ad5 vector expressing Arg Gly-Asp (RGD) enhances transduction of antigen-presenting cells (APC) in mice. In the current study, we assessed the efficacy of a fiber-modified Ad5 (Adt.O1C.2B.RGD) in cattle. Expression of FMDV capsid proteins was superior in cultured cells infected with the RGD-modified vector. Furthermore, transgene expression of Adt.O1C.2B.RGD was enhanced in cell lines that constitutively express integrin alphavbeta6, a known receptor for FMDV. In contrast, capsid expression in cattle-derived enriched APC populations was not enhanced by infection with this vector. Our data showed that vaccination with the two vectors yielded similar levels of protection against FMD in cattle. Although none of the vaccinated animals had detectable viremia, FMDV RNA was detected in serum samples from animals with clinical signs. Interestingly, CD4(+) and CD8(+) gamma interferon (IFN-gamma)(+) cell responses were detected at significantly higher levels in animals vaccinated with Adt.O1C.2B.RGD than in animals vaccinated with Ad5.O1C.2B. Our results suggest that inclusion of an RGD motif in the fiber of Ad5-vectored FMD vaccine improves transgene delivery and cell-mediated immunity but does not significantly enhance vaccine performance in cattle. PMID- 26607311 TI - Localized and Continuous Tuning of Monolayer MoS2 Photoluminescence Using a Single Shape-Controlled Ag Nanoantenna. AB - Localized photoluminescence manipulation of 1L-MoS2 is achieved by using single shape-controlled Ag nanoantenna. By varying the antenna morphology, the photoluminescence of 1L-MoS2 is continuously tunable from enhanced (>2-fold) to weakened (>2-fold) states. A heterogeneous optical platform is realized by depositing various antennas on the same 1L-MoS2 , with an unprecedented range of photoluminescence output being observed simultaneously. PMID- 26607312 TI - Development and validation of a GC-C-IRMS method for the confirmation analysis of pseudo-endogenous glucocorticoids in doping control. AB - Glucocorticoids are included in the S9 section of the World Anti-doping Agency (WADA) prohibited list international standard. Some among them are pseudo endogenous steroids, like cortisol and cortisone, which present the same chemical structure as endogenously produced steroids. We are proposing an analytical method based on gas chromatography coupled to isotope ratio mass spectrometry (GC C-IRMS) which allows discrimination between endogenous and synthetic origin of the urinary metabolites of the pseudo-endogenous glucocorticoids. A preliminary purification treatment by high-performance liquid chromatography (HPLC) of the target compounds (TC) (i.e., cortisol, tetrahydrocortisone (THE) 5alpha tetrahydrocortisone (aTHE), tetrahydrocortisol (THF), and 5alpha tetrahydrocortisol (aTHF)) allows collection of extracts with adequate purity for the subsequent analysis by IRMS. A population of 40 urine samples was analyzed for the TC and for the endogenous reference compounds (ERC: i.e., 11-desoxy tetrahydrocortisol (THS) or pregnanediol). For each sample, the difference between the delta values of the ERCs and TCs (Deltadelta values) were calculated and based on that, some decision limits for atypical findings are proposed. The limits are below 3% units except for cortisol. The fit to purpose of the method has been confirmed by the analysis of urine samples collected in two patients under treatment with 25 mg of cortisone acetate (p.o). The samples showed Deltadelta values higher than 3 for at least 24 h following administration depending on the TC considered. The method can easily be integrated into existing procedures already used for the HPLC purification and IRMS analysis of pseudo endogenous steroids with androgenic/anabolic activity. PMID- 26607313 TI - Multiresidual analysis of emerging amphetamine-like psychoactive substances in wastewater and river water. AB - Besides the common illicit drugs, such as cocaine, heroin, and marijuana, there is a growing concern about the use of modern "designer drugs" that have emerged in large numbers over the past few years. In this work, a sensitive and selective method for simultaneous determination of 25 synthetic amphetamine-like psychoactive compounds, including amphetamine, sympathomimetic substituted amphetamines, synthetic cathinones and ketamine, in raw wastewater (RW), secondary effluent (SE) and river water was developed. Samples were enriched by solid-phase extraction (SPE) on mixed-mode reversed-phase/strong cation-exchange sorbent (Oasis MCX) and analysed by reversed-phase liquid chromatography coupled to electrospray ionisation tandem mass spectrometry (LC-MS/MS). The target compounds were separated on a Synergi Polar column and detected using multiple reaction monitoring (MRM) in positive ionisation mode. Accurate quantification was achieved by using several deuterated analogues as surrogate standards. Careful optimisation and validation of the procedure resulted in a reliable determination of all target analytes in low ng/L range for all matrices, which makes the method suitable for the application in wastewater-based epidemiology. The method was applied for assessment of selected compounds in municipal wastewater and river water from Croatia. It was shown that most of the wastewater samples contained detectable levels of the well-known synthetic illicit drugs, amphetamine and 3,4-methylenedioxy-methamphetamine (MDMA) (concentrations up to 545ng/L and 55ng/L in RW, respectively), as well as ephedrine (up to 108ng/L) and pseudoephedrine (up to 698ng/L), which are used as ingredients of popular over the counter cough and cold medications. Other target amphetamine-like psychoactive substances, recently reported for their potential abuse, were detected only occasionally and in low concentrations (<10ng/L). PMID- 26607314 TI - Quantification of oxysterols in human plasma and red blood cells by liquid chromatography high-resolution tandem mass spectrometry. AB - Oxysterols are important intermediates in numerous metabolic and catabolic pathways and their biological significance is also proven. The present paper describes a reliable and short liquid chromatography-high-resolution mass spectrometry method (LC-MS/HR-MS) for the quantification of 8 different oxysterols (24(S)-hydroxycholesterol, 25-hydroxycholesterol, 27 hydroxycholesterol, 4beta-hydroxycholesterol, 7alpha-hydroxycholesterol, 7beta hydroxycholesterol, 7-ketocholesterol and cholestan-3beta,5alpha,6beta-triol) in human plasma and red blood cells. Oxysterols were extracted with iso-octane after saponification of esterified sterols. Due to the poor ionization efficiency of the target compounds in electrospray ionization (ESI) derivatization of the molecules has been performed with N,N-dimethylglycine (DMG). Within less than 8 min we were able to achieve baseline separation of the isobaric 24(S) hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol, 4beta hydroxycholesterol, 7alpha-hydroxycholesterol and 7beta-hydroxycholesterol. Moreover, high mass resolution was advantageously applied to resolve quasi isobaric interferences. The method was validated based on the recommendations of US Food and Drug Administration and the European Medicines Agency guidelines. Oxysterol concentrations were determined in human plasma and red blood cells from healthy volunteers. Furthermore, the applicability for clinical use has been proven by the analysis of oxysterols as biomarkers in Niemann-Pick type C or cerebrotendinous xanthomatosis patients. PMID- 26607315 TI - Development, optimization, validation and application of faster gas chromatography - flame ionization detector method for the analysis of total petroleum hydrocarbons in contaminated soils. AB - This paper presents an important new approach to improving the timeliness of Total Petroleum Hydrocarbon (TPH) analysis in the soil by Gas Chromatography - Flame Ionization Detector (GC-FID) using the CCME Canada-Wide Standard reference method. The Canada-Wide Standard (CWS) method is used for the analysis of petroleum hydrocarbon compounds across Canada. However, inter-laboratory application of this method for the analysis of TPH in the soil has often shown considerable variability in the results. This could be due, in part, to the different gas chromatography (GC) conditions, other steps involved in the method, as well as the soil properties. In addition, there are differences in the interpretation of the GC results, which impacts the determination of the effectiveness of remediation at hydrocarbon-contaminated sites. In this work, multivariate experimental design approach was used to develop and validate the analytical method for a faster quantitative analysis of TPH in (contaminated) soil. A fractional factorial design (fFD) was used to screen six factors to identify the most significant factors impacting the analysis. These factors included: injection volume (MUL), injection temperature ( degrees C), oven program ( degrees C/min), detector temperature ( degrees C), carrier gas flow rate (mL/min) and solvent ratio (v/v hexane/dichloromethane). The most important factors (carrier gas flow rate and oven program) were then optimized using a central composite response surface design. Robustness testing and validation of model compares favourably with the experimental results with percentage difference of 2.78% for the analysis time. This research successfully reduced the method's standard analytical time from 20 to 8min with all the carbon fractions eluting. The method was successfully applied for fast TPH analysis of Bunker C oil contaminated soil. A reduced analytical time would offer many benefits including an improved laboratory reporting times, and overall improved clean up efficiency. The method was successfully applied for the analysis of TPH of Bunker C oil in contaminated soil. PMID- 26607316 TI - Online screening of nitric oxide scavengers in natural products using high performance liquid chromatography coupled with tandem diode array and fluorescence detection. AB - Nitric oxide (NO) is an important cellular signaling molecule with extensive physiological and pathophysiological effects. NO scavengers have the potential to treat inflammation, septic shock and other related diseases, and numerous examples have been chemically synthesized or isolated from natural products. The chemical diversity of natural products, however, means that a huge effort is necessary to efficiently screen and identify bioactive compounds, especially NO scavengers. In this article, we propose an effective analytical method to screen for NO scavengers in three natural products using an online system that couples high performance liquid chromatography with tandem diode array and fluorescence detection (HPLC-DAD-FLD). Eighteen compounds from radix of Scutellaria baicalensis Georgi and green tea displayed significant NO scavenging activity whereas components of Pueraria lobata (Willd.) Ohwi had no discernable activity. The structures of the active compounds were elucidated using Agilent Accurate Mass Q-TOF LC/MS system. Preliminary analysis of structure-activity relationships indicated that, in flavonoids, a 2,3-double bond and a 3-H atom or a 3-OH group are essential for activity. In tannins, poly-hydroxyl groups are important for NO scavenging activity. Method validation indicated that the newly developed method is both reliable and repeatable. The online method that we present provides a simple, rapid and effective way to identify and characterize NO scavengers present in natural products. PMID- 26607317 TI - Introduction to "Fundamental challenges and opportunities for preparative supercritical fluid chromatography by G. Guiochon, A. Tarafder [J. Chromatogr. A 1218 (2011) 1037-1114]". PMID- 26607318 TI - Magnetic nanoparticles coated with maltose-functionalized polyethyleneimine for highly efficient enrichment of N-glycopeptides. AB - Hydrophilic interaction chromatography (HILIC) adsorbents have drawn increasing attention in recent years due to their high efficiency in N-glycopeptides enrichment. The hydrophilicity and binding capacity of HILIC adsorbents are crucial to the enrichment efficiency and mass spectrometry (MS) detection sensitivity of N-glycopeptides. Herein, magnetic nanoparticles coated with maltose-functionalized polyethyleneimine (Fe3O4-PEI-Maltose MNPs) were prepared by one-pot solvothermal reaction coupled with "click chemistry" and utilized for N-glycopeptides enrichment. Owing to the presence of hydrophilic and branched polyethyleneimine, the amount of immobilized disaccharide units was improved about four times. The N-glycopeptides capturing capacity was about 150mg/g (IgG/MNPs) and the MS detection limitation as low as 0.5fmol for IgG and 85% average enrichment recovery were feasibly achieved by using this hybrid magnetic adsorbent. Finally, 1237 unique N-glycosylation sites and 1567 unique N glycopeptides from 684 N-glycoproteins were reliably characterized from 60MUg protein sample extracted from mouse liver. Therefore, this maltose-functionalized polyethyleneimine coated adsorbent can play a promising role in highly efficient N-glycopeptides enrichment for glycoproteomic analyses of complex protein samples. PMID- 26607320 TI - Rigorous buoyancy driven bubble mixing for centrifugal microfluidics. AB - We present batch-mode mixing for centrifugal microfluidics operated at fixed rotational frequency. Gas is generated by the disk integrated decomposition of hydrogen peroxide (H2O2) to liquid water (H2O) and gaseous oxygen (O2) and inserted into a mixing chamber. There, bubbles are formed that ascent through the liquid in the artificial gravity field and lead to drag flow. Additionaly, strong buoyancy causes deformation and rupture of the gas bubbles and induces strong mixing flows in the liquids. Buoyancy driven bubble mixing is quantitatively compared to shake mode mixing, mixing by reciprocation and vortex mixing. To determine mixing efficiencies in a meaningful way, the different mixers are employed for mixing of a lysis reagent and human whole blood. Subsequently, DNA is extracted from the lysate and the amount of DNA recovered is taken as a measure for mixing efficiency. Relative to standard vortex mixing, DNA extraction based on buoyancy driven bubble mixing resulted in yields of 92 +/- 8% (100 s mixing time) and 100 +/- 8% (600 s) at 130g centrifugal acceleration. Shake mode mixing yields 96 +/- 11% and is thus equal to buoyancy driven bubble mixing. An advantage of buoyancy driven bubble mixing is that it can be operated at fixed rotational frequency, however. The additional costs of implementing buoyancy driven bubble mixing are low since both the activation liquid and the catalyst are very low cost and no external means are required in the processing device. Furthermore, buoyancy driven bubble mixing can easily be integrated in a monolithic manner and is compatible to scalable manufacturing technologies such as injection moulding or thermoforming. We consider buoyancy driven bubble mixing an excellent alternative to shake mode mixing, in particular if the processing device is not capable of providing fast changes of rotational frequency or if the low average rotational frequency is challenging for the other integrated fluidic operations. PMID- 26607319 TI - Tracking matrix effects in the analysis of DNA adducts of polycyclic aromatic hydrocarbons. AB - LC-MS using electrospray ionization is currently the method of choice in bio organic analysis covering a wide range of applications in a broad spectrum of biological media. The technique is noted for its high sensitivity but one major limitation that hinders achievement of its optimal sensitivity is the signal suppression due to matrix inferences introduced by the presence of co-extracted compounds during the sample preparation procedure. The analysis of DNA adducts of common environmental carcinogens is particularly sensitive to such matrix effects as sample preparation is a multistep process which involves "contamination" of the sample due to the addition of enzymes and other reagents for digestion of the DNA in order to isolate the analyte(s). This problem is further exacerbated by the need to reach low levels of quantitation (LOQ in the ppb level) while also working with limited (2-5 MUg) quantities of sample. We report here on the systematic investigation of ion signal suppression contributed by each individual step involved in the sample preparation associated with the analysis of DNA adducts of polycyclic aromatic hydrocarbon (PAH) using as model analyte BaP-dG, the deoxyguanosine (dG) adduct of benzo[a]pyrene (BaP). The individual matrix contribution of each one of these sources to analyte signal was systematically addressed as were any interactive effects. The information was used to develop a validated analytical protocol for the target biomarker at levels typically encountered in vivo using as little as 2 MUg of DNA and applied to a dose response study using a metabolically competent cell line. PMID- 26607321 TI - Genetic analysis of human clinical isolates of Lactococcus garvieae: Relatedness with isolates from foods. AB - Lactococcus garvieae is a Gram-positive bacterium well-known as an important pathogen in aquaculture, and it is also a human pathogen of increasing clinical significance. Forty-three human L. garvieae isolates from clinical specimens were characterized by Multilocus Sequence Typing (MLST). Twenty-six different sequence types (STs) were identified among the human isolates, of which 20 were novel STs. Most human isolates clustered into four clonal complexes, with a predominance of CC3. Within CC3, ST10 was the most common genotype, indicating the existence of a circulating genetic lineage among the human isolates analyzed. The four CCs also grouped L. garvieae strains isolated from meat, dairy and fish, indicating a genetic overlap between isolates from human and these foods. Genetic relatedness among human and food L. garvieae isolates was confirmed by phylogenetic analysis based on the concatenated sequences of the seven MLST genes. These results represent the first evidence of genetic relatedness between isolates of L. garvieae of human and those isolated meat, milk and dairy products and suggest that, in addition to fish and seafood, these foods might represent important sources of human L. garvieae infections. PMID- 26607322 TI - A three-miRNA signature as promising non-invasive diagnostic marker for gastric cancer. AB - BACKGROUND: Despite the declining incidence of gastric cancer, mortality rate remains high due to late presentation. We aimed to evaluate the sensitivity of miRNA as a diagnostic marker for gastric cancer in the circulation. METHODS: Plasma samples from 3 independent groups comprise 123 gastric cancer patients and 111 healthy controls for miRNA profiling from microarray screening. RESULTS: Microarray data showed that 25 miRNAs were upregulated in gastric cancer patients and 6 highly expressed miRNAs (miR-18a, miR-140-5p, miR-199a-3p, miR-627, miR-629 and miR-652) were selected for validation. In an independent validation set, levels of miR-627, miR-629 and miR-652 were significantly higher in gastric cancer patients than healthy controls (P <0.0001). An algorithm with improved sensitivity and specificity as gastric cancer classifier was adopted and validated in another random set of 15 plasma samples. Results showed that combination of 3 miRNAs obtained the highest area under curve, with a cut-off at 0.373, with a sensitivity of 86.7% and a specificity of 85.5%. CONCLUSION: This study revealed a three-miRNA signature as a promising classifier for gastric cancer, and greatly enhances the feasibility of circulating miRNAs as non invasive diagnostic marker for this disease. PMID- 26607323 TI - Discovery of keratinases using bacteria isolated from marine environments. AB - Bacteria are important for the biodegradation of keratin. Thus, a workflow to isolate keratin-degrading bacteria utilizing an optimized azo-keratin assay was established. Deteriorated feather samples, collected in marine shoreline environments from the intertidal zone, yielded 50 unique bacterial isolates exhibiting keratin degradation when feather meal was supplied as keratin substrate. The majority of isolates, identified by 16S sequencing, belonged to genera previously reported to produce keratinases: Bacillus spp. (42%) and Stenotrophomonas spp. (40%). The remaining 18% represented the genera Alcaligenes, Chryseobacterium, Salinivibrio, Delftia, Stappia, and Microbacterium, genera not previously been associated with keratinase production. The workflow, also applied to 21 Bacilli from our in-house culture collection, additionally revealed four Bacilli with remarkable feather degradation potential. The industrial applicability of their associated keratinases was evaluated and the most active keratinase expressed in E. coli to confirm keratinase expression. Enriched keratinase fractions demonstrated activity up to 75 degrees C and retained viability when stored lyophilized at 20 degrees C for up to 200d. PMID- 26607324 TI - Ciprofloxacin resistance in community- and hospital-acquired Escherichia coli urinary tract infections: a systematic review and meta-analysis of observational studies. AB - BACKGROUND: During the last decade the resistance rate of urinary Escherichia coli (E. coli) to fluoroquinolones such as ciprofloxacin has increased. Systematic reviews of studies investigating ciprofloxacin resistance in community and hospital-acquired E. coli urinary tract infections (UTI) are absent. This study systematically reviewed the literature and where appropriate, meta-analysed studies investigating ciprofloxacin resistance in community- and hospital acquired E. coli UTIs. METHODS: Observational studies published between 2004 and 2014 were identified through Medline, PubMed, Embase, Cochrane, Scopus and Cinahl searches. Overall and sub-group pooled estimates of ciprofloxacin resistance were evaluated using DerSimonian-Laird random-effects models. The I(2) statistic was calculated to demonstrate the degree of heterogeneity. Risk of bias among included studies was also investigated. RESULTS: Of the identified 1134 papers, 53 were eligible for inclusion, providing 54 studies for analysis with one paper presenting both community and hospital studies. Compared to the community setting, resistance to ciprofloxacin was significantly higher in the hospital setting (pooled resistance 0.38, 95% CI 0.36-0.41 versus 0.27, 95% CI 0.24-0.31 in community-acquired UTIs, P < 0.001). Resistance significantly varied by region and country with the highest resistance observed in developing countries. Similarly, a significant rise in resistance over time was seen in studies reporting on community-acquired E. coli UTI. CONCLUSIONS: Ciprofloxacin resistance in E. coli UTI is increasing and the use of this antimicrobial agent as empirical therapy for UTI should be reconsidered. Policy restrictions on ciprofloxacin use should be enhanced especially in developing countries without current regulations. PMID- 26607326 TI - Erratum. PMID- 26607325 TI - The role of Nav1.9 channel in the development of neuropathic orofacial pain associated with trigeminal neuralgia. AB - BACKGROUND: Trigeminal neuralgia is accompanied by severe mechanical, thermal and chemical hypersensitivity of the orofacial area innervated by neurons of trigeminal ganglion (TG). We examined the role of the voltage-gated sodium channel subtype Nav1.9 in the development of trigeminal neuralgia. RESULTS: We found that Nav1.9 is required for the development of both thermal and mechanical hypersensitivity induced by constriction of the infraorbital nerve (CION). The CION model does not induce change on Nav1.9 mRNA expression in the ipsilateral TG neurons when evaluated 9 days after surgery. CONCLUSIONS: These results demonstrate that Nav1.9 channels play a critical role in the development of orofacial neuropathic pain. New routes for the treatment of orofacial neuropathic pain focussing on regulation of the voltage-gated Nav1.9 sodium channel activity should be investigated. PMID- 26607327 TI - The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features. AB - INTRODUCTION: Chemotherapy resistance resulting in incomplete pathologic response is associated with high risk of metastasis and early relapse in breast cancer. The aim of this study was to identify and evaluate biomarkers of treatment resistant tumor cells. METHODS: We performed a cell surface marker screen in triple-negative breast cancer patient-derived xenograft models treated with standard care genotoxic chemotherapy. Global expression profiling was used to further characterize the identified treatment-resistant subpopulations. RESULTS: High expression of sialyl-glycolipid stage-specific embryonic antigen 4 (SSEA4) was found in residual tumor cells surviving chemotherapy and in samples from metastatic patients who relapsed after neoadjuvant chemotherapy. Gene and microRNA (miRNA) expression profiling linked SSEA4 positivity with a mesenchymal phenotype and a deregulation of drug resistance pathways. Functional assays demonstrated a direct link between epithelial-mesenchymal transition (EMT) and SSEA4 expression. Interestingly, SSEA4 expression, EMT, and drug resistance seemed to be regulated posttranscriptionally. Finally, high expression of CMP-N acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 2 (ST3GAL2), the rate-limiting enzyme of SSEA4 synthesis, was found to be associated with poor clinical outcome in breast and ovarian cancer patients treated with chemotherapy. CONCLUSIONS: In this study, we identified SSEA4 as highly expressed in a subpopulation of tumor cells resistant to multiple commonly used chemotherapy drugs, as well as ST3GAL2, the rate-limiting enzyme of SSEA4 synthesis, as a predictive marker of poor outcome for breast and ovarian cancer patients undergoing chemotherapy. Both biomarkers and additionally identified regulatory miRNAs may be used to further understand chemoresistance, to stratify patient groups in order to avoid ineffective and painful therapies, and to develop alternative treatment regimens for breast cancer patients. PMID- 26607328 TI - Analysis of nucleosome positioning landscapes enables gene discovery in the human malaria parasite Plasmodium falciparum. AB - BACKGROUND: Plasmodium falciparum, the deadliest malaria-causing parasite, has an extremely AT-rich (80.7 %) genome. Because of high AT-content, sequence-based annotation of genes and functional elements remains challenging. In order to better understand the regulatory network controlling gene expression in the parasite, a more complete genome annotation as well as analysis tools adapted for AT-rich genomes are needed. Recent studies on genome-wide nucleosome positioning in eukaryotes have shown that nucleosome landscapes exhibit regular characteristic patterns at the 5'- and 3'-end of protein and non-protein coding genes. In addition, nucleosome depleted regions can be found near transcription start sites. These unique nucleosome landscape patterns may be exploited for the identification of novel genes. In this paper, we propose a computational approach to discover novel putative genes based exclusively on nucleosome positioning data in the AT-rich genome of P. falciparum. RESULTS: Using binary classifiers trained on nucleosome landscapes at the gene boundaries from two independent nucleosome positioning data sets, we were able to detect a total of 231 regions containing putative genes in the genome of Plasmodium falciparum, of which 67 highly confident genes were found in both data sets. Eighty-eight of these 231 newly predicted genes exhibited transcription signal in RNA-Seq data, indicative of active transcription. In addition, 20 out of 21 selected gene candidates were further validated by RT-PCR, and 28 out of the 231 genes showed significant matches using BLASTN against an expressed sequence tag (EST) database. Furthermore, 108 (47%) out of the 231 putative novel genes overlapped with previously identified but unannotated long non-coding RNAs. Collectively, these results provide experimental validation for 163 predicted genes (70.6%). Finally, 73 out of 231 genes were found to be potentially translated based on their signal in polysome-associated RNA-Seq representing transcripts that are actively being translated. CONCLUSION: Our results clearly indicate that nucleosome positioning data contains sufficient information for novel gene discovery. As distinct nucleosome landscapes around genes are found in many other eukaryotic organisms, this methodology could be used to characterize the transcriptome of any organism, especially when coupled with other DNA-based gene finding and experimental methods (e.g., RNA-Seq). PMID- 26607329 TI - Long-term effects of lifetime trauma exposure in a rural community sample. AB - BACKGROUND: This study examines the long-term outcomes of lifetime trauma exposure, including factors that contribute to the development of PTSD, in a sample of rural adults. METHODS: In 623 rural community residents, lifetime trauma exposure, PTSD, other psychiatric disorders and lifetime suicidal ideation were assessed using the World Mental Health Composite International Diagnostic Interview. Logistic regressions were used to examine relationships between potentially traumatic events (PTEs) and lifetime PTSD and other diagnoses. RESULTS: 78.2% of participants reported at least on PTE. Rates were broadly comparable with Australian national data: the most commonly endorsed events were unexpected death of a loved one (43.7%); witnessing injury or death (26.3%); and life-threatening accident (19.3%). While the mean age of the sample was 55 years, the mean age of first trauma exposure was 19 years. The estimated lifetime rate of PTSD was 16.0%. Events with the strongest association with PTSD were physical assault and unexpected death of a loved one. Current functioning was lowest among those with current PTSD, with this group reporting elevated psychological distress, higher mental health service use, a greater number of comorbidities, and lower perceived social support. Respondents with a past PTE but no PTSD history were generally similar in terms of their current wellbeing to those with no lifetime PTE. CONCLUSIONS: PTEs may have diverse psychological and social consequences beyond the development of PTSD. Ensuring that adequate support services are available in rural areas, particularly in the period immediately following a PTE, may reduce the long-term impact of traumatic events. PMID- 26607330 TI - High-frequency intimate partner violence during pregnancy, postnatal depression and suicidal tendencies in Harare, Zimbabwe. AB - INTRODUCTION: Intimate partner violence (IPV) is a common form of violence experienced by pregnant women and is believed to have adverse mental health effects postnatally. This study investigated the association of postnatal depression (PND) and suicidal ideation with emotional, physical and sexual IPV experienced by women during pregnancy. METHODS: Data were collected from 842 women interviewed postnatally in six postnatal clinics in Harare, Zimbabwe. We used the World Health Organization versions of IPV and Centre for Epidemiological Studies - Depression Scale measures to assess IPV and PND respectively. We derived a violence severity variable and combined forms of IPV variables from IPV questions. Logistic regression was used to analyse data whilst controlling for past mental health and IPV experiences. RESULTS: One in five women [21.4% (95% CI 18.6-24.2)] met the diagnostic criteria for PND symptomatology whilst 21.6% (95% CI 18.8-24.4) reported postpartum suicide thoughts and 4% (95% CI 2.7-5.4) reported suicide attempts. Two thirds (65.4%) reported any form of IPV. Although individual forms of severe IPV were associated with PND, stronger associations were found between PND and severe emotional IPV or severe combined forms of IPV. Suicidal ideation was associated with emotional IPV. Other forms of IPV, except when combined with emotional IPV, were not individually associated with suicidal ideation. CONCLUSION: Emotional IPV during pregnancy negatively affects women's mental health in the postnatal period. Clinicians and researchers should include it in their conceptualisation of violence and health. Further research must look at possible indirect relationships between sexual and physical IPV on mental health. PMID- 26607331 TI - Investigation on bile acid receptor regulators. Discovery of cholanoic acid derivatives with dual G-protein coupled bile acid receptor 1 (GPBAR1) antagonistic and farnesoid X receptor (FXR) modulatory activity. AB - Bile acids, the end products of cholesterol metabolism, activate multiple mechanisms through the interaction with membrane G-protein coupled receptors including the bile acid receptor GPBAR1 and nuclear receptors such as the bile acid sensor, farnesoid X receptor (FXR). Even if dual FXR/GPBAR1 agonists are largely considered a novel opportunity in the treatment of several liver and metabolic diseases, selective targeting of one of these receptors represents an attractive therapeutic approach for a wide range of disorders in which dual modulation is associated to severe side effects. In the present study we have investigated around the structure of LCA generating a small library of cholane derivatives, endowed with dual FXR agonism/GPBAR1 antagonism. To the best of our knowledge, this is the first report of bile acid derivatives able to antagonize GPBAR1. PMID- 26607332 TI - Manual Cardiopulmonary Resuscitation Versus CPR Including a Mechanical Chest Compression Device in Out-of-Hospital Cardiac Arrest: A Comprehensive Meta analysis From Randomized and Observational Studies. AB - STUDY OBJECTIVE: Mechanical chest compression devices have been developed to facilitate continuous delivery of high-quality cardiopulmonary resuscitation (CPR). Despite promising hemodynamic data, evidence on clinical outcomes remains inconclusive. With the completion of 3 randomized controlled trials, we conduct a meta-analysis on the effect of in-field mechanical versus manual CPR on clinical outcomes after out-of-hospital cardiac arrest. METHODS: With a systematic search (PubMed, Web of Science, EMBASE, and the Cochrane Libraries), we identified all eligible studies (randomized controlled trials and nonrandomized studies) that compared a CPR strategy including an automated mechanical chest compression device with a strategy of manual CPR only. Outcome variables were survival to hospital admission, survival to discharge, and favorable neurologic outcome. RESULTS: Twenty studies (n=21,363) were analyzed: 5 randomized controlled trials and 15 nonrandomized studies, pooled separately. For survival to admission, the pooled estimate of the randomized controlled trials did not indicate a difference (odds ratio 0.94; 95% confidence interval 0.84 to 1.05; P=.24) between mechanical and manual CPR. In contrast, meta-analysis of nonrandomized studies demonstrated a benefit in favor of mechanical CPR (odds ratio 1.42; 95% confidence interval 1.21 to 1.67; P<.001). No interaction was found between the endorsed CPR guidelines (2000 versus 2005) and the CPR strategy (P=.27). Survival to discharge and neurologic outcome did not differ between strategies. CONCLUSION: Although there are lower-quality, observational data that suggest that mechanical CPR used at the rescuer's discretion could improve survival to hospital admission, the cumulative high-quality randomized evidence does not support a routine strategy of mechanical CPR to improve survival or neurologic outcome. These findings are irrespective of the endorsed CPR guidelines during the study periods. PMID- 26607333 TI - Prospective Validation of the Ottawa 3DY Scale by Geriatric Emergency Management Nurses to Identify Impaired Cognition in Older Emergency Department Patients. AB - STUDY OBJECTIVE: Assessment of older emergency department (ED) patients with cognitive impairment is challenging because few tools exist that can be quickly administered by front-line practitioners. Our objective is to validate the Ottawa 3DY Scale, a 4-question screening tool for cognitive impairment, in older ED patients and compare its performance with that of the Animal Fluency Test. METHODS: We conducted a prospective cohort study in 2 EDs and enrolled a convenience sample of patients aged 75 years or older with no history of cognitive impairment. Eligible patients were assessed by geriatric emergency management nurses who administered the Mini-Mental State Examination, ordered with the Ottawa 3DY Scale questions first, followed by the Animal Fluency Test. Mini-Mental State Examination score less than 25 was our criterion standard for cognitive impairment. RESULTS: Study patients (N=238) had a mean age of 81.9 years and were 60.1% women, and 26.5% were admitted to the hospital. The Ottawa 3DY Scale and Mini-Mental State Examination were in agreement for 75.6% of cases, with a sensitivity of 93.8% (95% confidence interval [CI] 77.8% to 98.9%) and specificity of 72.8% (95% CI 66.1% to 78.7%). The Animal Fluency Test score less than 15 and Mini-Mental State Examination score were in agreement for 46.2% of cases, with sensitivity 90.6% (95% CI 73.8% to 97.5%) and specificity 39.3% (95% CI 32.7% to 46.4%). CONCLUSION: Both the Ottawa 3DY Scale and the Animal Fluency Test demonstrated excellent sensitivity versus the Mini-Mental State Examination; however, the Animal Fluency Test exhibited poor specificity. The Ottawa 3DY Scale is an effective tool to screen for cognitive impairment in older ED patients, and its use may facilitate improved care in this vulnerable population. PMID- 26607334 TI - Prevalence of Chest Injury With the Presence of NEXUS Chest Criteria: Data to Inform Shared Decisionmaking About Imaging Use. AB - STUDY OBJECTIVE: The NEXUS chest decision instrument identifies a very-low-risk population of patients with blunt trauma for whom chest imaging can be avoided. However, it requires that all 7 National Emergency X-Ray Utilization Study (NEXUS) chest criteria be absent. To inform patient and physician shared decisionmaking about imaging, we describe the test characteristics of individual criteria of the NEXUS chest decision instrument and provide the prevalence of injuries when 1, 2, or 3 of the 7 criteria are present. METHODS: We conducted this secondary analysis of 2 prospectively collected cohorts of patients with blunt trauma who were older than 14 years and enrolled in NEXUS chest studies between December 2009 and January 2012. Physicians at 9 US Level I trauma centers recorded the presence or absence of the 7 NEXUS chest criteria. We calculated test characteristics of each criterion and combinations of criteria for the outcome measures of major clinical injuries and thoracic injury observed on chest imaging. RESULTS: We enrolled 21,382 patients, of whom 992 (4.6%) had major clinical injuries and 3,135 (14.7%) had thoracic injuries observed on chest imaging. Sensitivities of individual test characteristics ranged from 15% to 56% for major clinical injury and 14% to 53% for thoracic injury observed on chest imaging, with specificities varying from 71% to 84% for major clinical injury and 67% to 84% for thoracic injury observed on chest imaging. Individual criteria were associated with a prevalence of major clinical injury between 1.9% and 3.8% and of thoracic injury observed on chest imaging between 5.3% and 11.5%. CONCLUSION: Patients with isolated NEXUS chest criteria have low rates of major clinical injury. The risk of major clinical injury for patients with 2 or 3 factors range from 1.7% to 16.6%, depending on the combination of criteria. Criteria-specific risks could be used to inform shared decisionmaking about the need for imaging by patients and their physicians. PMID- 26607335 TI - The G protein estrogen receptor (GPER) is regulated by endothelin-1 mediated signaling in cancer cells. AB - Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor involved in many diseases, including certain cardiovascular disorders and cancer. As previous studies have shown that the G protein estrogen receptor (GPER) may regulate ET-1 dependent effects on the vascular system, we evaluated whether GPER could contribute to the effects elicited by ET-1 in breast cancer and hepatocarcinoma cells. Here, we demonstrate that ET-1 increases GPER expression through endothelin receptor A (ETAR) and endothelin receptor B (ETBR) along with the activation of PI3K/ERK/c-Fos/AP1 transduction pathway. In addition, we show that GPER is involved in important biological responses observed upon ET-1 exposure, as the migration of the aforementioned tumor cells and the formation of tube-like structures in human umbilical vein endothelial cells (HUVECs). Our data suggest that GPER may contribute to ET-1 action toward the progression of some types of tumor. PMID- 26607336 TI - Molecular characterisation of acquired and overproduced chromosomal blaAmpC in Escherichia coli clinical isolates. AB - Escherichia coli recovered from three hospitals in Barcelona (Spain) were studied to determine the prevalence of isolates with acquired AmpC (ac-AmpC) and/or overproduced chromosomal AmpC (c-AmpC). Mechanisms involved in blac-AmpC overexpression, blaac-AmpC and the plasmids associated with their distribution as well as the prevalence of plasmid-mediated quinolone resistance (PMQR) in AmpC producing isolates were also determined. Isolates were selected according to their resistance phenotype. blaac-AmpC, alterations in the blac-AmpC promoter/attenuator, and PMQR genes [qnrA, qnrB, qnrS, aac(6')-Ib-cr and qepA] were characterised by PCR and sequencing. blac-AmpC expression was determined by qRT-PCR. Population structure analysis was performed using PFGE, MLST and phylogenetic group PCR. Plasmids carrying blaac-AmpC were characterised by PCR based replicon typing and S1-PFGE. IncI1 and IncF plasmids were also analysed by plasmid MLST and replicon sequence typing, respectively. Among 21563 E. coli isolates, 240 (1.1%) overproduced AmpC beta-lactamases, including 180 (75.0%) harbouring ac-AmpC (132 CMY-2 variants and 48 DHA-1) and 60 (25.0%) c-AmpC enzymes. Three mutation profiles in the blac-AmpC promoter/attenuator were associated with a 72.5-, 19.9- and 5.8-fold increased expression, respectively. Moreover, 63.3% of ac-AmpC and 43.3% of c-AmpC isolates belonged to B2, D, E or F phylogenetic groups. PMQR was found in 31% of ac-AmpC isolates [38 qnrB4, 8 aac(6')-Ib-cr, 6 qnrS1 and 3 qnrB19] and in 10% of c-AmpC isolates [5 aac(6')-Ib cr and 1 qnrS1]. IncI1-ST12 and IncF were associated with blaCMY-2 and blaDHA-1, respectively. These results suggest that ac-AmpC beta-lactamases were the main mechanism of AmpC production. Isolates and plasmids both showed high genetic diversity. PMID- 26607337 TI - Intravenous combined with aerosolised polymyxin versus intravenous polymyxin alone in the treatment of pneumonia caused by multidrug-resistant pathogens: a systematic review and meta-analysis. AB - Colistin has been used to treat nosocomial pneumonia (NP) caused by multidrug resistant (MDR) Gram-negative bacteria (GNB) via different administration routes. Whether patients may benefit from aerosolised colistin as adjunctive treatment was contradictory. We aimed to clarify the safety and efficacy of administering aerosolised and intravenous (IV-AS) colistin versus intravenous (IV) colistin alone in patients with NP caused by MDR-GNB. Two reviewers independently evaluated and extracted data from PubMed, EMBASE and Cochrane databases. Primary outcomes were clinical response rate, all-cause mortality (ICU or hospital), microbiological eradication and nephrotoxicity. Pooled odds ratios (ORs) were calculated and significance was determined by the Z test. Nine eligible studies involving 672 participants were included. The overall clinical response rate (improvement and cure) was significantly higher in the IV-AS group than that in the IV group [OR=1.81, 95% confidence interval (CI) 1.30-2.53; P=0.0005]. Patients treated with IV-AS colistin showed a higher rate of pathogen eradication (OR=1.66, 95% CI 1.11-2.49; P=0.01) and lower all-cause mortality compared with IV colistin (OR=0.69, 95% CI 0.50-0.95; P=0.02). Nephrotoxicity did not differ significantly between IV-AS and IV groups (five studies; 383 patients) (OR=1.11, 95% CI 0.69-1.80; P=0.67). These data indicate that IV-AS colistin has additional benefits compared with IV colistin alone. Clinicians should be encouraged to give combined administration routes in critically ill patients with NP caused by MDR GNB. PMID- 26607339 TI - Intravenous ceftaroline 200 mg administered every 8 h is safe and adequate for meticillin-resistant Staphylococcus aureus bloodstream infections in end-stage renal failure patients on haemodialysis: a case study. PMID- 26607338 TI - Prospects of a new antistaphylococcal drug batumin revealed by molecular docking and analysis of the complete genome sequence of the batumin-producer Pseudomonas batumici UCM B-321. AB - Meticillin-resistant Staphylococcus aureus (MRSA) is a serious public health threat causing outbreaks of clinical infection around the world. Mupirocin is a promising anti-MRSA drug, however mupirocin-resistant strains of S. aureus are emerging at an increasing rate. The newly discovered antibiotic batumin may contribute to anti-MRSA therapy. The objective of this work was to identify possible molecular targets for batumin as well as mechanisms of its antistaphylococcal activity using computational molecular docking and by analysing the complete genome sequence of the batumin-producer Pseudomonas batumici UCM B-321. It was found that batumin acted very similarly to mupirocin by inhibiting aminoacyl tRNA synthetases. A previous hypothesis considering the trans-enoyl-CoA reductase FabI as a prime molecular target of batumin was rejected. However, indirect inhibition of fatty acid biosynthesis in sensitive bacteria does take place as a part of stringent response repression triggered by accumulation of uncharged tRNA molecules. Paralogues of diverse leucine-tRNA synthetases in the genome of P. batumici indicated that this protein might be the prime target of batumin. A batumin biosynthesis operon comprising 28 genes was found to be acquired through horizontal gene transfer. It was hypothesised that, in contrast to mupirocin, batumin could inhibit a broader range of aminoacyl tRNA synthetases and that acquired resistance to mupirocin might not endow S. aureus strains with resistance against batumin. PMID- 26607340 TI - Biomarkers in infection and sepsis: Can they really indicate final outcome? AB - Infectious diseases are among the most common reasons for admission to hospital and can easily lead to sepsis. Sepsis is globally associated with increased mortality, and although biomarkers could help clinicians in the early diagnosis of sepsis and immediate onset of antibiotics, there are always questions to be answered about their usefulness in the prognosis of infectious diseases. This article reviews some of the available biomarkers used in infectious diseases and sepsis in order to evaluate their utility to predict mortality and unfavourable outcome. Several studies present the pros and cons of each compound, but it is obvious that the ideal biomarker, with high sensitivity and specificity, cost effectiveness and with definite cut-off ranges and time of blood sampling, is yet to be found. PMID- 26607342 TI - Can we transfer pharmacokinetics/pharmacodynamics of antimicrobials into clinical practice? AB - In critically ill patients there is extensive evidence of subtherapeutic antibiotic exposure from standard doses across different antibiotic classes. This can be a direct consequence of pharmacokinetic alterations emanating from the complex pathophysiological processes associated with severe infection. Therapeutic drug monitoring (TDM) is being increasingly used for antibiotic dose optimisation in an attempt to improve the attainment of pharmacokinetic/pharmacodynamic (PK/PD) targets and the outcomes of severe infection in critically ill patients. In clinical practice, it is necessary to reduce the number of blood samples collected from the patient to a minimum because of the cost (personnel, devises and analysis). TDM to calculate PK/PD indices is easily feasible only when a single blood sample is adequate to perform the analysis. PMID- 26607341 TI - A pharmacokinetic analysis of posaconazole oral suspension in the serum and alveolar compartment of lung transplant recipients. AB - Invasive fungal infections cause significant morbidity and mortality after lung transplantation. Fungal prophylaxis following lung transplantation is not standardised, with transplant centres utilising a variety of regimens. Posaconazole is a broad-spectrum antifungal triazole that requires further investigation within the setting of lung transplantation. This prospective, single-centre, observational study explored the pharmacokinetics of posaconazole oral suspension (POS) in the early perioperative period following lung transplantation in 26 patients. Organ recipients were scheduled to receive 400mg POS twice daily for 6 weeks as primary antifungal prophylaxis. Therapeutic drug monitoring (TDM) of serum posaconazole levels was performed in accordance with local clinical protocols. Bronchoalveolar lavage fluid (BALF) was sampled during routine bronchoscopies. Posaconazole levels were measured both in serum and BALF using mass spectrometry. Posaconazole levels were highly variable within lung transplant recipients during the perioperative period and did not achieve 'steady state'. Serum posaconazole concentrations positively correlated with levels within the BALF (r=0.5527; P=0.0105). Of the 26 patients, 10 failed to complete the study for multiple reasons and so the trial was terminated early. Unlike study findings in stable recipients, serum posaconazole levels rarely achieved steady-state in the perioperative period; however, they do reflect the concentrations within the airways of newly transplanted lungs. The role of POS as primary prophylaxis in the perioperative period is uncertain, but if used TDM may be helpful for determining attainment of therapeutic levels. PMID- 26607343 TI - Procalcitonin to guide antibiotic therapy in the ICU. AB - The serum procalcitonin (PCT) concentration reflects both the systemic response to bacterial infection and its severity. However, its accuracy in distinguishing intensive care unit (ICU) patients with and without infection remains low owing to a lack of specificity and the time lapse between infection onset and the PCT rise. Hence, PCT cannot be used as a marker to start or withhold antibiotic therapy for ICU patients. However, the kinetics of the PCT concentration decrease under antibiotic therapy can adequately monitor infection evolution with therapy and can help to customise antibiotic duration. PCT-guided algorithms to guide antibiotic discontinuation were able to shorten antibiotic duration without impacting patient outcomes in several multicentre randomised studies. Notably, antibiotics can be stopped very early when PCT is low and remains low as this indicates that bacterial infection is unlikely. When PCT falls to <0.5 ng/mL or >80% from its peak value, antibiotics for non-localised infections can safely be stopped. PMID- 26607345 TI - Survival after in-hospital hyperkalaemic cardiac arrest--Does intravenous calcium or sodium bicarbonate influence outcome? PMID- 26607344 TI - Depicting the interplay between organisational tiers in the use of a national quality registry to develop quality of care in Sweden. AB - BACKGROUND: With a pending need to identify potential means to improved quality of care, national quality registries (NQRs) are identified as a promising route. Yet, there is limited evidence with regards to what hinders and facilitates the NQR innovation, what signifies the contexts in which NQRs are applied and drive quality improvement. Supposedly, barriers and facilitators to NQR-driven quality improvement may be found in the healthcare context, in the politico administrative context, as well as with an NQR itself. In this study, we investigated the potential variation with regards to if and how an NQR was applied by decision-makers and users in regions and clinical settings. The aim was to depict the interplay between the clinical and the politico-administrative tiers in the use of NQRs to develop quality of care, examining an established registry on stroke care as a case study. METHODS: We interviewed 44 individuals representing the clinical and the politico-administrative settings of 4 out of 21 regions strategically chosen for including stroke units representing a variety of outcomes in the NQR on stroke (Riksstroke) and a variety of settings. The transcribed interviews were analysed by applying The Consolidated Framework for Implementation Research (CFIR). RESULTS: In two regions, decision-makers and/or administrators had initiated healthcare process projects for stroke, engaging the health professionals in the local stroke units who contributed with, for example, local data from Riksstroke. The Riksstroke data was used for identifying improvement issues, for setting goals, and asserting that the stroke units achieved an equivalent standard of care and a certain level of quality of stroke care. Meanwhile, one region had more recently initiated such a project and the fourth region had no similar collaboration across tiers. Apart from these projects, there was limited joint communication across tiers and none that included all individuals and functions engaged in quality improvement with regards to stroke care. CONCLUSIONS: If NQRs are to provide for quality improvement and learning opportunities, advances must be made in the links between the structures and processes across all organisational tiers, including decision-makers, administrators and health professionals engaged in a particular healthcare process. PMID- 26607346 TI - The larger mammal fauna from the Lower Paleolithic Schoningen Spear site and its contribution to hominin subsistence. AB - The locality Schoningen (Germany) is an important source of knowledge about Lower Paleolithic hominin subsistence. The locality includes a series of sites dated to the late Middle Pleistocene with a Holsteinian (MIS 11) and Reinsdorf Interglacial (MIS 9) age. One of the youngest sites is Schoningen 13 II-4, the Spear Horizon site also known as the Horse Butchery site. The organic remains excavated here are exceptionally well-preserved as they were embedded in anaerobic, waterlogged sediments in an area where the groundwater is rich in calcium carbonate. The fossil assemblage is ideal for the study of patterns in hominin interference with the mammalian species encountered at the site. The vertebrate record is extensive and very diverse. The fossil larger carnivore guild of the Spear Horizon faunal assemblage includes saber-toothed cat, fox, and wolf. Herbivores are represented by an elephant species, two equid species, two rhinoceros species, two cervid species, and two large bovid species. Evidence of hominin interference presents itself as either marks on skeletal remains related to the use of bones as knapping tools or hammers, or as marks that indicate butchering activities such as skinning, dismembering, defleshing, filleting, and marrow extraction. The humerus of the saber-toothed cat clearly shows that the bone has been used as a knapping tool. The fossil remains of the other larger carnivores do not show any signs of hominin interference or exploitation. This also applies to the limited number of elephant and rhinoceros remains found at the site. The large horse Equus mosbachensis dominates the larger mammal record and played a major role in hominin subsistence. Marks on the horse bones indicate that a large number of carcasses have been butchered. Traces on the fossil remains of both red deer (Cervus elaphus) and the large bovids also indicate exploitation by Lower Paleolithic hominins. PMID- 26607348 TI - Puerarin protects mouse liver against nickel-induced oxidative stress and inflammation associated with the TLR4/p38/CREB pathway. AB - Nickel (Ni), one of hazardous environmental chemicals, is known to cause liver injury. Accumulating evidence showed that puerarin (PU) possessed comprehensive biological effects. The purpose of the current study was to test the hypothesis that the puerarin protects against enhanced liver injury caused by Ni in mice. ICR mice received intraperitoneally nickel sulfate (20 mg/kg/body weight, daily) for 20 days, and puerarin (200 and 400 mg/kg/body weight) was applied before Ni exposure. The results indicated that puerarin markedly inhibited Ni-induced liver injury, which was characterized by decreased aminotransferase activities and inflammation. Puerarin also inhibited the oxidative stress and decreased the metallothionein (MT) levels. Puerarin decreased the level of pro-inflammatory cytokines TNF-alpha and IL-6 in livers. Puerarin significantly inhibited the TLR4 activation and p38 MAPK phosphorylation, which in turn inhibited NF-kappaB activity. Likewise, Ni-induced inflammatory responses were diminished by puerarin as observed by a remarkable reduction in the levels of phosphorylated CREB. Furthermore, puerarin also reduced inflammatory mediators such as cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2) levels in livers. Data from this study suggested that the inhibition of Ni-induced oxidative stress and inflammatory responses by puerarin is due to its ability to modulate the TLR4/p38/CREB signaling pathway. PMID- 26607349 TI - Regulatory role of miR-125a/b in the suppression by selenium of cadmium-induced apoptosis via the mitochondrial pathway in LLC-PK1 cells. AB - Cadmium (Cd), a toxic heavy metal, is known to induce kidney damage and renal tubular dysfunction. Our previous studies have indicated that selenium (Se), as an essential trace element, protects against Cd-induced nephrotoxicity via the mitochondrial apoptotic pathway in vivo and in vitro. The available evidence suggests that the expression of miRNAs is altered after Cd exposure. However, the regulatory effects of miRNAs on Cd-induced apoptosis and on the suppression by Se of Cd-induced apoptosis remain unclear. The present study aimed to explore the effects of miRNAs on the suppression by Se of Cd-induced apoptosis in LLC-PK1 cells. miR-125a and miR-125b were downregulated in response to Cd exposure but were upregulated in the Se pretreatment group. Over-expression and low expression of miR-125a/b were simulated by their mimics and inhibitors, respectively. Both Se and over-expression of miR-125a/b attenuated Cd-induced apoptosis through significant enhancement of the anti-apoptotic protein Bcl-2, reduction of the pro apoptotic proteins Bax and Bak, the release of cytochrome c and the inactivation of caspase-9 and caspase-3. The effects of downregulation of miR-125a/b on apoptosis were similar to those of Cd treatment, and both effects were inhibited by Se. Moreover, miR-125a/b were observed to target Bak and caspase-3 directly. In summary, miR-125a/b play an important role in the suppression of Cd-induced apoptosis by Se via the mitochondrial pathway in LLC-PK1 cells. PMID- 26607350 TI - The Role of a Novel Arterial Stiffness Parameter, Cardio-Ankle Vascular Index (CAVI), as a Surrogate Marker for Cardiovascular Diseases. AB - Measurement of arterial stiffness in routine medical practice is important to assess the progression of arteriosclerosis. So far, many parameters have been proposed to quantitatively represent arterial stiffness. Among these, pulse wave velocity (PWV) has been most frequently applied to clinical medicine because those could be measured simply and non-invasively. PWV had established the usefulness of measuring arterial wall stiffness. However, PWV essentially depends on blood pressure at the time of measurement. Therefore, PWV is not appropriate as a parameter for the evaluation of arterial stiffness, particularly for the studies involving blood pressure changes.On the other hand, stiffness parameter beta is an index reflecting arterial stiffness without the influence of blood pressure. Recently, this parameter has been applied to develop a new arterial stiffness index called cardio-ankle vascular index (CAVI). Therefore, CAVI does not depend on blood pressure changes during the measurements; CAVI could represent the stiffness of the arterial tree from the origin of the aorta to the ankle.Many clinical studies obtained from CAVI are being accumulated. CAVI showed high value in arteriosclerotic diseases, such as coronary artery diseases, cerebral infarction, and chronic kidney diseases, and also in majority of people with various coronary risk factors. The improvement of those risk factors decreased CAVI. Furthermore, the role of CAVI as a predictor of cardio-vascular events was reported recently.We review the clinical studies on CAVI and discuss the clinical usefulness of CAVI as a candidate surrogate end-point marker for cardiovascular disease. PMID- 26607351 TI - Role of LCAT in Atherosclerosis. AB - Lecithin:cholesterol acyltransferase (LCAT) is the only enzyme capable of esterifying cholesterol in plasma, thus determining the maturation of high density lipoproteins. Because it maintains an unesterified cholesterol gradient between peripheral cells and extracellular acceptors, for a long time, LCAT has been considered as a key enzyme in reverse cholesterol transport. However, despite the fact that it has been more than 50 years since the identification of LCAT, the role of this enzyme in the pathogenesis of atherosclerosis is still debated. A number of studies have been conducted in different animal models, with contradictory results. Studies in humans, in particular in the general population, in subjects at high cardiovascular risk, and in carriers of genetic LCAT deficiency in an excellent model to evaluate the correlation between the reduction of LCAT activity and atherosclerosis also gave conflicting results. This review provides a comprehensive overview of the controversial findings obtained in animals and humans, strengthening the necessity of further investigation to establish how LCAT could be regulated in a promising therapeutic strategy to reduce cardiovascular risk. PMID- 26607352 TI - Heart Failure as a Comorbidity of Diabetes: Role of Dipeptidyl Peptidase 4. AB - Heart failure is a primary cause of death worldwide, and it is notable that heart failure patients exhibit a high incidence of diabetes. On the other hand, comorbid diabetes significantly worsens the prognosis of heart failure, even independently of complicated coronary artery disease.To date, heart failure caused by diabetes has been designated as "diabetic cardiomyopathy (DMC)," and a recent cohort study of the large-scale (1.9 million people) research platform of linked electronic medical records in UK (CALIBER registry) demonstrated that heart failure and peripheral arterial disease are the most common initial manifestations of cardiovascular disease in type 2 diabetes. The underlying pathophysiology has been characterized as microvasculopathy, myocardial hypertrophy, and cardiac fibrosis; however, these evidences are mostly obtained under a preclinical setting, and its clinical application on DMC in terms of its diagnosis and therapeutic intervention yet has reached practical. Our group has focused on and clarified the molecular mechanisms underlying DMC both in preclinical and clinical settings and has found the primary role of "dipeptidyl peptidase-4 (DPP4)" in the pathogenesis of diabetic microvasculopathy in the heart. Moreover, there are evidences implicating the potent role of circulating DPP4 activity in the diagnosis of diastolic heart failure. The present review aimed to review the current comprehension regarding diabetes and heart failure and discuss the therapeutic and diagnostic roles of DPP4. PMID- 26607353 TI - Nanoneurobiophysics: new challenges for diagnosis and therapy of neurologic disorders. PMID- 26607355 TI - Incidence of invasive meticillin-resistant Staphylococcus aureus infections in Germany, 2010 to 2014. AB - Voluntary surveillance systems in Germany suggest a recent decline in the incidence of infections (subsequent to at least 2010) with meticillin-resistant Staphylococcus aureus (MRSA) from various types of specimens and settings. We asked whether this decline is reflected by data from the mandatory national surveillance system for invasive MRSA infections. Our analysis is based on the population in Germany in 2010 to 2014. Cases were identified from passive reporting by microbiological laboratories of the diagnosis of MRSA from blood culture or cerebrospinal fluid. Respective clinical data were subsequently added to the notification. We calculated risk ratios (RR) between consecutive years, stratifying cases by sex, age and federal state of residence. The national incidence increased from 4.6 episodes per 100,000 persons in 2010 to 5.6 in 2012 (2011 vs 2010: RR: 1.13, 95% confidence interval (CI): 1.08-1.18; 2012 vs 2011: RR: 1.08, 95% CI: 1.04-1.13). It stagnated at 5.4 per 100,000 in 2013 (RR: 0.97, 95% CI: 0.93-1.01) before declining to 4.8 in 2014 (RR: 0.88, 95% CI: 0.84-0.91). This trend was observed in most, but not all federal states and strata of sex and age groups. Only 204 of 20,679 (1%) episodes of infection were notified as belonging to an outbreak. Our analysis corroborates previous findings that the incidence of invasive MRSA infections in Germany may be declining. PMID- 26607356 TI - Psoriasis: More Than Just Skin Deep. PMID- 26607354 TI - Solution Structure of the HIV-1 Intron Splicing Silencer and Its Interactions with the UP1 Domain of Heterogeneous Nuclear Ribonucleoprotein (hnRNP) A1. AB - Splicing patterns in human immunodeficiency virus type 1 (HIV-1) are maintained through cis regulatory elements that recruit antagonistic host RNA-binding proteins. The activity of the 3' acceptor site A7 is tightly regulated through a complex network of an intronic splicing silencer (ISS), a bipartite exonic splicing silencer (ESS3a/b), and an exonic splicing enhancer (ESE3). Because HIV 1 splicing depends on protein-RNA interactions, it is important to know the tertiary structures surrounding the splice sites. Herein, we present the NMR solution structure of the phylogenetically conserved ISS stem loop. ISS adopts a stable structure consisting of conserved UG wobble pairs, a folded 2X2 (GU/UA) internal loop, a UU bulge, and a flexible AGUGA apical loop. Calorimetric and biochemical titrations indicate that the UP1 domain of heterogeneous nuclear ribonucleoprotein A1 binds the ISS apical loop site-specifically and with nanomolar affinity. Collectively, this work provides additional insights into how HIV-1 uses a conserved RNA structure to commandeer a host RNA-binding protein. PMID- 26607357 TI - Deubiquitinases Modulate Rapid Functional Responses in Platelets. PMID- 26607358 TI - Correction. PMID- 26607359 TI - Loktanella aquimaris sp. nov., Isolated from Seawater. AB - Two novel bacterial strains, designated C5(T) and C9 were isolated from a fish cage at Tongyeong, South Korea and were characterized to determine their taxonomic position. The strains were Gram-negative, non-motile, strictly aerobic and short rod shaped. Growth occurred between 20 and 32 degrees C (optimum 30 degrees C) and at pH 6.0-9.0 (optimum pH 8.0) and at 0-10 % NaCl (optimum at 2 % NaCl). Based on the 16S rRNA gene sequence analysis, they were identified as a member of the genus Loktanella that belongs to the phylum Proteobacteria. Strains C5(T) and C9 were analyzed by a polyphasic approach, revealing variations in their phenotypic characters but reciprocal DNA-DNA hybridization values confirmed that they belong to the same species. Phylogenetic analysis of the 16S rRNA gene sequences of closely related species indicated their similarities were below 97 %. The predominant isoprenoid quinone is ubiquinone-10 (Q-10). The major cellular fatty acids were C16:0, and C18:1 omega7c. Major polar lipid contained phosphatidylglycerol (PG), phosphatidycholine (PC), diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE), unidentified amino lipid (AL) and unidentified lipids (L1-3). Based on phylogenetic and phenotypic data, the isolated strains represent a novel species of the genus Loktanella, for which the name Loktanella aquimaris sp. nov. is proposed. The type strains were C5(T) (=KEMB 3-892(T) = JCM 30382(T)), and a second strain is C9 (=KEMB 3-893 = JCM 30383). PMID- 26607360 TI - Enhanced Hydrogen Production by Co-cultures of Hydrogenase and Nitrogenase in Escherichia coli. AB - Rhodobacter sphaeroides is a bacterium that can produce hydrogen by interaction with hydrogenase and nitrogenase. We report a hydrogen production system using co cultivation of hydrogenase in liquid medium and immobilized nitrogenase in Escherichia coli. The recombinant plasmid has been constructed to analyze the effect of hydrogen production on the expression of hupSL hydrogenase and nifHDK nitrogenase isolated from R. sphaeroides. All recombinant E. coli strains were cultured anaerobically, and cells for nitrogenase were immobilized in agar gel, whereas cells for hydrogenase were supplemented on the nitrogenase agar gel. The hupSL hydrogenase has been observed to enhance hydrogen production and hydrogenase activity under co-culture with nifHDK nitrogenase. The maximum hydrogen production has been obtained at an agar gel concentration and a cell concentration for co-culture of 2 % and 6.4 * 10(8) CFU. Thus, co-culture of hupSL hydrogenase and nifHDK nitrogenase provides a promising route for enhancing the hydrogen production and hydrogenase activity. PMID- 26607361 TI - Safety and tolerability of intravenous regadenoson in healthy subjects: A randomized, repeat-dose, placebo-controlled study. AB - BACKGROUND: Regadenoson is a selective A2A adenosine receptor agonist indicated for radionuclide myocardial perfusion imaging in patients unable to undergo adequate exercise stress. However, the safety, tolerability, and plasma concentrations associated with repeated doses have not previously been assessed. METHOD AND RESULTS: Healthy males and females were randomized to receive intravenous regadenoson [100 MUg (3 doses), 200 MUg (3 doses), or 400 MUg (2 doses)], or placebo (2 or 3 doses; 0.9% sodium chloride); all doses 10 minutes apart. The primary endpoint was vital sign measurements (blood pressure and heart rate). Secondary endpoints included 12-lead electrocardiogram measurements, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and adverse events. Thirty-six subjects were randomized and completed the study. Plasma concentrations of regadenoson increased in a dose-related manner and with successive doses. No consistent effect was observed for systolic blood pressure, although diastolic blood pressure was slightly lower than placebo for all regadenoson groups. Transient, dose-dependent increases in heart rate were observed in all regadenoson groups. There were no serious adverse events; 27 adverse events occurred in 14 regadenoson-treated subjects vs two events in two placebo-treated subjects. CONCLUSION: Repeated doses of regadenoson appeared to be safe and well tolerated in healthy subjects. PMID- 26607362 TI - Utility of multimodality imaging in suspected prosthetic valve endocarditis. PMID- 26607363 TI - Alexithymic characteristics in pediatric patients with primary headache: a comparison between migraine and tension-type headache. AB - BACKGROUND: Alexithymia is a personality construct characterized by difficulties in verbal emotional expression and a limited ability to use one's imagination. Evidence of alexithymic characteristics was found in adults suffering from headache, while little is known about children. The aim of this study was to establish the prevalence of alexithymia in two different subgroups of children and adolescents suffering from primary headache. We also looked for correlation between alexithymia in children and in their mothers. METHODS: This study involved 89 participants: 47 (11 males, 36 females, aged 8 to 17 years) suffering from tension-type headache (TTH), and 42 (18 males, 24 females, aged 8 to 17 years) suffering from migraine (M), based on the International Classification of Headache Disorders (ICHD 2013). A control group of 32 headache-free subjects (26 females and 6 males, aged 8 to 17 years) was also considered. Two questionnaires were administered to measure alexithymia: the Alexithymia Questionnaire for Children to young patients and controls, and the Toronto Alexithymia Scale (TAS 20) to the mothers. RESULTS: Higher rates of alexithymia emerged in the TTH group compared to the M group. In particular, TTH sufferers had difficulty identifying their feelings. The mothers of children with headaches didn't score higher in alexithymia compared to other mothers. In the M and in the control group, there was a significant correlation between the rates of alexithymia in young people and in their mothers. CONCLUSIONS: To date no other study has investigated alexithymia in subgroups of primary headaches in developmental age. Our results suggest that patients suffering from TTH are more alexithymic than M patients. This pave the way to etiopathogenetic and clinical considerations, calling for a comprehensive and multidisciplinary approach to tackle the problem of headache. PMID- 26607364 TI - Mental illness stigma and disclosure in college students. AB - OBJECTIVE: The aim of this study was to investigate the relationship between mental illness identity, shame, secrecy, public stigma, and disclosure amongst college students. Participants included 1393 college students from five postsecondary institutions. METHODS: Structural equation modeling was used to examine two path models predicting disclosure and desire to join a program aiding with disclosure. RESULTS: Variables found to be significant in predicting disclosure included mental illness identity and public stigma. In turn, desire for disclosure predicted desire to join a program aiding in disclosure. Gender and race/ethnic differences were observed, with men and Whites more likely to want to disclose a mental illness or join a program aiding with disclosure compared with women and non-Whites, respectively. CONCLUSIONS: These findings suggest that some college students may find programs aiding in disclosure useful in assisting them to achieve their desire to be "out" with their mental illness. PMID- 26607374 TI - hcrcn81 promotes cell proliferation through Wnt signaling pathway in colorectal cancer. AB - The objective of the study was to investigate the role of hcrcn81 gene in Wnt/beta-catenin signaling pathway related to human colorectal cancer. A total of 30 pairs of human colorectal cancer tissues with control normal tissues were analyzed by qRT-PCR. The proliferation, apoptosis, cell cycle, cell colony and metastasis of LS174T(-hcrcn81), HCT116(-hcrcn81), LoVo(+hcrcn81) and SMMC 7721(+hcrcn81) cells were tested, of which hcrcn81 was knockdown in LS174T, HCT116 cells and hcrcn81 was overexpressed in LoVo, SMMC-7721 cells. Besides, the mRNA and protein levels of hcrcn81, beta-catenin, c-Myc, cyclinD1, GSK-3beta and survivin in colon cancer cell lines were evaluated by qRT-PCR and western blot. The mRNA levels of beta-catenin and Survivin were up-regulated in 76.7 % (23/30) and 63.3 % (19/30) of the tumor samples, respectively. hcrcn81 and GSK-3beta mRNA expression levels were down-regulated in 20/30 (66.7 %) and 21/30 (70.0 %) of the tumor samples as compared to the adjacent normal tissues, respectively. Furthermore, in LoVo(+hcrcn81) and SMMC-7721(+hcrcn81) cells, the mRNA and protein levels of beta-catenin, c-Myc, cyclinD1 and Survivin were up-regulated, whereas those of GSK-3 were down-regulated. In LS174T(-hcrcn81) and HCT116( hcrcn81) cells, the mRNA levels of beta-catenin, c-Myc, cyclinD1 and Survivin were down-regulated, whereas GSK-3betamRNA was up-regulated. Cell proliferation in LoVo(+hcrcn81) and SMMC-7721(+hcrcn81) groups was significantly enhanced (P < 0.05). Proliferation index in both LoVo(+hcrcn81) and SMMC-7721(+hcrcn81) groups was significantly higher than that in the control groups (P < 0.05). The number of colony in LoVo(+hcrcn81) and SMMC-7721(+hcrcn81) cells were significantly higher than that in the control groups (P < 0.05). In addition, the percentage of apoptotic cells in LoVo(+hcrcn81) and SMMC-7721(+hcrcn81) groups were significantly lower than that in the control groups (P < 0.01, P < 0.01). Finally, the number of migrating cells was significantly higher in LoVo(+hcrcn81) and SMMC-7721(+hcrcn81) groups than that in the control group (P < 0.05). hcrcn81 might promote carcinogenesis and progression through regulation of the Wnt/beta catenin signaling pathway and plays an important role in the carcinogenesis of colorectal cancer. PMID- 26607375 TI - HyPer Family Probes: State of the Art. AB - SIGNIFICANCE: Hydrogen peroxide (H2O2) is not only a key mediator of oxidative stress but also one of the most important cellular second messengers. This small short-lived molecule is involved in the regulation of a wide range of different biological processes, including regulation of cellular signaling pathways. Studying the role of H2O2 in living systems would be challenging without modern approaches. A genetically encoded fluorescent biosensor, HyPer, is one of the most effective tools for this purpose. RECENT ADVANCES: HyPer has been used by many investigators of redox signaling in various models of different scales: from cytoplasmic subcompartments and single cells to tissues of whole organisms. In many studies, the results obtained using HyPer have enabled a better understanding of the roles of H2O2 in these biological processes. However, much remains to be learned. CRITICAL ISSUES: In this review, we focus on the uses of HyPer. We provide a general description of HyPer and its improved versions. Separate chapters are devoted to the results obtained by various groups who have used this biosensor for their experiments in living cells and organisms. FUTURE DIRECTIONS: HyPer is an effective tool for H2O2 imaging in living systems as indicated by the increasing numbers of publications each year since its development. However, this biosensor requires further improvements. In particular, much brighter and more pH-stable versions of HyPer are necessary for imaging in mammalian tissues. Antioxid. Redox Signal. 24, 731-751. PMID- 26607376 TI - Editorial Comment. PMID- 26607377 TI - Editorial Comment. PMID- 26607378 TI - Animal models for plaque rupture: a biomechanical assessment. AB - Rupture of atherosclerotic plaques is the main cause of acute cardiovascular events. Animal models of plaque rupture are rare but essential for testing new imaging modalities to enable diagnosis of the patient at risk. Moreover, they enable the design of new treatment strategies to prevent plaque rupture. Several animal models for the study of atherosclerosis are available. Plaque rupture in these models only occurs following severe surgical or pharmaceutical intervention. In the process of plaque rupture, composition, biology and mechanics each play a role, but the latter has been disregarded in many animal studies. The biomechanical environment for atherosclerotic plaques is comprised of two parts, the pressure-induced stress distribution, mainly - but not exclusively - influenced by plaque composition, and the strength distribution throughout the plaque, largely determined by the inflammatory state. This environment differs considerably between humans and most animals, resulting in suboptimal conditions for plaque rupture. In this review we describe the role of the biomechanical environment in plaque rupture and assess this environment in animal models that present with plaque rupture. PMID- 26607379 TI - Sulfotanone, a new alkyl sulfonic acid derivative from Streptomyces sp. IFM 11694 with TRAIL resistance-overcoming activity. AB - One new alkyl sulfonic acid derivative, sulfotanone (1), and the known panosialin wA (2) were isolated from the methanolic extract of mycelium of Streptomyces sp. 11694. The structure of the new compound (1) was established by a combination of spectroscopic techniques, including HRESIMS, IR, 1D and 2D NMR measurements. Compound 1 (40 uM) in combination with TRAIL showed synergistic activity in sensitizing TRAIL-resistance in human gastric adenocarcinoma cell lines. PMID- 26607380 TI - Leukemia-Associated Cohesin Mutants Dominantly Enforce Stem Cell Programs and Impair Human Hematopoietic Progenitor Differentiation. AB - Recurrent mutations in cohesin complex proteins have been identified in pre leukemic hematopoietic stem cells and during the early development of acute myeloid leukemia and other myeloid malignancies. Although cohesins are involved in chromosome separation and DNA damage repair, cohesin complex functions during hematopoiesis and leukemic development are unclear. Here, we show that mutant cohesin proteins block differentiation of human hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo and enforce stem cell programs. These effects are restricted to immature HSPC populations, where cohesin mutants show increased chromatin accessibility and likelihood of transcription factor binding site occupancy by HSPC regulators including ERG, GATA2, and RUNX1, as measured by ATAC seq and ChIP-seq. Epistasis experiments show that silencing these transcription factors rescues the differentiation block caused by cohesin mutants. Together, these results show that mutant cohesins impair HSPC differentiation by controlling chromatin accessibility and transcription factor activity, possibly contributing to leukemic disease. PMID- 26607381 TI - Targeted Application of Human Genetic Variation Can Improve Red Blood Cell Production from Stem Cells. AB - Multipotent and pluripotent stem cells are potential sources for cell and tissue replacement therapies. For example, stem cell-derived red blood cells (RBCs) are a potential alternative to donated blood, but yield and quality remain a challenge. Here, we show that application of insight from human population genetic studies can enhance RBC production from stem cells. The SH2B3 gene encodes a negative regulator of cytokine signaling and naturally occurring loss of-function variants in this gene increase RBC counts in vivo. Targeted suppression of SH2B3 in primary human hematopoietic stem and progenitor cells enhanced the maturation and overall yield of in-vitro-derived RBCs. Moreover, inactivation of SH2B3 by CRISPR/Cas9 genome editing in human pluripotent stem cells allowed enhanced erythroid cell expansion with preserved differentiation. Our findings therefore highlight the potential for combining human genome variation studies with genome editing approaches to improve cell and tissue production for regenerative medicine. PMID- 26607382 TI - Frequent Somatic Mutation in Adult Intestinal Stem Cells Drives Neoplasia and Genetic Mosaicism during Aging. AB - Adult stem cells may acquire mutations that modify cellular behavior, leading to functional declines in homeostasis or providing a competitive advantage resulting in premalignancy. However, the frequency, phenotypic impact, and mechanisms underlying spontaneous mutagenesis during aging are unclear. Here, we report two mechanisms of genome instability in adult Drosophila intestinal stem cells (ISCs) that cause phenotypic alterations in the aging intestine. First, we found frequent loss of heterozygosity arising from mitotic homologous recombination in ISCs that results in genetic mosaicism. Second, somatic deletion of DNA sequences and large structural rearrangements, resembling those described in cancers and congenital diseases, frequently result in gene inactivation. Such modifications induced somatic inactivation of the X-linked tumor suppressor Notch in ISCs, leading to spontaneous neoplasias in wild-type males. Together, our findings reveal frequent genomic modification in adult stem cells and show that somatic genetic mosaicism has important functional consequences on aging tissues. PMID- 26607384 TI - Cardioselective beta blockers are safe to use in asthma. PMID- 26607383 TI - Cognitive Control Deficits in Shifting and Inhibition in Preschool Age Children are Associated with Increased Depression and Anxiety Over 7.5 Years of Development. AB - Although depression and anxiety are common in youth (Costello et al. 2003), factors that put children at risk for such symptoms are not well understood. The current study examined associations between early childhood cognitive control deficits and depression and anxiety over the course of development through school age. Participants were 188 children (at baseline M = 5.42 years, SD = 0.79 years) and their primary caregiver. Caregivers completed ratings of children's executive functioning at preschool age and measures of depression and anxiety severity over seven assessment waves (a period of approximately 7.5 years). Longitudinal multilevel linear models were used to examine the effect of attention shifting and inhibition deficits on depression and anxiety. Inhibition deficits at preschool were associated with significantly greater depression severity scores at each subsequent assessment wave (up until 7.5 years later). Inhibition deficits were associated with greater anxiety severity from 3.5 to 7.5 years later. Greater shifting deficits at preschool age were associated with greater depression severity up to 5.5 years later. Shifting deficits were also associated with significantly greater anxiety severity up to 3.5 years later. Importantly, these effects were significant even after accounting for the influence of other key predictors including assessment wave/time, gender, parental education, IQ, and symptom severity at preschool age, suggesting that effects are robust. Overall, findings indicate that cognitive control deficits are an early vulnerability factor for developing affective symptoms. Timely assessment and intervention may be beneficial as an early prevention strategy. PMID- 26607385 TI - Development of an Iridium(III) Complex as a G-Quadruplex Probe and Its Application for the G-Quadruplex-Based Luminescent Detection of Picomolar Insulin. AB - In this study, an unreported Ir(III) complex 1 was identified by screening as a versatile G-quadruplex probe. It exhibited highly selective response for different G-quadruplex DNA over double strand, single strand and triplex DNA. Compared with the organic G-quadruplex probe thioflavin T, complex 1 displays a longer lifetime, a larger Stokes shift, comparable G-quadruplex/ssDNA enhancement ratios, and higher G-quadruplex/triplex DNA enhancement ratios. In consideration of the encouraging G-quadruplex probe performance of complex 1, we employed 1 to develop a G-quadruplex-based detection system for the detection of insulin as a "proof-of-principle" concept. We also demonstrate an optimization process that enhanced the sensitivity of this sensing assay. Compared to previously reported methods, our "mix-and-detect" detection methodology is easy operated, quick, and cost-effective. A detection limit as low as 80 pM for insulin can be achieved by this sensing approach, with a linear relationship between luminescence intensity and insulin concentration established from 80 pM to 20 nM. Moreover, this assay could work effectively in diluted human serum. PMID- 26607386 TI - Copper nanocoils synthesized through solvothermal method. AB - Recently helical nanostructures such as nanosprings and nanocoils have drawn great interests in nanotechnology, due to their unique morphologies and physical properties, and they may be potential building blocks in sorts of electromechanical, magnetic, photoelectronic and plasmonic devices at micro/nanoscales. In this report, multi-turns copper nanocoils were synthesized through a modified solvothermal method, in which the mixture of water and N methyl-2-pyrrolidone (NMP) were selected as reaction medium and copolymer poly(1 vinylpyrrolidone-co-vinyl acetate) (PVP/VA 64E) as reductant. In the liquid solution, nanosprings could be formed from relaxed nanocoils and demonstrated high elasticity. These nanocoils and nanosprings are of single crystalline structure, with the characteristics wire diameters ranging from tens to a few hundreds of nanometers and the ring/coil diameters mostly ~10-35 microns. Their growth and deformation mechanisms were then investigated and discussed along with that of previously reported single-turn copper nanorings. This work could be of importance for researchers working on synthesis and applications of novel 1-D helical nanomaterials and their functional devices. PMID- 26607388 TI - Inflammatory myopathies: Anti-FHL1 antibodies linked to IIM. PMID- 26607387 TI - Navigating the bone marrow niche: translational insights and cancer-driven dysfunction. AB - The bone marrow niche consists of stem and progenitor cells destined to become mature cells such as haematopoietic elements, osteoblasts or adipocytes. Marrow cells, influenced by endocrine, paracrine and autocrine factors, ultimately function as a unit to regulate bone remodelling and haematopoiesis. Current evidence highlights that the bone marrow niche is not merely an anatomic compartment; rather, it integrates the physiology of two distinct organ systems, the skeleton and the marrow. The niche has a hypoxic microenvironment that maintains quiescent haematopoietic stem cells (HSCs) and supports glycolytic metabolism. In response to biochemical cues and under the influence of neural, hormonal, and biochemical factors, marrow stromal elements, such as mesenchymal stromal cells (MSCs), differentiate into mature, functioning cells. However, disruption of the niche can affect cellular differentiation, resulting in disorders ranging from osteoporosis to malignancy. In this Review, we propose that the niche reflects the vitality of two tissues - bone and blood - by providing a unique environment for stem and stromal cells to flourish while simultaneously preventing disproportionate proliferation, malignant transformation or loss of the multipotent progenitors required for healing, functional immunity and growth throughout an organism's lifetime. Through a fuller understanding of the complexity of the niche in physiologic and pathologic states, the successful development of more-effective therapeutic approaches to target the niche and its cellular components for the treatment of rheumatic, endocrine, neoplastic and metabolic diseases becomes achievable. PMID- 26607389 TI - Successes and failures of chemokine-pathway targeting in rheumatoid arthritis. AB - Chemokines and chemokine receptors are involved in leukocyte recruitment and angiogenesis underlying the pathogenesis of rheumatoid arthritis (RA) and other inflammatory rheumatic diseases. Numerous chemokines, along with both conventional and atypical cell-surface chemokine receptors, are found in inflamed synovia. Preclinical studies carried out in animal models of arthritis involving agents targeting chemokines and chemokine receptors have yielded promising results. However, most human trials of treatment of RA with antibodies and synthetic compounds targeting chemokine signalling have failed to show clinical improvements. Chemokines can have overlapping actions, and their activities can be altered by chemical modification or proteolytic degradation. Effective targeting of chemokine pathways must take acount of these properties, and can also require high levels of receptor occupancy by therapeutic agents to prevent signalling. CCR1 is a promising target for chemokine-receptor blockade. PMID- 26607391 TI - Science-in-brief: Report of the Havemeyer Foundation W.R. (Twink) Allen Symposium on Equine Fertility and Assisted Reproduction. PMID- 26607390 TI - Downregulation of the small GTPase SAR1A: a key event underlying alcohol-induced Golgi fragmentation in hepatocytes. AB - The hepatic asialoglycoprotein receptor (ASGP-R) is posttranslationally modified in the Golgi en route to the plasma membrane, where it mediates clearance of desialylated serum glycoproteins. It is known that content of plasma membrane associated ASGP-R is decreased after ethanol exposure, although the mechanisms remain elusive. Previously, we found that formation of compact Golgi requires dimerization of the largest Golgi matrix protein giantin. We hypothesize that ethanol-impaired giantin function may be related to altered trafficking of ASGP R. Here we report that in HepG2 cells expressing alcohol dehydrogenase and hepatocytes of ethanol-fed rats, ethanol metabolism results in Golgi disorganization. This process is initiated by dysfunction of SAR1A GTPase followed by altered COPII vesicle formation and impaired Golgi delivery of the protein disulfide isomerase A3 (PDIA3), an enzyme that catalyzes giantin dimerization. Additionally, we show that SAR1A gene silencing in hepatocytes mimics the effect of ethanol: dedimerization of giantin, arresting PDIA3 in the endoplasmic reticulum (ER) and large-scale alterations in Golgi architecture. Ethanol-induced Golgi fission has no effect on ER-to-Golgi transportation of ASGP R, however, it results in its deposition in cis-medial-, but not trans-Golgi. Thus, alcohol-induced deficiency in COPII vesicle formation predetermines Golgi fragmentation which, in turn, compromises the Golgi-to-plasma membrane transportation of ASGP-R. PMID- 26607392 TI - Effect of treatment with inhaled corticosteroid on serum periostin levels in asthma. AB - BACKGROUND AND OBJECTIVE: Periostin is a biomarker of eosinophilic airway inflammation and may contribute to airway remodeling in asthma. The anti inflammatory activity of inhaled corticosteroids (ICS) for asthma control is widely recognized. The aim of this study was to assess the effects of ICS on serum periostin levels and its relationships to inflammation and airway geometry. METHODS: Forty-two healthy controls and 20 patients with steroid-naive asthma before and after treatment with fluticasone propionate (800 MUg/day for 16 weeks) were examined. Serum periostin, lung function and inflammatory cell counts in sputum were measured. Airway dimensions were determined by quantitative computed tomography (total area of the airway (Ao), wall area (WA), wall thickness (T) and percentage wall area (WA%) ). RESULTS: Serum periostin concentrations were significantly higher in patients with asthma than in controls. Periostin levels were correlated with airway wall thickness and sputum eosinophilia and inversely correlated with airflow limitation in asthma. ICS significantly decreased serum periostin (P < 0.01), decreased WA corrected for body surface area (WA/BSA, P < 0.05), T/?BSA (P < 0.01) and WA% (P < 0.01), reduced the percentage of sputum eosinophils (P < 0.01) and improved airflow limitation. The decrease in serum periostin levels was associated with an increased per cent predicted forced expiratory volume in 1 s (r = -0.64, P < 0.01), decreased WA/BSA (r = 0.46, P < 0.05) and decreased sputum eosinophils (r = 0.71, P < 0.01). CONCLUSION: Serum periostin levels respond partially to ICS and may reflect a reduction in airway inflammation and wall thickening in asthma. PMID- 26607393 TI - Relationship between retinal blood flow and arterial oxygen. AB - KEY POINTS: Vascular reactivity, the response of the vessels to a vasoactive stimulus such as hypoxia and hyperoxia, can be used to assess the vascular range of adjustment in which the vessels are able to compensate for changes in PO2. Previous studies in the retina have not accurately quantified retinal vascular responses and precisely targeted multiple PaO2 stimuli at the same time as controlling the level of carbon dioxide, thus precluding them from modelling the relationship between retinal blood flow and oxygen. The present study modelled the relationship between retinal blood flow and PaO2, showing them to be a combined linear and hyperbolic function. This model demonstrates that the resting tonus of the vessels is at the mid-point and that they have great vascular range of adjustment, compensating for decreases in oxygen above a PETCO2 of 32-37 mmHg but being limited below this threshold. Retinal blood flow (RBF) increases in response to a reduction in oxygen (hypoxia) but decreases in response to increased oxygen (hyperoxia). However, the relationship between blood flow and the arterial partial pressure of oxygen has not been quantified and modelled in the retina, particularly in the vascular reserve and resting tonus of the vessels. The present study aimed to determine the limitations of the retinal vasculature by modelling the relationship between RBF and oxygen. Retinal vascular responses were measured in 13 subjects for eight different blood gas conditions, with the end-tidal partial pressure of oxygen (PETCO2) ranging from 40-500 mmHg. Retinal vascular response measurements were repeated twice; using the Canon laser blood flowmeter (Canon Inc., Tokyo, Japan) during the first visit and using Doppler spectral domain optical coherence tomography during the second visit. We determined that the relationship between RBF and PaO2 can be modelled as a combination of hyperbolic and linear functions. We concluded that RBF compensated for decreases in arterial oxygen content for all stages of hypoxia used in the present study but can no longer compensate below a PETCO2 of 32-37 mmHg. These vessels have a great vascular range of adjustment, increasing diameter (8.5% arteriolar and 21% total venous area) with hypoxia (40 mmHg P ETC O2; P < 0.001) and decreasing diameter (6.9% arteriolar and 23% total venous area) with hyperoxia (500 mmHg PETCO2; P < 0.001) to the same extent. This indicates that the resting tonus is near the mid-point of the adjustment ranges at resting PaO2 where sensitivity is maximum. PMID- 26607394 TI - Perceptions of health professionals on subcutaneous hydration in palliative care: A qualitative study. AB - BACKGROUND: Evidence indicates that hypodermoclysis is as safe and effective as intravenous rehydration in the treatment of the symptomatology produced by mild to moderate dehydration in patients for whom oral route administration is not possible. However, the knowledge about the use of the subcutaneous hydration and its correlates is still limited. AIM: To explore the perceptions, attitudes and opinions of health professionals in palliative care on the administration of subcutaneous hydration. DESIGN: This is a qualitative focus group study with health professionals of palliative care. Four focus groups were carried out until data saturation. A qualitative content analysis was performed. SETTING/PARTICIPANTS: A total of 37 participants, physicians and nurses, were recruited from different services of palliative care in Spain. RESULTS: In all, 856 meaning units were identified, from which 56 categories were extracted and grouped into 22 sub-themes, which were distributed among four themes: 'factors which influence the hydration decision', 'factors related to the choice of the subcutaneous route for hydration', 'the subcutaneous hydration procedure' and 'performance guidelines and/or protocols'. CONCLUSIONS: Variables which most often influence the use of subcutaneous route to hydration are those that are linked to the characteristics of the patient, the team and the family, and other like the context and professionals' subjective perceptions about this medical practice. PMID- 26607395 TI - Novel, low-cost solid-liquid-solid process for the synthesis of alpha-Si3N4 nanowires at lower temperatures and their luminescence properties. AB - Ultra-long, single crystal, alpha-Si3N4 nanowires sheathed with amorphous silicon oxide were synthesised by an improved, simplified solid-liquid-solid (SLS) method at 1150 degrees C without using flowing gases (N2, CH4, Ar, NH3, etc.). Phases, chemical composition, and structural characterisation using X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM/HRTEM), Fourier-transform infrared spectroscopy (FT-IR), and X ray photoelectron spectroscopy (XPS) showed that the nanowires had Si3N4@SiOx core-shell structures. The growth of the nanowires was governed by the solid liquid-solid (SLS) mechanism. The room temperature photoluminescence (PL) and cathodoluminescence (CL) spectra showed that the optical properties of the alpha Si3N4 nanowires can be changed along with the excitation wavelength or the excitation light source. This work can be useful, not only for simplifying the design and synthesis of Si-related nanostructures, but also for developing new generation nanodevices with changeable photoelectronic properties. PMID- 26607396 TI - Comparison of biological characteristics of mesenchymal stem cells derived from maternal-origin placenta and Wharton's jelly. AB - INTRODUCTION: Although mesenchymal stem cells (MSCs) from different sources share many similar characteristics, they also exhibit individual properties. In this study, we compared MSCs derived from Wharton's jelly in the umbilical cord with those derived from the decidual basalis in the maternal part of the placenta to better understand the similarities and differences between these two cell types. METHOD: The morphology, immunophenotype (as assessed using flow cytometry), and multi-lineage differentiation potential were analyzed. Karyotype analysis was carried out to determine the origin of the MSCs. Growth kinetics were evaluated using analysis of the population doubling time and cell cycle. Immunosuppressive function was analyzed using mixed lymphocyte culture. RESULTS: MSCs from Wharton's jelly and the decidua basalis exhibited similar morphology, immunophenotype, and differentiation potential to osteogenesis and adipogenesis. The percentage of MSCs in the G0/G1 phase was higher in the case of Wharton's jelly than in the case of the decidua basalis (P < 0.05). Decidual MSCs displayed more remarkable immunosuppressive effects on phytohemagglutinin-stimulated T-cell proliferation (P < 0.05). CONCLUSION: MSCs from both sources had similar basic biological properties, but decidual MSCs had slower proliferation and stronger immunosuppressive function. PMID- 26607398 TI - Melatonin facilitates adipose-derived mesenchymal stem cells to repair the murine infarcted heart via the SIRT1 signaling pathway. AB - Mesenchymal stem cells (MSCs)-based therapy provides a promising therapy for the ischemic heart disease (IHD). However, engrafted MSCs are subjected to acute cell death in the ischemic microenvironment, characterized by excessive inflammation and oxidative stress in the host's infarcted myocardium. Melatonin, an indole, which is produced by many organs including pineal gland, has been shown to protect bone marrow MSCs against apoptosis although the mechanism of action remains elusive. Using a murine model of myocardial infarction (MI), this study was designed to evaluate the impact of melatonin on adipose-derived mesenchymal stem cells (AD-MSCs)-based therapy for MI and the underlying mechanism involved with a focus on silent information regulator 1(SIRT1) signaling. Our results demonstrated that melatonin promoted functional survival of AD-MSCs in infarcted heart and provoked a synergetic effect with AD-MSCs to restore heart function. This in vivo effect of melatonin was associated with alleviated inflammation, apoptosis, and oxidative stress in infarcted heart. In vitro studies revealed that melatonin exert cytoprotective effects on AD-MSCs against hypoxia/serum deprivation (H/SD) injury via attenuating inflammation, apoptosis, and oxidative stress. Mechanistically, melatonin enhanced SIRT1 signaling, which was accompanied with the increased expression of anti-apoptotic protein Bcl2, and decreased the expression of Ac-FoxO1, Ac-p53, Ac-NF-KappaB, and Bax. Taken together, our findings indicated that melatonin facilitated AD-MSCs-based therapy in MI, possibly through promoting survival of AD-MSCs via SIRT1 signaling. Our data support the promise of melatonin as a novel strategy to improve MSC-based therapy for IHD, possibly through SIRT1 signaling evocation. PMID- 26607397 TI - CRISPR-mediated Activation of Latent HIV-1 Expression. AB - Complete eradication of HIV-1 infection is impeded by the existence of cells that harbor chromosomally integrated but transcriptionally inactive provirus. These cells can persist for years without producing viral progeny, rendering them refractory to immune surveillance and antiretroviral therapy and providing a permanent reservoir for the stochastic reactivation and reseeding of HIV-1. Strategies for purging this latent reservoir are thus needed to eradicate infection. Here, we show that engineered transcriptional activation systems based on CRISPR/Cas9 can be harnessed to activate viral gene expression in cell line models of HIV-1 latency. We further demonstrate that complementing Cas9 activators with latency-reversing compounds can enhance latent HIV-1 transcription and that epigenome modulation using CRISPR-based acetyltransferases can also promote viral gene activation. Collectively, these results demonstrate that CRISPR systems are potentially effective tools for inducing latent HIV-1 expression and that their use, in combination with antiretroviral therapy, could lead to improved therapies for HIV-1 infection. PMID- 26607399 TI - Carbonic anhydrase inhibition for the management of cerebral ischemia: in vivo evaluation of sulfonamide and coumarin inhibitors. AB - Ischemia of brain areas is a global health problem, causing death or long-term disability. Current pharmacological options have limited impact on ischemic damages. Recently, a relationship between hypoxia and carbonic anhydrase (CA) over-expression has been highlighted suggesting CA inhibition as a possible target. This study aimed to evaluate the pharmacological profile of sulfonamide and coumarin CA inhibitors in rats underwent permanent middle cerebral artery occlusion (pMCAO). The neurological score of pMCAO rats was dramatically reduced 24 h after occlusion. Repeated subcutaneous injections of the CA inhibitors 4 and 7 (1 mg kg(-1)) were able to increase the neurological score by 40%. Compound 7 showed the tendency to reduce the volume of hemisphere infarction. The standard CA inhibitor acetazolamide was ineffective. The properties of novel CA inhibitors to improve neurological functionalities after cerebral ischemic insult are shown. The CA involvement in cerebral hypoxic phenomena deserves deeper investigations. PMID- 26607400 TI - A novel experimental platform for toxigenic and non-toxigenic Corynebacterium ulcerans infection in mice. AB - Corynebacterium ulcerans is a zoonotic pathogen that can produce diphtheria toxin and causes an illness categorized as diphtheria in the European Union because its clinical appearance is similar to that of diphtheria caused by Corynebacterium diphtheriae. Despite the importance of the pathogen in public health, the organism's mechanism of infection has not been extensively studied, especially in experimental animal models. Therefore in the present study we constructed an intranasal infection system for mice. Mice are insensitive to diphtheria toxin and this has the advantage of excluding the cytotoxic effect of the toxin that might interfere with the analysis of the early stage of infection. Both the toxigenic and non-toxigenic C. ulcerans strains were capable of killing mice within 3 days after inoculation at 10(7) colony-forming units per mouse. In experimentally infected animals, C. ulcerans was detected in the respiratory tract but not in the intestinal tract. The bacterium was also detected in peripheral blood and it disseminated into the lung, kidney and spleen to produce a systemic infection. This experimental infection system provides a platform for analyzing the virulence of C. ulcerans in future studies. PMID- 26607401 TI - Adenylate cyclase toxin-mediated delivery of the S1 subunit of pertussis toxin into mammalian cells. AB - The adenylate cyclase toxin (ACT) of Bordetella pertussis internalizes its catalytic domain into target cells. ACT can function as a tool for delivering foreign protein antigen moieties into immune effector cells to induce a cytotoxic T lymphocyte response. In this study, we replaced the catalytic domain of ACT with an enzymatically active protein moiety, the S1 (ADP-ribosyltransferase) subunit of pertussis toxin (PT). The S1 moiety was successfully internalized independent of endocytosis into sheep erythrocytes. The introduced polypeptide exhibited ADP-ribosyltransferase activity in CHO cells and induced clustering typical to PT. The results indicate that ACT can act as a vehicle for not only epitopes but also enzymatically active peptides to mammalian cells. PMID- 26607402 TI - Transcriptomic landscape for lymphocyte count variation in poly I:C-induced porcine peripheral blood. AB - Lymphocyte count is an important phenotypic metric that has been reported to be related to the individual antiviral capacity of pigs and other mammals. To date, aside from information regarding several genes and pathways, little is known about the mechanism by which gene expression affects variation in lymphocyte count. In this work, we investigated the lymphocyte count variation after poly I:C stimulation and compared the transcriptomes of pigs with large and small differences of lymphocyte counts before and after poly I:C stimulation. Pigs with large and small differences of lymphocyte counts were designated as extreme response (ER) and moderate response (MR) pigs respectively. Lymphocyte counts in all animals were observed to decline after poly I:C stimulation. Transcriptomic analysis identified 1121 transcripts (981 differentially expressed genes) in MR pigs and 1045 transcripts (904 differentially expressed genes) in ER pigs. We found that the majority of the differentially expressed genes were involved in both innate and adaptive immune responses. However, the innate immune response of ER pigs was more rapid than that of MR pigs. Results indicated that the activation of signaling pathways associated with cell death, cytotoxicity and apoptosis may contribute to the poly I:C-induced decrease of lymphocyte counts in the periphery. Moreover, the differential expression patterns of chemokines and FAS either totally or partially provided an interpretation for the different degrees of decrease in the lymphocyte counts between MR and ER pigs. Overall, our study will provide further understanding of the molecular basis for the antiviral capacity of pigs and other mammals. PMID- 26607403 TI - A meta-analysis of nutrition interventions on mental development of children under-two in low- and middle-income countries. AB - Interventions to improve nutritional status of young children in low- and middle income countries (LMIC) may have the added benefit of improving their mental and motor development. This meta-analysis updates and goes beyond previous ones by answering two important questions: (1) do prenatal and postnatal nutritional inputs improve mental development, and (2) are effects on mental development associated with two theoretically interesting mediators namely physical growth and motor development? The meta-analysis of articles on Medline, PsycINFO, Global Health and Embase was limited to randomized trials in LMICs, with mental development of children from birth to age two years as an outcome. The initial yield of 2689 studies was reduced to 33; 12 received a global quality rating of strong. Of the 10 prenatal and 23 postnatal nutrition interventions, the majority used zinc, iron/folic acid, vitamin A or multiple micronutrients, with a few evaluating macronutrients. The weighted mean effect size, Cohen's d (95% CI) for prenatal and postnatal nutrition interventions on mental development was 0.042 ( 0.0084, 0.092) and 0.076 (0.019, 0.13), respectively. Postnatal supplements consisting of macronutrients yielded an effect size d (95% CI) of 0.14 (0.0067, 0.27), multiple micronutrients 0.082 (-0.012, 0.18) and single micronutrients 0.058 (-0.0015, 0.12). Motor development, but not growth status, effect sizes were significantly associated with mental development in postnatal interventions. In summary, nutrition interventions had small effects on mental development. Future studies might have greater effect if they addressed macronutrient deficiencies combined with child stimulation and hygiene and sanitation interventions. PMID- 26607405 TI - Blood-brain barrier damage in vascular dementia. AB - New findings on flow or drainage pathways of brain interstitial fluid and cerebrospinal fluid have been made. The interstitial fluid flow has an effect on the passage of blood-borne substances in the brain parenchyma, especially in areas near blood-brain barrier (BBB)-free regions. Actually, blood-borne substances can be transferred in areas with intact BBB function, such as the hippocampus, the corpus callosum, periventricular areas, and medial portions of the amygdala, presumably through leaky vessels in the subfornical organs or the choroid plexus. Increasing evidence indicates that dysfunction of the BBB function may play a significant role in the pathogenesis of vascular dementia. Accordingly, we have examined which insults seen in patients suffering from vascular dementia have an effect on the BBB using experimental animal models exhibiting some phenotypes of vascular dementia. The BBB in the hippocampus was clearly deteriorated in Mongolian gerbils exposed to acute ischemia followed by reperfusion and also in stroke-prone spontaneously hypertensive rats (SHRSP) showing hypertension. The BBB in the corpus callosum was clearly deteriorated in Wistar rats with permanent ligation of the bilateral common carotid arteries showing chronic hypoperfusion. The BBB in the hippocampus and the olfactory bulb was mildly deteriorated in aged senescence accelerated prone mice (SAMP8) showing cognitive dysfunction. The BBB in the hippocampus was mildly deteriorated in aged animals with hydrocephalus. Mild endothelial damage was seen in hyperglycemic db/db mice. In addition, mRNA expression of osteopontin, matrix metalloproteinase 13 (MMP-13), and CD36 was increased in vessels showing BBB damage in hypertensive SHRSP. As osteopontin, MMP-13 and CD36 are known to be related to brain injury and amyloid beta accumulation or clearance, BBB damage followed by increased gene expression of these molecules not only contributes to the pathogenesis of vascular dementia, but also bridges the gap between vascular dementia and Alzheimer's disease. PMID- 26607404 TI - Design, Synthesis and Evaluation of Triazole-Pyrimidine Analogues as SecA Inhibitors. AB - SecA, a key component of the bacterial Sec-dependent secretion pathway, is an attractive target for the development of new antimicrobial agents. Through a combination of virtual screening and experimental exploration of the surrounding chemical space, we identified a hit bistriazole SecA inhibitor, SCA-21, and studied a series of analogues by systematic dissections of the core scaffold. Evaluation of these analogues allowed us to establish an initial structure activity relationship in SecA inhibition. The best compounds in this group are potent inhibitors of SecA-dependent protein-conducting channel activity and protein translocation activity at low- to sub-micromolar concentrations. They also have minimal inhibitory concentration (MIC) values against various strains of bacteria that correlate well with the SecA and protein translocation inhibition data. These compounds are effective against methicillin-resistant Staphylococcus aureus strains with various levels of efflux pump activity, indicating the capacity of SecA inhibitors to null the effect of multidrug resistance. Results from studies of drug-affinity-responsive target stability and protein pull-down assays are consistent with SecA as a target for these compounds. PMID- 26607406 TI - Transient sinus node dysfunction following sinus node artery occlusion due to radiofrequency catheter ablation of the septal superior vena cava-right atrium junction. AB - We performed catheter ablation to septal superior vena cava (SVC)-right atrium (RA) junction rapid firing in a 57-year-old man with paroxysmal atrial fibrillation. He later experienced transient sinus node dysfunction resulting from injury to the sinus node artery (SNA), which branched only from the proximal region of the left circumflex artery. The direction of the SNA should be considered during catheter ablation at the septal SVC-RA junction, especially if the sinus node is supplied by only one SNA from the right coronary artery or the left circumflex artery. PMID- 26607407 TI - Identification of exercise-induced ischemia using QRS slopes. AB - In this work we studied a computer-aided approach using QRS slopes as unconventional ECG features to identify the exercise-induced ischemia during exercise stress testing and demonstrated that the performance is comparable to the experts' manual analysis using standard criteria involving ST-segment depression. We evaluated the performance of our algorithm using a database including 927 patients undergoing exercise stress tests and simultaneously collecting the ECG recordings and SPECT results. High resolution 12-lead ECG recordings were collected continuously throughout the rest, exercise, and recovery phases. Patients in the database were classified into three categories of moderate/severe ischemia, mild ischemia, and normal according to the differences in sum of the individual segment scores for the rest and stress SPECT images. Philips DXL 16-lead diagnostic algorithm was run on all 10-s segments of 12-lead ECG recordings for each patient to acquire the representative beats, ECG fiducial points from the representative beats, and other ECG parameters. The QRS slopes were extracted for each lead from the averaged representative beats and the leads with highest classification power were selected. We employed linear discriminant analysis and measured the performance using 10-fold cross validation. Comparable performance of this method to the conventional ST-segment analysis exhibits the classification power of QRS slopes as unconventional ECG parameters contributing to improved identification of exercise-induced ischemia. PMID- 26607409 TI - Silicon Nanocrystals and Silicon-Polymer Hybrids: Synthesis, Surface Engineering, and Applications. AB - Silicon nanocrystals (Si-NCs) are emerging as an attractive class of quantum dots owing to the natural abundance of silicon in the Earth's crust, their low toxicity compared to many Group II-VI and III-V based quantum dots, compatibility with the existing semiconductor industry infrastructure, and their unique optoelectronic properties. Despite these favorable qualities, Si-NCs have not received the same attention as Group II-VI and III-V quantum dots, because of their lower emission quantum yields, difficulties associated with synthesizing monodisperse particles, and oxidative instability. Recent advancements indicate the surface chemistry of Si-NCs plays a key role in determining many of their properties. This Review summarizes new reports related to engineering Si-NC surfaces, synthesis of Si-NC/polymer hybrids, and their applications in sensing, diodes, catalysis, and batteries. PMID- 26607408 TI - Treatment for Positive Urine Cultures in Hospitalized Adults: A Survey of Prevalence and Risk Factors in 3 Medical Centers. AB - BACKGROUND: Antibiotic treatment for asymptomatic bacteriuria (ASB) is prevalent but often contrary to published guidelines. OBJECTIVE: To evaluate risk factors for treatment of ASB. DESIGN: Retrospective observational study. SETTING: A tertiary academic hospital, county hospital, and community hospital. PATIENTS: Hospitalized adults with bacteriuria. METHODS: Patients without documented symptoms of urinary tract infection per Infectious Diseases Society of America (IDSA) criteria were classified as ASB. We examined ASB treatment risk factors as well as broad-spectrum antibiotic usage and quantified diagnostic concordance between IDSA and National Healthcare Safety Network criteria. RESULTS: Among 300 patients with bacteriuria, ASB was present in 71% by IDSA criteria. By National Healthcare Safety Network criteria, 71% of patients had ASB; within-patient diagnostic concordance with IDSA was moderate (kappa, 0.52). After excluding those given antibiotics for nonurinary indications, antibiotics were given to 38% (62/164) with ASB. Factors significantly associated with ASB treatment were elevated urine white cell count (65 vs 24 white blood cells per high-powered field, P<.01), hospital identity (hospital C vs A, odds ratio, 0.34 [95% CI, 0.14 0.80], P =.01), presence of leukocyte esterase (5.48 [2.35-12.79], P<.01), presence of nitrites (2.45 [1.11-5.41], P=.03), and Escherichia coli on culture (2.4 [1.2-4.7], P=.01). Of patients treated for ASB, broad-spectrum antibiotics were used in 84%. CONCLUSIONS: ASB treatment was prevalent across settings and contributed to broad-spectrum antibiotic use. Associating abnormal urinalysis results with the need for antibiotic treatment regardless of symptoms may drive unnecessary antibiotic use. PMID- 26607410 TI - Testing multiple primary endpoints in clinical trials with sample size adaptation. AB - In this paper, we propose a design that uses a short-term endpoint for accelerated approval at interim analysis and a long-term endpoint for full approval at final analysis with sample size adaptation based on the long-term endpoint. Two sample size adaptation rules are compared: an adaptation rule to maintain the conditional power at a prespecified level and a step function type adaptation rule to better address the bias issue. Three testing procedures are proposed: alpha splitting between the two endpoints; alpha exhaustive between the endpoints; and alpha exhaustive with improved critical value based on correlation. Family-wise error rate is proved to be strongly controlled for the two endpoints, sample size adaptation, and two analysis time points with the proposed designs. We show that using alpha exhaustive designs greatly improve the power when both endpoints are effective, and the power difference between the two adaptation rules is minimal. The proposed design can be extended to more general settings. PMID- 26607411 TI - The effect of physical activity on cognitive function in patients with dementia: A meta-analysis of randomized control trials. AB - Non-pharmacological therapies, such as physical activity interventions, are an appealing alternative or add-on to current pharmacological treatment of cognitive symptoms in patients with dementia. In this meta-analysis, we investigated the effect of physical activity interventions on cognitive function in dementia patients, by synthesizing data from 802 patients included in 18 randomized control trials that applied a physical activity intervention with cognitive function as an outcome measure. Post-intervention standardized mean difference (SMD) scores were computed for each study, and combined into pooled effect sizes using random effects meta-analysis. The primary analysis yielded a positive overall effect of physical activity interventions on cognitive function (SMD[95% confidence interval]=0.42[0.23;0.62], p<.01). Secondary analyses revealed that physical activity interventions were equally beneficial in patients with Alzheimer's disease (AD, SMD=0.38[0.09;0.66], p<.01) and in patients with AD or a non-AD dementia diagnosis (SMD=0.47[0.14;0.80], p<.01). Combined (i.e. aerobic and non-aerobic) exercise interventions (SMD=0.59[0.32;0.86], p<.01) and aerobic only exercise interventions (SMD=0.41[0.05;0.76], p<.05) had a positive effect on cognition, while this association was absent for non-aerobic exercise interventions (SMD=-0.10[-0.38;0.19], p=.51). Finally, we found that interventions offered at both high frequency (SMD=0.33[0.03;0.63], p<.05) and at low frequency (SMD=0.64[0.39;0.89], p<.01) had a positive effect on cognitive function. This meta-analysis suggests that physical activity interventions positively influence cognitive function in patients with dementia. This beneficial effect was independent of the clinical diagnosis and the frequency of the intervention, and was driven by interventions that included aerobic exercise. PMID- 26607412 TI - Does transcranial direct current stimulation enhance cognitive and motor functions in the ageing brain? A systematic review and meta- analysis. AB - The use of transcranial direct current stimulation (tDCS) to enhance cognitive and motor functions has enjoyed a massive increase in popularity. Modifying neuroplasticity via non-invasive cortical stimulation has enormous potential to slow or even reverse declines in functions associated with ageing. The current meta-analysis evaluated the effects of tDCS on cognitive and motor performance in healthy older adults. Of the 81 studies identified, 25 qualified for inclusion. A random effects model meta-analysis revealed a significant overall standardized mean difference equal to 0.53 (SE=0.09; medium heterogeneity: I(2)=57.08%; and high fail-safe: N=448). Five analyses on moderator variables indicated significant tDCS beneficial effects: (a) on both cognitive and motor task performances, (b) across a wide-range of cognitive tasks, (c) on specific brain areas, (d) stimulation offline (before) or online (during) the cognitive and motor tasks. Although the meta-analysis revealed robust support for enhancing both cognitive and motor performance, we outline a number of caveats on the use of tDCS. PMID- 26607413 TI - Optimizing SAR-PAGE. PMID- 26607414 TI - Geography and end use drive the diversification of worldwide winter rye populations. AB - To meet the current challenges in human food production, improved understanding of the genetic diversity of crop species that maximizes the selection efficacy in breeding programs is needed. The present study offers new insights into the diversity, genetic structure and demographic history of cultivated rye (Secale cereale L.). We genotyped 620 individuals from 14 global rye populations with a different end use (grain or forage) at 32 genome-wide simple sequence repeat markers. We reveal the relationships among these populations, their sizes and the timing of domestication events using population genetics and model-based inference with approximate Bayesian computation. Our main results demonstrate (i) a high within-population variation and genetic diversity, (ii) an unexpected absence of reduction in diversity with an increasing improvement level and (iii) patterns suggestive of multiple domestication events. We suggest that the main drivers of diversification of winter rye are the end use of rye in two early regions of cultivation: rye forage in the Mediterranean area and grain in northeast Europe. The lower diversity and stronger differentiation of eastern European populations were most likely due to more intensive cultivation and breeding of rye in this region, in contrast to the Mediterranean region where it was considered a secondary crop or even a weed. We discuss the relevance of our results for the management of gene bank resources and the pitfalls of inference methods applied to crop domestication due to violation of model assumptions and model complexity. PMID- 26607415 TI - 3D Biomaterial Microarrays for Regenerative Medicine: Current State-of-the-Art, Emerging Directions and Future Trends. AB - Three dimensional (3D) biomaterial microarrays hold enormous promise for regenerative medicine because of their ability to accelerate the design and fabrication of biomimetic materials. Such tissue-like biomaterials can provide an appropriate microenvironment for stimulating and controlling stem cell differentiation into tissue-specific lineages. The use of 3D biomaterial microarrays can, if optimized correctly, result in a more than 1000-fold reduction in biomaterials and cells consumption when engineering optimal materials combinations, which makes these miniaturized systems very attractive for tissue engineering and drug screening applications. PMID- 26607419 TI - A biocompatibility study of new nanofibrous scaffolds for nervous system regeneration. AB - The development of therapeutic approaches for spinal cord injury (SCI) is still a challenging goal to achieve. The pathophysiological features of chronic SCI are glial scar and cavity formation: an effective therapy will require contribution of different disciplines such as materials science, cell biology, drug delivery and nanotechnology. One of the biggest challenges in SCI regeneration is to create an artificial scaffold that could mimic the extracellular matrix (ECM) and support nervous system regeneration. Electrospun constructs and hydrogels based on self-assembling peptides (SAPs) have been recently preferred. In this work SAPs and polymers were assembled by using a coaxial electrospinning setup. We tested the biocompatibility of two types of coaxially electrospun microchannels: the first one made by a core of poly(epsilon-caprolactone) and poly(d,l-lactide co-glycolide) (PCL-PLGA) and a shell of an emulsion of PCL-PLGA and a functionalized self-assembling peptide Ac-FAQ and the second one made by a core of Ac-FAQ and a shell of PCL-PLGA. Moreover, we tested an annealed scaffold by PCL-PLGA microchannel heat-treatment. The properties of coaxial scaffolds were analyzed using scanning electron microscopy (SEM), Fourier transform spectroscopy (FTIR), contact angle measurements and differential scanning calorimetry (DSC). In vitro cytotoxicity was assessed via viability and differentiation assays with neural stem cells (NSCs); whereas in vivo inflammatory response was evaluated following scaffold implantation in rodent spinal cords. Emulsification of the outer shell turned out to be the best choice in terms of cell viability and tissue response: thus suggesting the potential of using functionalized SAPs in coaxial electrospinning for applications in regenerative medicine. PMID- 26607420 TI - Epidemiology and antimicrobial susceptibilities of wound isolates of obligate anaerobes from combat casualties. AB - Data from recent conflicts related to war wounds and obligate anaerobes are limited. We define the epidemiology and antimicrobial susceptibility of obligate anaerobes from Iraq and Afghanistan casualties (6/2009-12/2013), as well as their association with clinical outcomes. Susceptibility against eleven antibiotics (7 classes) was tested. Overall, 59 patients had 119 obligate anaerobes identified (83 were first isolates). Obligate anaerobes were isolated 7-13 days post-injury, primarily from lower extremity wounds (43%), and were largely Bacteroides spp. (42%) and Clostridium spp. (19%). Patients with pelvic wounds were more likely to have Bacteroides spp. and concomitant resistant gram-negative aerobes. Seventy three percent of isolates were resistant to >=1 antimicrobials. Bacteroides spp. demonstrated the most resistance (16% of first isolates). Patients with resistant isolates had similar outcomes to those with susceptible strains. Serial recovery of isolates occurred in 15% of patients and was significantly associated with isolation of Bacteroides spp., along with resistant gram-negative aerobes. PMID- 26607421 TI - Evaluation of FlaB1, FlaB2, FlaB3, and Tp0463 of Treponema pallidum for serodiagnosis of syphilis. AB - Syphilis is a multistage disease caused by the invasive spirochete Treponema pallidum subsp. pallidum, and accurate diagnosis is important for the prevention and treatment of syphilis. Here, to identify appropriate diagnostic antigens for serodiagnosis of syphilis, 6 recombinant proteins were expressed in Escherichia coli and purified, including flagellins (FlaB1 [Tp0868], FlaB2 [Tp0792], and FlaB3 [Tp0870]), Tp0463, Tp0751, and Tp1038. The sensitivities were determined by screening sera from individuals with primary (n=82), secondary (n=115), latent (n=105), and congenital (n=65) syphilis. The specificities were determined by screening sera from uninfected controls (n=30) and potentially cross-reactive infections including Lyme disease (n=30), leptospirosis (n=5), and hepatitis B (n=30). Our data showed that FlaB1, FlaB2, FlaB3, Tp0463, and Tp1038 exhibited higher overall sensitivities and specificities for detecting IgG antibody, with 95.4% and 98.9%, 92.6% and 95.8%, 95.1% and 95.8%, 92.6% and 97.9%, and 95.9% and 98.9%, respectively. In contrast, Tp0751 demonstrated only an overall sensitivity of 39.2%. For comparison, the sensitivity and specificity of Architect Syphilis TP were determined to be 98.1% and 93.7%, respectively. In addition, FlaB1, FlaB2, FlaB3, and Tp0463 demonstrated excellent performance for detecting IgM antibody in primary and congenital syphilis, with sensitivities of 76.8% and 83.1%, 72.0% and 87.7%, 74.4% and 89.2%, and 64.6% and 75.3%, respectively. These results indicate that FlaB1, FlaB2, FlaB3, and Tp0463 could be as novel diagnostic candidates for serodiagnosis of syphilis. PMID- 26607422 TI - Effect of short term aerobic exercise on fasting and postprandial lipoprotein subfractions in healthy sedentary men. AB - BACKGROUND: Our goal was to investigate the effect of short term exercise on fasting and postprandial lipoprotein profile. METHODS: Healthy sedentary men exercised 20 min for four days. The intensity of exercise was modulated to maintain 75-80 % of a calculated HRmax. Before and after the exercise program, fasting and postprandial (4 h after standard meal) concentrations of lipoprotein subfractions were measured by an electrophoresis in polyacrylamide gel and total concentrations of TAG, LDL and HDL by enzymatic colorimetric method. After 2 days of rest, fasting and postprandial concentrations of lipoprotein fractions and subfractions were measured to determine a persistency of a changes in the lipoprotein profile. RESULTS: 4 days of physical exercise led to statistically significant decrease of concentration of triacylglycerol in fasting (76.29 +/- 20.07, 53.92 +/- 10.90, p < 0.05) and postprandial state (139.06 +/- 23.72, 96.55 +/- 25.21, p < 0.05) VLDL in fasting (21.88 +/- 3.87, 18.00 +/- 3.93, p < 0.05) and postprandial state (23.88 +/- 3.52, 19.25 +/- 3.62, p < 0.05), total cholesterol in fasting (162.26 +/- 23.38, 148.91 +/- 17.72, p < 0.05) and postprandial state (163.73 +/- 23.02, 150.08 +/- 18.11, p < 0.05). Atherogenic medium LDL decreased also in fasting (9.89 +/- 3.27, 6.22 +/- 2.55, p < 0.001) and postprandial state (8.88 +/- 6.51, 6.88 +/- 5.57, p < 0.001). However decrease of large IDL (25.38 +/- 3.54, 23.88 +/- 3.91, p < 0.05) and large LDL particles (42.89 +/- 11.40, 38.67 +/- 9.30) was observed only in postprandial state. Total HDL concentration remained unchanged but we observed statistically significant decrease of small HDL particles in fasting (6.11 +/- 2.89, 4.22, p < 0.05) and postprandial state (6.44 +/- 3.21, 4.56 +/- 1.33, p < 0.05). Concentration of these particles are associated with progression of atherosclerosis. All changes of fasting and postprandial lipoprotein profile disappeared after 2 days of rest. CONCLUSION: Just 4 daily settings of 20 min of physical exercise can lead to significant positive changes of fasting and postprandial lipoprotein profile. PMID- 26607423 TI - Editorial Commentary: Colistin and a New Paradigm in Drug Development. PMID- 26607424 TI - Updated US and European Dose Recommendations for Intravenous Colistin: How Do They Perform? AB - BACKGROUND: The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved updated dose recommendations for intravenous colistin in patients with various degrees of renal function. We assessed the recommendations in relation to their ability to achieve clinically relevant plasma colistin concentrations. METHODS: Pharmacokinetic data from 162 adult critically ill patients (creatinine clearance range, 5.4-211 mL/min) were used to determine the average steady-state plasma colistin concentration (Css,avg) that would be achieved if each patient received the FDA or EMA dose. Target attainment rates for FDA- and EMA-approved daily doses to achieve colistin Css,avg of >=0.5, >=1, >=2, and >=4 mg/L were determined for each creatinine clearance category (>=80 mL/min, 50 to <80 mL/min, 30 to <50 mL/min, and <30 mL/min). RESULTS: For creatinine clearance <30 mL/min, 100% of patients receiving the EMA dose achieved a colistin Css,avg >=1 mg/L, but the attainment rate was as low as 53.1% for patients receiving the FDA-approved dose. For colistin Css,avg >=2 mg/L, the attainment rates were 87.5% with the EMA dose but only 6.3%-34.4% in patients receiving the FDA dose. Differences in attainment rates for a colistin Css,avg of >=2 mg/L and >=4 mg/L extended to patients with creatinine clearance 30 to <50 mL/min. For patients with creatinine clearance >=80 mL/min, only approximately 65%-75% of patients achieved a colistin Css,avg of >=1 mg/L with either set of recommendations. CONCLUSIONS: The study highlights important differences between the FDA- and EMA-approved dose recommendations and informs the setting of clinical breakpoints. CLINICAL TRIALS REGISTRATION: NCT00235690. PMID- 26607425 TI - Unexpected maspin immunoreactivity in Merkel cell carcinoma. AB - Merkel cell carcinoma (MCC) is a rare but aggressive cutaneous neuroendocrine tumor, which multifactorial etiopathogenesis seems to be related to ultraviolet radiation, Merkel cell polyomavirus (MCV), and immunosuppression. In this paper, we present three cases of diagnosed MCC in apparently healthy Caucasians, two of them located in a sun-exposed area. They represented 0.25 % of all cutaneous malignant tumors diagnosed in our department. In the first case, MCC was diagnosed in the frontal region of a 67-year-old male, the second case was located in the right thigh of a 55-year-old female, whereas the third case involved the upper trunk of a 62-year-old female. All of these cases were diagnosed in the pT1 stage, having a diameter smaller than 2 cm, but the invasion depth involved the hypodermis. Microscopically, they consisted of small cells with round-oval nuclei having finely dispersed chromatin and well-defined nucleoli. Immunohistochemically, the tumor cells displayed positivity for keratin 20 and neuroendocrine markers, being negative for keratin 7 and S100 protein. Maspin immunoreactivity was seen in cases 1 and 3. Not one of the cases expressed DOG-1 or even TTF-1. Furthermore, this is the first report in literature about maspin positivity in MCC that might be related to sun exposure. PMID- 26607426 TI - beta2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion. AB - INTRODUCTION: For efficient metastatic dissemination, tumor cells form invadopodia to degrade and move through three-dimensional extracellular matrix. However, little is known about the conditions that favor invadopodia formation. Here, we investigated the effect of beta-adrenoceptor signaling - which allows cells to respond to stress neurotransmitters - on the formation of invadopodia and examined the effect on tumor cell invasion. METHODS: To characterize the molecular and cellular mechanisms of beta-adrenergic signaling on the invasive properties of breast cancer cells, we used functional cellular assays to quantify invadopodia formation and to evaluate cell invasion in two-dimensional and three dimensional environments. The functional significance of beta-adrenergic regulation of invadopodia was investigated in an orthotopic mouse model of spontaneous breast cancer metastasis. RESULTS: beta-adrenoceptor activation increased the frequency of invadopodia-positive tumor cells and the number of invadopodia per cell. The effects were selectively mediated by the beta2 adrenoceptor subtype, which signaled through the canonical Src pathway to regulate invadopodia formation. Increased invadopodia occurred at the expense of focal adhesion formation, resulting in a switch to increased tumor cell invasion through three-dimensional extracellular matrix. beta2-adrenoceptor signaling increased invasion of tumor cells from explanted primary tumors through surrounding extracellular matrix, suggesting a possible mechanism for the observed increased spontaneous tumor cell dissemination in vivo. Selective antagonism of beta2-adrenoceptors blocked invadopodia formation, suggesting a pharmacological strategy to prevent tumor cell dissemination. CONCLUSION: These findings provide insight into conditions that control tumor cell invasion by identifying signaling through beta2-adrenoceptors as a regulator of invadopodia formation. These findings suggest novel pharmacological strategies for intervention, by using beta-blockers to target beta2-adrenoceptors to limit tumor cell dissemination and metastasis. PMID- 26607427 TI - Prevalence factors associated with equine herpesvirus type 1 infection in equids with upper respiratory tract infection and/or acute onset of neurological signs from 2008 to 2014. AB - The objective of the present case-control study was to determine prevalence factors associated with the detection of equine herpesvirus type 1 (EHV-1) by quantitative PCR (qPCR) in horses presented to veterinarians with clinical signs related to an upper respiratory tract infection and/or acute onset of neurological disease from March 2008 to December 2014. Nasal secretions and whole blood from 4228 equids with acute onset of fever, respiratory signs and/or neurological deficits were tested by qPCR for EHV-1. Categorical analyses were performed to determine the association between observations and EHV-1. A total of 117/4228 (2.7 per cent) equids tested qPCR-positive for EHV-1, with most of the isolates belonging to the non-neuropathogenic genotype (N752). EHV-1 PCR-positive equids were over-represented in racing horses. Depression, anorexia, nasal discharge and coughing were significantly less frequently reported in the EHV-1 qPCR-positive equids compared with the EHV-1 qPCR-negative cases. Neurological deficits were more frequently reported in the EHV-1 qPCR-positive cases. This study provides contemporary information on the frequency of EHV-1 detection by qPCR in blood and nasal secretions from horses with fever, respiratory signs and neurological deficits. PMID- 26607428 TI - A Bayesian model for detection of high-order interactions among genetic variants in genome-wide association studies. AB - BACKGROUND: A central question for disease studies and crop improvements is how genetics variants drive phenotypes. Genome Wide Association Study (GWAS) provides a powerful tool for characterizing the genotype-phenotype relationships in complex traits and diseases. Epistasis (gene-gene interaction), including high order interaction among more than two genes, often plays important roles in complex traits and diseases, but current GWAS analysis usually just focuses on additive effects of single nucleotide polymorphisms (SNPs). The lack of effective computational modelling of high-order functional interactions often leads to significant under-utilization of GWAS data. RESULTS: We have developed a novel Bayesian computational method with a Markov Chain Monte Carlo (MCMC) search, and implemented the method as a Bayesian High-order Interaction Toolkit (BHIT) for detecting epistatic interactions among SNPs. BHIT first builds a Bayesian model on both continuous data and discrete data, which is capable of detecting high order interactions in SNPs related to case--control or quantitative phenotypes. We also developed a pipeline that enables users to apply BHIT on different species in different use cases. CONCLUSIONS: Using both simulation data and soybean nutritional seed composition studies on oil content and protein content, BHIT effectively detected some high-order interactions associated with phenotypes, and it outperformed a number of other available tools. BHIT is freely available for academic users at http://digbio.missouri.edu/BHIT/. PMID- 26607429 TI - Engaging families in physical activity research: a family-based focus group study. AB - BACKGROUND: Family-based interventions present a much-needed opportunity to increase children's physical activity levels. However, little is known about how best to engage parents and their children in physical activity research. This study aimed to engage with the whole family to understand how best to recruit for, and retain participation in, physical activity research. METHODS: Families (including a 'target' child aged between 8 and 11 years, their parents, siblings, and others) were recruited through schools and community groups. Focus groups were conducted using a semi-structured approach (informed by a pilot session). Families were asked to order cards listing the possible benefits of, and the barriers to, being involved in physical activity research and other health promotion activities, highlighting the items they consider most relevant, and suggesting additional items. Duplicate content analysis was used to identify transcript themes and develop a coding frame. RESULTS: Eighty-two participants from 17 families participated, including 17 'target' children (mean age 9.3 +/- 1.1 years, 61.1% female), 32 other children and 33 adults (including parents, grandparents, and older siblings). Social, health and educational benefits were cited as being key incentives for involvement in physical activity research, with emphasis on children experiencing new things, developing character, and increasing social contact (particularly for shy children). Children's enjoyment was also given priority. The provision of child care or financial reward was not considered sufficiently appealing. Increased time commitment or scheduling difficulties were quoted as the most pertinent barriers to involvement (especially for families with several children), but parents commented these could be overcome if the potential value for children was clear. CONCLUSIONS: Lessons learned from this work may contribute to the development of effective recruitment and retention strategies for children and their families. Making the wide range of potential benefits clear to families, providing regular feedback, and carefully considering family structure, may prove useful in achieving desired research participation. This may subsequently assist in engaging families in interventions to increase physical activity in children. PMID- 26607430 TI - On joint subtree distributions under two evolutionary models. AB - In population and evolutionary biology, hypotheses about micro-evolutionary and macro-evolutionary processes are commonly tested by comparing the shape indices of empirical evolutionary trees with those predicted by neutral models. A key ingredient in this approach is the ability to compute and quantify distributions of various tree shape indices under random models of interest. As a step to meet this challenge, in this paper we investigate the joint distribution of cherries and pitchforks (that is, subtrees with two and three leaves) under two widely used null models: the Yule-Harding-Kingman (YHK) model and the proportional to distinguishable arrangements (PDA) model. Based on two novel recursive formulae, we propose a dynamic approach to numerically compute the exact joint distribution (and hence the marginal distributions) for trees of any size. We also obtained insights into the statistical properties of trees generated under these two models, including a constant correlation between the cherry and the pitchfork distributions under the YHK model, and the log-concavity and unimodality of the cherry distributions under both models. In addition, we show that there exists a unique change point for the cherry distributions between these two models. PMID- 26607431 TI - Bifactor structure of the schizotypal personality questionnaire (SPQ). AB - The schizotypal personality questionnaire (SPQ) is used to characterize schizotypy, a complex construct helpful for the investigation of schizophrenia related psychopathology and putative endophenotypes. The SPQ factor structure at item level has been rarely replicated and no study had tested a bifactor model of the SPQ so far. The unidimensional, the correlated, the second-order and the bifactor models of the SPQ were tested to evaluate whether the items converge into a major single factor defining the schizotypy-proneness of the participants, to be used for grouping purpose. Parallel principal component analysis (PCA) and confirmatory factor analysis (CFA) were used to determine the optimal number of factors and components in a cross-sectional, survey design involving 649 college students (males: 47%). The first-order, nine-subscale model was confirmed by CFA in the whole sample. The best evidence from parallel PCA in the training set was in favor of a two-factor model; the bifactor implementation of this model showed good fit in the subsequent CFA. Two main dimensions of positive and negative symptoms underlie schizotypy in non-clinical samples, entailing specific risk of psychosis. On a measurement level, the study provided support for the use of the total scores of the SPQ to characterize schizotypy. PMID- 26607432 TI - OSTA program: A French follow up intervention program for suicide prevention. AB - Attempted suicide is a strong risk factor for subsequent suicidal behavior. In recent years, a particular interest has been given to follow-up interventions as a potential effective strategy in preventing recurrent suicidal behavior. We developed a follow-up intervention program called OSTA (organization of a suitable monitoring for suicide attempters) aimed at addressing this issue and tested its effectiveness in a 1-year randomized controlled trial. Individuals who attempted suicide and were admitted to the emergency department (ED) of Bicetre Hospital (n=320) were randomly allocated to receive either the OSTA program or a control treatment. On an intention to treat basis, the proportion of patients who reattempted suicide did not differ significantly between the interventional group (IG) 14.5% (22/152) and the control group (CG) 14% (21/150). There were also no significant differences, between the two arms, in the number of suicide attempts. Although no significant difference has been found between the OSTA program and the control treatment concerning the rate of suicide reattempts, we believe that further studies should be conducted to test the effectiveness of more standardized follow-up studies in suicide prevention. PMID- 26607433 TI - Empowering patients in the hospital as a new approach to reducing the burden of health care-associated infections: The attitudes of hospital health care workers. AB - BACKGROUND: Any approach promoting a culture of safety and the prevention of health care-associated infections (HCAIs) should involve all stakeholders, including by definition the patients themselves. This qualitative study explored the knowledge and attitudes of health care workers toward the concept of patient empowerment focused on improving infection control practices. METHODS: Semi structured interviews were undertaken with 29 staff from a large hospital in Sydney, Australia. RESULTS: There was virtually unanimous agreement among the participants that patients should be thought of as a stakeholder and should have a role in the prevention of HCAI. However, the degree of patient responsibility and level of system engagement varied. Although very few had previously been exposed to the concept of empowerment, they were accepting of the idea and were surprised that hospitals had not yet adopted the concept. However, they felt that a lack of support, busy workloads, and negative attitudes would be key barriers to the implementation of any empowerment programs. CONCLUSION: Although the World Health Organization has recommended that patients have a role in encouraging hand hygiene as a means of preventing infection, patient engagement remains an underused method. By extending the concept of patient empowerment to a range of infection prevention opportunities, the positive impact of this intervention will not only extend to the patient but to the system itself. PMID- 26607434 TI - Acylation of arginine in goserelin-loaded PLGA microspheres. AB - Acylation of peptides is a well-known but unwanted phenomenon in polyester matrices such as poly(d,l-lactic-co-glycolic acid) (PLGA) microspheres used as controlled release formulations. Acylation normally occurs on lysine residues and the N-terminus of the peptide. The purpose of the present work was to assess other possible acylation sites on peptides. Goserelin was used as a model peptide that lacks lysine and a free N-terminus, but contains other nucleophilic residues, i.e. serine, tyrosine and arginine, which potentially can be acylated. Goserelin loaded PLGA microspheres were prepared by a double emulsion solvent evaporation technique. Liquid chromatography ion-trap mass spectrometry (LC-ITMS) was used for determining and monitoring acylation of released goserelin. It is demonstrated that arginine is subjected to acylation with glycolic acid and lactic acid units of PLGA, which was followed by loss of NH3 from the guanidine group to obtain 2-oxazolin-4-one and 5-methyl-2-oxazolin-4-one residues with masses that are 41 and 55Da higher, respectively, than the native goserelin. There was no evidence for acylation of serine and tyrosine in goserelin. Our results demonstrate that beside lysine also acylation of arginine can occur in peptides and proteins that are loaded and released from PLGA matrixes. PMID- 26607435 TI - A qualitative study of physician perspectives of cost-related communication and patients' financial burden with managing chronic disease. AB - BACKGROUND: Patient financial burden with chronic disease poses significant health risks, yet it remains outside the scope of clinical visits. Little is known about how physicians perceive their patients' health-related financial burden in the context of primary care. The purpose of this study was to describe physician experiences with patients' financial burden while managing chronic disease and the communication of these issues. METHODS: In November 2013, four focus groups were conducted in an academic medical center. A convenience sample of 29 internal and family medicine resident physicians was used in this study. A semi-structured interview protocol was employed by trained facilitators. Coded transcripts were analyzed for themes regarding physicians' experiences with identifying, managing, and communicating financial burden with their patients in the context of primary care. RESULTS: Major themes identified were 1) patient financial burden with chronic care is visible to physicians, 2) patient's financial burden with chronic care and discussing these issues is important to physicians, 3) ability to identify patients who perceive financial burden is imperfect, 4) communication of financial burden with patients is complex and difficult to navigate, 5) strategies utilized to address concerns are not always generalizable, and 6) physicians have ideas for widespread change to make these conversations easier for them. CONCLUSION: Awareness of physician perspectives in identifying and addressing their patients' disease-related financial burden may better equip researchers and medical educators to develop interventions that aid care teams in better understanding these patient concerns to promote compliance with treatment recommendations. PMID- 26607436 TI - The Relationship Between Serum Endocan Levels With the Presence of Slow Coronary Flow: A Cross-Sectional Study. AB - BACKGROUND: The aim of this study was to investigate the relationship between endocan levels with the presence of slow coronary flow (SCF). METHODS: In this cross-sectional study, a total of 88 patients, who admitted to our hospital, were included in this study. Of these, 53 patients with SCF and 35 patients with normal coronary flow were included in the final analysis. Coronary flow rates of all patients were determined by the Timi Frame Count (TFC) method. RESULTS: In correlation analysis, endocan levels revealed a significantly positive correlation with high sensitive C-reactive protein and corrected TFC. In multivariate logistic regression analysis, the endocan levels were found as independently associated with the presence of SCF. Finally, using a cutoff level of 2.3, endocan level predicted the presence of SCF with a sensitivity of 77.2% and specificity of 75.2%. CONCLUSION: In conclusion, our study showed that higher endocan levels were significantly and independently related to the presence of SCF. PMID- 26607437 TI - Reduction of Venous Thromboembolism in Surgical Patients Using a Mandatory Risk Scoring System: 5-Year Follow-Up of an American College of Surgeons National Surgical Quality Improvement Program. AB - BACKGROUND: Sheikh Khalifa Medical City's (SKMC) surgery institute was identified as a high outlier in the incidence of venous thromboembolism (VTE; deep vein thrombosis [DVT] and pulmonary embolism [PE]) based on the semiannual report of the American College of Surgeon's National Surgical Quality Improvement Program (ACS NSQIP) in June 2010. AIM: To report our rates of VTE at SKMC, the results, and 5-year follow-up after an ACS NSQIP quality improvement program. METHODS: A multidisciplinary VTE task force was established in June 2010. We instituted a compulsory risk assessment for VTE and utilized the ACS NSQIP best practice guidelines to review cases of VTE. We prospectively evaluated the observed/expected (O/E) ratio for DVT/PE after implementing the action plan. RESULTS: The O/E ratio for PE/DVT in general and general/vascular (GV) surgery was 6.00 and 4.86 in June 2010. Our compliance with ordering antithrombotic prophylactic measures was as low and it improved to 100% and our O/E ratio decreased to 1.18 and 1.5 in July 2011 and stabilized for the next 4 years. Currently, our compliance with ordering antithrombotic prophylactic measures is 100%, and our last 2 O/E ratio for DVT/PE are 0.74 and 0.75 in GV surgery and 0.82 and 0.78 in the entire surgery institute, respectively, and we are considered an exemplary site of the ACS NSQIP in GV surgery. CONCLUSION: A compulsory risk assessment for VTE has led to an overall improvement in DVT/PE rates in the surgery institute and for GV surgery to become an exemplary site for the ACS NSQIP. PMID- 26607438 TI - Apelin-13 promotes cardiomyocyte hypertrophy via PI3K-Akt-ERK1/2-p70S6K and PI3K induced autophagy. AB - Apelin is highly expressed in rat left ventricular hypertrophy Sprague Dawley rat models, and it plays a crucial role in the cardiovascular system. The aim this study was to clarify whether apelin-13 promotes hypertrophy in H9c2 rat cardiomyocytes and to investigate its underlying mechanism. The cardiomyocyte hypertrophy was observed by measuring the diameter, volume, and protein content of H9c2 cells. The activation of autophagy was evaluated by observing the morphology of autophagosomes by transmission electron microscopy, observing the subcellular localization of LC3 by light microscopy, and detecting the membrane associated form of LC3 by western blot analysis. The phosphatidylinositol 3 kinase (PI3K) signaling pathway was identified and the proteins expression was detected using western blot analysis. The results revealed that apelin-13 increased the diameter, volume, and protein content of H9c2 cells and promoted the phosphorylation of PI3K, Akt, ERK1/2, and p70S6K. Apelin-13 activated the PI3K-Akt-ERK1/2-p70S6K pathway. PI3K inhibitor LY294002, Akt inhibitor 1701-1, ERK1/2 inhibitor PD98059 attenuated the increase of the cell diameter, volume, protein content induced by apelin-13. Apelin-13 increased the autophagosomes and up-regulated the expressions of beclin 1 and LC3-II/I both transiently and stably. The autophagy inhibitor 3MA ameliorated the increase of cell diameter, volume, and protein content that were induced by apelin-13. These results suggested that apelin-13 promotes H9c2 rat cardiomyocyte hypertrophy via PI3K-Akt ERK1/2-p70S6K and PI3K-induced autophagy. PMID- 26607439 TI - Down-regulation of SDF1-alpha expression in tumor microenvironment is associated with aspirin-mediated suppression of the pro-metastasis effect of sorafenib in hepatocellular carcinoma. AB - Sorafenib is considered to be the first-line therapy for advanced hepatocellular carcinoma (HCC). It significantly delays tumor progression time; however, it increases the invasive and metastatic potential of HCC. Recent studies have shown that aspirin is effective in preventing and treating tumors, and the combination treatment of aspirin and sorafenib significantly suppresses sorafenib-induced intrahepatic metastasis. However, the mechanism through which aspirin suppresses the sorafenib-induced intrahepatic metastasis is still unclear. In this study, we find that sorafenib markedly increases stromal-derived factor 1-alpha (SDF1 alpha) expression in paratumor and intratumor tissues, and aspirin attenuates sorafenib-induced increase of SDF1-alpha expression in paratumor and intratumor tissues. Further studies show that SDF1-alpha improves cell invasion potential of HCC cells, and that AMD3100, a specific inhibitor of SDF1-alpha receptor CXCR4, suppresses the elevated intrahepatic metastatic potential of HCC induced by sorafenib in vivo. Collectively, this study reveals that the sorafenib-induced increase of SDF1-alpha expression in paratumor and intratumor microenvironments is suppressed by aspirin, which is associated with aspirin-mediated suppression of the pro-metastasis effect of sorafenib in HCC. PMID- 26607440 TI - Tailored first-line biologic therapy in patients with rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis. AB - OBJECTIVE: A multidisciplinary expert panel, the Italian board for the TAilored BIOlogic therapy (ITABIO), was constituted to formulate evidence-based decisional statements for the first-line tailored biologic therapy in patient with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA). METHODS: Systematic review of the literature to identify English-language articles on the variables influencing the first-line biologic choice, including the efficacy and safety of the drug, the route of administration, the availability of response predictor biomarkers, the need of monotherapy, the patient socio-economic status, lifestyle, cultural level, personality, fertility and childbearing potential in women, the presence of comorbidities, the host related risk factors for infection and latent tuberculosis infection (LTBI) reactivation, the cardiovascular (CV) risk, and costs. RESULTS: Some variables, including the patients' preference, the indication for anti-TNF monotherapy in potential childbearing women, and the intravenous route with dose titration in obese subjects resulted valid for all the three rheumatic conditions. Further, evidence of a better cost-effectiveness profile for etanercept (ETN) and biosimilar infliximab (IFX) in RA was found. Any biologic may be employed in absence of choice driving factors in RA. Otherwise, a high infection risk or LTBI positivity drive the choice toward abatacept (ABA), tocilizumab (TCZ), or ETN. TCZ should be the first choice if monotherapy is required. High rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) titers should drive the choice toward TCZ or ABA, while in patients at high CVD risk anti-TNF choice, with preference for ETN, seems appropriate. Presence of anterior uveitis or inflammatory bowel disease drives the choice to monoclonal antibody anti-TNFs (MoAb anti-TNFs). In PsA, ustekinumab (UTK), and to a lesser extent ETN, represents the first choice in patients at high infection and TB risk. Anti-TNFs or UTK choice is guided by skin or articular disease severity, enthesitis, and dactylitis, whereas ETN should be preferred if metabolic syndrome or high CV risk complicate PsA. CONCLUSION: Taking in account of multiple choice driving variables, first-line biologic therapy may be optimized in patients with RA, SpA, and PsA. PMID- 26607441 TI - The uncertainty of errors: Intolerance of uncertainty is associated with error related brain activity. AB - Errors are unpredictable events that have the potential to cause harm. The error related negativity (ERN) is the electrophysiological index of errors and has been posited to reflect sensitivity to threat. Intolerance of uncertainty (IU) is the tendency to perceive uncertain events as threatening. In the present study, 61 participants completed a self-report measure of IU and a flanker task designed to elicit the ERN. Results indicated that IU subscales were associated with the ERN in opposite directions. Cognitive distress in the face of uncertainty (Prospective IU) was associated with a larger ERN and slower reaction time. Inhibition in response to uncertainty (Inhibitory IU) was associated with a smaller ERN and faster reaction time. This study suggests that sensitivity to the uncertainty of errors contributes to the magnitude of the ERN. Furthermore, these findings highlight the importance of considering the heterogeneity of anxiety phenotypes in relation to measures of threat sensitivity. PMID- 26607442 TI - When the brain does not adequately feel the body: Links between low resilience and interoception. AB - This study examined neural processes of resilience during aversive interoceptive processing. Forty-six individuals were divided into three groups of resilience Low (LowRes), high (HighRes), and normal (NormRes), based on the Connor-Davidson Resilience Scale (2003). Participants then completed a task involving anticipation and experience of loaded breathing during functional magnetic resonance imaging (fMRI) recording. Compared to HighRes and NormRes groups, LowRes self-reported lower levels of interoceptive awareness and demonstrated higher insular and thalamic activation across anticipation and breathing load conditions. Thus, individuals with lower resilience show reduced attention to bodily signals but greater neural processing to aversive bodily perturbations. In low resilient individuals, this mismatch between attention to and processing of interoceptive afferents may result in poor adaptation in stressful situations. PMID- 26607443 TI - A smaller magnitude of exercise-induced hypoalgesia in African Americans compared to non-Hispanic Whites: A potential influence of physical activity. AB - This study compared exercise-induced hypoalgesia (EIH) between African Americans (AAs, n=16) and non-Hispanic Whites (NHWs, n=16), and examined the potential influence of physical activity (PA) on the racial/ethnic difference in EIH. The PA levels were quantified using a questionnaire, and intensity of electrical stimulus to produce moderate pain was individually determined. Participants squeezed a hand dynamometer at 25% of their maximal strength for three minutes, followed by a three-minute post-exercise rest. Numeric ratings to electrical stimulus at the pre-determined intensity were recorded every one minute during and after exercise. Compared to NHWs, AAs reported less lifestyle PA. Both AAs and NHWs showed EIH, but AAs exhibited a smaller magnitude of EIH than NHWs. However, this difference in EIH disappeared after controlling for the lifestyle PA levels. The results suggest that AAs exhibit less efficient pain modulation than NHWs, and AAs' reduced PA could potentially explain the observed difference in EIH. PMID- 26607444 TI - The spectrum of activity of the small RNA DsrA: not so narrow after all. AB - For a long time, the small regulatory RNA DsrA has been considered as a regulator with a narrow spectrum of action due to its restricted targetome. Since the first reports on DsrA characterization, only two targets of DsrA have been described: rpoS and hns mRNAs, encoding the sigma factor sigmaS and the nucleoid-associated protein H-NS, respectively. Recently, the scope of DsrA targetome has been expanded by the characterization of two negatively regulated mRNAs, mreB and rbsD, involved in cell wall biosynthesis and ribose metabolism, respectively. In this review, we summarize new insights in DsrA-mediated regulation and emphasize the versatility of DsrA modes of action. PMID- 26607445 TI - STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. AB - Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma. PMID- 26607446 TI - Molecular bases for the selection of the chromophore of animal rhodopsins. AB - The functions of microbial and animal rhodopsins are triggered by the isomerization of their all-trans and 11-cis retinal chromophores, respectively. To lay the molecular basis driving the evolutionary transition from the all-trans to the 11-cis chromophore, multiconfigurational quantum chemistry is used to compare the isomerization mechanisms of the sensory rhodopsin from the cyanobacterium Anabaena PCC 7120 (ASR) and of the bovine rhodopsin (Rh). It is found that, despite their evolutionary distance, these eubacterial and vertebrate rhodopsins start to isomerize via distinct implementations of the same bicycle pedal mechanism originally proposed by Warshel [Warshel A (1976) Nature 260:678 683]. However, by following the electronic structure changes of ASR (featuring the all-trans chromophore) during the isomerization, we find that ASR enters a region of degeneracy between the first and second excited states not found in Rh (featuring the 11-cis chromophore). We show that such degeneracy is modulated by the preorganized structure of the chromophore and by the position of the reactive double bond. It is argued that the optimization of the electronic properties of the chromophore, which affects the photoisomerization efficiency and the thermal isomerization barrier, provided a key factor for the emergence of the striking amino acid sequence divergence observed between the microbial and animal rhodopsins. PMID- 26607447 TI - Insights in how amphetamine ROCKs (Rho-associated containing kinase) membrane protein trafficking. PMID- 26607448 TI - Making sense: Determining the parameter space of electrical brain stimulation. PMID- 26607449 TI - Temporal fate mapping reveals age-linked heterogeneity in naive T lymphocytes in mice. AB - Understanding how our T-cell compartments are maintained requires knowledge of their population dynamics, which are typically quantified over days to weeks using the administration of labels incorporated into the DNA of dividing cells. These studies present snapshots of homeostatic dynamics and have suggested that lymphocyte populations are heterogeneous with respect to rates of division and/or death, although resolving the details of such heterogeneity is problematic. Here we present a method of studying the population dynamics of T cells in mice over timescales of months to years that reveals heterogeneity in rates of division and death with respect to the age of the host at the time of thymic export. We use the transplant conditioning drug busulfan to ablate hematopoetic stem cells in young mice but leave the peripheral lymphocyte compartments intact. Following their reconstitution with congenically labeled (donor) bone marrow, we followed the dilution of peripheral host T cells by donor-derived lymphocytes for a year after treatment. Describing these kinetics with mathematical models, we estimate rates of thymic production, division and death of naive CD4 and CD8 T cells. Population-averaged estimates of mean lifetimes are consistent with earlier studies, but we find the strongest support for a model in which both naive T-cell pools contain kinetically distinct subpopulations of older host-derived cells with self-renewing capacity that are resistant to displacement by naive donor lymphocytes. We speculate that these incumbent cells are conditioned or selected for increased fitness through homeostatic expansion into the lymphopenic neonatal environment. PMID- 26607450 TI - DNA polymerases delta and lambda cooperate in repairing double-strand breaks by microhomology-mediated end-joining in Saccharomyces cerevisiae. AB - Maintenance of genome stability is carried out by a suite of DNA repair pathways that ensure the repair of damaged DNA and faithful replication of the genome. Of particular importance are the repair pathways, which respond to DNA double-strand breaks (DSBs), and how the efficiency of repair is influenced by sequence homology. In this study, we developed a genetic assay in diploid Saccharomyces cerevisiae cells to analyze DSBs requiring microhomologies for repair, known as microhomology-mediated end-joining (MMEJ). MMEJ repair efficiency increased concomitant with microhomology length and decreased upon introduction of mismatches. The central proteins in homologous recombination (HR), Rad52 and Rad51, suppressed MMEJ in this system, suggesting a competition between HR and MMEJ for the repair of a DSB. Importantly, we found that DNA polymerase delta (Pol delta) is critical for MMEJ, independent of microhomology length and base pairing continuity. MMEJ recombinants showed evidence that Pol delta proofreading function is active during MMEJ-mediated DSB repair. Furthermore, mutations in Pol delta and DNA polymerase 4 (Pol lambda), the DNA polymerase previously implicated in MMEJ, cause a synergistic decrease in MMEJ repair. Pol lambda showed faster kinetics associating with MMEJ substrates following DSB induction than Pol delta. The association of Pol delta depended on RAD1, which encodes the flap endonuclease needed to cleave MMEJ intermediates before DNA synthesis. Moreover, Pol delta recruitment was diminished in cells lacking Pol lambda. These data suggest cooperative involvement of both polymerases in MMEJ. PMID- 26607451 TI - Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis. AB - The exocyst complex regulates the last steps of exocytosis, which is essential to organisms across kingdoms. In humans, its dysfunction is correlated with several significant diseases, such as diabetes and cancer progression. Investigation of the dynamic regulation of the evolutionarily conserved exocyst-related processes using mutants in genetically tractable organisms such as Arabidopsis thaliana is limited by the lethality or the severity of phenotypes. We discovered that the small molecule Endosidin2 (ES2) binds to the EXO70 (exocyst component of 70 kDa) subunit of the exocyst complex, resulting in inhibition of exocytosis and endosomal recycling in both plant and human cells and enhancement of plant vacuolar trafficking. An EXO70 protein with a C-terminal truncation results in dominant ES2 resistance, uncovering possible distinct regulatory roles for the N terminus of the protein. This study not only provides a valuable tool in studying exocytosis regulation but also offers a potentially new target for drugs aimed at addressing human disease. PMID- 26607453 TI - [Bisphosphonate and denosumab-related osteonecrosis of the jaw: Epidemiology, diagnosis and management]. AB - Bisphosphonate-related osteonecrosis of the jaw have been widely described. Denosumab has recently been associated to ONJ. Guidance to clinicians is based on criteria established by the American Association of Oral and Maxillofacial Surgeons (AAOMS). Treatment should be multidisciplinary. Two options are available and have to be discussed on the basis of associated therapeutic, patient's general state of health and possibility of therapeutic window during cancer treatment: conservative (medication and conservative surgery like superficial debridement) and extensive surgery. Therefore, we report an update about management strategies of osteonecrosis of the jaw and two cases of patients with a stage 2 osteonecrosis of the jaw only treated with mouth rinses, antibiotics and debridement and complete healing. PMID- 26607452 TI - Psychosocial and Clinical Correlates of Fatigue in Haemodialysis Patients: the Importance of Patients' Illness Cognitions and Behaviours. AB - PURPOSE: Fatigue is commonly experienced in end-stage kidney disease (ESKD) and is associated with poor outcomes. Currently, little research has examined the psychosocial correlates of fatigue severity and its impact on renal disease patients. We predicted that psychological factors (distress, cognitions and behaviours) would be associated with fatigue severity and impairment in ESKD patients even when controlling for clinical and disease factors. METHOD: One hundred seventy-four haemodialysis patients completed the Chalder Fatigue Questionnaire (fatigue severity) and the Work and Social Adjustment Scale (fatigue-related impairment) in addition to measures evaluating distress, fatigue perceptions, symptom beliefs and behaviours. Demographic and clinical data were also collected. RESULTS: Fatigue severity was not related to haemoglobin levels, serum albumin or dialysis vintage. In hierarchical regression models, demographic and clinical factors explained 20 % of the variance in fatigue (ethnicity, body mass index, exercise, log C-reactive protein and multimorbidity). Psychological distress (beta = 0.21, p < 0.01), negative beliefs about fatigue (beta = 0.10, p = 0.01) and unhelpful behaviours (all-or-nothing behaviour [beta = 0.28, p < 0.01] and avoidance [beta = 0.16, p < 0.01]) explained an additional 36.4 % of the variance. Fatigue-related impairment was associated with psychological distress, perceptions that symptoms indicate damage, avoidance behaviour and the level of fatigue severity. CONCLUSION: Patients' mood, beliefs and behaviours are associated with fatigue in dialysis patients. Psychological interventions to alter these factors may reduce fatigue severity and fatigue-related disability in ESKD patients. PMID- 26607455 TI - The Stress Check Program: a new national policy for monitoring and screening psychosocial stress in the workplace in Japan. AB - OBJECTIVES: The Japanese government launched a new occupational health policy called the Stress Check Program. This program mandates that all workplaces with 50 or more employees conduct the Stress Check Program for workers at least once a year. This article gives a brief overview and critical review of the program. METHODS: We reviewed relevant laws, guidelines, and manuals, as well as the policy development process. The policy and the components of the program were compared using available scientific evidence and trends in the management of psychosocial factors at work according to the policies and guidelines of international bodies and European countries. RESULTS: The process of program policy development was based on a discussion among employer and employee representatives, occupational health professionals, and mental health experts. Scientific evidence shows that mandated components of the program (i.e., feedback of stress survey results and physician's interview) may be ineffective. However, additional components recommended to employers, such as stress management skill provision and work environment improvement, in conjunction with the program may be effective in improving psychosocial stress at work. The Stress Check Program is unique compared with the global trend for psychosocial risk management because it focuses on the assessment of stress among individual workers. CONCLUSION: The new program may be effective in improving worker mental health by facilitating the psychosocial risk management approach in Japan. Concerns regarding the program include mass leakage of collected information, and possible disadvantages for workers labeled as having high stress. PMID- 26607456 TI - On-chip synthesis of fine-tuned bone-seeking hybrid nanoparticles. AB - AIMS: Here we report a one-step approach for reproducible synthesis of finely tuned targeting multifunctional hybrid nanoparticles (HNPs). MATERIALS & METHODS: A microfluidic-assisted method was employed for controlled nanoprecipitation of bisphosphonate-conjugated poly(D,L-lactide-co-glycolide) chains, while coencapsulating superparamagnetic iron oxide nanoparticles and the anticancer drug Paclitaxel. RESULTS: Smaller and more compact HNPs with narrower size distribution and higher drug loading were obtained at microfluidic rapid mixing regimen compared with the conventional bulk method. The HNPs were shown to have a strong affinity for hydroxyapatite, as demonstrated in vitro bone-binding assay, which was further supported by molecular dynamics simulation results. In vivo proof of concept study verified the prolonged circulation of targeted microfluidic HNPs. Biodistribution as well as noninvasive bioimaging experiments showed high tumor localization and suppression of targeted HNPs to the bone metastatic tumor. CONCLUSION: The hybrid bone-targeting nanoparticles with adjustable characteristics can be considered as promising nanoplatforms for various theragnostic applications. PMID- 26607458 TI - Atomistic modeling of BN nanofillers for mechanical and thermal properties: a review. AB - Due to their exceptional mechanical properties, thermal conductivity and a wide band gap (5-6 eV), boron nitride nanotubes and nanosheets have promising applications in the field of engineering and biomedical science. Accurate modeling of failure or fracture in a nanomaterial inherently involves coupling of atomic domains of cracks and voids as well as a deformation mechanism originating from grain boundaries. This review highlights the recent progress made in the atomistic modeling of boron nitride nanofillers. Continuous improvements in computational power have made it possible to study the structural properties of these nanofillers at the atomistic scale. PMID- 26607457 TI - Work productivity loss and indirect costs associated with new cardiovascular events in high-risk patients with hyperlipidemia: estimates from population-based register data in Sweden. AB - OBJECTIVES: To estimate productivity loss and associated indirect costs in high risk patients treated for hyperlipidemia who experience cardiovascular (CV) events. METHODS: Retrospective population-based cohort study conducted using Swedish medical records linked to national registers. Patients were included based on prescriptions of lipid-lowering therapy between 1 January 2006 and 31 December 2011 and followed until 31 December 2012 for identification of CV events and estimation of work productivity loss (sick leave and disability pension) and indirect costs. Patients were stratified into two cohorts based on CV risk level: history of major cardiovascular disease (CVD) and coronary heart disease (CHD) risk equivalent. Propensity score matching was applied to compare patients with new events (cases) to patients without new events (controls). The incremental effect of CV events was estimated using a difference-in-differences design, comparing productivity loss among cases and controls during the year before and the year after the cases' event. RESULTS: The incremental effect on indirect costs was largest in the CHD risk equivalent cohort (n = 2946) at ?3119 (P value <0.01). The corresponding figure in the major CVD history cohort (n = 4508) was ?2210 (P value <0.01). There was substantial variation in productivity loss depending on the type of event. Transient ischemic attack and revascularization had no significant effect on indirect costs. Myocardial infarction (?3465), unstable angina (?2733) and, most notably, ischemic stroke (?6784) yielded substantial incremental cost estimates (P values <0.01). CONCLUSIONS: Indirect costs related to work productivity losses of CV events are substantial in Swedish high-risk patients treated for hyperlipidemia and vary considerably by type of event. PMID- 26607459 TI - Prostanoid receptors mediating contraction in rat, macaque and human bladder smooth muscle in vitro. AB - Selective prostaglandin EP1 antagonists have been suggested for the treatment of bladder dysfunction. This study assessed the contractile prostanoid receptor subtypes in human and non-human bladder in vitro. Classical tissue bath studies were conducted using bladder strips exposed to prostanoid agonists and antagonists. Prostaglandin E2 (PGE2) contracted rat, macaque and human bladder smooth muscle strips (pEC50 7.91+/-0.06 (n=7), 6.40+/-0.13 (n=7), and 6.07+/-0.11 (n=5), respectively). The EP1 receptor antagonist, PF2907617 (300nM), caused a rightward shift of the PGE2 concentration-response curve in the rat bladder only (pKB 8.40+/-0.15, n=3). PGE2 responses in rat and macaque bladders, but not human, were antagonised by the EP3 antagonist CJ24979 (1uM). Sulprostone, a mixed EP1/EP3/FP receptor agonist, induced potent contractions of rat bladder muscle (pEC50 7.94+/-0.31, n=6). The FP receptor agonist, prostaglandin F2alpha (PGF2alpha), induced bladder contraction in all species tested, but with a lower potency in rat. The selective FP receptor agonist latanoprost caused potent contractions of macaque and human bladder strips only. SQ29548, a selective TP antagonist, and GW848687X, a mixed EP1/TP antagonist caused rightward shifts of the concentration-response curves to the selective TP agonist, U46619 (pKB estimates 8.53+/-0.07 and 7.56+/-0.06, n=3, respectively). Responses to U46619 were absent in rat preparations. These data suggest significant species differences exist in bladder contractile prostanoid receptor subtypes. We conclude that the EP1 subtype does not represent the best approach to the clinical treatment of bladder disorders targeting inhibition of smooth muscle contraction. PMID- 26607460 TI - Notoginsenoside R1 inhibits oxidized low-density lipoprotein induced inflammatory cytokines production in human endothelial EA.hy926 cells. AB - Notoginsenoside R1 (NG-R1), a unique and main active ingredient of Panax notoginseng, has been described to exhibit anti-inflammatory activity. However, its protective effects against oxidized low-density lipoprotein (oxLDL)-induced inflammatory injury in vascular endothelial cells have not been clarified. In the present study, we have evaluated the anti-inflammatory effects of NG-R1 on oxLDL induced endothelial cells and its possible molecular mechanism of action. Our results showed that NG-R1 treatment significantly attenuated oxLDL-induced expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. These effects were accompanied with suppression of oxLDL-induced activation of NF kappaB and Mitogen-activated protein kinases (MAPK). Moreover, NG-R1 also increased in Peroxisome proliferator-activated receptor gamma (PPARgamma) protein expression and transcription levels, and attenuated oxLDL-induced suppression of PPARgamma expression. The inhibition of NG-R1 on oxLDL-induced TNF-alpha and IL 1beta productions can be reversed by PPARgamma antagonist GW9662. In conclusion, these data suggested that NG-R1 could suppress oxLDL-induced inflammatory cytokines production via activating PPARgamma, which subsequently inhibiting oxLDL-induced NF-kappaB and MAPK activation. PMID- 26607461 TI - BX795, a TBK1 inhibitor, exhibits antitumor activity in human oral squamous cell carcinoma through apoptosis induction and mitotic phase arrest. AB - TANK-binding kinase 1 (TBK1), a member of IkappaB Kinase (IKK)-related kinases, plays a role in regulating innate immunity, inflammation and oncogenic signaling. This study aims to investigate the role of BX795, an inhibitor of TBK1, in a panel of oral squamous cell carcinoma (OSCC) cell lines. The antitumor effects and mechanisms of BX795 were assessed by MTT assays, flow cytometry, Western blotting, and confocal microscopy. BX795 exhibited a dose-responsive antiproliferative effect on OSCC cells with relative sparing of normal human oral keratinocytes. The compound caused apoptosis as evidenced by PARP cleavage, the presence of pyknotic nuclei in the TUNEL assay, and fragmented DNA tails in the Comet assay. BX795 inhibits Akt and NF-kappaB signaling, arrests cells in the mitotic phase, and increases generation of autophagy in oral cancer cells. Interestingly, the antiproliferative activity of BX795 does not correlate with TBK1 protein expression level in OSCC cells. We propose that the TBK1-independet effect is related to mitotic phase arrest. Pleiotropic anticancer activity with relative sparing of normal oral keratinocytes underscores the potential value of BX795 and warrants its further study in oral squamous cell carcinoma therapy. PMID- 26607462 TI - Furanodiene enhances the anti-cancer effects of doxorubicin on ERalpha-negative breast cancer cells in vitro. AB - Furanodiene is a natural product isolated from Rhizoma curcumae, and exhibits broad-spectrum anti-cancer activities in vitro and in vivo. Our previous study proved that furanodiene could increase growth inhibition of steroidal agent in ERalpha-positive breast cancer cells, but whether furanodiene can influence ER status is not clear. In this study, we confirmed that furanodiene down-regulated the ERalpha protein expression level and inhibited E2-induced estrogen response element (ERE)-driven reporter plasmid activity in ERalpha-positive MCF-7 cells. Actually, ERalpha-knockdown cells were more sensitive than ERalpha positive cells to furanodiene on the cytotoxicity effect. So the anti-cancer effects of furanodiene and non-steroidal agent in breast cancer cells still requires further investigation. Our results showed that furanodiene exposure could enhance growth inhibitory effects of doxorubicin in ERalpha-negative MDA-MB-231 cells and ERalpha-low expression 4T1 cells. However, furanodiene did not increase the cytotoxicity of doxorubicin in ERalpha-positive breast cancer cells, non tumorigenic breast epithelial cells, macrophage cells, hepatocytes cells, pheochromocytoma cells and cardiac myoblasts cells. Furanodiene enhances the anti cancer effects of doxorubicin in ERalpha-negative breast cancer cells through suppressing cell viability via inducing apoptosis in mitochondria-caspases dependent and reactive oxygen species-independent manners. These results indicate that furanodiene may be a promising and safety natural agent for cancer adjuvant therapy in the future. PMID- 26607463 TI - CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats. AB - The present study was designed to evaluate the antihypertensive and cardiorenal protective effects of CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, in Dahl salt-sensitive hypertensive rats (DS rats), and to compare the effects with spironolactone and eplerenone. DS rats were fed a control diet (0.3% NaCl) or high salt diet (8% NaCl) from 7 weeks of age. CS-3150 (0.25 2mg/kg), spironolactone (10-100mg/kg) or eplerenone (10-100mg/kg) were orally administered once a day to DS rats fed a high salt diet for 7 weeks. The high salt diet significantly increased systolic blood pressure, which was prevented by treatment with CS-3150 in a dose-dependent manner with no hyperkalemia (>5.5mEq/L). The antihypertensive effect of CS-3150 (0.5mg/kg) was equivalent to that of spironolactone (100mg/kg) and eplerenone (100mg/kg). CS-3150 also suppressed proteinuria and renal hypertrophy induced by the high salt diet. Histopathological examination of kidneys showed that CS-3150 markedly ameliorated glomerulosclerosis, tubular injury and tubulointerstitial fibrosis. In addition, CS-3150 inhibited left ventricular hypertrophy and elevation of plasma brain natriuretic peptide level. In contrast, the cardiorenal protective effects of spironolactone or eplerenone were partial, and the dose-dependency was not clear, especially in eplerenone-treated rats. These results indicate that chronic treatment with CS-3150 exerts antihypertensive and cardiorenal protective effects in a DS hypertensive rat model, and its potency is much superior to that of spironolactone or eplerenone. Thus, CS-3150 could be a promising agent for the treatment of hypertension and cardiorenal disorders. PMID- 26607464 TI - Carvacrol induces the apoptosis of pulmonary artery smooth muscle cells under hypoxia. AB - The abnormal apoptosis of pulmonary artery smooth muscle cells (PASMCs) is an important pathophysiological process in pulmonary vascular remodeling and pulmonary arterial hypertension (PAH). Carvacrol, an essential oil compound from oregano and thyme, has displayed antimicrobial, antitumor, and antioxidant properties. Although carvacrol has pro-apoptosis properties in tumor cells, the underlying mechanisms of carvacrol in PASMC apoptosis remain unclear. Thus, in this study, we aim to investigate the role of carvacrol in pulmonary vascular remodeling and PASMC apoptosis in hypoxia. Right Ventricular Hypertrophy Measurements and pulmonary pathomorphology data show that the ratio of the heart weight/tibia length (HW/TL), the right ventricle/left ventricle plus septum (RV/LV+S) and the medial width of the pulmonary artery increased in chronic hypoxia and were reversed by carvacrol treatment under hypoxia. Additionally, carvacrol inhibited PASMC viability, attenuated oxidative stress, induced mitochondria membrane depolarization, increased the percentage of apoptotic cells, suppressed Bcl-2 expression, decreased procaspase-3 expression, promoted caspase-3 activation, and inhibited the ERK1/2 and PI3K/Akt pathway. Taken together, these findings suggest that carvacrol attenuates the pulmonary vascular remodeling and promotes PASMC apoptosis by acting on, at least in part, the intrinsic apoptotic pathway. This process might provide us new insight into the development of hypoxic pulmonary hypertension. PMID- 26607465 TI - Nicorandil inhibits neutrophil recruitment in carrageenan-induced experimental pleurisy in mice. AB - Nicorandil is a drug characterized by the coupling of a nitric oxide (NO) donor to nicotinamide. We have previously demonstrated that nicotinamide exhibits activity in different models of pain and inflammation. Now, we investigated the effects induced by per os (p.o.) administration of nicorandil (25, 50 or 100mg/Kg) on neutrophil recruitment in a carrageenan-induced model of pleurisy in mice. Effects induced by nicorandil (100mg/kg) were compared with those induced by equimolar doses of nicotinamide (58mg/kg) and N-(2-hydroxyethyl)-nicotinamide (NHN; 79mg/kg). We also investigated whether effects on the production of inflammatory mediators play a role in the activity of nicorandil. P.o. nicorandil, 0.5h before and 1h after the i.pl. injection of carrageenan, reduced neutrophil recruitment. However, equimolar doses of nicotinamide or NHN failed to induce such effect. Single treatment (previous or late) with nicorandil (100mg/Kg, p.o.) also reduced neutrophils recruitment, although to a lesser extent when compared to the double treatment. Nicorandil reduced the concentrations of interleukin-1beta, CXCL-1 and prostaglandin E2 in the pleural exudate. Concluding, we demonstrated the activity of nicorandil in a model of pleurisy induced by carrageenan. This activity was characterized by reduction of the neutrophil accumulation and inhibition of production of inflammatory mediators. The effects induced by nicorandil on the leukocytes recruitment and production of inflammatory mediators contribute to a better understanding of its clinical benefits and indicate that these benefits may be due to its vasodilating and anti-inflammatory activities. PMID- 26607466 TI - Repressed Ca(2+) clearance in parthenolide-treated murine brain bEND.3 endothelial cells. AB - Parthenolide is a sesquiterpene lactone compound isolated from the leaves and flowerheads of the plant feverfew (Tanacetum parthenium). The anticancer effects of parthenolide have been well studied and this lactone compound is currently under clinical trials. Parthenolide is also a protective agent in cardiac reperfusion injury via its inhibition of nuclear factor-kappaB (NF-kappaB). Not much is known if this compound affects signal transduction in non-tumor cells. We investigated whether parthenolide affected Ca(2+) signaling in endothelial cells, key components in regulating the vascular tone. In this work using mouse cortical microvascular bEND.3 endothelial cells, we found that a 15-h treatment with parthenolide resulted in amplified ATP-triggered Ca(2+) signal; the latter had a very slow decay rate suggesting suppression of Ca(2+) clearance. Evidence suggests parthenolide suppressed Ca(2+) clearance by inhibiting the plasmalemmal Ca(2+) pump; such suppression did not result from decreased expression of the plasmalemmal Ca(2+) pump protein. Rather, such suppression was possibly a consequence of endoplasmic reticulum (ER) stress, since salubrinal (an ER stress protector) was able to alleviate parthenolide-induced Ca(2+) clearance suppression. Given the current deployment of parthenolide as an anti-cancer drug in clinical trials and the potential usage of this lactone as a cardioprotectant, it is important to examine in details the perturbing effects of parthenolide on Ca(2+) homeostasis in endothelial cells and neighboring vascular smooth muscle cells, activities of which exert profound effects on hemodynamics. PMID- 26607467 TI - Favorable effects of vildagliptin on metabolic and cognitive dysfunctions in streptozotocin-induced diabetic rats. AB - Progression of diabetes mellitus is accompanied by metabolic disorders together with psychological deficits including cognitive dysfunctions. Herein, we used a murine streptozotocin (STZ)-induced diabetes to investigate the beneficial effects of vildagliptin not only on metabolic abnormalities, but also on diabetes induced cognitive decline. Sixty rats were divided randomly and equally into 2 groups; one remains normal and the other serves as STZ- induced diabetic. Both groups were further divided equally into 2 groups; one received vehicle and the other received oral vildagliptin for 8 weeks. Cognitive behavior was assessed using novel object recognition test. Blood samples were collected to measure metabolic parameters and dipeptidyl peptidase (DPP)-IV activity. Brains were removed and investigated for the levels of inflammatory and oxidative stress markers malondialdehyde (MDA), superoxide dismutase (SOD) and tumor necrosis factor-alpha (TNF-alpha), in addition to brain-derived neurotrophic factor (BDNF) and relative expression of nuclear factor kappa B (NF-kappaB)/p65. Treatment of STZ-induced diabetic rats with vildagliptin increased their body weight and corrected diabetes-induced memory and learning impairment. Moreover, vildagliptin significantly decreased serum levels of glucose and lipids (except high density lipoprotein) together with brain MDA, TNF-alpha, serum DPP-IV activities and NF kappaB/p65 gene expression. On the other hand, vildagliptin significantly increased brain BDNF, SOD as well as serum insulin. Results suggested that vildagliptin has a protective role in counteracting both metabolic abnormalities and memory deficits in diabetic rats, possibly via its anti-hyperglycemic, anti inflammatory, antioxidant effects, together with reduction of brain NF-kappaB/p65 over expression. PMID- 26607468 TI - Regulation of cancer cell death by a novel compound, C604, in a c-Myc overexpressing cellular environment. AB - The proto-oncogene c-Myc has been implicated in a variety of cellular processes, such as proliferation, differentiation and apoptosis. Several c-Myc targets have been studied; however, selective regulation of c-Myc is not easy in cancer cells. Herein, we attempt to identify chemical compounds that induce cell death in c-Myc overexpressing cells (STF-cMyc and STF-Control) by conducting MTS assays on approximately 4000 chemical compounds. One compound, C604, induced cell death in STF-cMyc cells but not STF-Control cells. Apoptotic proteins, including caspase-3 and poly(ADP-ribose) polymerase (PARP), were cleaved in C604-treated STF-cMyc cells. In addition, SW620, HCT116 and NCI-H23 cells, which exhibit higher basal levels of c-Myc, underwent apoptotic cell death in response to C604, suggesting a role for C604 as an inducer of apoptosis in cancer cells with c-Myc amplification. C604 induced cell cycle arrest at the G2/M phase in cells, which was not affected by apoptotic inhibitors. Interestingly, C604 induced accumulation of c-Myc and Cdc25A proteins. In summary, a chemical compound was identified that may induce cell death in cancer cells with c-Myc amplification specifically through an apoptotic pathway. PMID- 26607469 TI - Comparative analysis of pharmacological treatments with N-acetyl-DL-leucine (Tanganil) and its two isomers (N-acetyl-L-leucine and N-acetyl-D-leucine) on vestibular compensation: Behavioral investigation in the cat. AB - Head roll tilt, postural imbalance and spontaneous nystagmus are the main static vestibular deficits observed after an acute unilateral vestibular loss (UVL). In the UVL cat model, these deficits are fully compensated over 6 weeks as the result of central vestibular compensation. N-Acetyl-dl-leucine is a drug prescribed in clinical practice for the symptomatic treatment of acute UVL patients. The present study investigated the effects of N-acetyl-dl-leucine on the behavioral recovery after unilateral vestibular neurectomy (UVN) in the cat, and compared the effects of each of its two isomers N-acetyl-L-leucine and N acetyl-D-leucine. Efficacy of these three drug treatments has been evaluated with respect to a placebo group (UVN+saline water) on the global sensorimotor activity (observation grids), the posture control (support surface measurement), the locomotor balance (maximum performance at the rotating beam test), and the spontaneous vestibular nystagmus (recorded in the light). Whatever the parameters tested, the behavioral recovery was strongly and significantly accelerated under pharmacological treatments with N-acetyl-dl-leucine and N-acetyl-L-leucine. In contrast, the N-acetyl-D-leucine isomer had no effect at all on the behavioral recovery, and animals of this group showed the same recovery profile as those receiving a placebo. It is concluded that the N-acetyl-L-leucine isomer is the active part of the racemate component since it induces a significant acceleration of the vestibular compensation process similar (and even better) to that observed under treatment with the racemate component only. PMID- 26607470 TI - Palmitoylethanolamide treatment reduces retinal inflammation in streptozotocin induced diabetic rats. AB - Although the pathogenesis of diabetic retinopathy (DR) is still insufficiently understood, new evidences indicate 'retinal inflammation' as an important player in the pathogenesis of the complication. Accordingly, common sets of upregulated inflammatory cytokines are found in serum, vitreous and aqueous samples obtained from subjects with DR, and these cytokines can have multiple interactions to impact the pathogenesis of the disease. Thus, based on previously published data, we investigated the effects of Palmitoylethanolamide (PEA), an endogenous lipid amide that belongs to the N-acyl-ethanolamines family, on DR in streptozotocin (STZ)-induced diabetic rats. PEA (10mg/kg) was administered orally daily starting 3 days after the iv administration of STZ. The rats were killed 15 and 60day later and eyes were enucleated to evaluate, through immunohistochemical analysis, the key inflammatory events involved in the breakdown of blood retinal barrier (BRB). Immunohistochemical analysis confirmed the presence of VEGF, ICAM-1, nitrotyrosine (a marker of peroxynitrite), and tight junctions in the retina of STZ-treated rats. Of interest, the extent of injury was significantly reduced after treatment with PEA. Altogether, this study provides the first evidence that PEA attenuates the degree of inflammation while preserving the blood-retinal barrier in rats with experimental DR. PMID- 26607471 TI - Hydroxysafflor yellow A exerts neuroprotective effects in cerebral ischemia reperfusion-injured mice by suppressing the innate immune TLR4-inducing pathway. AB - The innate immune response, which is tightly regulated by Toll-like receptor 4 (TLR4) pathway, has been shown to play a critical role in brain damage following cerebral ischemia-reperfusion injury. Hydroxysafflor yellow A (HSYA) is the active component extracted from the Flos Carthami and has been reported to decrease neurological deficit scores following ischemia-reperfusion injury. However, the precise mechanism by which it exerts these neuroprotective effects remains poorly understood. In this study, we demonstrated that the administration of HSYA could significantly down-regulate TLR4 expression in middle cerebral artery occlusion (MCAO) mice. Following the down-regulation of TLR4 by HSYA treatment, cerebral infarction and inflammatory neuronal damage was alleviated. The number of apoptotic neurons in the HSYA-treated group was significantly decreased along with the decrease in TLR4 expression in MCAO mice. Activation of the NF-kappaB and MAPK signaling pathways was observed at 1h following ischemia and at 24h post-reperfusion. HSYA could significantly inhibit NF-kappaB p-p65, ERE1/2, JNK and p38 phosphorylation, which coincided with the suppressed secretion of inflammatory cytokines such as tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta) and nitric oxide (NO). Moreover, brain derived neurotrophic factor (BDNF) was up-regulated following 1h of ischemia and continued to increase initially during reperfusion but was down-regulated at later stages. Following treatment with HSYA, BDNF was up-regulated relative to control MCAO mice at 1h post-ischemia and at 12 and 24h post-reperfusion. Our data suggest that HSYA exerts neurotrophic and anti-inflammatory functions against ischemic stroke by inhibiting TLR4 pathway-mediated signaling responses. PMID- 26607472 TI - Editorial (Thematic Issue: Supramolecular Systems in Nanomedicines: Therapeutic Applications and Future Perspectives - Part II). PMID- 26607473 TI - ECDC publishes 2014 surveillance data on antimicrobial resistance and antimicrobial consumption in Europe. PMID- 26607474 TI - High-performance perovskite light-emitting diodes via morphological control of perovskite films. AB - Solution-processable perovskite materials have garnered tremendous attention because of their excellent charge carrier mobility, possibility of a tunable optical bandgap, and high photoluminescence quantum efficiency (PLQE). In particular, the uniform morphology of a perovskite film is the most important factor in realizing perovskite light-emitting diodes (PeLEDs) with high efficiency and full-coverage electroluminescence (EL). In this study, we demonstrate highly efficient PeLEDs that contain a perovskite film with a uniform morphology by introducing HBr into the perovskite precursor. The introduction of HBr into the perovskite precursor results in a perovskite film with a uniform, continuous morphology because the HBr increases the solubility of the inorganic component in the perovskite precursor and reduces the crystallization rate of the perovskite film upon spin-coating. Moreover, PeLEDs fabricated using perovskite films with a uniform, continuous morphology, which were deposited using 6 vol% HBr in a dimethylformamide (DMF)/hydrobromic acid (HBr) cosolvent, exhibited full coverage of the green EL emission. Finally, the optimized PeLEDs fabricated with perovskite films deposited using the DMF/HBr cosolvent exhibited a maximum luminance of 3490 cd m(-2) (at 4.3 V) and a luminous efficiency of 0.43 cd A(-1) (at 4.3 V). PMID- 26607476 TI - Large-Scale Production of Adeno-Associated Viral Vector Serotype-9 Carrying the Human Survival Motor Neuron Gene. AB - Recombinant AAV (rAAV) vectors are a suitable vector for gene therapy studies because of desired characteristics such as low immunogenicity, transfection of non-dividing and dividing cells, and long-term expression of the transgene. In this study, the large-scale production of single stranded (ss) and self complementary (sc) AAV9 carrying the human survival motor neuron (SMN) gene (AAV9 SMN) suitable for in vivo gene therapy studies of SMA was described. SMN cDNA has been cloned into pAAV-CB6-PI and pAAVsc-CB6-PI with and without its specific UTRs, respectively. Both plasmids bear CMV enhancer/beta-actin (CB) promoter, CMV IE enhancer, and polyadenylation signal sequences. 2.5 MUg of constructed pAAV CB6-PI-SMN and pAAVsc-CB6-PI-SMN cause to, respectively, 4.853- and 2.321-fold increases in SMN protein levels in transfected cells compared to untransfected cells. Ss and scAAV9-SMN vectors were also produced from these plasmids by transient transfection of HEK293 cells using CaCl2 solution. The silver staining and electron microscopy analysis demonstrated good quality of both isolated vectors, ssAAV9-SMN and scAAV9-SMN, with the titers of 2.00E+13 and 1.00E+13 GC/ml. The results of this study show that, the plasmid containing UTR elements causes to twice more SMN gene expression in transfected cells. The quality control results show that both produced ss and scAAV9-SMN are suitable for in vivo studies. PMID- 26607477 TI - Exploring compulsory admission experiences of adults with psychosis in the UK using Grounded Theory. AB - BACKGROUND: There is a paucity of research into the experience of compulsory admissions under the Mental Health Act (MHA) 1983/2007, particularly for adults with psychosis, yet this diagnostic group reportedly account for the largest proportion of compulsory admissions. AIMS: This UK-based study's objective was to explore the compulsory admission experiences (under the MHA 1983/2007) of service users with psychosis, and to identify key characteristics of these experiences. DESIGN: The qualitative method "Grounded Theory" (Glaser & Strauss, 1967) was employed as it worked inductively from the data. Seventeen participants (eight service users with psychosis, nine psychiatrists) were interviewed. RESULTS: Five higher-order categories and 47 categories were identified and are displayed in a model entitled "A disturbing journey to and from detention". CONCLUSION: This small-scale qualitative study achieved its objectives, exploring compulsory admission experiences (under the MHA 1983/2007) of service users with psychosis in England, and identified key characteristics of these experiences. Service and clinical implications are highlighted, with scope for further research. PMID- 26607475 TI - The Toolbox for Modified Aptamers. AB - Aptamers are nucleic acid-based scaffolds that can bind with high affinity to a variety of biological targets. Aptamers are identified from large DNA or RNA libraries through a process of directed molecular evolution (SELEX). Chemical modification of nucleic acids considerably increases the functional and structural diversity of aptamer libraries and substantially increases the affinity of the aptamers. Additionally, modified aptamers exhibit much greater resistance to biodegradation. The evolutionary selection of modified aptamers is conditioned by the possibility of the enzymatic synthesis and replication of non natural nucleic acids. Wild-type or mutant polymerases and their non-natural nucleotide substrates that can support SELEX are highlighted in the present review. A focus is made on the efforts to find the most suitable type of nucleotide modifications and the engineering of new polymerases. Post-SELEX modification as a complementary method will be briefly considered as well. PMID- 26607478 TI - Selective and Reversible Approaches Toward Imaging Redox Signaling Using Small Molecule Probes. AB - SIGNIFICANCE: Recent research has identified key roles for reactive oxygen species (ROS)/reactive nitrogen species (RNS) in redox signaling, but much remains to be uncovered. Molecular imaging tools to study these processes must not only be selective to enable identification of the ROS/RNS involved but also reversible to distinguish signaling processes from oxidative stress. Fluorescent sensors offer the potential to image such processes with high spatial and temporal resolution. RECENT ADVANCES: A broad array of strategies has been developed that enable the selective sensing of ROS/RNS. More recently, attention has turned to the design of reversible small-molecule sensors of global redox state, with a further set of probes capable of reversible sensing of individual ROS/RNS. CRITICAL ISSUES: In this study, we discuss the key challenges in achieving simultaneous detection of reversible oxidative bursts with unambiguous determination of a particular ROS/RNS. FUTURE DIRECTIONS: We have highlighted key design features of small-molecule probes that show promise in enabling the study of redox signaling, identifying essential parameters that must be assessed for any new probe. Antioxid. Redox Signal. 24, 713-730. PMID- 26607479 TI - The Caledonian face test: A new test of face discrimination. AB - This study aimed to develop a clinical test of face perception which is applicable to a wide range of patients and can capture normal variability. The Caledonian face test utilises synthetic faces which combine simplicity with sufficient realism to permit individual identification. Face discrimination thresholds (i.e. minimum difference between faces required for accurate discrimination) were determined in an "odd-one-out" task. The difference between faces was controlled by an adaptive QUEST procedure. A broad range of face discrimination sensitivity was determined from a group (N=52) of young adults (mean 5.75%; SD 1.18; range 3.33-8.84%). The test is fast (3-4 min), repeatable (test-re-test r(2)=0.795) and demonstrates a significant inversion effect. The potential to identify impairments of face discrimination was evaluated by testing LM who reported a lifelong difficulty with face perception. While LM's impairment for two established face tests was close to the criterion for significance (Z scores of -2.20 and -2.27) for the Caledonian face test, her Z-score was -7.26, implying a more than threefold higher sensitivity. The new face test provides a quantifiable and repeatable assessment of face discrimination ability. The enhanced sensitivity suggests that the Caledonian face test may be capable of detecting more subtle impairments of face perception than available tests. PMID- 26607480 TI - Three-dimensional mapping and intracardiac echocardiography in the treatment of sinoatrial nodal tachycardias. AB - Three-dimensional mapping and intracardiac echocardiography are important tools for the study of the site of origin of an arrhythmia and its substrate. This review examines the application of these techniques in the diagnosis and treatment of sinoatrial tachycardias with a special focus on the syndrome of inappropriate sinus tachycardia. The use of these techniques in electrophysiologic mapping and interventions such as catheter ablation is discussed. Three-dimensional mapping provides unique insights into the generation of normal and abnormal sinus impulses in man and their propagation in the atrium. It permits precise placement of ablation lesions and assessment of real-time electrophysiologic impact of these interventions. Intracardiac echocardiography provides delineation of important anatomic structures in the vicinity of the sinoatrial node complex and monitors the safety of interventions such as catheter ablation. PMID- 26607481 TI - The role of circulating miRNAs in multiple myeloma. AB - Multiple myeloma (MM) is a common malignant hematological disease. Dysregulation of microRNAs (miRNAs) in MM cells and bone marrow microenviroment has important impacts on the initiation and progression of MM and drug resistance in MM cells. Recently, it was reported that MM patient serum and plasma contained sufficiently stable miRNA signatures, and circulating miRNAs could be identified and measured accurately from body fluid. Compared to conventional diagnostic parameters, the circulating miRNA profile is appropriate for the diagnosis of MM and estimates patient progression and therapeutic outcome with higher specificity and sensitivity. In this review, we mainly focus on the potential of circulating miRNAs as diagnostic, prognostic, and predictive biomarkers for MM and summarize the general strategies and methodologies for identification and measurement of circulating miRNAs in various cancers. Furthermore, we discuss the correlation between circulating miRNAs and the cytogenetic abnormalities and biochemical parameters assessed in multiple myeloma. PMID- 26607482 TI - Risk of chemotherapy-induced febrile neutropenia in cancer patients receiving pegfilgrastim prophylaxis: does timing of administration matter? AB - PURPOSE: Contrary to the approved indication for pegfilgrastim prophylaxis, some patients receive it on the same day as the last administration of chemotherapy in clinical practice, which could adversely impact risk of febrile neutropenia (FN). An evaluation of the timing of pegfilgrastim prophylaxis and FN risk was undertaken. METHODS: A retrospective cohort design and data from two US private health care claims repositories were employed. Study population comprised adults who received intermediate/high-risk chemotherapy regimens for solid tumors or non Hodgkin's lymphoma (NHL) and received pegfilgrastim prophylaxis in >=1 cycle; all cycles with pegfilgrastim were pooled for analyses. Odds ratios (OR) for FN during the cycle were estimated for patients who received pegfilgrastim on the same day (day 1) as the last administration of chemotherapy versus days 2-4 from chemotherapy completion. RESULTS: The study population included 45,592 patients who received pegfilgrastim in 179,152 cycles (n = 37,095 in cycle 1); in 12 % of cycles, patients received pegfilgrastim on the same day as chemotherapy. Odds of FN were higher for patients receiving pegfilgrastim prophylaxis on the same day as chemotherapy versus days 2-4 from chemotherapy in cycle 1 (OR = 1.6, 95 % CI = 1.3-1.9, p < 0.001) and all cycles (OR = 1.5, 95 % CI = 1.3-1.6, p < 0.001). CONCLUSIONS: In this large-scale evaluation of adults who received intermediate/high-risk regimens for solid tumors or NHL in US clinical practice, FN incidence was found to be significantly higher among those who received pegfilgrastim prophylaxis on the same day as chemotherapy completion versus days 2-4 from chemotherapy completion, underscoring the importance of adhering to the indicated administration schedule. PMID- 26607483 TI - Asynchronous Distributed Multielectrode Microstimulation Reduces Seizures in the Dorsal Tetanus Toxin Model of Temporal Lobe Epilepsy. AB - BACKGROUND: Electrical brain stimulation has shown promise for reducing seizures in drug-resistant epilepsy, but the electrical stimulation parameter space remains largely unexplored. New stimulation parameters, electrode types, and stimulation targets may be more effective in controlling seizures compared to currently available options. HYPOTHESIS: We hypothesized that a novel electrical stimulation approach involving distributed multielectrode microstimulation at the epileptic focus would reduce seizure frequency in the tetanus toxin model of temporal lobe epilepsy. METHODS: We explored a distributed multielectrode microstimulation (DMM) approach in which electrical stimulation was delivered through 15 33-um-diameter electrodes implanted at the epileptic focus (dorsal hippocampus) in the rat tetanus toxin model of temporal lobe epilepsy. RESULTS: We show that hippocampal theta (6-12 Hz brain oscillations) is decreased in this animal model during awake behaving conditions compared to control animals (p < 10(-4)). DMM with biphasic, theta-range (6-12 Hz/electrode) pulses delivered asynchronously on the 15 microelectrodes was effective in reducing seizures by 46% (p < 0.05). When theta pulses or sinusoidal stimulation was delivered synchronously and continuously on the 15 microelectrodes, or through a single macroelectrode, no effects on seizure frequency were observed. High frequency stimulation (>16.66 Hz/per electrode), in contrast, had a tendency to increase seizure frequency. CONCLUSIONS: These results indicate that DMM could be a new effective approach to therapeutic brain stimulation for reducing seizures in epilepsy. PMID- 26607484 TI - Lacosamide: A Review in Focal Seizures in Patients with Epilepsy. AB - Lacosamide (Vimpat((r))) is a functionalized amino acid available orally (as a solution or tablets) and as an intravenous infusion for use as monotherapy (only in the USA) or adjunctive therapy for the treatment of focal seizures in adult and adolescent (aged >=17 years in the USA) patients with epilepsy. As adjunctive therapy to other antiepileptic drugs (AEDs), lacosamide provided effective seizure control and was generally well tolerated in adults and adolescents (aged >=16 years) in randomized clinical trials and in the real-world setting. In clinical trials, adjunctive lacosamide provided significantly greater reductions in 28-day seizure rates than adjunctive placebo, with these benefits maintained after up to 8 years of therapy in open-label extension studies. Moreover, patients were effectively switched from oral to short-term intravenous adjunctive therapy at the same dosage, which may be particularly beneficial in situations where oral therapy is not suitable. Conversion to lacosamide monotherapy was superior to a historical-control cohort in patients with focal seizures converting from previous AED therapy. In the absence of head-to-head comparisons with other AEDs, the exact position of lacosamide relative to other AEDs remains to be fully determined. In the meantime, oral and intravenous lacosamide provides a useful option as monotherapy (only in the USA) or adjunctive therapy for the treatment of focal seizures in adult and adolescent (aged >=17 years in the USA) patients with epilepsy. PMID- 26607486 TI - European Union-28: An annualised cost-of-illness model for venous thromboembolism. AB - Annual costs for venous thromboembolism (VTE) have been defined within the United States (US) demonstrating a large opportunity for cost savings. Costs for the European Union-28 (EU-28) have never been defined. A literature search was conducted to evaluate EU-28 cost sources. Median costs were defined for each cost input and costs were inflated to 2014 Euros (?) in the study country and adjusted for Purchasing Power Parity between EU countries. Adjusted costs were used to populate previously published cost-models based on adult incidence-based events. In the base model, annual expenditures for total, hospital-associated, preventable, and indirect costs were ?1.5-2.2 billion, ?1.0-1.5 billion, ?0.5-1.1 billion and ?0.2-0.3 billion, respectively (indirect costs: 12 % of expenditures). In the long-term attack rate model, total, hospital-associated, preventable, and indirect costs were ?1.8-3.3 billion, ?1.2-2.4 billion, ?0.6-1.8 billion and ?0.2-0.7 billion (indirect costs: 13 % of expenditures). In the multiway sensitivity analysis, annual expenditures for total, hospital associated, preventable, and indirect costs were ?3.0-8.5 billion, ?2.2-6.2 billion, ?1.1-4.6 billion and ?0.5-1.4 billion (indirect costs: 22 % of expenditures). When the value of a premature life-lost increased slightly, aggregate costs rose considerably since these costs are higher than the direct medical costs. When evaluating the models aggregately for costs, the results suggests total, hospital-associated, preventable, and indirect costs ranging from ?1.5-13.2 billion, ?1.0-9.7 billion, ?0.5-7.3 billion and ?0.2-6.1 billion, respectively. Our study demonstrates that VTE costs have a large financial impact upon the EU-28's healthcare systems and that significant savings could be realised if better preventive measures are applied. PMID- 26607487 TI - Jump in winter deaths last year is blamed on ineffective flu vaccine. PMID- 26607489 TI - Analytical Devices Based on Direct Synthesis of DNA on Paper. AB - This paper addresses a growing need in clinical diagnostics for parallel, multiplex analysis of biomarkers from small biological samples. It describes a new procedure for assembling arrays of ssDNA and proteins on paper. This method starts with the synthesis of DNA oligonucleotides covalently linked to paper and proceeds to assemble microzones of DNA-conjugated paper into arrays capable of simultaneously capturing DNA, DNA-conjugated protein antigens, and DNA-conjugated antibodies. The synthesis of ssDNA oligonucleotides on paper is convenient and effective with 32% of the oligonucleotides cleaved and eluted from the paper substrate being full-length by HPLC for a 32-mer. These ssDNA arrays can be used to detect fluorophore-linked DNA oligonucleotides in solution, and as the basis for DNA-directed assembly of arrays of DNA-conjugated capture antibodies on paper, detect protein antigens by sandwich ELISAs. Paper-anchored ssDNA arrays with different sequences can be used to assemble paper-based devices capable of detecting DNA and antibodies in the same device and enable simple microfluidic paper-based devices. PMID- 26607485 TI - Insulin Aspart in the Management of Diabetes Mellitus: 15 Years of Clinical Experience. AB - Limiting excessive postprandial glucose excursions is an important component of good overall glycemic control in diabetes mellitus. Pharmacokinetic studies have shown that insulin aspart, which is structurally identical to regular human insulin except for the replacement of a single proline amino acid with an aspartic acid residue, has a more physiologic time-action profile (i.e., reaches a higher peak and reaches that peak sooner) than regular human insulin. As expected with this improved pharmacokinetic profile, insulin aspart demonstrates a greater glucose-lowering effect compared with regular human insulin. Numerous randomized controlled trials and a meta-analysis have also demonstrated improved postprandial control with insulin aspart compared with regular human insulin in patients with type 1 or type 2 diabetes, as well as efficacy and safety in children, pregnant patients, hospitalized patients, and patients using continuous subcutaneous insulin infusion. Studies have demonstrated that step-wise addition of insulin aspart is a viable intensification option for patients with type 2 diabetes failing on basal insulin. Insulin aspart has shown a good safety profile, with no evidence of increased receptor binding, mitogenicity, stimulation of anti-insulin antibodies, or hypoglycemia compared with regular human insulin. In one meta-analysis, there was evidence of a lower rate of nocturnal hypoglycemia compared with regular human insulin and, in a trial that specifically included patients with a history of recurrent hypoglycemia, a significantly lower rate of severe hypoglycemic episodes. The next generation of insulin aspart (faster-acting insulin aspart) is being developed with a view to further improving on these pharmacokinetic/pharmacodynamic properties. PMID- 26607490 TI - Genefu: an R/Bioconductor package for computation of gene expression-based signatures in breast cancer. AB - Breast cancer is one of the most frequent cancers among women. Extensive studies into the molecular heterogeneity of breast cancer have produced a plethora of molecular subtype classification and prognosis prediction algorithms, as well as numerous gene expression signatures. However, reimplementation of these algorithms is a tedious but important task to enable comparison of existing signatures and classification models between each other and with new models. Here, we present the genefu R/Bioconductor package, a multi-tiered compendium of bioinformatics algorithms and gene signatures for molecular subtyping and prognostication in breast cancer. AVAILABILITY AND IMPLEMENTATION: The genefu package is available from Bioconductor. http://www.bioconductor.org/packages/devel/bioc/html/genefu.html Source code is also available on Github https://github.com/bhklab/genefu CONTACT: bhaibeka@uhnresearch.ca SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26607488 TI - Amphibian chytridiomycosis: a review with focus on fungus-host interactions. AB - Amphibian declines and extinctions are emblematic for the current sixth mass extinction event. Infectious drivers of these declines include the recently emerged fungal pathogens Batrachochytrium dendrobatidis and Batrachochytrium salamandrivorans (Chytridiomycota). The skin disease caused by these fungi is named chytridiomycosis and affects the vital function of amphibian skin. Not all amphibians respond equally to infection and host responses might range from resistant, over tolerant to susceptible. The clinical outcome of infection is highly dependent on the amphibian host, the fungal virulence and environmental determinants. B. dendrobatidis infects the skin of a large range of anurans, urodeles and caecilians, whereas to date the host range of B. salamandrivorans seems limited to urodeles. So far, the epidemic of B. dendrobatidis is mainly limited to Australian, neotropical, South European and West American amphibians, while for B. salamandrivorans it is limited to European salamanders. Other striking differences between both fungi include gross pathology and thermal preferences. With this review we aim to provide the reader with a state-of-the art of host-pathogen interactions for both fungi, in which new data pertaining to the interaction of B. dendrobatidis and B. salamandrivorans with the host's skin are integrated. Furthermore, we pinpoint areas in which more detailed studies are necessary or which have not received the attention they merit. PMID- 26607491 TI - Synchronized navigation and comparative analyses across Ensembl complete bacterial genomes with INSYGHT. AB - MOTIVATION: High-throughput sequencing technologies provide access to an increasing number of bacterial genomes. Today, many analyses involve the comparison of biological properties among many strains of a given species, or among species of a particular genus. Tools that can help the microbiologist with these tasks become increasingly important. RESULTS: Insyght is a comparative visualization tool whose core features combine a synchronized navigation across genomic data of multiple organisms with a versatile interoperability between complementary views. In this work, we have greatly increased the scope of the Insyght public dataset by including 2688 complete bacterial genomes available in Ensembl thus vastly improving its phylogenetic coverage. We also report the development of a virtual machine that allows users to easily set up and customize their own local Insyght server. AVAILABILITY AND IMPLEMENTATION: http://genome.jouy.inra.fr/Insyght CONTACT: Thomas.Lacroix@jouy.inra.fr. PMID- 26607492 TI - RNA-Enrich: a cut-off free functional enrichment testing method for RNA-seq with improved detection power. AB - Tests for differential gene expression with RNA-seq data have a tendency to identify certain types of transcripts as significant, e.g. longer and highly expressed transcripts. This tendency has been shown to bias gene set enrichment (GSE) testing, which is used to find over- or under-represented biological functions in the data. Yet, there remains a surprising lack of tools for GSE testing specific for RNA-seq. We present a new GSE method for RNA-seq data, RNA Enrich, that accounts for the above tendency empirically by adjusting for average read count per gene. RNA-Enrich is a quick, flexible method and web-based tool, with 16 available gene annotation databases. It does not require a P-value cut off to define differential expression, and works well even with small sample sized experiments. We show that adjusting for read counts per gene improves both the type I error rate and detection power of the test. AVAILABILITY AND IMPLEMENTATION: RNA-Enrich is available at http://lrpath.ncibi.org or from supplemental material as R code. CONTACT: sartorma@umich.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26607493 TI - High nutrient-use efficiency during early seedling growth in diverse Grevillea species (Proteaceae). AB - Several hypotheses have been proposed to explain the rich floristic diversity in regions characterised by nutrient-impoverished soils; however, none of these hypotheses have been able to explain the rapid diversification over a relatively short evolutionary time period of Grevillea, an Australian plant genus with 452 recognised species/subspecies and only 11 million years of evolutionary history. Here, we hypothesise that the apparent evolutionary success of Grevillea might have been triggered by the highly efficient use of key nutrients. The nutrient content in the seeds and nutrient-use efficiency during early seedling growth of 12 species of Grevillea were compared with those of 24 species of Hakea, a closely related genus. Compared with Hakea, the Grevillea species achieved similar growth rates (root and shoot length) during the early stages of seedling growth but contained only approximately half of the seed nutrient content. We conclude that the high nutrient-use efficiency observed in Grevillea might have provided a selective advantage in nutrient-poor ecosystems during evolution and that this property likely contributed to the evolutionary success in Grevillea. PMID- 26607494 TI - Citrate anticoagulation: Are blood donors donating bone? AB - An estimated 2.4 million volunteer apheresis blood donation procedures were performed in the United States in 2010, and increases in the proportion of transfused blood products derived from apheresis blood collections have been consistently reported. Anticoagulation is required during apheresis and is achieved with citrate. Donor exposure to citrate causes an acute physiological response to maintain serum mineral homeostasis. Some data are available on the sequelae of this acute response in the days and weeks following exposure, raising questions about bone mineral density in regular apheresis donors. New research is emerging that addresses the potential long-term health outcomes of repeated citrate exposure. This article reviews the acute physiological response to citrate anticoagulation in volunteer blood donors, presents contrasting perspectives on the potential effects of citrate exposure on bone density, and identifies key knowledge gaps in our understanding of long-term health outcomes in apheresis donors. J. Clin. Apheresis 31:459-463, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26607495 TI - Nasal irrigation with saline solution significantly improves oxygen saturation in infants with bronchiolitis. AB - AIM: Published guidelines do not recommend nasal irrigation in bronchiolitis, but it is common practice in Italy, despite a lack of data on its benefits or adverse effects. This single-blind, multicentre, randomised controlled trial compared nasal irrigation using either isotonic 0.9% sodium chloride or hypertonic 3% sodium chloride with simple supportive care in infants with bronchiolitis. METHODS: We randomly assigned 133 infants up one year of age, who were admitted to the emergency department with bronchiolitis and an oxygen saturation (SpO2) of between 88 and 94%, to the isotonic (n = 47), hypertonic (n = 44) or standard care (n = 42) groups. Variations in SpO2 and the wheeze, air exchange, respiratory rate, muscle use (WARM) respiratory distress score were recorded at zero, five, 15, 20 and 50 minutes. RESULTS: Five minutes after the intervention, the median SpO2 value (95%) in the isotonic group was higher than both the hypertonic (94%) and the standard care (93%) groups. The differences between the isotonic and standard treatment groups were statistically significant at each time point, while the hypertonic group only reached significantly higher values after 50 minutes. However, the WARM score did not improve. CONCLUSION: A single nasal irrigation with saline solution significantly improved oxygen saturation in infants with bronchiolitis. PMID- 26607496 TI - Formation of Nanotwin Networks during High-Temperature Crystallization of Amorphous Germanium. AB - Germanium is an extremely important material used for numerous functional applications in many fields of nanotechnology. In this paper, we study the crystallization of amorphous Ge using atomistic simulations of critical nano metric nuclei at high temperatures. We find that crystallization occurs by the recurrent transfer of atoms via a diffusive process from the amorphous phase into suitably-oriented crystalline layers. We accompany our simulations with a comprehensive thermodynamic and kinetic analysis of the growth process, which explains the energy balance and the interfacial growth velocities governing grain growth. For the <111> crystallographic orientation, we find a degenerate atomic rearrangement process, with two zero-energy modes corresponding to a perfect crystalline structure and the formation of a Sigma3 twin boundary. Continued growth in this direction results in the development a twin network, in contrast with all other growth orientations, where the crystal grows defect-free. This particular mechanism of crystallization from amorphous phases is also observed during solid-phase epitaxial growth of <111> semiconductor crystals, where growth is restrained to one dimension. We calculate the equivalent X-ray diffraction pattern of the obtained nanotwin networks, providing grounds for experimental validation. PMID- 26607497 TI - Exploiting a moment of weakness: male spiders escape sexual cannibalism by copulating with moulting females. AB - Sexual cannibalism is a particularly extreme example of conflict between the sexes, depriving the male of future reproduction. Theory predicts that sexual conflict should induce counter-adaptations in the victim. Observations of male spiders mating with moulting and hence largely immobile females suggest that this behaviour functions to circumvent female control and cannibalism. However, we lack quantitative estimates of natural frequencies and fitness consequences of these unconventional matings. To understand the importance of mating while moulting in cannibalistic mating systems, we combined mating experiments and paternity assessment in the laboratory with extensive field observations using the sexually cannibalistic orb-web spider Argiope bruennichi. Copulations with moulting females resulted in 97% male survival compared with only 20% in conventional matings. Mating while moulting provided similar paternity benefits compared with conventional matings. Our findings support the hypothesis that mating with moulting females evolved under sexual conflict and safely evades sexual cannibalism. Despite male benefits, natural frequencies were estimated around 44% and directly predicted by a male guarding a subadult female. Since only adult females signal their presence, the difficulty for males to locate subadult females might limit further spreading of mating with moulting females. PMID- 26607498 TI - Antibiotic Prescribing for Urinary Tract Infections in the Emergency Department Based on Local Antibiotic Resistance Patterns: Implications for Antimicrobial Stewardship. PMID- 26607499 TI - Spontaneous activity in the microvasculature of visceral organs: role of pericytes and voltage-dependent Ca(2+) channels. AB - The microvasculature plays a primary role in the interchange of substances between tissues and the circulation. In visceral organs that undergo considerable distension upon filling, the microvasculature appears to display intrinsic contractile properties to maintain their flow. Submucosal venules in the bladder or gastrointestinal tract generate rhythmic spontaneous phasic constrictions and associated Ca(2+) transients. These events are initiated within either venular pericytes or smooth muscle cells (SMCs) arising from spontaneous Ca(2+) release from the sarcoplasmic reticulum (SR) and the opening of Ca(2+) -activated chloride channels (CaCCs) that trigger Ca(2+) influx through L-type voltage dependent Ca(2+) channels (VDCCs). L-type VDCCs also play a critical role in maintaining synchrony within the contractile mural cells. In the stomach myenteric layer, spontaneous Ca(2+) transients originating in capillary pericytes appear to spread to their neighbouring arteriolar SMCs. Capillary Ca(2+) transients primarily rely on SR Ca(2+) release, but also require Ca(2+) influx through T-type VDCCs for their synchrony. The opening of T-type VDCCs also contribute to the propagation of Ca(2+) transients into SMCs. In visceral microvasculature, pericytes act as either spontaneously active contractile machinery of the venules or as pacemaker cells generating synchronous Ca(2+) transients that drive spontaneous contractions in upstream arterioles. Thus pericytes play different roles in different vascular beds in a manner that may well depend on the selective expression of T-type and L-type Ca(2+) channels. PMID- 26607500 TI - Discordant associations of lipid parameters with albuminuria and chronic kidney disease: a population-based study. AB - BACKGROUND: Although dyslipidemia is related to the pathogenesis of renal insufficiency, which routinely available lipid measure is more applicable in estimation of kidney function is still uncertain. Our objective was to evaluate inconsistent associations of lipid profiles with both albuminuria and chronic kidney disease (CKD). METHODS: We performed a population-based study in 9730 subjects aged 40 years or older. Definitions of abnormalities in albumin excretion were according to the latest guidelines of American Diabetes Association's Standards of Medical Care. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m(2) or the presence of albuminuria. RESULTS: There were 2274 (23.4%) participants categorized as low-grade albuminuria, 639 (6.6%) participants categorized as increased urinary albumin excretion and 689 (7.1%) participants categorized as CKD. Triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), Non HDL-C to HDL-C ratio, TG to HDL C ratio were significantly correlated with urinary albumin to creatinine ratio (ACR), serum creatinine and eGFR (all P < 0.0001). Compare with other lipid parameters, TG to HDL-C ratio have shown the strongest correlation with increased odds of both increased urinary albumin excretion and CKD. No significant associations between lipid parameters and low-grade albuminuria were observed after adjustments for potential confounding factors. CONCLUSION: Our study lends support to discordant associations of lipid parameters with albuminuria and renal function. TG to HDL-C ratio is a better marker than other routine lipid measures for identifying renal insufficiency and should be given more consideration in the clinical practice. PMID- 26607502 TI - Introduction to the special issue: Psychophysiology and psychobiology in emotion development. PMID- 26607501 TI - A promising hypothesis of c-KIT methylation/ expression paradox in c-KIT (+) squamous cell carcinoma of uterine cervix ----- CTCF transcriptional repressor regulates c-KIT proto-oncogene expression. AB - We recently reported one interesting case showing mutation-free c-KIT proto oncogene overexpression and paradoxical hypermethylation in 54 cases of primary squamous cell carcinoma of uterine cervix (SCC). However, its molecular mechanisms still remain unknown. We propose the hypothesis that increased methylation at the CpG islands on the promoter near the first exon region might interfere with the binding of CTCF repressor with c-KIT promoter that regulates c KIT proto-oncogene expression in such case. Further studies focusing on the status of epigenetic modifications of mutation-free c-KIT (+) tumors are encouraged. PMID- 26607503 TI - The way forward is through Paris. PMID- 26607504 TI - Built on trust. PMID- 26607505 TI - Drugs on demand. PMID- 26607506 TI - A 'perfect' agreement in Paris is not essential. PMID- 26607518 TI - Salmon approval heralds rethink of transgenic animals. PMID- 26607519 TI - Climate optimism builds ahead of Paris talks. PMID- 26607520 TI - Green Climate Fund faces slew of criticism. PMID- 26607522 TI - Leap-second decision delayed by eight years. PMID- 26607521 TI - Brazilian courts tussle over unproven cancer treatment. PMID- 26607523 TI - 'Digital chimp' trove preserves brains of retired apes. PMID- 26607524 TI - All together now. PMID- 26607525 TI - The fragile framework. PMID- 26607526 TI - Is the 2 degrees C world a fantasy? PMID- 26607527 TI - Global climate agreement: After the talks. PMID- 26607528 TI - Materials science: Share corrosion data. PMID- 26607529 TI - Correction. PMID- 26607532 TI - Gene editing: Govern ability expectations. PMID- 26607533 TI - Gene editing: Survey invites opinions. PMID- 26607534 TI - Lessons from EPA on tracking pollutants. PMID- 26607535 TI - Climate change also creates expatriates. PMID- 26607536 TI - Crowdfunding not fit for clinical trials. PMID- 26607537 TI - Gene editing: Heed disability views. PMID- 26607538 TI - Imaging techniques: Super-resolution ultrasound. PMID- 26607541 TI - Planetary science: The Moon's tilt for gold. PMID- 26607539 TI - Ebola: Hidden reservoirs. PMID- 26607542 TI - Blindness: Assassins of eyesight. PMID- 26607543 TI - Correction. PMID- 26607544 TI - Collisionless encounters and the origin of the lunar inclination. AB - The Moon is generally thought to have formed from the debris ejected by the impact of a planet-sized object with the proto-Earth towards the end of planetary accretion. Models of the impact process predict that the lunar material was disaggregated into a circumplanetary disk and that lunar accretion subsequently placed the Moon in a near-equatorial orbit. Forward integration of the lunar orbit from this initial state predicts a modern inclination at least an order of magnitude smaller than the lunar value--a long-standing discrepancy known as the lunar inclination problem. Here we show that the modern lunar orbit provides a sensitive record of gravitational interactions with Earth-crossing planetesimals that were not yet accreted at the time of the Moon-forming event. The currently observed lunar orbit can naturally be reproduced via interaction with a small quantity of mass (corresponding to 0.0075-0.015 Earth masses eventually accreted to the Earth) carried by a few bodies, consistent with the constraints and models of late accretion. Although the encounter process has a stochastic element, the observed value of the lunar inclination is among the most likely outcomes for a wide range of parameters. The excitation of the lunar orbit is most readily reproduced via collisionless encounters of planetesimals with the Earth-Moon system with strong dissipation of tidal energy on the early Earth. This mechanism obviates the need for previously proposed (but idealized) excitation mechanisms, places the Moon-forming event in the context of the formation of Earth, and constrains the pristineness of the dynamical state of the Earth-Moon system. PMID- 26607545 TI - Type-II Weyl semimetals. AB - Fermions--elementary particles such as electrons--are classified as Dirac, Majorana or Weyl. Majorana and Weyl fermions had not been observed experimentally until the recent discovery of condensed matter systems such as topological superconductors and semimetals, in which they arise as low-energy excitations. Here we propose the existence of a previously overlooked type of Weyl fermion that emerges at the boundary between electron and hole pockets in a new phase of matter. This particle was missed by Weyl because it breaks the stringent Lorentz symmetry in high-energy physics. Lorentz invariance, however, is not present in condensed matter physics, and by generalizing the Dirac equation, we find the new type of Weyl fermion. In particular, whereas Weyl semimetals--materials hosting Weyl fermions--were previously thought to have standard Weyl points with a point like Fermi surface (which we refer to as type-I), we discover a type-II Weyl point, which is still a protected crossing, but appears at the contact of electron and hole pockets in type-II Weyl semimetals. We predict that WTe2 is an example of a topological semimetal hosting the new particle as a low-energy excitation around such a type-II Weyl point. The existence of type-II Weyl points in WTe2 means that many of its physical properties are very different to those of standard Weyl semimetals with point-like Fermi surfaces. PMID- 26607546 TI - Ultrafast ultrasound localization microscopy for deep super-resolution vascular imaging. AB - Non-invasive imaging deep into organs at microscopic scales remains an open quest in biomedical imaging. Although optical microscopy is still limited to surface imaging owing to optical wave diffusion and fast decorrelation in tissue, revolutionary approaches such as fluorescence photo-activated localization microscopy led to a striking increase in resolution by more than an order of magnitude in the last decade. In contrast with optics, ultrasonic waves propagate deep into organs without losing their coherence and are much less affected by in vivo decorrelation processes. However, their resolution is impeded by the fundamental limits of diffraction, which impose a long-standing trade-off between resolution and penetration. This limits clinical and preclinical ultrasound imaging to a sub-millimetre scale. Here we demonstrate in vivo that ultrasound imaging at ultrafast frame rates (more than 500 frames per second) provides an analogue to optical localization microscopy by capturing the transient signal decorrelation of contrast agents--inert gas microbubbles. Ultrafast ultrasound localization microscopy allowed both non-invasive sub-wavelength structural imaging and haemodynamic quantification of rodent cerebral microvessels (less than ten micrometres in diameter) more than ten millimetres below the tissue surface, leading to transcranial whole-brain imaging within short acquisition times (tens of seconds). After intravenous injection, single echoes from individual microbubbles were detected through ultrafast imaging. Their localization, not limited by diffraction, was accumulated over 75,000 images, yielding 1,000,000 events per coronal plane and statistically independent pixels of ten micrometres in size. Precise temporal tracking of microbubble positions allowed us to extract accurately in-plane velocities of the blood flow with a large dynamic range (from one millimetre per second to several centimetres per second). These results pave the way for deep non-invasive microscopy in animals and humans using ultrasound. We anticipate that ultrafast ultrasound localization microscopy may become an invaluable tool for the fundamental understanding and diagnostics of various disease processes that modify the microvascular blood flow, such as cancer, stroke and arteriosclerosis. PMID- 26607547 TI - Antibody anarchy: A call to order. PMID- 26607548 TI - Correction. PMID- 26607550 TI - Peroxygenase-Catalyzed Oxyfunctionalization Reactions Promoted by the Complete Oxidation of Methanol. AB - Peroxygenases catalyze a broad range of (stereo)selective oxyfunctionalization reactions. However, to access their full catalytic potential, peroxygenases need a balanced provision of hydrogen peroxide to achieve high catalytic activity while minimizing oxidative inactivation. Herein, we report an enzymatic cascade process that employs methanol as a sacrificial electron donor for the reductive activation of molecular oxygen. Full oxidation of methanol is achieved, generating three equivalents of hydrogen peroxide that can be used completely for the stereoselective hydroxylation of ethylbenzene as a model reaction. Overall we propose and demonstrate an atom-efficient and easily applicable alternative to established hydrogen peroxide generation methods, which enables the efficient use of peroxygenases for oxyfunctionalization reactions. PMID- 26607551 TI - Inspired by Nature: The 3-Halo-4,5-dihydroisoxazole Moiety as a Novel Molecular Warhead for the Design of Covalent Inhibitors. AB - Over the past few decades, there has been an increasing interest in the development of covalent enzyme inhibitors. As it was recently re-emphasized, the selective, covalent binding of a drug to the desired target can increase efficiency and lower the inhibitor concentration required to achieve a therapeutic effect. In this context, the naturally occurring antibiotic acivicin, and in particular its 3-chloro-4,5-dihydroisoxazole scaffold, has provided a wealth of inspiration to medicinal chemists and chemical biologists alike. In this Concept, to underline the great potentiality that the 3-halo-4,5 dihydroisoxazole warhead has in drug discovery, we present a number of examples, grouped by their potential biological activity and targets, in which this scaffold has been fruitfully used to develop novel biologically active compounds. Through these examples, we show that the 3-halo-4,5-dihydroisoxazole moiety represents an outstanding warhead with high potential for the design of novel covalent enzyme inhibitors. PMID- 26607553 TI - CMOS-Technology-Enabled Flexible and Stretchable Electronics for Internet of Everything Applications. AB - Flexible and stretchable electronics can dramatically enhance the application of electronics for the emerging Internet of Everything applications where people, processes, data and devices will be integrated and connected, to augment quality of life. Using naturally flexible and stretchable polymeric substrates in combination with emerging organic and molecular materials, nanowires, nanoribbons, nanotubes, and 2D atomic crystal structured materials, significant progress has been made in the general area of such electronics. However, high volume manufacturing, reliability and performance per cost remain elusive goals for wide commercialization of these electronics. On the other hand, highly sophisticated but extremely reliable, batch-fabrication-capable and mature complementary metal oxide semiconductor (CMOS)-based technology has facilitated tremendous growth of today's digital world using thin-film-based electronics; in particular, bulk monocrystalline silicon (100) which is used in most of the electronics existing today. However, one fundamental challenge is that state-of the-art CMOS electronics are physically rigid and brittle. Therefore, in this work, how CMOS-technology-enabled flexible and stretchable electronics can be developed is discussed, with particular focus on bulk monocrystalline silicon (100). A comprehensive information base to realistically devise an integration strategy by rational design of materials, devices and processes for Internet of Everything electronics is offered. PMID- 26607554 TI - On the origin of species: Factors shaping the establishment of infant's gut microbiota. AB - The human gut microbiota is a complex and dynamic ecosystem, which naturally lives in a symbiotic relationship with the host. Perturbations of the microbial composition (dysbiosis) and reduced diversity may promote disease susceptibility and recurrence. In contrast to the mature intestinal microbiota of healthy adults, which appears relatively stable over time, the infant's microbiome only establishes and matures during the first years of life. In this respect, early childhood seems to represent a crucial age-window in disease prevention, since microbial diversification and maturation of the microbiome primarily occurs during this period of life. A better understanding of ecological processes and pioneer consortia in microbial development is crucial, in order to support the development of a beneficial microbiota. Various deterministic and stochastic aspects seem to shape the microbiome in early life, including maternal, environmental, and host factors. Here, we review the current understanding of the origin of pioneer bacteria and the evolutionary factors that influence the development of the gut microbiota in infants. In addition, future perspectives, including manipulating and promoting the succession of initial bacteria during infancy, will be highlighted. PMID- 26607552 TI - Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models. AB - BACKGROUND: Trisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood. RESULTS: Here, we profile CpG methylation in DS and control cerebral and cerebellar cortex of adults and cerebrum of fetuses. We purify neuronal and non-neuronal nuclei and T lymphocytes and find biologically relevant genes with DS-specific methylation (DS-DM) in each of these cell types. Some genes show brain-specific DS-DM, while others show stronger DS-DM in T cells. Both 5-methyl cytosine and 5-hydroxy-methyl-cytosine contribute to the DS-DM. Thirty percent of genes with DS-DM in adult brain cells also show DS-DM in fetal brains, indicating early onset of these epigenetic changes, and we find early maturation of methylation patterns in DS brain and lymphocytes. Some, but not all, of the DS-DM genes show differential expression. DS-DM preferentially affected CpGs in or near specific transcription factor binding sites (TFBSs), implicating a mechanism involving altered TFBS occupancy. Methyl-seq of brain DNA from mouse models with sub-chromosomal duplications mimicking DS reveals partial but significant overlaps with human DS-DM and shows that multiple chromosome 21 genes contribute to the downstream epigenetic effects. CONCLUSIONS: These data point to novel biological mechanisms in DS and have general implications for trans effects of chromosomal duplications and aneuploidies on epigenetic patterning. PMID- 26607555 TI - Photodynamic therapy activated STAT3 associated pathways: Targeting intrinsic apoptotic pathways to increase PDT efficacy in human squamous carcinoma cells. AB - 5-Aminolaevulinic acid-based photodynamic therapy (ALA-PDT) has been used for part of squamous cell carcinoma (premalignant conditions or in situ cutaneous SCC Bowen disease). However, mechanism of ALA-PDT is not fully understood yet on the cell apoptosis pathway. The aim of this study was to further investigate the effect and mechanism of 5-ALA-PDT on human squamous carcinoma A431cells. Apoptosis and cell viability after PDT were evaluated using Annexin V-FITC apoptosis detection kit and MTT assay. The mRNA and protein levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Our data showed that 5-ALA-PDT significantly inhibited cell proliferation (p<0.05), but there was no significant difference when the photosensitizer reached to 4.8mM. The inhibition in cell proliferation after 5-ALA-PDT treatment was correlated to more cells being arrested in the G0/G1 phase of the cell cycle (p<0.01). Immunocytochemical observations using anti-active caspase-3 antibodies showed active caspase-3 was translocated from cytoplasm to nuclear during apoptosis. STAT3 and its downstream gene Bax and BCL-2 were changed after 5-ALA PDT treatment for the mRNA and protein expression. Our studies confirmed that 5 ALA-PDT might be an effective treatment for human squamous carcinoma by inhibiting the tumor cell A431growth and for the first time demonstrated that the expression of STAT3 was significantly reduced at 24h after 5-ALA-PDT treatment. PMID- 26607556 TI - Epidermal penetration and protoporphyrin IX formation of two different 5 aminolevulinic acid formulations in ex vivo human skin. AB - BACKGROUND: Photosensitizer formation and epidermal penetration depth represent basic predictors of drug efficacy in dermatological Photodynamic Therapy (PDT). Different drug formulations and application standards are used to perform PDT in clinical practice. METHODS: Thus, we developed a human ex vivo model suitable to explore drug permeation in human skin and compared in 10 patients the penetration of nanoemulsion formulation (BF-200 ALA) with that of a 20% ALA cream formulation frequently used in clinical practice. Protoporphyrin IX (PpIX) formation was assessed according to different durations of incubation with both preparations. RESULTS: BF-200 ALA led to more intense PpIX fluorescence than the 20% ALA cream formulation as assessed by fluorescence microscopy: after 12h of incubation, total measured fluorescence was at 101,995 fluorescence units with BF-200 ALA and 40,960 fluorescence units with 20% ALA cream, respectively. This could be reproduced using quantitative fluorimetric measurements in tissue lysates. After the clinically relevant incubation time of 3h the PpIX concentration induced by BF-200 ALA was more than three-fold higher than that induced by the 20% ALA formulation (7.1+/-5.5 and 1.9+/-1.8nmol/l, p<0.05, Mann-Whitney U-test) and four fold higher after 12h (30.0+/-4.6 and 6.7+/-2.0nmol/l, p<0.01, Mann-Whitney U test). CONCLUSIONS: In spite of the 50% lower ALA content BF-200 ALA triggers significantly higher PpIX concentrations than the 20% ALA formulation, indicating that clinical efficacy with BF-200 ALA may be higher. Moreover, the ex vivo eyelid skin model may represent a useful tool to investigate drug permeation in human skin. PMID- 26607557 TI - Morphological characteristics of eosinophilic neuronal death after transient unilateral forebrain ischemia in Mongolian gerbils. AB - Various types of eosinophilic neurons (ENs) are found in the post-ischemic brain. The aim of the present study was to elucidate the temporal and spatial profile of ENs, the expression of TUNEL staining and ultrastructural characteristics in the core and peripheral regions of the cortex post-ischemia. Unilateral forebrain ischemia was induced in Mongolian gerbils by transient common carotid artery occlusions, and the brains from 3 h to 2 weeks post-ischemia were prepared for morphometric, electron microscopy (EM) and TUNEL staining of the ENs. Light microscopy showed that ENs with minimally abnormal nuclei and swollen cell bodies appeared at 3 h in the ischemic core and at 12 h in the periphery. Thereafter, ENs with pyknosis and irregular atrophic cytoplasm peaked at 12 h, pyknosis with scant cytoplasm peaked at 4 days, and TUNEL-positive staining was observed in the ischemic core. In the ischemic periphery, ENs had slightly atrophic cytoplasm and sequentially developed pyknosis, karyorrhexis and karyolysis over 1 week. These cells were also positive for TUNEL. In EM, severe organelle dilation and vacuolization preceded chromatin fragmentation in the ischemic core, while chromatin fragmentation and homogenization were the vital characteristics in the ischemic periphery. There might be two region-dependent pathways for EN changes in the post-ischemic brain: pyknosis with cytoplasmic shrinkage in the core and nuclear disintegration with slightly atrophic cytoplasm in the periphery. These pathways were comparable to necrosis and proceeded from non-classical apoptosis to necrosis, respectively. PMID- 26607558 TI - Mitochondria and the hallmarks of cancer. AB - Mitochondria have traditionally been viewed as the powerhouse of the cell, where they serve, amongst other functions, as a major source of ATP generation. More recently, mitochondria have also been shown to have active roles in a variety of other processes, including apoptotic cell death and inflammation. Here we review the various ways in which mitochondrial functions affect cancer. Although there are many diverse types of cancer, hallmarks have been defined that are applicable to most cancer types. We provide an overview of how mitochondrial functions affect some of these hallmarks, which include evasion of cell death, de-regulated bioenergetics, genome instability, tumour-promoting inflammation and metastasis. In addition to discussing the underlying mitochondrial roles in each of these processes, we also highlight the considerable potential of targeting mitochondrial functions to improve cancer treatment. PMID- 26607559 TI - The 33rd Manfred Donike Workshop on Doping Analysis. PMID- 26607560 TI - Uncoupling of sodium and chloride to assist breeding for salinity tolerance in crops. AB - The separation of toxic effects of sodium (Na(+)) and chloride (Cl(-)) by the current methods of mixed salts and subsequent determination of their relevance to breeding has been problematic. We report a novel method (Na(+) humate) to study the ionic effects of Na(+) toxicity without interference from Cl(-), and ionic and osmotic effects when combined with salinity (NaCl). Three cereal species (Hordeum vulgare, Triticum aestivum and Triticum turgidum ssp. durum with and without the Na(+) exclusion gene Nax2) differing in Na(+) exclusion were grown in a potting mix under sodicity (Na(+) humate) and salinity (NaCl), and water use, leaf nutrient profiles and yield were determined. Under sodicity, Na(+)-excluding bread wheat and durum wheat with the Nax2 gene had higher yield than Na(+) accumulating barley and durum wheat without the Nax2 gene. However, under salinity, despite a 100-fold difference in leaf Na(+), all species yielded similarly, indicating that osmotic stress negated the benefits of Na(+) exclusion. In conclusion, Na(+) exclusion can be an effective mechanism for sodicity tolerance, while osmoregulation and tissue tolerance to Na(+) and/or Cl( ) should be the main foci for further improvement of salinity tolerance in cereals. This represents a paradigm shift for breeding cereals with salinity tolerance. PMID- 26607561 TI - The economic impact of epilepsy: a systematic review. AB - BACKGROUND: In this review we aimed to determine the economic impact of epilepsy and factors associated with costs to individuals and health systems. METHODS: A narrative systematic review of incidence and case series studies with prospective consecutive patient recruitment and economic outcomes published before July 2014 were retrieved from Medline, Embase and PsycInfo. RESULTS: Of 322 studies reviewed, 22 studies met the inclusion criteria and 14 were from high income country settings. The total costs associated with epilepsy varied significantly in relation to the duration and severity of the condition, response to treatment, and health care setting. Where assessed, 'out of pocket' costs and productivity losses were found to create substantial burden on households which may be offset by health insurance. However, populations covered ostensibly for the upfront costs of care can still bear a significant economic burden. CONCLUSIONS: Epilepsy poses a substantial economic burden for health systems and individuals and their families. There is uncertainty over the degree to which private health insurance or social health insurance coverage provides adequate protection from the costs of epilepsy. Future research is required to examine the role of different models of care and insurance programs in protecting against economic hardship for this condition, particularly in low and middle income settings. PMID- 26607562 TI - Systematic review with meta-analysis: mucosal healing is associated with improved long-term outcomes in Crohn's disease. AB - BACKGROUND: Clinical manifestations of Crohn's disease (CD) do not reliably correlate with endoscopic activity. While treating to achieve clinical remission (CR) has neither proven to improve CD outcomes nor alter the natural disease course, it is unclear whether targeting objective measures like mucosal healing (MH) is associated with improved long-term outcomes. AIM: To perform a systematic review and meta-analysis comparing long-term outcomes in active CD patients who achieve MH compared to those who do not. METHODS: We performed a systematic literature search to identify studies with prospective cohorts of active CD patients that included outcomes of patients who achieved MH at first endoscopic assessment (MH1) compared to those who did not. The primary outcome was long-term (>=50 weeks) CR. Secondary outcomes included CD-related surgery-free rate, hospitalisation-free rate and long-term MH rate. Pooled odds ratio (OR) and 95% confidence intervals (CI) were calculated. RESULTS: Twelve studies with 673 patients met inclusion criteria. Patients achieving MH1 had a pooled OR of 2.80 (95%CI, 1.91-4.10) for achieving long-term CR, 2.22 (95%CI, 0.86-5.69) for CD related surgery-free rate, and 14.30 (95%CI, 5.57-36.74) for long-term MH. Sensitivity analyses suggested no difference in outcomes if MH1 was achieved on biologics vs. non-biologics. No significant publication bias or heterogeneity was detected. CONCLUSIONS: Achieving MH1 is associated with increased rates of long term clinical remission, and maintenance of mucosal healing in active Crohn's disease and may therefore be a reasonable therapeutic target. PMID- 26607563 TI - Triple negative breast cancer chemosensitivity and chemoresistance: current advances in biomarkers indentification. AB - INTRODUCTION: Triple negative breast cancer (TNBC) is a heterogeneous clinicopathological entity constituting approximately 15 - 20% of all breast cancer (BC) patients. It shows high recurrence rate and poor prognosis. At this juncture, because of the lack of specific targeted therapies available and the development in patients of resistance to some therapeutic agents, clinical and translational settings have gained importance over the past decades. AREAS COVERED: The development of novel, safe and effective alternatives for the treatment of TNBC are in high demand. Therefore, this review aims to summarize the state of the art of TNBC, its current therapies and potential therapeutic targets. In particular, focus is put on recent advances regarding the identification of emerging biomarkers as prognostic and/or predictive markers, including surrogate markers for molecular tumor subtyping and identifying potential responders to new therapies. EXPERT OPINION: Effective development of informative markers could constitute an important armamentarium tool for identifying appropriate therapies to challenge the aggressiveness of TNBC. PMID- 26607564 TI - Audiovisual spoken word recognition as a clinical criterion for sensory aids efficiency in Persian-language children with hearing loss. AB - OBJECTIVES: The aim of this study was to examine the role of audiovisual speech recognition as a clinical criterion of cochlear implant or hearing aid efficiency in Persian-language children with severe-to-profound hearing loss. DESIGN: This research was administered as a cross-sectional study. The sample size was 60 Persian 5-7 year old children. The assessment tool was one of subtests of Persian version of the Test of Language Development-Primary 3. The study included two experiments: auditory-only and audiovisual presentation conditions. The test was a closed-set including 30 words which were orally presented by a speech-language pathologist. RESULTS: The scores of audiovisual word perception were significantly higher than auditory-only condition in the children with normal hearing (P<0.01) and cochlear implant (P<0.05); however, in the children with hearing aid, there was no significant difference between word perception score in auditory-only and audiovisual presentation conditions (P>0.05). CONCLUSIONS: The audiovisual spoken word recognition can be applied as a clinical criterion to assess the children with severe to profound hearing loss in order to find whether cochlear implant or hearing aid has been efficient for them or not; i.e. if a child with hearing impairment who using CI or HA can obtain higher scores in audiovisual spoken word recognition than auditory-only condition, his/her auditory skills have appropriately developed due to effective CI or HA as one of the main factors of auditory habilitation. PMID- 26607565 TI - Evaluation of long term outcome of auditory training programs in children with auditory processing disorders. AB - OBJECTIVES: To evaluate the long term effects of Arabic auditory training 'AT' programs in Egyptian school-aged children with auditory processing disorders 'APD'. METHODS: Thirty children with APD who received the proper regular AT for minimum duration of 2 months were included. They were subjected to functional measures 'questionnaire for APD' and psychophysical test battery. It comprised dichotic digits, pitch pattern sequence 'PPS', gap in noise detection 'GIN' and the memory tests. New bench mark battery was applied in the form of the duration pattern, the dichotic rhyme and the informal memory tests. The results of different tests were compared across the evaluation sessions 'pre-training, immediate post training, and the late outcome'. RESULTS: The children were evaluated after mean duration 24.5 months, ranged 7-42 months from the end of AT. No deterioration in the scores of Arabic questionnaire or the psychophysical tests was observed compared to the immediate post training evaluation. The bench mark tests scores matched the age based norms. A statistical significant correlation existed between PPS, GIN tests and the functional measures. CONCLUSION: The outcome of the AT program showed long term consistency. The temporal processing tests (PPS, GIN) were sensitive tools in monitoring the progress of training. The new bench mark test battery used was effective as the diagnostic test battery in assessing the long term effects of AT program. PMID- 26607566 TI - Neonatal peripheral facial paralysis' evaluation with photogrammetry: A case report. AB - Facial paralysis in newborns can leave functional sequelae. Determining the evolution and amount of functional losses requires consistent evaluation methods that measure, quantitatively, the evolution of clinical functionality. This paper reports an innovative method of facial assessment for the case of a child 28 days of age with unilateral facial paralysis. The child had difficulty breast feeding, and quickly responded to the physical therapy treatment. PMID- 26607567 TI - Nitrogen removal and mass balance in newly-formed Myriophyllum aquaticum mesocosm during a single 28-day incubation with swine wastewater treatment. AB - The aim of this research was to assess the applicability of Myriophyllum (M.) aquaticum for swine wastewater treatment. Nitrogen (N) removal processes were investigated in M. aquaticum mesocosms with swine wastewater (SW), 50% diluted swine wastewater (50% SW), and two strengths of synthetic wastewater, 200 mg [Formula: see text] L(-1) (200 [Formula: see text] ) and 400 mg [Formula: see text] L(-1) (400 [Formula: see text] ). During a 28-day incubation period, the average [Formula: see text] and TN removal rates were 99.8% and 94.2% for 50% SW and 99.8% and 93.8% for SW, which were greater than 86.5% and 83.7% for 200 [Formula: see text] , and 73.7% and 74.1% for 400 [Formula: see text] , respectively. A maximum areal total nitrogen (TN) removal rate of 157.8 mg N m( 2) d(-1) was found in M. aquaticum mesocosms with SW. During the incubation period, the observed dynamics of [Formula: see text] concentrations in water and gene copy numbers of ammonia-oxidizing archaea (AOA), ammonia-oxidizing bacteria (AOB), nirK and nirS in soil unraveled strong nitrification and denitrification processes occurring in M. aquaticum mesocosms with swine wastewater. The N mass balance analysis indicated that plant uptake and soil N accumulation accounted for 17.9-42.2% and 18.0-43.8% of the initial TN load, respectively. The coupled nitrification and denitrification process was calculated to account for, on average, 36.8% and 62.8% of TN removal for 50% SW and SW, respectively. These findings demonstrated that the N uptake by M. aquaticum contributed to a considerable proportion of N removal. In particular, the activities of ammonia oxidizing and denitrification microbes responsible for nitrification and denitrification processes in M. aquaticum mesocosm accelerated [Formula: see text] and TN removal from swine wastewater. PMID- 26607568 TI - Arsenite and arsenate removal from wastewater using cationic polymer-modified waste tyre rubber. AB - Waste tyre rubber (WTR) granulate was modified with a cationic polymer, poly(3 acrylamidopropyl)trimethylammonium chloride (p(APTMACl)). The resulting WTR/p(APTMACl) was utilized for the adsorption of arsenite, As(III) and arsenate, As(V) from aqueous medium in both batch and column methods. The level of adsorption increased gradually with increasing monomer concentration and contact time. The adsorption behavior obeyed the Freundlich model, and the rate of adsorption could be predicted by employing the pseudo-second order model. In the column method, As(V) could be adsorbed onto the sorbent more effectively than As(III). Remarkable desorption of As(III) and As(V) (99 and 92%, respectively) from the adsorbent was achieved using 0.10 M HCl as eluent. An approach of evaluation of adsorption capacity uncertainty is proposed. PMID- 26607569 TI - Evidence of recent interspecies horizontal gene transfer regarding nucleopolyhedrovirus infection of Spodoptera frugiperda. AB - BACKGROUND: Baculoviruses are insect-associated viruses carrying large, circular double-stranded-DNA genomes with significant biotechnological applications such as biological pest control, recombinant protein production, gene delivery in mammals and as a model of DNA genome evolution. These pathogens infect insects from the orders Lepidoptera, Hymenoptera and Diptera, and have high species diversity which is expressed in their diverse biological properties including morphology, virulence or pathogenicity. Spodoptera frugiperda (Lepidoptera: Noctuidae), the fall armyworm, represents a significant pest for agriculture in America; it is a host for baculoviruses such as the Spodoptera frugiperda multiple nucleopolyhedrovirus (SfMNPV) (Colombia strain, genotype A) having been classified as a Group II alphabaculovirus making it a very attractive target for bioinsecticidal use. RESULTS: Genome analysis by pyrosequencing revealed that SfMNPV ColA has 145 ORFs, 2 of which were not present in the other sequenced genotypes of the virus (SfMNPV-NicB, SfMNPV-NicG, SfMNPV-19 and SfMNPV-3AP2). An in-depth bioinformatics study showed that ORF023 and ORF024 were acquired by a recent homologous recombination process between Spodoptera frugiperda and Spodoptera litura (the Oriental leafworm moth) nucleopolyhedroviruses. Auxiliary genes are numerous in the affected locus which has a homologous region (hr3), a repetitive sequence associated with genome replication which became lost in SfColA along with 1 ORF. Besides, the mRNAs associated with two acquired genes appeared in the virus' life-cycle during the larval stage. Predictive studies concerning the theoretical proteins identified that ORF023 protein would be a phosphatase involved in DNA repair and that the ORF024 protein would be a membrane polypeptide associated with cell transport. CONCLUSIONS: The SfColA genome was thus revealed to be a natural recombinant virus showing evidence of recent horizontal gene transfer between different baculovirus species occurring in nature. This feature could be the cause of its high insecticidal power and therefore SfColA becomes a great candidate for bioinsecticide formulations. PMID- 26607570 TI - Potentially preventable premature deaths in women and men from the two leading causes of death in Austria, mortality statistics of the nine federal states 2010 2012. AB - BACKGROUND: In Austria, mortality from diseases of the circulatory system and malignant neoplasms is high and varies among the federal states. Lower mortality in some states indicates a preventive potential in those states with higher mortality. METHODS: We computed the number of premature deaths, for women and men separately, from the two leading causes of death, diseases of the circulatory system (ICD-10: I00-I09) and cancer (ICD-10: C00-C97), in the nine Austrian federal states between 2010-2012. The potentially preventable deaths per federal state and sex were calculated by subtracting expected deaths from observed deaths. RESULTS: The western federal states had the lowest death rates, and thus the smallest preventive potential. In death from circulatory diseases and from cancer the differences between women and men varied remarkably between the federal states. For circulatory diseases among all federal states the highest difference in percent was given in Vorarlberg (6.2%) with more potentially preventable deaths for men. For cancer, Burgenland had the highest difference (8.6%) in comparison with the other federal states, again with the higher preventive potential for men. CONCLUSIONS: Intervention programs as lifestyle modification interventions as well as improvements in health care services provision, should focus on the characteristics of the specific federal state, which are setting-oriented and account for social determinants including sex/gender differences and economic factors. Relevant data gathering is therefore, urgently needed. PMID- 26607571 TI - Looking into the past - the reaction of three grouse species to climate change over the last million years using whole genome sequences. AB - Tracking past population fluctuations can give insight into current levels of genetic variation present within species. Analysing population dynamics over larger timescales can be aligned to known climatic changes to determine the response of species to varying environments. Here, we applied the Pairwise Sequentially Markovian Coalescent (psmc) model to infer past population dynamics of three widespread grouse species; black grouse, willow grouse and rock ptarmigan. This allowed the tracking of the effective population size (Ne ) of all three species beyond 1 Mya, revealing that (i) early Pleistocene cooling (~2.5 Mya) caused an increase in the willow grouse and rock ptarmigan populations, (ii) the mid-Brunhes event (~430 kya) and following climatic oscillations decreased the Ne of willow grouse and rock ptarmigan, but increased the Ne of black grouse and (iii) all three species reacted differently to the last glacial maximum (LGM) - black grouse increased prior to it, rock ptarmigan experienced a severe bottleneck and willow grouse was maintained at large population size. We postulate that the varying psmc signal throughout the LGM depicts only the local history of the species. Nevertheless, the large population fluctuations in willow grouse and rock ptarmigan indicate that both species are opportunistic breeders while black grouse tracks the climatic changes more slowly and is maintained at lower Ne . Our results highlight the usefulness of the psmc approach in investigating species' reaction to climate change in the deep past, but also that caution should be taken in drawing general conclusions about the recent past. PMID- 26607572 TI - Erratum to: Wnt6 is required for maxillary palp formation in Drosophila. PMID- 26607573 TI - Classic articles in Psychology in the Science Citation Index Expanded: A bibliometric analysis. AB - Who today are the most highly cited psychologists listed in the Web of Science? This paper reports answers to this question by using the Science Citation Index Expanded to find out. This index covers over 280,350 documents in the Psychology category of the Web of Science from 1900 to 2013 and lists the most highly cited papers published between 1927 and 2012. For example, in 2013, an article published by Jacob Cohen in 1992 obtained (1) the highest ranking with 1,068 citations, (2) the highest for total citations per year, and (3) was ranked 3rd for the total number of citations since publication by 2013. New technology thus provides a seismic shift in the ways that we can obtain and analyse data like these. Indeed, the results for the top 10 articles indicate that practical and methodological papers now receive more citations than the more theoretical papers usually found in earlier surveys. PMID- 26607574 TI - Truncated amelogenin and LRAP transgenes improve Amelx null mouse enamel. AB - Amelogenin is the most abundant enamel protein involved in enamel mineralization. Our goal was to determine whether all three regions of amelogenin (N-terminus, C terminus, central core) are required for enamel formation. Amelogenin RNA is alternatively spliced, resulting in at least 16 different amelogenin isoforms in mice, with M180 and LRAP expressed most abundantly. Soon after secretion by ameloblasts, M180 is cleaved by MMP20 resulting in C-terminal truncated (CTRNC) amelogenin. We aimed to determine whether the 2 transgenes (Tg), LRAP and CTRNC together, can improve LRAPTg/Amelx-/- and CTRNCTg/Amelx-/- enamel thickness and prism organization, which were not rescued in Amelx-/- enamel. We generated CTRNCTg/LRAPTg/Amelx-/- mice and analyzed developing and mature incisor and molar enamel histologically, by microCT, SEM and microhardness testing. CTRNCTg and LRAPTg overexpression together significantly improved the enamel phenotype of LRAPTg/Amelx-/- and CTRNCTg/Amelx-/- mouse enamel, however enamel microhardness was recovered only when M180Tg was expressed, alone or with LRAPTg. We determined that both LRAP and CTRNC, which together express all three regions of the amelogenin protein (N-terminus, C-terminus and hydrophobic core) contribute to the final enamel thickness and prism organization in mice. PMID- 26607575 TI - The influence of precompression on elasticity of thyroid nodules estimated by ultrasound shear wave elastography. AB - OBJECTIVES: To investigate the influence of variations in resting pressure (precompression) on thyroid ultrasound supersonic shear wave elastography (SWE). METHODS: Thirty-five normal thyroid glands (Norm), 55 benign hyperplastic nodules (BHN), and 17 papillary thyroid cancers (PTC) in 96 subjects underwent thyroid SWE. Four precompression levels were applied manually by the operator, ranging from A (baseline, 0 % strain) to D (high, 22-30 % strain). SWE results at each precompression level were compared using ANOVA tests with P < 0.05 indicating significance. RESULTS: SWE indices were highest in PTC, followed by BHN and Norm at each precompression level (P < 0.05). All tissue types showed successive increases in SWE results as precompression increased, although the rate was higher for PTC than BHN and Norm (Ps < 0.05). SWE values (kPa) of Norm, BHN, and PTC at baseline precompression (A) were 10.3 +/- 3.3, 17.7 +/- 7.6, and 22.2 +/- 11.9 compared with 21.1 +/- 4.2, 42.3 +/- 16.0, and 97.6 +/- 46.8 at high precompression (D). SWE index differences between precompression levels A and D were 10.8 kPa for Norm, 24.6 kPa for BHN, and 75.4 kPa for PTC. CONCLUSION: PTCs show greater SWE stiffening than BHN as precompression rises. Precompression effects on thyroid nodules are not negligible and may account for wide discrepancies in published SWE discriminatory performance results for thyroid malignancy. KEY POINTS: * Increases in resting pressure (precompression) applied by the operator increases thyroid stiffness. * Papillary cancers show greater increases in stiffness (strain hardening) than benign nodules. * Precompression may affect the diagnostic performance of shearwave elastography for thyroid malignancy. PMID- 26607576 TI - The signal intensity ratio of the optic nerve to ipsilateral frontal white matter is of value in the diagnosis of acute optic neuritis. AB - OBJECTIVES: To evaluate the usefulness of the signal intensity ratio (SIR) of the optic nerve to the white matter (WM) on short tau inversion recovery (STIR) images to diagnose acute optic neuritis (AON). METHODS: The 405 consecutive patients with suspected orbital diseases underwent orbital magnetic resonance imaging (MRI) using a 3-T scanner between June 2008 and August 2011. Among them, 108 optic nerves (33 AON and 75 control) were retrospectively analysed. The averaged SIR (SIRave) and maximum SIR (SIRmax) were defined as the averaged signal intensity (SI) of the optic nerve divided by that of WM, and the maximum SI of the optic nerve divided by averaged SI of WM, respectively. These values were compared between AON and control using the Mann-Whitney U test. A P < 0.05 was considered statistically significant. RESULTS: SIRave and SIRmax were significantly (P < 0.001) higher in the AON compared to the control. At a cut-off SIRave value of 1.119, the sensitivity, specificity and accuracy were 0.939, 0.840, and 0.870; and at a cut-off SIRmax value of 1.281, these were 1.000, 0.720 and 0.806, respectively. CONCLUSION: The SIR of the optic nerve to WM on STIR images is of value in diagnosing AON. KEY POINTS: * We propose a method of diagnosing acute optic neuritis using 3-T MRI. * Our method is simple and objective and requires no novel imaging techniques. * Our method shows high diagnostic accuracy. PMID- 26607577 TI - Comparison of MR imaging findings in paediatric and adult patients with acute mastoiditis and incidental intramastoid bright signal on T2-weighted images. AB - OBJECTIVES: To compare MR imaging features in patients with incidental mastoid T2 hyperintensity with those of clinical acute mastoiditis, to ascertain characteristic differences between them. METHODS: MR images of 35 adult and paediatric patients with clinical acute mastoiditis and 34 consecutive age matched controls without relevant middle ear pathology and with incidental T2 hyperintensity that covered >= 50 % of the mastoid were retrospectively analysed with regard to signal, diffusion, and enhancement characteristics, and presence of complications. RESULTS: Incidental mastoid T2-hyperintensity that covered >= 50 % of the mastoid volume was found in 4.6 % of reviewed MR scans (n = 2341), and associated significantly (p < 0.05) less with the involvement of the tympanic cavity (38 % vs. 74 %) and mastoid antrum (56 % vs. 80 %), hypointense-to-CSF signal intensity on T2 FSE (6 % vs. 86 %), intramastoid diffusion restriction (0 % vs. 62 %), intense intramastoid enhancement (0 % vs. 51 %), periosteal enhancement (3 % vs. 69 %), perimastoid dural enhancement 3 % vs. 43 %), bone destruction (0 % vs 49 %), intratemporal abscess or cholesteatoma (0 % vs. 24 %), labyrinth involvement (0 % vs. 14 %), and extracranial abscesses (0 % vs. 20 %). CONCLUSION: Hypointense-to-CSF signal intensity on T2WI, restricted diffusion, intense intramastoid enhancement among other MR imaging characteristics favoured an acute mastoiditis diagnosis over clinically non-relevant incidental mastoid pathology. KEY POINTS: * Intramastoid T2-hyperintensity alone is not a reliable sign for acute mastoiditis. * In acute mastoiditis, intramastoid T2-weighted signal intensity is usually hypointense to CSF. * Diffusion restriction and intense intramastoid enhancement are absent in incidental mastoid effusion. * An ADC value >= 1.72 * 10 (-3) mm (2) /s contradicts the AM diagnosis. PMID- 26607579 TI - Are young physicians prepared to perform focused assessment with sonography in trauma examination? PMID- 26607578 TI - Human-, Ovine-, and Bovine-Specific Viral Source Tracking Tools to Discriminate Between the Major Fecal Sources in Agricultural Waters. AB - This study evaluated the sources of fecal contamination in different river catchments, using a combination of microbial source tracking tools, for human, ruminant, ovine and bovine livestock, in order to define appropriate water management strategies. Every source of waterway pollution was evaluated in river water samples from one urban river catchment and two important farming regions in New Zealand. Fecal pollution was initially measured by testing Escherichia coli and evaluating the presence of human- and ruminant-associated DNA markers of Bacteroidales (BiAdo, BacHum-UCD, BacH, and BacR) and human and ruminant fecal sterols/stanols ratios. Then specific fecal pollution sources were assessed with previously reported quantitative PCR assays targeting human-, bovine-, and ovine specific viruses: human adenoviruses (HAdV), human JC polyomaviruses, bovine polyomaviruses (BPyV), and ovine polyomaviruses (OPyV). High level of ruminant fecal contamination was detected all over the farming areas, whereas no ruminant sources were identified in the urban river sampling sites. BacR was the most frequently observed ruminant marker and OPyV and BPyV allowed the identification of ovine and bovine fecal sources. The human fecal viral marker (HAdV) was the most frequently observed human marker, highly abundant in the urban sites, and also present in farming areas. This is the first study using simultaneously the ovine and the bovine viral markers to identify and quantify both bovine and ovine fecal pollution. PMID- 26607582 TI - Nurses Sessions. PMID- 26607581 TI - Educational Objectives/Credit Hours. PMID- 26607583 TI - Annual Lecturers. PMID- 26607585 TI - Exhibits & Map. PMID- 26607584 TI - Index to Session Chairs. PMID- 26607586 TI - Past Presidents of AsMA. PMID- 26607587 TI - Council of AsMA. PMID- 26607589 TI - Headquarters Staff Photos. PMID- 26607588 TI - Wing Board of Directors. PMID- 26607590 TI - Bylaws of the Aerospace Medical Association. PMID- 26607591 TI - Muscle sympathetic nerve activity in frontotemporal lobar degeneration is similar to amyotrophic lateral sclerosis. AB - PURPOSE: To determine whether frontotemporal lobar degeneration (FTLD) is associated with similar cardiovascular autonomic dysfunction to that seen in amyotrophic lateral sclerosis (ALS), we compared cardiovascular parameters between ALS patients and patients with FTLD. METHODS: In ten patients with FTLD (mean age +/- SD: 71.6 +/- 4.6 years) and 12 patients with ALS (mean age +/- SD: 71.4 +/- 4.6 years), MSNA (using microneurography), heart rate (HR), and blood pressure (BP) were recorded simultaneously. RESULTS: MSNA was significantly higher in both groups of patients compared with the controls (p < 0.01), while there were no significant differences in MSNA between the patients with FTLD and those with ALS. During head-up tilt, changes in HR, BP, and the frequency of MSNA bursts were smaller in the patients than in controls (p < 0.05 or p < 0.01). CONCLUSIONS: Patients with FTLD and ALS showed similar dysfunction of HR, BP, and sympathetic outflow to muscles. PMID- 26607592 TI - Cervical vagotomy increased the distal colon distention to urinary bladder inhibitory reflex in male rats. AB - PURPOSE: Many studies have demonstrated the convergence of vagal inputs into brainstem centers with inputs from the urinary bladder and colon, as well as the convergence of vagal inputs into other centers controlling the urinary bladder and colon reflexes. However, the effect of the vagal inputs on the interaction between the urinary bladder and other pelvic organs has not been studied. In this study, the effect of bilateral cervical vagotomy on the distal colon to urinary bladder reflex was examined. METHODS: Changes to cystometry parameters in response to increased distal colon distensions (1, 2, and 3 ml) were tested in urethane-anesthetized male rats with or without bilateral cervical vagotomy. RESULTS: In animals with intact vagus nerves, 1 and 2 ml distal colon distentions had no significant effects on micturition frequency; however, 3 ml distal colon distention significantly decreased the frequency of micturition cycles. Also, 3 ml distal colon distention inhibited micturition cycles in 37.5 % of these animals. On the other hand, following cervical vagotomy, 1 ml distal colon distention was enough to significantly decrease the frequency of micturition cycles and to inhibit the cycles in 75 % of the animals. CONCLUSION: These results demonstrate the presence of supraspinal inhibitory regulation, via the vagus nerve, over the distal colon to urinary bladder inhibitory reflex. PMID- 26607593 TI - Unprecedented Melioidosis Cases in Northern Australia Caused by an Asian Burkholderia pseudomallei Strain Identified by Using Large-Scale Comparative Genomics. AB - Melioidosis is a disease of humans and animals that is caused by the saprophytic bacterium Burkholderia pseudomallei. Once thought to be confined to certain locations, the known presence of B. pseudomallei is expanding as more regions of endemicity are uncovered. There is no vaccine for melioidosis, and even with antibiotic administration, the mortality rate is as high as 40% in some regions that are endemic for the infection. Despite high levels of recombination, phylogenetic reconstruction of B. pseudomallei populations using whole-genome sequencing (WGS) has revealed surprisingly robust biogeographic separation between isolates from Australia and Asia. To date, there have been no confirmed autochthonous melioidosis cases in Australia caused by an Asian isolate; likewise, no autochthonous cases in Asia have been identified as Australian in origin. Here, we used comparative genomic analysis of 455 B. pseudomallei genomes to confirm the unprecedented presence of an Asian clone, sequence type 562 (ST 562), in Darwin, northern Australia. First observed in Darwin in 2005, the incidence of melioidosis cases attributable to ST-562 infection has steadily risen, and it is now a common strain in Darwin. Intriguingly, the Australian ST 562 appears to be geographically restricted to a single locale and is genetically less diverse than other common STs from this region, indicating a recent introduction of this clone into northern Australia. Detailed genomic and epidemiological investigations of new clinical and environmental B. pseudomallei isolates in the Darwin region and ST-562 isolates from Asia will be critical for understanding the origin, distribution, and dissemination of this emerging clone in northern Australia. PMID- 26607594 TI - Standardized Escherichia coli O157:H7 Exposure Studies in Cattle Provide Evidence that Bovine Factors Do Not Drive Increased Summertime Colonization. AB - The increased summertime prevalence of cattle carriage of enterohemorrhagic Shiga toxin-producing Escherichia coli O157:H7 (STEC O157) is associated with the increased summertime incidence of human infection. The mechanism driving the seasonality of STEC O157 carriage among cattle is unknown. We conducted experimental challenge trials to distinguish whether factors extrinsic or intrinsic to cattle underlie the seasonality of STEC O157 colonization. Holstein steers (n = 20) exposed to ambient environmental conditions were challenged with a standardized pool of STEC O157 strains four times at 6-month intervals. The densities and durations of rectoanal junction mucosa (RAJ) colonization with STEC O157 were compared by season (winter versus summer), dose (10(9) CFU versus 10(7) CFU), and route of challenge (oral versus rectal). Following summer challenges, the RAJ STEC O157 colonization density was significantly lower (P = 0.016) and the duration was shorter (P = 0.052) than for winter challenges, a seasonal pattern opposite to that observed naturally. Colonization was unaffected by the challenge route, indicating that passage through the gastrointestinal microbiome did not significantly affect the infectious dose to the RAJ. A 2-log reduction of the challenge doses in the second-year trials was accompanied by similarly reduced RAJ colonization in both seasons (P < 0.001). These results refute the hypothesis that cattle are predisposed to STEC O157 colonization during the summer months, either due to intrinsic factors or indirectly due to gastrointestinal tract microbiome effects. Instead, the data support the hypothesis that the increased summertime STEC O157 colonization results from increased seasonal oral exposure to this pathogen. PMID- 26607596 TI - Fms-like tyrosine kinase 3 (Flt3) ligand depletes erythroid island macrophages and blocks medullar erythropoiesis in the mouse. AB - The cytokines granulocyte colony-stimulating factor (G-CSF) and Flt3 ligand (Flt3 L) mobilize hematopoietic stem and progenitor cells into the peripheral blood of primates, humans, and mice. We recently reported that G-CSF administration causes a transient blockade of medullar erythropoiesis by suppressing erythroblastic island (EI) macrophages in the bone marrow. In the study described here, we investigated the effect of mobilizing doses of Flt3-L on erythropoiesis in mice in vivo. Similar to G-CSF, Flt3-L caused whitening of the bone marrow with significant reduction in the numbers of EI macrophages and erythroblasts. This was compensated by an increase in the numbers of EI macrophages and erythroblasts in the spleen. However, unlike G-CSF, Flt3-L had an indirect effect on EI macrophages, as it was not detected at the surface of EI macrophages or erythroid progenitors. PMID- 26607595 TI - Inefficient megakaryopoiesis in mouse hematopoietic stem-progenitor cells lacking T-bet. AB - Differentiation of hematopoietic stem-progenitor cells (HSPCs) into mature blood lineages results from the translation of extracellular signals into changes in the expression levels of transcription factors controlling cell fate decisions. Multiple transcription factor families are known to be involved in hematopoiesis. Although the T-box transcription factor family is known to be involved in the differentiation of multiple tissues, and expression of T-bet, a T-box family transcription factor, has been observed in HSPCs, T-box family transcription factors do not have a described role in HSPC differentiation. In the current study, we address the functional consequences of T-bet expression in mouse HSPCs. T-bet protein levels differed among HSPC subsets, with highest levels observed in megakaryo-erythroid progenitor cells (MEPs), the common precursor to megakaryocytes and erythrocytes. HSPCs from T-bet-deficient mice exhibited a defect in megakaryocytic differentiation when cultured in the presence of thrombopoietin. In contrast, erythroid differentiation in culture in the presence of erythropoietin was not substantially altered in T-bet-deficient HSPCs. Differences observed with respect to megakaryocyte number and maturity, as assessed by level of expression of CD41 and CD61, and megakaryocyte ploidy, in T bet-deficient HSPCs were not associated with altered proliferation or survival in culture. Gene expression micro-array analysis of MEPs from T-bet-deficient mice exhibited diminished expression of multiple genes associated with the megakaryocyte lineage. These data advance our understanding of the transcriptional regulation of megakaryopoiesis by supporting a new role for T-bet in the differentiation of MEPs into megakaryocytes. PMID- 26607597 TI - Deletion of Rb1 induces both hyperproliferation and cell death in murine germinal center B cells. AB - The retinoblastoma gene (RB1) has been implicated as a tumor suppressor in multiple myeloma (MM), yet its role remains unclear because in the majority of cases with 13q14 deletions, un-mutated RB1 remains expressed from the retained allele. To explore the role of Rb1 in MM, we examined the functional consequences of single- and double-copy Rb1 loss in germinal center B cells, the cells of origin of MM. We generated mice without Rb1 function in germinal center B cells by crossing Rb1(Flox/Flox) with C-gamma-1-Cre (Cgamma1) mice expressing the Cre recombinase in class-switched B cells in a p107(-/-) background to prevent p107 from compensating for Rb1 loss (Cgamma1-Rb1(F/F)-p107(-/-)). All mice developed normally, but B cells with two copies of Rb1 deleted (Cgamma1-Rb1(F/F)-p107(-/-)) exhibited increased proliferation and cell death compared with Cgamma1-Rb1(+/+) p107(-/-) controls ex vivo. In vivo, Cgamma1-Rb1(F/F)-p107(-/-) mice had a lower percentage of splenic B220+ cells and reduced numbers of bone marrow antigen specific secreting cells compared with control mice. Our data indicate that Rb1 loss induces both cell proliferation and death in germinal center B cells. Because no B-cell malignancies developed after 1 year of observation, our data also suggest that Rb1 loss is not sufficient to transform post-germinal center B cells and that additional, specific mutations are likely required to cooperate with Rb1 loss to induce malignant transformation. PMID- 26607599 TI - The Predictive and Prognostic Value of Early Metabolic Response Assessed by Positron Emission Tomography in Advanced Gastric Cancer Treated with Chemotherapy. AB - PURPOSE: To evaluate the feasibility of early metabolic change assessed by PET in predicting clinical response to chemotherapy and investigate its prognostic value in patients with advanced gastric cancer. EXPERIMENTAL DESIGN: A total of 64 patients with advanced gastric cancer were prospectively enrolled and examined by PET with (18)F-fluorodeoxyglucose (FDG) and (18)F-fluoro-3'-deoxy-3'-L fluorothymidine (FLT) at baseline and 14 days after treatment initiation. PET findings were analyzed for the correlation with best clinical response of patients, disease control status, and survival after identifying the threshold of metabolic change percentage by ROC analysis. RESULTS: For FDG-PET, the total uptake value reduction percentage (delta-SUV) of 40% was the cut-off point with the maximum of sensitivity (70%) and specificity (83%) to predict clinical responding and that of prediction for disease control status was 30%, with the highest sensitivity (58%) and specificity (100%). The delta-SUV of FLT-PET played no predictive role for clinical response (AUC = 0.62; P= 0.134) and disease control (AUC = 0.66; P= 0.157). The univariate Cox regression analysis revealed no significant prognostic impact. FDG uptake reduction in liver metastases could predict both clinical response (P= 0.010) and disease control status (P= 0.002) at thresholds of 35% and 15%, respectively. Those with greater FDG uptake reduction in liver lesions had a longer overall survival (P= 0.004). CONCLUSIONS: Early metabolic change in FDG-PET might be a predictive marker for response and disease control in advanced gastric cancer. Early FDG uptake change in liver metastases might be a useful prognostic factor and needs further exploration. PMID- 26607598 TI - Molecular Pathways: Increased Susceptibility to Infection Is a Complication of mTOR Inhibitor Use in Cancer Therapy. AB - As one of the earliest examples of "chemical biology," the M: echanistic T: arget of R: apamycin (mTOR) protein and its chemical inhibitors have been extensively studied across a spectrum of physiologic and pathologic processes at the molecular, organismal, and patient population levels. There are several FDA approved mTOR inhibitors (sirolimus, everolimus, and temsirolimus) with indications for cancer treatment and for prevention of solid organ rejection. Dozens of mTOR inhibitors are currently being evaluated in hundreds of ongoing clinical trials across a spectrum of diseases, including numerous cancer indications, autoimmune diseases, and a number of congenital disorders. As many of the approved and investigational indications for mTOR inhibitors require long term treatment, the magnitude and incidence of particular side effects differ from those observed in shorter-term treatments. Here, we focus on the increased risk of infections in patients being treated with mTOR inhibitors. While increased infection rates might be expected from a class of drugs approved as posttransplant immunosuppressants, we review reports from clinical, mechanistic, and genetically engineered mouse model studies detailing a much more nuanced view of mTOR inhibitor drug action and target biology. PMID- 26607601 TI - Clinical Trial Registration: The Time Has Come.... PMID- 26607600 TI - Identification of CD25 as STAT5-Dependent Growth Regulator of Leukemic Stem Cells in Ph+ CML. AB - PURPOSE: In chronic myelogenous leukemia (CML), leukemic stem cells (LSC) represent a critical target of therapy. However, little is known about markers and targets expressed by LSCs. The aim of this project was to identify novel relevant markers of CML LSCs. EXPERIMENTAL DESIGN: CML LSCs were examined by flow cytometry, qPCR, and various bioassays. In addition, we examined the multipotent CD25(+)CML cell line KU812. RESULTS: In contrast to normal hematopoietic stem cells, CD34(+)/CD38(-)CML LSCs expressed the IL-2 receptor alpha chain, IL-2RA (CD25). STAT5 was found to induce expression of CD25 in Lin(-)/Sca 1(+)/Kit(+)stem cells in C57Bl/6 mice. Correspondingly, shRNA-induced STAT5 depletion resulted in decreased CD25 expression in KU812 cells. Moreover, the BCR/ABL1 inhibitors nilotinib and ponatinib were found to decrease STAT5 activity and CD25 expression in KU812 cells and primary CML LSCs. A CD25-targeting shRNA was found to augment proliferation of KU812 cellsin vitroand their engraftmentin vivoin NOD/SCID-IL-2Rgamma(-/-)mice. In drug-screening experiments, the PI3K/mTOR blocker BEZ235 promoted the expression of STAT5 and CD25 in CML cells. Finally, we found that BEZ235 produces synergistic antineoplastic effects on CML cells when applied in combination with nilotinib or ponatinib. CONCLUSIONS: CD25 is a novel STAT5-dependent marker of CML LSCs and may be useful for LSC detection and LSC isolation in clinical practice and basic science. Moreover, CD25 serves as a growth regulator of CML LSCs, which may have biologic and clinical implications and may pave the way for the development of new more effective LSC-eradicating treatment strategies in CML. PMID- 26607603 TI - Plasmablastic lymphoma presenting as a large intracardiac mass and bilateral pleural effusions. AB - Plasmablastic lymphoma (PBL) is a rare aggressive lymphoma arising most frequently in the oral cavity of HIV-infected patients. Rare cases of PBL have been reported in extra-oral sites, as well as in HIV-negative patients. Cardiac involvement by lymphoma is very rare. The most common primary cardiac lymphoma is diffuse large B-cell lymphoma. We report an unusual case of PBL in a 49-year-old, HIV-positive man presenting with a large intracardiac mass and bilateral pleural effusions. Histological examination of the cardiac mass biopsy and cytological evaluation of the pleural fluid demonstrated large lymphoma cells with plasmablastic differentiation. By immunohistochemistry, the large lymphoma cells expressed CD30, CD45, CD138, MUM1, and kappa light chain, were weakly positive for EMA, and were negative for T-cell and B-cell markers, lambda light chain, and human herpes virus 8 (HHV8). In situ hybridization for Epstein Barr Virus-encoded RNA (EBER) was negative in large lymphoma cells. To our knowledge, in the English literature, this is the second reported case of PBL with cardiac origin and the first reported case of PBL that presents as a combination of intracardiac mass and pleural effusions. PMID- 26607602 TI - PGRN promotes migration and invasion of epithelial ovarian cancer cells through an epithelial mesenchymal transition program and the activation of cancer associated fibroblasts. AB - In this paper, we aimed to explore whether progranulin (PGRN) could induce epithelial ovarian cancer cells to undergo an epithelial mesenchymal transition (EMT) program directly and through its activation of cancer associated fibroblasts (CAFs) indirectly. Immunohistochemistry(IHC) staining of tissue samples of 78 cases of epithelial ovarian cancer (EOC) patients found that PGRN expression levels were negatively correlated with E-cadherin levels (r=-0.289, P=0.013) and positively correlated with Slug levels (r=0.332, P=0.003); Cell experiments showed that PGRN overexpression could increase the migratory and invasive abilities of A2780 cells significantly. Moreover, high doses (62ng/ml) of recombinant PGRN could induce 14.7 fold high expression of smooth muscle actin alpha (alpha-SMA) in human normal fibroblasts. In addition, patients with both high levels of PGRN and alpha-SMA in their tissue samples had the worst disease free survival (DFS) and overall survival (OS) than those with low levels of PGRN or alpha-SMA. All the results suggest that PGRN could promote invasiveness of EOC cells through an EMT program directly and through activation of CAFs indirectly. This may provide a new effective therapy target for EOC. PMID- 26607604 TI - Blocking IL-10 signalling at the time of immunization renders the tumour more accessible to T cell infiltration in mice. AB - We recently reported that blockade of IL-10 signalling at the time of a human papillomavirus (HPV) long E7 peptide/LPS immunization leads to the regression of established HPV-16 immortalized tumours in mice similar to that induced by long E7 peptide/incomplete Freund's adjuvant (IFA)-based vaccination. In this paper, we demonstrated that blockade of IL-10 signalling at the time of long E7 peptide/LPS could elicit stronger T cells responses and render the tumour more accessible for immune cell infiltration than vaccination with long E7 peptide/IFA. Furthermore, priming with long E7 peptide/LPS and IL10 signalling blockade then boosting with long E7 peptide/IFA elicits stronger CD8+ T cell responses than long E7 peptide/IFA immunization. The results suggest that priming with long E7 peptide/LPS and IL10 signalling inhibitor, then boosting with long E7 peptide/IFA elicits may lead to better HPV infection related tumour regression in clinic. PMID- 26607606 TI - We value your contribution. AB - Age UK's briefing on the health and care of older people in England 2015 ( page 8 ) paints a stark picture of the threat to future quality of care. Whether you work in the NHS or the wider care sector, you will need no reminder of the paradox in which costs must be saved while quality of care must be improved. At the time of writing, 13 of the 26 hospitals recently inspected by the Care Quality Commission were rated as 'requires improvement', four as 'inadequate', and only nine as 'good'. None was rated as 'outstanding'. PMID- 26607605 TI - Gene Expression Profiling of H9c2 Cells Subjected to H2O2-Induced Apoptosis with/without AF-HF001. AB - Heart failure represents a major health problem. The development of new drugs to treat this condition is essential. We previously discovered that AF-001 attenuates the cardiac defects caused by heart failure in zebrafish. In this paper, we report the identification of AF-HF001, an AF-001 derivative, and its effects on live cardiomyocytes subjected to oxidative damage. The in vitro results demonstrated that AF-HF001 attenuates the production of reactive oxygen species (ROS) and the myocardial cell apoptosis. A DNA microarray was performed to broadly analyze gene expression after H2O2 treatment with or without AF-HF001. Hierarchical clustering analysis revealed that AF-HF001 modifies the expression of certain genes (Ndufs2, Ndufb6, Ndufb8, Ndufa13, Ndufs3, Ndufs5, TPM1, MYH14, RyR1, and TIMP4) related to ROS production, cardiac contractility and extracellular matrix remodeling. AF-HF001 ameliorates oxidative damage, which may be related to the mitogen-activated protein kinase (MAPK) family and the intrinsic mitochondrial pathway. Altogether, this study suggests that AF-HF001 exhibits potential as a clinical drug candidate for the treatment of heart failure. PMID- 26607607 TI - More older people will have dementia and comorbidities. AB - ACUTE HOSPITALS must transform to meet the needs of an ageing population with multiple comorbidities, delegates at the International Dementia Conference in Birmingham heard. PMID- 26607608 TI - Northern Ireland's home care services at breaking point. AB - THE HEALTH service in Northern Ireland is failing to meet the needs of older people, according to a senior official in the ruling Assembly. PMID- 26607609 TI - Documentary series shows transformation in services. AB - MEDICATION REVIEW in care homes is the subject of the first in a series of mini documentaries developed by charity the Health Foundation and hosted on its website. PMID- 26607610 TI - Hospital-built care homes too expensive, say experts. AB - ENCOURAGING HOSPITALS to build care homes will not prevent delays in hospital discharge, experts say. PMID- 26607611 TI - Patients should have greater involvement in treatment plans. AB - A GUIDELINE to improve quality of life for older people with social care needs and multiple long-term conditions has been issued by the National Institute for Health and Care Excellence. PMID- 26607612 TI - Needs of older people exceed ability of services to respond, claims report. AB - ARGUABLY, THE greatest challenge faced by the UK's health and care sectors in the 21st century is trying to meet the needs of the country's ageing population. However, if a report by Age UK is accurate, services in England are failing to meet them. PMID- 26607617 TI - What to do when under scrutiny. AB - IN AUGUST, the Nursing and Midwifery Council (NMC) concluded an 81-day hearing into care failings at Brithdir Care Home in Caerphilly, Wales. The hearing ended the UK's biggest inquiry into allegations of neglect to date. It led to three nurses being struck off, a fourth being suspended for one year and a fifth being given a caution order. PMID- 26607623 TI - Practice question. AB - A hospital admission can be bewildering for people with dementia or delirium. Staff can have difficulty managing what they perceive to be unsafe behaviour and so adopt one-to-one nursing to minimise risk. However, one-to-one nursing is often applied haphazardly or is not managed robustly enough to ensure efficacy and cost effectiveness. Some organisations have policies to guide staff about when and how to apply observation, but these are often in place to minimise organisational risk rather than to consider the needs of the person experiencing distress. PMID- 26607624 TI - How a rapid response team is supporting people to remain at home. AB - This article explores the work of a rapid response team (RRT) in an English city. The RRT is a multiprofessional intermediate care team that is able to support patients to remain at home during clinical crises and changes to their social care needs. The service is popular with patients and cost effective. The National Audit of Intermediate Care is in its fourth year and benchmarks how intermediate care services are delivered across England. RRT data are compared with the national data, and show that keeping the team as a crisis intervention service has enabled it to maintain capacity to support patients at home without requiring hospital admission. PMID- 26607625 TI - Developing a nurse-led 'red legs' service. AB - As the population ages, more complex care is required to manage multiple comorbidities. In response, a nurse-led service was developed to care for patients with 'red legs'. This chronic inflammatory condition is often misdiagnosed as acute cellulitis and can result in unnecessary hospital admission and inappropriate treatment, with substantial resource and financial implications for trusts. Setting up the service required a multi-agency group to analyse current provision and identify gaps in care. Integrated care pathways were developed to focus on patient experience through referral, diagnostics and treatment. Evaluation showed that much of the prescribed care for patients with red legs could be carried out by patients at home and only a small number required a follow-up appointment. High levels of patient satisfaction were recorded. PMID- 26607626 TI - Enabling hospital staff to care for people with dementia. AB - This is the fourth and final article in a short series that presents case study examples of the positive work achieved by trusts who participated in the Royal College of Nursing's development programme to improve dementia care in acute hospitals. Dementia training in hospitals is often inadequate and staff do not always have sufficient knowledge of dementia to provide appropriate care. It can also be difficult for them to identify when patients with dementia are in pain, especially when their communication skills deteriorate. The case studies presented illustrate how two NHS trusts have worked to ensure that their staff are fully equipped to care for people with dementia in hospital. Basildon and Thurrock University Hospitals NHS Foundation Trust in Essex made dementia training a priority by including dementia awareness in staff induction across a range of roles and providing additional training activities tailored to meet staff needs. Nottingham University Hospitals NHS Trust focused on pain assessment, aiming to standardise its approach for patients with dementia. The pain assessment in advanced dementia tool was chosen and piloted, and is being implemented across the trust after a positive response. PMID- 26607627 TI - Reducing social isolation in a rural community through participation in creative arts projects. AB - This article reports the initial findings from the evaluation of four creative arts projects involving groups of older people living in a rural community. The purpose of the projects was to reduce social isolation among participants through providing direct access to arts and social activities. The view was that these activities would improve life skills and independence, increase levels of activity and improve the health, wellbeing and quality of life of participants. Evaluation of these projects demonstrated increased levels of self-worth and self esteem among participants. Many of the older people involved agreed that they had made new friends while having the opportunity to try out a new activity. PMID- 26607628 TI - Grand designs. AB - COMPASSION FOR others and a desire to be fair have been the guiding lights through April Dobson's eclectic professional life. PMID- 26607629 TI - Quantitative 3D analysis of huge nanoparticle assemblies. AB - Nanoparticle assemblies can be investigated in 3 dimensions using electron tomography. However, it is not straightforward to obtain quantitative information such as the number of particles or their relative position. This becomes particularly difficult when the number of particles increases. We propose a novel approach in which prior information on the shape of the individual particles is exploited. It improves the quality of the reconstruction of these complex assemblies significantly. Moreover, this quantitative Sparse Sphere Reconstruction approach yields directly the number of particles and their position as an output of the reconstruction technique, enabling a detailed 3D analysis of assemblies with as many as 10,000 particles. The approach can also be used to reconstruct objects based on a very limited number of projections, which opens up possibilities to investigate beam sensitive assemblies where previous reconstructions with the available electron tomography techniques failed. PMID- 26607630 TI - Short-Lived Human Umbilical Cord-Blood-Derived Neural Stem Cells Influence the Endogenous Secretome and Increase the Number of Endogenous Neural Progenitors in a Rat Model of Lacunar Stroke. AB - Stroke is the leading cause of severe disability, and lacunar stroke is related to cognitive decline and hemiparesis. There is no effective treatment for the majority of patients with stroke. Thus, stem cell-based regenerative medicine has drawn a growing body of attention due to the capabilities for trophic factor expression and neurogenesis enhancement. Moreover, it was shown in an experimental autoimmune encephalomyelitis (EAE) model that even short-lived stem cells can be therapeutic, and we have previously observed that phenomenon indirectly. Here, in a rat model of lacunar stroke, we investigated the molecular mechanisms underlying the positive therapeutic effects of short-lived human umbilical cord-blood-derived neural stem cells (HUCB-NSCs) through the distinct measurement of exogenous human and endogenous rat trophic factors. We have also evaluated neurogenesis and metalloproteinase activity as cellular components of therapeutic activity. As expected, we observed an increased proliferation and migration of progenitors, as well as metalloproteinase activity up to 14 days post transplantation. These changes were most prominent at the 7-day time point when we observed 30 % increases in the number of bromodeoxyuridine (BrdU) positive cells in HUCB-NSC transplanted animals. The expression of human trophic factors was present until 7 days post transplantation, which correlated well with the survival of the human graft. For these 7 days, the level of messenger RNA (mRNA) in the analyzed trophic factors was from 300-fold for CNTF to 10,000-fold for IGF, much higher compared to constitutive expression in HUCB-NSCs in vitro. What is interesting is that there was no increase in the expression of rat trophic factors during the human graft survival, compared to that in non transplanted animals. However, there was a prolongation of a period of increased trophic expression until 14 days post transplantation, while, in non-transplanted animals, there was a significant drop in rat trophic expression at that time point. We conclude that the positive therapeutic effect of short-lived stem cells may be related to the net increase in the amount of trophic factors (rat + human) until graft death and to the prolonged increase in rat trophic factor expression subsequently. PMID- 26607632 TI - nNOS Translocates into the Nucleus and Interacts with Sox2 to Protect Neurons Against Early Excitotoxicity via Promotion of Shh Transcription. AB - Cerebral ischemic stroke is a major public health problem leading to high mortality rates and disability in adults. The NMDA receptor (NMDAR)/neuronal nitric oxide synthase (nNOS)/NO-dependent excitotoxicity has been recognized to play an important role in cerebral ischemic stroke pathogenesis. Accumulating evidence suggests that the biological function of nNOS is associated with its ability to couple proteins and its subcellular localization. Previously, we and others determined that nNOS could translocate into the nucleus in cultured astrocytes, but the underlying mechanisms and biological significance remained unclear. In the present study, we identified a specific interaction between nNOS and Sox2 (SRY (sex determining region Y)-box 2), a member of the Sox family of transcription factors, both in vivo and in vitro. Our studies showed that nNOS is transported into the nucleus and interacted with Sox2 to form a nNOS-Sox2 complex in neurons at the early stage following glutamate stimulation. Mechanistically, via activating the transcription of Shh (Sonic hedgehog), the downstream target of Sox2, this nNOS-Sox2 complex exerted a neuroprotective function against glutamate-induced excitotoxicity. Utilizing the MCAO focal ischemia model on rats, we further verified that the 'nNOS-Sox2-Shh' axis was involved in the ischemic neuronal injury. Taken together, our studies revealed that the 'nNOS Sox2-Shh' axis functions as a novel feedback compensatory mechanism to protect neurons against the early excitotoxicity and ischemic injury. PMID- 26607631 TI - Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms. AB - Artemether, a lipid-soluble derivative of artemisinin has been reported to possess anti-inflammatory properties. In this study, we have investigated the molecular mechanisms involved in the inhibition of neuroinflammation by the drug. The effects of artemether on neuroinflammation-mediated HT22 neuronal toxicity were also investigated in a BV2 microglia/HT22 neuron co-culture. To investigate effects on neuroinflammation, we used LPS-stimulated BV2 microglia treated with artemether (5-40 MUM) for 24 h. ELISAs and western blotting were used to detect pro-inflammatory cytokines, nitric oxide, prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1). Beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) activity and Abeta levels were measured with ELISA kits. Protein levels of targets in nuclear factor kappa B (NF-kappaB) and p38 mitogen-activated protein kinase (MAPK) signalling, as well as heme oxygenase-1 (HO-1), NQO1 and nuclear factor-erythroid 2-related factor 2 (Nrf2) were also measured with western blot. NF-kappaB binding to the DNA was investigated using electrophoretic mobility shift assays (EMSA). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), DNA fragmentation and reactive oxygen species (ROS) assays in BV2-HT22 neuronal co-culture were used to evaluate the effects of artemether on neuroinflammation-induced neuronal death. The role of Nrf2 in the anti-inflammatory activity of artemether was investigated in BV2 cells transfected with Nrf2 siRNA. Artemether significantly suppressed pro-inflammatory mediators (NO/iNOS, PGE2/COX-2/mPGES-1, tumour necrosis factor-alpha (TNFalpha) and interleukin (IL)-6); Abeta and BACE-1 in BV2 cells following LPS stimulation. These effects of artemether were shown to be mediated through inhibition of NF kappaB and p38 MAPK signalling. Artemether produced increased levels of HO-1, NQO1 and GSH in BV2 microglia. The drug activated Nrf2 activity by increasing nuclear translocation of Nrf2 and its binding to antioxidant response elements in BV2 cells. Transfection of BV2 microglia with Nrf2 siRNA resulted in the loss of both anti-inflammatory and neuroprotective activities of artemether. We conclude that artemether induces Nrf2 expression and suggest that Nrf2 mediates the anti inflammatory effect of artemether in BV2 microglia. Our results suggest that this drug has a therapeutic potential in neurodegenerative disorders. PMID- 26607635 TI - Editorial: Neonatal and Pediatric Clinical Pharmacology. PMID- 26607633 TI - Oxidative Stress, Disrupted Energy Metabolism, and Altered Signaling Pathways in Glutaryl-CoA Dehydrogenase Knockout Mice: Potential Implications of Quinolinic Acid Toxicity in the Neuropathology of Glutaric Acidemia Type I. AB - We investigated the effects of an acute intrastriatal QUIN administration on cellular redox and bioenergetics homeostasis, as well as on important signaling pathways in the striatum of wild-type (Gcdh +/+ , WT) and knockout mice for glutaryl-CoA dehydrogenase (Gcdh -/- ) fed a high lysine (Lys, 4.7 %) chow. QUIN increased lactate release in both Gcdh +/+ and Gcdh -/- mice and reduced the activities of complex IV and creatine kinase only in the striatum of Gcdh -/- mice. QUIN also induced lipid and protein oxidative damage and increased the generation of reactive nitrogen species, as well as the activities of the antioxidant enzymes glutathione peroxidase, superoxide dismutase 2, and glutathione-S-transferase in WT and Gcdh -/- animals. Furthermore, QUIN induced DCFH oxidation (reactive oxygen species production) and reduced GSH concentrations (antioxidant defenses) in Gcdh -/- . An early increase of Akt and phospho-Erk 1/2 in the cytosol and Nrf2 in the nucleus was also observed, as well as a decrease of cytosolic Keap1caused by QUIN, indicating activation of the Nrf2 pathway mediated by Akt and phospho-Erk 1/2, possibly as a compensatory protective mechanism against the ongoing QUIN-induced toxicity. Finally, QUIN increased NF-kappaB and diminished IkappaBalpha expression, evidencing a pro inflammatory response. Our data show a disruption of energy and redox homeostasis associated to inflammation induced by QUIN in the striatum of Gcdh -/- mice submitted to a high Lys diet. Therefore, it is presumed that QUIN may possibly contribute to the pathophysiology of striatal degeneration in children with glutaric aciduria type I during inflammatory processes triggered by infections or vaccinations. PMID- 26607636 TI - Age at menarche and the risk of diabetic microvascular complications in patients with type 1 diabetes. AB - AIMS/HYPOTHESIS: The aim of this study was to evaluate the relationship among age at onset of diabetes, age at onset of menarche and risk of diabetic nephropathy and laser-treated retinopathy in type 1 diabetes. METHODS: Data related to age at menarche were collected through questionnaires and were available for 1,304 women who participated in the Finnish Diabetic Nephropathy Study (FinnDiane). A possible association between age at menarche and diabetic nephropathy and retinopathy was investigated. RESULTS: There was an inverse relationship between the age at onset of diabetes and age at menarche: the younger the age at onset of diabetes, the higher the age at menarche (p < 0.0001). A non-linear relationship between the age of menarche and risk of diabetic microvascular complications was found in patients with diabetes onset before menarche, but there was no such association in patients with diabetes onset after menarche. Women with delayed menarche (> mean age + 2 years) had a 2.30 (95% CI 1.27, 4.17; p < 0.006) times higher risk of nephropathy compared with the women who underwent menarche at the mean age +/- 2 years. Delayed menarche also increased the risk of retinopathy (OR 2.34 [95% CI 1.36, 4.01]). After excluding patients with nephropathy, the OR for retinopathy was 2.11 (95% CI 1.15, 3.90). Earlier menarche (< mean age - 2 years) did not have any effect on this risk. CONCLUSIONS/INTERPRETATION: Delayed menarche was associated with an increased risk of diabetic nephropathy and retinopathy, whereas early menarche was not. Delayed menarche may be used as a new tool to identify women at risk of diabetic microvascular complications. PMID- 26607637 TI - The impact of gender on the long-term morbidity and mortality of patients with type 2 diabetes receiving structured personal care: a 13 year follow-up study. AB - AIMS/HYPOTHESIS: The aim of this study was to assess gender differences in mortality and morbidity during 13 follow-up years after 6 years of structured personal care in patients with type 2 diabetes mellitus. METHODS: In the Diabetes Care in General Practice (DCGP) multicentre, cluster-randomised, controlled trial (ClinicalTrials.gov registration no. NCT01074762), 1,381 patients newly diagnosed with type 2 diabetes were randomised to receive 6 years of either structured personal care or routine care. The intervention included regular follow-up, individualised goal setting and continuing medical education of general practitioners participating in the intervention. Patients were re-examined at the end of intervention. This observational analysis followed 970 patients for 13 years thereafter using national registries. Outcomes were all-cause mortality, incidence of diabetes-related death, any diabetes-related endpoint, myocardial infarction, stroke, peripheral vascular disease and microvascular disease. RESULTS: In women, but not men, a lower HR for structured personal care vs routine care emerged for any diabetes-related endpoint (0.65, p = 0.004, adjusted; 73.4 vs 107.7 events per 1,000 patient-years), diabetes-related death (0.70, p = 0.031; 34.6 vs 45.7), all-cause mortality (0.74, p = 0.028; 55.5 vs 68.5) and stroke (0.59, p = 0.038; 15.6 vs 28.9). This effect was different between men and women for diabetes-related death (interaction p = 0.015) and all cause mortality (interaction p = 0.005). CONCLUSIONS/INTERPRETATION: Compared with routine care, structured personal diabetes care reduced all-cause mortality and diabetes-related death in women but not in men. This gender difference was also observed for any diabetes-related outcome and stroke but was not statistically significant after extensive multivariate adjustment. These observational results from a post hoc analysis of a randomised controlled trial cannot be explained by intermediate outcomes like HbA1c alone, but involves complex social and cultural issues of gender. There is a need to rethink treatment schemes for both men and women to gain benefit from intensified treatment efforts. PMID- 26607638 TI - Increased fat cell size: a major phenotype of subcutaneous white adipose tissue in non-obese individuals with type 2 diabetes. AB - AIMS/HYPOTHESIS: We aimed to elucidate the impact of fat cell size and inflammatory status of adipose tissue on the development of type 2 diabetes in non-obese individuals. METHODS: We characterised subcutaneous abdominal adipose tissue by examining stromal cell populations by 13 colour flow cytometry, measuring expression of adipogenesis genes in the progenitor cell fraction and determining lipolysis and adipose secretion of inflammatory proteins in 14 non obese men with type 2 diabetes and 13 healthy controls matched for age, sex, body weight and total fat mass. RESULTS: Individuals with diabetes had larger fat cells than the healthy controls but stromal cell population frequencies, adipose lipolysis and secretion of inflammatory proteins did not differ between the two groups. However, in the entire cohort fat cell size correlated positively with the ratio of M1/M2 macrophages, TNF-alpha secretion, lipolysis and insulin resistance. Expression of genes encoding regulators of adipogenesis and adipose morphology (BMP4, CEBPalpha [also known as CEBPA], PPARgamma [also known as PPARG] and EBF1) correlated negatively with fat cell size. CONCLUSIONS/INTERPRETATION: We show that a major phenotype of white adipose tissue in non-obese individuals with type 2 diabetes is adipocyte hypertrophy, which may be mediated by an impaired adipogenic capacity in progenitor cells. Consequently, this could have an impact on adipose tissue inflammation, release of fatty acids, ectopic fat deposition and insulin sensitivity. PMID- 26607639 TI - Exploring an increased role for Australian community pharmacy in mental health professional service delivery: evaluation of the literature. AB - BACKGROUND: Australian general practitioners primarily treat mental health problems by prescribing medication dispensed by community pharmacists. Pharmacists therefore have regular interactions with mental health consumers and carers. AIMS: This narrative review explored the potential role of community pharmacy in mental health services. METHOD: Medline, CINAHL, ProQuest, Emerald, PsycINFO, Science Direct, PubMed, Web of Knowledge and IPA were utilised. The Cochrane Library as well as grey literature and "lay" search engines such as GoogleScholar were also searched. RESULTS: Four systematic reviews and ten community pharmacy randomised controlled trials were identified. Various relevant reviews outlining the impact of community pharmacy based disease state or medicines management services were also identified. CONCLUSION: International studies involving professional service interventions for mental health consumers could be contextualised for the Australian setting. Australian studies of pharmacy professional services for chronic physical health conditions provided further guidance for the expansion of community pharmacy mental health professional services. PMID- 26607641 TI - Ultrasound imaging-guided percutaneous treatment of rotator cuff calcific tendinitis: success in short-term outcome. AB - OBJECTIVE: Rotator cuff calcific tendinitis (RCCT) is a common cause of shoulder pain in adults and typically presents as activity-related shoulder pain. Between non-surgical and surgical treatment options, today a few minimal invasive techniques are available to remove the calcific deposit, and they represent a cornerstone in the management of this painful clinical condition. The aim of the work was a retrospective evaluation of double-needle ultrasound-guided percutaneous fragmentation and lavage (DNL), focused on understanding the factors which are of major importance in determining a quick and good response at 1 month. METHODS: A series of 147 patients affected by RCCT and suitable for DNL were evaluated. A systematic review of anamnestic, clinical and imaging data was performed in 144 shoulders treated in a single-centre setting. Clinical reports and imaging examinations were revisited. The inclusion criteria were submission to DNL, therefore fitness for the percutaneous procedure, and following 1-month follow-up. There was no exclusion owing to risk of bias. The treatment was defined as successful for constant shoulder modified score (CSS) improvement of >50% at 1 month. RESULTS: In 70% of shoulders, the treatment resulted in a quick and significant reduction of symptoms (successful). On the whole, CSS increase at 1 month was estimated at 91.5 +/- 69.1%. CSS variations were significantly related to age of patients (better results between 30 and 40 years old), calcification size (more relevant improvement for middle-sized calcifications, 12 17 mm), sonographic and radiographic features of calcific deposits (softer calcifications) and thickening of subacromial/subdeltoid bursa walls. In the final model of stepwise regression for CSS variation, ultrasound score pre treatment and post-treatment, the distance between bursa and calcification before treatment and the size of post-treatment calcification area were shown to be independently correlated to success. Numeric rating scale score for pain showed similar results. Pain at admission was also related to age, calcification size, ultrasound and Gartner score, power Doppler positivity, bursal wall thickening and biceps tenosynovitis. CONCLUSION: The success of the procedure with quick improvement in function and symptoms is warranted in soft and middle-sized calcifications, in young adults. ADVANCES IN KNOWLEDGE: Ultrasound-guided percutaneous procedures for RCCT must be safe, effective and with prompt pain relief and function restoration. This study shows which clinical picture is more favourable to this purpose and actual prognostic factors for DNL (soft and middle sized calcifications, in young adults, are more favourable). PMID- 26607640 TI - MRI-guided focused ultrasound surgery in musculoskeletal diseases: the hot topics. AB - MRI-guided focused ultrasound surgery (MRgFUS) is a minimally invasive treatment guided by the most sophisticated imaging tool available in today's clinical practice. Both the imaging and therapeutic sides of the equipment are based on non-ionizing energy. This technique is a very promising option as potential treatment for several pathologies, including musculoskeletal (MSK) disorders. Apart from clinical applications, MRgFUS technology is the result of long, heavy and cumulative efforts exploring the effects of ultrasound on biological tissues and function, the generation of focused ultrasound and treatment monitoring by MRI. The aim of this article is to give an updated overview on a "new" interventional technique and on its applications for MSK and allied sciences. PMID- 26607642 TI - Phase I study of topical epigallocatechin-3-gallate (EGCG) in patients with breast cancer receiving adjuvant radiotherapy. AB - OBJECTIVE: The purpose of this study was to investigate the safety, tolerability and preliminary effectiveness of topical epigallocatechin-3-gallate (EGCG) for radiation dermatitis in patients with breast cancer receiving adjuvant radiotherapy. METHODS: Patients with breast cancer who received radiotherapy to the chest wall after mastectomy were enrolled. EGCG solution was sprayed to the radiation field from the initiation of Grade 1 radiation dermatitis until 2 weeks after completion of radiotherapy. EGCG concentration escalated from 40 to 660 MUmol l(-1) in 7 levels with 3-6 patients in each level. EGCG toxicity was graded using the NCI (National Cancer Institute Common Terminology Criteria for Adverse Events) v. 3.0. Any adverse event >Grade 1 attributed to EGCG was considered dose limiting toxicity. The maximum tolerated dose was defined as the dose level that induced dose-limiting toxicity in more than one-third of patients at a given cohort. Radiation dermatitis was recorded weekly by the Radiation Therapy Oncology Group scoring and patient-reported symptoms. RESULTS: From March 2012 to August 2013, 24 patients were enrolled. Acute skin redness was observed in 1 patient and considered to be associated with the EGCG treatment at 140 MUmol l( 1) level. Three more patients were enrolled at this level and did not experience toxicity to EGCG. The dose escalation stopped at 660 MUmol l(-1). No other reported acute toxicity was associated with EGCG. Grade 2 radiation dermatitis was observed in eight patients during or after radiotherapy, but all decreased to Grade 1 after EGCG treatments. Patient-reported symptom scores were significantly decreased at 2 weeks after the end of radiotherapy in pain, burning, itching and tenderness, p < 0.05. CONCLUSION: The topical administration of EGCG was well tolerated and the maximum tolerated dose was not found. EGCG may be effective in treating radiation dermatitis with preliminary investigation. ADVANCES IN KNOWLEDGE: EGCG solution seemed to be feasible for treating radiation dermatitis in patients with breast cancer after mastectomy. It should be tested as a way to reduce radiation-induced normal tissue toxicity and complications in future years. PMID- 26607643 TI - Determination of regional lymph node status using (18)F-FDG PET/CT parameters in oesophageal cancer patients: comparison of SUV, volumetric parameters and intratumoral heterogeneity. AB - OBJECTIVE: We aimed to investigate whether the standardized uptake values, volumetric parameters and intratumoral heterogeneity of fluorine-18 fludeoxyglucose ((18)F-FDG) uptake could predict regional lymph node (rLN) metastasis in oesophageal cancer. METHODS: 51 patients with surgically resected oesophageal cancer were included in the present study. The (18)F-FDG positron emission tomography (PET)/CT findings and rLN metastasis were compared with the histopathological results. The intratumoral metabolic heterogeneity was represented by the heterogeneity factor (HF), which was determined for each patient. Univariate and multivariate analyses were used to analyse the associations between the rLN metastasis and clinical findings, standardized uptake values, metabolic tumour volume (MTV), total lesion glycolysis (TLG) and HF. RESULTS: The rLN(+) group showed statistically significant higher values of MTV (median, 13.59 vs 6.6; p = 0.0085), TLG (median, 119.18 vs 35.96; p = 0.0072) and HF (median, 3.07 vs 2.384; p = 0.0002) than the rLN(-) group. Univariate analysis showed that maximum standardized uptake value, mean standardized uptake value, MTV, TLG and HF were significantly associated with pathologic rLN involvement. However, in multivariate analysis, the HF was a potent associated factor for the prediction of pathologic rLN metastasis in oesophageal cancer. CONCLUSION: In conclusion, (18)F-FDG PET/CT parameters such as maximum standardized uptake value, mean standardized uptake value, MTV, TLG and HF were useful for the prediction of pathologic rLN status in patients with oesophageal cancer. However, HF might be the most powerful predictor of rLN metastasis of patients with oesophageal cancer. ADVANCES IN KNOWLEDGE: Assessment of intratumoral heterogeneity of (18)F-FDG PET/CT may be a useful adjunct for rLN staging of oesophageal cancer. PMID- 26607644 TI - High-resolution CT findings of pulmonary Mycobacterium tuberculosis infection in renal transplant recipients. AB - OBJECTIVE: Renal transplantation recipients are at increased risk of Mycobacterium tuberculosis infection because of immunosuppression. The aim of this study was to assess high-resolution CT (HRCT) findings in renal transplantation recipients diagnosed with pulmonary tuberculosis (TB). METHODS: We reviewed HRCT findings from patients diagnosed with pulmonary TB, established by M. tuberculosis detection in bronchoalveolar lavage, sputum or biopsy sample. Two observers independently reviewed HRCT images and reached consensus decisions on the presence and distribution of: (i) miliary nodules, (ii) cavitation and centrilobular tree-in-bud nodules, (iii) ground-glass attenuation and consolidation, (iv) mediastinal lymph node enlargement and (v) pleural effusion. RESULTS: The sample comprised 40 patients [26 males, 14 females; median age, 45 years (range, 12-69 years)]. The main HRCT pattern was miliary nodules (40%), followed by cavitation and centrilobular tree-in-bud nodules (22.5%), ground glass attenuation and consolidation (15%), mediastinal lymph node enlargement (12.5%) and pleural effusion (10%). The distribution of findings in patients with miliary nodules was random. In patients with cavitation and centrilobular tree-in bud nodules, 66.6% of abnormalities were found in the upper lobes. Pleural effusion was unilateral in 75% of cases. The overall mortality rate was 27.5%. This rate was 50% in patients with miliary nodules, and 72.6% of all deaths occurred in this group. Thus, mortality was increased significantly in patients with miliary nodules (p < 0.05). CONCLUSION: The main HRCT finding in renal transplantation recipients with pulmonary TB was miliary nodules, followed by cavitation and centrilobular tree-in-bud nodules. Miliary nodules were associated with a worse prognosis in these patients. ADVANCES IN KNOWLEDGE: We report the first series on HRCT findings of microbiologically confirmed pulmonary TB exclusively in renal transplantation recipients. The main HRCT finding was miliary nodules, and mortality was increased significantly in these patients. PMID- 26607645 TI - The frequency of incidental pulmonary embolism in different CT examinations. AB - OBJECTIVE: Pulmonary embolism (PE) is commonly found in patients with oncologic and non-oncologic disease. The aim of the present study is to assess how frequently suspected, incidental and unreported PE occurs in particular CT examinations. In addition, differences in embolus distribution are to be considered. METHODS: In a retrospective, single-centre study that covered a 5.5 year period, every contrast-enhanced CT examination was reviewed. The study group included 7238 patients with 11,747 CT examinations. A detailed pulmonary artery obstruction index (Mastora score) was used to assess thrombus mass and distribution. RESULTS: PE frequency was 3.9% in oncologic patients and 6.6% in non-oncologic patients. PE was unsuspected in 54% of all PE events. Incidental PE was mostly often found in the following CT examinations: evaluation of acute pulmonary disease and follow-up staging. The thrombus mass was higher in non oncologic patients than in oncologic patients. Furthermore, the thrombus mass was significantly lower in unsuspected PE than in suspected PE. In addition, the thrombus mass was significantly lower in unreported PE than in incidental PE. CONCLUSION: The radiologist should pay special attention to pulmonary vessels, even when not asked for PE, in the following CT examinations: evaluation of acute pulmonary disease and follow-up staging. ADVANCES IN KNOWLEDGE: Particular CT indications are associated with a high frequency of PE. Whether PE is suspected or not and found or not highly depends on thrombus mass. PMID- 26607646 TI - Feasibility study of low tube voltage (80 kVp) coronary CT angiography combined with contrast medium reduction using iterative model reconstruction (IMR) on standard BMI patients. AB - OBJECTIVE: To investigate the feasibility of low-tube-voltage (80 kVp) coronary CT angiography (CCTA) combined with contrast medium (CM) reduction and iterative model reconstruction (IMR) on patients with standard body mass index compared with clinical routine protocol. METHODS: Retrospectively gated helical CCTA scans were acquired using a 256-slice multi-slice CT (Brilliance iCT; Philips Healthcare, Cleveland, OH) on 94 patients with standard body mass index (20-25 kg m(-2)) who were randomly assigned into 2 groups. The scan protocol for Group 1 was 100 kVp and 600 mAs with 70 ml CM at an injection rate of 4.5-5.5 ml s(-1); images were reconstructed by a hybrid iterative reconstruction technique (iDose(4); Philips Healthcare). Group 2 was scanned at 80 kVp and 600 mAs with 35 ml CM at an injection rate of 3.5-4.5 ml s(-1); images were reconstructed with IMR. Objective measurements such as the mean image noise and contrast-to-noise ratio of the two groups were measured on CT images and compared using the paired t-test. In addition, a subjective image quality evaluation was performed by two radiologists who were blinded to the scan protocol, using a 5-point scale [1 (poor) to 5 (excellent)]. The results of the two groups were compared using Mann Whitney U test. RESULTS: The iodine delivery rate of Group 2 was 1.0 +/- 0.5 gI s(-1) compared with 2.1 +/- 0.5 gI s(-1) in Group 1 resulting in a reduction of 52.4%. In addition, an effective radiation dose reduction of 56.4% was achieved in Group 2 (2.4 +/- 1.2 mSv) compared with Group 1 (5.5 +/- 1.4 mSv). The mean CT attenuation, contrast-to-noise ratio and image quality of all segments in Group 2 were significantly improved compared with those in Group 1 (all, p < 0.01). CONCLUSION: The use of IMR along with a low tube voltage (80 kVp) combined with a low CM protocol for CCTA can reduce both radiation and CM dose with improved image quality. ADVANCES IN KNOWLEDGE: In this study, we used a novel knowledge based IMR which remarkably reduced the image noise. We compared the quality of the images obtained when the tube voltage was reduced to 80 kVp and that of those obtained according to the clinical routine protocols to determine whether ultra low-dose imaging plus IMR is feasible in CCTA scans. We found that a low dose protocol combined with 80 kVp and reduced CM for CCTA can reduce both radiation dose and CM dose with improved image quality by the use of IMR in non-obese patients. PMID- 26607647 TI - Contrast-enhanced ultrasound (CEUS) in blunt abdominal trauma. AB - Baseline ultrasound is essential in the early assessment of patients with a huge haemoperitoneum undergoing an immediate abdominal surgery; nevertheless, even with a highly experienced operator, it is not sufficient to exclude parenchymal injuries. More recently, a new ultrasound technique using second generation contrast agents, named contrast-enhanced ultrasound (CEUS) has been developed. This technique allows all the vascular phase to be performed in real time, increasing ultrasound capability to detect parenchymal injuries, enhancing some qualitative findings, such as lesion extension, margins and its relationship with capsule and vessels. CEUS has been demonstrated to be almost as sensitive as contrast-enhanced CT in the detection of traumatic injuries in patients with low energy isolated abdominal trauma, with levels of sensitivity and specificity up to 95%. Several studies demonstrated its ability to detect lesions occurring in the liver, spleen, pancreas and kidneys and also to recognize active bleeding as hyperechoic bands appearing as round or oval spots of variable size. Its role seems to be really relevant in paediatric patients, thus avoiding a routine exposure to ionizing radiation. Nevertheless, CEUS is strongly operator dependent, and it has some limitations, such as the cost of contrast media, lack of panoramicity, the difficulty to explore some deep regions and the poor ability to detect injuries to the urinary tract. On the other hand, it is timesaving, and it has several advantages, such as its portability, the safety of contrast agent, the lack to ionizing radiation exposure and therefore its repeatability, which allows follow-up of those traumas managed conservatively, especially in cases of fertile females and paediatric patients. PMID- 26607648 TI - Imaging minor head injury (MHI) in emergency radiology: MRI highlights additional intracranial findings after measurement of trauma biomarker S-100B in patients with normal CCT. AB - OBJECTIVE: To investigate whether MRI in emergency radiology can detect (a) additional trauma-related findings after minor head injury (MHI) or (b) structural, non-trauma-related intracranial lesions when trauma biomarker S-100B concentration is raised, or clinical symptoms are unexplained, or both. METHODS: 41 patients with MHI were included. Concentrations of S-100B in serum were measured and categorized using an established cut-off at 0.1 MUg l(-1). Intracerebral trauma-related as well as non-trauma-related chronic structural findings (atrophy, microangiopathy and chronic parenchymal defects) were assessed by cranial CT (CCT) and MRI by two independent radiologists (UL and LLG). All CCT and MRI results were compared with biomarker S-100B. RESULTS: Compared with CCT, MRI detected 10 additional lesions. 5 patients had abnormal MRI with a total of 15 trauma-related lesions and showed elevated S-100B concentrations. Although sensitivity of S-100B was 100%, specificity was only 25%. Patients with structural brain lesions showed significantly higher S-100B serum levels (0.50 and 0.14 MUg l(-1), p = 0.01). CONCLUSION: Biomarker S-100B has proven its high negative-predictive value to rule out intracranial bleeding in patients after MHI even if MRI is used as imaging modality. Regarding the low specificity of S-100B, structural lesions of the brain parenchyma not related to the acute trauma may be associated with increased serum concentrations of protein S-100B. ADVANCES IN KNOWLEDGE: Biomarker S-100B has a high negative-predictive value to rule out intracranial bleeding after MHI. Biomarker S-100B's low specificity may be associated with non-traumatic brain parenchyma lesions. MRI is superior to CCT in detecting subtle findings in neuroimaging after MHI. Biomarker S-100B can potentially reduce the large number of normal CCT studies after MHI. PMID- 26607649 TI - Detailed description of anatomy of the fracture line in hangman's injury: a retrospective observational study on motor vehicle accident victims. AB - OBJECTIVE: To study the precise location of fracture line in hangman's fracture to determine the fracture patterns, symmetry and involvement of different vertebral elements. METHODS: 32 cases of hangman's fractures were retrospectively evaluated. All patients presented with motor vehicle accidents. CT scans were studied to accurately localize the fracture lines. Symmetry of fracture lines on both sides was assessed, and involvement of the vertebral bodies, lamina, facet joints and foramen transversarium was also determined. RESULTS: 20 patients showed asymmetric fracture locations, 13 of them had a unilateral pedicle fracture and a contralateral pars fracture which comprised the most common injury pattern (40% of cases). Less frequent combinations for the two sides of asymmetric C2 ring disruption include pars-vertebral body (3 patients), pedicle vertebral body (2 patients) and pedicle-lamina (2 patients). 12 patients showed symmetrical fractures (5 through the pars and 7 through the pedicles). Vertebral body and facet joint involvement were demonstrated in 15 (47%) and 16 (50%) cases, respectively. 18 cases had fractures extending into the foramen transversarium (56%). In total, 26 fracture lines primarily affected the pars (40%) and 31 affected the pedicles (49%). CONCLUSION: Asymmetric hangman's fracture is more common with the usual pattern being fracture pedicle on one side and pars on the other followed by the symmetric bilateral pedicle and bilateral pars fractures. Fracture lines running into the transverse foramen and facet joints are very frequent as well as those involving the vertebral bodies. ADVANCES IN KNOWLEDGE: There is controversy in literature regarding the fracture locations in hangman's injury owing to lack of studies that address this subject. This article is the first to describe precisely the anatomical locations and patterns of this injury. PMID- 26607651 TI - Emergency radiology in the United States--a stepchild finding its way. AB - Emergency radiology as an academic discipline and practice activity is clearly recognized as a distinct category within the community of radiologists in the USA. But, its place among the other branches of diagnostic imaging is as an outlier. Emergency radiology is not recognized as a separate course of study in the curriculum of training. It is not a component of the qualifying exam of the American Board of Radiology. It has few fellowships. It has not engendered a specific designation of care personnel for trauma centres. Moreover, its situation with respect to emergency physicians is bound, by neither regulation nor tradition, to be intellectually or physically close. Yet, it is recognized as encompassing an established society of teachers, practitioners and investigators. Its journal is a repository of new knowledge. Thus, it occupies a definitive if still anomalous position in American medicine in general and radiology in particular. PMID- 26607650 TI - MDCT imaging of traumatic brain injury. AB - The aim of emergency imaging is to detect treatable lesions before secondary neurological damage occurs. CT plays a primary role in the acute setting of head trauma, allowing accurate detection of lesions requiring immediate neurosurgical treatment. CT is also accurate in detecting secondary injuries and is therefore essential in follow-up. This review discusses the main characteristics of primary and secondary brain injuries. PMID- 26607652 TI - Interventional MSK special feature: an introduction. PMID- 26607653 TI - Distinguished prognosis after hepatectomy of HBV-related hepatocellular carcinoma with or without cirrhosis: a long-term follow-up analysis. AB - BACKGROUND: Conflicting results have often been observed for the prognosis of hepatocellular carcinoma (HCC) patients, but few studies have attempted to explore the reasons for the conflicting results. We aimed to distinguish the prognosis of patients with HCC with cirrhosis (HCC-C) and that of patients with HCC without cirrhosis (HCC-NC). METHODS: Patients with hepatitis B virus (HBV) associated HCC treated by curative liver resection at a single institution between 1995 and 2013 were retrospectively evaluated. Kaplan-Meier and multivariate analyses were performed to identify risk factors, including tumor related factors, hypoxia-inducible factor 1alpha expression, HBV X protein (HBx) expression, and HBx double mutations for overall survival and recurrence-free survival in these patients. RESULTS: The long-term prognosis of HCC-NC patients is better than that of HCC-C patients. Male sex, poor differentiation, preoperative serum alanine aminotransferase level greater than 80 IU/L, and alpha fetoprotein level greater than 400 ng/mL were risk factors for overall survival among HCC-NC patients but not among HCC-C patients, and age greater than 50 years was associated with poor overall survival only in cirrhotic patients. HCC-C patients benefit more from antiviral therapy following curative hepatectomy than do HCC-NC patients. The clinical value of the biomarkers hypoxia-inducible factor 1alpha, HBx, and HBx double mutations for predicting HCC prognosis was significantly different between these two groups. CONCLUSIONS: There were differences in tumor-related prognostic factors, effectiveness of the antiviral therapy after hepatectomy, and biomarkers between HCC-C and HCC-NC patients, indicating that subgroup analysis of the prognostic factors may result in better management of HCC and that HCC patients, especially those with liver cirrhosis, should be given antiviral therapy. PMID- 26607655 TI - Vascular risk levels affect the predictive value of platelet reactivity for the occurrence of MACE in patients on clopidogrel. Systematic review and meta analysis of individual patient data. AB - Prior studies have shown an association between high on-clopidogrel platelet reactivity (PR) and the risk of major adverse cardiovascular events (MACE). However, large intervention trials on PR-tailored treatments have been neutral. The role and usefulness of PR with regard to levels of cardiovascular risk are unclear. We undertook a systematic review and meta-analysis of individual patient data on MACE outcomes (acute coronary syndromes (ACS), ischaemic strokes, and vascular deaths) in relation to PR and its interaction with cardiovascular risk levels. PR was determined using ADP-induced light transmission aggregometry with a primary concentration of 20 uM ADP. Thirteen prospective studies totaled 6,478 clopidogrel-treated patients who experienced 421 MACE (6.5 %) during a median follow-up of 12 months. The strength of the association between the risk of MACE and PR increased significantly (p=0.04) with the number of risk factors present (age> 75 years, ACS at inclusion, diabetes, and hypertension). No association was detected in patients with no risk factor (p=0.48). In patients presenting one risk factor, only high-PR was associated with an increased risk of MACE (HR 3.2, p=0.001). In patients presenting >= 2 risk factors, the increase of risk started from medium-PR (medium-PR: HR=2.9, p=0.0004; high-PR: HR=3.7, p=0.0003). PR allowed the reclassification of 44 % of the total population to a different risk level for the outcome of MACE, mostly in intermediate or high risk patients. In conclusion, the magnitude of the association between PR and MACE risk is strongly dependent on the level of cardiovascular risk faced by patients on clopidogrel. PMID- 26607657 TI - WHO's role in Ebola crisis is criticised by all sides. PMID- 26607656 TI - Genetic polymorphisms of PCSK2 are associated with glucose homeostasis and progression to type 2 diabetes in a Chinese population. AB - Proprotein convertase subtilisin/kexin type 2 (PCSK2) is a prohormone processing enzyme involved in insulin and glucagon biosynthesis. We previously found the genetic polymorphism of PCSK2 on chromosome 20 was responsible for the linkage peak of several glucose homeostasis parameters. The aim of this study is to investigate the association between genetic variants of PCSK2 and glucose homeostasis parameters and incident diabetes. Total 1142 Chinese participants were recruited from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study, and 759 participants were followed up for 5 years. Ten SNPs of the PCSK2 gene were genotyped. Variants of rs6044695 and rs2284912 were associated with fasting plasma glucose, and variants of rs2269023 were associated with fasting plasma glucose and 1-hour plasma glucose during OGTT. Haplotypes of rs4814605/rs1078199 were associated with fasting plasma insulin levels and HOMA-IR. Haplotypes of rs890609/rs2269023 were also associated with fasting plasma glucose, fasting insulin and HOMA-IR. In the longitudinal study, we found individuals carrying TA/AA genotypes of rs6044695 or TC/CC genotypes of rs2284912 had lower incidence of diabetes during the 5-year follow up. Our results indicated that PCSK2 gene polymorphisms are associated with pleiotropic effects on various traits of glucose homeostasis and incident diabetes. PMID- 26607658 TI - Repurposed therapeutic agents targeting the Ebola virus: a protocol for a systematic review. AB - BACKGROUND: The recent Ebola epidemic in western Africa developed into an acute public health emergency of unprecedented level in modern times. The treatment provided in most cases has been limited to supportive care, as no approved therapies are available to date. Several established, licenced drugs have been suggested as potential repurposed therapeutic agents for Ebola. However, scientific data on their efficacy in treating Ebola is limited. The purpose of this review is to systematically assess scientific evidence on potential drugs targeting Ebola. In specific, we aim to (1) identify drug library screens involving therapeutic agents targeting the Ebola virus, (2) list potential approved drugs identified from drug screens and review their mechanism of action against the Ebola virus and (3) summarise the outcome of preclinical and clinical trials investigating approved drugs targeting the Ebola virus. METHODS/DESIGN: We will develop comprehensive systematic search strategies and will perform a systematic literature search in MEDLINE, Embase and Cochrane Central Register of Controlled Trials (CENTRAL). Two authors will independently screen the titles, abstracts and the references of all selected articles on the basis of inclusion criteria. These include any available drug screening, preclinical studies and clinical studies examining the efficacy of approved therapeutic agents targeting the Ebola virus. There will be no restrictions on the type of participants, the type of comparator, time or setting. Data extraction and quality assessment will be undertaken by two review authors working independently. DISCUSSION: This systematic review will provide systematic knowledge on potential repurposed therapeutic agents targeting Ebola. It aims to help guide future investigations on repurposed drugs and avoid repetitive studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015024349. PMID- 26607659 TI - How Much Can We Learn from a Single Chromatographic Experiment? A Bayesian Perspective. AB - In this work, we proposed and investigated a Bayesian inference procedure to find the desired chromatographic conditions based on known analyte properties (lipophilicity, pKa, and polar surface area) using one preliminary experiment. A previously developed nonlinear mixed effect model was used to specify the prior information about a new analyte with known physicochemical properties. Further, the prior (no preliminary data) and posterior predictive distribution (prior + one experiment) were determined sequentially to search towards the desired separation. The following isocratic high-performance reversed-phase liquid chromatographic conditions were sought: (1) retention time of a single analyte within the range of 4-6 min and (2) baseline separation of two analytes with retention times within the range of 4-10 min. The empirical posterior Bayesian distribution of parameters was estimated using the "slice sampling" Markov Chain Monte Carlo (MCMC) algorithm implemented in Matlab. The simulations with artificial analytes and experimental data of ketoprofen and papaverine were used to test the proposed methodology. The simulation experiment showed that for a single and two randomly selected analytes, there is 97% and 74% probability of obtaining a successful chromatogram using none or one preliminary experiment. The desired separation for ketoprofen and papaverine was established based on a single experiment. It was confirmed that the search for a desired separation rarely requires a large number of chromatographic analyses at least for a simple optimization problem. The proposed Bayesian-based optimization scheme is a powerful method of finding a desired chromatographic separation based on a small number of preliminary experiments. PMID- 26607660 TI - Ultrasound-guided peripheral deep vein cannulation to perform automated red cell exchange-A pilot study in a single centre. AB - BACKGROUND: Securing adequate vascular access is essential for a successful apheresis procedure. In most, peripheral access is preferred but it is not always technically possible. Ultrasound-Guided Peripheral Vascular Access (USG-PIVA) is a well-documented technique in the setting of Emergency departments. However, limited data exists reporting its use in the context of automated red cell exchanges (a-RCEx). PURPOSE: To assess the effectiveness and feasibility of USG PIVA to undertake successful a-RCEx. METHODS: Data was collected prospectively from patients with sickle cell disease and difficult venous access, undergoing a RCEx at a single centre. The USG-PIVA technique was attempted and data relating to each attempt was collected and analysed. RESULTS: Between April 2014 and July 2015 84 USG-PIVA procedures were performed on 38 patients. 71 USG-PIVA (85%) were successful, 13 (15%) were unsuccessful. Veins successfully cannulated: in the upper arm, basilic (22), brachial (33) and cephalic (2) veins; in the antecubital fossa, basilic (3) and median cubital (7) and in the lower arm, cephalic (2) and radial (2). Cannulas used: Introcan Safety(r) Braun 22 g (1), 20 g (9) and 18 g (61). Inlet flow rates achieved: 30-60 ml/min (mean 45 ml/min). Depth of veins cannulated: 2-12 mm (mean 5 mm). two complications were observed-one cannula displacement and one nerve injury. No arterial punctures occurred. Central Venous Catheters avoided (49). CONCLUSION: The US-PIVA method offers an effective alternative to Central Venous Access in patients requiring a-RCEx procedures who lack visual or palpable peripheral access, with minimal complications seen in this series. J. Clin. Apheresis 31:501-506, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26607662 TI - Catheter-Related Bloodstream Infections in Patients on Emergent Hemodialysis. AB - OBJECTIVE: This study had 2 objectives: (1) to describe the epidemiology of catheter-related bloodstream infections (CRBSI) in patients with end-stage renal disease (ESRD) who have no access to scheduled dialysis and (2) to evaluate whether a positive culture of the heparin-lock solution is associated with subsequent development of bacteremia. DESIGN: Retrospective observational cohort design for objective 1; and prospective cohort design for objective 2. SETTING AND PARTICIPANTS: The study was conducted in a 770-bed public academic tertiary hospital in Dallas, Texas. The participants were patients with ESRD undergoing scheduled or emergent hemodialysis. METHODS: We reviewed the records of 147 patients who received hemodialysis between January 2011 and May 2011 and evaluated the rate of CRBSI in the previous 5 years. For the prospective study, we cultured the catheter heparin-lock solution in 62 consecutive patients between June 2012 and August 2012 and evaluated the incidence of CRBSI at 6 months. RESULTS: Of the 147 patients on emergent hemodialysis, 125 had a tunneled catheter, with a CRBSI rate of 2.61 per 1,000 catheter days. The predominant organisms were Gram-negative rods (GNR). In the prospective study, we found that the dialysis catheter was colonized more frequently in patients on emergent hemodialysis than in those on scheduled hemodialysis. Colonization with GNR or Staphylococcus aureus was associated with subsequent CRBSI at 6 months follow-up. CONCLUSIONS: Patients undergoing emergent hemodialysis via tunneled catheter are predisposed to Gram-negative CRBSI. Culturing the heparin-lock solution may predict subsequent episodes of CRBSI if it shows colonization with GNR or Staphylococcus aureus. Prevention approaches in this population need to be studied further. PMID- 26607661 TI - SLCO1B1 Variants and Angiotensin Converting Enzyme Inhibitor (Enalapril)-Induced Cough: a Pharmacogenetic Study. AB - Clinical observations suggest that incidence of cough in Chinese taking angiotensin converting enzyme inhibitors is much higher than other racial groups. Cough is the most common adverse reaction of enalapril. We investigate whether SLCO1B1 genetic polymorphisms, previously reported to be important determinants of inter-individual variability in enalapril pharmacokinetics, are associated with the enalapril-induced cough. A cohort of 450 patients with essential hypertension taking 10 mg enalapril maleate were genotyped for the functional SLCO1B1 variants, 388A > G (Asn130Asp, rs2306283) and 521T > C (Val174Ala, rs4149056). The primary endpoint was cough, which was recorded when participants were bothered by cough and respiratory symptoms during enalapril treatment without an identifiable cause. SLCO1B1 521C allele conferred a 2-fold relative risk of enalapril-induced cough (95% confidence interval [CI] = 1.34-3.04, P = 6.2 * 10(-4)), and haplotype analysis suggested the relative risk of cough was 6.94-fold (95% CI = 1.30-37.07, P = 0.020) in SLCO1B1*15/*15 carriers. Furthermore, there was strong evidence for a gene-dose effect (percent with cough in those with 0, 1, or 2 copy of the 521C allele: 28.2%, 42.5%, and 71.4%, trend P = 6.6 * 10(-4)). Our study highlights, for the first time, SLCO1B1 variants are strongly associated with an increased risk of enalapril-induced cough. The findings will be useful to provide pharmacogenetic markers for enalapril treatment. PMID- 26607663 TI - The uses of Kenyan aloes: an analysis of implications for names, distribution and conservation. AB - BACKGROUND: The genus Aloe is renowned for its medicinal and cosmetic properties and long history of use. Sixty-three Aloe species occur in Kenya, of which around 50 % are endemic. Several species of aloes are threatened with extinction and knowledge about their use is of major importance for sound conservation strategies. The main aims of this study were to assess the biocultural value of Aloe in Kenya by documenting local uses of aloes and evaluating how the vernacular names reflect the relative importance in different ethnic groups. METHODS: Ethnobotanical and ethnotaxonomical data were collected using field observations and semi-structured interviews. Information was collected by interviewing 63 respondents from nine different ethnic groups, representing different ages, gender and occupations. Statistical analyses were performed using R version 3.1.2. RESULTS: A total of 19 species of Aloe were found in the study area, of which 16 were used. On the generic level Aloe was easily distinguished. At species level, the local and scientific delimitation were almost identical for frequently used taxa. Aloe secundiflora, with 57 unique use records was the most important species. The two most frequently mentioned Aloe treatments, were malaria and poultry diseases. In our study area neither age nor gender had a significant influence on the level of knowledge of Aloe use. Finally, no correlation was found between extent of use and people's perception of decrease in local aloe populations. The aloes are highly appreciated and are therefore propagated and transported over large areas when people relocate. CONCLUSION: Biocultural value is reflected in the ethnotaxonomy of Aloe in Kenya. Different ethnic groups recognise their most-valued Aloe at the genus level as "the aloe" and add explanatory names for the other species, such as the "spotted aloe" and the "one-legged aloe". Widespread species of Aloe have the highest number of uses. There is no obvious correlation with high use and decrease in abundance of aloes locally, and we found no compelling evidence for local uses causing devastating damage to populations of the 19 species in use, whereas habitat loss and commercial harvesting appear to be of urgent concern for these important plants. PMID- 26607665 TI - The Malay version of the Early Childhood Oral Health Impact Scale (Malay-ECOHIS)- assessing validity and reliability. AB - BACKGROUND: The Early Childhood Oral Health Impact Scale (ECOHIS) is used to assess oral impacts on the quality of life of preschool aged children and their families. The objective of this study was to perform a cross-cultural adaptation of the ECOHIS into Malay and assess its psychometric properties. METHODS: The cross-cultural adaptation of ECOHIS into Malay comprised of translating the ECOHIS into the Malay language (Malay-ECOHIS) by experts followed by face validation of the Malay-ECOHIS by a group of mothers. The Malay-ECOHIS was back translated into English and this was compared with the original ECOHIS. Minor changes were made to the Malay-ECOHIS before it was finalised. The Malay-ECOHIS' psychometric properties were assessed in terms of construct, convergent and discriminant validity as well as internal and test-retest reliability based on two separate studies involving 127 parents of 4-6 year old preschool children followed by oral examinations of 860 preschool children from 25 kindergartens from two districts in Selangor state, Malaysia. Non-parametric statistics were used to assess the relationships between the Malay-ECOHIS and the subjective and clinical outcome measures. RESULTS: The Cronbach's alpha was 0.83 and the weighted Kappa was 0.95 (intraclass correlation = 0.94). The Malay-ECOHIS demonstrated significant associations with different subjective and normative measures, i.e. levels of oral health satisfaction, perceived oral health status, perceived oral health need, toothache experience, pattern of dental attendance, and caries status of preschool children. These significant associations supported its construct, convergent and discriminant validity as well as internal and test retest reliability. CONCLUSION: This study showed that the Malay-ECOHIS is a valid and reliable instrument to assess the negative impacts of oral disorders/conditions on the quality of life of 4-6 year old preschool children and their families in Malaysia. PMID- 26607667 TI - Toroidal qubits: naturally-decoupled quiet artificial atoms. AB - The requirements of quantum computations impose high demands on the level of qubit protection from perturbations; in particular, from those produced by the environment. Here we propose a superconducting flux qubit design that is naturally protected from ambient noise. This decoupling is due to the qubit interacting with the electromagnetic field only through its toroidal moment, which provides an unusual qubit-field interaction, which is suppressed at low frequencies. PMID- 26607664 TI - Electrophysiological and Histological Characterization of Rod-Cone Retinal Degeneration and Microglia Activation in a Mouse Model of Mucopolysaccharidosis Type IIIB. AB - Sanfilippo syndrome Type B or Mucopolysaccharidosis IIIB (MPS IIIB) is a neurodegenerative autosomal recessive lysosomal storage disorder in which patients suffer severe vision loss from associated retinopathy. Here we sought to study the underlying retinal functional and morphological changes associated with MPS IIIB disease progression using the established model of MPS IIIB, the B6.129S6-Naglu(tm1Efn)/J mouse line. Electroretinogram (ERG) was recorded from MPS IIIB and wild-type (WT) mice at the age of 28 and 46 weeks, and retinal tissues were subsequently collected for immunohistochemistry analysis. At the 28th week, rod a- and b-wave amplitudes were significantly diminished in MPS IIIB compared to WT mice. The cone a- and b-waves of MPS IIIB mice were not significantly different from those of the control at the 28th week but were significantly diminished at the 46 th week, when MPS IIIB mice showed a major loss of rods and rod bipolar cells in both central and peripheral regions and a minor loss of cones in the periphery. Activation of microglia and neovascularization were also detected in the MPS IIIB retina. The new findings that cones and rod bipolar cells also undergo degeneration, and that retinal microglia are activated, will inform future development of therapeutic strategies. PMID- 26607666 TI - N-Acylethanolamines Bind to SIRT6. AB - Sirtuin 6 (SIRT6) is an NAD+-dependent histone deacetylase enzyme that is involved in multiple molecular pathways related to aging. Initially, it was reported that SIRT6 selectively deacetylated H3K9Ac and H3K56Ac; however, it has more recently been shown to preferentially hydrolyze long-chain fatty acyl groups over acetyl groups in vitro. Subsequently, fatty acids were demonstrated to increase the catalytic activity of SIRT6. In this study, we investigated whether a series of N-acylethanolamines (NAEs), quercetin, and luteolin could regulate SIRT6 activity. NAEs increased SIRT6 activity, with oleoylethanolamide having the strongest activity (EC50 value of 3.1 MUm). Quercetin and luteolin were demonstrated to have dual functionality with respect to SIRT6 activity; namely, they inhibited SIRT6 activity with IC50 values of 24 and 2 MUm, respectively, and stimulated SIRT6 activity more than sixfold (EC50 values of 990 and 270 MUm, respectively). PMID- 26607668 TI - Determining peripheral skin temperature: subjective versus objective measurements. AB - AIM: Diseases that affect peripheral vasculature or neurological function can manifest with peripheral skin temperature abnormalities. This pilot study investigates the accuracy of current physical examination techniques and determines whether a hand-held infrared device can be used to estimate peripheral skin temperature and detect temperature disparities. METHODS: Comparison between traditional physical examination of hands/feet by 30 healthcare professionals and a hand-held infrared device was made in 12 individuals (ages 4-25 years; 5 with disorders affecting peripheral skin temperature). Thermal camera measurements served as the reference temperature for comparison. RESULTS: A total of 231 extremity examinations by healthcare professionals were analysed. Healthcare professionals correctly identified subjects with colder or warmer than normal peripheral temperature. Hand-held device measurements were significantly different than reference measurements, with the size of the temperature difference diverging significantly between hands (1.20 degrees C) and feet (0.78 degrees C). When analysing temperature disparities, healthcare professionals identified fewer clinically significant disparities (>=3.0 degrees C) than the hand-held device (76% vs. 99%). CONCLUSION: Although different from reference temperatures, the hand-held infrared device provided a more accurate and objective method than traditional physical exam in identifying peripheral skin temperature asymmetries that may be related to chronic paediatric illness. PMID- 26607669 TI - PERC rule to exclude the diagnosis of pulmonary embolism in emergency low-risk patients: study protocol for the PROPER randomized controlled study. AB - BACKGROUND: The diagnosis of Pulmonary Embolism (PE) in the emergency department (ED) is crucial. As emergency physicians fear missing this potential life threatening condition, PE tends to be over-investigated, exposing patients to unnecessary risks and uncertain benefit in terms of outcome. The Pulmonary Embolism Rule-out Criteria (PERC) is an eight-item block of clinical criteria that can identify patients who can safely be discharged from the ED without further investigation for PE. The endorsement of this rule could markedly reduce the number of irradiative imaging studies, ED length of stay, and rate of adverse events resulting from both diagnostic and therapeutic interventions. Several retrospective and prospective studies have shown the safety and benefits of the PERC rule for PE diagnosis in low-risk patients, but the validity of this rule is still controversial. We hypothesize that in European patients with a low gestalt clinical probability and who are PERC-negative, PE can be safely ruled out and the patient discharged without further testing. METHODS/DESIGN: This is a controlled, cluster randomized trial, in 15 centers in France. Each center will be randomized for the sequence of intervention periods: a 6-month intervention period (PERC-based strategy) followed by a 6-month control period (usual care), or in reverse order, with 2 months of "wash-out" between the 2 periods. Adult patients presenting to the ED with a suspicion of PE and a low pre test probability estimated by clinical gestalt will be eligible. The primary outcome is the percentage of failure resulting from the diagnostic strategy, defined as diagnosed venous thromboembolic events at 3-month follow-up, among patients for whom PE has been initially ruled out. DISCUSSION: The PERC rule has the potential to decrease the number of irradiative imaging studies in the ED, and is reported to be safe. However, no randomized study has ever validated the safety of PERC. Furthermore, some studies have challenged the safety of a PERC-based strategy to rule-out PE, especially in Europe where the prevalence of PE diagnosed in the ED is high. The PROPER study should provide high-quality evidence to settle this issue. If it confirms the safety of the PERC rule, physicians will be able to reduce the number of investigations, associated subsequent adverse events, costs, and ED length of stay for patients with a low clinical probability of PE. TRIAL REGISTRATION: NCT02375919 . PMID- 26607672 TI - Large increases in carbon burial in northern lakes during the Anthropocene. AB - Northern forests are important ecosystems for carbon (C) cycling and lakes within them process and bury large amounts of organic-C. Current burial estimates are poorly constrained and may discount other shifts in organic-C burial driven by global change. Here we analyse a suite of northern lakes to determine trends in organic-C burial throughout the Anthropocene. We found burial rates increased significantly over the last century and are up to five times greater than previous estimates. Despite a correlation with temperature, warming alone did not explain the increase in burial, suggesting the importance of other drivers including atmospherically deposited reactive nitrogen. Upscaling mean lake burial rates for each time period to global northern forests yields up to 4.5 Pg C accumulated in the last 100 years--20% of the total burial over the Holocene. Our results indicate that lakes will become increasingly important for C burial under future global change scenarios. PMID- 26607670 TI - Social cognition as an RDoC domain. AB - While the bulk of research into neural substrates of behavior and psychopathology has focused on cognitive, memory and executive functions, there has been a recent surge of interest in emotion processing and social cognition, manifested in designating Social Cognition as a major RDoC domain. We describe the origins of this field's influence on cognitive neuroscience and highlight the most salient findings leading to the characterization of the "social brain" and the establishments of parameters that quantify normative and aberrant behaviors. Such parameters of behavior and neurobiology are required for a potentially successful RDoC construct, especially if heritability is established, because of the need to link with genomic systems. We proceed to illustrate how a social cognition measure can be used within the RDoC framework by presenting a task of facial emotion identification. We show that performance is sensitive to normative individual differences related to age and sex and to deficits associated with schizophrenia and other psychotic disorders. Neuroimaging studies with this task demonstrate that it recruits limbic and frontal regulatory activation in healthy samples as well as abnormalities in psychiatric populations. Evidence for its heritability was documented in genomic family studies and in patients with the 22q11.2 deletion syndrome. Measures that meet such criteria can help build translational bridges between cellular molecular mechanisms and behavior that elucidate aberrations related to psychopathology. Such links will transcend current diagnostic classifications and ultimately lead to a mechanistically based diagnostic nomenclature. Establishing such bridges will provide the elements necessary for early detection and scientifically grounded intervention. PMID- 26607673 TI - Polarization state-based refractive index sensing with plasmonic nanostructures. AB - Spectral-based methods are often used for label-free biosensing. However, practical implementations with plasmonic nanostructures suffer from a broad line width caused by strong radiative and nonradiative losses, and the sensing performance characterized by figure of merit is poor for these spectral-based methods. This study provides a polarization state-based method using plasmonic nanostructures to improve the sensing performance. Instead of the intensity spectrum, the polarization state of the transmitted field is monitored to analyze variations of the surrounding medium. The polarization state of incidence is strongly modified due to the excitation of surface plasmons, and the ellipticity of the transmitted field changes dramatically around plasmon resonances. Sharp resonances with line widths down to sub-nanometer are achieved by plotting the spectra of the reciprocal of ellipticity. Therefore, the sensing performance can be significantly improved, and a theoretical value of the figure of merit exceeding 1700 is achieved by using the polarization state-based sensing approach. PMID- 26607671 TI - Mechanistically based mapping of human cardiac fibrillation. AB - The mechanisms underpinning human cardiac fibrillation remain elusive. In his 1913 paper 'On dynamic equilibrium in the heart', Mines proposed that an activation wave front could propagate repeatedly in a circle, initiated by a stimulus in the vulnerable period. While the dynamics of activation and recovery are central to cardiac fibrillation, these physiological data are rarely used in clinical mapping. Fibrillation is a rapid irregular rhythm with spatiotemporal disorder resulting from two fundamental mechanisms - sources in preferred cardiac regions or spatially diffuse self-sustaining activity, i.e. with no preferred source. On close inspection, however, this debate may also reflect mapping technique. Fibrillation is initiated from triggers by regional dispersion in repolarization, slow conduction and wavebreak, then sustained by non-uniform interactions of these mechanisms. Notably, optical mapping of action potentials in atrial fibrillation (AF) show spiral wave sources (rotors) in nearly all studies including humans, while most traditional electrogram analyses of AF do not. Techniques may diverge in fibrillation because electrograms summate non coherent waves within an undefined field whereas optical maps define waves with a visually defined field. Also fibrillation operates at the limits of activation and recovery, which are well represented by action potentials while fibrillatory electrograms poorly represent repolarization. We conclude by suggesting areas for study that may be used, until such time as optical mapping is clinically feasible, to improve mechanistic understanding and therapy of human cardiac fibrillation. PMID- 26607674 TI - An All-Elastomeric Transparent and Stretchable Temperature Sensor for Body Attachable Wearable Electronics. AB - A transparent stretchable (TS) gated sensor array with high optical transparency, conformality, and high stretchability of up to 70% is demonstrated. The TS-gated sensor array has high responsivity to temperature changes in objects and human skin. This unprecedented TS-gated sensor array, as well as the integrated platform of the TS-gated sensor with a transparent and stretchable strain sensor, show great potential for application to wearable skin electronics for recognition of human activity. PMID- 26607675 TI - Hippo pathway and protection of genome stability in response to DNA damage. AB - The integrity of DNA is constantly challenged by exposure to the damaging effects of chemical and physical agents. Elucidating the cellular mechanisms that maintain genomic integrity via DNA repair and cell growth control is vital because errors in these processes lead to genomic damage and the development of cancer. By gaining a deep molecular understanding of the signaling pathways regulating genome integrity it is hoped to uncover new therapeutics and treatment designs to combat cancer. Components of the Hippo pathway, a tumor-suppressor cascade, have recently been defined to limit cancer transformation in response to DNA damage. In this review, we briefly introduce the Hippo signaling cascade in mammals and discuss in detail how the Hippo pathway has been established as part of the DNA damage response, activated by apical signaling kinases that recognize breaks in DNA. We also highlight the significance of the Hippo pathway activator RASSF1A tumor suppressor, a direct target of ataxia telangiectasia mutated and ataxia telangiectasia and Rad3 related ATR. Furthermore we discuss how Hippo pathway in response DNA lesions can induce cell death via Yes-associated protein (YAP) (the canonical Hippo pathway effector) or promote maintenance of genome integrity in a YAP-independent manner. PMID- 26607676 TI - The Craterostigma plantagineum glycine-rich protein CpGRP1 interacts with a cell wall-associated protein kinase 1 (CpWAK1) and accumulates in leaf cell walls during dehydration. AB - Craterostigma plantagineum tolerates extreme desiccation. Leaves of this plant shrink and extensively fold during dehydration and expand again during rehydration, preserving their structural integrity. Genes were analysed that may participate in the reversible folding mechanism. Analysis of transcripts abundantly expressed in desiccated leaves identified a gene putatively coding for an apoplastic glycine-rich protein (CpGRP1). We studied the expression, regulation and subcellular localization of CpGRP1 and its ability to interact with a cell wall-associated protein kinase (CpWAK1) to understand the role of CpGRP1 in the cell wall during dehydration. The CpGRP1 protein accumulates in the apoplast of desiccated leaves. Analysis of the promoter revealed that the gene expression is mainly regulated at the transcriptional level, is independent of abscisic acid (ABA) and involves a drought-responsive cis-element (DRE). CpGRP1 interacts with CpWAK1 which is down-regulated in response to dehydration. Our data suggest a role of the CpGRP1-CpWAK1 complex in dehydration-induced morphological changes in the cell wall during dehydration in C. plantagineum. Cell wall pectins and dehydration-induced pectin modifications are predicted to be involved in the activity of the CpGRP1-CpWAK1 complex. PMID- 26607677 TI - The Value and Significance of Metagenomics of Marine Environments. Preface. PMID- 26607678 TI - Nucleostemin promotes the proliferation of human glioma via Wnt/beta-Catenin pathway. AB - Nucleostemin, nucleolar guanosine triphosphate (GTP)-binding protein 3, is a member of the MMR1/HSR1 GTP-binding protein family. The important roles of nucleostemin in self-renewal, cell cycle regulation, apoptosis, and cell proliferation of various cancer types as been shown. Nevertheless, its expression and potential functions in human glioma is still unclear. In the present study, we demonstrated that up-regulation of nucleostemin was tightly related to poor 5 year-survival ratios. In serum-starved and re-feeding models of U251 and U373MG, we observed the rising expression of nucleostemin and p-beta-Catenin (p-Tyr645) were accompanied with cell proliferation markers (cyclin D1 and proliferating cell nuclear antigen (PCNA)). Employing nucleostemin-depletion models, we found down-regulated nucleostemin and p-beta-Catenin. The flow cytometry analysis proved the weakened cell proliferation. Moreover, we detected the translocation of beta-Catenin into the nucleus was impaired, meaning the inhibition of the Wnt/beta-Catenin pathway. Taken together, we identified a positive correlation between up-regulation of nucleostemin and human glioma cell proliferation and that knocking-down nucleostemin alleviated glioma proliferation by reducing beta Catenin transportation into the nucleus. All results suggested that nucleostemin might accelerate human glioma proliferation via the Wnt/beta-Catenin pathway. PMID- 26607679 TI - Development and validation of a multi-analyte LC-MS/MS approach for quantification of neuroleptics in whole blood, plasma, and serum. AB - Based on a similar approach for quantification of antidepressants, benzodiazepines, and z-drugs, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) multi-analyte approach with simple liquid-liquid extraction was extended for fast target screening and quantification of neuroleptics in whole blood, plasma, and serum. As this method is part of a multi-analyte procedure for over 100 analytes from different drug classes and as the extracts were additionally used in the authors' laboratory for gas chromatography-mass spectrometry (GC-MS) analysis, one universal stable-isotope-labelled internal standard (SIL-IS) was used to save time and resource. The method was validated with respect to international guidelines. For accuracy and precision, full calibration was performed with ranges from subtherapeutic to toxic concentrations. Selectivity problems could not be observed, but matrix effects ranged from 68 to 211% in all samples. For the low quality control (QC), recovery ranged from 32 to 112%, process efficiency from 31 to 165% and for the high QC recovery from 42 to 141%, process efficiency from 29 to 154%. In addition statistical data evaluation of the variances of the recovery, matrix effects, and process efficiency data between whole blood vs. plasma, whole blood vs. serum, and plasma vs. serum were done. The presented LC-MS/MS approach was applicable for selective detection of 33 neuroleptics as well as accurate and precise quantification of 25 neuroleptics in whole blood, 19 in plasma, and 17 in serum. More significant matrix effects (ME) for neuropletic drugs overall in plasma and serum as compared with whole blood were detected. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26607680 TI - Abnormal cardiac axis as a prenatal marker of left pulmonary artery sling. AB - Left pulmonary artery sling (LPAS) is a rare vascular anomaly. The left pulmonary artery arises distally from the right pulmonary artery on the right side of the trachea and passes between the trachea and esophagus towards the left lung, compressing the lower trachea. LPAS is associated with congenital tracheal stenosis, which frequently requires early surgical intervention and has a poor prognosis due to severe airway obstruction after birth. Therefore, LPAS should be prenatally diagnosed to prepare for surgical intervention for tracheal stenosis. To the best of our knowledge, there are few reports on prenatal echocardiographic findings in LPAS. We report three prenatal cases of LPAS, which resulted in respiratory symptoms. We discuss fetal ultrasound findings and highlight the abnormal rotation of the fetal cardiac axis to the right as a useful sign in the prenatal screening of LPAS. PMID- 26607681 TI - Secreted klotho protein attenuates osteogenic differentiation of human bone marrow mesenchymal stem cells in vitro via inactivation of the FGFR1/ERK signaling pathway. AB - Increasing evidence indicates that the osteogenic differentiation of mesenchymal stem cells (MSCs) is related to bone formation, heterotopic ossification, and even vascular calcification. Therefore, it is essential to understand the microenvironment that regulates these processes. The Klotho gene plays an important role in tissue mineralization, and its secreted protein functions as a hormone. We investigated the effects of secreted Klotho protein on the osteogenesis of human bone marrow MSC (hBMSCs). To this end, the cells received osteogenic medium with or without Klotho protein. The results showed that osteoblast-specific gene expression and mineral deposition were decreased when MSCs were incubated with Klotho. Klotho reduced the expression of fibroblast growth factor receptor 1 (FGFR1) and phosphorylated extracellular signal regulated kinase 1/2. However, both MEK and FGFR1 inhibitors delayed bone mineral formation more than Klotho. These data suggest that secreted Klotho protein attenuates the osteogenic differentiation of hBMSCs in vitro through FGFR1/ERK signaling. PMID- 26607682 TI - Follow-up after infants younger than 2 months of age with urinary tract infection in Southern Israel: epidemiologic, microbiologic and disease recurrence characteristics. AB - BACKGROUND: The timing of most recurrences after neonatal urinary tract infection is during the first year of life, with peak incidence 2-6 months after the initial infection. Information on the microbiologic characteristics of recurrent urinary tract infection episodes in relation to the microbiology of the initial episodes is limited. OBJECTIVES: To analyze the epidemiologic/microbiological characteristics of 1st and recurrent urinary tract infection in infants <2 months of age. METHODS: A retrospective study including all infants <2 months of age with urinary tract infection admitted during 2005-2009 and followed till the age of 1 year. RESULTS: 151 neonates were enrolled (2.7% of all 5617 febrile infants <2 months of age admitted). The overall incidence of urinary tract infection occurring during the first 2 months of life was 151/73,480 (0.2%) live births during 2005-2009 in southern Israel (2.1 cases/1000 live births). One pathogen was isolated in 133 (88.1%); Escherichia coli, Klebsiella spp., Enterococcus spp., Morganella morganii, Proteus spp., and Enterobacter spp. represented the most common pathogens (57.9%, 12.2%, 7.9%, 6.7%, 6.1%, and 5%, respectively). Trimethoprim/sulfamethoxazole, ampicillin, and cefuroxime-axetil were the most commonly recommended prophylactic antibiotics (45%, 13.2%, and 8%, respectively). Twenty-three recurrent urinary tract infection episodes were recorded in 20 (13.2%) patients; 6/23 (26%) were diagnosed within one month following 1st episode. E. coli was the most frequent recurrent urinary tract infection pathogen (12/23, 52.2%). No differences were recorded in E. coli distribution between first urinary tract infection vs. recurrent urinary tract infection. Seventeen (74%) recurrent urinary tract infection episodes were caused by pathogens different (phenotypically) from those isolated in 1st episode. Recurrent urinary tract infection occurred in 25.0%, 8.3%, and 0 patients recommended trimethoprim/sulfamethoxazole, cefuroxime-axetil, or amoxicillin prophylaxis, respectively. CONCLUSIONS: (1) The study determined the incidence of urinary tract infection in febrile infants <2 months of age in Southern Israel; (2) E. coli was responsible for the majority of first and recurrent urinary tract infection; (3) recurrent urinary tract infection was caused mostly by pathogens different than the pathogens isolated at initial episode. PMID- 26607683 TI - Reducing eating disorder symptoms and risk factors using the internet: A meta analytic review. AB - OBJECTIVE: The purpose of this meta-analytic review was, first, to evaluate the efficacy of Internet-based programs in decreasing eating disorder (ED) symptoms, and, second, to identify moderator variables these effects. METHOD: Twenty studies were identified and between-group effect sizes were calculated for ED symptoms and risk factors. RESULTS: Compared with control conditions, Internet based programs successfully decreased body dissatisfaction (d = 0.28, 95% CI [0.15-0.41], p < .001), internalization of the thin ideal (d = 0.36, 95% CI [0.07 0.65], p < .05), shape and weight concern (d = 0.42, 95% CI [0.13-0.71], p < .05), dietary restriction (d = 0.36, 95% CI [0.23-0.49], p < .001), drive for thinness (d = 0.47, 95% CI [0.33-0.60], p < .001), bulimic symptoms (d = 0.31, 95% CI [0.20-0.41], p < .001), purging frequency (d = 0.30, 95% CI [0.02-0.57], p < .05), and negative affect (d = 0.32, 95% CI [0.12-0.52], p < .001). Moderator analyses revealed no impact of data analytic strategy on intervention effects. Similarly, participant risk status was not a moderator for most outcomes. DISCUSSION: Internet-based programs are successful in decreasing ED symptoms and risk factors with small to moderate between-group effect sizes. PMID- 26607685 TI - Sonographic Parameters Predicting the Outcome of Patients With Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia Treated With Alpha1-Adrenoreceptor Antagonist. AB - OBJECTIVE: To define prostate and bladder sono-morphologic parameters that best predict the outcome of benign prostatic hyperplasia (BPH) in men treated with alpha1-adrenoreceptor antagonist. MATERIALS AND METHODS: Patients with BPH, candidates for medical treatment, were prospectively enrolled. Besides basic evaluation measures, all patients underwent transrectal ultrasonography. The main outcome was the response to treatment on the basis of International Prostatic Symptom Score, quality of life score, and maximum urine flow rate after taking daily oral dose of tamsulosin 0.4 mg for 6 months. The influences of baseline parameters on treatment response were statistically analyzed. RESULTS: A total of 166 patients completed the study. From these, 59 (35.5%) had ineffective treatment after 6 months. According to logistic regression analysis, baseline International Prostatic Symptom Score storage subscore, maximum urine flow rate, and transrectal ultrasonography-measured sono-morphologic parameters (bladder wall thickness [BWT], ultrasound estimated bladder weight [UEBW], and intravesical prostatic protrusion [IPP]) were the independent predictors of ineffective treatment (P < .05). Using receiver operating characteristics analysis, BWT, UEBW, and IPP had adequate area under the curve (0.939, 0.897, and 0.876, respectively). At cutoff values of 9.3 mm, 34.5 g, and 12.9 mm, the positive and negative predictive values for BWT, UEBW, and IPP were 83.6% and 92.4%; 78.2% and 85.6%; 80.3% and 90.5%; respectively. Combination of these sono morphologic parameters increased their positive predictive value to 97.6%. CONCLUSION: Sonographic measurements of BWT, UEBW, and IPP might aid in determining patients with BPH at high risk of alpha1-adrenoreceptor antagonist monotherapy failure, in turn determining the initial need for additional medical therapy or surgical intervention. PMID- 26607686 TI - Methodological quality of guidelines for management of Lyme neuroborreliosis. AB - BACKGROUND: Many aspects of clinical management of Lyme neuroborreliosis are subject to intense debates. Guidelines show considerable variability in their recommendations, leading to divergent treatment regimes. The most pronounced differences in recommendations exist between guidelines from scientific societies and from patient advocacy groups. Assessment of the methodological quality of these contradictory guideline recommendations can be helpful for healthcare professionals. METHODS: Systematic searches were conducted in MEDLINE and databases of four international and national guideline organizations for guidelines on Lyme neuroborreliosis published from 1999-2014. Characteristics (e.g., year of publication, sponsoring organization) and key recommendations were extracted from each guideline. Two independent reviewers assessed the methodological quality of each guideline according to the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. AGREE II scores from guidelines developed by scientific societies and from patient advocacy groups were compared across domains. RESULTS: We identified eight eligible guidelines of which n = 6 were developed by scientific societies and n = 2 by patient advocacy groups. Agreement on AGREE II scores was good (Cohen's weighted kappa = 0.87, 95% CI 0.83 0.92). Three guidelines, all from scientific societies, had an overall quality score of >= 50%. Two of them were recommended for use according to the AGREE II criteria. Across all guidelines, the AGREE II domain with the highest scores was "Clarity of Presentation" (65, SD 19%); all other domains had scores < 50% with the domain "Applicability" having the lowest scores (4, SD 4%). Guidelines developed by scientific societies had statistically significantly higher scores regarding clarity of presentation than guidelines from patient advocacy groups (p = 0.0151). No statistically significant differences were found in other domains. CONCLUSIONS: Current guidelines on Lyme neuroborreliosis vary in methodological quality and content. Health care providers and patients need to be aware of this variability in quality when choosing recommendations for their treatment decisions regarding Lyme neuroborreliosis. No statement can be given on quality of content and validity of recommendations, as these issues are not subject to assessment with the AGREE II tool and are prone to individual interpretation of the available evidence by the corresponding guideline panels. To enhance guideline quality, guideline panels should put more emphasis on linking recommendations to the available evidence, transparency in reporting how evidence was searched for and evaluated, and the implementation of recommendations into clinical practice. PMID- 26607684 TI - Neurocognitive Aging and the Hippocampus across Species. AB - There is extensive evidence that aging is associated with impairments in episodic memory. Many of these changes have been ascribed to neurobiological alterations to the hippocampal network and its input pathways. A cross-species consensus is beginning to emerge suggesting that subtle synaptic and functional changes within this network may underlie the majority of age-related memory impairments. In this review we survey convergent data from animal and human studies that have contributed significantly to our understanding of the brain-behavior relationships in this network, particularly in the aging brain. We utilize a cognitive as well as a neurobiological perspective and synthesize data across approaches and species to reach a more detailed understanding of age-related alterations in hippocampal memory function. PMID- 26607687 TI - Utility of Reporting the Percentage of High-grade Prostate Cancer. PMID- 26607688 TI - Variation in Bladder Cancer Spending: A Global Call to Action. PMID- 26607689 TI - Mental health disorders in home care elders: An integrative review. AB - Home care is the fastest growing U.S. health care sector, serving a predominance of highly vulnerable elderly patients. Mental health disorders (MHDs) are a major health concern in this population, however, current knowledge regarding their occurrence and associated correlates is inadequate. To address this gap, this integrative review examined existing findings regarding the prevalence and correlates of MHDs in home care elders. A search of six electronic databases and a hand search produced a final group of 36 articles for review. Poor data representativeness and methodological limitations impacted the quality of these studies, as reflected in an extremely wide range of prevalence estimates for these disorders (12% - 62%). A number of recommendations are made with respect to future research in this area. These include conducting multi-site investigations and the use of consistent and clear protocols for identification of MHDs in home care elders, a growing and significantly under-served population. PMID- 26607690 TI - A scoping study: children, policy and cultural shifts in homelessness services in South Australia: are children still falling through the gaps? AB - Homeless families are the fastest growing segment of the homelessness population. Homelessness services are often the first to know when children are at risk of disengagement with health, welfare and education services. Changes to Australian policy to explicitly attend to the needs of children are attempts to address the complexity of, and provide better outcomes for, homeless children. There are mounting levels of evidence describing some of the needs of children who are homeless. Using the scoping study methodological framework, this review of academic and grey literature identified the extent to which service providers provide for the needs of homeless children. The literature search was conducted from September 2012 to April 2013 using ProQuest, Science Direct, Sage and OVID databases. Therefore, the objectives of this scoping study were to: (i) identify the specific needs of children in homelessness; (ii) describe recent changes in policy relating to care for children in homelessness services; (iii) explore the evidence on how service providers can enact care for children in homelessness services; (iv) identify the types of practice changes that are needed to optimise outcomes for children; and (v) identify the gaps in service delivery. This article describes the Australian policy changes and explores the potential impact of subsequent sector reforms on the internal practices in front-line homelessness services, in order to overcome structural and systemic barriers, and promote opportunities for children in homeless families. This scoping study literature review contributes to the understanding of the impact of policy change on front line staff and suggests possible practice changes and future research options. PMID- 26607691 TI - Rescuing from oblivion: social characteristics and career destinations of early British 'sociology' graduates, 1907-39. AB - Those students who were among the first sociology graduates in the UK barely feature in standard histories of the discipline, which all have an intellectual and institutional focus. This article remedies this neglect by researching the social backgrounds and later careers of sociology graduates from the London School of Economics and Political Science [LSE] and Bedford College for Women from the first such graduate in 1907 until those graduating in the 1930s. Data for this exercise were compiled from a variety of sources. The more important are: UK censuses, especially that of 1911; various civil registration records; archived student files; and, for the graduates who entered university teaching, issues of the Yearbook of the Universities of the Empire [later the Commonwealth Universities' Yearbook]. The dataset includes all identified graduates in the BSc(Econ), Special Subject Sociology, degree from 1907 to 1935 and all in the BA (Honours) in Sociology degree from 1925 to 1939. LSE sociology graduates tended to be older and to have more cosmopolitan backgrounds, with fathers more likely than for Bedford College graduates to come from commercial rather than professional backgrounds. Both institutions' graduates' careers tended to the Civil Service and local government. LSE graduates gravitated to education, especially to higher education if male, whilst those of Bedford College went into welfare work, countering a stereotype from some previous literature that especially women graduates were heavily constrained to follow careers in schoolteaching. The article also gives comparisons with the social-class profile and career destinations of several cohorts of postwar sociology graduates, noting a number of similarities. PMID- 26607693 TI - Dose-dependent regulation of steroid receptor coactivator-1 and steroid receptors by testosterone propionate in the hippocampus of adult male mice. AB - Androgens have been proposed to play important roles in the regulation of hippocampus function either directly, through the androgen receptor (AR), or indirectly, through estrogen receptors (ERs), after aromatization into estradiol. Steroid receptor coactivator-1 (SRC-1) is present in the hippocampus of several species, and its expression is regulated by development and aging, as well as by orchidectomy and aromatase inhibitor letrozole administration, while ovariectomy only transiently downregulated hippocampal SRC-1. However, whether the expression of hippocampal SRC-1 can be directly regulated by testosterone, the principal male sex hormone, remains unclear. In the present study, we investigated the expression of hippocampal SRC-1 after orchidectomy and testosterone treatment using immunohistochemistry and Western blot analysis. We found that while hippocampal SRC-1 was significantly downregulated by orchidectomy (ORX), its expression was rescued by treatment with testosterone in a dose-dependent manner. Furthermore, we noticed that the decreased expression of hippocampal AR, ERs and the synaptic proteins GluR-1 and PSD-95 induced by ORX was also rescued by testosterone treatment in a dose-dependent manner. However, we found that hippocampal membrane estrogen receptor GPR30 and dendritic spine marker spinophilin were not altered by ORX or testosterone treatment. Together, the above results provided the first direct evidence for the androgenic regulation on hippocampal SRC-1, indicating that SRC-1 may be a direct target of androgenic regulation on the hippocampus. Furthermore, because AR and ERs can be differentially regulated by testosterone, and the transcriptional activity requires the involvement of local SRC-1, and considering the complicated regulatory pathway of each individual receptor, the converged hub regulator SRC-1 of these nuclear receptor networks is worthy of further investigation. PMID- 26607692 TI - Gonadal transcriptomic analysis and differentially expressed genes in the testis and ovary of the Pacific white shrimp (Litopenaeus vannamei). AB - BACKGROUND: The Pacific white shrimp (Litopenaeus vannamei) is the world's most prevalent cultured crustacean species. However, the supply of high-quality broodstocks is limited and baseline information related to its reproductive activity and molecular issues related to gonad development are scarce. In this study, we performed transcriptome sequencing on the gonads of adult male and female L. vannamei to identify sex-related genes. RESULTS: A total of 25.16 gigabases (Gb) of sequences were generated from four L. vannamei gonadal tissue libraries. After quality control, 24.11 Gb of clean reads were selected from the gonadal libraries. De-novo assembly of all the clean reads generated a total of 65,218 unigenes with a mean size of 1021 bp and a N50 of 2000 bp. A search of all unigene against Nr, SwissProt, KEGG, COG and NT databases resulted in 26,482, 23,062, 20,659, 11,935 and 14,626 annotations, respectively, providing a total of 30,304 annotated unigenes. Among annotated unigenes, 12,320 unigenes were assigned to gene ontology categories and 20,659 unigenes were mapped to 258 KEGG pathways. By comparing the ovary and testis libraries, 19,279 testicular up regulated and 3,529 ovarian up-regulated unigenes were identified. Enrichment analysis of differentially expressed unigenes resulted in 1060 significantly enriched GO terms and 34 significantly enriched KEGG pathways. Nine ovary specific, 6 testis-specific, 45 testicular up-regulated and 39 ovarian up regulated unigenes were then confirmed by semi-quantitative PCR and quantitative real-time PCR. In addition, using all-unigenes as a reference, a total of 13,233 simple sequence repeats (SSRs) were identified in 10,411 unigene sequences. CONCLUSIONS: The present study depicts the first large-scale RNA sequencing of shrimp gonads. We have identified many important sex-related functional genes, GO terms and pathways, all of which will facilitate future research into the reproductive biology of shrimp. We expect that the SSRs detected in this study can then be used as genetic markers for germplasm evaluation of breeding and imported populations. PMID- 26607694 TI - The role of income and occupation in the association of education with healthy aging: results from a population-based, prospective cohort study. AB - BACKGROUND: The beneficial effects of higher education on healthy aging are generally accepted, but the mechanisms are less well understood. Education may influence healthy aging through improved employment opportunities that enhance feelings of personal control and reduce hazardous exposures, or through higher incomes that enable individuals to access better health care or to reside in better neighbourhoods. Income and occupation have not been explored extensively as potential mediators of the effect of education on healthy aging. This study investigates the role of income and occupation in the association between education and healthy aging including potential effect modification by gender. METHODS: Logistic regression was used to explore the association of education, income (perceived income adequacy, life satisfaction with finances) and occupation (occupational prestige) with healthy aging five years later in 946 community-dwelling adults 65+ years from a population-based, prospective cohort study in Manitoba, Canada. RESULTS: Higher levels of education generally increased the likelihood of healthy aging. After adjusting for education, both income measures, but not occupation, predicted healthy aging among men; furthermore, the association between education and healthy aging was no longer significant. Income and occupation did not explain the significant association between education and healthy aging among women. CONCLUSIONS: Perceived income adequacy and life satisfaction with finances explained the beneficial effects of higher education on healthy aging among men, but not women. Identifying predictors of healthy aging and the mechanisms through which these factors exert their effects can inform strategies to maximize the likelihood of healthy aging. PMID- 26607695 TI - Naive Bayes classifiers for verbal autopsies: comparison to physician-based classification for 21,000 child and adult deaths. AB - BACKGROUND: Verbal autopsies (VA) are increasingly used in low- and middle-income countries where most causes of death (COD) occur at home without medical attention, and home deaths differ substantially from hospital deaths. Hence, there is no plausible "standard" against which VAs for home deaths may be validated. Previous studies have shown contradictory performance of automated methods compared to physician-based classification of CODs. We sought to compare the performance of the classic naive Bayes classifier (NBC) versus existing automated classifiers, using physician-based classification as the reference. METHODS: We compared the performance of NBC, an open-source Tariff Method (OTM), and InterVA-4 on three datasets covering about 21,000 child and adult deaths: the ongoing Million Death Study in India, and health and demographic surveillance sites in Agincourt, South Africa and Matlab, Bangladesh. We applied several training and testing splits of the data to quantify the sensitivity and specificity compared to physician coding for individual CODs and to test the cause-specific mortality fractions at the population level. RESULTS: The NBC achieved comparable sensitivity (median 0.51, range 0.48-0.58) to OTM (median 0.50, range 0.41-0.51), with InterVA-4 having lower sensitivity (median 0.43, range 0.36-0.47) in all three datasets, across all CODs. Consistency of CODs was comparable for NBC and InterVA-4 but lower for OTM. NBC and OTM achieved better performance when using a local rather than a non-local training dataset. At the population level, NBC scored the highest cause-specific mortality fraction accuracy across the datasets (median 0.88, range 0.87-0.93), followed by InterVA 4 (median 0.66, range 0.62-0.73) and OTM (median 0.57, range 0.42-0.58). CONCLUSIONS: NBC outperforms current similar COD classifiers at the population level. Nevertheless, no current automated classifier adequately replicates physician classification for individual CODs. There is a need for further research on automated classifiers using local training and test data in diverse settings prior to recommending any replacement of physician-based classification of verbal autopsies. PMID- 26607696 TI - Manual versus Mechanical Chest Compressions on Surfaces of Varying Softness with or without Backboards: A Randomized, Crossover Manikin Study. AB - BACKGROUND: Chest compression quality is decisive for overall outcome after cardiac arrest. Chest compression depth may decrease when cardiopulmonary resuscitation (CPR) is performed on a mattress, and the use of a backboard does not necessarily improve compression depth. Mechanical chest compression devices may overcome this problem. OBJECTIVES: We sought to investigate the effectiveness of manual chest compressions both with and without a backboard compared to mechanical CPR performed on surfaces of different softness. METHODS: Twenty-four advanced life support (ALS)-certified rescuers were enrolled. LUCAS2 (Physio Control, Redmond, WA) delivers 52 +/- 2 mm deep chest compressions and active decompressions back to the neutral position (frequency 102 min(-1); duty cycle, 50%). This simulated CPR scenario was performed on a Resusci-Anne manikin (Laerdal, Stavanger, Norway) that was lying on 3 different surfaces: 1) a concrete floor, 2) a firm standard mattress, and 3) a pressure-relieving mattress. Data were recorded by the Laerdal Skill Reporting System. RESULTS: Manual chest compression with or without a backboard were performed correctly less often than mechanical chest compressions (floor: 33% [interquartile range {IQR}, 27-48%] vs. 90% [IQR, 86-94%], p < 0.001; standard mattress: 32% [IQR, 20 45%] vs. 27% [IQR, 14-46%] vs. 91% [IQR, 51-94%], p < 0.001; and pressure relieving mattress 29% [IQR, 17-49%] vs. 30% [IQR, 17-52%] vs. 91% [IQR, 87-95%], p < 0.001). The mean compression depth on both mattresses was deeper with mechanical chest compressions (floor: 53 mm [range, 47-57 mm] vs. 56 mm [range, 54-57 mm], p = 0.003; standard mattress: 50 mm [range, 44-55 mm] vs. 51 mm [range, 47-55 mm] vs. 55 mm [range, 54-58 mm], p < 0.001; and pressure-relieving mattress: 49 mm [range, 44-55 mm] vs. 50 mm [range, 44-53 mm] vs. 55 mm [range, 55-56 mm], p < 0.001). In this ~6-min scenario, the mean hands-off time was ~15 to 20 s shorter in the manual CPR scenarios. CONCLUSIONS: In this experimental study, only ~30% of manual chest compressions were performed correctly compared to ~90% of mechanical chest compressions, regardless of the underlying surface. Backboard use did not influence the mean compression depth during manual CPR. Chest compressions were deeper with mechanical CPR. The mean hands-off time was shorter with manual CPR. PMID- 26607698 TI - Objectively-measured sedentary time and its association with markers of cardiometabolic health and fitness among cardiac rehabilitation graduates. AB - BACKGROUND: Sedentary time is an independent risk factor for cardiometabolic disease and mortality. It is unknown how much time individuals with coronary artery disease spend being sedentary or how their sedentary time relates to markers of health. The objectives of this study were to: (a) quantify sedentary time in a post-cardiac rehabilitation (CR) population, and (b) assess association with cardiometabolic risk, independent of moderate-to-vigorous physical activity. DESIGN: Cross-sectional. METHODS: As part of a larger trial, 263 recent CR graduates (~10 days post-CR, mean age 63.6 +/- 9.3 years, 75% male) wore an ActiGraph GT3X accelerometer during waking hours (>=4 days, >=10 hours/day) to quantify sedentary time (<=150 counts per minute). Spearman correlations were computed to assess relationships between sedentary time (adjusted for wear time) with markers of cardiometabolic health and fitness. Significant markers were examined using multiple linear regressions. RESULTS: Participants spent an average of 8 hours/day sedentary (~14 bouts/day). Sedentary time was negatively correlated with high-density lipoprotein and [Formula: see text]O2peak and positively correlated with triglycerides, body mass index and waist circumference. After adjusting for age, sex, medications and moderate-to-vigorous physical activity, hours/day of sedentary time remained significantly associated with log[Formula: see text]O2peak (beta = -0.02, p = 0.001) and body mass index (beta = 0.49, p = 0.02). CONCLUSIONS: Findings suggest that even among a group of post-CR individuals who are already probably more active than patients who have not undergone CR, sedentary time remains high and is associated with poorer cardiorespiratory fitness, suggesting a possible new area of focus among CR programs. PMID- 26607699 TI - Molecular Characterization of a Newly Identified Subfamily Member of Penaeidin from two Penaeid Shrimps, Fenneropenaeus indicus and Metapenaeus monoceros. AB - Penaeidins are a major group of antimicrobial peptides found in penaeid shrimps. This study reports a new isoform of penaeidin from the hemocytes of Indian white shrimp, Fenneropenaeus indicus (Fi-PEN, JX657680), and the pink shrimp, Metapenaeus monoceros (Mm-PEN, KF275674). Mm-PEN is also the first antimicrobial peptide to be identified from M. monoceros. The complete coding sequences of the newly identified Fi-PEN and Mm-PEN consisted of an ORF of 338 bp encoding 71 amino acids with a predicted molecular weight of 5.66 kDa and a pI of 9.38. The penaeidins had its characteristic signal peptide region (19 amino acids), which was followed by a mature peptide with a proline-rich domain (24 amino acids) at the N-terminal region and a cysteine-rich domain (28 amino acids) at the C terminal region, designating it to penaeidin-3 subgroup. Structural analysis revealed an alpha-helix in its secondary structure and an extended structure at the proline-rich domain. The newly identified penaeidin isoform showed maximum similarity of 63 % to a penaeidin-3 isoform of P. monodon, which further proves it to be a new isoform. Phylogenetic analysis showed that it possessed similar evolutionary status like other penaeidins, which has subsequently diverged at different phases of evolution. The wide distribution of penaeidins in penaeid shrimps indicates the importance of these AMPs in the innate immunity. PMID- 26607697 TI - Is robotic-assisted radical cystectomy (RARC) with intracorporeal diversion becoming the new gold standard of care? AB - BACKGROUND: Totally intracorporeal robotic-assisted radical cystectomy (RARC) has perceived difficulties compared to open radical cystectomy (ORC). As the technique is increasingly adopted around the world, the benefits of RARC with intra- or extracorporeal urinary diversion or ORC for the patients are still unclear. In this article, we consider the current evidence for this issue. METHODS: We assessed two questions through using expert opinion and the medical literature: (A) Is RARC better than ORC for removing the cancer surgery and outcome? (B) Is RARC better than ORC for the urinary diversion? OUTCOMES: (A) RARC is better than ORC for shorter length of stay, blood loss and complication rates. (B) Intracorporeal orthotopic neobladder may have a significant physiological and surgical benefit to the patient recovery. CONCLUSIONS: RARC with total intracorporeal reconstruction has potential benefits to the patient. We recommend that all surgeons document patient-related outcome measures, urodynamics and enhanced recovery protocols for cystectomy patients to help us understand the real improvements within bladder cancer surgery and reconstruction. PMID- 26607700 TI - A genetic marker of hyperuricemia predicts cardiovascular events in a meta analysis of three cohort studies in high risk patients. AB - INTRODUCTION: The strongest genetic marker of uric acid levels, the rs734553 SNP in the GLUT9 urate transporter gene, predicts progression to kidney failure in CKD patients and associates with systolic BP and carotid intima media thickness in family-based studies. METHODS: Since genes are transmitted randomly (Mendelian randomization) we used this gene polymorphism as an unconfounded research instrument to further explore the link between uric acid and cardiovascular disease (cardiovascular death, and non-fatal myocardial infarction and stroke) in a meta-analysis of three cohort studies formed by high risk patients (MAURO: 755 CKD patients; GHS: 353 type 2 diabetics and coronary artery disease and the TVAS: 119 patients with myocardial infarction). RESULTS: In separate analyses of the three cohorts, the incidence rate of CV events was higher in patients with the rs734553 risk (T) allele (TT/GT) than in those without (GG patients) and the HR in TT/GT patients in the three cohorts (range 1.72-2.14) coherently signaled an excessive cardiovascular risk with no heterogeneity (I2 = 0.01). The meta analytical estimate (total number of patients, n = 1227; total CV events, n = 222) of the HR for the combined end-point in TT/GT patients was twice higher (pooled HR: 2.04, 95% CI: 1.11-3.75, P = 0.02) than in GG homozygotes. CONCLUSIONS: The T allele of the rs734553 polymorphism in the GLUT9 gene predicts a doubling in the risk for incident cardiovascular events in patients at high cardiovascular risk. Findings in this study are compatible with the hypothesis of a causal role of hyperuricemia in cardiovascular disease in high risk conditions. PMID- 26607701 TI - Consumption of nuts and risk of total and cause-specific mortality over 15 years. AB - BACKGROUND AND AIMS: The published literature shows that nut consumption has a favorable impact on health. We aimed to assess the association between nut consumption and risk of 15-year total mortality, and mortality from cardiovascular disease (CVD) (including ischemic heart disease, IHD, and stroke), and cancer. METHODS AND RESULTS: Prospective analyses involved 2893 participants aged >=49 years at baseline. Dietary data were collected by using a semi quantitative food-frequency questionnaire, and nut intakes were calculated. Deaths and cause of death were confirmed by data linkage with the Australian National Death Index. Over 15 years, 1044 participants had died, of these 430 had died from stroke and another 430 had died from IHD. Participants in the second tertile of nut consumption versus those in the first tertile of intake had reduced risk of total mortality: multivariable-adjusted HR 0.76 (95% CI 0.65 0.89). Participants in the second tertile compared to those in the first tertile had 24% and 23% reduced risk of 15-year CVD and IHD mortality, respectively. Associations were more marked in women compared to men. Women in the second versus first tertile of nut consumption had 27%, 39%, 34% and 49% reduced risk of death from all causes (n = 489), CVD (n = 258), IHD (n = 188) and stroke mortality (n = 101), respectively. CONCLUSIONS: Nut consumption was independently associated with a decreased risk of overall and vascular-disease mortality, particularly in women. PMID- 26607702 TI - High salt exacerbates programmed hypertension in maternal fructose-fed male offspring. AB - BACKGROUND AND AIMS: Consumption of food and drinks containing high fructose (HF), which is associated with hypertension, is increasing steeply. Moreover, increased salt intake significantly increases hypertension risk. We examined whether maternal HF and postnatal high salt (HS) intake had synergistic effects on blood pressure (BP) elevation in adult offspring and determined the underlying mechanisms. METHODS AND RESULTS: Pregnant Sprague-Dawley rats received regular chow or chow supplemented with 60% fructose during the entire pregnancy and lactation periods. Half of the male offspring received 1% NaCl in drinking water from weaning to 3 months of age. Male offspring were assigned to 4 groups (control, HF, HS, and HF + HS) and were sacrificed at 12 weeks of age. Offspring in HF and HS groups developed hypertension, indicating that HF and HS synergistically increased BP. Postnatal HS intake increased Ace expression and decreased Agtr1b and Mas1 expression in the kidneys. Renal mRNA levels of Ace and Agtr1a were significantly higher in HF + HS group than in control group. Renal levels of Na-K-2Cl cotransporter, type 3 sodium hydrogen exchanger, and Na(+)/Cl( ) cotransporter were higher in HS and HF + HS groups than in control group. CONCLUSION: Postnatal HS intake exacerbated prenatal HF-induced programmed hypertension. HF and HS induced programmed hypertension by differentially inducing renin-angiotensin system and sodium transporters in the kidneys. Better understanding of the effect of the relationship between HF and HS on hypertension development will help prevent hypertension in mothers and children exposed to HF and HS. PMID- 26607703 TI - Associations between diet and cardiometabolic risk among Yup'ik Alaska Native people using food frequency questionnaire dietary patterns. AB - BACKGROUND AND AIMS: In previous analyses, we identified three dietary patterns from food frequency questionnaire data among a sample of Yup'ik Alaska Native people living in Southwest Alaska: a "subsistence foods" dietary pattern and two market-based dietary patterns "processed foods" and "fruits and vegetables". In this analysis, we aimed to characterize the association between the dietary patterns and cardiometabolic (CM) risk factors (lipids, blood pressure, glucose, adiposity). METHODS AND RESULTS: We used multilevel linear regression to estimate the mean of each CM risk factor, comparing participants in the 4th to the 1st quartile of each dietary pattern (n = 637). Models were adjusted for age, sex, past smoking, current smoking, and physical activity. Mean log triglyceride levels were significantly higher among participants in the 4th compared to the 1st quartile of the processed foods dietary pattern (beta = 0.11). Mean HbA1c percent was significantly lower (beta = -0.08) and mean diastolic blood pressure (DBP) mm Hg was significantly higher (beta = 2.87) among participants in the 4th compared to the 1st quartile of the fruits and vegetables dietary pattern. Finally, mean log triglyceride levels and mean DBP mm Hg were significantly lower among participants in the 4th compared to the 1st quartile of the subsistence foods dietary pattern (beta = -0.10 and beta = -3.99 respectively). CONCLUSIONS: We found increased CM risk, as reflected by increased triglycerides, associated with eating a greater frequency of processed foods, and reduced CM risk, as reflected by lower triglycerides and DBP, associated with eating a greater frequency of subsistence foods. PMID- 26607704 TI - IL-17 receptor A and adenosine deaminase 2 deficiency in siblings with recurrent infections and chronic inflammation. AB - BACKGROUND: Data on patients affected by chronic mucocutaneous candidiasis underscore the preponderant role of IL-17 receptor A (IL-17RA) in preserving mucocutaneous immunity. Little is known about the role of adenosine deaminase (ADA) 2 in regulation of immune responses, although recent reports linked ADA2 deficiency with inflammation and vasculitis. OBJECTIVE: We sought to investigate the mechanisms of chronic inflammation and vasculitis in a child lacking IL-17RA and ADA2 to identify therapeutic targets. METHODS: We report a family with 2 siblings who have had recurrent mucocutaneous infections with Candida albicans and Staphylococcus aureus and chronic inflammatory disease and vasculitis since early childhood, which were refractory to classical treatments. Array-based comparative genomic hybridization analysis showed that both siblings are homozygous for a 770-kb deletion on chr22q11.1 encompassing both IL17RA and cat eye critical region 1 (CECR1). Immunologic studies were carried out by means of flow cytometry, ELISA, and RIA. RESULTS: As expected, in the affected child we found a lack of IL-17RA expression, which implies a severe malfunction in the IL 17 signaling pathway, conferring susceptibility to recurrent mucocutaneous infections. Surprisingly, we detected an in vitro and in vivo upregulation of proinflammatory cytokines, notably IL-1beta and TNF-alpha, which is consistent with the persistent systemic inflammation. CONCLUSIONS: This work emphasizes the utility of whole-genome analyses combined with immunologic investigation in patients with unresolved immunodeficiency. This approach is likely to provide an insight into immunologic pathways and mechanisms of disease. It also provides molecular evidence for more targeted therapies. In addition, our report further corroborates a potential role of ADA2 in modulating immunity and inflammation. PMID- 26607707 TI - You're the Flight Surgeon. AB - Ramage MH. You're the flight surgeon: eosinophilic esophagitis. Aerosp Med Hum Perform. 2015; 86(4):418-421. PMID- 26607708 TI - You're the Flight Surgeon. AB - Moore JL, Jackson CR, Ellis JC, Norrid C. You're the flight surgeon: myelolipoma. Aerosp Med Hum Perform. 2015; 86(4):421-423. PMID- 26607705 TI - Extensive alopecia areata is reversed by IL-12/IL-23p40 cytokine antagonism. PMID- 26607709 TI - This Month in Aerospace Medicine History. PMID- 26607710 TI - PRIdictor: Protein-RNA Interaction predictor. AB - Several computational methods have been developed to predict RNA-binding sites in protein, but its inverse problem (i.e., predicting protein-binding sites in RNA) has received much less attention. Furthermore, most methods that predict RNA binding sites in protein do not consider interaction partners of a protein. This paper presents a web server called PRIdictor (Protein-RNA Interaction predictor) which predicts mutual binding sites in RNA and protein at the nucleotide- and residue-level resolutions from their sequences. PRIdictor can be used as a web based application or web service at http://bclab.inha.ac.kr/pridictor. PMID- 26607711 TI - Prognostic Accuracy of the Seventh Edition of the TNM Classification Compared with the Fifth and Sixth Edition for Distal Cholangiocarcinoma. AB - BACKGROUND: The TNM classification for distal cholangiocarcinoma was first introduced in the 7th edition, which was published in 2009; however, prognostic accuracy compared with the 5th and 6th editions has not yet been evaluated and requires validation. METHODS: A prospective histological database of patients with distal bile duct cancer was analyzed, and histological parameters and stage of the distal cholangiocarcinoma were assessed according to the 5th, 6th, and 7th editions of the TNM classification. RESULTS: Between 1994 and 2012, a total of 516 patients underwent pancreatic head resection, of whom 59 patients (11.4 %) experienced histologically confirmed distal cholangiocarcinoma. The median overall survival time was 22.2 months (13.1-31.4). Tumor recurrence occurred in 23 patients after a median disease-free survival time of 14.1 months. The 7th edition showed a monotonicity of all gradients, with a stepwise increase of mortality related to a stepwise increase of tumor stage (log-rank test; p < 0.05) demonstrating best discrimination of all tested editions [area under the receiver operating characteristic curve (AUC) 0.82; 95 % CI 0.70-0.95; p = 0.012]. The discrimination rate was low for the 5th (AUC 0.67; 95 % CI 0.42-0.91; p = 0.18) and 6th editions (AUC 0.70; 95 % CI 0.47-0.93; p = 0.11), while the log-rank test did not reach statistical significance. On multivariate analysis, lymph node involvement and positive resection margins were positive and independent predictors of inferior survival (p < 0.05). CONCLUSIONS: The 7th edition of the TNM classification was favorable in terms of predicting outcome, and generated a monotonicity of all grades. Strikingly, the 7th edition, but not the 5th and 6th editions, was of prognostic significance to predict outcome. PMID- 26607712 TI - Effect Modification of Long-Term Air Pollution Exposures and the Risk of Incident Cardiovascular Disease in US Women. AB - BACKGROUND: Ambient air pollution exposures have been frequently linked to cardiovascular disease (CVD) morbidity and mortality. However, less is known about the populations most susceptible to these adverse effects. METHODS AND RESULTS: We assessed the associations of long-term particulate matter (PM) exposures with incident CVD in a nationwide cohort of 114 537 women in the Nurses' Health Study, and performed analyses to identify subpopulations at the greatest risk. Residential address level time-varying monthly exposures to PM2.5, PM10, and PM2.5 to 10 microns in diameter were estimated from spatio-temporal prediction models. In multivariable models, increases in all size fractions of PM were associated with small, but not statistically significant, increased risks of total CVD, coronary heart disease, and stroke. PM-associated CVD risks were statistically significantly higher among women with diabetes as compared to those without (P-for-interaction <0.0001 for PM10 and PM2.5 and 0.007 for PM2.5 to 10). For each 10 MUg/m(3) increase in 12-month average PM2.5, PM2.5 to 10, and PM10, the multivariable adjusted hazard ratios were 1.44 (95% CI: 1.23 to 1.68), 1.17 (95% CI: 1.05 to 1.30), and 1.19 (95% CI: 1.10 to 1.28) among women with diabetes. There were also suggestions of higher risks among older (>=70 years) women, the obese, and those living in the Northeast and South. Smoking status and family history did not consistently modify the association between PM and CVD, and risks were most elevated with exposures in the previous 12 months. CONCLUSIONS: In this nationwide cohort, women with diabetes were identified as the subpopulation most sensitive to the adverse cardiovascular health effects of PM. PMID- 26607713 TI - Mechanosensitive components of integrin adhesions: Role of vinculin. AB - External forces play a key role in shaping development and normal physiology. Aberrant responses to forces, or changes in the nature of such forces, are implicated in a variety of diseases. Cells contain several types of adhesions, linking them to their external environment. It is through these adhesions that forces are both sensed (from the outside inwards) and applied (from inside to out). Furthermore, several adhesion-based proteins are sensitive to changes in intracellular forces, utilising them for activation and regulation. Here, we outline how vinculin, a key component of integrin-mediated adhesions linking the actin cytoskeleton to the extracellular matrix (ECM), is regulated by force and acts as force transducing protein. We discuss the role of vinculin in vivo and its place in health and disease; summarise the proposed mechanisms by which vinculin is recruited to and activated at integrin-ECM adhesions; and discuss recent findings that place vinculin as the major force sensing and transmitting component of cell-matrix adhesion complexes. Finally, we discuss the role of vinculin in regulating the cellular responses to both the physical properties of the external environment and to externally applied physical stimuli. PMID- 26607717 TI - Nicotine Induced Murine Spermatozoa Apoptosis via Up-Regulation of Deubiquitinated RIP1 by Trim27 Promoter Hypomethylation. AB - Nicotine significantly promoted apoptosis in stages I, VII, VIII, and XI spermatogonia, stages I, VII, VIII, X, and XI spermatocytes, and stages I-V, VII, and VIII elongating spermatids. To explore the underlying molecular mechanisms, sperm mRNA next-generation sequencing of nicotine-treated mice was conducted. Out of the 86 genes related to apoptosis, Tnf (tumor necrosis factor alpha) was screened to be the most significant varied transcript, and the Onto-pathway analysis indicated that the TNF apoptotic pathway was especially activated by nicotine exposure. The TNF pathway was further studied at the gene and protein levels. The results showed that RIP1, the key component in the TNF apoptotic pathway, was up-expressed in its deubiquitinated form in nicotine-treated mice testis. TRIM27, an E3 ubiquitin ligase that activated TNF apoptotic pathway through up-regulating deubiquitinated RIP1, was also overexpressed in nicotine treated spermatocytes; moreover, four consecutive CpG sites near the Trim27 transcription start site were less frequently methylated. Finally, in vitro experiments of Trim27 overexpression and RNA interference in GC-1 spermatogonial cells confirmed that the RIP1 deubiquitination and TRIM27 hyopmethylation were both positively correlated with spermatocyte apoptosis. In summary, our study suggests that nicotine may induce murine spermatozoal apoptosis via the TNF apoptotic pathway through up-regulation of deubiquitinated RIP1 by Trim27 promoter hypomethylation. PMID- 26607716 TI - Exposure of Female Rats to an Environmentally Relevant Mixture of Brominated Flame Retardants Targets the Ovary, Affecting Folliculogenesis and Steroidogenesis. AB - Brominated flame retardants (BFRs) are incorporated into various consumer products to prevent flame propagation. These compounds leach into the domestic environment, resulting in chronic exposure and contamination. Pregnancy failure is associated with high levels of BFRs in human follicular fluid, raising serious questions regarding their impact on female reproductive health. The goal of this study is to elucidate the effects of an environmentally relevant BFR mixture on female rat ovarian functions (i.e., folliculogenesis and steroidogenesis). A BFR dietary mixture formulated to mimic the relative BFR congener levels in North American house dust was administered to adult female Sprague-Dawley rats from 2 to 3 wk before mating until Gestational Day 20; these diets were designed to deliver nominal doses of 0, 0.06, 20, or 60 mg/kg/day of the BFR mixture. Exposure to BFRs triggered an approximately 50% increase in the numbers of preantral and antral follicles and an enlargement of the antral follicles in the ovaries of the dams. A significant reduction in the expression of catalase, an antioxidant enzyme, and downregulation of the expression of insulin-like factor 3 (Insl3) and 17alpha-hydroxylase (Cyp17a1) were observed in the ovary. In addition, BFR exposure affected steroidogenesis; we observed a significant decrease in circulating 17-hydroxypregnenolone and an increase in testosterone concentrations in BFR-exposed dams. Thus, BFRs target ovarian function in the rat, adversely affecting both folliculogenesis and steroidogenesis. PMID- 26607718 TI - The Mouse INO80 Chromatin-Remodeling Complex Is an Essential Meiotic Factor for Spermatogenesis. AB - The ability to faithfully transmit genetic information across generations via the germ cells is a critical aspect of mammalian reproduction. The process of germ cell development requires a number of large-scale modulations of chromatin within the nucleus. One such occasion arises during meiotic recombination, when hundreds of DNA double-strand breaks are induced and subsequently repaired, enabling the transfer of genetic information between homologous chromosomes. The inability to properly repair DNA damage is known to lead to an arrest in the developing germ cells and sterility within the animal. Chromatin-remodeling activity, and in particular the BRG1 subunit of the SWI/SNF complex, has been shown to be required for successful completion of meiosis. In contrast, remodeling complexes of the ISWI and CHD families are required for postmeiotic processes. Little is known regarding the contribution of the INO80 family of chromatin-remodeling complexes, which is a particularly interesting candidate due to its well described functions during DNA double-strand break repair. Here we show that INO80 is expressed in developing spermatocytes during the early stages of meiotic prophase I. Based on this information, we used a conditional allele to delete the INO80 core ATPase subunit, thereby eliminating INO80 chromatin-remodeling activity in this lineage. The loss of INO80 resulted in an arrest during meiosis associated with a failure to repair DNA damage during meiotic recombination. PMID- 26607720 TI - Enrichment of Mouse Spermatogonial Stem Cells by the Stem Cell Dye CDy1. AB - Spermatogonial stem cells (SSCs) comprise a small population of germ cells with self-renewal potential. Previous studies have shown that SSCs share several common features with stem cells in other self-renewing tissues, including surface markers and proliferative machinery. However, studies of SSCs are severely handicapped by the small number of SSCs and the lack of SSC-specific markers. In the present study, we examined the utility of CDy1 and Rh123, both of which are used for the collection of stem cells in several self-renewing tissues. CDy1 stained germline stem (GS) cells, cultured spermatogonia enriched for SSC activity, after in vitro incubation without exerting toxic effects. Unlike previously reported stem cell-specific dyes, CDy1 was also useful for enrichment of SSCs in both GS cell culture and mature adult testes. Spermatogonial transplantation showed that ~1 in 66.7 cells exhibited SSC activity after CDH1 based magnetic cell selection and CDy1 staining. In contrast, although Rh123 was previously used successfully to collect SSCs from cryptorchid testes, it was not possible to recover SSCs from both GS cell cultures and wild-type testes. Thus, CDy1 staining will provide a useful strategy for the enrichment of SSCs and may be used in conjunction with other reagents for the enrichment of SSCs. PMID- 26607721 TI - Differentially Expressed Genes in Endometrium and Corpus Luteum of Holstein Cows Selected for High and Low Fertility Are Enriched for Sequence Variants Associated with Fertility. AB - Despite the importance of fertility in humans and livestock, there has been little success dissecting the genetic basis of fertility. Our hypothesis was that genes differentially expressed in the endometrium and corpus luteum on Day 13 of the estrous cycle between cows with either good or poor genetic merit for fertility would be enriched for genetic variants associated with fertility. We combined a unique genetic model of fertility (cattle that have been selected for high and low fertility and show substantial difference in fertility) with gene expression data from these cattle and genome-wide association study (GWAS) results in ~20,000 cattle to identify quantitative trait loci (QTL) regions and sequence variants associated with genetic variation in fertility. Two hundred and forty-five QTL regions and 17 sequence variants associated primarily with prostaglandin F2alpha, steroidogenesis, mRNA processing, energy status, and immune-related processes were identified. Ninety-three of the QTL regions were validated by two independent GWAS, with signals for fertility detected primarily on chromosomes 18, 5, 7, 8, and 29. Plausible causative mutations were identified, including one missense variant significantly associated with fertility and predicted to affect the protein function of EIF4EBP3. The results of this study enhance our understanding of 1) the contribution of the endometrium and corpus luteum transcriptome to phenotypic fertility differences and 2) the genetic architecture of fertility in dairy cattle. Including these variants in predictions of genomic breeding values may improve the rate of genetic gain for this critical trait. PMID- 26607719 TI - Mouse Spermatogenesis Requires Classical and Nonclassical Testosterone Signaling. AB - Testosterone acts though the androgen receptor in Sertoli cells to support germ cell development (spermatogenesis) and male fertility, but the molecular and cellular mechanisms by which testosterone acts are not well understood. Previously, we found that in addition to acting through androgen receptor to directly regulate gene expression (classical testosterone signaling pathway), testosterone acts through a nonclassical pathway via the androgen receptor to rapidly activate kinases that are known to regulate spermatogenesis. In this study, we provide the first evidence that nonclassical testosterone signaling occurs in vivo as the MAP kinase cascade is rapidly activated in Sertoli cells within the testis by increasing testosterone levels in the rat. We find that either classical or nonclassical signaling regulates testosterone-mediated Rhox5 gene expression in Sertoli cells within testis explants. The selective activation of classical or nonclassical signaling pathways in Sertoli cells within testis explants also resulted in the differential activation of the Zbtb16 and c-Kit genes in adjacent spermatogonia germ cells. Delivery of an inhibitor of either pathway to Sertoli cells of mouse testes disrupted the blood-testis barrier that is essential for spermatogenesis. Furthermore, an inhibitor of nonclassical testosterone signaling blocked meiosis in pubertal mice and caused the loss of meiotic and postmeiotic germ cells in adult mouse testes. An inhibitor of the classical pathway caused the premature release of immature germ cells. Collectively, these observations indicate that classical and nonclassical testosterone signaling regulate overlapping and distinct functions that are required for the maintenance of spermatogenesis and male fertility. PMID- 26607722 TI - The value of control conditions for evaluating pharmacogenetic effects. PMID- 26607723 TI - Influence of network topology on cooperative problem-solving systems. AB - The idea of a collective intelligence behind the complex natural structures built by organisms suggests that the organization of social networks is selected so as to optimize problem-solving competence at the group level. Here we study the influence of the social network topology on the performance of a group of agents whose task is to locate the global maxima of NK fitness landscapes. Agents cooperate by broadcasting messages informing on their fitness and use this information to imitate the fittest agent in their influence networks. In the case those messages convey accurate information on the proximity of the solution (i.e., for smooth fitness landscapes), we find that high connectivity as well as centralization boosts the group performance. For rugged landscapes, however, these characteristics are beneficial for small groups only. For large groups, it is advantageous to slow down the information transmission through the network to avoid local maximum traps. Long-range links and modularity have marginal effects on the performance of the group, except for a very narrow region of the model parameters. PMID- 26607724 TI - Interplay between CRP, Atherogenic LDL, and LOX-1 and Its Potential Role in the Pathogenesis of Atherosclerosis. AB - BACKGROUND: Studies have shown that the classic acute-phase protein C-reactive protein (CRP) has proinflammatory effects on vascular cells and may play a causal role in the pathogenesis of coronary artery disease. A growing body of evidence has suggested that interplay between CRP, lectin-like oxidized LDL receptor-1 (LOX-1), and atherogenic LDL may underlie the mechanism of endothelial dysfunction that leads to atherosclerosis. CONTENT: We review the biochemical evidence for an association of CRP, LOX-1, and either oxidized LDL (OxLDL) or electronegative L5 LDL with the pathogenesis of coronary artery disease. Artificially oxidized OxLDL has been studied extensively for its role in atherogenesis, as has electronegative L5 LDL, which is present at increased levels in patients with increased cardiovascular risks. OxLDL and L5 have been shown to stimulate human aortic endothelial cells to produce CRP, indicating that CRP is synthesized locally in the endothelium. The ligand-binding face (B-face) of CRP has been shown to bind the LOX-1 scavenger receptor and increase LOX-1 expression in endothelial cells, thereby promoting the uptake of OxLDL or L5 by LOX-1 into endothelial cells to induce endothelial dysfunction. SUMMARY: CRP and LOX-1 may form a positive feedback loop with OxLDL or L5 in atherogenesis, whereby increased levels of atherogenic LDL in patients with cardiovascular risks induce endothelial cells to express CRP, which may in turn increase the expression of LOX-1 to promote the uptake of atherogenic LDL into endothelial cells. Further research is needed to confirm a causal role for CRP in atherogenesis. PMID- 26607725 TI - Clinical Trials in Precision Oncology. AB - BACKGROUND: Availability of genomic information used in the management of cancer treatment has outpaced both regulatory and reimbursement efforts. Many types of clinical trials are underway to validate the utility of emerging genome-based biomarkers for diagnostic, prognostic, and predictive applications. Clinical trials are a key source of evidence required for US Food and Drug Administration approval of therapies and companion diagnostics and for establishing the acceptance criteria for reimbursement. CONTENT: Determining the eligibility of patients for molecular-based clinical trials and the interpretation of data emerging from clinical trials is significantly hampered by 2 primary factors: the lack of specific reporting standards for biomarkers in clinical trials and the lack of adherence to official gene and variant naming standards. Clinical trial registries need specifics on the mutation required for enrollment as opposed to allowing a generic mutation entry such as, "EGFR mutation." The use of clinical trials data in bioinformatics analysis and reporting is also gated by the lack of robust, state of the art programmatic access support. An initiative is needed to develop community standards for clinical trial descriptions and outcome reporting that are modeled after similar efforts in the genomics research community. SUMMARY: Systematic implementation of reporting standards is needed to insure consistency and specificity of biomarker data, which will in turn enable better comparison and assessment of clinical trial outcomes across multiple studies. Reporting standards will facilitate improved identification of relevant clinical trials, aggregation and comparison of information across independent trials, and programmatic access to clinical trials databases. PMID- 26607727 TI - Genome-wide association study and biological pathway analysis of the Eimeria maxima response in broilers. AB - BACKGROUND: Coccidiosis is the most common and costly disease in the poultry industry and is caused by protozoans of the Eimeria genus. The current control of coccidiosis, based on the use of anticoccidial drugs and vaccination, faces serious obstacles such as drug resistance and the high costs for the development of efficient vaccines, respectively. Therefore, the current control programs must be expanded with complementary approaches such as the use of genetics to improve the host response to Eimeria infections. Recently, we have performed a large scale challenge study on Cobb500 broilers using E. maxima for which we investigated variability among animals in response to the challenge. As a follow up to this challenge study, we performed a genome-wide association study (GWAS) to identify genomic regions underlying variability of the measured traits in the response to Eimeria maxima in broilers. Furthermore, we conducted a post-GWAS functional analysis to increase our biological understanding of the underlying response to Eimeria maxima challenge. RESULTS: In total, we identified 22 single nucleotide polymorphisms (SNPs) with q value <0.1 distributed across five chromosomes. The highly significant SNPs were associated with body weight gain (three SNPs on GGA5, one SNP on GGA1 and one SNP on GGA3), plasma coloration measured as optical density at wavelengths in the range 465-510 nm (10 SNPs and all on GGA10) and the percentage of beta2-globulin in blood plasma (15 SNPs on GGA1 and one SNP on GGA2). Biological pathways related to metabolic processes, cell proliferation, and primary innate immune processes were among the most frequent significantly enriched biological pathways. Furthermore, the network based analysis produced two networks of high confidence, with one centered on large tumor suppressor kinase 1 (LATS1) and 2 (LATS2) and the second involving the myosin heavy chain 6 (MYH6). CONCLUSIONS: We identified several strong candidate genes and genomic regions associated with traits measured in response to Eimeria maxima in broilers. Furthermore, the post-GWAS functional analysis indicates that biological pathways and networks involved in tissue proliferation and repair along with the primary innate immune response may play the most important role during the early stage of Eimeria maxima infection in broilers. PMID- 26607728 TI - Assessing childhood maltreatment and mental health correlates of disordered eating profiles in a nationally representative sample of English females. AB - PURPOSE: Previous research suggests that childhood maltreatment is associated with the onset of eating disorders (ED). In turn, EDs are associated with alternative psychopathologies such as depression and posttraumatic stress disorder (PTSD), and with suicidality. Moreover, it has been reported that various ED profiles may exist. The aim of the current study was to examine the profiles of disordered eating and the associations of these with childhood maltreatment and with mental health psychopathology. METHODS: The current study utilised a representative sample of English females (N = 4206) and assessed for the presence of disordered eating profiles using Latent Class Analysis. Multinomial logistic regression was implemented to examine the associations of childhood sexual and physical abuse with the disordered eating profiles and the associations of these with PTSD, depression and suicidality. RESULTS: Results supported those of previous findings in that we found five latent classes of which three were regarded as disordered eating classes. Significant relationships were found between these and measures of childhood trauma and mental health outcomes. CONCLUSIONS: Childhood sexual and physical abuse increased the likelihood of membership in disordered eating classes and these in turn increased the likelihood of adverse mental health and suicidal outcomes. PMID- 26607729 TI - Young people who self-harm: a prospective 1-year follow-up study. AB - PURPOSE: To explore repetition, service provision and service engagement following presentation of young people to emergency services with self-harm. METHODS: 969 patients who presented to accident and emergency services after self harm were followed up prospectively for a period of 1 year. Data on rates, method, clinical history, initial service provision, engagement and repetition (defined as re-presenting to emergency services with further self-harm) were gathered from comprehensive electronic records. RESULTS: Young people were less likely to repeat self-harm compared to those aged 25 and above. A psychiatric history and a history of childhood trauma were significant predictors of repetition. Young people were more likely to receive self-help as their initial service provision, and less likely to receive acute psychiatric care or a hospital admission. There were no differences in engagement with services between young people and those aged 25 and above. CONCLUSION: Younger individuals may be less vulnerable to repetition, and are less likely to represent to services with repeated self-harm. All young people who present with self-harm should be screened for mental illness and asked about childhood trauma. Whilst young people are less likely to be referred to psychiatric services, they do attend when referred. This may indicate missed opportunity for intervention. PMID- 26607730 TI - The trees and the forest: mixed methods in the assessment of recovery based interventions' processes and outcomes in mental health. AB - BACKGROUND: Recent developments in mental health have emphasized recovery as an outcome for people with serious mental illness (SMI). Accordingly, several studies have attempted to evaluate the process and outcome of recovery-oriented psychosocial interventions. AIMS: To review and discuss quantitative and qualitative findings from previous efforts to study the impact of five recovery oriented interventions: Illness Management and Recovery (IMR), Narrative Enhancement and Cognitive Therapy (NECT), Supported Employment (SE), Supported Socialization (SS), and Family Psychoeducation. METHODS: Reviewing the literature on studies that examine the effectiveness of these interventions by using both quantitative and qualitative approach. RESULTS: Qualitative findings in these studies augment quantitative findings and at times draw attention to unexpected findings and uniquely illuminate the effects of these interventions on self reflective processes. CONCLUSIONS: There is a need for further exploration of how mixed-methods can be implemented to explore recovery-oriented outcomes. Critical questions regarding the implications of qualitative findings are posed. PMID- 26607732 TI - Confirmation of tracheal intubation time in adult patients. PMID- 26607731 TI - Delta9-Tetrahydrocannabinol (Delta9-THC) Promotes Neuroimmune-Modulatory MicroRNA Profile in Striatum of Simian Immunodeficiency Virus (SIV)-Infected Macaques. AB - Cannabinoid administration before and after simian immunodeficiency virus (SIV) inoculation ameliorated disease progression and decreased inflammation in male rhesus macaques. Delta9-tetrahydrocannabinol (Delta9-THC) did not increase viral load in brain tissue or produce additive neuropsychological impairment in SIV infected macaques. To determine if the neuroimmunomodulation of Delta9-THC involved differential microRNA (miR) expression, miR expression in the striatum of uninfected macaques receiving vehicle (VEH) or Delta9-THC (THC) and SIV infected macaques administered either vehicle (VEH/SIV) or Delta9-THC (THC/SIV) was profiled using next generation deep sequencing. Among the 24 miRs that were differentially expressed among the four groups, 16 miRs were modulated by THC in the presence of SIV. These 16 miRs were classified into four categories and the biological processes enriched by the target genes determined. Our results indicate that Delta9-THC modulates miRs that regulate mRNAs of proteins involved in 1) neurotrophin signaling, 2) MAPK signaling, and 3) cell cycle and immune response thus promoting an overall neuroprotective environment in the striatum of SIV-infected macaques. This is also reflected by increased Brain Derived Neurotrophic Factor (BDNF) and decreased proinflammatory cytokine expression compared to the VEH/SIV group. Whether Delta9-THC-mediated modulation of epigenetic mechanisms provides neuroprotection in other regions of the brain and during chronic SIV-infection remains to be determined. PMID- 26607733 TI - Pediatric anesthesia: current status and future directions. PMID- 26607735 TI - Painful Pagetic vertebra palliated with percutaneous vertebral augmentation. PMID- 26607734 TI - The Effect of Swimming During Childhood and Adolescence on Bone Mineral Density: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The effects of swimming on bone mineral density (BMD) have been studied by several researchers, with inconsistent results. AIM: This meta analysis aims to determine whether systematic swimming training may influence BMD during childhood and adolescence. METHODS: A systematic search was performed in PubMed, SPORTDiscus and ClinicalTrials.gov from the earliest possible year to March 2015, with data extraction and quality assessment performed independently by two researchers following the PRISMA methodology. Swimmers were compared to sedentary controls and to athletes performing highly osteogenic sports. Therefore, a total of two meta-analyses were developed. RESULTS: Fourteen studies met the inclusion criteria and were included in the meta-analyses. Swimmers presented similar BMD values to sedentary controls and lower than other high impact athletes. Femoral neck and lumbar spine BMD differences between swimmers and sedentary controls and between swimmers and athletes practicing osteogenic sports appeared to increase with age and favored the non-swimming groups. There were no differences by sex. CONCLUSION: While swimming is associated with several health benefits, it does not appear to be an effective sport for improving BMD. Swimmers might be in need of additional osteogenic exercises for increasing BMD values. PMID- 26607736 TI - Basic science behind the cardiovascular benefits of exercise. AB - Cardiorespiratory fitness is a strong predictor of cardiovascular (CV) disease and all-cause mortality, with increases in cardiorespiratory fitness associated with corresponding decreases in CV disease risk. The effects of exercise upon the myocardium and vascular system are dependent upon the frequency, intensity and duration of the exercise itself. Following a prolonged period (>= 6 months) of regular intensive exercise in previously untrained individuals, resting and submaximal exercising heart rates are typically 5-20 beats lower, with an increase in stroke volume of ~ 20% and enhanced myocardial contractility. Structurally, all four heart chambers increase in volume with mild increases in wall thickness, resulting in greater cardiac mass due to increased myocardial cell size. With this in mind, the present paper aims to review the basic science behind the CV benefits of exercise. Attention will be paid to understanding (1) the relationship between exercise and cardiac remodelling; (2) the cardiac cellular and molecular adaptations in response to exercise, including the examination of molecular mechanisms of physiological cardiac growth and applying these mechanisms to identify new therapeutic targets to prevent or reverse pathological remodelling and heart failure; and (3) vascular adaptations in response to exercise. Finally, this review will briefly examine how to optimise the CV benefits of exercise by considering how much and how intense exercise should be. PMID- 26607737 TI - Lung consequences in adults born prematurely. AB - Although survival has improved significantly in recent years, prematurity remains a major cause of infant and childhood mortality and morbidity. Preterm births (<37 weeks of gestation) account for 8% of live births representing >50,000 live births each year in the UK. Preterm birth, irrespective of whether babies require neonatal intensive care, is associated with increased respiratory symptoms, partially reversible airflow obstruction and abnormal thoracic imaging in childhood and in young adulthood compared with those born at term. Having failed to reach their optimal peak lung function in early adulthood, there are as yet unsubstantiated concerns of accelerated lung function decline especially if exposed to noxious substances leading to chronic respiratory illness; even if the rate of decline in lung function is normal, the threshold for respiratory symptoms will be crossed early. Few adult respiratory physicians enquire about the neonatal period in their clinical practice. The management of these subjects in adulthood is largely evidence free. They are often labelled as asthmatic although the underlying mechanisms are likely to be very different. Smoking cessation, maintaining physical fitness, annual influenza immunisation and a general healthy lifestyle should be endorsed irrespective of any symptoms. There are a number of clinical and research priorities to maximise the quality of life and lung health in the longer term not least understanding the underlying mechanisms and optimising treatment, rather than extrapolating from other airway diseases. PMID- 26607738 TI - Resilience: for and against. PMID- 26607739 TI - Differential roles of the hemerythrin-like proteins of Mycobacterium smegmatis in hydrogen peroxide and erythromycin susceptibility. AB - Hemerythrin-like proteins are oxygen-carrying non-heme di-iron binding proteins and their functions have effect on oxidation-reduction regulation and antibiotic resistance. Recent studies using bioinformatic analyses suggest that multiple hemerythrin-like protein coding sequences might have been acquired by lateral gene transfer and the number of hemerythrin-like proteins varies amongst different species. Mycobacterium smegmatis contains three hemerythrin-like proteins, MSMEG_3312, MSMEG_2415 and MSMEG_6212. In this study, we have systematically analyzed all three hemerythrin-like proteins in M. smegmatis and our results identified and characterized two functional classes: MSMEG_2415 plays an important role in H2O2 susceptibility, and MSMEG_3312 and MSMEG_6212 are associated with erythromycin susceptibility. Phylogenetic analysis indicated that these three proteins have different evolutionary origins, possibly explaining their different physiological functions. Here, combined with biological and phylogenetic analyses, our results provide new insights into the evolutionary divergence of the hemerythrin-like proteins in M. smegmatis. PMID- 26607740 TI - Optimized Protocol To Analyze Changes in the Lipidome of Xenografts after Treatment with 2-Hydroxyoleic Acid. AB - Xenografts are a popular model for the study of the action of new antitumor drugs. However, xenografts are highly heterogeneous structures, and therefore it is sometimes difficult to evaluate the effects of the compounds on tumor metabolism. In this context, imaging mass spectrometry (IMS) may yield the required information, due to its inherent characteristics of sensitivity and spatial resolution. To the best of our knowledge, there is still no clear analysis protocol to properly evaluate the changes between samples due to the treatment. Here we present a protocol for the evaluation of the effect of 2 hydroxyoleic acid (2-OHOA), an antitumor compound, on xenografts lipidome based on IMS. Direct treated/control comparison did not show conclusive results. As we will demonstrate, a more sophisticated protocol was required to evaluate these changes including the following: (1) identification of different areas in the xenograft, (2) classification of these areas (necrotic/viable) to compare similar types of tissues, (3) suppression of the effect of the variation of adduct formation between samples, and (4) normalization of the variables using the standard deviation to eliminate the excessive impact of the stronger peaks in the statistical analysis. In this way, the 36 lipid species that experienced the largest changes between treated and control were identified. Furthermore, incorporation of 2-hydroxyoleic acid to a sphinganine base was also confirmed by MS/MS. Comparison of the changes observed here with previous results obtained with different techniques demonstrates the validity of the protocol. PMID- 26607742 TI - Transparent Conductive Nanofiber Paper for Foldable Solar Cells. AB - Optically transparent nanofiber paper containing silver nanowires showed high electrical conductivity and maintained the high transparency, and low weight of the original transparent nanofiber paper. We demonstrated some procedures of optically transparent and electrically conductive cellulose nanofiber paper for lightweight and portable electronic devices. The nanofiber paper enhanced high conductivity without any post treatments such as heating or mechanical pressing, when cellulose nanofiber dispersions were dropped on a silver nanowire thin layer. The transparent conductive nanofiber paper showed high electrical durability in repeated folding tests, due to dual advantages of the hydrophilic affinity between cellulose and silver nanowires, and the entanglement between cellulose nanofibers and silver nanowires. Their optical transparency and electrical conductivity were as high as those of ITO glass. Therefore, using this conductive transparent paper, organic solar cells were produced that achieved a power conversion of 3.2%, which was as high as that of ITO-based solar cells. PMID- 26607741 TI - Predicting prognosis and therapeutic response from interactions between lymphocytes and tumor cells. AB - As epithelial tumors grow from single cells to a malignant mass of invasive tissue, they must exploit the innate inflammatory response, while evading the adaptive immune system. Prognosis of solid tumors has historically focused on macroscopic features such as size, grade, and mitotic index. It is now clear that prognosis assessment must also consider the stromal and immune cells that surround and infiltrate the tumor. Tumors promote growth, angiogenesis, and tissue remodeling by subverting the normal functions of macrophages and other cells of the innate immune system that inhabit their microenvironment. Simultaneously, tumor cells escape from and inactivate the adaptive immune system by exploiting the mechanisms preventing damaging auto-immune responses in cytotoxic T cells. The presence of CD8(+) T cells within epithelial tumors is now a well-supported marker of better prognosis in many tumor types. However, this benefit is counterbalanced by immune regulatory cell populations that promote tumor escape from immune surveillance and metastasis. Therapeutic approaches that kill tumor cells selectively by re-activating immune checkpoints are becoming an established therapeutic option, but it is not yet clear how to identify which patients will benefit from this treatment modality. Evidence is accumulating that identifying the presence of T cell-activating neoantigens, produced by mutated proteins in tumors, will play an important role in checkpoint inhibitor prognosis. This review provides an overview of the evidence that lymphocytic infiltration of tumors has prognostic value in many epithelial tumor types and is linked to the success of chemical and immune checkpoint therapeutic strategies. PMID- 26607743 TI - Efficacy and safety of onabotulinumtoxinA therapy are sustained over 4 years of treatment in patients with neurogenic detrusor overactivity: Final results of a long-term extension study. AB - AIMS: To present final efficacy/safety results from a prospective, long-term extension trial of onabotulinumtoxinA for urinary incontinence (UI) due to neurogenic detrusor overactivity (NDO); patients received treatment for up to 4 years. METHODS: Patients who completed a 52-week, phase III trial of onabotulinumtoxinA for NDO were eligible to enter a 3-year, multicenter, open label extension study of intradetrusor onabotulinumtoxinA (200U or 300U). Patients were treated "as needed" based on their request and fulfillment of prespecified qualification criteria (>=12 weeks since previous treatment and a UI episode threshold). Assessments included change from study baseline in UI episodes/day (primary efficacy measure), volume/void, and Incontinence Quality of Life (I-QOL) total score (week 6); duration of effect; adverse events (AEs); and initiation of de novo clean intermittent catheterization (CIC). Data are presented for up to six treatments. RESULTS: OnabotulinumtoxinA 200U consistently reduced UI episodes/day; reductions from baseline ranged from -3.2 to -4.1 across six treatments. Volume/void consistently increased, nearly doubling after treatment. I-QOL improvements were consistently greater than twice the minimally important difference (+11 points). Overall median duration of effect was 9.0 months (200U). Results were similar for onabotulinumtoxinA 300U. Most common AEs were urinary tract infections and urinary retention. De novo CIC rates were 29.5, 3.4, and 6.0% (200U), and 43.0, 15.0, and 4.8% (300U) for treatments 1-3, respectively; de novo CIC rates were 0% for treatments 4-6. CONCLUSIONS: OnabotulinumtoxinA treatments consistently improve UI, volume/void, and QOL in patients with UI due to NDO in this 4-year study, with no new safety signals. Neurourol. Urodynam. 36:368-375, 2017. (c) 2015 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc. PMID- 26607744 TI - In the Endemic Setting, Clostridium difficile Ribotype 027 Is Virulent But Not Hypervirulent - ERRATUM. PMID- 26607747 TI - "Rediscovering holism": Palliative Care Congress 2016. PMID- 26607745 TI - Pronator quadratus repair after volar plating of distal radius fractures or not? Results of a prospective randomized trial. AB - BACKGROUND: The purpose of the present study was to investigate the influence of the pronator quadratus (PQ) muscle repair following volar plate fixation of distal radius fractures with special regards to the forearm pronation strength. During the early recovery period of 3 months, an improvement of pronation strength and functional scorings was hypothesized for the PQ repair when compared to no repair. METHODS: The inclusion criteria were (1) men or women between 18 and 80 years, (2) isolated, closed fractures of the distal radius, (3) A2 to B2 types of fracture according to the AO fracture classification system, (4) primary volar locking plate osteosynthesis. Patients were randomized to group A = PQ repair and group B = no repair. Follow-up examinations after 6 and 12 weeks included bilateral isometric pronation strength measurement, range of motion, the QuickDASH and the Mayo-Wrist-Score, and a visual analog scale (VAS). RESULTS: 60 patients (n = 31 in group A and n = 29 in group B) with an average age of 54 years (range 22-77 years) returned for both follow-up visits. The pronation strength measurements showed no significant differences between groups (PQ repair vs. no repair) neither at 6 weeks nor at 12 weeks. Additionally, no statistical significant differences were noted for ROM, QuickDASH-Score or Mayo-Wrist-Score. The VAS scoring revealed a significant decreased pain level after PQ repair at 6 weeks postoperatively (p = 0.017). CONCLUSION: An improved pronation strength after PQ repair in the early rehabilitation period could not be confirmed. However, the PQ repair might reduce pain in the early postoperative period. TRIAL REGISTRATION NUMBER: NCT02595229 (ClinicalTrials.gov, registered 02 November 2015). PMID- 26607749 TI - A complete smoking ban in psychiatric hospitals is ethically wrong. PMID- 26607750 TI - Anomalous Near-Surface Low-Salinity Pulses off the Central Oregon Coast. AB - From mid-May to August 2011, extreme runoff in the Columbia River ranged from 14,000 to over 17,000 m(3)/s, more than two standard deviations above the mean for this period. The extreme runoff was the direct result of both melting of anomalously high snowpack and rainfall associated with the 2010-2011 La Nina. The effects of this increased freshwater discharge were observed off Newport, Oregon, 180 km south of the Columbia River mouth. Salinity values as low as 22, nine standard deviations below the climatological value for this period, were registered at the mid-shelf. Using a network of ocean observing sensors and platforms, it was possible to capture the onshore advection of the Columbia River plume from the mid-shelf, 20 km offshore, to the coast and eventually into Yaquina Bay (Newport) during a sustained wind reversal event. Increased freshwater delivery can influence coastal ocean ecosystems and delivery of offshore, river-influenced water may influence estuarine biogeochemistry. PMID- 26607751 TI - Photoinduced Electron Transfer between Psoralens and DNA: Influence of DNA Sequence and Substitution. AB - Psoralens are heterocyclic compounds which are, among other uses, used to treat skin deseases in the framework of PUVA therapy. In the dark, they intercalate into DNA and can form photoadducts with thymines upon UV-A excitation, which harms the affected cells. We have recently discovered that after excitation of intercalated psoralens, an efficient photoinduced electron transfer (PET) from DNA occurs. Here, the PET is studied in detail by means of femtosecond transient absorption spectroscopy. Using DNA samples that contain either only GC or AT base pairs, we show that only guanine donates the electrons. Additionally, the substituent effects on PET are studied relying on three different psoralen derivatives. The substitution alters spectroscopic and electrochemical properties of the psoralens, which are determined by cyclic voltammetry and steady state spectroscopy. These experiments allow us to estimate the PET energetics, which are in line with the measured kinetics. Implications for the applications of psoralens are discussed. PMID- 26607752 TI - Economic Assessment of Zoonoses Surveillance in a 'One Health' Context: A Conceptual Framework. AB - Collaboration between animal and public health sectors has been highlighted as a means to improve the management of zoonotic threats. This includes surveillance systems for zoonoses, where enhanced cross-sectoral integration and sharing of information are seen as key to improved public health outcomes. Yet, there is a lack of evidence on the economic returns of such collaboration, particularly in the development and implementation of surveillance programmes. The economic assessment of surveillance in this context needs to be underpinned by the understanding of the links between zoonotic disease surveillance in animal populations and the wider public health disease mitigation process and how these relations impact on the costs and benefits of the surveillance activities. This study presents a conceptual framework of these links as a basis for the economic assessment of cross-sectoral zoonoses surveillance with the aim of supporting the prioritization of resource allocation to surveillance. In the proposed framework, monetary, non-monetary and intermediate or intangible cost components and benefit streams of three conceptually distinct stages of zoonotic disease mitigation are identified. In each stage, as the final disease mitigation objective varies so does the use of surveillance information generated in the animal populations for public health decision-making. Consequently, the associated cost components and benefit streams also change. Building on the proposed framework and taking into account these links, practical steps for its application are presented and future challenges are discussed. PMID- 26607753 TI - An ethnobotany of the Lukomir Highlanders of Bosnia & Herzegovina. AB - BACKGROUND: This aim of this study is to report upon traditional knowledge and use of wild medicinal plants by the Highlanders of Lukomir, Bjelasnica, Bosnia and Herzegovina (B&H). The Highlanders are an indigenous community of approximately 60 transhumant pastoralist families who speak Bosnian (Bosanski) and inhabit a highly biodiverse region of Europe. This paper adds to the growing record of traditional use of wild plants within isolated communities in the Balkans. METHODS: An ethnobotanical study using consensus methodology was conducted in Lukomir in Bjelasnica's mountains and canyons. Field work involved individual semi-structured interviews during which informants described plants, natural product remedies, and preparation methods on field trips, garden tours, while shepherding, or in settings of their choice. Plant use categories were ranked with informant consensus factor and incorporated into a phylogenetic tree. Plants cited were compared to other ethnobotanical surveys of the country. RESULTS: Twenty five people were interviewed, resulting in identification of 58 species (including two subspecies) from 35 families, which were cited in 307 medicinal, 40 food, and seven material use reports. Individual plant uses had an average consensus of five and a maximum consensus of 15 out of 25. There were a number of rare and endangered species used as poisons or medicine that are endemic to Flora Europaea and found in Lukomir. Ten species (including subspecies) cited in our research have not previously been reported in the systematic ethnobotanical surveys of medicinal plant use in B&H: (Elymus repens (L.) Gould, Euphorbia myrsinites L., Jovibarba hirta (L.) Opiz, Lilium bosniacum (Beck) Fritsch, Matricaria matricarioides (Less.) Porter ex Britton, Phyllitis scolopendrium (L.) Newman, Rubus saxatilis L., Silene uniflora Roth ssp. glareosa (Jord.) Chater & Walters, Silene uniflora Roth ssp. prostrata (Gaudin) Chater & Walters, Smyrnium perfoliatum L.). New uses not reported in any of the aforementioned systematic surveys were cited for a total of 28 species. Thirteen percent of medicinal plants cited are endemic: Helleborus odorus Waldst. et Kit., Gentiana lutea L., Lilium bosniacum (Beck) Fritsch, Silene uniflora Roth ssp. glareosa (Jord.) Chater & Walters., Silene uniflora Roth ssp. prostrata (Gaudin) Chater & Walters, Salvia officinalis L., Jovibarba hirta (L.) Opiz, and Satureja montana L. CONCLUSIONS: These results report on the cohesive tradition of medicinal plant use among healers in Lukomir, Bosnia and Herzegovina. This work facilitates the community's development by facilitating local and international conversations about their traditional medicine and sharing insight for conservation in one of Europe's most diverse endemic floristic regions, stewarded by one of Europe's last traditional Highland peoples. PMID- 26607754 TI - Embedding Ba Monolayers and Bilayers in Boron Carbide Nanowires. AB - Aberration corrected high angle annular dark field scanning transmission electron microscopy (HAADF-STEM) was employed to study the distribution of barium atoms on the surfaces and in the interiors of boron carbide based nanowires. Barium based dopants, which were used to control the crystal growth, adsorbed to the surfaces of the boron-rich crystals in the form of nanometer-thick surficial films (a type of surface complexion). During the crystal growth, these dopant-based surface complexions became embedded inside the single crystalline segments of fivefold boron-rich nanowires collectively, where they were converted to more ordered monolayer and bilayer modified complexions. Another form of bilayer complexion stabilized at stacking faults has also been identified. Numerous previous works suggested that dopants/impurities tended to segregate at the stacking faults or twinned boundaries. In contrast, our study revealed the previously-unrecognized possibility of incorporating dopants and impurities inside an otherwise perfect crystal without the association to any twin boundary or stacking fault. Moreover, we revealed the amount of barium dopants incorporated was non-equilibrium and far beyond the bulk solubility, which might lead to unique properties. PMID- 26607755 TI - Assessing alcohol abstinence self-efficacy in undergraduate students: psychometric evaluation of the alcohol abstinence self-efficacy scale. AB - BACKGROUND: Alcohol use is a major public health concern with respect to its impact on youth morbidity and mortality. Self-efficacy to abstain from alcohol use in young people is an important prevention and intervention strategy in future alcohol dependence. However, research on the assessment of self-efficacy to abstain from alcohol use among undergraduate students is almost non-existent in Ghana, apparently due to the unavailability of a standardised testing instrument. The purpose of this study was to examine the factor validity, structure, and reliability of the 20-item Alcohol Abstinence Self-efficacy Scale (AASES) in undergraduate students in Ghana. FINDINGS: Two hundred and fifteen undergraduate students studying in a private university with a mean age of 23.5 years participated in the study by completing the AASES. Results of a confirmatory factor analysis showed that the data did not fit the initial four factor AASES model. Subsequent exploratory factor analysis showed that the AASES is a unidimensional construct (in the total sample and a subsample of drinkers), contrary to findings found in western cultures. The AASES also had a high Cronbach's alpha. Although the AASES was unidimensional in this study, each of the original four-factor model also had high and acceptable Cronbach's alpha. CONCLUSION: The original AASES structure was not confirmed in this study but a unidimensional factor was found suggesting that the AASES could be used as an instrument for assessing alcohol abstinence self-efficacy in undergraduate students in Ghana, although further validation research is needed in larger as well as in different samples. PMID- 26607756 TI - BTA. PMID- 26607757 TI - The development of a framework to integrate evidence into a national injury prevention strategy. AB - BACKGROUND: Injury is the leading cause of death from birth to age 34 in Canada (Statistics Canada, 2008). In 2013, a national injury prevention organization in Canada initiated a research-practitioner collaboration to establish a framework for incorporating evidence in the organization's decision-making. In this study, we outline the development process and provide an overview of the framework. METHODS: The process of development of the evidence-synthesis framework included consultation with national and international injury prevention experts, a review of the research literature to identify existing models for incorporating research evidence into public health practice and extensive interactions with the organization's leadership and staff. RESULTS: A framework emphasizing four types of research evidence was recommended: (i) epidemiologic evidence describing the burden and cause of injury, (ii) evidence concerning the effectiveness of interventions, (iii) evidence on effective methods for implementing promising interventions at a population level, and (iv) evidence and theory from the behavioral sciences. Through the evidence-synthesis process the framework prioritizes highly synthesized evidence-based strategies and draws attention to important research gaps. CONCLUSIONS: This study describes a novel opportunity to operationalize an organization's commitment to integrate evidence into practice. The framework provides guidance on how to use evidence strategically to maximize the potential impact of prevention efforts. Opportunities for further evaluation and dissemination are discussed. PMID- 26607758 TI - Protein tyrosine phosphatases receptor type D is a potential tumour suppressor gene inactivated by deoxyribonucleic acid methylation in paediatric acute myeloid leukaemia. AB - AIM: Protein tyrosine phosphatases receptor type D (PTPRD) is a tumour suppressor gene, and its epigenetic silencing is frequently found in glioblastoma. As aberrant deoxyribonucleic acid (DNA) methylation patterning has been shown to play a role in leukaemogenesis, we studied the promoter methylation, expression profiles and molecular functions of PTPRD in paediatric patients with acute myeloid leukaemia (AML). METHODS: Bone marrow specimens were obtained from 32 Chinese patients with a mean age of 7.2 years (range 1.1-16.5). PTPRD and methylation status were evaluated by real-time polymerase chain reaction (PCR) and methylation-specific PCR. Western blot and flow cytometry techniques were also used. RESULTS: PTPRD expression was decreased by promoter region methylation in six AML cells and methylated in 21 (65.6%) of the 32 samples. In addition, PTPRD expression could be induced by the DNA demethylating agent 5-aza-2' deoxycytidine. Furthermore, functional studies showed that overexpression of PTPRD in AML cells inhibited cell proliferation and clonogenicity as well as inducing apoptosis. However, PTPRD knockdown increased cell proliferation. These effects were associated with downregulation of cyclin D1, c-myc and upregulation of Bax. CONCLUSION: The results of this study demonstrated that PTPRD was a potential tumour suppressor gene inactivated by DNA methylation in paediatric AML. PMID- 26607759 TI - beta cell membrane remodelling and procoagulant events occur in inflammation driven insulin impairment: a GLP-1 receptor dependent and independent control. AB - Inflammation and hyperglycaemia are associated with a prothrombotic state. Cell derived microparticles (MPs) are the conveyors of active procoagulant tissue factor (TF) and circulate at high concentration in diabetic patients. Liraglutide, a glucagon-like peptide (GLP)-1 analogue, is known to promote insulin secretion and beta-cell preservation. In this in vitro study, we examined the link between insulin impairment, procoagulant activity and plasma membrane remodelling, under inflammatory conditions. Rin-m5f beta-cell function, TF activity mediated by MPs and their modulation by 1 MUM liraglutide were examined in a cell cross-talk model. Methyl-beta-cyclodextrine (MCD), a cholesterol depletor, was used to evaluate the involvement of raft on TF activity, MP shedding and insulin secretion as well as Soluble N-ethylmaleimide-sensitive factor Attachment protein Receptor (SNARE)-dependent exocytosis. Cytokines induced a two-fold increase in TF activity at MP surface that was counteracted by liraglutide. Microparticles prompted TF activity on the target cells and a two fold decrease in insulin secretion via protein kinase A (PKA) and p38 signalling, that was also abolished by liraglutide. Large lipid raft clusters were formed in response to cytokines and liraglutide or MCD-treated cells showed similar patterns. Cells pre-treated by saturating concentration of the GLP-1r antagonist exendin (9-39), showed a partial abolishment of the liraglutide-driven insulin secretion and liraglutide-decreased TF activity. Measurement of caspase 3 cleavage and MP shedding confirmed the contribution of GLP-1r-dependent and independent pathways. Our results confirm an integrative beta-cell response to GLP-1 that targets receptor-mediated signalling and membrane remodelling pointing at the coupling of insulin secretion and inflammation-driven procoagulant events. PMID- 26607760 TI - The pioneering work of George Mines on cardiac arrhythmias: groundbreaking ideas that remain influential in contemporary cardiac electrophysiology. AB - George Mines was a pioneering physiologist who, despite an extremely short period of professional activity and only primitive experimental methodology, succeeded in formulating concepts that continue to be of great influence today. Here, we review some of his most important discoveries and their impact on contemporary concepts and clinical practice. Mines' greatest contribution was his conceptualization and characterization of circus movement reentry. His observations and ideas about the basis for cardiac reentrant activity underlie how we understand and manage a wide range of important clinical rhythm disturbances today. The notions he introduced regarding the influence of premature extrastimuli on reentry (termination, resetting and entrainment) are central to contemporary assessment of arrhythmia mechanisms in clinical electrophysiology laboratories and modern device therapy of cardiac tachyarrhythmias. Refinements of his model of reentry have led to sophisticated biophysical theories of the mechanisms underlying cardiac fibrillation. His seminal observations on the influence of electrolyte derangements and autonomic tone on the heart are relevant to our understanding of the physiology and pharmacology of arrhythmias caused by cardiac pathology. In this era of advanced technology, it is important to appreciate that ideas of lasting impact come from great minds and do not necessarily require great tools. PMID- 26607761 TI - Acute loss of TET function results in aggressive myeloid cancer in mice. AB - TET-family dioxygenases oxidize 5-methylcytosine (5mC) in DNA, and exert tumour suppressor activity in many types of cancers. Even in the absence of TET coding region mutations, TET loss-of-function is strongly associated with cancer. Here we show that acute elimination of TET function induces the rapid development of an aggressive, fully-penetrant and cell-autonomous myeloid leukaemia in mice, pointing to a causative role for TET loss-of-function in this myeloid malignancy. Phenotypic and transcriptional profiling shows aberrant differentiation of haematopoietic stem/progenitor cells, impaired erythroid and lymphoid differentiation and strong skewing to the myeloid lineage, with only a mild relation to changes in DNA modification. We also observe progressive accumulation of phospho-H2AX and strong impairment of DNA damage repair pathways, suggesting a key role for TET proteins in maintaining genome integrity. PMID- 26607762 TI - Evaluation of recruitment methods for a trial targeting childhood obesity: Families for Health randomised controlled trial. AB - BACKGROUND: Recruitment to trials evaluating the effectiveness of childhood obesity management interventions is challenging. We report our experience of recruitment to the Families for Health study, a randomised controlled trial evaluating the effectiveness of a family-based community programme for children aged 6-11 years, versus usual care. We evaluated the effectiveness of active recruitment (contacting eligible families directly) versus passive recruitment (informing the community through flyers, public events, media). METHODS: Initial approaches included passive recruitment via the media (newspapers and radio) and two active recruitment methods: National Child Measurement Programme (letters to families with overweight children) and referrals from health-care professionals. With slow initial recruitment, further strategies were employed, including active (e.g. targeted letters from general practices) and passive (e.g. flyers, posters and public events) methods. At first enquiry from a potential participant, families were asked where they heard about the study. Further quantitative (questionnaire) and qualitative data (one-to-one interviews with parents/carers), were collected from recruited families at baseline and 3-month follow-up and included questions about recruitment. RESULTS: In total, 194 families enquired about Families for Health, and 115 (59.3 %) were recruited and randomised. Active recruitment yielded 85 enquiries, with 43 families recruited (50.6 %); passive recruitment yielded 99 enquiries with 72 families recruited (72.7 %). Information seen at schools or GP surgeries accounted for over a quarter of enquiries (28.4 %) and over a third (37.4 %) of final recruitment. Eight out of ten families who enquired this way were recruited. Media-led enquiries were low (5 %), but all were recruited. Children of families recruited actively were more likely to be Asian or mixed race. Despite extensive recruitment methods, the trial did not recruit as planned, and was awarded a no-cost extension to complete the 12-month follow-up. CONCLUSIONS: The higher number of participants recruited through passive methods may be due to the large number of potential participants these methods reached and because participants may see the information more than once. Recruiting to a child obesity treatment study is complex and it is advisable to use multiple recruitment strategies, some aiming at blanket coverage and some targeted at families with children who are overweight. TRIAL REGISTRATION: Current Controlled Trials ISRCTN45032201 (Date: 18 August 2011). PMID- 26607763 TI - Determining the 3D orientation of optically trapped upconverting nanorods by in situ single-particle polarized spectroscopy. AB - An approach to unequivocally determine the three-dimensional orientation of optically manipulated NaYF4:Er(3+),Yb(3+) upconverting nanorods (UCNRs) is demonstrated. Long-term immobilization of individual UCNRs inside single and multiple resonant optical traps allow for stable single UCNR spectroscopy studies. Based on the strong polarization dependent upconverted luminescence of UCNRs it is possible to unequivocally determine, in real time, their three dimensional orientation when optically trapped. In single-beam traps, polarized single particle spectroscopy has concluded that UCNRs orientate parallel to the propagation axis of the trapping beam. On the other hand, when multiple-beam optical tweezers are used, single particle polarization spectroscopy demonstrated how full spatial control over UCNR orientation can be achieved by changing the trap-to-trap distance as well as the relative orientation between optical traps. All these results show the possibility of real time three-dimensional manipulation and tracking of anisotropic nanoparticles with wide potential application in modern nanobiophotonics. PMID- 26607764 TI - A Superhydrophobic Surface Templated by Protein Self-Assembly and Emerging Application toward Protein Crystallization. AB - A proteinaceous superhydrophobic material for facile protein crystallization is reported. The lysozyme phase transition is rationally manipulated to form a reliable superhydrophobic coating on virtually arbitrary material surfaces with good thermostability and mechanical robustness. Such a surface exhibits a fascinating capability to drive protein crystallization, and the protein crystal array can be facilitated in a large area at an ultralow protein concentration. PMID- 26607765 TI - Analysis of urinary cathepsin C for diagnosing Papillon-Lefevre syndrome. AB - Papillon-Lefevre syndrome (PLS) (OMIM: 245000) is a rare disease characterized by severe periodontitis and palmoplantar keratoderma. It is caused by mutations in both alleles of the cathepsin C (CatC) gene CTSC that completely abrogate the proteolytic activity of this cysteine proteinase. Most often, a genetic analysis to enable early and rapid diagnosis of PLS is unaffordable or unavailable. In this study, we tested the hypothesis that active CatC is constitutively excreted and can be easily traced in the urine of normal subjects. If this is true, determining its absence in the urine of patients would be an early, simple, reliable, low-cost and easy diagnostic technique. All 75 urine samples from healthy control subjects (aged 3 months to 80 years) contained proteolytically active CatC and its proform, as revealed by kinetic analysis and immunochemical detection. Of the urine samples of 31 patients with a PLS phenotype, 29 contained neither proteolytically active CatC nor the CatC antigen, so that the PLS diagnosis was confirmed. CatC was detected in the urine of the other two patients, and genetic analysis revealed no loss-of-function mutation in CTSC, indicating that they suffer from a PLS-like condition but not from PLS. Screening for the absence of urinary CatC activity soon after birth and early treatment before the onset of PLS manifestations will help to prevent aggressive periodontitis and loss of many teeth, and should considerably improve the quality of life of PLS patients. PMID- 26607766 TI - Combining mapping of physiological quantitative trait loci and transcriptome for cold tolerance for counteracting male sterility induced by low temperatures during reproductive stage in rice. AB - Male sterility induced by low temperatures (LTs) during the reproductive stage is a major constraint for temperate zone rice. To detect physiological quantitative trait loci (QTLs), we modeled genotypic variation in the physiological processes involved in low temperature spikelet sterility on the basis of anther length (AL), a proxy for microspore and pollen grain number per anther. The model accounted for 83% of the genotypic variation in potential AL at normal temperature and the ability to maintain AL at LT. We tested the model on 208 recombinant inbred lines of cold-tolerant 'Tohoku-PL3' (PL3) * cold-sensitive 'Akihikari' (AH) for 2 years. QTLs for spikelet fertility (FRT) at LT were detected on chromosomes 5 (QTL for Cold Tolerance at Reproductive stage, qCTR5) and 12 (qCTR12). qCTR12 was annotated with the ability to maintain AL under LTs. qCTR5 was in a region shared with QTLs for culm length and heading date. Genome wide expression analysis showed 798 genes differentially expressed in the spikelets between the parents at LTs. Of these, 12 were near qCTR5 and 23 were near qCTR12. Gene expression analysis confirmed two candidate genes for qCTR5 (O methyltransferase ZRP4, Os05g0515600; beta-1,3-glucanase-like protein, Os05g0535100) and one for qCTR12 (conserved hypothetical protein, Os12g0550600). Nucleotide polymorphisms (21 deletions, 2 insertions and 10 single nucleotide polymorphisms) in PL3 were found near the candidate conserved hypothetical protein (Os12g0550600) and upstream in PL3, but not in AH. Haplotype analysis revealed that this gene came from 'Kuchum'. The combination of mapping physiological QTLs with gene expression analysis can be extended to identify other genes for abiotic stress response in cereals. PMID- 26607767 TI - Zwitterionic nanoparticles constructed from bioreducible RAFT-ROP double head agent for shell shedding triggered intracellular drug delivery. AB - Nanomedicines have emerged as indispensable platforms for cancer theranostics, however, the therapeutic outcomes were often compromised not only by the multiple biological barriers during the itinerary from the initial injection site to the intracellular action site but also the insufficient drug release at the pathological site. Herein, novel bioreducible double head agent, combining reversible addition-fragmentation chain transfer agent and ring opening polymerization initiator through disulfide linkage, was firstly prepared. Well defined cRGDfK-polycarboxybetaine methacrylate-SS-polycaprolactone block copolymers (termed as cRGD-PCSSL) were facilely synthesized using this initiator. Subsequently, shell sheddable and drug-encapsulated zwitterionic nanoparticles were constructed by one-step self-assembly with doxorubicin (DOX) (termed as cRGD PCSSL/DOX NPs). The reduction-responsive shedding of PCB shells resulted in the rapid loss of cRGD-PCSSL/DOX NPs stability in the presence of glutathione, facilitating the rapid DOX release. Results of flow cytometry and fluorescence microscopy demonstrated that cRGD-PCSSL/DOX NPs could be internalized by HepG2 cells via receptor-mediated endocytosis with fast intracellular drug release, leading to considerable cytotoxicity in comparison with free DOX. Importantly, the low protein adsorption and excellent serum stability properties of cRGD PCSSL/DOX NPs translated into prolonged systemic circulation and enhanced tumor accumulation. Furthermore, intravenous injection of cRGD-PCSSL/DOX NPs in tumor bearing mice exhibited significantly higher antitumor efficiency and lower systemic toxicity compared to free DOX. Consequently, the novel zwitterionic NPs, which facilely overcome the dilemma between multifunctionality and complexity by programmatically circumventing the multiple biological barriers, would represent a promising platform for enhanced anticancer drug delivery. STATEMENT OF SIGNIFICANCE: Herein, novel bioreducible RAFT and ROP double-head agent was first reported for the synthesis of cRGDfK-polycarboxybetaine methacrylate-SS polycaprolactone zwitterionic block copolymers (cRGD-PCB-SS-PCL, termed as cRGD PCSSL) through controllable polymerization methods. Firstly, this synthetic route surmounted the major disadvantage of most current used methods, which required thiol exchange reaction between active disulfide bond and free thiol groups at the chain ends. Secondly, the prepared cRGD-PCSSL/DOX NPs reasonably integrated cRGD for active tumor targeting and receptor-mediated endocytosis, zwitterionic PCB with nonfouling property for prolonged systemic circulation, disulfide linkage for reduction-responsive drug release, biodegradable PCL for hydrophobic anticancer drug loading. Finally, the systematic evaluation fully verified that the in vitro optimized cRGD-PCSSL/DOX NPs translated into significantly better therapeutic efficiency with reduced side effects in vivo. PMID- 26607768 TI - Stiffness, strength and adhesion characterization of electrochemically deposited conjugated polymer films. AB - Conjugated polymers such as poly(3,4-ethylenedioxythiphene) (PEDOT) are of interest for a variety of applications including interfaces between electronic biomedical devices and living tissue. The mechanical properties, strength, and adhesion of these materials to solid substrates are all vital for long-term applications. We have been developing methods to quantify the mechanical properties of conjugated polymer thin films. In this paper, the stiffness, strength and the interfacial shear strength (adhesion) of electrochemically deposited PEDOT and PEDOT-co-1,3,5-tri[2-(3,4-ethylene dioxythienyl)]-benzene (EPh) were studied. The estimated Young's modulus of the PEDOT films was 2.6+/ 1.4GPa, and the strain to failure was around 2%. The tensile strength was measured to be 56+/-27MPa. The effective interfacial shear strength was estimated with a shear-lag model by measuring the crack spacing as a function of film thickness. For PEDOT on gold/palladium-coated hydrocarbon film substrates an interfacial shear strength of 0.7+/-0.3MPa was determined. The addition of 5mole% of a tri-functional EDOT crosslinker (EPh) increased the tensile strength of the films to 283+/-67MPa, while the strain to failure remained about the same (2%). The effective interfacial shear strength was increased to 2.4+/-0.6MPa. STATEMENT OF SIGNIFICANCE: This paper describes methods for estimating the ultimate mechanical properties of electrochemically deposited conjugated polymer (here PEDOT and PEDOT copolymers) films. Of particular interest and novelty is our implementation of a cracking test to quantify the shear strength of the PEDOT thin films on these solid substrates. There is considerable interest in these materials as interfaces between biomedical devices and living tissue, however potential mechanisms and modes of failure are areas of continuing concern, and establishing methods to quantify the strengths of these interfaces are therefore of particular current interest. We are confident that these results will be useful to the broader biological materials community and are worthy of broader dissemination. PMID- 26607769 TI - Hierarchical structure and mechanical properties of snake (Naja atra) and turtle (Ocadia sinensis) eggshells. AB - After hundreds of million years of evolution, natural armors have evolved in various organisms, and has manifested in diverse forms such as eggshells, abalone shells, alligator osteoderms, turtle shells, and fish scales. Eggshells serve as multifunctional shields for successful embryogenesis, such as protection, moisture control and thermal regulation. Unlike calcareous avian eggshells which are brittle and hard, reptilians have leathery eggshells that are tough and flexible. Reptilian eggshells can withstand collision damages when laid in holes and dropped onto each other, and reduce abrasion caused by buried sand. In this study, we investigate structure and mechanical properties of eggshells of Taiwan cobra snake (Naja atra) and Chinese striped-neck turtle (Ocadia sinensis). From Acid Fuchsin Orange G (AFOG) staining and ATR-FTIR examination, we found that both eggshells are mainly composed of keratin. The mechanical properties of demineralized snake and turtle eggshells were evaluated by tensile and fracture tests and show distinctly difference. Turtle eggshells are relatively stiff and rigid, while snake eggshells behave as elastomers, which are highly extensible and reversible. The exceptional deformability (110-230% tensile strain) and toughness of snake eggshells are contributed by the wavy and random arrangement of keratin fibers as well as collagen layers. Multi-scale toughening mechanisms of snake eggshells were observed and elucidated, including crack deflection and twisting, fibers reorientation, sliding and bridging, inter-laminar shear effect, as well as the alpha-beta phase transition of keratin. Inspirations from the structural and mechanical designs of reptilian eggshells may lead to the synthesis of tough, extensible, lightweight composites which could be further applied in the flexible devices, packaging and bio-medical fields. STATEMENT OF SIGNIFICANCE: Amniotic eggshells serve as multifunctional shields for successful embryogenesis. The avian eggshells have been extensively studied while there are very few studies on reptilian eggshells and most of them focused on mineralization and embryotic development. For the first time, the hierarchical structure and mechanical properties of snake and turtle eggshells are comprehensively and comparatively studied. Both snake and turtle eggshells are multilayer, hierarchically-structured composites consisting mainly of keratin yet their mechanical behaviors are distinctly different. Turtle eggshells are stiff and rigid, while snake eggshells are highly extensible (>200%) and reversible due to multiple deformation stages, phase transition of keratin and various toughening mechanisms. We believe that this study will make positive scientific impact and interest the broad and multidisciplinary readership. PMID- 26607771 TI - Quantitative determination of opioids in whole blood using fully automated dried blood spot desorption coupled to on-line SPE-LC-MS/MS. AB - Opioids are well known, widely used painkillers. Increased stability of opioids in the dried blood spot (DBS) matrix compared to blood/plasma has been described. Other benefits provided by DBS techniques include point-of-care collection, less invasive micro sampling, more economical shipment, and convenient storage. Current methodology for analysis of micro whole blood samples for opioids is limited to the classical DBS workflow, including tedious manual punching of the DBS cards followed by extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalysis. The goal of this study was to develop and validate a fully automated on-line sample preparation procedure for the analysis of DBS micro samples relevant to the detection of opioids in finger prick blood. To this end, automated flow-through elution of DBS cards was followed by on-line solid-phase extraction (SPE) and analysis by LC-MS/MS. Selective, sensitive, accurate, and reproducible quantitation of five representative opioids in human blood at sub-therapeutic, therapeutic, and toxic levels was achieved. The range of reliable response (R(2) >=0.997) was 1 to 500 ng/mL whole blood for morphine, codeine, oxycodone, hydrocodone; and 0.1 to 50 ng/mL for fentanyl. Inter-day, intra-day, and matrix inter-lot accuracy and precision was less than 15% (even at lower limits of quantitation (LLOQ) level). The method was successfully used to measure hydrocodone and its major metabolite norhydrocodone in incurred human samples. Our data support the enormous potential of DBS sampling and automated analysis for monitoring opioids as well as other pharmaceuticals in both anti doping and pain management regimens. PMID- 26607770 TI - Polymer chain flexibility-induced differences in fetuin A adsorption and its implications on cell attachment and proliferation. AB - Tissue cells are known to respond to the stiffness of the polymer substrate on which they are grown. It has been suggested that material stiffness influences the composition of the protein layer that adsorbs to the material surface, which affects subsequent cell behavior. Previously, the stiffness of a biomaterial elastomer formed from an acrylated star-poly(d,l lactide-co-epsilon-caprolactone) was found to influence both fibroblast proliferation as well as the adsorption of certain proteins. However, it remained unresolved as to whether material stiffness influenced protein adsorption from serum supplemented environments and which protein(s) may have been responsible for the difference in fibroblast proliferation. Using quantitative proteomics, we show that polymer stiffness influenced the composition of the protein layers that adsorb from serum supplemented media. Fetuin A was identified as a protein that influenced fibroblast proliferation and, when combined with basic fibroblast growth factor as a medium supplement, improved fibroblast proliferation over 14days. This study is the first to correlate cell proliferation to surface adsorbed fetuin A and presents the potential new application for fetuin A as biomaterial coating or surface modifier. This work also demonstrates a novel application of quantitative proteomics for the investigation of competitive protein adsorption to biomaterial surfaces. STATEMENT OF SIGNIFICANCE: Cells are able to respond to the stiffness of their material substrate, but the method by which they sense material stiffness is still under investigation. Previously, material stiffness was found to impact the individual adsorption of fibronectin, a protein associated with cell attachment; however, it was unclear if stiffness was able to affect protein adsorption in environments with multiple proteins. This study shows that material stiffness affects the compositions of protein layers adsorbed from supplemented media, and suggests that cells may sense material stiffness via the adsorbed protein layer. Interestingly, fetuin A was found to be affecting cell proliferation and not fibronectin. Finally, this research demonstrates the use of relative quantitation proteomics as a potentially powerful method to improve biomaterial compatibility. PMID- 26607772 TI - Can absence of pyuria exclude urinary tract infection in febrile infants? About 2011 AAP guidelines on UTI. AB - BACKGROUND: The aim of this study was to describe clinical and laboratory characteristics of urinary tract infection (UTI) without significant pyuria in young children aged 2-24 months. METHODS: The subjects consisted of infants and young children with febrile UTI treated at Pusan National University Children's Hospital, Korea. Group A included 283 patients with definite UTI who fulfilled the revised American Academy of Pediatrics diagnostic criteria, and group B included 19 patients with presumed UTI who had significant culture of uropathogens without pyuria, bacteriuria or other focus of infection. RESULTS: Duration of fever before hospital visit in group B was significantly shorter than in group A (17.7 +/- 14.0 vs 34.5 +/- 30.7 h). Most patients in group B (17/19, 89.5%) came to the hospital within 24 h of onset of fever. Acute scintigraphic lesions were found in 47.8% of patients in group A and 50% in group B. Underlying urological abnormalities such as vesicoureteral reflux and obstructive uropathy were found in 24.5% of patients in group A and in 33.3% of patients in group B (P = 0.74). CONCLUSIONS: Clinicians cannot exclude UTI on the absence of pyuria in young children aged 2-24 months. PMID- 26607773 TI - Dasatinib attenuated bleomycin-induced pulmonary fibrosis in mice. AB - Anti-fibrotic effect of dasatinib, a platelet-derived growth factor receptor (PDGFR) and Src-kinase inhibitor, was tested on pulmonary fibrosis (PF). Adult mice were divided into four groups: mice dissected 21 d after the bleomycin (BLM) instillation (0.08 mg/kg in 200 ul) (I) and their controls (II), and mice treated with dasatinib (8 mg/kg in 100 ul, gavage) for one week 14 d after BLM instillation and dissected 21 d after instillation (III) and their controls (IV). The fibrosis score and the levels of fibrotic markers were analyzed in lungs. BLM treatment-induced cell proliferation and increased the levels of collagen-1, alpha smooth muscle actin, phospho (p)-PDGFR-alpha, p-Src, p-extracellular signal regulated kinases1/2 and p-cytoplasmic-Abelson-kinase (c-Abl) in lungs, and down regulated PTEN expression. Dasatinib reversed these alterations in the fibrotic lung. Dasatinib limited myofibroblast activation and collagen-1 accumulation by the inhibition of PDGFR-alpha, and Src and c-Abl activations. In conclusion, dasatinib may be a novel tyrosine and Src-kinase inhibitor for PF regression in mice. PMID- 26607774 TI - High-Resolution Genomic Profiling of Disseminated Tumor Cells in Prostate Cancer. AB - Circulating tumor cells and disseminated tumor cells (DTCs) are of great interest because they provide a minimally invasive window for assessing aspects of cancer biology, including tumor heterogeneity, a means to discover biomarkers of disease behavior, and a way to identify and prioritize therapeutic targets in the emerging era of precision oncology. However, the rarity of circulating tumor cells and DTCs poses a substantial challenge to the consistent success in analyzing their molecular features, including genomic aberrations. Herein, we describe optimized and robust methods to reproducibly detect genomic copy number alterations in samples of 2 to 40 cells after whole-genome amplification with the use of a high-resolution single-nuclear polymorphism-array platform and refined computational algorithms. We have determined the limit of detection for heterogeneity within a sample as 50% and also demonstrated success in analyzing single cells. We validated the genes in genomic regions that are frequently amplified or deleted by real-time quantitative PCR and nCounter copy number quantification. We further applied these methods to DTCs isolated from individuals with advanced prostate cancer to confirm their highly aberrant nature. We compared copy number alterations of DTCs with matched metastatic tumors isolated from the same individual to gain biological insight. These developments provide high-resolution genomic profiling of single and rare cell populations and should be applicable to a wide-range of sample sources. PMID- 26607775 TI - Varying Mutational Alterations in Multiple Primary Melanomas. AB - In melanoma, the mitogen-activated protein (MAP) kinase pathway plays a crucial oncogenic role. Recent studies identified additional genetic alterations, eg, TERT-promoter mutations. Up to 8% of melanoma patients present with multiple primary melanomas (MPMs). The pathogenesis is not fully understood, and data on the genetic diversity of MPMs are limited. To identify putative diagnostic and therapeutic consequences, we assessed the mutational status of the BRAF and NRAS genes and TERT promoter in patients with MPMs. The study cohort consisted of 96 patients with 237 malignant melanomas. The BRAF, NRAS, and TERT-promoter genotypes were assessed in all MPMs and were correlated with patients' clinicopathological characteristics. BRAF mutations were found in 84 melanomas (35.4%), NRAS mutations, in 33 (14.0%); and TERT-promoter mutations, in 112 (47.3%). Mutation patterns were concordant between first and subsequent primary tumors in 23.9% of patients and were discordant in 61.4% of patients. The genetic alterations were partially different in 14.7% of patients. By Cox regression analysis, only the NRAS mutation had a significant negative prognostic impact on time to progression to stage III (P = 0.016) and on distant metastasis-free survival (P = 0.032). In the majority of primary melanomas in patients with MPMs, BRAF, NRAS, and TERT-promoter genotypes were discordant. Thus, molecular testing for targeted therapy should be performed on metastatic tissue and not on primary tumors. PMID- 26607776 TI - Eating disorder examination: Factor structure and norms in a clinical female pediatric eating disorder sample. AB - OBJECTIVE: The factor structure of the eating disorder examination (EDE) has never been tested in a clinical pediatric sample, and no normative data exist. METHOD: The factor structure of an adapted EDE was examined in a clinical sample of 665 females aged 9-17 years with anorexia nervosa spectrum (70%), bulimia nervosa spectrum (12%), purging disorder (3%), and unspecified feeding and eating disorders (15%). RESULTS: The original four-factor model was a good fit in a confirmatory factor analysis as well a higher order model with three dimensions of restraint, eating concern, and combined weight concern/shape concern. Normative data are reported for clinicians to identify the percentiles in which their patients' score. DISCUSSION: The findings support dimensions of restraint, eating concern, weight concern, and shape concern in a clinical pediatric sample. This supports the factorial validity of the EDE, and the norms may assist clinicians to evaluate symptoms in females under 18 years. PMID- 26607777 TI - Diagnostic and prognostic values of preoperative serum levels of YKL-40, HE-4 and DKK-3 in endometrial cancer. AB - OBJECTIVE: The objective of this study is to determine the efficiency of YKL-40, HE-4 and DKK-3 levels in early diagnosis of patients with endometrial cancer and in the pre-operative estimation of the prognostic parameters such as stage, grade and the extension of the disease. METHODS: In this prospective study, 50 patients diagnosed with endometrial cancer and 50 women as a control group, who applied to Dokuz Eylul University and Ege University Faculties of Medicine, Obstetrics and Gynecology Clinics between May 2011-May 2012 were included. CA125, HE-4, YKL-40 and DKK-3 serum levels were measured by ELISA and compared between two groups. The relation between serum levels and histopathological results, extension of disease and prognostic factors were analyzed. RESULTS: Preoperative serum CA125, HE-4 and YKL-40 levels were significantly higher in endometrial cancer group (p<0.001). Serum HE-4 levels were significantly higher in advanced stages (p=0.004). When we examined early stage patients, YKL-40 levels were significantly higher in non-endometrioid histology compared with endometrioid adenocarcinoma (p=0.022). We also examined the relation between the markers and prognostic factors. Different from other markers, HE-4 levels were significantly higher in endometrial cancer patients who had lymphovascular space involvement, lower uterine segment involvement, endocervical stromal involvement, and deep myometrial invasion. CONCLUSION: YKL-40 and HE-4 were significantly higher in patients with endometrial cancer. HE-4 seems to be superior to YKL-40 in discriminating early and advanced stages. Additionally, HE4 is significantly correlated with prognostic factors. HE-4 and YKL-40 may be successful in early determination of endometrial cancer and in detection of high risk subsets before surgery. PMID- 26607778 TI - Adjuvant concurrent chemoradiation followed by chemotherapy for high-risk endometrial cancer. AB - OBJECTIVE: The adjuvant treatment of high-risk endometrial cancer (HREC) remains controversial. This prospective phase-II clinical trial was conducted to evaluate the adjuvant concurrent chemoradiotherapy followed by chemotherapy in patients with HREC. METHODS: Altogether 122 patients were enrolled between January 2007 and January 2013, in which 112 were analyzable. The inclusion criteria included endometrioid endometrial cancer of histological grade 3 and with greater than 50% myometrial invasion, cervical stromal invasion, pelvic and/or para-aortic lymph node metastases; non-endometrioid endometrial cancer; no residual disease and distant metastases. Pelvic radiation was administered with cisplatin on days 1 and 28. Para-aortic radiation was administered with confirmed para-aortic lymph node metastases, and vaginal afterloading brachytherapy with cervical stromal invasion after total hysterectomy. Four courses of paclitaxel and carboplatin (PC) or cisplatin, cyclophosphamide and epirubicin (CEP) were administered at three-week interval after radiation. RESULTS: Ninety-six patients (85.7%) completed the planned treatment. Treatment discontinuation was the result of toxicity (5/112, 4.5%), disease progression (8/112, 7.1%), and patients refusal (3/112, 2.7%). There was no life-threatening toxicity. Twenty-five (22.3%) patients recurred, in which 4 cases recurred in the field of radiation, and 13 (11.6%) patients died of endometrial cancer during follow-up. The estimated five year progression-free survival and overall survival were 73% and 84%, respectively. Adverse effects were less common in patients who received PC than CEP (p=0.001). CONCLUSIONS: This regimen demonstrated acceptable toxicity and good survival outcomes despite a preponderance (62.5%) of late stage disease. PC showed less adverse effects than CEP. A well designed randomized trial is under development. CLINICAL TRIAL ID: https://clinicaltrials.gov/: 070148-7. PMID- 26607779 TI - Prediction of incomplete primary debulking surgery in patients with advanced ovarian cancer: An external validation study of three models using computed tomography. AB - OBJECTIVE: To test the ability of three prospectively developed computed tomography (CT) models to predict incomplete primary debulking surgery in patients with advanced (International Federation of Gynecology and Obstetrics stages III-IV) ovarian cancer. METHODS: Three prediction models to predict incomplete surgery (any tumor residual >1cm in diameter) previously published by Ferrandina (models A and B) and by Gerestein were applied to a validation cohort consisting of 151 patients with advanced epithelial ovarian cancer. All patients were treated with primary debulking surgery in the Eastern part of the Netherlands between 2000 and 2009 and data were retrospectively collected. Three individual readers evaluated the radiographic parameters and gave a subjective assessment. Using the predicted probabilities from the models, the area under the curve (AUC) was calculated which represents the discriminative ability of the model. RESULTS: The AUC of the Ferrandina models was 0.56, 0.59 and 0.59 in model A, and 0.55, 0.60 and 0.59 in model B for readers 1, 2 and 3, respectively. The AUC of Gerestein's model was 0.69, 0.61 and 0.69 for readers 1, 2 and 3, respectively. AUC values of 0.69 and 0.63 for reader 1 and 3 were found for subjective assessment. CONCLUSIONS: Models to predict incomplete surgery in advanced ovarian cancer have limited predictive ability and their reproducibility is questionable. Subjective assessment seems as successful as applying predictive models. Present prediction models are not reliable enough to be used in clinical decision-making and should be interpreted with caution. PMID- 26607780 TI - The effect of diabetes and metformin on clinical outcomes is negligible in risk adjusted endometrial cancer cohorts. AB - OBJECTIVE: To examine the influence of diabetes and metformin therapy on overall survival (OS) and progression-free survival (PFS) in patients with endometrial cancer (EC) by using propensity score (PS) matching to account for confounding factors. METHODS: We retrospectively identified consecutive patients with stage I IV EC managed surgically from 1999 through 2008 and stratified patients by diabetes status. PS matching was used to adjust for confounding covariates. OS and PFS were compared between diabetic and nondiabetic matched pairs and between matched pairs of diabetic patients with or without metformin therapy. Cox proportional hazards models were fit to estimate the effects on outcomes. RESULTS: Among 1303 eligible patients (79% stage I, 28% grade 3), 277 (21.3%) had a history of diabetes. Among diabetic patients, treatment consisted of metformin in 116 (41.9%); 57 (20.6%) had other oral agents, 51 (18.4%) insulin with or without other oral agents, and 53 (19.1%) diet modification only. For PS-matched diabetic and nondiabetic patients with EC, OS (hazard ratio [HR], 1.01; 95% CI, 0.72-1.42) and PFS (HR, 1.01; 95% CI, 0.60-1.69) were similar between matched subsets. No differences in OS and PFS were observed when comparing PS-matched metformin users with nondiabetic patients (OS HR, 1.03; 95% CI, 0.57-1.85; PFS HR, 1.14; 95% CI, 0.49-2.62) or with other diabetic patients (OS HR, 0.61; 95% CI, 0.30-1.23; PFS HR, 1.06; 95% CI, 0.34-3.30). CONCLUSIONS: When adjusted for confounding covariates, OS and PFS are similar between diabetic and nondiabetic patients with EC and between metformin users and nonusers or nondiabetic patients. PMID- 26607781 TI - Therapy service use in children and adolescents with cerebral palsy: An Australian perspective. AB - AIM: The aim of this study was to describe the patterns of therapy service use for a sample of children and adolescents with cerebral palsy over a 1 year period and to identify factors associated with frequency of therapy and parental satisfaction with therapy frequency. METHODS: Parents of 83 children completed a survey on their child's use of occupational therapy, physiotherapy and speech and language pathology services over the previous year. Participants were randomly selected from a sample stratified by age and Gross Motor Function Classification System (GMFCS) level. RESULTS: During the year prior to survey completion, 83% of children had received occupational therapy, 88% had received physiotherapy and 60% had received speech and language pathology services. Frequency of therapy was higher for younger children (P < 0.01), those classified at GMFCS levels IV-V (P < 0.05) and those attending schools specifically for children with disabilities. CONCLUSIONS: Current structures for therapy service delivery for children with cerebral palsy are systems-based, and age-based funding systems and the organisation of services around the education system are preventing the delivery of needs-based therapy. Paediatricians that care for children and young people with cerebral palsy need to pay particular attention to those that may miss out on therapy due to age or school type, and support these families in accessing appropriate therapy. PMID- 26607782 TI - Amyloid PET imaging in multiple sclerosis: an (18)F-florbetaben study. AB - BACKGROUND: Positron emission tomography (PET) images with amyloid tracers show normal uptake in healthy white matter, which suggests that amyloid tracers are potentially useful for studying such white matter diseases as multiple sclerosis (MS). METHODS: Twelve patients diagnosed with MS (5 with RRMS, 5 with SPMS, and 2 with PPMS) and 3 healthy controls underwent studies with MRI and (18)F florbetaben-PET imaging. Images were preprocessed using Statistical Parametric Mapping software. We analysed (18)F-florbetaben uptake in demyelinating plaques (appearing as hyperintense lesions in FLAIR sequences), in normal-appearing white matter, and in grey matter. RESULTS: Mean standardized uptake value relative to cerebellum was higher in normally appearing white matter (NAWM) (1.51 +/- 0.12) than in damaged white matter (DWM) (1.24 +/- 0.12; P = .002). Mean percentage of change between NAWM and DWM was -17.56% +/- 6.22%. This percentage of change correlated negatively with EDSS scores (r = -0.61, p < .05) and with age (r = 0.83, p < 0.01). Progressive forms of MS showed a more pronounced reduction of the uptake in DWM in comparison to relapsing-remitting form. CONCLUSIONS: Uptake of (18)F-florbetaben in damaged white matter is lower than that occurring in normally-appearing white matter. These findings indicate that amyloid tracers may be useful in studies of MS, although further research is needed to evaluate the utility of amyloid-PET in monitoring MS progression. PMID- 26607783 TI - Risk adjustment models for short-term outcomes after surgical resection for oesophagogastric cancer. AB - BACKGROUND: Outcomes for oesophagogastric cancer surgery are compared with the aim of benchmarking quality of care. Adjusting for patient characteristics is crucial to avoid biased comparisons between providers. The study objective was to develop a case-mix adjustment model for comparing 30- and 90-day mortality and anastomotic leakage rates after oesophagogastric cancer resections. METHODS: The study reviewed existing models, considered expert opinion and examined audit data in order to select predictors that were consequently used to develop a case-mix adjustment model for the National Oesophago-Gastric Cancer Audit, covering England and Wales. Models were developed on patients undergoing surgical resection between April 2011 and March 2013 using logistic regression. Model calibration and discrimination was quantified using a bootstrap procedure. RESULTS: Most existing risk models for oesophagogastric resections were methodologically weak, outdated or based on detailed laboratory data that are not generally available. In 4882 patients with oesophagogastric cancer used for model development, 30- and 90-day mortality rates were 2.3 and 4.4 per cent respectively, and 6.2 per cent of patients developed an anastomotic leak. The internally validated models, based on predictors selected from the literature, showed moderate discrimination (area under the receiver operating characteristic (ROC) curve 0.646 for 30-day mortality, 0.664 for 90-day mortality and 0.587 for anastomotic leakage) and good calibration. CONCLUSION: Based on available data, three case-mix adjustment models for postoperative outcomes in patients undergoing curative surgery for oesophagogastric cancer were developed. These models should be used for risk adjustment when assessing hospital performance in the National Health Service, and tested in other large health systems. PMID- 26607784 TI - A mutation in the Warburg syndrome gene, RAB3GAP1, causes a similar syndrome with polyneuropathy and neuronal vacuolation in Black Russian Terrier dogs. AB - An autosomal recessive disease of Black Russian Terriers was previously described as a juvenile-onset, laryngeal paralysis and polyneuropathy similar to Charcot Marie Tooth disease in humans. We found that in addition to an axonal neuropathy, affected dogs exhibit microphthalmia, cataracts, and miotic pupils. On histopathology, affected dogs exhibit a spongiform encephalopathy characterized by accumulations of abnormal, membrane-bound vacuoles of various sizes in neuronal cell bodies, axons and adrenal cells. DNA from an individual dog with this polyneuropathy with ocular abnormalities and neuronal vacuolation (POANV) was used to generate a whole genome sequence which contained a homozygous RAB3GAP1:c.743delC mutation that was absent from 73 control canine whole genome sequences. An additional 12 Black Russian Terriers with POANV were RAB3GAP1:c.743delC homozygotes. DNA samples from 249 Black Russian Terriers with no known signs of POANV were either heterozygotes or homozygous for the reference allele. Mutations in human RAB3GAP1 cause Warburg micro syndrome (WARBM), a severe developmental disorder characterized by abnormalities of the eye, genitals and nervous system including a predominantly axonal peripheral neuropathy. RAB3GAP1 encodes the catalytic subunit of a GTPase activator protein and guanine exchange factor for Rab3 and Rab18 respectively. Rab proteins are involved in membrane trafficking in the endoplasmic reticulum, axonal transport, autophagy and synaptic transmission. The neuronal vacuolation and membranous inclusions and vacuoles in axons seen in this canine disorder likely reflect alterations of these processes. Thus, this canine disease could serve as a model for WARBM and provide insight into its pathogenesis and treatment. PMID- 26607785 TI - Translational approach for gene therapy in epilepsy: Model system and unilateral overexpression of neuropeptide Y and Y2 receptors. AB - Although novel treatment strategies based on the gene therapy approach for epilepsy has been encouraging, there is still a gap in demonstrating a proof-of concept in a clinically relevant animal model and study design. In the present study, a conceptually novel framework reflecting a plausible clinical trial for gene therapy of temporal lobe epilepsy was explored: We investigated (i) whether the post intrahippocampal kainate-induced status epilepticus (SE) model of chronic epilepsy in rats could be clinically relevant; and (ii) whether a translationally designed neuropeptide Y (NPY)/Y2 receptor-based gene therapy approach targeting only the seizure-generating focus unilaterally can decrease seizure frequency in this chronic model of epilepsy. Our data suggest that the intrahippocampal kainate model resembles the disease development of human chronic mesial temporal lobe epilepsy (mTLE): (i) spontaneous seizures originate in the sclerotic hippocampus; (ii) only a part of the animals develops chronic epilepsy; (iii) animals show largely variable seizure frequency that (iv) tends to progressively increase over time. Despite significant hippocampal degeneration caused by the kainate injection, the use of MRI allowed targeting the recombinant adeno-associated viral (rAAV) vectors encoding NPY and Y2 receptor genes to the remaining dorsal and ventral hippocampal areas ipsilateral to the kainate injection. Continuous video-EEG monitoring demonstrated not only prevention of the progressive increase in seizure frequency in rAAV-NPY/Y2 treated animals as compared to the controls, but even 45% decrease of seizure frequency in 80% of the epileptic animals. This translationally designed study in a clinically relevant model of epilepsy suggests that simultaneous overexpression of NPY and Y2 receptors unilaterally in the seizure focus is a relevant and promising approach that can be further validated in more extensive preclinical studies to develop a future treatment strategy for severe, often pharmacoresistant focal epilepsy cases that cannot be offered alternative therapeutic options. PMID- 26607786 TI - Mahogunin ring finger 1 confers cytoprotection against mutant SOD1 aggresomes and is defective in an ALS mouse model. AB - Proteotoxicity of misfolded, disease-causing proteins is deeply implicated in the pathomechanisms for neurodegenerative diseases including copper-zinc superoxide dismutase (SOD1)-linked amyotrophic lateral sclerosis (ALS). However, the precise cellular quality control (QC) mechanisms against aggregation of misfolded mutant SOD1 proteins remain elusive. Here, we found that the Mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase, which catalyzes mono-ubiquitination to the substrate, was dysregulated in the cellular and mouse models of ALS and that it preferentially interacted with various mutant forms of SOD1. Intriguingly, the motor neurons of presymptomatic ALS mice have diminished MGRN1 cytoplasmic distribution. MGRN1 was partially recruited to mutant SOD1 inclusions where they were positive for p62 and Lamp2. Moreover, overexpression of MGRN1 reduced mutant SOD1 aggregation and alleviated its proteotoxic effects on cells. Taken together, our findings suggest that MGRN1 contributes to the clearance of toxic mutant SOD1 inclusions likely through autophagic pathway, and, most likely, the sequestration of MGRN1 sensitizes motor neurons to degeneration in the ALS mouse model. Furthermore, the present study identifies the MGRN1-mediated protein QC mechanism as a novel therapeutic target in neurodegenerative diseases. PMID- 26607787 TI - Quality assessment of a sample of mobile app-based health behavior change interventions using a tool based on the National Institute of Health and Care Excellence behavior change guidance. AB - OBJECTIVE: To quality assess a sample of health behavior change apps from the NHS Apps Library using a rating tool based on the 2014 National Institute for Health and Care Excellence behavior change guidance (NICE BCG). METHODS: A qualitative analysis of the NICE BCG identified themes and questions for a quality assessment of health behavior change apps. These were refined by further discussion and piloting, and applied by two independent raters to a sample of NHS Library apps (N=49). Disagreements were resolved following discussions with a third rater. RESULTS: Themes identified were; purpose, planning, usability, tailoring, behavior change technique (BCT), maintenance, evaluation, data security and documentation. Overall, purpose of the apps was clear, but evidence for collaboration with users or professionals was lacking. Usability information was poor and tailoring disappointing. Most used recognized BCTs but paid less attention to behavior maintenance than initiation. Information on app evaluation and documentation was sparse. CONCLUSIONS: This study furthers the work of the NHS Apps Library, adapting the NICE (2014) behavior change guidance for quality assessment of behavior change apps. PRACTICE IMPLICATIONS: This study helps lay the foundations for development of a quality assurance tool for mobile health apps aimed at health behavior change. PMID- 26607788 TI - Promoter-based identification of novel non-coding RNAs reveals the presence of dicistronic snoRNA-miRNA genes in Arabidopsis thaliana. AB - BACKGROUND: In the past few decades, non-coding RNAs (ncRNAs) have emerged as important regulators of gene expression in eukaryotes. Most studies of ncRNAs in plants have focused on the identification of silencing microRNAs (miRNAs) and small interfering RNAs (siRNAs). Another important family of ncRNAs that has been well characterized in plants is the small nucleolar RNAs (snoRNAs) and the related small Cajal body-specific RNAs (scaRNAs). Both target chemical modifications of ribosomal RNAs (rRNAs) and small nuclear RNAs (snRNAs). In plants, the snoRNA genes are organized in clusters, transcribed by RNA Pol II from a common promoter and subsequently processed into mature molecules. The promoter regions of snoRNA polycistronic genes in plants are highly enriched in two conserved cis-regulatory elements (CREs), Telo-box and Site II, which coordinate the expression of snoRNAs and ribosomal protein coding genes throughout the cell cycle. RESULTS: In order to identify novel ncRNA genes, we have used the snoRNA Telo-box/Site II motifs combination as a functional promoter indicator to screen the Arabidopsis genome. The predictions generated by this process were tested by detailed exploration of available RNA-Seq and expression data sets and experimental validation. As a result, we have identified several snoRNAs, scaRNAs and 'orphan' snoRNAs. We also show evidence for 16 novel ncRNAs that lack similarity to any reported RNA family. Finally, we have identified two dicistronic genes encoding precursors that are processed to mature snoRNA and miRNA molecules. We discuss the evolutionary consequences of this result in the context of a tight link between snoRNAs and miRNAs in eukaryotes. CONCLUSIONS: We present an alternative computational approach for non-coding RNA detection. Instead of depending on sequence or structure similarity in the whole genome screenings, we have explored the properties of promoter regions of well characterized ncRNAs. Interestingly, besides expected ncRNAs predictions we were also able to recover single precursor arrangement for snoRNA-miRNA. Accompanied by analyses performed on rice sequences, we conclude that such arrangement might have interesting functional and evolutionary consequences and discuss this result in the context of a tight link between snoRNAs and miRNAs in eukaryotes. PMID- 26607789 TI - Exploring participant appreciation of group-based principles for action in community-based physical activity programs for socially vulnerable groups in the Netherlands. AB - BACKGROUND: Physical inactivity is a core risk factor for non-communicable diseases. In the Netherlands, socially vulnerable groups are relatively less active than groups with higher socio-economic status. Community-based health enhancing physical activity (CBHEPA) programs aim to empower socially vulnerable groups by improving participants' health and wellbeing through physical activity. CBHEPA programs often revolve around group-based principles for action, such as active participation, enjoyment, and fostering group processes. As such principles are rarely made explicit, our study aims to identify which of the group-based principles for action are considered important by participants. METHODS: Respondents (n = 76) from ten focus groups scored their individual appreciation of group-based principles for action - active participation, enjoyment, and fostering group processes - on a three-point, statement-based scale. Opinions were further discussed in the focus group. Focus group discussions were transcribed and analysed by a team of investigators. The coding procedures, identifying elements appreciated in group-based principles for action, were thematic and data driven. RESULTS: Statements about participatory programming generated much less consensus in appreciation among respondents than statements about enjoyment and fostering group processes. To some extent, group members participated in the development of program content. Participation in group formation or community initiatives was less frequently perceived as something within group members' control. Enjoyment, expressed as physical and emotional experiences, was found to be an individual driver of group exercise. Fostering group processes, expressed as social support, was found to contribute to enjoyment and learning achievements. Responsive leadership, ensuring responsive guidance, by an enthusiastic exercise trainer acting as a role model, were identified as additional necessary principles for action. CONCLUSIONS: Group based principles for action in CBHEPA programs are not clearly demarcated. Fostering group processes is an overarching principle, conditional for the spin off in terms of enjoyment and active participation. This, in turn, leads to a sense of ownership among participants, who take up responsibility for the exercise group as well as their individual activity behaviour. CBHEPA programs thrive on participants having fun together and exercise trainers' leadership skills. A professional, competent, responsive exercise trainer plays a key role in the organisation and maintenance of CBHEPA programs. PMID- 26607790 TI - The 2014 Ebola virus disease outbreak in Pujehun, Sierra Leone: epidemiology and impact of interventions. AB - BACKGROUND: In July 2014, an outbreak of Ebola virus disease (EVD) started in Pujehun district, Sierra Leone. On January 10th, 2015, the district was the first to be declared Ebola-free by local authorities after 49 cases and a case fatality rate of 85.7%. The Pujehun outbreak represents a precious opportunity for improving the body of work on the transmission characteristics and effects of control interventions during the 2014-2015 EVD epidemic in West Africa. METHODS: By integrating hospital registers and contact tracing form data with healthcare worker and local population interviews, we reconstructed the transmission chain and investigated the key time periods of EVD transmission. The impact of intervention measures has been assessed using a microsimulation transmission model calibrated with the collected data. RESULTS: The mean incubation period was 9.7 days (range, 6-15). Hospitalization rate was 89%. The mean time from the onset of symptoms to hospitalization was 4.5 days (range, 1-9). The mean serial interval was 13.7 days (range, 2-18). The distribution of the number of secondary cases (R 0 = 1.63) was well fitted by a negative binomial distribution with dispersion parameter k = 0.45 (95% CI, 0.19-1.32). Overall, 74.3% of transmission events occurred between members of the same family or extended family, 17.9% in the community, mainly between friends, and 7.7% in hospital. The mean number of contacts investigated per EVD case raised from 11.5 in July to 25 in September 2014. In total, 43.0% of cases were detected through contact investigation. Model simulations suggest that the most important factors determining the probability of disease elimination are the number of EVD beds, the mean time from symptom onset to isolation, and the mean number of contacts traced per case. By assuming levels and timing of interventions performed in Pujehun, the estimated probability of eliminating an otherwise large EVD outbreak is close to 100%. CONCLUSIONS: Containment of EVD in Pujehun district is ascribable to both the natural history of the disease (mainly transmitted through physical contacts, long generation time, overdispersed distribution of secondary cases per single primary case) and intervention measures (isolation of cases and contact tracing), which in turn strongly depend on preparedness, population awareness, and compliance. Our findings are also essential to determine a successful ring vaccination strategy. PMID- 26607791 TI - Aspiration, quadriplegia, incontinence. PMID- 26607792 TI - Perinuclear Anchoring of H3K9-Methylated Chromatin Stabilizes Induced Cell Fate in C. elegans Embryos. AB - Interphase chromatin is organized in distinct nuclear sub-compartments, reflecting its degree of compaction and transcriptional status. In Caenorhabditis elegans embryos, H3K9 methylation is necessary to silence and to anchor repeat rich heterochromatin at the nuclear periphery. In a screen for perinuclear anchors of heterochromatin, we identified a previously uncharacterized C. elegans chromodomain protein, CEC-4. CEC-4 binds preferentially mono-, di-, or tri methylated H3K9 and localizes at the nuclear envelope independently of H3K9 methylation and nuclear lamin. CEC-4 is necessary for endogenous heterochromatin anchoring, but not for transcriptional repression, in contrast to other known H3K9 methyl-binders in worms, which mediate gene repression but not perinuclear anchoring. When we ectopically induce a muscle differentiation program in embryos, cec-4 mutants fail to commit fully to muscle cell fate. This suggests that perinuclear sequestration of chromatin during development helps restrict cell differentiation programs by stabilizing commitment to a specific cell fate. PAPERCLIP. PMID- 26607793 TI - CD5L/AIM Regulates Lipid Biosynthesis and Restrains Th17 Cell Pathogenicity. AB - Th17 cells play a critical role in host defense against extracellular pathogens and tissue homeostasis but can induce autoimmunity. The mechanisms implicated in balancing "pathogenic" and "non-pathogenic" Th17 cell states remain largely unknown. We used single-cell RNA-seq to identify CD5L/AIM as a regulator expressed in non-pathogenic, but not in pathogenic Th17 cells. Although CD5L does not affect Th17 differentiation, it is a functional switch that regulates the pathogenicity of Th17 cells. Loss of CD5L converts non-pathogenic Th17 cells into pathogenic cells that induce autoimmunity. CD5L mediates this effect by modulating the intracellular lipidome, altering fatty acid composition and restricting cholesterol biosynthesis and, thus, ligand availability for Rorgammat, the master transcription factor of Th17 cells. Our study identifies CD5L as a critical regulator of the Th17 cell functional state and highlights the importance of lipid metabolism in balancing immune protection and disease induced by T cells. PMID- 26607795 TI - Hemimyeloschisis associated with hydrocephalus. AB - Hemimyeloschisis is a very rare congenital malformation of the spine which is characterized by a split cord malformation associated with complete exposureof the one hemicord to the exterior. We report a case of hemimyeloschisis on the right hemicord in a patient with hydrocephalus. The patient was a female neonate with myeloschisis, skin defect, and hypertrichosis visible at birth in the upper lumbar region. There was also skin defect around the myeloschisis. Computed tomography (CT) revealed a bony septum at the L2 level as well as the myeloschisis on the right hemicord, which enabled us to make a precise preoperative diagnosis of this rare malformation. There was also mild hydrocephalus in cranial CT scan. Closure of the myeloschisis and removal of the septum were successfully performed associated with the closure of the skin in one stage surgery to prevent subsequent infection and neurological deterioration. Ventriculoperitoneal shunt insertion was performed for hydrocephalus. The presence of combined split cord malformation and myeloschisis is consistent with the hypothesis of an ontogenic basis of development. This combination also emphasizes the importance of early imaging for diagnosis in this complex malformation. PMID- 26607796 TI - Ketamine as an adjunct to patient-controlled analgesia: why, for whom, and how much? PMID- 26607794 TI - Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. AB - Extensive cellular heterogeneity exists within specific immune-cell subtypes classified as a single lineage, but its molecular underpinnings are rarely characterized at a genomic scale. Here, we use single-cell RNA-seq to investigate the molecular mechanisms governing heterogeneity and pathogenicity of Th17 cells isolated from the central nervous system (CNS) and lymph nodes (LN) at the peak of autoimmune encephalomyelitis (EAE) or differentiated in vitro under either pathogenic or non-pathogenic polarization conditions. Computational analysis relates a spectrum of cellular states in vivo to in-vitro-differentiated Th17 cells and unveils genes governing pathogenicity and disease susceptibility. Using knockout mice, we validate four new genes: Gpr65, Plzp, Toso, and Cd5l (in a companion paper). Cellular heterogeneity thus informs Th17 function in autoimmunity and can identify targets for selective suppression of pathogenic Th17 cells while potentially sparing non-pathogenic tissue-protective ones. PMID- 26607797 TI - Severe spinal and chest deformity secondary to neurofibromatosis. PMID- 26607798 TI - Role of myosin light chain and myosin light chain kinase in advanced glycation end product-induced endothelial hyperpermeability in vitro and in vivo. AB - We have previously reported that advanced glycation end products activated Rho associated protein kinase and p38 mitogen-activated protein kinase, causing endothelial hyperpermeability. However, the mechanisms involved were not fully clarified. Here, we explored the role of myosin light chain kinase in advanced glycation end product-induced endothelial hyperpermeability. Myosin light chain phosphorylation significantly increased by advanced glycation end products in endothelial cells in a time- and dose-dependent manner, indicating that myosin light chain phosphorylation is involved in the advanced glycation end product pathway. Advanced glycation end products also induced myosin phosphatase targeting subunit 1 phosphorylation, and small interfering RNA knockdown of the receptor for advanced glycation end products, or blocking myosin light chain kinase with its inhibitor, ML-7, or small interfering RNA abated advanced glycation end product-induced myosin light chain phosphorylation. Advanced glycation end product-induced F-actin rearrangement and endothelial hyperpermeability were also diminished by inhibition of receptor for advanced glycation end product or myosin light chain kinase signalling. Moreover, inhibiting myosin light chain kinase with ML-7 or blocking receptor for advanced glycation end product with its neutralizing antibody attenuated advanced glycation end product-induced microvascular hyperpermeability. Our findings suggest a novel role for myosin light chain and myosin light chain kinase in advanced glycation end product-induced endothelial hyperpermeability. PMID- 26607800 TI - The Aerospace Medicine Specialist. PMID- 26607802 TI - You're the Flight Surgeon. AB - Mulagha EH. You're the flight surgeon: cholelithiasis. Aerosp Med Hum Perform. 2015; 86(6):577-580. PMID- 26607801 TI - You're the Flight Surgeon. AB - Tontz RC. You're the flight surgeon: complex regional pain syndrome. Aerosp Med Hum Perform. 2015; 86(6):574-577. PMID- 26607803 TI - AsMA Constituent Organization Presidents for 2015-2016. PMID- 26607804 TI - Protein disulfide isomerase ameliorates beta-cell dysfunction in pancreatic islets overexpressing human islet amyloid polypeptide. AB - Human islet amyloid polypeptide (hIAPP) is the major component of amyloid deposits in islets of type 2 diabetic patients. hIAPP misfolding and aggregation is one of the factors that may lead to beta-cell dysfunction and death. Endogenous chaperones are described to be important for the folding and functioning of proteins. Here, we examine the effect of the endoplasmic reticulum chaperone protein disulfide isomerase (PDI) on beta-cell dysfunction. Among other chaperones, PDI was found to interact with hIAPP in human islet lysates. Furthermore, intrinsically recovered PDI levels were able to restore the effect of high glucose- and palmitate-induced beta-cell dysfunction by increasing 3.9 fold the glucose-stimulated insulin secretion levels and restoring insulin content up to basal control values. Additionally, PDI transduction decreased induced apoptosis by glucolipotoxic conditions. This approach could reveal a new therapeutic target and aid in the development of strategies to improve beta-cell dysfunction in type 2 diabetic patients. PMID- 26607805 TI - Melatonin enhances arsenic trioxide-induced cell death via sustained upregulation of Redd1 expression in breast cancer cells. AB - Melatonin is implicated in various physiological functions, including anticancer activity. However, the mechanism(s) of its anticancer activity is not well understood. In the present study, we investigated the combined effects of melatonin and arsenic trioxide (ATO) on cell death in human breast cancer cells. Melatonin enhanced the ATO-induced apoptotic cell death via changes in the protein levels of Survivin, Bcl-2, and Bax, thus affecting cytochrome c release from the mitochondria to the cytosol. Interestingly, we found that the cell death induced by co-treatment with melatonin and ATO was mediated by sustained upregulation of Redd1, which was associated with increased production of reactive oxygen species (ROS). Combined treatment with melatonin and ATO induced the phosphorylation of JNK and p38 MAP kinase downstream from Redd1 expression. Rapamycin and S6K1 siRNA enhanced, while activation of mTORC1 by transfection with TSC2 siRNA suppressed the cell death induced by melatonin and ATO treatment. Taken together, our findings suggest that melatonin enhances ATO-induced apoptotic cell death via sustained upregulation of Redd1 expression and inhibition of mTORC1 upstream of the activation of the p38/JNK pathways in human breast cancer cells. PMID- 26607806 TI - Beneficial metabolic actions of a stable GIP agonist following pre-treatment with a SGLT2 inhibitor in high fat fed diabetic mice. AB - The purpose of the present study was to examine if a stable glucose-dependent insulinotropic polypeptide (GIP) agonist could exert beneficial metabolic control in diabetic mice which had been pre-treated with sodium-glucose-cotransporter-2 (SGLT2) inhibitor dapagliflozin (DAPA). High fat fed mice administered low dose streptozotocin (STZ) received vehicle, DAPA once-daily over 28 days, or DAPA once daily for 14 days followed by (DAla(2))GIP once-daily for 14 days. Energy intake, body weight, glucose and insulin concentrations were measured at regular intervals. Glucose tolerance, insulin tolerance test, dual-energy X-ray absorptiometry (DEXA) and pancreatic histology were examined. Once-daily administration of (DAla(2))GIP for 14 days in high fat fed diabetic mice pre treated with DAPA demonstrated significant decrease in body weight, blood glucose and increased insulin concentrations which were independent of changes in energy intake. Similarly, glucose tolerance, glucose-stimulated insulin secretion, insulin sensitivity and HOMA-beta were significantly enhanced in (DAla(2))GIP treated mice. DEXA analysis revealed sustained percentage body fat loss with no changes in lean mass, bone mineral content and density. Pancreatic immunohistochemical analysis revealed decreased islet number and increases in islet area, beta cell area and pancreatic insulin content. The DAPA-induced increase in alpha cell area was also reversed. Additional acute in vitro and in vivo experiments confirmed that the impaired action of (DAla(2))GIP under hyperglycaemic-induced conditions was significantly reversed by DAPA treatment. These data demonstrate that (DAla(2))GIP can exert beneficial metabolic control in high fat fed diabetic mice pre-treated with DAPA. The results highlight possibility of a targeted and personalized approach using a GIP agonist and SGLT2 inhibitor for the treatment of type 2 diabetes. PMID- 26607807 TI - Muller glia activation by VEGF-antagonizing drugs: An in vitro study on rat primary retinal cultures. AB - The effects of the anti-Vascular Endothelial Growth Factor (VEGF) drugs ranibizumab and aflibercept were studied in Muller glia in primary mixed cultures from rat neonatal retina. Treatment with both agents induced activation of Muller glia, demonstrated by increased levels of Glial Fibrillary Acidic Protein. In addition, phosphorylated Extracellular-Regulated Kinase 1/2 (ERK 1/2) showed enhanced immunoreactivity in activated Muller glia. Treatment with aflibercept induced an increase in K(+) channel (Kir) 4.1 levels and both drugs upregulated Aquaporin 4 (AQP4) in activated Muller glia. The results show that VEGF antagonizing drugs influence the homeostasis of Muller cells in primary retinal cultures, inducing an activated phenotype. Upregulation of Kir4.1 and AQP4 suggests that Muller glia activation following anti-VEGF drugs may not depict a detrimental gliotic reaction. Indeed, it could represent one of the mechanisms able to contribute to the therapeutic effects of these drugs, particularly in the presence of macular edema. PMID- 26607808 TI - Stability of limbal stem cell deficiency after mechanical and thermal injuries in mice. AB - We studied the reproducibility and stability of limbal stem cell deficiency (LSCD) in mice following controlled injuries to the corneal and limbal epithelia. In one method, corneal and limbal epithelia were entirely removed with a 0.5 mm metal burr. In the other, limbus to limbus epithelial removal with the burr was followed by thermal injury to the limbus. These two methods were compared with a previously published one. Unwounded corneas were used as control. The corneas were examined monthly for three months by slit lamp with fluorescein staining. Immunofluorescence staining for cytokeratin 12 and 8 on corneal wholemount and cross sections were performed to determine the phenotype of the epithelium. Mechanical shaving of the epithelium, with or without thermal injury, resulted in a reproducible state of LSCD marked by superficial neovascularization, reduce of keratin 12 expression and presence of goblet cells on the cornea. The phenotype was stable in 100% of the eyes up to at least three months. Thermal injury produced a more severe phenotype with more significant stromal opacification. These corneal injury models may be useful for studying the mechanisms leading to limbal stem cell deficiency. PMID- 26607809 TI - MR Imaging of Fetuses to Evaluate Placental Insufficiency. AB - PURPOSE: To evaluate morphological and signal intensity (SI) changes of placental insufficiency on magnetic resonance imaging (MRI) and to assess morphological changes and decreased flow voids (FVs) on T2-weighted rapid acquisition with relaxation enhancement (RARE) images for diagnosing placental insufficiency. METHODS: Fifty singleton fetuses underwent MRI using a 1.5-T MR scanner. Placental thickness, area, volume, SI, amniotic fluid SI, and size of FVs between the uterus and the placenta were measured on MR images. Two radiologists reviewed T2-weighted RARE images for globular appearance of the placenta and FVs between the uterus and the placenta. Data were analyzed using t-tests, McNemar's tests, and areas under the receiver operating characteristic curve (AUCs) at 5% level of significance. RESULTS: Twenty-five of the 50 pregnancies were categorized as having an insufficient placenta. Significant differences were observed between insufficient and normal placentas in mean placental thickness, area, volume, placenta to amniotic fluid SI ratio, and size of FVs (49.0 mm vs. 36.9 mm, 1.62 * 10(4) mm(2) vs. 2.67 * 10(4) mm(2), 5.13 * 10(5) mm(3) vs. 6.56 * 10(5) mm(3), 0.549 vs. 0.685, and 3.4 mm vs. 4.3 mm, respectively). The sensitivity and accuracy using globular appearance plus decreased FVs were greater than those using decreased FVs (P < 0.01). There was no significant difference among AUCs using globular appearance and decreased FVs, and globular appearance plus decreased FVs. CONCLUSIONS: Placental insufficiency was associated with placental thickness, area, volume, placenta to amniotic fluid SI ratio, and size of FVs. Evaluating FVs on T2-weighted RARE images can be useful for detecting placental insufficiency, particularly in placentas without globular appearance on MR images. PMID- 26607810 TI - A Layer of Decreased Apparent Diffusion Coefficient at the Endometrial-Myometrial Junction in Uterine Adenomyosis. AB - OBJECTIVES: To assess the detectability of a low-signal-intensity line within adenomyosis lesions adjacent to the endometrium on apparent diffusion coefficient (ADC) maps, and to establish correlations between these lesions and their possible causes, and more particularly the hormonal changes and magnetic resonance (MR) factors. MATERIALS AND METHODS: MR images were obtained from 110 patients with adenomyosis (age 30-57 y.o.) using 3.0 T or 1.5 T MR units. Recognition of the low-signal-intensity line on ADC map was scored using confidence level. The correlation between recognition of the line and the following factors were examined: magnetic field strength, age group, menstrual cycle phases, history of delivery, and hormonal treatments. Presence of the structure corresponding to the low-signal-intensity line on ADC map was evaluated pathologically in the cases that underwent surgery. RESULTS: The low-signal intensity line visible on ADC map was recognized in 55/110 patients. The visibility of the line was not significantly related to hormonal status, age, history of delivery, or magnetic resonance imaging (MRI) magnet strength. There were no corresponding pathological structures. CONCLUSION: One half of the adenomyosis patients showed discrepant appearances in T2-weighted (T2WI) vs. ADC map, but no significant relationship with hormonal changes was found in this study. This result may suggest that the low-signal-intensity line within the junctional zone may be related to a functional phenomenon. PMID- 26607811 TI - Cost-effectiveness of CYP2B6 genotyping to optimize efavirenz dosing in HIV clinical practice. AB - AIMS: To assess the cost-effectiveness of CYP2B6 genotyping to guide efavirenz dosing for initial HIV therapy in the USA. METHODS: We used the Cost Effectiveness of Preventing AIDS Complications (CEPAC) microsimulation model to project quality-adjusted life expectancy and lifetime costs (2014 US dollars) for efavirenz-based HIV therapy with or without CYP2B6 genotyping. We assumed that with genotyping 60% of patients would be eligible to receive lower doses. RESULTS: Current care without CYP2B6 genotyping has an incremental cost effectiveness ratio >$100,000/QALY compared with genotype-guided dosing, even if lower dosing reduces efficacy. When we assumed generic efavirenz availability, conclusions were similar unless lower dosing reduces efficacy by 6% or more. CONCLUSION: CYP2B6 genotyping can inform efavirenz dosing and decrease HIV therapy cost. PMID- 26607812 TI - Fully automated registration of vibrational microspectroscopic images in histologically stained tissue sections. AB - BACKGROUND: In recent years, hyperspectral microscopy techniques such as infrared or Raman microscopy have been applied successfully for diagnostic purposes. In many of the corresponding studies, it is common practice to measure one and the same sample under different types of microscopes. Any joint analysis of the two image modalities requires to overlay the images, so that identical positions in the sample are located at the same coordinate in both images. This step, commonly referred to as image registration, has typically been performed manually in the lack of established automated computational registration tools. RESULTS: We propose a corresponding registration algorithm that addresses this registration problem, and demonstrate the robustness of our approach in different constellations of microscopes. First, we deal with subregion registration of Fourier Transform Infrared (FTIR) microscopic images in whole-slide histopathological staining images. Second, we register FTIR imaged cores of tissue microarrays in their histopathologically stained counterparts, and finally perform registration of Coherent anti-Stokes Raman spectroscopic (CARS) images within histopathological staining images. CONCLUSIONS: Our validation involves a large variety of samples obtained from colon, bladder, and lung tissue on three different types of microscopes, and demonstrates that our proposed method works fully automated and highly robust in different constellations of microscopes involving diverse types of tissue samples. PMID- 26607813 TI - Standardization of Assays That Detect Anti-Rubella Virus IgG Antibodies. AB - Rubella virus usually causes a mild infection in humans but can cause congenital rubella syndrome (CRS). Vaccination programs have significantly decreased primary rubella virus infection and CRS; however, vaccinated individuals usually have lower levels of rubella virus IgG than those with natural infections. Rubella virus IgG is quantified with enzyme immunoassays that have been calibrated against the World Health Organization (WHO) international standard and report results in international units per milliliter. It is recognized that the results reported by these assays are not standardized. This investigation into the reasons for the lack of standardization found that the current WHO international standard (RUB-1-94) fails by three key metrological principles. The standard is not a pure analyte but is composed of pooled human immunoglobulin. It was not calibrated by certified reference methods; rather, superseded tests were used. Finally, no measurement uncertainty estimations have been provided. There is an analytical and clinical consequence to the lack of standardization of rubella virus IgG assays, which leads to misinterpretation of results. The current approach to standardization of rubella virus IgG assays has not achieved the desired results. A new approach is required. PMID- 26607815 TI - Be early for enteral, no rush for calories! PMID- 26607814 TI - Voices of Informal Caregivers and Community Stakeholders: Whether and How to Develop an Informal Caregiver Training Program. AB - Our primary objective was to gather pilot data from caregivers and stakeholders to guide the development of a training program to assist informal caregivers in re-entering the job market. The goal of the program would be to help caregivers rebound from their incurred economic burden by transitioning into a paid caregiving or other health-service role. The economic burden they bear often necessitates a return to the workforce following caregiving; yet the act of returning is complicated by an extended absence from the workforce and a lack of experience in other verifiably skilled and paid roles. We interviewed 37 stakeholders and 25 caregivers of a chronically or terminally ill family member or friend in a suburban collar county close to Chicago. The interview questions considered the economic impact of illness, as well as the feasibility, logistics, and options of a training program for caregivers. Our data gathered from caregivers and leaders within this community support the acceptability of such a training program for informal caregivers, and also provide practical advice for development and implementation related to training cost, length, content, and instructional practices. PMID- 26607817 TI - The complete chloroplast genome of Antarctic pearlwort, Colobanthus quitensis (Kunth) Bartl. (Caryophyllaceae). AB - We determined the complete chloroplast DNA sequence of an extremophile plant, Colobanthus quitensis (Antarctic pearlwort), by de novo assembly based on the sequencing results from Illumina MiSeq platform (Illumina Inc., San Diego, CA). The chloroplast genome of C. quitensis (NCBI accession no. KT737383) is a sequence of 151 276 bp long with a typical quadripartite structure composed of a large single copy region, a small single copy region and a pair of inverted repeats. The overall GC content of C. quitensis genome is 36.7% and it has 66 simple sequence repeats. It contains a total 112 genes including 78 protein coding genes, 30 tRNA genes, and four rRNA genes. PMID- 26607816 TI - Septic shock in chronic dialysis patients: clinical characteristics, antimicrobial therapy and mortality. AB - OBJECTIVES: To describe the clinical characteristics and in-hospital mortality of chronic dialysis-dependent end-stage kidney disease patients with septic shock in comparison to septic shock patients not receiving chronic dialysis. METHODS: Using an international, multicenter database, we conducted a retrospective analysis of data collected from 10,414 patients admitted to the intensive care unit (ICU) with septic shock from 1989 to 2013, of which 800 (7.7 %) were chronic dialysis patients. Data on demographic characteristics, sites of infection, microbial pathogens, antimicrobial usage patterns, and in-hospital mortality were aggregated and compared for chronic dialysis and non-dialysis patients. Multivariate time-varying Cox models with and without propensity score matching were constructed to determine the association between dialysis and in-hospital death. RESULTS: Septic shock secondary to central venous catheter infection, peritonitis, ischemic bowel, and cellulitis was more frequent in chronic dialysis patients. The isolation of resistant organisms (10.7 vs. 7.1 %; p = 0.005) and delays in receiving antimicrobials (6.0 vs. 5.0 h) were more common in chronic dialysis patients than in non-dialysis patients. Delayed appropriate antimicrobial therapy was associated with an increased risk of death in chronic dialysis patients (p < 0.0001). In-hospital death occurred in 54.8 and 49.0 % of chronic dialysis and non-dialysis patients, respectively. After propensity score matching, there was no difference in overall survival between chronic dialysis and non-dialysis patients, but survival in chronic dialysis patients decreased over time compared to non-dialysis patients. CONCLUSIONS: The demographic and clinical characteristics of chronic dialysis patients with septic shock differ from those of similar non-dialysis patients. However, there was no significant difference in mortality between the chronic dialysis and non-dialysis patients with septic shock enrolled in this analysis. PMID- 26607818 TI - Short-term glucagon stimulation test of C-peptide effect on glucose utilization in patients with type 1 diabetes mellitus. AB - This work aimed to evaluate the use of a four-point glucagon stimulation test of C-peptide effect on glucose utilization in type 1 diabetic patients using a new mathematical model. A group of 32 type 1 diabetic patients and a group of 10 healthy control subjects underwent a four-point glucagon stimulation test with blood sampling at 0, 6, 15 and 30 min after 1 mg glucagon bolus intravenous administration. Pharmacokinetic and pharmacokinetic/pharmacodynamic models of C peptide effect on glucose utilization versus area under curve (AUC) were used. A two-sample t test and ANOVA with Bonferroni correction were used to test the significance of differences between parameters. A significant difference between control and patient groups regarding the coefficient of whole-body glucose utilization and AUC C-peptide/AUC glucose ratio (p ? 0.001 and p = 0.002, respectively) was observed. The high correlation (r = 0.97) between modeled coefficient of whole-body glucose utilization and numerically calculated AUC C peptide/AUC glucose ratio related to entire cohort indicated the stability of used method. The short-term four-point glucagon stimulation test allows the numerically calculated AUC C-peptide/AUC glucose ratio and/or the coefficient of whole-body glucose utilization calculated from model to be used to diagnostically identify type 1 diabetic patients. PMID- 26607819 TI - In situ iodination and X-ray crystal structure of a foldamer helix bundle. AB - We report here the efficient in situ iodination of tyrosine-type side-chains located within a foldamer helix bundle, permitting structure determination using single-wavelength anomalous diffraction (SAD) methods. We suggest that this simple method may be of use to those engaged in structural foldamer research as a potential solution to the phase problem. PMID- 26607821 TI - Preventing pneumococcal infections in older adults. PMID- 26607820 TI - Atrial fibrillation, cognitive impairment, and neuroimaging. AB - INTRODUCTION: The objective of our study was to investigate cross-sectional associations of atrial fibrillation with neuroimaging measures of cerebrovascular disease and Alzheimer's disease and their interactions with mild cognitive impairment (MCI). METHODS: Magnetic resonance imaging scans of individuals from a population-based study were analyzed for infarctions, total gray matter, and hippocampal and white matter hyperintensity volumes. A subsample underwent positron emission tomography imaging. RESULTS: Atrial fibrillation was associated with infarctions and lower total gray matter volume. Compared with subjects with no atrial fibrillation and no infarction, the odds ratio (95% confidence intervals) for MCI was 2.99 (1.57-5.70; P = .001) among participants with atrial fibrillation and infarction, 0.90 (0.45-1.80; P = .77) for atrial fibrillation and no infarction, and 1.50 (0.96-2.34; P = .08) for no atrial fibrillation and any infarction. DISCUSSION: Participants with both atrial fibrillation and infarction are more likely to have MCI than participants with either infarction or atrial fibrillation alone. PMID- 26607823 TI - Olanzapine-induced atypical neuroleptic malignant syndrome in an adolescent man with anorexia nervosa. PMID- 26607824 TI - RAGE and CYBA polymorphisms are associated with microalbuminuria and end-stage renal disease onset in a cohort of type 1 diabetes mellitus patients over a 20 year follow-up. AB - AIMS: We investigated the association of polymorphisms of three genes implicated in oxidative stress: CYBA C242T, RAGE -374T/A and -429T/C, and ALOX12 Arg261Gln, with the delay of microalbuminuria onset in patients with type 1 diabetes mellitus (DT1). METHODS: A total of 162 T1D patients presenting with diabetes for 32.9 +/- 9 years were included in the study; 53 had persistent microalbuminuria (>30 mg/l) and 109 did not. Onset of diabetes, microalbuminuria and end-stage renal disease (ESRD) were recorded as bio-clinical data. We determined polymorphism association of microalbuminuria with a Cox regression model. RESULTS: All polymorphisms respected the Hardy-Weinberg equilibrium. The Cox regression model validated four significant variables associated with microalbuminuria: RAGE 374AA (HR 4.19 [1.84-9.58] (p = 0.001)), CYBA TT+TC (HR 2.1 [1.16-3.80], p = 0.015), male sex (HR 1.92 [1.07-3.43], p = 0.028) and diabetes diagnosis at the pediatric stage (HR 1.85 [1.03-3.32], p = 0.039). The same association was found with ESRD (p = 0.028 and p = 0.033 for CYBA TC+TT and RAGE 374AA, respectively). CYBA C242T and RAGE 374T/A were not significantly associated with diabetic retinopathy. CONCLUSIONS: CYBA C242T and RAGE -374T/A correlate with microalbuminuria onset in the French DT1 cohort. The same correlation with ESRD onset supports the argument for the involvement of a genetic predisposition involving kidney-specific oxidative stress for diabetic nephropathy. PMID- 26607825 TI - Polypharmacy in elderly people with diabetes admitted to hospital. PMID- 26607826 TI - Reply to Letter to the Editor "Polypharmacy in elderly people with diabetes admitted to hospital". PMID- 26607827 TI - Adaptation to acetaminophen exposure elicits major changes in expression and distribution of the hepatic proteome. AB - Acetaminophen overdose is the leading cause of acute liver failure. One dose of 10-15 g causes severe liver damage in humans, whereas repeated exposure to acetaminophen in humans and animal models results in autoprotection. Insight of this process is limited to select proteins implicated in acetaminophen toxicity and cellular defence. Here we investigate hepatic adaptation to acetaminophen toxicity from a whole proteome perspective, using quantitative mass spectrometry. In a rat model, we show the response to acetaminophen involves the expression of 30% of all proteins detected in the liver. Genetic ablation of a master regulator of cellular defence, NFE2L2, has little effect, suggesting redundancy in the regulation of adaptation. We show that adaptation to acetaminophen has a spatial component, involving a shift in regionalisation of CYP2E1, which may prevent toxicity thresholds being reached. These data reveal unexpected complexity and dynamic behaviour in the biological response to drug-induced liver injury. PMID- 26607828 TI - Slowing Translation between Protein Domains by Increasing Affinity between mRNAs and the Ribosomal Anti-Shine-Dalgarno Sequence Improves Solubility. AB - Recent studies have demonstrated that effective protein production requires coordination of multiple cotranslational cellular processes, which are heavily affected by translation timing. Until recently, protein engineering has focused on codon optimization to maximize protein production rates, mostly considering the effect of tRNA abundance. However, as it relates to complex multidomain proteins, it has been hypothesized that strategic translational pauses between domains and between distinct individual structural motifs can prevent interactions between nascent chain fragments that generate kinetically trapped misfolded peptides and thereby enhance protein yields. In this study, we introduce synthetic transient pauses between structural domains in a heterologous model protein based on designed patterns of affinity between the mRNA and the anti-Shine-Dalgarno (aSD) sequence on the ribosome. We demonstrate that optimizing translation attenuation at domain boundaries can predictably affect solubility patterns in bacteria. Exploration of the affinity space showed that modifying less than 1% of the nucleotides (on a small 12 amino acid linker) can vary soluble protein yields up to ~7-fold without altering the primary sequence of the protein. In the context of longer linkers, where a larger number of distinct structural motifs can fold outside the ribosome, optimal synonymous codon variations resulted in an additional 2.1-fold increase in solubility, relative to that of nonoptimized linkers of the same length. While rational construction of 54 linkers of various affinities showed a significant correlation between protein solubility and predicted affinity, only weaker correlations were observed between tRNA abundance and protein solubility. We also demonstrate that naturally occurring high-affinity clusters are present between structural domains of beta-galactosidase, one of Escherichia coli's largest native proteins. Interdomain ribosomal affinity is an important factor that has not previously been explored in the context of protein engineering. PMID- 26607829 TI - A prospective randomized study comparing 25-G and 22-G needles of a new platform for endoscopic ultrasound-guided fine needle aspiration of solid masses. AB - BACKGROUND: A new needle platform for endoscopic ultrasound-guided fine-needle aspiration biopsy has been developed that allows interchangeability of all needle sizes. AIMS: To prospectively compare the efficacy of the new 25-G needles and 22 G needles for obtaining an adequate aspirate of solid masses. METHODS: Randomized controlled trial of 144 patients referred for endoscopic ultrasound-guided fine needle aspiration of solid pancreatic masses, intraparietal tumours, or lymph nodes, randomized to the 25-G or 22-G needle arms. RESULTS: An adequate specimen was obtained from 74.3% of cases. The sample tended to be more adequate in the 25 G compared to the 22-G group (81% vs. 68%; p=0.09). Crossover was required in 14 (19%) and 12 (17%) cases in the 22-G and in the 25-G groups, respectively (p=0.7). The overall rate of adequacy improved from 74% before crossover to 90% after crossover (p<0.01). When comparing the two groups after crossover, the rate of obtaining adequate samples was significantly higher in the 25-G arm than in the 22-G arm (95.8% vs. 86.1%; p=0.03). CONCLUSIONS: The 25-G needle was superior to the 22-G needle for endoscopic ultrasound-guided fine-needle aspiration biopsy. The adequacy and diagnostic accuracy improved after crossover, reaching 90%. PMID- 26607830 TI - Endoscopic ultrasound-guided single-incision with needle knife and deep tissue biopsy for the diagnosis of gastric subepithelial tumor. PMID- 26607831 TI - Effect of butyrate enemas on gene expression profiles and endoscopic/histopathological scores of diverted colorectal mucosa: A randomized trial. AB - BACKGROUND: A temporary stoma is often created to protect a distal anastomosis in colorectal surgery. Short-chain fatty acids, mainly butyrate, are the major fuel source for the epithelium and their absence in the diverted tract may produce mucosal atrophy and inflammation. AIMS: To investigate whether the administration of sodium butyrate enemas (Naburen((c)), Promefarm, Italy) could prevent mucosal inflammation and atrophy and affect gene expression profiles after ileo/colostomy. METHODS: We performed a randomized, double-blind, placebo controlled clinical trial, in patients with enterostomy performed for inflammatory bowel disease, colorectal cancer or diverticulitis. Twenty patients were randomly allocated to receive 30ml of sodium butyrate 600mmol/L (group A) or saline (group B), b.i.d. for 30 days. RESULTS: In group A endoscopic scores were significantly improved (p<0.01) while mucosal atrophy was reduced or unchanged; in group B mucosal atrophy was increased in 42.8% of patients. Despite the high dose of butyrate used, no short-chain fatty acids were detectable by gas chromatography-mass spectrometry in colorectal biopsies. Group A patients showed up-regulation of genes associated with mucosal repair such as Wnt signalling, cytoskeleton regulation and bone morphogenetic protein-antagonists. CONCLUSION: Butyrate enemas may prevent the atrophy of the diverted colon/rectum, thus improving the recovery of tissue integrity. PMID- 26607832 TI - A chimeolysin with extended-spectrum streptococcal host range found by an induced lysis-based rapid screening method. AB - The increasing emergence of multi-drug resistant streptococci poses a serious threat to public health worldwide. Bacteriophage lysins are promising alternatives to antibiotics; however, their narrow lytic spectrum restricted to closely related species is a central shortcoming to their translational development. Here, we describe an efficient method for rapid screening of engineered chimeric lysins and report a unique "chimeolysin", ClyR, with robust activity and an extended-spectrum streptococcal host range against most streptococcal species, including S. pyogenes, S. agalactiae, S. dysgalactiae, S. equi, S. mutans, S. pneumoniae, S. suis and S. uberis, as well as representative enterococcal and staphylococcal species (including MRSA and VISA). ClyR is the first lysin that demonstrates activity against the dominant dental caries-causing pathogen as well as the first lysin that kills all four of the bovine mastitis causing pathogens. This study demonstrates the success of the screening method resulting in a powerful lysin with potential for treating most streptococcal associated infections. PMID- 26607833 TI - Environmental factors and public health policy associated with human and rodent infection by leptospirosis: a land cover-based study in Nan province, Thailand. AB - Leptospirosis incidence has increased markedly since 1995 in Thailand, with the eastern and northern parts being the most affected regions, particularly during flooding events. Here, we attempt to overview the evolution of human prevalence during the past decade and identify the environmental factors that correlate with the incidence of leptospirosis and the clinical incidence in humans. We used an extensive survey of Leptospira infection in rodents conducted in 2008 and 2009 and the human incidence of the disease from 2003 to 2012 in 168 villages of two districts of Nan province in Northern Thailand. Using an ad-hoc developed land use cover implemented in a geographical information system we showed that humans and rodents were not infected in the same environment/habitat in the land-use cover. High village prevalence was observed in open habitat near rivers for the whole decade, or in 2008-2009 mostly in rice fields prone to flooding, whereas infected rodents (2008-2009) were observed in patchy habitat with high forest cover, mostly situated on sloping ground areas. We also investigated the potential effects of public health campaigns conducted after the dramatic flood event of 2006. We showed that, before 2006, human incidence in villages was explained by the population size of the village according to the environmental source of infection of this disease, while as a result of the campaigns, human incidence in villages after 2006 appeared independent of their population size. This study confirms the role of the environment and particularly land use, in the transmission of bacteria, emphasized by the effects of the provincial public health campaigns on the epidemiological pattern of incidence, and questions the role of rodents as reservoirs. PMID- 26607834 TI - Inferring the hosts of coronavirus using dual statistical models based on nucleotide composition. AB - Many coronaviruses are capable of interspecies transmission. Some of them have caused worldwide panic as emerging human pathogens in recent years, e.g., severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). In order to assess their threat to humans, we explored to infer the potential hosts of coronaviruses using a dual-model approach based on nineteen parameters computed from spike genes of coronaviruses. Both the support vector machine (SVM) model and the Mahalanobis distance (MD) discriminant model achieved high accuracies in leave-one-out cross-validation of training data consisting of 730 representative coronaviruses (99.86% and 98.08% respectively). Predictions on 47 additional coronaviruses precisely conformed to conclusions or speculations by other researchers. Our approach is implemented as a web server that can be accessed at http://bioinfo.ihb.ac.cn/seq2hosts. PMID- 26607835 TI - Comparison of preoperative evaluation of malignant low-level biliary obstruction using plain magnetic resonance and coronal liver acquisition with volume acceleration technique alone and in combination. AB - BACKGROUND: To evaluate the clinical value of plain magnetic resonance (MR) imaging (including magnetic resonance cholangiopancreatography, MRCP) and coronal liver acquisition with volume acceleration (LAVA) technique in the diagnosis and preoperative assessment of malignant low-level biliary obstruction. METHODS: Forty-one patients with confirmed malignant low-level biliary obstruction were examined by plain MR, MRCP and coronal LAVA techniques. Group 1, plain MR (including MRCP); group 2, coronal LAVA; group 3, plain MR and coronal LAVA. Assessments included positioning, qualitative diagnosis and preoperative evaluation. The results were compared with pathological, endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography results. RESULTS: There were 14 pancreatic adenocarcinoma, 12 distal common bile duct carcinoma, 10 ampullary carcinoma, and 5 duodenal carcinoma cases. There was no significant difference in accuracy of the three groups' positioning diagnoses, 87.8, 90.2, and 92.7 %, respectively. The accuracy of the qualitative diagnoses was lower in group 1 at 78.0 %, but not significantly different in groups 2 and 3 at 92.7 and 95.1 %, respectively (P = 0.031, and 0.039, group 1 vs groups 2 and 3, respectively). Thirty-three patients underwent open surgery. There were 19 adjacent organ involvements, 9 vascular involvements, 13 lymph node metastases and 6 liver metastases. 22 patients were verified surgically and histologically for resectable lesions. Plain MR with coronal LAVA imaging showed 85.4 % accuracy, 90.9 % sensitivity, 78.9 % specificity, 83.3 % positive and 88.2 % negative predictive value for resectability. CONCLUSIONS: Plain MR and coronal LAVA techniques are potential noninvasive tools for diagnosis and preoperative assessment of malignant low-level biliary obstruction. PMID- 26607836 TI - Calpain-controlled detachment of major glycoproteins from the cytoskeleton regulates adhesive properties of activated phosphatidylserine-positive platelets. AB - In resting platelets, adhesive membrane glycoproteins are attached to the cytoskeleton. On strong activation, phosphatidylserine(PS)-positive and -negative platelet subpopulations are formed. Platelet activation is accompanied by cytoskeletal rearrangement, although the glycoprotein attachment status in these two subpopulations is not clear. We developed a new, flow cytometry-based, single cell approach to investigate attachment of membrane glycoproteins to the cytoskeleton in cell subpopulations. In PS-negative platelets, adhesive glycoproteins integrin alphaIIbbeta3, glycoprotein Ib and, as shown for the first time, P-selectin were associated with the cytoskeleton. In contrast, this attachment was disrupted in PS-positive platelets; it was retained to some extent only in the small convex regions or 'caps'. It correlated with the degradation of talin and filamin observed only in PS-positive platelets. Calpain inhibitors essentially prevented the disruption of membrane glycoprotein attachment in PS positive platelets, as well as talin and filamin degradation. With the suggestion that detachment of glycoproteins from the cytoskeleton may affect platelet adhesive properties, we investigated the ability of PS-positive platelets to resist shear-induced breakaway from the immobilized fibrinogen. Shear rates of 500/s caused PS-positive platelet breakaway, but their adhesion stability increased more than 10-fold after pretreatment of the platelets with calpain inhibitor. In contrast, the ability of PS-positive platelets to adhere to immobilized von Willebrand's factor at 100/s was low, but this was not affected by the preincubation of platelets with a calpain inhibitor. Our data suggest that calpain-controlled detachment of membrane glycoproteins is a new mechanism that is responsible for the loss of ability of the procoagulant platelets to resist detachment from thrombi by high shear stress. PMID- 26607839 TI - Margaret McCartney: Why less confidence may be a good thing. PMID- 26607838 TI - Stochastic density effects on adult fish survival and implications for population fluctuations. AB - The degree to which population fluctuations arise from variable adult survival relative to variable recruitment has been debated widely for marine organisms. Disentangling these effects remains challenging because data generally are not sufficient to evaluate if and how adult survival rates are regulated by stochasticity and/or population density. Using unique time series for a largely unexploited reef fish, we found both population density and stochastic food supply impacted adult survival. The estimated effect of variable survival on adult abundance (both mean and variability) rivalled that of variable recruitment. Moreover, we show density-dependent adult survival can dampen impacts of stochastic recruitment. Thus, food variability may alter population fluctuations by simultaneously regulating recruitment and compensatory adult survival. These results provide an additional mechanism for why intensified density-independent mortality (via harvest or other means) amplifies population fluctuations and emphasises need for research evaluating the causes and consequences of variability in adult survival. PMID- 26607837 TI - Actin polymerization is stimulated by actin cross-linking protein palladin. AB - The actin scaffold protein palladin regulates both normal cell migration and invasive cell motility, processes that require the co-ordinated regulation of actin dynamics. However, the potential effect of palladin on actin dynamics has remained elusive. In the present study, we show that the actin-binding immunoglobulin-like domain of palladin, which is directly responsible for both actin binding and bundling, also stimulates actin polymerization in vitro. Palladin eliminated the lag phase that is characteristic of the slow nucleation step of actin polymerization. Furthermore, palladin dramatically reduced depolymerization, slightly enhanced the elongation rate, and did not alter the critical concentration. Microscopy and in vitro cross-linking assays reveal differences in actin bundle architecture when palladin is incubated with actin before or after polymerization. These results suggest a model whereby palladin stimulates a polymerization-competent form of globular or monomeric actin (G actin), akin to metal ions, either through charge neutralization or through conformational changes. PMID- 26607840 TI - The scientific evidence of arterial line filtration in cardiopulmonary bypass. AB - BACKGROUND: The indication for arterial line filtration (ALF) is to inhibit embolisation during cardiopulmonary bypass. Filtration methods have developed from depth filters to screen filters and from a stand-alone component to an integral part of the oxygenator. For many years, ALF has been a standard adopted by a majority of cardiac centres worldwide. The following review aims to summarize the available evidence in support for ALF and report on its current practice in Europe. METHOD: The principles and application of ALF in Europe was investigated using a survey conducted in 2014. The scientific evidence for ALF was examined by performing a systematic literature search in six different databases, using the following search terms: "Cardiopulmonary bypass AND filters AND arterial". The primary endpoint was protection against cerebral injury verified by the degree of cerebral embolisation or cognitive tests. The secondary endpoint was improvement of the clinical outcome verified elsewise. Only randomised clinical trials were considered. RESULTS: The response rate was 31% (n=112). The great majority (88.5%) of respondents were using ALF, following more than 10 years of experience. Integrated arterial filtration was used by 55%. Of respondents not using ALF, fifty-four percent considered starting using integrated arterial filtration. The systematic literature database search returned 180 unique publications where 82 were specifically addressing ALF in cardiopulmonary bypass. Only four out of the 82 identified publications fulfilled our inclusion criteria. Of these, three were more than 20 years old and based on the use of bubble oxygenation. CONCLUSION: ALF is a standard implemented in a majority of cardiopulmonary bypass procedures in Europe. The level of scientific evidence available in support of current arterial line filtration methods in cardiopulmonary bypass is, however, poor. Large, well-designed, randomised trials are warranted. PMID- 26607841 TI - Glucose Variability and beta- Cell Response by GLP-1 Analogue added-on CSII for Patients with Poorly Controlled Type 2 Diabetes. AB - The effects of twice-daily GLP-1 analogue injections added on continuous subcutaneous insulin infusion (CSII) in patients with poorly controlled type 2 diabetes (T2DM) were unknown. After optimization of blood glucose in the first 3 days by CSII during hospitalization, patients with poorly controlled T2DM were randomized to receive CSII combined with injections of exenatide or placebo for another 3 days. A total of 51 patients (30 in exenatide and 21 in placebo groups) with mean A1C 11% were studied. There was no difference in mean glucose but a significant higher standard deviation of plasma glucose (SDPG) was found in the exenatide group (50.51 +/- 2.43 vs. 41.49 +/- 3.00 mg/dl, p = 0.027). The improvement of incremental area under the curve (AUC) of glucose and insulinogenic index (Insulin 0-peak/ Glucose 0-peak) in 75 g oral glucose tolerance test was prominent in the exenatide group (p < 0.01). The adiponectin level was significantly increased with exenatide added on (0.39 +/- 0.32 vs. 1.62 +/- 0.97 MUg/mL, in exenatide and placebo groups, respectively, p = 0.045). In conclusion, the add-on of GLP-1 analogue to CSII increased glucose variability and the beta - cell response in patients with poorly controlled T2DM. PMID- 26607842 TI - Efficacy of platelet rich fibrin in the reduction of the pain and swelling after impacted third molar surgery: randomized multicenter split-mouth clinical trial. AB - BACKGROUND: Impacted third molar removal is a routine procedure in oral and maxillofacial surgery. Platelet-rich fibrin (PRF) is a second generation platelet concentration which is produced by simplified protocol. The aim of this study was to assess the effectiveness of PRF in the healing process by evaluating the changes in pain and swelling after third molar surgery. METHODS: Fifty-six patients (23 male, 33 female) who provide the inclusion criteria were selected to participate in this study. The evaluation of the facial swelling was performed by using a horizontal and vertical guide. The pain was evaluated in the postoperative period using a visual analog scale (VAS) of 100 mm. RESULTS: Horizontal and vertical measurements showed more swelling at the control side (without PRF) in 3th day postoperatively (p < 0.05). There were no statistically significant differences regarding pain among the groups. CONCLUSION: As a conclusion, PRF seems to be effectiveness on postoperative horizontal swelling after third molar surgery. PRF could be used on a routine basis after third molar extraction surgery. PMID- 26607843 TI - Associations of outdoor play and screen time with nocturnal sleep duration and pattern among young children. AB - AIM: Sleep duration and pattern have important implications for children's health. This study aims to investigate nocturnal sleep duration, sleep pattern and their relationships with outdoor play and screen time among children aged 2 to five years. METHODS: The study used data from the Healthy Beginnings Trial undertaken in Sydney, Australia. Data on children's sleep, outdoor playtime and screen time were reported by mothers via face-to-face interviews when children were 2, 3.5 and five years old. Both cross-sectional and longitudinal analyses were conducted. RESULTS: At age 2, 3.5 and five years, 497, 415 and 369 mother child dyads participated. Significantly, there was an overall increase in children's nocturnal sleep duration, sleep latency and an earlier bedtime, and there was a decrease in the proportion of children who woke at night over time. Each additional hour of screen time was associated with three-minute (95% CI 0.6 5) shorter sleep, 1.6-minute (95% CI 0.59-2.63) longer sleep latency, four-minute (95% CI 1.8-6.0) later bedtime and less likely sleeping >=10 hours per night with adjusted odds ratio 0.88 (95% CI 0.77-1.00), after controlling for mothers' demographics. CONCLUSION: Among young children, screen time and outdoor playtime were associated with sleep duration and pattern. Reducing screen time and increasing outdoor playtime might help improving children's sleep. PMID- 26607844 TI - Prolonged Mechanical Ventilation After Lung Transplantation-A Single-Center Study. AB - This single-center study examines the incidence, etiology, and outcomes associated with prolonged mechanical ventilation (PMV), defined as time to definite spontaneous ventilation >21 days after double lung transplantation (LTx). A total of 690 LTx recipients between January 2005 and December 2012 were analyzed. PMV was necessary in 95 (13.8%) patients with decreasing incidence during the observation period (p < 0.001). Independent predictors of PMV were renal replacement therapy (odds ratio [OR] 11.13 [95% CI, 5.82-21.29], p < 0.001), anastomotic dehiscence (OR 8.74 [95% CI 2.42-31.58], p = 0.001), autoimmune comorbidity (OR 5.52 [95% CI 1.86-16.41], p = 0.002), and postoperative neurologic complications (OR 5.03 [95% CI 1.98-12.81], p = 0.001), among others. Overall 1-year survival was 86.0% (90.4% for LTx between 2010 and 2012); it was 60.7% after PMV and 90.0% in controls (p < 0.001). Conditional long term outcome among hospital survivors, however, did not differ between the groups (p = 0.78). Multivariate analysis identified renal replacement therapy (hazard ratio [HR] 3.55 [95% CI 2.40-5.25], p < 0.001), post-LTx extracorporeal membrane oxygenation (HR 3.47 [95% CI 2.06-5.83], p < 0.001), and prolonged inotropic support (HR 1.95 [95% CI 1.39-2.75], p < 0.001), among others, as independent predictors of mortality. In conclusion, PMV complicated 14% of LTx procedures and, although associated with increased in-hospital mortality, outcomes among patients surviving to hospital discharge were unaffected. PMID- 26607845 TI - Satellite cell response to erythropoietin treatment and endurance training in healthy young men. AB - KEY POINT: Erythropoietin (Epo) treatment may induce myogenic differentiation factor (MyoD) expression and prevent apoptosis in satellite cells (SCs) in murine and in vitro models. Endurance training stimulates SC proliferation in vivo in murine and human skeletal muscle. In the present study, we show, in human skeletal muscle, that treatment with an Epo-stimulating agent (darbepoetin-alpha) in vivo increases the content of MyoD(+) SCs in healthy young men. Moreover, we report that Epo receptor mRNA is expressed in adult human SCs, suggesting that Epo may directly target SCs through ligand-receptor interaction. Moreover, endurance training, but not Epo treatment, increases the SC content in type II myofibres, as well as the content of MyoD(+) SCs. Collectively, our results suggest that Epo treatment can regulate human SCs in vivo, supported by Epo receptor mRNA expression in human SCs. In effect, long-term Epo treatment during disease conditions involving anaemia may impact SCs and warrants further investigation. Satellite cell (SC) proliferation is observed following erythropoitin treatment in vitro in murine myoblasts and endurance training in vivo in human skeletal muscle. The present study aimed to investigate the effects of prolonged erythropoiesis-stimulating agent (ESA; darbepoetin-alpha) treatment and endurance training, separately and combined, on SC quantity and commitment in human skeletal muscle. Thirty-five healthy, untrained men were randomized into four groups: sedentary-placebo (SP, n = 9), sedentary-ESA (SE, n = 9), training placebo (TP, n = 9) or training-ESA (TE, n = 8). ESA/placebo was injected once weekly and training consisted of ergometer cycling three times a week for 10 weeks. Prior to and following the intervention period, blood samples and muscle biopsies were obtained and maximal oxygen uptake (VO2, max) was measured. Immunohistochemical analyses were used to quantify fibre type specific SCs (Pax7(+)), myonuclei and active SCs (Pax7(+)/MyoD(+)). ESA treatment led to elevated haematocrit, whereas endurance training increased VO2, max. Endurance training led to an increase in SCs associated with type II fibres (P < 0.05), whereas type I fibres showed no changes. Both ESA treatment and endurance training increased Pax7(+)/MyoD(+) cells, whereas only ESA treatment increased the total content of MyoD(+) cells. Epo-R mRNA presence in adult SC was tested with real-time RT-PCR using fluorescence-activated cell sorting (CD56(+)/CD45( )/CD31(-)) to isolate cells from a human rectus abdominis muscle and was found to be considerably higher than in whole muscle. In conclusion, endurance training and ESA treatment may separately stimulate SC commitment to the myogenic program. Furthermore, ESA-treatment may alter SC activity by direct interaction with the Epo-R expressed on SCs. PMID- 26607846 TI - Overexpression of G6PD is associated with high risks of recurrent metastasis and poor progression-free survival in primary breast carcinoma. AB - BACKGROUND: The present study aimed to investigate the expression of CYP27A1, CYP7B1, insulin-like growth factor-1 (IGF-1), glucose-6-phosphate-dehydrogenase (G6PD), glutathione S-transferase P1 (GSTP1), and pyruvate kinase isoform M2 (PKM2) in breast carcinoma tissue and evaluate their prognostic value for progression-free survival (PFS) and overall survival (OS). METHODS: A total of 20 patients treated with surgery for primary breast carcinoma were enrolled: 10 cases diagnosed with recurrent metastasis (A), along with their corresponding metastases specimen (AM) and 10 cases with no evidence of recurrence or metastasis (B). Baseline characteristics of patients including age, lymph node metastasis, molecular subtypes, tumor staging and size, and pathological classification were all collected. Immunohistochemistry was performed to detect the protein expression in tumor specimens. RESULTS: Elevated G6PD protein levels were noted in group A compared with group AM and B (both P < 0.05), and PKM2 expression was also higher in group A when compared to group AM (P = 0.019), but similar with group B (P > 0.05). No association between clinicopathological parameters and the two proteins expression was observed. The G6PD protein expression was strongly associated with PFS of breast carcinoma patients (P = 0.021) but not for OS. According to the Kaplan-Meier analysis, mean PFS time of patients with G6PD-negative and G6PD-positive expression tumor were 71.36 +/- 6.53 and 32.25 +/- 5.67 months, respectively (P = 0.002). CONCLUSIONS: The G6PD protein could be served as a potential prognostic biomarker for primary breast carcinoma, and overexpression of G6PD protein predicted a high risk of recurrent metastasis and poor PFS during follow-up. PMID- 26607847 TI - An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1. AB - PAK4 is a metazoan-specific kinase acting downstream of Cdc42. Here we describe the structure of human PAK4 in complex with Inka1, a potent endogenous kinase inhibitor. Using single mammalian cells containing crystals 50 MUm in length, we have determined the in cellulo crystal structure at 2.95 A resolution, which reveals the details of how the PAK4 catalytic domain binds cellular ATP and the Inka1 inhibitor. The crystal lattice consists only of PAK4-PAK4 contacts, which form a hexagonal array with channels of 80 A in diameter that run the length of the crystal. The crystal accommodates a variety of other proteins when fused to the kinase inhibitor. Inka1-GFP was used to monitor the process crystal formation in living cells. Similar derivatives of Inka1 will allow us to study the effects of PAK4 inhibition in cells and model organisms, to allow better validation of therapeutic agents targeting PAK4. PMID- 26607849 TI - Azafullerene C59 in Donor-Acceptor Dyads: Synthetic Approaches and Properties. AB - Energy conversion schemes have attracted considerable attention in recent years. A large amount of research effort has focused on fullerenes, particularly C60 and its derivatives, as suitable electron acceptors, owing to their outstanding properties. In this context, C59 N-based donor-acceptor systems have lately attracted attention, owing to their exceptional energy-and electron-transfer properties. As a result, chemical derivatization of C59 N plays an important role in the realization of the aforementioned systems. The current Minireview aims to familiarize researchers with the main aspects of azafullerene synthesis, chemistry, and photophysical properties, while it mainly focuses on the synthetic methodologies employed for as well as on energy conversion schemes of azafullerene-based donor-acceptor systems. PMID- 26607848 TI - Effects of propranolol on fear of dental extraction: study protocol for a randomized controlled trial. AB - BACKGROUND: Undergoing an extraction has been shown to pose a significantly increased risk for the development of chronic apprehension for dental surgical procedures, disproportionate forms of dental anxiety (that is, dental phobia), and symptoms of post-traumatic stress. Evidence suggests that intrusive emotional memories of these events both induce and maintain these forms of anxiety. Addressing these problems effectively requires an intervention that durably reduces both the intrusiveness of key fear-related memories and state anxiety during surgery. Moreover, evidence suggests that propranolol is capable of inhibiting "memory reconsolidation" (that is, it blocks the process of storing a recently retrieved fear memory). Hence, the purpose of this trial is to determine the anxiolytic and fear memory reconsolidation inhibiting effects of the beta adrenoreceptor antagonist propranolol on patients with high levels of fear in anticipation of a dental extraction. METHODS/DESIGN: This trial is designed as a multicenter, randomized, placebo-controlled, two-group, parallel, double-blind trial of 34 participants. Consecutive patients who have been referred by their dentist to the departments of oral and maxillofacial surgery of a University hospital or a secondary referral hospital in the Netherlands for at least two tooth and/or molar removals and with self-reported high to extreme fear in anticipation of a dental extraction will be recruited. The intervention is the administration of two 40 mg propranolol capsules 1 hour prior to a dental extraction, followed by one 40 mg capsule directly postoperatively. Placebo capsules will be used as a comparator. The primary outcome will be dental trait anxiety score reduction from baseline to 4-weeks follow-up. The secondary outcomes will be self-reported anxiety during surgery, physiological parameters (heart rate and blood pressure) during recall of the crucial fear-related memory, self-reported vividness, and emotional charge of the crucial fear-related memory. DISCUSSION: This randomized trial is the first to test the efficacy of 120 mg of perioperative propranolol versus placebo in reducing short-term ("state") anxiety during dental extraction, fear memory reconsolidation, and lasting dental ("trait") anxiety in a clinical population. If the results show a reduction in anxiety, this would offer support for routinely prescribing propranolol in patients who are fearful of undergoing dental extractions. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02268357 , registered on 7 October 2014. The Netherlands National Trial Register identifier: NTR5364 , registered on 16 August 2015. PMID- 26607850 TI - Current profile of cycling injuries: A retrospective analysis of a trauma centre level 1 in Queensland. AB - OBJECTIVES: One out of 50 injury-related presentations to an ED is a transport related cycling injury. Detailed information about the most frequent mechanism of cycling injuries, sustained injuries and patterns are under-reported. The objective of this research was to examine the pattern of injuries sustained by cyclists at a level 1 trauma centre. METHODS: A retrospective review of data of injured cyclists admitted and treated at a level 1 trauma centre between 2011 and 2012 evaluated demographic data, mechanism of injury, injury pattern, economic costs and outcome. RESULTS: Data of 261 patients (mean age of 39 years) were reviewed, of which 88% was male patients with an average age of 38 years. Non collision cycling injuries were reported in 55% of cases followed by collisions with other motor vehicles in 25.6% of cases. The mean injury severity score (ISS) was 9, but an ISS >= 12 was documented in 24%. Predominantly upper limb injuries (24.8%) were found, followed by injuries to the head and lower limb (each with 16.8%). Traumatic brain and chest injuries were equally seen in 8%. The overall length of stay was 4 days, and survival rate was 98%. CONCLUSION: This current data review reveals that non-collision traffic crashes accounted for the majority of injuries in cyclists treated in this facility, and the upper limb has replaced the head as the most injured body part. With a growing number of cyclists, this information contributes to considerations to improve road safety and trauma management. PMID- 26607851 TI - The need for evidence and new models of practice education to meet the 1000 hour requirement. PMID- 26607852 TI - Parathyroid surgery can be safely performed in a community hospital by experienced parathyroid surgeons: A retrospective cohort study. AB - BACKGROUND: There is ongoing debate about the effectiveness and safety of performing parathyroid surgery in low-volume community hospitals. STUDY DESIGN/METHODS: Cases performed at community hospital by a group of 4 parathyroid surgeons (group 1) were reviewed. Cure and complication rates were analyzed in light of outcomes of an expert endocrine surgeon from high-volume academic center (group 2) as point of reference. RESULTS: During the respective time periods, 204 patients met inclusion criteria in group1 and 218 patients in group 2. Patient characteristics, biochemical tests, and performed localizing studies (ultrasound and sestamibi scan) were comparable between the two groups. Pathological findings, including adenoma, double adenoma, hyperplasia, and cancer were comparable. Each had comparable cure rates (97% and 99%) (p < 0.18) and complication rates (1% and 1%) (p < 0.93) for group 1 and 2, respectively. CONCLUSION: Our results showed that experienced parathyroid surgeons will achieve comparable excellent outcomes of parathyroid surgery at both community and academic-based centers. As the field of endocrine surgery evolves and matures, producing young fellowship-trained endocrine surgeons, there will be growing need for expanding the niche of endocrine surgery into community-based hospital settings, which eventually will contribute to expanding and equalizing access to high-quality surgical care across urban and rural areas. PMID- 26607853 TI - Peritoneal carcinomatosis with synchronous liver metastases from colorectal cancer: Who will benefit from complete cytoreductive surgery? AB - PURPOSE: Selection of patients for resection of synchronous liver metastases (LM) and peritoneal carcinomatosis (PC) of colorectal cancer (CRC) remains a debated issue since morbidity of this surgery is not negligible. We aimed to define overall survival (OS) prognostic criteria in patients undergoing PC surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) and LM resection. METHODS: This monocentric and comparative study included all consecutive patients operated for LM (LM group, n = 77), PC (HIPEC group, n = 18) and PC + LM (LM + HIPEC group, n = 9) from January 2007 to May 2011. Characteristics of the 3 groups were prospectively collected and retrospectively compared. RESULTS: Median follow-up was 56,5 months. Major morbidity and mortality were respectively 14% and 3%. Two year disease free and overall survival rates were respectively 23% and 76%. There were significantly more Dindo grade III-IV complications in LM + HIPEC group. In multivariate analysis, grade II and III preoperative chemotherapy-induced toxicity and size of LM were identified as poor OS prognostic factors whereas response to preoperative chemotherapy significantly increases OS. OS was not different (p = 0.235) between the 3 groups. CONCLUSION: Toxicity to preoperative chemotherapy and size of LM were identified as poor prognostic factors in patients undergoing simultaneous PC and LM surgery. These criteria could help in better selecting patients for such extensive surgery. PMID- 26607854 TI - Roles of NOTES and LESS in management of small renal masses. AB - INTRODUCTION: Over the last 2 decades, open surgery has been largely displaced by laparoscopic surgery for the treatment of renal masses. Recently, minimally invasive surgical techniques, such as laparoendoscopic single-site surgery (LESS) and natural orifice transluminal endoscopic surgery (NOTES), have been developed for such purpose. METHODS: In the present literature review, the current status of treatment for small renal masses was investigated. The advantages and disadvantages of LESS and NOTES are presented to confirm the feasibility and reproducibility of these techniques. RESULTS: LESS significantly reduces pain and offers excellent cosmetic outcomes with comparable oncological and perioperative results, and NOTES offers the potential for surgery by various approach without any transcutaneous abdominal incision in management of small renal masses. CONCLUSION: When the technical limitations are overcome, clinical application of LESS and NOTES is expected to increase. Further prospective and comparative studies are needed to clarify the application of these new techniques. PMID- 26607855 TI - Primary central nervous system lymphomas and related diseases: Pathological characteristics and discussion of the differential diagnosis. AB - Although primary diffuse large B-cell lymphomas of the CNS are designated as primary CNS lymphomas according to the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue in 2008, a variety of other lymphomas (Burkitt lymphomas, EBV-positive diffuse large B-cell lymphoma of the elderly) and related diseases (lymphomatoid granulomatosis) that are also found in the CNS have been spotlighted in recent years. The histopathology of primary CNS Burkitt lymphomas mimics that of primary diffuse large B-cell lymphomas of the CNS after steroid administration. Therefore, for correct diagnosis of the involved lymphoma, comprehensive fluorescent in situ hybridization analysis for c-MYC and BCL2 is recommended in all primary CNS lymphoma cases with aggressive clinical course, multifocal involvement of the CNS, and a high proliferation index. The pathological characteristics of primary CNS EBV-positive diffuse large B-cell lymphoma of the elderly have similarities with those of the latency phenotype III, EBV lymphoproliferative disorders that arise in the setting of immunodeficiency. These age-related lymphomas usually occur in elderly immunocompetent patients, and the incidence of this disease was estimated to range from 4.0% to 13.6% of all primary CNS lymphomas. Shorter overall survival has been reported for patients with this disease. Lymphomatoid granulomatosis (LYG) is a systemic, EBV-driven, angiocentric and angiodestructive lymphoproliferative disorder. Primary LYG that shows distinct clinicopathological features compared with systemic LYG was recently reported. Finally, this review focuses on the relationship between primary CNS lymphomas and demyelinating diseases, and the concomitant use of intraoperative cytology and frozen sections that are helpful in rapid intraoperative diagnosis. PMID- 26607856 TI - Primary ovarian mixed strumal and mucinous carcinoid arising in an ovarian mature cystic teratoma. AB - A 39-year-old woman presented with low back pain lasting for several weeks. Abdominopelvic computed tomography showed an ovarian cystic mass with an enhancing solid portion, fat and internal calcification. A right salpingo oophorectomy was performed. A 9.7 cm round multiseptated cystic mass showed pathology of mature cystic teratoma and contained a solid portion, measuring 4.2 cm, composed mainly of carcinoid cells arranged in a trabecular-insular configuration admixed with surrounding thyroid follicles containing colloid. Juxtaposed were several nests of columnar cells interspersed with goblet cells and extracellular mucin pools. In the cyst wall of the teratoma, the lining of pseudostratified columnar cells was occasionally mixed with goblet cells transforming to the carcinoid portion. Immunohistochemically, both mucinous and strumal carcinoids were positive for polyclonal carcinoembryonic antigen, caudal type homeobox 2, cytokeratin (CK)7, CK20, synaptophysin, CD56 and focally positive for chromogranin. Thyroid follicles were positive for thyroid transcription factor-1 and thyroglobulin. After gastrointestinal and respiratory tract evaluation, no evidence of primary tumor, including omentum, was observed. The mass was diagnosed as a mixed strumal and mucinous type carcinoid associated with a mature cystic teratoma. PMID- 26607857 TI - Embryological outcomes in cycles with human oocytes containing large tubular smooth endoplasmic reticulum clusters after conventional in vitro fertilization. AB - There have been no studies analyzing the effect of large aggregates of tubular smooth endoplasmic reticulum (aSERT) after conventional in vitro fertilization (cIVF). The aim of this study was to investigate whether aSERT can be identified after cIVF and the association between the embryological outcomes of oocytes in cycles with aSERT. This is a retrospective study examining embryological data from cIVF cycles showing the presence of aSERT in oocytes 5-6 h after cIVF. To evaluate embryo quality, cIVF cycles with at least one aSERT-metaphase II (MII) oocyte observed (cycles with aSERT) were compared to cycles with normal-MII oocytes (control cycles). Among the 4098 MII oocytes observed in 579 cycles, aSERT was detected in 100 MII oocytes in 51 cycles (8.8%). The fertilization rate, the rate of embryo development on day 3 and day 5-6 did not significantly differ between cycles with aSERT and control group. However, aSERT-MII oocytes had lower rates for both blastocysts and good quality blastocysts (p < 0.05). aSERT can be detected in the cytoplasm by removing the cumulus cell 5 h after cIVF. However, aSERT-MII oocytes do not affect other normal-MII oocytes in cycles with aSERT. PMID- 26607858 TI - A preliminary evaluation of the validity of binge-eating disorder defining features in a community-based sample. AB - OBJECTIVE: Little empirical attention has been paid to the DSM-5 definition of binge-eating disorder (BED), particularly to the associated features of binge episodes. The present study sought to determine how the associated features and undue influence of weight/shape on self-evaluation contribute to evidence of a clinically significant eating disorder. METHOD: Secondary analyses were conducted on data (N = 80; 76.3% women, 76.3% Caucasian, ages 18-43) collected through an epidemiological study of eating patterns. Descriptive statistics were used to report the sample prevalence of the features, independently and in combination. Correlations and alpha reliability were employed to examine relationships among associated features, distress regarding bingeing, and clinical diagnosis. Regression models and receiver-operating characteristic (ROC) curves were used to determine the utility of the features for explaining variance in distress. RESULTS: Internal consistency reliability for indicators was low, and several features demonstrated low or nonsignificant associations with distress and diagnosis. Feeling disgusted/depressed/guilty was the only unique predictor of distress (p = 0.001). For the ROC curves, three features was the best threshold for predicting distress. DISCUSSION: Results support the need to refine the features to ensure better detection of clinically significant eating pathology for research inclusion and treatment of the illness. (c) 2015 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:524-528). PMID- 26607859 TI - An assessment of the accuracy and utility of the primary care electronic medical record as used by the British Army. AB - INTRODUCTION: For the purposes of patient safety, audit and research, the electronic patient record (EPR) must be accurate and searchable. No evaluation of the accuracy of EPRs compared with paper records has been made. Furthermore, the use of Read codes is known to be heterogeneous. This study was designed to evaluate the EPR used by the UK Armed Forces. METHODS: A cross-sectional study reviewing the paper records and EPRs of 50 consecutive soldiers posted to a British Army Training Regiment. RESULTS: There was a pre-enlistment summary in only 38% of the paper notes, although 24% had some primary care records from prior to enlistment. There were 357 entries that should have been transferred to the EPR. Of these, only 190 (53.2%) were transferred with appropriate Read codes, while only 24% of patients reviewed had all their entries appropriately Read coded. There were 168 secondary care letters discovered with 122 (72.6%) generically Read coded and 46 (27.4%) using an appropriate Read code. Of those letters with more than one potential Read code, 34 (73.9%) were coded using all appropriate Read codes. Several incidental errors in the medical records were also discovered with significant patient safety implications. CONCLUSIONS: The historical paper-based medical record was found to have many data missing. The transfer of these paper records to the EPR has been inaccurate with many records not transferred or transferred ineffectively. These findings have an impact on patient safety, audit and data security and should trigger a review of how the Armed Forces manage their primary care records. PMID- 26607860 TI - The prevalence of causative organisms of community-acquired urethritis in an age group at high risk for sexually transmitted infections in Korean Soldiers. AB - OBJECTIVES: This study was designed to evaluate the causative organisms in young male soldiers with clinical signs and symptoms after sexual contact that suggests a diagnosis of urethritis. METHODS: Between June 2012 and January 2015, male patients with urethritis symptoms that had resulted from sexual contact within 3 months participated in this study. All patients were evaluated using urinalysis and were screened for Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), Ureaplasma urealyticum (UU), Mycoplasma genitalium (MG), Mycoplasma hominis (MH), herpes simplex virus (HSV) type II and Trichomonas vaginalis (TV) using multiplex PCR (mPCR) assay in order to detect sexually transmitted infections (STI) or pathogens. RESULTS: A total of 436 male patients aged 18-28 years were included in the study. The median age was 22.0 years. The prevalence of STI pathogens were as follows: NG in 19.0%, CT in 36.6%, UU in 24.0%, MG in 21.5%, MH in 6.1%, HSV type II in 1.6%, TV in 0.2% and indeterminate STI pathogens in 9.4%. Coinfection of NG with non-NG was detected in 5.7% of the participants, while the coinfection rates for STI pathogens were: with CT in 3.4%, with UU in 2.7%, with MG in 0.2% and with MH in 0.2%. CONCLUSIONS: CT was the most prevalent STI pathogen and coinfections of NG with non-NG appeared less frequently. The young male soldiers with urethritis should be administered suitable antibiotics for STI pathogens that were found by mPCR results, rather than an experimental combination of antibiotics for coinfections. PMID- 26607861 TI - Impact of social media on the health of children and young people. AB - This paper reviews the literature on the impact of social media on the health of children and young people. Relevant papers were identified from Medline, Embase and PsycINFO databases. The studies identified that the health impact of social media on children and young people was greatest on mental health and specifically in the areas of self-esteem and well-being, with related issues around cyberbullying and 'Facebook Depression', with an association between the use of social media and self-esteem and body image. However, it is difficult to determine the cause and effect, which is likely to be related to the nature of the young person. There is little work on the impact of social media on younger children. More research is needed to identify those most at risk of harm from social media and risk mitigation strategies to assist health-care professionals to provide essential education for parents and young people. PMID- 26607862 TI - Systematic review of chronic pain in persons with Marfan syndrome. AB - The purpose of this study was to explore the literature on chronic pain in adults with Marfan syndrome (MFS), critically appraising and synthesizing relevant literature. A systematic review was conducted by searching the published literature databases using available medical, physical, psychological, social databases and other sources. All studies that addressed pain in MFS, published in peer-reviewed journals were assessed. Of 351 search results, 18 articles satisfied the eligibility criteria. All studies were cross-sectional and quantitative; no randomized controlled trials or intervention studies were found. Most studies had small sample sizes, low response rates and mainly dealt with other aspects of the diagnosis than pain. Only one article dealt mainly with pain. The research on chronic pain in MFS is limited in size and quality. Despite these limitations, studies describe that the prevalence of pain in patients with MFS is high, varying from 47 to 92% and affecting several anatomic sites. In addition, chronic pain limits daily function and few studies describe treatment options for pain in patients with MFS. Research is needed to obtain more evidence based knowledge for developing more appropriate rehabilitation programs for people with MFS. PMID- 26607863 TI - Pathophysiology and pharmacological targets of VEGF in diabetic macular edema. AB - Diabetic macular edema (DME) is a serious condition that can cause blindness in diabetic patients suffering from diabetic retinopathy (DR). Although vascular endothelial growth factor (VEGF) is known to play a role in the development of DME, the pathological processes leading to the onset of this disease are highly complex and the exact sequence in which they occur is still not completely understood. Angiogenesis and inflammation have been shown to be involved in the pathogenesis of this disease. However, it still remains to be clarified whether angiogenesis following VEGF over-expression is a cause or a consequence of inflammation. Here, we provide an overview of the current data available in the literature focusing on VEGF, angiogenesis, inflammation, DR and DME. Our analysis suggests that angiogenesis and inflammation act interdependently during the development of DME. VEGF is a critical player in the molecular crosstalk occurring between these two processes, reinforcing the use of anti-VEGF agents for the treatment of DME. PMID- 26607864 TI - Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism. AB - The alpha2-adrenergic receptor agonist Dexmedetomidine (Dex) is a sedative medication used by anesthesiologists. Dex protects the heart against ischemia reperfusion (IR) and can also act as a preconditioning mimetic. The mechanisms involved in Dex-dependent cardiac preconditioning, and whether this action occurs directly or indirectly on cardiomyocytes, still remain unclear. The endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling pathway and endothelial cells are known to play key roles in cardioprotection against IR injury. Therefore, the aims of this work were to evaluate whether the eNOS/NO pathway mediates the pharmacological cardiac effect of Dex, and whether endothelial cells are required in this cardioprotective action. Isolated adult rat hearts were treated with Dex (10nM) for 25min and the dimerization of eNOS and production of NO were measured. Hearts were then subjected to global IR (30/120min) and the role of the eNOS/NO pathway was evaluated. Dex promoted the activation of eNOS and production of NO. Dex reduced the infarct size and improved the left ventricle function recovery, but this effect was reversed when Dex was co administered with inhibitors of the eNOS/NO/PKG pathway. In addition, Dex was unable to reduce cell death in isolated adult rat cardiomyocytes subjected to simulated IR. Cardiomyocyte death was attenuated by co-culturing them with endothelial cells pre-treated with Dex. In summary, our results show that Dex triggers cardiac protection by activating the eNOS/NO signaling pathway. This pharmacological effect of Dex requires its interaction with the endothelium. PMID- 26607865 TI - Collet-Sicard syndrome caused by metastasis. PMID- 26607866 TI - Differences between chronic migraine with and without medication overuse. PMID- 26607867 TI - A novel mutation in the ABCD1 gene of a Moroccan patient with X-linked adrenoleukodystrophy: case report. AB - BACKGROUND: X-linked adrenoleukodystrophy (X-ALD; OMIM: 300100) is the most common peroxisomal disease caused by mutations in the ATP-binding cassette, sub family D member 1 gene or ABCD1 (geneID: 215), the coding gene for the adrenoleukodystrophy protein (ALDP), which is an ATP-binding transport protein associated to an active transport of very long chain fatty acids (VLCFAs). Dysfunction of ALDP induces an accumulation of VLCFAs in all tissues leading to a neurodegenerative disorder that involves the nervous system white matter. CASE PRESENTATION: In our case report, magnetic resonance imaging (MRI) as well as the high levels of VLCFAs prompted the diagnosis the X-ALD. Molecular analysis of ABCD1 gene have shown a pathogenic homozygous nonsense mutation (c.1677C > G; p.(Tyr559*)) in exon 7. CONCLUSION: Thus, we identified here a novel mutation in the ABCD1 gene in a Moroccan patient causing X-linked adrenoleukodystrophy. PMID- 26607868 TI - The associations between US state and local social spending, income inequality, and individual all-cause and cause-specific mortality: The National Longitudinal Mortality Study. AB - OBJECTIVE: To investigate government state and local spending on public goods and income inequality as predictors of the risks of dying. METHODS: Data on 431,637 adults aged 30-74 and 375,354 adults aged 20-44 in the 48 contiguous US states were used from the National Longitudinal Mortality Study to estimate the impacts of state and local spending and income inequality on individual risks of all cause and cause-specific mortality for leading causes of death in younger and middle-aged adults and older adults. To reduce bias, models incorporated state fixed effects and instrumental variables. RESULTS: Each additional $250 per capita per year spent on welfare predicted a 3-percentage point (-0.031, 95% CI: 0.059, -0.0027) lower probability of dying from any cause. Each additional $250 per capita spent on welfare and education predicted 1.6-percentage point (-0.016, 95% CI: -0.031, -0.0011) and 0.8-percentage point (-0.008, 95% CI: -0.0156, 0.00024) lower probabilities of dying from coronary heart disease (CHD), respectively. No associations were found for colon cancer or chronic obstructive pulmonary disease; for diabetes, external injury, and suicide, estimates were inverse but modest in magnitude. A 0.1 higher Gini coefficient (higher income inequality) predicted 1-percentage point (0.010, 95% CI: 0.0026, 0.0180) and 0.2 percentage point (0.002, 95% CI: 0.001, 0.002) higher probabilities of dying from CHD and suicide, respectively. CONCLUSIONS: Empirical linkages were identified between state-level spending on welfare and education and lower individual risks of dying, particularly from CHD and all causes combined. State-level income inequality predicted higher risks of dying from CHD and suicide. PMID- 26607869 TI - The relationship between psychological distress and multiple tender points across the adult lifespan. AB - Multiple tender points are common in the population and, in studies of mid-life adults, are strongly associated with high levels of psychological distress. Whether this relationship occurs in older adults is unclear. This cross-sectional study investigated whether high levels of psychological distress would be associated with a high tender point count and whether the relationship would be moderated by age. Three thousand three hundred and seventy-nine individuals were mailed a questionnaire which included the Hospital Anxiety and Depression (HAD) scale, the Pain Catastrophising Scale (PCS), the Brief Illness Perception Questionnaire (Brief IPQ), and the Pittsburgh Sleep Quality Index (PSQI). A random sample of approximately 10% of subjects who returned the questionnaire undertook a physical assessment, including a manual tender point count assessment. A total of 2385 (71%) subjects completed the questionnaire, of whom 798 (33%) were invited to take part in the physical assessment and 290 (12%) participated. Of the 290 participants the median age was 64 years (range 34-97) and 63% were female. The median HAD score was 9 (IQR 5-14) and the median number of tender points was 3 (range 0-7). Increasing HAD score was positively and significantly associated with tender point count, but this relationship was not moderated by age. In a final multivariable model, sex, HAD score and PSQI score were independent predictors of multiple tender points. Psychological distress was associated with multiple tender points independent of age. Psychological distress and trouble sleeping were important, potentially modifiable factors associated with the outcome. PMID- 26607870 TI - The relationships between hematogram and metabolic syndrome in elderly subgroups: A Taiwan cohort study. AB - BACKGROUND: Abnormal hematogram components could predict future metabolic syndrome (MetS) and diabetes. However, there was no study focusing on the subgroups of the elderly. In this ten-year longitudinal study, we investigated the association between hematogram components, future MetS and diabetes in the elderly. METHODS: Subjects above 65 years were divided into three groups by age (young old: ?65 and <75, old-old: ?75 and <85 and oldest-old ?85).By using multiple logistic regression, the hazard ratio (HR) of higher hemoglobin (Hb), white blood cell count (WBCC) and platelet (PLT) to have future MetS and diabetes were evaluated. RESULTS: There were 15169 subjects in the young-old group, 3536 in the old-old group and 202 in the oldest-old group, respectively. After 10 years follow-up, only higher WBCC and Hb levels (>5.0*10(3), 15 g/dL, respectively) was correlated to future MetS in young-old men (adjusted HR: 1.242, 1.166, respectively). In addition, higher Hb (>13.7 g/dL) was originally associated with future MetS in young-old and old-old women but failed in adjusted HR. Moreover, the PLT did not correlate with any of the endpoints. Finally, higher chances of diabetes could be noted with higher WBCC in both men and women (adjusted HR: 1.404, 1.206, respectively). CONCLUSIONS: The associations between hematogram and future MetS were different in each subgroup of the elderly. Higher WBCC and Hb levels could predict future MetS in young-old men. Moreover, Higher WBCC is positively correlated with future diabetes in both young-old men and women. PMID- 26607871 TI - Highlighting inconsistencies regarding metal biosorption. AB - Thousands of articles have been devoted to examine different types of biosorbents and their use in cleaning polluted waters. An important objective of some studies has been the identification of the biosorption mechanisms. This type of investigation is not always performed, as it can only be done if scientists are aware of all mechanisms that, at least theoretically, control the removal of the target substances. Mistakes are often made, even in highly cited review articles, where biosorption mechanisms are named and/or grouped. The aim of this article is to highlight errors and inaccuracies as well as to discuss different classification systems of the biosorption mechanisms. This article serves as a guide, as well as a platform for discussion among researchers involved in the investigation of biosorbents, in an effort to avoid reproducing errors in subsequent articles. PMID- 26607872 TI - Interobserver variability in physician-modified endograft planning by comparison with a three-dimensional printed aortic model. AB - BACKGROUND: With the increasing application of fenestrated and physician-modified endografting for aneurysm repair, there is increasing concern about the accuracy of vessel position measurements based on computed tomography scans. Inaccuracies in measurements may result in a "window-shutter" or "eclipsing" phenomenon whereby the fenestration may not overlie the vessel ostium completely. We hypothesized that vessel position measurements from reconstructed imaging do not represent the true vessel position as obtained from a three-dimensional (3D) printed physical model of the visceral aortic segment. METHODS: Medical 3D modeling software was used to develop the 3D reconstructions, which were then exported to the 3D printing software. This allowed 3D models to be physically generated. The distances to the top and bottom and the angle of each of the celiac, superior mesenteric, right renal, and left renal arteries were recorded. These same measurements were obtained by each of the blinded reviewers in addition to the aortic diameter at the midpoint of each of these vessels. Measurements were compared with intraclass correlation coefficient, nonparametric Spearman rank correlation test, and one-sample t-test to assess accuracy and precision. Statistical significance was set at P < .05 for all tests. RESULTS: Both the individual measurements and the average of the measurements were statistically accurate (significant) for the bottom of the superior mesenteric artery and the top and bottom of both the right and left renal arteries. There was variability and inaccuracy in all visceral vessel angles and in the bottom of the celiac artery (the top and the angle of the celiac artery were the arbitrary referents). CONCLUSIONS: Whereas the visceral vessel orifices are largely accurately assessed and measured, the vessel angles are not. This may lead to an eclipsing phenomenon, which may contribute to branch or fenestrated vessel failure and therefore reintervention. Further efforts should assess the clinical significance of the eclipsing phenomenon and should target accurate and appropriate fenestration construction to prevent long-term morbidity. PMID- 26607873 TI - Whole genome annotation and comparative genomic analyses of bio-control fungus Purpureocillium lilacinum. AB - BACKGROUND: The fungus Purpureocillium lilacinum is widely known as a biological control agent against plant parasitic nematodes. This research article consists of genomic annotation of the first draft of whole genome sequence of P. lilacinum. The study aims to decipher the putative genetic components of the fungus involved in nematode pathogenesis by performing comparative genomic analysis with nine closely related fungal species in Hypocreales. RESULTS: de novo genomic assembly was done and a total of 301 scaffolds were constructed for P. lilacinum genomic DNA. By employing structural genome prediction models, 13, 266 genes coding for proteins were predicted in the genome. Approximately 73% of the predicted genes were functionally annotated using Blastp, InterProScan and Gene Ontology. A 14.7% fraction of the predicted genes shared significant homology with genes in the Pathogen Host Interactions (PHI) database. The phylogenomic analysis carried out using maximum likelihood RAxML algorithm provided insight into the evolutionary relationship of P. lilacinum. In congruence with other closely related species in the Hypocreales namely, Metarhizium spp., Pochonia chlamydosporia, Cordyceps militaris, Trichoderma reesei and Fusarium spp., P. lilacinum has large gene sets coding for G-protein coupled receptors (GPCRs), proteases, glycoside hydrolases and carbohydrate esterases that are required for degradation of nematode-egg shell components. Screening of the genome by Antibiotics & Secondary Metabolite Analysis Shell (AntiSMASH) pipeline indicated that the genome potentially codes for a variety of secondary metabolites, possibly required for adaptation to heterogeneous lifestyles reported for P. lilacinum. Significant up-regulation of subtilisin like serine protease genes in presence of nematode eggs in quantitative real-time analyses suggested potential role of serine proteases in nematode pathogenesis. CONCLUSIONS: The data offer a better understanding of Purpureocillium lilacinum genome and will enhance our understanding on the molecular mechanism involved in nematophagy. PMID- 26607874 TI - HIV and alcohol knowledge, self-perceived risk for HIV, and risky sexual behavior among young HIV-negative men identified as harmful or hazardous drinkers in Katutura, Namibia. AB - BACKGROUND: Namibia's HIV prevalence is 13.3%. Alcohol is associated with sexual risk-taking, leading to increased HIV risk. Baseline sexual behaviors, HIV and alcohol knowledge, and self-perceived HIV risk were examined among men reporting high-risk drinking in Katutura, Namibia. METHODS: HIV negative men, >= 18 years, were screened for harmful or hazardous levels of drinking and >1 recent sex partner prior to randomization into control or intervention arm. SAS 9.3 and R 3.01 were used for descriptive baseline cohort analyses. RESULTS: A total of 501 participants who met criteria were included in analysis (mean Alcohol Use Disorders Identification Test [AUDIT] =12.4). HIV and alcohol knowledge were high with the majority (>85 and 89.8-98%, respectively) of respondents correctly answering assessment questions. Despite high knowledge levels, 66.7% of men felt they were at some or high risk of HIV acquisition. Among those respondents, 56.5% stated often wanting to have sex after drinking and 40.3% stated sex was better when drunk. Among respondents with non-steady partners [n = 188], 44.1% of last sexual encounters occurred while the participant was drunk and condoms were not used 32.5% of those times. Among persons who were not drunk condoms were not used 13.3% of those times. CONCLUSIONS: Sex with casual partners was high. Inconsistent condom use and alcohol use before sex were frequently reported. Increased emphasis on alcohol risk-reduction strategies, including drinking due to peer pressure and unsafe sexual behaviors, is needed. PMID- 26607875 TI - Developmental kinetics of in vitro-produced bovine embryos: An aid for making decisions. AB - Embryo developmental kinetics and embryo survival after cryopreservation have been correlated with embryo quality and viability. The main objectives of this work were to analyze developmental ability and quality of in vitro-produced bovine embryos in relation to their kinetics and to establish a criterion of quality to predict further viability. Embryos were classified and grouped by their specific stage of development (2, 3-4, or >= 5 cells) at 44 hours post insemination (hpi) and cultured separately up to Day 8. On Days 7 and 8, good quality expanded blastocysts were vitrified or frozen. Cryopreserved surviving hatched embryos were stained for cell counts. Embryos at a more advanced stage (3 4 cells, and >=5 cells) developed to morulae (P < 0.001) and blastocysts (P < 0.01) at higher rates than those embryos that had cleaved once by 44 hpi. Vitrification improved the hatching rates of blastocysts at 48 hours (P < 0.001) when compared with slow-rate freezing within each group of embryos (3-4 cells and >=5 cells). After vitrification/warming, blastocysts coming from 3- to 4-cell embryos had higher hatching rates at 48 hours than those that came from >=5-cell embryos. With regard to differential cell counts, no effect of the initial developmental stage was observed after warming/thawing. However, trophectoderm and total cells were higher in vitrified/warmed than in the frozen/thawed embryos (P < 0.001). These data show that selecting IVF embryos at 44 hpi, after the evaluation of their in vitro embryo development, could be used as noninvasive markers of embryo developmental competence and may help to select IVF embryos that would be more suitable for cryopreservation. PMID- 26607876 TI - Loss of heat shock protein 70 from apical region of buffalo (Bubalus bubalis) sperm head after freezing and thawing. AB - The post-thaw fertility of frozen-thawed mammalian spermatozoa is substantially low as compared with that of fresh sperm. Furthermore, the post-thaw fertility of the cryopreserved buffalo sperm has been reported to be poor as compared with that of cattle sperm. Recently, heat shock protein 70 (HSP70) has been found to play a critical role in mammalian fertilization and early embryonic development in boar and cattle. However, the presence of such fertility-related HSP70 in buffalo sperm and its status after cryopreservation has not been reported so far. Thus, a study was conducted to determine the effect of cryopreservation on the level and distribution pattern of HSP70 molecule in buffalo sperm after cryopreservation. Buffalo semen samples, after dilution in semen extender, were aliquoted in straws and divided into two groups. One group was not cryopreserved, and the other group was cryopreserved for 60 days. Sperm proteins were extracted from both non-cryopreserved (NC) and cryopreserved (C) sperm and subjected to Western blot analysis for detection of HSP70 using a monoclonal anti-HSP70 antibody. The distribution pattern of these proteins in buffalo sperm was also monitored before and after cryopreservation using indirect immunofluorescence technique. A prominent 70-kDa protein band of HSP70 protein was detected in protein extracts of both NC and C buffalo sperm. Densitometry analysis revealed that the intensity of 70-kDa HSP70 protein band of cryopreserved sperm decreased significantly (P < 0.05) compared with that of NC sperm. However, the level of HSP70 in cryopreserved extended seminal plasma (ESP) did not change as compared with that of NC samples indicating a possible degradation of HSP70 in the spermatozoa itself rather than leakage of the protein into the ESP. Furthermore, Western blot also confirmed that several HSP70 immunoreactive protein bands detected in the ESP were contributed by the egg yolk that was added to the extender. Immunocytochemistry revealed that HSP70 proteins were distributed over the apical region of sperm head and/or acrosome, post-acrosomal, and middle piece regions of NC buffalo spermatozoa. However, the fluorescence signal of apical region of sperm head was lost significantly (P < 0.05) after a cycle of freezing and thawing. Thus, the present study confirmed that there was loss of HSP70 from buffalo sperm head after freezing and thawing of buffalo spermatozoa, and this may be one of the causes of the reduced post-thaw fertility of sperm in this species. PMID- 26607877 TI - Association of early suspected acute exacerbations of idiopathic pulmonary fibrosis with subsequent clinical outcomes and healthcare resource utilization. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) may be complicated by episodes of acute exacerbation. This study quantified the association between occurrence of suspected acute exacerbations of IPF (AEx-IPF) in the 6 months post-IPF diagnosis with clinical outcomes and IPF-related healthcare resource utilization (HRU). METHODS: U.S. pulmonologists participated in a retrospective chart review of IPF patients. Patient eligibility criteria included: 1) >=40 years of age and a confirmed date of first IPF diagnosis with HRCT and/or lung biopsy between January 2011-June 2013; 2) 2 separate FVC results recorded around first diagnosis and 6 months post-diagnosis. Patients with a suspected AEx-IPF within 6 months post-diagnosis were categorized as "early AEx-IPF." Subsequent clinical outcomes and IPF-related HRU were assessed from 6 months post-diagnosis until the latest physician contact date. RESULTS: The sample included 490 IPF patients from 168 pulmonologists; 72 (15%) patients had a suspected early AEx-IPF. At IPF diagnosis, the mean (SD) age was 61 (11) years, 68% were male, and the mean FVC percent predicted was 60% (26%). Compared to patients without a suspected early AEx-IPF, patients with an early AEx-IPF had higher mortality risk (HR = 2.87, p < 0.001) and higher rates of subsequent suspected AEx-IPF (IRR = 3.87, p < 0.001), outpatient visits (IRR = 1.46, p < 0.001), ER visits (IRR = 4.39, p < 0.001), hospitalizations (IRR = 7.96, p < 0.001), and ICU stays (IRR = 9.74, p < 0.001). CONCLUSIONS: Using a large sample of IPF patients from varied practice settings, we found a strong relationship between suspected early AEx-IPF and worse subsequent clinical outcomes and increased IPF-related HRU. This relationship was particularly pronounced for acute resource use. PMID- 26607878 TI - Guidance on handheld inhalers in asthma and COPD guidelines: An update. PMID- 26607879 TI - Acinar ventilation heterogeneity in COPD relates to diffusion capacity, resistance and reactance. AB - The aim of this study was to investigate heterogenic ventilation in the acinar (Sacin) and conductive (Scond) airways of patients with varying chronic obstructive pulmonary disease (COPD) severity and how these relates to advanced lung function parameters, primarily measured by impulse oscillometry (IOS). A secondary aim was to investigate the effects of a short acting beta2-agonist and a muscarinic antagonist on the heterogenic ventilation. Eleven never smoking controls, 12 smoking controls, and 57 COPD patients (7 GOLD 1, 25 GOLD 2, 14 GOLD 3 and 11 GOLD 4) performed flow-volume spirometry, IOS, body plethysmography, single breath carbon monoxide diffusion, and N2-multiple breath washout. Six smoking controls and 13 of the COPD patients also performed double reversibility test by using salbutamol and its combination with ipratropium. Sacin was significantly higher in GOLD 2-4 compared to never smoking controls and smoking controls, but showed similar levels in GOLD 3 and 4. A factor analysis identified 4 components consisting of; 1) IOS parameters, 2) volume parameters, 3) diffusion parameters, Sacin and some IOS parameters and 4) Scond with central obstruction/air trapping. Salbutamol and its combination with ipratropium had no effect on Sacin and Scond. Increased Sacin in COPD was strongly related to diffusion capacity and lung volumes, but also weakly to resistance and reactance, showing a link between ventilation heterogeneity in the acinar airways and parameters measured by IOS. PMID- 26607881 TI - Complete Genome Sequence of a New Member of the Marseilleviridae Recovered from the Brackish Submarine Spring in the Cassis Port-Miou Calanque, France. AB - Marseilleviridae is a rapidly expanding family of Acanthamoeba-infecting large DNA viruses distributed worldwide. We report here the complete 349-kbp genome sequence of Port-Miou virus, which is surprisingly close to that of Lausannevirus (isolated from the Seine River upstream from Paris, France), despite the strong dissimilarities of their sampling locations. PMID- 26607882 TI - Draft Genome Sequence of the Dimorphic Yeast Yarrowia lipolytica Strain W29. AB - Here, we present the draft genome sequence of the dimorphic ascomycete yeast Yarrowia lipolytica strain W29 (ATCC 20460). Y. lipolytica is a commonly employed model for the industrial production of lipases, small molecules, and more recently for its ability to accumulate lipids. PMID- 26607880 TI - Genome-scale metabolic reconstructions and theoretical investigation of methane conversion in Methylomicrobium buryatense strain 5G(B1). AB - BACKGROUND: Methane-utilizing bacteria (methanotrophs) are capable of growth on methane and are attractive systems for bio-catalysis. However, the application of natural methanotrophic strains to large-scale production of value-added chemicals/biofuels requires a number of physiological and genetic alterations. An accurate metabolic model coupled with flux balance analysis can provide a solid interpretative framework for experimental data analyses and integration. RESULTS: A stoichiometric flux balance model of Methylomicrobium buryatense strain 5G(B1) was constructed and used for evaluating metabolic engineering strategies for biofuels and chemical production with a methanotrophic bacterium as the catalytic platform. The initial metabolic reconstruction was based on whole-genome predictions. Each metabolic step was manually verified, gapfilled, and modified in accordance with genome-wide expression data. The final model incorporates a total of 841 reactions (in 167 metabolic pathways). Of these, up to 400 reactions were recruited to produce 118 intracellular metabolites. The flux balance simulations suggest that only the transfer of electrons from methanol oxidation to methane oxidation steps can support measured growth and methane/oxygen consumption parameters, while the scenario employing NADH as a possible source of electrons for particulate methane monooxygenase cannot. Direct coupling between methane oxidation and methanol oxidation accounts for most of the membrane associated methane monooxygenase activity. However the best fit to experimental results is achieved only after assuming that the efficiency of direct coupling depends on growth conditions and additional NADH input (about 0.1-0.2 mol of incremental NADH per one mol of methane oxidized). The additional input is proposed to cover loss of electrons through inefficiency and to sustain methane oxidation at perturbations or support uphill electron transfer. Finally, the model was used for testing the carbon conversion efficiency of different pathways for C1-utilization, including different variants of the ribulose monophosphate pathway and the serine cycle. CONCLUSION: We demonstrate that the metabolic model can provide an effective tool for predicting metabolic parameters for different nutrients and genetic perturbations, and as such, should be valuable for metabolic engineering of the central metabolism of M. buryatense strains. PMID- 26607883 TI - Draft Genome Sequence of Pseudomonas sp. Strain In5 Isolated from a Greenlandic Disease Suppressive Soil with Potent Antimicrobial Activity. AB - Pseudomonas sp. In5 is an isolate of disease suppressive soil with potent activity against pathogens. Its antifungal activity has been linked to a gene cluster encoding nonribosomal peptide synthetases producing the peptides nunamycin and nunapeptin. The genome sequence will provide insight into the genetics behind the antimicrobial activity of this strain. PMID- 26607884 TI - Complete Genome Sequence of Mayaro Virus Imported from the Amazon Basin to Sao Paulo State, Brazil. AB - Mayaro (MAYV) is a neglected arbovirus from the tropical Americas. Here, we report the complete genome of an MAYV isolate from a patient returning from the Amazon basin and complaining of arthralgia, high fever, and headache, who was attended at an emergency service of Sao Jose do Rio Preto, Sao Paulo state, Brazil. PMID- 26607885 TI - Complete Genome Sequence of a Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Variant with a New Insertion in Glycoprotein 5, Isolated from a Stillborn Fetus. AB - Here, we report the complete genome sequence of strain GD-2011, a highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) that was isolated from a stillborn fetus. The GD-2011 strain is characterized by a discontinuous 30-amino acid deletion in the nonstructural protein 2. In addition, GD-2011 had a 1-amino acid insertion in glycoprotein 5, which does not exist in any other HP-PRRSV strains. PMID- 26607886 TI - Complete Genome Sequence of Campylobacter jejuni RM1285, a Rod-Shaped Morphological Variant. AB - Campylobacter jejuni is a spiral shaped Gram-negative food-borne bacterial pathogen of humans found on poultry products. Strain RM1285 is a rod-shaped variant of this species. The genome of RM1285 was determined to be 1,635,803 bp, with a G+C content of 30.5%. PMID- 26607887 TI - Nearly Complete Genome Sequence of Lactobacillus plantarum Strain NIZO2877. AB - Lactobacillus plantarum is a versatile bacterial species that is isolated mostly from foods. Here, we present the first genome sequence of L. plantarum strain NIZO2877 isolated from a hot dog in Vietnam. Its two contigs represent a nearly complete genome sequence. PMID- 26607888 TI - Complete Genome Sequence of Caulobacter crescentus Podophage Percy. AB - Podophage Percy infects Caulobacter crescentus, a Gram-negative bacterium that divides asymmetrically and is a commonly used model organism to study the cell cycle, asymmetric cell division, and cell differentiation. Here, we announce the sequence and annotated complete genome of the phiKMV-like podophage Percy and note its prominent features. PMID- 26607889 TI - Draft Genome Sequences of Eight Nontypeable Haemophilus influenzae Strains Previously Characterized Using an Electrophoretic Typing Scheme. AB - Nontypeable Haemophilus influenzae is an important cause of human disease. Strains were selected for genome sequencing to represent the breadth of nontypeable strains within the species, as previously defined by the electrophoretic mobility of 16 metabolic enzymes. PMID- 26607890 TI - Complete Genome Sequences of Four African Horse Sickness Virus Strains from a Commercial Tetravalent Live Attenuated Vaccine. AB - This is a report of the complete genome sequences of plaque-selected isolates of each of the four virus strains included in a South African commercial tetravalent African horse sickness attenuated live virus vaccine. PMID- 26607891 TI - Draft Genome Sequence of Streptococcus thermophilus C106, a Dairy Isolate from an Artisanal Cheese Produced in the Countryside of Ireland. AB - The lactic acid bacterium Streptococcus thermophilus is widely used for the fermentation of dairy products. Here, we present the draft genome sequence of S. thermophilus C106 isolated from an artisanal cheese produced in the countryside of Ireland. PMID- 26607892 TI - Resequencing of the Lactobacillus plantarum Strain WJL Genome. AB - Lactobacillus plantarum strain WJL is a symbiont isolated from the Drosophila melanogaster gut. The genome of L. plantarum WJL, first sequenced in 2013, was resequenced and rescaffolded in this study. A combination of Sanger and Illumina sequencing allowed us to reduce the number of contigs from 102 to 13. This work contributes to a better understanding of the genome and function of this organism. PMID- 26607893 TI - Complete Genome Sequence of Corynebacterium pseudotuberculosis Strain E19, Isolated from a Horse in Chile. AB - Corynebacterium pseudotuberculosis is related to several diseases infecting horses and small ruminants, causing economic losses to agribusiness. Here, we present the genome sequence of C. pseudotuberculosis strain E19. The genome includes one circular chromosome 2,367,956 bp (52.1% G+C content), with 2,112 genes predicted, 12 rRNAs, and 48 tRNAs. PMID- 26607894 TI - Genome Sequence of the Atypical Symbiotic Frankia R43 Strain, a Nitrogen-Fixing and Hydrogen-Producing Actinobacterium. AB - Frankia strain R43 is a nitrogen-fixing and hydrogen-producing symbiotic actinobacterium that was isolated from nodules of Casuarina cunninghamiana but infects only Elaeagnaceae. This communication reports the genome of the strain R43 and provides insights into the microbe genomics and physiological potentials. PMID- 26607895 TI - Complete Genome Sequences of Three Clinical Isolates of Dengue Virus Serotype 1 from South Korean Travelers. AB - In this study, we report the complete genome sequences of three clinical isolates of dengue virus serotype 1 isolated from South Korean travelers returning from different countries in Southeast Asia. The nucleotide sequence identities ranged from 91.5 to 92.2%, while the amino acid sequence identities ranged from 97.5 to 97.9% among the three clinical isolates. PMID- 26607896 TI - Complete Genome Sequences of Three Laboratory Strains of Dengue Virus (Serotypes 2, 3, and 4) Available in South Korea. AB - Here, we report the complete genome sequences of three laboratory strains of dengue virus serotype-2 (DENV-2/KBPV-VR-29), -3 (DENV-3/KBPV-VR-30), and -4 (DENV 4/KBPV-VR-31) obtained from the Korea Bank for Pathogenic Viruses (http://kbpv.knrrc.or.kr). The complete genetic information presented in this study on commonly used DENV laboratory strains provides valuable information for future studies. PMID- 26607897 TI - Genome Sequence of the Banana Plant Growth-Promoting Rhizobacterium Bacillus amyloliquefaciens BS006. AB - Bacillus amyloliquefaciens is an important plant growth-promoting rhizobacterium (PGPR). We report the first whole-genome sequence of PGPR Bacillus amyloliquefaciens evaluated in Colombian banana plants. The genome sequences encode genes involved in plant growth and defense, including bacteriocins, ribosomally synthesized antibacterial peptides, in addition to genes that provide resistance to toxic compounds. PMID- 26607898 TI - A Novel Chiropteran Circovirus Genome Recovered from a Brazilian Insectivorous Bat Species. AB - This report describes the identification and characterization of a novel circovirus using metagenomic approaches in respiratory fluid samples from Brazilian free-tailed bats (Tadarida brasiliensis). The genome and deduced protein sequences share low identity with another circovirus recovered in distantly related bats from China. PMID- 26607899 TI - Complete Genome Sequences of 11 Bordetella pertussis Strains Representing the Pandemic ptxP3 Lineage. AB - Pathogen adaptation has contributed to the resurgence of pertussis. To facilitate our understanding of this adaptation we report here 11 completely closed and annotated Bordetella pertussis genomes representing the pandemic ptxP3 lineage. Our analyses included six strains which do not produce the vaccine components pertactin and/or filamentous hemagglutinin. PMID- 26607900 TI - Draft Genome Sequence of a 16SrII-A Subgroup Phytoplasma Associated with Purple Coneflower (Echinacea purpurea) Witches' Broom Disease in Taiwan. AB - The bacterial genus "Candidatus Phytoplasma" contains a group of insect transmitted plant pathogens in the class Mollicutes. Here, we report a draft genome assembly and annotation of strain NCHU2014, which belongs to the 16SrII-A subgroup within this genus and is associated with purple coneflower witches' broom disease in Taiwan. PMID- 26607901 TI - Curcumin induces apoptosis by inhibiting sarco/endoplasmic reticulum Ca2+ ATPase activity in ovarian cancer cells. AB - Aberrant increase in the expression levels of sarco/endoplasmic reticulum calcium ATPase (SERCA), which regulates Ca(2+) homeostasis, has been observed in ovarian cancers. In this study, we demonstrated that curcumin increases cytosolic Ca(2+) concentration through inhibition of SERCA activity, causing apoptosis in ovarian cancer cells but not in normal cells, including peripheral blood mononuclear cells (PBMCs) and ovarian surface epithelial cells (OSE). Curcumin induced apoptosis in ovarian cancer cells in a concentration- and time-dependent manner. Cytosolic Ca(2+) flux was evident after the curcumin treatment (15 uM). Treatment with Ca(2+) chelator reduced curcumin-induced apoptosis, confirming the possible involvement of increased cytosolic Ca(2+) concentration in this response. Basal mRNA and protein levels of SERCA2 were significantly higher in ovarian cancer cells than in OSE. SERCA activity was suppressed by curcumin, with no effect on protein expression. Forced expression of the SERCA2b gene in ovarian cancer cells prevented curcumin-induced cytosolic Ca(2+) elevation and subsequent apoptosis, supporting an important role of SERCA in curcumin-induced apoptosis of ovarian cancer cells. Taken together, inhibition of SERCA activity by curcumin disrupts the Ca(2+) homeostasis and thereby promotes apoptosis in ovarian cancer cells. PMID- 26607902 TI - Autophagy-deficiency in hepatic progenitor cells leads to the defects of stemness and enhances susceptibility to neoplastic transformation. AB - Autophagy is a highly conserved and lysosome-dependent degradation process which assists in cell survival and tissue homeostasis. Although previous reports have shown that deletion of the essential autophagy gene disturbs stem cell maintenance in some cell types such as hematopoietic and neural cells, it remains unclear how autophagy-deficiency influences hepatic progenitor cells (HPCs). Here we report that Atg5-deficiency in HPCs delays HPC-mediated rat liver regeneration in vivo. In vitro researches further demonstrate that loss of autophagy decreases the abilities of colony and spheroid formations, and disrupts the induction of hepatic differentiation in HPCs. Meanwhile, autophagy-deficiency increases the accumulations of damaged mitochondria and mitochondrial reactive oxygen species (mtROS) and suppresses homologous recombination (HR) pathway of DNA damage repair in HPCs. Moreover, in both diethylnitrosamine (DEN) and CCl4 models, autophagy deficiency accelerates neoplastic transformation of HPCs. In conclusion, these findings demonstrate that autophagy contributes to stemness maintenance and reduces susceptibility to neoplastic transformation in HPCs. PMID- 26607903 TI - Perturbation of energy metabolism by fatty-acid derivative AIC-47 and imatinib in BCR-ABL-harboring leukemic cells. AB - In Ph-positive leukemia, imatinib brought marked clinical improvement; however, further improvement is needed to prevent relapse. Cancer cells efficiently use limited energy sources, and drugs targeting cellular metabolism improve the efficacy of therapy. In this study, we characterized the effects of novel anti cancer fatty-acid derivative AIC-47 and imatinib, focusing on cancer-specific energy metabolism in chronic myeloid leukemia cells. AIC-47 and imatinib in combination exhibited a significant synergic cytotoxicity. Imatinib inhibited only the phosphorylation of BCR-ABL; whereas AIC-47 suppressed the expression of the protein itself. Both AIC-47 and imatinib modulated the expression of pyruvate kinase M (PKM) isoforms from PKM2 to PKM1 through the down-regulation of polypyrimidine tract-binding protein 1 (PTBP1). PTBP1 functions as alternative splicing repressor of PKM1, resulting in expression of PKM2, which is an inactive form of pyruvate kinase for the last step of glycolysis. Although inactivation of BCR-ABL by imatinib strongly suppressed glycolysis, compensatory fatty-acid oxidation (FAO) activation supported glucose-independent cell survival by up regulating CPT1C, the rate-limiting FAO enzyme. In contrast, AIC-47 inhibited the expression of CPT1C and directly fatty-acid metabolism. These findings were also observed in the CD34(+) fraction of Ph-positive acute lymphoblastic leukemia cells. These results suggest that AIC-47 in combination with imatinib strengthened the attack on cancer energy metabolism, in terms of both glycolysis and compensatory activation of FAO. PMID- 26607904 TI - Activation of mitochondrial oxidation by PDK2 inhibition reverses cisplatin resistance in head and neck cancer. AB - Dichloroacetate (DCA), an orphan drug that promotes a shift from glycolysis to oxidative phosphorylation, has been repurposed for cancer therapy. The present study investigated whether DCA may overcome cisplatin resistance in head and neck cancer (HNC). Two cisplatin-resistant HNC cell lines (AMC-HN4R and -HN9R), their parental lines, and other human HNC lines were used. The effect of DCA, alone and in combination with cisplatin, was assessed by measuring cell cycle, viability, death, reactive oxygen species (ROS) production, mitochondrial membrane potential (DeltaPsim), and protein expression in preclinical mouse tumor xenograft models. Increased glycolysis correlated with decreased sensitivity to cisplatin and was reduced by DCA. Cisplatin-resistant cells overexpressed pyruvate dehydrogenase kinase 2 (PDK2). DCA induced HNC cell death by decreasing DeltaPsim and promoting mitochondrial ROS production. This effect was decreased by the antioxidant N acetyl-l-cysteine or by inhibition of caspase-mediated apoptosis. Activation of mitochondrial glucose oxidation by DCA eventually activated downstream mitochondrial apoptotic signaling, leading to the death of chemoresistant cancer cells. Therefore, DCA significantly sensitized resistant HNC cells to cisplatin in vitro and in vivo. High glycolysis and PDK2 overexpression are closely linked to cisplatin resistance in HNC cells; the latter can be overcome by DCA. PMID- 26607905 TI - The anthropometric definition of the rectum is highly variable. AB - PURPOSE: The precise definition of the rectum is essential for localizing colorectal pathology, yet current definitions are nebulous. The objective of this study is to determine the anthropometric definition of common pelvic landmarks in relation to patient characteristics. METHODS: Seventy-one patients underwent open proctectomy with intra-operative measurements from the anal verge to various pelvic landmarks, and patient characteristics were evaluated. Analyses were performed using Spearman correlation and Wilcoxon rank sum. RESULTS: The mean landmark distance was dentate line = 1.7 cm (range 0.8-4.0 cm), puborectalis muscle = 4.2 cm (range 2.0-8.0 cm), anterior peritoneal reflection = 13.2 cm (range 8.5-21.0 cm), sacral promontory = 17.9 cm (range 13.0-26.0 cm), and confluence of the taenia = 25.5 cm (range 16.0-44.0 cm). Men had longer mean distances to the dentate line (p = 0.0003), puborectalis muscle (p = 0.03), and anterior peritoneal reflection (p = 0.02). Patient weight significantly correlated with distance to all landmarks except for the confluence of the taenia, which did not correlate with any patient factor. CONCLUSIONS: The location of common pelvic landmarks is highly variable. The use of predefined absolute measurements from the anal verge to localize rectal pathology is inaccurate and fails to account for patient variability. PMID- 26607906 TI - Effects of colonic electrical stimulation using different individual parameter patterns and stimulation sites on gastrointestinal transit time, defecation, and food intake. AB - PURPOSE: This study aimed to compare the effects of colonic electrical stimulation (CES) on gastrointestinal transit time (GITT), energy consumption, stool frequency, stool consistency, and food intake using different individual parameter patterns and stimulation sites. METHODS: Eight beagle dogs underwent surgery and CES. First, CES was conducted to determine the individual parameters with different pulse configurations, based on symptoms. Second, influences on energy consumption and GITT were compared between CES sessions with different pulse configurations. Third, GITT, stool frequency, stool consistency, and food intake were compared to assess the effects of CES at different stimulation sites. RESULTS: The individual parameters varied greatly among the dogs. In proximal colon electrical stimulation (PCES) and rectosigmoid colon electrical stimulation (RCES), energy consumption was lower with the constant pulse width mode than with the constant pulse amplitude mode (p = 0.012 and p = 0.018, respectively). There was no statistical difference between the two pulse configurations in GITT assessment. The PCES, RCES, and sequential CES sessions significantly accelerated GITT compared to sham stimulation. There was no statistical difference in GITT between PCES, RCES, and sequential CES sessions. Compared to sham CES session, RCES and sequential CES sessions exhibited significant higher stool frequency (p < 0.001 and p = 0.001, respectively), and PCES and RCES sessions inhibited food intake (p = 0.003 and p = 0.002, respectively). CONCLUSIONS: Constant pulse width mode is an appropriate pulse configuration for individual CES. At different stimulation sites, CES may exert different effects on stool frequency and food intake. This study provides an experimental basis for the clinical application of CES. PMID- 26607907 TI - Rectal cancer with complete clinical response after neoadjuvant chemoradiotherapy, surgery, or "watch and wait". AB - PURPOSE: The purpose of this study was to compare the outcomes of patients treated with chemoradiotherapy with a complete clinical response followed by either a "watch and wait" strategy or a total mesorectal excision. METHODS: This was an observational retrospective study from a single institute. Patients with locally advanced rectal cancer following chemoradiotherapy with a complete clinical response from January 1, 2007 to December 31, 2014 were included. RESULTS: The study population consisted of 18 patients who opted for a "watch and wait" policy and 26 patients who underwent radical surgery after achieving a complete clinical response. Patients had no documented treatment complications under the watch and wait policy, while 13 patients who underwent radical surgery experienced significant morbidity. There were two local recurrences in the watch and wait group; both were treated with salvage resection and had no associated mortality. In the radical surgery group, 1 patient showed an incomplete pathologic response (ypT0N1), and the remaining 25 patients showed complete pathologic responses; 1 had a distant recurrence, which was managed non operatively, and 2 patients died of unrelated causes. The 5-year overall survival rate and median disease-free survival time were 100% and 69.78 months in the watch and wait group and 92.30% and 89.04 months in the radical surgery group. CONCLUSIONS: A watch and wait policy avoids the morbidity associated with radical surgery and preserves oncologic outcomes in our retrospective study from a single institute. It could be considered a therapeutic option in patients with locally advanced rectal cancer following chemoradiotherapy with a complete clinical response. PMID- 26607908 TI - E-PASS score as a useful predictor of postoperative complications and mortality after colorectal surgery in elderly patients. AB - PURPOSE: The aim of this study was to clarify whether a surgical-specific risk scoring system estimating the physiologic ability and surgical stress (E-PASS) score was useful for prediction of postoperative morbidity and mortality. METHODS: The E-PASS score consists of the preoperative risk score (PRS), surgical stress score (SSS), and the comprehensive risk score (CRS). Conventional scoring systems [colorectal physiologic and operative severity score for the enumeration of mortality (CR-POSSUM) and the prognostic nutritional index (PNI)] were also examined. We retrospectively compared these scores in patients with or without postoperative complications. We assessed the relationship between these scores, clinicopathological features and postoperative mortality. RESULTS: Postoperative complications developed in 78 patients (33%). American Society of Anesthesiologists score, performance status, PNI score, PRS, SSS, and CRS were significantly higher in patients with postoperative complications than in those without postoperative complications (p < 0.05). The area under the receiver operating characteristic curve (AUC) was highest for E-PASS [E-PASS (PRS, 0.74; SSS, 0.62; CRS, 0.78), PNI (0.62), CR-POSSUM (PS, 0.57; OSS, 0.52)]. Multivariate logistic analysis identified CRS >= 0.2 as a significant determinant of postoperative complications (p < 0.01; hazard ratio, 4.84). Overall survival was significantly better in the CRS < 0.2 group than in the CRS > 0.2 group (p < 0.01). CONCLUSIONS: The E-PASS score system was a useful predictor of postoperative complications and mortality, especially in patients with advanced age. PMID- 26607910 TI - Comparison Impairments of Spatial Cognition and Hippocampal Synaptic Plasticity Between Prenatal and Postnatal Melamine Exposure in Male Adult Rats. AB - Our previous investigation showed that melamine in offspring hippocampus appeared to not be the critical factor for cognitive defects. The present study was to investigate whether the cognitive impairments induced by prenatal and postnatal melamine exposure and persisted into adulthood, and to evaluate the differences of the exposures in affecting hippocampus-depended cognition and synaptic plasticity. Wistar rats were exposed to melamine through the whole gestational period or from postnatal day (PD) 21 to PD41, and then tested on PD90. The experiments of water maze and hippocampal synaptic plasticity in vivo were performed to assess the effects on spatial cognition and synaptic impairments. The results indicated that cognitive defects were induced by exposures to either prenatal or postnatal melamine, whereas there was a more serious damage in prenatal. Histological evidence further showed that there were the detrimental effects of both prenatal and postnatal effects. Paired-pulse facilitation ratio and post-tetanic potentiation were severely impacted in prenatal-exposed rats but not postnatal-exposed ones. Both exposures to prenatal and postnatal melamine impaired long-term potentiation, while there was severe damage to prenatal animals. These data suggest that the detrimental effects of prenatal and postnatal melamine on cognition and hippocampal synaptic plasticity could persist into adulthood, and the impairment of prenatal exposure was to some extent more severe. Hence, prenatal and postnatal exposures to melamine may have different effects on hippocampus-dependent learning and memory, which would most likely result from differentially adversely properties on the hippocampal CA1 synaptic function. PMID- 26607911 TI - Glycyrrhizic acid Attenuates Neuroinflammation and Oxidative Stress in Rotenone Model of Parkinson's Disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting humans. It is characterized by dopaminergic neurodegeneration, mitochondrial impairment, and oxidative stress, enhanced lipid peroxidation, and induction of pro-inflammatory cytokines. We evaluated the neuroprotective efficacy of glycyrrhizic acid (GA), an active component of licorice, against rotenone-induced-oxidative stress and neuroinflammation in a PD rat model. Since PD is progressive and chronic, we investigated the effect of chronic administration of GA for 4 weeks (50 mg/kg/day), 30 min prior to rotenone administration. Rotenone administration significantly reduced the activity of superoxide dismutase and catalase, and caused the depletion of reduced glutathione. A concomitant increase in the levels of the lipid peroxidation product malondialdehyde was observed. It also significantly enhanced the levels of pro-inflammatory cytokines in the midbrain and elevated the levels of inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Immunohistochemical analysis revealed significant increments in ionized calcium-binding adaptor molecule-1 (Iba-1) levels, and in glial fibrillary acidic protein (GFAP) levels, and loss of dopamine neurons in the substantia nigra pars compacta upon rotenone challenge. GA treatment significantly attenuated the dopamine neuron loss and decreased the Iba-1 and GFAP activation induced by the rotenone insult. GA also improved antioxidant enzyme activity, prevented glutathione depletion, inhibited lipid peroxidation, and attenuated induction of pro-inflammatory cytokines. Subsequently, GA attenuated the increased levels of the inflammatory mediators COX-2 and iNOS. In conclusion, GA protects against rotenone-induced-PD. The neuroprotective effects of GA are attributed to its potent antioxidative and anti-inflammatory properties. PMID- 26607912 TI - TrkB gene therapy by adeno-associated virus enhances recovery after cervical spinal cord injury. AB - Unilateral cervical spinal cord hemisection at C2 (C2SH) interrupts descending bulbospinal inputs to phrenic motoneurons, paralyzing the diaphragm muscle. Recovery after C2SH is enhanced by brain derived neurotrophic factor (BDNF) signaling via the tropomyosin-related kinase subtype B (TrkB) receptor in phrenic motoneurons. The role for gene therapy using adeno-associated virus (AAV) mediated delivery of TrkB to phrenic motoneurons is not known. The present study determined the therapeutic efficacy of intrapleural delivery of AAV7 encoding for full-length TrkB (AAV-TrkB) to phrenic motoneurons 3 days post-C2SH. Diaphragm EMG was recorded chronically in male rats (n=26) up to 21 days post-C2SH. Absent ipsilateral diaphragm EMG activity was verified 3 days post-C2SH. A greater proportion of animals displayed recovery of ipsilateral diaphragm EMG activity during eupnea by 14 and 21 days post-SH after AAV-TrkB (10/15) compared to AAV GFP treatment (2/11; p=0.031). Diaphragm EMG amplitude increased over time post C2SH (p<0.001), and by 14 days post-C2SH, AAV-TrkB treated animals displaying recovery achieved 48% of the pre-injury values compared to 27% in AAV-GFP treated animals. Phrenic motoneuron mRNA expression of glutamatergic AMPA and NMDA receptors revealed a significant, positive correlation (r(2)=0.82), with increased motoneuron NMDA expression evident in animals treated with AAV-TrkB and that displayed recovery after C2SH. Overall, gene therapy using intrapleural delivery of AAV-TrkB to phrenic motoneurons is sufficient to promote recovery of diaphragm activity, adding a novel potential intervention that can be administered after upper cervical spinal cord injury to improve impaired respiratory function. PMID- 26607914 TI - Extensor Digitorum Brevis Transfer Technique to Correct Multiplanar Deformity of the Lesser Digits. AB - Lesser digital deformities may present a surgical challenge to even the most skilled foot and ankle surgeon. Multiplanar toe deformities, including the crossover toe, are especially difficult to correct with reproducible results. Undercorrection, pain, stiffness, and recurrent deformity are well reported throughout foot and ankle literature. The goal of this article is to describe a method of correcting digital deformity utilizing the extensor digitorum brevis tendon transfer and a biotenodesis screw. The controlled tension established with the extensor tendon provides the necessary stability for multiplanar correction of multiplanar digital deformities. This technical tip article should serve as pilot study for future evaluation of this method of correction. LEVELS OF EVIDENCE: Level IV: Case series. PMID- 26607915 TI - Pulmonary nodules again? The 2015 British Thoracic Society guidelines on the investigation and management of pulmonary nodules. PMID- 26607913 TI - Pycnogenol protects CA3-CA1 synaptic function in a rat model of traumatic brain injury. AB - Pycnogenol (PYC) is a patented mix of bioflavonoids with potent anti-oxidant and anti-inflammatory properties. Previously, we showed that PYC administration to rats within hours after a controlled cortical impact (CCI) injury significantly protects against the loss of several synaptic proteins in the hippocampus. Here, we investigated the effects of PYC on CA3-CA1 synaptic function following CCI. Adult Sprague-Dawley rats received an ipsilateral CCI injury followed 15 min later by intravenous injection of saline vehicle or PYC (10 mg/kg). Hippocampal slices from the injured (ipsilateral) and uninjured (contralateral) hemispheres were prepared at seven and fourteen days post-CCI for electrophysiological analyses of CA3-CA1 synaptic function and induction of long-term depression (LTD). Basal synaptic strength was impaired in slices from the ipsilateral, relative to the contralateral, hemisphere at seven days post-CCI and susceptibility to LTD was enhanced in the ipsilateral hemisphere at both post injury timepoints. No interhemispheric differences in basal synaptic strength or LTD induction were observed in rats treated with PYC. The results show that PYC preserves synaptic function after CCI and provides further rationale for investigating the use of PYC as a therapeutic in humans suffering from neurotrauma. PMID- 26607916 TI - Cardiac magnetic resonance assessment of takotsubo cardiomyopathy. AB - Takotsubo cardiomyopathy is an important condition that can be difficult to differentiate from acute coronary syndrome on the basis of clinical, electrocardiogram, and cardiac enzyme assessment alone. Although coronary angiography remains important in the acute assessment of patients with suspected takotsubo cardiomyopathy, cardiac magnetic resonance (CMR) has emerged over the last decade as an important non-invasive imaging tool in the diagnosis and follow up of this condition. We present a review highlighting the CMR features of takotsubo cardiomyopathy and its complications with particular focus on differentiating this condition from acute myocardial infarction and myocarditis. PMID- 26607917 TI - Lesions of uncertain malignant potential in the breast (B3): what do we know? AB - Breast lesions classified as of uncertain malignant potential (B3) on biopsy form a diverse group of abnormalities, which pose a diagnostic and management challenge. In this paper, we discuss the imaging and pathology features as well as the management of the most controversial B3 lesions, consisting of papillary lesions, complex sclerosing lesions/radial scars, lobular intraepithelial neoplasia, and atypical epithelial proliferation of ductal type. As there is an association with malignancy at the time of diagnosis, as well as an increase in the risk of subsequent development of cancer, a multidisciplinary discussion is almost always required to tailor treatment. PMID- 26607918 TI - [Association between medical institution characteristics and patients' dissatisfaction based on the Patient's Behavior Survey in Japan]. AB - OBJECTIVES: Patients' dissatisfaction with medical practice is driven by several patient- and institution-related factors. However, little is known about the effect of institutional factors on patients' satisfaction. Accordingly, we examined institutional factors in determining patients' dissatisfaction using the Patient's Behavior Survey in Japan. METHODS: The combined database of the Patient's Behavior Survey, the Patient Survey, and the Survey of Medical Institutions from 2011 was used for the analysis. The item "overall patients' satisfaction" was used as the outcome for patient dissatisfaction. Medical institution factors were selected from the Survey of Medical Institutions, and patient factors, such as age, sex, and disease, were drawn from the Patient Survey. The analyses were conducted separately for inpatients and outpatients. Mixed-effects logistic regression, which accounts for the heterogeneity of institution type, was used to investigate the relationship between patients' dissatisfaction and institutional factors. RESULTS: There were 27,842 outpatients and 17,770 inpatients. In outpatients, founders (P<0.001), preventive measures for passive smoking (P<0.001), and training for new employees (P=0.002) were significantly related to patients' dissatisfaction. In inpatients, founders (P=0.037), preventive measures for passive smoking (P<0.001), the palliative care team (P=0.001), and training for new employees (P=0.013) were significant predictors. The heterogeneity among medical institution types was negligible for both outpatients and inpatients. CONCLUSION: Patient dissatisfaction was significantly associated with founders, preventive measures for passive smoking, and training for new employees for both outpatients and inpatients and with palliative care team only for inpatients. These items were indicators of improved hospital environments, and they represent key elements to ensure patient satisfaction in hospitals. PMID- 26607919 TI - [Gender and regional differences in going-out, social, and leisure activities among older adults. Findings from the JAGES Project]. AB - OBJECTIVES: Promoting social and leisure activity participation in older adults could be effective in preventing their health decline. However, gender or regional differences in those activities remain unclear despite the necessity of gender- or region-specific approaches to their promotion. This study examined gender and urban-rural differences in going-out, social, and leisure activities among community-dwelling older adults. METHODS: Data were obtained from the Japan Gerontological Evaluation Study (JAGES). Those analyzed were 103,621 people aged 65 or older who were functionally independent and lived in one of 31 municipalities. A total of seven activity variables were assessed with weekly going out, engagement in paid work, monthly and any frequency of engagement in group activities, monthly and any frequency of contact with friends, and having hobbies. We additionally assessed the contents of the group activities and hobbies. Gender, age groups (young-old: 65-74; old-old: 75 and over), and region groups, which were categorized as rural, urban, or metropolitan, were assessed along with education, depression, and other covariates. A chi-square test and multivariate logistic regression analysis were conducted to examine the age group stratified differences in the going-out, social, and leisure activities among gender and region groups (P<.01). RESULTS: Multivariate logistic regression analysis showed that men were more likely to engage in weekly going out, paid work, and hobbies but less likely to engage in group activities and contact with friends, either monthly or at any frequency. Most activities were also found to differ significantly among the region groups. For instance, people in metropolitan areas were 2.3 times more likely to engage in weekly going out but were 0.4 (old-old group) or 0.5 times (young-old group) less likely to engage in contact with friends. Percentages of engagement in hobby- or sport-groups were over 20% in all gender and region groups; on the other hand, about 30% differences were found in the percentages of engagement in senior clubs or neighborhood associations between metropolitan and rural men. As for having hobbies, walking/jogging and gardening were popular across all gender and region groups, while the percentages of engagement in a variety of hobbies differed among gender and region groups. CONCLUSION: Our findings suggest 1) differences in the levels of social and leisure activities among gender and region groups and 2) both similarities and differences in the popular group activities or hobbies among gender and region groups. Activity promotion for older adults should be targeted considering these gender and region group characteristics. PMID- 26607920 TI - [Fact-finding survey on regional healthcare services for patients with epilepsy based on a questionnaire administered to public health centers in Japan]. AB - OBJECTIVES: Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures. The prevalence of epilepsy is about 1%, and its incidence is increasing with the aging population. In addition to their medical problems, epilepsy patients face many social problems, including schooling, working, and maintaining their driver's licenses. However, these problems are not fully recognized by the regional healthcare centers (HCCs), and the inadequacy of collaboration between medical services, healthcare, and welfare is sometimes pointed out. Under these circumstances, this fact-finding survey was administered in the form of a questionnaire to HCCs across the nation for the purpose of improving the support system and educational activities for epilepsy in Japan. METHODS: A mail-back survey on regional healthcare services for epilepsy patients was sent out to 490 HCCs across the nation. Public health nurses (PHNs) responded to the self-completed questionnaire on behalf of each HCC. The questionnaire was comprised of the presence or absence of consultations on epilepsy, content of the consultations, and holding of workshops, lectures, or conferences in the community covered by the HCC. RESULTS: We obtained responses from 347 HCCs (response rate 71%). Seventy-three percent of the PHNs had experience with consultations regarding the medical and healthcare issues associated with epilepsy. However, only 10% of the PHNs responded that they could provide appropriate consultation for these issues. The content of the consultations mainly included medical services, clinical symptoms of epilepsy, and anxieties about their social life and their future. Workshops, lectures, or conferences on epilepsy were held for residents or health and welfare professionals in only 8% of the communities. This percentage is lower than those (21-70%) for other intractable or mental disorders that are mainly managed by HCCs (P<0.01). On the other hand, 76% of PHNs in the HCCs felt the need for knowledge about epilepsy, and 60% wanted to join the epilepsy educational programs. CONCLUSION: Although many PHNs belonging to HCCs conduct consultations regarding epilepsy-related issues, many feel they cannot adequately respond to these issues. Furthermore, they feel the need for further knowledge about epilepsy but are not able to gain such knowledge because of financial and geographical restrictions. To improve these situations, regional education programs for epilepsy should be established in each local municipality in the future with support provided by medical facilities, regional medical associations, the Japan Epilepsy Society, and the Government. PMID- 26607921 TI - [Complementary estimate of the Great East Japan Earthquake for the numbers of households and patients from national health statistics surveys]. PMID- 26607922 TI - [Comments on the "subjective symptoms and incidence of miscarriage following exposure to diphenyl alcine contained in well water for drinking"]. PMID- 26607925 TI - An electric double layer of colloidal particles in salt-free concentrated suspensions including non-uniform size effects and orientational ordering of water dipoles. AB - The response of a suspension under a variety of static or alternating external fields strongly depends on the equilibrium electric double layer that surrounds the colloidal particles in the suspension. The theoretical models for salt-free suspensions can be improved by incorporating non-uniform size effects and orientational ordering of water dipoles neglected in previous mean-field approaches, which are based on the Poisson-Boltzmann approach. Our model including non-uniform size effects and orientational ordering of water dipoles seems to have quite a promising effect because the model can predict the phenomena like a heavy decrease in relative permittivity of the suspension and counterion stratification near highly charged colloidal particles. In this work we numerically obtain the electric potential, the counterion concentration and the relative permittivity around a charged particle in a concentrated salt-free suspension corrected by non-uniform size effects and orientational ordering of water dipoles. The results show the worth of such corrections for medium to high particle charges at every particle volume fraction. We conclude that non-uniform size effects and orientational ordering of water dipoles are necessary for the development of new theoretical models to study non-equilibrium properties in concentrated colloidal suspensions. PMID- 26607926 TI - HIV Testing and Cross Border Migrant Vulnerability: Social Integration and Legal/Economic Status Among Cross Border Migrant Workers in Thailand. AB - The objective of this paper was to identify factors related to the use of HIV testing among cross border migrants in Thailand. Two measures of vulnerability (social integration and legal/economic status) as well as HIV knowledge, risk behaviour, and demographic factors were tested for association with HIV testing. Data were drawn from a survey of 2600 sexually active migrants age 15-59 in multiple provinces of Thailand. The measures of social integration (AOR = 1.14(95 % CI 1.09, 1.20) female; AOR = 1.12 (95 %CI 1.05, 1.19) male) and legal-income status (AOR = 1.12 (95 % CI 1.07, 1.18) female; AOR = 1.31 (95 %CI 1.20, 1.42) male) were positively related to the odds of reporting an HIV test for both male and female migrants. Exposure to AIDS programming including attending an AIDS meeting and possessing AIDS knowledge was also related to an increase in HIV testing. In addition, reproductive health factors including sexual risk behavior and childbirth increased the rate of HIV testing. PMID- 26607927 TI - Bisexual Behavior Among Male Injection Drug Users in New York City. AB - Drug using men who have sex with men and women (MSMW) may be at high risk for HIV infection and transmitting HIV to sex partners. In 2012, injection drug users (IDUs) were sampled in New York City for the National HIV Behavioral Surveillance cross-sectional study using respondent-driven sampling. Logistic regression was used to calculate crude and adjusted odds ratios (aOR) and 95 % confidence intervals (95 %CI) to determine correlates of bisexual behavior in the past 12 months. Of 333 participants, 47(14.1 %) reported MSMW. Variables independently associated (p < 0.05) with MSMW included bisexual sexual identity (vs. "straight") (adjusted odds ratio (aOR) 92.6; 95 % CI 18.9, 454.5), Bronx residence [vs. Manhattan (aOR 8.4; 95 %CI 1.6,43.7)], past 12 month behaviors of having sex with >=3 sex partners (aOR 18.1; 95 % CI 3.3,98.4), "sold" sex (aOR 8.5; 95 % CI 2.3, 31.5), "bought" sex (aOR 0.2; 95 % CI 0.1, 0.9), and injection methamphetamine use (aOR 20.5; 95 % CI 3.0, 139.7). MSM IDUs are an important subgroup to consider for HIV interventions, as they may not be reached through HIV prevention programming aimed at MSM. PMID- 26607928 TI - The Effect of a Community-Based Exercise Program on Inflammation, Metabolic Risk, and Fitness Levels Among Persons Living with HIV/AIDS. AB - The human immunodeficiency virus (HIV) pandemic remains a top national health priority. Chronic inflammation may be a critical component in the disease course of HIV as C-reactive protein (CRP) is elevated and associated with increased mortality. This study examined the effect of 3 months of combined aerobic and resistance exercise training among a diverse cohort of HIV-infected men and women. The fixed effect of time for CRP was found to be non-significant (F[1,57.3] = 1.7, p = 0.19). There was a significant fixed effect for time for upper body (F[1,51.6] = 18.1, p < 0.05) and lower body strength (F[1,48.0] = 15.7, p < 0.05) and significant declines in diastolic blood pressure (p = 0.002) and waist circumference (p = 0.027). Though levels of CRP were not impacted after 3 months training, participants demonstrated a significant increase in muscular strength as well as beneficial changes in metabolic risk factors. Future studies should focus on determining the optimal exercise intervention length and mode to reduce inflammation among individuals living with HIV. PMID- 26607929 TI - Higher Frequency of Unprotected Insertive Anal Sex Among Young Black MSM Who are Circumcised. PMID- 26607930 TI - Biliary tract cancers: SEOM clinical guidelines. AB - Biliary tract cancer (BTC) is an uncommon and highly fatal malignancy. It is composed of three main different entities; Gall bladder carcinoma (GBC), intrahepatic cholangiocarcinoma (iCC) and extrahepatic cholangiocarcinoma (eCC) sharing different genetic, risk factors and clinical presentation. Multidetector row computed tomography (MDCT) and magnetic resonance cholangio-pancreatography (MRCP) are the more important diagnostic techniques. Surgery is the only potentially curative therapy but disease recurrence is frequent. Treatment with chemotherapy, radiotherapy or both has not demonstrated survival benefit in the adjuvant setting. Cisplatin plus gemcitabine constitutes the gold standard in metastatic disease. New ongoing studies mainly in the adjuvant and neoadjuvant setting along with molecular research will hopefully help to improve survival and quality of life of this disease. PMID- 26607931 TI - Clinical guideline SEOM: hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) represents the second leading cause of cancer related death worldwide. Surveillance with abdominal ultrasound every 6 months should be offered to patients with a high risk of developing HCC: Child-Pugh A-B cirrhotic patients, all cirrhotic patients on the waiting list for liver transplantation, high-risk HBV chronic hepatitis patients (higher viral load, viral genotype or Asian or African ancestry) and patients with chronic hepatitis C and bridging fibrosis. Accurate diagnosis, staging and functional hepatic reserve are crucial for the optimal therapeutic approach. Characteristic findings on dynamic CT/MR of arterial hyperenhancement with "washout" in the portal venous or delayed phase are highly specific and sensitive for a diagnosis of HCC in patients with previous cirrhosis, but a confirmed histopathologic diagnosis should be done in patients without previous evidence of chronic hepatic disease. BCLC classification is the most common staging system used in Western countries. Surgical procedures, local therapies and systemic treatments should be discussed and planned for each patient by a multidisciplinary team according to the stage, performance status, liver function and comorbidities. Surgical interventions remain as the only curative procedures but both local and systemic approaches may increase survival and should be offered to patients without contraindications. PMID- 26607932 TI - Quality of life in patients treated by adjuvant radiotherapy for endometrial and cervical cancers: correlation with dose-volume parameters. AB - INTRODUCTION: Modern multidisciplinary cancer treatments aim at obtaining minimal influence on patients' quality of life (QoL). The purpose of this study was to assess QoL and correlate it with dose-volume parameters of organ at risks (OARs) in patients who received adjuvant radiotherapy for endometrial and cervical cancers. MATERIALS AND METHODS: We administered the EORTC QLQ-C30 and EN24 or CX24 questionnaires to 124 patients, 100 with endometrial cancer and 24 with cervical cancer treated with postoperative radiotherapy +/- chemotherapy in regular follow-up. Bladder function, fecal incontinence or urgency and sexual functioning were investigated and correlated with dose-volume parameters of OAR by multiple linear regression analysis. This correlation was assessed by R (2) value. RESULTS: QoL was very high in the majority of patients (82.3 % of patients). Few patients referred urinary incontinence (3.2 %) or abdominal discomfort of high grade (4.0 %). We found a significant correlation between bladder V40, i.e., absolute percentage of bladder volume that received a dose of 40 Gy, and global health status (p < 0.05, R (2) = 0.17), urinary urgency (p < 0.05, R (2) = 0.24), urinary incontinence (p < 0.05, R (2) = 0.23) and dyspareunia (p < 0.05, R (2) = 0.04). We found also a correlation between global health status and mean dose to vagina (p < 0.05, R (2) = 0.17) and between maximum dose to lumbo-sacral plexus and abdominal pain (p < 0.05, R (2) = 0.07). CONCLUSIONS: Women treated with surgery and adjuvant radiotherapy for endometrial and cervical cancers have good QoL with minimal limitations of daily activities. QoL was correlated with dose-volume parameters such as bladder V40, mean dose to vagina, maximum dose to trigone and LSP. PMID- 26607933 TI - Analysis of in vivo single cell behavior by high throughput, human-in-the-loop segmentation of three-dimensional images. AB - BACKGROUND: Analysis of single cells in their native environment is a powerful method to address key questions in developmental systems biology. Confocal microscopy imaging of intact tissues, followed by automatic image segmentation, provides a means to conduct cytometric studies while at the same time preserving crucial information about the spatial organization of the tissue and morphological features of the cells. This technique is rapidly evolving but is still not in widespread use among research groups that do not specialize in technique development, perhaps in part for lack of tools that automate repetitive tasks while allowing experts to make the best use of their time in injecting their domain-specific knowledge. RESULTS: Here we focus on a well-established stem cell model system, the C. elegans gonad, as well as on two other model systems widely used to study cell fate specification and morphogenesis: the pre implantation mouse embryo and the developing mouse olfactory epithelium. We report a pipeline that integrates machine-learning-based cell detection, fast human-in-the-loop curation of these detections, and running of active contours seeded from detections to segment cells. The procedure can be bootstrapped by a small number of manual detections, and outperforms alternative pieces of software we benchmarked on C. elegans gonad datasets. Using cell segmentations to quantify fluorescence contents, we report previously-uncharacterized cell behaviors in the model systems we used. We further show how cell morphological features can be used to identify cell cycle phase; this provides a basis for future tools that will streamline cell cycle experiments by minimizing the need for exogenous cell cycle phase labels. CONCLUSIONS: High-throughput 3D segmentation makes it possible to extract rich information from images that are routinely acquired by biologists, and provides insights - in particular with respect to the cell cycle that would be difficult to derive otherwise. PMID- 26607934 TI - Vegetable and fruit consumption and the risk of hormone receptor-defined breast cancer in the EPIC cohort. AB - BACKGROUND: The recent literature indicates that a high vegetable intake and not a high fruit intake could be associated with decreased steroid hormone receptor negative breast cancer risk. OBJECTIVE: This study aimed to investigate the association between vegetable and fruit intake and steroid hormone receptor defined breast cancer risk. DESIGN: A total of 335,054 female participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were included in this study (mean +/- SD age: 50.8 +/- 9.8 y). Vegetable and fruit intake was measured by country-specific questionnaires filled out at recruitment between 1992 and 2000 with the use of standardized procedures. Cox proportional hazards models were stratified by age at recruitment and study center and were adjusted for breast cancer risk factors. RESULTS: After a median follow-up of 11.5 y (IQR: 10.1-12.3 y), 10,197 incident invasive breast cancers were diagnosed [3479 estrogen and progesterone receptor positive (ER+PR+); 1021 ER and PR negative (ER-PR-)]. Compared with the lowest quintile, the highest quintile of vegetable intake was associated with a lower risk of overall breast cancer (HRquintile 5-quintile 1: 0.87; 95% CI: 0.80, 0.94). Although the inverse association was most apparent for ER-PR- breast cancer (ER-PR-: HRquintile 5 quintile 1: 0.74; 95% CI: 0.57, 0.96; P-trend = 0.03; ER+PR+: HRquintile 5 quintile 1: 0.91; 95% CI: 0.79, 1.05; P-trend = 0.14), the test for heterogeneity by hormone receptor status was not significant (P-heterogeneity = 0.09). Fruit intake was not significantly associated with total and hormone receptor-defined breast cancer risk. CONCLUSION: This study supports evidence that a high vegetable intake is associated with lower (mainly hormone receptor-negative) breast cancer risk. PMID- 26607935 TI - Lipid-based nutrient supplements for pregnant women reduce newborn stunting in a cluster-randomized controlled effectiveness trial in Bangladesh. AB - BACKGROUND: Maternal undernutrition and newborn stunting [birth length-for-age z score (LAZ) <-2] are common in Bangladesh. OBJECTIVE: The objective was to evaluate the effect of lipid-based nutrient supplements for pregnant and lactating women (LNS-PLs) on birth outcomes. DESIGN: We conducted a cluster randomized effectiveness trial (the Rang-Din Nutrition Study) within a community health program in rural Bangladesh. We enrolled 4011 pregnant women at <=20 gestational weeks; 48 clusters received iron and folic acid (IFA; 60 mg Fe + 400 MUg folic acid) and 16 clusters received LNS-PLs (20 g/d, 118 kcal) containing essential fatty acids and 22 vitamins and minerals. Both of the supplements were intended for daily consumption until delivery. Primary outcomes were birth weight and length. RESULTS: Infants in the LNS-PL group had higher birth weights (2629 +/- 408 compared with 2588 +/- 413 g; P = 0.007), weight-for-age z scores (-1.48 +/- 1.01 compared with -1.59 +/- 1.02; P = 0.006), head-circumference-for-age z scores (HCZs; -1.26 +/- 1.08 compared with -1.34 +/- 1.12; P = 0.028), and body mass index z scores (-1.57 +/- 1.05 compared with -1.66 +/- 1.03; P = 0.005) than those in the IFA group; in adjusted models, the differences in length (47.6 +/- 0.07 compared with 47.4 +/- 0.04 cm; P = 0.043) and LAZ (-1.15 +/- 0.04 compared with -1.24 +/- 0.02; P = 0.035) were also significant. LNS-PLs reduced the risk of newborn stunting (18.7% compared with 22.6%; RR: 0.83; 95% CI: 0.71, 0.97) and small head size (HCZ <-2) (20.7% compared with 24.9%; RR: 0.85; 95% CI: 0.73, 0.98). The effects of LNS-PL on newborn stunting were greatest in infants born before a 10-wk interruption in LNS-PL distribution (n = 1301; 15.7% compared with 23.6%; adjusted RR: 0.69; 95% CI: 0.53, 0.89) and in infants born to women <=24 y of age or with household food insecurity. CONCLUSION: Prenatal lipid-based nutrient supplements can improve birth outcomes in Bangladeshi women, especially those at higher risk of fetal growth restriction. This trial was registered at clinicaltrials.gov as NCT01715038. PMID- 26607936 TI - Associations of red and processed meat with survival after colorectal cancer and differences according to timing of dietary assessment. AB - BACKGROUND: Little is known about the prognostic impact of red and processed meat intake or about changes in consumption after a diagnosis of colorectal cancer (CRC). OBJECTIVES: We investigated associations of baseline red and processed meat with survival outcomes and explored changes in intake among CRC survivors 5 y after diagnosis. DESIGN: A total of 3122 patients diagnosed with CRC between 2003 and 2010 were followed for a median of 4.8 y [DACHS (Darmkrebs: Chancen der Verhutung durch Screening) study]. Patients provided information on diet and other factors in standardized questionnaires at baseline and at the 5-y follow up. Cox proportional hazards regression models were used to estimate HRs and 95% CIs. RESULTS: Among patients with stage I-III CRC, baseline red and processed meat intake was not associated with overall (>1 time/d compared with <1 time/d; HR: 0.85; 95% CI: 0.67, 1.09), CRC-specific (HR: 0.83; 95% CI: 0.61, 1.14), cardiovascular disease-specific (HR: 0.92; 95% CI: 0.51, 1.68), non-CRC-specific (HR: 0.88; 95% CI: 0.59, 1.30), and recurrence-free (HR: 1.03; 95% CI: 0.80, 1.33) survival; results among stage IV patients were comparable. An association with worse overall survival was found among patients with Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated CRC (HR: 1.99; 95% CI: 1.10, 3.56) but not with microsatellite instability or CpG island methylator phenotype (CIMP) positivity. A much lower proportion of survivors reported daily consumption of red and processed meat at the 5-y follow-up than at baseline (concordance rate: 39%; kappa-value: 0.10; 95% CI: 0.07, 0.13). CONCLUSIONS: Our findings suggest that baseline red and processed meat intake is not associated with poorer survival among patients with CRC. The potential interaction with KRAS mutation status warrants further evaluation. Major changes in consumption measured at the 5-y follow-up may have had an impact on our survival estimates. PMID- 26607937 TI - Vitamin B-12 treatment of asymptomatic, deficient, elderly Chileans improves conductivity in myelinated peripheral nerves, but high serum folate impairs vitamin B-12 status response assessed by the combined indicator of vitamin B-12 status. AB - BACKGROUND: It is uncertain whether vitamin B-12 supplementation can improve neurophysiologic function in asymptomatic elderly with low vitamin B-12 status or whether folate status affects responses to vitamin B-12 supplementation. OBJECTIVE: We assessed the effects of a single intramuscular injection of 10 mg vitamin B-12 (which also contained 100 mg vitamin B-6 and 100 mg vitamin B-1) on vitamin B-12 status and neurophysiologic function in elderly community-dwelling Chileans with low serum vitamin B-12 concentrations who were consuming bread fortified with folic acid. DESIGN: A pretreatment and posttreatment study was conducted in 51 participants (median +/- SD age: 73 +/- 3 y; women: 47%) with serum vitamin B-12 concentrations <120 pmol/L at screening. Vitamin B-12 status was defined by combining vitamin B-12, plasma total homocysteine (tHcy), methylmalonic acid (MMA), and holotranscobalamin into one variable [combined indicator of vitamin B-12 status (cB-12)]. The response to treatment was assessed by measuring cB-12 and neurophysiologic variables at baseline and 4 mo after treatment. RESULTS: Treatment increased serum vitamin B-12, holotranscobalamin, and cB-12 (P < 0.001) and reduced plasma tHcy and serum MMA (P < 0.001). Treatment produced consistent improvements in conduction in myelinated peripheral nerves; the sensory latency of both the left and right sural nerves improved on the basis of faster median conduction times of 3.1 and 3.0 ms and 3.3 and 3.4 ms, respectively (P < 0.0001). A total of 10 sensory potentials were newly observed in sural nerves after treatment. Participants with high serum folate at baseline (above the median, >=33.9 nmol/L) had less improvement in cB-12 (P < 0.001) than did individuals whose serum folate was less than the median concentration (i.e., with a concentration <33.9 nmol/L). CONCLUSION: Asymptomatic Chilean elderly with poor vitamin B-12 status displayed improved conductivity in myelinated peripheral nerves after vitamin B-12 treatment and an interaction with folate status, which was detected only with the use of cB-12. This trial was registered at www.controlled-trials.com as ISRCTN02694183. PMID- 26607938 TI - Dietary nitrate improves vascular function in patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled study. AB - BACKGROUND: The beneficial cardiovascular effects of vegetables may be underpinned by their high inorganic nitrate content. OBJECTIVE: We sought to examine the effects of a 6-wk once-daily intake of dietary nitrate (nitrate-rich beetroot juice) compared with placebo intake (nitrate-depleted beetroot juice) on vascular and platelet function in untreated hypercholesterolemics. DESIGN: A total of 69 subjects were recruited in this randomized, double-blind, placebo controlled parallel study. The primary endpoint was the change in vascular function determined with the use of ultrasound flow-mediated dilatation (FMD). RESULTS: Baseline characteristics were similar between the groups, with primary outcome data available for 67 patients. Dietary nitrate resulted in an absolute increase in the FMD response of 1.1% (an ~24% improvement from baseline) with a worsening of 0.3% in the placebo group (P < 0.001). A small improvement in the aortic pulse wave velocity (i.e., a decrease of 0.22 m/s; 95% CI: -0.4, -0.3 m/s) was evident in the nitrate group, showing a trend (P = 0.06) to improvement in comparison with the placebo group. Dietary nitrate also caused a small but significant reduction (7.6%) in platelet-monocyte aggregates compared with an increase of 10.1% in the placebo group (P = 0.004), with statistically significant reductions in stimulated (ex vivo) P-selectin expression compared with the placebo group (P < 0.05) but no significant changes in unstimulated expression. No adverse effects of dietary nitrate were detected. The composition of the salivary microbiome was altered after the nitrate treatment but not after the placebo treatment (P < 0.01). The proportions of 78 bacterial taxa were different after the nitrate treatment; of those taxa present, 2 taxa were responsible for >1% of this change, with the proportions of Rothia mucilaginosa trending to increase and Neisseria flavescens (P < 0.01) increased after nitrate treatment relative to after placebo treatment. CONCLUSIONS: Sustained dietary nitrate ingestion improves vascular function in hypercholesterolemic patients. These changes are associated with alterations in the oral microbiome and, in particular, nitrate-reducing genera. Our findings provide additional support for the assessment of the potential of dietary nitrate as a preventative strategy against atherogenesis in larger cohorts. This trial was registered at clinicaltrials.gov as NCT01493752. PMID- 26607939 TI - Nutrient-wide association study of 57 foods/nutrients and epithelial ovarian cancer in the European Prospective Investigation into Cancer and Nutrition study and the Netherlands Cohort Study. AB - BACKGROUND: Studies of the role of dietary factors in epithelial ovarian cancer (EOC) development have been limited, and no specific dietary factors have been consistently associated with EOC risk. OBJECTIVE: We used a nutrient-wide association study approach to systematically test the association between dietary factors and invasive EOC risk while accounting for multiple hypothesis testing by using the false discovery rate and evaluated the findings in an independent cohort. DESIGN: We assessed dietary intake amounts of 28 foods/food groups and 29 nutrients estimated by using dietary questionnaires in the EPIC (European Prospective Investigation into Cancer and Nutrition) study (n = 1095 cases). We selected 4 foods/nutrients that were statistically significantly associated with EOC risk when comparing the extreme quartiles of intake in the EPIC study (false discovery rate = 0.43) and evaluated these factors in the NLCS (Netherlands Cohort Study; n = 383 cases). Cox regression models were used to estimate HRs and 95% CIs. RESULTS: None of the 4 dietary factors that were associated with EOC risk in the EPIC study (cholesterol, polyunsaturated and saturated fat, and bananas) were statistically significantly associated with EOC risk in the NLCS; however, in meta-analysis of the EPIC study and the NLCS, we observed a higher risk of EOC with a high than with a low intake of saturated fat (quartile 4 compared with quartile 1; overall HR: 1.21; 95% CI: 1.04, 1.41). CONCLUSION: In the meta-analysis of both studies, there was a higher risk of EOC with a high than with a low intake of saturated fat. PMID- 26607940 TI - Effect of Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding on gastrointestinal metabolism of ingested glucose. AB - BACKGROUND: Data from studies conducted in animal models suggest that intestinal glucose uptake and metabolism are upregulated after Roux-en-Y gastric bypass (RYGB) surgery, which contributes to a weight-loss-independent improvement in glycemic control. OBJECTIVE: We conducted a cohort study to evaluate whether an increase in gastrointestinal metabolism of ingested glucose occurs in obese people who underwent RYGB compared with those who underwent laparoscopic adjustable gastric banding (LAGB). DESIGN: A mixed meal containing stable isotope labeled glucose was used to determine the gastrointestinal (small intestine and liver) retention, and presumably metabolism, of ingested glucose in obese subjects before and after matched weight loss (~21%) induced by RYGB (n = 16) or LAGB (n = 9). RESULTS: The total percentage of ingested glucose that appeared in the systemic circulation was slightly lower after than before RYGB (85% +/- 9% and 90% +/- 8%, respectively) but was slightly higher after than before LAGB (89% +/- 3% and 85% +/- 4%, respectively) (P-interaction < 0.05). Accordingly, gastrointestinal clearance of ingested glucose (cumulative percentage cleared over 6 h postprandially) increased after RYGB (from 10% +/- 8% before to 15% +/- 9% after surgery) but decreased after LAGB (from 15% +/- 4% before to 11% +/- 3% after surgery) (P < 0.05). Surgery-induced weight loss caused a similar decrease in the 6-h postprandial plasma glucose area under the curve in both RYGB and LAGB groups (-4% +/- 9% and -6% +/- 5%, respectively; P = 0.475). CONCLUSIONS: These data support the notion that intestinal glucose disposal increases after RYGB surgery. However, the magnitude of the effect was small and did not result in weight-loss-independent therapeutic effects on postprandial glycemic control. This trial was registered at clinicaltrials.gov as NCT00981500. PMID- 26607941 TI - Reduced dietary intake of simple sugars alters perceived sweet taste intensity but not perceived pleasantness. AB - BACKGROUND: Individuals who adhere to reduced-sodium diets come to prefer less salt over time, but it is unclear whether sweet taste perception is modulated by reduced sugar intake. OBJECTIVE: The objective was to determine how a substantial reduction in dietary intake of simple sugars affects sweetness intensity and pleasantness of sweet foods and beverages. DESIGN: Healthy men and women aged 21 54 y participated for 5 mo. After the baseline month, 2 subject groups were matched for demographic characteristics, body mass index, and intake of simple sugars. One group (n = 16; 13 of whom completed key experimental manipulations) was randomly assigned to receive a low-sugar diet during the subsequent 3 mo, with instructions to replace 40% of calories from simple sugars with fats, proteins, and complex carbohydrates. The other (control) group (n = 17; 16 of whom completed the study) did not change their sugar intake. During the final month, both groups chose any diet they wished. Each month subjects rated the sweetness intensity and pleasantness of vanilla puddings and raspberry beverages that varied in sucrose concentration. RESULTS: ANOVA showed no systematic differences between groups in rated sweetness during the baseline or first diet month. During the second diet month, the low-sugar group rated low-sucrose pudding samples as more intense than did the control group (significant group-by concentration interaction, P = 0.002). During the third diet month, the low-sugar subjects rated both low and high concentrations in puddings as ~40% sweeter than did the control group (significant effect of group, P = 0.01). A weaker effect on rated sweetness was obtained for the beverages. Rated pleasantness was not affected for either of the stimuli. CONCLUSIONS: This experiment provides empirical evidence that changes in consumption of simple sugars influence perceived sweet taste intensity. More work is needed to determine whether sugar intake ultimately shifts preferences for sweet foods and beverages. This trial was registered at clinicaltrials.gov as NCT02090478. PMID- 26607943 TI - Glycemic index, glycemic load, and common psychological disorders. AB - BACKGROUND: Potential associations between dietary glycemic index (GI) and glycemic load (GL) with psychological disorders remain uncertain. OBJECTIVE: We investigated the relations of dietary GI and GL with psychological distress, anxiety, and depression. DESIGN: A total of 3363 nonacademic members of the staff of Isfahan University of Medical Sciences were included in this cross-sectional study. GI and GL were assessed by using a validated, self-administered, dish based, semiquantitative food-frequency questionnaire. Validated Iranian versions of the Hospital Anxiety and Depression Scale and General Health Questionnaire-12 were used to assess anxiety, depression, and psychological distress. RESULTS: After control for potential confounders, individuals in the top tertile of GI had greater odds of depression (OR: 1.44; 95% CI: 1.03, 2.02; P-trend = 0.03) and a trend for greater odds of anxiety (OR: 1.52; 95% CI: 0.97, 2.38; P trend = 0.06) compared with those in the first tertile. Higher GL values were linked to lower odds for mental disorders (OR: 0.66; 95% CI: 0.49, 0.90; P-trend = 0.009), depression (OR: 0.69; 95% CI: 0.51, 0.93; P-trend = 0.02), and psychological distress (OR: 0.67; 95% CI: 0.48, 0.92; P-trend = 0.01). Significant interactions were observed between GI and sex for depression (P = 0.01) and psychological distress (P = 0.046) in the crude model. In stratified analyses by sex, after control for potential confounders, a greater GI was linked to a higher odds of depression (OR: 1.52; 95% CI: 1.20, 1.94; P-trend = 0.001) and psychological distress (OR: 1.66; 95% CI: 1.28, 2.14; P-trend = 0.001) in women but not in men. CONCLUSION: Our findings support a direct link between the odds of depression and dietary GI but inverse associations between GL and mental disorders, depression, and psychological distress. This trial was registered at clinicaltrials.gov as NCT02362113. PMID- 26607942 TI - Administration of resveratrol for 5 wk has no effect on glucagon-like peptide 1 secretion, gastric emptying, or glycemic control in type 2 diabetes: a randomized controlled trial. AB - BACKGROUND: Resveratrol has been reported to lower glycemia in rodent models of type 2 diabetes associated with the stimulation of glucagon-like peptide 1 (GLP 1), which is known to slow gastric emptying, stimulate insulin secretion, and suppress glucagon secretion and energy intake. OBJECTIVE: We evaluated the effects of 5 wk of resveratrol treatment on GLP-1 secretion, gastric emptying, and glycemic control in type 2 diabetes. DESIGN: Fourteen patients with diet controlled type-2 diabetes [mean +/- SEM glycated hemoglobin (HbA1c): 6.4 +/- 0.2% (46.4 +/- 2.2 mmol/mol)] received resveratrol (500 mg twice daily) or a placebo over two 5-wk intervention periods with a 5-wk washout period in between in a double-blind, randomized, crossover design. Before and after each intervention period (4 visits), body weight and HbA1c were measured, and patients were evaluated after an overnight fast with a standardized mashed-potato meal labeled with 100 MUg (13)C-octanoic acid to measure blood glucose and plasma GLP 1 concentrations and gastric emptying (breath test) over 240 min. Daily energy intake was estimated from 3-d food diaries during the week before each visit. RESULTS: Fasting and postprandial blood glucose and plasma total GLP-1 as well as gastric emptying were similar at each assessment, and the change in each variable from weeks 0 to 5 did not differ between resveratrol and placebo groups. Similarly, changes in HbA1c, daily energy intake, and body weight after 5 wk did not differ between the 2 treatments. CONCLUSIONS: In patients with diet controlled type 2 diabetes, 5 wk of twice-daily 500 mg-resveratrol supplementation had no effect on GLP-1 secretion, glycemic control, gastric emptying, body weight, or energy intake. Our observations do not support the use of resveratrol for improving glycemic control. This trial was registered at www.anzctr.org.au as ACTRN12613000717752. PMID- 26607944 TI - Various factors contribute to graft extrusion in lateral meniscus allograft transplantation. AB - PURPOSE: Lateral meniscus allograft transplantation (LMAT) is a feasible surgical option for young meniscus-deficient patients. Although several studies have explored the factors that contribute to graft extrusion, they have not been fully elucidated. The aim of this study was to determine the various factors that contribute to graft extrusion. METHODS: Patients with knees that had received LMAT using a keyhole technique (n = 87 knees in 82 patients) were reviewed. The median age of these patients was 22 years (range 19-54 years), and the median postprocedural follow-up interval was 5 days (range 1-136 days). Twelve magnetic resonance imaging (MRI) measurement parameters (axial and coronal location of the bone block) that could potentially influence graft extrusion were evaluated, along with absolute graft extrusion and relative percentage of extrusion (RPE). RESULTS: A significant correlation was found between 8 of the 12 MRI measurement parameters and both the absolute extrusion and RPE (r = 0.241-0.438, p < 0.05). The absolute middle distance and depth of the bone block were independent predictors of the absolute extrusion (beta = 0.30 and 0.15, respectively; p < 0.05), and the relative middle distance and relative bone-block elevation were found to be predictors of RPE (beta = 2.29 and 1.44, respectively; p < 0.05). CONCLUSION: The rate of graft extrusions after LMAT was high in this study. Both the coronal and axial locations of the bone block were found to influence graft extrusion in LMAT. Therefore, correct positioning of the bone block, including in both the axial and coronal planes, is essential to minimize graft extrusion. Future studies need to investigate the long-term clinical outcome and longevity of extruded menisci after transplantation. LEVEL OF EVIDENCE: Therapeutic case series, Level IV. PMID- 26607946 TI - Development and characterization of vancomycin-loaded levan-based microparticular system for drug delivery. AB - Encapsulation of vancomycin (VANCO) into biodegradable levan microparticles was achieved using a simple preparation technique. Microparticles were prepared by using levan polysaccharide produced by a halophilic bacterium Halomonas smyrnensis AAD6T. To optimize efficiency of encapsulation process by precipitation method, three parameters were studied: drug and polymer concentrations and preparation rotating speed. The particles were characterized in vitro. The size of levan microparticles was changed between 0.404 MUm and 1.276 MUm. The surface charge was detected between +4.1 mV and +6.5 mV. The highest drug encapsulation capacity of the system was 74.7% and was depending on the polymer concentration. In dissolution studies, initial burst effect around 10 20% from all the formulations was observed and then the release was slowed down and continued at a constant level. In vitro antibiotic release from the microparticles was controlled with the drug carrier system and release fit to Higuchi kinetic model. All the released samples collected at different time intervals during dissolution studies have exhibited intrinsic bactericidal activity against Bacillus subtilis ATCC 6633. WST-1 cell proliferation and viability studies showed that VANCO-loaded levan microparticles at concentrations between 100 MUg/mL and 1000 MUg/mL were nontoxic to L929 cells. As conclusion, levan microparticulate system could be a potential carrier of antibiotic drugs such as VANCO. PMID- 26607947 TI - SymbioGenomesDB: a database for the integration and access to knowledge on host symbiont relationships. AB - Symbiotic relationships occur naturally throughout the tree of life, either in a commensal, mutualistic or pathogenic manner. The genomes of multiple organisms involved in symbiosis are rapidly being sequenced and becoming available, especially those from the microbial world. Currently, there are numerous databases that offer information on specific organisms or models, but none offer a global understanding on relationships between organisms, their interactions and capabilities within their niche, as well as their role as part of a system, in this case, their role in symbiosis. We have developed the SymbioGenomesDB as a community database resource for laboratories which intend to investigate and use information on the genetics and the genomics of organisms involved in these relationships. The ultimate goal of SymbioGenomesDB is to host and support the growing and vast symbiotic-host relationship information, to uncover the genetic basis of such associations. SymbioGenomesDB maintains a comprehensive organization of information on genomes of symbionts from diverse hosts throughout the Tree of Life, including their sequences, their metadata and their genomic features. This catalog of relationships was generated using computational tools, custom R scripts and manual integration of data available in public literature. As a highly curated and comprehensive systems database, SymbioGenomesDB provides web access to all the information of symbiotic organisms, their features and links to the central database NCBI. Three different tools can be found within the database to explore symbiosis-related organisms, their genes and their genomes. Also, we offer an orthology search for one or multiple genes in one or multiple organisms within symbiotic relationships, and every table, graph and output file is downloadable and easy to parse for further analysis. The robust SymbioGenomesDB will be constantly updated to cope with all the data being generated and included in major databases, in order to serve as an important, useful and timesaving tool. Database URL: http://symbiogenomesdb.uv.es. PMID- 26607948 TI - Efficacy and Safety of Mammalian Target of Rapamycin Inhibitors in Vascular Anomalies: A Systematic Review. AB - Mammalian target of rapamycin (mTOR) inhibitors are a promising new treatment in vascular anomalies, but no published randomized controlled trials are available. The aim of this systematic review of all reported cases was to assess the efficacy and safety of mTOR inhibitors in all vascular anomalies, except cancers, in children and adults. In November 2014 MEDLINE, CENTRAL, LILACS and EMBASE were searched for studies of mTOR inhibitors in any vascular condition, except for malignant lesions, in humans. Fourteen publications and 9 posters, with data on 25 and 59 patients, respectively, all < 18 years old were included. Of these patients, 35.7% (n = 30) had vascular tumours, and 64.3% (n = 54) had malformations. Sirolimus was the most frequent mTOR inhibitor used (98.8%, n = 83). It was efficient in all cases, at a median time of 2 weeks (95% confidence interval 1-10 weeks). Sirolimus was well tolerated, the main side-effect being mouth sores, which led to treatment withdrawal in one case. The dosage of sirolimus was heterogeneous, the most common being 1.6 mg/m2/day. PMID- 26607949 TI - Mathematical Modelling of Plankton-Oxygen Dynamics Under the Climate Change. AB - Ocean dynamics is known to have a strong effect on the global climate change and on the composition of the atmosphere. In particular, it is estimated that about 70% of the atmospheric oxygen is produced in the oceans due to the photosynthetic activity of phytoplankton. However, the rate of oxygen production depends on water temperature and hence can be affected by the global warming. In this paper, we address this issue theoretically by considering a model of a coupled plankton oxygen dynamics where the rate of oxygen production slowly changes with time to account for the ocean warming. We show that a sustainable oxygen production is only possible in an intermediate range of the production rate. If, in the course of time, the oxygen production rate becomes too low or too high, the system's dynamics changes abruptly, resulting in the oxygen depletion and plankton extinction. Our results indicate that the depletion of atmospheric oxygen on global scale (which, if happens, obviously can kill most of life on Earth) is another possible catastrophic consequence of the global warming, a global ecological disaster that has been overlooked. PMID- 26607950 TI - Induced Developmental Arrest of Early Hematopoietic Progenitors Leads to the Generation of Leukocyte Stem Cells. AB - Self-renewal potential and multipotency are hallmarks of a stem cell. It is generally accepted that acquisition of such stemness requires rejuvenation of somatic cells through reprogramming of their genetic and epigenetic status.We show here that a simple block of cell differentiation is sufficient to induce and maintain stem cells. By overexpression of the transcriptional inhibitor ID3 in murine hematopoietic progenitor cells and cultivation under B cell induction conditions, the cells undergo developmental arrest and enter a self-renewal cycle. These cells can be maintained in vitro almost indefinitely, and the long term cultured cells exhibit robust multi-lineage reconstitution when transferred into irradiated mice. These cells can be cloned and re-expanded with 50% plating efficiency, indicating that virtually all cells are self-renewing. Equivalent progenitors were produced from human cord blood stem cells, and these will ultimately be useful as a source of cells for immune cell therapy. PMID- 26607951 TI - Comparison of Human Embryonic Stem Cell-Derived Cardiomyocytes, Cardiovascular Progenitors, and Bone Marrow Mononuclear Cells for Cardiac Repair. AB - Cardiomyocytes derived from human embryonic stem cells (hESC-CMs) can improve the contractility of injured hearts.We hypothesized that mesodermal cardiovascular progenitors (hESC-CVPs), capable of generating vascular cells in addition to cardiomyocytes, would provide superior repair by contributing to multiple components of myocardium. We performed a head-to-head comparison of hESC-CMs and hESC-CVPs and compared these with the most commonly used clinical cell type, human bone marrow mononuclear cells (hBMMNCs). In a nude rat model of myocardial infarction, hESC-CMs and hESC-CVPs generated comparable grafts. Both similarly improved systolic function and ventricular dilation. Furthermore, only rare human vessels formed from hESC-CVPs. hBM-MNCs attenuated ventricular dilation and enhanced host vascularization without engrafting long-term or improving contractility. Thus, hESC-CMs and CVPs show similar efficacy for cardiac repair, and both are more efficient than hBM-MNCs. However, hESC-CVPs do not form larger grafts or more significant numbers of human vessels in the infarcted heart. PMID- 26607952 TI - Enhancer Analysis Unveils Genetic Interactions between TLX and SOX2 in Neural Stem Cells and In Vivo Reprogramming. AB - The orphan nuclear receptor TLX is a master regulator of postnatal neural stem cell (NSC) self-renewal and neurogenesis; however, it remains unclear how TLX expression is precisely regulated in these tissue-specific stem cells. Here, we show that a highly conserved cis-element within the Tlx locus functions to drive gene expression in NSCs. We demonstrate that the transcription factors SOX2 and MYT1 specifically interact with this genomic element to directly regulate Tlx enhancer activity in vivo. Knockdown experiments further reveal that SOX2 dominantly controls endogenous expression of TLX, whereas MYT1 only plays a modulatory role. Importantly, TLX is essential for SOX2-mediated in vivo reprogramming of astrocytes and itself is also sufficient to induce neurogenesis in the adult striatum. Together, these findings unveil functional genetic interactions among transcription factors that are critical to NSCs and in vivo cell reprogramming. PMID- 26607953 TI - Glioblastoma Stem Cells Respond to Differentiation Cues but Fail to Undergo Commitment and Terminal Cell-Cycle Arrest. AB - Glioblastoma (GBM) is an aggressive brain tumor whose growth is driven by stemcell-like cells. BMP signaling triggers cell-cycle exit and differentiation of GBM stemcells (GSCs) and, therefore, might have therapeutic value. However, the epigenetic mechanisms that accompany differentiation remain poorly defined. It is also unclear whether cell-cycle arrest is terminal. Herewe find only a subset ofGSCcultures exhibit astrocyte differentiation in response to BMP. Although overtly differentiated non-cycling astrocytes are generated, they remain vulnerable to cell-cycle re-entry and fail to appropriately reconfigure DNA methylation patterns. Chromatin accessibility mapping identified loci that failed to alter in response to BMP and these were enriched in SOX transcription factor binding motifs. SOX transcription factors, therefore, may limit differentiation commitment. A similar propensity for cell-cycle re-entry and de-differentiation was observed in GSC-derived oligodendrocyte-like cells. These findings highlight significant obstacles to BMP-induced differentiation as therapy forGBM. PMID- 26607954 TI - Dynamics of Lgr6+ Progenitor Cells in the Hair Follicle, Sebaceous Gland, and Interfollicular Epidermis. AB - The dynamics and interactions between stem cell pools in the hair follicle (HF), sebaceous gland (SG), and interfollicular epidermis (IFE) of murine skin are still poorly understood. In this study, we used multicolor lineage tracing to mark Lgr6+ -expressing basal cells in the HF isthmus, SG, and IFE.We show that these Lgr6+ cells constitute long-term self-renewing populations within each compartment in adult skin. Quantitative analysis of clonal dynamics revealed that the Lgr6+ progenitor cells compete neutrally in the IFE, isthmus, and SG, indicating population asymmetry as the underlying mode of tissue renewal. Transcriptional profiling of Lgr6+ and Lgr6+ cells did not reveal a distinct Lgr6+ -associated gene expression signature, raising the question of whether Lgr6+ expression requires extrinsic niche signals. Our results elucidate the interrelation and behavior of Lgr6+ populations in the IFE, HF, and SG and suggest population asymmetry as a common mechanism for homeostasis in several epithelial skin compartments. PMID- 26607955 TI - Clinicopathologic significance of legumain overexpression in cancer: a systematic review and meta-analysis. AB - Since reports on the clinical significance of legumain in cancer have shown inconsistent results, we systematically evaluated clinical indicators of legumain in cancer. We searched the Cochrane Library, PubMed, Embase, and EBSCO databases and the Wangfang and CNKI databases in China by using "legumain" and ("neoplasms" OR "cancer") as search terms. We included case-controlled studies of legumain and cancer. The quality of the studies was evaluated by using Lichtenstein's guidelines, and valid data was extracted for analysis. In total, 10 articles were included in this study. Meta-analysis showed that legumain was overexpressed in cancer compared with in normal tissue and was higher in stage III-IV disease than in I-II disease. Moreover, legumain overexpression was correlated with poor prognosis and clinical stage. Furthermore, Cancer Genome Atlas data showed that among patients with rectal cancer, those with tumors overexpressing legumain had shorter overall survival than those in the low expression group (P < 0.05). Legumain appears to be involved in tumor development and deterioration; thus, it can potentially be developed into both a marker for monitoring and diagnosing tumors and a therapeutic target. PMID- 26607956 TI - The coexistence of peripheral nerve sheath tumors and vitiligo: more than coincidence? AB - Neurocristopathies arise from abnormal migration, differentiation, or proliferation of neural crest derivatives, leading to diverse clinical and pathological features. They are classified into dysgenetic or neoplastic, and can affect single or multiple sites (simple versus complex). Examples include congenital melanocytic nevi, neuroblastoma, Hirshsprung's disease, Waardenburg's syndrome, neurofibromatosis (NF) 1 and multiple endocrine neoplasia (MEN) 2A and 2B. We report two cases of peripheral nerve sheath tumors associated with vitiligo and discuss the possible implicated embryologic, genetic and molecular mechanisms. To our knowledge, we also report the first case of de novo malignant peripheral nerve sheath tumor (MPNST) associated with vitiligo. PMID- 26607957 TI - Executive function is necessary for the regulation of the stepping activity when stepping in place in older adults. AB - To determine the effect of age on stepping performance and to compare the cognitive demand required to regulate repetitive stepping between older and younger adults while performing a stepping in place task (SIP). Fourteen younger (25.4 +/- 6.5) and 15 older adults (71.0 +/- 9.0) participated in this study. They performed a seated category fluency task and Stroop test, followed by a 60 s SIP task. Following this, both the cognitive and motor tasks were performed simultaneously. We assessed cognitive performance, SIP cycle duration, asymmetry, and arrhythmicity. Compared to younger adults, older adults had larger SIP arrhythmicity both as a single task and when combined with the Category (p < 0.001) and Stroop (p < 0.01) tasks. Older adults also had larger arrhythmicity when dual tasking compared to SIP alone (p < 0.001). Older adults showed greater SIP asymmetry when combined with Category (p = 0.006) and Stroop (p = 0.06) tasks. Finally, they had lower cognitive performance than younger adults in both single and dual tasks (p < 0.01). Age and type of cognitive task performed with the motor task affected different components of stepping. While SIP arrhythmicity was larger for all conditions in older compared to younger adults, cycle duration was not different, and asymmetry tended to be larger during SIP when paired with a verbal fluency task. SIP does not require a high level of control for dynamic stability, therefore demonstrating that higher-level executive function is necessary for the regulation of stepping activity independently of the regulation of postural balance. Furthermore, older adults may lack the cognitive resources needed to adequately regulate stepping activity while performing a cognitive task relying on the executive function. PMID- 26607958 TI - Beyond Psoriasis: Novel Uses for Biologic Response Modifiers in Pediatric Dermatology. AB - Dermatologists have witnessed the increasing availability of novel biologic response modifiers for the treatment of inflammatory and autoimmune diseases in recent years. The most common dermatologic indication for the use of biologic response modifiers in adults is psoriasis, but the U.S. Food and Drug Administration has not approved any of these agents for use in any dermatologic disease in children with the exception of omalizumab, and as such, use in this population is considered off-label. In this review, we focus on the use of these agents in children to treat inflammatory skin diseases other than psoriasis, including atopic dermatitis, hidradenitis suppurativa, pemphigus vulgaris, bullous pemphigoid, and toxic epidermal necrolysis, with an emphasis on the use of etanercept, infliximab, rituximab, omalizumab, and ustekinumab. By highlighting novel uses of these agents, particularly for the treatment of dermatologic conditions for which optimal therapies are yet to be established, we hope to raise awareness of the potential use of this class of medications to treat inflammatory skin diseases in children. PMID- 26607959 TI - Moving from Q fever to C. burnetii infection. PMID- 26607960 TI - Vasculitis after blood pressure monitoring. AB - INTRODUCTION: Description of appearance of ecchymosis on an arm, simultaneously with a classical Leukocytoclastic Vasculitis, the proposal of alternative utilities of measuring blood pressure, and the study of side effects to that measure. PATIENT: Case 80-year-old male came to ER with dyspnea, heart failure, predialysis renal failure with hyperkalemia and hemodynamic instability. During his stay he developed a skin lesion that looks like palpable purpura, from the lower limit of the blood pressure cuff to the distal area of the hand that not disappeared with vitropression, and pruritus. During admission the arm injury was extended to all members, both upper and lower. RESULTS: The study concluded with diagnosis of Leukocytoclastic Vasculitis given the presence of eosinophils, that which suggested probable drug etiology to an antibiotic that had been taken since seven days prior to admission to ER. DISCUSION: The need for serial monitoring of blood pressure, and the duration of such monitoring in unstable patients considering the side effects of those techniques was questioned. In addition, the study of other utilities of measuring blood pressure. PMID- 26607961 TI - Injectable and Thermosensitive Soluble Extracellular Matrix and Methylcellulose Hydrogels for Stem Cell Delivery in Skin Wounds. AB - Extracellular matrix (ECM) provides structural support and biochemical cues for tissue development and regeneration. Here we report a thermosensitive hydrogel composed of soluble ECM (sECM) and methylcellulose (MC) for injectable stem cell delivery. The sECM was prepared by denaturing solid ECM extracted from human adipose tissue and then blended with a MC solution. At low temperatures, the sECM MC solution displayed a viscous solution state in which the loss modulus (G") was predominant over the storage modulus (G'). With increasing temperature, G' increased dramatically and eventually exceeded G" around 34 degrees C, characteristic of the transition from a liquid-like state to an elastic gel-like state. After a single injection of the stem cell-embedded hydrogel in full thickness cutaneous wound, the wound healed rapidly through re-epithelialization and neovascularization with minimum scar formation. The overall results suggest that in-situ-forming sECM-MC hydrogels are a promising injectable vehicle for stem cell delivery and tissue regeneration. PMID- 26607962 TI - The Molecular Karyotype of 25 Clinical-Grade Human Embryonic Stem Cell Lines. AB - The application of human embryonic stem cell (hESC) derivatives to regenerative medicine is now becoming a reality. Although the vast majority of hESC lines have been derived for research purposes only, about 50 lines have been established under Good Manufacturing Practice (GMP) conditions. Cell types differentiated from these designated lines may be used as a cell therapy to treat macular degeneration, Parkinson's, Huntington's, diabetes, osteoarthritis and other degenerative conditions. It is essential to know the genetic stability of the hESC lines before progressing to clinical trials. We evaluated the molecular karyotype of 25 clinical-grade hESC lines by whole-genome single nucleotide polymorphism (SNP) array analysis. A total of 15 unique copy number variations (CNVs) greater than 100 kb were detected, most of which were found to be naturally occurring in the human population and none were associated with culture adaptation. In addition, three copy-neutral loss of heterozygosity (CN-LOH) regions greater than 1 Mb were observed and all were relatively small and interstitial suggesting they did not arise in culture. The large number of available clinical-grade hESC lines with defined molecular karyotypes provides a substantial starting platform from which the development of pre-clinical and clinical trials in regenerative medicine can be realised. PMID- 26607963 TI - Nap sleep spindle correlates of intelligence. AB - Sleep spindles are thalamocortical oscillations in non-rapid eye movement (NREM) sleep, that play an important role in sleep-related neuroplasticity and offline information processing. Several studies with full-night sleep recordings have reported a positive association between sleep spindles and fluid intelligence scores, however more recently it has been shown that only few sleep spindle measures correlate with intelligence in females, and none in males. Sleep spindle regulation underlies a circadian rhythm, however the association between spindles and intelligence has not been investigated in daytime nap sleep so far. In a sample of 86 healthy male human subjects, we investigated the correlation between fluid intelligence and sleep spindle parameters in an afternoon nap of 100 minutes. Mean sleep spindle length, amplitude and density were computed for each subject and for each derivation for both slow and fast spindles. A positive association was found between intelligence and slow spindle duration, but not any other sleep spindle parameter. As a positive correlation between intelligence and slow sleep spindle duration in full-night polysomnography has only been reported in females but not males, our results suggest that the association between intelligence and sleep spindles is more complex than previously assumed. PMID- 26607964 TI - The effects of topical parasympatholytic drugs on pupil diameter and intraocular pressure in healthy dogs treated with 0.005% latanoprost. AB - PURPOSE: Prostaglandin analogs induce miosis and lower intraocular pressure (IOP). As pupils of latanoprost-treated eyes may have to be dilated for ophthalmoscopy or intraocular surgery, we studied whether 0.5% tropicamide or 1% atropine alter the effects of 0.005% latanoprost on pupil diameter (PD) and IOP in healthy dogs. METHODS: IOP and PD were measured hourly, 8 AM-4 PM, with the right and left eyes serving as control (CE) and treated (TE) eyes, respectively. Measurements were conducted in ten Labrador retrievers with one-week washout: (i) baseline values, (ii) latanoprost at 8 AM, (iii) tropicamide at 8 AM, (iv) latanoprost at 8 AM and tropicamide at 11 AM, and (v) latanoprost at 8 AM and atropine at 11 AM (n = 4). RESULTS: At 4 PM, TE PD was 5.88 +/- 0.59, 3.62 +/- 0.66, 6.33 +/- 1.00, 5.42 +/- 0.57, and 8.12 +/- 1.24 mm in sessions 1-5, respectively. TE PD was significantly different between treatment sessions 2, 4, and 5 (P = 0.018, Friedman), being most mydriatic in session 5. At 4 PM, TE IOP was 11.27 +/- 2.07, 7.10 +/- 1.07, 11.1 +/- 2.21, 7.70 +/- 1.85, and 8.87 +/- 1.42 mm Hg in sessions 1-5, respectively, with no differences between treatment sessions 2, 4, and 5 (P = 0.105, Friedman). CONCLUSIONS: Tropicamide and atropine counteracted latanoprost's miotic effect, with atropine causing significantly larger mydriasis, sufficient for indirect ophthalmoscopy. Neither drug counteracted the hypotensive effect of latanoprost during this study period. Further studies are necessary to evaluate the potential risks in glaucomatous dogs. PMID- 26607965 TI - Metagenomic analysis of the microbiota in the highly compartmented hindguts of six wood- or soil-feeding higher termites. AB - BACKGROUND: Termites are important contributors to carbon and nitrogen cycling in tropical ecosystems. Higher termites digest lignocellulose in various stages of humification with the help of an entirely prokaryotic microbiota housed in their compartmented intestinal tract. Previous studies revealed fundamental differences in community structure between compartments, but the functional roles of individual lineages in symbiotic digestion are mostly unknown. RESULTS: Here, we conducted a highly resolved analysis of the gut microbiota in six species of higher termites that feed on plant material at different levels of humification. Combining amplicon sequencing and metagenomics, we assessed similarities in community structure and functional potential between the major hindgut compartments (P1, P3, and P4). Cluster analysis of the relative abundances of orthologous gene clusters (COGs) revealed high similarities among wood- and litter-feeding termites and strong differences to humivorous species. However, abundance estimates of bacterial phyla based on 16S rRNA genes greatly differed from those based on protein-coding genes. CONCLUSION: Community structure and functional potential of the microbiota in individual gut compartments are clearly driven by the digestive strategy of the host. The metagenomics libraries obtained in this study provide the basis for future studies that elucidate the fundamental differences in the symbiont-mediated breakdown of lignocellulose and humus by termites of different feeding groups. The high proportion of uncultured bacterial lineages in all samples calls for a reference-independent approach for the correct taxonomic assignment of protein-coding genes. PMID- 26607966 TI - Parity and Risk of Stroke among Chinese Women: Cross-sectional Evidence from the Dongfeng-Tongji Cohort Study. AB - Epidemiological studies have investigated the association between parity and the risk of stroke, but the results have been inconsistent. The objective of this study was to assess the association among middle-aged and older Chinese women. We used data from the Dongfeng-Tongji Cohort Study. In total, 14,277 women were included in the analysis. Participants were classified into four groups according to parity. Stroke cases were self-reported during face-to-face interviews. Multivariable logistic regression models were used to investigate the association between parity and the risk of stroke while controlling for potential confounders. The prevalence of stroke among the study subjects was 2.7% (380 of 14,277). In the fully adjusted model, women who had experienced two, three, or four or more live births had 1.24 times (95% CI, 0.85-1.81), 1.97 times (95% CI, 1.30-2.98) and 1.86 times (95% CI, 1.14-3.03), higher risk of stroke, respectively, compared with women who had experienced one live birth. High parity was associated with an increasing risk of stroke in the present study. Further longitudinal studies are needed to confirm the association and to explore the unclear mechanism underlying the link between parity and stroke risk. PMID- 26607967 TI - Functional residual capacity and lung clearance index in infants treated for esophageal atresia and tracheoesophageal fistula. AB - BACKGROUND: Newborn babies with esophageal atresia/tracheoesophageal fistula (EA/TEF) are prone to respiratory tract disorders. Functional residual capacity (FRC) and lung clearance index (LCI) are commonly considered useful and sensitive tools to investigate lung function and early detecting airways diseases. The aim of the present study is to report the first series of EA/TEF infants prospectively evaluated for FRC and LCI. METHODS: Prospective observational cohort study of all patients treated for EA/TEF. Lung volume and ventilation inhomogeneity were measured by helium gas dilution technique using an ultrasonic flow meter. Babies were studied both in assisted controlled ventilation (sedated) and in spontaneous breathing (quiet sleep). Three consecutive FRC and LCI measurements were collected for each test at three different time points: before surgery (T0), 24hours after surgery (T1) and after extubation (T2). RESULTS: 16 EA newborns were eligible for the study between December 2011 and July 2013. Three were excluded because of technical problems. At T0 FRC values were in the normal range regardless the presence of TEF but worsened afterwards at T1, with a subsequent recovering after extubation; a significant improvement after surgery was observed concerning LCI while no differences were found in tidal volume. CONCLUSION: Helium gas dilution technique is a suitable method to measure the effect of surgery on lung physiology, even in ventilated infants with EA. The changes observed could be related to the ventilatory management and lung compression during surgical procedure. PMID- 26607968 TI - Relapsed hepatoblastoma confined to the lung is effectively treated with pulmonary metastasectomy. AB - BACKGROUND: In children diagnosed with hepatoblastoma (HB), the lungs are the most common site of metastasis at both initial presentation and relapse. Previous studies have encouraged pulmonary metastasectomy to achieve a disease-free state after resection of the primary hepatic lesion. However, there is no consensus about how to manage recurrent pulmonary metastasis. PROCEDURE: A retrospective, multi-institutional review was performed from 2005 to 2014 to identify HB patients <=18years of age who had disease recurrence associated with pulmonary metastases alone. RESULTS: Ten patients between the ages of 8 and 33months were identified. Pulmonary metastatic recurrence was detected by measuring alpha fetoprotein (AFP) levels and/or with CT scans of the chest. All patients subsequently underwent pulmonary metastasectomy without post-operative complications. At last follow-up, 8 patients were alive and had normal AFP levels. The 8 survivors had a median follow-up from therapy completion of 18.5months. Two patients who presented with extrapulmonary recurrence subsequently died of treatment refractory disease. CONCLUSIONS: This review supports surgical resection as a safe and, in the context of multimodal therapy, efficacious approach to manage HB patients who present with isolated pulmonary relapse. PMID- 26607969 TI - Should we question early feminizing genitoplasty for patients with congenital adrenal hyperplasia and XX karyotype? AB - BACKGROUND: There is a wide difference of opinion between the medical-surgical community and advocacy group regarding Disorders of Sexual Development (DSD) secondary to congenital adrenal hyperplasia (CAH) being ranked in the intersex category. This rupture is even more evident when the issue of genitoplasty is brought up. For physicians it is obvious and unequivocal that a person with CAH and an XX karyotype has a female gender identity, whereas associations tend to rank persons with CAH in the intersex category and advocate holding-off on surgical management. MATERIAL/METHODS: A retrospective case study vs. control group, spanning over 40years, included 21 patients who were treated in 3 different centers. Each patient and their parents were contacted independently and interviewed regarding interpersonal relationships, psychological impact of genitoplasty, gender identity and opinion on optimal care management for this disorder. Three couples controls (parent-child) per CAH patients were used and matched according to age, sex assigned at birth and ethnic origin. RESULTS: Sex assigned at birth seemed to concord with the gender identity perceived by the patients in 85.7% of cases. In fact, 89.7% of patients and 100% of parents felt that feminizing genitoplasty should be performed within the first year of life. There is however a significant difference compared to controls who felt that surgical management should occur later on in life. No difference was highlighted during childhood regarding parents-child relationships or social integration. However, during adolescence, the parents-child relationship tended to be significantly more painful for the CAH group. Integrating their parenting role was significantly harder for patients in the CAH-DSD group. In the population of CAH-DSD patients who had genitoplasty the level of sexual fulfillment was not lower to the one reported by the control group. CONCLUSION: Female sex assignment seems legitimate according to this study and the development of gender identity in these patients matches the sex assigned at birth. Resolving early on the adequacy of the genital anatomy with the sex assigned is promoted by patients as well as their parents. Proper psychomotor development and sexual satisfaction underline the absence of complications related to the surgical technique and the relevance of early surgical management. PMID- 26607970 TI - Assessment and comparison of fecal continence in children following primary posterior sagittal anorectoplasty and abdominoperineal pull through for anorectal anomaly using clinical scoring and MRI. AB - INTRODUCTION: We aimed to compare and contrast these main surgical procedures for ARM in terms of structural outcome through pelvic MRI & functional outcome through Kelly's scoring. MATERIAL AND METHOD: A prospective study was conducted from August 2011 to July 2013 including all the cases of ARM managed in single stage (operated by one surgeon, first author) since 1995 that came for follow up at age of 3 years or more. Patients were divided in three groups: Group 8.A, PSARP (60 patients); Group B, Abdomino-PSARP (40 patients); and Group C, APPT (40 patients). The functional assessment of anal continence was carried out at the age of 3years or more using Kelly's method. Structural assessment was done by 1.5 T Magnetic Resonance Imaging (MRI). RESULTS: In 24 patients with rectobulbar fistula, 71.5% of Group A patients had good continence. In 50 patients with rectoprostatic fistula, 73.7% of Group A, 70% of group B and only 36% of Group C had good outcomes. Better development of each muscle was associated with better outcomes in terms of anal continence (P=0.001). CONCLUSION: There is better outcome with PSARP and Abdomino-PSARP in patients with rectobulbar and rectoprostatic fistula. MRI is a valuable modality for postoperative structural analysis of patients with ARM and is also useful for predicting the long term functional outcome of these cases. PMID- 26607971 TI - Tyrosinase immobilized on a hydrophobic membrane. AB - Polyvinylidene fluoride (PVDF) membrane surfaces were ad hoc functionalized chemically to make them suitable for enzymatic immobilization. The process was performed by grafting the membrane surface with 1,4-diaminobutane and subsequently by activating it with glutarhaldehyde. The chemico-physical properties of the original PVDF membrane and of the modified membranes were studied by infrared spectroscopy, scanning electron microscopy, and static contact angle measurements. The activated membranes were used as a support for covalent immobilization of tyrosinase. The activity of free and immobilized enzyme was studied and compared. The experimental data showing the specific activity of the immobilized enzyme are similar to the value obtained with the free one. This means that the immobilization procedure did not alter the catalytic properties of the tyrosinase. In addition, the surface modification of the PVDF made it a promising material to use in enzyme or biomolecule immobilization processes. PMID- 26607972 TI - S-sulfhydration as a cellular redox regulation. AB - For many years reactive oxygen and nitrogen species (ROS and RNS) have been recognized as key messengers in the process of thiol-based redox regulation. Relatively recently, literature reports began to mention reactive sulfur species (RSS) and their role in thiol regulation. This review is focused on biogenesis and biological properties of RSS, including: hydropersulfides, polysulfides and hydrogen sulfide (H2S). Based on the most up-to-date literature data, the paper presents biological significance of S-sulfhydration process. In this reaction, sulfane sulfur is transferred to the-SH groups forming hydropersulfides. Protein cysteine residues, called 'redox switches' are susceptible to such reversible modifications. In line with the most recent reports, it was emphasized that sulfane sulfur-containing compounds (mainly hydrogen persulfides and polysulfides) are real and better mediators of S-sulfhydration-based signalling than H2S. We also overviewed proteins participating in the formation and transport of RSS and in mitochondrial H2S oxidation. In addition, we reviewed many reports about proteins unrelated to sulfur metabolism which are modified by S-sulfhydration that influences their catalytic activity. We also addressed the problem of the regulatory function of S-sulfhydration reaction in the activation of KATP channels (vasorelaxant) and transcription factors (e.g. NFkappaB) as well as in the mechanism of therapeutic action of garlic-derived sulfur compounds. Some aspects of comparison between RNS and RSS are also discussed in this review. PMID- 26607974 TI - Beneficial Immune Effects of Myeloid-Related Proteins in Kidney Transplant Rejection. AB - Acute rejection is a risk factor for inferior long-term kidney transplant survival. Although T cell immunity is considered the main effector in clinical acute rejection, the role of myeloid cells is less clear. Expression of S100 calcium-binding protein A8 (S100A8) and S100A9 was evaluated in 303 biopsies before and after transplantation from 190 patients. In two independent cohorts of patients with acute rejection (n = 98 and n = 11; mostly cellular rejections), high expression of S100 calcium-binding protein A8 (S100A8) and A9 (S100A9) was related to improved graft outcome. Mechanisms of action of the S100 molecules were investigated. In the graft and peripheral blood cells, S100A8 and S100A9 expression correlated with myeloid-derived suppressor markers. In line with this finding, recombinant S100A8 and S100A9 proteins inhibited maturation and the allogeneic T cell stimulatory capacity of dendritic cells. S100A9 enhanced the production of reactive oxygen species by macrophages, which suppressed T cell activity at low concentrations in the form of hydrogen peroxide. Intragraft S100A8 and S100A9 expression linked to reduced expression of T cell immunity and tissue injury markers and higher expression of immune regulatory molecules. This study sheds new light on the importance of myeloid cell subsets in directing the outcome of T cell-mediated acute rejection. PMID- 26607975 TI - Predicting pre-eclampsia. PMID- 26607973 TI - Calorie restriction as an intervention in ageing. AB - Ageing causes loss of function in tissues and organs, is accompanied by a chronic inflammatory process and affects life- and healthspan. Calorie restriction (CR) is a non-genetic intervention that prevents age-associated diseases and extends longevity in most of the animal models studied so far. CR produces a pleiotropic effect and improves multiple metabolic pathways, generating benefits to the whole organism. Among the effects of CR, modulation of mitochondrial activity and a decrease in oxidative damage are two of the hallmarks. Oxidative damage is reduced by the induction of endogenous antioxidant systems and modulation of the peroxidability index in cell membranes. Mitochondrial activity changes are regulated by inhibition of IGF-1 and Target of Rapamycin (TOR)-dependent activities and activation of AMP-dependent kinase (AMPK) and the sirtuin family of proteins. The activity of PGC-1alpha and FoxO is regulated by these systems and is involved in mitochondria biogenesis, oxidative metabolism activity and mitochondrial turnover. The use of mimetics and the regulation of common factors have demonstrated that these molecular pathways are essential to explain the effect of CR in the organism. Finally, the anti-inflammatory effect of CR is an interesting emerging factor to be taken into consideration. In the present revision we focus on the general effect of CR and other mimetics in longevity, focusing especially on the cardiovascular system and skeletal muscle. PMID- 26607976 TI - The Evolutionary Basis of Honor Cultures. AB - Around the globe, people fight for their honor, even if it means sacrificing their lives. This is puzzling from an evolutionary perspective, and little is known about the conditions under which honor cultures evolve. We implemented an agent-based model of honor, and our simulations showed that the reliability of institutions and toughness of the environment are crucial conditions for the evolution of honor cultures. Honor cultures survive when the effectiveness of the authorities is low, even in very tough environments. Moreover, the results show that honor cultures and aggressive cultures are mutually dependent in what resembles a predator-prey relationship described in the renowned Lotka-Volterra model. Both cultures are eliminated when institutions are reliable. These results have implications for understanding conflict throughout the world, where Western based strategies are exported, often unsuccessfully, to contexts of weak institutional authority wherein honor-based strategies have been critical for survival. PMID- 26607977 TI - A prospective study of nomogram-based adaptation of prostate radiotherapy target volumes. AB - BACKGROUND: A prospective clinical trial was conducted to evaluate the feasibility of a novel approach to the treatment of patients with high risk prostate cancer (HRPC) through the use of a nomogram to tailor radiotherapy target volumes. METHODS: Twenty seven subjects with HRPC were treated with a mildly hypofractionated radiotherapy regimen using image-guided IMRT technique between Jun/2013-Jan/2015. A set of validated prognostic factors were inputted into the Memorial-Sloan-Kettering Cancer Center (MSKCC) prostate cancer nomogram to estimate risk of loco-regional spread (LRS). The nomogram risk estimates for extra-capsular extension (ECE), seminal vesicles involvement (SVI), and pelvic lymph nodes involvement (LNI) were used to adapt radiotherapy treatment volumes based on a risk threshold of >=15 % in all cases. A planning guide was used to delineate target volumes and organs at risk (OAR). Up to three dose levels were administered over 28 fractions; 70Gy for gross disease in the prostate +/- seminal vesicles (2.5Gy/fraction), 61.6Gy for subclinical peri-prostatic disease (2.2Gy/fraction) and 50.4Gy to pelvic nodes (1.8Gy/fraction). Data regarding protocol adherence, nomogram use, radiotherapy dose distribution, and acute toxicity were collected. RESULTS: Nomogram use 100 % of patients were treated for ECE, 88.9 % for SVI, and 70.4 % for LNI. The three areas at risk of LRS were appropriately treated according to the study protocol in 98.8 % cases. The MSKCC nomogram estimates for LRS differed significantly between the time of recruitment and analysis. Contouring protocol compliance Compliance with the trial contouring protocol for up to seven target volumes was 93.0 % (159/171). Compliance with protocol for small bowel contouring was poor (59.3 %). Dose constraints compliance Compliance with dose constraints for target volumes was 97.4 % (191/196). Compliance with dose constraints for OAR was 88.2 % (285/323). Acute toxicity There were no grade 3 acute toxicities observed. 20/27 (74.1 %) and 6/27 (22.2 %) patients experienced a grade 2 genitourinary and gastrointestinal toxicity respectively. CONCLUSIONS: We have demonstrated the feasibility of this novel risk-adapted radiation treatment protocol for HRPC. This study has identified key learning points regarding this approach, including the importance of standardization and updating of risk quantification tools, and the utility of an observer to verify their correct use. TRIAL REGISTRATION: ClincialTrials.gov identifier NCT01418040 . Hunter New England Human Research Ethics Committee (HNEHREC) reference number 12/08/15/4.02. PMID- 26607979 TI - Detection of Carbapenemase Production in a Collection of Enterobacteriaceae with Characterized Resistance Mechanisms from Clinical and Environmental Origins by Use of Both Carba NP and Blue-Carba Tests. AB - Rapid-screening methods to confirm the presence of resistance mechanisms in multidrug-resistant bacteria are currently recommended. Carba NP and Blue-Carba tests were evaluated in carbapenemase-producing Enterobacteriaceae from hospital (n = 102) and environmental (n = 57) origins for detecting the different molecular classes among them. Both methods showed to be fast and cost-effective, with high sensitivity (98% to 100%) and specificity (100%), and may be easily introduced in the routine laboratory. PMID- 26607978 TI - Prospective Whole-Genome Sequencing Enhances National Surveillance of Listeria monocytogenes. AB - Whole-genome sequencing (WGS) has emerged as a powerful tool for comparing bacterial isolates in outbreak detection and investigation. Here we demonstrate that WGS performed prospectively for national epidemiologic surveillance of Listeria monocytogenes has the capacity to be superior to our current approaches using pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), multilocus variable-number tandem-repeat analysis (MLVA), binary typing, and serotyping. Initially 423 L. monocytogenes isolates underwent WGS, and comparisons uncovered a diverse genetic population structure derived from three distinct lineages. MLST, binary typing, and serotyping results inferred in silico from the WGS data were highly concordant (>99%) with laboratory typing performed in parallel. However, WGS was able to identify distinct nested clusters within groups of isolates that were otherwise indistinguishable using our current typing methods. Routine WGS was then used for prospective epidemiologic surveillance on a further 97 L. monocytogenes isolates over a 12-month period, which provided a greater level of discrimination than that of conventional typing for inferring linkage to point source outbreaks. A risk-based alert system based on WGS similarity was used to inform epidemiologists required to act on the data. Our experience shows that WGS can be adopted for prospective L. monocytogenes surveillance and investigated for other pathogens relevant to public health. PMID- 26607980 TI - Comparative Evaluation of Inoculation of Urine Samples with the Copan WASP and BD Kiestra InoqulA Instruments. AB - This study evaluated the quantitative results from and quality of the inoculation patterns of urine specimens produced by two automated instruments, the Copan WASP and the BD InoqulA. Five hundred twenty-six urine samples submitted in 10-ml canisters containing boric acid were processed within 30 min on an InoqulA instrument plating 10 MUl of specimen, and on two WASP instruments, one plating 1 MUl of specimen (WASP-1), and the second plating 10 MUl of WASP (WASP-10). All samples were incubated, analyzed, and digitally imaged using the BD Kiestra total lab automation system. The results were evaluated using a quantitative protocol and assessed for the presence or absence of >=5 distinct colonies. Separate studies were conducted using quality control (QC) organisms to determine the relative accuracy of WASP-1, WASP-10, and InoqulA instruments compared to the results obtained with a calibrated pipette. The results with QC organisms were calculated as the ratios of the counts of the automated instruments divided by the counts for the calibrated pipette (the gold standard method). The ratios for the InoqulA instrument were closest to 1.0, with the smallest standard deviations indicating that compared to a calibrated pipette, the InoqulA results were more accurate than those with the WASP instrument. For clinical samples, the WASP instruments produced higher colony counts and more commensals than the InoqulA instrument, with differences most notable for WASP-1. The InoqulA instrument was significantly better at dispersing organisms with counts of >=10(5) bacteria/ml of urine than were the WASP-1 and WASP-10 instruments (P < 0.05). Our results suggest that the InoqulA quantitative results are more accurate than the WASP results, and, moreover, the number of isolated colonies produced by the InoqulA instrument was significantly greater than that produced by the WASP instrument. PMID- 26607981 TI - Improved Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS)-Based Identification of Mycobacterium spp. by Use of a Novel Two-Step Cell Disruption Preparatory Technique. PMID- 26607982 TI - BioFire FilmArray Respiratory Panel for Detection of Enterovirus D68. AB - During the enterovirus D68 (EV-D68) outbreak of 2014, the BioFire FilmArray (FA) respiratory panel was used to detect rhinovirus/enterovirus in respiratory specimens; suspected EV-D68-positive specimens were sent to CDC for confirmation. Positive rhinovirus/enterovirus FA targets revealed patterns loosely associated with EV-D68 that may be useful for confirmation triaging. PMID- 26607983 TI - Evaluation of an Immunochromatographic Lateral Flow Assay (OXA-48 K-SeT) for Rapid Detection of OXA-48-Like Carbapenemases in Enterobacteriaceae. AB - We evaluated an immunochromatographic lateral flow assay to detect OXA-48-like carbapenemases (OXA-48 K-SeT) in Enterobacteriaceae (n = 82). One hundred percent sensitivity and specificity were observed using bacteria recovered from both solid medium and spiked blood culture bottles, and the results were obtained in <10 min. PMID- 26607984 TI - Use of an Enrichment Broth Improves Detection of Extended-Spectrum-Beta-Lactamase Producing Enterobacteriaceae in Clinical Stool Samples. AB - This study evaluated the impact of preenrichment on the detection of extended spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) in clinical stool samples. ESBL-E were detected in 41 of 343 patients (12.0%). As 31.7% of the ESBL E carriers were identified by preenrichment, only this additional diagnostic step significantly improved the detection of ESBL-E. PMID- 26607985 TI - Agreement of Direct Antifungal Susceptibility Testing from Positive Blood Culture Bottles with the Conventional Method for Candida Species. AB - Early availability of antifungal susceptibilities can ensure timely institution of targeted therapy in candidemia, which can improve patient outcomes. This study prospectively determines the agreement between the results of direct testing of antifungal susceptibilities from blood culture bottles by disk diffusion and Etest and the results of standardized susceptibility testing methods; direct testing would allow susceptibility results to be available 1 to 2 days earlier. A total of 104 blood cultures with different Candida species (28% C. albicans, 27% C. parapsilosis, 26% C. tropicalis, etc.) were evaluated between January 2012 and May 2013 for agreement of fluconazole, voriconazole, and amphotericin B susceptibility results by disk diffusion. Agreement in MICs obtained by Etest was determined for fluconazole (21 isolates), voriconazole (28 isolates), amphotericin (29 isolates), and caspofungin (29 isolates). The kappa scores for categorical agreement were highest for fluconazole by disk diffusion (0.902, standard error [SE] = 0.076) and Etest (1.00, SE = 0.218) and for amphotericin B by disk diffusion (1.00, SE = 0.098). The Pearson correlation (r) of zone diameters was strongest for fluconazole (0.69) and amphotericin (0.70) and moderate for voriconazole (0.60), and the Pearson correlation of MICs was strongest for fluconazole (0.94) and caspofungin (0.88). However, the moderate correlation of amphotericin MICs with zone diameters (-0.42) precludes the use of amphotericin B disk diffusion for susceptibility testing. There were no very major errors; however, there were 1 (1%) major and 5 (4.8%) minor errors with disk diffusion and 4 (13.3%) minor errors with Etest. Thus, antifungal disk diffusion directly from blood culture bottles is a rapid and easy method for fluconazole and voriconazole susceptibility testing for timely tailoring of candidemia therapy. PMID- 26607986 TI - Performance of the Cryptococcal Antigen Lateral Flow Assay in Non-HIV-Related Cryptococcosis. AB - The cryptococcal antigen lateral flow assay (CrAg LFA) was evaluated for the diagnosis of cryptococcosis in HIV-negative patients. The sensitivity was excellent, suggesting that this assay can replace conventional testing based on latex agglutination (LA). CrAg LFA and LA titers were correlated but were not directly comparable, with implications for conversion between assays. PMID- 26607987 TI - Epidemiologic and Genotypic Review of Carbapenemase-Producing Organisms in British Columbia, Canada, between 2008 and 2014. AB - Carbapenemase-producing organisms (CPOs) are a serious emerging problem for health care facilities worldwide. Owing to their resistance to most antimicrobial therapies, CPOs are difficult to treat and pose a challenge for infection prevention and control. Since 2010, lab-based surveillance for CPOs and PCR-based testing were implemented in British Columbia (BC), Canada. A review of CPOs in BC from 2008 to March 2014 was done to characterize the resistance mechanisms and possible clonal strain transmission and to compare pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and plasmid restriction fragment length polymorphism (RFLP) as molecular typing tools. During this study period, a total of 177 CPO cases were identified. Patient demographics and travel history were reviewed, and a descriptive analysis was carried out. PFGE profiles, MLST, and plasmid RFLP analysis for a subset of Escherichia coli, Klebsiella pneumoniae, and Enterobacter species isolates were obtained and analyzed. Our findings demonstrate that CPOs have been increasing in number in BC over time, from 1 isolate/year retrospectively identified in 2008 and 2009 to 82 isolates in 2013 and 30 isolates in the first quarter of 2014. Overall, K. pneumoniae isolates lack clonality, although some seemingly related clusters have been found. Plasmid analysis showed evidence of the spread of plasmids carrying carbapenemase-encoding genes between the examined isolates. Analysis of Enterobacter cloacae isolates revealed a more clonal nature of these CPOs in BC. The presence of related clusters provides evidence of interpatient organism transmission both within and between institutions. Although in our study, NDM harboring E. cloacae isolates appeared to spread clonally, the spread of carbapenem resistance in K. pneumoniae seems to be plasmid mediated. PMID- 26607988 TI - Evaluation of Oxacillin and Cefoxitin Disk and MIC Breakpoints for Prediction of Methicillin Resistance in Human and Veterinary Isolates of Staphylococcus intermedius Group. AB - Staphylococcus pseudintermedius is a coagulase-positive species that colonizes the nares and anal mucosa of healthy dogs and cats. Human infections with S. pseudintermedius range in severity from bite wounds and rhinosinusitis to endocarditis; historically, these infections were thought to be uncommon, but new laboratory methods suggest that their true incidence is underreported. Oxacillin and cefoxitin disk and MIC tests were evaluated for the detection of mecA- or mecC-mediated methicillin resistance in 115 human and animal isolates of the Staphylococcus intermedius group (SIG), including 111 Staphylococcus pseudintermediusand 4 Staphylococcus delphini isolates, 37 of which were mecA positive. The disk and MIC breakpoints evaluated included the Clinical and Laboratory Standards Institute (CLSI) M100-S25 Staphylococcus aureus/Staphylococcus lugdunensis oxacillin MIC breakpoints and cefoxitin disk and MIC breakpoints, the CLSI M100-S25 coagulase-negative Staphylococcus (CoNS) oxacillin MIC breakpoint and cefoxitin disk breakpoint, the CLSI VET01-S2 S. pseudintermedius oxacillin MIC and disk breakpoints, and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) S. pseudintermedius cefoxitin disk breakpoint. The oxacillin results interpreted by the VET01-S2 (disk and MIC) and M100-S25 CoNS (MIC) breakpoints agreed with the results of mecA/mecC PCR for all isolates, with the exception of one false-resistant result (1.3% of mecA/mecC PCR-negative isolates). In contrast, cefoxitin tests performed poorly, ranging from 3 to 89% false susceptibility (very major errors) and 0 to 48% false resistance (major errors). BD Phoenix, bioMerieux Vitek 2, and Beckman Coulter MicroScan commercial automated susceptibility test panel oxacillin MIC results were also evaluated and demonstrated >95% categorical agreement with mecA/mecC PCR results if interpreted by using the M100-S25 CoNS breakpoint. The Alere penicillin-binding protein 2a test accurately detected all mecA-positive isolates, although for four isolates, cefoxitin induction was required prior to testing. These data demonstrate that the cefoxitin surrogate test does not reliably detect the presence of mecA in S. pseudintermedius isolates and that laboratories should perform oxacillin disk or MIC tests of these isolates when they are encountered. PMID- 26607989 TI - Giant barocaloric effects at low pressure in ferrielectric ammonium sulphate. AB - Caloric effects are currently under intense study due to the prospect of environment-friendly cooling applications. Most of the research is centred on large magnetocaloric effects and large electrocaloric effects, but the former require large magnetic fields that are challenging to generate economically and the latter require large electric fields that can only be applied without breakdown in thin samples. Here we use small changes in hydrostatic pressure to drive giant inverse barocaloric effects near the ferrielectric phase transition in ammonium sulphate. We find barocaloric effects and strengths that exceed those previously observed near magnetostructural phase transitions in magnetic materials. Our findings should therefore inspire the discovery of giant barocaloric effects in a wide range of unexplored ferroelectric materials, ultimately leading to barocaloric cooling devices. PMID- 26607990 TI - The detail of the en bloc technique and prognosis of spleen-preserving laparoscopic distal pancreatectomy for pancreatic cancer. AB - BACKGROUND: Although laparoscopic spleen-preserving distal pancreatectomy surgery is more and more popular, the reports about the en bloc technique used for pancreatic cancer were still rare. The aim of our study was to illustrate the detail of the spleen-preserving en bloc technique as well as the short-term and long-term outcomes. METHODS: The detail of the en bloc technique with pictures was described. The prognosis of the successive 23 cases that underwent the laparoscopic distal pancreatectomy (LDP) surgery was evaluated. RESULTS: There were 17 cases that underwent spleen-preserving LDP while six cases underwent spleen-resecting LDP. The average surgery time was 203 +/- 54 min, and the average blood loss volume was 208 +/- 264 ml; one case transferred to open surgery because of severe adhesion. The complication rate was 47 % (n = 8) shortly after surgery. Pancreatic fistula rate was 41 % (n = 7). No lethal case occurred. The average diameter of the tumor was 32 +/- 12 mm. The average number of the lymph nodes obtained was 19.8 +/- 9.3. All the cutting edges were negative. Survival rates of the patient after 1, 3, and 5 years are 64.7, 52.9, and 41.2 %, respectively. These records showed no statistical significance compared with spleen-resecting LDP and open distal pancreatectomy (ODP) surgeries. CONCLUSIONS: The en bloc spleen-preserving LDP can be performed by experienced surgeons. This surgery has good short-term and long-term outcomes. PMID- 26607991 TI - An Experimental and Theoretical Investigation on Pentacoordinated Cobalt(III) Complexes with an Intermediate S=1 Spin State: How Halide Ligands Affect their Magnetic Anisotropy. AB - Understanding the factors that control the magnitude and symmetry of magnetic anisotropy should facilitate the rational design of mononuclear metal complexes in the quest for single-molecule magnets (SMMs), based on a single metal ion, with high blocking temperatures and large energy barriers. The best strategy is to define magnetostructural correlations through the investigation of a series of metal complexes. It has been demonstrated that the main contribution to the magnetic anisotropy arises from the spin-orbit coupling (SOC) effect in metal-ion based systems, so current studies focus particularly on the use of both ligands and metal ions possessing a large SOC. In this context, we report a unique series of halide Co(III) complexes, [CoL(X)], with X=Cl, Br, I (CoX) and L=2,2'-(2,2' bipyridine-6,6'-diyl)bis(1,1-diphenylethanethiolate), which possess a rare intermediate S=1 spin ground state. The S=1 Co(III) complexes are attractive species because they possess a remarkably large axial zero-field splitting (defined by D from the following Hamiltonian: H=DSz (2) ), as well as the halide ligands inducing large SOC constants. The single-crystal X-ray structures reveal that the CoBr and CoI complexes are isostructural with the previously described CoCl complex. Their coordination sphere displays a distorted pentacoordinated square pyramidal geometry, with the halide located in the Co(III) axial position. Large positive D values of 35, 26, and 18 cm(-1) are found for CoCl, CoBr, and CoI, respectively, through analysis of the magnetic susceptibility data as a function of temperature. To rationalize this trend, theoretical calculations based on both density functional theory (DFT) and complete active space self consistent field (CASSCF) methods are performed successfully. Both the sign and magnitude of D are predicted remarkably well by these theoretical approaches. The DFT calculations also show that the resulting D values originate from a balance of several contributions, and that many factors, including differences in their structural properties and in the contribution of the halide, should be taken into account to explain the trend of D in this series of complexes. PMID- 26607992 TI - A goal-directed woodwork group for men in community rehabilitation--A pilot project. AB - AIMS: Male clients who attend community rehabilitation programs often have low engagement in meaningful occupations and thus suffer a disconnect with their community. The primary aim of this mixed methods study was to explore the feasibility of using a therapeutic woodwork group to engage male clients in community rehabilitation. METHOD: In the context of a community rehabilitation setting, fourteen clients attended an 8-week woodwork group to engage in meaningful projects developed with an occupational therapist to achieve specific goals. The group also aimed to encourage male peer support and interaction in an outpatient group setting. Clients identified three rehabilitation goals which guided their rehabilitation intervention. Goal achievement was rated pre- and post-group using the Goal Attainment Scale; one of two Quality of Life scales were administered to measure change in self-reported quality of life. Participants were interviewed pre- and post-group to measure woodwork experience and the group process. RESULTS: Results from the pilot project indicate that 85.7% of clients attained their expected level of goal achievement or higher on set rehabilitation goals. Consistent positive feedback was received from those who attended the group, particularly in the area of skill development and socialisation, although patients reported minimal changes in quality of life from baseline to end-of-group (P > 0.05). CONCLUSION: There remains an unmet need for meaningful engagement for men in the community who are not currently engaged in paid work. Community-based occupational therapy programs have the opportunity to play an important role in engaging clients in meaningful occupations, including woodwork, which was shown to increase socialisation and lead to goal attainment in our small sample. Future research should explore if rehabilitation woodwork groups can assist people to transition to participate in community-based Men's Sheds. PMID- 26607993 TI - Can insecticide-treated netting provide protection for Equids from Culicoides biting midges in the United Kingdom? AB - BACKGROUND: Biting midges of the genus Culicoides Latreille, 1809 (Diptera: Ceratopogonidae) cause a significant biting nuisance to equines and are responsible for the biological transmission of African horse sickness virus (AHSV). While currently restricted in distribution to sub-Saharan Africa, AHSV has a history of emergence into southern Europe and causes one of the most lethal diseases of horses and other species of Equidae. In the event of an outbreak of AHSV, the use of insecticide treated nets (ITNs) to screen equine accomodation is recommended by competent authorities including the Office International des Epizooties (OIE) in order to reduce vector-host contact. METHODS: Seven commercially avaliable pyrethroid insecticides and three repellent compounds, all of which are licensed for amateur use, were assessed in modified World Health Organization (WHO) cone bioassay trials in the laboratory using a colony line of Culicoides nubeculosus (Meigen), 1830. Two field trials were subsequently conducted to test the efficiency of treated net screens in preventing entry of Culicoides. RESULTS: A formulation of cypermethrin (0.15 % w/w) and pyrethrins (0.2 % w/w) (Tri-Tec 14(r), LS Sales (Farnham) Ltd, Bloxham, UK) applied to black polyvinyl-coated polyester insect screen (1.6 mm aperture; 1.6 mm thickness) inflicted 100 % mortality on batches of C. nubeculosus following a three minute exposure in the WHO cone bioassays at 1, 7 and 14 days post-treatment. Tri-Tec 14(r) outperformed all other treatments tested and was subsequently selected for use in field trials. The first trial demonstrated that treated screens placed around an ultraviolet light-suction trap entirely prevented Culicoides being collected, despite their collection in identical traps with untreated screening or no screening. The second field trial examined entry of Culicoides into stables containing horses and found that while the insecticide treated screens reduced entry substantially, there was still a small risk of exposure to biting. CONCLUSIONS: Screened stables can be utilised as part of an integrated control program in the event of an AHSV outbreak in order to reduce vector-host contact and may also be applicable to protection of horses from Culicoides during transport. PMID- 26607994 TI - Platform for high-throughput antibody selection using synthetically-designed antibody libraries. AB - Synthetic humanized antibody libraries are frequently generated by random incorporation of changes at multiple positions in the antibody hypervariable regions. Although these libraries have very large theoretical diversities (>10(20)), the practical diversity that can be achieved by transformation of Escherichia coli is limited to about 10(10). To constrain the practical diversity to sequences that more closely mimic the diversity of natural human antibodies, we generated a scFv phage library using entirely pre-defined complementarity determining regions (CDR). We have used this library to select for novel antibodies against four human protein targets and demonstrate that identification of enriched sequences at each of the six CDRs in early selection rounds can be used to reconstruct a consensus antibody with selectivity for the target. PMID- 26607995 TI - Effect of preoperative chemotherapy on survival of patients with upper urinary tract urothelial carcinoma clinically involving regional lymph nodes. AB - OBJECTIVES: To determine the effect of preoperative chemotherapy on survival in patients with upper urinary tract urothelial carcinoma clinically involving regional lymph nodes. METHODS: We retrospectively analyzed 55 consecutive patients who received radical nephroureterectomy with or without preoperative chemotherapy for upper urinary tract urothelial carcinoma clinically involving regional lymph nodes at a single institution between January 1991 and December 2013. RESULTS: Median follow up was 18 months (range 2-193). Of 55 patients, 24 (43.6%) received preoperative chemotherapy (study group) and 31 (56.4%) underwent primary surgery (control group). Preoperative chemotherapy consisted of two to four cycles (median 3) of cisplatin-containing regimens. The fraction of patients with lower pathological T stage and N stage than clinical T stage and N stage was higher in the study group (29.2% and 54.2%) compared with the control group (3.2% and 16.1%; P = 0.013 and 0.010, respectively). The 5-year overall survival rate was significantly higher in the study group than in the control group (44.0% vs 12.9%, log-rank, P = 0.003). In multivariate analysis incorporating age at diagnosis, Eastern Cooperative Oncology Group Performance Status, clinical N stage and the number of removed lymph nodes, preoperative chemotherapy was a predictor of better overall survival (P = 0.047, HR 0.47, 95% CI 0.22-0.99). CONCLUSIONS: Preoperative chemotherapy might provide better survival outcomes in patients with upper urinary tract urothelial carcinoma clinically involving regional lymph nodes. PMID- 26607996 TI - A case report of urothelial carcinoma with combined micropapillary and plasmacytoid morphology in the urinary bladder. AB - A case of combined micropapillary and plasmacytoid urothelial carcinoma (UC) of the urinary bladder is presented for a 74-year-old male who was admitted to the hospital with gross hematuria and multifocal papillary bladder tumors. Abdominal computed tomography showed a large enhancing mass on the left lateral and anterior wall of the urinary bladder, which was highly suspicious for extravesicular extension and focal extension of the anterior lesion to the pubic bone. In voided urine, cancer cells were scattered as micropapillae or nests as well as single cells on the low power view. On a higher power view, micropapillae or nests were composed of pleomorphic, high grade tumor cells with an inverted nuclear arrangement and with acinar structures occasionally identified. Single cells were discohesive and large with a thick cytoplasm and eccentrically located nuclei. Histologically, the tumor from the resected bladder showed diffusely infiltrating micropapillae or nests with a surrounding halo and dense singly scattered plasmacytoid cells. Immunohistochemically, the cancer cells were positive for cytokeratin-7 and cytokeratin-20 but negative for S-100, leukocyte common antigen, and vimentin. At the time of radical cystectomy, severe adhesions and peritoneal metastases were found and the surgery was discontinued. The patient received systemic chemotherapy, but died of bladder cancer 14 months after surgery. PMID- 26607997 TI - Herbage intake and ruminal digestion of dairy cows grazed on perennial ryegrass pasture either in the morning or evening. AB - This study aimed to clarify diurnal fluctuations of herbage intake, ruminal fermentation of herbage carbohydrates and proteins, and digesta particulate weight in the rumen of grazing dairy cows. Six ruminally cannulated, non lactating dairy cows were grazed on perennial ryegrass/white clover pasture either in the morning (04.00 to 08.00 hours) or the evening (16.00 to 20.00 hours). Cows grazed in the evening spent more time (P < 0.01) and consumed more herbage (P < 0.01) compared with cows grazed in the morning. Higher (P < 0.05) daily mean concentrations of total volatile fatty acid, propionate and n-butyrate in rumen fluid were observed for cows grazed in the evening compared with cows grazed in the morning. Although cows grazed in the evening ingested more crude protein compared with cows grazed in the morning, no significant difference in NH3 -N concentration in rumen fluid was observed between them. The ratio of purine-derivative concentration to creatinine concentrations was higher (P < 0.01) in the urine of cows grazed in the evening than in cows grazed in the morning. These results clearly indicated that evening grazing was advantageous for dairy cows compared with morning grazing, in terms of ruminal fermentable energy intake and nitrogen utilization efficiency. PMID- 26607998 TI - Combined 17alpha-hydroxylase/17,20-lyase deficiency with short stature: case study. AB - BACKGROUNDS: 17alpha-hydroxylase/17,20-lyase deficiency (17-OHD) is an uncommon form of congenital adrenal hyperplasia. Most patients are tall owing to delayed closure of epiphyses as a result of deficiency of sex hormones. METHODS: We present a 17-OHD case with unusual short stature and reviewed related literature. RESULTS: A 17-year-old female patient presented with primary amenorrhea, hypertension, hypokalemia and hypergonadotropic hypogonadism (HH). Sequencing of the CYP17A1 gene identified a homozygous c.985_987delTACinsAA in exon 6 that confirmed the diagnosis of 17-OHD. However, her height (148 cm, height standard deviation score [HSDS] -2.28) was unusually low compared with that of other 17 OHD patients. Levels of growth hormone (GH) and insulin-like growth factor (IGF) 1 were normal, and the GH provocation test excluded the possibility of GH deficiency. She underwent glucocorticoid and sex-hormone replacement therapy, reaching a final height of 152 cm (HSDS -1.59). These data suggest that tall stature is not a requisite characteristic of 17-OHD. Further studies are needed to clarify the effects of sex hormone on linear bone growth (LBG) in 17-OHD patients. PMID- 26607999 TI - A systematic review of interventions on body image and disordered eating outcomes among women in midlife. AB - OBJECTIVE: Body dissatisfaction and disordered eating are widely recognized as issues that warrant attention among women in midlife, particularly the development and delivery of effective interventions. This article systematically reviews existing research on interventions among midlife women on body image and disordered eating outcomes, in order to inform intervention delivery and provide strategic directions for future research. METHOD: Fourteen electronic databases were searched for articles published between 1992 and 2015 that evaluated interventions with nonclinical samples of women (M age 35-55 years) in controlled trials with at least one body image measure. Data were extracted and evaluated, and the methodological quality of studies was assessed using the Cochrane Collaboration tool for assessing risk of bias. RESULTS: From 7,475 records identified, nine articles evaluating 11 interventions met the inclusion criteria. Seven interventions significantly improved body image at post-test (d's = 0.19 2.22), with significant improvements on disordered eating achieved by two of these interventions (d's = 0.90-1.72). Sustained improvements were achieved by three interventions that employed a multisession, therapeutically based, group intervention format; two with sustained body image and disordered eating improvements, and one with sustained body image improvements only (d's = 0.55 1.21; 2 weeks to 6 months). Methodological quality varied between studies. DISCUSSION: To date, three interventions have demonstrated sustained improvements and are indicated for practitioners aiming to improve body image and disordered eating among women in midlife. Replication and more rigorous randomised controlled trials are required to enhance the methodological quality of intervention studies in this field. PMID- 26608000 TI - Hospitalisations up to adulthood for children born with orofacial clefts. AB - AIM: The aim of this study was to compare hospital admissions from infancy to adulthood, between children born with orofacial clefts (OFC) and those without OFC. METHODS: The method used was a cohort study using record-linked administrative datasets. Participants included all children liveborn in Western Australia (WA) between 1980 and 2010 diagnosed with OFC, who were frequency matched by year of birth to randomly selected liveborn children without OFC. We calculated rate ratios (RR) of hospital admission, number and reason of admissions, cumulative length of stay, for each cleft type (cleft lip only (CLO), cleft lip and palate (CL+P), cleft palate only (CPO), no OFC) and by age period (infancy, pre-school, primary and high school ages, and early adulthood). RESULTS: Overall, 1396 children were diagnosed with an OFC and compared with 6566 children without OFC. Individuals born with OFC were up to three times more likely to be admitted to hospital, had more admissions and longer cumulative length of stay in all age periods. Children with OFC were also more likely to be admitted for ear and digestive system conditions (RR up to 30 and six times higher, respectively). Children with CL+P and CPO were more likely to be admitted for respiratory conditions (RR 1.3-2.0) and children with CPO were six times more likely to be admitted for care for other congenital anomalies. CONCLUSIONS: Throughout childhood, individuals born with OFC were more likely to be admitted, and had more hospitalisations than those without OFC. Children born with CL+P or CPO had a higher hospitalisation burden than children born with CLO. PMID- 26608001 TI - Prenatal stress and early-life exposure to fluoxetine have enduring effects on anxiety and hippocampal BDNF gene expression in adult male offspring. AB - With the growing use of selective serotonin reuptake inhibitor medications (SSRIs) for the treatment of depression during the perinatal period, questions have been raised about the longterm impact of these medications on development. We aimed to investigate how developmental SSRI exposure may alter affect-related behaviors and associated molecular processes in offspring using a rodent model of maternal stress and depression. For this purpose, prenatally stressed or non stressed male offspring were exposed to fluoxetine (5 mg/kg/day) or vehicle, via lactation, until weaning. Primary results show that postnatal fluoxetine exposure differentially altered anxiety-like behavior by increasing anxiety in non stressed offspring and decreasing anxiety in prenatally stressed offspring. In the hippocampus, developmental fluoxetine exposure decreased BDNF IV and TrkB mRNA expression. Prenatal stress alone also decreased escape behaviors and decreased hippocampal BDNF IV mRNA expression. These data provide important evidence for the long-term programming effects of early-life exposure to SSRIs on brain and behavior. PMID- 26608002 TI - Neurodevelopmental origins of bipolar disorder: iPSC models. AB - Bipolar disorder (BP) is a chronic neuropsychiatric condition characterized by pathological fluctuations in mood from mania to depression. Adoption, twin and family studies have consistently identified a significant hereditary component to BP, yet there is no clear genetic event or consistent neuropathology. BP has been suggested to have a developmental origin, although this hypothesis has been difficult to test since there are no viable neurons or glial cells to analyze, and research has relied largely on postmortem brain, behavioral and imaging studies, or has examined proxy tissues including saliva, olfactory epithelium and blood cells. Neurodevelopmental factors, particularly pathways related to nervous system development, cell migration, extracellular matrix, H3K4 methylation, and calcium signaling have been identified in large gene expression and GWAS studies as altered in BP. Recent advances in stem cell biology, particularly the ability to reprogram adult somatic tissues to a pluripotent state, now make it possible to interrogate these pathways in viable cell models. A number of induced pluripotent stem cell (iPSC) lines from BP patient and healthy control (C) individuals have been derived in several laboratories, and their ability to form cortical neurons examined. Early studies suggest differences in activity, calcium signaling, blocks to neuronal differentiation, and changes in neuronal, and possibly glial, lineage specification. Initial observations suggest that differentiation of BP patient-derived neurons to dorsal telencephalic derivatives may be impaired, possibly due to alterations in WNT, Hedgehog or Nodal pathway signaling. These investigations strongly support a developmental contribution to BP and identify novel pathways, mechanisms and opportunities for improved treatments. PMID- 26608003 TI - A fast and specific method to screen for intracellular amyloid inhibitors using bacterial model systems. AB - The aggregation of a large variety of amyloidogenic proteins is linked to the onset of devastating human disorders. Therefore, there is an urgent need for effective molecules able to modulate the aggregative properties of these polypeptides in their natural environment, in order to prevent, delay or halt the progression of such diseases. On the one hand, the complexity and cost of animal models make them inefficient at early stages of drug discovery, where large chemical libraries are usually screened. On the other hand, in vitro aggregation assays in aqueous solutions hardly reproduce (patho)physiological conditions. In this context, because the formation of insoluble aggregates in bacteria shares mechanistic and functional properties with amyloid self-assembly in higher organisms, they have emerged as a promising system to model aggregation in the cell. Here we show that bacteria provide a powerful and cost-effective system to screen for amyloid inhibitors using fluorescence spectroscopy and flow cytometry, thanks to the ability of the novel red fluorescent ProteoStat dye to detect specifically intracellular amyloid-like aggregates. We validated the approach using the Alzheimer's linked Abeta40 and Abeta42 peptides and tacrine- and huprine-based aggregation inhibitors. Overall, the present method bears the potential to replace classical in vitro anti-aggregation assays. PMID- 26608004 TI - Identification of a new alpha-2-macroglobulin: Multi-spectroscopic and isothermal titration calorimetry study. AB - A alpha2M homologue was isolated from sheep (Ovis aries) blood plasma, using a simple two-step procedure, ammonium sulphate fractionation and gel filtration chromatography. Sheep alpha2M was found to be a large tetrameric glycoprotein of 630 kDa with monomeric subunit of 133 kDa each. Each subunit of sheep alpha2M was found to be made up of two fragments of 102 and 31 kDa respectively. The proteinase inhibitor from sheep was found to have Stokes radius of 79A, which makes it much more compact than its human homologue. It entraps only 1 mol of trypsin per mole of inhibitor, like its caprine counterpart. The use of isothermal titration calorimetry has become gold standard for exploring thermodynamics of binding interactions. In this study, binding interaction of trypsin with alpha-2-macroglobulin is studied using ITC. The thermodynamic signatures--enthalpy change (DeltaH), entropy change (DeltaS) and Gibb's free energy change (DeltaG), along with number of binding sites (N) and affinity constant (K) are explored for alpha2M-trypsin binding for the first time for any known alpha2M molecule. The thermodynamics of proteinase-antiproteinase association suggests that trypsin-alpha2M interaction is enthalpy driven event. PMID- 26608005 TI - Asp577 mutations enhance the catalytic efficiency of cyclodextrin glycosyltransferase from Bacillus circulans. AB - The amino acid residue Asp 577 is located in calcium-binding site III (CaIII) of the cyclodextrin glycosyltransferase (EC 2.4.1.19, CGTase) from Bacillus circulans STB01. In the present study, the effects of replacing Asp577 with glycine, alanine, valine, leucine, and isoleucine on the catalytic efficiency of this CGTase were investigated. Two of these replacements, D577G and D577A, increased the beta-cyclization activity of CGTase. Kinetic studies showed that the Km values of D577G and D577A were 36.1% and 18.0% lower and the kcat/Km values were 43.9% and 23.0% higher than those of the wild-type enzyme, respectively. These mutations increased both the affinity of CGTase for maltodextrin and the catalytic efficiency of the cyclization reaction. Furthermore, although D577G and D577A only slightly enhanced beta-cyclodextrin production, compared with the wild-type enzyme, their higher beta-cyclization activities resulted in a significant reduction in the amount of mutant protein required during the cyclodextrin production process. Thus, the two mutants are more suitable for the industrial production of beta-cyclodextrin than the wild type enzyme. The enhancement of catalytic efficiency may be due to the smaller size of the glycine and alanine side chains, which may weaken the impact of this residue on CaIII. PMID- 26608006 TI - Studies of the plasticizing effect of different hydrophilic inorganic salts on starch/poly (vinyl alcohol) films. AB - The effects of different inorganic salts LiCl, MgCl2.6H2O, CaCl2, and AlCl3.6H2O on the crystalline, thermal, water vapor barrier, and tensile properties of starch/PVA films were studied. The high plasticizing efficiency of all these four inorganic salts for starch/PVA film was confirmed by the obtained results. These four salts all had a good compatibility with starch/PVA within the content of 15 wt% and starch/PVA became completely miscible with the addition of 15 wt% inorganic salts. All these four salts had a strong destroying effect on the crystals of starch and PVA. Among these four salts, AlCl3.6H2O had the largest negative effect on the thermal stability of starch/PVA and LiCl had the largest improving effect on the water sorption rate of starch/PVA film. On the whole MgCl2.6H2O and CaCl2 were the more suitable plasticizer for starch/PVA film among these four inorganic salts. With the addition of 15 wt% MgCl2.6H2O and CaCl2, the elongation at break of starch/PVA film could reach to 418.83% and 434.80%, respectively. PMID- 26608007 TI - Alginate-based bipolymeric-nanobioceramic composite matrices for sustained drug release. AB - Alginate-based bipolymeric-nanobioceramic composite matrices for sustained drug release were developed through incorporation of nano-hydroxyapatite [nHAp] powders within ionotropically-gelled calcium ion-induced alginate-poly (vinyl pyrrolidone) blends polymeric systems. nHAp powders were synthesized by precipitation technique using calcium hydroxide [Ca(OH)2] and orthophosphoric acid [H3PO4] as raw materials. The average particle size of these was synthesized. nHAp powders was found as 19.04 nm and used to prepare nHAp-alginate PVP beads containing DS. These beads exhibited drug entrapment efficiency (%) of 65.82+/-1.88 to 94.45+/-3.72% and average bead sizes of 0.98+/-0.07 to 1.23+/ 0.15 mm. These beads were characterized by scanning electron microscopy (SEM) and Fourier transform-infra red (FTIR) spectroscopy analyses. Various nHAp-alginate PVP beads containing DS exhibited prolonged sustained drug release and followed the Koresmeyer-Peppas model of drug release (R2=0.9908-0.9978) with non-Fickian release (anomalous transport) mechanism (n=0.73-0.84) for drug release over 8 h. PMID- 26608009 TI - A bridge over troubled water: Functional assessment of a myocardial bridge by Gili S Taha S, Omede P et al. PMID- 26608008 TI - Oral anticoagulant therapy and thrombosis. A case of failure of therapy with vitamin K antagonists. PMID- 26608010 TI - Non-sustained ventricular tachycardia in a pregnant woman with repaired Tetralogy of Fallot: A challenging case. PMID- 26608011 TI - Spinal cord stimulation: A potential therapeutic approach for post-myocardial infarction patients. PMID- 26608012 TI - Right heart/pulmonary circulation unit assessment during exercise, a need for a global view of the loop. PMID- 26608013 TI - Influenza virus infection, myocarditis, "myocarditis", and Takotsubo syndrome: A need for scrutiny. PMID- 26608014 TI - Is vasospasm overestimated in acute coronary syndromes presenting with non obstructive coronary artery disease? The case for intravascular imaging. PMID- 26608015 TI - Long distance walking man after a combination of percutaneous mitral annuloplasty and coronary revascularization. PMID- 26608016 TI - Galectin-3: A potential new target for upstream therapy of atrial fibrillation. PMID- 26608017 TI - K-wire assisted split-thickness skin graft harvesting from the anterior trunk. AB - Split thickness skin graft (STSG) harvesting from the anterior chest and abdominal wall skin is quite a difficult process. The main reason for the difficulty to perform this process is the unsuitable anatomic characteristics of the anterior trunk, such as irregular wavy-like surface over the ribs and lax abdominal wall skin resulting in collapse due to lack of adequate underneath supporting structures when a downward force is applied by the skin graft dermatome. Lower extremity and especially the thigh are generally chosen as the donor site where the STSGs are easily harvested from. However, extensive lower extremity burns, with or without other region burns, preclude harvesting auto STSGs from this invaluable anatomic site. We harvested K-wire assisted STSGs from the anterior chest and abdominal wall skin of 7 patients with lower extremity burns and also a patient that sustained motor vehicle collision. We encountered no problems in any of our patients both intra and postoperatively by using K-wire assisted STSG harvesting. All of the STSGs donor sites healed uneventfully without complications. In our opinion, K-wire assisted STSG harvesting must always be in the tool-box of any surgeon who deals with extensive burns with or without lower extremity burns and extensive traumas of lower extremities. PMID- 26608018 TI - [Opposition to health care in dementia: Pregabalin can be useful to facilitate the management]. PMID- 26608019 TI - Boerhaave's syndrome presenting as a mid-esophageal perforation associated with a right-sided pleural effusion. AB - There are few published case reports of Boerhaave's syndrome presenting as a mid esophageal perforation associated with a right-sided pleural effusion. We present an unusual case of spontaneous perforation of the mid-esophagus and discuss the surgical management and outcome. Our case underscores the importance of a meticulous diagnostic and therapeutic approach to the management of an often elusive and difficult disease process. PMID- 26608020 TI - Combined Endodontic Therapy and Intentional Replantation for the Treatment of Palatogingival Groove. AB - A palatogingival groove is an anatomic malformation that predisposes the involved tooth to a severe periodontal defect. When the condition is complicated by pulpal necrosis, affected teeth often present a dilemma in terms of diagnosis and treatment planning. In this report, we describe the case of a patient with a maxillary lateral incisor with a deep palatogingival groove extending to the root apex and severe periodontal destruction (local pocketing). Suggested treatment modalities included curettage of the affected tissues, elimination of the groove by grinding and/or sealing with a variety of filling materials, and surgical procedures. In this case, a combined treatment approach, involving both endodontic therapy and intentional replantation after restoration with a self etching flowable composite, resulted in periodontal healing and significant healing of the periradicular radiolucency at 12 months. In short, intentional replantation offers a predictable procedure and should be considered a viable treatment modality for the management of palatogingival grooves, especially for single-rooted teeth. PMID- 26608021 TI - Overnutrition during lactation leads to impairment in insulin signaling, up regulation of GLUT1 and increased mitochondrial carbohydrate oxidation in heart of weaned mice. AB - Several studies have demonstrated that overnutrition during early postnatal period can increase the long-term risk of developing obesity and cardiac disorders, yet the short-term effects of postnatal overfeeding in cardiac metabolism remains unknown. The aim of our study was to investigate the cardiac metabolism of weaned mice submitted to overnutrition during lactation, particularly as to mitochondrial function, substrate preference and insulin signaling. Postnatal overfeeding was induced by litter size reduction in mice at postnatal day 3. At 21 days of age (weaning), mice in the overfed group (OG) presented biometric and biochemical parameters of obesity, including increased body weight, visceral fat, liver weight and increased left ventricle weight/tibia length ratio; indicating cardiac hypertrophy, hyperglycemia, hyperinsulinemia and increased liver glycogen content compared to control group. In the heart, we detected impaired insulin signaling, mainly due to decreased IRbeta, pTyr-IRS1, PI3K, GLUT4 and pAkt/Akt and increased PTP1B, GLUT1 and pAMPKalpha/AMPKalpha content. Activities of lactate dehydrogenase and citrate synthase were increased, accompanied by enhanced carbohydrate oxidation, as observed by high-resolution respirometry. Moreover, OG hearts had lower CPT1, PPARalpha and increased UCP2 mRNA expression, associated with increased oxidative stress (4-HNE content), BAX/BCL2 ratio and cardiac fibrosis. Ultrastructural analysis of OG hearts demonstrated mild mitochondrial damage without alterations in OXPHOS complexes. In conclusion, overnutrition during early life induces short-term metabolic disturbances, impairment in heart insulin signaling, up-regulates GLUT-1 and switch cardiac fuel preference in juvenile mice. PMID- 26608022 TI - Medication use during pregnancy, gestational age and date of delivery: agreement between maternal self-reports and health database information in a cohort. AB - BACKGROUND: Health databases are a promising resource for epidemiological studies on medications safety during pregnancy. The reliability of information on medications exposure and pregnancy timing is a key methodological issue. This study (a) compared maternal self-reports and database information on medication use, gestational age, date of delivery; (b) quantified the degree of agreement between sources; (c) assessed predictors of agreement. METHODS: Pregnant women recruited in a prenatal clinic in Friuli Venezia Giulia (FVG) region, Italy, from 2007 to 2009, completed a questionnaire inquiring on medication use during pregnancy, gestational age and date of delivery. Redeemed prescriptions and birth certificate records were extracted from regional databases through record linkage. Percent agreement, Kappa coefficient, prevalence and bias-adjusted Kappa (PABAK) were calculated. Odds Ratio (OR), with 95% confidence interval (95% CI), of >= 1 agreement was calculated through unconditional logistic regression. RESULTS: The cohort included 767 women, 39.8% reported medication use, and 70.5% were dispensed at least one medication. Kappa and PABAK indicated almost perfect to substantial agreement for antihypertensive medications (Kappa 0.86, PABAK 0.99), thyroid hormones (0.88, 0.98), antiepileptic medications (1.00, 1.00), antithrombotic agents (0.70, 0.96). PABAK value was greater than Kappa for medications such as insulin (Kappa 0.50, PABAK 0.99), antihistamines for systemic use (0.50, 0.99), progestogens (0.28, 0.79), and antibiotics (0.12, 0.63). Adjusted OR was 0.48 (95% CI 0.26; 0.90) in ex- vs. never smokers, 0.64 (0.38; 1.08) in < high school vs. university, 1.55 (1.01; 2.37) in women with comorbidities, 2.25 (1.19; 4.26) in those aged 40+ vs. 30-34 years. Gestational age matched exactly in 85.2% and date of delivery in 99.5%. CONCLUSIONS: For selected medications used for chronic conditions, the agreement between self reports and dispensing data was high. For medications with low to very low prevalence of use, PABAK provides a more reliable measure of agreement. Maternal reports and dispensing data are complementary to each other to increase the reliability of information on the use of medications during pregnancy. Birth certificates provide reliable data on the timing of pregnancy. FVG health databases are a valuable source of data for pregnancy research. PMID- 26608023 TI - Low-frequency rTMS over the Parieto-frontal network during a sensorimotor task: The role of absolute beta power in the sensorimotor integration. AB - Several studies have demonstrated that Repetitive Transcranial Magnetic Stimulation (rTMS) promotes alterations in the Central Nervous System circuits and networks. The focus of the present study is to examine the absolute beta power patterns in the Parieto-frontal network. We hypothesize that rTMS alters the mechanisms of the sensorimotor integration process during a visuomotor task. Twelve young healthy volunteers performed a visuomotor task involving decision making recorded (Catch a ball in a free fall) by Electroencephalography. rTMS was applied on the Superior Parietal Cortex (SPC; Brodmann area [BA] 7) with low frequency (1 Hz - 15 min - 80% Resting Motor Threshold). For each Frontal and Parietal region, a two-way ANOVA was used to compare the absolute beta power before and after TMS for each condition of the study (Rest 1, Task and Rest 2). The results demonstrated interactions (TMS vs. Condition) for the Frontal electrodes: Fp1, Fp2 and F7 and an effect of TMS (before and after) for F4.The results for the Parietal region showed a main effect of Condition for the P3, PZ and P4 electrodes. Thus, our paradigm was useful to better understand the reorganization and neural plasticity mechanisms in the parieto-frontal network during the sensorimotor integration process. PMID- 26608024 TI - Corrections in saccade endpoints scale to the amplitude of target displacements in a double-step paradigm. AB - It is widely held that discrete goal-directed eye movements (saccades) are ballistic in nature because their durations are too short to allow for sensory based online correction. Recent studies, however, have provided evidence that saccadic endpoints can be mediated via online corrections. Specifically, it has been reported that saccade trajectories adapt to the eccentricity of an unexpectedly perturbed target location (i.e., target 'jump' paradigm). If saccades are subject to online correction mechanisms, then the magnitude of such changes should scale to the amplitude of the target jump. To test this hypothesis, saccadic endpoints for trials on which the target jumped one of three amplitudes (Small: 2.5 degrees , Medium: 5.0 degrees , and Large: 7.5 degrees ; i.e., Jump trials) immediately after saccade onset were compared with the endpoints of trials in which the target location did not change (i.e., Reference trials). Results showed that primary saccade endpoints for Jump trials were longer than for Reference trials. Importantly, the magnitude of this increase in endpoint scaled with the amplitude of the target jump. Thus, these results support emerging and coalescent evidence that saccade trajectories are subject to online corrections. PMID- 26608025 TI - Soluble RANKL expression in Lactococcus lactis and investigation of its potential as an oral vaccine adjuvant. AB - BACKGROUND: To initiate mucosal immune responses, antigens in the intestinal lumen must be transported into gut-associated lymphoid tissue through M cells. Recently, it has been increasingly recognized that receptor activator of NF-kB ligand (RANKL) controls M cell differentiation by interacting with RANK expressed on the sub-epithelium of Peyer's patches. In this study, we increased the number of M cells using soluble RANKL (sRANKL) as a potent mucosal adjuvant. RESULTS: For efficient oral delivery of sRANKL, we constructed recombinant Lactococcus lactis (L. lactis) IL1403 secreting sRANKL (sRANKL-LAB). The biological activity of recombinant sRANKL was confirmed by observing RANK-RANKL signaling in vitro. M cell development in response to oral administration of recombinant L. lactis was determined by 1.51-fold higher immunohistochemical expression of M cell marker GP 2, compared to that of non-treatment group. In addition, an adjuvant effect of sRANKL was examined by immunization of mice with M-BmpB as a model antigen after treatment with sRANKL-LAB. Compared with the wild-type L. lactis group, the sRANKL-LAB group showed significantly increased systemic and mucosal immune responses specific to M-BmpB. CONCLUSIONS: Our results show that the M cell development by sRANKL-LAB can increase the antigen transcytotic capability of follicle-associated epithelium, and thereby enhance the mucosal immune response, which implies that oral administration of sRANKL is a promising adjuvant strategy for efficient oral vaccination. PMID- 26608026 TI - Influence of progressive addition lenses on reading posture in myopic children. AB - AIMS: To determine the influence of single-vision lenses (SVLs) and progressive addition lenses (PALs) on the near vision posture of myopic children based on their near phoria. METHODS: Sixty-two myopic children were assigned to wear SVLs followed by PALs. Eighteen children were esophoric (greater than +1), 18 were orthophoric (-1 to 1) and 26 were exophoric (less than -1) at near. Reading distance, head tilt and ocular gaze angles were measured using an electromagnetic system after adaptation to each lens type. RESULTS: The lens type did not influence reading distance or head tilt angle (p>0.05 for both), but ocular gaze angle decreased significantly with the PALs (F=9.25, p=0.004). With the PALs, exophoric children exhibited significantly increased head tilt angle (p=0.003) and reduced ocular gaze angle (p=0.004) compared with esophoric children. Near non-exophoric children exhibited similar eye and head postures when wearing SVLs and PALs, whereas exophoric children exhibited reduced ocular gaze angle (t= 3.18, p=0.04) with PALs compared with SVLs. Using PALs for reading, the mean addition power employed by esophoric children was significantly greater than exophoric children (p=0.04). CONCLUSIONS: The lens type and the near phoria state affected near vision posture. During reading, myopic esophoric children used a lower portion of their PALs compared with exophoric children, resulting in greater addition power. These results may partially explain why myopic children with near esophoria exhibited superior treatment effects in myopia control trials using PALs. PMID- 26608027 TI - Anxiety in visual field testing. AB - BACKGROUND: To determine if Humphrey visual field (HVF) testing induces anxiety and how anxiety relates to visual field parameters of reliability and severity. DESIGN: A prospective cohort study at a university affiliated private ophthalmic practice. PARTICIPANTS: 137 consecutive age-matched and gender-matched patients with glaucoma undergoing either HVF testing only (n=102) or Heidelberg retinal tomography (HRT) only (n=35) were enrolled. METHODS: Prior to testing, participants completed the State-Trait Anxiety Inventory questionnaire. A 5-point Likert scale was used to grade pretest anxiety and was repeated after testing to grade intratest anxiety. Subjective discomfort parameters were also recorded. MAIN OUTCOME MEASURES: Anxiety scores were used to make non-parametrical comparisons and correlations between cohorts and also against visual field reliability and severity indices. RESULTS: Trait anxiety (p=0.838) and pretest anxiety (p=0.802) were not significantly different between test groups. Within the HVF group, intratest anxiety was 1.2 times higher than pretest anxiety (p=0.0001), but was not significantly different in the HRT group (p=0.145). Pretest anxiety was correlated with test unreliability (Spearman's r=0.273, p=0.006), which was predictive of worse test severity (p=0.0027). Subjects who had undergone more than 10 visual field tests had significantly lower pretest and intratest anxiety levels than those who had not (p=0.0030 and p=0.0004, respectively). CONCLUSIONS: HVF testing induces more anxiety than HRT. Increased pretest anxiety may reduce HVF test reliability. Increased test experience or interventions aimed at reducing pretest anxiety may result in improved test reliability and accuracy. PMID- 26608028 TI - The efficacy of lens removal plus IOL implantation for the treatment of spherophakia with secondary glaucoma. AB - AIMS: To evaluate the efficacy of lens removal plus intraocular lens (IOL) implantation for spherophakia with secondary glaucoma. METHODS: A series of 19 patients (n=24 eyes) were split into two groups according to the degree of zonular abnormality as follows: group 1 (within the range of one quadrant, n=7 eyes) and group 2 (beyond the range of one quadrant, n=17 eyes). The patients in group 1 underwent phacoemulsification+capsular tension ring (CTR)+IOL, whereas patients in group 2 underwent pars plana lensectomy with scleral-fixated posterior chamber (PC) IOL implantation. The best corrected visual acuity (BCVA) (logMAR unit) and intraocular pressure (IOP) were documented at presentation and at 1 day, 7 days, 3 months, 1 year and 3 years postoperatively. RESULTS: The IOP in both groups significantly decreased after surgery (group 1:28.84+/-5.36 mm Hg at presentation, 15.86+/-0.79 mm Hg at the 3-year visit, t=6.34, p=0.000; group 2:26.18+/-12.16 mm Hg at presentation, 14.54+/-3.40 mm Hg at the 3-year visit, t=3.80, p=0.01). The BCVA increased from 0.79+/-0.36 at baseline to 0.44+/-0.38 at the 3-year follow-up but did not reach a significantly different level in group 1 (t=1.72, p=0.11), whereas the BCVA significantly increased from 1.15+/ 0.75 at baseline to 0.43+/-0.38 at the 3-year visit in group 2 (t=3.45, p=0.02). CONCLUSIONS: Both phacoemulsification+CTR+IOL and lensectomy with scleral-fixated PC IOL implantation are effective in lowering the IOP and enhancing the visual acuity in patients with spherophakia and secondary glaucoma. PMID- 26608029 TI - What influences availability of medicines for the community management of childhood illnesses in central Uganda? Implications for scaling up the integrated community case management programme. AB - BACKGROUND: The integrated Community Case Management (iCCM) of childhood illnesses strategy has been adopted world over to reduce child related ill health and mortality. Community Health workers (CHWs) who implement this strategy need a regular supply of drugs to effectively treat children under 5 years with malaria, pneumonia and diarrhea. In this paper, we report the prevalence and factors influencing availability of medicines for managing malaria, pneumonia and diarrhea in communities in central Uganda. METHODS: A cross sectional study was conducted among 303 CHWs in Wakiso district in central Uganda. Eligible CHWs from two randomly selected Health Sub Districts (HSDs) were interviewed. Questionnaires, check lists, record reviews were used to collect information on CHW background characteristics, CHW's prescription behaviors, health system support factors and availability of iCCM drugs. Multivariable logistic regression analysis was done to assess factors associated with availability of iCCM drugs. RESULTS: Out of 300 CHWs, 239 (79.9%) were females and mean age was 42.1 (standard deviation =11.1 years). The prevalence of iCCM drug availability was 8.3% and 33 respondents (11%) had no drugs at all. Factors associated with iCCM drug availability were; being supervised within the last month (adjusted OR = 3.70, 95% CI 1.22-11.24), appropriate drug prescriptions (adjusted OR = 3.71, 95% CI 1.38-9.96), regular submission of drug reports (adjusted OR = 4.02, 95% CI 1.62-10.10) and having a respiratory timer as a diagnostic tool (adjusted OR =3.11, 95% CI 1.08-9.00). CONCLUSIONS: The low medicine stocks for the community management of childhood illnesses calls for strengthening of CHW supervision, medicine prescription and reporting, and increasing availability of functional diagnostic tools. PMID- 26608030 TI - Oral delivery of Lactococcus lactis that secretes bioactive heme oxygenase-1 alleviates development of acute colitis in mice. AB - BACKGROUND: Mucosal delivery of therapeutic proteins using genetically modified strains of lactic acid bacteria (gmLAB) is being investigated as a new therapeutic strategy. METHODS: We developed a strain of gmLAB, Lactococcus lactis NZ9000 (NZ-HO), which secretes the anti-inflammatory molecule recombinant mouse heme oxygenase-1 (rmHO-1). The effects of short-term continuous oral dosing with NZ-HO were evaluated in mice with dextran sulfate sodium (DSS)-induced acute colitis as a model of inflammatory bowel diseases (IBD). RESULTS: We identified the secretion of rmHO-1 by NZ-HO. rmHO-1 was biologically active as determined with spectroscopy. Viable NZ-HO was directly delivered to the colon via oral administration, and rmHO-1 was secreted onto the colonic mucosa in mice. Acute colitis in mice was induced by free drinking of 3 % DSS in water and was accompanied by an increase in the disease activity index score and histopathological changes. Daily oral administration of NZ-HO significantly improved these colitis-associated symptoms. In addition, NZ-HO significantly increased production of the anti-inflammatory cytokine interleukin (IL)-10 and decreased the expression of pro-inflammatory cytokines such as IL-1alpha and IL-6 in the colon compared to a vector control strain. CONCLUSIONS: Oral administration of NZ-HO alleviates DSS-induced acute colitis in mice. Our results suggest that NZ-HO may be a useful mucosal therapeutic agent for treating IBD. PMID- 26608031 TI - Global DNA hypomethylation coupled to cellular transformation and metastatic ability. AB - Global DNA hypomethylation and DNA hypermethylation of promoter regions are frequently detected in human cancers. Although many studies have suggested a contribution to carcinogenesis, it is still unclear whether the aberrant DNA hypomethylation observed in tumors is a consequence or a cause of cancer. Here, we show that the enforced expression of Stella (also known as PGC7 and Dppa3) induced not only global DNA demethylation but also transformation of NIH3T3 cells. Furthermore, overexpression of Stella enhanced the metastatic ability of B16 melanoma cells, presumably through the induction of metastasis-related genes. These results provide new insights into the function of global DNA hypomethylation in carcinogenesis. PMID- 26608032 TI - Extracellular heat shock protein 70 promotes osteogenesis of human mesenchymal stem cells through activation of the ERK signaling pathway. AB - Heat shock proteins have protective effects when cells are exposed to stress. However, the relationship between extracellular heat shock protein 70 (eHSP70) and osteogenesis of hMSCs has not been reported. The results of this study showed that HSP70 (200 ng/ml) increases alkaline phosphatase activity and promotes hMSC mineralization. Under osteogenic induction conditions, HSP70 significantly upregulated the expression of osteo-specific genes, such as the runt family transcription factor Runx2 and osterix (OSX). Comparative expression profiling by microarray and pathway analyses revealed that HSP70 promotes osteogenesis of hMSCs through activation of the ERK signaling pathway. HSP70 may be a potential therapeutic agent for the treatment of bone nonunion. PMID- 26608033 TI - Structural in silico dissection of the collagen V interactome to identify genotype-phenotype correlations in classic Ehlers-Danlos Syndrome (EDS). AB - Collagen V mutations are associated with Elhers-Danlos syndrome (EDS), a group of heritable collagenopathies. Collagen V structure is not available and the disease causing mechanism is unclear. To address this issue, we manually curated missense mutations suspected to promote classic type EDS (cEDS) insurgence from the literature and performed a genotype-phenotype correlation study. Further, we generated a homology model of the collagen V triple helix to evaluate the pathogenic effects. The resulting structure was used to map known protein-protein interactions enriched with in silico predictions. An interaction network model for collagen V was created. We found that cEDS heterogeneous manifestations may be explained by the involvement in two different extracellular matrix pathways, related to cell adhesion and tissue repair or cell differentiation, growth and apoptosis. PMID- 26608034 TI - A bacterial homologue of the human iron exporter ferroportin. AB - A bacterial homologue of the human iron exporter ferroportin found in the predatory Gram-negative bacterium Bdellovibrio bacteriovorus has been investigated. Molecular modelling, expression in recombinant form and iron binding and transport assays demonstrate that B. bacteriovorus ferroportin (bdFpn) is indeed an orthologue of human ferroportin. Key residues corresponding to those essential for iron binding and transport in human ferroportin are conserved in the bacterial homologue and are predicted to be correctly clustered in the central cavity of the protein. Mutation of these residues grossly affects the iron binding and transport ability of bdFpn. PMID- 26608036 TI - [Living will, durable power of attorney and legal guardianship in the trauma surgery routine : Data from a geriatric trauma center]. AB - BACKGROUND: Due to the increasing number of elderly patients, trauma surgeons are often confronted with end-of-life treatment decisions. Advance directives can help reduce the lack of clarity in those situations. OBJECTIVES: The aim of this study was to identify the presence of living wills, durable power of attorney, legal guardianship and appointment of guardianship in the geriatric trauma center of a university hospital. MATERIALS AND METHODS: The data of all patients treated in our geriatric trauma center from 01/01/2013 to 03/31/2014 were analyzed regarding the presence of a living will, durable power of attorney, legal guardianship and appointment of guardianship as well as the procedure of documenting those items. RESULTS: Out of 181 patients, 63 % (n = 114) had one or more of these documents. Most frequently used was the durable power of attorney in 33 % (n = 59), followed by a living will in 27 % (n = 48), legal guardianship in 20 % (n = 37) and appointment of guardianship in 7 % (n = 12). The existence of those documents was recorded in 88 % (n = 100) of patients within 24 h after admission; documentation in the medical records was found in 58 % (n = 66). CONCLUSION: A large proportion of patients had one or more of the documents named above. In this respect, standardized documentation of advance directives in the medical record is an important issue for all persons involved. PMID- 26608037 TI - [Age(ing), ambivalence and mimicry]. AB - This essay aims to show that the concept of ambivalence could prove especially productive for gerontology. It is known that age(ing) is a category that is characterized by difference and at the same time delineates a process. Ambivalence is eminently suitable for capturing this duality as it enables us to take into account the dynamics peculiar to age(ing) and move beyond those conventional rigid distinctions which fail to grasp key nuances. These theoretical considerations will be put to the test by looking at the so-called young-old and their ambivalent positioning as well as their own mimicry of the middle-agers. PMID- 26608035 TI - miR-190a inhibits epithelial-mesenchymal transition of hepatoma cells via targeting the long non-coding RNA treRNA. AB - treRNA is a long non-coding RNA (lncRNA) involved in cancer progression. In this study, we show that miR-190a can silence treRNA post-transcriptionally. Suppression of treRNA by miR-190a led to significant changes of mesenchymal epithelial transition markers and impaired migration and invasion capability of hepatoma cells. TCGA data indicated that miR-190a exhibited lower expression in hepatoma tissues, especially from patients with vascular tumor invasion, compared to normal tissues. Our results reveal the involvement of miR-190a-treRNA axis in hepatoma progression and shed light on lncRNA-based cancer therapies for hepatoma patients at high risk of metastasis. PMID- 26608038 TI - [Concentration enhancement for retaining daily living competence in dementia]. AB - BACKGROUND: Dementia is characterized by reduced memory and concentration abilities leading to a decrease in activities of daily living. Various studies have shown that various forms of physical exercise have a positive therapeutic effect at an early stage of dementia. OBJECTIVE: In the present study the effects of an exercise-based Brain-Gym concept on the concentration and routine daily competences were evaluated in dementia patients. MATERIAL AND METHODS: During a 4 month intervention period specially trained nursing staff and healthcare students put this exercise program into practice. Using an intervention and control group design, the concentration abilities of the dementia patients were tested on a monthly base. Additionally, the routine daily competence of the patients was evaluated by the nursing staff. RESULTS: Even though no significant differences could be detected, the intervention group achieved higher scores in concentration abilities than the control group on all four testing dates. Furthermore, the routine daily competence was improved in the intervention group throughout the intervention period. CONCLUSION: This concept can be used for dementia patients. Due to the low requirements concerning coordination and condition Brain-Gym is suitable for the target group and can easily be implemented by caregivers; however, significant evidence of positive impacts on concentration and everyday life competence could not yet be found in this study. PMID- 26608039 TI - [Ambivalence, old age and agency: Meaning of age-specific ambivalence for the construction of narrative identity]. AB - Different models of the formation of age identity explain the empirically determined difference between the chronological age and the age which is subjectively perceived by elderly people themselves. From a biographical point of view and on the basis of two maximally contrasting empirical cases, this article investigates the ways ambivalence appears in the narrations of elderly people about personal aging and the narrative strategies of coping with this experience of ambivalence. The results of the analysis indicate that the conceptualization of age identity in the different models should be seen more as descriptions of potential but not necessary forms of coping with age-specific ambivalences. PMID- 26608040 TI - Cowden syndrome. PMID- 26608041 TI - Endoscopic management of radio-opaque bile duct stones. AB - BACKGROUND: Majority of the bile duct stones (BDS) are radiolucent (RL) and are amenable to conventional endoscopic extraction techniques. There is no publication that specifically discusses the optimal management of radio-opaque (RO) BDS and makes a distinction from the strategy followed for RL BDS. METHODS: Data of patients with BDS managed endoscopically from January 2009 till June 2015 were retrospectively reviewed. Diagnosis of RO stone was established during initial fluoroscopy, just prior to obtaining a cholangiogram. Endoscopic retrograde cholangiopancreatography (ERCP) was done using therapeutic duodenoscope. Stone extraction was attempted initially using conventional techniques. Balloon sphincteroplasty or mechanical lithotripsy (ML) or both were done if conventional techniques failed. Cholangioscopy-guided intracorporeal holmium laser lithotripsy (LL) was done when all the above techniques failed. RESULTS: Fifteen patients were found to have RO stones in the bile duct during the study period. ERCP was successful in all patients. Discrepancy of the stone size in relation to the lower CBD diameter was seen in eight patients (53.34 %). Stone extraction with conventional techniques was successful in 2/15 patients (13 %). Successful controlled radial expansion (CRE) balloon sphincteroplasty/ML was possible in 5/15 patients (33 %). Cholangioscopy guided LL was done in eight patients (53.34 %) with successful pulverization of RO BDS (100 %). CONCLUSIONS: RO bile duct stones provide unique challenges for endoscopic management with success of conventional techniques in only about half of them (46 %). RO stones detected on fluoroscopy are extremely hard and difficult to crush with lithotripsy basket probably due to high calcium content. Cholangioscopy guided LL provides an excellent alternative management strategy. PMID- 26608042 TI - An experimental investigation of mentalization ability in borderline personality disorder. AB - OBJECTIVE: Deficits in mentalization ability have been theorized to underlie borderline personality disorder (BPD) and have led to mentalization-based treatments. Yet there has been little empirical investigation into whether mentalization deficits do differentiate the BPD population from healthy controls, and the specific nature of these differences. METHOD: Five pre-existing Theory of Mind (ToM) tasks that assessed simple to complex mentalization capacity in both the affective and cognitive domains were administered to the same groups of age and gender matched patients with BPD and controls. Self-report measures assessed cognitive and affective empathy and childhood trauma and abuse. RESULTS: The BPD group did not differ significantly from the healthy control group on basic cognitive false-belief picture-sequencing tasks, or on overall accuracy when discriminating mental states from viewing images of eyes, and attributing emotions based on social events. They were, however, significantly less accurate in identifying positive mental states on the Reading the Mind in the Eyes (RME) task and showed significantly more mentalization errors on affective and cognitive understanding of faux pas (faux pas total score p<.01) and on a Joke Appreciation task (p=.01), that required integration of multiple perspectives. They also self-reported less empathic perspective taking (p<.01). Observation of patterns of performance hinted at specific underlying biases (e.g. a default tendency to use superficial black-and-white attributions to others, such as, "he is mean", when explaining behavior). It was also found that as childhood experiences of punishment increased, adulthood mentalization ability decreased on all affective ToM tasks and on the cognitive and affective components of understanding faux pas. CONCLUSIONS: The BPD group was as capable as controls in undertaking simple mentalization. However, deficits in mentalization capacity became evident when mentalization tasks became more complex and required the integration of multiple perspectives. Increasing childhood experiences of punishment were related to decreasing mentalization ability in adulthood. Findings support the use of treatments to improve mentalization skills in BPD, however, further research is needed to better specify the nature of underlying mentalizing biases in this population. PMID- 26608043 TI - Psycho-social activity factors associated with self-rated health among community dwelling elderly people A five-year longitudinal study. AB - OBJECTIVES: This longitudinal study examined psychological and social activity factors related to poor self-rated health (SRH) in community-dwelling elderly people. METHODS: The general health of 7,413 elderly individuals aged 65 years and over in Toon City, Ehime Prefecture, Japan was surveyed. We followed 4,372 participants, over a five-year period, after excluding those who were aged 85 years and over, had a disability, had moved away, or had died. The data from 3,358 respondents (response rate: 76.8%) were analyzed. We divided the patients into two groups based on their SRH responses: healthy, including those who answered "excellent" or "good," and unhealthy, including those who answered "not good" or "poor." We examined changes in SRH for both groups between the first survey and the survey conducted after five years. Among the healthy subjects at the first survey, we analyzed the relationship between SRH, after five years, and psycho-social activity factors using a logistic regression analysis. These factors included physical and social competence, life satisfaction, and tendency towards dementia and/or depression. RESULTS: SRH of both men and women significantly declined over five years. The percentage of men and women, who maintained SRH as healthy, after the 5-year follow-up period, was approximately 60% in those aged 65-74 years and 40% in those aged 75-84 years. In those aged 65 74 years, the odds ratio (OR) for a SRH of unhealthy (after five years), associated with Life Satisfaction Index-K (LSI-K) scores (at the first survey), was significantly lower at 0.85 (95% confidence interval [CI]: 0.77-0.93) for men and 0.79 (95% CI: 0.72-0.87) for women. The OR of tendency toward depression was significantly higher at 1.68 (95% CI: 1.11-2.56) for women only. In those aged 75 84 years, the OR for a SRH of unhealthy (after five years), associated with LSI-K scores (at the first survey), was significantly lower at 0.87 (95% CI: 0.77-1.00) for men and 0.89 (95% CI: 0.80-0.99) for women. The OR for higher Tokyo Metropolitan Institute of Gerontology scores was significantly lower at 0.80 (95% CI: 0.70-0.91) for men and 0.88 (95% CI: 0.80-0.97) for women. CONCLUSION: This study shows that it is necessary to increase life satisfaction for preventing a decline in SRH in community-dwelling elderly. It also shows that preventing depression in elderly women under the age of 75 years and maintaining physical and social competence in both elderly men and women aged 75-84 years are important for maintaining the SRH status. PMID- 26608044 TI - A survey of sleepiness and occupational stress in hospital nurses. PMID- 26608045 TI - Investigation of the relationship between convenient visits and doctors' fatigue using burnout and work engagement scales. AB - OBJECTIVES: Fatigue caused by high workload is often responsible for the high attrition among doctors, and has contributed to a disruption in community medicine. In order to address this problem, institutional mechanisms at the hospital level are required. Previous studies have shown that systemic measures at the hospital level and a change in the mindset of patients can help manage the problem. "Convenient visits" refer to emergency visits for non-emergency problems. It is an avoidable cause of high workload on doctors. Convenient visits also refer to emergency consultation for non-emergency symptoms. As this is a new phenomenon, its relationship with doctors' fatigue needs further research. We investigated the relationship between convenient visits and doctors' fatigue using burnout and work engagement scales. METHODS: We selected 44 hospitals, with >200 beds each, in provincial cities of prefectures with a doctor-population ratio lower than the national average. These cities were considered likely to manifest the phenomenon of 24-hour society and include overworked doctors. Ordinance-designated cities were excluded from this study owing to wide population variability. Three doctors from each hospital were randomly selected from among physicians, surgeons, and pediatricians. We distributed questionnaires (a questionnaire concerning convenient visits, Maslach Burnout Inventory-Human Services Survey, and Utrecht Work Engagement Scale) to 132 doctors. RESULTS: Forty-two doctors responded to the survey. The median proportion of convenient visits among emergency visits was 50%. Sixty percent of the doctors surveyed were annoyed by convenient visits. Other doctors indicated good collaboration between the hospitals and communities or that they were not currently annoyed by convenient visits, although they had been annoyed previously. The emotional exhaustion in doctors, who worked in hospitals that did not restrict convenient visits, was significantly higher than in those who worked in hospitals that restricted these visits. A significant risk of serious burnout was found via crude and multiple logistic regression analysis (adjusted for age and gender, or adjusted for age, gender, clinical department, frequency of work shifts, and sleep duration during work shifts). CONCLUSION: Doctors working in hospitals that do not protect them against convenient visits are more prone to burnout. Although the number of convenient visitors is increasing, many hospitals lack systemic measures to manage them. This contributes to doctors' burnout. We suggest that hospitals control convenient visits for preventing doctors' burnout. Collaboration between hospitals and communities is required to help alleviate this problem. PMID- 26608046 TI - The 2014 measles outbreak in Osaka An epidemiological study for the elimination of measles. AB - OBJECTIVES: To examine and analyze the spread of measles in Osaka in 2014 and determine effective measures to prevent such occurrences. METHODS: We analyzed 47 cases of measles reported in Osaka, including one measles patient living in another prefecture where there was an outbreak. We focused on age distribution, the number of patients reported each week, estimated infection routes, history of measles vaccination, detection of viruses, and number of days it took to report the case after the onset of measles. RESULTS: Patients aged 20-39 years accounted for 24 cases (51.1%). The number of patients reported started from 2nd week with relatively broad peak to 27(th) week, and the measles epidemic was brought under control in the 47(th) week. Among the 47 cases, no source could be identified in 16 cases (34.0%). Household exposure was the main cause of the infection (25.5%), followed by imported cases (21.3%). Eighty-three percent of the overall patients had not received a measles vaccination at all or it was unclear whether they previously had been vaccinated. Genotype B3, H1, and D8 were detected in our patients and these genotypes originated overseas. It took significantly more days, from the onset of measles, for the case to be reported in patients aged 15 years and over compared with those aged under 15 years (P=0.001). CONCLUSION: For eradicating measles in Osaka, it is important to raise awareness about this issue among medical institutions, especially institutions for adults, in order for them to report cases as soon as possible, upon discovery in their patients. In addition, "catch-up" supplementary immunizations are effective for all people, including adults who are susceptible to measles. PMID- 26608047 TI - Particle size distribution and perchlorate levels in settled dust from urban roads, parks, and roofs in Chengdu, China. AB - A total of 27 settled dust samples were collected from urban roads, parks, and roofs in Chengdu, China to investigate particle size distribution and perchlorate levels in different size fractions. Briefly, fine particle size fractions (<250 MUm) were the dominant composition in the settled dust samples, with mean percentages of 80.2%, 69.5%, and 77.2% for the urban roads, roofs, and the parks, respectively. Perchlorate was detected in all of the size-fractionated dust samples, with concentrations ranging from 73.0 to 6160 ng g(-1), and the median perchlorate levels increased with decreasing particle size. The perchlorate level in the finest fraction (<63 MUm) was significantly higher than those in the coarser fractions. To our knowledge, this is the first report on perchlorate concentrations in different particle size fractions. The calculated perchlorate loadings revealed that perchlorate was mainly associated with finer particles (<125 MUm). An exposure assessment indicated that exposure to perchlorate via settled road dust intake is safe to both children and adults in Chengdu, China. However, due to perchlorate mainly existing in fine particles, there is a potential for perchlorate to transfer into surface water and the atmosphere by runoff and wind erosion or traffic emission, and this could act as an important perchlorate pollution source for the indoor environment, and merits further study. PMID- 26608048 TI - When and Why Threats Go Undetected: Impacts of Event Rate and Shift Length on Threat Detection Accuracy During Airport Baggage Screening. AB - OBJECTIVE: We aimed to assess the impact of task demands and individual characteristics on threat detection in baggage screeners. BACKGROUND: Airport security staff work under time constraints to ensure optimal threat detection. Understanding the impact of individual characteristics and task demands on performance is vital to ensure accurate threat detection. METHOD: We examined threat detection in baggage screeners as a function of event rate (i.e., number of bags per minute) and time on task across 4 months. We measured performance in terms of the accuracy of detection of Fictitious Threat Items (FTIs) randomly superimposed on X-ray images of real passenger bags. RESULTS: Analyses of the percentage of correct FTI identifications (hits) show that longer shifts with high baggage throughput result in worse threat detection. Importantly, these significant performance decrements emerge within the first 10 min of these busy screening shifts only. CONCLUSION: Longer shift lengths, especially when combined with high baggage throughput, increase the likelihood that threats go undetected. APPLICATION: Shorter shift rotations, although perhaps difficult to implement during busy screening periods, would ensure more consistently high vigilance in baggage screeners and, therefore, optimal threat detection and passenger safety. PMID- 26608050 TI - High-order dynamic Bayesian Network learning with hidden common causes for causal gene regulatory network. AB - BACKGROUND: Inferring gene regulatory network (GRN) has been an important topic in Bioinformatics. Many computational methods infer the GRN from high-throughput expression data. Due to the presence of time delays in the regulatory relationships, High-Order Dynamic Bayesian Network (HO-DBN) is a good model of GRN. However, previous GRN inference methods assume causal sufficiency, i.e. no unobserved common cause. This assumption is convenient but unrealistic, because it is possible that relevant factors have not even been conceived of and therefore un-measured. Therefore an inference method that also handles hidden common cause(s) is highly desirable. Also, previous methods for discovering hidden common causes either do not handle multi-step time delays or restrict that the parents of hidden common causes are not observed genes. RESULTS: We have developed a discrete HO-DBN learning algorithm that can infer also hidden common cause(s) from discrete time series expression data, with some assumptions on the conditional distribution, but is less restrictive than previous methods. We assume that each hidden variable has only observed variables as children and parents, with at least two children and possibly no parents. We also make the simplifying assumption that children of hidden variable(s) are not linked to each other. Moreover, our proposed algorithm can also utilize multiple short time series (not necessarily of the same length), as long time series are difficult to obtain. CONCLUSIONS: We have performed extensive experiments using synthetic data on GRNs of size up to 100, with up to 10 hidden nodes. Experiment results show that our proposed algorithm can recover the causal GRNs adequately given the incomplete data. Using the limited real expression data and small subnetworks of the YEASTRACT network, we have also demonstrated the potential of our algorithm on real data, though more time series expression data is needed. PMID- 26608051 TI - Does High Protein Intake During First Week of Life Improve Growth and Neurodevelopmental Outcome at 18 months Corrected Age in Extremely Preterm Infants? AB - OBJECTIVE: To examine whether high protein intake during the first week of life alters the growth and neurodevelopmental outcomes at 18 mo corrected age (CA) in preterm infants born < 29 wk. METHODS: This was a retrospective cohort study of preterm infants (<29 wk) before and after introduction of nutritional policy targeting higher protein intake during the first week of life. The authors compared the growth and neurodevelopmental outcomes at 18 mo CA between infants born before (epoch 1) and after (epoch 2) the introduction of nutrition policy. RESULTS: Of 171 eligible infants who completed follow-up at 18 mo CA, 87 (51 %) were in post intervention group (epoch 2). The mean (+/- SD) gestational age (26.3 +/- 1.49 wk vs. 26.2 +/- 1.48 wk) and birth weight (947 +/- 220 g vs. 924 +/- 225 g) were similar between the two groups. At 18 mo CA, there were no significant differences in the growth and neurodevelopmental impairment rates between the two groups. Logistic regression analysis revealed that high protein intake (>3.5 g/kg/d) was not associated with improved neurodevelopmental outcome (OR 1.49, 95 % CI 0.52-4.26). CONCLUSIONS: High protein intake during the first week of age was not associated with better growth or neurodevelopmental outcome at 18 mo CA in preterm infants. PMID- 26608052 TI - Carbonic anhydrase mimics for enhanced CO2 absorption in an amine-based capture solvent. AB - Two new small-molecule enzyme mimics of carbonic anhydrase were prepared and characterized. These complexes contain the salen-like ligand bis(hydroxyphenyl)phenanthroline. This ligand is similar to the salen-type ligands previously incorporated into carbonic anhydrase mimics but contains no hydrolyzable imine groups and therefore serves as a promising ligand scaffold for the synthesis of a more robust CO2 hydration catalyst. These homogeneous catalysts were investigated for CO2 hydration in concentrated primary amine solutions through which a dilute CO2 (14%) fluid stream was flowed and showed exceptional activity for increased CO2 absorption rates. PMID- 26608053 TI - Would you like to play together? Adults' attachment and the mirror game. AB - Why is it easy for some people to play together and difficult for others? In this interdisciplinary pilot study, we looked at dyadic interaction in motion as a paradigm to explore the expression of attachment in adulthood. We used a device that gives simple, quantitative and automated indicators for the quality of interaction while playing the mirror game. Forty-seven participants played the mirror game with the same gender-matched expert players. In addition, participants were interviewed on the Adult Attachment Interview to assess their quality of attachment. Using high resolution kinematic measures, we found that secure attachment was correlated with high complexity of the game and low synchrony compared to insecure attachment. The findings suggest that security of attachment is related to a more exploratory and less rigid game than insecure dismissing attachment. These preliminary findings imply that high resolution analysis of simple movement interaction could carry information about attachment behavior. PMID- 26608054 TI - The prospective self-controlled study of unilateral transverse process-pedicle and bilateral puncture techniques in percutaneous kyphoplasty. AB - Many previous studies have reported excellent clinical results with percutaneous kyphoplasty (PKP). In contrast, numerous complications and problems have also been reported, such as puncture difficulty, cement leakage, and adjacent vertebral fracture. INTRODUCTION: This study is to evaluate the application and clinical outcomes of unilateral transverse process-pedicle and bilateral PKP in the treatment of osteoporotic vertebral compression fractures (OVCF). METHODS: A total of 56 cases with two levels thoracolumbar OVCF were randomly assigned for treatment with unilateral transverse process-pedicle and bilateral PKP. The patients were followed up postoperatively and were assessed mainly with regard to clinical and radiologic outcomes. Clinical outcomes were evaluated with mainly the use of a visual analogue scale (VAS) for pain. Radiologic outcomes were assessed mainly on the basis of radiation dose and bone cement distribution. RESULTS: The operation was completed successfully in 56 cases. In the unilateral level, the operation time, the volume of the injected cement, and radiation dose were significantly less than bilateral level. All patients had significantly improvement on VAS score after the procedures, compared with their preoperative period. In the bilateral level, 7 patients had obvious pain in the puncture sites at 1 month postoperatively caused by facet joint violation. With local block treatment, the pain disappeared in all patients at the last follow-up. CONCLUSION: Both bilateral and unilateral PKP are relatively safe and effective treatments for patients with painful OVCF. But unilateral PKP received less radiation dose and operation time, offered a higher degree of deformity correction, and resulted in less complication than bilateral. PMID- 26608055 TI - Trabecular bone score in kidney transplant recipients. AB - SUMMARY: It is uncertain whether bone mineral density (BMD) can accurately predict fracture in kidney transplant recipients. Trabecular bone score (TBS) provides information independent of BMD. Kidney transplant recipients had abnormal bone texture as measured by lumbar spine TBS, and a lower TBS was associated with incident fractures in recipients. INTRODUCTION: Trabecular bone score (TBS) is a texture measure derived from dual energy X-ray absorptiometry (DXA) lumbar spine images, providing information independent of bone mineral density. We assessed characteristics associated with TBS and fracture outcomes in kidney transplant recipients. METHODS: We included 327 kidney transplant recipients from Manitoba, Canada, who received a post-transplant DXA (median 106 days post-transplant). We matched each kidney transplant recipient (mean age 45 years, 39% men) to three controls from the general population (matched on age, sex, and DXA date). Lumbar spine (L1-L4) DXA images were used to derive TBS. Non traumatic incident fracture (excluding hand, foot, and craniofacial) (n = 31) was assessed during a mean follow-up of 6.6 years. We used multivariable linear regression models to test predictors of TBS, and multivariable Cox proportional hazard regression was used to estimate hazard ratios (HRs) per standard deviation decrease in TBS to express the gradient of risk. RESULTS: Compared to the general population, kidney transplant recipients had a significantly lower lumbar spine TBS (1.365 +/- 0.129 versus 1.406 +/- 0.125, P < 0.001). Multivariable linear regression revealed that receipt of a kidney transplant was associated with a significantly lower mean TBS compared to controls (-0.0369, 95% confidence interval [95% CI] -0.0537 to -0.0202). TBS was associated with fractures independent of the Fracture Risk Assessment score including BMD (adjusted HR per standard deviation decrease in TBS 1.64, 95% CI 1.15-2.36). CONCLUSION: Kidney transplant recipients had abnormal bone texture as assessed by TBS and a lower lumbar spine TBS was associated with fractures in recipients. PMID- 26608056 TI - Transmission of Work Ethic in African-American Families and Its Links with Adolescent Adjustment. AB - A strong work ethic generally has positive implications for achievements in work and school settings, but we know little about how it develops. This study aimed to describe the intra-familial transmission of work ethic and the associations between work ethic and adjustment in African American youth. Mothers, fathers, and two adolescent siblings (M age = 14.1 years) in 158 families were interviewed on two occasions. Path models revealed that fathers' work ethic was positively linked with older siblings' work ethic, which in turn was linked with more positive youth adjustment in the domains of school functioning and externalizing and internalizing problems. Moreover, the results indicated that the work ethics of older siblings, but not parents, was linked to those of younger siblings. The discussion focuses on the importance of African American fathers and siblings in youth adjustment and how work ethic may promote positive development. PMID- 26608057 TI - Repetitive DNA and Plant Domestication: Variation in Copy Number and Proximity to Genes of LTR-Retrotransposons among Wild and Cultivated Sunflower (Helianthus annuus) Genotypes. AB - The sunflower (Helianthus annuus) genome contains a very large proportion of transposable elements, especially long terminal repeat retrotransposons. However, knowledge on the retrotransposon-related variability within this species is still limited. We used next-generation sequencing (NGS) technologies to perform a quantitative and qualitative survey of intraspecific variation of the retrotransposon fraction of the genome across 15 genotypes--7 wild accessions and 8 cultivars--of H. annuus. By mapping the Illumina reads of the 15 genotypes onto a library of sunflower long terminal repeat retrotransposons, we observed considerable variability in redundancy among genotypes, at both superfamily and family levels. In another analysis, we mapped Illumina paired reads to two sets of sequences, that is, long terminal repeat retrotransposons and protein-encoding sequences, and evaluated the extent of retrotransposon proximity to genes in the sunflower genome by counting the number of paired reads in which one read mapped to a retrotransposon and the other to a gene. Large variability among genotypes was also ascertained for retrotransposon proximity to genes. Both long terminal repeat retrotransposon redundancy and proximity to genes varied among retrotransposon families and also between cultivated and wild genotypes. Such differences are discussed in relation to the possible role of long terminal repeat retrotransposons in the domestication of sunflower. PMID- 26608059 TI - A Genome-Scale Investigation of Incongruence in Culicidae Mosquitoes. AB - Comparison of individual gene trees in several recent phylogenomic studies from diverse lineages has revealed a surprising amount of topological conflict or incongruence, but we still know relatively little about its distribution across the tree of life. To further our understanding of incongruence, the factors that contribute to it and how it can be ameliorated, we examined its distribution in a clade of 20 Culicidae mosquito species through the reconstruction and analysis of the phylogenetic histories of 2,007 groups of orthologous genes. Levels of incongruence were generally low, the three exceptions being the internodes concerned with the branching of Anopheles christyi, with the branching of the subgenus Anopheles as well as the already reported incongruence within the Anopheles gambiae species complex. Two of these incongruence events (A. gambiae species complex and A. christyi) are likely due to biological factors, whereas the third (subgenus Anopheles) is likely due to analytical factors. Similar to previous studies, the use of genes or internodes with high bootstrap support or internode certainty values, both of which were positively correlated with gene alignment length, substantially reduced the observed incongruence. However, the clade support values of the internodes concerned with the branching of the subgenus Anopheles as well as within the A. gambiae species complex remained very low. Based on these results, we infer that the prevalence of incongruence in Culicidae mosquitoes is generally low, that it likely stems from both analytical and biological factors, and that it can be ameliorated through the selection of genes with strong phylogenetic signal. More generally, selection of genes with strong phylogenetic signal may be a general empirical solution for reducing incongruence and increasing the robustness of inference in phylogenomic studies. PMID- 26608060 TI - Recent progress in transdermal sonophoresis. AB - Transdermal drug administration has a number of advantages that cannot be leveraged for therapeutic benefits because of the robust barrier provided by the stratum corneum. One of the promising techniques for circumventing the stratum corneum is sonophoresis - the use of ultrasound for facilitating transdermal drug delivery. In this review, the mechanisms underlying sonophoresis and the utilization of the technique for transdermal delivery are discussed. The challenges of this mode of drug administration have also been highlighted and insight from a number of toxicological studies is described. PMID- 26608058 TI - Eukaryotic Components Remodeled Chloroplast Nucleoid Organization during the Green Plant Evolution. AB - Chloroplast (cp) DNA is thought to originate from the ancestral endosymbiont genome and is compacted to form nucleoprotein complexes, cp nucleoids. The structure of cp nucleoids is ubiquitously observed in diverse plants from unicellular algae to flowering plants and is believed to be a multifunctional platform for various processes, including cpDNA replication, repair/recombination, transcription, and inheritance. Despite its fundamental functions, the protein composition for cp nucleoids in flowering plants was suggested to be divergent from those of bacteria and algae, but the evolutionary process remains elusive. In this research, we aimed to reveal the evolutionary history of cp nucleoid organization by analyzing the key organisms representing the three evolutionary stages of eukaryotic phototrophs: the chlorophyte alga Chlamydomonas reinhardtii, the charophyte alga Klebsormidium flaccidum, and the most basal land plant Marchantia polymorpha. To clarify the core cp nucleoid proteins in C. reinhardtii, we performed an LC-MS/MS analysis using highly purified cp nucleoid fractions and identified a novel SAP domain-containing protein with a eukaryotic origin as a constitutive core component. Then, homologous genes for cp nucleoid proteins were searched for in C. reinhardtii, K. flaccidum, and M. polymorpha using the genome databases, and their intracellular localizations and DNA binding activities were investigated by cell biological/biochemical analyses. Based on these results, we propose a model that recurrent modification of cp nucleoid organization by eukaryotic factors originally related to chromatin organization might have been the driving force for the diversification of cp nucleoids since the early stage of green plant evolution. PMID- 26608061 TI - Brain gadolinium deposition after administration of gadolinium-based contrast agents. AB - Gadolinium-based contrast agents (GBCAs) consist of gadolinium ions and a chelating agent that binds the gadolinium ion tightly so that its toxicity is not manifested. However, in 2013, an association between brain MRI abnormalities and a history of GBCA administration was first reported. Even in patients with normal renal function, increased signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted images showed a positive correlation with previous exposure to linear chelate type GBCAs, but not to macrocyclic chelate type ones. This difference of GBCAs is speculated to reflect the stability of GBCAs, and de-chelated gadolinium deposition has been strongly suspected. Using inductively coupled plasma mass spectroscopy, gadolinium was detected from patients' brains with a history of repeated GBCA administration. In some cases, the gadolinium concentration of a patient's brain with normal renal function exceeded the gadolinium concentration of the skin in nephrogenic systemic fibrosis patients, but without any histological change. The actual risk has not been documented yet, but it seems important to consider the potential unknown risks of residual gadolinium in our decisions regarding GBCA administration, and to make efforts to minimize any residual gadolinium in the patient's body. PMID- 26608062 TI - The Hidden Ethics Curriculum in Two Canadian Psychiatry Residency Programs: A Qualitative Study. AB - OBJECTIVE: The authors describe the hidden ethics curriculum in two postgraduate psychiatry programs. METHODS: Researchers investigated the formal, informal, and hidden ethics curricula at two demographically different postgraduate psychiatry programs in Canada. Using a case study design, they compared three sources: individual interviews with residents and with faculty and a semi-structured review of program documents. They identified the formal, informal, and hidden curricula at each program for six ethics topics and grouped the topics under two thematic areas. They tested the applicability of the themes against the specific examples under each topic. Results pertaining to one of the themes and its three topics are reported here. RESULTS: Divergences occurred between the curricula for each topic. The nature of these divergences differed according to local program characteristics. Yet, in both programs, choices for action in ethically challenging situations were mediated by a minimum standard of ethics that led individuals to avoid trouble even if this meant their behavior fell short of the accepted ideal. CONCLUSIONS: Effective ethics education in postgraduate psychiatry training will require addressing the hidden curriculum. In addition to profession-wide efforts to articulate high-level values, program-specific action on locally relevant issues constitutes a necessary mechanism for handling the impact of the hidden curriculum. PMID- 26608063 TI - Competence in Psychotherapy: The Role of E-Learning. PMID- 26608065 TI - Sustainable financing: the Achilles heel of the non-communicable diseases response. PMID- 26608066 TI - Management of advanced medullary thyroid cancer. AB - Medullary thyroid cancer arises from calcitonin-producing C-cells and accounts for 3-5% of all thyroid cancers. The discovery of a locally advanced medullary thyroid cancer that is not amenable to surgery or of distant metastases needs careful work-up, including measurement of serum calcitonin and carcinoembryonic antigen (and their doubling times), in addition to comprehensive imaging to determine the extent of the disease, its aggressiveness, and the need for any treatment. In the past, cytotoxic chemotherapy was used for treatment but produced little benefit. For the past 10 years, tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors and RET (rearranged during transfection) have been used when a systemic therapy is indicated for large tumour burden and documented disease progression. Vandetanib and cabozantinib have shown benefits on progression-free survival compared with placebo in this setting, but their toxic effect profiles need thorough clinical management in specialised centres. This Review describes the management and treatment of patients with advanced medullary thyroid cancer with emphasis on current targeted therapies and perspectives to improve patient care. Most treatment responses are transient, emphasising that mechanisms of resistance need to be better understood and that the efficacy of treatment approaches should be improved with combination therapies or other drugs that might be more potent or target other pathways, including immunotherapy. PMID- 26608064 TI - Reorganization and expansion of the nidoviral family Arteriviridae. AB - The family Arteriviridae presently includes a single genus Arterivirus. This genus includes four species as the taxonomic homes for equine arteritis virus (EAV), lactate dehydrogenase-elevating virus (LDV), porcine respiratory and reproductive syndrome virus (PRRSV), and simian hemorrhagic fever virus (SHFV), respectively. A revision of this classification is urgently needed to accommodate the recent description of eleven highly divergent simian arteriviruses in diverse African nonhuman primates, one novel arterivirus in an African forest giant pouched rat, and a novel arterivirus in common brushtails in New Zealand. In addition, the current arterivirus nomenclature is not in accordance with the most recent version of the International Code of Virus Classification and Nomenclature. Here we outline an updated, amended, and improved arterivirus taxonomy based on current data. Taxon-specific sequence cut-offs are established relying on a newly established open reading frame 1b phylogeny and pairwise sequence comparison (PASC) of coding-complete arterivirus genomes. As a result, the current genus Arterivirus is replaced by five genera: Equartevirus (for EAV), Rodartevirus (LDV + PRRSV), Simartevirus (SHFV + simian arteriviruses), Nesartevirus (for the arterivirus from forest giant pouched rats), and Dipartevirus (common brushtail arterivirus). The current species Porcine reproductive and respiratory syndrome virus is divided into two species to accommodate the clear divergence of the European and American "types" of PRRSV, both of which now receive virus status. The current species Simian hemorrhagic fever virus is divided into nine species to accommodate the twelve known simian arteriviruses. Non-Latinized binomial species names are introduced to replace all current species names to clearly differentiate them from virus names, which remain largely unchanged. PMID- 26608068 TI - When evidence doesn't generalise: the case of ACE inhibition. PMID- 26608067 TI - Ramipril versus placebo in kidney transplant patients with proteinuria: a multicentre, double-blind, randomised controlled trial. AB - BACKGROUND: Angiotensin-converting enzyme inhibitors have been shown to reduce the risk of end-stage renal disease and death in non-transplant patients with proteinuria. We examined whether ramipril would have a similar beneficial effect on important clinical outcomes in kidney transplant recipients with proteinuria. METHODS: In this double-blind, placebo-controlled, randomised trial, conducted at 14 centres in Canada and New Zealand, we enrolled adult renal transplant recipients at least 3-months post-transplant with an estimated glomerular filtration rate (GFR) of 20 mL/min/1.73m(2) or greater and proteinuria 0.2 g per day or greater and randomly assigned them to receive either ramipril (5 mg orally twice daily) or placebo for up to 4 years. Patients completing the final 4-year study visit were invited to participate in a trial extension phase. Treatment was assigned by centrally generated randomisation with permuted variable blocks of 2 and 4, stratified by centre and estimated GFR (above or below 40 mL/min/1.73 m(2)). The primary outcome was a composite consisting of doubling of serum creatinine, end-stage renal disease, or death in the intention-to-treat population. The principal secondary outcome was the change in measured GFR. We ascertained whether any component of the primary outcome had occurred at each study visit (1 month and 6 months post-randomisation, then every 6 months thereafter). This trial is registered with ISRCTN, number 78129473. FINDINGS: Between Aug 23, 2006, and March 28, 2012, 213 patients were randomised. 109 were allocated to placebo and 104 were allocated to ramipril, of whom 109 patients in the placebo group and 103 patients in the ramipril group were analysed and the trial is now complete. The intention to treat population (placebo n=109, ramipril n=103) was used for the primary analysis and the trial extension phase analysis. The primary outcome occurred in 19 (17%) of 109 patients in the placebo group and 14 (14%) of 103 patients in the ramipril group (hazard ratio [HR] 0.76 [95% CI 0.38-1.51]; absolute risk difference -3.8% [95% CI -13.6 to 6.1]). With extended follow-up (mean 48 months), the primary outcome occurred in 27 patients (25%) in the placebo group and 25 (24%) patients in the ramipril group (HR 0.96 [95% CI 0.55-1.65]); absolute risk difference: -0.5% (95% CI -12.0 to 11.1). There was no significant difference in the rate of measured GFR decline between the two groups (mean difference per 6-month interval: -0.16 mL/min/1.73m(2) (SE 0.24); p=0.49). 14 (14%) of patients died in the ramipril group and 11 (10%) in the placebo group, but the difference between groups was not statistically significant (HR 1.45 [95% CI 0.66 to 3.21]). Adverse events were more common in the ramipril group (39 [38%]) than in the placebo group (24 [22%]; p=0.02). INTERPRETATION: Treatment with ramipril compared with placebo did not lead to a significant reduction in doubling of serum creatinine, end-stage renal disease, or death in kidney transplant recipients with proteinuria. These results do not support the use of angiotensin-converting enzyme inhibitors with the goal of improving clinical outcomes in this population. FUNDING: Canadian Institutes of Health Research. PMID- 26608069 TI - Silicon nanocrystal growth under irradiation of electron beam. AB - In our experiment, it was observed that silicon nanocrystal rapidly grows with irradiation of electron beam on amorphous silicon film prepared by pulsed laser deposition, and shape of silicon nanocrystal is usually sphere in smaller nanoscale with less exposure time under electron beam, in which the quantum dots are prepared in nanoscale near 3 nm. In the electron interaction process, it was investigated that the various crystals structures in different orientations occur in the same time and the condensed structures of silicon nanocrystal are changed with different impurity atoms in silicon film. PMID- 26608070 TI - Association of a Single Nucleotide Polymorphism in a Late Cornified Envelope-like Proline-rich 1 Gene (LELP1) with Atopic Dermatitis. AB - There is some evidence that genes involved in the pathogenesis of atopic dermatitis, in addition to the filaggrin (FLG) gene, may be located at chromosome region 1q21. The aim of this study was to examine the association of single nucleotide polymorphisms in the region of the late cornified envelope-like proline-rich 1 (LELP1), hornerin (HRNR) and FLG genes with the course and risk of atopic dermatitis. Single nucleotide polymorphisms and mutations were genotyped by PCR restriction fragment length polymorphism and real-time PCR in a group of 152 patients with atopic dermatitis and 104 healthy volunteers. CC genotype and C allele of LELP1 rs7534334 were found in patients with atopic dermatitis and were associated with elevated levels of serum immunoglobulin E, severity of atopic dermatitis and concomitant asthma. LELP1 rs7534334 enhanced the risk of atopic dermatitis nearly 2.5-fold. This pilot study suggests that rs7534334 SNP, located in the LELP1 region, may be a potential genetic marker for the risk and course of atopic dermatitis. PMID- 26608071 TI - Identification of altered protein abundances in cholesteatoma matrix via mass spectrometry-based proteomic analysis. AB - BACKGROUND: Cholesteatoma are cyst-like structures lined with a matrix of differentiated squamous epithelium overlying connective tissue. Although epithelium normally exhibits self-limited growth, cholesteatoma matrix erodes mucosa and bone suggesting changes in matrix protein constituents that permit destructive behaviour. Differential proteomic studies can measure and compare the cholesteatoma proteome to normal tissues, revealing protein alterations that may propagate the destructive process. METHODS: Human cholesteatoma matrix, cholesteatoma-involved ossicles, and normal middle ear mucosa, post-auricular skin, and non-involved ossicles were harvested. These tissues were subjected to multiplex peptide labeling followed by liquid chromatography and tandem mass spectrometry analysis. Relative protein abundances were compared and evaluated for ontologic function and putative involvement in cholesteatoma. RESULTS: Our methodology detected 10 764 peptides constituting 1662 unique proteins at 95 % confidence or greater. Twenty-nine candidate proteins were identified in soft tissue analysis, with 29 additional proteins showing altered abundances in bone samples. Ontologic functions and known relevance to cholesteatoma are discussed, with several candidates highlighted for their roles in epithelial integrity, evasion of apoptosis, and immunologic function. CONCLUSION: This study produced an extensive cholesteatoma proteome and identified 58 proteins with altered abundances contributing to disease pathopathysiology. As well, potential biomarkers of residual disease were highlighted. Further investigation into these proteins may provide useful options for novel therapeutics or monitoring disease status. PMID- 26608072 TI - Medication Adherence in Children and Adolescents with Acne Vulgaris in Medicaid: A Retrospective Study Analysis. AB - OBJECTIVES: The objectives of the study were to evaluate and compare medication adherence associated with acne drugs in children and adolescents with acne vulgaris. METHODS: Data from MarketScan Medicaid enrollees with acne vulgaris were included if patients were ages 6 to 17 years on the index date, had at least one acne-related medication claim, and were enrolled in Medicaid during January 2004 to December 2007. The adherence rate was measured using the medication possession ratio. The medication possession ratio was dichotomized to categorize patients as adherent (>=0.8) or nonadherent (<0.8). Multivariate logistic regressions were used for analyses of the medication possession ratio. RESULTS: Of 20,039 eligible patients, 2,860 patients were children and 17,179 patients were adolescent. Approximately 6.96% of children and 16.75% of adolescents had at least one acne-related medication refill. The mean adherence rate to acne medication was significantly different between children (0.22) and adolescents (0.32). In addition, only 3.71% of children were adherent to acne medication while 13.38% of adolescents were adherent. After controlling for covariates, adolescents were 2.06 times more likely to get an acne-related medication refilled and were 2.40 times more likely to be adherent to acne-related medication. The analyses also showed that acne-related medication adherence was associated with the patient's characteristics and acne medication type. CONCLUSION: Neither patient population was considered adherent to acne-related medications, nor was there a significant difference between the two patient populations. This study also revealed that medication type is a contributing factor towards adherence. Health care providers should strive to educate patients on the importance of medication adherence. PMID- 26608074 TI - Tapping Into Traditional Norms for Preventing HIV and Unintended Pregnancy: Harnessing the Influence of Grandmothers (Agogos) in Malawi. AB - Young girls in Malawi must be able to acquire sexual health information and skills to protect themselves from HIV/AIDS and prevent unintended pregnancies. The purpose of this study was to evaluate a pilot training program that sought to enhance the skills of grandmothers (Agogos) to discuss issues related to sex and sexuality with young girls. Data from eight focus group discussions were analyzed, comparing trained Agogos and the girls they counseled to untrained Agogos and the girls they counseled. Trained Agogos and the girls they counseled, compared with untrained Agogos and the girls they counseled, reported being more comfortable in communicating sexual issues with young girls at earlier ages, were more likely to have interactive discussions, and were more likely to stress the importance of finishing school as reasons to delay sexual activity. More research is needed to determine if such an approach is effective and sustainable. PMID- 26608073 TI - Identification of a novel cathelicidin antimicrobial peptide from ducks and determination of its functional activity and antibacterial mechanism. AB - The family of antimicrobial peptide, cathelicidins, which plays important roles against infections in animals, has been identified from many species. Here, we identified a novel avian cathelicidin ortholog from ducks and named dCATH. The cDNA sequence of dCATH encodes a predicted 146-amino-acid polypeptide composed of a 17-residue signal peptide, a 109-residue conserved cathelin domain and a 20 residue mature peptide. Phylogenetic analysis demonstrated that dCATH is highly divergent from other avian peptides. The alpha-helical structure of the peptide exerted strong antimicrobial activity against a broad range of bacteria in vitro, with most minimum inhibitory concentrations in the range of 2 to 4 MUM. Moreover, dCATH also showed cytotoxicity, lysing 50% of mammalian erythrocytes in the presence or absence of 10% fetal calf serum at concentrations of 32 MUM or 20 MUM and killing 50% HaCaT cells at a concentration of 10 MUM. The effects on bacterial outer and inner membranes, as examined by scanning electron microscope and transmission electron microscopy, indicate that dCATH kills microbial cells by increasing permeability, causing a loss of membrane integrity. PMID- 26608075 TI - Consequences of reaming with flat and convex reamers for bone volume and surface area of the glenoid; a basic science study. AB - BACKGROUND: The effect of reaming on bone volume and surface area of the glenoid is not precisely known. We hypothesize that (1) convex reamers create a larger surface area than flat reamers, (2) flat reamers cause less bone loss than convex reamers, and (3) the amount of bone loss increases with the amount of version correction. METHODS: Reaming procedures with different types of reamers are performed on similar-sized uniconcave and biconcave glenoids created from Sawbones foam blocks. The loss of bone volume, the size of the remaining surface area, and the reaming depth are measured and evaluated. RESULTS: Reaming with convex reamers results in a significantly larger surface area than with flat reamers for both uniconcave and biconcave glenoids (p = 0.013 and p = 0.001). Convex reamers cause more bone loss than flat reamers, but the difference is only significant for uniconcave glenoids (p = 0.007). CONCLUSIONS: In biconcave glenoids, convex reamers remove a similar amount of bone as flat reamers, but offer a larger surface area while maximizing the correction of the retroversion. In pathological uniconcave glenoids, convex reamers are preferred because of the conforming shape. PMID- 26608076 TI - TAL effectors mediate high-efficiency transposition of the piggyBac transposon in silkworm Bombyx mori L. AB - The piggyBac (PB) transposon is one of the most useful transposable elements, and has been successfully used for genetic manipulation in more than a dozen species. However, the efficiency of PB-mediated transposition is still insufficient for many purposes. Here, we present a strategy to enhance transposition efficiency using a fusion of transcription activator-like effector (TALE) and the PB transposase (PBase). The results demonstrate that the TALE-PBase fusion protein which is engineered in this study can produce a significantly improved stable transposition efficiency of up to 63.9%, which is at least 7 times higher than the current transposition efficiency in silkworm. Moreover, the average number of transgene-positive individuals increased up to 5.7-fold, with each positive brood containing an average of 18.1 transgenic silkworms. Finally, we demonstrate that TALE-PBase fusion-mediated PB transposition presents a new insertional preference compared with original insertional preference. This method shows a great potential and value for insertional therapy of many genetic diseases. In conclusion, this new and powerful transposition technology will efficiently promote genetic manipulation studies in both invertebrates and vertebrates. PMID- 26608077 TI - Decidualisation of human endometrial stromal cells is associated with increased expression and secretion of prorenin. AB - BACKGROUND: In pregnancy, the decidualised endometrium expresses high levels of prorenin and other genes of the renin-angiotensin system (RAS) pathway. In this study we aimed to determined if the RAS was present in endometrial stromal cells and if decidualisation upregulated the expression of prorenin, the prorenin receptor ((P)RR) and associated RAS pathways. Immortalised human endometrial stromal cells (HESCs) can be stimulated to decidualise by combined treatment with medroxyprogesterone acetate (MPA), 17beta-estradiol (E2) and cAMP (MPA-mix) or with 5-aza-2'-deoxycytidine (AZA), a global demethylating agent. METHODS: HESCs were incubated for 10 days with one of the following treatments: vehicle, MPA mix, a combination of medroxyprogesterone acetate (MPA) and estradiol-17beta alone, or AZA. Messenger RNA abundance and protein levels of prorenin (REN), the (P)RR (ATP6AP2), angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1), vascular endothelial growth factor (VEGF), and plasminogen activator inhibitor-1 (PAI-1) were measured by real-time PCR and ELISA's, respectively. Promyelocytic zinc finger (PLZF) and phospho inositol-3 kinase (PIK3R1) mRNA abundances were also measured. RESULTS: HESCs expressed the prorenin receptor (ATP6AP2), REN, AGT, ACE and low levels of AGTR1. MPA-mix and AZA stimulated expression of REN. Prorenin protein secretion was increased in MPA-mix treated HESCs. E2 + MPA had no effect on any RAS genes. MPA mix treatment was associated with increased VEGF (VEGFA) and PAI-1 (SERPINE1) mRNA and VEGF protein. CONCLUSIONS: An endometrial prorenin receptor/renin angiotensin system is activated by decidualisation. Since (P)RR is abundant, the increase in prorenin secretion could have stimulated VEGF A and SERPINE1 expression via Ang II, as both ACE and AGTR1 are present, or by Ang II independent pathways. Activation of the RAS in human endometrium with decidualisation, through stimulation of VEGF expression and secretion, could be critical in establishing an adequate blood supply to the developing maternal placental vascular bed. PMID- 26608078 TI - Cardiomyocyte-specific overexpression of oestrogen receptor beta improves survival and cardiac function after myocardial infarction in female and male mice. AB - ERbeta (oestrogen receptor beta) activation has been shown to be cardioprotective, but the cell types and mechanisms involved are not understood. To investigate whether ERbeta restricted to cardiomyocytes contributes to the observed cardioprotection, we tested the effects of cardiomyocyte-specific ERbeta OE (ERbeta overexpression) on survival, cardiac remodelling and function after MI (myocardial infarction) and studied the molecular pathways potentially involved. Female and male mice with cardiomyocyte-specific ERbeta-OE and WT (wild-type) littermates were subjected to chronic anterior coronary artery ligation or sham surgery. Two weeks after MI, ERbeta-OE mice showed improved survival (100% and 83% compared with 76% and 58% in WT females and males respectively). ERbeta-OE was associated with attenuated LV (left ventricular) dilatation, smaller increase in heart weight, less lung congestion at similar MI size, and improved systolic and diastolic function in both sexes. We identified two potential pathways for ERbeta-mediated myocardial protection. First, male and female ERbeta-OE mice had a lower reduction of SERCA2a (sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 2a) expression after MI, suggesting less reduction in diastolic Ca(2+)-reuptake into the sarcoplasmic reticulum post-MI. Secondly, male ERbeta-OE revealed attenuated cardiac fibrosis in the remote LV tissue and expression of fibrosis markers collagen I and III, periostin and miR-21. Cardiomyocyte-specific ERbeta OE improved survival associated with reduced maladaptive remodelling, improved cardiac function and less heart failure development after MI in both sexes. These effects seem to be related, at least in part, to a better maintenance of Ca(2+) cycling in both sexes and a lower induction of cardiac fibrosis in males after MI. PMID- 26608079 TI - Regulation of amino acid transporter trafficking by mTORC1 in primary human trophoblast cells is mediated by the ubiquitin ligase Nedd4-2. AB - Changes in placental amino acid transfer directly contribute to altered fetal growth, which increases the risk for perinatal complications and predisposes for the development of obesity, diabetes and cardiovascular disease later in life. Placental amino acid transfer is critically dependent on the expression of specific transporters in the plasma membrane of the trophoblast, the transporting epithelium of the human placenta. However, the molecular mechanisms regulating this process are largely unknown. Nedd4-2 is an ubiquitin ligase that catalyses the ubiquitination of proteins, resulting in proteasomal degradation. We hypothesized that inhibition of mechanistic target of rapamycin complex 1 (mTORC1) decreases amino acid uptake in primary human trophoblast (PHT) cells by activation of Nedd4-2, which increases transporter ubiquitination resulting in decreased transporter expression in the plasma membrane. mTORC 1 inhibition increased the expression of Nedd4-2, promoted ubiquitination and decreased the plasma membrane expression of SNAT2 (an isoform of the System A amino acid transporter) and LAT1 (a System L amino acid transporter isoform), resulting in decreased cellular amino acid uptake. Nedd4-2 silencing markedly increased the trafficking of SNAT2 and LAT1 to the plasma membrane, which stimulated cellular amino acid uptake. mTORC1 inhibition by silencing of raptor failed to decrease amino acid transport following Nedd4-2 silencing. In conclusion, we have identified a novel link between mTORC1 signalling and ubiquitination, a common posttranslational modification. Because placental mTORC1 is inhibited in fetal growth restriction and activated in fetal overgrowth, we propose that regulation of placental amino acid transporter ubiquitination by mTORC1 and Nedd4-2 constitutes a molecular mechanisms underlying abnormal fetal growth. PMID- 26608080 TI - Cynomolgus Monkey as a Clinically Relevant Model to Study Transport Involving Renal Organic Cation Transporters: In Vitro and In Vivo Evaluation. AB - Organic cation transporter (OCT) 2, multidrug and toxin extrusion protein (MATE) 1, and MATE2K mediate the renal secretion of various cationic drugs and can serve as the loci of drug-drug interactions (DDI). To support the evaluation of cynomolgus monkey as a surrogate model for studying human organic cation transporters, monkey genes were cloned and shown to have a high degree of amino acid sequence identity versus their human counterparts (93.7, 94.7, and 95.4% for OCT2, MATE1, and MATE2K, respectively). Subsequently, the three transporters were individually stably expressed in human embryonic kidney (HEK) 293 cells and their properties (substrate selectivity, time course, pH dependence, and kinetics) were found to be comparable to the corresponding human form. For example, six known human cation transporter inhibitors, including pyrimethamine (PYR), showed generally similar IC50 values against the monkey transporters (within sixfold). Consistent with the in vitro inhibition of metformin (MFM) transport by PYR (IC50 for cynomolgus OCT2, MATE1, and MATE2K; 1.2 +/- 0.38, 0.17 +/- 0.04, and 0.25 +/- 0.04 uM, respectively), intravenous pretreatment of monkeys with PYR (0.5 mg/kg) decreased the clearance (54 +/- 9%) and increased in the area under the plasma concentration-time curve of MFM (AUC ratio versus control = 2.23; 90% confidence interval of 1.57 to 3.17). These findings suggest that the cynomolgus monkey may have some utility in support of in vitro-in vivo extrapolations (IVIVEs) involving the inhibition of renal OCT2 and MATEs. In turn, cynomolgus monkey enabled IVIVEs may inform human DDI risk assessment. PMID- 26608081 TI - Pharmacokinetics and Disposition of the Thiouracil Derivative PF-06282999, an Orally Bioavailable, Irreversible Inactivator of Myeloperoxidase Enzyme, Across Animals and Humans. AB - The thiouracil derivative PF-06282999 [2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2 thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide] is an irreversible inactivator of myeloperoxidase and is currently in clinical trials for the potential treatment of cardiovascular diseases. Concerns over idiosyncratic toxicity arising from bioactivation of the thiouracil motif to reactive species in the liver have been largely mitigated through the physicochemical (molecular weight, lipophilicity, and topological polar surface area) characteristics of PF-06282999, which generally favor elimination via nonmetabolic routes. To test this hypothesis, pharmacokinetics and disposition studies were initiated with PF-06282999 using animals and in vitro assays, with the ultimate goal of predicting human pharmacokinetics and elimination mechanisms. Consistent with its physicochemical properties, PF-06282999 was resistant to metabolic turnover from liver microsomes and hepatocytes from animals and humans and was devoid of cytochrome P450 inhibition. In vitro transport studies suggested moderate intestinal permeability and minimal transporter-mediated hepatobiliary disposition. PF-06282999 demonstrated moderate plasma protein binding across all of the species. Pharmacokinetics in preclinical species characterized by low to moderate plasma clearances, good oral bioavailability at 3- to 5-mg/kg doses, and renal clearance as the projected major clearance mechanism in humans. Human pharmacokinetic predictions using single-species scaling of dog and/or monkey pharmacokinetics were consistent with the parameters observed in the first-in-human study, conducted in healthy volunteers at a dose range of 20-200 mg PF-06282999. In summary, disposition characteristics of PF-06282999 were relatively similar across preclinical species and humans, with renal excretion of the unchanged parent emerging as the principal clearance mechanism in humans, which was anticipated based on its physicochemical properties and supported by preclinical studies. PMID- 26608083 TI - Application of a Micropatterned Cocultured Hepatocyte System To Predict Preclinical and Human-Specific Drug Metabolism. AB - Laboratory animal models are the industry standard for preclinical risk assessment of drug candidates. Thus, it is important that these species possess profiles of drug metabolites that are similar to those anticipated in human, since metabolites also could be responsible for biologic activities or unanticipated toxicity. Under most circumstances, preclinical species reflect human in vivo metabolites well; however, there have been several notable exceptions, and understanding and predicting these exceptions with an in vitro system would be very useful. Human micropatterned cocultured (MPCC) hepatocytes have been shown to recapitulate human in vivo qualitative metabolic profiles, but the same demonstration has not been performed yet for laboratory animal species. In this study, we investigated several compounds that are known to produce human unique metabolites through CYP2C9, UGT1A4, aldehyde oxidase (AO), or N acetyltransferase that were poorly covered or not detected at all in the selected preclinical species. To perform our investigation we used 24-well MPCC hepatocyte plates having three individual human donors and a single donor each of monkey, dog, and rat to study drug metabolism at four time points per species. Through the use of the multispecies MPCC hepatocyte system, the metabolite profiles of the selected compounds in human donors effectively captured the qualitative in vivo metabolite profile with respect to the human metabolite of interest. Human unique metabolites that were not detected in vivo in certain preclinical species (normally dog and rat) were also not generated in the corresponding species in vitro, confirming that the MPCC hepatocytes can provide an assessment of preclinical species metabolism. From these results, we conclude that multispecies MPCC hepatocyte plates could be used as an effective in vitro tool for preclinical understanding of species metabolism relative to humans and aid in the choice of appropriate preclinical models. PMID- 26608082 TI - Developmental Expression of CYP2B6: A Comprehensive Analysis of mRNA Expression, Protein Content and Bupropion Hydroxylase Activity and the Impact of Genetic Variation. AB - Although CYP2B6 catalyzes the biotransformation of many drugs used clinically for children and adults, information regarding the effects of development on CYP2B6 expression and activity are scarce. Utilizing a large panel of human liver samples (201 donors: 24 fetal, 141 pediatric, and 36 adult), we quantified CYP2B6 mRNA and protein expression levels, characterized CYP2B6 (bupropion hydroxylase) activity in human liver microsomes (HLMs), and performed an extensive genotype analysis to differentiate CYP2B6 haplotypes such that the impact of genetic variation on these parameters could be assessed. Fetal livers contained extremely low levels of CYP2B6 mRNA relative to postnatal samples and fetal HLMs did not appear to catalyze bupropion hydroxylation; however, fetal CYP2B6 protein levels were not significantly different from postnatal levels. Considerable interindividual variation in CYP2B6 mRNA expression, protein levels, and activity was observed in postnatal HLMs (mRNA, ~40,000-fold; protein, ~300-fold; activity, ~600-fold). The extremely wide range of interindividual variability in CYP2B6 expression and activity was significantly associated with age (P < 0.01) following log transformation of the data. Our data suggest that CYP2B6 activity appears as early as the first day of life, increases through infancy, and by 1 year of age, CYP2B6 levels and activity may approach those of adults. Surprisingly, CYP2B6 interindividual variability was not significantly associated with genetic variation in CYP2B6, nor was it associated with differences in gender or ethnicity, suggesting that factors other than these are largely responsible for the wide range of variability in CYP2B6 expression and activity observed among a large group of individuals/samples. PMID- 26608084 TI - Staffing levels are not to blame for worse obstetric outcomes at weekends, study finds. PMID- 26608085 TI - Sleep Duration and School Readiness of Chinese Preschool Children. AB - OBJECTIVES: To examine the average sleep duration in Chinese preschoolers and to investigate the association between sleep duration and school readiness. STUDY DESIGN: This is a cross-sectional study that included 553 Chinese children (mean age = 5.46 years) from 20 preschools in 2 districts of Hong Kong. Average daily sleep duration in the last week was reported by parents and school readiness as measured by the teacher-rated Chinese Early Development Instrument (CEDI). RESULTS: Most Chinese preschoolers had 9-10 hours of sleep per day. Only 11% of preschoolers had the recommended 11-12 hours of sleep per day. This group was associated with more "very ready" CEDI domains. Sleep deprivation (<=7 hours per day) was associated with a lower CEDI total score, lower scores in the emotional maturity and language/cognitive domain, and prosocial behaviors subdomain but a greater score in the hyperactivity/inattention subdomain. Children with a lower family socioeconomic index, lower maternal education level, infrequent parent child interactions, and who used electronic devices for more than 3 hours per day had shortened sleep durations. CONCLUSIONS: Optimal sleep duration was associated with better school readiness in preschool children, whereas sleep deprivation was associated with lower school readiness, more hyperactivity and inattention, and less prosocial behavior. PMID- 26608086 TI - Pediatric Ocular Tuberculosis - Choroidal Tubercles. PMID- 26608087 TI - Abnormal Eating Behaviors Are Common in Children with Fetal Alcohol Spectrum Disorder. AB - OBJECTIVE: To compare the eating behaviors and nutrition-related concerns in children with fetal alcohol spectrum disorder (FASD) with those in typically developing children. STUDY DESIGN: A survey that assessed eating behaviors was completed between October 2013 and May 2014 by the caregivers of children screened for FASD at the University of Minnesota's Fetal Alcohol Spectrum Disorders Program, and typically developing children recruited from that clinic or from the Research Participation Core of the Waisman Center, University of Wisconsin. RESULTS: Compared with controls (N = 81), children with FASD (N = 74) had delayed acquisition of self-feeding behavior (P < .001) and solid food introduction (P < .001). Impaired satiety was common and independent of medication use: 23.0% were never full/satisfied, 31.1% snacked constantly, and 27.0% concealed food (all P <= .002). They consumed the equivalent of an additional meal/snack daily (P < .01). Children with FASD were more likely to have a past diagnosis of underweight (P < .001). Mean body mass index was significantly reduced for males (P = .009) but not females (P = .775) with FASD, and only 2 children with FASD were currently underweight. Children with FASD were more physically active (P < .01). CONCLUSIONS: Abnormal eating patterns are common in children with FASD and may contribute to their delayed growth and nutritional inadequacies. Their poor satiety may reflect poor impulse control. Children with FASD may benefit from diet counseling. Conversely, some children with hyperphagia may warrant referral for FASD screening. PMID- 26608088 TI - Obstetric and Neonatal Adversities, Parity, and Tourette Syndrome: A Nationwide Registry. AB - OBJECTIVE: To determine the relationships between parity, obstetric adversities, neonatal factors, and Tourette syndrome in a large nationwide cohort. STUDY DESIGN: This nationwide, register-based, nested case-control study identified all children diagnosed with Tourette syndrome born between 1991 and 2010 from the Finnish Hospital Discharge Register (n = 767). Each case was matched to 4 controls. Information on parity, obstetric, and neonatal factors was obtained from the Finnish Medical Birth Register. Conditional logistic regression was used to determine the relationship between parity, obstetric, and neonatal factors, and Tourette syndrome. RESULTS: Nulliparity was associated with increased odds for Tourette syndrome (OR 1.7, 95% CI 1.4-2.2), and 3 or more previous births was associated with decreased odds for Tourette syndrome (OR 0.5, 95% CI 0.3-0.9) compared with parity 1-2. Birth weight 4000-4499 g was associated with decreased odds for Tourette syndrome (OR 0.7, 95% CI 0.5-0.9). Low birth weight, gestational age, weight for gestational age, Apgar score at 1 minute, induced labor, birth type or presentation, neonatal treatment, or maternal blood pressure were not associated with Tourette syndrome. CONCLUSIONS: Increasing parity and high birth weight are associated with decreased odds for Tourette syndrome. PMID- 26608089 TI - Preterm Toddlers' Inhibitory Control Abilities Predict Attention Regulation and Academic Achievement at Age 8 Years. AB - OBJECTIVE: To determine if adverse effects of preterm birth on attention and academic abilities at age 8 years are mediated by children's inhibitory control abilities. STUDY DESIGN: Five hundred fifty-eight children born at 26-41 weeks gestation were studied as part of a prospective geographically defined longitudinal investigation in Germany. Toddlers' inhibitory control abilities were observed at age 20 months. At 8 years, attention and academic abilities were assessed. RESULTS: Preterm birth negatively affected children's inhibitory control abilities (B = .25, 95% CI [.11, .39], P < .001) and directly predicted subsequent low attention regulation (B = .23, 95% CI [.07, .38], P < .001) and academic achievement (B = .10, 95% CI [.03, .17], P < .001), after adjusting for other factors. Higher ability to inhibit unwanted behaviors predicted better later attention regulation (B = .24, 95% CI [.07, .41], P < .001) and academic achievement (B = .10, 95% CI [.03, .17], P < .001). CONCLUSIONS: The lower a child's gestational age, the lower the inhibitory control and the more likely that the child had poor attention regulation and low academic achievement. Adverse effects of preterm birth on attention and academic outcomes are partially mediated by toddlers' inhibitory control abilities. These findings provide new information about the mechanisms linking preterm birth with long-term attention difficulties and academic underachievement. PMID- 26608090 TI - Epidemiology and factors associated with candidaemia following Clostridium difficile infection in adults within metropolitan Atlanta, 2009-2013. AB - We assessed prevalence of and risk factors for candidaemia following Clostridium difficile infection (CDI) using longitudinal population-based surveillance. Of 13 615 adults with CDI, 113 (0.8%) developed candidaemia in the 120 days following CDI. In a matched case-control analysis, severe CDI and CDI treatment with vancomycin + metronidazole were associated with development of candidaemia following CDI. PMID- 26608091 TI - Ocular lesions produced by pine processionary caterpillar setae (Thaumetopoea pityocampa) in dogs: a descriptive study. AB - OBJECTIVE: To describe, for the first time in dogs, the ocular lesions induced by the pine processionary caterpillar (PPC) setae, and the associated corneal histopathology, medical treatment, and outcome. ANIMAL STUDIED: One hundred and forty client-owned dogs from Spain were studied. One hundred and twenty dogs came from the central area of Spain, 13 from the southern area, six from the northern area, and one dog came from the Mediterranean area. PROCEDURE: Medical records from four veterinary ophthalmology practices were reviewed. Dogs that were presented from endemic areas and that had PPC setae identified during their ophthalmic examination were included in the study. RESULTS: The following ocular lesions were identified: keratitis with crescent- or circular-shaped white stromal cellular infiltrates (98.57% [n = 138]), anterior uveitis (78.57% [n = 110]), conjunctival hyperemia and chemosis (33.57% [n = 47]), blepharitis (8.57% [n = 12]), and corneal ulcers (2.86% [n = 4]). Removal of the hairs by saline hydropulsion and medical treatment was successful in 99.29% (n = 139) of the cases. A single case healed following additional corneal reconstructive surgery to remove the deep corneal lesion and subsequent histopathology revealed an acute lesion with necrotic neutrophilic infiltrate and corneal edema. All ocular lesions resolved completely within 15 and 30 days after presentation, with the exception of one case that developed endophthalmitis. CONCLUSION: Pine processionary caterpillar should be included in the differential diagnosis of acute ocular lesions, especially if keratitis with corneal cellular infiltrate and anterior uveitis are present, in dogs from endemic areas during the months of spring and summer. In the majority of cases, irrigation and removal of the hairs together with medical treatment leads to a good outcome. PMID- 26608092 TI - The expanding relevance of executive functioning in occupational therapy: Is it on your radar? PMID- 26608093 TI - Symptomatic BK Virus Infection Is Associated With Kidney Function Decline and Poor Overall Survival in Allogeneic Hematopoietic Stem Cell Recipients. AB - Nephropathy due to BK virus (BKV) infection is an evolving challenge in patients undergoing hematopoietic stem cell transplantation (HSCT). We hypothesized that BKV infection was a marker of kidney function decline and a poor prognostic factor in HSCT recipients who experience this complication. In this retrospective study, we analyzed all patients who underwent their first allogeneic HSCT at our institution between 2004 and 2012. We evaluated the incidence of persistent kidney function decline, which was defined as a confirmed reduction in estimated glomerular filtration rate of at least 25% from baseline using the Chronic Kidney Disease Epidemiology equation. Cox proportional hazard regression was used to model the cause-specific hazard of kidney function decline, and the Fine-Gray method was used to account for the competing risks of death. Among 2477 recipients of a first allogeneic HSCT, BK viruria was detected in 25% (n = 629) and kidney function decline in 944 (38.1%). On multivariate analysis, after adjusting for age, sex, acute graft-versus-host disease (GVHD), chronic GVHD, preparative conditioning regimen, and graft source, BK viruria remained a significant risk factor for kidney function decline (p < 0.001). In addition, patients with BKV infection and kidney function decline experienced worse overall survival. After allogeneic HSCT, BKV infection was strongly and independently associated with subsequent kidney function decline and worse patient survival after HSCT. PMID- 26608095 TI - Hepatocellular Carcinoma Presenting as an Incidental Right Atrial Mass. PMID- 26608094 TI - Whole-exome and targeted sequencing identify ROBO1 and ROBO2 mutations as progression-related drivers in myelodysplastic syndromes. AB - The progressive mechanism underlying myelodysplastic syndrome remains unknown. Here we identify ROBO1 and ROBO2 as novel progression-related somatic mutations using whole-exome and targeted sequencing in 6 of 16 (37.5%) paired MDS patients with disease progression. Further deep sequencing detects 20 (10.4%) patients with ROBO mutations in a cohort of 193 MDS patients. In addition, copy number loss and loss of heterogeneity (LOH) of ROBO1 and ROBO2 are frequently observed in patients with progression or carrying ROBO mutations. In in vitro experiments, overexpression of ROBO1 or ROBO2 produces anti-proliferative and pro-apoptotic effects in leukaemia cells. However, this effect was lost in ROBO mutants and ROBO-SLIT2 signalling is impaired. Multivariate analysis shows that ROBO mutations are independent factors for predicting poor survival. These findings demonstrate a novel contribution of ROBO mutations to the pathogenesis of MDS and highlight a key role for ROBO-SLIT2 signalling in MDS disease progression. PMID- 26608096 TI - The roles of c-Jun NH2-terminal kinases (JNKs) in obesity and insulin resistance. AB - Obesity is currently at epidemic levels worldwide and is associated with a wide range of diseases such as type 2 diabetes, cardiovascular disease, fatty liver disease and certain forms of cancer. Obesity-induced chronic inflammation is central to the disrupted metabolic homeostasis which underlies many of these conditions. While research over the past decade has identified many of the cells and signalling molecules that contribute to obesity-induced inflammation, perhaps the best characterised are the stress-activated c-Jun NH2 -terminal kinases (JNKs). JNKs are activated in obesity in numerous metabolically important cells and tissues such as adipose tissue, macrophages, liver, skeletal muscle and regions of the brain and pituitary. Elegant in vivo mouse studies using Cre-LoxP mediated recombination of the JNK1 and JNK2 genes have revealed the remarkably diverse roles that JNKs play in the development of obesity-induced inflammation, impaired glucose homeostasis and hepatic steatosis. While JNK activation in classical metabolically active tissues such as skeletal muscle and adipose tissue only appears to play a minor role on the induction of the above-mentioned pathologies, recent studies have clearly established the important roles JNK signalling fulfils in macrophages, the liver and cells of the anterior pituitary. Collectively, these studies place JNKs as important mediators of obesity and obesity-associated disruptions to metabolic homeostasis. PMID- 26608098 TI - Near-IR BODIPY Dyes a la Carte-Programmed Orthogonal Functionalization of Rationally Designed Building Blocks. AB - Herein, we report the synthesis of polyfunctional BODIPY building blocks suitable to be subjected to several reaction sequences with complete chemoselectivity, thereby allowing the preparation of complex BODIPY derivatives in a versatile and programmable manner. The reactions included the Liebeskind-Srogl cross-coupling reaction (LSCC), nucleophilic aromatic substitution (SN Ar), Suzuki, Sonogashira, and Stille couplings, and a desulfitative reduction of the MeS group. This novel synthetic protocol is a powerful route to design a library of compounds with tailored photophysical properties for advanced applications. In this context, it is noteworthy that it offers a straightforward and cost-effective strategy to shift the BODIPY emission deep into the near-infrared spectral region while retaining high fluorescence quantum yields as well as highly efficient and stable laser action. These new dyes outperform the lasing behaviour of dyes considered as benchmarks over the red spectral region, overcoming the important drawbacks associated with these commercial laser dyes, namely low absorption at the standard pump wavelengths (355 and 532 nm) and/or poor photostability. PMID- 26608097 TI - Protein-protein interaction networks identify targets which rescue the MPP+ cellular model of Parkinson's disease. AB - Neurodegenerative diseases are complex multifactorial disorders characterised by the interplay of many dysregulated physiological processes. As an exemplar, Parkinson's disease (PD) involves multiple perturbed cellular functions, including mitochondrial dysfunction and autophagic dysregulation in preferentially-sensitive dopamine neurons, a selective pathophysiology recapitulated in vitro using the neurotoxin MPP(+). Here we explore a network science approach for the selection of therapeutic protein targets in the cellular MPP(+) model. We hypothesised that analysis of protein-protein interaction networks modelling MPP(+) toxicity could identify proteins critical for mediating MPP(+) toxicity. Analysis of protein-protein interaction networks constructed to model the interplay of mitochondrial dysfunction and autophagic dysregulation (key aspects of MPP(+) toxicity) enabled us to identify four proteins predicted to be key for MPP(+) toxicity (P62, GABARAP, GBRL1 and GBRL2). Combined, but not individual, knockdown of these proteins increased cellular susceptibility to MPP(+) toxicity. Conversely, combined, but not individual, over-expression of the network targets provided rescue of MPP(+) toxicity associated with the formation of autophagosome-like structures. We also found that modulation of two distinct proteins in the protein-protein interaction network was necessary and sufficient to mitigate neurotoxicity. Together, these findings validate our network science approach to multi-target identification in complex neurological diseases. PMID- 26608099 TI - Can prehospital Modified Early Warning Score identify non-trauma patients requiring life-saving intervention in the emergency department? AB - OBJECTIVE: We aim to investigate whether prehospital Modified Early Warning Score (MEWS) can identify non-trauma patients requiring life-saving intervention (LSI) within 4 h of presentation to the ED. METHODS: It was a prospective study of non trauma ED patients by ambulance who were 16 years or older from 1 to 27 November 2013. Prehospital MEWS was calculated according to vital signs measured by the ambulance crew. Data on patients' demographics, triage category, LSI within 4 h of ED presentation and 24 h mortality were retrieved. LSI was defined as emergency interventions to airway, breathing and circulation, emergency procedures and medications administered. The performance of prehospital MEWS was analysed with sensitivity, specificity, predictive values (PV), likelihood ratios (LR) and the receiver operating characteristic curve. RESULTS: Recruited during the study period were 1493 patients. The median age was 78 years. Of the patients, 49.9% belonged to critical, emergent or urgent triage categories. LSI was required in 321 patients (21.5%). Thirteen died within 24 h of ED presentation. The area under the receiver operating characteristic curve of prehospital MEWS relating to LSI was 0.72 (95% confidence interval 0.69 to 0.75). The sensitivity, specificity, positive PV, negative PV, positive LR and negative LR were 0.57, 0.76, 0.40, 0.87, 2.43 and 0.56, respectively, when prehospital MEWS >=3 was chosen as the cut-off value. CONCLUSIONS: Prehospital MEWS is useful in identifying non-trauma patients requiring LSI within 4 h of ED presentation. This may in turn enhance the triage accuracy in the ED in addition to clinical assessment. PMID- 26608100 TI - Birt-Hogg-Dube syndrome: Clinical and molecular aspects of recently identified kidney cancer syndrome. AB - Birt-Hogg-Dube syndrome is an autosomal dominantly inherited disease that predisposes patients to develop fibrofolliculoma, lung cysts and bilateral multifocal renal tumors, histologically hybrid oncocytic/chromophobe tumors, chromophobe renal cell carcinoma, oncocytoma, papillary renal cell carcinoma and clear cell renal cell carcinoma. The predominant forms of Birt-Hogg-Dube syndrome associated renal tumors, hybrid oncocytic/chromophobe tumors and chromophobe renal cell carcinoma are typically less aggressive, and a therapeutic principle for these tumors is a surgical removal with nephron-sparing. The timing of surgery is the most critical element for postoperative renal function, which is one of the important prognostic factors for Birt-Hogg-Dube syndrome patients. The folliculin gene (FLCN) that is responsible for Birt-Hogg-Dube syndrome was isolated as a novel tumor suppressor for kidney cancer. Recent studies using murine models for FLCN, a protein encoded by the FLCN gene, and its two binding partners, folliculin-interacting protein 1 (FNIP1) and folliculin-interacting protein 2 (FNIP2), have uncovered important roles for FLCN, FNIP1 and FNIP2 in cell metabolism, which include AMP-activated protein kinase-mediated energy sensing, Ppargc1a-driven mitochondrial oxidative phosphorylation and mTORC1 dependent cell proliferation. Birt-Hogg-Dube syndrome is a hereditary hamartoma syndrome, which is triggered by metabolic alterations under a functional loss of FLCN/FNIP1/FNIP2 complex, a critical regulator of kidney cell proliferation rate; a mechanistic insight into the FLCN/FNIP1/FNIP2 pathway could provide us a basis for developing new therapeutics for kidney cancer. PMID- 26608101 TI - iTRAQ protein profile analysis provides integrated insight into mechanisms of tolerance to TMV in tobacco (Nicotiana tabacum). AB - To further investigate the mechanism of the plant tolerance to tobacco mosaic virus (TMV) infection, tobacco NC89 (N) hypersensitive to TMV and its natural mutant Yuyan8 (Y) with tolerance to TMV were employed for differential accumulation proteome analysis. There were 260 specifically accumulated proteins in Yuyan8 after 24 h inoculation (Yd), and the accumulations of 285 proteins inherent in Y have changed after TMV infection. Equally, there were 183 specifically accumulated proteins in NC89 after 24 h inoculation (Nd), and 132 proteins inherent in N have changed after TMV infection. These differential proteins were respectively enriched in two pathways, of which photosynthesis pathway was the common pathway in two varieties. In photoreaction system, the accumulations of differential proteins, especially D1 protein, were not decreased in Yd compared to Nd. The results indicated that maintaining the stability of D1 protein and reasonable utilization of the energy was the essential for tolerance to TMV infection. It was also revealed that 14-3-3 protein and PR4 was specific expressed, and the expression of LRR was enhanced in Yd, suggesting that regulation of defense protein mediated by 14-3-3 protein quickly activated resistance system and enhanced the plant tolerance to TMV infection. SIGNIFICANCE: This is the first work that the molecular basis of tobacco tolerance was discussed basic on proteomic investigation performed on wild type and its natural mutant. Our results lay the foundation for development of molecular breeding and further proteome research in tobacco. PMID- 26608102 TI - A case of Langerhans' cell histiocytosis associated with Hodgkin's lymphoma: Fine needle aspiration cytologic and histopathological features. AB - Langerhans cell histiocytosis (LCH) can be associated with a variety of malignant neoplasms, the most common being malignant lymphoma, especially Hodgkin's lymphoma (HL). In this report, we describe the fine needle aspiration (FNA) cytologic features of a case with concurrent LCH and HL in a lymph node. A 20 year-old man presented with an enlarged left upper cervical lymph node. FNA smears from the swelling revealed numerous CD1a+ and S-100+ Langerhans-type cells (LCs) along with many eosinophils, neutrophils, and lymphocytes; there were also large atypical cells with enlarged nuclei having prominent nucleoli. The cytodiagnosis was LCH and the possibility of association with or trans differentiation into a lymphoma was suggested. The histopathological diagnosis of the excised left cervical lymph node was classical HL-nodular sclerosis type (CHL NS) with LCH. The lacunar type Reed-Sternberg (RS) cells were positive for CD30 and CD15, and the LCs were positive for CD1a and S-100 protein. PET/CT imaging demonstrated hypermetabolic lymph nodes in neck, abdomen, thorax and pelvis as well as pulmonary nodules and a splenic mass. The patient received 13 courses of chemotherapy and two years later, the enhanced CT revealed regressive course of the disease. PMID- 26608103 TI - New lenses to look at preeclampsia. PMID- 26608104 TI - Effects of different forages on the chemical compositions and antiosteoporotic activities of velvet antlers. AB - For this study, we aimed to assess the dose-response antiosteoporotic effects of the middle section of velvet antlers (VAs) from sika deers (Cervus nippon) fed with different types of fodders. VAs prepared from farmed sika deers fed with feed mixtures containing sorghum distillery residue (VA-SDR) or without SDR (SDR replaced with hay, VA-Hay) were divided into upper (VAU), middle (VAM) and basal (VAB) sections. The chemical constituents of the middle sections obtained from each VA type were compared, and their antiosteoporotic activities were evaluated using rats with ovaries removed surgically (ovariectomy, OVX). The VA-Hay exhibited markedly increased iron and cysteine levels, whereas the VA-SDR exhibited markedly increased level of alcoholic extract and testosterone. Both VA Hay- and VA-SDR-treated rats exhibited increased femur strength compared with the control group. However, VA-SDR exhibited greater bone-strengthening effects than did VA-Hay. The serum osteocalcin and estradiol levels were significantly moderated in the VA-Hay group alone. These results suggest that VA-SDR and VA-Hay prevent the loss of bone strength, and preserve trabecular architecture connectivity in an estrogen-deficient state. However, differences in the chemical compositions of different forages may be responsible for the varying antiosteoporotic mechanisms observed. Thus, the addition of SDR in deer forage may enhance antiosteoporosis activity in VAs, and confer considerable economic and ecological benefits. PMID- 26608106 TI - Practice-Readiness of U.S. Pharmacy Graduates to Provide Direct Patient Care. PMID- 26608105 TI - Effects of albendazole combined with TSII-A (a Chinese herb compound) on optic neuritis caused by Angiostrongylus cantonensis in BALB/c mice. AB - BACKGROUND: Angiostrongylus cantonensis (A. cantonensis) infection can lead to optic neuritis, retinal inflammation, damage to ganglion cells, demyelination of optic nerve and visual impairment. Combined therapy of albendazole and dexamethasone is a common treatment for the disease in the clinic, but it plays no role in vision recovery. Therefore, it has been necessary to explore alternative therapies to treat this disease. Previous studies reported the neuro productive effects of two constituents of Danshen (a Chinese herb)-tanshinone II A (TSII-A) and cryptotanshinone (CPT), and this study aims to evaluate the impacts of TSII-A or CPT combined with albendazole on optic neuritis caused by A. cantonensis infection in a murine model. METHODS: To assess the effects of TSII-A or CPT combined with albendazole on optic neuritis due to the infection, mice were divided into six groups, including the normal control group, infection group and four treatment groups (albendazole group, albendazole combined with dexamethasone group, albendazole combined with CPT group and albendazole combined with TSII-A group). The infection group and treatment groups were infected with A. cantonensis and the treatment groups received interventions from 14 dpi (days post infection), respectively. At 21 dpi, the visual acuity of mice in each group was examined by visual evoked potential (VEP). The pathologic alteration of the retina and optic nerve were observed by hematoxylin and eosin (H&E) staining and transmission electronic microscopy (TEM). RESULTS: Infection of A. cantonensis caused prolonged VEP latency, obvious inflammatory cell infiltration in the retina, damaged retinal ganglions and retinal swelling, followed by optic nerve fibre demyelination and a decreasing number of axons at 21 dpi. In treatment groups, albendazole could not alleviate the above symptoms; albendazole combined with dexamethasone lessened the inflammation of the retina, but was futile for the other changes; however, albendazole combined with CPT and albendazole combined with TSII-A showed obvious effects on the recovery of prolonged VEP latency, destruction and reduction of ganglion cells, optic nerve demyelination and axon loss. Compared with albendazole-CPT compound, albendazole combined with TSII-A was more effective. CONCLUSIONS: The current study demonstrates that albendazole combined with TSII-A plays a more effective role in treating optic neuritis caused by A. cantonensis in mice than with dexamethasone, as applied in conventional treatment, indicating that albendazole combined with TSII-A might be an alternate therapy for this parasitic disease in the clinic. PMID- 26608107 TI - Managing simple food allergy in community settings: A pilot study investigating a new model of care. AB - AIM: The prevalence of food allergy in Australia has increased, paralleled by an increase in waiting time to access tertiary paediatric allergy care. We aimed to test whether a new model of care, based on serum specific IgE testing, was feasible and acceptable to Australian families. METHODS: A prospective pilot intervention study was conducted in community paediatric practices within 20-40 km of The Royal Children's Hospital, Melbourne. Children <=7 years with likely food allergy referred to the Department of Allergy and Immunology at RCH were included; children with anaphylaxis, drug allergy or complex food allergy (>three food groups) were excluded. Community general paediatricians, recruited through the Australian Paediatric Research Network, were trained via webinars on the management of four common food allergy-related scenarios. Paediatrician and child and family parameters were assessed at baseline and 3 months, including safety. RESULTS: 34/45 (76%) eligible families and 10/12 (83%) paediatricians participated. Paediatricians managed 27/34 (80%) of children independently, with 7/34 (20%) requiring referral to an allergist for more complex food allergy. Paediatricians reported improved knowledge and competency in managing food allergy: (mean (standard deviation) scores pre = 35 (5.3) and post = 43.3 (3.9) training). The majority of children received appropriate management; there were no anaphylaxis episodes. There was no significant change in child quality of life or parent mental health. CONCLUSIONS: Management of simple food allergy by community paediatricians appears feasible and acceptable to paediatricians and families alike. Future research will evaluate this approach in an adequately powered and controlled trial. PMID- 26608108 TI - Health-related behaviors and comorbidities in people with epilepsy: Changes in the past decade. AB - OBJECTIVE: We aimed to explore the patterns of health-related behaviors (HRBs) such as smoking and physical activity in people with epilepsy in the community and examine whether behaviors have changed over the past decade. METHODS: We conducted a repeated cross-sectional study using data from a series of five cycles (2001-2011) of the Canadian Community Health Survey, a national population based survey. The proportions and odds ratios with 95% confidence intervals for HRBs and comorbidities in people with epilepsy (PWE) compared to respondents without epilepsy were calculated for each survey over the 10-year period, and estimates were examined for changes over time. RESULTS: The study included 522,722 participants of whom 3,220 (0.6%) had epilepsy. The proportion of PWE who did not participate in physical activity decreased over time (2001 = 17.2%, 2010/2011 = 8.5%), as did the proportion of PWE who smoked cigarettes (2001 = 32.3%, 2010/2011 = 18.0%). PWE had consistently reduced alcohol consumption in comparison to the general population. Fewer than half of participants met the recommended daily guidelines for fruit and vegetable consumption. An apparent reduction in the prevalence of heart disease occurred in PWE (2001 = 11.7%, 2010/2011 = 4.0%), but not in people without epilepsy; however, similar trends were not observed for other cardiovascular comorbidities studied. SIGNIFICANCE: Apparent improvements in smoking cessation and physical activity occurred in PWE. Despite these improvements, physicians should continue to counsel their patients on the importance of healthy lifestyle choices. Further exploration into the reasons for the apparent decrease in the prevalence of heart disease in PWE is warranted. PMID- 26608109 TI - A high-content platform to characterise human induced pluripotent stem cell lines. AB - Induced pluripotent stem cells (iPSCs) provide invaluable opportunities for future cell therapies as well as for studying human development, modelling diseases and discovering therapeutics. In order to realise the potential of iPSCs, it is crucial to comprehensively characterise cells generated from large cohorts of healthy and diseased individuals. The human iPSC initiative (HipSci) is assessing a large panel of cell lines to define cell phenotypes, dissect inter and intra-line and donor variability and identify its key determinant components. Here we report the establishment of a high-content platform for phenotypic analysis of human iPSC lines. In the described assay, cells are dissociated and seeded as single cells onto 96-well plates coated with fibronectin at three different concentrations. This method allows assessment of cell number, proliferation, morphology and intercellular adhesion. Altogether, our strategy delivers robust quantification of phenotypic diversity within complex cell populations facilitating future identification of the genetic, biological and technical determinants of variance. Approaches such as the one described can be used to benchmark iPSCs from multiple donors and create novel platforms that can readily be tailored for disease modelling and drug discovery. PMID- 26608111 TI - [About a case of calcifying fibrous tumor of the pleura]. AB - Calcifying fibrous tumor is a rare soft tissue benign tumor (OMS 2002). Some pleural localisations are described, which affect slightly older individuals than the other soft tissue forms. The calcifying fibrous tumor is included in the 2004 World Health Organization classification of pleural tumors. A pleural tumor located in the right inferior pulmonary lobe is diagnosed in a 59-year-old man. This pleural tumor is macroscopically well-circumscribed. Histologically, the rare spindle tumoral cells are located between bundles of a collagenous tissue, sometimes hyalinized, with psammomatous or dystrophic calcifications. The tumoral cells have a fibrohistiocytic origin. They stain positively for antibodies against vimentin, factor XIIIa, CD68, CD163, CD34. Antibodies against smooth muscle actin, desmin, PS100, ALK1 and EBV are negative. Main differencial diagnoses are other benign pleural tumors (solitary fibrous tumor, inflammatory myofibroblastique tumor), some malignant tumors (desmoplastic malignant pleural mesothelioma) and pleural pseudotumors (calcified pleural plaques, chronic fibrous pleuritis, amylose, hyalinizing granuloma). Our case is the 15th pleural calcifying fibrous tumor being reported. PMID- 26608110 TI - High-throughput imaging: Focusing in on drug discovery in 3D. AB - 3D organotypic culture models such as organoids and multicellular tumor spheroids (MCTS) are becoming more widely used for drug discovery and toxicology screening. As a result, 3D culture technologies adapted for high-throughput screening formats are prevalent. While a multitude of assays have been reported and validated for high-throughput imaging (HTI) and high-content screening (HCS) for novel drug discovery and toxicology, limited HTI/HCS with large compound libraries have been reported. Nonetheless, 3D HTI instrumentation technology is advancing and this technology is now on the verge of allowing for 3D HCS of thousands of samples. This review focuses on the state-of-the-art high-throughput imaging systems, including hardware and software, and recent literature examples of 3D organotypic culture models employing this technology for drug discovery and toxicology screening. PMID- 26608112 TI - The LBP/BPI multigenic family in invertebrates: Evolutionary history and evidences of specialization in mollusks. AB - LBPs (lipopolysaccharide binding proteins) and BPIs (bactericidal permeability increasing proteins) are important proteins involved in defense against bacterial pathogens. We recently discovered a novel biocidal activity of a LBP/BPI from the gastropod Biomphalaria glabrata and demonstrated its role in parental immune protection of eggs, highlighting the importance of LBP/BPIs in invertebrate immunity. Here we characterize four additional LBP/BPI from B. glabrata, presenting conserved sequence architecture and exon-intron structure. Searches of invertebrate genomes revealed that existence of LBP/BPIs is not a conserved feature since they are absent from phyla such as arthropods and platyhelminths. Analyses of LBP/BPI transcripts from selected mollusk species showed recent parallel duplications in some species, including B. glabrata. In this snail species, LBP/BPI members vary in their expression tissue localization as well as their change in expression levels after immune challenges (Gram-negative bacterium; Gram-positive bacterium or yeast). These results, together with the predicted protein features provide evidences of functional specialization of LBP/BPI family members in molluscs. PMID- 26608113 TI - Does home care for dependent elderly people improve their mental health? AB - While theoretical models on long-term care decisions assume that the health production function of dependent elderly depends positively on the care received, it has not received much attention in the empirical literature. We estimate the effects of both informal and formal home care on the mental health of elderly individuals in France needing help with daily activities. We adjust for the endogeneity of care with instrumental variables, using characteristics of adult children and geographical disparities in access to public long-term care coverage. The results show that informal care reduces the risk of depression of dependent elderly and that formal care increases their general mental health. PMID- 26608114 TI - Maintenance strategy in metastatic colorectal cancer: A systematic review. AB - PURPOSE: Colorectal cancer is the third most common cancer in men and second in women, estimated to cause 694,000 deaths worldwide in 2012. Although 5-year survival rate of CRC has increased, inoperable metastatic colorectal cancer (mCRC) is almost always fatal. The aim of this systematic review is to outline the maintenance strategies that increase the chance and duration of survival with less toxicity and sustained quality of life. DESIGN: Literature search in PubMed, in American Society of Clinical Oncology (ASCO) Annual Meetings and in ASCO Gastrointestinal Symposia and European Society for Medical Oncology (ESMO) Congresses was performed. Studies conducted in adult patients were written in English language and were published in peer-reviewed journals as phase II or III randomized controlled trials (RCTs) comparing continuous chemotherapy to intermittent chemotherapy, each with or without maintenance therapy was included along with at least one of the outcomes of interest. RESULTS: Twenty randomized controlled trials and systematic reviews were included from Medline search, together with 4 abstracts from ASCO meetings and 2 abstracts from ESMO meetings. CONCLUSION: Existing evidence-based data show that prolonged progression free survival (PFS) can be achieved with less toxic regimens compared to complete drug holidays or continued treatment. However, the impact of maintenance on overall survival is less clear. The specific data for maintenance with biological agents are evolving, while in general fluoropyrimidine based maintenance with bevacizumab is better than Bev alone or observation for PFS. Data regarding Cetuximab maintenance are less pronounced than that of Bev maintenance. Preliminary data show that erlotinib-Bev combination may be of benefit as maintenance. Although maintenance may provide significant clinical benefit in clinical studies, the optimal strategy should still be individualized. PMID- 26608115 TI - Serial B-Type Natriuretic Peptide in Aortic Stenosis: A Practical Tool for Prediction of Outcome and Intervention Timing? PMID- 26608116 TI - Peripartum Cardiomyopathy in 2015. PMID- 26608117 TI - First-in-Man Computed Tomography-Guided Percutaneous Revascularization of Coronary Chronic Total Occlusion Using a Wearable Computer: Proof of Concept. AB - We report a case of successful computed tomography-guided percutaneous revascularization of a chronically occluded right coronary artery using a wearable, hands-free computer with a head-mounted display worn by interventional cardiologists in the catheterization laboratory. The projection of 3-dimensional computed tomographic reconstructions onto the screen of virtual reality glass allowed the operators to clearly visualize the distal coronary vessel, and verify the direction of the guide wire advancement relative to the course of the occluded vessel segment. This case provides proof of concept that wearable computers can improve operator comfort and procedure efficiency in interventional cardiology. PMID- 26608118 TI - Monomer conversion, microhardness, internal marginal adaptation, and shrinkage stress of bulk-fill resin composites. AB - OBJECTIVE: To evaluate degree of conversion (DC), Knoop microhardness (KHN), internal marginal adaptation (IA), and polymerization shrinkage stress (PS) of one conventional and four bulk-fill composites. METHODS: Bulk-fill composites tested were Surefil SDR (SDR), Filtek Bulk-Fill (FBF), Tetric EvoCeram Bulk-Fill (TEC), and EverX Posterior (EXP). The conventional composite Herculite Classic (HER) was tested using both incremental and bulk-fill insertion techniques. Standardized Class I preparations (4-mm-depth) were made in extracted molars and restored with each product system (N=5). After 1-week wet storage, restorations were cross-sectioned and DC and KHN were evaluated at four depths (1, 2, 3, and 4mm) using confocal Raman spectroscopy and KHN techniques, respectively. Epoxy resin replicas of restorations were evaluated using scanning electron microscopy for IA. PS was determined using composite bonded to acrylic rods attached to a universal testing machine (N=5). RESULTS: Within bulk-fill products, only SDR and FBF demonstrated similar DC at all depths, and KHN values did not statistically differ among depths, except for TEC. Neither placement method nor depth affected KHN or DC, except the DC of HER bulk-fill at 4mm. Incrementally layered HER, and bulk-fills SDR and TEC demonstrated the lowest proportion of internal gaps. Highest and lowest PS values were measured for EXP and TEC, respectively. SIGNIFICANCE: DC with depth was not uniform among all bulk-fill materials, although no difference in KHN was found. Higher PS correlated positively with higher proportion of interfacial gaps. The incremental technique using conventional composite showed reduced gap formation. PMID- 26608119 TI - The use of gene expression profiling and mutation analysis increases the cost of care for patients with carcinoma of unknown primary; does it also improve survival? PMID- 26608121 TI - The influence of industry sponsorship on the reporting of subgroup analyses within phase III randomised controlled trials in gastrointestinal oncology. AB - PURPOSE: Correct interpretation of subgroup analyses (SGA) is important as it influences selection of therapeutic interventions for patient subsets. The primary aim of our study was to compare reporting of SGA between industry and non industry sponsored trials. METHODS: We performed a systematic literature review and extracted data from journal articles (JA) and conference abstracts (CA) published over a decade reporting SGA results of phase III randomised controlled gastrointestinal (GI) oncology trials with patient participants of >=150. RESULTS: In JA, SGA was reported in 100/145 (69%) trials: 41/54 industry sponsored (76%; 95% confidence interval [CI]: 63-86%) and 59/91 non-industry sponsored (65%; 95% CI: 55-74%) trials (p = 0.16). In CA, SGA was reported in 86/204 (42%) trials: 43/83 industry sponsored (52%; 95% CI: 41-62%) and 43/121 non-industry sponsored (36%; 95% CI: 28-44%) trials (p = 0.02). Number of SGA performed per trial was significantly larger for industry compared to non industry sponsored trials in both JA (median 6 versus 2, p = 0.003) and CA (median 1 versus 0, p = 0.023). Claims of subgroup effect were made in 52% of trials in JA and 50% in CA, with significant test of interaction evident in only 25% of JA and 16% of CA, with no difference between industry and non-industry trials. Industry sponsored trials with a significant primary end-point reported more SGA (p < 0.001 JA; p = 0.046 CA). CONCLUSIONS: Industry sponsored trials reported more SGA. Claimed subgroup effects were often not accompanied by significant interaction test; thus circumspection should be adopted when using SGA to deviate from standard therapeutic decision-making in GI oncology. PMID- 26608123 TI - Cortical control of anticipatory postural adjustments prior to stepping. AB - Human bipedal balance control is achieved either reactively or predictively by a distributed network of neural areas within the central nervous system with a potential role for cerebral cortex. While the role of the cortex in reactive balance has been widely explored, only few studies have addressed the cortical activations related to predictive balance control. The present study investigated the cortical activations related to the preparation and execution of anticipatory postural adjustment (APA) that precede a step. This study also examined whether the preparatory cortical activations related to a specific movement is dependent on the context of control (postural component vs. focal component). Ground reaction forces and electroencephalographic (EEG) data were recorded from 14 healthy adults while they performed lateral weight shift and lateral stepping with and without initially preloading their weight to the stance leg. EEG analysis revealed that there were distinct movement-related potentials (MRPs) with concurrent event-related desynchronization (ERD) of mu and beta rhythms prior to the onset of APA and also to the onset of foot-off during lateral stepping in the fronto-central cortical areas. Also, the MRPs and ERD prior to the onset of APA and onset of lateral weight shift were not significantly different suggesting the comparable cortical activations for the generation of postural and focal movements. The present study reveals the occurrence of cortical activation prior to the execution of an APA that precedes a step. Importantly, this cortical activity appears independent of the context of the movement. PMID- 26608120 TI - Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms. AB - BACKGROUND: Acquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance. METHODS: We compiled clinical and genetic data from 100 patients with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole-exome sequencing and/or polymerase chain reaction-based genetic testing. RESULTS: Among 132 samples, putative resistance mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAF(V600E/K) amplifications (13%), MEK1/2 mutations (7%), and non-mitogen-activated protein kinase pathway alterations (11%). Marked heterogeneity was observed within tumors and patients; 18 of 19 patients (95%) with more than one progression biopsy had distinct/unknown drivers of resistance between samples. NRAS mutations were associated with vemurafenib use (p = 0.045) and intracranial metastases (p = 0.036), and MEK1/2 mutations correlated with hepatic progression (p = 0.011). Progression-free survival and overall survival were similar across resistance mechanisms. The median survival after disease progression was 6.9 months, and responses to subsequent BRAF and MEK inhibition were uncommon (2 of 15; 13%). Post-progression outcomes did not correlate with specific acquired BRAFi resistance mechanisms. CONCLUSIONS: This is the first study to systematically characterise the clinical implications of particular acquired BRAFi-resistance mechanisms in patients with BRAF-mutant melanoma largest study to compile the landscape of resistance. Despite marked heterogeneity of resistance mechanisms within patients, NRAS mutations correlated with vemurafenib use and intracranial disease involvement. PMID- 26608122 TI - Individual differences in impulsive action and dopamine transporter function in rat orbitofrontal cortex. AB - Impulsivity, which can be subdivided into impulsive action and impulsive choice, is implicated as a factor underlying drug abuse vulnerability. Although previous research has shown that dopamine (DA) systems in prefrontal cortex are involved in impulsivity and substance abuse, it is not known if inherent variation in DA transporter (DAT) function contributes to impulsivity. The current study determined if individual differences in either impulsive action or impulsive choice are related to DAT function in orbitofrontal (OFC) and/or medial prefrontal cortex (mPFC). Rats were first tested both for impulsive action in a cued go/no-go task and for impulsive choice in a delay-discounting task. Following behavioral evaluation, in vitro [(3)H]DA uptake assays were performed in OFC and mPFC isolated from individual rats. Vmax in OFC, but not mPFC, was correlated with performance in the cued go/no-go task, with decreased OFC DAT function being associated with high impulsive action. In contrast, Vmax in OFC and mPFC was not correlated with performance in the delay-discounting task. The current results demonstrate that impulsive behavior in cued go/no-go performance is associated with decreased DAT function in OFC, suggesting that hyperdopaminergic tone in this prefrontal subregion mediates, at least in part, increased impulsive action. PMID- 26608124 TI - Effects of prostaglandin E2 on cells cultured from the rat organum vasculosum laminae terminalis and median preoptic nucleus. AB - The time course of the induction of enzymes responsible for the formation of prostaglandin E2 (PGE2) after an inflammatory insult, in relation to the concomitant febrile response, suggests that peripherally generated PGE2 is involved in the induction of the early phase of fever, while centrally produced PGE2 exerts pyrogenic capacities during the later stages of fever within the hypothalamic median preoptic nucleus (MnPO). The actions of peripherally derived PGE2 on the brain might occur at the level of the organum vasculosum laminae terminalis (OVLT), which lacks a tight blood-brain barrier and is implicated in fever, while the effects of PGE2 within the MnPO might interfere with glutamatergic neurotransmission within a recently characterized central efferent pathway for the activation of cold-defence reactions. Using the fura-2 ratio imaging technique we, therefore, measured changes of the intracellular Ca(2+) concentration in primary neuroglial microcultures of rat OVLT and MnPO stimulated with PGE2 and/or glutamate. In cultures from the OVLT, as opposed to those derived from the MnPO, substantial numbers of neurons (8% of 385), astrocytes (19% of 645) and microglial cells (28% of 43) directly responded to PGE2 with a transient increase of intracellular Ca(2+). The most pronounced effect of PGE2 on cells from MnPO microcultures was its modulatory influence on the strength of glutamate-induced Ca(2+)-signals. In 72 out of 512 neurons and in 105 out of 715 astrocytes PGE2 significantly augmented glutamate-induced Ca(2+)-signals. About 30% of these neurons were GABAergic. These observations are in agreement with putative roles of peripheral PGE2 as a directly acting circulating agent at the level of the OVLT, and of central MnPO-intrinsic PGE2 as an enhancer of glutamatergic neurotransmission, which causes disinhibition of thermogenic heat production, a crucial component for the manifestation of fever. In microcultures from both brain sites investigated incubation with PGE2 significantly reduced the lipopolysaccharide-induced release of cytokines (tumor necrosis factor-alpha and interleukin-6) into the supernatant. PGE2, thus, seems to be involved in a negative feed-back loop to limit the strength of the brain inflammatory process and to play a dual role with pro- as well as anti-inflammatory properties. PMID- 26608125 TI - Salvage photodynamic therapy for local failure after chemoradiotherapy for esophageal squamous cell carcinoma. AB - BACKGROUND AND AIMS: Photodynamic therapy (PDT) is a less-invasive salvage treatment option for local failure at the primary site after chemoradiotherapy (CRT) for esophageal squamous cell carcinoma. The objective of this study was to clarify the long-term outcomes and prognostic factors of salvage PDT. METHODS: One hundred thirteen consecutive patients treated in our institution with PDT for local failure limited to within T2 without any metastases after definitive CRT performed between 1998 and 2008 were retrospectively enrolled. The complete response rate, adverse events, and survival outcomes were assessed and prognostic factors were investigated using a multivariate analysis. RESULTS: The complete response rate was 58.4% (95% confidence interval [CI], 49.3%-67.5%). The progression-free survival (PFS) and the overall survival (OS) rates at 5 years after salvage PDT were 22.1% (95% CI, 14.3%-30.0%) and 35.9% (95% CI, 26.7% 45.1%). N0 before CRT was significantly associated with OS (hazard ratio [HR], 0.54; 95% CI, 0.33-0.91, P = .020), whereas the impact of T1 or T2 before CRT on PFS (HR, 0.63; 95% CI, 0.38-1.04, P = .068) and that of a longer period between CRT and PDT on OS (HR, 0.64; 95% CI, 0.39-1.05, P = .078) were marginal. The treatment-related death rate was 1.8%. CONCLUSIONS: Salvage PDT was found to have a superior outcome and a satisfactory safety profile. An earlier clinical stage before CRT and a longer interval between CRT and PDT may be associated with a longer survival period. PMID- 26608126 TI - A novel fully synthetic and self-assembled peptide solution for endoscopic submucosal dissection-induced ulcer in the stomach. AB - BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) can remove early stage GI tumors of various sizes en bloc; however, success requires reducing the relatively high postprocedure bleeding rate. The aim of this study was to assess the safety and efficacy of a novel, fully synthetic, and self-assembled peptide solution that functions as an extracellular matrix scaffold material to facilitate reconstruction of normal tissues in ESD-induced ulcers. METHODS: Consecutive patients who underwent gastric ESD were prospectively enrolled. Immediately after the resection, the solution was applied to the site with a catheter. Gastric ulcers were evaluated by endoscopy and classified as active, healing, or scarring stages at weeks 1, 4, and 8 after ESD. RESULTS: Forty-seven patients with 53 lesions, including 14 (29.8%) previously on antithrombotic therapy and 2 (4.3%) requiring heparin bridge therapy, were analyzed; 2 patients were excluded, 1 with perforations and 1 with persistent coagulopathy. The mean size of the en bloc resected specimens was 36.5 +/- 11.3 mm. The rate of post-ESD bleeding was 2.0% (1/51; 95% CI, 0.03-10.3). Transitional rate to the healing stage of ESD-induced ulcers at week 1 was 96% (49/51). Subsequent endoscopies demonstrated the scarring stage in 19% (9/48) and 98% (41/42) at weeks 4 and 8, respectively. No adverse effects related to this solution occurred. CONCLUSIONS: The use of this novel peptide solution may potentially aid in reducing the delayed bleeding rate by promoting mucosal regeneration and speed of ulcer healing after large endoscopic resections in the stomach. Further studies, particularly randomized controlled studies, are needed to fully evaluate its efficacy. ( CLINICAL TRIAL REGISTRATION NUMBER: 000011548.). PMID- 26608128 TI - Size does matter: endoscopic closure of a large gastrocutaneous fistula. PMID- 26608127 TI - The extremely narrow-caliber esophagus is a treatment-resistant subphenotype of eosinophilic esophagitis. AB - BACKGROUND AND AIMS: Some patients with eosinophilic esophagitis (EoE) have an extremely narrow esophagus, but the characteristics of this group have not been extensively described. We aimed to characterize the narrow-caliber phenotype of EoE, determine associated risk factors, and identify differences in treatment response in this subgroup of patients. METHODS: This retrospective cohort study from 2001 to 2014 included subjects with a new diagnosis of EoE per consensus guidelines. Demographic, endoscopic, histologic, and treatment response data were extracted from medical records. An extremely narrow-caliber esophagus was defined when a neonatal endoscope was required to traverse the esophagus due to the inability to pass an adult endoscope. Patients with and without an extremely narrow-caliber esophagus were compared. Multivariable logistical regression was performed to assess treatment outcomes. RESULTS: Of 513 patients with EoE, 46 (9%) had an extremely narrow-caliber esophagus. These patients were older (33 vs 22 years; P < .01), had longer symptom duration (11 vs 3 years; P < .01), more dysphagia (98% vs 66%; P < .01), and food impactions (53% vs 31%; P < .01). Dilation was more common with extreme narrowing (69% vs 17%; P < .01). Patients with a narrow-caliber esophagus were more refractory to steroid treatment, with lower symptom (56% vs 85%), endoscopic (52% vs 76%), and histologic (33% vs 63%) responses (P < .01 for all), and these differences persisted after multivariate analysis. CONCLUSION: The extremely narrow-caliber esophagus is a more treatment resistant subphenotype of EoE and is characterized by longer symptom duration and the need for multiple dilations. Recognition of an extremely narrow-caliber esophagus at diagnosis of EoE can provide important prognostic information. PMID- 26608129 TI - Endoscopic resection is cost-effective compared with laparoscopic resection in the management of complex colon polyps: an economic analysis. AB - BACKGROUND AND AIMS: Endoscopic resection (ER) is an efficacious treatment for complex colon polyps (CCPs). Many patients are referred for surgical resection because of concerns over procedural safety, incomplete polyp resection, and adenoma recurrence after ER. Efficacy data for both resection strategies are widely available, but a paucity of data exist on the cost-effectiveness of each modality. The aim of this study was to perform an economic analysis comparing ER and laparoscopic resection (LR) strategies in patients with CCP. METHODS: A decision analysis tree was constructed using decision analysis software. The 2 strategies (ER vs LR) were evaluated in a hypothetical cohort of patients with CCPs. A hybrid Markov model with a 10-year time horizon was used. Patients entered the model after colonoscopic diagnosis at age 50. Under Strategy I, patients underwent ER followed by surveillance colonoscopy at 3 to 6 months and 12 months. Patients with failed ER and residual adenoma at 12 months were referred for LR. Under Strategy II, patients underwent LR as primary treatment. Patients with invasive cancer were excluded. Estimates regarding ER performance characteristics were obtained from a systematic review of published literature. The Centers for Medicare & Medicaid Services (2012-2013) and the 2012 Healthcare Cost and Utilization Project databases were used to determine the costs and loss of utility. We assumed that all procedures were performed with anesthesia support, and patients with adverse events in both strategies required inpatient hospitalization. Baseline estimates and costs were varied by using a sensitivity analysis through the ranges. RESULTS: LR was found to be more costly and yielded fewer quality-adjusted life-years (QALYs) compared with ER. The cost of ER of a CCP was $5570 per patient and yielded 9.640 QALYs. LR of a CCP cost $18,717 per patient and yielded fewer QALYs (9.577). For LR to be more cost-effective, the thresholds of 1-way sensitivity analyses were (1) technical success of ER for complete resection in <75.8% of cases, (2) adverse event rates for ER > 12%, and (3) LR cost of <$14,000. CONCLUSIONS: Our data suggest that ER is a cost effective strategy for removal of CCPs. The effectiveness is driven by high technical success and low adverse event rates associated with ER, in addition to the increased cost of LR. PMID- 26608130 TI - A brief history of the ASGE. PMID- 26608131 TI - Pregnant women's navigation of information on everyday household chemicals: phthalates as a case study. AB - BACKGROUND: Current developments in science and the media have now placed pregnant women in a precarious situation as they are charged with the responsibility to navigate through information sources to make the best decisions for her pregnancy. Yet little is known regarding how pregnant women want to receive and use health information in general, let alone information regarding the uncertain risks to pregnancy in everyday household products such as phthalates found in cosmetics and canned food liners. Using phthalates as an example, this study investigated how pregnant women obtain, evaluate, and act on information regarding their pregnancy. METHODS: Pregnant women were recruited using pamphlets and posters distributed in prenatal clinics, prenatal fairs and physician offices in Southwestern Ontario Canada. Research participants were engaged in 20 to 40 min semi-structured interviews regarding their use of information sources in pregnancy, particularly regarding phthalates in cosmetics and canned food liners. Interviews were transcribed verbatim and analyzed using constructivist grounded theory techniques supported by NVivo 9TM software. RESULTS: Theoretical sufficiency was reached after 23 pregnant women were interviewed and their transcripts analyzed. Three overlapping themes resulted from the co-constructed analysis: I-Strength of Information Sources; II-Value Modifiers; and III-Deciding to Control Exposure. The research participants reported receiving information from a wide range of sources that they perceived varying in strength or believability. They then described the strategies employed to increase the validity of the message in order to avoid risk exposure. Pregnant women preferred a strong source of information such as physician, government but frequently used weak sources such as the internet or the opinions of friends. A model was developed from the relationship between themes that describes how pregnant women navigate the multiple sources of information available to them. CONCLUSION: Our study provides insight into how pregnant women receive, appraise, and act on information regarding everyday household chemicals. Clinicians and their professional organizations should produce specific educational materials to assist women in understanding exposure to everyday products in pregnancy. PMID- 26608133 TI - Awareness of female malignancies among women and their partners in Southern Sri Lanka and implications for screening: a cross sectional study. AB - BACKGROUND: The incidences of breast, cervical and uterine malignancies continue to increase in Sri Lanka. It is important to explore the awareness of both women and their male partners regarding these malignancies and available screening services as it would determine the health seeking behaviours of females. METHODS: This was a cross sectional survey of couples residing in the Galle District of the Southern province of Sri Lanka. The sample was selected from all 17 health administrative divisions of the district. An interviewer administered questionnaire was used to collect data on demography and level of awareness (risk factors, symptoms, signs, screening services) of breast, cervical and uterine cancers. Same questionnaire was used for both sexes except for gender specific questions. RESULTS: A total of 282 (n-282, 564 individuals) couples were interviewed. The level of awareness regarding all malignancies was low. More than 50% of participants in both sexes scored less than half the points on a questionnaire testing awareness. Better family income, better education and permanent employment showed a significant association with better awareness in both sexes (univariate analysis). Encouragement by male partner was associated with better participation in some instances. CONCLUSIONS: Community based health education on female malignancies needs to target both sexes. Educating males is important as, i) male partners can encourage females to utilize screening services and ii) some screening and preventive measures are relevant to males also. Better awareness of males may increase the uptake of screening services by females in societies with male dominant gender roles. PMID- 26608132 TI - Impact of microRNA-130a on the neutrophil proteome. AB - BACKGROUND: MicroRNAs (miRNAs) are important for the development and function of neutrophils. miR-130a is highly expressed during early neutrophil development and regulates target proteins important for this process. miRNA targets are often identified by validating putative targets found by in silico prediction algorithms one at a time. However, one miRNA can have many different targets, which may vary depending on the context. Here, we investigated the effect of miR 130a on the proteome of a murine and a human myeloid cell line. RESULTS: Using pulsed stable isotope labelling of amino acids in cell culture and mass spectrometry for protein identification and quantitation, we found 44 and 34 proteins that were significantly regulated following inhibition of miR-130a in a miR-130a-overexpressing 32Dcl3 clone and Kasumi-1 cells, respectively. The level of miR-130a inhibition correlated with the impact on protein levels. We used RAIN, a novel database for miRNA-protein and protein-protein interactions, to identify putative miR-130a targets. In the 32Dcl3 clone, putative targets were more up-regulated than the remaining quantified proteins following miR-130a inhibition, and three significantly derepressed proteins (NFYC, ISOC1, and CAT) are putative miR-130a targets with good RAIN scores. We also created a network including inferred, putative neutrophil miR-130a targets and identified the transcription factors Myb and CBF-beta as putative miR-130a targets, which may regulate the primary granule proteins MPO and PRTN3 and other proteins differentially expressed following miR-130a inhibition in the 32Dcl3 clone. CONCLUSION: We have experimentally identified miR-130a-regulated proteins within the neutrophil proteome. Linking these to putative miR-130a targets, we provide an association network of potential direct and indirect miR-130a targets that expands our knowledge on the role of miR-130a in neutrophil development and is a valuable platform for further experimental studies. PMID- 26608134 TI - Accelerated return to sport after anterior cruciate ligament injury: a risk factor for early knee osteoarthritis? PMID- 26608135 TI - Production of phenylacetyl-homoserine lactone analogs by artificial biosynthetic pathway in Escherichia coli. AB - BACKGROUND: Quorum sensing (QS) networks are more commonly known as acyl homoserine lactone (HSL) networks. Recently, p-coumaroyl-HSL has been found in a photosynthetic bacterium. p-coumaroyl-HSL is derived from a lignin monomer, p coumaric acid, rather than a fatty acyl group. The p-coumaroyl-HSL may serve an ecological role in diverse QS pathways between p-coumaroyl-HSL producing bacteria and specific plants. Interference with QS has been regarded as a novel way to control bacterial infections. Heterologous production of the QS molecule, p coumaroyl-HSL, could provide a sustainable and controlled means for its large scale production, in contrast to the restricted feedback regulation and extremely low productivity of natural producers. RESULTS: We developed an artificial biosynthetic process for phenylacetyl-homoserine lactone analogs, including cinnamoyl-HSL, p-coumaroyl-HSL, caffeoyl-HSL, and feruloyl-HSL, using a bioconversion method via E. coli (CB1) in the co-expression of the codon optimized LuxI-type synthase (RpaI) and p-coumaroyl-CoA ligase (4CL2nt). In addition to this, we show the de novo production of p-coumaroyl-HSL in heterologous host E. coli (DN1) and tyrosine overproducing E. coli (DN2), containing the rpaI gene in addition to p-coumaroyl-CoA biosynthetic genes. The yields for p-coumaroyl-HSL reached 93.4 +/- 0.6 and 142.5 +/- 1.0 mg/L in the S adenosyl-L-methionine and L-methionine feeding culture in the DN2 strain, respectively. CONCLUSIONS: This is the first report of a de novo biosynthesis in a heterologous host yielding a QS molecule, p-coumaroyl-HSL from a glucose medium using a single vector system combining p-coumaroyl-CoA biosynthetic genes and the LuxI-type synthase gene. PMID- 26608136 TI - Preface. PMID- 26608137 TI - Late Reconstruction of the Orbit With Patient-Specific Implants Using Computer Aided Planning and Navigation. AB - PURPOSE: Reconstruction of orbital deformities is a challenging task. Virtual 3 dimensional (3D) planning and the use of patient-specific implants (PSIs) could improve anatomic and functional outcomes in the orbital region. MATERIALS AND METHODS: A retrospective study was performed of patients who underwent late orbital reconstruction from 2009 to 2013. To be included in the study, patients had a unilateral orbital deformity by involvement of at least 2 orbital wall defects. No orbital osteotomies could be used to correct the deformity. All patients underwent 3D virtual treatment planning. The unaffected orbit was mirrored onto the affected orbit. The PSI was fabricated according to this plan. Navigation was used to check the implant position. RESULTS: Six patients were included in this study. All patients had diplopia or motility limitations and enophthalmos. The ophthalmic parameters showed improvement in all patients. Enophthalmos was corrected adequately by the PSI. Four patients received a poly ether-ether-ketone PSI. Two patients received a titanium mesh PSI. The position of the PSI was controlled by intraoperative navigation. Superimposition of the planned and postoperative positions of the PSI showed good correlation. CONCLUSION: PSIs placed with intraoperative navigation facilitate late or secondary correction of orbital deformities. PMID- 26608138 TI - Developing an Immunotherapy Strategy for the Effective Treatment of Oral, Head and Neck Squamous Cell Carcinoma. PMID- 26608139 TI - Regenerative Technologies for Craniomaxillofacial Surgery. PMID- 26608140 TI - Demineralized Bone and BMPs: Basic Science and Clinical Utility. AB - The clinical demand for bone void fillers led to the development of off-the-shelf banked bone and synthetic and biologic substitute materials to be used either alone or as bone graft volume extenders. Demineralized bone (DB) has a remarkable capacity to induce new bone formation even when implanted subcutaneously in experimental animals, a phenomenon termed "osteoinduction." DB products are now widely available through tissue bank procurement of bone from rigorously screened donors. When properly processed, DB products are useful in craniomaxillofacial, oral, hand, and orthopedic applications. The isolation of proteins believed to be responsible for the osteoinductive activity of DB, termed bone morphogenetic proteins (BMPs), led to the cloning of a family of genes and synthesis of recombinant human BMPs (rhBMPs). They have been approved for distribution and use in specific maxillofacial and orthopedic applications. Clinical trials and studies of orthopedic and craniofacial applications have indicated that supraphysiologic doses of a single recombinant protein are needed to promote bone repair. Information about the biology, chemistry, and actions of rhBMPs and DB has called into question whether a single recombinant BMP would result in clinically useful bone induction and morphogenesis. Compelling preclinical and specific clinical evidence has indicated the efficacy of DB and for rhBMPs either combined with autograft or compared with an autograft alone. In light of questions about potency and safety, however, additional high-level evidence is needed for specific clinical indications and appropriate patient populations that would benefit from their use. PMID- 26608141 TI - The Partnership of Medical Genetics and Oral and Maxillofacial Surgery When Evaluating Craniofacial Anomalies. AB - A medical geneticist who has an interest in craniofacial anomalies forms a natural partnership with an oral and maxillofacial surgeon, which facilitates patient care. Using complementary diagnostic and therapeutic skills, the search for a recognizable pattern can lead to a syndrome diagnosis. After the initial examination, there is usually genetic testing to confirm the clinical diagnosis. Once established, care coordination and genetic counseling can be provided for the parents and the patient. Enrolling the patient into a research study could be helpful to understand the diagnosis but, in some circumstances, might not have immediate clinical relevance. A multidisciplinary craniofacial team is generally necessary for long-term management. This article discusses illustrative patients evaluated from 2007 through 2011 with the senior oral and maxillofacial surgeon at the Massachusetts General Hospital (Leonard B. Kaban, DMD, MD). These include single patients with the Nablus mask-like facies syndrome and auriculo-condylar syndrome and a series of 20 patients with Gorlin syndrome followed by a multispecialty team. A successful collaboration between a medical geneticist and an oral and maxillofacial surgeon optimizes the treatment of patients with craniofacial anomalies. PMID- 26608143 TI - Mandibular Tissue Engineering: Past, Present, Future. AB - Almost 2 decades ago, the senior author's (M.T.J.) first article was with our mentor, Dr Leonard B. Kaban, a review article titled "Distraction Osteogenesis: Past, Present, Future." In 1998, many thought it would be impossible to have a remotely activated, small, curvilinear distractor that could be placed using endoscopic techniques. Currently, a U.S. patent for a curvilinear automated device and endoscopic techniques for minimally invasive access for jaw reconstruction exist. With minimally invasive access for jaw reconstruction, the burden to decrease donor site morbidity has increased. Distraction osteogenesis (DO) is an in vivo form of tissue engineering. The DO technique eliminates a donor site, is less invasive, requires a shorter operative time than usual procedures, and can be used for multiple reconstruction applications. Tissue engineering could further reduce morbidity and cost and increase treatment availability. The purpose of the present report was to review our experience with tissue engineering of bone: the past, present, and our vision for the future. The present report serves as a tribute to our mentor and acknowledges Dr Kaban for his incessant tutelage, guidance, wisdom, and boundless vision. PMID- 26608142 TI - The Neurobiology of Cancer Pain. AB - Oral cancers are often severely painful and clinically difficult to manage. Few researchers have investigated the neurobiologic factors responsible for cancer pain; however, the study of oral cancer pain might inform us about the fundamental biology of cancer. The purpose of the present report was to summarize the clinical challenges inherent in oral cancer pain management, oral cancer pain mechanisms and mediators, and the convergence of the investigation of carcinogenesis and pain. PMID- 26608144 TI - From Here to There; An Academic Journey. PMID- 26608145 TI - Leading Others Toward Excellence. AB - This essay puts forth the proposition that academic program excellence does not arise by accident. Effective leadership is required. To support this proposition, the essay discusses the characteristics common to effective leaders. It then proceeds to use the example of a successful academic oral-maxillofacial surgery department and characteristics of its leader to provide evidence that excellence derives from effective leadership. PMID- 26608146 TI - Do the Science, Own the Field. Are We Doing the Science? AB - For oral and maxillofacial surgery to continue being a premier specialty in the management of patients with craniomaxillofacial conditions, contributions to the better treatment of these patients must be continuously offered. Without performing the science, these offerings will not come or will not be valid. Environmental and funding challenges to performing the science have increased in the past 2 decades. The incorporation of protected research time and a research sabbatical for residents within their training program might be effective ways to meet these challenges. PMID- 26608147 TI - Oral and Maxillofacial Surgery 2025: 50 Years of Evolution of a Surgical Specialty. PMID- 26608148 TI - Writing a Scientific Paper Is Not Rocket Science! PMID- 26608149 TI - Beyond Surgery: Treating the Whole Person. PMID- 26608150 TI - Heads, Hands and Jaws: The Role of the Hand Specialist in the Craniofacial Clinic. PMID- 26608151 TI - Upper Airway Length is Predictive of Obstructive Sleep Apnea in Syndromic Craniosynostosis. AB - PURPOSE: Midfacial hypoplasia is a characteristic feature of the syndromic craniosynostoses and predisposes these patients to developing obstructive sleep apnea (OSA). The purpose of this study was to identify anatomic factors associated with airway obstruction in patients with syndromic craniosynostoses. MATERIALS AND METHODS: This was a retrospective cohort study. The authors enrolled a study sample composed of patients with syndromic craniosynostoses. The predictor variables were age, gender, body mass index (BMI), syndromic diagnosis, and parameters of upper airway length and size measured on lateral cephalograms. To control for age, upper airway length was corrected for differences in patient height. The outcome variable was OSA status (present or absent). Descriptive, bivariate, and regression statistics were computed. For all analyses, a P value less than or equal to .05 was considered statistically significant. RESULTS: The sample was composed of 50 patients with a mean age of 10.3 +/- 0.6 years, 50% were boys, and 24 (48%) had OSA. Patients with and without OSA did not differ statistically in age, gender, BMI, or syndromic diagnosis. Those with OSA had increased upper airway length (P = .016), decreased posterior airway space (P = .001), and more severe midfacial retrusion (P = .022) compared to patients without OSA. After adjusting for covariates, the odds ratio for OSA was 32.9 in patients with an upper airway longer than 45.3 mm per meter of height (P = .018), and for every 1-mm decrease in posterior airway space, the risk of OSA increased by 30% (P = .022). CONCLUSIONS: Patients with syndromic craniosynostosis and OSA have a longer upper airway, smaller posterior airway space, and more severe midfacial retrusion than those without OSA. PMID- 26608152 TI - A Geometric Classification of Jaw Deformities. PMID- 26608153 TI - Is It Safe to Re-Harvest the Anterior Iliac Crest to Manage Le Fort I Interpositional Defects in Young Adults With a Repaired Cleft? AB - PURPOSE: Re-harvesting the anterior iliac crest to obtain autogenous bone grafts is a controversial practice. The purpose of this study was to assess the feasibility and associated disability of re-harvesting the anterior iliac crest. MATERIAL AND METHODS: To address the research purpose, the authors executed a retrospective case series study. The sample consisted of young adult patients with cleft (<26 yr old) with prior harvesting of the anterior iliac crest during mixed dentition for management of an alveolar cleft(s) and then re-harvesting of the same donor site for management of interpositional defects after Le Fort I advancement. Wound-healing parameters were reviewed at the donor and recipient sites. A survey questionnaire was provided after completion of treatment to document patient perception of early and any long-term donor-site disability. Descriptive statistics were computed for the variables. RESULTS: The sample was composed of 27 patients with a mean age at re-harvesting of 17 years (range, 14 to 25 yr). Patients underwent on average 7.4-mm horizontal advancement, 2.4-mm lengthening, and 2.6-mm transverse expansion of the maxilla. Adequate bone graft was re-harvested to accomplish objectives in all cases. There were no perioperative complications at the donor or recipient sites. Twenty-six of the 27 patients (97%) had fewer donor-site recovery difficulties at the time of re harvesting compared with the first time graft was taken. There were no cases of lateral femoral cutaneous nerve injury and no long-term discomfort with walking, running, or other activities. CONCLUSIONS: The study confirms the safety and efficacy of re-harvesting corticocancellous bone from the anterior iliac crest for management of interpositional defects associated with Le Fort I advancement in young adults with a repaired cleft. PMID- 26608154 TI - Three-Dimensional Analysis and Surgical Planning in Craniomaxillofacial Surgery. AB - PURPOSE: Three-dimensional (3D) analysis and planning are powerful tools in craniofacial and reconstructive surgery. The elements include 1) analysis, 2) planning, 3) virtual surgery, 4) 3D printouts of guides or implants, and 5) verification of actual to planned results. The purpose of this article is to review different applications of 3D planning in craniomaxillofacial surgery. MATERIALS AND METHODS: Case examples involving 3D analysis and planning were reviewed. Common threads pertaining to all types of reconstruction are highlighted and contrasted with unique aspects specific to new applications in craniomaxillofacial surgery. RESULTS: Six examples of 3D planning are described: 1) cranial reconstruction, 2) craniosynostosis, 3) midface advancement, 4) mandibular distraction, 5) mandibular reconstruction, and 6) orthognathic surgery. CONCLUSIONS: Planning in craniomaxillofacial surgery is useful and has applicability across different procedures and reconstructions. Three-dimensional planning and virtual surgery enhance efficiency, accuracy, creativity, and reproducibility in craniomaxillofacial surgery. PMID- 26608155 TI - Is the Pyriform Ligament Important for Alar Width Maintenance After Le Fort I Osteotomy? AB - PURPOSE: To determine whether identification and incorporation of the pyriform ligament in the alar cinch results in decreased alar base widening compared with standard alar cinch techniques. MATERIALS AND METHODS: This was a retrospective case series and the sample was composed of patients undergoing Le Fort I osteotomy. Intraoperatively, the pyriform ligament was identified and incorporated in the alar cinch suture. Greatest alar width (GAW) measured immediately after closure was compared with GAW measured at least 5 months postoperatively. The change in alar base width was compared with that reported in the literature using other alar cinch techniques. Two case examples are reported. RESULTS: The sample was composed of 15 patients (mean age, 27.1 yr; 27% female). The mean postoperative change in GAW was 1.0 +/- 0.6 mm (2.59 +/- 1.59%). Postoperative change in alar base width reported in the literature ranged from 0.5 to 10.8%. CONCLUSION: The pyriform ligament is easily identified during exposure of the maxilla and pyriform aperture and can be used to control widening of the alar base after Le Fort I osteotomy. PMID- 26608156 TI - Correlation of Airway Volume With Orthognathic Surgical Movement Using Cone-Beam Computed Tomography. AB - PURPOSE: Orthognathic surgery can induce changes in airway volume. The aim of this study was to determine whether there is a correlation of surgical movement of the maxilla or mandible to airway volume changes. MATERIALS AND METHODS: This was a prospective cohort study and the sample was composed of patients undergoing single-jaw orthognathic procedures from 2004 through 2007. Cone-beam computed tomograms were obtained before surgery (T0), immediately after surgery (T1), and at least 6 months after surgery (T2). The airway was segmented from 3-dimensional images and identified as the whole airway, consisting of the naso-, oro-, and hypopharynx. The volumetric percentage of change of the airway between time points was compared and correlated to the surgical movements using paired t test and cubic regression analysis. The level of statistical significance was set at a P value less than or equal to .05. RESULTS: The sample was composed of 33 patients. Sixteen patients underwent maxillary advancement with mean advancement of 5.4 mm (3 to 8 mm), 13 underwent mandibular advancement with mean advancement of 8.0 mm (5 to 15 mm), and 4 underwent mandibular setback of 4.0 mm. For maxillary advancement at T1, volume percentages of change for the whole airway and the naso-, oro-, and hypopharynx were 18.4 (P <= .05), 53.8 (P <= .05), 26.3, and 5.5%, respectively, and at T2, the changes were 10.0, 46.7 (P <= .05), 6.8, and 1.0%, respectively. For mandibular advancement at T1, volume percentages of change were 34.6 (P <= .05), 26.1, 54.1 (P <= .05), and 17.4%, respectively, and at T2, the changes were 15.0 (P <= .05), -3.7, 23.5 (P <= .05), and 12.1%, respectively. There were no meaningful long-term airway changes with mandibular setback. CONCLUSION: The study results suggest that there might be an anatomic limit to pharyngeal airway expansion associated with single-jaw orthognathic surgery. PMID- 26608157 TI - Nevoid Basal Cell Carcinoma Syndrome and the Keratocystic Odontogenic Tumor. AB - PURPOSE: To analyze the clinical and radiographic manifestations of nevoid basal cell carcinoma syndrome (NBCCS) with a particular emphasis on the presence, treatment, and outcomes of keratocystic odontogenic tumors (KOTs) in these patients. PATIENTS AND METHODS: The authors implemented a prospective case series and enrolled a sample of patients with KOTs and NBCCS. The primary study variables were the demographics, treatment, and outcomes of managing KOTs in this sample. Descriptive statistics were computed. RESULTS: The sample was composed of 16 patients (10 male and 6 female; mean age, 24 yr). These patients presented with 32 previously untreated KOTs. Fifteen patients with 31 KOTs consented to surgery that consisted of a total of 61 procedures during the study period. These procedures included 19 primary enucleation and curettage surgeries and 12 marsupialization procedures followed by secondary enucleation and curettage surgeries. During the course of clinical and radiographic follow-up examinations, 14 new primary and 5 persistent KOTs (refractory to enucleation and curettage surgeries) were diagnosed, of which 13 new primary KOTs and 5 persistent KOTs were treated. A total of 51 KOTs (32 primary, 14 new lesions that developed during follow-up, and 5 persistent lesions) were diagnosed, and 15 patients consented to operative treatment of 49 KOTs. Forty-eight enucleation and curettage surgeries were performed for 49 KOTs that showed effective treatment without persistence in 43 cases (90%) during a follow-up period from 2 to 20 years (mean, 7 yr). One resection was performed for a persistent KOT. The 5-year disease-free estimate after primary enucleation and curettage was 86% (95% confidence interval, 74.8-97.4). Other clinical and radiographic stigmata of the syndrome were diagnosed, including calcified falx cerebri, frontal bossing, hypertelorism, multiple basal cell carcinomas, and others. CONCLUSIONS: The results of this study identify the variable expressivity of this syndrome and the favorable outcomes of marsupialization and enucleation and curettage of syndromic KOTs. PMID- 26608158 TI - Central Cemento-Ossifying Fibroma: Primary Odontogenic or Osseous Neoplasm? AB - Currently, central cemento-ossifying fibroma is classified by the World Health Organization as a primary bone-forming tumor of the jaws. However, histopathologically, it is often indistinguishable from cemento-osseous dysplasias in that it forms osteoid and cementicles (cementum droplets) in varying proportions. It is believed that pluripotent cells within the periodontal membrane can be stimulated to produce either osteoid or woven bone and cementicles when stimulated. If this is true, cemento-ossifying fibroma would be better classified as a primary odontogenic neoplasm arising from the periodontal ligament. Cemento-ossifying fibromas also do not occur in the long bones. The present report compares several entities that fall within the diagnostic realm of benign fibro-osseous lesions and reviews the evidence for reclassifying central cemento-ossifying fibroma as a primary odontogenic neoplasm. PMID- 26608159 TI - Disease Stage and Mode of Therapy Are Important Determinants of Treatment Outcomes for Medication-Related Osteonecrosis of the Jaw. AB - PURPOSE: The treatment of patients with medication-related osteonecrosis of the jaw (MRONJ) is challenging. The purpose of the present study was to estimate the frequency and identify the factors associated with clinical improvement during treatment. PATIENTS AND METHODS: We designed and implemented a retrospective cohort study and enrolled a sample of subjects diagnosed with MRONJ between 2004 and 2015. The primary predictor variables were a set of heterogeneous variables grouped into the following categories: demographic (age and gender) and clinical (location of necrosis, therapy duration, medication type, disease stage, and treatment type). The primary outcome variable was the treatment outcome, defined as stable or worse and improved or healed. The descriptive, bivariate, and multiple logistic statistics were computed, and statistical significance was defined as P < .05. RESULTS: The sample included 337 subjects with a mean age of 68.9 years. Of the 337 subjects, 256 were women (76%). A total of 143 patients (42.2%) experienced spontaneous necrosis. Twenty-four (7.1%) had had exposure to targeted antiangiogenic agents. Those with stage 1 or 2 disease were more likely to have better outcomes than those with stage 3 disease (stage 1, adjusted odds ratio [OR] 3.4, P = .005; stage 2, adjusted OR 2.2, P = .03). Treatment type was a significant variable. Subjects undergoing surgery were 28 times more likely to have a positive outcome than those receiving nonoperative therapy (adjusted OR 28.7, P < .0001). CONCLUSIONS: Subjects with MRONJ who presented with less severe disease or who underwent operative treatment were most likely to have improvement or complete healing of their MRONJ-related lesions. PMID- 26608162 TI - Ruthenium olefin metathesis catalysts featuring unsymmetrical N-heterocyclic carbenes. AB - New ruthenium Grubbs' and Hoveyda-Grubbs' second generation catalysts bearing N alkyl/N-isopropylphenyl N-heterocyclic carbene (NHC) ligands with syn or anti backbone configuration were obtained and compared in model olefin metathesis reactions. Different catalytic efficiencies were observed depending on the size of the N-alkyl group (methyl or cyclohexyl) and on the backbone configuration. The presence of an N-cyclohexyl substituent determined the most significant reactivity differences between catalysts with syn or anti phenyl groups on the backbone. In particular, anti catalysts proved highly efficient, especially in the ring-closing metathesis (RCM) of encumbered diolefins, while syn catalysts showed low efficiency in the RCM of less hindered diolefins. This peculiar behavior, rationalized through DFT studies, was found to be related to the high propensity of these catalysts to give nonproductive metathesis events. Enantiopure anti catalysts were also tested in asymmetric metathesis reactions, where moderate enantioselectivities were observed. The steric and electronic properties of unsymmetrical NHCs with the N-cyclohexyl group were then evaluated using the corresponding rhodium complexes. While steric factors proved unimportant for both syn and anti NHCs, a major electron-donating character was found for the unsymmetrical NHC with anti phenyl substituents on the backbone. PMID- 26608160 TI - Cannulation strategies for percutaneous extracorporeal membrane oxygenation in adults. AB - Extracorporeal membrane oxygenation (ECMO) has revolutionized treatment of severe isolated or combined failure of lung and heart. Due to remarkable technical development the frequency of use is growing fast, with increasing adoption by interventional cardiologists independent of cardiac surgery. Nevertheless, ECMO support harbors substantial risk such as bleeding, thromboembolic events and infection. Percutaneous ECMO circuits usually comprise cannulation of two large vessels ('dual' cannulation), either veno-venous for respiratory and veno arterial for circulatory support. Recently experienced centers apply more advanced strategies by cannulation of three large vessels ('triple' cannulation), resulting in veno-veno-arterial or veno-arterio-venous cannulation. While the former intends to improve drainage and unloading, the latter represents a very potent method to provide circulatory and respiratory support at the same time. As such triple cannulation expands the field of application at the expense of increased complexity of ECMO systems. Here, we review percutaneous dual and triple cannulation strategies for different clinical scenarios of the critically ill. As there is no unifying terminology to date, we propose a nomenclature which uses "A" and all following letters for supplying cannulas and all letters before "A" for draining cannulas. This general and unequivocal code covers both dual and triple ECMO cannulation strategies (VV, VA, VVA, VAV). Notwithstanding the technical evolution, current knowledge of ECMO support is mainly based on observational experience and mostly retrospective studies. Prospective controlled trials are urgently needed to generate evidence on safety and efficacy of ECMO support in different clinical settings. PMID- 26608161 TI - Short tip-big difference? First-in-man experience and procedural efficacy of pulmonary vein isolation using the third-generation cryoballoon. AB - BACKGROUND: The second-generation cryoballoon (CB2) provides effective and durable pulmonary vein isolation (PVI) associated with encouraging clinical outcome data. The novel third-generation cryoballoon (CB3) incorporates a 40 % shorter distal tip. This design change may translate into an increased rate of PVI real-time signal recording, facilitating an individualized ablation strategy using the time to effect (TTE). METHODS AND RESULTS: Thirty consecutive patients with paroxysmal or short-standing persistent atrial fibrillation underwent CB3 based PVI and were compared to 30 patients treated with the CB2. Individual freeze-cycle duration was set to TTE + 120 s for both groups. A total of 118 (CB3) and 119 (CB2) pulmonary veins (PV) were identified and all PVs successfully isolated utilizing the CB3 and CB2, respectively. The real-time PVI visualization rate was 74 % (CB3) and 40 % (CB2; p = 0.001) and the mean freeze-cycle duration 204 +/- 88 s (CB3) and 215 +/- 90 s (CB2; p = 0.15). Per individual PV, a shorter mean freeze-duration was found for the CB3 and the right superior PVs (188 +/- 92 vs. 211 +/- 124 s, p = 0.04) and right inferior PVs (192 +/- 75 vs. 200 +/- 37 s, p = 0.02). No differences were found for the left-sided PVs. CONCLUSIONS: A higher rate of real-time electrical PV recordings is seen using the novel CB3 as compared to CB2, which may facilitate an individualized ablation strategy using the TTE. PMID- 26608163 TI - The clinical characteristics and prognosis of lesions with in-stent eccentric tissue proliferation and strong signal attenuation detected by optical coherence tomography. AB - There are still some patients who require repeat revascularization despite of drug-eluting stent (DES) implantation. The present study aimed to investigate the relationship between optical coherence tomography (OCT) findings and recurring target lesion revascularization (TLR) after percutaneous coronary intervention (PCI) for in-stent restenosis (ISR). We reviewed 50 patients (54 coronary lesions) who underwent PCI for ISR, which included 25 DES-ISR lesions. The PCI strategy depended on the interventionalist's discretion, and DES implantation was performed for 38 (70 %) lesions. Tissue characteristics were assessed qualitatively and quantitatively using the frame showing maximal lumen narrowing (minimal lumen area). In qualitative analysis, OCT detected coexistence of eccentric tissue proliferation and strong signal attenuation (ESA). ESA was observed in six lesions (11 %) in five patients (10 %). Hemodialysis (80 vs. 20 %, p = 0.013) and DES-ISR (100 vs. 40 %, p = 0.0069) were significantly more frequent in ESA patients/lesions than in others. One-year follow-up revealed that re-TLR was more frequently performed for ESA lesions (83 vs. 8 %, p = 0.0002). The findings reveal that ESA detected in OCT images of ISR is related to TLR after PCI for DES-ISR especially in patients undergoing maintenance hemodialysis. PMID- 26608164 TI - Interspecies Complementation of the LuxR Family Pathway-Specific Regulator Involved in Macrolide Biosynthesis. AB - PikD is a widely known pathway-specific regulator for controlling pikromycin production in Streptomyces venezuelae ATCC 15439, which is a representative of the large ATP-binding regulator of the LuxR family (LAL) in Streptomyces sp. RapH and FkbN also belong to the LAL family of transcriptional regulators, which show greatest homology with the ATP-binding motif and helix-turn-helix DNA-binding motif of PikD. Overexpression of pikD and heterologous expression of rapH and fkbN led to enhanced production of pikromycin by approximately 1.8-, 1.6-, and 1.6-fold in S. venezuelae, respectively. Cross-complementation of rapH and fkbN in the pikD deletion mutant (DeltapikD) restored pikromycin and derived macrolactone production. Overall, these results show that heterologous expression of rapH and fkbN leads to the overproduction of pikromycin and its congeners from the pikromycin biosynthetic pathway in S. venezuelae, and they have the same functionality as the pathwayspecific transcriptional activator for the pikromycin biosynthetic pathway in the DeltapikD strain. These results also show extensive "cross-communication" between pathway-specific regulators of streptomycetes and suggest revision of the current paradigm for pathwayspecific versus global regulation of secondary metabolism in Streptomyces species. PMID- 26608165 TI - Enhanced Acid Tolerance in Bifidobacterium longum by Adaptive Evolution: Comparison of the Genes between the Acid-Resistant Variant and Wild-Type Strain. AB - Acid stress can affect the viability of probiotics, especially Bifidobacterium. This study aimed to improve the acid tolerance of Bifidobacterium longum BBMN68 using adaptive evolution. The stress response, and genomic differences of the parental strain and the variant strain were compared by acid stress. The highest acid-resistant mutant strain (BBMN68m) was isolated from more than 100 asexual lines, which were adaptive to the acid stress for 10(th), 20(th), 30(th), 40(th), and 50(th) repeats, respectively. The variant strain showed a significant increase in acid tolerance under conditions of pH 2.5 for 2 h (from 7.92 to 4.44 log CFU/ml) compared with the wildtype strain (WT, from 7.87 to 0 log CFU/ml). The surface of the variant strain was also smoother. Comparative whole-genome analysis showed that the galactosyl transferase D gene (cpsD, bbmn68_1012), a key gene involved in exopolysaccharide (EPS) synthesis, was altered by two nucleotides in the mutant, causing alteration in amino acids, pI (from 8.94 to 9.19), and predicted protein structure. Meanwhile, cpsD expression and EPS production were also reduced in the variant strain (p < 0.05) compared with WT, and the exogenous WT-EPS in the variant strain reduced its acid-resistant ability. These results suggested EPS was related to acid responses of BBMN68. PMID- 26608166 TI - Phytoncide Extracted from Pinecone Decreases LPS-Induced Inflammatory Responses in Bovine Mammary Epithelial Cells. AB - Mastitis is a prevalent inflammatory disease that remains one of the main causes of poor quality of milk. Phytoncides are naturally occurring anti-inflammatory compounds derived from plants and trees. To determine if treatment with phytoncide could decrease the severity of lipopolysaccharide (LPS)-induced inflammatory responses, mammary alveolar epithelial cells (MAC-T) were pretreated with phytoncide (0.02% and 0.04% (v/v)) followed by LPS treatment (1 and 25 MUg/ml). The results demonstrated that phytoncide downregulated LPS-induced pro inflammatory cyclooxygenase-2 (COX-2) expression. Additionally, LPS-induced activation of ERK1/2, p38, and Akt was attenuated by phytoncide. Treatment of cells with known pharmacological inhibitors of ERK1/2 (PD98059), p38 (SB203580), and Akt (LY294002) confirmed the association of these signaling pathways with the observed alterations in COX-2 expression. Moreover, phytoncide attenuated LPS induced NF-kappaB activation and superoxide production, and, finally, treatment with phytoncide increased Nrf2 activation. Results suggest that phytoncide can decrease LPS-induced inflammation in MAC-T cells. PMID- 26608167 TI - Surface-Displayed IL-10 by Recombinant Lactobacillus plantarum Reduces Th1 Responses of RAW264.7 Cells Stimulated with Poly(I:C) or LPS. AB - Recently, poly-gamma-glutamic acid synthetase A (pgsA) has been applied to display exogenous proteins on the surface of Lactobacillus casei or Lactococcus lactis, which results in a surfacedisplayed component of bacteria. However, the ability of carrying genes encoded by plasmids and the expression efficiency of recombinant bacteria can be somewhat affected by the longer gene length of pgsA (1,143 bp); therefore, a truncated gene, pgsA, was generated based on the characteristics of pgsA by computational analysis. Using murine IL-10 as an exogenous gene, recombinant Lactobacillus plantarum was constructed and the capacity of the surface-displayed protein and functional differences between exogenous proteins expressed by these strains were evaluated. Surface expression of IL-10 on both recombinant bacteria with anchorins and the higher expression levels in L. plantarum-pgsA'-IL-10 were confirmed by western blot assay. Most importantly, up-regulation of IL-1beta, IL-6, TNF-alpha, IFN-gamma, and the nuclear transcription factor NF-kappaB p65 in RAW264.7 cells after stimulation with Poly(I:C) or LPS was exacerbated after co-culture with L. plantarum-pgsA. By contrast, IL-10 expressed by these recombinant strains could reduce these factors, and the expression of these factors was associated with recombinant strains that expressed anchorin (especially in L. plantarum-pgsA'-IL-10) and was significantly lower compared with the anchorin-free strains. These findings indicated that exogenous proteins could be successfully displayed on the surface of L. plantarum by pgsA or pgsA', and the expression of recombinant bacteria with pgsA' was superior compared with bacteria with pgsA. PMID- 26608168 TI - High-Level Production of Human Papillomavirus (HPV) Type 16 L1 in Escherichia coli. AB - Human papillomavirus (HPV), a non-enveloped, double-stranded DNA tumor virus, is a primary etiological agent of cervical cancer development. As a potential tool for prophylactic vaccination, the development of virus-like particles (VLPs) containing the HPV16 L1 capsid protein is highly desired. In this study, we developed a high-level expression system of the HPV16 L1 in Escherichia coli for the purpose of VLP development. The native gene of HPV16 L1 has many rare codons that cause the early termination of translation and result in the production of truncated forms. First, we optimized the codon of the HPV16 L1 gene to the preferable codons of E. coli, and we succeeded in producing the full-size HPV16 L1 protein without early termination. Next, to find the best host for the production of HPV16 L1, we examined a total of eight E. coli strains, and E. coli BL21(DE3) with the highest yield among the strains was selected. With the selected host-vector system, we did a fed-batch cultivation in a lab-scale bioreactor. Two different feeding solutions (complex and defined feeding solutions) were examined and, when the complex feeding solution was used, a 6 fold higher production yield (4.6 g/l) was obtained compared with that with the defined feeding solution. PMID- 26608169 TI - Natural and artificial photosynthesis: general discussion. PMID- 26608171 TI - Synthesis, structure and the dehydrogenation mechanism of calcium amidoborane hydrazinates. AB - The calcium amidoborane hydrazinates, Ca(NH2BH3)2.nN2H4, were firstly synthesized by reacting different molar ratios of Ca(NH2BH3)2 and N2H4. In particular, Ca(NH2BH3)2 and N2H4 with a molar ratio of 1 : 2 crystallizes into the orthorhombic symmetry P212121 space group with the lattice parameters of a = 6.6239(4) A, b = 13.7932(6) A, c = 4.7909(2) A. The dehydrogenations of calcium amidoborane hydrazinates are two-step reactions, exhibiting superior dehydrogenation properties compared with those of pristine Ca(NH2BH3)2. For Ca(NH2BH3)2-1/2N2H4, approximately 4.6 equiv. hydrogen (or 7.9 wt% hydrogen) can be released at 150 degrees C. Kinetic analysis shows that the activation energies for the two steps of hydrogen desorption from Ca(NH2BH3)2.2N2H4 are much lower than those of pristine Ca(NH2BH3)2, suggesting an improvement in the dehydrogenation kinetics of Ca(NH2BH3)2 after coordinating with N2H4. Isotopic labeling results show that the driving force for the dehydrogenation of calcium amidoborane hydrazinates is the combination mechanism of protonic hydrogen and hydridic hydrogen (H(delta+) and H(delta-)). In addition, initial H2 release from calcium amidoborane hydrazinates originates from the interaction of [-BH3] and N2H4, rather than [-BH3] and [-NH2] (in [-NH2BH3]). PMID- 26608172 TI - Streptomyces formicae sp. nov., a novel actinomycete isolated from the head of Camponotus japonicus Mayr. AB - During a screening for novel and biotechnologically useful actinobacteria in insects, a novel actinomycete with antifungal activity, designated strain 1H GS9(T), was isolated from the head of a Camponotus japonicus Mayr ant, which were collected from Northeast Agricultural University (Harbin, Heilongjiang, China). Strain 1H-GS9(T) was characterised using a polyphasic approach. The organism was found to have morphological and chemotaxonomic characteristics typical of members of the genus Streptomyces. 16S rRNA gene sequence similarity studies showed that strain 1H-GS9(T) belongs to the genus Streptomyces with high sequence similarities to Streptomyces scopuliridis DSM 41917(T) (98.8 %) and Streptomyces mauvecolor JCM 5002(T) (98.6 %). However, phylogenetic analysis based on the 16S rRNA gene sequence indicated that it forms a monophyletic clade with Streptomyces kurssanovii JCM 4388(T) (98.6 %), Streptomyces xantholiticus JCM 4282(T) (98.6 %) and Streptomyces peucetius JCM 9920(T) (98.5 %). Thus, a combination of DNA-DNA hybridization experiments and phenotypic tests were carried out between strain 1H GS9(T) and the above-mentioned five strains, which further clarified their relatedness and demonstrated that strain 1H-GS9(T) could be distinguished from these strains. Therefore, the strain is concluded to represent a novel species of the genus Streptomyces, for which the name Streptomyces formicae sp. nov. is proposed. The type strain is 1H-GS9(T) (=CGMCC 4.7277(T) = DSM 100524(T)). PMID- 26608173 TI - Erratum to: Erysipelothrix larvae sp. nov., isolated from the larval gut of the rhinoceros beetle, Trypoxylus dichotomus (Coleoptera: Scarabaeidae). PMID- 26608174 TI - Reads2Type: a web application for rapid microbial taxonomy identification. AB - BACKGROUND: Identification of bacteria may be based on sequencing and molecular analysis of a specific locus such as 16S rRNA, or a set of loci such as in multilocus sequence typing. In the near future, healthcare institutions and routine diagnostic microbiology laboratories may need to sequence the entire genome of microbial isolates. Therefore we have developed Reads2Type, a web-based tool for taxonomy identification based on whole bacterial genome sequence data. RESULTS: Raw sequencing data provided by the user are mapped against a set of marker probes that are derived from currently available bacteria complete genomes. Using a dataset of 1003 whole genome sequenced bacteria from various sequencing platforms, Reads2Type was able to identify the species with 99.5 % accuracy and on the minutes time scale. CONCLUSIONS: In comparison with other tools, Reads2Type offers the advantage of not needing to transfer sequencing files, as the entire computational analysis is done on the computer of whom utilizes the web application. This also prevents data privacy issues to arise. The Reads2Type tool is available at http://www.cbs.dtu.dk/~dhany/reads2type.html. PMID- 26608175 TI - Are couple-based interventions more effective than interventions delivered to individuals in promoting HIV protective behaviors? A meta-analysis. AB - Despite several advantages to bringing couples together to learn how to protect themselves and new-born children from the risk of HIV infection, most interventions are designed for individuals or groups, not for dyads. This meta analysis provides a direct test of whether couple-based interventions are more effective in promoting HIV protective behaviors than interventions delivered to individuals. We conducted systematic searches of five electronic databases and 60 journals. Eligible studies were controlled trials or prospective cohort designs; evaluated a couple-based intervention compared to an individual-level intervention; assessed at least one HIV prevention outcome (e.g., protective sex, drug use, HIV testing, medication adherence, and sexually transmitted infections [STI]); and were published between 1988 and 2014. Fifteen interventions, including 21,882 participants from China, Kenya, Rwanda, Tanzania, Trinidad, Zambia, and the USA, were evaluated. The results of random-effects models showed statistically significant intervention effects for protective sex (OR = 1.60, 95% CI = 1.21, 2.11), HIV testing (OR = 1.79, 95% CI = 1.31, 2.45), and Nevirapine uptake (OR = 1.51, 95% CI = 1.02, 2.24). The evidence demonstrates the usefulness of couple-based interventions in protecting individuals, partners, and new-born children from the risk of HIV transmission and infection. PMID- 26608176 TI - Synthesis and evaluation of a new vesamicol analog o-[(11)C]methyl-trans decalinvesamicol as a PET ligand for the vesicular acetylcholine transporter. AB - INTRODUCTION: We focused on the vesicle acetyl choline transporter (VAChT) as target for early diagnosis of Alzheimer's diseases because the dysfunction of the cholinergic nervous system is closely associated with the symptoms of AD, such as problem in recognition, memory, and learning. Due to its low binding affinity for the sigma receptors (sigma-1 and sigma-2), o-methyl-trans-decalinvesamicol (OMDV) demonstrated a high binding affinity and selectivity for vesicular acetyl choline transporter (VAChT). [(11)C]OMDV was prepared and investigated the potential as a new PET ligand for VAChT imaging through in vivo evaluation. METHOD: [(11)C]OMDV was prepared by a palladium-promoted cross-coupling reaction using [(11)C]methyl iodide, with a radiochemical yield of 60-75%, a radiochemical purity of greater than 98%, and a specific activity of 5-10 TBq/mmol 30 min after EOB. In vivo biodistribution study of [(11)C]OMDV in blood, brain regions and major organs of rats was performed at 2, 10, 30 and 60 min post-injection. In vivo blocking study and PET-CT imaging study were performed to check the binding selectivity of [(11)C]OMDV for VAChT. RESULTS: In vivo studies demonstrated [(11)C]OMDV passage through the blood-brain barrier (BBB) and accumulation in the rat brain. The regional brain accumulation of [(11)C]OMDV was significantly inhibited by co administration of vesamicol. In contrast, brain accumulation of [(11)C]OMDV was not significantly altered by co-administration of (+)-pentazocine, a selective sigma-1 receptor ligand, or (+)-3-(3-hydroxyphenyl)-N-propylpiperidine [(+)-3 PPP], a sigma-1 and sigma-2 receptor ligand. PET-CT imaging revealed inhibition of [(11)C]OMDV accumulation in the brain by co-administration of vesamicol. CONCLUSION: [(11)C]OMDV selectively binds to VAChT with high affinity in the rat brain in vivo, and that [(11)C]OMDV may be utilized in the future as a specific VAChT ligand for PET imaging. PMID- 26608177 TI - Longitudinal pathways from early maternal depression to children's dysregulated representations: a moderated mediation analysis of harsh parenting and gender. AB - There is some evidence linking maternal depression, harsh parenting, and children's internal representations of attachment, yet, longitudinal examinations of these relationships and differences in the developmental pathways between boys and girls are lacking. Moderated mediation growth curves were employed to examine harsh parenting as a mechanism underlying the link between maternal depression and children's dysregulated representations using a nationally-representative, economically-vulnerable sample of mothers and their children (n = 575; 49% boys, 51% girls). Dysregulation representations were measured using the MacArthur Story Stem Battery at five years of age (M = 5.14, SD = 0.29). Harsh parenting mediated the association between early maternal depression and dysregulated representations for girls. Though initial harsh parenting was a significant mediator for boys, a stronger direct effect of maternal depression to dysregulated representations emerged over time. Results are discussed in terms of their implications for intervention efforts aimed at promoting early supportive parenting. PMID- 26608178 TI - Synthesis and characterisation of Li11RE18M4O39-delta: RE = Nd or Sm; M = Al, Co or Fe. AB - Four new phases of general formula, Li11RE18M4O39-delta: REM = NdAl, NdCo, SmCo, SmFe, have been synthesised and characterised. The NdAl phase, and probably the others, is isostructural with the NdFe analogue, but some cation disorder and partial site occupancies prevent full structural refinement of powder neutron diffraction data. The NdCo phase also forms a solid solution with variable Li content (and charge compensation by either oxygen vacancies or variable transition metal oxidation state). The NdAl phase is a modest conductor of Li(+) ions whereas the other three phases are electronic conductors, attributed to mixed valence of the transition metal ions. Subsolidus phase diagrams for the systems Li2O-Nd2O3-Al2O3, 'CoO' have been determined and an additional new phase, LiCoNd4O8, which appears to have a K2NiF4-related superstructure, identified. PMID- 26608179 TI - Reprint of: "Demographic factors predict magnitude of conditioned fear". AB - There is substantial variability across individuals in the magnitudes of their skin conductance (SC) responses during the acquisition and extinction of conditioned fear. To manage this variability, subjects may be matched for demographic variables, such as age, gender and education. However, limited data exist addressing how much variability in conditioned SC responses is actually explained by these variables. The present study assessed the influence of age, gender and education on the SC responses of 222 subjects who underwent the same differential conditioning paradigm. The demographic variables were found to predict a small but significant amount of variability in conditioned responding during fear acquisition, but not fear extinction learning or extinction recall. A larger differential change in SC during acquisition was associated with more education. Older participants and women showed smaller differential SC during acquisition. Our findings support the need to consider age, gender and education when studying fear acquisition but not necessarily when examining fear extinction learning and recall. Variability in demographic factors across studies may partially explain the difficulty in reproducing some SC findings. PMID- 26608180 TI - In vitro/in vivo correlation and modeling of emitted dose and lung deposition of inhaled salbutamol from metered dose inhalers with different types of spacers in noninvasively ventilated patients. AB - Substituting spacer by another in noninvasive ventilation (NIV) involves many variables, e.g. total emitted dose (TED), mass median aerodynamic diameter (MMAD), type of spacer, total lung deposition and total systemic absorption, which must be adjusted to ensure patient optimum therapy. Data mining based on artificial neural networks and genetic algorithms were used to model in vitro inhalation process, predict and optimize bioavailability from inhaled doses delivered by metered dose inhaler (MDI) using different spacers in NIV. Modeling of data indicated that in vitro performance of MDI-spacer systems was dependent mainly on fine particle dose (FPD), fine particle fraction (FPF), MMAD and to lesser extent on spacer type. Ex vivo model indicated that amount of salbutamol collected on facemask filter was directly affected by FPF. In vivo model (24hQ) depended directly on spacer type, FPF and TED. Female patients showed higher 0.5hQ and 24hQ values than males. AeroChamber VC spacer demonstrated higher TED and 24hQ in vivo values. Results indicated suitability of MDI-spacer systems in achieving appropriate in vitro inhalation performance. The possibility of modeling and predicting both ex vivo and in vivo capabilities of MDI-spacer systems from knowledge of in vitro attributes enabled detailed focus on important variables required to deliver safe and accurate doses of salbutamol to ventilated patients. PMID- 26608182 TI - N-Acetyltransferase 2: ultra-slow acetylators enter the stage. PMID- 26608181 TI - Arginase inhibitor attenuates pulmonary artery hypertension induced by hypoxia. AB - Hypoxia-induced pulmonary arterial hypertension (HPAH) is a refractory disease characterized by increased proliferation of pulmonary vascular smooth cells and progressive pulmonary vascular remodeling. The level of nitric oxide (NO), a potential therapeutic vasodilator, is low in PAH patients. L-arginine can be converted to either beneficial NO by nitric oxide synthases or to harmful urea by arginase. In the present study, we aimed to investigate whether an arginase inhibitor, S-(2-boronoethyl)-L-cysteine ameliorates HPAH in vivo and vitro. In a HPAH mouse model, we assessed right ventricle systolic pressure (RVSP) by an invasive method, and found that RSVP was elevated under hypoxia, but was attenuated upon arginase inhibition. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured under hypoxic conditions, and their proliferative capacity was determined by cell counting and flow cytometry. The levels of cyclin D1, p27, p-Akt, and p-ERK were detected by RT-PCR or Western blot analysis. Compared to hypoxia group, arginase inhibitor inhibited HPASMCs proliferation and reduced the levels of cyclin D1, p-Akt, p-ERK, while increasing p27 level. Moreover, in mouse models, compared to control group, hypoxia increased cyclin D1 expression but reduced p27 expression, while arginase inhibitor reversed the effects of hypoxia. Taken together, these results suggest that arginase plays an important role in increased proliferation of HPASMCs induced by hypoxia and it is a potential therapeutic target for the treatment of pulmonary hypertensive disorders. PMID- 26608183 TI - Metabolism and elimination of methyl, iso- and n-butyl paraben in human urine after single oral dosage. AB - Parabens are used as preservatives in personal care and consumer products, food and pharmaceuticals. Their use is controversial because of possible endocrine disrupting properties. In this study, we investigated metabolism and urinary excretion of methyl paraben (MeP), iso-butyl paraben (iso-BuP) and n-butyl paraben (n-BuP) after oral dosage of deuterium-labeled analogs (10 mg). Each volunteer received one dosage per investigated paraben separately and at least 2 weeks apart. Consecutive urine samples were collected over 48 h. In addition to the parent parabens (free and conjugated) which are already used as biomarkers of internal exposure and the known but non-specific metabolites, p-hydroxybenzoic acid (PHBA) and p-hydroxyhippuric acid (PHHA), we identified new, oxidized metabolites with hydroxy groups on the alkyl side chain (3OH-n-BuP and 2OH-iso BuP) and species with oxidative modifications on the aromatic ring. MeP represented 17.4 % of the dose excreted in urine, while iso-BuP represented only 6.8 % and n-BuP 5.6 %. Additionally, for iso-BuP, about 16 % was excreted as 2OH iso-BuP and for n-BuP about 6 % as 3OH-n-BuP. Less than 1 % was excreted as ring hydroxylated metabolites. In all cases, PHHA was identified as the major but non specific metabolite (57.2-63.8 %). PHBA represented 3.0-7.2 %. For all parabens, the majority of the oral dose captured by the above metabolites was excreted in the first 24 h (80.5-85.3 %). Complementary to the parent parabens excreted in urine, alkyl-chain-oxidized metabolites of the butyl parabens are introduced as valuable and contamination-free biomarkers of exposure. PMID- 26608184 TI - Identification of sample annotation errors in gene expression datasets. AB - The comprehensive transcriptomic analysis of clinically annotated human tissue has found widespread use in oncology, cell biology, immunology, and toxicology. In cancer research, microarray-based gene expression profiling has successfully been applied to subclassify disease entities, predict therapy response, and identify cellular mechanisms. Public accessibility of raw data, together with corresponding information on clinicopathological parameters, offers the opportunity to reuse previously analyzed data and to gain statistical power by combining multiple datasets. However, results and conclusions obviously depend on the reliability of the available information. Here, we propose gene expression based methods for identifying sample misannotations in public transcriptomic datasets. Sample mix-up can be detected by a classifier that differentiates between samples from male and female patients. Correlation analysis identifies multiple measurements of material from the same sample. The analysis of 45 datasets (including 4913 patients) revealed that erroneous sample annotation, affecting 40 % of the analyzed datasets, may be a more widespread phenomenon than previously thought. Removal of erroneously labelled samples may influence the results of the statistical evaluation in some datasets. Our methods may help to identify individual datasets that contain numerous discrepancies and could be routinely included into the statistical analysis of clinical gene expression data. PMID- 26608186 TI - The role of liver progenitor cells during liver regeneration, fibrogenesis, and carcinogenesis. AB - The growing worldwide challenge of cirrhosis and hepatocellular carcinoma due to increasing prevalence of excessive alcohol consumption, viral hepatitis, obesity, and the metabolic syndrome has sparked interest in stem cell-like liver progenitor cells (LPCs) as potential candidates for cell therapy and tissue engineering, as an alternative approach to whole organ transplantation. However, LPCs always proliferate in chronic liver diseases with a predisposition to cancer; they have been suggested to play major roles in driving fibrosis, disease progression, and may even represent tumor-initiating cells. Hence, a greater understanding of the factors that govern their activation, communication with other hepatic cell types, and bipotential differentiation as opposed to their potential transformation is needed before their therapeutic potential can be harnessed. PMID- 26608185 TI - Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling. AB - Bile acids (BAs) are synthesized in the liver and secreted into the intestine. In the lumen, enteric bacteria metabolize BAs from conjugated, primary forms into more toxic unconjugated, secondary metabolites. Secondary BAs can be injurious to the intestine and may contribute to disease. The epidermal growth factor receptor (EGFR) and the nuclear farnesoid X receptor (FXR) are known to interact with BAs. In this study we examined the effects of BAs on intestinal epithelial cell proliferation and investigated the possible roles for EGFR and FXR in these effects. We report that taurine-conjugated cholic acid (TCA) induced proliferation, while its unconjugated secondary counterpart deoxycholic acid (DCA) inhibited proliferation. TCA stimulated phosphorylation of Src, EGFR, and ERK 1/2. Pharmacological blockade of any of these pathways or genetic ablation of EGFR abrogated TCA-stimulated proliferation. Interestingly, Src or EGFR inhibitors eliminated TCA-induced phosphorylation of both molecules, suggesting that their activation is interdependent. In contrast to TCA, DCA exposure diminished EGFR phosphorylation, and pharmacological or siRNA blockade of FXR abolished DCA-induced inhibition of proliferation. Taken together, these results suggest that TCA induces intestinal cell proliferation via Src, EGFR, and ERK activation. In contrast, DCA inhibits proliferation via an FXR-dependent mechanism that may include downstream inactivation of the EGFR/Src/ERK pathway. Since elevated secondary BA levels are the result of specific bacterial modification, this may provide a mechanism through which an altered microbiota contributes to normal or abnormal intestinal epithelial cell proliferation. PMID- 26608187 TI - Normal systemic iron homeostasis in mice with macrophage-specific deletion of transferrin receptor 2. AB - Iron is an essential element, since it is a component of many macromolecules involved in diverse physiological and cellular functions, including oxygen transport, cellular growth, and metabolism. Systemic iron homeostasis is predominantly regulated by the liver through the iron regulatory hormone hepcidin. Hepcidin expression is itself regulated by a number of proteins, including transferrin receptor 2 (TFR2). TFR2 has been shown to be expressed in the liver, bone marrow, macrophages, and peripheral blood mononuclear cells. Studies from our laboratory have shown that mice with a hepatocyte-specific deletion of Tfr2 recapitulate the hemochromatosis phenotype of the global Tfr2 knockout mice, suggesting that the hepatic expression of TFR2 is important in systemic iron homeostasis. It is unclear how TFR2 in macrophages contributes to the regulation of iron metabolism. We examined the role of TFR2 in macrophages by analysis of transgenic mice lacking Tfr2 in macrophages by crossing Tfr2(f/f) mice with LysM-Cre mice. Mice were fed an iron-rich diet or injected with lipopolysaccharide to examine the role of macrophage Tfr2 in iron- or inflammation-mediated regulation of hepcidin. Body iron homeostasis was unaffected in the knockout mice, suggesting that macrophage TFR2 is not required for the regulation of systemic iron metabolism. However, peritoneal macrophages of knockout mice had significantly lower levels of ferroportin mRNA and protein, suggesting that TFR2 may be involved in regulating ferroportin levels in macrophages. These studies further elucidate the role of TFR2 in the regulation of iron homeostasis and its role in regulation of ferroportin and thus macrophage iron homeostasis. PMID- 26608188 TI - JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines. AB - The inflammatory diseases ulcerative colitis and Crohn's disease constitute the two main forms of inflammatory bowel disease (IBD). They are characterized by chronic, relapsing inflammation of the gastrointestinal tract, significantly impacting on patient quality of life and often requiring prolonged treatment. Existing therapies for IBD are not effective for all patients, and an unmet need exists for additional therapies to induce and maintain remission. Here we describe the mechanism of action of the Janus kinase (JAK) inhibitor, tofacitinib, for the treatment of IBD and the effect of JAK inhibition on the chronic cycle of inflammation that is characteristic of the disease. The pathogenesis of IBD involves a dysfunctional response from the innate and adaptive immune system, resulting in overexpression of multiple inflammatory cytokines, many of which signal through JAKs. Thus JAK inhibition allows multiple cytokine signaling pathways to be targeted and is expected to modulate the innate and adaptive immune response in IBD, thereby interrupting the cycle of inflammation. Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated as a targeted immunomodulator for IBD. Clinical development of tofacitinib and other JAK inhibitors is ongoing, with the aspiration of providing new treatment options for IBD that have the potential to deliver prolonged efficacy and clinically meaningful patient benefits. PMID- 26608189 TI - A novel, protective role of ursodeoxycholate in bile-induced pancreatic ductal injury. AB - We have previously shown that chenodeoxycholic acid (CDCA) strongly inhibits pancreatic ductal HCO3 (-) secretion through the destruction of mitochondrial function, which may have significance in the pathomechanism of acute pancreatitis (AP). Ursodeoxycholic acid (UDCA) is known to protect the mitochondria against hydrophobic bile acids and has an ameliorating effect on cell death. Therefore, our aim was to investigate the effect of UDCA pretreatment on CDCA-induced pancreatic ductal injury. Guinea pig intrainterlobular pancreatic ducts were isolated by collagenase digestion. Ducts were treated with UDCA for 5 and 24 h, and the effect of CDCA on intracellular Ca(2+) concentration ([Ca(2+)]i), intracellular pH (pHi), morphological and functional changes of mitochondria, and the rate of apoptosis were investigated. AP was induced in rat by retrograde intraductal injection of CDCA (0.5%), and the disease severity of pancreatitis was assessed by measuring standard laboratory and histological parameters. Twenty four-hour pretreatment of pancreatic ducts with 0.5 mM UDCA significantly reduced the rate of ATP depletion, mitochondrial injury, and cell death induced by 1 mM CDCA and completely prevented the inhibitory effect of CDCA on acid-base transporters. UDCA pretreatment had no effect on CDCA-induced Ca(2+) signaling. Oral administration of UDCA (250 mg/kg) markedly reduced the severity of CDCA induced AP. Our results clearly demonstrate that UDCA 1) suppresses the CDCA induced pancreatic ductal injury by reducing apoptosis and mitochondrial damage and 2) reduces the severity of CDCA-induced AP. The protective effect of UDCA against hydrophobic bile acids may represent a novel therapeutic target in the treatment of biliary AP. PMID- 26608190 TI - Young Investigator Perspectives. Choosing an intellectually generous mentor. PMID- 26608191 TI - Why health care corruption needs a new approach. AB - While corruption has been at the center of academic studies and on the agenda of international organizations for a couple of decades, in the health care sector corruption has not generated much interest or progress. At the centre of this issue is the lack of an interdisciplinary approach, which is warranted given the complexity of the issue and the lack of cooperation between STET scientifically rigorous academics and policy-makers, leaving room for more cooperation and progress. PMID- 26608192 TI - Trends in job satisfaction among German nurses from 1990 to 2012. AB - OBJECTIVE: Improving the job satisfaction of nurses is essential to enhance their productivity and retention and to improve patient care. Our aim was to analyse trends in German nurses' job satisfaction to enhance understanding of the nursing labour market and inform future policies. METHODS: We used 1990-2012 German Socioeconomic Panel data for trends in nurses' job satisfaction. Comparisons were drawn with doctors, other health care workers, and employees in other sectors of employment. Analysis explored associations between job satisfaction trends and other aspects of employment, such as whether full time or part time and pay. To account for fluctuations across the period of analysis, linear trends were generated using ordinary least squares. RESULTS: Over 23 years, job satisfaction of German nurses underwent a steady and gradual decline, dropping by an average 7.5%, whereas that of doctors and other health care workers increased by 14.4% and 1%, respectively. The decline for part-time nurses (13%) was more pronounced than that for full-time nurses (3%). At the same time, nurses' pay rose by only 3.8% compared to a 23.8% increase for doctors. CONCLUSIONS: The steady decline in nurses' job satisfaction over the last two decades may be attributable to the multiple reforms and associated policy changes that generally disadvantaged nurses. Contributing factors to job satisfaction decline include lower pay and the demanding and strenuous work environment. Irrespective of the reason, health services researchers, leaders, and policy makers should investigate the reasons for this decline given the forecast growth in work load and complexity of care. Supportive policies for nurses would help enhance the quality and sustainability of German health care. PMID- 26608193 TI - Criteria for discharge of patients with Ebola virus diseases in high-income countries. PMID- 26608194 TI - Associations Between Patient Perceptions of Communication, Cure, and Other Patient-Related Factors Regarding Patient-Reported Quality of Care Following Surgical Resection of Lung and Colorectal Cancer. AB - BACKGROUND: The objective of the current study was to analyze various patient related factors related to patient-reported quality of overall and surgical care following surgical resection of lung or colorectal cancer. METHODS: Between 2003 and 2005, 3,954 patients who underwent cancer-directed surgery for newly diagnosed lung (30.3%) or colorectal (69.7%) cancer were identified from a population- and health system-based survey of participants from multiple US regions. Factors associated with patient-perceived quality of overall and surgical care were analyzed with multivariable logistic regression models. RESULTS: Overall, 56.7% of patients reported excellent quality of overall care and 67.9% of patients reported excellent quality of surgical care; there was no difference by cancer type (P > 0.05). Factors associated with lower likelihood to report excellent quality of overall and surgical care included female sex, minority race, and the presence of multiple comorbidities (all odds ratio [OR] <1, all P < 0.05). Patients who had higher levels of education (overall quality: OR 1.62; surgical quality: OR 1.26), higher annual income (overall quality: OR 1.29; surgical quality: OR 1.23), and good physical function (overall quality: OR 1.35; surgical quality: OR 1.24) were all more likely to report excellent quality of overall and surgical care (all P < 0.05). Furthermore, patients who reported their physician as having excellent communication skills (overall quality: OR 6.49; surgical quality: OR 3.74) as well as patients who perceived their cancer as likely curable (overall quality: OR 1.17; surgical quality: OR 1.11) were more likely to report excellent quality of overall and surgical care (all P < 0.05). CONCLUSION: Patient-reported quality of care is associated with several factors including race, income, and educational status, as well as physician communication and patient perception of likelihood of cure. Future studies are needed to more closely examine patient-physician relationships and communication barriers, particularly among minority patients and those with lower income and educational status. PMID- 26608196 TI - Trends of pH decrease in the Mediterranean Sea through high frequency observational data: indication of ocean acidification in the basin. AB - A significant fraction of anthropogenic carbon dioxide (CO2) released to the atmosphere is absorbed by the oceans, leading to a range of chemical changes and causing ocean acidification (OA). Assessing the impact of OA on marine ecosystems requires the accurate detection of the rate of seawater pH change. This work reports the results of nearly 3 years of continuous pH measurements in the Mediterranean Sea at the Strait of Gibraltar GIFT time series station. We document a remarkable decreasing annual trend of -0.0044 +/- 0.00006 in the Mediterranean pH, which can be interpreted as an indicator of acidification in the basin based on high frequency records. Modeling pH data of the Mediterranean outflow allowed to discriminate between the pH values of its two main constituent water masses, the Levantine Intermediate Water (LIW) and the Western Mediterranean Deep Water (WMDW). Both water masses also exhibited a decline in pH with time, particularly the WMDW, which can be related to their different biogeochemical nature and processes occurring during transit time from formation sites to the Strait of Gibraltar. PMID- 26608195 TI - Transanal Minimally Invasive Surgery: State of the Art. AB - The treatment for rectal cancer and benign rectal lesions continues to progress in the arena of minimally invasive surgery. While surgical excision of the primary mass remains essential for eradication of disease, there has been a paradigm shift towards less invasive resection methods. Local excision is increasing in popularity for its low morbidity and excellent functional results in select patients. Transanal minimally invasive surgery (TAMIS) is a new technology developed to elevate the practice of local excision to state-of-the art resection. The goal of this article is to evaluate the history, short-term outcomes, and evolution of the TAMIS technique for excision of benign and malignant rectal neoplasia. PMID- 26608197 TI - Introduction to microRNAs: Biogenesis, Action, Relevance of Tissue microRNAs in Disease Pathogenesis, Diagnosis and Therapy-The Concept of Circulating microRNAs. AB - MicroRNAs as the endogenous mediators of RNA interference have principal roles in gene expression regulation. Since their discovery in the early 1990s, their number has steadily grown to approximately 2500 known microRNAs at present in humans. MicroRNAs encoded by distinct genes regulate the expression of about 30 60 % of human protein coding genes by targeting their messenger RNAs (mRNAs) and induce mostly posttranscriptional inhibition, or in some cases enhancement. MicroRNAs, as fine regulators of the gene expression, have important roles in development, the physiological functioning of the organism, e.g. organogenesis, immune functioning, vascular system, etc. The deregulation of microRNA expression has been observed in many disorders, such as in carcinogenesis. Given their tissue specificity and stability, and specific disease-related alterations, tissue microRNAs can be exploited as excellent biomarkers in the diagnosis. Moreover, microRNAs might also be envisaged as novel therapeutic targets. Beside tissue microRNAs, novel data show that microRNAs are also present in body fluids that could further extend their diagnostic utility as minimally invasive biomarkers of various diseases, but also raises intriguing questions regarding their biological relevance. In this introductory chapter, we summarise the most relevant features of microRNAs including their biogenesis, action, the biological, pathological, diagnostic and potential therapeutical relevance of tissue microRNAs. PMID- 26608198 TI - Extracellular microRNAs in Membrane Vesicles and Non-vesicular Carriers. AB - Great excitement has surrounded the finding that small RNAs are stable in various biofluids and carry specific signatures reflecting physiological and pathological states. In this chapter, we briefly describe the impact of this revolutionary discovery and introduce different subclasses of circulating microRNAs based on their mode of transport. Subsequently, we review the current state-of-the art knowledge on microRNA selection for export, secretion and possible uptake mechanisms and their potential function in circulation. Furthermore, we give an overview on the possible use of cell-free microRNAs as biomarkers and as therapeutic targets. Overall, we aim to highlight open questions and address some of the pitfalls of current extracellular RNA research. PMID- 26608199 TI - Technical Aspects Related to the Analysis of Circulating microRNAs. AB - Specific and sensitive noninvasive biofluid-based biomarkers are always needed in the laboratory diagnosis of diseases. Biomarkers are applied not only for diagnostic purposes but for stratifying a disease and for assessing the therapy response or disease progression. MicroRNAs (miRNAs) are short noncoding RNA molecules regulating gene expression posttranscriptionally. They are frequently dysregulated in many physiological and pathophysiological conditions. miRNAs are present in the circulation and in other biofluids that are common matrices for clinical laboratory testing that has raised the possibility that miRNAs may serve as novel biomarkers. Their excellent stability also supports the possibility that miRNAs once will be routinely used biomarkers in clinical practice. From an analytical point of view, there are many factors (starting material, sample storage and processing, different RNA extraction and detection methods, intra- and interassay variability, and assay interferences) to consider if a miRNA as biomarker is aimed to be introduced as a clinical laboratory test. Despite several pre-analytical and analytical factors that still need standardization, a significant number of studies have been published about the potential role of circulating miRNAs as biomarkers. Due to the lack of standardization of methods, there are a lot of discrepancies among results. In this chapter, we aimed to summarize the current findings about circulating miRNAs focusing on the analytical points related to miRNAs measurements from biofluids. PMID- 26608200 TI - Circulating Blood-Borne microRNAs as Biomarkers in Solid Tumors. AB - One of the major challenges in cancer research is the identification of stable biomarkers that could be routinely measured in easily accessible samples. Human blood and other body fluids represent rich sources for the identification of novel biomarkers. It is apparent that the availability of these biomarkers would improve an early detection of asymptomatic disease and the clinical management of cancer. MicroRNAs have been described to be present in various types of body fluids including cell-free serum and plasma. These days, the involvement of microRNAs in molecular pathology of cancer is well established. Moreover, it seems that these molecules could be optimal noninvasive biomarkers owing to their high stability under storage and handling conditions and high sensitivity and specificity in various diseases. To date, more than 100 circulating microRNAs with the potential to serve as novel diagnostic, prognostic, or predictive biomarkers for different types of cancers have been identified, and this number is still increasing. However, there are major discrepancies in the findings by different research groups, and few commonly altered microRNAs have been reported in these studies. Further studies on large cohorts using uniform methodology are warranted to establish the clinical applicability of circulating microRNAs for solid tumors. Here, we summarize the tumor-specific profiles of blood-borne microRNAs and discuss their potential utility for personalized medicine of solid tumors. PMID- 26608201 TI - Circulating microRNA as Biomarkers in Hematological Malignancies. AB - Hematopoiesis is a highly regulated process controlled by a complex network of molecular mechanisms that simultaneously regulate differentiation, proliferation, and apoptosis of hematopoietic stem cells. Aberrant microRNA (miRNA) expression could affect normal hematopoiesis, leading to the development of hematological malignancies. Hematologic cancers, which are caused by malignant transformation of cells of the bone marrow and the lymphatic system, are usually divided into three major groups: leukemias, lymphomas, and monoclonal gammopathies. Hematologic malignancies are highly aggressive diseases with high morbidity and mortality. For these reasons, early and easily obtainable markers for diagnosis, risk stratification, and follow-up are essential for improvement of outcome and survival of these patients. Recent studies have provided new insights about the diagnostic value of expression patterns of miRNAs in serum/plasma in these diseases. While the use of circulating miRNAs is only at the experimental level, it appears to have a great potential. This chapter deals with the use of circulating miRNAs as minimally invasive biomarkers in hematologic malignancies. PMID- 26608202 TI - Circulating microRNAs as Biomarkers in Cardiovascular Diseases. AB - MicroRNAs, key regulators of biological processes, are involved in the pathophysiological mechanisms underlying human diseases, including cardiovascular diseases. Their recent discovery revealed a previously unknown layer of pathophysiologic regulators, which also play a key role in the regulation of several aspects of cardiovascular diseases. More recently, it was demonstrated that circulating microRNAs can be measured in the blood. Hence, the potential use of microRNAs as disease biomarkers attracted many research groups. Indeed, their unusual stability in the bloodstream and during prolonged storage make circulating miRs very interesting as potential biomarkers. Circulating microRNAs are emerging as the next generation "smart" biomarkers and could be helpful in further improving the diagnostic and therapeutic processes of cardiovascular diseases. The present chapter summarizes the most relevant experimental evidence on circulating microRNAs in cardiovascular diseases, including arterial remodeling, restenosis, coronary artery disease, acute coronary syndromes, hypertension, heart failure, and ischemic stroke, highlighting potential pathophysiological correlations to the mechanisms underlying cardiovascular diseases. PMID- 26608203 TI - Circulating microRNAs in Neurodegenerative Diseases. AB - Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are caused by a combination of events that impair normal neuronal function. Although they are considered different disorders, there are overlapping features among them from the clinical, pathological, and genetic points of view. Synaptic dysfunction and loss, neurite retraction, and the appearance of other abnormalities such as axonal transport defects normally precede the neuronal loss that is a relatively late event. The diagnosis of many neurodegenerative diseases is mainly based on patient's cognitive function analysis, and the development of diagnostic methods is complicated by the brain's capacity to compensate for neuronal loss over a long period of time. This results in the late clinical manifestation of symptoms, a time when successful treatment is no longer feasible. Thus, a noninvasive diagnostic method based on early events detection is particularly important. In the last years, some biomarkers expressed in human body fluids have been proposed. microRNAs (miRNAs), with their high stability, tissue- or cell type specific expression, lower cost, and shorter time in the assay development, could constitute a good tool to obtain an early disease diagnosis for a wide number of human pathologies, including neurodegenerative diseases. The possibilities and challenges of using these small RNA molecules as a signature for neurodegenerative disorders is a highly promising approach for developing minimally invasive screening tests and to identify new therapeutic targets. PMID- 26608204 TI - Circulating Extracellular microRNA in Systemic Autoimmunity. AB - MicroRNAs (miRNAs) are differentially regulated in healthy, activated, inflamed, neoplastic, or otherwise pathological cells and tissues. While their main functions are executed intracellularly, many miRNAs can reproducibly be detected extracellularly in plasma and serum. This circulating, extracellular miRNA is protected against degradation by complexation with carrier proteins and/or by being enclosed in subcellular membrane vesicles. This, together with their tissue and disease-specific expression, has fuelled the interest in using circulating microRNA profiles as harbingers of disease, i.e., as diagnostic analytes and as clues to dysregulated pathways in disease. Many studies show that inflammation and immune dysregulation, e.g., in autoimmune diseases, are associated with distinct miRNA expression changes in targeted tissues and in innate and adaptive immunity cells such as lymphocytes, natural killer cells, neutrophil granulocytes, and monocyte-macrophages. Exploratory studies (only validated in a few cases) also show that specific profiles of circulating miRNAs are associated with different systemic autoimmune diseases including systemic lupus erythematosus (SLE), systemic sclerosis, and rheumatoid arthritis. Even though the link between cellular alterations and extracellular profiles is still unpredictable, the data suggest that circulating miRNAs in autoimmunity may become diagnostically useful. Here, we review important circulating miRNAs in animal models of inflammation and in systemic autoimmunity and summarize some proposed functions of miRNAs in immune regulation and dysregulation. We conclude that the studies suggest new hypotheses and additional experiments, and that further diagnostic development is highly dependent on analytical method development and on obtaining sufficient numbers of uniformly processed samples from clinically well-characterized patients and controls. PMID- 26608205 TI - Circulating microRNAs in Inflammatory Bowel Diseases. AB - Inflammatory bowel diseases (IBD) are chronic, idiopathic, polygenic diseases with significant genetic heterogeneity. The two major types of IBD are Crohn's disease (CD) and ulcerative colitis (UlC). It is well known that chronic intestinal inflammation results from the interplay of genetic, immunologic, and environmental factors, so the failure to properly downregulate nonspecific inflammation started by an environmental trigger may lead to the development of IBD. Recent studies indicate several microRNAs (miRNAs) as regulators of important pathways of the immune response and immune cell development, which are crucial to the pathogenesis of a variety of inflammatory diseases, including IBD. Additionally, miRNAs are shown to be crucial regulators of intestinal epithelial barrier function, colonic epithelial cell-derived chemokine expression, and autophagy mechanisms. About 100 miRNAs have been indicated to exhibit altered expression in tissues and blood for UlC and CD, when compared to healthy normal controls. Taking into consideration that to date the diagnosis and follow-up of IBD are performed by invasive colonoscopy, it is well suggested that circulating microRNAs might be promising noninvasive biomarkers for IBD. Therefore, recent studies have focused on comparing miRNAs expression profile in tissue to miRNAs profile in blood, in order to introduce the analysis of circulating microRNAs in the future clinical practice. In this chapter, the role of microRNAs in IBD and the most promising circulating microRNAs will be discussed that could be used as noninvasive biomarkers for IBD diagnosis. PMID- 26608206 TI - Circulating microRNAs in Diabetes Progression: Discovery, Validation, and Research Translation. AB - Diabetes, in all of its forms, is a disease state that demonstrates wide ranging pathological effects throughout the body. Until now, the only method of diagnosing and monitoring the progression of diabetes was through the measurement of blood glucose. Unfortunately, beta cell dysfunction initiates well before the clinical onset of diabetes, and so the development of an effective biomarker signature is of paramount importance to predict and monitor the progression of this disease. MicroRNAs (miRNAs/miRs) are small (18-22 nucleotide) noncoding (nc)RNAs that post-transcriptionally regulate endogenous gene expression by targeted inhibition or degradation of messenger (m)RNA. Recently, miRNAs have shown great promise as biomarkers as some exhibit differential expression in multiple disease states, including type 1 and type 2 diabetes (T1D/T2D). Furthermore, miRNAs are quite stable in circulation, resistant to freeze-thaw and pH-mediated degradation, and are relatively easy to detect using quantitative (q)PCR. Here, we discuss microRNAs that may form a diabetes biomarker signature. To identify these transcripts we outline miRNAs that play a central role in pancreas development and diabetes, as well as previously identified miRNAs with differential expression in individuals with T1D and T2D. Validation and refinement of a miRNA biomarker signature for diabetes would allow identification and intervention of individuals at risk of this disease, as well as stratification and monitoring of patients with established diabetes. PMID- 26608207 TI - Diagnostic Relevance of microRNAs in Other Body Fluids Including Urine, Feces, and Saliva. AB - Beside blood-borne circulating miRNAs, miRNAs have been identified in other body fluid and excrements including stool, bile, saliva, and urine. Given the direct link of these body fluids to certain organs, their analysis for potential diagnostic miRNA markers is plausible. Several independent findings underline the potential utility of stool-derived miRNAs in the diagnosis of colorectal and pancreatic cancer. Given the difficulties in the diagnosis of cholangiocellular cancer, biliary miRNAs might be envisaged as useful markers. Several miRNAs have been identified in the saliva that could be associated with diseases, including tumors of the oral cavity. The urinary pool of miRNAs could be exploited for the diagnosis of urinary tract diseases and some appear to enable early diagnosis. In this chapter, we present findings supporting the potential diagnostic utility of fecal, biliary, salivary, and urinary miRNAs focusing mostly on tumors. PMID- 26608208 TI - Circulating microRNAs as Hormones: Intercellular and Inter-organ Conveyors of Epigenetic Information? AB - The discovery of microRNAs (miRNAs) has created a paradigm shift not only in the traditional central dogma of molecular biology but also in the research of a variety of human diseases. Fourteen years after the discovery of miRNAs, there was another revolutionary finding: cells can shuttle miRNAs between each other via small lipid bilayer vesicles called exosomes. This exosome-mediated horizontal transfer of genetically encoded messages is now recognized as a means of intercellular communication. This chapter reviews the concept that miRNAs can function as hormones conveying epigenetic information. PMID- 26608209 TI - Are Circulating microRNAs Involved in Tumor Surveillance? AB - By studying literature data and having performed an in silico analysis, the circulating microRNA expression profiles of healthy individuals appear to show an abundance of microRNAs with predominant tumor suppressor activity. We hypothesize that circulating tumor suppressor microRNAs might constitute a sort of continuous tumor surveillance, whereby circulating microRNAs delivering gene expression modulating epigenetic information might halt cell transformation and tumorigenesis. This mechanism might complement the well-known cancer immune surveillance. A further hypothesis is also discussed, supposing that the tissue specific action of microRNAs might represent a putative defense mechanism against the potential tumor-promoting actions of secreted miRNA. PMID- 26608210 TI - Hypothetic Interindividual and Interspecies Relevance of microRNAs Released in Body Fluids. AB - MicroRNAs may not only be relevant within the organism, but microRNAs released in body fluids might affect other individuals and hypothetically also other species. Such interindividual and cross-species activity of microRNAs appears to be very interesting, but these actions are largely hypothetic at present warranting extensive experimental validation. Food-derived microRNAs might extend the relevance of food for epigenetic regulation; however, the efficient gastrointestinal transfer of microRNAs needs to be demonstrated. We have raised the hypothesis that the nonprotein coding "dark matter" of the genome containing microRNA genes might be relevant in the regulation of interindividual and interspecies epigenetic communication. PMID- 26608211 TI - Lignified and nonlignified fiber cables in the lacunae of Typha angustifolia. AB - The leaves of Typha are noteworthy in terms of their mechanical properties. We determined the mechanical properties of the fiber cables within the leaf. We found that in vegetative plants, the lignified fiber cables isolated from the leaf sheath and nonlignified fiber cables isolated from the leaf blade of Typha angustifolia differ in their diameter, swelling capacity, Young's modulus, tensile strength, and break load. These differing properties are related to their contributions to stability in the two regions of the leaf. PMID- 26608213 TI - Treatment of Molluscum Contagiosum with Imiquimod in the United States: A Retrospective Cross-Sectional Study. AB - Since there are concerns that imiquimod is being overprescribed for children with molluscum despite its limited efficacy, we used data from two nationally representative surveys to determine the rate at which imiquimod was being prescribed for molluscum contagiosum in the United States. From 1999-2010, there were an estimated 6.4 million visits for molluscum (95% CI: 5.5, 7.3 million), and imiquimod was prescribed at 7.0% of these visits (95% CI: 3.4, 11). Given the low frequency of patients being treated with imiquimod for molluscum, the concerns of its overuse may be unfounded. PMID- 26608214 TI - Pemphigoid Gestationis Complicating an Egg Donation Pregnancy. PMID- 26608212 TI - Interaction between allergic asthma and atherosclerosis. AB - Prior studies have established an essential role of mast cells in allergic asthma and atherosclerosis. Mast cell deficiency or inactivation protects mice from allergen-induced airway hyper-responsiveness and diet-induced atherosclerosis, suggesting that mast cells share pathologic activities in both diseases. Allergic asthma and atherosclerosis are inflammatory diseases that contain similar sets of elevated numbers of inflammatory cells in addition to mast cells in the airway and arterial wall, such as macrophages, monocytes, T cells, eosinophils, and smooth muscle cells. Emerging evidence from experimental models and human studies points to a potential interaction between the 2 seemingly unrelated diseases. Patients or mice with allergic asthma have a high risk of developing atherosclerosis or vice versa, despite the fact that asthma is a T-helper (Th)2 oriented disease, whereas Th1 immunity promotes atherosclerosis. In addition to the preferred Th1/Th2 responses that may differentiate the 2 diseases, mast cells and many other inflammatory cells also contribute to their pathogenesis by more than just T cell immunity. Here, we summarize the different roles of airway and arterial wall inflammatory cells and vascular cells in asthma and atherosclerosis and propose an interaction between the 2 diseases, although limited investigations are available to delineate the molecular and cellular mechanisms by which 1 disease increases the risk of the other. Results from mouse allergic asthma and atherosclerosis models and from human population studies lead to the hypothesis that patients with atherosclerosis may benefit from antiasthmatic medications or that the therapeutic regimens targeting atherosclerosis may also alleviate allergic asthma. PMID- 26608215 TI - Magnetite-Amyloid-beta deteriorates activity and functional organization in an in vitro model for Alzheimer's disease. AB - The understanding of the key mechanisms behind human brain deterioration in Alzheimer' disease (AD) is a highly active field of research. The most widespread hypothesis considers a cascade of events initiated by amyloid-beta peptide fibrils that ultimately lead to the formation of the lethal amyloid plaques. Recent studies have shown that other agents, in particular magnetite, can also play a pivotal role. To shed light on the action of magnetite and amyloid-beta in the deterioration of neuronal circuits, we investigated their capacity to alter spontaneous activity patterns in cultured neuronal networks. Using a versatile experimental platform that allows the parallel monitoring of several cultures, the activity in controls was compared with the one in cultures dosed with magnetite, amyloid-beta and magnetite-amyloid-beta complex. A prominent degradation in spontaneous activity was observed solely when amyloid-beta and magnetite acted together. Our work suggests that magnetite nanoparticles have a more prominent role in AD than previously thought, and may bring new insights in the understanding of the damaging action of magnetite-amyloid-beta complex. Our experimental system also offers new interesting perspectives to explore key biochemical players in neurological disorders through a controlled, model system manner. PMID- 26608216 TI - Fluoride-containing podophyllum derivatives exhibit antitumor activities through enhancing mitochondrial apoptosis pathway by increasing the expression of caspase 9 in HeLa cells. AB - This work aims to provide sampling of halogen-containing aniline podophyllum derivatives and their mode of action with an in-depth comparison among fluorine, chloride and bromide for clarifying the important role and impact of fluorine substitution on enhancing antitumor activity, with an emphasis on the development of drug rational design for antitumor drug. The tumor cytotoxicity of fluoride containing aniline podophyllum derivatives were in general improved by 10-100 times than those of the chloride and bromide-containing aniline podophyllum derivatives since fluoride could not only strongly solvated in protic solvents but also forms tight ion pairs in most aprotic solvents. When compared with chloride and bromide, the higher electronegativity fluoride substituted derivatives significantly enhanced mitochondrial apoptosis pathway by remarkably increasing the expression of caspase-9 in HeLa cells. The current findings would stimulate an enormous amount of research directed toward exploiting novel leading compounds based on podophyllum derivatives, especially for the fluoride substituted structures with promising antitumor activity. PMID- 26608217 TI - Stress and stability of plate-screw fixation and screw fixation in the treatment of Schatzker type IV medial tibial plateau fracture: a comparative finite element study. AB - PURPOSE: The purpose of this study is to compare the stress and stability of plate-screw fixation and screw fixation in the treatment of Schatzker type IV medial tibial plateau fracture. METHODS: A three-dimensional (3D) finite element model of the medial tibial plateau fracture (Schatzker type IV fracture) was created. An axial force of 2500 N with a distribution of 60% to the medial compartment was applied to simulate the axial compressive load on an adult knee during single-limb stance. The equivalent von Mises stress, displacement of the model relative to the distal tibia, and displacement of the implants were used as the output measures. RESULTS: The mean stress value of the plate-screw fixation system was 18.78 MPa, which was significantly (P < 0.001) smaller than that of the screw fixation system. The maximal value of displacement (sum) in the plate screw fixation system was 2.46 mm, which was lower than that in the screw fixation system (3.91 mm). The peak stress value of the triangular fragment in the plate-screw fixation system model was 42.04 MPa, which was higher than that in the screw fixation model (24.18 MPa). But the mean stress of the triangular fractured fragment in the screw fixation model was significantly higher in terms of equivalent von Mises stress (EVMS), x-axis, and z-axis (P < 0.001). CONCLUSIONS: This study demonstrated that the load transmission mechanism between plate-screw fixation system and screw fixation system was different and the stability provided by the plate-screw fixation system was superior to the screw fixation system. PMID- 26608218 TI - Density of Stromal Cells and Macrophages Associated With Collagen Remodeling in the Human Cervix in Preterm and Term Birth. AB - Remodeling of the cervix occurs in advance of labor both at term and at preterm birth. Morphological characteristics associated with remodeling in rodents were assessed in cervix biopsies from women at term (39 weeks' gestation) and preterm (<33 weeks' gestation). Collagen I and III messenger RNA and hydroxyproline concentrations declined in cervix biopsies from women in labor at term and preterm compared to that in the cervix from nonlaboring women. Extracellular collagen was more degraded in sections of cervix from women at term, based on optical density of picrosirius red stain, versus that in biopsies from nonpregnant women. However, collagen structure was unchanged in the cervix from women at preterm labor versus the nonpregnant group. As an indication of inflammation, cell nuclei density was decreased in cervix biopsies from pregnant women irrespective of labor compared to the nonpregnant group. Moreover, CD68 stained macrophages increased to an equivalent extent in cervix subepithelium and stroma from groups in labor, both at term and preterm, as well as in women not in labor at term. Evidence for a similar inflammatory process in the remodeled cervix of women at term and preterm birth parallels results in rodent models. Thus, a conserved final common mechanism involving macrophages and inflammation may characterize the transition to a ripe cervix before birth at term and in advance of premature birth. PMID- 26608220 TI - Capnocytophaga canimorsus meningitis diagnosed by 16S rRNA PCR. AB - Capnocytophaga canimorsus is a common Gram-negative anaerobic bacterium from the oral flora of dogs, typically transmitted to humans by dog bites. We report a case of C. canimorsus meningitis where there was (on presentation) no apparent predisposing risk factor and in whom we used 16S rRNA PCR gene sequencing to identify the pathogen quickly and to switch to appropriate antibiotic therapy. Physicians should be aware of potential C. canimorsus meningitis if conventional cerebrospinal fluid bacterial culture is negative but Gram staining identifies bacteria, especially in patients with a recent dog bite or known immunodeficiency. PMID- 26608219 TI - Validity and responsiveness of four measures of occupational sitting and standing. AB - BACKGROUND: Evidence on the detrimental health effects of prolonged sedentary behavior is accumulating. Interventions need to have a specific focus on sedentary behavior in order to generate clinically meaningful decreases in sedentary time. When evaluating such intervention, the question whether a participant improved or deteriorated their behavior is fundamental and instruments that are able to detect those changes are essential. Therefore, the aim of this study was to determine the criterion validity against activPAL and responsiveness to change of two activity monitors (ActiGraph and activPAL) and two questionnaires for the assessment of occupational sitting and standing time. METHODS: 42 participants took part in the Stand@Work intervention trial. Six (T0) and two (T1) weeks before they received a sit-stand workstation and three weeks thereafter (T2), participants wore an ActiGraph and an activPAL activity monitor, and completed the Occupational Sitting and Physical Activity Questionnaire (OSPAQ) and the Workforce Sitting Questionnaire (WSQ). The activPAL was used as the criterion validity measure. RESULTS: The ActiGraph showed strong validity for occupational sedentary time at T0 and T1 (Spearman rho = 0.77 and 0.69), but its validity dropped substantially after introduction of the sit-stand workstation (rho = 0.19). Correlations between occupational light-intensity activity assessed by the ActiGraph and occupational standing time assessed by the activPAL varied between 0.25-0.63. The occupational sitting validity correlation of the OSPAQ and WSQ varied from 0.35-0.48 and 0.25-0.30, respectively, and between 0.16-0.68 for the OSPAQ for occupational standing time. The intervention-induced changes in occupational sitting and standing time were well detected by the activPAL, OSPAQ and WSQ (sitting only), but not by the ActiGraph, which had the lowest responsiveness to change. CONCLUSIONS: This study suggests that studies aimed at determining differences in occupational sitting and standing time should use activPAL-type inclinometers as a preferred type of objective measure. Simple questionnaires showed sufficient validity and are usable in addition to an objective measure or alone when objective monitoring is not possible. The hip worn ActiGraph was unable to distinguish between occupational sitting and standing time, when using uniaxial data and traditional cut-points for sedentary time and light-intensity activity. TRIAL REGISTRATION: The study was registered with the Australian New Zealand Clinical Trials Registry (No. ACTRN 12612000072819). PMID- 26608221 TI - HIV pre-exposure prophylaxis could help 1.2 million in US. PMID- 26608222 TI - Autocrine embryotropins revisited: how do embryos communicate with each other in vitro when cultured in groups? AB - In the absence of the maternal genital tract, preimplantation embryos can develop in vitro in culture medium where all communication with the oviduct or uterus is absent. In several mammalian species, it has been observed that embryos cultured in groups thrive better than those cultured singly. Here we argue that group cultured embryos are able to promote their own development in vitro by the production of autocrine embryotropins that putatively serve as a communication tool. The concept of effective communication implies an origin, a signalling agent, and finally a recipient that is able to decode the message. We illustrate this concept by demonstrating that preimplantation embryos are able to secrete autocrine factors in several ways, including active secretion, passive outflow, or as messengers bound to a molecular vehicle or transported within extracellular vesicles. Likewise, we broaden the traditional view that inter-embryo communication is dictated mainly by growth factors, by discussing a wide range of other biochemical messengers including proteins, lipids, neurotransmitters, saccharides, and microRNAs, all of which can be exchanged among embryos cultured in a group. Finally, we describe how different classes of messenger molecules are decoded by the embryo and influence embryo development by triggering different pathways. When autocrine embryotropins such as insulin-like growth factor-I (IGF I) or platelet activating factor (PAF) bind to their appropriate receptor, the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway will be activated which is important for embryo survival. On the other hand, the mitogen-activated protein kinase (MAPK) pathway is activated when compounds such as hyaluronic acid and serotonin bind to their respective receptors, thereby acting as growth factors. By activating the peroxisome-proliferator-activated receptor family (PPAR) pathway, lipophilic autocrine factors such as prostaglandins or fatty acids have both survival and anti-apoptotic functions. In conclusion, considering different types of messenger molecules simultaneously will be crucial to understanding more comprehensively how embryos communicate with each other in group-culture systems. This approach will assist in the development of novel media for single-embryo culture. PMID- 26608223 TI - Long-Term Data of Efficacy, Safety, and Tolerability in a Real-Life Setting of THC/CBD Oromucosal Spray-Treated Multiple Sclerosis Patients. AB - Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was approved as add-on therapy for spasticity in patients with multiple sclerosis (MS). We show our 40-week postmarketing experience regarding efficacy and safety of THC/CBD spray in an Italian cohort of 102 MS patients. Patients were evaluated using the Expanded Disability Status Scale (EDSS) score, the Numerical Rating Scale (NRS) for spasticity, the Ambulation Index (AI), and Timed 25-Foot Walk (T25-FW) at the beginning of treatment and then every 3 months. After 4 weeks, if a clinically significant improvement in spasticity (at least 20% of baseline NRS score) was not seen, administration of the drug was stopped. In our cohort, patients received an average of 6.5 +/- 1.6 sprays each day. The mean reduction to the NRS spasticity score was 2.5 +/- 1.2 points (P < .0001). Thirty-seven patients (36.2%) discontinued the treatment. The incidence of adverse events (AEs) was 40.2%. Fifty-eight patients (56.9%) were also assessed using the NRS for pain, and 46 patients (45.1%) with bladder dysfunction were assessed for the IPSS (International Prostatic Symptoms Score) score, showing a significant improvement in these scales (P = .011 and P = .001, respectively). In conclusion, treatment with THC/CBD spray appears to be a valid answer to some of the unmet needs in MS patients, such as spasticity and other refractory-to-treatment symptoms. PMID- 26608224 TI - Binding of an Oligomeric Ellagitannin Series to Bovine Serum Albumin (BSA): Analysis by Isothermal Titration Calorimetry (ITC). AB - A unique series of oligomeric ellagitannins was used to study their interactions with bovine serum albumin (BSA) by isothermal titration calorimetry. Oligomeric ellagitannins, ranging from monomer to heptamer and a mixture of octamer undecamers, were isolated as individual pure compounds. This series allowed studying the effects of oligomer size and other structural features. The monomeric to trimeric ellagitannins deviated most from the overall trends. The interactions of ellagitannin oligomers from tetramers to octa-undecamers with BSA revealed strong similarities. In contrast to the equilibrium binding constant, enthalpy showed an increasing trend from the dimer to larger oligomers. It is likely that first the macrocyclic part of the ellagitannin binds to the defined binding sites on the protein surface and then the "flexible tail" of the ellagitannin coats the protein surface. The results highlight the importance of molecular flexibility to maximize binding between the ellagitannin and protein surfaces. PMID- 26608225 TI - Respond to the letter of McIsaac (2015). PMID- 26608226 TI - Intestinal Leiomyositis: A Cause of Chronic Intestinal Pseudo-Obstruction in 6 Dogs. AB - BACKGROUND: Intestinal leiomyositis is a suspected autoimmune disorder affecting the muscularis propria layer of the gastrointestinal tract and is a cause of chronic intestinal pseudo-obstruction in humans and animals. OBJECTIVE: To characterize the clinical presentation, histopathologic features, and outcome of dogs with intestinal leiomyositis in an effort to optimize treatment and prognosis. ANIMALS: Six client-owned dogs. METHODS: Retrospective case series. Medical records were reviewed to describe signalment, clinicopathologic and imaging findings, histopathologic diagnoses, treatment, and outcome. All biopsy specimens were reviewed by a board-certified pathologist. RESULTS: Median age of dogs was 5.4 years (range, 15 months-9 years). Consistent clinical signs included vomiting (6/6), regurgitation (2/6), and small bowel diarrhea (3/6). Median duration of clinical signs before presentation was 13 days (range, 5-150 days). Diagnostic imaging showed marked gastric distension with dilated small intestines in 4/6 dogs. Full-thickness intestinal biopsies were obtained in all dogs by laparotomy. Histopathology of the stomach and intestines disclosed mononuclear inflammation, myofiber degeneration and necrosis, and fibrosis centered within the region of myofiber loss in the intestinal muscularis propria. All dogs received various combinations of immunomodulatory and prokinetic treatment, antimicrobial agents, antiemetics, and IV fluids, but none of the dogs showed a clinically relevant improvement with treatment. Median survival was 19 days after diagnosis (range, 3-270 days). CONCLUSIONS AND CLINICAL IMPORTANCE: Intestinal leiomyositis is a cause of intestinal pseudo-obstruction and must be diagnosed by full-thickness intestinal biopsy. This disease should be considered in dogs with acute and chronic vomiting, regurgitation, and small bowel diarrhea. PMID- 26608227 TI - Concordance between the delirium motor subtyping scale (DMSS) and the abbreviated version (DMSS-4) over longitudinal assessment in elderly medical inpatients. AB - BACKGROUND: Delirium is a common neuropsychiatric syndrome that includes clinical subtypes identified by the Delirium Motor Subtyping Scale (DMSS). We explored the concordance between the DMSS and an abbreviated 4-item version in elderly medical inpatients. METHODS: Elderly general medical admissions (n = 145) were assessed for delirium using the Revised Delirium Rating scale (DRS-R98). Clinical subtype was assessed with the DMSS (which includes the four items included in the DMSS 4). Motor subtypes were generated for all patient assessments using both versions of the scale. The concordance of the original and abbreviated DMSS was examined. RESULTS: The agreement between the DMSS and DMSS-4 was high, both at initial and subsequent assessments (kappa range 0.75-0.91). Intraclass Correlation Coefficient (ICC) for all three raters for the DMSS was high (0.70) and for DMSS 4 was moderate (0.59). Analysis of the agreement between raters for individual DMSS items found higher concordance in respect of hypoactive features compared to hyperactive. CONCLUSIONS: The DMSS-4 allows for rapid assessment of clinical subtype in delirium and has high concordance with the longer and well-validated DMSS, including over longitudinal assessment. There is good inter-rater reliability between medical and nursing staff. More consistent clinical subtyping can facilitate better delirium management and more focused research effort. PMID- 26608228 TI - Pie-like electrode design for high-energy density lithium-sulfur batteries. AB - Owing to the overwhelming advantage in energy density, lithium-sulfur (Li-S) battery is a promising next-generation electrochemical energy storage system. Despite many efforts in pursuing long cycle life, relatively little emphasis has been placed on increasing the areal energy density. Herein, we have designed and developed a 'pie' structured electrode, which provides an excellent balance between gravimetric and areal energy densities. Combining lotus root-like multichannel carbon nanofibers 'filling' and amino-functionalized graphene 'crust', the free-standing paper electrode (S mass loading: 3.6 mg cm(-2)) delivers high specific capacity of 1,314 mAh g(-1) (4.7 mAh cm(-2)) at 0.1 C (0.6 mA cm(-2)) accompanied with good cycling stability. Moreover, the areal capacity can be further boosted to more than 8 mAh cm(-2) by stacking three layers of paper electrodes with S mass loading of 10.8 mg cm(-2). PMID- 26608230 TI - Efficient Synchronization of Dipolarly Coupled Vortex-Based Spin Transfer Nano Oscillators. AB - Due to their nonlinear properties, spin transfer nano-oscillators can easily adapt their frequency to external stimuli. This makes them interesting model systems to study the effects of synchronization and brings some opportunities to improve their microwave characteristics in view of their applications in information and communication technologies and/or to design innovative computing architectures. So far, mutual synchronization of spin transfer nano-oscillators through propagating spinwaves and exchange coupling in a common magnetic layer has been demonstrated. Here we show that the dipolar interaction is also an efficient mechanism to synchronize neighbouring oscillators. We experimentally study a pair of vortex-based spin transfer nano-oscillators, in which mutual synchronization can be achieved despite a significant frequency mismatch between oscillators. Importantly, the coupling efficiency is controlled by the magnetic configuration of the vortices, as confirmed by an analytical model and micromagnetic simulations highlighting the physics at play in the synchronization process. PMID- 26608229 TI - Functional properties of in vitro excitatory cortical neurons derived from human pluripotent stem cells. AB - The in vitro derivation of regionally defined human neuron types from patient derived stem cells is now established as a resource to investigate human development and disease. Characterization of such neurons initially focused on the expression of developmentally regulated transcription factors and neural markers, in conjunction with the development of protocols to direct and chart the fate of differentiated neurons. However, crucial to the understanding and exploitation of this technology is to determine the degree to which neurons recapitulate the key functional features exhibited by their native counterparts, essential for determining their usefulness in modelling human physiology and disease in vitro. Here, we review the emerging data concerning functional properties of human pluripotent stem cell-derived excitatory cortical neurons, in the context of both maturation and regional specificity. PMID- 26608231 TI - A Versatile Precursor System for Supercritical Fluid Electrodeposition of Main Group Materials. AB - For the first time, a versatile electrolyte bath is described that can be used to electrodeposit a wide range of p-block elements from supercritical difluoromethane (scCH2 F2 ). The bath comprises the tetrabutylammonium chlorometallate complex of the element in an electrolyte of 50*10(-3) mol dm(-3) tetrabutylammonium chloride at 17.2 MPa and 358 K. Through the use of anionic ([GaCl4 ](-) , [InCl4 ](-) , [GeCl3 ](-) , [SnCl3 ](-) , [SbCl4 ](-) , and [BiCl4 ](-) ) and dianionic ([SeCl6 ](2-) and [TeCl6 ](2-) ) chlorometallate salts, the deposition of elemental Ga, In, Ge, Sn, Sb, Bi, Se, and Te is demonstrated. In all cases, with the exception of gallium, which is a liquid under the deposition conditions, the resulting deposits are characterised by SEM, energy-dispersive X ray analysis, XRD and Raman spectroscopy. An advantage of this electrolyte system is that the reagents are all crystalline solids, reasonably easy to handle and not highly water or oxygen sensitive. The results presented herein significantly broaden the range of materials accessible by electrodeposition from supercritical fluid and open up the future possibility of utilising the full scope of these unique fluids to electrodeposit functional binary or ternary alloys and compounds of these elements. PMID- 26608232 TI - Development of a productive research culture in emergency medicine: Report of the outcomes of a research forum. AB - In recent years, the Australasian College for Emergency Medicine (ACEM) has increasingly focused on the need for high-quality research in emergency medicine (EM). One important initiative was the establishment of the ACEM Foundation, which among other responsibilities, is required to support clinical research through the provision of research funding and other measures. In February 2015, the Foundation held a Research Forum that was attended by the leading EM researchers from Australasia. The Forum aimed to determine how a productive research culture could be developed within the ACEM. Nine key objectives were determined including that research should be a core business of the ACEM and a core activity of the EM workforce, and that EM research should be sustainable and adequately supported. This report describes the background and conduct of the Forum, its recommendations and the way in which they could be implemented. PMID- 26608234 TI - Loss of the Mediator subunit Med20 affects transcription of tRNA and other non coding RNA genes in fission yeast. AB - Mediator is a co-regulator of RNA polymerase II (Pol II), transducing signals from regulatory elements and transcription factors to the general transcription machinery at the promoter. We here demonstrate that Med20 influences ribosomal protein expression in fission yeast. In addition, loss of Med20 leads to an accumulation of aberrant, readthrough tRNA transcripts. These transcripts are polyadenylated and targeted for degradation by the exosome. Similarly, other non coding RNA molecules, such as snRNA, snoRNA and rRNA, are also enriched in the polyadenylate preparations in the absence of Med20. We suggest that fission yeast Mediator takes part in a regulatory pathway that affects Pol III-dependent transcripts. PMID- 26608233 TI - The suitability of some blood gas and biochemical parameters as diagnostic tools or early indicators of ascites syndrome in broiler sire lines. AB - In recent few years, there have been some attempts to find a reliable indicator trait as a selection criterion against susceptibility to ascites syndrome (AS). Blood parameters were of great interest as they could be measured in live animals without implementing an ascites-inducing challenge (AIC). In this work, the suitability of some blood parameters was evaluated for diagnosing AS-susceptible chicks in later steps of the disease in trial 1 as well as their early predictive ability in trial 2. In the first trial, one hundred 1-day-old chicks from two pure broiler lines namely S1 and S2 and, in the second trial, 226 1-day-old chicks from line S2 were subjected to AIC. Saline drinking water (1200 mg/l) and lower-than-standard ambient temperatures were the implemented AICs in trials 1 and 2 respectively. The blood parameters including pH, partial pressure of O2 (pO2 ), partial pressure of CO2 (pCO2 ), bicarbonate ion concentration (BIC), percentage of haematocrit (HCT) and saturated haemoglobin (SaO2 ) were measured twice per each bird at days 28 and 35 in trial 1 and once in trial 2 at day 21. The results of the first trial revealed that in line S2 some of the blood parameters differed significantly between the ascitic and non-ascitic groups following exposure to AIC. In this line, the incidence of AS was accompanied by a lower pO2 , SaO2 and BIC, while with higher pCO2 and HCT values. In the second trial, however, although almost all of the parameters showed meaningful differences between the ascitic and non-ascitic broilers, only mean difference of BIC parameter was statistically significant. The general conclusion of this study is that the blood parameters can somewhat have diagnostic ability in the condition in which the AIC is already present, whereas the results did not approve their usefulness as early predictors of AS. PMID- 26608235 TI - Cervical adenocarcinoma with stromal micropapillary pattern. AB - Adenocarcinoma with a stromal micropapillary pattern (SMP) has been described in various organs, but not in the uterus. We encountered a case of uterine cervical carcinoma with SMP. A54-year-old Japanese woman was referred to the hospital with abnormal vaginal bleeding. The cervical cytodiagnosis was adenocarcinoma with features resembling serous adenocarcinoma. Cervical cytology showed many small clusters of tumor cells, present in up to two or three layers, composed of atypical cells with markedly increased nucleus: cytoplasm ratios. A radical hysterectomy with bilateral adnexectomy and retroperitoneal lymph node dissection was performed. Microscopically, the tumor was composed predominantly of adenocarcinoma with SMP. The outer surface of the SMP cell clusters showed membranous expression of mucin-1 (MUC-1). Many lymph node metastases were detected. The tumor was diagnosed as a cervical adenocarcinoma with SMP and coexistent squamous cell carcinoma in situ. The pathology was classified as T1b1N1M1, stage IVB. The patient underwent postoperative adjuvant chemotherapy and is without local recurrence or distant metastasis 48 months after the operation. To the best of our knowledge, this is the first reported case of cervical adenocarcinoma with SMP. PMID- 26608236 TI - Gonadal malignancy in 202 female patients with disorders of sex development containing Y-chromosome material. AB - The objective of this study was to examine risks for gonadal malignancy in a large sample of adult female patients with disorders of sex development (DSD). A retrospective-observational study was conducted from July 1992 to March 2015 and 202 women with DSD were enrolled. Tumor risks for different types of DSD were measured. We found that the patients' total gonadal-malignancy risk was 18.3% (37/202). Tumors included gonadoblastoma (n = 11), seminoma (n = 8), dysgerminoma (n = 5), choriocarcinoma (n = 1), sertoli cell tumors (n = 11), and leydig cell tumors (n = 1). The incidence of gonadal malignancy in patients with complete androgen insensitivity syndrome (CAIS), pure 46, XY gonadal dysgenesis, 45 X/46 XY mixed gonadal dysgenesis, 17alpha-hydroxylase/17, 20-lyase deficiency and partial androgen insensitivity syndrome (PAIS) were 27.1% (13/48), 22.4% (15/67), 10.9% (5/46), 10% (2/20) and 9.5% (2/21), respectively. Our results suggest that the incidence of gonadal malignancy increases with age for female patients with Y chromosome material. Upon diagnoses, immediate, prophylactic gonadectomies should be considered for adult female patients with DSD containing Y chromosome material if they cannot receive regular follow-ups. PMID- 26608237 TI - Correlated responses of respiratory disease and immune capacity traits of Landrace pigs selected for Mycoplasmal pneumonia of swine (MPS) lesion. AB - Five generations of Landrace pigs selected for average daily gain, backfat thickness, Mycoplasmal pneumonia of swine (MPS) lesion score, and plasma cortisol levels, was executed to decrease the MPS lesion score. Genetic parameters and correlated genetic responses for respiratory disease and peripheral blood immune traits were estimated in 1395 Landrace pigs. We estimated the negative genetic correlation of MPS lesion score with phagocytic activity (PA) at 7 weeks of age ( 0.67). The breeding values of PA at 7 weeks of age and 105 kg body weight and the correlated selection response of the ratio of granular leukocytes to lymphocytes at 105 kg body weight were significantly increased, and sheep red blood cell specific antibody production (AP) was significantly decreased in a selection dependent manner. Increasing of natural immunological indicators (e.g. PA) and decreasing of humoral immunological indicator (e.g. AP) were observed due to genetically decreasing MPS lesion score. PMID- 26608238 TI - Gibbs distribution for statistical analysis of graphical data with a sample application to fcMRI brain images. AB - This paper develops object-oriented data analysis (OODA) statistical methods that are novel and complementary to existing methods of analysis of human brain scan connectomes, defined as graphs representing brain anatomical or functional connectivity. OODA is an emerging field where classical statistical approaches (e.g., hypothesis testing, regression, estimation, and confidence intervals) are applied to data objects such as graphs or functions. By analyzing data objects directly we avoid loss of information that occurs when data objects are transformed into numerical summary statistics. By providing statistical tools that analyze sets of connectomes without loss of information, new insights into neurology and medicine may be achieved. In this paper we derive the formula for statistical model fitting, regression, and mixture models; test their performance in simulation experiments; and apply them to connectomes from fMRI brain scans collected during a serial reaction time task study. Software for fitting graphical object-oriented data analysis is provided. PMID- 26608239 TI - Altered self-identity and autobiographical memory in epilepsy. AB - OBJECTIVE: Research suggests that individuals with chronic epilepsy display differences in their self-identity. The mechanisms by which self-identity is altered, however, are not well understood. Neural networks supporting autobiographical memory retrieval in the mesial temporal (MT) lobe are thought to be fundamental to self-identity processes. Thus, we examined differences in self identity and autobiographical memory in patients with either MT or non-mesial temporal (NMT) foci with early or late age of habitual seizure onset. METHODS: Participants included 102 adults: 51 healthy individuals and 51 patients with drug-resistant focal seizures (19 MT, 32 NMT). We used the Ego Identity Process Questionnaire to profile the identity development of participants, and examined how this related to memory function assessed using the Autobiographical Memory Test. RESULTS: Patients and controls had strikingly different self-identity profiles, with early onset MT patients showing the least identity development compared to controls and other patient groups. In contrast, late-onset NMT patients showed the highest level of identity development of the patient groups and closely resembled healthy controls (p < 0.05 for all comparisons). For all MT patients, poor autobiographical memory retrieval was correlated with altered self identity (p < 0.001). No associations between autobiographical memory and self identity were evident in the NMT group. SIGNIFICANCE: Self-identity in epilepsy may be modulated by the extent to which seizure foci impinge on the autobiographical memory network and the timing of seizure onset. Early disruption to MT regions of the autobiographical memory network may constitute a neurocognitive mechanism by which self-identity is altered in chronic focal epilepsy. PMID- 26608240 TI - Regular source of primary care and emergency department use of children in Victoria. AB - AIM: The aim of this paper was to study the prevalence of a regular source of primary care for Victorian children attending one of four emergency departments (EDs) and to determine associated characteristics, including ED use. METHODS: Responses were collected via an electronic survey from parents attending EDs with their child (<=9 years of age) for a lower-urgency condition. Single, multiple choice, and Likert scale responses were analysed using bivariate and logistic regression tests. RESULTS: Of the 1146 parents who provided responses, 80% stated their child has a regular source of primary care. Of these, care is mostly received by a general practitioner (GP) (95%) in GP group practices (71%). Approximately 20% have changed where their child receives primary care in the last year. No associations were observed between having a regular source of primary care and frequency of ED attendance in the past 12 months, although parents whose child did not have a regular source of primary care were more likely to view the ED as a more convenient place to receive care than the primary care provider (39% without regular source vs. 18% with regular source; P < 0.0001). Children were less likely to have a regular source of primary care if their parents were younger, had a lower household income, lower education, and were visiting a hospital in a lower socio-economic indexes for areas rank. CONCLUSIONS: Policy options to improve continuity of care for children may require investigation. Increasing the prevalence of regular source of primary care for children may in turn reduce ED visits. PMID- 26608241 TI - An integrated framework for targeting functional networks via transcranial magnetic stimulation. AB - Transcranial magnetic stimulation (TMS) is a powerful investigational tool for in vivo manipulation of regional or network activity, with a growing number of potential clinical applications. Unfortunately, the vast majority of targeting strategies remain limited by their reliance on non-realistic brain models and assumptions that anatomo-functional relationships are 1:1. Here, we present an integrated framework that combines anatomically realistic finite element models of the human head with resting functional MRI to predict functional networks targeted via TMS at a given coil location and orientation. Using data from the Human Connectome Project, we provide an example implementation focused on dorsolateral prefrontal cortex (DLPFC). Three distinct DLPFC stimulation zones were identified, differing with respect to the network to be affected (default, frontoparietal) and sensitivity to coil orientation. Network profiles generated for DLPFC targets previously published for treating depression revealed substantial variability across studies, highlighting a potentially critical technical issue. PMID- 26608243 TI - Conflict monitoring in speech processing: An fMRI study of error detection in speech production and perception. AB - To minimize the number of errors in speech, and thereby facilitate communication, speech is monitored before articulation. It is, however, unclear at which level during speech production monitoring takes place, and what mechanisms are used to detect and correct errors. The present study investigated whether internal verbal monitoring takes place through the speech perception system, as proposed by perception-based theories of speech monitoring, or whether mechanisms independent of perception are applied, as proposed by production-based theories of speech monitoring. With the use of fMRI during a tongue twister task we observed that error detection in internal speech during noise-masked overt speech production and error detection in speech perception both recruit the same neural network, which includes pre-supplementary motor area (pre-SMA), dorsal anterior cingulate cortex (dACC), anterior insula (AI), and inferior frontal gyrus (IFG). Although production and perception recruit similar areas, as proposed by perception-based accounts, we did not find activation in superior temporal areas (which are typically associated with speech perception) during internal speech monitoring in speech production as hypothesized by these accounts. On the contrary, results are highly compatible with a domain general approach to speech monitoring, by which internal speech monitoring takes place through detection of conflict between response options, which is subsequently resolved by a domain general executive center (e.g., the ACC). PMID- 26608244 TI - Different coupling modes mediate cortical cross-frequency interactions. AB - Cross-frequency coupling (CFC) has been suggested to constitute a highly flexible mechanism for cortical information gating and processing, giving rise to conscious perception and various higher cognitive functions in humans. In particular, it might provide an elegant tool for information integration across several spatiotemporal scales within nested or coupled neuronal networks. However, it is currently unknown whether low-frequency (theta/alpha) or high frequency gamma oscillations orchestrate cross-frequency interactions, raising the question of who is master and who is slave. While correlative evidence suggested that at least two distinct CFC modes exist, namely, phase-amplitude coupling (PAC) and amplitude-envelope correlations (AEC), it is currently unknown whether they subserve distinct cortical functions. Novel non-invasive brain stimulation tools, such as transcranial alternating current stimulation (tACS), now provide the unique opportunity to selectively entrain the low- or high frequency component and study subsequent effects on CFC. Here, we demonstrate the differential modulation of CFC during selective entrainment of alpha or gamma oscillations. Our results reveal that entrainment of the low-frequency component increased PAC, where gamma power became preferentially locked to the trough of the alpha oscillation, while gamma-band entrainment enhanced AECs and reduced alpha power. These results provide causal evidence for the functional role of coupled alpha and gamma oscillations for visual processing. PMID- 26608242 TI - Perception drives production across sensory modalities: A network for sensorimotor integration of visual speech. AB - Sensory information is critical for movement control, both for defining the targets of actions and providing feedback during planning or ongoing movements. This holds for speech motor control as well, where both auditory and somatosensory information have been shown to play a key role. Recent clinical research demonstrates that individuals with severe speech production deficits can show a dramatic improvement in fluency during online mimicking of an audiovisual speech signal suggesting the existence of a visuomotor pathway for speech motor control. Here we used fMRI in healthy individuals to identify this new visuomotor circuit for speech production. Participants were asked to perceive and covertly rehearse nonsense syllable sequences presented auditorily, visually, or audiovisually. The motor act of rehearsal, which is prima facie the same whether or not it is cued with a visible talker, produced different patterns of sensorimotor activation when cued by visual or audiovisual speech (relative to auditory speech). In particular, a network of brain regions including the left posterior middle temporal gyrus and several frontoparietal sensorimotor areas activated more strongly during rehearsal cued by a visible talker versus rehearsal cued by auditory speech alone. Some of these brain regions responded exclusively to rehearsal cued by visual or audiovisual speech. This result has significant implications for models of speech motor control, for the treatment of speech output disorders, and for models of the role of speech gesture imitation in development. PMID- 26608245 TI - Interaction matters: A perceived social partner alters the neural processing of human speech. AB - Mounting evidence suggests that social interaction changes how communicative behaviors (e.g., spoken language, gaze) are processed, but the precise neural bases by which social-interactive context may alter communication remain unknown. Various perspectives suggest that live interactions are more rewarding, more attention-grabbing, or require increased mentalizing-thinking about the thoughts of others. Dissociating between these possibilities is difficult because most extant neuroimaging paradigms examining social interaction have not directly compared live paradigms to conventional "offline" (or recorded) paradigms. We developed a novel fMRI paradigm to assess whether and how an interactive context changes the processing of speech matched in content and vocal characteristics. Participants listened to short vignettes--which contained no reference to people or mental states--believing that some vignettes were prerecorded and that others were presented over a real-time audio-feed by a live social partner. In actuality, all speech was prerecorded. Simply believing that speech was live increased activation in each participant's own mentalizing regions, defined using a functional localizer. Contrasting live to recorded speech did not reveal significant differences in attention or reward regions. Further, higher levels of autistic-like traits were associated with altered neural specialization for live interaction. These results suggest that humans engage in ongoing mentalizing about social partners, even when such mentalizing is not explicitly required, illustrating how social context shapes social cognition. Understanding communication in social context has important implications for typical and atypical social processing, especially for disorders like autism where social difficulties are more acute in live interaction. PMID- 26608246 TI - Transcranial electrical stimulation of the occipital cortex during visual perception modifies the magnitude of BOLD activity: A combined tES-fMRI approach. AB - The aim of this study was to investigate if the blood oxygenation level-dependent (BOLD) changes in the visual cortex can be used as biomarkers reflecting the online and offline effects of transcranial electrical stimulation (tES). Anodal transcranial direct current stimulation (tDCS) and 10Hz transcranial alternating current stimulation (tACS) were applied for 10min duration over the occipital cortex of healthy adults during the presentation of different visual stimuli, using a crossover, double-blinded design. Control experiments were also performed, in which sham stimulation as well as another electrode montage were used. Anodal tDCS over the visual cortex induced a small but significant further increase in BOLD response evoked by a visual stimulus; however, no aftereffect was observed. Ten hertz of tACS did not result in an online effect, but in a widespread offline BOLD decrease over the occipital, temporal, and frontal areas. These findings demonstrate that tES during visual perception affects the neuronal metabolism, which can be detected with functional magnetic resonance imaging (fMRI). PMID- 26608247 TI - Spatiotemporal brain mapping during preparation, perception, and action. AB - Deciding whether to act or not to act is a fundamental cognitive function. To avoid incorrect responses, both reactive and proactive modes of control have been postulated. Little is known, however, regarding the brain implementation of proactive mechanisms, which are deployed prior to an actual need to inhibit a response. Via a combination of electrophysiological and neuroimaging measures (recorded in 21 and 16 participants, respectively), we describe the brain localization and timing of neural activity that underlies the anticipatory proactive mechanism. From these results, we conclude that proactive control originates in the inferior Frontal gyrus, is established well before stimulus perception, and is released concomitantly with stimulus appearance. Stimulus perception triggers early activity in the anterior insula and intraparietal cortex contralateral to the responding hand; these areas likely mediate the transition from perception to action. The neural activities leading to the decision to act or not to act are described in the framework of a three-stage model that includes perception, action, and anticipatory functions taking place well before stimulus onset. PMID- 26608248 TI - Dopamine and anorexia nervosa. AB - We have suggested that reduced food intake increases the risk for anorexia nervosa by engaging mesolimbic dopamine neurons, thereby initially rewarding dieting. Recent fMRI studies have confirmed that dopamine neurons are activated in anorexia nervosa, but it is not clear whether this response is due to the disorder or to its resulting nutritional deficit. When the body senses the shortage of nutrients, it rapidly shifts behavior toward foraging for food as a normal physiological response and the mesolimbic dopamine neurons may be involved in that process. On the other hand, the altered dopamine status of anorexics has been suggested to result from a brain abnormality that underlies their complex emotional disorder. We suggest that the outcomes of the treatments that emerge from that perspective remain poor because they target the mental symptoms that are actually the consequences of the food deprivation that accompanies anorexia. On the other hand, a method that normalizes the disordered eating behavior of anorexics results in much better physiological, behavioral, and emotional outcomes. PMID- 26608249 TI - Natural hybrid of Leishmania infantum/L. donovani: development in Phlebotomus tobbi, P. perniciosus and Lutzomyia longipalpis and comparison with non-hybrid strains differing in tissue tropism. AB - BACKGROUND: Infection caused by parasites from L. donovani complex can manifest as a serious visceral disease or a self-healing milder cutaneous form. The different tropism and pathology in humans is caused by the interaction between parasites, host and vector determinants but the mechanisms are not well understood. In Cukurova region in Turkey we previously identified a major focus of cutaneous leishmaniasis caused by L. donovani/infantum hybrids (CUK strain) and isolated this parasite from the locally abundant sand fly, Phlebotomus tobbi. Here, we present the first experimental study with P. tobbi. We tested the susceptibility of this species to various Leishmania under laboratory conditions, characterized glycoproteins in the P. tobbi midgut putatively involved in parasite-vector interaction and compared the development of the CUK strain in the sand fly with one other dermotropic and three viscerotropic strains belonging to the L. donovani complex. METHODS: Females of laboratory reared P. tobbi, P. perniciosus and Lutzomyia longipalpis were infected using membrane feeding on rabbit blood containing promastigotes of various Leishmania species with different tropisms. The individual guts were checked microscopically for presence and localization of Leishmania parasites; the number of parasites was assessed more precisely by qPCR. In addition, glycosylation of midgut proteins of P. tobbi was studied by lectin blotting of midgut lysate with lectins specific for terminal sugars of N-type and O-type glycans. RESULTS: High infection rates, heavy parasite loads and late-stage infection with colonization of the stomodeal valve were observed in P. tobbi infected by Leishmania major or L. infantum CUK hybrid. In parallel, lectin blotting revealed the presence of O-glycosylated proteins in the P. tobbi midgut. In P. perniciosus and L. longipalpis all five Leishmania strains tested developed well. In both vectors, significantly higher parasite numbers were detected by qPCR for dermotropic L. donovani from Cyprus, however, in all other parameters studied, including localization of infection and colonization of stomodeal valve, dermotropic and viscerotropic strains were not significantly different. CONCLUSIONS: We showed high susceptibility of P. tobbi to various Leishmania spp. This, together with the presence of O-glycosylated midgut proteins in their midguts demonstrate that P. tobbi is a permissive vector. Two dermotropic and three viscerotropic strains from the L. donovani complex developed late-stage infections in natural L. infantum vectors, P. perniciosus and L. longipalpis and none of the parameters studied seem to be linked with different tropism of parasites in the vertebrate host. PMID- 26608250 TI - [Clinical usefulness of salivary gland ultrasonography in Sjogren's syndrome: Where are we now?]. AB - Salivary gland ultrasonography is a simple, noninvasive and inexpensive procedure, which provides valuable information for the diagnosis of primary Sjogren's syndrome (pSS). The main sonographic characteristic of the major salivary glands (parotid and submandibular) in pSS patients is the heterogeneity of the parenchyma, with the appearance of hypoechoic areas. Numerous studies published over the past 20 years report a sensitivity of 70% and a specificity of more than 90% for the diagnosis of pSS. Before the widespread use of this procedure in daily practice and its integration into classification criteria of the disease, it has yet to be validated in terms of reproducibility and a consensus score should be established. This work is being conducted by an international group of experts. Other ultrasound techniques such as elastography could also be of interest to objectively quantify changes in the glandular tissue that occur during the disease. PMID- 26608251 TI - [Bisalbuminemia occurring outside usual situations]. PMID- 26608252 TI - Seasonality and selective trends in viral acute respiratory tract infections. AB - Influenza A and B, and many unrelated viruses including rhinovirus, RSV, adenovirus, metapneumovirus and coronavirus share the same seasonality, since these viral acute respiratory tract infections (vARIs) are much more common in winter than summer. Unfortunately, early investigations that used recycled "pedigree" virus strains seem to have led microbiologists to dismiss the common folk belief that vARIs often follow chilling. Today, incontrovertible evidence shows that ambient temperature dips and host chilling increase the incidence and severity of vARIs. This review considers four possible mechanisms, M1 - 4, that can explain this link: (M1) increased crowding in winter may enhance viral transmission; (M2) lower temperatures may increase the stability of virions outside the body; (M3) chilling may increase host susceptibility; (M4) lower temperatures or host chilling may activate dormant virions. There is little evidence for M1 or M2, which are incompatible with tropical observations. Epidemiological anomalies such as the repeated simultaneous arrival of vARIs over wide geographical areas, the rapid cessation of influenza epidemics, and the low attack rate of influenza within families are compatible with M4, but not M3 (in its simple form). M4 seems to be the main driver of seasonality, but M3 may also play an important role. PMID- 26608253 TI - Radiation Dose Survey for Common Computed Tomography Exams: 2013 British Columbia Results. AB - In 2013 Health Canada conducted a national survey of computed tomography (CT) radiation usage. We analysed contributions from all 7 public health authorities in the province of British Columbia, which covered scanner age, number of slices, and common adult protocols (>= 19 years: 70 +/- 20 kg, head, chest, abdomen/pelvis, and trunk). Patient doses were recorded for common protocols. Diagnostic reference levels (DRLs) was calculated using scanner data with >10 patient doses recorded for each protocol. Data was analysed based on image reconstruction (filtered backprojection vs iterative reconstruction [IR] vs IR available but not in use). Provincial response was 92%, with 59 of 64 CT data used for analysis. The average scanner age was 5.5 years old, with 39% of scanners installed between 2008-2013; 78.5% of scanners were multislice (>64 slices), and 44% of scanners had IR available. Overall British Columbia DRLs were: head = 1305, chest = 529, abdomen/pelvis = 819, and trunk = 1225. DRLs were consistent with Health Canada recommendations and other Canadian published values, but above international standards. For sites with IR available, less than 50% used this technology routinely for head, chest and trunk exams. Overall, use of IR reduced radiation usage between 11%-32% compared to filtered backprojection, while sites using IR vs IR available used 30%/43% less radiation for head/chest exams (P < .05). No significant difference was observed for abdomen/pelvis exams (P = .385). With the fast pace of CT technical advancement, DRLs should reflect the technology used, instead of just globally applied to anatomical regions. Federal guidelines should be updated at a higher frequency to reflect new technology. In addition, new technologies must be utilised to optimize image quality vs radiation usage. PMID- 26608254 TI - Systemic administration of resveratrol suppress the nociceptive neuronal activity of spinal trigeminal nucleus caudalis in rats. AB - Although a modulatory role has been reported for the red wine polyphenol resveratrol on several types of ion channels and excitatory synaptic transmission in the nervous system, the acute effects of resveratrol in vivo, particularly on nociceptive transmission of the trigeminal system, remain to be determined. The aim of the present study was to investigate whether acute intravenous resveratrol administration to rats attenuates the excitability of wide dynamic range (WDR) spinal trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical stimulation in vivo. Extracellular single unit recordings were made from 18 SpVc neurons in response to orofacial mechanical stimulation of pentobarbital-anesthetized rats. Responses to both non-noxious and noxious mechanical stimuli were analyzed in the present study. The mean firing frequency of SpVc WDR neurons in response to both non-noxious and noxious mechanical stimuli was inhibited by resveratrol (0.5-2 mg/kg, i.v.) and maximum inhibition of the discharge frequency of both non-noxious and noxious mechanical stimuli was seen within 10 min. These inhibitory effects were reversed after approximately 20 min. The relative magnitude of inhibition by resveratrol of SpVc WDR neuronal discharge frequency was significantly greater for noxious than non noxious stimulation. These results suggest that, in the absence of inflammatory or neuropathic pain, acute intravenous resveratrol administration suppresses trigeminal sensory transmission, including nociception, and so resveratrol may be used as a complementary and alternative medicine therapeutic agent for the treatment of trigeminal nociceptive pain, including hyperalgesia. PMID- 26608255 TI - Rhythmic activity in EEG and sleep in rats with absence epilepsy. AB - This study examines the hypothesis that absence epilepsy is accompanied by disturbances of rhythmic activity in EEG during sleep. Sleep-wake architecture and time-frequency parameters of EEG were analyzed during drowsiness and sleep in WAG/Rij rats with genetic predisposition to absence epilepsy. The incidence of seizures varied in a group of 10 rats, in which 5 individuals did not develop epileptic discharges in their EEG (asymptomatic rats). In contrast to asymptomatic, symptomatic subjects (1) displayed less percentage of wakefulness EEG pattern and more non-REM sleep, (2) showed higher beta and less delta EEG power in frontal cortex during non-REM sleep. Mid-frequency oscillations, such as sleep spindles and 5-9 Hz oscillations, were detected in EEG automatically and underwent time-frequency analysis by means of skeletons of wavelet surfaces. Some mid-frequency oscillations showed "complex" frequency structure, consisting of the dominant and subdominant components. "Complex" sleep spindles more frequently appeared in asymptomatic rats than in symptomatic, whereas the dominant frequency of these spindles in symptomatic rats was higher than in asymptomatic (12.7 vs 11.9 Hz). In general, low-frequency components were readily integrated in sleep spindles in asymptomatic WAG/Rij rats, and decrease in number of "complex" sleep spindles may be associated with epileptic phenotype. PMID- 26608257 TI - A LEAN treatment for non-alcoholic steatohepatitis. PMID- 26608256 TI - Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. AB - BACKGROUND: Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogues are licensed for type 2 diabetes, but their efficacy in patients with non-alcoholic steatohepatitis is unknown. We assessed the safety and efficacy of the long-acting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis. METHODS: This multicentre, double blinded, randomised, placebo-controlled phase 2 trial was conducted in four UK medical centres to assess subcutaneous injections of liraglutide (1.8 mg daily) compared with placebo for patients who are overweight and show clinical evidence of non-alcoholic steatohepatitis. Patients were randomly assigned (1:1) using a computer-generated, centrally administered procedure, stratified by trial centre and diabetes status. The trial was designed using A'Hern's single-group method, which required eight (38%) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinically significant. Patients, investigators, clinical trial site staff, and pathologists were masked to treatment assignment throughout the study. The primary outcome measure was resolution of definite non-alcoholic steatohepatitis with no worsening in fibrosis from baseline to end of treatment (48 weeks), as assessed centrally by two independent pathologists. Analysis was done by intention-to-treat analysis, which included all patients who underwent end-of-treatment biopsy. The trial was registered with ClinicalTrials.gov, number NCT01237119. FINDINGS: Between Aug 1, 2010, and May 31, 2013, 26 patients were randomly assigned to receive liraglutide and 26 to placebo. Nine (39%) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with two (9%) of 22 such patients in the placebo group (relative risk 4.3 [95% CI 1.0-17.7]; p=0.019). Two (9%) of 23 patients in the liraglutide group versus eight (36%) of 22 patients in the placebo group had progression of fibrosis (0.2 [0.1-1.0]; p=0.04). Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the two treatment groups for all organ classes and symptoms, with the exception of gastrointestinal disorders in 21 (81%) of 23 patients in the liraglutide group and 17 (65%) of 22 patients in the placebo group, which included diarrhoea (ten [38%] patients in the liraglutide group vs five [19%] in the placebo group), constipation (seven [27%] vs none), and loss of appetite (eight [31%] vs two [8%]). INTERPRETATION: Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies. FUNDING: Wellcome Trust, National Institute of Health Research, and Novo Nordisk. PMID- 26608258 TI - 7alpha-Hydroxypregnenolone regulates diurnal changes in sexual behavior of male quail. AB - In the Japanese quail, 7alpha-hydroxypregnenolone, a previously undescribed avian neurosteroid, is actively produced in the brain. 7alpha-Hydroxypregnenolone acts as a novel neuronal activator to stimulate locomotor activity of quail. Therefore, in this study, we determined whether 7alpha-hydroxypregnenolone changes the expression of sexual behavior in Japanese quail. We first measured diurnal changes in sexual behavior of male quail exposed to a long-day photoperiod. We found that sexual behavior of male quail was high in the morning when endogenous 7alpha-hydroxypregnenolone level is high. Subsequently, we centrally administered 7alpha-hydroxypregnenolone in the evening when endogenous 7alpha-hydroxypregnenolone level is low. In the 30 min after intracerebroventricular (ICV) injection, 7alpha-hydroxypregnenolone dose dependently increased the frequency of sexual behavior of male quail. However, 7beta-hydroxypregnenolone, a stereoisomer of 7alpha-hydroxypregnenolone, did not effect on the frequency of sexual behavior of male quail. In addition, to confirm the action of 7alpha-hydroxypregnenolone on sexual behavior, male birds received an ICV injection of ketoconazole, an inhibitor of cytochrome P450s, and behavioral experiments were performed in the morning. Ketoconazole significantly decreased the frequency of sexual behavior of male quail, whereas administration of 7alpha-hydroxypregnenolone to ketoconazole-treated males increased the frequency of their sexual behavior. These results indicate that 7alpha hydroxypregnenolone regulates diurnal changes in sexual behavior of male quail. PMID- 26608259 TI - Deprivation and poor psychosocial support are key determinants of late antenatal presentation and poor fetal outcomes--a combined retrospective and prospective study. AB - BACKGROUND: Published guidelines emphasise the need for early antenatal care to promote maternal and neonatal health. Inadequate engagement with antenatal care is associated with adverse pregnancy outcomes including maternal death. The factors that influence the uptake and utilisation of maternity care services are poorly understood. We retrospectively explore a large maternity database of births in a large referral UK hospital to capture the socio-demographic factors that influence late pregnancy booking, and then prospectively compare the stress and social support status of consenting early and late-booking women. METHODS: Retrospective socio-demographic and clinical outcome data on 59,487 women were collected from the maternity database record of births between 2002 and 2010 at the Jessop Wing Hospital, Sheffield UK. In a follow-on prospective survey between October 2012 and May 2013 a convenience cohort of early and late bookers for antenatal care were then studied using validated scales for fetomaternal attachment, stress and anxiety, and social support. RESULTS: In our retrospective study, pregnancy during the teenage years, higher parity, non-white ethnic background, unemployment and smoking were significantly associated with late access to antenatal services and poor fetal outcomes (P < 0.001). However, late booking per se did not predict adverse fetal outcomes, when socio-demographic factors were accounted for. A high index of multiple deprivation (IMD) score remained independently associated with late booking when confounding factors such as ethnicity and employment status were controlled for in the model (P = 0.03). Our prospective data demonstrated that women who book late were more likely to be unmarried (OR: 3.571, 95 % CI: 1.464-8.196, p = .005), of high parity (OR: 1.759, 95 % CI: 1.154-2.684, P = 0.009), and have lower social support than early bookers (P = 0.047). CONCLUSIONS: Of the many complex sociocultural factors that influence the timing of maternal engagement with antenatal care, multiple deprivation and poor social support remain key factors. Improving access to prenatal care requires in-depth exploration of the relationship between maternal psychosocial health indices, social support mechanisms and engagement with antenatal care. Findings from these studies should inform interventions aimed at improving access to care. PMID- 26608262 TI - Non-precious metal complexes with an anionic PCP pincer architecture. AB - This perspective article provides an overview of the advancements in the field of non-precious metal complexes featuring anionic PCP pincer ligands with the inclusion of aliphatic systems. It covers research from the beginning in 1976 until late 2015 and provides a summary of key developments in this area, which is, to date, limited to the metals nickel, cobalt, iron, and molybdenum. While the research in nickel PCP complexes is already quite extensive, the chemistry of cobalt, iron, and molybdenum PCP complexes is comparatively sparse. With other non-precious metals such as copper, manganese, chromium or vanadium no PCP complexes are known as yet. In the case of nickel PCP complexes already many catalytic applications such as Suzuki-Miyaura coupling, C-S cross coupling, Kharasch and Michael additions, hydrosilylation of aldehydes and ketones, cyanomethylation of aldehydes, and hydroamination of nitriles were reported. While iron PCP complexes were found to be active catalysts for the hydrosilylation of aldehydes and ketones as well as the dehydrogenation of ammonia-borane, cobalt PCP complexes were not applied to any catalytic reactions. Surprisingly, only one molybdenum PCP complex is reported, which was capable of cleaving dinitrogen to give a nitride complex. This perspective underlines that the combination of cheap and abundant metals such as nickel, cobalt, and iron with PCP pincer ligands may result in the development of novel, versatile, and efficient catalysts for atom-efficient catalytic reactions. PMID- 26608261 TI - Nutritional parameters affecting severity of pneumonia and length of hospital stay in patients with pneumococcal pneumonia: a retrospective cross-sectional study. AB - BACKGROUND: Pneumococcal pneumonia is the most common form of community-acquired pneumonia (CAP). Although a pneumococcal conjugate vaccine has contributed to a reduction in the incidence of pneumococcal pneumonia among older children and adults, no significant decrease in the incidence has been observed among persons aged >=65 years. A low body mass index and hypoalbuminemia are common in Japanese patients with CAP, but the association of other nutritional parameters with the severity of pneumonia or length of hospital stay in patients with pneumococcal pneumonia is unclear. METHODS: Fifty-seven previously healthy inpatients who presented with pneumococcal pneumonia were divided into two groups: those aged >=65 years (n = 36) and those aged <65 years (n = 21). Patients' characteristics (the Confusion, Urea, Respiratory rate, Blood pressure, age >65 years (CURB-65) score), the pneumonia severity index (PSI), and inflammatory and metabolic nutritional parameters were compared between the two groups. RESULTS: The older group showed significantly lower serum albumin and cholinesterase (ChE) levels. Multivariate linear regression analysis revealed that the PSI was positively correlated with age in both groups. In the younger age group, both the CURB-65 score and PSI showed significant negative correlations with the serum ChE level, and there was a significant negative correlation between the length of stay and serum total cholesterol (T-cho) level. In the older group, the fasting period, lymphocyte count, and age showed significant positive correlations with the length of stay. There was a significant negative correlation between the length of stay and serum albumin level, but no correlation with the serum ChE or T-cho levels, in the older patients. CONCLUSIONS: Our findings suggest that in patients aged <65 years, age and serum ChE and T-cho levels were associated with both the severity of pneumococcal pneumonia and length of stay. In contrast, the length of stay in older patients was associated with multiple factors that differed from those in younger patients. These differences may reflect age-related immunosenescence in older patients and a greater effect of serum ChE and T-cho levels on immunity in younger patients. PMID- 26608260 TI - Quantitative differential proteomics of yeast extracellular matrix: there is more to it than meets the eye. AB - BACKGROUND: Saccharomyces cerevisiae multicellular communities are sustained by a scaffolding extracellular matrix, which provides spatial organization, and nutrient and water availability, and ensures group survival. According to this tissue-like biology, the yeast extracellular matrix (yECM) is analogous to the higher Eukaryotes counterpart for its polysaccharide and proteinaceous nature. Few works focused on yeast biofilms, identifying the flocculin Flo11 and several members of the HSP70 in the extracellular space. Molecular composition of the yECM, is therefore mostly unknown. The homologue of yeast Gup1 protein in high Eukaryotes (HHATL) acts as a regulator of Hedgehog signal secretion, therefore interfering in morphogenesis and cell-cell communication through the ECM, which mediates but is also regulated by this signalling pathway. In yeast, the deletion of GUP1 was associated with a vast number of diverse phenotypes including the cellular differentiation that accompanies biofilm formation. METHODS: S. cerevisiae W303-1A wt strain and gup1? mutant were used as previously described to generate biofilm-like mats in YPDa from which the yECM proteome was extracted. The proteome from extracellular medium from batch liquid growing cultures was used as control for yECM-only secreted proteins. Proteins were separated by SDS PAGE and 2DE. Identification was performed by HPLC, LC-MS/MS and MALDI-TOF/TOF. The protein expression comparison between the two strains was done by DIGE, and analysed by DeCyder Extended Data Analysis that included Principal Component Analysis and Hierarchical Cluster Analysis. RESULTS: The proteome of S. cerevisiae yECM from biofilm-like mats was purified and analysed by Nano LC MS/MS, 2D Difference Gel Electrophoresis (DIGE), and MALDI-TOF/TOF. Two strains were compared, wild type and the mutant defective in GUP1. As controls for the identification of the yECM-only proteins, the proteome from liquid batch cultures was also identified. Proteins were grouped into distinct functional classes, mostly Metabolism, Protein Fate/Remodelling and Cell Rescue and Defence mechanisms, standing out the presence of heat shock chaperones, metalloproteinases, broad signalling cross-talkers and other putative signalling proteins. The data has been deposited to the ProteomeXchange with identifier PXD001133. CONCLUSIONS: yECM, as the mammalian counterpart, emerges as highly proteinaceous. As in higher Eukaryotes ECM, numerous proteins that could allow dynamic remodelling, and signalling events to occur in/and via yECM were identified. Importantly, large sets of enzymes encompassing full antagonistic metabolic pathways, suggest that mats develop into two metabolically distinct populations, suggesting that either extensive moonlighting or actual metabolism occurs extracellularly. The gup1? showed abnormally loose ECM texture. Accordingly, the correspondent differences in proteome unveiled acetic and citric acid producing enzymes as putative players in structural integrity maintenance. PMID- 26608263 TI - Metabolic pathway engineering using the central signal processor PII. AB - BACKGROUND: PII signal processor proteins are wide spread in prokaryotes and plants where they control a multitude of anabolic reactions. Efficient overproduction of metabolites requires relaxing the tight cellular control circuits. Here we demonstrate that a single point mutation in the PII signaling protein from the cyanobacterium Synechocystis sp. PCC 6803 is sufficient to unlock the arginine pathway causing over accumulation of the biopolymer cyanophycin (multi-L-arginyl-poly-L-aspartate). This product is of biotechnological interest as a source of amino acids and polyaspartic acid. This work exemplifies a novel approach of pathway engineering by designing custom tailored PII signaling proteins. Here, the engineered Synechocystis sp. PCC6803 strain with a PII-I86N mutation over-accumulated arginine through constitutive activation of the key enzyme N-acetylglutamate kinase (NAGK). RESULTS: In the engineered strain BW86, in vivo NAGK activity was strongly increased and led to a more than tenfold higher arginine content than in the wild-type. As a consequence, strain BW86 accumulated up to 57 % cyanophycin per cell dry mass under the tested conditions, which is the highest yield of cyanophycin reported to date. Strain BW86 produced cyanophycin in a molecular mass range of 25 to >100 kDa; the wild-type produced the polymer in a range of 30 to >100 kDa. CONCLUSIONS: The high yield and high molecular mass of cyanophycin produced by strain BW86 along with the low nutrient requirements of cyanobacteria make it a promising means for the biotechnological production of cyanophycin. This study furthermore demonstrates the feasibility of metabolic pathway engineering using the PII signaling protein, which occurs in numerous bacterial species. PMID- 26608265 TI - The protean manifestations of IgG4-RD in gastrointestinal disorders. PMID- 26608264 TI - [Biomarkers for chronic inflammatory diseases]. AB - Inflammatory disorders of childhood, such as juvenile idiopathic arthritis (JIA) and inflammatory bowel disease (IBD) are a challenge for laboratory diagnostics. Firstly, the classical inflammatory markers, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) often inadequately reflect disease activity but on the other hand there are few specific biomarkers that can be helpful in managing these diseases. Acute phase proteins reflect the systemic inflammatory response insufficiently as their increase is only the indirect result of local inflammatory processes. Modern inflammation diagnostics aim to reflect these local processes and to allow precise monitoring of disease activity. Experimental biomarkers, such as S100 proteins can detect subclinical inflammatory activity. In addition, established laboratory parameters exist for JIA [antinuclear antibodies (ANA), rheumatoid factor (RF), antibodies against cyclic citrullinated peptide (anti-CCP)] and for chronic IBD (fecal calprotectin) that are useful in the treatment of these diseases. PMID- 26608266 TI - Luminescence sensing and imaging: general discussion. PMID- 26608268 TI - Geometrical and energetical structural changes in organic dyes for dye-sensitized solar cells probed using photoelectron spectroscopy and DFT. AB - The effects of alkoxy chain length in triarylamine based donor-acceptor organic dyes are investigated with respect to the electronic and molecular surface structures on the performance of solar cells and the electron lifetime. The dyes were investigated when adsorbed on TiO2 in a configuration that can be used for dye-sensitized solar cells (DSCs). Specifically, the two dyes D35 and D45 were compared using photoelectron spectroscopy (PES) and density functional theory (DFT) calculations. The differences in solar cell characteristics when longer alkoxy chains are introduced in the dye donor unit are attributed to geometrical changes in dye packing while only minor differences were observed in the electronic structure. A higher dye load was observed for D45 on TiO2. However, D35 based solar cells result in higher photocurrent although the dye load is lower. This is explained by different geometrical structures of the dyes on the surface. PMID- 26608270 TI - [Eclampsia at the University hospital Yalgado of Ouagadougou (Burkina Faso) from 1 April 2013 to 31 March 2014]. AB - The objective of this study was to describe the epidemiological, clinical, therapeutic and prognostic aspects of the eclampsia in the obstetrics and gynecology department at the University Teaching Hospital Yalgado Ouedraogo of Ouagadougou. It has been a descriptive crosssectional study over a period of 12 months from 1 April 2013 to 31 March 2014. The main criterion for inclusion in our sample was the occurrence of seizures in a pregnant more than 20 weeks of gestation or recently delivered with elevation of blood pressure and the presence of albumin in the urine. The patients were followed from the onset of the crisis until hospital discharge. Data were collected and analyzed using Epi Info 3.5.1. The significance level of 5% was used for data comparison. We identified 203 cases of eclampsia for 6063 deliveries that to say a frequency of 3.3%. The average age of patients was 27.5 years [14-46]. In socio-demographic terms, patients were housewives in 62.5% of cases, the average rate of the past-deliver number was 4.2 [0-11] and 47.7% of patients were living as married. Clinically, they were referred in 72.4% of cases and were initially admitted into the service for elevation of blood pressure in 40.3% of cases. The mean gestational age was 31.5 weeks [23-41]; diastolic blood pressure exceeded 110 mmHg in 63.1% of cases. Therapeutically, all the patients benefited from a treatment based in anticonvulsant by magnesium sulfate and antihypertensive therapy by nicardipine, clonidine or alpha-methyl-dopa. Maternal prognosis was marked by significant morbidity in 46 cases (22.6%) and mortality in 13 patients that to say a fatality rate of 6.4%. The fetal one was dominated by a perinatal lethality in 31.5% of the cases. Eclampsia is a major cause of maternal and perinatal mortality in the University Teaching Hospital of Ouagadougou. The adoption of strategies for screening during antenatal consultations and early management should contribute to the reduction of the mortality in the mother and child couple in Burkina Faso. PMID- 26608271 TI - [Tetanus in Ho Chi Minh City, Vietnam: epidemiological, clinical and outcome features of 389 cases at the Hospital for Tropical Diseases]. AB - The objective of this study is to describe the different aspects of tetanus during the past recent years in southern Vietnam: epidemiology, clinical picture, management, and death risk factors. It is a retrospective study concerning 389 cases admitted in 2007 and 2008 at the reference Hospital for Tropical Diseases in Ho Chi Minh City. 93% of all cases were generalized tetanus, and 50% were severe cases. A majority of patients were adult males (medium age 43, M/ F sex ratio 2.9). Half of them underwent tracheotomy and 39% assisted ventilation. Case fatality rate was 6.4%, the lowest reported rate worldwide in the last ten years. Fatalities resulted mainly from neuro-vegetative disorders, essentially cardiogenic shock (28% of all deaths) [OR = 16.95; p < 0.001], sepsis (24%) [OR = 3.25; (p < 0,114], and acute renal failure (16%) [OR = 7,22; p < 0.004]. Age over 60-year [OR = 4.53; p < 0.0001] and a leukocyte count>12.000/mm(3) [OR = 2.32; p < 0.020] were significantly associated with fatal outcome, contrarily to incubation and extension phase durations, or delayed serum administration. Systematic extension of vaccination to all adult males, and improved access to post exposure sero-immunization at all levels of health centres throughout the country may further reduce tetanus burden in Vietnam. PMID- 26608272 TI - [Analysis of a series of 44 cases of peritoneal tuberculosis diagnosed in the pathology laboratory of the Tokoin teaching hospital of Lome (1993-2014)]. AB - It is a descriptive and cross-sectional study on all issues relating to peritoneal tuberculosis histological diagnosed in the pathology department (LAP) of the Lome Tokoin CHU from January 1993 to December 2014 (20 years). A total of 44 cases of peritoneal tuberculosis were included. They were 18 women and 26 men, with a mean age of 37.6+/-0.2 years. The circumstances of discovery were dominated by ascites (84.1%), fever (75%), weight loss (63.6%) and abdominal pain (59.1%). The peritoneal involvement was isolated in 31.8% of cases, and associated with pleuropulmonary tuberculosis in 54.5% of cases. Co-infection with HIV was present in 63.9% of cases. Twenty-five patients (69.4%) with information about their social conditions had low socioeconomic level: unemployed (10 cases; 40%), workers (10 cases; 40%) and retired (5 cases; 20%). An increase in cell count was observed in 94.6% of cases. Histology revealed the epithelial giant cell granuloma associated with caseous necrosis in 38 cases (86.4%) and cheesy isolated in 6 patients. Peritoneal tuberculosis is not exceptional in our country. The diagnosis should be considered in febrile ascites, and will be confirmed by laparoscopy with histological samples for a histological diagnosis. PMID- 26608273 TI - Screening for cervical cancer in French Guiana: screening rates from 2006 to 2011. AB - In French Guiana, the age-standardized incidence rate of cervical cancer is four times higher than in France and the mortality rate 5.5 times higher. A survival study revealed that stage at diagnosis was the main factor influencing the prognosis, showing that early detection is crucial to increase cervical cancer survival. The present study aimed at evaluating the cervical cancer screening rate between 2006 and 2011 by age and for a 3-year period in French Guiana. All pap smears realised in French Guiana were analysed in two laboratories allowing exhaustive review of screening data. The screening rate was estimated at about 54% from 2006 to 2011, with a statistical difference between coastal and rural area (56.3% versus 18.7%). Although the methodological difference did not allow comparisons with metropolitan France, these results could be used to evaluate the impact of organised cervical cancer screening by the French Guiana Association for Organized Screening of Cancers which has been implemented in French Guiana since 2012. PMID- 26608274 TI - [Vesicular contact dermatitis due to Paederus in Cameroon and review of the literature]. AB - This irritant blister dermatitis is caused by the genus Paederus whose geographical distribution is worldwide, with a higher incidence in tropical areas. It is induced by direct skin contact with pederin, a blistering and caustic substance found in the abdomen (coelome) of Paederus insects (insect order Coleoptera: family Staphylinidae). The diagnosis is based on the presence of typical clinical features combined with compatible epidemiological features. Our goal is to describe the epidemiological and clinical features of this irritant contact dermatitis in Cameroon through a retrospective study conducted at the end of the rainy season at the Oku Hospital in Northwest Cameroon and to also include cases reported at the medical center of the French Embassy in Yaounde during this same timeframe. In addition, we conducted a literature review of paederus dermatitis. Nineteen patients were included in this study. More than half of the patients presented with more than two lesions predominantly localized to the face or the neck; less than half had complications manifesting as either localized or respiratory reactions and three patients presented periorbital involvement. This study confirms the presence of paederus dermatitis in Cameroon. It is mainly localized in the unusual geoclimatic region of the western high mountains within the country, as well as the usual warm, moist areas of Yaounde. The clinical evolution of this dermatitis is usually one of spontaneous and uneventful resolution with complications being rare. Curative treatment is one of localized topical therapies while oral antibiotic therapy should be reserved for more complicated cases. PMID- 26608275 TI - RNA interference and the vaccine effect of a subolesin homolog from the tick Rhipicephalus haemaphysaloides. AB - Subolesin is a well-characterized protective antigen in many ticks and, thus, it is potentially useful in the development of a broad-spectrum vaccine or an autocidal gene silencing strategy to control tick infestations. A subolesin homolog was cloned from the tick Rhipicephalus haemaphysaloides, which is widespread in China, by rapid amplification of complementary DNA (cDNA) ends. Its full-length cDNA was 1386 base pairs (bp), containing a 483 bp open reading frame with a predicted molecular mass of 18.7 kilodaltons and an isoelectric point of 9.26. The subolesin protein had a typical nuclear localization signal in its amino-terminus. The full-length cDNA of R. haemaphysaloides showed 52 and 80% identities to those from Ixodes scapularis and R. microplus, respectively, whereas amino acid sequence alignments showed 80 and 97% identities, respectively. Native subolesin was recognized in the unfed tick midgut by an antibody against recombinant subolesin. Transcriptional analysis showed that subolesin was expressed in the tick's four developmental stages and in all of the tissues examined, except for the synganglion. The pathogen Babesia microti induced the subolesin transcript by fourfold. Subolesin gene silencing by RNA interference significantly decreased the larval engorgement rate, the attachment rate and body weight of engorged nymphs, and the body weight and attachment and engorgement rates of adults, as well as the egg weight per female tick. Vaccinating mice and rabbits with recombinant subolesin induced a significant protective effect, resulting in a reduction of blood feeding and oviposition. These results encourage further studies of using subolesin to control tick infestations in China. PMID- 26608276 TI - Complex routes into HIV care for migrant workers: a qualitative study from north India. AB - Migrant workers are designated a bridge population in the spread of HIV and therefore if infected, should be diagnosed and treated early. This study examined pathways to HIV diagnosis and access to care for rural-to-urban circular migrant workers and partners of migrants in northern India, identifying structural, social and individual level factors that shaped their journeys into care. We conducted a qualitative study using in-depth interviews with HIV-positive men (n = 20) and women (n = 13) with a history of circular migration, recruited from an antiretroviral therapy centre in one district of Uttar Pradesh, north India. Migrants and partners of migrants faced a complex series of obstacles to accessing HIV testing and care. Employment insecurity, lack of entitlement to sick pay or subsidised healthcare at destination and the household's economic reliance on their migration-based livelihood led many men to continue working until they became incapacitated by HIV-related morbidity. During periods of deteriorating health they often exhausted their savings on private treatments focused on symptom management, and sought HIV testing and treatment at a public hospital only following a medical or financial emergency. Wives of migrants had generally been diagnosed following their husbands' diagnosis or death, with access to testing and treatment mediated via family members. For some, a delay in disclosure of husband's HIV status led to delays in their own testing. Diagnosing and treating HIV infection early is important in slowing down the spread of the epidemic and targeting those at greatest risk should be a priority. However, despite targeted campaigns, circumstances associated with migration may prevent migrant workers and their partners from accessing testing and treatment until they become sick. The insecurity of migrant work, the dominance of private healthcare and gender differences in health-seeking behaviour delay early diagnosis and treatment initiation. PMID- 26608277 TI - The transmission of trauma in refugee families: associations between intra-family trauma communication style, children's attachment security and psychosocial adjustment. AB - This study explores the transmission of trauma in 30 Middle Eastern refugee families in Denmark, where one or both parents were referred for treatment of PTSD symptoms and had non-traumatized children aged 4-9 years. The aim of the study was to explore potential risk and protective factors by examining the association between intra-family communication style regarding the parents' traumatic experiences from the past, children's psychosocial adjustment and attachment security. A negative impact of parental trauma on children might be indicated, as children's Total Difficulties Scores on the Strengths and Difficulties Questionnaire (SDQ) were significantly higher than the Danish norms. A negative association between children's attachment security as measured by the Attachment and Traumatization Story Task and higher scores on the SDQ Total Difficulties Scale approached significance, suggesting that the transmission of trauma may be associated with disruptions in children's attachment representations. Furthermore a significant association between parental trauma communication and children's attachment style was found. PMID- 26608278 TI - The clustered protocadherin endolysosomal trafficking motif mediates cytoplasmic association. AB - BACKGROUND: Clustered protocadherins (Pcdhs) are a large family of neural cadherin-like proteins encoded by individual exons located within three gene clusters. Each exon codes an extracellular, transmembrane, and proximal cytoplasmic domain. These "variable" regions may be spliced to a constant cytoplasmic moiety encoded at the end of a cluster. Pcdh extracellular domains mediate homophilic cell-cell binding but their cytoplasmic domains cause intracellular retention and may negatively regulate Pcdh cell-cell binding. Pcdhs can be found at the cell surface in neurons and other cells but are also, unlike classical cadherins, prominently trafficked to the endolysosome system. It was previously found that a segment within the variable portion of the Pcdh-gammaA3 cytoplasmic domain (VCD) was shown to be necessary for endolysosomal trafficking. RESULTS: Here it is shown that this same VCD segment can mediate cytoplasmic association among Pcdhs from the different clusters. Internal deletions within this VCD region (termed here the VCD motif) that disrupt the association altered trafficking of Pcdh-gammaA3 in the endolysosomal system while deletions outside VCD motif did not affect trafficking. CONCLUSIONS: The results show that Pcdhs associate cytoplasmically via a motif within the VCD and that this is critical for Pcdh trafficking. Given that truncation at the VCD motif alters endolysosomal trafficking of Pcdhs, the VCD interaction described here may provide new insights into the dynamic nature of Pcdh mediated cell-cell interactions. PMID- 26608279 TI - Prevention of Stress-Provoked Endothelial Injury by Values Affirmation: a Proof of Principle Study. PMID- 26608280 TI - A Confirmatory Factor Analysis of Facets of Psychological Flexibility in a Sample of People Seeking Treatment for Chronic Pain. AB - BACKGROUND: Evidence supports the validity of individual components of the psychological flexibility model in the context of chronic pain. However, there is a need to test the inter-relationships amongst measures of individual components of psychological flexibility in a more integrative manner. In particular, research is needed to examine whether a model with discrete facets as proposed is indeed reflected in data from currently used assessment measures in people with chronic pain. PURPOSE: This cross-sectional study investigated the underlying structure of measures of processes of psychological flexibility amongst individuals with chronic pain and the associations between this measurement model and patient functioning. METHODS: Five-hundred and seventy-three adults with chronic pain completed measures of pain, physical and social functioning, mental health, depression and processes of psychological flexibility, including acceptance, cognitive defusion, decentering and committed action. Confirmatory factor analyses tested lower-order, higher-order and bifactor models to examine the structure of psychological flexibility process measures. RESULTS: A single general factor reflecting openness explained variability in items across all of the psychological flexibility process measures. In addition to this general factor, distinct decentering and committed action group factors emerged in the data. As expected, the general factor was strongly correlated with measures of social functioning, mental health and depression. CONCLUSIONS: Future research is needed to determine the most useful means by which the presence of the general factor can be reflected in the measurement and theory of psychological flexibility. PMID- 26608281 TI - Stressors, Appraisal of Stressors, Experienced Stress and Cardiac Response: A Real-Time, Real-Life Investigation of Work Stress in Nurses. AB - BACKGROUND: Stress in health care professionals may reflect both the work and appraisal of work and impacts on the individuals, their patients, colleagues and managers. PURPOSE: The purpose of the present study is to examine physiological and psychological effects of stressors (tasks) and theory-based perceptions of work stressors within and between nurses in real time. METHODS: During two work shifts, 100 nurses rated experienced stress, affect, fatigue, theory-based measures of work stress and nursing tasks on electronic diaries every 90 min, whereas heart rate and activity were measured continuously. RESULTS: Heart rate was associated with both demand and effort. Experienced stress was related to demand, control, effort and reward. Effort and reward interacted as predicted (but only within people). Results were unchanged when allowance was made for work tasks. CONCLUSIONS: Real-time appraisals were more important than actual tasks in predicting both psychological and physiological correlates of stress. At times when effort was high, perceived reward reduced stress. PMID- 26608282 TI - Chemical, molecular, and eco-toxicological investigation of Ostreopsis sp. from Cyprus Island: structural insights into four new ovatoxins by LC-HRMS/MS. AB - Blooms of benthic dinoflagellates of the genus Ostreopsis (mainly O. cf. ovata and occasionally O. cf. siamensis) represent a serious concern for humans in the Mediterranean area, due to production of palytoxin-like compounds listed among the most potent marine toxins known. In this work, six strains of Ostreopsis sp. from Cyprus Island were analyzed through an integrated approach based on molecular, chemical, and eco-toxicological methods. Cypriot Ostreopsis sp. was found to be a species distinct from O. cf. ovata and O. cf. siamensis, belonging to the Atlantic/Mediterranean Ostreopsis spp. clade. Some variability in toxin profiles emerged: three strains produced ovatoxin-a (OVTX-a), OVTX-d, OVTX-e, and isobaric palytoxin, so far found only in O. cf. ovata; the other three strains produced only new palytoxin-like compounds, which we named ovatoxin-i, ovatoxin j1, ovatoxin-j2, and ovatoxin-k. The new ovatoxins present the same carbon skeleton as ovatoxin-a, differing primarily in an additional C2H2O2 moiety and an unsaturation in the region C49-C52. Other minor structural differences were found, including the presence of a hydroxyl group at C44 (in OVTX-j1 and OVTX-k) and the lack of a hydroxyl group in the region C53-C78 (in OVTX-i and OVTX-j1). The toxin content of the analyzed Ostreopsis sp. strains was in the range 0.06 2.8 pg cell(-1), definitely lower than that of a Ligurian O. cf. ovata strain cultured under the same conditions. Accordingly, an eco-toxicological test on Artemia salina nauplii demonstrated that Ostreopsis sp. presents a very low toxicity compared to O. cf. ovata. The whole of these data suggest that Ostreopsis sp. from Cyprus Island poses a relatively low risk to humans. PMID- 26608283 TI - Modification of a deoxynivalenol-antigen-mimicking nanobody to improve immunoassay sensitivity by site-saturation mutagenesis. AB - A nanobody (N-28) which can act as a deoxynivalenol (DON) antigen has been generated, and its residues Thr102-Ser106 were identified to bind with anti-DON monoclonal antibody by alanine-scanning mutagenesis. Site-saturation mutagenesis was used to analyze the plasticity of five residues and to improve the sensitivity of the N-28-based immunoassay. After mutagenesis, three mutants were selected by phage immunoassay and were sequenced. The half-maximal inhibitory concentrations of the immunoassay based on mutants N-28-T102Y, N-28-V103L, and N 28-Y105F were 24.49 +/- 1.0, 51.83 +/- 2.5, and 35.65 +/- 1.6 ng/mL, respectively, showing the assay was, respectively, 3.2, 1.5, and 2.2 times more sensitive than the wild-type-based assay. The best mutant, N-28-T102Y, was used to develop a competitive phage ELISA to detect DON in cereals with high specificity and accuracy. In addition, the structural properties of N-28-T102Y and N-28 were investigated, revealing that the affinity of N-28-T102Y decreased because of increased steric hindrance with the large side chain. The lower binding-affinity antigen mimetic may contribute to the improvement of the sensitivity of competitive immunoassays. These results demonstrate that nanobodies would be a favorable tool for engineering. Moreover, our results have laid a solid foundation for site-saturation mutagenesis of antigen-mimicking nanobodies to improve immunoassay sensitivity for small molecules. PMID- 26608285 TI - Controlled Delivery of Chemopreventive Agents by Polymeric Implants. AB - The clinical development of cancer chemopreventive agents has been hampered by poor oral bioavailability issue. Several compounds have low aqueous solubility and undergo extensive first pass metabolism following oral dosing. To overcome this limitation, we developed polymeric implants from biodegradable epsilon polycaprolactone (PCL) that can deliver both lipophilic as well as hydrophilic compounds. Implants furnish controlled release of compounds for long duration and provide dose-dependent release. The rate of release in vitro correlated well with the in vivo release. The polymeric implant technology thus overcomes the oral bioavailability issues, lowers the total required dose and minimizes or eliminates toxicity generally associated with high doses. PMID- 26608284 TI - Reestablishment of the hyperglycemia to the normal levels seems not to be essential to the anxiolytic-like effect induced by insulin. AB - Diabetes is a chronic metabolic disease accompanied by several comorbidities, including neuropsychiatric conditions. Since the hyperglycemia appears to be the primary factor involved in diabetic conditions, we examined the effect of insulin treatment in diabetic rats on behavioral responses related to anxiety and aversive memory extinction. For this, normoglycemic (NGL) or streptozotocin diabetic (DBT) rats were submitted to the elevated T maze (ETM) and the contextual conditioned fear (CCF) tests. Therefore, animals were subjected to the prolonged treatment with insulin (6 IU/day, s.c.) to investigate the effect of the treatment on distinct behaviors. When anxiety-like responses such as the inhibitory avoidance (IA) on the ETM and the time of freezing in the first session of the CCF test were evaluated, our data showed a more pronounced anxiogenic-like behavior in DBT animals when compared to NGL ones. In addition, an increased freezing time was observed in DBT animals exposed to the CCF test (sessions 2 and 3) when compared to the NGL group, suggestive of an impairment in the extinction of aversive memory. Insulin treatment induced an anxiolytic-like effect when IA and freezing time (session 1) was evaluated, but did not alter the impaired extinction of aversive memory (sessions 2 and 3). To better understand the involvement of a rigorous control of glycaemia, we also investigated the effect of a lower dose of insulin (3 IU/day, s.c.), unable to reestablish the hyperglycemia to the normal levels, on the same behavioral parameters. Our data show that independent of the dose of insulin, the same effects were observed when animals were evaluated in the ETM and CCF tests. However, only the highest dose of insulin was able to reduce the hyperglycemia to the normal levels. To conclude, our data suggest that a severe glycemic control by insulin treatment seems to be important, but not essential in improving diabetes-induced anxiety. PMID- 26608286 TI - Use of Buffy Coat miRNA Profiling for Breast Cancer Prediction in Healthy Women. AB - MicroRNAs are key regulators of different biological processes and their deregulation is associated with the occurrence of many diseases among which cancer. Due to the higher stability of microRNAs and to the easiness in their detection both in organs than in biological fluids, many studies are turned toward potential use of this small molecules as biomarkers for the prediction and diagnosis of different types of cancer. Here we describe the experiment protocol that we have used for microRNA profiling analysis in buffy coat samples of women who developed breast cancer versus women who remained healthy during a 20 year follow-up period, with the aim to identify predictive microRNAs of breast cancer occurrence. PMID- 26608287 TI - microRNAs in Cancer Chemoprevention: Method to Isolate Them from Fresh Tissues. AB - microRNAs are 22-nucleotide-long double-strand small RNAs, able to modulate gene expression at posttranscriptional level, degrading mRNA and/or impairing translation. They have been shown to regulate mRNA and protein abundance and to participate in many regulatory circuits controlling developmental timing, cell proliferation and differentiation, apoptosis and stress response. Notably, microRNA activity has been correlated to the pathogenesis of cancer; they are aberrantly expressed in solid and hematological tumors, suggesting that they could function as oncogenes or tumor suppressors. The emerging role of miRNAs in the carcinogenesis and tumor progression has provided opportunities for their clinical application in the capacity of cancer detection, diagnosis, and prognosis prediction. Here, we describe the experimental protocol used to isolate microRNAs from human tissues coming from head and neck, mesothelioma, and thymoma tumors in order to perform microarray and RT-qPCR experiments. PMID- 26608288 TI - Application of RNA-Seq Technology in Cancer Chemoprevention. AB - RNA-sequencing is a revolutionary tool to follow differential expression after treatment with cancer chemopreventive agents. It allows a real genome-wide screening independent of prior assumptions and is well suited for analyzing coding but also long noncoding RNAs. It still consents the discovery of new genes and isoforms and increased our knowledge of antisense and other noncoding RNAs in a tremendous manner. Moreover, it permits to detect low-abundance and biologically critical isoforms and reveals genetic variants and gene fusions in one single assay. Here, we provide a detailed protocol for stranded RNA sequencing. PMID- 26608289 TI - Detection of Circulating Tumor DNA in the Blood of Cancer Patients: An Important Tool in Cancer Chemoprevention. AB - Liquid biopsies represent novel promising tools to determine the impact of clonal heterogeneity on clinical outcomes with the potential to identify novel therapeutic targets in cancer patients. We developed a low-coverage whole-genome sequencing approach in order to noninvasively establish copy number aberrations in plasma DNA from metastasized cancer patients. Using plasma-Seq we were able to monitor genetic evolution including the acquirement of novel copy number changes, such as focal amplifications and chromosomal polysomies. The big advantage of our approach is that it can be performed on a benchtop sequencer, speed, and cost effectiveness. Therefore, plasma-Seq represents an easy, fast, and affordable tool to provide the urgently needed genetic follow-up data. Here we describe our method including plasma DNA extraction, library preparation, and bioinformatic analyses. PMID- 26608290 TI - The Methylated DNA Immunoprecipitation [MeDIP] to Investigate the Epigenetic Remodeling in Cell Fate Determination and Cancer Development. AB - Epigenetic mechanisms such as DNA methylation, posttranslational modifications of histone proteins, remodeling of nucleosomes, and the expression of noncoding RNAs contribute to the regulation of gene expression for the cell fate determination and tissue development. The disruption of these epigenetic mechanisms, in conjunction with genetic alterations, is a decisive element for cancer development and progression. The cancer phenotype is characterized by global DNA hypomethylation and gene-specific hypermethylation. The methylated DNA immunoprecipitation [MeDIP] is a useful approach currently used to clarify the functional consequences of DNA methylation on cell fate determination and cancer development. PMID- 26608291 TI - LC-MS-Based Metabolomic Investigation of Chemopreventive Phytochemical-Elicited Metabolic Events. AB - Phytochemicals are under intensive investigation for their potential use as chemopreventive agents in blocking or suppressing carcinogenesis. Metabolic interactions between phytochemical and biological system play an important role in determining the efficacy and toxicity of chemopreventive phytochemicals. However, complexities of phytochemical biotransformation and intermediary metabolism pose challenges for studying phytochemical-elicited metabolic events. Metabolomics has become a highly effective technical platform to detect subtle changes in a complex metabolic system. Here, using green tea polyphenols as an example, we describe a workflow of LC-MS-based metabolomics study, covering the procedures and techniques in sample collection, preparation, LC-MS analysis, data analysis, and interpretation. PMID- 26608292 TI - (1)H NMR Metabolomic Footprinting Analysis for the In Vitro Screening of Potential Chemopreventive Agents. AB - Metabolomics is the quantification and analysis of the concentration profiles of low-molecular-weight compounds present in biological samples. In particular metabolic footprinting analysis, based on the monitoring of metabolites consumed from and secreted into the growth medium, is a valuable tool for the study of pharmacological and toxicological effects of drugs. Mass spectrometry and nuclear magnetic resonance (NMR) are the two main complementary techniques used in this field. Although less sensitive, NMR gives a direct fingerprint of the system, and the spectra obtained contain metabolic information that can be distilled by chemometric techniques. In this chapter, we present how metabolomic footprinting can be used to assess in vitro a potential chemopreventive molecule as metformin. PMID- 26608293 TI - Comet Assay in Cancer Chemoprevention. AB - The comet assay can be useful in monitoring DNA damage in single cells caused by exposure to genotoxic agents, such as those causing air, water, and soil pollution (e.g., pesticides, dioxins, electromagnetic fields) and chemo- and radiotherapy in cancer patients, or in the assessment of genoprotective effects of chemopreventive molecules. Therefore, it has particular importance in the fields of pharmacology and toxicology, and in both environmental and human biomonitoring. It allows the detection of single strand breaks as well as double strand breaks and can be used in both normal and cancer cells. Here we describe the alkali method for comet assay, which allows to detect both single- and double strand DNA breaks. PMID- 26608294 TI - Angiogenesis Assays. AB - Neoangiogenesis constitutes one of the first steps of tumor progression beyond a critical size of tumor growth, which supplies a dormant mass of cancerous cells with the required nutrient supply and gaseous exchange through blood vessels essentially needed for their sustained and aggressive growth. In order to understand any biological process, it becomes imperative that we use models, which could mimic the actual biological system as closely as possible. Hence, finding the most appropriate model is always a vital part of any experimental design. Angiogenesis research has also been much affected due to lack of simple, reliable, and relevant models which could be easily quantitated. The angiogenesis models have been used extensively for studying the action of various molecules for agonist or antagonistic behaviour and associated mechanisms. Here, we have described two protocols or models which have been popularly utilized for studying angiogenic parameters. Rat aortic ring assay tends to bridge the gap between in vitro and in vivo models. The chorioallantoic membrane (CAM) assay is one of the most utilized in vivo model system for angiogenesis-related studies. The CAM is highly vascularized tissue of the avian embryo and serves as a good model to study the effects of various test compounds on neoangiogenesis. PMID- 26608295 TI - AlgiMatrixTM-Based 3D Cell Culture System as an In Vitro Tumor Model: An Important Tool in Cancer Research. AB - Routinely used two-dimensional cell culture-based models often fail while translating the observations into in vivo models. This setback is more common in cancer research, due to several reasons. The extracellular matrix and cell-to cell interactions are not present in two-dimensional (2D) cell culture models. Diffusion of drug molecules into cancer cells is hindered by barriers of extracellular components in in vivo conditions, these barriers are absent in 2D cell culture models. To better mimic or simulate the in vivo conditions present in tumors, the current study used the alginate based three-dimensional cell culture (AlgiMatrixTM) model, which resembles close to the in vivo tumor models. The current study explains the detailed protocols involved in AlgiMatrixTM based in vitro non-small-cell lung cancer (NSCLC) models. The suitability of this model was studied by evaluating, cytotoxicity, apoptosis, and penetration of nanoparticles into the in vitro tumor spheroids. This study also demonstrated the effect of EphA2 receptor targeted docetaxel-loaded nanoparticles on MDA-MB-468 TNBC cell lines. The methods section is subdivided into three subsections such as (1) preparation of AlgiMatrixTM-based 3D in vitro tumor models and cytotoxicity assays, (2) free drug and nanoparticle uptake into spheroid studies, and (3) western blot, IHC, and RT-PCR studies. PMID- 26608296 TI - Cancer Gastric Chemoprevention: Isolation of Gastric Tumor-Initiating Cells. AB - Gastric cancer is an important healthcare problem and represents the second leading cause of death for malignant disease worldwide. In the Western world, the diagnosis is done at late stage when treatments can be only palliative. Searches for new therapeutic regimens as well as for new biomarkers are in progress. To reduce cancer mortality is crucial the prevention of the lesion at earlier stages. Therefore, new bullets to prevention are needed. Nowadays, studies relating to different kinds of tumor are unanimous in considering cancer stem cells (CSCs) as "the core" of the tumor and the responsible of tumor chemoresistance and relapse. This chapter aims to provide the instructions to (1) isolate, (2) grow, and (3) validate, both in vivo and in vitro, the gastric CSC subpopulation. PMID- 26608297 TI - Isolation of Chemoresistant Cell Subpopulations. AB - Chemoresistance is a major challenge for cancer therapy and drives tumor relapse. The emergence, within the treated tumor mass, of specific cancer cell subpopulations endowed with high tolerance to the microenvironment stress induced by therapy is being growingly recognized as a mechanism of tumor progression. To obtain detailed information with regard to the pathways underlying survival, expansion, and microenvironmental cross talk of such chemoresistant cell subpopulations may be instrumental for cancer chemoprevention. Additionally, the obtained cell subpopulations may be used for direct screening of cancer chemopreventive compounds, in appropriate experimental settings. Here we report detailed experimental procedures that we and others have setup in order to obtain cell cultures enriched for chemoresistant cells from both malignant pleural mesothelioma specimens and primary cell cultures. We provide indications for the purification and characterization of those chemoresistant cell populations and to generally validate the obtained enriched cell populations for their chemoresistance. PMID- 26608298 TI - Autophagy in Cancer Chemoprevention: Identification of Novel Autophagy Modulators with Anticancer Potential. AB - Cancer cells have the ability to tolerate extreme conditions, autophagy-related stress tolerance enables cancer cells to survive by maintaining energy production that leads to cell growth and therapeutic resistance. Insufficient activation of autophagy in nutrient-deprived cancer cells may sensitize cancer cells to a broad array of chemotherapeutic agents and ionizing radiation. Therefore, identification of novel autophagy modulators with lower toxicity and better therapeutic index would be beneficial for cancer therapy. Here, we describe several currently used biochemical methods to assess autophagic activity and lysosomal function in cultured cancer cells. We also discuss both in vitro and in vivo assays to clarify the anticancer potential of novel autophagy modulators. PMID- 26608299 TI - Protocol for a Steady-State FRET Assay in Cancer Chemoprevention. AB - Cancer chemoprevention is an important strategy to prevent, reverse, or suppress the development of cancer. One of the target pathways that has emerged in recent years is the Keap1-Nrf2-ARE system that regulates the protection of cells against various carcinogens and their metabolites. Increased concentrations of the redox transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) induces the activation of antioxidant and phase 2 detoxifying genes. Nrf2 is regulated by substrate adaptor protein Kelch-like ECH-associated protein 1 (Keap1) that can target Nrf2 for ubiquitination and degradation by the proteasome. The interaction between Nrf2 and Keap1 can be disrupted at the protein-protein interface in order to increase Nrf2 activity for potential therapeutic purposes. This chapter describes a protocol for a steady-state fluorescence or Forster resonance energy transfer (FRET) assay to examine the Keap1-Nrf2 protein-protein interaction (PPI), to investigate the effects of Nrf2 mutations on Keap1 binding and finally to identify potential inhibitors of this PPI. In the assay system Keap1 is conjugated to an YFP protein at the N-terminus whereas an Nrf2-derived 16-mer peptide containing a high-affinity "ETGE" motif is conjugated to a CFP protein at the N-terminus. PMID- 26608300 TI - 3D Tumor Models and Time-Lapse Analysis by Multidimensional Microscopy. AB - The 3D culture is advantageous in reflecting the in vivo condition compared to the 2D culture; however, imaging 3D-cultured cells may be a challenge due to technical restrictions. Recent development of confocal spinning disc microscope system as well as sophisticated software has enabled us to monitor dynamism of cell movement in multiple dimensions. Here we describe the method for time-lapse imaging of 3D-cultured cancer cells co-cultured with non-cancerous cells and discuss current limitations and future perspectives. PMID- 26608301 TI - Antibody Array as a Tool for Screening of Natural Agents in Cancer Chemoprevention. AB - The efficacy of a given drug resides mainly on its ability to specifically target disease mechanisms. Natural products represent the leading source of bioactive molecules with a broad range of activities. It is becoming increasingly clear that natural compounds exert their chemopreventive or antitumoral activities targeting simultaneously diverse cellular pathways. Here we describe the use of antibody array to assess the effects of natural compounds on the expression of multiple proteins and of their posttranslational modifications in cellular systems. This might turn to be a very flexible application for cancer chemoprevention studies. PMID- 26608302 TI - South African Herbal Extracts as Potential Chemopreventive Agents: Screening for Anticancer Splicing Activity. AB - RT-PCR is an invaluable tool for the detection and characterization of mRNA. Cancer cell lines are treated with crude plant extracts and RNA is extracted and purified with DNase prior to RT-PCR. RT-PCR first-strand cDNA synthesis is done using random primers and can be refrigerated at 4 degrees C. PCR from the stored cDNA is performed using transcript-specific primers and electrophoresed on a molecular grade agarose gel to separate the splice variants. PMID- 26608303 TI - Assessment of psychometric properties of the Postpartum Bonding Questionnaire (PBQ) in Spanish mothers. AB - The Postpartum Bonding Questionnaire (PBQ) was developed to assess mother-infant bonding disturbances in the postpartum period. The aim of this study was to examine the psychometric properties of the Spanish version of the PBQ in a sample of Spanish postpartum women. Eight hundred forty mothers were recruited in the postpartum visit (4-6 weeks after delivery): 513 from a gynecology unit (forming the general population sample) and 327 mothers from a perinatal psychiatry program (forming the clinical sample). All women were assessed by means of the Edinburgh Postnatal Depression Scale (EPDS) and the PBQ. Neither the original four-factor structure nor alternative structures (Reck et al. 2006; Wittkowski et al. 2010) were replicated by the confirmatory factor analyses. An exploratory factor analysis showed a four-factor solution. The Schmid-Leiman transformation found a general factor that accounted for 61% of the variance of the PBQ. Bonding impairment showed higher associations with depressive symptomatology in both samples. The Spanish version of the PBQ showed adequate psychometric properties for use with clinical and general populations of Spanish postpartum women. The results suggest that the PBQ could be summarized by a general factor and confirm the utility of the use of the total score for detecting bonding impairment. PMID- 26608304 TI - Digit-Threatening Severe Tophaceous Gout. PMID- 26608305 TI - Differential urinary glycoproteome analysis of type 2 diabetic nephropathy using 2D-LC-MS/MS and iTRAQ quantification. AB - BACKGROUND: Diabetic nephropathy (DN) is the leading cause of chronic kidney failure and end-stage kidney disease. More accurate and non-invasive test for the diagnosis and monitoring the progression of DN is urgently needed for the better care of such patients. METHODS: In this study we utilized urinary glycoproteome to discover the differential proteins during the course of type 2 DN. The urinary glycoproteins from normal controls, normalbuminuira, microalbuminura, and macroalbuminuria patients were enriched by concanavalin A (ConA) and analyzed by 2DLC/MS/MS and isobaric tags for relative and absolute quantitation quantification. RESULTS: A total of 478 proteins were identified and 408 were annotated as N-linked glycoproteins. A total of 72, 107 and 123 differential proteins were identified in normalbuminuria, microalbuminuria and macroalbuminuria, respectively. By bioinformatics analysis, in normalbuminruia state, cell proliferation and cell movement were activated, which might reflect the compensatory phase during the disease development. In micro- and macro albuminuria, cell death and apoptosis was activated, which might reflect the de compensatory phase. Pathway analysis showed acute phase proteins, the member of high density lipoprotein and low density lipoprotein proteins were changed, indicating the role of the inflammatory response and lipid metabolism abnormality in the pathogenesis of DN. Six selected differential proteins were validated by Western Blot. Alpha-1-antitrypsin (SERPINA1) and Ceruloplasmin are the two markers with excellent area under curve values (0.929 and 1.000 respectively) to distinguish the microalbuminuria and normalbuminuria. For the first time, we found pro-epidermal growth factor and prolactin-inducible protein were decreased in macroalbuminuria stage, which might reflect the inhibition of cell viability and the activation of cell death in kidney. CONCLUSIONS: Above data indicated that urinary glycoproteome could be useful to distinguish the differences in protein profiles in different stages in DN, which will help better individualized care of patients in DN. PMID- 26608306 TI - Long-term medical treatment in congenital hyperinsulinism: a descriptive analysis in a large cohort of patients from different clinical centers. AB - BACKGROUND: Up to now, only limited data on long-term medical treatment in congenital hyperinsulinism (CHI) is available. Moreover, most of the drugs used in CHI are therefore not approved. We aimed to assemble more objective information on medical treatment in CHI with regard to type and duration, dosage as well as side effects. METHODS: We searched MEDLINE (from 1947) and EMBASE (from 1988) using the OVID interface for relevant data to evaluate medical treatment in a large cohort of patients with CHI from different clinical centers. Randomized, controlled trials were not available. We evaluated case reports and case series. No language restrictions were made. RESULTS: A total number of 619 patients were medically treated and information regarding conservative treatment was available. Drugs used were diazoxide (in 84% of patients), somatostatin analogues (16%), calcium channel antagonists (4%) and glucagon (1%). Mean dose of diazoxide was 12.5 (+/-4.3) mg/kg ? d (range 2-60 mg/kg ? d), mean duration of diazoxide treatment until remission was 57 months. Side effects of diazoxide were usually not severe. The causal relation between diazoxide and severe side effects, e.g. heart failure (3.7%) remains doubtful. Mean dose of octreotide was 14.9 (+/-7.5) MUg/kg ? d (range 2.3-50 MUg/kg ? d), of lanreotide 67.3 (+/-39.8) mg ? month (range 10-120 mg ? month). Mean duration of treatment with somatostatin analogues until remission was 49 months. Frequent side effects included tachyphylaxis and mild gastrointestinal symptoms. The risk of persistent growth deceleration was low (<5%). CONCLUSIONS: Severe side effects are rare and a causal relation remains disputable. We conclude that long-term conservative treatment of CHI is feasible. PMID- 26608307 TI - Genome-wide transcriptome induced by Porphyromonas gingivalis LPS supports the notion of host-derived periodontal destruction and its association with systemic diseases. AB - Chronic periodontitis (CP) is a prevalent pathogen-associated inflammatory disorder characterized by the destruction of tooth-supporting tissues, and linked to several systemic diseases. Both the periodontopathogen Porphyromonas gingivalis (Pg), and the genetically determined host immune response, are hypothesized to play a crucial role in this association. To identify new target genes for CP and its associated systemic diseases, we investigated the transcriptome induced by Pg in human monocytes using a genome-wide approach. Monocytes were isolated from healthy male volunteers of European origin and challenged with the Pg virulence factor LPS. Array-based gene expression analysis comprising >47,000 transcripts was performed followed by pathway analyses. Transcriptional data were validated by protein and cell surface markers. LPS Pg challenge led to the significant induction of 902 transcripts. Besides known periodontitis-associated targets, several new candidates were identified (CCL23?, INDO?, GBP 1/4?, CFB?, ISG20?, MIR155HG?, DHRS9?). Moreover, various transcripts correspond to the host immune response, and have been linked to cancer, atherosclerosis and arthritis, thus highlighting the systemic impact of CP. Protein data of immunological markers validated our results. The present findings expand understanding of Pg elicited immune responses, and indicate new target genes and pathways of relevance to diagnostic and therapeutic strategies. PMID- 26608308 TI - Neutrophil proteolytic activation cascades: a possible mechanistic link between chronic periodontitis and coronary heart disease. AB - Cardiovascular diseases are chronic inflammatory diseases that affect a large segment of society. Coronary heart disease (CHD), the most common cardiovascular disease, progresses over several years and affects millions of people worldwide. Chronic infections may contribute to the systemic inflammation and enhance the risk for CHD. Periodontitis is one of the most common chronic infections that affects up to 50% of the adult population. Under inflammatory conditions the activation of endogenous degradation pathways mediated by immune responses leads to the release of destructive cellular molecules from both resident and immigrant cells. Matrix metalloproteinases (MMPs) and their regulators can activate each other and play an important role in immune response via degrading extracellular matrix components and modulating cytokines and chemokines. The action of MMPs is required for immigrant cell recruitment at the site of inflammation. Stimulated neutrophils represent the major pathogen-fighting immune cells that upregulate expression of several proteinases and oxidative enzymes, which can degrade extracellular matrix components (e.g. MMP-8, MMP-9 and neutrophil elastase). The activity of MMPs is regulated by endogenous inhibitors and/or candidate MMPs (e.g. MMP-7). The balance between MMPs and their inhibitors is thought to mirror the proteolytic burden. Thus, neutrophil-derived biomarkers, including myeloperoxidase, may activate proteolytic destructive cascades that are involved in subsequent immune-pathological events associated with both periodontitis and CHD. Here, we review the existing studies on the contribution of MMPs and their regulators to the infection-related pathology. Also, we discuss the possible proteolytic involvement and role of neutrophil-derived enzymes as an etiological link between chronic periodontitis and CHD. PMID- 26608310 TI - Deaths at high altitude: Reducing the risk. A preliminary field study. AB - BACKGROUND AND AIMS: Altitude-related medical literature provides very few simple clinical studies relating to those on 'adventure holidays'. Systemic blood pressure has seldom been studied closely in relation to altitude. This study aimed to address both these issues and to assist GPs approached by patients for pre-trek advice. METHODS AND RESULTS: A total of 17 hillwalkers, evenly distributed for gender and age, trekked gradually from moderate to extreme altitude on Mera Peak in the Himalaya, noting any altitude sickness symptoms. Heart rate, blood pressure, oxygen saturation, peak expiratory flow and core temperature were measured daily. Altitude was double-checked hourly and synchronised with each set of measurements. On each day, two individuals wore 24 h ambulatory blood pressure monitors for assessment of altitude effects. Two principal findings emerged. Firstly, none of our 17 developed altitude-related symptoms below 4000 m, consistent with the recognised protective effect of slow rate of ascent; at 3500-4000 m all showed a sharp fall on O2sat and above 4500 m symptoms arose unpredictably. Secondly, hourly blood pressure monitoring showed no altitude effect below 3500 m, but above 5000 m a marked yet asymptomatic rise with delayed and prolonged peak. CONCLUSION: There may be a critical altitude above which extra vigilance is required; blood pressure here needs further research. PMID- 26608309 TI - Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. AB - STUDY QUESTION: Is methylphenidate beneficial or harmful for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents? METHODS: Electronic databases were searched up to February 2015 for parallel and crossover randomised clinical trials comparing methylphenidate with placebo or no intervention in children and adolescents with ADHD. Meta-analyses and trial sequential analyses (TSA) were conducted. Quality was assessed using GRADE. Teachers, parents, and observers rated ADHD symptoms and general behaviour. STUDY ANSWER AND LIMITATIONS: The analyses included 38 parallel group trials (n=5111, median treatment duration 49 days) and 147 crossover trials (n=7134, 14 days). The average age across all studies was 9.7 years. The analysis suggested a beneficial effect of methylphenidate on teacher rated symptoms in 19 parallel group trials (standardised mean difference (SMD) -0.77, n=1698), corresponding to a mean difference of -9.6 points on the ADHD rating scale. There was no evidence that methylphenidate was associated with an increase in serious adverse events (risk ratio 0.98, nine trials, n=1532; TSA adjusted intervention effect RR 0.91). Methylphenidate was associated with an increased risk of non-serious adverse events (1.29, 21 trials, n=3132; TSA adjusted RR 1.29). Teacher rated general behaviour seemed to improve with methylphenidate (SMD -0.87, five trials, n=668) A change of 7 points on the child health questionnaire (CHQ) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a mean difference of 8.0 points on the CHQ (range 0 100 points), which suggests that methylphenidate may improve parent reported quality of life (SMD 0.61, three trials, n=514). 96.8% of trials were considered high risk of bias trials according to the Cochrane guidelines. All outcomes were assessed very low quality according to GRADE. WHAT THIS STUDY ADDS: The results suggest that among children and adolescents with a diagnosis of ADHD, methylphenidate may improve teacher reported symptoms of ADHD and general behaviour and parent reported quality of life. However, given the risk of bias in the included studies, and the very low quality of outcomes, the magnitude of the effects is uncertain. Methylphenidate is associated with an increased risk of non serious but not serious adverse events. FUNDING, COMPETING INTERESTS, DATA SHARING: Region Zealand Research Foundation and Copenhagen Trial Unit. Competing interests are given in the full paper on bmj.com. Full data are available in the version of this review published in The Cochrane Library. PMID- 26608311 TI - The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment. AB - Human respiratory syncytial virus (RSV) is a single-stranded RNA virus that causes acute, and occasionally fatal, lower respiratory illness in young infants, the elderly, and immunocompromised patients. Therapeutic interventions able to cut short viral replication and quickly return the airways to normal function are needed. An understanding of antiviral activities and their effects on host defense mechanisms is important for the design of safe and effective therapy. We targeted functionally and temporally distinct steps within the viral life cycle using small-molecule RSV inhibitors and studied their antiviral activities and their effects on innate interferon responses of airway epithelial cells in vitro. Antivirals acting upstream of RSV polymerase activity (i.e., compounds targeting the fusion protein or the nucleoprotein) reduced viral load immediately postinfection and partially attenuated interferon responses. In contrast, antivirals directed to the RSV polymerase demonstrated activity throughout the viral replication cycle and specifically modulated the RIG-I/mitochondrial antiviral signaling protein (MAVS)/TBK1/IRF3/interferon-stimulated gene (ISG) axis, causing either an upregulation or a downregulation of interferon responses, depending on the mechanism of polymerase inhibition. Notably, polymerase inhibition leading to the accumulation of abortive RNA products correlated with the amplification of interferon-stimulated genes to up to 10 times above normal infection levels. Understanding how antiviral activities and their modulation of innate immunity may affect recovery from RSV infection will help guide the development of safe and effective therapies. IMPORTANCE: RSV circulates seasonally, causing acute lower respiratory disease. Therapeutic interventions with efficacy throughout the viral replication cycle, rapid viral clearance, and prevention of potentially harmful inflammatory responses are desirable. Compounds targeting the RSV polymerase inhibited virus replication late in the viral life cycle and, depending on the functional domain targeted, either attenuated or amplified RIG-I and downstream interferon pathways in infected cells. These data will help guide the development of safe and effective therapies by providing new molecular evidence that the mechanism of inhibition by an antiviral compound can directly impact innate antiviral immune responses in the airway epithelium. PMID- 26608312 TI - Structure of an HIV-2 gp120 in Complex with CD4. AB - HIV-2 is a nonpandemic form of the virus causing AIDS, and the majority of HIV-2 infected patients exhibit long-term nonprogression. The HIV-1 and HIV-2 envelope glycoproteins, the sole targets of neutralizing antibodies, share 30 to 40% identity. As a first step in understanding the reduced pathogenicity of HIV-2, we solved a 3.0-A structure of an HIV-2 gp120 bound to the host receptor CD4, which reveals structural similarity to HIV-1 gp120 despite divergence in amino acid sequence. PMID- 26608313 TI - Human T Cell Leukemia Virus Type 1 Infection of the Three Monocyte Subsets Contributes to Viral Burden in Humans. AB - Because the viral DNA burden correlates with disease development, we investigated the contribution of monocyte subsets (classical, intermediate, and nonclassical monocytes) to the total viral burden in 22 human T cell leukemia virus type 1 (HTLV-1)-infected individuals by assessing their infectivity status, frequency, as well as chemotactic and phagocytic functions. All three monocyte subsets sorted from HTLV-1-infected individuals were positive for viral DNA, and the frequency of classical monocytes was lower in the blood of HTLV-1-infected individuals than in that of uninfected individuals, while the expression levels of the chemokine receptors CCR5, CXCR3, and CX3CR1 in classical monocytes were higher in HTLV-1-infected individuals than uninfected individuals; the percentage of intermediate monocytes and their levels of chemokine receptor expression did not differ between HTLV-1-infected and uninfected individuals. However, the capacity of intermediate monocytes to migrate to CCL5, the ligand for CCR5, was higher, and a higher proportion of nonclassical monocytes expressed CCR1, CXCR3, and CX3CR1. The level of viral DNA in the monocyte subsets correlated with the capacity to migrate to CCL2, CCL5, and CX3CL1 for classical monocytes, with lower levels of phagocytosis for intermediate monocytes, and with the level of viral DNA in CD8(+) and CD4(+) T cells for nonclassical monocytes. These data suggest a model whereby HTLV-1 infection augments the number of classical monocytes that migrate to tissues and become infected and the number of infected nonclassical monocytes that transmit virus to CD4(+) and CD8(+) T cells. These results, together with prior findings in a macaque model of HTLV-1 infection, support the notion that infection of monocytes by HTLV-1 is likely a requisite for viral persistence in humans. IMPORTANCE: Monocytes have been implicated in immune regulation and disease progression in patients with HTLV-1-associated inflammatory diseases. We detected HTLV-1 DNA in all three monocyte subsets and found that infection impacts surface receptor expression, migratory function, and subset frequency. The frequency of nonclassical patrolling monocytes is increased in HTLV-1-infected individuals, and they have increased expression of CCR1, CXCR3, and CX3CR1. The viral DNA level in nonclassical monocytes correlated with the viral DNA level in CD4(+) and CD8(+) T cells. Altogether, these data suggest an increased recruitment of classical monocytes to inflammation sites that may result in virus acquisition and, in turn, facilitate virus dissemination and viral persistence. Our findings thus provide new insight into the importance of monocyte infection in viral spread and suggest targeting of monocytes for therapeutic intervention. PMID- 26608314 TI - Directed Molecular Evolution of an Engineered Gammaretroviral Envelope Protein with Dual Receptor Use Shows Stable Maintenance of Both Receptor Specificities. AB - We have previously reported the construction of a murine leukemia virus-based replication-competent gammaretrovirus (SL3-AP) capable of utilizing the human G protein-coupled receptor APJ (hAPJ) as its entry receptor and its natural receptor, the murine Xpr1 receptor, with equal affinities. The apelin receptor has previously been shown to function as a coreceptor for HIV-1, and thus, adaptation of the viral vector to this receptor is of significant interest. Here, we report the molecular evolution of the SL3-AP envelope protein when the virus is cultured in cells harboring either the Xpr1 or the hAPJ receptor. Interestingly, the dual receptor affinity is maintained even after 10 passages in these cells. At the same time, the chimeric viral envelope protein evolves in a distinct pattern in the apelin cassette when passaged on D17 cells expressing hAPJ in three separate molecular evolution studies. This pattern reflects selection for reduced ligand-receptor interaction and is compatible with a model in which SL3-AP has evolved not to activate hAPJ receptor internalization. IMPORTANCE: Few successful examples of engineered retargeting of a retroviral vector exist. The engineered SL3-AP envelope is capable of utilizing either the murine Xpr1 or the human APJ receptor for entry. In addition, SL3-AP is the first example of an engineered retrovirus retaining its dual tropism after several rounds of passaging on cells expressing only one of its receptors. We demonstrate that the virus evolves toward reduced ligand-receptor affinity, which sheds new light on virus adaptation. We provide indirect evidence that such reduced affinity leads to reduced receptor internalization and propose a novel model in which too rapid receptor internalization may decrease virus entry. PMID- 26608315 TI - An Adenovirus DNA Replication Factor, but Not Incoming Genome Complexes, Targets PML Nuclear Bodies. AB - Promyelocytic leukemia protein nuclear bodies (PML-NBs) are subnuclear domains implicated in cellular antiviral responses. Despite the antiviral activity, several nuclear replicating DNA viruses use the domains as deposition sites for the incoming viral genomes and/or as sites for viral DNA replication, suggesting that PML-NBs are functionally relevant during early viral infection to establish productive replication. Although PML-NBs and their components have also been implicated in the adenoviral life cycle, it remains unclear whether incoming adenoviral genome complexes target PML-NBs. Here we show using immunofluorescence and live-cell imaging analyses that incoming adenovirus genome complexes neither localize at nor recruit components of PML-NBs during early phases of infection. We further show that the viral DNA binding protein (DBP), an early expressed viral gene and essential DNA replication factor, independently targets PML-NBs. We show that DBP oligomerization is required to selectively recruit the PML-NB components Sp100 and USP7. Depletion experiments suggest that the absence of one PML-NB component might not affect the recruitment of other components toward DBP oligomers. Thus, our findings suggest a model in which an adenoviral DNA replication factor, but not incoming viral genome complexes, targets and modulates PML-NBs to support a conducive state for viral DNA replication and argue against a generalized concept that PML-NBs target incoming viral genomes. IMPORTANCE: The immediate fate upon nuclear delivery of genomes of incoming DNA viruses is largely unclear. Early reports suggested that incoming genomes of herpesviruses are targeted and repressed by PML-NBs immediately upon nuclear import. Genome localization and/or viral DNA replication has also been observed at PML-NBs for other DNA viruses. Thus, it was suggested that PML-NBs may immediately sense and target nuclear viral genomes and hence serve as sites for deposition of incoming viral genomes and/or subsequent viral DNA replication. Here we performed a detailed analyses of the spatiotemporal distribution of incoming adenoviral genome complexes and found, in contrast to the expectation, that an adenoviral DNA replication factor, but not incoming genomes, targets PML NBs. Thus, our findings may explain why adenoviral genomes could be observed at PML-NBs in earlier reports but argue against a generalized role for PML-NBs in targeting invading viral genomes. PMID- 26608316 TI - Mutated but Not Deleted Ovine PrP(C) N-Terminal Polybasic Region Strongly Interferes with Prion Propagation in Transgenic Mice. AB - Mammalian prions are proteinaceous infectious agents composed of misfolded assemblies of the host-encoded, cellular prion protein (PrP). Physiologically, the N-terminal polybasic region of residues 23 to 31 of PrP has been shown to be involved in its endocytic trafficking and interactions with glycosaminoglycans or putative ectodomains of membrane-associated proteins. Several recent reports also describe this PrP region as important for the toxicity of mutant prion proteins and the efficiency of prion propagation, both in vitro and in vivo. The question remains as to whether the latter observations made with mouse PrP and mouse prions would be relevant to other PrP species/prion strain combinations given the dramatic impact on prion susceptibility of minimal amino acid substitutions and structural variations in PrP. Here, we report that transgenic mouse lines expressing ovine PrP with a deletion of residues 23 to 26 (KKRP) or mutated in this N-terminal region (KQHPH instead of KKRPK) exhibited a variable, strain dependent susceptibility to prion infection with regard to the proportion of affected mice and disease tempo relative to findings in their wild-type counterparts. Deletion has no major effect on 127S scrapie prion pathogenesis, whereas mutation increased by almost 3-fold the survival time of the mice. Deletion marginally affected the incubation time of scrapie LA19K and ovine bovine spongiform encephalopathy (BSE) prions, whereas mutation caused apparent resistance to disease. IMPORTANCE: Recent reports suggested that the N-terminal polybasic region of the prion protein could be a therapeutic target to prevent prion propagation or toxic signaling associated with more common neurodegenerative diseases such as Alzheimer's disease. Mutating or deleting this region in ovine PrP completes the data previously obtained with the mouse protein by identifying the key amino acid residues involved. PMID- 26608317 TI - Cholesterol Flux Is Required for Endosomal Progression of African Swine Fever Virions during the Initial Establishment of Infection. AB - African swine fever virus (ASFV) is a major threat for porcine production that has been slowly spreading in Eastern Europe since its first appearance in the Caucasus in 2007. ASFV enters the cell by endocytosis and gains access to the cytosol to start replication from late endosomes and multivesicular bodies. Cholesterol associated with low-density lipoproteins entering the cell by endocytosis also follows a trafficking pathway similar to that of ASFV. Here we show that cholesterol plays an essential role in the establishment of infection as the virus traffics through the endocytic pathway. In contrast to the case for other DNA viruses, such as vaccinia virus or adenovirus 5, cholesterol efflux from endosomes is required for ASFV release/entry to the cytosol. Accumulation of cholesterol in endosomes impairs fusion, resulting in retention of virions inside endosomes. ASFV also remodels intracellular cholesterol by increasing its cellular uptake and redistributes free cholesterol to viral replication sites. Our analysis reveals that ASFV manipulates cholesterol dynamics to ensure an appropriate lipid flux to establish productive infection. IMPORTANCE: Since its appearance in the Caucasus in 2007, African swine fever (ASF) has been spreading westwards to neighboring European countries, threatening porcine production. Due to the lack of an effective vaccine, ASF control relies on early diagnosis and widespread culling of infected animals. We investigated early stages of ASFV infection to identify potential cellular targets for therapeutic intervention against ASF. The virus enters the cell by endocytosis, and soon thereafter, viral decapsidation occurs in the acid pH of late endosomes. We found that ASFV infection requires and reorganizes the cellular lipid cholesterol. ASFV requires cholesterol to exit the endosome to gain access to the cytoplasm to establish productive replication. Our results indicate that there is a differential requirement for cholesterol efflux for vaccinia virus or adenovirus 5 compared to ASFV. PMID- 26608318 TI - The Oncogenic Small Tumor Antigen of Merkel Cell Polyomavirus Is an Iron-Sulfur Cluster Protein That Enhances Viral DNA Replication. AB - Merkel cell polyomavirus (MCPyV) plays an important role in Merkel cell carcinoma (MCC). MCPyV small T (sT) antigen has emerged as the key oncogenic driver in MCC carcinogenesis. It has also been shown to promote MCPyV LT-mediated replication by stabilizing LT. The importance of MCPyV sT led us to investigate sT functions and to identify potential ways to target this protein. We discovered that MCPyV sT purified from bacteria contains iron-sulfur (Fe/S) clusters. Electron paramagnetic resonance analysis showed that MCPyV sT coordinates a [2Fe-2S] and a [4Fe-4S] cluster. We also observed phenotypic conservation of Fe/S coordination in the sTs of other polyomaviruses. Since Fe/S clusters are critical cofactors in many nucleic acid processing enzymes involved in DNA unwinding and polymerization, our results suggested the hypothesis that MCPyV sT might be directly involved in viral replication. Indeed, we demonstrated that MCPyV sT enhances LT-mediated replication in a manner that is independent of its previously reported ability to stabilize LT. MCPyV sT translocates to nuclear foci containing actively replicating viral DNA, supporting a direct role for sT in promoting viral replication. Mutations of Fe/S cluster-coordinating cysteines in MCPyV sT abolish its ability to stimulate viral replication. Moreover, treatment with cidofovir, a potent antiviral agent, robustly inhibits the sT mediated enhancement of MCPyV replication but has little effect on the basal viral replication driven by LT alone. This finding further indicates that MCPyV sT plays a direct role in stimulating viral DNA replication and introduces cidofovir as a possible drug for controlling MCPyV infection. IMPORTANCE: MCPyV is associated with a highly aggressive form of skin cancer in humans. Epidemiological surveys for MCPyV seropositivity and sequencing analyses of healthy human skin suggest that MCPyV may represent a common component of the human skin microbial flora. However, much of the biology of the virus and its oncogenic ability remain to be investigated. In this report, we identify MCPyV sT as a novel Fe/S cluster protein and show that conserved cysteine clusters are important for sT's ability to enhance viral replication. Moreover, we show that sT sensitizes MCPyV replication to cidofovir inhibition. The discovery of Fe/S clusters in MCPyV sT opens new avenues to the study of the structure and functionality of this protein. Moreover, this study supports the notion that sT is a potential drug target for dampening MCPyV infection. PMID- 26608319 TI - H1N1 Swine Influenza Viruses Differ from Avian Precursors by a Higher pH Optimum of Membrane Fusion. AB - The H1N1 Eurasian avian-like swine (EAsw) influenza viruses originated from an avian H1N1 virus. To characterize potential changes in the membrane fusion activity of the hemagglutinin (HA) during avian-to-swine adaptation of the virus, we studied EAsw viruses isolated in the first years of their circulation in pigs and closely related contemporary H1N1 viruses of wild aquatic birds. Compared to the avian viruses, the swine viruses were less sensitive to neutralization by lysosomotropic agent NH4Cl in MDCK cells, had a higher pH optimum of hemolytic activity, and were less stable at acidic pH. Eight amino acid substitutions in the HA were found to separate the EAsw viruses from their putative avian precursor; four substitutions-T492S, N722D, R752K, and S1132F-were located in the structural regions of the HA2 subunit known to play a role in acid-induced conformational transition of the HA. We also studied low-pH-induced syncytium formation by cell-expressed HA proteins and found that the HAs of the 1918, 1957, 1968, and 2009 pandemic viruses required a lower pH for fusion induction than did the HA of a representative EAsw virus. Our data show that transmission of an avian H1N1 virus to pigs was accompanied by changes in conformational stability and fusion promotion activity of the HA. We conclude that distinctive host determined fusion characteristics of the HA may represent a barrier for avian-to swine and swine-to-human transmission of influenza viruses. IMPORTANCE: Continuing cases of human infections with zoonotic influenza viruses highlight the necessity to understand which viral properties contribute to interspecies transmission. Efficient binding of the HA to cellular receptors in a new host species is known to be essential for the transmission. Less is known about required adaptive changes in the membrane fusion activity of the HA. Here we show that adaptation of an avian influenza virus to pigs in Europe in 1980s was accompanied by mutations in the HA, which decreased its conformational stability and increased pH optimum of membrane fusion activity. This finding represents the first formal evidence of alteration of the HA fusion activity/stability during interspecies transmission of influenza viruses under natural settings. PMID- 26608320 TI - PACT- and RIG-I-Dependent Activation of Type I Interferon Production by a Defective Interfering RNA Derived from Measles Virus Vaccine. AB - The live attenuated measles virus vaccine is highly immunostimulatory. Identification and characterization of its components that activate the innate immune response might provide new strategies and agents for the rational design and development of chemically defined adjuvants. In this study, we report on the activation of type I interferon (IFN) production by a defective interfering (DI) RNA isolated from the Hu-191 vaccine strain of measles virus. We found that the Hu-191 virus induced IFN-beta much more potently than the Edmonston strain. In the search for IFN-inducing species in Hu-191, we identified a DI RNA specifically expressed by this strain. This DI RNA, which was of the copy-back type, was predicted to fold into a hairpin structure with a long double-stranded stem region of 206 bp, and it potently induced the expression of IFN-beta. Its IFN-beta-inducing activity was further enhanced when both cytoplasmic RNA sensor RIG-I and its partner, PACT, were overexpressed. On the contrary, this activity was abrogated in cells deficient in PACT or RIG-I. The DI RNA was found to be associated with PACT in infected cells. In addition, both the 5'-di/triphosphate end and the double-stranded stem region on the DI RNA were essential for its activation of PACT and RIG-I. Taken together, our findings support a model in which a viral DI RNA is sensed by PACT and RIG-I to initiate an innate antiviral response. Our work might also provide a foundation for identifying physiological PACT ligands and developing novel adjuvants or antivirals. IMPORTANCE: The live attenuated measles virus vaccine is one of the most successful human vaccines and has largely contained the devastating impact of a highly contagious virus. Identifying the components in this vaccine that stimulate the host immune response and understanding their mechanism of action might help to design and develop better adjuvants, vaccines, antivirals, and immunotherapeutic agents. We identified and characterized a defective interfering RNA from the Hu-191 vaccine strain of measles virus which has safely been used in millions of people for many years. We further demonstrated that this RNA potently induces an antiviral immune response through cellular sensors of viral RNA known as PACT and RIG-I. Similar types of viral RNA that bind with and activate PACT and RIG-I might retain the immunostimulatory property of measles virus vaccines but would not induce adaptive immunity. They are potentially useful as chemically defined vaccine adjuvants, antivirals, and immunostimulatory agents. PMID- 26608321 TI - 3C Protease of Enterovirus D68 Inhibits Cellular Defense Mediated by Interferon Regulatory Factor 7. AB - Human enterovirus 68 (EV-D68) is a member of the EV-D species, which belongs to the EV genus of the Picornaviridae family. Over the past several years, clusters of EV-D68 infections have occurred worldwide. A recent outbreak in the United States is the largest one associated with severe respiratory illness and neurological complication. Although clinical symptoms are recognized, the virus remains poorly understood. Here we report that EV-D68 inhibits innate antiviral immunity by downregulation of interferon regulatory factor 7 (IRF7), an immune factor with a pivotal role in viral pathogenesis. This process depends on 3C(pro), an EV-D68-encoded protease, to mediate IRF7 cleavage. When expressed in host cells, 3C(pro) targets Q167 and Q189 within the constitutive activation domain, resulting in cleavage of IRF7. Accordingly, wild-type IRF7 is fully active. However, IRF7 cleavage abrogated its capacity to activate type I interferon expression and limit replication of EV-D68. Notably, IRF7 cleavage strictly requires the protease activity of 3C(pro). Together, these results suggest that a dynamic interplay between 3C(pro) and IRF7 may determine the outcome of EV-D68 infection. IMPORTANCE: EV-D68 is a globally emerging pathogen, but the molecular basis of EV-D68 pathogenesis is unclear. Here we report that EV D68 inhibits innate immune responses by targeting an immune factor, IRF7. This involves the 3C protease encoded by EV-D68, which mediates the cleavage of IRF7. These observations suggest that the 3C(pro)-IRF7 interaction may represent an interface that dictates EV-D68 infection. PMID- 26608322 TI - High-Throughput Single-Cell Kinetics of Virus Infections in the Presence of Defective Interfering Particles. AB - Defective interfering particles (DIPs) are virus mutants that lack essential genes for growth. In coinfections with helper virus, the diversion of viral proteins to the replication and packaging of DIP genomes can interfere with virus production. Mounting cases of DIPs and DIP-like genomes in clinical and natural isolates, as well as growing interest in DIP-based therapies, underscore a need to better elucidate how DIPs work. DIP activity is primarily measured by its inhibition of virus infection yield, an endpoint that masks the dynamic and potentially diverse individual cell behaviors. Using vesicular stomatitis virus (VSV) as a model, we coinfected BHK cells with VSV DIPs and recombinant helper virus carrying a gene encoding a red fluorescent protein (RFP) whose expression correlates with the timing and level of virus release. For single cells within a monolayer, 10 DIPs per cell suppressed the reporter expression in only 1.2% of the cells. In most cells, it slowed and reduced viral gene expression, manifested as a shift in mean latent time from 4 to 6 h and reduced virus yields by 10-fold. For single cells isolated in microwells, DIP effects were more pronounced, reducing virus yields by 100-fold and extending latent times to 12 h, including individual instances above 20 h. Together, these results suggest that direct or indirect cell-cell interactions prevent most coinfected cells from being completely suppressed by DIPs. Finally, a gamma distribution model captures well how the infection kinetics quantitatively depends on the DIP dose. Such models will be useful for advancing a predictive biology of DIP-associated virus growth and infection spread. IMPORTANCE: During the last century, basic studies in virology have focused on developing a molecular mechanistic understanding of how infectious viruses reproduce in their living host cells. However, over the last 10 years, the advent of deep sequencing and other powerful technologies has revealed in natural and patient infections that viruses do not act alone. Instead, viruses are often accompanied by defective virus-like particles that carry large deletions in their genomes and fail to replicate on their own. Coinfections of viable and defective viruses behave in unpredictable ways, but they often interfere with normal virus growth, potentially enabling infections to evade host immune surveillance. In the current study, controlled levels of defective viruses are coinfected with viable viruses that have been engineered to express a fluorescent reporter protein during infection. Unique profiles of reporter expression acquired from thousands of coinfected cells reveal how interference acts at multiple stages of infection. PMID- 26608323 TI - Persistent Simian Immunodeficiency Virus Infection Drives Differentiation, Aberrant Accumulation, and Latent Infection of Germinal Center Follicular T Helper Cells. AB - CD4(+) follicular T helper (Tfh) cells play a prominent role in humoral immune responses, but the mechanisms of their accumulation and infection in AIDS remain unclear. Here we found that germinal center (GC) Tfh cells, defined here as CXCR5(+) PD-1(HIGH) CD4(+) T cells, do not express the HIV coreceptor CCR5 yet serve as a latent reservoir in GCs. With disease progression, an expansion of GC Tfh cells is accompanied by increases in dysfunctional CD8(+) T cells. In contrast, Tfh precursor (CXCR5(-) CD4(+) T) cells in lymph nodes do express CCR5 and differentiate into GC Tfh cells following interleukin-6 (IL-6) and IL-21 stimulation, and viral DNA is detectable in fully differentiated GC Tfh cells ex vivo. This suggests that SIV-infected GC Tfh cells may be derived from Tfh precursor cell subsets that become infected in marginal zones and then migrate into GCs as fully mature GC Tfh cells that serve as persistent virus reservoirs. These findings suggest that viral persistence in lymph nodes drives compensatory differentiation, aberrant accumulation, and latent infection of GC Tfh cells, resulting in marked impairment of humoral immune responses. IMPORTANCE: Generation of antibodies that can effectively eliminate viruses requires interactions of B cells with highly specialized T cells in GCs of lymphoid tissues called follicular T helper cells. Here we show that in simian immunodeficiency virus infection, these cells are initially infected in a precursor stage that leads to alterations in their homing, accumulation, and function that may be responsible for the inability of human immunodeficiency virus-infected patients to generate effective antibody responses. PMID- 26608324 TI - Canine Distemper Virus Fusion Activation: Critical Role of Residue E123 of CD150/SLAM. AB - Measles virus (MeV) and canine distemper virus (CDV) possess tetrameric attachment proteins (H) and trimeric fusion proteins, which cooperate with either SLAM or nectin 4 receptors to trigger membrane fusion for cell entry. While the MeV H-SLAM cocrystal structure revealed the binding interface, two distinct oligomeric H assemblies were also determined. In one of the conformations, two SLAM units were sandwiched between two discrete H head domains, thus spotlighting two binding interfaces ("front" and "back"). Here, we investigated the functional relevance of both interfaces in activating the CDV membrane fusion machinery. While alanine-scanning mutagenesis identified five critical regulatory residues in the front H-binding site of SLAM, the replacement of a conserved glutamate residue (E at position 123, replaced with A [E123A]) led to the most pronounced impact on fusion promotion. Intriguingly, while determination of the interaction of H with the receptor using soluble constructs revealed reduced binding for the identified SLAM mutants, no effect was recorded when physical interaction was investigated with the full-length counterparts of both molecules. Conversely, although mutagenesis of three strategically selected residues within the back H binding site of SLAM did not substantially affect fusion triggering, nevertheless, the mutants weakened the H-SLAM interaction recorded with the membrane-anchored protein constructs. Collectively, our findings support a mode of binding between the attachment protein and the V domain of SLAM that is common to all morbilliviruses and suggest a major role of the SLAM residue E123, located at the front H-binding site, in triggering the fusion machinery. However, our data additionally support the hypothesis that other microdomain(s) of both glycoproteins (including the back H-binding site) might be required to achieve fully productive H-SLAM interactions. IMPORTANCE: A complete understanding of the measles virus and canine distemper virus (CDV) cell entry molecular framework is still lacking, thus impeding the rational design of antivirals. Both viruses share many biological features that partially rely on the use of analogous Ig like host cell receptors, namely, SLAM and nectin 4, for entering immune and epithelial cells, respectively. Here, we provide evidence that the mode of binding between the membrane-distal V domain of SLAM and the attachment protein (H) of morbilliviruses is very likely conserved. Moreover, although structural information revealed two discrete conformational states of H, one of the structures displayed two H-SLAM binding interfaces ("front" and "back"). Our data not only spotlight the front H-binding site of SLAM as the main determinant of membrane fusion promotion but suggest that the triggering efficiency of the viral entry machinery may rely on a local conformational change within the front H-SLAM interactive site rather than the binding affinity. PMID- 26608325 TI - Mumps Virus Nucleoprotein Enhances Phosphorylation of the Phosphoprotein by Polo Like Kinase 1. AB - The viral RNA-dependent RNA polymerases (vRdRps) of nonsegmented, negative-sense viruses (NNSVs) consist of the enzymatic large protein (L) and the phosphoprotein (P). P is heavily phosphorylated, and its phosphorylation plays a critical role in viral RNA synthesis. Since NNSVs do not encode kinases, P is phosphorylated by host kinases. In this study, we investigate the roles that viral proteins play in the phosphorylation of mumps virus (MuV) P. We found that nucleoprotein (NP) enhances the phosphorylation of P. We have identified the serine/threonine kinase Polo-like kinase 1 (PLK1) as a host kinase that phosphorylates P and have found that phosphorylation of P by PLK1 is enhanced by NP. The PLK1 binding site in MuV P was mapped to residues 146 to 148 within the S(pS/T)P motif, and the phosphorylation site was identified as residues S292 and S294. IMPORTANCE: It has previously been shown that P acts as a chaperone for NP, which encapsidates viral genomic RNA to form the NP-RNA complex, the functional template for viral RNA synthesis. Thus, it is assumed that phosphorylation of P may regulate NP's ability to form the NP-RNA complex, thereby regulating viral RNA synthesis. Our work demonstrates that MuV NP affects phosphorylation of P, suggesting that NP can regulate viral RNA synthesis by regulating phosphorylation of P. PMID- 26608326 TI - An approach to death as an adverse event following immunization. AB - Co-incidental death occurring proximate to vaccination may be reported as an adverse event following immunization. Such events are particularly concerning because they may raise community and health provider concerns about the safety of the specific vaccine and often the immunization programme in general. Coincidental events need to be differentiated from vaccine reactions, such as anaphylaxis, which may very rarely result in death. In 2013, the World Health Organization (WHO) released an updated manual for the Causality Assessment of an AEFI. The purpose of this review is to apply the WHO causality methodology to death when this is reported as an AEFI. The causality assessment scheme recommends a four step process to enable classification of the AEFI and to differentiate events which are causally consistent from those that are inconsistent with immunization. However, for some events causality maybe indeterminate. Consistent causal reactions that may result in death are very rare and maybe related to the vaccine product (e.g. anaphylaxis, viscerotrophic disease), vaccine quality defect (e.g. an incompletely attenuated live vaccine agent) or an immunization error (e.g. vaccine vial contamination). Events that are inconsistent with immunizations are due to co-incidental conditions that may account for infant and childhood mortality. In countries with a high infant mortality rate the coincidental occurrence of death and immunization may occur not infrequently and a robust mechanism to obtain information from autopsy and perform an AEFI investigation and causality assessment is essential. Communication with the community and all stakeholders to maintain confidence in the immunization programme is critical. PMID- 26608327 TI - Immunogenicity, safety and tolerability of inactivated trivalent influenza vaccine in overweight and obese children. AB - Obesity may be a risk factor for increased hospitalization and deaths from infections due to respiratory pathogens. Additionally, obese patients appear to have impaired immunity after some vaccinations. To evaluate the immunogenicity, safety and tolerability of an inactivated trivalent influenza vaccine (TIV) in overweight and obese children, 28 overweight/obese pediatric patients and 23 healthy normal weight controls aged 3-14 years received a dose of TIV. Four weeks after vaccine administration, significantly higher seroprotection rates against the A/H1N1 strain were observed among overweight/obese children compared with normal weight controls (p<0.05). Four months after vaccination, similar or slightly higher seroconversion and seroprotection rates against the A/H1N1 and A/H3N2 strains were detected in overweight/obese than in normal weight children, whereas significantly higher rates of seroconversion and seroprotection against the B strain were found in overweight/obese patients than in normal weight controls (p<0.05 for seroconversion and seroprotection). Geometric mean titers (GMTs) and fold increase against B strains were significantly higher in overweight/obese patients than in normal weight controls 4 months after vaccine administration (p<0.01 for GMT values and p<0.05 for fold increase). The frequency of local and systemic reactions was similar between the groups, and there were no serious adverse events. The results of this study indicate that in overweight and obese children, antibody response to TIV administration is similar or slightly higher than that evidenced in normal weight subjects of similar age and this situation persists for at least 4 months after vaccine administration in the presence of a favorable safety profile. PMID- 26608328 TI - Impact of Out-of-Pocket Expenditure on Physical Therapy Utilization for Nonspecific Low Back Pain: Secondary Analysis of the Medical Expenditure Panel Survey Data. AB - BACKGROUND: Physical therapy decreases low back pain, improves function, and may lead to decreased use of medical services. However, factors predicting physical therapy utilization for patients with low back pain are not well understood. OBJECTIVES: The purpose of this study was to identify the impact of out-of-pocket expenditure on physical therapy utilization for US adults with nonspecific low back pain. DESIGN: This study was a secondary analysis of retrospective Medical Expenditure Panel Survey data. METHODS: The participants were US adults with nonspecific low back pain. The outcome variable was the number of visits per episode of care. The research variable was out-of-pocket expenditure. Covariate variables were Medical Outcomes Study 12-Item Short-Form Health Survey (SF-12) component scores. Descriptive statistics and multiple linear regression analyses were performed. RESULTS: Three hundred fourteen adults met the inclusion criteria and submitted SF-12 scores, representing nearly 4 million adults. Out-of-pocket expenditure, physical component score, and the age-insurance category "18-64 years with public coverage only for all of the year or uninsured all of the year" negatively predicted visits per episode of care in the final regression model. LIMITATIONS: Limitations of the study included use of a nonexperimental design, lack of information about symptom severity and content of physical therapy, and SF-12 scores were not taken coincidental with the episode of care. CONCLUSIONS: Out-of-pocket expenditure negatively predicts physical therapy utilization. More research is needed to identify all factors influencing physical therapy utilization so that effective health policies may be developed. PMID- 26608329 TI - Thrombin and fibrinogen gamma' impact clot structure by marked effects on intrafibrillar structure and protofibril packing. AB - Previous studies have shown effects of thrombin and fibrinogen gamma' on clot structure. However, structural information was obtained using electron microscopy, which requires sample dehydration. Our aim was to investigate the role of thrombin and fibrinogen gamma' in modulating fibrin structure under fully hydrated conditions. Fibrin fibers were studied using turbidimetry, atomic force microscopy, electron microscopy, and magnetic tweezers in purified and plasma solutions. Increased thrombin induced a pronounced decrease in average protofibril content per fiber, with a relatively minor decrease in fiber size, leading to the formation of less compact fiber structures. Atomic force microscopy under fully hydrated conditions confirmed that fiber diameter was only marginally decreased. Decreased protofibril content of the fibers produced by high thrombin resulted in weakened clot architecture as analyzed by magnetic tweezers in purified systems and by thromboelastometry in plasma and whole blood. Fibers produced with fibrinogen gamma' showed reduced protofibril packing over a range of thrombin concentrations. High-magnification electron microscopy demonstrated reduced protofibril packing in gamma' fibers and unraveling of fibers into separate protofibrils. Decreased protofibril packing was confirmed in plasma for high thrombin concentrations and fibrinogen-deficient plasma reconstituted with gamma' fibrinogen. These findings demonstrate that, in fully hydrated conditions, thrombin and fibrinogen gamma' have dramatic effects on protofibril content and that protein density within fibers correlates with strength of the fibrin network. We conclude that regulation of protofibril content of fibers is an important mechanism by which thrombin and fibrinogen gamma' modulate fibrin clot structure and strength. PMID- 26608330 TI - Macrophage receptor SR-AI is crucial to maintain normal plasma levels of coagulation factor X. AB - Beside its classical role in the coagulation cascade, coagulation factor X (FX) is involved in several major biological processes including inflammation and enhancement of virus-induced immune responses. We recently reported that the long circulatory half-life of FX is linked to its interaction with liver-resident macrophages. Importantly, we now observed that macrophages, but not undifferentiated monocytes, support this interaction. Using cell biology approaches with primary and THP1-derived macrophages as well as transfected cells, we further identified the scavenger receptor type A member I (SR-AI) to be a macrophage-specific receptor for FX. This result was confirmed using SR-AI deficient mice, which exhibit reduced circulating levels of FX in vivo and loss of FX-macrophage interactions in vitro. Binding studies using purified proteins revealed that FX binds specifically (half-maximal binding, 3 MUg/mL) to the extracellular domain of SR-AI. Altogether, we demonstrate that macrophages regulate FX plasma levels in an SR-AI-dependent manner. PMID- 26608331 TI - Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with frequent progression to myelofibrosis. AB - Frameshift mutations in the calreticulin (CALR) gene are seen in about 30% of essential thrombocythemia and myelofibrosis patients. To address the contribution of the CALR mutants to the pathogenesis of myeloproliferative neoplasms, we engrafted lethally irradiated recipient mice with bone marrow cells transduced with retroviruses expressing these mutants. In contrast to wild-type CALR, CALRdel52 (type I) and, to a lesser extent, CALRins5 (type II) induced thrombocytosis due to a megakaryocyte (MK) hyperplasia. Disease was transplantable into secondary recipients. After 6 months, CALRdel52-, in contrast to rare CALRins5-, transduced mice developed a myelofibrosis associated with a splenomegaly and a marked osteosclerosis. Monitoring of virus-transduced populations indicated that CALRdel52 leads to expansion at earlier stages of hematopoiesis than CALRins5. However, both mutants still specifically amplified the MK lineage and platelet production. Moreover, a mutant deleted of the entire exon 9 (CALRdelex9) did not induce a disease, suggesting that the oncogenic property of CALR mutants was related to the new C-terminus peptide. To understand how the CALR mutants target the MK lineage, we used a cell-line model and demonstrated that the CALR mutants, but not CALRdelex9, specifically activate the thrombopoietin (TPO) receptor (MPL) to induce constitutive activation of Janus kinase 2 and signal transducer and activator of transcription 5/3/1. We confirmed in c-mpl- and tpo-deficient mice that expression of Mpl, but not of Tpo, was essential for the CALR mutants to induce thrombocytosis in vivo, although Tpo contributes to disease penetrance. Thus, CALR mutants are sufficient to induce thrombocytosis through MPL activation. PMID- 26608332 TI - Reporting Policy Regarding Drivers with Dementia. AB - PURPOSE OF THE STUDY: States have various policies regarding physician reporting of drivers with dementia to the Department of Motor Vehicles (DMV) for testing. Some states have mandatory reporting policies, others have optional reporting policies, and some have no policy regarding this issue. Arkansas has no reporting policy. Physicians in Arkansas face the risk of liability if they report a patient against their will to the DMV. DESIGN AND METHODS: Three research questions were developed to identify how the problem of drivers with dementia is defined among neurologists and geriatricians in Arkansas: (i) What knowledge do these specialists have of state policy regarding reporting of drivers with dementia to the DMV; (ii) What are their opinions regarding various policy options for reporting such drivers; and (iii) What are their reporting practices for drivers with dementia? A survey was distributed to Arkansas neurologists and geriatricians. RESULTS: There was considerable uncertainty among respondents, regarding the process of assessing and reporting at-risk drivers with dementia. Support for optional reporting policy was strong. Mandatory reporting policy was less favored. Conversations with patients and caregivers regarding cessation of driving were described as being contentious and ongoing. IMPLICATIONS: These findings lead to the recommendation that the Arkansas legislature adopt an optional reporting policy. There is also a need for physician education regarding state reporting policy, as well as training for assessment of fitness to drive for patients with dementia. PMID- 26608333 TI - Delivery Characteristics, Acceptability, and Depression Outcomes of a Home-based Depression Intervention for Older African Americans: The Get Busy Get Better Program. AB - PURPOSE OF THE STUDY: To facilitate replication, we examined delivery characteristics, acceptability, and depression outcomes of a home-based intervention, Get Busy Get Better, Helping Older Adults Beat the Blues (GBGB). GBGB, previously tested in a randomized trial, reduced depressive symptoms and enhanced quality of life in African Americans. DESIGN AND METHODS: A total of 208 African Americans aged above 55 years with Patient Health Questionnaire (PHQ-9) scores >=5 on two subsequent screenings were randomized to receive GBGB immediately or 4 months later. GBGB involves up to 10 home sessions consisting of care management, referral/linkage, depression education/symptom recognition, stress reduction, and behavioral activation. Interventionists recorded delivery characteristics (dose, intensity) and perceived acceptability of sessions. Baseline and post-tests were used to characterize participants and examine associations between dose/intensity and depression scores. Participant satisfaction and perceived benefits were examined at 8 months. RESULTS: Of 208 participants, 181 (87%, mean age = 69.6) had treatment data. Of these, 165 (91.2%) had >=3 treatment sessions (minimal dose). Participants had on average 8.1 sessions (SD = 2.6) for an average of 65.4min (SD = 18.3) each. Behavioral activation and care management were provided the most (average of six sessions for average duration = 17.9 and 22.2min per session respectively), although all participants received each treatment component. GBGB was perceived as highly acceptable and beneficial by interventionists and participants. More sessions and time in program were associated with greater symptom reduction. IMPLICATIONS: GBGB treatment components were highly acceptable to participants. Future implementation and sustainability challenges include staffing, training requirements, reimbursement limitations, competing agency programmatic priorities, and generalizability to other groups. PMID- 26608334 TI - Valued Activities among Individuals with and without Cognitive Impairments: Findings from the National Health and Aging Trends Study. AB - Purpose of the study: Using the National Health and Aging Trends Study (NHATS), we examined activity preferences and participation among individuals with and without cognitive impairments. Design and methods: Respondents were classified as having No Dementia (n = 5,264), Possible Dementia (n = 893), or Probable Dementia (n = 518). Respondents rated importance of and actual participation (yes/no) in four activities (visiting friends/family, religious services, clubs/classes, going out for enjoyment). We also examined whether transportation or health limited participation. Results: Overall, visiting friends/family was most important (64.03%); although relative importance of activities varied with cognitive status. Compared to cognitively healthy individuals, those with possible and probable dementia were less likely to indicate activities were important and engage in valued activities (ps < .0001). Additionally, poor health limited participation in activities for those cognitively intact or with possible dementia; this was not true for those with probable dementia. Transportation difficulty limited going out for enjoyment for a greater percentage of those with cognitive impairment than those without impairment. Implications: Regardless of cognitive level, older adults highly value activities; however, actual participation may decrease with greater impairment in cognitive and physical health and with transportation challenges. Developing tailored interventions for specific populations to achieve desired activity goals is needed. PMID- 26608335 TI - Home and Community-Based Service Use by Vulnerable Older Adults. AB - Purpose of the Study: The purpose of this study was to identify different types of clients who use home and community-based services. Design and Methods: Enrollment characteristics of 76 clients at risk of nursing home placement and Medicaid spend-down who were enrolled in the Virginia Community Living Program were analyzed. Two-step cluster analysis identified 4 groups of service users. Results: Enabling resources (caregiver relationship to participant, participant living arrangement, and length of time caregiver provided assistance to participant) and disability type (physical, cognitive, traumatic brain injury, or other) differentiated the client groups. Groups differed on average service cost per day and likelihood of nursing home placement if services were not provided. Implications: Findings point to the value of having practitioners assist vulnerable clients in tailoring services to meet different care needs and the need for refining policies guiding home and community-based care. PMID- 26608336 TI - A computational analysis of cell-mediated compaction and collagen remodeling in tissue-engineered heart valves. AB - One of the most critical problems in heart valve tissue engineering is the progressive development of valvular insufficiency due to leaflet retraction. Understanding the underlying mechanisms of this process is crucial for developing tissue-engineered heart valves (TEHVs) that maintain their functionality in the long term. In the present study, we adopted a computational approach to predict the remodeling process in TEHVs subjected to dynamic pulmonary and aortic pressure conditions, and to assess the risk of valvular insufficiency. In addition, we investigated the importance of the intrinsic cell contractility on the final outcome of the remodeling process. For valves implanted in the aortic position, the model predictions suggest that valvular insufficiency is not likely to occur as the blood pressure is high enough to prevent the development of leaflet retraction. In addition, the collagen network was always predicted to remodel towards a circumferentially aligned network, which is corresponding to the native situation. In contrast, for valves implanted in the pulmonary position, our model predicted that there is a high risk for the development of valvular insufficiency, unless the cell contractility is very low. Conversely, the development of a circumferential collagen network was only predicted at these pressure conditions when cell contractility was high. Overall, these results, therefore, suggest that tissue remodeling at aortic pressure conditions is much more stable and favorable compared to tissue remodeling at pulmonary pressure conditions. PMID- 26608337 TI - Distinct neurohumoral biomarker profiles in children with hemodynamically defined orthostatic intolerance may predict treatment options. AB - Studies of adults with orthostatic intolerance (OI) have revealed altered neurohumoral responses to orthostasis, which provide mechanistic insights into the dysregulation of blood pressure control. Similar studies in children with OI providing a thorough neurohumoral profile are lacking. The objective of the present study was to determine the cardiovascular and neurohumoral profile in adolescent subjects presenting with OI. Subjects at 10-18 yr of age were prospectively recruited if they exhibited two or more traditional OI symptoms and were referred for head-up tilt (HUT) testing. Circulating catecholamines, vasopressin, aldosterone, renin, and angiotensins were measured in the supine position and after 15 min of 70 degrees tilt. Heart rate and blood pressure were continuously measured. Of the 48 patients, 30 patients had an abnormal tilt. Subjects with an abnormal tilt had lower systolic, diastolic, and mean arterial blood pressures during tilt, significantly higher levels of vasopressin during HUT, and relatively higher catecholamines and ANG II during HUT than subjects with a normal tilt. Distinct neurohumoral profiles were observed when OI subjects were placed into the following groups defined by the hemodynamic response: postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension (OH), syncope, and POTS/syncope. Key characteristics included higher HUT-induced norepinephrine in POTS subjects, higher vasopressin in OH and syncope subjects, and higher supine and HUT aldosterone in OH subjects. In conclusion, children with OI and an abnormal response to tilt exhibit distinct neurohumoral profiles associated with the type of the hemodynamic response during orthostatic challenge. Elevated arginine vasopressin levels in syncope and OH groups are likely an exaggerated response to decreased blood flow not compensated by higher norepinephrine levels, as observed in POTS subjects. These different compensatory mechanisms support the role of measuring neurohumoral profiles toward the goal of selecting more focused and mechanistic-based treatment options for pediatric patients with OI. PMID- 26608340 TI - Early detection of acute transmural myocardial ischemia by the phasic systolic diastolic changes of local tissue electrical impedance. AB - Myocardial electrical impedance is influenced by the mechanical activity of the heart. Therefore, the ischemia-induced mechanical dysfunction may cause specific changes in the systolic-diastolic pattern of myocardial impedance, but this is not known. This study aimed to analyze the phasic changes of myocardial resistivity in normal and ischemic conditions. Myocardial resistivity was measured continuously during the cardiac cycle using 26 different simultaneous excitation frequencies (1 kHz-1 MHz) in 7 anesthetized open-chest pigs. Animals were submitted to 30 min regional ischemia by acute left anterior descending coronary artery occlusion. The electrocardiogram, left ventricular (LV) pressure, LV dP/dt, and aortic blood flow were recorded simultaneously. Baseline myocardial resistivity depicted a phasic pattern during the cardiac cycle with higher values at the preejection period (4.19 +/- 1.09% increase above the mean, P < 0.001) and lower values during relaxation phase (5.01 +/- 0.85% below the mean, P < 0.001). Acute coronary occlusion induced two effects on the phasic resistivity curve: 1) a prompt (5 min ischemia) holosystolic resistivity rise leading to a bell-shaped waveform and to a reduction of the area under the LV pressure-impedance curve (1,427 +/- 335 vs. 757 +/- 266 Omega.cm.mmHg, P < 0.01, 41 kHz) and 2) a subsequent (5-10 min ischemia) progressive mean resistivity rise (325 +/- 23 vs. 438 +/- 37 Omega.cm at 30 min, P < 0.01, 1 kHz). The structural and mechanical myocardial dysfunction induced by acute coronary occlusion can be recognized by specific changes in the systolic-diastolic myocardial resistivity curve. Therefore these changes may become a new indicator (surrogate) of evolving acute myocardial ischemia. PMID- 26608338 TI - Advances and challenges in skeletal muscle angiogenesis. AB - The role of capillaries is to serve as the interface for delivery of oxygen and removal of metabolites to/from tissues. During the past decade there has been a proliferation of studies that have advanced our understanding of angiogenesis, demonstrating that tissue capillary supply is under strict control during health but poorly controlled in disease, resulting in either excessive capillary growth (pathological angiogenesis) or losses in capillarity (rarefaction). Given that skeletal muscle comprises nearly 40% of body mass in humans, skeletal muscle capillary density has a significant impact on metabolism, endocrine function, and locomotion and is tightly regulated at many different levels. Skeletal muscle is also high adaptable and thus one of the few organ systems that can be experimentally manipulated (e.g., by exercise) to study physiological regulation of angiogenesis. This review will focus on the methodological concerns that have arisen in determining skeletal muscle capillarity and highlight the concepts that are reshaping our understanding of the angio-adaptation process. We also summarize selected new findings (physical influences, molecular changes, and ultrastructural rearrangement of capillaries) that identify areas of future research with the greatest potential to expand our understanding of how angiogenesis is normally regulated, and that may also help to better understand conditions of uncontrolled (pathological) angiogenesis. PMID- 26608339 TI - LRRC10 is required to maintain cardiac function in response to pressure overload. AB - We previously reported that the cardiomyocyte-specific leucine-rich repeat containing protein (LRRC)10 has critical functions in the mammalian heart. In the present study, we tested the role of LRRC10 in the response of the heart to biomechanical stress by performing transverse aortic constriction on Lrrc10-null (Lrrc10(-/-)) mice. Mild pressure overload induced severe cardiac dysfunction and ventricular dilation in Lrrc10(-/-) mice compared with control mice. In addition to dilation and cardiomyopathy, Lrrc10(-/-) mice showed a pronounced increase in heart weight with pressure overload stimulation and a more dramatic loss of cardiac ventricular performance, collectively suggesting that the absence of LRRC10 renders the heart more disease prone with greater hypertrophy and structural remodeling, although rates of cardiac fibrosis and myocyte dropout were not different from control mice. Lrrc10(-/-) cardiomyocytes also exhibited reduced contractility in response to beta-adrenergic stimulation, consistent with loss of cardiac ventricular performance after pressure overload. We have previously shown that LRRC10 interacts with actin in the heart. Here, we show that His(150) of LRRC10 was required for an interaction with actin, and this interaction was reduced after pressure overload, suggesting an integral role for LRRC10 in the response of the heart to mechanical stress. Importantly, these experiments demonstrated that LRRC10 is required to maintain cardiac performance in response to pressure overload and suggest that dysregulated expression or mutation of LRRC10 may greatly sensitize human patients to more severe cardiac disease in conditions such as chronic hypertension or aortic stenosis. PMID- 26608341 TI - Longitudinal analysis of the peripheral B cell repertoire reveals unique effects of immunization with a new influenza virus strain. AB - BACKGROUND: Despite the potential to produce antibodies that can neutralize different virus (heterotypic neutralization), there is no knowledge of why vaccination against influenza induces protection predominantly against the utilized viral strains (homotypic response). Identification of structural patterns of the B cell repertoire associated to heterotypic neutralization may contribute to identify relevant epitopes for a universal vaccine against influenza. METHODS: Blood samples were collected from volunteers immunized with 2008/2009 trivalent inactivated vaccine (TIV), pandemic H1N1 (pdmH1N1) monovalent inactivated vaccine (MIV) and the 2014/2015 TIV. Neutralization was assessed by hemagglutination and microneutralization test. IgG V(H) amplicons derived from peripheral blood RNA from pre-immune and 7 days post vaccination were subjected to 454-Roche sequencing. Full reconstruction of the sampled repertoires was done with ImmunediveRsity. RESULTS: The TIV induced a predominantly homotypic neutralizing serologic response, while the 09 MIV induced a heterotypic neutralizing seroconversion in 17% of the individuals. Both the 08/09 and the 14/15 TIV were associated with a reduction in clonotypic diversity, whereas 09 MIV was the opposite. Moreover, TIV and MIV induced distinctive patterns of IGHV segment use that are consistent with B cell selection by conserved antigenic determinants shared by the pre-pandemic and the pandemic strains. However, low somatic hypermutation rates in IgG after 09 MIV immunization, but not after 08/09 and 14/15 TIV immunization were observed. Furthermore, no evidence of the original antigenic sin was found in the same individuals after vaccination with the three vaccines. CONCLUSIONS: Immunization with a new influenza virus strain (2009 pdmH1N1) induced unique effects in the peripheral B cell repertoire clonal structure, a stereotyped response involving distinctive IGHV segment use and low somatic hypermutation levels. These parameters were contrastingly different to those observed in response to pre-pandemic and post-pandemic vaccination, and may be the result of clonal selection of common antigenic determinants, as well as germinal center-independent responses that wane as the pandemic strain becomes seasonal. Our findings may contribute in the understanding of the structural and cellular basis required to develop a universal influenza vaccine. PMID- 26608342 TI - Use of mouth rinse during pregnancy to improve birth and neonatal outcomes: a randomized controlled trial. AB - BACKGROUND: Poor oral health, such as periodontal (gum) disease, has been found to be associated with an increased risk of adverse pregnancy outcomes including preterm birth, low birth weight, and neonatal and infant mortality, especially in low-and middle-income countries. However, there is little or no access to preventive dental care in most low-and middle-income countries. We propose to develop and test a "Mouth Rinse Intervention" among pregnant women to prevent the progression of periodontal disease during pregnancy and reduce adverse birth and neonatal outcomes in a rural county of China. METHODS/DESIGN: This is a randomized controlled clinical trial. A sample of 468 (234 in each arm of the study) women in early pregnancy with periodontal disease will be recruited for the study. Periodontal disease will be diagnosed through the methods of Periodontal Screening and Recording. All women diagnosed with periodontal disease will be randomly allocated into the intervention or control group. Women assigned in the intervention group will be provided with non-alcohol antimicrobial mouth rinse containing cetylpyridinium chloride throughout the pregnancy and oral health education. Women in the control group will receive a package of tooth brush and paste, plus oral hygiene education. Women will be followed-up to childbirth until the 42nd day postpartum. The main outcomes include mean birthweight (gram) and mean gestational age (week). DISCUSSION: Compared with conventional mechanical 'scaling and root planning' periodontal treatment during pregnancy, our proposed mouth rinse intervention could be a simple, cost effective, and sustainable solution to improve both mother's oral health and neonate outcomes. If the mouth rinse is confirmed to be effective, it would demonstrate great potential for the application in other low- or middle-income countries to prevent adverse birth outcomes such as preterm birth and low birth weight and to reduce neonatal and infant mortality. TRIAL REGISTRATION: This trial was registered with Chinese Clinical Trial Registry (ChiCTR): ( #ChiCTR-TRC 13003768 ) on November 06, 2013. PMID- 26608343 TI - The view from 10,000 procedures: technical tips and wisdom from master pancreatic surgeons to avoid hemorrhage during pancreaticoduodenectomy. AB - Pancreaticoduodenectomy remains the exclusive technique for surgical resection of cancers located within both the pancreatic head and periampullary region. Amongst peri-procedural complications, hemorrhage is particularly problematic given that allogenic blood transfusions are known to increase the risk of infection, acute lung injury, cancer recurrence and overall 30-day morbidity and mortality rates. Because blood loss can be considered a modifiable factor that reflects surgical technique, rates of perioperative blood loss and transfusion have been advocated as robust quality indicators. We present a correspondence manuscript that outlines peri-procedural concepts detailing a successful pancreaticoduodenectomy with minimal hemorrhage. These tips were collated from master pancreatic surgeons throughout the globe who have performed over 10,000 cumulative pancreaticoduodenectomies. At risk scenarios for hemorrhage include dissections of the superior mesenteric - portal vein, gastroduodenal artery, and retroperitoneal soft tissue margin. General principles in limiting slow continuous hemorrhage that may accumulate into larger total case losses are also discussed. While many of the techniques and tips proposed by master pancreas surgeons are intuitive and straight forward, when taken as a collective they represent a significant contribution to improved outcomes associated with the pancreaticoduodenectomy over the past 100 years. PMID- 26608345 TI - In vivo polyester immobilized sortase for tagless protein purification. AB - BACKGROUND: Laboratory scale recombinant protein production and purification techniques are often complicated, involving multiple chromatography steps and specialized equipment and reagents. Here it was demonstrated that recombinant proteins can be expressed as covalently immobilized to the surface of polyester (polyhydroxyalkanoate, PHA) beads in vivo in Escherichia coli by genetically fusing them to a polyester synthase gene (phaC). The insertion of a self-cleaving module, a modified sortase A (SrtA) from Staphylococcus aureus and its five amino acid recognition sequence between the synthase and the target protein led to a simple protein production and purification method. RESULTS: The generation of hybrid genes encoding tripartite PhaC-SrtA-Target fusion proteins, enabled immobilization of proteins of interest to the surface of PHA beads in vivo. After simple cell lysis and isolation of the PHA beads, the target proteins could be selectively and efficiently released form the beads by activating the sortase with CaCl2 and triglycine. Up to 6 mg/l of soluble proteins at a purity of ~98 % could be isolated in one step with no optimization. This process was used to produce and isolate three proteins: Green fluorescent protein, maltose binding protein and the Mycobacterium tuberculosis vaccine candidate Rv1626. CONCLUSIONS: We have developed a new technique for easy production and purification of recombinant proteins. This technique is capable of producing and purifying high yields of proteins suitable for research application in less than 2 days. No costly or specialized protein chromatography equipment, resins, reagents or expertise are required. PMID- 26608344 TI - Temperature-induced variation in gene expression burst size in metazoan cells. AB - BACKGROUND: Gene expression is an inherently stochastic process, owing to its dynamic molecular nature. Protein amount distributions, which can be acquired by cytometry using a reporter gene, can inform about the mechanisms of the underlying microscopic molecular system. RESULTS: By using different clones of chicken erythroid progenitor cells harboring different integration sites of a CMV driven mCherry protein, we investigated the dynamical behavior of such distributions. We show that, on short term, clone distributions can be quickly regenerated from small population samples with a high accuracy. On longer term, on the contrary, we show variations manifested by correlated fluctuation in the Mean Fluorescence Intensity. In search for a possible cause of this correlation, we demonstrate that in response to small temperature variations cells are able to adjust their gene expression rate: a modest (2 degrees C) increase in external temperature induces a significant down regulation of mean expression values, with a reverse effect observed when the temperature is decreased. Using a two-state model of gene expression we further demonstrate that temperature acts by modifying the size of transcription bursts, while the burst frequency of the investigated promoter is less systematically affected. CONCLUSIONS: For the first time, we report that transcription burst size is a key parameter for gene expression that metazoan cells from homeotherm animals can modify in response to an external thermal stimulus. PMID- 26608346 TI - Visual Assessment of Chest Computed Tomography Findings in Anti-cyclic Citrullinated Peptide Antibody Positive Rheumatoid Arthritis: Is it Associated with Airway Abnormalities? AB - INTRODUCTION: We aimed to evaluate the association between specific anti-cyclic citrullinated peptide antibody (ACCPA) and pulmonary abnormalities in rheumatoid arthritis (RA) subjects. METHODS: Computed tomography (CT) images of 83 subjects with RA were evaluated in a blind fashion. Enrolled subjects underwent autoantibody testing to determinate titer of ACCPA and rheumatoid factor, and pulmonary function testing. Visual CT assessment included lobar analysis for extent of semi-quantitative total interstitial lung disease score (ILDS) and each airway abnormality score (bronchiectasis, bronchial wall thickening, centrilobular nodules, and expiratory air trapping). Correlation tests, and simple and multiple regression analyses were performed to determine the relationship between the visual CT abnormalities, physiologic parameters, and autoantibody titers. RESULTS: ACCPA-positive subjects had a greater extent and higher prevalence of small airway abnormalities including centrilobular nodules and air trapping compared to ACCPA-negative subjects (all p < 0.05). Bronchiectasis and bronchial wall thickening correlated with the ratio of forced expiratory volume in 1 s and forced vital capacity (FVC) (r = -0.236 and r = 0.329, all p < 0.05), and ILDS correlated with FVC and the diffusing capacity of the lung for carbon monoxide (r = -0.218 and r = -0.366, all p < 0.05). Bronchial wall thickening and air trapping correlated with ACCPA titers (r = 0.235 and r = 0.264, all p < 0.05). Air trapping and bronchial wall thickening were significantly associated with ACCPA titers. CONCLUSION: In ACCPA (+) RA, visual CT assessment of large and small airways beyond RA-ILD, which is attributable to RA-related autoimmunity, can provide valuable information regarding airway abnormalities, regardless of the patients' physiologic airflow limitations. PMID- 26608348 TI - Palladium-Catalyzed Double-Suzuki-Miyaura Reactions Using Cyclic Dibenziodoniums: Synthesis of o-Tetraaryls. AB - Palladium-catalyzed double-Suzuki-Miyaura couplings between cyclic dibenziodoniums and arylboronic acids have been developed. As such, a wide range of o-tetraaryls were synthesized in good to excellent yields of 22-94%. Furthermore, tetraphenylene was prepared in 21% isolated yield with 2,2' biphenyldiboronic acid by using this method. PMID- 26608347 TI - IMP3 Predicts Invasion and Prognosis in Human Lung Adenocarcinoma. AB - PURPOSE: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is an oncofetal protein associated with several aggressive and advanced cancers. Whether IMP3 can predict invasion, and prognosis in patients with human lung adenocarcinoma (LAC) remains unclear. METHODS: Ninety-five LAC and 75 non-tumor lung tissue samples were included in a tissue microarray. IMP3 expression was assessed by immunohistochemical examination. Correlation between IMP3 expression levels, clinicopathological characteristics, and overall prognosis was evaluated. In a separate in vitro study, RNA interference method was applied for knockdown of IMP3 gene in human LAC cell lines. Invasive potential of LAC cells was then evaluated by transwell migration assay. RESULTS: IMP3 immunoreactivity was observed in 39 out of 95 (41.1 %) LAC patients, but not in non-tumor lung tissues. IMP3 expression levels were closely associated with histological grade (P = 0.037), TNM stage (P = 0.034), and lymph node metastasis (P = 0.011). Patients presenting with positive IMP3 expression (P = 0.000), an advanced TNM stage (P = 0.000), and lymph node metastasis (P = 0.001) had a worse overall survival, compared to those lacking these characteristics. Both IMP3 expression (hazard ratio [HR], 2.310; 95 % confidence interval [CI] 1.192-4.476; P = 0.013) and TNM stage (HR 2.338; 95 % CI 1.393-3.925; P = 0.001) were independent predictors of poor prognosis. The invasive potential of LAC cells was significantly inhibited by IMP3 knockdown. CONCLUSION: IMP3 appears to play an important role in tumor invasion in patients with LAC and may serve as a useful prognostic biomarker in these patients. PMID- 26608349 TI - Ultra High-Speed Radio Frequency Switch Based on Photonics. AB - Microwave switches, or Radio Frequency (RF) switches have been intensively used in microwave systems for signal routing. Compared with the fast development of microwave and wireless systems, RF switches have been underdeveloped particularly in terms of switching speed and operating bandwidth. In this paper, we propose a photonics based RF switch that is capable of switching at tens of picoseconds speed, which is hundreds of times faster than any existing RF switch technologies. The high-speed switching property is achieved with the use of a rapidly tunable microwave photonic filter with tens of gigahertz frequency tuning speed, where the tuning mechanism is based on the ultra-fast electro-optics Pockels effect. The RF switch has a wide operation bandwidth of 12 GHz and can go up to 40 GHz, depending on the bandwidth of the modulator used in the scheme. The proposed RF switch can either work as an ON/OFF switch or a two-channel switch, tens of picoseconds switching speed is experimentally observed for both type of switches. PMID- 26608350 TI - Fatal Outcome from Brain Vascular Lesions in a Neonate with Blue Rubber Bleb Nevus Syndrome. AB - The most common cause of death in blue rubber bleb nevus syndrome is gastrointestinal bleeding. Here we present a case of central nervous system bleeding that resulted in death. PMID- 26608351 TI - The consequences of introducing stochasticity in nutrient utilisation models: the case of phosphorus utilisation by pigs. AB - Simulation models of nutrient utilisation ignore that variation in pig system components can influence the predicted mean and variance of the performance of a group of pigs. The objective of this study was to develop a methodology to investigate how variation in feed composition would (a) affect the outputs of a nutrient utilisation model and (b) interact with variation that arises from the traits of individual pigs. We used a P intake and utilisation model to address these characteristics. Introduction of stochasticity gave rise to a number of methodological challenges--for example, how to generate variation in both feed composition and pigs and account for correlations between ingredients when modelling variation associated with feed mixing efficiency. Introducing variation in feed composition and pig phenotype resulted in moderate decreases in mean digested, retained and excreted P predicted for a population of pigs and an increase in their associated CV. A lower percentage of pigs in the population were predicted to meet their requirements during the feeding period considered, by comparison with the no-variation scenario. Variation in feed ingredient composition contributed more to performance variation than variation due to mixing efficiency. When variations in both feed composition and pig traits were considered, it was the former rather than the latter that had the dominant influence on variability in pig performance. The developed framework emphasises the consequences of random variability on the predictions of nutrient utilisation models. Such consequences will have a significant impact on decisions about management strategies such as feeding that are subject to variation. PMID- 26608352 TI - Effects of different dl-selenomethionine and sodium selenite levels on growth performance, immune functions and serum thyroid hormones concentrations in broilers. AB - This trial was conducted in a 2 * 3 + 1 factorial arrangement based on a completely randomized design to evaluate the effects of different dl selenomethionine (dl-Se-Met) and sodium selenite (SS) levels on growth performance, immune functions and serum thyroid hormones concentrations in broilers. A total of 840 Ross 308 broilers (7 days old) were allocated by body weight to seven treatments (three replicates of 40 birds each treatment) including (1) basal diet (containing 0.04 mg of selenium (Se)/kg; control) without supplementary Se; (2, 3 and 4) basal diet + 0.05, 0.15 or 0.25 mg/kg Se as SS; (5, 6 and 7) basal diet + 0.05, 0.15 or 0.25 mg/kg Se as dl-Se-Met. The experiment lasted 42 days. The results revealed that dietary Se supplementation improved (p < 0.05) average daily gain, feed efficiency, immune organ index, serum immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM) and triiodothyronine (T3 ) concentrations and decreased (p < 0.01) thyroxine (T4 )/T3 ratio in serum compared with the control. Broilers receiving the dl-Se-Met supplemented diets had higher (p < 0.05) feed efficiency, thymus index, the amounts of IgA, IgG, IgM and T3 as well as lower (p < 0.05) serum T4 concentrations and T4 /T3 ratio than those consuming the SS-supplemented diets. Serum IgA and IgM levels of broilers fed 0.15 mg Se/kg were significantly higher (p < 0.05) than those of broilers fed 0.05 or 0.25 mg Se/kg. In summary, we concluded that dl-Se-Met is more effective than SS in increasing immunity and promoting conversion of T4 to T3 , thus providing an effective way to improve the growth performance of broilers. Besides, based on a consideration of all experiment indices, 0.15 mg Se/kg was suggested to be the optimal level of Se supplementation under the conditions of this study. PMID- 26608353 TI - A French national survey of obstructive sleep apnoea screening. PMID- 26608354 TI - Enhanced or Weakened Western North Pacific Subtropical High under Global Warming? AB - The Western North Pacific Subtropical High (WNPSH) regulates East Asian climate in summer. Anomalous WNPSH causes floods, droughts and heat waves in China, Japan and Korea. The potential change of the WNPSH under global warming is concerned by Asian people, but whether the WNPSH would be enhanced or weakened remains inconclusive. Based on the multi-model climate change projection from the 5th phase of Coupled Model Intercomparison Project (CMIP5), we show evidences that the WNPSH tends to weaken and retreat eastward in the mid-troposphere in response to global warming, accompanied by an eastward expansion of East Asian rain belt along the northwestern flank of WNPSH. Weakened meridional temperature gradient on the northern flank of WNPSH and the associated thermal wind account for the weakened WNPSH in the mid troposphere. We recommend the WNPSH be measured by eddy geopotential height (He) instead of traditionally used geopotential height, especially in climate change studies. PMID- 26608355 TI - Relationship of rumen fill and fermentation to diurnal and seasonal variation of herbage intake in dairy cows grazed on perennial ryegrass pasture. AB - To clarify the effect of digesta weight in the reticulorumen on diurnal and seasonal fluctuations in herbage intake, six ruminally cannulated, non-lactating dairy cows were grazed on perennial ryegrass/white clover pasture during morning and evening sessions in spring and autumn. The digesta weight of fresh matter, dry matter (DM) and fiber in the reticulorumen at the beginning and the end of each grazing session was lower in spring than in autumn (P < 0.01). Although the digesta weight was similar between the sessions at the beginning of grazing, it was greater for the evening than for the morning at the end of grazing (P < 0.01). The large particles proportion in the digesta was lower for the morning than the evening (P < 0.01), and it was lower in spring than in autumn (P < 0.01). The concentrations of volatile fatty acids in rumen fluid were generally higher in spring compared with autumn. The herbage DM intake during the evening was greater compared with the morning in both seasons (P < 0.01). However, there was no difference in herbage DM intake between seasons. The results showed that the rumen digesta fill was not the sole factor explaining diurnal and seasonal variation of herbage intake in grazing dairy cows. PMID- 26608356 TI - Enhancement of cycle performance of Li-S batteries by redistribution of sulfur. AB - A practically available strategy is employed to improve the cycle life of lithium sulfur batteries. The simple process of activation cycling at the polysulfide dissolution region leads to the partial dissolution of polysulfides and the redistribution of sulfur on the electrode. After 50 cycles, the modified activation-cycled sulfur cathode exhibits a capacity that is roughly double that of a cathode without activation cycling. PMID- 26608357 TI - Critical realism in nursing: an emerging approach. AB - Critical realism, a philosophical framework originally developed by Roy Bhaskar in the 1970s, represents a relatively new approach to research generally and to nursing research in particular. This article explores the ontological and epistemological tenets of critical realism and examines the application of critical realist principles to nursing research and practice through a review of the literature. It is evident that few published nursing research studies have, as of yet, utilized critical realism as their paradigm of choice. Both the strengths and limitations of the presentation and use of critical realism in these studies are discussed in this article. Given the varying degrees of success of the authors in explicating critical realism as a philosophical framework, the value of critical realism to the research study, and the ways in which usage of the critical realist framework influenced development of the study and interpretation of findings, it is evident that the quality of future publications espousing the use of critical realism must continue to be strengthened significantly. PMID- 26608358 TI - Development and evaluation of an up-converting phosphor technology-based lateral flow assay for rapid detection of Francisella tularensis. AB - Francisella tularensis is a potential biowarfare/bioterrorism agent and zoonotic pathogen that causes tularemia; thus, surveillance of F. tularensis and first level emergency response using point-of-care testing (POCT) are essential. The UPT-LF POCT assay was established to quantitatively detect F. tularensis within 15 min, and the sensitivity of the assay was 10(4) CFU . mL(-1) (100 CFU/test). The linear quantitative range covered five orders of magnitude, and the coefficients of variation were less than 10%. Except Shigella dysenteriae, UPT-LF showed excellent specificity to four strains that are also potential biowarfare/bioterrorism agents and 13 food-borne pathogenic strains. Samples with pH 2-13, high ion strengths (>= 2 mol . L(-1) solution of KCl and NaCl), high viscosities (<= 50 mg . mL(-1) PEG20000 or >= 20% glycerol), and high concentrations of biomacromolecules (>= 400 mg . mL(-1) bovine serum albumin or >= 80 mg . mL(-1) casein) showed little influence on the assay. For practical utilization, the tolerance limits for seven powders and eight viscera were determined, and operation errors of liquid measurement demonstrated a minor influence on the strip. Ftu-UPT-LF is a candidate POCT method because of its excellent sensitivity, specificity, and stability in complex samples, as well as low operation error. PMID- 26608359 TI - Mitochondrial Efficiency-Dependent Viability of Saccharomyces cerevisiae Mutants Carrying Individual Electron Transport Chain Component Deletions. AB - Mitochondria play a crucial role in eukaryotic cells; the mitochondrial electron transport chain (ETC) generates adenosine triphosphate (ATP), which serves as an energy source for numerous critical cellular activities. However, the ETC also generates deleterious reactive oxygen species (ROS) as a natural byproduct of oxidative phosphorylation. ROS are considered the major cause of aging because they damage proteins, lipids, and DNA by oxidation. We analyzed the chronological life span, growth phenotype, mitochondrial membrane potential (MMP), and intracellular ATP and mitochondrial superoxide levels of 33 single ETC component deleted strains during the chronological aging process. Among the ETC mutant strains, 14 (sdh1Delta, sdh2Delta, sdh4Delta, cor1Delta, cyt1Delta, qcr7Delta, qcr8Delta, rip1Delta, cox6Delta, cox7Delta, cox9Delta, atp4Delta, atp7Delta, and atp17Delta) showed a significantly shorter life span. The deleted genes encode important elements of the ETC components succinate dehydrogenase (complex II) and cytochrome c oxidase (complex IV), and some of the deletions lead to structural instability of the membrane-F1F0-ATP synthase due to mutations in the stator stalk (complex V). These short-lived strains generated higher superoxide levels and produced lower ATP levels without alteration of MMP. In summary, ETC mutations decreased the life span of yeast due to impaired mitochondrial efficiency. PMID- 26608360 TI - The 18-kDa Translocator Protein Inhibits Vascular Cell Adhesion Molecule-1 Expression via Inhibition of Mitochondrial Reactive Oxygen Species. AB - Translocator protein 18 kDa (TSPO) is a mitochondrial outer membrane protein and is abundantly expressed in a variety of organ and tissues. To date, the functional role of TSPO on vascular endothelial cell activation has yet to be fully elucidated. In the present study, the phorbol 12-myristate 13-acetate (PMA, 250 nM), an activator of protein kinase C (PKC), was used to induce vascular endothelial activation. Adenoviral TSPO overexpression (10-100 MOI) inhibited PMA induced vascular cell adhesion molecule-1 (VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1) expression in a dose dependent manner. PMA-induced VCAM-1 expressions were inhibited by Mito-TEMPO (0.1-0.5 MUM), a specific mitochondrial antioxidants, and cyclosporin A (1-5 MUM), a mitochondrial permeability transition pore inhibitor, implying on an important role of mitochondrial reactive oxygen species (ROS) on the endothelial activation. Moreover, adenoviral TSPO overexpression inhibited mitochondrial ROS production and manganese superoxide dismutase expression. On contrasts, gene silencing of TSPO with siRNA increased PMA-induced VCAM-1 expression and mitochondrial ROS production. Midazolam (1-50 MUM), TSPO ligands, inhibited PMA-induced VCAM-1 and mitochondrial ROS production in endothelial cells. These results suggest that mitochondrial TSPO can inhibit PMA-induced endothelial inflammation via suppression of VCAM-1 and mitochondrial ROS production in endothelial cells. PMID- 26608361 TI - Change in the Gastro-Intestinal Tract by Overexpressed Activin Beta A. AB - Originally, activins were identified as stimulators of FSH release in reproduction. Other activities, including secondary axis formation in development, have since been revealed. Here, we investigated the influence of activin betaA on the body, including the gastro-intestinal (GI) tract. Initially, the activin betaA protein was detected in the serum proportional to the amount of pCMV-rAct plasmid injected. The induced level of activin betaA in muscle was higher in female than male mice. Subsequent results revealed that stomach and intestine were severely damaged in pCMV-rAct-injected mice. At the cellular level, loss of parietal cells was observed, resulting in increased pH within the stomach. This phenomenon was more severe in male than female mice. Consistent with damage of the stomach and intestine, activin betaA often led to necrosis in the tip of the tail or foot, and loss of body weight was observed in pCMV-rAct injected male but not female mice. Finally, in pCMV-rAct-injected mice, circulating activin betaA led to death at supraphysiological doses, and this was dependent on the strain of mice used. Taken together, these results indicate that activin betaA has an important role outside of reproduction and development, specifically in digestion. These data also indicate that activin betaA must be controlled within a narrow range because of latent lethal activity. In addition, our approach can be used effectively for functional analysis of secreted proteins. PMID- 26608362 TI - MiR-29a and MiR-140 Protect Chondrocytes against the Anti-Proliferation and Cell Matrix Signaling Changes by IL-1beta. AB - As a degenerative joint disease, osteoarthritis (OA) constitutes a major cause of disability that seriously affects the quality of life of a large population of people worldwide. However, effective treatment that can successfully reverse OA progression is lacking until now. The present study aimed to determine whether two small non-coding RNAs miR-29a and miR-140, which are significantly down regulated in OA, can be applied together as potential therapeutic targets for OA treatment. MiRNA synergy score was used to screen the miRNA pairs that potentially synergistically regulate OA. An in vitro model of OA was established by treating murine chondrocytes with IL-1beta. Transfection of miR-29a and miR 140 via plasmids was investigated on chondrocyte proliferation and expression of nine genes such as ADAMTS4, ADAMTS5, ACAN, COL2A1, COL10A1, MMP1, MMP3, MMP13 and TIMP metal-lopeptidase inhibitor 1 (TIMP1). Western blotting was used to determine the protein expression level of MMP13 and TIMP1, and ELISA was used to detect the content of type II collagen. Combined use of miR-29a and miR-140 successfully reversed the destructive effect of IL-1beta on chondrocyte proliferation, and notably affected the MMP13 and TIMP1 gene expression that regulates extracellular matrix. Although co-transfection of miR-29a and miR-140 did not show a synergistic effect on MMP13 protein expression and type II collagen release, but both of them can significantly suppress the protein abundance of MMP13 and restore the type II collagen release in IL-1beta treated chondrocytes. Compared with single miRNA transfection, cotransfection of both miRNAs exceedingly abrogated the suppressed the protein production of TIMP1 caused by IL-1beta, thereby suggesting potent synergistic action. These results provided novel insights into the important function of miRNAs' collaboration in OA pathological development. The reduced MMP13, and enhanced TIMP1 protein production and type II collagen release also implies that miR-29a and miR-140 combination treatment may be a possible treatment for OA. PMID- 26608363 TI - Eight Novel Mutations Confirm the Role of AAGAB in Punctate Palmoplantar Keratoderma Type 1 (Buschke-Fischer-Brauer) and Show Broad Phenotypic Variability. AB - Punctate palmoplantar keratoderma (PPKP1; Buschke-Fischer-Brauer) is a rare autosomal dominant inherited skin disease characterized by multiple hyperkeratotic papules involving the palms and soles. Mutations have been found at 2 loci, on chromosomes 15q22-15q24 and 8q24.13-8q24.21. We recently identified mutations in 3 families, in the AAGAB gene on 15q, which encodes the alpha- and gamma-adaptin-binding protein p34. The current study examined 14 additional families, comprising a total of 26 affected individuals and identified 8 novel mutations in 9 families. In one family a mutation that was present only in the affected individuals was found, and in 4 other families, previously reported mutations were found (1, 2). These results confirm the role of AAGAB in PPKP1. Our findings suggest that there is no correlation with age, but with mechanical factors. No additional obvious genotype-phenotype correlation was observed, even when comparing different types of mutations. Rather, identical genotypes presented a very broad interfamilial and intrafamilial variability of phenotypes. PMID- 26608364 TI - Bone marrow-derived mesenchymal stem cells (JR-031) for steroid-refractory grade III or IV acute graft-versus-host disease: a phase II/III study. AB - Following a phase I/II study using mesenchymal stem cells (MSCs; JR-031) for steroid-refractory grade II or III acute graft-versus-host disease (aGVHD), a phase II/III study using the cells focused on steroid-refractory grade III or IV aGVHD was conducted. The number of infused MSCs and the number of MSC infusions were the same as the phase I/II study. No additional immunosuppressant was given for steroid-refractory aGVHD during the course of MSC infusions. Twenty-five patients (grade III, 22 patients and grade IV, 3 patients) were enrolled in this study. At 4 weeks after the first MSC infusions, six (24 %) and nine patients (36 %) achieved a complete response (CR) and partial response (PR), respectively. Durable CR by 24 weeks, which was the primary end-point, was obtained in 12 of 25 patients (48 %). At 52 weeks, 12 patients (48 %) treated with MSCs only (six patients) and MSCs plus additional treatments (six patients) were alive in CR. The survival was significantly better in patients showing overall response (OR; CR+PR) than in those showing no OR at 4 weeks. Adverse effects commonly associated with MSC infusions were not observed. Taken together, our two clinical trials suggest JR-031 to be effective for steroid-refractory aGVHD. PMID- 26608365 TI - Proposal of criteria for dyserythropoiesis in the diagnosis of myelodysplastic syndromes. AB - The percentage manifesting dysplasia in bone marrow needed to qualify as significant is >=10 % in each lineage. However, detailed analyses of this threshold have not been reported. Here, we analyzed dyserythropoiesis (dysE) in 109 myelodysplastic syndromes (MDS) patients with 21 immune thrombocytopenia (ITP)/12 hemolytic anemia (HA) patients as a control. In present study, mild megaloblastic erythroblasts were specifically named 'red cell with abnormal chromatin clumping (RCACC)'. RCACC >=10 % in erythroblasts was observed in 29 % of ITP patients and 58 % of HA patients. The numbers of MDS patients with RCACC in erythroblasts <10, 10-19 and >=20 % were 1, 3, and 105, respectively. We analyzed dysE criteria according to the WHO classification (original WHO dysE). Most of our MDS patients (98 %) had original WHO dysE >=20 %. The ITP patients with original WHO dysE >=10 % was 48 %, and there were no ITP patients had original WHO dysE >=20 %. Sixty-seven percent of HA patients had original WHO dysE >=10 %, and three patients (25 %) had original WHO dysE >=20 %. Raising the threshold of the original WHO dysE from 10 to 20 or 30 % may provide more suitable criteria. If RCACC is not included in dysE criteria, we think that '10 %' is a suitable threshold for the determination of dyserythropoiesis. PMID- 26608366 TI - ALDH2 polymorphism in patients with Diamond-Blackfan anemia in Japan. PMID- 26608367 TI - Regulatory effects of DeltaFosB on proliferation and apoptosis of MCF-7 breast cancer cells. AB - Matrix metalloproteinase-9 (MMP-9) plays a vital role in tumor angiogenesis, cell migration, and invasiveness because it can degrade almost all basement membrane and extracellular matrix components. MMP-9 has been reported in many cancers including breast cancer, lung cancer, and colon cancer. DeltaFosB in mammary epithelial cells has been shown to regulate cell proliferation, differentiation, and death. We found that DeltaFosB increased the expression of MMP-9 in MCF-7 breast cancer cells. DeltaFosB overexpression in MCF-7 cells increased cellular viability and decreased cell apoptosis. SB-3CT, an inhibitor of MMP-9, promoted apoptosis, inhibited cell proliferation, induced cell cycle arrest, and downregulated the expression of antiapoptotic genes Bcl-2 and Bcl-xl in MCF-7 cells. DeltaFosB increased the number of MCF-7 cells in G2/M and S phases, upregulated the expression of Bcl-2 and Bcl-xl, and protected MCF-7 cells from apoptosis induced by MMP-9 inhibition. We also found that DeltaFosB overexpression in MCF-7 cells inhibited Ca(2+)-induced apoptosis and promoted cell proliferation. Therefore, DeltaFosB may be a potential target in breast cancer cell apoptosis by regulating the expression of MMP-9. PMID- 26608368 TI - Influence of the interaction between long noncoding RNAs and hypoxia on tumorigenesis. AB - The interaction between cancer and its microenvironment is crucial for survival and development of cancerous cells. Tumor microenvironment is usually under hypoxia, which promotes tumor aggressiveness like growth, angiogenesis, and metastasis. How cancer cells respond to hypoxia and the resultant impact on tumorigenesis are not yet fully explored. Long noncoding RNAs (lncRNAs) have been attracting more and more attention since their functions in regulating gene expression at chromatic, transcriptional, and posttranscriptional levels were found. lncRNAs are dysregulated in cancer and act as oncogenes or tumor suppressors. Moreover, emerging evidence has been provided that the expression of lncRNAs changes with the stimulus of hypoxia and they in turn produce a significant influence on the hypoxia-inducible factor (HIF), the most common transcription regulator in response to hypoxia. In this review, we discuss the recent findings of hypoxia-responsive lncRNAs and summarize their interaction with hypoxia to further understand their roles in cancer growth, metabolism, angiogenesis, and metastasis and their potential for cancer diagnosis and treatment. PMID- 26608369 TI - Norcantharidin modulates miR-655-regulated SENP6 protein translation to suppresses invasion of glioblastoma cells. AB - Norcantharidin (NCTD) is currently used as an anticancer drug for the treatment of some malignant cancers. However, whether it may have therapeutic effects on glioblastoma multiforme (GBM) remains unknown. Moreover, the underlying mechanisms have not been completely elucidated. Recently, SUMO-specific protease 6 (SENP6) has been shown as a tumor suppressor in some cancers. Nevertheless, whether it is involved in the pathogenesis of GBM has not been examined. Here, we studied the effects of NCTD on GBM cells. We found that NCTD dose-dependently increased SENP6 protein, but not messenger RNA (mRNA), in GBM cells, resulting in the suppression of cell invasion. Depletion of SENP6 in GBM cells significantly attenuated the NCTD-induced suppression of GBM cell invasion, while overexpression of SENP6 in GBM cells mimicked the effects of NCTD on cell invasion. Moreover, NCTD dose-dependently decreased the levels of microRNA-655 (miR-655), which bound to 3'-UTR of SENP6 mRNA to inhibit its translation. Overexpression of miR-655 decreased SENP6 in GBM cells, while depletion of miR 655 increased SENP6 protein in GBM cells. Taken together, our data demonstrates a previously unappreciated control of NCTD to suppress GBM cell invasion through modulation of miR-655-regulated SENP6 protein translation. PMID- 26608370 TI - MPT0B169, a novel tubulin inhibitor, induces apoptosis in taxol-resistant acute myeloid leukemia cells through mitochondrial dysfunction and Mcl-1 downregulation. AB - Acute myeloid leukemia (AML) is a hematological malignant disorder. AML cells are not susceptible to chemotherapeutic drugs because of their multidrug resistance (MDR). Antitubulin agents are currently employed in cancer treatments; however, drug resistance results in treatment failures because of MDR1 expressing cancer cells. We previously synthesized a new tubulin inhibitor, 2-dimethylamino-N-[1-(4 methoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-acetamide (MPT0B169), which inhibits AML cell proliferation by arresting cell cycle at the G2/M phase. In this study, we explored the effect of MPT0B169 on apoptosis in AML HL60 and NB4 cells and MDR1-mediated taxol-resistant HL60/TaxR cells and the underlying mechanism. MPT0B169 induced concentration- and time-dependent apoptosis in these cancer cells, as observed through annexin V/propidium iodide double staining and flow cytometry. Furthermore, DNA fragmentation analysis confirmed MPT0B169 induced apoptosis. MPT0B169 induced a loss of mitochondrial membrane potential, release of cytochrome c into the cytosol, cleavage and activation of caspase-9 and caspase-3, and consequently cleavage of poly (ADP ribose) polymerase. Western blot analysis showed that MPT0B169 markedly reduced Mcl-1 (an antiapoptotic protein) levels; however, it caused no changes in Bcl-2 or BAX (a proapoptotic protein). Knockdown of Mcl-1 using small interfering RNA (siRNA) slightly induced growth inhibition and apoptosis in the HL60 and HL60/TaxR cells. Further investigation revealed that Mcl-1 siRNA enhanced the sensitivity of HL60 and HL60/TaxR cells to MPT0B169-induced growth inhibition and apoptosis. Together, these results demonstrated that MPT0B169-induced apoptosis in nonresistant and MDR1-mediated taxol-resistant AML cells through Mcl-1 downregulation and a mitochondria-mediated pathway. MPT0B169 can overcome MDR1-mediated drug resistance in AML cells. PMID- 26608371 TI - CD24 promotes HCC progression via triggering Notch-related EMT and modulation of tumor microenvironment. AB - CD24 is known as a cell surface molecule in hematopoiesis and also described as a diagnostic marker for tumors. Previous studies suggested the important role of CD24 in hepatocellular carcinoma (HCC) pathogenesis. However, precise functions of CD24 in HCC are still unknown. Here, we found that CD24 is highly expressed in HCC both in mRNA and protein levels. Further, the epithelial-mesenchymal transition (EMT) and Notch1 signaling activations mediated by CD24 were elucidated as potential mechanisms of HCC promotion in Hepa1-6/Hepa1-6-CD24 cell models. Additionally, possible systemic immune reaction was explored through immune cells and Hepa1-6/Hepa1-6-CD24 cell co-culture. We demonstrated that the EMT process of HCC cell was effectively induced by CD24; also, the tumor immune microenvironment was changed by facilitating Notch-related EMT in vivo. These results reveal the underlying link between the HCC processes mediated by CD24. Moreover, as a clear tumor promoter, CD24 is considered a potential new target for HCC treatment. PMID- 26608372 TI - Wnt5a and Ror2 expression associate with the disease progress of primary thyroid lymphoma. AB - Primary thyroid lymphoma (PTL) is a rare malignant thyroid tumor; its pathogenesis is closely related to chronic lymphocytic thyroiditis. The different pathological subtypes and stages of PTL have distinct clinical characteristics and prognosis, but the specific reasons are not clear. Wnt5a is a representative protein of non-canonical Wnt signaling. It plays an important role in many different types of tumors. This study is to explore the changes of Wnt5a and its receptor Ror2 in PTL development process and the clinical significance of their represent. We collected 22 PTL patient tumor specimens and clinical data. We observed the expression of Wnt5a and Ror2 in PTL tumor tissues by immunohistochemistry. Wnt5a was expressed positively in 12 (54.5 %) cases, and Ror2 was expressed positively in 18 (81.8 %) cases. The expression of Wnt5a had a significant difference in different pathological subtypes of PTL (P < 0.05). Wnt5a and Ror2 expression were associated with local invasion and clinical stage, respectively (P < 0.05), and had no significant correlation with age, gender, and tumor size. Although, no significant difference in overall survival was found between positive and negative groups of Wnt5a (P = 0.416) or Ror2 (P = 0.256), respectively. We still consider that Wnt5a and Ror2 play a complex and subtle role in the pathogenesis and progression of PTL and may become potential biomarkers and therapeutic targets of PTL. PMID- 26608373 TI - The involvement of anterior gradient 2 in the stromal cell-derived factor 1 induced epithelial-mesenchymal transition of glioblastoma. AB - In recent years, it has been widely identified that the stromal cell-derived factor 1 (SDF-1) and anterior gradient 2 (AGR2) were implicated in the development of epithelial-mesenchymal transition (EMT) in a variety of cancers. However, the involvement of SDF-1-AGR2 pathway in the EMT of glioblastoma has not been investigated. In the present study, the in vitro assays were used to investigate the role of AGR2 in cell cycle, migration, and invasion. We found that the expressions of AGR2 and chemokine (C-X-C motif) receptor 4 (CXCR4) were obviously upregulated in glioblastoma cells T98G, A172, U87, and U251 than those in normal human astrocytes (NHA) (all p < 0.01), among which both U87 and U251 cells presented the highest expression (p > 0.05). Western blot revealed that SDF 1 induced the expression of p-AKT, AGR2, and EMT markers (N-cadherin, matrix metalloproteinase-2 (MMP2), and Slug) in a dose-dependent manner in U87 and U251 cells. However, the depletion of AGR2 reversed SDF-1-induced upregulation of EMT markers rather than p-AKT. Furthermore, functional analysis identified that knockdown of AGR2 induced cell cycle arrest in G0/G1 phase and suppressed the migration and invasion of U87 and U251 cells. Taken together, SDF-1-CXCR4 pathway induced the expression of AGR2 to control the progression of EMT likely via AKT pathway in the development of glioblastoma. Our findings lay a promising foundation for the SDF-1-AGR2 axis-targeting therapy in patients with glioblastoma. PMID- 26608374 TI - State of Stress-Marker Organs in Rats with Various Behavioral Characteristics during Repeated Stress Exposures. AB - Changes in the relative weight of stress-marker organs in rats with various behavioral patterns in the open-field test were studied after repeated stress exposures on the model of daily 4-h immobilization over 8 days. Involution of the thymus and spleen in behaviorally passive specimens was found after single stress, as well as under conditions of 3- and 8-fold immobilizations. The weight of these organs in active animals remained practically unchanged after acute stress, but decreased on day 3 and particularly on day 8 of repeated stress exposures. As differentiated from passive rats (open-field test), behaviorally active specimens were characterized by hypertrophy of the adrenal glands after single and 3-fold stress procedures. Our results complement the data on individual features of the peripheral and central mechanisms for the stress response in mammals. These data illustrate the importance of individual approach to studying systemic organization of physiological functions under normal conditions and during negative emotiogenic exposures. PMID- 26608375 TI - Role of JNK and Involvement of p53 in Stimulation of Growth Potential Realization of Mesenchymal Precursor Cells by Alkaloid Songorine. AB - The role of JNK-mediated signal pathway and participation of p53 transcription factor in stimulation of realization of the growth potential of the mesenchymal precursor cells by alkaloid songorine were examined in vitro. Specific inhibitors of JNK and p53 enhanced stimulation of fibroblast colony/cluster formation and proliferative activity of mesenchymal precursor cells. Under these conditions, more pronounced effects were observed with early precursors of fibroblast CFU and in both cases were accompanied by a decrease in differentiation index of progenitor elements. PMID- 26608376 TI - Effect of Combined Stress on Morphological Changes and Expression of NO Synthases in Rat Ventral Hippocampus. AB - Adult rats were subjected to 7-day combined stress with stochastic changes of stressors of different modalities (noise, vibration, pulsating bright light) along with mobility restriction and elevated temperature in the chamber during stress exposures (daily 30-min sessions). Circulatory disorders, inhibition of endothelial NO-synthase expression in endothelial cells of the microcirculatory bed, perivascular edema, pronounced degenerative changes, and enhanced expression of inducible NO synthase in CA3 pyramidal neurons in the ventral hippocampus of stressed 12-month-old rats were observed. These findings can attest to the involvement NOdependent mechanisms and different contribution of NO synthase isoforms into the formation of hippocampal neuronal damage. PMID- 26608377 TI - Biocompatibility and Structural Features of Biodegradable Polymer Scaffolds. AB - We performed a comparative analysis of physicochemical properties and biocompatibility of scaffolds of different composition on the basis of biodegradable polymers fabricated by casting and electrospinning methods. For production of polyhydroxyalkanoate-based scaffolds by electrospinning method, the optimal concentration of the polymer was 8-10%. Fiber diameter and properties of the scaffold produced by electrospinning method depended on polymer composition. Addition of polycaprolactone increased elasticity of the scaffolds. Bio- and hemocompatibility of the scaffolds largely depended on the composition formulation and method of scaffold fabrication. Polylactide introduced into the composition of polyhydroxybutyrate-oxyvalerate scaffolds accelerated degradation and increased adhesive properties of the scaffolds. PMID- 26608378 TI - The Use of Release-Active Antibody-Based Preparations for Vertigo Prevention in Adults. AB - The effectiveness of antibody-based release-active preparations Impaza (antibodies to eNOS), Tenoten (antibodies to brain-specific protein S-100), Dietressa (antibodies to type 1 cannabinoid receptor), Brizantin (combined preparation, antibodies to brain-specific protein S-100 and type 1 cannabinoid receptor), and Divaza (combined preparation, antibodies to brain-specific protein S-100 and eNOS) in the prevention of vertigo was studied on the model of intermittent accumulation of Coriolis accelerations (ICCA). Modification of activity of vestibular receptors and signal systems by release-active preparations contributed to an increase in ICCA tolerance time. Combined preparation Impaza possessed the most significant antinaupathic properties. Brizantin was less potent in this respect. PMID- 26608379 TI - Cellular Composition of the Spleen and Changes in Splenic Lysosomes in the Dynamics of Dyslipidemia in Mice Caused by Repeated Administration of Poloxamer 407. AB - We studied the effect of dyslipidemia induced by poloxamer 407 (300 mg/kg twice a week for 30 days) on cellular composition of the spleen and splenocyte lysosomes in mice. Changes in blood lipid profile included elevated concentrations of total cholesterol, aterogenic LDL, and triglycerides most pronounced in 24 h after the last poloxamer 407 injection; gradual normalization of lipid profile was observed in 4 days (except triglycerides) and 10 days. The most pronounced changes in the spleen (increase in organ weight and number of cells, inhibition in apoptosis, and reduced accumulation of vital dye acridine orange in lysosomes) were detected on day 4; on day 10, the indices returned to normal. Cathepsin D activity in the spleen also increased at these terms. The relationship between changes in the cellular composition of the spleen and dynamics of serum lipid profile in mice in dyslipidemia caused by repeated administrations of relatively low doses of poloxamer 407 is discussed. PMID- 26608380 TI - Detection and screening of chromosomal rearrangements in uterine leiomyomas by long-distance inverse PCR. AB - Genome instability is a hallmark of many tumors and recently, next-generation sequencing methods have enabled analyses of tumor genomes at an unprecedented level. Studying rearrangement-prone chromosomal regions (putative "breakpoint hotspots") in detail, however, necessitates molecular assays that can detect de novo DNA fusions arising from these hotspots. Here we demonstrate the utility of a long-distance inverse PCR-based method for the detection and screening of de novo DNA rearrangements in uterine leiomyomas, one of the most common types of human neoplasm. This assay allows in principle any genomic region suspected of instability to be queried for DNA rearrangements originating there. No prior knowledge of the identity of the fusion partner chromosome is needed. We used this method to screen uterine leiomyomas for rearrangements at genomic locations known to be rearrangement-prone in this tumor type: upstream HMGA2 and within RAD51B. We identified a novel DNA rearrangement upstream of HMGA2 that had gone undetected in an earlier whole-genome sequencing study. In more than 30 additional uterine leiomyoma samples, not analyzed by whole-genome sequencing previously, no rearrangements were observed within the 1,107 bp and 1,996 bp assayed in the RAD51B and HMGA2 rearrangement hotspots. Our findings show that long-distance inverse PCR is a robust, sensitive, and cost-effective method for the detection and screening of DNA rearrangements from solid tumors that should be useful for many diagnostic applications. PMID- 26608381 TI - Serological Investigation into Paracoccidioides brasiliensis Infection in Dogs from Southern Rio Grande do Sul, Brazil. AB - Paracoccidioides brasiliensis is a dimorphic fungus and major cause of paracoccidioidomycosis (PCM), which is a systemic and endemic mycosis in Brazil. In Southern Brazil, an increased number of cases were detected since the 1990 s. Therefore, in order to determine areas with the presence of the fungus, this study aimed to investigate infection by P. brasiliensis in dogs from Southern Brazil. Indirect ELISA was used to detect antibodies against P. brasiliensis gp43. One hundred and ninety-six stray and semi-domiciled dogs from the municipalities of Pelotas and Capao do Leao, Rio Grande do Sul were included in this study. P. brasiliensis infection was detected in 58 animals (29.6%) with no significant difference for gender, age and breed. Seropositive animals were detected in all neighborhoods in the city of Pelotas as well as in the neighboring municipality Capao do Leao. The detection of antibodies against gp43 in dogs suggests the presence and wide distribution of the fungus in Pelotas and Capao do Leao, warning for the possibility of PCM disease in dogs as well as in humans from this region. PMID- 26608383 TI - Senior Smiles: preliminary results for a new model of oral health care utilizing the dental hygienist in residential aged care facilities. AB - OBJECTIVES: The aim of this study was to determine whether a qualified dental hygienist could improve oral health outcomes for residents living in residential aged care facilities on the Central Coast of New South Wales, Australia. METHODS: A qualified dental hygienist undertook a 24-week oral hygiene intervention in five residential aged care facilities to test the Senior Smiles, oral health model of care. The facilities were invited to take part in the research, which was funded by a grant from NSW Medicare Local, Erina. Residents were asked to consent to having oral health risk assessments, oral healthcare plans and to receiving referrals for treatment where needed. Pre- and post-intervention plaque scores were recorded for residents and P values calculated using a paired t-test. In addition, the number of residents examined, treated and referred for more complex dental care was recorded. RESULTS: The statistical analysis program, SPSS, was used to conduct a paired t-test to compare pre- and post-intervention plaque scores on residents from the 5 RACFs. A statistically significant result of P < 0.0001 showed the intervention of the dental hygienist was effective in reducing plaque scores in residents across the 5 RACFs. CONCLUSION: The Senior Smiles model of care provided residents with preventive oral hygiene care, referral pathways for complex dental treatment needs and established a formal management programme for ongoing oral health care within the RACFs. The Senior Smiles model of care is successful and transportable. PMID- 26608382 TI - Impact of UGT2B17 Gene Deletion on the Pharmacokinetics of 17-Hydroexemestane in Healthy Volunteers. AB - Exemestane is an aromatase inhibitor drug used for the treatment of hormone dependent breast cancer. 17-Hydroexemestane, the major and biologically active metabolite of exemestane in humans, is eliminated via glucuronidation by the polymorphic UGT2B17 phase II drug-metabolizing enzyme. Previous microsomal studies have shown that UGT2B17 gene deletion affects the intrinsic hepatic clearances of 17-hydroexemestane in vitro. In this open-label study we set out to assess the effect of UGT2B17 gene deletion on the pharmacokinetics of 17 hydroexemestane in healthy female volunteers with and without UGT2B17. To achieve this goal, 14 healthy postmenopausal women (8 carriers of the homozygous UGT2B17 wild-type allele and 6 carriers of the homozygous UGT2B17 gene-deletion allele) were enrolled and invited to receive a single 25-mg oral dose of exemestane. Pharmacokinetics was assessed over 72 hours postdosing. Our results showed that there were statistically significant differences in plasma 17-hydroexemestane AUC0-infinity (P = .0007) and urine 17-hydroexemestane C24h (P = .001) between UGT2B17 genotype groups. Our data suggest that UGT2B17 gene deletion influences 17-hydroexemestane pharmacokinetics in humans. PMID- 26608384 TI - Ventricular Neuroendoscopic Surgery: Lessons Learned from the Literature. PMID- 26608385 TI - How to Be a Neurosurgeon with Good Hands. PMID- 26608386 TI - Dural Tuberculoma Mimicking Meningioma: A Clinicoradiologic Review of Dural En Plaque Lesions. AB - BACKGROUND: Tuberculosis has long been a major health concern in developing countries and now has troubled developed world as well, owing to increase in patients with human immunodeficiency virus and immigration. Central nervous system tuberculosis accounts for approximately 1% of cases of tuberculosis. The pathologic presentation is varied, with intraparenchymal tuberculomas and pachymeningitis being the most common. Being a great mimicker, it simulates numerous diseases radiologically, and this is best realized when atypical forms are encountered. Here an atypical case of dural en-plaque tuberculoma is presented with comprehensive review of dural en-plaque lesions with their differentiating features. CASE REPORT: A 20-year-old man presented with features of increased intracranial pressure. On imaging, there was an enhancing dural based lesion in the left frontoparietal region. In view of herniation syndrome, urgent surgical decompression of the lesion was performed. Histopathology showed features of tuberculosis. The patient is now asymptomatic with antitubercular therapy without any residual lesion at 6 months of follow-up. CONCLUSIONS: Tuberculoma en-plaque is an unusual entity characterized by a plaque-like meningitic process without exudation. It is easily confused with meningiomas as can other dural-based lesions comprising benign to malignant neoplastic, infectious, and granulomatous lesions. A preoperative diagnosis is imperative to differentiate it at least from neoplastic lesions, which are usually curable with surgical intervention in contrast to tuberculosis, which needs only optimal chemotherapy in most of the cases. Knowledge of differentiating imaging features, in corroboration with clinical history and high index of suspicion, helps in a proper preoperative diagnosis and optimal patient treatment. PMID- 26608387 TI - Perspective on Ionizing Radiation Exposure to Neurosurgery Residents in the Modern Era. PMID- 26608388 TI - The attitudes of student nurses towards obese patients: A questionnaire study exploring the association between perceived causal factors and advice giving. AB - BACKGROUND: Nurses acting in primary care roles are central in addressing obesity as a public health priority. Nurses with a lower Body Mass Index have been shown to have negative attitudes towards obesity. Additionally, where the patient is perceived as being responsible for their excess weight, a negative attitude may also be held. The extent to which negative attitudes may influence the advice provided by nurses to obese patients is unknown. OBJECTIVES: The present paper sought to examine whether the level of advice offered to obese patients by student nurses is associated with (i) the perceived causal factors of obesity, (ii) attitudes towards obesity and (iii) body mass index of the nurse. METHOD: Participants were 92 student nurses from a university in the Midlands, UK. Participants received one of four patient vignettes; three were affected by obesity, with reference to either a behavioural, social, or medical cause; and the fourth was normal weight. Student nurses elected advice they would offer from five staged options (from no active involvement in advising the patient, through to discussing dietary advice). Attitudes towards obesity and social desirability were measured using validated questionnaires. RESULTS: No association was found between the level of advice offered and either the causal factor of obesity, the student nurses' attitude towards obesity, or the nurses' Body Mass Index. Most students endorsed the highest level of advice-a patient centred discussion. CONCLUSION: Findings show that advice giving by student nurses was not associated with perceived cause of obesity, or attitude, but is in line with the current Nursing and Midwifery Council (2015) recommendations. That is, most students endorsed a patient centred discussion. This suggests that professional training guidelines for the non-judgemental treatment of obese patients are not only being recognised, but implemented. PMID- 26608389 TI - Using Simulation for Clinical Practice Hours in Nurse Practitioner Education in The United States: A Systematic Review. AB - OBJECTIVES: The National Organization for Nurse Practitioner Faculty (NONPF) does not allow simulation to be used in lieu of traditional clinical hours. The NONPF cites a lack of empirical evidence related to learning outcomes with simulation as rationale for its stance. The purpose of this systematic review was to search, extract, appraise, and synthesize research related to the use of simulation in Nurse Practitioner (NP) education in order to answer the two following questions: 1) What research related to simulation in NP education has emerged in the literature between 2010 and April 2015?, and 2) Of the research studies that have emerged, what level of Kirkpatrick's Training Evaluation Model (1994) is evaluated? DESIGN: This review was reported in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). DATA SOURCES: A literature search was completed in PubMed and CINAHL using a combination of medical subject headings, or Mesh terms, as well as keywords to retrieve non indexed citations. REVIEW METHODS: The inclusion criteria for this review were broad in order to disseminate information on future research needed. The review considered studies related to NP education that included any form of simulation intervention, e.g. role-playing and standardized patients. The review considered studies that described original research, but no other design restrictions were imposed. The review was limited to studies published in the English language. RESULTS: The database search strategy yielded 198 citations. These results were narrowed down to 15 studies based on identified inclusion criteria. CONCLUSIONS: There is a lack of empirical evidence in the literature to support using simulation in lieu of direct patient care clinical hours in NP education. The evidence in this systematic review affirms NONPF's statement. Five years after the inception of NONPF's position statement, research to support learning outcomes with simulation in nurse practitioner education remains lacking. There is a need to produce rigorous scientific studies in the future in order to provide quantitative support to allow simulation to be counted as clinical hours in NP programs. PMID- 26608391 TI - A Highly Diverse Portrait: Heterogeneity of Neuropsychological Profiles in cblC Defect. AB - Cobalamin C is a rare inborn disorder of metabolism that results in multisystemic abnormalities, including progressive visual deficits. Although the cellular pathophysiology of cblC is a field of active study, little attention has been dedicated to documenting the cognitive consequences of the defect. The neuropsychological assessment of nine individuals aged between 23 months and 24 years was conducted to establish cognitive profiles. Results reveal a marked heterogeneity, with intellectual functioning ranging from extremely low to average, and cognitive difficulties (e.g., attention) evidenced even in those who are not intellectually disabled. Central nervous system abnormalities and multisystem disease are likely to be major contributing factors to the observed cognitive impairments, with the presence of visual deficits constituting an additional impediment to normal cognitive development. This study underscores the importance of conducting in-depth neuropsychological assessments in individuals with cblC, the results of which may be particularly helpful for clinical management, guidance toward rehabilitation services, and educational/vocational planning. PMID- 26608392 TI - Heterozygous Monocarboxylate Transporter 1 (MCT1, SLC16A1) Deficiency as a Cause of Recurrent Ketoacidosis. AB - We describe two half-siblings with monocarboxylate transporter 1 (MCT1, SLC16A1) deficiency, a defect on ketone body utilization, that has only recently been identified (van Hasselt et al., N Engl J Med, 371:1900-1907, 2014) as a cause for recurrent ketoacidoses. Our index patient is a boy with non-consanguineous parents who had presented acutely with impaired consciousness and severe metabolic ketoacidosis following a 3-day history of gastroenteritis at age 5 years. A 12.5-year-old half-brother who shared the proband's mother also had a previous history of recurrent ketoacidoses. Results of mutation and enzyme activity analyses in proband samples advocated against methylacetoacetyl-coenzyme A thiolase ("beta-ketothiolase") and succinyl-coenzyme A: 3-oxoacyl coenzyme A transferase (SCOT) deficiencies. A single heterozygous c.982C>T transition in the SLC16A1 gene resulting in a stop mutation (p.Arg328Ter) was detected in both boys. It was shared by their healthy mother and by the proband's half-sister, but was absent in the proband's father. MCT1 deficiency may be more prevalent than is apparent, as clinical manifestations can occur both in individuals with bi- and monoallelic mutations. It may be an important differential diagnosis in recurrent ketoacidosis with or without hypoglycemia, particularly in the absence of any specific metabolic profiles in blood and urine. Early diagnosis may enable improved disease management. Careful identification of potential triggers of metabolic decompensations in individuals even with single heterozygous mutations in the SLC16A1 gene is indicated. PMID- 26608390 TI - Physiologically generated presenilin 1 lacking exon 8 fails to rescue brain PS1-/ phenotype and forms complexes with wildtype PS1 and nicastrin. AB - The presenilin 1 (PSEN1) L271V mutation causes early-onset familial Alzheimer's disease by disrupting the alternative splicing of the PSEN1 gene, producing some transcripts harboring the L271V point mutation and other transcripts lacking exon 8 (PS1(?exon8)). We previously reported that PS1 L271V increased amyloid beta (Abeta) 42/40 ratios, while PS1(?exon8) reduced Abeta42/40 ratios, indicating that the former and not the exon 8 deletion transcript is amyloidogenic. Also, PS1(?exon8) did not rescue Abeta generation in PS1/2 double knockout cells indicating its identity as a severe loss-of-function splice form. PS1(?exon8) is generated physiologically raising the possibility that we had identified the first physiological inactive PS1 isoform. We studied PS1(?exon8) in vivo by crossing PS1(?exon8) transgenics with either PS1-null or Dutch APP(E693Q) mice. As a control, we crossed APP(E693Q) with mice expressing a deletion in an adjacent exon (PS1(?exon9)). PS1(?exon8) did not rescue embryonic lethality or Notch-deficient phenotypes of PS1-null mice displaying severe loss of function in vivo. We also demonstrate that this splice form can interact with wildtype PS1 using cultured cells and co-immunoprecipitation (co-IP)/bimolecular fluorescence complementation. Further co-IP demonstrates that PS1(?exon8) interacts with nicastrin, participating in the gamma-secretase complex formation. These data support that catalytically inactive PS1(?exon8) is generated physiologically and participates in protein-protein interactions. PMID- 26608393 TI - Renal Involvement in a French Paediatric Cohort of Patients with Lysinuric Protein Intolerance. AB - Lysinuric protein intolerance (LPI) is a rare autosomal recessive metabolic disorder, caused by defective transport of cationic amino acids at the basolateral membrane of epithelial cells, typically in intestines and kidneys. The SLC7A7 gene, mutated in LPI patients, encodes the light subunit (y+LAT1) of a member of the heterodimeric amino acid transporter family.The diagnosis of LPI is difficult due to unspecific clinical features: protein intolerance, failure to thrive and vomiting after weaning. Later on, patients may present delayed growth osteoporosis, hepatosplenomegaly, muscle hypotonia and life-threatening complications such as alveolar proteinosis, haemophagocytic lymphohistiocytosis and macrophage activation syndrome. Renal involvement is also a serious complication with tubular and more rarely, glomerular lesions that may lead to end-stage kidney disease (ESKD). We report six cases of LPI followed in three different French paediatric centres who presented LPI-related nephropathy during childhood. Four of them developed chronic kidney disease during follow-up, including one with ESKD. Five developed chronic tubulopathies and one a chronic glomerulonephritis. A histological pattern of membranoproliferative glomerulonephritis was first associated with a polyclonal immunoglobulin deposition, treated by immunosuppressive therapy. He then required a second kidney biopsy after a relapse of the nephrotic syndrome; the immunoglobulin deposition was then monoclonal (IgG1 kappa). This is the first observation of an evolution from a polyclonal to a monotypic immune glomerulonephritis. Immune dysfunction potentially attributable to nitric oxide overproduction secondary to arginine intracellular trapping is a debated complication in LPI. Our results suggest all LPI patients should be monitored for renal disease regularly. PMID- 26608395 TI - Is Australasia producing too many emergency physicians? No. PMID- 26608394 TI - The association of educational attainment, cognitive level of job, and leisure activities during the course of adulthood with cognitive performance in old age: the role of openness to experience. AB - BACKGROUND: The relevance of mental health for everyday life functioning and well being is crucial. In this context, higher educational attainment, higher cognitive level of one's occupation, and more engaging in stimulating leisure activities have been found to be associated with better cognitive functioning in old age. Yet, the detailed pattern of the potential interplay of such a cognitively engaged lifestyle with personality dimensions, such as openness to experience, in their relations to cognitive functioning remains unclear. METHODS: Two thousand eight hundred and twelve older adults served as sample for the present study. Psychometric tests on verbal abilities and processing speed were administered. In addition, individuals were retrospectively interviewed on their educational attainment, occupation, and regarding 18 leisure activities that had been carried out in mid-life. Moreover, openness to experience was assessed. RESULTS: We found that the effect of openness to experience on cognitive functioning was mediated by educational attainment, cognitive level of job, and engaging in different leisure activities. Data were not better described by alternative moderation models testing for interactive (i.e. dependent) effects of openness to experience and cognitively stimulating engagement. CONCLUSIONS: To explain interindividual differences in cognitive functioning in old age, present data are in line with a mechanism in which individuals with high openness to experience may have been more engaged in stimulating activities in early and mid life. Possibly by increasing their cognitive reserve throughout adulthood, this may finally enhance their cognitive performance level later in old age. PMID- 26608397 TI - Unraveling origins of the heterogeneous curvature dependence of polypeptide interactions with carbon nanostructures. AB - Emerging nanotechnology has rapidly broadened interfacial prospects of biological molecules with carbon nanomaterials (CNs). A prerequisite for effectively harnessing such hybrid materials is a multi-faceted understanding of their complex interfacial interactions as functions of the physico-chemical characteristics and the surface topography of the individual components. In this article, we address the origins of the curvature dependence of polypeptide adsorption on CN surfaces (CNSs), a phenomenon bearing an acute influence upon the behavior and activity of CN-protein conjugates. Our benchmark molecular dynamics (MD) simulations with the amphiphilic full-length amyloid beta (Abeta) peptide demonstrate that protein adsorption is strongest on the concave (inner) CN surface, weakest on the convex (outer) surface, and intermediary on the planar surface, in agreement with recent experimental reports. The curvature effects, however, are found to manifest non-uniformly between the amino acid subtypes. To understand the underlying interplay of the chemical nature of the amino acids and surface topography of the CNs, we performed high-level quantum chemical (QM) calculations with amino acid analogs (AAA) representing their five prominent classes, and convex, concave and planar CN fragments. Molecular electrostatic potential maps reveal pronounced curvature dependence in the mixing of electron densities, and a resulting variance in the stabilization of the non-covalently bound molecular complexes. Interestingly, our study revealed that the interaction trends of the high-level QM calculations were captured well by the empirical force field. The findings in this study have important bearing upon the design of carbon based bio-nanomaterials, and additionally, provide valuable insights into the accuracy of various computational techniques for probing non-bonded interfacial interactions. PMID- 26608398 TI - Thermodynamic controls of the Atlantic Nino. AB - Prevailing theories on the equatorial Atlantic Nino are based on the dynamical interaction between atmosphere and ocean. However, dynamical coupled ocean atmosphere models poorly simulate and predict equatorial Atlantic climate variability. Here we use multi-model numerical experiments to show that thermodynamic feedbacks excited by stochastic atmospheric perturbations can generate Atlantic Nino s.d. of ~0.28+/-0.07 K, explaining ~68+/-23% of the observed interannual variability. Thus, in state-of-the-art coupled models, Atlantic Nino variability strongly depends on the thermodynamic component (R(2)=0.92). Coupled dynamics acts to improve the characteristic Nino-like spatial structure but not necessarily the variance. Perturbations of the equatorial Atlantic trade winds (~+/-1.53 m s(-1)) can drive changes in surface latent heat flux (~+/-14.35 W m(-2)) and thus in surface temperature consistent with a first-order autoregressive process. By challenging the dynamical paradigm of equatorial Atlantic variability, our findings suggest that the current theories on its modelling and predictability must be revised. PMID- 26608399 TI - Light activated molecular machines and logic gates: general discussion. PMID- 26608396 TI - The mechano-gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in decerebrate rats. AB - KEY POINTS: Mechanical and metabolic stimuli from contracting muscles evoke reflex increases in blood pressure, heart rate and sympathetic nerve activity. Little is known, however, about the nature of the mechano-gated channels on the thin fibre muscle afferents that contribute to evoke this reflex, termed the exercise pressor reflex. We determined the effect of GsMTx4, an inhibitor of mechano-gated Piezo channels, on the exercise pressor reflex evoked by intermittent contraction of the triceps surae muscles in decerebrated, unanaesthetized rats. GsMTx4 reduced the pressor, cardioaccelerator and renal sympathetic nerve responses to intermittent contraction but did not reduce the pressor responses to femoral arterial injection of compounds that stimulate the metabolically-sensitive thin fibre muscle afferents. Expression levels of Piezo2 channels were greater than Piezo1 channels in rat dorsal root ganglia. Our findings suggest that mechanically-sensitive Piezo proteins contribute to the generation of the mechanical component of the exercise pressor reflex in rats. Mechanical and metabolic stimuli within contracting skeletal muscles evoke reflex autonomic and cardiovascular adjustments. In cats and rats, gadolinium has been used to investigate the role played by the mechanical component of this reflex, termed the exercise pressor reflex. Gadolinium, however, has poor selectivity for mechano-gated channels and exerts multiple off-target effects. We tested the hypothesis that GsMTX4, a more selective mechano-gated channel inhibitor than gadolinium and a particularly potent inhibitor of mechano-gated Piezo channels, reduced the exercise pressor reflex in decerebrate rats. Injection of 10 MUg of GsMTx4 into the arterial supply of the hindlimb reduced the peak pressor (control: 24 +/- 5, GsMTx4: 12 +/- 5 mmHg, P < 0.01), cardioaccelerator and renal sympathetic nerve responses to tendon stretch, a purely mechanical stimulus, but had no effect on the pressor responses to intra-arterial injection of alpha,beta methylene ATP or lactic acid. Moreover, injection of 10 MUg of GsMTx4 into the arterial supply of the hindlimb reduced the peak pressor (control: 24 +/- 2, GsMTx4: 14 +/- 3 mmHg, P < 0.01), cardioaccelerator and renal sympathetic nerve responses to electrically-induced intermittent hindlimb muscle contractions. By contrast, injection of 10 MUg of GsMTx4 into the jugular vein had no effect on the pressor, cardioaccelerator, or renal sympathetic nerve responses to contraction. Quantitative RT-PCR and western blot analyses indicated that both Piezo1 and Piezo2 channel isoforms were natively expressed in rat dorsal root ganglia tissue. We conclude that GsMTx4 reduced the exercise pressor reflex in decerebrate rats and that the reduction was attributable, at least in part, to its effect on mechano-gated Piezo channels. PMID- 26608400 TI - Prognostic value of indoleamine 2,3-dioxygenase activity and expression in nasopharyngeal carcinoma. AB - Indoleamine 2,3-dioxygenase (IDO) is an enzyme with an immunosuppressive effect whose function is diverted by tumor cells to counteract immune cell functions, inducing immune escape of tumor cells. The aim of this study was to investigate the clinical significance of IDO in nasopharyngeal carcinoma (NPC). Compared to controls, NPC patients' plasma IDO activity was significantly higher, especially among patients with metastatic cancer (p=0.005). The immunohistochemical analysis revealed that high IDO expression was observed in 74% of NPC tissues and the epithelial IDO expression was inversely correlated to T-cell infiltration. Kaplan Meier survival analysis showed that whatever the localization, intratumoral or stromal, patients with a high IDO expression and low T-cell infiltration have significantly lower survival rates. Moreover, in multivariate analysis, intratumoral and stromal IDO expression were found to be independent prognostic factors for disease-free survival (p=0.016; HR: 3.52) and overall survival (p=0.015; HR: 4.76) respectively. Our findings provide evidence that IDO is involved in tumor immune evasion of NPC, suggesting that it could be a relevant therapeutic target for NPC. PMID- 26608401 TI - Cytotoxic diterpenoids from Rabdosia lophanthoides var. gerardianus. AB - Two new abietane diterpenoids, Gerardianin B (1) and Gerardianin C (2), one new lignan glycoside, Gerardianin D (3) and one new lupane-type triterpenoid, Gerardianol A (4), together with seven known abietane diterpenoids were isolated from the aerial parts of Rabdosia lophanthoides var. gerardianus. Their structures were determined by 1D and 2D NMR spectroscopic data. The cytotoxic activities of the nine diterpenoids were evaluated on human cancer cell lines. Compounds 6-11 exhibited significant cytotoxic activities against HepG2 cell lines with IC50 from 4.68 to 9.43MUM and HCF-8 cell lines with IC50 from 9.12 to 13.53MUM. PMID- 26608402 TI - Child and adolescent internalizing and externalizing problems 12 months postburn: the potential role of preburn functioning, parental posttraumatic stress, and informant bias. AB - Adjustment after pediatric burn injury may be a challenge for children as well as their parents. This prospective study examined associations of internalizing and externalizing problems in children and adolescents 12 months postburn with preburn functioning, and parental acute and chronic posttraumatic stress symptoms (PTSS) from different perspectives. Child, mother, and father reports of 90 children (9-18 years), collected within the first month and 12 months postburn, were analyzed. Results indicated that overall, child and parental appraisals of pre- and postburn behavioral problems were not significantly different from reference data. Rates of (sub)clinical postburn behavioral problems ranged from 6 to 17 %, depending on the informant. Pre- and postburn behavioral problems were significantly related, but only from the parents' perspective. Path models showed an association between parental PTSS 12 months postburn and parental reports of child internalizing problems, as well as a significant indirect relationship from parental acute stress symptoms via PTSS 12 months postburn. Notably, no associations between parental PTSS and child reports of postburn behavioral problems were found. In conclusion, parental observations of child externalizing problems appear to be influenced by their perspectives on the child's preburn functioning, while parental observations of internalizing problems are also related to long-term parental PTSS. However, these factors seem of no great value in predicting behavioral problems from the child's perspective, suggesting substantial informant deviations. To optimize adjustment, clinical burn practice is recommended to adopt a family perspective including parent perception of preburn functioning and parental PTSS in assessment and intervention. PMID- 26608404 TI - Effect of Low-Magnitude, High-Frequency Vibration Treatment on Retardation of Sarcopenia: Senescence-Accelerated Mouse-P8 Model. AB - Sarcopenia-related falls and fall-related injuries in community-dwelling elderly people garnered more and more interest in recent years. Low-magnitude high frequency vibration (LMHFV) was proven beneficial to musculoskeletal system and recommended for sarcopenia treatment. This study aimed to evaluate the effects of LMHFV on the sarcopenic animals and explore the mechanism of the stimulatory effects. Senescence-accelerated mouse P8 (SAMP8) mice at month 6 were randomized into control (Ctrl) and vibration (Vib) groups and the mice in the Vib group were given LMHFV (0.3 g, 20 min/day, 5 days/week) treatment. At months 0, 1, 2, 3, and 4 post-treatment, muscle mass, structure, and function were assessed. The potential proliferation capacity of the muscle was also evaluated by investigating satellite cells (SCs) pool and serum myostatin expression. At late stage, the mice in the Vib group showed higher muscle strength (month 4, p = 0.028). Generally, contractibility was significantly improved by LMHFV (contraction time [CT], p = 0.000; half-relaxation time [RT50], p = 0.000). Enlarged cross-sectional area of fiber type IIA was observed in the Vib group when compared with Ctrl group (p = 0.000). No significant difference of muscle mass was observed. The promotive effect of LMHFV on myoregeneration was reflected by suppressed SC pool reduction (month 3, p = 0.000; month 4, p = 0.000) and low myostatin expression (p = 0.052). LMHFV significantly improved the structural and functional outcomes of the skeletal muscle, hence retarding the progress of sarcopenia in SAMP8. It would be a good recommendation for prevention of the diseases related to skeletal muscle atrophy. PMID- 26608403 TI - Variability in emotional/behavioral problems in boys with oppositional defiant disorder or conduct disorder: the role of arousal. AB - It is often reported that children with oppositional defiant disorder (ODD) or conduct disorder (CD) are under-aroused. However, the evidence is mixed, with some children with ODD/CD displaying high arousal. This has led to the hypothesis that different profiles of arousal dysfunction may exist within children with ODD/CD. This knowledge could explain variability within children with ODD/CD, both in terms of specific types of aggression as well as comorbid symptoms (e.g., other emotional/behavioral problems). We measured heart rate variability (HRV), heart rate (HR) and skin conductance level (SCL) during rest and stress, and obtained parent and teacher reports of aggression, anxiety, attention problems and autism traits in a sample of 66 ODD/CD and 36 non-clinical boys (aged 8-12 years). The ODD/CD group scored significantly higher on aggression, anxiety, attention problems and autism traits than the controls; boys with ODD/CD also had higher resting HRs than controls, but HR stress, HRV and SCL did not differ. Hierarchical regressions showed different physiological profiles in subgroups of boys with ODD/CD based on their type of aggression; a pattern of high baseline HR and SCL, but low stress HRV was related to reactive aggression, whereas the opposite physiological pattern (low HR, low stress SCL, high stress HRV) was related to proactive aggression. Furthermore, high stress SCL was related to anxiety symptoms, whereas low stress SCL was related to attention problems. These findings are important because they indicate heterogeneity within boys with ODD/CD and highlight the importance of using physiology to differentiate boys with different ODD/CD subtypes. PMID- 26608405 TI - Equivalence of binormal likelihood-ratio and bi-chi-squared ROC curve models. AB - A basic assumption for a meaningful diagnostic decision variable is that there is a monotone relationship between it and its likelihood ratio. This relationship, however, generally does not hold for a decision variable that results in a binormal receiver operating characteristic (ROC) curve. As a result, ROC curve estimation based on the assumption of a binormal ROC-curve model produces improper ROC curves, which have 'hooks', are not concave over the entire domain and cross the chance line. Although in practice this 'improperness' is usually not noticeable, sometimes it is evident and problematic. To avoid this problem, Metz and Pan proposed basing ROC-curve estimation on the assumption of a binormal likelihood-ratio (binormal-LR) model, which states that the decision variable is an increasing transformation of the likelihood-ratio function of a random variable having normal conditional diseased and nondiseased distributions. However, their development is not easy to follow. I show that the binormal-LR model is equivalent to a bi-chi-squared model in the sense that the families of corresponding ROC curves are the same. The bi-chi-squared formulation provides an easier-to-follow development of the binormal-LR ROC curve and its properties in terms of well-known distributions. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26608406 TI - The risk factors for fractures and trabecular bone-score value in patients with endogenous Cushing's syndrome. AB - In a cohort study of 182 consecutive patients with active endogenous Cushing's syndrome, the only predictor of fracture occurrence after adjustment for age, gender bone mineral density (BMD) and trabecular bone score (TBS) was 24-h urinary free cortisol (24hUFC) levels with a threshold of 1472 nmol/24 h (odds ratio, 3.00 (95% confidence interval (CI), 1.52-5.92); p = 0.002). INTRODUCTION: The aim was to estimate the risk factors for fracture in subjects with endogenous Cushing's syndrome (CS) and to evaluate the value of the TBS in these patients. METHODS: All enrolled patients with CS (n = 182) were interviewed in relation to low-traumatic fractures and underwent lateral X-ray imaging from T4 to L5. BMD measurements were performed using a DXA Prodigy device (GEHC Lunar, Madison, Wisconsin, USA). The TBS was derived retrospectively from existing BMD scans, blinded to clinical outcome, using TBS iNsight software v2.1 (Medimaps, Merignac, France). Urinary free cortisol (24hUFC) was measured by immunochemiluminescence assay (reference range, 60-413 nmol/24 h). RESULTS: Among enrolled patients with CS (149 females; 33 males; mean age, 37.8 years (95% confidence interval, 34.2 39.1); 24hUFC, 2370 nmol/24 h (2087-2632), fractures were confirmed in 81 (44.5%) patients, with 70 suffering from vertebral fractures, which were multiple in 53 cases; 24 patients reported non-vertebral fractures. The mean spine TBS was 1.207 (1.187-1.228), and TBS Z-score was -1.86 (-2.07 to -1.65); area under the curve (AUC) was used to predict fracture (mean spine TBS) = 0.548 (95% CI, 0.454 0.641)). In the final regression model, the only predictor of fracture occurrence was 24hUFC levels (p = 0.001), with an increase of 1.041 (95% CI, 1.019-1.063), calculated for every 100 nmol/24-h cortisol elevation (AUC (24hUFC) = 0.705 (95% CI, 0.629-0.782)). CONCLUSIONS: Young patients with CS have a low TBS. However, the only predictor of low traumatic fracture is the severity of the disease itself, indicated by high 24hUFC levels. PMID- 26608408 TI - Factors associated with polypharmacy and the prescription of multiple medications among persons living with HIV (PLWH) compared to non-PLWH. AB - Persons living with HIV (PLWH) may be at increased risk for polypharmacy (>=5 concomitant medications) over non-PLWH, presumably due to antiretroviral therapy (ARV). Potential concerns associated with polypharmacy include clinically significant drug-drug interactions, adverse drug reactions, increased pill burden, and rising treatment-related costs. Our objective was to evaluate prescription of multiple non-ARV medications to PLWH, compared to non-PLWH, in US outpatient clinics and to identify factors associated with polypharmacy. Cross sectional data from the 2006-2010 National Hospital Ambulatory Medical Care Survey were used for this study. Visits for PLWH were identified using HIV ICD9 CM codes 042, V08, and 079.53. Patients < 18 years of age were excluded. Relevant demographics included sex, age, race/ethnicity, and insurance status, while comorbid conditions included hypertension, diabetes, and hyperlipidemia. Multivariate logistic regression analyses evaluated factors independently associated with prescription of >= 5 medications. In total, 7,360,000 weighted visits for PLWH (13% aged 18-29 y; 55% aged 30-49 y; 32% aged >= 50 y) and 374,626,000 weighted visits for non-PLWH (18% aged 18-29 y; 32% aged 30-49 y; 50% aged >= 50 y) met study criteria. The greatest prevalence of hypertension, diabetes, and hyperlipidemia was in those >= 50 years of age (p < .001 for all comorbidities in PLWH and non-PLWH). In 2006, 16% of PLWH were prescribed >= 5 medications, doubling to 35% in 2010. In 2006, 24% of non-PLWH were prescribed >= 5 medications, only increasing to 32% in 2010. Older age (30-49 y and >= 50 y) was associated with >= 5 prescription medications in PLWH (adjusted odds ratio [aOR] = 2.538, 95% CI; 1.31-4.918 and aOR = 2.703, 95% CI; 1.678-4.354) and in non-PLWH (aOR = 2.546, 95% CI; 2.235-2.9 and aOR = 5.208, 95% CI; 4.486-6.047), respectively. Prescription of multiple medications is on the rise in PLWH, more so than in non-PLWH. Additional research is needed to explore how prescription of multiple medications differentially affects younger PLWH vs. older PLWH. PMID- 26608407 TI - Hippocampal-medial prefrontal circuit supports memory updating during learning and post-encoding rest. AB - Learning occurs in the context of existing memories. Encountering new information that relates to prior knowledge may trigger integration, whereby established memories are updated to incorporate new content. Here, we provide a critical test of recent theories suggesting hippocampal (HPC) and medial prefrontal (MPFC) involvement in integration, both during and immediately following encoding. Human participants with established memories for a set of initial (AB) associations underwent fMRI scanning during passive rest and encoding of new related (BC) and unrelated (XY) pairs. We show that HPC-MPFC functional coupling during learning was more predictive of trial-by-trial memory for associations related to prior knowledge relative to unrelated associations. Moreover, the degree to which HPC MPFC functional coupling was enhanced following overlapping encoding was related to memory integration behavior across participants. We observed a dissociation between anterior and posterior MPFC, with integration signatures during post encoding rest specifically in the posterior subregion. These results highlight the persistence of integration signatures into post-encoding periods, indicating continued processing of interrelated memories during rest. We also interrogated the coherence of white matter tracts to assess the hypothesis that integration behavior would be related to the integrity of the underlying anatomical pathways. Consistent with our predictions, more coherent HPC-MPFC white matter structure was associated with better performance across participants. This HPC-MPFC circuit also interacted with content-sensitive visual cortex during learning and rest, consistent with reinstatement of prior knowledge to enable updating. These results show that the HPC-MPFC circuit supports on- and offline integration of new content into memory. PMID- 26608410 TI - Hierarchical structures composed of MnCo2O4@MnO2 core-shell nanowire arrays with enhanced supercapacitor properties. AB - In this paper, hierarchical MnCo2O4@MnO2 core-shell nanowire arrays (MnCo2O4@MnO2 NWAs) with mesoporous and large surface area are synthesized on 3D nickel foam via a facile, two-step hydrothermal approach without any adscititious surfactant and binder. The electrode architecture takes advantage of the synergistic effects contributed from both the porous MnCo2O4 nanowire core and the MnO2 shell layer. The fabricated MnCo2O4@MnO2 NWA electrode for supercapacitors in aqueous electrolyte exhibits a significantly enhanced specific capacitance (858 F g(-1) at 1 A g(-1)), high energy density (36.0 Wh kg(-1) at 252 W kg(-1)) and long-life cycling stability (retaining 88% of the initial capacitance after 5000 cycles). Then, a symmetrical supercapacitor is fabricated by assembling two MnCo2O4@MnO2 NWA-based electrodes, which shows a high specific capacitance of 678 F g(-1) at 1 A g(-1) and a high energy density of 135.6 Wh kg(-1) at 513 W kg(-1). Thereby, the hierarchical core-shell MnCo2O4@MnO2 NWAs are very promising as next generation high-performance long-life cycling supercapacitors. PMID- 26608409 TI - Assessment of ovarian reserve in euthyroid adolescents with Hashimoto thyroiditis. AB - AIM: We aimed to investigate the ovarian function and reserve in euthyroid adolescents (TSH < 2.5 mIU/L) diagnosed with Hashimoto thyroiditis (HT). METHODS: This case-control study included 30 adolescent girls (mean age 15.1 +/- 1.4 years) newly diagnosed as HT with presence of high thyroid antibodies with gland heterogeneity in ultrasound and age-matched 30 healthy female subjects. Anti ovarian antibody (AOAb), LH/FSH ratio, estradiol, anti-mullerian hormone (AMH), inhibin-B, total testosterone, antral follicle count, ovarian volumes and uterine length were measured. The clinical, laboratory, and ultrasound data of the HT and control groups were compared. RESULTS: There were no significant differences between the girls with HT and healthy controls in relation to LH/FSH ratio, estradiol and inhibin-B levels. AOAb (p = 0.02), AMH (p = 0.007) and total testosterone levels were higher in HT group than the control group (p = 0.03). AOAb level was found to be positively correlated with LH/FSH ratio (p = 0.03), AMH (p = 0.01) and inhibin-B (p < 0.001) in HT group. CONCLUSION: This study demonstrated that the adolescent girls diagnosed with autoimmune thyroiditis had normal ovarian reserve based on measurements of AMH, inhibin B, FSH, LH/FSH ratio, estradiol and antral follicle counts. PMID- 26608411 TI - Future climate change is predicted to shift long-term persistence zones in the cold-temperate kelp Laminaria hyperborea. AB - Global climate change is shifting species distributions worldwide. At rear edges (warmer, low latitude range margins), the consequences of small variations in environmental conditions can be magnified, producing large negative effects on species ranges. A major outcome of shifts in distributions that only recently received attention is the potential to reduce the levels of intra-specific diversity and consequently the global evolutionary and adaptive capacity of species to face novel disturbances. This is particularly important for low dispersal marine species, such as kelps, that generally retain high and unique genetic diversity at rear ranges resulting from long-term persistence, while ranges shifts during climatic glacial/interglacial cycles. Using ecological niche modelling, we (1) infer the major environmental forces shaping the distribution of a cold-temperate kelp, Laminaria hyperborea (Gunnerus) Foslie, and we (2) predict the effect of past climate changes in shaping regions of long-term persistence (i.e., climatic refugia), where this species might hypothetically harbour higher genetic diversity given the absence of bottlenecks and local extinctions over the long term. We further (3) assessed the consequences of future climate for the fate of L. hyperborea using different scenarios of greenhouse gas emissions (RCP 2.6 and RCP 8.5). Results show NW Iberia, SW Ireland and W English Channel, Faroe Islands and S Iceland, as regions where L. hyperborea may have persisted during past climate extremes until present day. All predictions for the future showed expansions to northern territories coupled with the significant loss of suitable habitats at low latitude range margins, where long-term persistence was inferred (e.g., NW Iberia). This pattern was particularly evident in the most agressive scenario of climate change (RCP 8.5), likely driving major biodiversity loss, changes in ecosystem functioning and the impoverishment of the global gene pool of L. hyperborea. Because no genetic baseline is currently available for this species, our results may represent a first step in informing conservation and mitigation strategies. PMID- 26608412 TI - Editorial--Accelerating precision oncology in the 21st century. PMID- 26608413 TI - Immunohistochemical expression of cancer stem cell related markers CD44 and CD133 in endometrial cancer. AB - The goal of this study was to detect the presence of cancer stem cell markers CD44 and CD133 in immunohistochemically stained samples of endometrial cancer and correlate their expression with clinicopathological variables to identify the impact of CD44 or CD133 expression on tumor behavior and endometrial carcinogenesis. Marker expression was analyzed in 62 endometrial cancer samples (57 endometrioid carcinoma and 5 carcinosarcoma) and 15 proliferative endometrium samples. We detected CD133 and CD44 expression in 87.09% and 79.03% respectively of the studied endometrial cancers, and the expression was significantly different from the normal group. CD44 expression decreased with myometrial invasive depth and lymph-vascular space invasion (LVSI), and these inverse relationships were significant (p=0.034, p=0.019, respectively). CD133 was more expressed by early stage tumor (FIGO I-II) compared with those having FIGO III to IV stage disease (p=0.021). The most notable conclusion of the present study is that CD44 and CD133 might participate in early-stage endometrial cancer carcinogenesis, and their overexpression may facilitate the early diagnosis of endometrial cancers. Analysis of our results supports the hypothesis that CD44 expression tends to decrease as the disease becomes invasive and progressive. So, we concluded that CD44 down-regulation might warn of a more aggressive course and may have a link with poorly prognosis carcinosarcomas. Further examination of the expression and function of CD44 and CD133 with a greater number of carcinosarcomas is warranted. PMID- 26608414 TI - Gastric pyogenic granuloma: Report of two cases and review of the literature. AB - Pyogenic granuloma (PG) is a polypoid lobular capillary hemangioma rarely described in the stomach. We report two cases aged 72 and 66 years. A review of the literature on gastric PG, including the present cases, yielded ten patients. There were six males and four females. The age of the patients ranged from 35 to 82 years with a mean of 58.9 years. The lesions were all solitary, except one case of multiple lesions in the corpus and antrum. PG can be located in any part of the stomach. The most common site was the antrum. The mean maximum diameter of the lesions was 14.5mm (range 7-30mm). Most lesions were pedunculated. Pain or discomfort (epigastric, right upper quadrant or chest), upper gastrointestinal bleeding, and melena were the most common clinical symptoms. Iron deficiency anemia was the rule, often requiring blood transfusion. Five patients underwent snare polypectomy, four endoscopic mucosal resection, and one laser irradiation. The follow-up ranged from two weeks to two years. There were no recurrences. Pathologists should be familiar with this condition in order to avoid overdiagnosis as a malignant vascular tumor. PMID- 26608415 TI - Unique genetic alterations and clinicopathological features of hepatocellular adenoma in Chinese population. AB - Hepatocellular adenoma (HCA) is a benign hepatocyte-derived tumor commonly seen in reproductive-aged women with long-term use of oral contraceptives (OCs) in European and North American countries. Accordingly, HCA is currently classified into four molecular subtypes as adopted by the World Health Organization. The present study was firstly to characterize and determine the genetic alterations and clinicopathological features of the largest series of HCAs in China. We reviewed 189 patients with HCA who underwent hepatectomies at our liver center from January 1984 to January 2012, among which 36 HCAs were randomly selected for the sequencing of HNF1alpha, beta-catenin and gp130 genes, and 60 HCAs were randomly selected for detecting microsatellite instability (MSI). Compared with Western studies, our data showed distinctive findings including male (69.8%) and overweight/obese (50.3%) predominance. Only 3.5% of female patients had a documented history of OCs use for 2-4 years. All 36 sequenced HCAs showed HNF1alpha mutations (72% missense, 28% synonymous), 2 hotspot polymorphisms of HNF1alpha (I27L: rs1169288 and S487N: rs2464196) were seen in 17 (47%) and 10 (27.8%) cases, respectively, and a novel single nucleotide polymorphism site (rs1169304) in intron 9 of HNF1alpha was detected in 32 (88%) cases, but no beta catenin or gp130 gene mutation was detected, and no nuclear beta-catenin staining was detected by immunohistochemistry. The frequency of MSI was 75% for D12S1398 (HNF1alpha inactivated pathway) and 78.5% for D6S1064 (HIPPO signaling pathway) in 34 overweight/obese patients with HCA. Our results firstly indicate that patients with HCA in China frequently occur in male overweigh and obese adult population, lack an association with OCs use and exhibit unique genetic alterations. Taken together, these observations suggest that alternative pathogenetic pathways involve in HCA tumorigenesis in Chinese patients. PMID- 26608416 TI - Detection of human papillomavirus in esophageal and gastroesophageal junction tumors: A retrospective study by real-time polymerase chain reaction in an instutional experience from Turkey and review of literature. AB - Esophageal cancer is a poor-prognosis malignancy that ranks eighth among all cancer types, and its prevalence shows differences among geographical regions. Although the most important risk factors for esophageal carcinoma are alcohol and smoking, viral infections, particularly HPV infection, are also considered among etiological agents. Our study aims to detect the presence of HPV in esophageal cancers in our patient population and to investigate its correlation with clinico pathological parameters. We investigated the presence of HPV-DNA by real-time polymerase chain reaction in a total of 52 patients with esophageal cancer. Subtype analysis was performed in positive cases and was correlated with selected clinico-pathological parameters. Five (9.6%) of 52 tumor samples, 3 squamous cell carcinomas (3/33 cases) and 2 adenocarcinomas (2/19 cases), were HPV-DNA positive. Subtype analysis could be performed in four HPV-DNA-positive cases, of which three were HPV type-39 and 1 was type-16. The Marmara region, where the present study was carried out, is a region with low-moderate risk for esophageal cancer, and the prevalence of HPV-DNA in these tumors is similar to the prevalence of HPV-DNA reported in the literature for regions with similar risk. In conclusion, we detected HPV DNA in a subset of esophageal and gastroesophageal junction tumors. HPV infection may have a role in esophageal carcinogenesis and high-risk HPV subtypes can particularly be considered among risk factors since the prevalence of high risk HPV infection has also been found to be increased in regions with a high risk for esophageal cancer compared to low-moderate risk regions. PMID- 26608417 TI - Role of tumor-associated macrophages in the Hexim1 and TGFbeta/SMAD pathway, and their influence on progression of prostatic adenocarcinoma. AB - BACKGROUND: Hexamethylene bisacetamide-inducible protein 1 (Hexim1) regulates transforming growth factor-beta (TGFbeta) activity and turnover of SMAD proteins in a cyclin-dependent kinase 9-dependent way. It does so specifically through inhibiting function of this enzyme and by inhibiting the transcriptional activity of positive transcription elongation factor b (P-TEFb). Tumor-associated macrophages (TAMs) play a role in the progression of prostate adenocarcinomas. We investigated the clinicopathological significance of Hexim1, TGFbeta, SMAD2, and SMAD7 expression in prostate adenocarcinoma cells, and assessed associations between TAMs density and these proteins. METHODS: The cases of 100 patients diagnosed with prostate acinar adenocarcinoma who had undergone radical prostatectomy were retrospectively examined. Each was reviewed for Gleason score, cancer stage, and specific histopathological features. Original slides were re examined, and new slides were prepared and immunostained with Hexim1, TGFbeta, SMAD2, SMAD7 and CD68. RESULTS: Hexim1 expression was positively correlated with Gleason score, cancer stage, lymphovascular invasion, perineural invasion, extracapsular extension, and positive surgical margin. TAMs density was positively correlated with Gleason score, cancer stage, perineural invasion, extracapsular extension, and positive surgical margin. TAMs density was positively correlated with Hexim1 expression and TGFbeta expression. More advanced cancer stage, lymphovascular invasion, perineural invasion, and extracapsular extension were correlated with strong Hexim1 expression, strong SMAD2 expression, and mild SMAD7 expression, respectively. Strong Hexim1 expression, strong TGFbeta expression, and mild SMAD7 expression were associated with higher Gleason score. Strong Hexim1 expression was correlated with strong TGFbeta expression and mild SMAD7 expression. Strong Hexim1 expression, strong SMAD2 expression, and mild expression of SMAD7 were associated with disease progression. Strong SMAD2 expression was associated with shorter disease-free survival. CONCLUSION: The results suggest that greater TAMs density, strong Hexim1 expression, strong SMAD2 expression, and mild SMAD7 expression play important roles in the progression of prostate adenocarcinoma. Further investigation of these proteins will help facilitate the definitive prognosis of prostate adenocarcinomas. Ultimately, these proteins may be therapeutic targets for patients with prostate cancer. PMID- 26608418 TI - The prognostic value of morphologic findings for lung squamous cell carcinoma patients. AB - BACKGROUND: Novel histopathological prognostic features for squamous cell carcinoma (SCC) of lung, such as tumor budding, mitotic rate, tumor stroma ratio, stroma type, stromal inflammation and necrosis, have been evaluated in the literature. In this study, the prognostic value of multiple morphological features is assessed in lung SCC. MATERIALS AND METHODS: This study reports on seventy-six patients with lung SCC treated with complete surgical excision. Tumor size, tumor stage, lymph node status, lymphovascular invasion, histopathologic grade, mitotic count, necrosis, tumor budding, tumor stroma ratio, stroma type, stromal lymphoplasmacytic reaction and ratios of stromal plasma cells and their relationship with the prognosis were evaluated. Univariate and multivariate analyses were performed for histopathological markers for local disease free survival (LDFS), distant disease free survival (DDFS), overall disease free survival (ODFS) and overall survival (OS). RESULTS: The univariate prognostic analysis of the pathological factors revealed that the pathological stage (OS: p=0.001, DDFS: p=0.040), lymph node metastases (OS: p=0.013), mitotic index (OS: p=0.026), tumor necrosis (DDFS: p=0.013, ODFS: p=0.021) and tumor size (OS: p=0.002) had a prognostic significance. The multivariate analysis demonstrated that the pathological stage (OS: p=0.021), tumor size (OS: p=0.044), lymph node status (DDFS: p=0.019, ODFS; p=0.041) and necrosis (ODFS: p=0.048) were independent prognostic factors. CONCLUSIONS: Although many histopathological factors have recently been proposed as important prognostic markers, we only found significant results for mitotic index and tumor necrosis, as well as the well known parameters such as tumor stage and lymph node status. To the best of our knowledge, this is the first study evaluating such a wide range of morphological prognostic factors in lung SCC. PMID- 26608419 TI - Isolation of soluble scFv antibody fragments specific for small biomarker molecule, L-Carnitine, using phage display. AB - Isolation of single chain antibody fragment (scFv) clones from naive Tomlinson I+J phage display libraries that specifically bind a small biomarker molecule, L Carnitine, was performed using iterative affinity selection procedures. L Carnitine has been described as a conditionally essential nutrient for humans. Abnormally high concentrations of L-Carnitine in urine are related to many health disorders including diabetes mellitus type 2 and lung cancer. ELISA-based affinity characterization results indicate that selectants preferentially bind to L-Carnitine in the presence of key bioselecting component materials and closely related L-Carnitine derivatives. In addition, the affinity results were confirmed using biophysical fluorescence quenching for tyrosine residues in the V segment. Small-scale production of the soluble fragment yielded 1.3mg/L using immunopure immobilized protein A affinity column. Circular Dichroism data revealed that the antibody fragment (Ab) represents a folded protein that mainly consists of beta sheets. These novel antibody fragments may find utility as molecular affinity interface receptors in various electrochemical biosensor platforms to provide specific L-Carnitine binding capability with potential applications in metabolomic devices for companion diagnostics and personalized medicine applications. It may also be used in any other biomedical application where detection of the L-Carnitine level is important. PMID- 26608420 TI - Human papillomavirus 16-specific cell-mediated immunity in children born to mothers with incident cervical intraepithelial neoplasia (CIN) and to those constantly HPV negative. AB - OBJECTIVES: HPV infections are detected in sexually naive children. This has raised the question about the role of early HPV infections in either protecting or predisposing to further HPV infections. HPV16-specific cell-mediated immunity (CMI) was studied in 10 case-children born to mothers with an incident cervical intraepithelial neoplasia (CIN) diagnosed during their 14-year follow-up (FU), and in 21 children born to mothers, who remained constantly HPV-negative (controls). The mean age of children was 12.3 years. METHODS: Peripheral blood mononuclear cells were isolated from blood and stimulated with peptide pools covering HPV16 E2, E6 and E7. Proliferation of lymphocytes, their secretion of cytokines, and the frequency of regulatory T-cells were determined. The results were correlated with the HPV status and analyzed in a nested case-control setting. RESULTS: All children, except two controls, displayed CMI against HPV16 E2, E6 and/or E7 peptides associated with type 1 and 2 cytokine secretion. Only two statistically significant differences were found in the nested case-control setting; (1) case-children had a higher TNF-alpha response to HPV16 E2 (p = 0.004) than controls and (2) controls had no response to HPV16 E7.2 peptide pool while 3/10 case-children had (p = 0.013). Totally, 50 and 57 % of the cases and controls, respectively, had HPV positive oral samples at some FU-visit. In addition, the children without any HPV antibodies before the age of 6 months showed proliferative responses of PBMC after HPV16 exposure more frequently than other children (p = 0.045). CONCLUSIONS: HPV16-specific CMI is common in young, sexually inexperienced children. This suggests that oral HPV infections occur frequently in children. Our results might also explain the previous findings that half of healthy adults demonstrate HPV-specific CMI irrespective of their partner/sexual status. PMID- 26608421 TI - Vaccination against Staphylococcus aureus mastitis in two Swedish dairy herds. AB - BACKGROUND: Staphylococcus aureus is a common udder pathogen in dairy cows, and may cause severe mastitis problems in some herds. In herds where normal control measures are not successful, vaccination might be an additional tool to use if sufficiently efficient. The aim of the present study was to evaluate the efficacy of a commercially available vaccine (Startvac((r)), Hipra, Spain) in two commercial Swedish dairy herds where the control programs for S. aureus mastitis had been unsuccessful. Within each herd cows were randomly assigned to vaccine or control groups, and effects on udder health and milk production during 120 days after calving, and survival during the following lactation were evaluated. RESULTS: A field study was performed in two high producing Swedish herds having approximately 600 (herd A) and 200 (herd B) cows. During 12 months, cows with odd numbers were vaccinated three times around calving according to label protocol, while cows with even numbers constituted the not vaccinated control group. Quarter milk samples for bacteriological culturing were collected from all cases of clinical and subclinical mastitis. The outcome was evaluated during 120 days after calving using data on SCC and daily milk yield at monthly milk recordings, and incidence of mastitis due to S. aureus, coagulase-negative staphylococci, streptococci and coliforms. Cow survival throughout lactation was also studied. In herd A, 239 and 240 cows were included in the vaccinated and control groups, respectively. Corresponding numbers for herd B was 126 and 151 cows. Significant differences between vaccinated and control groups were not found in any of the parameters investigated. CONCLUSIONS: Vaccination with a commercial polyvalent vaccine did not have any beneficial effects on udder health, milk production or survival in two commercial dairy herds with mastitis problems due to S. aureus. PMID- 26608422 TI - Interpersonal relations and nurses' job satisfaction through knowledge and usage of relational skills. AB - BACKGROUND/RATIONALE: Many interpersonal labor disputes stem from the lack of communication skills and the relational problems in the interactions between health professionals. AIMS/METHODS: A qualitative study was conducted in a Spanish hospital in order to get to know how the communicative interaction between hospital nurses is like in relation to the nurses' interpersonal interaction and communication skills developed in their working relationships. Twenty-one hospital nurses between 29 and 55 years old, working in different wards, were interviewed. Open-ended interview discourses were transcribed verbatim and analyzed using qualitative content analysis. RESULTS: The following four key themes were analyzed: communication and sender; communication and awareness of who has the problem; non-verbal communication; communication and recipient. CONCLUSION: The results of this study highlight the need to broaden nurses' relational-communication skills in order to increase job satisfaction. PMID- 26608423 TI - A method comparison of photovoice and content analysis: research examining challenges and supports of family caregivers. AB - PURPOSE: The purpose of this manuscript is to compare methods and thematic representations of the challenges and supports of family caregivers identified with photovoice methodology contrasted with content analysis, a more traditional qualitative approach. METHODS: Results from a photovoice study utilizing a participatory action research framework was compared to an analysis of the audio transcripts from that study utilizing content analysis methodology. RESULTS: Major similarities between the results are identified with some notable differences. Content analysis provides a more in-depth and abstract elucidation of the nature of the challenges and supports of the family caregiver. CONCLUSIONS: The comparison provides evidence to support the trustworthiness of photovoice methodology with limitations identified. The enhanced elaboration of theme and categories with content analysis may have some advantages relevant to the utilization of this knowledge by health care professionals. PMID- 26608424 TI - Premedication and preoperative information reduces pain intensity and increases satisfaction in patients undergoing ablation for atrial fibrillation. A randomised controlled study. AB - BACKGROUND: Pain and discomfort are common during radiofrequency ablation (RFA) for atrial fibrillation. AIMS: To compare and evaluate the effect of premedication, standardised preoperative information and preoperative anxiety on pain intensity, drug consumption and patients' satisfaction. METHODS: Preoperative anxiety at baseline, pain intensity during RFA, and patient satisfaction after the procedure were measured in 3 random groups. Group A (n=20) received standard pain management, group B (n=20) received premedication and group C (n=20) received premedication and standardised preoperative information. RESULTS: Patients in groups B and C experienced less pain intensity (p<0.001) and needed fewer anxiolytics (p=0.023) and analgesics (p=0.031) compared to group A. Patient satisfaction was higher in group C (p=0.005) compared to group A. Increased preoperative anxiety is related to elevated drug demand (p<0.05). CONCLUSION: Premedication alone or combined with preoperative information reduces and higher preoperative anxiety increases pain intensity and drug consumption during RFA. Preoperative information improves patient satisfaction. PMID- 26608425 TI - Health-related quality of life, psychological well-being, and sexual function in patients with benign prostatic hyperplasia after prostatic surgery. AB - AIMS AND BACKGROUND: Patients with benign prostatic hyperplasia (BPH) may receive prostatic surgery due to severe lower urinary tract symptoms (LUTS). This study aimed to investigate the health-related quality of life (HRQoL), psychological well-being, and sexual function of patients with BPH after prostatic surgery and identify the predictors of HRQoL among this group of patients. METHODS: This was a cross-sectional, descriptive, correlational study. A convenience sample of 94 participants was recruited from a urology center in a tertiary public hospital in Singapore. The 12-item Short Form Health Survey version 2 (SF-12v2), International Prostate Symptom Score (IPSS), Hospital Anxiety and Depression Scale (HADS), and 5-item International Index of Erectile Function (IIEF-5) were used to measure the study variables. RESULTS: Compared to the general population norms and the findings of similar studies conducted in western countries, this group of patients reported poorer physical health but better mental health as assessed by SF-12v2. Despite the prostatic surgery, over a quarter of the patients experienced moderate LUTS, and 13.8% experienced severe erectile dysfunction. Multiple linear regression analysis identified that LUTS (B=-0.51, p=0.02) and maximum flow rate (B=-0.23, p=0.02) predicted poor physical health, accounting for 45.9% of variance, while HADS-Anxiety (B=-1.07, p<0.01) and LUTS (B=-0.32, p=0.03) predicted poor mental health, accounting for 57.2% of variance. CONCLUSION: The physical health of BPH patients with prostatic surgery was poor, with many suffering moderate LUTS and sexual dysfunction. Special attention should be given to those patients with severe LUTS who have a low maximum flow rate or have anxiety symptoms. PMID- 26608426 TI - Family experience survey in the surgical intensive care unit. AB - The experience of critical care is stressful for both patients and their families. This is especially true when patients are not able to make their own care decisions. This article details the creation of a Family Experience Survey in a surgical intensive care unit (SICU) to capture and improve overall experience. Kolcaba's "Enhanced Comfort Theory" provided the theoretical basis for question formation, specifically in regards to the four aspects of comfort: "physical," "psycho-spiritual," "sociocultural" and "environmental." Survey results were analyzed in real-time to identify and implement interventions needed for issues raised. Overall, there was a high level of satisfaction reported especially with quality of care provided to patients, communication and availability of nurses and doctors, explanations from staff, inclusion in decision making, the needs of patients being met, quality of care provided to patients and cleanliness of the unit. It was noted that 'N/A' was indicated for cultural needs and spiritual needs, a chaplain now rounds on all patients daily to ensure these services are more consistently offered. In addition, protocols for doctor communication with families, palliative care consults, daily bleach cleaning of high touch areas in patient rooms and nurse-led progressive mobility have been implemented. Enhanced comfort theory enabled the opportunity to identify and provide a more 'broad' approach to care for patients and families. PMID- 26608427 TI - Exploring a self-help coping intervention for pregnant women with a miscarriage history. AB - Pregnant women with a history of miscarriages experience symptoms of anxiety and depression in a subsequent pregnancy and are in need of support in the period after miscarriage, when trying to get pregnant again and during the first phase of pregnancy. The aim of this study was to investigate whether a Positive Reappraisal Coping Intervention (PRCI) and Daily Record Keeping (DRK) chart, developed for use in assisted conception treatment, are also appropriate for use in pregnant women with a history of miscarriage(s). In this convergent parallel mixed method study, thirteen women visiting an Early Pregnancy Unit and/or Recurrent Miscarriage Clinic in a university medical center in the Netherlands were selected on the basis of the number of miscarriages and age. Exclusion criteria were not speaking the Dutch language, pregnancy after fertility treatment and having a medical cause identified for the miscarriages. Women used the PRCI and DRK for 3 weeks in a subsequent pregnancy. Quantitative data were obtained from the DRK and were analyzed by reporting frequencies and means for each case. Qualitative data were collected by semi-structured interviews and were analyzed by using thematic analysis. The majority of the women were able to use the PRCI and DRK for 3weeks. Women adapted the way in which they used the PRCI and DRK based on their judgment about the effect, the intensity of the emotions they experienced, or whether they felt the effort to use these instruments to be worthwhile or not. PMID- 26608428 TI - Impact of emotional intelligence and spiritual intelligence on the caring behavior of nurses: a dimension-level exploratory study among public hospitals in Malaysia. AB - PURPOSE: The purpose of this research is to study the impact of individual factors such as emotional intelligence (EI) and spiritual intelligence (SI) on the caring behavior of nurses. METHODS: A cross-sectional survey using questionnaire was conducted by sampling 550 nurses working in seven major public hospitals in Malaysia. Data were analyzed using structural equation modeling (SEM). RESULTS: The main findings are: (1) critical existential thinking and transcendental awareness dimensions of SI have significant impacts on assurance of human presence dimension of caring behavior; (2) personal meaning production and conscious state expansion dimensions of SI have significant impacts on perception of emotion and managing own emotions dimensions of EI; and (3) managing own emotions dimension of EI has significant impacts on respectful deference to other and assurance of human presence dimensions of caring behavior of nurses. CONCLUSION: The results can be used to recruit and educate nurses. PMID- 26608429 TI - Predicting health-promoting self-care behaviors in people with pre-diabetes by applying Bandura social learning theory. AB - AIMS: The aim of this study was to apply Bandura social learning theory in a model for identifying personal and environmental factors that predict health promoting self-care behaviors in people with pre-diabetes. BACKGROUND: The theoretical basis of health-promoting self-care behaviors must be examined to obtain evidence-based knowledge that can help improve the effectiveness of pre diabetes care. However, such behaviors are rarely studied in people with pre diabetes. METHODS: This quantitative, cross-sectional survey study was performed in a convenience sample of two hospitals in southern Taiwan. Two hundred people diagnosed with pre-diabetes at a single health examination center were recruited. A questionnaire survey was performed to collect data regarding personal factors (i.e., participant characteristics, pre-diabetes knowledge, and self-efficacy) and data regarding environmental factors (i.e., social support and perceptions of empowerment process) that may have associations with health-promoting self-care behaviors in people with pre-diabetes. RESULTS: Multiple linear regression showed that the factors that had the largest influence on the practice of health promoting self-care behaviors were self-efficacy, diabetes history, perceptions of empowerment process, and pre-diabetes knowledge. These factors explained 59.3% of the variance in health-promoting self-care behaviors. CONCLUSIONS: To prevent the development of diabetes in people with pre-diabetes, healthcare professionals should consider both the personal and the environmental factors identified in this study when assessing health promoting self-care behaviors in patients with pre-diabetes and when selecting the appropriate interventions. PMID- 26608430 TI - Delivering best care and maintaining emotional wellbeing in the intensive care unit: the perspective of experienced nurses. AB - AIM: This study explored the perspective of experienced intensive care nurses regarding maintenance of their emotional wellbeing. BACKGROUND: Caring for critically ill patients has been identified as stressful. The demand for critical care nurses continues to grow in a climate of an ongoing nursing shortage and an aging workforce. This study sought to understand what environmental elements optimized the maintenance of emotional wellbeing. METHODS: Grounded theory. RESULTS: Fifteen experienced intensive care unit registered nurses from a metropolitan hospital in Western Australia, were interviewed. Five categories were identified: 'achieving best care', 'caring for the patient's family', 'autonomy within the ICU environment', 'teamwork', and 'previous nursing and life experience'. CONCLUSIONS: The findings from this study increase our understanding of the environmental elements that can optimize the emotional wellbeing of intensive care nurses. These findings will assist in the development of strategies to retain nurses in the ICU area. PMID- 26608431 TI - Symptom frequency, severity, and quality of life among persons with three disease trajectories: cancer, ALS, and CHF. AB - PURPOSE: National reports on end-of-life symptom management reveal a gap in the evidence regarding symptoms other than pain and studies of diseases other than cancer. This study examines the frequency and severity of symptoms and quality of life (QOL) in persons with advanced cancer, amyotrophic lateral sclerosis (ALS), and congestive heart failure (CHF). METHODS: The present study is a cross sectional examination of symptoms and QOL measured using the McGill QOL Questionnaire, among 147 participants. RESULTS: Forty one percent of participants had advanced cancer, 22% had ALS, and 37% had advanced CHF. A total of 266 symptoms were reported, with the common symptom categories being discomfort/pain, weakness/fatigue/sleep, and respiratory. Participants with CHF had the highest mean symptom severity and the lowest QOL. CONCLUSION: Clinicians should be aware and attentive for symptoms other than pain in patients with advanced illness. Studies on diseases other than cancer, such as CHF and ALS, are important to improve symptom management in all disease groups. PMID- 26608432 TI - Factors contributing to infant overfeeding in low-income immigrant Latina mothers. AB - BACKGROUND: Approximately 10% of U.S. infants and toddlers are considered overweight. Hispanic infants persistently show higher prevalence rates for being overweight compared to other infants. Little is known about factors promoting excessive infant weight gain in Latinos. PURPOSE: The aim of this study was to describe multidimensional factors and maternal feeding practices that may correlate with infant overfeeding in Latina mothers. METHODS: Participants were 62 low-income immigrant Latina mothers and their infants. Study measures were: acculturation; maternal feeding beliefs and practices; food availability; temperament; 24-hour dietary recall; and infant's weight-for-height z score. RESULTS: In regression models adjusted for infant's age, healthier feeding practices were significantly predicted by maternal education and infant's age. Most mothers preferred feeding their infants either formula or a combination of breast milk and formula. A significant proportion of the infants were overweight or obese and yet some mothers displayed difficulty recognizing this problem. CONCLUSION: Future intervention efforts should focus primarily on the promotion of healthy feeding practices that discourage overfeeding and support exclusive breastfeeding among this ethnic group. PMID- 26608433 TI - To adjust and endure: a qualitative study of symptom burden in older people with multimorbidity. AB - CONTEXT: Older people with multimorbidity are vulnerable and often suffer from conditions that produce a multiplicity of symptoms and a reduced health-related quality of life. OBJECTIVES: The aim of this study is to explore the experience of living with a high symptom burden from the perspective of older community dwelling people with multi-morbidity. METHOD: A qualitative descriptive design with semi-structured interviews, including 20 community-dwelling older people with multi-morbidity and a high symptom burden. The participants were 79-89 years old with a mean of 12 symptoms per person. Data were analyzed using content analyses. RESULTS: The experience of living with a high symptom burden revealed the overall theme, "To adjust and endure" and three sub-themes. The first sub theme was "To feel inadequate and limited". Participants reported that they no longer had the capacity or the ability to manage, and they felt limited and isolated from friends or family. The second sub-theme was "To feel dependent". This was a new and inconvenient experience; the burden they put on others caused a feeling of guilt. The final sub-theme was "To feel dejected". The strength to manage and control their conditions was gone; the only thing left to do was to sit or lie down and wait for it all to pass. CONCLUSION: This study highlights the importance of a holistic approach when taking care of older people with multi morbidity. This approach should employ a broad symptom assessment to reveal diseases and conditions that are possible to treat or improve. PMID- 26608434 TI - Psychometric testing of the Chinese version of the Medical Outcomes Study Social Support Survey among people living with HIV/AIDS in China. AB - PURPOSE: The aim of this study was to assess the psychometric properties of the Chinese (Mandarin) version of the Medical Outcomes Study Social Support Survey (MOS-SSS-CM) among people living with HIV/AIDS (PLWHA) in Mainland China. METHODS: A cross-sectional study was conducted with a convenience sample of 200 Chinese PLWHA. They completed the MOS-SSS-CM along with the Chinese version of the Beck Depression Inventory Revised (BDI-II) scale, the Zung Self-Rating Anxiety Scale (SAS), the Perceived Stress Scale (PSS-10), and the World Health Organization Quality of Life Brief (WHOQOL-BREF) scale. RESULTS: Internal consistency (Cronbach's alpha) was 0.97 for the overall MOS-SSS-CM and 0.82-0.91 for the five subscales originally proposed. However, 11 of the 19 items demonstrated unsatisfactory item discriminant validity. An exploratory factor analysis yielded a two-factor solution with tangible and social-emotional dimensions, which demonstrated satisfactory reliability and better discrimination between different subscales than did the original five-factor model. The concurrent validity of the two-factor scale was further confirmed by its significant negative correlations with the BDI-II (r=-0.41, p<0.01); the SAS (r= 0.27, p<0.01); and the PSS-10 (r=-0.30, p<0.01), and significant positive correlation with the WHOQOL-BREF scale (r=0.61, p<0.01). CONCLUSION: We found a two-factor solution for the MOS-SSS-CM, which demonstrated good reliability and validity when applied to Chinese PLWHA. This was consistent with results from a study of Taiwanese caregivers. Further validation in other populations and disease states is warranted. PMID- 26608435 TI - Screening and evaluation tools for sleep disorders in older adults. AB - The negative effects of impaired sleep on physical and mental well-being in older adults have recently been recognized by health care professionals. However, researchers and clinicians may be unaware of reliable and valid screening and evaluation tools for evaluating sleep disorders in older adults. The purpose of this article is to present subjective and objective instruments that measure sleep quality, excessive daytime sleepiness, obstructive sleep apnea, insomnia and restless leg syndrome that are appropriate for use in adult and older adult patients. PMID- 26608436 TI - Nurse reported patient safety in low-resource settings: a cross-sectional study of MNCH nurses in Nigeria. AB - PURPOSE: Repeated international studies demonstrate the critical role of nursing and the associations between patient safety and nurse staffing and the nurse practice environment in high resource countries, yet nurse reported patient safety studies are sparse in Sub-Saharan Africa. This study explored nurse reported patient safety in Nigeria and examined the extent that patient safety is associated with nurse staffing levels and the nurse practice environment. METHODS: A cross-sectional study of 27 public health facilities in Nigeria used anonymous nurse surveys (N=222) to examine associations between nurse staffing, the nurse practice environment and nurse reported safety. Descriptive statistics and generalized linear mixed models (GLMM) were used to account for clustering of nurses within facilities. RESULTS: Of the 222 nurse participants, 26% reported patient safety as poor/fair. Nurses who cared for greater than 20 patients had higher percentages of poor/fair patient safety. With the GLMM models adjusted for type of facility and nurse staffing, the nurse practice environments had the strongest association with patient safety. As the nurse practice environment score increased, nurses were nearly three times more likely to rank patient safety as excellent/good OR=2.9 (1.5, 5.7). CONCLUSIONS: The taxonomy used globally with nurse safety research was comparable in Nigeria. Enhancing the nurse practice environment could offer opportunities to improve nurse reported patient safety in public health facilities in Nigeria. Further research is needed to better understand nurse reports of worse patient safety in secondary level health facilities and facilities with worse nurse staffing. PMID- 26608437 TI - A cross-sectional survey of self-rated health and its determinants in patients with hypertension. AB - AIM: The purpose of the study is to investigate the levels of self-rated health, blood pressure control, understand their relationships between the self-rated health and blood pressure control, and to identify the extent to which demographic, disease and psychosocial factors predict the self-rated health of hypertensive patients. METHODS: The study adopted a cross-sectional design. Nine hundred forty-two subjects with essential hypertension were invited to join the study, 807 completed the survey. Self-report questionnaires were used to collect data. The hierarchical logistic regression was used to test the determinants of self-rated health status. RESULTS: Of all the subjects, 59.3% rated their health status as good, and 41.7% perceived their health status as poor. In terms of levels of blood pressure control, nurse-measured blood pressure showed that 40.2% of the subjects had good control levels, 59.8% for poor control levels. There were positive relationships between good self-rated health and controlled blood pressure of hypertensive patients (p<0.05). The logistic regression model showed that the determinants of subjects' self-rated health included income (OR=4.28; 95% CI=1.86-6.25), duration of hypertension diagnosis (OR=4.06; 95% CI=2.17 6.35), treatment adherence (OR=9.02; 95% CI=5.36-15.51), physical activity (OR=13.81; 95% CI=10.16-19.57) and social support (OR=8.63; 95% CI=7.17-11.35). CONCLUSIONS: The self-rated health status and blood pressure control for patients with hypertension is suboptimal, effective strategies should be developed to improve patients' general health. PMID- 26608438 TI - Barriers in implementing research among registered nurses working in the care of the elderly: a multicenter study in Spain. AB - OBJECTIVE: This study identified barriers to the utilization of research results perceived by nurses who work in nursing homes in Spain. METHODS: An observational, cross-sectional, descriptive, and multicentre study was conducted in 126 nursing homes in different Spanish cities. The BARRIERS to Research Utilization Scale (BARRIERS scale) was used to identify barriers. RESULTS: A total of 756 nurses responded (92.48%). BARRIERS scale variables with the highest scores included Characteristics of the organization (mean=24.89, SD=4.37), followed by Professional features (mean=21.87, SD=4.85). The specific barriers that were rated the highest included "not enough time on the job to implement new ideas" (mean=3.89, SD=0.98), followed by "unknown nursing research" (mean=2.75; SD=1.22) and "Doctors do not cooperate in the implementation" (mean=3.01, SD=1.85). CONCLUSIONS: Geriatric nurses perceive time as the main barrier to implementing the results of research in practice. The number and nature of the barriers are consistent with studies from other countries. Knowledge of the barriers is crucial for institutions and educators to instigate measures that improve the implementation of nursing research, especially in an area like elderly care. To our knowledge, this is the first study conducted among geriatric nurses in Spain. PMID- 26608440 TI - Efficacy of an empowerment program for Taiwanese patients with type 2 diabetes: A randomized controlled trial. AB - AIM: To examine the efficacy of an empowerment program on glycosylated hemoglobin, self-care behaviors, self-efficacy, and quality of life in Taiwanese patients with type 2 diabetes. BACKGROUND: Although empowerment interventions have proven beneficial in western populations, they are rarely applied in Taiwanese populations. METHODS: A randomized controlled trial was conducted. The experimental group (n=33) participated in a 3-month empowerment program for motivating patient self-awareness, assessing the causes of problems, goal setting, individual self-care plan development, and checking whether the goal is reached (MAGIC). The control group (n=32) received routine clinical care. RESULTS: The experimental group had significantly decreased glycosylated hemoglobin at 3 months after the end of the intervention and significantly improved self-care behaviors, self-efficacy, and quality of life at the end of the intervention and at 3 months after the end of the intervention. CONCLUSIONS: An empowerment program effectively improves diabetes control in Taiwanese patients with type 2 diabetes. PMID- 26608439 TI - Single subject design: Use of time series analyses in a small cohort to understand adherence with a prescribed fluid restriction. AB - PURPOSE: This paper presents a secondary in-depth analysis of five persons with heart failure randomized to receive an education and behavioral intervention on fluid restriction as part of a larger study. METHODS: Using a single subject analysis design, time series analyses models were constructed for each of the five patients for a period of 180 days to determine correlations between daily measures of patient reported fluid intake, thoracic impedance, and weights, and relationships between patient reported outcomes of symptom burden and health related quality of life over time. RESULTS: Negative relationships were observed between fluid intake and thoracic impedance, and between impedance and weight, while positive correlations were observed between daily fluid intake and weight. CONCLUSIONS: By constructing time series analyses of daily measures of fluid congestion, trends and patterns of fluid congestion emerged which could be used to guide individualized patient care or future research endeavors. Employment of such a specialized analysis technique allows for the elucidation of clinically relevant findings potentially disguised when only evaluating aggregate outcomes of larger studies. PMID- 26608441 TI - Improving sleep quality interventions among menopausal women with sleep disturbances in Taiwan: a preliminary study. AB - AIM: The aim of this study was to evaluate the effectiveness of improving sleep quality interventions in menopausal women with sleep disturbance. BACKGROUND: Sleep disturbances are an extensive and common problem among menopausal women. There is an increased trend in the use of non-pharmacological methods to alleviate sleep disturbances. Studies that have implemented two or more non pharmacological strategies for menopausal women are scant. METHODS: A repeat measurement with a randomized assignment was conducted. A total of 59 menopausal women with sleep disturbance were recruited and randomly assigned to experimental (n = 29) and control (n = 30) groups. Participants in the experimental group received four 2-hour improving sleep quality activities, whereas the control group received regular greeting calls. Sleep quality was measured prior to intervention, and on the 5th and 8th weeks by using the Pittsburg's Sleep Quality Index, and Actiwatch was worn before and during the 8 weeks of intervention. Generalized estimating equation was used to analyze data. RESULTS: The results revealed that subjective sleep quality had significant main effect in group and time. The findings of the objective measurement showed that participants in the experimental group had significantly shorter frequency of awakening time and increased sleep efficiency. CONCLUSION: The improving sleep quality intervention is a healthy and cost-effective method to improve sleep quality in community dwelling menopausal women with sleep disturbance. PMID- 26608442 TI - Maternal-Infant interaction in women with unipoloar and bipolar depression. AB - BACKGROUND: One percent of women experience bipolar disorder and are likely to suffer from mood disorders during the postpartum period, potentially impacting interaction with their infants. The purpose of this study was to describe maternal-infant interactions in women with bipolar depression at 12 months postpartum and to compare interactions to women with unipolar depression and a control group. METHODS: Using a descriptive design, maternal-infant interactions in women with bipolar disorder (n=40) were videotaped, coded, and analyzed for maternal sensitivity and maternal-infant reciprocity and compared to maternal infant interaction in women with unipolar depression (n=50) and women without depression (n=40). RESULTS: Women with bipolar depression had lower scores on both maternal sensitivity and infant reciprocity, but differences were nonsignificant. CONCLUSIONS: This research is the first study to examine maternal infant interaction in women with bipolar disorder, and important trends were noted. Future research should examine maternal-infant interaction at earlier time periods. PMID- 26608443 TI - Outcome results of self-efficacy in children with sickle disease pain who were trained to use guided imagery. AB - PURPOSE: The aim of this study was to describe self-efficacy as a theoretical component of behavior change in various therapeutic treatments such as the management of SCD pain. METHOD: The participants were prepared to self-initiate the GI for 5 to 10 minutes three times each day regardless of pain and also during each pain episode. As part of the GI training a tape or CD with guided imagery messages was provided. Participants were monitored for 4 weeks pre and 4 weeks post intervention (GI training). Children kept a daily record of pain episodes. During this time, children continued to record as before in their personal study diary: pain episodes (intensity and treatment), school attendance, and also the frequency of GI use. At the conclusion of this 4-week period, usual pain patterns (PAT), visual imagery ability (KIAQ), and disease specific self efficacy scale were measured again. The Sickle Cell Self-Efficacy Scale (SCSES) is a new nine-item scale measuring disease-specific perceptions of self-efficacy. The instrument's developers established internal consistency by Cronbach's alpha of 0.89. RESULTS: H1: Children with SCD who are trained in guided imagery will have greater disease-specific self-efficacy following the training than they had prior to learning guided imagery; the hypothesis was tested and supported using t tests of mean interval-level scores on the SCSES. CONCLUSION: Eighteen children had positive gained scores and sixteen children raised their scores more than one standard deviation above the mean score for this sample distribution. Greater self-efficacy scores are associated with better physical and psychological functioning. PMID- 26608444 TI - Preliminary testing using Mokken scaling of an Italian translation of the Edinburgh Feeding Evaluation in Dementia (EdFED-I) scale. AB - PURPOSE: To study the psychometric properties of an Italian version of the Edinburgh Feeding Evaluation in Dementia (EdFED-I) Scale. BACKGROUND: The EdFED Scale is the only validated instrument that measures difficulty with feeding in older people with dementia. The original English version of the EdFED had three factors measuring: behavioral aspects of feeding difficulty (obstinacy/passivity); indicators of feeding difficulty; and nursing interventions. METHODS: Participants affected by dementia and living in nursing homes (n=210) were selected. Data collectors were trained to observe the residents' eating problems and their food intake. The data were analyzed using Mokken scaling and Pearson's correlation. RESULTS: The Italian version of the EdFED Scale formed a Mokken scale which correlated in the expected direction with measures of residents' weight, Body Mass Index, time taken to eat, Mini Mental State Examination score and Barthel Index according to the unmet needs model of Cohen-Mansfield. CONCLUSIONS: The EdFED-I shows reasonable psychometric properties and can be used for the assessment of feeding difficulty in Italian samples of older people with dementia. However, further work with larger samples is required to test the utility of the whole range of items and the necessity of their inclusion in the EdFED-I. PMID- 26608445 TI - 2015: The year of ethics and the National Nursing Summit blueprint for 21st century nursing ethics. PMID- 26608446 TI - Anger, anger expression, cardiovascular risk factors, and gastrointestinal symptoms by hwa-byung symptoms in Korean adult women. AB - PURPOSE: This study explored relationships of anger and anger expression to cardiovascular (CV) risk factors and gastrointestinal (GI) symptoms in Korean women based on hwa-byung (HB) symptoms. METHODS: A descriptive, comparative design was used. One-hundred four women who are from 20 to 65years old were recruited. Based on the HB score, 22 women indicated for HB and the rest were classified as normal. Data collection was done with several questionnaires including HB symptom scale, state-trait anger expression inventory, and GI symptom questionnaire and clinical information. RESULTS: Women with HB demonstrated significantly higher levels of trait anger and dysfunctional anger expression such as anger suppression and anger expression than normal group. Although blood pressure was higher in women with HB, the differences were not significant. Self-report of GI symptoms were significantly more in women with HB, however no significant difference was found in gastroscopy results. CONCLUSIONS: Women with HB were younger and might lack of sufficient social support. This study suggests relationship of anger and anger expression to functional GI symptoms. Characteristics of women with HB should be considered in developing intervention programs for healthy coping. Future studies need more women with HB for better comparison. PMID- 26608447 TI - Humor intervention program for children with chronic diseases. AB - PURPOSE: This study developed and implemented a humor intervention program for school-aged children with chronic diseases. METHODS: Thirty-three children with atopic dermatitis and type 1 diabetes were divided into experimental and control groups. The experimental group included 17 children while the control group included 16 children. The experimental group participated in 6 weekly sessions of a 60-minute humor intervention. The subject and type of humorous material was collected from a survey of parents and children. Outcome measures assessed pre- and post-intervention included stress, behavior profile scores, and resilience. RESULTS: There was a significant decrease in behavior problems and increase in resiliency in experimental group compared to control group. There was no difference in stress cortisol measures between the groups. CONCLUSIONS: This study was the first to examine a humor intervention for children with chronic diseases in South Korea and offers practical implications for humor interventions in pediatric nursing. PMID- 26608450 TI - Topical corticosteroid misuse in India is harmful and out of control. PMID- 26608448 TI - Mining continuous intracranial EEG in focal canine epilepsy: Relating interictal bursts to seizure onsets. AB - OBJECTIVE: Brain regions are localized for resection during epilepsy surgery based on rare seizures observed during a short period of intracranial electroencephalography (iEEG) monitoring. Interictal epileptiform bursts, which are more prevalent than seizures, may provide complementary information to aid in epilepsy evaluation. In this study, we leverage a long-term iEEG dataset from canines with naturally occurring epilepsy to investigate interictal bursts and their electrographic relationship to seizures. METHODS: Four dogs were included in this study, each monitored previously with continuous iEEG for periods of 475.7, 329.9, 45.8, and 451.8 days, respectively, for a total of >11,000 h. Seizures and bursts were detected and validated by two board-certified epileptologists. A published Bayesian model was applied to analyze the dynamics of interictal epileptic bursts on EEG and compare them to seizures. RESULTS: In three dogs, bursts were stereotyped and found to be statistically similar to periods before or near seizure onsets. Seizures from one dog during status epilepticus were markedly different from other seizures in terms of burst similarity. SIGNIFICANCE: Shorter epileptic bursts explored in this work have the potential to yield significant information about the distribution of epileptic events. In our data, bursts are at least an order of magnitude more prevalent than seizures and occur much more regularly. Our finding that bursts often display pronounced similarity to seizure onsets suggests that they contain relevant information about the epileptic networks from which they arise and may aide in the clinical evaluation of epilepsy in patients. PMID- 26608451 TI - IL-10 Indirectly Regulates Corneal Lymphangiogenesis and Resolution of Inflammation via Macrophages. AB - The role of IL-10, a primarily anti-inflammatory cytokine, in the regulation of inflammatory lymphangiogenesis is undetermined. Herein, we show that IL-10 modulates corneal lymphangiogenesis and resolution of inflammation. IL-10 was not expressed in healthy corneas but was up-regulated in inflamed corneas by infiltrating macrophages. Macrophages up-regulated the expression of prolymphangiogenic vascular endothelial growth factor-C upon stimulation with IL 10. Consistently, corneal inflammation resulted in reduced expression of vascular endothelial growth factor-C and decreased corneal lymphangiogenesis in IL-10 deficient mice (IL-10(-/-)). The effect of IL-10 on lymphangiogenesis was indirect via macrophages, because IL-10 did not directly affect lymphatic endothelial cells. The expression of proinflammatory cytokines and the numbers of infiltrating macrophages increased and remained elevated in inflamed corneas of IL-10(-/-) mice, indicating that IL-10 deficiency led to more severe and prolonged inflammation. The corneal phenotype of IL-10 deficient mice was mimicked in mice with conditional deletion of Stat3 in myeloid cells (lysozyme M Cre mice Stat3(fl/fl) mice), corroborating the critical role of macrophages in the regulation of lymphangiogenesis. Furthermore, local treatment with IL-10 promoted lymphangiogenesis and faster egress of macrophages from inflamed corneas. Taken together, we demonstrate that IL-10 indirectly regulates inflammatory corneal lymphangiogenesis via macrophages. Reduced lymphangiogenesis in IL-10(-/-) and lysozyme M Cre Stat3(fl/fl) mice is associated with more severe inflammatory responses, whereas IL-10 treatment results in faster resolution of inflammation. IL-10 might be used therapeutically to terminate pathological inflammation. PMID- 26608453 TI - Neuroscience Application to Noncontact Anterior Cruciate Ligament Injury Prevention. AB - CONTEXT: Many factors, including anatomy, neuromuscular control, hormonal regulation, and genetics, are known to contribute to the noncontact anterior cruciate ligament (ACL) injury risk profile. The neurocognitive and neurophysiological influences on the noncontact ACL injury mechanism have received less attention despite their implications to maintain neuromuscular control. Sex-specific differences in neurocognition may also play a critical role in the elevated female ACL injury risk. This report serves to frame existing literature in a new light to consider neurocognition and its implications for movement control, visual-motor function, and injury susceptibility. EVIDENCE ACQUISITION: Sources were obtained from PubMed, MEDLINE, Web of Science, and LISTA (EBSCO) databases from 1990 onward and ranged from diverse fields including psychological and neuroscience reviews to injury epidemiology and biomechanical reports. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 5. RESULTS: Neurological factors may contribute to the multifactorial ACL injury risk paradigm and the increased female injury susceptibility. CONCLUSION: When developing ACL injury prevention programs, considering neurocognition and its role in movement, neuromuscular control, and injury risk may help improve intervention effectiveness. PMID- 26608452 TI - Retinal Dystrophy and Optic Nerve Pathology in the Mouse Model of Mucolipidosis IV. AB - Mucolipidosis IV is a debilitating developmental lysosomal storage disorder characterized by severe neuromotor retardation and progressive loss of vision, leading to blindness by the second decade of life. Mucolipidosis IV is caused by loss-of-function mutations in the MCOLN1 gene, which encodes the transient receptor potential channel protein mucolipin-1. Ophthalmic pathology in patients includes corneal haze and progressive retinal and optic nerve atrophy. Herein, we report ocular pathology in Mcoln1(-/-) mouse, a good phenotypic model of the disease. Early, but non-progressive, thinning of the photoreceptor layer, reduced levels of rhodopsin, disrupted rod outer segments, and widespread accumulation of the typical storage inclusion bodies were the major histological findings in the Mcoln1(-/-) retina. Electroretinograms showed significantly decreased functional response (scotopic a- and b-wave amplitudes) in the Mcoln1(-/-) mice. At the ultrastructural level, we observed formation of axonal spheroids and decreased density of axons in the optic nerve of the aged (6-month-old) Mcoln1(-/-) mice, which indicates progressive axonal degeneration. Our data suggest that mucolipin 1 plays a role in postnatal development of photoreceptors and provides a set of outcome measures that can be used for ocular therapy development for mucolipidosis IV. PMID- 26608454 TI - Corticotomies and Orthodontic Tooth Movement: A Systematic Review. AB - PURPOSE: A systematic review was conducted to examine the evidence for the effectiveness and safety of corticotomy-facilitated orthodontics. MATERIALS AND METHODS: Electronic databases (Ovid Medline, EMBASE, Cochrane, SCOPUS, and Web of Science) were searched for articles that examined the rate of corticotomy facilitated orthodontic tooth movement and its effects on the periodontium, root resorption, and tooth vitality. Unpublished literature was searched electronically through ClinicalTrials.gov (http://www.clinicaltrials.gov) and the ISRCTN registry (http://www.controlled-trials.com). Relevant orthodontic journals and reference lists also were checked for eligible studies. Randomized clinical trials (RCTs) and controlled clinical trials (CCTs) were considered. Two article reviewers independently assessed the search results, screened the relevant articles, performed data extraction, and evaluated the methodologic quality of the studies. RESULTS: Fourteen eligible articles (6 RCTs and 8 CCTs) were included in the review. There was a statistically meaningful increase in the rate of tooth movement compared with controls for all corticotomy techniques assessed. Some studies reported that acceleration in tooth movement was only temporary (lasting a few months). Corticotomy procedures did not seem to produce unwanted adverse effects on the periodontium, root resorption, and tooth vitality. The quality of the body of evidence was regarded as low owing to the presence of multiple methodologic issues, high risks of bias, and heterogeneity in the included articles. CONCLUSION: Corticotomy procedures can produce statistically and clinically meaningful temporary increases in the rate of orthodontic tooth movement with minimal side-effects. Additional high-quality randomized clinical trials are needed to allow more definitive conclusions. PMID- 26608455 TI - Clinical and Retrospective Evaluation of 4.1- or 4.3-mm-Diameter Implants Placed Immediately in the Molar Region: A Preliminary Study. AB - PURPOSE: The purpose of this study was to evaluate the clinical and radiographic performance of 4.1- or 4.3-mm-diameter implants placed immediately in the molar region. MATERIALS AND METHODS: Twenty-nine patients (14 men and 15 women, aged 21 71 years) received 38 implants that were placed immediately in the molar region. Of the implants, 19 (50%) were placed in the maxilla and 19 (50%) in the mandible. Thirty-eight prostheses (19 single restoration and 19 partial fixed prostheses) were fabricated. The diameter of the implant type was 4.1 mm (15 implants, 39%) or 4.3 mm (23 implants, 61%). Clinical and radiographic assessments of implants, prostheses, and peri-implant tissues were performed at 1 month, 3 months, and 6 months and then every 6 months after definitive restoration. RESULTS: Kaplan-Meier survival estimates showed a 97.4% probability of implant survival to 36 months. The mean time of implant follow-up was 36 months, with a maximum of 75 months and minimum of 4 months. Cement dissolution occurred in 1 partial fixed prosthesis. Screw loosening occurred in 2 single crown restorations in 1 patient. No abutment, screw, or implant fixture fractures were observed during the follow-up periods. The mean cervical bone loss of 38 implants measured 0.31 +/- 0.06 mm mesially and 0.31 +/- 0.07 mm distally 1 year after implant installation. There were no significant differences in implant survival and cervical bone loss based on anatomic location, gender, and prosthesis type. CONCLUSIONS: This study describes successful outcomes after the use of 4.1- or 4.3-mm-diameter implants placed immediately in the molar region. Further comprehensive maintenance practices and follow-up schedules are required. PMID- 26608456 TI - Rapid cycle development of a multifactorial intervention achieved sustained reductions in central line-associated bloodstream infections in haematology oncology units at a children's hospital: a time series analysis. AB - BACKGROUND: Immunocompromised children are at high risk for central line associated bloodstream infections (CLABSIs) and its associated morbidity and mortality. Prevention of CLABSIs depends on highly reliable care. PURPOSE: Since the summer of 2013, we saw an increase in patient volume and acuity in our centre. Additionally, CLABSIs rates more than tripled during this period. The purpose of this initiative was to rapidly identify and mitigate potential underlying drivers to the increased CLABSI rate. METHODS: Through small tests of change, we implemented a standard process for daily hygiene; increased awareness of high-risk patients with CLABSI; improved education/assistance for nurses performing high-risk central venous catheter procedures; and developed a system to improve allocation of resources to de-escalate system stress. RESULTS: The CLABSI rate from June 2013 to May 2014 was 2.03 CLABSIs/1000 line days. After implementation of our interventions, we saw a significant decrease in the CLABSI rate to 0.39 CLABSIs/1000 line days (p=0.008). Key processes have become more reliable: 100% of dressing changes are completed with the new two-person standard; daily hygiene adherence has increased from 25% to 70%; 100% of nurses are approached daily by senior nursing for assistance with high-risk procedures; and patients at risk for a CLABSI are identified daily. CONCLUSIONS: Stress to a complex system caring for high-risk patients can challenge CLABSI rates. Identifying key processes and executing them reliably can stabilise outcomes during times of system stress. PMID- 26608457 TI - Endoscopic cubital tunnel release: a systematic review. AB - INTRODUCTION: Theoretical advantages of endoscopic cubital tunnel release are the short incision, lower risk of nerve damage, reduced manipulation of the nerve and possible faster recovery. SOURCES OF DATA: We systematically searched Medline (PubMed), Web of Science and Scopus databases using the following keywords: 'endoscopic ulnar nerve', 'endoscopic cubital nerve', 'endoscopic ulnar compression' and 'endoscopic ulnar neuropathy'. Twenty-one studies were included in this review. The quality of the studies was assessed using the Coleman Methodological Score. AREAS OF AGREEMENT: Endoscopic release is effective for cubital tunnel entrapment and allows adequate visualization of the site of entrapment. There is a negative association between the severity of the compression and reported outcomes. Injury to the medial branch of the antebrachial cutaneous nerve is less frequent thanks to the limited dissection. The most frequent complication is the development of a hematoma. AREAS OF CONTROVERSY: It is unclear whether ulnar nerve instability is a contraindication to simple decompression. GROWING POINTS: The shorter time to return to work and the cosmetic appearance of the scar can be considered advantages of the endoscopic technique. AREAS TIMELY FOR DEVELOPING RESEARCH: There is a need to perform randomized clinical trials with common and validated scoring system with a longer duration of follow-up. The literature pertinent to endoscopic cubital tunnel release is lacking in the evaluation of the learning curve. Further investigations are necessary to assess the role of ulnar nerve instability. PMID- 26608458 TI - Radiosensitization of TPGS-emulsified docetaxel-loaded poly(lactic-co-glycolic acid) nanoparticles in CNE-1 and A549 cells. AB - Docetaxel is among the most effective radiosensitizers. It is widely used as radiosensitizer in many tumors, including head and neck carcinoma. Nevertheless, poor solubility and severe hypersensitivity limit its clinical use and its therapeutic effect remains to be improved. In this study, docetaxel-loaded polymeric nanoparticles were prepared by nanoprecipitation method to be new radiosensitizer with lower side effects and higher efficacy. The physiochemical characteristics of the nanoparticles were studied. Two human tumor cell lines which are resistant to radiotherapy were used in this research. We have compared the radioenhancement efficacy of docetaxel-loaded nanoparticles with docetaxel in A549 and CNE-1 cells. Compared with docetaxel, radiosensitization of docetaxel loaded nanoparticles was improved significantly (sensitization enhancement ratio in A549 increased 1.24-fold to 1.68-fold when the radiation was applied 2 h after the drug, p < 0.01, sensitization enhancement ratio in CNE-1 increased 1.32-fold to 1.61-fold, p < 0.05). We explored the mechanisms for the radiosensitization efficiency and the difference between docetaxel and docetaxel-loaded poly(lactic co-glycolic acid) (PLGA) nanoparticles. The improved radiosensitization efficacy was associated with enhanced G2/M arrest, promoted apoptosis and the role of D alpha-tocopheryl polyethylene glycol 1000 succinate which will enhance the cell uptake and inhibit the multiple drug resistance. Moreover, the radiosensitization efficacy of docetaxel-loaded nanoparticles was more prominent than docetaxel. In conclusion, tocopheryl polyethylene glycol 1000 succinate-emulsified docetaxel loaded PLGA nanoparticles were more efficacious and fewer adverse effects were observed than with the commercial docetaxel formulation. Thus, PLGA nanoparticles hold promise as a radiosensitizing agent. PMID- 26608459 TI - Development and in vitro evaluation of infection resistant materials: A novel surface modification process for silicone and Dacron. AB - Silicone and Dacron are used in a wide spectrum of implantable and indwelling medical products. They elicit a foreign body response, which results in a chronic inflammatory environment and collagenous encapsulation of the medical device that compromises the immune system's ability to effectively fight infections at the biomaterial surface. The objective of this work is to evaluate a novel process to modify silicone and Dacron with a bioactive collagen surface coupled to a gentamicin impregnated hydrogel graft and assess the surface's cytocompatibility and infection resistance properties. Samples of silicone and polyethylene terephthalate (Dacron velour) were modified by plasma deposition and activation followed by a co-polymer acrylic acid (AA)/acrylamide (AAm) hydrogel graft and covalent immobilization of a bioactive collagen surface. The modified surfaces were characterized using FTIR, contact angle, staining, SEM, and XPS. The poly (AA-AAm) hydrogel was impregnated with gentamicin and tested for controlled release characteristics. Each modified surface was evaluated for its ability to resist infection and to promote normal healing as measured by bacterial growth inhibition (Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa) in both broth and agar conditions as well as using fluorescence microscopy to observe adherence of 3T3-NIH fibroblasts. The addition of the poly (AA-AAm) hydrogel with gentamicin inhibited bacterial growth and the subsequent addition of the collagen surface promoted robust fibroblast adhesion on both silicone and Dacron materials. Thorough surface characterization and in vitro bacterial and fibroblast evaluation results suggest that this novel surface bioengineering process generated a highly effective surface on silicone and Dacron with the potential to reduce infection and promote healing. PMID- 26608461 TI - Vesicle-associated microRNAs are released from blood cells on incubation of blood samples. AB - MicroRNAs (miRNAs) circulating extracellularly in the blood are currently intensively studied as novel disease markers. However, the preanalytical factors influencing the levels of the extracellular miRNAs are still incompletely explored. In particular, it is unknown, whether the incubation of blood samples as occurring in clinical routine can lead to a release of miRNAs from blood cells and thus alter the extracellular miRNA levels before the preparation of serum or plasma from the blood cells. Using a set of marker miRNAs and quantitative RT PCR, we found that the levels of extracellular miRNA-1, miRNA-16, and miRNA-21 were increased in EDTA and serum collection tubes incubated for 1-3 hours at room temperature and declined thereafter; the levels of the liver-specific miRNA-122 declined monophasically. These events occurred in the absence of significant hemolysis. When the blood was supplemented with Ribonuclease A inhibitor, the levels of miRNA-1, miRNA-16, and miRNA-21 increased substantially during the initial 3 hours of incubation and those of miRNA-122 remained unchanged, indicating that the release of blood cell-derived miRNAs occurred during the initial 3 hours of incubation of the blood tubes, but not at later time points. Separation of 5-hour preincubated blood into vesicle and nonvesicle fractions revealed a selective increase in the portion of vesicle-associated miRNAs. Together, these data indicate that the release of vesicle-associated miRNAs from blood cells can occur in blood samples within the time elapsing in normal clinical practice until their processing without significant hemolysis. This becomes particularly visible on the inhibition of miRNA degradation by Ribonuclease A inhibitor. PMID- 26608462 TI - Curcumin inhibits apoptosis by regulating intracellular calcium release, reactive oxygen species and mitochondrial depolarization levels in SH-SY5Y neuronal cells. AB - Neurological diseases such as Alzheimer's and Parkinson's diseases are incurable progressive neurological disorders caused by the degeneration of neuronal cells and characterized by motor and non-motor symptoms. Curcumin, a turmeric product, is an anti-inflammatory agent and an effective reactive oxygen and nitrogen species scavenging molecule. Hydrogen peroxide (H2O2) is the main source of oxidative stress, which is claimed to be the major source of neurological disorders. Hence, in this study we aimed to investigate the effect of curcumin on Ca(2+) signaling, oxidative stress parameters, mitochondrial depolarization levels and caspase-3 and -9 activities that are induced by the H2O2 model of oxidative stress in SH-SY5Y neuronal cells. SH-SY5Y neuronal cells were divided into four groups namely, the control, curcumin, H2O2, and curcumin + H2O2 groups. The dose and duration of curcumin and H2O2 were determined from published data. The cells in the curcumin, H2O2, and curcumin + H2O2 groups were incubated for 24 h with 5 uM curcumin and 100 uM H2O2. Lipid peroxidation and cytosolic free Ca(2+) concentrations were higher in the H2O2 group than in the control group; however, their levels were lower in the curcumin and curcumin + H2O2 groups than in the H2O2 group alone. Reduced glutathione (GSH) and glutathione peroxidase (GSH-Px) values were lower in the H2O2 group although they were higher in the curcumin and curcumin + H2O2 groups than in the H2O2 group. Caspase-3 activity was lower in the curcumin group than in the H2O2 group. In conclusion, curcumin strongly induced modulator effects on oxidative stress, intracellular Ca(2+) levels, and the caspase-3 and -9 values in an experimental oxidative stress model in SH-SY5Y cells. PMID- 26608460 TI - Detection of gluten immunogenic peptides in the urine of patients with coeliac disease reveals transgressions in the gluten-free diet and incomplete mucosal healing. AB - OBJECTIVE: Gluten-free diet (GFD) is the only management for coeliac disease (CD). Available methods to assess GFD compliance are insufficiently sensitive to detect occasional dietary transgressions that may cause gut mucosal damage. We aimed to develop a method to determine gluten intake and monitor GFD compliance in patients with CD and to evaluate its correlation with mucosal damage. DESIGN: Urine samples of 76 healthy subjects and 58 patients with CD subjected to different gluten dietary conditions were collected. A lateral flow test (LFT) with the highly sensitive and specific G12 monoclonal antibody for the most dominant gluten immunogenic peptides (GIP) and a LFT reader were used to quantify GIP in solid-phase extracted urines. RESULTS: GIP were detectable in concentrated urines from healthy individuals previously subjected to GFD as early as 4-6 h after single gluten intake, and remained detectable for 1-2 days. The urine assay revealed infringement of the GFD in about 50% of the patients. Analysis of duodenal biopsies revealed that most of patients with CD (89%) with no villous atrophy had no detectable GIP in urine, while all patients with quantifiable GIP in urine showed incomplete intestinal mucosa recovery. CONCLUSION: GIP are detected in urine after gluten consumption, enabling a new and non-invasive method to monitor GFD compliance and transgressions. The method was sensitive, specific and simple enough to be convenient for clinical monitoring of patients with CD as well as for basic and clinical research applications including drug development. TRIAL REGISTRATION NUMBER: NCT02344758. PMID- 26608463 TI - Osteoprotegerin secreted by inflammatory and invasive breast cancer cells induces aneuploidy, cell proliferation and angiogenesis. AB - BACKGROUND: Osteoprotegerin (OPG) is a glycoprotein that has multifaceted role and is associated with several cancer malignancies like that of bladder carcinoma, gastric carcinoma, prostate cancer, multiple myeloma and breast cancer. Also OPG has been associated with several organ pathologies. The widespread expression of OPG suggests that OPG may have multiple biological activities that are yet to be explored. METHODS: The anchorage-independent sphere cultures of the adherent cells were instrumental in our study as it provided a deeper insight into the complexity of a 3D tumor. Cytokine profiling was performed for OPG's detection in the microenvironment. ELISA and western blotting were performed to quantify the OPG secretion and measure the protein levels respectively. OPG expression was detected in human breast cancer tissue samples by IHC. To decipher OPG's role in tumor aggressiveness both recombinant human OPG as well as OPG rich and depleted breast cancer cell conditioned media were tested. Western blotting and MTT assay were performed to detect changes in signaling pathways and proliferation that were induced in presence of OPG. Onset of aneuploidy, in presence of OPG, was measured by cell cycle analysis and western blotting. Finally, human Breast Cancer qBiomarker Copy Number PCR Array was used to detect how OPG remarkably induced gene copy numbers for oncogenic pathway regulators. RESULTS: SUM149PT and SUM1315M02 cells secrete high levels of the cytokine OPG compared to primary human mammary epithelial cells (HMEC). High expression of OPG was also detected in human breast cancer tissue samples compared to the uninvolved tissue from the same patient. OPG induced proliferation of control HMEC spheres and triggered the onset of aneuploidy in HMEC sphere cultures. OPG induced the expression of aneuploidy related kinases Aurora-A Kinase (IAK-1), Bub1 and BubR1 probably through the receptor activator of nuclear factor kappa-B ligand (RANKL) and syndecan-1 receptors via the Erk, AKT and GSK3(3 signaling pathway. Gene copy numbers for oncogenic pathway regulators such AKT1, Aurora-A Kinase (AURKA or IAK-1), epidermal growth factor receptor (EGFR) and MYC with a reduction in the copy numbers of cyclin dependent kinase inhibitor 2A (CDKN2A), PTEN and DNA topoisomerase 2 alpha (TOP2A) were induced in presence of OPG. CONCLUSIONS: These results highlight the role of OPG in reprogramming normal mammary epithelial cells to a tumorigenic state and suggest promising avenues for treating inflammatory breast cancer as well as highly invasive breast cancer with new therapeutic targets. PMID- 26608464 TI - Soluble PD-1 aggravates progression of collagen-induced arthritis through Th1 and Th17 pathways. AB - INTRODUCTION: The programmed cell death 1 (PD-1) protein is a critical regulator of T-cell activation and is also an important therapeutic target for autoimmune diseases. Little is known about the regulation and functional properties of the soluble PD-1 (sPD-1) variant. The aim of this study was to examine the role of sPD-1 in the regulation of human and murine rheumatoid arthritis (RA). METHODS: Expression of cytokines and sPD-1 in sera, synovial fluid, and peripheral blood (PB) mononuclear cells of patients with RA were analyzed by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. PD-1 function was assessed in PB T cells after stimulation of the cells with anti-CD3 and PD-L1-Fc to crosslink PD-1. Recombinant PD-1-Fc was injected intraperitoneally into DBA/1 mice with collagen-induced arthritis (CIA) to analyze the function of sPD-1 in vivo. RESULTS: High concentrations of sPD-1 were found in sera and synovial fluid of patients with RA. The levels of serum sPD-1 were significantly correlated with titers of rheumatoid factor (RF) (r = 0.306, p = 0.005) and 28-joint Disease Activity Score (r = 0.545, p < 0.001). Further characterization of sPD-1 revealed that it functionally blocked the inhibitory effect of membrane-bound PD-1 on T cell activation. Interferon gamma, tumor necrosis factor alpha, and interleukin 17A were identified as inducers of sPD-1 in vitro. Moreover, PD-1-Fc enhanced proinflammatory cytokine expression, generation of Th1 cells and Th17 cells, and joint pathology in a CIA model. CONCLUSIONS: sPD-1 regulates peripheral T-cell responses in both human and murine RA. Thus, sPD-1 may represent an additional biomarker or target in immunomodulatory therapy for RA. PMID- 26608467 TI - Understanding bruxism in children and adolescents. AB - Screening for the various forms of bruxism in children and adolescents requires a sound knowledge of the physiopathology of this parafunction in addition to the etiologic and associated factors and comorbidities. The international literature contains various suggestions for suitable treatment. The optimal therapeutic approach often involves multidisciplinary management of these young patients. Sleep bruxism (SB) is a common sleep disorder which can cause serious problems to the stomatognathic system such as damaged teeth, headaches, muscle pain and TMD. Dental professionals are responsible for the detection and prevention of these harmful impacts on the patient's oral health. However, SB is much more than a question of worn teeth. Patients with SB consult for other medical comorbidities such as nighttime breathing problems, insomnia, attention deficit hyperactivity disorder, depression, moodiness and gastroesophogeal reflux before any course of treatment is initiated. If a comorbidity is diagnosed, the treatment approach will be aimed in the first instance at the medical disorder, while concurrently managing the repercussions of SB. On the other hand, in as far as the majority of young bruxers cease to grind their teeth before adolescence or adulthood, it is feasible to adopt wait-and-see and non-interventionist strategies for young children. However, it is preferable to have a better understanding of SB, notably on account of its potential association with psychological disorders during childhood. Daytime bruxism is characterized by teeth clenching (TC). First-line treatment involves encouraging patients to monitor their harmful parafunctional behavior and, consequently, change and cease it. This protocol is not always easy to apply, particularly in younger children. In such cases, cognitive-behavioral treatments and biofeedback techniques can also be used in daytime bruxism. PMID- 26608465 TI - Identification and characterization of a novel stress-responsive outer membrane protein Lip40 from Actinobacillus pleuropneumoniae. AB - BACKGROUND: Actinobacillus pleuropneumoniae, a Gram-negative bacterium, is the causative agent of porcine pleuropneumonia, a highly contagious and often fatal disease. Because current vaccines confer limited protection against A. pleuropneumoniae infection, the development of more effective vaccines is urgently required. The identification of immunogenic and protective antigens, such as an outer-membrane lipoprotein, will advance this purpose. RESULTS: Sixty putative lipoproteins were predicted from the genomic sequence of A. pleuropneumoniae using multiple algorithms. Here, we focused on the characteristics of the putative lipoprotein Lip40 from A. pleuropneumoniae strain SLW01 (serovar 1). Lip40 shares sequence similarity with many bacterial lipoproteins, and the structural prediction of Lip40 suggests that it is similar to A. pleuropneumoniae TbpB. The N-terminus of Lip40 contains an interesting tandemly repeated sequence, Q(E/D/P)QPK. Real-time RT-PCR indicated that the expression of lip40 was significantly upregulated at 42 degrees C, at 16 degrees C, and under anaerobic conditions. Recombinant Lip40 (rLip40) produced in Escherichia coli BL21(DE3) was specifically recognized by porcine convalescent serum directed against A. pleuropneumoniae. Lip40 was confirmed to localize at the bacterial outer membrane, and its expression was significantly stimulated when A. pleuropneumoniae was cultured under various stress conditions. Lip40 also protected 75% of mice from fatal virulent A. pleuropneumoniae infection. CONCLUSIONS: The immunogenic outer-membrane protein Lip40 is stress responsive, protects mice against infection, and might be a virulence determinant. Further investigation of Lip40 should expedite vaccine development and provide insight into the pathogenesis of A. pleuropneumoniae. PMID- 26608468 TI - ? PMID- 26608466 TI - Scutellarin regulates microglia-mediated TNC1 astrocytic reaction and astrogliosis in cerebral ischemia in the adult rats. AB - BACKGROUND: Scutellarin, an anti-inflammatory agent, effectively suppressed microglia activation in rats with middle cerebral artery occlusion (MCAO). Robust microglia activation, acute in onset, was followed by astrogliosis. This study was aimed to determine if scutellarin would also affect the reactive astrocytes that play an important role in tissue repair. Expression of GFAP and Notch-1 and its members: Notch receptor intracellular domain (NICD), and transcription factor hairy and enhancer of split-1 (HES-1), together with nestin and proinflammatory mediators was assessed by immunofluorescence staining in TNC1 astrocytes treated, respectively, with BV-2 conditioned medium (CM) and CM + lipopolysaccharide (LPS) (CM + L) serving as the controls, and conditioned medium derived from LPS activated BV-2 cells pretreated with scutellarin (CM + SL). Study of the above biomarkers was then extended to reactive astrocytes in scutellarin injected MCAO rats. RESULTS: TNC1 astrocytes remained relatively unreactive in terms of expression of different biomarkers to direct scutellarin treatment when compared with the control cells. In comparison to cells in the control medium (CM, CM + L), they responded vigorously to CM + SL as evidenced by the enhanced protein expression of GFAP, Notch-1, NICD and HES-1 coupled with that of nestin, TNF alpha, IL-1beta, and iNOS by Western and immunofluorescence analysis. Electron microscopy showed marked hypertrophy and cell expansion of TNC1 astrocytes bearing many filamentous processes indicative of enhanced astrocyte reaction when treated with CM + SL. In MCAO rats, scutellarin also augmented the expression of the above markers in reactive astrocytes; moreover, astrocytes were evidently hypertrophic. CONCLUSIONS: The results suggest that scutellarin regulates astrogliosis; more importantly, it is microglia-mediated as demonstrated in vitro. Increased expression of Notch signaling in synchrony with nestin may be linked to proliferation and "de-differentiation" of reactive astrocytes; the significance of enhanced TNF-alpha, IL-1beta and iNOS expression in reactive astrocytes by scutellarin may be neuroprotective but this remains speculative. PMID- 26608470 TI - Avian Influenza H5N1 Surveillance and its Dynamics in Poultry in Live Bird Markets, Egypt. AB - H5N1, a highly pathogenic avian influenza (H5N1 HPAI), is an endemic disease that is significant for public health in Egypt. Live bird markets (LBMs) are widespread in Egypt and play an important role in HPAI disease dynamics. The aim of the study was to evaluate the H5N1 HPAI prevalence in representative LBMs from 2009 to 2014, assess the effects of other variables and evaluate past outbreaks and human cases. It was found that ducks and geese are high-risk species and that the prevalence of H5N1 HPAI was higher immediately after the political crises of 2011. The end of a calendar year (June to December) was a high-risk period for positive samples, and the risk in urban LBMs was twice the risk in rural LBMs. Winter and political unrest was associated with higher H5N1 HPAI prevalence. Both human and poultry populations will continue to rise in Egypt, so continued poultry outbreaks are likely to be linked to more human cases. LBMs will continue to play a role in the dynamics of poultry disease in Egypt, and there is a need to reorganize markets in terms of biosecurity and traceability. It may also be beneficial to reduce inter-governorate inter-regional movements associated with poultry trade through promotion of regional trade or in the alternative provide sanitary features along the poultry market chain to reduce the speed of H5N1 HPAI infections. Policy formulation, design and enforcement must be pro-poor, and consideration of the sociocultural and economic realities in Egypt is important. The LBMs provide ideal platforms to carry out sound surveillance plans and mitigate zoonotic risks of H5N1 HPAI to humans. PMID- 26608471 TI - Low-Pressure Photolysis of 2,3-Pentanedione in Air: Quantum Yields and Reaction Mechanism. AB - Dicarbonyls in the atmosphere mainly arise from secondary sources as reaction products in the degradation of a large number of volatile organic compounds (VOC). Because of their sensitivity to solar radiation, photodissociation of dicarbonyls can dominate the fate of these VOC and impact the atmospheric radical budget. The photolysis of 2,3-pentanedione (PTD) has been investigated for the first time as a function of pressure in a static reactor equipped with continuous wave cavity ring-down spectroscopy to measure the HO2 radical photostationary concentrations along with stable species. We showed that (i) Stern-Volmer plots are consistent with low OH-radical formation yields in RCO + O2 reactions, (ii) the decrease of the photodissociation rate due to pressure increase from 26 to 1000 mbar is of about 30%, (iii) similarly to other dicarbonyls, the Stern-Volmer analysis shows a curvature at the lower pressure investigated, which may be assigned to the existence of excited singlet and triplet PTD states, (iv) PTD photolysis at 66 mbar leads to CO2, CH2O and CO with yields of (1.16 +/- 0.04), (0.33 +/- 0.02) and (0.070 +/- 0.005), respectively, with CH2O yield independent of pressure up to 132 mbar and CO yield in agreement with that obtained at atmospheric pressure by Bouzidi et al. (2014), and (v) the PTD photolysis mechanism remains unchanged between atmospheric pressure and 66 mbar. As a part of this work, the O2 broadening coefficient for the absorption line of HO2 radicals at 6638.21 cm(-1) has been determined (gammaO2 = 0.0289 cm(-1) atm(-1)). PMID- 26608469 TI - Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate dispersible tablets in paediatric patients with acute uncomplicated Plasmodium falciparum malaria: a phase II, multicentric, open-label study. AB - BACKGROUND: The World Health Organization (WHO) recommends artemisinin combination therapy (ACT) for the treatment of uncomplicated Plasmodium falciparum malaria. The present study investigated the efficacy and safety of fixed dose combination (FDC) of arterolane maleate 37.5 mg and piperaquine phosphate (PQP) 187.5 mg dispersible tablets in paediatric patients aged 6 months to 12 years. METHODS: Male and female patients aged 6 months to 12 years who were confirmed cases of P. falciparum mono-infection with fever or documented history of fever in the previous 24 h were included. The patients were administered FDC of arterolane maleate and PQP as single daily doses for three consecutive days based on their age. The primary efficacy outcome was proportion of patients with polymerase chain reaction (PCR)-corrected adequate clinical and parasitological response (ACPR) on day 28. Safety was analysed based on adverse events (AE), laboratory abnormalities and abnormalities on electrocardiograph. RESULTS: A total of 141 eligible paediatric patients received FDC of arterolane maleate and PQP in a 42-day follow-up study. All the enrolled patients (141) were included in intention to treat (ITT) and safety analyses, and 126 patients were considered in per protocol (PP) population. The PCR-corrected ACPR on day 28 was achieved in all patients (100 %; 95 % CI 97.11-100) included in PP population. The median parasite clearance time (PCT) and fever clearance time (FCT) were 24 h (95 % CI 18.0-24.0) and 10 h (95 % CI 4.0-18.0), respectively. The most frequently reported clinical AE was vomiting. Majority of the AEs were mild to moderate in severity and resolved without sequelae. No patient was discontinued for any QTc (corrected QT interval) prolongation. No deaths or serious AEs were reported during the study. CONCLUSION: The findings from this study showed that FDC of arterolane maleate and PQP effectively cures P. falciparum malaria and attains acceptable level of cure by day 28 in paediatric patients. The efficacy and safety results observed in children warrants further studies on FDC of arterolane maleate and PQP dispersible tablets. TRIAL REGISTRATION: Clinical Trial Registry India: CTRI/2009/091/000531. PMID- 26608472 TI - The rate of RNA degradation in human dental pulp reveals post-mortem interval. AB - Post-mortem interval (PMI) is the amount of time elapsed since the time of death. Over the years, many methods were developed to assess PMI, but their precision and time frame of applicability are often limited. Our present pilot study aimed to prove if RNA degradation of human dental pulp can be used for PMI estimation. RNA was isolated from the pulps of healthy wisdom teeth and premolars. RNA degradation was determined as RNA integrity number (RIN) with Agilent Bioanalyzer and subsequently by amplification of different length products by PCR after reverse transcription. The RNA integrity analysis allowed us to determine the time of post-mortem interval with high confidence level in the first 21 days. With the PCR-based method, we were able to perform a crude estimation of incubation time of teeth between 20 and 42 days post extraction. These results show that this method might be a promising new tool for PMI estimation despite the limitations. PMID- 26608473 TI - A community split among dolphins: the effect of social relationships on the membership of new communities. AB - Little is known about community splitting among dolphins because such events are rare in dolphin populations. A case of a community split was confirmed in a population of Indo-Pacific bottlenose dolphins (Tursiops aduncus) in Japan, where a group of approximately 30 dolphins moved to a new habitat some 60 km from the original habitat. We examined the associations among the dolphins before the community split to determine whether the new community members were already socially different before the split, using 7-year identification data. Before the split, the males in the same community after the split more often associated with each other than they did with those in different community. In contrast, the association patterns among females and between sexes showed no relationships with their post-split community membership. These results indicate that the males of new community were socially different from the other males for a long time before the split, but the females might not have been different. Our findings suggest that at time of the community split, the factors determining the memberships of the subsequent communities are sex-linked. The long-term social relationships among males could be maintained in the subsequent communities. PMID- 26608474 TI - Pedicled posteromedial thigh (PMT) flap: A new alternative for groin defect reconstruction. AB - The posterior medial thigh is mainly vascularized by the profunda femoris artery (PFA), which nourishes the adductor magnus muscle and overlying skin, to supply a number of perforators that can potentially be used as pedicles for local perforator flaps. Here we present two cases utilizing the pedicled posteromedial thigh flap (PMT) to reconstruct the groin defects. Two patients underwent resection for metastatic malignant melanoma resulting in large defects of the groin with exposure of major inguinal vessels; the dimensions of the skin defects were 15 cm * 5 cm and 16 cm * 6 cm, two ipsilateral pedicled PMT flaps were designed to cover the defects. The pedicled PMT flaps were based on perforators arising from the PFA and were transposed through a submuscular tunnel into the defect. The postoperative course was uneventful and the wounds were reconstructed successfully. The pedicled PMT flap may be an option for reconstruction of groin defects and could be incorporated into the armamentarium of the reconstructive microsurgeon. (c) 2015 Wiley Periodicals, Inc. Microsurgery 37:339-343, 2017. PMID- 26608476 TI - ACE inhibitors in African Americans with hypertension associated with worse outcomes as compared to other antihypertensives. PMID- 26608475 TI - Changes in milk composition in obese rats consuming a high-fat diet. AB - Maternal obesity programmes offspring development. We addressed maternal obesity effects induced by high-fat diets on maternal mammary gland (MG) structure and function and offspring brain, liver and fat outcomes. Mothers were fed control (C, n 5) or obesogenic (MO, n 5) diet from the time they were weaned through pregnancy beginning at 120 d, through lactation. At offspring postnatal day (PND) 20, milk leptin and nutrients were determined. At the end of lactation, maternal liver and MG fatty acid profile were measured. Desaturase (Delta6D and Delta5D) and elongase (ELOVL 5 and ELOVL 2) protein was measured by immunohistochemistry and Western blotting (WB) in the liver and WB in the MG. In mothers, liver, MG and milk fat content were higher in MO than in C. Liver arachidonic acid (AA) and EPA and MG EPA were lower in MO than in C. Liver desaturases were higher in MO. The MG was heavier in MO than in C, with decreased Delta5D expression in MO. Desaturases and elongases were immunolocalised in parenchymal cells of both groups. Milk yield, water, carbohydrate content, EPA and DHA were lower, whereas milk leptin and AA were higher in MO than in C. At PND 21 and 36, brain weight was less and fat depots were greater in MO offspring than in C. MO decreased male absolute brain weight but not female absolute brain weight. In conclusion, maternal obesity induced by an obesogenic diet negatively affects maternal liver and MG function with the production of significant changes in milk composition. Maternal obesity adversely affects offspring metabolism and development. PMID- 26608477 TI - Improving reporting and utility of evaluations of complex interventions. PMID- 26608478 TI - Effect of zinc bacitracin and phytase on growth performance, nutrient digestibility, carcass and meat traits of broilers. AB - A total of 336 one-day-old Hubbard broiler chickens were randomly distributed among 8 groups, each containing six replicates (7 chickens/replicate). From 1 to 40 days of age, the groups fed the same starter, grower and finisher diets. The control group was unsupplemented; zinc bacitracin (ZnB) group received the antibiotic at 0.5 g/kg; fungal phytase (FP) groups received 250, 500 and 1000 U/kg diet of Aspergillus niger phytase (FP_250, FP_500 and FP_1000 groups), respectively; bacterial phyatse (BP) groups received 250, 500 and 1000 U/kg diet of Escherichia coli phytase (BP_250EP, BP_500EP and BP_1000EP groups) respectively. Considering the whole experimental period, body weight gain was unaffected by ZnB and different concentrations of bacterial and fungal phytase; however, the feed conversion ratio of the group fed a diet supplemented with 500 U of BP was better (p < 0.01) than those fed with a diet supplemented with 500 U of FP. BP_250 group had a higher (p < 0.05) apparent digestibility of ether extract compared to FP_250 group. In conclusion, bacterial phytase at 500 U may enhance performance of broiler chickens fed during days 1-40 of age and yield similar growth performance and economic efficiency to those of eB-supplemented groups. PMID- 26608479 TI - Role of different scattering mechanisms on the temperature dependence of transport in graphene. AB - Detailed experimental and theoretical studies of the temperature dependence of the effect of different scattering mechanisms on electrical transport properties of graphene devices are presented. We find that for high mobility devices the transport properties are mainly governed by completely screened short range impurity scattering. On the other hand, for the low mobility devices transport properties are determined by both types of scattering potentials - long range due to ionized impurities and short range due to completely screened charged impurities. The results could be explained in the framework of Boltzmann transport equations involving the two independent scattering mechanisms. PMID- 26608480 TI - Laryngeal adenocarcinoma with metastasis in penis. PMID- 26608482 TI - Being human in a global age of technology. AB - This philosophical enquiry considers the impact of a global world view and technology on the meaning of being human. The global vision increases our awareness of the common bond between all humans, while technology tends to separate us from an understanding of ourselves as human persons. We review some advances in connecting as community within our world, and many examples of technological changes. This review is not exhaustive. The focus is to understand enough changes to think through the possibility of healthcare professionals becoming cyborgs, human-machine units that are subsequently neither human and nor machine. It is seen that human technology interfaces are a different way of interacting but do not change what it is to be human in our rational capacities of providing meaningful speech and freely chosen actions. In the highly technical environment of the ICU, expert nurses work in harmony with both the technical equipment and the patient. We used Heidegger to consider the nature of equipment, and Descartes to explore unique human capacities. Aristotle, Wallace, Sokolowski, and Clarke provide a summary of humanity as substantial and relational. PMID- 26608481 TI - Chemical characterization of milk oligosaccharides of the common wombat (Vombatus ursinus). AB - Previous structural characterizations of marsupial milk oligosaccharides have been performed in the tammar wallaby, red kangaroo, koala, common brushtail possum and the eastern quoll. To clarify the homology and heterogeneity of milk oligosaccharides among marsupial species, which could provide information on their evolution, the oligosaccharides of wombat milk carbohydrate were characterized in this study. Neutral and acidic oligosaccharides were isolated from the carbohydrate fractions of two samples of milk of the common wombat and characterized by (1) H-nuclear magnetic resonance spectroscopy. The structures of six neutral saccharides were found to be Gal(beta1-4)Glc (lactose), Gal(beta1 3)Gal(beta1-4)Glc (3'-galactosyllactose), Gal(beta1-3)Gal(beta1-3)Gal(beta1-4)Glc (3',3"-digalactosyllactose), Gal(beta1-3)Gal(beta1-3)Gal(beta1-3)Gal(beta1-4)Glc, Gal(beta1-3)Gal(beta1-3)[Gal(beta1-4)GlcNAc(beta1-6)]Gal(beta1-4)Glc (galactosyl lacto-N-novopentaose I) and Gal(beta1-3)[Gal(beta1-4)GlcNAc(beta1-6)]Gal(beta1 3)[Gal(beta1-4)GlcNAc(beta1-6)]Gal(beta1-4)Glc (lacto-N-novooctaose), while those of six acidic saccharides were Neu5Ac(alpha2-3)Gal(beta1-3)Gal(beta1-4)Glc. (sialyl 3'-galactosyllactose), Neu5Ac(alpha2-3)Gal(beta1-3)Gal(beta1-3)Gal(beta1 4)Glc (sialyl 3',3"-digalactosyllactose), Neu5Ac(alpha2-3)Gal(beta1-3)[Gal(beta1 4)GlcNAc(beta1-6)]Gal(beta1-4)Glc (sialyl lacto-N-novopentaose a), Gal(beta1 3)[Neu5Ac(alpha2-3)Gal(beta1-4)GlcNAc(beta1-6)]Gal(beta1-4)Glc (sialyl lacto-N novopentaose c), Neu5Ac(alpha2-3)Gal(beta1-3)Gal(beta1-3)Gal(beta1-3)Gal(beta1 4)Glc,, Neu5Ac(alpha2-3)Gal(beta1-3)Gal(beta1-3)[Gal(beta1-4)GlcNAc(beta1 6)]Gal(beta1-4)Glc and Gal(beta1-3)Gal(beta1-3)[Neu5Ac(alpha2-3)Gal(beta1 4)GlcNAc(beta1-6)]Gal(beta1-4)Glc. In addition, small amounts of sulfated oligosaccharides but no oligosaccharides containing Neu5Gc or alpha(2-6) linked Neu5Ac were detected. PMID- 26608484 TI - [Epidemiology, microbiology and diagnostics of dog and cat bites related infections]. AB - Animal bites represent a significant global health problem and account for approximately 1-2% of all visits to the emergency department. The vast majority of animal bite injuries are inflicted by dogs (80-90%,) and cats (5-15%). The most common complication following an animal bite is a wound infection, which tends to be polymicrobial and include both aerobic and anaerobic bacteria mainly of oropharyngeal origin. The likelihood of a cat bite becoming infected is double of that of a dog bite. Pasteurella spp. predominates in infected dog and cat bites. Dog bite injuries can be also associated with Capnocytophaga canimorsus, an aggressive organism which can cause disseminated infections (sepsis) and death, particularly in immunocompromised individuals. Early aggressive local wound cleansing is the most important therapy to prevent infection after animal bites. Due to the polymicrobial etiology of infected bite wounds, broad-spectrum antibiotics, covering both aerobic and anerobic bacteria, are often recommended as empiric treatment of animal bites. PMID- 26608483 TI - Analysis of volatile organic compounds in exhaled breath to diagnose ventilator associated pneumonia. AB - Ventilator-associated pneumonia (VAP) is a nosocomial infection occurring in the intensive care unit (ICU). The diagnostic standard is based on clinical criteria and bronchoalveolar lavage (BAL). Exhaled breath analysis is a promising non invasive method for rapid diagnosis of diseases and contains volatile organic compounds (VOCs) that can differentiate diseased from healthy individuals. The aim of this study was to determine whether analysis of VOCs in exhaled breath can be used as a non-invasive monitoring tool for VAP. One hundred critically ill patients with clinical suspicion of VAP underwent BAL. Before BAL, exhaled air samples were collected and analysed by gas chromatography time-of-flight mass spectrometry (GC-tof-MS). The clinical suspicion of VAP was confirmed by BAL diagnostic criteria in 32 patients [VAP(+)] and rejected in 68 patients [VAP(-)]. Multivariate statistical comparison of VOC profiles between VAP(+) and VAP(-) revealed a subset of 12 VOCs that correctly discriminated between those two patient groups with a sensitivity and specificity of 75.8% +/- 13.5% and 73.0% +/ 11.8%, respectively. These results suggest that detection of VAP in ICU patients is possible by examining exhaled breath, enabling a simple, safe and non-invasive approach that could diminish diagnostic burden of VAP. PMID- 26608485 TI - [Is a single application soft tissues techniques of spine area may cause increase trunk mobility?]. AB - The primary goal of application soft tissue techniques is to restore the proper mobility of fascia. Disturbance of soft tissue mobility can cause disorder in deep tissues and lead to musculoskeletal dysfunction. AIM: The aim of the study was to evaluate the effectiveness of soft tissues techniques of spine area to thoracic and spine mobility. MATERIALS AND METHODS: Examined 30 subjects (15 women and 15 men) aged: x=19.9+/-1.2. Were performed measurements: mobility of the thorax, flexibility of the trunk in planes: sagittal and frontal. Then applied selected soft tissue techniques of spine area. Immediately after the therapy measurements were repeated. RESULTS: Occurred increase mobility and flexibility among women statistically significant. Among men, the increase in mobility occurred in all measurements in addition to the finger-floor test and horizontal range of arms. CONCLUSIONS: The application of soft tissue techniques may favorably influence on increasing mobility of thoracic and trunk flexibility. Confirmation results of the observations in other studies may be part of the improvement in the rehabilitation proceedings. PMID- 26608486 TI - [Causes of suicide attempts in patients undergoing psychiatric hospitalization--a preliminary study]. AB - Suicide is difficult and dramatic act of deliberately taking one's own life. The causes of suicidal behavior are complex and include both sociological as well as psychological and neurobiological factors associated with the dysfunction of the central nervous system. AIM: The aim of study was to analyse tha causes of suicidal behavior. MATERIALS AND METHODS: The study comprised of 76 individuals. The study group included 48 patients hospitalized in the Babinski Memorial Hospital in Lodz, Poland who have attempted suicide act recently or in the past. Each patient completed psychological tests: Basic Hope Inventory (BHI-12), in evaluating Evaluation Crisis Questionnaire (KKW), The Beliefs about Pain Control Questionnaire (BPCQ). RESULTS: Statistical analysis revealed personality disorders and affective disorders to be the most frequent psychiatric diagnosis among patients, who attempted suicide. Patients from the study group had specific psychological characteristics. The most common suicide method was drug intoxication. CONCLUSIONS: Suicide prevention should include somatic and psychiatric morbidity and a thorough analysis of psychological functioning. This would help to better understand the mechanisms underlying suicide and extract a group of people with a significantly increased risk of suicidal behavior so that we could apply adequate prevention methods. PMID- 26608487 TI - [Number of teeth and hormonal profile of postmenopausal women with osteoporosis, osteopenia and normal bone mineral density--a preliminary study]. AB - Profound hypoestrogenism causes increased risk of osteoporosis and bone fracture in menopause. This period of women life is also characterized by decrease number of teeth and deterioration of oral cavity health. AIM: The aim of the study was to assess the number of teeth, hormonal profile (Follicle-stimualting hormone (FSH), estradiol (E2), testosterone (T) and dehydroepiandrosterone sulphate (DHEA S) and the bone mineral density (BMD) of the lumbar part of the spine in postmenopausal women with osteoporosis, osteopenia and normal BMD. The next step of the study was to determine whether there was a correlation between vertebral mineral bone density, the hormonal profile and the number of teeth. MATERIALS AND METHODS: A total number of 47 women was involved in the study. Based on the results of densitometry tests (DEXA) of vertebral column the subjects were divided into 3 groups: 10 with osteoporosis, 20 with osteopenia and 17 with normal BMD. All the subjects had undergone a hormonal assessment which included blood serum estimation for FSH, E2, DHEA-S and T levels. Also the total number of teeth present was recorded. RESULTS: Serum estradiol and testosterone levels in postmenopausal women were found to be positively correlated with the number of teeth present. A negative correlation was found between age and the number of maxillary teeth in postmenopausal women with osteopenia. There was no influence of serum FSH, estradiol, testosterone and DHEA-S levels on vertebral BMD loss in postmenopausal women. There was no correlation between teeth number and BMD of vertebral column. CONCLUSIONS: Serum levels of estradiol and testosterone in postmenopausal women positively correlate with teeth numbers. Age is the main risk factor for teeth loss in postmenopausal women. PMID- 26608488 TI - [Severe sepsis after dog bite caused by Capnocytophaga canimorsus]. AB - We describe a case of a life-threatening septicemia resulting from a previous dog bite wound. The isolated bacterium was Capnocytophaga canimorsus, a slow-growing Gram-negative bacillus commonly found in dog saliva. Known risk factors for invasive C. canimorsus infections are alcohol abuse, cigarette smoking, splenectomy or other forms of immunosuppression. Any clinician seeing patients with a history of a dog bite should consider this pathogen as a causative agent and take detailed history regarding exposure to animals. PMID- 26608489 TI - [Cardiac safety of electroconvulsive therapy in an elderly patient--a case report]. AB - Since electroconvulsive therapy (ECT) was introduced as treatment for psychiatric disorders in 1938, it has remained one of the most effective therapeutic methods. ECT is often used as a "treatment of last resort" when other methods fail, and a life-saving procedure in acute clinical states when a rapid therapeutic effect is needed. Mortality associated with ECT is lower, compared to the treatment with tricyclic antidepressants, and comparable to that observed in so-called minor surgery. In the literature, cases of effective and safe electroconvulsive therapy have been described in patients of advanced age, with a burden of many somatic disorders. However, cases of acute cardiac episodes have also been reported during ECT. The qualification of patients for ECT and the selection of a group of patients at the highest risk of cardiovascular complications remains a serious clinical problem. An assessment of the predictive value of parameters of standard electrocardiogram (ECG), which is a simple, cheap and easily available procedure, deserves special attention. This paper reports a case of a 74-year-old male patient treated with ECT for a severe depressive episode, in the context of cardiologic safety. Both every single ECT session and the full course were assessed to examine their impact on levels of troponin T, which is a basic marker of cardiac damage, and selected ECG parameters (QTc, QRS). In the presented case ECT demonstrated its high general and cardiac safety with no negative effect on cardiac troponin (TnT) levels, corrected QT interval (QTc) duration, or other measured ECG parameters despite initially increased troponin levels, the patient's advanced age, the burden of a severe somatic disease and its treatment (anticancer therapy). PMID- 26608490 TI - [Hemoptysis during concomitant treatment with rivaroxaban and amiodarone in a patient with a history of pulmonary disease]. AB - Rivaroxaban, a selective inhibitor of active factor X, is metabolized by cytochrom P450 3A4 (CYP3A4) and is a substrate for transporter protein--P glycoprotein (P-gp). Amiodarone, an antiarrhytmic agent, is classified as moderate CYP3A4 and P-gp inhibitor. A CASE REPORT: A 75-year-old male, who underwent lobectomy for bronchiectasis many years ago, is presented. For one year the patient was treated with rivaroxaban (20 mg/d) due to venous thromboembolism and recurrent episodes of atrial fibrillation. Two weeks after amiodarone initiation (200 mg/d) hemoptysis occurred and computed tomography revealed unilateral pulmonary infiltrates with ground-glass opacities limited to the lower lobe of the left lung. The symptoms disappeared following discontinuation of the two medications and did not recur while rivaroxaban was reintroduced in a dose of 15 mg/d; measurement of anti-Xa activity confirmed it as a therapeutic dose. Amiodarone, that had been used for a short time and well tolerated a few years before, was definitely withdrawn. CONCLUSIONS: The authors suggest, that the concomitant use of rivaroxaban and amiodarone should be very careful in patients with a history of pulmonary disease. PMID- 26608491 TI - [Treatment failure as a consequence of the diagnostic difficulties in a 52-year old patient treated for the pancreatic abscess]. AB - Hodgkin Lymphoma (HL) is a neoplastic disease of the lymphatic system, primary involving lymph nodes and extranodular organs. Despite successful combined chemotherapy, a proper and prompt diagnosis remains a difficult challenge. The case report documents the case of a 52-year-old patient, who had been diagnosed in various internal medicine wards for nonspecific diseases during last two years. Due to the worsening of patient's general condition and suspected inflammatory, probably purulent, abdominal process, he was operated twice. Unexplained symptoms of the uncertain origin resulted in the further lack of successful diagnosis and therapy. The patient died from multiple organ failure on the 2nd day after the second operation. The final histopathological and immunohistochemical examination of the liver biopsy revealed the primary cause of death, i.e. Hodgkin lymphoma. The thorough analysis of the patient's documentation revealed a full-featured image of the classic HL. A special emphasis was placed upon misleading symptoms and difficulties in correct interpretation of more sophisticated diagnostic methods. The significant features of these patients can provide sufficient guidance to proper diagnosis and treatment of this rare disease. PMID- 26608492 TI - [Biliary endoprosthesis causing ileal perforation--a case report]. AB - We experienced ileal perforation caused by dislocated biliary endoprosthesis in 59 years old female patient. The endoprosthesis was implanted due to biliary fistula after laparoscopic cholecystectomy 2 years before the perforation. It seems that endoprosthesis dislocation and the perforation were the result of too long stay of endoprosthesis. After the surgical management and the removal of the prosthesis patient was cured. Although ileal perforation caused by dislocated biliary endoprosthesis is rare, clinicians should be aware of the possibility of its occurrence. PMID- 26608493 TI - [Is physiological saline really physiological? Hyponatreamia treatment--small deviations from the rules of appropriate therapy create serious complications and side effects]. AB - Physiological saline can hardly be treated as physiological as it contains qualitatively and quantitatively different amounts of electrolytes. In particular, it contains 50% more chlorine ions than serum. Physiological saline can cause metabolic acidosis and in diabetic patients hyperchloremic acidosis. In comparison with Ringer solution and plasma-lyte, physiological saline is causing higher number of untoward effects and mortality associated with surgery. Ringer solution should be used in the situations requiring expansion of extracellular fluid. Physiological saline is a solution of choice in hypochloremic alkalosis in the case of brain injuries quite unfavourable is unnecessary rapid correction with physiological saline which can lead to serious sequelae in form of brain oedema and central extrapontine myelinolysis (osmotic demyelinisation) and permanent brain lesions. The hyponatremia's treatment depends on severity of symptoms, neurological deficit motivates immediate 4-6 mmol/l infusion, but further correction should be prolonged to 24-hrs; cautious correction corresponds to 8-mmol/l for 24 hrs. The modern treatment encompasses the introduction of vasopressin receptors antagonist--vaptans. PMID- 26608494 TI - [Pitfalls in the diagnosis of hypercortisolemia]. AB - Cushing's syndrome (CS) is relatively rare disorder affecting 2-5 per million per year, although the issue of establishing the diagnosis of CS and differential diagnosis of the disease are a significant clinical problem. CS is usually the result of excessive exogenous glucocorticoids usage (iatrogenic CS), endogenous CS can be divided into ACTH-dependent and ACTH-independent. Regardless of its etiology, the most important steps in establishing the diagnosis of CS are taking careful history and examination. The symptoms with high discriminatory value are myopathy, reddish purple striae, easy bruising and plethora. Knowledge of the pathomechanisms leading to the development of CS symptoms, facilitates establishing the diagnosis and understanding the importance of early diagnosis. Although the sensitivity and specificity of laboratory test have increased and imaging techniques developed, establishing the diagnosis of CS is still a challenging problem in clinical practice. When choosing appropriate diagnostic test we should remember of both advantages and limitations of each of them. The increasing popularity of late night/midnight salivary cortisol measurement as a first line diagnostic test is observed, also urinary free cortisol measurement, 1mg dexamethasone overnight suppression test and midnight serum cortisol measurement are used in the initial testing for hypercortisolemia. Subclinical CS as well as cyclical or episodic CS may be challenging especially. Another diagnostic problem is differentiation between functional hypercortisolism (pseudo Cushing's syndrome) and pathological hypercortisolism with organic changes (CS). Right and early diagnosis is of vital importance in patients with CS because of large extent of complications resulting from untreated hypercortisolemia. In the course of CS many different organs and systems can be affected, leading to increase in total morbidity and mortality. PMID- 26608495 TI - [Ventilatory disorders in patients with chronic heart failure]. AB - Chronic heart failure (CHF) is a condition in which both structure and functional capacity of cardiac muscle are impaired, resulting in ineffective peripheral tissue perfusion. Affecting numerous organs and systems, it is currently considered to be a systemic illness. Among significant, however until now, hardly recognized consequences of CHF there are ventilatory disorders. Their presence may be explained by proximity of heart and lungs inside rib cage or by close functional cooperation between these two organs. Ventilatory disorders clinically manifest as exacerbations of the underlying disease, i.e. intense dyspnea- primarily exertional in nature, over time, present even at rest. On the basis of functional pulmonary tests, ventilatory disorders may be classified into three categories: restrictive, obstructive and most commonly--mixed. The restrictive model is represented in bodypletysmography as reduction in the total lung capacity to values less than 5th percentile of the predicted values for normals, while Tiffeneau index remains intact. Such condition may probably result from the chronic inflammatory process affecting lung tissue, for which the reaction of macrophage cells to both pulmonary stasis, as well as increased volume of interstitial and alveolar fluid remains the underlying cause. The increased formation of connective tissue fibers engenders thickening of alveolar-capillary membrane, occurrence of disturbed oxygen diffusion and emergence of hypoxemic respiratory failure. Ventilatory disorders of obstructive nature are characterised by reduction of Tiffeneau index--the calculated ratio between forced expiratory volume in 1. second and forced vital capacity--to values below 5th percentile of the predicted range. The research results indicate for the presence of bronchiolar narrowing--dominant in small-diameter bronchi and bronchioles, with larger structures being unaffected--clearly depicted in spirometry as reduced levels of forced expiratory flow after exhaling 50% and 75% of forced vital capacity. Due to a considerable epidemiological problem, as well as significance of the clinical symptoms manifesting ventilatory disorders in course of chronic heart failure, there should be put emphasis on cardiac injury prevention in individuals from risk groups and the proper treatment of patients already suffering from chronic heart failure. PMID- 26608496 TI - [Role of office hysteroscopy in the diagnosis and treatment of uterine pathology]. AB - Nowadays endoscopic techniques are one of the basic diagnostic and operative methods in gynecology. Laparoscopy and hysteroscopy are the most popular of them. Office hysteroscopy is a modern diagnostic and therapeutic method feasible in an outpatient room because no necessity of anesthesia. It is the first-line procedure in the infertility diagnosis and treatment of uterine pathology such as polyps, submucosal fibroids and adhesions. Limitation of this method is the cervical canal atresia. Contraindications to it are: pregnancy, uterine bleeding, active inflammation of pelvic organs, cervical cancer. Due to the high sensitivity and specificity, simplicity of execution and no need for patient hospitalization, office hysteroscopy becomes important diagnostic and therapeutic procedure in uterine pathologies. PMID- 26608497 TI - [The oral cavity condition in patients with high blood pressure]. AB - The incidence of high blood pressure in adults is estimated at ca. 30-40% of the general population. Both hypertension disease and hypertensive drugs affect the condition of the patients' oral cavity. A review of the current literature shows that disorders most frequently found in the masticatory organ of patients with hypertension include: xerostomia, changes in salivary glands, gum hypertrophy, lichenoid lesions, taste disorders, and paraesthesias. The authors emphasize that patients with high blood pressure, along with the treatment of the underlying disease, should receive prophylactic and therapeutic dental care. This would enable reduction and/or elimination of unpleasant complaints, and also help prevent the emergence of secondary disorders in the patients' oral cavity as a result of hypertension pharmacotherapy. PMID- 26608498 TI - Hypothiocyanite produced by human and rat respiratory epithelial cells inactivates extracellular H1N2 influenza A virus. AB - OBJECTIVE AND DESIGN: Our aim was to study whether an extracellular, oxidative antimicrobial mechanism inherent to tracheal epithelial cells is capable of inactivating influenza H1N2 virus. MATERIAL OR SUBJECTS: Epithelial cells were isolated from tracheas of male Sprague-Dawley rats. Both primary human and rat tracheobronchial epithelial cells were differentiated in air-liquid interface cultures. TREATMENT: A/swine/Illinois/02860/09 (swH1N2) influenza A virions were added to the apical side of airway cells for 1 h in the presence or absence of lactoperoxidase or thiocyanate. METHODS: Characterization of rat epithelial cells (morphology, Duox expression) occurred via western blotting, PCR, hydrogen peroxide production measurement and histology. The number of viable virions was determined by plaque assays. Statistical difference of the results was analyzed by ANOVA and Tukey's test. RESULTS: Our data show that rat tracheobronchial epithelial cells develop a differentiated, polarized monolayer with high transepithelial electrical resistance, mucin production and expression of dual oxidases. Influenza A virions are inactivated by human and rat epithelial cells via a dual oxidase-, lactoperoxidase- and thiocyanate-dependent mechanism. CONCLUSIONS: Differentiated air-liquid interface cultures of rat tracheal epithelial cells provide a novel model to study airway epithelium-influenza interactions. The dual oxidase/lactoperoxidase/thiocyanate extracellular oxidative system producing hypothiocyanite is a fast and potent anti-influenza mechanism inactivating H1N2 viruses prior to infection of the epithelium. PMID- 26608499 TI - Cytokines and matrix metalloproteinases in the cerebrospinal fluid of patients with acute transverse myelitis: an outcome analysis. AB - BACKGROUND: Role of cytokines as well as matrix metalloproteinases (MMPs) is well defined in various central nervous system inflammatory diseases. However, the role of these cytokines and MMPs in acute transverse myelitis is inadequately studied. MATERIALS AND METHODS: Patients with acute transverse myelitis, fulfilling the inclusion and exclusion criteria defined by Transverse Myelitis Consortium Working Group, were enrolled along with age and sex matched controls. A detailed clinical evaluation and magnetic resonance imaging of patients was done. Cerebrospinal fluid (CSF) samples both from patients and controls were collected. CSF samples were analyzed for cytokines [interleukin (IL)-6, IL-8, IL 10 and IL-17)] and matrix metalloproteinases (MMP-2, MMP-9). Patients were followed up for 3 months. Disability was assessed using modified Barthel index (MBI). RESULTS: CSF levels of all cytokines IL-6, IL-8, IL-10, MMP-2 and MMP-9, except IL-17, were significantly higher in patients with acute transverse myelitis (p < 0.001). CSF IL-6 and IL-8 were significantly associated with severity of the disease (MBI <= 12). After 3 months, quadriparesis (p = 0.001, odd's ratio 19.5, 95 % CI 2.34-62.39) and long-segment myelitis (p = 0.035, odd's ratio 4.37, 95 % CI 1.17-5.95) were significantly associated with poor outcome. Among cytokines and MMPs, IL-6 levels at baseline correlated significantly with the MBI at 3 months (Spearmen's rho = -0.335, p = 0.01). CONCLUSION: In conclusion, both anti-inflammatory and pro-inflammatory cytokines, MMP-2, and MMP 9 are elevated in the acute phase of transverse myelitis. Possibly, IL-6 plays a role in determining the disability. PMID- 26608502 TI - To swim or not to swim? A disagreement between microbial indicators on beach water quality assessment in Hong Kong. AB - The USEPA and the WHO now advocate the use of enterococci as indicators for marine water quality. This study investigated the outcomes for Hong Kong beach water quality assessment by comparing enterococcus measures with data from the HKEPD's monitoring programme. Six beaches were tested once every 2-3 months from November 2013 to June 2014 in order to identify the most contaminated sites, followed by intensive water sampling in sites found to have the highest enterococci densities (Clear Water Bay Second and Golden) every five to six days for six sampling events over a 30-day period in 2014. The geometric means of enterococci were found to be 124 and 41 cfu/100 mL at Clear Water Bay Second and Golden respectively, indicating that there may be higher risks of illness associated with swimming at both beaches than previously known. Moreover, beach sediments contained higher concentrations of enterococci than water, and warrant further study. PMID- 26608501 TI - High dose of formaldehyde exposure during pregnancy increases neutrophils lung influx evoked by ovalbumin in the offspring. AB - OBJECTIVE: Considering that asthma might have their onset in the intrauterine life and the exposure to FA during pregnancy interferes in the immune system of offspring, here we hypothesized that high dose of FA exposure during pregnancy could to contribute for development and severity of asthma in the offspring. METHODS: Pregnant Wistar rats were submitted to FA inhalation (6.13 mg/m(3), 1 h/day, 5 days/week, for 21 days) or vehicle (distillated water). After 30 days of birth, the offspring was sensitized with ovalbumin (OVA)-alum and challenged with aerosolized OVA (1%, 15 min, 3 days). After 24 h the OVA challenge, the analyses were performed. Non-manipulated rats were used as basal parameters. RESULTS: Our data show that the exposure to high dose of FA during pregnancy predisposes the development of neutrophilic lung inflammation in the offspring, as observed by the profile of cells and cytokines in the lung. CONCLUSION: This study contributes to the understanding of effects of pollution on the development of lung diseases. PMID- 26608503 TI - Species-specific trends in the reproductive output of corals across environmental gradients and bleaching histories. AB - Coral populations in the Persian Gulf have a reputation for being some of the toughest in the world yet little is known about the energetic constraints of living under temperature and salinity extremes. Energy allocation for sexual reproduction in Gulf corals was evaluated relative to conspecifics living under milder environmental conditions in the Oman Sea. Fecundity was depressed at Gulf sites in two Indo-Pacific merulinid species (Cyphastrea microphthalma and Platygyra daedalea) but not in a regionally endemic acroporid (Acropora downingi). Gulf populations of each species experienced high temperature bleaching at the onset of gametogenesis in the study but fecundity was only negatively impacted in P. daedalea and A. downingi. Large population sizes of C. microphthalma and P. daedalea in the Gulf are expected to buffer reductions on colony-level fecundity. However, depleted population sizes of A. downingi at some Gulf sites equate to low reef-wide fecundity and likely impede outcrossing success. PMID- 26608500 TI - Anti-inflammatory effects of fimasartan via Akt, ERK, and NFkappaB pathways on astrocytes stimulated by hemolysate. AB - OBJECTIVE: The aim of this study was to investigate whether fimasartan, a novel angiotensin II receptor blocker, modulates hemolysate-induced inflammation in astrocytes. METHODS: We stimulated astrocytes with hemolysate to induce hemorrhagic inflammation in vitro. Astrocytes were pretreated with fimasartan and then incubated with hemolysate at different durations. Anti-inflammatory cell signaling molecules including Akt, extracellular signal regulated kinase (ERK), NFkappaB and cyclooxygenase-2 (COX-2) were assessed by western blotting. Pro inflammatory mediators were evaluated by real-time RT-PCR and ELISA. RESULTS: The stimulation by hemolysate generated a robust activation of inflammatory signaling pathways in astrocytes. Hemolysate increased the phosphorylation of Akt at 1 h, and ERK1/2 at 20 min compared with the control group and promoted the degradation of IkappaBalpha. Pretreated fimasartan significantly decreased hemolysate-induced phosphorylation of Akt and ERK1/2. In addition, fimasartan also suppressed NFkappaB-related inflammatory pathways induced by hemolysate, including reduction of the gene expression of NFkappaB, and decreased nuclear translocation of NFkappaB and degradation of IkappaB. This reduction of inflammatory upstream pathways decreased the expression of inflammatory end-products: COX-2 and interleukin-1 (IL-1beta). Furthermore, the expression of COX-2 was attenuated by both Akt inhibitor (LY294002) and ERK inhibitor (U0126), and IkappaBalpha degradation was suppressed by LY294002. CONCLUSIONS: These results demonstrate that pretreatment with fimasartan to astrocytes suppresses the inflammatory responses induced by hemolysate. Akt, ERK and NFkappaB were associated with hemolysate-induced COX-2 and IL-1beta expression. Based on these mechanisms, fimasartan could be a candidate anti-inflammatory regulator for the treatment of intracerebral hemorrhage. PMID- 26608504 TI - Homogeneity of coral reef communities across 8 degrees of latitude in the Saudi Arabian Red Sea. AB - Coral reef communities between 26.8 degrees N and 18.6 degrees N latitude in the Saudi Arabian Red Sea were surveyed to provide baseline data and an assessment of fine-scale biogeography of communities in this region. Forty reefs along 1100 km of coastline were surveyed using depth-stratified visual transects of fish and benthic communities. Fish abundance and benthic cover data were analyzed using multivariate approaches to investigate whether coral reef communities differed with latitude. A total of 215 fish species and 90 benthic categories were recorded on the surveys. There were no significant differences among locations in fish abundance, species richness, or among several diversity indices. Despite known environmental gradients within the Red Sea, the communities remained surprisingly similar. The communities do, however, exhibit subtle changes across this span of reefs that likely reflect the constrained distributions of several species of reef fish and benthic fauna. PMID- 26608505 TI - Regional variation in the structure and function of parrotfishes on Arabian reefs. AB - Parrotfishes (f. Labridae) are a unique and ubiquitous group of herbivorous reef fishes. We compared the distribution and ecosystem function (grazing and erosion) of parrotfishes across 75 reefs in Arabia. Our results revealed marked regional differences in the abundance, and taxonomic and functional composition of parrotfishes between the Red Sea, Arabian Sea, and Arabian Gulf. High densities and diversity of parrotfishes, and high rates of grazing (210% year(-1)) and erosion (1.57 kgm(-2)year(-1)) characterised Red Sea reefs. Despite Arabian Sea and Red Sea reefs having broadly comparable abundances of parrotfishes, estimates of grazing (150% year(-1)) and erosion (0.43 kgm(-2)year(-1)) were markedly lower in the Arabian Sea. Parrotfishes were extremely rare within the southern Arabian Gulf, and as such rates of grazing and erosion were negligible. This regional variation in abundance and functional composition of parrotfishes appears to be related to local environmental conditions. PMID- 26608506 TI - Ingestion of microplastics by commercial fish off the Portuguese coast. AB - The digestive tract contents of 263 individuals from 26 species of commercial fish were examined for microplastics. These were found in 17 species, corresponding to 19.8% of the fish of which 32.7% had ingested more than one microplastic. Of all the fish that ingested microplastics, 63.5% was benthic and 36.5% pelagic species. A total of 73 microplastics were recorded, 48 (65.8%) being fibres and 25 (34.2%) being fragments. Polymers were polypropylene, polyethylene, alkyd resin, rayon, polyester, nylon and acrylic. The mean of ingested microplastics was 0.27 +/- 0.63 per fish, (n=263). Pelagic fish ingested more particles and benthic fish ingested more fibres, but no significant differences were found. Fish with the highest number of microplastics were from the mouth of the Tagus river. Scomber japonicus registered the highest mean of ingested microplastics, suggesting its potential as indicator species to monitor and investigate trends in ingested litter, in the MSFD marine regions. PMID- 26608507 TI - Trace metal concentrations in tropical mangrove sediments, NE Brazil. AB - Sediment cores were taken from the mangroves of the Coreau River estuary off the northeast coast of Brazil. They were analyzed for grain size, CaCO3, organic matter, and trace metal (Cd, Pb, Zn, Cu, Al, and Fe) contents. Mud texture was the predominant texture. Levels of trace metals in surface sediments indicated strong influence of anthropogenic processes, and diagenetic processes controlled the trace metal enrichment of core sediments of this estuary. The positive relationships between trace metals and Al and Fe indicate that Cu, Zn, Pb, and Cd concentrations are associated mainly with Al and Fe oxy-hydroxides and have natural sources. PMID- 26608508 TI - Recurrent translocation t(10;17)(p15;q21) in minimally differentiated acute myeloid leukemia results in ZMYND11/MBTD1 fusion. AB - Pediatric acute myeloid leukemia (AML) is a heterogeneous disease, characterized by different collaborating karyotypic and molecular abnormalities, which are used in risk group stratification. In ~20% of the pediatric AML cases a specific genetic aberration is still unknown. Minimally differentiated myeloid leukemia or FAB-type M0 is a rare morphological subtype of AML. The translocation t(10;17)(p15;q21) is described to be recurrent in minimally differentiated AML, but the involved genes and location of the breakpoints have so far not been identified. In this study, we show that this translocation results in an in-frame translocation fusing exon 12 of the tumor suppressor gene ZMYND11 to exon 3 of the chromatin protein MBTD1, encoding a protein of 1,054 amino acids, while the reciprocal fusion product is predicted to lack a productive start codon. Gene expression profiling of the leukemic cells showed high HOXA expression. ZMYND11, also known as BS69, is a tumor suppressor that specifically recognizes H3K36me3, which is linked to aberrant HOXA expression in leukemogenesis. Aberrant expression of the genes involved in this fusion may thus contribute to the HOXA phenotype observed with gene expression profiling. PMID- 26608510 TI - The Importance of Weight Change Experiences for Performance of Diabetes Self Care: A Patient-Centered Approach to Evaluating Clinical Outcomes in Type 2 Diabetes. AB - INTRODUCTION: The aim of this study was to examine the influence of weight change experiences over time on motivation to perform diabetes self-care behaviors using data from a study of canagliflozin (an agent that inhibits sodium glucose co transporter 2) versus glimepiride in dual therapy with metformin and background diet/exercise. METHODS: Weight and motivation for performing healthy behaviors were collected at baseline and over time. The motivation questionnaire enabled categorization into two groups: those performing or not performing health behaviors. Four distinct patterns of weight change were determined: losing weight, gaining weight, and two patterns for fluctuating weight. The relationships between these patterns and motivation for weight loss, following a diet, and exercise were examined using logistic regression models. RESULTS: Of 1182 subjects, more than half were already performing behaviors to lose weight, diet, and exercise at baseline. Among those who were not, 52% (246/474) started taking action to lose weight after baseline, 54% (241/448) started following a diet, and 42% (232/556) started exercising. Weight change patterns were significantly related to performance of healthy behaviors at follow-up (week 36). Compared to the weight gain pattern, those who experienced a continuous weight loss pattern from baseline to week 36 were 2.2 (95% confidence interval 1.49, 3.37) times more likely to perform the healthy behaviors. Baseline behavior and confidence were also predictive of performing healthy behaviors. CONCLUSION: The current work highlights the importance of weight change patterns for performance of diabetes self-care. Tracking weight patterns over time, assessing confidence for performance of healthy behaviors, and being aware of the relationship between weight changes and diabetes self-care behaviors are viable, concrete ways to practice patient-centered care. FUNDING: Janssen Global Services, LLC. PMID- 26608511 TI - Comparison of Adipose Distribution Indices with Gold Standard Body Composition Assessments in the EMPA-REG H2H SU Trial: A Body Composition Sub-Study. AB - INTRODUCTION: Excess adiposity contributes to cardiometabolic disease. Although adipose depots can be measured using imaging, implementation remains limited in practice. Data comparing surrogate indices of total and visceral adiposity with gold standard measurements in the context of a clinical trial population are lacking. We explored the relationships between adipose distribution indices and imaging assessments of body composition using baseline data from the EMPA-REG H2H SUTM trial. METHODS: 118 participants from the Phase III trial of empagliflozin 25 mg vs. glimepiride 1-4 mg enrolled in a dedicated sub-study underwent assessment of total fat and fat-free mass by dual x-ray absorptiometry (n = 93) and abdominal visceral (VAT) and subcutaneous adipose tissue by magnetic resonance imaging (n = 99). Correlations with waist circumference (WC), estimated total body fat (eTBF), index of central obesity (ICO), and visceral adiposity index (VAI) were assessed. RESULTS: eTBF was highly representative of total body fat (Spearman's rho = 0.73, P < 0.001) but not associated with VAT. WC and ICO were strongly, and VAI to a lesser degree, correlated with VAT (rho = 0.66, P < 0.001; rho = 0.52, P < 0.001; rho = 0.24, P = 0.02, respectively). CONCLUSION: These findings support the use of eTBF and WC or ICO as surrogate indices for total body fat and VAT, respectively, in the absence of gold standard imaging methodology. PMID- 26608509 TI - Salivary extracellular heat shock protein 70 (eHSP70) levels increase after 59 min of intense exercise and correlate with resting salivary secretory immunoglobulin A (SIgA) levels at rest. AB - This study aimed to identify the response of a salivary stress protein, extracellular heat shock protein (eHSP70), to intense exercise and to investigate the relationship between salivary eHSP70 and salivary immunoglobulin A (SIgA) levels in response to exercise. Sixteen healthy sedentary young males (means +/- SD 23.8 +/- 1.5 years, 172.2 +/- 6.4 cm, 68.3 +/- 7.4 kg) performed 59 min of cycling exercise at 75% VO2max. Saliva and whole blood samples were collected before (Pre), immediately after (Post), and at 1, 2, 3, and 4 h after completion of the exercise (1, 2, 3, and 4 h). The salivary eHSP70 and SIgA levels were measured by enzyme-linked imunosorbent assay (ELISA), and the secretion rates were computed by multiplying the concentration by the saliva flow rate. White blood cells were analyzed using an automated cell counter with a direct-current detection system. The salivary eHSP70 secretion rates were 1.11 +/- 0.86, 1.51 +/ 1.47, 1.57 +/- 1.32, 2.21 +/- 2.04, 3.36 +/- 2.72, and 6.89 +/- 4.02 ng . min( 1) at Pre, Post, and 1, 2, 3, and 4 h, respectively. The salivary eHSP70 secretion rate was significantly higher at 4 h than that at Pre, Post, 1, and 3 h (p < 0.05). The SIgA secretion rates were 26.9 +/- 12.6, 20.3 +/- 10.4, 19.6 +/- 11.0, 21.8 +/- 12.8, 21.5 +/- 11.9, and 21.9 +/- 11.7 MUg . min(-1) at Pre, Post, 1, 2, 3, and 4 h, respectively. The salivary SIgA secretion rate was significantly lower between 1 and 4 h than that at Pre (p < 0.05). There was a positive correlation between salivary eHSP70 and SIgA in both concentration and secretion rates before exercise (p < 0.05). The absolute number of white blood cells significantly increased after exercise, with a maximum at 2 h (p < 0.05). The neutrophil/lymphocyte ratio was significantly increased from 1 to 4 h when compared with that in the Pre samples (p < 0.05). The present study revealed that salivary eHSP70 significantly increased at 4 h after the 59 min of intense exercise in sedentary male subjects. Exercise stress can induce elevated salivary eHSP70 level and upregulate oral immune function partially. PMID- 26608512 TI - Serum Paraoxonase Activity and Malondialdehyde Serum Concentrations Remain Unaffected in Response to Hydroxyurea Therapy in beta-Thalassemia Patients. AB - beta-Thalassemia is the most common hereditary disorder characterized by reduced production of beta-globin chains of hemoglobin A (HbA). In recent years, hydroxyurea (HU) has shown promising therapeutic benefits in patients with beta thalassemia by fetal hemoglobin augmentation. We have analyzed effects of hydroxyurea treatment on oxidative stress in beta-thalassemia patients by assessing activities of paraoxonase (PON) and arylesterase along with malondialdehyde (MDA) and total reactive oxygen species (ROS) concentrations. Blood samples from 159 individuals including 56 HU-treated and 58 untreated beta thalassemia patients and 45 healthy controls were analyzed. PON activity was found to be highest in healthy individuals (177.76 +/- 4.44 U/mL) as compared to treated (52.67 +/- 3.65 U/mL) and untreated (55.11 +/- 3.26 U/mL) patients. A similar trend was observed in the case of arylesterase activity in normal, beta thalassemia-treated, and untreated (210.0 +/- 11.25 U/mL, 163.03 +/- 9.04 U/mL, 139.77 +/- 10.10 U/mL) subjects. Serum MDA concentrations (2.59 +/- 0.09 nmol/mL, 2.45 +/- 0.08 nmol/mL, and 1.15 +/- 0.05 nmol/mL) and total ROS concentrations (3.73 +/- 0.20 nmol/mL, 3.54 +/- 0.23 nmol/mL, and 2.45 +/- 0.14 nmol/mL) were significantly elevated in both groups (untreated and treated) as compared to healthy individuals (P < .01). Oxidative stress was found to be markedly elevated in beta-thalassemia patients as compared to healthy controls. Insignificant differences were, however, observed in mean concentrations of PON1 paraoxonase and arylesterase activities, serum MDA concentration and total ROS concentrations between HU-treated and untreated patients. We propose that HU therapy alone seems to be ineffective in managing oxidative stress and is likely to offer a better clinical outcome when supplemented with efficient iron chelation therapy and antioxidants. PMID- 26608513 TI - Fortunes and misfortunes of political leaders reflected in the eyes of their electors. AB - Gaze-following is a pivotal social behaviour that, although largely automatic, is permeable to high-order variables like political affiliation. A few years ago we reported that the gaze of Italian right-wing voters was selectively captured by the gaze of their leader Silvio Berlusconi. This effect was particularly evident in voters who saw themselves as similar to Berlusconi. Two years later, we were able to run the present follow-up study because Berlusconi's popularity had drastically dropped due to sex and political scandals, and he resigned from office. In a representative subsample of our original group, we investigated whether perceived similarity and gaze-following reflected Berlusconi's loss in popularity. We were also able to test the same hypothesis in an independent group of right-wing voters when their leader, Renata Polverini, resigned as Governor of 'Regione Lazio' due to political scandals. Our results show that the leaders' fall in popularity paralleled the reduction of their gaze's attracting power, as well as the decrease in similarity perceived by their voters. The less similar right-wing voters felt to their leader, the less they followed his/her gaze. Thus, the present experimental findings suggest that gaze-following can be modulated by complex situational and dispositional factors such as leader's popularity and voter-leader perceived similarity. PMID- 26608516 TI - An epigenetic clock controls aging. AB - We are accustomed to treating aging as a set of things that go wrong with the body. But for more than twenty years, there has been accumulating evidence that much of the process takes place under genetic control. We have seen that signaling chemistry can make dramatic differences in life span, and that single molecules can significantly affect longevity. We are frequently confronted with puzzling choices the body makes which benefit neither present health nor fertility nor long-term survival. If we permit ourselves a shift of reference frame and regard aging as a programmed biological function like growth and development, then these observations fall into place and make sense. This perspective suggests that aging proceeds under control of a master clock, or several redundant clocks. If this is so, we may learn to reset the clocks with biochemical interventions and make an old body behave like a young body, including repair of many of the modes of damage that we are accustomed to regard as independent symptoms of the senescent phenotype, and for which we have assumed that the body has no remedy. PMID- 26608515 TI - Redox modulation of curcumin stability: Redox active antioxidants increase chemical stability of curcumin. AB - SCOPE: Substantial studies have shown that curcumin, a dietary compound from turmeric, has beneficial effects on many diseases. However, curcumin rapidly degrades at physiological pH, making it difficult to interpret whether the observed actions of curcumin are from curcumin itself or its degradation products. Therefore, it is important to better understand the mechanisms involved in curcumin degradation and the roles of degradation in its biological actions. METHODS AND RESULTS: Here, we show that a series of redox active antioxidants with diverse chemical structures, including gallic acid, ascorbate (vitamin C), tert-butylhydroquinone (TBHQ), caffeic acid, rosmarinic acid, and Trolox (a water soluble analog of vitamin E), dramatically increased curcumin stability in phosphate buffer at physiological pH. When treated in basal cell culture medium in MC38 colon cancer cells, curcumin rapidly degraded with a half-life of several minutes and showed a weak antiproliferative effect; co-addition of antioxidants enhanced stability and antiproliferative effect of curcumin. Finally, co administration of antioxidant significantly increased plasma level of curcumin in animal models. CONCLUSION: Together, these studies strongly suggest that a redox dependent mechanism plays a critical role in mediating curcumin degradation. In addition, curcumin itself, instead of its degradation products, is largely responsible for the observed biological actions of curcumin. PMID- 26608514 TI - Relationship of diminished interjoint coordination after stroke to hand path consistency. AB - Differences between 12 left-brain (LCVA, 65.4 +/- 11.7 years old) and 10 right brain (RCVA, 61 +/- 12.1 years old) chronic stroke survivors and 10 age-matched control adults in coordinating specific joint motions of the arm to stabilize hand path when reaching to a central target were investigated in this study. The importance of coordinating joints to stabilize hand path was tested by comparing results from uncontrolled manifold (UCM) analysis performed on experimental data versus simulated data where the covariation (coordination) between particular joint motions was removed from the original data set. UCM analysis allowed estimation of the joint configuration variance magnitude that led to hand path variability (V ORT), where the extent of increase in V ORT after removing a joint's covariation indicated how well coordinated its motion actually was with those of the other joints. The more strongly coordinated a joint was with other joints, the greater effect removal of its covariance should have on indices of hand path stability. For the paretic arm of stroke survivors, simulated removal of a joint's covariation, mainly that of shoulder with elbow and wrist, led to less change in the magnitude of V ORT compared to the same arm of control subjects. These findings confirm a reduced ability of the motion of proximal joint from paretic arm to combine flexibly with motions of the distal joints to stabilize hand path. PMID- 26608517 TI - Dinuclear Cobalt Complexes with a Decadentate Ligand Scaffold: Hydrogen Evolution and Oxygen Reduction Catalysis. AB - A new decadentate dinucleating ligand containing a pyridazine bridging group and pyridylic arms has been synthesized and characterized by analytical and spectroscopic techniques. Four new dinuclear cobalt complexes featuring this ligand have been prepared and thoroughly characterized both in the solid state (X ray diffraction) and in solution (1D and 2D NMR spectroscopy, ESI-MS, and electrochemical techniques). The flexible but stable coordination environment provided by the ligand scaffold when coordinating Co in different oxidation states is shown to play a crucial role in the performance of the set of complexes when tested as catalysts for the photochemical hydrogen evolution reaction (HER) and chemical oxygen reduction reaction (ORR). PMID- 26608519 TI - New insights into bone marrow adipocytes: Report from the First European Meeting on Bone Marrow Adiposity (BMA 2015). PMID- 26608520 TI - TERT promoter mutations and rs2853669 polymorphism: prognostic impact and interactions with common alterations in glioblastomas. AB - TERT promoter (TERTp) mutation is the most common mutation in glioblastomas. It creates a putative binding site for Ets/TCF transcription factors, enhancing telomerase expression and activity, whereas the rs2853669 variant disrupts another Ets/TCF binding. We explore here the interaction between these two alterations, tumor genomic profile and the impact on prognosis. The TERTp and rs2853669 statuses were determined and confronted with the outcome and molecular profile, i.e., loss of chromosome 10q, CDKN2A deletion, IDH mutation, EGFR amplification, MGMT promoter methylation. 651 glioblastomas were selected (sex ratio = 1.35, median age 60.4 years, median survival 13.5 months). The TERTp mutation found in 481 patients (74 %) was independent from rs2853669 genotypes. TERTp mutation, but not rs2853669 status, was associated with older age (61.4 vs. 52.8 years). rs2853669 status had no impact on overall survival (OS) either in mutated TERTp or wild-type TERTp. Neither rs2736100 (TERT, 5q15.33) nor rs192011116 (TERC, 3q26.2) status had any impact on survival or showed any association with a TERTp mutation. The TERTp mutation was associated with EGFR amplification chromosome 10q loss, CDKN2A deletion and IDH wt. EGFR amplification was associated with a better outcome in TERTp mutated GBM, and a worse outcome in TERTp WT. This study-the largest analyzing the TERTp mutation and the rs2853669 polymorphism-fails to find any prognostic impact of rs2853669. It confirms the dual prognostic impact of EGFR amplification depending on TERTp status. PMID- 26608521 TI - Pseudoprogression in glioblastoma patients: the impact of extent of resection. AB - Pseudoprogression (psPD) is a radiation-induced toxicity that has substantial neurological consequence in glioblastoma (GBM) patients. MGMT promoter methylation has been shown to be an important prognostic factor of psPD, but the significance of extent of resection (EOR) remains unclear. We performed a retrospective analysis on newly diagnosed GBM patients with assessable MGMT promoter status who underwent the Stupp protocol. EOR was grouped into gross total resection (GTR), subtotal resection (STR), partial resection (PR) and stereotactic biopsy. Contrast enhancing lesion enlargement was classified as psPD or non-psPD. Among a total of 101 patients, GTR, STR, PR and stereotactic biopsy was performed in 57 (56.4%), 34 (33.7%), 9 (8.9%) and 1 patient (1%), respectively. Follow-up imaging at the end of Stupp protocol classified 45 patients (44.6%) as psPD and 56 (55.4%) as non-psPD. psPD was observed in 24 (61.5%) of 39 patients with methylated MGMT promoter and 21 (33.9%) of 62 patients with unmethylated MGMT promoter (p < 0.01). psPD was documented in 17 (29.8%), 19 (55.9%), 8 (88.9%) and 1 (100%) patient with GTR, STR, PR and stereotactic biopsy (p < 0.01), respectively. On multivariate analysis MGMT promoter status (OR 3.36, 95% CI 1.36-8.34) and EOR (OR 4.12, 95% CI 1.71-9.91) were independent predictors of psPD. A Cox proportional hazards model showed that MGMT status (HR 2.51, p < 0.01) and EOR (HR 2.99, p < 0.01) significantly influenced survival. MGMT status and EOR have a significant impact on psPD. GTR can reduce the side effects of psPD and prolong survival. PMID- 26608518 TI - Tissue engineering strategies for promoting vascularized bone regeneration. AB - This review focuses on current tissue engineering strategies for promoting vascularized bone regeneration. We review the role of angiogenic growth factors in promoting vascularized bone regeneration and discuss the different therapeutic strategies for controlled/sustained growth factor delivery. Next, we address the therapeutic uses of stem cells in vascularized bone regeneration. Specifically, this review addresses the concept of co-culture using osteogenic and vasculogenic stem cells, and how adipose derived stem cells compare to bone marrow derived mesenchymal stem cells in the promotion of angiogenesis. We conclude this review with a discussion of a novel approach to bone regeneration through a cartilage intermediate, and discuss why it has the potential to be more effective than traditional bone grafting methods. PMID- 26608522 TI - Multimodal therapy in children and adolescents with newly diagnosed atypical teratoid rhabdoid tumor: individual pooled data analysis and review of the literature. AB - Atypical teratoid rhabdoid tumour (ATRT) is a malignant tumour of the central nervous system with a dismal prognosis. There is no consensus on optimal treatment and different multimodal strategies are currently being used in an attempt to improve outcomes. To evaluate the impact of high-dose chemotherapy followed by autologous stem-cell rescue (HD48 SCR), radiotherapy (RT) at first line, intrathecal chemotherapy (IT) and extent of surgical resection upon recurrence-free survival (RFS) and overall survival (OS). An online database search identified prospective and retrospective studies focused on the treatment of children and adolescents with newly diagnosed ATRT. Clinical, therapeutic and outcome data were extracted and an individual pooled data analysis was conducted. Out of 389 publications, 12 manuscripts were included in our review. Data from 332 patients were analysed. Median age at diagnosis was 37 months (range 1-231). HD-SCR, RT and IT had been administered to 28.6% (58/203), 49.6% (118/238) and 21% (65/310) of the patients, respectively. Gross total resection (GTR) had been achieved in 46.5% (152/327) of the cases. In the multivariate analysis, hazard ratios (95% Confidence Interval) for HD-SCR were: RFS-HR = 0.570 (0.357-0.910) p = 0.019, and OS-HR = 0.388 (0.214-0.704) p = 0.002; and for RT: RFS-HR = 0.551 (0.351-0.866) p = 0.01, and OS-HR = 0.393 (0.216-0.712) p = 0.002. IT and GTR were not significantly associated with improved RFS or OS in the multivariate analysis. In our pooled data review, HD-SCR and RT at first line were associated with improved outcomes in children and adolescents with newly diagnosed ATRT. PMID- 26608524 TI - Reply to Letter to the Editor - Therapeutic effect of high-dose green tea extract on weight reduction: A randomized, double-blind, placebo-controlled clinical trial. PMID- 26608523 TI - Neuro-oncological patients admitted in intensive-care unit: predictive factors and functional outcome. AB - The prognosis of oncology patients admitted to the intensive care unit (ICU) is considered poor. Our objective was to analyze the characteristics and predictive factors of death in the ICU and functional outcome following ICU treatment for neuro-oncology patients. A retrospective study was conducted on all patients with primary brain tumor admitted to our institutional ICU for medical indications. Predictive impact on the risk of death in the ICU was analyzed as well as the functional status was evaluated prior and following ICU discharge. Seventy-one patients were admitted to the ICU. ICU admission indications were refractory seizures (41 %) and septic shock (17 %). On admission, 16 % had multi-organ failure. Ventilation was necessary for 41 % and catecholamines for 13 %. Twenty two percent of patients died in the ICU. By multivariate analysis, predictive factors associated with an increased risk of ICU death were: non-neurological cause of admission [p = 0.045; odds ratio (OR) 5.405], multiple organ failure (p = 0.021; OR 8.027), respiratory failure (p = 0.006; OR 9.615), and hemodynamic failure (p = 0.008; OR 10.111). In contrast, tumor type (p = 0.678) and disease control status (p = 0.380) were not associated with an increased risk of ICU death. Among the 35 evaluable patients, 77 % presented with a stable or improved Karnofsky performance status following ICU hospitalization compared with the ongoing status before discharge. In patients with primary brain tumor admitted to the ICU, predictive factors of death appear to be similar to those described in non-oncology patients. ICU hospitalization is generally not associated with a subsequent decrease in the functional status. PMID- 26608525 TI - At Your Request((r)) room service dining improves patient satisfaction, maintains nutritional status, and offers opportunities to improve intake. AB - BACKGROUND: Malnutrition in hospitals may be combatted by improving the meal service. AIM: To evaluate whether At Your Request((r)), a meal service concept by Sodexo with a restaurant style menu card and room service, improved patient satisfaction, nutritional status, and food intake compared to the traditional 3 meals per day service. METHODS: We prospectively collected data in Hospital Gelderse Vallei (Ede, the Netherlands) before (2011/2012; n = 168, age 63 +/- 15 y) and after (2013/2014; n = 169, 66 +/- 15 y) implementing At Your Request((r)). RESULTS: Patient satisfaction increased after implementing At Your Request((r)) from 7.5 to 8.1 (scale 1-10) and from 124.5 to 132.9 points on a nutrition related quality of life questionnaire (p < 0.05). Body weight and handgrip strength did not significantly change in both periods. At admission, more patients in the At Your Request((r)) period had risk of malnutrition (MUST >= 1; 47 vs 37). MUST scores improved in 18 patients in both periods. With At Your Request((r)) 0.92 g protein per kg (g/kg) bodyweight was ordered. Protein intake based on food records from patients on an energy and protein enriched diet was 0.84 g/kg during At Your Request((r)) (n = 38) versus 0.91 g/kg during the traditional meal service (n = 34). CONCLUSION: At Your Request((r)) is a highly rated hospital menu concept that helps patients to maintain nutritional status. The concept offers options for improving the intake of specific nutrients and foods, which should be evaluated in further studies. PMID- 26608526 TI - Protein-energy nutrition in the ICU is the power couple: A hypothesis forming analysis. AB - BACKGROUND & AIMS: We hypothesize that an optimal and simultaneous provision of energy and protein is favorable to clinical outcome of the critically ill patients. METHODS: We conducted a review of the literature, obtained via electronic databases and focused on the metabolic alterations during critical illness, the estimation of energy and protein requirements, as well as the impact of their administration. RESULTS: Critically ill patients undergo severe metabolic stress during which time a great amount of energy and protein is utilized in a variety of reactions essential for survival. Energy provision for critically ill patients has drawn attention given its association with morbidity, survival and long-term recovery, but protein provision is not sufficiently taken into account as a critical component of nutrition support that influences clinical outcome. Measurement of energy expenditure is done by indirect calorimetry, but protein status cannot be measured with a bedside technology at present. CONCLUSIONS: Recent studies suggest the importance of optimal and combined provision of energy and protein to optimize clinical outcome. Clinical randomized controlled studies measuring energy and protein targets should confirm this hypothesis and therefore establish energy and protein as a power couple. PMID- 26608527 TI - Structural bases for neurophysiological investigations of amygdaloid complex of the brain. AB - Amygdala (Am) as a part of limbic system of the brain defines such important functions as adaptive behavior of animals, formation of emotions and memory, regulation of endocrine and visceral functions. We worked out, with the help of mathematic modelling of the pattern recognition theory, principles for organization of neurophysiological and neuromorphological studies of Am nuclei, which take into account the existing heterogeneity of its formations and optimize, to a great extent, the protocol for carrying out of such investigations. The given scheme of studies of Am's structural-functional organization at its highly-informative sections can be used as a guide for precise placement of electrodes', cannulae's and microsensors into particular Am nucleus in the brain with the registration not only the nucleus itself, but also its extensions. This information is also important for defining the number of slices covering specific Am nuclei which must be investigated to reveal the physiological role of a particular part of amygdaloid complex. PMID- 26608528 TI - Nicotinic acetylcholine receptor expression in human airway correlates with lung function. AB - Nicotine and its derivatives, by binding to nicotinic acetylcholine receptors (nAChRs) on bronchial epithelial cells, can regulate cellular signaling and inflammatory processes. Delineation of nAChR subtypes and their responses to nicotine stimulation in bronchial epithelium may provide information for therapeutic targeting in smoking-related inflammation in the airway. Expression of nAChR subunit genes in 60 bronchial epithelial biopsies and immunohistochemical staining for the subcellular locations of nAChR subunit expression were evaluated. Seven human bronchial epithelial cell lines (HBECs) were exposed to nicotine in vitro for their response in nAChR subunit gene expression to nicotine exposure and removal. The relative normalized amount of expression of nAChR alpha4, alpha5, and alpha7 and immunohistochemical staining intensity of nAChR alpha4, alpha5, and beta3 expression showed significant correlation with lung function parameters. Nicotine stimulation in HBECs resulted in transient increase in the levels of nAChR alpha5 and alpha6 but more sustained increase in nAChR alpha7 expression. nAChR expression in bronchial epithelium was found to correlate with lung function. Nicotine exposure in HBECs resulted in both short and longer term responses in nAChR subunit gene expression. These results gave insight into the potential of targeting nAChRs for therapy in smoking-related inflammation in the airway. PMID- 26608529 TI - Sexual maturation protects against development of lung inflammation through estrogen. AB - Increasing levels of estrogen and progesterone are suggested to play a role in the gender switch in asthma prevalence during puberty. We investigated whether the process of sexual maturation in mice affects the development of lung inflammation in adulthood and the contributing roles of estrogen and progesterone during this process. By inducing ovalbumin-induced lung inflammation in sexually mature and immature (ovariectomized before sexual maturation) adult mice, we showed that sexually immature adult mice developed more eosinophilic lung inflammation. This protective effect of "puberty" appears to be dependent on estrogen, as estrogen supplementation at the time of ovariectomy protected against development of lung inflammation in adulthood whereas progesterone supplementation did not. Investigating the underlying mechanism of estrogen mediated protection, we found that estrogen-treated mice had higher expression of the anti-inflammatory mediator secretory leukoprotease inhibitor (SLPI) and lower expression of the proasthmatic cytokine IL-33 in parenchymal lung tissue and that their expressions colocalized with type II alveolar epithelial cells (AECII). Treating AECII directly with SLPI significantly inhibited IL-33 production upon stimulation with ATP. Our data suggest that estrogen during puberty has a protective effect on asthma development, which is accompanied by induction of anti-inflammatory SLPI production and inhibition of proinflammatory IL-33 production by AECII. PMID- 26608530 TI - MCPIP1 mediates silica-induced cell migration in human pulmonary fibroblasts. AB - Silicosis is a systemic disease caused by inhaling silicon dioxide (SiO2). Phagocytosis of SiO2 in the lungs initiates an inflammatory cascade that results in fibroblast proliferation and migration followed by fibrosis. According to previous data from our laboratory, monocyte chemotactic protein-1 (MCP-1) plays a critical role in fibroblast proliferation and migration in conventional two dimensional (2D) monolayer cultures. The present study aimed to explore the downstream cascade of MCP-1 in both 2D and three-dimensional (3D) cell culture models of silicosis. Experiments using primary cultured adult human pulmonary fibroblasts (HPF-a) demonstrated the following: 1) SiO2 treatment induces expression of MCP-1-induced protein (MCPIP1) in a time- and dose-dependent manner in both 2D and 3D cultures; 2) the MAPK and phosphatidylinositol-3-kinase (PI3K)/Akt pathways are involved in SiO2-induced MCPIP1 expression; and 3) MCPIP1 induction mediates the SiO2-induced increase in cell migration in both 2D and 3D cultures. The effect of MCP-1 in silicosis occurs mainly through MCPIP1, which, in turn, mediates the observed SiO2-induced increase in pulmonary fibroblast migration. However, the time frame for MCPIP1 induction differed between 2D and 3D cultures, indicating that, compared with conventional 2D cell culture systems, 3D culture may be useful for analyses of fibroblast physiology under conditions that more closely resemble in vivo environments. Our study determined the link between fibroblast-derived MCPIP1 and SiO2-induced cell migration, and this finding provides novel evidence of the potential of MCPIP1 in the development of novel therapeutic strategies for silicosis. PMID- 26608531 TI - IL-27 enhances innate immunity of human pulmonary fibroblasts and epithelial cells through upregulation of TLR4 expression. AB - Lung tissue cells play an active role in the pathogenesis of pulmonary inflammatory diseases by releasing a variety of cytokines and chemokines. However, how lung tissue cells respond to microbial stimuli during pulmonary infections remains unclear. In this study, we found that patients with community acquired pneumonia displayed increased IL-27 levels in bronchoalveolar lavage fluid and serum. We subsequently examined the immunopathological mechanisms for the activation of primary human lung fibroblasts and bronchial epithelial cells by IL-27. We demonstrated that IL-27 priming enhanced LPS-induced production of IL-6 and IL-8 from lung fibroblasts and bronchial epithelia cells via upregulating Toll-like receptor-4 (TLR4) expression. IL-27 upregulated TLR4 expression in lung fibroblasts through activation of Janus-activated kinase (JAK) and Jun NH2-terminal kinase (JNK) signaling pathways, and inhibition of the JAK pathway could partially decrease IL-27-induced TLR4 expression, while inhibition of JNK pathway could completely suppress IL-27-induced TLR4 expression. Our data suggest that IL-27 modulates innate immunity of lung tissue cells through upregulating TLR4 expression during pulmonary infections. PMID- 26608532 TI - Ventilation-induced lung injury is not exacerbated by growth restriction in preterm lambs. AB - Intrauterine growth restriction (IUGR) and preterm birth are frequent comorbidities and, combined, increase the risk of adverse respiratory outcomes compared with that in appropriately grown (AG) infants. Potential underlying reasons for this increased respiratory morbidity in IUGR infants compared with AG infants include altered fetal lung development, fetal lung inflammation, increased respiratory requirements, and/or increased ventilation-induced lung injury. IUGR was surgically induced in preterm fetal sheep (0.7 gestation) by ligation of a single umbilical artery. Four weeks later, preterm lambs were euthanized at delivery or delivered and ventilated for 2 h before euthanasia. Ventilator requirements, lung inflammation, early markers of lung injury, and morphological changes in lung parenchymal and vascular structure and surfactant composition were analyzed. IUGR preterm lambs weighed 30% less than AG preterm lambs, with increased brain-to-body weight ratio, indicating brain sparing. IUGR did not induce lung inflammation or injury or alter lung parenchymal and vascular structure compared with AG fetuses. IUGR and AG lambs had similar oxygenation and respiratory requirements after birth and had significant, but similar, increases in proinflammatory cytokine expression, lung injury markers, gene expression, and surfactant phosphatidylcholine species compared with unventilated controls. IUGR does not induce pulmonary structural changes in our model. Furthermore, IUGR and AG preterm lambs have similar ventilator requirements in the immediate postnatal period. This study suggests that increased morbidity and mortality in IUGR infants is not due to altered lung tissue or vascular structure, or to an altered response to early ventilation. PMID- 26608533 TI - Decoding the molecular mechanisms of neuronal migration using in utero electroporation. AB - During the development of the cerebral cortex, excitatory neurons are produced in the ventricular zone lining the lateral ventricle or in the adjacent subventricular zone and migrate toward the brain surface in a process known as radial migration. During radial migration, neurons undergo multiple steps including a multipolar cell phase, a multipolar-bipolar transition, and a locomotion phase. Many genes tightly regulate the cell behavior in each phase. We have established an in utero electroporation method as a rapid in vivo gene transfer system, and this system has greatly contributed to recent advances in our knowledge of the molecular mechanisms underlying each migration phase. Here, we review the cell behaviors of neurons during each phase of radial migration and the molecular mechanisms involved in these phases. Knockdown or functional blocking of these genes using in utero electroporation results in various migration defects and abnormal cell morphologies. Here, we describe these phenotypes as much as possible so that this review can be used as a chart to evaluate the phenotypes of novel gene knockdown experiments. We also discuss the recent application of in utero electroporation in studies examining the functions of neurodevelopmental disorder-related genes. PMID- 26608534 TI - Self-organization of photo-active nanostructures: general discussion. PMID- 26608535 TI - Evolution of Zinc Oxide Nanostructures Grown on Graphene by Ultrasonic Spray Pyrolysis and Its Statistical Growth Modelling. AB - The evolution of zinc oxide nanostructures grown on graphene by alcohol-assisted ultrasonic spray pyrolysis was investigated. The evolution of structures is strongly depended on pyrolysis parameters, i.e., precursor molarity, precursor flow rate, precursor injection/deposition time, and substrate temperature. Field effect scanning electron microscope analysis, energy dispersive X-ray spectroscopy, X-ray diffraction, and transmission electron microscopy were used to investigate the properties of the synthesized nanostructures and to provide evidence for the structural changes according to the changes in the pyrolysis parameters. The optimum parameters to achieve maximum density and well-defined hexagonally shaped nanorods were a precursor molarity of 0.2 M, an injection flow rate of 6 ml/min, an injection time of 10 min, and a substrate temperature of 250 355 degrees C. Based on the experimental results, the response surface methodology (RSM) was used to model and optimize the independent pyrolysis parameters using the Box-Behnken design. Here, the responses, i.e., the nanostructure density, size, and shape factor, are evaluated. All of the computations were performed using the Design-Expert software package. Analysis of variance (ANOVA) was used to evaluate the results of the model and to determine the significant values for the independent pyrolysis parameters. The evolution of zinc oxide (ZnO) structures are well explained by the developed modelling which confirms that RSM is a reliable tool for the modelling and optimization of the pyrolysis parameters and prediction of nanostructure sizes and shapes. PMID- 26608536 TI - Enhanced Antiproliferative Effect of Carboplatin in Cervical Cancer Cells Utilizing Folate-Grafted Polymeric Nanoparticles. AB - Carboplatin (CRB) possesses superior anticancer effect in cervical cancer cells with lower incidence of side effects compared to that of cisplatin. However, CRB suffers from severe side effects due to undesirable tissue distributions which contribute to the low therapeutic efficacy. Here, we report a unique folic acid conjugated chitosan-coated poly(D-L-lactideco-glycolide) (PLGA) nanoparticles (FPCC) prepared for the selective delivery of carboplatin to the cervical cancer cells. The particles were nanosized and spherical shaped with size less than <200 nm. The presence of protective chitosan layer controlled the overall release rate of CRB from chitosan-coated PLGA nanoparticles (PCC) and FPCC. FPCC displayed a higher cellular uptake capacity in HeLa cells than compared to non-targeted nanoparticles. Selective uptake of FPCC was due to an interaction of folic acid (FA) with the folate receptors alpha (FRs-alpha) which is overexpressed on the HeLa and promoted active targeting. These results indicated that FPCC had a specific affinity for the cancerous, HeLa cells owing to ligand-receptor (FA-FR alpha) recognition. Consistently, FPCC showed superior cytotoxic effect than any other formulations. The IC50 (concentration of the drug required to kill 50 % of the cells) value of FPCC was 0.65 MUg/ml while it was 1.08, 1.56, and 2.35 MUg/ml for PCC, PLGA NP, and free CRB, respectively. Consistent with the cytotoxicity assay, FPCC induced higher fraction of early as well as late apoptosis cells. Especially, FPCC induced nearly 45 % of early apoptosis cells and more than 35 % in late apoptosis. Therefore, we propose that folate-conjugated nanoparticles might have potential applications in cervical cancer therapy. PMID- 26608537 TI - A Facile Way to Fabricate High-Performance Solution-Processed n-MoS2/p-MoS2 Bilayer Photodetectors. AB - Two-dimensional (2D) material has many advantages including high carrier mobilities and conductivity, high optical transparency, excellent mechanical flexibility, and chemical stability, which made 2D material an ideal material for various optoelectronic devices. Here, we developed a facile method of preparing MoS2 nanosheets followed by a facile liquid exfoliation method via ethyl cellulose-assisted doping and utilizing a plasma-induced p-doping approach to generate t effectively the partially oxided MoS2 (p-MoS2) nanosheets from the pristine n-type nanosheets. Moreover, an n-p junction type MoS2 photodetector device with the built-in potentials to separate the photogenerated charges is able to significantly improved visible light response. We have fabricated photodetector devices consisting of a vertically stacked indium tin oxide (ITO)/pristine n-type MoS2 nanosheets/p-MoS2/Ag structure, which exhibit reasonably good performance illumination, as well as high current values in the range of visible wavelength from 350 to 600 nm. We believe that this work provides important scientific insights for photoelectric response properties of emerging atomically layered 2D materials for photovoltaic and other optoelectronic applications. PMID- 26608538 TI - CaMKII inhibition in the prefrontal cortex specifically increases the positive reinforcing effects of sweetened alcohol in C57BL/6J mice. AB - Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional enzyme that is required for synaptic plasticity and has been proposed to be a primary molecular component of the etiology of alcohol addiction. Chronic alcohol intake upregulates CaMKIIalpha protein expression in reward-related brain regions including the amygdala and nucleus accumbens, and CaMKIIalpha activity in the amygdala is required for the positive reinforcing effects of alcohol, suggesting this system promotes consumption in the early stages of alcohol addiction. Alternatively, the medial prefrontal cortex (mPFC) is known to inhibit limbic activity via CaMKII-dependent excitatory projections and may, therefore, enable top-down regulation of motivation. Here we sought to remove that regulatory control by site-specifically inhibiting CaMKII activity in the mPFC, and measured effects on the positive reinforcing effects of sweetened alcohol in C57BL/6J mice. Infusion of the CAMKII inhibitor KN-93 (0-10.0 MUg) in the mPFC primarily increased alcohol+sucrose reinforced response rate in a dose- and time-dependent manner. KN-93 infusion reduced response rate in behavior-matched sucrose-only controls. Importantly, potentiation of operant responding for sweetened alcohol occurred immediately after infusion, at a time during which effects on sucrose responding were not observed, and persisted through the session. These results suggest that endogenous CaMKII activity in the mPFC exerts inhibitory control over the positive reinforcing effects of alcohol. Downregulation of CaMKII signaling in the mPFC might contribute to escalated alcohol use. PMID- 26608539 TI - Ambient temperature influences the neural benefits of exercise. AB - Many of the neural benefits of exercise require weeks to manifest. It would be useful to accelerate onset of exercise-driven plastic changes, such as increased hippocampal neurogenesis. Exercise represents a significant challenge to the brain because it produces heat, but brain temperature does not rise during exercise in the cold. This study tested the hypothesis that exercise in cold ambient temperature would stimulate hippocampal neurogenesis more than exercise in room or hot conditions. Adult female rats had exercise access 2h per day for 5 days at either room (20 degrees C), cold (4.5 degrees C) or hot (37.5 degrees C) temperature. To label dividing hippocampal precursor cells, animals received daily injections of BrdU. Brains were immunohistochemically processed for dividing cells (Ki67+), surviving cells (BrdU+) and new neurons (doublecortin, DCX) in the hippocampal dentate gyrus. Animals exercising at room temperature ran significantly farther than animals exercising in cold or hot conditions (room 1490 +/- 400 m; cold 440 +/- 102 m; hot 291 +/- 56 m). We therefore analyzed the number of Ki67+, BrdU+ and DCX+ cells normalized for shortest distance run. Contrary to our hypothesis, exercise in either cold or hot conditions generated significantly more Ki67+, BrdU+ and DCX+ cells compared to exercise at room temperature. Thus, a limited amount of running in either cold or hot ambient conditions generates more new cells than a much greater distance run at room temperature. Taken together, our results suggest a simple means by which to augment exercise effects, yet minimize exercise time. PMID- 26608540 TI - Dopaminergic impact on local and global cortical circuit processing during learning. AB - We have learned to detect, predict and behaviorally respond to important changes in our environment on short and longer time scales. Therefore, brains of humans and higher animals build upon a perceptual and semantic salience stored in their memories mainly generated by associative reinforcement learning. Functionally, the brain needs to extract and amplify a small number of features of sensory input with behavioral relevance to a particular situation in order to guide behavior. In this review, I argue that dopamine action, particularly in sensory cortex, orchestrates layer-dependent local and long-range cortical circuits integrating sensory associated bottom-up and semantically relevant top-down information, respectively. Available evidence reveals that dopamine thereby controls both the selection of perceptually or semantically salient signals as well as feedback processing from higher-order areas in the brain. Sensory cortical dopamine thereby governs the integration of selected sensory information within a behavioral context. This review proposes that dopamine enfolds this function by temporally distinct actions on particular layer-dependent local and global cortical circuits underlying the integration of sensory, and non-sensory cognitive and behavioral variables. PMID- 26608541 TI - Contrast-enhanced ultrasound of both kidneys in healthy, non-anaesthetized cats. AB - BACKGROUND: Changes in perfusion are considered to play a key role in the pathophysiology of renal disease. Contrast-enhanced ultrasound (CEUS) has shown a promising diagnostic imaging technique to non-invasively and repetitively quantify tissue perfusion. Examination protocols have varied between studies regarding US equipment, quantification software, the use of sedation or anaesthesia, and animals. The purpose of the present study was, to assess the feasibility of a standardized CEUS protocol for perfusion analysis of both kidneys in nine healthy, non-anaesthetized cats. RESULTS: CEUS was fairly tolerable for all but one cat. In 6/18 kidneys (2 left, 4 right), a second contrast medium injection was needed due to motion artifacts. Perfusion variables such as peak intensity (PI), wash-in slope (WIS), wash-out slope (WOS) and mean transit time (MTT) did not significantly differ between left and right renal cortex and medulla nor between the cranial and caudal renal cortex within each kidney. In contrast, for all kidneys, mean PI, WIS, and MTT were significantly higher in the cortex than in the medulla (P = 0.001, 0.012 and <0.001, respectively). CONCLUSIONS: The herein reported CEUS protocol and the perfusion measurements may serve as a baseline protocol and normal reference values for the evaluation of feline patients. However, the protocol and results may be of limited value in uncooperative animals. PMID- 26608543 TI - Hands-on defibrillation and electrocardiogram artefact filtering technology increases chest compression fraction and decreases peri-shock pause duration in a simulation model of cardiac arrest. AB - BACKGROUND: Reducing pauses during cardiopulmonary resuscitation (CPR) compressions result in better outcomes in cardiac arrest. Artefact filtering technology (AFT) gives rescuers the opportunity to visualize the underlying electrocardiogram (ECG) rhythm during chest compressions, and reduces the pauses that occur before and after delivering a shock. We conducted a simulation study to measure the reduction of peri-shock pause and impact on chest compression fraction (CCF) through AFT. METHODS: In a simulator setting, participants were given a standardized cardiac arrest scenario and were randomly assigned to perform CPR/defibrillation using the protocol from one of three experimental arms: 1) Standard of Care (pauses for rhythm analysis and shock delivery); 2) AFT (no pauses for rhythm analysis, but a pause for defibrillation); or 3) AFT with hands-on defibrillation (no pauses for rhythm analysis or defibrillation). The primary outcomes were CCF and peri-shock pause duration, with secondary outcomes of pre- and post-shock pause duration. RESULTS: AFT with hands-on defibrillation was found to have the highest CCF (86.4%), as compared to AFT alone (83.8%, p<0.001), and both groups significantly improved CCF in comparison with the Standard of Care (76.7%, p<0.001). AFT with hands-on defibrillation was associated with a reduced peri-shock pause (2.6 seconds) as compared to AFT alone (5.3 seconds, p<0.001), and the Standard of Care (7.4 seconds, p<0.001). CONCLUSIONS: In this cardiac arrest model, AFT results in a greater CCF by reducing peri-shock pause duration. There is also a small but detectable improvement in CCF with the addition of hands-on defibrillation. PMID- 26608544 TI - What lies beyond: Findings from the Early Careers Survey of new Fellows of the Australasian College for Emergency Medicine 2013-2014. PMID- 26608545 TI - Prognostic utility of cardiovascular magnetic resonance upright maximal treadmill exercise testing. AB - BACKGROUND: Left ventricular wall motion abnormalities (LVWMA) observed during cardiovascular magnetic resonance (CMR) pharmacologic stress testing can be used to determine cardiac prognosis, but currently, information regarding the prognostic utility of upright maximal treadmill induced LVWMA is unknown. Our objective was to determine the prognostic utility of upright maximal treadmill exercise stress CMR. METHODS: One hundred and fifteen (115) men and women with known or suspected coronary arteriosclerosis and an appropriate indication for cardiovascular (CV) imaging to supplement ST segment stress testing underwent an upright treadmill exercise CMR stress test in which LVWMA were identified before and immediately after exercise. Personnel blinded to results determined the post test incidence of cardiac events (cardiac death, myocardial infarctions [MI], and unstable angina warranting hospital admission or coronary arterial revascularization). RESULTS: All participants completed the testing protocol, with 90% completing image acquisition within 60 s of exercise cessation. MI or cardiac death occurred in 3% of individuals without and 17% of individuals with inducible LVWMA (p = 0.024). The combination of MI, cardiac death, and unstable angina warranting hospitalization occurred in 14% of individuals without and 47% of individuals with inducible LVWMA (p = 0.002). The addition of CMR imaging identified those at risk for future events (p = 0.002), as opposed to the electrocardiogram stress test alone (p = 0.63). CONCLUSIONS: In patients with or suspected of coronary arteriosclerosis and appropriate indication for imaging to supplement ST segment analysis during upright treadmill exercise, the presence of inducible LVWMA during treadmill exercise stress CMR supplements ST segment monitoring and helps identify those at risk of the future combined endpoints of myocardial infarction, cardiac death, and unstable angina warranting hospitalization. PMID- 26608547 TI - A new method to assess oxidative stress in ART cycles. AB - The role of oxidative stress (OS) in female reproduction is an understudied area for investigation. The aim of the study was to assess reactive oxygen species (ROS) levels both in follicular fluid (FF) and in serum samples of women undergoing IVF and to relate them to clinical outcomes. A total of 56 women were enrolled. From each patient a sample of serum and FF were collected at oocyte retrieval day and analyzed for OS, by measuring a class of reactive oxygen metabolites (ROMs) (dROMs test) and for biological anti-oxidant potential levels (BAP test). The data analyzed in serum and in FF were related to pregnancy outcomes. There was no significant relationship between d-ROMs and BAP levels in serum or FF GROUP A and B and the clinical parameters of prognosis of women: age, number of oocytes retrieved number of oocytes methaphase II, FSH, fertilization rate and cleavage rate, number of embryos transferred and embryo score. There was a positive association between systemic levels of OS measured in serum GROUP A and pregnancy outcomes (p = 0.007) suggesting that the evaluation of OS in FF needs more investigation about markers in follicular microenvironment in order to predict IVF success. PMID- 26608546 TI - Double Asymmetric Induction During the Addition of (RP)-Menthyl Phenyl Phosphine Oxide to Chiral Aldimines. AB - P,C-Stereogenic alpha-amino phosphine oxides were prepared from the addition of (RP )-menthyl phenyl phosphine oxide to chiral aldimines under neat condition at 80 degrees C in up to 91:9 drC and 99% yields. The diastereoselectivity was mainly induced by chiral phosphorus that showed matched or mismatched induction with (S)- or (R)-aldimines, respectively. PMID- 26608548 TI - Diversity of Clostridium perfringens isolates from various sources and prevalence of conjugative plasmids. AB - Clostridium perfringens is an important pathogen, causing food poisoning and other mild to severe infections in humans and animals. Some strains of C. perfringens contain conjugative plasmids, which may carry antimicrobial resistance and toxin genes. We studied genomic and plasmid diversity of 145 C. perfringens type A strains isolated from soils, foods, chickens, clinical samples, and domestic animals (porcine, bovine and canine), from different geographic areas in the United States between 1994 and 2006, using multiple-locus variable-number tandem repeat analysis (MLVA) and/or pulsed-field gel electrophoresis (PFGE). MLVA detected the genetic diversity in a majority of the isolates. PFGE, using SmaI and KspI, confirmed the MLVA results but also detected differences among the strains that could not be differentiated by MLVA. All of the PFGE profiles of the strains were different, except for a few of the epidemiologically related strains, which were identical. The PFGE profiles of strains isolated from the same domestic animal species were clustered more closely with each other than with other strains. However, a variety of C. perfringens strains with distinct genetic backgrounds were found among the clinical isolates. Variation was also observed in the size and number of plasmids in the strains. Primers for the internal fragment of a conjugative tcpH gene of C. perfringens plasmid pCPF4969 amplified identical size fragments from a majority of strains tested; and this gene hybridized to the various-sized plasmids of these strains. The sequences of the PCR-amplified tcpH genes from 12 strains showed diversity among the tcpH genes. Regardless of the sources of the isolates, the genetic diversity of C. perfringens extended to the plasmids carrying conjugative genes. PMID- 26608550 TI - Synthesis of beta-boswellic acid derivatives as cytotoxic and apoptotic agents. AB - A series of beta-boswellic acid derivatives were synthesized and evaluated for anticancer activity. One of the lead analog 4f displayed significant anticancer activity against a panel of cancer cells as well as substantially inhibited colony formation in HCT-116 cells. Furthermore, 4f was found to be a potent inducer of apoptosis confirmed by loss of mitochondrial membrane potential, DAPI staining, Western blotting and ROS generation. PMID- 26608549 TI - Promoting rotational-invariance in object recognition despite experience with only a single view. AB - Different processes are assumed to underlie invariant object recognition across affine transformations, such as changes in size, and non-affine transformations, such as rotations in depth. From this perspective, promoting invariant object recognition across rotations in depth requires visual experience with the object from multiple viewpoints. One learning mechanism potentially contributing to invariant recognition is the error-driven learning of associations between relatively view-invariant visual properties and motor responses or object labels. This account uniquely predicts that experience with affine transformations of a single object view may also promote view-invariance, if view-invariant properties are also invariant across such affine transformations. We empirically confirmed this prediction in both people and pigeons, thereby suggesting that: (a) the hypothesized mechanism participates in view-invariance learning, (b) this mechanism is present across distantly-related vertebrates, and (c) the distinction between affine and non-affine transformations may not be fundamental for biological visual systems, as previously assumed. PMID- 26608551 TI - Synthesis of (3S,4S)-4-aminopyrrolidine-3-ol derivatives and biological evaluation for their BACE1 inhibitory activities. AB - Synthesis, SAR study and BACE1 inhibitory activity of (3S,4S)-4-aminopyrrolidine 3-ol derivatives (2) were described. The compound 7c exhibited more inhibition activity than 11a (IC50: 0.05MUM vs 0.12MUM, respectively), but the latter was more effective in cell-based assay (IC50: 1.7MUM vs 40% inhibition by 7c @ 10MUM) due to the relatively higher cell permeability. Most of the compounds showed high selectivity over BACE2 and cathepsin D. This work will provide useful information for further structural modifications to develop potent BACE1 inhibitors in cell. PMID- 26608552 TI - Discovery of substituted-2,4-dimethyl-(naphthalene-4-carbonyl)amino-benzoic acid as potent and selective EP4 antagonists. AB - A novel series of EP4 antagonists, based on a quinoline scaffold, has been discovered. Medicinal chemistry efforts to optimize the potency of the initial hit are described. A highly potent compound in a clinically relevant human whole blood assay was identified. Selectivity and pharmacokinetic profiles of this compound are discussed. PMID- 26608553 TI - Synthesis, characterization and biological evaluation of anti-cancer indolizine derivatives via inhibiting beta-catenin activity and activating p53. AB - Diversity-oriented construction of new indolizine scaffolds was accomplished by utilizing domino Knoevenagel condensation/intramolecular aldol cyclization. Biological evaluation revealed anticancer activity of these compounds through inhibition of beta-catenin and activation of p53. PMID- 26608555 TI - Classical group theory adapted to the mechanism of Pt3Ni nanoparticle growth: the role of W(CO)6 as the "shape-controlling" agent. AB - Classical group theory was applied to prove the Pt3Ni crystallographic transformation from Platonic cubic to Archimedean cuboctahedral structures and the formation of Pt3Ni polypods. The role of W(CO)6 as a shape-controlling agent is discussed with respect to the crystallographic features of the clusters and superstructures generated as control samples. PMID- 26608554 TI - Following the infection process of vibriosis in Manila clam (Ruditapes philippinarum) larvae through GFP-tagged pathogenic Vibrio species. AB - Vibriosis represents the main bottleneck for the larval production process in shellfish aquaculture. While the signs of this disease in bivalve larvae are well known, the infection process by pathogenic Vibrio spp. during episodes of vibriosis has not been elucidated. To investigate the infection process in bivalves, the pathogens of larvae as V. tubiashii subsp. europaensis, V. neptunius and V. bivalvicida were tagged with green fluorescent protein (GFP). Larvae of Manila clam (Ruditapes philippinarum) were inoculated with the GFP labeled pathogens in different infection assays and monitored by microscopy. Manila clam larvae infected by distinct GFP-tagged Vibrio spp. in different challenges showed the same progression in the infection process, defining three infection stages. GFP-tagged Vibrio spp. were filtered by the larvae through the vellum and entered in the digestive system through the esophagus and stomach and colonized the digestive gland and particularly the intestine, where they proliferated during the first 2h of contact (Stage I), suggesting a chemotactic response. Then, GFP-tagged Vibrio spp. expanded rapidly to the surrounding organs in the body cavity from the dorsal to ventral region (Stage II; 6-8h), colonizing the larvae completely at the peak of infection (Stage III) (14-24h). Results demonstrated for the first time that the vibriosis is asymptomatic in Manila clam larvae during the early infection stages. Thus, the early colonization and the rapid proliferation of Vibrio pathogens within the body cavity supported the sudden and fatal effect of the vibriosis, since the larvae exhibited the first signs of disease when the infection process is advanced. As a first step in the elucidation of the potential mechanisms of bacterial pathogenesis in bivalve larvae the enzymatic activities of the extracellular products released from the wild type V. neptunius, V. tubiashii subsp. europaensis and V. bivalvicida were determined and their cytotoxicity was demonstrated in fish and homeothermic cell lines for the first time. That activity was lost after heat treatment. PMID- 26608557 TI - CCG advises patients to pay privately for treatments it plans to stop funding on NHS. PMID- 26608556 TI - The Effect of Intravenous Infiltration Management Program for Hospitalized Children. AB - This study aimed to identify the effect of IV infiltration management program among hospitalized children. DESIGN AND METHODS: This was a quasi-experimental study with history comparison group design with 2,894 catheters inserted during 3 months comparison phase and 3,651 catheters inserted during 4 months experimental phase. The intervention was composed of seven activities including applying poster, documentation of catheter insertion, parents education, making infiltration report, assessment of vein condition before inserting catheter, appropriate site selection, and documentation of catheter insertion, and assessment of peripheral catheter insertion site every shift. Data were analyzed using of X2-test, Fisher's exact test. RESULTS: The infiltration incidence rate was 0.9% for experimental group and 4.4% for comparison group, which was significantly different (x2=80.42, p<.001). The catheter maintenance period (p=.035) and infiltration state (p=.039) were significantly different among participants with infiltration between comparison and experimental groups. CONCLUSIONS: IV Infiltration management program was founded to be effective in reducing the IV infiltration incidence rate and increasing early detection of IV infiltration. PRACTICE IMPLICATIONS: Considering the effect of IV Infiltration management program, we recommend that this infiltration management program would be widely used in the clinical settings. PMID- 26608558 TI - Rapid Holocene thinning of an East Antarctic outlet glacier driven by marine ice sheet instability. AB - Outlet glaciers grounded on a bed that deepens inland and extends below sea level are potentially vulnerable to 'marine ice sheet instability'. This instability, which may lead to runaway ice loss, has been simulated in models, but its consequences have not been directly observed in geological records. Here we provide new surface-exposure ages from an outlet of the East Antarctic Ice Sheet that reveal rapid glacier thinning occurred approximately 7,000 years ago, in the absence of large environmental changes. Glacier thinning persisted for more than two and a half centuries, resulting in hundreds of metres of ice loss. Numerical simulations indicate that ice surface drawdown accelerated when the otherwise steadily retreating glacier encountered a bedrock trough. Together, the geological reconstruction and numerical simulations suggest that centennial-scale glacier thinning arose from unstable grounding line retreat. Capturing these instability processes in ice sheet models is important for predicting Antarctica's future contribution to sea level change. PMID- 26608559 TI - Addressing HIV stigma in protected medical settings. AB - Previous studies suggest that the implementation of universal precaution (UP) plays a role in reducing HIV stigma. In this study we investigate the efficacy of a stigma reduction intervention on UP compliance and explore whether UP compliance could potentially influence HIV stigma reduction in medical settings. A randomized controlled intervention trial was conducted in two provinces of China with 1760 healthcare service providers recruited from 40 county-level hospitals. Longitudinal analyses included data collection at baseline, 6-, and 12 month follow-up assessments. Using a hierarchical modeling approach, we estimated the intervention effect for each provider's UP compliance and its potential mediating role on HIV stigma with the bootstrapping method. A significant intervention effect on UP compliance was observed at both the 6- and 12-month follow-up assessments. The intervention effect on provider avoidance intent was partially mediated by the provider's own UP compliance at the two follow-up points. This study provides evidence that UP compliance should be part of HIV stigma reduction programs, especially in resource-restrained countries. Findings suggest that a protected work environment may be necessary but not sufficient to address HIV stigma in medical settings. PMID- 26608560 TI - The impact of elevated CO2 and temperature on grain quality of rice grown under open-air field conditions. AB - BACKGROUND: Rising atmospheric CO2 is accompanied by global warming. However, interactive effects of elevated CO2 and temperature have not been well studied on grain quality of rice. A japonica cultivar was grown in the field using a free air CO2 enrichment facility in combination with a canopy air temperature increase system in 2014. The gas fumigation (200 umol mol(-1) above ambient CO2 ) and temperature increase (1 degrees C above ambient air temperature) were performed from tillering until maturity. RESULTS: Compared with the control (ambient CO2 and air temperature), elevated CO2 increased grain length and width as well as grain chalkiness but decreased protein concentrations. In contrast, the increase in canopy air temperature had less effect on these parameters except for grain chalkiness. The starch pasting properties of rice flour and taste analysis of cooked rice indicated that the palatability of rice was improved by CO2 and/or temperature elevation, with the combination of the two treatments showing the most significant changes compared with ambient rice. CONCLUSION: It is concluded that projected CO2 in 2050 may have larger effects on rice grain quality than the projected temperature increase. Although deterioration in milling suitability, grain appearance and nutritional quality can be expected, the taste of cooked rice might be better in the future environment. (c) 2015 Society of Chemical Industry. PMID- 26608561 TI - Synthetic and theoretical investigation on the one-pot halogenation of beta-amino alcohols and nucleophilic ring opening of aziridinium ions. AB - Aziridinium ions are useful reactive intermediates for the synthesis of enantiomerically enriched building blocks. However, N,N-dialkyl aziridinium ions are relatively underutilized in the synthesis of optically active molecules as compared to other three-membered ring cogeners, aziridines and epoxides. The characterization of both optically active aziridinium ions and secondary beta halo amines as the precursor molecules of aziridinium ions has been scarcely reported and is often unclear. In this paper, we report for the first time the preparation and experimental and theoretical characterization of optically active aziridinium ions and secondary beta-halo amines. Optically active secondary N,N substituted beta-halo amines were efficiently synthesized from N,N-substituted alaninol via formation and ring opening at the more hindered carbon of aziridinium ions by halides. Optically active beta-halo amines and aziridinium ions were characterized by NMR and computational analyses. The structure of an optically active beta-chloro amine was confirmed via X-ray crystallographic analysis. The aziridinium ions derived from N,N-dibenzyl alaniol remained stable only for several hours, which was long enough for analyses of NMR and optical activity. The stereospecific ring opening of aziridinium ions by halides was computationally studied using DFT and highly-accurate DLPNO-CCSD(T) methods. The highly regioselective and stereoselective ring opening of aziridinium ions was applied for efficient one-pot conversion of beta-alaninols to enantiomerically enriched beta-amino alcohols, beta-amino nitriles, and vicinal diamine derivatives. PMID- 26608563 TI - Deletion of the Complex I Subunit NDUFS4 Adversely Modulates Cellular Differentiation. AB - The vast majority of cellular ATP is produced by the oxidative phosphorylation (OXPHOS) system, which comprises the four complexes of the electron transfer chain plus the ATP synthase. Complex I is the largest of the OXPHOS complexes, and mutation of the genes encoding either the subunits or assembly factors of Complex I can result in Complex I deficiency, which is the most common OXPHOS disorder. Mutations in the Complex I gene NDUFS4 lead to Leigh syndrome, which is the most frequent presentation of Complex I deficiency in children presenting with progressive encephalopathy shortly after birth. Symptoms include motor and intellectual retardation, often accompanied by dystonia, ataxia, and growth retardation, and most patients die by 3 years of age. To understand the origins of this disease, we have generated a series of mouse embryonic stem cell lines from blastocysts that were wild type, heterozygous, and homozygous for the deletion of the Ndufs4 gene. We have demonstrated their pluripotency and potential to differentiate into all cell types of the body. Although the loss of Ndufs4 did not affect the stability of the mitochondrial and nuclear genomes, there were significant differences in patterns of chromosomal gene expression following both spontaneous differentiation and directed neural differentiation into astrocytes. The defect also affected the potential of the cells to generate beating embryoid bodies. These outcomes demonstrate that defects associated with Complex I deficiency affect early gene expression patterns, which escalate during early and later stages of differentiation and are mediated by the defect and not other chromosomal or mitochondrial DNA defects. PMID- 26608562 TI - Clinical implications of nonsarcomeric gene polymorphisms in hypertrophic cardiomyopathy. AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by cardiomyocyte hypertrophy and fibrosis. Although is an autosomal dominant trait, a group of nonsarcomeric genes have been postulated as modifiers of the phenotypic heterogeneity. MATERIAL AND METHODS: We prospectively recruited 168 HCM patients and 136 healthy controls from three referral centres. Patients and controls were clinically stable at entry in the study. Nine polymorphisms previously associated with ventricular remodelling were determined: I/D ACE, AGTR1(A1666C), CYP11B2(C344T), PGC1-alpha(G482S), COLIA1(G2046T), ADRB1(R389G), NOS3(G894T), RETN(-420C>G) and CALM3(-34T>A). Their potential influence on prognosis, assessed by hospital admissions, and their cause were recorded. RESULTS: The median follow up time was 49.5 months. Allele and genotype frequencies did not differ between patients and controls. Thirty-six patients (21.5%) required urgent hospitalization (18.5% for heart failure, 22.2% for atrial arrhythmias, 11.1% for ventricular arrhythmias, 29.6% for ischaemic heart disease, 14.8% for stroke and 3.7% for other reasons) with a hospitalization rate of 8.75% per year. Multivariate analysis showed an independent predictive value for noncarriers of polymorphic COL1A1 allele [HR: 2.76(1.26-6.05), P = 0.011] and a trend in homozygous carriers of ADRB1 Arg389 variant [HR: 1.98(0.99-4.02); P = 0.057]. CONCLUSION: Our study suggests that COL1A1 polymorphism (2046G>T) is an independent predictor of prognosis in HCM patients supporting the importance of nonsarcomeric genes on clinical prognosis in HCM. PMID- 26608564 TI - Serum tenascin-C discriminates patients with active SLE from inactive patients and healthy controls and predicts the need to escalate immunosuppressive therapy: a cohort study. AB - INTRODUCTION: The aim of this study was to examine whether circulating levels of the proinflammatory glycoprotein tenascin-C (TNC) are useful as an activity specific or predictive biomarker in systemic lupus erythematosus (SLE). METHODS: Serum TNC levels were determined by enzyme-linked immunosorbent assay at inception visit in a prospective cohort of 59 SLE patients, and in 65 healthy controls (HC). SLE patients were followed for a mean of 11 months, disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K) and British Isles Lupus Assessment Group disease activity index (BILAG-2004), clinical and laboratory data were recorded every 3-6 months, and changes in glucocorticoids (GC) and immunosuppressants (IS) were recorded serially. We examined cross-sectionally the relationships between serum concentrations of TNC and SLE status, SLEDAI-2 K scores, strata of disease activity, and levels of conventional biomarkers [anti-double-stranded DNA (dsDNA), anti-nucleosome antibodies, C3 and C4]. We also explored the utility of TNC levels for predicting disease flares, defined as (i) new/increased GC, (ii) new/increased GC or IS, and (iii) increase in SLEDAI by >=3 or (iv) BILAG A or B flare. RESULTS: There was no significant difference in the mean levels of TNC between the SLE patients and HC. However, in SLE patients with active disease (SLEDAI >=6), the TNC levels were significantly higher than in the HC (p = 0.004) or in patients with no/low disease activity (p = 0.004). In SLE patients, TNC levels were significantly associated with positivity of anti-dsDNA (p = 0.03) and anti-nucleosome antibodies (p = 0.008). Flares defined by a need to escalate immunosuppressive therapy were captured more frequently and earlier than flares defined by standard activity indices. Higher baseline levels of serum TNC presented a significantly greater risk of flare (i) [hazard ratio (HR) 1.39, 95% confidence interval (CI) 1.11-1.73] or (ii) (HR 1.25, 95% CI 1.02-1.52) but not of flares (iii) or (iv). The baseline serum TNC level was the single most important independent predictor of flare (i) compared with conventional biomarkers. CONCLUSIONS: TNC is not disease-specific, but it seems to indicate the activity of SLE and may predict the need to escalate immunosuppressive therapy. TNC levels may thus serve as a useful activity-specific and predictive biomarker in SLE. PMID- 26608565 TI - Evaluation of environmental genotoxicity by comet assay in Columba livia. AB - The concentrations of recognized or suspected genotoxic and carcinogenic agents found in the air of large cities and, in particular, developing countries, have raised concerns about the potential for chronic health effects in the populations exposed to them. The biomonitoring of environmental genotoxicity requires the selection of representative organisms as "sentinels," as well as the development of suitable and sensitive assays, such as those aimed at assessing DNA damage. The aim of this study was to evaluate DNA damage levels in erythrocytes from Columba livia living in the metropolitan area of Monterrey, Mexico, compared with control animals via comet assay, and to confirm the results via Micronuclei test (MN) and DNA breakage detection-fluorescence in situ hybridization (DBD-FISH). Our results showed a significant increase in DNA migration in animals from the area assayed compared with that observed in control animals sampled in non contaminated areas. These results were confirmed by MN test and DBD-FISH. In conclusion, these observations confirm that the examination of erythrocytes from Columba livia via alkaline comet assay provides a sensitive and reliable end point for the detection of environmental genotoxicants. PMID- 26608566 TI - [Pathological and clinical correlations in renal AA amyloidosis: A Moroccan series of 30 cases]. AB - OBJECTIVE: Study of histological and clinical correlations of 30 cases of renal amyloidosis AA diagnosed between November 2010 and December 2012. RESULTS: The main causes associated with amyloidosis AA were represented by chronic infectious diseases (60%). Nephrotic syndrome and renal failure were observed in 94% and 73% respectively. The distribution of amyloid deposits: 90% of patients had a glomerular form and 10% had a vascular form. Inflammatory reaction associated with AA renal amyloidosis was present in 50% of cases. This inflammation was observed near amyloid deposits associated with a deposition of immunoglobulin chains and/or complement factors. CONCLUSION: Our study confirms the predominance of AA amyloidosis complicating chronic infectious diseases, especially tuberculosis. Our data point out a relationship between the morphology of renal AA amyloidosis, its clinical presentation and prognosis. PMID- 26608568 TI - The contribution of online content to the promotion and normalisation of female genital cosmetic surgery: a systematic review of the literature. AB - BACKGROUND: Women considering female genital cosmetic surgery (FGCS) are likely to use the internet as a key source of information during the decision-making process. The aim of this systematic review was to determine what is known about the role of the internet in the promotion and normalisation of female genital cosmetic surgery and to identify areas for future research. METHODS: Eight social science, medical, and communication databases and Google Scholar were searched for peer-reviewed papers published in English. Results from all papers were analysed to identify recurring and unique themes. RESULTS: Five papers met inclusion criteria. Three of the papers reported investigations of website content of FGCS providers, a fourth compared motivations for labiaplasty publicised on provider websites with those disclosed by women in online communities, and the fifth analysed visual depictions of female genitalia in online pornography. Analysis yielded five significant and interrelated patterns of representation, each functioning to promote and normalise the practice of FGCS: pathologisation of genital diversity; female genital appearance as important to wellbeing; characteristics of women's genitals are important for sex life; female body as degenerative and improvable through surgery; and FGCS as safe, easy, and effective. A significant gap was identified in the literature: the ways in which user-generated content might function to perpetuate, challenge, or subvert the normative discourses prevalent in online pornography and surgical websites. CONCLUSIONS: Further research is needed to contribute to knowledge of the role played by the internet in the promotion and normalisation of female genital cosmetic surgery. PMID- 26608567 TI - Isolation and Characterization of Madariaga Virus from a Horse in Paraiba State, Brazil. AB - Madariaga virus (MADV), the new species designation for the South American isolates of eastern equine encephalitis virus (EEEV), is genetically divergent and substantially different in ecology and pathogenesis from North American EEEV strains. We isolated and characterized a MADV isolate obtained from a horse in Brazil. Our results support previous phylogenetic studies showing there are three genetically distinct MADV lineages. The MADV isolate from Paraiba State belongs to the South American lineage III and is closely related to Peruvian, Colombian and Venezuelan isolates. PMID- 26608569 TI - Understanding of BRCA VUS genetic results by breast cancer specialists. AB - BACKGROUND: Mainstreaming genetic medicine, increased media coverage and clinical trials for BRCA mutation carriers are leading oncologists into more patient discussions about BRCA genetic testing. BRCA variants of uncertain significance (VUS) occur in 10-20% of tests. VUS detection introduces additional uncertainty for patient and potentially clinician. We aimed to explore the ability of breast cancer specialists (BCS) in the UK to correctly respond to a VUS report. METHODS: A survey sent to 800 UK BCS collected demographics data, VUS general knowledge and interpretation and communication based on two genetics reports. A separate survey of UK clinical geneticists collected demographics data, laboratory reporting practice and methods used to clarify VUS pathogenicity including classification systems. RESULTS: Of the 155 BCS (22.5%) who completed the survey, 12% reported no genetics training. Ninety five percent referred patients for BRCA genetic tests, 71% felt unsure about the clinical implications of the test reports presented here. A VUS report from a patient with a positive family history was interpreted and theoretically communicated correctly by 94% but when presented with a different VUS report with no management guidance and negative family history, 39% did not know how to communicate this result to the patient. Geneticists reported multiple VUS classification systems; the most commonly used was word-based in 32%. CONCLUSIONS: A consistent and standardised format to report particularly VUS results across all diagnostic laboratories plus additional training of UK BCS will be necessary for effective mainstreaming of BRCA testing to the oncology clinic. PMID- 26608571 TI - Diffuse Vibrational Signature of a Single Proton Embedded in the Oxalate Scaffold, HO2CCO2(-). AB - To understand how the D2d oxalate scaffold (C2O4)(2-) distorts upon capture of a proton, we report the vibrational spectra of the cryogenically cooled HO2CCO2(-) anion and its deuterated isotopologue DO2CCO2(-). The transitions associated with the skeletal vibrations and OH bending modes are sharp and are well described by inclusion of cubic terms in the normal mode expansion of the potential surface through an extended Fermi resonance analysis. The ground state structure features a five-membered ring with an asymmetric intramolecular proton bond. The spectral signatures of the hydrogen stretches, on the contrary, are surprisingly diffuse, and this behavior is not anticipated by the extended Fermi scheme. We trace the diffuse bands to very strong couplings between the high-frequency OH-stretch and the low-frequency COH bends as well as heavy particle skeletal deformations. A simple vibrationally adiabatic model recovers this breadth of oscillator strength as a 0 K analogue of the motional broadening commonly used to explain the diffuse spectra of H-bonded systems at elevated temperatures, but where these displacements arise from the configurations present at the vibrational zero-point level. PMID- 26608570 TI - Effects of sex and gonadectomy on social investigation and social recognition in mice. AB - BACKGROUND: An individual's ability to recognise and pay attention to others is crucial in order to behave appropriately in various social situations. Studies in humans have shown a sex bias in sociability as well as social memory, indicating that females have better face memory and gaze more at the eyes of others, but information about the factors that underpin these differences is sparse. Our aim was therefore to investigate if sociability and social recognition differ between female and male mice, and if so, to what extent gonadal hormones may be involved. Intact and gonadectomised male and female mice were assessed for sociability and social recognition using the three-chambered sociability paradigm, as well as the social discrimination test. Furthermore, we conducted a novel object recognition test, a locomotor activity test and an odour habituation/dishabituation test. RESULTS: The present study showed that the ability to recognise other individuals is intact in males with and without gonads, as well as in intact females, whereas it is hampered in gonadectomised females. Additionally, intact male mice displayed more persistent investigatory behaviour compared to the other groups, although the intact females showed elevated basal locomotor activity. In addition, all groups had intact object memory and habituated to odours. CONCLUSIONS: Our results suggest that intact male mice investigate conspecifics more than females do, and these differences seem to depend upon circulating hormones released from the testis. As these results seem to contrast what is known from human studies, they should be taken into consideration when using the three-chambered apparatus, and similar paradigms as animal models of social deficits in e.g. autism. Other behavioural tests, and animal models, may be more suitable for translational studies between patients and experimental animals. PMID- 26608572 TI - Distribution and frequency of G119S mutation in ace-1 gene within Anopheles sinensis populations from Guangxi, China. AB - BACKGROUND: Malaria is one of the most serious vector-borne diseases in the world. Vector control is an important measure for malaria prevention and elimination. However, this strategy is under threat as disease vectors are developing resistance to insecticides. Therefore, it is important to monitor mechanisms responsible for insecticide resistance. In this study, the presence of G119S mutation in the acetyl cholinesterase-encoding gene (ace-1) was investigated in nine Anopheles sinensis populations sampled across Guangxi Zhuang Autonomous Region China. METHODS: PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) method was used to genotype each individual adult of An. sinensis. Direct sequencing of PCR products was performed to verify the accuracy of PCR-RFLP genotyping result. Population genetics analysis was conducted using Genepop programme. RESULTS: The frequencies of susceptible homozygotes, heterozygotes and resistant homozygotes in the nine populations ranged between 0-0.296, 0.143-0.500 and 0.333-0.857, respectively. Overall, a high frequency (0.519-0.929) of mutant 119S allele was observed and the genotype frequency of the ace-1 gene of An. sinensis was at Hardy-Weinberg equilibrium in each of the nine examined populations. CONCLUSION: The G119S mutation has become fixed and is widespread in An. sinensis field populations in Guangxi, China. These findings are useful in helping design strategies for An. sinensis control. PMID- 26608575 TI - 25-hydroxyvitamin D circulates in different fractions of calf plasma if the parent compound is vitamin D2 or vitamin D3, respectively. AB - Vitamin D has become one of the most discussed nutrients in human nutrition, which has led to an increased interest in milk as a vitamin D source. Problems related to fortifying milk with synthetic vitamin D can be avoided by securing a high content of natural vitamin D in the milk by supplying dairy cows with sufficient vitamin D. However, choosing the most efficient route and form of supplementation requires insight into how different vitamin D metabolites are transported in the body of cattle. There are two forms of vitamin D: vitamin D2 (D2) and vitamin D3 (D3). Vitamin D2 originates from fungi on roughage. Vitamin D3 originates either from endogenous synthesis in the skin or from feed supplements. Vitamin D2 is chemically different from, and less physiologically active than, D3. Endogenous and dietary D3 is chemically similar but dietary D3 is toxic, whereas endogenous D3 appears well regulated in the body. PMID- 26608573 TI - In-depth proteomic analysis of shell matrix proteins of Pinctada fucata. AB - The shells of pearl oysters, Pinctada fucata, are composed of calcite and aragonite and possess remarkable mechanical properties. These shells are formed under the regulation of macromolecules, especially shell matrix proteins (SMPs). Identification of diverse SMPs will lay a foundation for understanding biomineralization process. Here, we identified 72 unique SMPs using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of proteins extracted from the shells of P. fucata combined with a draft genome. Of 72 SMPs, 17 SMPs are related to both the prismatic and nacreous layers. Moreover, according to the diverse domains found in the SMPs, we hypothesize that in addition to controlling CaCO3 crystallization and crystal organization, these proteins may potentially regulate the extracellular microenvironment and communicate between cells and the extracellular matrix (ECM). Immunohistological localization techniques identify the SMPs in the mantle, shells and synthetic calcite. Together, these proteomic data increase the repertoires of the shell matrix proteins in P. fucata and suggest that shell formation in P. fucata may involve tight regulation of cellular activities and the extracellular microenvironment. PMID- 26608576 TI - Effect of arginine and threonine administered in ovo on digestive organ developments and subsequent growth performance of broiler chickens. AB - This trial was conducted to investigate the effect of arginine (Arg), threonine (Thr) and Arg + Thr administered in ovo on growth performance, digestive organs and intestinal morphology in broiler chickens. On day 14 of incubation, 400 fertile eggs were randomly allotted to five experimental treatments through injection in the amniotic fluid including: (i) control (none injected), (ii) sham (0.5 ml of 0.5% saline), (iii) Arg (35 mg/egg), (iv) Thr (25 mg/egg) and (v) Arg + Thr (35 + 25 mg/egg). After hatching, chicks were given a commercial corn-soya bean diet up to 42 days of age. Daily feed intake (FI) and body weight (BW) of chicks were measured during different periods of the trial. Digestive organs were measured for their relative weight and intestinal length on days 11 and 42 of age. Intestinal morphometric traits were evaluated on day 11 of the experiment. Supplementing amino acids affected the performance of broiler chicks as Thr significantly increased FI and BW across starter, grower and finisher periods compared with sham and control (p < 0.05). Furthermore, Arg + Thr injection increased jejunal weight compared with control on day 42 (p < 0.05). Moreover, Arg inclusion led to the greatest villus height and crypt depth among treatments in duodenum (p > 0.05); however, amino acid supplemented groups had lower villus height than control in jejunum (p < 0.05). Negative correlations found between digestive organs related to day 11 of age containing pancreas (r = -0.484; p = 0.030), duodenal (r = -0.577; p = 0.007) as well as ileal lengths (r = -0.471; p = 0.035) and FI of entire period. Otherwise, positive relationships were observed between duodenum (r = 0.580; p = 0.007) and ileum (r = 0.582; p = 0.007) weights on day 42 and FI of chickens across the entire phase. In conclusion, Arg and particularly Thr injection into amnion can improve FI and post-hatch growth performance of chickens which may be mediated by the development of digestive organs. PMID- 26608577 TI - 2015 European guideline on the management of Chlamydia trachomatis infections. AB - Chlamydia trachomatis infections, which most frequently are asymptomatic, are major public health concerns globally. The 2015 European C. trachomatis guideline provides: up-to-date guidance regarding broader indications for testing and treatment of C. trachomatis infections; a clearer recommendation of using exclusively-validated nucleic acid amplification tests for diagnosis; advice on (repeated) C. trachomatis testing; the recommendation of increased testing to reduce the incidence of pelvic inflammatory disease and prevent exposure to infection; and recommendations to identify, verify and report C. trachomatis variants. Improvement of access to testing, test performance, diagnostics, antimicrobial treatment and follow-up of C. trachomatis patients are crucial to control its spread. For detailed background, evidence base and discussions, see the background review for the present 2015 European guideline on the management of Chlamydia trachomatis infections (Lanjouw E, et al. Int J STD AIDS. 2015). PMID- 26608578 TI - Background review for the '2015 European guideline on the management of Chlamydia trachomatis infections'. AB - SummaryChlamydia trachomatis infections are major public health concerns globally. Of particular grave concern is that the majority of persons with anogenital Chlamydia trachomatis infections are asymptomatic and accordingly not aware of their infection, and this silent infection can subsequently result in severe reproductive tract complications and sequelae. The current review paper provides all background, evidence base and discussions for the 2015 European guideline on the management of Chlamydia trachomatis infections (Lanjouw E, et al. Int J STD AIDS 2015). Comprehensive information and recommendations are included regarding the diagnosis, treatment and prevention of anogenital, pharyngeal and conjunctival Chlamydia trachomatis infections in European countries. However, Chlamydia trachomatis also causes the eye infection trachoma, which is not a sexually transmitted infection. The 2015 European Chlamydia trachomatis guideline provides up-to-date guidance regarding broader indications for testing and treatment of Chlamydia trachomatis infections; clearer recommendation of using validated nucleic acid amplification tests only for diagnosis; advice on (repeated) Chlamydia trachomatis testing; recommendation of increased testing to reduce the incidence of pelvic inflammatory disease and prevent exposure to infection and recommendations to identify, verify and report Chlamydia trachomatis variants. Improvement of access to testing, test performance, diagnostics, antimicrobial treatment and follow-up of Chlamydia trachomatis patients are crucial to control its spread. PMID- 26608579 TI - Dentin Bonding Testing Using a Mini-interfacial Fracture Toughness Approach. AB - Measurement of interfacial fracture toughness (iFT) is considered a more valid method to assess bonding effectiveness as compared with conventional bond strength testing. Common fracture toughness tests are, however, laborious and require a relatively bulky specimen size. This study aimed to evaluate a new simplified and miniaturized iFT (mini-iFT) test. Four dentin adhesives, representing the main adhesive classes, and 1 glass ionomer cement were applied onto flat dentin. Mini-iFT (1.5 * 2.0 * 16 to 18 mm) and microtensile bond strength (uTBS; 1.5 * 1.5 * 16 to 18 mm) specimens were prepared from the same tooth. For the mini-iFT specimens, a single notch was cut at the adhesive-dentin interface with a 150-um diamond blade under water cooling; the specimens were loaded until failure in a 4-point bending test setup. Finite element analysis was used to analyze stress distribution during mini-iFT testing. The correlation between the mean mini-iFT and uTBS was examined and found to be significant; a strong positive correlation was found (r(2) = 0.94, P = 0.004). Weibull data analysis suggested the mini-iFT to vary less than the uTBS. Both the mini-iFT and the uTBS revealed the same performance order, with the 3-step etch-and-rinse adhesive outperforming the 2-step self-etch and 2-step etch-and-rinse adhesive, followed by the 1-step SE adhesive and, finally, the glass ionomer cement. Scanning electron microscopy failure analysis revealed the adhesive-dentin interface to fail more at the actual interface with the mini-iFT test, while uTBS specimens failed more within dentin and composite. This finding was corroborated by finite element analysis showing stress to concentrate at the interface during mini-iFT loading and crack propagation. In conclusion, the new mini-iFT test appeared more discriminative and valid than the uTBS to assess bonding effectiveness; the latter test nevertheless remains more versatile. Specimen size and workload were alike, making the mini-iFT test a valid alternative for the popular uTBS test. PMID- 26608581 TI - Risk factors of persistent diplopia following secondary intraocular lens implantation in patients with sensory strabismus from uncorrected monocular aphakia. AB - PURPOSE: We aimed to compare clinical characteristics between diplopia-free and diplopia-persistent patients after successful strabismus surgery, when patients complained of diplopia following secondary intraocular lens (IOL) implantation after prolonged aphakia accompanied by sensory strabismus. METHODS: Retrospective review of medical records of patients who complained of diplopia following secondary IOL placement with sensory strabismus after prolonged uncorrected monocular aphakia from isolated ocular trauma was done. We classified patients into two groups according to persistency of diplopia, 6 months after successful strabismus surgery. Clinical characteristics were compared between groups. RESULTS: A total of 31 patients were included. The diplopia-persistent group showed longer duration of uncorrected aphakia (p = 0.02), less severe corneal astigmatism (p = 0.04), a smaller exodeviation angle (p = 0.02), and more frequent vertical deviation (p = 0.015), extorsion (p = 0.022) and monocular nystagmus (p = 0.028) than the diplopia-free group. In all patients in the diplopia-free group, diplopia could be eliminated prior to strabismus surgery using loose prisms in free space, whereas seven patients in the diplopia persistent group prior to surgery could not resolve diplopia. CONCLUSIONS: Our data will be helpful for ocular surgeons in determining whether to insert secondary IOL in prolonged aphakia with sensory strabismus, or whether strabismus surgery will eliminate diplopia that develops following secondary IOL placement in this situation. PMID- 26608580 TI - Regenerative Medicine for Periodontal and Peri-implant Diseases. AB - The balance between bone resorption and bone formation is vital for maintenance and regeneration of alveolar bone and supporting structures around teeth and dental implants. Tissue regeneration in the oral cavity is regulated by multiple cell types, signaling mechanisms, and matrix interactions. A goal for periodontal tissue engineering/regenerative medicine is to restore oral soft and hard tissues through cell, scaffold, and/or signaling approaches to functional and aesthetic oral tissues. Bony defects in the oral cavity can vary significantly, ranging from smaller intrabony lesions resulting from periodontal or peri-implant diseases to large osseous defects that extend through the jaws as a result of trauma, tumor resection, or congenital defects. The disparity in size and location of these alveolar defects is compounded further by patient-specific and environmental factors that contribute to the challenges in periodontal regeneration, peri-implant tissue regeneration, and alveolar ridge reconstruction. Efforts have been made over the last few decades to produce reliable and predictable methods to stimulate bone regeneration in alveolar bone defects. Tissue engineering/regenerative medicine provide new avenues to enhance tissue regeneration by introducing bioactive models or constructing patient specific substitutes. This review presents an overview of therapies (e.g., protein, gene, and cell based) and biomaterials (e.g., resorbable, nonresorbable, and 3-dimensionally printed) used for alveolar bone engineering around teeth and implants and for implant site development, with emphasis on most recent findings and future directions. PMID- 26608582 TI - ABCA1 rs1883025 polymorphism and risk of age-related macular degeneration. AB - PURPOSE: To evaluate the association of the ABCA1 rs1883025 polymorphism and susceptibility to age-related macular degeneration (AMD). METHODS: A systematic search of the PubMed, EMBASE, and ISI web of science databases was performed to identify eligible published studies without language restrictions up to September 2015. Pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were estimated under different genetic models using meta-analytic methods. Stratified analysis and sensitivity analysis were performed to explore potential sources of heterogeneity. RESULTS: A total of 12 articles with 25,445 cases and 36,460 controls were eligible in this meta-analysis. The ABCA1 rs1883025 variant showed significant association with the lower risk of overall AMD under the allelic model (OR= 0.81, 95 % CI=0.74-0.89). Stratified analysis based on ethnicity demonstrated a strong association between rs1883025 polymorphism and AMD in the Caucasian population, but not in Asian population. For late AMD, the ABCA1 rs1883025 variant was observed to have a significant association with the lower risk of this disease (OR = 0.81, 95 % CI, 0.72-0.91). In early-stage AMD, significant associations of the rs1883025 polymorphism with lower risk of early AMD were observed in different genetic models (OR ranging from 0.45 to 0.65, all P < 0.05). CONCLUSIONS: The present meta-analysis indicated that the T allelic in rs1883025 variant was significantly associated with the risk of developing AMD, particularly at the early stage. The associations of the ABCA1 locus with AMD risk in various populations need further exploration. PMID- 26608584 TI - Task shifting-perception of stake holders about adequacy of training and supervision for community mental health workers in Ghana. AB - There is growing interest in the effectiveness of task shifting as a strategy for addressing expanding health care challenges in settings with shortages of qualified health personnel. The aim of this study is to examine the perception of stakeholders about the adequacy of training, supervision and support offered to community mental health workers (CMHWs) in Ghana. To address this aim we designed and administered self-completed, semi-structured questionnaires adapted to three specific stakeholder groups in Ghana. The questionnaires were administered to 11 psychiatrists, 29 health policy implementers/coordinators and 164 CMHWs, across Ghana, including 71 (43.3%) Community Psychiatric Nurses (CPNs), 19 (11.6%) Clinical Psychiatric Officers (CPOs) and 74 (45.1%) Community Mental Health Officers (CMHOs). Almost all the stakeholders believed CMHWs in Ghana receive adequate training for the role they are expected to play although many identify some gaps in the training of these mental health workers for the expanded roles they actually play. There were statistically significant differences between the different CMHW groups and the types of in-service training they said they had attended, the frequency with which their work was supervised, and the frequency with which they received feedback from supervisors. CPOs were more likely to attend all the different kinds of in-service training than CMHOs and CPNs, while CMHOs were more likely than CPOs and CPNs to report that their work is never supervised or that they rarely or never receive feedback from supervisors. There was disparity between what CMHWs said were their experiences and the perception of policy makers with respect to the types of in-service training that is available to CMHWs. There is a need to review the task shifting arrangements, perhaps with a view to expanding it to include more responsibilities, and therefore review the curriculum of the training institution for CMHWs and also to offer them regular in-service training and formal supervision. PMID- 26608586 TI - Double M-plasty for Excisional Biopsy of Suspected Melanoma. PMID- 26608585 TI - Access to integrated community case management of childhood illnesses services in rural Ethiopia: a qualitative study of the perspectives and experiences of caregivers. AB - BACKGROUND: In 2010, Ethiopia began scaling up the integrated community case management (iCCM) of childhood illness strategy throughout the country allowing health extension workers (HEWs) to treat children in rural health posts. After 2 years of iCCM scale up, utilization of HEWs remains low. Little is known about factors related to the use of health services in this setting. This research aimed to elicit perceptions and experiences of caregivers to better understand reasons for low utilization of iCCM services. METHODS: A rapid ethnographic assessment was conducted in eight rural health post catchment areas in two zones: Jimma and West Hararghe. In total, 16 focus group discussions and 78 in-depth interviews were completed with mothers, fathers, HEWs and community health volunteers. RESULTS: In spite of the HEW being a core component of iCCM, we found that the lack of availability of HEWs at the health post was one of the most common barriers to the utilization of iCCM services mentioned by caregivers. Financial and geographic challenges continue to influence caregiver decisions despite extension of free child health services in communities. Acceptability of HEWs was often low due to a perceived lack of sensitivity of HEWs and concerns about medicines given at the health post. Social networks acted both to facilitate and hinder use of HEWs. Many mothers stated a preference for using the health post, but some were unable to do so due to objections or alternative care seeking preferences of gatekeepers, often mothers-in-law and husbands. CONCLUSION: Caregivers in Ethiopia face many challenges in using HEWs at the health post, potentially resulting in low demand for iCCM services. Efforts to minimize barriers to care seeking and to improve demand should be incorporated into the iCCM strategy in order to achieve reductions in child mortality and promote equity in access and child health outcomes. PMID- 26608583 TI - Isocaloric Pair-Fed High-Carbohydrate Diet Induced More Hepatic Steatosis and Inflammation than High-Fat Diet Mediated by miR-34a/SIRT1 Axis in Mice. AB - To investigate the different effects of isocaloric high-fat diet (HFD) and high carbohydrate diet (HCD) on hepatic steatosis and the underlying mechanisms, especially the role of microRNA-34a/silent information regulator T1 (SIRT1) axis, C57BL/6J mice (n = 12/group) were isocaloric pair-fed with Lieber-DeCarli liquid diet containing either high fat (HFLD) or high carbohydrate (HCLD) for 16 weeks. As compared to the HFLD fed mice, despite the similar final body weights, HCLD feeding: (1) induced more severe hepatic steatosis; (2) up-regulated hepatic expression of miR-34a accompanied with significant decrease of SIRT1 and nicotinamide phosphoribosyltransferase (NAMPT), SIRT1 activity and phosphorylation of AMPK; (3) up-regulated de novo lipogenesis (DNL) related proteins expression (ACC, SCD1), and down-regulated expressions of miR-122, miR 370 and miR-33; (4) decreased mRNA expressions of genes Cpt1, Pparalpha and Pgc1alpha related to fatty acid oxidation; (5) increased hepatic total cholesterol concentration and decreased expression of cholesterol metabolism related genes Abcg5, Abcg8, Abcg11, Cyp7a1 and Cyp8b1; and (6) induced higher hepatic inflammatory response accompanied with significant increased mRNA expressions of Il1beta, Tnfalpha and Mcp1. Thus, isocaloric HCLD feeding induced greater severity in hepatic steatosis and inflammatory response than HFLD feeding, potentially through miR-34a/SIRT1 axis mediated promotion of DNL, inhibition of fatty acid oxidation and cholesterol metabolism. PMID- 26608588 TI - A bibliometric study of scientific literature in Scopus on botanicals for treatment of androgenetic alopecia. AB - BACKGROUND: In androgenetic alopecia, a number of botanicals are available that can effectively slow or reduce hair loss and inflammation or stimulate partial hair regrowth. The aim of this study was to provide a descriptive overview of the impact and production of literature on botanicals used for androgenetic alopecia and to perform a citation analysis of the related research articles. METHODS: We searched for "alopecia" OR "androgenetic alopecia" OR "hair loss" AND "Camelia sinensis" OR (and other 15 botanicals) in ARTICLE (Title/Abstract/Keyword) in Scopus database. RESULTS: A total of 29 references, that is, research articles, were retrieved by SCOPUS search, and 93.1% had been published since 2000. The majority (48.3%) describe applications of hair grow stimulants, followed by inhibitors of 5-alpha-reductase applications (27.6%), and studies concerning inhibitors of inflammation (24.1%). The citation analysis revealed a growing interest for this topic and the papers on hair grow stimulants are most cited. Citation trend of inhibition of 5-alpha-reductase articles is growing in the last years. CONCLUSIONS: This study has highlighted three important aspects: (1) growing interest for this topic; (2) evidences mainly in hair grow stimulants and recently in the inhibition of 5-alpha-reductase, as demonstrated by article and citation counts across years; (3) in addition, all major studies have been focused on green tea epigallocatechin-3-gallate, Serenoa repens, Citrullus colocynthis and Cuscuta reflexa. PMID- 26608587 TI - Overexpression of natural killer group 2 member D ligands predicts favorable prognosis in cholangiocarcinoma. AB - The natural killer group 2 member D (NKG2D) receptor and its ligands are important mediators of immune responses to tumors. NKG2D ligands are overexpressed in several malignant tumor types; however, the prognostic value of these ligands is unclear. Here, we aimed to elucidate the role of NKG2D ligands in extrahepatic cholangiocarcinoma (EHCC). We therefore investigated the expression of the NKG2D receptor and its ligands MHC class I chain-related proteins A and B (MICA/B), unique long 16 binding protein (ULBP) 1, and ULBP2/5/6 in resected specimens from 82 patients with EHCC. All NKG2D ligands were highly expressed in EHCC. High expression of MICA/B or ULBP2/5/6 correlated with overall and disease-free survival. In contrast, high expression of ULBP1 was significantly associated with improved overall survival, but not disease-free survival. Concurrent high expression of multiple NKG2D ligands revealed significantly better overall and disease-free survival than that observed with the overexpression of any one NKG2D ligand. Co-expression of multiple NKG2D ligands was an independent prognostic indicator of improved survival. Furthermore, co-overexpression of multiple NKG2D ligands was significantly correlated with high expression of the NKG2D receptor. Inhibiting interactions between multiple NKG2D ligands and the NKG2D receptor might be a promising approach for controlling cancer progression and improving patient prognosis in EHCC. PMID- 26608589 TI - Time-lapse electrical impedance spectroscopy for monitoring the cell cycle of single immobilized S. pombe cells. AB - As a complement and alternative to optical methods, wide-band electrical impedance spectroscopy (EIS) enables multi-parameter, label-free and real-time detection of cellular and subcellular features. We report on a microfluidics based system designed to reliably capture single rod-shaped Schizosaccharomyces pombe cells by applying suction through orifices in a channel wall. The system enables subsequent culturing of immobilized cells in an upright position, while dynamic changes in cell-cycle state and morphology were continuously monitored through EIS over a broad frequency range. Besides measuring cell growth, clear impedance signals for nuclear division have been obtained. The EIS system has been characterized with respect to sensitivity and detection limits. The spatial resolution in measuring cell length was 0.25 MUm, which corresponds to approximately a 5-min interval of cell growth under standard conditions. The comprehensive impedance data sets were also used to determine the occurrence of nuclear division and cytokinesis. The obtained results have been validated through concurrent confocal imaging and plausibilized through comparison with finite-element modeling data. The possibility to monitor cellular and intracellular features of single S. pombe cells during the cell cycle at high spatiotemporal resolution renders the presented microfluidics-based EIS system a suitable tool for dynamic single-cell investigations. PMID- 26608591 TI - A qualitative examination of women's self-presentation and social physique anxiety during injury rehabilitation. AB - OBJECTIVE: To understand women's self-presentation experiences in the rehabilitation setting, and their attitudes and preferences toward the social and physical features of the rehabilitation environment. DESIGN: Qualitative study. SETTING: Outpatient physiotherapy clinic. PARTICIPANTS: Ten women (age 18 to 64) with high social physique anxiety (Social Physique Anxiety Scale score >=25) referred for physiotherapy following acute injury. MAIN OUTCOME MEASURES: Semi structured interviews were conducted prior to commencement of treatment, and again after a third treatment session. RESULTS: Participants experienced extensive self-presentational concerns that were intensified due to the nature of the physiotherapy environment. The women reported that their self-presentational anxiety did not diminish over time, and was related to others' negative perceptions regarding their physical appearance and inability to perform exercises as well as expected. The presence of men or younger women in the clinic was identified as a barrier to appointment attendance, along with open concept clinic settings, which were associated with the most potential for evaluation. Mirrors and windows in the physiotherapy clinic were highlighted as anxiety provoking. The women suggested that they would feel apprehensive about advocating for themselves if they felt uncomfortable with the area in which they were receiving treatment, and instead used avoidance coping strategies (e.g., hiding behind equipment, preventing eye contact) to manage their anxiety. CONCLUSIONS: Physique-anxious women experience extensive self-presentational concerns in the rehabilitation environment, which could affect treatment adherence. Modifying the treatment setting, providing protective self-presentational strategies such as positive self-talk, and open patient-therapist communication could be implemented to help mitigate these concerns. PMID- 26608590 TI - Long-Term Renal Function in Liver Transplant Recipients After Conversion From Calcineurin Inhibitors to mTOR Inhibitors. AB - BACKGROUND: Renal dysfunction often occurs in liver transplant (LT) recipients receiving calcineurin inhibitor (CNI)-based immunosuppressive regimens, increasing morbidity and mortality rates. Replacement of CNIs by mTOR inhibitor based immunosuppressive protocols may prevent renal impairment in LT recipients. MATERIAL/METHODS: Outcomes in patients who underwent LT between 1996 and 2010 at our center and who were switched from CNI-based to mTOR inhibitor-based immunosuppression were retrospectively analyzed. Renal course, hyperlipidemia, and graft rejection were assessed in patients maintained on this CNI-free regimen for at least 24 months. RESULTS: Of the 85 patients switched from CNI-based to mTOR inhibitor-based, CNI-free immunosuppression, 78 met the inclusion criteria. Within the first 6 weeks after switching, the covariable adjusted estimated glomerular filtration rate (eGFR) increased 5.6 mL/min [95% confidence interval 2.6-8.7 mL/min, p<0.001], but there were no further statistically noticeable changes in eGFR. Concentrations of cholesterol and triglycerides increased statistically, noticeable within the first 12 months after drug conversion. Histologically proven graft rejection was observed in 4 patients (5.1%) after conversion. CONCLUSIONS: Conversion from CNI-based to CNI-free, mTOR inhibitor based immunosuppression after LT is safe and can result in significant renal recovery. CNI-free, mTOR inhibitor-based immunosuppression is a potential option for patients with contraindications for CNIs and for LT recipients with rapid reduction in kidney function due to CNIs. PMID- 26608592 TI - Does the use of a university lecturer as a visiting tutor support learning and assessment during physiotherapy students' clinical placements? A survey of higher education institution providers. AB - OBJECTIVES: To establish the rationale for using a lecturer as a visiting tutor, and to identify the activities undertaken during clinical placements to support student learning and assessment in practice. DESIGN: A secure electronic survey was used to incorporate qualitative and quantitative data collection procedures. SETTING: Thirty-three higher education institution (HEI) providers of physiotherapy education in the UK, registered with the Chartered Society of Physiotherapy. PARTICIPANTS: UK HEI physiotherapy placement coordinators. MAIN OUTCOME MEASURES: A questionnaire was used to examine HEI perceptions. A pilot focus group consultation informed the questionnaire content. Surveys were analysed based on the proportion of responses to closed questions on an adapted Likert scale, with further thematic analysis of open questions. RESULTS: All 25 respondents (25/33, 76%) indicated their provision of support for students and clinical educators throughout their clinical placements. 'Face-to-face' engagement during the placement visit was viewed as essential to guide the clinical educator to provide a consistent approach to learning and assessment strategies; ensuring cohesion between theoretical and clinical components of the curriculum was viewed as a core objective by visiting academic tutors. However, the emergent themes highlighted key differences between HEIs' perspectives of what this support for clinical placement learning should entail. CONCLUSIONS: The majority of HEIs endorse the use of a lecturer as a visiting tutor to inform and maintain the standard of learning and assessment within the clinical placement. However, the value of this interaction requires confirmation via other stakeholders, and exploration of other forms of non-face-to-face support processes warrant further investigation. PMID- 26608593 TI - Whole exome sequencing of relapsed/refractory patients expands the repertoire of somatic mutations in diffuse large B-cell lymphoma. AB - Despite the many efforts already spent to enumerate somatic mutations in diffuse large B-cell lymphoma (DLBCL), previous whole-genome and whole-exome studies conducted on patients of mixed outcomes failed at characterizing the 30% of patients who will relapse or resist current immunochemotherapies. To address this issue, we performed whole-exome sequencing of normal/tumoral DNA pairs in 14 relapsed/refractory (R/R) patients subclassified by full-transcriptome arrays (six activated B-cell like, three germinal center B-cell like, and five primary mediastinal B-cell lymphomas), from the LNH-03 LYSA clinical trial program. Aside from well-known DLBCL features, gene and pathway level recurrence analyses proposed several interesting leads including TBL1XR1 and activating mutations in IRF4 or in the insulin regulation pathway. Sequencing-based copy number analysis defined 23 short recurrently altered regions involving genes such as REL, CDKN2A, HYAL2, and TP53. Moreover, it highlighted mutations in genes such as GNA13, CARD11, MFHAS1, and PCLO as associated with secondary variant allele amplification events. The five primary mediastinal B-cell lymphomas (PMBL), while unexpected in a R/R cohort, showed a significantly higher mutation rate (P = 0.003) and provided many insights on this classical Hodgkin lymphoma related subtype. Novel genes such as XPO1, MFHAS1, and ITPKB were found particularly mutated, along with various cytokine-based signaling pathways. Among these analyses, somatic events in the NF-kappaB pathway were found preponderant in the three DLBCL subtypes, confirming its major implication in DLBCL aggressiveness and pinpointing several new candidate genes. PMID- 26608594 TI - Mosquito salivary allergen Aed a 3: cloning, comprehensive molecular analysis, and clinical evaluation. AB - BACKGROUND: Allergic reactions to mosquito bites are an increasing clinical concern. Due to the lack of availability of mosquito salivary allergens, they are underdiagnosed. Here, we reported a newly cloned mosquito Aedes (Ae.) aegypti salivary allergen. METHODS: A cDNA encoding a 30-kDa Ae. aegypti salivary protein, designated Aed a 3, was isolated from an expression library. The full length cDNA was cloned into a baculovirus expression vector, and recombinant Aed a 3 (rAed a 3) was expressed, purified, and characterized. Skin prick tests with purified rAed a 3 and Ae. aegypti bite tests were performed in 43 volunteers. Serum rAed a 3-specific IgE levels were measured in 28 volunteers. RESULTS: The primary nucleotide sequence, deduced amino acid sequence, and IgE-binding sites of Aed a 3 were identified. rAed a 3-selected antibodies recognized a 30-kDa Ae. aegypti saliva protein. rAed a 3 bound IgE in mosquito-allergic volunteers and the binding could be inhibited by the addition of natural mosquito extract dose dependently. Immediate skin test reactions to rAed a 3 correlated significantly with mosquito bite-induced reactions. Of the bite test-positive volunteers, 32% had a positive rAed a 3 skin test and 46% had specific IgE. No bite test-negative volunteers reacted to rAed a 3 in either the skin tests or the IgE assays, confirming the specificity of the assay. CONCLUSIONS: Aed a 3 that corresponds to the Aegyptin protein is a major mosquito salivary allergen. Its recombinant form has biological activity and is suitable for use in skin tests and specific IgE assays in mosquito-allergic individuals. PMID- 26608595 TI - Rapid determination of flavonoids in licorice and comparison of three licorice species. AB - A simple, sensitive and fast method for the simultaneous quantitation of 15 flavonoids in licorice based on an ultra high performance liquid chromatography coupled with triple quadrupole electrospray tandem mass spectrometry had been established and validated in this study. The analysis was performed on an ACQUITY HSS T3 column with gradient elution using a mobile phase consisted of A (0.1% formic acid in water)/B (acetonitrile) at a flow rate of 0.4 mL/min. Satisfactory separation of these compounds was obtained in less than 9 min. All calibration curves showed good linearity (r(2) = 0.9940) during the test ranges. The precision, repeatability, accuracy, limit of detection and limit of quantification were also fully investigated. The validated method was successfully applied for the simultaneous quantitation of 15 flavonoids in 106 licorice samples which contained 83 batches of G. uralensis, 14 batches of G. glabra and 9 batches of G. inflata. Furthermore, multivariate statistical analysis (using principal components analysis) was performed to classify the samples based on the contents of the 15 analyzed compounds. The results showed that all of these licorice samples were rich in flavonoids, although their contents were obviously various, and the proposed method could serve as a prerequisite for quality control of licorice products. PMID- 26608598 TI - The Resurgence of the Highly Ylidic N-Heterocyclic Olefins as a New Class of Organocatalysts. AB - In recent decades, N-heterocyclic carbenes have become established as a prevalent family of organocatalysts. N-Heterocyclic olefins, the alkylidene derivatives of N-heterocyclic carbenes, have recently also emerged as efficient promoters for CO2 fixation and polymerization reactions. Their extraordinarily strong Lewis/Bronsted basicity suggests great potential as a new class of organocatalysts for a broad range of reactions in synthetic chemistry. PMID- 26608599 TI - An update on emergency care and emergency medicine in Russia. AB - Russia's national healthcare system is undergoing significant changes. Those changes which affect healthcare financing are particularly vital. As has often been the case in other nations, the emergency care field is at the forefront of such reforms. The ongoing challenges constitute the environment in which the hospital-based specialty of emergency medicine needs to develop as part of a larger system. Emergency care has to evolve in order to match true needs of the population existing today. New federal regulations recently adopted have recognized emergency departments as the new in-hospital component of emergency care, providing the long-needed legal foundation upon which the new specialty can advance. General knowledge of Western-style emergency departments in terms of their basic setup and function has been widespread among Russia's medical professionals for some time. Several emergency departments are functioning in select regions as pilots. Preliminary data stemming from their operation have supported a positive effect on efficiency of hospital bed utilization and on appropriate use of specialists and specialized hospital departments. In the pre hospital domain, there has been a reduction of specialized ambulance types and of the number of physicians staffing all ambulances in favor of midlevel providers. Still, a debate continues at all levels of the medical hierarchy regarding the correct future path for emergency care in Russia with regard to adaptation and sustainability of any foreign models in the context of the country's unique national features. PMID- 26608596 TI - microRNAs as neuroregulators, biomarkers and therapeutic agents in neurodegenerative diseases. AB - The last decade has experienced the emergence of microRNAs as a key molecular tool for the diagnosis and prognosis of human diseases. Although the focus has mostly been on cancer, neurodegenerative diseases present an exciting, yet less explored, platform for microRNA research. Several studies have highlighted the significance of microRNAs in neurogenesis and neurodegeneration, and pre-clinical studies have shown the potential of microRNAs as biomarkers. Despite this, no bona fide microRNAs have been identified as true diagnostic or prognostic biomarkers for neurodegenerative disease. This is mainly due to the lack of precisely defined patient cohorts and the variability within and between individual cohorts. However, the discovery that microRNAs exist as stable molecules at detectable levels in body fluids has opened up new avenues for microRNAs as potential biomarker candidates. Furthermore, technological developments in microRNA biology have contributed to the possible design of microRNA-mediated disease intervention strategies. The combination of these advancements, with the availability of well-defined longitudinal patient cohort, promises to not only assist in developing invaluable diagnostic tools for clinicians, but also to increase our overall understanding of the underlying heterogeneity of neurodegenerative diseases. In this review, we present a comprehensive overview of the existing knowledge of microRNAs in neurodegeneration and provide a perspective of the applicability of microRNAs as a basis for future therapeutic intervention strategies. PMID- 26608597 TI - MicroRNA target prediction using thermodynamic and sequence curves. AB - BACKGROUND: MicroRNAs (miRNAs) are small regulatory RNA that mediate RNA interference by binding to various mRNA target regions. There have been several computational methods for the identification of target mRNAs for miRNAs. However, these have considered all contributory features as scalar representations, primarily, as thermodynamic or sequence-based features. Further, a majority of these methods solely target canonical sites, which are sites with "seed" complementarity. Here, we present a machine-learning classification scheme, titled Avishkar, which captures the spatial profile of miRNA-mRNA interactions via smooth B-spline curves, separately for various input features, such as thermodynamic and sequence features. Further, we use a principled approach to uniformly model canonical and non-canonical seed matches, using a novel seed enrichment metric. RESULTS: We demonstrate that large number of seed-match patterns have high enrichment values, conserved across species, and that majority of miRNA binding sites involve non-canonical matches, corroborating recent findings. Using spatial curves and popular categorical features, such as target site length and location, we train a linear SVM model, utilizing experimental CLIP-seq data. Our model significantly outperforms all established methods, for both canonical and non-canonical sites. We achieve this while using a much larger candidate miRNA-mRNA interaction set than prior work. CONCLUSIONS: We have developed an efficient SVM-based model for miRNA target prediction using recent CLIP-seq data, demonstrating superior performance, evaluated using ROC curves, specifically about 20% better than the state-of-the-art, for different species (human or mouse), or different target types (canonical or non-canonical). To the best of our knowledge we provide the first distributed framework for microRNA target prediction based on Apache Hadoop and Spark. AVAILABILITY: All source code and data is publicly available at https://bitbucket.org/cellsandmachines/avishkar. PMID- 26608600 TI - Two coexisting heterozygous frameshift mutations in PROP1 are responsible for a different phenotype of combined pituitary hormone deficiency. AB - The role of genetic background in childhood-onset combined pituitary hormone deficiency (CPHD) has been extensively studied. The major contributors are the PROP1, POU1F1, LHX3, LHX4 and HESX1 genes coding transcription factors implicated in pituitary organogenesis. The clinical consequences of mutations encompass impaired synthesis of a growth hormone (GH) and one or more concurrent pituitary hormones (i.e. LH, FSH, TSH, PRL). Manifestation of the disorder may vary due to various mutation impacts on the final gene products or an influence of environmental factors during pituitary organogenesis. We describe the clinical and molecular characteristics of two brothers aged 47 and 39 years presenting an uncommon manifestation of congenital hypopituitarism. Sequencing of the PROP1, POU1F1, LHX3, LHX4 and HESX1 genes was performed to confirm the genetic origin of the disorder. A compound heterozygosity in the PROP1 gene has been identified for both probands. The first change represents a mutational hot spot (c.150delA, p.R53fsX164), whereas the second is a novel alteration (p.R112X) that leads to protein disruption. Based on precise genetic diagnosis, an in silico prediction of a p.R112X mutation on protein architecture was performed. The resulting clinical phenotype was surprisingly distinct compared to most patients with genetic alterations in PROP1 reported in the current literature. This may be caused by a residual activity of a newly identified p.R112X protein that preserves over 70 % of the homeodomain structure. This examination may confirm a key role of a DNA-binding homeodomain in maintaining PROP1 functionality and suggests a conceivable explanation of an unusual phenotype. PMID- 26608602 TI - A unified analytic solution approach to static bending and free vibration problems of rectangular thin plates. AB - A unified analytic solution approach to both static bending and free vibration problems of rectangular thin plates is demonstrated in this paper, with focus on the application to corner-supported plates. The solution procedure is based on a novel symplectic superposition method, which transforms the problems into the Hamiltonian system and yields accurate enough results via step-by-step rigorous derivation. The main advantage of the developed approach is its wide applicability since no trial solutions are needed in the analysis, which is completely different from the other methods. Numerical examples for both static bending and free vibration plates are presented to validate the developed analytic solutions and to offer new numerical results. The approach is expected to serve as a benchmark analytic approach due to its effectiveness and accuracy. PMID- 26608601 TI - Expanding the spectrum of human ganglionic eminence region anomalies on fetal magnetic resonance imaging. AB - INTRODUCTION: Ganglionic eminence (GE) is a transient fetal brain structure that harvests a significant amount of precursors of cortical GABA-ergic interneurons. Prenatal magnetic resonance (MR) imaging features of GE anomalies (i.e., cavitations) have already been reported associated with severe micro lissencephaly. The purpose of this report was to illustrate the MR imaging features of GE anomalies in conditions other than severe micro-lissencephalies. METHODS: Among all the fetuses submitted to prenatal MR imaging at our center from 2005 to 2014, we collected eight cases with GE anomalies and only limited associated brain anomalies. The median gestational age at the time of MR imaging was 21 weeks ranging from 19 to 29 weeks. Two senior pediatric neuroradiologists categorized the anomalies of the GE region in two groups: group one showing cavitation in the GE region and group two showing enlarged GE region. For each fetal case, associated cranial anomalies were also reported. RESULTS: Five out of the eight cases were included in group one and three in group two. Besides the GE region abnormality, all eight cases had additional intracranial anomalies, such as mild partial callosal agenesis, vermian hypoplasia and rotation, cerebellar hypoplasia, ventriculomegaly, enlarged subarachnoid spaces, molar tooth malformation. Ultrasound generally detected most of the associated intracranial anomalies, prompting the MR investigation; on the contrary in none of the cases, GE anomalies had been detected by ultrasound. CONCLUSIONS: Our observation expands the spectrum of human GE anomalies, demonstrating that these may take place also without associated severe micro-lissencephalies. PMID- 26608603 TI - Two acetyl-CoA synthetase isoenzymes are encoded by distinct genes in marine yeast Rhodosporidium diobovatum. AB - OBJECTIVES: Two genes encoding two acetyl-CoA synthetase (ACS) isoenzymes have been identified in the marine yeast Rhodosporidium diobovatum MCCC 2A00023. RESULTS: ACS1 encoded a polypeptide with a sequence of 578 amino acid residues, a predicted molecular weight of 63.73 kDa, and pI of 8.14, while the ACS2 encoded a polypeptide containing 676 amino acid residues with a deduced molecular mass of 75.61 kDa and a pI of 5.95. Biological activity of Acs1p and Acs2p was confirmed by heterologous expression in Escherichia coli. A 1.5-kb DNA fragment of the ACS1 gene and a 2.7-kb DNA fragment of the ACS2 gene were deleted using the RNA guide CRISPR-Cas9 system. The strain lacking ACS1 was unable to grow on acetate and ethanol media, while the ACS2 deletant was unable to grow on glucose medium. ACS1 ACS2 double mutants of R. diobovatum were non-viable. CONCLUSIONS: ACS isoenzymes are essential to the yeast metabolism, and other sources of ACSs cannot compensate for the lack of ACSs encoded by the two genes. PMID- 26608604 TI - Concentrated polymer brushes do not induce the expression of inflammatory and angiogeneic genes in human umbilical vein endothelial cells. AB - OBJECTIVE: When polymer brushes are applied as the inner coating for artificial blood vessels, they may induce unwanted responses in vascular endothelial cells continuously exposed to the polymer surface. Accordingly, we have examined the in vitro effect of non-biofouling concentrated polymer brushes (CPBs) on pro inflammatory and angiogenic responses of human umbilical vein endothelial cells (HUVECs). RESULTS: Micro-patterned CPBs were prepared on silicon wafers using biocompatible polymers, poly(poly(ethylene glycol)methyl ether methacrylate) (PPEGMA) and poly(2-hydroxyethyl methacrylate) (PHEMA). HUVECs were cultured on PPEGMA-CPBs and PHEMA-CPBs with different channel widths (20, 50, and 80 um) and analyzed for mRNA expression of the pro-inflammatory cytokines IL-6 and IL-8 and angiogeneic vascular endothelial growth factor (VEGF). Irrespective of channel width, PHEMA-CPBs reduced the expression of all target genes, whereas PPEGMA-CPBs reduced VEGF and did not affect IL-6 and IL-8 levels. CONCLUSION: Micro-patterned CPBs, irrespective of chemical structure or adhesion area, do not induce the expression of important pro-inflammatory and angiogenic mediators in endothelial cells. PMID- 26608606 TI - Systematic analysis of structural and spectroscopic properties of neptunimine (HN=NpH2) and plutonimine (HN=PuH2). AB - The structures, stabilities, nature of bonding, and spectroscopic properties of the new actinide imine molecules, neptunimine (HN=NpH2) and plutonimine (HN=PuH2), in the gas phase have been systematically explored at different levels of theory. Our calculation indicates that HN=AnH2 (An=Np, Pu) should be nonplanar and have a quartet ([Formula: see text]) and quintet ([Formula: see text]) ground state, respectively. The nature of the chemical bonding in these molecules were investigated by employing topological methods including electron localization function (ELF), atoms in molecules (AIM) as well as natural bond orbital analysis (NBO). The results showed that these actinide complexes possess relatively strong An=N multiple bonds between the An 6d-5f hybrid orbitals with N 2s-2p orbitals. The charge decomposition analysis (CDA) diagram demonstrated that the transition of electrons mainly happened inside the AnH2 of HN=AnH2. Total and partial density of state (TDOS and PDOS) and also overlap population density of state (OPDOS) diagrams analysis were implemented. The IR and Raman spectra were theoretically simulated as a convenient way to confirm the existence of the actinide imine complexes in further experiments. PMID- 26608607 TI - Post-transcriptional modulation of interleukin 8 by CNOT6L regulates skeletal muscle differentiation. AB - CNOT6L is a deadenylase subunit belonging to the CCR4-NOT complex, a major deadenylase complex in eukaryotes involved at multiple levels in regulation of gene expression. While CNOT6L is expressed in skeletal muscle cells, its specific functions in this tissue are still largely unknown. Our previous work highlighted the functional of CNOT6L in skeletal muscle cell differentiation. To further explore how CNOT6L regulates myogenesis, we used here gene expression analysis to identify CNOT6L mRNA targets in human myoblasts. Among these novel targets, IL-8 (interleukin 8) mRNA was the most upregulated in CNOT6L knock-down (KD) cells. Biochemical approaches and poly (A) tail length assays showed that IL-8 mRNA is a direct target of CNOT6L, and further investigations by loss- and gain-of-function assays pointed out that IL-8 is an important effector of myogenesis. Therefore, we have characterized CNOT6L-IL-8 as a new signaling axis that regulates myogenesis. PMID- 26608605 TI - High Frequency Deep Brain Stimulation and Neural Rhythms in Parkinson's Disease. AB - High frequency (HF) deep brain stimulation (DBS) is an established therapy for the treatment of Parkinson's disease (PD). It effectively treats the cardinal motor signs of PD, including tremor, bradykinesia, and rigidity. The most common neural target is the subthalamic nucleus, located within the basal ganglia, the region most acutely affected by PD pathology. Using chronically-implanted DBS electrodes, researchers have been able to record underlying neural rhythms from several nodes in the PD network as well as perturb it using DBS to measure the ensuing neural and behavioral effects, both acutely and over time. In this review, we provide an overview of the PD neural network, focusing on the pathophysiological signals that have been recorded from PD patients as well as the mechanisms underlying the therapeutic benefits of HF DBS. We then discuss evidence for the relationship between specific neural oscillations and symptoms of PD, including the aberrant relationships potentially underlying functional connectivity in PD as well as the use of different frequencies of stimulation to more specifically target certain symptoms. Finally, we briefly describe several current areas of investigation and how the ability to record neural data in ecologically-valid settings may allow researchers to explore the relationship between brain and behavior in an unprecedented manner, culminating in the future automation of neurostimulation therapy for the treatment of a variety of neuropsychiatric diseases. PMID- 26608608 TI - The calcium-sensing receptor and the hallmarks of cancer. AB - The calcium-sensing receptor (CaSR) plays a pivotal role in systemic calcium metabolism by regulating parathyroid hormone secretion and urinary calcium excretion. The CaSR is ubiquitously expressed, implying a wide range of functions regulated by this receptor. Abnormal CaSR function affects the development of both calciotropic disorders such as hyperparathyroidism, and non-calciotropic disorders such as cardiovascular disease and cancer, which are the leading causes of mortality worldwide. The CaSR is able to bind a plethora of ligands; it interacts with multiple G protein subtypes, and regulates highly divergent downstream signalling pathways, depending on the cellular context. The CaSR is a key regulator for such diverse processes as hormone secretion, gene expression, inflammation, proliferation, differentiation, and apoptosis. Due to this pleiotropy, the CaSR is able to regulate cell fate and is implicated in the development of many types of benign or malignant tumours of the breast, prostate, parathyroid, and colon. In cancer, the CaSR appears to have paradoxical roles, and depending on the tissue involved, it is able to prevent or promote tumour growth. In tissues like the parathyroid or colon, the CaSR inhibits proliferation and induces terminal differentiation of the cells. Therefore, loss of the receptor, as seen in colorectal or parathyroid tumours, confers malignant potential, suggestive of a tumour suppressor role. In contrast, in prostate and breast tumours the expression of the CaSR is increased and it seems that it favours metastasis to the bone, acting as an oncogene. Deciphering the molecular mechanism driving the CaSR in the different tissues could lead to development of new allosteric drug compounds that selectively target the CaSR and have therapeutic potential for cancer. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen. PMID- 26608609 TI - Hemodynamics driven cardiac valve morphogenesis. AB - Mechanical forces are instrumental to cardiovascular development and physiology. The heart beats approximately 2.6 billion times in a human lifetime and heart valves ensure that these contractions result in an efficient, unidirectional flow of the blood. Composed of endocardial cells (EdCs) and extracellular matrix (ECM), cardiac valves are among the most mechanically challenged structures of the body both during and after their development. Understanding how hemodynamic forces modulate cardiovascular function and morphogenesis is key to unraveling the relationship between normal and pathological cardiovascular development and physiology. Most valve diseases have their origins in embryogenesis, either as signs of abnormal developmental processes or the aberrant re-expression of fetal gene programs normally quiescent in adulthood. Here we review recent discoveries in the mechanobiology of cardiac valve development and introduce the latest technologies being developed in the zebrafish, including live cell imaging and optical technologies, as well as modeling approaches that are currently transforming this field. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID- 26608611 TI - A pressure gradient facilitates mass flow in the oomycete Achlya bisexualis. AB - We have used a single cell pressure probe and observed movement of microinjected oil droplets to investigate mass flow in the oomycete Achlya bisexualis. To facilitate these experiments, split Petri dishes that had media containing different sorbitol concentrations (and hence a different osmotic potential) on each side of the dish were inoculated with a single zoospore. An initial germ tube grew out from this and formed a mycelium that extended over both sides of the Petri dish. Hyphae growing on the 0 M sorbitol side of the dish had a mean turgor ( +/- sem) of 0.53 +/- 0.03 MPa (n = 13) and on the 0.3 M sorbitol side had a mean turgor ( +/- sem) of 0.3 +/- 0.027 MPa (n = 9). Oil droplets that had been microinjected into the hyphae moved towards the lower turgor area of the mycelia (i.e. retrograde movement when microinjected into hyphae on the 0 M sorbitol side of the split Petri dish and anterograde movement when microinjected into hyphae on the 0.3 M sorbitol side of the Petri dish). In contrast, the movement of small refractile vesicles occurred in both directions irrespective of the pressure gradient. Experiments with neutral red indicate that the dye is able to move through the mycelia from one side of a split Petri dish to the other, suggesting that there is no compartmentation. This study shows that hyphae that are part of the same mycelia can have different turgor pressures and that this pressure gradient can drive mass flow. PMID- 26608612 TI - alpha 1-acid glycoprotein inhibits lipogenesis in neonatal swine adipose tissue. AB - Serum alpha1-acid glycoprotein (AGP) is elevated during late gestation and at birth in the pig and rapidly declines postnatally. In contrast, the pig is born with minimal lipid stores in the adipose tissue, but rapidly accumulates lipid during the first week. The present study examined if AGP can affect adipose tissue metabolism in the neonatal pig. Isolated cell cultures or tissue explants were prepared from dorsal subcutaneous adipose tissue of preweaning piglets. Porcine AGP was used at concentrations of 0, 100, 1000 and 5000 ng/ml medium in 24 h incubations. AGP reduced the messenger RNA (mRNA) abundance of the lipogenic enzymes, malic enzyme (ME), fatty acid synthase and acetyl coA carboxylase by at least 40% (P<0.001). The activity of ME and citrate lyase were also reduced by AGP (P<0.05). Glucose oxidation was reduced by treatment with 5000 ng AGP/ml medium (P<0.05). The 14C-glucose incorporation into fatty acids was reduced by ~25% by AGP treatment for 24 h with 1000 ng AGP/ml medium (P<0.05). The decrease in glucose metabolism by AGP appears to function through an inhibition in insulin mediated glucose oxidation and incorporation into fatty acids. This was supported by the analysis of the mRNA abundance for sterol regulatory element-binding protein (SREBP), carbohydrate regulatory element-binding protein (ChREBP) and insulin receptor substrate 1 (IRS1), which all demonstrated reductions of at least 23% in response to AGP treatment (P<0.05). These data demonstrate an overall suppression of lipogenesis due to AGP inhibition of lipogenic gene expression in vitro, which the metabolic data and SREBP, ChREBP and IRS1 gene expression analysis suggest is through an inhibition in insulin-mediated events. Second, these data suggest that AGP may contribute to limiting lipogenesis within adipose tissue during the perinatal period, as AGP levels are highest for any serum protein at birth. PMID- 26608610 TI - Calcium-ATPases: Gene disorders and dysregulation in cancer. AB - Ca(2+)-ATPases belonging to the superfamily of P-type pumps play an important role in maintaining low, nanomolar cytoplasmic Ca(2+) levels at rest and priming organellar stores, including the endoplasmic reticulum, Golgi, and secretory vesicles with high levels of Ca(2+) for a wide range of signaling functions. In this review, we introduce the distinct subtypes of Ca(2+)-ATPases and their isoforms and splice variants and provide an overview of their specific cellular roles as they relate to genetic disorders and cancer, with a particular emphasis on recent findings on the secretory pathway Ca(2+)-ATPases (SPCA). Mutations in human ATP2A2, ATP2C1 genes, encoding housekeeping isoforms of the endoplasmic reticulum (SERCA2) and secretory pathway (SPCA1) pumps, respectively, confer autosomal dominant disorders of the skin, whereas mutations in other isoforms underlie various muscular, neurological, or developmental disorders. Emerging evidence points to an important function of dysregulated Ca(2+)-ATPase expression in cancers of the colon, lung, and breast where they may serve as markers of differentiation or novel targets for therapeutic intervention. We review the mechanisms underlying the link between calcium homeostasis and cancer and discuss the potential clinical relevance of these observations. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen. PMID- 26608613 TI - Kaposi's varicelliform eruption in herpes simplex encephalitis. PMID- 26608614 TI - Securing a consultant position as a new Fellow of the Australasian College for Emergency Medicine. PMID- 26608615 TI - Coronary arteries of the European bison (Bison bonasus). AB - BACKGROUND: The European bison (Bison bonasus) is an endangered species. More information on its anatomy is needed as only few studies have been published. This study is the first report on the morphology of the coronary vessels. Given the anatomical similarity between the European bison and other ruminants, the results of this study can be applied to other species, including endangered ones. RESULTS: The study was conducted on 70 hearts of European bisons of both sexes, aged 5-20 years, with an average body weight of 449 kg. A distinct view of subepicardial arterial vessels was obtained by filling them with dyed synthetic latex (LBS 3060) and Plastogen G. There was a division of the common trunk of the left coronary artery into the interventricular paraconal branch and the left circumflex branch in 63 individuals (90 %). In five individuals (7.1 %), the presence of a third vessel, which was a branch of the interventricular septum, was observed. There was a lack of a common trunk in two individuals (2.9 %). Ramifications of the interventricular paraconal branch to the wall of the left ventricle were significantly larger than those to the wall of the right ventricle. In 17 individuals (24.3 %), the right coronary artery extended into the subsinuosal interventricular branch. CONCLUSION: The blood supply to the heart in bisons is provided by the left and right coronary arteries. In all the studied specimens, the left coronary artery was better developed than the right coronary artery. PMID- 26608616 TI - Altered interhemispheric resting state functional connectivity during passive hyperthermia. AB - PURPOSE: This study examines the effect of passive hyperthermia on interhemispheric resting state functional connectivity and the correlation between interhemispheric resting state functional connectivity and efficiency of a succedent working memory task. MATERIALS AND METHODS: We performed voxel mirrored homotopic connectivity (VMHC) analyses on resting state MRI data and a one-back task from 14 healthy subjects in both HT (hyperthermia, 50 degrees C) conditions and normal control (NC, 25 degrees C) conditions. The group analyses of the differences for VMHC between the two conditions and the correlation analysis between the VMHC and the reaction time (RT) of the one-back task were performed with the statistical parametric mapping software package and the software REST. RESULTS: Compared with NC conditions, HT conditions increased VMHC in the cuneus, the postcentral gyrus, and the fusiform gyrus. No region showed decreased VMHC in the HT group in comparison with the NC group. For NC conditions, negative correlations were demonstrated between RT of the one-back task and VMHC in bilateral superior temporal gyrus, and bilateral middle frontal gyrus; for HT conditions, negative correlations were demonstrated between RT and VMHC in bilateral inferior frontal gyrus, bilateral middle frontal gyrus, as well as cerebellum posterior lobe. CONCLUSION: Passive heat stress can impact the interhemispheric information interactions at resting state and the VMHC deficits may play an important role in cognitive dysfunction. PMID- 26608617 TI - Twice-daily therapeutical plasma exchange-based salvage therapy in severe autoimmune thrombotic thrombocytopenic purpura: the French TMA Reference Center experience. AB - BACKGROUND: Daily therapeutic plasma exchange (TPE) and rituximab improved thrombotic thrombocytopenic purpura (TTP) prognosis. In the more severe cases, salvage therapies including twice-daily TPE and/or cyclophosphamide may be proposed and require evaluation. METHODS: TTP was defined as a thrombotic microangiopathy (TMA) with severe (<10%) acquired ADAMTS13 deficiency. Among patients included in the French Reference Center for TMA registry, we considered those with a severe disease (i.e., unresponsive to daily TPE and rituximab) who received twice-daily TPE. RESULTS: Nineteen of 289 (6.6%) patients with TTP were treated by twice-daily TPE between 2008 and 2014. Twice-daily TPE was associated with rituximab in 16 cases. The median duration of twice-daily TPE treatment was 3 d (2-22 d). In 6 patients (31.6%), additional treatments (mainly pulses of cyclophosphamide) were performed because of a persistently refractory disease (4 cases) or an exacerbation (2 cases), despite twice-daily TPE. Only one patient (5.3%) died. The other 18 achieved a durable complete remission 25.5 d (13-68 d) after the first TPE. The median follow-up was 14.4 months (7 d-45 months). CONCLUSIONS: Twice-daily TPE may be an efficient strategy in the more severe TTP patients with a short-term life-threatening disease that could overcome their poor prognosis. PMID- 26608618 TI - Genetics of mating in members of the Chaetomiaceae as revealed by experimental and genomic characterization of reproduction in Myceliophthora heterothallica. AB - Members of the Chaetomiaceae are among the most studied fungi in industry and among the most reported in investigations of biomass degradation in both natural and laboratory settings. The family is recognized for production of carbohydrate active enzymes and antibiotics. Thermophilic species are of special interest for their abilities to produce thermally stable enzymes and to be grown under conditions that are unsuitable for potential contaminant microorganisms. Such interests led to the recent acquisition of genome sequences from several members of the family, including thermophilic species, several of which are reported here for the first time. To date, however, thermophilic fungi in industry have served primarily as parts reservoirs and there has been no good genetic model for species in the family Chaetomiaceae or for thermophiles in general. We report here on the reproductive biology of the thermophile Myceliophthora heterothallica, which is heterothallic, unlike most described species in the family. We confirmed heterothallism genetically by following the segregation of mating type idiomorphs and other markers. We have expanded the number of known sexually-compatible individuals from the original isolates from Indiana and Germany to include several isolates from New Mexico. An interesting aspect of development in M. heterothallica is that ascocarp formation is optimal at approximately 30 degrees C, whereas vegetative growth is optimal at 45 degrees C. Genome sequences obtained from several strains, including isolates of each mating type, revealed mating-type regions whose genes are organized similarly to those of other members of the Sordariales, except for the presence of a truncated version of the mat A-1 (MAT1-1-1) gene in mating-type a (MAT1-2) strains. In M. heterothallica and other Chaetomiaceae, mating-type A (MAT1-1) strains have the full-length version of mat A-1 that is typical of mating-type A strains of diverse Ascomycota, whereas a strains have only the truncated version. This truncated mat A-1 has an intact open reading frame and a derived start codon that is not present in mat A-1 from A strains. The predicted protein contains a region that is conserved across diverse mat A-1 genes, but it lacks the major alpha1 domain, which characterizes proteins in this family and is known to be required for fertility in A strains from other Ascomycota. Finally, we have used genes from M. heterothallica to probe for mating genes in other homothallic and heterothallic members of the Chaetomiaceae. The majority of homothallic species examined have a typical mat A-1,2,3 (MAT1-1-1,2,3) region in addition to an unlinked mat a-1 (MAT1-2-1) gene, reflecting one type of homothallism commonly observed in diverse Ascomycota. PMID- 26608620 TI - Development and characterisation of sustained release solid dispersion oral tablets containing the poorly water soluble drug disulfiram. AB - Administration of drugs via the oral route is the most common and preferred route due to its ease of administration, cost-effectiveness and flexibility in design. However, if the drug being administered has limited aqueous solubility it can result in poor bioavailability. Furthermore, the low pH of the stomach as well as enzymatic activity can result in drugs delivered via the oral route being rapidly metabolised and degraded. Here we demonstrate the development and characterisation of sustained release solid dispersion oral tablets, containing the poorly water-soluble drug disulfiram (DSF). The tablets, which are manufactured from two different polymers (Kolliphor((r)) P 188 and P 237) specifically designed for the manufacture of solid dispersions and two different polymers (Kollidon((r)) SR and HPMC) specifically designed to provide sustained release, can enhance the solubility of DSF, sustain its release, while protecting it from degradation in simulated gastric fluid (SGF). The paper demonstrates that when using the hot melt method at 80 degrees C the DSF loading capacity of the Kolliphor((r)) P 188 and P 237 polymers is approximately 43 and 46% respectively, with the DSF completely in an amorphous state. The addition of 80% Kollidon((r)) SR to the formulation completely protected the DSF in SGF for up to 70 min with 16% degradation after 120 min, while 75% degradation occurred after 120 min with the addition of 80% HPMC. The release rate of DSF can be manipulated by both the loading and type of sustained release polymer used, with HPMC providing for a much faster release rate compared to Kollidon((r)) SR. PMID- 26608619 TI - Nanocomposite hydrogel incorporating gold nanorods and paclitaxel-loaded chitosan micelles for combination photothermal-chemotherapy. AB - Development of combination photothermal-chemotherapy platform is of great interest for enhancing antitumor efficacy and inhibiting tumor recurrence, which supports selective and dose-controlled delivery of heat and anticancer drugs to tumor. Here, an injectable nanocomposite hydrogel incorporating PEGylated gold nanorods (GNRs) and paclitaxel-loaded chitosan polymeric micelles (PTX-M) is developed in pursuit of improved local tumor control. After intratumoral injection, both GNRs and PTX-M can be simultaneously delivered and immobilized in the tumor tissue by the thermo-sensitive hydrogel matrix. Exposure to the laser irradiation induces the GNR-mediated photothermal damage confined to the tumor with sparing the surrounding normal tissue. Synergistically, the co-delivered PTX M shows prolonged tumor retention with the sustained release of anticancer drug to efficiently kill the residual tumor cells that evade the photothermal ablation due to the heterogeneous heating in the tumor region. This combination photothermal-chemotherapy presents superior effects on suppressing the tumor recurrence and prolonging the survival in the Heps-bearing mice, compared to the photothermal therapy alone. PMID- 26608621 TI - In-line near infrared spectroscopy during freeze-drying as a tool to measure efficiency of hydrogen bond formation between protein and sugar, predictive of protein storage stability. AB - Sugars are often used as stabilizers of protein formulations during freeze drying. However, not all sugars are equally suitable for this purpose. Using in line near-infrared spectroscopy during freeze-drying, it is shown here that hydrogen bond formation during freeze-drying, under secondary drying conditions in particular, can be related to the preservation of the functionality and structure of proteins during storage. The disaccharide trehalose was best capable of forming hydrogen bonds with the model protein, lactate dehydrogenase, thereby stabilizing it, followed by the molecularly flexible oligosaccharide inulin 4kDa. The molecularly rigid oligo- and polysaccharides dextran 5kDa and 70kDa, respectively, formed the least amount of hydrogen bonds and provided least stabilization of the protein. It is concluded that smaller and molecularly more flexible sugars are less affected by steric hindrance, allowing them to form more hydrogen bonds with the protein, thereby stabilizing it better. PMID- 26608622 TI - Evaluation of muscle oxygenation by near infrared spectroscopy in patients with facioscapulohumeral muscular dystrophy. AB - The purpose of the study was to determine muscle metabolism adaptation to exercise in facioscapulohumeral muscular dystrophy patients (FSHD) and to study the correlation with clinical functional status (6-min walk test). 8 FSHD patients and 15 age-matched healthy controls (Controls) performed two isokinetic constant-load knee extension exercises: (1) at 20% of their maximal extensors' peak torque (i.e., the same relative workload) and (2) at (20N?m) (the same absolute workload) for up to 4 min. All exercises consisted of rhythmic, voluntary, isokinetic, concentric contractions of the quadriceps femoris at 90 degrees /s, whereas the flexion was performed passively at the same speed. Muscle oxygenation in the vastus lateralis was evaluated using near-infrared spectroscopy (NIRS). The FSHD patients displayed a lower maximal peak torque than controls (-41%, p < 0.05). During the two-exercise modalities, deoxygenated haemoglobin (HHb) and total haemoglobin volume (tHb) were lower in the FSHD patients (p < 0.05). The initial muscle deoxygenation time delay was shorter in the control group (FSHD: 15.1 +/- 4.1 s vs. CONTROLS: 10.4 +/- 2.1 s, p < 0.05). Mean response time and maximal peak torque were both correlated with functional impairment (walking endurance). The results suggest that FSHD patients present an impairment in their capacity to deliver or to use oxygen. PMID- 26608624 TI - C-S@PANI composite with a polymer spherical network structure for high performance lithium-sulfur batteries. AB - A unique C-S@PANI composite with a conductive polymer spherical network (PSN) has been successfully designed and synthesized by a simple processing approach. The PSN framework is formed at the surface of the oxidized carbon black by conductive polymer self-assembly and grafting, followed by pouring elemental sulfur into the pores of the polymer matrix. As the cathode material for lithium-sulfur batteries, the C-S@PANI composite delivered a high specific capacity of 1453 mA h g(-1) at a 0.1 C current rate and a stable cycling performance of 948 mA h g(-1) after 200 cycles. The composite also demonstrated high capacities of 922 and 581 mA h g(-1) at 50 degrees C and 0 degrees C, respectively, after 200 cycles. The conductive PANI coatings were connected with the C-S core-shell composites to form a three-dimensional conducting network, which improves the utilization of the active mass and dual conduction of Li(+) and electrons, while at the same time encapsulating sulfur into the PANI hollow spherical network. The structure effectively inhibits the dissolution and migration of polysulfides into the electrolyte, while improving the cycling stability and the coulombic efficiency of the electrode at high current rates, especially the low temperature electrochemical properties of Li-S batteries. PMID- 26608625 TI - Phthalate monoesters in association with uterine leiomyomata in Shanghai. AB - Phthalates are ubiquitous environmental pollutants because of the broad use of plastics. We conducted a case-control study to determine whether uterine leiomyomata were related to exposure to phthalates. Urine specimens and questionnaires were collected from 61 cases and 61 age-matched controls. Nine phthalate monoesters were determined by ultra performance liquid chromatography coupled with tandem mass spectroscopy. Cases had significantly higher levels of creatinine-adjusted mono-iso-butyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate, mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), total di(2-ethylhexyl) phthalate metabolites (?DEHPmet), and total dibutyl phthalate metabolites (?DBP(met)) than controls. After adjusting for potential confounders, logistic regression analyses demonstrated that leiomyomata were positively associated with MiBP, MnBP, MEHP, MEHHP, MECPP, ?DEHP(met), and ?DBP(met). In summary, our data support the hypothesis that uterine leiomyomata are related to phthalate exposure. PMID- 26608626 TI - Enhanced spin-phonon-electronic coupling in a 5d oxide. AB - Enhanced coupling of material properties offers new fundamental insights and routes to multifunctional devices. In this context 5d oxides provide new paradigms of cooperative interactions that drive novel emergent behaviour. This is exemplified in osmates that host metal-insulator transitions where magnetic order appears intimately entwined. Here we consider such a material, the 5d perovskite NaOsO3, and observe a coupling between spin and phonon manifested in a frequency shift of 40 cm(-1), the largest measured in any material. The anomalous modes are shown to involve solely Os-O interactions and magnetism is revealed as the driving microscopic mechanism for the phonon renormalization. The magnitude of the coupling in NaOsO3 is primarily due to a property common to all 5d materials: the large spatial extent of the ion. This allows magnetism to couple to phonons on an unprecedented scale and in general offers multiple new routes to enhanced coupled phenomena in 5d materials. PMID- 26608627 TI - Migraine doctor loses appeal against findings of dishonesty. PMID- 26608623 TI - Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit. AB - BACKGROUND: Disruption of the blood-brain barrier (BBB) occurs in many diseases and is often mediated by inflammatory and neuroimmune mechanisms. Inflammation is well established as a cause of BBB disruption, but many mechanistic questions remain. METHODS: We used lipopolysaccharide (LPS) to induce inflammation and BBB disruption in mice. BBB disruption was measured using (14)C-sucrose and radioactively labeled albumin. Brain cytokine responses were measured using multiplex technology and dependence on cyclooxygenase (COX) and oxidative stress determined by treatments with indomethacin and N-acetylcysteine. Astrocyte and microglia/macrophage responses were measured using brain immunohistochemistry. In vitro studies used Transwell cultures of primary brain endothelial cells co- or tri-cultured with astrocytes and pericytes to measure effects of LPS on transendothelial electrical resistance (TEER), cellular distribution of tight junction proteins, and permeability to (14)C-sucrose and radioactive albumin. RESULTS: In comparison to LPS-induced weight loss, the BBB was relatively resistant to LPS-induced disruption. Disruption occurred only with the highest dose of LPS and was most evident in the frontal cortex, thalamus, pons-medulla, and cerebellum with no disruption in the hypothalamus. The in vitro and in vivo patterns of LPS-induced disruption as measured with (14)C-sucrose, radioactive albumin, and TEER suggested involvement of both paracellular and transcytotic pathways. Disruption as measured with albumin and (14)C-sucrose, but not TEER, was blocked by indomethacin. N-acetylcysteine did not affect disruption. In vivo, the measures of neuroinflammation induced by LPS were mainly not reversed by indomethacin. In vitro, the effects on LPS and indomethacin were not altered when brain endothelial cells (BECs) were cultured with astrocytes or pericytes. CONCLUSIONS: The BBB is relatively resistant to LPS-induced disruption with some brain regions more vulnerable than others. LPS-induced disruption appears is to be dependent on COX but not on oxidative stress. Based on in vivo and in vitro measures of neuroinflammation, it appears that astrocytes, microglia/macrophages, and pericytes play little role in the LPS-mediated disruption of the BBB. PMID- 26608628 TI - Physicochemical and sensory characteristics of meat from young Nellore bulls fed different levels of palm kernel cake. AB - BACKGROUND: Palm kernel cake is a biodiesel byproduct and an alternative feed additive in cattle production. This study evaluated the effects of palm kernel cake added to bulls' diets on the physicochemical and sensory characteristics of their meat. Thirty-two young Nellore bulls were used, distributed in a randomized experimental design with four treatments: 0, 7, 14 or 21% (w/w) palm kernel cake in the dry matter of the diet. Hay was used at 35% (w/w) in the diets, which were balanced to provide 150 g kg(-1) crude protein and 33 Mcal kg(-1) metabolizable energy. RESULTS: The moisture (P = 0.40), ash (P = 0.70), protein (P = 0.10) and ether extract (P = 0.31) contents of the meat samples were not affected by the inclusion of palm kernel cake. The qualitative characteristics of the meat, including pH (P = 0.69), water-holding capacity (P = 0.22), cooking loss (P = 0.14), shear force (P = 0.32) and instrumental color indices L* (P = 0.75), a* (P = 0.44) and b* (P = 0.41), were not affected by the substitution of palm kernel cake for soybean meal. CONCLUSION: Palm kernel cake may be included at up to 21% (w/w) in cattle feed without compromising the physicochemical, sensory and acceptance characteristics of the meat. (c) 2015 Society of Chemical Industry. PMID- 26608629 TI - Acute atherosis in vacuum suction biopsies of decidua basalis: An evidence based research definition. AB - BACKGROUND: Acute atherosis (AA) of the uteroplacental spiral arteries has been characterised by subendothelial lipid-laden foam cells, perivascular leukocyte infiltrates (PVI) and fibrinoid necrosis. Because precise diagnostic criteria are not available for comparative research studies we developed and tested new simplified criteria based on 237 cases. METHODS: Decidual basalis samples were collected by vacuum suction at elective cesarean deliveries. Spiral arteries were evaluated in serial decidual tissue sections from women with normal pregnancy, preeclampsia, and diabetes. Features of AA were sought in parallel sections stained with H&E and immunostained for CD68, cytokeratin CK7 and desmin, and costained with Periodic Acid Schiff (PAS). RESULTS: Foam cell lesions were defined as two or more adjacent, intramural, vacuolated CD68 positive cells, PVI as a focal perivascular lymphocyte accumulation, more dense than in the surrounding decidua. Increased fibrinoid (PAS positive) was identified if present in >=75% of the arterial wall circumference. PVI and increased fibrinoid were significantly associated with preeclampsia but not specifically associated with the presence of foam cell lesions. Hence we diagnosed decidua basalis AA lesions solely by the presence of foam cell lesions, occurring in preeclampsia (37%), diabetes (10%) and healthy normotensive women (11%). The simplified criterion was reproducible by different investigators. Decidua basalis AA occurred most commonly and extensively in preeclampsia, but did not distinguish between preterm and term disease. DISCUSSION: Our evidence based criterion for decidua basalis AA diagnosis in vacuum suction biopsies may not apply to myometrial or decidua parietalis arteries. In decidual basalis samples it should facilitate comparisons between research studies, to improve pathophysiological understanding of AA and preeclampsia. PMID- 26608630 TI - Ophthalmic applications of lipid-based drug nanocarriers: an update of research and patenting activity. AB - Ophthalmic diseases collect great attention by researchers and pharmaceutical technologists, since they can dramatically worsen the quality of life. Because of the limited duration of action on the eye surface, and anatomical/physiological barriers to drug penetration from it into the inner eye structures, conventional ocular formulations are generally unable to perform at their best. Nanotechnology approaches can represent a solution to improve the therapeutic efficiency, compliance and safety of ocular drugs. In this respect, lipid-based nanocarriers are among the most interesting systems. Their composition and production methods make them highly biocompatible and safe formulations. This review illustrates the developments achieved in ocular drug delivery using lipid-based nanocarriers, with a critical revision of recent scientific articles and filed patents. PMID- 26608631 TI - Antimullerian hormone, antral follicle count and ovarian volume predict menstrual cycle length in healthy women. AB - OBJECTIVE: Although menstrual cycle length is one of the main concerns of women and may have important health consequences, little is known about its predictors. The aim of this study was to identify predictors of menstrual cycle length variability in healthy women. DESIGN: Prospective cross-sectional study. PATIENTS: Two hundred healthy women aged 21-45. MEASUREMENTS: A questionnaire was administered to determine lifestyle factors. Ovarian parameters, metabolic parameters, pituitary hormones, sex steroids and antimullerian hormone (AMH) were measured. RESULTS: Women with long (>=35 days) and normal (25-34 days) menstrual cycles had >5-fold and >2-fold higher serum AMH levels, respectively, compared to those with short cycles (<25 days). Menstrual cycle length was associated with age but not lifestyle factors. Only one factor group (AMH, antral follicle count [AFC], ovarian volume, testosterone and LH) was significantly associated with menstrual cycle length. Within this factor group, only the ovarian parameters (AMH, AFC, ovarian volume) predicted menstrual cycle length. Each SD increase in AMH (32.9 pmol/l) and ovarian volume (2.29 cm(3) ) was associated with 2.80-fold (95% CI: 1.67-4.69) and 1.62-fold (95% CI: 1.08-2.43) increased risks, respectively, for longer menstrual cycles. CONCLUSIONS: AMH, AFC and ovarian volume are positively associated with menstrual cycle length in healthy women. Our identification of AMH as an independent predictor of menstrual cycle length puts forth a new notion of utilizing menstrual cycle length to predict possible AMH-dependent/-associated outcomes. In addition, this novel relationship may facilitate the interpretation of AMH levels and its clinico-pathological significance across different centres. PMID- 26608632 TI - Association between the rs12255372 variant of the TCF7L2 gene and obesity in a Cameroonian population. AB - BACKGROUND: The transcription factor 7-like 2 (TCF7L2) is one of the genes that have been identified as possible determinants of diabetes which is associated with obesity. Data on the genetic causes of obesity in sub-Saharan African populations are very scares. The aim of this study was to assess the association between the transcription factor 7-like 2 (TCF7L2) gene polymorphism (rs12255372 G/T) and obesity and weight-related traits in a Cameroonian population. METHODS: A case-control study was conducted on 35 obese and 30 non-obese Cameroonian adults. TCF7L2 rs12255372 genotypes were determined using PCR-RFLP and correlated with BMI and weight-related traits. RESULTS: No significant association was observed between the rs12255372 T allele (chi(2) = 0.0684, p = 0.79) or the TT genotype (chi(2) = 0.372, p = 0.54) of the TCF7L2 gene and obesity in the Cameroonian population. However, amongst the weight-related traits, triglycerides were significantly associated with the T risk allele of the TCF7L2 gene (p = 0.012). CONCLUSION: This study on Cameroonian subjects replicates the absence of association between the TCF7L2 rs12255372 variant and obesity as observed in European and American populations. PMID- 26608633 TI - Acculturation, sociodemographic and lifestyle factors associated with compliance with physical activity recommendations in the Mexican-American Mano A Mano cohort. AB - OBJECTIVES: Being physically active is important for health, and few Mexican Americans meet national US physical activity recommendations. The aim of this study was to investigate sociodemographic, acculturation and lifestyle factors that were associated with meeting physical activity recommendations in this group. DESIGN AND SETTING: A cross-sectional analysis of a large population-based cohort study in southern Texas, USA. PARTICIPANTS: Between 2001 and 2011, 21 551 adult members of the Mexican-American Mano A Mano cohort completed baseline questionnaires on physical activity and other lifestyle factors. OUTCOMES: Meeting US physical activity recommendations was defined as participating in 150 min of moderate, or 75 min of vigorous, activity per week. Factors contributing to the likelihood of meeting physical activity recommendations were examined by sex and country of birth in multivariate logistic regression models. RESULTS: Less than half of all men and less than a quarter of all women met US physical activity recommendations. Having some college education, greater acculturation and current alcohol use were each associated with greater odds of meeting physical activity recommendations in all groups except US-born men. Higher body mass index was associated with lower odds of meeting recommendations in US-born and Mexico-born women. CONCLUSIONS: Results demonstrate that factors associated with meeting physical activity recommendations differ by sex and country of birth. Tailored interventions to increase Mexican-Americans' activity levels to achieve health benefits should consider education, acculturation and alcohol use. PMID- 26608634 TI - Specialised teams or personal continuity across inpatient and outpatient mental healthcare? Study protocol for a natural experiment. AB - INTRODUCTION: Mental healthcare organisation can either pursue specialisation, that is, distinct clinicians and teams for inpatient and outpatient care or personal continuity of care, that is, the same primary clinician for a patient across the two settings. Little systematic research has compared these approaches. Existing studies subject have serious methodological shortcomings. Yet, costly reorganisations of services have been carried out in different European countries, inconsistently aiming to achieve specialisation or personal continuity of care. More reliable evidence is required on whether specialisation or continuity of care is more effective and cost-effective, and whether this varies for different patient groups and contexts. DESIGN AND METHODS: In a natural experiment, we aim to recruit at least 6000 patients consecutively admitted to inpatient psychiatric care in Belgium, Germany, Italy, Poland, and the UK. In each country, care approaches supporting specialisation and personal continuity coexist. Patients will be followed up at 1 year to compare outcomes, costs and experiences. Inclusion criteria are: 18 years of age or older; clinical diagnosis of psychosis, affective disorder or anxiety/somatisation disorder; sufficient command of the language of the host country; absence of cognitive deterioration and/or organic brain disorders; and capacity to provide informed consent. ETHICS AND DISSEMINATION: Ethical approval was obtained in all countries: (1) England: NRES Committee North East-Newcastle & North Tyneside (ref: 14/NE/1017); (2) Belgium: Comite d'Ethique hospitalo-facultaire des Cliniques St-Luc; (3) Germany: Ethical Board, Technische Universitat Dresden; (4) Italy: Comitati Etici per la sperimentazione clinica (CESC) delle provincie di Verona, Rovigo, Vicenza, Treviso, Padova; (5) Poland: Komisja Bioetyczna przy Instytucie Psychiatrii i Neurologii w Warszawie. We will disseminate the findings through scientific publications and a study-specific website. At the end of the study, we will develop recommendations for policy decision-making, and organise national and international workshops with stakeholders. TRIAL REGISTRATION NUMBER: ISRCTN registry: ISRCTN40256812. PMID- 26608635 TI - Bereaved relatives' experiences during the incurable phase of cancer: a qualitative interview study. AB - OBJECTIVE: To examine bereaved relatives' experiences from time of diagnosis of incurable cancer until death with specific emphasis on their role in the (end-of life) decision-making concerning chemotherapy. DESIGN: Qualitative interview study. SETTING: Hospital-based. PARTICIPANTS AND METHODS: In-depth interviews with 15 close relatives of patients who died from non-small cell lung cancer or pancreatic cancer, using a thematic content analysis. RESULTS: All relatives reported that patients' main reason to request chemotherapy was the possibility to prolong life. Relatives reported that patients receiving chemotherapy had more difficulty to accept the incurable nature of their disease than patients who did not. They mostly followed the patients' treatment wish and only infrequently suggested ceasing chemotherapy (because of side effects) despite sometimes believing that this would be a better option. Relatives continuously tried to support the patient in either approaching the death or in attaining hope to continue life satisfactorily. Most relatives considered the chemotherapy period meaningful, since it sparked patients' hope and was what patients wanted. Cessation of chemotherapy caused a relief but coincided with physical deterioration and an increased caregivers' role; many relatives recalled this latter period as more burdensome. CONCLUSIONS: Relatives tend to follow patients' wish to continue or cease chemotherapy, without expressing their own feelings, although they were more inclined to opt cessation. They experience a greater caregiver role after cessation and their feelings of responsibility associated with the disease can be exhausting. More attention is needed to reduce relatives' distress at the end of life, also to fully profit from this crucial form of (informal) healthcare. PMID- 26608636 TI - Methods for estimating causal relationships of adverse events with dietary supplements. AB - OBJECTIVE: Dietary supplement use has increased over past decades, resulting in reports of potentially serious adverse events. The aim of this study was to develop optimised methods to evaluate the causal relationships between adverse events and dietary supplements, and to test these methods using case reports. DESIGN: Causal relationship assessment using prospectively collected data. SETTING AND PARTICIPANTS: 4 dietary supplement experts, 4 pharmacists and 11 registered dietitians (5 men and 14 women) examined 200 case reports of suspected adverse events using the modified Naranjo scale and the modified Food and Drug Administration (FDA) algorithm. PRIMARY OUTCOME MEASURES: The distribution of evaluation results was analysed and inter-rater reliability was evaluated for the two modified methods employed using intraclass correlation coefficients (ICC) and Fleiss' kappa. RESULTS: Using these two methods, most of the 200 case reports were categorised as 'lack of information' or 'possible' adverse events. Inter rater reliability among entire assessors ratings for the two modified methods, based on ICC and Fleiss' kappa, were classified as more than substantial (modified Naranjo scale: ICC (95% CI) 0.873 (0.850 to 0.895); Fleiss' kappa (95% CI) 0.615 (0.615 to 0.615). Modified FDA algorithm: Fleiss' kappa (95% CI) 0.622 (0.622 to 0.622). CONCLUSIONS: These methods may help to assess the causal relationships between adverse events and dietary supplements. By conducting additional studies of these methods in different populations, researchers can expand the possibilities for the application of our methods. PMID- 26608637 TI - How common is isolated dysphasia among patients with stroke treated with intravenous thrombolysis, and what is their outcome? Results from the SITS-ISTR. AB - OBJECTIVES: To describe the frequency and outcome of isolated dysphasia among patients treated with intravenous thrombolysis (IVT). DESIGN: Patients registered in the SITS International Stroke Thrombolysis Register (SITS-ISTR). PARTICIPANTS: Patients with stroke (N=58,293) treated with IVT between December 2002 and December 2012. SETTING: A multinational, prospective, observational monitoring register. MAIN OUTCOME MEASURES: Isolated dysphasia and modified Rankin Scale (mRS). METHODS: We identified patients presenting with isolated dysphasia by reviewing items within the baseline National Institutes of Health Stroke Scale (NIHSS). We performed descriptive statistics for baseline and demographic data, and reported patients' characteristics, radiological data and changes in their NIHSS score within 7 days and mRS score at 3 months. We also reported corresponding data from the general SITS-ISTR cohort. RESULTS: We found isolated dysphasia at baseline in 1.14% (663/58,293) of all patients treated with IVT patients. Patients with isolated dysphasia had a longer onset to treatment time, lower proportion of visible infarctions on admission imaging scan and atrial fibrillation, and were less often classified as having large vessels causing strokes, in comparison with the rest of the SITS-ISTR. Symptomatic intracerebral haemorrhage occurred in 2.3% of patients per SITS-MOST definition and fatal outcome in 5.5%. At 7 days, 50% of patients with isolated dysphasia recovered completely and at 3 months, 86.3% patients were functionally independent (mRS score 0-2), 71.7% had an excellent outcome (mRS score 0-1) and 45.5% had an mRS score of 0. CONCLUSIONS: A low proportion of patients with isolated dysphasia are treated with IVT. Half of these patients were fully recovered at 7 days. PMID- 26608638 TI - Are suicide deaths under-reported? Nationwide re-evaluations of 1800 deaths in Scandinavia. AB - OBJECTIVE: Valid mortality statistics are important for healthcare planning and research. Suicides and accidents often present a challenge in the classification of the manner of death. The aim of this study was to analyse the reliability of the national suicide statistics by comparing the classification of suicide in the Scandinavian cause of death registers with a reclassification by 8 persons with different medical expertise (psychiatry, forensic pathology and public health) from each of the 3 Scandinavian countries. METHODS: The cause of death registers in Norway, Sweden and Denmark retrieved available information on a sample of 600 deaths in 2008 from each country. 200 were classified in the registers as suicides, 200 as accidents or undetermined and 200 as natural deaths. The reclassification comprised an assessment of the manner and cause of death as well as the level of certainty. RESULTS: In total, 81%, 88% and 90% of deaths registered as suicide in the official mortality statistics were confirmed by experts using the Swedish, Norwegian and Danish data sets, respectively. About 3% of deaths classified as accidents or natural deaths in the cause of death registers were reclassified as suicides. However, after a second reclassification based on additional information, 9% of the natural deaths and accidents were reclassified as suicides in the Norwegian data set, and 21% of the undetermined deaths were reclassified as suicides in the Swedish data set. In total, the levels of certainty of the experts were 87% of suicides in the Norwegian data set, 77% in the Swedish data set and 92% in Danish data set; the uncertainty was highest in poisoning suicides. CONCLUSIONS: A high percentage of reported suicides were confirmed as being suicides. Few accidents and natural deaths were reclassified as suicides. Hence, reclassification did not increase the overall official suicide statistics of the 3 Scandinavian countries. PMID- 26608639 TI - The disciplined healthcare professional: a qualitative interview study on the impact of the disciplinary process and imposed measures in the Netherlands. AB - OBJECTIVE: It is known that doctors who receive complaints may have feelings of anger, guilt, shame and depression, both in the short and in the long term. This might lead to functional impairment. Less is known about the impact of the disciplinary process and imposed measures. Previous studies of disciplinary proceedings have mainly focused on identifying characteristics of disciplined doctors and on sentencing policies. Therefore, the aim of this study is to explore what impact the disciplinary process and imposed measures have on healthcare professionals. DESIGN: Semistructured interview study, with purposive sampling and inductive qualitative content analysis. PARTICIPANTS: 16 healthcare professionals (9 medical specialists, 3 general practitioners, 2 physiotherapists and 2 psychologists) that were sanctioned by the disciplinary tribunal. SETTING: The Netherlands. RESULTS: Professionals described feelings of misery and insecurity both during the process as in its aftermath. Furthermore, they reported to fear receiving new complaints and provide care more cautiously after the imposed measure. Factors that may enhance psychological and professional impact are the publication of measures online and in newspapers, media coverage, the feeling of treated as guilty before any verdict has been reached, and the long duration of the process. CONCLUSIONS: This study shows that the disciplinary process and imposed measures can have a profound psychological and professional impact on healthcare professionals. Although a disciplinary measure is meant to have a corrective effect, our results suggest that the impact that is experienced by professionals might hamper optimal rehabilitation afterwards. Therefore, organising emotional support should be considered during the disciplinary process and in the period after the verdict. PMID- 26608640 TI - Neighbourhood urban form and individual-level correlates of leisure-based screen time in Canadian adults. AB - OBJECTIVES: Despite evidence for an association between the built environment and physical activity, less evidence exists regarding relations between the built environment and sedentary behaviour. This study investigated the extent to which objectively assessed and self-reported neighbourhood walkability, in addition to individual-level characteristics, were associated with leisure-based screen time in adults. We hypothesised that leisure-based screen time would be lower among adults residing in objectively assessed and self-reported 'high walkable' versus 'low walkable' neighbourhoods. SETTING: The study was undertaken in Calgary, Alberta, Canada in 2007/2008. PARTICIPANTS: A random cross-section of adults who provided complete telephone interview and postal survey data (n=1906) was included. Captured information included leisure-based screen time, moderate intensity and vigorous-intensity physical activity, perceived neighbourhood walkability, sociodemographic characteristics, self-reported health status, and self-reported height and weight. Based on objectively assessed built characteristics, participant's neighbourhoods were identified as being low, medium or high walkable. PRIMARY AND SECONDARY OUTCOME MEASURES: Using multiple linear regression, hours of leisure-based screen time per day was regressed on self-reported and objectively assessed walkability adjusting for sociodemographic and health-related covariates. RESULTS: Compared to others, residing in an objectively assessed high walkable neighbourhood, women, having a college education, at least one child at home, a household income >=$120 000/year, and a registered motor vehicle at home, reporting very good-to-excellent health and healthy weight, and achieving 60 min/week of vigorous-intensity physical activity were associated (p<0.05) with less leisure-based screen time. Marital status, dog ownership, season, self-reported walkability and achieving 210 min of moderate intensity physical activity were not significantly associated with leisure-based screen time. CONCLUSIONS: Improving neighbourhood walkability could decrease leisure-based television and computer screen time. Programmes aimed at reducing sedentary behaviour may want to consider an individual's sociodemographic characteristics, physical activity level, health status and weight status, in addition to the walkability of their neighbourhood as these factors were found to be important independent correlates of leisure-based screen time. PMID- 26608641 TI - Postdischarge mortality in children with acute infectious diseases: derivation of postdischarge mortality prediction models. AB - OBJECTIVES: To derive a model of paediatric postdischarge mortality following acute infectious illness. DESIGN: Prospective cohort study. SETTING: 2 hospitals in South-western Uganda. PARTICIPANTS: 1307 children of 6 months to 5 years of age were admitted with a proven or suspected infection. 1242 children were discharged alive and followed up 6 months following discharge. The 6-month follow up rate was 98.3%. INTERVENTIONS: None. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was postdischarge mortality within 6 months following the initial hospital discharge. RESULTS: 64 children died during admission (5.0%) and 61 died within 6 months of discharge (4.9%). Of those who died following discharge, 31 (51%) occurred within the first 30 days. The final adjusted model for the prediction of postdischarge mortality included the variables mid-upper arm circumference (OR 0.95, 95% CI 0.94 to 0.97, per 1 mm increase), time since last hospitalisation (OR 0.76, 95% CI 0.61 to 0.93, for each increased period of no hospitalisation), oxygen saturation (OR 0.96, 95% CI 0.93 to 0.99, per 1% increase), abnormal Blantyre Coma Scale score (OR 2.39, 95% CI 1.18 to 4.83), and HIV-positive status (OR 2.98, 95% CI 1.36 to 6.53). This model produced a receiver operating characteristic curve with an area under the curve of 0.82. With sensitivity of 80%, our model had a specificity of 66%. Approximately 35% of children would be identified as high risk (11.1% mortality risk) and the remaining would be classified as low risk (1.4% mortality risk), in a similar cohort. CONCLUSIONS: Mortality following discharge is a poorly recognised contributor to child mortality. Identification of at-risk children is critical in developing postdischarge interventions. A simple prediction tool that uses 5 easily collected variables can be used to identify children at high risk of death after discharge. Improved discharge planning and care could be provided for high risk children. PMID- 26608642 TI - Assessing potentially inappropriate prescribing (PIP) and predicting patient outcomes in Ontario's older population: a population-based cohort study applying subsets of the STOPP/START and Beers' criteria in large health administrative databases. AB - INTRODUCTION: Adverse drug events (ADEs) are common in older people and contribute significantly to emergency department (ED) visits, unplanned hospitalisations, healthcare costs, morbidity and mortality. Many ADEs are avoidable if attention is directed towards identifying and preventing inappropriate drug use and undesirable drug combinations. Tools exist to identify potentially inappropriate prescribing (PIP) in clinical settings, but they are underused. Applying PIP assessment tools to population-wide health administrative data could provide an opportunity to assess the impact of PIP on individual patients as well as on the healthcare system. This would open new possibilities for interventions to monitor and optimise medication management on a broader, population-level scale. METHODS AND ANALYSIS: The aim of this study is to describe the occurrence of PIP in Ontario's older population (aged 65 years and older), and to assess the health outcomes and health system costs associated with PIP-more specifically, the association between PIP and the occurrence of ED visits, hospitalisations and death, and their related costs. This will be done within the framework of a population-based retrospective cohort study using Ontario's large health administrative and population databases. Eligible patients aged 66 years and older who were issued at least 1 prescription between 1 April 2003 and 31 March 2014 (approximately 2 million patients) will be included. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Ottawa Health Services Network Ethical Review Board and from the Bruyere Research Institute Ethics Review Board. Dissemination will occur via publication, presentation at national and international conferences, and ongoing exchanges with regional, provincial and national stakeholders, including the Ontario Drug Policy Research Network and the Ontario Ministry of Health and Long-Term Care. TRIAL REGISTRATION NUMBER: Registered with clinicaltrials.gov (registration number: NCT02555891). PMID- 26608644 TI - Elevated CO2-induced production of nitric oxide (NO) by NO synthase differentially affects nitrate reductase activity in Arabidopsis plants under different nitrate supplies. AB - CO2 elevation often alters the plant's nitrate reductase (NR) activity, the first enzyme acting in the nitrate assimilation pathway. However, the mechanism underlying this process remains unknown. The association between elevated CO2 induced alterations of NR activity and nitric oxide (NO) was examined in Col-0 Arabidopsis fed with 0.2-10 mM nitrate, using NO donors, NO scavenger, and NO synthase (NOS) inhibitor. The noa1 mutant, in which most NOS activity was lost, and the NR activity-null mutant nia1 nia2 were also used to examine the above association. In response to CO2 elevation, NR activity increased in low-nitrate Col-0 plants but was inhibited in high-nitrate Col-0 plants. NO scavenger and NOS inhibitor could eliminate these two responses, whereas the application of NO donors mimicked these distinct responses in ambient CO2-grown Col-0 plants. Furthermore, in both low- and high-nitrate conditions, elevated CO2 increased NOS activity and NO levels in Col-0 and nia1 nia2 plants but had little effect on NO level and NR activity in noa1 plants. Considering all of these findings, this study concluded that, in response to CO2 elevation, either the NR activity induction in low-nitrate plants or the NR activity inhibition in high-nitrate plants is regulated by NOS-generated NO. PMID- 26608643 TI - FLOURY ENDOSPERM7 encodes a regulator of starch synthesis and amyloplast development essential for peripheral endosperm development in rice. AB - In cereal crops, starch synthesis and storage depend mainly on a specialized class of plastids, termed amyloplasts. Despite the importance of starch, the molecular machinery regulating starch synthesis and amyloplast development remains largely unknown. Here, we report the characterization of the rice (Oryza sativa) floury endosperm7 (flo7) mutant, which develops a floury-white endosperm only in the periphery and not in the inner portion. Consistent with the phenotypic alternation in flo7 endosperm, the flo7 mutant had reduced amylose content and seriously disrupted amylopectin structure only in the peripheral endosperm. Notably, flo7 peripheral endosperm cells showed obvious defects in compound starch grain development. Map-based cloning of FLO7 revealed that it encodes a protein of unknown function. FLO7 harbors an N-terminal transit peptide capable of targeting functional FLO7 fused to green fluorescent protein to amyloplast stroma in developing endosperm cells, and a domain of unknown function 1338 (DUF1338) that is highly conserved in green plants. Furthermore, our combined beta-glucuronidase activity and RNA in situ hybridization assays showed that the FLO7 gene was expressed ubiquitously but exhibited a specific expression in the endosperm periphery. Moreover, a set of in vivo experiments demonstrated that the missing 32 aa in the flo7 mutant protein are essential for the stable accumulation of FLO7 in the endosperm. Together, our findings identify FLO7 as a unique plant regulator required for starch synthesis and amyloplast development within the peripheral endosperm and provide new insights into the spatial regulation of endosperm development in rice. PMID- 26608646 TI - Plant cell wall extensibility: connecting plant cell growth with cell wall structure, mechanics, and the action of wall-modifying enzymes. AB - The advent of user-friendly instruments for measuring force/deflection curves of plant surfaces at high spatial resolution has resulted in a recent outpouring of reports of the 'Young's modulus' of plant cell walls. The stimulus for these mechanical measurements comes from biomechanical models of morphogenesis of meristems and other tissues, as well as single cells, in which cell wall stress feeds back to regulate microtubule organization, auxin transport, cellulose deposition, and future growth directionality. In this article I review the differences between elastic modulus and wall extensibility in the context of cell growth. Some of the inherent complexities, assumptions, and potential pitfalls in the interpretation of indentation force/deflection curves are discussed. Reported values of elastic moduli from surface indentation measurements appear to be 10- to >1000-fold smaller than realistic tensile elastic moduli in the plane of plant cell walls. Potential reasons for this disparity are discussed, but further work is needed to make sense of the huge range in reported values. The significance of wall stress relaxation for growth is reviewed and connected to recent advances and remaining enigmas in our concepts of how cellulose, hemicellulose, and pectins are assembled to make an extensible cell wall. A comparison of the loosening action of alpha-expansin and Cel12A endoglucanase is used to illustrate two different ways in which cell walls may be made more extensible and the divergent effects on wall mechanics. PMID- 26608645 TI - AtCNGC2 is involved in jasmonic acid-induced calcium mobilization. AB - Calcium (Ca(2+)) mobilization is a central theme in various plant signal transduction pathways. We demonstrate that Arabidopsis thaliana cyclic nucleotide gated channel 2 (AtCNGC2) is involved in jasmonic acid (JA)-induced apoplastic Ca(2+) influx in Arabidopsis epidermal cells. Ca(2+) imaging results showed that JA can induce an elevation in the cytosolic cAMP concentration ([cAMP]cyt), reaching a maximum within 3 min. Dibutyryl cAMP (db-cAMP), a cell membrane permeable analogue of cAMP, induced an increase in the cytosolic Ca(2+) concentration ([Ca(2+)]cyt), with a peak at 4 min. This [Ca(2+)]cyt increase was triggered by the JA-induced increase in [cAMP]cyt. W-7[N-(6-aminohexyl)-5-chloro 1-naphthalenesulfonamide], an antagonist of calmodulin, positively modulated the JA-induced increase in [Ca(2+)]cyt, while W-5[N-(6-aminohexyl)-1 naphthalenesulfonamide], an inactive antagonist of calmodulin, had no apparent effect. db-cAMP and JA positively induced the expression of primary (i.e. JAZ1 and MYC2) and secondary (i.e. VSP1) response genes in the JA signalling pathway in wild-type Arabidopsis thaliana, whereas they had no significant effect in the AtCNGC2 mutant 'defense, no death (dnd1) plants. These data provide evidence that JA first induces the elevation of cAMP, and cAMP, as an activating ligand, activates the AtCNGC2 channel, resulting in apoplastic Ca(2+) influx through AtCNGC2. PMID- 26608647 TI - Gonadotropin-mediated chemoresistance: Delineation of molecular pathways and targets. AB - BACKGROUND: Human chorionic gonadotropin (hCG) has essential roles in pregnancy. Reports linking hCG in non-trophoblastic tumors with poor patient prognosis has spurred interest in patho-physiological roles the hormone might play. METHODS: The ability of hCG to prevent tumor cell death and sustain viability in the presence of chemotherapeutic drugs was assessed and potential synergies with TLR ligands explored. hCG-induced up-modulation of genes involved in chemoresistance was documented and targets validated by siRNA knock-down. Whether hCG could drive collaboration between tumor cells and macrophages in the production of IL-6 and consequent chemoresistance was assessed. The effects of concurrent anti-hCG immunization and chemotherapy on the growth of syngeneic murine tumors were evaluated. RESULTS: hCG maintained basal levels of cytokine secretion by tumor cells exposed to chemotherapeutic drugs, and enhanced viability and proliferation; pre-treatment with hCG also decreased apoptosis, as assessed by Annexin-V binding and the cleavage of caspase 3. While co-incubation with hCG along with several TLR ligands mediated heightened chemo-resistance, TLR-2/6 and TLR-9 ligands increased the phosphorylation of JNK, and TLR-2 and TLR-8 ligands the phosphorylation of ERK in presence of hCG and curcumin, providing evidence of tri-molecular synergy. The hormone increased the transcription and/or expression of molecular intermediates (SURVIVIN, HIF-1alpha, PARP-1, Bcl-2, c-FLIP, KLK-10, XIAP, c-IAP-1) associated with chemo-resistance and increased levels of stress modulators (PON2, HO-1, HSP27 and NRF-2). siRNAs to SURVIVIN, NRF-2, HO-1 and HIF 1alpha attenuated hCG-mediated chemo-resistance. hCG-conditioned tumor cell supernatants induced heightened secretion of IL-6 and TNF-alpha from peripheral blood adherent cells and secreted IL-6 imparted chemo-resistance to naive tumor cells. Co-administration of curcumin along with an anti-hCG vaccine (hCGbeta conjugated to Tetanus Toxoid (TT)) to mice carrying syngeneic tumors resulted in significantly enhanced benefits on animal survival; synergy was demonstrated between anti-hCG antibodies and curcumin in the reduction of tumor cell viability. CONCLUSIONS: The data suggest that hCG, via direct as well as collaborative effects with TLR ligands and accessory cell-secreted cytokines, mediates chemo-resistance in gonadotropin-sensitive tumors and outlines the potential benefits of combination therapy. PMID- 26608648 TI - Lithium protects dopaminergic cells from rotenone toxicity via autophagy enhancement. AB - BACKGROUND: Previous studies have indicated that enhancement of autophagy lysosome pathway may be beneficial for Parkinson's disease (PD), in which aberrant accumulation of aggregated/misfolded proteins and mitochondrial dysfunction are considered as crucial pathogenesis. Recently, a number of studies have suggested the neuroprotective effects of lithium in models of several neurodegenerative diseases including PD. However, the exact mechanisms underlying this neuroprotection remain unclear. In our study, rotenone-exposed SH-SY5Y cells were used as an in vitro parkinsonian model to assess the autophagy-enhancing effect of lithium and the underlying mechanisms were further investigated. RESULTS: Similar to the common used autophagy enhancer rapamycin (Rap, 0.2 MUM), lithium (LiCl, 10 mM) significantly recovered the shrinkage of SH-SY5Y cells, and alleviated rotenone-induced cell apoptosis, mitochondrial membrane potential reduction and reactive oxygen species accumulation. Furthermore, the protective effects induced by LiCl were partially blocked by the co-treatment of autophagy inhibitors such as 3-methyladenine (3-MA, 10 mM) or chloroquine (CHL, 10 MUM). Moreover, 3-MA or Chl suppressed LiCl-induced autophagy in the immunoblot assay. In addition, the co-localization of LC3 and mitochondria and the preservation of mitochondrial function within LiCl-treated cells were observed, confirming that the damaged mitochondria were cleared through autophagy (mitophagy). CONCLUSIONS: These findings suggested that lithium exerted neuroprotection against rotenone induced injuries partially through the autophagy pathway. Pharmacologically induction of autophagy by lithium may represent a novel therapeutic strategy as a disease-modifier in PD. PMID- 26608649 TI - Weight loss therapy for clinical management of patients with some atherosclerotic diseases: a randomized clinical trial. AB - BACKGROUND: The prevalence and burden of atherosclerotic (AS) diseases are increasing during the last twenty years. Some studies show a close relationship between overweight and AS, but influence on AS diseases of different weight loss methods are still studying. The purpose of the research was to study the effectiveness of a weight loss program in AS patients in randomized controlled trial, and to develop a conception of evolution of AS. METHODS: A randomized controlled prospective clinical trial including 97 people, from them 71 patients with various AS manifestations. Patients were divided in 2 subgroups for non-drug weight loss program, and conventional drug therapy. The weight loss program included calorie restriction with 100-150 kcal/day, fat-free vegetables, salt diet, and optimum physical activity. Statistical analysis was performed using SPSS for Windows version 17.0. RESULTS: The weight loss subgroup lost ranging between 7-20% from an initial weight (P = 0.016). Weight loss was achieved due to fatty mass reduction only (P = 0.005). Hemoglobin levels (P < 0.001), bone mineral density (P < 0.001), percentages of water (P = 0.006) and muscle masses (P = 0.0038) were increased in weight loss subgroup. Ejection fraction (P < 0.0001), systolic output (P < 0.0001) were increased in patients with coronary artery disease. The weight loss program led to a decrease in symptomatic drugs doses up to total abolition. A conception of AS was developed. CONCLUSIONS: The weight loss program treated the AS diseases; improved laboratory and instrumental parameters, decreased symptomatic drugs doses. AS development is a logical way of ontogenetic ageing of body fat. TRIAL INTERNATIONAL REGISTRATION: ClinicalTrials.gov NCT01700075. TRIAL NATIONAL REGISTRATION: State registration is # 0109RK000079, code is O.0475 at the National Center for Scientific and Technical Information of the Republic of Kazakhstan. PMID- 26608650 TI - Acculturation, perceived discrimination, and psychological distress: Experiences of South Asians in Hong Kong. AB - Although migration itself may not compromise the mental health of immigrants, the acculturative process can involve highly stressful factors that are specific to immigrant and minority status. Using structural equation modeling, this study examined the relations between acculturation orientations, perceived discrimination, acculturative stress, and psychological distress among 229 Pakistani and 218 Nepalese migrants living in Hong Kong. Although the initial hypothesized model was not confirmed, a modified model with good fit indices showed that acculturation orientation mediated the relationships of perceived discrimination and acculturative stress with psychological distress. Of all the factors in the model, acculturative stress had the strongest association with psychological distress. PMID- 26608651 TI - Visualization of the glomerular endothelial glycocalyx by electron microscopy using cationic colloidal thorium dioxide. AB - Biological material itself appears with poor contrast in electron microscopy (EM), due to its composition mostly of light elements. Classical staining agents such as osmium tetroxide, uranyl acetate, and lead citrate preserve and/or stain cellular structures such as membranes, cytoplasm, and organelles well for EM. However, extracellular polymeric substances (EPS) show no or only poor contrast with these staining agents. The endothelial glycocalyx in blood vessels consists mainly of proteoglycans. It can be visualized by EM only by additional staining with heavy metal ions such as copper (Alcian blue, cupromeronic blue), ruthenium (ruthenium red), or lanthanum. Best results are achieved by combined perfusion of fixative and stain. Cationic hydrous thorium dioxide colloids (named here cThO2) trace acidic groups in EPS. We describe here the use of cThO2 to visualize the glomerular endothelial glycocalyx in the mouse kidney. cThO2 shows high electron density and binds to a continuous layer of up to a few hundred nanometers thickness on the glomerular endothelium, as well as on epithelia in other blood vessels in perfused animals. The observed staining pattern gives rise to periodic densities, with a spacing varying between 50 and 200 nm, depending on the overall layer thickness, which varies between below 50 up to 300 nm. Due to high electron density of the used cThO2 particles, the introduced method allows distinct imaging and precise fine structural analysis of the endothelial glycocalyx. PMID- 26608652 TI - Patient prosthesis mismatch in adult congenital heart disease. PMID- 26608654 TI - Human insulin dynamics in women: a physiologically based model. AB - Currently available models of insulin dynamics are mostly based on the classical compartmental structure and, thus, their physiological utility is limited. In this work, we describe the development of a physiologically based model and its application to data from 154 patients who underwent an insulin-modified intravenous glucose tolerance test (IM-IVGTT). To determine the time profile of endogenous insulin delivery without using C-peptide data and to evaluate the transcapillary transport of insulin, the hepatosplanchnic, renal, and peripheral beds were incorporated into the circulatory model as separate subsystems. Physiologically reasonable population mean estimates were obtained for all estimated model parameters, including plasma volume, interstitial volume of the peripheral circulation (mainly skeletal muscle), uptake clearance into the interstitial space, hepatic and renal clearance, as well as total insulin delivery into plasma. The results indicate that, at a population level, the proposed physiologically based model provides a useful description of insulin disposition, which allows for the assessment of muscle insulin uptake. PMID- 26608653 TI - Evaluation of chemopreventive potential of Strobilanthes crispus against colon cancer formation in vitro and in vivo. AB - BACKGROUND: With cancer being one of the major causes of death around the world, studies are ongoing to find new chemotherapeutic leads. There are common mechanisms for colorectal cancer (CRC) formation. Several are connected with oxidative stress-induced cell apoptosis and others are related to imbalanced homeostasis or intake of drugs/toxins. Plants that have been used for decades in folk and traditional medicine have been accepted as one of the commonest sources of discovered natural agents of cancer chemotherapy and chemoprevention. The aim was to study the antioxidant and chemopreventive effects of Strobilanthes crispus on colorectal cancer formation. METHODS: Five groups of rats were injected subcutaneously with AOM, 15 mg/kg body weight, each once weekly for 2 weeks. The cancer group was continued on 10 % Tween-20 feeding for 8 weeks. The standard drug group was continued on 35 mg/kg 5-fluorouracil intraperitoneal injection twice a week for 8 weeks, and the experimental groups were continued on 250 and 500 mg/kg S. crispus extract oral feeding for 8 weeks, respectively. The normal group was injected subcutaneously with normal saline once a week for 2 weeks, followed by oral administration of 10 % Tween-20 for 8 weeks. All the rats were sacrificed after 10 weeks. The colons were evaluated grossly and histopathologically for aberrant crypt foci (ACF). Gene expression was performed for Bax, Bcl2, Defa24, Slc24a3, and APC genes by real-time PCR. S. crispus and its fractions were evaluated for their chemopreventive effects against human colorectal adenocarcinoma cell line HT29 and cytotoxicity for normal human colon epithelial cell line CCD 841, and the active fraction was assessed for its components. RESULTS: We observed significant decrease in total colonic ACF formation, malonaldehyde (MDA) and lactate dehydrogenase (LDH), increase in superoxide dismutase (SOD), up-regulation of APC, Bax and Slc24a3, and down regulation of Defa24 and Bcl-2 in rats treated with Strobilanthes crispus. CONCLUSION: Our results support the in vivo protection of S. crispus against CRC formation (azoxymethane-induced aberrant crypt foci) and suggest that the mechanism is highly specific to protect from oxidative insults and the following apoptotic cascade. PMID- 26608655 TI - Phenotypic plasticity in the common snapping turtle (Chelydra serpentina): long term physiological effects of chronic hypoxia during embryonic development. AB - Studies of embryonic and hatchling reptiles have revealed marked plasticity in morphology, metabolism, and cardiovascular function following chronic hypoxic incubation. However, the long-term effects of chronic hypoxia have not yet been investigated in these animals. The aim of this study was to determine growth and postprandial O2 consumption (Vo2), heart rate (fH), and mean arterial pressure (Pm, in kPa) of common snapping turtles (Chelydra serpentina) that were incubated as embryos in chronic hypoxia (10% O2, H10) or normoxia (21% O2, N21). We hypothesized that hypoxic development would modify posthatching body mass, metabolic rate, and cardiovascular physiology in juvenile snapping turtles. Yearling H10 turtles were significantly smaller than yearling N21 turtles, both of which were raised posthatching in normoxic, common garden conditions. Measurement of postprandial cardiovascular parameters and O2 consumption were conducted in size-matched three-year-old H10 and N21 turtles. Both before and 12 h after feeding, H10 turtles had a significantly lower fH compared with N21 turtles. In addition, Vo2 was significantly elevated in H10 animals compared with N21 animals 12 h after feeding, and peak postprandial Vo2 occurred earlier in H10 animals. Pm of three-year-old turtles was not affected by feeding or hypoxic embryonic incubation. Our findings demonstrate that physiological impacts of developmental hypoxia on embryonic reptiles continue into juvenile life. PMID- 26608656 TI - Noninflammatory upregulation of nerve growth factor underlies gastric hypersensitivity induced by neonatal colon inflammation. AB - Gastric hypersensitivity is one of the key contributors to the postprandial symptoms of epigastric pain/discomfort, satiety, and fullness in functional dyspepsia patients. Epidemiological studies found that adverse early-life experiences are risk factors for the development of gastric hypersensitivity. Preclinical studies found that neonatal colon inflammation elevates plasma norepinephrine (NE), which upregulates expression of nerve growth factor (NGF) in the muscularis externa of the gastric fundus. Our goal was to investigate the cellular mechanisms by which NE upregulates the expression of NGF in gastric hypersensitive (GHS) rats, which were subjected previously to neonatal colon inflammation. Neonatal colon inflammation upregulated NGF protein, but not mRNA, in the gastric fundus of GHS rats. Western blotting showed upregulation of p110gamma of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), phosphoinositide-dependent kinase-1 (PDK1), pAKT(Ser473), and phosphorylated 4E binding protein (p4E-BP1)(Thr70), suggesting AKT activation and enhanced NGF protein translation. AKT inhibitor MK-2206 blocked the upregulation of NGF in the fundus of GHS rats. Matrix metalloproteinase 9 (MMP-9), the major NGF-degrading protease, was suppressed, indicating that NGF degradation was impeded. Incubation of fundus muscularis externa with NE upregulated NGF by modulating the protein translation and degradation pathways. Yohimbine, an alpha2-adrenergic receptor antagonist, upregulated plasma NE and NGF expression by activating the protein translation and degradation pathways in naive rats. In contrast, a cocktail of adrenergic receptor antagonists suppressed the upregulation of NGF by blocking the activation of the protein translation and degradation pathways. Our findings provide evidence that the elevation of plasma NE induces NGF expression in the gastric fundus. PMID- 26608657 TI - Physiological and molecular ontogeny of branchial and extra-branchial urea excretion in posthatch rainbow trout (Oncorhynchus mykiss). AB - All teleost fish produce ammonia as a metabolic waste product. In embryos, ammonia excretion is limited by the chorion, and fish must detoxify ammonia by synthesizing urea via the ornithine urea cycle (OUC). Although urea is produced by embryos and larvae, urea excretion (J(urea)) is typically low until yolk sac absorption, increasing thereafter. The aim of this study was to determine the physiological and molecular characteristics of J(urea) by posthatch rainbow trout (Oncorhynchus mykiss). Following hatch, whole body urea concentration decreased over time, while J(urea) increased following yolk sac absorption. From 12 to 40 days posthatch (dph), extra-branchial routes of excretion accounted for the majority of J(urea), while the gills became the dominant site for J(urea) only after 55 dph. This represents the most delayed branchial ontogeny of any process studied to date. Urea transporter (UT) gene expression in the gills and skin increased over development, consistent with increases in branchial and extra branchial J(urea). Following exposure to 25 mmol/l urea, the accumulation and subsequent elimination of exogenous urea was much greater at 55 dph than 12 dph, consistent with increased UT expression. Notably, UT gene expression in the gills of 55 dph larvae increased in response to high urea. In summary, there is a clear increase in urea transport capacity over posthatch development, despite a decrease in OUC activity. PMID- 26608658 TI - Dahl SS rats demonstrate enhanced aortic perivascular adipose tissue-mediated buffering of vasoconstriction through activation of NOS in the endothelium. AB - Perivascular adipose tissue (PVAT) mediates buffering of vasoconstriction through activation of endothelium-derived factors. We hypothesized that the PVAT of Dahl salt-sensitive (Dahl SS) rats has reduced ability to buffer vasoconstriction. Vascular reactivity experiments were performed on aortic rings with PVAT intact (+PVAT) or removed (-PVAT), and endothelium intact (+ENDO) or removed (-ENDO) from Dahl SS rats and control SS.13(BN) rats (Dahl SS rats that have had chromosome 13 completely replaced with that of the Brown Norway rat, rendering this strain insensitive to high-salt or high-fat diet-induced hypertension). Endothelial dysfunction, assessed by ACh-mediated vasorelaxation, was confirmed in aortic rings of Dahl SS rats. The +PVAT+ENDO aortic rings had indistinguishable phenylephrine-induced vasoconstriction between genotypes. In both strains, removal of PVAT significantly enhanced vasoconstriction. Dahl SS rat -PVAT+ENDO aortic rings displayed exaggerated vasoconstriction to phenylephrine vs. SS.13(BN) rats, indicating that PVAT-mediated buffering of vasoconstriction was greater in Dahl SS rats. Removal of both the ENDO and PVAT restored vasoconstriction in both strains. The nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), produced a similar effect as that seen with -ENDO. These data indicate that the function of the PVAT to activate endothelium-derived NOS is enhanced in Dahl SS compared with SS.13(BN) rats and, most likely, occurs through a pathway that is distinct from ACh-mediated activation of NOS. PVAT weight and total PVAT leptin levels were greater in Dahl SS rats. Leptin induced a significantly decreased vasoconstriction in -PVAT+ENDO aortic rings from Dahl SS rats, but not SS.13(BN) rats. In contrast to our initial hypothesis, PVAT in Dahl SS rats buffers vasoconstriction by activating endothelial NOS via mechanisms that may include the involvement of leptin. Thus, the PVAT serves a vasoprotective role in Dahl SS rats on normal-salt diet. PMID- 26608659 TI - Norepinephrine-evoked salt-sensitive hypertension requires impaired renal sodium chloride cotransporter activity in Sprague-Dawley rats. AB - Recent studies have implicated a role of norepinephrine (NE) in the activation of the sodium chloride cotransporter (NCC) to drive the development of salt sensitive hypertension. However, the interaction between NE and increased salt intake on blood pressure remains to be fully elucidated. This study examined the impact of a continuous NE infusion on sodium homeostasis and blood pressure in conscious Sprague-Dawley rats challenged with a normal (NS; 0.6% NaCl) or high salt (HS; 8% NaCl) diet for 14 days. Naive and saline-infused Sprague-Dawley rats remained normotensive when placed on HS and exhibited dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide. NE infusion resulted in the development of hypertension, which was exacerbated by HS, demonstrating the development of the salt sensitivity of blood pressure [MAP (mmHg) NE+NS: 151 +/- 3 vs. NE+HS: 172 +/- 4; P < 0.05]. In these salt-sensitive animals, increased NE prevented dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide, suggesting impaired NCC activity contributes to the development of salt sensitivity [peak natriuresis to hydrochlorothiazide (MUeq/min) Naive+NS: 9.4 +/- 0.2 vs. Naive+HS: 7 +/- 0.1; P < 0.05; NE+NS: 11.1 +/- 1.1; NE+HS: 10.8 +/- 0.4). NE infusion did not alter NCC expression in animals maintained on NS; however, dietary sodium-evoked suppression of NCC expression was prevented in animals challenged with NE. Chronic NCC antagonism abolished the salt-sensitive component of NE-mediated hypertension, while chronic ANG II type 1 receptor antagonism significantly attenuated NE-evoked hypertension without restoring NCC function. These data demonstrate that increased levels of NE prevent dietary sodium-evoked suppression of the NCC, via an ANG II independent mechanism, to stimulate the development of salt-sensitive hypertension. PMID- 26608660 TI - Mapping murine diabetic kidney disease using chemical exchange saturation transfer MRI. AB - PURPOSE: Diabetic nephropathy (DN) is the leading cause of renal failure; however, current clinical tests are insufficient for assessing this disease. DN is associated with changes in renal metabolites, so we evaluated the utility of chemical exchange saturation transfer (CEST) imaging to detect changes characteristic of this disease. METHODS: Sensitivity of CEST imaging at 7 Tesla to DN was evaluated by imaging diabetic mice [db/db, db/db endothelial nitric oxide synthase (eNOS)-/-] that show different levels of nephropathy as well as by longitudinal imaging (8 to 24 weeks). Nondiabetic (db/m) mice were used as controls. RESULTS: Compared with nondiabetic mice, the CEST contrasts of hydroxyl metabolites that correspond to glucose and glycogen were significantly increased in papilla (P), inner medulla (IM), and outer medulla (OM) in db/db and db/db eNOS-/- kidneys at 16 weeks. The db/db eNOS-/- mice that showed advanced nephropathy exhibited greater CEST effects in OM and significant CEST contrasts were also observed in cortex. Longitudinally, db/db mice exhibited progressive increases in hydroxyl signals in IM+P and OM from 12 to 24 weeks and an increase was also observed in cortex at 24 weeks. CONCLUSION: CEST MRI can be used to measure changes of hydroxyl metabolites in kidney during progression of DN. Magn Reson Med 76:1531-1541, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26608661 TI - Wellington-bootstrap: differential DNase-seq footprinting identifies cell-type determining transcription factors. AB - BACKGROUND: The analysis of differential gene expression is a fundamental tool to relate gene regulation with specific biological processes. Differential binding of transcription factors (TFs) can drive differential gene expression. While DNase-seq data can provide global snapshots of TF binding, tools for detecting differential binding from pairs of DNase-seq data sets are lacking. RESULTS: In order to link expression changes with changes in TF binding we introduce the concept of differential footprinting alongside a computational tool. We demonstrate that differential footprinting is associated with differential gene expression and can be used to define cell types by their specific TF occupancy patterns. CONCLUSIONS: Our new tool, Wellington-bootstrap, will enable the detection of differential TF binding facilitating the study of gene regulatory systems. PMID- 26608662 TI - Detection of Capripoxvirus DNA Using a Field-Ready Nucleic Acid Extraction and Real-Time PCR Platform. AB - Capripoxviruses, comprising sheep pox virus, goat pox virus and lumpy skin disease virus cause serious diseases of domesticated ruminants, notifiable to The World Organization for Animal Health. This report describes the evaluation of a mobile diagnostic system (Enigma Field Laboratory) that performs automated sequential steps for nucleic acid extraction and real-time PCR to detect capripoxvirus DNA within laboratory and endemic field settings. To prepare stable reagents that could be deployed into field settings, lyophilized reagents were used that employed an established diagnostic PCR assay. These stabilized reagents demonstrated an analytical sensitivity that was equivalent, or greater than the established laboratory-based PCR test which utilizes wet reagents, and the limit of detection for the complete assay pipeline was approximately one log10 more sensitive than the laboratory-based PCR assay. Concordant results were generated when the mobile PCR system was compared to the laboratory-based PCR using samples collected from Africa, Asia and Europe (n = 10) and experimental studies (n = 9) representing clinical cases of sheep pox, goat pox and lumpy skin disease. Furthermore, this mobile assay reported positive results in situ using specimens that were collected from a dairy cow in Morogoro, Tanzania, which was exhibiting clinical signs of lumpy skin disease. These data support the use of mobile PCR systems for the rapid and sensitive detection of capripoxvirus DNA in endemic field settings. PMID- 26608663 TI - The distribution and characteristics of LDL receptor mutations in China: A systematic review. AB - Familial hypercholesterolemia (FH) is a common and serious dominant genetic disease, and its main pathogenic gene is the low-density lipoprotein receptor (LDLR) gene. This study aimed to perform a systematic review of LDLR mutations in China. Using PubMed, Embase, Wanfang (Chinese), the Chinese National Knowledge Infrastructure (Chinese), and the Chinese Biological and Medical database (Chinese), public data were limited to December 2014. The Medical Subject Headings terms and the following key words were used: "familial hypercholesterolemia", "Chinese", "China", "Hong Kong", and "Taiwan". A total of 74 studies including 295 probands with 131 LDLR mutations were identified. Most of the mutations were located in exon 4 of LDLR and approximately 60% of the mutations were missense mutations. Thirty new mutations that were not recorded in the LDLR databases were found. In silico analysis revealed that most of the mutations were pathogenic. The primary LDLR mutations were C308Y, H562Y, and A606T, and all of the mutations had functional significance. Prevalence data suggest that there are nearly 3.8 million FH patients in China, although reported numbers are much smaller, suggesting that FH is widely misunderstood. This systematic review provides information that is specific to China for inclusion in the international FH database. PMID- 26608665 TI - The effects of increasing garlic powder and monensin supplementation on feed intake, nutrient digestibility, growth performance and blood parameters of growing calves. AB - The objective of this study was to evaluate the effects of increasing garlic powder and monensin supplementation on feed intake, nutrient digestibility, growth performance and blood metabolites of growing calves. Forty Holstein calves (BW = 100 +/- 11 kg) were randomly assigned to four dietary treatments (n = 10) in a complete randomized design. Experimental treatments consisted of the following: (i) basal diet (control), (ii) basal diet supplemented with 0.0003% of dietary dry matter (DM) sodium monensin, (iii) low level of garlic powder (Low GAR; 0.5% of dietary DM) and (iv) high level of garlic powder (High-GAR; 1% of dietary DM). DM intake (DMI) and DM digestibility were (p < 0.05) decreased by High-GAR. However, calves supplemented with Low-GAR had a similar DMI to the control calves and similar DM digestibility to the control and monensin groups. The digestibility of other nutrients were not affected by the treatments. Although supplementing monensin relative to Low-GAR increased the DMI (p < 0.05), average daily gain was similar between Low-GAR and monensin supplemented calves, which were higher than the control and High-GAR groups (p < 0.05). As a result, feed conversion ratio was improved in the Low-GAR group versus other treatment groups (p < 0.05). Administrating garlic powder decreased the blood low-density lipoprotein (LDL) and non-esterified fatty acids (p < 0.05) without affecting the blood triglyceride, high-density lipoprotein and beta-hydroxybutyric acid concentrations. In conclusion, the calves fed the Low-GAR showed an improved FCR and blood metabolites without changing the DMI and nutrient digestibility. It suggests that garlic powder could be used as an alternative to monensin for growing calves under the current feeding conditions. PMID- 26608664 TI - Effectiveness of acupuncture and related therapies for palliative care of cancer: overview of systematic reviews. AB - Acupuncture and related therapies such as moxibustion and transcutaneous electrical nerve stimulation are often used to manage cancer-related symptoms, but their effectiveness and safety are controversial. We conducted this overview to summarise the evidence on acupuncture for palliative care of cancer. Our systematic review synthesised the results from clinical trials of patients with any type of cancer. The methodological quality of the 23 systematic reviews in this overview, assessed using the Methodological Quality of Systematic Reviews Instrument, was found to be satisfactory. There is evidence for the therapeutic effects of acupuncture for the management of cancer-related fatigue, chemotherapy induced nausea and vomiting and leucopenia in patients with cancer. There is conflicting evidence regarding the treatment of cancer-related pain, hot flashes and hiccups, and improving patients' quality of life. The available evidence is currently insufficient to support or refute the potential of acupuncture and related therapies in the management of xerostomia, dyspnea and lymphedema and in the improvement of psychological well-being. No serious adverse effects were reported in any study. Because acupuncture appears to be relatively safe, it could be considered as a complementary form of palliative care for cancer, especially for clinical problems for which conventional care options are limited. PMID- 26608666 TI - The chemoattractant potential of ginsenosides in the ginseng - Pythium irregulare pathosystem. AB - Ginsenosides produced by ginseng (Panax quinquefolius L.) are mildly fungitoxic saponins; however, exposure of the ginseng root pathogen Pythium irregulare Buisman to ginsenosides enhances its growth in a dose dependent manner, leading to speculation that ginsenosides may function as chemoattractants and/or growth regulators in the context of the ginseng - P. irregulare pathosystem. In the present work, it was demonstrated that the treatment of ginseng plants with a relatively high dose of ginsenosides by dipping their roots into a solution of ginsenosides prior to planting results in delayed infection by P. irregulare in pot experiments, as monitored by non-invasive chlorophyll fluorescence imaging. In an attempt to determine whether this observation results from a protective effect of the ginsenosides, or from a modification of P. irregulare growth habit in response to ginsenosides present in the soil, standard in vitro disk diffusion assays were conducted. Here, exposure of P. irregulare to crude ginsenosides or pure ginsenoside Rb1, resulted in delayed hyphal progression, while enhancing aerial hyphae build-up around ginsenoside-treated disks. By contrast, assays with pure ginsenoside F2 resulted in clear zones of inhibition around treated disks. While it remains unclear whether ginsenosides act as chemoattractants for P. irregulare in vivo, the results here suggest that these saponins serve to alter the growth habit of this organism, both in vivo and in vitro. PMID- 26608667 TI - ARF7 increases the endogenous contents of castasterone through suppression of BAS1 expression in Arabidopsis thaliana. AB - Homeostasis of brassinosteroids (BRs) maintained by the balance between their biosynthesis and inactivation is important to coordinate the diverse physiological and developmental responses of plants. Although BR signaling regulates the endogenous levels of BRs via negative feedback regulation, it remains largely unknown how the biosynthesis and inactivation of BR are triggered. BAS1 encodes CYP734A1, which inactivates the biologically active BRs via C-26 hydroxylation and is down-regulated by a BR-responsive transcription factor, BZR1. Here it is demonstrated that the expression of the BAS1 gene is regulated by auxin response factors (ARFs) in Arabidopsis thaliana. Two successive E-box motifs on the BAS1 promoter function as BZR1 binding sites and are essential for BR-regulated BAS1 expression. The expression of BAS1 is increased in the arf7 and arf7arf19 mutants. The endogenous level of bioactive BR, castasterone, is greatly decreased in those mutants. ARF7 can bind to the E box motifs of the BAS1 promoter where BZR1 binds, suggesting that ARF7 and BZR1 mutually compete for the same cis-element of the BAS1 promoter. Additionally, ARF7 directly interacts with BZR1, which inhibits their DNA binding activities and regulation of BAS1 expression. In conclusion, auxin signaling via ARF7 directly modulates the expression of BAS1 by competition with BZR1, thereby increasing the level of castasterone and promoting growth and development in A. thaliana. PMID- 26608668 TI - Intraspecific variation in essential oil composition of the medicinal plant Lippia integrifolia (Verbenaceae). Evidence for five chemotypes. AB - The aerial parts of Lippia integrifolia (incayuyo) are widely used in northwestern and central Argentina for their medicinal and aromatic properties. The essential oil composition of thirty-one wild populations of L. integrifolia covering most of its natural range was analyzed by GC and GC-MS. A total of one hundred and fifty two terpenoids were identified in the essential oils. Sesquiterpenoids were the dominant components in all but one of the collections analyzed, the only exception being a sample collected in San Juan province where monoterpenoids amounted to 51%. Five clearly defined chemotypes were observed. One possessed an exquisite and delicate sweet aroma with trans-davanone as dominant component (usually above 80%). Another with an exotic floral odour was rich in oxygenated sesquiterpenoids based on the rare lippifoliane and africanane skeletons. The trans-davanone chemotype is the first report of an essential oil containing that sesquiterpene ketone as the main constituent. The absolute configuration of trans-davanone from L. integrifolia was established as 6S, 7S, 10S, the enantiomer of trans-davanone from 'davana oil' (Artemisia pallens). Wild plants belonging to trans-davanone and lippifolienone chemotypes were propagated and cultivated in the same parcel of land in Santa Maria, Catamarca. The essential oil compositions of the cultivated plants were essentially identical to the original plants in the wild, indicating that the essential oil composition is largely under genetic control. Specimens collected near the Bolivian border that initially were identified as L. boliviana Rusby yielded an essential oil practically identical to the trans-davanone chemotype of L. integrifolia supporting the recent view that L. integrifolia (Gris.) Hieron. and L. boliviana Rusby are synonymous. PMID- 26608669 TI - Triterpenes from the exudate of Gardenia urvillei. AB - A cycloartane gardurvilleic acid, three 3,4-seco-cycloartanes securvienol, secodienurvilleic acid, securvitriol, a 3,4;9,10-seco-cycloartane gardheptlactone, two dammaranes urvilone, urvilol, along with eight known cycloartanes and 3,4-seco-cycloartanes and four known dammaranes have been isolated from the bud exudate of Gardenia urvillei, an endemic tree to the New Caledonian dry forest. Two other dammarane derivatives have been obtained by semisynthesis. The structures of the original compounds were determined by spectroscopic methods and chemical correlations. In association with previously published data, the description of oxidized side-chains in position 17 are now available for two couples of diastereoisomers. Evaluation of anti-parasite activity and cytotoxicity has shown noticeable results for some of the isolated triterpenes. PMID- 26608670 TI - Temperature-Dependent Hydrocarbon Chain Disorder in Phosphatidylcholine Bilayers Studied by Raman Spectroscopy. AB - Raman scattering of five phosphatidylcholines [1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine (POPC), 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine (DPPC), 1,2 dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dilinoleoyl-sn-glycero-3 phosphocholine (DLPC), and 1,2-dilignoceroyl-sn-glycero-3-phosphocholine (PC24)] was studied in a wide temperature range. These phospholipid bilayers differ in the temperature of the gel-fluid transition Tm (from -57 to +80 degrees C) and in the number of unsaturated bonds. For all lipids, the temperature dependence of both asymmetrical methylene stretching and C-C stretching bands provides evidence that the disordering processes occur significantly below Tm. Temperature onset of the decrease of Raman intensity of the asymmetrical methylene stretching band is the same for unsaturated lipids (DLPC, POPC, and DOPC), which was interpreted as the importance of packing defects in the bilayers of these phospholipids. The chain conformational order was characterized by Raman intensity of the high frequency C-C stretching mode. An approach was used where the Raman intensity of this mode serves as a measure of hydrocarbon chains in the ground conformational state. Temperature dependence of the chains in the ground conformational state was well described by a simple model with the ground and two excited states: the kinked state and the highly disordered, fluidlike state. PMID- 26608671 TI - Evaluation of drug-drug interaction between henagliflozin, a novel sodium-glucose co-transporter 2 inhibitor, and metformin in healthy Chinese males. AB - 1. Henagliflozin is a novel sodium-glucose transporter 2 inhibitor and presents a complementary therapy to metformin for patients with T2DM due to its insulin independent mechanism of action. This study evaluated the potential pharmacokinetic drug-drug interaction between henagliflozin and metformin in healthy Chinese male subjects. 2. In open-label, single-center, single-arm, two period, three-treatment self-control study, 12 subjects received 25 mg henagliflozin, 1000 mg metformin or the combination. Lack of PK interaction was defined as the ratio of geometric means and 90% confidence interval (CI) for combination: monotherapy being within the range of 0.80-1.25. 3. Co administration of henagliflozin with metformin had no effect on henagliflozin area under the plasma concentration-time curve (AUC0-24) (GRM: 1.08; CI: 1.05, 1.10) and peak plasma concentration (Cmax) (GRM: 0.99; CI: 0.92, 1.07). Reciprocally, co-administration of metformin with henagliflozin had no clinically significant on metformin AUC0-24 (GRM: 1.09, CI: 1.02, 1.16) although there was an 11% increase in metformin Cmax (GRM 1.12; CI 1.02, 1.23). All monotherapies and combination therapy were well tolerated. 4. Henagliflozin can be co administered with metformin without dose adjustment of either drug. PMID- 26608673 TI - Healthcare professionals in war zones are vulnerable too. PMID- 26608672 TI - Matrix metalloproteinase-12 is an essential mediator of acute and chronic arterial stiffening. AB - Arterial stiffening is a hallmark of aging and risk factor for cardiovascular disease, yet its regulation is poorly understood. Here we use mouse modeling to show that matrix metalloproteinase-12 (MMP12), a potent elastase, is essential for acute and chronic arterial stiffening. MMP12 was induced in arterial smooth muscle cells (SMCs) after acute vascular injury. As determined by genome-wide analysis, the magnitude of its gene induction exceeded that of all other MMPs as well as those of the fibrillar collagens and lysyl oxidases, other common regulators of tissue stiffness. A preferential induction of SMC MMP12, without comparable effect on collagen abundance or structure, was also seen during chronic arterial stiffening with age. In both settings, deletion of MMP12 reduced elastin degradation and blocked arterial stiffening as assessed by atomic force microscopy and immunostaining for stiffness-regulated molecular markers. Isolated MMP12-null SMCs sense extracellular stiffness normally, indicating that MMP12 causes arterial stiffening by remodeling the SMC microenvironment rather than affecting the mechanoresponsiveness of the cells themselves. In human aortic samples, MMP12 levels strongly correlate with markers of SMC stiffness. We conclude that MMP12 causes arterial stiffening in mice and suggest that it functions similarly in humans. PMID- 26608674 TI - Using workload measurement tools in diverse care contexts: the experience of staff in mental health and learning disability inpatient settings. AB - ACCESSIBLE SUMMARY: What is known on the subject? Difficulties with the recruitment and retention of qualified nursing staff have resulted in nursing shortages worldwide with a consequential impact on the quality of care. It is increasingly recommended that evidence-based staffing levels are central to the development of workforce plans. Due to a paucity of empirical research in mental health and learning disability services the staffing needs and requirements for these settings are undefined and the availability of tools to aid staffing decisions is limited. What this paper adds to existing knowledge? This paper provides a valuable insight into the practical uses of these tools as perceived by staff members with day-to-day experience of the requirements of mental health and learning disability wards. It reveals that while workload measurement tools are considered a valuable aid for the development of workforce plans, they are limited in their ability to capture all aspects of care provision in these settings. It further emphasizes the inapplicability of a one-shoe-fits-all approach for determining nurse staffing levels and the need for individual and customized workforce plans. What are the implications for practice? This study demonstrates that the development of tools for use in mental health and learning disability services is in its infancy, yet no tool that has been validated as such. It highlights the potential for workload measurement tools to aid staffing decisions; however, a more holistic approach that considers additional factors is needed to ensure robust workforce planning models are developed for these services. ABSTRACT: INTRODUCTION: The critical challenge of determining the correct level and skill mix of nursing staff required to deliver safe and effective health care has become an international concern. It is recommended that evidence-based staffing decisions are central to the development of future workforce plans. Workforce planning in mental health and learning disability nursing is largely under-researched with few tools available to aid the development of evidence-based staffing levels in these environments. AIM: It was the aim of this study to explore the experience of staff using the Safer Nursing Care Tool and the Mental Health and Learning Disability Workload Tool in mental health and learning disability environments. METHOD: Following a 4-week trial period of both tools, a survey was distributed via Qualtrics online survey software to staff members who used the tools during this time. RESULTS: The results of the survey revealed that the tools were considered a useful resource to aid staffing decisions; however, specific criticisms were highlighted regarding their suitability to psychiatric intensive care units and learning disability wards. DISCUSSION: This study highlights that further development of workload measurement tools is required to support the implementation of effective workforce planning strategies within mental health and learning disability services. IMPLICATIONS FOR PRACTICE: With increasing fiscal pressures, the need to provide cost-effective care is paramount within the services of the National Health Service. Evidence-based workforce planning is therefore necessary to ensure that appropriate levels of staff are determined. This is of particular importance within mental health and learning disability services due to the reduction in the number of available beds and an increasing focus on purposeful admission and discharge. PMID- 26608675 TI - Putting 'quality' in qualitative research: a guide to grounded theory for mental health nurses. PMID- 26608676 TI - Towards a critical understanding of mutuality in mental healthcare: relationships, power and social capital. PMID- 26608677 TI - Mental health nurses: a key resource for tackling the challenges of public mental health. PMID- 26608679 TI - Potential use of scotta, the by-product of the ricotta cheese manufacturing process, for the production of fermented drinks. AB - In the present work, the use of scotta as substrate for bacterial fermentation was studied with the objective of obtaining a drink from transformation of this by-product. Scotta retains most of the lactose of the milk and it is normally colonized by a natural microbiota. A treatment was devised to reduce the autochthonous microbial populations in order to reduce competition towards the inoculated bacterial strains. Nine lactic acid bacteria (LAB) were assessed for their capability to develop in scotta. They evidenced different behaviors regarding growth rate, acidification capability and nitrogen consumption. A co inoculum of three LAB, namely a Streptococcus thermophilus, a Lactobacillus delbrueckii subsp. bulgaricus and a Lb. acidophilus strains, chosen among those giving the best performances in single-strain fermentation trials, gave abundant (close to 10(9) cfu/ml) and balanced growth and lowered pH to 4.2, a value similar to that of yogurt. These results show that scotta may have potential as a substrate for bacterial growth for the production of a fermented drink. Further studies are needed to optimize the organoleptic aspects of the final product. PMID- 26608678 TI - Small molecule RL71 targets SERCA2 at a novel site in the treatment of human colorectal cancer. AB - While targeted agents are an important part of the treatment arsenal for colorectal cancer, there is still a lack of efficient small-molecule targeted agents based on the understanding of pathogenic molecular mechanisms. In this study, curcumin analog RL71 displayed potent cytotoxicity towards human colon cancer cells with an IC50 of 0.8 uM in SW480 cells and inhibited xenotransplanted tumor growth in a dose-dependent manner. Using affinity chromatography, we identified sarco/endoplasmic reticulum calcium-ATPase (SERCA) 2 as the binding target of RL71. Most notably, RL71 demonstrated special binding to SERCA2 at a novel site with the lowest estimated free energy -8.89 kcal mol(-1), and the SERCA2 residues critical for RL71 binding were identified. RL71 suppressed the Ca(2+)-ATPase activity of SERCA2 both in vitro and in vivo, accompanied by the induction of endoplasmic reticulum stress leading to apoptosis and G2/M cycle arrest in SW480 cells. In addition, RL71 showed synergistic cytotoxicity with the pan-SERCA inhibitor thapsigargin. These results suggest that RL71 could be a selective small-molecule inhibitor of SERCA2, and that it may serve as a lead compound for the study of targeted colorectal cancer therapy. PMID- 26608680 TI - Controlling confounding of treatment effects in administrative data in the presence of time-varying baseline confounders. AB - PURPOSE: Confounding, a concern in nonexperimental research using administrative claims, is nearly ubiquitous in claims-based pharmacoepidemiology studies. A fixed-length look-back window for assessing comorbidity from claims is common, but it may be advantageous to use all historical claims. We assessed how the strength of association between a baseline-identified condition and subsequent mortality varied by when the condition was measured and investigated methods to control for confounding. METHODS: For Medicare beneficiaries undergoing maintenance hemodialysis on 1 January 2008 (n = 222 343), we searched all Medicare claims, 1 January 2001 to 31 December 2007, for four conditions representing chronic and acute diseases, and classified claims by number of months preceding the index date. We used proportional hazard models to estimate the association between time of condition and subsequent mortality. We simulated a confounded comorbidity-exposure relationship and investigated an alternative method of adjustment when the association between the condition and mortality varied by proximity to follow-up start. RESULTS: The magnitude of the mortality hazard ratio estimates for each condition investigated decreased toward unity as time increased between index date and most recent manifestation of the condition. Simulation showed more biased estimates of exposure-outcome associations if proximity to follow-up start was not considered. CONCLUSIONS: Using all-available claims information during a baseline period, we found that for all conditions investigated, the association between a comorbid condition and subsequent mortality varied considerably depending on when the condition was measured. Improved confounding control may be achieved by considering the timing of claims relative to follow-up start. PMID- 26608681 TI - Combinative application of pH-zone-refining and conventional high-speed counter current chromatography for preparative separation of caged polyprenylated xanthones from gamboge. AB - An efficient method for the preparative separation of four structurally similar caged xanthones from the crude extracts of gamboge was established, which involves the combination of pH-zone-refining counter-current chromatography and conventional high-speed counter-current chromatography for the first time. pH zone-refining counter-current chromatography was performed with the solvent system composed of n-hexane/ethyl acetate/methanol/water (7:3:8:2, v/v/v/v), where 0.1% trifluoroacetic acid was added to the upper organic stationary phase as a retainer and 0.03% triethylamine was added to the aqueous mobile phase as an eluter. From 3.157 g of the crude extract, 1.134 g of gambogic acid, 180.5 mg of gambogenic acid and 572.9 mg of a mixture of two other caged polyprenylated xanthones were obtained. The mixture was further separated by conventional high speed counter-current chromatography with a solvent system composed of n hexane/ethyl acetate/methanol/water (5:5:10:5, v/v/v/v) and n-hexane/methyl tert butyl ether/acetonitrile/water (8:2:6:4,v/v/v/v), yielding 11.6 mg of isogambogenic acid and 10.4 mg of beta-morellic acid from 218.0 mg of the mixture, respectively. The purities of all four of the compounds were over 95%, as determined by high-performance liquid chromatography, and the chemical structures of the four compounds were confirmed by electrospray ionization mass spectrometry and NMR spectroscopy. The combinative application of pH-zone refining counter-current chromatography and conventional high-speed counter current chromatography shows great advantages in isolating and enriching the caged polyprenylated xanthones. PMID- 26608682 TI - Colon Adenocarcinoma Associated with Synchronous Extramural Gastrointestinal Stromal Tumor (GIST) of the Ileum. AB - BACKGROUND: GISTs are mesenchymal tumors representing approximately 1% of all gastrointestinal neoplasia. Their concurrence with colorectal cancers is rare. CASE REPORT: We present a case of coexistence of colon adenocarcinoma and GIST of the ileum in a 68-year-old white woman. CONCLUSIONS: The coexistence of mesenchymal and epithelial neoplasia is very challenging; further research is needed to clarify the role of oncogenic mutations and signalling pathways in carcinogenesis of neoplasia of various histiogenic origins. PMID- 26608683 TI - Azidoethoxyphenylalanine as a Vibrational Reporter and Click Chemistry Partner in Proteins. AB - An unnatural amino acid, 4-(2-azidoethoxy)-L-phenylalanine (AePhe, 1), was designed and synthesized in three steps from known compounds in 54% overall yield. The sensitivity of the IR absorption of the azide of AePhe was established by comparison of the frequency of the azide asymmetric stretch vibration in water and dimethyl sulfoxide. AePhe was successfully incorporated into superfolder green fluorescent protein (sfGFP) at the 133 and 149 sites by using the amber codon suppression method. The IR spectra of these sfGFP constructs indicated that the azide group at the 149 site was not fully solvated despite the location in sfGFP and the three-atom linker between the azido group and the aromatic ring of AePhe. An X-ray crystal structure of sfGFP-149-AePhe was solved at 1.45 A resolution and provides an explanation for the IR data as the flexible linker adopts a conformation which partially buries the azide on the protein surface. Both sfGFP-AePhe constructs efficiently undergo a bioorthogonal strain-promoted click cycloaddition with a dibenzocyclooctyne derivative. PMID- 26608684 TI - Polymer-surfactant systems in bulk and at fluid interfaces. AB - The interest of polymer-surfactant systems has undergone a spectacular development in the last thirty years due to their complex behavior and their importance in different industrial sectors. The importance can be mainly associated with the rich phase behavior of these mixtures that confers a wide range of physico-chemical properties to the complexes formed by polymers and surfactants, both in bulk and at the interfaces. This latter aspect is especially relevant because of the use of their mixture for the stabilization of dispersed systems such as foams and emulsions, with an increasing interest in several fields such as cosmetic, food science or fabrication of controlled drug delivery structures. This review presents a comprehensive analysis of different aspects related to the phase behavior of these mixtures and their intriguing behavior after adsorption at the liquid/air interface. A discussion of some physical properties of the bulk is also included. The discussion clearly points out that much more work is needed for obtaining the necessary insights for designing polymer-surfactant mixtures for specific applications. PMID- 26608686 TI - Numb chin syndrome as initial manifestation of bisphosphonate-related osteomyelitis of the jaw and methotrexate-associated lymphoproliferative disorders: a rare case. PMID- 26608685 TI - The impact of temperature on microbial diversity and AOA activity in the Tengchong Geothermal Field, China. AB - Using a culture-independent method that combines CARD-FISH, qPCR and 16S rDNA, we investigated the abundance, community structure and diversity of microbes along a steep thermal gradient (50-90 degrees C) in the Tengchong Geothermal Field. We found that Bacteria and Archaea abundance changed markedly with temperature changes and that the number of cells was lowest at high temperatures (90.8 degrees C). Under low-temperature conditions (52.3-74.6 degrees C), the microbial communities were dominated by Bacteria, which accounted for 60-80% of the total number of cells. At 74.6 degrees C, Archaea were dominant, and at 90.8 degrees C, they accounted for more than 90% of the total number of cells. Additionally, the microbial communities at high temperatures (74.6-90.8 degrees C) were substantially simpler than those at the low-temperature sites. Only a few genera (e.g., bacterial Caldisericum, Thermotoga and Thermoanaerobacter, archaeal Vulcanisaeta and Hyperthermus) often dominated in high-temperature environments. Additionally, a positive correlation between Ammonia-Oxidizing Archaea (AOA) activity and temperature was detected. AOA activity increased from 17 to 52 pmol of NO2(-) per cell d(-1) with a temperature change from 50 to 70 degrees C. PMID- 26608687 TI - Bismuth toxicity in patients treated with bismuth iodoform paraffin packs. AB - Bismuth is a heavy metal used in bismuth iodoform paraffin paste (BIPP) antiseptic dressings and in a number of other medical preparations. It can be absorbed systemically and cause toxicity. We report 2 cases of such neurotoxicity after it was used in operations on the jaws. PMID- 26608688 TI - An excellent review and praise to the BMA library. PMID- 26608689 TI - Raised Schneiderian membrane compared with peeled bony walls in the formation of bone. PMID- 26608690 TI - Microvascular reconstruction of facial defects in settings where resources are limited. AB - The surgical treatment of defects caused by noma is challenging for the surgeon and the patient. Local flaps are preferred, but sometimes, because of the nature of the disease, there is not enough local tissue available. We describe our experience of free tissue transfer in Ethiopia. Between 2008 and 2014, 34 microsurgical procedures were done over 11 missions with the charity Facing Africa, predominantly for the treatment of defects caused by noma (n=32). The mean duration of operation was 442 minutes (range 200 - 720). Six minor wound infections were treated conservatively and did not affect outcome, a return to theatre was required in 4 patients with wound infections and one with a haemorrhage; 2 flaps failed and 2 partially failed, one patient developed an oronasal fistula, and one had an infection at the donor site that required a repeat graft. In settings where resources are limited, free flaps can be used when local tissue is not available and they cause less morbidity than pedicled tissue transfer. PMID- 26608691 TI - Bilateral hypoplasia of the coronoid process. PMID- 26608692 TI - Data trimming procedure can eliminate bilingual cognitive advantage. AB - Bilingualism and its cognitive impacts have drawn increasing interest. Recently, inconsistencies in the findings have raised discussions on what might have caused such discrepancies and how evidence should be evaluated. This review tries to shed new light onto the reasons for the inconsistencies by taking a novel perspective. Motivated by the finding that bilingualism affects response time distribution profiles, particularly findings that suggest bilinguals have fewer long responses, we investigated the relation between maximum response times allowed/included in the analysis of an experiment and the finding of a bilingual advantage. We reviewed 68 experiments from 33 articles that compared monolingual and bilingual speakers' performance in three commonly used non-verbal interference tasks (Simon, Spatial Stroop and Flanker). We found that studies that included longer responses in their analysis were more likely to report a bilingualism effect. We conclude that seemingly insignificant details such as the data trimming procedure can have a potential impact on whether an effect is observed. We also discuss the implication of our findings and suggest the usefulness of more fine-grid analytical procedures. PMID- 26608693 TI - Examining Manufacturing Readiness for Breakthrough Drug Development. PMID- 26608694 TI - Differential Accumulation of Mercury and Selenium in Brown Trout Tissues of a High-Gradient Urbanized Stream in Colorado, USA. AB - Total mercury (THg) and selenium (Se) were analyzed by Inductively Coupled Plasma Mass Spectrometry in 11 internal and external tissues and stomach contents from 23 brown trout, Salmo trutta, of a 22.9-km reach of a high-gradient stream (upper Fountain Creek) in Colorado, USA, impacted by coal-fired power plants, shale deposits, and urbanization. Trout and water were sampled from four sites ranging from 2335 to 1818 m elevation. Lengths, weights, and ages of fish between pairs of the four sites were not significantly different. The dry weight (dw) to wet weight (ww) conversion factor for each tissue was calculated with egg-ovary highest at 0.379 and epaxial muscle fourth highest at 0.223. THg and Se in stomach contents indicated diet and not ambient water was the major source of Hg and Se bioaccumulated. Mean THg ww in kidney was 40.33 ug/kg, and epaxial muscle second highest at 36.76 ug/kg. None of the tissues exceeded the human critical threshold for Hg. However, all 23 trout had at least one tissue type that exceeded 0.02 mg/kg THg ww for birds, and four trout tissues exceeded 0.1 mg/kg THg ww for mammals, indicating that piscivorous mammals and birds should be monitored. Se concentrations in tissues varied depending on ww or dw listing. Mean Se dw in liver was higher than ovary at the uppermost site and the two lower sites. Liver tissue, in addition to egg-ovary, should be utilized as an indicator tissue for Se toxicity. PMID- 26608695 TI - Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction. AB - BACKGROUND: Infertility is a condition affecting 10% to 15% of couples of reproductive age. It is generally defined as "the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse". The treatment of infertility may involve manipulation of gametes or of the embryos themselves. These techniques are together known as assisted reproductive technology (ART). Practitioners are constantly seeking alternative or adjunct treatments, or both, in the hope that they may improve the outcome of assisted reproductive techniques. This Cochrane review focusses on the adjunct use of synthetic versions of two naturally-produced hormones, dehydroepiandrosterone (DHEA) and testosterone (T), in assisted reproduction.DHEA and its derivative testosterone are steroid hormones proposed to increase conception rates by positively affecting follicular response to gonadotrophin stimulation, leading to greater oocyte yields and, in turn, increased chance of pregnancy. OBJECTIVES: To assess the effectiveness and safety of DHEA and testosterone as pre- or co treatments in subfertile women undergoing assisted reproduction. SEARCH METHODS: We searched the following electronic databases, trial registers and websites up to 12 March 2015: the Cochrane Central Register of Controlled Trials (CENTRAL), the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, MEDLINE, EMBASE, PsycINFO, CINAHL, electronic trial registers for ongoing and registered trials, citation indexes, conference abstracts in the Web of Science, PubMed and OpenSIGLE. We also carried out handsearches. There were no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing DHEA or testosterone as an adjunct treatment to any other active intervention, placebo, or no treatment in women undergoing assisted reproduction. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted relevant data and assessed them for risk of bias. We pooled studies using fixed-effect models. We calculated odds ratios (ORs) for each dichotomous outcome. Analyses were stratified by type of treatment. There were no data for the intended groupings by dose, mode of delivery or after one/more than one cycle.We assessed the overall quality of the evidence for the main findings using the GRADE working group methods. MAIN RESULTS: We included 17 RCTs with a total of 1496 participants. Apart from two trials, the trial participants were women identified as 'poor responders' to standard IVF protocols. The included trials compared either testosterone or DHEA treatment with placebo or no treatment.When DHEA was compared with placebo or no treatment, pre-treatment with DHEA was associated with higher rates of live birth or ongoing pregnancy (OR 1.88, 95% CI 1.30 to 2.71; eight RCTs, N = 878, I2 statistic = 27%, moderate quality evidence). This suggests that in women with a 12% chance of live birth/ongoing pregnancy with placebo or no treatment, the live birth/ongoing pregnancy rate in women using DHEA will be between 15% and 26%. However, in a sensitivity analysis removing trials at high risk of performance bias, the effect size was reduced and no longer reached significance (OR 1.50, 95% CI 0.88 to 2.56; five RCTs, N = 306, I2 statistic = 43%). There was no evidence of a difference in miscarriage rates (OR 0.58, 95% CI 0.29 to 1.17; eight RCTs, N = 950, I2 statistic = 0%, moderate quality evidence). Multiple pregnancy data were available for five trials, with one multiple pregnancy in the DHEA group of one trial (OR 3.23, 95% CI 0.13 to 81.01; five RCTs, N = 267, very low quality evidence).When testosterone was compared with placebo or no treatment we found that pre-treatment with testosterone was associated with higher live birth rates (OR 2.60, 95% CI 1.30 to 5.20; four RCTs, N = 345, I2 statistic = 0%, moderate evidence). This suggests that in women with an 8% chance of live birth with placebo or no treatment, the live birth rate in women using testosterone will be between 10% and 32%. On removal of studies at high risk of performance bias in a sensitivity analysis, the remaining study showed no evidence of a difference between the groups (OR 2.00, 95% CI 0.17 to 23.49; one RCT, N = 53). There was no evidence of a difference in miscarriage rates (OR 2.04, 95% CI 0.58 to 7.13; four RCTs, N = 345, I2 = 0%, low quality evidence). Multiple pregnancy data were available for three trials, with four events in the testosterone group and one in the placebo/no treatment group (OR 3.09, 95% CI 0.48 to 19.98; three RCTs, N = 292, very low quality evidence).One study compared testosterone with estradiol and reported no evidence of a difference in live birth rates (OR 2.06, 95% CI 0.43 to 9.87; one RCT, N = 46, very low quality evidence) or miscarriage rates (OR 0.70, 95% CI 0.11 to 4.64; one RCT, N = 46, very low quality evidence).The quality of the evidence was moderate, the main limitations being lack of blinding in the included trials, inadequate reporting of study methods, and low event and sample sizes in some trials. AUTHORS' CONCLUSIONS: In women identified as poor responders undergoing ART, pre-treatment with DHEA or testosterone may be associated with improved live birth rates. The overall quality of the evidence is moderate. There is insufficient evidence to draw any conclusions about the safety of either androgen. Definitive conclusions regarding the clinical role of either androgen awaits evidence from further well-designed studies. PMID- 26608696 TI - The therapy with negative pressure as a valid device to treat chronic breast infections. PMID- 26608697 TI - The persistent influence of concussion on attention, executive control and neuroelectric function in preadolescent children. AB - The aim of this investigation was to examine the influence of pediatric sport related concussion on brain and cognitive function. To do so, we used a between participants design, measures of executive control, and event-related potentials (ERPs). The findings demonstrate that children with a history of concussion exhibit behavioral deficits in attention, working memory and impulse control, as well as neuroelectric alterations in ERP indices of visual attention (N1), conflict resolution (N2) and attentional resource allocation (P3). Furthermore, the age at injury related to the magnitude of several concussion-related deficits. Accordingly, a single sports-related concussive incident during childhood (m=2.1years prior to testing) may lead to subtle, yet pervasive alterations in the behavioral and neural indices of attention and executive control, and age at injury may moderate injury outcomes. PMID- 26608700 TI - Conflicts Within the Family and Within the Couple as Contextual Factors in the Determinism of Male Sexual Dysfunction. AB - INTRODUCTION: The deterioration of a couple's relationship has been previously associated with impairment in male sexual function. Besides a couple's dystonic relationship, other stressors can unfavorably influence dyadic intimacy. A largely neglected etiopathogenetic factor affecting couple sexuality is the frustration caused by conflicts within the family. AIM: To evaluate the possible associations between male sexual dysfunction (SD) and conflictual relationships within the couple or the family. METHODS: A consecutive series of 3,975 men, attending the Outpatient Clinic for SD for the first time, was retrospectively studied. Conflicts within the family and within the couple were assessed using two standard questions: "Are there any conflicts at home," and "Do you have a difficult relationship with your partner?" respectively, rating 0 = normal relationships, 1 = occasional quarrels, and 2 = frequent quarrels or always. MAIN OUTCOME MEASURES: Several clinical, biochemical, and psychological (Middlesex Hospital Questionnaire) parameters were studied. RESULTS: Among the 3,975 patients studied, we observed a high prevalence of conflicts within the family and within the couple (32% vs. 21.2%). When compared with the rest of the sample, subjects reporting both type of conflicts showed a higher prevalence of psychiatric comorbidities. Hence, all data were adjusted for this parameter and for age. Family and couple conflicts were significantly associated with free floating anxiety, depression symptoms, and with a higher risk of subjective (self reported) and objective (peak systolic velocity at the penile color Doppler ultrasound <35 mm/sec2) erectile dysfunction and hypoactive sexual desire. Female sexual function parameters, as reported by the patient, retained a significant association with both type of conflicts. CONCLUSIONS: This study indicates that the presence of often unexplored issues, like conflicts within the family or within the couple, can represent an important contextual factor in the determinism of male SD. PMID- 26608699 TI - Animal board invited review: precision livestock farming for dairy cows with a focus on oestrus detection. AB - Dairy cows are high value farm animals requiring careful management to achieve the best results. Since the advent of robotic and high throughput milking, the traditional few minutes available for individual human attention daily has disappeared and new automated technologies have been applied to improve monitoring of dairy cow production, nutrition, fertility, health and welfare. Cows milked by robots must meet legal requirements to detect healthy milk. This review focuses on emerging technical approaches in those areas of high cost to the farmer (fertility, metabolic disorders, mastitis, lameness and calving). The availability of low cost tri-axial accelerometers and wireless telemetry has allowed accurate models of behaviour to be developed and sometimes combined with rumination activity detected by acoustic sensors to detect oestrus; other measures (milk and skin temperature, electronic noses, milk yield) have been abandoned. In-line biosensors have been developed to detect markers for ovulation, pregnancy, lactose, mastitis and metabolic changes. Wireless telemetry has been applied to develop boluses for monitoring the rumen pH and temperature to detect metabolic disorders. Udder health requires a multisensing approach due to the varying inflammatory responses collectively described as mastitis. Lameness can be detected by walk over weigh cells, but also by various types of video image analysis and speed measurement. Prediction and detection of calving time is an area of active research mostly focused on behavioural change. PMID- 26608698 TI - Arabidopsis pab1, a mutant with reduced anthocyanins in immature seeds from banyuls, harbors a mutation in the MATE transporter FFT. AB - Forward genetics approaches have helped elucidate the anthocyanin biosynthetic pathway in plants. Here, we used the Arabidopsis banyuls (ban) mutant, which accumulates anthocyanins, instead of colorless proanthocyanidin precursors, in immature seeds. In contrast to standard screens for mutants lacking anthocyanins in leaves/stems, we mutagenized ban plants and screened for mutants showing differences in pigmentation of immature seeds. The pale banyuls1 (pab1) mutation caused reduced anthocyanin pigmentation in immature seeds compared with ban. Immature pab1 ban seeds contained less anthocyanins and flavonols than ban, but showed normal expression of anthocyanin biosynthetic genes. In contrast to pab1, introduction of a flavonol-less mutation into ban did not produce paler immature seeds. Map-based cloning showed that two independent pab1 alleles disrupted the MATE-type transporter gene FFT/DTX35. Complementation of pab1 with FFT confirmed that mutation in FFT causes the pab1 phenotype. During development, FFT promoter activity was detected in the seed-coat layers that accumulate flavonoids. Anthocyanins accumulate in the vacuole and FFT fused to GFP mainly localized in the vacuolar membrane. Heterologous expression of grapevine MATE-type anthocyanin transporter gene partially complemented the pab1 phenotype. These results suggest that FFT acts at the vacuolar membrane in anthocyanin accumulation in the Arabidopsis seed coat, and that our screening strategy can reveal anthocyanin related genes that have not been found by standard screening. PMID- 26608701 TI - Microwave ablation in treating intrahepatic recurrence of hepatocellular carcinoma after liver transplantation: An analysis of 11 cases. AB - PURPOSE: This study was designed to evaluate the efficacy and safety of microwave ablation (MWA) in the treatment of intrahepatic recurrence of hepatocellular carcinoma (HCC) after liver transplantation. MATERIALS AND METHODS: Between October 2008 and August 2014, a total of 11 cases with 19 lesions were enrolled. All the subjects had confirmed HCC recurrence after liver transplantation by at least two types of enhanced imaging. Real-time monitoring and small ethanol doses were used as an additional technique to assist with ablation. Contrast imaging was performed to evaluate the technique efficacy. The technique efficacy rate, local tumour progression rate, 3, 6, 9, 12, 18 and 24 months survival rates, and the incidence of complications were comprehensively analysed. RESULTS: The follow up period ranged from 5-33 months. All tumours achieved full ablation. The first MWA technique efficacy rate was 84.2% (16/19), while the second technique efficacy rate was 100%. Local tumour progression was identified in three cases (15.8%) at 1, 3 and 7 months after MWA. The 3, 6, 9, 12, 18 and 24 months accumulative survival rates were 90.9%, 81.8%, 71.6%, 51.5%, 30.7% and 15.3%, respectively, the average survival time was 17.3 months (3.5-33 months). Mild side effects included five patients (45.4%) with fevers, three with (27.3%) nausea and vomiting, five (45.4%) with local pain, and eight (72.7%) with increased blood transaminase levels; no serious complications occurred. CONCLUSION: MWA treatment is a promising technique for intrahepatic recurrence after liver transplantation without serious complications or side effects. PMID- 26608702 TI - Changes in quality of life and disease-related symptoms in patients with polycythemia vera receiving ruxolitinib or standard therapy. AB - OBJECTIVES: Polycythemia vera (PV)-related symptoms may not be adequately controlled with conventional therapy. This current analysis of the RESPONSE trial evaluated the effects of ruxolitinib compared with standard therapy on quality of life (QoL) and symptoms in patients with PV who were hydroxyurea resistant/intolerant. METHODS: In the previously reported primary analysis, ruxolitinib achieved the primary composite endpoint of hematocrit control and >=35% reduction in spleen volume at Week 32. The current analysis evaluated patient-reported outcomes using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), the Pruritus Symptom Impact Scale (PSIS), and the Patient Global Impression of Change (PGIC). RESULTS: Compared with standard therapy, ruxolitinib was associated with greater improvements in global health status/QoL, functional subscales, and individual symptom scores of the EORTC QLQ-C30. At Week 32, more patients in the ruxolitinib arm (44%) achieved a >=10-point improvement in global health status/QoL vs. standard therapy (9%). Improvements in MPN-SAF symptom scores were consistent with improvements in EORTC QLQ-C30, PSIS, and PGIC scores. CONCLUSIONS: Ruxolitinib provides clinically relevant improvements in QoL and ameliorates symptom burden in patients with PV who are hydroxyurea resistant/intolerant. PMID- 26608703 TI - Annular management during aortic valve repair: a systematic review. AB - Annuloplasty is considered to play a key role to control aortic valve regurgitation (AR) and prevent recurrence of AR after aortic valve repair, because aortic root dilatation has emerged as a risk factor for recurrence of AR. Various modifications of annuloplasty have been advocated, however, none of them has become standardized. Thus in this review they are outlined and classified (internal/external, with/without ring, rigid/flexible ring), and their advantages and disadvantages are clarified. Their clinical outcomes seem currently acceptable in general, and external flexible annuloplasty has been performed more frequently with favorable outcomes. However, they are still performed for a minority of patients by special experienced teams with limited follow-up periods. Therefore, it seems too early to determine the superiority or inferiority of each approach. We must carefully conduct evaluation to clarify which approach will become reproducible, effective, and standardized. PMID- 26608704 TI - A study on the involvement of GABA-transaminase in MCT induced pulmonary hypertension. AB - Increased sympathetic nervous system (SNS) activity is associated with cardiovascular diseases but its role has not been completely explored in pulmonary hypertension (PH). Increased SNS activity is distinguished by elevated level of norepinephrine (NE) and activity of gamma-Amino butyric acid Transminase (GABA-T) which degrades GABA, an inhibitory neurotransmitter within the central and peripheral nervous system. Therefore, we hypothesized that GABA-T may contribute in pathophysiology of PH by modulating level of GABA and NE. The effect of daily oral administration of GABA-T inhibitor, Vigabatrin (GVG, 50 and 75 mg/kg/day, 35 days) was studied following a single subcutaneous administration of monocrotaline (MCT, 60 mg/kg) in male SD rats. The pressure and hypertrophy of right ventricle (RV), oxidative stress, inflammation, pulmonary vascular remodelling were assessed after 35 days in MCT treated rats. The expression of GABA-T and HIF-1alpha was studied in lung tissue. The levels of plasma NE (by High performance liquid chromatography coupled with electrochemical detector; HPLC-ECD) and lung GABA (by liquid chromatography-mass spectrometry) were also estimated. GVG at both doses significantly attenuated increased in pressure (35.82 +/- 4.80 mm Hg, p < 0.001; 28.37 +/- 3.32 mm Hg, p < 0.001 respectively) and hypertrophy of RV, pulmonary vascular remodelling, oxidative stress and inflammation in lungs of MCT exposed rats. GVG also reduced the expression of GABA-T and HIF-1alpha in MCT treated rats. Increased NE level and decreased GABA level was also reversed by GVG in MCT exposed rats. GABA-T plays an important role in PH by modulating SNS activity and may be considered as a therapeutic target in PH. PMID- 26608705 TI - Electropharmacogram of Sceletium tortuosum extract based on spectral local field power in conscious freely moving rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The endemic succulent South African plant, Sceletium tortuosum (L.) N.E. Br. (synonym Mesembryanthemum tortuosum L.), of the family Mesembryathemaceae, has an ancient oral tradition history of use by San and Khoikhoi people as an integral part of the indigenous culture and materia medica. A special standardized extract of Sceletium tortuosum (Zembrin(r)) has been developed and tested pre-clinically in rats, and clinically in healthy subjects. AIM OF THE STUDY: The present investigation aimed at the construction of electropharmacograms of Zembrin(r) in the presence of three dosages (2.5, 5.0 and 10.0 mg/kg), and comparative electropharmacograms and discriminatory analyses for other herbal extracts, citicoline and rolipram. MATERIAL AND METHODS: Seventeen adult Fischer rats were each implanted with a set consisting of four bipolar concentric steel electrodes fixed by dental cement and three screws driven into the scalp. After two weeks of recovery from surgery the animals were adapted to oral administration by gavage and to experimental conditions (45 min pre-drug period and 5h of recording after a rest of 5 min for calming down). Data were transmitted wirelessly and processed using a Fast Fourier Transformation (FFT). Spectral power was evaluated for 8 frequency ranges, namely delta, theta, alpha1, alpha2, beta1a, beta1b, beta2 and gamma power. RESULTS: Zembrin(r) dose dependently attenuated all frequency ranges, to varying degrees. The most prominent was the statistically significant reduction in alpha2 and beta1a waves, correlated with activation of the dopaminergic and glutamatergic transmitter systems respectively. This feature is common to all synthetic and herbal stimulants tested to date. The second strongest effects were reduction in both the delta and the theta frequency ranges, correlated with changes in the cholinergic and norepinephrine systems respectively, a pattern seen in preparations prescribed for neurodegenerative diseases. Theta wave reduction in common with the delta, alpha2 and beta1 attenuation has been noted for analgesic drugs. Attenuation of alpha1 waves emerged during the highest dosage in all brain areas, a feature seen in all antidepressants. DISCUSSION: The electropharmacogram of Zembrin(r) was compared to the electropharmacograms of herbal extracts archived in our database. Extracts of Oenothera biennis and Cimicifuga racemosa gave a very similar electropharmacograms to that of Zembrin(r), and extracts of Ginkgo biloba and Rhodiola rosea gave rather similar electropharmacograms to Zembrin(r). Linear discriminant analysis confirmed these similarities and demonstrated that all three dosages of Zembrin(r) plotted in close neighbourhood to each other. Citocoline, a synthetic compound originally developed for cognitive enhancement, had a similar electropharmacogram to Zembrin(r). Similarity to the electropharmacograms of the synthetic phosphodiesterase-4 inhibitor, rolipram, suggests Zembrin(r) has antidepressant and cognitive function enhancing potential. CONCLUSION: The combined results from the electropharmacograms and comparative discriminatory analyses suggest that Zembrin(r) has dose dependent activity, with potential applications as a cognitive function enhancer, as an antidepressant, and as an analgesic. PMID- 26608706 TI - Modulation of glucocorticoid, mineralocorticoid and androgen production in H295 cells by TrimesemineTM, a mesembrine-rich Sceletium extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Stress-related illnesses rate among the most prevalent non-fatal diseases globally. With the global trend for consumer bias towards natural medicine, the Sceletium plant has become more prominent in the field of natural products. Although potentially useful effects of Sceletium tortuosum on the central nervous system have been reported, limited data is available on effects of the plant in the peripheral compartment. AIM OF THE STUDY: The current study aimed to elucidate the effect(s) of a Sceletium extract (TRI) rich in mesembrine (1% of plant extract w/w), on adrenal steroid biosynthesis. MATERIALS AND METHODS: Steroidogenesis was assessed basally and in response to stimuli (forskolin, angiotensin II, KCl), in human adrenocortical carcinoma cells (H295R). Steroid hormone levels were assessed using UPLC-MS/MS. UPLC-MS analyses of TRI identified major alkaloids Delta7-mesembrenone, mesembrenone and mesembrine. RESULTS: Highest dose TRI treatment (1 mg/ml, 34.5 MUM mesembrine) increased pregnenolone and decreased 16-hydroxyprogesterone levels (both P<0.00001) in forskolin-stimulated conditions only, suggesting CYP17 enzyme inhibition. This led to significant inhibition of forskolin-associated increases in cortisol levels at the highest dose (P<0.001) and basal cortisol levels across all doses (P<0.0001). Independently of forskolin, TRI inhibited androstenedione and testosterone production across all doses (both P<0.00001), suggesting inhibition of 3betaHSD and 17betaHSD respectively. TRI decreased both the angiotensin II- (P<0.05) and forskolin-induced (P<0.0001) increases in aldosterone production. CONCLUSIONS: Our data suggest potentially beneficial effects of TRI in the context of stress and hypertension. These should be further investigated in a whole organism model, while the effects on the androgenic pathway should also be further elucidated. PMID- 26608707 TI - CTX-M-1 and CTX-M-15-producing Escherichia coli in dog faeces from public gardens. AB - BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli are increasingly reported in dogs. The objective of this study was to provide data on the prevalence of ESBL-producing E. coli in dog faecal deposits in public gardens. RESULTS: A total of 209 faecal deposits collected in nine public gardens in Copenhagen, Denmark were screened by selective enrichment followed by plating on MacConkey agar supplemented with cefotaxime. Presumptive ESBL-producing E. coli were confirmed by MALDI-TOF MS and polymerase chain reaction (PCR) for detection of common cefotaxime resistance determinants (bla TEM, bla SHV, bla CTX M and bla CMY-2). ESBL-producers were further characterized by multilocus sequence typing (MLST) and antimicrobial susceptibility testing using broth microdilution. Plasmids harbouring ESBL genes were characterized by S1 nuclease pulsed field gel electrophoresis, PCR-based replicon typing, and pMLST. Cefotaxime-resistant E. coli were detected in four (1.9 %) samples. Three samples harboured CTX-M-1-producing isolates, and one sample contained two CTX-M-15 producing isolates displaying distinct colony morphology. All isolates belonged to distinct sequence types (STs), including one E. coli lineage previously associated to a human-specific pathotype (ST59). bla CTX-M-1 was carried on IncI1 plasmids classified as ST3 or ST58 by pMLST, whereas bla CTX-M-15 was located on IncF/Y and non-typeable plasmids in the two strains isolated from the same sample. CONCLUSIONS: The study shows that dog faeces are a vector for dissemination of CTX-M-producing E. coli within urban areas. The risk derived from human exposure to dog faeces in public gardens depends on the prevalence of these bacteria in the local dog population as well as on the owners' practice to remove and dispose their dog's faeces. PMID- 26608709 TI - Probing the microsolvation of a quaternary ion complex: gas phase vibrational spectroscopy of (NaSO4(-))2(H2O)(n=0-6, 8). AB - We report infrared multiple photon dissociation spectra of cryogenically-cooled (NaSO4(-))2(H2O)n dianions (n = 0-6, 8) in the spectral range of the sulfate stretching and bending modes (580-1750 cm(-1)). Characteristic absorption bands and structural trends are identified based on a comparison to harmonic spectra of minimum-energy structures. The bare quarternary complex (NaSO4(-))2 exhibits a C2h structure containing two fourfold-coordinated sodium cations in-between the two chelating sulfate dianions. Its stepwise solvation is driven by an interplay of SO4(2-)-H2O and Na(+)-H2O interactions. The first water binds in a tridentate intersulfate-bridging fashion. The second and third water molecules bind to the sulfate groups at either end of the complex, which is followed by the onset of water hydrogen-bond network formation. In contrast to the binary ion pair, NaSO4( ), no clear evidence for the disruption of the quaternary ion complex upon microhydration is found up to n = 8, underlining its remarkable stability and suggesting that the formation of quaternary ion complexes plays a central role in the initial stages of prenucleation in aqueous Na2SO4 solutions. PMID- 26608710 TI - Neurological Manifestations of Medical Child Abuse. AB - BACKGROUND: Medical child abuse occurs when a child receives unnecessary and harmful, or potentially harmful, medical care at the instigation of a caretaker through exaggeration, falsification, or induction of symptoms of illness in a child. Neurological manifestations are common with this type of maltreatment. OBJECTIVES: We sought to review common reported neurological manifestations that may alert the clinician to consider medical child abuse. In addition, the possible sequelae of this form of child maltreatment is discussed, as well as practice recommendations for establishing the diagnosis and stopping the abuse once it is identified. METHODS: A review of the medical literature was conducted regarding the reported neurological presentations of this entity. RESULTS: Neurological manifestations of medical child abuse include false reports of apparent life-threatening events and seizures and reports of induction of symptoms from poisoning. Failure to correlate objective findings with subjective complaints may lead to unnecessary and potentially harmful testing or treatment. This form of child maltreatment puts a child at significant risk of long-term morbidity and mortality. CONCLUSIONS: A wide variety of neurological manifestations have been reported in cases of medical child abuse. It is important for the practicing neurologist to include medical child abuse on the differential diagnosis. PMID- 26608708 TI - Computational modeling of cardiac fibroblasts and fibrosis. AB - Altered fibroblast behavior can lead to pathologic changes in the heart such as arrhythmia, diastolic dysfunction, and systolic dysfunction. Computational models are increasingly used as a tool to identify potential mechanisms driving a phenotype or potential therapeutic targets against an unwanted phenotype. Here we review how computational models incorporating cardiac fibroblasts have clarified the role for these cells in electrical conduction and tissue remodeling in the heart. Models of fibroblast signaling networks have primarily focused on fibroblast cell lines or fibroblasts from other tissues rather than cardiac fibroblasts, specifically, but they are useful for understanding how fundamental signaling pathways control fibroblast phenotype. In the future, modeling cardiac fibroblast signaling, incorporating -omics and drug-interaction data into signaling network models, and utilizing multi-scale models will improve the ability of in silico studies to predict potential therapeutic targets against adverse cardiac fibroblast activity. PMID- 26608711 TI - High volume hydraulic fracturing operations: potential impacts on surface water and human health. AB - High volume, hydraulic fracturing (HVHF) processes, used to extract natural gas and oil from underground shale deposits, pose many potential hazards to the environment and human health. HVHF can negatively affect the environment by contaminating soil, water, and air matrices with potential pollutants. Due to the relatively novel nature of the process, hazards to surface waters and human health are not well known. The purpose of this article is to link the impacts of HVHF operations on surface water integrity, with human health consequences. Surface water contamination risks include: increased structural failure rates of unconventional wells, issues with wastewater treatment, and accidental discharge of contaminated fluids. Human health risks associated with exposure to surface water contaminated with HVHF chemicals include increased cancer risk and turbidity of water, leading to increased pathogen survival time. Future research should focus on modeling contamination spread throughout the environment, and minimizing occupational exposure to harmful chemicals. PMID- 26608712 TI - Nanoscale measurements of unoccupied band dispersion in few-layer graphene. AB - The properties of any material are fundamentally determined by its electronic band structure. Each band represents a series of allowed states inside a material, relating electron energy and momentum. The occupied bands, that is, the filled electron states below the Fermi level, can be routinely measured. However, it is remarkably difficult to characterize the empty part of the band structure experimentally. Here, we present direct measurements of unoccupied bands of monolayer, bilayer and trilayer graphene. To obtain these, we introduce a technique based on low-energy electron microscopy. It relies on the dependence of the electron reflectivity on incidence angle and energy and has a spatial resolution ~10 nm. The method can be easily applied to other nanomaterials such as van der Waals structures that are available in small crystals only. PMID- 26608713 TI - Modeling optimal treatment strategies in a heterogeneous mixing model. AB - BACKGROUND: Many mathematical models assume random or homogeneous mixing for various infectious diseases. Homogeneous mixing can be generalized to mathematical models with multi-patches or age structure by incorporating contact matrices to capture the dynamics of the heterogeneously mixing populations. Contact or mixing patterns are difficult to measure in many infectious diseases including influenza. Mixing patterns are considered to be one of the critical factors for infectious disease modeling. METHODS: A two-group influenza model is considered to evaluate the impact of heterogeneous mixing on the influenza transmission dynamics. Heterogeneous mixing between two groups with two different activity levels includes proportionate mixing, preferred mixing and like-with like mixing. Furthermore, the optimal control problem is formulated in this two group influenza model to identify the group-specific optimal treatment strategies at a minimal cost. We investigate group-specific optimal treatment strategies under various mixing scenarios. RESULTS: The characteristics of the two-group influenza dynamics have been investigated in terms of the basic reproduction number and the final epidemic size under various mixing scenarios. As the mixing patterns become proportionate mixing, the basic reproduction number becomes smaller; however, the final epidemic size becomes larger. This is due to the fact that the number of infected people increases only slightly in the higher activity level group, while the number of infected people increases more significantly in the lower activity level group. Our results indicate that more intensive treatment of both groups at the early stage is the most effective treatment regardless of the mixing scenario. However, proportionate mixing requires more treated cases for all combinations of different group activity levels and group population sizes. CONCLUSIONS: Mixing patterns can play a critical role in the effectiveness of optimal treatments. As the mixing becomes more like-with-like mixing, treating the higher activity group in the population is almost as effective as treating the entire populations since it reduces the number of disease cases effectively but only requires similar treatments. The gain becomes more pronounced as the basic reproduction number increases. This can be a critical issue which must be considered for future pandemic influenza interventions, especially when there are limited resources available. PMID- 26608714 TI - The social distraction of facial paralysis: Objective measurement of social attention using eye-tracking. AB - OBJECTIVES: To measure the attentional distraction to the facial paralysis deformity using eye-tracking, and to distinguish between attention paid to the upper and lower facial divisions in patients with complete paralysis. We hypothesized that features affected by the paralysis deformity would distract the casual observer, leading to an altered pattern of facial attention as compared to normals. STUDY DESIGN: Randomized controlled experiment. METHODS: Sixty casual observers viewed images of paralyzed faces (House-Brackmann [HB] IV-VI) and normal faces smiling and in repose. The SMI iView X RED (SensoMotoric, Inc., Boston, MA) eye-gaze tracker recorded eye movements of observers gazing on the faces. Fixation durations for predefined areas of interest were analyzed using three separate multivariate analyses. RESULTS: Casual observers gazing on both paralyzed and normal faces directed the majority of their attention to the central triangle (CT) region. Significant differences occurred in the distribution of attention among individual features in the CT and to individual sides of the face. Observers directed more attention to the mouth of paralyzed faces, smiling (analysis of variance [ANOVA] > F 0.0001) and in repose (ANOVA > F 0.0000). Attention was asymmetrically distributed between the two halves of paralyzed faces (paralyzed smiling minus normal smiling P > |z| 0.000). CONCLUSIONS: Casual observers directed attention in a measurably different way when gazing on paralyzed faces as compared to normal faces, a finding exacerbated with smiling. These findings help explain society's perceptions of attractiveness and affect display that differ for paralyzed and normal faces and can be used to direct our reconstructive efforts. LEVEL OF EVIDENCE: N/A. PMID- 26608715 TI - Facile synthesis of the NNRTI microbicide MC-1220 and synthesis of its phosphoramidate prodrugs. AB - A facile and novel synthetic route to MC-1220 was achieved by condensation of 4,6 dichloro-N,N-5-trimethylpyrimidin-2-amine (1) with the sodium salt of 2,6 difluorophenylacetonitrile, followed by methylation and strong acidic hydrolysis. The prodrugs of MC-1220 were synthesized by reaction of chlorophosphoramidate derivatives (7a-e) or alpha-acetobromoglucose with the sodium salt of MC-1220. The stability and anti-HIV-1 activity of phosphoramidate prodrugs turned out to be comparable to those of the parent drug MC-1220. PMID- 26608716 TI - Innovative Payment and Practice Models. PMID- 26608717 TI - Hospital-Based Rehabilitation for Recurrent Glioblastoma. PMID- 26608718 TI - Effect of curcumin on serum brain-derived neurotrophic factor levels in women with premenstrual syndrome: A randomized, double-blind, placebo-controlled trial. AB - Premenstrual syndrome (PMS) is a variety of physical, mental, and behavioral symptoms that start during the late luteal phase of the menstrual cycle, and the symptoms disappear after the onset of menses. Serum brain-derived neurotrophic factor (BDNF) levels during luteal phase in women associated with PMS have more alterations than women not suffering from PMS. In this regard, altered luteal BDNF levels in women with PMS might play a role in a set of psychological and somatic symptoms of the PMS. Studies of last decade revealed neuroprotective effects of curcumin and its ability to increase BDNF levels. In the present study, we evaluated the effect of curcumin on serum BDNF level and PMS symptoms severity in women with PMS. Present study is a Randomized, Double-Blinded, Placebo-Controlled Clinical Trial. Curcumin treatment was given for three successive menstrual cycles and each cycle ran 10 days. After having identified persons with PMS, participants were randomly allocated into placebo (n=35) and curcumin (n=35) groups. Each sample in placebo and curcumin groups received two capsules daily for seven days before menstruation and for three days after menstruation for three successive menstrual cycles. Participants noted the severity of the symptoms mentioned in the daily record questionnaire. Self-report was used to determine menstrual cycle phase of participants. At the fourth day of each menstrual cycle venous blood samples were collected for BDNF measurement by ELISA method. Before intervention, BDNF levels and mean scores of PMS symptoms (mood, behavioral and physical symptoms) between two groups showed no significant differences. But in curcumin group first, second and third cycles after interventions BDNF levels were significantly higher and mean scores of PMS symptoms were significantly less than placebo group. Based on our results part of these beneficial effects of curcumin may be mediated through enhancing serum BDNF levels in women with PMS. PMID- 26608719 TI - Upper thermal limits of the hearts of Arctic cod Boreogadus saida: adults compared with larvae. AB - Wild adult and reared larval Boreogadus saida were acclimated to 3.5 degrees C before testing their cardiac response to acute warming. Heart rate transition temperatures during warming were similar for adult and larval hearts, except that the maximum temperature for heart rate was 3 degrees C warmer for adults. Thus, in a rapidly warming Arctic Ocean, the upper temperature limit for larval rather than adult B. saida appears more likely to dictate the southern range of the species. PMID- 26608720 TI - Effect of charge ratio on lipoplex-mediated gene delivery and liver toxicity. AB - BACKGROUND: The vast majority of studies investigating gene delivery have utilized cationic delivery vehicles, but anionic nanoparticles can also possess high transfection activity, and offer significant benefits in terms of ease of preparation and reduced toxicity. RESULTS: Our study on lipoplexes possessing cholesterol nanodomains demonstrates that in vitro transfection after exposure to serum can be high at anionic charge ratios, and that this effect is also evident in studies assessing delivery to tumors in vivo, despite reduced circulation times. In addition, accumulation in the liver and lungs is reduced as compared with lipoplexes formulated at cationic charge ratios. CONCLUSION: Lipoplexes prepared at anionic charge ratios offer comparable tumor delivery and reduced liver toxicity despite shorter circulation times. PMID- 26608721 TI - MarA and ramA regulate virulence in Salmonella enterica serovar Choleraesuis. AB - Salmonella enterica serovar Choleraesuis is considered as an important porcine pathogen that causes serious systemic infections and exhibits poor response to treatment because of an increase in multidrug resistance (MDR). Among the various regulators of resistance, multiple antibiotic resistance factor A (marA) and regulator of acetate metabolism A (ramA) are the most effective in conferring antibiotic tolerance by activation of multidrug efflux pumps. Here we investigated the regulation of virulence in Salmonella Choleraesuis through these two transcriptional regulators. We showed that marA andramA are important for the survival of Salmonella Choleraesuis in an environment of acid and bile salts, since marA- or ramA-deficient Salmonella Choleraesuis strains failed to increase protective responses, as observed by quantitative RT-PCR (qPCR). Further, reduced invasion and survival in host cells was observed in the marA and ramA mutant strains. The results from in vitrostudies with marA- and ramA-deficient strains showed attenuated characteristics in comparison to those in the wild-type strain of Salmonella Choleraesuis when it was used to challenge BALB/c mice. The mutant strains had higher LD50 and presented poor clearance efficiency compared to the parental strain. These findings indicate that MarA and RamA not only regulate drug resistance but also play a role in the virulence of SalmonellaCholeraesuis. PMID- 26608722 TI - Introduction of quinolone resistant Escherichia coli to Swedish broiler population by imported breeding animals. AB - During recent years a rapid increase of quinolone resistant Escherichia coli have been noted in the Swedish broiler population, despite the lack of a known selective pressure. The current study wanted to investigate if imported breeding birds could be a source for the quinolone resistant E. coli. The occurrence of quinolone resistant E. coli was investigated, using selective cultivation with nalidixic acid, in grand-parent birds on arrival to Sweden and their progeny. In addition, sampling in hatcheries and empty cleaned poultry houses was performed. Clonality of isolates was investigated using a 10-loci multiple-locus variable number tandem repeat analysis (MLVA). To identify the genetic basis for the resistance isolates were also analysed for occurrence of plasmid-mediated quinolone resistance (PMQR) determinants and characterization of chromosomal mutations. E. coli resistant to nalidixic acid occurred in grandparent birds imported to Sweden for breeding purposes. Four predominant MLVA types were identified in isolates from grandparent birds, parent birds and broilers. However, resistant E. coli with identical MLVA patterns were also present in hatcheries and poultry houses suggesting that the environment plays a role in the occurrence. Nalidixic acid resistance was due to a mutation in the gyrA gene and no PMQR could be identified. The occurrence of identical clones in all levels of the production pyramid points to that quinolone resistant E. coli can be introduced through imported breeding birds and spread by vertical transmission to all levels of the broiler production pyramid. PMID- 26608723 TI - Routine measurement of plasma chromogranin B has limited clinical utility in the management of patients with neuroendocrine tumours. AB - OBJECTIVE: Chromogranin A (CgA) and B (CgB) are markers for monitoring disease status in patients with gastroenteropancreatic neuroendocrine tumours (NETs). These are specialized diagnostic tests often necessitating referral of specimens to a supraregional assay service (SAS) laboratory for analysis. The aim of this audit was to assess whether measurement of either plasma CgA or CgB alone provides sufficient clinical information in comparison with the current practice of measuring both markers together. DESIGN: A retrospective analysis was undertaken for all chromogranin tests requested for patients with a known NET diagnosis. Results were categorized based on whether plasma concentrations were elevated for one or both CgA and CgB. RESULTS: A total of 325 sequential patients with a NET diagnosis had plasma chromogranin levels measured during the period of review. Baseline CgA was elevated in 60.9% of patients. Isolated elevations in CgA (with normal CgB) were found in 44.9% of patients, whilst combined elevations in both CgA and CgB were found in 16% of patients. Combined CgA and CgB concentrations within the normal range were observed for 38.5% of patients. Only two patients (0.6%) had an isolated elevation in CgB at baseline. Both patients had a diagnosis of pancreatic NET and were radiologically stable. Plasma CgA and CgB corresponded with disease stage (localized vs metastatic). CgB in addition to CgA did not provide any significant improvement in diagnostic performance for identification of metastatic disease compared to CgA alone. CONCLUSIONS: Based on this NET population and specific assay performance characteristics, CgA alone provides sufficient information for the management of NET patients; the routine estimation of CgB in all patients is not informative in clinical practice. PMID- 26608724 TI - Intradomiciliary and peridomiciliary captures of sand flies (Diptera: Psychodidae) in the leishmaniasis endemic area of Chapare province, tropic of Cochabamba, Bolivia. AB - In South America, cutaneous leishmaniasis is the most frequent clinical form of leishmaniasis. Bolivia is one of the countries with higher incidence, with 33 cases per 100,000 individuals, and the disease is endemic in 70% of the territory. In the last decade, the number of cases has increased, the age range has expanded, affecting children under 5 years old, and a similar frequency between men and women is found. An entomological study with CDC light traps was conducted in three localities (Chipiriri, Santa Elena and Pedro Domingo Murillo) of the municipality of Villa Tunari, one of the main towns in the Chapare province (Department of Cochabamba, Bolivia). A total of 16 specimens belonging to 6 species of the genus Lutzomyia were captured: Lu. aragaoi, Lu. andersoni, Lu. antunesi, Lu. shawi, Lu. yuilli yuilli and Lu. auraensis. Our results showed the presence of two incriminated vectors of leishmaniasis in an urbanized area and in the intradomicile. More entomological studies are required in the Chapare province to confirm the role of vector sand flies, the intradomiciliary transmission of the disease and the presence of autochthonous cases of cutaneous leishmaniasis. PMID- 26608725 TI - The distribution of probability values in medical abstracts: an observational study. AB - BACKGROUND: A relatively high incidence of p values immediately below 0.05 (such as 0.047 or 0.04) compared to p values immediately above 0.05 (such as 0.051 or 0.06) has been noticed anecdotally in published medical abstracts. If p values immediately below 0.05 are over-represented, such a distribution may reflect the true underlying distribution of p values or may be due to error (a false distribution). If due to error, a consistent over-representation of p values immediately below 0.05 would be a systematic error due either to publication bias or (overt or inadvertent) bias within studies. METHODS: We searched the Medline 2012 database to identify abstracts containing a p value. Two thousand abstracts out of 80,649 abstracts were randomly selected. Two independent researchers extracted all p values. The p values were plotted and compared to a predicted curve. Chi square test was used to test assumptions and significance was set at 0.05. RESULTS: 2798 p value ranges and 3236 exact p values were reported. 4973 of these (82%) were significant (<0.05). There was an over-representation of p values immediately below 0.05 (between 0.01 and 0.049) compared to those immediately above 0.05 (between 0.05 and 0.1) (p = 0.001). CONCLUSION: The distribution of p values in reported medical abstracts provides evidence for systematic error in the reporting of p values. This may be due to publication bias, methodological errors (underpowering, selective reporting and selective analyses) or fraud. PMID- 26608726 TI - A relational approach to saviour siblings? PMID- 26608729 TI - Silicon oxide nanowire growth mechanisms revealed by real-time electron microscopy. AB - Growth of one-dimensional materials is possible through numerous mechanisms that affect the nanowire structure and morphology. Here, we explain why a wide range of morphologies is observed when silicon oxide nanowires are grown on silicon substrates using liquid gallium catalyst droplets. We show that a gallium oxide overlayer is needed for nanowire nucleation at typical growth temperatures, and that it can decompose during growth and, hence, dramatically alter the nanowire morphology. Gallium oxide decomposition is attributed to etching caused by hydrogen that can be supplied by thermal dissociation of H2O (a common impurity). We show that H2O dissociation is catalyzed by silicon substrates at temperatures as low as 320 degrees C, identify the material supply pathways and processes that rate-limit nanowire growth under dry and wet atmospheres, and present a detailed growth model that explains contradictory results reported in prior studies. We also show that under wet atmospheres the Ga droplets can be mobile and promote nanowire growth as they traverse the silicon substrate. PMID- 26608728 TI - Oxygen transfer rate identifies priming compounds in parsley cells. AB - BACKGROUND: In modern agriculture, the call for an alternative crop protection strategy increases because of the desired reduction of fungicide and pesticide use and the continuously evolving resistance of pathogens and pests to agrochemicals. The direct activation of the plant immune system does not provide a promising plant protection measure because of high fitness costs. However, upon treatment with certain natural or synthetic compounds, plant cells can promote to a fitness cost-saving, primed state of enhanced defense. In the primed state, plants respond to biotic and abiotic stress with faster and stronger activation of defense, and this is often associated with immunity and abiotic stress tolerance. Until now, the identification of chemical compounds with priming inducing activity (so-called plant activators) relied on tedious and invasive approaches, or required the late detection of secreted furanocoumarin phytoalexins in parsley cell cultures. Thus, simple, fast, straightforward, and noninvasive techniques for identifying priming-inducing compounds for plant protection are very welcome. RESULTS: This report demonstrates that a respiration activity-monitoring system (RAMOS) can identify compounds with defense priming inducing activity in parsley cell suspension in culture. RAMOS relies on the quasi-continuous, noninvasive online determination of the oxygen transfer rate (OTR). Treatment of parsley culture cells with the known plant activator salicylic acid (SA), a natural plant defense signal, resulted in an OTR increase. Addition of the defense elicitor Pep13, a cell wall peptide of Phythophthora sojae, induced two distinctive OTR peaks that were higher in SA-primed cells than in unprimed cells upon Pep13 challenge. Both, the OTR increase after priming with SA and the Pep13 challenge were dose-dependent. Furthermore, there was a close correlation of a compound's activity to enhance the oxygen consumption in parsley cells and its capacity to prime Pep13-induced furanocoumarin secretion as evaluated by fluorescence spectroscopy. CONCLUSIONS: RAMOS noninvasively determines the OTR as a measure of the metabolic activity of plant cells. Chemical enhancement of oxygen consumption by salicylic derivatives in parsley cell suspension cultures correlates with the induction of the primed state of enhanced defense that enhances the quantity of Pep13-induced furanocoumarin phytoalexins. Treatment with the priming-active compounds methyl jasmonate and pyraclostrobin also resulted in an enhanced respiration activity. Thus, RAMOS is a novel technology for identifying priming-inducing compounds for agriculture. PMID- 26608727 TI - The effect of direct access to CT scan in early lung cancer detection: an unblinded, cluster-randomised trial. AB - BACKGROUND: Lower lung cancer survival rates in Britain and Denmark compared with surrounding countries may, in part, be due to late diagnosis. The aim of this study was to evaluate the effect of direct access to low-dose computed tomography (LDCT) from general practice in early lung cancer detection on time to diagnosis and stage at diagnosis. METHODS: We conducted a cluster-randomised, controlled trial including all incident lung cancer patients (in 19-month period) listed with general practice in the municipality of Aarhus (300,000 citizens), Denmark. Randomisation and intervention were applied at general practice level. A total of 266 GPs from 119 general practices. In the study period, 331 lung cancer patients were included. The intervention included direct access to low-dose CT from primary care combined with a 1 h lung cancer update meeting. Indication for LDCT was symptoms or signs that raised the GP's suspicion of lung cancer, but fell short of satisfying the fast-track referral criteria on red flag' symptoms. RESULTS: The intervention did not significantly influence stage at diagnosis and had limited impact on time to diagnosis. However, when correcting for non compliance, we found that the patients were at higher risk of experiencing a long diagnostic interval if their GPs were in the control group. CONCLUSION: Direct low-dose CT from primary care did not statistically significantly decrease time to diagnosis or change stage at diagnosis in lung cancer patients. Case finding with direct access to LDCT may be an alternative to lung cancer screening. Furthermore, a recommendation of low-dose CT screening should consider offering symptomatic, unscreened patients an access to CT directly from primary care. TRIAL REGISTRATION: www.clinicaltrials.gov, registration ID number NCT01527214. PMID- 26608730 TI - PDE based scheme for multi-modal medical image watermarking. AB - BACKGROUND: This work deals with copyright protection of digital images, an issue that needs protection of intellectual property rights. It is an important issue with a large number of medical images interchanged on the Internet every day. So, it is a challenging task to ensure the integrity of received images as well as authenticity. Digital watermarking techniques have been proposed as valid solution for this problem. METHODS: It is worth mentioning that the Region Of Interest (ROI)/Region Of Non Interest (RONI) selection can be seen as a significant limitation from which suffers most of ROI/RONI based watermarking schemes and that in turn affects and limit their applicability in an effective way. Generally, the ROI/RONI is defined by a radiologist or a computer-aided selection tool. And thus, this will not be efficient for an institute or health care system, where one has to process a large number of images. Therefore, developing an automatic ROI/RONI selection is a challenge task. The major aim of this work is to develop an automatic selection algorithm of embedding region based on the so called Partial Differential Equation (PDE) method. Thus avoiding ROI/RONI selection problems including: (1) computational overhead, (2) time consuming, and (3) modality dependent selection. RESULTS: The algorithm is evaluated in terms of imperceptibility, robustness, tamper localization and recovery using MRI, Ultrasound, CT and X-ray grey scale medical images. From experimental results that we have conducted on a database of 100 medical images of four modalities, it can be inferred that our method can achieve high imperceptibility, while showing good robustness against attacks. Furthermore, the experiment results confirm the effectiveness of the proposed algorithm in detecting and recovering the various types of tampering. The highest PSNR value reached over the 100 images is 94,746 dB, while the lowest PSNR value is 60,1272 dB, which demonstrates the higher imperceptibility nature of the proposed method. Moreover, the Normalized Correlation (NC) between the original watermark and the corresponding extracted watermark for 100 images is computed. We get a NC value greater than or equal to 0.998. This indicates that the extracted watermark is very similar to the original watermark for all modalities. CONCLUSION: The key features of our proposed method are to (1) increase the robustness of the watermark against attacks; (2) provide more transparency to the embedded watermark. (3) provide more authenticity and integrity protection of the content of medical images. (4) provide minimum ROI/RONI selection complexity. PMID- 26608731 TI - Experimental considerations for fast kurtosis imaging. AB - PURPOSE: The clinical use of kurtosis imaging is impeded by long acquisitions and postprocessing. Recently, estimation of mean kurtosis tensor W- and mean diffusivity ( D-) was made possible from 13 distinct diffusion weighted MRI acquisitions (the 1-3-9 protocol) with simple postprocessing. Here, we analyze the effects of noise and nonideal diffusion encoding, and propose a new correction strategy. We also present a 1-9-9 protocol with increased robustness to experimental imperfections and minimal additional scan time. This refinement does not affect computation time and also provides a fast estimate of fractional anisotropy (FA). THEORY AND METHODS: 1-3-9/1-9-9 data are acquired in rat and human brains, and estimates of D-, FA, W- from human brains are compared with traditional estimates from an extensive diffusion kurtosis imaging data set. Simulations are used to evaluate the influence of noise and diffusion encodings deviating from the scheme, and the performance of the correction strategy. Optimal b-values are determined from simulations and data. RESULTS: Accuracy and precision in D- and W- are comparable to nonlinear least squares estimation, and is improved with the 1-9-9 protocol. The compensation strategy vastly improves parameter estimation in nonideal data. CONCLUSION: The framework offers a robust and compact method for estimating several diffusion metrics. The protocol is easily implemented. Magn Reson Med 76:1455-1468, 2016. (c) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 26608732 TI - Counting is a spatial process: evidence from eye movements. AB - Spatial-numerical associations (small numbers-left/lower space and large numbers right/upper space) are regularly found in simple number categorization tasks. These associations were taken as evidence for a spatially oriented mental number line. However, the role of spatial-numerical associations during more complex number processing, such as counting or mental arithmetic is less clear. Here, we investigated whether counting is associated with a movement along the mental number line. Participants counted aloud upward or downward in steps of 3 for 45 s while looking at a blank screen. Gaze position during upward counting shifted rightward and upward, while the pattern for downward counting was less clear. Our results, therefore, confirm the hypothesis of a movement along the mental number line for addition. We conclude that space is not only used to represent number magnitudes but also to actively operate on numbers in more complex tasks such as counting, and that the eyes reflect this spatial mental operation. PMID- 26608733 TI - Novel screening metric for the identification of at-risk peripheral artery disease patients using administrative claims data. AB - Despite high morbidity and mortality associated with peripheral artery disease (PAD), it remains under-diagnosed and under-treated. The objective of this study was to develop a screening metric to identify undiagnosed patients at high risk of developing PAD using administrative data. Commercial claims data from 2010 to 2012 were utilized to develop and internally validate a PAD screening metric. Medicare data were used for external validation. The study population included adults, aged 30 years or older, with new cases of PAD identified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis/procedure codes or the Healthcare Common Procedure Coding System (HCPCS) codes. Multivariate logistic regression was conducted to determine PAD risk factors used in the development of the screening metric for the identification of at-risk PAD patients. The cumulative incidence of PAD was 6.6%. Sex, age, congestive heart failure, hypertension, chronic renal insufficiency, stroke, diabetes, acute myocardial infarction, transient ischemic attack, hyperlipidemia, and angina were significant risk factors for PAD. A cut-off score of ?20 yielded sensitivity, specificity, positive predictive value, negative predictive value, and c-statistics of 83.5%, 60.0%, 12.8%, 98.1%, and 0.78, respectively. By identifying patients at high risk for developing PAD using only administrative data, the use of the current pre-screening metric could reduce the number of diagnostic tests, while still capturing those patients with undiagnosed PAD. PMID- 26608734 TI - Farm Community Impacts of Foot-and-Mouth Disease Outbreaks in Cattle and Buffaloes in Karnataka State, India. AB - This study was conducted to assess the impact of Foot-and-mouth Disease (FMD) outbreak in cattle and buffaloes on farming community in Kolar district, Karnataka state, India. Primary data were collected using pre-tested schedule from 178 sample farms using multistage random cluster sample technique. The results revealed that 78% of surveyed villages were affected with FMD. The FMD incidence risk was high across the herd sizes, whereas the mortality risk was high in small herds. In indigenous cattle, the highest loss due to FMD was distress sale (208 USD) followed by other losses, whereas, in Crossbred cattle, the highest loss was mortality loss (515 USD) followed by distress sale (490 USD), milk yield loss (327 USD), treatment cost (38 USD) and extra labour engagement expenses for nursing of FMD-affected bovines (30 USD). In local and upgraded buffaloes, the mean total loss per affected animal was 440 USD and 513 USD, respectively. A very high variability in the loss per animal was observed across the type of losses in the Crossbred cattle, and it may be due to differences in age of the FMD-infected animal, value of the animal, milking stage, lactation levels, herd sizes and labour engagement levels, etc. In local and upgraded buffaloes, the mean total loss per animal was 639 USD and 1008 USD, respectively. The sensitivity analysis for 5% change in price revealed that the mean total loss per animal was positively correlated with price. Further, the social impact elicitation revealed that majority of the livestock owners perceived FMD had caused permanent asset loss, which in turn increased psychological stress of the family. The estimated losses and social impact due to FMD signify the importance of the intervention to control the disease and thus socio-economic gain to the farmer and society at large. PMID- 26608736 TI - Characterizing and Exploring the Formation Mechanism of Salt Deposition by Reusing Advanced-softened, Silica-rich, Oilfield-produced Water (ASOW) in Superheated Steam Pipeline. AB - To dispose of large volumes of oilfield-produced water, an environmentally friendly method that reuses advanced-softened, silica-rich, oilfield-produced water (ASOW) as feedwater was implemented via a 10-month pilot-scale test in oilfield. However, salt deposition detrimental to the efficiency and security of steam injection system was generated in superheated steam pipeline. To evaluate the method, the characteristics and formation mechanism of the deposition were explored. The silicon content and total hardness of the ASOW were 272.20 mg/L and 0.018 mg/L, respectively. Morphology and composition of the deposition were determined by scanning electron microscope-energy dispersive spectrometry (SEM EDS), inductively coupled plasma-mass spectroscopy (ICP-MS), X-ray diffraction (XRD), laser Raman spectroscopy (LRS) and X-ray photoelectron spectroscopy (XPS). Na2Si2O5, Na2CO3 and trace silanes were identified in the deposition. In addition, the solubility of the deposition was about 99%, suggesting that it is very different from traditional scaling. The results of a simulation experiment and thermal analysis system (TGA and TG-FTIR) proved that Na2CO3 and Si(OH)4 (gas) are involved in the formation of Na2Si2O5, which is ascribed mainly to the temperature difference between the superheated steam and the pipe wall. These findings provide an important reference for improving the reuse of ASOW and reducing its deposition. PMID- 26608735 TI - The effect of 3beta, 6beta, 16beta-trihydroxylup-20(29)-ene lupane compound isolated from Combretum leprosum Mart. on peripheral blood mononuclear cells. AB - BACKGROUND: The Combretum leprosum Mart. plant, popularly known as mofumbo, is used in folk medicine for inflammation, pain and treatment of wounds. From this species, it is possible to isolate three triterpenes: (3beta, 6beta, 16beta trihydroxylup-20(29)-ene) called lupane, arjunolic acid and molic acid. In this study, through preclinical tests, the effect of lupane was evaluated on the cytotoxicity and on the ability to activate cellular function by the production of TNF-alpha, an inflammatory cytokine, and IL-10, an immuno regulatory cytokine was assessed. The effect of lupane on the enzymes topoisomerase I and II was also evaluated. METHODS: For this reason, peripheral blood mononuclear cells (PBMCs) were obtained and cytotoxicity was assessed by the MTT method at three different times (1, 15 and 24 h), and different concentrations of lupane (0.3, 0.7, 1.5, 6, 3 and 12 MUg/mL). The cell function was assessed by the production of TNF-alpha and IL-10 by PBMCs quantified by specific enzyme immunoassay (ELISA). The activity of topoisomerases was assayed by in vitro biological assays and in silico molecular docking. RESULTS: The results obtained showed that lupane at concentrations below 1.5 MUg/mL was not toxic to the cells. Moreover, lupane was not able to activate cellular functions and did not alter the production of IL-10 and TNF-alpha. Furthermore, the data showed that lupane has neither interfered in the action of topoisomerase I nor in the action of topoisomerase II. CONCLUSION: Based on preclinical results obtained in this study, we highlight that the compound studied (lupane) has moderate cytotoxicity, does not induce the production of TNF-alpha and IL-10, and does not act on human topoisomerases. Based on the results of this study and taking into consideration the reports about the anti-inflammatory and leishmanicidal activity of 3beta, 6beta, 16beta trihydroxylup-20(29)-ene, we suggest that this compound may serve as a biotechnological tool for the treatment of leishmaniasis in the future. PMID- 26608737 TI - How to estimate the health benefits of additional research and changing clinical practice. PMID- 26608738 TI - The title "Doctor" is an anachronism that disrespects patients. PMID- 26608739 TI - Patient commentary: Empowered patients aren't belittled by doctors' titles. PMID- 26608740 TI - Recurrent aortic regurgitation after valve-sparing aortic root replacement due to dilatation of a previously implanted Valsalva graft. PMID- 26608741 TI - Do Contrast-Fill Patterns Immediately After Coil Embolization of Small Saccular Aneurysms Impact Long-Term Results? AB - PURPOSE: It is generally accepted that filling of a saccular aneurysm with contrast immediately after coil embolization predisposes to later recanalization. However, not all such scenarios evolve similarly over time. We investigated outcomes of small (<= 7 mm) aneurysms with contrast-filled sacs immediately after coil embolization, evaluating the impact of pattern and degree of filling on subsequent recanalization. METHODS: Between January, 2008 and December, 2010, 186 small (<= 7 mm) saccular aneurysms that retained contrast after coil embolization accrued for this study. Lesions were categorized by pattern (eccentric vs. concentric) and degree of filling on working projections. Clinical and morphologic factors were also analyzed to assess impact on subsequent recanalization. Morphologic outcomes at 6 months or more were assessed. RESULTS: In 93.5 % (174/186) of aneurysms with visible contrast retention, complete occlusion was evident on follow-up imaging studies at 6 months. Multiple logistic regression analysis indicated that eccentric (vs. concentric) contrast filling carried greater risk of subsequent recanalization (p = 0.020). Stent placement and progressive occlusion were also linked, falling short of statistical significance (p = 0.089). Of 166 progressively occluded aneurysms followed for more than 12 months (mean, 30.8 +/- 7.3 months), 158 (95.2 %) exhibited stable occlusion. CONCLUSION: Small (<= 7 mm) aneurysms that retain contrast immediately after coil embolization are more likely to become completely occluded over time through progressive thrombosis. However, an eccentric fill pattern may predispose to recanalization. PMID- 26608742 TI - High-Resolution Vessel Wall Magnetic Resonance Imaging in Angiogram-Negative Non Perimesencephalic Subarachnoid Hemorrhage. AB - PURPOSE: Standard magnetic resonance imaging (MRI) rarely identifies the cause of hemorrhage in patients with an angiogram-negative, non-perimesencephalic subarachnoid hemorrhage (SAH). Yet up to 10 % of these patients have recurrent hemorrhage. The aim of the study was to explore the potential role of high resolution contrast-enhanced 3-Tesla vessel wall-MRI in patients with angiogram negative SAH. METHODS: We performed intracranial vessel wall-MRI of the circle of Willis using a 3-Tesla scanner in consecutive patients presenting with a spontaneous, angiogram-negative, non-perimesencephalic SAH. Vessel wall-MRI included T1-, T2-, and gadolinium-enhanced T1-weighted two-dimensional black blood sequences in multiple planes (voxel size 0.4 * 0.4 * 2.0 mm). Two neuroradiologists independently scored abnormalities of the arterial wall. RESULTS: In all, 11 patients (mean age 59 years) underwent vessel wall-MRI. A total of seven patients had vessel wall abnormalities despite normal catheter angiography. Two patients had focal abnormalities contiguous with the outer margin of the basilar artery wall for which we considered a differential of ruptured blood blister aneurysm, thrombosed aneurysm, and loculated extramural blood from elsewhere. Two patients had arterial wall enhancement involving multiple arteries, possibly secondary to SAH. Three patients had arterial wall enhancement at sites of dural penetration, remote from the SAH, likely related to age and atherosclerotic risk factors. Vessel wall-MRI did not alter patient management in this cohort. CONCLUSION: Vessel wall-MRI showed abnormalities in seven patients with angiogram-negative SAH. These findings did not alter patient management, but the findings may be useful for other physicians who choose to perform vessel wall-MRI in this patient population. PMID- 26608743 TI - Comprehensive characterization of a time-course transcriptional response induced by autotoxins in Panax ginseng using RNA-Seq. AB - BACKGROUND: As a valuable medicinal plant, the yield of Panax ginseng is seriously affected by autotoxicity, which is a common phenomenon due to continuous cropping. However, the mechanism of autotoxicity in P. ginseng is still unknown. RESULTS: In total, high throughput sequencing of 18 RNA-Seq libraries produced 996,000,000 100-nt reads that were assembled into 72,732 contigs. Compared with control, 3697 and 2828 genes were significantly up- and down-regulated across different tissues and time points, respectively. Gene Ontology enrichment analysis showed that 'enzyme inhibitor activity', 'carboxylesterase activity', 'pectinesterase activity', 'centrosome cycle and duplication' and 'mitotic spindle elongation' were enriched for the up-regulated genes. Transcription factors including AP2s/ERFs, MYBs, and WRKYs were up regulated in roots after benzoic acid treatment. Moreover, reactive oxygen species, peroxidases and superoxide dismutase contigs were up-regulated in roots after benzoic acid treatment. Physiological and biochemical indexes showed that the proline and malondialdehyde content were restored to lower levels at a later stage after benzoic acid treatment. Benzoic acid inhibited the root hair development in a dose-dependent manner, and several differential expressed genes potentially involved in hair development were identified. Several key contigs in the flavonoid and ginsenoside biosynthesis pathways were repressed. Finally, 58,518 alternative splicing (AS) events from 12,950 genes were found after benzoic acid treatment. Interestingly, contigs in the ginsenoside biosynthetic pathway underwent AS, providing useful information about post-transcriptional regulation in P. ginseng. CONCLUSIONS: This study revealed the stress-response molecular mechanisms in P. ginseng induced by benzoic acid. PMID- 26608744 TI - Seizure control by decanoic acid through direct AMPA receptor inhibition. AB - The medium chain triglyceride ketogenic diet is an established treatment for drug resistant epilepsy that increases plasma levels of decanoic acid and ketones. Recently, decanoic acid has been shown to provide seizure control in vivo, yet its mechanism of action remains unclear. Here we show that decanoic acid, but not the ketones beta-hydroxybutryate or acetone, shows antiseizure activity in two acute ex vivo rat hippocampal slice models of epileptiform activity. To search for a mechanism of decanoic acid, we show it has a strong inhibitory effect on excitatory, but not inhibitory, neurotransmission in hippocampal slices. Using heterologous expression of excitatory ionotropic glutamate receptor AMPA subunits in Xenopus oocytes, we show that this effect is through direct AMPA receptor inhibition, a target shared by a recently introduced epilepsy treatment perampanel. Decanoic acid acts as a non-competitive antagonist at therapeutically relevant concentrations, in a voltage- and subunit-dependent manner, and this is sufficient to explain its antiseizure effects. This inhibitory effect is likely to be caused by binding to sites on the M3 helix of the AMPA-GluA2 transmembrane domain; independent from the binding site of perampanel. Together our results indicate that the direct inhibition of excitatory neurotransmission by decanoic acid in the brain contributes to the anti-convulsant effect of the medium chain triglyceride ketogenic diet. PMID- 26608745 TI - Early detection of intentional harm in the human amygdala. AB - A decisive element of moral cognition is the detection of harm and its assessment as intentional or unintentional. Moral cognition engages brain networks supporting mentalizing, intentionality, empathic concern and evaluation. These networks rely on the amygdala as a critical hub, likely through frontotemporal connections indexing stimulus salience. We assessed inferences about perceived harm using a paradigm validated through functional magnetic resonance imaging, eye-tracking and electroencephalogram recordings. During the task, we measured local field potentials in three patients with depth electrodes (n = 115) placed in the amygdala and in several frontal, temporal, and parietal locations. Direct electrophysiological recordings demonstrate that intentional harm induces early activity in the amygdala (<200 ms), which--in turn--predicts intention attribution. The amygdala was the only site that systematically discriminated between critical conditions and predicted their classification of events as intentional. Moreover, connectivity analysis showed that intentional harm induced stronger frontotemporal information sharing at early stages. Results support the 'many roads' view of the amygdala and highlight its role in the rapid encoding of intention and salience--critical components of mentalizing and moral evaluation. PMID- 26608746 TI - HIV-1 Tat protein enhances the intracellular growth of Leishmania amazonensis via the ds-RNA induced protein PKR. AB - HIV-1 co-infection with human parasitic diseases is a growing public health problem worldwide. Leishmania parasites infect and replicate inside macrophages, thereby subverting host signaling pathways, including the response mediated by PKR. The HIV-1 Tat protein interacts with PKR and plays a pivotal role in HIV-1 replication. This study shows that Tat increases both the expression and activation of PKR in Leishmania-infected macrophages. Importantly, the positive effect of Tat addition on parasite growth was dependent on PKR signaling, as demonstrated in PKR-deficient macrophages or macrophages treated with the PKR inhibitor. The effect of HIV-1 Tat on parasite growth was prevented when the supernatant of HIV-1-infected macrophages was treated with neutralizing anti-HIV 1 Tat prior to Leishmania infection. The addition of HIV-1 Tat to Leishmania infected macrophages led to inhibition of iNOS expression, modulation of NF-kB activation and enhancement of IL-10 expression. Accordingly, the expression of a Tat construct containing mutations in the basic region (49-57aa), which is responsible for the interaction with PKR, favored neither parasite growth nor IL 10 expression in infected macrophages. In summary, we show that Tat enhances Leishmania growth through PKR signaling. PMID- 26608749 TI - The Cornell Peripartum Psychosis Management Tool: A Case Series and Template. PMID- 26608748 TI - Establishing an essential amino acid profile for maintenance in poultry using deletion method. AB - This study aimed to estimate the essential amino acid profile and the ideal ratio for the maintenance of poultry by deletion method. A nitrogen balance (NB) trial was conducted using 198 adult roosters, housed individually in metabolic cages. The treatments were 33 purified diets being 11 diets with an amino acid mixture providing high protein intake of 500 mg N/BWkg (0.75) per day, 11 diets providing medium protein intake of 250 mg N/BWkg (0.75) per day (in each diet, one amino acid tested was diluted 50%) and 11 diets providing low protein intake of 125 mg N/BWkg (0.75) per day (made by omitting the amino acid tested). Each treatment had six replicates. After 48 h of fasting receiving water plus sucrose, the roosters were fed 40 g of the diets by tube once a day for 3 days. The excreta were collected within 72 h after the first feeding. The diets and excreta were analysed for nitrogen content. For each amino acid studied, a linear regression was fitted by NB and amino acid intake (AAI). The maintenance requirements were estimated as the AAI to maintain the NB equal to zero. The daily amino acid requirements for maintenance were estimated to be Lys 11, Met 29, Thr 23, Trp 5, Arg 50, Val 29, His 6, Gly 54, Phe 49, Leu 78 and Ile 21 mg/BWkg (0.75) per day. Therefore, the amino acid ratio for maintenance was concluded to be Lys 100, Met 276, Thr 220, Trp 48, Arg 467, Val 275, His 60, Gly 511, Phe 467, Leu 735 and Ile 198% independent of the scale. The essential amino acid profile and the ideal ratio for the maintenance of poultry estimated in this study contributed to improve the factorial model for estimating essential amino acid requirements for poultry. PMID- 26608747 TI - Differential Effects of Alcohol on Excitatory and Inhibitory Puberty-Related Peptides in the Basal Hypothalamus of the Female Rat. AB - BACKGROUND: An increase in development of excitatory inputs along with a decline in inhibitory inputs ultimately govern the timely increased secretion of hypothalamic luteinizing hormone-releasing hormone (LHRH) at the time of puberty. As chronic alcohol (ALC) exposure acts at the hypothalamic level to suppress LHRH secretion and delay puberty, we assessed its ability to differentially affect the expression of key puberty-related proteins. METHODS: ALC was administered to female rats from days 27 to 33, at which time animals were killed and tissues collected for protein expression. In the medial basal hypothalamus (MBH), we assessed kisspeptin (Kp) 10, an excitatory peptide critical for prepubertal LHRH secretion, and Lin28b, a peptide with an inhibitory influence on puberty. As a direct mechanism of action of Lin28b was not known, we determined whether its central administration could induce dynorphin (DYN), a peptide that is inhibitory on LHRH secretion. Also, ALC's effect on DYN protein expression was assessed, as well as its effect on DYN release in vitro. RESULTS: ALC markedly suppressed (p < 0.01) the expression of the excitatory Kp protein, while at the same time increased (p < 0.001) the expression of inhibitory Lin28b protein. Subsequently, we showed for the first time that the central administration of Lin28b stimulated (p < 0.01) the synthesis of DYN. Finally, ALC also induced (p < 0.01) the protein expression and stimulated (p < 0.01) the in vitro release of DYN from the MBH. CONCLUSIONS: These results indicate that ALC can simultaneously and differentially alter both excitatory and inhibitory influences governing pubertal development, show for the first time a mechanism of action by which Lin28b exerts its prepubertal inhibitory tone, and further demonstrate the negative influences of ALC on the pubertal process. PMID- 26608750 TI - Prediction of kinase-substrate relations based on heterogeneous networks. AB - Protein phosphorylation catalyzed by kinases plays essential roles in various intracellular processes. With an increasing number of phosphorylation sites verified experimentally by high-throughput technologies and assigned as substrates of specific kinases, prediction of potential kinase-substrate relations (KSRs) attracts increasing attention. Although a large number of computational methods have been designed, most of them only focus on local protein sequence information. A few KSR prediction approaches integrate protein protein interaction and protein sequence information into existing machine learning algorithms at the cost of high feature dimensions or reduced sensitivity. In this work, we introduce two novel heterogeneous networks, HetNet PPI and HetNet-SEQ, by incorporating PPI and similarity of protein sequences into the kinase-substrate heterogeneous networks, respectively. Based on these two heterogeneous networks, we further propose two new KSR prediction methods, HeteSim-PPI and HeteSim-SEQ, by adopting the HeteSim algorithm, which is recently proposed for relevance measure in heterogeneous information networks. Comprehensive evaluation results of the two methods show that similarity of protein sequences is more effective in improving KSR prediction performance as HeteSim-SEQ outperforms HeteSim-PPI in most cases. Further comparison results demonstrate that HeteSim-SEQ is superior to existing methods including BDT, SVM and iGPS, suggesting the effectiveness of the proposed network-based method in predicting potential KSRs. PMID- 26608751 TI - Detecting differentially expressed genes by smoothing effect of gene length on variance estimation. AB - Next-generation sequencing technologies are widely used in genome research, and RNA sequencing (RNA-Seq) is becoming the main application for gene expression profiling. A large number of computational methods have been developed for analyzing differentially expressed (DE) genes in RNA-Seq data. However, most existing algorithms prefer to call long genes as DE. Short DE genes are rarely detected. In this work, we set out to gain insight into the influence of gene length on RNA-Seq data analysis and to figure out the effect of gene length on variance estimation of RNA-Seq read counts, which is important for statistic test to identify DE genes. We proposed a balanced method of hunting for short DE genes with significance by smoothing a gene length factor. Computational experiments indicate that our method performs well. Software available: http://www.iipl.fudan.edu.cn/lenseq/. PMID- 26608752 TI - Surveying the endomicrobiome and ectomicrobiome of bark beetles: The case of Dendroctonus simplex. AB - Many bark beetles belonging to the Dendroctonus genus carry bacterial and fungal microbiota, forming a symbiotic complex that helps the insect to colonize the subcortical environment of the host tree. However, the biodiversity of those bacteria at the surface of the cuticle or inside the body parts of bark beetles is not well established. The aim of this study was to characterize the bacterial microbiome associated with the eastern larch beetle, Dendroctonus simplex, using bacterial 16S rRNA gene pyrosequencing. The ecto- and endomicrobiome and the subcortical galleries were investigated. Several bacterial genera were identified, among which Pseudomonas, Serratia and Yersinia are associated with the surface of the beetle cuticle, and genera belonging to Enterobacteriaceae and Gammaproteobacteria with the interior of the insect body. The index of dissimilarity indicates that the bacterial microbiome associated with each environment constitutes exclusive groups. These results suggest the presence of distinct bacterial microbiota on the surface of the cuticle and the interior of D. simplex body. Additionally, the bacterial diversity identified in the galleries is substantially different from the ectomicrobiome, which could indicate a selection by the insect. This study reports for the first time the identification of the eastern larch beetle microbiome. PMID- 26608753 TI - Gait as a biomarker of cognitive impairment and dementia syndromes. Quo vadis? PMID- 26608754 TI - One-pot sequential 1,2-addition, Pd-catalysed cross-coupling of organolithium reagents with Weinreb amides. AB - An efficient sequential 1,2-addition/cross-coupling of Weinreb amides with two organolithium reagents is reported. This synthetic approach allows access to a wide variety of functionalized ketones in a modular way. The one-pot procedure presented here takes advantage of a kinetically stable tetrahedral Weinreb intermediate during subsequent Pd-catalyzed cross-coupling with the second organolithium reagent leading, within short reaction times and under mild conditions, to the formation of ketones in excellent overall yields. PMID- 26608755 TI - Screening for antimicrobial and proteolytic activities of lactic acid bacteria isolated from cow, buffalo and goat milk and cheeses marketed in the southeast region of Brazil. AB - Lactic acid bacteria (LAB) can be isolated from different sources such as milk and cheese, and the lipolytic, proteolytic and glycolytic enzymes of LAB are important in cheese preservation and in flavour production. Moreover, LAB produce several antimicrobial compounds which make these bacteria interesting for food biopreservation. These characteristics stimulate the search of new strains with technological potential. From 156 milk and cheese samples from cow, buffalo and goat, 815 isolates were obtained on selective agars for LAB. Pure cultures were evaluated for antimicrobial activities by agar antagonism tests and for proteolytic activity on milk proteins by cultivation on agar plates. The most proteolytic isolates were also tested by cultivation in skim milk followed by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of the fermented milk. Among the 815 tested isolates, three of them identified as Streptococcus uberis (strains FT86, FT126 and FT190) were bacteriocin producers, whereas four other ones identified as Weissella confusa FT424, W. hellenica FT476, Leuconostoc citreum FT671 and Lactobacillus plantarum FT723 showed high antifungal activity in preliminary assays. Complementary analyses showed that the most antifungal strain was L. plantarum FT723 that inhibited Penicillium expansum in modified MRS agar (De Man, Rogosa, Sharpe, without acetate) and fermented milk model, however no inhibition was observed against Yarrowia lipolytica. The proteolytic capacities of three highly proteolytic isolates identified as Enterococcus faecalis (strains FT132 and FT522) and Lactobacillus paracasei FT700 were confirmed by SDS-PAGE, as visualized by the digestion of caseins and whey proteins (beta-lactoglobulin and alpha-lactalbumin). These results suggest potential applications of these isolates or their activities (proteolytic activity or production of antimicrobials) in dairy foods production. PMID- 26608757 TI - Assessment of molecular methods as a tool for detecting pathogenic protozoa isolated from water bodies. AB - Several species belong to the Cryptosporidium and Giardia genus, the main parasitic protozoa occurring in water, but only some of them are infectious to humans. We investigated the occurrence of Cryptosporidium and Giardia and identified their species in the water samples collected from natural water bodies in north-western Poland. A total of 600 samples from water bodies used for bathing, sewage discharge, as drinking water sources and watering places for animals were screened. The samples were collected during a 3-year period in each of the four seasons and filtered using Filta-Max (IDEXX Laboratories, USA). Genomic DNA was extracted from all samples and used as a target sequence for polymerase chain reaction (PCR) and TaqMan real-time PCR, as well as for reverse line blotting (RLB) methods. PCR methods seem to be more sensitive to detect Giardia and Cryptosporidium DNA in water samples than RLB methods. All PCR products were sequenced and three were identified as C. parvum and four as G. intestinalis. The overall prevalence of C. parvum (0.5%) and G. intestinalis (0.6%) in the samples suggests that the risk of Cryptosporidium and Giardia infections in north-western Poland is minimal. PMID- 26608756 TI - The application of computational fluid dynamics and small-scale physical models to assess the effects of operational practices on the risk to public health within large indoor swimming pools. AB - Swimming pools provide an excellent facility for exercise and leisure but are also prone to contamination from microbial pathogens. The study modelled a 50-m * 20-m swimming pool using both a small-scale physical model and computational fluid dynamics to investigate how water and pathogens move around a pool in order to identify potential risk spots. Our study revealed a number of lessons for pool operators, designers and policy-makers: disinfection reaches the majority of a full-scale pool in approximately 16 minutes operating at the maximum permissible inlet velocity of 0.5 m/s. This suggests that where a pool is designed to have 15 paired inlets it is capable of distributing disinfectant throughout the water body within an acceptable time frame. However, the study also showed that the exchange rate of water is not uniform across the pool tank and that there is potential for areas of the pool tank to retain contaminated water for significant periods of time. 'Dead spots' exist at either end of the pool where pathogens could remain. This is particularly significant if there is a faecal release into the pool by bathers infected with Cryptosporidium parvum, increasing the potential for waterborne disease transmission. PMID- 26608758 TI - The cleaning method selected for new PEX pipe installation can affect short-term drinking water quality. AB - The influence of four different cleaning methods used for newly installed polyethylene (PEX) pipes on chemical and odor quality was determined. Bench-scale testing of two PEX (type b) pipe brands showed that the California Plumbing Code PEX installation method does not maximize total organic carbon (TOC) removal. TOC concentration and threshold odor number values significantly varied between two pipe brands. Different cleaning methods impacted carbon release, odor, as well the level of drinking water odorant ethyl tert-butyl ether. Both pipes caused odor values up to eight times greater than the US federal drinking water odor limit. Unique to this project was that organic chemicals released by PEX pipe were affected by pipe brand, fill/empty cycle frequency, and the pipe cleaning method selected by the installer. PMID- 26608759 TI - Comparison of commercial analytical techniques for measuring chlorine dioxide in urban desalinated drinking water. AB - Most drinking water industries are closely examining options to maintain a certain level of disinfectant residual through the entire distribution system. Chlorine dioxide is one of the promising disinfectants that is usually used as a secondary disinfectant, whereas the selection of the proper monitoring analytical technique to ensure disinfection and regulatory compliance has been debated within the industry. This research endeavored to objectively compare the performance of commercially available analytical techniques used for chlorine dioxide measurements (namely, chronoamperometry, DPD (N,N-diethyl-p phenylenediamine), Lissamine Green B (LGB WET) and amperometric titration), to determine the superior technique. The commonly available commercial analytical techniques were evaluated over a wide range of chlorine dioxide concentrations. In reference to pre-defined criteria, the superior analytical technique was determined. To discern the effectiveness of such superior technique, various factors, such as sample temperature, high ionic strength, and other interferences that might influence the performance were examined. Among the four techniques, chronoamperometry technique indicates a significant level of accuracy and precision. Furthermore, the various influencing factors studied did not diminish the technique's performance where it was fairly adequate in all matrices. This study is a step towards proper disinfection monitoring and it confidently assists engineers with chlorine dioxide disinfection system planning and management. PMID- 26608760 TI - Fecal pollution source tracking in waters intended for human supply based on archaeal and bacterial genetic markers. AB - The determination of fecal pollution sources in aquatic ecosystems is essential to estimate associated health risks. In this study, we evaluate eight microbial source tracking (MST) markers including host-specific Bacteroidales and Methanobrevibacter spp. for discrimination between human, bovine, equine, and swine fecal contamination in waters intended for human supply. Overall, the novel host-specific archaeal and bacterial primers proposed in this study demonstrated high sensitivity and specificity. Markers for the Archaea domain were more prevalent in the fecal and water samples studied. We conclude that the investigations regarding the sources of fecal pollution in public water supplies can contribute to improve the quality of human health. To our knowledge, this is the first analysis using both archaeal and bacterial fecal MST markers on tropical water bodies of Rio de Janeiro city, Brazil. PMID- 26608761 TI - Controlling Legionella and Pseudomonas aeruginosa re-growth in therapeutic spas: implementation of physical disinfection treatments, including UV/ultrafiltration, in a respiratory hydrotherapy system. AB - The study aimed to assess the efficacy of an integrated water safety plan (WSP) in controlling Legionella re-growth in a respiratory hydrotherapy system located in a spa centre, supplied with sulphurous water, which was initially colonized by Legionella pneumophila. Heterotrophic plate counts, Pseudomonas aeruginosa, Legionella spp. were detected in water samples taken 6-monthly from the hydrotherapy equipment (main circuit, entry to benches, final outlets). On the basis of the results obtained by the continuous monitoring and the changes in conditions, the original WSP, including physical treatments of water and waterlines, environmental surveillance and microbiological monitoring, was integrated introducing a UV/ultrafiltration system. The integrated treatment applied to the sulphurous water (microfiltration/UV irradiation/ultrafiltration), waterlines (superheated stream) and distal outlets (descaling/disinfection of nebulizers and nasal irrigators), ensured the removal of Legionella spp. and P. aeruginosa and a satisfactory microbiological quality over time. The environmental surveillance was successful in evaluating the hazard and identifying the most suitable preventive strategies to avoid Legionella re growth. Ultrafiltration is a technology to take into account in the control of microbial contamination of therapeutic spas, since it does not modify the chemical composition of the water, thus allowing it to retain its therapeutic properties. PMID- 26608762 TI - Functional diversity and dynamics of bacterial communities in a membrane bioreactor for the treatment of metal-working fluid wastewater. AB - An extensive microbiological study has been carried out in a membrane bioreactor fed with activated sludge and metal-working fluids. Functional diversity and dynamics of bacterial communities were studied with different approaches. Functional diversity of culturable bacterial communities was studied with different BiologTM plates. Structure and dynamics of bacterial communities were studied in culturable and in non-culturable fractions using a 16S rRNA analysis. Among the culturable bacteria, Alphaproteobacteria and Gammaproteobacteria were the predominant classes. However, changes in microbial community structure were detected over time. Culture-independent analysis showed that Betaproteobacteria was the most frequently detected class in the membrane bioreactor (MBR) community with Zoogloea and Acidovorax as dominant genera. Also, among non-culturable bacteria, a process of succession was observed. Longitudinal structural shifts observed were more marked for non-culturable than for culturable bacteria, pointing towards an important role in the MBR performance. Microbial community metabolic abilities assessed with BiologTM Gram negative, Gram positive and anaerobic plates also showed differences over time for Shannon's diversity index, kinetics of average well colour development, and the intensely used substrates by bacterial community in each plate. PMID- 26608763 TI - Sensitivity of antibiotic resistant and antibiotic susceptible Escherichia coli, Enterococcus and Staphylococcus strains against ozone. AB - Tolerance of antibiotic susceptible and antibiotic resistant Escherichia coli, Enterococcus and Staphylococcus strains from clinical and wastewater samples against ozone was tested to investigate if ozone, a strong oxidant applied for advanced wastewater treatment, will affect the release of antibiotic resistant bacteria into the aquatic environment. For this purpose, the resistance pattern against antibiotics of the mentioned isolates and their survival after exposure to 4 mg/L ozone was determined. Antibiotic resistance (AR) of the isolates was not correlating with higher tolerance against ozone. Except for ampicillin resistant E. coli strains, which showed a trend towards increased resistance, E. coli strains that were also resistant against cotrimoxazol, ciprofloxacin or a combination of the three antibiotics were similarly or less resistant against ozone than antibiotic sensitive strains. Pigment-producing Enterococcus casseliflavus and Staphylococcus aureus seemed to be more resistant against ozone than non-pigmented species of these genera. Furthermore, aggregation or biofilm formation apparently protected bacteria in subsurface layers from inactivation by ozone. The relatively large variance of tolerance against ozone may indicate that resistance to ozone inactivation most probably depends on several factors, where AR, if at all, does not play a major role. PMID- 26608764 TI - Evaluating spatial-temporal variations and correlation between fecal indicator bacteria (FIB) in marine bathing beaches. AB - The horizontal distribution and temporal variation of bacterial indicators (total coliforms (TC), fecal coliforms (FC), enterococcus (EC) and Escherichia coli (E. coli)) were investigated to identify the proper bacterial indicators for a marine bathing beach in China. Two different sampling efforts were conducted during dry weather and two large rain events at Xinghai Bathing Beach in Dalian, China. Samples were collected from three different water depths and analyzed for the four indicator bacteria. The results indicated that all four bacterial indicators exceeded the single sample standards at different levels. Specifically, the water quality exceeded the standard for TC, FC, EC and E. coli in 7%, 28%, 38% and 10% of the samples, respectively. Comparison of the rate of the indicators before and after rainfall revealed a significant increasing post-rainfall. The concentrations of bacteria differed significantly with distance from the shoreline, with knee-depth near the shore exceeding the standard most frequently. This was primarily due to contamination by excessive sewage discharge and rainfall. Based upon the concentration of indicators and exceedance rates, as well as the correlation between indicators, both EC and FC should be evaluated at the same time as fecal pollution bacterial indicators in marine bathing beaches in China. PMID- 26608765 TI - A positive association between cryptosporidiosis notifications and ambient temperature, Victoria, Australia, 2001-2009. AB - Increased temperatures provide optimal conditions for pathogen survival, virulence and replication as well as increased opportunities for human-pathogen interaction. This paper examined the relationship between notifications of cryptosporidiosis and temperature in metropolitan and rural areas of Victoria, Australia between 2001 and 2009. A negative binomial regression model was used to analyse monthly average maximum and minimum temperatures, rainfall and the monthly count of cryptosporidiosis notifications. In the metropolitan area, a 1 degrees C increase in monthly average minimum temperature of the current month was associated with a 22% increase in cryptosporidiosis notifications (incident rate ratio (IRR) 1.22; 95% confidence interval (CI) 1.13-1.31). In the rural area, a 1 degrees C increase in monthly average minimum temperature, lagged by 3 months, was associated with a 9% decrease in cryptosporidiosis notifications (IRR 0.91; 95% CI 0.86-0.97). Rainfall was not associated with notifications in either area. These relationships should be considered when planning public health response to ecological risks as well as when developing policies involving climate change. Rising ambient temperature may be an early warning signal for intensifying prevention efforts, including appropriate education for pool users about cryptosporidiosis infection and management, which might become more important as temperatures are projected to increase as a result of climate change. PMID- 26608766 TI - Integrating surveillance data on water-related diseases and drinking-water quality; action-research in a Brazilian municipality. AB - The Brazilian Ministry of Health proposed a research study involving municipal professional staff conducting both epidemiological and water quality surveillance to facilitate the integration of the data which they collected. It aimed to improve the intersectoral collaboration and health promotion activities in the municipalities, especially regarding drinking-water quality. We then conducted a study using the action-research approach. At its evaluation phase, a technique which we called 'the tree analogy' was applied in order to identify both possibilities and challenges related to the proposed interlinkage. Results showed that integrating the two data collection systems cannot be attained without prior institutional adjustments. It suggests therefore the necessity to unravel issues that go beyond the selection and the interrelation of indicators and compatibility of software, to include political, administrative and personal matters. The evaluation process led those involved to re-think their practice by sharing experiences encountered in everyday practice, and formulating constructive criticisms. All this inevitably unleashes a process of empowerment. From this perspective, we have certainly gathered some fruit from the Tree, but not necessarily the most visible. PMID- 26608767 TI - Quantification and molecular characterisation of human sapoviruses in water sources impacted by highly polluted discharged wastewater in South Africa. AB - Sapoviruses (SaVs) were detected and quantified in 8/10 water samples collected from wastewater treatment works (WWTWs) and water sources impacted by these WWTWs in Limpopo Province, South Africa. The median SaV concentration was 2.45 * 106 copies/L and SaV genotypes I.2 and IV were characterised. This study provides new data on the high concentrations of clinically relevant SaVs in rivers and dams impacted by poor-performing WWTWs. PMID- 26608768 TI - Algal control and enhanced removal in drinking waters in Cairo, Egypt. AB - Algal blooms at the major water treatment plants in Egypt have been reported since 2006. While previous studies focused on algal types and their correlation with disinfection by-products, correlation between raw water quality and algal blooms were not explored. Therefore, a survey of Nile water quality parameters at a major water intake in the Greater Cairo Urban Region was conducted from December 2011 to November 2012. Bench-scale experiments were conducted to evaluate the effectiveness of the conventional chloride/alum treatment compared with combined Cl/permanganate pre-oxidation with Al and Fe coagulants during the outbreak period. Addition of permanganate (0.5 mg/L) significantly reduced the chlorine demand from 5.5 to 2.7 mg/L. The applied alum coagulant dose was slightly reduced while residual Al was reduced by 27% and the algal count by 50% in the final treated waters. Applying ferric chloride and ferric sulfate as coagulants to waters treated with the combined pre-oxidation procedure effectively reduced algal count by 60% and better the total organic carbon reduction and residual aluminum in the treated water. Multivariate statistical analysis was used to identify the relationship between water quality parameters and occurrence of algae and to explain the impact of coagulants on the final water quality. PMID- 26608769 TI - Arsenic and heavy metals contamination, risk assessment and their source in drinking water of the Mardan District, Khyber Pakhtunkhwa, Pakistan. AB - The present study was conducted to investigate the physico-chemical characteristics in drinking water of Mardan District, Pakistan. Furthermore, water quality was evaluated for the risk assessment of arsenic and heavy metals (HMs) and their contamination sources. Representative groundwater samples of shallow and deep sources were collected in the study area. These samples were analyzed for physical parameters, anions, light metals (LMs) and HMs. Results were compared with the drinking water guideline values set by the World Health Organization and the US Environmental Protection Agency. Average concentrations of anions, LMs and HMs were found within the maximum allowable contaminant levels except for bicarbonates, Fe, Cu, and Pb. Results revealed that hazard quotients >1 were observed for shallow groundwater for 10% samples only, suggesting potential health risk from water consumption. Correlation analysis and principal component analysis showed a relationship among various physico-chemical parameters in both shallow and deep groundwater. Statistical analyses suggested the geogenic and anthropogenic sources for possible enhancement of various physico-chemical parameters in the aquifer system of the study area. PMID- 26608770 TI - Antibiotic resistance among aquatic bacteria in natural freshwater environments of Korea. AB - The taxonomic diversity and antibiotic resistance among freshwater bacterial communities in the major water bodies of Korea was examined using 437 penicillin resistant, and 110 tetracycline-resistant bacterial isolates. Based on 16S rRNA gene sequence analysis, most isolates were assigned to Proteobacteria, which was then followed by Bacteroidetes. Strains of Aeromonas were found as the most abundant penicillin-resistant populations, whereas those affiliated to diverse species including enteric groups were found as the most abundant tetracycline resistant populations. Most strains exhibited multiple antibiotic resistance, and all tested strains were resistant to penicillin and hygromycin. High levels of resistance were observed for antibiotics acting on cell wall synthesis, whereas low levels were for those acting on DNA replication or transcription in general. It is apparent from this study that penicillin resistance is widespread among environmental bacteria, although the antibiotic has been generally non-detectable in the environment. It is also likely from the taxonomic composition of the resistant communities that various sources including terrestrial animals and humans may contribute to antibiotic resistance in the freshwater environment. PMID- 26608771 TI - Detection of human enteric viruses in Umgeni River, Durban, South Africa. AB - The prevalence of adenovirus (AdV), rotaviruses (RV) and enteroviruses (EV) in Umgeni River waters of Durban, South Africa was assessed qualitatively and quantitatively during April 2011 to January 2012 using polymerase chain reaction (PCR)/reverse transcription-polymerase chain reaction (RT-PCR), nested PCR and quantitative PCR (qPCR), as well as nested integrated cell culture PCR (nested ICC-PCR). The phylogenetic analysis of the adenovirus and enterovirus amplicons was also performed. The nested PCR results effectively detected the presence of AdV and EV in all water samples. The results of qPCR demonstrated that higher populations of EV and of AdV were widely found in the Umgeni River. Rotavirus could only be detected in the upper Umgeni River, mainly during drier seasons. Nested ICC-PCR further confirmed the presence of infectious AdV and EV particles in 100% of water samples using various cell lines. The present study identifies potential viral hazards of Umgeni River water for domestic water supply and recreational activities. PMID- 26608772 TI - Effectiveness of solar disinfection (SODIS) in rural coastal Bangladesh. AB - Scarcity of drinking water in the coastal area of Bangladesh compels the inhabitants to be highly dependent on alternative water supply options like rainwater harvesting system (RWHS), pond sand filter (PSF), and rain-feed ponds. Susceptibility of these alternative water supply options to microbial contamination demands a low-cost water treatment technology. This study evaluates the effectiveness of solar disinfection (SODIS) to treat drinking water from available sources in the southwest coastal area of Bangladesh. A total of 50 households from Dacope upazila in Khulna district were selected to investigate the performance of SODIS. Data were collected in two rounds to examine fecal coliform (FC) and Escherichia coli (E. coli) contamination of drinking water at the household water storage containers and SODIS bottles, and thereby determined the effectiveness of SODIS in reducing fecal contamination. All water samples were analyzed for pH, electrical conductivity, turbidity and salinity. SODIS significantly reduced FC and E. coli contamination under household conditions. The median health risk reduction by SODIS was more than 96 and 90% for pond and RWHS, respectively. Besides, turbidity of the treated water was found to be less than 5 NTU, except pond water. Only 34% of the participating households routinely adopted SODIS during the study. PMID- 26608773 TI - Adenovirus, enterovirus and thermotolerant coliforms in recreational waters from Lake Guaiba beaches, Porto Alegre, Brazil. AB - In the present study, molecular detection of human adenoviruses (HAdV) and enteroviruses (EV) was performed in surface water samples collected from beaches Ipanema and Lami, located on the shores of Lake Guaiba, city of Porto Alegre, RS, southern Brazil. Furthermore, water safety was evaluated by counting thermotolerant coliforms (TC), following local government regulations. A total of 36 samples were collected monthly from six different sites along the beaches. Viral genomes were found in 30 (83.3%) samples. The higher detection rate was observed for HAdV (77.8%), followed by EV (22.2%). Although low concentrations of TC have been found, the occurrence of viral genomes in water samples was frequent and may pose a potential risk of infection for people bathing in these beaches. PMID- 26608774 TI - Role of mafic and ultramafic rocks in drinking water quality and its potential health risk assessment, Northern Pakistan. AB - This study investigates the drinking water (groundwater and surface water) quality and potential risk assessment along mafic and ultramafic rocks in the Swat district of Khyber Pakhtunkhwa Provence, Pakistan. For this purpose, 82 groundwater and 33 surface water samples were collected and analyzed for physico chemical parameters. Results showed that the majority of the physico-chemical parameters were found to be within the drinking water guidelines set by the World Health Organization. However, major cationic metals such as magnesium (Mg), and trace metals (TM) including iron (Fe), manganese (Mn), nickel (Ni), chromium (Cr) and cobalt (Co) showed exceeded concentrations in 13%, 4%, 2%, 20%, 20% and 55% of water samples, respectively. Health risk assessment revealed that the non carcinogenic effects or hazard quotient values through the oral ingestion pathway of water consumption for the TM (viz., Fe, Cr and Mn) were found to be greater than 1, could result in chronic risk to the exposed population. Results of statistical analyses revealed that mafic and ultramafic rocks are the main sources of metal contamination in drinking water, especially Ni and Cr. Both Ni and Cr have toxic health effects and therefore this study suggests that contaminated sites should be avoided or treated for drinking and domestic purposes. PMID- 26608775 TI - Analysis of physico-chemical and bacteriological quality of drinking water in Mafikeng, South Africa. AB - Mafikeng, the capital of the North West Province, receives water from two sources, namely the Molopo eye and the Modimola dam. Once treated, the potable water is mixed and supplied to the city via distribution systems. This study was designed to assess the quality of drinking water in Mafikeng and also to determine whether the water from the two sources has an impact on the mixed water quality. Physico-chemical parameters and bacteriological quality (faecal coliforms (FCs), total coliforms (TCs), heterotrophic bacteria and Peudomonas spp.) was monitored at three drinking water sites weekly for 4 months. The results revealed that the physico-chemical quality of the water was generally acceptable. The pH ranged from 5.7 +/- 0.18 to 8.6 +/- 0.14, the temperature ranged from 18.3 +/- 0.69 to 25.1 +/- 0.69 degrees C and the total dissolved solids (TDS) ranged from 159.9 +/- 22.44 to 364.4 +/- 12.44 mg/l. These values are within the target water quality range for drinking water as prescribed by WHO, Department of Water Affairs and SANS 241. What is of concern was the microbial quality of the water. FCs, TCs, heterotrophic bacteria and Pseudomonas spp. were present in some of the treated water samples. The most significant finding of this study is that all drinking water samples were positive for Pseudomonas spp. (>100/100 ml). PMID- 26608777 TI - Effect of oxidative phosphorylation signaling pathway on silkworm midgut following exposure to phoxim. AB - Organophosphate pesticides are applied widely in the world for agricultural purposes, and their exposures often resulted in non-cocooning of Bombyx mori in China. Silkworm midgut is the major organ for digestion and nutrient absorption, importantly it is also a barrier against foreign substances and chemical pesticides. The purpose of this study was to determine the mechanism of oxidative injury in silkworm midgut with phoxim induction. The results showed that the transcription level of oxidative phosphorylation signaling pathway genes of midgut under phoxim stress. Digital gene expression (DGE) analysis revealed that 24 electron transport chain (ETC)-related genes were upregulated. Quantitative real time polymerase chain reaction results indicated that the ETC the genes encoding NADH-CoQ1, Succinic-Q, cyt c reductase-S, cyt c oxidase-S, cytochrome c oxidase polypeptide IV, ATP synthase, and vacuolar H+ ATP synthase were all significantly up-regulated by 1.50-, 1.31-, 1.42-, 1.44-, 1.70-, 2.03- and 1.43 fold, respectively. Phoxim induction enhanced the activity of ETC complex in mitochondria, and induced the accumulation of ROS in midgut. These results indicated that trace phoxim enhanced respiration in midgut, and the imbalance between the activity changes of ETC may led to reactive oxygen species accumulation. The ETC of mitochondria may be potential biomarkers of midgut toxicity in B. mori caused by phoxim exposure. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 167-175, 2017. PMID- 26608776 TI - Diffusion of responsibility attenuates altruistic punishment: A functional magnetic resonance imaging effective connectivity study. AB - Humans altruistically punish violators of social norms to enforce cooperation and pro-social behaviors. However, such altruistic behaviors diminish when others are present, due to a diffusion of responsibility. We investigated the neural signatures underlying the modulations of diffusion of responsibility on altruistic punishment, conjoining a third-party punishment task with event related functional magnetic resonance imaging and multivariate Granger causality mapping. In our study, participants acted as impartial third-party decision makers and decided how to punish norm violations under two different social contexts: alone (i.e., full responsibility) or in the presence of putative other third-party decision makers (i.e., diffused responsibility). Our behavioral results demonstrated that the diffusion of responsibility served as a mediator of context-dependent punishment. In the presence of putative others, participants who felt less responsible also punished less severely in response to norm violations. Our neural results revealed that underlying this behavioral effect was a network of interconnected brain regions. For unfair relative to fair splits, the presence of others led to attenuated responses in brain regions implicated in signaling norm violations (e.g., AI) and to increased responses in brain regions implicated in calculating values of norm violations (e.g., vmPFC, precuneus) and mentalizing about others (dmPFC). The dmPFC acted as the driver of the punishment network, modulating target regions, such as AI, vmPFC, and precuneus, to adjust altruistic punishment behavior. Our results uncovered the neural basis of the influence of diffusion of responsibility on altruistic punishment and highlighted the role of the mentalizing network in this important phenomenon. Hum Brain Mapp 37:663-677, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26608779 TI - Metagenome Analysis Exploiting High-Throughput Chromosome Conformation Capture (3C) Data. AB - Microbial communities are complex and constitute important parts of our environment. Genomic analysis of these populations is a dynamic research area but remains limited by the difficulty in assembling full genomes of individual species. Recently, a new method for metagenome assembly/analysis based on chromosome conformation capture has emerged (meta3C). This approach quantifies the collisions experienced by DNA molecules to identify those sharing the same cellular compartments, allowing the characterization of genomes present within complex mixes of species. The exploitation of these chromosome 3D signatures holds promising perspectives for genome sequencing of discrete species in complex populations. It also has the potential to assign correctly extra-chromosomal elements, such as plasmids, mobile elements and phages, to their host cells. PMID- 26608778 TI - DNA Editing by APOBECs: A Genomic Preserver and Transformer. AB - Information warfare is not limited to the cyber world because it is waged within our cells as well. The unique AID (activation-induced cytidine deaminase)/APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide) family comprises proteins that alter DNA sequences by converting deoxycytidines to deoxyuridines through deamination. This C-to-U DNA editing enables them to inhibit parasitic viruses and retrotransposons by disrupting their genomic content. In addition to attacking genomic invaders, APOBECs can target their host genome, which can be beneficial by initiating processes that create antibody diversity needed for the immune system or by accelerating the rate of evolution. AID can also alter gene regulation by removing epigenetic modifications from genomic DNA. However, when uncontrolled, these powerful agents of change can threaten genome stability and eventually lead to cancer. PMID- 26608780 TI - The burden of infectious diseases in the Brazilian Southern state of Santa Catarina. AB - Infectious diseases are still significant causes of deaths in Brazil. The objective of this study was to estimate the burden of selected infectious diseases in the Brazilian Southern state of Santa Catarina in 2011. An ecological study was conducted. The infectious diseases included were HIV/AIDS, tuberculosis, hepatitis B, hepatitis C, Chagas disease, diarrheal diseases and other infectious diseases. Data were collected from official health information systems. Disability Adjusted Life Years (DALY) were estimated by the sum of Years of Life Lost (YLL) and Years Lived with Disability (YLD). 45,237.33 DALYs were estimated, with a rate of 685.46 DALYs per 100,000 population. 92.9% was due to YLL and 7.1% to YLD. Men and the age range of 0-4 years presented higher burden. The highest burden was attributed to HIV/AIDS. There was a high concentration of burden rates in the coast regions of the state. It could be concluded that more than 90% of the burden was attributed to the early mortality component. The highest burden was observed among men, children under 5 years of age and at the coast regions of the state. The highest levels of burden were due to HIV/AIDS. PMID- 26608781 TI - Selective isolation of hydrophobin SC3 by solid-phase extraction with polytetrafluoroethylene microparticles and subsequent mass spectrometric analysis. AB - Hydrophobins are small proteins that play a role in a number of processes during the filamentous fungi growth and development. These proteins are characterized by the self-assembly of their molecules into an amphipathic membrane at hydrophilic hydrophobic interfaces. Isolation and purification of hydrophobins generally present a challenge in their analysis. Hydrophobin SC3 from Schizophyllum commune was selected as a representative of class I hydrophobins in this work. A novel procedure for selective and effective isolation of hydrophobin SC3 based on solid phase extraction with polytetrafluoroethylene microparticles loaded in a small self-made microcolumn is reported. The tailored binding of hydrophobins to polytetrafluoroethylene followed by harsh elution conditions resulted in a highly specific isolation of hydrophobin SC3 from the model mixture of ten proteins. The presented isolation protocol can have a positive impact on the analysis and utilization of these proteins including all class I hydrophobins. Hydrophobin SC3 was further subjected to reduction of its highly stable disulfide bonds and to chymotryptic digestion followed by mass spectrometric analysis. The isolation and digestion protocols presented in this work make the analysis of these highly hydrophobic and compact proteins possible. PMID- 26608782 TI - Association Between Single-Nucleotide Polymorphism (SNP) in miR-146a, miR-196a2, and miR-499 and Risk of Ischemic Stroke: A Meta-Analysis. AB - BACKGROUND The association between 3 well known SNPs - miR-146a C/G (rs2910164), miR-196a2 T/C (rs11614913), and miR-499 A/G (rs3746444) - in pre-miRNA sequences and ischemic stroke (IS) are still conflicting and inconclusive. This meta analysis aimed to pool previous studies get a more precise assessment of the association between these 3 SNPs and the risk of IS. MATERIAL AND METHODS Relevant studies were searched in online databases. The strength of the association between the SNPs and IS were estimated by pooling odds ratios (OR) and 95% confidence intervals (CI) using Review Manager (version 5.3). RESULTS Rs2910164 C allele was associated with lower IS risk. But this trend was only observed in Koreans under the allele model (OR=0.81, 95% CI=0.68-0.95, p=0.009), dominant model (OR=0.68, 95% CI=0.50-0.93, p=0.02), recessive model (OR=0.79, 95% CI=0.63-1.00, p=0.05), and homozygous model (OR=0.63, 95%CI=0.45-0.88, p=0.007). Rs11614913 T allele might be associated with higher IS risk under the dominant model (OR=1.45, 95% CI=1.19-1.78, p=0.0003), while rs3746444 A allele might be associated with decreased IS risk under the homozygous model (OR=0.48, 95% CI=0.23-0.98, p=0.04) only in Chinese, but not in Koreans. CONCLUSIONS Although the 3 SNPs might be associated with IS, the association varied significantly in different countries. PMID- 26608783 TI - The shutter-speed paradigm: not your father's DCE-MRI. PMID- 26608784 TI - RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans. AB - Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exome sequencing. Two candidate autozygous intervals were identified, and the second round of exome sequencing revealed a single intronic variant therein (c.2885+8A>G [p.Ser963(*)] in RTTN exon 23). RT-PCR confirmed that this change creates a cryptic splice donor and thus causes retention of the intervening 7 bp of the intron and leads to premature truncation. On the basis of this finding, we reanalyzed the exome file of a second consanguineous family affected by a similar phenotype and identified another homozygous change in RTTN as the likely causal mutation. Combined linkage analysis of the two families confirmed that RTTN maps to the only significant linkage peak. Finally, through international collaboration, a Canadian multiplex family affected by microcephalic primordial dwarfism and biallelic mutation of RTTN was identified. Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration. PMID- 26608785 TI - Histone Modifier Genes Alter Conotruncal Heart Phenotypes in 22q11.2 Deletion Syndrome. AB - We performed whole exome sequence (WES) to identify genetic modifiers on 184 individuals with 22q11.2 deletion syndrome (22q11DS), of whom 89 case subjects had severe congenital heart disease (CHD) and 95 control subjects had normal hearts. Three genes including JMJD1C (jumonji domain containing 1C), RREB1 (Ras responsive element binding protein 1), and SEC24C (SEC24 family member C) had rare (MAF < 0.001) predicted deleterious single-nucleotide variations (rdSNVs) in seven case subjects and no control subjects (p = 0.005; Fisher exact and permutation tests). Because JMJD1C and RREB1 are involved in chromatin modification, we investigated other histone modification genes. Eighteen case subjects (20%) had rdSNVs in four genes (JMJD1C, RREB1, MINA, KDM7A) all involved in demethylation of histones (H3K9, H3K27). Overall, rdSNVs were enriched in histone modifier genes that activate transcription (Fisher exact p = 0.0004, permutations, p = 0.0003, OR = 5.16); however, rdSNVs in control subjects were not enriched. This implicates histone modification genes as influencing risk for CHD in presence of the deletion. PMID- 26608787 TI - A wall of information? Exploring the public health component of maternity care in England. AB - BACKGROUND: midwives have traditionally had an important role in providing public health messages to women. The range and diversity of the public health remit within maternity services has expanded rapidly over the past decade and maternity support workers as well as midwives are now engaged in public health work in many areas. Given these changes a review of current practice was indicated. OBJECTIVE: to identify student midwives', midwives' and midwifery support workers' current knowledge of and involvement in the public health agenda in England. DESIGN: descriptive qualitative study using online discussion forums. SETTING: England, United Kingdom PARTICIPANTS: undergraduate student midwives, midwives and maternity support workers employed by the National Health Service in England and University employed Leads for Midwifery Education. FINDINGS: key themes identified were: the scope of the midwives' public health role, training and support for public health role, barriers and facilitators, specific client groups, specialist referral services. Student midwives, midwives and maternity support workers view engagement with, and delivery of, public health initiatives as an integral component of their roles, but are on occasions frustrated by constraints of time, training and public engagement. KEY CONCLUSIONS: the National Health Service in England aims to engage pregnant women and new mothers in a diverse range of population based and individualised, public health initiatives. Currently, there are high levels of involvement in the public health agenda from the maternity workforce across a wide range of activities. However, midwives and maternity support workers are restricted by barriers of time, training and resources. These barriers will need addressing for optimal maternity care engagement in public health to be realised. IMPLICATIONS FOR PRACTICE: policy makers, commissioners and National Health Service providers need to provide clear guidance on the expectations of the public health remit of midwives and maternity support workers and ensure that such expectations are appropriately resourced to provide effective delivery. PMID- 26608786 TI - Diverse Roles of Axonemal Dyneins in Drosophila Auditory Neuron Function and Mechanical Amplification in Hearing. AB - Much like vertebrate hair cells, the chordotonal sensory neurons that mediate hearing in Drosophila are motile and amplify the mechanical input of the ear. Because the neurons bear mechanosensory primary cilia whose microtubule axonemes display dynein arms, we hypothesized that their motility is powered by dyneins. Here, we describe two axonemal dynein proteins that are required for Drosophila auditory neuron function, localize to their primary cilia, and differently contribute to mechanical amplification in hearing. Promoter fusions revealed that the two axonemal dynein genes Dmdnah3 (=CG17150) and Dmdnai2 (=CG6053) are expressed in chordotonal neurons, including the auditory ones in the fly's ear. Null alleles of both dyneins equally abolished electrical auditory neuron responses, yet whereas mutations in Dmdnah3 facilitated mechanical amplification, amplification was abolished by mutations in Dmdnai2. Epistasis analysis revealed that Dmdnah3 acts downstream of Nan-Iav channels in controlling the amplificatory gain. Dmdnai2, in addition to being required for amplification, was essential for outer dynein arms in auditory neuron cilia. This establishes diverse roles of axonemal dyneins in Drosophila auditory neuron function and links auditory neuron motility to primary cilia and axonemal dyneins. Mutant defects in sperm competition suggest that both dyneins also function in sperm motility. PMID- 26608788 TI - PTH modulation of NCC activity regulates TRPV5 Ca2+ reabsorption. AB - Since parathyroid hormone (PTH) is known to increase transient receptor potential vanilloid (TRPV)5 activity and decrease Na(+)-Cl(-) cotransporter (NCC) activity, we hypothesized that decreased NCC-mediated Na(+) reabsorption contributes to the enhanced TRPV5 Ca(2+) reabsorption seen with PTH. To test this, we used mDCT15 cells expressing functional TRPV5 and ruthenium red-sensitive (45)Ca(2+) uptake. PTH increased (45)Ca(2+) uptake to 8.8 +/- 0.7 nmol.mg(-1).min(-1) (n = 4, P < 0.01) and decreased NCC activity from 75.4 +/- 2.7 to 20.3 +/- 1.3 nmol.mg( 1).min(-1) (n = 4, P < 0.01). Knockdown of Ras guanyl-releasing protein (RasGRP)1 had no baseline effect on (45)Ca(2+) uptake but significantly attenuated the response to PTH from a 45% increase (6.0 +/- 0.2 to 8.7 +/- 0.4 nmol.mg(-1).min( 1)) in control cells to only 20% in knockdown cells (6.1 +/- 0.1 to 7.3 +/- 0.2 nmol.mg(-1).min(-1), n = 4, P < 0.01). Inhibition of PKC and PKA resulted in further attenuation of the PTH effect. RasGRP1 knockdown decreased the magnitude of the TRPV5 response to PTH (7.9 +/- 0.1 nmol.mg(-1).min(-1) for knockdown compared with 9.1 +/- 0.1 nmol.mg(-1).min(-1) in control), and the addition of thiazide eliminated this effect (a nearly identical 9.0 +/- 0.1 nmol.mg(-1).min( 1)). This indicates that functionally active NCC is required for RasGRP1 knockdown to impact the PTH effect on TRPV5 activity. Knockdown of with no lysine kinase (WNK)4 resulted in an attenuation of the increase in PTH-mediated TRPV5 activity. TRPV5 activity increased by 36% compared with 45% in control (n = 4, P < 0.01 between PTH-treated groups). PKC blockade further attenuated the PTH effect, whereas combined PKC and PKA blockade in WNK4KD cells abolished the effect. We conclude that modulation of NCC activity contributes to the response to PTH, implying a role for hormonal modulation of NCC activity in distal Ca(2+) handling. PMID- 26608790 TI - Remote effects of acute kidney injury in a porcine model. AB - Acute kidney injury (AKI) is a common and serious condition with no specific treatment. An episode of AKI may affect organs distant from the kidney, further increasing the morbidity associated with AKI. The mechanism of organ cross talk after AKI is unclear. The renal and immune systems of pigs and humans are alike. Using a preclinical animal (porcine) model, we tested the hypothesis that early effects of AKI on distant organs is by immune cell infiltration, leading to inflammatory cytokine production, extravasation, and edema. In 29 pigs exposed to either sham surgery or renal ischemia-reperfusion (control, n = 12; AKI, n = 17), we assessed remote organ (liver, lung, brain) effects in the short (from 2- to 48 h reperfusion) and longer term (5 wk later) using immunofluorescence (for leukocyte infiltration, apoptosis), a cytokine array, tissue elemental analysis (e.g., electrolytes), blood hematology and chemistry (e.g., liver enzymes), and PCR (for inflammatory markers). AKI elicited significant, short-term (~24 h) increments in enzymes indicative of acute liver damage (e.g. , AST: ALT ratio; P = 0.02) and influenced tissue biochemistry in some remote organs (e.g., lung tissue [Ca(2+)] increased; P = 0.04). These effects largely resolved after 48 h, and no further histopathology, edema, apoptosis, or immune cell infiltration was noted in the liver, lung, or hippocampus in the short and longer term. AKI has subtle biochemical effects on remote organs in the short term, including a transient increment in markers of acute liver damage. These effects resolved by 48 h, and no further remote organ histopathology, apoptosis, edema, or immune cell infiltration was noted. PMID- 26608789 TI - Vasopressin/V2 receptor stimulates renin synthesis in the collecting duct. AB - Renin is synthesized in the principal cells of the collecting duct (CD), and its production is increased via cAMP in angiotensin (ANG) II-dependent hypertension, despite suppression of juxtaglomerular (JG) renin. Vasopressin, one of the effector hormones of the renin-angiotensin system (RAS) via the type 2-receptor (V2R), activates the cAMP/PKA/cAMP response element-binding protein (CREB) pathway and aquaporin-2 expression in principal cells of the CD. Accordingly, we hypothesized that activation of V2R increases renin synthesis via PKA/CREB, independently of ANG II type 1 (AT1) receptor activation in CD cells. Desmopressin (DDAVP; 10(-6) M), a selective V2R agonist, increased renin mRNA (~3 fold), prorenin (~1.5-fold), and renin (~2-fold) in cell lysates and cell culture media in the M-1 CD cell line. Cotreatment with DDAVP+H89 (PKA inhibitor) or CREB short hairpin (sh) RNA prevented this response. H89 also blunted DDAVP-induced CREB phosphorylation and nuclear localization. In 48-h water-deprived (WD) mice, prorenin-renin protein levels were increased in the renal inner medulla (~1.4- and 1.8-fold). In WD mice treated with an ACE inhibitor plus AT1 receptor blockade, renin mRNA and prorenin protein levels were still higher than controls, while renin protein content was not changed. In M-1 cells, ANG II or DDAVP increased prorenin-renin protein levels; however, there were no further increases by combined treatment. These results indicate that in the CD the activation of the V2R stimulates renin synthesis via the PKA/CREB pathway independently of RAS, suggesting a critical role for vasopressin in the regulation of renin in the CD. PMID- 26608791 TI - Unilateral ureteral obstruction induces DNA repair by APE1. AB - Ureteral obstruction is associated with oxidative stress and the development of fibrosis of the kidney parenchyma. Apurinic/apyrimidinic endonuclease (APE1) is an essential DNA repair enzyme for repair of oxidative DNA lesions and regulates several transcription factors. The aim of the present study was to investigate whether APE1 is regulated by acute (24 h) and chronic (7 days) unilateral ureteral obstruction (UUO). APE1 was expressed in essentially all kidney cells with the strongest expression in proximal tubuli. After 24 h of UUO, APE1 mRNA was induced in the cortex, inner stripe of the outer medulla (ISOM), and inner medulla (IM). In contrast, the APE1 protein level was not regulated in the IM and ISOM and only slightly increased in the cortex. APE1 DNA repair activity was not significantly changed. A different pattern of regulation was observed after 7 days of UUO, with an increase of the APE1 mRNA level in the cortex but not in the ISOM and IM. The APE1 protein level in the cortex, ISOM, and IM increased significantly. Importantly, we observed a significant increase in APE1 DNA repair activity in the cortex and IM. To confirm our model, we investigated heme oxygenase-1, collagen type I, fibronectin I, and alpha-smooth muscle actin levels. In vitro, we found the transcriptional regulatory activity of APE1 to be involved in the upregulation of the profibrotic factor connective tissue growth factor. In summary, APE1 is regulated at different levels after acute and chronic UUO. Thus, our results suggest that DNA repair activity is regulated in response to progressive (7 days) obstruction and that APE1 potentially could play a role in the development of fibrosis in kidney disease. PMID- 26608792 TI - The impact of medical errors on Swiss Anesthesiologists: a cross-sectional survey. PMID- 26608793 TI - Hydroxytyrosol decreases the oxidative and nitrosative stress levels and promotes angiogenesis through HIF-1 independent mechanisms in renal hypoxic cells. AB - In the kidney, tissue oxygen tension is comparatively low and this renders this organ more prone to hypoxic injury. In fact, hypoxia has a central role in the development and progression of renal disease. The recovery from this situation is dependent on the degree to which sublethally damaged cells restore normal function. The master regulator of the hypoxic response is hypoxia-inducible factor-1 (HIF-1). HIF-1 activity depends on the HIF-1alpha subunit level which is regulated by oxygen, nitric oxide (NO), reactive oxygen species and mTOR. Given the antioxidant and antinitrosative properties ascribed to hydroxytyrosol (HT), this study evaluates the impact of this olive oil polyphenol on the response to hypoxia in kidney cells. For this purpose, the human embryonic kidney HEK293T cell line was treated with HT and cultured under sublethal hypoxic conditions. Our results demonstrate that HT treatment decreases both, post-hypoxic reactive oxygen species and NO levels and, consequently, HIF-1alpha accumulation. However, HT does not affect mTOR activation or the factor inhibiting HIF level but promotes the expression of angiogenic proteins, suggesting that HT activates an adaptive response to hypoxia in a HIF-1alpha-independent pathway. In fact, this effect could be ascribed to the up-regulation of estrogen-related receptor alpha. In conclusion, our results suggest that in renal hypoxia, HT treatment might act as an effective preventive therapeutic approach to decrease stress and to improve the adaptive response to this pathological situation. PMID- 26608794 TI - Determination of the thermal properties of leaves by non-invasive contact-free laser probing. AB - The thermal properties of materials provide valuable data for quality monitoring and the rational design of process steps where heating is required. Here we report a rapid, simple and reliable technique that determines the most important thermal properties of leaves, i.e. the specific heat capacity (cp) and thermal conductivity (lambda). Such data are useful when leaves are heated during processing, e.g. for the precipitation of host cell proteins during the extraction of high-value products such as recombinant proteins produced by molecular farming. The cp of tobacco (Nicotiana tabacum) and Nicotiana benthamiana leaves was determined by infrared measurement of the temperature increase caused by a near-infrared laser pulse of defined length and intensity. We used the sample temperature profiles to calculate lambda based on exponential fits of the temperature decline, taking convective heat transfer and thermal radiation into account. We found that the average cp was 3661 +/- 323 J kg(-1) K( 1) (n=19) for tobacco and 2253 +/- 285 J kg(-1) K(-1) (n=25) for N. benthamiana, whereas the average lambda was 0.49 +/- 0.13 (n=19) for tobacco and 0.41 +/- 0.20 (n=25) Jm(-1) s(-1)K(-1) for N. benthamiana. These values are similar to those established for other plant species by photothermal imaging and other methods. The cp and lambda values of leaves can be determined easily using our non invasive method, which is therefore suitable for the in-line or at-line monitoring of plants, e.g. during the highly regulated production of biopharmaceutical proteins. PMID- 26608795 TI - Family Complexity, Siblings, and Children's Aggressive Behavior at School Entry. AB - As family structure in the United States has become increasingly dynamic and complex, children have become more likely to reside with step- or half-siblings through a variety of pathways. When these pathways are accounted for, more than one in six U.S. children live with a step- or half-sibling at age 4. We use data from the Early Childhood Longitudinal Study-Birth Cohort (N ~ 6,550) to assess the independent and joint influences of residing with a single parent or stepparent and with step- or half-siblings on children's aggressive behavior at school entry. The influences of parents' union status and complex sibship status on aggressive behavior are independent. Family resources partially explain the association between residing with an unpartnered mother and aggressive behavior regardless of sibship status. However, the resource hypothesis does not explain the association of complex sibship with aggressive behavior. PMID- 26608796 TI - Variants Near CCK Receptors are Associated With Electrophysiological Responses to Pre-pulse Startle Stimuli in a Mexican American Cohort. AB - Neurophysiological measurements of the response to pre-pulse and startle stimuli have been suggested to represent an important endophenotype for both substance dependence and other select psychiatric disorders. We have previously shown, in young adult Mexican Americans (MA), that presentation of a short delay acoustic pre-pulse, prior to the startle stimuli can elicit a late negative component at about 400 msec (N4S), in the event-related potential (ERP), recorded from frontal cortical areas. In the present study, we investigated whether genetic factors associated with this endophenotype could be identified. The study included 420 (age 18-30 years) MA men (n = 170), and women (n = 250). DNA was genotyped using an Affymetrix Axiom Exome1A chip. An association analysis revealed that the CCKAR and CCKBR (cholecystokinin A and B receptor) genes each had a nearby variant that showed suggestive significance with the amplitude of the N4S component to pre pulse stimuli. The neurotransmitter cholecystokinin (CCK), along with its receptors, CCKAR and CCKBR, have been previously associated with psychiatric disorders, suggesting that variants near these genes may play a role in the pre pulse/startle response in this cohort. PMID- 26608798 TI - Commentary on: Clinical and Demographic Correlates of Ejaculatory Dysfunctions Other than Premature Ejaculation: A Prospective, Observational Study. PMID- 26608797 TI - Breast Cancer Invasion and Metastasis by mPRalpha Through the PI3K/Akt Signaling Pathway. AB - Invasive breast cancer is the most common type of malignancy in women worldwide. However, the mechanism responsible for breast cancer metastasis is still unclear and needs further illustration. It has been proven that matrix metallopeptidase 9 (MMP-9) promotes metastasis of the cancer cells. However, the interaction between mPRalpha and MMP-9 has not been studied. Therefore, in the present research, the effect of MMP-9 on the malignant progression of invasive breast cancer promoted by membrane progesterone receptoralpha (mPRalpha) was investigated. The results showed that the protein expression of mPRalpha, p-Akt and MMP-9 increased in the cancerous tissues compared to that of the noncancerous breast tissue. Furthermore, a positive correlation was found between mPRalpha and C-erbB-2, as well as the number of involved local lymph nodes. On the other hand, a negative correlation was observed between mPRalpha and estrogen receptors (ER) along with progesterone receptors (PR). Similarly, a positive association was found between MMP-9 and the number of involved local lymph nodes. Besides, the high expression of MMP-9 also had a positive correlation with the tumor size. However, the high level of MMP-9 had a negative correlation with ER and PR. In addition, there was a positive correlation between mPRalpha and p-Akt together with MMP-9. The results confirm that mPRalpha was a major marker of harmful prognosis and it promoted the expression of MMP-9 during invasion to the local lymph nodes through the pathway of PI3K/Akt. The present study provided a novel therapeutic strategy to inhibit breast cancer growth by preventing mPRalpha signaling pathway. PMID- 26608799 TI - Responses to the letters to the editor for "battery powered bone drill: caution needed in densely blastic lesions". PMID- 26608800 TI - The extent to which the public health 'war on obesity' reflects the ethical values and principles of critical health promotion: a multimedia critical discourse analysis. AB - ISSUE ADDRESSED: The discipline of health promotion is responsible for implementing strategies within weight-related public health initiatives (WR-PHI). It is imperative that such initiatives be subjected to critical analysis through a health promotion ethics lens to help ensure ethical health promotion practice. METHODS: Multimedia critical discourse analysis was used to examine the claims, values, assumptions, power relationships and ideologies within Australian WR-PHI. The Health Promotion Values and Principles Continuum was used as a heuristic to evaluate the extent to which the WR-PHI reflected the ethical values of critical health promotion: active participation of people in the initiative; respect for personal autonomy; beneficence; non-maleficence; and strong evidential and theoretical basis for practice. RESULTS: Ten initiatives were analysed. There was some discourse about the need for participation of people in the WR-PHI, but people were routinely labelled as 'target groups' requiring 'intervention'. Strong evidence of a coercive and paternalistic discourse about choice was identified, with minimal attention to respect for personal autonomy. There was significant emphasis on the beneficiaries of the WR-PHI but minimal attention to the health benefits, and nothing about the potential for harm. Discourse about the evidence of need was objectivist, and there was no discussion about the theoretical foundations of the WR-PHI. CONCLUSION: The WR-PHI were not reflective of the ethical values and principles of critical health promotion. So what? Health promotion researchers and practitioners engaged in WR-PHI should critically reflect on the extent to which they are consistent with the ethical aspects of critical health promotion practice. PMID- 26608801 TI - Epicardial myocardial strain abnormalities may identify the earliest stages of arrhythmogenic cardiomyopathy. AB - The aim of this cohort study was to evaluate the value of echocardiographic multilayer strain analysis in the identification of arrhythmogenic cardiomyopathy (AC) in its earliest stages in which sudden cardiac death can occurs. Twenty seven asymptomatic relatives of AC probands (mean age 39.6 +/- 19.5 years, 37 % male) with a desmosomal pathogenic mutation but no additional criteria for AC (group II) were compared to age and sex-matched healthy controls (group I). In addition, 70 patients harboring a pathogenic desmosomal mutation with "definitive" diagnosis of AC (group IV), and 19 subjects with "borderline" diagnosis (group III) were also studied. A standard echocardiographic evaluation plus left (LV) and right ventricular global and regional transmural, endocardial, and epicardial longitudinal strain (LS) analysis, was performed. In group II, while LV ejection fraction, fractional shortening, and S' were not significantly reduced compared to controls, transmural global LS was significantly reduced to 19.3 +/- 1.8 % in group II versus 20.9 +/- 1.1 % in controls (p = 0.0003). Compared to controls, group II presented significant (p < 0.05) regional LS decrease in the basal infero-lateral, antero-lateral, latero-apical, infero septal, and septo-apical segments. Moreover, LS of the latero-apical and the basal antero-lateral segments was significantly altered in the epicardium (p < 0.05) but not significantly in the endocardium. Global and regional LV LS analysis allows detection of AC in an early or non-diagnostic stage of the disease. Moreover, epicardial LS analysis allows the detection of abnormalities earlier than endocardial LS. PMID- 26608803 TI - Realistic biological approaches for improving thermoradiotherapy. AB - There is now definitive clinical evidence that hyperthermia can successfully improve the response of certain human tumour types to radiation therapy, but, there is still the need for improvement. From a biological standpoint this can be achieved by either targeting the cellular or vascular components of tumours. Strategies include targeting the radiation DNA repair processes, improving drug delivery using nanoparticles, exploiting immunotherapy mechanisms, reducing tumour pH, or modifying the tumour vascular supply. All of these approaches have been combined with either hyperthermia or radiation in preclinical models and clear benefits in tumour response observed. But few of these methods have actually been combined with thermoradiotherapy. Furthermore, very few combinations have been tested in relevant normal tissue studies, despite the fact that it is the normal tissue response that controls the maximal heat or radiation treatment that can be applied. Here we review the most clinically relevant biological approaches that have been shown to enhance thermoradiotherapy, or have the potential to be applied in this context, and suggest how these should be moved forward into the clinic. PMID- 26608802 TI - Sequential radial and circumferential strain and oxidative stress assessment in dogs with tachycardia-induced cardiac dysfunction. AB - Quantitative analysis of left ventricular (LV) deformation based on two dimensional speckle tracking echocardiography (2D STE) has increasingly been used to assess segmental and global function because conventional echocardiography is influenced by tethering effects of adjacent myocardium and cardiac translational motion. HYPOTHESIS: (1) 2D STE can be useful to detect subtle regional changes in the LV contractility during development of tachycardia-induced cardiomyopathy (TIC) to heart failure in awake dog; (2) oxidized glutathione (GSSG) and reduced glutathione (GSH) levels are associated with the development of its respective segmental wall motion abnormalities (WMA). 6 healthy canine female Beagles were examined using 2D STE myocardial strain analysis before and for 8 weeks on week basis of rapid ventricular pacing (RVP) and at the end of study each myocardial segment were evaluated for oxidative status (GSH:GSSG ratio). 2D STE showed an initial peak of reduced global radial strain at 2 weeks of RVP in all three cardiac levels analyzed in which the affected segments showed a decreased transmural fiber shortening from anteroseptal to inferior segments distributed in helical pattern suggesting impaired contractility from part of left band to apical loop of spiral muscle band while global circumferential strain showed to be reduced since the fifth week of RVP particularly in the base and midventricular levels of ascending segment in clockwise direction from lateral to inferior segments. The most affected segments are localized in the lateral to posterior wall, however, segmental oxidative stress analysis did not show correlation with WMA detected by strain. 2D STE strain demonstrated to be a reliable tool for evaluation of LV myocardial deformation in TIC canine model showing an earlier significant WMA using radial strain and later using circumferential strain which may be of importance for improvement of diagnosis and therapy in naturally occurring canine cardiomyopathy and for earlier detection of WMA after suboptimal pacemaker lead placement. PMID- 26608804 TI - Molecular epidemiological characteristics of Salmonella enterica serovars Enteritidis, Typhimurium and Livingstone strains isolated in a Tunisian university hospital. AB - Enteritidis, Typhimurium and Livingstone are the main Salmonella enterica serovars recovered in Tunisia. Here, we aimed to assess the genetic diversity of fifty-seven Salmonella enterica strains from different sampling periods, origins and settings using pulsed-field gel electrophoresis (PFGE), multi-locus sequence typing (MLST) and multi-locus variable-number tandem repeat analysis (MLVA). Salmonella Enteritidis, isolated from human and food sources from two regions in Sfax in 2007, were grouped into one cluster using PFGE. However, using MLVA these strains were divided into two clusters. Salmonella Typhimurium strains, recovered in 2012 and represent sporadic cases of human clinical isolates, were included in one PFGE cluster. Nevertheless, the MLVA technique, divided Salmonella Typhimurium isolates into six clusters with diversity index reaching (DI = 0.757). For Salmonella Livingstone which was responsible of two nosocomial outbreaks during 2000-2003, the PFGE and MLVA methods showed that these strains were genetically closely related. Salmonella Enteritidis and Salmonella Livingstone populations showed a single ST lineage ST11 and ST543 respectively. For Salmonella Typhimurium, two MLST sequence types ST19 and ST328 were defined. Salmonella Enteritidis and Salmonella Typhimurium strains were clearly differentiated by MLVA which was not the case using PFGE. PMID- 26608806 TI - Pulsatile support using a rotary left ventricular assist device with an electrocardiography-synchronized rotational speed control mode for tracking heart rate variability. AB - We previously developed a novel control system for a continuous-flow left ventricular assist device (LVAD), the EVAHEART, and demonstrated that sufficient pulsatility can be created by increasing its rotational speed in the systolic phase (pulsatile mode) in a normal heart animal model. In the present study, we assessed this system in its reliability and ability to follow heart rate variability. We implanted an EVAHEART via left thoracotomy into five goats for the Study for Fixed Heart Rate with ventricular pacing at 80, 100, 120 and 140 beats/min and six goats for the Study for native heart rhythm. We tested three modes: the circuit clamp, the continuous mode and the pulsatile mode. In the pulsatile mode, rotational speed was increased during the initial 35 % of the RR interval by automatic control based on the electrocardiogram. Pulsatility was evaluated by pulse pressure and dP/dt max of aortic pressure. As a result, comparing the pulsatile mode with the continuous mode, the pulse pressure was 28.5 +/- 5.7 vs. 20.3 +/- 7.9 mmHg, mean dP/dt max was 775.0 +/- 230.5 vs 442.4 +/- 184.7 mmHg/s at 80 bpm in the study for fixed heart rate, respectively (P < 0.05). The system successfully determined the heart rate to be 94.6 % in native heart rhythm. Furthermore, pulse pressure was 41.5 +/- 7.9 vs. 27.8 +/- 5.6 mmHg, mean dP/dt max was 716.2 +/- 133.9 vs 405.2 +/- 86.0 mmHg/s, respectively (P < 0.01). In conclusion, our newly developed the pulsatile mode for continuous-flow LVADs reliably provided physiological pulsatility with following heart rate variability. PMID- 26608807 TI - Molecular diagnosis: Implications for ophthalmology. AB - The effort to subdivide diseases and to individualize therapies based on characteristics of the patient has been labeled precision medicine. Jameson and Longo define precision medicine as "treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations" (Jameson and Longo, 2015). We illustrate how molecular diagnosis can be applied to orbital inflammatory disease to achieve the goals of precision medicine. PMID- 26608808 TI - Molecular mechanisms of osteoporotic hip fractures in elderly women. AB - A common manifestation of age-related bone loss and resultant osteoporosis are fractures of the hip. Age-related osteoporosis is thought to be determined by a number of intrinsic factors including genetics, hormonal changes, changes in levels of oxidative stress, or an inflammatory status associated with the aging process. The aim of this study was to investigate gene expression and bone architecture in bone samples derived from elderly osteoporotic women with hip fractures (OP) in comparison to bone samples from age matched women with osteoarthritis of the hip (OA). Femoral heads and adjacent neck tissue were collected from 10 women with low-trauma hip fractures (mean age 83+/-6) and consecutive surgical hip replacement. Ten bone samples from patients undergoing hip replacement due to osteoarthritis (mean age 80+/-5) served as controls. One half of each bone sample was subjected to gene expression analysis. The second half of each bone sample was analyzed by microcomputed tomography. From each half, samples from four different regions, the central and subcortical region of the femoral head and neck, were analyzed. We could show a significantly decreased expression of the osteoblast related genes RUNX2, Osterix, Sclerostin, WNT10B, and Osteocalcin, a significantly increased ratio of RANKL to Osteoprotegerin, and a significantly increased expression of the enzymes superoxide dismutase 2 (SOD2) and glutathione peroxidase GPX3, and of the inflammatory cytokine IL6 in bone samples from hip fracture patients compared to controls. Major microstructural changes in OP bone were seen in the neck and were characterized by a significant decrease of bone volume, trabecular number, and connectivity density and a significant increase of trabecular separation. In conclusion, our data give evidence for a decreased expression of osteoblast related genes and increased expression of osteoclast related genes. Furthermore, increased expression of SOD2 and GPX3 suggest increased antioxidative activity in bone samples from elderly osteoporotic women with hip fractures. PMID- 26608809 TI - The presence of the ovary prevents hepatic mitochondrial oxidative stress in young and aged female mice through glutathione peroxidase 1. AB - BACKGROUND: For unknown reasons a woman's risk for developing Metabolic Syndrome (MetS) increases dramatically with age and/or loss of ovarian function. The MetS is characterized by hepatic insulin resistance (IR), which is strongly associated with intrahepatic lipid (IHL) accumulation, mitochondrial dysfunction, and oxidative stress. Although circumstantial evidence suggests that the endocrine function of the ovary can directly impact hepatic mitochondrial function, this hypothesis remains untested. Thus, the purpose of this study was to assess the influence of age and secretory function of the ovary on mechanisms that regulate hepatic mitochondrial function. METHODS: Adult (10 week-old) and aged (88 week old) female C57BL/6 mice were separated into two groups to undergo bilateral ovariectomy (OVX) or control surgery (SHAM). Eight weeks after surgery hepatic tissue was removed for measurements of total IHL and fatty acid species within hepatic triglycerides, mitochondrial function, and reactive oxygen species (ROS) production. RESULTS: Hepatic IHL content was not affected by OVX, but was increased by age. OVX had no effect on mitochondrial respiration, however, hepatic mitochondria from aged mice had lower O2 consumption, lower complex IV and higher complex I content. Mitochondrial H2O2 production was highest in OVX groups and exacerbated by age, while mitochondrial lipid peroxidation was highest in the aged mice and exacerbated by OVX. Regardless of age, OVX resulted in lower mitochondrial content of antioxidant glutathione peroxidase 1 (Gpx1). Isolated liver tissue from a sub-set of animals were acutely treated with conditioned ovarian media which increased Gpx1 mRNA expression compared to vehicle treated liver tissue. CONCLUSION: Ovarian secretory function is necessary for the maintenance of hepatic ROS buffering capacity in the mitochondria, while age significantly influences mitochondrial respiration. These data suggest that when age is coupled with loss of ovarian function there is an increased risk for developing hepatic mitochondrial dysfunction, which may influence the onset of metabolic disease. Thus, in females there is critical organ cross-talk occurring between hepatic tissue and the ovary that impacts hepatic mitochondrial function. PMID- 26608810 TI - Direct Evidence for Packaging Signal-Mediated Assembly of Bacteriophage MS2. AB - Using cross-linking coupled to matrix-assisted laser desorption/ionization mass spectrometry and CLIP-Seq sequencing, we determined the peptide and oligonucleotide sequences at the interfaces between the capsid proteins and the genomic RNA of bacteriophage MS2. The results suggest that the same coat protein (CP)-RNA and maturation protein (MP)-RNA interfaces are used in every viral particle. The portions of the viral RNA in contact with CP subunits span the genome, consistent with a large number of discrete and similar contacts within each particle. Many of these sites match previous predictions of the locations of multiple, dispersed and degenerate RNA sites with cognate CP affinity termed packaging signals (PSs). Chemical RNA footprinting was used to compare the secondary structures of protein-free genomic fragments and the RNA in the virion. Some PSs are partially present in protein-free RNA but others would need to refold from their dominant solution conformations to form the contacts identified in the virion. The RNA-binding peptides within the MP map to two sections of the N-terminal half of the protein. Comparison of MP sequences from related phages suggests a similar arrangement of RNA-binding sites, although these N-terminal regions have only limited sequence conservation. In contrast, the sequences of the C-termini are highly conserved, consistent with them encompassing pilin binding domains required for initial contact with host cells. These results provide independent and unambiguous support for the assembly of MS2 virions via a PS-mediated mechanism involving a series of induced-fit viral protein interactions with RNA. PMID- 26608811 TI - Programmed Ribosomal Frameshifting Mediates Expression of the alpha-Carboxysome. AB - Many bacteria employ a protein organelle, the carboxysome, to catalyze carbon dioxide fixation in the Calvin Cycle. Only 10 genes from Halothiobacillus neapolitanus are sufficient for heterologous expression of carboxysomes in Escherichia coli, opening the door to detailed mechanistic analysis of the assembly process of this complex (more than 200MDa). One of these genes, csoS2, has been implicated in assembly but ascribing a molecular function is confounded by the observation that the single csoS2 gene yields expression of two gene products and both display an apparent molecular weight incongruent with the predicted amino acid sequence. Here, we elucidate the co-translational mechanism responsible for the expression of the two protein isoforms. Specifically, csoS2 was found to possess -1 frameshifting elements that lead to the production of the full-length protein, CsoS2B, and a truncated protein, CsoS2A, which possesses a C terminus translated from the alternate frame. The frameshifting elements comprise both a ribosomal slippery sequence and a 3' secondary structure, and ablation of either sequence is sufficient to eliminate the slip. Using these mutants, we investigated the individual roles of CsoS2B and CsoS2A on carboxysome formation. In this in vivo formation assay, cells expressing only the CsoS2B isoform were capable of producing intact carboxysomes, while those with only CsoS2A were not. Thus, we have answered a long-standing question about the nature of CsoS2 in this model microcompartment and demonstrate that CsoS2B is functionally distinct from CsoS2A in the assembly of alpha-carboxysomes. PMID- 26608814 TI - Bone elongation using monolateral external fixation: a practical guide. AB - In the literature, we can find many articles that describe in detail specific complex procedures related to the limb reconstruction. However, the general information on the biological and mechanical bases of callotasis is out of date, and the surgeons must relate to works dating from the early 1980s. These articles also come from a period in which the callotasis technique was being developed and, therefore, incur in discrepancies depending on the year they were written or the school of the author. This paper provides a general and summarised overview of the theoretical and practical aspects interesting to a surgeon that needs clear information on the bone elongations performed with the help of a monolateral external fixator. PMID- 26608813 TI - Origin and Functional Evolution of the Cdc48/p97/VCP AAA+ Protein Unfolding and Remodeling Machine. AB - The AAA+ Cdc48 ATPase (alias p97 or VCP) is a key player in multiple ubiquitin dependent cell signaling, degradation, and quality control pathways. Central to these broad biological functions is the ability of Cdc48 to interact with a large number of adaptor proteins and to remodel macromolecular proteins and their complexes. Different models have been proposed to explain how Cdc48 might couple ATP hydrolysis to forcible unfolding, dissociation, or remodeling of cellular clients. In this review, we provide an overview of possible mechanisms for substrate unfolding/remodeling by this conserved and essential AAA+ protein machine and their adaption and possible biological function throughout evolution. PMID- 26608816 TI - Proton triggered emission and selective sensing of picric acid by the fluorescent aggregates of 6,7-dimethyl-2,3-bis-(2-pyridyl)-quinoxaline. AB - A heteroatom containing organic fluorophore 6,7-dimethyl-2,3-bis-(2-pyridyl) quinoxaline (BPQ) is weakly emissive in solution but its emission properties are highly enhanced in the aggregated state due to the restriction of intramolecular rotation (RIR) and large amplitude vibrational modes, demonstrating the phenomenon, aggregation induced emission enhancement (AIEE). It has strong proton capture capability, allowing reversible fluorescence switching in basic and acidic medium and the emission color changes from blue to green in the aggregated state through protonation. It has been explained as a competition between intramolecular charge transfers (ICTs) and the AIEE phenomena at a lower pH range (pH ~1-4). Such behavior enables it as a fluorescent pH sensor for detection in acidic and basic medium. Morphologies of the particles are characterized using optical and field emission scanning electron microscopic (FESEM) studies. The turn off fluorescence properties of aggregated BPQ have been utilized for the selective detection of picric acid and the fluorescence quenching is explained due to ground state complexation with a strong quenching constant, 7.81 * 10(4) M(-1). PMID- 26608815 TI - Hematopoietic neoplasms in Prkar2a-deficient mice. AB - BACKGROUND: Protein kinase A (PKA) is a holoenzyme that consists of a dimer of regulatory subunits and two inactive catalytic subunits that bind to the regulatory subunit dimer. Four regulatory subunits (RIalpha, RIbeta, RIIalpha, RIIbeta) and four catalytic subunits (Calpha, Cbeta, Cgamma, Prkx) have been described in the human and mouse genomes. Previous studies showed that complete inactivation of the Prkar1a subunit (coding for RIalpha) in the germline leads to embryonic lethality, while Prkar1a-deficient mice are viable and develop schwannomas, thyroid, and bone neoplasms, and rarely lymphomas and sarcomas. Mice with inactivation of the Prkar2a and Prkar2b genes (coding for RIIalpha and RIIbeta, respectively) are also viable but have not been studied for their susceptibility to any tumors. METHODS: Cohorts of Prkar1a (+/-) , Prkar2a (+/-) , Prkar2a (-/-) , Prkar2b (+/-) and wild type (WT) mice have been observed between 5 and 25 months of age for the development of hematologic malignancies. Tissues were studied by immunohistochemistry; tumor-specific markers were also used as indicated. Cell sorting and protein studies were also performed. RESULTS: Both Prkar2a (-/-) and Prkar2a (+/-) mice frequently developed hematopoietic neoplasms dominated by histiocytic sarcomas (HS) with rare diffuse large B cell lymphomas (DLBCL). Southern blot analysis confirmed that the tumors diagnosed histologically as DLBCL were clonal B cell neoplasms. Mice with other genotypes did not develop a significant number of similar neoplasms. CONCLUSIONS: Prkar2a deficiency predisposes to hematopoietic malignancies in vivo. RIIalpha's likely association with HS and DLBCL was hitherto unrecognized and may lead to better understanding of these rare neoplasms. PMID- 26608818 TI - Zn/Sc bimetallic relay catalysis: one pot cycloisomerization/carbonyl-ene reaction toward oxazole derivatives. AB - A novel tandem metal relay catalytic system combining Zn(II)-catalyzed cycloisomerization and a Sc(III)-catalyzed carbonyl-ene reaction has been successfully developed. By using this unprecedented Zn/Sc bimetallic relay catalytic system, a variety of oxazole derivatives were obtained from easily available N-(propargyl)arylamides and aldehydes under mild conditions. PMID- 26608812 TI - Mechanistic and Structural Insights into the Prion-Disaggregase Activity of Hsp104. AB - Hsp104 is a dynamic ring translocase and hexameric AAA+ protein found in yeast, which couples ATP hydrolysis to disassembly and reactivation of proteins trapped in soluble preamyloid oligomers, disordered protein aggregates, and stable amyloid or prion conformers. Here, we highlight advances in our structural understanding of Hsp104 and how Hsp104 deconstructs Sup35 prions. Although the atomic structure of Hsp104 hexamers remains uncertain, volumetric reconstruction of Hsp104 hexamers in ATPgammaS, ADP-AlFx (ATP hydrolysis transition-state mimic), and ADP via small-angle x-ray scattering has revealed a peristaltic pumping motion upon ATP hydrolysis. This pumping motion likely drives directional substrate translocation across the central Hsp104 channel. Hsp104 initially engages Sup35 prions immediately C-terminal to their cross-beta structure. Directional pulling by Hsp104 then resolves N-terminal cross-beta structure in a stepwise manner. First, Hsp104 fragments the prion. Second, Hsp104 unfolds cross beta structure. Third, Hsp104 releases soluble Sup35. Deletion of the Hsp104 N terminal domain yields a hypomorphic disaggregase, Hsp104(?N), with an altered pumping mechanism. Hsp104(?N) fragments Sup35 prions without unfolding cross-beta structure or releasing soluble Sup35. Moreover, Hsp104(?N) activity cannot be enhanced by mutations in the middle domain that potentiate disaggregase activity. Thus, the N-terminal domain is critical for the full repertoire of Hsp104 activities. PMID- 26608817 TI - Nitric oxide mediates glial-induced neurodegeneration in Alexander disease. AB - Glia play critical roles in maintaining the structure and function of the nervous system; however, the specific contribution that astroglia make to neurodegeneration in human disease states remains largely undefined. Here we use Alexander disease, a serious degenerative neurological disorder caused by astrocyte dysfunction, to identify glial-derived NO as a signalling molecule triggering astrocyte-mediated neuronal degeneration. We further find that NO acts through cGMP signalling in neurons to promote cell death. Glial cells themselves also degenerate, via the DNA damage response and p53. Our findings thus define a specific mechanism for glial-induced non-cell autonomous neuronal cell death, and identify a potential therapeutic target for reducing cellular toxicity in Alexander disease, and possibly other neurodegenerative disorders with glial dysfunction. PMID- 26608819 TI - Cost-effectiveness Analysis of Apixaban against Warfarin for Stroke Prevention in Patients with Nonvalvular Atrial Fibrillation in Japan. AB - PURPOSE: The aim of this study was to evaluate the cost-effectiveness of apixaban compared with to warfarin, current standard of care, for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) in Japan. METHODS: A previously published lifetime Markov model was adapted to evaluate the cost effectiveness of apixaban compared with warfarin in patients with NVAF in Japan. In the same model, the costs associated with each clinical event and background mortality were replaced with Japanese data. Whenever available, some of the utility parameters were derived from Japanese published literature. Lifetime horizon was selected to evaluate the value of the treatment benefit (stroke prevention) against potential risks (such as major bleedings) among patients with NVAF. Direct medical cost, long-term care cost, and quality-adjusted life years (QALYs) were calculated from the payers' perspective. FINDINGS: Compared with warfarin, treatment with apixaban was estimated to increase life expectancy by 0.231 year or 0.240 QALYs while treatment cost increased by Y511,692 (US $5117 at an exchange rate of US $1 = Y100). The incremental cost-effectiveness ratio was Y2,135,743 per QALY (US $21,357 per QALY). On the basis of the results of the probabilistic sensitivity analysis, when the willingness-to-pay threshold was set at approximately >=Y2,250,000 (US $22,500) per QALY, the probability of apixaban being cost-effective was >=50%. Assuming a willingness-to-pay threshold of Y5,000,000 (US $50,000) and Y6,700,000 (US $67,000) in Japan, the probability of apixaban being cost-effective was 85% and 91%, respectively. CONCLUSION: Although most participants in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial used for the efficacy data of apixaban in the model were non-Japanese patients, the impact of the limitations on our results was considered small, and our results were deemed robust because of the additional effect in Japanese patients compared with that in the global population according to the subanalysis of Japanese patients in the trial. Therefore, based on an adaptation of a published Markov model, apixaban is a cost-effective alternative to warfarin in Japan for stroke prevention among patients with NVAF. PMID- 26608820 TI - Tumoral calcinosis in the neck region involving an unusual site in a hemodialysis patient. AB - Tumoral calcinosis is a rare disorder characterized by calcium salt deposition in the periarticular soft tissue region. It often occurs in the hip, elbow, shoulder, foot, and wrist. Soft tissue calcification associated with tumoral calcinosis is rare in the head and neck. The present case describes a 65- year old male who had been on hemodialysis for 3 years. A bulky mass, containing chalky amorphous calcified material, occurred at the lower neck and superior mediastinum. Chronic renal failure is a common condition associated with secondary tumoral calcinosis. The pathogenesis has been progressively unraveled, which indicates that secondary hyperparathyroidism and tissue injury play a part in multifactorial calcification. Laryngoscope, 126:E196-E198, 2016. PMID- 26608821 TI - Manganese neurotoxicity: behavioral disorders associated with dysfunctions in the basal ganglia and neurochemical transmission. AB - Manganese (Mn) is an essential element required for many physiological functions. While it is essential at physiological levels, excessive accumulation of Mn in the brain causes severe dysfunctions in the central nervous system known as manganism. Manganism is an extrapyramidal disorder characterized by motor disturbances associated with neuropsychiatric and cognitive disabilities similar to Parkinsonism. As the primary brain regions targeted by Mn are the basal ganglia, known to be involved in the pathophysiology of extrapyramidal disorders, this review will examine the impact of Mn exposure on the basal ganglia circuitry and neurotransmitters in relation to motor and non-motor disorders. The collected data from recent available studies in humans and experimental animal models provide new information about the mechanisms by which Mn affects behavior, neurotransmitters, and basal ganglia function observed in manganism. The effects of the alterations of metals on basal ganglia and neurochemical functioning are critical to develop effective modalities not only for the treatment of vulnerable populations (e.g., Mn-exposed workers) but also for understanding the etiology of neurodegenerative diseases where brain metal imbalances are involved, such as Parkinson's disease. We examine the impact of manganese (Mn) exposure on the basal ganglia circuitry and neurotransmitters in relation with motor and non motor disorders. The collected data from available studies show that when accumulated in the globus pallidus, Mn influences the subthalamic (STN) and substantia nigra (SN) neurons, which are at the origin of changes in the thalamus and the cortex. PMID- 26608822 TI - Factors influencing the care provided for periviable babies in Australia: a narrative review. AB - Survival at extreme prematurity is becoming increasingly common. Neurodisability is an increasing risk with decreasing gestation. This review outlines the risks of extreme prematurity and the attitudes of health care providers and families in Australia of periviable babies. High quality data is difficult to find due to differing definitions and methods of assessment of disability. Meta-analyses of outcomes of prematurity published from 2008 to 2013, including babies born from 1990 onwards, suggest a severe disability rate of around 20 % at 22 to 26 weeks completed gestation, with moderate disability decreasing with increasing gestation. Studies show that Australian health care providers underestimate the survival and positive outcomes of these babies. The majority of Australian health care providers state that parental preference would determine the decision to offer care to babies at 23 weeks gestation, however, all had a threshold above which parental preference would be ignored in favour of resuscitation .This ranged from 22 to 27 completed weeks gestation. The few studies examining Australian parental involvement in resuscitation decisions, showed that the majority of parents felt that health professionals alone had made the decision to resuscitate their extremely preterm babies and the parents themselves did not wish to be the primary decision makers in withholding care. The babies progressed better than parents had expected following antenatal counselling. The attitudes of health care providers, experiences and opinions of parents seem to be at odds with the current move to increase parental decision making at the most extremes of gestation. Current Australian guidelines suggest parental decision making below 25 weeks gestation, and primarily clinician decision making over this gestation. The increased risks of prematurity and adverse outcomes for the North Queensland population is also explored. This population has a high proportion of Aboriginal and Torres Strait Islanders who have increased risks which are primarily linked to poor socioeconomic factors and are highest for the most remote residents. Attitudes towards delivery of care to these highest risk babies from health professionals and in the populations themselves have not been studied. PMID- 26608823 TI - Influence of race/ethnicity on cardiovascular risk factors in polycystic ovary syndrome, the Dallas Heart Study. AB - OBJECTIVE: Polycystic ovarian syndrome (PCOS) is estimated to affect up to 20% of women. PCOS is associated with insulin resistance and cardiovascular (CV) risk factors. We aimed to evaluate the impact of race/ethnicity on the prevalence of CV risk factors and subclinical predictors of CV events. DESIGN: Cross-sectional analysis of data collected by the Dallas Heart Study, an urban, population-based cohort oversampled for blacks. PATIENTS: A previously described cohort of women with PCOS and control subjects of the same racial/ethnic group, matched for age and body mass index. MEASUREMENTS: Hormonal and clinical measures associated with PCOS and CV risk factors. RESULTS: The study included 117 women with PCOS and 204 controls. Women with PCOS had significant differences across racial/ethnic groups in the prevalence of hypertension, hypercholesterolaemia, hypertriglyceridaemia and impaired fasting glucose (P < 0.05). Controls showed significant racial/ethnic differences in the prevalence of hypertension and impaired fasting glucose (P < 0.05). The odds of hypertension were significantly greater among women with PCOS than controls after adjusting for race/ethnicity (odds ratio, 1.50 [95% CI, 1.03-2.30]; P = 0.04). However, we did not see an interaction of race/ethnicity that significantly changed CV risk factor prevalence between PCOS and controls. In addition, subclinical measures of CV disease were not different between women with PCOS vs controls, even among hypertensive women. CONCLUSIONS: Race/ethnicity affects the prevalence of CV risk factors for women with and without PCOS. However, race/ethnicity does not interact with PCOS to additionally increase CV risk factor prevalence or subclinical CV disease. PMID- 26608824 TI - Detection of respiratory syncytial virus and rhinovirus in healthy infants. AB - BACKGROUND: Despite the research importance of rhinovirus detection in asymptomatic healthy infants, the literature remains sparse. OBJECTIVE: To investigate the prevalence of respiratory syncytial virus (RSV) and rhinovirus (and its species). METHODS: We conducted a cross-sectional study of 110 healthy, non-hospitalized infants without acute illness at an academic medical center from November 2013 through May 2014. We tested nasal swab specimens by using polymerase chain reaction and genetic sequencing. RESULTS: Overall, the median age was 3.8 months (IQR 2.0-5.1 months), 56 % were male, and 90% were born >37 weeks. RSV was detected in nasal swabs from infants (1.8%). By contrast, rhinovirus was detected in nasal swabs from 16 infants (14.5%). Molecular typing assay revealed rhinovirus species: six rhinovirus-A (5.5%), one rhinovirus-B (0.9%), eight rhinovirus-C (7.3%), and one untypeable (0.9%). CONCLUSIONS: In this cross-sectional study of healthy, community-based infants, RSV was rare (<2%) in nasal swabs, while rhinovirus was detected in 14.5% with a predominance of rhinovirus-A and -C. These finding are important for understanding the clinical significance of rhinovirus detection among infants hospitalized for bronchiolitis. PMID- 26608825 TI - TSG101, a tumor susceptibility gene, bidirectionally modulates cell invasion through regulating MMP-9 mRNA expression. AB - BACKGROUND: Tumor susceptibility gene 101 (TSG101) was initially identified in fibroblasts as a tumor suppressor gene but subsequent studies show that TSG101 also functions as a tumor-enhancing gene in some epithelial tumor cells. Although previous studies have unraveled diverse biological functions of TSG101, the precise mechanism by which TSG101 is involved in carcinogenesis and tumor progression in a bidirectional and multifaceted manner remains unclear. METHODS: To reveal the mechanism underlying bidirectional modulation of cell invasion by TSG101, we used RNA interference to examine whether TSG101 depletion bidirectionally modulated matrix metalloproteinase (MMP)-9 expression in different cell types. RESULTS: TSG101 depletion promoted cell invasion of HT1080 cells but contrarily reduced cell invasion of HeLaS3 cells. In HT1080 cells, TSG101 depletion increased both baseline and phorbol 12-myristate 13-acetate (PMA)-induced MMP-9 secretion through enhancing MMP-9 mRNA expression, but did not affect the expression or activation of MMP-2. In contrast, TSG101 depletion decreased PMA-induced MMP-9 secretion through reducing MMP-9 mRNA expression in HeLaS3 cells. TSG101 depletion had little impact on the signaling pathways required for the activation of transcription of MMP-9 or MMP-9 mRNA stability in either cell line. CONCLUSION: TSG101 bidirectionally modulates cell invasion through regulating MMP-9 mRNA expression in different cell types. Our results provide a mechanistic context for the role of TSG101 in cell invasion as a multifaceted gene. PMID- 26608827 TI - The role of the circle of Willis in internal carotid artery stenosis and anatomical variations: a computational study based on a patient-specific three dimensional model. AB - BACKGROUND: The aim of this study is to provide better insights into the cerebral perfusion patterns and collateral mechanism of the circle of Willis (CoW) under anatomical and pathological variations. METHODS: In the current study, a patient specific three-dimensional computational model of the CoW was reconstructed based on the computed tomography (CT) images. The Carreau model was applied to simulate the non-Newtonian property of blood. Flow distributions in five common anatomical variations coexisting with different degrees of stenosis in the right internal carotid artery (RICA) were investigated to obtain detailed flow information. RESULTS: With the development of stenosis in unilateral internal carotid artery (ICA), the cerebral blood supply decreased when the degree of stenosis increased. The blood supply of the ipsilateral middle cerebral artery (MCA) was most affected by the stenosis of ICA. The anterior communicating artery (ACoA) and ipsilateral posterior communicating artery (PCoA) functioned as the important collateral circulation channels when unilateral stenosis occurred. The blood flow of the anterior circulation and the total cerebral blood flow (CBF) reached to the minimum in the configuration of the contralateral proximal anterior cerebral artery (A1) absence coexisting with unilateral ICA stenosis. CONCLUSIONS: Communicating arteries provided important collateral channels in the complete CoW when stenosis in unilateral ICA occurred. The cross-flow in the ACoA is a sensitive indicator of the morphological change of the ICA. The collateral function of the PCoA on the affected side will not be fully activated until a severe stenosis occurred in unilateral ICA. The absence of unilateral A1 coexisting with the stenosis in the contralateral ICA could be the most dangerous configuration in terms of the total cerebral blood supply. The findings of this study would enhance the understanding of the collateral mechanism of the CoW under different anatomical variations. PMID- 26608826 TI - The effect of UV-B on Arabidopsis leaves depends on light conditions after treatment. AB - BACKGROUND: Ultraviolet B (UV-B) irradiation can influence many cellular processes. Irradiation with high UV-B doses causes chlorophyll degradation, a decrease in the expression of genes associated with photosynthesis and its subsequent inhibition. On the other hand, sublethal doses of UV-B are used in post-harvest technology to prevent yellowing in storage. To address this inconsistency the effect of short, high-dose UV-B irradiation on detached Arabidopsis thaliana leaves was examined. RESULTS: Two different experimental models were used. After short treatment with a high dose of UV-B the Arabidopsis leaves were either put into darkness or exposed to constant light for up to 4 days. UV-B inhibited dark-induced chlorophyll degradation in Arabidopsis leaves in a dose-dependent manner. The expression of photosynthesis-related genes, chlorophyll content and photosynthetic efficiency were higher in UV-B -treated leaves left in darkness. UV-B treatment followed by constant light caused leaf yellowing and induced the expression of senescence-related genes. Irrespective of light treatment a high UV-B dose led to clearly visible cell death 3 days after irradiation. CONCLUSIONS: High doses of UV-B have opposing effects on leaves depending on their light status after UV treatment. In darkened leaves short UV-B treatment delays the appearance of senescence symptoms. When followed by light treatment, the same doses of UV-B result in chlorophyll degradation. This restricts the potential usability of UV treatment in postharvest technology to crops which are stored in darkness. PMID- 26608828 TI - Experimental and computational study of mechanical and transport properties of a polymer coating for drug-eluting stents. AB - BACKGROUND: Experimental and computational characterizations in the preclinical development of biomedical devices are complementary and can significantly help in a thorough analysis of the performances before clinical evaluation. METHODOLOGY: Here mechanical and drug delivery properties of a polymer platform, ad hoc prepared to obtain coatings for drug-eluting stents, is reported; polymer formulation and starting drug loading were varied to study the behavior of the platform; a finite element model was constructed starting from experimental data. RESULTS: Different platform formulations affected mechanical and drug transport properties; these properties can be fine tuned by varying the starting platform formulation. Finite element analysis allowed visualizing drug distribution maps over time in biological tissues for different commercial stents and polymer platform formulations. PMID- 26608829 TI - Response mode-dependent differences in neurofunctional networks during response inhibition: an EEG-beamforming study. AB - Response inhibition processes are one of the most important executive control functions and have been subject to intense research in cognitive neuroscience. However, knowledge on the neurophysiology and functional neuroanatomy on response inhibition is biased because studies usually employ experimental paradigms (e.g., sustained attention to response task, SART) in which behavior is susceptible to impulsive errors. Here, we investigate whether there are differences in neurophysiological mechanisms and networks depending on the response mode that predominates behavior in a response inhibition task. We do so comparing a SART with a traditionally formatted task paradigm. We use EEG-beamforming in two tasks inducing opposite response modes during action selection. We focus on theta frequency modulations, since these are implicated in cognitive control processes. The results show that a response mode that is susceptible to impulsive errors (response mode used in the SART) is associated with stronger theta band activity in the left temporo-parietal junction. The results suggest that the response modes applied during response inhibition differ in the encoding of surprise signals, or related processes of attentional sampling. Response modes during response inhibition seem to differ in processes necessary to update task representations relevant to behavioral control. PMID- 26608830 TI - Multiscale single-cell analysis reveals unique phenotypes of raphe 5-HT neurons projecting to the forebrain. AB - Serotonergic neurons of the raphe nuclei exhibit anatomical, neurochemical and elecrophysiological heterogeneity that likely underpins their specific role in multiple behaviors. However, the precise organization of serotonin (5-HT) neurons to orchestrate 5-HT release patterns throughout the brain is not well understood. We compared the electrophysiological and neurochemical properties of dorsal and median raphe 5-HT neurons projecting to the medial prefrontal cortex (mPFC), amygdala (BLA) and dorsal hippocampus (dHP), combining retrograde tract tracing with brain slice electrophysiology and single-cell RT-PCR in Pet1-EGFP mice. Our results show that 5-HT neurons projecting to the dHP and the mPFC and the BLA form largely non-overlapping populations and that BLA-projecting neurons have characteristic excitability and membrane properties. In addition, using an unbiased clustering method that correlates anatomical, molecular and electrophysiological phenotypes, we find that 5-HT neurons with projections to the mPFC and the dHP segregate from those projecting to the BLA. Single-cell gene profiling showed a restricted expression of the peptide galanin in the population of 5-HT neurons projecting to the mPFC. Finally, cluster analysis allowed identifying an atypical subtype of 5-HT neuron with low excitability, long firing delays and preferential expression of the vesicular glutamate transporter type 3. Overall, these findings allow to define correlated anatomical and physiological identities of serotonin raphe neurons that help understanding how discrete raphe cells subpopulations account for the heterogeneous activities of the midbrain serotonergic system. PMID- 26608831 TI - Reply. PMID- 26608832 TI - Perinatal and obstetric outcomes of dichorionic vs trichorionic triplet pregnancies. AB - BACKGROUND: Clinical management and outcome of multiple gestation can be affected by chorionicity. In triplet pregnancies, fetal death has been associated with dichorionic (DC) and monochorionic placentation. Studies evaluating triplet pregnancy outcomes in relation to chorionicity have been few and may not reflect contemporary antenatal and neonatal care. OBJECTIVE: The objective of this study was to compare obstetric and perinatal outcomes in DC and trichorionic (TC) triplet pregnancies. STUDY DESIGN: We performed a retrospective cohort study of triplet pregnancies that delivered at >=20 weeks' gestation at 2 Chicago area hospitals from January 1999 through December 2010. Chorionicity was determined by pathology specimen. Maternal and infant charts were reviewed for obstetric and perinatal outcomes. RESULTS: The study population included 159 pregnancies (477 neonates) of which 108 were TC (67.9%) and 51 were DC (32.1%). Over 94% of mothers in this study had all 3 infants survive to discharge regardless of chorionicity. No difference was found in perinatal mortality rate between DC and TC triplets (3.3% vs 4.6%; P = .3). DC triplets were significantly more likely to be very low birthweight (41.8% vs 22.2%; odds ratio, 2.2; 95% confidence interval, 1.2-4.2; P = .02) and to deliver at <30 weeks (25.5% vs 8.3%; odds ratio, 6.1; 95% confidence interval, 1.9-19.4; P = .002) compared to TC triplets. Criteria for twin-twin transfusion syndrome (TTTS) were present in 3 DC triplet pregnancies (5.9%). Neonates in pregnancies complicated by TTTS were less likely to survive 28 days as compared to neonates from DC pregnancies that were not affected by TTTS (P = .02) or TC neonates (P = .02) Neonatal survival was similar in DC pregnancies not affected by TTTS and TC pregnancies (98.6% and 96.6%; P = .7). CONCLUSION: Although perinatal mortality did not correlate with chorionicity, DC pregnancies were more likely to deliver <30 weeks' gestational age and have very low birthweight neonates. Neonatal mortality appears to be mediated by the presence or absence of TTTS as 28-day survival was worse in DC pregnancies complicated by TTTS, but similar between DC pregnancies not affected by TTTS and TC pregnancies. PMID- 26608833 TI - Does twin gestation really have long-term maternal cardiac sequelae? PMID- 26608835 TI - Five minutes with . . . Johann Malawana, chair of BMA's Junior Doctors Committee. PMID- 26608834 TI - Simultaneous and interleaved acquisition of NMR signals from different nuclei with a clinical MRI scanner. AB - PURPOSE: Modification of a clinical MRI scanner to enable simultaneous or rapid interleaved acquisition of signals from two different nuclei. METHODS: A device was developed to modify the local oscillator signal fed to the receive channel(s) of an MRI console. This enables external modification of the frequency at which the receiver is sensitive and rapid switching between different frequencies. Use of the device was demonstrated with interleaved and simultaneous 31 P and 1 H spectroscopic acquisitions, and with interleaved 31 P and 1 H imaging. RESULTS: Signal amplitudes and signal-to-noise ratios were found to be unchanged for the modified system, compared with data acquired with the MRI system in the standard configuration. CONCLUSION: Interleaved and simultaneous 1 H and 31 P signal acquisition was successfully demonstrated with a clinical MRI scanner, with only minor modification of the RF architecture. While demonstrated with 31 P, the modification is applicable to any detectable nucleus without further modification, enabling a wide range of simultaneous and interleaved experiments to be performed within a clinical setting. Magn Reson Med 76:1636-1641, 2016. (c) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 26608837 TI - The sensitivity and specificity of the social communication questionnaire for autism spectrum with respect to age. AB - The age neutrality of the Social Communication Questionnaire (SCQ) was examined as a common screener for ASD. Mixed findings have been reported regarding the recommended cutoff score's ability to accurately classify an individual as at risk for autism spectrum disorder (ASD) (sensitivity) versus accurately classifying an individual as not at-risk for ASD (specificity). With a sample from the National Database for Autism Research, this study examined the SCQ's sensitivity versus specificity. Analyses indicated that the actual sensitivity and specificity scores were lower than initially reported by the creators of the SCQ. Autism Res 2016, 9: 838-845. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26608838 TI - Current concepts for the treatment of acute scaphoid fractures. AB - Fractures of the scaphoid are common injuries, accounting for approximately 80 % of carpal fractures. Differentiation between stable and unstable fractures (Herbert classification) cannot be made with conventional X-rays, so evaluation by computed tomography should additionally be performed. Under most circumstances, minimally invasive surgery with cannulated screws is the treatment of choice. A longer cast immobilization after minimal-invasive surgery is not necessary. Conservative treatment still has a place if the fracture is not dislocated nor unstable, but operative treatment can be offered to reduce the period of cast immobilization. Displaced fractures have a greater risk for nonunion and therefore should be treated operatively. Proximal pole fractures are definitely unstable, requiring treatment with screw fixation. The surgical approach depends on the location of the fracture and the preference of the surgeon. PMID- 26608836 TI - The influence of students' prior clinical skills and context characteristics on mini-CEX scores in clerkships--a multilevel analysis. AB - BACKGROUND: In contrast to objective structured clinical examinations (OSCEs), mini-clinical evaluation exercises (mini-CEXs) take place at the clinical workplace. As both mini-CEXs and OSCEs assess clinical skills, but within different contexts, this study aims at analyzing to which degree students' mini CEX scores can be predicted by their recent OSCE scores and/or context characteristics. METHODS: Medical students participated in an end of Year 3 OSCE and in 11 mini-CEXs during 5 different clerkships of Year 4. The students' mean scores of 9 clinical skills OSCE stations and mean 'overall' and 'domain' mini CEX scores, averaged over all mini-CEXs of each student were computed. Linear regression analyses including random effects were used to predict mini-CEX scores by OSCE performance and characteristics of clinics, trainers, students and assessments. RESULTS: A total of 512 trainers in 45 clinics provided 1783 mini CEX ratings for 165 students; OSCE results were available for 144 students (87%). Most influential for the prediction of 'overall' mini-CEX scores was the trainers' clinical position with a regression coefficient of 0.55 (95%-CI: 0.26 0.84; p < .001) for residents compared to heads of department. Highly complex tasks and assessments taking place in large clinics significantly enhanced 'overall' mini-CEX scores, too. In contrast, high OSCE performance did not significantly increase 'overall' mini-CEX scores. CONCLUSION: In our study, Mini CEX scores depended rather on context characteristics than on students' clinical skills as demonstrated in an OSCE. Ways are discussed which focus on either to enhance the scores' validity or to use narrative comments only. PMID- 26608839 TI - Effect of limited ischemia time on the amount and function of mitochondria within human skeletal muscle cells. AB - INTRODUCTION: The clinical success of total knee arthroplasty (TKA) depends substantially on the quadriceps muscle function. A frequently applied thigh tourniquet during TKA may induce ischemia related injuries to quadriceps muscle cells. Animal limb muscles subjected to 2-5 h ischemia revealed dysfunctional mitochondria, which in turn compromised the cellular bioenergetics and increased the level of reactive oxygen species. The hypothesis of the present study was that tourniquet application during TKA for 60 min (min) affects the amount and function of mitochondria within musculus vastus medialis cells. MATERIALS AND METHODS: In a randomized clinical trial, 10 patients enrolled to undergo primary TKA. The patients were randomly assigned to the tourniquet (n = 5) or non tourniquet group (n = 5) after obtaining a written informed consent. For each of the groups, the first muscle biopsy was harvested immediately after performing the surgical approach and the second biopsy exactly 60 min later. All biopsies (5 * 5 * 5 mm) 125 mm3 were harvested from musculus vastus medialis and snap-frozen in liquid nitrogen. The biochemical analysis of the prepared muscle tissues included the measurement of activities of mitochondrial respiratory chain enzyme complexes I-III and citrate synthase. RESULTS: Tourniquet-induced 60 min ischemia time did not significantly change the activities of the mitochondrial respiratory chain enzymes complexes I-III of the skeletal muscle cells. The citrate synthase activities found to be not significantly different between both groups. CONCLUSIONS: The use of tourniquet during TKA within a limited time period of 60 min remained without substantial effects on the amount and function of mitochondria within human skeletal muscle cells. PMID- 26608840 TI - Aortic valve replacement with Edwards INTUITY sutureless bioprosthesis through right anterior minithoracotomy. AB - Minimally invasive aortic valve replacement through right anterior minithoracotomy has been shown as a reliable and interesting approach. However, the placement of a sutured valve may be challenging and time-consuming in some cases. Sutureless bioprosthesis is an elegant alternative in order to facilitate its placement and to reduce the aortic cross-clamp time. In this video, we report our surgical technique of minimally invasive aortic valve replacement with an Edwards INTUITY sutureless bioprosthesis. Postoperative course was uneventful and the patient was discharged after 6 days. PMID- 26608841 TI - Parvalbumin-positive interneurons of the prefrontal cortex support working memory and cognitive flexibility. AB - Dysfunction of parvalbumin (PV)-positive GABAergic interneurons (PVIs) within the prefrontal cortex (PFC) has been implicated in schizophrenia pathology. It is however unclear, how impaired signaling of these neurons may contribute to PFC dysfunction. To identify how PVIs contribute to PFC-dependent behaviors we inactivated PVIs in the PFC in mice using region- and cell-type-selective expression of tetanus toxin light chain (TeLC) and compared the functional consequences of this manipulation with non-cell-type-selective perturbations of the same circuitry. By sampling for behavioral alterations that map onto distinct symptom categories in schizophrenia, we show that dysfunction of PVI signaling in the PFC specifically produces deficits in the cognitive domain, but does not give rise to PFC-dependent correlates of negative or positive symptoms. Our results suggest that distinct aspects of the complex symptomatology of PFC dysfunction in schizophrenia can be attributed to specific prefrontal circuit elements. PMID- 26608842 TI - Resting-state cerebellar-cerebral networks are differently affected in first episode, drug-naive schizophrenia patients and unaffected siblings. AB - Dysconnectivity hypothesis posits that schizophrenia is a disorder with dysconnectivity of the cortico-cerebellar-thalamic-cortical circuit (CCTCC). However, it remains unclear to the changes of the cerebral connectivity with the cerebellum in schizophrenia patients and unaffected siblings. Forty-nine patients with first-episode, drug-naive schizophrenia patients, 46 unaffected siblings of schizophrenia patients and 46 healthy controls participated in the study. Seed based resting-state functional connectivity approach was employed to analyze the data. Compared with the controls, the patients and the siblings share increased default-mode network (DMN) seed - right Crus II connectivity. The patients have decreased right dorsal attention network (DAN) seed - bilateral cerebellum 4,5 connectivity relative to the controls. By contrast, the siblings exhibit increased FC between the right DAN seed and the right cerebellum 6 and right cerebellum 4,5 compared to the controls. No other abnormal connectivities (executive control network and salience network) are observed in the patients/siblings relative to the controls. There are no correlations between abnormal cerebellar-cerebral connectivities and clinical variables. Cerebellar cerebral connectivity of brain networks within the cerebellum are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings. Increased DMN connectivity with the cerebellum may serve as potential endophenotype for schizophrenia. PMID- 26608843 TI - Biodegradable polymer iron oxide nanocomposites: the future of biocompatible magnetism. PMID- 26608844 TI - Pseudozyma aphidis fungaemia with invasive fungal pneumonia in a patient with acute myeloid leukaemia: case report and literature review. AB - Pseudozyma species rarely cause invasive diseases in humans, which are usually isolated from plants. There have been anecdotal reports regarding Pseudozyma species infections in patients with underlying diseases or in neonates. However, clinical data and the pathogenicity in humans are still insufficient. We experienced a case of Pseudozyma aphidis fungaemia with invasive fungal pneumonia that developed during reinduction chemotherapy in a 51-year-old male with acute myeloid leukaemia (AML). P. aphidis was suspected based on the morphology of the yeast isolated from the blood and was confirmed via rDNA gene sequencing analysis. The patient successfully underwent stem cell transplantation with continuing antifungal treatment and finally completely recovered from both the AML and infectious complications. Here, we report a case of P. aphidis infection that developed during neutropenia in an AML patient and review the global literature. PMID- 26608846 TI - Base catalysed decomposition of anthracene endoperoxide. AB - Catalytic amounts of a weak base are sufficient to induce the decomposition of anthracene endoperoxides to anthraquinone. The mechanism has been elucidated by isolation of intermediates in combination with DFT calculations. The whole process is suitable for the convenient generation of hydrogen peroxide under very mild conditions. PMID- 26608845 TI - Rescue from tau-induced neuronal dysfunction produces insoluble tau oligomers. AB - Aggregation of highly phosphorylated tau is a hallmark of Alzheimer's disease and other tauopathies. Nevertheless, animal models demonstrate that tau-mediated dysfunction/toxicity may not require large tau aggregates but instead may be caused by soluble hyper-phosphorylated tau or by small tau oligomers. Challenging this widely held view, we use multiple techniques to show that insoluble tau oligomers form in conditions where tau-mediated dysfunction is rescued in vivo. This shows that tau oligomers are not necessarily always toxic. Furthermore, their formation correlates with increased tau levels, caused intriguingly, by either pharmacological or genetic inhibition of tau kinase glycogen-synthase kinase-3beta (GSK-3beta). Moreover, contrary to common belief, these tau oligomers were neither highly phosphorylated, and nor did they contain beta pleated sheet structure. This may explain their lack of toxicity. Our study makes the novel observation that tau also forms non-toxic insoluble oligomers in vivo in addition to toxic oligomers, which have been reported by others. Whether these are inert or actively protective remains to be established. Nevertheless, this has wide implications for emerging therapeutic strategies such as those that target dissolution of tau oligomers as they may be ineffective or even counterproductive unless they act on the relevant toxic oligomeric tau species. PMID- 26608847 TI - Type D personality, anxiety, depression and personality traits in patients with isolated itching of the external auditory canal. AB - OBJECTIVE: This study evaluated type D personality, anxiety, depression and personality traits in patients with isolated itching of the external auditory canal. METHOD: A hundred consecutive out-patients with isolated itching of the external auditory canal and 100 controls were enrolled in the study. The Type D Scale, the abbreviated form of the Eysenck Personality Questionnaire Revised and the Hospital Anxiety and Depression Scale were used for data collection. Patients were also evaluated using the Modified Itch Severity Scale. RESULTS: In all, 43 per cent of patients and 15 per cent of controls met the criteria for a type D personality. Patients with a type D personality had higher anxiety and itching severity but lower extraversion compared with those without a type D personality. Multiple linear regression analysis showed that extraversion and type D personality were independently associated with itch severity. CONCLUSION: These data suggest that clinicians should consider psychological and personality features when evaluating and treating patients with isolated itching of the external auditory canal. PMID- 26608848 TI - [Mechanism of bone and cartilage damage in rheumatoid arthritis]. AB - Rheumatoid arthritis(RA)is an autoimmune diseases characterized by inflammation and destruction of bone and cartilage. Bone destruction in RA is triggered by abnormal activation of immune system and osteoclasts induced by RANKL. Advances in osteoimmunology clarified that immune-factors such as inflammatory cytokines and antibodies promote not only inflammation but also bone destruction in RA. Importantly, a newly identified Th17 subset induces osteoclastogenesis potently by upregulating RANKL on synovial fibroblasts, indicating a synergy between T synovial fibroblast plays a primary role in the inflammatory bone destruction. Recently, novel bone-regulating factors are identified and can be attractive therapeutic targets for destruct ion of bone and cartilage in RA. PMID- 26608850 TI - [Genetic factors of rheumatoid arthritis]. AB - Rheumatoid arthritis(RA)is one of common autoimmune diseases. As with other complex disorders, recent genome-wide association studies(GWASs)have greatly contributed to our understanding of RA etiology. In this review, the genetic configuration of RA as revealed through GWASs is described. In addition, I discuss the pathologic mechanisms of RA as suggested by the findings of genetic and functional studies of individual RA-associated genes, and the potential use of genetic information for novel drug discovery. PMID- 26608849 TI - [The "treat-to-target" strategies for rheumatoid arthritis and managing for bone cartilage destructions]. AB - Sometime ago, there was little choice for the treatment of rheumatoid arthritis(RA)that was regarded as an untreateble disease but supportive analgesics and mild disease modified drugs. The advent of biological agents with abundant clinical researches regarding remarkable efficacy has cased dramatically the paradigm shift in the treatment of RA. The strategy for medical care to RA has now entered a new era in that treatment target should be clarified and shared between patient and rheumatologist aiming the prevention of structural damage and the maintain of long-term quality of life(QOL)by tight-control. In this review, we summarize the "treat to target"(T2T)strategies for RA and its impact to manage for bone and cartilage destructions. PMID- 26608851 TI - [Biomarker of bone and cartilage destruction in rheumatoid arthritis]. AB - Recent progress in treatment and imaging enables us to aim the clinical remission in rheumatoid arthritis. In terms of achieving deep remission (structural remission) and predicting prognosis, useful serological biomarkers are now expected. Recently, some of the serological biomarkers, such as RANKL (receptor activator of NF-kappaB ligand) and TRACP (tartrate-resistant acid phopshatate) 5b, are used to assess the activity of rheumatoid arthritis. The levels of these biomarkers well reflect bone erosion but are less affected by age or physiological variation. PMID- 26608852 TI - [Imaging assessment of bone and cartilage destruction in rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) is characterized by synovitis and subsequent joint destruction involving bone and cartilage. Recent therapeutic development have improved outcomes including disease activity and structural progression in RA, and standardized procedures of imaging assessment including modified total Sharp score (mTSS) have contributed largely for the development of therapeutic strategy. In addition, ultrasonography and MRI of joints have been recently emerging as novel imaging methods for RA. Here, we review current imaging assessments of bone and cartilage destruction in RA. PMID- 26608853 TI - [Anti-RANKL antibody for the treatment of bone and cartilage destruction in rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) is characterized by chronic synovitis and RANKL dependent osteoclastogenesis leading to bone damage, which causes severe physical disability. Focal and systemic bone and cartilage destruction including secondary osteoporosis contributes to the morbidity associated with RA. The biologics targeting TNF and IL-6 has revolutionized the treatment of RA, producing significant improvements in clinical and structural outcomes. Furthermore, an anti-RANKL antibody denosumab possesses a potential to inhibit joint destruction as well as systemic osteoporosis. Targeting RANKL therapy will most likely enlarge the possibilities of osteoporosis treatment and improve the prognosis in RA patients. PMID- 26608854 TI - [Semaphorins as treatment targets for cartilage and bone damage caused by rheumatoid arthritis]. AB - Semaphorins family consists of more than 20 proteins, categorized into 8 subclasses. Semaphorins play critical roles in neural development, immune response, and bone metabolism. Rheumatoid arthritis (RA) is a disease which shows abnormality in immunity and bone homeostasis. Therefore, semaphorins are suggested to be relevant to RA. Here, we described the role of semaphorins in bone metabolism and the association with semaphorins and RA which are found by basic and translational research. PMID- 26608855 TI - [Regenerative medicine for cartilage defect in rheumatic disease]. AB - Persistent inflammation in rheumatoid arthritis (RA) can lead to the profound degradation and defect of articular cartilage. We can treat or induce the regeneration for the partial cartilage defect using the autologous chondrocytes implantation (ACI) or the matrix-assisted ACI. However, these regenerative methods cannot be applicable for the large size defect due to their limitation of the formable size or available cell numbers. The cell sheet technology or the intra-articular injection technique using the mesenchymal stem cells or the induced pluripotent stem cells (iPS cells) could be applied for the large size cartilage defect in RA patients in the future after additional studies. PMID- 26608856 TI - [Trends in orthopaedic surgery for patients with rheumatoid arthritis]. AB - Significant advancement in pharmacological treatment including biological agents has gradually changed the role and content of surgical treatments for patients with rheumatoid arthritis. The number of joint replacements in the large joints of lower limbs has decreased, while the number of surgeries in the small joints of hand and feet has increased. Favorable disease control by pharmacological treatment has changed the needs of patients for surgeries and expanded the options of operative procedures for surgeons. The changing needs of patients demanding the higher level of quality of life may seek a change in the surgical treatments. PMID- 26608857 TI - [The regulation of CTLA4-Ig in bone and cartilage destruction of rheumatoid arthritis]. AB - CTLA4-Ig is a regulator of co-stimulation and inhibits the activation of T cells through interfering with the interaction of CD80/86 on antigen-presenting cells with CD28. Recently CTLA4-Ig has shown additional effect beyond T cell inhibition, such as direct inhibition of differentiation of osteoclast, enhancement of osteogenesis. These effects may contribute to prevention of bone destruction in rheumatoid arthritis. PMID- 26608858 TI - [Management of osteoporosis associated with rheumatoid arthritis and glucocorticoid-induced osteoporosis]. AB - Mechanism of generalized osteoporosis associated with rheumatoid arthritis(RA)is multifactorial and following factors has been proposed:systemic effect of RA synovitis, glucocorticoids, weight loss, and endocrine changes. In addition to control of RA inflammation and management of glucocorticoid-induced osteoporosis(GIO), antiresorptive therapy, such as bisphosphonates is expected to show efficacy. Recently, anti-RANKL monoclonal antibodies have been shown to inhibit bone erosion and bone loss in combination with methotrexate in RA. GC induced bone loss is most rapid during the initial 3 ~ 6 months and more slowly thereafter. Therefore, both primary and secondary prevention are important. The Japanese Society for Bone and Mineral Research(JSBMR)has updated the Guidelines on the Management and Treatment of GIO and has incorporated a new scoring method. By analyzing five GIO cohorts from primary and secondary prevention studies, age, GC dose, lumbar BMD, and prior fragility fractures were identified as risk factors and the fracture risk for an individual can be calculated as the sum of the scores for each risk factor. Pharmacological intervention should be started on the basis of a score of 3 as the optimal cut-off score. Both alendronate and risedronate are recommended as first-line treatment. Ibandronate,teriparatide, and active vitamin D3 derivatives are recommended as alternative option. PMID- 26608859 TI - [Efficacy of disease modifying anti-rheumatic drugs on bone destruction in rheumatoid arthritis]. AB - There had been proved the efficacy of preventing bone destruction by using disease modifying anti-rheumatic drugs (DMARDS) such as methotrexate(MTX). A certain combination of DMARDS is more effective than treated alone. But the data about DMARDS combination therapy or DMARDS used mainly in Japan is not abundant, and there needed to establish the evidences of them. PMID- 26608860 TI - [Control of bone and cartilage lesions in rheumatoid arthritis with TNF inhibitors]. AB - TNF inhibitors have provided the paradigm shift in the field of rheumatology. Now 5 TNF inhibitors(infliximab, etanercept, adalimumab, golimumab and certolizumab pegol)are available. Each agent has not only clinical efficacy but also suppressive effect of radiographic progression based on the large clinical trials. Prompt use of a TNF inhibitor after making a diagnosis of RA may be important to prevent joint deformities and to obtain better quality of life for RA patients. PMID- 26608861 TI - [IL-6 inhibitors prevent bone loss and cartilage degeneration in rheumatoid arthritis]. AB - Dysregulation of cytokines, including interleukin-6 (IL-6), is involved in joint destruction in rheumatoid arthritis (RA). The concentration of IL-6 is increased not only in the affected joints but also in the serum. Locally, IL-6 provides the formation of pannus through the synthesis of vascular endothelial growth factor (VEGF). In addition, IL-6 contributes to the production of matrix metalloproteinases which digest collagen and proteoglycan of cartilage. Furthermore, IL-6 induces the differentiation and activation of osteoclasts. IL-6 can be delivered systemically to a similar extent as hormones, may induce systemic osteoporosis. Tocilizumab (TCZ), a humanized anti-IL-6 receptor antibody, inhibiting IL-6 signaling, has provided beneficial outcomes, such as achievement of clinical remission, protective effects against bone and cartilage destruction. Because of the beneficial outcomes, new drugs inhibiting IL-6 signaling are developed, and the clinical trials are ongoing. PMID- 26608862 TI - [Zinc signaling-mediated regulation of dentin and periodontal tissues]. AB - An essential trace element zinc is required for variety of cellular functions and physiological responses, therefore, downregulation of zinc homeostasis cause serious problems in health, such as growth retardation and abnormal bone formation. Recent technical advances contributed to reveal that zinc ion regulated by zinc transporters acts as a signaling mediator, called zinc signaling that involves in mammalian physiology and pathogenesis. This review will address the current understanding of the roles of zinc signaling in regulation of dentin formation and periodontal tissues homeostasis. PMID- 26608864 TI - Theranostic reduction-sensitive gemcitabine prodrug micelles for near-infrared imaging and pancreatic cancer therapy. AB - A biodegradable and reduction-cleavable gemcitabine (GEM) polymeric prodrug with in vivo near-infrared (NIR) imaging ability was reported. This theranostic GEM prodrug PEG-b-[PLA-co-PMAC-graft-(IR820-co-GEM)] was synthesized by ring-opening polymerization and "click" reaction. The as-prepared reduction-sensitive prodrug could self-assemble into prodrug micelles in aqueous solution confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release studies showed that these prodrug micelles were able to release GEM in an intracellular-mimicking reductive environment. These prodrug micelles could be effectively internalized by BxPC-3 pancreatic cancer cells, which were observed by confocal laser scanning microscopy (CLSM). Meanwhile, a methyl thiazolyl tetrazolium (MTT) assay demonstrated that this prodrug exhibited high cytotoxicity against BxPC-3 cells. The in vivo whole-animal near-infrared (NIR) imaging results showed that these prodrug micelles could be effectively accumulated in tumor tissue and had a longer blood circulation time than IR820 COOH. The endogenous reduction-sensitive gemcitabine prodrug micelles with the in vivo NIR imaging ability might have great potential in image-guided pancreatic cancer therapy. PMID- 26608863 TI - Using Zinc Finger Nuclease Technology to Generate CRX-Reporter Human Embryonic Stem Cells as a Tool to Identify and Study the Emergence of Photoreceptors Precursors During Pluripotent Stem Cell Differentiation. AB - The purpose of this study was to generate human embryonic stem cell (hESC) lines harboring the green fluorescent protein (GFP) reporter at the endogenous loci of the Cone-Rod Homeobox (CRX) gene, a key transcription factor in retinal development. Zinc finger nucleases (ZFNs) designed to cleave in the 3' UTR of CRX were transfected into hESCs along with a donor construct containing homology to the target region, eGFP reporter, and a puromycin selection cassette. Following selection, polymerase chain reaction (PCR) and sequencing analysis of antibiotic resistant clones indicated targeted integration of the reporter cassette at the 3' of the CRX gene, generating a CRX-GFP fusion. Further analysis of a clone exhibiting homozygote integration of the GFP reporter was conducted suggesting genomic stability was preserved and no other copies of the targeting cassette were inserted elsewhere within the genome. This clone was selected for differentiation towards the retinal lineage. Immunocytochemistry of sections obtained from embryoid bodies and quantitative reverse transcriptase PCR of GFP positive and negative subpopulations purified by fluorescence activated cell sorting during the differentiation indicated a significant correlation between GFP and endogenous CRX expression. Furthermore, GFP expression was found in photoreceptor precursors emerging during hESC differentiation, but not in the retinal pigmented epithelium, retinal ganglion cells, or neurons of the developing inner nuclear layer. Together our data demonstrate the successful application of ZFN technology to generate CRX-GFP labeled hESC lines, which can be used to study and isolate photoreceptor precursors during hESC differentiation. PMID- 26608866 TI - Stenosis map for volume visualization of constricted tubular structures: Application to coronary artery stenosis. AB - Although direct volume rendering (DVR) has become a commodity, effective rendering of interesting features is still a challenge. In one of active DVR application fields, the medicine, radiologists have used DVR for the diagnosis of lesions or diseases that should be visualized distinguishably from other surrounding anatomical structures. One of most frequent and important radiologic tasks is the detection of lesions, usually constrictions, in complex tubular structures. In this paper, we propose a 3D spatial field for the effective visualization of constricted tubular structures, called as a stenosis map which stores the degree of constriction at each voxel. Constrictions within tubular structures are quantified by using newly proposed measures (i.e. line similarity measure and constriction measure) based on the localized structure analysis, and classified with a proposed transfer function mapping the degree of constriction to color and opacity. We show the application results of our method to the visualization of coronary artery stenoses. We present performance evaluations using twenty eight clinical datasets, demonstrating high accuracy and efficacy of our proposed method. The ability of our method to saliently visualize the constrictions within tubular structures and interactively adjust the visual appearance of the constrictions proves to deliver a substantial aid in radiologic practice. PMID- 26608867 TI - Planovalgus foot deformity in cerebral palsy corrected by botulinum toxin injection in the peroneus longus: Clinical and radiological evaluations in young children. AB - BACKGROUND: In children with cerebral palsy (CP), overactivity of the peroneus longus (PL) muscle is a major contributor to pes planovalgus. This retrospective study assessed whether abobotulinumtoxinA injections into a PL showing premature activity on electromyography (EMG) clinically improved foot morphology in children with CP. METHODS: Study participants were <6 years old, had a diagnosis of CP, good functional abilities (Gross Motor Function Classification System level 1 or 2), equinovalgus (initial contact with the hallux or head of the first metatarsal) and overactive PL on EMG. The fore-, mid- and hindfoot were evaluated clinically and radiologically before and after injection of abobotulinumtoxinA (6 7 U/kg) into the PL. Radiological data were compared with reference values for children without pes planovalgus. RESULTS: In total, 16 children (8 males; 10 hemiplegia, 6 diplegia; mean age: 3.2+/-1.5 years) received treatment. Mean pre and post-treatment angles in clinical assessment of dorsiflexion of the talocrural articulation did not differ with both knees flexed (24.4+/-7.5 vs. 22.2+/-8.0 degrees; P=0.19) or extended (17.2+/-8.0 vs. 16.6+/-6.8 degrees; P=0.36). Radiographic data pre-treatment versus reference data revealed forefoot pronation (metatarsal stacking angle 2.1+/-8.3 vs. 8.0+/-2.9 degrees; P=0.002), midfoot planus (lateral talo-first metatarsal 28.5+/-15.0 vs. 13.0+/-7.5 degrees; P<0.001; talocalcaneal angle 54.6+/-8.6 vs. 49.0+/-6.9 degrees; P=0.004) and significantly decreased calcaneus dorsiflexion, without hindfoot equinus (calcaneal pitch angle 7.9+/-6.0 vs. 17.0+/-6.0 degrees; P<0.001). After treatment, the metatarsal stacking angle did not differ from reference values (P=0.15). As compared with before treatment, treatment improved mean angles for metatarsal stacking (2.1+/-8.3 vs. 7.1+/-3.9 degrees, respectively, P=0.002), lateral talo-first metatarsal and talocalcaneal (both P<0.001), with no change in the hindfoot. CONCLUSION: PL may be an early target for abobotulinumtoxinA treatment in pes planovalgus associated with premature PL activity in children with CP. PMID- 26608868 TI - Multiple monolithic fiber solid-phase microextraction based on a polymeric ionic liquid with high-performance liquid chromatography for the determination of steroid sex hormones in water and urine. AB - The development of a simple and sensitive analytical approach that combines multiple monolithic fiber solid-phase microextraction with liquid desorption followed by high-performance liquid chromatography with diode array detection is proposed for the determination of trace levels of seven steroid sex hormones (estriol, 17beta-estradiol, testosterone, ethinylestradiol, estrone, progesterone and mestranol) in water and urine matrices. To extract the target analytes effectively, multiple monolithic fiber solid-phase microextraction based on a polymeric ionic liquid was used to concentrate hormones. Several key extraction parameters including desorption solvent, extraction and desorption time, pH value and ionic strength in sample matrix were investigated in detail. Under the optimal experimental conditions, the limits of detection were found to be in the range of 0.027-0.12 MUg/L. The linear range was 0.10-200 MUg/L for 17beta estradiol, 0.25-200 MUg/L estriol, ethinylestradiol and estrone, and 0.50-200 MUg/L for the other hormones. Satisfactory linearities were achieved for analytes with the correlation coefficients above 0.99. Acceptable method reproducibility was achieved by evaluating the repeatability and intermediate precision with relative standard deviations of both less than 8%. The enrichment factors ranged from 54- to 74-fold. Finally, the proposed method was successfully applied to the analysis of steroid sex hormones in environmental water samples and human urines with spiking recoveries ranged from 75.6 to 116%. PMID- 26608870 TI - Triple-doped KMnF3:Yb3+/Er3+/Tm3+ nanocubes: four-color upconversion emissions with strong red and near-infrared bands. AB - Triple-doped (Yb(3+)/Er(3+)/Tm(3+)) KMnF3 nanocubes with uniform sizes of 250 nm were synthesized by a facile hydrothermal route using the oleic acid as the capping agent. It was found that these nanocubes can simultaneously exhibited four-color (blue, green, red and NIR) upconversion emissions under a single 980 nm near-infrared (NIR) laser excitation, which should have potential multicolor in vivo imaging applications. Specifically, the red (660 nm) and NIR (800 nm) peaks, known as two "optical windows" for imaging biological tissues, were strong. The spectral and pump analyses indicated the two-photon processes were responsible for the both red and NIR emissions. PMID- 26608869 TI - Initial evaluation of hepatic T1 relaxation time as an imaging marker of liver disease associated with autosomal recessive polycystic kidney disease (ARPKD). AB - Autosomal recessive polycystic kidney disease (ARPKD) is a potentially lethal multi-organ disease affecting both the kidneys and the liver. Unfortunately, there are currently no non-invasive methods to monitor liver disease progression in ARPKD patients, limiting the study of potential therapeutic interventions. Herein, we perform an initial investigation of T1 relaxation time as a potential imaging biomarker to quantitatively assess the two primary pathologic hallmarks of ARPKD liver disease: biliary dilatation and periportal fibrosis in the PCK rat model of ARPKD. T1 relaxation time results were obtained for five PCK rats at 3 months of age using a Look-Locker acquisition on a Bruker BioSpec 7.0 T MRI scanner. Six three-month-old Sprague-Dawley (SD) rats were also scanned as controls. All animals were euthanized after the three-month scans for histological and biochemical assessments of bile duct dilatation and hepatic fibrosis for comparison. PCK rats exhibited significantly increased liver T1 values (mean +/- standard deviation = 935 +/- 39 ms) compared with age-matched SD control rats (847 +/- 26 ms, p = 0.01). One PCK rat exhibited severe cholangitis (mean T1 = 1413 ms), which occurs periodically in ARPKD patients. The observed increase in the in vivo liver T1 relaxation time correlated significantly with three histological and biochemical indicators of biliary dilatation and fibrosis: bile duct area percent (R = 0.85, p = 0.002), periportal fibrosis area percent (R = 0.82, p = 0.004), and hydroxyproline content (R = 0.76, p = 0.01). These results suggest that hepatic T1 relaxation time may provide a sensitive and non invasive imaging biomarker to monitor ARPKD liver disease. PMID- 26608871 TI - Feline leishmaniosis in Portugal--some remarks on disease and infection. PMID- 26608872 TI - Temperature modulates phototrophic periphyton response to chronic copper exposure. AB - Streams located in vineyard areas are highly prone to metal pollution. In a context of global change, aquatic systems are generally subjected to multi-stress conditions due to multiple chemical and/or physical pressures. Among various environmental factors that modulate the ecological effects of toxicants, special attention should be paid to climate change, which is driving an increase in extreme climate events such as sharp temperature rises. In lotic ecosystems, periphyton ensures key ecological functions such as primary production and nutrient cycling. However, although the effects of metals on microbial communities are relatively well known, there is scant data on possible interactions between temperature increase and metal pollution. Here we led a study to evaluate the influence of temperature on the response of phototrophic periphyton to copper (Cu) exposure. Winter communities, collected in a 8 degrees C river water, were subjected for six weeks to four thermal conditions in microcosms in presence or not of Cu (nominal concentration of 15 MUg L(-1)). At the initial river temperature (8 degrees C), our results confirmed the chronic impact of Cu on periphyton, both in terms of structure (biomass, distribution of algal groups, diatomic composition) and function (photosynthetic efficiency). At higher temperatures (13, 18 and 23 degrees C), Cu effects were modulated. Indeed, temperature increase reduced Cu effects on algal biomass, algal class proportions, diatom assemblage composition and photosynthetic efficiency. This reduction of Cu effects on periphyton may be related to lower bioaccumulation of Cu and/or to selection of more Cu-tolerant species at higher temperatures. PMID- 26608873 TI - Physiological differences in response to di-n-butyl phthalate (DBP) exposure between low- and high-DBP accumulating cultivars of Chinese flowering cabbage (Brassica parachinensis L.). AB - To increase understanding on the mechanisms of cultivar difference in contaminant accumulation in crops, this study was designed to compare the physiological responses to di-n-butyl phthalate (DBP) exposure between low (Lvbao70) and high (Huaguan) DBP cultivars of Chinese flowering cabbage (Brassica parachinensis L.). Under high DBP exposure, significant differences in various physiological responses were observed between the two cultivars, which might account for the variation in DBP accumulation. Ultrastructure observation also showed different alterations or damages in the mesophyll cell structures between both cultivars, especially for the chloroplast disintegration, starch grain quantity, and plastoglobuli accumulation. Compared with Huaguan, Lvbao70 suffered greater decreases in biomass, chlorophyll content, carbon assimilation, gas exchange parameters, photosynthetic electron transport capacity, and antioxidase activities, which would have resulted in a great reduction of photosynthetic capacity. Although Lvbao70 enhanced energy dissipation and activities of some antioxidant enzymes, they did not provide sufficient protection against oxidative damage caused by DBP. The result suggested that the lower DBP tolerance of Lvbao70 might be associated with its poor physiological performances, which was responsible for its lower DBP accumulation to protect itself from toxicity. Additionally, Lvbao70 had a significantly lower transpiration rate and stomatal conductance than Huaguan, which might be the factors regulating DBP-accumulation variation. PMID- 26608874 TI - Australian atmospheric lead deposition reconstructed using lead concentrations and isotopic compositions of archival lichen and fungi. AB - Lead concentrations and their isotopic compositions were measured in lichen genera Cladonia and Usnea and fungi genus Trametes from the Greater Sydney region (New South Wales, Australia) that had been collected and archived over the past 120 years. The median lead contents were elevated in lichens and fungi prior to the introduction of leaded petrol (Cladonia 12.5 mg/kg; Usnea 15.6 mg/kg; Trametes 1.85 mg/kg) corresponding to early industrial development. During the use of leaded petrol for automobiles in Australia from 1932 to 2002, total median lead concentrations rose: Cladonia 18.8 mg/kg; Usnea 21.5 mg/kg; Trametes 4.3 mg/kg. Following the cessation of leaded petrol use, median total lead concentrations decreased sharply in the 2000s: Cladonia 4.8 mg/kg; Usnea 1.7 mg/kg. The lichen and fungi isotopic compositions reveal a significant decrease in (206)Pb/(207)Pb values from the end of 19th century to the 1970s. The following decades were characterised by lower allowable levels of lead additive in fuel and the introduction of unleaded petrol in 1985. The environmental response to these regulatory changes was that lichen and fungi (206)Pb/(207)Pb values increased, particularly from 1995 onwards. Although the lead isotope ratios of lichens continued to increase in the 2000s they do not return to pre leaded petrol values. This demonstrates that historic leaded petrol emissions, inter alia other sources, remain a persistent source of anthropogenic contamination in the Greater Sydney region. PMID- 26608875 TI - Long-term toxicity assessment of soils in a recovered area affected by a mining spill. AB - Residual pollution in the Guadiamar Green Corridor still remains after Aznalcollar mine spill in 1998. The polluted areas are identified by the absence of vegetation, soil acidic pH and high concentrations of As, Pb, Zn and Cu. Soil toxicity was assessed by lettuce root elongation and induced soil respiration bioassays. In bare soils, total As and Pb concentrations and water-extractable levels for As, Zn and Cu exceeded the toxicity guidelines. Pollutants responsible for toxicity were different depending on the tested organism, with arsenic being most toxic for lettuce and the metal mixture to soil respiration. Soil properties, such as pH or organic carbon content, are key factors to control metal availability and toxicity in the area. According to our results, there is a risk of pollution to living organisms and the soil quality criteria established in the area should be revised to reduce the risk of toxicity. PMID- 26608876 TI - Randomised controlled trial of spinal anaesthesia with bupivacaine or 2 chloroprocaine during caesarean section. AB - BACKGROUND: Neuraxial anaesthesia is the desired method for Caesarean section. Bupivacaine is a well-known local anaesthetic. It has a long duration of action and can cause unpredictable levels of anaesthesia with subsequent prolonged discharge time. 2-Chloroprocaine has a rapid onset of action, producing an excellent sensory and motor block and has a rapid hydrolysis in the bloodstream by pseudocholinesterase. We compared bupivacaine and 2-chloroprocaine for spinal anaesthesia during Caesarean section. The primary endpoint was the earliest reversal sign of the motor block. METHODS: Sixty ASAI/II patients, planned for elective singleton Caesarean section, were equally randomised to three groups. All patients received a combined spinal-epidural anaesthesia. The first group received 2-chloroprocaine (40 mg) without sufentanil, the second group received 2 chloroprocaine (40 mg) with sufentanil (1 MUg) and the third group received hyperbaric bupivacaine (7.5 mg) with sufentanil (1 MUg) as a spinal anaesthetic. Motor and sensory blockade were assessed at specific time points. RESULTS: There was no difference between the three groups regarding the time to regression of the motor block. However, at 5 min post spinal injection, the level of sensory block was higher for both groups with 2-chloroprocaine, in comparison with the bupivacaine group. CONCLUSION: 2-Chloroprocaine can be used for low risk Caesarean section in healthy parturients. There is no difference in time to motor block resolution compared to bupivacaine. Motor recovery seems more predictable for 2-chloroprocaine and may be beneficial for the breastfeeding initiation. PMID- 26608877 TI - An integrated assessment of morphology, size, and complement activation of the PEGylated liposomal doxorubicin products Doxil(r), Caelyx(r), DOXOrubicin, and SinaDoxosome. AB - In order to improve patient's benefit and safety, comprehensive regulatory guidelines on specificities of Non-Biological Complex Drugs (NBCDs), such as doxorubicin-encapsulated liposomes, and their follow-on versions are needed. Here, we compare Doxil(r) and its European analog Caelyx(r) with the two follow on products DOXOrubicin (approved by the US Food and Drug Administration) and SinaDoxosome (produced in Iran) by cryogenic transmission electron microscopy, dynamic light scattering and Nanoparticle Tracking Analysis, and assess their potential in activating the complement system in human sera. We found subtle physicochemical differences between the tested liposomal products and even between the tested batches of Doxil(r) and Caelyx(r). Notably, these included differences in vesicular population aspect ratios and particle number. Among the tested products, only SinaDoxosome, in addition to the presence of unilamellar vesicles with entrapped doxorubicin crystals, contained empty circular disks. Differences were also found in complement responses, which may be related to some morphological differences. This study has demonstrated an integrated biophysical and immunological toolbox for improved analysis and detection of physical differences among vesicular populations that may modulate their clinical performance. Combined, these approaches may help better product selection for infusion to the patients as well as for improved design and characterization of future vesicular NBCDs with enhanced clinical performance and safety. PMID- 26608878 TI - Impact of Early Environment on Children's Mental Health: Lessons From DNA Methylation Studies With Monozygotic Twins. AB - Over the past decade, epigenetic analyses have made important contributions to our understanding of healthy development and a wide variety of adverse conditions such as cancer and psychopathology. There is increasing evidence that DNA methylation is a mechanism by which environmental factors influence gene transcription and, ultimately, phenotype. However, differentiating the effects of the environment from those of genetics on DNA methylation profiles remains a significant challenge. Monozygotic (MZ) twin study designs are unique in their ability to control for genetic differences because each pair of MZ twins shares essentially the same genetic sequence with the exception of a small number of de novo mutations and copy number variations. Thus, differences within twin pairs in gene expression and phenotype, including behavior, can be attributed in the majority of cases to environmental effects rather than genetic influence. In this article, we review the literature showing how MZ twin designs can be used to study basic epigenetic principles, contributing to understanding the role of early in utero and postnatal environmental factors on the development of psychopathology. We also highlight the importance of initiating longitudinal and experimental studies with MZ twins during pregnancy. This approach is especially important to identify: (1) critical time periods during which the early environment can impact brain and mental health development, and (2) the specific mechanisms through which early environmental effects may be mediated. These studies may inform the optimum timing and design for early preventive interventions aimed at reducing risk for psychopathology. PMID- 26608879 TI - Sex in Its Daily Relational Context. AB - INTRODUCTION: The present study measured the daily correlates of sexual behavior in an ecologically valid context by relying on a daily diary approach. AIM: Examining the dyadic and multicomponent nature of sexual behavior is essential to create valid models of sexual responding that are better aligned with the day-to day context of having sex in a relationship. METHODS AND MAIN OUTCOME MEASURES: During 3 weeks, heterosexual couples completed, two times a day, an electronic diary to report on mood, own and perceived partner behavior, relational feelings (in the evening), sexual activity, physical intimacy, and masturbation (in the morning). This design allowed testing bidirectional temporal associations between daily context and different types of sexual behavior. RESULTS: Positive mood, displays of positive partner behavior, perceived positive partner behavior, and positive relational feelings predicted more sexual activity and intimacy in men, which then further increased their positive mood, perceived positive partner behavior, and positive feelings about the relationship on the following day. Women showed a similar pattern of predictors regarding sexual activity as men, though the effect of sexual behavior on next-day feelings and behavior was more relationship-oriented rather than affecting personal mood. Intimacy was related to almost all daily variables in women, but related only to own and perceived positive partner behavior and positive relational feelings the next day. Several partner effects also reached significance, and these were more influential in predicting male than female intimacy. Solitary sexual activity showed a different pattern of results than dyadic sexual activity, with men experiencing masturbation as negatively in the context of their relationship. CONCLUSION: These results confirm the regulatory function of sex and intimacy in maintaining a positive relational climate and indicate that the quality of the everyday relational context is important to get partners in the mood to act in a sexual way. PMID- 26608880 TI - Diabetes Pathology and Risk of Primary Open-Angle Glaucoma: Evaluating Causal Mechanisms by Using Genetic Information. AB - Although type 2 diabetes (T2D) predicts glaucoma, the potential for unmeasured confounding has hampered causal conclusions. We performed separate sample genetic instrumental variable analyses using the Genetic Epidemiology Research Study on Adult Health and Aging cohort (n = 69,685; 1995-2013) to estimate effects of T2D on primary open-angle glaucoma (POAG; 3,554 cases). Genetic instrumental variables for overall and mechanism-specific (i.e., linked to T2D via influences on adiposity, beta-cell function, insulin regulation, or other metabolic processes) T2D risk were constructed by using 39 genetic polymorphisms established to predict T2D in other samples. Instrumental variable estimates indicated that T2D increased POAG risk (odds ratio = 2.53, 95% confidence interval: 1.04, 6.11). The instrumental variable for beta-cell dysregulation also significantly predicted POAG (odds ratiobeta-cell = 5.26, 95% confidence interval: 1.75, 15.85), even among individuals without diagnosed T2D, suggesting that metabolic dysregulation may increase POAG risk prior to T2D diagnosis. The T2D risk variant in the melatonin receptor 1B gene (MTNR1B) predicted risk of POAG independently of T2D status, indicating possible pleiotropic physiological functions of melatonin, but instrumental variable effect estimates were significant even excluding MTNR1B variants. To our knowledge, this is the first genetic instrumental variable study of T2D and glaucoma, providing a novel approach to evaluating this hypothesized relationship. Our findings substantially bolster observational evidence that T2D increases POAG risk. PMID- 26608881 TI - Investigation of a staphylococcal food poisoning outbreak combining case-control, traditional typing and whole genome sequencing methods, Luxembourg, June 2014. AB - In June 2014, a staphylococcal food poisoning outbreak occurred at an international equine sports event in Luxembourg requiring the hospitalisation of 31 persons. We conducted a microbiological investigation of patients and buffet items, a case-control study and a carriage study of catering staff. Isolates of Staphylococcus aureus from patients, food and catering staff were characterised and compared using traditional typing methods and whole genome sequencing. Genotypically identical strains (sequence type ST8, spa-type t024, MLVA-type 4698, enterotoxin A FRI100) were isolated in 10 patients, shiitake mushrooms, cured ham, and in three members of staff. The case-control study strongly suggested pasta salad with pesto as the vehicle of infection (p<0.001), but this food item could not be tested, because there were no leftovers. Additional enterotoxigenic strains genetically unrelated to the outbreak strain were found in four members of staff. Non-enterotoxigenic strains with livestock-associated sequence type ST398 were isolated from three food items and two members of staff. The main cause of the outbreak is likely to have been not maintaining the cold chain after food preparation. Whole genome sequencing resulted in phylogenetic clustering which concurred with traditional typing while simultaneously characterising virulence and resistance traits. PMID- 26608882 TI - [(111)In]PSMA-I&T: expanding the spectrum of PSMA-I&T applications towards SPECT and radioguided surgery. AB - BACKGROUND: The relevance of prostate-specific membrane antigen (PSMA) targeting in the clinical management of prostate cancer (PCa) is continually increasing, entailing the development of PSMA-targeted molecular probes. Recently, a first PSMA-targeted theranostic concept has been successfully implemented by [(68)Ga/(177)Lu]PSMA-I&T. To further exploit the excellent PSMA-targeting characteristics and in vivo performance of the PSMA-I&T platform, [(111)In]PSMA I&T was evaluated as a complementary probe for radioguided surgery and SPECT imaging. FINDINGS: Compared to [(68)Ga/(177)Lu]PSMA-I&T, [(111)In]PSMA-I&T showed unchangedly high PSMA-affinity and enhanced internalization into PSMA-expressing LNCaP PCa cells. Biodistribution studies in LNCaP xenograft-bearing mice (1 h p.i.) revealed slightly reduced background accumulation of [(111)In]PSMA-I&T compared to [(177)Lu]PSMA-I&T and identical tumor uptake of both compounds, leading to increased tumor/background ratios for [(111)In]PSMA-I&T. An exemplary patient with metastatic PCa underwent preoperative [(68)Ga]HBED-CC-PSMA PET/CT (1 h p.i.) and [(111)In]PSMA-I&T SPECT/CT (4 h p.i.), followed by prostatectomy and radioguided extended pelvic lymphadenectomy (24 h p.i.). In [(111)In]PSMA-I&T SPECT/CT, the previously identified PCa lesions ([(68)Ga]HBED-CC-PSMA PET/CT) showed high tracer accumulation and were also detectable using planar scintigraphy. The intraoperative use of a hand-held gamma probe allowed detection and resection of all [(111)In]PSMA-I&T-accumulating lesions. The presence of PSMA positive tumor tissue in the resected specimens was confirmed histopathologically and via [(111)In]PSMA-I&T autoradiography. CONCLUSIONS: [(111)In]PSMA-I&T shows efficient PSMA targeting in vitro and in vivo, combined with low background accumulation. In an exemplary PCa patient, [(111)In]PSMA-I&T was successfully applied for preoperative SPECT/CT visualization and radioguided resection of PSMA positive lesions, hinting towards a high value of [(111)In]PSMA-I&T as a complementary tool to [(68)Ga/(177)Lu]PSMA-I&T in the clinical management of prostate cancer. PMID- 26608883 TI - Hyperthermic isolated limb perfusion in locally advanced limb soft tissue sarcoma: A 24-year single-centre experience. AB - BACKGROUND: Hyperthermic isolated limb perfusion (HILP) is a locoregional treatment aimed at avoiding amputation in patients with advanced extremity soft tissue sarcomas (STS). Over the last 25 years, HILP procedure has been implemented to maximise its therapeutic ratio. METHODS: A retrospective analysis including 117 patients who underwent HILP from 1989 to 2013 was performed. Three different drug schedules were applied: 1) doxorubicin (n = 47), 2) high dose (3-4 mg) tumour necrosis factor-alpha (TNF-alpha) plus doxorubicin (n = 30), 3) low dose (1 mg) TNF-alpha plus melphalan (L-PAM) (n = 40). Tumour response was evaluated by MRI or CT and surgical specimens. Toxicity and local progression free survival (LPFS) were also evaluated. RESULTS: In total 92 (78.6%) patients had primary, 25 (21.4%) had recurrent and 17 (14.5%) had metastatic disease. The subjects in the three groups were homogeneous for clinical-pathological features. Pathological response was complete in 55 patients (47%), partial in 35 (29.9%), regardless of drug schedule (p = 0.501) and tumour presentation (p = 0.094). Wieberdink III-V toxicity was registered in 19.1%, 20% and 2.5% of patients, respectively (p < 0.051). Twenty-eight patients (23.9%) received adjuvant radiotherapy with no relevant toxicity. Five-year LPFS was 81.6% and 74.2% in patients with primary or recurrent disease, respectively (p = 0.652). After a median follow-up of 36.5 months, the limb sparing rate was 77.8%. CONCLUSIONS: HILP performed with different drugs was equally active, either in primary, recurrent or metastatic STS, providing effective limb sparing and durable local control. Low dose TNF-alpha plus L-PAM had the most favourable toxicity profile. Adjuvant radiotherapy was not associated with relevant toxicity. PMID- 26608884 TI - Systems biology approaches to study the molecular effects of caloric restriction and polyphenols on aging processes. AB - Worldwide population is aging, and a large part of the growing burden associated with age-related conditions can be prevented or delayed by promoting healthy lifestyle and normalizing metabolic risk factors. However, a better understanding of the pleiotropic effects of available nutritional interventions and their influence on the multiple processes affected by aging is needed to select and implement the most promising actions. New methods of analysis are required to tackle the complexity of the interplay between nutritional interventions and aging, and to make sense of a growing amount of -omics data being produced for this purpose. In this paper, we review how various systems biology-inspired methods of analysis can be applied to the study of the molecular basis of nutritional interventions promoting healthy aging, notably caloric restriction and polyphenol supplementation. We specifically focus on the role that different versions of network analysis, molecular signature identification and multi-omics data integration are playing in elucidating the complex mechanisms underlying nutrition, and provide some examples on how to extend the application of these methods using available microarray data. PMID- 26608885 TI - Barriers and Solutions to Smart Water Grid Development. AB - This limited review of smart water grid (SWG) development, challenges, and solutions provides an initial assessment of early attempts at operating SWGs. Though the cost and adoption issues are critical, potential benefits of SWGs such as efficient water conservation and distribution sustain the development of SWGs around the world. The review finds that the keys to success are the new regulations concerning data access and ownership to solve problems of security and privacy; consumer literacy to accept and use SWGs; active private sector involvement to coordinate SWG development; government-funded pilot projects and trial centers; and integration with sustainable water management. PMID- 26608887 TI - Bis-(benzothiazol-2-yl)-amines and their metal amides: a structural comparison in the solid state. AB - Within this work, the field of amide ligand platforms for group 13 metal complexation, especially for Al(iii) is investigated in a synthetic as well as in a structural comparative approach. Starting from bis-heterocyclo methanides, which mimic the omnipresent nacnac ligand, the next enhancement in this class of ligands includes the exchange of the central methylene bridge by an amine nitrogen atom. With this modification three different sec. amines, each symmetrically substituted, could be synthesised as parent neutral benzothiazole containing ligand systems: (NCSC6H4)2NH (1), (4-MeNCSC6H3)2NH (2) and (4 OMeNCSC6H3)2NH (3). Apart from these compounds also a lithiated species and a row of group 13 metal complexes of the deprotonated ligands could be examined by applying single crystal X-ray diffraction analyses. In this course three new dimethyl aluminium containing complexes [Me2Al{(NCSC6H4)2N}] (4), [Me2Al{(4 MeNCSC6H3)2N}] (5) and [Me2Al{(4-OMeNCSC6H3)2N}.AlMe3] (6) as well as two lithiated compounds [Li{(NCSC6H4)2N}]4 (7), [Li{(4-MeNCSC6H3)2N}]4 (8) were structurally and spectroscopically characterised. A subsequent structural comparison of 1-6 and 8 in the solid state shows that the parent ligand systems prefer a planar cis-trans alignment due to hydrogen bond formation. In contrast to that, the metallated species favour a planar but trans-trans or cis-cis alignment depending on the metal cation. PMID- 26608886 TI - Impact of morbid obesity and bariatric surgery on antioxidant/oxidant balance of the unstimulated and stimulated human saliva. AB - OBJECTIVE: There is no study evaluating the influence of morbid obesity and bariatric surgery on antioxidant/oxidant homeostasis of the unstimulated and stimulated human saliva. MATERIALS AND METHODS: Salivary flow rate, total antioxidant status (TAS), total oxidant status (TOS), oxidative status index (OSI), the total amount of uric acid (UA), polyphenols (pPh), catalase (CAT), superoxide dismutase 2 (SOD2), specific activity of peroxidase (Px), as well as malondialdehyde (MDA), and advanced glycation end products (AGE) concentrations were determined in the unstimulated (UWS) and stimulated (SWS) whole saliva of patients with morbid obesity before and after bariatric surgery. RESULTS: In both UWS and SWS, the total amount of TOS, OSI, SOD2, and MDA was statistically higher in patients with morbid obesity as compared to the healthy controls, as well as significantly lower in the patients treated surgically as compared to the obese patients. The median values of the total amount of TAS, CAT, UA, pPh, and specific activity of Px were significantly reduced in UWS and SWS in patients with morbid obesity as compared to the control group and also statistically elevated in patients after bariatric surgery as compared to the patients with morbid obesity. CONCLUSIONS: In morbid obesity, reduced unstimulated and stimulated salivary flow can be observed. Bariatric surgery restored only unstimulated salivary flow to normal values. Disturbances in oxidant/antioxidant homeostasis may be observed in UWS and SWS of obese patients before and after treatment. PMID- 26608888 TI - Adenosine A1 receptors contribute to immune regulation after neonatal hypoxic ischemic brain injury. AB - Neonatal brain hypoxic ischemia (HI) often results in long-term motor and cognitive impairments. Post-ischemic inflammation greatly effects outcome and adenosine receptor signaling modulates both HI and immune cell function. Here, we investigated the influence of adenosine A1 receptor deficiency (A1R(-/-)) on key immune cell populations in a neonatal brain HI model. Ten-day-old mice were subjected to HI. Functional outcome was assessed by open locomotion and beam walking test and infarction size evaluated. Flow cytometry was performed on brain infiltrating cells, and semi-automated analysis of flow cytometric data was applied. A1R(-/-) mice displayed larger infarctions (+33%, p < 0.05) and performed worse in beam walking tests (44% more mistakes, p < 0.05) than wild type (WT) mice. Myeloid cell activation after injury was enhanced in A1R(-/-) versus WT brains. Activated B lymphocytes expressing IL-10 infiltrated the brain after HI in WT, but were less activated and did not increase in relative frequency in A1R(-/-). Also, A1R(-/-) B lymphocytes expressed less IL-10 than their WT counterparts, the A1R antagonist DPCPX decreased IL-10 expression whereas the A1R agonist CPA increased it. CD4(+) T lymphocytes including FoxP3(+) T regulatory cells, were unaffected by genotype, whereas CD8(+) T lymphocyte responses were smaller in A1R(-/-) mice. Using PCA to characterize the immune profile, we could discriminate the A1R(-/-) and WT genotypes as well as sham operated from HI-subjected animals. We conclude that A1R signaling modulates IL 10 expression by immune cells, influences the activation of these cells in vivo, and affects outcome after HI. PMID- 26608889 TI - Conformational stability and self-association equilibrium in biologics. AB - Biologics exist in equilibrium between native, partially denatured, and denatured conformational states. The population of any of these states is dictated by their Gibbs energy and can be altered by changes in physical and solution conditions. Some conformations have a tendency to self-associate and aggregate, an undesirable phenomenon in protein therapeutics. Conformational equilibrium and self-association are linked thermodynamic functions. Given that any associative reaction is concentration dependent, conformational stability studies performed at different protein concentrations can provide early clues to future aggregation problems. This analysis can be applied to the selection of protein variants or the identification of better formulation solutions. In this review, we discuss three different aggregation situations and their manifestation in the observed conformational equilibrium of a protein. PMID- 26608890 TI - The ELF Honest Data Broker: informatics enabling public-private collaboration in a precompetitive arena. AB - New precompetitive ways of working in the pharmaceutical industry are driving the development of new informatics systems to enable their execution and management. The European Lead Factory (ELF) is a precompetitive, 30-partner collaboration between academic groups, small-medium enterprises and pharmaceutical companies created to discover small molecule hits against novel biological targets. A unique HTS screening and triage workflow has been developed to balance the intellectual property and scientific requirements of all the partners. Here, we describe the ELF Honest Data Broker, a cloud-based informatics system providing the scientific triage tools, fine-grained permissions and management tools required to implement the workflow. PMID- 26608891 TI - Administration of branched-chain amino acids alters the balance between pro inflammatory and anti-inflammatory cytokines. AB - Acute leucine intoxication and neurologic deterioration can develop rapidly at any age as a result of net protein degradation precipitated by infection or psychological stress in patients with maple syrup urine disease (MSUD). Here, we investigated the effects of acute and chronic Hyper-BCAA (H-BCAA) administration on pro- and anti-inflammatory cytokines in the brains of rats. For acute administration, Wistar rats (10 and 30 days) received three injections of BCAA pool (15.8 MUL/g at 1-h intervals) or saline, subcutaneously. For chronic administration, Wistar rats (7 days) received of BCAA pool or saline twice a day for 21 days, subcutaneously. Our results showed that acute administration of H BCAA increased IL-1beta (~ 78%; p <= 0.009) and TNF-alpha (~ 155%; p <= 0.026) levels in the cerebral cortex but not in the hippocampus of infant rats. Moreover, IL-6 levels were increased in the hippocampus (~ 135%; p <= 0.009) and cerebral cortex (~ 417%; p <= 0.008), whereas IL-10 levels were decreased only in the hippocampus (~ 42%; p <= 0.009). However, repeated administration of H-BCAA decreased IL-1beta (~ 59%; p <= 0.047), IL-6 (~ 70%; p <= 0.009) and IFN-gamma (~ 70%; p <= 0.008) levels in the cerebral cortex, whereas the IL-6 (~ 67%; p <= 0.009), IL-10 (~ 58%; p <= 0.01) and IFN-gamma (~ 67%; p <= 0.009) levels were decreased in the hippocampus. These findings suggest that a better understanding of the inflammatory response in MSUD patients may be useful to develop therapeutic strategies to modulate the hyperinflammatory/hypoinflammatory axis. PMID- 26608896 TI - CRUK Launches "Grand Challenges". AB - Cancer Research UK says it will invest L100 million, or about $150 million, over the next 5 years in an ambitious grant program aimed at tackling some of the most vexing unsolved problems in cancer research. The group has issued seven initial Grand Challenges and will present its first award next fall. PMID- 26608897 TI - Optimisation of water-cannon cleaning for deposit removal on water walls inside waste incinerators. AB - Deposits in municipal waste incinerators are very inhomogeneous in structure and constitution. They cause corrosion and reduce the efficiency, so they need to be removed frequently. Among other systems, operators use water cannons for the deposit removal. Two different removal mechanisms of water-cannon cleaning are suggested: A direct shattering of the deposit by the impact of the water jet, as well as the cracking caused by thermal stresses where droplets cool the deposits. As the contribution of each of the aforementioned mechanisms to the overall cleaning efficiency is unknown, we performed empirical investigations to determine the dominating effect. In a first experimental setup focusing on thermal stress, cold droplets were applied onto hot deposits taken from a waste incinerator. Results showed that the cleaning effect strongly depends on the deposit thickness and structure, so that the deposits could be categorised in three different groups. A second measurement campaign focused on the influence of deposit material, deposit temperature and water jet momentum. It could be shown that both deposit material and temperature have a significant effect on the cleaning efficiency, whereas an increase in water jet momentum only led to modest improvements. The combination of these two parameter studies implies that the influence of the thermal stress outweighs that of the momentum. This knowledge is applicable to the cleaning setup by increasing the temperature gradient. PMID- 26608898 TI - Elemental balance of SRF production process: solid recovered fuel produced from municipal solid waste. AB - In the production of solid recovered fuel (SRF), certain waste components have excessive influence on the quality of product. The proportion of rubber, plastic (hard) and certain textiles was found to be critical as to the elemental quality of SRF. The mass flow of rubber, plastic (hard) and textiles (to certain extent, especially synthetic textile) components from input waste stream into the output streams of SRF production was found to play the decisive role in defining the elemental quality of SRF. This paper presents the mass flow of polluting and potentially toxic elements (PTEs) in SRF production. The SRF was produced from municipal solid waste (MSW) through mechanical treatment (MT). The results showed that of the total input chlorine content to process, 55% was found in the SRF and 30% in reject material. Of the total input arsenic content, 30% was found in the SRF and 45% in fine fraction. In case of cadmium, lead and mercury, of their total input content to the process, 62%, 38% and 30%, respectively, was found in the SRF. Among the components of MSW, rubber material was identified as potential source of chlorine, containing 8.0 wt.% of chlorine. Plastic (hard) and textile components contained 1.6 and 1.1. wt.% of chlorine, respectively. Plastic (hard) contained higher lead and cadmium content compared with other waste components, i.e. 500 mg kg(-1) and 9.0 mg kg(-1), respectively. PMID- 26608899 TI - Greenhouse gas emissions from municipal solid waste management in Vientiane, Lao PDR. AB - Municipal solid waste (MSW) is one of the major environmental problems throughout the world including in Lao PDR. In Vientiane, due to the lack of a collection service, open burning and illegal dumping are commonly practised. This study aims to estimate the greenhouse gas (GHG) emission from the current situation of MSW management (MSWM) in Vientiane and proposes an alternative solution to reduce the GHG emission and environmental impacts. The 2006 Intergovernmental Panel on Climate Change (IPCC) Guidelines for National Greenhouse Gas Inventories (IPCC 2006 model) are used for the estimation of GHG emission from landfill and composting. For the estimation of GHG emission from open burning, the Atmospheric Brown Clouds Emission Inventory Manual (ABC EIM) is used. In Vientiane, a total of 232, 505 tonnes year(-1) of MSW was generated in 2011. Waste generation in Vientiane is 0.69 kg per capita per day, and about 31% of the total MSW generated was directly sent to landfill (71,162 tonnes year(-1)). The total potential GHG emission from the baseline scenario in 2011 was 110,182 tonnes year(-1) CO2-eq, which is 0.15 tonne year(-1) CO2-eq per capita. From the three MSWM scenarios proposed, scenario S3, which includes recycling, composting and landfilling, seems to be an effective solution for dealing with MSW in Vientiane with less air pollution, and is environmentally friendly. The total GHG emission in scenario S3 is reduced to 91,920 tonnes year(-1) CO2-eq (47% reduction), compared with the S1 scenario where all uncollected waste is diverted to landfill. PMID- 26608900 TI - Effect of pyrolysis temperatures and times on the adsorption of cadmium onto orange peel derived biochar. AB - The mechanism and capacity of adsorption of cadmium (Cd) on orange peel (OP) derived biochar at various pyrolysis temperatures (400, 500, 600, 700 and 800 degrees C) and heating times (2 and 6 h) were investigated. Biochar was characterized using proximate analysis, point of zero charge (PZC) analysis, Fourier transform infrared spectroscopy, scanning electron microscopy, energy dispersive X-ray spectroscopy and X-ray diffraction. Equilibrium and kinetic experiments of Cd adsorption on biochar were performed. The results indicated that the pH value at PZC of biochar approached 9.5. Equilibrium can be reached rapidly (within 1 min) in kinetic experiments and a removal rate of 80.6-96.9% can be generated. The results fitted the pseudo-second-order model closely. The adsorption capacity was estimated using the Langmuir model. The adsorption capacity of Cd on biochar was independent of the pyrolysis temperature and heating time (p>0.01). The maximum adsorption capacity of Cd was 114.69 (mg g( 1)). The adsorption of Cd on biochar was regarded as chemisorption. The primary adsorption mechanisms were regarded as Cpi-cation interactions and surface precipitation. Cadmium can react with calcite to form the precipitation of (Ca,Cd)CO3 on the surface of biochar. The OP-derived biochar can be considered a favourable alternative and a new green adsorbent for removing Cd(2+) ions from an aqueous solution. PMID- 26608901 TI - Feasibility study for an innovative industrial red mud utilisation method. AB - Red mud is a high volume industrial waste, and its management poses a unique challenge. For the utilisation of red mud, an economical, energy saving, environmental friendly and widely applicable method has been found. The proposed novel method is purely chemical, and achieves the recovery of all the oxides contained in red mud totally and transforms them into high value added products. The present work shows that an investment in an industrial plant, treating red mud and turning a toxic industrial waste in commercial products, is safe and viable. PMID- 26608902 TI - Requirement analysis to promote small-sized E-waste collection from consumers. AB - The collection and recycling of small-sized waste electrical and electronic equipment is an emerging problem, since these products contain certain amounts of critical metals and rare earths. Even if the amount is not large, having a few supply routes for such recycled resources could be a good strategy to be competitive in a world of finite resources. The small-sized e-waste sometimes contains personal information, therefore, consumers are often reluctant to put them into recycling bins. In order to promote the recycling of E-waste, collection of used products from the consumer becomes important. Effective methods involving incentives for consumers might be necessary. Without such methods, it will be difficult to achieve the critical amounts necessary for an efficient recycling system. This article focused on used mobile phones among information appliances as the first case study, since it contains relatively large amounts of valuable metals compared with other small-sized waste electrical and electronic equipment and there are a large number of products existing in the market. The article carried out surveys to determine what kind of recycled material collection services are preferred by consumers. The results clarify that incentive or reward money alone is not a driving force for recycling behaviour. The article discusses the types of effective services required to promote recycling behaviour. The article concludes that securing information, transferring data and providing proper information about resources and environment can be an effective tool to encourage a recycling behaviour strategy to promote recycling, plus the potential discount service on purchasing new products associated with the return of recycled mobile phones. PMID- 26608903 TI - Pathological Outcome following Radical Prostatectomy in Men with Prostate Specific Antigen Greater than 10 ng/ml and Histologically Favorable Risk Prostate Cancer. AB - PURPOSE: Active surveillance is now the treatment of choice in men with low risk prostate cancer. Although there is no consensus on which patients are eligible for active surveillance, prostate specific antigen above 10 ng/ml is generally excluded. In an attempt to determine the validity of using a prostate specific antigen cutoff of 10 ng/ml to counsel men considering active surveillance we analyzed a multi-institution database to determine the pathological outcome in men with prostate specific antigen greater than 10 ng/ml but histologically favorable risk prostate cancer. MATERIALS AND METHODS: We queried a prospectively maintained database of men with histologically favorable risk prostate cancer who underwent radical prostatectomy between 2003 and 2015. The cohort was categorized into 3 groups based on prostate specific antigen level, including low-less than 10 ng/ml, intermediate-10 or greater to less than 20 and high-20 or greater. Associations of prostate specific antigen group with adverse pathological and oncologic outcomes were analyzed. RESULTS: Of 2,125 patients 1,327 were categorized with histologically favorable risk disease. However on multivariate analyses the rates of up staging and upgrading were similar between the intermediate and low prostate specific antigen groups. In contrast compared to the intermediate prostate specific antigen group the high group had higher incidences of up staging (p = 0.02) and upgrading to 4 + 3 or greater disease (p = 0.046). Biochemical recurrence-free survival rates revealed no pairwise intergroup differences except between the low and high groups. CONCLUSIONS: Patients with preoperatively elevated prostate specific antigen between 10 and less than 20 ng/ml who otherwise had histologically favorable risk prostate cancer were not at higher risk for adverse pathological outcomes than men with prostate specific antigen less than 10 ng/ml. PMID- 26608904 TI - Variables associated to fetal microchimerism in systemic lupus erythematosus patients. AB - In the present study, we sought to identify the factors during the pregnancy of systemic lupus erythematosus (SLE) patients that could be linked to the presence and proliferation of male fetal cells (MFC) and the possible relation between these factors and development of lupus nephritis (LN). We evaluated 18 healthy women (control group) and 28 women affected by SLE. Genomic DNA was extracted from peripheral blood and quantified using the technique of quantitative real time polymerase chain reaction (qPCR) for specific Y chromosome sequences. The amount of MFC was significantly higher in the SLE group compared with the controls (SLE 252 +/- 654 vs control 2.13 +/- 3.7; P = 0.029). A higher amount of MFC was detected among multiparous SLE patients when compared with the control group (SLE 382 +/- 924 vs control 0.073 +/- 0.045; P = 0.019). LN was associated with reduced amount of MFC (LN 95.5 +/- 338 vs control 388 +/- 827; P = 0.019) especially when they have delivered their child before age 18 (LN 0.23 +/- 0.22 vs control 355 +/- 623; P = 0.028). SLE patients present a higher amount of MFC, which may increase with the time since birth of the first male child. LN patients showed an inverse correlation with MFC, suggesting that the role of the cells may be ambiguous during the various stages of development of the disease. PMID- 26608905 TI - Interaction of C60 fullerenes with asymmetric and curved lipid membranes: a molecular dynamics study. AB - Interaction of fullerenes with asymmetric and curved DOPC/DOPS bicelles is studied by means of coarse-grained molecular dynamics simulations. The effects caused by asymmetric lipid composition of the membrane leaflets and the curvature of the membrane are analyzed. It is shown that the aggregates of fullerenes prefer to penetrate into the membrane in the regions of the moderately positive mean curvature. Upon penetration into the hydrophobic core of the membrane fullerenes avoid the regions of the extreme positive or the negative curvature. Fullerenes increase the ordering of lipid tails, which are in direct contact with them, but do not influence other lipids significantly. Our data suggest that the effects of the membrane curvature should be taken into account in the studies concerning permeability of the membranes to fullerenes and fullerene-based drug delivery systems. PMID- 26608906 TI - Fractionally charged skyrmions in fractional quantum Hall effect. AB - The fractional quantum Hall effect has inspired searches for exotic emergent topological particles, such as fractionally charged excitations, composite fermions, abelian and nonabelian anyons and Majorana fermions. Fractionally charged skyrmions, which support both topological charge and topological vortex like spin structure, have also been predicted to occur in the vicinity of 1/3 filling of the lowest Landau level. The fractional skyrmions, however, are anticipated to be exceedingly fragile, suppressed by very small Zeeman energies. Here we show that, slightly away from 1/3 filling, the smallest manifestations of the fractional skyrmion exist in the excitation spectrum for a broad range of Zeeman energies, and appear in resonant inelastic light scattering experiments as well-defined resonances slightly below the long wavelength spin wave mode. The spectroscopy of these exotic bound states serves as a sensitive tool for investigating the residual interaction between composite fermions, responsible for delicate new fractional quantum Hall states in this filling factor region. PMID- 26608907 TI - Ethics in Publishing: Complexity Science and Human Factors Offer Insights to Develop a Just Culture. AB - While ethics in publishing has been increasingly debated, there seems to be a lack of a theoretical framework for making sense of existing rules of behavior as well as for designing, managing and enforcing such rules. This letter argues that systems-oriented disciplines, such as complexity science and human factors, offer insights into new ways of dealing with ethics in publishing. Some examples of insights are presented. Also, a call is made for empirical studies that unveil the context and details of both retracted papers and the process of writing and publishing academic papers. This is expected to shed light on the complexity of the publication system as well as to support the development of a just culture, in which all participants are accountable. PMID- 26608908 TI - An intense NIR emission from Ca14Al10Zn6O35:Mn(4+),Yb(3+)via energy transfer for solar spectral converters. AB - To date, most current reports on the development and optimization of solar spectral converters have described the utilization of energy transfer among rare earth ions. Here, we introduce non-rare-earth ion Mn(4+) to transfer energy to Yb(3+), which can exhibit strong near-infrared luminescence. It can harvest UV blue photons and exhibits intense NIR emission of Yb(3+) around 1000 nm, perfectly matching the maximum spectral response of Si solar cells. It demonstrates for the first time that efficient energy transfer occurs with a decrease in the excited state lifetime and red photoluminescence (PL) from Mn(4+) with increasing Yb(3+) concentration. These results demonstrate that the Mn(4+) ions can be an efficient and direct sensitizer harvesting UV-blue photons. It could provide new avenues for developing harvesting Si-based solar cells. PMID- 26608909 TI - Impaired SNX9 Expression in Immune Cells during Chronic Inflammation: Prognostic and Diagnostic Implications. AB - Chronic inflammation is associated with immunosuppression and downregulated expression of the TCR CD247. In searching for new biomarkers that could validate the impaired host immune status under chronic inflammatory conditions, we discovered that sorting nexin 9 (SNX9), a protein that participates in early stages of clathrin-mediated endocytosis, is downregulated as well under such conditions. SNX9 expression was affected earlier than CD247 by the generated harmful environment, suggesting that it is a potential marker sensing the generated immunosuppressive condition. We found that myeloid-derived suppressor cells, which are elevated in the course of chronic inflammation, are responsible for the observed SNX9 reduced expression. Moreover, SNX9 downregulation is reversible, as its expression levels return to normal and immune functions are restored when the inflammatory response and/or myeloid-derived suppressor cells are neutralized. SNX9 downregulation was detected in numerous mouse models for pathologies characterized by chronic inflammation such as chronic infection (Leishmania donovani), cancer (melanoma and colorectal carcinoma), and an autoimmune disease (rheumatoid arthritis). Interestingly, reduced levels of SNX9 were also observed in blood samples from colorectal cancer patients, emphasizing the feasibility of its use as a diagnostic and prognostic biomarker sensing the host's immune status and inflammatory stage. Our new discovery of SNX9 as being regulated by chronic inflammation and its association with immunosuppression, in addition to the CD247 regulation under such conditions, show the global impact of chronic inflammation and the generated immune environment on different cellular pathways in a diverse spectrum of diseases. PMID- 26608910 TI - The Tumor Antigen NY-ESO-1 Mediates Direct Recognition of Melanoma Cells by CD4+ T Cells after Intercellular Antigen Transfer. AB - NY-ESO-1-specific CD4(+) T cells are of interest for immune therapy against tumors, because it has been shown that their transfer into a patient with melanoma resulted in tumor regression. Therefore, we investigated how NY-ESO-1 is processed onto MHC class II molecules for direct CD4(+) T cell recognition of melanoma cells. We could rule out proteasome and autophagy-dependent endogenous Ag processing for MHC class II presentation. In contrast, intercellular Ag transfer, followed by classical MHC class II Ag processing via endocytosis, sensitized neighboring melanoma cells for CD4(+) T cell recognition. However, macroautophagy targeting of NY-ESO-1 enhanced MHC class II presentation. Therefore, both elevated NY-ESO-1 release and macroautophagy targeting could improve melanoma cell recognition by CD4(+) T cells and should be explored during immunotherapy of melanoma. PMID- 26608911 TI - Glucose Oxidation Is Critical for CD4+ T Cell Activation in a Mouse Model of Systemic Lupus Erythematosus. AB - We have previously shown that CD4(+) T cells from B6.Sle1Sle2.Sle3 lupus mice and patients present a high cellular metabolism, and a treatment combining 2-deoxy-D glucose, which inhibits glucose metabolism, and metformin, which inhibits oxygen consumption, normalized lupus T cell functions in vitro and reverted disease in mice. We obtained similar results with B6.lpr mice, another model of lupus, and showed that a continuous treatment is required to maintain the beneficial effect of metabolic inhibitors. Further, we investigated the relative roles of glucose oxidation and pyruvate reduction into lactate in this process. Treatments of B6.Sle1Sle2.Sle3 mice with either 2-deoxy-D-glucose or metformin were sufficient to prevent autoimmune activation, whereas their combination was necessary to reverse the process. Treatment of B6.Sle1Sle2.Sle3 mice with dichloroacetate, an inhibitor of lactate production, failed to effectively prevent or reverse autoimmune pathology. In vitro, CD4(+) T cell activation upregulated the expression of genes that favor oxidative phosphorylation. Blocking glucose oxidation inhibited both IFN-gamma and IL-17 production, which could not be achieved by blocking pyruvate reduction. Overall, our data show that targeting glucose oxidation is required to prevent or reverse lupus development in mice, which cannot be achieved by simply targeting the pyruvate-lactate conversion. PMID- 26608912 TI - Priming of Qualitatively Superior Human Effector CD8+ T Cells Using TLR8 Ligand Combined with FLT3 Ligand. AB - The quality of Ag-specific CD8(+) T cell responses is central to immune efficacy in infectious and malignant settings. Inducing effector CD8(+) T cells with potent functional properties is therefore a priority in the field of immunotherapy. However, the optimal assessment of new treatment strategies in humans is limited by currently available testing platforms. In this study, we introduce an original model of in vitro CD8(+) T cell priming, based on an accelerated dendritic cell coculture system, which uses unfractionated human PBMCs as the starting material. This approach enables the rapid evaluation of adjuvant effects on the functional properties of human CD8(+) T cells primed from Ag-specific naive precursors. We demonstrate that a selective TLR8 agonist, in combination with FLT3L, primes high-quality CD8(+) T cell responses. TLR8L/FLT3L primed CD8(+) T cells displayed enhanced cytotoxic activity, polyfunctionality, and Ag sensitivity. The acquisition of this superior functional profile was associated with increased T-bet expression induced via an IL-12-dependent mechanism. Collectively, these data validate an expedited route to vaccine delivery or optimal T cell expansion for adoptive cell transfer. PMID- 26608914 TI - Cutting Edge: Nonobese Diabetic Mice Deficient in Chromogranin A Are Protected from Autoimmune Diabetes. AB - T cells reactive to beta cell Ags are critical players in the development of autoimmune type 1 diabetes. Using a panel of diabetogenic CD4 T cell clones derived from the NOD mouse, we recently identified the beta cell secretory granule protein, chromogranin A (ChgA), as a new autoantigen in type 1 diabetes. CD4 T cells reactive to ChgA are pathogenic and rapidly transfer diabetes into young NOD recipients. We report in this article that NOD.ChgA(-/-) mice do not develop diabetes and show little evidence of autoimmunity in the pancreatic islets. Using tetramer analysis, we demonstrate that ChgA-reactive T cells are present in these mice but remain naive. In contrast, in NOD.ChgA(+/+) mice, a majority of the ChgA-reactive T cells are Ag experienced. Our results suggest that the presence of ChgA and subsequent activation of ChgA-reactive T cells are essential for the initiation and development of autoimmune diabetes in NOD mice. PMID- 26608913 TI - Bidirectional Counterregulation of Human Lung Mast Cell and Airway Smooth Muscle beta2 Adrenoceptors. AB - Human lung mast cells (HLMCs) play a central role in asthma pathogenesis through their relocation to the airway smooth muscle (ASM) bundles. beta2 adrenoceptor (beta2-AR)-agonists are used to relieve bronchoconstriction in asthma, but may reduce asthma control, particularly when used as monotherapy. We hypothesized that HLMC and human ASM cell (HASMC) responsiveness to beta2-AR agonists would be attenuated when HLMCs are in contact with HASMCs. Cells were cultured in the presence of the short-acting beta2-agonist albuterol, and the long-acting beta2 agonists formoterol and olodaterol. Constitutive and FcepsilonRI-dependent HLMC histamine release, HASMC contraction, and beta2-AR phosphorylation at Tyr(350) were assessed. Constitutive HLMC histamine release was increased in HLMC-HASMC coculture and this was enhanced by beta2-AR agonists. Inhibition of FcepsilonRI dependent HLMC mediator release by beta2-agonists was greatly reduced in HLMC HASMC coculture. These effects were reversed by neutralization of stem cell factor (SCF) or cell adhesion molecule 1 (CADM1). beta2-AR agonists did not prevent HASMC contraction when HLMCs were present, but this was reversed by fluticasone. beta2-AR phosphorylation at Tyr(350) occurred within 5 min in both HLMCs and HASMCs when the cells were cocultured, and was inhibited by neutralizing SCF or CADM1. HLMC interactions with HASMCs via CADM1 and Kit inhibit the potentially beneficial effects of beta2-AR agonists on these cells via phosphorylation of the beta2-AR. These results may explain the potentially adverse effects of beta2-ARs agonists when used for asthma therapy. Targeting SCF and CADM1 may enhance beta2-AR efficacy, particularly in corticosteroid-resistant patients. PMID- 26608915 TI - S100A8 Production in CXCR2-Expressing CD11b+Gr-1high Cells Aggravates Hepatitis in Mice Fed a High-Fat and High-Cholesterol Diet. AB - Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease with a spectrum of presentations. S100A8 has been suggested to play a pivotal role as an endogenous immune-activator in inflammatory diseases. In this study, we investigated the involvement of S100A8 in the development of NAFLD. We used a diet model of NAFLD, in which mice were fed either a high-fat and high cholesterol diet (HFHCD) or a normal diet (ND) as a control. We also assessed liver tissues from patients with NAFLD, including patients with nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). HFHCD-fed mice, but not ND-fed mice, developed steatohepatitis. S100A8 expression was significantly elevated in the livers of HFHCD-fed mice compared with the controls. S100A8 was exclusively expressed in CXCR2-expressing CD11b(+)Gr-1(high) cells, which significantly increased in the livers of HFHCD-fed mice. These cells were F4/80 negative and did not possess a suppressor function. TNF-alpha expression was enhanced by S100A8 in primary liver leukocytes or a hepatocyte cell line and significantly elevated in the livers of HFHCD-fed mice. TNF-alpha was primarily produced from CD11b(+)F4/80(+) cells in liver leukocytes in response to S100A8. TNF-alpha deficiency attenuated hepatitis in HFHCD-fed mice. S100A8 was significantly more expressed in the liver tissues of patients with NASH than in those of patients with NAFL. In conclusion, these results suggest that S100A8 is primarily produced from CXCR2-expressing CD11b(+)Gr-1(high) cells, and it upregulates TNF-alpha production in CD11b(+)F4/80(+) cells through cellular cross talk, which is an important mechanism in the development of NAFLD. PMID- 26608916 TI - Monocyte Stabilin-1 Suppresses the Activation of Th1 Lymphocytes. AB - In this study, we analyzed the putative functions of stabilin-1 in blood monocytes. Microarray analysis revealed downregulation of several proinflammatory genes in the stabilin-1(high) monocytes when compared with stabilin-1(low) monocytes. When cocultured with stabilin-1(high) monocytes, IFN-gamma synthesis by T cells was diminished in Ag-recall assays. Knockdown of stabilin-1 in monocytes increased the synthesis of several proinflammatory molecules, including TNF-alpha, and supported high IFN-gamma and low IL-4 and IL-5 production by T cells in Ag-specific stimulation assays. Anti-stabilin-1 Ab treatment also led to increased IFN-gamma synthesis in the recall assays. In clinical settings, the expression of stabilin-1 was diminished on blood monocytes and tissue macrophages under proinflammatory conditions. These data define stabilin-1 as a new immunosuppressive molecule and suggest that stabilin-1(high) monocytes may dampen proinflammatory reactions in vivo. PMID- 26608917 TI - The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining. AB - Hypomorphic mutations in the nonhomologous end-joining (NHEJ) DNA repair protein DNA ligase IV (LIG4) lead to immunodeficiency with varying severity. In this study, using a murine knock-in model, we investigated the mechanisms underlying abnormalities in class switch recombination (CSR) associated with the human homozygous Lig4 R278H mutation. Previously, we found that despite the near absence of Lig4 end-ligation activity and severely reduced mature B cell numbers, Lig4(R278H/R278H) (Lig4(R/R)) mice exhibit only a partial CSR block, producing near normal IgG1 and IgE but substantially reduced IgG3, IgG2b, and IgA serum levels. In this study, to address the cause of these abnormalities, we assayed CSR in Lig4(R/R) B cells generated via preassembled IgH and IgK V region exons (HL). This revealed that Lig4(R278H) protein levels while intact exhibited a higher turnover rate during activation of switching to IgG3 and IgG2b, as well as delays in CSR kinetics associated with defective proliferation during activation of switching to IgG1 and IgE. Activated Lig4(R/R)HL B cells consistently accumulated high frequencies of activation-induced cytidine deaminase-dependent IgH locus chromosomal breaks and translocations and were more prone to apoptosis, effects that appeared to be p53-independent, as p53 deficiency did not markedly influence these events. Importantly, NHEJ instead of alternative end-joining (A EJ) was revealed as the predominant mechanism catalyzing robust CSR. Defective CSR was linked to failed NHEJ and residual A-EJ access to unrepaired double strand breaks. These data firmly demonstrate that Lig4(R278H) activity renders NHEJ to be more error-prone, and they predict increased error-prone NHEJ activity and A-EJ suppression as the cause of the defective B lymphopoiesis in Lig4 patients. PMID- 26608918 TI - Lunatic, Manic, and Radical Fringe Each Promote T and B Cell Development. AB - Lunatic, Manic, and Radical Fringe (LFNG, MFNG, and RFNG) are N acetylglucosaminyltransferases that modify Notch receptors and regulate Notch signaling. Loss of LFNG affects thymic T cell development, and LFNG and MFNG are required for marginal zone (MZ) B cell development. However, roles for MFNG and RFNG in T cell development, RFNG in B cell development, or Fringes in T and B cell activation are not identified. In this study, we show that Lfng/Mfng/Rfng triple knockout (Fng tKO) mice exhibited reduced binding of DLL4 Notch ligand to CD4/CD8 double-negative (DN) T cell progenitors, and reduced expression of NOTCH1 targets Deltex1 and CD25. Fng tKO mice had reduced frequencies of DN1/cKit(+) and DN2 T cell progenitors and CD4(+)CD8(+) double-positive (DP) T cell precursors, but increased frequencies of CD4(+) and CD8(+) single-positive T cells in the thymus. In spleen, Fng tKO mice had reduced frequencies of CD4(+), CD8(+), central memory T cells and MZ B cells, and an increased frequency of effector memory T cells, neutrophils, follicular, and MZ P B cells. The Fng tKO phenotype was cell-autonomous and largely rescued in mice expressing one allele of a single Fng gene. Stimulation of Fng tKO splenocytes with anti-CD3/CD28 beads or LPS gave reduced proliferation compared with controls, and the generation of activated T cells by Concanavalin A or L-PHA was also reduced in Fng tKO mice. Therefore, each Fringe contributes to T and B cell development, and Fringe is required for optimal in vitro stimulation of T and B cells. PMID- 26608919 TI - TCRVgamma9 gammadelta T Cell Response to IL-33: A CD4 T Cell-Dependent Mechanism. AB - The availability of specific stimuli to induce the anticancer cytotoxicity of human TCRVgamma9-expressing T lymphocytes has allowed the development of gammadelta T cell-based cancer immunotherapies. However, the stringent dependence of such strategies on the inherently toxic IL-2 has raised safety concerns for patients, justifying a search for alternative methods for inducing gammadelta T cell stimulation. IL-33 is a gamma-chain receptor-independent cytokine of the IL 1 superfamily that is expressed by endothelial cells from a tumor microenvironment and can sustain Th1 and Th2 immune responses. Therefore, we investigated its ability to support the stimulation of human TCRVgamma9(+) gammadelta T cells. In this study, we report that IL-33 efficiently sustained the in vitro activation of Vgamma9 T lymphocytes by synthetic phosphoantigens, zoledronate, and a BTN3A1 Ab in the absence of an exogenous supply of IL-2. IL-33 was as potent as IL-2 in allowing the proliferative amplification of Vgamma9 T cells isolated from PBMC following activation by the synthetic phosphoantigen bromohydrin pyrophosphate. IL-33 also induced an identical maturation into TNF alpha- and IFN-gamma-producing Th1 effector memory cells, and IL-33-stimulated cells showed an equivalent cytotoxicity for various tumor cells in vitro. Finally, we found that the bioactivity of IL-33 on the Vgamma9 T cell was indirectly mediated through contact with CD4 T cells and IL-2 production by CD4 T cells and Vgamma9 T cells themselves. These data posit IL-33 as an alternative to IL-2 for Vgamma9 T cell-based cancer immunotherapies. PMID- 26608920 TI - CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity. AB - Recent successes in immune therapeutic strategies aimed to improve control over tumor growth have sparked hope that long-lived control of cancer through stimulation of the immune system can be possible. However, the underlying immunological mechanisms that are induced by immunotherapeutic strategies are not well understood. In this study, we used the highly immunogenic Friend virus induced FBL-3 tumor as a model to study the mechanisms of immunological tumor control by CD4(+) T cells in the course of CD137 (4-1BB) agonist immunotherapy in the absence of a CD8 T cell response. We demonstrate that treatment with a CD137 agonist resulted in complete FBL-3 tumor regression in CD8(+) T cell-deficient mice. CD137 signaling enhanced the production of proinflammatory cytokines and cytotoxic molecules in tumor-specific CD4(+) T cells. Interestingly, a subset of CD4(+)Foxp3(+) regulatory T cells was reprogrammed to eliminate immunogenic virus induced tumor cells in response to CD137 agonist treatment. These cells expressed markers characteristic for Th cells (CD154) and produced the cytokine TNF-alpha or the T-box transcriptional factor Eomesodermin and granzyme B without loss of Foxp3 expression. Foxp3 Eomes double-positive CD4(+) T cells were capable of eliminating immunogenic virus-induced tumor cells in vivo. Thus, our data show that tumor-induced Foxp3(+)CD4(+) T cells can be reprogrammed into cytotoxic effector cells upon therapeutic costimulatory signaling and restore antitumor immunity. PMID- 26608921 TI - Calpains Released by T Lymphocytes Cleave TLR2 To Control IL-17 Expression. AB - Calpains are intracellular proteases that play a key role in inflammation/immunity. Rare studies show that they are partially externalized. However, the mechanism of this secretion and the functions of exteriorized calpains remain poorly understood. In this study, we found that mouse and human lymphocytes secreted calpains through an ABCA1-driven process. In turn, extracellular calpains inhibited IL-17A expression. We were able to attribute this function to a cleavage of the TLR2 extracellular domain, which prevented TLR2-induced transcription of molecules essential for IL-17A induction. Calpain exteriorization and TLR2 cleavage were critical for the control of IL-17A expression by low doses of IL-2. By using newly developed transgenic mice in which extracellular calpains are specifically inactivated, we provide evidence for the relevance of calpain externalization in vivo in regulating IL-17A expression and function in experimental sterile peritonitis and autoimmune arthritis, respectively. Thus, this study identifies calpain exteriorization as a potential target for immune modulation. PMID- 26608922 TI - The Group B Streptococcus-Secreted Protein CIP Interacts with C4, Preventing C3b Deposition via the Lectin and Classical Complement Pathways. AB - The group B Streptococcus (GBS) is a leading cause of neonatal invasive disease. GBS bacteria are surrounded by a thick capsular polysaccharide that is a potent inhibitor of complement deposition via the alternative pathway. Several of its surface molecules can however activate the classical and lectin complement pathways, rendering this species still vulnerable to phagocytic killing. In this study we have identified a novel secreted protein named complement interfering protein (CIP) that downregulates complement activation via the classical and lectin pathways, but not the alternative pathway. The CIP protein showed high affinity toward C4b and inhibited its interaction with C2, presumably preventing the formation of the C4bC2a convertase. Addition of recombinant CIP to GBS cip negative bacteria resulted in decreased deposition of C3b on their surface and in diminished phagocytic killing in a whole-blood assay. Our data reveal a novel strategy exploited by GBS to counteract innate immunity and could be valuable for the development of anti-infective agents against this important pathogen. PMID- 26608923 TI - Serum Lipoproteins Are Critical for Pulmonary Innate Defense against Staphylococcus aureus Quorum Sensing. AB - Hyperlipidemia has been extensively studied in the context of atherosclerosis, whereas the potential health consequences of the opposite extreme, hypolipidemia, remain largely uninvestigated. Circulating lipoproteins are essential carriers of insoluble lipid molecules and are increasingly recognized as innate immune effectors. Importantly, severe hypolipidemia, which may occur with trauma or critical illness, is clinically associated with bacterial pneumonia. To test the hypothesis that circulating lipoproteins are essential for optimal host innate defense in the lung, we used lipoprotein-deficient mice and a mouse model of Staphylococcus aureus pneumonia in which invasive infection requires virulence factor expression controlled by the accessory gene regulator (agr) operon. Activation of agr and subsequent virulence factor expression is inhibited by apolipoprotein B, the structural protein of low-density lipoprotein, which binds and sequesters the secreted agr-signaling peptide (AIP). In this article, we report that lipoprotein deficiency impairs early pulmonary innate defense against S. aureus quorum-sensing-dependent pathogenesis. Specifically, apolipoprotein B levels in the lung early postinfection are significantly reduced with lipoprotein deficiency, coinciding with impaired host control of S. aureus agr-signaling and increased agr-dependent morbidity (weight loss) and inflammation. Given that lipoproteins also inhibit LTA- and LPS-mediated inflammation, these results suggest that hypolipidemia may broadly impact posttrauma pneumonia susceptibility to both Gram-positive and -negative pathogens. Together with previous reports demonstrating that hyperlipidemia also impairs lung innate defense, these results suggest that maintenance of normal serum lipoprotein levels is necessary for optimal host innate defense in the lung. PMID- 26608925 TI - A concise synthesis of tubuphenylalanine and epi-tubuphenylalanine via a diastereoselective Mukaiyama aldol reaction of silyl ketene acetal. AB - We have developed a straightforward and auxiliary-free synthetic route towards tBu-tubuphenylalanine (tBu-Tup) and tBu-epi-tubuphenylalanine (tBu-epi-Tup), which are the key components of tubulysins and their analogs. A Lewis acid mediated diastereoselective Mukaiyama aldol reaction using silyl ketene acetal and N-Boc-L-phenylalaninal provided gamma-amino-beta-hydroxyl-alpha-methyl esters, which were deoxygenated to gamma-amino-alpha-methyl esters under Barton McCombie deoxygenation conditions. Notably, the desired tBu-Tup and tBu-epi-Tup were obtained in good overall yields in four steps. PMID- 26608924 TI - A CpG-Ficoll Nanoparticle Adjuvant for Anthrax Protective Antigen Enhances Immunogenicity and Provides Single-Immunization Protection against Inhaled Anthrax in Monkeys. AB - Nanoparticulate delivery systems for vaccine adjuvants, designed to enhance targeting of secondary lymphoid organs and activation of APCs, have shown substantial promise for enhanced immunopotentiation. We investigated the adjuvant activity of synthetic oligonucleotides containing CpG-rich motifs linked to the sucrose polymer Ficoll, forming soluble 50-nm particles (DV230-Ficoll), each containing >100 molecules of the TLR9 ligand, DV230. DV230-Ficoll was evaluated as an adjuvant for a candidate vaccine for anthrax using recombinant protective Ag (rPA) from Bacillus anthracis. A single immunization with rPA plus DV230 Ficoll induced 10-fold higher titers of toxin-neutralizing Abs in cynomolgus monkeys at 2 wk compared with animals immunized with equivalent amounts of monomeric DV230. Monkeys immunized either once or twice with rPA plus DV230 Ficoll were completely protected from challenge with 200 LD50 aerosolized anthrax spores. In mice, DV230-Ficoll was more potent than DV230 for the induction of innate immune responses at the injection site and draining lymph nodes. DV230 Ficoll was preferentially colocalized with rPA in key APC populations and induced greater maturation marker expression (CD69 and CD86) on these cells and stronger germinal center B and T cell responses, relative to DV230. DV230-Ficoll was also preferentially retained at the injection site and draining lymph nodes and produced fewer systemic inflammatory responses. These findings support the development of DV230-Ficoll as an adjuvant platform, particularly for vaccines such as for anthrax, for which rapid induction of protective immunity and memory with a single injection is very important. PMID- 26608926 TI - Mannose-binding lectin polymorphisms and rheumatoid arthritis: A short review and meta-analysis. AB - Mannose-binding lectin (MBL) is a pattern recognition receptor of the lectin pathway of complement system. MBL binds to carbohydrates on microorganism's surfaces leading to complement activation, opsonization and phagocytosis. Polymorphisms in the MBL gene (MBL2) are associated with variations on MBL serum levels and with the susceptibility to various infectious and autoimmune diseases. The involvement of the lectin pathway in rheumatoid arthritis (RA) has been demonstrated by several studies and although MBL has been considered to have a dual role in the pathogenesis of the disease, the association between MBL and RA remains inconclusive. In an attempt to clarify this relationship, we developed this short review summarizing accumulated evidences in regard to MBL and RA and a meta-analysis to evaluate the influence of MBL2 polymorphisms on the susceptibility to RA. Among a total of 217 articles that were identified following a predefined search strategy on PubMed, Scopus, Scielo, EMBASE and Cochrane databases, only 13 met all inclusion criteria and were included in the meta-analysis. Data assessment was conducted by three independent investigators and presented in odds ratio (OR) and 95% confidence intervals (CIs) using forest plot charts. Both heterogeneity and publication bias were analyzed. The results of the meta-analysis evidenced that MBL2 low producing OO and XX genotypes do not confer higher risk to RA, even when data were analyzed according to cohort's ethnicity. Further studies are needed in order to clarify the importance of other genes of the lectin pathway in the pathogenesis of RA. PMID- 26608927 TI - Cigarette smoke induces mucin hypersecretion and inflammatory response through the p66shc adaptor protein-mediated mechanism in human bronchial epithelial cells. AB - The p66Shc adaptor protein is a newly recognized mediator of mitochondrial dysfunction and might play a role in cigarette smoke (CS)-induced airway epithelial cell injury. CS can induce an excessive amount of reactive oxygen species (ROS) generation, which can cause mitochondrial depolarization and injury through the oxidative stress-mediated Serine36 phosphorylation of p66Shc. The excessive production of ROS can trigger an inflammatory response and mucin hypersecretion by enhancing the transcriptional activity of pro-inflammatory cytokines and mucin genes. Therefore, we speculate that p66Shc plays an essential role in airway epithelial cell injury and the process of mucin generation in CS induced chronic inflammatory airway diseases. Our present study focuses on the role of p66Shc in ROS generation, and on the resulting mitochondrial dysfunction, inflammatory response and mucus hypersecretion in CS-stimulated human bronchial epithelial cells (16HBE). We found that CS disturbed the mitochondrial function by increasing the level of phosphorylated p66Shc in these cells and that the effects were significantly reduced by silencing p66Shc. Conversely, the ectopic overexpression of wild-type p66Shc enhanced these effects. We also found that high levels of ROS inhibited FOXO3a transcriptional activity, which led to NF kappaB activation. Subsequently, activated NF-kappaB promoted pro-inflammatory cytokine production and mucin hypersecretion. Thus, manipulating p66Shc might offer a new therapeutic modality with which to treat chronic inflammatory airway diseases. PMID- 26608929 TI - Invertebrates: Why No Adaptive Immune System? PMID- 26608928 TI - Is recurrent respiratory papillomatosis a manageable or curable disease? AB - OBJECTIVES: Recurrent respiratory papillomatosis (RRP) is a relatively rare disease with potentially devastating consequences for the patient. The purpose of this study was to evaluate the patterns of recurrence of RRP after surgery and determine the effectiveness of combined concurrent adjuvant therapy. METHODS: A total of 86 patients were diagnosed with and operated on for RRP. The clinical characteristics of 29 of the 86 patients who had undergone operations at other hospitals and who were followed up for >2 years were evaluated retrospectively. A combined concurrent adjuvant therapy was performed with microlaryngeal surgery, 585-nm pulsed dye laser (PDL) application, and an intralesional cidofovir injection. To evaluate the recurrence pattern, the larynx was divided into 10 subsites, and patients were investigated for the frequency of recurrence at the subsites after the operation. RESULTS: Twenty-nine subjects required a mean of 3.0 operations to achieve complete remission for 2 years. The most common subsites for recurrence were the anterior commissure, subglottis, and epiglottis according to increasing number of operations. The subsites of recurrence tended to be closely correlated with the laryngeal submucosal glandular density distribution. A complete en-bloc layer excision, including the submucosal glands, using cold instruments decreased the recurrence rate of RRP. Applying PDL minimized scarring and provided significant posttreatment voice-quality improvement. CONCLUSIONS: The results of the recurrent pattern analysis suggest that a combined concurrent adjunctive treatment might be promising as a cure for RRP and restoration of vocal function after treatment. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1359-1364, 2016. PMID- 26608930 TI - Membrane-bound tetramer and trimer Abeta oligomeric species correlate with toxicity towards cultured neurons. AB - Amyloid beta (Abeta) peptide is the major constituent of the extracellular amyloid plaques deposited in the brains of Alzheimer's disease patients and is central to the pathogenic pathway causing this disease. The identity of the neurotoxic Abeta species remains elusive. We previously reported that Abeta toxicity correlates strongly with its neuronal cell binding leading us to hypothesize that neuronal cell death is caused by the binding of a specific oligomeric Abeta species. To identify the specific oligomeric Abeta species that is associated with cell death, we treated mouse cortical neuronal cultures with synthetic Abeta40 and Abeta42 peptides and identified that the cellular Abeta binding and neurotoxicity were time and concentration dependent. We found a significant correlation between the amount of trimer and tetramer species bound to neurons with increasing neurotoxicity. We prepared Abeta40 oligomers (up to tetramers) using photo-induced cross-linking of unmodified peptides to confirm this oligomer-specific neurotoxic activity. Our results identify the Abeta tetramer, followed by the trimer, as the most toxic low-order oligomers Abeta species. Our findings suggested that binding of amyloid-beta (Abeta) tetramer and trimer, not monomer or dimer, to neurons is critical to induce neuronal cell death associated with Alzheimer's Disease. We proposed that Abeta trimer and tetramer are the potential neurotoxic Abeta species. This would provide more specific therapeutic target for Alzheimer's Disease. PMID- 26608931 TI - Acute hemorrhagic edema of young children: a prospective case series. AB - Acute hemorrhagic edema of young children is a rare leukocytoclastic vasculitis that has been reported exclusively in small retrospective cases series, case reports, or quizzes. Considering that retrospective experience deserves confirmation in at least one observational prospective study, we present our experience with 16 children (12 boys and 4 girls, 5-28 months of age) affected by acute hemorrhagic edema. The patients were in good general conditions and with a low-grade or even absent fever. They presented with non-itching red to purpuric targetoid lesions not changing location within hours, with non-pitting and sometimes tender indurative swelling, and without mucous membrane involvement or scratch marks. Signs for articular, abdominal, or kidney involvement were absent. Antinuclear or antineutrophil cytoplasmic autoantibodies were never detected. The cases were managed symptomatically as outpatients and fully resolved within 4 weeks or less. No recurrence or familiarity was noted. CONCLUSION: This is the first prospective evaluation of hemorrhagic edema. Our findings emphasize its distinctive tetrad: a well-appearing child; targetoid lesions that do not change location within hours; non-pitting, sometimes tender edema; complete resolution without recurrence. What is known * Acute hemorrhagic edema of young children is considered a benign vasculitis. * There have been ~100 cases reported in small retrospective case series. What is new * The first prospective evaluation of this condition emphasizes its features: febrile prodrome; well-appearing child; targetoid lesions not changing location within hours; non-pitting, sometimes tender indurative edema; absent extracutaneous involvement; resolution within 3 weeks. * Antineutrophil cytoplasmic autoantibodies do not play a pathogenic role. PMID- 26608932 TI - Incidence and case-fatality of varicella-zoster virus infection among pediatric cancer patients in developing countries. AB - Limited evidence is available about varicella-zoster virus (VZV) infection among pediatric cancer patients in developing countries, which raises questions about the generalizability of VZV vaccine recommendations for pediatric cancer patients (derived from developed countries) to these settings. We assessed the incidence and case-fatality of VZV infection at three institutions in developing countries (Argentina, Mexico, and Nicaragua). Individuals eligible for our study were aged <20 years and actively receiving cancer-directed therapy. We estimated a summary incidence rate (IR) and case-fatality risk with corresponding 95 % confidence limits (CL) of VZV infection across sites using random-effects models. Our study population comprised 511 pediatric cancer patients, of whom 64 % were aged <10 years, 58 % were male, and 58 % were diagnosed with leukemia. We observed a total of 10 infections during 44,401 person-days of follow-up across the 3 sites (IR = 2.3, 95 % CL 1.2, 4.2). The summary case-fatality risk was 10 % (95 % CL 1.4, 47 %) based on one death. CONCLUSION: Our results suggest low incidence and case fatality of VZV infections among pediatric cancer patients in three developing countries. VZV vaccine recommendations for pediatric cancer patients in developed countries may be generalizable to developing countries. WHAT IS KNOWN: * Current recommendations, based on evidence from pediatric cancer patients in developed countries, contraindicate varicella-zoster virus (VZV) vaccination until completion of cancer-directed therapy and recovery of immune function. * The generalizability of these VZV vaccine recommendations to pediatric cancer patients in developing countries is unknown because of limited information about the incidence and case-fatality of VZV in these settings. What is New: * Our results suggest low incidence and case-fatality of VZV infections among pediatric cancer patients in three developing countries. * VZV vaccine recommendations based on evidence from pediatric cancer patients in developed countries may be generalizable to pediatric cancer patients in developing countries. PMID- 26608933 TI - Uterine and placenta characteristics during early vascular development in the pig from day 22 to 42 of gestation. AB - Insufficient placenta development is one of the primary causes of fetal death and reduced fetal growth after 35 days of gestation. Between day 22 and 42 the placenta consists of a central highly vascular placenta (HVP), adjacent to the fetus, a less vascular placenta (LVP), on either side of the fetus, and necrotic tips (NT). The objective of this study was to comprehensively evaluate uterine placenta characteristics during early gestation in the gilt and determine time points and physiological changes. Gilts (n=25) were artificially inseminated at first detection of estrus (day 0) and 24h later, and harvested at 22, 27, 32, 37 or 42 days of gestation. Litter size, 12.1+/-3.4, was similar for all days of gestation. Fetal and placenta weight increased with day of gestation. The greatest increase in placenta weight occurred between 37 and 42 days of gestation. The LVP zones had no measurable fold formation until day 27. Necrotic tips became apparent after 27 days of gestation. Unoccupied areas of the uterus developed folds with changes in endometrial cell size and morphology from day 32 to 42 of gestation. Limited changes occurred in either fetal growth or placenta weight from day 27 through 32 of gestation; however, significant morphological changes occur at the maternal-fetal interface, demonstrating the dynamic architecture of the developing porcine placenta during early gestation. This work establishes fundamental time points in placenta development corresponding to fetal growth and microfold formation that may influence fetal growth and impact fetal survival. PMID- 26608934 TI - Retrograde and destination transfer of sex steroid hormones in the spermatic cord vessels of the mature boar (Sus scrofa) in short-daylight and long-daylight periods, as well as vernal and autumnal equinox. AB - The aim of this study was to examine the seasonal changes in concentration of steroid hormones in the spermatic cord vessels of the mature boar. Cytochrome P450 aromatase (P450arom) was also localized in the arteries and veins of the spermatic cord. Arterial blood was collected from the common carotid artery and from two branches of the testicular artery supplying the testis and epididymis to determine progesterone (P4), androstenedione (A2), testosterone (T2) and estradiol (E2) plasma concentrations. The greatest concentration of P4 was found in testicular artery during December (P<0.001), when compared with other periods and vessels. In contrast, the greatest A2 concentration was observed in the epididymal artery during the same season (P<0.001). Greater T2 concentrations were found in both testis and epididymal arteries than in common artery in March (P<0.001, P<0.001; respectively) and in September (P<0.01, P<0.001; respectively). The E2 concentration was weakly affected by seasonal periods, but greater E2 concentrations were found within vessels in the testis and epididymis than in the common artery. The P450arom was immunolocalized in all layers of the arteries and veins of the testicular spermatic cord. The intensity of P450arom staining was greater in December than in June (P<0.001). There were greater steroid concentrations in arterial vessels during December in comparison to June and this may explain the summer infertility in boars and may be related to the local retrograde and destination transfer into the spermatic cord area. The P450arom gene expression in this area seems to be involved in the conversion of T2 into E2 to enrich the testes and epididymis. PMID- 26608935 TI - Assessment of in vitro metabolic stability, plasma protein binding, and pharmacokinetics of E- and Z-guggulsterone in rat. AB - Guggulsterone is a racemic mixture of two stereoisomers (E- and Z-), obtained from the gum resin of Commiphora mukul and it is marketed as an antihyperlipidemic drug. The aim of our study was to assess the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties namely solubility, in vitro metabolism, plasma protein binding and oral pharmacokinetic studies of E- and Z-guggulsterone. In vitro metabolism experiments were performed by using rat liver and intestinal microsomes. In vitro intrinsic clearance (CLint ) was found to be 33.34 +/- 0.51 and 39.23 +/- 8.12 MUL/min/mg protein in rat liver microsomes for E- and Z-isomers, respectively. Plasma protein binding was determined by equilibrium dialysis method and in vivo pharmacokinetic studies were performed in male Sprague Dawley (SD) rats. Both isomers were highly bound to rat plasma proteins (>95% bound). Plasma concentration of E- and Z-isomers decreased rapidly following oral administration and were eliminated from systemic circulation with a terminal half-life of 0.63 +/- 0.25 and 0.74 +/- 0.35 h, respectively. The clearance (CL) for E-isomer was 2.79 +/- 0.73 compared to 3.01 +/- 0.61 L/h/kg for Z-isomer, indicating no significant difference (student t test; p <0.05) in their elimination.The pharmacokinetics of both isomers was characterized by extensive hepatic metabolism as seen with rat liver microsomes with high clearance and low systemic availability in rats. In brief, first-pass metabolism seems to be responsible factor for low bioavailability of guggulsterone. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26608937 TI - Improved Outcome of Cardiac Extracorporeal Membrane Oxygenation in Infants and Children Using Magnetic Levitation Centrifugal Pumps. AB - Extracorporeal membrane oxygenation (ECMO) has traditionally been and, for the most part, still is being performed using roller pumps. Use of first-generation centrifugal pumps has yielded controversial outcomes, perhaps due to mechanical properties of the same and the ensuing risk of hemolysis and renal morbidity. Latest-generation centrifugal pumps, using magnetic levitation (ML), exhibit mechanical properties which may have overcome limitations of first-generation devices. This retrospective study aimed to assess the safety and efficacy of veno arterial (V-A) ECMO for cardiac indications in neonates, infants, and children, using standard (SP) and latest-generation ML centrifugal pumps. Between 2002 and 2014, 33 consecutive neonates, infants, and young children were supported using V A ECMO for cardiac indications. There were 21 males and 12 females, with median age of 29 days (4 days-5 years) and a median body weight of 3.2 kg (1.9-18 kg). Indication for V-A ECMO were acute circulatory collapse in ICU or ward after cardiac repair in 16 (49%) patients, failure to wean after repair of complex congenital heart disease in 9 (27%), fulminant myocarditis in 4 (12%), preoperative sepsis in 2 (6%), and refractory tachy-arrhythmias in 2 (6%). Central cannulation was used in 27 (81%) patients and peripheral in 6. Seven (21%) patients were supported with SP and 26 (79%) with ML centrifugal pumps. Median duration of support was 82 h (range 24-672 h), with 26 (79%) patients weaned from support. Three patients required a second ECMO run but died on support. Seventeen (51%) patients required peritoneal dialysis for acute renal failure. Overall survival to discharge was 39% (13/33 patients). All patients with fulminant myocarditis and with refractory arrhythmias were weaned, and five (83%) survived, whereas no patient supported for sepsis survived. Risk factors for hospital mortality included lower (<2.5 kg) body weight (P = 0.02) and rescue ECMO after cardiac repair (P = 0.03). During a median follow-up of 34 months (range 4-62 months), there were three (23%) late deaths and two late survivors with neurological sequelae. Weaning rate (5/7 vs. 21/26, P = NS) and prevalence of renal failure requiring dialysis (4/7 vs. 13/26, P = NS) were comparable between SP and ML ECMO groups. Patients supported with ML had a trend toward higher hospital survival (1/7 vs. 12/26, P = 0.07) and significantly higher late survival (0/7 vs. 10/26, P = 0.05). The present experience shows that V-A ECMO for cardiac indications using centrifugal pumps in infants and children yields outcomes absolutely comparable to international registry (ELSO) data using mostly roller pumps. Although changes in practice may have contributed to these results, use of ML centrifugal pumps appears to further improve end-organ recovery and hospital and late survival. PMID- 26608936 TI - Correction of inter-scan motion artifacts in quantitative R1 mapping by accounting for receive coil sensitivity effects. AB - PURPOSE: Inter-scan motion causes differential receive field modulation between scans, leading to errors when they are combined to quantify MRI parameters. We present a robust and efficient method that accounts for inter-scan motion by removing this modulation before parameter quantification. THEORY AND METHODS: Five participants moved between two high-resolution structural scans acquired with different flip angles. Before each high-resolution scan, the effective relative sensitivity of the receive head coil was estimated by combining two rapid low-resolution scans acquired receiving on each of the body and head coils. All data were co-registered and sensitivity variations were removed from the high resolution scans by division with the effective relative sensitivity. R1 maps with and without this correction were calculated and compared against reference maps unaffected by inter-scan motion. RESULTS: Even after coregistration, inter scan motion significantly biased the R1 maps, leading to spurious variation in R1 in brain tissue and deviations with respect to a no-motion reference. The proposed correction scheme reduced the error to within the typical scan-rescan error observed in datasets unaffected by motion. CONCLUSION: Inter-scan motion negatively impacts the accuracy and precision of R1 mapping. We present a validated correction method that accounts for position-specific receive field modulation. Magn Reson Med 76:1478-1485, 2016. (c) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 26608938 TI - What are the consequences when doctors strike? PMID- 26608939 TI - Combinatorial Approach to Nanoarchitectonics for Nonviral Delivery of Nucleic Acids. AB - Nanoparticles based on cationic polymers, lipids or lipidoids are of great interest in the field of gene delivery applications. The research on these nanosystems is rapidly growing as they hold promise to treat wide variety of human diseases ranging from viral infections to genetic disorders and cancer. Recently, combinatorial design principles have been adopted for rapid generation of large numbers of chemically diverse polymers and lipids capable of forming multifunctional nanocarriers for the use in gene delivery applications. At the same time, current high-throughput screening systems as well as convenient cell assays and readout techniques allow for fast evaluation of cell transfection efficiencies and toxicities of libraries of novel gene delivery agents. This allows for a rapid evaluation of structure-function relationship as well as identification of novel efficient nanocarriers for cell transfection and gene therapy. Here, the recent contribution of high-throughput synthesis to the development of novel nanocarriers for gene delivery applications is described. PMID- 26608940 TI - Improving detection of familial hypercholesterolaemia in primary care using electronic audit and nurse-led clinics. AB - RATIONALE, AIMS AND OBJECTIVES: In the UK fewer than 15% of familial hypercholesterolemia (FH) cases are diagnosed, representing a major gap in coronary heart disease prevention. We wished to support primary care doctors within the Medway Clinical Commissioning Group (CCG) to implement NICE guidance (CG71) and consider the possibility of FH in adults who have raised total cholesterol concentrations, thereby improving the detection of people with FH. METHODS: Utilizing clinical decision support software (Audit+) we developed an FH Audit Tool and implemented a systematic audit of electronic medical records within GP practices, first identifying all patients diagnosed with FH or possible FH and next electronically flagging patients with a recorded total cholesterol of >7.5 mmol L(-1) or LDL-C > 4.9 mmol L(-1) (in adults), for further assessment. After a 2-year period, a nurse-led clinic was introduced to screen more intensely for new FH index cases. We evaluated if these interventions increased the prevalence of FH closer to the expected prevalence from epidemiological studies. RESULTS: The baseline prevalence of FH within Medway CCG was 0.13% (1 in 750 persons). After 2 years, the recorded prevalence of diagnosed FH increased by 0.09% to 0.22% (1 in 450 persons). The nurse advisor programme ran for 9 months (October 2013-July 2014) and during this time, the recorded prevalence of patients diagnosed with FH increased to 0.28% (1 in 357 persons) and the prevalence of patients 'at risk and unscreened' reduced from 0.58% to 0.14%. CONCLUSIONS: Our study shows that two simple interventions increased the detection of FH. This systematic yet simple electronic case-finding programme with nurse-led review allowed the identification of new index cases, more than doubling the recorded prevalence of detected disease to 1 in 357 (0.28%). This study shows that primary care has an important role in identifying patients with this condition. PMID- 26608941 TI - Multiplex detection of histone-modifying enzymes by total internal reflection fluorescence-based single-molecule detection. AB - We develop a sensitive and selective method for the multiplex detection of histone-modifying enzymes (HMEs) through the integration of antibody-based fluorescence labeling with total internal reflection fluorescence (TIRF)-based single-molecule detection. This method exhibits excellent specificity and high sensitivity with a detection limit of 21 pM for histone acetyltransferase GcN5 and 12 pM for histone methyltransferase G9a, and it can be applied for the screening of HME inhibitors as well. PMID- 26608942 TI - Obesity-induced sperm DNA methylation changes at satellite repeats are reprogrammed in rat offspring. AB - There is now strong evidence that the paternal contribution to offspring phenotype at fertilisation is more than just DNA. However, the identity and mechanisms of this nongenetic inheritance are poorly understood. One of the more important questions in this research area is: do changes in sperm DNA methylation have phenotypic consequences for offspring? We have previously reported that offspring of obese male rats have altered glucose metabolism compared with controls and that this effect was inherited through nongenetic means. Here, we describe investigations into sperm DNA methylation in a new cohort using the same protocol. Male rats on a high-fat diet were 30% heavier than control-fed males at the time of mating (16-19 weeks old, n = 14/14). A small (0.25%) increase in total 5-methyl-2?-deoxycytidine was detected in obese rat spermatozoa by liquid chromatography tandem mass spectrometry. Examination of the repetitive fraction of the genome with methyl-CpG binding domain protein-enriched genome sequencing (MBD-Seq) and pyrosequencing revealed that retrotransposon DNA methylation states in spermatozoa were not affected by obesity, but methylation at satellite repeats throughout the genome was increased. However, examination of muscle, liver, and spermatozoa from male 27-week-old offspring from obese and control fathers (both groups from n = 8 fathers) revealed that normal DNA methylation levels were restored during offspring development. Furthermore, no changes were found in three genomic imprints in obese rat spermatozoa. Our findings have implications for transgenerational epigenetic reprogramming. They suggest that postfertilization mechanisms exist for normalising some environmentally-induced DNA methylation changes in sperm cells. PMID- 26608943 TI - Vasal vessels preserving microsurgical vasoepididymostomy in cases of previous varicocelectomy: a case report and literature review. PMID- 26608944 TI - Effects of velvet antler polypeptide on sexual behavior and testosterone synthesis in aging male mice. AB - Twenty-four-month-old male C57BL/6 mice with low serum testosterone levels were used as a late-onset hypogonadism (LOH) animal model for examining the effects of velvet antler polypeptide (VAP) on sexual function and testosterone synthesis. These mice received VAP for 5 consecutive weeks by daily gavage at doses of 100, 200, or 300 mg kg-1 body weight per day (n = 10 mice per dose). Control animals (n = 10) received the same weight-based volume of vehicle. Sexual behavior and testosterone levels in serum and interstitial tissue of testis were measured after the last administration of VAP. Furthermore, to investigate the mechanisms of how VAP affects sexual behavior and testosterone synthesis in vivo, the expression of steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) in Leydig cells was also measured by immunofluorescence staining and quantitative real-time PCR. As a result, VAP produced a significant improvement in the sexual function of these aging male mice. Serum testosterone level and intratesticular testosterone (ITT) concentration also increased in the VAP-treated groups. The expression of StAR, P450scc, and 3beta-HSD was also found to be enhanced in the VAP-treated groups compared with the control group. Our results suggested that VAP was effective in improving sexual function in aging male mice. The effect of velvet antler on sexual function was due to the increased expression of several rate-limiting enzymes of testosterone synthesis (StAR, P450scc, and 3beta-HSD) and the following promotion of testosterone synthesis in vivo. PMID- 26608945 TI - Plastins regulate ectoplasmic specialization via its actin bundling activity on microfilaments in the rat testis. AB - Plastins are a family of actin binding proteins (ABPs) known to cross-link actin microfilaments in mammalian cells, creating actin microfilament bundles necessary to confer cell polarity and cell shape. Plastins also support cell movement in response to changes in environment, involved in cell/tissue growth and development. They also confer plasticity to cells and tissues in response to infection or other pathological conditions (e.g., inflammation). In the testis, the cell-cell anchoring junction unique to the testis that is found at the Sertoli cell-cell interface at the blood-testis barrier (BTB) and at the Sertoli spermatid (e.g., 8-19 spermatids in the rat testis) is the basal and the apical ectoplasmic specialization (ES), respectively. The ES is an F-actin-rich anchoring junction constituted most notably by actin microfilament bundles. A recent report using RNAi that specifically knocks down plastin 3 has yielded some insightful information regarding the mechanism by which plastin 3 regulates the status of actin microfilament bundles at the ES via its intrinsic actin filament bundling activity. Herein, we provide a brief review on the role of plastins in the testis in light of this report, which together with recent findings in the field, we propose a likely model by which plastins regulate ES function during the epithelial cycle of spermatogenesis via their intrinsic activity on actin microfilament organization in the rat testis. PMID- 26608946 TI - Quality of Life, Body Image and Sexual Functioning in Bariatric Surgery Patients. AB - This article provides an overview of the literature on quality of life, body image and sexual behaviour in individuals with extreme obesity and who undergo bariatric surgery. Quality of life is a psychosocial construct that includes multiple domains, including health-related quality of life, weight-related quality of life, as well as other psychological constructs such as body image and sexual functioning. A large literature has documented the impairments in quality of life and these other domains in persons with obesity and extreme obesity in particular. These impairments are believed to play an influential role in the decision to undergo bariatric surgery. Individuals who undergo bariatric surgery typically report significant improvements in these and other areas of psychosocial functioning, often before they reach their maximum weight loss. The durability of these changes as patients maintain or regain weight, however, is largely unknown. PMID- 26608947 TI - Gastric leak after sleeve gastrectomy: Salvage procedure by intraluminal drainage. PMID- 26608948 TI - Oral Presentation. PMID- 26608950 TI - Reversed-phase ion-pair high-performance liquid chromatography assay of polyprenyl diphosphate oligomer homologues. AB - A reversed-phase ion-pair high-performance liquid chromatography procedure was developed for the separation of polyprenyl diphosphate oligomer homologues obtained chemically from plant polyprenols. Tetrabutylammonium phosphate was used as the ion-pair reagent, and the dependence of the separation quality on pH of ion-pair reagent was investigated for the first time. The procedure is applicable for the control of commercial available polyprenyl monophosphates (the active components of veterinary drugs Phosprenyl and Gamapren) for the possible presence of polyprenyl diphosphate byproducts. PMID- 26608949 TI - High-temporospatial-resolution dynamic contrast-enhanced (DCE) wrist MRI with variable-density pseudo-random circular Cartesian undersampling (CIRCUS) acquisition: evaluation of perfusion in rheumatoid arthritis patients. AB - This study is to evaluate highly accelerated three-dimensional (3D) dynamic contrast-enhanced (DCE) wrist MRI for assessment of perfusion in rheumatoid arthritis (RA) patients. A pseudo-random variable-density undersampling strategy, circular Cartesian undersampling (CIRCUS), was combined with k-t SPARSE-SENSE reconstruction to achieve a highly accelerated 3D DCE wrist MRI. Two healthy volunteers and 10 RA patients were studied. Two patients were on methotrexate (MTX) only (Group I) and the other eight were treated with a combination therapy of MTX and anti-tumor necrosis factor (TNF) therapy (Group II). Patients were scanned at baseline and 3 month follow-up. DCE MR images were used to evaluate perfusion in synovitis and bone marrow edema pattern in the RA wrist joints. A series of perfusion parameters was derived and compared with clinical disease activity scores of 28 joints (DAS28). 3D DCE wrist MR images were obtained with a spatial resolution of 0.3 * 0.3 * 1.5 mm(3) and temporal resolution of 5 s (with an acceleration factor of 20). The derived perfusion parameters, most notably transition time (dT) of synovitis, showed significant negative correlations with DAS28-ESR (r = -0.80, p < 0.05) and DAS28-CRP (r = -0.87, p < 0.05) at baseline and also correlated significantly with treatment responses evaluated by clinical score changes between baseline and 3 month follow-up (with DAS28-ESR r = -0.79, p < 0.05, and DAS28-CRP r = -0.82, p < 0.05). Highly accelerated 3D DCE wrist MRI with improved temporospatial resolution has been achieved in RA patients and provides accurate assessment of neovascularization and perfusion in RA joints, showing promise as a potential tool for evaluating treatment responses. PMID- 26608951 TI - A video-oculographic study of acute vestibular syndromes. AB - OBJECTIVES: To quantitate the vestibulo-ocular reflex (VOR) gain in patients with acute vestibular neuritis (VN) and repeat this daily using a portable video head impulse test device to assess vestibular recovery in the acute stage of VN. MATERIALS AND METHODS: We enrolled adults with symptoms and signs of VN presenting to the emergency department within 48 h of symptom onset. We recorded the eye movement response to rapid head impulses using the ICS Impulse(TM) video head impulse test device on each day of their hospital admission. RESULTS: There were eight patients (75% men, aged 35-85 years) who had marked variation in their initial vestibulo-ocular reflex gains. Three patients had vestibulo-ocular reflex gains in the normal range initially, despite having physical signs of VN. Two patients had initial contralesional gains below the normal range, associated with markedly reduced ipsilesional gains. Most patients' vestibulo-ocular reflex gains increased during admission, but four patients' ipsilesional gains remained in the abnormal range. Patients with lower vestibulo-ocular reflex gains were less likely to improve into the normal range. No patient with initially abnormal VOR gain recovered normal vestibulo-ocular reflex gain along with resolution of physical signs. CONCLUSION: Early video head impulse testing in the emergency department and each day of admission is feasible and well tolerated. There is marked variation in VOR gain in patients with symptoms and signs of VN, and low initial VOR gains are a predictor for low VOR gains on subsequent days. Improvement in VOR gains was seen in most patients. PMID- 26608952 TI - Silica Measurement with High Flow Rate Respirable Size Selective Samplers: A Field Study. AB - High and low flow rate respirable size selective samplers including the CIP10-R (10 l min(-1)), FSP10 (11.2 l min(-1)), GK2.69 (4.4 l min(-1)), 10-mm nylon (1.7 l min(-1)), and Higgins-Dewell type (2.2 l min(-1)) were compared via side-by side sampling in workplaces for respirable crystalline silica measurement. Sampling was conducted at eight different occupational sites in the USA and five different stonemasonry sites in Ireland. A total of 536 (268 pairs) personal samples and 55 area samples were collected. Gravimetric analysis was used to determine respirable dust mass and X-ray diffraction analysis was used to determine quartz mass. Ratios of respirable dust mass concentration, quartz mass concentration, respirable dust mass, and quartz mass from high and low flow rate samplers were compared. In general, samplers did not show significant differences greater than 30% in respirable dust mass concentration and quartz mass concentration when outliers (ratio <0.3 or >3.0) were removed from the analysis. The frequency of samples above the limit of detection and limit of quantification of quartz was significantly higher for the CIP10-R and FSP10 samplers compared to low flow rate samplers, while the GK2.69 cyclone did not show significant difference from low flow rate samplers. High flow rate samplers collected significantly more respirable dust and quartz than low flow rate samplers as expected indicating that utilizing high flow rate samplers might improve precision in quartz measurement. Although the samplers did not show significant differences in respirable dust and quartz concentrations, other practical attributes might make them more or less suitable for personal sampling. PMID- 26608953 TI - Synthesis, structural elucidation and bioevaluation of 4-amino-1,2,4-triazole-3 thione's Schiff base derivatives. AB - In this study, a series of ten triazole Schiff base derivatives 6a-j were synthesized through microwave assisted imine formation by reacting substituted amino triazole 5 with different substituted aldehydes. All the synthesized compounds were evaluated for their inhibitory activity against mushroom tyrosinase. Two of the compounds 6a and 6b among the series 6a-j were found to be highly potent tyrosinase inhibitors with IC50 values of 10.09 +/- 1.03 and 6.23 +/- 0.85 uM, respectively, which were even higher than that of the reference inhibitor kojic acid (IC50 = 16.6 +/- 2.8 uM). Compounds 6e and 6f with IC50 values of 20.27 +/- 2.78 and 26.02 +/- 4.14 uM, respectively, were comparable to the reference inhibitor, and the remaining compounds had a moderate inhibitory activity against mushroom tyrosinase. The most potent compounds (6a, 6b) were used in the kinetic and optical analyses. The inhibition kinetics analyzed with Lineweaver-Burk plots revealed that both compounds 6a and 6b were non-competitive inhibitors of tyrosinase with inhibition constant values of 0.023 and 0.022 mM, respectively. PMID- 26608954 TI - Competition between health maintenance organizations and nonintegrated health insurance companies in health insurance markets. AB - This article examines a model of competition between two types of health insurer: Health Maintenance Organizations (HMOs) and nonintegrated insurers. HMOs vertically integrate health care providers and pay them at a competitive price, while nonintegrated health insurers work as indemnity plans and pay the health care providers freely chosen by policyholders at a wholesale price. Such difference is referred to as an input price effect which, at first glance, favors HMOs. Moreover, we assume that policyholders place a positive value on the provider diversity supplied by their health insurance plan and that this value increases with the probability of disease. Due to the restricted choice of health care providers in HMOs a risk segmentation occurs: policyholders who choose nonintegrated health insurers are characterized by higher risk, which also tends to favor HMOs. Our equilibrium analysis reveals that the equilibrium allocation only depends on the number of HMOs in the case of exclusivity contracts between HMOs and providers. Surprisingly, our model shows that the interplay between risk segmentation and input price effects may generate ambiguous results. More precisely, we reveal that vertical integration in health insurance markets may decrease health insurers' premiums. PMID- 26608955 TI - Zanamivir-resistant influenza viruses with Q136K or Q136R neuraminidase residue mutations can arise during MDCK cell culture creating challenges for antiviral susceptibility monitoring. AB - Surveillance of circulating influenza strains for antiviral susceptibility is important to ensure patient treatment guidelines remain appropriate. Influenza A(H3N2) and A(H1N1)pdm09 virus isolates containing mutations at the Q136 residue of the neuraminidase (NA) that conferred reduced susceptibility to the NA inhibitor (NAI) zanamivir were detected during antiviral susceptibility monitoring. Interestingly, the mutations were not detectable in the viruses from respective clinical specimens, only in the cultured isolates. We showed that variant viruses containing the Q136K and Q136R NA mutations were preferentially selected in Madin-Darby canine kidney epithelial (MDCK) cells, but were less well supported in MDCK-SIAT1 cells and embryonated eggs. The effect of Q136K, Q136R, Q136H and Q136L substitutions in NA subtypes N1 and N2 on NAI susceptibility and in vitro viral fitness was assessed. This study highlights the challenges that cell culture derived mutations can pose to the NAI susceptibility analysis and interpretation and reaffirms the need to sequence viruses from respective clinical specimens to avoid misdiagnosis. However, we also demonstrate that NA mutations at residue Q136 can confer reduced zanamivir, peramivir or laninamivir susceptibility, and therefore close monitoring of viruses for mutations at this site from patients being treated with these antivirals is important. PMID- 26608957 TI - Improving Safety in Laparoscopic Cholecystectomy: Reply. PMID- 26608956 TI - Postoperative Outcomes of Enucleation and Standard Resections in Patients with a Pancreatic Neuroendocrine Tumor. AB - BACKGROUND: Either enucleation or more extended resection is performed to treat patients with pancreatic neuroendocrine tumor (pNET). Aim was to analyze the postoperative complications for each operation separately. Furthermore, independent risk factors for complications and incidence of pancreatic insufficiency were analyzed. METHODS: Retrospective all resected patients from two academic hospitals in The Netherlands between 1992 and 2013 were included. Postoperative complications were scored by both ISGPS and Clavien-Dindo criteria. Based on tumor location, operations were compared. Independent risk factors for overall complications were identified. During long-term follow-up, pancreatic insufficiency and recurrent disease were analyzed. RESULTS: Tumor enucleation was performed in 60/205 patients (29%), pancreatoduodenectomy in 65/205 (31%), distal pancreatectomy in 72/205 (35%) and central pancreatectomy in 8/205 (4%) patients. Overall complications after tumor enucleation of the pancreatic head and pancreatoduodenectomy were comparable, 24/35 (69%) versus 52/65 (80%). The same was found after tumor enucleation and resection of the pancreatic tail (36 vs.58%). Number of re-interventions and readmissions were comparable between all operations. After pancreatoduodenectomy, 33/65 patients had lymph node metastasis and in patients with tumor size <=2 cm, 55% had lymph node metastasis. Tumor in the head and BMI >=25 kg/m(2) were independent risk factors for complications after enucleation. During follow-up, incidence of exocrine and endocrine insufficiency was significant higher after pancreatoduodenectomy (resp. 55 and 19%) compared to the tumor enucleation and distal pancreatectomy (resp. 5 and 7% vs. 8 and 13%). After tumor enucleation 19% developed recurrent disease. CONCLUSION: Since the complication rate, need for re-interventions and readmissions were comparable for all resections, tumor enucleation may be regarded as high risk. Appropriate operation should be based on tumor size, location, and functional status of the pNET. PMID- 26608958 TI - Immunohistochemical expression of cyclooxygenase-2 (COX-2) in oral nevi and melanoma. AB - BACKGROUND: Cyclooxygenase-2 (COX-2) catalyses the conversion of arachidonic acid to prostaglandin, and its overexpression has been demonstrated in different malignant tumors, including cutaneous melanoma. However, no data about the expression of this protein in oral melanocytic lesions are available to date. The aim of this study was to evaluate the immunohistochemical expression of COX-2 in oral nevi and melanomas, comparing the results with correspondent cutaneous lesions. METHODS: COX-2 was evaluated by immunohistochemistry in 49 oral melanocytic lesions, including 36 intramucosal nevi and 13 primary oral melanomas, and in four cutaneous nevi and eight melanomas. RESULTS: All cases of oral and cutaneous melanomas were positive for COX-2. On the other hand, all oral and cutaneous melanocytic nevi were negative. CONCLUSION: COX-2 is highly positive in oral melanomas and negative in oral nevi and might represent a useful marker to distinguish melanocytic lesions of the oral cavity. PMID- 26608959 TI - Identification and characterization of transcriptional control region of the human beta 1,4-mannosyltransferase gene. AB - All asparagine-linked glycans (N-glycans) on the eukaryotic glycoproteins are primarily derived from dolichol-linked oligosaccharides (DLO), synthesized on the rough endoplasmic reticulum membrane. We have previously reported cloning and identification of the human gene, HMT-1, which encodes chitobiosyldiphosphodolichol beta-mannosyltransferase (beta1,4-MT) involved in the early assembly of DLO. Considering that N-glycosylation is one of the most ubiquitous post-translational modifications for many eukaryotic proteins, the HMT 1 could be postulated as one of the housekeeping genes, but its transcriptional regulation remains to be investigated. Here we screened a 1 kb region upstream from HMT-1 open reading frame (ORF) for transcriptionally regulatory sequences by using chloramphenicol acetyl transferase (CAT) assay, and found that the region from -33 to -1 positions might act in HMT-1 transcription at basal level and that the region from -200 to -42 should regulate its transcription either positively or negatively. In addition, results with CAT assays suggested the possibility that two GATA-1 motifs and an Sp1 motif within a 200 bp region upstream from HMT 1 ORF might significantly upregulate HMT-1 transcription. On the contrary, the observations obtained from site-directed mutational analyses revealed that an NF 1/AP-2 overlapping motif located at -148 to -134 positions should serve as a strong silencer. The control of the HMT-1 transcription by these motifs resided within the 200 bp region could partially explain the variation of expression level among various human tissues, suggesting availability and importance of this region for regulatory role in HMT-1 expression. PMID- 26608960 TI - A New Online Calibration Method for Multidimensional Computerized Adaptive Testing. AB - Multidimensional-Method A (M-Method A) has been proposed as an efficient and effective online calibration method for multidimensional computerized adaptive testing (MCAT) (Chen & Xin, Paper presented at the 78th Meeting of the Psychometric Society, Arnhem, The Netherlands, 2013). However, a key assumption of M-Method A is that it treats person parameter estimates as their true values, thus this method might yield erroneous item calibration when person parameter estimates contain non-ignorable measurement errors. To improve the performance of M-Method A, this paper proposes a new MCAT online calibration method, namely, the full functional MLE-M-Method A (FFMLE-M-Method A). This new method combines the full functional MLE (Jones & Jin in Psychometrika 59:59-75, 1994; Stefanski & Carroll in Annals of Statistics 13:1335-1351, 1985) with the original M-Method A in an effort to correct for the estimation error of ability vector that might otherwise adversely affect the precision of item calibration. Two correction schemes are also proposed when implementing the new method. A simulation study was conducted to show that the new method generated more accurate item parameter estimation than the original M-Method A in almost all conditions. PMID- 26608961 TI - A Hierarchical Model for Accuracy and Choice on Standardized Tests. AB - This paper assesses the psychometric value of allowing test-takers choice in standardized testing. New theoretical results examine the conditions where allowing choice improves score precision. A hierarchical framework is presented for jointly modeling the accuracy of cognitive responses and item choices. The statistical methodology is disseminated in the 'cIRT' R package. An 'answer two, choose one' (A2C1) test administration design is introduced to avoid challenges associated with nonignorable missing data. Experimental results suggest that the A2C1 design and payout structure encouraged subjects to choose items consistent with their cognitive trait levels. Substantively, the experimental data suggest that item choices yielded comparable information and discrimination ability as cognitive items. Given there are no clear guidelines for writing more or less discriminating items, one practical implication is that choice can serve as a mechanism to improve score precision. PMID- 26608962 TI - Factor analysis models via I-divergence optimization. AB - Given a positive definite covariance matrix [Formula: see text] of dimension n, we approximate it with a covariance of the form [Formula: see text], where H has a prescribed number [Formula: see text] of columns and [Formula: see text] is diagonal. The quality of the approximation is gauged by the I-divergence between the zero mean normal laws with covariances [Formula: see text] and [Formula: see text], respectively. To determine a pair (H, D) that minimizes the I-divergence we construct, by lifting the minimization into a larger space, an iterative alternating minimization algorithm (AML) a la Csiszar-Tusnady. As it turns out, the proper choice of the enlarged space is crucial for optimization. The convergence of the algorithm is studied, with special attention given to the case where D is singular. The theoretical properties of the AML are compared to those of the popular EM algorithm for exploratory factor analysis. Inspired by the ECME (a Newton-Raphson variation on EM), we develop a similar variant of AML, called ACML, and in a few numerical experiments, we compare the performances of the four algorithms. PMID- 26608963 TI - The Trojan Horse Tale Revisited: An Eye on Metastatic Spread of Carcinoma Cells. AB - The metastatic spread of carcinoma cells is not fully understood. Here, we compare the peripheral blood mononuclear cells (PBMC) and intraocular metastatic cells in parotid gland carcinoma with the PBMCs of healthy donors by immunohistochemistry and flow cytometry. We found Ber-EP4 tumor marker-positive carcinoma cells in the aqueous humor of the patient's right eye and a CD45 and Ber-EP4-expressing PBMC population in his blood. These Ber-EP4-expressing cells exhibited a monocytic-myeloid phenotype with coexpression of CD11b, CD115, and the macrophage marker CD172a (SIRP-alpha). Uptake of pHrodogreen revealed their phagocytic activity. Our findings suggest that the tumor cells in the anterior chamber originally derived from cell fusions between tumor cells and myeloid cells in the peripheral blood. Thus, metastases of a solid malignancy could use monocytes-macrophages as the Trojan horse to enter the eye. PMID- 26608964 TI - Metabolic activity of odontoblast-like cells irradiated with blue LED (455 nm). AB - Blue light emitting diodes (LEDs) are frequently used in dentistry for light activation of resin-based materials; however, their photobiostimulatory effects have not yet been fully investigated. This study aimed to investigate the effect of blue LED (455 nm) on the metabolism of odontoblast-like cells MDPC-23. Energy doses of 2 and 4 J/cm(2) were used at 20 mW/cm(2) fixed power density. MDPC-23 cells were seeded at 10,000 cells/cm(2) density in Dulbecco's modified Eagle's medium (DMEM) containing 10 % fetal bovine serum (FBS). After 12 h, the culture medium was replaced with new DMEM supplemented with 0.5 % of FBS, and the cells were incubated for further 12 h. After that, single irradiation was performed to the culture, under selected parameters. Cell viability evaluations (Alamar Blue Assay, n = 12), number of viable cells (Trypan Blue Assay, n = 12), morphological analysis by scanning electron microscopy (SEM, n = 2), gene expression (n = 6) of alkaline phosphatase (Alp), collagen (Col-1a1), and dental matrix protein (Dmp-1) (quantitative polymerase chain reaction (qPCR)) were performed 72 h after irradiation. Data were analyzed by Kruskal-Wallis, ANOVA, and Tukey tests (p < 0.05). Direct light application at 4 J/cm(2) energy dose had no negative effects on cell viability, while irradiation with 2 J/cm(2) reduced cell metabolism. None of doses affected the number of viable cells compared with the control group. The two energy doses downregulated the expression of Alp; however, expression of Col 1a1 and Dmp-1 had no alteration. Cells presented change in the cytoskeleton only when irradiated with 2 J/cm(2). In conclusion, the blue LED (455 nm) irradiation, under the evaluated parameters, had no biostimulatory effects on MDPC-23 cells. PMID- 26608965 TI - Cryptic Species or Inadequate Taxonomy? Implementation of 2D Geometric Morphometrics Based on Integumental Organs as Landmarks for Delimitation and Description of Copepod Taxa. AB - Discovery of cryptic species using molecular tools has become common in many animal groups but it is rarely accompanied by morphological revision, creating ongoing problems in taxonomy and conservation. In copepods, cryptic species have been discovered in most groups where fast-evolving molecular markers were employed. In this study at Yeelirrie in Western Australia we investigate a subterranean species complex belonging to the harpacticoid genus Schizopera Sars, 1905, using both the barcoding mitochondrial COI gene and landmark-based two dimensional geometric morphometrics. Integumental organs (sensilla and pores) are used as landmarks for the first time in any crustacean group. Complete congruence between DNA-based species delimitation and relative position of integumental organs in two independent morphological structures suggests the existence of three distinct evolutionary units. We describe two of them as new species, employing a condensed taxonomic format appropriate for cryptic species. We argue that many supposedly cryptic species might not be cryptic if researchers focus on analyzing morphological structures with multivariate tools that explicitly take into account geometry of the phenotype. A perceived supremacy of molecular methods in detecting cryptic species is in our view a consequence of disparity of investment and unexploited recent advancements in morphometrics among taxonomists. Our study shows that morphometric data alone could be used to find diagnostic morphological traits and gives hope to anyone studying small animals with a hard integument or shell, especially opening the door to assessing fossil diversity and rich museum collections. We expect that simultaneous use of molecular tools with geometry-oriented morphometrics may yield faster formal description of species. Decrypted species in this study are a good example for urgency of formal descriptions, as they display short-range endemism in small groundwater calcrete aquifers in a paleochannel, where their conservation may be threatened by proposed mining. PMID- 26608966 TI - Does Sclerostin Depletion Stimulate Fracture Healing in a Mouse Model? AB - BACKGROUND: Sclerostin is a secreted glycoprotein that inhibits the intracellular Wnt signaling pathway, which, when inactivated, stimulates bone formation. This has been seen in fracture studies, which have shown larger and stronger calluses with accelerated fracture healing in sclerostin knockout and sclerostin antibody injection models. However, the effects of these two mechanisms have not been compared in the context of fracture healing. QUESTIONS/PURPOSES: We sought to determine the degree to which sclerostin inhibition (Scl-Ab injection) and complete sclerostin depletion inhibit fracture healing in a mouse model as evaluated by (1) morphometric trabecular bone measures at the fracture site, and (2) fracture site structural strength. METHODS: Ten-week-old male sclerostin knockout (n = 20) and wild type (n = 40) mice underwent insertion of a tibial intramedullary pin after which a midshaft tibial osteotomy was performed. The mice were divided in three groups: sclerostin knockout (n = 20), wild type with sclerostin antibody injection (intravenous dose of 100 mg/kg weekly) (n = 20), and wild type with saline injection (n = 20). The mice for each group where subdivided and euthanized at 14, 21, 28, and 35 days after surgery, at which time the fractured tibias were assessed with microCT (to assess morphometric trabecular bone measures: bone volume to total volume (BV/TV), trabecular thickness, trabecular number, and structural model index at the fracture site. Biomechanical testing in the form of three-point bending also was done to assess fracture site structural strength. A difference greater than 3.7% in our primary outcome (BV/TV) would be required to detect a difference between groups with a power of 80%, as per our power analysis. RESULTS: The wild type with sclerostin antibody and the sclerostin knockout groups showed increased trabecular BV/TV at the fracture site compared with the wild type group with saline at all times, however no difference was seen between the treatment groups with the numbers available, except at 28 days postoperatively when the sclerostin knockout group showed greater BV/TV than the wild type sclerostin antibody group (47.0 +/- 3.5 vs 40.1 +/- 2.1; p < 0.05). On biomechanical testing the wild type sclerostin antibody showed increased stiffness at Days 14 and 28 compared with the wild type with saline group (70.9 +/- 6.4 vs 14.8 +/- 8.1; p = 0.001), (106.8 +/- 24.3 vs 74.9 +/- 16.0; p = 0.004); respectively. However, with the numbers available, no differences were detected between the wild type with sclerostin antibody and the sclerostin knockout groups in terms of whole-bone structural strength. CONCLUSIONS: Sclerostin antibody injections showed promising results, which were not different with the numbers available, from results achieved with complete depletion of sclerostin, especially at earlier stages of the healing process, and therefore completed the healing process at an earlier time. CLINICAL RELEVANCE: Sclerostin antibody injections appear to enhance fracture healing to a degree that is not different than complete sclerostin depletion, but larger animal studies are required to assess the accurate dosage and timing of administration in the fracture healing process to further evaluate its potential clinical utility to enhance fracture healing. PMID- 26608967 TI - CORR Insights((r)): Revision Distal Femoral Arthroplasty With the Compress((r)) Prosthesis Has a Low Rate of Mechanical Failure at 10 Years. PMID- 26608968 TI - CORR Insights((r)): Open Surgical Treatment for Snapping Scapula Provides Durable Pain Relief, but so Does Nonsurgical Treatment. PMID- 26608969 TI - Revision neural monitored surgery for recurrent thyroid cancer: Safety and thyroglobulin response. AB - OBJECTIVES/HYPOTHESIS: To evaluate the quantitative biochemical response, recurrence rate, and rate of surgical complications for thyroid cancer revision surgery. STUDY DESIGN: Retrospective review. METHODS: This is a single institution analysis of a prospective database of 181 patients undergoing reoperation for local recurrent thyroid cancer by the same surgeon from 2004 to 2013 with intraoperative neural monitoring. Main outcome measures included pathologic findings, surgical complications, effect of reoperation on thyroglobulin (Tg) levels, and recurrence rate. We defined biochemical complete remission as postoperative stimulated Tg of 0.2 ng/mL or less. RESULTS: Fourteen percent of the patients presented with permanent vocal cord palsy (VCP), and 20% of the patients presented with hypocalcemia prior to surgery. Among them, 70% of the patients underwent first revision surgery; whereas in 30% the surgery represented second or higher revision surgery, with 8% being a third or higher revision. None developed temporary or permanent VCP. Temporary hypocalcemia occurred in 9% of the patients, and permanent hypocalcemia occurred in 4.2%. The rate of cervical node recurrence was 5% at a median follow-up of 3.4 years. There were no disease-specific deaths. Mean preoperative basal Tg was 22.3 ng/mL and mean postoperative Tg was 5.7 ng/mL, a decline of 74% (P = 0.023, paired t test). Biochemical complete remission was achieved in 58% of all revision cases. CONCLUSION: Reoperative neural monitored surgery for recurrent thyroid cancer is a safe and effective procedure with limited morbidity in experienced hands, even in the setting of multiple prior revision surgeries and existing comorbidities such as VCP and hypocalcemia. LEVEL OF EVIDENCE: 4. PMID- 26608970 TI - Metabolomics: a state-of-the-art technology for better understanding of male infertility. AB - Male factor infertility affects approximately half of the infertile couples, in spite of many years of research on male infertility treatment and diagnosis; several outstanding questions remain to be addressed. In this regard, metabolomics as a novel field of omics has been suggested to be applied for male infertility problems. A variety of terms associated with metabolite quantity and quality have been established to demonstrate mixtures of metabolites. Despite metabolomics and metabolite analyses have been around more than decades, a limited number of studies concerning male infertility have been carried out. In this review, we summarised the latest finding in metabolomics techniques and metabolomics biomarkers correlated with male infertility. The rapid progress of a variety of metabolomics platforms, such as nonoptical and optical spectroscopy, could ease separation, recognition, classification and quantification of several metabolites and their metabolic pathways. Here, we recommend that the novel biomarkers determined in the course of metabolomics analysis may stand for potential application of treatment and future clinical practice. PMID- 26608971 TI - Multiple roles for TGFbeta receptor type II in regulating the pancreatic response in acute pancreatitis. AB - In their recent publication in Journal of Pathology, Grabliauskaite and Sapanora and their colleagues in Zurich use a conditional ablation of the TGFbeta type II receptor (TBRII) to analyse its specific role in pancreatic epithelial cells in response to a caerulein-induced model of acute pancreatitis. These experiments help to clarify some confusion that has existed in the literature stemming from the use of a dominant-negative transgenic TBRII mouse. The results point to a central role for TBRII in acinar cells in mitigating the overall response of the pancreas to the damage and inflammation of acute pancreatitis. PMID- 26608973 TI - Parents' preferences on pain treatment, even when faced with medication dilemmas, influence their decisions to administer opioids in children. PMID- 26608974 TI - Methylphenidate for ADHD. PMID- 26608972 TI - Multibiomarker disease activity score and C-reactive protein in a cross-sectional observational study of patients with rheumatoid arthritis with and without concomitant fibromyalgia. AB - OBJECTIVES: To examine the association between a multibiomarker disease activity (MBDA) score, CRP and clinical disease activity measures among RA patients with and without concomitant FM. METHODS: In an observational cohort of patients with established RA, we performed a cross-sectional analysis comparing MBDA scores with CRP by rank correlation and cross-classification. MBDA scores, CRP and clinical measures of disease activity were compared between patients with RA alone and RA with concomitant FM (RA and FM) by univariate and multivariate analyses. RESULTS: CRP was ?1.0 mg/dl for 184 of 198 patients (93%). MBDA scores correlated with CRP (r = 0.755, P < 0.001), but were often discordant, being moderate or high for 19%, 55% and 87% of patients with CRP ?0.1, 0.1 to ?0.3, or 0.3 to ?1.0 mg/dl, respectively. Among patients with CRP ?1.0 mg/dl, swollen joint count (SJC) increased linearly across levels of MBDA score, both with (P = 0.021) and without (P = 0.004) adjustment for CRP, whereas CRP was not associated with SJC. The 28-joint-DAS-CRP, other composite measures, and their non-joint count component measures were significantly greater for patients with RA and FM (n = 25) versus RA alone (n = 173) (all P ? 0.005). MBDA scores and CRP were similar between groups. CONCLUSION: MBDA scores frequently indicated RA disease activity when CRP did not. Neither one was significantly greater among patients with RA and FM versus RA alone. Thus, MBDA score may be a useful objective measure for identifying RA patients with active inflammation when CRP is low (?1.0 mg/dl), including RA patients with concomitant FM. PMID- 26608975 TI - Elevated Serum Liver Enzymes in Patients with Obstructive Sleep Apnea-hypopnea Syndrome. AB - BACKGROUND: Obstructive sleep apnea-hypopnea syndrome (OSAS) is associated with elevated liver enzymes and fatty liver. The purpose of this study was to measure serum liver enzyme levels in patients evaluated by polysomnography (PSG) and the factors associated with liver injury in OSAS patients. METHODS: All patients referred to PSG for evaluation of sleep apnea symptoms between June 2011 and November 2014 were included in this study. Demographic data and PSG parameters were recorded. Serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase levels were systematically measured. OSAS patients were divided into mild, moderate, and severe groups according to the apnea hypopnea index (AHI) values of 5-14 events/h, 15-29 events/h, and >=30 events/h. RESULTS: A total of 540 patients were enrolled in this study; among these patients, 386 were male. Elevated liver enzymes were present in 42.3% of OSAS patients (32.4% in mild/moderate group; 51.0% in severe group) and 28.1% patients without OSAS. Patients with OSAS had higher body mass index (BMI) (P < 0.01). In the bivariate correlation, the liver enzymes level was negatively correlated with age and the lowest arterial oxygen saturation (SaO 2 ), and was positively correlated with BMI, oxygen desaturation index, percent of total time with oxygen saturation level <90% (TS90%), AHI, total cholesterol (TC), and triglyceride (TG). In logistic regression analysis, Age, BMI, TS90%, TC, and TG were included in the regression equation. CONCLUSIONS: Our data suggest that OSAS is a risk factor for elevated liver enzymes. The severity of OSAS is correlated with liver enzyme levels; we hypothesize that hypoxia is one of main causes of liver damage in patients with OSAS. PMID- 26608977 TI - Qualitative Analysis of Diagnostic Value of 24-h Proteinuria for Preeclampsia. AB - BACKGROUND: Preeclampsia (PE) is a serious idiopathic disease posing a threat to both mothers and fetuses' lives during pregnancy, whose main diagnostic criteria include hypertension with proteinuria. However, American College of Obstetricians and Gynecologists (ACOG) updated the diagnostic criteria for PE and reduced the diagnostic value of proteinuria for patients with PE. Qualitative analysis of the diagnostic value of 24-h proteinuria for patients with PE in China was conducted to evaluate the diagnostic criteria value in the latest ACOG guideline. METHODS: Complete clinical data of 65 patients with hypertensive disorder in pregnancy (HDP) were collected. All patients were delivered to and hospitalized in Renji Hospital. Adverse outcome was defined in case of the emergence of any serious complication for a mother or the fetus. A retrospective study was conducted according to ACOG guideline, to analyze the relationship between each diagnostic criteria of ACOG guideline and maternal and perinatal outcomes. Spearman correlation test was used to detect the association between each diagnostic criterion, its corresponding value, and the adverse pregnancy outcome. Logistic regression was performed to verify the result of Spearman correlation test. RESULTS: Of 65 HDP patients, the percentage of adverse pregnancy outcome was 63.1%. Adverse pregnancy outcomes constitute diversification. There were 55 cases with 24-h proteinuria value >=0.3 g, of which the adverse outcome rate was 74.5%. While adverse pregnancy outcomes did not appear in the rest 10 HDP patients with proteinuria <0.3 g/24 h. The statistic difference was significant (P = 0.000). However, no significant difference was found in other criteria groups (impaired liver function: P = 0.417; renal insufficiency: P = 0.194; thrombocytopenia: P = 0.079; and cerebral or visual symptoms: P = 0.296). The correlation coefficient between 24-h proteinuria >=0.3 g and adverse pregnancy outcomes was 0.557 (P < 0.005). Impaired liver function (P = 0.180), renal insufficiency (P = 0.077) and cerebral or visual symptoms (P = 0.118) were not related to adverse outcomes. The 24-h proteinuria value (HDP: r = 0.685; PE: r = 0.521), liver enzyme value (HDP: r = 0.519; PE: r = 0.501), and creatinine value (HDP: r = 0.511; PE: r = 0.398) were associated with adverse pregnancy outcomes both in PE and HDP, and the corresponding logistic regression equation can be produced. CONCLUSIONS: The 24-h proteinuria value is still an important diagnostic criterion for PE, and deletion of 24-h proteinuria value from diagnostic criteria for severe PE was not recommended. The diagnostic criteria in ACOG guideline need to be verified in Chinese women. PMID- 26608976 TI - An Open-label, Self-control, Prospective Study on Cognitive Function, Academic Performance, and Tolerability of Osmotic-release Oral System Methylphenidate in Children with Attention-deficit Hyperactivity Disorder. AB - BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is the most common mental and behavioral disorder in school-aged children. This study evaluated the effect of osmotic-release oral system (OROS) methylphenidate (MPH) on cognitive function and academic performance of Chinese school-aged children with ADHD. METHODS: This 12-week, prospective, multicenter, open-label, self-controlled study enrolled 153 Chinese school-aged children with ADHD and 41 non-ADHD children. Children with ADHD were treated with once-daily OROS-MPH (18 mg, 36 mg, or 54 mg). The primary endpoints were Inattention/Overactivity (I/O) with Aggression Conners Behavior Rating Scale (IOWA) and Digit Span Test at week 12 compared with baseline. Secondary endpoints included opposition/defiant (O/D) subscale of IOWA, Clinical Global Impression (CGI), Coding Test, Stroop Color word Test, Wisconsin Card Sorting Test (WCST), academic performance on teacher rated school examinations, and safety at week 12 compared with baseline. Both non ADHD and ADHD children received the same frequency of cognitive operational test to avoid the possible bias caused by training. RESULTS: A total of 128 patients were evaluated with cognitive assessments. The OROS-MPH treatment significantly improved IOWA Conners I/O subscale scores at week 12 (3.8 +/- 2.3) versus baseline (10.0 +/- 2.4; P < 0.0001). Digit Span Test scores improved significantly (P < 0.0001) with a high remission rate (81.1%) at week 12 versus baseline. A significant (P < 0.0001) improvement was observed in O/D subscale of IOWA, CGI, Coding Test, Stroop Color-word Test, WCST, and academic performance at week 12 versus baseline. Very few practice-related improvements were noticed in the non-ADHD group at week 12 compared with baseline. No serious adverse events and deaths were reported during the study. CONCLUSIONS: The OROS-MPH treatment effectively controlled symptoms of ADHD and significantly improved academic performance and cognitive function of Chinese school-aged children with ADHD. The treatment was found to be safe and generally well-tolerated over 12 weeks. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01933880; http://clinicaltrials.gov/ct2/show/NCT01933880?term=CONCERTAATT4099&rank=1. PMID- 26608978 TI - An Interdisciplinary Nutrition Support Team Improves Clinical and Hospitalized Outcomes of Esophageal Cancer Patients with Concurrent Chemoradiotherapy. AB - BACKGROUND: The prevalence of malnutrition is very high in patients with cancer. The purpose of this study was to investigate whether or not a nutrition support team (NST) could benefit esophageal cancer patients undergoing chemoradiotherapy (CRT). METHODS: Between June 2012 and April 2014, 50 esophageal cancer patients undergoing concurrent CRT were randomly assigned into two groups: The NST group and the control group. The nutritional statuses of 25 patients in the NST group were managed by the NST. The other 25 patients in the control group underwent the supervision of radiotherapy practitioners. At the end of the CRT, nutritional status, the incidence of complications, and completion rate of radiotherapy were evaluated. Besides, the length of hospital stay (LOS) and the in-patient cost were also compared between these two groups. RESULTS: At the completion of CRF, the nutritional status in the NST group were much better than those in the control group, as evidenced by prealbumin (ALB), transferrin, and ALB parameters (P = 0.001, 0.000, and 0.000, respectively). The complication incidences, including bone marrow suppression (20% vs. 48%, P = 0.037) and complications related infections (12% vs. 44%, P = 0.012), in the NST group were lower and significantly different from the control group. In addition, only one patient in the NST group did not complete the planned radiotherapy while 6 patients in the control group had interrupted or delayed radiotherapy (96% vs. 76%, P = 0.103). Furthermore, the average LOS was decreased by 4.5 days (P = 0.001) and in-patient cost was reduced to 1.26 +/- 0.75 thousand US dollars person-times (P > 0.05) in the NST group. CONCLUSIONS: A NST could provide positive effects in esophageal cancer patients during concurrent CRT on maintaining their nutrition status and improving the compliance of CRF. Moreover, the NST could be helpful on reducing LOS and in-patient costs. PMID- 26608979 TI - Association of Estrogen Receptor Gene Polymorphisms and Primary Biliary Cirrhosis in a Chinese Population: A Case-Control Study. AB - BACKGROUND: Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease characterized by destruction of the interlobular bile ducts and a striking female predominance. The aim of this study was to identify associations between estrogen receptor (ESR) gene polymorphisms with the risk of developing PBC and abnormal serum liver tests in a Chinese population. METHODS: Thirty-six patients with PBC (case group) and 35 healthy individuals (control group) from the First Hospital of Jilin University were studied. Whole genomic DNA was extracted from all the participants. Three single-nucleotide polymorphisms (rs2234693, rs2228480, and rs3798577) from ESR1 and two (rs1256030 and rs1048315) from ESR2 were analyzed by a pyrosequencing method. Demographic data and liver biochemical data were collected. RESULTS: Subjects with the T allele at ESR2 rs1256030 had 1.5 times higher risk of developing PBC than those with the C allele (odds ratio [OR] = 2.1277, 95% confidence interval [CI] = 1.1872-4.5517). Haplotypes TGC of ESR1 rs2234693, rs2228480, and rs3798577 were risk factors for having PBC. The C allele at ESR1 rs2234693 was associated with abnormal alkaline phosphatase (OR = 5.2469, 95% CI = 1.3704-20.0895) and gamma glutamyl transferase (OR = 3.4286, 95% CI = 1.0083-13.6578) levels in PBC patients. CONCLUSIONS: ESR2 rs1256030 T allele may be a significant risk factor for the development of PBC. Screening for patients with gene polymorphisms may help to make early diagnoses in patients with PBC. PMID- 26608980 TI - Long-term Effectiveness of Antiepileptic Drug Monotherapy in Partial Epileptic Patients: A 7-year Study in an Epilepsy Center in China. AB - BACKGROUND: It is important to choose an appropriate antiepileptic drug (AED) to manage partial epilepsy. Traditional AEDs, such as carbamazepine (CBZ) and valproate (VPA), have been proven to have good therapeutic effects. However, in recent years, a variety of new AEDs have increasingly been used as first-line treatments for partial epilepsy. As the studies regarding the effectiveness of new drugs and comparisons between new AEDs and traditional AEDs are few, it is determined that these are areas in need of further research. Accordingly, this study investigated the long-term effectiveness of six AEDs used as monotherapy in patients with partial epilepsy. METHODS: This is a retrospective, long-term observational study. Patients with partial epilepsy who received monotherapy with one of six AEDs, namely, CBZ, VPA, topiramate (TPM), oxcarbazepine (OXC), lamotrigine (LTG), or levetiracetam (LEV), were identified and followed up from May 2007 to October 2014, and time to first seizure after treatment, 12-month remission rate, retention rate, reasons for treatment discontinuation, and adverse effects were evaluated. RESULTS: A total of 789 patients were enrolled. The median time of follow-up was 56.95 months. CBZ exhibited the best time to first seizure, with a median time to first seizure of 36.06 months (95% confidential interval: 30.64-44.07). CBZ exhibited the highest 12-month remission rate (85.55%), which was significantly higher than those of TPM (69.38%, P = 0.006), LTG (70.79%, P = 0.001), LEV (72.54%, P = 0.005), and VPA (73.33%, P = 0.002). CBZ, OXC, and LEV had the best retention rate, followed by LTG, TPM, and VPA. Overall, adverse effects occurred in 45.87% of patients, and the most common adverse effects were memory problems (8.09%), rashes (7.76%), abnormal hepatic function (6.24%), and drowsiness (6.24%). CONCLUSION: This study demonstrated that CBZ, OXC, and LEV are relatively effective in managing focal epilepsy as measured by time to first seizure, 12-month remission rate, and retention rate. PMID- 26608981 TI - Limbic Encephalitis Associated with Anti-gamma-aminobutyric Acid B Receptor Antibodies: A Case Series from China. AB - BACKGROUND: Autoimmune encephalitis associated with antibodies against gamma aminobutyric acid B receptor (GABA B R) in patients with limbic encephalitis (LE) was first described in 2010. We present a series of Han Chinese patients for further clinical refinement. METHODS: Serum and cerebrospinal fluid (CSF) samples from patients referred to the program of encephalitis and paraneoplastic syndrome of Peking Union Medical College Hospital were tested with indirect immunofluorescence. Clinical information of patients with anti-GABA B R antibody positivity was retrospectively reviewed, and descriptive statistical analysis was performed. RESULTS: All eighteen anti-GABA B R antibody-positive cases had limbic syndromes, and electroencephalogram (EEG) or neuroimaging evidence fulfilled the diagnostic criteria of LE. Four patients had additional antibodies against Hu in serum and one had anti-N-methyl-d-aspartate receptor antibody in both sera and CSF. Seventeen (17/18) patients presented with new-onset refractory seizure or status epileptics. Twelve (12/18) patients had memory deficits, 11 (11/18) patients had personality change, 7 (7/18) patients had disturbance of consciousness, and 3 (3/18) patients showed cerebellar dysfunction. One patient with LE had progressive motor and sensory polyneuropathy. Lung cancer was detected in 6 (6/18) patients. Ten (10/18) patients showed abnormality in bilateral or unilateral mediotemporal region on magnetic resonance imaging. Ten (10/18) patients had temporal lobe epileptic activity with or without general slowing on EEG. Seventeen patients received immunotherapy and 15 of them showed neurological improvement. Four patients with lung cancer died within 1-12 months due to neoplastic complications. CONCLUSIONS: Our study demonstrates that most Han Chinese patients with anti-GABA B R antibody-associated LE have prominent refractory epilepsy and show neurological improvement on immunotherapy. Patients with underlying lung tumor have a relatively poor prognosis. Testing for anti GABA B R antibodies is necessary for patients with possible LE or new-onset epilepsy with unknown etiology. PMID- 26608982 TI - Comparison of the Developmental Potential and Clinical Results of In Vivo Matured Oocytes Cryopreserved with Different Vitrification Media. AB - BACKGROUND: Oocyte vitrification is widely used throughout the world, but its clinical efficacy is inconsistent and depends on the vitrification media. This study compared the developmental potential and clinical results of in vivo matured oocytes cryopreserved with different vitrification media. METHODS: This retrospective study involved vitrified-warmed oocytes at one in vitro fertilization laboratory. Vitrification media kits comprised the MC kit (ethylene glycol [EG] plus 1,2-propanediol [PROH]), the KT kit (EG plus dimethyl sulphoxide [DMSO]), and the Modified kit (EG plus DMSO and PROH kit). Rates of oocyte survival and subsequent developmental potential were recorded and analyzed. The t test and the Chi-square test were used to evaluate each method's efficacy. RESULTS: Oocyte survival rate was significantly higher for the Modified kit (92.0%) than for the MC kit (88.2%) (P < 0.05) and the KT kit (77.3%) (P < 0.001). The rate of high-quality embryo development in the Modified kit group (35.8%) was significantly higher than in the MC kit group (29.0%) and the KT kit group (28.3%) (P < 0.001). No significant differences were observed in the clinical pregnancy and implantation rates among the MC, KT, and Modified kit groups (37.2% vs. 30.2% vs. 39.6%; 21.9% vs. 18.8% vs. 27.4%, respectively) (P > 0.05). The high-quality embryo rate per warmed oocyte was significantly higher (23.4%) in the Modified kit group than in the other groups (P < 0.001). The embryo utilization and live birth rates per warmed oocyte were the highest in the Modified kit group, but not significantly (P > 0.05). CONCLUSIONS: Modified vitrification media are efficient for oocyte vitrification and, with further verification, may be able to replace commercially available media in future clinical applications. PMID- 26608983 TI - Open and Endovascular Treatment of Trans-Atlantic Inter-Society Consensus II D Aortoiliac Occlusive Lesions: What Determines the Rate of Restenosis? AB - BACKGROUND: Open surgery is the preferred approach for the treatment of type D lesions according to the Trans-Atlantic Inter-Society Consensus (TASC) II guideline, but endovascular solutions also appear to be a valid option in selected patients. The study aimed to identify the risk factors of restenosis after open and endovascular reconstruction of symptomatic TASC II D aortoiliac occlusive lesions (AIOLs). METHODS: Fifty-six patients (82 limbs) who underwent open repair and endovascular treatment (ET) for symptomatic TASC IotaIota D AIOLs between March 2005 and December 2012 were retrospectively reviewed. Baseline characteristics, preoperative and postoperative imaging, and operation procedure reports were reviewed and analyzed. Restenosis after revascularization was assessed by duplex ultrasound or computed tomography angiogram. Kaplan-Meier survival analysis, Log-rank test, and multivariate Cox regression were used to evaluate the relevance between risk factors and patency. RESULTS: The mean duration of follow-up was 42.8 +/- 23.5 months (ranging from 3 to 90 months). Primary patency rates at 1-, 3-, 5-, and 7-year were 93.6%, 89.3%, 87.0%, and 70.3%, respectively. Restenosis after revascularization occurred in 11 limbs. Kaplan-Meier survival analysis and the Log-rank test revealed that diabetes, Rutherford classification >=5 th and concurrent femoropopliteal TASC II type C/D lesions were significantly related to the duration of primary patency. According to the result of Cox regression, diabetes and femoropopliteal TASC IotaIota type C/D lesions were identified as the risk factors for restenosis after revascularization. CONCLUSION: This study demonstrated that diabetes and femoropopliteal TASC IotaIota type C/D lesions are risk factors associated with restenosis after open and ET of TASC II D AIOLs. PMID- 26608984 TI - Clinical Analysis of Intraperitoneal Lymphangioma. AB - BACKGROUND: Intraperitoneal lymphangioma (IL) used to be thought of as a benign lymphatic malformation with a low rate of preoperative diagnosis. This retrospective study aimed to explore the connection between the cysts and clinical manifestation and imaging characteristics, and to study diagnostic confusion, therapeutic principles and potential recurrent reasons, to further enhance the comprehension of this rare disease. METHODS: Here, we retrospectively reviewed 21 patients diagnosed with IL. Age, sex, complaints, physical findings, and imaging features of each patient were documented. The therapies, postoperative complications and treatments were discussed. RESULTS: Symptomatology included eight patients (38%) with intermittent dull pain in the abdomen, and three patients (14%) complained of abdominal persistent pain. The physical examination revealed an abdominal mass in 16 patients (76%), and eight (38%) were reported no discomfort. IL was correctly established preoperatively in 19 patients (90%). Patients were treated using laparotomy, except one who was treated with laparoscopy. Two recurrences were noted during follow-up. CONCLUSIONS: IL should be suspected in any patient with a mobile abdominal mass and surgery is required immediately after discovery of the tumor. PMID- 26608985 TI - Thalidomide Effects in Patients with Hereditary Hemorrhagic Telangiectasia During Therapeutic Treatment and in Fli-EGFP Transgenic Zebrafish Model. AB - BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by recurrent epistaxis, mucocutaneous telangiectasia, and arteriovenous malformations. The efficacy of traditional treatments for HHT is very limited. The aim of this study was to investigate the therapeutic role of thalidomide in HHT patients and the effect in FLI-EGFP transgenic zebrafish model. METHODS: HHT was diagnosed according to Shovlin criteria. Five HHT patients were treated with thalidomide (100 mg/d). The Epistaxis Severity Score (ESS), telangiectasia spots, and hepatic computed tomography angiography (CTA) were used to assess the clinical efficacy of thalidomide. The Fli-EGFP zebrafish model was investigated for the effect of thalidomide on angiogenesis. Dynamic real-time polymerase chain reaction assay, ELISA and Western blotting from patient's peripheral blood mononuclear cells and plasma were used to detect the expression of transforming growth factor beta 3 (TGF-beta3) messenger RNA (mRNA) and vascular endothelial growth factor (VEGF) protein before and after 6 months of thalidomide treatment. RESULTS: The average ESS before and after thalidomide were 6.966 +/- 3.093 and 1.799 +/- 0.627, respectively (P = 0.009). The "telangiectatic spot" on the tongue almost vanished; CTA examination of case 2 indicated a smaller proximal hepatic artery and decreased or ceased hepatic artery collateral circulation. The Fli-EGFP zebrafish model manifested discontinuous vessel development and vascular occlusion (7 of 10 fishes), and the TGF-beta3 mRNA expression of five patients was lower after thalidomide therapy. The plasma VEGF protein expression was down-regulated in HHT patients. CONCLUSIONS: Thalidomide reverses telangiectasia and controls nosebleeds by down regulating the expression of TGF-beta3 and VEGF in HHT patients. It also leads to vascular remodeling in the zebrafish model. PMID- 26608986 TI - Association between Long Interspersed Nuclear Element-1 Methylation and Relative Telomere Length in Wilms Tumor. AB - BACKGROUND: DNA hypomethylation of long interspersed nuclear elements-1 (LINEs-1) occurs during carcinogenesis, whereas information addressing LINE-1 methylation in Wilms tumor (WT) is limited. The main purpose of our study was to quantify LINE-1 methylation levels and evaluate their relationship with relative telomere length (TL) in WT. METHODS: We investigated LINE-1 methylation and relative TL using bisulfite-polymerase chain reaction (PCR) pyrosequencing and quantitative PCR, respectively, in 20 WT tissues, 10 normal kidney tissues and a WT cell line. Significant changes were analyzed by t-tests. RESULTS: LINE-1 methylation levels were significantly lower (P < 0.05) and relative TLs were significantly shorter (P < 0.05) in WT compared with normal kidney. There was a significant positive relationship between LINE-1 methylation and relative TL in WT (r = 0.671, P = 0.001). LINE-1 Methylation levels were significantly associated with global DNA methylation (r = 0.332, P < 0.01). In addition, relative TL was shortened and LINE-1 methylation was decreased in a WT cell line treated with the hypomethylating agent 5-aza-2'-deoxycytidine compared with untreated WT cell line. CONCLUSION: These results suggest that LINE-1 hypomethylation is common and may be linked to telomere shortening in WT. PMID- 26608987 TI - Variants of Interleukin-7/Interleukin-7 Receptor Alpha are Associated with Both Neuromyelitis Optica and Multiple Sclerosis Among Chinese Han Population in Southeastern China. AB - BACKGROUND: Neuromyelitis optica (NMO) and multiple sclerosis (MS) are autoimmune demyelinating diseases of the central nerve system. Interleukin-7 (IL-7) and interleukin-7 receptor alpha (IL-7Ralpha) were proved to be important in the pathogenesis of both diseases because of the roles they played in the differentiations of autoimmune lymphocytes. The variants of both genes had been identified to be associated with MS susceptibility in Caucasian, Japanese and Korean populations. However, the association of these variants with NMO and MS has not been well studied in Chinese Southeastern Han population. Here, we aimed to evaluate the association of six IL-7 variants (rs1520333, rs1545298, rs4739140, rs6993386, rs7816065, and rs2887502) and one variant of IL-7RA (rs6897932) with NMO and MS among Chinese Han population in southeastern China. METHODS: Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MassARRAY system) and Sanger sequencing were used to determine the variants of IL-7 and IL-7RA in 167 NMO patients, 159 MS patients and 479 healthy controls among Chinese Han population in southeastern China. Samples were excluded if the genotyping success rate <90%. RESULTS: Statistical differences were observed in the genotypes of IL-7 rs1520333 in MS patients and IL-7RA rs6897932 in NMO patients, compared with healthy controls (P = 0.035 and 0.034, respectively). There was a statistically significant difference in the genotypes of IL-7 rs2887502 between MS and NMO patients (P = 0.014). And there were statistically significant differences in the rs6897932 genotypes (P = 0.004) and alleles (P = 0.042) between NMO-IgG positive patients and healthy controls. CONCLUSIONS: The study suggested that among Chinese Han population in southeastern China, the variant of IL-7RA (rs6897932) was associated with NMO especially NMO-IgG positive patients while the variant of IL-7 (rs1520333) with MS patients. And the genotypic differences of IL-7 rs2887502 between MS and NMO indicated the different genetic backgrounds of these two diseases. PMID- 26608988 TI - Renal Doppler and Novel Biomarkers to Assess Acute Kidney Injury in a Swine Model of Ventricular Fibrillation Cardiac Arrest. AB - BACKGROUND: Majority of the research on cardiac arrest (CA) have focused on post CA brain injury and myocardial dysfunction, the renal dysfunction and acute kidney injury (AKI) in other critical illnesses after CA have not been well described. This study was designed to assess AKI with renal Doppler and novel AKI biomarkers in a swine model of ventricular fibrillation cardiac arrest (VFCA). METHODS: Thirty healthy piglets were divided into VFCA group (n = 22) and Sham group (n = 8) in a blinded manner. Mean arterial pressure, heart rate, and cardiac output were recorded continuously. Cardiac arrest (CA) was induced by programmed electric stimulation in the VFCA group, and then cardiopulmonary resuscitation was performed. Twenty piglets returned of spontaneous circulation (ROSC) and received intensive care. Blood and urine samples were collected for AKI biomarkers testing, and Color Doppler flow imaging was performed at baseline, 6 h, 12 h, and 24 h, respectively after ROSC. At ROSC 24 h, the animals were sacrificed and a semi-quantitative evaluation of pathologic kidney injury was performed. RESULTS: In the VFCA group, corrected resistive index (cRI) increased from 0.47 +/- 0.03 to 0.64 +/- 0.06, and pulsatility index (PI) decreased from 0.82 +/- 0.03 to 0.68 +/- 0.04 after ROSC. Cystatin C (CysC) in both serum and urine samples increased at ROSC 6 h, but neutrophil gelatinase-associated lipocalin (NGAL) in serum increased to 5.34 +/- 1.68 ng/ml at ROSC 6 h, and then decreased to 3.16 +/- 0.69 ng/ml at ROSC 24 h while CysC increasing constantly. According to the renal histopathology, 18 of 20 animals suffered from kidney injury. The grade of renal injury was highly correlated with RI, cRI, NGAL, and CysC. Linear regression equation was established: Grade of renal injury = 0.002 * serum CysC + 6.489 * PI + 4.544 * cRI - 8.358 (r2 = 0.698, F = 18.506, P < 0.001). CONCLUSIONS: AKI is common in post-CA syndrome. Renal Doppler and novel AKI biomarkers in serum and urine are of significant importance as early predictors of post-CA AKI. PMID- 26608989 TI - Effect of Shen-Fu Injection Pretreatment to Myocardial Metabolism During Untreated Ventricular Fibrillation in a Porcine Model. AB - BACKGROUND: Shen-Fu injection (SFI) can attenuate ischemia-reperfusion injury, protect cardiac function, and improve microcirculation during cardiopulmonary resuscitation. We hypothesized that SFI may also have an influence on myocardial metabolism during ventricular fibrillation (VF). In this study, we used SFI pretreatment prior to VF to discuss the changes of myocardial metabolism and catecholamine (CA) levels during untreated VF, trying to provide new evidence to the protection of SFI to myocardium. METHODS: Twenty-four pigs were divided into three groups: Saline group (SA group), SFI group, and SHAM operation group (SHAM group). Thirty minutes prior to the induction of VF, the SFI group received 0.24 mg/ml SFI through an intravenous injection; the SA group received an equal amount of sodium chloride solution. The interstitial fluid from the left ventricle (LV) wall was collected through the microdialysis tubes during VF. Adenosine diphosphate (ADP), adenosine triphosphate (ATP), and Na + -K + -ATPase and Ca2 + ATPase enzyme activities were measured after untreated VF. Peak-to-trough VF amplitude and median frequency were analyzed for each of these 5-s intervals. RESULTS: The levels of glucose and glutamate were lower after VF in both the SA and SFI groups, compared with baseline, and the levels in the SFI group were higher than those in the SA group. Compared with baseline, the levels of lactate and the lactate/pyruvate ratio increased after VF in both SA and SFI groups, and the levels in the SFI group were lower than those in the SA group. In both the SA and SFI groups, the levels of dopamine, norepinephrine, and epinephrine increased significantly. There were no statistical differences between the two groups. The content of ATP, ADP, and phosphocreatine in the SFI group was higher than those in the SA group. The activity of LV Na + -K + -ATPase was significantly higher in the SFI group than in the SA group. Amplitude mean spectrum area (AMSA) was significantly lower in the SA and SFI groups at 8- and 12-min compared with 4 min. The AMSA in the SFI group was higher than that in the SA group at each time point during untreated VF. CONCLUSIONS: SFI pretreatment can improve myocardial metabolism and reduce energy exhaustion during VF, and it does not aggravate the excessive secretion of endogenous CAs. PMID- 26608990 TI - Na (+) /Ca (2+) Exchanger 3 is Downregulated in the Hippocampus and Cerebrocortex of Rats with Hyperthermia-induced Convulsion. AB - BACKGROUND: Na + /Ca 2+ exchanger (NCX) plays a crucial role in pentylenetetrazol induced convulsion. However, it is unclear whether NCX is critically involved in hyperthermia-induced convulsion. In this study, we examined the potential changes in NCX3 in the hippocampus and cerebrocortex of rats with hyperthermia-induced convulsion. METHODS: Twenty-one Sprague Dawley rats were randomly assigned to control group, convulsion-prone group and convulsion-resistant group (n = 7 in each group). Whole-cell patch-clamp method was used to record NCX currents. Both the Western blotting analysis and immunofluorescence labeling techniques were used to examine the expression of NCX3. RESULTS: NCX currents were decreased in rats after febrile convulsion. Compared to the control group, NCX3 expression was decreased by about 40% and 50% in the hippocampus and cerebrocortex of convulsion prone rats, respectively. Furthermore, the extent of reduction in NCX3 expression seemed to correlate with the number of seizures. CONCLUSIONS: There is a significant reduction in NCX3 expression in rats with febrile convulsions. Our findings also indicate a potential link between NCX3 expression, febrile convulsion in early childhood, and adult onset of epilepsy. PMID- 26608991 TI - Hyperbaric Oxygen and Ginkgo Biloba Extract Ameliorate Cognitive and Memory Impairment via Nuclear Factor Kappa-B Pathway in Rat Model of Alzheimer's Disease. AB - BACKGROUND: Hyperbaric oxygen (HBO) and Ginkgo biloba extract (e.g., EGB 761) were shown to ameliorate cognitive and memory impairment in Alzheimer's disease (AD). However, the exact mechanism remains elusive. The aim of the present study was to investigate the possible mechanisms of HBO and EGB 761 via the function of nuclear factor kappa-B (NF-kappaB) pathway. METHODS: AD rats were induced by injecting beta-amyloid 25-35 into the hippocampus. All animals were divided into six groups: Normal, sham, AD model, HBO (2 atmosphere absolute; 60 min/d), EGB 761 (20 mg.kg-1.d-1 ), and HBO/EGB 761 groups. Morris water maze tests were used to assess cognitive, and memory capacities of rats; TdT-mediated dUTP Nick-End Labeling staining and Western blotting were used to analyze apoptosis and NF kappaB pathway-related proteins in hippocampus tissues. RESULTS: Morris water maze tests revealed that EGB 761 and HBO significantly improved the cognitive and memory ability of AD rats. In addition, the protective effect of combinational therapy (HBO/EGB 761) was superior to either HBO or EGB 761 alone. In line, reduced apoptosis with NF-kappaB pathway activation was observed in hippocampus neurons treated by HBO and EGB 761. CONCLUSIONS: Our results suggested that HBO and EGB 761 improve cognitive and memory capacity in a rat model of AD. The protective effects are associated with the reduced apoptosis with NF-kappaB pathway activation in hippocampus neurons. PMID- 26608992 TI - Effect of Culture Supernatant Derived from Trichophyton Rubrum Grown in the Nail Medium on the Innate Immunity-related Molecules of HaCaT. AB - BACKGROUND: Trichophyton rubrum is superficial fungi characteristically confined to dead keratinized tissues. These observations suggest that the soluble components released by the fungus could influence the host immune response in a cell in contact-free manner. Therefore, this research aimed to analyze whether the culture supernatant derived from T. rubrum grown in the nail medium could elicit the immune response of keratinocyte effectively. METHODS: The culture supernatants of two strains (T1a, T XHB ) were compared for the beta-glucan concentrations and their capacity to impact the innate immunity of keratinocytes. The beta-glucan concentrations in the supernatants were determined with the fungal G-test kit and protein concentrations with bicinchoninic acid protein quantitative method, then HaCaT was stimulated with different concentrations of culture supernatants by adopting morphological method to select a suitable dosage. Expressions of host defense genes were assessed by quantitative polymerase chain reaction after the HaCaT was stimulated with the culture supernatants. Data were analyzed with one-way analysis of variance, followed by the least significant difference test. RESULTS: The T. rubrum strains (T1a and T XHB ) released beta-glucan of 87.530 +/- 37.581 pg/ml and 15.747 +/- 6.453 pg/ml, respectively into the media. The messenger RNA (mRNA) expressions of toll-like receptor-2 (TLR2), TLR4, and CARD9 were moderately up-regulated in HaCaT within 6 h applications of both supernatants. HaCaT cells were more responsive to T1a than T XHB . The slight increase of dendritic cells-specific intercellular adhesion molecule 3-grabbing nonintegrin expression was faster and stronger, induced by T1a supernatant than T XHB . The moderate decreases of RNase 7, the slight up regulations of Dectin-1 and interleukin-8 at the mRNA level were detected only in response to T1a rather than T XHB . After a long-time contact, all the elevated defense genes decreased after 24 h. CONCLUSION: The culture supernatant of T. rubrum could directly and transiently activate the innate immune response of keratinocytes. PMID- 26608993 TI - Helicobacter Pylori and Gastric Cancer: Clinical Aspects. AB - OBJECTIVE: Although Helicobacter pylori (H. pylori) is considered as the main etiological factor for gastric cancer, the strategy of screening and treating the oncogenic bacterium is still controversial. The objective was to evaluate the status and progress of the cognition about the relationship between H. pylori infection and gastric cancer from a clinical aspect. DATA SOURCES: The data used in this review were mainly from the PubMed articles published in English from 1984 to 2015. STUDY SELECTION: Clinical research articles were selected mainly according to their level of relevance to this topic. RESULTS: Gastric cancer is the fifth most common malignancy and the third leading cause of cancer deaths worldwide. The main etiological factor for gastric cancer is H. pylori infection. About 74.7-89.0% gastric cancer was related to H. pylori infection. Up to date, some regional gastric cancer prevention programs including the detection and treatment of H. pylori infection are under way. Current data obtained from the randomized controlled trials suggest that population-based H. pylori screening and treatment is feasible and cost-effective in preventing gastric cancer; however, a population-based H. pylori eradication campaign would potentially lead to bacterial resistance to the corresponding antibiotics, as well as a negative impact on the normal flora. CONCLUSIONS: The important questions of feasibility, program costs, appropriate target groups for intervention, and the potential harm of mass therapy with antibiotics must first be answered before implementing any large-scale program. PMID- 26608994 TI - A Study on the Connection between the Incidence of Postherpetic Neuralgia and Serum Ionized Calcium. PMID- 26608995 TI - A Novel Semi-rigid Nephroscope Percutaneous Nephrolithotomy: The Best Therapy for Renal Staghorn Calculi. PMID- 26608996 TI - Neuromyelitis Optica Spectrum Disorder Associated with Cervical Spondylosis. PMID- 26608997 TI - Male Paraurethral Duct Infection and Subsequent Paraurethral Duct Dilation. PMID- 26608998 TI - Peripheral Pulmonary Emboli Detected by Radial Probe Endobronchial Ultrasound. PMID- 26608999 TI - Spontaneous Ureteropelvic Junction Rupture Caused by a Small Distal Ureteral Calculus. PMID- 26609000 TI - Euthyrox Induced Drug Rash in an Aged Patient. PMID- 26609001 TI - Dermatopathic Lymphadenitis. PMID- 26609002 TI - Rational Study Design is Important for Assessing Myocardial Protection of Anesthetics. PMID- 26609003 TI - Youth Group Engagement in Noncompliant Communities During Supplemental Immunization Activities in Kaduna, Nigeria, in 2014. AB - INTRODUCTION: One of the major challenges being faced in the Global Polio Eradication Initiative program is persistent refusal of oral polio vaccine (OPV) and harassment of vaccination team members by youths. The objective of the study was to describe the strategy of collaborating with recognized youth groups to reduce team harassment during vaccination campaigns and improve vaccination coverage in noncompliant communities. METHODS: We assessed data from polio vaccination activities in OPV-refusing communities in the Igabi and Zaria local government areas (LGAs) of Kaduna State in Nigeria. We evaluated the following factors to determine trends: enhanced independent monitoring data on the proportion of children missed by vaccination activities (hereafter, "missed children"), lot quality assurance surveys, and vaccination team harassment. RESULTS: The proportion of missed children decreased in both LGAs after the intervention. In Igabi LGA and Zaria LGA, the lowest proportions of missed children before and after the intervention decreased from 7% to 2% and from 5% to 1%, respectively. Lot quality assurance survey trends showed an improvement in immunization coverage 1 year after youth groups' engagement in both LGAs. CONCLUSIONS: Systematic engagement of youth groups has a great future in polio interruption as we approach the endgame strategy for polio eradication. It promises to be a veritable innovation in reaching chronically missed children in OPV-refusing communities. PMID- 26609004 TI - Tracking Vaccination Teams During Polio Campaigns in Northern Nigeria by Use of Geographic Information System Technology: 2013-2015. AB - INTRODUCTION: Nigeria is among the 3 countries in which polio remains endemic. The country made significant efforts to reduce polio transmission but remains challenged by poor-quality campaigns and poor team performance in some areas. This article demonstrates the application of geographic information system technology to track vaccination teams to monitor settlement coverage, reduce the number of missed settlements, and improve team performance. METHODS: In each local government area where tracking was conducted, global positioning system enabled Android phones were given to each team on a daily basis and were used to record team tracks. These tracks were uploaded to a dashboard to show the level of coverage and identify areas missed by the teams. RESULTS: From 2012 to June 2015, tracking covered 119 immunization days. A total of 1149 tracking activities were conducted. Of these, 681 (59%) were implemented in Kano state. There was an improvement in the geographic coverage of settlements and an overall reduction in the number of missed settlements. CONCLUSIONS: The tracking of vaccination teams provided significant feedback during polio campaigns and enabled supervisors to evaluate performance of vaccination teams. The reports supported other polio program activities, such as review of microplans and the deployment of other interventions, for increasing population immunity in northern Nigeria. PMID- 26609006 TI - On Sonder. PMID- 26609005 TI - Transient Hyperglycemia in Patients With Tuberculosis in Tanzania: Implications for Diabetes Screening Algorithms. AB - BACKGROUND: Diabetes mellitus (DM) increases tuberculosis risk while tuberculosis, as an infectious disease, leads to hyperglycemia. We compared hyperglycemia screening strategies in controls and patients with tuberculosis in Dar es Salaam, Tanzania. METHODS: Consecutive adults with tuberculosis and sex- and age-matched volunteers were included in a case-control study between July 2012 and June 2014. All underwent DM screening tests (fasting capillary glucose [FCG] level, 2-hour CG [2-hCG] level, and glycated hemoglobin A1c [HbA1c] level) at enrollment, and cases were tested again after receipt of tuberculosis treatment. Association of tuberculosis and its outcome with hyperglycemia was assessed using logistic regression analysis adjusted for sex, age, body mass index, human immunodeficiency virus infection status, and socioeconomic status. Patients with tuberculosis and newly diagnosed DM were not treated for hyperglycemia. RESULTS: At enrollment, DM prevalence was significantly higher among patients with tuberculosis (n = 539; FCG level > 7 mmol/L, 4.5% of patients, 2-hCG level > 11 mmol/L, 6.8%; and HbA1c level > 6.5%, 9.3%), compared with controls (n = 496; 1.2%, 3.1%, and 2.2%, respectively). The association between hyperglycemia and tuberculosis disappeared after tuberculosis treatment (adjusted odds ratio [aOR] for the FCG level: 9.6 [95% confidence interval {CI}, 3.7-24.7] at enrollment vs 2.4 [95% CI, .7-8.7] at follow-up; aOR for the 2-hCG level: 6.6 [95% CI, 4.0-11.1] vs 1.6 [95% CI, .8-2.9]; and aOR for the HbA1c level, 4.2 [95% CI, 2.9-6.0] vs 1.4 [95% CI, .9-2.0]). Hyperglycemia, based on the FCG level, at enrollment was associated with tuberculosis treatment failure or death (aOR, 3.3; 95% CI, 1.2-9.3). CONCLUSIONS: Transient hyperglycemia is frequent during tuberculosis, and DM needs confirmation after tuberculosis treatment. Performance of DM screening at tuberculosis diagnosis gives the opportunity to detect patients at risk of adverse outcome. PMID- 26609007 TI - Specialised commissioning for severe asthma: oxymoron or opportunity? PMID- 26609009 TI - Can ovarian suppression with gonadotropin-releasing hormone analogs (GnRHa) preserve fertility in cancer patients? PMID- 26609012 TI - Group work: Facilitating the learning of international and domestic undergraduate nursing students. AB - BACKGROUND: Devising innovative strategies to address internationalization is a contemporary challenge for universities. A Participatory Action Research (PAR) project was undertaken to identify issues for international nursing students and their teachers. The findings identified group work as a teaching strategy potentially useful to facilitate international student learning. METHODS: The educational intervention of structured group work was planned and implemented in one subject of a Nursing degree. Groups of four to five students were formed with one or two international students per group. Structural support was provided by the teacher until the student was learning independently, the traditional view of scaffolding. The group work also encouraged students to learn from one another, a contemporary understanding of scaffolding. Evaluation of the group work teaching strategy occurred via anonymous, self-completed student surveys. The student experience data were analysed using descriptive statistical techniques, and free text comments were analysed using content analysis. RESULTS: Over 85% of respondents positively rated the group work experience. Overwhelmingly, students reported that class discussions and sharing nursing experiences positively influenced their learning and facilitated exchange of knowledge about nursing issues from an international perspective. DISCUSSION: This evaluation of a structured group work process supports the use of group work in engaging students in learning, adding to our understanding of purposeful scaffolding as a pathway to enhance learning for both international and domestic students. By explicitly using group work within the curriculum, educators can promote student learning, a scholarly approach to teaching and internationalization of the curriculum. PMID- 26609008 TI - Does Gleason score at initial diagnosis predict efficacy of abiraterone acetate therapy in patients with metastatic castration-resistant prostate cancer? An analysis of abiraterone acetate phase III trials. AB - BACKGROUND: The usefulness of Gleason score (<8 or >=8) at initial diagnosis as a predictive marker of response to abiraterone acetate (AA) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) was explored retrospectively. PATIENTS AND METHODS: Initial diagnosis Gleason score was obtained in 1048 of 1195 (COU-AA-301, post-docetaxel) and 996 of 1088 (COU-AA 302, chemotherapy-naive) patients treated with AA 1 g plus prednisone 5 mg twice daily by mouth or placebo plus prednisone. Efficacy end points included radiographic progression-free survival (rPFS) and overall survival (OS). Distributions and medians were estimated by Kaplan-Meier method and hazard ratio (HR) and 95% confidence interval (CI) by Cox model. RESULTS: Baseline characteristics were similar across studies and treatment groups. Regardless of Gleason score, AA treatment significantly improved rPFS in post-docetaxel [Gleason score <8: median, 6.4 versus 5.5 months (HR = 0.70; 95% CI 0.56-0.86), P = 0.0009 and Gleason score >=8: median, 5.6 versus 2.9 months (HR = 0.58; 95% CI 0.48-0.72), P < 0.0001] and chemotherapy-naive patients [Gleason score <8: median, 16.5 versus 8.2 months (HR = 0.50; 95% CI 0.40-0.62), P < 0.0001 and Gleason score >=8: median, 13.8 versus 8.2 months (HR = 0.61; 95% CI 0.49-0.76), P < 0.0001]. Clinical benefit of AA treatment was also observed for OS, prostate specific antigen (PSA) response, objective response and time to PSA progression across studies and Gleason score subgroups. CONCLUSION: OS and rPFS trends demonstrate AA treatment benefit in patients with pre- or post-chemotherapy mCRPC regardless of Gleason score at initial diagnosis. The initial diagnostic Gleason score in patients with mCRPC should not be considered in the decision to treat with AA, as tumour metastases may no longer reflect the histology at the time of diagnosis. CLINICAL TRIALS NUMBER: COU-AA-301 (NCT00638690); COU-AA-302 (NCT00887198). PMID- 26609011 TI - Residents' and attendings' perceptions of a night float system in an internal medicine program in Canada. AB - BACKGROUND: The Night Float system (NFS) is often used in residency training programs to meet work hour regulations. The purpose of this study was to examine resident and attendings' perceptions of the NFS on issues of resident learning, well-being, work, non-educational activities and the health care system (patient safety and quality of care, inter-professional teams, workload on attendings and costs of on-call coverage). METHODS: A survey questionnaire with closed and open ended questions (26 residents and eight attendings in an Internal Medicine program), informal discussions with the program and moonlighting and financial data were collected. RESULTS AND DISCUSSION: The main findings included, (i) an overall congruency in opinions between resident and attendings across all mean comparisons, (ii) perceptions of improvement for most aspects of resident well being (e.g. stress, fatigue) and work environment (e.g. supervision, support), (iii) a neutral effect on the resident learning environment, except resident opinions on an increase in opportunities for learning, (iv) perceptions of improved patient safety and quality of care despite worsened continuity of care, and (v) no increases in work-load on attendings or the health care system (cost neutral call coverage). Patient safety, handovers and increased utilization of moonlighting opportunities need further exploration. PMID- 26609013 TI - Improving health literacy of women about iron deficiency anemia and civic responsibility of students through service learning. AB - BACKGROUND: Service-learning (S-L) is an educational approach that integrates community service with academic learning. S-L helps educate youth about their civic role and responsibility in society, and empowers them to tackle societal problems, strengthening communities through civic engagement. The objectives of this study were to demonstrate the effectiveness of S-L in fostering civic responsibility and communication skills in college students and to increase health literacy regarding iron-deficiency anemia (IDA) among both students and community women. METHODS: This interventional exploratory study used a mixed methods approach. Thirteen first-year students from a women's college participated in the project. The authors held small interactive group sessions to teach the students about IDA and communication skills. A questionnaire measured the students' perceived knowledge about civic responsibility, communication skills, and IDA. The students then developed and delivered a health education campaign for sixty five community women and measured changes in the women's health literacy about IDA. A focus group discussion was conducted to collect students' reflections after the S-L experience. The changes in the civic responsibility and communication skills were determined by Wilcoxon rank test, while health literacy in women by a McNemar test. RESULTS: Students showed significant improvement in all three constructs of civic responsibility and in perceptions of their communication skills. Increases in civic responsibility and in acquisition of knowledge emerged as the main themes of the focus group discussion with students. The community women showed substantial improvement in health literacy of IDA. DISCUSSION: In this study, S-L achieves two purposes: (a) Increases students' knowledge of health topics, their sense of civic responsibility and improves their communication skills, and (b) educates women in the community about common and preventable health issues. PMID- 26609014 TI - Application of Kern's Six-step approach to curriculum development by global health residents. AB - BACKGROUND: Global health practitioners have a responsibility to deliver appropriate and effective health education to patients and families. We demonstrate how residents in a global health elective can utilize Kern's six-step approach to develop educational products for patients and their families. METHODS: Residents completed a pre-curricular survey of knowledge, skills and attitudes regarding curriculum development. Kern's six-steps were introduced through a series of lectures; workshop exercises highlighted the application of each step: (i) Problem identification and general needs assessment, (ii) targeted needs assessment, (iii) goals and objectives, (iv) educational strategies, (v) implementation and (vi) evaluation and feedback. Residents used the six-steps to develop health education projects they subsequently implemented locally and abroad. Reflective exercises were conducted after utilization of each of the six steps. Residents also completed a post-curricular assessment of knowledge, skills and attitudes regarding curriculum development. RESULTS: Mean scores on pre- and post-curricular self-assessment of knowledge were 18 and 26.5 (out of 28); skills 19.8 and 33.5 (out of 35); and attitudes 13.3 and 19.8 (out of 21), respectively. Reflective exercises highlighted resident sentiment that the six steps enabled them to be more thoughtful of the interventions they were undertaking in communities locally and abroad. They were impressed how the model allowed them to ensure their goals were aligned with those of patients and their families, fully engage their audience and effectively implement the curricula. DISCUSSION: Kern's six-step approach to curriculum development is an effective method for global health residents to develop educational products for patients and families. PMID- 26609015 TI - Higher acceptance rates for abstracts written in English at a national research student meeting in a non-English speaking country. AB - BACKGROUND: The rate of English-written submissions is increasing in local meetings of non-English speaking countries. However, it seems that the quality of research and methodology of the studies has not progressed. This study aimed to evaluate the association of English writing and the acceptance for presentation following the peer-review process in the 13th Annual Research Congress of Iran's Medical Sciences Students (ARCIMSS). METHODS: All 1817 complete abstracts submitted to the meeting were included in this cross-sectional study. Each was evaluated for the language of the text (English or Persian), final decision after peer review (accepted vs. rejected), presentation type (oral, poster discussion and poster) and the scores of reviewing process. RESULTS: There were 395 (21.7%) abstracts written in English and 1422 (78.3%) in Persian. The acceptance rate for English abstracts was 33.7% and for Persian 24.6% (OR = 1.56, 95% CI: 1.22-1.98). The rate of abstracts' acceptance for presentation in oral panels was significantly higher for English abstracts than for those in Persian (25.6% versus 15.7%, OR = 1.84, 95% CI: 1.14-2.99). By contrast, Persian abstracts were more likely to be accepted as poster panels than were English abstracts (74.9% versus 63.9%, OR = 1.68, 95% CI: 1.10-2.58). DISCUSSION: English-written abstracts have higher chance of acceptation in a non-English speaker country like Iran. PMID- 26609016 TI - Ongoing faculty development for peer tutors: A widely neglected need. PMID- 26609017 TI - Hand hygiene and health care hierarchy by year of medical education. PMID- 26609018 TI - Medical students hanging by a thread. PMID- 26609019 TI - Knowledge, attitude and practices of evidence-based medicine among Sudanese medical doctors. PMID- 26609020 TI - Evidence-based practice among physiotherapy practitioners in Mumbai, India. PMID- 26609021 TI - Distance training of medical laboratory professionals in Sub-Saharan Africa: Concern over assessment method. PMID- 26609022 TI - Snake bite: emulating the Indian model might help save thousands of lives. PMID- 26609023 TI - Is Admission to the Intensive Care Unit Associated With Chronic Opioid Use? A 4 Year Follow-Up of Intensive Care Unit Survivors. AB - PURPOSE: To describe opioid use before and after intensive care unit (ICU) admission and to identify factors associated with chronic opioid use upto 4 years after ICU discharge. METHODS: Retrospective review of adult patients admitted to the ICU at a tertiary care center between January 1, 2005, to December 31, 2008. We defined "nonuser," "intermittent," and "chronic" opioid status by abstinence, use in <70%, and >70% of days for a given time period, respectively. We assessed opioid use at 3 months prior to ICU admission, at discharge, and annually for upto 4 years following ICU discharge. RESULTS: A total of 2595 ICU patients were included for surgical (48.6%), medical (38.4%), and undetermined (13%) indications. The study population included both elective (26.9%) and emergent (73.1%) admissions. Three months prior to ICU admission, 76.9% were nonusers, 16.9% used opioids intermittently, and 6.2% used opioids chronically. We found an increase in nonuser patients from 87.8% in the early post-ICU period to 95.6% at 48-month follow-up. Consequently, intermittent and chronic opioid use dropped to 8.6% and 3.6% at discharge and 2.6% and 1.8% at 48-month follow-up, respectively. Prolonged hospital length of stay was associated with chronic opioid use. CONCLUSION: Admission to ICU and duration of ICU stay were not associated with chronic opioid use. PMID- 26609024 TI - Dignity--a fundamental principle of mental health care. PMID- 26609025 TI - Mobile mental health care--an opportunity for India. PMID- 26609026 TI - Cancer stem cells in hepatocellular carcinomas. PMID- 26609027 TI - Pain relief during minor procedures: a challenge for gynaecologists. PMID- 26609029 TI - The need for better evidence to evaluate the health & economic benefits of India's Rashtriya Swasthya Bima Yojana. AB - In this review the existing evidence on the impact of Rashtriya Swasthya Bima Yojana (RSBY) is discussed in the context of international literature available on health insurance. We describe potential pathways through which health insurance can affect health and economic outcomes, discuss evidence from other developing countries, and identify potential biases and inconsistencies in existing studies on RSBY impact. Given the relatively recent introduction of RSBY, lack of quality, verifiable data on utilization patterns, and the absence of reliable evaluation studies, there is a need to exercise caution while assessing the merits of the programme. Considering the enormous potential and cost of the programme, we emphasize the need for a rigorous impact evaluation of RSBY. It will not only help capture the real impact of the scheme, but may also be able to estimate the extent of systemic inefficiencies at the level of the consumer. PMID- 26609028 TI - Alzheimer's disease: Unique markers for diagnosis & new treatment modalities. AB - Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease. In humans, AD becomes symptomatic only after brain changes occur over years or decades. Three contiguous phases of AD have been proposed: (i) the AD pathophysiologic process, (ii) mild cognitive impairment due to AD, and (iii) AD dementia. Intensive research continues around the world on unique diagnostic markers and interventions associated with each phase of AD. In this review, we summarize the available evidence and new therapeutic approaches that target both amyloid and tau pathology in AD and discuss the biomarkers and pharmaceutical interventions available and in development for each AD phase. PMID- 26609030 TI - Cancer stem cells in hepatocellular carcinoma--an immunohistochemical study with histopathological association. AB - BACKGROUND & OBJECTIVES: Cancer stem cells (CSCs) may be responsible for tumour recurrence and resistance to chemotherapy in hepatocellular carcinoma (HCC). This study was carried out to evaluate the association between histological parameters and liver CSCs (LCSC) in HCC, and to compare distribution of liver CSCs in HCC associated with and without hepatitis B virus (HBV) infection. METHODS: Seventy nine tumours (49 surgical resections from 46 patients, and 30 from autopsy) were reviewed. Immunohistochemical staining for the LCSC marker EpCAM (epithelial cell adhesion molecule), liver progenitor cell (LPC) markers CK19 (cytokeratin 19) and neural cell adhesion molecule (NCAM) were performed and were associated with histological features of tumour behaviour. RESULTS: Thirty three tumours (41.8%) showed positive staining for EpCAM. CK19 and NCAM expression were seen in 26 (32.9%) and four (5.1%) tumours, respectively. The expression of EpCAM and CK19 was significantly associated with each other ( P<0.001). EpCAM expression was significantly associated with clinical and histological features indicating aggressive tumour behaviour, including younger age of onset, higher serum alpha foetoprotein (AFP) levels, tumour cell dedifferentiation, increased mitotic activity, and vascular invasiveness. There was no significant difference in expression of EpCAM, CK19 and NCAM between HBV positive and negative HCC. INTERPRETATION & CONCLUSIONS: The LCSC marker EpCAM was expressed in less than half of HCC, was independent of HBV aetiology, and was strongly associated with clinical and histological features of aggressive tumour behaviour. Positive staining for CK19 suggests a possible LPC origin of the EpCAM positive HCCs. PMID- 26609031 TI - Effect of paracetamol, dexketoprofen trometamol, lidocaine spray, pethidine & diclofenac sodium application for pain relief during fractional curettage: A randomized controlled trial. AB - BACKGROUND & OBJECTIVES: Patients frequently experience pain of moderate to severe degree during gynaecologic procedures. This prospective, randomized, placebo-controlled trial was aimed to investigate the analgesic efficacy of preoperative oral dexketoprofen trometamol, intravenous paracetamol, lidocaine spray, pethidine and diclofenac sodium on fractional curettage procedure. METHODS: A total of 144 multiparous women were randomly allocated to one of the six groups. The first group (control group) consisted of 22 participants and they did not receive any treatment. The second group had 26 participants receiving oral 25 mg dexketoprofen trometamol. The 23 participants of the third group received two puff lidocaine sprays on cervical mucosa. t0 he forth group consisted of 25 participants receiving 100 mg pethidine. In the fifth group, the 23 participants received 1000 mg intravenous paracetamol and the sixth group consisted of 25 participants receiving diclofenac sodium. RESULTS: Pethidine was the best choice for reducing pain score during curettage procedure (t2:intra operative). All analgesic procedures were significantly effective in reducing pain during postoperative period (t3). Significant pain reduction was achieved for both intra- and postoperative period by using analgesics. INTERPRETATION & CONCLUSIONS: The results of our study showed that lidocaine puffs provided the best pain relief than the other analgesics used. Therefore, lidocaine may be considered as the first choice analgesic in fractional curettage (NCT ID: 01993589). PMID- 26609032 TI - Regulation of T cell lineage commitment by SMAR1 during inflammatory & autoimmune diseases. AB - BACKGROUND & OBJECTIVES: CD4 + T cells are involved in abnormal inflammatory responses causing adverse effects to the body. Th17 cells play a major role in immune disorders and the exact mechanism by which CD4 + T cells regulate its effector Th1 and Th17 phenotype at chromatin level is not clearly understood. This study was aimed to understand the role of matrix associated region (MAR) binding protein SMAR1 (scaffold/matrix attachment region binding protein 1) in T cell differentiation during inflammatory and autoimmune condition using SMAR1 transgenic mice as model. METHODS: Wild type (C57BL/6J) and SMAR1 transgenic mice were used for isolation of T cells and further identification of different T cell lineages, along with histological analysis. Further, we studied autoimmune and inflammatory diseases using chemically induced and T cell transfer model of colitis and rheumatoid arthritis to better understand the role of SMAR1 in immune responses. RESULTS: SMAR1 transgenic mice were resistant to dextran sodium sulphate (DSS) induced colitis with decreased expression of Th1 and Th17 specific cytokines. Overexpression of SMAR1 repressed Th17 response by negatively regulating RORgammat and IL-17 expression. Downregulation of SMAR1 upregulated signal transducer and activator of transcription 3 (pSTAT3) and IL-17 expression that caused generation of more proinflammatory Th1 and Th17 cells leading to inflammation and disease. INTERPRETATION & CONCLUSIONS: Our results show an important role of SMAR1 in regulating CD4 + T cell differentiation during inflammatory disorders via regulation of both Th1 and Th17 signaling pathways. This study reveals a critical role of SMAR1 in maintaining the proinflammatory immune responses by repressing Th1 and Th17 cell function and it gives the novel insight into immune regulatory mechanisms. PMID- 26609033 TI - Novel mutations of the arylsulphatase B (ARSB) gene in Indian patients with mucopolysaccharidosis type VI. AB - BACKGROUND & OBJECTIVES: Mucopolysaccharidosis type VI (MPS VI) is a rare, autosomal recessive lysosomal storage disorder caused by deficient enzymatic activity of N-acetyl galactosamine-4-sulphatase resulting from mutations in the arylsulphatase B (ARSB) gene. The ARSB gene is located on chromosome 5q11-q13 and is composed of eight exons. More than hundred ARSB mutations have been reported so far, but the mutation spectrum of MPS VI in India is still unknown. Hence, the aim of the present study was to identify the mutational spectrum in patients with MPS VI in India and to study the genotype-phenotype association and functional outcomes of these mutations. METHODS: Molecular characterization of the ARSB gene by Sanger sequencing was done for 15 patients (aged 15 months to 11 yr) who were enzymatically confirmed to have MPS VI. Age of onset, clinical progression and enzyme activity levels in each patient were studied to look for genotype phenotype association. Haplotype analysis performed for unrelated patients with the recurring mutation W450C, was suggestive of a founder effect. Sequence and structural analyses of the ARSB protein using standard software were carried out to determine the impact of detected mutations on the function of the ARSB protein. RESULTS: A total of 12 mutations were identified, of which nine were novel mutations namely, p.D53N, p.L98R, p.Y103SfsX9, p.W353X, p.H393R, p.F166fsX18, p.I220fsX5, p.W450L, and p.W450C, and three were known mutations (p.D54N, p.A237D and p.S320R). The nine novel sequence variants were confirmed not to be polymorphic variants by performing sequencing in 50 unaffected individuals from the same ethnic population. INTERPRETATION & CONCLUSIONS: Nine novel mutations were identified in MPS VI cases from India in the present study. The study also provides some insights into the genotype-phenotype association in MPS VI. PMID- 26609034 TI - Haematological profile of 21 patients with hairy cell leukaemia in a tertiary care centre of north India. AB - BACKGROUND & OBJECTIVES: Hairy cell leukaemia (HCL) is a B cell neoplasm which constitutes around 2 per cent of all the lymphoid leukaemias. It has a characteristic morphology and immunophenotypic profile. It is important to distinguish HCL from other B cell lymphoproliferative disorders due to availability of different chemotherapeutic agents. This study presents clinical, haematological and immunophenotypic profile of patients with HCL seen over a period of four years in a tertiary care hospital in north India. METHODS: Twenty one cases of hairy cell leukaemia were analyzed for their clinical details, haemogram, bone marrow examination and immunophenotypic findings. RESULTS: Age of the patients ranged from 28-76 yr with male predominance. Weakness and fever were commonest presentations. Splenomegaly, hepatomegaly, lymphadenopathy were seen in decreasing order of frequency. Anaemia was noted in all 21 patients, leukopenia in 15 and thrombocytopenia in 19 cases. Fourteen patients were pancytopenic. Bone marrow examination showed typical hairy cells in all cases. Immunophenotyping showed expression of CD19, CD20, CD103, CD25 and CD11c in all cases, while positivity was seen for CD79b in 93.7 per cent, kappa light chain restriction in 60 per cent and lambda in 40 per cent cases. Notably, 20 per cent showed CD10 and 12 per cent showed CD23 expression. INTERPRETATION & CONCLUSIONS: This study reveals some unusual findings in otherwise classical disease entity, like absence of palpable spleen, presence of lymphadenopathy, normal or elevated leukocyte counts, expression of CD10, which at times could be diagnostically challenging. PMID- 26609035 TI - Relation of serum 25 hydroxyvitamin D levels to bone mineral density in southern Chinese postmenopausal women: A preliminary study. AB - BACKGROUND & OBJECTIVES: Vitamin D insufficiency is prevalent in postmenopausal women and has been related to low bone mineral density (BMD). However, controversial results have been reported for the relationship between serum 25 hydroxyvitamin D [25(OH)D] levels and BMD. This study was done to investigate whether serum 25(OH)D levels were associated with BMD in postmenopausal women living in Guangzhou in southern China. METHODS: This cross-sectional study involved 119 asymptomatic postmenopausal women, aged 48-85 yr, who were consecutively selected from Guangzhou city. BMD was measured at the lumbar spine and femoral neck. The correlation between serum 25(OH)D levels and BMD wes investigated. RESULTS: With increasing serum 25(OH)D levels categorized as <20, 20-30, and >= 30ng/ml, the PTH levels decreased gradually ( P=0.031). Bivariate correlation analyses showed an inverse relationship between serum 25(OH)D and PTH levels after controlling for age and BMI (r=-0.209, P=0.023). Although subjects with vitamin D<30 ng/ml had significantly lower BMD, age- and BMI-adjusted serum 25(OH)D was weakly correlated with BMD at femoral neck (r=0.185, P0.045), and not at lumbar spine (r=0.172, p =0 0.063). In multiple regression analyses, serum 25(OH)D was a predictor for BMD at femoral neck (R 2= 0.424). However, serum beta CTX was a determinant for BMD at lumbar spine (R 2= 0.361). INTERPRETATION & CONCLUSIONS: Serum 25(OH)D levels showed a positive correlation with BMD at femoral neck and serum beta-CTX levels were inversely correlated with BMD at lumbar spine in postmenopausal women. Further studies are needed to elucidate the clinical impact of these findings. PMID- 26609036 TI - A study on the characterization of Propionibacterium acnes isolated from ocular clinical specimens. AB - BACKGROUND & OBJECTIVES: There are only a few reports available on characterization of Propionibacterium acnes isolated from various ocular clinical specimens. We undertook this study to evaluate the role of P. acnes in ocular infections and biofilm production, and also do the phylogenetic analysis of the bacilli. METHODS: One hundred isolates of P. acnes collected prospectively from ocular clinical specimens at a tertiary care eye hospital between January 2010 and December 2011, were studied for their association with various ocular disease conditions. The isolates were also subjected to genotyping and phylogenetic analysis, and were also tested for their ability to produce biofilms. RESULTS: Among preoperative conjunctival swabs, P. acnes was a probably significant pathogen in one case; a possibly significant pathogen in two cases. In other clinical conditions, 13 per cent isolates were probably significant pathogens and 38 per cent as possibly significant pathogens. The analysis of 16S rRNA gene revealed four different phylogenies whereas analysis of recA gene showed two phylogenies confirming that recA gene was more reliable than 16S rRNA with less sequence variation. Results of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) had 100 per cent concordance with phylogenetic results. No association was seen between P. acnes subtypes and biofilm production. INTERPRETATION & CONCLUSIONS: RecA gene phylogenetic studies revealed two different phylogenies. RFLP technique was found to be cost-effective with high sensitivity and specificity in phylogenetic analysis. No association between P. acnes subtypes and pathogenetic ability was observed. Biofilm producing isolates showed increased antibiotic resistance compared with non-biofilm producing isolates. PMID- 26609037 TI - Effects of whole body vibration on hormonal & functional indices in patients with multiple sclerosis. AB - BACKGROUND & OBJECTIVES: Multiple sclerosis (MS) is a neurodegenerative disease, which affects the patients' mobility, and exercise training is considered to be beneficial for these patients. The aim of this study was to determine the effects of 10 wk of low intensity exercise and whole body vibration (WBV) training on fatigue, quality of life, functional and physical indices, and serum levels of ghrelin, leptin, and testosterone in MS patients. METHODS: Thirty four MS patients with mild to moderate disability were recruited and randomly divided into two groups, the training group (n=17) and control group (n=17). Patients in the training group did low intensity exercise and WBV training programme three times a week for 10 wk. The control group continued their routine life. Intended variables like expanded disability status scale (EDSS), fatigue, quality of life, functional and physical indices consisted of balance, walking speed, functional mobility, functional muscle endurance, and walking endurance, and serum levels of ghrelin, leptin, and testosterone were measured before and after the protocol. RESULTS: Thirty subjects completed the study (23 females, 7 males; mean age =38.80 +/- 9.50 yr). Statistical analysis demonstrated that EDSS in the WBV training group was significantly decreased (P=0.01), balance (P=0.01), and walking endurance significantly increased (P=0.01) in MS patients (P<0.05). INTERPRETATION & CONCLUSIONS: The results suggest that low intensity exercise and WBV training have some beneficial impact on functional and physical indices of MS patients. PMID- 26609038 TI - Persistence of Corynebacterium diphtheriae in Delhi & National Capital Region (NCR). AB - Despite the introduction of mass immunization, diphtheria continues to play a major role as a potentially lethal infectious disease in many countries. Delay in the specific therapy of diphtheria may result in death and, therefore, accurate diagnosis of diphtheria is imperative. This study was carried out at National Centre for Disease Control (NCDC), Delhi, India, on samples of suspected diphtheria cases referred from various government hospitals of Delhi and neighbouring areas during 2012-2014. Primary identification of Corynebacterium diphtheriae was done by standard culture, staining and biochemical tests followed by toxigenicity testing by Elek's test on samples positive for C. diphtheriae. The results showed persistence of toxigenic C. diphtheriae in our community indicating the possibility of inadequate immunization coverage. PMID- 26609039 TI - Potentiation of anti-cholelithogenic influence of dietary tender cluster beans (Cyamopsis tetragonoloba) by garlic (Allium sativum) in experimental mice. AB - BACKGROUND & OBJECTIVES: Dietary fibre-rich tender cluster beans (Cyamopsis tetragonoloba; CB) are known to exert beneficial cholesterol lowering influence. We examined the influence of a combination of dietary tender CB and garlic (Allium sativum) in reducing the cholesterol gallstone formation in mice. METHODS: Cholesterol gallstones were induced in Swiss mice by feeding a high cholesterol diet (HCD) for 10 wk. Dietary interventions were made with 10 per cent CB and 1 per cent garlic included individually or together along with HCD. A total of 100 mice were divided into five groups of 20 mice each. RESULTS: Dietary CB, garlic and CB+garlic reduced the formation of cholesterol gallstones by 44, 25 and 56 per cent, respectively, lowered cholesterol by 23-48, 16-24, and 24-58 in bile, serum, and liver, respectively. Cholesterol saturation index in bile and cholesterol: phospholipid ratio in circulation and hepatic tissue were significantly lowered by these dietary interventions, with highest beneficial effect from CB+garlic. Activities of hepatic cholesterol metabolizing enzymes were modulated by CB, garlic and CB+garlic. Elevation in lipid peroxides caused by HCD was also countered by these dietary interventions, the combination producing the highest effect. INTERPRETATION & CONCLUSIONS: The results showed that the prevention of experimentally induced formation of cholesterol gallstones by dietary CB and garlic was due to decreased biliary cholesterol secretion and increased cholesterol saturation index. In addition of anti-lithogenic effect, dietary CB and garlic in combination had a beneficial antioxidant effect. PMID- 26609040 TI - Real-time reverse transcription-polymerase chain reaction assays for identification of wild poliovirus 1 & 3. AB - BACKGROUND & OBJECTIVES: The poliovirus serotype identification and intratypic differentiation by real-time reverse transcription-polymerase chain reaction (rRT PCR) assay is suitable for serotype mixtures but not for intratypic mixtures of wild and vaccine poliovirus strains. This study was undertaken to develop wild poliovirus 1 and 3 (WPV1 and WPV3) specific rRT-PCR assays for use. METHODS: Specific primers and probes for rRT-PCR were designed based on VP1 sequences of WPV1 and WPV3 isolated in India since 2000. The specificity of the rRT-PCR assays was evaluated using WPV1 and WPV3 of different genetic lineages, non-polio enteroviruses (NPEVs) and mixtures of wild/wild and wild/Sabin vaccine strains. The sensitivity of the assays was determined by testing serial 10-fold dilutions of wild poliovirus 1 and 3 stock suspensions of known titre. RESULTS: No cross reactivity with Sabin strains, intertypic wild poliovirus isolates or 27 types of NPEVs across all the four Enterovirus species was found for both the wild poliovirus 1 and 3 rRT-PCR assays. All WPV1 and WPV3 strains isolated since 2000 were successfully amplified. The rRT-PCR assays detected 10 4.40 CCID 50 /ml of WPV1 and 10 4.00 CCID 50 /ml of WPV3, respectively either as single isolate or mixture with Sabin vaccine strains or intertypic wild poliovirus. INTERPRETATION & CONCLUSIONS: rRT-PCR assays for WPV1 and WPV3 have been validated to detect all the genetic variations of the WPV1 and WPV3 isolated in India for the last decade. When used in combination with the current rRT-PCR assay testing was complete for confirmation of the presence of wild poliovirus in intratypic mixtures. PMID- 26609041 TI - Prevalence & factors associated with chronic obstetric morbidities in Nashik district, Maharashtra. AB - BACKGROUND & OBJECTIVES: In India, community based data on chronic obstetric morbidities (COM) are scanty and largely derived from hospital records. The main aim of the study was to assess the community based prevalence and the factors associated with the defined COM--obstetric fistula, genital prolapse, chronic pelvic inflammatory disease (PID) and secondary infertility among women in Nashik district of Maharashtra State, India. METHODS: The study was cross-sectional with self-reports followed by clinical and gynaecological examination. Six primary health centre areas in Nashik district were selected by systematic random sampling. Six months were spent on rapport development with the community following which household interviews were conducted among 1560 women and they were mobilized to attend health facility for clinical examination. RESULTS: Of the 1560 women interviewed at household level, 1167 women volunteered to undergo clinical examination giving a response rate of 75 per cent. The prevalence of defined COM among 1167 women was genital prolapse (7.1%), chronic PID (2.5%), secondary infertility (1.7%) and fistula (0.08%). Advancing age, illiteracy, high parity, conduction of deliveries by traditional birth attendants (TBAs) and obesity were significantly associated with the occurrence of genital prolapse. History of at least one abortion was significantly associated with secondary infertility. Chronic PID had no significant association with any of the socio demographic or obstetric factors. INTERPRETATION & CONCLUSIONS: The study findings provided an insight in the magnitude of community-based prevalence of COM and the factors associated with it. The results showed that COM were prevalent among women which could be addressed by interventions at personal, social and health services delivery level. PMID- 26609042 TI - First confirmed case of Crimean-Congo haemorrhagic fever from Sirohi district in Rajasthan State, India. PMID- 26609043 TI - Antimicrobial susceptibility pattern of Burkholderia cepacia complex & Stenotrophomonas maltophilia over six years (2007-2012). PMID- 26609044 TI - Round pneumonia. PMID- 26609045 TI - Metastatic Crohn's disease. PMID- 26609046 TI - Donor pretreatment with adenosine monophosphate-activated protein kinase activator protects cardiac grafts from cold ischaemia/reperfusion injury. AB - OBJECTIVES: Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy metabolism and has been shown to be protective in ischaemia/reperfusion injury (IRI). We hypothesized that preactivation of AMPK with an activator before donor heart procurement could protect heart grafts from cold IRI. METHODS: Donor Sprague-Dawley rats were injected intravenously with AMPK activator 5-amino-imidazole-4-carboxamide ribonucleotide (AICAR) or vehicle 30 min before heart procurement. Heart grafts were then preserved in histidine tryptophan-ketoglutarate (HTK) solution at 4 degrees C for 8 h. After preservation, grafts were immediately mounted on the Langendorff perfusion system and perfused with Krebs-Henseleit buffer at 37 degrees C for 1 h. Adenosine triphosphate (ATP) and malondialdehyde (MDA) content in graft tissue were quantified post-preservation and post-reperfusion. After reperfusion, isolated heart function was assessed using a pressure transducer; cumulative release of creatine kinase (CK) and lactate dehydrogenase (LDH) into the perfusate was measured to assess cardiomyocyte necrosis; ultrastructural changes in the mitochondria of the grafts were examined using transmission electron microscopy (TEM). RESULTS: After preservation, myocardial ATP content in the pretreated hearts was significantly higher than in the control hearts (3.247 +/- 0.3034 vs 1.817 +/- 0.2533 umol/g protein; P < 0.05). AICAR-pretreated heart grafts exhibited significantly higher coronary flow (9.667 +/- 0.3159 vs 8.033 +/- 0.2459 ml/min; P < 0.05) and left ventricular developing pressure (58.67 +/- 2.894 vs 42.67 +/- 3.333 mmHg; P < 0.05) than the vehicle treated after reperfusion. Cumulative release of CK (300.0 +/- 25.30 vs 431.7 +/- 42.39 U/l; P < 0.05) and LDH (228.0 +/- 16.68 vs 366.8 +/- 57.41 U/l; P < 0.05) in the perfusate was significantly lower in the AICAR-pretreated group than that in the control group. Myocardial MDA content was also reduced in the pretreated group (0.5167 +/- 0.1046 vs 0.9333 +/- 0.1333 nmol/mg protein; P < 0.05). TEM suggested that the mitochondrial structure of AICAR-pretreated hearts was much better preserved. Moreover, AICAR-pretreated hearts significantly diminished cytosolic cytochrome c release after reperfusion. CONCLUSIONS: This study demonstrates that pretreatment with AMPK activator AICAR significantly protects heart grafts from extended cold IRI. This novel protocol may be useful and feasible in clinical heart transplantation. PMID- 26609047 TI - Unequal pressure distribution along the jaws of currently available vascular clamps: do we need a new aortic clamp? AB - OBJECTIVES: The pressure along vascular clamp jaws may be unequally distributed, with greater pressure near the clamp hinge than at its top. Such unequal pressure distribution may cause aortic injury, especially in large aortas. We evaluated pressure distribution along different currently availably clamp jaws. METHODS: Seven descending thoracic aortas from pigs (diameter 2.0-3.0 cm) were plainly dissected and all side arteries closed. Aortas were filled up with water and cross-clamped. The pressure inside the aorta was raised to 100 mmHg and the aorta was clamped so tightly that no water exited from the distal aortic end. Each aorta was clamped seven times at different sites with the following clamps: DeBakey, Satinsky, femoral, iliac, Chitwood, angled handle Fogarty and straight handle Fogarty. The pressure along the clamp jaws was measured with a pressure detecting film placed between the clamp jaws and aorta. The collagen-fibre disorganization was examined in haemotoxylin-eosin- and Elastica van Gieson stained tissue samples. RESULTS: The DeBakey clamp revealed the lowest maximum pressure along the clamp jaws after complete aortic occlusion (1.43 +/- 0.49 MPa), whereas the Chitwood clamp's pressure was the highest (3.26 +/- 1.93 MPa, P < 0.001). The angled handle Fogarty clamp displayed the lowest difference between maximum pressures across the jaws (33%), with the greatest difference measured in the iliac (72%) and Chitwood (66%) clamps. The highest collagen-fibre disorganization score was observed in the proximal-to-the-clamp-hinge quartile after clamping with the angled handle Fogarty (2.8 +/- 0.4), straight handle Fogarty (2.3 +/- 0.8) and Chitwood (2.3 +/- 0.5) clamps. CONCLUSIONS: The pressure along clamp jaws is unequally distributed in all the currently available vascular clamps. The Chitwood clamp is associated with the highest maximum pressure during complete aortic occlusion and with the most unequal pressure distribution along the jaws. PMID- 26609048 TI - Antiretroviral therapy in HIV-1-infected individuals with CD4 count below 100 cells/mm3 results in differential recovery of monocyte activation. AB - Reversal of monocyte and macrophage activation and the relationship to viral suppression and T cell activation are unknown in patients with advanced HIV-1 infection, initiating antiretroviral therapy. This study aimed to determine whether reduction in biomarkers of monocyte and macrophage activation would be reduced in conjunction with viral suppression and resolution of T cell activation. Furthermore, we hypothesized that the addition of CCR5 antagonism (by maraviroc) would mediate greater reduction of monocyte/macrophage activation markers than suppressive antiretroviral therapy alone. In the CCR5 antagonism to decrease the incidence of immune reconstitution inflammatory syndrome study, antiretroviral therapy-naive patients received maraviroc or placebo in addition to standard antiretroviral therapy. PBMCs and plasma from 65 patients were assessed during 24 wk of antiretroviral therapy for biomarkers of monocyte and macrophage activation. Markers of monocyte and macrophage activation were reduced significantly by 24 wk, including CD14(++)CD16(+) intermediate monocytes (P < 0.0001), surface CD163 (P = 0.0004), CD169 (P < 0.0001), tetherin (P = 0.0153), and soluble CD163 (P < 0.0001). A change in CD38(+), HLA-DR(+) CD8 T cells was associated with changes in CD169 and tetherin expression. Maraviroc did not affect biomarkers of monocyte/macrophage activation but resulted in greater percentages of CCR5-positive monocytes in PBMC. HIV-1 suppression after 24 wk of antiretroviral therapy, with or without maraviroc, demonstrates robust recovery in monocyte subset activation markers, whereas soluble markers of activation demonstrate minimal decrease, qualitatively differentiating markers of monocyte/macrophage activation in advanced disease. PMID- 26609049 TI - Association of eukaryotic translation initiation factor eIF2B with fully solubilized CXCR4. AB - Chemokine receptors are key regulators of leukocyte trafficking but also have an important role in development, tumor growth, and metastasis. Among the chemokine receptors, CXCR4 is the only one that leads to perinatal death when genetically ablated in mice, indicating a more-widespread function in development. To identify pathways that are activated downstream of CXCR4, a solubilization protocol was elaborated, which allows for the isolation of the endogenous receptor from human cells in its near-native conformation. Solubilized CXCR4 is recognized by the conformation-sensitive monoclonal antibody 12G5 and retains the ability to bind CXCL12 in solution, which was abolished in the presence of receptor antagonists. Mass spectrometry of CXCR4 immunoprecipitates revealed a specific interaction with the pentameric eukaryotic translation initiation factor 2B. The observation that the addition of CXCL12 leads to the dissociation of eukaryotic translation initiation factor 2B from CXCR4 suggests that stimulation of the receptor may trigger the local protein synthesis required for efficient cell movement. PMID- 26609050 TI - Reasons not to ban smoking in psychiatric hospitals. PMID- 26609052 TI - In Silico Constraint-Based Strain Optimization Methods: the Quest for Optimal Cell Factories. AB - Shifting from chemical to biotechnological processes is one of the cornerstones of 21st century industry. The production of a great range of chemicals via biotechnological means is a key challenge on the way toward a bio-based economy. However, this shift is occurring at a pace slower than initially expected. The development of efficient cell factories that allow for competitive production yields is of paramount importance for this leap to happen. Constraint-based models of metabolism, together with in silico strain design algorithms, promise to reveal insights into the best genetic design strategies, a step further toward achieving that goal. In this work, a thorough analysis of the main in silico constraint-based strain design strategies and algorithms is presented, their application in real-world case studies is analyzed, and a path for the future is discussed. PMID- 26609053 TI - Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells. AB - Papillary thyroid cancer (PTC) is one of the most common endocrine malignancies associated with significant morbidity and mortality. Although multiple studies have contributed to a better understanding of the genetic alterations underlying this frequently arising disease, the downstream molecular effectors that impact PTC pathogenesis remain to be further defined. Here, we report that the regulator of cell fate specification, PROX1, becomes inactivated in PTC through mRNA downregulation and cytoplasmic mislocalization. Expression studies in clinical specimens revealed that aberrantly activated NOTCH signaling promoted PROX1 downregulation and that cytoplasmic mislocalization significantly altered PROX1 protein stability. Importantly, restoration of PROX1 activity in thyroid carcinoma cells revealed that PROX1 not only enhanced Wnt/beta-catenin signaling but also regulated several genes known to be associated with PTC, including thyroid cancer protein (TC)-1, SERPINA1, and FABP4. Furthermore, PROX1 reexpression suppressed the malignant phenotypes of thyroid carcinoma cells, such as proliferation, motility, adhesion, invasion, anchorage-independent growth, and polyploidy. Moreover, animal xenograft studies demonstrated that restoration of PROX1 severely impeded tumor formation and suppressed the invasiveness and the nuclear/cytoplasmic ratio of PTC cells. Taken together, our findings demonstrate that NOTCH-induced PROX1 inactivation significantly promotes the malignant behavior of thyroid carcinoma and suggest that PROX1 reactivation may represent a potential therapeutic strategy to attenuate disease progression. PMID- 26609054 TI - Agonists of the TRAIL Death Receptor DR5 Sensitize Intestinal Stem Cells to Chemotherapy-Induced Cell Death and Trigger Gastrointestinal Toxicity. AB - The combination of TRAIL death receptor agonists and radiochemotherapy to treat advanced cancers continues to be investigated in clinical trials. We previously showed that normal cells with a functional DNA damage response (DDR) upregulate the expression of death-inducing receptor DR5/TRAILR2/TNFRSF10B in a p53 dependent manner that sensitizes them to treatment with DR5 agonists. However, it is unclear if targeting DR5 selectively sensitizes cancer cells to agonist treatment following exposure to DNA-damaging chemotherapy, and to what extent normal tissues are targeted. Here, we show that the combined administration of the DR5 agonistic monoclonal antibody (mAb) and chemotherapy to wild-type mice triggered synergistic gastrointestinal toxicities (GIT) that were associated with the death of Lgr5(+) crypt base columnar stem cells in a p53- and DR5-dependent manner. Furthermore, we confirmed that normal human epithelial cells treated with the human DR5-agonistic mAb and chemotherapeutic agents were also greatly sensitized to cell death. Interestingly, our data also indicated that genetic or pharmacologic targeting of Chk2 may counteract GIT without negatively affecting the antitumor responses of combined DR5 agonist/chemotherapy treatment, further linking the DDR to TRAIL death receptor signaling in normal cells. In conclusion, the combination of DR5-targeting agonistic mAbs with DNA damaging chemotherapy may pose a risk of developing toxicity-induced conditions, and the effects of mAb based strategies on the dose-limiting toxicity of chemotherapy must be considered when establishing new combination therapies. PMID- 26609055 TI - Uniportal video-assisted thoracoscopic bronchovascular, tracheal and carinal sleeve resections?. AB - Locally advanced lung tumours often require complex surgical techniques to achieve an oncological and safe procedure. Sleeve resections when operating on endobronchial lesions or hilar tumours should be attempted whenever possible rather than performing a pneumonectomy. These procedures result in improved survival, better quality of life, a reduced loss of lung function and an improved operative mortality compared with pneumonectomy. Although the most common approach is an open thoracotomy, these complex surgical techniques can be performed in a thoracoscopic way with the skills and the experience gained from major video-assisted thoracoscopic procedures (VATS). However, despite the multiple advantages of VATS compared with thoracotomy, such as decreased postoperative pain and better recovery, this minimally invasive approach is still not widely adopted for advanced stages of lung cancer and complex resections. Concerns about performing an adequate oncological resection and safe reconstruction VATS are the main reasons for the low adoption of these minimally invasive approaches. Like other thoracoscopic techniques, VATS sleeve procedures also have a steep learning curve, and should therefore be performed either by or with skilled and experienced VATS surgeons to ensure safety and avoid complications. In this article, we describe the technique of thoracoscopic sleeve procedures through a single-incision (uniportal) approach for bronchial, bronchovascular, tracheal and carinal reconstruction, and review the literature reporting sleeve resections by VATS. PMID- 26609057 TI - New health promotion for chemsex and gamma-hydroxybutyrate (GHB). PMID- 26609056 TI - FADS2 genotype regulates delta-6 desaturase activity and inflammation in human adipose tissue. AB - Obesity is associated with disturbed lipid metabolism and low-grade inflammation in tissues. The aim of this study was to investigate the association between FA metabolism and adipose tissue (AT) inflammation in the Kuopio Obesity Surgery study. We investigated the association of surgery-induced weight loss and FA desaturase (FADS)1/2 genotypes with serum and AT FA profile and with AT inflammation, measured as interleukin (IL)-1beta and NFkappaB pathway gene expression, in order to find potential gene-environment interactions. We demonstrated an association between serum levels of saturated and polyunsaturated n-6 FAs, and estimated enzyme activities of FADS1/2 genes with IL-1beta expression in AT both at baseline and at follow-up. Variation in the FADS1/2 genes associated with IL-1beta and NFkappaB pathway gene expression in SAT after weight reduction, but not at baseline. In addition, the FA composition in subcutaneous and visceral fat correlated with serum FAs, and the associations between serum PUFAs and estimated D6D enzyme activity with AT inflammation were also replicated with corresponding AT FAs and AT inflammation. We conclude that the polymorphism in FADS1/2 genes associates with FA metabolism and AT inflammation, leading to an interaction between weight loss and FADS1/2 genes in the regulation of AT inflammation. PMID- 26609058 TI - Cardiomyocyte exosomes regulate glycolytic flux in endothelium by direct transfer of GLUT transporters and glycolytic enzymes. AB - AIMS: Cardiomyocytes (CMs) and endothelial cells (ECs) have an intimate anatomical relationship, which is essential for maintaining the metabolic requirements of the heart. Little is known about the mechanisms that regulate nutrient flow from ECs to associated CMs, especially in situations of acute stress when local active processes are required to regulate endothelial transport. We examined whether CM-derived exosomes can modulate glucose transport and metabolism in ECs. METHODS AND RESULTS: In conditions of glucose deprivation, CMs increase the synthesis and secretion of exosomes. These exosomes are loaded with functional glucose transporters and glycolytic enzymes, which are internalized by ECs, leading to increased glucose uptake, glycolytic activity, and pyruvate production in recipient cells. CONCLUSION: These findings establish CM-derived exosomes as key components of the cardio-endothelial communication system which, through intercellular protein complementation, would allow a rapid response from ECs to increase glucose transport and a putative uptake of metabolic fuels from blood to CMs. This CM-EC protein complementation process might have implications for metabolic regulation in health and disease. PMID- 26609059 TI - Incidence and lifetime costs of injuries in the United States. AB - BACKGROUND: Standardized methodologies for assessing economic burden of injury at the national or international level do not exist. OBJECTIVE: To measure national incidence, medical costs, and productivity losses of medically treated injuries using the most recent data available in the United States, as a case study for similarly developed countries undertaking economic burden analyses. METHOD: The authors combined several data sets to estimate the incidence of fatal and non fatal injuries in 2000. They computed unit medical and productivity costs and multiplied these costs by corresponding incidence estimates to yield total lifetime costs of injuries occurring in 2000. MAIN OUTCOME MEASURES: Incidence, medical costs, productivity losses, and total costs for injuries stratified by age group, sex, and mechanism. RESULTS: More than 50 million Americans experienced a medically treated injury in 2000, resulting in lifetime costs of $406 billion; $80 billion for medical treatment and $326 billion for lost productivity. Males had a 20% higher rate of injury than females. Injuries resulting from falls or being struck by/against an object accounted for more than 44% of injuries. The rate of medically treated injuries declined by 15% from 1985 to 2000 in the US. For those aged 0-44, the incidence rate of injuries declined by more than 20%; while persons aged 75 and older experienced a 20% increase. CONCLUSIONS: These national burden estimates provide unequivocal evidence of the large health and financial burden of injuries. This study can serve as a template for other countries or be used in intercountry comparisons. PMID- 26609060 TI - Championing research on traumatised and injured children. PMID- 26609061 TI - Childhood family disruption and adult height: is there a mediating role of puberty? AB - BACKGROUND AND OBJECTIVES: Childhood family background is known to be associated with child growth and development, including the onset of puberty, but less is known about the influence of childhood family disruption on outcomes in later life. Given the associations between early family disruption and childhood development, we predicted that there may be long-term health-relevant consequences of childhood disruption. METHODOLOGY: Using data from a large US interview sample (n = 16 207), we test if death or divorce of parents, at different childhood periods, was associated with adult stature, and whether age at puberty mediated this relationship, for men and women. RESULTS MEN: : parental death and divorce during early childhood was associated with shorter adult height, and later puberty. Later puberty was associated with shorter adult height. Path analyses demonstrated that the relationship between parental divorce and height was completely mediated by age at puberty; although parental death was only partially mediated by age at puberty. WOMEN: the father's death during early childhood was associated with earlier puberty, which was in turn associated with shorter adult stature. The relationship between paternal death and height is entirely mediated by age at puberty; no evidence of a direct relationship between childhood family disruption and adult height. CONCLUSIONS: Early childhood familial disruption is associated with shorter height for men, and is partially mediated by later puberty. For women, the relationship between father's death, and height was completely mediated by earlier puberty. These findings indicate that disruption during childhood can have long-reaching health repercussions, particularly for boys. PMID- 26609062 TI - Authors' reply to Devitt. PMID- 26609051 TI - Taxonomy, Physiology, and Natural Products of Actinobacteria. AB - Actinobacteria are Gram-positive bacteria with high G+C DNA content that constitute one of the largest bacterial phyla, and they are ubiquitously distributed in both aquatic and terrestrial ecosystems. Many Actinobacteria have a mycelial lifestyle and undergo complex morphological differentiation. They also have an extensive secondary metabolism and produce about two-thirds of all naturally derived antibiotics in current clinical use, as well as many anticancer, anthelmintic, and antifungal compounds. Consequently, these bacteria are of major importance for biotechnology, medicine, and agriculture. Actinobacteria play diverse roles in their associations with various higher organisms, since their members have adopted different lifestyles, and the phylum includes pathogens (notably, species of Corynebacterium, Mycobacterium, Nocardia, Propionibacterium, and Tropheryma), soil inhabitants (e.g., Micromonospora and Streptomyces species), plant commensals (e.g., Frankia spp.), and gastrointestinal commensals (Bifidobacterium spp.). Actinobacteria also play an important role as symbionts and as pathogens in plant-associated microbial communities. This review presents an update on the biology of this important bacterial phylum. PMID- 26609063 TI - The organization of biological sequences into constrained and unconstrained parts determines fundamental properties of genotype-phenotype maps. AB - Biological information is stored in DNA, RNA and protein sequences, which can be understood as genotypes that are translated into phenotypes. The properties of genotype-phenotype (GP) maps have been studied in great detail for RNA secondary structure. These include a highly biased distribution of genotypes per phenotype, negative correlation of genotypic robustness and evolvability, positive correlation of phenotypic robustness and evolvability, shape-space covering, and a roughly logarithmic scaling of phenotypic robustness with phenotypic frequency. More recently similar properties have been discovered in other GP maps, suggesting that they may be fundamental to biological GP maps, in general, rather than specific to the RNA secondary structure map. Here we propose that the above properties arise from the fundamental organization of biological information into 'constrained' and 'unconstrained' sequences, in the broadest possible sense. As 'constrained' we describe sequences that affect the phenotype more immediately, and are therefore more sensitive to mutations, such as, e.g. protein-coding DNA or the stems in RNA secondary structure. 'Unconstrained' sequences, on the other hand, can mutate more freely without affecting the phenotype, such as, e.g. intronic or intergenic DNA or the loops in RNA secondary structure. To test our hypothesis we consider a highly simplified GP map that has genotypes with 'coding' and 'non-coding' parts. We term this the Fibonacci GP map, as it is equivalent to the Fibonacci code in information theory. Despite its simplicity the Fibonacci GP map exhibits all the above properties of much more complex and biologically realistic GP maps. These properties are therefore likely to be fundamental to many biological GP maps. PMID- 26609064 TI - A discrete spectral analysis for determining quasi-linear viscoelastic properties of biological materials. AB - The viscoelastic behaviour of a biological material is central to its functioning and is an indicator of its health. The Fung quasi-linear viscoelastic (QLV) model, a standard tool for characterizing biological materials, provides excellent fits to most stress-relaxation data by imposing a simple form upon a material's temporal relaxation spectrum. However, model identification is challenging because the Fung QLV model's 'box'-shaped relaxation spectrum, predominant in biomechanics applications, can provide an excellent fit even when it is not a reasonable representation of a material's relaxation spectrum. Here, we present a robust and simple discrete approach for identifying a material's temporal relaxation spectrum from stress-relaxation data in an unbiased way. Our 'discrete QLV' (DQLV) approach identifies ranges of time constants over which the Fung QLV model's typical box spectrum provides an accurate representation of a particular material's temporal relaxation spectrum, and is effective at providing a fit to this model. The DQLV spectrum also reveals when other forms or discrete time constants are more suitable than a box spectrum. After validating the approach against idealized and noisy data, we applied the methods to analyse medial collateral ligament stress-relaxation data and identify the strengths and weaknesses of an optimal Fung QLV fit. PMID- 26609065 TI - Stochastic focusing coupled with negative feedback enables robust regulation in biochemical reaction networks. AB - Nature presents multiple intriguing examples of processes that proceed with high precision and regularity. This remarkable stability is frequently counter to modellers' experience with the inherent stochasticity of chemical reactions in the regime of low-copy numbers. Moreover, the effects of noise and nonlinearities can lead to 'counterintuitive' behaviour, as demonstrated for a basic enzymatic reaction scheme that can display stochastic focusing (SF). Under the assumption of rapid signal fluctuations, SF has been shown to convert a graded response into a threshold mechanism, thus attenuating the detrimental effects of signal noise. However, when the rapid fluctuation assumption is violated, this gain in sensitivity is generally obtained at the cost of very large product variance, and this unpredictable behaviour may be one possible explanation of why, more than a decade after its introduction, SF has still not been observed in real biochemical systems. In this work, we explore the noise properties of a simple enzymatic reaction mechanism with a small and fluctuating number of active enzymes that behaves as a high-gain, noisy amplifier due to SF caused by slow enzyme fluctuations. We then show that the inclusion of a plausible negative feedback mechanism turns the system from a noisy signal detector to a strong homeostatic mechanism by exchanging high gain with strong attenuation in output noise and robustness to parameter variations. Moreover, we observe that the discrepancy between deterministic and stochastic descriptions of stochastically focused systems in the evolution of the means almost completely disappears, despite very low molecule counts and the additional nonlinearity due to feedback. The reaction mechanism considered here can provide a possible resolution to the apparent conflict between intrinsic noise and high precision in critical intracellular processes. PMID- 26609066 TI - The impact of antiretroviral therapy on population-level virulence evolution of HIV-1. AB - In HIV-infected patients, an individual's set point viral load (SPVL) strongly predicts disease progression. Some think that SPVL is evolving, indicating that the virulence of the virus may be changing, but the data are not consistent. In addition, the widespread use of antiretroviral therapy (ART) has the potential to drive virulence evolution. We develop a simple deterministic model designed to answer the following questions: what are the expected patterns of virulence change in the initial decades of an epidemic? Could administration of ART drive changes in virulence evolution and, what is the potential size and direction of this effect? We find that even without ART we would not expect monotonic changes in average virulence. Transient decreases in virulence following the peak of an epidemic are not necessarily indicative of eventual evolution to avirulence. In the short term, we would expect widespread ART to cause limited downward pressure on virulence. In the long term, the direction of the effect is determined by a threshold condition, which we define. We conclude that, given the surpassing benefits of ART to the individual and in reducing onward transmission, virulence evolution considerations need have little bearing on how we treat. PMID- 26609067 TI - Searching for motifs in the behaviour of larval Drosophila melanogaster and Caenorhabditis elegans reveals continuity between behavioural states. AB - We present a novel method for the unsupervised discovery of behavioural motifs in larval Drosophila melanogaster and Caenorhabditis elegans. A motif is defined as a particular sequence of postures that recurs frequently. The animal's changing posture is represented by an eigenshape time series, and we look for motifs in this time series. To find motifs, the eigenshape time series is segmented, and the segments clustered using spline regression. Unlike previous approaches, our method can classify sequences of unequal duration as the same motif. The behavioural motifs are used as the basis of a probabilistic behavioural annotator, the eigenshape annotator (ESA). Probabilistic annotation avoids rigid threshold values and allows classification uncertainty to be quantified. We apply eigenshape annotation to both larval Drosophila and C. elegans and produce a good match to hand annotation of behavioural states. However, we find many behavioural events cannot be unambiguously classified. By comparing the results with ESA of an artificial agent's behaviour, we argue that the ambiguity is due to greater continuity between behavioural states than is generally assumed for these organisms. PMID- 26609068 TI - Acute coronary syndromes: key role of rehabilitation and primary care in long term secondary prevention. PMID- 26609069 TI - Dynamic relocation of the TORC1-Gtr1/2-Ego1/2/3 complex is regulated by Gtr1 and Gtr2. AB - TORC1 regulates cellular growth, metabolism, and autophagy by integrating various signals, including nutrient availability, through the small GTPases RagA/B/C/D in mammals and Gtr1/2 in budding yeast. Rag/Gtr is anchored to the lysosomal/vacuolar membrane by the scaffold protein complex Ragulator/Ego. Here we show that Ego consists of Ego1 and Ego3, and novel subunit Ego2. The ?ego2 mutant exhibited only partial defects both in Gtr1-dependent TORC1 activation and Gtr1 localization on the vacuole. Ego1/2/3, Gtr1/2, and Tor1/Tco89 were colocalized on the vacuole and associated puncta. When Gtr1 was in its GTP-bound form and TORC1 was active, these proteins were preferentially localized on the vacuolar membrane, whereas when Gtr1 was in its GDP-bound form, they were mostly localized on the puncta. The localization of TORC1 to puncta was further facilitated by direct binding to Gtr2, which is involved in suppression of TORC1 activity. Thus regulation of TORC1 activity through Gtr1/Gtr2 is tightly coupled to the dynamic relocation of these proteins. PMID- 26609070 TI - Microhomology-mediated end joining is the principal mediator of double-strand break repair during mitochondrial DNA lesions. AB - Mitochondrial DNA (mtDNA) deletions are associated with various mitochondrial disorders. The deletions identified in humans are flanked by short, directly repeated mitochondrial DNA sequences; however, the mechanism of such DNA rearrangements has yet to be elucidated. In contrast to nuclear DNA (nDNA), mtDNA is more exposed to oxidative damage, which may result in double-strand breaks (DSBs). Although DSB repair in nDNA is well studied, repair mechanisms in mitochondria are not characterized. In the present study, we investigate the mechanisms of DSB repair in mitochondria using in vitro and ex vivo assays. Whereas classical NHEJ (C-NHEJ) is undetectable, microhomology-mediated alternative NHEJ efficiently repairs DSBs in mitochondria. Of interest, robust microhomology-mediated end joining (MMEJ) was observed with DNA substrates bearing 5-, 8-, 10-, 13-, 16-, 19-, and 22-nt microhomology. Furthermore, MMEJ efficiency was enhanced with an increase in the length of homology. Western blotting, immunoprecipitation, and protein inhibition assays suggest the involvement of CtIP, FEN1, MRE11, and PARP1 in mitochondrial MMEJ. Knockdown studies, in conjunction with other experiments, demonstrated that DNA ligase III, but not ligase IV or ligase I, is primarily responsible for the final sealing of DSBs during mitochondrial MMEJ. These observations highlight the central role of MMEJ in maintenance of mammalian mitochondrial genome integrity and is likely relevant for deletions observed in many human mitochondrial disorders. PMID- 26609071 TI - Integration of linear and dendritic actin nucleation in Nck-induced actin comets. AB - The Nck adaptor protein recruits cytosolic effectors such as N-WASP that induce localized actin polymerization. Experimental aggregation of Nck SH3 domains at the membrane induces actin comet tails--dynamic, elongated filamentous actin structures similar to those that drive the movement of microbial pathogens such as vaccinia virus. Here we show that experimental manipulation of the balance between unbranched/branched nucleation altered the morphology and dynamics of Nck induced actin comets. Inhibition of linear, formin-based nucleation with the small-molecule inhibitor SMIFH2 or overexpression of the formin FH1 domain resulted in formation of predominantly circular-shaped actin structures with low mobility (actin blobs). These results indicate that formin-based linear actin polymerization is critical for the formation and maintenance of Nck-dependent actin comet tails. Consistent with this, aggregation of an exclusively branched nucleation-promoting factor (the VCA domain of N-WASP), with density and turnover similar to those of N-WASP in Nck comets, did not reconstitute dynamic, elongated actin comets. Furthermore, enhancement of branched Arp2/3-mediated nucleation by N-WASP overexpression caused loss of the typical actin comet tail shape induced by Nck aggregation. Thus the ratio of linear to dendritic nucleation activity may serve to distinguish the properties of actin structures induced by various viral and bacterial pathogens. PMID- 26609073 TI - Implant-based three-dimensional superimposition of the growing mandible in a rabbit model. AB - BACKGROUND: The reliable assessment of craniofacial morphological changes during growth requires invariant regions for image registration. As these regions have not yet been identified in three dimensions, intra-osseous implants are required as fiducial markers for the reliable assessment of three-dimensional (3D) mandibular growth changes. The objective of this study was to develop an animal model for the assessment of the 3D morphological changes of the mandible during growth, using implants as fiducial markers. MATERIALS AND METHODS: Titanium implants were placed in the body of the mandible of six New Zealand White rabbits. Cone beam computed tomography (CBCT) scans were taken 1-week following implant placement and after an additional 8-weeks of growth. Segmentations of CBCT images were exported into custom-made scripts, implant centroids were identified, implant stability during growth calculated, and the segmented mandibles were registered on the implant centroids. RESULTS: The buccal cortical bone of the body of the mandible was stable during growth and suitable for fiducial marker placement. Bilateral implants resulted in more accurate rigid registration of the growing rabbit mandible than only unilateral implants. 3D mandibular growth changes were visualised by means of semi-transparencies. CONCLUSIONS: This animal model appears to be feasible for the assessment of the 3D morphological changes occurring during mandibular growth. To the best of our knowledge this is the first time that the implant superimposition method has been combined with 3D imaging to accurately reveal mandibular growth changes. PMID- 26609074 TI - The use of Bjork's indications of growth for evaluation of extremes of skeletal morphology. AB - BACKROUND: Morphological indicators within the cranium for prediction of mandibular growth patterns as reported by Bjork are: (1) inclination of the condylar head (ICH), (2) curvature of mandibular canal (CMC), (3) shape of the lower border of the mandible and specifically depth of the antegonial notch (AN), (4) inclination of the symphysis (ISY), (5) interincisal angle (IIA), (6) intermolar angle (IMA), and (7) lower anterior face height (LAFH). The purpose of this study was to examine the association of these indicators as they relate to extreme skeletal patterns observed in skeletally mature subjects. MATERIALS: The pre-treatment lateral cephalometric radiographs of 395 post-growth subjects were randomly selected from the archives of a university orthodontic department. These were divided in three groups according to their MP-SN angle [normal: 28-36degrees (G1), hypodivergent: <=26degrees (G2), hyperdivergent: >=38degrees (G3)]. RESULTS: It was found that only LAFH was correlated to age across all groups. However, within G1, G2, and G3, and between genders, it was found that there were statistically significant differences for all indicators in relation to age, except IMA (P > 0.05). In addition, ISY and IMA had a predictive value lower than the chance level (0.5). CONCLUSION: Bjork's implant studies have contributed much to understanding facial-skeletal growth; however, this study suggests that their utilization as a tool in classifying extreme skeletal patterns requires careful evaluation of all the parameters involved. PMID- 26609072 TI - Incomplete proteasomal degradation of green fluorescent proteins in the context of tandem fluorescent protein timers. AB - Tandem fluorescent protein timers (tFTs) report on protein age through time dependent change in color, which can be exploited to study protein turnover and trafficking. Each tFT, composed of two fluorescent proteins (FPs) that differ in maturation kinetics, is suited to follow protein dynamics within a specific time range determined by the maturation rates of both FPs. So far, tFTs have been constructed by combining slower-maturing red fluorescent proteins (redFPs) with the faster-maturing superfolder green fluorescent protein (sfGFP). Toward a comprehensive characterization of tFTs, we compare here tFTs composed of different faster-maturing green fluorescent proteins (greenFPs) while keeping the slower-maturing redFP constant (mCherry). Our results indicate that the greenFP maturation kinetics influences the time range of a tFT. Moreover, we observe that commonly used greenFPs can partially withstand proteasomal degradation due to the stability of the FP fold, which results in accumulation of tFT fragments in the cell. Depending on the order of FPs in the timer, incomplete proteasomal degradation either shifts the time range of the tFT toward slower time scales or precludes its use for measurements of protein turnover. We identify greenFPs that are efficiently degraded by the proteasome and provide simple guidelines for the design of new tFTs. PMID- 26609075 TI - Three-dimensional shape of the Golgi apparatus in different cell types: serial section scanning electron microscopy of the osmium-impregnated Golgi apparatus. AB - Although many studies of the Golgi apparatus structure have been performed by light and electron microscopy, the full shape of the Golgi apparatus remained unclear due to the technical limitations of the previously applied microscopy techniques. In this study, we used serial section scanning electron microscopy (SEM) for the morphological study of the Golgi apparatus. This method is useful for three-dimensional (3D) reconstruction of cellular structures without requiring specialized instruments, unlike focused ion beam SEM (FIB-SEM) and serial block face SEM (SBF-SEM). Using the serial section SEM method developed by our laboratory, we investigate the 3D shape of the osmium-impregnated Golgi apparatus in rat epididymal cells, pancreatic acinar cells and gonadotropes. The combination of serial section SEM and a 3D reconstruction technique enabled us to elucidate the entire shape of the Golgi apparatus in these cells. The full shape of the Golgi apparatus in epididymal cells formed a basket-like structure with oval-shaped cisterns, while the Golgi apparatus in an acinar cell from the pancreas was composed of elongated ribbon-like structures that were connected to each other, making a coarse network. The overall image of the Golgi apparatus cisterns from a gonadotrope looked like a spherical cage. This study has clearly shown that entire 3D shape of the Golgi apparatus varies depending on the cell type and that the Golgi cisterns network appears as a single mass located in the large region of the cytoplasm. PMID- 26609076 TI - Longevity of implantable cardioverter defibrillators: a comparison among manufacturers and over time. AB - AIMS: Longevity of implantable cardioverter defibrillators (ICDs) is crucial for patients and healthcare systems as replacements impact on infection rates and cost-effectiveness. Aim was to determine longevity using very large databases of two teaching hospitals with a high number of replacements and a rather homogeneous distribution among manufacturers. METHODS AND RESULTS: The study population consists of all patients in whom an ICD was inserted in. All ICD manufacturers operating in Switzerland and the Netherlands and all implanted ICDs were included. Implantable cardioverter defibrillator replacements due to normal battery depletion were considered events, and other replacements were censored. Longevity was assessed depending on manufacturers, pacing mode, implant before/after 2006, and all parameters combined. We analysed data from 3436 patients in whom 4881 ICDs [44.2% VVI-ICDs, 27.4% DDD-ICDs, 26.3% cardiac resynchronization therapy (CRT)-ICDs, 2.0% subcutaneous ICDs] were implanted. The four major manufacturers had implant shares between 18.4 and 31.5%. Replacement due to battery depletion (27.4%) was performed for 1339 ICDs. Patient survival at 5 years was 80.1%. Longevity at 5 years improved in contemporary compared with elderly ICDs [63.9-80.6% across all ICDs, of 73.7-92.1% in VVIs, 58.2-76.1% in DDDs, and of 47.1-66.3% in CRT defibrillators, all P value < 0.05]. Remarkable differences were seen among manufacturers, and those with better performance in elderly ICDs were not those with better performance in contemporary ones. CONCLUSION: Implantable cardioverter defibrillator longevity increased in contemporary models independent of manufacturer and pacing mode. Still, significant differences exist among manufacturers. These results might impact on device selection. PMID- 26609078 TI - On the Causes of Evolutionary Transition:Transversion Bias. AB - A pattern in which nucleotide transitions are favored several fold over transversions is common in molecular evolution. When this pattern occurs among amino acid replacements, explanations often invoke an effect of selection, on the grounds that transitions are more conservative in their effects on proteins. However, the underlying hypothesis of conservative transitions has never been tested directly. Here we assess support for this hypothesis using direct evidence: the fitness effects of mutations in actual proteins measured via individual or paired growth experiments. We assembled data from 8 published studies, ranging in size from 24 to 757 single-nucleotide mutations that change an amino acid. Every study has the statistical power to reveal significant effects of amino acid exchangeability, and most studies have the power to discern a binary conservative-vs-radical distinction. However, only one study suggests that transitions are significantly more conservative than transversions. In the combined set of 1,239 replacements (544 transitions, 695 transversions), the chance that a transition is more conservative than a transversion is 53 % (95 % confidence interval 50 to 56) compared with the null expectation of 50 %. We show that this effect is not large compared with that of most biochemical factors, and is not large enough to explain the several-fold bias observed in evolution. In short, the available data have the power to verify the "conservative transitions" hypothesis if true, but suggest instead that selection on proteins plays at best a minor role in the observed bias. PMID- 26609077 TI - Adaptation to Parasites and Costs of Parasite Resistance in Mutator and Nonmutator Bacteria. AB - Parasitism creates selection for resistance mechanisms in host populations and is hypothesized to promote increased host evolvability. However, the influence of these traits on host evolution when parasites are no longer present is unclear. We used experimental evolution and whole-genome sequencing of Escherichia coli to determine the effects of past and present exposure to parasitic viruses (phages) on the spread of mutator alleles, resistance, and bacterial competitive fitness. We found that mutator alleles spread rapidly during adaptation to any of four different phage species, and this pattern was even more pronounced with multiple phages present simultaneously. However, hypermutability did not detectably accelerate adaptation in the absence of phages and recovery of fitness costs associated with resistance. Several lineages evolved phage resistance through elevated mucoidy, and during subsequent evolution in phage-free conditions they rapidly reverted to nonmucoid, phage-susceptible phenotypes. Genome sequencing revealed that this phenotypic reversion was achieved by additional genetic changes rather than by genotypic reversion of the initial resistance mutations. Insertion sequence (IS) elements played a key role in both the acquisition of resistance and adaptation in the absence of parasites; unlike single nucleotide polymorphisms, IS insertions were not more frequent in mutator lineages. Our results provide a genetic explanation for rapid reversion of mucoidy, a phenotype observed in other bacterial species including human pathogens. Moreover, this demonstrates that the types of genetic change underlying adaptation to fitness costs, and consequently the impact of evolvability mechanisms such as increased point-mutation rates, depend critically on the mechanism of resistance. PMID- 26609079 TI - Intein Clustering Suggests Functional Importance in Different Domains of Life. AB - Inteins, also called protein introns, are self-splicing mobile elements found in all domains of life. A bioinformatic survey of genomic data highlights a biased distribution of inteins among functional categories of proteins in both bacteria and archaea, with a strong preference for a single network of functions containing replisome proteins. Many nonorthologous, functionally equivalent replicative proteins in bacteria and archaea carry inteins, suggesting a selective retention of inteins in proteins of particular functions across domains of life. Inteins cluster not only in proteins with related roles but also in specific functional units of those proteins, like ATPase domains. This peculiar bias does not fully fit the models describing inteins exclusively as parasitic elements. In such models, evolutionary dynamics of inteins is viewed primarily through their mobility with the intein homing endonuclease (HEN) as the major factor of intein acquisition and loss. Although the HEN is essential for intein invasion and spread in populations, HEN dynamics does not explain the observed biased distribution of inteins among proteins in specific functional categories. We propose that the protein splicing domain of the intein can act as an environmental sensor that adapts to a particular niche and could increase the chance of the intein becoming fixed in a population. We argue that selective retention of some inteins might be beneficial under certain environmental stresses, to act as panic buttons that reversibly inhibit specific networks, consistent with the observed intein distribution. PMID- 26609080 TI - Molecular Mechanism of the Two-Component Suicidal Weapon of Neocapritermes taracua Old Workers. AB - In termites, as in many social insects, some individuals specialize in colony defense, developing diverse weaponry. As workers of the termite Neocapritermes taracua (Termitidae: Termitinae) age, their efficiency to perform general tasks decreases, while they accumulate defensive secretions and increase their readiness to fight. This defensive mechanism involves self-sacrifice through body rupture during which an enzyme, stored as blue crystals in dorsal pouches, converts precursors produced by the labial glands into highly toxic compounds. Here, we identify both components of this activated defense system and describe the molecular basis responsible for the toxicity of N. taracua worker autothysis. The blue crystals are formed almost exclusively by a specific protein named BP76. By matching N. taracua transcriptome databases with amino acid sequences, we identified BP76 to be a laccase. Following autothysis, the series of hydroquinone precursors produced by labial glands get mixed with BP76, resulting in the conversion of relatively harmless hydroquinones into toxic benzoquinone analogues. Neocapritermes taracua workers therefore rely on a two-component activated defense system, consisting of two separately stored secretions that can react only after suicidal body rupture, which produces a sticky and toxic cocktail harmful to opponents. PMID- 26609081 TI - Reproductive health needs of female sex workers and opportunities for enhanced prevention of mother-to-child transmission efforts in sub-Saharan Africa. AB - INTRODUCTION: HIV infection and pregnancy are both common among female sex workers (FSW), indicating the need for prevention of mother-to-child transmission (PMTCT) among FSW. METHODS: FSW were enrolled into studies in Swaziland, Burkina Faso and Togo using respondent-driven sampling. Women completed interview administered socio-behavioural surveys and HIV counselling and testing. This secondary analysis describes contraceptive use and attempted pregnancy among reproductive-aged FSW (16-49 years). Robust Poisson regression with generalised estimating equations to account for clustering within recruitment networks was used to separately estimate associations between current unmet contraceptive need and attempted pregnancy among FSW. RESULTS: Overall 1666 FSW were enrolled, 1372 (82.4%) of whom had ever been pregnant. In Togo and Burkina Faso, 83 FSW reported a prior HIV diagnosis and having a child, of which 12.1% (10/83) reported a child known to be HIV-positive. Twenty-five per cent of FSW had an unmet need for contraception; 9% of FSW employed dual contraception, including highly effective non-barrier methods and consistent condom use. Consistent condom use varied substantially by partner type and was higher with clients than non-paying partners. Nineteen per cent (n=313/1666) of FSW were trying to conceive. HIV positive, undiagnosed FSW were more likely to be trying to conceive as compared to HIV-negative FSW; among 98 HIV-positive women trying to conceive, 25.5% were on antiretroviral therapy. CONCLUSIONS: FSW have varying reproductive goals and contraceptive usage. Efforts to improve coverage of comprehensive family planning - including efforts to increase HIV testing and engagement in treatment among FSW trying to conceive - are necessary for PMTCT. PMID- 26609082 TI - When the going gets tough: behavioural type-dependent space use in the sleepy lizard changes as the season dries. AB - Understanding space use remains a major challenge for animal ecology, with implications for species interactions, disease spread, and conservation. Behavioural type (BT) may shape the space use of individuals within animal populations. Bolder or more aggressive individuals tend to be more exploratory and disperse further. Yet, to date we have limited knowledge on how space use other than dispersal depends on BT. To address this question we studied BT dependent space-use patterns of sleepy lizards (Tiliqua rugosa) in southern Australia. We combined high-resolution global positioning system (GPS) tracking of 72 free-ranging lizards with repeated behavioural assays, and with a survey of the spatial distributions of their food and refuge resources. Bayesian generalized linear mixed models (GLMM) showed that lizards responded to the spatial distribution of resources at the neighbourhood scale and to the intensity of space use by other conspecifics (showing apparent conspecific avoidance). BT (especially aggressiveness) affected space use by lizards and their response to ecological and social factors, in a seasonally dependent manner. Many of these effects and interactions were stronger later in the season when food became scarce and environmental conditions got tougher. For example, refuge and food availability became more important later in the season and unaggressive lizards were more responsive to these predictors. These findings highlight a commonly overlooked source of heterogeneity in animal space use and improve our mechanistic understanding of processes leading to behaviourally driven disease dynamics and social structure. PMID- 26609083 TI - Predicting community structure in snakes on Eastern Nearctic islands using ecological neutral theory and phylogenetic methods. AB - Predicting species presence and richness on islands is important for understanding the origins of communities and how likely it is that species will disperse and resist extinction. The equilibrium theory of island biogeography (ETIB) and, as a simple model of sampling abundances, the unified neutral theory of biodiversity (UNTB), predict that in situations where mainland to island migration is high, species-abundance relationships explain the presence of taxa on islands. Thus, more abundant mainland species should have a higher probability of occurring on adjacent islands. In contrast to UNTB, if certain groups have traits that permit them to disperse to islands better than other taxa, then phylogeny may be more predictive of which taxa will occur on islands. Taking surveys of 54 island snake communities in the Eastern Nearctic along with mainland communities that have abundance data for each species, we use phylogenetic assembly methods and UNTB estimates to predict island communities. Species richness is predicted by island area, whereas turnover from the mainland to island communities is random with respect to phylogeny. Community structure appears to be ecologically neutral and abundance on the mainland is the best predictor of presence on islands. With regard to young and proximate islands, where allopatric or cladogenetic speciation is not a factor, we find that simple neutral models following UNTB and ETIB predict the structure of island communities. PMID- 26609084 TI - Testing mechanistic models of growth in insects. AB - Insects are typified by their small size, large numbers, impressive reproductive output and rapid growth. However, insect growth is not simply rapid; rather, insects follow a qualitatively distinct trajectory to many other animals. Here we present a mechanistic growth model for insects and show that increasing specific assimilation during the growth phase can explain the near-exponential growth trajectory of insects. The presented model is tested against growth data on 50 insects, and compared against other mechanistic growth models. Unlike the other mechanistic models, our growth model predicts energy reserves per biomass to increase with age, which implies a higher production efficiency and energy density of biomass in later instars. These predictions are tested against data compiled from the literature whereby it is confirmed that insects increase their production efficiency (by 24 percentage points) and energy density (by 4 J mg( 1)) between hatching and the attainment of full size. The model suggests that insects achieve greater production efficiencies and enhanced growth rates by increasing specific assimilation and increasing energy reserves per biomass, which are less costly to maintain than structural biomass. Our findings illustrate how the explanatory and predictive power of mechanistic growth models comes from their grounding in underlying biological processes. PMID- 26609085 TI - Nature of the coupling between neural drive and force-generating capacity in the human quadriceps muscle. AB - The force produced by a muscle depends on both the neural drive it receives and several biomechanical factors. When multiple muscles act on a single joint, the nature of the relationship between the neural drive and force-generating capacity of the synergistic muscles is largely unknown. This study aimed to determine the relationship between the ratio of neural drive and the ratio of muscle force generating capacity between two synergist muscles (vastus lateralis (VL) and vastus medialis (VM)) in humans. Twenty-one participants performed isometric knee extensions at 20 and 50% of maximal voluntary contractions (MVC). Myoelectric activity (surface electromyography (EMG)) provided an index of neural drive. Physiological cross-sectional area (PCSA) was estimated from measurements of muscle volume (magnetic resonance imaging) and muscle fascicle length (three dimensional ultrasound imaging) to represent the muscles' force-generating capacities. Neither PCSA nor neural drive was balanced between VL and VM. There was a large (r = 0.68) and moderate (r = 0.43) correlation between the ratio of VL/VM EMG amplitude and the ratio of VL/VM PCSA at 20 and 50% of MVC, respectively. This study provides evidence that neural drive is biased by muscle force-generating capacity, the greater the force-generating capacity of VL compared with VM, the stronger bias of drive to the VL. PMID- 26609086 TI - Perinatal and juvenile social environments interact to shape cognitive behaviour and neural phenotype in prairie voles. AB - Social environments experienced at different developmental stages profoundly shape adult behavioural and neural phenotypes, and may have important interactive effects. We asked if social experience before and after weaning influenced adult social cognition in male prairie voles. Animals were raised either with or without fathers and then either housed singly or in sibling pairs. Males that were socially deprived before (fatherless) and after (singly housed) weaning did not demonstrate social recognition or dissociate spatial from social information. We also examined oxytocin and vasopressin receptors (OTR and V1aR) in areas of the forebrain associated with social behaviour and memory. Pre- and post-wean experience differentially altered receptor expression in several structures. Of note, OTR in the lateral septum-an area in which oxytocin inhibits social recognition-was greatest in animals that did not clearly demonstrate social recognition. The combination of absentee fathers on V1aR in the retrosplenial cortex and single housing on OTR in the septohippocampal nucleus produced a unique phenotype previously found to be associated with poor reproductive success in nature. We demonstrate that interactive effects of early life experiences throughout development have tremendous influence over brain-behaviour phenotype and can buffer potentially negative outcomes due to social deprivation. PMID- 26609087 TI - Fish can show emotional fever: stress-induced hyperthermia in zebrafish. AB - Whether fishes are sentient beings remains an unresolved and controversial question. Among characteristics thought to reflect a low level of sentience in fishes is an inability to show stress-induced hyperthermia (SIH), a transient rise in body temperature shown in response to a variety of stressors. This is a real fever response, so is often referred to as 'emotional fever'. It has been suggested that the capacity for emotional fever evolved only in amniotes (mammals, birds and reptiles), in association with the evolution of consciousness in these groups. According to this view, lack of emotional fever in fishes reflects a lack of consciousness. We report here on a study in which six zebrafish groups with access to a temperature gradient were either left as undisturbed controls or subjected to a short period of confinement. The results were striking: compared to controls, stressed zebrafish spent significantly more time at higher temperatures, achieving an estimated rise in body temperature of about 2-4 degrees C. Thus, zebrafish clearly have the capacity to show emotional fever. While the link between emotion and consciousness is still debated, this finding removes a key argument for lack of consciousness in fishes. PMID- 26609089 TI - Correction to 'The corpus callosum in primates: processing speed of axons and the evolution of hemispheric asymmetry'. PMID- 26609088 TI - Phenotypic variability in unicellular organisms: from calcium signalling to social behaviour. AB - Historically, research has focused on the mean and often neglected the variance. However, variability in nature is observable at all scales: among cells within an individual, among individuals within a population and among populations within a species. A fundamental quest in biology now is to find the mechanisms that underlie variability. Here, we investigated behavioural variability in a unique unicellular organism, Physarum polycephalum. We combined experiments and models to show that variability in cell signalling contributes to major differences in behaviour underpinning some aspects of social interactions. First, following thousands of cells under various contexts, we identified distinct behavioural phenotypes: 'slow-regular-social', 'fast-regular-social' and 'fast-irregular asocial'. Second, coupling chemical analysis and behavioural assays we found that calcium signalling is responsible for these behavioural phenotypes. Finally, we show that differences in signalling and behaviour led to alternative social strategies. Our results have considerable implications for our understanding of the emergence of variability in living organisms. PMID- 26609094 TI - No transformation without reconciliation. PMID- 26609095 TI - Intubation trauma and the head and neck surgeon: issues with a shared airway. PMID- 26609096 TI - The Swedish randomised controlled trial on mammography screening has been properly designed, conducted and analysed. PMID- 26609097 TI - Systematic review of the breast cancer screening trials is error-ridden. PMID- 26609098 TI - Screening mammography: Authors' response to Nystrom and Tabar and colleagues. PMID- 26609099 TI - Ambroise Pare's accounts of new methods for treating gunshot wounds and burns. PMID- 26609103 TI - A DOSE CALCULATION MODEL APPLICATION FOR INDOOR EXPOSURE TO TWO-LAYER WALLS GAMMA IRRADIATION: THE CASE STUDY OF CERAMIC TILES. AB - A calculation model for determining the indoor dose due to building materials with significant concentration of radioactivity has been applied to the case study of ceramic tiles; the model allows the contribution of bearing walls and wall covering materials to be calculated. The model is implemented in FORTRAN 77 and provides a quantification of the gamma radiation field (in terms of external dose rate in air, nGyh-1) inside a room with known dimensions. Application model results have been validated both by comparison with the results obtained by other authors and by experimental measurements. Model sensitivity and performances have been analysed and lastly the case studies focused on ceramic tiles have been proposed. PMID- 26609104 TI - Atypical Femur Fractures Associated With Diphosphonate Use. PMID- 26609105 TI - Using Mathematical Modeling to Design Effective Regenerative Medicine Strategies for Orthopaedics. PMID- 26609106 TI - Heterogeneity in brain reactivity to pleasant and food cues: evidence of sign tracking in humans. AB - Aberrant brain reward responses to food-related cues are an implied characteristic of human obesity; yet, findings are inconsistent. To explain these inconsistencies, we aimed to uncover endophenotypes associated with heterogeneity in attributing incentive salience to food cues in the context of other emotionally salient cues; a phenomenon described as sign- vs goal tracking in preclinical models. Data from 64 lean and 88 obese adults who were 35.5 +/- 9.4 years old and predominantly women (79%) were analyzed. Participants viewed food related, pleasant, neutral and unpleasant images while recording electroencephalograph. Late positive potentials were used to assess incentive salience attributed to the visual stimuli. Eating and affective traits were also assessed. Findings demonstrated that obese individuals, in general, do not demonstrate aberrant brain reward responses to food-related cues. As hypothesized, latent profile analysis of the late positive potential uncovered two distinct groups. 'Sign-trackers' showed greater responses to food-related cues (P < 0.001) but lower responses to pleasant stimuli (P < 0.001) compared with 'goal-trackers'. There were proportionally more obese than lean 'sign trackers' (P = 0.03). Obese 'sign-trackers' reported significantly higher levels of emotional eating and food craving (P < 0.001). By examining the heterogeneity in brain reactivity to various emotional stimuli, this translational study highlights the need to consider important neurobehavioral endophenotypes of obesity. PMID- 26609107 TI - Theory-of-mind-related neural activity for one's romantic partner predicts partner well-being. AB - Healthy social relationships are linked to myriad positive physical and mental health outcomes, raising the question of how to enhance relationship formation and quality. Behavioral data suggest that theory of mind (ToM) may be one such process. ToM is supported by a network of brain regions including the temporo parietal junction (TPJ), medial prefrontal cortex and precuneus (PC). However, little research has investigated how the ToM network supports healthy social relationships. Here, we investigate whether recruitment of the ToM network when thinking about the mental states of one's romantic partner predicts the partner's well-being. We find that selectivity in left TPJ (LTPJ) and PC for beliefs vs physical attributes of one's partner is positively associated with partner well being the day of and day after a meaningful encounter. Furthermore, LTPJ and PC selectivity moderated how the partner's perception of being understood during the encounter affected their later well-being. Finally, we find the association between ToM-related neural selectivity and well-being robust to other factors related to the relationship and the encounter. Together, these data suggest that selective engagement of the neural network supporting ToM may be a key ingredient for the development and maintenance of healthy romantic relationships. PMID- 26609109 TI - Hypermutation of DPYD Deregulates Pyrimidine Metabolism and Promotes Malignant Progression. AB - New strategies are needed to diagnose and target human melanoma. To this end, genomic analyses was performed to assess somatic mutations and gene expression signatures using a large cohort of human skin cutaneous melanoma (SKCM) patients from The Cancer Genome Atlas (TCGA) project to identify critical differences between primary and metastatic tumors. Interestingly, pyrimidine metabolism is one of the major pathways to be significantly enriched and deregulated at the transcriptional level in melanoma progression. In addition, dihydropyrimidine dehydrogenase (DPYD) and other important pyrimidine-related genes: DPYS, AK9, CAD, CANT1, ENTPD1, NME6, NT5C1A, POLE, POLQ, POLR3B, PRIM2, REV3L, and UPP2 are significantly enriched in somatic mutations relative to the background mutation rate. Structural analysis of the DPYD protein dimer reveals a potential hotspot of recurring somatic mutations in the ligand-binding sites as well as the interfaces of protein domains that mediated electron transfer. Somatic mutations of DPYD are associated with upregulation of pyrimidine degradation, nucleotide synthesis, and nucleic acid processing while salvage and nucleotide conversion is downregulated in TCGA SKCM. IMPLICATIONS: At a systems biology level, somatic mutations of DPYD cause a switch in pyrimidine metabolism and promote gene expression of pyrimidine enzymes toward malignant progression. PMID- 26609110 TI - Evidence against perfect integration of sensory information during perceptual decision making. AB - Perceptual decision making is often modeled as perfect integration of sequential sensory samples until the accumulated total reaches a fixed decision bound. In that view, the buildup of neural activity during perceptual decision making is attributed to temporal integration. However, an alternative explanation is that sensory estimates are computed quickly with a low-pass filter and combined with a growing signal reflecting the urgency to respond and it is the latter that is primarily responsible for neural activity buildup. These models are difficult to distinguish empirically because they make similar predictions for tasks in which sensory information is constant within a trial, as in most previous studies. Here we presented subjects with a variant of the classic constant-coherence motion discrimination (CMD) task in which we inserted brief motion pulses. We examined the effect of these pulses on reaction times (RTs) in two conditions: 1) when the CMD trials were blocked and subjects responded quickly and 2) when the same CMD trials were interleaved among trials of a variable-motion coherence task that motivated slower decisions. In the blocked condition, early pulses had a strong effect on RTs but late pulses did not, consistent with both models. However, when subjects slowed their decision policy in the interleaved condition, later pulses now became effective while early pulses lost their efficacy. This last result contradicts models based on perfect integration of sensory evidence and implies that motion signals are processed with a strong leak, equivalent to a low-pass filter with a short time constant. PMID- 26609108 TI - Differential Regulation of ZEB1 and EMT by MAPK-Interacting Protein Kinases (MNK) and eIF4E in Pancreatic Cancer. AB - Human pancreatic ductal adenocarcinoma (PDAC) tumors are associated with dysregulation of mRNA translation. In this report, it is demonstrated that PDAC cells grown in collagen exhibit increased activation of the MAPK-interacting protein kinases (MNK) that mediate eIF4E phosphorylation. Pharmacologic and genetic targeting of MNKs reverse epithelial-mesenchymal transition (EMT), decrease cell migration, and reduce protein expression of the EMT-regulator ZEB1 without affecting ZEB1 mRNA levels. Paradoxically, targeting eIF4E, the best characterized effector of MNKs, increases ZEB1 mRNA expression through repression of ZEB1-targeting miRNAs, miR-200c and miR-141. In contrast, targeting the MNK effector hnRNPA1, which can function as a translational repressor, increases ZEB1 protein without increasing ZEB1 mRNA levels. Importantly, treatment with MNK inhibitors blocks growth of chemoresistant PDAC cells in collagen and decreases the number of aldehyde dehydrogenase activity-positive (Aldefluor+) cells. Significantly, MNK inhibitors increase E-cadherin mRNA levels and decrease vimentin mRNA levels in human PDAC organoids without affecting ZEB1 mRNA levels. Importantly, MNK inhibitors also decrease growth of human PDAC organoids. IMPLICATIONS: These results demonstrate differential regulation of ZEB1 and EMT by MNKs and eIF4E, and identify MNKs as potential targets in pancreatic cancer. PMID- 26609112 TI - Velocity of motion across the skin influences perception of tactile location. AB - We investigated the influence of motion context on tactile localization, using a paradigm similar to the cutaneous rabbit or sensory saltation (Geldard FA, Sherrick CE. Science 178: 178-179, 1972). In one of its forms, the rabbit stimulus consists of a tap in one location quickly followed by another tap elsewhere, creating the illusion that the two taps are near each other. Instead of taps, we used position of a halted brush and instead of distance judgment, localization responses. The brush moved across the skin of the left forearm, creating a clear motion signal before and after a rabbitlike leap of 10 cm (at 100 cm/s). Three before-and-after velocities (7.5, 15, or 30 cm/s) were used. Participants (n = 13) pointed with their right arm at the felt location of the brush when it halted either 1 cm before or after the leap. These stops were 12 cm apart, but distances computed from localization responses were only 5.4, 6.5, and 7.5 cm for the three velocities, respectively (F[2,11] = 15.19, P = 0.001). Thus the leap resulted in compressive position shift, as described previously for sensory saltation, but modulated by motion velocity before the leap: the slower the motion, the greater the shift opposite to motion direction. No gap in stimulation was perceived. We propose that velocity extrapolation causes the position shift: extrapolated motion does not have enough time to bridge the real spatial gap and thus assigns a closer location to the skin on the opposite side of the gap. PMID- 26609111 TI - The importance of decision onset. AB - The neural mechanisms of decision making are thought to require the integration of evidence over time until a response threshold is reached. Much work suggests that response threshold can be adjusted via top-down control as a function of speed or accuracy requirements. In contrast, the time of integration onset has received less attention and is believed to be determined mostly by afferent or preprocessing delays. However, a number of influential studies over the past decade challenge this assumption and begin to paint a multifaceted view of the phenomenology of decision onset. This review highlights the challenges involved in initiating the integration of evidence at the optimal time and the potential benefits of adjusting integration onset to task demands. The review outlines behavioral and electrophysiolgical studies suggesting that the onset of the integration process may depend on properties of the stimulus, the task, attention, and response strategy. Most importantly, the aggregate findings in the literature suggest that integration onset may be amenable to top-down regulation, and may be adjusted much like response threshold to exert cognitive control and strategically optimize the decision process to fit immediate behavioral requirements. PMID- 26609113 TI - Modulation of cognitive control levels via manipulation of saccade trial-type probability assessed with event-related BOLD fMRI. AB - Cognitive control supports flexible behavior adapted to meet current goals and can be modeled through investigation of saccade tasks with varying cognitive demands. Basic prosaccades (rapid glances toward a newly appearing stimulus) are supported by neural circuitry, including occipital and posterior parietal cortex, frontal and supplementary eye fields, and basal ganglia. These trials can be contrasted with complex antisaccades (glances toward the mirror image location of a stimulus), which are characterized by greater functional magnetic resonance imaging (MRI) blood oxygenation level-dependent (BOLD) signal in the aforementioned regions and recruitment of additional regions such as dorsolateral prefrontal cortex. The current study manipulated the cognitive demands of these saccade tasks by presenting three rapid event-related runs of mixed saccades with a varying probability of antisaccade vs. prosaccade trials (25, 50, or 75%). Behavioral results showed an effect of trial-type probability on reaction time, with slower responses in runs with a high antisaccade probability. Imaging results exhibited an effect of probability in bilateral pre- and postcentral gyrus, bilateral superior temporal gyrus, and medial frontal gyrus. Additionally, the interaction between saccade trial type and probability revealed a strong probability effect for prosaccade trials, showing a linear increase in activation parallel to antisaccade probability in bilateral temporal/occipital, posterior parietal, medial frontal, and lateral prefrontal cortex. In contrast, antisaccade trials showed elevated activation across all runs. Overall, this study demonstrated that improbable performance of a typically simple prosaccade task led to augmented BOLD signal to support changing cognitive control demands, resulting in activation levels similar to the more complex antisaccade task. PMID- 26609114 TI - Alpha-Dendrotoxin-sensitive Kv1 channels contribute to conduction failure of polymodal nociceptive C-fibers from rat coccygeal nerve. AB - It is known that some patients with diabetic neuropathy are usually accompanied by abnormal painful sensations. Evidence has accumulated that diabetic neuropathic pain is associated with the hyperexcitability of peripheral nociceptors. Previously, we demonstrated that reduced conduction failure of polymodal nociceptive C-fibers and enhanced voltage-dependent sodium currents of small dorsal root ganglion (DRG) neurons contribute to diabetic hyperalgesia. To further investigate whether and how potassium channels are involved in the conduction failure, alpha-dendrotoxin (alpha-DTX), a selective blocker of the low threshold sustained Kv1 channel, was chosen to examine its functional capability in modulating the conduction properties of polymodal nociceptive C-fibers and the excitability of sensory neurons. We found that alpha-DTX reduced the conduction failure of C-fibers from coccygeal nerve in vivo accompanied by an increased initial conduction velocity but a decreased activity-dependent slowing of conduction velocity. In addition, the number of APs evoked by step currents was significantly enhanced after the treatment with alpha-DTX in small-diameter sensory neurons. Further study of the mechanism indicates alpha-DTX-sensitive K(+) current significantly reduced and the activation of this current in peak and steady state shifted to depolarization for diabetic neurons. Expression of Kv channel subunits Kv1.2 and Kv1.6 was downregulated in both small dorsal root ganglion neurons and peripheral C-fibers. Taken together, these results suggest that alpha-DTX-sensitive Kv1 channels might play an important role in regulating the conduction properties of polymodal nociceptive C-fibers and firing properties of sensory neurons. PMID- 26609116 TI - The time course of natural scene perception with reduced attention. AB - Attention is thought to impose an informational bottleneck on vision by selecting particular information from visual scenes for enhanced processing. Behavioral evidence suggests, however, that some scene information is extracted even when attention is directed elsewhere. Here, we investigated the neural correlates of this ability by examining how attention affects electrophysiological markers of scene perception. In two electro-encephalography (EEG) experiments, human subjects categorized real-world scenes as manmade or natural (full attention condition) or performed tasks on unrelated stimuli in the center or periphery of the scenes (reduced attention conditions). Scene processing was examined in two ways: traditional trial averaging was used to assess the presence of a categorical manmade/natural distinction in event-related potentials, whereas single-trial analyses assessed whether EEG activity was modulated by scene statistics that are diagnostic of naturalness of individual scenes. The results indicated that evoked activity up to 250 ms was unaffected by reduced attention, showing intact categorical differences between manmade and natural scenes and strong modulations of single-trial activity by scene statistics in all conditions. Thus initial processing of both categorical and individual scene information remained intact with reduced attention. Importantly, however, attention did have profound effects on later evoked activity; full attention on the scene resulted in prolonged manmade/natural differences, increased neural sensitivity to scene statistics, and enhanced scene memory. These results show that initial processing of real-world scene information is intact with diminished attention but that the depth of processing of this information does depend on attention. PMID- 26609115 TI - Response recovery in the locust auditory pathway. AB - Temporal resolution and the time courses of recovery from acute adaptation of neurons in the auditory pathway of the grasshopper Locusta migratoria were investigated with a response recovery paradigm. We stimulated with a series of single click and click pair stimuli while performing intracellular recordings from neurons at three processing stages: receptors and first and second order interneurons. The response to the second click was expressed relative to the single click response. This allowed the uncovering of the basic temporal resolution in these neurons. The effect of adaptation increased with processing layer. While neurons in the auditory periphery displayed a steady response recovery after a short initial adaptation, many interneurons showed nonlinear effects: most prominent a long-lasting suppression of the response to the second click in a pair, as well as a gain in response if a click was preceded by a click a few milliseconds before. Our results reveal a distributed temporal filtering of input at an early auditory processing stage. This set of specified filters is very likely homologous across grasshopper species and thus forms the neurophysiological basis for extracting relevant information from a variety of different temporal signals. Interestingly, in terms of spike timing precision neurons at all three processing layers recovered very fast, within 20 ms. Spike waveform analysis of several neuron types did not sufficiently explain the response recovery profiles implemented in these neurons, indicating that temporal resolution in neurons located at several processing layers of the auditory pathway is not necessarily limited by the spike duration and refractory period. PMID- 26609117 TI - Time course of human motoneuron recovery after sustained low-level voluntary activity. AB - Motoneurons often fire repetitively and for long periods. In sustained voluntary contractions the excitability of motoneurons declines. We provide the first detailed description of the time course of human motoneuron recovery after sustained activity at a constant discharge rate. We recorded the discharge of single motor units (MUs, n = 30) with intramuscular wire electrodes inserted in triceps brachii during weak isometric contractions. Subjects (n = 15) discharged single MUs at a constant frequency (~10 Hz) with visual feedback for prolonged durations (3-7 min) until rectified surface electromyogram (sEMG) of triceps brachii increased by ~100%. After a rest of 1-2, 15, 30, 60, 120, or 240 s, subjects briefly resumed the contraction with the target MU at the same discharge rate. Each MU was tested with three to four rest periods. The magnitude of sEMG was increased when contractions were resumed, and the target motoneuron discharged at the test frequency following rest intervals of 2-60 s (P = 0.001 0.038). The increased sEMG indicates that greater excitatory drive was needed to discharge the motoneuron at the test rate. The increase in EMG recovered exponentially with a time constant of 28 s but did not return to baseline even after a rest period of ~240 s. Thus the decline in motoneuron excitability from a weak contraction takes several minutes to recover fully. PMID- 26609118 TI - Microsaccade direction reflects the economic value of potential saccade goals and predicts saccade choice. AB - Microsaccades are small-amplitude (typically <1 degrees ), ballistic eye movements that occur when attempting to fixate gaze. Initially thought to be generated randomly, it has recently been established that microsaccades are influenced by sensory stimuli, attentional processes, and certain cognitive states. Whether decision processes influence microsaccades, however, is unknown. Here, we adapted two classic economic tasks to examine whether microsaccades reflect evolving saccade decisions. Volitional saccade choices of monkey and human subjects provided a measure of the subjective value of targets. Importantly, analyses occurred during a period of complete darkness to minimize the known influence of sensory and attentional processes on microsaccades. As the time of saccadic choice approached, microsaccade direction became the following: 1) biased toward targets as a function of their subjective value and 2) predictive of upcoming, voluntary choice. Our results indicate that microsaccade direction is influenced by and is a reliable tell of evolving saccade decisions. Our results are consistent with dynamic decision processes within the midbrain superior colliculus; that is, microsaccade direction is influenced by the transition of activity toward caudal saccade regions associated with high saccade value and/or future saccade choice. PMID- 26609119 TI - Abnormal cell-intrinsic and network excitability in the neocortex of serotonin deficient Pet-1 knockout mice. AB - Neurons originating from the raphe nuclei of the brain stem are the exclusive source of serotonin (5-HT) to the cortex. Their serotonergic phenotype is specified by the transcriptional regulator Pet-1, which is also necessary for maintaining their neurotransmitter identity across development. Transgenic mice in which Pet-1 is genetically ablated (Pet-1(-/-)) show a dramatic reduction (~80%) in forebrain 5-HT levels, yet no investigations have been carried out to assess the impact of such severe 5-HT depletion on the function of target cortical neurons. Using whole cell patch-clamp methods, two-dimensional (2D) multielectrode arrays (MEAs), 3D morphological neuronal reconstructions, and animal behavior, we investigated the impact of 5-HT depletion on cortical cell intrinsic and network excitability. We found significant changes in several parameters of cell-intrinsic excitability in cortical pyramidal cells (PCs) as well as an increase in spontaneous synaptic excitation through 5-HT3 receptors. These changes are associated with increased local network excitability and oscillatory activity in a 5-HT2 receptor-dependent manner, consistent with previously reported hypersensitivity of cortical 5-HT2 receptors. PC morphology was also altered, with a significant reduction in dendritic complexity that may possibly act as a compensatory mechanism for increased excitability. Consistent with this interpretation, when we carried out experiments with convulsant-induced seizures to asses cortical excitability in vivo, we observed no significant differences in seizure parameters between wild-type and Pet-1(-/-) mice. Moreover, MEA recordings of propagating field potentials showed diminished propagation of activity across the cortical sheath. Together these findings reveal novel functional changes in neuronal and cortical excitability in mice lacking Pet-1. PMID- 26609120 TI - Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage. AB - Mitochondrial dysfunction causes increased oxidative stress and depletion of ATP, which are involved in the etiology of a variety of renal diseases, such as CKD, AKI, and steroid-resistant nephrotic syndrome. Antioxidant therapies are being investigated, but clinical outcomes have yet to be determined. Recently, we reported that a newly synthesized indole derivative, mitochonic acid 5 (MA-5), increases cellular ATP level and survival of fibroblasts from patients with mitochondrial disease. MA-5 modulates mitochondrial ATP synthesis independently of oxidative phosphorylation and the electron transport chain. Here, we further investigated the mechanism of action for MA-5. Administration of MA-5 to an ischemia-reperfusion injury model and a cisplatin-induced nephropathy model improved renal function. In in vitro bioenergetic studies, MA-5 facilitated ATP production and reduced the level of mitochondrial reactive oxygen species (ROS) without affecting activity of mitochondrial complexes I-IV. Additional assays revealed that MA-5 targets the mitochondrial protein mitofilin at the crista junction of the inner membrane. In Hep3B cells, overexpression of mitofilin increased the basal ATP level, and treatment with MA-5 amplified this effect. In a unique mitochondrial disease model (Mitomice with mitochondrial DNA deletion that mimics typical human mitochondrial disease phenotype), MA-5 improved the reduced cardiac and renal mitochondrial respiration and seemed to prolong survival, although statistical analysis of survival times could not be conducted. These results suggest that MA-5 functions in a manner differing from that of antioxidant therapy and could be a novel therapeutic drug for the treatment of cardiac and renal diseases associated with mitochondrial dysfunction. PMID- 26609123 TI - Cardiorenal syndrome: review of our current understanding. AB - Renal and cardiac diseases are both prevalent and carry significant morbidity and mortality. They share common vascular risk factors and are physiologically interlinked. Dysfunction in one organ affects the other. Concurrent renal and cardiac disease is associated with a poor prognosis. This close relationship is reflected through cardiorenal syndrome. A classification system has been proposed; however, the underlying process is complex and multifactorial. Management of this syndrome focuses on improving heart function, reducing volume overload, and managing heart failure and chronic kidney disease. This, however, is challenging, limited by paucity of evidence and may lead to suboptimal therapy. Increased recognition of this syndrome should raise awareness in providing early therapy and avoiding adverse outcomes due to under-treatment. In this article, we provide an overview of our current understanding of cardiorenal syndrome, as well as its pathophysiology and treatment options. PMID- 26609122 TI - Trauma-Focused Treatment in PTSD Patients With Psychosis: Symptom Exacerbation, Adverse Events, and Revictimization. AB - OBJECTIVES: Most clinicians refrain from trauma treatment for patients with psychosis because they fear symptom exacerbation and relapse. This study examined the negative side effects of trauma-focused (TF) treatment in patients with psychosis and posttraumatic stress disorder (PTSD). METHODS: Analyses were conducted on data from a single-blind randomized controlled trial comparing TF treatment (N = 108; 8 sessions prolonged exposure or eye movement desensitization) and waiting list (WL; N = 47) among patients with a lifetime psychotic disorder and current chronic PTSD. Symptom exacerbation, adverse events, and revictimization were assessed posttreatment and at 6-month follow-up. Also investigated were symptom exacerbation after initiation of TF treatment and the relationship between symptom exacerbation and dropout. RESULTS: Any symptom exacerbation (PTSD, paranoia, or depression) tended to occur more frequently in the WL condition. After the first TF treatment session, PTSD symptom exacerbation was uncommon. There was no increase of hallucinations, dissociation, or suicidality during the first 2 sessions. Paranoia decreased significantly during this period. Dropout was not associated with symptom exacerbation. Compared with the WL condition, fewer persons in the TF treatment condition reported an adverse event (OR = 0.48, P = .032). Surprisingly, participants receiving TF treatment were significantly less likely to be revictimized (OR = 0.40, P = .035). CONCLUSIONS: In these participants, TF treatment did not result in symptom exacerbation or adverse events. Moreover, TF treatment was associated with significantly less exacerbation, less adverse events, and reduced revictimization compared with the WL condition. This suggests that conventional TF treatment protocols can be safely used in patients with psychosis without negative side effects. PMID- 26609121 TI - Exploring Transcription Factors-microRNAs Co-regulation Networks in Schizophrenia. AB - BACKGROUND: Transcriptional factors (TFs) and microRNAs (miRNAs) have been recognized as 2 classes of principal gene regulators that may be responsible for genome coexpression changes observed in schizophrenia (SZ). METHODS: This study aims to (1) identify differentially coexpressed genes (DCGs) in 3 mRNA expression microarray datasets; (2) explore potential interactions among the DCGs, and differentially expressed miRNAs identified in our dataset composed of early-onset SZ patients and healthy controls; (3) validate expression levels of some key transcripts; and (4) explore the druggability of DCGs using the curated database. RESULTS: We detected a differential coexpression network associated with SZ and found that 9 out of the 12 regulators were replicated in either of the 2 other datasets. Leveraging the differentially expressed miRNAs identified in our previous dataset, we constructed a miRNA-TF-gene network relevant to SZ, including an EGR1-miR-124-3p-SKIL feed-forward loop. Our real-time quantitative PCR analysis indicated the overexpression of miR-124-3p, the under expression of SKIL and EGR1 in the blood of SZ patients compared with controls, and the direction of change of miR-124-3p and SKIL mRNA levels in SZ cases were reversed after a 12-week treatment cycle. Our druggability analysis revealed that many of these genes have the potential to be drug targets. CONCLUSIONS: Together, our results suggest that coexpression network abnormalities driven by combinatorial and interactive action from TFs and miRNAs may contribute to the development of SZ and be relevant to the clinical treatment of the disease. PMID- 26609124 TI - Robotic total mesorectal excision - precision surgery with even more precise tools. PMID- 26609125 TI - Parity of esteem for mental and physical healthcare in England: a hundred years war? PMID- 26609126 TI - The importance of 'Choosing Wisely'. PMID- 26609127 TI - Trends in hospital admission rates for anorexia nervosa in Oxford (1968-2011) and England (1990-2011): database studies. AB - OBJECTIVES: To report on long-term trends in hospital admission rates for anorexia nervosa using two English datasets. DESIGN: We used data on hospital day case and inpatient care across five decades in the Oxford Record Linkage Study (ORLS), and similar data for all England from 1990. We analysed rates of admission for anorexia nervosa in people aged 10-44 years, using hospital episodes (counting every admission) and first-recorded admissions (counting only the first record for each person). SETTING: Former Oxford NHS Region; and England. PARTICIPANTS: None; anonymous statistical records were used. RESULTS: In the longstanding ORLS, the age-standardised first-recorded admission rate for women was 2.7 (95% confidence interval 1.6-3.8) per 100,000 female population aged 10-44 years in 1968-1971; 2.7 (2.1-3.3) in 1992-1996; and 6.3 (5.5-7.2) in 2007-2011. Male rates were zero in the 1960s; 0.07 (0.0-0.1) per 100,000 men in 1992-1996; and 0.4 (0.2-0.6) in 2007-2011. In England, female rates increased from 4.2 (4.0-4.4) in 1998-2001 to 6.9 (6.7-7.1) in 2007-2011; and the corresponding male rates were 0.2 (0.1-0.3) and 0.5 (0.4-0.6). Episode-based admission rates rose more than person-based rates. The highest rates by far were in girls and women aged 15-19 years. CONCLUSIONS: In recent years, anorexia nervosa has become a greater burden on secondary care: not only have admission rates increased but so too have multiple admissions per person with anorexia nervosa. The increase in admission rates might reflect an increase in prevalence rates of anorexia nervosa in the general population, but other explanations, including lower clinical thresholds for admission, are possible and are discussed. PMID- 26609128 TI - Family-centred care: the 'captive mother' revisited. PMID- 26609129 TI - Modifying influence of occupational inflammatory diseases on the level of chromosome aberrations in coal miners. AB - Coal miners are exposed to a wide range of genotoxic agents that can induce genome damage. In addition, miners are characterised by a high risk of the initiation of different occupational inflammatory as well as non-inflammatory diseases. The aim of this investigation is to analyse the modifying influence of occupational pulmonary inflammatory diseases on the level of chromosome aberrations (CAs) in miners working in underground coal mines in Kemerovo Region (Russian Federation). The study group included 90 coal miners with the following pulmonary diseases: chronic dust-induced bronchitis (CDB) and coal-workers' pneumoconiosis (CWP) (mean age = 53.52+/-2.95 years; mean work experience in coal mining conditions = 27.70+/-3.61 years). As a population control (control 1), we have used venous blood extracted from 124 healthy unexposed men. The mean age in this group was 50.92+/-4.56 years. Control 2 was the venous blood extracted from 42 healthy coal miners (mean age = 51.56+/-6.38 years; mean work experience in coal-mining conditions = 25.43+/-8.14 years). We have discovered that coal miners are characterised by an increased general level of CAs as well as an increased frequency of several types of CAs. The significant increase in the frequency of aberration per 100 cells and aberration of chromosome type was discovered in the group of pulmonary disease patients (study group). No correlations of the level of chromosome damage with age, smoking status and work experience in coal-mining conditions were discovered. PMID- 26609130 TI - Euthanasia using gaseous agents in laboratory rodents. AB - Several questions have been raised in recent years about the euthanasia of laboratory rodents. Euthanasia using inhaled agents is considered to be a suitable aesthetic method for use with a large number of animals simultaneously. Nevertheless, its aversive potential has been criticized in terms of animal welfare. The data available regarding the use of carbon dioxide (CO2), inhaled anaesthetics (such as isoflurane, sevoflurane, halothane and enflurane), as well as carbon monoxide and inert gases are discussed throughout this review. Euthanasia of fetuses and neonates is also addressed. A table listing currently available information to ease access to data regarding euthanasia techniques using gaseous agents in laboratory rodents was compiled. Regarding better animal welfare, there is currently insufficient evidence to advocate banning or replacing CO2 in the euthanasia of rodents; however, there are hints that alternative gases are more humane. The exposure to a volatile anaesthetic gas before loss of consciousness has been proposed by some scientific studies to minimize distress; however, the impact of such a measure is not clear. Areas of inconsistency within the euthanasia literature have been highlighted recently and stem from insufficient knowledge, especially regarding the advantages of the administration of isoflurane or sevoflurane over CO2, or other methods, before loss of consciousness. Alternative methods to minimize distress may include the development of techniques aimed at inducing death in the home cage of animals. Scientific outcomes have to be considered before choosing the most suitable euthanasia method to obtain the best results and accomplish the 3Rs (replacement, reduction and refinement). PMID- 26609132 TI - Translational Biomarkers of Neurotoxicity: A Health and Environmental Sciences Institute Perspective on the Way Forward. AB - Neurotoxicity has been linked to a number of common drugs and chemicals, yet efficient and accurate methods to detect it are lacking. There is a need for more sensitive and specific biomarkers of neurotoxicity that can help diagnose and predict neurotoxicity that are relevant across animal models and translational from nonclinical to clinical data. Fluid-based biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid (CSF) have great potential due to the relative ease of sampling compared with tissues. Increasing evidence supports the potential utility of fluid-based biomarkers of neurotoxicity such as microRNAs, F2-isoprostanes, translocator protein, glial fibrillary acidic protein, ubiquitin C-terminal hydrolase L1, myelin basic protein, microtubule associated protein-2, and total tau. However, some of these biomarkers such as those in CSF require invasive sampling or are specific to one disease such as Alzheimer's, while others require further validation. Additionally, neuroimaging methodologies, including magnetic resonance imaging, magnetic resonance spectroscopy, and positron emission tomography, may also serve as potential biomarkers and have several advantages including being minimally invasive. The development of biomarkers of neurotoxicity is a goal shared by scientists across academia, government, and industry and is an ideal topic to be addressed via the Health and Environmental Sciences Institute (HESI) framework which provides a forum to collaborate on key challenging scientific topics. Here we utilize the HESI framework to propose a consensus on the relative potential of currently described biomarkers of neurotoxicity to assess utility of the selected biomarkers using a nonclinical model. PMID- 26609134 TI - Functional dichotomy in the 16S rRNA (m1A1408) methyltransferase family and control of catalytic activity via a novel tryptophan mediated loop reorganization. AB - Methylation of the bacterial small ribosomal subunit (16S) rRNA on the N1 position of A1408 confers exceptionally high-level resistance to a broad spectrum of aminoglycoside antibiotics. Here, we present a detailed structural and functional analysis of the Catenulisporales acidiphilia 16S rRNA (m(1)A1408) methyltransferase ('CacKam'). The apo CacKam structure closely resembles other m(1)A1408 methyltransferases within its conserved SAM-binding fold but the region linking core beta strands 6 and 7 (the 'beta6/7 linker') has a unique, extended structure that partially occludes the putative 16S rRNA binding surface, and sequesters the conserved and functionally critical W203 outside of the CacKam active site. Substitution of conserved residues in the SAM binding pocket reveals a functional dichotomy in the 16S rRNA (m(1)A1408) methyltransferase family, with two apparently distinct molecular mechanisms coupling cosubstrate/ substrate binding to catalytic activity. Our results additionally suggest that CacKam exploits the W203-mediated remodeling of the beta6/7 linker as a novel mechanism to control 30S substrate recognition and enzymatic turnover. PMID- 26609133 TI - The 3D folding of metazoan genomes correlates with the association of similar repetitive elements. AB - The potential roles of the numerous repetitive elements found in the genomes of multi-cellular organisms remain speculative. Several studies have suggested a role in stabilizing specific 3D genomic contacts. To test this hypothesis, we exploited inter-chromosomal contacts frequencies obtained from Hi-C experiments and show that the folding of the human, mouse and Drosophila genomes is associated with a significant co-localization of several specific repetitive elements, notably many elements of the SINE family. These repeats tend to be the oldest ones and are enriched in transcription factor binding sites. We propose that the co-localization of these repetitive elements may explain the global conservation of genome folding observed between homologous regions of the human and mouse genome. Taken together, these results support a contribution of specific repetitive elements in maintaining and/or reshaping genome architecture over evolutionary times. PMID- 26609135 TI - Genome-wide analysis of the specificity and mechanisms of replication infidelity driven by imbalanced dNTP pools. AB - The absolute and relative concentrations of the four dNTPs are key determinants of DNA replication fidelity, yet the consequences of altered dNTP pools on replication fidelity have not previously been investigated on a genome-wide scale. Here, we use deep sequencing to determine the types, rates and locations of uncorrected replication errors that accumulate in the nuclear genome of a mismatch repair-deficient diploid yeast strain with elevated dCTP and dTTP concentrations. These imbalanced dNTP pools promote replication errors in specific DNA sequence motifs suggesting increased misinsertion and increased mismatch extension at the expense of proofreading. Interestingly, substitution rates are similar for leading and lagging strand replication, but are higher in regions replicated late in S phase. Remarkably, the rate of single base deletions is preferentially increased in coding sequences and in short rather than long mononucleotides runs. Based on DNA sequence motifs, we propose two distinct mechanisms for generating single base deletions in vivo. Collectively, the results indicate that elevated dCTP and dTTP pools increase mismatch formation and decrease error correction across the nuclear genome, and most strongly increases mutation rates in coding and late replicating sequences. PMID- 26609138 TI - Natriuretic Peptides as Cardiovascular Safety Biomarkers in Rats: Comparison With Blood Pressure, Heart Rate, and Heart Weight. AB - Cardiovascular (CV) toxicity is an important cause of failure during drug development. Blood-based biomarkers can be used to detect CV toxicity during preclinical development and prioritize compounds at lower risk of causing such toxicities. Evidence of myocardial degeneration can be detected by measuring concentrations of biomarkers such as cardiac troponin I and creatine kinase in blood; however, detection of functional changes in the CV system, such as blood pressure, generally requires studies in animals with surgically implanted pressure transducers. This is a significant limitation because sustained changes in blood pressure are often accompanied by changes in heart rate and together can lead to cardiac hypertrophy and myocardial degeneration in animals, and major adverse cardiovascular events (MACE) in humans. Increased concentrations of NPs in blood correlate with higher risk of cardiac mortality, all-cause mortality, and MACE in humans. Their utility as biomarkers of CV function and toxicity in rodents was investigated by exploring the relationships between plasma concentrations of NTproANP and NTproBNP, blood pressure, heart rate, and heart weight in Sprague Dawley rats administered compounds that caused hypotension or hypertension, including nifedipine, fluprostenol, minoxidil, L-NAME, L-thyroxine, or sunitinib for 1-2 weeks. Changes in NTproANP and/or NTproBNP concentrations were inversely correlated with changes in blood pressure. NTproANP and NTproBNP concentrations were inconsistently correlated with relative heart weights. In addition, increased heart rate was associated with increased heart weights. These studies support the use of natriuretic peptides and heart rate to detect changes in blood pressure and cardiac hypertrophy in short-duration rat studies. PMID- 26609137 TI - An 8-Month Systems Toxicology Inhalation/Cessation Study in Apoe-/- Mice to Investigate Cardiovascular and Respiratory Exposure Effects of a Candidate Modified Risk Tobacco Product, THS 2.2, Compared With Conventional Cigarettes. AB - Smoking cigarettes is a major risk factor in the development and progression of cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD). Modified risk tobacco products (MRTPs) are being developed to reduce smoking related health risks. The goal of this study was to investigate hallmarks of COPD and CVD over an 8-month period in apolipoprotein E-deficient mice exposed to conventional cigarette smoke (CS) or to the aerosol of a candidate MRTP, tobacco heating system (THS) 2.2. In addition to chronic exposure, cessation or switching to THS2.2 after 2 months of CS exposure was assessed. Engaging a systems toxicology approach, exposure effects were investigated using physiology and histology combined with transcriptomics, lipidomics, and proteomics. CS induced nasal epithelial hyperplasia and metaplasia, lung inflammation, and emphysematous changes (impaired pulmonary function and alveolar damage). Atherogenic effects of CS exposure included altered lipid profiles and aortic plaque formation. Exposure to THS2.2 aerosol (nicotine concentration matched to CS, 29.9 mg/m(3)) neither induced lung inflammation or emphysema nor did it consistently change the lipid profile or enhance the plaque area. Cessation or switching to THS2.2 reversed the inflammatory responses and halted progression of initial emphysematous changes and the aortic plaque area. Biological processes, including senescence, inflammation, and proliferation, were significantly impacted by CS but not by THS2.2 aerosol. Both, cessation and switching to THS2.2 reduced these perturbations to almost sham exposure levels. In conclusion, in this mouse model cessation or switching to THS2.2 retarded the progression of CS-induced atherosclerotic and emphysematous changes, while THS2.2 aerosol alone had minimal adverse effects. PMID- 26609136 TI - Ribonucleoprotein particles of bacterial small non-coding RNA IsrA (IS61 or McaS) and its interaction with RNA polymerase core may link transcription to mRNA fate. AB - Coupled transcription and translation in bacteria are tightly regulated. Some small RNAs (sRNAs) control aspects of this coupling by modifying ribosome access or inducing degradation of the message. Here, we show that sRNA IsrA (IS61 or McaS) specifically associates with core enzyme of RNAP in vivo and in vitro, independently of sigma factor and away from the main nucleic-acids-binding channel of RNAP. We also show that, in the cells, IsrA exists as ribonucleoprotein particles (sRNPs), which involve a defined set of proteins including Hfq, S1, CsrA, ProQ and PNPase. Our findings suggest that IsrA might be directly involved in transcription or can participate in regulation of gene expression by delivering proteins associated with it to target mRNAs through its interactions with transcribing RNAP and through regions of sequence complementarity with the target. In this eukaryotic-like model only in the context of a complex with its target, IsrA and its associated proteins become active. In this manner, in the form of sRNPs, bacterial sRNAs could regulate a number of targets with various outcomes, depending on the set of associated proteins. PMID- 26609139 TI - MicroRNA Responses to the Genotoxic Carcinogens Aflatoxin B1 and Benzo[a]pyrene in Human HepaRG Cells. AB - Recent advances in toxicogenomics present an opportunity to develop new in vitro testing methodologies to identify human carcinogens. We have investigated microRNA expression responses to the treatment of human liver HepaRG cells with the human genotoxic carcinogens aflatoxin B1 (AFB1) and benzo[a]pyrene (B[a]P), and the structurally similar compounds aflatoxin B2 (AFB2) and benzo[e]pyrene (B[e]P) that exhibit minimal carcinogenic potential. We demonstrate that treatment of HepaRG cells with AFB1 or B[a]P resulted in specific changes in the expression of miRNAs as compared with their non-carcinogenic analogues, particularly in a marked over-expression of miR-410. An additional novel finding is the dose- and time-dependent inhibition of miR-122 in AFB1-treated HepaRG cells. Mechanistically, the AFB1-induced down-regulation of miR-122 was attributed to inhibition of the HNF4A/miR-122 regulatory pathway. These results demonstrate that HepaRG cells can be used to investigate miRNA responses to xenobiotic exposure, and illustrate the existence of early non-genotoxic events, in addition to a well-established genotoxic mode of action changes, in the mechanism of AFB1 and B[a]P carcinogenicity. PMID- 26609140 TI - Calcium Contributes to the Cytotoxic Interaction Between Diclofenac and Cytokines. AB - Diclofenac (DCLF) is a widely used non-steroidal anti-inflammatory drug that is associated with idiosyncratic, drug-induced liver injury (IDILI) in humans. The mechanisms of DCLF-induced liver injury are unknown; however, patients with certain inflammatory diseases have an increased risk of developing IDILI, which raises the possibility that immune mediators play a role in the pathogenesis. DCLF synergizes with the cytokines tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN) to cause hepatocellular apoptosis in vitro by a mechanism that involves activation of the endoplasmic reticulum (ER) stress response pathway and of the mitogen-activated protein kinases, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). DCLF also causes an increase in intracellular calcium (Ca(++)) in hepatocytes, but the role of this in the cytotoxic synergy between DCLF and cytokines is unknown. We tested the hypothesis that Ca(++) contributes to DCLF/cytokine-induced cytotoxic synergy. Treatment of HepG2 cells with DCLF led to an increase in intracellular Ca(++) at 6 and 12 h, and this response was augmented in the presence of TNF and IFN at 12 h. The intracellular Ca(++) chelator BAPTA/AM reduced cytotoxicity and caspase-3 activation caused by DCLF/cytokine cotreatment. BAPTA/AM also significantly reduced DCLF-induced activation of the ER stress sensor, protein kinase RNA-like ER kinase (PERK), as well as activation of JNK and ERK. Treatment of cells with an inositol trisphosphate receptor antagonist almost completely eliminated DCLF/cytokine-induced cytotoxicity and decreased DCLF-induced activation of PERK, JNK, and ERK. These findings indicate that Ca(++) contributes to DCLF/cytokine induced cytotoxic synergy by promoting activation of the ER stress-response pathway and JNK and ERK. PMID- 26609142 TI - Commentary on: An Assessment of Gender Differences in Plastic Surgery Marketing in the United States: Are We Neglecting Our Male Patients? PMID- 26609141 TI - Classical and Alternative Activation of Cyanobacterium Oscillatoria sp. Lipopolysaccharide-Treated Rat Microglia in vitro. AB - The purpose of this investigation was to test the hypothesis that an in vitro exposure to cyanobacterium Oscillatoria sp. Lipopolysaccharide (LPS) might result in classical and alternative activation of rat neonatal microglia. Using Escherichia coli LPS-primed microglia as a positive control, this study revealed that treatment of rat microglia with Oscillatoria sp. LPS for 17 h in vitro resulted in both classical and alternative activation as well as concomitant pro inflammatory and anti-inflammatory mediator release, in a concentration-dependent manner: (1) treatment with 0.1-10 000 ng/ml Oscillatoria sp. LPS resulted in minimal lactic dehydrogenase (LDH) release, induced concentration-dependent and statistically significant O2 (-) generation, matrix metalloproteinase-9 (MMP-9) release, generation of the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and the chemokines macrophage inflammatory protein-2 (MIP 2/CXCL2), interferon gamma-induced protein 10 kDa (IP-10/CXCL-10), (MIP 1alpha/CCL3), monocyte chemotactic protein-1 (MCP-1/CCL2), regulated on activation, normal T cell expressed and secreted (RANTES/CCL5), and the alternative activation cytokine IL-10; (3) in contrast, treatment with 100 000 ng/ml Oscillatoria sp. LPS appeared to damage the microglia cell membrane, because it resulted in minimal O2 (-) generation, statistically significant LDH release, and a decrease in the generation of all the cytokines and chemokines investigated, with the exception of IL-1alpha and cytokine-induced neutrophil chemoattractant 1 (CINC-1/CXCL1) generation, which was increased. Thus, our results provide experimental support for our working hypothesis, namely that Oscillatoria sp. LPS induces classical and alternative activation of rat brain microglia in vitro in a concentration-dependent manner, namely 0.1-10 000 ng/ml Oscillatoria sp. LPS, when microglia cells were shown to be viable. Furthermore, should cyanobacterium Oscillatoria sp. LPS gain entry into the CNS, our findings suggest that classical and alternative activation of rat brain microglia in vivo, might lead to concomitant mediator release that could result in an interplay between neuroinflammation and neural repair in a concentration-dependent manner. PMID- 26609143 TI - Commentary on: Prospective 1-Year Follow-Up Study of Breast Augmentation by Cell Assisted Lipotransfer. PMID- 26609144 TI - The Rainbow Scale: A Simple, Validated Online Method to Score the Outcome of Aesthetic Treatments. PMID- 26609146 TI - The Relationship Between Glenohumeral Internal Rotational Deficits, Total Range of Motion, and Shoulder Strength in Professional Baseball Pitchers. AB - INTRODUCTION: Although the lack of internal rotation (IR) and total range of motion (TRM) has been identified as a significant contributing factor of shoulder injuries, our goal was to determine whether a relationship exists between glenohumeral internal rotational deficits (GIRD), TRM, and shoulder strength in professional baseball pitchers. Our hypothesis was that GIRD with TRM differences within 5 degrees will not lead to decreased shoulder strength; however, a shoulder with >5 degrees of TRM difference with GIRD will lead to decreased shoulder strength. METHODS: The study was conducted over a 4-year period and included 193 major and minor league pitchers. All measurements were taken prior to the pitcher's engaging in any baseball-related activities on the day of measurements. The entire measurement arc of passive range of motion (PROM), including external rotation (ER) and IR, was defined as the TRM. GIRD was defined as a loss of 25 degrees or more of IR of the throwing shoulder compared with the nonthrowing shoulder. Shoulder strength measurements were obtained using a validated digital dynamometer with the arm in 90 degrees of abduction and with the arm in 110 degrees of flexion and 30 degrees of abduction measured in pounds. RESULTS: The IR deficit was 5.89 degrees (SD = 9.24 degrees ) in non GIRD pitchers and 25.52 degrees (SD = 4.35 degrees ) in GIRD pitchers (P > 0.001). The ER change was 124.08 degrees (SD = 11.21 degrees ) in non-GIRD pitchers and 127.79 degrees (SD = 9.15 degrees ) in GIRD pitchers. The total arc of motion was 179.54 degrees (SD = 14.53 degrees ) in non-GIRD pitchers and 171.93 degrees (SD = 12.34 degrees ) in GIRD pitchers (P > 0.001). The strength in the shoulder, measured with the arm in 90 degrees of abduction, was 29.61 lb (SD = 4.76 lb) in non-GIRD pitchers versus 28.65 lb (SD = 4.81 lb) in GIRD pitchers. The strength with the arm in 110 degrees of flexion and 30 degrees of abduction was 29.43 lb (SD = 5.01 lb) in non-GIRD pitchers versus 28.13 lb (SD = 4.76 lb) in pitchers with GIRD (P = 0.043). Deficiencies in total arc of motion (P < 0.001) and shoulder strength (P < 0.043) were significantly associated with GIRD. DISCUSSION: In our evaluation of 193 pitchers examined during their preseason physical examinations, we identified a statistically significant association between decreased total arc of motion, decreased shoulder strength, and GIRD. PMID- 26609145 TI - Chikungunya virus-associated encephalitis: A cohort study on La Reunion Island, 2005-2009. AB - OBJECTIVE: To estimate the cumulative incidence rate (CIR) of Chikungunya virus (CHIKV)-associated CNS disease during the La Reunion outbreak, and assess the disease burden and patient outcome after 3 years. METHODS: CHIKV-associated CNS disease was characterized retrospectively in a cohort of patients with positive CHIKV reverse transcriptase PCR or anti-CHIKV immunoglobulin M antibodies in the CSF and fulfilling International Encephalitis Consortium criteria for encephalitis or encephalopathy. Neurologic sequelae were assessed after 3 years. RESULTS: Between September 2005 and June 2006, 57 patients were diagnosed with CHIKV-associated CNS disease, including 24 with CHIKV-associated encephalitis, the latter corresponding to a CIR of 8.6 per 100,000 persons. Patients with encephalitis were observed at both extremes of age categories. CIR per 100,000 persons were 187 and 37 in patients below 1 year and over 65 years, respectively, both far superior to those of cumulated causes of encephalitis in the United States in these age categories. The case-fatality rate of CHIKV-associated encephalitis was 16.6% and the proportion of children discharged with persistent disabilities estimated between 30% and 45%. Beyond the neonatal period, the clinical presentation and outcomes were less severe in infants than in adults. CONCLUSIONS: In the context of a large outbreak, CHIKV is a significant cause of CNS disease. As with other etiologies, CHIKV-associated encephalitis case distribution by age follows a U-shaped parabolic curve. PMID- 26609147 TI - State Dependency of Chemosensory Coding in the Gustatory Thalamus (VPMpc) of Alert Rats. AB - The parvicellular portion of the ventroposteromedial nucleus (VPMpc) is the part of the thalamus that processes gustatory information. Anatomical evidence shows that the VPMpc receives ascending gustatory inputs from the parabrachial nucleus (PbN) in the brainstem and sends projections to the gustatory cortex (GC). Although taste processing in PbN and GC has been the subject of intense investigation in behaving rodents, much less is known on how VPMpc neurons encode gustatory information. Here we present results from single-unit recordings in the VPMpc of alert rats receiving multiple tastants. Thalamic neurons respond to taste with time-varying modulations of firing rates, consistent with those observed in GC and PbN. These responses encode taste quality as well as palatability. Comparing responses to tastants either passively delivered, or self administered after a cue, unveiled the effects of general expectation on taste processing in VPMpc. General expectation led to an improvement of taste coding by modulating response dynamics, and single neuron ability to encode multiple tastants. Our results demonstrate that the time course of taste coding as well as single neurons' ability to encode for multiple qualities are not fixed but rather can be altered by the state of the animal. Together, the data presented here provide the first description that taste coding in VPMpc is dynamic and state dependent. SIGNIFICANCE STATEMENT: Over the past years, a great deal of attention has been devoted to understanding taste coding in the brainstem and cortex of alert rodents. Thanks to this research, we now know that taste coding is dynamic, distributed, and context-dependent. Alas, virtually nothing is known on how the gustatory thalamus (VPMpc) processes gustatory information in behaving rats. This manuscript investigates taste processing in the VPMpc of behaving rats. Our results show that thalamic neurons encode taste and palatability with time varying patterns of activity and that thalamic coding of taste is modulated by general expectation. Our data will appeal not only to researchers interested in taste, but also to a broader audience of sensory and systems neuroscientists interested in the thalamocortical system. PMID- 26609148 TI - Active Dendrites and Differential Distribution of Calcium Channels Enable Functional Compartmentalization of Golgi Cells. AB - Interneurons are essential to controlling excitability, timing, and synaptic integration in neuronal networks. Golgi cells (GoCs) serve these roles at the input layer of the cerebellar cortex by releasing GABA to inhibit granule cells (grcs). GoCs are excited by mossy fibers (MFs) and grcs and provide feedforward and feedback inhibition to grcs. Here we investigate two important aspects of GoC physiology: the properties of GoC dendrites and the role of calcium signaling in regulating GoC spontaneous activity. Although GoC dendrites are extensive, previous studies concluded they are devoid of voltage-gated ion channels. Hence, the current view holds that somatic voltage signals decay passively within GoC dendrites, and grc synapses onto distal dendrites are not amplified and are therefore ineffective at firing GoCs because of strong passive attenuation. Using whole-cell recording and calcium imaging in rat slices, we find that dendritic voltage-gated sodium channels allow somatic action potentials to activate voltage gated calcium channels (VGCCs) along the entire dendritic length, with R-type and T-type VGCCs preferentially located distally. We show that R- and T-type VGCCs located in the dendrites can boost distal synaptic inputs and promote burst firing. Active dendrites are thus critical to the regulation of GoC activity, and consequently, to the processing of input to the cerebellar cortex. In contrast, we find that N-type channels are preferentially located near the soma, and control the frequency and pattern of spontaneous firing through their close association with calcium-activated potassium (KCa) channels. Thus, VGCC types are differentially distributed and serve specialized functions within GoCs. SIGNIFICANCE STATEMENT: Interneurons are essential to neural processing because they modulate excitability, timing, and synaptic integration within circuits. At the input layer of the cerebellar cortex, a single type of interneuron, the Golgi cell (GoC), carries these functions. The extent of inhibition depends on both spontaneous activity of GoCs and the excitatory synaptic input they receive. In this study, we find that different types of calcium channels are differentially distributed, with dendritic calcium channels being activated by somatic activity, boosting synaptic inputs and enabling bursting, and somatic calcium cannels promoting regular firing. We therefore challenge the current view that GoC dendrites are passive and identify the mechanisms that contribute to GoCs regulating the flow of sensory information in the cerebellar cortex. PMID- 26609150 TI - Glutamate Receptors within the Mesolimbic Dopamine System Mediate Alcohol Relapse Behavior. AB - Glutamatergic input within the mesolimbic dopamine (DA) pathway plays a critical role in the development of addictive behavior. Although this is well established for some drugs of abuse, it is not known whether glutamate receptors within the mesolimbic system are involved in mediating the addictive properties of chronic alcohol use. Here we evaluated the contribution of mesolimbic NMDARs and AMPARs in mediating alcohol-seeking responses induced by environmental stimuli and relapse behavior using four inducible mutant mouse lines lacking the glutamate receptor genes Grin1 or Gria1 in either DA transporter (DAT) or D1R-expressing neurons. We first demonstrate the lack of GluN1 or GluA1 in either DAT- or D1R expressing neurons in our mutant mouse lines by colocalization studies. We then show that GluN1 and GluA1 receptor subunits within these neuronal subpopulations mediate the alcohol deprivation effect, while having no impact on context- plus cue-induced reinstatement of alcohol-seeking behavior. We further validated these results pharmacologically by demonstrating similar reductions in the alcohol deprivation effect after infusion of the NMDAR antagonist memantine into the nucleus accumbens and ventral tegmental area of control mice, and a rescue of the mutant phenotype via pharmacological potentiation of AMPAR activity using aniracetam. In conclusion, dopamine neurons as well as D1R-expressing medium spiny neurons and their glutamatergic inputs via NMDARs and AMPARs act in concert to influence relapse responses. These results provide a neuroanatomical and molecular substrate for relapse behavior and emphasize the importance of glutamatergic drugs in modulating relapse behavior. SIGNIFICANCE STATEMENT: Here we provide genetic and pharmacological evidence that glutamate receptors within the mesolimbic dopamine system play an essential role in alcohol relapse. Using various inducible and site-specific transgenic mouse models and pharmacological validation experiments, we show that critical subunits of NMDARs and AMPARs expressed either in dopamine neurons or in dopamine receptor D1-containing neurons play an important role in the alcohol deprivation effect (the increase in alcohol intake after a period of abstinence) while having no impact on context- plus cue-induced reinstatement of alcohol-seeking responses. Medications targeting glutamatergic neurotransmission by selective inactivation of these glutamate receptors might have therapeutic efficacy. PMID- 26609149 TI - The Global Spike: Conserved Dendritic Properties Enable Unique Ca2+ Spike Generation in Low-Threshold Spiking Neurons. AB - Low-threshold Ca(2+) spikes (LTS) are an indispensible signaling mechanism for neurons in areas including the cortex, cerebellum, basal ganglia, and thalamus. They have critical physiological roles and have been strongly associated with disorders including epilepsy, Parkinson's disease, and schizophrenia. However, although dendritic T-type Ca(2+) channels have been implicated in LTS generation, because the properties of low-threshold spiking neuron dendrites are unknown, the precise mechanism has remained elusive. Here, combining data from fluorescence targeted dendritic recordings and Ca(2+) imaging from low-threshold spiking cells in rat brain slices with computational modeling, the cellular mechanism responsible for LTS generation is established. Our data demonstrate that key somatodendritic electrical conduction properties are highly conserved between glutamatergic thalamocortical neurons and GABAergic thalamic reticular nucleus neurons and that these properties are critical for LTS generation. In particular, the efficiency of soma to dendrite voltage transfer is highly asymmetric in low threshold spiking cells, and in the somatofugal direction, these neurons are particularly electrotonically compact. Our data demonstrate that LTS have remarkably similar amplitudes and occur synchronously throughout the dendritic tree. In fact, these Ca(2+) spikes cannot occur locally in any part of the cell, and hence we reveal that LTS are generated by a unique whole-cell mechanism that means they always occur as spatially global spikes. This all-or-none, global electrical and biochemical signaling mechanism clearly distinguishes LTS from other signals, including backpropagating action potentials and dendritic Ca(2+)/NMDA spikes, and has important consequences for dendritic function in low threshold spiking neurons. SIGNIFICANCE STATEMENT: Low-threshold Ca(2+) spikes (LTS) are critical for important physiological processes, including generation of sleep-related oscillations, and are implicated in disorders including epilepsy, Parkinson's disease, and schizophrenia. However, the mechanism underlying LTS generation in neurons, which is thought to involve dendritic T-type Ca(2+) channels, has remained elusive due to a lack of knowledge of the dendritic properties of low-threshold spiking cells. Combining dendritic recordings, two photon Ca(2+) imaging, and computational modeling, this study reveals that dendritic properties are highly conserved between two prominent low-threshold spiking neurons and that these properties underpin a whole-cell somatodendritic spike generation mechanism that makes the LTS a unique global electrical and biochemical signal in neurons. PMID- 26609151 TI - Defects in Synaptic Plasticity, Reduced NMDA-Receptor Transport, and Instability of Postsynaptic Density Proteins in Mice Lacking Microtubule-Associated Protein 1A. AB - Microtubule-associated protein 1A (MAP1A) is a member of the major non-motor microtubule-binding proteins. It has been suggested that MAP1A tethers NMDA receptors (NRs) to the cytoskeleton by binding with proteins postsynaptic density (PSD)-93 and PSD-95, although the function of MAP1A in vivo remains elusive. The present study demonstrates that mouse MAP1A plays an essential role in maintaining synaptic plasticity through an analysis of MAP1A knock-out mice. The mice exhibited learning disabilities, which correlated with decreased long-term potentiation and long-term depression in the hippocampal neurons, as well as a concomitant reduction in the extent of NR-dependent EPSCs. Surface expression of NR2A and NR2B subunits also decreased. Enhanced activity-dependent degradation of PSD-93 and reduced transport of NR2A/2B in dendrites was likely responsible for altered receptor function in neurons lacking MAP1A. These data suggest that tethering of NR2A/2B with the cytoskeleton through MAP1A is fundamental for synaptic function. SIGNIFICANCE STATEMENT: This work is the first report showing the significance of non-motor microtubule-associated protein in maintaining synaptic plasticity thorough a novel mechanism: anchoring of NMDA receptors to cytoskeleton supports transport of NMDA receptors and stabilizes postsynaptic density scaffolds binding to NMDA receptors. Newly generated mutant mice lacking MAP1A exhibited learning disabilities and reduced synaptic plasticity attributable to disruptions of the anchoring machinery. PMID- 26609152 TI - Cortical Interneuron Subtypes Vary in Their Axonal Action Potential Properties. AB - The role of interneurons in cortical microcircuits is strongly influenced by their passive and active electrical properties. Although different types of interneurons exhibit unique electrophysiological properties recorded at the soma, it is not yet clear whether these differences are also manifested in other neuronal compartments. To address this question, we have used voltage-sensitive dye to image the propagation of action potentials into the fine collaterals of axons and dendrites in two of the largest cortical interneuron subtypes in the mouse: fast-spiking interneurons, which are typically basket or chandelier neurons; and somatostatin containing interneurons, which are typically regular spiking Martinotti cells. We found that fast-spiking and somatostatin-expressing interneurons differed in their electrophysiological characteristics along their entire dendrosomatoaxonal extent. The action potentials generated in the somata and axons, including axon collaterals, of somatostatin-expressing interneurons are significantly broader than those generated in the same compartments of fast spiking inhibitory interneurons. In addition, action potentials back-propagated into the dendrites of somatostatin-expressing interneurons much more readily than fast-spiking interneurons. Pharmacological investigations suggested that axonal action potential repolarization in both cell types depends critically upon Kv1 channels, whereas the axonal and somatic action potentials of somatostatin expressing interneurons also depend on BK Ca(2+)-activated K(+) channels. These results indicate that the two broad classes of interneurons studied here have expressly different subcellular physiological properties, allowing them to perform unique computational roles in cortical circuit operations. SIGNIFICANCE STATEMENT: Neurons in the cerebral cortex are of two major types: excitatory and inhibitory. The proper balance of excitation and inhibition in the brain is critical for its operation. Neurons contain three main compartments: dendritic, somatic, and axonal. How the neurons receive information, process it, and pass on new information depends upon how these three compartments operate. While it has long been assumed that axons are simply for conducting information from the cell body to the synapses, here we demonstrate that the axons of different types of interneurons, the inhibitory cells, possess differing electrophysiological properties. This result implies that differing types of interneurons perform different tasks in the cortex, not only through their anatomical connections, but also through how their axons operate. PMID- 26609153 TI - Expression of Quinone Reductase-2 in the Cortex Is a Muscarinic Acetylcholine Receptor-Dependent Memory Consolidation Constraint. AB - Learning of novel information, including novel taste, requires activation of neuromodulatory transmission mediated, for example, by the muscarinic acetylcholine receptors (mAChRs) in relevant brain structures. In addition, drugs enhancing the function of mAChRs are used to treat memory impairment and decline. However, the mechanisms underlying these effects are poorly understood. Here, using quantitative RT-PCR in Wistar Hola rats, we found quinone reductase 2 (QR2) to be expressed in the cortex in an mAChR-dependent manner. QR2 mRNA expression in the insular cortex is inversely correlated with mAChR activation both endogenously, after novel taste learning, and exogenously, after pharmacological manipulation of the muscarinic transmission. Moreover, reducing QR2 expression levels through lentiviral shRNA vectors or activity via inhibitors is sufficient to enhance long-term memories. We also show here that, in patients with Alzheimer's disease, QR2 is overexpressed in the cortex. It is suggested that QR2 expression in the cortex is a removable limiting factor of memory formation and thus serves as a new target to enhance cognitive function and delay the onset of neurodegenerative diseases. SIGNIFICANCE STATEMENT: We found that: (1) quinone reductase 2 (QR2) expression is a muscarinic-receptor-dependent removable constraint on memory formation in the cortex, (2) reducing QR2 expression or activity in the cortex enhances memory formation, and (3) Alzheimer's disease patients overexpressed QR2. We believe that these results propose a new mechanism by which muscarinic acetylcholine receptors affect cognition and suggest that inhibition of QR2 is a way to enhance cognition in normal and pathological conditions. PMID- 26609154 TI - Progressive Hearing Loss in Mice Carrying a Mutation in Usp53. AB - Disordered protein ubiquitination has been linked to neurodegenerative disease, yet its role in inner ear homeostasis and hearing loss is essentially unknown. Here we show that progressive hearing loss in the ethylnitrosourea-generated mambo mouse line is caused by a mutation in Usp53, a member of the deubiquitinating enzyme family. USP53 contains a catalytically inactive ubiquitin specific protease domain and is expressed in cochlear hair cells and a subset of supporting cells. Although hair cell differentiation is unaffected in mambo mice, outer hair cells degenerate rapidly after the first postnatal week. USP53 colocalizes and interacts with the tight junction scaffolding proteins TJP1 and TJP2 in polarized epithelial cells, suggesting that USP53 is part of the tight junction complex. The barrier properties of tight junctions of the stria vascularis appeared intact in a biotin tracer assay, but the endocochlear potential is reduced in adult mambo mice. Hair cell degeneration in mambo mice precedes endocochlear potential decline and is rescued in cochlear organotypic cultures in low potassium milieu, indicating that hair cell loss is triggered by extracellular factors. Remarkably, heterozygous mambo mice show increased susceptibility to noise injury at high frequencies. We conclude that USP53 is a novel tight junction-associated protein that is essential for the survival of auditory hair cells and normal hearing in mice, possibly by modulating the barrier properties and mechanical stability of tight junctions. SIGNIFICANCE STATEMENT: Hereditary hearing loss is extremely prevalent in the human population, but many genes linked to hearing loss remain to be discovered. Forward genetics screens in mice have facilitated the identification of genes involved in sensory perception and provided valuable animal models for hearing loss in humans. This involves introducing random mutations in mice, screening the mice for hearing defects, and mapping the causative mutation. Here, we have identified a mutation in the Usp53 gene that causes progressive hearing loss in the mambo mouse line. We demonstrate that USP53 is a catalytically inactive deubiquitinating enzyme and a novel component of tight junctions that is necessary for sensory hair cell survival and inner ear homeostasis. PMID- 26609155 TI - Ischemic Preconditioning in White Matter: Magnitude and Mechanism. AB - Ischemic preconditioning (IPC) is a robust neuroprotective phenomenon whereby brief ischemic exposure confers tolerance to a subsequent ischemic challenge. IPC has not been studied selectively in CNS white matter (WM), although stroke frequently involves WM. We determined whether IPC is present in WM and, if so, its mechanism. We delivered a brief in vivo preconditioning ischemic insult (unilateral common carotid artery ligation) to 12- to 14-week-old mice and determined WM ischemic vulnerability [oxygen-glucose deprivation (OGD)] 72 h later, using acutely isolated optic nerves (CNS WM tracts) from the preconditioned (ipsilateral) and control (contralateral) hemispheres. Functional and structural recovery was assessed by quantitative measurement of compound action potentials (CAPs) and immunofluorescent microscopy. Preconditioned mouse optic nerves (MONs) showed better functional recovery after OGD than the non preconditioned MONs (31 +/- 3 vs 17 +/- 3% normalized CAP area, p < 0.01). Preconditioned MONs also showed improved axon integrity and reduced oligodendrocyte injury compared with non-preconditioned MONs. Toll-like receptor 4 (TLR4) and type 1 interferon receptor (IFNAR1), key receptors in innate immune response, are implicated in gray matter preconditioning. Strikingly, IPC-mediated WM protection was abolished in both TLR4(-/-) and IFNAR1(-/-) mice. In addition, IPC-mediated protection in WM was also abolished in IFNAR1(fl/fl) LysM(cre), but not in IFNAR1(fl/fl) control, mice. These findings demonstrated for the first time that IPC was robust in WM, the phenomenon being intrinsic to WM itself. Furthermore, WM IPC was dependent on innate immune cell signaling pathways. Finally, these data demonstrated that microglial-specific expression of IFNAR1 plays an indispensable role in WM IPC. SIGNIFICANCE STATEMENT: Ischemic preconditioning (IPC) has been studied predominantly in gray matter, but stroke in humans frequently involves white matter (WM) as well. Here we describe a novel, combined in vivo/ex vivo mouse model to determine whether IPC occurs in WM. It does. Using genetically altered mice, we identified two innate immune cell receptors, Toll-like receptor 4 and type 1 interferon receptor (IFNAR1), that are required for IPC-mediated protection in WM. Furthermore, using microglia-targeted IFNAR1 knockdown, we demonstrate that interferon signaling specifically in microglia is essential for this protection. The discovery of IPC as an intrinsic capability of WM is novel and important. This is also the first in vivo demonstration that cell-type-specific expression of an individual gene plays an indispensable role in IPC-mediated protection. PMID- 26609156 TI - Actin-Cytoskeleton- and Rock-Mediated INM Are Required for Photoreceptor Regeneration in the Adult Zebrafish Retina. AB - Loss of retinal neurons in adult zebrafish (Danio rerio) induces a robust regenerative response mediated by the reentry of the resident Muller glia into the cell cycle. Upon initiating Muller glia proliferation, their nuclei migrate along the apicobasal axis of the retina in phase with the cell cycle in a process termed interkinetic nuclear migration (INM). We examined the mechanisms governing this cellular process and explored its function in regenerating the adult zebrafish retina. Live-cell imaging revealed that the majority of Muller glia nuclei migrated to the outer nuclear layer (ONL) to divide. These Muller glia formed prominent actin filaments at the rear of nuclei that had migrated to the ONL. Inhibiting actin filament formation or Rho-associated coiled-coil kinase (Rock) activity, which is necessary for phosphorylation of myosin light chain and actin myosin-mediated contraction, disrupted INM with increased numbers of mitotic nuclei remaining in the basal inner nuclear layer, the region where Muller glia typically reside. Double knockdown of Rho-associated coiled-coil kinase 2a (Rock2a) and Rho-associated coiled-coil kinase 2b (Rock2b) similarly disrupted INM and reduced Muller glial cell cycle reentry. In contrast, Rock inhibition immediately before the onset of INM did not affect Muller glia proliferation, but subsequently reduced neuronal progenitor cell proliferation due to early cell cycle exit. Long-term, Rock inhibition increased the generation of mislocalized ganglion/amacrine cells at the expense of rod and cone photoreceptors. In summary, INM is driven by an actin-myosin-mediated process controlled by Rock2a and Rock2b activity, which is required for sufficient proliferation and regeneration of photoreceptors after light damage. SIGNIFICANCE STATEMENT: The human retina does not replace lost or damaged neurons, ultimately causing vision impairment. In contrast, zebrafish are capable of regenerating lost neurons. Understanding the mechanisms that regulate retinal regeneration in these organisms will help to elucidate approaches to stimulate a similar response in humans. In the damaged zebrafish retina, Muller glia dedifferentiate and proliferate to generate neuronal progenitor cells (NPCs) that differentiate into the lost neurons. We show that the nuclei of Muller glia and NPCs migrate apically and basally in phase with the cell cycle. This migration is facilitated by the actin cytoskeleton and Rho-associated coiled-coil kinases (Rocks). We demonstrate that Rock function is required for sufficient proliferation and the regeneration of photoreceptors, likely via regulating nuclear migration. PMID- 26609157 TI - Brain State Is a Major Factor in Preseizure Hippocampal Network Activity and Influences Success of Seizure Intervention. AB - Neural dynamics preceding seizures are of interest because they may shed light on mechanisms of seizure generation and could be predictive. In healthy animals, hippocampal network activity is shaped by behavioral brain state and, in epilepsy, seizures selectively emerge during specific brain states. To determine the degree to which changes in network dynamics before seizure are pathological or reflect ongoing fluctuations in brain state, dorsal hippocampal neurons were recorded during spontaneous seizures in a rat model of temporal lobe epilepsy. Seizures emerged from all brain states, but with a greater likelihood after REM sleep, potentially due to an observed increase in baseline excitability during periods of REM compared with other brains states also characterized by sustained theta oscillations. When comparing the firing patterns of the same neurons across brain states associated with and without seizures, activity dynamics before seizures followed patterns typical of the ongoing brain state, or brain state transitions, and did not differ until the onset of the electrographic seizure. Next, we tested whether disparate activity patterns during distinct brain states would influence the effectiveness of optogenetic curtailment of hippocampal seizures in a mouse model of temporal lobe epilepsy. Optogenetic curtailment was significantly more effective for seizures preceded by non-theta states compared with seizures that emerged from theta states. Our results indicate that consideration of behavioral brain state preceding a seizure is important for the appropriate interpretation of network dynamics leading up to a seizure and for designing effective seizure intervention. SIGNIFICANCE STATEMENT: Hippocampal single-unit activity is strongly shaped by behavioral brain state, yet this relationship has been largely ignored when studying activity dynamics before spontaneous seizures in medial temporal lobe epilepsy. In light of the increased attention on using single-unit activity for the prediction of seizure onset and closed-loop seizure intervention, we show a need for monitoring brain state to interpret correctly whether changes in neural activity before seizure onset is pathological or normal. Moreover, we also find that the brain state preceding a seizure determines the success of therapeutic interventions to curtail seizure duration. Together, these findings suggest that seizure prediction and intervention will be more successful if tailored for the specific brain states from which seizures emerge. PMID- 26609158 TI - Human Umbilical Tissue-Derived Cells Promote Synapse Formation and Neurite Outgrowth via Thrombospondin Family Proteins. AB - Cell therapy demonstrates great potential for the treatment of neurological disorders. Human umbilical tissue-derived cells (hUTCs) were previously shown to have protective and regenerative effects in animal models of stroke and retinal degeneration, but the underlying therapeutic mechanisms are unknown. Because synaptic dysfunction, synapse loss, degeneration of neuronal processes, and neuronal death are hallmarks of neurological diseases and retinal degenerations, we tested whether hUTCs contribute to tissue repair and regeneration by stimulating synapse formation, neurite outgrowth, and neuronal survival. To do so, we used a purified rat retinal ganglion cell culture system and found that hUTCs secrete factors that strongly promote excitatory synaptic connectivity and enhance neuronal survival. Additionally, we demonstrated that hUTCs support neurite outgrowth under normal culture conditions and in the presence of the growth-inhibitory proteins chondroitin sulfate proteoglycan, myelin basic protein, or Nogo-A (reticulon 4). Furthermore, through biochemical fractionation and pharmacology, we identified the major hUTC-secreted synaptogenic factors as the thrombospondin family proteins (TSPs), TSP1, TSP2, and TSP4. Silencing TSP expression in hUTCs, using small RNA interference, eliminated both the synaptogenic function of these cells and their ability to promote neurite outgrowth. However, the majority of the prosurvival functions of hUTC-conditioned media was spared after TSP knockdown, indicating that hUTCs secrete additional neurotrophic factors. Together, our findings demonstrate that hUTCs affect multiple aspects of neuronal health and connectivity through secreted factors, and each of these paracrine effects may individually contribute to the therapeutic function of these cells. SIGNIFICANCE STATEMENT: Human umbilical tissue-derived cells (hUTC) are currently under clinical investigation for the treatment of geographic atrophy secondary to age-related macular degeneration. These cells show great promise for the treatment of neurological disorders; however, the therapeutic effects of these cells on CNS neurons are not fully understood. Here we provide compelling evidence that hUTCs secrete multiple factors that work synergistically to enhance synapse formation and function, and support neuronal growth and survival. Moreover, we identified thrombospondins (TSPs) as the hUTC-secreted factors that mediate the synaptogenic and growth promoting functions of these cells. Our findings highlight novel paracrine effects of hUTC on CNS neuron health and connectivity and begin to unravel potential therapeutic mechanisms by which these cells elicit their effects. PMID- 26609159 TI - A Smaug2-Based Translational Repression Complex Determines the Balance between Precursor Maintenance versus Differentiation during Mammalian Neurogenesis. AB - Here, we have asked about post-transcriptional mechanisms regulating murine developmental neurogenesis, focusing upon the RNA-binding proteins Smaug2 and Nanos1. We identify, in embryonic neural precursors of the murine cortex, a Smaug2 protein/nanos1 mRNA complex that is present in cytoplasmic granules with the translational repression proteins Dcp1 and 4E-T. We show that Smaug2 inhibits and Nanos1 promotes neurogenesis, with Smaug2 knockdown enhancing neurogenesis and depleting precursors, and Nanos1 knockdown inhibiting neurogenesis and maintaining precursors. Moreover, we show that Smaug2 likely regulates neurogenesis by silencing nanos1 mRNA. Specifically, Smaug2 knockdown inappropriately increases Nanos1 protein, and the Smaug2 knockdown-mediated neurogenesis is rescued by preventing this increase. Thus, Smaug2 and Nanos1 function as a bimodal translational repression switch to control neurogenesis, with Smaug2 acting in transcriptionally primed precursors to silence mRNAs important for neurogenesis, including nanos1 mRNA, and Nanos1 acting during the transition to neurons to repress the precursor state. SIGNIFICANCE STATEMENT: The mechanisms instructing neural stem cells to generate the appropriate progeny are still poorly understood. Here, we show that the RNA-binding proteins Smaug2 and Nanos1 are critical regulators of this balance and provide evidence supporting the idea that neural precursors are transcriptionally primed to generate neurons but translational regulation maintains these precursors in a stem cell state until the appropriate developmental time. PMID- 26609161 TI - The Neuropeptide Oxytocin Induces a Social Altruism Bias. AB - Current psychological concepts of social and ecological responsibility emphasize the relevance of altruism, suggesting that more altruistic individuals are more likely to engage in sustainable behaviors. Emerging evidence indicates a central role of the neuropeptide oxytocin in promoting altruism. Whether this influence extends to ecological responsibility or is limited to the social domain remains unknown. In two independent experiments involving 172 human participants, we addressed this question by exposing subjects to a sustainability-related monetary donation task, with the option to support either socially or ecologically framed charities. We found that oxytocin induced a context-dependent change in altruistic behavior away from pro-environmental toward pro-social donations, while keeping constant the overall proportion of donated money. This pro-social bias transcended to the domain of sustainable consumption. Collectively, our findings demonstrate that altruistic priorities vary as a function of oxytocin system activity, which has implications for the promotion of pro-environmental attitudes and eco-friendly behaviors. SIGNIFICANCE STATEMENT: Individual responses to ecological and social sustainability require a shift in personal priorities away from selfish to more altruistic behaviors. Emerging evidence indicates a central role of the hypothalamic peptide oxytocin in promoting altruism, but whether the influence of oxytocin benefits altruistic decision making in the context of ecological and social sustainability is unclear. In two independent behavioral experiments involving 172 human subjects, we show that heightened oxytocin system activity induces a social altruism bias at the cost of ecological responsibility. Our results have fundamental implications for policy interventions and business strategies designed to sustain ecological resources by suggesting that a social framing may attract more individuals to engage in pro environmental and eco-friendly behaviors. PMID- 26609160 TI - Resonant Interneurons Can Increase Robustness of Gamma Oscillations. AB - Gamma oscillations are believed to play a critical role in in information processing, encoding, and retrieval. Inhibitory interneuronal network gamma (ING) oscillations may arise from a coupled oscillator mechanism in which individual neurons oscillate or from a population oscillator in which individual neurons fire sparsely and stochastically. All ING mechanisms, including the one proposed herein, rely on alternating waves of inhibition and windows of opportunity for spiking. The coupled oscillator model implemented with Wang-Buzsaki model neurons is not sufficiently robust to heterogeneity in excitatory drive, and therefore intrinsic frequency, to account for in vitro models of ING. Similarly, in a tightly synchronized regime, the stochastic population oscillator model is often characterized by sparse firing, whereas interneurons both in vivo and in vitro do not fire sparsely during gamma, but rather on average every other cycle. We substituted so-called resonator neural models, which exhibit class 2 excitability and postinhibitory rebound (PIR), for the integrators that are typically used. This results in much greater robustness to heterogeneity that actually increases as the average participation in spikes per cycle approximates physiological levels. Moreover, dynamic clamp experiments that show autapse-induced firing in entorhinal cortical interneurons support the idea that PIR can serve as a network gamma mechanism. Furthermore, parvalbumin-positive (PV(+)) cells were much more likely to display both PIR and autapse-induced firing than GAD2(+) cells, supporting the view that PV(+) fast-firing basket cells are more likely to exhibit class 2 excitability than other types of inhibitory interneurons. SIGNIFICANCE STATEMENT: Gamma oscillations are believed to play a critical role in information processing, encoding, and retrieval. Networks of inhibitory interneurons are thought to be essential for these oscillations. We show that one class of interneurons with an abrupt onset of firing at a threshold frequency may allow more robust synchronization in the presence of noise and heterogeneity. The mechanism for this robustness depends on the intrinsic resonance at this threshold frequency. Moreover, we show experimentally the feasibility of the proposed mechanism and suggest a way to distinguish between this mechanism and another proposed mechanism: that of a stochastic population oscillator independent of the dynamics of individual neurons. PMID- 26609162 TI - Electrical and Optical Activation of Mesoscale Neural Circuits with Implications for Coding. AB - Artificial activation of neural circuitry through electrical microstimulation and optogenetic techniques is important for both scientific discovery of circuit function and for engineered approaches to alleviate various disorders of the nervous system. However, evidence suggests that neural activity generated by artificial stimuli differs dramatically from normal circuit function, in terms of both the local neuronal population activity at the site of activation and the propagation to downstream brain structures. The precise nature of these differences and the implications for information processing remain unknown. Here, we used voltage-sensitive dye imaging of primary somatosensory cortex in the anesthetized rat in response to deflections of the facial vibrissae and electrical or optogenetic stimulation of thalamic neurons that project directly to the somatosensory cortex. Although the different inputs produced responses that were similar in terms of the average cortical activation, the variability of the cortical response was strikingly different for artificial versus sensory inputs. Furthermore, electrical microstimulation resulted in highly unnatural spatial activation of cortex, whereas optical input resulted in spatial cortical activation that was similar to that induced by sensory inputs. A thalamocortical network model suggested that observed differences could be explained by differences in the way in which artificial and natural inputs modulate the magnitude and synchrony of population activity. Finally, the variability structure in the response for each case strongly influenced the optimal inputs for driving the pathway from the perspective of an ideal observer of cortical activation when considered in the context of information transmission. SIGNIFICANCE STATEMENT: Artificial activation of neural circuitry through electrical microstimulation and optogenetic techniques is important for both scientific discovery and clinical translation. However, neural activity generated by these artificial means differs dramatically from normal circuit function, both locally and in the propagation to downstream brain structures. The precise nature of these differences and the implications for information processing remain unknown. The significance of this work is in quantifying the differences, elucidating likely mechanisms underlying the differences, and determining the implications for information processing. PMID- 26609163 TI - In Vivo Detection of Age- and Disease-Related Increases in Neuroinflammation by 18F-GE180 TSPO MicroPET Imaging in Wild-Type and Alzheimer's Transgenic Mice. AB - Alzheimer's disease (AD) is the most common cause of dementia. Neuroinflammation appears to play an important role in AD pathogenesis. Ligands of the 18 kDa translocator protein (TSPO), a marker for activated microglia, have been used as positron emission tomography (PET) tracers to reflect neuroinflammation in humans and mouse models. Here, we used the novel TSPO-targeted PET tracer (18)F-GE180 (flutriciclamide) to investigate differences in neuroinflammation between young and old WT and APP/PS1dE9 transgenic (Tg) mice. In vivo PET scans revealed an overt age-dependent elevation in whole-brain uptake of (18)F-GE180 in both WT and Tg mice, and a significant increase in whole-brain uptake of (18)F-GE180 (peak uptake and retention) in old Tg mice compared with young Tg mice and all WT mice. Similarly, the (18)F-GE180 binding potential in hippocampus was highest to lowest in old Tg > old WT > young Tg > young WT mice using MRI coregistration. Ex vivo PET and autoradiography analysis further confirmed our in vivo PET results: enhanced uptake and specific binding (SUV75%) of (18)F-GE180 in hippocampus and cortex was highest in old Tg mice followed by old WT, young Tg, and finally young WT mice. (18)F-GE180 specificity was confirmed by an in vivo cold tracer competition study. We also examined (18)F-GE180 metabolites in 4-month-old WT mice and found that, although total radioactivity declined over 2 h, of the remaining radioactivity, ~90% was due to parent (18)F-GE180. In conclusion, (18)F GE180 PET scans may be useful for longitudinal monitoring of neuroinflammation during AD progression and treatment. SIGNIFICANCE STATEMENT: Microglial activation, a player in Alzheimer's disease (AD) pathogenesis, is thought to reflect neuroinflammation. Using in vivo microPET imaging with a novel TSPO radioligand, (18)F-GE180, we detected significantly enhanced neuroinflammation during normal aging in WT mice and in response to AD-associated pathology in APP/PS1dE9 Tg mice, an AD mouse model. Increased uptake and specific binding of (18)F-GE180 in whole brain and hippocampus were confirmed by ex vivo PET and autoradiography. The binding specificity and stability of (18)F-GE180 was further confirmed by a cold tracer competition study and a metabolite study, respectively. Therefore, (18)F-GE180 PET imaging may be useful for longitudinal monitoring of neuroinflammation during AD progression and treatment and may also be useful for other neurodegenerative diseases. PMID- 26609165 TI - Investigating the Neural Correlates of Schemas: Ventromedial Prefrontal Cortex Is Necessary for Normal Schematic Influence on Memory. AB - Schemas, as memory representations of typical contexts, allow for generalization from previous experiences while often improving memory organization and accuracy. However, these advantageous characteristics of schematic memory may come at the cost of episode-specific information. In the human brain, this tradeoff between general and specific knowledge has been linked to differential contributions of the medial temporal lobes (MTL) to episode-specific memory and the ventromedial prefrontal cortex (vmPFC) to generalized, schematic memory. Here, we used a neuropsychological approach to test whether participants with focal vmPFC damage (n = 6) would show a reduced influence of schematic memory relative to healthy normal comparison participants (n = 12) in a recognition task that presented schematically congruent or incongruent contexts at study. As predicted, normal comparison participants were more likely to identify items as old after studying them in congruent contexts, and this effect was reflected in increased true and false recognition. These effects of prior context on recognition were not observed in the vmPFC group, suggesting that vmPFC damage reduced the influence of schematic memory. These findings are consistent with the proposition that the vmPFC plays an important role in integrating previous experience into ongoing memory processes while acting as part of a larger memory network. SIGNIFICANCE STATEMENT: In the human brain, new memories are strongly influenced by existing knowledge of relevant context (sometimes called "schemas"). Schemas can benefit memory by expediting learning and increasing capacity in familiar contexts, but these benefits may simultaneously reduce episode-specific memory. Here we show that damage to the human ventromedial prefrontal cortex (vmPFC) reduced the influence of existing knowledge on new memories. Our findings suggest that the vmPFC plays a key role in schematic memory processes by integrating previous experiences and contextual information to influence memory. These findings provide novel insight into the brain regions necessary for normal schematic memory and enhance our understanding of the brain networks supporting memory processes. PMID- 26609166 TI - Retinoic Acid Signaling Mediates Hair Cell Regeneration by Repressing p27kip and sox2 in Supporting Cells. AB - During development, otic sensory progenitors give rise to hair cells and supporting cells. In mammalian adults, differentiated and quiescent sensory cells are unable to generate new hair cells when these are lost due to various insults, leading to irreversible hearing loss. Retinoic acid (RA) has strong regenerative capacity in several organs, but its role in hair cell regeneration is unknown. Here, we use genetic and pharmacological inhibition to show that the RA pathway is required for hair cell regeneration in zebrafish. When regeneration is induced by laser ablation in the inner ear or by neomycin treatment in the lateral line, we observe rapid activation of several components of the RA pathway, with dynamics that position RA signaling upstream of other signaling pathways. We demonstrate that blockade of the RA pathway impairs cell proliferation of supporting cells in the inner ear and lateral line. Moreover, in neuromast, RA pathway regulates the transcription of p27(kip) and sox2 in supporting cells but not fgf3. Finally, genetic cell-lineage tracing using Kaede photoconversion demonstrates that de novo hair cells derive from FGF-active supporting cells. Our findings reveal that RA has a pivotal role in zebrafish hair cell regeneration by inducing supporting cell proliferation, and shed light on the underlying transcriptional mechanisms involved. This signaling pathway might be a promising approach for hearing recovery. SIGNIFICANCE STATEMENT: Hair cells are the specialized mechanosensory cells of the inner ear that capture auditory and balance sensory input. Hair cells die after acoustic trauma, ototoxic drugs or aging diseases, leading to progressive hearing loss. Mammals, in contrast to zebrafish, lack the ability to regenerate hair cells. Here, we find that retinoic acid (RA) pathway is required for hair cell regeneration in vivo in the zebrafish inner ear and lateral line. RA pathway is activated very early upon hair cell loss, promotes cell proliferation of progenitor cells, and regulates two key genes, p27(kip) and sox2. Our results position RA as an essential signal for hair cell regeneration with relevance in future regenerative strategies in mammals. PMID- 26609164 TI - Neuronal RARbeta Signaling Modulates PTEN Activity Directly in Neurons and via Exosome Transfer in Astrocytes to Prevent Glial Scar Formation and Induce Spinal Cord Regeneration. AB - Failure of axonal regeneration in the central nervous system (CNS) is mainly attributed to a lack of intrinsic neuronal growth programs and an inhibitory environment from a glial scar. Phosphatase and tensin homolog (PTEN) is a major negative regulator of neuronal regeneration and, as such, inhibiting its activity has been considered a therapeutic target for spinal cord (SC) injuries (SCIs). Using a novel model of rat cervical avulsion, we show that treatment with a retinoic acid receptor beta (RARbeta) agonist results in locomotor and sensory recovery. Axonal regeneration from the severed roots into the SC could be seen by biotinylated dextran amine labeling. Light micrographs of the dorsal root entry zone show the peripheral nervous system (PNS)-CNS transition of regrown axons. RARbeta agonist treatment also resulted in the absence of scar formation. Mechanism studies revealed that, in RARbeta-agonist-treated neurons, PTEN activity is decreased by cytoplasmic phosphorylation and increased secretion in exosomes. These are taken up by astrocytes, resulting in hampered proliferation and causing them to arrange in a normal-appearing scaffold around the regenerating axons. Attribution of the glial modulation to neuronal PTEN in exosomes was demonstrated by the use of an exosome inhibitor in vivo and PTEN siRNA in vitro assays. The dual effect of RARbeta signaling, both neuronal and neuronal-glial, results in axonal regeneration into the SC after dorsal root neurotmesis. Targeting this pathway may open new avenues for the treatment of SCIs. SIGNIFICANCE STATEMENT: Spinal cord injuries (SCIs) often result in permanent damage in the adult due to the very limited capacity of axonal regeneration. Intrinsic neuronal programs and the formation of a glial scar are the main obstacles. Here, we identify a single target, neuronal retinoic acid receptor beta (RARbeta), which modulates these two aspects of the postinjury physiological response. Activation of RARbeta in the neuron inactivates phosphatase and tensin homolog and induces its transfer into the astrocytes in small vesicles, where it prevents scar formation. This may open new therapeutic avenues for SCIs. PMID- 26609167 TI - Vitamin D Supplementation Affects the Beck Depression Inventory, Insulin Resistance, and Biomarkers of Oxidative Stress in Patients with Major Depressive Disorder: A Randomized, Controlled Clinical Trial. AB - BACKGROUND: Vitamin D may decrease depression symptoms through its beneficial effects on neurotransmitters, metabolic profiles, biomarkers of inflammation, and oxidative stress. OBJECTIVE: This study was designed to assess whether vitamin D supplementation can reduce symptoms of depression, metabolic profiles, serum high sensitivity C-reactive protein (hs-CRP), and biomarkers of oxidative stress in patients with major depressive disorder (MDD). METHODS: This randomized, double blind, placebo-controlled clinical trial was performed in 40 patients between 18 and 65 y of age with a diagnosis of MDD based on criteria from the Diagnostic and Statistical Manual of Mental Disorders. Patients were randomly assigned to receive either a single capsule of 50 kIU vitamin D/wk (n = 20) or placebo (n = 20) for 8 wk. Fasting blood samples were taken at baseline and postintervention to quantify relevant variables. The primary [Beck Depression Inventory (BDI), which examines depressive symptoms] and secondary (glucose homeostasis variables, lipid profiles, hs-CRP, and biomarkers of oxidative stress) outcomes were assessed. RESULTS: Baseline concentrations of mean serum 25-hydroxyvitamin D were significantly different between the 2 groups (9.2 +/- 6.0 and 13.6 +/- 7.9 MUg/L in the placebo and control groups, respectively, P = 0.02). After 8 wk of intervention, changes in serum 25-hydroxyvitamin D concentrations were significantly greater in the vitamin D group (+20.4 MUg/L) than in the placebo group (-0.9 MUg/L, P < 0.001). A trend toward a greater decrease in the BDI was observed in the vitamin D group than in the placebo group (-8.0 and -3.3, respectively, P = 0.06). Changes in serum insulin (-3.6 compared with +2.9 MUIU/mL, P = 0.02), estimated homeostasis model assessment of insulin resistance (-1.0 compared with +0.6, P = 0.01), estimated homeostasis model assessment of beta cell function (-13.9 compared with +10.3, P = 0.03), plasma total antioxidant capacity (+63.1 compared with -23.4 mmol/L, P = 0.04), and glutathione (+170 compared with -213 MUmol/L, P = 0.04) in the vitamin D group were significantly different from those in the placebo group. CONCLUSION: Overall, vitamin D supplementation of patients with MDD for 8 wk had beneficial effects on the BDI, indicators of glucose homeostasis, and oxidative stress. This trial was registered at www.irct.ir as IRCT201412065623N29. PMID- 26609168 TI - Rural Beninese Children Are at Risk of Zinc Deficiency According to Stunting Prevalence and Plasma Zinc Concentration but Not Dietary Zinc Intakes. AB - BACKGROUND: Three commonly recommended indicators for risk assessment of population zinc deficiency are stunting rates among children aged <5 y, prevalence of inadequate dietary zinc intake, and prevalence of low plasma zinc (PZn). Data on zinc status in Benin are mainly drawn from stunting rates and data on PZn and dietary zinc intake are lacking. OBJECTIVES: The aims of this study were 1) to assess the risk of zinc deficiency in preschool and school-age children from rural communities in northern Benin by means of the 3 indicators for population assessment, 2) to evaluate their level of agreement, and 3) to identify predictors of PZn and height-for-age z scores (HAZ). METHODS: We analyzed preintervention data collected during 2 efficacy trials and cross sectionally assessed the risk of zinc deficiency in preschool (1-5 y, n = 326) and school-age children (5-10 y, n = 272) by 1) conducting a 3-d weighed food record survey, coupled with direct zinc and phytic acid analysis of consumed foodstuffs, and calculating usual dietary zinc intakes in a subsample of school age children (n = 36); 2) analyzing PZn in all children (n = 598); and 3) measuring anthropometry indexes for assessment of stunting (HAZ <-2 SD) in all children (n = 594) and in <5-y-old children only (n = 273). We derived predictors of PZn and HAZ by using multivariate regression with mixed-effect models. RESULTS: Prevalence of inadequate intakes of zinc ranged from 11% to 80% depending on whether the estimated average requirements (EARs) by the International Zinc Nutrition Consultative Group or the EARs derived from the WHO's recommended nutrient intakes were used. Prevalence of low PZn adjusted for acute-phase protein status was 45.7%, with higher rates among preschoolers than school-age children (P = 0.002). The stunting rate in <5-y-old children was 51.3%. PZn was predicted by age, methodologic factors, and socioeconomic status, whereas HAZ was predicted by age, sex, hemoglobin, and socioeconomic status. CONCLUSIONS: The prevalence of <5-y stunting and the prevalence of low PZn indicate that the risk of zinc deficiency is elevated in this population. Risk estimates based on the prevalence of inadequacy of zinc intakes varied depending on the EARs used, and a consensus would facilitate nutrition survey evaluations. These trials were registered at clinicaltrials.gov as NCT01472211 and NCT01790321. PMID- 26609169 TI - Plasma 3-Epi-25-Hydroxycholecalciferol Can Alter the Assessment of Vitamin D Status Using the Current Reference Ranges for Pregnant Women and Their Newborns. AB - BACKGROUND: Vitamin D is critical for healthy pregnancies and normal fetal development. It is important to accurately ascertain vitamin D status in mothers and their newborns to establish the optimal vitamin D concentration during pregnancy. There are many different metabolites and epimers of vitamin D in peripheral blood and controversy as to the importance of epimers in estimating vitamin D status in maternal and infant health. OBJECTIVES: We undertook this study to measure 25-hydroxyvitamin D metabolites and epimers and their relations in maternal and cord blood and to evaluate the impact of the inclusion of epimers on assessing vitamin D status. METHODS: We performed a substudy in a longitudinal cohort of pregnant women and their infants in Alberta, Canada [APrON (Alberta Pregnancy Outcomes and Nutrition) Study]. Maternal and cord blood plasma collected at the time of newborn delivery was stored at -70 degrees C until testing and assayed for 25-hydroxyergocalciferol [25(OH)D2], 25 hydroxycholecalciferol [25(OH)D3], and 3-epi-25-hydroxycholecalciferol [3-epi 25(OH)D3] by using LC-tandem mass spectrometry. The effect of 3-epi-25(OH)D3 on estimates of vitamin D adequacy was explored by using McNemar's chi-square test at both recommended thresholds of 50 and 75 nmol/L. RESULTS: Ninety-two pairs of maternal and cord blood samples were obtained. 3-Epi-25(OH)D3 was detected in all samples, comprising 6.0% and 7.8% of 25(OH)D3 in maternal and cord blood, respectively. Positive correlations were found between 25(OH)D3 and 3-epi 25(OH)D3 for both maternal and cord blood (maternal blood: r = 0.34, P = 0.01; cord blood: r = 0.44, P = 0.01). In addition, regression analysis showed a significant association between vitamin D supplementation and 3-epi-25(OH)D3 in maternal and cord blood (beta: 0.423; 95% CI: 0.173, 0.672). When 3-epi-25(OH)D3 was not included in plasma vitamin D estimations, 38% of women and 80% of neonates were classified as having an insufficient concentration (<75 nmol/L); however, with 3-epi-25(OH)D3 included, the estimates of insufficiency were significantly lower: 33% and 73% for women and neonates, respectively. CONCLUSIONS: Using LC-MS/MS we showed the presence of 3-epi-25(OH)D3 in all samples of pregnant women and their cord blood, and when the 3-epimer was included in the estimation of status the prevalence of vitamin D insufficiency (<75 nmol/L) was significantly lower. Our data suggest that the high use of dietary supplements in this group of women contributes to 3-epi-25(OH)D3 concentrations in both maternal and cord blood. Further research on the role of the epimers in characterizing vitamin D status in pregnancy and infancy is imperative. PMID- 26609170 TI - Dietary Amino Acid Deficiency Reduces the Utilization of Amino Acids for Growth in Growing Pigs after a Period of Poor Health. AB - BACKGROUND: During immune system activation, partitioning of amino acids (AAs) changes between protein gain and use by the immune system. OBJECTIVE: We determined the effects of health status and dietary AA deficiency on nitrogen retention and AA utilization in pigs. METHODS: Barrows (55 d of age) were obtained from good health (GH, n = 14) or poor health (PH, n = 14) status farms and allocated to a diet either adequate in essential amino acids (Adq) or 25% deficient in Met + Cys, Thr, and Trp (Def). Nitrogen balance was measured and AA irreversible loss rates (ILRs) were measured after an intravenous bolus of U (13)C-labeled L-AAs. RESULTS: On arrival at the experimental facilities, the PH pigs had 14% lower serum albumin and 50% greater serum haptoglobin and blood leukocyte counts than the GH pigs (P < 0.01), but the PH pigs showed signs of recovery during the trial. Total tract nitrogen digestibility was 3 percentage points lower in the PH pigs (P < 0.01). The PH-Adq pigs had compensatory body weight gain after arrival, coinciding with 7% greater nitrogen retention (P < 0.01) in the PH pigs than in the GH pigs. The PH pigs had a 24% greater ILR for Lys. Health status * diet interactions for Lys (P = 0.07), Val (P = 0.03), and Leu (P = 0.10) pool sizes and a greater urea pool size in the PH pigs (P = 0.01) support the observation that the increase in the ILR of Lys in the PH pigs was related to oxidation when feeding the Def diet, but to synthesis when feeding the Adq diet. Feeding Def diets increased monocyte counts by 30% (P < 0.01). CONCLUSIONS: This study illustrates how the competition for AAs between protein synthesis associated with immune system activation and body protein deposition is greater when the dietary supply of Met + Cys, Thr, and Trp is limited in pigs during and after a period of poor health. PMID- 26609171 TI - Inactivation of Adenomatous Polyposis Coli Reduces Bile Acid/Farnesoid X Receptor Expression through Fxr gene CpG Methylation in Mouse Colon Tumors and Human Colon Cancer Cells. AB - BACKGROUND: The farnesoid X receptor (FXR) regulates bile acid (BA) metabolism and possesses tumor suppressor functions. FXR expression is reduced in colorectal tumors of subjects carrying inactivated adenomatous polyposis coli (APC). Identifying the mechanisms responsible for this reduction may offer new molecular targets for colon cancer prevention. OBJECTIVE: We investigated how APC inactivation influences the regulation of FXR expression in colonic mucosal cells. We hypothesized that APC inactivation would epigenetically repress nuclear receptor subfamily 1, group H, member 4 (FXR gene name) expression through increased CpG methylation. METHODS: Normal proximal colonic mucosa and normal appearing adjacent colonic mucosa and colon tumors were collected from wild-type C57BL/6J and Apc-deficient (Apc(Min) (/+)) male mice, respectively. The expression of Fxr, ileal bile acid-binding protein (Ibabp), small heterodimer partner (Shp), and cyclooxygenase-2 (Cox-2) were determined by real-time polymerase chain reaction. In both normal and adjacent colonic mucosa and colon tumors, we measured CpG methylation of Fxr in bisulfonated genomic DNA. In vitro, we measured the impact of APC inactivation and deoxycholic acid (DCA) treatment on FXR expression in human colon cancer HCT-116 cells transfected with silencing RNA for APC and HT-29 cells carrying inactivated APC. RESULTS: In Apc(Min) (/+) mice, constitutive CpG methylation of the Fxralpha3/4 promoter was linked to reduced (60-90%) baseline Fxr, Ibabp, and Shp and increased Cox-2 expression in apparently normal adjacent mucosa and colon tumors. Apc knockdown in HCT-116 cells increased cellular myelocytomatosis (c-MYC) and lowered (~50%) FXR expression, which was further reduced (~80%) by DCA. In human HCT-116 but not HT 29 colon cancer cells, DCA induced FXR expression and lowered CpG methylation of FXR. CONCLUSIONS: We conclude that the loss of APC function favors the silencing of FXR expression through CpG hypermethylation in mouse colonic mucosa and human colon cells, leading to reduced expression of downstream targets (SHP, IBABP) involved in BA homeostasis while increasing the expression of factors (COX-2, c MYC) that contribute to inflammation and colon cancer. PMID- 26609173 TI - 24-Hour Urine Samples Are More Reproducible Than Spot Urine Samples for Evaluation of Iodine Status in School-Age Children. AB - BACKGROUND: Variation in different urinary measurements for evaluation of iodine status is of concern to clinicians and researchers. OBJECTIVE: This study evaluated variations between urine iodine concentration (UIC), spot and 24-h urine sample creatinine concentrations, and 24-h urine iodine excretion (24-h UIE) in repeated samples from school-age children. METHODS: Urine samples (24 h and morning spot) were collected on 2 occasions from 981 children in Ningjin and Lingxian counties, China. Samples from Ningjin were collected in October and November 2013, and samples from Lingxian were collected in April and May 2014. Morning spot urine iodine concentration (MUIC), morning spot urine creatinine, 24 h UIC, and 24-h urine creatinine were measured in all samples. The 24-h UIE was calculated by multiplying the 24-h UIC by the 24-h urine volume. RESULTS: In Ningjin County, the 24-h UIC and 24-h UIE did not differ between repeated collections [192 and 172 MUg/L, respectively, for 24-h UIC (P = 0.08); 123 and 120 MUg/L, respectively, for 24-h UIE (P = 0.56)], whereas the MUIC was lower in November 2013 than in October 2013 (170 and 190 MUg/L, respectively; P = 0.034). In Lingxian County, no significant differences were observed in 24-h UIC between the repeated collections (230 and 218 MUg/L, respectively; P = 0.79), whereas the 24-h UIE and MUIC were higher in the samples collected in May 2014 than in April 2014 [161 and 155 MUg/L, respectively, for 24-h UIE (P = 0.002); 244 and 203 MUg/L, respectively, for MUIC (P < 0.001)]. When data from both counties were combined, no difference was observed between repeated 24-h UIC (214 compared with 196 MUg/L; P = 0.17) and 24-h UIE (143 compared with 143 MUg/d; P = 0.06), but MUICs were lower in the first collection than in the second collection (199 and 207 MUg/L, respectively; P = 0.002). The kappa values were >0.4 for 24-h UIC and mean UIE, whereas relatively low kappa values were observed for MUIC and mean UIE. CONCLUSION: The 24-h UIC was more accurate and reproducible than the MUIC in evaluating iodine status in a large-scale population study of school-age children. PMID- 26609172 TI - A Randomized Controlled Trial Offering Higher- Compared with Lower-Dairy Second Meals Daily in Preschools in Guinea-Bissau Demonstrates an Attendance-Dependent Increase in Weight Gain for Both Meal Types and an Increase in Mid-Upper Arm Circumference for the Higher-Dairy Meal. AB - BACKGROUND: Controversy remains over the most effective approaches to prevent childhood malnutrition. OBJECTIVES: We tested the feasibility and effectiveness of delivering ready-to-use supplementary foods (RUSFs) as a second daily meal in preschool children aged 3-5 y in Guinea-Bissau, and compared RUSFs with different levels of dairy protein. METHODS: This study was a 3 mo cluster-randomized controlled pilot trial of 2 RUSFs differing in dairy protein in 533 boys and girls from 9 preschools. Children receiving RUSFs were compared with wait-listed controls, and all students received a daily school lunch. The RUSFs were delivered 5 d/wk for 3 mo and contained 478 kcal and 11.5 g protein per 92-g daily serving. Deliveries included a ready-to-use supplementary food with 15% of protein from dairy sources (RUSF-15%) or one with 33% of protein from dairy sources (RUSF-33%). Intention-to-treat (ITT) and per-protocol analyses (>50 d of RUSF consumption) were conducted. Changes in the weight-for-age z score (WAZ) and height-for-age z score were primary outcomes. Additional outcomes included changes in mid-upper arm circumference (MUAC), hemoglobin, and retinol binding protein. RESULTS: Baseline anthropometry was not different between groups (WAZ, 0.48 +/- 1.04) and increased significantly over time (P < 0.01) with no effects of the RUSFs in ITT analyses. However, children consuming RUSFs for >50 d had a significantly greater increase in WAZ relative to the increase in controls (+0.40 and +0.32 for RUSF-15% and RUSF-33%, respectively, compared with +0.24 in controls, P < 0.01 and P < 0.05, respectively). RUSF-33%, but not RUSF-15%, also eliminated a decrease in MUAC observed in controls (-0.01 cm in RUSF-33% compared with -0.34 cm in controls, P < 0.05). The only difference between RUSF-15% and RUSF-33% was a mean decrease in hemoglobin in children receiving RUSF-15% (-0.5 compared with -0.002 g/dL, P = 0.05). CONCLUSIONS: Implementation of 2-meal preschool feeding programs is feasible in low-income countries, and there are measurable benefits relative to 1-meal programs in children attending preschool regularly. In addition, MUAC and hemoglobin measurements indicate that meals with 33% compared with 15% of protein from dairy may help prevent wasting and anemia. PMID- 26609175 TI - Differences in Sympathetic Nervous Stimulation of Brown Adipose Tissue Between the Young and Old, and the Lean and Obese. AB - Brown adipose tissue (BAT) could facilitate weight loss by increasing energy expenditure. Cold is a potent stimulator of BAT, activating BAT primarily through the sympathetic nervous system (SNS). Older or overweight individuals have less metabolic BAT activity than the lean and young, but the role of the SNS in this decline is unknown. We aimed to determine whether this lower metabolic BAT activity in older or overweight individuals can be explained by a lower SNS response to cold. METHODS: This was a prospective observational study. We included 10 young obese, 11 old lean, and 14 young lean healthy men. All subjects underwent (18)F-FDG PET/CT and (123)I-meta-iodobenzylguanidine ((123)I-mIBG) SPECT/CT after an overnight fast and 2 h of cold exposure. Metabolic BAT activity was expressed as volume and as SUVmax of (18)F-FDG. BAT SNS activity was expressed as volume and as the ratio between (123)I-mIBG uptake in BAT and a reference region (SQUVmax of (123)I-mIBG). RESULTS: SUVmax, BAT volume, and SQUVmax were significantly different between young and old (SUVmax, 7.9 [range, 4.2-17.3] vs. 2.9 [range, 0.0-4.0]; volume, 124.8 [range, 10.9-338.8] vs. 3.4 [range, 0.0-10.9]; and SQUVmax, 2.7 [range, 1.9-4.7] vs. 0.0 [range, 0.0-2.2], respectively) (all P < 0.01) but not between lean and obese (SUVmax, 7.9 [range, 4.2-17.3] vs. 4.0 [range, 0.0-13.5] [P = 0.69]; volume, 124.8 [range, 10.9-338.8] vs. 11.8 [range, 0.0-190.2] [P = 0.64]; and SQUVmax, 2.7 [range, 1.9-4.7] vs. 1.7 [range, 0-3.5] [P = 0.69], respectively). We found a strong positive correlation between BAT activity measured with (18)F-FDG and (123)I-mIBG in the whole group of BAT-positive subjects (rho = 0.82, P < 0.01). CONCLUSION: Both sympathetic drive and BAT activity are lower in older but not in obese men. PMID- 26609174 TI - Plasma alpha-Linolenic and Long-Chain omega-3 Fatty Acids Are Associated with a Lower Risk of Acute Myocardial Infarction in Singapore Chinese Adults. AB - BACKGROUND: Long-chain marine omega-3 polyunsaturated fatty acids (n-3 PUFAs) are associated with a lower risk of acute myocardial infarction (AMI), but results for plant-derived alpha-linolenic acid (ALA; 18:3n-3) are inconsistent. OBJECTIVE: We aimed to examine the association between plasma n-3 PUFAs and AMI risk and to explore potential mediation by cardiovascular disease risk factors. METHODS: A nested case-control study with 744 incident AMI cases and 744 matched controls was conducted within the Singapore Chinese Health Study for participants aged 47-83 y. Conditional logistic regression was used to calculate the multivariable ORs for AMI with and without adjustment for cardiovascular disease risk factors, including blood lipids, blood pressure, C-reactive protein, serum creatinine, and glycated hemoglobin. RESULTS: Plasma long-chain n-3 PUFAs were associated with lower AMI risk (multivariable OR: 0.62; 95% CI: 0.41, 0.94; for the highest compared with the lowest quartile; P-trend = 0.03). This association was not substantially changed after adjustment for cardiovascular disease risk factors. Dietary intakes of fish and long-chain n-3 PUFAs were similarly inversely associated with AMI risk. Plasma ALA was marginally associated with a lower risk of AMI (multivariable OR: 0.73; 95% CI: 0.51, 1.05; P-trend = 0.07) even in persons with high plasma concentrations of long-chain n-3 PUFAs. This association became significantly weaker after adjustment for blood pressure and LDL cholesterol. CONCLUSIONS: Plasma long-chain n-3 PUFAs are associated with a lower risk of AMI in this Asian population. Plasma ALA may be marginally associated with reduced AMI risk, even in persons with high concentrations of long-chain n-3 PUFAs, and this association may be partially mediated by lower blood pressure and LDL cholesterol. PMID- 26609176 TI - Use of PERCIST for Prediction of Progression-Free and Overall Survival After Radioembolization for Liver Metastases from Pancreatic Cancer. AB - We evaluated the prognostic accuracy of established PET response criteria in patients with liver metastases from pancreatic cancer after treatment with (90)Y microspheres. METHODS: Seventeen patients underwent (18)F-FDG PET/CT before and 3 mo after radioembolization for liver metastases from pancreatic cancer. Overall survival, progression-free survival, and time to intrahepatic progression were among other factors correlated with metabolic response as revealed by PERCIST 1.0 defined declining SUVpeak and total-lesion glycolysis. RESULTS: Metabolic response by change in SUVpeak (7/17) and change in total-lesion glycolysis (7/17) was a predictor for overall survival (P = 0.039; hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.06-0.93), progression-free survival (P = 0.016; HR, 0.15; 95% CI, 0.03-0.69), and time to intrahepatic progression (P = 0.010; HR, 0.16; 95% CI, 0.04-0.65). A summed baseline CT diameter of less than 8 cm for the 2 largest liver metastases predicted time to intrahepatic progression (P = 0.013; HR, 0.21; 95% CI, 0.06-0.72) but did not predict overall or progression-free survival. Patient outcome was not predicted by other parameters, including baseline SUVpeak, baseline total-lesion glycolysis, or change in serum level of carcinoembryonic antigen or carbohydrate antigen 19-9 from baseline to follow-up (each, P > 0.05). CONCLUSION: Metabolic response by (18)F-FDG PET/CT predicts overall survival, progression-free survival, and time to intrahepatic progression after radioembolization for liver metastases from pancreatic cancer. PMID- 26609177 TI - Significance of a Single-Time-Point Somatostatin Receptor SPECT/Multiphase CT Protocol in the Diagnostic Work-up of Gastroenteropancreatic Neuroendocrine Neoplasms. AB - This prospective study compared a 1-d SPECT/CT protocol with the commonly used 3 d protocol for somatostatin receptor scintigraphy in patients with gastroenteropancreatic neuroendocrine neoplasms. Additionally, the influence of SPECT/CT on patient management was evaluated. METHODS: From October 2011 to October 2012, all gastroenteropancreatic neuroendocrine neoplasm patients undergoing restaging with somatostatin receptor scintigraphy on a modern SPECT/CT device were enrolled in this study. The protocol consisted of planar imaging at 4, 24, and 48 h; low-dose SPECT/CT at 24 and 48 h; diagnostic CT at 24 h using a triple-phase delay after administration of contrast; and diagnostic SPECT/CT at 24 h. All components of the imaging data were reassessed by 3 masked interpreters. The results were compared with a reference standard based on all clinical, imaging, and histopathology follow-up data available (follow-up range, 24-36 mo; mean, 29.9 mo). The reference standard was defined by a study-specific interdisciplinary tumor board that also reassessed treatment decisions. RESULTS: Thirty-one patients were eligible for analysis (18 men and 13 women; mean age, 60.4 y). Ten had no imaging signs of disease and remained disease-free during follow-up. Twenty-one had persistent or recurrent disease (82 lesions: 24 in the liver, 21 in the lymph nodes, 16 in bone, 12 in the pancreas, and 9 in other locations). The respective lesion detection rates for interpreters 1, 2, and 3 were 51.9%, 49.4%, and 71.6% for low-dose SPECT/CT at 24 h; 51.9%, 55.6%, and 67.9% for low-dose SPECT/CT at 48 h; 63.0%, 70.4%, and 85.2% for diagnostic CT; and 77.8%, 84.0%, and 88.9% for diagnostic SPECT/CT. Interobserver agreement was moderate for diagnostic SPECT/CT (kappa = 0.44), diagnostic CT (kappa = 0.43), low-dose SPECT/CT at 48 h (kappa = 0.61), and low-dose SPECT/CT at 24 h (kappa = 0.55). For planar imaging, interobserver agreement was fair after 48 h (kappa = 0.36) and 24 h (kappa = 0.38) and moderate after 4 h (kappa = 0.42). Every lesion detectable on planar imaging or low-dose SPECT/CT was also detectable on diagnostic SPECT/CT. The CT and SPECT components of diagnostic SPECT/CT strongly complemented each other, as 34 of 82 lesions (41.4%) were detected on only the CT component or only the SPECT component. Therapeutic management was influenced by the diagnostic SPECT/CT interpretation in 8 of 31 patients (25.8%). CONCLUSION: The highest detection rates were achieved by diagnostic SPECT/CT. Thus, a more patient-friendly 1-d protocol is feasible. Furthermore, multiphase SPECT/CT affected management in about a quarter of patients. PMID- 26609178 TI - Feasibility of 18F-Fluoromisonidazole Kinetic Modeling in Head and Neck Cancer Using Shortened Acquisition Times. AB - (18)F-fluoromisonidazole dynamic PET (dPET) is used to identify tumor hypoxia noninvasively. Its routine clinical implementation, however, has been hampered by the long acquisition times required. We investigated the feasibility of kinetic modeling using shortened acquisition times in (18)F-fluoromisonidazole dPET, with the goal of expediting the clinical implementation of (18)F-fluoromisonidazole dPET protocols. METHODS: Six patients with squamous cell carcinoma of the head and neck and 10 HT29 colorectal carcinoma-bearing nude rats were studied. In addition to an (18)F-FDG PET scan, each patient underwent a 45-min (18)F fluoromisonidazole dPET scan, followed by 10-min acquisitions at 96 +/- 4 and 163 +/- 17 min after injection. Ninety-minute (18)F-fluoromisonidazole dPET scans were acquired in animals. Intratumor voxels were classified into 4 clusters based on their kinetic behavior using k-means clustering. Kinetic modeling was performed using the foregoing full datasets (FD) and repeated for each of 2 shortened datasets corresponding to the first approximately 100 min (SD1; patients only) or the first 45 min (SD2) of dPET data. The kinetic rate constants (KRCs) as calculated with a 2-compartment model for both SD1 and SD2 were compared with those derived from FD by correlation (Pearson), regression (Passing Bablok), deviation (Bland-Altman), and classification (area-under-the-receiver operating characteristic curve) analyses. Simulations were performed to assess uncertainties due to statistical noise. RESULTS: Strong correlation (r >= 0.75, P < 0.001) existed between all KRCs deduced from both SD1 and SD2, and from FD. Significant differences between KRCs were found only for FD-SD2 correlations in patient studies. K1 and k3 were reproducible to within approximately 6% and approximately 30% (FD-SD1; patients) and approximately 4% and approximately 75% (FD-SD2; animals). Area-under-the-receiver-operating characteristic curve values for classification of patient clusters as hypoxic, using a tumor-to-blood ratio greater than 1.2, were 0.91 (SD1) and 0.86 (SD2). The percentage SD in estimating K1 and k3 from 45-min shortened datasets due to noise was less than 1% and between 2% and 12%, respectively. CONCLUSION: Using single-session 45-min shortened (18)F-fluoromisonidazole dPET datasets appears to be adequate for the identification of intratumor regions of hypoxia. However, k3 was significantly overestimated in the clinical cohort. Further studies are necessary to evaluate the clinical significance of differences between the results as calculated from full and shortened datasets. PMID- 26609179 TI - Age-Related Sex-Specific Changes in Brain Metabolism and Morphology. AB - With a large database, we aimed to evaluate sex-specific distinctive changes in brain glucose metabolism and morphology during normal aging using MRI and (18)F FDG PET. METHODS: A total of 963 cognitively healthy adults were included in this study. All subjects completed a medical questionnaire, took the mini-mental state examination, and underwent brain MRI and whole-body (18)F-FDG PET. The MR and PET images were statistically analyzed using 3-dimensional stereotactic surface projection. All images were corrected for whole-brain pixel value to identify the brain regions with significant changes, and regions of interest were set up with reference to Brodmann areas. We evaluated morphologic and glucose metabolic changes by cross-sectional analysis. The baseline database consisted of subjects from 30 to 40 y old, and the age-step for comparison was 5-y ranges. We also compared sex-specific differences in MR and PET images in each age group. RESULTS: Regarding age-related changes, in both sexes brain atrophy was observed in the lateral frontal and parietal regions and glucose hypometabolism in the medial frontal regions. There were significant differences in these parameters between the sexes; parallel changes in volume and metabolism were manifested in the medial frontal cortex in men and in the lateral and medial temporal cortex in women. By contrast, metabolism-dominant reductions were manifested in the lateral and medial parietal cortex in men and in the ventrolateral prefrontal cortex, including the Broca area, in women. These differences became insignificant in individuals 66 y or older. CONCLUSION: Our brain mapping study with a large number of reference human brain data demonstrated age-related parallel changes between morphology and metabolism in the medial frontal regions and sex-specific hypometabolism in the parietal (male) and ventrolateral prefrontal (female) cortices. These findings may suggest an aging vulnerability in sex-specific brain regions: the parietal cortex for visuospatial ability in men and the Broca area for speech processing in women. PMID- 26609180 TI - 124I PET/CT to Predict the Outcome of Blind 131I Treatment in Patients with Biochemical Recurrence of Differentiated Thyroid Cancer: Results of a Multicenter Diagnostic Cohort Study (THYROPET). AB - Patients with suspected recurrence from differentiated thyroid carcinoma, based on an increased thyroglobulin (Tg) level and negative neck ultrasound (US), pose a clinical dilemma. Because standard imaging has a low yield identifying potential recurrence, blind (131)I treatment is often applied. However, a tumor negative (131)I whole-body scintigraphy (WBS) prevails in 38%-50% of patients. We performed a prospective multicenter observational cohort study to test the hypothesis that (124)I PET/CT can identify the patients with a tumor-negative posttherapy (131)I WBS. METHODS: Our study was designed to include 100 patients with detectable Tg and a negative neck US, who were planned for blind (131)I therapy. All patients underwent (124)I PET/CT after administration of recombinant human thyroid-stimulating hormone. Subsequently, after 4-6 wk of thyroid hormone withdrawal patients were treated with 5.5-7.4 GBq of (131)I, followed by WBS a week later. The primary endpoint was the number of (131)I therapies that could have been omitted using the predicted outcome of the (124)I PET/CT, operationalized as the concordance of tumor detection by (124)I PET/CT, using post-(131)I therapy WBS as the reference test. The study would be terminated if 3 patients had a negative (124)I PET/CT and a positive posttherapy (131)I scan. RESULTS: After inclusion of 17 patients, we terminated the study preliminarily because the stopping rule had been met. Median Tg level at (131)I therapy was 28 MUg/L (interquartile range, 129). Eight posttherapy WBS were negative (47%), all of which were correctly predicted by negative (124)I PET/CT. Nine posttherapy WBS showed iodine-avid tumor, of which 4 also had positive (124)I PET/CT findings. Sensitivity, specificity, negative predictive value, and positive predictive value of (124)I PET/CT were 44% (confidence interval [CI], 14%-79%), 100% (CI, 63%-100%), 62% (CI, 32%-86%), and 100% (CI, 40%-100%), respectively. Implementation of (124)I PET in this setting would have led to 47% (8/17) less futile (131)I treatments, but 29% of patients (5/17) would have been denied potentially effective therapy. CONCLUSION: In patients with biochemical evidence of recurrent differentiated thyroid carcinoma and a tumor-negative neck US, the high false-negative rate of (124)I PET/CT after recombinant human thyroid stimulating hormone (124)I PET/CT as implemented in this study precludes its use as a scouting procedure to prevent futile blind (131)I therapy. PMID- 26609181 TI - RGD PET: From Lesion Detection to Therapy Response Monitoring. PMID- 26609182 TI - 99mTc-CXCL8 SPECT to Monitor Disease Activity in Inflammatory Bowel Disease. AB - Inflammatory bowel diseases (IBDs) are defined as chronic relapsing immune mediated disorders of the gastrointestinal tract. IBD exacerbations are characterized by recruitment of mainly CXCL8 receptor-expressing activated neutrophils into the intestinal wall, leading to severe damage. Considering its chronic relapsing character, accurate and timely diagnosis of an exacerbation is pivotal for early adaptation of the treatment and reduction of the disease burden. However, endoscopic evaluation is invasive and associated with an increased risk of perforation. We previously developed a (99m)Tc-labeled CXCL8 preparation in preclinical models including colitis and clinical studies. METHODS: In this study, we investigate the accuracy of (99m)Tc-CXCL8 SPECT to detect and localize disease activity in a prospective series of patients with IBD. Thirty patients (15 Crohns disease, 15 ulcerative colitis) participated, and 92 segmental pairs of histology and (99m)Tc-CXCL8 scans were studied. Imaging was performed after injection of 400 MBq of (99m)Tc-CXCL8. Planar and SPECT images of the abdomen were acquired at 30 min and 4 h after the injection. RESULTS: The overall sensitivity and specificity on a per-patient basis for the detection of active disease were 95% and 44% for (99m)Tc-CXCL8 scan and 71% and 70% for endoscopy. The degree of (99m)Tc-CXCL8 accumulation correlated to the degree of neutrophilic influx in affected mucosa. Sensitivity and specificity on a per segment basis, calculated from the 92 segmental pairs, were 82% and 72%, negative predictive value was 81%, and overall positive predictive value was 74%. Specificity could be increased at the expense of sensitivity using different cutoffs. In 74 segmental pairs, overall sensitivity and specificity for endoscopy were 74% and 85%, positive predictive value was 81%, and negative predictive value was 79%. CONCLUSION: (99m)Tc-CXCL8 SPECT provides a novel imaging technique to target neutrophil recruitment to the intestinal wall, especially in moderate to severe exacerbations of IBD. Further validation studies are warranted to potentiate (99m)Tc-CXCL8 SPECT as a biomarker to scale up or step down treatment with immune-modulating drugs in a personalized fashion. PMID- 26609184 TI - Pioneers in Pediatric Psychology: Helping Shape a New Field. PMID- 26609183 TI - Maternal Coping and Depressive Symptoms as Predictors of Mother-Child Communication About a Child's Cancer. AB - OBJECTIVE: This study sought to identify possible associations between maternal coping and depression and subsequent mother-child communication about cancer following the child's diagnosis. METHOD: Mothers (N = 100) reported on coping and depressive symptoms shortly after the child's diagnosis (M = 1.9 months). Subsequently, we observed children (age 5-17 years; M = 10.2 years; 48% female; 81% White) and mothers discussing cancer and coded maternal communication. RESULTS: Higher primary and secondary control coping, and lower depressive symptoms, were generally correlated with more positive, and less harsh and withdrawn communication. In regression models, higher primary control coping (i.e., coping efforts to change the stressor or one's emotional reaction to the stressor) independently predicted less withdrawn communication, and depressive symptoms mediated relations between coping and harsh communication. CONCLUSIONS: Maternal primary control coping and depressive symptoms predict mothers' subsequent harsh and withdrawn communication about cancer. PMID- 26609185 TI - The Time Dependent Propensity Function for Acceleration of Spatial Stochastic Simulation of Reaction-Diffusion Systems. AB - The inhomogeneous stochastic simulation algorithm (ISSA) is a fundamental method for spatial stochastic simulation. However, when diffusion events occur more frequently than reaction events, simulating the diffusion events by ISSA is quite costly. To reduce this cost, we propose to use the time dependent propensity function in each step. In this way we can avoid simulating individual diffusion events, and use the time interval between two adjacent reaction events as the simulation stepsize. We demonstrate that the new algorithm can achieve orders of magnitude efficiency gains over widely-used exact algorithms, scales well with increasing grid resolution, and maintains a high level of accuracy. PMID- 26609186 TI - A Nation of Immigrants: Assimilation and Economic Outcomes in the Age of Mass Migration. AB - During the Age of Mass Migration (1850-1913), the United States maintained an open border, absorbing 30 million European immigrants. Prior cross-sectional work finds that immigrants initially held lower-paid occupations than natives but converged over time. In newly assembled panel data, we show that, in fact, the average immigrant did not face a substantial occupation-based earnings penalty upon first arrival and experienced occupational advancement at the same rate as natives. Cross-sectional patterns are driven by biases from declining arrival cohort skill level and departures of negatively selected return migrants. We show that assimilation patterns vary substantially across sending countries and persist in the second generation. PMID- 26609187 TI - Modeling of the biodynamic responses distributed at the fingers and palm of the hand in three orthogonal directions. AB - The objectives of this study were to develop models of the hand-arm system in the three orthogonal directions (xh, yh , and zh ) and to enhance the understanding of the hand vibration dynamics. A four-degrees-of-freedom (DOF) model and 5-DOF model were used in the simulation for each direction. The driving-point mechanical impedances distributed at the fingers and palm of the hand reported in a previous study were used to determine the parameters of the models. The 5-DOF models were generally superior to the 4-DOF models for the simulation. Hence, as examples of applications, the 5-DOF models were used to predict the transmissibility of a vibration-reducing glove and the vibration transmissibility on the major substructures of the hand-arm system. The model-predicted results were also compared with the experimental data reported in two other recent studies. Some reasonable agreements were observed in the comparisons, which provided some validation of the developed models. This study concluded that the 5 DOF models are acceptable for helping to design and analyze vibrating tools and anti-vibration devices. This study also confirmed that the 5-DOF model in the zh direction is acceptable for a coarse estimation of the biodynamic responses distributed throughout the major substructures of the hand-arm system. Some interesting phenomena observed in the experimental study of the biodynamic responses in the three directions were also explained in this study. PMID- 26609188 TI - Preschool Outcomes of Children Who Lived as Infants in a Prison Nursery. AB - This study examined long-term outcomes of children who spent their first one to eighteen months in a US prison nursery. Behavioral development in 47 preschool children who lived in a prison nursery was compared with 64 children from a large national dataset who were separated from their mothers because of incarceration. Separation was associated with significantly worse anxious/depressed scores, even after controlling for risks in the caregiving environment. Findings suggest that prison nursery co-residence with developmental support confers some resilience in children who experience early maternal incarceration. Co-residence programs should be promoted as a best practice for incarcerated childbearing women. PMID- 26609189 TI - Circulatory Diseases in the U.S. Elderly in the Linked National Long-Term Care Survey-Medicare Database: Population-Based Analysis of Incidence, Comorbidity, and Disability. AB - Incidence rates of acute coronary heart disease (ACHD; including myocardial infarction and angina pectoris), stroke, and heart failure (HF) were studied for their age, disability, and comorbidity patterns in the U.S. elderly population using the National Long Term Care Survey (NLTCS) data linked to Medicare records for 1991-2005. Incidence rates increased with age with a decrease in the oldest old (stroke and HF) or were stable at all ages (ACHD). For all diseases, incidence rates were lower among institutionalized individuals and higher in individuals with higher comorbidity indices. The results could be used for understanding currently debated effects of biomedical research, screening, and therapeutic innovations on changes in disease incidence with advancing age as well as for projecting future Medicare costs. PMID- 26609190 TI - Magnetic Resonance Imaging as a Biomarker for Renal Cell Carcinoma. AB - As the most common neoplasm arising from the kidney, renal cell carcinoma (RCC) continues to have a significant impact on global health. Conventional cross sectional imaging has always served an important role in the staging of RCC. However, with recent advances in imaging techniques and postprocessing analysis, magnetic resonance imaging (MRI) now has the capability to function as a diagnostic, therapeutic, and prognostic biomarker for RCC. For this narrative literature review, a PubMed search was conducted to collect the most relevant and impactful studies from our perspectives as urologic oncologists, radiologists, and computational imaging specialists. We seek to cover advanced MR imaging and image analysis techniques that may improve the management of patients with small renal mass or metastatic renal cell carcinoma. PMID- 26609192 TI - Have the poor always been less likely to migrate? Evidence from inheritance practices during the age of mass migration. AB - Using novel data on 50,000 Norwegian men, we study the effect of wealth on the probability of internal or international migration during the Age of Mass Migration (1850-1913), a time when the US maintained an open border to European immigrants. We do so by exploiting variation in parental wealth and in expected inheritance by birth order, gender composition of siblings, and region. We find that wealth discouraged migration in this era, suggesting that the poor could be more likely to move if migration restrictions were lifted today. We discuss the implications of these historical findings to developing countries. PMID- 26609191 TI - Metabolic Serum Profiles for Patients Receiving Allogeneic Stem Cell Transplantation: The Pretransplant Profile Differs for Patients with and without Posttransplant Capillary Leak Syndrome. AB - Allogeneic stem cell transplantation is commonly used in the treatment of younger patients with severe hematological diseases, and endothelial cells seem to be important for the development of several posttransplant complications. Capillary leak syndrome is a common early posttransplant complication where endothelial cell dysfunction probably contributes to the pathogenesis. In the present study we investigated whether the pretreatment serum metabolic profile reflects a risk of posttransplant capillary leak syndrome. We investigated the pretransplant serum levels of 766 metabolites for 80 consecutive allotransplant recipients. Patients with later capillary leak syndrome showed increased pretherapy levels of metabolites associated with endothelial dysfunction (homocitrulline, adenosine) altered renal regulation of fluid and/or electrolyte balance (betaine, methoxytyramine, and taurine) and altered vascular function (cytidine, adenosine, and methoxytyramine). Additional bioinformatical analyses showed that capillary leak syndrome was also associated with altered purine/pyrimidine metabolism (i.e., metabolites involved in vascular regulation and endothelial functions), aminoglycosylation (possibly important for endothelial cell functions), and eicosanoid metabolism (also involved in vascular regulation). Our observations are consistent with the hypothesis that the pretransplant metabolic status can be a marker for posttransplant abnormal fluid and/or electrolyte balance. PMID- 26609193 TI - Poverty and Proximate Barriers to Learning: Vision Deficiencies, Vision Correction and Educational Outcomes in Rural Northwest China. AB - Uncorrected vision may present a significant barrier to educational mobility in poor communities in low and middle income countries. Focusing on the case of rural Northwest China, we analyze the Gansu Survey of Children and Families (2,000 children; 100 rural villages) and the Gansu Vision Intervention Project (a randomized trial; 19,185 students, 165 schools, two counties). Four main findings emerge: significant unmet need for vision correction; socioeconomic gradients in vision correction; somewhat greater vulnerability to vision problems among higher socioeconomic status and more academically engaged children; and significant favorable effects of vision correction on math and literacy performance and class failure. PMID- 26609194 TI - Poverty, Food Insecurity and Nutritional Deprivation in Rural China: Implications for Children's Literacy Achievement. PMID- 26609195 TI - Rh(I)-Catalyzed Cycloisomerization of 1,6-Enynes. AB - A new and unexpected Rh(I)-catalyzed cycloisomerization of 1,6-enynes is reported. Several different alkyne substitution patterns were evaluated under the reaction conditions, including a deuterated derivative that provides some insight into the reaction mechanism. PMID- 26609196 TI - Role of Ceramide from Glycosphingolipids and Its Metabolites in Immunological and Inflammatory Responses in Humans. AB - Glycosphingolipids (GSLs) are composed of hydrophobic ceramide and hydrophilic sugar chains. GSLs cluster to form membrane microdomains (lipid rafts) on plasma membranes, along with several kinds of transducer molecules, including Src family kinases and small G proteins. However, GSL-mediated biological functions remain unclear. Lactosylceramide (LacCer, CDw17) is highly expressed on the plasma membranes of human phagocytes and mediates several immunological and inflammatory reactions, including phagocytosis, chemotaxis, and superoxide generation. LacCer forms membrane microdomains with the Src family tyrosine kinase Lyn and the Galphai subunit of heterotrimeric G proteins. The very long fatty acids C24:0 and C24:1 are the main ceramide components of LacCer in neutrophil plasma membranes and are directly connected with the fatty acids of Lyn and Galphai. These observations suggest that the very long fatty acid chains of ceramide are critical for GSL-mediated outside-in signaling. Sphingosine is another component of ceramide, with the hydrolysis of ceramide by ceramidase producing sphingosine and fatty acids. Sphingosine is phosphorylated by sphingosine kinase to sphingosine-1-phosphate, which is involved in a wide range of cellular functions, including growth, differentiation, survival, chemotaxis, angiogenesis, and embryogenesis, in various types of cells. This review describes the role of ceramide moiety of GSLs and its metabolites in immunological and inflammatory reactions in human. PMID- 26609197 TI - Sepsis and ARDS: The Dark Side of Histones. AB - Despite advances in management over the last several decades, sepsis and acute respiratory distress syndrome (ARDS) still remain major clinical challenges and the leading causes of death for patients in intensive care units (ICUs) due to insufficient understanding of the pathophysiological mechanisms of these diseases. However, recent studies have shown that histones, also known as chromatin-basic structure proteins, could be released into the extracellular space during severe stress and physical challenges to the body (e.g., sepsis and ARDS). Due to their cytotoxic and proinflammatory effects, extracellular histones can lead to excessive and overwhelming cell damage and death, thus contributing to the pathogenesis of both sepsis and ARDS. In addition, antihistone-based treatments (e.g., neutralizing antibodies, activated protein C, and heparin) have shown protective effects and have significantly improved the outcomes of mice suffering from sepsis and ARDS. Here, we review researches related to the pathological role of histone in context of sepsis and ARDS and evaluate the potential value of histones as biomarkers and therapeutic targets of these diseases. PMID- 26609199 TI - Moringa oleifera Flower Extract Suppresses the Activation of Inflammatory Mediators in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages via NF-kappaB Pathway. AB - Aim of Study. Moringa oleifera Lam. (M. oleifera) possess highest concentration of antioxidant bioactive compounds and is anticipated to be used as an alternative medicine for inflammation. In the present study, we investigated the anti-inflammatory activity of 80% hydroethanolic extract of M. oleifera flower on proinflammatory mediators and cytokines produced in lipopolysaccharide- (LPS-) induced RAW 264.7 macrophages. Materials and Methods. Cell cytotoxicity was conducted by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Nitric oxide (NO) production was quantified through Griess reaction while proinflammatory cytokines and other key inflammatory markers were assessed through enzyme-linked immunosorbent assay (ELISA) and immunoblotting. Results. Hydroethanolic extract of M. oleifera flower significantly suppressed the secretion and expression of NO, prostaglandin E2 (PGE2), interleukin- (IL-) 6, IL 1beta, tumor necrosis factor-alpha (TNF-alpha), nuclear factor-kappa B (NF kappaB), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2). However, it significantly increased the production of IL-10 and IkappaB-alpha (inhibitor of kappaB) in a concentration dependent manner (100 MUg/mL and 200 MUg/mL). Conclusion. These results suggest that 80% hydroethanolic extract of M. oleifera flower has anti-inflammatory action related to its inhibition of NO, PGE2, proinflammatory cytokines, and inflammatory mediator's production in LPS stimulated macrophages through preventing degradation of IkappaB-alpha in NF kappaB signaling pathway. PMID- 26609198 TI - Dengue Virus-Induced Inflammation of the Endothelium and the Potential Roles of Sphingosine Kinase-1 and MicroRNAs. AB - One of the main pathogenic effects of severe dengue virus (DENV) infection is a vascular leak syndrome. There are no available antivirals or specific DENV treatments and without hospital support severe DENV infection can be life threatening. The cause of the vascular leakage is permeability changes in the endothelial cells lining the vasculature that are brought about by elevated vasoactive cytokine and chemokines induced following DENV infection. The source of these altered cytokine and chemokines is traditionally believed to be from DENV-infected cells such as monocyte/macrophages and dendritic cells. Herein we discuss the evidence for the endothelium as an additional contributor to inflammatory and innate responses during DENV infection which may affect endothelial cell function, in particular the ability to maintain vascular integrity. Furthermore, we hypothesise roles for two factors, sphingosine kinase 1 and microRNAs (miRNAs), with a focus on several candidate miRNAs, which are known to control normal vascular function and inflammatory responses. Both of these factors may be potential therapeutic targets to regulate inflammation of the endothelium during DENV infection. PMID- 26609202 TI - Raising the Index of Suspicion: Red Flags That Represent Credible Threats to Patient Safety. AB - The index of suspicion: red flags warn of safety threats. PMID- 26609201 TI - Adjustment of costly extra-group paternity according to inbreeding risk in a cooperative mammal. AB - Females of many animal species seek mating opportunities with multiple males, despite being able to obtain sufficient sperm to father their offspring from a single male. In animals that live in stable social groups, females often choose to mate outside their group resulting in extra-group paternity (EGP). One reason proposed to explain female choice for extra-group males is to obtain compatible genes, for example, in order to avoid inbreeding depression in offspring. The benefits of such extra-group paternities could be substantial if they result in fitter, outbred offspring. However, avoiding inbreeding in this way could be costly for females, for example, through retaliation by cuckolded males or through receiving aggression while prospecting for extra-group mating opportunities. We investigate the costs and benefits of EGP in the banded mongoose Mungos mungo, a cooperatively breeding mammal in which within-group mates are sometimes close relatives. We find that pups born to females that mate with extra-group males are more genetically heterozygous are heavier and are more likely to survive to independence than pups born to females that mate within their group. However, extra-group matings also involve substantial costs as they occur during violent encounters that sometimes result in injury and death. This appears to lead femalebanded mongooses to adaptively adjust EGP levels according to the current risk of inbreeding associated with mating within the group. For group-living animals, the costs of intergroup interactions may help to explain variation in both inbreeding rates and EGP within and between species. PMID- 26609200 TI - HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis Is Not Associated with SNP rs12979860 of the IL-28B Gene. AB - The present study investigated the association between the rs12979860 polymorphism in the IL-28B gene and HTLV-1 infection as well as the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 infected patients (26 HAM/TSP symptomatic and 53 asymptomatic) and 300 seronegative healthy controls were investigated. Plasma levels of the cytokines TNF-alpha, TNF-beta, IL-8, IL-10, IL-6, and IFN-gamma from infected patients were measured using an indirect enzyme-linked immunosorbent assay. The HTLV proviral load was measured using a real-time PCR assay, and T-cell subset counts were determined by flow cytometry. Real-time PCR was used to genotype the rs12979860 SNP. The allelic and genotypic distributions displayed no significant differences among the investigated groups. No significant association between the serum cytokine levels and the presence of the rs12979860 SNP in symptomatic and asymptomatic subjects was observed. A positive correlation (p = 0.0015) between TNF-beta and IFN-gamma was observed in the asymptomatic group, but a positive correlation was only observed (p = 0.0180) between TNF-alpha and IL-6 in the HAM/TSP group. The proviral load was significantly higher in HAM/TSP patients than in asymptomatic subjects. The present results do not support a previous report indicating an association between the SNP rs12979860 and HAM/TSP outcome. PMID- 26609203 TI - Pharmacies Wrestle With Drug-Tracing Rule: Confusion as Deadline Passes: Paper, Digital, or Web Portal? AB - Pharmacies wrestle with the FDA's new drug-tracing rule. PMID- 26609204 TI - New Medical Devices. PMID- 26609205 TI - Pharmaceutical Approval Update. AB - Evolocumab (Repatha) for patients with hypercholesterolemia whose condition has not been controlled by statins and other therapies; trifluridine/tipiracil (Lonsurf) for metastatic colorectal cancer; and blood coagulation factor VIII (Nuwiq) for adults and children with hemophilia A. PMID- 26609206 TI - Afrezza (Insulin Human) Inhalation Powder: A New Inhaled Insulin for the Management Of Type-1 or Type-2 Diabetes Mellitus. AB - Afrezza (insulin human) inhalation powder: a new inhaled insulin for the management of type-1 or type-2 diabetes mellitus. PMID- 26609207 TI - A Dissenting Viewpoint on the ACA. PMID- 26609208 TI - Imperatives for Oversight Of Professional Personnel. AB - Although the health care marketplace is changing rapidly, some things have not changed, including the need for P&T committees and organizations' management to beware of ethical and legal issues such as discrimination, quotas, and understaffing. PMID- 26609209 TI - Parkinson's Disease and Its Management: Part 4: Treatment of Motor Complications. AB - Parkinson's motor complications include wearing-off, a delayed or absent response to carbidopa/levodopa therapy, freezing of gait, dyskinesias, and dystonias. Treatment may include medication adjustments, such as increased dopaminergic stimulation. PMID- 26609211 TI - European Cancer Congress 2015. AB - The European Cancer Congress, which attracts a range of European cancer groups, reflected intense interest in immunotherapies. we review key sessions, including three on the anti-programmed death-1 agent nivolumab, each in a different disease setting. PMID- 26609212 TI - Long-Acting Therapies Will Expand Growth Hormone Deficiency Market. AB - Future therapies for growth hormone deficiency are expected to include long acting formulations that may encourage increased use of and adherence to these products. PMID- 26609210 TI - Pharmacological Treatment of Insomnia. AB - Up to 70 million U.S. adults have chronic sleep and wakefulness disorders. Therapies may include prescription medications approved by the Food and Drug Administration, off-label treatments, over-the-counter drugs, and herbal therapies. PMID- 26609213 TI - Multivariate Boosting for Integrative Analysis of High-Dimensional Cancer Genomic Data. AB - In this paper, we propose a novel multivariate component-wise boosting method for fitting multivariate response regression models under the high-dimension, low sample size setting. Our method is motivated by modeling the association among different biological molecules based on multiple types of high-dimensional genomic data. Particularly, we are interested in two applications: studying the influence of DNA copy number alterations on RNA transcript levels and investigating the association between DNA methylation and gene expression. For this purpose, we model the dependence of the RNA expression levels on DNA copy number alterations and the dependence of gene expression on DNA methylation through multivariate regression models and utilize boosting-type method to handle the high dimensionality as well as model the possible nonlinear associations. The performance of the proposed method is demonstrated through simulation studies. Finally, our multivariate boosting method is applied to two breast cancer studies. PMID- 26609215 TI - Spectrophotometric Investigations of Macrolide Antibiotics: A Brief Review. AB - Macrolides, one of the most commonly used class of antibiotics, are a group of drugs produced by Streptomyces species. They belong to the polyketide class of natural products. Their activity is due to the presence of a large macrolide lactone ring with deoxy sugar moieties. They are protein synthesis inhibitors and broad-spectrum antibiotics, active against both gram-positive and gram-negative bacteria. Different analytical techniques have been reported for the determination of macrolides such as chromatographic methods, flow injection methods, spectrofluorometric methods, spectrophotometric methods, and capillary electrophoresis methods. Among these methods, spectrophotometric methods are sensitive and cost effective for the analysis of various antibiotics in pharmaceutical formulations as well as biological samples. This article reviews different spectrophotometric methods for the determination of macrolide antibiotics. PMID- 26609214 TI - Precision Medicine for Molecularly Targeted Agents and Immunotherapies in Early Phase Clinical Trials. AB - Precision medicine in oncology promises the matching of genomic, molecular, and clinical data with underlying mechanisms of a range of novel anticancer therapeutics to develop more rational and effective antitumor strategies in a timely manner. However, despite the remarkable progress made in the understanding of novel drivers of different oncogenic processes, success rates for the approval of oncology drugs remain low with substantial fiscal consequences. In this article, we focus on how recent rapid innovations in technology have brought greater clarity to the biological and clinical complexities of different cancers and advanced the development of molecularly targeted agents and immunotherapies in clinical trials. We discuss the key challenges of identifying and validating predictive biomarkers of response and resistance using both tumor and surrogate tissues, as well as the hurdles associated with intratumor heterogeneity. Finally, we outline evolving strategies employed in early-phase trial designs that incorporate omics-based technologies. PMID- 26609216 TI - Management of Diabetes Associated with Nephrotic Syndrome: Therapeutic Potential of Dapagliflozin for Protracted Volume Retention. AB - A 48-year-old female was admitted to our hospital presenting with a chief complaint of progressive swelling because of diabetic nephrotic syndrome. Dapagliflozin seemed to play a role in accelerating the patient's urinary sodium excretion as well as reducing gross fluid retention despite the fact that her nephrotic condition was resistant to furosemide. Our experience emphasizes a potential novel approach to overcoming loop diuretic resistance using this agent among some subsets of type 2 diabetic subjects complicated with severe volume accumulation. We believe that combination treatment consisting of dapagliflozin and furosemide may produce diuretic synergy via sequential nephron blockade. The accumulation of more experience with additional cases similar to ours requires continuous and careful attention. PMID- 26609217 TI - Evaluating the different laser fragmentation patterns used in laser cataract surgeries in terms of effective phacoemulsification time and power. AB - PURPOSE: To evaluate the effects of the different fragmentation patterns for the lens nucleus in terms of the effective phacoemulsification time (EPT) and power. SETTING: Shinagawa LASIK Center, Tokyo, Japan. DESIGN: Comparison study. METHODS: Seventy-one eyes of 71 patients had preoperative lens opacity grading based on the Emery-Little Classification (Grade 1 and Grade 2). Eyes underwent femtosecond laser-assisted cataract surgery (CatalysTM Precision Laser System), for capsulotomy and lens fragmentation. For the lens fragmentation, either the quadrants softened (Quadrant) or the quadrants complete (Complete) pattern was used. The mean EPT and phacoemulsification (phaco) power for each cutting pattern of Grades 1 and 2 cataracts were evaluated. RESULTS: The mean EPT was 28.96 seconds in the Quadrant Group and 16.31 seconds in the Complete Group (P=0.006). The mean phaco power was 8.07% in the Quadrant Group and 4.77% in the Complete Group (P=0.0002). Comparing the Quadrant and Complete Groups of Grade 1 cataract showed no significant difference in EPT (P=0.16), but showed a significant difference in phaco power (P=0.033). Comparing the Quadrant and Complete patterns of Grade 2 cataract showed significant differences in both EPT (P=0.012) and phaco power (P=0.003). Using the Complete pattern showed a 44.7% reduction in EPT and a 40.9% reduction in phaco power when compared to the Quadrant Group. CONCLUSION: Using the smaller fragmentation pattern in femtosecond laser cataract surgery, the phaco time and power were reduced significantly when compared to the procedure with the larger fragmentation pattern. PMID- 26609218 TI - Changes in corneal endothelium cell characteristics after cataract surgery with and without use of viscoelastic substances during intraocular lens implantation. AB - PURPOSE: To evaluate whether the use of balanced salt solution (BSS) or an ophthalmic viscoelastic device (OVD) during hydrophilic acrylic intraocular lens (IOL) implantation variously impacts corneal endothelial cell characteristics in eyes undergoing uneventful phacoemulsifications. METHODS: Prospective nonrandomized observational clinical trial. Patients were assigned either to the BSS plus((r)) or to the OVD Z-CelcoatTM group depending on the substance used during IOL implantation. Corneal endothelium cell characteristics were obtained before, 1 week, and 6 weeks after surgery. Intraoperative parameters (eg, surgery time, phacoemulsification energy) were recorded. RESULTS: Ninety-seven eyes were assigned to the BSS plus and 86 eyes to the Z-Celcoat group. Preoperative corneal endothelium cell density (ECD) and endothelium cell size were 2,506+/-310 cells/mm(2)/2,433+/-261 cells/mm(2) and 406+/-47 um(2)/416+/-50 um(2) (P=0.107/P=0.09). After 1 and 6 weeks, ECD decreased and endothelium cell size increased significantly in both groups (each P<0.001) without significant differences between both groups (each P>0.05). Irrigation-aspiration suction time (30.3+/-16.6 versus 36.3+/-14.5 seconds) and overall surgical time (7.2+/-1.2 versus 8.0+/-1.4 minutes) were significantly longer in the OVD Z-Celcoat group (each P<0.001). No complications or serious side effects occurred. CONCLUSION: Implantation of a hydrophilic acrylic IOL under BSS infusion seems to be a useful and faster alternative in experienced hands without generating higher ECD loss rates. PMID- 26609219 TI - A retrospective analysis of the postoperative use of loteprednol etabonate gel 0.5% following laser-assisted in situ keratomileusis or photorefractive keratectomy surgery. AB - BACKGROUND: While loteprednol etabonate ophthalmic gel 0.5% (LE gel) is approved for treatment of postoperative ocular inflammation and pain, there have been no reported studies in patients undergoing laser-assisted in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK). METHODS: This was a retrospective chart review conducted at five refractive surgical centers in the USA. Data were collected from primary LASIK or PRK surgery cases in which LE gel was used postoperatively as the clinician's routine standard of care and in which patients were followed-up for up to 6 months. Data extracted from charts included patient demographics, surgical details, LE gel dosing regimen, pre- and postsurgical refractive characteristics, intraocular pressure (IOP) measurements, and visual acuity. Primary outcomes included postoperative IOP elevations, adverse events, and early discontinuations. RESULTS: Data were collected on 189 LASIK eyes (96 patients) and 209 PRK eyes (108 patients). Mean (standard deviation [SD]) years of age at surgery was 36.0 (11.7) and 33.9 (11.3) in LASIK and PRK patients. LE gel was prescribed most often four times daily during the first postoperative week, regardless of procedure; the most common treatment duration was 7-14 days in LASIK and >=30 days in PRK patients. No unusual corneal findings or healing abnormalities were reported. Mean postoperative uncorrected distance visual acuity was 20/24 in LASIK and 20/30 in PRK eyes. Mild/trace corneal haze was reported in 20% of PRK patients; two PRK patients with moderate/severe corneal haze were switched to another corticosteroid. Mean postoperative IOP did not increase over time in either LASIK or PRK eyes (P>=0.331); clinically significant elevations from baseline in IOP (>=10 mmHg) were noted in only three eyes of two PRK patients. CONCLUSION: LE gel appears to have a high level of safety and tolerability when used for the management of postoperative pain and inflammation following LASIK and PRK surgery. PMID- 26609220 TI - Inferior rectus nasal transposition as a procedure of choice for acquired superior oblique palsy. PMID- 26609221 TI - Progesterone regulates the proliferation of breast cancer cells - in vitro evidence. AB - Reports state that surgery performed at different phases of the menstrual cycle may significantly affect breast cancer treatment outcome. From previous studies, we identified differentially expressed genes in each menstrual cycle phase by microarray, then subjected them to functional in vitro analyses. Microarray studies disclosed genes that are upregulated in the luteal phase and follicular phase. TOB-1 is a tumor suppressor gene and was expressed exclusively in the luteal phase in our microarray study. Therefore, we further functionally characterized the protein product of TOB-1 in vitro. To our knowledge, no studies have yet been conducted on reactive oxygen species-regulated tumor suppressor interactions in accordance with the biphasic nature of progesterone. This work demonstrates that progesterone can produce reactive oxygen species in MCF-7 cells and that TOB-1 exerts a series of non-genomic interactions that regulate antiproliferative activity by modulating the antioxidant enzyme superoxide dismutase. Furthermore, this study implicates PTEN as an interacting partner for TOB-1, which may regulate the downstream expression of cell cycle control protein p27 via multiple downstream signaling pathways of progesterone through a progesterone receptor, purely in a time- and concentration-dependent manner. These results support the hypothesis that surgery conducted during the luteal phase of the menstrual cycle may facilitate improved patient survival. PMID- 26609222 TI - Glucose abnormalities in Asian patients with chronic hepatitis C. AB - Many studies have demonstrated a potential association between type 2 diabetes (T2D) and hepatitis C virus infection in Western countries, while similar evidence is limited in Asia. We compared the prevalence of glucose abnormalities (impaired fasting glucose [IFG] and T2D) and their risk factors between Asian and non-Asian chronic hepatitis C (CHC) patients, and evaluated whether glucose abnormalities impacted the viral responses to peginterferon plus ribavirin treatment (current standard of care in most Asian countries). This study retrospectively analyzed data of 1,887 CHC patients from three Phase II/III studies with alisporivir (DEB025) as treatment for CHC. The chi-square test was used to compare the prevalence of IFG/T2D between Asian and non-Asian CHC patients, and logistic regression was used to adjust for sex, age, and cirrhosis status. Risk factors for IFG/T2D were evaluated using univariate and multivariate analysis. Our results indicated that the prevalence of IFG/T2D was high in both Asian and non-Asian CHC patients (23.0% vs 20.9%), and no significant difference was found between these two populations (adjusted odds ratio: 1.3, 95% confidence interval: 0.97, 1.7; P=0.08). Age, sex, and cirrhosis status were risk factors for IFG/T2D in both populations, while body mass index was positively associated with IFG/T2D in non-Asian but not in Asian participants. No significant differences in sustained virological response rates were seen between patients with normal fasting glucose and patients with IFG/T2D for both populations. These results demonstrate that the prevalence of glucose abnormalities in Asian CHC patients was similar to that in non-Asians, and glucose abnormalities had no impact on viral response to peginterferon plus ribavirin. PMID- 26609223 TI - 6-Gingerol alleviates exaggerated vasoconstriction in diabetic rat aorta through direct vasodilation and nitric oxide generation. AB - The aim of the present study is to investigate the effect and potential mechanism of action of 6-gingerol on alterations of vascular reactivity in the isolated aorta from diabetic rats. Male Wistar rats were divided into two experimental groups, control and diabetics. Diabetes was induced by a single intraperitoneal injection of streptozotocin (50 mg kg(-1)), and the rats were left for 10 weeks to develop vascular complications. The effect of in vitro incubation with 6 gingerol (0.3-3 MUM) on the vasoconstrictor response of the isolated diabetic aortae to phenylephrine and the vasodilator response to acetylcholine was examined. Effect of 6-gingerol was also examined on aortae incubated with methylglyoxal as an advanced glycation end product (AGE). To investigate the mechanism of action of 6-gingerol, the nitric oxide synthase inhibitor Nomega nitro-l-arginine methyl ester hydrochloride (100 MUM), guanylate cyclase inhibitor methylene blue (5 MUM), calcium-activated potassium channel blocker tetraethylammonium chloride (10 mM), and cyclooxygenase inhibitor indomethacin (5 MUM) were added 30 minutes before assessing the direct vasorelaxant effect of 6 gingerol. Moreover, in vitro effects of 6-gingerol on NO release and the effect of 6-gingerol on AGE production were examined. Results showed that incubation of aortae with 6-gingerol (0.3-10 MUM) alleviated the exaggerated vasoconstriction of diabetic aortae to phenylephrine in a concentration-dependent manner with no significant effect on the impaired relaxatory response to acetylcholine. Similar results were seen in the aortae exposed to methylglyoxal. In addition, 6-gingerol induced a direct vasodilation effect that was significantly inhibited by Nomega nitro-l-arginine methyl ester hydrochloride and methylene blue. Furthermore, 6 gingerol stimulated aortic NO generation but had no effect on AGE formation. In conclusion, 6-gingerol ameliorates enhanced vascular contraction in diabetic aortae, which may be partially attributed to its ability to increase the production of NO and stimulation of cyclic guanosine monophosphate. PMID- 26609225 TI - Caregiver burden, productivity loss, and indirect costs associated with caring for patients with poststroke spasticity. AB - OBJECTIVE: Many stroke survivors experience poststroke spasticity and the related inability to perform basic activities, which necessitates patient management and treatment, and exerts a considerable burden on the informal caregiver. The current study aims to estimate burden, productivity loss, and indirect costs for caregivers of stroke survivors with spasticity. METHODS: Internet survey data were collected from 153 caregivers of stroke survivors with spasticity including caregiving time and difficulty (Oberst Caregiver Burden Scale), Work Productivity and Activity Impairment measures, and caregiver and patient characteristics. Fractional logit models examined predictors of work-related restriction, and work losses were monetized (2012 median US wages). RESULTS: Mean Oberst Caregiver Burden Scale time and difficulty scores were 46.1 and 32.4, respectively. Employed caregivers (n=71) had overall work restriction (32%), absenteeism (9%), and presenteeism (27%). Caregiver characteristics, lack of nursing home coverage, and stroke survivors' disability predicted all work restriction outcomes. The mean total lost-productivity cost per employed caregiver was US$835 per month (>$10,000 per year; 72% attributable to presenteeism). CONCLUSION: These findings demonstrate the substantial burden of caring for stroke survivors with spasticity illustrating the societal and economic impact of stroke that extends beyond the stroke survivor. PMID- 26609226 TI - Oral treatment with the herbal formula B401 protects against aging-dependent neurodegeneration by attenuating oxidative stress and apoptosis in the brain of R6/2 mice. AB - BACKGROUND: Neurodegeneration is characterized by progressive neurological deficits due to selective neuronal loss in the nervous system. Huntington's disease (HD) is an incurable neurodegenerative disorder. Neurodegeneration in HD patients shows aging-dependent pattern. Our previous study has suggested that a herbal formula B401 may have neuroprotective effects in the brains of R6/2 mice. OBJECTIVE: To clarify possible mechanisms for neurodegeneration, which improves the understanding the aging process. This study focuses on clarifying neurodegenerative mechanisms and searching potential therapeutic targets in HD patients. METHODS: The oxidative stress and apoptosis were compared in the brain tissue between R6/2 HD mice with and without oral B401 treatment. Expressions of proteins for oxidative stress and apoptosis in the brain tissue of R6/2 HD mice were examined by using immunostaining and Western blotting techniques. RESULTS: R6/2 HD mice with oral B401 treatment significantly reduced reactive oxygen species levels in the blood, but markedly increased expressions of superoxide dismutase 2 in the brain tissue. Furthermore, R6/2 HD mice with oral B401 treatment significantly increased expressions of B-cell lymphoma 2 (Bcl-2), but significantly reduced expressions of Bcl-2-associated X protein (Bax), calpain, and caspase-3 in the brain tissue. CONCLUSION: Our findings provide evidence that the herbal formula B401 can remedy for aging-dependent neurodegeneration of R6/2 mice via suppressing oxidative stress and apoptosis in the brain. We suggest that the herbal formula B401 can be developed as a potential health supplement for ameliorating aging-dependent neurodegeneration. PMID- 26609224 TI - Advanced Applications of RNA Sequencing and Challenges. AB - Next-generation sequencing technologies have revolutionarily advanced sequence based research with the advantages of high-throughput, high-sensitivity, and high speed. RNA-seq is now being used widely for uncovering multiple facets of transcriptome to facilitate the biological applications. However, the large-scale data analyses associated with RNA-seq harbors challenges. In this study, we present a detailed overview of the applications of this technology and the challenges that need to be addressed, including data preprocessing, differential gene expression analysis, alternative splicing analysis, variants detection and allele-specific expression, pathway analysis, co-expression network analysis, and applications combining various experimental procedures beyond the achievements that have been made. Specifically, we discuss essential principles of computational methods that are required to meet the key challenges of the RNA-seq data analyses, development of various bioinformatics tools, challenges associated with the RNA-seq applications, and examples that represent the advances made so far in the characterization of the transcriptome. PMID- 26609227 TI - Increased serum TRAIL and DR5 levels correlated with lung function and inflammation in stable COPD patients. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with abnormal systemic inflammation, and apoptosis is one of the pathogenic mechanisms of COPD. Several studies have suggested that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors were not only involved in diseases associated with apoptosis but also in inflammatory diseases. However, limited data about the possible relationship between COPD and TRAIL/TRAIL receptors are available. OBJECTIVE: To evaluate the potential relationship between TRAIL/TRAIL-receptors and COPD. METHODS: Serum levels of TRAIL, decoy receptor 5 (DR5), C-reactive protein, and tumor necrosis factor-alpha were analyzed using multiplex enzyme-linked immunosorbent assay kits. Then, serum levels of TRAIL and DR5 in 57 COPD patients with 35 healthy controls were compared and correlated with lung function and systemic inflammation. RESULTS: Mean levels of serum TRAIL and DR5 were significantly higher in COPD patients than those in controls (50.17+/-17.70 versus 42.09+/-15.49 pg/mL, P=0.029; 48.15+/-22.88 versus 38.94+/-10.95 pg/mL, P=0.032, respectively). Serum levels of TRAIL and DR5 correlated inversely with forced expiratory volume in 1 second % predicted, an index of lung function in COPD (r=-0.354, P=0.007 for TRAIL; r= 0.394, P=0.002 for DR5) in all participants (r=-0.291, P=0.005 for TRAIL; r= 0.315, P=0.002 for DR5), while DR5 correlated positively with C-reactive protein (r=0.240, P=0.021 for total subjects) and TRAIL correlated positively with tumor necrosis factor-alpha (r=0.371, P=0.005 for COPD; r=0.349, P=0.001 for total subjects). CONCLUSION: Our results suggested that circulating TRAIL and DR5 increased in COPD patients and were associated with lung function and systemic inflammation in COPD. Future studies are needed to verify whether and how TRAIL and its receptors play roles in COPD. PMID- 26609228 TI - Development of an integral assessment approach of health status in patients with obstructive airway diseases: the CORONA study. AB - BACKGROUND: Traditional assessment of patients with obstructive lung diseases (asthma and chronic obstructive pulmonary disease; COPD) relies on physiological tests. The COPD and Asthma Rotterdam Integrated Care Approach (CORONA) study aims to develop a diagnostic pathway with a more comprehensive approach to the assessment of patients with asthma and COPD in secondary care. METHODS: An eight step method was used to develop and implement the pathway for patients with asthma or COPD referred to an outpatient hospital setting. RESULTS: The diagnostic pathway consists of an evidence-based set of measurements prioritized by a Delphi procedure. The pathway incorporates three innovative diagnostics: the metronome-paced hyperventilation test to measure dynamic hyperinflation, an activity monitor to objectively evaluate physical activity in daily life, and the Nijmegen Clinical Screening Instrument as a comprehensive assessment tool to acquire detailed insight into symptoms, functional limitations, and quality of life. CONCLUSION: An innovative diagnostic pathway was developed and implemented for patients with obstructive lung diseases referred to secondary care. As this pathway aims to provide a comprehensive analysis of health status, it focuses on biomedical aspects and also reviews behavioral aspects that further elucidate the patient's health status. The added value of the diagnostic pathway needs to be determined from both an organizational perspective and from the individual patient's viewpoint. PMID- 26609229 TI - Predicting frequent COPD exacerbations using primary care data. AB - PURPOSE: Acute COPD exacerbations account for much of the rising disability and costs associated with COPD, but data on predictive risk factors are limited. The goal of the current study was to develop a robust, clinically based model to predict frequent exacerbation risk. PATIENTS AND METHODS: Patients identified from the Optimum Patient Care Research Database (OPCRD) with a diagnostic code for COPD and a forced expiratory volume in 1 second/forced vital capacity ratio <0.7 were included in this historical follow-up study if they were >=40 years old and had data encompassing the year before (predictor year) and year after (outcome year) study index date. The data set contained potential risk factors including demographic, clinical, and comorbid variables. Following univariable analysis, predictors of two or more exacerbations were fed into a stepwise multivariable logistic regression. Sensitivity analyses were conducted for subpopulations of patients without any asthma diagnosis ever and those with questionnaire data on symptoms and smoking pack-years. The full predictive model was validated against 1 year of prospective OPCRD data. RESULTS: The full data set contained 16,565 patients (53% male, median age 70 years), including 9,393 patients without any recorded asthma and 3,713 patients with questionnaire data. The full model retained eleven variables that significantly predicted two or more exacerbations, of which the number of exacerbations in the preceding year had the strongest association; others included height, age, forced expiratory volume in 1 second, and several comorbid conditions. Significant predictors not previously identified included eosinophilia and COPD Assessment Test score. The predictive ability of the full model (C statistic 0.751) changed little when applied to the validation data set (n=2,713; C statistic 0.735). Results of the sensitivity analyses supported the main findings. CONCLUSION: Patients at risk of exacerbation can be identified from routinely available, computerized primary care data. Further study is needed to validate the model in other patient populations. PMID- 26609230 TI - Ganglioside-magnetosome complex formation enhances uptake of gangliosides by cells. AB - Bacterial magnetosomes, because of their nano-scale size, have a large surface-to volume ratio and are able to carry large quantities of bioactive substances such as enzymes, antibodies, and genes. Gangliosides, a family of sialic acid containing glycosphingolipids, function as distinctive cell surface markers and as specific determinants in cellular recognition and cell-to-cell communication. Exogenously added gangliosides are often used to study biological functions, transport mechanisms, and metabolism of their endogenous counterparts. Absorption of gangliosides into cells is typically limited by their tendency to aggregate into micelles in aqueous media. We describe here a simple strategy to remove proteins from the magnetosome membrane by sodium dodecyl sulfate treatment, and efficiently immobilize a ganglioside (GM1 or GM3) on the magnetosome by mild ultrasonic treatment. The maximum of 11.7+/-1.2 ug GM1 and 11.6+/-1.5 MUg GM3 was loaded onto 1 mg magnetosome, respectively. Complexes of ganglioside-magnetosomes stored at 4 degrees C for certain days presented the consistent stability. The use of GM1-magnetosome complex resulted in the greatest enhancement of ganglioside incorporation by cells. GM3-magnetosome complex significantly inhibited EGF-induced phosphorylation of the epidermal growth factor receptor. Both of these effects were further enhanced by the presence of a magnetic field. PMID- 26609231 TI - Nanoshell-mediated photothermal therapy can enhance chemotherapy in inflammatory breast cancer cells. AB - Nanoshell-mediated photothermal therapy (PTT) is currently being investigated as a standalone therapy for the treatment of cancer. The cellular effects of PTT include loss of membrane integrity, so we hypothesized that nanoshell-mediated PTT could potentiate the cytotoxicity of chemotherapy by improving drug accumulation in cancer cells. In this work, we validated our hypothesis using doxorubicin as a model drug and SUM149 inflammatory breast cancer cells as a model cancer subtype. In initial studies, SUM149 cells were exposed to nano shells and near-infrared light and then stained with ethidium homodimer-1, which is excluded from cells with an intact plasma membrane. The results confirmed that nanoshell-mediated PTT could increase membrane permeability in SUM149 cells. In complementary experiments, SUM149 cells treated with nanoshells, near-infrared light, or a combination of the two to yield low-dose PTT were exposed to fluorescent rhodamine 123. Analyzing rhodamine 123 fluorescence in cells via flow cytometry confirmed that increased membrane permeability caused by PTT could enhance drug accumulation in cells. This was validated using fluorescence microscopy to assess intracellular distribution of doxorubicin. In succeeding experiments, SUM149 cells were exposed to subtherapeutic levels of doxorubicin, low-dose PTT, or a combination of the two treatments to determine whether the additional drug uptake induced by PTT is sufficient to enhance cell death. Analysis revealed minimal loss of viability relative to controls in cells exposed to subtherapeutic levels of doxorubicin, 15% loss of viability in cells exposed to low-dose PTT, and 35% loss of viability in cells exposed to combination therapy. These data indicate that nanoshell-mediated PTT is a viable strategy to potentiate the effects of chemotherapy and warrant further investigation of this approach using other drugs and cancer subtypes. PMID- 26609232 TI - Engineering iodine-doped carbon dots as dual-modal probes for fluorescence and X ray CT imaging. AB - X-ray computed tomography (CT) is the most commonly used imaging technique for noninvasive diagnosis of disease. In order to improve tissue specificity and prevent adverse effects, we report the design and synthesis of iodine-doped carbon dots (I-doped CDs) as efficient CT contrast agents and fluorescence probe by a facile bottom-up hydrothermal carbonization process. The as-prepared I-doped CDs are monodispersed spherical nanoparticles (a diameter of ~2.7 nm) with favorable dispersibility and colloidal stability in water. The aqueous solution of I-doped CDs showed wavelength-dependent excitation and stable photoluminescence similar to traditional carbon quantum dots. Importantly, I doped CDs displayed superior X-ray attenuation properties in vitro and excellent biocompatibility. After intravenous injection, I-doped CDs were distributed throughout the body and excreted by renal clearance. These findings validated that I-doped CDs with high X-ray attenuation potency and favorable photoluminescence show great promise for biomedical research and disease diagnosis. PMID- 26609234 TI - Association of epicardial adipose tissue thickness and inflammation parameters with CHA2DS2-VASASc score in patients with nonvalvular atrial fibrillation. AB - BACKGROUND: Epicardial adipose tissue (EAT), mean platelet volume (MPV), platelet to- lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) have been shown to be helpful in predicting adverse cardiovascular events. However, to date, in the literature, there have been no studies demonstrating the relationship between EAT, MPV, PLR, NLR, and thromboembolism risk in atrial fibrillation (AF). Therefore, we examined the relationship between EAT, MPV, PLR, NLR, and CHA2DS2-VASc score used for the evaluation of thromboembolism risk in patients with AF. METHODS: The study included 96 consecutive patients with AF and 52 age- and sex-matched control subjects. We calculated CHA2DS2-VASc risk score for each patient and measured baseline EAT thickness, MPV, PLR, NLR, left atrial volume index, and left ventricular ejection fraction. RESULTS: The group with high CHA2DS2-VASc score had higher EAT (7.2+/-1.5 vs 5.9+/-1.2 mm, P<0.001), MPV (9.1+/-1.1 vs 8.4+/-1.0 fL, P=0.004), PLR (152.3+/-28.4 vs 126.7+/-25.4, P=0.001), and NLR (4.0+/-1.6 vs 3.2+/-1.3, P<0.001) compared to group with low intermediate CHA2DS2-VASc score. Moreover, CHA2DS2-VASc score was found to be positively correlated with EAT (r=0.623, P<0.001), MPV (r=0.350, P=0.004), PLR (r=0.398, P=0.001), and NLR (r=0.518, P<0.001). CONCLUSION: Our study results demonstrated that EAT thickness, MPV, PLR, and NLR were associated with the thromboembolic risk exhibited by CHA2DS2-VASc score in patients with nonvalvular AF. PMID- 26609235 TI - Hemogram parameters for predicting pulmonary embolism in patients with deep venous thrombosis. PMID- 26609233 TI - Bortezomib in mantle cell lymphoma: comparative therapeutic outcomes. AB - Mantle cell lymphoma (MCL) is an incurable, typically aggressive subtype of non Hodgkin lymphoma, accounting for 4%-7% of newly diagnosed non-Hodgkin lymphoma cases. Chemoresistance commonly ensues in MCL, and patients with this heterogeneous disease invariably relapse, underscoring the unmet need for better therapies. Over the past few years, several novel agents with promising activity and unique mechanisms of action have been deemed effective in MCL. Bortezomib is a reversible proteasome inhibitor, approved as a single agent for patients with relapsed/refractory MCL who have received at least one prior line of therapy. Addition of bortezomib to chemoimmunotherapies has demonstrated good tolerability and superior efficacy, both in the upfront and salvage settings, and recently one such combination of bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone was approved as a frontline regimen in untreated patients with MCL. This review examines the role of bortezomib in a multitude of clinical settings and ongoing clinical trials designed to optimize its integration in the current treatment paradigms of MCL. PMID- 26609236 TI - Experienced Harm from Other People's Drinking: A Comparison of Northern European Countries. AB - OBJECTIVE: This study addresses how experienced harm from other people's drinking varies between six Northern European countries by comparing 1) the prevalence of experienced harm and 2) the correlates of harm. METHOD: The data comprise 18-69 year olds who participated in general population surveys in Denmark, Finland, Iceland, Norway, Sweden, and Scotland during the period 2008-2013. Comparative data were available on five types of harm: physical abuse, damage of clothes/belongings, verbal abuse, being afraid, and being kept awake at night. RESULTS: This study shows that harms from other's drinking are commonly experienced in all six countries. Being kept awake at night is the most common harm, while being physically harmed is the least common. The proportions that reported at least one of the five problems were highest in Finland and Iceland and lowest in Norway, but also relatively low in Sweden. Across countries, the level of harm was highest among young, single, urban residents, and for some countries among women and those who frequently drank to intoxication themselves. CONCLUSIONS: The study revealed large differences in the prevalence of harm in countries with fairly similar drinking cultures. However, the correlates of such experiences were similar across countries. Possible explanations of the findings are discussed, including differences in study design. PMID- 26609238 TI - Exposure Path Perceptions and Protective Actions in Biological Water Contamination Emergencies. AB - This study extends the Protective Action Decision Model, developed to address disaster warning responses in the context of natural hazards, to "boil water" advisories. The study examined 110 Boston residents' and 203 Texas students' expectations of getting sick through different exposure paths for contact with contaminated water. In addition, the study assessed respondents' actual implementation (for residents) or behavioral expectations (for students) of three different protective actions - bottled water, boiled water, and personally chlorinated water - as well as their demographic characteristics and previous experience with water contamination. The results indicate that people distinguish among the exposure paths, but the differences are small (one-third to one-half of the response scale). Nonetheless, the perceived risk from the exposure paths helps to explain why people are expected to consume (or actually consumed) bottled water rather than boiled or personally chlorinated water. Overall, these results indicate that local authorities should take care to communicate the relative risks of different exposure paths and should expect that people will respond to a boil water order primarily by consuming bottled water. Thus, they should make special efforts to increase supplies of bottled water in their communities during water contamination emergencies. PMID- 26609237 TI - Cancer Stem and Progenitor-Like Cells as Pharmacological Targets in Breast Cancer Treatment. AB - The present review is focused on the current role of neoplastic stem and progenitor-like cells as primary targets in the pharmacotherapy of cancer as well as in the development of new anticancer drugs. We begin by summarizing the main characteristics of these tumor-initiating cells and key concepts that support their participation in therapeutic failure. In particular, we discuss the differences between the major carcinogenesis models (ie, clonal evolution vs cancer stem cell (CSC) model) with emphasis on breast cancer (given its importance to the study of CSCs) and their implications for the development of new treatment strategies. In addition, we describe the main ways to target these cells, including the main signaling pathways that are more activated or altered in CSCs. Finally, we provide a comprehensive compilation of the most recently tested drugs. PMID- 26609239 TI - Implication of lncRNAs in pathogenesis of esophageal cancer. AB - Long non-coding RNAs (lncRNAs), transcripts as longer than 200 nt in length with a great number of varieties in human genomics, play important roles in the regulation of genetics and epigenetics including gene transcription and post transcription. Increasing evidence have demonstrated the upregulation of lncRNAs in tumorigenesis and metastasis of esophageal cancer (EC), a type of malignant tumors particularly in Asia. In this review, we briefly discuss the profiles and functions of lncRNAs involved in the progression of EC, which may provide a new approach to improve EC diagnosis and treatment. PMID- 26609240 TI - The association between XRCC1 Arg399Gln polymorphism and risk of leukemia in different populations: a meta-analysis of case-control studies. AB - BACKGROUND: Associations between Arg399Gln single-nucleotide polymorphism (SNP) in the XRCC1 gene and leukemia susceptibility have been studied extensively, however, the results are inconsistent. The aim of this study was to determine these associations using meta-analytical methods. METHODS: A meta-analysis was performed to examine the associations between XRCC1 Arg399-Gln SNP and leukemia risk. A literature search of PubMed and Web of Science databases was conducted to identify relevant studies published up to March 10, 2015. The references of the retrieved articles were also screened. All the statistical analyses were conducted using Review Manager software. RESULTS: The XRCC1 Arg399Gln SNP was found to be associated with increased childhood risk of acute lymphoblastic leukemia among Asians under the dominant (odds ratio [OR] 2.11, 95% confidence interval [CI] 1.50-2.97, P<0.0001), allele contrast (OR 1.72, 95% CI 1.33-2.23, P<0.0001), and homozygote contrast (OR 2.34, 95% CI 1.25-4.36, P=0.008) models. However, no association was found in Caucasians between the SNP and risk of either chronic myeloid leukemia or chronic lymphocytic leukemia under any contrast model. CONCLUSION: The findings of the current meta-analysis indicate that the XRCC1 Arg399Gln SNP is a risk factor for childhood lymphoblastic leukemia in Asians. PMID- 26609241 TI - Detection of epidermal growth factor receptor mutation in plasma as a biomarker in Chinese patients with early-stage non-small cell lung cancer. AB - PURPOSE: This preplanned exploratory analysis was conducted to reveal the true status of correlation between tissue and plasma detection for early-stage non small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) mutations, knowing that specific subgroups of NSCLC patients may be potential candidates for EGFR mutation analysis by using plasma samples. MATERIALS AND METHODS: Tissue samples were surgically resected from 198 patients with stage I-IV NSCLC, where stage IA to IIIA accounted for 92.4%. EGFR mutations in all these tissues were positive. Paired plasma EGFR mutations were detected by real-time polymerase chain reaction; concentration of cell-free DNA (cfDNA) in plasma was measured by ultraviolet spectrophotometry. RESULTS: EGFR-activating mutation was detected in 34 plasma samples, and their mutation types were matched with that in tissue. The sensitivity of EGFR mutation for the 198 paired tissue and plasma samples was 17.2%. The sensitivity positively correlated with disease stage and negatively correlated with tumor differentiation. The sensitivity of stage IA, IB, IIA, IIB, and IIIA was 1.6%, 7.9%, 11.1%, 20%, and 33.3%, respectively; the sensitivity of high differentiation was 0% versus 36.8% for poor differentiation. There was no correlation between plasma cfDNA concentration and patient characteristics. CONCLUSION: We recommend using plasma cfDNA as a biomarker in stage IIIA or poorly differentiated tumors for gene diagnosis, especially in patients whose tissue samples cannot be obtained by surgery. Plasma samples can really reflect the patients' EGFR mutation types and may contain comprehensive genotypic information that comes from different parts of the tumor than tissue specimens. The concentration of plasma cfDNA does not vary with patient characteristics. PMID- 26609242 TI - SGLT2 inhibitors - an insulin-independent therapeutic approach for treatment of type 2 diabetes: focus on canagliflozin. AB - Despite the availability of a great variety of medications, a significant proportion of people with type 2 diabetes mellitus (T2DM) are not able to achieve or maintain adequate glycemic control. Beyond improved glucose control, novel treatments would ideally provide a reduction of cardiovascular risk, with a favorable impact on excess weight, and a low intrinsic hypoglycemia risk, as well as a synergistic mechanism of action for broad combination therapy. With the development of sodium glucose cotransporter 2 (SGLT2) inhibitors, an antidiabetic pharmacologic option has recently become available that comes close to meeting these requirements. For the first time, SGLT2 inhibitors offer a therapeutic approach acting directly on the kidneys without requiring insulin secretion or action. Canagliflozin, dapagliflozin, and empagliflozin are the SGLT2 inhibitors approved to date. Taken once a day, these medications can be combined with all other antidiabetic medications including insulin, due to their insulin independent mechanism of action, with only a minimal risk of hypoglycemia. SGLT2 inhibitors provide additional reductions in body weight and blood pressure due to the therapeutically induced excretion of glucose and sodium through the kidneys. These "concomitant effects" are particularly interesting with regard to the increased cardiovascular risk in T2DM. In many cases, T2DM treatment requires a multidimensional approach where the treatment goals have to be adapted to the individual patient. While there is a consensus on the use of metformin as a first line drug therapy, various antidiabetics are used for treatment intensification. New mechanisms of action like that of SGLT2 inhibitors such as canagliflozin, which can be used both in early and late stages of diabetes, are a welcome addition to expand the treatment options for patients at every stage of T2DM. The efficacy and tolerability of canagliflozin have been tested in an extensive clinical trial program described in this review article. PMID- 26609243 TI - Large-scale survey to describe acne management in Brazilian clinical practice. AB - BACKGROUND: Acne is a chronic disease of the pilosebaceous unit that mainly affects adolescents. It is the most common dermatological problem, affecting approximately 80% of teenagers between 12 and 18 years of age. Diagnosis is clinical and is based on the patient's age at the time the lesions first appear, and on its polymorphism, type of lesions, and their anatomical location. The right treatment for the right patient is key to treating acne safely. The aim of this investigational survey was to evaluate how Brazilian dermatologists in private practice currently manage acne. MATERIALS AND METHODS: Dermatologists practicing in 12 states of Brazil were asked how they manage patients with grades I, II, III, and IV acne. Each dermatologist completed a written questionnaire about patient characteristics, acne severity, and the therapy they usually prescribe for each situation. RESULTS: In total, 596 dermatologists were interviewed. Adolescents presented as the most common acneic population received by dermatologists, and the most common acne grade was grade II. The doctors could choose more than one type of treatment for each patient, and treatment choices varied according to acne severity. A great majority of dermatologists considered treatment with drugs as the first alternative for all acne grades, choosing either topical or oral presentation depending on the pathology severity. Dermocosmetics were chosen mostly as adjunctive therapy, and their inclusion in the treatment regimen decreased as acne grades increased. CONCLUSION: This survey illustrates that Brazilian dermatologists employ complex treatment regimens to manage acne, choosing systemic drugs, particularly isotretinoin, even in some cases of grade I acne, and heavily prescribe antibiotics. Because complex regimens are harder for patients to comply with, this result notably raises the question of adherence, which is a key factor in successful treatment. PMID- 26609244 TI - Management of knee osteoarthritis by combined stromal vascular fraction cell therapy, platelet-rich plasma, and musculoskeletal exercises: a case series. AB - INTRODUCTION: Knee osteoarthritis is associated with persistent joint pain, stiffness, joint deformities, ligament damage, and surrounding muscle atrophy. The complexity of the disease makes treatment difficult. There are no therapeutic drugs available to halt the disease progression, leaving patients dependent on pain medication, anti-inflammatory drugs, or invasive joint replacement surgery. CASE PRESENTATIONS: Four patients with a history of unresolved symptomatic knee osteoarthritis were investigated for the therapeutic outcome of combining an exercise rehabilitation program with intra-articular injections of autologous StroMed (ie, stromal vascular fraction cells concentrated by ultrasonic cavitation from lipoaspirate) and platelet-rich plasma (PRP). The Knee Injury and Osteoarthritis Outcome Score questionnaire (KOOS) was administered along with physical function tests over a 12-month period. The first patient achieved a maximum therapeutic outcome of 100 in all five KOOS subscales (left knee), and 100 for four subscales (right knee). The second patient scored 100 in all five KOOS subscales (left knee), and greater than 84 in all subscales (right knee). Treatment of the third patient resulted in improved outcomes in both knees of >93 for four KOOS subscales, and 60 for the Function in Sport and Recreation subscale. The fourth patient improved to 100 in all five KOOS subscales. In all patients, the physical function "Get-up and Go" test and "Stair Climbing Test" returned to normal (a value of zero). CONCLUSION: This case series indicates that improved outcomes may be obtained when autologous stromal vascular fraction (StroMed) cell therapy is combined with traditional exercise practices and PRP for osteoarthritis. Of the seven joints treated: all patients' scores of pain improved to >96; and quality of life scores to >93. Functional performance measures of mobility returned to normal. This simple treatment appears to be extremely effective for osteoarthritis disorders that have no drug treatment to halt disease progression. PMID- 26609246 TI - Block them when it hurts. PMID- 26609245 TI - Regional anesthesia for pediatric knee surgery: a review of the indications, procedures, outcomes, safety, and challenges. AB - The indications for surgery on the knee in children and adolescents share some similarity to adult practice in that there are an increasing number of sports related injuries requiring surgical repair. In addition, there are some unique age-related conditions or congenital abnormalities that may present as indications for orthopedic intervention at the level of the knee. The efficacy and safety of peripheral nerve blocks (PNBs) for postoperative analgesia following orthopedic surgery has been well established in adults. Recent studies have also demonstrated earlier functional recovery after surgery in patients who received PNBs. In children, PNB is gaining popularity, and increasing data are emerging to demonstrate the feasibility, efficacy, and safety in this population. In this paper, we will review some of the most common indications for surgery involving the knee in children and the anatomy of knee, associated dermatomal and osteotomal innervation, and the PNBs most commonly used to produce analgesia at the level of the knee. We will review the evidence in support of regional anesthesia in children in terms of both the quality conferred to the immediate postoperative care and the role of continuous PNBs in maintaining effective analgesia following discharge. Also we will discuss some of the subtle challenges in utilizing regional anesthesia in the pediatric patient including the use of general anesthesia when performing regional anesthesia and the issue of monitoring for compartment syndrome. Finally, we will offer some thoughts about areas of practice that are in need of further investigation. PMID- 26609247 TI - Spinal Tuberculosis. AB - Spinal tuberculosis (TB) is a significant form of TB, causing spinal deformity and paralysis. Early diagnosis and treatment are crucial for avoiding multivertebral destruction and are critical for improving outcomes in spinal TB. We believe that appropriate treatment method should be implemented at the early stage of this disease and that the Gulhane Askeri Tip Akademisi classification system can be considered a practical guide for spinal TB treatment planning in all countries. PMID- 26609248 TI - Improving outcomes in patients with melanoma: strategies to ensure an early diagnosis. AB - Patients with thin, low-risk melanomas have an excellent long-term prognosis and higher quality of life than those who are diagnosed at later stages. From an economic standpoint, treatment of early stage melanoma consumes a fraction of the health care resources needed to treat advanced disease. Consequently, early diagnosis of melanoma is in the best interest of patients, payers, and health care systems. This review describes strategies to ensure that patients receive an early diagnosis through interventions ranging from better utilization of primary care clinics, to in vivo diagnostic technologies, to new "apps" available in the market. Strategies for screening those at high risk due to age, male sex, skin type, nevi, genetic mutations, or family history are discussed. Despite progress in identifying those at high risk for melanoma, there remains a lack of general consensus worldwide for best screening practices. Strategies to ensure early diagnosis of recurrent disease in those with a prior melanoma diagnosis are also reviewed. Variations in recurrence surveillance practices by type of provider and country are featured, with evidence demonstrating that various imaging studies, including ultrasound, computed tomography, positron emission tomography, and magnetic resonance imaging, provide only minimal gains in life expectancy, even for those with more advanced (stage III) disease. Because the majority of melanomas are attributable to ultraviolet radiation in the form of sunlight, primary prevention strategies, including sunscreen use and behavioral interventions, are reviewed. Recent international government regulation of tanning beds is described, as well as issues surrounding the continued use artificial ultraviolet sources among youth. Health care stakeholder strategies to minimize UV exposure are summarized. The recommendations encompass both specific behaviors and broad intervention targets (eg, individuals, social spheres, organizations, celebrities, governments). PMID- 26609249 TI - Therapeutic Challenges to End-Stage Kidney Disease in a Patient with Tetralogy of Fallot. AB - In this report, we describe the case of an end-stage kidney disease patient with tetralogy of Fallot (TOF). A 33-year-old female with TOF was admitted to our hospital with complaints of general fatigue and appetite loss probably due to uremic milieu. She was ultimately treated with peritoneal dialysis (PD) with a favorable clinical course. TOF patients with chronic kidney disease are not exceptional, although the currently available information regarding the association between TOF and renal failure severe enough to require dialysis treatment is limited. We also discuss the complex processes of how and why PD was selected as a mode of chronic renal replacement therapy in this case. PMID- 26609250 TI - Management of Pneumocystis jirovecii Pneumonia in Kidney Transplantation to Prevent Further Outbreak. AB - The outbreak of Pneumocystis jirovecii pneumonia (PJP) among kidney transplant recipients is emerging worldwide. It is important to control nosocomial PJP infection. A delay in diagnosis and treatment increases the number of reservoir patients and the number of cases of respiratory failure and death. Owing to the large number of kidney transplant recipients compared to other types of organ transplantation, there are greater opportunities for them to share the same time and space. Although the use of trimethoprim-sulfamethoxazole (TMP-SMX) as first choice in PJP prophylaxis is valuable for PJP that develops from infections by trophic forms, it cannot prevent or clear colonization, in which cysts are dominant. Colonization of P. jirovecii is cleared by macrophages. While recent immunosuppressive therapies have decreased the rate of rejection, over-suppressed macrophages caused by the higher levels of immunosuppression may decrease the eradication rate of colonization. Once a PJP cluster enters these populations, which are gathered in one place and uniformly undergoing immunosuppressive therapy for kidney transplantation, an outbreak can occur easily. Quick actions for PJP patients, other recipients, and medical staff of transplant centers are required. In future, lifelong prophylaxis may be required even in kidney transplant recipients. PMID- 26609251 TI - The IMSI Procedure Improves Laboratory and Clinical Outcomes Without Compromising the Aneuploidy Rate When Compared to the Classical ICSI Procedure. AB - PURPOSE: The intracytoplasmic morphologically selected sperm injection (IMSI) procedure has been associated with better laboratory and clinical outcomes in assisted reproduction technologies. Less information is available regarding the relationship between embryo aneuploidy rate and the IMSI procedure. The aim of this study is to compare the clinical outcomes and chromosomal status of IMSI derived embryos with those obtained from intracytoplasmic sperm injection (ICSI) in order to establish a clearer view of the benefits of IMSI in infertile patients. METHODS: We retrospectively analyzed a total of 11 cycles of IMSI and 20 cycles of ICSI with preimplantation genetic diagnosis. The fertilization rate, cleavage rate, embryo quality, blastocyst development, aneuploidy rate, pregnancy rate, implantation rate, and miscarriage rate were compared between the groups. RESULTS: Similar rates of fertilization (70% and 73%), cleavage (98% and 100%), and aneuploidy (76.9% and 70.9%) were observed in the IMSI and ICSI groups, respectively. The IMSI group had significantly more good quality embryos at day 3 (95% vs 73%), higher blastocyst development rates (33% vs 19%), and greater number of hatching blastocysts (43% vs 28%), cycles with at least one blastocyst at day 5 (55% vs 35%), and blastocysts with good trophoectoderm morphology (21% vs 6%) compared with the ICSI group (P < 0.001). Significantly higher implantation rates were observed in the IMSI group compared with the ICSI group (57% vs 27%; P < 0.05). Pregnancy and miscarriage rates were similar in both groups (80% vs 50% and 0% vs 33%, respectively). CONCLUSION: The IMSI procedure significantly improves the embryo quality/development by increasing the implantation rates without affecting the chromosomal status of embryos. There is a tendency for the IMSI procedure to enhance the pregnancy rates and lower the miscarriage rates when compared with ICSI. PMID- 26609253 TI - Anxiety and IBS revisited: ten years later. AB - BACKGROUND AND AIM: Irritable bowel syndrome (IBS) has been associated with high prevalence of psychological and psychiatric disorders. However, the association between IBS and each of its subtypes (diarrhea IBS-D, constipation IBS-C, mixed IBS-M) with anxiety still remains unclear. The purpose of this study was to perform a comparative analysis of the association between anxiety and IBS on a period of ten years. METHODS: PubMed was searched for studies analyzing IBS and anxiety, published at 10 years interval. The study presents a comparative analysis of the articles that were published between 2003-2005 and 2013-2015, investigating the correlation between anxiety and IBS. RESULTS: The initial search identified 220 articles, from which 156 were published between 2013 and 2015, and 64 were published between 2003 and 2005. Of these articles, 15 articles were included in the review. Out of these 15 articles, 10 articles analyzed the correlation between anxiety-depression status in IBS patients using specific questionnaires, 2 articles analyzed genetic variables in IBS, 1 article analyzed serotonin and monoamine oxidase levels in IBS, 1 article analyzed serum levels of IL-1beta and IL-10 in IBS, 1 article analyzed somatostatin and vasoactive intestinal peptide levels in IBS. The result was a review of 15 studies that analyzed the association between IBS and anxiety. CONCLUSIONS: IBS is a heterogeneous disorder caused by numerous psychological, immunological, infectious, endocrine and genetic factors. In recent years, the number of studies concentrating on genetic factors, cytokines and hormones has increased in comparison with the 2003-2005 period, when clinical investigation, using mainly questionnaires was the essential method. Also, the total number of papers investigating anxiety and IBS, considerably increased. The recent studies have confirmed the fact that IBS symptoms are often exacerbated during stressful events and the psychiatric treatment has a positive effect on gastro-intestinal symptomatology. PMID- 26609252 TI - VEGF involvement in psoriasis. AB - Vascular endothelial growth factor (VEGF) is a key growth factor, regulating the neovascularization, during embryogenesis, skeletal growth, reproductive functions and pathological processes. The VEGF receptors (VEGFR) are present in endothelial cells and other cell types, such as vascular smooth muscle cells, hematopoietic stem cells, monocytes, neurons, macrophages, and platelets. Angiogenesis is initiated by the activation of vascular endothelial cells through several factors. The excess dermal vascularity and VEGF production are markers of psoriasis. The pathological role of VEGF/VEGFR signaling during the psoriasis onset and evolution makes it a promising target for the treatment of psoriasis. Antibodies and other types of molecules targeting the VEGF pathway are currently evaluated in arresting the evolution of psoriasis. PMID- 26609254 TI - Serum biomarkers for irritable bowel syndrome. AB - BACKGROUND AND AIM: Irritable bowel syndrome (IBS) is one of the most frequent and common functional gastrointestinal diseases. For its diagnosis, clinical criteria are still used. Our objective was to asses if there are specific serum biomarkers for the diagnosis of IBS, and as secondary purpose we aimed to analyze the specificity and sensitivity - where determined - for the proposed biomarkers. METHODS: We performed a review in order to find potential serum biomarkers useful for the diagnosis of IBS. MEDLINE and Cochrane databases were searched in May 2015. Inclusion criteria were: original studies that assessed serological markers in IBS patients, markers potentially useful for diagnosing IBS or in differentiating subtypes of IBS. Exclusion criteria were biomarkers assessed in IBS patients not for the diagnosis of IBS, but used in order to exclude other conditions or diseases in these patients; or markers that were not addressed to IBS; or papers that assessed only fecal biomarkers, or histological or surrogate indirect biomarkers. RESULTS: From the 268 papers retrieved by our initial search, using a modified strategy we identified 58 papers. Out of the 58 papers retrieved by the search, six papers were selected and other nine studies were eventually analyzed. Of the results of the computerized search, a number of papers were not included for various reasons: some were not related to the subject (26), others were not appropriate for the subject (19) because they addressed inflammatory bowel disorders, in others fecal markers were the subject of the study, six were reviews, others were impossible to gain access to (1). Twelve out of the 14 studies included are case-control studies, IBS diagnosis being established in all of the selected results based on the Rome criteria. A higher sensitivity of 81% was found using a combination of markers but with lower specificity, while one study that assessed also a combination of markers, found a higher specificity but sensitivity was only 50 %; none reached the characteristics for an ideal biomarker. CONCLUSIONS: For the moment, just one serum biomarker with a high specificity and sensitivity useful in the diagnosis of IBS was identified. We consider that in the future a combination of several biomarkers could better identify IBS than a single biomarker. Therefore, clinical criteria are still to be used for the diagnosis of IBS in attendance for newer research or validation of results. PMID- 26609255 TI - Stem cells - biological update and cell therapy progress. AB - In recent years, the advances in stem cell research have suggested that the human body may have a higher plasticity than it was originally expected. Until now, four categories of stem cells were isolated and cultured in vivo: embryonic stem cells, fetal stem cells, adult stem cells and induced pluripotent stem cells (hiPSCs). Although multiple studies were published, several issues concerning the stem cells are still debated, such as: the molecular mechanisms of differentiation, the methods to prevent teratoma formation or the ethical and religious issues regarding especially the embryonic stem cell research. The direct differentiation of stem cells into specialized cells: cardiac myocytes, neural cells, pancreatic islets cells, may represent an option in treating incurable diseases such as: neurodegenerative diseases, type I diabetes, hematologic or cardiac diseases. Nevertheless, stem cell-based therapies, based on stem cell transplantation, remain mainly at the experimental stages and their major limitation is the development of teratoma and cancer after transplantation. The induced pluripotent stem cells (hiPSCs) represent a prime candidate for future cell therapy research because of their significant self-renewal and differentiation potential and the lack of ethical issues. This article presents an overview of the biological advances in the study of stem cells and the current progress made in the field of regenerative medicine. PMID- 26609256 TI - Iron, inflammation and invasion of cancer cells. AB - Chronic inflammation is associated with the metastasis of tumor cells evolving from a benign tumor to disseminating cancer. Such a metastatic progression is fostered by the angiogenesis propelled by various mediators interacting at the site of tumor growth. Angiogenesis causes two major changes that are assisted by altered glycosylation and neo-antigen presentation by the cancer cells. The angiogenesis-promoted pathological changes include enhanced inflammation and degradation of tissue matrices releasing tumor cells from the site of its origin. The degraded tumor cells release the neo-antigens resulting from altered glycosylation. Presentation of neo-antigens to T cells escalates metastasis and inflammation. Inflammasome activation and inflammation in several infections are regulated by iron. Based on the discrete reports, we propose a link between iron, inflammation, angiogenesis and tumor growth. Knowing the link better may help us formulate a novel strategy for cancer immunotherapy. PMID- 26609257 TI - Next generation sequencing applications for breast cancer research. AB - For some time, cancer has not been thought of as a disease, but as a multifaceted, heterogeneous complex of genotypic and phenotypic manifestations leading to tumorigenesis. Due to recent technological progress, the outcome of cancer patients can be greatly improved by introducing in clinical practice the advantages brought about by the development of next generation sequencing techniques. Biomedical suppliers have come up with various applications which medical researchers can use to characterize a patient's disease from molecular and genetic point of view in order to provide caregivers with rapid and relevant information to guide them in choosing the most appropriate course of treatment, with maximum efficiency and minimal side effects. Breast cancer, whose incidence has risen dramatically, is a good candidate for these novel diagnosis and therapeutic approaches, particularly when referring to specific sequencing panels which are designed to detect germline or somatic mutations in genes that are involved in breast cancer tumorigenesis and progression. Benchtop next generation sequencing machines are becoming a more common presence in the clinical setting, empowering physicians to better treat their patients, by offering early diagnosis alternatives, targeted remedies, and bringing medicine a step closer to achieving its ultimate goal, personalized therapy. PMID- 26609258 TI - Genetic testing in patients with global developmental delay / intellectual disabilities. A review. AB - Genetic factors are responsible for up to 40% developmental disability cases, such as global developmental delay/intellectual disability (GDD/DI). The American and more recently the European guidelines on this group of diseases state that genetic testing is essential and should become a standardized diagnostic practice. The main arguments for the necessity of implementing such a practice are: (1) the high prevalence of developmental disabilities (3% of the population); (2) the high genetic contribution to this type of pathology; (3) insufficient referral for genetic consultation. In an attempt to address these issues, the purpose of this paper is to present the genetic etiology of global developmental delay / intellectual disability with emphasis on the need to implement a genetic testing protocol for the patients with GDD/DI, as indicated by the current guidelines. Chromosomal abnormalities and fragile X syndrome are the most frequent causes of developmental disabilities and the techniques employed to detect such genetic disorders should be used as first line investigations of GDD/DI. PMID- 26609259 TI - Dynamic perfusion assessment during perforator flap surgery: an up-to-date. AB - Flap monitoring technology has progressed alongside flap design. The highly variable vascular anatomy and the complexity associated with modern perforator flaps demands dynamic, real-time, intraoperative information about the vessel location, perfusion patterns and flap physiology. Although most surgeons still assess flap perfusion and viability based solely on clinical experience, studies have shown that results may be highly variable and often misleading. Poor judgment of intraoperative perfusion leads to major complications. Employing dynamic perfusion imaging during flap reconstruction has led to a reduced complication rate, lower morbidity, shorter hospital stay, and an overall better result. With the emergence of multiple systems capable of intraoperative flap evaluation, the purpose of this article is to review the two systems that have been widely accepted and are currently used by plastic surgeons: Indocyanine green angiography (ICGA) and dynamic infrared thermography (DIRT). PMID- 26609260 TI - In vivo orthodontic retainer survival - a review. AB - BACKGROUND: Relapse following orthodontic treatment is a constant concern of orthodontists. Fixed retention is preferred especially for the lower arch by most orthodontists. OBJECTIVES: This review focuses on in vivo studies. The main objective is to determine the survival rates of different types of retainer: glass-fiber reinforced composite resin, polyethylene or multistrand stainless steel wire bonded to each tooth from canine to canine in the mandibular arch. A second objective is to assess which of these types is less likely to cause additional problems and the third objective is to evaluate the factors that may influence retainer survival. RESULTS AND CONCLUSIONS: There were 8 studies identified that matched the objectives stated. Current in vivo studies on survival rate take little notice of the role of the material used for bonding of the fixed retainer. It is not possible to draw a conclusion on reliability of new types of retainers glass fiber reinforced composite resin or polyethylene compared to multistrand stainless steel wire. The multistrand wire remains the gold standard for fixed retention. Although it is a logical outcome that retainer survival is dependent on the application technique, there seems to be no research outcome proving that operator experience, moisture control are essential, nor does patient age or sex have statistically proven effects on survival rates. Adequate studies that involve such aspects should be performed. PMID- 26609261 TI - Heart rate variability and heart rate recovery as prognostic factors. AB - BACKGROUND AND AIM: Heart rate (HR) can appear static and regular at rest, during exercise or recovery after exercise. However, HR is constantly adjusted due to factors such as breathing, blood pressure control, thermoregulation and the renin angiotensin system, leading to a more dynamic response that can be quantified using HRV (heart rate variability). HRV is defined as the deviation in time between successive normal heart beat and is a noninvasive method to measure the total variation in a number of HR interval. HRV can serve as measure of autonomic activity of sino-atrial node. The aim of the study was to determine the influence of certain clinical and paraclinical parameters on heart rate recovery after exercise in patients with ischemic heart disease and the relation with HRV using 24 h Holter monitoring. METHODS: The study included 46 patients who were submitted to cardiovascular exercise stress test and also to 24 h Holter EKG monitoring. Subjects had a mean age of 56.2+/-11.2 years, with a minimum of 25 and a maximum of 79 years. The study included 22 (47.8%) men and 24 (52.2%) women. Statistical analysis was performed using MedCalc software version 14.8.1. Multivariate analysis consisted of the construction of several multiple linear regression models. A p value of 0.05 was considered statistically significant. RESULTS: The HRV values (time domain) were all lower in the IHD compared with the group without coronary heart disease, even if the difference is not statistically significant. Also rest and maximal HR values were similar but during the test varies in the sense that those with IHD had higher values of rest and maximal HR and lower HRR, but not statistically significant. CONCLUSIONS: HRV is a very easy and safe method if there is an available device and it is used for evaluation of the autonomic nervous system in many cardiovascular diseases, but also in other pathologies. In uncomplicated ischemic heart disease HRV is depressed, but not significant. HRR, which is also considered an indicator of the parasympathetic activity after exercise termination, is also non-significantlly decreased in ischemic patients and the correlation between them is weak. Both HRV and HRR parameters can be easily measured, but the best algorithm of this issue requires further studies, conducted in larger patient populations. Although HRR and HRV are tools to measure the autonomic nervous system activity the relation between them need more studies to be able to quantify the arrhythmogenic risk. PMID- 26609262 TI - Effects of combination therapy: somatostatin analogues and dopamine agonists on GH and IGF1 levels in acromegaly. AB - BACKGROUND AND AIMS: Acromegaly is a complex endocrine disorder caused by excessive secretion of GH, secondary to a GH secreting pituitary adenoma or a mixed pituitary adenoma secreting GH and PRL. METHODS: The aim of this study was to evaluate the effects of combination therapy: dopamine agonist and somatostatin analogue on GH and IGF1 levels in a group of 30 patients with acromegaly. Cabergoline in a dose of 2 mg/week and 4 mg/week respectively was associated with Sandostatin LAR in a dose of 20 mg/month and 30 mg/months respectively. Eight patients were treated with Lanreotide 30 mg/week and Cabergoline 2 mg/week and 3 patients were treated with Bromocriptine 10 mg/day and Sandostatin LAR 30 mg/month. RESULTS: Combination therapy: Cabergoline and Sandostatin achieved normal levels of IGF1 in 32% of the patients, better results being obtained after 12 months of treatment in the group treated with 4 mg Cabergoline/week. In 37% of cases the levels of IGF1 decreased by 50% after 12 months of treatment. In the group treated with Cabergoline and Somatuline a normal level of IGF1 was achieved in 25% of patients after 12 months of treatment. The outcome for the group treated with Sandostatin and Bromocriptine was similar to that obtained under Cabergoline 2 mg/week. There was no significant correlation between the level of GH and the type or dose of dopamine agonist used. CONCLUSIONS: In conclusion, combination therapy consisting of dopamine agonist and somatostatin analogue achieves a significant reduction of IGF1 levels in patients with mixed adenomas secreting GH and PRL. A decrease in IGF1 levels is directly correlated with the dose of Cabergoline used. PMID- 26609263 TI - Causes of death among detainees: a statistical study on the casework of the Forensic Medicine Institute in Cluj-Napoca during the period 2000-2014. AB - BACKGROUND AND AIMS: The detainees' right to healthcare is granted by laws, in accordance with EU directives and recommendations to which our country has consented. Prison population is a particularly vulnerable and marginalized group characterized by mortality rates different from the general population. This study aims at providing a picture of the causes of death, quality of healthcare and measures needed to reduce the number of in-prison deaths, including legal medicine expertise in view of sentence postponement/interruption. METHODS: The present paper is based on the statistical analysis of in-prison deaths casework recorded at the Forensic Medicine Institute of Cluj-Napoca and provided by territorially subordinated counties forensic services. The data collected cover over 15 years (2000-2014), a period long enough for significant retrospective statistical analysis. RESULTS: The total number of deaths among the inmates was 113, the majority of male sex (110). Distribution by age groups shows a greater incidence among inmates aged 50 to 59 years (32 cases, 28.31%), followed by those in their 40s' (30 cases, 26.54%) and 30s' (25 cases, 22.12%). The most frequent pathological causes of death were cardiovascular (53 cases) followed by tumors (26 cases) and infectious diseases. A significant number of deaths were due to violent causes (14 cases-12,38%). CONCLUSIONS: Special problems are raised by the high number of deaths among prisoners, especially at a young age, while the high frequency of violent deaths from self- or non-self-inflicted traumatic causes requires supervision, monitoring and continuous analysis. Despite recent improvements, healthcare in prisons still poses some problems, mainly regarding diagnosis and treatment of heart diseases, neurosurgery and cancer. PMID- 26609264 TI - Assesment of the Duke criteria for the diagnosis of infective endocarditis after twenty-years. An analysis of 241 cases. AB - BACKGROUND AND AIMS: In the absence of classical features (fever, cardiac murmur, and peripheral vascular stigmata) the diagnosis of infective endocarditis (IE) may be difficult. Current clinical guidelines for the diagnosis and management of IE recommend the use of modified Duke criteria. Correct and prompt diagnosis of IE is crucial for the treatment and outcome of the patients. The aim of this study was to evaluate the presence and the individual value of each criterion of the modified Duke criteria in our patients with infective endocarditis. METHODS: We performed a prospective observational study between January 2008 - June 2014, in which we enrolled consecutive adult patients admitted for suspicion of IE to the Hospital of Infectious Diseases and at the Heart Institute . We used and extensive database in order to collect demographic data, laboratory and echocardiography results, evolution and outcome of the patients. Using the modified Duke criteria we identified 3 categories of IE: definite, possible and rejected. In order to evaluate the importance of each criterion in the diagnosis of IE we tested two hypotheses. First, we excluded each criterion from the final diagnosis and we counted how many cases felt into a lower category. Second, after adding each major and minor criterion, we tested how many cases would have been classifiable as definite IE. RESULTS: The study included 241 adult patients with a mean age 58.16 years and sex ratio male/female 1.94. According to the modified Duke criteria 137 patients had definite IE, 79 patients had possible IE and 25 cases had rejected IE We had blood cultures positive IE in 109 cases and blood culture negative IE (BCNE) in 132 (71.21%) cases. Antibiotic treatment prior to blood culture was recorded in 152 (63.07%) patients. In the absence of the echocardiography major criterion, 43% of cases would become possible. After extraction of major microbiological criterion, only one third of definite cases would become possible. Minor criteria such as fever and predisposition contributed to the diagnosis only in 10% of cases. In the presence of vascular or immunological phenomena, or in the presence of minor microbiological criterion, half of the possible IE cases could become possible. CONCLUSION: Twenty-years after their launch, the Duke criteria for the diagnosis of IE continue to be important tools. Low index of suspicion of IE and inappropriate use of antibiotics may have a great negative impact on the diagnosis of IE. Nowadays, the scarcity of classical Osler manifestations - bacteremia, fever and peripheral stigmata - makes the diagnosis of IE a challenge. PMID- 26609265 TI - Resistant hypertension in type 2 diabetes: prevalence and patients characteristics. AB - BACKGROUND AND AIMS: Resistant hypertension is defined as failure to achieve blood pressure lower than 140/90 mmHg when using three antihypertensive agents or controlled blood pressure with four or more drugs. We aimed at assessing the prevalence of resistant hypertension and to describe a type 2 diabetes population with resistant hypertension. METHODS: The retrospective observational study included (n=73) type 2 diabetes subjects with resistant hypertension selected from (n=728) subjects admitted to the Centre of Diabetes, Cluj, Romania. RESULTS: The subjects (70% women) had a mean age of 65.0+/-8.9 yrs. and diabetes duration 11(6-19) yrs. Prevalence of resistant hypertension was 10%. Chronic diabetes complications and cardiovascular disease were present in 77% and 56% of subjects respectively. On admission, antihypertensive drugs used were: angiotensin converting enzyme inhibitors or angiotensin II receptors blockers 93%, beta blockers 88%, diuretics 78%, calcium channels blockers 59%, adrenergic alpha antagonists 11%. Systolic and diastolic blood pressure were lower in the last compared to first admission day. Diuretics and calcium channels blockers were the most frequently newly added antihypertensive agents. CONCLUSION: Although the prevalence of resistant hypertension in type 2 diabetes did not differ from the general population, we observed that these patients had increased frequency of chronic diabetic complications. Angiotensin-converting enzyme inhibitors or angiotensin II receptors and beta-blockers were the most used antihypertensive drugs, while the most frequently newly prescribed drugs were diuretics and calcium channel blockers. PMID- 26609266 TI - p53 siRNA - a therapeutic tool with significant implication in the modulation of apoptosis and angiogenic pathways. AB - BACKGROUND AND AIMS: siRNAs represent an encouraging novel alternative in cancer therapy as a result of targeting the mutated tumour suppressor genes or activated oncogenes. Targeting oncogenic signals, as the mutated p53 gene that gains oncogenic role, we observed inhibition of migration, a downregulation of specific genes involved in apoptosis but also in angiogenesis, connected with a reduction in invasion rate in the case of p53siRNA therapy. METHODS: The study was designed to assess the role of p53 by using RNAi (RNA interference) in Hela in vitro cell culture model. Therefore cell migration rate was assessed by using xCELLigence Systems, gene expression for a panel of genes involved in apoptosis and angiogenesis, and validation of gene expression data at protein level. RESULTS: On the selected in vitro model p53 siRNA therapy was correlated with the reduction of cell migration. The downregulation of p53, PTEN, TNFalpha, NFkB, BCL 2, ICAM-2, VEGF, and FGFb was evidenced as response to p53 inhibition. CONCLUSION: RNAi may be a valuable technology in order to restore the normal cellular phenotype. The results in the current research may also have an important significance outside the context of cervical cancer, by using specific inhibitors for p53 for increasing the therapeutic response in a wide range of tumoral pathology. PMID- 26609267 TI - Surgical outcomes in native valve infectious endocarditis: the experience of the Cardiovascular Surgery Department - Cluj-Napoca Heart Institute. AB - BACKGROUND AND AIMS: The introduction of Duke's criteria and the improvement of imaging methods has lead to an earlier and a more accurate diagnosis of infectious endocarditis (IE). The options for the best therapeutic approach and the timing of surgery are still a matter of debate and require a close colaboration between the cardiologist, the infectionist and the cardiac surgeon. METHODS: We undertook a retrospective, descriptive study, spanning over a period of five years (from January 1st, 2007 to December 31st, 2012), on 100 patients who underwent surgery for native valve infectious endocarditis in our unit. RESULTS: The patients' age varied between 13 and 77 years (with a mean of 54 years), of which 85 were males (85%). The main microorganisms responsible for IE were: Streptococcus Spp. (21 cases - 21%), Staphylococcus Spp. (15 cases - 15%), and Enterococcus Spp. (9 cases - 9%). The potential source of infection was identified in 26 patients (26%), with most cases being in the dental area (16 cases - 16%). The lesions caused by IE were situated in the left heart in 96 patients (96%), mostly on the aortic valve (50 cases - 50%). In most cases (82%) we found preexisting endocardial lesions which predisposed to the development of IE, most of them being degenerative valvular lesions (38 cases - 38%). We performed the following surgical procedures: surgery on a single valve - aortic valve replacement (40 cases), mitral valve replacement (19 cases), mitral valve repair (1 case), surgery on more than one valve - mitral and aortic valve replacement (20 cases), aortic and tricuspid valve replacement (1 case), aortic valve replacement with a mechanical valve associated with mitral valve repair (5 cases), aortic valve replacement with a biological valve associated with mitral valve repair (2 cases), and mitral valve replacement with a mechanical valve combined with De Vega procedure on the tricuspid valve (1 case). In 5 patients (5%) the bacteriological examination of valve pieces excised during surgery was positive. In 3 cases it matched the germ identified in the hemocultures, and in 2 cases it evidenced another bacterium. CONCLUSION: The overall mortality of 5% is well between the limits presented in literature, being higher (30%) in patients who required emergency surgery. For the patients who return into our clinic with prosthetic valve endocarditis, the mortality after surgery was even higher (50%). PMID- 26609268 TI - Perforator flaps in hand reconstruction: the effect of blood vessel twisting. AB - BACKGROUND AND AIMS: Perforator flaps increasingly find acceptance and use in hand reconstructive surgery. A propeller flap is an island flap that moves from one orientation to another by rotating around its vascular pedicle. It is now possible to design propeller flaps based on a single perforator, so-called "perforator-based propeller flaps," but they are more prone to vascular impairment when twisted more than 90 degrees . METHODS: We present a prospective study conducted in the Plastic and Reconstructive Surgery Department of the Rehabilitation Hospital over 17 months. All perforator-based propeller flaps that were used for hand reconstruction were analyzed. The parameters studied included the size and location of the defect, the size and shape of the flap, the perforator (length and location) that was used, the degree of twisting of the perforator, the degree of perforator dissection, the management of the donor site, and flap survival area. RESULTS: In this study we investigated the circulatory impairment induced by twisting of the pedicle on a true perforator flap. All flaps survived completely with the exception of partial skin necrosis in few cases. Some of these cases required debridement and skin grafting. CONCLUSIONS: Perforator-based propeller flaps provide a reliable option for covering small- to medium-size hand complex tissue defects. They have the advantages of using similar tissues in reconstruction, not damaging another area, they do not require main vessels sacrifice, and the donor site can be generally directly closed. PMID- 26609269 TI - The accuracy of endorectal ultrasonography in rectal cancer staging. AB - BACKGROUND AND AIMS: The incidence of rectal cancer in the European Union is about 35% of the total colorectal cancer incidence. Staging rectal cancer is important for planning treatment. It is essential for the management of rectal cancer to have adequate preoperative imaging, because accurate staging can influence the therapeutic strategy, type of resection, and candidacy for neoadjuvant therapy. The aim of this work is to evaluate the accuracy of endorectal ultrasound (ERUS) in rectal cancer staging. METHODS: A retrospective study was performed to assess the accuracy of ERUS by analyzing patients discharged from Regional Institute of Gastroenterology and Hepatology (IRGH) Cluj Napoca, Romania, diagnosed with rectal cancer between 01 January 2011 and 31 December 2013. Patients who were preoperatively staged by other imaging methods and those who had ERUS performed in another service were excluded from the analysis. As inclusion criteria remained ERUS performed for patients with rectal cancer in IRGH Cluj-Napoca where they were also operated. We analyzed preoperative T stage obtained by ERUS and it was compared with the histopathology findings. RESULTS: The number of patients discharged with a diagnosis of rectal cancer were 200 (operated - 157) in 2011, 193 (operated - 151) in 2012, and 198 (operated - 142) in 2013. We analyzed a total of 51 cases diagnosed with rectal cancer who performed ERUS in IRGH Cluj-Napoca. The results according to the T stage obtained by ERUS and histopathology test were: Under-stage T2= 25.0%, T3=7.9% of cases;Over-stage T2=25.0%, T3=31.6% and T4=60.0% of cases.Less than 20% of patients underwent preoperative radio-chemotherapy. CONCLUSIONS: ERUS is a method of staging rectal cancer which is human dependent. ERUS is less accurate for T staging of stenotic tumours, but the accuracy may still be within acceptable limits. Surgeons use ERUS to adopt a treatment protocol, knowing the risk of under-staging and over-staging of this method. The accuracy of ERUS is higher in diagnosing rectal cancer in stages T1, T2 and even in stage T3 with malignant tumor which is not occlusive. ERUS is less accurate for T staging of locally advanced and stenotic tumours. PMID- 26609270 TI - Development of enoxaparin sodium polymeric microparticles for colon-specific delivery. AB - BACKGROUND AND AIMS: Recent studies have shown that low molecular weight heparins are effective in the treatment of inflammatory bowel disease. Therefore, there is considerable interest in the development of an oral colonic delivery pharmaceutical system allowing targeted release of heparin in the inflamed tissue. The objective of this study was to prepare microparticles for the oral administration and colonic release of enoxaparin and to evaluate the influence of certain formulation factors on their characteristics. METHODS: Microparticles were prepared by water/oil/water double emulsion technique followed by solvent evaporation. The influence of several formulation factors on the characteristics of microparticles were evaluated. The formulation factors were alginate concentration in the inner aqueous phase, polymer (Eudragit((r)) FS 30D and Eudragit((r)) RS PO) concentration in the organic phase and ratios between the two polymers. The microparticles were characterized in terms of morphology, size, entrapment efficiency and enoxaparin release. RESULTS: The results showed that increasing sodium alginate percentage reduced the encapsulation efficiency of enoxaparin and accelerated enoxaparin release. Regarding the influence of the two polymers, reducing polymer concentration in the organic phase led to a smaller size of microparticles, a lower entrapment efficiency and an important retardation of enoxaparin release. The formulation prepared with Eudragit((r)) FS 30D limited the release to a maximum of 3% in gastric simulated environment, a specific characteristic of oral systems for colonic delivery, and fulfilled our objective to delay the release. CONCLUSIONS: Microparticles prepared with Eudragit((r)) FS 30D represent a suitable and potential oral system for the colonic delivery of enoxaparin. PMID- 26609271 TI - Optimization of the sonication process for meloxicam nanocrystals preparation. AB - BACKGROUND AND AIMS: Meloxicam, a widely recommended AINS, presents poor water solubility, which limits its bioavailability and effect onset. The objective of this study is the investigation of the most important factors that influence the efficiency of sonication in the preparation of meloxicam nanocrystals. METHODS: The effects of crucial technological sonication parameters (amplitude, time and applied cycle) on the crystal sizes and dissolution were investigated using a central composite experimental design with three factors and three levels. Different mathematical models were applied for the evaluation of the influence of each factor on the measured responses. RESULTS: The amplitude and the time were found as the most important variables. Their increase determined significant size reduction and homogeneity due to cavitation phenomenon, while the applied cycle was less important. The crystal size greatly influenced dissolution; a strong correlation was noted between small crystals and fast dissolution after freeze drying the nanosuspensions. The optimal formulation was obtained by sonication at 100% amplitude, for 45 minutes and cycle 1, conditions which led to 600 nm crystals with 0.521 polydispersion index. The morphological analysis revealed small, round-shaped crystals with narrow size distribution. CONCLUSIONS: The results provided the optimal sonication conditions needed to obtain meloxicam nanosuspensions with high drug dissolution capacity. PMID- 26609272 TI - Assessment of isoflavone aglycones variability in soy food supplements using a validated HPLC-UV method. AB - BACKGROUND AND AIMS: Soy supplements are often recommended in the management of menopause symptoms. The declared content of soy supplements is commonly expressed as total isoflavones per dosage form. Given that soy isoflavones have different estrogenic potencies, pharmacokinetics and metabolism, the aim of this study was to evaluate the total isoflavone content and the aglycone profile of seven soy supplements and one soy seed extract. Label accuracy was assessed, in relation to the precise content and the recommended posology for estimating whether the optimal dose is achieved for alleviating menopause symptoms. METHODS: A high performance liquid chromatography method was developed for evaluating the aglycone content (genistein, daidzein, glycitein). After extraction and acidic hydrolysis, the aglycones were separated on a C18 column, using 0.1% acetic acid and acetonitrile as mobile phases. The flow rate was 1.5mL min(-1) and the UV detector wavelength was set at 260nm. A linear relationship was found in the range 5-80MUg mL(-1). The method was validated using the accuracy profile methodology. RESULTS: The total isoflavone content ranged from 6.07 to 41.68mg dosage form(-1). Various aglycone profiles were obtained for each supplement which can result in a different estrogenic activity, bioavailability and finally, in a different efficiency in alleviating menopause symptoms. In most clinical trials where soy isoflavones were evaluated, little attention was paid to determining the exact aglycone profile of the employed soy extracts. CONCLUSIONS: As clinical outcomes continue to be controversial, this study highlights the need of standardization in genistein, rather than total isoflavones and labeling accuracy for soy supplements. PMID- 26609273 TI - Estrogenic/antiestrogenic activity of selected selective serotonin reuptake inhibitors. AB - BACKGROUND AND AIMS: Selective serotonin reuptake inhibitors (SSRIs) are one of the most prescribed classes of psychotropics. Even though the SSRI class consists of 6 molecules (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline), only fluoxetine was intensively studied for endocrine disruptive effects, while the other SSRIs received less attention. This study was designed to evaluate the estrogenic/antiestrogenic effect of fluoxetine, sertraline and paroxetine. METHODS: The in vitro (anti)estrogenic activity was assessed using a firefly luciferase reporter construct in the T47D-KBluc breast cancer cell line. These cells express nuclear estrogen receptors that can activate the transcription of the luciferase reporter gene upon binding of estrogen receptor agonists. RESULTS: All three compounds were found to interact with the estrogen receptor. Fluoxetine had dual properties, weak estrogenic at lower concentrations and antiestrogenic effect at higher concentrations. Sertraline shared the same properties with fluoxetine, but also increased the estradiol-mediated transcriptional activity. Paroxetine presented only one type of effect, the ability to increase the estradiol-mediated transcriptional activity. CONCLUSIONS: Overall, our results indicate a possible interaction of SSRIs with the estrogen receptor. As SSRIs are being used by all categories of population, including pregnant women or children, establishing whether they can affect the endocrine mediated mechanisms should be a priority. PMID- 26609274 TI - In vitro modulation of estrogen receptor activity by norfluoxetine. AB - BACKGROUND AND AIMS: Selective serotonin reuptake inhibitors (SSRIs) are antidepressants increasingly prescribed for pregnancy and postpartum depression. However, these compounds can cross the placenta and also pass into breast milk, thus reaching the fetus and infant during critical developmental stages, potentially causing adverse effects. Fluoxetine, a widely used SSRI, has been shown to affect (neuro)endocrine signaling in various organisms, including humans. This compound can also interact with estrogen receptors in vitro and cause an estrogen-dependent uterotrophic response in rodents. Consequently, the aim of the present study was to assess if the active metabolite of fluoxetine, namely norfluoxetine (NFLX), shares the same capacity for estrogen receptor interaction. METHODS: The in vitro (anti)estrogenic activity of norfluoxetine was assessed using a firefly luciferase reporter construct in the T47D-Kbluc breast cancer cell line. These cells express nuclear estrogen receptors (ERs) that can activate the transcription of the luciferase reporter gene upon binding of ER agonists. Light emission was monitored in case of cells exposed to norfluoxetine or mixtures of norfluoxetine-estradiol. Cell viability was assessed using a resazurin-based assay. RESULTS: During individual testing, NFLX was able to induce a significant increase in luciferase activity compared to control, but only at the highest concentration tested (10 MUM). In binary mixtures with estradiol (30 pM constant concentration) a significant increase in luminescence was observed at low submicromolar norfluoxetine concentrations compared to estradiol alone. CONCLUSION: Norfluoxetine can induce estrogenic effects in vitro and can potentiate the activity of estradiol. However, further studies are needed to clarify if these observed estrogenic effects may have detrimental consequences for human exposure. PMID- 26609275 TI - Mandibular reconstruction using free vascularized iliac crest grafts and dental implants. AB - BACKGROUND AND AIM: The mandible is frequently affected by tumor masses present in the oral cavity and is included in the tumor ablation procedure, with major functional and esthetic consequences for the patient. A method of high current interest in mandibular reconstruction is based on the use of free vascularized iliac crest grafts, followed by reconstruction using dental implants. METHODS: This study presents the case of four patients benefiting from this treatment method, and monitors the treatment stages and their clinical evolution after mandibular reconstruction and dental implant placement. RESULTS: The postoperative evolution of the patients was favorable, with the integration of the iliac crest grafts and dental implants. After prosthetic loading, the masticatory as well as the esthetic function of the patients was restored to a standard close to the initial one. CONCLUSIONS: This mandibular reconstruction method proved to be effective, with a high degree of reliability and a significant improvement of the patients' quality of life. PMID- 26609276 TI - In vitro evaluation of root canal preparation with two rotary instrument systems Pro Taper and Hero Shaper. AB - BACKGROUND AND AIMS: The purpose of this study was to compare several parameters of root canal preparation using two different rotary Nickel-Titanium instruments: Pro-Taper (Dentsply Maillefer, Ballagigues, Switzerland) and Hero-Shaper (Micro Mega, Besancon, France). METHODS: Twelve extracted maxillary premolars were randomly divided into two groups and embedded into a muffle system. All root canals were prepared to size 25 using Pro-Taper or Hero-Shaper rotary instruments. The following parameters were evaluated: root canal form, centering capacity of the instrument, the presence of residual dentinal debris and smear layer on the root canal walls, working time and the occurrence of intraoperative accidents. Statistical analysis was performed using the chi(2) test (p=0.05). RESULTS: The majority of the root canals prepared with Hero Shaper (88.89%) and ProTaper (77.78%) showed a round or oval cross-section postoperatively. Superposition of pre- and postoperative photographs of the cross-sections showed that for the coronal third of the root canals the Hero Shaper performed in a superior manner, while for the apical third better results were obtained with the Pro Taper system. Cleanliness of the root canal walls was investigated under the SEM, in the middle third of the canal, using a five-score system for debris and smear layer. For debris Hero Shaper and Pro Taper rotary systems achieved 66.67% and 50% scores of 1 or 2, respectively. The results for the smear layer were similar: cleaner root canal walls were found after preparation with Hero Shaper (66.67% scores 1, 2), followed by Pro Taper (50%). Mean working time was shorter for Hero Shaper (124s) than for Pro Taper (184s); the difference was not significant. CONCLUSIONS: Within the limits of this study, both systems had almost the same cleaning ability and excellent centering capacity. PMID- 26609277 TI - Deleterious oral habits in children with hearing impairment. AB - BACKGROUND AND AIMS: Deleterious oral habits represent a serious public health issue. The information available about this problem in children with hearing impairment is insufficient. The purpose of this study was to investigate the prevalence of deleterious oral habits among children with hearing impairment and comparing results against children without hearing impairment. METHOD: This epidemiological study was carried out in a sample size of 315 children. We used a random sampling technique that included 150 children with hearing impairment and 165 without hearing impairment. All subjects were submitted to a clinical examination. The parents/legal guardians were asked to complete a questionnaire regarding the deleterious habits of their children. RESULTS: The data collected indicated a higher prevalence of deleterious oral habits among children with hearing impairment: 53.3% as opposed to 40.6% among children without hearing impairment. There was a higher incidence of malocclusion in children with hearing impairment (79.3%) compared to children without hearing impairment (57%). CONCLUSIONS: This study highlighted the need to establish protocols for preventive orthodontic treatment at an early age, in order to reduce the deleterious oral habits and prevent malocclusion. Dental institutions/clinicians need to implement oral care programs including proper oral education aiming to promote oral health. PMID- 26609278 TI - Micro-CT and histological analysis of Ti6Al7Nb custom made implants with hydroxyapatite and SiO2-TiO2 coatings in a rabbit model. AB - BACKGROUND AND AIM: Bone defect reconstruction in the maxillofacial area comes as a necessity after traumatic, oncological or congenital pathology. Custom made implant manufacturing, such as selective laser melting (SLM), is very helpful when bone reconstruction is needed. In the present study we assessed the osseointegration of custom made implants made of Ti6Al7Nb with two different coatings: SiO2-TiO2 and hydroxyapatite, by comparing the bone mineral density (BMD) measured on micro-CT and the histological mineralized bone surrounding the implants. METHODS: Custom made - cylindrical type - implants were produced by selective laser melting, coated with SiO2-TiO2 and hydroxyapatite and implanted in the rabbit femur. The animals (divided into 3 groups) were sacrificed at 1, 3 and 6 months and the implants were removed together with the surrounding bone. Bone mineral density and histological examination of the bone-implant surface was performed for each group. RESULTS: BMD and histological examination of the samples determined the quantity of mineralized bone at the implant site, showing a good percentage of mineralized bone for the coated implants at 1, 3 and 6 months. The measurements for the implants without coating showed a significant lower quantity of mineralized bone at 3 months compared with the implants with coating, and a good quantity of mineralized bone at 6 months, showing a process of demineralization followed by remineralization in the last month. The measurements of BMD showed similar results with the histological examination. CONCLUSIONS: The use of micro-CT and the measurement of BMD are a reliable, minimally invasive and a quick method of osseointegration assessment. PMID- 26609279 TI - Laparoscopic simultaneous partial pericystectomy and total cystectomy for hydatid liver cysts - case report. AB - Surgery remains the gold standard for the treatment of patients with echinococcosis, despite significant economic costs, advances in medical treatment and interventional radiology; in the past decades there has been a tendency toward laparoscopic surgery. We present a 66-year-old patient, from a rural area, who was admitted to our service complaining of spontaneous and palpatory pains in the right hypocondrium, headaches and dizziness. Abdominal CT scan highlighted 2 round calcified tumors, one of 7.2 cm diameter (VIII(th) segment) with liquid densities, and the other one localized higher, with a diameter of 2.3 cm (IV(th) segment). Under general anesthesia, after the neutralization of the content of the cyst with hypertonic saline irrigation, we performed laparoscopic partial pericystectomy of the VIII(th) segment liver cyst and total laparoscopic cystectomy of the IV(th) segment liver cyst. Postoperative evolution was favorable without biliary fistula formation, postoperative infections or cystic cavities abscesses. Laparoscopic surgery seems to be effective and safe for uncomplicated cysts in accessible segments of the liver, combined with adjuvant albendazole therapy to reduce complications and postoperative morbidity, but the procedure has its own disadvantages such as a limited area of surgical manipulation. PMID- 26609280 TI - Anatomical variant of the liver blood supply. AB - Vascular variations are significant for liver transplantations, radiological procedures, laparoscopic method of operation and for the healing of penetrating injuries, including the space close to the hepatic area. These variants are very common in the abdominal region, and their description will be useful. During a routine dissection of a 73 year old female cadaver, we found in the subhepatic region that the blood supply of the liver differed from a normal one. The difference was found in the absence of the right liver branch and the cystic artery, which normally arises from the common hepatic artery. After a detailed dissection of the superior mesenteric artery we distinguished a branchthat was routed to the right lobe of the liver. The diameter of this vessel was 3.7 mm and the length 8.2 cm. In the artery pathway, three consecutive branches were observed. The first branch was found about 2.02 cm before the portal region of the liver. The second one became visible after another millimeter and finally the artery made one little curve and became a cystic artery. PMID- 26609281 TI - The challenge of consolation: nurses' experiences with spiritual and existential care for the dying-a phenomenological hermeneutical study. AB - BACKGROUND: A majority of people in Western Europe and the USA die in hospitals. Spiritual and existential care is seen to be an integral component of holistic, compassionate and comprehensive palliative care. Yet, several studies show that many nurses are anxious and uncertain about engaging in spiritual and existential care for the dying. The aim of this study is to describe nurses' experiences with spiritual and existential care for dying patients in a general hospital. METHODS: Individual narrative interviews were conducted with nurses in a medical and oncological ward. Data were analyzed using a phenomenological hermeneutical method. RESULTS: The nurses felt that it was challenging to uncover dying patients' spiritual and existential suffering, because it usually emerged as elusive entanglements of physical, emotional, relational, spiritual and existential pain. The nurses' spiritual and existential care interventions were aimed at facilitating a peaceful and harmonious death. The nurses strove to help patients accept dying, settle practical affairs and achieve reconciliation with their past, their loved ones and with God. The nurses experienced that they had been able to convey consolation when they had managed to help patients to find peace and reconciliation in the final stages of dying. This was experienced as rewarding and fulfilling. The nurses experienced that it was emotionally challenging to be unable to relieve dying patients' spiritual and existential anguish, because it activated feelings of professional helplessness and shortcomings. CONCLUSIONS: Although spiritual and existential suffering at the end of life cannot be totally alleviated, nurses may ease some of the existential and spiritual loneliness of dying by standing with their patients in their suffering. Further research (qualitative as well as quantitative) is needed to uncover how nurses provide spiritual and existential care for dying patients in everyday practice. Such research is an important and valuable knowledge supplement to theoretical studies in this field. PMID- 26609283 TI - Production, purification and characterization of novel beta glucosidase from newly isolated Penicillium simplicissimum H-11 in submerged fermentation. AB - beta-Glucosidase is an important component of the cellulase complex. It not only hydrolyzes cellobiose and short-chain cellooligosaccharides to glucose, but also removes the inhibitory effect of cellobiose on the beta-1, 4-endoglucanase and exoglucanase, thereby increasing the overall rate of cellulose biodegradation. beta-glucosidasefrom culture supernatant of a fungus Penicillium simplicissimum was purified to homogeneity, by using ammonium sulfate fraction, Sephadex G-100 chromatography, and its properties were studied. The molecular mass of the enzyme was about 126.0 kDa, as identified by 12% SDS-PAGE. The optimum pH and temperature were 4.4 ~ 5.2 and 60 degrees C, respectively. The enzyme was stable in pH 5.2 ~ 6.4 and under 40 degrees C. Metal profile of the enzyme showed that Mn(2+) enhances its activity, while Cu(2+), Co(2+)and Fe(3+) cause obvious inhibition. The K m and V max was 14.881 mg/ml and 0.364 mg ml/min against salicin as a Substrate. This enzyme had secondary protein structure as evidenced by FTIR spectrum. PMID- 26609282 TI - Examining the effect of Withania somnifera supplementation on muscle strength and recovery: a randomized controlled trial. AB - BACKGROUND: Withania somnifera (ashwagandha) is a prominent herb in Ayurveda. This study was conducted to examine the possible effects of ashwagandha root extract consumption on muscle mass and strength in healthy young men engaged in resistance training. METHODS: In this 8-week, randomized, prospective, double blind, placebo-controlled clinical study, 57 young male subjects (18-50 years old) with little experience in resistance training were randomized into treatment (29 subjects) and placebo (28 subjects) groups. Subjects in the treatment group consumed 300 mg of ashwagandha root extract twice daily, while the control group consumed starch placebos. Following baseline measurements, both groups of subjects underwent resistance training for 8 weeks and measurements were repeated at the end of week 8. The primary efficacy measure was muscle strength. The secondary efficacy measures were muscle size, body composition, serum testosterone levels and muscle recovery. Muscle strength was evaluated using the 1-RM load for the bench press and leg extension exercises. Muscle recovery was evaluated by using serum creatine kinase level as a marker of muscle injury from the effects of exercise. RESULTS: Compared to the placebo subjects, the group treated with ashwagandha had significantly greater increases in muscle strength on the bench-press exercise (Placebo: 26.4 kg, 95% CI, 19.5, 33.3 vs. Ashwagandha: 46.0 kg, 95% CI 36.6, 55.5; p = 0.001) and the leg-extension exercise (Placebo: 9.8 kg, 95% CI, 7.2,12.3 vs. Ashwagandha: 14.5 kg, 95 % CI, 10.8,18.2; p = 0.04), and significantly greater muscle size increase at the arms (Placebo: 5.3 cm(2), 95% CI, 3.3,7.2 vs. Ashwagandha: 8.6 cm(2), 95% CI, 6.9,10.8; p = 0.01) and chest (Placebo: 1.4 cm, 95% CI, 0.8, 2.0 vs. Ashwagandha: 3.3 cm, 95% CI, 2.6, 4.1; p < 0.001). Compared to the placebo subjects, the subjects receiving ashwagandha also had significantly greater reduction of exercise-induced muscle damage as indicated by the stabilization of serum creatine kinase (Placebo: 1307.5 U/L, 95% CI, 1202.8, 1412.1, vs. Ashwagandha: 1462.6 U/L, 95% CI, 1366.2, 1559.1; p = 0.03), significantly greater increase in testosterone level (Placebo: 18.0 ng/dL, 95% CI, -15.8, 51.8 vs. Ashwagandha: 96.2 ng/dL, 95% CI, 54.7, 137.5; p = 0.004), and a significantly greater decrease in body fat percentage (Placebo: 1.5%, 95% CI, 0.4%, 2.6% vs. Ashwagandha: 3.5%, 95% CI, 2.0%, 4.9%; p = 0.03). CONCLUSION: This study reports that ashwagandha supplementation is associated with significant increases in muscle mass and strength and suggests that ashwagandha supplementation may be useful in conjunction with a resistance training program. PMID- 26609284 TI - Design, synthesis and anticonvulsant activity of some new 5,7-dibromoisatin semicarbazone derivatives. AB - A series of 5,7-dibromoisatin semicarbazones have been synthesized in good yield, involving aryl urea and aryl semicarbazide formation. The structures of the synthesized compounds were confirmed on the basis of their spectral data. All the compounds were evaluated for anticonvulsant and CNS depressant activities. Anticonvulsant activity was determined after intraperitoneal (i.p.) administration to mice by maximal electroshock (MES) induced seizure method and minimal motor impairment was determined by rotarod test. A computational study was carried out for prediction of pharmacokinetic properties and making them potentially promising agents for the treatment of epilepsy. Compounds (Z)-1-(5,7 dibromo-2-oxoindolin-3-ylidene)-4-(4-chlorophenyl)semicarbazide (DH-05), (Z)-1 (5,7-dibromo-2-oxoindolin-3-ylidene)-4-(3-chloro-4-fluorophenyl)semicarbazide (DH 11) and (Z)-1-(5,7-dibromo-1-methyl-2-oxoindolin-3-ylidene)-4-(3-chloro-4 fluorophenyl)semicarbazide (DH-12) exhibited prominent anticonvulsant effect in the series with little or no neurotoxicity and little CNS depressant effect as compared to standard drug. PMID- 26609285 TI - Contralateral cortical role on functional recovery in a rat model of hemiplegia. AB - The role of the contralateral cerebral cortical plasticity in functional recovery after cerebral infarction is controversial. To clarify this role, we made a second contralateral cortical infarction after recovery from the first cerebral infarction. To produce the first infarction, Wistar rats were intravenously injected with Rose Bengal to the sensorimotor area of the right hemisphere of the cerebral cortex under green-light irradiation. Two weeks after the first hemiplegia, a secondary infarction was induced in the left cerebral cortex. Functional recovery was evaluated in a beam-walking test. Hemiplegia observed 1 day after both the first and second infarctions was given a score of 1. At 14 days after the first infarction, the average recovery score (+/- standard error) was 6.8 +/- 0.1. In contrast, functional recovery was slower after the second infarction, reaching an average score of only 3.5 +/- 0.5 after 14 days. Therefore, recovery after the contralateral secondary infarction was slower than that from the first, and received a lower recovery score compared to the recovery after the first infarction. These results suggest that the undamaged contralateral cortex plays an important role in motor recovery after hemiplegia caused by cerebral infarction. PMID- 26609287 TI - The scholar role in the National Competence Based Catalogues of Learning Objectives for Undergraduate Medical Education (NKLM) compared to other international frameworks. AB - BACKGROUND: In Germany, a national competence based catalogue of learning objectives in medicine (NKLM) was developed by the Society for Medical Education and the Council of Medical Faculties. As many of its international counterparts the NKLM describes the qualifications of medical school graduates. The definition of such outcome frameworks indents to make medical education transparent to students, teachers and society. The NKLM aims to amend existing lists of medical topics for assessment with learnable competencies. All outcome frameworks are structured into chapters, domains or physician roles. The definition of the scholar-role poses a number of questions such as: What distinguishes necessary qualifications of a scientifically qualified physician from those of a medical scientist? METHODS: 13 outcome frameworks were identified through a systematic three-step literature review and their content compared to the scholar role in the NKLM by means of a qualitative text analysis. The three steps consist of (1) search for outcome frameworks, (2) in- and exclusion, and (3) data extraction, categorization, and validation. The results were afterwards matched with the scholar role of the NKLM. RESULTS: Extracted contents of all frameworks may be summarized into the components Common Basics, Clinical Application, Research, Teaching and Education, and Lifelong Learning. Compared to the included frameworks the NKLM emphasises competencies necessary for research and teaching while clinical application is less prominently mentioned. CONCLUSION: The scholar role of the NKLM differs from other international outcome frameworks. Discussing these results shall increase propagation and understanding of the NKLM and thus contribute to the qualification of future medical graduates in Germany. PMID- 26609288 TI - Smoking determines the 10-year (2004-2014) prognosis in patients with Acute Coronary Syndrome: the GREECS observational study. AB - BACKGROUND: Smoking has long been positively associated with the development and progression of coronary heart disease. However, longitudinal cohort studies evaluating smoking habits among cardiac patients as well as the role of socio demographic factors determining such behaviours are scarce and have been focused on primary care practice. Thus the aim of the present work was to examine the association of active smoking and behaviours and exposure to second-hand smoke, with the 10-year Acute Coronary Syndrome (ACS) prognosis, among cardiovascular patients. METHODS: From October 2003 to September 2004, a sample of six Greek hospitals was selected and almost allconsecutive 2172 ACS patients were enrolled. In 2013-14, the 10-year follow-up was performed in 1918 participants (11 % loss to follow-up). Smoking habits at the time of entry to the study, as well as during the follow-up period were studied using a standard questionnaire. RESULTS: Patients who had >60 pack-years of smoking had 57.8 % higher ACS mortality and 24.6 % higher risk for any ACS event. Nested model, adjusted only for age and sex, revealed that for every 30 pack-years of smoking increase, the associated ACS risk increased by 13 % (95 % CI 1.03, 1.30, p = 0.001). When further adjusted analysis, including several potential confounders, was applied the tested relationship was still significant (95 %CI 1.03, 1.30, p = 0.09). Accordingly, the risk for fatal ACS events increased by 8 % for every 30 pack-years of smoking increase (95 % CI 1.03, 1.63, p = 0.06). Moreover, 52 % of the patients reported being exposed to secondhand smoke and when further adjustments were made, it was revealed that they had 33 % (95 % CI 1.12, 1.60, p = 0.01) higher risk of having recurrent ACS events. CONCLUSIONS: Active smoking and second-hand smoke among cardiac patients still represent a substantial clinical burden. Thus, smoking cessation policies should be incorporated into the long-term therapeutic management. PMID- 26609289 TI - Quantitative assessment of bio-aerosols contamination in indoor air of University dormitory rooms. AB - OBJECTIVES: The purpose of this study is to provide insight into how students are exposed to indoor bio-aerosols in the dormitory rooms and to figure out the major possible factors that govern the contamination levels. METHODOLOGY: The Bio aerosols concentration level of indoor air of thirty dormitory rooms of Jimma University was determined by taking 120 samples. Passive air sampling technique; the settle plate method using open Petri-dishes containing different culture media was employed to collect sample twice daily. RESULTS: The range of bio aerosols contamination detected in the dormitory rooms was 511-9960 CFU/m(3) for bacterial and 531-6568 CFU/m(3) for fungi. Based on the criteria stated by WHO expert group, from the total 120 samples 95 of the samples were above the recommended level. The statistical analysis showed that, occupancy were significantly affected the concentrations of bacteria that were measured in all dormitory rooms at 6:00 am sampling time (p-value=0.000) and also the concentrations of bacteria that were measured in all dormitory rooms were significantly different to each other (p-value=0.013) as of their significance difference in occupancy (p-value=0.000). Moreover, there were a significant different on the contamination level of bacteria at 6:00 am and 7:00 pm sampling time (p=0.015), whereas there is no significant difference for fungi contamination level for two sampling times (p= 0.674). CONCLUSION: There is excessive bio-aerosols contaminant in indoor air of dormitory rooms of Jimma University and human occupancy produces a marked concentration increase of bacterial contamination levels and most fungi species present into the rooms air of Jimma University dormitory were not human-borne. PMID- 26609290 TI - Hypertriglyceridemia in Infants and Children with Hypernatremia. AB - BACKGROUND: Hypertriglyceridemia in association with hypernatremia was reported in a few children; however, studies exploring this association are limited. OBJECTIVE: To determine the pattern of change in serum triglycerides levels in hypernatremia patients. DESIGN AND SETTING: A prospective case-control study done at North West Armed Forces Hospital, Tabuk, Saudi Arabia from April 2008 to March 2011. PATIENTS AND METHOD: serum triglycerides and sodium were measured in 16 patients with hypernatremic dehydration as a study group and 14 patients with isonatremic dehydration as a control group. The trend of serum sodium and triglycerides was followed during treatment in the study group. RESULTS: There were 6 boys and 8 girls in the control group (isonatremic dehydration). Their age ranged between 4 months and five years (M+/-SD = 1.7+/-1.3 years). In the study group (hypernatremic dehydration), there were 6 boys and 10 girls. The age range was 2-14 months (M+/-SD = 0.6+/-0.4 years). The serum sodium and triglycerides (M+/-SD = 165.8+/-9.1 mmol/l, 5.1+/-8.1 mmol/l respectively) were significantly higher compared with the control group (M+/-SD = 137.5+/-3.9 mmol/l, 0.7+/-0.3 mmol/l and P < 0.001, P < 0.05 respectively). Duration of symptoms in patients with hypernatremic dehydration (M+/-SD = 2.9+/-2.4 days) were comparable to control group (M+/-SD = 2.0+/-0.9 days, P = 0.18). Four patients from the study group had normal serum triglycerides (M+/-SD = 1.1+/-0.1 mmol/l). With treatment, serum sodium was normalized in all patients followed by serum triglycerides. CONCLUSION: Hypertriglyceridemia is present in most children with hypernatremia and it disappears when serum sodium returns to normal. PMID- 26609291 TI - The anti-inflammatory and analgesic properties of prosopis chilenses in rats. AB - BACKGROUND: Prosopis chilensis is used locally in Sudan for inflammatory conditions of joints; however, literature lacks scientific evidence for anti inflammatory effect of this plant. AIMS: To evaluate anti-inflammatory and analgesic effects of prosopis chilenses. MATERIAL AND METHODS: Edema inhibition percent (EI %) and hot plate method were used to evaluate anti-inflammatory and analgesic effects of Prosopis chilenses in Wistar albino rats. Anti-inflammatory and analgesic effects of Prosopis chilenses were compared to indomethacin and acetylsalicylic acid respectively. RESULTS: Ethanolic extract of prosopis chilensis at a dose of 200 and 100mg/kg body weight achieved peak EI% (EI% = 96.1%) and (EI% = 94.4%) three and four hours after oral dosing respectively. The maximum EI% for indomethacin was 97.0% and was recorded after 4 hours following oral administration of the drug at a dose of 5 mg/kg body weight. Prosopis chilensis extracts at doses of 100 and 200 mg/kg body weight significantly increased the rats' response time to hot plate compared to acetylsalicylic acid at a dose rate of 100mg/kg body weight (P<0.05). CONCLUSION: The current results suggest potential anti-inflammatory and analgesic effects of prosopis chilenses. Relevance of these effects to prosopis chilenses phy-to-constituents was discussed. PMID- 26609292 TI - Prevalence of endometriosis among adolescent school girls with severe dysmenorrhea: A cross sectional prospective study. AB - OBJECTIVES: To determine the prevalence of endometriosis among adolescent school girls with severe dysmenorrhea. METHODOLOGY: Data was collected via interviewed questionnaire. Patients with symptoms and signs suggestive of endometriosis were further evaluated by abdominal ultrasonography (AUS), serum cancer antigen 125 (CA125). Laparoscopy was done for confirmation in those who agreed. Those who declined laparoscopy were offered magnetic resonance imaging (MRI). RESULTS: A total number of 654 adolescents were interviewed. Their mean age was 15.2 +/- 3.53 SD years. The mean duration of cycles and flow days was 29 +/- 8.4 SD and 4 +/- 2.8 SD respectively. The age of menarche in years was 13 +/- 1.2 SD. Cycles were regular in 77.4 % (n=506) while irregular in 22.6 % (n=148). Of all studied girls, 48.9% (n=320) had menstrual pain of varying degree of severity. Severe dysmenorrhea was reported in 68.8 % (n=220/320) of them. Fifty six of these cases (25.5 %) had ultrasound findings suggestive of endometriosis. CA125 was elevated in 41.5 % (n= 27/56) of them. Patients accepted laparoscopic confirmations were 34, of them 79.4%, (n=27) had positive histo-pathological evidence of endometriosis. MRI was offered to those declined laparoscopy (n=22). Endometriosis was suggested in 77.3% of them. CONCLUSION: The study concluded the prevalence of endometriosis in adolescents with severe dysmenorrhea was 12.3 % despite some declined laparoscopy. The unacceptability of laparoscopy and unfeasibility of local examination and trans-vaginal ultrasound add more to the difficulty of diagnosis. PMID- 26609286 TI - Evidence and consensus based guideline for the management of delirium, analgesia, and sedation in intensive care medicine. Revision 2015 (DAS-Guideline 2015) - short version. AB - In 2010, under the guidance of the DGAI (German Society of Anaesthesiology and Intensive Care Medicine) and DIVI (German Interdisciplinary Association for Intensive Care and Emergency Medicine), twelve German medical societies published the "Evidence- and Consensus-based Guidelines on the Management of Analgesia, Sedation and Delirium in Intensive Care". Since then, several new studies and publications have considerably increased the body of evidence, including the new recommendations from the American College of Critical Care Medicine (ACCM) in conjunction with Society of Critical Care Medicine (SCCM) and American Society of Health-System Pharmacists (ASHP) from 2013. For this update, a major restructuring and extension of the guidelines were needed in order to cover new aspects of treatment, such as sleep and anxiety management. The literature was systematically searched and evaluated using the criteria of the Oxford Center of Evidence Based Medicine. The body of evidence used to formulate these recommendations was reviewed and approved by representatives of 17 national societies. Three grades of recommendation were used as follows: Grade "A" (strong recommendation), Grade "B" (recommendation) and Grade "0" (open recommendation). The result is a comprehensive, interdisciplinary, evidence and consensus-based set of level 3 guidelines. This publication was designed for all ICU professionals, and takes into account all critically ill patient populations. It represents a guide to symptom-oriented prevention, diagnosis, and treatment of delirium, anxiety, stress, and protocol-based analgesia, sedation, and sleep management in intensive care medicine. PMID- 26609293 TI - Distinct perturbations of oral squamous cell carcinoma patients: A quantitative cytomorphometric analysis. AB - OBJECTIVE: Oral cancer constitutes a major health issue in developing countries, representing the leading cause of death. Quantitative assessment by sophisticated diagnostic techniques is becoming increasingly important. Hence, a histochemical staining procedure and morphometric evaluation are used to obtain optimal information on the cellular events. The objective of present study is to assess the variation in cellular area, nuclear area, cellular diameter, nuclear diameter and nuclear/cytoplasmic ratio respectively in normal subjects, smokeless tobacco users, (smokers, combination and oral squamous cell carcinoma patients. METHODS: Total 125 number of subjects were divided into five groups, each comprising 25 subjects of more than 40 years of age. These groups were: a. Normal, b. smokeless tobacco users, c. smokers d. combination and e. oral squamous cell carcinoma. Oral smears were obtained, stained with Feulgen stain and the cells were measured cytomorphometrically using Nikon imaging software. RESULTS: Our study showed a significant reduction in the cellular diameter, cellular area and increase in the nuclear diameter, nuclear area and nuclear/cytoplasmic ratio in oral squamous cell carcinoma patients as compared to tobacco users and normal patients. Significant changes were found in group I, II, III and IV when compared with group V but as such no significant intergroup variation was found in cellular and nuclear dimensions in smokers, smokeless tobacco users, combination and control group. CONCLUSION: Quantitative parameters could be assessed by cytomorphometry. Cytomorphological changes in exfoliated squames could serve as a useful adjunct in the early diagnosis of oral squamous cell carcinomas. PMID- 26609294 TI - Understanding Patients' Perspectives on Opt-Out, Incentivized, and Mandatory HIV Testing. AB - BACKGROUND: Currently, widespread HIV testing is the best preventive action against further spread of the HIV epidemic. However, over 40% of the U.S. population has never been tested for HIV and 25% of those with HIV have never been tested. To increase testing rates, in 2006 the CDC advised healthcare settings to conduct testing on an opt-out basis. METHODS: Qualitative, semi structured interviews with ten seropositive patients and ten seronegative were conducted to address the lack of studies investigating patients' acceptance of and attitude towards this and more novel testing models, e.g. incentivized or anonymous mandatory testing. Participants were asked about their HIV testing history and attitudes towards opt-out, incentivized, and mandatory anonymous HIV testing. RESULTS: Major themes were identified using grounded theory data analysis. All participants were receptive to opt-out testing, and saw the removal of separate written consent as beneficial as long as patients were given the opportunity to consent in some form. CONCLUSION: Ultimately, both mandatory and opt-out testing were equally indicated by participants as being the most effective testing model at increasing testing rates. A firm understanding of patients' perspectives allows for development of effective HIV testing initiatives that are patient-sensitive and can substantially reduce HIV infection rates. PMID- 26609295 TI - Male Partner's Role during Pregnancy, Labour and Delivery: Expectations of Pregnant women in Nigeria. AB - OBJECTIVES: To evaluate the expectations of pregnant women on the role of the male partner during conception and delivery. METHODOLOGY: A prospective multi centre observational study comprising 506 pregnant women at eight health facilities in Ilorin, Nigeria from January to June 2014. Consenting women were recruited at antenatal clinics using multistage purposive sampling and a self administered questionnaire was administered with provision for interpreters in local dialects for those without western education. The data was analyzed using SPSS using percentages and chi-square test; p <0.05 was termed significant. RESULTS: Participants were aged 17 to 49 years (mean 30.23+/-4.81), 82.4% desire male partners company during antenatal clinic visits and 59.1% experienced this in index pregnancy. During labour and delivery, 427(84.4%) want company; 345(80.8%) chose the male partner with 211(57.7%) hoping men will appreciate the value of females afterwards although 27.9% feared the men may disturb the health workers, 72(14.2%) male partners attended previous delivery and 84.8% of the women were satisfied with the experience. Significant predictors of support for male partner's presence at delivery were maternal age (p=0.001), secondary or higher education (p=0.001) and parity less than four (p=0.001); religion (x(2)1.010; p>0.001) and social status (p>0.001) were statistically insignificant. Pregnant women wanted education for male partners on care of pregnant women (77.0%) and sex during conception (25.2%). CONCLUSION: Parturient desire male partners' presence at deliveries but their past participation was low; health facility modifications and education for men are required to meet the desires. PMID- 26609296 TI - Impacts of health education on knowledge and practice of hospital staff with regard to Healthcare waste management at White Nile State main hospitals, Sudan. AB - OBJECTIVES: The present study aims at assessing nursing and sanitation staff knowledge and practice regarding Healthcare Waste (HCW) management before and after the implementation of an educational intervention program at the main hospitals of the White Nile State in Sudan. METHODOLOGY: Quasi-experimental study design was applied to assess the impact of an intervention program on knowledge and practice regarding HCW management. The same questionnaire used in the pre test was used immediately after the end of the intervention program and then again three months later for a second post-test. RESULTS: The results showed that the majority of nursing and sanitation staff had fair knowledge regarding HCW management before the educational intervention program (17% good, 58% fair, and 25% poor). After implementation of the educational program, the majority had good knowledge (56% good, 34% fair, and 10% poor) in the immediate post-test, and also in the post-test three months later (59% good, 35% fair, and 6% poor). More than half the nursing and sanitation staff had fair level of practice before the educational intervention program (42% good, 55% fair, and 3% poor). After the implementation of the intervention program, the immediate post-test showed a similar result (45% good, 54% fair, and 1% poor), while the post-test three months later showed that the majority demonstrated good practice level (55% good, 42% fair, and 3% poor). CONCLUSION: The nursing and sanitation staff at the main hospitals of the White Nile State in Sudan recorded significant improvement in their knowledge and practice with regard to HCW management immediately after the educational intervention program and three months later. PMID- 26609297 TI - Hand Foot Syndrome Secondary to Low Dose Docetaxel. AB - Hand-foot syndrome (palmoplantar erythrodysesthesia or Burgdorf reaction), is a distinctive skin toxicity affecting the palms and soles after certain chemotherapeutic drugs. Docetaxel induced hand-foot syndrome is rare, dose dependent adverse event. Here in we report a case of Docetaxel induced grade III hand-foot syndrome at low doses (75/m(2)). PMID- 26609298 TI - Endovascular treatment for acute pulmonary embolism in neurological patient. AB - Among the spectrum of venous thrombo-embolic disease, acute pulmonary embolism accounts for the most life threatening manifestations with mortality exceeding 50%. It can affect many patient populations across various disciplines, hence immediate attention and aggressive treatment is crucial. With the advancement of technologies, various catheter-based devices are available to treat massive or submassive PE. In this paper we report two patients of acute pulmonary embolism with neurological issues where the life threatening emergency was successfully managed by utilizing endovascular directed thrombolytic reperfusion therapy. PMID- 26609299 TI - Glycemic Control among Patients with Type 2 Diabetes Mellitus in Countries of Arabic Gulf. AB - Type 2 diabetes mellitus is a growing, worldwide public health concern. The countries of Arabic Gulf appear to have a higher prevalence of diabetes than the global average. The recent and rapid socio-economic development of these countries has been associated with this rising prevalence. Although the rate of type 2 diabetes management based on glycosylated hemoglobin level in the countries of Arabic Gulf is labeled as poor, the outcomes are almost similar to those reported from elsewhere. Unfortunately, overweight and obesity are driving the global diabetes epidemic. A minority of patients with type 2 diabetes had a normal body weight which might make the control of diabetes difficult. Anyhow, Greater efforts are urgently needed to properly manage diabetes early in order to prevent short and long-term complications. Practical strategies aimed at more effective management of type 2 diabetes patients are strongly needed. PMID- 26609300 TI - Improving Dermatology Clinical Efficiency in Academic Medical Centers. PMID- 26609301 TI - Burden of Diabetes Mellitus in Saudi Arabia. PMID- 26609303 TI - Information Dissemination of Public Health Emergency on Social Networks and Intelligent Computation. AB - Due to the extensive social influence, public health emergency has attracted great attention in today's society. The booming social network is becoming a main information dissemination platform of those events and caused high concerns in emergency management, among which a good prediction of information dissemination in social networks is necessary for estimating the event's social impacts and making a proper strategy. However, information dissemination is largely affected by complex interactive activities and group behaviors in social network; the existing methods and models are limited to achieve a satisfactory prediction result due to the open changeable social connections and uncertain information processing behaviors. ACP (artificial societies, computational experiments, and parallel execution) provides an effective way to simulate the real situation. In order to obtain better information dissemination prediction in social networks, this paper proposes an intelligent computation method under the framework of TDF (Theory-Data-Feedback) based on ACP simulation system which was successfully applied to the analysis of A (H1N1) Flu emergency. PMID- 26609302 TI - In vitro activity of phospholipase A2 and of peptides from Crotalus durissus terrificus venom against amastigote and promastigote forms of Leishmania (L.) infantum chagasi. AB - BACKGROUND: American visceral leishmaniasis is caused by the intracellular parasite Leishmania (L.) infantum chagasi, and transmitted by the sand fly Lutzomyia longipalpis. Since treatment is based on classical chemotherapeutics with significant side effects, the search for new drugs remains the greatest global challenge. Thus, this in vitro study aimed to evaluate the leishmanicidal effect of Crotalus durissus terrificus venom fractions on promastigote and amastigote forms of Leishmania (L.) infantum chagasi. METHODS: Phospholipase A2 (PLA2) and a pool of peptide fraction (<3 kDa) were purified from Crotalus venom. Furthermore, promastigotes and peritoneal macrophages of mice infected by amastigotes were exposed to serial dilutions of the PLA2 and peptides at intervals varying between 1.5625 MUg/mL and 200 MUg/mL. Both showed activity against promastigotes that varied according to the tested concentration and the time of incubation (24, 48 and 72 h). RESULTS: MTT assay for promastigotes showed IC50 of 52.07 MUg/mL for PLA2 and 16.98 MUg/mL for the peptide fraction of the venom. The cytotoxicity assessment in peritoneal macrophages showed IC50 of 98 MUg/mL and 16.98 MUg/mL for PLA2 and peptide by MTT assay, respectively. In peritoneal macrophages infected by Leishmania (L.) infantum chagasi amastigotes, the PLA2 stimulated growth of parasites, and at higher doses reduced growth by 23 %. The peptide fraction prevented 43 % of the intracellular parasite growth at a dose of 16.98 MUg/mL, demonstrating the toxicity of this dose to macrophages. Both fractions stimulated H2O2 production by macrophages but only PLA2 was able to stimulate NO production. CONCLUSION: We have demonstrated the in vitro leishmanicidal activity of the PLA2 and peptide fraction of Crotalus venom. The results encourage further studies to describe the metabolic pathways involved in cell death, as well as the prospecting of molecules with antiparasitic activity present in the peptide fraction of Crotalus durissus terrificus venom. PMID- 26609304 TI - An Enhanced Differential Evolution Algorithm Based on Multiple Mutation Strategies. AB - Differential evolution algorithm is a simple yet efficient metaheuristic for global optimization over continuous spaces. However, there is a shortcoming of premature convergence in standard DE, especially in DE/best/1/bin. In order to take advantage of direction guidance information of the best individual of DE/best/1/bin and avoid getting into local trap, based on multiple mutation strategies, an enhanced differential evolution algorithm, named EDE, is proposed in this paper. In the EDE algorithm, an initialization technique, opposition based learning initialization for improving the initial solution quality, and a new combined mutation strategy composed of DE/current/1/bin together with DE/pbest/bin/1 for the sake of accelerating standard DE and preventing DE from clustering around the global best individual, as well as a perturbation scheme for further avoiding premature convergence, are integrated. In addition, we also introduce two linear time-varying functions, which are used to decide which solution search equation is chosen at the phases of mutation and perturbation, respectively. Experimental results tested on twenty-five benchmark functions show that EDE is far better than the standard DE. In further comparisons, EDE is compared with other five state-of-the-art approaches and related results show that EDE is still superior to or at least equal to these methods on most of benchmark functions. PMID- 26609305 TI - Dermatological Diseases Associated with Pregnancy: Pemphigoid Gestationis, Polymorphic Eruption of Pregnancy, Intrahepatic Cholestasis of Pregnancy, and Atopic Eruption of Pregnancy. AB - Dermatoses unique to pregnancy are important to recognize for the clinician as they carry considerable morbidity for pregnant mothers and in some instances constitute a risk to the fetus. These diseases include pemphigoid gestationis, polymorphic eruption of pregnancy, intrahepatic cholestasis of pregnancy, and atopic eruption of pregnancy. This review discusses the pathogenesis, clinical importance, and management of the dermatoses of pregnancy. PMID- 26609306 TI - Current State of Vascular Resections in Pancreatic Cancer Surgery. AB - Pancreatic cancer (PDAC) is the fourth leading cause of cancer-related mortality in the Western world and, even in 2014, a therapeutic challenge. The only chance for long-term survival is radical surgical resection followed by adjuvant chemotherapy which can be performed in about 20% of all PDAC patients by the time of diagnosis. As pancreatic surgery has significantly changed during the past years, extended operations, including vascular resections, have become more frequently performed in specialized centres and the border of resectability has been pushed forward to achieve a potentially curative approach in the respective patients in combination with neoadjuvant and adjuvant treatment strategies. In contrast to adjuvant treatment which has to be regarded as a cornerstone to achieve long-term survival after resection, neoadjuvant treatment strategies for locally advanced findings are currently under debate. This overview summarizes the possibilities and evidence of vascular, namely, venous and arterial, resections in PDAC surgery. PMID- 26609307 TI - Mesenteric-Portal Vein Resection during Pancreatectomy for Pancreatic Cancer. AB - The aim of the present study was to determine the outcome of patients undergoing pancreatic resection with (VR+) or without (VR-) mesenteric-portal vein resection for pancreatic carcinoma. Between January 1998 and December 2012, 241 patients with pancreatic cancer underwent pancreatic resection: in 64 patients, surgery included venous resection for macroscopic invasion of mesenteric-portal vein axis. Morbidity and mortality did not differ between the two groups (VR+: 29% and 3%; VR-: 30% and 4.0%, resp.). Radical resection was achieved in 55/64 (78%) in the VR+ group and in 126/177 (71%) in the VR- group. Vascular invasion was histologically proven in 44 (69%) of the VR+ group. Survival curves were not statistically different between the two groups. Mean and median survival time were 26 and 15 months, respectively, in VR- versus 20 and 14 months, respectively, in VR+ group (p = 0.52). In the VR+ group, only histologically proven vascular invasion significantly impacted survival (p = 0.02), while, in the VR- group, R0 resection (p = 0.001) and tumor's grading (p = 0.01) significantly influenced long-term survival. Vascular resection during pancreatectomy can be performed safely, with acceptable morbidity and mortality. Long-term survival was the same, with or without venous resection. Survival was worse for patients with histologically confirmed vascular infiltration. PMID- 26609308 TI - Total Phenolic, Flavonoid, Tomatine, and Tomatidine Contents and Antioxidant and Antimicrobial Activities of Extracts of Tomato Plant. AB - The purpose of this study was to evaluate the antioxidant and antimicrobial properties of extracts of different fractions of two tomato plant cultivars. The stems, roots, leaves, and whole-plant fractions were evaluated. Tomatine and tomatidine were identified by HPLC-DAD. The leaf extracts from the two varieties showed the highest flavonoids, chlorophyll, carotenoids, and total phenolics contents and the highest antioxidant activity determined by DPPH, ABTS, and ORAC. A positive correlation was observed between the antioxidant capacities of the extracts and the total phenolic, flavonoid, and chlorophyll contents. The Pitenza variety extracts inhibited the growth of pathogens such as E. coli O157:H7, Salmonella Typhimurium, Staphylococcus aureus, and Listeria ivanovii, yielding inhibition halos of 8.0 to 12.9 mm in diameter and MIC values of 12.5 to 3.125 mg/mL. These results suggest that tomato plant shows well potential as sources of various bioactive compounds, antioxidants, and antimicrobials. PMID- 26609309 TI - Dual Effect of Ziconotide in Primary Erythromelalgia. AB - Erythromelalgia (EM) is a rare disabling clinical syndrome more commonly known to affect the lower extremities. There is no single effective treatment for this disease that often requires a multidisciplinary approach. Herein, we report the case of a 31-year-old woman affected by primary erythromelalgia who was successfully treated with intrathecal Ziconotide. We also observed an unexpected result following therapy with Ziconotide. The legs and feet of the patient that at the time of admission were swollen and tumefied dramatically improved after one week of the drug administration. PMID- 26609310 TI - Effectiveness and Safety of Manufactured Chinese Herbal Formula for Knee Osteoarthritis: Insights from a Systematic Review. AB - Objective. To assess the current clinical evidence of manufactured Chinese herbal formulae (MCHF) for knee osteoarthritis (KOA). Methods. Seven databases were searched from inception to May 2015. Eligible randomized controlled trials investigating the effectiveness of MCHF for KOA were included. Data extraction, methodological assessment, and meta-analyses were conducted according to the Cochrane standards. Results. A total of 17 kinds of MCHF were identified from the twenty-six included trials. Meta-analyses showed that MCHF significantly relieved the global pain of knee joints, either used alone or combined with routine treatments. Additionally, MCHF plus routine treatments significantly decreased the scores of WOMAC and Lequesne index. However, there were no statistical differences between MCHF group and routine treatment group in walk-related pain and WOMAC scores. No significant differences were found in Lysholm scores. There were twenty-one trials that mentioned adverse events. A pooled analysis showed that adverse events occurred more frequently in control group compared with MCHF group. Conclusions. Our results indicated that MCHF showed some potential benefits for KOA. However, we still cannot draw firm conclusions due to the poor methodological quality of included trials. More high-quality RCTs would help to confirm the evidence. PMID- 26609311 TI - High-Energy Extracorporeal Shock Wave for Early Stage Osteonecrosis of the Femoral Head: A Single-Center Case Series. AB - Our retrospective study assessed the effects of treatment of early stage ONFH with extracorporeal shock wave therapy. 335 patients (528 hips) were treated with shockwave therapy in our institution. Each patient underwent two sessions. The hips were divided into two groups according to whether the lateral pillar of the femoral head (LPFH) was preserved: LPFH and non-LPFH groups. Patients were followed up at 3, 6, and 12 months after the treatment. Most of the patients (83.9% hips) demonstrated pain reduction and improved mobility of the treated joint (visual analogue scale score, P = 0.00006; Harris hip score, P = 0.00091). During the follow-up period, 16 hips failed following femoral head collapse and required hip arthroplasty (2 hips in LPFH group and 14 hips in non-LPFH group). The lesion size decreased after ESWT. However, the differences were statistically not significant (LPFH group, P = 0.091; non-LPFH group, P = 0.087). A significant reduction in bone marrow edema was observed after treatment (LPFH group, P = 0.007; non-LPFH group, P = 0.016). High-energy extracorporeal shock wave therapy resulted in considerable improvement in early stage ONFH, which can effectively relieve pain and improve the function of the hip. PMID- 26609312 TI - The Combination of Resveratrol and Quercetin Attenuates Metabolic Syndrome in Rats by Modifying the Serum Fatty Acid Composition and by Upregulating SIRT 1 and SIRT 2 Expression in White Adipose Tissue. AB - Resveratrol (RSV) and quercetin (QRC) modify energy metabolism and reduce cardiovascular risk factors included in the metabolic syndrome (MetS). These natural compounds upregulate and activate sirtuins (SIRTs), a family of NAD dependent histone deacetylases. We analyzed the effect of two doses of a commercial combination of RSV and QRC on serum fatty acid composition and their regulation of SIRTs 1-3 and PPAR-gamma expression in white adipose tissue. MetS was induced in Wistar rats by adding 30% sucrose to drinking water for five months. Rats were divided into control and two groups receiving the two different doses of RSV and QRC in drinking water daily for 4 weeks following the 5 months of sucrose treatment. Commercial kits were used to determine serum parameters and the expressions of SIRTs in WAT were analysed by western blot. In MetS rats body mass, central adiposity, insulin, triglycerides, non-HDL-C, leptin, adiponectin, monounsaturated fatty acids (MUFAs), and nonesterified fatty acids (NEFAs) were increased, while polyunsaturated fatty acids (PUFAs) and HDL-C were decreased. SIRT 1 and SIRT 2 were downregulated, while PPAR-gamma was increased. RSV + QRC administration improved the serum health parameters modified by MetS and upregulate SIRT 1 and SIRT 2 expression in white abdominal tissue in MetS animals. PMID- 26609313 TI - Chemical cues and pheromones in the sea lamprey (Petromyzon marinus). AB - Chemical cues and pheromones guide decisions in organisms throughout the animal kingdom. The neurobiology, function, and evolution of olfaction are particularly well described in insects, and resulting concepts have driven novel approaches to pest control. However, aside from several exceptions, the olfactory biology of vertebrates remains poorly understood. One exception is the sea lamprey (Petromyzon marinus), which relies heavily upon olfaction during reproduction. Here, we provide a broad review of the chemical cues and pheromones used by the sea lamprey during reproduction, including overviews of the sea lamprey olfactory system, chemical cues and pheromones, and potential applications to population management. The critical role of olfaction in mediating the sea lamprey life cycle is evident by a well-developed olfactory system. Sea lamprey use chemical cues and pheromones to identify productive spawning habitat, coordinate spawning behaviors, and avoid risk. Manipulation of olfactory biology offers opportunities for management of populations in the Laurentian Great Lakes, where the sea lamprey is a destructive invader. We suggest that the sea lamprey is a broadly useful organism with which to study vertebrate olfaction because of its simple but well-developed olfactory organ, the dominant role of olfaction in guiding behaviors during reproduction, and the direct implications for vertebrate pest management. PMID- 26609314 TI - Cognitive impairment in manic bipolar patients: important, understated, significant aspects. AB - BACKGROUND: Bipolar disorder is a chronic mood disorder with episodic progress and high relapse rate. Growing evidence suggests that individuals with bipolar disorder display cognitive impairment which persists even throughout periods of symptom's remission. METHOD: 137 bipolar patients met the inclusion criteria (depressive episode: DSM-IV-TR criteria for major depressive episode, HAMD score >=17; manic/hypomanic episode: DSM-IV-TR criteria for manic/hypomanic episode, YMRS score >=12, euthymic: 6 months of remission, HAMD score <=8, YMRS score <=6; and mixed: DSM-IV-TR criteria for mixed episode, HAMD score >8 and YMRS score >6) and were therefore enrolled in the study. Patients were free of psychotic symptoms (hallucinations/delusions) at the moment of testing. Control group consisted of 62 healthy subjects without history of neurological and/or psychiatric disorder. Cognitive battery has been applied in order to assess verbal memory, working memory, psychomotor speed, verbal fluency, attention and speed of information processing, and executive function. Following data were collected: demographics, psychiatric history, age of illness onset; current and previous treatment (including hospitalizations). Cognitive deficits were assessed in bipolar patients experiencing manic, depressive, mixed episodes or who were euthymic in mood. Results were compared between the subgroups and with healthy individuals. The association of impaired cognition with illness course was analyzed. RESULTS: Bipolar patients showed cognitive deficits in all evaluated domains when compared to controls. The lowest scores were obtained for the verbal fluency test. After adjusting for current episode, manic subgroup showed greater cognitive impairment in verbal and working memory, executive function/reasoning and problem solving, compared to depressive, mixed, and euthymic subgroup. Low neurocognitive performance was directly associated with a predominance of manic episodes and severe course of bipolar illness. An increased number of past manic episodes was the strongest correlated event with the poorest outcomes in verbal memory testing. Other factors correlated with poor verbal memory scores in manic subgroup were age at illness onset (positive correlation), illness length, and hospitalizations (negative correlations). CONCLUSIONS: Bipolar patients showed cognitive deficits regardless of the phase of illness. Subjects experiencing a manic episode displayed higher deficits in verbal and working memory, executive function/reasoning, and problem solving. Severe course of illness also showed significant contribution in terms of cognitive impairment. PMID- 26609315 TI - Piloting a classroom-based intervention in after-school programmes: a case study in science migration. AB - Policy-makers are looking to after-school programs to improve family and child well-being and are searching for evidence-based ways to improve the quality of after-school programs. This study examines whether the Good Behavior Game, a behavior management curriculum designed for school classrooms, can be easily migrated to academically-focused after-school programs. Our results are based on program observations, qualitative interviews, and ratings of implementation fidelity. We provide a description of the structure and activities in these after school programs, then identify challenges to implementing and evaluating classroom-based interventions in the after-school setting. PMID- 26609317 TI - Update on the prevention and treatment of endophthalmitis. AB - Endophthalmitis remains a rare but serious cause of visual loss. Over time, changes have been noted in endophthalmitis in terms of predominant causes, infecting organisms, and antibiotic susceptibilities. There is controversy regarding the use of intracameral prophylactic antimicrobials during cataract surgery. Alternatively, there appears to be increasing evidence against using routine topical antibiotics for intravitreal injections. There are also increasing reports of multidrug-resistant organisms causing endophthalmitis, but the combination of vancomycin and ceftazidime appears effective for the vast majority of cases. Future trends may involve increasing utilization of polymerase chain reaction for diagnosis, and possibly office-based pars plana vitrectomy for treatment of endophthalmitis. PMID- 26609318 TI - Analyzing the Correlation between the Level of Serum Markers and Ischemic Cerebral Vascular Disease by Multiple Parameters. AB - OBJECTIVE: To explore the serum markers associated with ischemic cerebral vascular disease (ICVD) and discuss their diagnostic value. METHODS: Two hundred and eighty-eight patients with ICVD and one hundred and eighty healthy persons were enrolled as the case group and the control group, respectively. This paper then carried out the univariate and multivariate logistic regression analyses of their respective levels of serum markers, made combined analysis of related factors, and detected the diagnostic value. RESULTS: Meta-analysis results showed that for ICVD patients the levels of CRP, S-100, TNF-alpha, HCY, NSE, and IL-6 were higher than those of the healthy persons, while the level of HDL was obviously lower than that of the healthy persons. The multivariate regression analysis indicated that the association between the level of HDL and TNF-alpha and the occurrence of ICVD was statistically significant (P < 0.05). The area under the curves (AUC) of receiver operating characteristic (ROC) curve of HDL and TNF-alpha was 0.916, with sensitivity of 90.91% and specificity of 76.47%. CONCLUSION: HDL has negative correlation with the occurrence of ICVD, while TNF alpha was positively correlated with it. The combination test of HDL and TNF alpha could raise the accuracy of ICVD diagnosis. PMID- 26609316 TI - Retinal Gene Therapy: Current Progress and Future Prospects. AB - Clinical trials treating inherited retinal dystrophy caused by RPE65 mutations had put retinal gene therapy at the forefront of gene therapy. Both successes and limitations in these clinical trials have fueled developments in gene vectors, which continue to further advance the field. These novel gene vectors aim to more safely and efficiently transduce retinal cells, expand the gene packaging capacity of AAV, and utilize new strategies to correct the varying mechanisms of dysfunction found with inherited retinal dystrophies. With recent clinical trials and numerous pre-clinical studies utilizing these novel vectors, the future of ocular gene therapy continues to hold vast potential. PMID- 26609319 TI - Stimulating effect of graphene oxide on myogenesis of C2C12 myoblasts on RGD peptide-decorated PLGA nanofiber matrices. AB - BACKGROUND: In the field of biomedical engineering, many studies have focused on the possible applications of graphene and related nanomaterials due to their potential for use as scaffolds, coating materials and delivery carriers. On the other hand, electrospun nanofiber matrices composed of diverse biocompatible polymers have attracted tremendous attention for tissue engineering and regenerative medicine. However, their combination is intriguing and still challenging. RESULTS: In the present study, we fabricated nanofiber matrices composed of M13 bacteriophage with RGD peptide displayed on its surface (RGD-M13 phage) and poly(lactic-co-glycolic acid, PLGA) and characterized their physicochemical properties. In addition, the effect of graphene oxide (GO) on the cellular behaviors of C2C12 myoblasts, which were cultured on PLGA decorated with RGD-M13 phage (RGD/PLGA) nanofiber matrices, was investigated. Our results revealed that the RGD/PLGA nanofiber matrices have suitable physicochemical properties as a tissue engineering scaffold and the growth of C2C12 myoblasts were significantly enhanced on the matrices. Moreover, the myogenic differentiation of C2C12 myoblasts was substantially stimulated when they were cultured on the RGD/PLGA matrices in the presence of GO. CONCLUSION: In conclusion, these findings propose that the combination of RGD/PLGA nanofiber matrices and GO can be used as a promising strategy for skeletal tissue engineering and regeneration. PMID- 26609320 TI - Awakening the endogenous Leloir pathway for efficient galactose utilization by Yarrowia lipolytica. AB - BACKGROUND: Production of valuable metabolites by Yarrowia lipolytica using renewable raw materials is of major interest for sustainable food and energy. Galactose is a monosaccharide found in galactomannans, hemicelluloses, gums, and pectins. RESULTS: Yarrowia lipolytica was found to express all the Leloir pathway genes for galactose utilization, which encode fully functional proteins. Gene organization and regulation in Y. lipolytica resembles filamentous fungi rather than Saccharomyces cerevisiae. After Y. lipolytica was grown on mixture of glucose and galactose, it was then able to metabolize galactose, including when glucose concentrations were higher than 4 g/L. However, glucose was still the preferred carbon source. Nonetheless, a strain overexpressing the four ylGAL genes of the Leloir pathway was able to efficiently use galactose as its sole carbon source. This mutant was used to produce citric acid and lipids from galactose; the yields were comparable to or greater than that obtained for the parental strain (W29) on glucose. CONCLUSIONS: The construction of a Y. lipolytica strain able to produce citric acid and lipids from galactose is a very important step in bypassing issues related to the use of food-based substrates in industrial applications. PMID- 26609321 TI - A novel biocatalyst for efficient production of 2-oxo-carboxylates using glycerol as the cost-effective carbon source. AB - BACKGROUND: The surplus of glycerol has increased remarkably as a main byproduct during the biofuel's production. Exploiting an alternative route for glycerol utilization is significantly important for sustainability of biofuels. RESULTS: A novel biocatalyst that could be prepared from glycerol for producing 2-oxo carboxylates was developed. First, Pseudomonas putida KT2440 was reconstructed by deleting lldR to develop a mutant expressing the NAD-independent lactate dehydrogenases (iLDHs) constitutively. Then, the Vitreoscilla hemoglobin (VHb) was heterologously expressed to further improve the biotransformation activity. The reconstructed strain, P. putida KT2440 (DeltalldR)/pBSPPcGm-vgb, exhibited high activities of iLDHs when cultured with glycerol as the carbon source. This cost-effective biocatalyst could efficiently produce pyruvate and 2-oxobutyrate from dl-lactate and dl-2-hydroxybutyrate with high molar conversion rates of 91.9 and 99.8 %, respectively. CONCLUSIONS: The process would not only be a promising alternative for the production of 2-oxo-carboxylates, but also be an example for preparation of efficient biocatalysts for the value-added utilization of glycerol. PMID- 26609322 TI - Harnessing the potential of LPMO-containing cellulase cocktails poses new demands on processing conditions. AB - BACKGROUND: The emerging bioeconomy depends on improved methods for processing of lignocellulosic biomass to fuels and chemicals. Saccharification of lignocellulose to fermentable sugars is a key step in this regard where enzymatic catalysis plays an important role and is a major cost driver. Traditionally, enzyme cocktails for the conversion of cellulose to fermentable sugars mainly consisted of hydrolytic cellulases. However, the recent discovery of lytic polysaccharide monooxygenases (LPMOs), which cleave cellulose using molecular oxygen and an electron donor, has provided new tools for biomass saccharification. RESULTS: Current commercial enzyme cocktails contain LPMOs, which, considering the unique properties of these enzymes, may change optimal processing conditions. Here, we show that such modern cellulase cocktails release up to 60 % more glucose from a pretreated lignocellulosic substrate under aerobic conditions compared to anaerobic conditions. This higher yield correlates with the accumulation of oxidized products, which is a signature of LPMO activity. Spiking traditional cellulase cocktails with LPMOs led to increased saccharification yields, but only under aerobic conditions. LPMO activity on pure cellulose depended on the addition of an external electron donor, whereas this was not required for LPMO activity on lignocellulose. CONCLUSIONS: In this study, we demonstrate a direct correlation between saccharification yield and LPMO activity of commercial enzyme cocktails. Importantly, we show that the LPMO contribution to overall efficiency may be large if process conditions are adapted to the key determinants of LPMO activity, namely the presence of electron donors and molecular oxygen. Thus, the advent of LPMOs has a great potential, but requires rethinking of industrial bioprocessing procedures. PMID- 26609323 TI - The first draft genome of the aquatic model plant Lemna minor opens the route for future stress physiology research and biotechnological applications. AB - BACKGROUND: Freshwater duckweed, comprising the smallest, fastest growing and simplest macrophytes has various applications in agriculture, phytoremediation and energy production. Lemna minor, the so-called common duckweed, is a model system of these aquatic plants for ecotoxicological bioassays, genetic transformation tools and industrial applications. Given the ecotoxic relevance and high potential for biomass production, whole-genome information of this cosmopolitan duckweed is needed. RESULTS: The 472 Mbp assembly of the L. minor genome (2n = 40; estimated 481 Mbp; 98.1 %) contains 22,382 protein-coding genes and 61.5 % repetitive sequences. The repeat content explains 94.5 % of the genome size difference in comparison with the greater duckweed, Spirodela polyrhiza (2n = 40; 158 Mbp; 19,623 protein-coding genes; and 15.79 % repetitive sequences). Comparison of proteins from other monocot plants, protein ortholog identification, OrthoMCL, suggests 1356 duckweed-specific groups (3367 proteins, 15.0 % total L. minor proteins) and 795 Lemna-specific groups (2897 proteins, 12.9 % total L. minor proteins). Interestingly, proteins involved in biosynthetic processes in response to various stimuli and hydrolase activities are enriched in the Lemna proteome in comparison with the Spirodela proteome. CONCLUSIONS: The genome sequence and annotation of L. minor protein-coding genes provide new insights in biological understanding and biomass production applications of Lemna species. PMID- 26609324 TI - Efficient conversion of acetate into lipids by the oleaginous yeast Cryptococcus curvatus. AB - BACKGROUND: Acetic acid is routinely generated during lignocelluloses degradation, syngas fermentation, dark hydrogen fermentation and other anaerobic bioprocesses. Acetate stream is commonly regarded as a by-product and detrimental to microbial cell growth. Conversion of acetate into lipids by oleaginous yeasts may be a good choice to turn the by-product into treasure. RESULTS: Ten well known oleaginous yeasts were evaluated for lipid production on acetate under flask culture conditions. It was found that all of those yeasts could use acetate for microbial lipid production. In particular, Cryptococcus curvatus accumulated lipids up to 73.4 % of its dry cell mass weight. When the culture was held in a 3 L stirred-tank bioreactor, cell mass, lipid content, lipid yield and acetate consumption rate were 8.1 g/L, 49.9 %, 0.15 g/g and 0.64 g/L/h, respectively. The fatty acid compositional profiles of the acetate-derived lipids were similar to those of vegetable oil, suggesting their potential for biodiesel production. Continuous cultivation of C. curvatus was conducted under nitrogen-rich condition at a dilution rate of 0.04 h(-1), the maximal lipid content and lipid yield were 56.7 % and 0.18 g/g, respectively. The specific lipid formation rate, lipid content and lipid yield were all higher under nitrogen-rich conditions than those obtained under nitrogen-limited conditions at the same dilution rates. Effective lipid production by C. curvatus was observed on corn stover hydrolysates containing 15.9 g/L acetate. CONCLUSIONS: Acetate is an effective carbon source for microbial lipid production by oleaginous yeasts. Continuous cultivation of C. curvatus on acetate was promising for lipid production under both nitrogen-rich and nitrogen-limited conditions. These results provide valuable information for developing and designing more efficient acetate-into-lipids bioprocess. PMID- 26609325 TI - Are radiographic indices reliable indicators for quantitative bone mineral density and vitamin D status after femoral neck fractures? A retrospective study in 112 elderly patients. AB - BACKGROUND: Radiographic parameters and indices obtained from hip x-rays are a potential tool to promptly estimate bone quality in elderly hip fracture patients. Preoperative decision in whether to use cemented or cement augmented implants might be supported by this information and thus improve patient safety. Subsequently, this study was conducted to evaluate radiographic parameters as a prescreening tool for bone quality. METHODS: A retrospective analysis of 112 elderly patients with a femoral neck fracture after low-energy trauma was performed (81 % female, 19 % male). Three radiological indices were calculated on hip x-rays: cortical index antero-posterior CTI (ap), cortical index lateral CTI (lat) and canal to calcar ratio CCR. These indices were analyzed for correlations with DXA T-Scores and serum 25-hydroxyvitamin D (25(OH)D) using the Spearman test. RESULTS: Median age of patients was 80 (IQR 72-86) years. A linear correlation was found for CTI (lat) and T-Score at the total hip (p < 0.001, r = 0.589), femoral neck (p = 0.005, r = 0.405) and the lumbar spine (p = 0.002, r = 0.299). A significant correlation was also indicated between CTI (lat) and 25(OH)D (p = 0.002, r = 0.293). CTI (lat) at a cut-off level of 0.4 showed a sensitivity of 79 % and a specificity of 56 % in predicting a T-score <= -2.5 at the total hip. Gender specific analysis revealed a higher sensitivity (100 %) and specificity (73 %) of CTI (lat) at a cut-off level of 0.4 for men. For severe vitamin D deficiency (<10 ng/ml) sensitivity and specificity were 75 % and 65 %. CONCLUSION: Radiographic indices as the CTI (lat) exhibit a direct correlation to BMD and serum 25OH vitamin D levels. A CTI (lat) cut-off level of 0.4 is recommended for identifying patients at risk of osteoporosis expressed by T Scores <= -2.5 and severe vitamin D deficiency. PMID- 26609327 TI - Angle-torque relationship of the subtalar pronators and supinators in younger and elderly males and females. AB - BACKGROUND: The angle-dependent torque capacity of the subtalar pronators and supinators is important to maintain dynamic ankle stabilisation. Based on the peak torques during maximum voluntary isometric pronation and supination across the subtalar range of motion, the strength curves of younger and elderly males and females were investigated. METHODS: Maximum voluntary isometric subtalar pronator and supinator strength tests were administered to 30 younger and 30 elderly volunteers (each 15 male and 15 female subjects). Total active subtalar range of motion and peak pronator and supinator torques were measured in five anatomical subtalar joint angles using a custom-built apparatus with two force transducers. Furthermore, relative torques (normalised to the individual peak torque) and pronator-to-supinator strength-ratios were also calculated. RESULTS: Pronator-to-supinator strength ratio, and peak pronator and supinator torques are affected by age and by joint angle x age interactions. All supinator strength curves show a steadily descending characteristic from the pronated to the supinated positions. The pronator strength curve had an inverted U-shaped characteristic, except for younger women of whom 47 % exert highest peak values in the end-range pronation angle. Both relative pronator and supinator strength are dependent on sex (P < 0.05). Relative pronator strength is also affected by joint angle x sex (P < 0.0001) and joint angle x sex x age (P < 0.05) interactions. Beside age effects on all range of motion parameters, pronation range of motion is influenced by a sex x age interaction (P < 0.05). CONCLUSIONS: Age- and sex-related differences in both subtalar strength profile and range of motion have to be considered when testing strength across subtalar range of motion. Younger females have higher pronator strength capacity in the most pronated joint angle, which may be due in part to their greater subtalar joint range of motion compared to the other groups. In the most supinated position both pronator and supinator strength capacity is reduced in younger females compared to younger males. PMID- 26609326 TI - Ethnicity-specific epigenetic variation in naive CD4+ T cells and the susceptibility to autoimmunity. AB - BACKGROUND: Genetic and epigenetic variability contributes to the susceptibility and pathogenesis of autoimmune diseases. T cells play an important role in several autoimmune conditions, including lupus, which is more common and more severe in people of African descent. To investigate inherent epigenetic differences in T cells between ethnicities, we characterized genome-wide DNA methylation patterns in naive CD4+ T cells in healthy African-Americans and European-Americans, and then confirmed our findings in lupus patients. RESULTS: Impressive ethnicity-specific clustering of DNA methylation profiling in naive CD4+ T cells was revealed. Hypomethylated loci in healthy African-Americans were significantly enriched in pro-apoptotic and pro-inflammatory genes. We also found hypomethylated genes in African-Americans to be disproportionately related to autoimmune diseases including lupus. We then confirmed that these genes, such as IL32, CD226, CDKN1A, and PTPRN2 were similarly hypomethylated in lupus patients of African-American compared to European-American descent. Using patch DNA methylation and luciferase reporter constructs, we showed that methylation of the IL32 promoter region reduces gene expression in vitro. Importantly, bisulfite DNA sequencing demonstrated that cis-acting genetic variants within and directly disrupting CpG sites account for some ethnicity-specific variability in DNA methylation. CONCLUSION: Ethnicity-specific inherited epigenetic susceptibility loci in CD4+ T cells provide clues to explain differences in the susceptibility to autoimmunity and possibly other T cell-related diseases between populations. PMID- 26609328 TI - DPP-4 inhibitor sitagliptin prevents inflammation and oxidative stress of heart and kidney in two kidney and one clip (2K1C) rats. AB - BACKGROUND: Hyperglycemia and insulin resistance often develop cardiovascular and nephrological dysfunction in diabetic patients. Sitagliptin is used to treat diabetes and showed potential benefit in lowering increased blood glucose level in diabetes. This investigation reports the effect of sitagliptin treatment on oxidative stress in kidney and heart of 2K1C rats. METHODS: Male Long Evans rats underwent unilateral surgical stenosis of the renal artery [2-kidney-1-clip (2K1C) method]. These animals entered a 4-weeks dosing period with sitagliptin. Blood and urine sampling and organ harvesting were finally performed. Blood plasma, heart, kidney tissues and urine were tested for the assessment of inflammation and oxidative stress in kidney and heart of 2K1C rats after 4 weeks of surgery. RESULTS: 2K1C rats showed cardiac hypertrophy, increased left ventricular wet weight compared to sham which was not significantly altered by sitagliptin treatment. Uric acid and creatinin concentrations were also increased in 2K1C rats. Sitagliptin significantly prevented the elevation of uric acid and creatinin concentration in plasma and urine in this rat model. Oxidative stress markers in plasma such as malondialdehyde (MDA), nitric oxide (NO), and advanced protein oxidation product (APOP) concentrations were increased in the 2K1C rats as compared to sham-operated animals. Increased concentrations of these oxidative stress markers were also normalized by sitagliptin treatment. 2K1C rats also showed increased level of uric acid and creatinine both in plasma and urine; which are also reduced to normal level in sitagliptin treated rats. Moreover, 2K1C surgery initiated inflammatory cell infiltration, increased MPO activity and fibrosis in both heart and kidneys which were further ameliorated by sitagliptin treatment. CONCLUSION: Our study suggests that sitagliptin treatment in 2K1C rats prevented inflammation and fibrosis of heart and kidney by ameliorating elevated oxidative stress in heart and kidney tissues. PMID- 26609330 TI - Mindfulness and Metta-based Trauma Therapy (MMTT): Initial Development and Proof of-Concept of an Internet Resource. AB - Trauma and stressor-related disorders, including post-traumatic stress disorder (PTSD) and related comorbid disorders such as anxiety, depression, and dissociative disorders, are difficult to treat. Mindfulness-based clinical interventions have proven efficacy for mental health treatment in face-to-face individual and group modalities, although the feasibility and efficacy of delivering these interventions via the internet has not been evaluated. The present research developed mindfulness and metta-based trauma therapy (MMTT) as an internet resource to support the practice of mindfulness and metta (lovingkindness) meditations for self-regulation and healing from trauma and stressor-related disorders. In the present "proof-of-concept" study, research participants (n = 177) recruited online practiced mindfulness and metta meditations and related therapeutic exercises available via the website and rated their perceived credibility as interventions for improving self-regulation and well-being and reducing PTSD symptoms, anxiety, depressive, and dissociative experiences, as well as their experienced ease, helpfulness, and informational value. Results suggest that, independent of level of self-reported current and past psychiatric history and PTSD symptoms, participants considered the MMTT website as a credible and helpful therapeutic intervention for improving self regulation and well-being and reducing PTSD, anxiety, depression, and dissociation. Overall, participants considered guided and non-guided meditation practices more helpful than a journaling exercise, and participants with increased PTSD symptoms preferred metta (lovingkindness) meditations less than other participants. We conclude that MMTT should be piloted in clinical trials as an adjunctive intervention to evidence-based treatments for persons with mood, anxiety, and trauma and stressor-related disorders, as well as more generally as an online resource to support self-regulation and well-being practices. PMID- 26609329 TI - Myeloproliferative Neoplasms in Children. AB - Myeloproliferative neoplasms (MPN) are a group of clonal hematopoietic stem cell disorders characterized by aberrant proliferation of one or more myeloid lineages often with increased immature cells in the peripheral blood. The three classical BCR-ABL-negative MPNs are: 1) polycythemia vera (PV), 2) essential thrombocythemia (ET), and 3) primary myelofibrosis (PMF), which are typically disorders of older adults and are exceedingly rare in children. The diagnostic criteria for MPNs remain largely defined by clinical, laboratory and histopathology assessments in adults, but they have been applied to the pediatric population. The discovery of the JAK2 V617F mutation, and more recently, MPL and CALR mutations, are major landmarks in the understanding of MPNs. Nevertheless, they rarely occur in children, posing a significant diagnostic challenge given the lack of an objective, clonal marker. Therefore, in pediatric patients, the diagnosis must rely heavily on clinical and laboratory factors, and exclusion of secondary disorders to make an accurate diagnosis of MPN. This review focuses on the clinical presentation, diagnostic work up, differential diagnosis, treatment and prognosis of the classical BCR-ABL-negative MPNs (PV, ET and PMF) in children and highlights key differences to the adult diseases. Particular attention will be given to pediatric PMF, as it is the only disorder of this group that is observed in infants and young children, and in many ways appears to be a unique entity compared to adult PMF. PMID- 26609332 TI - Large benign retroperitoneal tumour in pregnancy. AB - A 31-year-old female was in the 13th week of pregnancy when an abdominal ultrasound examination revealed a large retroperitoneal tumour. Magnetic resonance imaging was carried out and the imaging described a 10-cm mass in diameter extending from the right kidney. Given that the patient was in her first trimester and that there was a suspicion of malignancy, further surgical exploration of the tumour was warranted. During the operation, the tumour was removed, but nephrectomy was not necessary. Histologic analysis of the resected tumour showed a mucinous cystic adenoma, and no signs of malignancy were present. Following the surgery, the pregnancy was otherwise uneventful and further complications did not occur. This case illustrates that surgery is recommended in patients with a retroperitoneal tumour early during a pregnancy, when a malignancy cannot be excluded. PMID- 26609331 TI - Do severe obese patients with stress urinary incontinence benefit from transobturator tape procedure? 3-year surgical outcome. AB - INTRODUCTION: We evaluate the impact of severe obesity on surgical outcomes of the transobturator tape (TOT) procedure in patients with stress urinary incontinence (SUI). METHODS: In total, 32 women with severe obesity (body mass index [BMI] >35 kg/m(2)) were included in the study. All patients were preoperatively evaluated with history, pelvic examination, ultrasonography, and cough stress test. All patients completed the International Consultation on Incontinence Questionnaire-Short form (ICIQ-SF) preoperatively and at the postoperative follow-up. Cure of incontinence was defined as being completely dry after surgery. Cure was assessed subjectively and objectively. Subjective improvement defined as an International Consultation on Incontinence Questionnaire-Short form (ICIQ-SF) score <=12 and satisfaction with surgery. Failure was defined as having no change or worsening of urinary incontinence after surgery. Postoperative patient satisfaction was assessed using a visual analog scale. RESULTS: The mean follow-up time and mean BMI were 40.9 +/- 20.9 months and 38 +/- 3 kg/m(2), respectively. According to preoperative ICIQ-SF questionnaire scores, 20 patients (62.5%) had severe and 12 patients (37.5 %) had very severe urinary incontinence symptoms. No patient had slight or moderate symptoms. None of the patients experienced worsening symptoms after surgery. Objective cure, subjective cure, subjective improvement and patient satisfaction rates were 81.2%, 46.8%, 37.5%, and 84.3% respectively. Our overall complication rate was 9.3%. None of the patients experienced intraoperative complications. CONCLUSION: In experienced hands, TOT is an effective and safe procedure to treat SUI, with minimal complications in severe obese women. PMID- 26609333 TI - Single ectopic ureteral orifice with bilateral duplicated renal collecting systems in an adult girl: Diagnosis by magnetic resonance urography. AB - Renal duplication accompanied by ureteral ectopia is an uncommon urinary congenital abnormality. We report the case of a 21-year-old girl who suffered from lifelong continuous urinary leakage. She was finally diagnosed with bilateral duplicated collecting systems complicated with right ectopic ureteral orifice - an extremely rare case. The patient underwent ureteric re-implantation for the ectopic side, and her urinary incontinence ceased soon thereafter. In this case, traditional imaging failed to show the exact insertion of an ectopic ureter. However, magnetic resonance urography combined with retrograde intubation radiography successfully depicted the point of ureteric insertion, which may make the diagnostic process accurate and efficient. PMID- 26609334 TI - [Not Available]. PMID- 26609335 TI - Resistant pediatric priapism: A real challenge for the urologist. AB - Priapism in pediatric patients is a rare entity. We present an 8-year-old boy with known cerebral palsy. He came to the emergency department with sustained painful erection for 12 hours. Physical examination showed rigid penis. Blood count and biochemical analysis were normal. Although penile Doppler ultrasound revealed normal arterial and venous flow, cavernosal blood gas was hypoxic. A total of 50 mL of dark blood was aspirated, and 2 mL of 0.001% adrenalin solution was applied to both corpus cavernosum, twice within 20 minutes, which eventually did not achieve detumescence. A distal Winter shunt was performed at the end of which the penis was semi-flaccid. By the 18th hour of surgery, the penis re gained painful erection status, so an Al-Ghorab shunt was performed. After the Al Ghorab shunt, the penis was still in the semi-flaccid state. The next day, an angiography was performed and an arteriovenous fistula was discovered and treated by embolization. The flaccid state was achieved and the patient was discharged the day after the embolization. PMID- 26609336 TI - Minimal fat renal angiomyolipoma with lymph node involvement: A case report and literature review. AB - Renal angiomyolipomas (AML), consisting of fatty tissue, blood vessels, and smooth muscular cells in various proportions, is a relatively common benign renal neoplasm. Simultaneous involvement of the kidney and lymph nodes is uncommon and might be confused with an advanced renal cancer. AML is divided into minimal fat AML and fat-predominant AML. However, minimal fat AML with lymph node involvement is extremely rare and difficult to differentiate from RCC on images. We report such a case and review the literature. PMID- 26609337 TI - Imaging hallmark of Xp11.2 translocation renal cell carcinoma. PMID- 26609338 TI - Predictors of completed childhood vaccination in Bolivia. AB - This project examines how access issues, ethnicity, and geographic region affect vaccination of children by two years of age in Bolivia. Bolivia's rich variation in culture and geography results in unequal healthcare utilization even for basic interventions such as childhood vaccination. This study utilizes secondary data from the 2008 Demographic and Health Survey for Bolivia to examine predictors of vaccination completion in children by two years of age. Using logistic regression methods, we control for health system variables (difficulty getting to a health center and type of health center as well as demographic and socio-economic covariates). The results indicated that children whose parents reported distance as a problem in obtaining health care were less likely to have completed all vaccinations. Ethnicity was not independently statistically significant, however, in a sub-analysis, people from the Quechua ethnic group were more likely to report 'distance as a problem in obtaining healthcare.' Surprisingly, living in a rural environment has a protective effect on completed vaccinations. However, geographic region did predict significant differences in the probability that children would be fully vaccinated; children in the region with the lowest vaccination completion coverage were 80% less likely to have completed vaccination compared to children in the best performing region, which may indicate unequal access and utilization of health services nationally. Further study of regional differences, urbanicity, and distance as a healthcare access problem will help refine implications for the Bolivian health system. PMID- 26609339 TI - Pil1 cytoplasmic rods contain bundles of crosslinked tubules. AB - Cytoskeletal polymers are organized into a wide variety of higher-order structures in cells. The yeast BAR domain protein Pil1 self-assembles into tubules in vitro, and forms linear polymers at cortical eisosomes in cells. In the fission yeast S. pombe, over-expressed Pil1 forms thick rods that detach from the plasma membrane. In this study, we used thin-section electron microscopy to determine the ultrastructure of these cytoplasmic Pil1 rods. We found that cytoplasmic rods contained crosslinked Pil1 tubules that displayed regular, hexagonal spacing. These bundles were stained by filipin, a sterol-binding fluorescent dye, suggesting that they contained lipids. Cytoplasmic Pil1 rods were present but less abundant in sle1Delta and fhn1Delta mutant cells. We also found that endogenous Pil1 formed thick rods under saturated growth conditions. Taken together, our findings suggest the presence of cellular mechanisms that assemble Pil1 tubules into higher-order structures. PMID- 26609340 TI - Wnt-/-beta-catenin pathway signaling in human hepatocellular carcinoma. AB - The molecular basis of the carcinogenesis of hepatocellular carcinoma (HCC) has not been adequately clarified, which negatively impacts the development of targeted therapy protocols for this overwhelming neoplasia. The aberrant activation of signaling in the HCC is primarily due to the deregulated expression of the components of the Wnt-/-beta-catenin. This leads to the activation of beta catenin/T-cell factor-dependent target genes that control cell proliferation, cell cycle, apoptosis, and cell motility. The deregulation of the Wnt pathway is an early event in hepatocarcinogenesis. An aggressive phenotype was associated with HCC, since this pathway is implicated in the proliferation, migration, and invasiveness of cancer cells, regarding the cell's own survival. The disruption of the signaling cascade Wnt-/-beta-catenin has shown anticancer properties in HCC's clinical evaluations of therapeutic molecules targeted for blocking the Wnt signaling pathway for the treatment of HCC, and it represents a promising perspective. The key to bringing this strategy in to clinical practice is to identify new molecules that would be effective only in tumor cells with aberrant signaling beta-catenin. PMID- 26609341 TI - Strategies to optimize the use of marginal donors in liver transplantation. AB - Liver transplantation is the treatment of choice for end stage liver disease, but availability of liver grafts is still the main limitation to its wider use. Extended criteria donors (ECD) are considered not ideal for several reasons but their use has dramatically grown in the last decades in order to augment the donor liver pool. Due to improvement in surgical and medical strategies, results using grafts from these donors have become acceptable in terms of survival and complications; nevertheless a big debate still exists regarding their selection, discharge criteria and allocation policies. Many studies analyzed the use of these grafts from many points of view producing different or contradictory results so that accepted guidelines do not exist and the use of these grafts is still related to non-standardized policies changing from center to center. The aim of this review is to analyze every step of the donation-transplantation process emphasizing all those strategies, both clinical and experimental, that can optimize results using ECD. PMID- 26609342 TI - Hepatocellular carcinoma: A comprehensive review. AB - Hepatocellular carcinoma (HCC) is rapidly becoming one of the most prevalent cancers worldwide. With a rising rate, it is a prominent source of mortality. Patients with advanced fibrosis, predominantly cirrhosis and hepatitis B are predisposed to developing HCC. Individuals with chronic hepatitis B and C infections are most commonly afflicted. Different therapeutic options, including liver resection, transplantation, systemic and local therapy, must be tailored to each patient. Liver transplantation offers leading results to achieve a cure. The Milan criteria is acknowledged as the model to classify the individuals that meet requirements to undergo transplantation. Mean survival remains suboptimal because of long waiting times and limited donor organ resources. Recent debates involve expansion of these criteria to create options for patients with HCC to increase overall survival. PMID- 26609343 TI - Challenges of liver cancer: Future emerging tools in imaging and urinary biomarkers. AB - Chronic liver disease has become a global health problem as a result of the increasing incidence of viral hepatitis, obesity and alcohol misuse. Over the past three decades, in the United Kingdom alone, deaths from chronic liver disease have increased both in men and in women. Currently, 2.5% of deaths worldwide are attributed to liver disease and projected figures suggest a doubling in hospitalisation and associated mortality by 2020. Chronic liver diseases vary for clinical manifestations and natural history, with some individuals having relatively indolent disease and others with a rapidly progressive course. About 30% of patients affected by hepatitis C has a progressive disease and develop cirrhosis over a 20 years period from the infection, usually 5-10 years after initial medical presentation. The aim of the current therapeutic strategies is preventing the progression from hepatitis to fibrosis and subsequently, cirrhosis. Hepatic steatosis is a risk factor for chronic liver disease and is affecting about the half of patients who abuse alcohol. Moreover non-alcoholic fatty liver disease is part of the metabolic syndrome, associated with obesity, hypertension, type II diabetes mellitus and dyslipidaemia, and a subgroup of patients develops non-alcoholic steatohepatitis and fibrosis with subsequent cirrhosis. The strengths and pitfalls of liver biopsy are discussed and a variety of new techniques to assess liver damage from transient elastography to experimental techniques, such as in vitro urinary nuclear magnetic resonance spectroscopy. Some of the techniques and tests described are already suitable for more widespread clinical application, as is the case with ultrasound-based liver diagnostics, but others, such as urinary metabonomics, requires a period of critical evaluation or development to take them from the research arena to clinical practice. PMID- 26609344 TI - Hepatitis C virus: A global view. AB - Hepatitis C virus (HCV) is a global challenge; 130-175 million are chronically infected. Over 350000 die each year from HCV. Chronic HCV is the primary cause of cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver disease. Management of chronic HCV is aimed at preventing cirrhosis, reducing the risk of HCC, and treating extra hepatic complications. New treatments for chronic HCV has been devoted based on direct-acting antivirals, as pegylated interferon (peginterferon) is responsible for many side effects and limits treatment access. Sofosbuvir is the first compound to enter the market with Peginterferon-free combination regimens. PMID- 26609345 TI - Factors associated with the response to interferon-based antiviral therapies for chronic hepatitis C. AB - Hepatitis C virus (HCV) infection is a major health concern worldwide. Interferon alpha (IFN-alpha) therapy has been the main antiviral treatment for more than 20 years. Because of its established antitumor effects, IFN-based treatments for chronic HCV infection still have a clinical impact, particularly for patients with high risk conditions of developing hepatocellular carcinoma, such as older age and advanced liver fibrosis. As a result of exhaustive research, several viral factors, including NS5A amino acid mutations such as the IFN sensitivity determining region and the IFN/ribavirin resistance-determining region, and mutations of amino acids in the core protein region (core 70 and 91) were shown to be associated with the response to IFN-alpha treatment. In addition, among the host factors related to the response to IFN-alpha treatment, polymorphisms of the interleukin-28B gene were identified to be the most important factor. In this article, we review the factors associated with the efficacy of IFN-alpha treatment for chronic HCV infection. In addition, our recent findings regarding the possible involvement of anti-IFN-alpha neutralizing antibodies in a non response to pegylated-IFN-alpha treatment are also described. PMID- 26609346 TI - Importance of virological response in the early stage of telaprevir-based triple therapy for hepatitis C. AB - AIM: To investigate the efficacy of virological response (VR) to telaprevir (TVR) based triple therapy in predicting treatment outcome of hepatitis C. METHODS: This prospective, multicenter study consisted of 253 Japanese patients infected with hepatitis C virus (HCV) genotype 1b. All received 12 wk of TVR in combination with 24 wk of pegylated-interferon-alpha (IFN-alpha) and ribavirin. Serum HCV RNA was tested at weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24. VR was defined as undetectable serum HCV RNA. Sustained virological response (SVR) was VR at 24 wk after the end of treatment and was regarded as a successful outcome. RESULTS: Of 253 patients, 207 (81.8%) achieved SVR. The positive predictive value of VR for SVR was 100% at week 2, after which it gradually decreased, and was over 85% to week 12. The negative predictive value (NPV) gradually increased, reaching 100% at week 12. The upslope of the NPV showed a large increase from week 4 (40.6%) to week 6 (82.4%). There was a moderate concordance between the SVR and VR at week 6 (kappa coefficient = 0.44), although other VRs had poor concordance to SVR. Multiple logistic regression analysis extracted VR at week 6 (P < 0.0001, OR = 63.8) as an independent factor contributing to SVR. In addition, the interleukin-28B single nucleotide polymorphism and response to previous pegylated-IFN-alpha and ribavirin therapy were identified as independent factors for SVR. CONCLUSION: VR at week 6, but not at week 4, is an efficient predictor of both SVR and non-SVR to TVR-based triple therapy. PMID- 26609347 TI - Pseudolymphoma (reactive lymphoid hyperplasia) of the liver: A clinical challenge. AB - Reactive lymphoid hyperplasia (RLH), also known as pseudolymphoma or nodular lymphoid lesion of the liver is an extremely rare condition, and only 51 hepatic RLH cases have been described in the literature since the first case was described in 1981. The majority of these cases were asymptomatic and incidentally found through radiological imaging. The precise etiology of hepatic RLH is still unknown, but relative high prevalence of autoimmune disorder in these cases suggests an immune-based liver disorder. Imaging features of hepatic RLH often suggest malignant lesions such as hepatocellular carcinoma and cholangiocarcinoma. In this report, we discuss two cases of hepatic RLH in patients with autoimmune hepatitis. We also present pathologic and magnetic resonance imaging findings, including one case utilizing a hepatocellular contrast agent, Eovist. Definitive diagnosis of hepatic RLH often requires surgical excision. PMID- 26609349 TI - Mean Polyp per Patient Is an Accurate and Readily Obtainable Surrogate for Adenoma Detection Rate: Results from an Opportunistic Screening Colonoscopy Program. AB - BACKGROUND The incidence of colorectal cancer is rising in several developing countries. In the absence of integrated endoscopy and pathology databases, adenoma detection rate (ADR), as a validated quality indicator of screening colonoscopy, is generally difficult to obtain in practice. We aimed to measure the correlation of polyp-related indicators with ADR in order to identify the most accurate surrogate(s) of ADR in routine practice. METHODS We retrospectively reviewed the endoscopic and histopathological findings of patients who underwent colonoscopy at a tertiary gastrointestinal clinic. The overall ADR and advanced ADR were calculated using patient-level data. The Pearson's correlation coefficient (r) was applied to measure the strength of the correlation between the quality metrics obtained by endoscopists. RESULTS A total of 713 asymptomatic adults aged 50 and older who underwent their first-time screening colonoscopy were included in this study. The ADR and advanced-ADR were 33.00% (95% CI: 29.52 36.54) and 13.18% (95% CI: 10.79-15.90), respectively. We observed good correlations between polyp detection rate (PDR) and ADR (r=0.93), and mean number of polyp per patient (MPP) and ADR (r=0.88) throughout the colon. There was a positive, yet insignificant correlation between advanced ADRs and non-advanced ADRs (r=0.42, p=0.35). CONCLUSION MPP is strongly correlated with ADR, and can be considered as a reliable and readily obtainable proxy for ADR in opportunistic screening colonoscopy programs. PMID- 26609350 TI - Expression of Cyclin D1 and P16 in Esophageal Squamous Cell Carcinoma. AB - BACKGROUND Esophageal squamous cell carcinoma (ESCC) is one of the lethal cancers with a high incidence rate in Asia. Many genes including cyclin D1 and p16 play important role in its carcinogenesis. We aimed to analyze the expressions of cyclin D1 and p16 with the various clinicopathological characteristics of ESCC. METHODS We examined 30 biopsy samples of ESCC for cyclin D1 and p16 protein expressions using immunohistochemistry. Immunointensity was classified as no immunostaining (-), weakly immunostaining (+), weak immunostaining (++) and strongly positive immunostaining (+++). RESULTS Out of the 30 cases, positive expression of cyclin D1 was detected in 26 cases (86.7%). The percentage of tumors with invasion to the adventitia (88.2%), lymph node metastasis (87.5%), and tumors which were poorly differentiated (92.9%) were higher in cyclin D1 positive tumors than in the cyclin D1 negative tumors. However no significant association was found between cyclin D1 expression and the different clinicopathological parameters.There were 22 cases of ESCC (73.3 %) which showed negativity for p16. The percentage of tumors with invasion to the adventitia (82.4%) and poorly differentiated tumors (92.9%) were higher in the p16 negative tumors than in the p16 positive tumors. There was significant association between the histological grade and p16 expression (p=0.012). However, there were no significant association with regard to site, size and lymph node status of the tumors and p16 expression. CONCLUSION The study shows that alterations of cyclin D1 and p16 play an important role in ESCC. Loss of p16 expression was associated with poor differentiation. PMID- 26609348 TI - Burden of Gastrointestinal and Liver Diseases in Middle East and North Africa: Results of Global Burden of Diseases Study from 1990 to 2010. AB - BACKGROUND Gastrointestinal and liver diseases (GILDs) are major causes of death and disability in Middle East and North Africa (MENA). However, they have different patterns in countries with various geographical, cultural, and socio economic status. We aimed to compare the burden of GILDs in Iran with its neighboring countries using the results of the Global Burden of Disease (GBD) Study in 2010. METHODS Classic metrics of GBD have been used including: age standardized rates (ASRs) of death, years of life lost due to premature death (YLL), years of life lost due to disability (YLD), and disability adjusted life years (DALY). All countries neighboring Iran have been selected. In addition, all other countries classified in the MENA region were included. Five major groups of gastrointestinal and hepatic diseases were studied including: infections of gastrointestinal tract, gastrointestinal and pancreatobilliary cancers, acute hepatitis, cirrhosis, and other digestive diseases. RESULTS The overall burden of GILDs is highest in Afghanistan, Pakistan, and Egypt. Diarrheal diseases have been replaced by gastrointestinal cancers and cirrhosis in most countries in the region. However, in a number of countries including Afghanistan, Pakistan, Turkmenistan, Egypt, and Yemen, communicable GILDs are still among top causes of mortality and morbidity in addition to non-communicable GILDs and cancers. These countries are experiencing the double burden. In Iran, burden caused by cancers of stomach and esophagus are considerably higher than other countries. Diseases that are mainly diagnosed in outpatient settings have not been captured by GBD. CONCLUSION Improving the infrastructure of health care system including cancer registries and electronic recording of outpatient care is a necessity for better surveillance of GILDs in MENA. In contrast to expensive treatment, prevention of most GILDs is feasible and inexpensive. The health care systems in the region can be strengthened for prevention and control. PMID- 26609351 TI - The Early Results of a New Health Care Program Implementation in HBV Screening: an Iranian Experience. AB - BACKGROUND According to the reports of World Health Organization (WHO) and Centers for Disease Control and Prevention, the prevalence of chronic hepatitis B infection in Iran has decreased from 2-7% in 2001 to 1.3-0.8% in children aged 2 14 years. In 2010 the Institute of Medicine recommended more comprehensive screening by primary care physicians (PCPs) for evaluation, vaccination, and management of infected patients for further decrease in the prevalence of chronic HBV infection. Thus, with contribution of the Health Department, we developed a practical flowchart for PCPs to start active screening of hepatitis B virus (HBV) in all visited patients and refer the positive cases for further evaluation and management to Taleghani Hospital. METHODS With collaboration of Health Department of Shahid Beheshti University of Medical Sciences), physicians of health centers were asked to screen all their patients for HBsAg. Positive cases were referred to Taleghani Hospital. They were first registered and educated about their disease, life style, and prevention methods. Their first degree families were screened for HBV infection too and were referred for vaccination if needed. According to the results of lab tests, appropriate management was done by a hepatologist. RESULTS Since implementation of this program, we have encountered a significant rise in patient detection (even in high risk groups). Many of them were not aware of their disease and most of those who were aware of their disease were not managed appropriately. Family screening and vaccination were inadequate and need more emphasis. CONCLUSION Although health system is active about screening of HBV infection in high risk populations, it is not perfect. It seems that health system needs to upgrade the screening and management programs of HBV infection. PMID- 26609352 TI - Significance of Response to Hepatitis B Recombinant Vaccine in Subjects with Isolated Antibody to Hepatitis B Core Antigen. AB - BACKGROUND It is important to differentiate whether isolated anti-HBc is due to false positive results or the prior exposure to hepatitis B virus, because individuals with false-positive anti-HBc can benefit from vaccination and their blood can be safely transfused. To distinguish between these two conditions, we evaluated the serologic response to hepatitis B vaccine. METHODS Ninety subjects with isolated anti-HBc (cases) and 100 subjects with totally negative hepatitis B serologic markers (controls) were recruited to receive three doses of hepatitis-B (HB) vaccine. Thirty days after the first dose of the vaccine, anti-HBs titers were checked and individuals with anti-HBs titer >50 mIU/mL did not receive additional doses of the vaccine. However, others completed the vaccination course, and another blood sample was collected 30 days after the third dose to measure anti-HBs level. RESULTS Nineteen (21.1%) cases and three (3%) controls had no sero-conversion (anti-HBs titers <10 mIU/mL) 30 days after the third dose (p<0.0001). Primary response, defined as the development of anti-HBs antibody titers >=10 mIU/mL 30 days after the third dose, was observed in 43 (47.8%) cases and 92 (92%) controls (p<0.0001). Also, 31.1% of cases developed anti-HBs titers >= 50 mIU/mL 30 days after the first dose of vaccine, but the rate was significantly lower (5%) in the control group (p<0.0001). Furthermore, half of the individuals with positive isolated anti-HBc developed protective levels of anti-HBs after three doses of HB vaccination. CONCLUSION More than 75% of individuals with positive isolated anti-HBc can benefit from vaccination and can be included in donor pool. Also, one fifth seemed to have occult HBV infection. So HB vaccination may be used as a diagnostic tool for clarifying the situation of the subjects with isolated anti-HBc. PMID- 26609353 TI - Prevalence of Helicobacter Pylori-Negative, Non-Steroidal Anti-Inflammatory Drug Related Peptic Ulcer Disease in Patients Referred to Afzalipour Hospital. AB - BACKGROUND Although Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs) are the main causes of peptic ulcers disease (PUD), recently the prevalence of idiopathic peptic ulcer (IPU) is increasing in most parts of the world. The aim of this study was to assess the prevalence of IPU in Kerman, the center of largest province in south-east Iran. METHODS We included 215 patients with peptic ulcer in our study. Combined methods rapid urease test (RUT), histology, and real time polymerase chain reaction (PCR) was performed on endoscopic samples of peptic ulcers. NSAID use was determined by medical history. SPSS software version 16 was used for data analysis. p value<0.05 was considered as statistically significant. RESULTS Of 215 consecutive patients with peptic ulcer, four (1.8%) had H.pylorinegative and NSAID-negative PUD. There were not significant differences between patients with IPU and patients with peptic ulcer associated with H.pylori or NSAIDs regarding the sex, age, cigarette smoking, and opioid abuse. CONCLUSION Our study showed that in contrast to other reports from western and some Asian countries, the prevalence of IPU is low in Kerman and H.pylori infection is still the major cause of PUD. We recommend a large and multi-central study to determine the prevalence of IPU in Iran. PMID- 26609354 TI - Determination of Vitamin D Serum Levels and Status of the C3435T Polymorphism of Multidrug Resistance 1 Gene in Southeastern Iranian Patients with Ulcerative Colitis. AB - BACKGROUND Ulcerative colitis (UC) is a multi-factorial autoimmune disease. P glycoprotein is encoded by the multidrug resistance 1 (MDR1) gene. The C3435T polymorphism in the MDR1 gene is correlated with low P-glycoprotein expression. Additionally, vitamin D has regulatory effects on the immune system. The aim of our study was to determine the association between the C3435T MDR1 polymorphism and UC and to detect the vitamin D serum levels in patients with UC. METHODS One hundred healthy controls and 85 patients with UC were evaluated. Polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP) was used to detect the C3435T MDR1 polymorphisms. Serum levels of vitamin D were measured by Enzyme linked immunosorbent assay (ELISA). The research was performed in Kerman, Iran, from 2011 to 2013. RESULTS We could not find any association between the C3435T MDR1 polymorphism and susceptibility to UC. There was a significant decrease in serum levels of vitamin D in patients with UC compared with healthy controls (p<0.001). CONCLUSION Controversies regarding the association between the C3435T MDR1 polymorphism with UC have been reported in different populations. The difference between our results and others may be attributed to the heterogeneity of the Iranian population and the sample size. Additionally, our data indicated that UC might be correlated with vitamin D insufficiency. Therefore, the administration of vitamin D might be suggested as a valuable treatment for patients with UC. PMID- 26609355 TI - Large Bowel Obstruction after Colonoscopy; A Case Report. AB - Postpolypectomy bleeding and perforation are the major complications of colonoscopy. This report presents a rare case of colon obstruction immediately after colonoscopy. A 56-year-old man underwent colonoscopy because of 6 months lower abdominal pain. Colonoscopy revealed diverticulosis and multiple small sessile polyps in sigmoid colon. Biopsy samples were taken from the polyps and the procedure was continued up to cecum. Soon after the procedure, the patient complained of colicky abdominal pain accompanied by diaphoresis. In physical examination, the abdomen seemed distended and bowel sounds were high-pitched. There was no abdominal tenderness or guarding. Plain and upright abdominal radiography showed multiple colonic air-fluid levels. Immediately, the patient underwent second colonoscopy, but passage of scope through sigmoid colon (at the site of biopsies) was somewhat hard because of edema and spasm. The colonoscope proceeded gently up to cecum and decompressed the entire colon by suctioning the air that was entrapped in proximal parts. By second colonoscopy and further conservative treatments, the patient's condition improved without any surgical procedure and was discharged after 24 hours. PMID- 26609356 TI - Simultaneous Esophageal Squamous Cell Carcinoma and Adenocarcinoma: A Case Report. AB - Esophageal squamous cell carcinoma is a rather common cancer in northern Iran. Incidence of adenocarcinoma of esophagus has an increasing trend in Iran. Co existence of both cancers in one patient is very rare. We report a middle age woman from northern Iran with a typical presentation of esophageal cancer, who was found to have a dual esophageal cancer. The disease was found in the advanced stage with pulmonary metastasis at the presentation. Palliative chemo radiotherapy induced partial clinical response. PMID- 26609357 TI - Allele and Genotype Frequency of IL28B (rs12979860) in South Iranian population. PMID- 26609358 TI - Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation. AB - BACKGROUND: Exposure to a moderate to high dose of ionizing radiation (IR) not only causes acute radiation syndrome but also induces long-term (LT) bone marrow (BM) injury. The latter effect of IR is primarily attributed to the induction of hematopoietic stem cell (HSC) senescence. Granulocyte colony-stimulating factor (G-CSF) is the only treatment recommended to be given to radiation victims soon after IR. However, clinical studies have shown that G-CSF used to treat the leukopenia induced by radiotherapy or chemotherapy in patients can cause sustained low white blood cell counts in peripheral blood. It has been suggested that this adverse effect is caused by HSC and hematopoietic progenitor cell (HPC) proliferation and differentiation stimulated by G-CSF, which impairs HSC self renewal and may exhaust the BM capacity to exacerbate IR-induced LT-BM injury. METHODS: C57BL/6 mice were exposed to 4 Gy gamma-rays of total body irradiation (TBI) at a dose-rate of 1.08 Gy per minute, and the mice were treated with G-CSF (1 MUg/each by ip) or vehicle at 2 and 6 h after TBI on the first day and then twice every day for 6 days. All mice were killed one month after TBI for analysis of peripheral blood cell counts, bone marrow cellularity and long-term HSC (CD34 lineage-sca1+c-kit+) frequency. The colony-forming unit-granulocyte and macrophage (CFU-GM) ability of HPC was measured by colony-forming cell (CFC) assay, and the HSC self-renewal capacity was analyzed by BM transplantation. The levels of ROS production, the expression of phospho-p38 mitogen-activated protein kinase (p-p38) and p16(INK4a) (p16) mRNA in HSCs were measured by flow cytometry and RT-PCR, respectively. RESULTS: The results of our studies show that G-CSF administration mitigated TBI-induced decreases in WBC and the suppression of HPC function (CFU-GM) (p < 0.05), whereas G-CSF exacerbated the suppression of long term HSC engraftment after transplantation one month after TBI (p < 0.05); The increase in HSC damage was associated with increased ROS production, activation of p38 mitogen-activated protein kinase (p38), induction of senescence in HSCs. CONCLUSION: Our findings suggest that although G-CSF administration can reduce ARS, it can also exacerbate TBI-induced LT-BM injury in part by promoting HSC senescence via the ROS-p38-p16 pathway. PMID- 26609359 TI - Family history intake: a challenge to personalized approaches in health promotion and disease prevention. AB - BACKGROUND: Family history is considered an essential, obligatory part of the primary physician's intake interview. Including coded FH in a unified medical file can save expensive genetic tests and detect the early onset of diseases in young people who are not recommended to be screened routinely. The objectives of this study are to explore the frequency and point in time of recording the coded family history (FH) as a first step to increasing awareness of the importance of such information. METHODS: All ICD-9 coded diagnoses of familial histories of disease (ICD-9 coded V16.0 - V19.8), including diseases related to gender, age, and indications of chronic diseases, were collected from the electronic medical records of patients ages 18 and above in Israel's Maccabi Health Care system. The study was carried out in 2012 on the basis of coded data for 1.9 million Maccabi members, which were collected from 2004 through 2011. RESULTS: Of the Maccabi members (the second biggest HMO in Israel covering 2 million people), only 10 % had FH coded documentation. FH was significantly more frequent for females than for males (13.5 % vise 10.1 %) and increased with age. About 10 % of the FH documentation occurred before any disease was diagnosed. The most frequent FH documentation was observed for cardiovascular disease, hypertension, and diabetes. In the case of cancer FH was more frequent in females, whereas in the case of males it was cardiovascular disease. DISCUSSION: Family history is an easy tool and need to be coded and implimented in most visits in order to get the best information of the potential health and disease of the patients. CONCLUSIONS: FH frequency is very low and varies with gender and age. The literature suggests that implementing it routinely in primary care will improve health care. Further research is needed to identify the factors that impede primary care givers from complying with FH guidelines. PMID- 26594326 TI - Personal attributes of authors and reviewers, social bias and the outcomes of peer review: a case study. AB - Peer review is the "gold standard" for evaluating journal and conference papers, research proposals, on-going projects and university departments. However, it is widely believed that current systems are expensive, conservative and prone to various forms of bias. One form of bias identified in the literature is "social bias" linked to the personal attributes of authors and reviewers. To quantify the importance of this form of bias in modern peer review, we analyze three datasets providing information on the attributes of authors and reviewers and review outcomes: one from Frontiers - an open access publishing house with a novel interactive review process, and two from Spanish and international computer science conferences, which use traditional peer review. We use a random intercept model in which review outcome is the dependent variable, author and reviewer attributes are the independent variables and bias is defined by the interaction between author and reviewer attributes. We find no evidence of bias in terms of gender, or the language or prestige of author and reviewer institutions in any of the three datasets, but some weak evidence of regional bias in all three. Reviewer gender and the language and prestige of reviewer institutions appear to have little effect on review outcomes, but author gender, and the characteristics of author institutions have moderate to large effects. The methodology used cannot determine whether these are due to objective differences in scientific merit or entrenched biases shared by all reviewers. PMID- 26594334 TI - An unexpected effect of TNF-alpha on F508del-CFTR maturation and function. AB - Cystic fibrosis (CF) is a multifactorial disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene ( CFTR), which encodes a cAMP-dependent Cl (-) channel. The most frequent mutation, F508del, leads to the synthesis of a prematurely degraded, otherwise partially functional protein. CFTR is expressed in many epithelia, with major consequences in the airways of patients with CF, characterized by both fluid transport abnormalities and persistent inflammatory responses. The relationship between the acute phase of inflammation and the expression of wild type (WT) CFTR or F508del-CFTR is poorly understood. The aim of the present study was to investigate this effect. The results show that 10 min exposure to TNF-alpha (0.5-50ng/ml) of F508del-CFTR transfected HeLa cells and human bronchial cells expressing F508del-CFTR in primary culture (HBE) leads to the maturation of F508del-CFTR and induces CFTR chloride currents. The enhanced CFTR expression and function upon TNFalpha is sustained, in HBE cells, for at least 24 h. The underlying mechanism of action involves a protein kinase C (PKC) signaling pathway, and occurs through insertion of vesicles containing F508del-CFTR to the plasma membrane, with TNFalpha behaving as a corrector molecule. In conclusion, a novel and unexpected action of TNFalpha has been discovered and points to the importance of systematic studies on the roles of inflammatory mediators in the maturation of abnormally folded proteins in general and in the context of CF in particular. PMID- 26594345 TI - Hippocampal development and the dissociation of cognitive-spatial mapping from motor performance. AB - The publication of a recent article in F1000Research has led to discussion of, and correspondence on a broader issue that has a long history in the fields of neuroscience and psychology. Namely, is it possible to separate the cognitive components of performance, in this case spatial behavior, from the motoric demands of a task? Early psychological experiments attempted such a dissociation by studying a form of spatial maze learning where initially rats were allowed to explore a complex maze, termed "latent learning," before reinforcement was introduced. Those rats afforded the latent learning experience solved the task faster than those that were not, implying that cognitive map learning during exploration aided in the performance of the task once a motivational component was introduced. This form of latent learning was interpreted as successfully demonstrating that an exploratory cognitive map component was acquired irrespective of performing a learned spatial response under deprivation/motivational conditions. The neural substrate for cognitive learning was hypothesized to depend on place cells within the hippocampus. Subsequent behavioral studies attempted to directly eliminate the motor component of spatial learning by allowing rats to passively view the distal environment before performing any motor response using a task that is widely considered to be hippocampal-dependent. Latent learning in the water maze, using a passive placement procedure has met with mixed results. One constraint on viewing cues before performing a learned swimming response to a hidden goal has been the act of dynamically viewing distal cues while moving through a part of the environment where an optimal learned spatial escape response would be observed. We briefly review these past findings obtained with adult animals to the recent efforts of establishing a "behavioral topology" separating cognitive-spatial learning from tasks differing in motoric demands in an attempt to define when cognitive-spatial behavior emerges during development. PMID- 26609363 TI - Wealth status and sex differential of household head: implication for source of drinking water in Nigeria. AB - BACKGROUND: Source of potable water has implication on the population health. Availability of Improved Drinking Water Sources (IDWS) is a problem in developing countries, but variation exists across segments of the population. This study therefore examined the relationship between wealth status, sex of household head and source of potable water. METHODS: The 2013 Nigeria Demographic and Health Survey data was used. A representative sample of 40,680 households was selected for the survey, with a minimum target of 943 completed interviews per state covering the entire population residing in non-institutional dwelling units in the country. Households where information on drinking water sources was not reported were excluded, thus reducing the sample to 38021. The dependent and key independent variables were IDWS and Wealth Index respectively. Data were analysed using Chi-square and binary logistic regression (alpha = .05). RESULTS: Households that used IDWS were headed by females (66.7 %) than males (58.7 %). Highest proportion of households who used IDWS was found in the rich wealth index group (76.7 %). The likelihood of using IDWS was higher in household headed by females (OR = 1.41; C.I = 1.33-1.49, p <0.001). Households that belong to rich wealth index and middle class were 5.06(C.I = 4.81-5.32, p <0.001) and 2.62(C.I = 2.46-2.78, p <0.001) respectively times more likely to IDWS than the poor. This pattern was sustained when other confounding variables were introduced into the regression equation as control. CONCLUSIONS: Households headed by women used improved drinking water sources than those headed by men. However, wealth index has strong influence on the strength of relationship between sex of household head and improved drinking water sources. PMID- 26609364 TI - Proportion of night eating syndrome in Arab population of Oman. AB - OBJECTIVE: Globally obesity has reached epidemic proportions with alarming rates in the Arabian Gulf countries. The impact of behavioral eating habits and in particular night eating syndrome (NES) have not been emphasized in the region. This study assessed the proportion of NES in an Omani Arab adult population sample. METHOD: A night eating syndrome questionnaire (NEQ) was distributed to Omani adults above the age of 20. RESULTS: Out of the 454 respondents, 26.4 % endorsed evening hyperphagia while nocturnal ingestion was present in 4.7 % of the respondents. In addition, 1.5 % of the respondents met the NES criteria. CONCLUSIONS AND IMPLICATIONS: The proportion of NES in Omani adult population is similar to the reported rates in general world populations. In conclusion, night eating syndrome is present in the Omani Arab adults and should be taken into account in national management for increased obesity trends in the region. PMID- 26609365 TI - An unusual presentation of X-linked adrenoleukodystrophy. AB - X-linked adrenoleukodystrophy (X-ALD) is a rare genetic condition caused by mutations in the ABCD1 gene that result in accumulation of very long chain fatty acids (VLCFAs) in various tissues. This leads to demyelination in the CNS and impaired steroidogenesis in the adrenal cortex and testes. A 57-year-old gentleman was referred for the assessment of bilateral gynaecomastia of 6 months duration. He had skin hyperpigmentation since 4 years of age and spastic paraparesis for the past 15 years. Physical examination findings included generalised hyperpigmentation (including skin, buccal mucosa and palmar creases), blood pressure of 90/60 mmHg, non-tender gynaecomastia and bilateral hypoplastic testes. Lower limb findings were those of a profoundly ataxic gait associated with significant paraparesis and sensory loss. Primary adrenal insufficiency was confirmed and investigations for gynaecomastia revealed normal testosterone with mildly elevated luteinising hormone level and normal prolactin. The combination of primary adrenal insufficiency (likely childhood onset), partial testicular failure (leading to gynaecomastia) and spastic paraparesis suggested X-ALD as a unifying diagnosis. A serum VLCFA panel was consistent with X-ALD. Subsequent genetic testing confirmed the diagnosis. Treatment with replacement doses of corticosteroid resulted in improvement in blood pressure and increased energy levels. We have reported the case of a 57-year-old man with a very late diagnosis of X-ALD manifested by childhood onset of primary adrenal insufficiency followed by paraparesis and primary hypogonadism in adulthood. Thus, X-ALD should be considered as a possibility in a patient with non-autoimmune primary adrenal insufficiency and neurological abnormalities. LEARNING POINTS: Adult patients with X-ALD may be misdiagnosed as having multiple sclerosis or idiopathic spastic paraparesis for many years before the correct diagnosis is identified.Screening for X-ALD with a VLCFA panel should be strongly considered in male children with primary adrenal insufficiency and in male adults presenting with non-autoimmune primary adrenal insufficiency.Confirmation of a genetic diagnosis of X-ALD can be very useful for a patient's family as genetic testing enables detection of pre symptomatic female heterozygotes who can then be offered pre-natal testing to avoid transmission of the disease to male offsprings. PMID- 26609366 TI - Editorial: "We are now more and more interested in 'wellness', with technologies developed to promote wellness, change behaviour, and influence future wellbeing". PMID- 26609367 TI - When change happens: computer assistance and image guidance for minimally invasive therapy. AB - Computer-assisted interventions are medical procedures that rely on image guidance and computer-based systems to provide visualisation and navigation information to the clinician, when direct vision of the sites or targets to be treated is not available, during minimally invasive procedures. Recent advances in medical image acquisition and processing, accompanied by technological breakthroughs in image fusion, visualisation and display have accelerated the adoption of minimally invasive approaches for a variety of medical procedures. This Letter is intended to serve as a brief overview of available image guidance and computer-assisted technology in the context of popular minimally invasive applications, while outlining some of the limitations and challenges in the transition from laboratory to clinical care. PMID- 26609368 TI - Compressive sampling for time critical microwave imaging applications. AB - Across all biomedical imaging applications, there is a growing emphasis placed on reducing data acquisition and imaging times. This research explores the use of a technique, known as compressive sampling or compressed sensing (CS), as an efficient technique to minimise the data acquisition time for time critical microwave imaging (MWI) applications. Where a signal exhibits sparsity in the time domain, the proposed CS implementation allows for sub-sampling acquisition in the frequency domain and consequently shorter imaging times, albeit at the expense of a slight degradation in reconstruction quality of the signals as the compression increases. This Letter focuses on ultra wideband (UWB) radar MWI applications where reducing acquisition is of critical importance therefore a slight degradation in reconstruction quality may be acceptable. The analysis demonstrates the effectiveness and suitability of CS with UWB applications. PMID- 26609369 TI - Towards personalised management of atherosclerosis via computational models in vascular clinics: technology based on patient-specific simulation approach. AB - The development of a new technology based on patient-specific modelling for personalised healthcare in the case of atherosclerosis is presented. Atherosclerosis is the main cause of death in the world and it has become a burden on clinical services as it manifests itself in many diverse forms, such as coronary artery disease, cerebrovascular disease/stroke and peripheral arterial disease. It is also a multifactorial, chronic and systemic process that lasts for a lifetime, putting enormous financial and clinical pressure on national health systems. In this Letter, the postulate is that the development of new technologies for healthcare using computer simulations can, in the future, be developed as in-silico management and support systems. These new technologies will be based on predictive models (including the integration of observations, theories and predictions across a range of temporal and spatial scales, scientific disciplines, key risk factors and anatomical sub-systems) combined with digital patient data and visualisation tools. Although the problem is extremely complex, a simulation workflow and an exemplar application of this type of technology for clinical use is presented, which is currently being developed by a multidisciplinary team following the requirements and constraints of the Vascular Service Unit at the University College Hospital, London. PMID- 26609370 TI - Towards enhancing the performance of multi-parameter patient monitors. AB - Multi-parameter patient monitors (MPMs) have become increasingly important in providing quality healthcare to patients. It is well known in the medical community that there exists an intrinsic relationship between different vital parameters in a healthy person, these include heart rate, blood pressure, respiration rate and oxygen saturation. For example, an increase in blood pressure would lead to a decrease in the heart rate, and vice versa. Although it is likely to improve the performance of MPM systems, this fact is not explored in engineering research. In this work, experiments show that deriving additional features to capture the intrinsic relationship between the vital parameters, the alarm accuracy (sensitivity), no-alarm accuracy (specificity) and the overall performance of MPMs can be improved. The geometric mean of the product of all the vital parameters taken in pairs of two was used to capture the intrinsic relationship between the different parameters. An improvement of 10.55% for sensitivity, 0.32% for specificity and an overall performance improvement of 1.03% was obtained, compared to the baseline system using classification and regression tree with the four vital parameters. PMID- 26609371 TI - Multi-coil approach to reduce electromagnetic energy absorption for wirelessly powered implants. AB - Near-field inductive coupling is a commonly used technique for wireless power transfer (WPT) in biomedical implants. Owing to the close proximity of the implant coil(s) with the tissue ( ~1 mm) and high current ( ~100-300 mA) in the magnetic coil(s), a significant induced electric field can be generated for the operating frequency (1-20 MHz). In this Letter, a multi-coil-based WPT technique is proposed to selectively control the currents in the external and implant coils to reduce the specific absorption rate (SAR). A three-coil WPT system, that can achieve 26% reduction in peak 1-g SAR and 15% reduction in peak 10-g SAR, as compared to a two-coil WPT system with the same dimensions, is implemented and used to demonstrate the effectiveness of the proposed approach. To achieve the seamless design for the external and implant electronics, the multi-coil system achieves the same voltage gain and bandwidth as the two-coil design with 46% improvement in the power transfer efficiency. PMID- 26609372 TI - DCT domain feature extraction scheme based on motor unit action potential of EMG signal for neuromuscular disease classification. AB - A feature extraction scheme based on discrete cosine transform (DCT) of electromyography (EMG) signals is proposed for the classification of normal event and a neuromuscular disease, namely the amyotrophic lateral sclerosis. Instead of employing DCT directly on EMG data, it is employed on the motor unit action potentials (MUAPs) extracted from the EMG signal via a template matching-based decomposition technique. Unlike conventional MUAP-based methods, only one MUAP with maximum dynamic range is selected for DCT-based feature extraction. Magnitude and frequency values of a few high-energy DCT coefficients corresponding to the selected MUAP are used as the desired feature which not only reduces computational burden, but also offers better feature quality with high within-class compactness and between-class separation. For the purpose of classification, the K-nearest neighbourhood classifier is employed. Extensive analysis is performed on clinical EMG database and it is found that the proposed method provides a very satisfactory performance in terms of specificity, sensitivity and overall classification accuracy. PMID- 26609373 TI - New approach for automatic classification of Alzheimer's disease, mild cognitive impairment and healthy brain magnetic resonance images. AB - Explored is the utility of modelling brain magnetic resonance images as a fractal object for the classification of healthy brain images against those with Alzheimer's disease (AD) or mild cognitive impairment (MCI). More precisely, fractal multi-scale analysis is used to build feature vectors from the derived Hurst's exponents. These are then classified by support vector machines (SVMs). Three experiments were conducted: in the first the SVM was trained to classify AD against healthy images. In the second experiment, the SVM was trained to classify AD against MCI and, in the third experiment, a multiclass SVM was trained to classify all three types of images. The experimental results, using the 10-fold cross-validation technique, indicate that the SVM achieved 97.08% +/- 0.05 correct classification rate, 98.09% +/- 0.04 sensitivity and 96.07% +/- 0.07 specificity for the classification of healthy against MCI images, thus outperforming recent works found in the literature. For the classification of MCI against AD, the SVM achieved 97.5% +/- 0.04 correct classification rate, 100% sensitivity and 94.93% +/- 0.08 specificity. The third experiment also showed that the multiclass SVM provided highly accurate classification results. The processing time for a given image was 25 s. These findings suggest that this approach is efficient and may be promising for clinical applications. PMID- 26609374 TI - Ultra-low-power wireless transmitter for neural prostheses with modified pulse position modulation. AB - An ultra-low-power wireless transmitter for embedded bionic systems is proposed, which achieves 40 pJ/b energy efficiency and delivers 500 kb/s data using the medical implant communication service frequency band (402-405 MHz). It consumes a measured peak power of 200 uW from a 1.2 V supply while occupying an active area of 0.0016 mm(2) in a 130 nm technology. A modified pulse position modulation technique called saturated amplified signal is proposed and implemented, which can reduce the overall and per bit transferred power consumption of the transmitter while reducing the complexity of the transmitter architectures, and hence potentially shrinking the size of the implemented circuitry. The design is capable of being fully integrated on single-chip solutions for surgically implanted bionic systems, wearable devices and neural embedded systems. PMID- 26609375 TI - Straightforward and robust QRS detection algorithm for wearable cardiac monitor. AB - This Letter presents a fairly straightforward and robust QRS detector for wearable cardiac monitoring applications. The first stage of the QRS detector contains a powerful l1-sparsity filter with overcomplete hybrid dictionaries for emphasising the QRS complexes and suppressing the baseline drifts, powerline interference and large P/T waves. The second stage is a simple peak-finding logic based on the Gaussian derivative filter for automatically finding locations of R peaks in the ECG signal. Experiments on the standard MIT-BIH arrythmia database show that the method achieves an average sensitivity of 99.91% and positive predictivity of 99.92%. Unlike existing methods, the proposed method improves detection performance under small-QRS, wide-QRS complexes and noisy conditions without using the searchback algorithms. PMID- 26609376 TI - Temporal epilepsy seizures monitoring and prediction using cross-correlation and chaos theory. AB - Temporal seizures due to hippocampal origins are very common among epileptic patients. Presented is a novel seizure prediction approach employing correlation and chaos theories. The early identification of seizure signature allows for various preventive measures to be undertaken. Electro-encephalography signals are spectrally broken down into the following sub-bands: delta; theta; alpha; beta; and gamma. The proposed approach consists of observing a high correlation level between any pair of electrodes for the lower frequencies and a decrease in the Lyapunov index (chaos or entropy) for the higher frequencies. Power spectral density and statistical analysis tools were used to determine threshold levels for the lower frequencies. After studying all five sub-bands, the analysis has revealed that the seizure signature can be extracted from the delta band and the high frequencies. High frequencies are defined as both the gamma band and the ripples occurring within the 60-120 Hz sub-band. To validate the proposed approach, six patients from both sexes and various age groups with temporal epilepsies originating from the hippocampal area were studied using the Freiburg database. An average seizure prediction of 30 min, an anticipation accuracy of 72%, and a false-positive rate of 0% were accomplished throughout 200 h of recording time. PMID- 26609377 TI - RF communication with implantable wireless device: effects of beating heart on performance of miniature antenna. AB - The frequency response of an implantable antenna is key to the performance of a wireless implantable sensor. If the antenna detunes significantly, there are substantial power losses resulting in loss of accuracy. One reason for detuning is because of a change in the surrounding environment of an antenna. The pulsating anatomy of the human heart constitutes such a changing environment, so detuning is expected but this has not been quantified dynamically before. Four miniature implantable antennas are presented (two different geometries) along with which are placed within the heart of living swine the dynamic reflection coefficients. These antennas are designed to operate in the short range devices frequency band (863-870 MHz) and are compatible with a deeply implanted cardiovascular pressure sensor. The measurements recorded over 27 seconds capture the effects of the beating heart on the frequency tuning of the implantable antennas. When looked at in the time domain, these effects are clearly physiological and a combination of numerical study and posthumous autopsy proves this to be the case, while retrospective simulation confirms this hypothesis. The impact of pulsating anatomy on antenna design and the need for wideband implantable antennas is highlighted. PMID- 26609378 TI - A continuous point measure for quantifying skull deformation in medical diagnostics. AB - Deformational plagiocephaly (DP) manifests in a deformed skull primarily caused by retaining a constant sleeping position in infants. Manual measures of skull asymmetry based on MRI or CT scans combined with the cranial vault asymmetry index (CVAI) provides information on the extent of asymmetry. CVAI uses four points on the skull as markers for the asymmetry index but tends to underestimate the deformity because of the lack of sampling points. Computer-based continuous point methods may be a more objective measure with better sensitivity for the skull contour. The outline of the skull circumference of infants with confirmed cranial deformity was obtained from the literature and analysed applying the mean bending energy (MBE) obtained from the Hermitian wavelet. MBE was shown to correlate with CVAI in the current sample and has the potential to add both quantitative and visual information in 2D or 3D space for the clinician to diagnose DP. Wavelet-based continuous-point estimation of skull asymmetry is a useful method as it is more sensitive to mild deformation anywhere along the skull outline and in assessing slow but progressive improvement as a result of treatment. The broader significance is that this method can be applied to other structural pathology analysis in clinical practice. PMID- 26609379 TI - Inverse dynamics modelling of upper-limb tremor, with cross-correlation analysis. AB - A method to characterise upper-limb tremor using inverse dynamics modelling in combination with cross-correlation analyses is presented. A 15 degree-of-freedom inverse dynamics model is used to estimate the joint torques required to produce the measured limb motion, given a set of estimated inertial properties for the body segments. The magnitudes of the estimated torques are useful when assessing patients or evaluating possible intervention methods. The cross-correlation of the estimated joint torques is proposed to gain insight into how tremor in one limb segment interacts with tremor in another. The method is demonstrated using data from a single patient presenting intention tremor because of multiple sclerosis. It is shown that the inertial properties of the body segments can be estimated with sufficient accuracy using only the patient's height and weight as a priori knowledge, which ensures the method's practicality and transferability to clinical use. By providing a more detailed, objective characterisation of patient-specific tremor properties, the method is expected to improve the selection, design and assessment of treatment options on an individual basis. PMID- 26609380 TI - E-servant: an intelligent, programmable system to support and integrate assisted living technologies. AB - The 'E-servant', a programmable system to control and manage assistive technologies, telehealth and telecare devices in a home environment is presented. The E-servant is programmed using a simple graphical interface that allows the user to build a dialogue in the form of a production rule system, which is triggered by a patient- or technology-initiated event. The patient interacts with the system through a personalised user interface to reach their goal of completing a task. These tasks, which the authors call 'scenarios', can be designed for users of different abilities (cognitive and/or physical). They can also be given priority levels, for example if a potential emergency situation arises in the patient's home, a scenario associated with the sensing of this event takes highest priority. The research presented in this Letter outlines the E-servant, its programming tool and reports its evaluation in living laboratory settings. The results suggest that it can be used as a central management system for supporting an integrated support environment for facilitating healthcare and activities of daily living, especially for older patients. PMID- 26609381 TI - On ECG reconstruction using weighted-compressive sensing. AB - The potential of the new weighted-compressive sensing approach for efficient reconstruction of electrocardiograph (ECG) signals is investigated. This is motivated by the observation that ECG signals are hugely sparse in the frequency domain and the sparsity changes slowly over time. The underlying idea of this approach is to extract an estimated probability model for the signal of interest, and then use this model to guide the reconstruction process. The authors show that the weighted-compressive sensing approach is able to achieve reconstruction performance comparable with the current state-of-the-art discrete wavelet transform-based method, but with substantially less computational cost to enable it to be considered for use in the next generation of miniaturised wearable ECG monitoring devices. PMID- 26609382 TI - Facilitating and securing offline e-medicine service through image steganography. AB - E-medicine is a process to provide health care services to people using the Internet or any networking technology. In this Letter, a new idea is proposed to model the physical structure of the e-medicine system to better provide offline health care services. Smart cards are used to authenticate the user singly. A very unique technique is also suggested to verify the card owner's identity and to embed secret data to the card while providing patients' reports either at booths or at the e-medicine server system. The simulation results of card authentication and embedding procedure justify the proposed implementation. PMID- 26609383 TI - Respiratory rate detection algorithm based on RGB-D camera: theoretical background and experimental results. AB - Both the theoretical background and the experimental results of an algorithm developed to perform human respiratory rate measurements without any physical contact are presented. Based on depth image sensing techniques, the respiratory rate is derived by measuring morphological changes of the chest wall. The algorithm identifies the human chest, computes its distance from the camera and compares this value with the instantaneous distance, discerning if it is due to the respiratory act or due to a limited movement of the person being monitored. To experimentally validate the proposed algorithm, the respiratory rate measurements coming from a spirometer were taken as a benchmark and compared with those estimated by the algorithm. Five tests were performed, with five different persons sat in front of the camera. The first test aimed to choose the suitable sampling frequency. The second test was conducted to compare the performances of the proposed system with respect to the gold standard in ideal conditions of light, orientation and clothing. The third, fourth and fifth tests evaluated the algorithm performances under different operating conditions. The experimental results showed that the system can correctly measure the respiratory rate, and it is a viable alternative to monitor the respiratory activity of a person without using invasive sensors. PMID- 26609384 TI - Continuous non-contact vital sign monitoring in neonatal intensive care unit. AB - Current technologies to allow continuous monitoring of vital signs in pre-term infants in the hospital require adhesive electrodes or sensors to be in direct contact with the patient. These can cause stress, pain, and also damage the fragile skin of the infants. It has been established previously that the colour and volume changes in superficial blood vessels during the cardiac cycle can be measured using a digital video camera and ambient light, making it possible to obtain estimates of heart rate or breathing rate. Most of the papers in the literature on non-contact vital sign monitoring report results on adult healthy human volunteers in controlled environments for short periods of time. The authors' current clinical study involves the continuous monitoring of pre-term infants, for at least four consecutive days each, in the high-dependency care area of the Neonatal Intensive Care Unit (NICU) at the John Radcliffe Hospital in Oxford. The authors have further developed their video-based, non-contact monitoring methods to obtain continuous estimates of heart rate, respiratory rate and oxygen saturation for infants nursed in incubators. In this Letter, it is shown that continuous estimates of these three parameters can be computed with an accuracy which is clinically useful. During stable sections with minimal infant motion, the mean absolute error between the camera-derived estimates of heart rate and the reference value derived from the ECG is similar to the mean absolute error between the ECG-derived value and the heart rate value from a pulse oximeter. Continuous non-contact vital sign monitoring in the NICU using ambient light is feasible, and the authors have shown that clinically important events such as a bradycardia accompanied by a major desaturation can be identified with their algorithms for processing the video signal. PMID- 26609385 TI - Smartphone-based analysis of biochemical tests for health monitoring support at home. AB - In the context of home-based healthcare monitoring systems, it is desirable that the results obtained from biochemical tests - tests of various body fluids such as blood and urine - are objective and automatically generated to reduce the number of man-made errors. The authors present the StripTest reader - an innovative smartphone-based interpreter of biochemical tests based on paper-based strip colour using image processing techniques. The working principles of the reader include image acquisition of the colour strip pads using the camera phone, analysing the images within the phone and comparing them with reference colours provided by the manufacturer to obtain the test result. The detection of kidney damage was used as a scenario to illustrate the application of, and test, the StripTest reader. An extensive evaluation using laboratory and human urine samples demonstrates the reader's accuracy and precision of detection, indicating the successful development of a cheap, mobile and smart reader for home monitoring of kidney functioning, which can facilitate the early detection of health problems and a timely treatment intervention. PMID- 26609386 TI - Patient-specific ECG beat classification technique. AB - Electrocardiogram (ECG) beat classification plays an important role in the timely diagnosis of the critical heart condition. An automated diagnostic system is proposed to classify five types of ECG classes, namely normal (N), ventricular ectopic beat (V), supra ventricular ectopic beat (S), fusion (F) and unknown (Q) as recommended by the Association for the Advancement of Medical Instrumentation (AAMI). The proposed method integrates the Stockwell transform (ST), a bacteria foraging optimisation (BFO) algorithm and a least mean square (LMS)-based multiclass support vector machine (SVM) classifier. The ST is utilised to extract the important morphological features which are concatenated with four timing features. The resultant combined feature vector is optimised by removing the redundant and irrelevant features using the BFO algorithm. The optimised feature vector is applied to the LMS-based multiclass SVM classifier for automated diagnosis. In the proposed technique, the LMS algorithm is used to modify the Lagrange multiplier, which in turn modifies the weight vector to minimise the classification error. The updated weights are used during the testing phase to classify ECG beats. The classification performances are evaluated using the MIT BIH arrhythmia database. Average accuracy and sensitivity performances of the proposed system for V detection are 98.6% and 91.7%, respectively, and for S detections, 98.2% and 74.7%, respectively over the entire database. To generalise the capability, the classification performance is also evaluated using the St. Petersburg Institute of Cardiological Technics (INCART) database. The proposed technique performs better than other reported heartbeat techniques, with results suggesting better generalisation capability. PMID- 26609387 TI - Comparative study of ECG signal denoising by wavelet thresholding in empirical and variational mode decomposition domains. AB - Hybrid denoising models based on combining empirical mode decomposition (EMD) and discrete wavelet transform (DWT) were found to be effective in removing additive Gaussian noise from electrocardiogram (ECG) signals. Recently, variational mode decomposition (VMD) has been proposed as a multiresolution technique that overcomes some of the limits of the EMD. Two ECG denoising approaches are compared. The first is based on denoising in the EMD domain by DWT thresholding, whereas the second is based on noise reduction in the VMD domain by DWT thresholding. Using signal-to-noise ratio and mean of squared errors as performance measures, simulation results show that the VMD-DWT approach outperforms the conventional EMD-DWT. In addition, a non-local means approach used as a reference technique provides better results than the VMD-DWT approach. PMID- 26609388 TI - Method to classify elderly subjects as fallers and non-fallers based on gait energy image. AB - Falls are one of the leading causes of injuries among the elderly. Therefore, distinguishing fallers and performing preventive actions is vitally important. A new variation of the gait energy image (GEI) called coloured gait energy image (CGEI) is proposed for classifying subjects as fallers and non-fallers and for visualising their gait patterns. Eight elderly fallers, eight elderly non-fallers and eight young subjects performed timed up and go (TUG) test, which is one of the well-known clinical tools for fall risk assessment and contains two gait sequences. Subjects were also asked to perform two other variations of the TUG test, namely TUG with manual load and TUG with cognitive load. Gait sequences were extracted from the TUG test based on the opinion of three human observers. Then the gait cycles were automatically extracted from the walking sequence and divided into three phases, corresponding to double support and first and second half of single support. Next, the GEI of each phase was generated and formed one of the colour components of CGEI. Histogram-based features obtained from CGEI were then used to classify the video collected from walking sequences of elderly fallers and non-fallers. Correct classification rate was improved by approximately 27% compared with the standard TUG test. PMID- 26609389 TI - Electrical bioimpedance measurement as a tool for dysphagia visualisation. AB - A non-invasive and portable bioimpedance method and a device for detecting superior to inferior closure of the pharynx during swallowing have been developed. The 2-channel device measures electric impedance across the neck at two levels of the pharynx via injected currents at 40 and 70 kHz. The device has been trialled on both healthy and dysphagic subjects. Results from these trials revealed a relationship (r = 0.59) between the temporal separation of the second peaks in the bioimpedance waveforms and descending pressure sequence in the pharynx as measured by pharyngeal manometry. However, these features were only clearly visible in the bioimpedance waveforms for 64% of swallows. Further research is underway to improve the bioimpedance measurement reliability and validate waveform feature correlation to swallowing to maximise the device's efficacy in dysphagia rehabilitation. PMID- 26609390 TI - Ferrite core non-linearity in coils for magnetic neurostimulation. AB - The need to correctly predict the voltage across terminals of mm-sized coils, with ferrite core, to be employed for magnetic stimulation of the peripheral neural system is the motivation for this work. In such applications, which rely on a capacitive discharge on the coil to realise a transient voltage curve of duration and strength suitable for neural stimulation, the correct modelling of the non-linearity of the ferrite core is critical. A demonstration of how a finite-difference model of the considered coils, which include a model of the current-controlled inductance in the coil, can be used to correctly predict the time-domain voltage waveforms across the terminals of a test coil is presented. Five coils of different dimensions, loaded with ferrite cores, have been fabricated and tested: the measured magnitude and width of the induced pulse are within 10% of simulated values. PMID- 26609391 TI - Monitoring changes in behaviour from multi-sensor systems. AB - Behavioural patterns are important indicators of health status in a number of conditions and changes in behaviour can often indicate a change in health status. Currently, limited behaviour monitoring is carried out using paper-based assessment techniques. As technology becomes more prevalent and low-cost, there is an increasing movement towards automated behaviour-monitoring systems. These systems typically make use of a multi-sensor environment to gather data. Large data volumes are produced in this way, which poses a significant problem in terms of extracting useful indicators. Presented is a novel method for detecting behavioural patterns and calculating a metric for quantifying behavioural change in multi-sensor environments. The data analysis method is shown and an experimental validation of the method is presented which shows that it is possible to detect the difference between weekdays and weekend days. Two participants are analysed, with different sensor configurations and test environments and in both cases, the results show that the behavioural change metric for weekdays and weekend days is significantly different at 95% confidence level, using the methods presented. PMID- 26609392 TI - A new way of quantifying diagnostic information from multilead electrocardiogram for cardiac disease classification. AB - A new measure for quantifying diagnostic information from a multilead electrocardiogram (MECG) is proposed. This diagnostic measure is based on principal component (PC) multivariate multiscale sample entropy (PMMSE). The PC analysis is used to reduce the dimension of the MECG data matrix. The multivariate multiscale sample entropy is evaluated over the PC matrix. The PMMSE values along each scale are used as a diagnostic feature vector. The performance of the proposed measure is evaluated using a least square support vector machine classifier for detection and classification of normal (healthy control) and different cardiovascular diseases such as cardiomyopathy, cardiac dysrhythmia, hypertrophy and myocardial infarction. The results show that the cardiac diseases are successfully detected and classified with an average accuracy of 90.34%. Comparison with some of the recently published methods shows improved performance of the proposed measure of cardiac disease classification. PMID- 26609393 TI - Automated pathologies detection in retina digital images based on complex continuous wavelet transform phase angles. AB - An automated diagnosis system that uses complex continuous wavelet transform (CWT) to process retina digital images and support vector machines (SVMs) for classification purposes is presented. In particular, each retina image is transformed into two one-dimensional signals by concatenating image rows and columns separately. The mathematical norm of phase angles found in each one dimensional signal at each level of CWT decomposition are relied on to characterise the texture of normal images against abnormal images affected by exudates, drusen and microaneurysms. The leave-one-out cross-validation method was adopted to conduct experiments and the results from the SVM show that the proposed approach gives better results than those obtained by other methods based on the correct classification rate, sensitivity and specificity. PMID- 26609394 TI - Non-invasive method to analyse the risk of developing diabetic foot. AB - Foot complications (diabetic foot) are among the most serious and costly complications of diabetes mellitus. Amputation of all or part of a lower extremity is usually preceded by a foot ulcer. To prevent diabetic foot, an automatic non-invasive method to identify patients with diabetes who have a high risk of developing diabetic foot is proposed. To design the proposed method, information concerning social scope and self-care of 153 diabetic patients was presented to the K-means clustering algorithm, which divided the data into two groups: high risk and low risk of developing diabetic foot. In the operational stage, the Euclidian distance from the information vector to the centroids of each group of risk is used as criterion for classification. Both real and simulated data were used to evaluate the method in which promising results were achieved with accuracy of 0.97 +/- 0.06 for simulated data and 0.68 +/- 0.16 considering the classification of specialists as the gold standard for real data. The method requires a simple computational processing and can be useful for basic health units to triage diabetic patients helping the health-care team to reduce the number of cases of diabetic foot. PMID- 26609395 TI - Editorial: "Longer term monitoring through wearables brings with it the promise of predicting the onset of disease - moving from managing illness to maintaining wellness.". PMID- 26609396 TI - Wearable technologies - future challenges for implementation in healthcare services. AB - The growing use of wearable technologies increases the ability to have more information from the patient including clinical, behavioural and self-monitored data. The availability and large amounts of data that did not exist before brings an opportunity to develop new tools with intelligent analyses and decision support tools for use in clinical practice. It also opens new possibilities for the patients by providing them with more information and decision support tools specially designed for them, and empowers them in managing their own health conditions, keeping their autonomy. These new developments drive a change in healthcare delivery models and the relationship between patients and healthcare providers. It raises challenges for the healthcare systems in how to implement these new technologies and the growing amount of information in clinical practice, integrate it into the clinical workflows of the various healthcare providers. The future challenge for healthcare will be how to use the developing knowledge in a way that will bring added value to healthcare professionals, healthcare organisations and patients without increasing the workload and cost of the healthcare services. For wearable technology developers, the challenge is to develop solutions that can be easily integrated and used by healthcare professionals considering the existing constraints. PMID- 26609397 TI - Lightweight wrist photoplethysmography for heavy exercise: motion robust heart rate monitoring algorithm. AB - The challenge of heart rate monitoring based on wrist photoplethysmography (PPG) during heavy exercise is addressed. PPG is susceptible to motion artefacts, which have to be mitigated for accurate heart rate estimation. Motion artefacts are particularly apparent for wrist devices, for example, a smart watch, because of the high mobility of the arms. Proposed is a low complexity highly accurate heart rate estimation method for continuous heart rate monitoring using wrist PPG. The proposed method achieved 2.57% mean absolute error in a test data set where subjects ran for a maximum speed of 17 km/h. PMID- 26609398 TI - Wireless wearable range-of-motion sensor system for upper and lower extremity joints: a validation study. AB - Range-of-motion (ROM) assessment is a critical assessment tool during the rehabilitation process. The conventional approach uses the goniometer which remains the most reliable instrument but it is usually time-consuming and subject to both intra- and inter-therapist measurement errors. An automated wireless wearable sensor system for the measurement of ROM has previously been developed by the current authors. Presented is the correlation and accuracy of the automated wireless wearable sensor system against a goniometer in measuring ROM in the major joints of upper (UEs) and lower extremities (LEs) in 19 healthy subjects and 20 newly disabled inpatients through intra (same) subject comparison of ROM assessments between the sensor system against goniometer measurements by physical therapists. In healthy subjects, ROM measurements using the new sensor system were highly correlated with goniometry, with 95% of differences < 20 degrees and 10 degrees for most movements in major joints of UE and LE, respectively. Among inpatients undergoing rehabilitation, ROM measurements using the new sensor system were also highly correlated with goniometry, with 95% of the differences being < 20 degrees and 25 degrees for most movements in the major joints of UE and LE, respectively. PMID- 26609399 TI - Smart radio-frequency identification tag for diaper moisture detection. AB - A passive smart tag is described that responds to dampness in diapers once a pre defined threshold value is reached. A high-frequency (HF) system at 13.56 MHz is used as this allows operation through water or human tissues with less absorption that would occur for an ultra-HF signal. A circular spiral coil and swelling substrate facilitate a reaction to dampness that can be detected without contact to the diaper wearer. A prototype design is simulated and measured results are provided together with a demonstration of a tag integrated into a worn diaper. PMID- 26609400 TI - Radio-frequency energy harvesting for wearable sensors. AB - The use of wearable biomedical sensors for the continuous monitoring of physiological signals will facilitate the involvement of the patients in the prevention and management of chronic diseases. The fabrication of small biomedical sensors transmitting physiological data wirelessly is possible as a result of the tremendous advances in ultra-low power electronics and radio communications. However, the widespread adoption of these devices depends very much on their ability to operate for long periods of time without the need to frequently change, recharge or even use batteries. In this context, energy harvesting (EH) is the disruptive technology that can pave the road towards the massive utilisation of wireless wearable sensors for patient self-monitoring and daily healthcare. Radio-frequency (RF) transmissions from commercial telecommunication networks represent reliable ambient energy that can be harvested as they are ubiquitous in urban and suburban areas. The state-of-the art in RF EH for wearable biomedical sensors specifically targeting the global system of mobile 900/1800 cellular and 700 MHz digital terrestrial television networks as ambient RF energy sources are showcased. Furthermore, guidelines for the choice of the number of stages for the RF energy harvester are presented, depending on the requirements from the embedded system to power supply, which is useful for other researchers that work in the same area. The present authors' recent advances towards the development of an efficient RF energy harvester and storing system are presented and thoroughly discussed too. PMID- 26609401 TI - Algorithm for heart rate extraction in a novel wearable acoustic sensor. AB - Phonocardiography is a widely used method of listening to the heart sounds and indicating the presence of cardiac abnormalities. Each heart cycle consists of two major sounds - S1 and S2 - that can be used to determine the heart rate. The conventional method of acoustic signal acquisition involves placing the sound sensor at the chest where this sound is most audible. Presented is a novel algorithm for the detection of S1 and S2 heart sounds and the use of them to extract the heart rate from signals acquired by a small sensor placed at the neck. This algorithm achieves an accuracy of 90.73 and 90.69%, with respect to heart rate value provided by two commercial devices, evaluated on more than 38 h of data acquired from ten different subjects during sleep in a pilot clinical study. This is the largest dataset for acoustic heart sound classification and heart rate extraction in the literature to date. The algorithm in this study used signals from a sensor designed to monitor breathing. This shows that the same sensor and signal can be used to monitor both breathing and heart rate, making it highly useful for long-term wearable vital signs monitoring. PMID- 26609402 TI - Preliminary study on activity monitoring using an android smart-watch. AB - The global trend for increasing life expectancy is resulting in aging populations in a number of countries. This brings to bear a pressure to provide effective care for the older population with increasing constraints on available resources. Providing care for and maintaining the independence of an older person in their own home is one way that this problem can be addressed. The EU Funded Unobtrusive Smart Environments for Independent Living (USEFIL) project is an assistive technology tool being developed to enhance independent living. As part of USEFIL, a wrist wearable unit (WWU) is being developed to monitor the physical activity (PA) of the user and integrate with the USEFIL system. The WWU is a novel application of an existing technology to the assisted living problem domain. It combines existing technologies and new algorithms to extract PA parameters for activity monitoring. The parameters that are extracted include: activity level, step count and worn state. The WWU, the algorithms that have been developed and a preliminary validation are presented. The results show that activity level can be successfully extracted, that worn state can be correctly identified and that step counts in walking data can be estimated within 3% error, using the controlled dataset. PMID- 26609403 TI - BioKin: an ambulatory platform for gait kinematic and feature assessment. AB - A platform to move gait analysis, which is normally restricted to a clinical environment in a well-equipped gait laboratory, into an ambulatory system, potentially in non-clinical settings is introduced. This novel system can provide functional measurements to guide therapeutic interventions for people requiring rehabilitation with limited access to such gait laboratories. BioKin system consists of three layers: a low-cost wearable wireless motion capture sensor, data collection and storage engine, and the motion analysis and visualisation platform. Moreover, a novel limb orientation estimation algorithm is implemented in the motion analysis platform. The performance of the orientation estimation algorithm is validated against the orientation results from a commercial optical motion analysis system and an instrumented treadmill. The study results demonstrate a root-mean-square error less than 4 degrees and a correlation coefficient more than 0.95 when compared with the industry standard system. These results indicate that the proposed motion analysis platform is a potential addition to existing gait laboratories in order to facilitate gait analysis in remote locations. PMID- 26609404 TI - Classification of mammogram using two-dimensional discrete orthonormal S transform for breast cancer detection. AB - An efficient approach for classification of mammograms for detection of breast cancer is presented. The approach utilises the two-dimensional discrete orthonormal S-transform (DOST) to extract the coefficients from the digital mammograms. A feature selection algorithm based the on null-hypothesis test with statistical 'two-sample t-test' method has been suggested to select most significant coefficients from a large number of DOST coefficients. The selected coefficients are used as features in the classification of mammographic images as benign or malignant. This scheme utilises an AdaBoost algorithm with random forest as its base classifier. Two standard databases Mammographic Image Analysis Society (MIAS) and Digital Database for Screening Mammography (DDSM) are used for the validation of the proposed scheme. Simulation results show an optimal classification performance with respect to accuracies of 98.3 and 98.8% and AUC (receiver operating characteristic) values of 0.9985 and 0.9992 for MIAS and DDSM, respectively. Comparative analysis shows that the proposed scheme outperforms its competent schemes. PMID- 26609405 TI - Colour-reproduction algorithm for transmitting variable video frames and its application to capsule endoscopy. AB - Presented is a new power-efficient colour generation algorithm for wireless capsule endoscopy (WCE) application. In WCE, transmitting colour image data from the human intestine through radio frequency (RF) consumes a huge amount of power. The conventional way is to transmit all R, G and B components of all frames. Using the proposed dictionary-based colour generation scheme, instead of sending all R, G and B frames, first one colour frame is sent followed by a series of grey-scale frames. At the receiver end, the colour information is extracted from the colour frame and then added to colourise the grey-scale frames. After a certain number of grey-scale frames, another colour frame is sent followed by the same number of grey-scale frames. This process is repeated until the end of the video sequence to maintain the colour similarity. As a result, over 50% of RF transmission power can be saved using the proposed scheme, which will eventually lead to a battery life extension of the capsule by 4-7 h. The reproduced colour images have been evaluated both statistically and subjectively by professional gastroenterologists. The algorithm is finally implemented using a WCE prototype and the performance is validated using an ex-vivo trial. PMID- 26609406 TI - Reliability of the step phase detection using inertial measurement units: pilot study. AB - The use of inertial sensors for the gait event detection during a long-distance walking, for example, on different surfaces and with different walking patterns, is important to evaluate the human locomotion. Previous studies demonstrated that gyroscopes on the shank or foot are more reliable than accelerometers and magnetometers for the event detection in case of normal walking. However, these studies did not link the events with the temporal parameters used in the clinical practice; furthermore, they did not clearly verify the optimal position for the sensors depending on walking patterns and surface conditions. The event detection quality of the sensors is compared with video, used as ground truth, according to the parameters proposed by the Gait and Clinical Movement Analysis Society. Additionally, the performance of the sensor on the foot is compared with the one on the shank. The comparison is performed considering both normal walking and deviations to the walking pattern, on different ground surfaces and with or without constraints on movements. The preliminary results show that the proposed methodology allows reliable detection of gait events, even in case of abnormal footfall and in slipping surface conditions, and that the optimal location to place the sensors is the shank. PMID- 26609407 TI - Bilateral photoplethysmography analysis for arteriovenous fistula dysfunction screening with fractional-order feature and cooperative game-based embedded detector. AB - The bilateral photoplethysmography (PPG) analysis for arteriovenous fistula (AVF) dysfunction screening with a fractional-order feature and a cooperative game (CG) based embedded detector is proposed. The proposed detector uses a feature extraction method and a CG to evaluate the risk level for AVF dysfunction for patients undergoing haemodialysis treatment. A Sprott system is used to design a self-synchronisation error formulation to quantify the differences in the changes of blood volume for the sinister and dexter thumbs' PPG signals. Bilateral PPGs exhibit a significant difference in rise time and amplitude, which is proportional to the degree of stenosis. A less parameterised CG model is then used to evaluate the risk level. The proposed detector is also studied using an embedded system and bilateral optical measurements. The experimental results show that the risk of AVF stenosis during haemodialysis treatment is detected earlier. PMID- 26609408 TI - Classification of Alzheimer's disease from quadratic sample entropy of electroencephalogram. AB - Currently accepted input parameter limitations in entropy-based, non-linear signal processing methods, for example, sample entropy (SampEn), may limit the information gathered from tested biological signals. The ability of quadratic sample entropy (QSE) to identify changes in electroencephalogram (EEG) signals of 11 patients with a diagnosis of Alzheimer's disease (AD) and 11 age-matched, healthy controls is investigated. QSE measures signal regularity, where reduced QSE values indicate greater regularity. The presented method allows a greater range of QSE input parameters to produce reliable results than SampEn. QSE was lower in AD patients compared with controls with significant differences (p < 0.01) for different parameter combinations at electrodes P3, P4, O1 and O2. Subject- and epoch-based classifications were tested with leave-one-out linear discriminant analysis. The maximum diagnostic accuracy and area under the receiver operating characteristic curve were 77.27 and more than 80%, respectively, at many parameter and electrode combinations. Furthermore, QSE results across all r values were consistent, suggesting QSE is robust for a wider range of input parameters than SampEn. The best results were obtained with input parameters outside the acceptable range for SampEn, and can identify EEG changes between AD patients and controls. However, caution should be applied because of the small sample size. PMID- 26609409 TI - Towards sparse characterisation of on-body ultra-wideband wireless channels. AB - With the aim of reducing cost and power consumption of the receiving terminal, compressive sensing (CS) framework is applied to on-body ultra-wideband (UWB) channel estimation. It is demonstrated in this Letter that the sparse on-body UWB channel impulse response recovered by the CS framework fits the original sparse channel well; thus, on-body channel estimation can be achieved using low-speed sampling devices. PMID- 26609410 TI - Editorial: "The lack of specificity in fall risk assessment, a limited effectiveness in fall prediction and the inability to reliably monitor spontaneous falls in real life conditions with un-obstructive technological solutions remain key unsolved problems.". PMID- 26609411 TI - Review: Are we stumbling in our quest to find the best predictor? Over-optimism in sensor-based models for predicting falls in older adults. AB - The field of fall risk testing using wearable sensors is bustling with activity. In this Letter, the authors review publications which incorporated features extracted from sensor signals into statistical models intended to estimate fall risk or predict falls in older people. A review of these studies raises concerns that this body of literature is presenting over-optimistic results in light of small sample sizes, questionable modelling decisions and problematic validation methodologies (e.g. inherent problems with the overly-popular cross-validation technique, lack of external validation). There seem to be substantial issues in the feature selection process, whereby researchers select features before modelling begins based on their relation to the target, and either perform no validation or test the models on the same data used for their training. This, together with potential issues related to the large number of features and their correlations, inevitably leads to models with inflated accuracy that are unlikely to maintain their reported performance during everyday use in relevant populations. Indeed, the availability of rich sensor data and many analytical options provides intellectual and creative freedom for researchers, but should be treated with caution, and such pitfalls must be avoided if we desire to create generalisable prognostic tools of any clinical value. PMID- 26609412 TI - Automatic classifier based on heart rate variability to identify fallers among hypertensive subjects. AB - Accidental falls are a major problem of later life. Different technologies to predict falls have been investigated, but with limited success, mainly because of low specificity due to a high false positive rate. This Letter presents an automatic classifier based on heart rate variability (HRV) analysis with the goal to identify fallers automatically. HRV was used in this study as it is considered a good estimator of autonomic nervous system (ANS) states, which are responsible, among other things, for human balance control. Nominal 24 h electrocardiogram recordings from 168 cardiac patients (age 72 +/- 8 years, 60 female), of which 47 were fallers, were investigated. Linear and nonlinear HRV properties were analysed in 30 min excerpts. Different data mining approaches were adopted and their performances were compared with a subject-based receiver operating characteristic analysis. The best performance was achieved by a hybrid algorithm, RUSBoost, integrated with feature selection method based on principal component analysis, which achieved satisfactory specificity and accuracy (80 and 72%, respectively), but low sensitivity (51%). These results suggested that ANS states causing falls could be reliably detected, but also that not all the falls were due to ANS states. PMID- 26609413 TI - Implementation study of wearable sensors for activity recognition systems. AB - This Letter investigates and reports on a number of activity recognition methods for a wearable sensor system. The authors apply three methods for data transmission, namely 'stream-based', 'feature-based' and 'threshold-based' scenarios to study the accuracy against energy efficiency of transmission and processing power that affects the mote's battery lifetime. They also report on the impact of variation of sampling frequency and data transmission rate on energy consumption of motes for each method. This study leads us to propose a cross-layer optimisation of an activity recognition system for provisioning acceptable levels of accuracy and energy efficiency. PMID- 26609414 TI - Unified framework for triaxial accelerometer-based fall event detection and classification using cumulants and hierarchical decision tree classifier. AB - In this Letter, the authors present a unified framework for fall event detection and classification using the cumulants extracted from the acceleration (ACC) signals acquired using a single waist-mounted triaxial accelerometer. The main objective of this Letter is to find suitable representative cumulants and classifiers in effectively detecting and classifying different types of fall and non-fall events. It was discovered that the first level of the proposed hierarchical decision tree algorithm implements fall detection using fifth-order cumulants and support vector machine (SVM) classifier. In the second level, the fall event classification algorithm uses the fifth-order cumulants and SVM. Finally, human activity classification is performed using the second-order cumulants and SVM. The detection and classification results are compared with those of the decision tree, naive Bayes, multilayer perceptron and SVM classifiers with different types of time-domain features including the second-, third-, fourth- and fifth-order cumulants and the signal magnitude vector and signal magnitude area. The experimental results demonstrate that the second- and fifth-order cumulant features and SVM classifier can achieve optimal detection and classification rates of above 95%, as well as the lowest false alarm rate of 1.03%. PMID- 26609415 TI - Microwave non-contact imaging of subcutaneous human body tissues. AB - A small-size microwave sensor is developed for non-contact imaging of a human body structure in 2D, enabling fitness and health monitoring using mobile devices. A method for human body tissue structure imaging is developed and experimentally validated. Subcutaneous fat tissue reconstruction depth of up to 70 mm and maximum fat thickness measurement error below 2 mm are demonstrated by measurements with a human body phantom and human subjects. Electrically small antennas are developed for integration of the microwave sensor into a mobile device. Usability of the developed microwave sensor for fitness applications, healthcare, and body weight management is demonstrated. PMID- 26609417 TI - Optical wireless connected objects for healthcare. AB - In this Letter the authors explore the communication capabilities of optical wireless technology for a wearable device dedicated to healthcare application. In an indoor environment sensible to electromagnetic perturbations such as a hospital, the use of optical wireless links can permit reducing the amount of radio frequencies in the patient environment. Moreover, this technology presents the advantage to be secure, low-cost and easy to deploy. On the basis of commercially available components, a custom-made wearable device is presented, which allows optical wireless transmission of accelerometer data in the context of physical activity supervision of post-stroke patients in hospital. Considering patient mobility, the experimental performance is established in terms of packet loss as a function of the number of receivers fixed to the ceiling. The results permit to conclude that optical wireless links can be used to perform such mobile remote monitoring applications. Moreover, based on the measurements obtained with one receiver, it is possible to theoretically determine the performance according to the number of receivers to be deployed. PMID- 26609416 TI - Exploiting multi-lead electrocardiogram correlations using robust third-order tensor decomposition. AB - In this Letter, a robust third-order tensor decomposition of multi-lead electrocardiogram (MECG) comprising of 12-leads is proposed to reduce the dimension of the storage data. An order-3 tensor structure is employed to represent the MECG data by rearranging the MECG information in three dimensions. The three-dimensions of the formed tensor represent the number of leads, beats and samples of some fixed ECG duration. Dimension reduction of such an arrangement exploits correlations present among the successive beats (intra-beat and inter-beat) and across the leads (inter-lead). The higher-order singular value decomposition is used to decompose the tensor data. In addition, multiscale analysis has been added for effective care of ECG information. It grossly segments the ECG characteristic waves (P-wave, QRS-complex, ST-segment and T-wave etc.) into different sub-bands. In the meantime, it separates high-frequency noise components into lower-order sub-bands which helps in removing noise from the original data. For evaluation purposes, we have used the publicly available PTB diagnostic database. The proposed method outperforms the existing algorithms where compression ratio is under 10 for MECG data. Results show that the original MECG data volume can be reduced by more than 45 times with acceptable diagnostic distortion level. PMID- 26609418 TI - Identifying radiotherapy target volumes in brain cancer by image analysis. AB - To establish the optimal radiotherapy fields for treating brain cancer patients, the tumour volume is often outlined on magnetic resonance (MR) images, where the tumour is clearly visible, and mapped onto computerised tomography images used for radiotherapy planning. This process requires considerable clinical experience and is time consuming, which will continue to increase as more complex image sequences are used in this process. Here, the potential of image analysis techniques for automatically identifying the radiation target volume on MR images, and thereby assisting clinicians with this difficult task, was investigated. A gradient-based level set approach was applied on the MR images of five patients with grades II, III and IV malignant cerebral glioma. The relationship between the target volumes produced by image analysis and those produced by a radiation oncologist was also investigated. The contours produced by image analysis were compared with the contours produced by an oncologist and used for treatment. In 93% of cases, the Dice similarity coefficient was found to be between 60 and 80%. This feasibility study demonstrates that image analysis has the potential for automatic outlining in the management of brain cancer patients, however, more testing and validation on a much larger patient cohort is required. PMID- 26609420 TI - Renal tubular acidosis complicated with hyponatremia due to cortisol insufficiency. AB - Adrenocortical insufficiency such as occurs in Addison's disease causes hyponatremia and renal tubular acidosis (RTA). Hyponatremia results from both aldosterone and cortisol insufficiency. RTA is due to aldosterone insufficiency. The involvement of cortisol in RTA is unclear. Here, we report a woman in her 70s who was admitted to our hospital with severe hyponatremia (106 mEq/l) and RTA. The patient exhibited low plasma cortisol levels with little response to rapid adrenocorticotropic hormone loading. In contrast, the plasma aldosterone concentration was maintained at or above the normal range. Hydrocortisone replacement greatly improved both the hyponatremia and RTA. This case suggests that both aldosterone and cortisol are involved in acid secretion from the kidney. PMID- 26609419 TI - Design and development of a low-cost biphasic charge-balanced functional electric stimulator and its clinical validation. AB - Functional electric stimulators that produce near-ideal, charge-balanced biphasic stimulation waveforms with interphase delay are considered safer and more efficacious than conventional stimulators. An indigenously designed, low-cost, portable FES device named InStim is developed. It features a charge-balanced biphasic single channel. The authors present the complete design, mathematical analysis of the circuit and the clinical evaluation of the device. The developed circuit was tested on stroke patients affected by foot drop problems. It was tested both under laboratory conditions and in clinical settings. The key building blocks of this circuit are low dropout regulators, a DC-DC voltage booster and a single high-power current source OP-Amp with current-limiting capabilities. This allows the device to deliver high-voltage, constant current, biphasic pulses without the use of a bulky step-up transformer. The advantages of the proposed design over the currently existing devices include improved safety features (zero DC current, current-limiting mechanism and safe pulses), waveform morphology that causes less muscle fatigue, cost-effectiveness and compact power efficient circuit design with minimal components. The device is also capable of producing appropriate ankle dorsiflexion in patients having foot drop problems of various Medical Research Council scale grades. PMID- 26609421 TI - Methicillin resistant Staphylococcus aureus meningitis. AB - Methicillin resistant Staphylococcus aureus (MRSA) meningitis is rarely known to occur in children. We report an 11-year-old girl with fever, headache and vomiting, right hemiparesis with left-sided upper motor neuron facial nerve palsy and bladder incontinence. On investigation, she was found to have MRSA meningitis with an acute left thalamo-corpuscular infarct. She was treated with vancomycin, linezolid and rifampicin. She recovered successfully with residual right-sided lower limb monoparesis. MRSA meningitis is rare but can occur in children. PMID- 26609422 TI - Isolating the Norepinephrine Pathway Comparing Lithium in Bipolar Patients to SSRIs in Depressive Patients. AB - INTRODUCTION: The purpose of this investigatory neuroimaging analysis was done to better understand the pharmacodynamics of Lithium by isolating the norepinephrine pathway in the brain. To accomplish this, we compared patients with Bipolar Disorder treated with Lithium to patients diagnosed with Major Depression or Depressive Disorder who are treated with Selective Serotonin Reuptake Inhibitors (SSRIs). METHODOLOGY: We used Standardized Low Resolution Brain Electrotomography to calculate the whole brain, voxel-by-voxel, unpaired t-tests Statistical non Parametric Maps. For our first electrophysiological neuroimaging investigation, we compared 46 patients (average age = 34 +/- 16.5) diagnosed with Bipolar Affective Disorder to three patient groups all diagnosed with Major Depression or Depressive Episode. The first is with 48 patients diagnosed with Major Depression or Depressive Episode (average age = 49 +/- 12.9), the second to 16 male depressive patients (average age = 45 +/- 15.1), and the final comparison to 32 depressive females (average age = 50 +/- 11.7). RESULTS: The results of sLORETA three-dimensional statistical non-parametric maps illustrated that Lithium influenced an increase in neurotransmission in the right Superior Temporal Gyrus (t=1.403, p=0.00780), Fusiform Gyrus (t=1.26), and Parahippocampal Gyrus (t=1.29). Moreover, an increased in neuronal function was found was also identified at the Cingulate Gyrus (t=1.06, p=0.01200). CONCLUSION: We are proposing a translational clinical biological marker for patients diagnosed with Bipolar Disorder to guide physicians during the course of Lithium therapy and have identified neuroanatomical structures influenced by norepinephrine. PMID- 26609423 TI - Electrophysiological Neuroimaging using sLORETA Comparing 100 Schizophrenia Patients to 48 Patients with Major Depression. AB - In this retrospective analysis of electroencephalograms were to identify a surrogate biomarker for the Dopamine D2 receptors in the brain by comparing patients diagnosed with Schizophrenia taking Atypical Antipsychotics to Depressive patients medicated with Selective Serotonin Reuptake Inhibitors. To achieve this, thirty-seconds of resting EEG were spectrally transformed in sLORETA. Three-dimensional statistical non-paramentric maps (SnPM) for the sLORETA Global Field Power within each band were then computed. Our results illustrated that the Right Superior Frontal Gyrus (t=2.049, p=0.007), along the dopamine mesolimbic pathway, had higher neuronal oscillations in the delta frequency band in the 100 Schizophrenia patients as compared to the 32-depressive female patients. The comparisons with both the 48 depressive patient cohort or the sixteen male depressive patient cohort did not yield any statistically significant findings. We conclude that the Superior Frontal Gyrus should be investigated as a possible surrogate biomarker for preclinical and clinical drug discovery in neuropharmacology. PMID- 26609424 TI - Electrophysiological Neuroimaging using sLORETA Comparing 12 Anorexia Nervosa Patients to 12 Controls. AB - Anorexia Nervosa (AN) is characterized by Diagnostic and Statistical Manual of Mental Disorders Volume 4 (DSM IV), as one's refusal to maintain a body weight that is above the calculated limit, which is determined by an algorithm involving one's height and weight. As more emphasis in society is placed on one's body image and appearance there has been an increase in the prevalence of this disease. Previously, the sole diagnostic imaging modality was fMRI. Studies determined that there was reduced blood flood in the Parahippocampal Gyrus, and Left Fusiform Gyrus, of those afflicted with AN. Electroencephalography (EEG) was utilized as an alternative imaging modality that was more cost effect. It was determined that the activated regions localized on the fMRI study coincided with those highlighted on the EEG report and previous fMRI studies. The goal of this study was to determine a more cost effective way to earlier detect a diagnosis of AN. The desired outcome would be for patients afflicted with AN to be diagnosed and treated at an earlier stage, increasing their overall long-term survival. PMID- 26609425 TI - The Brain and Propranolol Pharmacokinetics in the Elderly. AB - Propranolol, a non-selective beta-blocker, has been found to have a tremendous array of indications. Recent evidence has suggested that propranolol may be effective in patients suffering from post-traumatic stress disorder by suppressing activity in the amygdala and thereby inhibiting emotional memory formation. Dosage requirements have been well established in the pediatric and adult population, however, there has been no definitive geriatric dose recommended in the package inserts made available to the public. The aim of this paper is to use pharmacokinetic simulations in order to establish a pharmacokinetic profile dosage equivalent for the elderly as has been found in young patients. After completing the Monte-Carlo simulations for the elderly and young patients, a single 10mg dose in the elderly has shown comparable pharmacokinetic profiles as found in young patients administered a 40mg single dose. PMID- 26609426 TI - Effects of Lutein and Zeaxanthin on LPS-Induced Secretion of IL-8 by Uveal Melanocytes and Relevant Signal Pathways. AB - The effects of lutein and zeaxanthin on lipopolysaccharide- (LPS-) induced secretion of IL-8 by uveal melanocytes (UM) were tested in cultured human UM. MTT assay revealed that LPS (0.01-1 MUg/mL) and lutein and zeaxanthin (1-10 MUM) did not influence the cell viability of cultured UM. LPS caused a dose-dependent increase of secretion of IL-8 by cultured UM. Lutein and zeaxanthin did not affect the constitutive secretion of IL-8. However, lutein and zeaxanthin decreased LPS-induced secretion of IL-8 in cultured UM in a dose-dependent manner. LPS significantly increased NF-kappaB levels in cell nuclear extracts and p-JNK levels in the cell lysates from UM, but not p-p38 MAPK and p-ERG. Lutein or zeaxanthin significantly reduced LPS-induced increase of NF-kappaB and p-JNK levels, but not p38 MAPK and ERG levels. The present study demonstrated that lutein and zeaxanthin inhibited LPS-induced secretion of IL-8 in cultured UM via JNK and NF-kappaB signal pathways. The anti-inflammatory effects of lutein and zeaxanthin might be explored as a therapeutic approach in the management of uveitis and other inflammatory diseases of the eye. PMID- 26609427 TI - Macular Thickness Assessed with Optical Coherence Tomography in Young Chinese Myopic Patients. AB - Purpose. To evaluate the variations in macular thickness in young Chinese myopic persons and the association with axial length (AL), spherical equivalence refraction (SE), age, intraocular pressure, and sex. Methods. In total, 133 young Chinese myopic subjects between 18 and 30 years of age were selected. The macular thickness was assessed using third-generation optical coherence tomography. AL, intraocular pressure, and SE were also measured. Results. The mean central foveal thickness was 191.1 +/- 15.3 um. The macula was consistently thinner in women than in men. Central foveal thickness had a significant positive correlation with AL and a negative correlation with SE. In the inner and outer regions, the macular thickness had a positive correlation with SE and negative correlation with AL. Conclusions. The retina was thinner in women than in men. Associated with myopic progression and AL extension, the central foveal thickness increased, while the retinal thickness of the inner and outer regions decreased. PMID- 26609428 TI - Usefulness of Implantation of Diffractive Multifocal Intraocular Lens in Eyes with Long Axial Lengths. AB - Purpose. This study retrospectively analyzed the postoperative visual functions of myopic eyes implanted with multifocal intraocular lens (IOL) to evaluate the efficacy of multifocal IOL in highly myopic eyes. Methods. We studied 61 patients (96 eyes) who were implanted with multifocal IOL ZMA00 or ZMB00 (Abbott Medical Optics). The patients were stratified into two groups by axial length: 26 mm or above (AL >= 26 group) and below 26 mm (AL < 26 group). Postoperative corrected and uncorrected distance (5 m) and near (30 cm) visual acuity (VA), contrast sensitivity, and depth of focus were compared between two groups. Results. In the AL >= 26 group and the AL < 26 group, the mean +/- standard deviation uncorrected distance logMAR VA at 12-month postoperative follow-up was -0.04 +/- 0.11 and 0.01 +/- 0.14, respectively; and the corrected distance VA was -0.17 +/- 0.08 and -0.14 +/- 0.07, with no significant differences between two groups (p = 0.558 and 0.101; Mann-Whitney U test). For near VA, the corresponding uncorrected VA was 0.06 +/- 0.08 and 0.05 +/- 0.09; and distance-corrected VA was 0.01 +/- 0.06 and 0.01 +/- 0.02, with no significant differences between two groups (p = 0.572, and 0.157; Mann-Whitney U test). Conclusion. The present study demonstrates that it is possible to achieve good uncorrected near and distance VA following implantation of multifocal IOL in eyes with long axial lengths. PMID- 26609429 TI - Telemedicine and Plastic Surgery: A Pilot Study. AB - Background. Telemedicine can be defined as the use of electronic media for transmission of information and medical data from one site to another. The objective of this study is to demonstrate an experience of telemedicine in plastic surgery. Methods. 32 plastic surgeons received a link with password for real-time streaming of a surgery. At the end of the procedure, the surgeons attending the procedure by the Internet answered five questions. The results were analyzed with descriptive statistics. Results. 27 plastic surgeons attended the online procedure in real-time. 96.3% considered the access to the website as good or excellent and 3.7% considered it bad. 14.8% reported that the transmission was bad and 85.2% considered the quality of transmission as good or excellent. 96.3% classified the live broadcasting as a good or excellent learning experience and 3.7% considered it a bad experience. 92.6% reported feeling able to perform this surgery after watching the demo and 7.4% did not feel able. 100% of participants said they would like to participate in other surgical demonstrations over the Internet. Conclusion. We conclude that the use of telemedicine can provide more access to education and medical research, for plastic surgeons looking for medical education from distant regions. PMID- 26609430 TI - The Perception of Evidence for Venous Thromboembolism Prophylaxis Current Practices after Cardiac Surgery: A Canadian Cross-Sectional Survey. AB - Background. Venous thromboembolism (VTE) is the third leading cause of cardiovascular death in patients undergoing surgery. However, VTE prophylaxis practices in cardiac surgery are based on noncardiac surgical literature. The objective of our study was to extract current patterns of VTE prophylaxis practices in cardiac surgery patients. We also aimed to identify health care professionals knowledge of available evidence supporting VTE prophylaxis in adult cardiac surgery patients. Methods. A web-based survey was developed and sent to all Canadian cardiac surgery centers with the intent to have the survey distributed to all personnel involved in the perioperative care of adult cardiac surgery patients. Participation in the questionnaire was voluntary and anonymized. Results. Thirty-five responses were obtained. Sixty-nine percent reported having an established protocol for VTE prophylaxis. However, 83% reported using VTE prophylaxis in their daily practice despite lack of protocol. The majority (60%) believed that the class of recommendation was high despite the lack of evidence. Conclusions. Our survey demonstrated the following. (a) Majority of Canadian centers employ VTE prophylaxis, with considerable variability. (b) There is a misconception among health care professionals about the strength of evidence supporting VTE prophylaxis in cardiac surgery. Our findings highlight the need for appropriately designed studies to fill this knowledge gap. PMID- 26609431 TI - Morphine versus Hydromorphone: Does Choice of Opioid Influence Outcomes? AB - Morphine has traditionally been considered the first line agent for analgesia in hospitals; however, in the last few years there has been a shift towards the use of hydromorphone as a first line agent. We conducted a hospital population based observational study to evaluate the increasing use of hydromorphone over morphine in both medical and surgical populations. Additionally, we assessed the effect of this trend on three key outcomes, including adverse events, length of stay, and readmission rates. We evaluated data from the University Health Systems Consortium. Data from 38 hospitals from October 2010 to September 2013 was analyzed for patients treated with either hydromorphone or morphine. The use of morphine steadily decreased while use of hydromorphone increased in both medical and surgical groups. Rescue drugs were used more frequently in patients treated with hydromorphone in comparison to patients treated with morphine (p < 0.01). Patients receiving morphine tended to stay in the hospital for almost one day longer than patients receiving hydromorphone. However, 30-day all cause readmission rates were significantly higher in patients treated with hydromorphone (p < 0.01). Our study highlights that the choice of hydromorphone versus morphine may influence outcomes. There are implications related to resource utilization and these outcomes. PMID- 26609432 TI - Cone-Beam Computed Tomography Evaluation of Mental Foramen Variations: A Preliminary Study. AB - Background. Mental foramen is important in surgical operations of premolars because it transfers the mental nerves and vessels. This study evaluated the variations of mental foramen by cone-beam computed tomography among a selected Iranian population. Materials and Methods. A total number of 180 cone-beam computed tomography projections were analyzed in terms of shape, size, direction, and horizontal and vertical positions of mental foramen in the right and left sides. Results. The most common shape was oval, opening direction was posterior superior, horizontal position was in line with second premolar, and vertical position was apical to the adjacent dental root. The mean of foremen diameter was 3.59 mm. Conclusion. In addition to the most common types of mental foramen, other variations exist, too. Hence, it reflects the significance of preoperative radiographic examinations, especially 3-dimensional images to prevent nerve damage. PMID- 26609433 TI - Development and Initial Psychometric Evaluation of the Post-Acute Acuity Rating for Children. AB - The Post-Acute Acuity Rating for Children (PAARC) is the first known acuity rating intended to reflect medical severity based on age, reason for admission, diagnoses, dependence in activities of daily living, and technology reliance for children admitted to post-acute care rehabilitation hospitals. Content validity was tested using an expert panel scoring the Content Validity Index (CVI). Concurrent validity was examined using clinician's opinion of acuity at admission, the Complexity Index, and All Patient Refined Diagnosis Related Group (APR-DRG) codes. Predictive validity was examined with acute care readmission within 30 days. Interrater reliability was assessed using admission histories from closed cases. Content validity was established and concurrent validity was moderate to high with clinician opinion (rho = .76, p < .001), the Complexity Index (rho = .76, p < .001), and APR-DRGs (rho = .349, p = .001). Predictive validity was moderate (rho = .504, p = .005) and returns to acute care within 30 days. Interrater reliability was excellent (ICC = 0.97; 95% CI = 0.92-0.90, p < .001). Experts agreed that the PAARC's content is relevant, simple, and representative of the population. The PAARC measured well against indicators of medical complexity for pediatric outpatient care and medical record coding and was reliable between raters. This work supports proceeding with additional development and validity testing of the PAARC. PMID- 26609435 TI - Extracellular alpha-Galactosidase from Trichoderma sp. (WF-3): Optimization of Enzyme Production and Biochemical Characterization. AB - Trichoderma spp. have been reported earlier for their excellent capacity of secreting extracellular alpha-galactosidase. This communication focuses on the optimization of culture conditions for optimal production of enzyme and its characterization. The evaluation of the effects of different enzyme assay parameters such as stability, pH, temperature, substrate concentrations, and incubation time on enzyme activity has been made. The most suitable buffer for enzyme assay was found to be citrate phosphate buffer (50 mM, pH 6.0) for optimal enzyme activity. This enzyme was fairly stable at higher temperature as it exhibited 72% activity at 60 degrees C. The enzyme when incubated at room temperature up to two hours did not show any significant loss in activity. It followed Michaelis-Menten curve and showed direct relationship with varying substrate concentrations. Higher substrate concentration was not inhibitory to enzyme activity. The apparent Michaelis-Menten constant (K m ), maximum rate of reaction (V max), K cat, and catalytic efficiency values for this enzyme were calculated from the Lineweaver-Burk double reciprocal plot and were found to be 0.5 mM, 10 mM/s, 1.30 U mg(-1), and 2.33 U mg(-1) mM(-1), respectively. This information would be helpful in understanding the biophysical and biochemical characteristics of extracellular alpha-galactosidase from other microbial sources. PMID- 26609434 TI - Human Papillomavirus Infection, Infertility, and Assisted Reproductive Outcomes. AB - The human papillomavirus (HPV) is a sexually transmitted infection common among men and women across all geographic and socioeconomic subgroups worldwide. Recent evidence suggests that HPV infection may affect fertility and alter the efficacy of assisted reproductive technologies. In men, HPV infection can affect sperm parameters, specifically motility. HPV-infected sperm can transmit viral DNA to oocytes, which may be expressed in the developing blastocyst. HPV can increase trophoblastic apoptosis and reduce the endometrial implantation of trophoblastic cells, thus increasing the theoretical risk of miscarriage. Vertical transmission of HPV during pregnancy may be involved in the pathophysiology of preterm rupture of membranes and spontaneous preterm birth. In patients undergoing intrauterine insemination for idiopathic infertility, HPV infection confers a lower pregnancy rate. In contrast, the evidence regarding any detrimental impact of HPV infection on IVF outcomes is inconclusive. It has been suggested that vaccination could potentially counter HPV-related sperm impairment, trophoblastic apoptosis, and spontaneous miscarriages; however, these conclusions are based on in vitro studies rather than large-scale epidemiological studies. Improvement in the understanding of HPV sperm infection mechanisms and HPV transmission into the oocyte and developing blastocyst may help explain idiopathic causes of infertility and miscarriage. PMID- 26609436 TI - Mass and Energy Balances of Dry Thermophilic Anaerobic Digestion Treating Swine Manure Mixed with Rice Straw. AB - To evaluate the feasibility of swine manure treatment by a proposed Dry Thermophilic Anaerobic Digestion (DT-AD) system, we evaluated the methane yield of swine manure treated using a DT-AD method with rice straw under different C/N ratios and solid retention time (SRT) and calculated the mass and energy balances when the DT-AD system is used for swine manure treatment from a model farm with 1000 pigs and the digested residue is used for forage rice production. A traditional swine manure treatment Oxidation Ditch system was used as the study control. The results suggest that methane yield using the proposed DT-AD system increased with a higher C/N ratio and shorter SRT. Correspondently, for the DT-AD system running with SRT of 80 days, the net energy yields for all treatments were negative, due to low biogas production and high heat loss of digestion tank. However, the biogas yield increased when the SRT was shortened to 40 days, and the generated energy was greater than consumed energy when C/N ratio was 20 : 1 and 30 : 1. The results suggest that with the correct optimization of C/N ratio and SRT, the proposed DT-AD system, followed by using digestate for forage rice production, can attain energy self-sufficiency. PMID- 26609437 TI - Cortical Reorganization Is Associated with Surgical Decompression of Cervical Spondylotic Myelopathy. AB - BACKGROUND: Cervical spondylotic myelopathy (CSM) results in sensorimotor limb deficits, bladder, and bowel dysfunction, but mechanisms underlying motor plasticity changes before and after surgery are unclear. METHODS: We studied 24 patients who underwent decompression surgery and 15 healthy controls. Patients with mixed upper and lower limb dysfunction (Group A) and only lower limb dysfunction (Group B) were then analysed separately. RESULTS: The sum amplitude of motor evoked potentials sMEP (p < 0.01) and number of focal points where MEPs were elicited (N) (p < 0.001) were significantly larger in CSM patients compared with controls. For Group A (16 patients), sMEP (p < 0.01) and N (p < 0.001) showed similar findings. However, for Group B (8 patients), only N (p = 0.03) was significantly larger in patients than controls. Group A had significantly increased grip strength (p = 0.02) and reduced sMEP (p = 0.001) and N (p = 0.003) after surgery. Changes in sMEP (cMEP) significantly correlated inversely with improved feeding (p = 0.03) and stacking (p = 0.04) times as was the change in number of focal points (NDiff) with improved writing times (p = 0.03). Group B did not show significant reduction in sMEP or N after surgery, or significant correlation of cMEP or NDiff with all hand function tests. No significant differences in H reflex parameters obtained from the flexor carpi radialis, or central motor conduction time changes, were noted after surgery. DISCUSSION: Compensatory expansion of motor cortical representation occurs largely at cortical rather than spinal levels, with a tendency to normalization after surgery. These mirrored improvements in relevant tasks requiring utilization of intrinsic hand muscles. PMID- 26609439 TI - A comparative study between full-dose and half-dose intravesical immune bacille Calmette-Guerin injection in the management of superficial bladder cancer. AB - OBJECTIVES: To determine whether a half-dose of bacille Calmette-Guerin (BCG) can reduce toxicity without affecting its efficacy in the management of non-muscle invasive bladder cancer. PATIENTS AND METHODS: From January 2012 to January 2014, 80 patients with superficial bladder cancer and in the intermediate-risk group were simply randomised to receive two different doses of BCG, i.e., a full dose of 90 mg (group A) or a half-dose of 45 mg (group B). There were no significant differences in clinical and pathological characteristics between the groups. At completion of the study, 40 patients could be evaluated in each group. RESULTS: All patients were evaluated for a follow-up of 12 months after treatment. There was no significant difference in recurrence rate (15 patients, 38%, in group A and 16, 40%, in group B) in the two groups, and no difference in progression rate of the disease, at eight patients (20%) in each group. There were significant differences between groups A and B in toxicity (grade 1 adverse events, 70% vs. 60%; grade 2, 18% vs. 7.5%, respectively). Grade 3 adverse events were only reported in group A (2.5%). CONCLUSION: The half dose of intravesical BCG instillation can reduce the toxicity and side-effects that are associated with the treatment of superficial bladder cancer, without affecting the efficacy of therapy. PMID- 26609438 TI - A Novel Nitronyl Nitroxide with Salicylic Acid Framework Attenuates Pain Hypersensitivity and Ectopic Neuronal Discharges in Radicular Low Back Pain. AB - Evidence has accumulated that reactive oxygen species and inflammation play crucial roles in the development of chronic pain, including radicular low back pain. Nonsteroid anti-inflammatory drugs (NSAIDs), for example, salicylic acid, aspirin, provided analgesic effects in various types of pain. However, long-term use of these drugs causes unwanted side effects, which limits their implication. Stable nitronyl (NIT) nitroxide radicals have been extensively studied as a unique and interesting class of new antioxidants for protection against oxidative damage. The present study synthesized a novel NIT nitroxide radical with salicylic acid framework (SANR) to provide synergistic effect of both antioxidation and antiinflammation. We demonstrated for the first time that both acute and repeated SANR treatment exerted dramatic analgesic effect in radicular low back pain mimicked by chronic compression of dorsal root ganglion in rats. This analgesic potency was more potent than that produced by classical NSAIDs aspirin and traditional nitroxide radical Tempol alone. Furthermore, SANR-induced behavioral analgesia is found to be mediated, at least in partial, by a reduction of ectopic spontaneous discharges in injured DRG neurons. Therefore, the synthesized NIT nitroxide radical coupling with salicylic acid framework may represent a novel potential therapeutic candidate for treatment of chronic pain, including radicular low back pain. PMID- 26609440 TI - Low-dose bacille Calmette-Guerin for non-muscle-invasive bladder cancer: Results of a prospective study. AB - OBJECTIVE: To evaluate the efficacy and safety of low-dose (45 mg) intravesical bacille Calmette-Guerin (BCG) therapy in the treatment of patients with non muscle-invasive bladder cancer (NMIBC), as intravesical BCG is the most acceptable adjuvant therapy for NMI transitional cell carcinoma of the bladder. However, in the standard regimen, undesirable effects are the main cause of treatment discontinuation. PATIENTS AND METHODS: The present study included 37 men with primary NIMBC. All patients underwent complete TURB and 2 weeks later, a 6-week course of 45 mg BCG diluted in 50 mL isotonic saline was instilled into the bladder and retained for 2 h. Patients were evaluated for BCG efficacy (recurrence with or without progression) and safety by documentation of minor and/or major side-effects. RESULTS: There were no major or severe side-effects and no treatment discontinuations. Local adverse effects occurred in 20 patients, while systemic effects, in the form of fever, occurred in six patients (16.2%). There was recurrence in 14 patients (37.8%) after 18-34 months, with disease progression (muscle invasion) in four (10.8%) after 6-18 months. The recurrence index was 0.39/100 patients/month and the mean (range) tumour-free period was 30.97 (7-36) months. CONCLUSION: Low-dose BCG intravesical therapy is an effective adjuvant treatment in NMIBC. However, this needs to be validated in future studies and in comparison with other proposed doses and/or regimens. PMID- 26609441 TI - Bacille Calmette-Guerin dosage; challenging dogmas and changing paradigms. PMID- 26609442 TI - Long-term follow-up after ileocaecal continent cutaneous urinary diversion (Mainz I pouch): A retrospective study of a monocentric experience. AB - OBJECTIVE: To assess the long-term follow-up after ileocaecal continent cutaneous reservoir (ICCR) and to review the late complications. PATIENTS AND METHODS: In all, 756 patients underwent an ICCR in our department, with long-term follow-up data available in 50 patients. The inclusion criterion was ICCR regardless of the indication and the exclusion criteria were orthotopic neobladder or other continent urinary diversions not performed with the ileocaecum. Patients were followed to record primary outcomes and late complications. Complications were stratified according to the Clavien-Dindo classification. RESULTS: The mean patient age was 44 years and pelvic malignancies were the first indication for urinary diversion. The mean (range) follow-up was 19 (9-36) years. A stoma stenosis was the most frequent outlet-related complication requiring re intervention, followed by ischaemic outlet degeneration, and stoma incontinence. Six renal units (RUs) developed obstruction at the anastomotic site and were managed by open surgery. Three RUs had to be removed due to deterioration. A dederivation was necessary in three patients (6%). CONCLUSION: The ICCR is a safe and established technique when an orthotopic pouch is impossible. The long-term follow-up shows acceptable complication rates and satisfactory continence conditions. However, large population studies are necessary to confirm this observation. PMID- 26609443 TI - Immediate and late management of iatrogenic ureteric injuries: 28 years of experience. AB - OBJECTIVE: To evaluate the long-term results after managing intraoperative and late-diagnosed cases of iatrogenic ureteric injury (IUI), treated endoscopically or by open surgery. PATIENTS AND METHODS: Patients immediately diagnosed with IUI were managed under the same anaesthetic, while those referred late had a radiological assessment of the site of injury, and endoscopic management. Open surgical procedures were used only for the failed cases with previous diversion. RESULTS: In all, 98 patients who were followed had IUI after gynaecological, abdominopelvic and ureteroscopic procedures in 60.2%, 14.3% and 25.5%, respectively. The 27 patients diagnosed during surgery were managed immediately, while in the late-referred 71 patients ureteroscopic ureteric realignment with stenting was successful in 26 (36.6%). Complex open reconstruction with re implantation or ureteric substitution, using bladder-tube or intestinal-loop procedures, was used in 27 (60%), 16 (35.5%) and two (4.5%) patients of the late group, respectively. A long-term radiological follow-up with a mean (range) of 46.6 (24.5-144) months showed recurrent obstruction in 16 (16.3%) patients managed endoscopically and reflux in six (8.3%) patients. Three renal units only (3%) were lost in the late-presenting patients. CONCLUSION: Patients managed immediately had better long-term results. More than a third of the late-diagnosed patients were successfully managed endoscopically with minimal morbidity. Open reconstruction by an experienced urologist who can perform a complex substitutional procedure was mandatory to preserve renal units in the long-term. PMID- 26609444 TI - After urgent drainage of an obstructed kidney by internal ureteric stenting; is ureteroscopic stone extraction always needed? AB - OBJECTIVES: To assess the probability of spontaneous stone passage and its predictors after drainage of obstructed kidney by JJ stent, as insertion of an internal ureteric stent is often used for renal drainage in cases of calcular ureteric obstruction. PATIENTS AND METHODS: Between January 2011 and June 2013, patients for whom emergent drainage by ureteric stents were identified. The patients' demographics, presentation, and stone characteristics were reviewed. The primary endpoint for this study was stone-free status at the time of stent removal, where all patients underwent non-contrast spiral computed tomography (NCCT) before stent removal. Ureteroscopic stone extraction was performed for CT detectable ureteric stones at the time of stent removal. Potential factors affecting the need for ureteroscopic stone extraction at the time of stent removal were assessed using univariate and multivariate statistical analyses. RESULTS: Emergent ureteric stents were undertaken in 196 patients (112 males, 84 females) with a mean (SD) age of 53.7 (16.2) years, for renal obstruction drainage. At the time of stent removal, 83 patients (42.3%) were stone free; with the remaining 113 patients (57.7%) undergoing ureteroscopic stone extraction. On multivariate analysis, stone width [odds ratio (OR) 15.849, 95% confidence interval (CI) 2.83; P = 0.002) and radio-opaque stones (OR 12.035, 95% CI 4.65; P < 0.001) were independent predictors of the need for ureteroscopic stone extraction at the time of stent removal. CONCLUSION: Spontaneous ureteric stone passage is possible after emergent drainage of an obstructed kidney by ureteric stenting. Stone opacity, larger stone width, and positive preoperative urine culture are associated with a greater probability of requiring ureteroscopic stone extraction after emergent drainage by ureteric stenting. PMID- 26609445 TI - Prospective evaluation of outcome of percutaneous nephrolithotomy using the 'STONE' nephrolithometry score: A single-centre experience. AB - OBJECTIVE: To assess the prediction of stone clearance and complications of percutaneous nephrolithotomy (PCNL) using the 'STONE' nephrolithometry score, assessing stone size, tract length (skin-to-stone distance), degree of obstruction, number of calyces involved and stone essence (density). PATIENTS AND METHODS: This was a prospective study of patients undergoing single-tract PCNL while prone, conducted at a university hospital. All patients had non-contrast enhanced computed tomography within 3 weeks of the procedure. Only patients with a unilateral procedure and radio-opaque stones were included. The five variables of the STONE nephrolithometry score were calculated before the procedure. The stone-free rates were assessed with a plain abdominal film at 4 weeks and complications were graded using the modified Clavien system. RESULTS: In all, 107 patients were included in the final analysis. Overall, 80% of patients were rendered stone-free. Among the individual variables, a larger stone (P = 0.002) and the involvement of multiple calyces (P = 0.04) were associated with residual stones, while tract length (skin-to-stone distance), stone density and presence of hydronephrosis were not. Patients who were rendered stone-free had a statistically significant lower overall STONE score than those with residual stones, at 7.24 vs. 8.14 (P = 0.02). The score also correlated with operative duration, which was significantly longer with a higher STONE score (P = 0.03). The complication rate was 18% and most complications were Clavien grade 2, with bleeding requiring a blood transfusion (11 patients) being the commonest. There were no deaths within 30 days of surgery, but there was no correlation between the STONE score and complications. CONCLUSION: The STONE nephrolithometry score is a simple and easy to apply system for predicting complexity in stone clearance with PCNL. PMID- 26609446 TI - Modular training for percutaneous nephrolithotripsy: The safe way to go. AB - Objectives should be describe a modular training scheme (MTS) which aims to provide training in percutaneous nephrolithotripsy (PCNL) and ensure the safety of the patients. SUBJECTS AND METHODS: Two trainees with no experience in PCNL attended the MTS under the supervision of an experienced mentor. The MTS included five modules, comprising an initial animal laboratory course (using pigs), to acquire basic skills (Module 1), and Modules 2-5 included making the puncture, tract dilatation, single-stone and large-stone management in clinical cases, respectively. Each participant progressed from one module to the next under constant mentoring and evaluation by the mentor. When the trainees completed the MTS they proceeded to perform 60 PCNL procedures independently while the mentor performed 25 for comparison purposes. A global rating scale was used for the objective evaluation of the trainees. Peri-operative variables were recorded and statistically compared as appropriate. Statistical significance was defined as P < 0.05. RESULTS: One pig and 16 patients, and two pigs and 22 patients, were necessary to complete the MTS by each subject. There were no significant differences among the characteristics of the independently performed operations. The duration of surgery and fluoroscopy achieved a plateau similar to those of the mentor after ~ 30 patients. The decrease in haemoglobin level, stone-free and complication rates in the patients were similar among the two trainees and the mentor. The complication rate of the trainees and the mentor never exceeded 13.3%. CONCLUSION: The MTS successfully combined animal and stepwise clinical training based on a standardised technique and objective evaluation. PMID- 26609447 TI - Is there a way to predict failure after direct vision internal urethrotomy for single and short bulbar urethral strictures? AB - OBJECTIVE: To identify patient and stricture characteristics predicting failure after direct vision internal urethrotomy (DVIU) for single and short (<2 cm) bulbar urethral strictures. PATIENTS AND METHODS: We retrospectively analysed the records of adult patients who underwent DVIU between January 2002 and 2013. The patients' demographics and stricture characteristics were analysed. The primary outcome was procedure failure, defined as the need for regular self-dilatation (RSD), redo DVIU or substitution urethroplasty. Predictors of failure were analysed. RESULTS: In all, 430 adult patients with a mean (SD) age of 50 (15) years were included. The main causes of stricture were idiopathic followed by iatrogenic in 51.6% and 26.3% of patients, respectively. Most patients presented with obstructive lower urinary tract symptoms (68.9%) and strictures were proximal bulbar, i.e. just close to the external urethral sphincter, in 35.3%. The median (range) follow-up duration was 29 (3-132) months. In all, 250 (58.1%) patients did not require any further instrumentation, while RSD was maintained in 116 (27%) patients, including 28 (6.5%) who required a redo DVIU or urethroplasty. In 64 (6.5%) patients, a redo DVIU or urethroplasty was performed. On multivariate analysis, older age at presentation [odds ratio (OR) 1.017; P = 0.03], obesity (OR 1.664; P = 0.015), and idiopathic strictures (OR 3.107; P = 0.035) were independent predictors of failure after DVIU. CONCLUSION: The failure rate after DVIU accounted for 41.8% of our present cohort with older age at presentation, obesity, and idiopathic strictures independent predictors of failure after DVIU. This information is important in counselling patients before surgery. PMID- 26609448 TI - Contemporary practice of testicular prosthesis insertion. AB - OBJECTIVES: To assess the practice of testicular prosthesis insertion (TPI) related to orchidectomy in one geographical region and to identify the difference in the rates of insertion among different age groups. PATIENTS AND METHODS: Males who underwent orchidectomy between 1989 and 2009 were identified from data collected from Scottish Morbidity Records. Patients were classified into six age groups. The TPI rate and relation to original orchidectomy were analysed according to different age groups. RESULTS: In all, 3364 patients underwent orchidectomy in the 20-year period of the study. The most common indications for orchidectomy were atrophy, undescended testes, torsion, and tumour. In the same period, 530 patients had a TPI, with 59.4% of them (316 patients) having TPI at initial surgery, 17.3% (92) as a second surgical procedure, and 22.8% (122) having the TPI without prior history of orchidectomy. Among patients who underwent TPI, postpubertal males were more likely to have simultaneous insertion at the time of orchidectomy than prepubertal males (83% vs 32%; odds ratio 10.44, 95% confidence interval 5.23-20.82; P < 0.01). CONCLUSION: Younger males are more likely to have TPI at a later date. Paediatric urologists should be mindful of the possibility of concurrent TPI at the time of initial scrotal/groin exploration. PMID- 26609449 TI - The Egydio geometrical procedure for managing penile curvature using a single relaxing incision: A single-centre experience with 330 patients. AB - OBJECTIVE: To present our 3-year experience with the Egydio's geometrical procedure for managing penile curvature with some modifications. PATIENTS AND METHODS: In all, 330 patients (mean age 51 years) that underwent the Egydio's procedure as day cases were included in this study. RESULTS: The mean penile curvature was 45 degrees and 27.3% of the patients reported mild erectile dysfunction (ED) preoperatively. Partial excision of the calcified plaque was performed in 12.1% of the patients. Partial glans necrosis was recorded in one patient, while haematoma was recorded in 9%, and delayed wound healing in 3%. There was residual curvature (mean 20 degrees ) requiring reoperation in 8.2% of the patients. In all, 10% of the patients were dissatisfied with their results, while of the remainder, 75.2% were totally satisfied and 14.8% partially satisfied. ED was reported in 31.8% of the patients (moderate: 17.3% and significant: 2.7%). CONCLUSIONS: The Egydio geometrical technique for the treatment of penile curvature seems to be a simple, reproducible, safe, and efficient operation. PMID- 26609450 TI - Laparoscopic and cystoscopic-assisted suprapubic catheter insertion: A case study and technical note. AB - OBJECTIVE: To describe a new technique for suprapubic urinary catheterisation that can be used in selected patients with high anaesthetic risk, and previous lower abdominal surgery and bowel adhesions. PATIENT AND METHODS: In a 33-year old woman, laparoscopic guidance with cystoscopic vision was used to ensure the safe passage of a suprapubic catheter. RESULTS: The suprapubic catheter was successfully inserted in this challenging patient; release of adhesions allowed for the passage of the catheter without bowel injury. CONCLUSION: Laparoscopic and cystoscopic-assisted suprapubic catheter insertion is a novel technique to avoid significant morbidity and mortality in selected patients with high anaesthetic risk, and previous lower abdominal surgery and bowel adhesions. PMID- 26609451 TI - Outcome of glomerulonephritis in live-donor renal transplant recipients: A single centre experience. AB - OBJECTIVES: To investigate the frequency and risk factors affecting the incidence of post-transplantation glomerulonephritis (GN) and the impact of GN on the survival of the graft and the patient. PATIENTS AND METHODS: Patients were classified based on histological findings into three groups. Graft survival was ascertained using the Kaplan-Meier method and significance calculated using log rank tests. For multivariate analysis the Cox model was used. RESULTS: Transplant glomerulopathy was the most prevalent glomerular disease in our series followed by recurrent GN and lastly de novo GN. In all, 50% of the de novo GN group had diabetes. The worst graft outcomes were in the recurrent GN group (P = 0.044). Multivariate analysis revealed ageing of the graft and mammalian target of rapamycin (mTOR) immunosuppression as risk factors for development of GN. While, the age of the recipient and donor, anti-lymphocyte globulin induction therapy, and acute rejection were risk factors for poor graft outcomes. CONCLUSIONS: GN is an important issue after transplantation. Tracking the incidence and progression of histological findings in the graft may help to guide proper management and improve graft outcome. PMID- 26609453 TI - Type VI Aplasia Cutis Congenita: Bart's Syndrome. AB - Bart's syndrome is characterized by aplasia cutis congenita and epidermolysis bullosa. We present the case of a newborn male who developed blisters on the mucous membranes and the skin following congenital localized absence of skin. Bart's syndrome (BS) is diagnosed clinically based on the disorder's unique signs and symptoms but histologic evaluation of the skin can help to confirm the final diagnosis. The patient was managed conservatively with topical antibacterial ointment and wet gauze dressing. Periodic follow-up examinations showed complete healing. We emphasized that it is important to use relatively simple methods for optimal healing without the need for complex surgical interventions. PMID- 26609452 TI - Aesthetic Surgical Crown Lengthening Procedure. AB - The aim of this case report was to describe the surgical sequence of crown lengthening to apically reposition the dentogingival complex, in addition to an esthetic restorative procedure. Many different causes can be responsible for short clinical crown. In these cases, the correct execution of a restorative or prosthetic rehabilitation requires an increasing of the crown length. According to the 2003 American Academy of Periodontology (Practice Profile Survey), crown lengthening is the most habitual surgical periodontal treatment. PMID- 26609454 TI - Ischemic Colitis Caused by Intra-Aortic Balloon Pump Counterpulsation. AB - Intra-aortic balloon pump counterpulsation (IABP) has been shown to prolong life in critically ill cardiac patients. However, complications including distal emboli, balloon rupture, bleeding, limb loss, and bowel ischemia continue to be associated with them. We present a case of a 56-year-old male who suffered bowel ischemia as a result of a malpositioned IABP. While the benefit of such devices in critically ill patients is not disputed, patients as well as clinicians should be aware of the potential side effects and patients undergoing IABP placement should be monitored for complications. PMID- 26609455 TI - Vitamin B12 Deficiency and Hemoglobin H Disease Early Misdiagnosed as Thrombotic Thrombocytopenic Purpura: A Series of Unfortunate Events. AB - We herein would like to report an interesting case of a patient who presented with anemia and thrombocytopenia combined with high serum Lactic Dehydrogenase where Thrombotic Thrombocytopenic Purpura was originally considered. As indicated a central venous catheter was inserted in his subclavian vein which led to mediastinal hematoma and finally intubation and Intensive Care Unit (ICU) hospitalization. After further examination patient was finally diagnosed with B12 deficiency in a setting of H hemoglobinopathy. There have been previous reports where pernicious anemia was originally diagnosed and treated as Thrombotic Thrombocytopenic Purpura but there has been none to our knowledge that was implicated with hemothorax and ICU hospitalization or correlated with thalassemia and we discuss the significance of accurate diagnosis in order to avoid adverse reactions and therapy implications. PMID- 26609456 TI - GABAB Encephalitis: A Fifty-Two-Year-Old Man with Seizures, Dysautonomia, and Acute Heart Failure. AB - Autoantibodies to the gamma-aminobutyric acid receptor, subtype B (GABAB), are a known cause of limbic encephalitis. The spectrum of clinical manifestations attributable to this antibody is not well defined at the present time. Here we present a case of GABAB encephalitis presenting with encephalopathy, status epilepticus, dysautonomia, and acute heart failure. To our knowledge, heart failure and dysautonomia have not yet been reported with this syndrome. PMID- 26609457 TI - Corrigendum to "The Treatment of Giant Periurethral Condyloma in Pregnancy Using an Ultrasonic Thermal Scalpel: A Case Report and New Single Session Treatment Option". AB - [This corrects the article DOI: 10.1155/2015/792412.]. PMID- 26609458 TI - Leclercia adecarboxylata Musculoskeletal Infection in an Immune Competent Pediatric Patient: An Emerging Pathogen? AB - Case. An immune competent pediatric patient presented with a persistent lower extremity infection with Leclercia adecarboxylata after a penetrating injury. This case report details the presentation, clinical course, and treatment. Conclusion. Leclercia adecarboxylata has increasing reports in immunosuppressed and adult patients with musculoskeletal infection. This case now indicates that Leclercia adecarboxylata is a potential pathogen in immune competent children in musculoskeletal tissue. PMID- 26609459 TI - Efficacy of Adalimumab in a Girl with Refractory Intestinal Behcet's Disease. AB - We describe our experience with a juvenile patient who had refractory intestinal Behcet's disease that responded to adalimumab, a fully humanized antibody against soluble TNF-alpha and its receptor. The patient, a 13-year-old girl, presented with oral aphthous ulcers, vulvar pain, and rashes on the lower extremities. She gradually developed a low-grade fever, abdominal pain, diarrhea, and hematochezia. Lower gastrointestinal endoscopy revealed ulcers in the terminal ileum, consistent with intestinal Behcet's disease. Methylprednisolone pulse therapy was initiated, after which the symptoms transiently improved, but, during the corticosteroid taper, the abdominal pain recurred. The symptoms resolved soon after the administration of adalimumab. Of importance, the dose of corticosteroids was successfully reduced without exacerbation during 8 months of observation. This is the first reported case in which adalimumab was used for pediatric gastrointestinal Behcet's disease. Adalimumab is a good choice for intestinal Behcet's disease refractory to conventional treatment. PMID- 26609460 TI - A Rare Case of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia. AB - Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare clinical condition with only about 100 cases reported in the literature. It is characterized by primary hyperplasia of pulmonary neuroendocrine cells (PNECs) which are specialized epithelial cells located throughout the entire respiratory tract, from the trachea to the terminal airways. DIPNECH appears in various forms that include diffuse proliferation of scattered neuroendocrine cells, small nodules, or a linear proliferation. It is usually seen in middle-aged, nonsmoking women with symptoms of cough, dyspnea, and wheezing. We present a 45-year-old, nonsmoking woman who presented with symptoms of DIPNECH associated with bilateral pulmonary nodules and left hilar adenopathy. Of interest, DIPNECH in our patient was associated with metastatic pulmonary carcinoids, papillary carcinoma of the left breast, oncocytoma and angiomyolipoma of her left kidney, and cortical nodules suggestive of tuberous sclerosis. She had video assisted thoracoscopic surgery (VATS), modified radical mastectomy with reconstruction, and radical nephrectomy. She is currently symptom-free most of the time with over two years of follow-up. PMID- 26609461 TI - Sternalis Muscle: An Unexpected Finding during Mastectomy. AB - Sternalis muscle also called rectus sternalis, rectus thoracis, or episternalis is an anomalous muscle of the anterior chest wall with unknown anatomical function. It is regularly observed in lower animal but infrequently in humans. Presence of this muscle can create confusion with tumours of the anterior chest wall during routine mammography. Although less is known about its origin and innervations, knowledge about this muscle can have many clinical implications. A case of unilateral sternalis muscle detected during mastectomy, in a female with carcinoma of the right breast, is being reported with a brief review of the literature and highlighting its clinical significance. PMID- 26609462 TI - Abnormal Cerebrovascular Reactivity in Parkinson's Disease. PMID- 26609463 TI - Separation of Berberine Hydrochloride and Tetrahydropalmatine and Their Quantitative Analysis with Thin Layer Chromatography Involved with Ionic Liquids. AB - [BMIM]OH was used in mobile and stationary phase of thin layer chromatography (TLC) to analyze berberine hydrochloride and tetrahydropalmatine for the first time. Supported imidazole ionic liquid with hydroxide ion on silica gel (SiO2.Im(+).OH(-)) was synthesized through simple procedure and characterized by Fourier transform infrared spectroscopy (FT-IR), elemental analysis, and scanning electron microscope (SEM). Moreover, on the plates prepared by SiO2.Im(+).OH(-), the contents of the above alkaloids in the Chinese patent medicine (CPM) of "Stomacheasy" capsule were successfully determined by TLC scanner. The key conditions and chromatographic behaviors were also investigated in detail. According to similar ways, ionic liquids (ILs) also can be used in other planar chromatographies in two modes. This study is expected to be helpful in expanding the application of IL and its bonded silica gel in TLC separation field. PMID- 26609464 TI - Incidental Findings of Bacterial Vaginosis and Other Infections in Papanicolaou Smears of HIV-infected and HIV-uninfected Adolescent Females in South Africa. AB - Bacterial vaginosis (BV) is a widely prevalent infection that is associated with a range of adverse outcomes. We compared the rates of incidentally identified BV and other cervico-vaginal infections on Papanicolaou (Pap) smears of HIV-infected and HIV-uninfected adolescent females in South Africa. Cervical specimens from 50 HIV-uninfected and 32 HIV-infected sexually active South African adolescent females age 17-21 were collected and analyzed in accordance with the Bethesda system. We found a high overall prevalence of BV (54.9%) in our cohort. While previous research has found an increased prevalence of BV among HIV-infected women, the difference in the prevalence of BV between our HIV-infected group (62.5%) and HIV-uninfected group (50.0%) was not found to be statistically significant. The high rate of BV in both of these groups has significant implications for their risk of HIV acquisition and/or transmission in addition to other associated risks of BV. Given that the Pap smear is specific in incidentally diagnosing BV, it may be utilized as a screening method for BV in the adolescent population. PMID- 26609465 TI - Metabolite Signatures in Hydrophilic Extracts of Mouse Lungs Exposed to Cigarette Smoke Revealed by 1H NMR Metabolomics Investigation. AB - 1H-NMR metabolomics was used to investigate the changes of metabolites in the lungs of mice with and without being exposed to a controlled amount of cigarette smoke. It was found that the concentrations of adenosine derivatives (i.e. ATP, ADP and AMP), inosine and uridine were significantly changed in the lungs of mice exposed to cigarette smoke when compared with controls regardless the mice were obese or of regular weight. The decreased ATP, ADP, AMP and elevated inosine suggested that the deaminases in charge of adenosine derivatives to inosine derivatives conversion would be significantly changed in the lungs of mice exposed to cigarette smoke. Indeed, transcriptional study confirmed that the concentrations of adenosine monophosphate deaminase 2 and adenosine deaminase 2 were significantly changed in the lungs of mice exposed to cigarette smoke. We also found that the ratio of glycerophosphocholine (GPC) to phosphocholine (PC) was significantly increased in the lungs of obese mice compared with those of the regular weight mice. The GPC/PC ratio was further elevated in the lungs of obese group exposed to cigarette smoke. PMID- 26609466 TI - Metabolic Profiling Comparison of Human Pancreatic Ductal Epithelial Cells and Three Pancreatic Cancer Cell Lines using NMR Based Metabonomics. AB - Metabolic profiles of hydrophilic and lipophilic cell extracts from three cancer cell lines, Miapaca-2, Panc-1 and AsPC-1, and a non-cancerous pancreatic ductal epithelial cell line, H6C7, were examined by proton nuclear magnetic resonance spectroscopy. Over twenty five hydrophilic metabolites were identified by principal component and statistical significance analyses as distinguishing the four cell types. Fifteen metabolites were identified with significantly altered concentrations in all cancer cells, e.g. absence of phosphatidylgrycerol and phosphatidylcholine, and increased phosphatidylethanolamine and cholesterols. Altered concentrations of metabolites involved in glycerophospholipid metabolism, lipopolysaccharide and fatty acid biosynthesis indicated differences in cellular membrane composition between non-cancerous and cancer cells. In addition to cancer specific metabolites, several metabolite changes were unique to each cancer cell line. Increased N-acetyl groups in AsPC-1, octanoic acids in Panc-1, and UDP species in Miapaca-2 indicated differences in cellular membrane composition between the cancer cell lines. Induced glutamine metabolism and protein synthesis in cancer cells were indicated by absence of glutamine other metabolites such as acetate, lactate, serine, branched amino acids, and succinate. Knowledge of the specifically altered metabolic pathways identified in these pancreatic cancer cell lines may be useful for identifying new therapeutic targets and studying the effects of potential new therapeutic drugs. PMID- 26609468 TI - PAQR3: a novel tumor suppressor gene. AB - PAQR3, also known as RKTG (Raf kinase trapping to Golgi), is a member of the progestin and adipoQ receptor (PAQR) family. The role of PAQR3 as a tumor suppressor has recently been established in different types of human cancer in which PAQR3 exerts its biological function through negative regulation of the oncogenic Raf/MEK/ERK signaling. Multiple studies have found that PAQR3 downregulation frequently occurs in human cancers and is very often associated with tumor progression and shortened patients' survival. Moreover, restoring the expression of PAQR3 could induce apoptosis and inhibit proliferation and invasiveness of cancer cells. Downregulation of PAQR3 by oncogenic microRNAs has also been reported. In this review, we summarized current knowledge concerning the role of PAQR3 in tumor development. To our knowledge, this is the first review on the role of this novel tumor suppressor. PMID- 26609470 TI - Muc1 promotes migration and lung metastasis of melanoma cells. AB - Early stages of melanoma can be successfully treated by surgical resection of the tumor, but there is still no effective treatment once it is progressed to metastatic phases. Although growing family of both melanoma metastasis promoting and metastasis suppressor genes have been reported be related to metastasis, the molecular mechanisms governing melanoma metastatic cascade are still not completely understood. Therefore, defining the molecules that govern melanoma metastasis may aid the development of more effective therapeutic strategies for combating melanoma. In the present study, we found that muc1 is involved in the metastasis of melanoma cells and demonstrated that muc1 disruption impairs melanoma cells migration and metastasis. The requirement of muc1 in the migration of melanoma cells was further confirmed by gene silencing in vitro. In corresponding to this result, over-expression of muc1 significantly promoted the migratory of melanoma cells. Moreover, down-regulation of muc1 expression strikingly inhibits melanoma cellular metastasis in vivo. Finally, we found that muc1 promotes melanoma migration through the protein kinase B (Akt) signaling pathway. To conclude, our findings suggest a novel mechanism underlying the metastasis of melanoma cells which might serve as a new intervention target for the treatment of melanoma. PMID- 26609467 TI - Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence. AB - An increasing number of tumors, including breast cancer, overexpress proteins of the epidermal growth factor receptor (EGFR) family. The interaction between family members activates signaling pathways that promote tumor progression and resistance to treatment. Human epidermal growth factor receptor type II (HER2) positive breast cancer represents a clinical challenge for current therapy. It has motivated the development of novel and more effective therapeutic EGFR family target drugs, such as tyrosine kinase inhibitors (TKIs). This review focuses on the effects of three TKIs mostly studied in HER2- positive breast cancer, lapatinib, gefitinib and neratinib. Herein, we discuss the mechanism of action, therapeutic advantages and clinical applications of these TKIs. To date, TKIs seem to be promising therapeutic agents for the treatment of HER2-overexpressing breast tumors, either as monotherapy or combined with other pharmacological agents. PMID- 26609469 TI - Induction of autophagy and apoptosis by miR-148a through the sonic hedgehog signaling pathway in hepatic stellate cells. AB - Autophagy is an evolutionarily conserved biological process that is activated in response to stress. Increasing evidence indicate that dysregulated miRNAs significantly contribute to autophagy and are thus implicated in various pathological conditions, including hepatic fibrosis. MiR-148a, a member of the miR-148/152 family, has been found to be downregulated in hepatic fibrosis and human hepatocellular carcinoma. However, the role of miR-148a in the development of hepatic fibrosis remains largely unknown. In this study, we describe the epigenetic regulation of miR-148a and its impact on autophagy in hepatic stellate cells (HSCs), exploring new targets of miR-148a. We found that miR-148a expression was significantly increased under starvation-induced conditions in LX 2 and T-6 cells. In addition, dual-luciferase reporter assays showed that miR 148a suppressed target gene expression by directly interacting with the 3' untranslated regions (3'-UTRs) of growth arrest-specific gene 1 (Gas1) transcripts. Intriguingly, Gas1, which encodes a Hedgehog surface binding receptor and facilitates the Hedgehog (Hh) signaling pathway, inhibited autophagosome synthesis. Furthermore, we demonstrated a novel function for miR 148a as a potent inducer of autophagy in HSCs. Overexpressing of miR-148a increased autophagic activity, which inhibited proliferation and promoted apoptosis in HSCs. In conclusion, these data support a novel role for miR-148a as a key regulator of autophagy through the Hh signaling pathway, making miR-148a a potential candidate for the development of novel therapeutic strategies. PMID- 26609471 TI - Differential network analysis reveals dysfunctional regulatory networks in gastric carcinogenesis. AB - Gastric Carcinoma is one of the most common cancers in the world. A large number of differentially expressed genes have been identified as being associated with gastric cancer progression, however, little is known about the underlying regulatory mechanisms. To address this problem, we developed a differential networking approach that is characterized by including a nascent methodology, differential coexpression analysis (DCEA), and two novel quantitative methods for differential regulation analysis. We first applied DCEA to a gene expression dataset of gastric normal mucosa, adenoma and carcinoma samples to identify gene interconnection changes during cancer progression, based on which we inferred normal, adenoma, and carcinoma-specific gene regulation networks by using linear regression model. It was observed that cancer genes and drug targets were enriched in each network. To investigate the dynamic changes of gene regulation during carcinogenesis, we then designed two quantitative methods to prioritize differentially regulated genes (DRGs) and gene pairs or links (DRLs) between adjacent stages. It was found that known cancer genes and drug targets are significantly higher ranked. The top 4% normal vs. adenoma DRGs (36 genes) and top 6% adenoma vs. carcinoma DRGs (56 genes) proved to be worthy of further investigation to explore their association with gastric cancer. Out of the 16 DRGs involved in two top-10 DRG lists of normal vs. adenoma and adenoma vs. carcinoma comparisons, 15 have been reported to be gastric cancer or cancer related. Based on our inferred differential networking information and known signaling pathways, we generated testable hypotheses on the roles of GATA6, ESRRG and their signaling pathways in gastric carcinogenesis. Compared with established approaches which build genome-scale GRNs, or sub-networks around differentially expressed genes, the present one proved to be better at enriching cancer genes and drug targets, and prioritizing disease-related genes on the dataset we considered. We propose this extendable differential networking framework as a promising way to gain insights into gene regulatory mechanisms underlying cancer progression and other phenotypic changes. PMID- 26609472 TI - Beclin-1-independent autophagy mediates programmed cancer cell death through interplays with endoplasmic reticulum and/or mitochondria in colbat chloride induced hypoxia. AB - Autophagy has dual functions in cell survival and death. However, the effects of autophagy on cancer cell survival or death remain controversial. In this study, we show that Autophagy can mediate programmed cell death (PCD) of cancer cells in responding to cobalt chloride (CoCl2)-induced hypoxia in a Beclin-1-independent but autophagy protein 5 (ATG5)-dependent manner. Although ATG5 is not directly induced by CoCl2, its constitutive expression is essential for CoCl2-induced PCD. The ATG5-mediated autophagic PCD requires interplays with endoplasmic reticulum (ER) and/or mitochondria. In this process, ATG5 plays a central role in regulating ER stress protein CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) and mitochondrial protein second mitochondria derived activator of caspases (Smac). Two pathways for autophagic PCD in cancer cells responding to hypoxia have been identified: ATG5/CHOP/Smac pathway and ATG5/Smac pathway, which are probably dependent on the context of cell lines. The former is more potent than the latter for the induction of PCD at the early stage of hypoxia, although the ultimate efficiency of both pathways is comparable. In addition, both pathways may require ATG5-mediated conversion of LC3-I into LC3-II. Therefore, we have defined two autophagy-mediated pathways for the PCD of cancer cells in hypoxia, which are dependent on ATG5, interplayed with ER and mitochondria and tightly regulated by hypoxic status. The findings provide a new evidence that autophagy may inhibit tumor cell proliferation through trigger of PCD, facilitating the development of novel anti-cancer drugs. PMID- 26609473 TI - LIN28B suppresses microRNA let-7b expression to promote CD44+/LIN28B+ human pancreatic cancer stem cell proliferation and invasion. AB - Although the highly proliferative, migratory, and multi-drug resistant phenotype of human pancreatic cancer stem cells (PCSCs) is well characterized, knowledge of their biological mechanisms is limited. We used CD44 and LIN28B as markers to screen, isolate, and enrich CSCs from human primary pancreatic cancer. Using flow cytometry, we identified a human primary pancreatic cancer cell (PCC) subpopulation expressing high levels of both CD44 and LIN28B. CD44+/LIN28B+ PCSCs expressed high levels of stemness marker genes and possessed higher migratory and invasive ability than CD44-/LIN28B- PCCs. CD44+/LIN28B+ PCSCs were more resistant to growth inhibition induced by the chemotherapeutic drugs cisplatin and gemcitabine hydrochloride, and readily established tumors in vivo in a relatively short time. Moreover, microarray analysis revealed significant differences between the cDNA expression patterns of CD44+/LIN28B+ PCSCs and CD44-/LIN28B- PCCs. Following siRNA interference of endogenous LIN28B gene expression in CD44+/LIN28B+ PCSCs, not only was their proliferation decreased, there was also cell cycle arrest due to suppression of cyclin D1 expression following the stimulation of miRNA let-7b expression. In conclusion, CD44+/LIN28B+ cells, which possess CSC characteristics, can be reliably sorted from human primary PCCs and represent a valuable model for studying cancer cell physiology and multi-drug resistance. PMID- 26609474 TI - Selective inhibition of EGFR downstream signaling reverses the irradiation enhanced migration of HNSCC cells. AB - Irradiation, which is one of the standard therapies used to treat squamous cell carcinoma of the head and neck (HNSCC), has been linked to enhanced tumor migration in carcinomas. In this study, we demonstrated that irradiation induced the phosphorylation of AKT, p38 MAPK and ERK. The combined activation of these pathways caused inactivation of GSK3beta kinase, resulting in enhanced tumor cell migration. Here, we describe that the exclusive and specific inhibition of just one of the aforementioned key signaling molecules is sufficient to restore GSK3beta activity and to reduce radiation-induced migration in HNSCC. These data indicate that pharmacological inhibition of pathways targeting GSK3beta could decrease radiation-induced cell migration in HNSCC and thus potentially reduce metastasis and locoregional recurrence in patients. PMID- 26609475 TI - 3-bromopyruvate enhanced daunorubicin-induced cytotoxicity involved in monocarboxylate transporter 1 in breast cancer cells. AB - Increasing evidence demonstrates that the hexokinase inhibitor 3-bromopyruvate (3 BrPA) induces the cell apoptotic death by inhibiting ATP generation in human cancer cells. Interestingly, some tumor cell lines are less sensitive to 3-BrPA induced apoptosis than others. Moreover, the molecular mechanism of 3-BrPA trigged apoptosis is unclear. In the present study, we examined the effects of 3 BrPA on the viability of the breast cancer cell lines MDA-MB-231 and MCF-7. We further investigated the potential roles of monocarboxylate transporter 1 (MCT1) in drug accumulation and efflux of breast cancer cells. Finally, we explored whether 3-BrPA enhanced daunorubicin (DNR)-induced cytotoxicity through regulation of MCT1 in breast cancer cells. MTT and colony formation assays were used to measure cell viability. Western blot analysis, flow cytometric analysis and fluorescent microscopy were used to determine the molecular mechanism of actions of MCT1 in different breast cancer cell lines. Whole-body bioluminescence imaging was used to investigate the effect of 3-BrPA in vivo. We found that 3 BrPA significantly inhibited cell growth and induced apoptosis in MCF-7 cell line, but not in MDA-MB-231 cells. Moreover, we observed that 3-BrPA efficiently enhanced DNR-induced cytotoxicity in MCF-7 cells by inhibiting the activity of ATP-dependent efflux pumps. We also found that MCT1 overexpression increased the efficacy of 3-BrPA in MDA-MB-231 cells. 3-BrPA markedly suppressed subcutaneous tumor growth in combination with DNR in nude mice implanted with MCF-7 cells. Lastly, our whole-body bioluminescence imaging data indicated that 3-BrPA promoted DNR accumulation in tumors. These findings collectively suggest that 3 BrPA enhanced DNR antitumor activity in breast cancer cells involved MCT-1, suggesting that inhibition of glycolysis could be an effective therapeutic approach for breast cancer treatment. PMID- 26609476 TI - Three-dimensional assessment of bystander effects of mesenchymal stem cells carrying a cytosine deaminase gene on glioma cells. AB - Stem cells carrying a suicide gene have emerged as therapeutic candidates for their cytotoxic bystander effects on neighboring cancers, while being non-toxic to other parts of the body. However, traditional cytotoxicity assays are unable to adequately assess the therapeutic effects of bystander cells. Here, we report a method to assess bystander effects of therapeutic stem cells against 3 dimensionally grown glioma cells in real time. U87 glioma cells were stably transduced to express a green fluorescence protein and co-cultivated with mesenchymal stem cells engineered to carry a bacterial cytosine deaminase gene (MSC/CD). Following addition of a 5-fluorocytine (5-FC) prodrug to the co culture, fluorescence from U87 cells was obtained and analyzed in real time. Notably, the IC50 of 5-FC was higher when U87 cells were grown 3-dimensionally in soft agar medium for 3 weeks, as compared to those grown for one week in two dimensional monolayer cultures. Additionally, more MSC/CD cells were required to maintain a similar level of efficacy. Since three-dimensional growth of glioma cells under our co-culture condition mimics the long-term expansion of cancer cells in vivo, our method can extend to an in vitro assay system to assess stem cell-mediated anti-cancer effects before advancing into preclinical animal studies. PMID- 26609477 TI - microRNA-506 regulates proliferation, migration and invasion in hepatocellular carcinoma by targeting F-spondin 1 (SPON1). AB - Our previous study indicates microRNA-506 (miR-506) is downregulated in hepatocellular carcinoma (HCC). In the current study, we investigate the effects of miR-506 on proliferation, migration and invasion in HCC. We report that enforced expression of miR-506 inhibits proliferation, migration and invasion in vitro, and suppresses tumor growth in vivo. Conversely, suppression of miR-506 exhibits promoting effects on proliferation, migration and invasion in vitro, and on tumor growth in vivo. In addition, miR-506 binds to the 3'UTR of F-spondin 1(SPON1), and enforced expression of miR-506 decreases accumulation of SPON1. Moreover, enforced expression of SPON1 and suppression of SPON1 alleviates effects of miR-506 mimics and inhibitors on proliferation, migration and invasion in vitro, respectively. In conclusion, microRNA-506 regulates proliferation, migration and invasion in HCC by targeting SPON1. PMID- 26609478 TI - Up-regulated CKS2 promotes tumor progression and predicts a poor prognosis in human colorectal cancer. AB - Cyclin-dependent kinases regulatory subunit 2 (CKS2) is a cyclin-dependent kinase interacting protein, which is essential for cell cycle regulation. Elevated expression of CKS2 has been demonstrated in multiple types of human malignancies. However, the clinical significance, oncogenic functions and related mechanisms of CKS2 in colorectal cancer (CRC) remain largely unexplored. In this study, data from Oncomine database revealed that CKS2 is significantly up-regulated in CRC tissues compared with their normal counterparts. Immunohistochemical analysis of a CRC tissue microarray demonstrated that elevated CKS2 expression is closely associated with enhanced TNM stage, larger tumor size and a poor prognosis in patients with CRC. Multivariate Cox regression analysis revealed that CKS2 and TNM stage are two independent prognostic factors for CRC. Suppression of CKS2 expression resulted in decreased cell viability, increased cell apoptosis, cell cycle arrest and reduced expression of cyclins in Caco-2 and SW620 cells. Furthermore, gain and loss of function studies demonstrated that CKS2 promotes cell invasion in CRC cells through regulating claudin1. Taken together, our study reveal that CKS2 is promising prognostic indicator and contributes to tumor progression in CRC, and support that CKS2-related signaling may represent a novel target for CRC therapy. PMID- 26609479 TI - MicroRNA-320a inhibits proliferation and invasion of breast cancer cells by targeting RAB11A. AB - MicroRNAs (miRNAs) are deregulated in many types of cancer including breast cancer (BC). miR-320a dysregulation has been associated with different malignancies although its prognostic significance remains unclear. Here, we examined the role of miR-320a in BC and explored the underlying mechanisms. Our results showed that miR-320a was significantly downregulated in BC cell lines and tissues, and its ectopic expression inhibited cell proliferation, migration, and invasion in vitro and tumor growth in a mouse xenograft model. We identified Rab11a as a direct target of miR-320a and showed that its expression was upregulated in tumor samples and inversely correlated with the expression of miR 320a. In BC cells, the downregulation of Rab11a through miR-320a was concomitant with the inactivation of Akt. Overexpression of Rab11a abrogated miR-320a-induced inhibition of BC growth and invasion. These results suggest that miR-320a may act as a tumor suppressor in BC through a mechanism involving the modulation of Rab11a expression and the activation of the Akt signaling pathway. miR-320a may therefore serve as a biomarker for BC, and the modulation of its expression may represent a novel therapeutic strategy in BC treatment. PMID- 26609480 TI - MiR-449a suppresses cell invasion by inhibiting MAP2K1 in non-small cell lung cancer. AB - Increasing evidence reveals that deregulation of miRNAs contributes to carcinogenesis of the human non-small cell lung cancer (NSCLC). Our study discovered that the expression of miR-449a was markedly decreased in NSCLC cells with high metastatic capacity and tissues of positive lymph node metastasis. Moreover, our results showed that miR-449a could act as a tumor suppressor by inhibiting the invasion of NSCLC cells in vitro and in vivo. Mechanistically, miR 449a inhibited the expression of MAP2K1 by direct targeting its 3'UTR, and regulated the activity of MEK1/ERK1/2/c-Jun pathway through an auto-regulatory feedback loop. Furthermore, the histone methylation mediated the decreased expression of miR-449a through SUZ12. Taken together, the novel connection between miR-449a and MAP2K1 demonstrated here provided a new, potential therapeutic target for the treatment of non-small cell lung cancer. PMID- 26609481 TI - Methylation associated genes contribute to the favorable prognosis of gliomas with isocitrate dehydrogenase 1 mutation. AB - Gliomas, the most common primary brain tumors, are characterized by isocitrate dehydrogenase 1 mutation (IDH1-M). High mutation frequency of IDH1 indicates it's promoting role in tumorgenesis. However, the observation that patients with IDH1 M have better survival comparing with patients with IDH1 wild-type (IDH1-W) suggests that this alteration has other significant beneficial features for patients. Currently, temozolomide (TMZ) is a standard of care for patients which play a major role in DNA methylation that is similar with the role of IDH1-M in genome-wide methylation. In this study, we collected 323 gliomas samples with genome-wide methylation microarray, 502 samples with genome-wide mRNA expression microarray and 295 samples with RNA-seq. By significance analysis of microarray (SAM), we identified 18 genes which are hypermethylation and low expression in samples with IDH1-M comparing with IDH1-W (FDR<0.01). Furthermore, 18 candidate genes were downregulated in TMZ-treated samples. Finally, we obtained two candidate genes, F3 and RBP1. Survival analysis showed that hypermethylation or low expression of the two genes indicated a favorable prognosis, which was consistent with IDH1-M and administration of TMZ in glioma patients. F3 and RBP1 were further validated by qPCR on an independent validation cohort containing 145 samples. Our data suggest that these candidate genes were suppressed by TMZ or IDH1-M induced hypermethylation, resulting in the favorable prognosis of patients with gliomas. PMID- 26609482 TI - Transglutaminase 2 in cancer. AB - The significant influence of tumor microenvironment on malignant cells has been investigated with enthusiasm in this era of targeted therapy. Transglutaminase 2 (TG2, EC 2.3.2.13), a multi-functional enzyme that catalyzes the formation of intermolecular isopeptide bonds between glutamine and lysine side-chains, has been reported to exert important pathophysiological functions. The aim of this review was to investigate the correlation between TG2 and malignant behaviors, which could provide the rationale for novel approaches in anti-cancer therapy. We performed a systematic and electronic search on Medline, Scopus, and Web of Science for relevant publications from inception to April 2015. The bibliographic references of retrieved articles were further reviewed for additional relevant studies. TG2 exerts important physiological functions and plays vital roles in inflammation mainly through its modulation on the structure and stability of extracellular matrix (ECM). It also regulates EMT of diverse malignant cells through various intracellular and extracellular pathways. TG2 also plays an important role in tumor progression and may serve as a novel prognostic biomarker and therapeutic target in various cancer types. TG2 promotes malignant cell mobility, invasion, and metastasis, and induces chemo-resistance of cancer cells, mainly through its pro-crosslink and signaling transduction mediation propensities. In conclusion, TG2 plays vital roles in malignancy progression, and may have important prognostic and therapeutic significances. PMID- 26609483 TI - Lewis Y antigen modified CD47 is an independent risk factor for poor prognosis and promotes early ovarian cancer metastasis. AB - CD47 is a membrane receptor that belongs to the immunoglobulin superfamily and plays an important role in the mechanisms of tumor immune escape. CD47 participates in tumor immune escape by combining with SIRPalpha to reduce the phagocytic activity of macrophages. There are six potential N-glycosylation sites on CD47, and glycosylation is known to be necessary for its membrane localization. However, it is still unknown to what extent glycosylation influences CD47 ligand binding properties and subsequent signaling. By using immunoprecipitation and confocal laser scanning microscopy, we showed that CD47 contains Lewis y antigen. Immunohistochemical analysis demonstrated that both the positive expression and the overexpression of CD47 and Lewis y antigen in cancer tissues and borderline tumors were significantly higher than those in benign ovarian tumors and normal ovarian tissues (P < 0.05). A linear correlation between the expression patterns of CD47 and Lewis y antigen was evident (r = 0.47, P < 0.01). The high expression of CD47 and Lewis y antigen showed significant correlations with the clinical pathological parameters of ovarian cancer [International Federation of Gynecology and Obstetrics (FIGO) standards, lymph node metastasis, and degree of differentiation] (P < 0.05). The Cox model and Kaplan-Meier tests showed that high expression of CD47 was an independent adverse risk factor for the prognosis of ovarian cancer. Cases with both high CD47 and Lewis y antigen expression had poor prognoses. Our study demonstrates that Lewis y antigens of CD47 may play a crucial role in the development of ovarian cancer, and could be new targets for immunotherapy for ovarian cancer. PMID- 26609484 TI - Oxidative stress measured by thioredoxin reductase level as potential biomarker for prostate cancer. AB - The aims of this study were to determine if Thioredoxin reductase (TR) is detected in the serum, and to establish the sensitivity and specificity of serum TR for diagnosing prostate cancer (PC). We assessed serum TR in 380 participants in the training cohort: 160 patients with PC, 120 with benign prostatic hyperplasia and 100 healthy individuals. The validation cohort comprised 320 participants: 120 with PC, 100 with BPH and 100 healthy individuals. TR was measured in serum by ELISA by independent researchers. The patients with PC were graded using the Gleason system. Receiver operating characteristic (ROC) curves were utilized to evaluate the accuracy of biomarkers to diagnose PC. The influence of serum levels of TR on tumor grade and metastasis was performed by binary logistic regression analysis. The median levels of serum TR in PC were significantly higher than that of healthy subjects and patients with BPH (P < 0.0001). Based on the ROC curve, the optimal cutoff value of serum TR levels as an indicator for auxiliary diagnosis of PC from BPH was projected to be 8.2 U/ml, which yielded a sensitivity of 81.8% and a specificity of 68.9%, with the area under the curve at 0.862 (95% CI, 0.821-0.903). Combined model (TR and PSA) showed a significantly greater discriminatory ability as compared with those markers alone. In regression analysis, after adjusting for other significant predictors, TR remained an independent metastasis predictor with an adjusted OR of 4.99 (95% CI, 2.64-8.09). Similarly, TR also was an independent High-grade tumors (HGT) predictor with an adjusted OR of 5.15 (95% CI, 2.52-9.14). Our study has demonstrated the additional benefit of TR measurement in the diagnosis of PC in the Chinese population. Further studies of the application of TR in this region may be beneficial. PMID- 26609485 TI - The long non-coding RNA lnc-ZNF180-2 is a prognostic biomarker in patients with clear cell renal cell carcinoma. AB - Clear cell renal cell carcinoma (ccRCC) is among the most common human malignancies. Long non-coding RNAs (lncRNA) regulate various cellular functions and have been implicated in ccRCC pathogenesis. In order to decipher the molecular biology of this tumor and to identify potential prognostic biomarkers and therapeutic targets, we re-evaluated published lncRNA expression profiling data. An expression profile of 49 lncRNAs allowed discrimination of localized and advanced ccRCC. The expression profile of six lncRNAs transcripts (lnc-ACO1625, lnc-CYP4A22-2/3, lnc-PEAK1.1-1, lnc-PCYOX1L, lnc-VCAN-1, lnc-ZNF180-2) with potential prognostic interest were validated in a cohort of 50 normal renal, 57 localized ccRCC and 45 advanced ccRCC tissues. lnc-ZNF180-2 levels were similar in localized ccRCC and normal renal tissue, but we observed a significant increase of lnc-ZNF180-2 expression in advanced ccRCC tissue. Furthermore, lnc ZNF180-2 expression levels were an independent predictor of progression-free survival, cancer-specific survival and overall survival in ccRCC patients. We also observed that lnc-CYP4A22-2/3 expression levels allowed discrimination of ccRCC and normal renal tissue. In conclusion, lncRNAs are involved in renal carcinogenesis, and quantification of lnc-ZNF180-2 may be useful for the prediction of ccRCC patients outcome following nephrectomy. PMID- 26609486 TI - Up regulation of the long non-coding RNA NEAT1 promotes esophageal squamous cell carcinoma cell progression and correlates with poor prognosis. AB - Dysregulation of NEAT1 plays critical oncogenic roles and facilitates tumorigenesis on various human tumor entities. However, little information is available about the expression pattern of NEAT1 in esophageal squamous cell carcinoma (ESCC). The contributions of this lncRNA to tumorigenesis and progression of ESCC aslo remains unclear. By performing quantitative real-time polymerase chain reaction (qRT-PCR) in 96 cases of ESCC, we found that the expression of NEAT1 was higher in ESCC tissues and cells compared with the normal counterparts. Pearson analysis showed that elevated NEAT1 levels were extraordinarily correlated with the tumor size (P=0.026), lymph node metastasis (P=0.035) and clinical stage (P=0.004). Moreover, Kaplan-Meier curves with the log-rank test showed that higher expression of NEAT1 led to a significantly poorer survival and multivariate Cox proportional hazards analysis revealed that NEAT1 was an independent risk factor of overall survival (OS). We also assessed the function of NEAT1 in vitro by gain-/loss-of-function studies. Results showed that enhanced expression of NEAT1 stimulated the proliferation of ESCC cells, and promoted their ability of forming foci, migration, and invasion. Conversely, knockdown of NEAT1 showed the opposite effect. Overall, our study indicated that the inappropriate activation of NEAT1 predicts poor prognosis and has a crucial regulatory role in in ESCC. Targeting NEAT1 could be a novel therapeutic choice for treating ESCC patients. PMID- 26609487 TI - NDUFA4 expression in clear cell renal cell carcinoma is predictive for cancer specific survival. AB - Like other cancers, renal cell carcinoma (RCC) derives the essential energy for proliferation and survival from high rates of glycolysis rather than from oxidative phosphorylation of the mitochondrial respiration pathway. NDUFA4 (NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex, 4) is encoding a protein belonging to the respiratory chain of mitochondria. For a better understanding of the tumor biology and for identification of a potential new biomarker, we analyzed the regulation of NDUFA4 in RCC compared to normal tissue cells. Downregulation of NDUFA4 mRNA and protein was detected in RCC compared to normal renal tissues in quantitative real-time PCR as well as in western blot and immunohistochemical staining. Histological analysis revealed higher NDUFA4 expression in the distal tubules compared to the proximal tubules and the loop of Henle. A higher molecular weight of the NDUFA4 protein was discovered in RCC samples, possibly indicating a posttranslational modification. Moreover, NDUFA4 protein expression was predictive for cancer-specific survival. Our analysis revealed a potential new biomarker, but future studies are warranted to investigate the prognostic value of NDUF4A expression. PMID- 26609489 TI - Phospho-4e-BP1 and eIF4E overexpression synergistically drives disease progression in clinically confined clear cell renal cell carcinoma. AB - Clear cell renal cell carcinoma (ccRCC), the most aggressive and lethal form of renal cell carcinoma accounts for over 90% of metastasis that occur following curative surgery for clinically confined disease. High relapse rates have prompted the evaluation of targeted therapies for the prevention or delay of metastatic disease in high-risk patients, with biomarkers offering significant potential to guide and improve patient management in this setting. In this current study we examined the value of the 4E-BP1/eIF4E axis for prognostic significance and risk stratification in patients with clinically confined ccRCC. This axis is a critical convergence point for many signalling pathways that are targeted by current therapies for the treatment of advanced RCC. Immunohistochemistry for phosphorylated 4E-BP1 (p4E-BP1) and total eIF4E was performed on tissue microarrays containing tumour cores from 135 patients with localised ccRCC. For both biomarkers 39% of all evaluable cores stained positive, with a strong correlation observed between the presence of p4E-BP1 and the overexpression of eIF4E within the same tumour (P = 0.005). Further, the combined expression of p4E-BP1 and eIF4E was associated with significantly worse disease free survival of 2.9 vs 5.7 yrs compared to patients whose tumours expressed only one, or neither, of the biomarkers (P < 0.001). Cox-regression analysis confirmed the ability of the p4EBP1/eIF4E signature to independently identify high-risk patients with a Hazard Ratio of 4.2 (CI = 2.1-8.6; P < 0.001), compared to 3.3 for tumour grade 3 and 4, and 2.3 for tumour stage 3 and 4. These data show the powerful prognostic value of the p4E-BP1/eIF4E signature for potential management of patients with clinically confined ccRCC, and in addition provides insights into the possible key synergistic determinants of disease progression and treatment response. PMID- 26609488 TI - The histone methyltransferase DOT1L: regulatory functions and a cancer therapy target. AB - DOT1L is a unique histone methyltransferase that targets the histone H3 lysine 79 (H3K79) residue for mono-, di- and tri- methylation. Histone H3K79 mono- and di methylation results in active gene transcription, while H3K79 tri-methylation is associated with gene repression. DOT1L has a critical role in regulating gene transcription, development, cell cycle progression, somatic reprogramming and DNA damage repair. DOT1L interacts with Mixed Lineage Leukemia (MLL) fusion proteins, leading to enhanced H3K79 methylation, maintenance of open chromatin, overexpression of downstream oncogenes and leukemogenesis. Importantly, small molecule DOT1L inhibitors have been recently developed, and one of the DOT1L inhibitors is already under investigation in a Phase I clinical trial in patients with MLL fusion gene-driven leukemia. PMID- 26609490 TI - Elevated RABEX-5 expression predicts poor prognosis in non-small-cell lung cancer. AB - RABEX-5 has been studied in various solid tumors, but its role in non-small-cell lung cancer (NSCLC) remains unknown. This study is aimed to investigate the expression, the potential relevance to clinicopathological characters and prognostic significance of RABEX-5 in patients with NSCLC. A total of 120 NSCLC patients who underwent radical surgery between 2005 and 2010 were enrolled in the study. The clinicopathological data and survival time were reviewed. The mRNA and protein expression of RABEX-5 from the paired tumor specimens and adjacent normal tissues were determined, and its relationship with clinicopathological variables and prognosis was analyzed. Univariate and multivariate analyses were performed to investigate the prognostic significance of RABEX-5 for NSCLC. We found the mRNA and protein expression levels of RABEX-5 were significantly elevated in NSCLC tissues. The increased RABEX-5 expression was correlated strongly with tumor recurrence (P=0.005). The 5-year median OS and DFS were significantly shorter in the higher RABEX-5 expression group compared to that in the lower RABEX-5 expression group. Multivariate Cox analysis indicated that high RABEX-5 expression was an independent prognostic factor for OS and DFS (P<0.001). This data suggests that RABEX-5 is a potentially useful indicator for a poor prognosis for NSCLC. PMID- 26609491 TI - High preoperative serum globulin in rectal cancer treated with neoadjunctive chemoradiation therapy is a risk factor for poor outcome. AB - An elevated serum albumin (ALB) and albumin/globulin ratio (AGR) has been reported to be associated with a favorable prognosis for certain malignancies; however, little is known about the prognostic significance of globulin (GLB) in rectal cancer treated with neoadjuvant chemoradiation therapy (NCRT). The purpose of this study was to evaluate whether GLB analysis could predict the prognosis of patients received NCRT. A retrospective cohort of 293 locally advanced rectal cancer patients receiving NCRT followed by radical surgery was recruited between January 2006 and December 2012 at Fudan University Shanghai Cancer Center. Levels for preoperative GLB and ALB were obtained and used to calculate the AGR. Survival analysis was used to evaluate the predictive value of GLB. X-tile program determined 28.50, 36.20 and 1.20 as optimal cut-off value for GLB, ALB and AGR in terms of survival. Univariate and multivariate analysis revealed that low GLB levels were significantly associated with favorable rectal cancer specific survival (RCSS) (P < 0.05). Conversely, low ALB levels were associated with a significantly worse RCSS (P = 0.010). Collectively, high preoperative GLB level was a significantly unfavorable factor for rectal cancer patients treated with NCRT. This easily obtained variable may serve as a valuable marker to predict the outcomes of such patient population. PMID- 26609492 TI - Clinicopathological significance of Fas and Fas ligand expressions in esophageal cancer. AB - Esophageal carcinomas have recently been shown to express Fas ligand (FasL) and down-regulate Fas to escape from host immune surveillance. However, the prognostic importance of Fas/FasL and their correlation with clinicopathological characteristics are yet to be delineated in this highly malignant carcinoma. Specimens from 106 esophageal squamous cell carcinoma patients were used for immuno-histochemical evaluation of Fas, FasL, and CD8 expressions. Fifty-two (49%) and 34 (32%) patients were positive for FasL and Fas, respectively. There were no associations between FasL expression and clinicopathological characteristics except lymph vessel invasion. Strong FasL expression correlated with significant (P < 0.001) decrease in tumor nest CD81 cells. However, neither FasL nor CD81 had any impact on patient survival. Strong Fas expression was correlated with depth of invasion (40.3% in pT1, T2 versus 20.5% in pT3, T4; P5 0.0308), histological differentiation (45.7% in well versus 25.4% in nonwell; P < 0.05), and lymph node metastasis (22.6% in positive versus 45.5% in negative; P < 0.01). Fas expression was one of the independent favorable prognosticators for patients' survival (risk ratio, 3.26; P < 0.01) in esophageal SCC. Fas expression was an independent prognosticator for recurrencefree survival, whereas FasL expression did not influence the survival in esophageal squamous cell carcinoma. Down-regulation of tumor Fas may be the hallmark of immune privilege for the tumor, thus causing the patients' poorer outcome. Tumor FasL may counterattack the host immune cells to such an extent that the prognosis is not affected. PMID- 26609493 TI - Role of "oncogenic nexus" of CIP2A in breast oncogenesis: how does it work? AB - The CIP2A gene is an oncogene associated with solid and hematologic malignancies [1]. CIP2A protein is an oncoprotein and a potential cancer therapy target [2]. Literature shows that CIP2A inhibits the tumor suppressor protein PP2A [3] which downregulates phophorylation of AKT, a hallmark of cancers [4] and stabilizes the proto-oncogene, c-MYC in tumor cells [5], the comprehensive action of CIP2A and its functional interaction(s) with other oncoproteins and tumor suppressors is not clearly established. Recently we tried to put forward a contextual mode-of action of CIP2A protein in a review which proposed that CIP2A influences oncogenesis via an "oncogenic nexus" [1]. In this review we critically evaluated the potential relevance of the mode-of-action of the "oncogenic nexus" of CIP2A in breast carcinogenesis and appraised the role of this nexus in different PAM50 luminal A, PAM50 luminal B, PAM50 HER2-enriched and PAM50 basal BC. This review has a novel approach. Here we have not only compiled and discussed the latest developments in this field but also presented data obtained from c-BioPortal and STRING10 in order to substantiate our view regarding the mode-of-action of the "oncogenic nexus" of CIP2A. We functionally correlated alterations of genes pertaining to the "oncogenic nexus" of CIP2A with protein-protein interactions between the different components of the nexus including (1) subunits of PP2A, (2) multiple transcription factors including MYC oncogene and (3) components of the PI3K-mTOR and the MAPK-ERK oncogenic pathways. Using these proteins as "input" to STRING10 we studied the association, Action view, at the highest Confidence level. OncoPrints (c-BioPortal) showed alterations (%) of regulatory subunits genes of PP2A (PPP2R1A and PPP2R1B) along with alterations of CIP2A in breast invasive carcinoma (TCGA, Nature 2012 & TCGA, Provisional). Similar genetic alterations of PP2A were also observed in samples of breast tumors at our Avera Research Institute, SD. In an attempt to critically evaluate the role of "oncogenic nexus" of CIP2A in subtypes of BC, we used PPP2R1A and PPP2R1B as "inputs" into the STRING10 and obtained their predicted association (Action view) in respect to CIP2A. The outcome of this exercise has been discussed in the light of the literature in the BC research in the context of "oncogenic nexus" of CIP2A. In summary, herein we review the progress in our understanding of how CIP2A regulates oncogenic transformations of breast cells via PP2A-CIP2A "oncogenic nexus" and how we can prospect the clinical relevance of CIP2A in the context of BC. PMID- 26609495 TI - The advances of Midkine with peripheral invasion in pancreatic cancer. AB - Pancreatic cancer is a deadly malignancy associated with rapid progression and poor prognosis. Perineural invasion (PNI) in pancreatic cancer is one of the most common characteristics of this disease, with incidence of nerve invasion between 53.3% and 90%. PNI is also associated with disease recurrence and pain. Despite research efforts, the detailed mechanisms underlying PNI in pancreatic cancer remains unknown. The main factors of PNI in pancreatic cancer will be introduced in the following: 1. The anatomy of the pancreas nerve: The cancer cells along the blood vessels, lymphatic vessels, peripheral nerve gap and perineurium to Invasion. 2. Adhesion molecules in PNI: Neural cell adhesion molecules. 3. Growth factor: For example, nerve growth factor and tyrosine kinase receptor A; Neurotrophic factor and its receptor, etc. 4. The others: Such as matrix metalloproteinases, integrin. A neurite growth promoting factor and neuritrophic factor known to have a role in the pathophysiology of pancreatic cancer by inducing neuritis growth is midkine. In this review, we discuss the role of midkine and other growth and neurotrophic factors on the pathophysiology of PNI in pancreatic cancer. PMID- 26609496 TI - MicroRNA miR-182 cluster mediated modulation of RECK without changes in cell surface membrane type-1 matrix metalloproteinase (MT1-MMP). AB - Cell surface localized membrane type 1-matrix metalloproteinase (MT1-MMP) plays an important role in physiological and pathological processes and its function can be regulated by proteins such as RECK. We examined the ability of miR-182 (one of the miR-183 cluster miRNAs), which can target RECK, to control cell surface MT1-MMP activity. Expression of RECK mRNA and protein was increased with anti-miRs to miR-182, miR-183 or miR-96 in HT1080 fibrosarcoma cells, but, decreased RECK mRNA and increased its protein in the benign prostatic hyperplasia cell line BPH-1. Treatment of BPH-1 and HT-1080 cells with the anti-miRs did not change the level of cell surface MT1-MMP activity, nor their rate of migration in an in vitro wound-healing assay. Trichostatin A (TSA) did not increase the level of RECK, but blocked cell surface MT1-MMP activity and decreased cell motility. Anti-miRs mediated increased RECK levels did not interfere with cell surface MT1 MMP function, and TSA may block cell surface localization of MT1-MMP by a mechanism independent of RECK. PMID- 26609494 TI - EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). AB - Mutations in the epidermal growth factor receptor (EGFR) gene are commonly observed in non-small-cell lung cancer (NSCLC), particularly in tumors of adenocarcinoma (ADC) histology (NSCLC/ADC). Robust data exist regarding the prevalence of EGFR mutations in Western and Asian patients with NSCLC/ADC, yet there is a lack of data for patients of other ethnicities. This review collated available data with the aim of creating a complete, global picture of EGFR mutation frequency in patients with NSCLC/ADC by ethnicity. Worldwide literature reporting EGFR mutation frequency in patients with NSCLC/ADC was reviewed, to create a map of the world populated with EGFR mutation frequency by country (a 'global EGFR mutMap'). A total of 151 worldwide studies (n=33162 patients with NSCLC/ADC, of which 9749 patients had EGFR mutation-positive NSCLC/ADC) were included. There was substantial variation in EGFR mutation frequency between studies, even when grouped by geographic region or individual country. As expected, the Asia-Pacific NSCLC/ADC subgroup had the highest EGFR mutation frequency (47% [5958/12819; 87 studies; range 20%-76%]) and the lowest EGFR mutation frequency occurred in the Oceania NSCLC/ADC subgroup (12% [69/570; 4 studies; range 7%-36%]); however, comparisons between regions were limited due to the varying sizes of the patient populations studied. In all regional (geographic) subgroups where data were available, EGFR mutation frequency in NSCLC/ADC was higher in women compared with men, and in never-compared with ever smokers. This review provides the foundation for a global map of EGFR mutation frequency in patients with NSCLC/ADC. The substantial lack of data from several large geographic regions of the world, notably Africa, the Middle East, Central Asia, and Central and South America, highlights a potential lack of routine mutation testing and the need for further investigations in these regions. PMID- 26609497 TI - Identification of Social Anxiety in Schools: The Utility of a Two-Step Screening Process. AB - Social anxiety disorder (SAD) is highly prevalent yet largely undetected and untreated in adolescents despite the availability of effective treatments. Implementing interventions in schools enhances recognition and access to treatment for SAD. However, without reliable means to accurately identify youth in need of services, school-based interventions are not feasible. The purpose of this study is to evaluate the utility of a two-step, school-based screening approach to identify youth with SAD. Students at three public high schools were screened with self-report questionnaires or nominated by school personnel. Subsequently, a brief telephone assessment of student symptoms was completed with students' parents. Results showed that using both questionnaires and telephone assessments yielded acceptable detection rates, while school staff nominations were not beneficial. This study provides support for the use of a two-step screening procedure consisting of student self-reports followed by brief parent telephone interviews to identify youth with clinically impairing social anxiety. Implications for enhancing school-based detection of and intervention for socially anxious adolescents are discussed. PMID- 26609498 TI - Dealing with the Data Deluge: Handling the Multitude Of Chemical Biology Data Sources. AB - Over the last 20 years, there has been an explosion in the amount and type of biological and chemical data that has been made publicly available in a variety of online databases. While this means that vast amounts of information can be found online, there is no guarantee that it can be found easily (or at all). A scientist searching for a specific piece of information is faced with a daunting task - many databases have overlapping content, use their own identifiers and, in some cases, have arcane and unintuitive user interfaces. In this overview, a variety of well known data sources for chemical and biological information are highlighted, focusing on those most useful for chemical biology research. The issue of using multiple data sources together and the associated problems such as identifier disambiguation are highlighted. A brief discussion is then provided on Tripod, a recently developed platform that supports the integration of arbitrary data sources, providing users a simple interface to search across a federated collection of resources. PMID- 26609499 TI - Childhood Poverty, Cumulative Risk Exposure, and Mental Health in Emerging Adults. AB - One out of four American children are born into poverty, but little is known about the long-term, mental health implications of early deprivation. The more time in poverty from birth-age-9, the worse mental health as emerging adults (n = 196, M = 17.30 years, 53% male). These results maintain independently of concurrent, adult income levels for self-reported externalizing symptoms and a standard learned helplessness behavioral protocol, but internalizing symptoms were unaffected by childhood poverty. We then demonstrate that part of the reason why early poverty exposure is harmful to mental health among emerging adults is because of elevated cumulative risk exposure assessed at age 13. The significant, prospective, longitudinal relations between early childhood poverty and externalizing symptoms plus learned helplessness behavior are mediated, in part, by exposure to a confluence of psychosocial (violence, family turmoil, child separation from family) and physical (noise, crowding, substandard housing) risk factors during adolescence. PMID- 26609501 TI - Detection of Cardiac Quiescence from B-Mode Echocardiography Using a Correlation Based Frame-to-Frame Deviation Measure. AB - Two novel methods for detecting cardiac quiescent phases from B-mode echocardiography using a correlation-based frame-to-frame deviation measure were developed. Accurate knowledge of cardiac quiescence is crucial to the performance of many imaging modalities, including computed tomography coronary angiography (CTCA). Synchronous electrocardiography (ECG) and echocardiography data were obtained from 10 healthy human subjects (four male, six female, 23-45 years) and the interventricular septum (IVS) was observed using the apical four-chamber echocardiographic view. The velocity of the IVS was derived from active contour tracking and verified using tissue Doppler imaging echocardiography methods. In turn, the frame-to-frame deviation methods for identifying quiescence of the IVS were verified using active contour tracking. The timing of the diastolic quiescent phase was found to exhibit both inter- and intra-subject variability, suggesting that the current method of CTCA gating based on the ECG is suboptimal and that gating based on signals derived from cardiac motion are likely more accurate in predicting quiescence for cardiac imaging. Two robust and efficient methods for identifying cardiac quiescent phases from B-mode echocardiographic data were developed and verified. The methods presented in this paper will be used to develop new CTCA gating techniques and quantify the resulting potential improvement in CTCA image quality. PMID- 26609500 TI - A Two-Hit Model of Autism: Adolescence as the Second Hit. AB - Adolescence brings dramatic changes in behavior and neural organization. Unfortunately, for some 30% of individuals with autism, there is marked decline in adaptive functioning during adolescence. We propose a two-hit model of autism. First, early perturbations in neural development function as a "first hit" that sets up a neural system that is "built to fail" in the face of a second hit. Second, the confluence of pubertal hormones, neural reorganization, and increasing social demands during adolescence provides the "second hit" that interferes with the ability to transition into adult social roles and levels of adaptive functioning. In support of this model, we review evidence about adolescent-specific neural and behavioral development in autism. We conclude with predictions and recommendations for empirical investigation about several domains in which developmental trajectories for individuals with autism may be uniquely deterred in adolescence. PMID- 26609503 TI - Bacterial profile and antimicrobial susceptibility patterns of otitis media in Ayder Teaching and Referral Hospital, Mekelle University, Northern Ethiopia. AB - Middle Ear infection is a common problem for both children and adults particularly in resource limited countries. Nevertheless, in Ethiopia and particularly in the study area, there is scarcity of recent data that indicate the magnitude of the problem. Thus this study aimed to identify bacterial isolates and determine their drug susceptibility patterns from patients who had ear infection. Cross sectional study was carried out on patients with ear infection and who visited the Ear, Nose and Throat clinic of Ayder referral and teaching hospital from November 2014 to June 2015. Middle ear discharges were collected and processed for bacterial culture and antimicrobial susceptibility testing using standard bacteriological techniques. Clinical and demographic data were collected using standard questionnaire. Data were entered and analyzed using SPSS version 20 software and p value of < 0.05 was considered statistically significant. Of the total of 162 patients with ear discharges, 68.5 % were from rural areas, 71 % with chronic infection, 54.9 % referred cases and 67.3 % of them had decreased hearing status. Pathogens were isolated from 157 (98.2 %) of the patients with a total of 216 isolates. Staphylococcus aureus 46 (28.4 %), Proteus mirabilis 39 (24.1 %), Pseudomonas aeruginosa 27 (16.7 %), Klebsiella spp. and Haemophilus influenzae 18 (11.1 % each) were the dominant bacteria. Out of the individuals with ear infection, single and mixed bacterial infection was seen among 185 (90.7 %) and 59 (39.5 %) respectively. Age group of 0-5 years (p = 0.02), chronic patients (p = 0.042) and referred cases (p = 0.045) showed high bacterial isolates. High resistance was seen to most antibiotics. Ciprofloxacin, Gentamicin Norfloxacin and Erythromycin were effective against isolated bacteria. The overall multi drug resistance rate of bacteria in this study was 74.5 %. Prevalence of bacteria associated with otitis media and multidrug resistance was very high in the study area. Ciprofloxacin, gentamicin, norfloxacin and erythromycin can be used to treat otitis media. Treatment of patients should be based on antimicrobial susceptibility test to prevent complications, development of further antibiotic resistance and extra treatment costs. PMID- 26609502 TI - Being alone and expectations lost: a critical realist study of maternal depression in South Western Sydney. AB - The study reported here is part of a critical realist multilevel study. It seeks to identify and explain complex perinatal contextual social and psychosocial mechanisms that may influence the developmental origins of health and disease, with a focus on the role of postnatal depression. The aims of the greater study are to: (1) describe the phenomenon of postnatal depression in South Western Sydney; and (2) identify mechanisms that would add to our understanding of the psycho-social causes of maternal depression. This paper will move beyond our previous quantitative descriptions of individual-level predictors of depressive symptoms by seeking the views of local mothers and practitioners, to explain the mechanisms that might be involved. The study was set in South Western Sydney, New South Wales, Australia. An Explanatory Theory Building Method was used. The previously reported quantitative study was a non-linear principal component analysis and logistic regression study of 15,389 months delivering in 2002 and 2003. This intensive qualitative study used open coding of interviews, of seven practitioners and three naturally occurring mothers groups, to enable maximum emergence. The theoretical concepts identified were: attachment and nurturing, infant temperament, unplanned pregnancy and sole parenthood, support for mothers, access to services, stress, financial hardship, isolation and marginalisation, mothers' "loss of control" and "power", and expectations and dreams. Being alone and expectations lost emerged as possible triggers of stress and depression for mothers. These findings might also apply to others who have their dreams shattered during life's transitions. In these situations social and cultural context can either nurture and support or marginalise and isolate. The challenge for policy and practice is to support mothers and their partners during the transition to parenthood within a challenging social and material context. PMID- 26609504 TI - Behavioral effects of mefloquine in tail suspension and light/dark tests. AB - Mefloquine hydrochloride has been used widely in the past few decades for malaria prophylaxis and treatment. However, in recent years, it has fallen out of favor due to reports of exposure being linked to numerous neuropsychiatric effects, including emotional disturbances. In this study we examined the effects of different doses (5, 25, or 100 mg/kg) of mefloquine relative to vehicle on male C57BL/6 J mice in two tests of emotional behavior, the light-dark box and the tail suspension test. It was found that mefloquine exposure reduced anxiety linked behaviors in the light-dark box and reduced total immobility times in the tail suspension test, especially at higher doses. Our results lend support to the notion that mefloquine exposure could induce emotional disinhibition. PMID- 26609505 TI - Effect of difference in occlusal contact area of mandibular free-end edentulous area implants on periodontal mechanosensitive threshold of adjacent premolars. AB - Implant treatment is believed to cause minimal invasion of remaining teeth. However, few studies have examined teeth adjacent to an implant region. Therefore, this study investigated the effect of occlusal contact size of implants on the periodontal mechanosensitive threshold of adjacent premolars. A cross-sectional study design was adopted. The Department of Oral Implantology, Osaka Dental University, was the setting where patients underwent implant treatment in the mandibular free-end edentulous area. The study population comprised of 87 patients (109 teeth) who underwent follow-up observation for at least 3 years following implant superstructure placement. As variables, age, sex, duration following superstructure placement, presence or absence of dental pulp, occlusal contact area, and periodontal mechanosensitive threshold were considered. The occlusal contact area was measured using Blue Silicone((r))and Bite Eye BE-I((r)). Periodontal mechanosensitive threshold were measured using von Frey hair. As quantitative variables for periodontal mechanosensitive threshold, we divided subjects into two groups: normal (<=5 g) and high (>=5.1 g). For statistical analysis, we compared the two groups for the sensation thresholds using the Chi square test for categorical data and the Mann-Whitney U test for continuous volume data. For variables in which a significant difference was noted, we calculated the odds ratio (95 % confidence interval) and the effective dose. There were 93 teeth in the normal group and 16 teeth in the high group based on periodontal mechanosensitive threshold. Comparison of the two groups indicated no significant differences associated with age, sex, duration following superstructure placement, or presence or absence of dental pulp. A significant difference was noted with regard to occlusal contact area, with several high group subjects belonging to the small contact group (odds ratio: 4.75 [1.42-15.87]; effective dose: 0.29). The results of this study suggest an association between implant occlusal contact area and the periodontal mechanosensitive threshold of adjacent premolars. Smaller occlusal contact application resulted in an increased threshold. It appears that prosthodontic treatment should aim not only to improve occlusal function but also to maintain oromandibular function with regard to the preservation of remaining teeth. PMID- 26609506 TI - A Survey On Spine Surgeons' Opinions On The Release Of The Centers for Medicare and Medicaid Services Data. AB - BACKGROUND: In April 2014 the Centers for Medicare and Medicaid Services (CMS) released a dataset for the public which included information on services provided by physicians and healthcare providers for Medicare beneficiaries in the 2012 calendar year. The objective of this study is to determine spine surgeons' opinions on the release of the CMS data, and determine how they feel this information may affect patient care. METHODS: A survey was sent to members of the Association for Collaborative Spine Research (ACSR) regarding their practice patterns and opinions on the release of the CMS data. Determinants included surgical subspecialty, practice setting, years in practice and region. The average response was collected for each question and compared across groups. Additionally, questions in which greater than 75% of respondents either agreed (agree or strongly agree) or disagreed (disagree or strongly disagree) were identified. RESULTS: Seventy-six surgeons completed the survey, and while the overall interobserver reliability between each question was only slight (kappa = 0.11), more than 75% of respondents either agreed or strongly agreed with five statements and, more than 75% of respondents either disagreed or strongly disagreed with six statements. While 86% of surgeons are in favor of more transparency, 83% of respondents felt that without the proper context, the data released does not accurately portray spine surgery. Additionally, 96% of spine surgeons do not believe the CMS data helps patients decide which spine surgeon is best for them. CONCLUSIONS: The small percentage of spine surgeons who responded to this survey are in favor of more transparency but do not feel the release of the CMS data either accurately represents spine surgeons or will help patients better identify the appropriate surgeon. In spite of these concerns, it is unlikely the release of the CMS data will significantly impact the accessibility of a spine surgeon to a Medicare beneficiary. PMID- 26609507 TI - Cartilage Derived Morphogenetic Protein-2 Induces Cell Migration and Its Chondrogenic Potential in C28/I2 Cells. AB - BACKGROUND: Intervertebral disc degeneration is a major cause of low back pain. Previous researches have demonstrated local administration of signalling molecules as potential biological therapies for disc regeneration. Our laboratory has published encouraging results for effectiveness of injection of the cartilage derived morphogenetic protein-2 (CDMP-2) into ovine discs following annular injury. To elucidate the mechanisms underpinning these in vivo effects, this project aimed to investigate the potential of CDMP-2 on cellular migration, proliferation and extracellular matrix production in a human chondrocytic cell line. METHODS: To evaluate cell motility, cells were seeded into Boyden chambers and CDMP-2 as a chemo-attractant or a stimulant was placed into either the bottom or top chambers respectively. Cells that had completed migration through the porous membrane were visualized by immunocytochemical staining and analysed using Image J. The effect of CDMP-2 on cell proliferation, proteoglycan and collagen production, as well as chondrogenic gene expression in human chondrocytic cell line C28/I2 was also examined. RESULTS: The results revealed that cells migrated significantly under the influence of CDMP-2 (200 ng/ml) stimulation compared to control (3-fold increase, p = 0.033) and demonstrated a significant chemotactic movement towards a solution of 200ng/ml CDMP-2 (>2-fold increase, p = 0.027). A 35% increase in C28/I2 proliferation was observed after CDMP-2 stimulation (p < 0.0001) compared to control, and in the presence of 100ng/ml CDMP-2, proteoglycan synthesis had an 8-fold increase (p = 0.048). Similarly, gene expression analysis demonstrated increased expression of aggrecan, collagen types II, X and XXVII, BMPR-1A and BMPR-2 when cells were treated with CDMP-2. CONCLUSION: The study shows that C28/I2 cells can migrate under the influence of CDMP-2 as a chemoattractant or migration stimulator, suggestive of an effect on chondrocytic cells in the intervertebral disc. Further, CDMP-2 can stimulate C28/I2 cells to proliferate and synthesize key extracellular matrix proteins. PMID- 26609508 TI - Contribution of Round vs. Rectangular Expandable Cage Endcaps to Spinal Stability in a Cadaveric Corpectomy Model. AB - BACKGROUND: Expandable cages are gaining popularity in anterior reconstruction of the thoracolumbar spine following corpectomy as they can provide adjustable distraction and deformity correction. Rectangular, rather than circular, endcaps provide increased resistance to subsidence by spanning the apophyseal ring; however their impact on construct stability is not known. The objective of this study was to investigate the contribution of expandable corpectomy cage endcap shape (round vs. rectangular) and fixation method (anterior plate vs. posterior pedicle screws) to the stability of an L1 sub-total corpectomy construct. METHODS: Eight fresh-frozen cadaveric specimens (T11-L3) were subjected to multi directional flexibility testing to 6 N.m with a custom spine simulator. Test conditions were: intact, L1 sub-total corpectomy defect, expandable cage (round endcap) alone, expandable cage (round endcap) with anterior plate, expandable cage (round endcap) with bilateral pedicle screws, expandable cage (rectangular endcap) alone, expandable cage (rectangular endcap) with anterior plate, expandable cage (rectangular endcap) with bilateral pedicle screws. Range-of motion across T12-L2 was measured with an optoelectronic system. RESULTS: The expandable cage alone with either endcap provided significant stability to the corpectomy defect, reducing motion to intact levels in flexion-extension with both endcap types, and in lateral bending with rectangular endcaps. Round endcaps allowed greater motion than intact in lateral bending, and axial rotation ROM was greater than intact for both endcaps. Supplemental fixation provided the most rigid constructs, although there were no significant differences between instrumentation or endcap types. CONCLUSIONS: These results suggest anterior-only fixation may be adequate when using an expandable cage in a sub-total corpectomy application and choice of endcap type may be driven by other factors such as subsidence resistance. PMID- 26609509 TI - Fluoroscopy-guided pedicle screw accuracy with a mini-open approach: a tomographic evaluation of 470 screws in 125 patients. AB - BACKGROUND: Transpedicular screws are currently placed with open free hand and minimally invasive techniques assisted with either fluoroscopy or navigation. Screw placement accuracy had been investigated with several methods reaching accuracy rates from 71.9% to 98.8%. The objective of this study was to assess the accuracy and safety for 2-D fluoroscopy-guided screw placement assisted with electrophysiological monitoring and the inter-observer agreement for the breach classification. METHODS: A retrospective review was performed on 125 consecutive patients who underwent minimally invasive transforaminal lumbar interbody fusion and transpedicular screws placement between the levels of T-12 and S-1. Screw accuracy was evaluated using a postoperative computed tomography by three independent observers. Pedicle breach was documented when there was a violation in any direction of the pedicle. Inter-observer agreement was assessed with the Kappa coefficient. RESULTS: A total of 470 transpedicular screws were evaluated between the levels of T-12 and S-1. In 57 patients the instrumentation was bilateral and in 68 unilateral. A substantial degree of agreement was found between the observers AB (kappa=0.769) and A-C (kappa=0.784) and almost perfect agreement between observers B-C (kappa=0.928). There were a total of 427.33 (90.92%) screws without breach, 39.33 (8.37%) minor breach pedicles and 3.33 (0.71%) major breach pedicles. The pedicle breach rate was 9.08% Trajectory pedicle breach percentages were as follows: minor medial pedicle breach 4.68%, minor lateral pedicle breach 3.47%, minor inferior pedicle breach 0.22%, and major medial breach 0.70%. No intraoperative instrumentation-related or postoperative clinical complications were encountered and no surgical revision was needed. CONCLUSIONS: Our study demonstrated a high accuracy (90.2%) for 2-D fluoroscopy-guided pedicle screw using electromonitoring. Only 0.71% of the 470 screws had a major breach. Knowing the radiological spine pedicle anatomy and the correct interpretation of EMG are the key factors for this technique. PMID- 26609510 TI - Video-assisted thoracoscopic surgery as a diagnostic and therapeutic instrument in non-tubercular spondylodiscitis. AB - BACKGROUND: Spondylodiscitis refers to an infection of one or more intervertebral disks and vertebrae, most commonly caused by tuberculosis. Initial therapy for spondylodiscitis is drug treatment. Indications for surgical treatment include compression of neural elements, spinal instability or severe deformities. When surgery is indicated, an open technique is still the standard, although video assisted thoracoscopic surgery (VATS) is described in cases of thoracic disk herniation, scoliosis and tubercular spondylitis. CASE REPORT: We report a case of a 79-year-old man with progressive back pain, paraparesis and paresthesias in both legs. During assessment, spondylodiscitis with spinal cord compression was diagnosed. Immediate surgical decompression took place by means of VATS. Culture of the tissue obtained revealed Proteus mirabilis. Blood and urine cultures also revealed Proteus mirabilis, a rare cause of spondylodiscitis with an occurrence rate of 0.9%. CONCLUSION: VATS offered a minimally invasive access to obtain the diagnosis of pyogenic spondylodiscitis following urosepsis with Proteus mirabilis. Moreover, it provided treatment with abscess drainage and decompression of the spinal cord. PMID- 26609511 TI - Anterior Microscopic Transtubular (MITR) Surgical Approach for Cervical Pyogenic C1-2 Abscess: A Case Report. AB - Osteomyelitis of the spine is a fairly uncommon event following an orthopedic surgical procedure. However, a solitary osteomyelitic abscess of the upper cervical spine is very rare. Surgical intervention is often the only life-saving treatment method. A 70-year-old female patient with diabetes was received from a rural community with symptoms of progressive quadraparesis and progressive respiratory failure. A CT scan of the cervical spine showed a destruction of the C1 and C2 complex, as well as the left occipital condyle, and clear evidence of craniocervical instability. She underwent surgical debridement of the abscess via an anterior microscopic transtubular approach, followed by a posterior occipital cervical fusion. While a transoral approach is a well-established procedure for the anterior clivus/C1-2 area, it is fraught with a high degree of morbidity and mortality. The use of the transtubular anterior cervical approach in this case allowed us to access the C1-2 area with ease and minimal effort. From a technical standpoint, this type of approach for treatment of this condition has not been previously documented in the literature. PMID- 26609512 TI - Pedicle Reduction Osteotomy in the Upper Cervical Spine: Technique, Case Report and Review of the Literature. AB - OBJECTIVE: To present a case report of the correction of a degenerative cervical 45-degree kyphosis centered at C4 with a single stage PSO. SUMMARY OF BACKGROUND DATA: Correction of a fixed cervical kyphosis is a surgical challenge that is frequently managed with a combination of anterior and posterior surgical procedures. An alternative the three stage operation is a single stage pedicle subtraction osteotomy (PSO). A PSO releases the posterior, middle and anterior columns of the spine by resecting the facet joints, pedicles, and a portion of the vertebral body at the apex of a kyphosis through a posterior approach. METHODS: This was a case report of a patient who had degenerative cervical 45 degree kyphosis and was corrected with a single stage pedicle subtraction osteotomy. We did a literature review to provide information on current techniques to treat these patients. RESULTS: With careful resection of the lateral mass and decompression of the vertebral artery by removal of the posterior margin of the foramen transversarium the upper cervical pedicles can be accessed and a PSO can be performed. The vertebral arteries were not obstructed or kinked with posterior reduction of the PSO in this case. CONCLUSIONS: A closing wedge PSO is a useful tool for correcting fixed kyphotic deformities in the upper cervical spine. Further studies are necessary to evaluate the long-term outcomes in these patients. PMID- 26609513 TI - How Much Work Effort is Involved in Minimally Invasive Sacroiliac Joint Fusion? AB - BACKGROUND: Minimally invasive sacroiliac joint fusion is increasing significantly. Starting January 1, 2015, it has a category I CPT code. The current RVU for this procedure is not equal to the amount of work involved. There is not a published RUC validated survey to establish the work effort of MI SI fusion. Our hospital system has been doing this procedure for 4 years and has been tracking surgeon time through a commercial tracking system (Navicare). Our study looks at time utilization for performance of MI SI joint fusion and a comparator of primary lumbar discectomy (PLD), presumably similar in time and work effort. METHODS: This study was a retrospective review of prospectively collected data using Navicare. The data for 3 surgeons who perform MI SI joint fusion and lumbar discectomies from January 1, 2013 through November 30, 2014 was retrieved. Surgeon room time was identified as the time the patient entered the OR to the time they exited the OR. This was used as opposed to skin to skin time seen in similar studies as it was more accurately and consistently recorded in the medical record. Mean and standard deviations were then compared using student's t-test. RESULTS: In 50 primary MI SI joint fusions, the average in-room time was 112 minutes (SD=23). In 89 cases of PLD, the average in-room time was 119 minutes (SD=26). When comparing mean in-room times, MI SI and PLD were not statistically significantly different (p=0.135, 2-tailed t-test). Post-operative work effort was found to be greater for MI SI joint fusion than PLD. CONCLUSIONS / LEVEL OF EVIDENCE: Surgical time was found to be comparable between MI SI joint fusion and PLD, while work effort was found to be greater for MI SI joint fusion. This signifies at a minimum an equal RVU for PLD should be used for MI SI joint fusion. This study was approved by the Institutional Review Board at the University of Minnesota. LEVEL OF EVIDENCE: 3. PMID- 26609514 TI - Rare case of conus medullaris syndrome from a metastatic yolk sac tumor originating from the mediastinum of an adult male: a case report and review of the literature. AB - BACKGROUND: Yolk sac tumors (YST) are malignant neoplasms. They are a subtype of germ cell tumors and typically originate in the gonads although extragonadal origins of such tumors have been described. Yolk sac tumors are commonly found in the gonads of infants and children and are extremely rare in adults. The goal of this case report is to describe the clinical presentation of a rare case of metastatic extragonadal yolk sac tumor originating from the mediastinum and causing an acute conus medullaris syndrome in an adult male. METHODS: A 47-year old male presented to our emergency department with a one-day history of bilateral lower extremity weakness, urinary retention and bowel incontinence. Imaging revealed a destructive lesion and a burst fracture of the first lumbar vertebral body (L1) with severe spinal canal stenosis. An urgent spinal decompression and fusion was performed. Oncologic workup revealed a yolk sac tumor originating from the mediastinum. RESULTS: His neurologic function, including motor strength, bowel and bladder function improved in the postoperative period. Chemotherapy regimen of ifosfamide, etoposide and cisplatin was administered and radiation therapy was administered to the spine tumor bed. CONCLUSIONS: Yolk sac tumors, although rare, should be considered in the long list differential diagnosis of an otherwise healthy male presenting with conus medullaris or spinal cord compression from metastatic disease without evidence of a testicular mass. Prompt diagnosis with urgent decompression of neural structures and stabilization of the spine may result in improvement in neurological function. PMID- 26609515 TI - Association between single nucleotide polymorphisms in MiR219-1 and MiR137 and susceptibility to schizophrenia in a Chinese population. AB - Schizophrenia is one of the most common mental disorders to severely affect human health worldwide. Single nucleotide polymorphisms (SNPs) within related genes are candidate susceptible factors for the disorder. Rs107822 within MiR219-1 and rs1625579 within MiR137 were genotyped in 589 cases and 622 controls to investigate the possible association between the loci and schizophrenia in a Chinese population. Our results showed significant association between rs107822 and the disorder in allele (C vs. T: adjusted OR = 0.773, 95%CI = 0.655-0.912), co-dominant (TC vs. TT: adjusted OR = 0.734, 95%CI = 0.571-0.943; CC vs. TT: adjusted OR = 0.655, 95%CI = 0.459-0.936), dominant (TC + CC vs. TT: adjusted OR = 0.707, 95%CI = 0.559-0.895), and recessive (CC vs. TC + TT: adjusted OR = 0.724, 95%CI = 0.524-0.999) models, respectively. Meanwhile, negative associations were also observed between rs107822 and the disorder in male and female subgroups, and genotype CC of the locus was significantly associated with a lower positive symptom score of PANSS compared to genotype TT carrier in the cases group. However, we didn't observe a significant association between rs1625579 and the disorder. These findings indicate that rs107822 within MiR219-1 might be involved in pathogenesis of schizophrenia and that genotypes TC, CC and allele C of the locus are protective factors for schizophrenia in a Chinese population. PMID- 26609516 TI - Biomarker-directed Targeted Therapy in Colorectal Cancer. AB - With advances in the understanding of the biology and genetics of colorectal cancer (CRC), diagnostic biomarkers that may predict the existence or future presence of cancer or a hereditary condition, and prognostic and treatment biomarkers that may direct the approach to therapy have been developed. Biomarkers can be ascertained and assayed from any tissue that may demonstrate the diagnostic or prognostic value, including from blood cells, epithelial cells via buccal swab, fresh or archival cancer tissue, as well as from cells shed into fecal material. For CRC, current examples of biomarkers for screening and surveillance include germline testing for suspected hereditary CRC syndromes, and stool DNA tests for screening average at-risk patients. Molecular biomarkers for CRC that may alter patient care and treatment include the presence or absence of microsatellite instability, the presence or absence of mutant KRAS, BRAF or PIK3CA, and the level of expression of 15-PGDH in the colorectal mucosa. Molecularly targeted therapies and some general therapeutic approaches rely on biomarker information. Additional novel biomarkers are on the horizon that will undoubtedly further the approach to precision or individualized medicine. PMID- 26609517 TI - Glossectomy in the severe maxillofacial vascular malformation with jaw deformity: a rare case report. AB - In the field of oral-maxillofacial surgery, vascular malformations present in various forms. Abnormalities in the size of the tongue by vascular malformations can cause mandibular prognathism and skeletal deformity. The risk in surgical treatment for patients with vascular malformation is high, due to bleeding from vascular lesions. We report a rare case of macroglossia that was treated by partial glossectomy, resulting in an improvement in the swallowing and mastication functions in the patient. A 25-year-old male patient with severe open bite and mandibular prognathism presented to our department for the management of macroglossia. The patient had a difficulty in food intake because of the large tongue. Orthognathic surgery was not indicated because the patient had severe jaw bone destruction and alveolar bone resorption. Therefore, the patient underwent partial glossectomy under general anesthesia. There was severe hemorrhaging during the surgery, but the bleeding was controlled by local procedures. PMID- 26609519 TI - MR Prediction of Liver Function and Pathology Using Gd-EOB-DTPA: Effect of Liver Volume Consideration. AB - PURPOSE: To evaluate whether the diagnostic performance of Gd-EOB-DTPA-enhanced MRI in evaluating liver function and pathology is improved by considering liver volume (LV). METHODS: This retrospective study included 104 patients who underwent Gd-EOB-DTPA-enhanced MRI before liver surgery. For each patient, using the precontrast and hepatobiliary phase images, we calculated the increase rate of the liver-to-spleen signal intensity ratio (LSR), that is, the "DeltaLSR," and the increase rate of the liver-to-muscle signal intensity ratio (LMR), that is, the "DeltaLMR." DeltaLSR * LV and DeltaLMR * LV were also calculated. The correlation of each MR parameter with liver function data or liver pathology was assessed. The correlation coefficients were compared between DeltaLSR (DeltaLMR) and DeltaLSR (DeltaLMR) * LV. RESULTS: The correlation coefficient between DeltaLSR (DeltaLMR) * LV and cholinesterase was significantly higher than that between DeltaLSR (DeltaLMR) and cholinesterase. The correlation coefficient between DeltaLSR (DeltaLMR) * LV and the degree of fibrosis or necroinflammatory activity was significantly lower than that between DeltaLSR (DeltaLMR) and the degree of fibrosis or necroinflammatory activity. CONCLUSION: The inclusion of liver volume may improve Gd-EOB-DTPA-based predictions of liver function, but not in predictions of liver pathology. PMID- 26609518 TI - Identification of Immune Related LRR-Containing Genes in Maize (Zea mays L.) by Genome-Wide Sequence Analysis. AB - A large number of immune receptors consist of nucleotide binding site-leucine rich repeat (NBS-LRR) proteins and leucine rich repeat-receptor-like kinases (LRR RLK) that play a crucial role in plant disease resistance. Although many NBS-LRR genes have been previously identified in Zea mays, there are no reports on identifying NBS-LRR genes encoded in the N-terminal Toll/interleukin-1 receptor (TIR) motif and identifying genome-wide LRR-RLK genes. In the present study, 151 NBS-LRR genes and 226 LRR-RLK genes were identified after performing bioinformatics analysis of the entire maize genome. Of these identified genes, 64 NBS-LRR genes and four TIR-NBS-LRR genes were identified for the first time. The NBS-LRR genes are unevenly distributed on each chromosome with gene clusters located at the distal end of each chromosome, while LRR-RLK genes have a random chromosomal distribution with more paired genes. Additionally, six LRR-RLK/RLPs including FLS2, PSY1R, PSKR1, BIR1, SERK3, and Cf5 were characterized in Zea mays for the first time. Their predicted amino acid sequences have similar protein structures with their respective homologues in other plants, indicating that these maize LRR-RLK/RLPs have the same functions as their homologues act as immune receptors. The identified gene sequences would assist in the study of their functions in maize. PMID- 26609520 TI - Intake of Meals Containing High Levels of Carbohydrates or High Levels of Unsaturated Fatty Acids Induces Postprandial Dysmetabolism in Young Overweight/Obese Men. AB - Postprandial metabolic response depends on the meals' components and can be different in normal weight and obese people. However, there are some discrepancies between various reports. The aim of this study was to determine the metabolic response after intake of standardised meals with various fat and carbohydrate contents and to determine the differences among normal weight and overweight/obese individuals. The study group comprised 46 healthy men. The participants were divided into two groups and study was carried out using a crossover method. Group I received high- and normal-carbohydrate meals, whereas group II received high-carbohydrate and high-fat meals. Glucose, insulin, triglyceride, and free fatty acids levels were measured at fasting state and at 30, 60, 120, 180, and 240 minutes after meal intake. Despite the lack of differences in glucose levels, insulin levels were higher among overweight/obese individuals after each meal. TG and FFA levels were higher after normal carbohydrate and high-fat meals. Moreover, in overweight/obese young men after high-fat meal intake postprandial hypertriglyceridemia was observed, even if meals contained predominantly unsaturated fatty acids, and fasting triglycerides levels were in normal range. The conducted study showed that postprandial metabolic response depends not only on the meal macronutrient content but also on the current body mass index (BMI). PMID- 26609521 TI - Evaluation of Mediterranean Agricultural Residues as a Potential Feedstock for the Production of Biogas via Anaerobic Fermentation. AB - Hydrothermal, dilute acid, and steam explosion pretreatment methods, were evaluated for their efficiency to improve the methane production yield of three Mediterranean agricultural lignocellulosic residues such as olive tree pruning, grapevine pruning, and almond shells. Hydrothermal and dilute acid pretreatments provided low to moderate increase in the digestibility of the biomass samples, whereas steam explosion enabled the highest methane yields to be achieved for almond shells at 232.2 +/- 13.0 mL CH4/gVS and olive pruning at 315.4 +/- 0.0 mL CH4/gVS. Introduction of an enzymatic prehydrolysis step moderately improved methane yields for hydrothermal and dilute acid pretreated samples but not for the steam exploded ones. PMID- 26609522 TI - The Role and Mechanism of alpha-Klotho in the Calcification of Rat Aortic Vascular Smooth Muscle Cells. AB - OBJECTIVE: To investigate the role and possible mechanism of alpha-Klotho in the calcification and the osteogenic transition of cultured VSMCs. METHODS: VSMCs were cultured in vitro and divided into 5 groups, each using a different medium: (1) control; (2) beta-GP; (3) beta-GP + Klotho; (4) beta-GP + LiCl; (5) beta-GP + Klotho + LiCl. Calcium deposits were visualized using Alizarin Red S staining. The calcium concentrations were determined by the o-cresolphthalein complexone method. BMP2, Runx2 and beta-catenin levels were estimated by western blotting, and the level of alpha-SMA was determined by using immunofluorescence at day 12. RESULTS: beta-GP induced an increase in the expression of BMP2, Runx2, and beta catenin. The calcium content increased, and the expression of alpha-SMA decreased. Alizarin Red S staining was positive under the high phosphorus conditions. BMP2, Runx2, and beta-catenin levels and the calcium content decreased when the cells were cultured with rmKlotho; however, the levels of each were upregulated after treatment with the LiCl. CONCLUSIONS: Klotho can ameliorate the calcification and osteogenic transition of VSMCs induced by beta GP. The mechanism of Klotho in preventing calcification in VSMCs may be partially mediated by the inhibition of the Wnt/beta-catenin signaling pathway. PMID- 26609523 TI - Phylogenetic Analysis of Hemagglutinin Genes of H9N2 Avian Influenza Viruses Isolated from Chickens in Shandong, China, between 1998 and 2013. AB - Since H9N2 avian influenza virus (AIV) was first isolated in Guangdong province of China, the virus has been circulating in chicken flocks in mainland China. However, a systematic phylogenetic analysis of H9N2 AIV from chickens in Shandong of China has not been conducted. Based on hemagglutinin (HA) gene sequences of H9N2 AIVs isolated from chickens in Shandong of China between 1998 and 2013, genetic evolution of 35 HA gene sequences was systematically analyzed in this study. Our findings showed that the majority of H9N2 AIVs (21 out of 35) belonged to the lineage h9.4.2.5. Most of isolates (33 out of 35) had a PSRSSR?GLF motif in HA cleavage site. Importantly, 29 out of these 35 isolates had an amino acid exchange (Q226L) in the receptor-binding site. The substitution showed that H9N2 AIVs had the potential affinity to bind to human-like receptor. The currently prevalent H9N2 AIVs in Shandong belonged to the lineage h9.4.2.5 which are different from the vaccine strain SS/94 clade h9.4.2.3. Therefore, the long-term surveillance of H9N2 AIVs is of significance to combat the possible H9N2 AIV outbreaks. PMID- 26609524 TI - Synergistic Effects of BMP9 and miR-548d-5p on Promoting Osteogenic Differentiation of Mesenchymal Stem Cells. AB - Various stimulators have been reported to promote MSC osteogenic differentiation via different pathways such as bone morphogenetic protein 9 (BMP9) through influencing COX-2 and miR-548d-5p through targeting peroxisome proliferator activated receptor-gamma (PPARgamma). Whether synergistic effects between BMP9 and miR-548d-5p existed in promoting osteogenesis from MSCs was unclear. In the study, the potential synergistic effects of BMP9 and miR-548d-5p on human MSC differentiation were investigated. Osteogenic differentiation of MSCs treated with BMP9 or miR-548d-5p was detected with multimodality of methods. The results demonstrated that BMP9 and miR-548d-5p significantly influenced COX-2 and PPARgamma, respectively. BMP9 also influenced the expression of PPARgamma, but no significant effect of miR-548d-5p on COX-2 was observed. When BMP9 and miR-548d 5p were combined, more potent effects on both COX-2 and PPARgamma were observed than BMP9 or miR-548d-5p alone. Consistently, osteogenic analysis at different timepoints demonstrated that osteogenic genes, ALP activity, calcium deposition, OPN protein, and matrix mineralization were remarkably upregulated by BMP9/miR 548d-5p compared with BMP9 or miR-548d-5p alone, indicating the synergetic effects of BMP9 and miR-548d-5p on osteogenic differentiation of MSCs. Our study demonstrated that regulating different osteogenic regulators may be an effective strategy to promote bone tissue regeneration for bone defects. PMID- 26609525 TI - Isoflurane Damages the Developing Brain of Mice and Induces Subsequent Learning and Memory Deficits through FASL-FAS Signaling. AB - Background. Isoflurane disrupts brain development of neonatal mice, but its mechanism is unclear. We explored whether isoflurane damaged developing hippocampi through FASL-FAS signaling pathway, which is a well-known pathway of apoptosis. Method. Wild type and FAS- or FASL-gene-knockout mice aged 7 days were exposed to either isoflurane or pure oxygen. We used western blotting to study expressions of caspase-3, FAS (CD95), and FAS ligand (FASL or CD95L) proteins, TUNEL staining to count apoptotic cells in hippocampus, and Morris water maze (MWM) to evaluate learning and memory. Result. Isoflurane increased expression of FAS and FASL proteins in wild type mice. Compared to isoflurane-treated FAS- and FASL-knockout mice, isoflurane-treated wild type mice had higher expression of caspase-3 and more TUNEL-positive hippocampal cells. Expression of caspase-3 in wild isoflurane group, wild control group, FAS/FASL-gene-knockout control group, and FAS/FASL-gene-knockout isoflurane group showed FAS or FASL gene knockout might attenuate increase of caspase-3 caused by isoflurane. MWM showed isoflurane treatment of wild type mice significantly prolonged escape latency and reduced platform crossing times compared with gene-knockout isoflurane-treated groups. Conclusion. Isoflurane induces apoptosis in developing hippocampi of wild type mice but not in FAS- and FASL-knockout mice and damages brain development through FASL-FAS signaling. PMID- 26609526 TI - Parameterization of the Age-Dependent Whole Brain Apparent Diffusion Coefficient Histogram. AB - PURPOSE: The distribution of apparent diffusion coefficient (ADC) values in the brain can be used to characterize age effects and pathological changes of the brain tissue. The aim of this study was the parameterization of the whole brain ADC histogram by an advanced model with influence of age considered. METHODS: Whole brain ADC histograms were calculated for all data and for seven age groups between 10 and 80 years. Modeling of the histograms was performed for two parts of the histogram separately: the brain tissue part was modeled by two Gaussian curves, while the remaining part was fitted by the sum of a Gaussian curve, a biexponential decay, and a straight line. RESULTS: A consistent fitting of the histograms of all age groups was possible with the proposed model. CONCLUSIONS: This study confirms the strong dependence of the whole brain ADC histograms on the age of the examined subjects. The proposed model can be used to characterize changes of the whole brain ADC histogram in certain diseases under consideration of age effects. PMID- 26609528 TI - Hepatic and Splenic Acoustic Radiation Force Impulse Shear Wave Velocity Elastography in Children with Liver Disease Associated with Cystic Fibrosis. AB - BACKGROUND: Liver disease associated with cystic fibrosis (CFLD) is the second cause of mortality in these patients. The diagnosis is difficult because none of the available tests are specific enough. Noninvasive elastographic techniques have been proven to be useful to diagnose hepatic fibrosis. Acoustic radiation force impulse (ARFI) imaging is an elastography imaging system. The purpose of the work was to study the utility of liver and spleen ARFI Imaging in the detection of CFLD. Method. 72 patients with cystic fibrosis (CF) were studied and received ARFI imaging in the liver and in the spleen. SWV values were compared with the values of 60 healthy controls. Results. Comparing the SWV values of CFLD with the control healthy group, values in the right lobe were higher in patients with CFLD. We found a SWV RHL cut-off value to detect CFLD of 1.27 m/s with a sensitivity of 56.5% and a specificity of 90.5%. CF patients were found to have higher SWC spleen values than the control group. Conclusions. ARFI shear wave elastography in the right hepatic lobe is a noninvasive technique useful to detect CFLD in our sample of patients. Splenic SWV values are higher in CF patients, without any clinical consequence. PMID- 26609529 TI - Prognostic Significance of the Tumor-Stroma Ratio in Epithelial Ovarian Cancer. AB - Tumor-stroma ratio (TSR) has recently been identified as a promising prognostic parameter for several solid tumors. This study aimed to evaluate the prognostic role of TSR in epithelial ovarian cancer (EOC) and 838 EOC patients were enrolled in this study. TSR was estimated on hematoxylin-and-eosin-stained tissue sections from the most invasive part of the primary tumor. Patients were classified as stroma-rich or stroma-poor according to the proportion of stroma >=50% or <50%. Chi-square test analysis revealed that TSR were significantly associated with FIGO stage, LN status, and recurrence or not (all of them P < 0.001). The higher stroma-rich proportions were found in EOC patients with advanced stage (36.13% versus 19.75%), LN metastasis (51.93% versus 27.25%), and recurrence (34.27% versus 6.82%). Stroma-rich EOC patients had obvious shorter median time of progression-free survival (29 versus 39 months) and overall survival (50 versus 58 months), respectively. TSR was an independent prognostic factor for the evaluation of PFS in EOC. Stroma-rich tumors had worse prognosis and higher risk of relapse compared with those in stroma-poor tumors in EOC patients. Considered easy to determine for routine pathological examination, TSR may serve as a new prognostic histological parameter in EOC. PMID- 26609527 TI - Coevolution between Cancer Activities and Food Structure of Human Being from Southwest China. AB - Yunnan and Tibet are the lowest cancer mortality and the largest producer for anticancer crops (brown rice, barley, buckwheat, tea, walnut, mushrooms, and so forth). Shanghai and Jiangsu province in China have the highest mortality of cancers, which are associated with the sharp decline of barley. PMID- 26609530 TI - Big Data and Network Biology 2015. PMID- 26609531 TI - A Tetrameric Peptide Derived from Bovine Lactoferricin Exhibits Specific Cytotoxic Effects against Oral Squamous-Cell Carcinoma Cell Lines. AB - Several short linear peptides derived from cyclic bovine lactoferricin were synthesized and tested for their cytotoxic effect against the oral cavity squamous-cell carcinoma (OSCC) cell lines CAL27 and SCC15. As a control, an immortalized and nontumorigenic cell line, Het-1A, was used. Linear peptides based on the RRWQWR core sequence showed a moderate cytotoxic effect and specificity towards tumorigenic cells. A tetrameric peptide, LfcinB(20-25)4, containing the RRWQWR motif, exhibited greater cytotoxic activity (>90%) in both OSCC cell lines compared to the linear lactoferricin peptide or the lactoferrin protein. Additionally, this tetrameric peptide showed the highest specificity towards tumorigenic cells among the tested peptides. Interestingly, this effect was very fast, with cell shrinkage, severe damage to cell membrane permeability, and lysis within one hour of treatment. Our results are consistent with a necrotic effect rather than an apoptotic one and suggest that this tetrameric peptide could be considered as a new candidate for the therapeutic treatment of OSCC. PMID- 26609532 TI - Endogenous Ouabain: An Old Cardiotonic Steroid as a New Biomarker of Heart Failure and a Predictor of Mortality after Cardiac Surgery. AB - Cardiovascular diseases remain the main cause of mortality and morbidity worldwide; primary prevention is a priority for physicians. Biomarkers are useful tools able to identify high-risk individuals, guide treatments, and determine prognosis. Our aim is to investigate Endogenous Ouabain (EO), an adrenal stress hormone with hemodynamic effects, as a valuable biomarker of heart failure. In a population of 845 patients undergoing elective cardiac surgery, we have investigated the relationships between EO and echocardiography parameters/plasmatic biomarker of cardiac function. EO was found to be correlated negatively with left ventricular EF (p = 0.001), positively with Cardiac End Diastolic Diameter (p = 0.047), and positively with plasmatic NT-proBNP level (p = 0.02). Moreover, a different plasmatic EO level (both preoperative and postoperative) was found according to NYHA class (p = 0.013). All these results have been replicated on an independent cohort of patients (147 subjects from US). Finally, a higher EO level in the immediate postoperative time was indicative of a more severe cardiological condition and it was associated with increased perioperative mortality risk (p = 0.023 for 30-day morality). Our data suggest that preoperative and postoperative plasmatic EO level identifies patients with a more severe cardiovascular presentation at baseline. These patients have a higher risk of morbidity and mortality after cardiac surgery. PMID- 26609533 TI - Magnetic Resonance Image Sequence Influences the Relationship between Bone Marrow Lesions Volume and Pain: Data from the Osteoarthritis Initiative. AB - Subchondral bone marrow lesions (BMLs) are related to structural and symptomatic osteoarthritis progression. However, it is unclear how sequence selection influences a quantitative BML measurement and its construct validity. We compared quantitative assessment of BMLs on intermediate-weighted fat suppressed (IW FS) turbo spin echo and 3-dimensional dual echo steady state (3D DESS) sequences. We used a customized software to measure 30 knees' (24- and 48-month MR images) BMLs on both sequences. The results showed that the IW FS sequences have much larger BML volumes (median: IW FS = 1840 mm(3); DESS = 191 mm(3)) and BML volume change (between 24 and 48 months) than DESS sequence and demonstrate more BML volume change. The 24-month BML volume on IW FS is correlated with BML volume on DESS (r s = 0.83). BML volume change on IW FS is not significantly correlated with change on DESS. The 24-month WOMAC pain is correlated with the 24-month BMLs on IW FS (r s = 0.39) but not DESS. The change in WOMAC pain is correlated with BML volume change on IW FS (r s = 0.37) but not DESS. Overall, BML quantification on IW FS offers better validity and statistical power than BML quantification on a 3D DESS sequence. PMID- 26609534 TI - Nanoparticle Probes for Structural and Functional Photoacoustic Molecular Tomography. AB - Nowadays, nanoparticle probes have received extensive attention largely due to its potential biomedical applications in structural, functional, and molecular imaging. In addition, photoacoustic tomography (PAT), a method based on the photoacoustic effect, is widely recognized as a robust modality to evaluate the structure and function of biological tissues with high optical contrast and high acoustic resolution. The combination of PAT with nanoparticle probes holds promises for detecting and imaging diseased tissues or monitoring their treatments with high sensitivity. This review will introduce the recent advances in the emerging field of nanoparticle probes and their preclinical applications in PAT, as well as relevant perspectives on future development. PMID- 26609535 TI - The Impact of Sequence of Chemotherapy and EGFR-TKI Treatment on Different EGFR Mutation Lung Adenocarcinoma. AB - OBJECTIVES: Chemotherapy as first-/second-line treatment in different epidermal growth factor receptor (EGFR) mutation lung adenocarcinoma remains controversial. METHODS: Consecutive patients were collected between 2009 and 2012. Patients were divided into two groups (1st-line chemotherapy: n = 56 and 2nd-line chemotherapy: n = 55). Their outcomes profiles were analyzed. RESULTS: The overall survival (OS) of all patients (390 versus 662 days, p < 0.0001), as well as both progression-free survival (PFS, 151 versus 252 days, p = 0.0001) and OS (308 versus 704 days, p = 0.0001) of patients with L858R mutation (n = 63), who received 2nd-line chemotherapy, was significantly poor. By univariate and multivariate analysis, 2nd-line chemotherapy, and L858R mutation were significantly related to poor PFS and OS. CONCLUSION: In advanced lung adenocarcinoma, L858R mutation and 2nd-line chemotherapy caused a poor outcome. It is a consideration to choice of 1st-line chemotherapy in these subjects. A prospective design is warranted to confirm this finding. PMID- 26609536 TI - Novel Sensor-Enabled Ex Vivo Bioreactor: A New Approach towards Physiological Parameters and Porcine Artery Viability. AB - The aim of the present work is to design and construct an ex vivo bioreactor system to assess the real time viability of vascular tissue. Porcine carotid artery as a model tissue was used in the ex vivo bioreactor setup to monitor its viability under physiological conditions such as oxygen, pressure, temperature, and flow. The real time tissue viability was evaluated by monitoring tissue metabolism through a fluorescent indicator "resorufin." Our ex vivo bioreactor allows real time monitoring of tissue responses along with physiological conditions. These ex vivo parameters were vital in determining the tissue viability in sensor-enabled bioreactor and our initial investigations suggest that, porcine tissue viability is considerably affected by high shear forces and low oxygen levels. Histological evaluations with hematoxylin and eosin and Masson's trichrome staining show intact endothelium with fresh porcine tissue whereas tissues after incubation in ex vivo bioreactor studies indicate denuded endothelium supporting the viability results from real time measurements. Hence, this novel viability sensor-enabled ex vivo bioreactor acts as model to mimic in vivo system and record vascular responses to biopharmaceutical molecules and biomedical devices. PMID- 26609539 TI - Same-sex sexuality and psychiatric disorders in the second Netherlands Mental Health Survey and Incidence Study (NEMESIS-2). AB - PURPOSE: Sexual orientation has been shown to be a risk factor for psychiatric disorders. This study compared whether sexual orientation-related disparities in the prevalence of psychiatric disorders are similar based on homosexual behavior versus attraction and tested whether, with increased acceptance of homosexuality, these disparities have diminished over time. METHODS: The Composite International Diagnostic Interview 3.0 was administered with a total of 6,646 Dutch persons, aged 18 to 64 years. RESULTS: Between 2.0% and 2.5% of the participants reported same-sex sexual behavior in the preceding year or same-sex attraction. Homosexually active persons and persons with same-sex attraction reported a higher prevalence of disorders than heterosexual persons. There were more disparities in the prevalence of disorders based on sexual attraction than based on sexual behavior. Comparing these results with a previous study, showed that no significant changes over time have occurred in the pattern of health disparities. CONCLUSIONS: Sexual orientation continues to be a risk factor for psychiatric disorders, stressing the need for understanding the origins of these disparities. PMID- 26609538 TI - Comparative Immunogenicity in Rabbits of the Polypeptides Encoded by the 5' Terminus of Hepatitis C Virus RNA. AB - Recent studies on the primate protection from HCV infection stressed the importance of immune response against structural viral proteins. Strong immune response against nucleocapsid (core) protein was difficult to achieve, requesting further experimentation in large animals. Here, we analyzed the immunogenicity of core aa 1-173, 1-152, and 147-191 and of its main alternative reading frame product F-protein in rabbits. Core aa 147-191 was synthesized; other polypeptides were obtained by expression in E. coli. Rabbits were immunized by polypeptide primes followed by multiple boosts and screened for specific anti-protein and anti-peptide antibodies. Antibody titers to core aa 147-191 reached 10(5); core aa 1-152, 5 * 10(5); core aa 1-173 and F-protein, 10(6). Strong immunogenicity of the last two proteins indicated that they may compete for the induction of immune response. The C-terminally truncated core was also weakly immunogenic on the T cell level. To enhance core-specific cellular response, we immunized rabbits with the core aa 1-152 gene forbidding F-protein formation. Repeated DNA immunization induced a weak antibody and sustained proliferative response of broad specificity confirming a gain of cellular immunogenicity. Epitopes recognized in rabbits overlapped those in HCV infection. Our data promotes the use of rabbits for the immunogenicity tests of prototype HCV vaccines. PMID- 26609540 TI - Continuing Decline in Varicella Incidence After the 2-Dose Vaccination Recommendation-Connecticut, 2009-2014. AB - Background. Varicella is a highly contagious vaccine-preventable illness. In 1996, the Advisory Committee for Immunization Practices recommended 1 dose of vaccine for children, and in 2006 it recommended 2 doses; Connecticut required 1 dose for school entry in 2000 and 2 doses for school entry starting in 2011. Connecticut varicella incidence overall and among persons aged 1-14 years declined during 2005-2008. We analyzed varicella surveillance data for 2009-2014 to characterize overall and age group-specific trends in the setting of the 2 dose requirement. Methods. Passive surveillance was used to collect data and identify incidence trends and changes in proportions, and these were assessed by chi(2) tests for trend and proportion, respectively. Results. Varicella incidence decreased from 13.8 cases/100 000 persons during 2009 to 5.1 cases/100 000 persons during 2014 (P < .001); significant declines in incidence occurred among children aged 1-4, 5-9, and 10-14 years (P < .01 for each age group). Cases classified as preventable decreased from 44% during 2009 to 25% during 2014 (P < .01); significant declines in percentages of preventable cases occurred only among those aged 5-9 years (P < .05) and 10-14 (P < .01) years. Conclusions. Varicella incidence continued to decline in Connecticut in the setting of the 2 dose school-entry program. Continued surveillance is needed to assess the full influence of the 2-dose recommendation. PMID- 26609541 TI - Mood Disorders: From Psychopathogenesis to Treatment. PMID- 26609537 TI - Regulators and Effectors of Arf GTPases in Neutrophils. AB - Polymorphonuclear neutrophils (PMNs) are key innate immune cells that represent the first line of defence against infection. They are the first leukocytes to migrate from the blood to injured or infected sites. This process involves molecular mechanisms that coordinate cell polarization, delivery of receptors, and activation of integrins at the leading edge of migrating PMNs. These phagocytes actively engulf microorganisms or form neutrophil extracellular traps (NETs) to trap and kill pathogens with bactericidal compounds. Association of the NADPH oxidase complex at the phagosomal membrane for production of reactive oxygen species (ROS) and delivery of proteolytic enzymes into the phagosome initiate pathogen killing and removal. G protein-dependent signalling pathways tightly control PMN functions. In this review, we will focus on the small monomeric GTPases of the Arf family and their guanine exchange factors (GEFs) and GTPase activating proteins (GAPs) as components of signalling cascades regulating PMN responses. GEFs and GAPs are multidomain proteins that control cellular events in time and space through interaction with other proteins and lipids inside the cells. The number of Arf GAPs identified in PMNs is expanding, and dissecting their functions will provide important insights into the role of these proteins in PMN physiology. PMID- 26609543 TI - Negative Pressure Incision Management System in the Prevention of Groin Wound Infection in Vascular Surgery Patients. AB - Objectives. Groin wounds following vascular surgery are highly susceptible to healing disturbances, with reported site infections reaching 30%. Negative pressure incision management systems (NPIMS) are believed to positively influence the prevention of surgical wound-healing disturbances (WHD) and surgical site infections (SSI). NPIMS placed directly after closure of the surgical wound is thought to result in fewer infections; we analysed its effect on postoperative wound infections in patients after vascular surgery via the groin. Methods. From May 2012 to March 2013 we included 90 surgical patients; 40 received a NPIMS. All patients with WHDs were labelled and subanalysed for surgical site infection in case of positive microbiological culture. These infections were graded according to Szilagyi. Number of WHDs and SSIs were compared across cohorts. Results. Patient and perioperative characteristics were equal, except for a significantly higher number of emergency procedures among non-NPIMS patients. We found no significant differences in number of WHDs, SSIs, or Szilagyi grades between the two cohorts. Conclusion. The equal number of SSIs across cohorts showed that NPIMS could not reduce the number of surgical site infections after vascular groin surgery. PMID- 26609542 TI - Genetic Evaluation of E. coli Strains Isolated from Asymptomatic Children with Neurogenic Bladders. AB - This study was conducted to describe the genetic profiles of E. coli that colonize asymptomatic pediatric neurogenic bladders. E. coli was isolated from 25 of 80 urine samples. Patients were excluded if they presented with symptomatic urinary tract infection or received treatment with antibiotics in the preceding three months. Multiplex PCR was performed to determine E. coli phylotype (A, B1, B2, and D) and the presence of seven pathogenicity islands (PAIs) and 10 virulence factors (VFs). E. coli strains were predominantly of the B1 and B2 phylotype, with few strains in the A or D phylotype. The PAIs IV536, ICFT073, and IICFT073 had the highest prevalence: 76%, 64%, and 48%, respectively. The PAIs II536, IJ96, and IIJ96 were less prevalent: 28%, 20%, and 24%, respectively. The most prevalent VF was vat (40%), while the least prevalent VFs were sfa (8%) and iha (12%). None of the strains carried the VF fyuA, which is very common in uropathogenic E. coli (UPEC). The genetic profiles of E. coli in this cohort seem to be more similar to UPEC than to commensal E. coli. However, they appear to have reduced virulence potential that allows them to colonize asymptomatically. PMID- 26609544 TI - A EWTD Compliant Rotation Schedule Which Protects Elective Training Opportunities Is Safe and Provides Sufficient Exposure to Emergency General Surgery: A Prospective Study. AB - Introduction. Training opportunities have decreased dramatically since the introduction of the European Working Time Directive (EWTD). In order to maximise training we introduced a rotation schedule in which registrars do not work night shifts and elective training opportunities are protected. We aimed to determine the safety and effectiveness of this EWTD compliant rotation schedule in achieving exposure of trainees to acute general surgical admissions and operations. Methods. A prospective study of consecutive emergency surgical admissions over a 6-month period. Exposure to acute admissions and operative procedures and patient outcomes during day and night shifts was compared. Results. There were 1156 emergency admissions covering a broad range of acute conditions. Significantly more patients were admitted during the day shift and almost all emergency procedures were performed during the day shift (2.1 versus 0.3, p < 0.001). A registrar was the primary operating surgeon in 49% of cases and was directly involved in over 65%. There were no significant differences between patients admitted during the day and night shifts in mortality rate, length of stay, admission to ICU, requirement for surgery, or readmission rates. Conclusion. A EWTD compliant rotation schedule that protects elective training opportunities is safe for patients and provides adequate exposure to training opportunities in emergency surgery. PMID- 26609545 TI - Metabolic vulnerability of KRAS-driven cancer cells. AB - Interfering with anaplerotic utilization of glutamine (Gln) was recently reported to sensitize KRAS-driven cancer cells to the cytotoxic effects of capecitabine and paclitaxel. This effect was due to bypass of a Gln-dependent G1 cell cycle checkpoint in these cells. This study highlights therapeutic opportunities created by metabolic reprogramming in cancer cells. PMID- 26609546 TI - Long-term Maintenance of Sterility Following Skin Transplantation in Germ-free Mice. AB - BACKGROUND: There is considerable interest in investigating the role of the microbiota in various diseases, including transplant rejection. Germ-free (GF) and gnotobiotic mice are powerful models for this line of investigation, but performing surgery within the confines of a sterile housing isolator is exceptionally challenging. Development of rigorous protocols to be able to remove axenic mice from their sterile isolator for surgical intervention in a Class II biological safety cabinet (BSC) without compromising sterility would give many investigators access to this model and broaden possible studies. However, it is assumed that GF animals will most often become colonized with environmental microbiota upon leaving the isolator. In this study, we tested whether applying sterile techniques for animal transport out of the isolator and skin transplantation in a Class II BSC could maintain animal sterility. METHODS: Quantitative polymerase chain reaction (qPCR) of the bacterial 16S ribosomal RNA gene, and cultures in various aerobic and anaerobic conditions were used to probe for bacterial contamination before and after transplantation. RESULTS: Out of 28 surgeries performed, only 3 mice acquired bacterial contamination coincident with a transient shutdown of the ventilation system in the BSC. CONCLUSION: Our results indicate that skin transplantation can be successfully performed in GF mice using sterile conditions for transport and surgery in a Class II BSC, but requires continuous positive airflow. Our approach paves the way to investigating the role of the microbiota in modulating immune responses to skin allografts as a first model of solid organ transplantation in GF mice. PMID- 26609547 TI - Confident Surgical Decision Making in Temporal Lobe Epilepsy by Heterogeneous Classifier Ensembles. AB - In medical domains with low tolerance for invalid predictions, classification confidence is highly important and traditional performance measures such as overall accuracy cannot provide adequate insight into classifications reliability. In this paper, a confident-prediction rate (CPR) which measures the upper limit of confident predictions has been proposed based on receiver operating characteristic (ROC) curves. It has been shown that heterogeneous ensemble of classifiers improves this measure. This ensemble approach has been applied to lateralization of focal epileptogenicity in temporal lobe epilepsy (TLE) and prediction of surgical outcomes. A goal of this study is to reduce extraoperative electrocorticography (eECoG) requirement which is the practice of using electrodes placed directly on the exposed surface of the brain. We have shown that such goal is achievable with application of data mining techniques. Furthermore, all TLE surgical operations do not result in complete relief from seizures and it is not always possible for human experts to identify such unsuccessful cases prior to surgery. This study demonstrates the capability of data mining techniques in prediction of undesirable outcome for a portion of such cases. PMID- 26609548 TI - A method developed to fractionate intact proteins based on capillary electrophoresis. AB - Reduction in the sample complexity enables more thorough intact protein analysis using MS-based proteomics. A capillary electrophoresis method, namely the velocity gap mode of capillary electrophoresis (VGCE), is proposed to separate protein mixtures with high resolution. Although the separation mechanism of VGCE is also based on the difference of the mass-to-charge ratios of the proteins, it fractionates the sample zone into small pieces of subunits. In this way, the resolution can be dramatically improved due to less longitudinal dispersion of the sample. The effect of the new approach is evaluated by separation of three groups of reference protein mixtures, i.e. a mixture of lysozyme and BSA; a mixture of lysozyme, beta-lactoglobulin, and ribonuclease A; and a mixture of cytochrome C, lysozyme, BSA, beta-lactoglobulin, ribonuclease A, conalbumin, carbonic anhydrase, and hemoglobin. The results indicate that the new approach shows great potential to couple with MS for top-down analysis of complex mixtures. PMID- 26609549 TI - Multivariate analysis of 3D ToF-SIMS images: method validation and application to cultured neuronal networks. AB - Advanced data analysis tools are crucial for the application of ToF-SIMS analysis to biological samples. Here, we demonstrate that by using a training set approach principal components analysis (PCA) can be performed on large 3D ToF-SIMS images of neuronal cell cultures. The method readily provides access to sample component information and significantly improves the images' signal-to-noise ratio (SNR). PMID- 26609550 TI - Visible light-induced ion-selective optodes based on a metastable photoacid for cation detection. AB - A new platform of ion-selective optodes is presented here to detect cations under thermodynamic equilibrium via ratiometric analysis. This novel platform utilizes a 'one of a kind' visible light-induced metastable photoacid as a reference ion indicator to achieve activatable and controllable sensors. These ion-selective optodes were studied in terms of their stability, sensitivity, selectivity, and theoretical aspects. PMID- 26609551 TI - Mechanism of the biomolecular synthesis of PEDOT:PSS: importance of heme degradation by hydrogen peroxide. AB - The use of biomolecules as oxidants for the synthesis of conducting polymers provides an important tool for the control of polymer properties. Using PEDOT: PSS as a representative conducting polymer, we compare a set of heme proteins (soybean peroxidase, cytochrome c, and horseradish peroxidase) used as oxidants. The resulting PEDOT: PSS was characterized with visible and near IR spectroscopy, Fourier transform infrared spectroscopy, electron spin resonance spectroscopy, and four point probe conductivity measurements. We find that the relative concentrations of bipolarons and polarons vary as a function of the protein used for polymerization. We then show that heme degradation by hydrogen peroxide plays a critical role in determining polymer properties. PMID- 26609552 TI - Magnetic Graphene Nanosheet-Based Microfluidic Device for Homogeneous Real-Time Electronic Monitoring of Pyrophosphatase Activity Using Enzymatic Hydrolysate Induced Release of Copper Ion. AB - A novel flow-through microfluidic device based on a magneto-controlled graphene sensing platform was designed for homogeneous electronic monitoring of pyrophosphatase (PPase) activity; enzymatic hydrolysate-induced release of inorganic copper ion (Cu(2+)) from the Cu(2+)-coordinated pyrophosphate ions (Cu(2+)-PPi) complex was assessed to determine enzyme activity. Magnetic graphene nanosheets (MGNS) functionalized with negatively charged Nafion were synthesized by using the wet-chemistry method. The Cu(2+)-PPi complexes were prepared on the basis of the coordination reaction between copper ion and inorganic pyrophosphate ions. Upon target PPase introduction into the detection system, the analyte initially hydrolyzed pyrophosphate ions into phosphate ions and released the electroactive copper ions from Cu(2+)-PPi complexes. The released copper ions could be readily captured through the negatively charged Nafion on the magnetic graphene nanosheets, which could be quantitatively monitored by using the stripping voltammetry on the flow-through detection cell with an external magnet. Under optimal conditions, the obtained electrochemical signal exhibited a high dependence on PPase activity within a dynamic range from 0.1 to 20 mU mL(-1) and allowed the detection at a concentration as low as 0.05 mU mL(-1). Coefficients of variation for reproducibility of the intra-assay and interassay were below 7.6 and 9.8%, respectively. The inhibition efficiency of sodium fluoride (NaF) also received good results in pyrophosphatase inhibitor screening research. In addition, the methodology afforded good specificity and selectivity, simplification, and low cost without the need of sample separations and multiple washing steps, thus representing a user-friendly protocol for practical utilization in a quantitative PPase activity. PMID- 26609553 TI - Receiving the news of a diagnosis of motor neuron disease: What does it take to make it better? AB - Our objectives were to identify the experiences of people with MND in receiving the diagnosis and to determine which aspects of breaking this bad news were associated with greater satisfaction with the way the diagnosis was delivered to them. An anonymous postal survey was facilitated by all MND associations in Australia, in 2014, and centred on the SPIKES protocol for communicating bad news. Of the patients (n = 248, response rate 29%), 36% were dissatisfied with the delivery of the diagnosis and gave low ratings on the ability/skills of their neurologists to deliver the diagnosis. It was evident that the longer the patients spent with their neurologists during breaking such bad news, the more they were satisfied and the higher they rated the neurologists' abilities/skills. The largest significant differences between neurologists rated as having high or low skills in delivering the diagnosis were in four domains: 1) responding empathically to the feelings of patient/family; 2) sharing the information and suggesting realistic goals; 3) exploring what patient/family are expecting or hoping for; and 4) making a plan and following through. In conclusion, with over one-third of patients dissatisfied with their experience, there is room for improvement in the practice of neurologists in specified areas that could form the basis for changing practice, and the development of standards and protocols likely to have implications at the international level. PMID- 26609555 TI - How do people respond to health news? The role of personality traits. AB - When a patient receives a health diagnosis, their response (e.g. changes in behaviour, seeking support) can have significant consequences for long-term health and well-being. Characteristics of health news are known to influence these responses, but personality traits have been omitted from this line of research. The current study examines the role of personality traits in predicting response to health news. Participants (N = 298) read scenarios in which they received health news that was manipulated to vary in severity, controllability and likelihood of outcomes. Participants then rated how likely they were to engage in a number of response behaviours. We examined the main effects and interaction of situational manipulations and personality traits on ratings of these behaviours. Both situations and personality traits influenced behavioural responses to health events. In particular, conscientiousness predicted taking action and seeking social support. Neuroticism predicted both maladaptive and adaptive behavioural responses, providing support for the 'healthy neurotic' hypothesis. Moreover, personality traits predicted best in weak (unlikely, controllable) situations. Both personality traits and situational characteristics contribute to behavioural responses to health news. PMID- 26609554 TI - Quantitative risk assessment on the dietary exposure of Finnish children and adults to nitrite. AB - Nitrite intake from the consumption of cured meat and tap water was estimated for Finnish children of 1, 3 and 6 years as well as Finnish adults of 25-74 years. Nitrite content in the foods was measured by capillary electrophoresis, and was then used together with individual food consumption data from the FINDIET 2007 and DIPP studies in a stochastic exposure assessment by a Monte Carlo Risk Assessment (MCRA) program. Nitrite intake from additive sources and tap water was assessed, and more than every 10th child between the ages 3 and 6 years was estimated to have a nitrite intake exceeding the acceptable daily intake (ADI) of nitrite. The high exposure levels were caused by frequent consumption of large portions of sausages, up to 350 g day(-1) or 750 g in 3 days, among the children. Median nitrite intake from cured meat was 0.016, 0.040, 0.033 and 0.005 mg kg(-1) body weight day(-1) for children of 1, 3 and 6 years and adults, respectively. Bayesian estimation was employed to determine safe consumption levels of sausages and cold cuts for children, and these results gave rise to new national food consumption advice. PMID- 26609556 TI - Controllable and Reversible Dimple-Shaped Aggregates Induced by Macrocyclic Recognition Effect. AB - A novel dimethyl acrylate 18-membered macrocycle (DMECE), acting as both bifunctional monomer and cross-linker, was designed and synthesized, and thus employed to construct a series of macrocycle-containing amphiphilic hyperbranched polymers (HBPs). The macrocyclic recognition effect between the HBPs and alkali metal ions showed that Na(+) was introduced in 1:1 interactive mode, whereas K(+) and Rb(+) were in 2:1 ratio. Through the formation of the DMECE/K(+) = 2:1 rigid "sandwich" complex of amphiphilic hyperbranched polymers, dimple-shaped aggregates were observed by TEM, SEM and AFM. Moreover, the initial concentration, the nature of solvent, the mode and affinity of the macrocyclic recognition effect as well as the amount of K(+), were essential control factors for the formation of dimple-shaped aggregates. Most importantly, the macrocyclic recognition effect endows the reversibility of the dimple-shaped aggregates and the size controllability of its circular opening, which provides a new strategy for design novel macrocycle-containing HBPs and great potential application in the field of capture and release. PMID- 26609557 TI - The influence of lexical-access ability and vocabulary knowledge on measures of speech recognition in noise. AB - OBJECTIVE: The main objective was to investigate the effect of linguistic abilities (lexical-access ability and vocabulary size) on different measures of speech-in-noise recognition in normal-hearing listeners with various levels of language proficiency. DESIGN: Speech reception thresholds (SRTs) were measured for sentences in steady-state (SRTstat) and fluctuating noise (SRTfluc), and for digit-triplets in steady-state noise (DIN). Lexical-access ability was measured with a lexical-decision test and a word-naming test. Vocabulary size was also measured. For the SRT, keyword scoring and sentence scoring were compared. STUDY SAMPLE: To introduce variation in linguistic abilities, three groups of 24 young normal-hearing listeners were included: higher-educated native, lower-educated native, and higher-educated non-native listeners. RESULTS: Lexical-access ability was most accurately measured with combined results of lexical decision and word naming. Lexical-access ability explained 60% of the variance in SRT. The effect of linguistic abilities on SRTs was up to 5.6 dB for SRTstat and 8 dB for SRTfluc. Using keyword scoring reduced this effect by approximately 1.5 dB. For DIN the effect of linguistic ability was less than 1 dB. CONCLUSIONS: Lexical access ability is an important predictor of SRTs in normal-hearing listeners. These results are important to consider in the interpretation of speech-in-noise scores of hearing-impaired listeners. PMID- 26609558 TI - Superposition of Fragment Excitations for Excited States of Large Clusters with Application to Helium Clusters. AB - We develop a local excited-state method, based on the configuration interaction singles (CIS) wave function, for large atomic and molecular clusters. This method exploits the properties of absolutely localized molecular orbitals (ALMOs), which strictly limits the total number of excitations, and results in formal scaling with the third power of the system size for computing the full spectrum of ALMO CIS excited states. The derivation of the equations and design of the algorithm are discussed in detail, with particular emphasis on the computational scaling. Clusters containing ~500 atoms were used in evaluating the scaling, which agrees with the theoretical predictions, and the accuracy of the method is evaluated with respect to standard CIS. A pioneering application to the size dependence of the helium cluster spectrum is also presented for clusters of 25-231 atoms, the largest of which results in the computation of 2310 excited states per sampled cluster geometry. PMID- 26609559 TI - Curcumin inhibits activation of TRPM2 channels in rat hepatocytes. AB - Oxidative stress is a hallmark of many liver diseases including viral and drug induced hepatitis, ischemia-reperfusion injury, and non-alcoholic steatohepatitis. One of the consequences of oxidative stress in the liver is deregulation of Ca(2+) homeostasis, resulting in a sustained elevation of the free cytosolic Ca(2+) concentration ([Ca(2+)]c) in hepatocytes, which leads to irreversible cellular damage. Recently it has been shown that liver damage induced by paracetamol and subsequent oxidative stress is, in large part, mediated by Ca(2+) entry through Transient Receptor Potential Melastatin 2 (TRPM2) channels. Involvement of TRPM2 channels in hepatocellular damage induced by oxidative stress makes TRPM2 a potential therapeutic target for treatment of a range of oxidative stress-related liver diseases. We report here the identification of curcumin ((1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6 heptadiene-3,5-dione), a natural plant-derived polyphenol in turmeric spice, as a novel inhibitor of TRPM2 channel. Presence of 5uM curcumin in the incubation medium prevented the H2O2- and paracetamol-induced [Ca(2+)]c rise in rat hepatocytes. Furthermore, in patch clamping experiments incubation of hepatocytes with curcumin inhibited activation of TRPM2 current by intracellular ADPR with IC50 of approximately 50nM. These findings enhance understanding of the actions of curcumin and suggest that the known hepatoprotective properties of curcumin are, at least in part, mediated through inhibition of TRPM2 channels. PMID- 26609560 TI - L-dehydroascorbic acid can substitute l-ascorbic acid as dietary vitamin C source in guinea pigs. AB - Vitamin C deficiency globally affects several hundred million people and has been associated with increased morbidity and mortality in numerous studies. In this study, bioavailability of the oxidized form of vitamin C (l-dehydroascorbic acid or DHA)-commonly found in vitamin C containing food products prone to oxidation was studied. Our aim was to compare tissue accumulation of vitamin C in guinea pigs receiving different oral doses of either ascorbate or DHA. In all tissues tested (plasma, liver, spleen, lung, adrenal glands, kidney, muscle, heart, and brain), only sporadic differences in vitamin C accumulation from ascorbate or DHA were observed except for the lowest dose of DHA (0.25mg/ml in the drinking water), where approximately half of the tissues had slightly yet significantly less vitamin C accumulation than from the ascorbate source. As these results contradicted data from rats, we continued to explore the ability to recycle DHA in blood, liver and intestine in guinea pigs, rats and mice. These investigations revealed that guinea pigs have similar recycling capacity in red blood cells as observed in humans, while rats and mice do not have near the same ability to reduce DHA in erythrocytes. In liver and intestinal homogenates, guinea pigs also showed a significantly higher ability to recycle DHA compared to rats and mice. These data demonstrate that DHA in guinea pigs-as in humans-is almost as effective as ascorbate as vitamin C source when it comes to taking up and storing vitamin C and further suggest that the guinea pig is superior to other rodents in modeling human vitamin C homeostasis. PMID- 26609562 TI - The role of implantable devices to treat atrial fibrillation. AB - In the last decades several nonpharmacological therapies for the treatment and prevention of atrial fibrillation (AF) have been developed. Pacemakers play a potential important role in the nonpharmacological management of AF. In patients with sinus node dysfunction both, atrial and dual-chamber pacing, have been proven to prevent or delay progression to permanent AF compared with ventricular pacing alone. However, in patients without conventional indications for pacing, the utility of pacemakers as a stand-alone therapy has not yet proven. Following the positive results obtained by low energy internal defibrillation, specific implantable devices for AF cardioversion have been developed. Despite implantable atrial defibrillators being possible alternatives for drug refractory AF, industry did not further develop these due to shock discomfort. Newer implantable pulse generators also offer data storage that permits detection of asymptomatic AF. Such a help provided by implantable devices, has been enhanced by the development and spread out of remote monitoring systems. PMID- 26609561 TI - Cysteines 208 and 241 in Ero1alpha are required for maximal catalytic turnover. AB - Endoplasmic reticulum (ER) oxidoreductin 1alpha (Ero1alpha) is a disulfide producer in the ER of mammalian cells. Besides four catalytic cysteines (Cys(94), Cys(99), Cys(394), Cys(397)), Ero1alpha harbors four regulatory cysteines (Cys(104), Cys(131), Cys(208), Cys(241)). These cysteines mediate the formation of inhibitory intramolecular disulfide bonds, which adapt the activation state of the enzyme to the redox environment in the ER through feedback signaling. Accordingly, disulfide production by Ero1alpha is accelerated by reducing conditions, which minimize the formation of inhibitory disulfides, or by mutations of regulatory cysteines. Here we report that reductive stimulation enhances Ero1alpha activity more potently than the mutation of cysteines. Specifically, mutation of Cys(208)/Cys(241) does not mechanistically mimic reductive stimulation, as it lowers the turnover rate of Ero1alpha in presence of a reducing agent. The Cys(208)/Cys(241) pair therefore fulfills a function during catalysis that reaches beyond negative regulation. In agreement, we identify a reciprocal crosstalk between the stabilities of the Cys(208)-Cys(241) disulfide and the inhibitory disulfide bonds involving Cys(104) and Cys(131), which also controls the recruitment of the H2O2 scavenger GPx8 to Ero1alpha. Two possible mechanisms by which thiol-disulfide exchange at the Cys(208)/Cys(241) pair stimulates the catalytic turnover under reducing conditions are discussed. PMID- 26609563 TI - From emergency to sustainability: shifting objectives in the US Government's HIV response in Tanzania. AB - The US President's Emergency Plan for AIDS Relief (PEPFAR) was originally designed as an emergency initiative, operating with considerable funds, immediate roll-out, fast scale-up, and top-down technocratic administration. In a more recent iteration, PEPFAR shifted its focus from an emergency response to more closely account for healthcare sustainability. This transition came on the heels of the 2008 financial crisis, which threatened to stall the 'marvellous momentum' of the 2000's boom in donor aid for global health overall. Now many programmes are having to do more with less as funding flattens or decreases. This paper examines how this transition took shape in Tanzania in 2011-2012, and the successes and challenges associated with it, using participant observation and interview data from 20 months of fieldwork in rural and urban healthcare settings. In particular, I discuss (1) efforts to increase sustainability and country ownership of HIV programmes in Tanzania, focusing on the shift from PEPFAR-funded American non-governmental organisations to Tanzanian partner organisations; (2) principal challenges stakeholders encountered during the transition, including fragmented systems of healthcare delivery and a weakened healthcare workforce; and (3) strategies informants identified to better integrate services in order to build a stronger, more equitable, and sustainable health system in Tanzania. PMID- 26609564 TI - Is there a role of depressive symptoms in the fear-avoidance model? A structural equation approach. AB - The fear-avoidance (FA) model has gained widespread acceptance as a conceptual framework for investigating psychological factors such as FA beliefs and avoidance behavior, which contribute to chronic back pain and reduced functioning. Depressive symptoms are supposed to be related to FA beliefs and to foster avoidance behavior. This study aims to investigate the multivariate assumptions of the FA model with a focus on the role of depressive symptoms. A total of N = 360 patients with chronic nonspecific low back pain at admission of inpatient orthopedic rehabilitation participated in the survey. Measures included a numeric pain rating scale, Fear-Avoidance Beliefs Questionnaire, Pain Anxiety Symptoms Scale, Hannover Functional Ability Questionnaire and Patient Health Questionnaire. Using structural equation modeling (SEM), we construed a basic FA model and subsequently extended it by adding symptoms of depression as a covariate. The results of SEM indicated a good model fit for a basic FA model (chi2(263) = 431.069, p < .001, RMSEA = .042, CFI = .964, WRMR = .986). They confirmed the hypothesized relations and supported single mediations of the relationship between pain and functioning by FA beliefs and avoidance behavior. A second model including symptoms of depression as additional covariate (chi2(511) = 722.761, p < .001, RMSEA = .034, CFI = .956, WRMR = .949) showed a high impact of depressive symptoms on all FA model variables leading to a decrease of the FA mediations. The findings provide empirical support for the multivariate FA model and underline the importance of considering depressive symptoms in a multiple target approach to understand the mechanisms of chronic pain. PMID- 26609566 TI - Comparing LDA-1/2, HSE03, HSE06 and G0W0 approaches for band gap calculations of alloys. AB - It has long been known that the local density approximation and the generalized gradient approximation do not furnish reliable band gaps, and one needs to go beyond these approximations to reliably describe these properties. Among alternatives are the use of hybrid functionals (HSE03 and HSE06 being popular), the GW approximation or the recently proposed LDA-1/2 method. In this work, we compare rigorously the performance of these four methods in describing the band gaps of alloys, employing the generalized quasi-chemical approach to treat the disorder of the alloy and to obtain judiciously the band gap for the entire compositional range. Zincblende InGaAs and InGaN were chosen as prototypes due to their importance in optoelectronic applications. The comparison between these four approaches was guided both by the agreement between the predicted band gap and the experimental one, and by the demanded computational effort (time and memory). We observed that the HSE06 method provided the most accurate results (in comparison with experiments), whereas, surprisingly, the LDA-1/2 method gave the best compromise between accuracy and computational resources. Due to its low computational cost and good accuracy, we decided to double the supercell used to describe the alloys, and employing LDA-1/2 we observed that the bowing parameter changed remarkably, only agreeing with the measured one for the larger supercell, where LDA-1/2 plays an important role. PMID- 26609565 TI - The effect of gene polymorphisms on patient responses to rheumatoid arthritis therapy. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a systemic disease leading to joint destruction. The therapy of RA is mainly based on disease-modifying anti rheumatic drugs (DMARDs) and biological drugs. The response to treatment is different among patients. Therefore, we have searched for factors that may predict the efficacy and toxicity during therapy in individual patients. AREAS COVERED: This review presents the role of genetic polymorphisms as predictors of the efficacy and toxicity during the therapy of RA patients with DMARDs (methotrexate, leflunomide, sulfasalazine) and biological drugs (anti-TNF-alpha antagonists, Tocilizumab, Rituximab). EXPERT OPINION: Despite studies having shown an association between genetic polymorphisms and response to therapy in RA patients, the majority of these findings are still inconclusive and inconsistent. We are still far from applying pharmacogenetic tests in routine clinical practice that can predict the outcome of treatment. Several factors, such as small sample size with low statistical power, variability in the outcome definitions and the heterogeneity of the cohorts, limited number of tested single nucleotide polymorphisms (SNPs), small effect for the selected variant, and a lack of consideration of epigenetic factors, may contribute to the inconsistency observed and may lead to limited success in personalizing therapy. PMID- 26609567 TI - Circulating concentrations of glucagon-like peptide 1, glucose-dependent insulinotropic peptide, peptide YY, and insulin in client-owned lean, overweight, and diabetic cats. AB - Our objectives were to measure plasma concentrations of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) in client-owned newly diagnosed diabetic cats and nondiabetic lean or overweight cats and to determine whether circulating concentrations of these hormones differed between study groups and if they increased postprandially as seen in other species. A total of 31 cats were recruited and placed into 1 of 3 study groups: lean (body condition score 4-5 on a scale of 1-9; n = 10), overweight (body condition score 6-8; n = 11), or diabetic (n = 10). Diabetics were newly diagnosed and had not had prior insulin therapy. Preprandial (fasting) and postprandial (60 min after meal) plasma hormone and glucose concentrations were measured at baseline and 2 and 4 wk. All cats were exclusively fed a commercially available high-protein and low-carbohydrate diet commonly prescribed to feline diabetic patients for 2 wk before the 2-wk assessment and continued through the 4 wk assessment. Results showed that plasma concentrations of GLP-1, GIP, PYY, and insulin increased in general after a meal in all study groups. Plasma PYY concentrations did not differ (P > 0.10) between study groups. Diabetics had greater plasma concentrations of GLP-1 and GIP compared with the other study groups at baseline (P < 0.05), and greater preprandial and postprandial GLP-1 concentrations than lean cats at 2 and 4 wk (P < 0.05). Preprandial plasma GIP concentrations were greater in diabetics than obese and lean (P < 0.05) cats at week 4. Postprandial plasma GIP concentrations in diabetics were greater than lean (P < 0.05) at week 2 and obese and lean cats (P < 0.05) at week 4. Together, our findings suggest that diabetic status is an important determinant of circulating concentrations of GLP-1 and GIP, but not PYY, in cats. The role of GLP-1, GIP, and PYY in the pathophysiology of feline obesity and diabetes remains to be determined. PMID- 26609568 TI - The vascular plant-pathogenic bacterium Ralstonia solanacearum produces biofilms required for its virulence on the surfaces of tomato cells adjacent to intercellular spaces. AB - The mechanism of colonization of intercellular spaces by the soil-borne and vascular plant-pathogenic bacterium Ralstonia solanacearum strain OE1-1 after invasion into host plants remains unclear. To analyse the behaviour of OE1-1 cells in intercellular spaces, tomato leaves with the lower epidermis layers excised after infiltration with OE1-1 were observed under a scanning electron microscope. OE1-1 cells formed microcolonies on the surfaces of tomato cells adjacent to intercellular spaces, and then aggregated surrounded by an extracellular matrix, forming mature biofilm structures. Furthermore, OE1-1 cells produced mushroom-type biofilms when incubated in fluids of apoplasts including intercellular spaces, but not xylem fluids from tomato plants. This is the first report of biofilm formation by R. solanacearum on host plant cells after invasion into intercellular spaces and mushroom-type biofilms produced by R. solanacearum in vitro. Sugar application led to enhanced biofilm formation by OE1-1. Mutation of lecM encoding a lectin, RS-IIL, which reportedly exhibits affinity for these sugars, led to a significant decrease in biofilm formation. Colonization in intercellular spaces was significantly decreased in the lecM mutant, leading to a loss of virulence on tomato plants. Complementation of the lecM mutant with native lecM resulted in the recovery of mushroom-type biofilms and virulence on tomato plants. Together, our findings indicate that OE1-1 produces mature biofilms on the surfaces of tomato cells after invasion into intercellular spaces. RS-IIL may contribute to biofilm formation by OE1-1, which is required for OE1-1 virulence. PMID- 26609570 TI - The costs of medical education assessment. PMID- 26609569 TI - Antibodies against pneumococcal capsular polysaccharide in Malawian HIV-positive mothers and their HIV-exposed uninfected children. AB - : Background HIV-exposed uninfected children have a higher risk of infection and mortality compared to HIV-unexposed children and the reasons for this vulnerability are still under investigation. AIM: This study aimed to evaluate the influence of maternal HIV parameters on the passive transfer of anti pneumococcal capsular polysaccharide (PCP) IgG and to determine whether the concentrations of specific IgG might be related to the morbidity and mortality in HIV-exposed uninfected children. Methods One hundred and twenty-six Malawian HIV infected pregnant women and their uninfected children were studied. Antiretroviral treatment-naive women started a nevirapine-based triple combination regimen from the third trimester of pregnancy until at least 6 months of exclusive breastfeeding. Mother/child pairs were followed until 2 years after delivery. Plasma anti-PCP IgG titers (in mothers at 26 weeks of gestation and in infants at 1 and 6 months) were determined by an enzyme-linked immunosorbent assay. None of these women and children had received any vaccination against pneumococcal polysaccharides. Results Maternal anti-PCP IgG concentration was independent from viral load (p = 0.848), CD4 count (p = 0.740) and WHO stage (p = 0.450). However, the child/mother ratio of anti-PCP IgG measured at 1 month among infants was significantly reduced in pairs whose mothers had HIV-RNA > 10 000 copies/ml (p = 0.043) and CD4 < 350 cells/MUl (p = 0.090) before antiretroviral therapy (ART). No clear associations between anti-PCP IgG and respiratory-related deaths were found, but respiratory infection episodes were more frequent among children with lower anti-PCP IgG ratio (p = 0.046). Conclusion This study indicates that HIV pre-ART conditions in mothers may influence the rate of specific immunoglobulins transfer, increasing infants vulnerability to respiratory infections. PMID- 26609571 TI - Special Issue in Honor of John P. Perdew for His 65th Birthday. PMID- 26609572 TI - Evaluation of Density Functionals and Basis Sets for Carbohydrates. AB - Correlated ab initio wave function calculations using MP2/aug-cc-pVTZ model chemistry have been performed for three test sets of gas phase saccharide conformations to provide reference values for their relative energies. The test sets consist of 15 conformers of alpha- and beta-d-allopyranose, 15 of 3,6 anhydro-4-O-methyl-d-galactitol, and four of beta-d-glucopyranose. For each set, conformational energies varied by about 7 kcal/mol. Results obtained with the Hartree-Fock method, with pure density functional approximations (DFAs) like LSDA, PBEsol, PBE, and TPSS and with hybrid DFAs like B3PW91, B3LYP, PBEh, and M05-2X, were then compared to the reference and local MP2 relative energies. Basis sets included 6-31G*, 6-31G**, 6-31+G*, 6-31+G**, 6-311+G**, 6-311++G**, cc pVTZ(-f), cc-pVTZ, and aug-cc-pVTZ(-f). The smallest basis set that gives good DFA relative energies is 6-31+G**, and more converged results can be obtained with 6-311+G**. The optimized geometries obtained from a smaller basis set, 6 31+G*, were useful for subsequent single point energy calculations with larger basis sets. The best agreement with MP2 was shown by M05-2X, but only when using a dense DFT grid. The popular B3LYP functional is not the best for saccharide conformational studies. The B3PW91 functional gives systematically better results, but other hybrid functionals like PBEh or TPSSh are even better. Overall, the nonempirical PBE GGA and TPSS meta-GGA functionals also performed better than B3LYP. PMID- 26609573 TI - Dependence of Response Functions and Orbital Functionals on Occupation Numbers. AB - Explicitly orbital-dependent approximations to the exchange-correlation energy functional of density functional theory typically not only depend on the single particle Kohn-Sham orbitals but also on their occupation numbers in the ground state Slater determinant. The variational calculation of the corresponding exchange-correlation potentials with the optimized effective potential (OEP) method therefore also requires a variation of the occupation numbers with respect to a variation in the effective single-particle potential, which is usually not taken into account. Here it is shown under which circumstances this procedure is justified. PMID- 26609574 TI - Reconstruction of Density Functionals from Kohn-Sham Potentials by Integration along Density Scaling Paths. AB - We demonstrate by specific examples that if a Kohn-Sham exchange-correlation potential is given explicitly in terms of the electron density and its derivatives, then one can easily reconstruct the parent density functional by evaluating analytically (or numerically with one-dimensional quadratures) the van Leeuwen-Baerends line integral (Phys. Rev. A 1995, 51, 170-178) along a path of (coordinate)-scaled densities. The choice of a density scaling path amounts to defining the gauge of the resultant exchange-correlation energy density. The well known Levy-Perdew virial relation for exchange potentials can be viewed as an analytical line integral along the electron-number-conserving uniform density scaling path. Energies obtained from model exchange-correlation potentials should be interpreted with caution because the reconstructed density functional is unique (up to a gauge transformation) only if the model Kohn-Sham potential is a functional derivative. PMID- 26609575 TI - Extension to Negative Values of the Coupling Constant of Adiabatic Connection for Interaction-Strength Interpolation. PMID- 26609576 TI - Polarizabilities of Polyacetylene from a Field-Counteracting Semilocal Functional. AB - Predicting the polarizabilities of extended conjugated molecules with semilocal functionals has been a long-standing problem in density functional theory. These difficulties are due to the absence of a term in the typical semilocal Kohn-Sham exchange potentials that has been named "ultranonlocal". Such a term should develop in extended systems when an external electric field is applied, and it should counteract the field. We calculate the polarizabilities of polyacetylene molecules using the recently developed extended Becke-Johnson functional. Our results show that this functional predicts the polarizabilities with much better accuracy than typical semilocal functionals. Thus, the field-counteracting term in this functional, which is semilocal in the Kohn-Sham orbitals, can realistically describe real molecules. We discuss approaches of constructing an energy functional that corresponds to this potential functional, for example, via the Levy-Perdew virial relation. PMID- 26609577 TI - Van der Waals Interactions in Density-Functional Theory: Rare-Gas Diatomics. AB - The application of conventional GGA and meta-GGA density functionals to van der Waals interactions is fraught with difficulties. Conventional functionals do not contain the physics of the dispersion interaction. To make matters worse, the exchange part alone can yield anything from severe overbinding to severe over repulsion depending on the choice of functional. We have assessed a variety of exchange GGAs for their ability to reproduce exact Hartree-Fock repulsion energies in rare-gas systems, and we find that PW86 [ Phys. Rev. B 1986 , 33 , 8800 ] performs remarkably well. The addition of a dynamical correlation GGA and the nonempirical dispersion model of Becke and Johnson [ J. Chem. Phys. 2007 , 127 , 154108 ] to PW86 gives a simple GGA plus dispersion theory yielding excellent rare-gas interaction curves for pairs involving He through Kr, with only two adjustable parameters for damping of the dispersion terms. PMID- 26609578 TI - Modified Ehrenfest Formalism for Efficient Large-Scale ab initio Molecular Dynamics. AB - We present in detail the recently derived ab initio molecular dynamics (AIMD) formalism [Alonso et al. Phys. Rev. Lett. 2008, 101, 096403], which due to its numerical properties, is ideal for simulating the dynamics of systems containing thousands of atoms. A major drawback of traditional AIMD methods is the necessity to enforce the orthogonalization of the wave functions, which can become the bottleneck for very large systems. Alternatively, one can handle the electron-ion dynamics within the Ehrenfest scheme where no explicit orthogonalization is necessary, however the time step is too small for practical applications. Here we preserve the desirable properties of Ehrenfest in a new scheme that allows for a considerable increase of the time step while keeping the system close to the Born Oppenheimer surface. We show that the automatically enforced orthogonalization is of fundamental importance for large systems because not only it improves the scaling of the approach with the system size but it also allows for an additional very efficient parallelization level. In this work, we provide the formal details of the new method, describe its implementation, and present some applications to some test systems. Comparisons with the widely used Car-Parrinello molecular dynamics method are made, showing that the new approach is advantageous above a certain number of atoms in the system. The method is not tied to a particular wave function representation, making it suitable for inclusion in any AIMD software package. PMID- 26609579 TI - Electronic Zero-Point Oscillations in the Strong-Interaction Limit of Density Functional Theory. AB - The exchange-correlation energy in Kohn-Sham density functional theory can be expressed exactly in terms of the change in the expectation of the electron electron repulsion operator when, in the many-electron Hamiltonian, this same operator is multiplied by a real parameter lambda varying between 0 (Kohn-Sham system) and 1 (physical system). In this process, usually called adiabatic connection, the one-electron density is kept fixed by a suitable local one-body potential. The strong-interaction limit of density functional theory, defined as the limit lambda->infinity, turns out to be like the opposite noninteracting Kohn Sham limit (lambda->0) mathematically simpler than the physical (lambda = 1) case and can be used to build an approximate interpolation formula between lambda->0 and lambda->infinity for the exchange-correlation energy. Here we extend the systematic treatment of the lambda->infinity limit [Phys. Rev. A 2007, 75, 042511] to the next leading term, describing zero-point oscillations of strictly correlated electrons, with numerical examples for small spherical atoms. We also propose an improved approximate functional for the zero-point term and a revised interpolation formula for the exchange-correlation energy satisfying more exact constraints. PMID- 26609580 TI - Long-Range-Corrected Hybrids Based on a New Model Exchange Hole. AB - By admixing a fraction of exact Hartree-Fock-type exchange with conventional semilocal functionals, global hybrids greatly improve the accuracy of Kohn-Sham density functional theory. However, because global hybrids exhibit incorrect asymptotic decay of the exchange-correlation potential, they can have large errors for diverse quantities such as reaction barrier heights, nonlinear optical properties, and Rydberg and charge-transfer excitation energies. These errors can be removed by using a long-range-corrected hybrid, which uses exact exchange in the long range. Evaluating the long-range-corrected exchange energy requires a model for the semilocal exchange hole, and such models are scarce. Recently, two of us introduced one such model (J. Chem. Phys. 2008, 128, 194105). This model obeys several exact constraints and was designed specifically for use in long range-corrected hybrids. Here, we give sample results for three long-range corrected hybrids based upon our exchange hole model and show how the model can easily be applied to any generalized gradient approximation (GGA) for the exchange energy to create a long-range-corrected GGA. PMID- 26609582 TI - Revisiting Molecular Dissociation in Density Functional Theory: A Simple Model. AB - A two-electron one-dimensional model of a heteroatomic molecule composed of two open-shell atoms is considered. Including only two electrons isolates and examines the effect that the highest occupied molecular orbital has on the Kohn Sham potential as the molecule dissociates. We reproduce the characteristic step and peak that previous high-level wave function methods have shown to exist for real molecules in the low-density internuclear region. The simplicity of our model enables us to investigate in detail their development as a function of bond length, with little computational effort, and derive properties of their features in the dissociation limit. We show that the onset of the step is coincident with the internuclear separation at which an avoided crossing between the ground-state and lowest charge-transfer excited-state is approached. Although the step and peak features have little effect on the ground-state energetics, we discuss their important consequences for dynamics and response. PMID- 26609581 TI - Regularized Gradient Expansion for Atoms, Molecules, and Solids. AB - A new, regularized gradient expansion (RGE) approximation density functional (i.e., a generalized gradient approximation or GGA that recovers the second-order gradient expansion for exchange in the slowly varying limit) was designed in an attempt to obtain good solid-state and molecular properties at the same time from a single GGA. We assess the performance of this functional for molecular atomization energies, solid lattice constants, and jellium surface energies. We compare the performance of this functional to the modified Perdew-Burke-Ernzerhof generalized gradient approximation (PBEsol GGA), the original PBE GGA, and the Tao-Perdew-Staroverov-Scuseria (TPSS) meta-GGA. PMID- 26609583 TI - Qualitatively Correct Charge-Transfer Excitation Energies in HeH(+) by Time Dependent Density-Functional Theory Due to Exact Exchange Kohn-Sham Eigenvalue Differences. AB - Time-dependent density-functional theory in the response regime is shown to yield qualitatively correct charge-transfer excitation energies in the system HeH(+) if the exact Kohn-Sham exchange potential is employed to determine the Kohn-Sham orbitals and eigenvalues entering the time-dependent density-functional calculation. The employed exact-exchange kernel is frequency-independent and, like conventional kernels in the local density approximation or in generalized gradient approximations, does not contribute to the charge-transfer excitation energy. This shows that it can be that not the exchange-correlation kernel, as generally believed, but the exchange-correlation potential plays the crucial role in the description of charge-transfer excitations. PMID- 26609584 TI - Second-Order Perturbation Theory with Fractional Charges and Fractional Spins. AB - In this work the behavior of MP2 for fractional occupations is investigated. The consideration of fractional charge behavior gives a simple derivation of an expression for the chemical potential (or the derivative of energy with respect to the number of electrons) of MP2. A generalized optimized effective potential formalism (OEP) has been developed in which the OEP is a nonlocal potential, which can be applied to explicit functionals of the orbitals and eigenvalues and also facilitates the evaluation of the chemical potential. The MP2 derivative improves upon the corresponding Koopmans' theorem in Hartree-Fock theory for the ionization energy and also gives a good estimate of the electron affinity. In strongly correlated systems with degeneracies and fractional spins, MP2 diverges, and another corrected second-order perturbative method ameliorates this failure for the energy but still does not recapture the correct behavior for the energy derivatives that yield the gap. Overall we present a view of wave function based methods and their behavior for fractional charges and spins that offers insight into the application of these methods to challenging chemical problems. PMID- 26609585 TI - Validity of the Extended Koopmans' Theorem. AB - The generalized Koopmans' theorem (EKT) yields an estimate of ionization potentials (IPs) of an N-electron system. This estimate (IP(EKT)) is obtained as an eigenvalue of a generalized eigenvalue problem. Katriel and Davidson provided a proof [ Katriel , J. ; Davidson , E. R. Proc. Natl. Acad. Sci. U.S.A. , 1980, 77 , 1403. ] that the EKT predicts the exact lowest IP for ground states of Coulomb systems. However, subsequently, several articles have been published challenging the exactness of the EKT and providing disproofs. This apparent contradiction is resolved by demonstrating that the lowest eigenvalue of the generalized Koopmans' procedure does, in general, not exist. This explains why contradictory results are obtained about the lowest IP(EKT) since its existence has implicitly been assumed. Nonetheless, it will also be shown here that the generalized Koopmans' approach gives IPs that are arbitrarily close to the exact lowest ionization energy. The eigenvalues obtained according to the EKT have an accumulation point given by the exact lowest IP. PMID- 26609586 TI - Tightened Lieb-Oxford Bound for Systems of Fixed Particle Number. AB - The Lieb-Oxford bound is a constraint upon approximate exchange-correlation functionals. We explore a nonempirical tightening of that bound in both universal and electron number-dependent form. The test functional is PBE. Regarding both atomization energies (slightly worsened) and bond lengths (slightly improved), we find the PBE functional to be remarkably insensitive to the value of the Lieb Oxford bound. This both rationalizes the use of the original Lieb-Oxford constant in PBE and suggests that enhancement factors more sensitive to sharpened constraints await discovery. PMID- 26609587 TI - The DBH24/08 Database and Its Use to Assess Electronic Structure Model Chemistries for Chemical Reaction Barrier Heights. AB - The diverse barrier height database DBH24 is updated by using W4 and W3.2 data (Karton, A.; Tarnopolsky, A.; Lamere, J.-F.; Schatz, G. C.; Martin, J. M. L. J. Phys. Chem. A 2008, 112, 12868) to replace previous W1 values; we call the new database DBH24/08. We used the new database to assess 348 model chemistries, each consisting of a combination of a wave function theory level or a density functional approximation with a one-electron basis set. All assessments are made by simultaneous consideration of accuracy and cost. The assessment includes several electronic structure methods and basis sets that have not previously been systematically tested for barrier heights. Some conclusions drawn in our previous work (Zheng, J.; Zhao, Y.; Truhlar, D. G. J. Chem. Theory Comput. 2007, 3, 569) are still valid when using this improved database and including more model chemistries. For example, BMC-CCSD is again found to be the best method whose cost scales as N(6), and its cost is an order of magnitude smaller than the N(7) method with best performance-to-cost ratio, G3SX(MP3), although the mean unsigned error is only marginally higher, namely 0.70 kcal/mol vs 0.57 kcal/mol. Other conclusions are now broader in scope. For example, among single-reference N(5) methods (that is, excluding MRMP2), we now conclude not only that doubly hybrid density functionals and multicoefficient extrapolated density functional methods perform better than second-order Moller-Plesset-type perturbation theory (MP2) but also that they perform better than any correlation-energy-scaled MP2 method. The most recommended hybrid density functionals, if functionals are judged only on the basis of barrier heights, are M08-SO, M06-2X, M08-HX, BB1K, BMK, PWB6K, MPW1K, BHandHLYP, and TPSS25B95. MOHLYP and HCTH are found to be the best performing local density functionals for barrier heights. The basis set cc-pVTZ+ is more efficient than aug-cc-pVTZ with similar accuracy, especially for density functional theory. The basis sets cc-pVDZ+, 6-31+G(d,p), 6-31B(d,p), 6-31B(d), MIDIY+, MIDIX+, and MIDI! are recommended for double-zeta-quality density functional calculations on large systems for their good balance between accuracy and cost, and the basis sets cc-pVTZ+, MG3S, MG3SXP, and aug-cc-pVDZ are recommended for density functional calculations when larger basis sets are affordable. The best performance of any methods tested is attained by CCSD(T)(full)/aug-cc-pCV(T+d)Z with a mean unsigned error of 0.46 kcal/mol; however, this is several orders of magnitude more expensive than M08-SO/cc-pVTZ+, which has a mean unsigned error of only 0.90 kcal/mol. PMID- 26609588 TI - Potential-Driven Adiabatic Connection in Density Functional Theory. AB - As density functional theory conventionally assumes that the density of a chosen model system (e.g., the Kohn-Sham system) is the same as the exact one, one might expect that approximations to the exact density introduce supplementary errors by falsifying the density. In fact, this is not true: by modeling the exchange correlation holes for all densities, density functional approximations avoid this problem. The technique used to show it is a potential-driven adiabatic connection which hopefully will also permit constructing new approximations in the spirit of DFT. PMID- 26609589 TI - Density Functional Partition Theory with Fractional Occupations. AB - Partition theory (PT) is a formally exact methodology for calculating the density of any molecule or solid via separate calculations on individual fragments. Just as Kohn-Sham density functional theory (DFT) introduces noninteracting fermions in an effective potential that is defined to yield the exact density of the interacting problem, in PT a global effective potential is found that ensures that the sum of the fragment densities is that of the full system. By combining the two, density functional partition theory (DFPT) produces a DFT scheme that yields the (in principle) exact molecular density and energy via Kohn-Sham calculations on fragments. We give the full formalism and illustrate DFPT in the general case of noninteger fragment occupations. PMID- 26609590 TI - DFT Calculations on Charge-Transfer States of a Carotenoid-Porphyrin-C60 Molecular Triad. AB - We present a first-principles study on the ground and excited electronic states of a carotenoid-porphyrin-C60 molecular triad. In addition, we illustrate a method for using DFT-based wave functions and densities to simulate complicated charge-transfer dynamics. Since fast and efficient calculations of charge transfer excitations are required to understand these systems, we introduce a simple DFT-based method for calculating total energy differences between ground and excited states. To justify the procedure, we argue that some charge-transfer excitations are asympototically ground-state properties of the separated systems. Further justification is provided from numerical experiments on separated alkali atoms. The donor-chromophore-acceptor system studied here can absorb and store light energy for several hundreds of nanoseconds. Our density-functional calculations show that the triad can possess a dipole moment of 171 D in a charge separated state. The charge-transfer energy technique is used to obtain the energies of the excited states. The charge separated excited states with a large dipole moment will create large polarization of the solvent. We use a model to estimate the stabilization of the excited-state energies in the presence of polarization. The calculated excited-state energies are further used to calculate the Einstein's A and B coefficients for this molecular system. We use these transition rates in a kinetic Monte-Carlo simulation to examine the electronic excitations and possible charging of the molecule. Our calculations show that the solvent polarization plays a crucial role in reordering the excited-state energies and thereby in the charge-separation process. PMID- 26609591 TI - Adiabatic Connection and the Kohn-Sham Variety of Potential-Functional Theory. PMID- 26609592 TI - Structure Dependence of Hyperpolarizability in Octopolar Molecules. AB - Recent Hyper Rayleigh Scattering measurements report a significant increase of second-order hyperpolarizability upon introduction of positive charges at the pyridyl end groups in trispyridyl octopolar chromophores. We calculated the geometries, linear response, and first-order hyperpolarizabilities of a series of six trispyridyl molecules both in the neutral and protonated forms. The calculations were performed with ab initio and semiempirical methods. The results are in good agreement with the experimental values and a correlation between the first hyperpolarizability and two structural properties, the N-C bond elongation and the C-C bond length alternation, ?Deltar? was established. To test these effects we computed the hyperpolarizability for several constrained geometries and confirmed the importance of planarity on the hyperpolarizability values. However the ?Deltar? values alone seem to have little influence both on the hyperpolarizability and on the gap values. Replacing the triple C=C bond by a double C=C bond in the conjugation bridge has no significant effect due to the strong hyperpolarizability dependence on the pyridyl-benzene dihedral angle. PMID- 26609593 TI - Excitation Energies in Time-Dependent (Current-) Density-Functional Theory: A Simple Perspective. AB - This paper gives a simple and pedagogical explanation, using density matrices of two-level systems, how to calculate excitation energies with time-dependent density-functional theory. The well-known single-pole approximation for excitation energies is derived here in an alternative way and extended to time dependent current-density-functional theory. PMID- 26609594 TI - Optical Absorptions of New Blue-Light Emitting Oligoquinolines Bearing Pyrenyl and Triphenyl Endgroups Investigated with Time-Dependent Density Functional Theory. AB - The optical absorption spectra of a family of four n-type conjugated oligomers, oligoquinolines, which can be commercially used to develop high-performance light emitting diodes for their many desirable properties, have been recently calculated from time-depedent density functional theory (TDDFT) within the adiabatic approximation for the dynamical exchange-correlation potential. In this work, we investigate the optical absorption of two new family members of the blue light emitting oligoquinolines bearing pyrenyl and triphenyl endgroups in gas phase and chloroform (CHCl3) solution employing the adiabatic TDDFT. The ionization potentials and electron affinities of these two oligoquinoline molecules are also calculated with the ground-state DFT, from which the adiabatic dynamical exchange-correlation potential is constructed. We show that the calculated optical absorptions are in good agreement with experiments. The ionization potentials obtained with the DFT methods agree well with the experimental estimates, while the electron affinities are significantly underestimated in comparison with experiments. A natural transition orbital analysis for selected excited states with the largest oscillator strengths shows that the electronic charge is slightly redistributed in the process of electronic excitations. PMID- 26609595 TI - Forster Energy Transfer and Davydov Splittings in Time-Dependent Density Functional Theory: Lessons from 2-Pyridone Dimer. AB - The Davydov or exciton splitting of vertical excitation energies is commonly used to estimate the excitation energy transfer rate between chromophores. Here we investigate the S1-S2 Davydov splitting in 2-pyridone dimer as a function of the monomer separation, R. We assess the ability of various functionals to reproduce the Davydov splitting at finite R predicted by the approximate coupled cluster singles doubles method CC2. While semilocal functionals fail qualitatively because of spurious charge-transfer intruder states, global hybrids with a large fraction of exact exchange, such as BHandH-LYP, reproduce the CC2 splittings within few wavenumbers. We analyze our results by comparison to lowest-order intermolecular perturbation theory in the spirit of Forster and Dexter. At equilibrium hydrogen bond distance, the Forster-Dexter splittings are too small by up to a factor of 2. PMID- 26609596 TI - Calculation of Quasi-Particle Energies of Aromatic Self-Assembled Monolayers on Au(111). AB - We present many-body perturbation theory calculations of the electronic properties of phenylene diisocyanide self-assembled monolayers (SAMs) on a gold surface. Using structural models obtained within density functional theory (DFT), we have investigated how the SAM molecular energies are modified by self-energy corrections and how they are affected by the presence of the surface. We have employed a combination of GW (G = Green's function; W = screened Coulomb interaction) calculations of the SAM quasi-particle energies and a semiclassical image potential model to account for surface polarization effects. We find that it is essential to include both quasi-particle corrections and surface screening in order to provide a reasonable estimate of the energy level alignment at a SAM metal interface. In particular, our results show that within the GW approximation the energy distance between phenylene diisocyanide SAM energy levels and the gold surface Fermi level is much larger than that found within DFT, e.g., more than double in the case of low packing densities of the SAM. PMID- 26609597 TI - AM05 Density Functional Applied to the Water Molecule, Dimer, and Bulk Liquid. AB - We compare results for water obtained with the AM05 exchange-correlation density functional ( Armiento, R.; Mattsson, A. E. Phys. Rev. B 2005, 72, 085108 ) with those obtained with five other pure functionals: LDA, PBE, PBEsol, RPBE, and BLYP. For liquid water, AM05 yields an O-O pair correlation function that is more structured than the ones of PBE and BLYP, which, in turn, are more structured than the one of RPBE. However, LDA and PBEsol yields more structured water than AM05. We show that AM05 yields a H2O dimer binding energy of 4.9 kcal/mol. The result is thus within 0.15 kcal/mol of CCSD(T) level theory (5.02 +/- 0.05 kcal/mol). We confirm that accuracy in the water dimer binding energy is not a strong indicator for the fidelity of the resulting structure of liquid water. PMID- 26609598 TI - The Many-Body Exchange-Correlation Hole at Metal Surfaces. AB - We present a detailed study of the coupling-constant-averaged exchange correlation hole density at a jellium surface, which we obtain in the random phase approximation of many-body theory. We report contour plots of the exchange only and exchange-correlation hole densities, the integration of the exchange correlation hole density over the surface plane, the on-top correlation hole, and the energy density. We find that the on-top correlation hole is accurately described by local and semilocal density-functional approximations. We also find that for electrons that are localized far outside the surface the main part of the corresponding exchange-correlation hole is localized at the image plane. PMID- 26609599 TI - Some Fundamental Issues in Ground-State Density Functional Theory: A Guide for the Perplexed. AB - Some fundamental issues in ground-state density functional theory are discussed without equations: (1) The standard Hohenberg-Kohn and Kohn-Sham theorems were proven for a Hamiltonian that is not quite exact for real atoms, molecules, and solids. (2) The density functional for the exchange-correlation energy, which must be approximated, arises from the tendency of electrons to avoid one another as they move through the electron density. (3) In the absence of a magnetic field, either spin densities or total electron density can be used, although the former choice is better for approximations. (4) "Spin contamination" of the determinant of Kohn-Sham orbitals for an open-shell system is not wrong but right. (5) Only to the extent that symmetries of the interacting wave function are reflected in the spin densities should those symmetries be respected by the Kohn-Sham noninteracting or determinantal wave function. Functionals below the highest level of approximations should however sometimes break even those symmetries, for good physical reasons. (6) Simple and commonly used semilocal (lower-level) approximations for the exchange-correlation energy as a functional of the density can be accurate for closed systems near equilibrium and yet fail for open systems of fluctuating electron number. (7) The exact Kohn-Sham noninteracting state need not be a single determinant, but common approximations can fail when it is not. (8) Over an open system of fluctuating electron number, connected to another such system by stretched bonds, semilocal approximations make the exchange-correlation energy and hole-density sum rule too negative. (9) The gap in the exact Kohn-Sham band structure of a crystal underestimates the real fundamental gap but may approximate the first exciton energy in the large gap limit. (10) Density functional theory is not really a mean-field theory, although it looks like one. The exact functional includes strong correlation, and semilocal approximations often overestimate the strength of static correlation through their semilocal exchange contributions. (11) Only under rare conditions can excited states arise directly from a ground-state theory. PMID- 26609600 TI - Standard Free Energy of Binding from a One-Dimensional Potential of Mean Force. AB - A practical approach that enables one to calculate the standard free energy of binding from a one-dimensional potential of mean force (PMF) is proposed. Umbrella sampling and the weighted histogram analysis method are used to generate a PMF along the reaction coordinate of binding. At each point, a restraint is applied orthogonal to the reaction coordinate to make possible the determination of the volume sampled by the ligand. The free energy of binding from an arbitrary unbound volume to the restrained bound form is calculated from the ratio of the PMF integrated over the bound region to that of the unbound. Adding the free energy changes from the standard-state volume to the unbound volume and from the restrained to the unrestrained bound state gives the standard free energy of binding. Exploration of the best choice of binding paths is also made. This approach is first demonstrated on a model binding system and then tested on the benzamidine-trypsin system for which reasonable agreement with experiment is found. A comparison is made with other methods to obtain the standard free energy of binding from the PMF. PMID- 26609601 TI - Computations of Absolute Solvation Free Energies of Small Molecules Using Explicit and Implicit Solvent Model. AB - Accurate determination of absolute solvation free energy plays a critical role in numerous areas of biomolecular modeling and drug discovery. A quantitative representation of ligand and receptor desolvation, in particular, is an essential component of current docking and scoring methods. Furthermore, the partitioning of a drug between aqueous and nonpolar solvents is one of the important factors considered in pharmacokinetics. In this study, the absolute hydration free energy for a set of 239 neutral ligands spanning diverse chemical functional groups commonly found in drugs and drug-like candidates is calculated using the molecular dynamics free energy perturbation method (FEP/MD) with explicit water molecules, and compared to experimental data as well as its counterparts obtained using implicit solvent models. The hydration free energies are calculated from explicit solvent simulations using a staged FEP procedure permitting a separation of the total free energy into polar and nonpolar contributions. The nonpolar component is further decomposed into attractive (dispersive) and repulsive (cavity) components using the Weeks-Chandler-Anderson (WCA) separation scheme. To increase the computational efficiency, all of the FEP/MD simulations are generated using a mixed explicit/implicit solvent scheme with a relatively small number of explicit TIP3P water molecules, in which the influence of the remaining bulk is incorporated via the spherical solvent boundary potential (SSBP). The performances of two fixed-charge force fields designed for small organic molecules, the General Amber force field (GAFF), and the all-atom CHARMm-MSI, are compared. Because of the crucial role of electrostatics in solvation free energy, the results from various commonly used charge generation models based on the semiempirical (AM1-BCC) and QM calculations [charge fitting using ChelpG and RESP] are compared. In addition, the solvation free energies of the test set are also calculated using Poisson-Boltzmann (PB) and Generalized Born model of solvation (GB), which are two widely used continuum electrostatic implicit solvent models. The protocol for running the absolute solvation free energy calculations used throughout is automated as much as possible, with minimum user intervention, so that it can be used in large-scale analysis and force field optimization. PMID- 26609602 TI - A Single Reference Perturbation Theory beyond the Moller-Plesset Partition. AB - A new single reference perturbation partition is proposed for restricted open shell Hartree-Fock (ROHF) and complete active space self-consistent field (CASSCF) orbitals. It is a sum of one-particle operator which is implicitly defined. When the operator acts on a ROHF or CASSCF orbital, the resultant eigenvalue is the orbital's corresponding orbital energy coming from the ROHF or CASSCF calculation. HF, F2, and N2 with stretched bonds are used for the size extensivity test. Results indicate that the first three-order energies calculated with the new partition are size extensive. Single reference perturbation calculations for H2O, NH3, and CH4 with CASSCF orbitals have been performed and compared with other methods like MRCI, MRCI+Q, MRPT2, and MRPT3. The single reference nature of the present perturbation theory is also shown with computations of the singlet-triplet separation of the CH2 and SiH2 radicals. PMID- 26609603 TI - Adaptive Finite Element Method for Solving the Exact Kohn-Sham Equation of Density Functional Theory. PMID- 26609604 TI - Distributed Gaussian Valence Bond Surface Derived from Ab Initio Calculations. AB - The experimental and computational results for the tautomerization reaction of 2 pyridone are reviewed. G3, G4, CBS-APNO, and W1 model chemistries are used to generate state-of-the-art reaction energetics for the tautomerization reaction with and without catalytic water molecules in both the gas and aqueous phases. Reactive, electronic potential energy surface surfaces for use in molecular dynamics simulations were generated for these reactions following a recently improved empirical valence bond formulation. The form of molecular mechanics potentials needed for a satisfactory fit is also discussed. PMID- 26609605 TI - A Combined Charge and Energy Decomposition Scheme for Bond Analysis. AB - In the present study we have introduced a new scheme for chemical bond analysis by combining the Extended Transition State (ETS) method [ Theor. Chim. Acta 1977, 46, 1 ] with the Natural Orbitals for Chemical Valence (NOCV) theory [ J. Phys. Chem. A 2008, 112, 1933 ; J. Mol. MODEL: 2007, 13, 347 ]. The ETS-NOCV charge and energy decomposition scheme based on the Kohn-Sham approach makes it not only possible to decompose the deformation density, Deltarho, into the different components (such as sigma, pi, delta, etc.) of the chemical bond, but it also provides the corresponding energy contributions to the total bond energy. Thus, the ETS-NOCV scheme offers a compact, qualitative, and quantitative picture of the chemical bond formation within one common theoretical framework. Although, the ETS-NOCV approach contains a certain arbitrariness in the definition of the molecular subsystems that constitute the whole molecule, it can be widely used for the description of different types of chemical bonds. The applicability of the ETS-NOCV scheme is demonstrated for single (H3X-XH3, for X = C, Si, Ge, Sn) and multiple (H2X?XH2, H3CX=XCH3, for X = C, Ge) covalent bonds between main group elements, for sextuple and quadruple bonds between metal centers (Cr2, Mo2, W2, [Cl4CrCrCl4](4-)), and for double bonds between a metal and a main group element ((CO)5Cr?XH2, for X = C, Si, Ge, Sn). We include finally two applications involving hydrogen bonding. The first covers the adenine-thymine base pair and the second the interaction between C-H bonds and the metal center in the alkyl complex. PMID- 26609606 TI - Water Dimer Cation: Density Functional Theory vs Ab Initio Theory. AB - By using density functional theory (DFT) and high-level ab initio theory, the structure, interaction energy, electronic property, and IR spectra of the water dimer cation [(H2O)2(+)] are investigated. Two previously reported structures of the water dimer cation [disproportionated ionic (Ion) structure and hydrazine like (OO) structure] are compared. For the complete basis set (CBS) limit of coupled cluster theory with single, double, and perturbative triple excitations [CCSD(T)], the Ion structure is much more stable (by 11.7 kcal/mol). This indicates that the ionization of water clusters produce the hydronium cation moiety (H3O(+)) and the hydroxy radical. The transition barrier for the interconversion from the Ion/OO structure is ~15/~9 kcal/mol. It is interesting to note that the calculation results of the water dimer cation vary seriously depending on calculation methods. Moller-Pleset second-order perturbation (MP2) theory gives reasonable relative energies in favor of the Ion structure but reports unreasonable frequencies for the OO structure. On the other hand, most DFT calculations with various functionals overstabilize the OO structure. However, the DFT results with MPW1K and BH&HLYP functionals are very close to the CCSD(T)/CBS results. Thus, as for the validity test of the DFT functionals for ionized molecular systems, the energy comparison of two water dimer cation structures would be a very important criterion. PMID- 26609608 TI - "Mindless" DFT Benchmarking. AB - A diversity-oriented approach for the generation of thermochemical benchmark sets is presented. Test sets consisting of randomly generated "artificial molecules" (AMs) are proposed that rely on systematic constraints rather than uncontrolled chemical biases. In this way, the narrow structural space of chemical intuition is opened up and electronically difficult cases can be produced in an unforeseeable manner. For the calculation of chemically meaningful relative energies, AMs are systematically decomposed into small molecules (hydrides and diatomics). Two different example test sets containing eight-atom, single reference, main group AMs with chemically very diverse and unusual structures are generated. Highly accurate all-electron, estimated CCSD(T)/complete basis set reference energies are also provided. They are used to benchmark the density functionals S-VWN, BP86, B-LYP, B97-D, PBE, TPSS, PBEh, BH-LYP, B3-PW91, B3-LYP, B2-PLYP, B2GP-PLYP, BMK, MPW1B95, M05, M05-2X, PW6B95, M06, M06-L, and M06-2X. In selected cases, an empirical dispersion correction (DFT-D) has been applied. Due to the composition of the sets, it is expected that a good performance indicates "robustness" in many different chemical applications. The results of a statistical analysis of the errors for the entire set with 165 entries (average reaction energy of 117 kcal/mol, dubbed as the MB08-165 set) perfectly fit to the "Jacob's ladder" metaphor for the ordering of density functionals according to their theoretical complexity. The mean absolute deviation (MAD) decreases very strongly from LDA (20 kcal/mol) to GGAs (MAD of about 10 kcal/mol) but then was less pronounced to hybrid-GGAs (MAD of about 6-8 kcal/mol). The best performance (MAD of 4.1-4.2 kcal/mol) is found for the (fifth-rung) double-hybrid functionals B2-PLYP-D and B2GP-PLYP-D, followed by the M06-2X meta-hybrid (MAD of 4.8 kcal/mol). The significance of the proposed approach for thermodynamic benchmarking is discussed and related to the observed performance ranking also regarding wave function based methods. PMID- 26609607 TI - Representative Amino Acid Side Chain Interactions in Proteins. A Comparison of Highly Accurate Correlated ab Initio Quantum Chemical and Empirical Potential Procedures. AB - Interactions between amino acid side chains play a crucial role both within a folded protein and between the interacting protein molecules. Here we have selected a representative set of 24 of the 400 (20 * 20) possible interacting side chain pairs based on data from Atlas of Protein Side-Chain Interactions. For each pair, we obtained its most favorable interaction geometry from the structural data and computed the interaction energy in the gas phase using several different, commonly used, ab initio and force field methods, namely Moller-Plesset perturbation theory (MP2), density functional theory combined with symmetry-adapted perturbation theory (DFT-SAPT), density functional theory empirically augmented with an empirical dispersion term (DFT-D), and empirical potentials using the OPLS-AA/L and Amber03 force fields. All the methods were compared against a reference method taken to be the CCSD(T) level of theory extrapolated to the complete basis set limit. We found a high degree of agreement between the different methods, even though the range of binding energies obtained was extremely large. The most computationally intensive methods yielded the best results. Among the less computationally time-consuming methods, the DFT-D method as well as parm03 force field provided consistently good results when compared to the reference values. We also tested how representative the chosen geometries of the side chains were and investigated the effect on the binding energies of the dielectric constant of the surrounding medium. PMID- 26609609 TI - Quantum Chemistry on Graphical Processing Units. 2. Direct Self-Consistent-Field Implementation. AB - We demonstrate the use of graphical processing units (GPUs) to carry out complete self-consistent-field calculations for molecules with as many as 453 atoms (2131 basis functions). Speedups ranging from 28* to 650* are achieved as compared to a mature third-party quantum chemistry program (GAMESS) running on a traditional CPU. The computational organization used to construct the Coulomb and exchange operators is discussed. We also present results using three GPUs in parallel, combining coarse and fine-grained parallelism. PMID- 26609610 TI - Evaluation of B3LYP, X3LYP, and M06-Class Density Functionals for Predicting the Binding Energies of Neutral, Protonated, and Deprotonated Water Clusters. AB - In this paper we assess the accuracy of the B3LYP, X3LYP, and newly developed M06 L, M06-2X, and M06 functionals to predict the binding energies of neutral and charged water clusters including (H2O)n, n = 2-8, 20), H3O(+)(H2O)n, n = 1-6, and OH(-)(H2O)n, n = 1-6. We also compare the predicted energies of two ion hydration and neutralization reactions on the basis of the calculated binding energies. In all cases, we use as benchmarks calculated binding energies of water clusters extrapolated to the complete basis set limit of the second-order Moller-Plesset perturbation theory with the effects of higher order correlation estimated at the coupled-cluster theory with single, double, and perturbative triple excitations in the aug-cc-pVDZ basis set. We rank the accuracy of the functionals on the basis of the mean unsigned error (MUE) between calculated benchmark and density functional theory energies. The corresponding MUE (kcal/mol) for each functional is listed in parentheses. We find that M06-L (0.73) and M06 (0.84) give the most accurate binding energies using very extended basis sets such as aug-cc-pV5Z. For more affordable basis sets, the best methods for predicting the binding energies of water clusters are M06-L/aug-cc-pVTZ (1.24), B3LYP/6-311++G(2d,2p) (1.29), and M06/aug-cc-PVTZ (1.33). M06-L/aug-cc-pVTZ also gives more accurate energies for the neutralization reactions (1.38), whereas B3LYP/6-311++G(2d,2p) gives more accurate energies for the ion hydration reactions (1.69). PMID- 26609611 TI - Robust and Reliable Multilevel Minimization of the Kohn-Sham Energy. AB - Kohn-Sham density-functional calculations are used in many branches of science to obtain information about the electronic structure of molecular systems and materials. Conventional algorithms for minimization of the Kohn-Sham energy have certain deficiencies, however, that may cause divergence or, worse, convergence to unphysical saddle points. We here present a three-level hierarchical minimization strategy which is both more efficient and robust than the conventional algorithms and which does not suffer from the flaws of these algorithms. Using the three-level minimization strategy, the molecular density is built up in a hierarchical fashion in accordance with chemical insight: First, the molecular density is composed by a superposition of atomic densities; next, bonds are formed by performing a simple valence-shell optimization; finally, the molecular description is refined by an optimization in the full molecular basis. Importantly, the density matrix generated at each of the two lower levels in this hierarchy is transferred to the next without loss of information. Examples demonstrate the efficacy and robustness of the proposed scheme. PMID- 26609612 TI - Intramolecular Nonbonded Attractive Interactions: 1-Substituted Propenes. AB - Whereas cis-substituted alkenes are normally significantly less stable than the trans-isomers, there is a group of 1-substituted propenes (X = F, OMe, Cl, Br, SMe) where the cis-isomers are the more stable. The calculated structures show that there is steric repulsion with the cis-isomers. However, this is overcome by attractive Coulombic interactions when X = F or OMe and by attractive dispersive interactions when X = Cl or Br. It was possible to calculate the magnitude of the latter term via the summation of the appropriate MP2 pair energies. The calculated and observed energy differences could be reproduced by a summation of steric, electrostatic, and dispersive interactions. PMID- 26609613 TI - Development of OPLS-AA Force Field Parameters for 68 Unique Ionic Liquids. AB - OPLS-AA force field parameters have been developed and validated for use in the simulation of 68 unique combinations of room temperature ionic liquids featuring 1-alkyl-3-methylimidazolium [RMIM] (R = Me, Et, Bu, Hex, Oct), N-alkylpyridinium [RPyr], and choline cations, along with Cl(-), PF6(-), BF4(-), NO3(-), AlCl4(-), Al2Cl7(-), TfO(-), saccharinate, and acesulfamate anions. The new parameters were fit to conformational profiles from gas-phase ab initio calculations at the LMP2/cc-pVTZ(-f)//HF/6-31G(d) theory level and compared to experimental condensed phase structural and thermodynamic data. Monte Carlo simulations of the ionic liquids gave relative deviations from experimental densities of ca. 1-3% at 25 degrees C for most combinations and also yielded close agreement over a temperature range of 5 to 90 degrees C. Predicted heats of vaporization compared well with available experimental data and estimates. Transferability of the new parameters to multiple alkyl side-chain lengths for [RMIM] and [RPyr] was determined to give excellent agreement with charges and torsion potentials developed specific to desired alkyl lengths in 35 separate ionic liquid simulations. As further validation of the newly developed parameters, the Kemp elimination reaction of benzisoxazole via piperidine was computed in 1-butyl-3 methylimidazolium hexafluorophosphate [BMIM][PF6] using mixed quantum and molecular mechanics (QM/MM) simulations and was found to give close agreement with the experimental free energy of activation. PMID- 26609614 TI - Modeling of the Chiroptical Response of Chiral Amino Acids in Solution Using Explicit Solvation and Molecular Dynamics. AB - Molecular dynamics (MD) simulations and TDDFT linear response computations were employed to model the molar rotations of the zwitterionic forms of glycine, alanine, proline, and phenylalanine in aqueous solution. The MD simulations inherently take into account averaging the chiroptical response of different amino acid conformers and also allow the effects from vibrational distortions and explicit solvent perturbations on the optical rotation to be modeled. The results show that the chiroptical response correlates strongly to the conformations of these molecules relative to their carboxylate functional groups. Additionally, the molar rotation of phenylalanine shows a correspondence to the molecule's internal rotation about its phenyl group. These findings may be rationalized with established and revised "sector rules" for optical activity. PMID- 26609615 TI - Investigation of the Ligand-Field States of the Hexaammine Cobalt(III) Ion with Quantum Chemical Methods. AB - The ligand-field (LF) transition energies of the Co(NH3)6(3+) ion have been computed with multiconfiguration quasidegenerate second-order perturbation theory (MCQDPT2). The water solvent was treated with the polarizable continuum model (PCM), and the environment in crystals was modeled by the Co(NH3)6.Cl4(-) complex. The Co-N bond lengths, calculated for the hydrated cation and the Co(NH3)6.Cl4(-) model compound, agree with those in the crystal structures. The vertical transition energies agree with experiment, whereby those based on Co(NH3)6.Cl4(-) are more accurate than those for the hydrated ion. The 0-0 transitions were based on the OPBE geometries of ground and excited (1)T1g, (3)T1g, (5)T2g states of the hydrated ion. The (3)T1g state is the lowest excited state; the (5)T2g state lies higher by >0.6 eV. PMID- 26609616 TI - Vibrational Spectra of Small Protonated Peptides from Finite Temperature MD Simulations and IRMPD Spectroscopy. AB - Finite temperature Born-Oppenheimer DFT-based molecular dynamics simulations are presented for the vibrational spectroscopy of the prototype gas-phase Ala2H(+) and Ala3H(+) protonated peptides. The dynamics and the vibrational signatures are used to interpret IR-MPD spectra recorded in the NH/OH stretch region. Molecular dynamics simulations are one way to go beyond the harmonic approximations commonly applied for the calculations of infrared spectra, naturally including all anharmonicities, i.e. mode couplings, vibrational and dipole anharmonicities. The dynamics of the peptides allows understanding of the evolution of the shape and width of the N-H bands when increasing the size of the peptide, as demonstrated here with the two small prototypes Ala2H(+) and Ala3H(+). Hence, the conformational dynamics of Ala2(+) at room temperature participates to the broadening of the IR active bands. The complex N-H broadband of Ala3H(+) is shown to result from the dynamics of the N-H groups in the different peptide families, with a special role from breaking/reforming of hydrogen bonds involving the N-H groups. Taking this dynamics into account is thus mandatory for the understanding of this band in the 300-400 K experimental spectrum. PMID- 26609617 TI - Exact Analytic Result of Contact Value for the Density in a Modified Poisson Boltzmann Theory of an Electrical Double Layer. AB - For a simple modified Poisson-Boltzmann (SMPB) theory, taking into account the finite ionic size, we have derived the exact analytic expression for the contact values of the difference profile of the counterion and co-ion, as well as of the sum (density) and product profiles, near a charged planar electrode that is immersed in a binary symmetric electrolyte. In the zero ionic size or dilute limit, these contact values reduce to the contact values of the Poisson-Boltzmann (PB) theory. The analytic results of the SMPB theory, for the difference, sum, and product profiles were compared with the results of the Monte-Carlo (MC) simulations [ Bhuiyan, L. B.; Outhwaite, C. W.; Henderson, D. J. Electroanal. Chem. 2007, 607, 54 ; Bhuiyan, L. B.; Henderson, D. J. Chem. Phys. 2008, 128, 117101 ], as well as of the PB theory. In general, the analytic expression of the SMPB theory gives better agreement with the MC data than the PB theory does. For the difference profile, as the electrode charge increases, the result of the PB theory departs from the MC data, but the SMPB theory still reproduces the MC data quite well, which indicates the importance of including steric effects in modeling diffuse layer properties. As for the product profile, (i) it drops to zero as the electrode charge approaches infinity; (ii) the speed of the drop increases with the ionic size, and these behaviors are in contrast with the predictions of the PB theory, where the product is identically 1. PMID- 26609618 TI - Computational DFT Study of Ruthenium Tetracarbonyl Polymer. AB - Ruthenium tetracarbonyl polymer, [Ru(CO)4]n, a chainlike compound formed by metal metal interactions, was studied computationally. We first performed tests with selected pure and hybrid GGA density functionals and ab initio methods at HF and MP2 levels of theory to find the most suitable method. Calculated geometries and molecular orbitals were compared to see effectiveness and possible differences of the methods. Hybrid functionals, especially PBE1PBE and MPW1K, were found to produce accurate geometrical parameters compared to the experimental structure, with reasonable computational cost. Bonding in [Ru(CO)4]n chains was studied by calculation of Mayer bond order and theoretical structure factors followed by multipole refinement to get bond critical points according to the quantum theory of atoms in molecules. Ruthenium-ruthenium bonding comparable to that in a Ru3(CO)12 cluster was found with both methods. PMID- 26609619 TI - Transferable Coarse-Grained Models for Ionic Liquids. AB - The effective force coarse-graining (EF-CG) method was applied to the imidazolium based nitrate ionic liquids with various alkyl side-chain lengths. The nonbonded EF-CG forces for the ionic liquid with a short side chain were extended to generate the nonbonded forces for the ionic liquids with longer side chains. The EF-CG force fields for the ionic liquids exhibit very good transferability between different systems at various temperatures and are suitable for investigating the mesoscopic structural properties of this class of ionic liquids. The good additivity and ease of manipulation of the EF-CG force fields can allow for an inverse design methodology of ionic liquids at the coarse grained level. With the EF-CG force field, the molecular dynamics (MD) simulation at a very large scale has been performed to check the significance of finite size effects on the structural properties. From these MD simulation results, it can be concluded that the finite size effect on the phenomenon of ionic liquid spatial heterogeneity (Wang, Y.; Voth, G. A. J. Am. Chem. Soc. 2005, 127, 12192) is small and that this phenomenon is indeed a nanostructural behavior which leads to the experimentally observed mesoscopic heterogeneous structure of ionic liquids. PMID- 26609620 TI - Can Silicon Carbide Nanotubes Sense Carbon Dioxide? AB - Detection of carbon dioxide (CO2) is very important in environmental, biological, and industrial processes. Recent experiment showed that carbon nanotubes can act as chemical sensors for detecting certain gaseous molecules such as NH3, NO2, and O2. Unfortunately, the intrinsic stability of CO2 makes its sensing by CNTs unsuccessful due to the rather weak adsorption energy on the tube surface. In the present Article, we study the CO2 adsorption on various zigzag (n,0) (n = 6, 8, 10, 12, and 18) single-walled SiC nanotubes to explore the possibility of the SiC tube as potential gas sensors for CO2-detection by density functional theory (DFT) calculations. It is found that tube diameter and CO2 coverage play important roles in the tube-CO2 interaction. A single CO2 can be chemisorbed to the Si-C bonds of SiCNT with appreciable adsorption energy and can draw significant charge transfer from the SiCNT. The adsorption energy decreases gradually with increased tube diameter. The addition of more CO2 molecules in different patterns has been considered for the exemplified (8,0) tube, and CO2 molecules prefer to be as far from each other as possible. With the increase of CO2 coverage, the interaction between CO2 molecules and tube becomes weaker, and up to eight CO2 molecules can be adsorbed on the tube. In addition, we find that the band gap is lowered to a different degree due to the different adsorption. Because of the sufficient charge transfer and high concentration of CO2, SiCNT could be a perfect material for efficiently detecting the CO2 molecule. PMID- 26609621 TI - Conformational Motions of HIV-1 Protease Identified Using Reversible Digitally Filtered Molecular Dynamics. AB - HIV-1 protease performs a vital step in the propagation of the HIV virus and is therefore an important drug target in the treatment of AIDS. It consists of a homodimer, with access to the active site limited by two protein flaps. NMR studies have identified two time scales of motions that occur in these flaps, and it is thought that the slower of these is responsible for a conformational change that makes the protein ligand-accessible. This motion occurs on a time scale outside that achievable using traditional molecular dynamics simulations. Reversible Digitally Filtered Molecular Dynamics (RDFMD) is a method that amplifies low frequency motions associated with conformational change and has recently been applied to, among others, E. coli dihydrofolate reductase, inducing a conformational change between known crystal structures. In this paper, the conformational motions of HIV-1 protease produced during MD and RDFMD simulations are presented, including movement between the known semiopen and closed conformations, and the opening and closing of the protein flaps. PMID- 26609622 TI - Using Molecular Strain and Aromaticity To Create Ultraweak C-H Bonds and Stabilized Carbon-Centered Radicals. AB - An approach based on relief of molecular strain in the parent hydrocarbon, extended conjugation in the radical, and the driving force toward aromaticity is used to design molecules with ultraweak C-H bonds. The molecular strain is generated by two fused rings containing (5,5)-, (5,6)-, or (6,6)-membered ring structures. Homodesmotic reactions are used to calculate the molecular strain enthalpy (MSE) of the parent hydrocarbons and the corresponding radicals, and to analyze how it changes through these reactions. B3LYP calculations are used to obtain the bond dissociation enthalpies (BDEs) for breaking one or more C-H bonds as well as the C-O bond formed after oxygen addition to the radical. Loss of a second H-atom can lead to very low R-H BDE values, especially when the ultimate product is aromatic. Molecular structures based on these ideas may be of interest as novel antioxidants based on carbon-centered radicals. PMID- 26609623 TI - Density Functional Theory Calculation of Bonding and Charge Parameters for Molecular Dynamics Studies on [FeFe] Hydrogenases. AB - We have developed and tested molecular mechanics parameters for [FeS] clusters found in known [FeFe] hydrogenases. Bond stretching, angle bending, dihedral and improper torsion parameters for models of the oxidized and reduced catalytic H cluster, [4Fe4S](+,2+)Cys4, [4Fe4S](+,2+)Cys3His, and [2Fe2S](+,2+)Cys4, were calculated solely from Kohn-Sham density functional theory and Natural Population Analysis. Circumsphere analysis of the cubane clusters in the energy-minimized structure of the full Clostridium pasteurianum hydrogenase I showed the resulting metallocluster structures to be similar to known cubane structures. All clusters were additionally stable in molecular dynamics simulations over the course of 1.0 ns in the fully oxidized and fully reduced enzyme models. Normal modes calculated by quasiharmonic analysis from the dynamics data show unexpected couplings among internal coordinate motions, which may reflect the effects of the protein structure on metallocluster dynamics. PMID- 26609624 TI - Conformational Transition Map of an RNA GCAA Tetraloop Explored by Replica Exchange Molecular Dynamics Simulation. AB - A 120 ns replica-exchange molecular dynamics simulation in explicit solvent is performed to probe the conformational transitions in 5'-GGGCGCAAGCCU-3' RNA GCAA tetraloop. The ample structural transition information of the loop is detected on the basis of extensive clustering analysis. The resultant loop structural transition map nicely agrees with the recent ultrafast fluorescence measurement, which confirms the dynamical properties of this tetraloop. Moreover, a new transition pattern that was not disclosed previously is predicted. Meanwhile, the folding free energy landscapes were characterized: the global folding dynamics is coupled mainly with the stem rather than the loop part. PMID- 26609625 TI - High-Level ab Initio Calculations To Improve Protein Backbone Dihedral Parameters. AB - We present new molecular mechanical dihedral parameters for the Ramachandran angles phi and psi of a protein backbone based on high-level ab initio molecular orbital calculations for hydrogen-blocked or methyl-blocked glycine and alanine dipeptides. Fully relaxed 15 degrees (phi, psi) contour maps were calculated at the MP2/6-31G(d) level of theory. Finding out the lowest energy path for phi (or psi) to change from -180 degrees to 180 degrees in the contour map, we performed a DF-LCCSD(T0)/Aug-cc-pVTZ//DF-LMP2/Aug-cc-pVTZ level calculation to get the torsional energy profiles of phi (or psi). Molecular mechanical torsion profiles with AMBER force field variants significantly differed from the ab initio profiles, so we derived new molecular mechanical dihedral parameters of a protein backbone to fit the ab initio profiles. PMID- 26609626 TI - Reference Quantum Chemical Calculations on RNA Base Pairs Directly Involving the 2'-OH Group of Ribose. AB - The folded structures of RNA molecules and large ribonucleoprotein particles are stabilized by a wide range of base pairs that actively utilize the 2'-OH groups of ribose for base pairing. Such base pairing does not occur in DNA and is essential for functional RNAs. We report reference quantum chemical calculations of base pairing energies for a representative selection of 25 RNA base pairs utilizing the ribose moiety for base pairing, including structures with amino acceptor interactions. All base pairs are evaluated at the MP2 level with extrapolation to the complete basis set (CBS) of atomic orbitals. CCSD(T) correction terms were obtained for four base pairs. In addition, the base pairing is evaluated using the DFT-SAPT perturbational procedure along with the aug-cc pVDZ basis set, which allows for the decomposition of the interaction energies into separate, physically meaningful, components. These calculations confirm that, compared to canonical base pairs, many RNA base pairs exhibit a modestly increased role of dispersion attraction compared to canonical base pairs. However, the effect is smaller than one would assume based on assessment of the ratio of HF and correlation components of the interaction energies. Interaction energies are further calculated using the SCS(MI)-MP2 and DFT-D methods. Finally, we estimate the effect of aqueous solvent screening on the base pairing stability using the continuum solvent approach. PMID- 26609627 TI - On the Nature of Bonding in Lone Pair...pi-Electron Complexes: CCSD(T)/Complete Basis Set Limit Calculations. AB - The nature of the stabilization in lone pair...pi-electron complexes was investigated using the highly accurate CCSD(T) method based on the complete basis set limit, as well as the DFT-SAPT perturabative method. Specifically, we studied various structures of benzene...water, benzene...dimethylether, and 1,2,4,5 tetracyanobenzene...water complexes. The lone pair...pi-electron interactions between an unsubstituted aromatic ring and a water molecule are repulsive in the whole range of vertical distances. Partial stabilization results by rotating the water molecule by 90 degrees (with the water and aromatic ring being localized in parallel planes) or by decreasing the negative charge at oxygen and simultaneously increasing the polarizability of the system, which provides stabilization even for genuine lone pair...pi-electron interactions. In these cases, a substantial part of the stabilization stems from dispersion energy. Substituting an aromatic ring by electron-withdrawing cyano groups represents the most powerful way to achieve a substantial stabilization of genuine lone pair...pi-electron interactions. This stabilization is comparable to quite strong H-bonding, originating in electrostatic and, to a slightly lesser degree, dispersion energies. PMID- 26609628 TI - Simultaneous Interaction of Tetrafluoroethene with Anions and Hydrogen-Bond Donors: A Cooperativity Study. AB - A computational study of the complexes formed by tetrafluoroethylene, C2F4, with anions has been carried out by means of density functional theory (DFT) and second-order Moller-Plesset (MP2) computational methods, up to MP2/aug-cc-pVTZ level. In addition, the possibility of cooperativity in the interaction of anions and hydrogen-bond donors (FH, ClH, and H2O) when interacting with different faces of the C2F4 molecule has been explored. Electron density of the complexes has been analyzed by means of atoms in molecules (AIM) methodology, while natural bond orbital (NBO) methodology has been used to characterize the orbital interaction. In addition, natural energy decomposition analysis (NEDA) has been applied to analyze the source of the interaction. The energetic results indicate that C2F4 is a weaker anion receptor than C6F6, but in combination with the anions, it became a stronger hydrogen acceptor than C2H4. Cooperativity effects are observed in YH.C2F4.X(-) clusters. In C2F4.X(-) complexes the dominant attractive terms are the electrostatic and polarization ones, while in YH.C2F4.X( ) complexes the charge transfer increases significantly, becoming the most important term for most of the FH and ClH complexes studied here. PMID- 26609629 TI - Molecular Modeling of Geometries, Charge Distributions, and Binding Energies of Small, Druglike Molecules Containing Nitrogen Heterocycles and Exocyclic Amino Groups in the Gas Phase and Aqueous Solution. PMID- 26609630 TI - Sesquiterpene-neolignans from Manglietia hookeri. AB - The comet assay-guided fractionation of the twigs of Manglietia hookeri resulted in the isolation of three sesquiterpene-neolignans, including a new one 5-allyl-2 (4-allyl-phenoxy)-3-[7-(1-hydroxy-1-methyl-ethyl)-1, 4a-dimethyl-decahydro naphthalen-1-yloxy]-phenol (1), and eudesobovatol A (2) and eudesobovatol B (3), together with three lignans, obovatol (4), honokiol (5) and magnolol (6). Their structures were elucidated on the basis of spectral analysis and by comparison with related literature data. Compounds 1, 4-6 showed a protective effect on UV inductive DNA damage in mice lymphocyte cells, while compound 1 indicated the smallest Olive Tail Moment 7.34 +/- 2.09 at 6 * 10(-6) MUM. PMID- 26609631 TI - Quercetin inhibits multiple pathways involved in interleukin 6 secretion from human lung fibroblasts and activity in bronchial epithelial cell transformation induced by benzo[a]pyrene diol epoxide. AB - The interaction between epithelial and stromal cells through soluble factors such as cytokines plays an important role in carcinogenesis. Breaking this cancer promoting interaction poses an opportunity for cancer prevention. The tumor promoting function of interleukin 6 (IL-6) has been documented; however, the underlying mechanisms of this function in lung carcinogenesis are not well elucidated. Here, we show that benzo[a]pyrene diol epoxide (BPDE, the active metabolite of cigarette smoke carcinogen benzo[a]pyrene)-induced human bronchial epithelial cell (HBEC) transformation was enhanced by IL-6 in vitro. The carcinogen/IL-6-transformed cells exhibited higher expression of STAT3 (signal transducer and activator of transcription 3) when compared with cells transformed by BPDE alone. Constitutive STAT3 activation drove cell proliferation and survival through anti-apoptosis gene expression. We further show that quercetin, a dietary compound having preventive properties for lung cancer, decreased BPDE stimulated IL-6 secretion from human lung fibroblasts through inhibition of the NF-kappaB and ERK pathways. The inhibition was accomplished at clinically achievable concentrations of the compound. Finally, quercetin blocked IL-6 induced STAT3 activation in HBECs, and IL-6 enhancement of HBEC transformation by BPDE was abolished by quercetin treatment. Altogether, our data reveal novel mechanisms for IL-6 in lung carcinogenesis and for the preventive role of quercetin in the process. (c) 2015 Wiley Periodicals, Inc. PMID- 26609634 TI - Clinical significance of IL-2 and IL-10 gene polymorphisms and serum levels in patients with basal-cell carcinoma. AB - MATERIALS & METHODS: Polymorphic variants of IL-2 gene (-330 T/G and +166 G/T), IL-10 gene (-1082 G/A and -819 C/T) and serum cytokines concentrations in the group of 179 patients with BCC and 173 controls were analyzed. RESULTS: The presence of the IL-2 -330 GG genotype or IL-10 -1082 GA increased the risk of BCC (OR 3.68) (OR 3.07). IL-10 -1082 AA or GA and IL-2 -330 GG genotype increased the risk of BCC (OR 9.63). IL-2 serum levels were significantly lower (p < 0.0004) in BCC patients while IL-10 concentration was significantly higher (p < 0.00001). CONCLUSION: The polymorphisms in IL-2 and IL-10 genes may contribute to BCC susceptibility and influence the clinical course of BCC in polish population. PMID- 26609635 TI - Efficacy and safety of lacosamide as an adjunctive therapy for refractory focal epilepsy in paediatric patients: a retrospective single-centre study. AB - AIM: Lacosamide is an antiepileptic drug approved for the treatment of focal epilepsy in adult patients. The aim of this observational study was to review our centre's experience with lacosamide and to characterize its effectiveness and tolerability as an adjunctive antiepileptic drug in a retrospective cohort of children with refractory focal epilepsy. METHODS: We retrospectively reviewed the medical records of 22 patients who received lacosamide from November 2009 to April 2014 at the CHU Ste-Justine, University of Montreal. Treatment responders were defined as children with a >=50% reduction in seizure frequency compared to baseline, and this was determined three months after the initiation of treatment and at the last follow-up visit. RESULTS: We included 14 boys and eight girls with a mean age of 12.9 years (SD: 5.2; range: 5.2-20.7 years) at the initiation of treatment. The average length of follow-up was 11.9 months. Patients had previously received an average of 7.5 antiepileptic drugs. The mean number of concomitant antiepileptic drugs was 2.3. The mean initial and maintenance doses were 2.9 and 8.4 mg/kg/d, respectively. Thirteen (59%) and ten (45%) patients were responders after three months of treatment and at the last follow-up visit, respectively. One became seizure-free. Adverse effects were reported in 11 patients and none were severe. Responders and non-responders were identical with respect to all studied parameters except gender, with the proportion of responders being greater in girls than in boys (75% vs 29%; p=0.035). CONCLUSION: Our study adds evidence that lacosamide appears to be a safe and effective adjunctive therapy for children with refractory focal epilepsy. PMID- 26609636 TI - Li2C2, a High-Capacity Cathode Material for Lithium Ion Batteries. AB - As a typical alkaline earth metal carbide, lithium carbide (Li2C2) has the highest theoretical specific capacity (1400 mA h g(-1)) among all the reported lithium-containing cathode materials for lithium ion batteries. Herein, the feasibility of using Li2C2 as a cathode material was studied. The results show that at least half of the lithium can be extracted from Li2C2 and the reversible specific capacity reaches 700 mA h g(-1). The C=C bond tends to rotate to form C4 (C=C???C=C) chains during lithium extraction, as indicated with the first principles molecular dynamics (FPMD) simulation. The low electronic and ionic conductivity are believed to be responsible for the potential gap between charge and discharge, as is supported with density functional theory (DFT) calculations and Arrhenius fitting results. These findings illustrate the feasibility to use the alkali and alkaline earth metal carbides as high-capacity electrode materials for secondary batteries. PMID- 26609637 TI - New insights into the complex regulation of the glycolytic pathway in Lactococcus lactis. I. Construction and diagnosis of a comprehensive dynamic model. AB - This article and the companion paper use computational systems modeling to decipher the complex coordination of regulatory signals controlling the glycolytic pathway in the dairy bacterium Lactococcus lactis. In this first article, the development of a comprehensive kinetic dynamic model is described. The model is based on in vivo NMR data that consist of concentration trends in key glycolytic metabolites and cofactors. The model structure and parameter values are identified with a customized optimization strategy that uses as its core the method of dynamic flux estimation. For the first time, a dynamic model with a single parameter set fits all available glycolytic time course data under anaerobic operation. The model captures observations that had not been addressed so far and suggests the existence of regulatory effects that had been observed in other species, but not in L. lactis. The companion paper uses this model to analyze details of the dynamic control of glycolysis under aerobic and anaerobic conditions. PMID- 26609638 TI - Molecular, serological and in vitro culture-based characterization of Bourbon virus, a newly described human pathogen of the genus Thogotovirus. AB - BACKGROUND: In June of 2014, a previously healthy man from Kansas with a recent history of tick exposure died from complications related to an illness marked by fever, thrombocytopenia and leukopenia. An isolate was derived from the blood of this patient during the course of diagnostic testing. This isolate was subsequently identified as a novel orthomyxovirus of the genus Thogotovirus by next generation sequencing and was named Bourbon virus after the patient's county of residence. OBJECTIVES: To support research and diagnostic aims, we provide a basic description of Bourbon virus at both the molecular and serological levels. Furthermore, to preliminarily identify potential host and vector range associations we have characterized the growth kinetics of Bourbon virus in a variety of vertebrate and invertebrate cell lines. STUDY DESIGN: Bourbon virus was subjected to next generation-high throughput sequencing, phylogenetic, and basic structural protein analyses as well as 2-way plaque reduction neutralization assays. Also, we inoculated a variety of cell types with Bourbon virus and evaluated the growth kinetics by determining viral titers in the supernatants taken from infected cells over time. RESULTS: Bourbon virus possesses 24-82% identity at the amino acid sequence level and low serological cross-reactivity with other Thogotoviruses. In vitro growth kinetics reveal robust replication of Bourbon virus in mammalian and tick cells. CONCLUSIONS: Molecular and serological characterizations identify Bourbon virus as a novel member of the genus Thogotovirus. Results from cell culture analyses suggest an association between Bourbon virus and mammalian and tick hosts. PMID- 26609639 TI - Delayed ischaemic preconditioning in the presence of galectin-9 protects against renal ischaemic injury through a regulatory T-cell dependent mechanism. AB - AIM: Renal ischaemia/reperfusion injury (IRI) is a complication of major surgeries. Regulatory T cells (Tregs) can suppress immunologic damage in the renal IR. Previous studies indicated that delayed ischaemic preconditioning (IPC) partially attenuates IR by inducing Treg expansion. Galectin-9 also attenuates inflammation-related organ injury by expanding Tregs, but it was not used in renal IR yet. Our aim was to test whether IPC combined with galectin-9 has an increased renoprotective effect. METHODS: Mice were divided into five treatment groups (n = 6 per group): (i) IR group: renal ischaemia/reperfusion group; (ii) IPC-IR group: IPC followed by renal IR; (iii) IPC-Gal9-IR group: Gal-9 injections during the time between IPC and IR; (iv) IPC-Gal9-PC61-IR group: anti-CD25 antibody administration apart from IPC, Gal-9 and IR; (v) sham-sham group. We assessed the renal function, histopathological scores, and percentages of Tregs and interferon-gamma (IFN-gamma) cells in peripheral bood, spleen, and kidney and compared these values among the different groups. RESULTS: Serum creatinine measured was significantly lower after IPC and even lower in combination with Gal 9 injection. The histopathological scores for tubulo-interstitial injury were decreased following IPC and markedly lower after the addition of Gal-9. The number of kidney infiltrating neutrophils and IFN-gamma secreting CD4+ T cells was diminished in the IPC/Gal9 combination group, while the percentage of Treg cells in the peripheral blood, spleen, and kidney of animals from the IPC-Gal9-IR group was also markedly increased. CONCLUSION: The renoprotective effect of delayed IPC combined with galectin-9 was superior to IPC alone, through a mechanism related to expansion of regulatory T cells. PMID- 26609640 TI - CLONING, EXPRESSION, AND FUNCTIONAL ANALYSIS OF THREE ODORANT-BINDING PROTEINS OF THE ORIENTAL FRUIT MOTH, Grapholita molesta (BUSCK) (LEPIDOPTERA: TORTRICIDAE). AB - Odorant-binding proteins (OBPs) act in insect olfactory processes. OBPs are expressed in the olfactory organs and serve in binding and transport of hydrophobic odorants through the sensillum lymph to olfactory receptor neurons within the antennal sensilla. In this study, three OBP genes were cloned from the antennal transcriptome database of Grapholita molesta via reverse-transcription PCR. Recombinant GmolOBPs (rGmolOBPs) were expressed in a prokaryotic expression system and enriched via Ni ion affinity chromatography. The binding properties of the three rGmolOBPs to four sex pheromones and 30 host-plant volatiles were investigated in fluorescence ligand-binding assays. The results demonstrated that rGmolOBP8, rGmolOBP11, and rGmolOBP15 exhibited high binding affinities with the major sex pheromone components (E)-8-dodecenyl acetate, (Z)-8-dodecenyl alcohol, and dodecanol. The volatiles emitted from peach and pear, decanal, butyl hexanoate, and alpha-ocimene, also showed binding affinities to rGmolOBP8 and rGmolOBP11. Hexanal, heptanal, and alpha-pinene showed strong binding affinities to rGmolOBP15. Results of the electrophysiological recording experiments and previous behavior bioassays indicated that adult insects had strong electroantennogram and behavioral responses toward butyl hexanoate, hexanal, and heptanal. We infer that the GmolOBP8 and GmolOBP11 have dual functions in perception and recognition of host-plant volatiles and sex pheromones, while GmolOBP15 was mainly involved in plant volatile odorants' perception. PMID- 26609641 TI - Bioinspired Synthesis of CaCO3 Superstructures through a Novel Hydrogel Composite Membranes Mineralization Platform: A Comprehensive View. AB - Hydrogel composite membranes (HCMs) are used as novel mineralization platforms for the bioinspired synthesis of CaCO3 superstructures. A comprehensive statistical analysis of the experimental results reveals quantitative relationships between crystallization conditions and crystal texture and a strong selectivity toward complex morphologies when monomers bearing carboxyl and hydroxyl groups are used together in the hydrogel layer synthesis in HCMs. PMID- 26609643 TI - Synthesis of digermylene-stabilized linear tetraboronate and boroxine. AB - Two newly discovered linear compounds tetraboronate and boroxine stabilized by digermylene are reported, which feature a B4O5 chain and a B3O3 ring, respectively. DFT calculations reveal that not only can digermylene stabilize the electron-deficient boron centers, but also increase the energies of the LUMOs of the boron moiety. Our results provide a hint for the development of boronate covalent organic frameworks. PMID- 26609644 TI - Animal models of source memory. AB - Source memory is the aspect of episodic memory that encodes the origin (i.e., source) of information acquired in the past. Episodic memory (i.e., our memories for unique personal past events) typically involves source memory because those memories focus on the origin of previous events. Source memory is at work when, for example, someone tells a favorite joke to a person while avoiding retelling the joke to the friend who originally shared the joke. Importantly, source memory permits differentiation of one episodic memory from another because source memory includes features that were present when the different memories were formed. This article reviews recent efforts to develop an animal model of source memory using rats. Experiments are reviewed which suggest that source memory is dissociated from other forms of memory. The review highlights strengths and weaknesses of a number of animal models of episodic memory. Animal models of source memory may be used to probe the biological bases of memory. Moreover, these models can be combined with genetic models of Alzheimer's disease to evaluate pharmacotherapies that ultimately have the potential to improve memory. PMID- 26609645 TI - Basic aspects in selecting a suitable transgenic rodent model for Alzheimer's disease. AB - Due to Alzheimer's disease (AD) great aggressiveness, many worldwide health associations began to globalize research efforts in order to find a suitable treatment and to clarify once and for all its controversial aetiology. Moreover, the animal modelling research is one of the best tools to evaluate molecular mechanisms and to correlate them with clinical features and behaviours. However, in order to provide valuable scientific data correlated to low error sources, a rigorous algorithm of selecting the proper animal model for testing is required. An ideal animal model for AD research has probably not yet been developed, but by a careful selection of the existent models or even by developing new models suitable to research conditions, consistent progress in this area of research can be achieved. This paper aims to show and centralize some of the valuable information gathered along the past years of failure and success in Alzheimer's disease animal modelling, in order to provide a theoretical ground for new and innovative aspects in this rather new area of research. PMID- 26609642 TI - Multicenter prospective randomized study comparing the technique of using a bovine pericardium biological prosthesis reinforcement in parietal herniorrhaphy (Tutomesh TUTOGEN) with simple parietal herniorrhaphy, in a potentially contaminated setting. AB - The use of parietal synthetic prosthetic reinforcement material in potentially contaminated settings is not recommended, as there is a risk that the prosthesis may become infected. Thus, simple parietal herniorrhaphy, is the conventional treatment, even though there is a significant risk that the hernia may recur. Using new biomaterials of animal origin presently appears to offer a new therapeutic solution, but their effectiveness has yet to be demonstrated. The purpose of this multicenter prospective randomized single-blind study was to compare the surgical treatment of inguinal hernia or abdominal incisional hernia by simple parietal herniorrhaphy without prosthetic reinforcement (Group A), with Tutomesh TUTOGEN biological prosthesis reinforcement parietal herniorrhaphy (Group B), in a potentially contaminated setting. We examined early postoperative complications in the first month after the operation, performed an assessment after one year of survival without recurrence and analyzed the quality of life and pain of the patients (using SF-12 health status questionnaire and Visual Analog Pain Scale) at 1, 6, and 12 months, together with an economic impact study. Hundred and thirty four patients were enrolled between January 2009 and October 2010 in 20 French hospitals. The groups were comparable with respect to their enrollment characteristics, their history, types of operative indications and procedures carried out. At one month post-op, the rate of infectious complications (n(A) = 11(18.33%) vs. n(B) = 12(19.05%), p = 0.919) was not significantly different between the two groups. The assessment after one year of survival without recurrence revealed that survival was significantly greater in Group B (Group A recurrence: 10, Group B: 3; p = 0.0475). No difference in the patients' quality of life was demonstrated at 1, 6, or 12 months. However, at the 1 month follow-up, the "perceived health" rating seemed better in the group with Tutomesh (p = 0.022). No significant difference between the two parietal repair groups was observed during the follow-ups with respect to the criterion of pain (using a visual analog scale). There was a significant difference between the two parietal repair groups with regard to the number of days spent in intensive care unit, in favor of the Tutomesh technique (p = 0.010). The use of a Tutomesh bioprosthesis for hernia repair or postincisional hernia in a potentially contaminated workplace reduces the risk of short-term recurrence without increasing overall comorbidity. PMID- 26609646 TI - Altered pain perception in self-injurious behavior and the association of psychological elements with pain perception measures: a systematic review. AB - BACKGROUND: The pathophysiology of non-suicidal self-injury (NSSI) is controversial. There is growing evidence of altered pain perception in people engaging in NSSI. Some hypotheses have been made on addictive aspects of this behavior. Pain and addictive behavior are modulated by the opioid system, which makes the endogenous opioids one of the candidate neurotransmitters related to NSSI. This article explains the theoretical background on NSSI as an addictive behavior, endogenous opioids involvement and pain perception changes in NSSI and updates the latest findings in this field. The main aim of this paper is a comprehensive review of published studies on pain perception in NSSI and an evaluation of the impact of NSSI functions and other psychological elements on pain perception measures. SUBJECTS AND METHODS: We have reviewed six studies of pain perception in participants with NSSI compared with controls. The participants of these studies were not mentally disabled or autistic and did not have a diagnosed personality disorder. RESULTS: The reviewed studies have demonstrated a higher pain threshold and longer pain tolerance or endurance in five of six studies. Emotional dysregulation was significantly associated with all pain perception variables in one study. Neuroticism, self-criticism and painful and provocative experiences revealed correlated with pain endurance or pain tolerance. No correlation between pain perception measures and dissociation, hopelessness or locus of control was found. CONCLUSIONS: Pain perception was altered in participants with NSSI. Pain perception was associated to emotional dysregulation, self-criticism, neuroticism and painful and provocative experiences. Because of the small number of studies reviewed, results should be seen as guidelines for further studies. They should be replicated on a bigger sample of studies. Further research should focus on pain perception measures in participants with NSSI and an excluded personality disorder. PMID- 26609648 TI - Treatment effectiveness in patients with schizophrenia as measured by the ASSESS battery - first longitudinal data. AB - BACKGROUND: Effective pharmacological treatment with a favorable side-effect profile increases treatment adherence and is therefore very important for patients with schizophrenia. Psychiatrists need easy to use and reliable assessments instruments to evaluate treatment effectiveness in their patients. SUBJECTS AND METHODS: A group of European leading psychiatrists have proposed a framework for the assessment of treatment effectiveness in patients with schizophrenia - the ASSESS battery (The ASseSsment of EffectivenesS in Schizophrenia Battery) which evaluates the effectiveness of treatment during both the remission and the relapse periods. ASSESS includes: 10 items of Positive and Negative Symptoms Scale (PANSS), Brief Assessment of Cognition in Schizophrenia (BACS), Medication Satisfaction Questionnaire (MSQ), and Personal and Social Performance Scale (PSP). The battery assesses five domains: symptomatic remission and retention of treatment, affective symptoms, cognitive functioning, treatment satisfaction and personal and social functioning. The aim of the present study was to evaluate the applicability of ASSESS in real world practice. RESULTS: The variations of the PANSS items rated during the study indicate a significant improvement of psychopathology. A similar improvement was observed in cognition, social functioning and treatment satisfaction as shown by BACS, PSP and MSQ scales. Cognitive impairment, personal and social functioning, and treatment satisfaction were correlated with the remission or augmentation of positive symptoms. CONCLUSIONS: This pilot study revealed that ASSESS is easy to apply in clinical practice and is a suitable tool for psychiatrists since it covers all the relevant aspects of the course of schizophrenia in a compact form. PMID- 26609647 TI - Evidence-based Neuro Linguistic Psychotherapy: a meta-analysis. AB - BACKGROUND: Neuro Linguistic Programming (NLP) Framework has enjoyed enormous popularity in the field of applied psychology. NLP has been used in business, education, law, medicine and psychotherapy to identify people's patterns and alter their responses to stimuli, so they are better able to regulate their environment and themselves. NLP looks at achieving goals, creating stable relationships, eliminating barriers such as fears and phobias, building self confidence, and self-esteem, and achieving peak performance. Neuro Linguistic Psychotherapy (NLPt) encompasses NLP as framework and set of interventions in the treatment of individuals with different psychological and/or social problems. We aimed systematically to analyse the available data regarding the effectiveness of Neuro Linguistic Psychotherapy (NLPt). SUBJECTS AND METHODS: The present work is a meta-analysis of studies, observational or randomized controlled trials, for evaluating the efficacy of Neuro Linguistic Programming in individuals with different psychological and/or social problems. The databases searched to identify studies in English and German language: CENTRAL in the Cochrane Library; PubMed; ISI Web of Knowledge (include results also from Medline and the Web of Science); PsycINFO (including PsycARTICLES); Psyndex; Deutschsprachige Diplomarbeiten der Psychologie (database of theses in Psychology in German language), Social SciSearch; National library of health and two NLP-specific research databases: one from the NLP Community (http://www.nlp.de/cgi bin/research/nlprdb.cgi?action=res_entries) and one from the NLP Group (http://www.nlpgrup.com/bilimselarastirmalar/bilimsel-arastirmalar 4.html#Zweig154). RESULTS: From a total number of 425 studies, 350 were removed and considered not relevant based on the title and abstract. Included, in the final analysis, are 12 studies with numbers of participants ranging between 12 and 115 subjects. The vast majority of studies were prospective observational. The actual paper represents the first meta-analysis evaluating the effectiveness of NLP therapy for individuals with social/psychological problems. The overall meta-analysis found that the NLP therapy may add an overall standardized mean difference of 0.54 with a confidence interval of CI=[0.20; 0.88]. CONCLUSION: Neuro-Linguistic Psychotherapy as a psychotherapeutic modality grounded in theoretical frameworks, methodologies and interventions scientifically developed, including models developed by NLP, shows results that can hold its ground in comparison with other psychotherapeutic methods. PMID- 26609649 TI - Exploring the association between the Iowa Gambling Task and community functioning in people with schizophrenia. AB - BACKGROUND: Decision making (DM) consists of a number of complex processes involving higher-order cognitive functions involved in outcome evaluation. Problems in DM may have significant negative repercussions on community functioning. We hypothesise in individuals with schizophrenia difficulties in community functioning will be associated with DM problems. SUBJECTS AND METHODS: DM performance was assessed using the Iowa Gambling Task (IGT) in 30 individuals with schizophrenia and 32 healthy controls. Participants' choices on the IGT were grouped as: Ambiguous Decisions, where the outcome is uncertain and cannot be predicted (i.e. IGT initial phase), and Risky Decisions, where the outcome can be predicted with an error margin (i.e. IGT final phase). People with schizophrenia were also assessed with measures of community functioning and symptoms. RESULTS: Controls outperformed individuals with schizophrenia in risky decisions. In patients, levels of community functioning positively correlated with DM performance. Symptomatology was not associated with DM proficiency or functioning. CONCLUSIONS: DM impairment may represent an important contributor to poor functional outcomes in people with schizophrenia. Interventions targeting decision making and higher order cognitive problems in people with schizophrenia may have a greater impact on functional difficulties. PMID- 26609650 TI - Metabolic syndrome in schizophrenia - who is more to blame: FGA polypharmacy or clozapine monotherapy? AB - BACKGROUND: To establish the prevalence of metabolic syndrome and its parameters in group of patients with schizophrenia in polypharmacy - receiving first generation antipsychotics versus clozapine alone treated group. SUBJECTS AND METHODS: 48 outpatients with schizophrenia divided into two groups: the first group of 21 patients in polypharmacy with first generation antipsychotics, and the second group of 27 patients treated with clozapine alone were assessed for the presence of metabolic syndrome. We used logistic regression models to assess the relationship between metabolic syndrome and antipsychotic therapy, gender and age. RESULTS: Metabolic syndrome was found in 52.1% of all subjects. Compared to first generation antipsychotics polypharmacy, the monopharmacy with clozapine was associated with elevated rates of metabolic syndrome (28.6% vs. 70.4%, p=0.004). With regard to particular parameters of metabolic syndrome, the elevated plasma triglycerides were significantly more present in subjects within Clozapine group (p=0.03). Logistic regression analysis showed that female gender (p=0.004), and clozapine treatment (p=0.005) were significantly associated with metabolic syndrome. CONCLUSION: Compared to polypharmacy with first generation antipsychotics, the higher prevalence of metabolic syndrome is found in patients treated with Clozapine alone. The most prevalent metabolic disorder is dyslipidemia. PMID- 26609651 TI - COX-2 gene variants in bipolar disorder-I. AB - BACKGROUND: Bipolar disorder-I (BD-I) is a complex illness, and multiple genes and environmental factors determine its pathogenesis. Several studies have ascertained that BD-I and inflammation are linked through shared genetic polymorphisms and gene expression, as well as altered cytokine levels. COX-2 gene polymorphisms affecting COX-2 levels may be associated with BD-I by altering the inflammatory response. SUBJECTS AND METHODS: We investigated COX-2-765G->C and COX-2-1195A->G gene polymorphisms, which might be related for BD-I. The present analyses are based on 180 subjects with bipolar I disorder-I and 170 non-bipolar subjects. Genotyping of COX-2 gene polymorphisms (COX-2-765G->C, COX-2-1195A->G) were detected by PCR-RFLP. RESULTS: We found a positive association of COX-2 gene variants for development of BD-I. There were statistically significant differences in COX-2-1195A->G genotypes and alleles between the controls and patients (p:0.000; p:0.000). The indivuals with COX-2-1195A->G AA genotype had seems to be associated for BD-I (p:0.000). CONCLUSIONS: It seems that there is a protective role of COX-2-1195A->G G+ genotype against BD-I (p:0.000). In addition, there was a weak linkage disequilibrium between COX-2-765G->C and COX-2 1195A->G polymorphisms. Our findings suggest that COX-2-1195A->G AA genotype may faciliate the development of BD-I. PMID- 26609652 TI - Temperament and character traits in patients with conversion disorder and their relations with dissociation. AB - BACKGROUND: The purpose of this study was to investigate temperament and character traits in patients with conversion disorder and the relation of these traits with dissociative symptoms. SUBJECTS AND METHODS: Sixty patients (60) diagnosed with conversion disorder according to DSM-IV-TR and 60 healthy volunteers were included in the study. All participants' temperament and character traits were determined using Cloninger's Temperament and Character Inventory (TCI). Patients with conversion disorder were divided into two subgroups using the Dissociative Experiences Scale (DES), dissociative (n=30, 50%) and non-dissociative (n=30, 50%). The two conversion disorder subgroups were compared with the control group in terms of temperament and character traits. Correlation analysis was also performed between TCI and DES scores in the entire conversion group. RESULTS: Novelty seeking (NS) scores were lower in both the dissociative and non-dissociative groups compared to the control group. Harm avoidance (HA) scores were higher in the dissociative group than in the control group. Reward dependence (RD) scores were lower in the dissociative group than in the non-dissociative and control group. Self-directedness (SD) scores were lower in the dissociative group than in the control group. Self-transcendence (ST) scores were higher in the dissociative group than in the non-dissociative group. DES scores were negatively correlated with RD and SD scores in the entire conversion group and positively correlated with ST scores. CONCLUSIONS: Low NS temperament traits may be associated with conversion disorder. High HA and low RD temperament traits and low SD and high ST character traits may be associated with pathological dissociation in patients with conversion disorder. PMID- 26609654 TI - Fatigue during multiple sclerosis relapse and its relationship to depression and neurological disability. AB - BACKGROUND: Fatigue is a common symptom of multiple sclerosis patients that may be present at all stages of the disease. The aim of this study was to determine presence of fatigue in multiple sclerosis patients during relapse and its relation to neurological disability and depression. SUBJECTS AND METHODS: This cross-sectional study included 120 patients who were assessed during the acute relapse of relapsing-remitting multiple sclerosis. Applied research instruments were: general questionnaire, Expanded Disability Status Scale (EDSS), Beck Depression Inventory-II (BDI-II) and Fatigue Severity Scale (FSS). All patients were examined at the same appointment. RESULTS: 54 (45%) patients were grouped into MS fatigue (MSF) group (FSS>=5) and 48 (40%) as non-fatigue (MSNF) group (FSS<=4). Mean FSS score was 4.83+/-1.49. Difference between MSF and MSNF patients was significant considering age (p<0.001), relapse severity (p=0.044), BDI score (p<0.001) and EDSS score (p<0.001). Positive correlations of fatigue (FSS) with age (rho=0.41, p<0.001), depression (BDI score) (rho=0.61, p<0.001) and neurological disability (EDSS score) (rho=0.55, p<0.001) were confirmed. After adjusting for depression, there was only weak positive correlation between fatigue and neurological disability (rs=0.38; P<0.001), while after adjusting for EDSS score, fatigue continued to correlate moderately with depression (r=0.48; p<0.001). Multiple linear regression analysis showed that BDI score (beta=0.380; p<0.001), EDSS score (beta=0.336, p<0.001) and the age (beta=0.202; p<0.05) are independently related to fatigue severity in this patients. CONCLUSION: Fatigue is a frequent symptom during multiple sclerosis relapse. Depression and, to a lesser degree, disability but not relapse severity are independently related to the presence of fatigue. Depression and fatigue should be recognized and treated during standard relapse treatment. Further research might focus on other factors influencing fatigue during multiple sclerosis relapse including evaluation of fatigue at the different time points. PMID- 26609653 TI - Symptom Dimensions, Smoking and Impulsiveness in Obsessive-Compulsive Disorder. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) has distinct symptom dimensions with possibly subtle differences in the underlying neurobiology. One behavioral habit, smoking, has been widely investigated in psychiatric disorders, though received less attention in OCD. Here, we aimed to investigate the relationship between symptom dimensions and smoking behavior in OCD. SUBJECTS AND METHODS: OCD patients (n=167) with the symptom dimensions of washing, taboo thoughts and symmetry-counting-repeating-ordering (S+C+R+O) were questioned in terms of smoking status and assessed with the Yale-Brown Obsessive Compulsive Scale (Y BOCS), Fagerstrom Test for Nicotine Dependence (FTND), Hamilton Depression Rating Scale-17 Items (HDRS-17), Beck Anxiety Inventory (BAI) and Barratt Impulsiveness Scale-11 (BIS 11). RESULTS: Smoking status differed significantly among patients with distinct symptom dimensions (p=0.009).The ratio of smokers was the lowest in those with the washing (30%, N=12) and the highest in the S+C+R+O (68.2%, N=15) group. Those with taboo thoughts had a smoking ratio of 37.14% (N=39). In post hoc analysis, smoking ratio was significantly higher in the S+C+R+O group than in those with washing symptoms (p=0.004) and taboo thoughts (p=0.007) though it did not differ significantly between washers and taboo thought groups. The BIS-11 did not differ across symptom dimensions. CONCLUSIONS: OCD is a heterogeneous disorder in terms of smoking. Impulsiveness, which does not significantly vary across distinct symptom dimensions, cannot explain this heterogeneity. The severity of addiction does not differ in smokers with OCD across symptom dimensions. PMID- 26609655 TI - Effects of exercise dependence on psychological health of Chinese college students. AB - BACKGROUND: The aim of this study was to investigate the effects of exercise dependence on the psychological health of Chinese college students. SUBJECTS AND METHODS: A total of 1601 college students from three universities in Hunan, China, were selected as research subjects. Several measurement scales, including the Exercise Addiction Inventory, the State-Trait Anxiety Inventory, the Center for Epidemiologic Studies Depression Scale, and the Subjective Well-being Scale, were used to survey the psychological health problem of these students and to analyze the effects of exercise dependence on their psychological health. RESULTS: Exercise dependence, based on the structural equation model analysis, can positively influence state anxiety (P<0.05), depression (P<0.05), and subjective well-being (P<0.05) of Chinese students. By contrast, exercise dependence negatively influences students' self-satisfaction (P<0.05), social behavior (P<0.05), and vigor (P<0.05). CONCLUSIONS: Exercise dependence adversely affects the psychological health of college students. Further research using multi-dimensional exercise addiction scales should be conducted to identify all the negative effects of exercise addiction factors on psychological health. PMID- 26609656 TI - Could alexithymia predict suicide attempts - a study of Croatian war veterans with post-traumatic stress disorder. AB - BACKGROUND: To investigate the possibility if alexithymia could be used as a predictor of attempted suicide among patients suffering from post-traumatic stress disorder. SUBJECTS AND METHODS: The study was based on 127 veterans from the 1991-1995 war in Croatia. All the patients involved in this study were previously diagnosed with PTSD. The questionnaires (socio-demographic questionnaire, Mississippi scale for combat related PTSD questionnaire, and 20 item Toronto Alexithymia Scale questionnaire) were administered by investigators. RESULTS: The results suggest that alexithymia was significantly associated with attempted suicide (P=0.020). Furthermore, alexithymia remained a significant predictor of an attempted suicide even in the multivariate regression model, which yielded an odds ratio (OR) of 2.87 (95% confidence intervals 1.18-7.00). CONCLUSIONS: These results point out that alexithymia can be considered as a potential risk factor for suicide in this population, suggesting that it may also be used as an indicator of worsening psychological status and attempted suicide in other population groups with higher alexithymia prevalence. PMID- 26609657 TI - Severe acute pancreatitis, neuroleptic malignant syndrome and grand mal seizures associated with elevated amisulpride and low clozapine serum levels. PMID- 26609658 TI - Late diagnosis of Asperger syndrome in Croatia - a low-income country. PMID- 26609659 TI - Koro, Othello and Capgras syndromes in one patient with drug induced psychosis. PMID- 26609660 TI - Social Psychiatric Aspects of Dementia. AB - The future of a dementia-appropriate care rests on early diagnosis and treatment (also in terms of a timely information, counselling and assistance), developing mobile medical healthcare, integrating and coordinating all dementia care partners and stakeholders, appropriate assessments of the stages of care allowance, providing new forms of housing, addressing the migration issue, and reducing unnecessary administrative bureaucracy - as well as, last but not least, the fight against prejudice. People affected by dementia suffer not only from symptoms of their illness but also from society's reaction towards this illness. Stigmatisation of dementia prevents an early diagnosis and treatment which could improve the course of the illness and create a "better everyday life", a more of inclusion for the affected people and their environment. But Albert Einstein already knew: "It's harder to crack prejudice than an atom." Nevertheless, it is paramount to work towards it - for dementia can affect each and every one of us. Dementia matters, for all of us. PMID- 26609661 TI - Careways of dementia care. AB - This paper presents first before the clinical picture of dementia and is further on dedicated to ways of dealing with people who suffer from dementia. They often show - from the perspective of this often loaded and challenged social environment - unexpected and/or unpredictable behavior. There is no panacea for the ends of successful dealing with people with dementia. But experience in terms of both - general and specialized nursing strategies - may facilitate the handling and may ease the situation of affected. After a number of general strategies the specialist care strategies Fordernde Prozesspflege, Validation, Basale Stimulation((c)) and Psychobiographisches Pflegemodell are presented. PMID- 26609662 TI - [Dementia and Nutrition - a brief overview]. AB - The continued ageing of our society results in an increased prevalence of dementia. It is therefore of interest to question possible effects of a balanced right diet in the prevention of dementia as well as focus on the specific dietary needs of patients suffering from dementia. Epidemiologic studies have linked a Mediterranean diet to a decreased risk of developing dementia. Various current studies are being done to determine which nutritional components are causing the effect and whether single food components can cause similar outcomes. Malnutrition, Sarcopenia and Frailty are frequent co morbidities in moderate to severe dementia resulting in an increased care-dependency as well as a higher mortality rate. To prevent this, a timely intervention with a suitable diet is required. PMID- 26609663 TI - [Projections about the future number of dementia sufferers: increasing life expectancy not sufficiently considered?]. AB - BACKGROUND: Several authors pointed out that in the next decades dementia will affect a considerably increasing number of the elderly. The question was raised if life-expectancy was projected to conservative, resulting in revisions with higher life-expectancy and larger numbers of the oldest population. The present paper analyses the influence of such revisions on the future numbers of dementia sufferers in Austria. SUBJECTS AND METHODS: For this purpose we used meta analyses of epidemiological studies and the population projections for the period until 2050 of the Austrian Bureau of Statistics as well as of the United Nations Population Division of the year 2001 as well of the year 2005. RESULTS: Using the extrapolations of the Austrian Bureau of Statistics of the year 1999 as well as of the United Nations Population Division of the year 2001, the number of dementia cases in Austria in the year 2050 will rise to about 233 thousands. According to the four years later performed extrapolations of the United Nations Population Division of the year 2005, dementia cases in Austria will raise to about 262 thousands in the year 2050. CONCLUSIONS: In the next decades, the number of persons suffering from dementia will rise considerably. Increasing life expectancy will result in markedly higher numbers of persons with dementia than estimated from earlier population projections. Nevertheless, this is the first analysis of future dementia cases based on projections from two different dates, but using the same source. We must conclude that the dramatically increasing number of dementia cases requires comprehensive planning of the health and social care system. PMID- 26609664 TI - Cognitive impairment in Parkinson's disease. AB - Parkinson's disease is the second most frequent neurodegenerative disorder. There is significantly elevated risk of cognitive decline and associated neuropsychiatric symptoms. Dementia may develop insidiously several years after manifestation of Parkinson motor symptoms (dementia associated with Parkinson's disease; Parkinson's disease dementia) or in close temporal relationship (within one year) after onset of motor symptoms (Dementia with Lewy bodies). There are clinical, pathophysiological and therapeutic similarities between these two conditions. Men are more frequently affected than women. Risk factor or indicators are advanced age at disease onset, disease duration, rigidity, akinesia and posture and gait impairment and falls as opposed to tremor dominance, and associated neuropsychiatric symptoms (depression, apathy, hallucinosis, delirium). Dementia is treatable with cholinesterase inhibitors (rivastigmine, donepezil), memantine, and adjustment of the pharmacological regimen of parkinsonian motor symptoms. Concomitant autonomic nervous system symptoms and neuropsychiatric complications warrant early clinical awareness and are accessible to pharmacological therapy. PMID- 26609665 TI - Diagnostic value of miRNA-96-5p/3p in dysplastic nodules and well-differentiated small hepatocellular carcinoma. AB - AIM: Hepatocarcinogenesis is a multistep process from cirrhosis through low-grade dysplastic nodule, high-grade dysplastic nodule to hepatocellular carcinoma. Differential diagnosis between high-grade dysplastic nodules and early hepatocellular carcinomas is particularly difficult. The present study aims to identify a novel biological marker for differential diagnosis of the two lesions. METHODS: The expression level of an miRNA pair, miRNA-96-5p and 3p, was assessed by reverse transcription polymerase chain reaction in hepatic tissues. RESULTS: We showed that mature miRNA-96-5p and passenger strand miRNA-96-3p were differentially expressed in multistep hepatocarcinogenesis. miRNA-96-5p was significantly upregulated from cirrhosis, dysplastic nodules to hepatocellular carcinoma. However, significance of determination of miRNA-96-5p expression level for differential diagnosis between high-grade dysplastic nodule and hepatocellular carcinoma is limited. In contrast, the expression of miRNA-96-3p was detectable in cirrhosis and dysplastic nodules. Also, it was completely undetectable in the majority of hepatocellular carcinomas (30/34, 88.2%). The sensitivity and specificity of miRNA-96-3p negative expression for differential diagnosis of hepatocellular carcinomas from high-grade dysplastic nodules were 88.2% and 84.2%, respectively. In addition, a more specific diagnosis could be carried out by combining miRNA-96-3p with glypican 3, with the specificity of 100%. CONCLUSION: These findings demonstrated that miRNA-96-3p is a helpful diagnostic biomarker in differential diagnosis between high-grade dysplastic nodules and well-differentiated small hepatocellular carcinomas, especially in combination with glypican 3. PMID- 26609666 TI - Built environment effects on cyclist injury severity in automobile-involved bicycle crashes. AB - This analysis uses a generalized ordered logit model and a generalized additive model to estimate the effects of built environment factors on cyclist injury severity in automobile-involved bicycle crashes, as well as to accommodate possible spatial dependence among crash locations. The sample is drawn from the Seattle Department of Transportation bicycle collision profiles. This study classifies the cyclist injury types as property damage only, possible injury, evident injury, and severe injury or fatality. Our modeling outcomes show that: (1) injury severity is negatively associated with employment density; (2) severe injury or fatality is negatively associated with land use mixture; (3) lower likelihood of injuries is observed for bicyclists wearing reflective clothing; (4) improving street lighting can decrease the likelihood of cyclist injuries; (5) posted speed limit is positively associated with the probability of evident injury and severe injury or fatality; (6) older cyclists appear to be more vulnerable to severe injury or fatality; and (7) cyclists are more likely to be severely injured when large vehicles are involved in crashes. One implication drawn from this study is that cities should increase land use mixture and development density, optimally lower posted speed limits on streets with both bikes and motor vehicles, and improve street lighting to promote bicycle safety. In addition, cyclists should be encouraged to wear reflective clothing. PMID- 26609667 TI - Helper-dependent adenoviral vectors for liver-directed gene therapy of primary hyperoxaluria type 1. AB - Primary hyperoxaluria type 1 (PH1) is an inborn error of liver metabolism due to deficiency of the peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT), which catalyzes conversion of glyoxylate into glycine. AGT deficiency results in overproduction of oxalate that ultimately leads to end-stage renal disease and death. Organ transplantation as either preemptive liver transplantation or combined liver/kidney transplantation is the only available therapy to prevent disease progression. Gene therapy is an attractive option to provide an alternative treatment for PH1. Toward this goal, we investigated helper-dependent adenoviral (HDAd) vectors for liver-directed gene therapy of PH1. Compared with saline controls, AGT-deficient mice injected with an HDAd encoding the AGT under the control of a liver-specific promoter showed a significant reduction of hyperoxaluria and less increase of urinary oxalate following challenge with ethylene glycol, a precursor of glyoxylate. These studies may thus pave the way to clinical application of HDAd for PH1 gene therapy. PMID- 26609669 TI - Psychometric properties of the English Food Cravings Questionnaire-Trait-reduced (FCQ-T-r). AB - Food cravings have been implicated in the development and maintenance of a range of eating- and weight-related pathology. The rapid and accurate assessment of food cravings is thus critical in clinical and research settings. Existing measures of specific food cravings are often not suitable for capturing the multiple facets of the craving experience. A short version of the Food Cravings Questionnaire-Trait (FCQ-T), the most widely used measure of general food cravings, was recently developed in German and shown to be a one-factorial, internally reliable measure. Other recent studies validated an Italian and Spanish version of the FCQ-T-reduced (FCQ-T-r) and successfully replicated its basic psychometrics. This study sought to examine the psychometric properties of the English version of the FCQ-T-r. Undergraduate students (n=610, 51.0% female, 53.9% white/Caucasian) completed a battery of questionnaires containing the FCQ-T r and measures of specific food cravings, eating style, eating disorder symptoms, weight dissatisfaction, and impulsivity. Even though results of a confirmatory factor analysis suggested poor fit with a one-factorial model, the FCQ-T-r was found to be a one-factorial measure in both principal component and parallel analysis. The FCQ-T-r demonstrated excellent internal consistency reliability (Cronbach's alpha=.94), and scores were significantly and positively correlated with measures of specific food cravings, restrained eating, eating disorder symptoms, and impulsivity. More work is needed to confirm the factor structure of the English FCQ-T-r, but preliminary findings suggest that it constitutes a valid and reliable alternative to lengthier measures of general food cravings. PMID- 26609670 TI - Involvement of opioid system in antidepressant-like effect of the cannabinoid CB1 receptor inverse agonist AM-251 after physical stress in mice. AB - Cannabinoid inverse agonists possess antidepressant-like properties, but the mechanism of this action is unknown. Numerous studies have reported the interaction between opioid and cannabinoid pathways. In this study, acute foot shock stress was used in mice to investigate the involvement of the opioid pathway in the antidepressant-like effect of the cannabinoid CB1 receptor inverse agonist AM-251. Stress was induced by intermittent foot-shock stimulation for 30 min. Then, using the forced swimming test (FST) and tail suspension test (TST), the immobility time was measured. Results show that the immobility time was significantly prolonged in animals subjected to foot-shock stress, compared with non-stressed controls (P < 0.01). Also, the serum corticosterone level was significantly increased after stress induction (P < 0.001). Administration of AM 251 (0.5 and 0.3 mg/kg, intraperitoneally (i.p.)), significantly decreased the immobility time of stressed mice in the FST (P < 0.001 and P < 0.01, respectively) and TST (P < 0.01 and P < 0.05, respectively). The lowest dose of AM-251 (0.1 mg/kg), naltrexone (0.3 mg/kg), and morphine (1.0 mg/kg) did not show any significant effect on stressed animals (P > 0.05). Co-administration of AM 251 with sub-effective dose of naltrexone decreased the effective dose of this cannabinoid inverse agonist, to 0.1 mg/kg (P < 0.01). On the other hand, administration of the sub-effective dose of morphine reversed the anti-immobility effect of AM-251 (0.5 mg/kg; P < 0.001). In conclusion, the present study for the first time reveals the possible role of opioid signalling in the antidepressant like properties of AM-251 in a foot-shock stress model. PMID- 26609668 TI - Socio-demographic, anthropometric, and psychosocial predictors of attrition across behavioral weight-loss trials. AB - Preventing attrition is a major concern in behavioral weight loss intervention studies. The purpose of this analysis was to identify baseline and six-month predictors associated with participant attrition across three independent clinical trials of behavioral weight loss interventions (PREFER, SELF, and SMART) that were conducted over 10 years. Baseline measures included body mass index, Barriers to Healthy Eating, Beck Depression Inventory-II (BDI), Hunger Satiety Scale (HSS), Binge Eating Scale (BES), Medical Outcome Study Short Form (MOS SF 36 v2) and Weight Efficacy Lifestyle Questionnaire (WEL). We also examined early weight loss and attendance at group sessions during the first 6 months. Attrition was recorded at the end of the trials. Participants included 504 overweight and obese adults seeking weight loss treatment. The sample was 84.92% female and 73.61% white, with a mean (+/- SD) age of 47.35 +/- 9.75 years. After controlling for the specific trial, for every one unit increase in BMI, the odds of attrition increased by 11%. For every year increase in education, the odds of attrition decreased by 10%. Additional predictors of attrition included previous attempts to lose 50-79 lbs, age, not possessing health insurance, and BES, BDI, and HSS scores. At 6 months, the odds of attrition increased by 10% with reduced group session attendance. There was also an interaction between percent weight change and trial (p<.001). Multivariate analysis of the three trials showed education, age, BMI, and BES scores were independently associated with attrition (ps <= .01). These findings may inform the development of more robust strategies for reducing attrition. PMID- 26609671 TI - [MALT Lymphoma of the Conjunctiva in a 13-year old Child--5-Year Relapse-free Follow-up Following Antibiotic Treatment]. AB - MEDICAL HISTORY: In February 2007, a 13-year old boy presented with a livid tumour in the lower conjunctival fornix of the left eye. OPHTHALMOLOGICAL FINDINGS: The tumor was salmon-coloured, bulging and elastic and filled the whole lower conjunctival fornix of the left eye. There was no other pathological finding in the left eye. Uncorrected visual acuity was 20/20. Intraocular pressure was 12 mmHg. The eye was fully motile. TREATMENT: Incisional biopsy was performed in February 2007. The tumor was histologically an extranodal MALT lymphoma. DNA testing for Chlamydophila trachomatis and Chlamydophila pneumonia was negative. Systemic treatment was started with doxycycline (200 mg daily). After six weeks, the tumour was slightly smaller. Azithromycin 500 mg once a week was added. 18 months after initiation of the treatment, the tumour had completely regressed. A second sample taking in the former tumor area showed tumor-free conjunctiva and subconjunctival tissue. As a precaution, the combined antibiotic therapy was continued for 10 months and the patient was followed for five more years. The lymphoma did not relapse in the conjunctiva and orbit or in the whole body. CONCLUSION: We showed that extranodal MALT lymphomas of the conjunctiva can be successfully treated with antibiotics alone. At the start of therapy, the child was 13 years old. To our knowledge, this patient is the first child in Germany and one of the first in the world with ocular adnexal lymphoma who could be successfully treated with combined antibiotic therapy and who could be followed up for 5 years without relapse. Thus, we could avoid radiotherapy or chemotherapy in childhood and eliminate the risk of a therapy-induced secondary malignancy. PMID- 26609672 TI - [Traumatic Lacrimal Duct Stenosis: Demographics and Success Rate of Surgical Procedures for Secondary Treatment]. AB - BACKGROUND: Traumatic lacrimal duct stenosis can be the result of sharp trauma of the eyelid, indirect trauma or surgery in the nasoorbital region, as well as burns, chemotherapy and radiation of the facial region. The aim of the study is to present the demographics, patient satisfaction, and course of different surgical procedures for secondary treatment of traumatic lacrimal duct stenosis. METHODS: We retrospectively reviewed the medical records of 50 patients who required surgery for traumatic lacrimal duct stenosis from 2009 to 2011 at the University Eye Hospital in Muenster. The evaluation included the following criteria: age, sex, duration of symptoms, complication rate and the rate of recurrence. We systematically evaluated the medical data and asked the patients about the recent symptoms via telephone questionnaire. RESULTS: 60 eyes of 50 patients were included (18 women; 32 men; age: 51.8 +/- 17.1 years); 34 eyes (56.7 %) had already had operations of the lacrimal system. The success rate was 58.1 %. The mean postoperative follow-up was 52.3 +/- 10.7 months. In 11 cases (18.3 %), a dakryocystorhinostomy (DCR) was necessary. CONCLUSION: Traumatic lacrimal stenosis is more common in men, and has a poorer prognosis than lacrimal duct stenosis from other causes. PMID- 26609673 TI - [Half-Dose Verteporfin Photodynamic Therapy (hdPDT) in the Treatment of Central Serous Chorioretinopathy]. AB - BACKGROUND: To estimate the efficacy and safety profile of half-dose photodynamic therapy (hdPDT) for treating central serous chorioretinopathy (CSC). PATIENTS AND METHODS: An interventional, retrospective case series of patients with CSC (symptoms ? 3 months) receiving half-dose PDT (3 mg/m2 verteporfin). The ophthalmic examination at baseline and at 8 and 16 weeks after treatment included slit-lamp biomicroscopy, indirect ophthalmoscopy, measurement of intraocular pressure (IOP), ETDRS best-corrected visual acuity (BCVA), Amsler grid screening and contrast visual acuity (CVA). Fluorescein angiography (FA), autofluorescence (FAF) and optical coherence tomography (OCT) were measured at each visit. Central macular thickness (CMT) was measured automatically. RESULTS: 12 eyes of 12 patients (10 male and 2 female patients; mean age 46.6 +/- 7.91 years) were included in this study. Anatomical resolution was obtained in 10 eyes (83.4 %) at week 16, but 2 eyes (16.6 %) exhibited persistent SRD throughout the follow-up period. Baseline CMT decreased from initially 330.1 um +/- 131.3 to 205.6 um +/- 97.6 (p = 0.034) at week 8 and to 220.3 um +/- 120.1 (p = 0.05) at week 16. Visual acuity (number of total letters read) significantly improved from initially 82.8 +/- 11.5 to 86.8 +/- 13.9 at week 8 and 91.3 +/- 13.8 at week 16 (p = 0.012). Contrast visual acuity (calculated decimal visual acuity) significantly improved from initially 0.14 +/- 0.09 to 0.38 +/- 0.28 (p = 0.002) at week 16. After therapy, no significant changes in RPE could be detected with FAF and no ocular adverse events were observed. CONCLUSION: PDT with half-dose verteporfin resulted in reduced leakage in FA, enhanced visual acuity and resolution of subretinal fluid in OCT in patients with CSC, with no detected side effects of treatment. PMID- 26609674 TI - [Transcanalicular Laser Dacryocystorhinostomy: One-Year-Experience in the Treatment of Acquired Nasolacrimal Duct Obstructions]. AB - BACKGROUND: External dacryocystorhinostomy (DCR) is at present the gold standard for the surgical treatment of acquired nasolacrimal duct obstructions, but tremendous progress has been made in recent years in improving minimally invasive techniques, sparing not only the skin, but also the medial lid structures, which contribute to the physiological palpebral-canalicular pump mechanism. The purpose of this study is to report our 1-year experience with the surgical technique, complications and results of transcanalicular laser assisted DCR. PATIENTS AND METHODS: 48 consecutive transcanalicular laser-assisted DCRs combined with bicanalicular silicone intubation were performed for acquired nasolacrimal duct obstruction, and evaluated for intra- and postoperative complications, as well as subjective and objective success rates. RESULTS: Transcanalicular laser-assisted DCR combined with bicanalicular silicone intubation was surgically feasible in 45 cases (94 %). In 3 patients (6 %) it was impossible to position the aiming beam correctly at the anteroinferior rim of the middle turbinate using the superior canalicular approach, due to superior orbital rim prominence. Therefore 2 patients received no silicone intubation, despite a patent osteotomy at the back of the middle turbinate, and 1 patient underwent intraoperative conversion to external DCR due to anatomical narrowness of the nasal cavity. Perioperatively, 1 patient developed canalicular infection, 1 patient exhibited thermal injury to the canaliculus, and 4 patients exhibited premature prolapse of the silicone tube. At 6-months follow-up, functional success--defined as resolution of preoperative symptoms--was achieved in 35 of 45 surgically successful transcanalicular laser-assisted DCRs (78 %). Of the 10 postoperative failures (22 %), all patients reported epiphora, 6 patients were unable to irrigate the lacrimal drainage system, and 6 patients required surgical revision using external DCR. CONCLUSIONS: Transcanalicular laser assisted DCR is a promising minimally invasive approach for the surgical treatment of acquired nasolacrimal duct obstruction, in order to fill the gap between recanalising first step procedures and external DCR. PMID- 26609675 TI - [Self-tonometry with a Telemetric Intraocular Pressure Sensor in Patients With Glaucoma]. AB - BACKGROUND: Accurate acquisition of intraocular pressure (IOP) data, particularly short-term and long-term fluctuations, plays an important role in the medical care of glaucoma patients. Non-invasive self-tonometry with a telemetric IOP sensor can provide important data on the individual IOP profile. METHODS: Within the framework of a prospective, single-centre pilot clinical trial, a ring-shaped telemetric IOP sensor was inserted into the ciliary sulcus after implantation of the intracapsular lens during planned cataract surgery. In accordance with the protocol, at the 5-month visit, all patients received a reading unit for one month self-tonometry assessment. All patients were asked to measure the IOP at least once daily, and, if possible, at many different times. The first IOP measurement of each day was evaluated (covering one measurement daily per patient on 20 different days within the assessment interval). Furthermore, IOP data were analysed according to the time of day, divided into early phase (5 am to 11 am), midday (11 am to 4 pm) and late phase (4 am to 11 pm) (patients with at least 10 measurements and max. 20 measurements were included). Descriptive statistics of the original ARGOS system values were calculated, with evaluation of the percentiles and presentation in box plots. RESULTS: All patients successfully performed self-tonometry at home after receiving brief instructions. The first IOP measurement of each day covered a very wide interindividual range (between 3.1 mmHg in patient 5 and 21.7 mmHg in patient 4). Analysis of IOP values by time of day showed that patient 1 had significantly higher IOP values in the late day phase. For patient 5, the highest values were at midday. Patients 3 and 4 showed no significant fluctuations during the day. CONCLUSIONS: Self-tonometry encourages patients to be actively involved in the management of their own illness and allows non-invasive assessment of IOP at different times and during diverse activities. However, the analysis and interpretation of these new data require further study, especially in relation to Goldmann applanation tonometry. PMID- 26609677 TI - Changes of protein glycosylation in the course of radiotherapy. AB - This is the first study of changes in protein glycosylation due to exposure of human subjects to ionizing radiation. Site specific glycosylation patterns of 7 major plasma proteins were analyzed; 171 glycoforms were identified; and the abundance of 99 of these was followed in the course of cancer radiotherapy in 10 individual patients. It was found that glycosylation of plasma proteins does change in response to partial body irradiation (~ 60 Gy), and the effects last during follow-up; the abundance of some glycoforms changed more than twofold. Both the degree of changes and their time-evolution showed large inter-individual variability. PMID- 26609676 TI - Redox-dependent disulfide bond formation in SAP30L corepressor protein: Implications for structure and function. AB - Sin3A-associated protein 30-like (SAP30L) is one of the key proteins in a multi subunit protein complex involved in transcriptional regulation via histone deacetylation. SAP30L, together with a highly homologous SAP30 as well as other SAP proteins (i.e., SAP25, SAP45, SAP130, and SAP180), is an essential component of the Sin3A corepressor complex, although its actual role has remained elusive. SAP30L is thought to function as an important stabilizing and bridging molecule in the complex and to mediate its interactions with other corepressors. SAP30L has been previously shown to contain an N-terminal Cys3 His type zinc finger (ZnF) motif, which is responsible for the key protein-protein, protein-DNA, and protein-lipid interactions. By using high-resolution mass spectrometry, we studied a redox-dependent disulfide bond formation in SAP30L ZnF as a regulatory mechanism for its structure and function. We showed that upon oxidative stress SAP30L undergoes the formation of two specific disulfide bonds, a vicinal Cys29 Cys30 and Cys38-Cys74, with a concomitant release of the coordinated zinc ion. The oxidized protein was shown to remain folded in solution and to bind signaling phospholipids. We also determined a solution NMR structure for SAP30L ZnF that showed an overall fold similar to that of SAP30, determined earlier. The NMR titration experiments with lipids and DNA showed that the binding is mediated by the C-terminal tail as well as both alpha-helices of SAP30L ZnF. The implications of these results for the structure and function of SAP30L are discussed. PMID- 26609678 TI - Rapid screening of guar gum using portable Raman spectral identification methods. AB - Guar gum is a well-known inactive ingredient (excipient) used in a variety of oral pharmaceutical dosage forms as a thickener and stabilizer of suspensions and as a binder of powders. It is also widely used as a food ingredient in which case alternatives with similar properties, including chemically similar gums, are readily available. Recent supply shortages and price fluctuations have caused guar gum to come under increasing scrutiny for possible adulteration by substitution of cheaper alternatives. One way that the U.S. FDA is attempting to screen pharmaceutical ingredients at risk for adulteration or substitution is through field-deployable spectroscopic screening. Here we report a comprehensive approach to evaluate two field-deployable Raman methods--spectral correlation and principal component analysis--to differentiate guar gum from other gums. We report a comparison of the sensitivity of the spectroscopic screening methods with current compendial identification tests. The ability of the spectroscopic methods to perform unambiguous identification of guar gum compared to other gums makes them an enhanced surveillance alternative to the current compendial identification tests, which are largely subjective in nature. Our findings indicate that Raman spectral identification methods perform better than compendial identification methods and are able to distinguish guar gum from other gums with 100% accuracy for samples tested by spectral correlation and principal component analysis. PMID- 26609679 TI - Practical method development for the separation of monoclonal antibodies and antibody-drug-conjugate species in hydrophobic interaction chromatography, part 1: optimization of the mobile phase. AB - The goal of this work is to provide some recommendations for method development in HIC using monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs) as model drug candidates. The effects of gradient steepness, mobile phase pH, salt concentration and type, as well as organic modifier were evaluated for tuning selectivity and retention in HIC. Except the nature of the stationary phase, which was not discussed in this study, the most important parameter for modifying selectivity was the gradient steepness. The addition of organic solvent (up to 15% isopropanol) in the mobile phase was also found to be useful for mAbs analysis, since it could provide some changes in elution order, in some cases. On the contrary, isopropanol was not beneficial with ADCs, since the most hydrophobic DAR species (DAR6 and DAR8) cannot be eluted from the stationary phase under these conditions. This study also illustrates the possibility to perform HIC method development using optimization software, such as Drylab. The optimum conditions suggested by the software were tested using therapeutic mAbs and commercial cysteine linked ADC (brentuximab-vedotin) and the average retention time errors between predicted and experimental retention times were ~ 1%. PMID- 26609680 TI - Structural characterization of cevimeline and its trans-impurity by single crystal XRD. AB - Cevimeline is muscarinic receptor agonist which increases secretion of exocrine glands. Cevimeline base is a liquid (m.p. 20-25 degrees C) at ambient conditions, therefore its pharmaceutical formulation as a solid hydrochloride hemihydrate has been developed. The synthesis of cevimeline yields its cis- and trans-isomers and only the cis-isomer is recognized as the API and used in the finished formulation. In this study structural and physicochemical investigations of hydrochloride hemihydrates of cis- and trans-cevimelines have been performed. Single crystal X-ray analyses of both cis- and trans-isomers of cevimeline are reported here for the first time. It was found that the cis-isomer, the API, has less dense crystal packing, lower melting point and higher solubility in comparison to the trans-isomer. PMID- 26609682 TI - Increasing the accuracy of radiotracer monitoring in one-dimensional flow using polynomial deconvolution correction. AB - Factors such as type of fluid movement and gamma-ray scattering may decrease the precision of the radiotracer monitoring as the response to a short tracer injection. Practical experiences using polynomial deconvolution techniques are presented. These techniques were successfully applied for correcting the obtained experimental results and increasing the time resolution of the method. PMID- 26609681 TI - Pretransplant echocardiographic parameters as markers of posttransplant outcomes in liver transplant recipients. AB - Despite advances in liver transplantation and preoperative risk stratification, there remains significant posttransplant morbidity and mortality from cardiovascular and renal disease. There are limited and conflicting data on the role of pretransplant echocardiography to predict these outcomes. The purpose of our study was to determine if pretransplant echocardiographic parameters were associated with posttransplant survival and the development of incident cardiovascular events and chronic kidney disease (CKD). We conducted a retrospective cohort study of 397 adult liver transplant recipients at the University of Pennsylvania from January 1, 2005 to September 30, 2014. Patients with acute liver failure, those without a diagnosis of cirrhosis (eg, polycystic liver disease without portal hypertension), retransplants, and multiorgan transplants were excluded. In multivariable Cox regression models, tricuspid regurgitation graded greater than mild was associated with significantly increased posttransplant mortality (hazard ratio, 1.68; 95% confidence interval [CI], 1.03-2.75; P = 0.04). In multivariable competing risk models, increasing pulmonary artery systolic pressure (PASP) was associated with significantly increased risk of hospitalization for myocardial infarction or heart failure (subhazard ratio per 5 mm Hg increase in PASP, 1.79; 95% CI, 1.48-2.17; P < 0.001). In multivariable competing risk models, increased left ventricular ejection fraction (LVEF) was associated with a numerical but nonsignificant increased risk of stage 4 or 5 CKD (subhazard ratio, 1.11 per 5% increase in LVEF; 95% CI, 0.99-1.24; P = 0.07). In a post hoc analysis, LVEF >= 65% was the best cutoff for increased risk of CKD (subhazard ratio, 1.75; 95% CI, 1.06-2.89; P = 0.03). In conclusion, several pretransplant echocardiographic parameters were associated with posttransplant morbidity and mortality, suggesting that pretransplant echocardiography may be used as a tool to risk-stratify patients for posttransplant outcomes. PMID- 26609683 TI - Thermoluminescent dosimeters for low dose X-ray measurements. AB - The response of TLD-100, CaSO4:Dy and LiF:Mg,Cu,P for a range of X-ray low dose was measured. For calibration, the TLDs were arranged at the center of the X-ray field. The dose output of the X-ray machine was determined using an ACCU-Gold. All dosimeters were exposed at the available air kerma values of 14.69 mGy within a field 10*10 cm(2) at 80 cm of SSD. Results of LiF:Mg,Cu,P X-ray irradiated showed 4.8 times higher sensitivity than TLD-100. Meanwhile, TL response of CaSO4:Dy exposed at the same dose was 5.6 time higher than TLD-100. Experimental results show for low dose X-ray measurements a better linearity for LiF:Mg,Cu,P compared with that of TLD-100. CaSO4:Dy showed a linearity from 0.1 to 60 mGy. PMID- 26609684 TI - Design and simulation of betavoltaic angle sensor Based on 63Ni-Si. AB - A theoretical design and simulation of betavoltaic angle sensor (beta-AS) based on (63)Ni-Si using MCNP code is presented in this article. It can measure the full angle of 0-360 degrees in the temperature range of 233-353 K. Beta-AS is composed of semicircular (63)Ni as the beta source, which rotates along the circular (four-quadrant) surface of Si as a semiconductor (in p-n structure), so that the change in the source angle in relation to Si surface can be measured based on the changes in V(oc) observed in each quadrant of Si. For better performance, characteristics of Si and (63)Ni have been optimized: N(D) and N(A) values of 8e19 and 4e18 cm(-3) (donor and acceptor doping concentration in Si, respectively), source thickness and activity of 1.5 um and 18 mCi, respectively. The relation between angle and V(oc) is also investigated. The maximum difference between measured and real values of angle (the worst case, i.e., 0.18 degrees for the angle of 45 degrees ) occurs at 233 K. It has been shown that sensitivity of the sensor decreases with an increase of angle. The results also show that the change in activity does not affect the sensitivity. PMID- 26609685 TI - New analytical approach for neutron beam-hardening correction. AB - In neutron imaging, the beam-hardening effect has a significant effect on quantitative and qualitative image interpretation. This study aims to propose a linearization method for beam-hardening correction. The proposed method is based on a new analytical approach establishing the attenuation coefficient as a function of neutron energy. Spectrum energy shift due to beam hardening is studied on the basis of Monte Carlo N-Particle (MCNP) simulated data and the analytical data. Good agreement between MCNP and analytical values has been found. Indeed, the beam-hardening effect is well supported in the proposed method. A correction procedure is developed to correct the errors of beam hardening effect in neutron transmission, and therefore for projection data correction. The effectiveness of this procedure is determined by its application in correcting reconstructed images. PMID- 26609686 TI - Hypertrophic or hypertensive cardiomyopathy? PMID- 26609687 TI - Abnormal adrenergic activation is the major determinant of reduced functional capacity in heart failure with preserved ejection fraction. PMID- 26609688 TI - Vorapaxar and optimal aspirin dose: The FDA outlook. AB - Vorapaxar, a novel thrombin PAR-1 inhibitor, approved for post-myocardial infarction, and peripheral artery disease indications has been tested in 2 major clinical trials. In the successful TRA2P, antecedent aspirin (ASA) has been used in 94% of patients, and in failed TRACER in over 96% of patients. However, both trial publications were silent on the impact of ASA dose on clinical outcomes after voraparax. We determined which ASA dose range should be used in combination with voraparax based on the TRA2P and TRACER secondary FDA review. The data suggest that for both voraparax trials, younger patients, males, and diabetics received higher ASA doses. The interactions between voraparax efficacy and ASA dose >= 300 mg was marginally significant by Cox regressions for TRA2P (CI=1.00 1.61; p=0.048) and strongly trended in TRACER (CI=0.98-1.47; p=0.073). Bleeding rates were overall slightly higher with voraparax than with placebo, and were the highest in patients receiving ASA dosages >= 300 mg. However, there were no interactions between ASA dose and GUSTO moderate/severe bleeding. In conclusion, the efficacy of voraparax in TRA2P and TRACER, was slightly worse while bleeding was substantially worse with the higher over 300 mg/day of ASA dosages. Voraparax label should recommend ASA daily use in 75 to 100mg range for concomitant use. PMID- 26609689 TI - Do single-arm trials have a role in drug development plans incorporating randomised trials? AB - Often, single-arm trials are used in phase II to gather the first evidence of an oncological drug's efficacy, with drug activity determined through tumour response using the RECIST criterion. Provided the null hypothesis of 'insufficient drug activity' is rejected, the next step could be a randomised two arm trial. However, single-arm trials may provide a biased treatment effect because of patient selection, and thus, this development plan may not be an efficient use of resources. Therefore, we compare the performance of development plans consisting of single-arm trials followed by randomised two-arm trials with stand-alone single-stage or group sequential randomised two-arm trials. Through this, we are able to investigate the utility of single-arm trials and determine the most efficient drug development plans, setting our work in the context of a published single-arm non-small-cell lung cancer trial. Reference priors, reflecting the opinions of 'sceptical' and 'enthusiastic' investigators, are used to quantify and guide the suitability of single-arm trials in this setting. We observe that the explored development plans incorporating single-arm trials are often non-optimal. Moreover, even the most pessimistic reference priors have a considerable probability in favour of alternative plans. Analysis suggests expected sample size savings of up to 25% could have been made, and the issues associated with single-arm trials avoided, for the non-small-cell lung cancer treatment through direct progression to a group sequential randomised two-arm trial. Careful consideration should thus be given to the use of single-arm trials in oncological drug development when a randomised trial will follow. PMID- 26609690 TI - How can health systems be strengthened to control and prevent an Ebola outbreak? A narrative review. AB - The emergence and re-emergence of infectious diseases are now more than ever considered threats to public health systems. There have been over 20 outbreaks of Ebola in the past 40 years. Only recently, the World Health Organization has declared a public health emergency of international concern (PHEIC) in West Africa, with a projected estimate of 1.2 million deaths expected in the next 6 months. Ebola virus is a highly virulent pathogen, often fatal in humans and non human primates. Ebola is now a great priority for global health security and often becomes fatal if left untreated. This study employed a narrative review. Three major databases - MEDLINE, EMBASE, and Global Health - were searched using both 'text-words' and 'thesaurus terms'. Evidence shows that low- and middle income countries (LMICs) are not coping well with the current challenges of Ebola, not only because they have poor and fragile systems but also because there are poor infectious disease surveillance and response systems in place. The identification of potential cases is problematic, particularly in the aspects of contact tracing, infection control, and prevention, prior to the diagnosis of the case. This review therefore aims to examine whether LMICs' health systems would be able to control and manage Ebola in future and identifies two key elements of health systems strengthening that are needed to ensure the robustness of the health system to respond effectively. PMID- 26609691 TI - Molecular methods routinely used to detect Coxiella burnetii in ticks cross-react with Coxiella-like bacteria. AB - BACKGROUND: Q fever is a widespread zoonotic disease caused by Coxiella burnetii. Ticks may act as vectors, and many epidemiological studies aim to assess C. burnetii prevalence in ticks. Because ticks may also be infected with Coxiella like bacteria, screening tools that differentiate between C. burnetii and Coxiella-like bacteria are essential. METHODS: In this study, we screened tick specimens from 10 species (Ornithodoros rostratus, O. peruvianus, O. capensis, Ixodes ricinus, Rhipicephalus annulatus, R. decoloratus, R. geigy, O. sonrai, O. occidentalis, and Amblyomma cajennense) known to harbor specific Coxiella-like bacteria, by using quantitative PCR primers usually considered to be specific for C. burnetii and targeting, respectively, the IS1111, icd, scvA, p1, and GroEL/htpB genes. RESULTS: We found that some Coxiella-like bacteria, belonging to clades A and C, yield positive PCR results when screened with primers initially believed to be C. burnetii-specific. CONCLUSIONS: These results suggest that PCR-based surveys that aim to detect C. burnetii in ticks by using currently available methods must be interpreted with caution if the amplified products cannot be sequenced. Future molecular methods that aim at detecting C. burnetii need to take into account the possibility that cross-reactions may exist with Coxiella-like bacteria. PMID- 26609693 TI - Pulmonary Retention of Adipose Stromal Cells Following Intravenous Delivery Is Markedly Altered in the Presence of ARDS. AB - Transplantation of mesenchymal stromal cells (MSCs) has been shown to effectively prevent lung injury in several preclinical models of acute respiratory distress syndrome (ARDS). Since MSC therapy is tested in clinical trials for ARDS, there is an increased need to define the dynamics of cell trafficking and organ specific accumulation. We examined how the presence of ARDS changes retention and organ-specific distribution of intravenously delivered MSCs isolated from subcutaneous adipose tissue [adipose-derived stem cells (ADSCs)]. This type of cell therapy was previously shown to ameliorate ARDS pathology. ARDS was triggered by lipopolysaccharide (LPS) aspiration, 4 h after which 300,000 murine CRE+ ADSCs were delivered intravenously. The distribution of ADSCs in the lungs and other organs was assessed by real-time polymerase chain reaction (PCR) of genomic DNA. As anticipated, the majority of delivered ADSCs accumulated in the lungs of both control and LPS-challenged mice, with minor amounts distributed to the liver, kidney, spleen, heart, and brain. Interestingly, within 2 h following ADSC administration, LPS-challenged lungs retained significantly lower levels of ADSCs compared to control lungs (~7% vs. 15% of the original dose, respectively), whereas the liver, kidney, spleen, and brain of ARDS-affected animals retained significantly higher numbers of ADSCs compared to control animals. In contrast, 48 h later, only LPS-challenged lungs continued to retain ADSCs (~3% of the original dose), whereas the lungs of control animals and nonpulmonary organs in either control or ARDS mice had no detectable levels of ADSCs. Our data suggest that the pulmonary microenvironment during ARDS may lessen the pulmonary capillary occlusion by MSCs immediately following cell delivery while facilitating pulmonary retention of the cells. PMID- 26609694 TI - Cell Responses to Conditioned Media Produced by Patient-Matched Stem Cells Derived From Healthy and Inflamed Periodontal Ligament Tissues. AB - BACKGROUND: Periodontal ligament stem cells (PDLSCs) derived from clinically compromised teeth with periodontitis are considered a readily accessible cell source, but their impaired stem cell functionalities, as observed in various in vitro and in vivo models, necessitate further investigation of these inflamed cells before their translation into therapeutic applications. In this study, the effects of conditioned media (CM) produced by stem cells derived from human healthy periodontal ligament tissues (H-PDLSCs) or inflamed periodontal ligament tissues (I-PDLSCs), referred to as H-CM and I-CM, respectively, on the biologic properties of H-PDLSCs and I-PDLSCs from the same donor are compared to explore the extent to which inflamed cells can be rescued by their extrinsic environment (i.e., by H-CM). METHODS: H-CM and I-CM were prepared from in vitro cell cultures, and the cellular responses of H-PDLSCs and I-PDLSCs to patient-matched H-CM and I-CM were investigated in terms of colony-forming ability, cell proliferation, and adipogenic/osteogenic differentiation. RESULTS: In H-CM and I CM, H-PDLSCs and I-PDLSCs exhibited similar adipogenic potential. However, when incubated in I-CM, both cell types demonstrated an increased capacity to proliferate but a decreased capacity to differentiate into osteoblasts. Significantly, the impaired osteogenic differentiation of I-PDLSCs was partially rescued by incubation in H-CM under osteo-inducing conditions. CONCLUSION: The CM of patient-matched H-PDLSCs and I-PDLSCs differed, and the impaired osteogenic differentiation of inflamed stem cells had the potential to be rescued, at least partially, for therapeutic use via changing the cell culture microenvironment in vitro. PMID- 26609692 TI - Serologic screening for 13 infectious agents in roe deer (Capreolus capreolus) in Flanders. AB - INTRODUCTION: In order to investigate the role of roe deer in the maintenance and transmission of infectious animal and human diseases in Flanders, we conducted a serologic screening in 12 hunting areas. MATERIALS AND METHODS: Roe deer sera collected between 2008 and 2013 (n=190) were examined for antibodies against 13 infectious agents, using indirect enzyme-linked immunosorbent assay, virus neutralisation, immunofluorescence, or microagglutination test, depending on the agent. RESULTS AND DISCUSSION: High numbers of seropositives were found for Anaplasma phagocytophilum (45.8%), Toxoplasma gondii (43.2%) and Schmallenberg virus (27.9%), the latter with a distinct temporal distribution pattern following the outbreak in domestic ruminants. Lower antibody prevalence was found for Chlamydia abortus (6.7%), tick-borne encephalitis virus (5.1%), Neospora caninum (4.8%), and Mycobacterium avium subsp paratuberculosis (4.1%). The lowest prevalences were found for Leptospira (1.7%), bovine viral diarrhoea virus 1 (1.3%), and Coxiella burnetii (1.2%). No antibodies were found against Brucella sp., bovine herpesvirus 1, and bluetongue virus. A significant difference in seroprevalence between ages (higher in adults >1 year) was found for N. caninum. Four doubtful reacting sera accounted for a significant difference in seroprevalence between sexes for C. abortus (higher in females). CONCLUSIONS: Despite the more intensive landscape use in Flanders, the results are consistent with other European studies. Apart from maintaining C. abortus and MAP, roe deer do not seem to play an important role in the epidemiology of the examined zoonotic and domestic animal pathogens. Nevertheless, their meaning as sentinels should not be neglected in the absence of other wild cervid species. PMID- 26609695 TI - Periodontal Conditions in Human Immunodeficiency Virus-Positive Patients Under Highly Active Antiretroviral Therapy From a Metropolitan Area of Rio De Janeiro. AB - BACKGROUND: The aim of this study is to evaluate the periodontal status and the presence of opportunistic oral lesions in human immunodeficiency virus-positive (HIV+) patients under highly active antiretroviral therapy (HAART) and their association with cluster of differentiation (CD)4+ and CD4+ nadir T-cell counts and viral load levels. METHODS: Clinical periodontal parameters and the presence of opportunistic oral lesions along with records of CD4+ counts and viral load levels were evaluated in 29 individuals (16 females; mean age: 42.7 years) with previous serologic diagnosis of HIV, from the acquired immunodeficiency syndrome program of the Health Center of Duque de Caxias, Rio de Janeiro, Brazil. RESULTS: All individuals presented gingivitis or periodontitis. A higher non-significant prevalence of periodontitis was found in smokers (93.8%) compared with non smokers (76.9%). A significant weak positive correlation was observed between CD4+ counts and missing teeth (rho = 0.380, P <0.05), CD4+ nadir and periodontal diagnosis (rho = 0.418, P <0.005), and CD4+ nadir and moderate probing depth (PD) (rho = 0.424, P <0.05). When only non-smokers were analyzed, a significant moderate positive association was found between viral load and moderate clinical attachment level (CAL) (rho = 0.638, P <0.05), CD4+ nadir and diagnosis (rho = 0.586, P <0.05), and CD4+ nadir and moderate CAL (rho = 0.680, P <0.05). Analysis considering only smokers found no correlations between serologic parameters and demographic or clinical parameters. CONCLUSIONS: The current investigation demonstrates that HIV+ individuals under HAART presents a high prevalence of mild to moderate periodontal disease. Viral load levels, CD4+ nadir, and CD4+ counts may present a weak to moderate correlation to the number of missing teeth, periodontal diagnosis, moderate PD, and moderate CAL, which may also reflect some effect of these systemic conditions on the periodontal status. PMID- 26609696 TI - Effect of Surgical Intervention for Removal of Mandibular Third Molar on Periodontal Healing of Adjacent Mandibular Second Molar: A Systematic Review and Bayesian Network Meta-Analysis. AB - BACKGROUND: The aim of this systematic review is to evaluate and synthesize scientific evidence on the effect of surgical interventions for removal of mandibular third molar (M3M) on periodontal healing of adjacent mandibular second molar (M2M). METHODS: The protocol was registered at PROSPERO (International Prospective Register of Systematic Reviews) as CRD42012003059. Medline, Cochrane, and EMBASE databases were interrogated to identify randomized controlled trials (RCTs) up to December 22, 2014. Patients with M3Ms fully developed, unilaterally or bilaterally impacted, were considered. Outcomes were clinical attachment level gain (CALg) and probing depth reduction (PDr) with a follow-up >= 6 months. Patient-subjective outcomes, such as pain, discomfort, and complications, and financial aspects and chair time, were also explored. A Bayesian network meta analysis model was used to estimate direct and indirect effects and to establish a ranking of treatments. RESULTS: Sixteen RCTs were included and categorized into four groups investigating the following: 1) regenerative/grafting procedures (10 RCTs); 2) flap design (three RCTs); 3) type of suturing (one RCT); and 4) periodontal care of M2M (two RCTs). Guided tissue regeneration (GTR) with resorbable (GTRr) and non-resorbable (GTRnr) membrane and GTRr with anorganic xenograft (GTRr + AX) showed the highest mean ranking for CALg (2.99, 90% credible interval [CrI] = 1 to 5; 2.80, 90% CrI = 1 to 6; and 2.29, 90% CrI = 1 to 6, respectively) and PDr (2.83, 90% CrI = 1 to 5; 2.52, 90% CrI = 1 to 5; and 2.77, 90% CrI = 1 to 6, respectively). GTRr + AX showed the highest probability (Pr) of being the best treatment for CALg (Pr = 45%) and PDr (Pr = 32%). Direct and network quality of evidence were rated from very low to moderate. CONCLUSIONS: To the best of the authors' knowledge, the present review is the first one to evaluate quantitatively and qualitatively the effect of different interventions on periodontal healing distal to the second molar after extraction of the third molar. GTR-based procedures with or without combined grafting therapies provide some adjunctive clinical benefit compared to standard non regenerative/non-grafting procedures. However, the overall low quality of evidence suggests a low degree of confidence and certainty in treatment effects. Evidence on variations of surgical M3M removal techniques based on flap design, type of suturing, and periodontal care of M2M is limited both qualitatively and quantitatively. PMID- 26609697 TI - Periodontal Disease in Individuals With a Genetic Risk of Developing Arthritis and Early Rheumatoid Arthritis: A Cross-Sectional Study. AB - BACKGROUND: Recent consensus emphasizes the importance of studying individuals at risk for rheumatoid arthritis (pre-RA) and those with early RA (eRA). Periodontal tissues have been recently evaluated, but these studies are limited. To evaluate the periodontal condition, immunoglobulin (Ig)G subclasses against Porphyromonas gingivalis in individuals with pre-RA and eRA were compared with controls to establish an association between periodontal infection markers and rheumatic activity. METHODS: Rheumatologic and periodontal condition was evaluated in 119 individuals with pre-RA, 48 patients with eRA, and matched controls. P. gingivalis IgG1 and IgG2 were analyzed. C-reactive protein, erythrocyte sedimentation rate (ESR), rheumatoid factor, anticitrullinated protein antibodies (ACPAs), and RA activity were measured. The groups were compared with McNemar test and paired t-test. Conditional logistic regression was performed for pre-RA confounders, and chi(2) test was used to evaluate periodontal variables and RA activity indices. RESULTS: Pre-RA individuals showed significantly higher levels of plaque index (P = 0.01) and bleeding on probing (P = 0.03) and higher severity of periodontal disease (P = 0.02). Periodontitis was associated with pre-RA (odds ratio, 3.39; 95% confidence interval, 1.64 to 7.01) but not with eRA. In pre-RA, P. gingivalis-specific IgG2 was associated with ACPAs (P = 0.049) and disease severity visual analog scale (P = 0.03). In eRA, IgG2 against P. gingivalis was associated with ESR (P = 0.046) and ACPAs (P = 0.04). P. gingivalis was associated with ACPAs (P = 0.04). CONCLUSIONS: This study shows that individuals with pre-RA have significant inflammatory periodontal involvement. There was a significant association between IgG against P. gingivalis and ACPAs in pre-RA and markers of RA activity in individuals with eRA. PMID- 26609698 TI - Associations Between Salivary Bone Metabolism Markers and Periodontal Breakdown. AB - BACKGROUND: A dual relationship between glycemic status and bone remodeling was suggested recently. The present study aimed to 1) analyze salivary levels of receptor activator for nuclear factor kappa-B ligand (RANKL), osteoprotegerin, osteocalcin, and osteopontin as potential biomarkers of alveolar bone loss and 2) determine whether the glycemic status affects the relationship between bone remodeling markers and periodontal status. METHODS: Salivary levels of RANKL, osteoprotegerin, osteocalcin, osteopontin, and serum glycosylated hemoglobin A1c, insulin, and glucose were analyzed in 220 participants divided into four groups according to their periodontal health status: 1) 79 participants had at least 14 teeth with probing depth (PD) >=4 mm (generalized periodontitis [GP]); 2) 65 participants had either two or seven teeth with PD >=4 mm (two groups of localized periodontitis [LP1 and LP2, respectively]); and 3) 76 participants had no teeth with PD >=4 mm (non-periodontitis control group). RESULTS: Salivary concentrations of RANKL, osteocalcin, and osteopontin were higher, and osteoprotegerin was lower in females than in males. Salivary osteoprotegerin concentrations were higher in the GP and LP2 groups than in the control group, whereas RANKL, osteocalcin, and osteopontin were not related with periodontal status. Salivary osteopontin correlated positively with serum and salivary insulin. The association observed between increased osteoprotegerin concentrations and periodontitis was lost after salivary insulin was included into the analyses as a confounding factor. CONCLUSIONS: Salivary concentrations of bone markers are either affected by glycemic status or detected at very low levels. These factors hinder their use as salivary biomarkers of periodontitis. PMID- 26609699 TI - Comparison of innate and Th1-type host immune responses in Oesophagostomum dentatum and Trichuris suis infections in pigs. AB - This study investigated the details of the innate and Th1/Treg-type-associated host immune responses in Trichuris suis and Oesophagostomum dentatum mono- and co infected pigs and in vitro in stimulated porcine dendritic cell cultures. Forty eight pigs were allocated into a 2-factorial design with two groups trickle inoculated with 10 T. suis eggs/kg/day (Group T) or 20 O. dentatum L3/kg/day (O). Another group (OT) was infected with both parasites. Group C remained uninfected. Expression of innate and Th1/Treg-cell-associated genes in gut mucosa and associated lymph nodes was determined by qPCR at necropsy day 35 and 71. Gene expression showed suppressed/inhibited Th1 and Treg-type immune reactions, in accordance with previous findings of a predominant Th2-type immune response to both nematodes. The in vitro part examined the production of TNF-alpha in porcine dendritic cells (DC) exposed to T. suis and/or O. dentatum excretory/secretory (E/S) products. Further, binding capacity and structure of E/S products were characterized. Glycan and lectin-binding capacity were generally lower in O. dentatum E/S products compared to T. suis which may explain the earlier found weaker Th2 response to the former. Surprisingly, O. dentatum E/S products induced a significant (P < 0.0001) increase in TNF-alpha DC production, potentially indicating a new mode of helminth-host immune response interaction. PMID- 26609700 TI - Demoralization and Response to Psychotherapy: A Pilot Study Comparing the Sequential Combination of Cognitive-Behavioral Therapy and Well-Being Therapy with Clinical Management in Cyclothymic Disorder. PMID- 26609702 TI - Examining the Application of the DC-IA-A Diagnostic Criteria for Internet Addiction Disorder in At-Risk College Students. AB - Internet addiction disorder is a relatively new condition, and the criteria for its diagnosis have been developed only over the last several years. The criteria for Internet addiction remain controversial. We strive to further elucidate the clinical validity of the diagnostic criteria for Internet addiction. To test items of the diagnostic criteria for Internet addiction among adolescents, we conducted a clinical interview study of college students based on longitudinal data on their risky use of the Internet. Forty-one high-risk cases were selected from a 3-year 5-time point longitudinal survey of 716 college freshmen. We examined disputes relevant to symptoms and impairment in the DC-IA-A (Diagnostic Criteria for Internet Addiction among Taiwanese Adolescents). Of the 41 cases, 21 were diagnosed with Internet addiction via a psychiatric interview. In the Internet addiction disorder group, 23.8% of cases had a diagnosis of depression, whereas only 15.0% of the cases in the non-Internet addiction group had a diagnosis of depression. Two major criteria (A8 and A3) had low incidences in these high-risk college students and thus did not help provide a differential diagnosis between the groups. We suggest that A8, 'excessive effort spent on activities necessary to obtain access to the Internet', should be omitted, and that A3, 'tolerance: a marked increase in the duration of Internet use needed to achieve satisfaction', should be modified. A1 and A9 should be discussed regarding their role in the diagnosis of Internet addiction disorder. Additional well-designed studies examining the diagnostic criteria and the relationship between factors are needed. PMID- 26609701 TI - Skewed X Inactivation in Women Carrying the FMR1 Premutation and Its Relation with Fragile-X-Associated Tremor/Ataxia Syndrome. AB - BACKGROUND: Fragile-X-associated tremor/ataxia syndrome (FXTAS) is a late-onset multisystem neurological disorder characterized by intention tremor and cerebellar ataxia. OBJECTIVE: We hypothesized that in FMR1 premutation females with FXTAS, a normal X chromosome might more frequently be inactivated; therefore, the aim of this study was to determine the relationship between skewed X chromosome inactivation (XCI) and FXTAS. METHODS: We studied the XCI patterns of cases of FMR1 premutation in 10 women with FXTAS and 21 without FXTAS. RESULTS: The distribution of XCI patterns in the FXTAS and no-FXTAS groups showed differences regarding the allele presenting severe skewed XCI. In the FXTAS group, all cases preferentially inactivated the non-expanded X chromosome, whereas in the no-FXTAS group, all inactivated the expanded X chromosome. Nevertheless, no significant differences were found on comparing XCI frequencies among FMR1 premutation carriers with and without FXTAS. As expected, we found statistically significant differences in the skewed XCI on comparing FMR1 premutation women and controls. CONCLUSION: Although the reduced sample size and blood XCI patterns are two limitations of this study, our results suggest that the skewed XCI of the normal FMR1 allele may be a risk factor for the development of FXTAS. Furthermore, our findings also support the protective effect of the expression of a normal FMR1 allele. PMID- 26609703 TI - Frequency, Clinical Features and Factors Associated with Pouchitis after Proctocolectomy with Ileo-Pouch-Anal Anastomosis in Patients with Ulcerative Colitis: A Latin-American Country Retrospective-Cohort Study. AB - BACKGROUND: Pouchitis is the most common complication of proctocolectomy with ileo-pouch-anal anastomosis (IPAA) for ulcerative colitis (UC). No previous study in Mexico has evaluated this issue; our aim was to evaluate its frequency, clinical characteristics and factors associated with its presence in Mexican patients with UC and IPAA. METHODS: Retrospective-cohort study including 70 patients with histopathological diagnosis of UC and IPAA between 1983 and 2014 from inflammatory bowel disease clinic of a tertiary care center. The statistical analysis used descriptive statistics, chi-square and Fisher's exact test for categorical variables and Student's t test for numeric variables. Univariate analysis was performed to identify the factors associated. RESULTS: Patients presenting with pouchitis accounted for 48.6%. From the 34 cases, 12 (35.3%) had inactive pouchitis; 7 (20.6%) active acute pouchitis; 15 (44.1%) chronic active pouchitis. On average, pouchitis occurred 5.37 years after IPPA. Factors probably associated with its occurrence were the presence of autoimmune concomitant diseases (ACDs; p = 0.06, OR 4.40, 95% CI 0.84-22.9) and extra-intestinal manifestations (EIMs; p = 0.05, OR 2.53, 95% CI 0.96-6.64), which was also probably associated with chronic active pouchitis (p = 0.06, OR 0.31, 95% CI 0.07 1.31). CONCLUSIONS: The frequency of pouchitis is high in Mexican UC patients after IPAA. ACDs and EIMs were probably associated with its development. PMID- 26609704 TI - Fostering Social Cognition through an Imitation- and Synchronization-Based Dance/Movement Intervention in Adults with Autism Spectrum Disorder: A Controlled Proof-of-Concept Study. AB - BACKGROUND: Since social cognition is impaired in individuals with autism spectrum disorder (ASD), this study aimed at establishing the efficacy of a newly developed imitation- and synchronization-based dance/movement intervention (SI DMI) in fostering emotion inference and empathic feelings (emotional reaction to feelings of others) in adults with high-functioning ASD. METHODS: Fifty-five adults with ASD (IQ >=85) who were blinded to the aim of the study were assigned to receive either 10 weeks of a dance/movement intervention focusing on interpersonal movement imitation and synchronization (SI-DMI, n = 27) or a control movement intervention (CMI, n = 24) focusing on individual motor coordination (2 participants from each group declined before baseline testing). The primary outcome measure was the objective Multifaceted Empathy Test targeting emotion inference and empathic feelings. Secondary outcomes were scores on the self-rated Interpersonal Reactivity Index. The well-established automatic imitation task and synchronization finger-tapping task were used to quantify effects on imitation and synchronization functions, complemented by the more naturalistic Assessment of Spontaneous Interaction in Movement. RESULTS: Intention-to-treat analyses revealed that from baseline to 3 months, patients treated with SI-DMI showed a significantly larger improvement in emotion inference (d = 0.58), but not empathic feelings, than those treated with CMI (d = -0.04). On the close generalization level, SI-DMI increased synchronization skills and imitation tendencies, as well as whole-body imitation/synchronization and movement reciprocity/dialogue, compared to CMI. CONCLUSIONS: SI-DMI can be successful in promoting emotion inference in adults with ASD and warrants further investigation. PMID- 26609705 TI - Low molecular weight heparin in one or two doses for the initial treatment of venous thromboembolic disease? AB - The preferred dosification for low molecular weight heparins is in two doses for most patients with venous thromboembolic disease. A daily dose would make treatment simpler, less expensive and more comfortable while retaining a similar benefit and safety. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified two systematic reviews including five randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded it is not clear whether the risk of recurrence differs between the two alternatives because the certainty of the evidence is very low, and that administering low molecular weight heparin in two doses might be associated to little or no difference in the risk of major bleeding and mortality. PMID- 26609706 TI - Selective Detection of Single-Stranded DNA Molecules Using a Glass Nanocapillary Functionalized with DNA. AB - We describe glass nanocapillaries with single-stranded DNA molecules (ssDNA) covalently attached to the capillary surface. These DNA-functionalized nanocapillaries selectively facilitate the translocation of target ssDNA that is complementary to the probe ssDNA. In addition, the complementary target ssDNA exhibits an event duration time longer than that of the noncomplementary target ssDNA. The temperature dependence measurements of translocation events show that the longer duration time is a result of an interaction between probe and target ssDNA and is dependent on the base pair binding strength. These results demonstrate that single-base mismatch transport selectivity can be achieved using the DNA-functionalized nanocapillaries. PMID- 26609707 TI - The Particle-Hole Map: A Computational Tool To Visualize Electronic Excitations. AB - We introduce the particle-hole map (PHM), which is a visualization tool to analyze electronic excitations in molecules in the time or frequency domain, to be used in conjunction with time-dependent density-functional theory (TDDFT) or other ab initio methods. The purpose of the PHM is to give detailed insight into electronic excitation processes that is not obtainable from local visualization methods, such as transition densities, density differences, or natural transition orbitals. The PHM is defined as a nonlocal function of two spatial variables and provides information about the origins, destinations, and connections of charge fluctuations during an excitation process; it is particularly valuable to analyze charge-transfer excitonic processes. In contrast with the transition density matrix, the PHM has a statistical interpretation involving joint probabilities of individual states and their transitions; it satisfies several sum rules and exact conditions, and it is easier to read and interpret. We discuss and illustrate the properties of the PHM and give several examples and applications to excitations in one-dimensional model systems, in a hydrogen chain, and in a benzothiadiazole (BT)-based molecule. PMID- 26609708 TI - Sulfosuccinate and Sulfocarballylate Surfactants As Charge Control Additives in Nonpolar Solvents. AB - A series of eight sodium sulfonic acid surfactants with differently branched tails (four double-chain sulfosuccinates and four triple-chain sulfocarballylates) were studied as charging agents for sterically stabilized poly(methyl methacrylate) (PMMA) latexes in dodecane. Tail branching was found to have no significant effect on the electrophoretic mobility of the latexes, but the number of tails was found to influence the electrophoretic mobility. Triple chain, sulfocarballylate surfactants were found to be more effective. Several possible origins of this observation were explored by comparing sodium dioctylsulfosuccinate (AOT1) and sodium trioctylsulfocarballylate (TC1) using identical approaches: the inverse micelle size, the propensity for ion dissociation, the electrical conductivity, the electrokinetic or zeta potential, and contrast-variation small-angle neutron scattering. The most likely origin of the increased ability of TC1 to charge PMMA latexes is a larger number of inverse micelles. These experiments demonstrate a small molecular variation that can be made to influence the ability of surfactants to charge particles in nonpolar solvents, and modifying molecular structure is a promising approach to developing more effective charging agents. PMID- 26609709 TI - Comparison of spin dynamics and magnetic properties in antiferromagnetic closed and open molecular Cr-based rings. AB - We present magnetization and (1)H nuclear magnetic resonance (NMR) measurements performed in both closed Cr8 and open Cr8Zn antiferromagnetic molecular rings in the temperature range 1.65 < T < 300 K at different external magnetic fields. The magnetization measurements on Cr8Zn are consistent with a small decrease of the exchange constant J(Cr-Cr) and a much smaller gap between the singlet ground state and the first magnetic excited state when compared with the same properties of the closed ring Cr8, in agreement with previous inelastic neutron scattering results. The temperature dependence of the (1)H NMR nuclear spin lattice relaxation rate (NSLR), 1/T1(T), was found to be similar in both open and closed rings with a magnetic field dependent peak centered at a temperature of the order of the corresponding exchange constant J(Cr-Cr). Such main peak in the NSLR could be fitted with a single correlation frequency omega(c1) as in most molecular magnets. At low temperature T < 4 K, a new feature not observed in previous NMR measurements on antiferromagnetic rings and consisting in a smaller peak of 1/T1(T) which is well resolved only in Cr8Zn, was singled out. This low-T peak indicates the presence of a second correlation frequency omega(c2) of the magnetization, found to be quite different between the two rings and thus possibly reflecting the different low temperature level structure associated with the different spin topology. The presence of omega(c2) is confirmed by the NMR spin-spin relaxation rate enhancement, which generates a two-steps wipe-out effect of the NMR signal intensity. PMID- 26609710 TI - Efficient Diffuse Basis Sets: cc-pVxZ+ and maug-cc-pVxZ. AB - We combine the diffuse basis functions from the 6-31+G basis set of Pople and co workers with the correlation-consistent basis sets of Dunning and co-workers. In both wave function and density functional calculations, the resulting basis sets reduce the basis set superposition error almost as much as the augmented correlation-consistent basis sets, although they are much smaller. In addition, in density functional calculations the new basis sets, called cc-pVxZ+ where x = D, T, Q, ..., or x = D+d, T+d, Q+d, ..., give very similar energetic predictions to the much larger aug-cc-pVxZ basis sets. However, energetics calculated from correlated wave function calculations are more slowly convergent with respect to the addition of diffuse functions. We also examined basis sets with the same number and type of functions as the cc-pVxZ+ sets but using the diffuse exponents of the aug-cc-pVxZ basis sets and found very similar performance to cc-pVxZ+; these basis sets are called minimally augmented cc-pVxZ, which we abbreviate as maug-cc-pVxZ. PMID- 26609711 TI - Mobile Block Hessian Approach with Adjoined Blocks: An Efficient Approach for the Calculation of Frequencies in Macromolecules. AB - In an earlier work, the authors developed a new method, the mobile block Hessian (MBH) approach, to accurately calculate vibrational modes for partially optimized molecular structures [ J. Chem. Phys. 2007 , 126 ( 22 ), 224102. ]. It is based on the introduction of blocks, consisting of groups of atoms, that can move as rigid bodies. The internal geometry of the blocks need not correspond to an overall optimization state of the total molecular structure. The standard MBH approach considers free blocks with six degrees of freedom. In the extended MBH approach introduced herein, the blocks can be connected by one or two adjoining atoms, which further reduces the number of degrees of freedom. The new approach paves the way for the normal-mode analysis of biomolecules such as proteins. It rests on the hypothesis that low-frequency modes of proteins can be described as pure rigid-body motions of blocks of consecutive amino acid residues. The method is validated for a series of small molecules and further applied to alanine dipeptide as a prototype to describe vibrational interactions between two peptide units; to crambin, a small protein with 46 amino acid residues; and to ICE/caspase-1, which contains 518 amino acid residues. PMID- 26609712 TI - Neutral and Anionic Gold Decamers: Planar Structure with Unusual Spatial Charge Spin Separation. AB - We have investigated the issue of two-dimensional (2D) versus three-dimensional (3D) structures for neutral-state Au10 and clarified the lowest-energy structure among a few 2D Au10(-) isomers. Though almost all previous works were based on density functional theory (DFT), we here carried out not only extensive DFT calculations but also high levels of ab initio calculations of Moller-Plesset second order perturbation theory (MP2), and coupled cluster theory with single and double excitations (CCSD) including perturbative triple excitations [CCSD(T)]. While DFT favors 2D structures, MP2 and CCSD(T) favor 3D structures for moderate-sized basis sets. However, we note that the basis-set superposition error (BSSE) corrections make the ab intio results favor 2D structures too. The near-degeneracy (driven by relativistic effects) of 5d and 6s orbitals of gold helps stabilize acute apex gold atoms, resulting in 2D structures. The planar triangular structures of a local minimum Au10 (triplet) and the global minimum Au10(-) show remarkable spatial charge-spin separation due to their singly occupied molecular orbital(s). By the same reason, Au10(-) shows much larger vertical detachment energy than other even-numbered gold cluster anions. PMID- 26609713 TI - Quartic-Scaling Analytical Gradient of Quasidegenerate Scaled Opposite Spin Second-Order Perturbation Corrections to Single Excitation Configuration Interaction. AB - Quasidegenerate scaled second-order perturbation correction to single excitation configuration interaction (SOS-CIS(D0)) is a viable method that can describe excited-state potential energy surfaces of various chemical systems both reliably and efficiently [J. Chem. Phys. 2008, 128, 164106]. In this work, its analytical gradient theory is developed and implemented into an efficient quartic-scaling algorithm. This low order scaling, as opposed to the traditional quintic scaling of various second-order perturbation methods, is attained by using the resolution of-the-identity approximation and the Laplace transform. The efficiency of the method is demonstrated by calculating the excited-state gradients of molecules with varying sizes. The proposed gradient method will thus be useful in studying various chemical systems, ranging from finding the optimized stable geometry on the excited surface to elucidating interesting excited-state dynamics around the avoided crossing region. PMID- 26609714 TI - Conformational Stability and Spin States of Cobalt(II) Acetylacetonate: CASPT2 and DFT Study. AB - Electronic structure and conformation of bis(acetylacetonate) cobalt(II), Co(acac)2, a prototypical mediator in controlled radical polymerization of olefins, is reinvestigated. The ab initio multiconfigurational CASSCF/CASPT2 method is used to resolve the doubts stemming from density functional theory results. We assign the quartet ground state for a single molecule and point at tetrahedral conformation as the preferred one. Several density functionals are tested against the ab initio calculations, and their performance is assessed. The strength of intermolecular interactions in the crystal structure composed of square-planar Co(acac)2 molecules ( Burgess , J. ; et al. Acta Crystallogr. 2000 , C56 , 649 - 650 ) is estimated to be sufficient for their planarization (suggested by Matyjaszewski , K. ; et al. Chem.-Eur. J. 2007 , 13 , 2480 - 2492 ). PMID- 26609715 TI - Molecular Orbital-Averaged Fukui Function for the Reactivity Description of Alkaline Earth Metal Oxide Clusters. AB - This paper concerns the accurate description of the surface oxygen reactivity for the alkaline earth metal oxides using local DFT-based reactivity indices. The cumbersome periodic boundary conditions calculations, typically required to probe the reactivity of such systems, are avoided by the construction of a reliable cluster model. The standard Fukui function concept of conceptual DFT is generalized to include the contribution from not only the HOMO and the LUMO but also from other chemically relevant orbitals. Results prove that this approach is a valuable and straightforward alternative to the reactivity calculation of extended systems. PMID- 26609716 TI - Energies, Geometries, and Charge Distributions of Zn Molecules, Clusters, and Biocenters from Coupled Cluster, Density Functional, and Neglect of Diatomic Differential Overlap Models. AB - We present benchmark databases of Zn-ligand bond distances, bond angles, dipole moments, and bond dissociation energies for Zn-containing small molecules and Zn coordination compounds with H, CH3, C2H5, NH3, O, OH, H2O, F, Cl, S, and SCH3 ligands. The test set also includes clusters with Zn-Zn bonds. In addition, we calculated dipole moments and binding energies for Zn centers in coordination environments taken from zinc metalloenzyme X-ray structures, representing both structural and catalytic zinc centers. The benchmark values are based on relativistic-core coupled cluster calculations. These benchmark calculations are used to test the predictions of four density functionals, namely B3LYP and the more recently developed M05-2X, M06, and M06-2X levels of theory, and six semiempirical methods, including neglect of diatomic differential overlap (NDDO) calculations incorporating the new PM3 parameter set for Zn called ZnB, developed by Brothers and co-workers, and the recent PM6 parametrization of Stewart. We found that the best DFT method to reproduce dipole moments and dissociation energies of our Zn compound database is M05-2X, which is consistent with a previous study employing a much smaller and less diverse database and a much larger set of density functionals. Here we show that M05-2X geometries and single point coupled cluster calculations with M05-2X geometries can also be used as benchmarks for larger compounds, where coupled cluster optimization is impractical, and in particular we use this strategy to extend the geometry, binding energy, and dipole moment databases to additional molecules, and we extend the tests involving crystal-site coordination compounds to two additional proteins. We find that the most predictive NDDO methods for our training set are PM3 and MNDO/d. Notably, we also find large errors in B3LYP for the coordination compounds based on experimental X-ray geometries. PMID- 26609717 TI - Theoretical Study of BeN Linear Chains: Optimized Geometries and Harmonic Frequencies. AB - The electronic structure of linear beryllium chains has been theoretically studied at an ab initio level. By using a CAS-SCF approach, geometries have been optimized and harmonic frequencies computed. The optimized geometries present almost equal bond lengths, while all the harmonic frequencies are real. This fact indicates the presence of a local minimum, at this level of theory, having a linear geometry. The energy splitting between the singlet ground state, (1)Sigmag, and the quasi-degenerated excited triplet, (3)Sigmau, has been computed at CAS-SCF and MR-CI level. It was found that the splitting goes exponentially to zero as the number of atoms in the chain is increased. PMID- 26609718 TI - Confined But-2-ene Catalytic Isomerization Inside H-ZSM-5 Models: A DFT Study. AB - The isomerization of cis-but-2-ene to trans-but-2-ene within a 22T H-ZSM-5 zeolite model, also in the presence of two adsorbed Pd atoms, has been studied by DFT calculations. The results obtained allow us to state that the cis/trans but-2 ene isomerization can easily proceed inside unsupported zeolite cavities. In this case, differently than in the gas phase reaction, the trans-but-2-ene is less stable than the cis-but-2-ene, when adsorbed on the zeolite inner surface. Excluding the adsorption-desorption steps, the isomerization process involves two intermediates and three transition states, whose energy content is always very low with respect to that of reagents and intermediate species. The reaction is in principle allowed also in the presence of two Pd atoms embedded inside the zeolite cavity. However, strong H-Pd interactions seem to cause higher activation energies along the formation of the involved intermediates and transition states. To evaluate the confining effects of the zeolite room on the cis/trans isomerization process, the latter has been also analyzed on protonated (Pd2H(+)) and unprotonated (Pd2) bare palladium fragments at different multiplicity states. The but-2-ene adsorption on the considered systems and the mutual influence occurring between the metal atoms and the hydrogen acidic sites at different multiplicity states have also been taken into consideration. PMID- 26609719 TI - Theoretical Study of the Reaction Mechanism of Streptomyces coelicolor Type II Dehydroquinase. AB - The reaction mechanism of a type II dehydroquinase (DHQase) from Streptomyces coelicolor was investigated using molecular dynamics simulation and density functional theory (DFT) calculations. DHQase catalyzes the elimination of a water molecule from dehydroquinate (DHQ), a key step in the biosynthesis of aromatic amino acids in bacteria, fungi, and plants. In the DFT calculations, 10 models, containing up to 230 atoms, were used to investigate different proposals for the reaction mechanism, suggested on the basis of crystal structures and kinetic data. Probing the flexibility of the active site, molecular dynamics simulation reveals that deprotonated Tyr28 can act as the base that catalyzes the first reaction step, the proton abstraction of the pro-S proton at C2 of DHQ, and formation of the enolate intermediate. The computed barrier for the first transition state (TS1), 13-15 kcal/mol, is only slightly affected by the active site model used and is in good agreement with the corresponding experimental barrier of 13.4 kcal/mol for the rate-determining step. The previously proposed enol form of the intermediate is found to be significantly higher in energy than the enolate form and is thus thermodynamically not competitive. In the second and final reaction step, protonation of the hydroxyl group at C1 by His106 followed by water elimination, there is a substantial buildup of dipole moment due to the net transfer of a proton from His106 to Tyr28. A barrier for the second transition state (TS2) that fits well with the corresponding experimental barrier could only be found if the buildup of dipole moment is at least partly compensated during the second reaction step. We speculate that this could be facilitated by regeneration of the Tyr28 anion or by proton transfer to the vicinity of His106 before TS2 is reached. A revised mechanism for type II DHQase is discussed in light of the results of the present calculations. PMID- 26609720 TI - CBS-QB3 + VTST Study of Methyl N-Methylcarbamate + OH Gas-Phase Reaction: Mechanism, Kinetics, and Branching Ratios. AB - Different paths of reaction have been modeled, at high level of theory, accounting for the possible atmospheric fate of methyl N-methylcarbamate (MMC). The OH hydrogen abstractions from the methyl groups are predicted to account for almost 100% of the MMC + OH gas-phase reaction. The H abstraction from the methyl group at the N side of MMC was found to be the main path of reaction, with contributions to the overall reaction from 96% at 260 K to 89.2% at 400 K. Hydrogen abstractions from the other methyl group were identified as a secondary, but significant path. The Arrhenius activation energy, in the temperature range 260-400 K, was found to be close to zero, but slightly negative. The proposed value is (-0.10 +/- 0.02) kcal/mol. The excellent agreement with the scarce experimental data available supports the reliability of the data reported here for the first time. Different IVTST-M-H/G schemes were tested for dynamic calculations. According to our results, including the Hessians and gradients, as few as four nonstationary points along the MEP is sufficient to achieve an excellent accuracy, provided that the data for these few points were obtained from high-quality levels of theory. PMID- 26609721 TI - Ab Initio Molecular Dynamics Simulations of the Infrared Spectra of H3O2(-) and D3O2(.). AB - We present the infrared spectra of H3O2(-) and D3O2(-) calculated using MP2 direct molecular dynamics approach at temperatures of 100 and 300 K. The spectral peaks were assigned using the normal-mode analysis, instantaneous normal-mode analysis, isotopic substitution, polarized infrared absorptions, and analysis of the position-position correlation function. Our results predict the bridging hydrogen stretch between 600 and 900 cm(-1) and bridging hydrogen bend vibrations between 1250 and 1650 cm(-1). We also examine two DFT methods (B3PW91 and B3LYP) and report on the differences between them and the MP2 spectra. PMID- 26609722 TI - Influence of Adsorbate-Free Atoms on Delta-XANES Signatures. AB - The use of differential X-ray Absorption Near Edge Spectroscopy (Delta-XANES) for analysis of site specific adsorption on metallic electrodes relies on theoretical Delta-XANES signatures for analysis of experimental Delta-XANES fingerprints. A simple model, currently used in the analysis, considers changes in X-ray absorption properties of adsorbing atoms only. This model has been extended to include changes in X-ray absorption for other atoms of the same type that remain adsorbate-free. Configurational averaging has been applied to calculate difference spectra of a Pt6 cluster with an oxygen atom adsorbed at different sites. The extended theory shows that contribution of the adsorbate-free atoms might become significant as it affects the shape profiles of the theoretical signatures. The effect, most prominent at the absorption edge energy, is interpreted in terms of change in the electronic structure of the cluster due to oxygen adsorption. In addition to model dependence of the theoretical signatures, challenges to the application of Delta-XANES to the experimentally obtained fingerprints are discussed. PMID- 26609723 TI - Calculation of Hypershielding Contribution to Isotropic Nitrogen Shielding in Strong Magnetic Fields. PMID- 26609724 TI - Adsorption of Ethylene, Vinyl, Acetic Acid, and Acetate Species on PdAu(111) and PdAu(100) Surface Alloys: A Cluster Model Study. AB - The adsorption properties on PdAu surface alloys of ethylene and acetic acid molecules along with their derived vinyl and acetate surface species have been investigated by density functional theory calculations. Large clusters have been used to model second-neighbor Pd monomer pair ensembles on PdAu(100) and PdAu(111) surface alloys. Ethylene and acetic acid are weakly bonded to the Pd monomers, while vinyl and acetate are strongly bonded to both Pd and Au atoms being very stable surface species. The ligand effect of the gold atoms surrounding the Pd monomers has been shown to be stronger in the more dense PdAu(111) surface alloy. Cluster model results are in good agreement with experimental evidence providing important insight on the adsorption bonding modes, the assignment of the infrared features, and the preferred adsorption sites. PMID- 26609725 TI - Electro-Optical Parameters for Computation of Nonresonance Raman Scattering Intensities of Peptides. AB - A set of electro-optical parameters (EOPs) of cylindrical zero-order bond polarizability model (BPM) for chemical bonds found in peptides was obtained from the results of quantum-chemical computations. The calculation of the polarizability tensors and the Raman scattering activities of four test molecules (N-methylacetamide, N,N-dimethylacetamide, dialanine, and diglycine) has shown that the BPM calculated quantities are in good agreement with the reference data obtained in experiments or derived by quantum-chemical calculations. The mean molecular polarizabilities are reproduced with the maximum relative error of 1.6%. A good agreement was obtained for the Raman activity of stretching vibrations, whereas a limited performance of the EOPs was found for the vibrational modes with a significant contribution of the bending internal coordinates involving H atoms. The origins of the discrepancies are analyzed, and the ways of improvement of the model performance are discussed. PMID- 26609726 TI - Computer Simulations of Peptides from the p53 DNA Binding Domain. AB - We have studied the dynamics and thermodynamics of two of the four evolutionarily conserved segments from the p53 DNA binding domain, using molecular dynamics and replica exchange simulations. These two regions contain well-defined elements of secondary structure (a beta hairpin for region II and an alpha helix for region V) and bind to DNA in the intact protein. They are also mutational hot spots. The goal of our study was to determine the stability and folding propensity of these peptides in isolation. We used three force fields and solvent models (CHARMM19 with EEF1, CHARMM27 with GBMV, GROMOS96 with SPC). The predicted stability, folding propensity, and secondary structures depend upon the potential. Secondary structure predictors identify helical propensity for region II, in agreement with one of the force fields (CHARMM/GBMV). However, the other two potentials favor beta structure for this peptide, although the conformations may differ from the crystal. For region V secondary structure predictions are unclear. Only one force field (CHARMM/GBMV) produces low-lying free energy minima that retain some of the alpha helical structure from the crystal structure. The other two potentials appear to favor beta structure for this peptide. PMID- 26609727 TI - Evidence for Stabilization of DNA/RNA-Protein Complexes Arising from Nucleobase Amino Acid Stacking and T-Shaped Interactions. AB - The stacking and T-shaped interactions between the natural DNA or RNA nucleobases (adenine, cytosine, guanine, thymine, uracil) and all aromatic amino acids (histidine, phenylalanine, tyrosine, tryptophan) were investigated using ab initio quantum mechanical calculations. We characterized the potential energy surface of nucleobase-amino acid dimers using the MP2/6-31G*(0.25) method. The stabilization energies in dimers with the strongest interactions were further examined at the CCSD(T)/CBS level of theory. Results at the highest level of theory possible for these systems indicate that both stacking and T-shaped interactions are very close in magnitude to biologically relevant hydrogen bonds. Additionally, T-shaped interactions are as strong, if not stronger, than the corresponding stacking interactions. Our systematic consideration of the interaction energies in 485 possible combinations of monomers shows that a variety of these contacts are essential when considering the role of aromatic amino acids in the binding of proteins to DNA or RNA. This work also illustrates how our calculated binding strengths can be used by biochemists to estimate the magnitude of these noncovalent interactions in a variety of DNA/RNA-protein active sites. PMID- 26609728 TI - Reduced Catalytic Activity of P450 2A6 Mutants with Coumarin: A Computational Investigation. AB - Human cytochrome P450 2A6 is the major enzyme to catalyze coumarin 7 hydroxylation, and this enzyme also plays an important role in the metabolism of nicotine and other tobacco-specific compounds. Recent experimental data showed that the N297S and A481T mutants of P450 2A6 decreased the catalytic activity toward coumarin by about 4-fold and 10-fold, respectively. These two mutants also had about 30-fold decrease in binding affinity for coumarin when compared to its wild type. At present, however, how the mutations affect the enzymatic activity and/or the substrate binding remains unclear. In this study, a combination of molecular docking and molecular dynamics (MD) simulation was employed to investigate the above question. Our results demonstrated that the N297S mutation altered the hydrogen-bonding network mediated by a water molecule between the B' C loop and the I helix and thus a shift of the B' helix/B'-C loop region, whereas the A481T mutation triggered the conformational changes of its adjacent residues including Phe209 and Phe280 via an indirect manner to affect the substrate binding. However, the mutations did not significantly alter the substrate binding orientation because the only polar residue 297 in the active site provided the hydrogen-bonding donor to guide the binding of coumarin. Both mutations perturbed the shape of "Phe-cluster" in the active site and thus weakened the interactions with coumarin. The calculated binding free energies were in agreement with the relative potency of the experimental binding affinities. PMID- 26609729 TI - Can the Formation of Pharmaceutical Cocrystals Be Computationally Predicted? 2. Crystal Structure Prediction. AB - We report a multistage lattice energy minimization methodology for generating stable packing arrangements of cocrystals containing flexible molecules. In the first approximation, the intermolecular electrostatic interactions are modeled with atomic charges and the molecular deformation energy is interpolated over a set of precomputed quantum mechanical values. At subsequent stages, the accuracy is improved by first using analytically rotated and then conformation-dependent multipole moments, computed from the isolated-molecule charge density, and "on the-fly" quantum mechanical calculations to compute the intramolecular deformation energy. This multistage approach increases the efficiency of the search and establishes the molecule-dependent error due to the atomic charge representation of the charge density and the neglect of the conformational dependence of atomic multipole moments. The methodology is used to study the lattice energy landscapes of the cocrystals of 4-aminobenzoic acid with 2,2' bipyridine and 4-nitrophenylacetic acid, as well as the single-component crystals. All single-component, experimentally determined crystal structures within the scope of the search were found at, or very close to, the global minimum. The experimental cocrystal with 2,2'-bipyridine is also predicted to be among the most stable packing arrangements. On the contrary, the lattice energy landscape of the cocrystal with 4-nitrophenylacetic acid contains several low energy structures that are more stable than the experimentally observed form and have different hydrogen bonding motifs. Overall, the methodology can provide worthwhile crystal energy landscapes for multicomponent organic solids and thereby contribute to understanding cocrystal formation. PMID- 26609730 TI - Epileptic spasms: a previously unreported manifestation of WDR45 gene mutation. AB - WDR45 mutations cause neurodegeneration with brain iron accumulation, usually presenting with early childhood developmental delay and followed by early adulthood extrapyramidal symptoms. Although various seizure types may occur, epileptic spasms have not been reported for this disease. Our patient initially developed a prolonged, focal-onset seizure at three months of age and was subsequently noted to have psychomotor delay. At 11 months of age, she developed epileptic spasms. Her EEG showed hypsarrhythmia. An extensive neurogenetic workup and brain MRI, revealing normal data, ruled out other detectable causes of epileptic spasms. Whole-exome sequencing revealed a de novo, heterozygous deleterious mutation c.400C>T (p.R13X) in WDR45, previously reported to be disease-causing and associated with early childhood global developmental delay and seizures other than epileptic spasms. We conclude that WDR45 mutations should be considered as a possible aetiology in infants with early-onset focal seizures and/or in otherwise undiagnosed cases of epileptic spasms. PMID- 26609731 TI - An atrial fibrosis-based approach for atrial fibrillation ablation. AB - Since the emergence of atrial fibrillation (AF) ablation as a reliable method of restoring sinus rhythm, various approaches have been used to improve the efficacy while maximizing the safety of ablation. A major hurdle to optimizing outcomes for AF ablation has been the failure to recognize that the substrate of the individual patient plays a significant role in optimizing AF treatment. Using delayed-enhancement MRI for the detection of left atrial fibrosis, our group has been able to correlate these structural remodeling changes to outcomes of stroke, AF recurrence and congestive heart failure. This has provided us with information to optimize care of our AF patients based on screening for a fibrotic atrial cardiomyopathy, for which AF is the arrhythmic manifestation. By employing an MRI guided approach for AF ablation, we have been able to optimize AF management and enhance the delivery of personalized medicine for our patients. PMID- 26609732 TI - Pure cerebellar ataxia linked to large C9orf72 repeat expansion. PMID- 26609733 TI - Highly respirable dry powder inhalable formulation of voriconazole with enhanced pulmonary bioavailability. AB - OBJECTIVE: To develop and characterize a highly respirable dry powder inhalable formulation of voriconazole (VRZ). METHODS: Powders were prepared by spray drying aqueous/alcohol solutions. Formulations were characterized in terms of particle size, morphology, thermal, moisture responses and aerosolization performance. Optimized powder was deposited onto an air-interface Calu-3 model to assess their uptake across Calu-3 lung epithelia. Optimized formulation was evaluated for stability (drug content and aerosol performance) for 3 months. Additionally, Calu 3 cell viability, lung bioavailability and tissue distribution of optimized formulation were evaluated. RESULTS: Particle size and aerosol performance of dry powder containing 80% w/w VRZ and 20% w/w leucine was appropriate for inhalation therapy. Optimized formulation showed irregular morphology, crystalline nature, low moisture sensitivity and was stable for 3 months at room temperature. Leucine did not alter the transport kinetics of VRZ, as evaluated by air-interface Calu-3 model. Formulation was non-cytotoxic to pulmonary epithelial cells. Moreover, lung bioavailability and tissue distribution studies in murine model clearly showed that VRZ dry powder inhalable formulation has potential to enhance therapeutic efficacy at the pulmonary infection site whilst minimizing systemic exposure and related toxicity. CONCLUSION: This study supports the potential of inhaled dry powder VRZ for the treatment of fungal infections. PMID- 26609734 TI - Increase in use of protective earplugs by Rock and Roll concert attendees when provided for free at concert venues. AB - OBJECTIVE: To determine the prevalence of hearing protection use among attendees of Rock and Roll concerts at baseline and in concerts where earplugs are provided for free at concert venue entrances. DESIGN: Six concerts performed at two music venues in Toronto, Canada were evaluated. Study personnel observed and recorded the use of hearing protection at three concerts where no earplugs were distributed, and three concerts where earplugs were provided for free at the concert venue entrance. STUDY SAMPLE: A total of 955 individuals over the age of 18 were observed at six concerts. Six hundred and thirty-seven individuals (64% male) were observed at concerts where no earplugs were provided, and 318 individuals (68% male) were observed at concerts where free earplugs were provided. RESULTS: Multivariate logistic regression demonstrated a significant increase in hearing protection usage at concerts where earplugs were provided for free at the concert venue entrance, odds ratio 7.27 (95% CI: 3.24-16.30). CONCLUSION: The provision of free earplugs at concert venues may be a simple and inexpensive intervention that could be a component of a larger public health campaign to prevent non-occupational noise-induced hearing loss. PMID- 26609735 TI - Coping strategies among conflict-affected adults in low- and middle-income countries: A systematic literature review. AB - Mental health is recognised as a key issue for populations affected by conflict. The aim of this systematic literature review is to examine coping strategies among conflict-affected civilians in low- and middle-income countries. The objectives were to examine (1) the types of coping strategies used by conflict affected civilians; (2) factors influencing coping strategies; (3) relationships between coping strategies and mental health outcomes. A database search was conducted on May 13, 2014. Qualitative and quantitative studies that report on coping strategies used by adult conflict-affected civilians in LMICs were included, yielding 50 articles. Coping strategies were organised into a typology of problem-solving, support seeking, escape-avoidance, distraction, and positive cognitive restructuring domains. Support-seeking, positive cognitive restructuring, and problem-solving domains were the most frequently reported coping domains across the articles. Significant factors influencing coping included gender and exposure to trauma. The relationship between coping and mental health outcomes was nuanced. The diverse findings reported across the studies reflect the variety of contexts from which the samples are drawn, the range of coping typologies, and differing methodological approaches to exploring coping and mental health. Context-specific studies are needed in order to capture the social and cultural influences on coping and mental health. PMID- 26609736 TI - What are threshold concepts and how can they inform medical education? AB - The notion of "threshold concepts" is being widely applied and researched in many disciplines but is rarely discussed within medical education. This article is written by three medical educators who regularly draw on threshold concept theory in their work. They explore here the nature of threshold concepts and describe how the theory can offer medical educators new perspectives in terms of how they design curricula, approach teaching and support learners. PMID- 26609737 TI - Sex differences in trauma symptoms, body image and intensity of pain in a Polish sample of patients suffering from chronic pain. AB - The main goal of the current study was to investigate sex differences in the relationship between the level of trauma symptoms appearing in posttraumatic stress disorder (PTSD) and intensity of pain in a sample of 300 Polish patients suffering from chronic pain, specifically rheumatoid arthritis and lower back pain. We also focused on participants' body image with body esteem as a mediator. To assess the intensity of pain among participants, we used the Numerical Rating Scale. The level of trauma symptoms was assessed with the PTSD Factorial Version Inventory. To measure body image among participants, we used the Body Esteem Scale. The results of our study suggest that trauma symptoms and body image dimensions were significant predictors of pain intensity among men suffering from chronic pain. Moreover, trauma symptoms and age were significant predictors of pain intensity among women suffering from chronic pain. Finally, we demonstrated that sex differentiates the reaction to chronic pain. PMID- 26609738 TI - Erratum. Estimation of residue depletion of cyadox and its marker residue in edible tissues of pigs using physiologically based pharmacokinetic modeling. PMID- 26609740 TI - An Index and Test of Linear Moderated Mediation. AB - I describe a test of linear moderated mediation in path analysis based on an interval estimate of the parameter of a function linking the indirect effect to values of a moderator-a parameter that I call the index of moderated mediation. This test can be used for models that integrate moderation and mediation in which the relationship between the indirect effect and the moderator is estimated as linear, including many of the models described by Edwards and Lambert ( 2007 ) and Preacher, Rucker, and Hayes ( 2007 ) as well as extensions of these models to processes involving multiple mediators operating in parallel or in serial. Generalization of the method to latent variable models is straightforward. Three empirical examples describe the computation of the index and the test, and its implementation is illustrated using Mplus and the PROCESS macro for SPSS and SAS. PMID- 26609741 TI - Direction of Effects in Multiple Linear Regression Models. AB - Previous studies analyzed asymmetric properties of the Pearson correlation coefficient using higher than second order moments. These asymmetric properties can be used to determine the direction of dependence in a linear regression setting (i.e., establish which of two variables is more likely to be on the outcome side) within the framework of cross-sectional observational data. Extant approaches are restricted to the bivariate regression case. The present contribution extends the direction of dependence methodology to a multiple linear regression setting by analyzing distributional properties of residuals of competing multiple regression models. It is shown that, under certain conditions, the third central moments of estimated regression residuals can be used to decide upon direction of effects. In addition, three different approaches for statistical inference are discussed: a combined D'Agostino normality test, a skewness difference test, and a bootstrap difference test. Type I error and power of the procedures are assessed using Monte Carlo simulations, and an empirical example is provided for illustrative purposes. In the discussion, issues concerning the quality of psychological data, possible extensions of the proposed methods to the fourth central moment of regression residuals, and potential applications are addressed. PMID- 26609742 TI - The Importance of Temporal Design: How Do Measurement Intervals Affect the Accuracy and Efficiency of Parameter Estimates in Longitudinal Research? AB - The timing (spacing) of assessments is an important component of longitudinal research. The purpose of the present study is to determine methods of timing the collection of longitudinal data that provide better parameter recovery in mixed effects nonlinear growth modeling. A simulation study was conducted, varying function type, as well as the number of measurement occasions, in order to examine the effect of timing on the accuracy and efficiency of parameter estimates. The number of measurement occasions was associated with greater efficiency for all functional forms and was associated with greater accuracy for the intrinsically nonlinear functions. In general, concentrating measurement occasions toward the left or at the extremes was associated with increased efficiency when estimating the intercepts of intrinsically linear functions, and concentrating values where the curvature of the function was greatest generally resulted in the best recovery for intrinsically nonlinear functions. Results from this study can be used in conjunction with theory to improve the design of longitudinal research studies. In addition, an R program is provided for researchers to run customized simulations to identify optimal sampling schedules for their own research. PMID- 26609743 TI - A Bivariate Generalized Linear Item Response Theory Modeling Framework to the Analysis of Responses and Response Times. AB - A generalized linear modeling framework to the analysis of responses and response times is outlined. In this framework, referred to as bivariate generalized linear item response theory (B-GLIRT), separate generalized linear measurement models are specified for the responses and the response times that are subsequently linked by cross-relations. The cross-relations can take various forms. Here, we focus on cross-relations with a linear or interaction term for ability tests, and cross-relations with a curvilinear term for personality tests. In addition, we discuss how popular existing models from the psychometric literature are special cases in the B-GLIRT framework depending on restrictions in the cross-relation. This allows us to compare existing models conceptually and empirically. We discuss various extensions of the traditional models motivated by practical problems. We also illustrate the applicability of our approach using various real data examples, including data on personality and cognitive ability. PMID- 26609744 TI - Effects of Modeling the Heterogeneity on Inferences Drawn from Multilevel Designs. AB - This article uses Monte Carlo techniques to examine the effect of heterogeneity of variance in multilevel analyses in terms of relative bias, coverage probability, and root mean square error (RMSE). For all simulated data sets, the parameters were estimated using the restricted maximum-likelihood (REML) method both assuming homogeneity and incorporating heterogeneity into multilevel models. We find that (a) the estimates for the fixed parameters are unbiased, but the associated standard errors are frequently biased when heterogeneity is ignored; by contrast, the standard errors of the fixed effects are almost always accurate when heterogeneity is considered; (b) the estimates for the random parameters are slightly overestimated; (c) both the homogeneous and heterogeneous models produce standard errors of the variance component estimates that are underestimated; however, taking heterogeneity into account, the REML-estimations give correct estimates of the standard errors at the lowest level and lead to less underestimated standard errors at the highest level; and (d) from the RMSE point of view, REML accounting for heterogeneity outperforms REML assuming homogeneity; a considerable improvement has been particularly detected for the fixed parameters. Based on this, we conclude that the solution presented can be uniformly adopted. We illustrate the process using a real dataset. PMID- 26609745 TI - Identifying Longitudinal Patterns for Individuals and Subgroups: An Example with Adherence to Treatment for Obstructive Sleep Apnea. AB - To improve complex behaviors such as adherence to medical recommendations, a better understanding of behavior change over time is needed. The focus of this study was adherence to treatment for obstructive sleep apnea (OSA). Adherence to the most common treatment for OSA is poor. This study involved a sample of 161 participants, each with approximately 180 nights of data. First, a time series analysis was performed for each individual. Time series parameters included the mean (average hours of use per night), level, slope, variance, and autocorrelation. Second, a dynamic cluster analysis was performed to find homogenous subgroups of individuals with similar adherence patterns. A four cluster solution was found, and the subgroups were labeled: Great Users (17.2%; high mean and level, no slope), Good Users (32.8%; moderate mean and level, no slope), Low Users (22.7%; low mean and level, negative slope), and Slow Decliners (moderate mean and level, negative slope, high variance). Third, participants in the identified subgroups were compared to establish external validity. These steps represent a Typology of Temporal Patterns (TTP) approach. Combining time series analysis and dynamic cluster analysis is a useful way to evaluate longitudinal patterns at both the individual level and subgroup level. PMID- 26609746 TI - Identification of Real and Artifactual Moderators of Effect Size in Meta Analysis. AB - This article argues that while meta-analytic studies are widely used in psychological literature, heterogeneity and the potential for confounding remain major problems in the interpretation of meta-analytic study results. The article demonstrates the use of exploratory analysis including graphical methods prior to meta-analysis, and introduces a methodology to screen for artifactual effects. These procedures are illustrated on effect size data comparing depression treatment outcome from psychotherapy versus pharmacotherapy. Results support prior findings of a nonsignificant difference in effect size between the two treatments. They also support findings that treatment type accounts for only a very small proportion of outcome variance. However, the results indicate that some previously reported covariates of depression treatment outcome may be artifactual. PMID- 26609747 TI - Special MBR Section: SMEP Student Paper Competition Abstracts, 2014. PMID- 26609748 TI - Abstract: Advantages of a Bayesian Approach for Examining Class Structure in Finite Mixture Models. PMID- 26609749 TI - Abstract: On the Complexity of IRT Models. PMID- 26609750 TI - Abstract: Genome-Wide Complex Trait Analysis of Shared Genetic Effects Between Brain Electrophysiology Measures and Alcohol Dependence. PMID- 26609751 TI - Abstract: Assessing Trend in Single-Case Designs Using Generalized Additive Models. PMID- 26609752 TI - Abstract: Sensitivity to Restricted Factor Analysis Model Misspecification. PMID- 26609753 TI - Abstract: Psychological Distress and Recurrent Herpetic Disease: A Dynamic Study of Lesion Recurrence and Viral Shedding Episodes in Adults. PMID- 26609754 TI - Abstract: Measurement Invariance Prior to Covariate Adjustment. PMID- 26609756 TI - Abstract: IRT and SVD: Implementing Psychometric Methods in New and Complex Situations. PMID- 26609755 TI - Abstract: Cluster Analysis of Distributions: Development and Demonstration of a Method. PMID- 26609757 TI - Abstract: Probing Interactions in Multiple Regression: Frequentist Versus Bayesian Approaches. PMID- 26609758 TI - Abstract: Extraction of Latent Class Progressions in Behavioral Data. PMID- 26609759 TI - Abstract: Identifying Average Causal Mediation Effects with Multiple Mediators in the Presence of Treatment Noncompliance. PMID- 26609760 TI - Abstract: Revisiting the Model Size Effect in Structural Equation Modeling (SEM). PMID- 26609761 TI - Abstract: Classification Quality and Locally Optimal Solutions in a Mixture Model. PMID- 26609762 TI - Abstract: Evaluating Methods for Moderation Analysis with Missing Data in the Predictors. PMID- 26609763 TI - A novel 10-hydroxycamptothecin-glucoside from the fruit of Camptotheca acuminata. AB - Glycosides were isolated from the fruit of Camptotheca acuminata and identified using NMR, MS, UV and IR spectrometries. 10-O-(1-beta-D-glycosyl) camptothecin (1) was identified for the first time in a natural material. In addition, compounds 2-4 were firstly reported from the fruits of C. acuminata and indentified as syringaresinol-4, 4'-O-bis-beta-D-glucoside (2), hyperoside (3) and pumiloside (4), respectively. Two known compounds, vincoside-lactam (5) and strictosidinic acid (6), were also obtained. PMID- 26609764 TI - Effects of antidiabetic agents on pancreatic beta-cell function in gestational diabetes: is there enough evidence? AB - Gestational diabetes mellitus (GDM) is typically characterized by the presence of insulin resistance. However, recent studies showed that both insulin resistance and pancreatic beta-cell function impairment may contribute to the development of type 2 diabetes in women with history of GDM. In fact, beta-cell function decline was found as significant predictor of later disease in former GDM women progressing towards type 2 diabetes. Despite the evidence of the relevance of beta-cell function quantification in GDM, a low number of studies focused on the effects of GDM treatments on beta-cell function. We briefly present the evidence of the effects on beta-cell function of pharmacological agents, as well as nutrition supplements or medical nutrition therapy, used in the management of GDM. We found that few studies reported information on beta-cell function effects in GDM, despite some agents, such as glyburide, are well known insulin secretagogues. Therefore, further studies should be carried out to clearly assess the effects on beta-cell function of the treatments in GDM women. PMID- 26609765 TI - Structure prediction and docking-based molecular insights of human YB-1 and nucleic acid interaction. AB - Y-box-binding protein 1 (YB-1), a cold shock domain protein, is one of the most conserved nucleic acid-binding proteins. The multifunctional human YB-1 is a member of a large family of proteins with an evolutionary ancient cold shock domain. The presence of a cold shock domain is a specific feature of Y-box binding proteins and allows attributing them to a wider group of proteins containing a cold shock domain. This protein is involved in a number of cellular processes including proliferation, differentiation and stress response. The YB-1 performs its function both in the cytoplasm and in the cell nucleus. In this study, we present the structure of full-length human YB-1 protein along with investigation of their nucleic acid-binding preferential. The study also focuses on biases for particular purine and pyrimidine bases. The overall goal of this study was to model and validate full-length YB-1 protein and to compare its nucleic acid-binding studies with previous reports. PMID- 26609766 TI - Feasibility study of a single-blind randomised controlled trial of an occupational therapy intervention. AB - BACKGROUND: Several factors facilitate or hinder efficacy research in occupational therapy. Strategies are needed, therefore, to support the successful implementation of trials. AIM: To assess the feasibility of conducting a randomised controlled trial (RCT). The main feasibility objectives of this study were to assess the process, resources, management, and scientific basis of a trial RCT. MATERIAL AND METHODS: A total of 10 occupational therapists, between the ages of 30 and 55 (M 43.4; SD 8.3) with seven to 26 years' (M 14.3; SD 6.1) experience, participated in this study. Qualitative data collected included minutes of meetings, reports, and field notes. The data were analysed based on the principles of content analysis, using feasibility objectives as the main categories. RESULTS: Data analysis revealed strengths in relation to retention and inclusion criteria of participants, the study protocol, study organisation, and the competence of researchers. Weaknesses were found related to recruitment, randomisation, data collection, time for training and communication, commitment, and design. CONCLUSION: The findings indicated that there are several factors which had a considerable impact on the implementation of an RCT in practice. However, it was useful to assess methods and procedures of the trial RCT as a basis to refine research plans. PMID- 26609767 TI - Dietary but not in ovo feeding of Silybum marianum extract resulted in an improvement in performance, immunity and carcass characteristics and decreased the adverse effects of high temperatures in broilers. AB - A total of 360 fertile eggs from a broiler breeder strain (Ross 308) were used for in ovo feeding (IOF) of 0, 100 and 200 mg/kg Silybum marianum water extract at 17.5 d of incubation. After hatching, 240 chicks were transferred to the experimental cages. The diets consisted of two types; one of them without extract and the other one containing 100 mg/kg of Silybum marianum extract. Then chicks were exposed to elevated temperatures 4 degrees C above optimum from 7 to 28 d of age for 4 h per d and after 28 d they were kept at optimum temperature. The chicks were divided into 6 treatments with 4 replicates as a completely randomised 2 * 3 factorial design. There was no effect of IOF of Silybum marianum extract on hatchability, body weight (BW) of hatched chicks or hatched chick BW/initial egg weight ratio. Chickens fed on the diet containing the extract had the highest feed intake, daily weight gains (DWGs), final BW and lowest feed conversion ratio. At 28 d, the weights of heart, spleen and bursa of birds in the treatment groups given extract were higher, but abdominal fat weights were lower. At 42 d in those fed extract in the diet, the weights of spleen and bursa were higher and abdominal fat weights were lower than the other groups. No differences were observed between groups in body temperature before application of the higher temperature but at 21 d and 28 d the body temperature of chicks given the Silybum marianum extract was lower than the other treatments during the elevated temperatures. In birds fed on the extract in the diet, HDL and cholesterol concentrations were lowest at 28 d, whereas blood glucose levels were higher in the other treatments. At 42 d the cholesterol concentration was significantly lower in birds given extract in their diet. These results indicated that dietary feeding of Silybum marianum extract resulted in an improvement in performance, immunity and carcass characteristics and decreased the adverse effects of the higher temperatures, specifically in reducing blood fat reduction, but IOF of the extract did not have an effect. PMID- 26609768 TI - Spherulites: onion-like vesicles as nanomedicines. AB - Spherulites are onion-like structures composed of phospholipids and excipients. Initially discovered in an academic laboratory, these autoassembled nano-objects have been developed further by the start-up Capsulis (Bordeaux, France), and commercialized for veterinary and dermatological applications. Owing to economical strategies, the development of these objects have not been pursued, however, they are very interesting systems, which should be exploited further. The autoassembly of amphiphiles followed by a shear stress allows the formation of nano- to micrometer range nanoparticles, which could be interesting either for systemic or local delivery. Small molecules to macromolecules have been encapsulated in spherulites in the nanometer range. All have shown promising results. Hence, spherulite-encapsulated oligonucleotides have shown increased cell internalization. DNA was shown to be encapsulated in these neutral nanoparticles. Proof-of-concept of protein encapsulation was obtained leading to immune stimulation. This review summarizes the different ways to obtain spherulites, the results of the various investigations performed to date and indicates the limits and the interests of theses nanocarriers and proposes future prospects. PMID- 26609769 TI - Potassium channels as promising new targets for pharmacologic treatment of tinnitus: Can Internet-based 'crowd sensing' initiated by patients speed up the transition from bench to bedside? PMID- 26609770 TI - Patterns of pharmacologic treatment in US patients with acromegaly. AB - OBJECTIVE: To establish a baseline pattern of care across academic and community settings, it is important to examine the contemporary treatment of acromegaly. We characterized medical treatment patterns for acromegaly in the US to develop a basis for tracking concordance with guidelines. RESEARCH DESIGN AND METHODS: Acromegaly patients were identified in two commercial claims databases for this retrospective analysis. Study subjects had >=2 medical claims with acromegaly (ICD-9-CM code 253.0) and >=1 claim for pharmacotherapy (bromocriptine, cabergoline, octreotide SA, octreotide LAR, lanreotide, or pegvisomant) in the study timeframe (1 January 2002-31 December 2013). Patients were considered newly treated if they were continuously enrolled for >=6 months before first observed treatment and had no claim for pharmacologic treatment during that time. Outcomes included various pharmacotherapies, including combination treatments, and differences between lines of therapy. RESULTS: A total of 3150 patients had >=1 pharmacotherapy (mean age: 46.5 years; 50.1% were female); 1471 were newly treated. Somatostatin receptor ligands (SRLs) were the most common drug class used first line (57.2%); cabergoline (27.8%) was the most common treatment, followed by octreotide LAR (22.3%) and lanreotide (19.7%). SRLs were also the most commonly used second-line (42.8%) and third-line pharmacotherapies (43.9%), with combination therapy (23.2%) and octreotide LAR (19.8%) as the most commonly used treatments, respectively. CONCLUSIONS: This study, representing the largest claims-based analysis of acromegaly to date, used two databases across a 12 year period to examine complex treatment patterns in a difficult-to-study disease. Although wide variation in acromegaly treatment patterns exists in US clinical practice, in first-line, second-line, and third-line therapy, SRL was the most commonly used drug class. Drug combinations also varied considerably across lines of therapy. The switching between different monotherapies and varied use of drugs in combination may suggest an unmet need for alternative treatment options. Our claims-based technique of examining treatment patterns may be used for other rare diseases, although high censoring rates may be a challenge. PMID- 26609771 TI - The Role and Effects of ANXA1 in Temporal Lobe Epilepsy: A Protection Mechanism? AB - BACKGROUND The endogenous protein annexin A1 (ANXA1) is an anti-inflammatory mediator in the brain that is thought to contribute to the progression of many neurological conditions. However, its exact role in temporal lobe epilepsy (TLE) remains unclear. We hypothesized that ANXA1 exerts negative actions on TLE by alleviating inflammatory damage in neurons. To identify the potential mechanism of TLE by assessing ANXA1 expression in TLE rats. MATERIAL AND METHODS TLE was induced in rats (n=70) via an intraperitoneal injection of lithium chloride (LiCl) and pilocarpine (PILO). The control group (n=10) received an injection of the equivalent amount of saline. ANXA1 expression was detected via immunohistochemistry and Western blotting. RESULTS Successful establishment of the TLE model in rats resulted in epileptic seizures. ANXA1 was immunohistochemically detected as brownish yellow particles in the dentate gyrus and the CA1 region of the door zone; this expression was predominantly localized to the cytoplasm of glia rather than neurons. ANXA1 expression was stronger in TLE rats compared with the control group. ANXA1 expression in TLE was also assessed via Western blotting, and compared between groups at various time points. ANXA1 expression was significantly increased in the acute (the first 24 h) and chronic (after 1 month) phases (P<0.001) but significantly decreased during the recovery phase (72 h, 1 week, and 2 weeks) (P<0.001). These findings suggest that ANXA1 expression is correlated with TLE activity. CONCLUSIONS Our data suggest that ANXA1 plays an important role in TLE by alleviating inflammatory damage and protecting neurons. PMID- 26609772 TI - [Lysosomal storage diseases]. PMID- 26609780 TI - New insights into the complex regulation of the glycolytic pathway in Lactococcus lactis. II. Inference of the precisely timed control system regulating glycolysis. AB - The dairy bacterium Lactococcus lactis has to master a complicated task. It must control its essentially linear glycolytic pathway in such a fashion that, when the substrate, glucose, runs out, it retains enough phosphoenolpyruvate and fructose-1,6-bisphosphate to be able to restart glycolysis as soon as new glucose becomes available. Although glycolysis is arguably the best-studied metabolic pathway, its details in L. lactis are still unclear, and it is, in particular, not understood how the bacterium manages the stop-and-start task. The primary purpose of this paper and its companion is a clarification of some of the details of the governing regulatory strategies with which L. lactis manages to retain the necessary metabolites for the restart of glycolysis after periods of starvation. The paper furthermore discusses how the bacterium changes these strategies when it is subjected to aerobic rather than anaerobic conditions. PMID- 26609781 TI - Cytotoxic properties of a new organometallic platinum(II) complex and its gold(I) heterobimetallic derivatives. AB - A novel platinum(ii) organometallic complex, [Pt(pbi)(Me)(DMSO)], bearing the 2 (2'-pyridyl)-benzimidazole (pbiH) ligand, was synthesized and fully characterized. Interestingly, the reaction of this organometallic platinum(ii) complex with two distinct gold(i) phosphane compounds afforded the corresponding heterobimetallic derivatives with the pbi ligand bridging the two metal centers. The antiproliferative properties in vitro of [Pt(pbi)(Me)(DMSO)] and its gold(i) derivatives as well as those of the known coordination platinum(ii) and palladium(ii) complexes with the same ligand, of the general formula [MCl2(pbiH)], were comparatively evaluated against A2780 cancer cells, either sensitive or resistant to cisplatin. A superior biological activity of the organometallic compound clearly emerged compared to the corresponding platinum(ii) complex; the antiproliferative effects are further enhanced upon attaching the gold(i) triphenylphosphine moiety to the organometallic Pt compound. Remarkably, these novel metal species are able to overcome nearly complete resistance to cisplatin. Significant mechanistic insight into the study compounds was gained after investigating their reactions with a few representative biomolecules by electrospray mass spectrometry and X-ray crystallography. The obtained results are comprehensively discussed. PMID- 26609782 TI - Correction: One-pot synthesis of carbazoles via tandem C-C cross-coupling and reductive amination. AB - Correction for 'One-pot synthesis of carbazoles via tandem C-C cross-coupling and reductive amination' by Deuk-Young Goo, et al., Org. Biomol. Chem., 2016, DOI: 10.1039/c5ob01952d. PMID- 26609783 TI - Gram-negative phytopathogenic bacteria, all hemibiotrophs after all? PMID- 26609784 TI - Catalytic Asymmetric Mannich Reactions with Fluorinated Aromatic Ketones: Efficient Access to Chiral beta-Fluoroamines. AB - Reported herein is a Zn/Prophenol-catalyzed Mannich reaction using fluorinated aromatic ketones as nucleophilic partners for the direct enantio- and diastereoselective construction of beta-fluoroamine motifs featuring a fluorinated tetrasubstituted carbon. The reaction can be run on a gram scale with a low catalyst loading without impacting its efficiency. Moreover, a related aldol reaction was also developed. Together, these reactions provide a new approach for the preparation of pharmaceutically relevant products possessing tetrasubstituted C-F centers. PMID- 26609785 TI - A simple method to measure the gas-phase SVOC concentration adjacent to a material surface. AB - Assessing human exposure to semivolatile organic compounds (SVOCs) emitted from materials and products is difficult because methods are not available to easily measure the key emission parameters. A simple method based on a passive sampling technique was thus developed to measure the gas-phase SVOC concentration (y0 ) immediately adjacent to the material surface in a consumer product. The method employs standard stainless steel thermal desorption tubes, with values of y0 and an additional unknown parameter, K, the tube surface/air partition coefficient inside the desorption tube, obtained by fitting a diffusion model to the sampling data. Phthalates in two types of polyvinyl chloride flooring were selected to test the method. The values of y0 and K agree well with those measured in independent chamber tests. The y0 measurement method is shown to be applicable to chemicals with a wide range of vapor pressures. This novel method should be useful for assessing potential exposure to SVOCs in consumer products as well as for exposure-based prioritization of chemicals and their associated products in indoor environments. PMID- 26609786 TI - Arterial line versus venous line administration of low molecular weight heparin, enoxaparin for prevention of thrombosis in the extracorporeal blood circuit of patients on haemodialysis or haemodiafiltration: A randomized cross-over trial. AB - STUDY OBJECTIVE: The objective of the study is to compare the anti-factor Xa (AXa) level in the blood, after arterial and venous line administration of equivalent doses of enoxaparin for prevention of thrombosis in the extracorporeal blood circuit. DESIGN: The design of the study is a dual centre, prospective, open-labelled randomized crossover, 7 weeks trial. SETTING: The setting of the study is on a patient on long-term haemodialysis (HD) or haemodiafiltration (HDF) using high-flux membrane. PARTICIPANT: There were eight patients on HD and eight on HDF. INTERVENTION: Participants were randomly assigned to receive enoxaparin either through the arterial line or venous line of extracorporeal blood circuit for an initial study interval of 2 weeks, followed by 2 weeks of alternate route administration. During the run-in period of 1 week and the follow-up period of 2 weeks, enoxaparin was administered through the arterial line. OUTCOMES: The primary outcome measure was to compare AXa blood level 4 h after enoxaparin administration. The secondary outcome measures were manual compression time to stop bleeding from arteriovenous fistula, extracorporeal circuit clotting and systemic bleeding episodes. RESULTS: The mean AXa blood level, 4 h after venous circuit administration (0.58 +/- 0.21 (HD), 0.82 +/- 0.29 (HDF)) of enoxaparin, was significantly greater than that after arterial administration of enoxaparin (0.39 +/- 0.25 (HD), 0.39 +/- 0.14 (HDF) U/mL), (P < 0.001). CONCLUSION: In patients on HD or HDF, venous line administration of enoxaparin achieves greater 4 h blood AXa level compared with arterial line administration of equivalent dose. Based on this, we suggest a 25% or 50% reduction in the dose of venous line enoxaparin, compared with the dose administered through arterial line in patients receiving either HD or HDF, respectively. PMID- 26609787 TI - A Distinctive Pattern of Beauveria bassiana-biotransformed Ginsenoside Products Triggers Mitochondria/FasL-mediated Apoptosis in Colon Cancer Cells. AB - Ginseng is one of the most commonly used adaptogens. Transformation into the minor ginsenosides produces compounds with more effective action. Beauveria bassiana, a teleomorph of Cordyceps bassiana, is a highly efficient producer of mammalian steroids and produces large amounts of sugar-utilizing enzymes. However, the fermentation of steroid glycosides in ginseng with B. bassiana has never been studied. Thus, we evaluated the bioconversion of the major ginsenosides in white ginseng by B. bassiana. Interestingly, B. bassiana increased the total amount of protopanaxadiols and hydrolyzed Rb1 into minor ginsenosides, exhibiting high levels of Rd and Rg3, as well as moderate levels of Rb2 and Rc analyzed by high-performance liquid chromatography coupled with evaporative light-scattering detection. The beta-glucosidase activity was highly increased, which led to the selective elimination of sugar moiety at the 20-C position of Rb1 to Rd, followed by Rg3. Rb2 and Rc accumulated because of the minimal activities of alpha-L-arabinopyranosidase and alpha-L arabinofuranosidase, respectively. The fermentation product exerted dose dependent cytotoxicity in HCT-15 cells, which are resistant to ginseng. The product, but not white ginseng, exhibited apoptotic effects via the Fas ligand and caspase 8/9. This study demonstrates for the first time that the B. bassiana fermented metabolites have potent apoptotic activity in colon cancer cells, linking to a therapeutic use. PMID- 26609788 TI - Epidemiology of chronic wounds in Germany: Analysis of statutory health insurance data. AB - Epidemiologic analyses in routine care of chronic wounds are scarce, and published studies show wide variations. This study analyzes the population-based prevalence and incidence of chronic wounds in Germany. Secondary analyses of data from a German statutory health insurance with about 9 million insured persons were examined (2010 to 2012). Internal diagnostic validations were used to control for different inclusion criteria. In 2012, 1.04% (95% CI 1.03-1.05) of insured patients had a wound diagnosis, including 0.70% with leg ulcers and 0.27% with diabetic ulcers. Wound treatment was received by 0.43% (0.43-0.44) of patients. Prevalence and incidence increased over 3 years. Extrapolated to the German population, there were 786,407 prevalent and 196,602 incident chronic wounds, including 326,334/172,026 patients who underwent wound-relevant treatment in 2012. There is an annually increasing frequency of chronic wounds in Germany. Chronic wound epidemiology is sensitive to wound treatment as a filter criterion. PMID- 26609789 TI - MOLECULAR IDENTIFICATION OF CYSTEINE AND TRYPSIN PROTEASE, EFFECT OF DIFFERENT HOSTS ON PROTEASE EXPRESSION, AND RNAI MEDIATED SILENCING OF CYSTEINE PROTEASE GENE IN THE SUNN PEST. AB - Sunn pest, Eurygaster integriceps, is a serious pest of cereals in the wide area of the globe from Near and Middle East to East and South Europe and North Africa. This study described for the first time, identification of E. integriceps trypsin serine protease and cathepsin-L cysteine, transcripts involved in digestion, which might serve as targets for pest control management. A total of 478 and 500 base pair long putative trypsin and cysteine gene sequences were characterized and named Tryp and Cys, respectively. In addition, the tissue-specific relative gene expression levels of these genes as well as gluten hydrolase (Gl) were determined under different host kernels feeding conditions. Result showed that mRNA expression of Cys, Tryp, and Gl was significantly affected after feeding on various host plant species. Transcript levels of these genes were most abundant in the wheat-fed E. integriceps larvae compared to other hosts. The Cys transcript was detected exclusively in the gut, whereas the Gl and Tryp transcripts were detectable in both salivary glands and gut. Also possibility of Sunn pest gene silencing was studied by topical application of cysteine double stranded RNA (dsRNA). The results indicated that topically applied dsRNA on fifth nymphal stage can penetrate the cuticle of the insect and induce RNA interference. The Cys gene mRNA transcript in the gut was reduced to 83.8% 2 days posttreatment. Also, it was found that dsRNA of Cys gene affected fifth nymphal stage development suggesting the involvement of this protease in the insect growth, development, and molting. PMID- 26609790 TI - Conversion of Biomass Derivatives to Electricity in Photo Fuel Cells using Undoped and Tungsten-doped Bismuth Vanadate Photoanodes. AB - The photo fuel cell (PFC) is a promising technology for simultaneously converting solar energy and bioenergy into electricity. Here, we present a miniature air breathing PFC that uses either BiVO4 or W-doped BiVO4 as the photoanode and a Pt/C catalyst as the air-breathing cathode. The PFC exhibited excellent performance under solar illumination and when fed with several types of biomaterial. We found the PFC performance could be significantly enhanced using W doping into the BiVO4 photoanode. With glucose as the fuel and simulated sunlight (AM 1.5 G) as the light source, the open-circuit voltage increased from 0.74 to 0.92 V, the short-circuit current density rose from 0.46 to 1.62 mA cm(-2) , and the maximum power density was boosted from 0.05 to 0.38 mW cm(-2) , compared to a PFC using undoped BiVO4 as the anode. PMID- 26609791 TI - Characterizing a partially ordered miniprotein through folding molecular dynamics simulations: Comparison with the experimental data. AB - The villin headpiece helical subdomain (HP36) is one of the best known model systems for computational studies of fast-folding all-alpha miniproteins. HP21 is a peptide fragment-derived from HP36-comprising only the first and second helices of the full domain. Experimental studies showed that although HP21 is mostly unfolded in solution, it does maintain some persistent native-like structure as indicated by the analysis of NMR-derived chemical shifts. Here we compare the experimental data for HP21 with the results obtained from a 15-MUs long folding molecular dynamics simulation performed in explicit water and with full electrostatics. We find that the simulation is in good agreement with the experiment and faithfully reproduces the major experimental findings, namely that (a) HP21 is disordered in solution with <10% of the trajectory corresponding to transiently stable structures, (b) the most highly populated conformer is a native-like structure with an RMSD from the corresponding portion of the HP36 crystal structure of <1 A, (c) the simulation-derived chemical shifts-over the whole length of the trajectory-are in reasonable agreement with the experiment giving reduced chi(2) values of 1.6, 1.4, and 0.8 for the Deltadelta(13) C(alpha) , Deltadelta(13) CO, and Deltadelta(13) C(beta) secondary shifts, respectively (becoming 0.8, 0.7, and 0.3 when only the major peptide conformer is considered), and finally, (d) the secondary structure propensity scores are in very good agreement with the experiment and clearly indicate the higher stability of the first helix. We conclude that folding molecular dynamics simulations can be a useful tool for the structural characterization of even marginally stable peptides. PMID- 26609793 TI - Fimbrolide Natural Products Disrupt Bioluminescence of Vibrio By Targeting Autoinducer Biosynthesis and Luciferase Activity. AB - Vibrio is a model organism for the study of quorum sensing (QS) signaling and is used to identify QS-interfering drugs. Naturally occurring fimbrolides are important tool compounds known to affect QS in various organisms; however, their cellular targets have so far remained elusive. Here we identify the irreversible fimbrolide targets in the proteome of living V. harveyi and V. campbellii via quantitative mass spectrometry utilizing customized probes. Among the major hits are two protein targets with essential roles in Vibrio QS and bioluminescence. LuxS, responsible for autoinducer 2 biosynthesis, and LuxE, a subunit of the luciferase complex, were both covalently modified at their active-site cysteines leading to inhibition of activity. The identification of LuxE unifies previous reports suggesting inhibition of bioluminescence downstream of the signaling cascade and thus contributes to a better mechanistic understanding of these QS tool compounds. PMID- 26609792 TI - Exenatide acutely increases heart rate in parallel with augmented sympathetic nervous system activation in healthy overweight males. AB - AIM: Clinical use of glucagon-like peptide-1 receptor agonists (GLP-1RA) is consistently associated with heart rate (HR) acceleration in type 2 diabetes patients. We explored the mechanisms underlying this potential safety concern. METHODS: Ten healthy overweight males (aged 20-27 years) were examined in an open label, crossover study. Automated oscillometric blood pressure measurements and finger photoplethysmography were performed throughout intravenous administration of placebo (saline 0.9%), exenatide (targeting therapeutic concentrations) and a combination of exenatide and the nitric oxide synthase inhibitor L-N(G) monomethyl arginine (L-NMMA). Sympathetic nervous system (SNS) activity was measured by heart rate variability and rate-pressure product. RESULTS: Exenatide increased HR by a mean maximum of 6.8 (95% CI 1.7, 11.9) beats min(-1) (P < 0.05), systolic blood pressure (SBP) by 9.8 (95% CI 3.5, 16.1) mmHg (P < 0.01) and markers of SNS activity (P < 0.05). No changes in total peripheral resistance were observed. Increases in HR, SBP and sympathetic activity were preserved during concomitant L-NMMA infusion. CONCLUSIONS: Our data argue against exenatide induced reflex tachycardia as a response to vasodilation and rather suggest the involvement of SNS activation in humans. PMID- 26609794 TI - Usefulness of liver stiffness measurement during acute cellular rejection in liver transplantation. AB - Liver stiffness measurement (LSM) is a useful method to estimate liver fibrosis and portal hypertension. The inflammatory process that takes place in post-liver transplant acute cellular rejection (ACR) may also increase liver stiffness. We aimed to explore the association between liver stiffness and the severity of ACR, as well as to assess the relationship between liver stiffness and response to rejection treatment in a prospective study that included 27 liver recipients with biopsy-proven ACR, 30 stable recipients with normal liver tests, and 30 hepatitis C virus (HCV)-infected LT recipients with histologically diagnosed HCV recurrence. Patients with rejection were stratified into 2 groups (mild and moderate/severe) according to the severity of rejection evaluated with the Banff score. Routine biomarkers and LSM with FibroScan were performed at the time of liver biopsy (baseline) and at 7, 30, and 90 days in patients with rejection and at baseline in control patients. Median baseline liver stiffness was 5.9 kPa in the mild rejection group, 11 kPa in the moderate/severe group (P = 0.001), 4.2 kPa in stable recipients (P = 0.02 versus mild rejection), and 13.6 kPa in patients with recurrent HCV (P = 0.17 versus moderate/severe rejection). The area under the receiver operator characteristic curve of LSM to discriminate mild versus moderate/severe ACR was 0.924, and a LSM value of 8.5 kPa yielded a positive predictive value of 100% to diagnose moderate/severe rejection. Liver stiffness improved in 7%, 21%, and 64% of patients with moderate/severe rejection at 7, 30, and 90 days. In conclusion, according to the results of this exploratory study, LSM is associated with the severity of ACR in liver transplantation and thus may be of help in its assessment. PMID- 26609795 TI - Order of Activity of Nitrogen, Iron Oxide, and FeNx Complexes towards Oxygen Reduction in Alkaline Medium. AB - In alkaline medium, it seems that both metal-free and iron-containing carbon based catalysts, such as nitrogen-doped nanocarbon materials, FeOx -doped carbon, and Fe/N/C catalysts, are active for the oxygen reduction reaction (ORR). However, the order of activity of these different active compositions has not been clearly determined. Herein, we synthesized nitrogen-doped carbon black (NCB), Fe3 O4 /CB, Fe3 O4 /NCB, and FeN4 /CB. Through the systematic study of the ORR catalytic activity of these four catalysts in alkaline solution, we confirmed the difference in the catalytic activity and catalytic mechanism for nitrogen, iron oxides, and Fe-N complexes, respectively. In metal-free NCB, nitrogen can improve the ORR catalytic activity with a four-electron pathway. Fe3 O4 /CB catalyst did not exhibit improved activity over that of NCB owing to the poor conductivity and spinel structure of Fe3 O4 . However, FeN4 coordination compounds as the active sites showed excellent ORR catalytic activity. PMID- 26609796 TI - The effect of display timing on change blindness in pigeons (Columba livia). AB - Change blindness is a phenomenon in which even obvious changes in a visual scene may go unnoticed. Recent research has indicated that this phenomenon may not be exclusive to humans. Two experiments investigated change blindness in pigeons, using a variant of the widely-used flicker task to investigate the influence of display timing on change blindness. Results indicate that the duration of time during which a stimulus display is visible influences change detection accuracy, with the effect due to additional search time. The results are discussed in relation to the value of comparative cognition and cross-species investigations of behavior. PMID- 26609797 TI - Central Galphai2 proteins, sympathetic nervous system and blood pressure regulation. PMID- 26609798 TI - Predictors of health-related quality of life and participation after brain injury rehabilitation: The role of neuropsychological factors. AB - The aims of this longitudinal study were: (1) to assess associations between neuropsychological factors and health-related quality of life (HRQoL) and participation three months after discharge from inpatient acquired brain injury (ABI) rehabilitation; and (2) to determine the best neuropsychological predictor of HRQoL and participation after controlling for demographic and injury-related factors. Patients with ABI (n = 100) were assessed within approximately two weeks of enrolment in inpatient rehabilitation. Predictor variables included demographic and injury-related characteristics and the following neuropsychological factors: active and passive coping, attention, executive functioning, verbal memory, learning potential, depressive symptoms, motivation, extraversion, neuroticism and self-awareness. Bivariate analyses revealed that passive coping, executive functioning, depressive symptoms, extraversion, and neuroticism were significantly associated with HRQoL and/or participation. Neuropsychological factors significantly explained additional variance in HRQoL (18.1-21.6%) and participation (6.9-20.3%) after controlling for demographic and injury-related factors. However, a higher tendency towards passive coping was the only significant neuropsychological predictor (beta = -0.305 to -0.464) of lower HRQoL and participation. This study shows that neuropsychological functioning, and in particular passive coping, plays a role in predicting HRQoL and participation after inpatient ABI rehabilitation and emphasises the importance of addressing patients' coping styles in an early phase of ABI rehabilitation. PMID- 26609799 TI - A robust electrochemiluminescence immunoassay for carcinoembryonic antigen detection based on a microtiter plate as a bridge and Au@Pd nanorods as a peroxidase mimic. AB - The common drawbacks of most traditional electrochemiluminescence (ECL) immunoassays are the strict storage conditions for the ECL electrode and the steric hindrance caused by bovine serum albumin and antigen. The strict storage conditions require that the modified electrode must be stored at 4 degrees C before measurement, which may cause the degradation of protein molecules and low reproducibility as the time goes by. The steric hindrance can hinder electron transfer between the electrode and the electrochemical active substance unable to transmit proteins on the electrode surface. The current study takes a 96-well microtiter plate (MTP) as a bridge for analyte pre-treatment and Au@Pd nanorods as a peroxidase mimic to assemble a simple and robust ECL immunoassay. Advantages of such assay include not only high sensitivity but also robust detection circumstance. We demonstrated the method by detecting carcinoembryonic antigen from human serum and obtained a good detection limit of 3 fg mL(-1). PMID- 26609800 TI - The Dilemma of Supporting Electrolytes for Electroorganic Synthesis: A Case Study on Kolbe Electrolysis. AB - Remarkably, coulombic efficiency (CE, about 50 % at 1 Farad equivalent), and product composition resulting from aqueous Kolbe electrolysis are independent of reactor temperature and initial pH value. Although numerous studies on Kolbe electrolysis are available, the interrelations of different reaction parameters (e.g., acid concentration, pH, and especially electrolytic conductivity) are not addressed. A systematic analysis based on cyclic voltammetry reveals that solely the electrolytic conductivity impacts the current-voltage behavior. When using supporting electrolytes, not only their concentration, but also the type is decisive. We show that higher concentrations of KNO3 result in reduced CE and thus in significant increase in electric energy demand per converted molecule, whereas Na2 SO4 allows improved space-time yields. Pros and cons of adding supporting electrolytes are discussed in a final cost assessment. PMID- 26609801 TI - Transcriptome profiling in Parkinson's leukocytes: from early diagnostics to neuroimmune therapeutic prospects. AB - Parkinson's disease (PD) involves motor symptoms reflecting the progressive degeneration of dopaminergic neurons in the substantia nigra. However, diagnosis is only enabled late in the disease, limiting treatment to palliative assistance. Here, we review recently generated transcriptional profiling datasets from blood and brain RNA of human PD cohorts and animal models that may offer unprecedented progress in PD research. Specifically, advanced analysis techniques demonstrated functionally inter-related underlying impairments of RNA metabolism and neuroimmune signalling processes. Identifying novel biomarkers in serum and nucleated blood cells, including protein networks and non-coding RNAs can drive discovery of the molecular mechanisms involved and reveal new targets for therapeutic intervention, posing a dual diagnosis/treatment opportunity for limiting the exacerbation of neuroinflammatory events in PD. PMID- 26609802 TI - Analysis of the impact of digital watermarking on computer-aided diagnosis in medical imaging. AB - Medical images (MI) are relevant sources of information for detecting and diagnosing a large number of illnesses and abnormalities. Due to their importance, this study is focused on breast ultrasound (BUS), which is the main adjunct for mammography to detect common breast lesions among women worldwide. On the other hand, aiming to enhance data security, image fidelity, authenticity, and content verification in e-health environments, MI watermarking has been widely used, whose main goal is to embed patient meta-data into MI so that the resulting image keeps its original quality. In this sense, this paper deals with the comparison of two watermarking approaches, namely spread spectrum based on the discrete cosine transform (SS-DCT) and the high-capacity data-hiding (HCDH) algorithm, so that the watermarked BUS images are guaranteed to be adequate for a computer-aided diagnosis (CADx) system, whose two principal outcomes are lesion segmentation and classification. Experimental results show that HCDH algorithm is highly recommended for watermarking medical images, maintaining the image quality and without introducing distortion into the output of CADx. PMID- 26609803 TI - Biomechanical optimization of a custom-made positioning and fixing bone plate for Le Fort I osteotomy by finite element analysis. AB - This study integrates image-processing, finite element (FE) analysis, optimization and CAM techniques to develop a bone plate that can provide precise positioning and fixation for the Le Fort I osteotomy. Two FE 3D models using commercial mini-plate and continuous bone plates were generated by integrating computed tomography images and CAD system for simulations under the worst load condition. The goal driven optimization method was used to examine the system performance using certain minimum output values for relative micro-movement between the two maxillary bone segments and stress for the bone plate to seek maximum reduction volume in a continuous plate. The simulation results indicated that the maximum stress/relative micro-movement was 1269.20MPa/133.66MUm and 418.37MPa/92.37MUm for the commercial straight mini-plate and continuous fixation types, respectively. The optimal design plate found the volume reduction rate reach 24.3% compared to the continuous bone plate and the decreased variations in stress/relative micro-movement were 65.14% (442.36MPa) and 29.36% (96.53MUm) when compared to values obtained from the commercial mini-plate plate. The optimal bone plate can be manufactured using a 5-axes milling machine and fixed onto the freed separate maxillary segments of a rapid prototyping model to provide precise positioning/fixation and present adequate strength/stability in the Le Fort I osteotomy. PMID- 26609804 TI - Interaction between mDia1 and ROCK in Rho-induced migration and adhesion of human dental pulp cells. AB - AIM: To investigate the effects of mammalian homologue of Drosophila diaphanous 1(mDia1) and Rho-associated coiled-coil-containing protein kinase (ROCK) on the migration and adhesion of dental pulp cells (DPCs). METHODOLOGY: Lysophosphatidic acid (LPA) was used to activate Rho signalling. mDia1 and ROCK were inhibited by short interfering RNA and the specific inhibitor, Y-27632, respectively. The migration of DPCs was assessed using the transwell migration assay and scratch test. Formation of cytoskeleton and focal adhesions(FAs) was observed by confocal laser scanning microscopy. Cell adhesion and spreading assays were performed. Phosphorylation of focal adhesion kinase (FAK) and paxillin was detected by Western blotting, and the bands were analysed using Adobe Photoshop CS5 software. All experiments were performed at least three times, and data were analysed with one-way anova and a post hoc test. RESULTS: LPA-triggered activation of Rho and inhibition of ROCK significantly increased the cell migration rate. Cell migration was inhibited by silencing mDia1. mDia1 silencing and ROCK inhibition suppressed the LPA-induced formation of the cytoskeleton, FA and phosphorylation of FAK and paxillin. Inhibition of ROCK or mDia1 facilitated early cell adhesion and spreading; by contrast, the combined inhibition of ROCK and mDia1 neutralized these effects. CONCLUSIONS: mDia1 promoted RhoA-induced migration of DPCs, but ROCK had an opposite effect. Both mDia1 and ROCK participated in cytoskeleton formation and adhesion of DPCs. The interactions between mDia1 and ROCK might influence dental pulp repair by determining the migration and adhesion of DPCs. PMID- 26609805 TI - Coherence across consciousness levels: Symmetric visual displays spare working memory resources. AB - Two studies demonstrate that the need for coherence could nudge individuals to use structural similarities between binary visual displays and two concurrent cognitive tasks to unduly solve the latter in similar fashion. In an overt truth judgement task, participants decided whether symmetric colourful displays matched conjunction or disjunction descriptions (e.g., "the black and/or the orange"). In the simultaneous covert categorisation task, they decided whether a colour name (e.g., "black") described a two-colour object or half of a single-colour object. Two response patterns emerged as follows. Participants either acknowledged or rejected matches between disjunction descriptions and two visual stimuli and, similarly, either acknowledged or rejected matches between single colour names and two-colour objects or between single colour names and half of single-colour objects. These findings confirm the coherence hypothesis, highlight the role of coherence in preserving working-memory resources, and demonstrate an interaction between high-level and low-level consciousness. PMID- 26609806 TI - Circulating microparticles, protein C, free protein S and endothelial vascular markers in children with sickle cell anaemia. AB - INTRODUCTION: Circulating microparticles (MP) have been described in sickle cell anaemia (SCA); however, their interaction with endothelial markers remains unclear. We investigated the relationship between MP, protein C (PC), free protein S (PS), nitric oxide (NO), endothelin-1 (ET-1) and adrenomedullin (ADM) in a large cohort of paediatric patients. METHOD: A total of 111 children of African ethnicity with SCA: 51 in steady state; 15 in crises; 30 on hydroxyurea (HU) therapy; 15 on transfusion; 17 controls (HbAA) of similar age/ethnicity. MP were analysed by flow cytometry using: Annexin V (AV), CD61, CD42a, CD62P, CD235a, CD14, CD142 (tissue factor), CD201 (endothelial PC receptor), CD62E, CD36 (TSP-1), CD47 (TSP-1 receptor), CD31 (PECAM), CD144 (VE-cadherin). Protein C, free PS, NO, pro-ADM and C-terminal ET-1 were also measured. RESULTS: Total MP AV was lower in crisis (1.26*10(6) ml(-1); 0.56-2.44*10(6)) and steady state (1.35*10(6) ml(-1); 0.71-3.0*10(6)) compared to transfusion (4.33*10(6) ml(-1); 1.6-9.2*10(6), p<0.01). Protein C levels were significantly lower in crisis (median 0.52 IU ml(-1); interquartile range 0.43-0.62) compared with all other groups: HbAA (0.72 IU ml(-1); 0.66-0.82, p<0.001); HU (0.67 IU ml(-1); 0.58-0.77, p<0.001); steady state (0.63 IU ml(-1); 0.54-0.70, p<0.05) and transfusion (0.60 IU ml(-1); 0.54-0.70, p<0.05). In addition, levels were significantly reduced in steady state (0.63 IU ml(-1); 0.54-0.70) compared with HbAA (0.72 IU ml(-1); 0.66 0.80, p<0.01). PS levels were significantly higher in HbAA (0.85 IU ml(-1); 0.72 0.97) compared with crisis (0.49 IU ml(-1); 0.42-0.64, p<0.001), HU (0.65 IU ml( 1); 0.56-0.74, p<0.01) and transfusion (0.59 IU ml(-1); 0.47-0.71, p<0.01). There was also a significant difference in crisis patients compared with steady state (0.49 IU ml(-1); 0.42-0.64 vs. 0.68 IU ml(-1); 0.58-0.79, p<0.05). There was high correlation (R>0.9, p<0.05) between total numbers of AV-positive MP (MP AV) and platelet MP expressing non-activation platelet markers. There was a lower correlation between MP AV and MP CD62P (R=0.73, p<0.05) (platelet activation marker), and also a lower correlation between percentage of MP expressing CD201 (%MP CD201) and %MP CD14 (R=0.627, p<0.001). %MP CD201 was higher in crisis (11.6%) compared with HbAA (3.2%, p<0.05); %MP CD144 was higher in crisis (7.6%) compared with transfusion (2.1%, p<0.05); %CD14 (0.77%) was higher in crisis compared with transfusion (0.0%, p<0.05) and steady state (0.0%, p<0.01); MP CD14 was detectable in a higher number of samples (92%) in crisis compared with the rest (40%); %MP CD235a was higher in crisis (17.9%) compared with transfusion (8.9%), HU (8.7%) and steady state (9.9%, p<0.05); %CD62E did not differ significantly across the groups and CD142 was undetectable. Pro-ADM levels were raised in chest crisis: 0.38 nmol L(-1) (0.31-0.49) versus steady state: 0.27 nmol L(-1) (0.25-0.32; p<0.01) and control: 0.28 nmol L(-1) (0.27-0.31; p<0.01). CT-proET-1 levels were reduced in patients on HU therapy: 43.6 pmol L(-1) (12.6 49.6) versus control: 55.1 pmol L(-1) (45.2-63.9; p<0.05). NO levels were significantly lower in chest crisis (19.3 mmol L(-1) plasma; 10.7-19.9) compared with HU (22.2 mmol L(-1) plasma; 18.3-28.4; p<0.05), and HbSC (30.6 mmol L(-1) plasma; 20.8-39.5; p<0.05) and approach significance when compared with steady state (22.5mmol L(-1) plasma; 16.9-28.2; p=0.07). CONCLUSION: Protein C and free PS are reduced in crisis with lower numbers of platelet MP and higher percentage of markers of endothelial damage and of red cell origin. During chest crisis, ADM and ET-1 were elevated suggesting a role for therapy inhibiting ET-1 in chest crisis. PMID- 26609807 TI - Characterisation of adipocyte-derived extracellular vesicles released pre- and post-adipogenesis. AB - Extracellular vesicles (EVs) are submicron vesicles released from many cell types, including adipocytes. EVs are implicated in the pathogenesis of obesity driven cardiovascular disease, although the characteristics of adipocyte-derived EVs are not well described. We sought to define the characteristics of adipocyte derived EVs before and after adipogenesis, hypothesising that adipogenesis would affect EV structure, molecular composition and function. Using 3T3-L1 cells, EVs were harvested at day 0 and day 15 of differentiation. EV and cell preparations were visualised by electron microscopy and EVs quantified by nanoparticle tracking analysis (NTA). EVs were then assessed for annexin V positivity using flow cytometry; lipid and phospholipid composition using 2D thin layer chromatography and gas chromatography; and vesicular protein content by an immuno phenotyping assay. Pre-adipogenic cells are connected via a network of protrusions and EVs at both time points display classic EV morphology. EV concentration is elevated prior to adipogenesis, particularly in exosomes and small microvesicles. Parent cells contain higher proportions of phosphatidylserine (PS) and show higher annexin V binding. Both cells and EVs contain an increased proportion of arachidonic acid at day 0. PREF-1 was increased at day 0 whilst adiponectin was higher at day 15 indicating EV protein content reflects the stage of adipogenesis of the cell. Our data suggest that EV production is higher in cells before adipogenesis, particularly in vesicles <300 nm. Cells at this time point possess a greater proportion of PS (required for EV generation) whilst corresponding EVs are enriched in signalling fatty acids, such as arachidonic acid, and markers of adipogenesis, such as PREF-1 and PPARgamma. PMID- 26609808 TI - EGF-dependent re-routing of vesicular recycling switches spontaneous phosphorylation suppression to EGFR signaling. AB - Autocatalytic activation of epidermal growth factor receptor (EGFR) coupled to dephosphorylating activity of protein tyrosine phosphatases (PTPs) ensures robust yet diverse responses to extracellular stimuli. The inevitable tradeoff of this plasticity is spontaneous receptor activation and spurious signaling. We show that a ligand-mediated switch in EGFR trafficking enables suppression of spontaneous activation while maintaining EGFR's capacity to transduce extracellular signals. Autocatalytic phosphorylation of tyrosine 845 on unliganded EGFR monomers is suppressed by vesicular recycling through perinuclear areas with high PTP1B activity. Ligand-binding results in phosphorylation of the c-Cbl docking tyrosine and ubiquitination of the receptor. This secondary signal relies on EGF-induced EGFR self-association and switches suppressive recycling to directional trafficking. The re-routing regulates EGFR signaling response by the transit-time to late endosomes where it is switched-off by high PTP1B activity. This ubiquitin-mediated switch in EGFR trafficking is a uniquely suited solution to suppress spontaneous activation while maintaining responsiveness to EGF. PMID- 26609809 TI - The brown adipocyte protein CIDEA promotes lipid droplet fusion via a phosphatidic acid-binding amphipathic helix. AB - Maintenance of energy homeostasis depends on the highly regulated storage and release of triacylglycerol primarily in adipose tissue, and excessive storage is a feature of common metabolic disorders. CIDEA is a lipid droplet (LD)-protein enriched in brown adipocytes promoting the enlargement of LDs, which are dynamic, ubiquitous organelles specialized for storing neutral lipids. We demonstrate an essential role in this process for an amphipathic helix in CIDEA, which facilitates embedding in the LD phospholipid monolayer and binds phosphatidic acid (PA). LD pairs are docked by CIDEA trans-complexes through contributions of the N-terminal domain and a C-terminal dimerization region. These complexes, enriched at the LD-LD contact site, interact with the cone-shaped phospholipid PA and likely increase phospholipid barrier permeability, promoting LD fusion by transference of lipids. This physiological process is essential in adipocyte differentiation as well as serving to facilitate the tight coupling of lipolysis and lipogenesis in activated brown fat. PMID- 26609810 TI - Actin filaments target the oligomeric maturation of the dynamin GTPase Drp1 to mitochondrial fission sites. AB - While the dynamin GTPase Drp1 plays a critical role during mitochondrial fission, mechanisms controlling its recruitment to fission sites are unclear. A current assumption is that cytosolic Drp1 is recruited directly to fission sites immediately prior to fission. Using live-cell microscopy, we find evidence for a different model, progressive maturation of Drp1 oligomers on mitochondria through incorporation of smaller mitochondrially-bound Drp1 units. Maturation of a stable Drp1 oligomer does not forcibly lead to fission. Drp1 oligomers also translocate directionally along mitochondria. Ionomycin, a calcium ionophore, causes rapid mitochondrial accumulation of actin filaments followed by Drp1 accumulation at the fission site, and increases fission rate. Inhibiting actin polymerization, myosin IIA, or the formin INF2 reduces both un-stimulated and ionomycin-induced Drp1 accumulation and mitochondrial fission. Actin filaments bind purified Drp1 and increase GTPase activity in a manner that is synergistic with the mitochondrial protein Mff, suggesting a role for direct Drp1/actin interaction. We propose that Drp1 is in dynamic equilibrium on mitochondria in a fission independent manner, and that fission factors such as actin filaments target productive oligomerization to fission sites. PMID- 26609811 TI - Optimal level activity of matrix metalloproteinases is critical for adult visual plasticity in the healthy and stroke-affected brain. AB - The ability of the adult brain to undergo plastic changes is of particular interest in medicine, especially regarding recovery from injuries or improving learning and cognition. Matrix metalloproteinases (MMPs) have been associated with juvenile experience-dependent primary visual cortex (V1) plasticity, yet little is known about their role in this process in the adult V1. Activation of MMPs is a crucial step facilitating structural changes in a healthy brain; however, upon brain injury, upregulated MMPs promote the spread of a lesion and impair recovery. To clarify these seemingly opposing outcomes of MMP-activation, we examined the effects of MMP-inhibition on experience-induced plasticity in healthy and stoke-affected adult mice. In healthy animals, 7-day application of MMP-inhibitor prevented visual plasticity. Additionally, treatment with MMP inhibitor once but not twice following stroke rescued plasticity, normally lost under these conditions. Our data imply that an optimal level of MMP-activity is crucial for adult visual plasticity to occur. PMID- 26609813 TI - De novo centriole formation in human cells is error-prone and does not require SAS-6 self-assembly. AB - Vertebrate centrioles normally propagate through duplication, but in the absence of preexisting centrioles, de novo synthesis can occur. Consistently, centriole formation is thought to strictly rely on self-assembly, involving self oligomerization of the centriolar protein SAS-6. Here, through reconstitution of de novo synthesis in human cells, we surprisingly found that normal looking centrioles capable of duplication and ciliation can arise in the absence of SAS-6 self-oligomerization. Moreover, whereas canonically duplicated centrioles always form correctly, de novo centrioles are prone to structural errors, even in the presence of SAS-6 self-oligomerization. These results indicate that centriole biogenesis does not strictly depend on SAS-6 self-assembly, and may require preexisting centrioles to ensure structural accuracy, fundamentally deviating from the current paradigm. PMID- 26609812 TI - ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA. AB - The cytosolic antiviral innate immune sensor RIG-I distinguishes 5' tri- or diphosphate containing viral double-stranded (ds) RNA from self-RNA by an incompletely understood mechanism that involves ATP hydrolysis by RIG-I's RNA translocase domain. Recently discovered mutations in ATPase motifs can lead to the multi-system disorder Singleton-Merten Syndrome (SMS) and increased interferon levels, suggesting misregulated signaling by RIG-I. Here we report that SMS mutations phenocopy a mutation that allows ATP binding but prevents hydrolysis. ATPase deficient RIG-I constitutively signals through endogenous RNA and co-purifies with self-RNA even from virus infected cells. Biochemical studies and cryo-electron microscopy identify a 60S ribosomal expansion segment as a dominant self-RNA that is stably bound by ATPase deficient RIG-I. ATP hydrolysis displaces wild-type RIG-I from this self-RNA but not from 5' triphosphate dsRNA. Our results indicate that ATP-hydrolysis prevents recognition of self-RNA and suggest that SMS mutations lead to unintentional signaling through prolonged RNA binding. PMID- 26609815 TI - Triarylporphyrin meso-Oxy Radicals: Remarkable Chemical Stabilities and Oxidation to Oxophlorin pi-Cations. AB - 5-Hydroxy-10,15,20-triarylporphyrin (oxophlorin) and its Ni(II) and Zn(II) complexes were oxidized with PbO2 to give the corresponding porphyrin meso-oxy radicals as remarkably stable species. These radicals were fully characterized with X-ray diffraction analysis, UV/vis/NIR absorption and ESR spectroscopies, magnetic susceptibility measurement, electrochemical studies, and theoretical calculations. Free-base radical and its Ni(II) complex have been shown to exist as a monoradical in solution, while the Zn(II) complex exists in an equilibrium between monomer (doublet monoradical) and dimer (a non-Kekule singlet biradicaloid) with a dimerization constant of KD = 3.0 * 10(5) M(-1) in noncoordinating CH2Cl2 but becomes a pyridine-coordinated monoradical upon addition of pyridine. Variable temperature magnetic susceptibility measurements of these radicals revealed different magnetic interactions in the solid-states, which has been interpreted in terms of their different packing structures in a microscopic sense. These radicals undergo one-electron oxidation and reduction in a reversible manner within narrow potential windows of 0.57-0.82 V. Finally, one electron oxidation of Ni(II) and Zn(II) porphyrin meso-oxy radicals with tris(4 bromophenyl)aminium hexachloroantimonate furnished oxophlorin pi-cations, which displayed nonaromatic closed-shell character, NIR absorption, and significant double bond character of the C-O bond. PMID- 26609814 TI - Multiple abiotic stimuli are integrated in the regulation of rice gene expression under field conditions. AB - Plants rely on transcriptional dynamics to respond to multiple climatic fluctuations and contexts in nature. We analyzed the genome-wide gene expression patterns of rice (Oryza sativa) growing in rainfed and irrigated fields during two distinct tropical seasons and determined simple linear models that relate transcriptomic variation to climatic fluctuations. These models combine multiple environmental parameters to account for patterns of expression in the field of co expressed gene clusters. We examined the similarities of our environmental models between tropical and temperate field conditions, using previously published data. We found that field type and macroclimate had broad impacts on transcriptional responses to environmental fluctuations, especially for genes involved in photosynthesis and development. Nevertheless, variation in solar radiation and temperature at the timescale of hours had reproducible effects across environmental contexts. These results provide a basis for broad-based predictive modeling of plant gene expression in the field. PMID- 26609816 TI - Accurate DFT Descriptions for Weak Interactions of Molecules Containing Sulfur. AB - Dispersion corrected atom centered potentials (DCACPs) have been shown to significantly improve the density functional theory (DFT) description of weak interactions. In this work, we have calibrated a DCACP for sulfur in combination with the widely used Generalized Gradient Approximation (GGA) BLYP, thereby augmenting the existing library of DCACPs for the first- and second-row elements H, C, N, O, and rare gases. Three weakly bound complexes as well as elemental (orthorhombic) sulfur are used as test cases to evaluate the transferability of the DCACP to different chemical environments. It is found that the sulfur DCACP systematically improves the agreement of DFT-calculated weak interactions with respect to MP2 and CCSD(T) level results. PMID- 26609817 TI - First-Principle Calculations of Large Fullerenes. AB - State of-the-art density functional theory calculations have been performed for the large fullerenes C180, C240, C320, and C540 using the linear combination of Gaussian-type orbitals density functional theory (LCGTO-DFT) approach. For the calculations all-electron basis sets were employed. All fullerene structures were fully optimized without symmetry constrains. The analysis of the obtained structures as well as a study on the evolution of the bond lengths and calculated binding energies are presented. The fullerene results are compared to diamond and graphene which were calculated at the same level of theory. This represents the first systematic study on these large fullerenes based on nonsymmetry adapted first-principle calculations, and it demonstrates the capability of DFT calculations for energy and structure computations of large scale structures without any symmetry constraint. PMID- 26609818 TI - A DFT Study of the Kinetic Isotope Effects on the Competing SN2 and E2 Reactions between Hypochlorite Anion and Ethyl Chloride. AB - Kinetic isotope effects (KIEs) on the two alternative reactions, SN2 and E2, between hypochlorite anion and ethyl chloride in water have been studied theoretically using B3LYP and M06-2X functionals. It has been found that the latter one yields more correct geometries and energetics. Although, in the qualitative sense, KIEs obtained using both DFT functionals are in agreement, interpretation of some of them, like (18)O-KIE in the present case, leads to different mechanistic conclusions. PMID- 26609819 TI - A Multiscale Treatment of Angeli's Salt Decomposition. AB - Sodium trioxodinitrate's (Na2N2O3, Angeli's salt) unique cardiovascular effects have been associated with its ability to yield HNO upon dissociation under physiological conditions. Due to its potential applications in new therapies for heart failure, the dissociation of Angeli's salt has recently received increased attention. The decomposition mechanism has been previously studied by quantum mechanical methods using a continuum approximation (PCM) for the solvent effects. In this work we use our recently developed interface of the Amber and Gaussian packages via the PUPIL package to study Angeli's salt dissociation in a hybrid QM/MM scheme where the water solvent molecules are treated explicitly with classical mechanics while the solute is treated with full quantum mechanics (UB3LYP/6-31+G(d) and UMP2/6-31+G(d)) level. Multiple steered molecular dynamics was used with the Jarzynski relationship to extract the free energy profile for the process. We obtain 4.8 kcal mol(-1) and 6.4 kcal mol(-1) free energy barriers for the N-N bond breaking for UB3LYP and UMP2, respectively. The geometries and Mulliken charges for reactant, transition state, and products have been characterized through a number of hybrid QM/MM molecular dynamics runs with the N N distance restrained to representative values of each species. The results highlight the role of individual solvent molecules for the reaction energetics and provide a comparison point against implicit solvation methods. PMID- 26609820 TI - Mechanistic Analysis of the Base-Catalyzed HF Elimination from 4-Fluoro-4-(4' nitrophenyl)butane-2-one Based on Liquid-Phase Kinetic Isotope Effects Calculated by Dynamics Modeling with Multidimensional Tunneling. AB - The primary and secondary deuterium kinetic isotope effects as well as leaving group fluorine kinetic isotope effects have been calculated for the base-promoted elimination of hydrogen fluoride from 4-fluoro-4-(4'-nitrophenyl)butane-2-one in 75% aqueous methanol solution. The elimination was studied for both formate and imidazole as the catalytic base; and reactant and transition state structures and vibrational frequencies have been calculated by including the base explicitly and by including the solvent by an implicit solvation model that includes both electrostatics by class IV charges and first-solvation-shell effects by atomic surface tensions. We used the M06-L density functional for all calculations. The optimized stationary points, the geometry changes along the solution-phase minimum free energy path, and the solution-phase free energy profile indicate that the elimination reaction occurs concertedly but asynchronously via an E1cb like transition state. Reaction rates were calculated by the equilibrium solvation path method, using variational transition state theory with multidimensional tunneling. The primary deuterium kinetic isotope effects are calculated to be large: 1.67 and 5.13 for formate and imidazole, respectively. The corresponding C4-secondary deuterium kinetic isotope effects are 1.044 and 1.044, and the leaving group fluorine kinetic isotope effects are respectively 1.020 and 1.015. PMID- 26609821 TI - Comparison of Semiempirical ZILSH and DFT Calculations of Exchange Constants in Fe4 Butterfly Complexes. AB - Magnetic interactions in a series of tetranuclear Fe(3+) complexes with the butterfly core structure have been studied with semiempirical ZILSH and density functional theory (DFT) calculations (B3LYP functional). A theoretical analysis of a previously used method of estimating exchange constants from a restricted number of spin configurations reveals systematic errors arising from asymmetry in the complexes, which cause large variations in results with different choices of spin configurations. Correction factors are derived that yield the correct results obtained from full configuration space (FCS) calculations. Exchange constants obtained from DFT FCS calculations for the "body-body" interaction were large and ferromagnetic, in disagreement with values obtained from empirical fits of magnetic susceptibility data for the complexes, established magnetostructural correlations in polynuclear Fe(3+) complexes, and ZILSH calculations. DFT calculations also gave unreasonably large antiferromagnetic exchange constants for interaction between "wingtip" ions that are not directly bridged, again in disagreement with ZILSH calculations. Estimates of exchange constants for interaction of body and wingtip ions obtained with ZILSH and DFT were similar, with the ZILSH values in slightly better agreement with empirical fits. Considering all interactions, the ZILSH method provides results in better accord with experiment than DFT for these complexes. Additional comparisons of exchange constants obtained with different spin coupling schemes showed that values appropriate for two-center spin eigenfunctions gave consistently better results than values calculated with the local spin operator. The effect of basis set was found to be very small. A brief analysis of these findings is given. PMID- 26609822 TI - Automatic Selection of Integral Thresholds by Extrapolation in Coulomb and Exchange Matrix Constructions. AB - We present a method to compute Coulomb and exchange matrices with predetermined accuracy as measured by a matrix norm. The computation of these matrices is fundamental in Hartree-Fock and Kohn-Sham electronic structure calculations. We show numerically that, when modern algorithms for Coulomb and exchange matrix evaluation are applied, the Euclidean norm of the error matrix epsilon is related to the threshold value tau as epsilon = ctau(alpha). The presented extrapolation method automatically selects the integral thresholds so that the Euclidean norm of the error matrix is at the requested accuracy. This approach is demonstrated for a variety of systems, including protein-like systems, water clusters, and graphene sheets. The proposed method represents an important step toward complete error control throughout the self-consistent field calculation as described in [J. Math. Phys. 2008, 49, 032103]. PMID- 26609823 TI - Performance of Several Density Functional Theory Methods on Describing Hydrogen Bond Interactions. AB - We have investigated eleven density functionals, including LDA, PBE, mPWPW91, TPSS, B3LYP, X3LYP, PBE0, O3LYP, B97-1, MPW1K, and TPSSh, for their performances on describing hydrogen bond (HB) interactions. The emphasis has been laid not only on their abilities to calculate the intermolecular hydrogen bonding energies but also on their performances in predicting the relative energies of intermolecular H-bonded complexes and the conformer stabilities due to intramolecular hydrogen bondings. As compared to the best theoretical values, we found that although PBE and PBE0 gave the best estimation of HB strengths, they might fail to predict the correct order of relative HB energies, which might lead to a wrong prediction of the global minimum for different conformers. TPSS and TPSSh did not always improve over PBE and PBE0. B3LYP was found to underestimate the intermolecular HB strengths but was among the best performers in calculating the relative HB energies. We showed here that X3LYP and B97-1 were able to give good values for both absolute HB strengths and relative HB energies, making these functionals good candidates for HB description. PMID- 26609824 TI - Influence of Guest-Host Interactions on the Structural, Energetic, and Mossbauer Spectroscopy Properties of Iron(II)tris(2,2'-bipyridine) in the Low-Spin and High Spin States: A Density-Functional Theory Study of the Zeolite-Y Embedded Complex. PMID- 26609825 TI - Gradient Projection Method for Constraint Optimization and Relaxed Energy Paths on Conical Intersection Spaces and Potential Energy Surfaces. AB - A gradient projection algorithm is presented that permits the application of several constraints during geometry optimization on electronic potential energy surfaces (PES) or conical intersection (CI) seams. The algorithm generalizes the idea recently published in this journal (Sicilia et al. J. Chem. Theory Comput. 2008, 4, 257) for the optimization of conical intersection geometries. Singular value decomposition is used to transform all constraints, including those related to maintaining the CI, to a new set of constraints with orthogonal gradients. The constraints need not be satisfied at the initial geometry but will be upon convergence. A procedure is presented that determines relaxed energy paths (REP) connecting two reference structures on a potential energy surface, or the conical intersection space, without the need to assign an internal coordinate as the reaction coordinate. Examples are presented of optimizations of minimum energy structures and REPs in the CI space and REPs on a single electronic PES. PMID- 26609826 TI - SEST: Simulated Electronic Structure Theory. AB - A novel approach to empirically modeling the electronic structure of molecules is introduced. The theory is based on relationships between molecular orbital energy components and the average distance between electrons and electrons and nuclei. The electron-electron and electron-nucleus distances are subsequently related to interatomic distances which provides a means for modeling the electronic structure of molecules. The general energy expression for a simulated electronic structure theory is defined, along with the functional form of the interatomic distance dependent energy functions. The theory is used to model the hydrogen molecule, the first-row hydrides, and ethane. The models, which have the correct RHF/6-31G(d) optimized geometries, also fit the RHF/6-31G(d) energy at equilibrium and the UHF/6-31G(d) energy at the bond dissociation limit as well as some vibrational frequencies. PMID- 26609827 TI - Electronic Structure Calculations under Periodic Boundary Conditions Based on the Gaussian and Fourier Transform (GFT) Method. AB - We developed the Gaussian and Fourier transform method for crystalline systems. In this method, the Hartree (Coulomb) term of valence electron contribution is taken into account by solving the Poisson equation based on Fourier transform technique. We compared the band structures obtained by the Hartee-Fock (HF) approximation and the density functional theory (DFT). We used three different types of density functional approximations such as the local density approximation (LDA), generalized gradient approximation (GGA), and hybrid density functional. In this paper, we confirm that our calculation technique yields similar results to previous studies. PMID- 26609828 TI - A Few Comments on the Application of Density Functional Theory to the Calculation of the Magnetic Structure of Oligo-Nuclear Transition Metal Clusters. AB - First principle calculations of the magnetic structure of high nuclearity clusters appears challenging in order to validate fits of magnetic experiments. Density Functional Theory (DFT)-Broken Symmetry approach pair became, in the past few years, the most widely applied computational tool to investigating the chemical-physical properties of complex systems, in particular magnetic molecular compounds. However, the application of the Broken Symmetry formalism requires the knowledge of the energies of 2(N)/2 single Slater determinants, and this task can easily become difficult for large N. Three main approximations are therefore usually done in order to limit the computational efforts: the model dimer approach (MDA), the doped cluster approach (DCA), and the minimum cluster approach (MCA). The whole cluster approach (WCA) will be also applied as reference and in order to check the importance of spin Hamiltonian high order terms. A systematic comparison between these different approaches has been, therefore, performed. Since this study is aimed for being of help in choosing the best method of calculation, we check here the validity of the above approaches by computing the magnetic structure of some test systems: the tetrahedral system (HeH)4 and linear [Cu(II)]3 and [Mn(II)]4 complexes. PMID- 26609829 TI - Br...O Complexes as Probes of Factors Affecting Halogen Bonding: Interactions of Bromobenzenes and Bromopyrimidines with Acetone. AB - Halogen bonding is a unique type of noncovalent binding phenomenon in which a halogen atom interacts attractively with an electronegative atom such as oxygen or nitrogen. These types of interactions have been the subject of many recent investigations because of their potential in the development of new materials and pharmaceutical compounds. Recently, it was observed that most halogen bonding interactions in biological contexts involve close contacts between a halogen bound to an aromatic ring and a carbonyl oxygen on a protein's backbone structure. In this work we investigate interactions of substituted bromobenzenes and bromopyrimidines with acetone to ascertain the effects of various substituents upon the strengths of these interactions. It was found that replacement of ring hydrogens in these systems has dramatic effects upon the interaction strengths of the resulting complexes, which have interaction energies between -1.80 and -7.11 kcal/mol. Examination of the electrostatic potentials of the substituted bromobenzene and bromopyrimidine monomers indicates that the addition of substituents has a large influence upon the most positive electrostatic potential on the surface of the interacting bromine and thus modulates these halogen bonding interactions. Results obtained using the symmetry adapted perturbation theory (SAPT) interaction energy decomposition procedure also indicate that electrostatic interactions play the key role in these halogen bonding interactions. These results have important implications in drug design and crystal engineering. Halogen bonds have been a subject of great interest in these fields because of their unique noncovalent bonding characteristics. PMID- 26609830 TI - Computation of Local and Global Properties of the Electron Localization Function Topology in Crystals. AB - We present a novel computational procedure, general, automated, and robust, for the analysis of local and global properties of the electron localization function (ELF) in crystalline solids. Our algorithm successfully faces the two main shortcomings of the ELF analysis in crystals: (i) the automated identification and characterization of the ELF induced topology in periodic systems, which is impeded by the great number and concentration of critical points in crystalline cells, and (ii) the localization of the zero flux surfaces and subsequent integration of basins, whose difficulty is due to the diverse (in many occasions very flat or very steep) ELF profiles connecting the set of critical points. Application of the new code to representative crystals exhibiting different bonding patterns is carried out in order to show the performance of the algorithm and the conceptual possibilities offered by the complete characterization of the ELF topology in solids. PMID- 26609831 TI - Location of Two Seams in the Proximity of the C2v pipi* Minimum Energy Path of Formaldehyde. AB - Photochemical reactions rationalization is a key aspect for the understanding and setup of novel experiment and novel photoinitiated pathways. In this respect, the relationship between minimum energy paths over an excited-state and the intersection to lower potential energy surfaces is fundamental. In order to help the understanding of this relationship, in this study we present a novel kind of constraint for geometry optimizations, namely, an "orthogonality" constraint. Its possible applications are described. A complete example on how to retrieve the direct relationship between a minimum energy path over an excited-state potential energy surface and a conical intersection seam is given for C2v symmetry constrained formaldehyde. The advantages of using the novel constraint when rationalizing a (photo)chemical reaction are presented. PMID- 26609832 TI - Validation of the B3LYP/N07D and PBE0/N07D Computational Models for the Calculation of Electronic g-Tensors. AB - Calculations on a large set of free radicals containing atoms of the second and third row show that the computational model defined by the new N07D basis set and hybrid density functionals (B3LYP and PBE0) provides remarkably accurate g-tensor values at reasonable computational costs. Since in previous works it has been shown that the same computational model delivers reliable results also for structural parameters and hyperfine couplings, the route seems paved toward full a priori computation of EPR spectra of large free radicals both in vacuo and in condensed phases. PMID- 26609833 TI - Simulation of Vibrational Spectra of Large Molecules by Arbitrary Time Propagation. AB - Modern ab initio and multiscale methods enable the simulation of vibrational properties of very large molecules. Within the harmonic approximation, the traditional generation of the spectra based on the force field diagonalization can become inefficient due to the excessive demands on computer time and memory. The present study proposes to avoid completely the matrix diagonalization with a direct generation of the spectral shapes. For infrared absorption (IR) and vibrational circular dichroism (VCD) electric and magnetic dipole moments are propagated in a fictitious time and spectral intensities are obtained by Fourier transformation. The algorithm scales quasi-linearly, and for model polypeptide molecules the method was found numerically stable and faithfully reproduced exact transition frequencies and relative intensities. PMID- 26609834 TI - Systematic Comparison of Second-Order Polarization Propagator Approximation (SOPPA) and Equation-of-Motion Coupled Cluster Singles and Doubles (EOM-CCSD) Spin-Spin Coupling Constants for Molecules with C, N, and O Double and Triple Bonds and Selected F-Substituted Derivatives. AB - Ab initio EOM-CCSD and SOPPA calculations with the Ahlrichs (qzp,qz2p) basis set have been carried out to evaluate one-, two-, and three-bond spin-spin coupling constants for molecules HmX?YHn and HmX?YHn for X, Y = (13)C, (15)N, and (17)O, and selected (19)F-substituted derivatives. In the great majority of cases, EOM CCSD one-bond C-C, C-N, C-O, C-F, N-N, N-O, and N-F coupling constants and three bond F-F coupling constants are smaller in absolute value than the corresponding SOPPA coupling constants, with the EOM-CCSD values in better agreement with experimental data. SOPPA tends to significantly overestimate the absolute values of large one- and three-bond couplings involving fluorine. The majority of two bond SOPPA coupling constants are in better agreement with experiment than EOM CCSD, although differences between EOM-CCSD and experimental values are not dramatic. A statistical analysis of thirty EOM-CCSD and SOPPA coupling constants versus experimental coupling constants demonstrates that better agreement with experiment is found when EOM-CCSD is the computational method. PMID- 26609835 TI - Dissociative Electron Attachment to Formamide: Direct and Indirect Pathways from Resonant Intermediates. PMID- 26609836 TI - Transition States in a Protein Environment - ONIOM QM:MM Modeling of Isopenicillin N Synthesis. AB - To highlight the role of the protein in metal enzyme catalysis, we optimize ONIOM QM:MM transition states and intermediates for the full reaction of the nonheme iron enzyme isopenicillin N synthase (IPNS). Optimizations of transition states in large protein systems are possible using our new geometry optimizer with quadratic coupling between the QM and MM regions [Vreven, T. et al. Mol. Phys. 2006, 104, 701-704]. To highlight the effect of the metal center, results from the protein model are compared to results from an active site model containing only the metal center and coordinating residues [Lundberg, M. et al. Biochemistry 2008, 47, 1031-1042]. The analysis suggests that the main catalytic effect comes from the metal center, while the protein controls the reactivity to achieve high product specificity. As an example, hydrophobic residues align the valine substrate radical in a favorable conformation for thiazolidine ring closure and contribute to product selectivity and high stereospecificity. A low-barrier pathway for beta-lactam formation is found where the proton required for heterolytic O-O bond cleavage comes directly from the valine N-H group of the substrate. The alternative mechanism, where the proton in O-O bond cleavage initially comes from an iron water ligand, can be disfavored by the electrostatic interactions with the surrounding protein. Explicit protein effects on transition states are typically 1-6 kcal/mol in the present enzyme and can be understood by considering whether the transition state involves large movements of the substrate as well as whether it involves electron transfer. PMID- 26609837 TI - Characterization of Self-Assembled Monolayers of Peptide Mimotopes of CD20 Antigen and Their Binding with Rituximab. AB - CD20, expressed in greater than 90% of B-lymphocytic lymphomas, is a target for antibody therapy. Rituximab is a chimeric therapeutic monoclonal antibody (mAb) against the protein CD20, allowing it to destroy B cells and to treat lymphoma, leukemia, transplant rejection, and autoimmune disorder. In this work, the binding of rituximab to self-assembled monolayers (SAMs) of peptide mimotopes of CD20 antigen was systematically characterized. Four peptide mimotopes of CD 20 antigen were selected from the literature and redesigned to allow their SAM immobilizations on gold electrodes through a peptide linker with cysteine. The bindings of these peptides with rituximab and control mAbs (trastuzumab and bevacizumab) were characterized by quartz crystal microbalance (QCM). Among the four peptide mimotopes initially selected, the peptide designated as CN-14 (CGSGSGSWPRWLEN) was the most selective and sensitive for rituximab binding. The CN-14 SAM was further characterized by ellipsometry and atomic force microscopy. The thickness of the CN-14 SAM film was approximately 32 A, and the CN-14 SAM is suggested to be stabilized by a salt bridge of Arg-10 and Glu-13 between CN-14 peptides. The CN-14 salt bridge was evaluated by a series of modifications to the CN-14 peptide sequence and characterized by QCM. The CN-14 amide variant produced a better affinity to rituximab than CN-14 without a significant impact on selectivity. As the pKa of the Glu residue of CN-14 increased, the affinity of the SAM to rituximab increased, whereas the selectivity decreased. This was attributed to the weakening of the salt bridge between the CN-14 Arg-10 and Glu 13 at higher pKa values for Glu-13. Our study shows that peptide mimotopes have potential benefits in sensor applications, as the peptide-peptide interactions in the SAMs can be manipulated by the addition of functional groups to the peptide to influence the binding of target proteins. PMID- 26609839 TI - On Ion and Molecular Polarization of Halides in Water. AB - The high polarizability of halide anions affects, in aqueous solutions, many phenomena ranging from hydrogen bond dynamics to water interfaces' structure. In this Letter dipolar interactions of halides in water are investigated through Car Parrinello Molecular Dynamics simulations. Contrary to previous studies, a different polarization of first and second hydration shell water molecules is found. The analysis hints that existing classical polarizable force fields lack a description of short-range interactions which causes an overestimation of polarization effects. PMID- 26609838 TI - An assessment of the doses received by members of the public in Japan following the nuclear accident at Fukushima Daiichi nuclear power plant. AB - The earthquake and tsunami on 11 March 2011, centred off the east coast of Japan, caused considerable destruction and substantial loss of life along large swathes of the Japanese coastline. The tsunami damaged the Fukushima Daiichi nuclear power plant (NPP), resulting in prolonged releases of radioactive material into the environment. This paper assesses the doses received by members of the public in Japan. The assessment is based on an estimated source term and atmospheric dispersion modelling rather than monitoring data. It is evident from this assessment that across the majority of Japan the estimates of dose are very low, for example they are estimated to be less than the annual average dose from natural background radiation in Japan. Even in the regions local to Fukushima Daiichi NPP (and not affected by any form of evacuation) the maximum lifetime effective dose is estimated to be well below the cumulative natural background dose over the same period. The impact of the urgent countermeasures on the estimates of dose was considered. And the relative contribution to dose from the range of exposure pathways and radionuclides were evaluated. Analysis of estimated doses focused on the geographic irregularity and the impact of the meteorological conditions. For example the dose to an infant's thyroid received over the first year was estimated to be greater in Hirono than in the non evacuated region of Naraha, despite Hirono being further from the release location. A number of factors were identified and thought to contribute towards this outcome, including the local wind pattern which resulted in the recirculation of part of the release. The non-uniform nature of dose estimates strengthens the case for evaluations based on dispersion modelling. PMID- 26609840 TI - Non-Hermitian Multiconfiguration Molecular Mechanics. AB - We present a new version of the multiconfiguration molecular mechanics (MCMM) algorithm for fitting potential energy surfaces of complex reactive systems. The main improvement consists in allowing the valence bond configuration interaction matrix to be non-Hermitian, which broadens the range of geometries over which the potential energy surface can be fit accurately. A second improvement is that the new algorithm has simpler gradients and Hessians and executes faster. The performance of the new algorithm is evaluated using the example of two model reactions. PMID- 26609841 TI - Dynamically Polarizable Water Potential Based on Multipole Moments Trained by Machine Learning. AB - It is widely accepted that correctly accounting for polarization within simulations involving water is critical if the structural, dynamic, and thermodynamic properties of such systems are to be accurately reproduced. We propose a novel potential for the water dimer, trimer, tetramer, pentamer, and hexamer that includes polarization explicitly, for use in molecular dynamics simulations. Using thousands of dimer, trimer, tetramer, pentamer, and hexamer clusters sampled from a molecular dynamics simulation lacking polarization, we train (artificial) neural networks (NNs) to predict the atomic multipole moments of a central water molecule. The input of the neural nets consists solely of the coordinates of the water molecules surrounding the central water. The multipole moments are calculated by the atomic partitioning defined by quantum chemical topology (QCT). This method gives a dynamic multipolar representation of the water electron density without explicit polarizabilities. Instead, the required knowledge is stored in the neural net. Furthermore, there is no need to perform iterative calculations to self-consistency during the simulation nor is there a need include damping terms in order to avoid a polarization catastrophe. PMID- 26609842 TI - Optimization of Capping Potentials for Spectroscopic Parameters in Hybrid Quantum Mechanical/Mechanical Modeling Calculations. AB - We present a capping scheme for hybrid calculations which is designed for a systematic optimization to reproduce the molecular structure, frontier bond potential, and spectroscopic properties for the quantum subsystem. Our technique is capable of reducing the perturbations of the electronic structure which are normally caused by conventional link atoms between quantum and classical regions. Specifically, we propose analytic effective core potentials with a small set of adjustable parameters, which are optimized to reproduce the full-quantum mechanical (full-QM) properties in the direct environment of the bond cleavage. The capping potentials are conceptually simple and easy to employ in most instances without significant code modifications. They do not require any further external geometry constraints and yield also reasonable results for the potential energy surface. We benchmark these potentials for a series of chemically and biologically relevant molecules calculating NMR chemical shifts, protonation energies, and optimized geometries. Our optimized QM/mechanical modeling (MM) potentials are another step toward a realistic first-principles prediction of spectroscopic parameters in complex chemical environments using hybrid QM/MM calculations. PMID- 26609843 TI - Non-self-consistent Density-Functional Theory Exchange-Correlation Forces for GGA Functionals. AB - When using density functional theory (DFT), generalized gradient approximation (GGA) functionals are often necessary for accurate modeling of important properties of biomolecules, including hydrogen-bond strengths and relative energies of conformers. We consider the calculations of forces using non-self consistent (NSC) methods based on the Harris-Foulkes expression for energy. We derive an expression for the GGA NSC force on atoms, valid for a hierarchy of methods based on local orbitals, and discuss its implementation in the linear scaling DFT code Conquest, using a standard (White-Bird) approach. We investigate the use of NSC structural relaxations before full self-consistent relaxations as a method for improving convergence. Example calculations for glycine and small alanine peptides suggest that NSC pre-relaxations of the structure are indeed useful to save computer effort and time. PMID- 26609844 TI - Addressing Through-H Magnetic Interactions: A Comprehensive ab Initio Analysis of This Efficient Coupler. AB - The exchange coupling in a structuraly characterized Cu(II)2 complex is analyzed to highlight the role of H bonds in the generation of efficient magnetic interactions. The interest for complementary insights which are not accessible through DFT calculations (Desplanches, C. et al. J. Am. Chem. Soc. 2002, 124, 5197) has driven this state-of-the-art ab initio inspection. The wave function expansion based upon localized orbitals allows us to selectively turn on specific mechanisms and quantitatively evaluate their roles in the exchange interactions. Our singlet-triplet splitting calculations demonstrate the enhancement of the magnetic coupling through a concerted oxygen-to-metal charge transfer and electronic redistribution within the OH bond of the OH...O magnetic linker. This mechanism accounts for ~35% of the total experimentally measured singlet-triplet energy difference. This analysis strongly suggests that H bonds might be particularly useful not only in the establishment of intermolecular contacts but also within the basic units of magnetic materials. PMID- 26609845 TI - Conformers of Gaseous Cysteine. AB - Structures, accurate relative energies, equilibrium and vibrationally averaged rotational constants, quartic and sextic centrifugal distortion constants, dipole moments, (14)N nuclear quadrupole coupling constants, anharmonic vibrational frequencies, and double-harmonic infrared intensities have been determined from ab initio electronic structure computations for conformers of the neutral form of the natural amino acid l-cysteine (Cys). A systematic scan located 71 unique conformers of Cys using the MP2(FC)/cc-pVTZ method. The large number of structurally diverse low-energy conformers of Cys necessitates the highest possible levels of electronic structure theory to determine their relative energies with some certainty. For this reason, we determined the relative energies of the lowest-energy eleven conformers, accurate within a standard error (1sigma) of about 0.3 kJ mol(-1), through first-principles composite focal-point analyses (FPA), which employed extrapolations using basis sets as large as aug-cc pV(5+d)Z and correlation treatments as extensive as CCSD(T). Three and eleven conformers of l-cysteine fall within a relative energy of 6 and 10 kJ mol(-1), respectively. The vibrationally averaged rotational constants computed in this study agree well with Fourier-transform microwave spectroscopy results. The effects determining the relative energies of the low-energy conformers of cysteine are analyzed in detail on the basis of hydrogen bond additivity schemes and natural bond orbital analysis. PMID- 26609846 TI - Balance of Attraction and Repulsion in Nucleic-Acid Base Stacking: CCSD(T)/Complete-Basis-Set-Limit Calculations on Uracil Dimer and a Comparison with the Force-Field Description. AB - We have carried out reference quantum-chemical calculations for about 100 geometries of the uracil dimer in stacked conformations. The calculations have been specifically aimed at geometries with unoptimized distances between the monomers including geometries with mutually tilted monomers. Such geometries are characterized by a delicate balance between local steric clashes and local unstacking and had until now not been investigated using reference quantum mechanics (QM) methods. Nonparallel stacking geometries often occur in nucleic acids and are of decisive importance, for example, for local conformational variations in B-DNA. Errors in the short-range repulsion region would have a major impact on potential energy scans which were often used in the past to investigate local geometry variations in DNA. An incorrect description of such geometries may also partially affect molecular dynamics (MD) simulations in applications when quantitative accuracy is required. The reference QM calculations have been carried out using the MP2 method extrapolated to the complete basis-set limit and corrected for higher-order electron-correlation contributions using CCSD(T) calculations with a medium-sized basis set. These reference calculations have been used as benchmark data to test the performance of the DFT-D, SCS(MI)-MP2, and DFT-SAPT QM methods and of the AMBER molecular mechanics (MM) force field. The QM methods show close to quantitative agreement with the reference data, albeit the DFT-D method tends to modestly exaggerate the repulsion of steric clashes. The force field in general also provides a good description of base stacking for the systems studied here. However, for geometries with close interatomic contacts and clashes, the repulsion effects are rather severely exaggerated. The discrepancy reported here should not affect the overall stability of MD simulations and qualitative applications of the force field. However, it may affect the description of subtle quantitative effects such as the local conformational variations in B-DNA. Preliminary calculations for two H-bonded uracil base pairs, including one with a C-H...O H-bond, indicate excellent performance of the tested QM methods for all intermonomer distances. The force field, on the other hand, is less satisfactory, especially in the repulsive regions. PMID- 26609847 TI - Ab Initio Density Fitting: Accuracy Assessment of Auxiliary Basis Sets from Cholesky Decompositions. AB - The accuracy of auxiliary basis sets derived by Cholesky decompositions of the electron repulsion integrals is assessed in a series of benchmarks on total ground state energies and dipole moments of a large test set of molecules. The test set includes molecules composed of atoms from the first three rows of the periodic table as well as transition metals. The accuracy of the auxiliary basis sets are tested for the 6-31G**, correlation consistent, and atomic natural orbital basis sets at the Hartree-Fock, density functional theory, and second order Moller-Plesset levels of theory. By decreasing the decomposition threshold, a hierarchy of auxiliary basis sets is obtained with accuracies ranging from that of standard auxiliary basis sets to that of conventional integral treatments. PMID- 26609848 TI - Comparison of the Properties of Bent and Straight Single-Walled Carbon Nanotube Intramolecular Junctions. AB - The properties of four finite-length bent and straight intramolecular junctions (IMJs) connecting two armchair and zigzag single-walled carbon nanotube segments, viz. (3,3)-(6,0) and (4,4)-(8,0), were investigated. Their structures were calculated using the density functional theory (DFT) methods at the B3LYP/6 31G(d) level of theory. The results indicate that the bent junctions are more stable than the straight ones due to the energetically favored defect structures. Remarkable differences of the HOMO and LUMO orbitals appear between the straight and the bent IMJs. The spin-unrestricted calculations at the same level of theory were also performed to obtain the antiferromagnetic-type ground state, suggesting that the spin polarizations mainly occur on the zigzag edge and the defect rings of the straight (4,4)-(8,0) IMJ and induce marked changes of the electronic structures. Additionally, the energy band structures of the four junctions with periodic boundary conditions were calculated based on DFT calculations using generalized gradient approximation with the Perdew and Wang function. The calculated band gaps suggest that the conductance of the straight IMJs is higher than the bent ones. PMID- 26609849 TI - Non-Covalent Interactions with Dual-Basis Methods: Pairings for Augmented Basis Sets. AB - Basis set pairings for dual-basis calculations are presented for the aug-cc-pVXZ (X = D, T, Q) series of basis sets. Fidelity with single-basis results is assessed at the second-order Moller-Plesset perturbation theory (MP2) level within the resolution-of-the-identity (RI) approximation, using the S22 set of noncovalent interactions and a series of electron affinities from the G3 set. Root-mean-squared errors for the S22 set are 0.019 kcal mol(-1) or lower, with a maximum deviation of 0.44%, and errors in nuclear structures are 0.09% or lower. Cost savings of 60-93% (RI-MP2 energies) and 50-88% (RI-MP2 gradients) are demonstrated. Spin-component-scaled MP2 [SCS(MI)-MP2] scaling parameters are provided for the aug-cc-pVXZ series, and dual-basis results are shown to be consistent without reoptimization of the single-basis parameters. Explicit handling of linear dependence in the basis set projection scheme is also provided. These dual-basis pairings will be helpful for accelerating accurate Hartree-Fock, density functional theory (DFT), MP2 and scaled MP2, and so-called doubly hybrid DFT calculations of intermolecular interactions (and other systems), where augmented basis sets are physically important. PMID- 26609850 TI - Electrostatically Embedded Many-Body Approximation for Systems of Water, Ammonia, and Sulfuric Acid and the Dependence of Its Performance on Embedding Charges. AB - This work tests the capability of the electrostatically embedded many-body (EE MB) method to calculate accurate (relative to conventional calculations carried out at the same level of electronic structure theory and with the same basis set) binding energies of mixed clusters (as large as 9-mers) consisting of water, ammonia, sulfuric acid, and ammonium and bisulfate ions. This work also investigates the dependence of the accuracy of the EE-MB approximation on the type and origin of the charges used for electrostatically embedding these clusters. The conclusions reached are that for all of the clusters and sets of embedding charges studied in this work, the electrostatically embedded three-body (EE-3B) approximation is capable of consistently yielding relative errors of less than 1% and an average relative absolute error of only 0.3%, and that the performance of the EE-MB approximation does not depend strongly on the specific set of embedding charges used. The electrostatically embedded pairwise approximation has errors about an order of magnitude larger than EE-3B. This study also explores the question of why the accuracy of the EE-MB approximation shows such little dependence on the types of embedding charges employed. PMID- 26609851 TI - Symmetry-Adapted Perturbation Theory Applied to Endohedral Fullerene Complexes: A Stability Study of H2@C60 and 2H2@C60. AB - Because of difficulties in a description of host-guest interactions, various theoretical methods predict different numbers of hydrogen molecules which can be inserted into the C60 cavity, ranging from one to more than 20. On the other hand, only one H2 molecule inside the C60 fullerene has been detected experimentally. Moreover, a recently synthesized H2@C70 complex prevails in the mixture formed with 2H2@C70. To get a deeper insight into the stability of the complexes created from C60 and hydrogen molecules, we carried out highly accurate calculations for complexes of one or two hydrogen molecules with fullerene applying symmetry-adapted perturbation theory (SAPT) and a large TZVPP basis set for selected points on the potential energy surfaces of H2@C60 and 2H2@C60. The electron correlation in the host and guests has been treated by density functional theory. Our calculations yield the stability of the recently synthesized H2@C60 complex. In addition, for all tried positions of the H2 dimer inside the C60 cage, the 2H2@C60 complex has been characterized by a positive interaction energy corresponding to the instability of this species. Contrary to the conclusions of several theoretical studies, this finding, as well as model considerations and literature experimental data, indicates that only one hydrogen molecule can reside inside the C60 cage. The calculated energy components have been analyzed to identify the most important contributions to the interaction energy. Supermolecular interaction energies obtained with MP2, SCS-MP2, and DFT+Disp methods are also reported and compared to those of DFT-SAPT. The DFT SAPT interaction energy has also been calculated for several points on the potential energy surface for a larger 2H2@C70 complex, confirming, in agreement with recent experimental findings, that this species is stable. The DFT-SAPT approach has been used for the first time to obtain interaction energies for van der Waals endohedral complexes, demonstrating that the method is capable of handling such difficult cases. PMID- 26609852 TI - Exploring the Reactivity Trends in the E2 and SN2 Reactions of X(-) + CH3CH2Cl (X = F, Cl, Br, HO, HS, HSe, NH2 PH2, AsH2, CH3, SiH3, and GeH3). AB - The reactivity order of 12 anions toward ethyl chloride has been investigated by using the G2(+) method, and the competitive E2 and SN2 reactions are discussed and compared. The reactions studied are X(-) + CH3CH2Cl -> HX + CH2?CH2 + Cl(-) and X(-) + CH3CH2Cl -> CH3CH2X + Cl(-), with X = F, Cl, Br, HO, HS, HSe, NH2 PH2, AsH2, CH3, SiH3, and GeH3. Our results indicate that there is no general and straightforward relationship between the overall barriers and the proton affinity (PA) of X(-); instead, discernible linear correlations only exist for the X's within the same group of the periodic table. Similar correlations are also found with the electronegativity of central atoms in X, deformation energy of the E2 transition state (TS), and the overall enthalpy of reaction. It is revealed that the electronegativity will significantly affect the barrier height, and a more electronegative X will stabilize the E2 and SN2 transition states. Multiple linear regression analysis shows that there is a reasonable linear correlation between E2 (or SN2) overall barriers and the linear combination of PA of X(-) and electronegativity of the central atom. PMID- 26609853 TI - Theoretical Mechanistic Study of the Oxidative Degradation of Benzene in the Troposphere: Reaction of Benzene-HO Radical Adduct with O2. AB - Competing pathways arising from the reaction of hydroxycyclohexadienyl radical (1) with O2, a key reaction in the oxidative degradation of benzene under tropospheric conditions, have been investigated by means of density functional theory (UB3LYP) and quantum-mechanical (UCCSD(T) and RCCSD(T)) electronic structure calculations. The energetic, structural, and vibrational results furnished by these calculations were subsequently used to perform conventional transition-state computations to predict the rate coefficients and evaluate the product yields. The trans stereoisomer of the peroxyl radical (4) produced by the O2 addition to position 2 of benzene ring in radical 1 is energetically more stable than the cis one, although the rate coefficients at 298 K for the formation of both isomers are predicted to be similar. The cyclization of the cis isomer of 4 to a bicyclic allyl radical (5) involves calculated barrier heights (DeltaU(?), DeltaE(?), DeltaH(?), and DeltaG(?)) significantly lower than those of the cyclization of the trans isomer of 4. This implies that the formation of the cis isomer of 4 can lead to irreversible loss of radical 1 and that the observed chemical equilibrium 1 + O2 <-> 4 essentially involves the trans isomer of 4. Although the reaction enthalpies computed for the O2 addition to position 4 of benzene ring in radical 1, affording the cis and trans stereoisomers of a peroxyl radical (6), are similar to those for the addition to position 2, the latter addition mode is clearly preferred because it involves lower barrier heights. The barrier heights computed for the cyclization of either the cis or the trans isomers of 6 to a bicyclic radical bearing a peroxy bridge (7) are about twice those computed for the cyclization of either the cis or the trans isomers of 4. Thus, under tropospheric conditions, it is unlikely that the O2 addition to position 4 of the benzene ring in radical 1 can contribute to the formation of benzene oxidation products. PMID- 26609854 TI - Bad Seeds Sprout Perilous Dynamics: Stochastic Thermostat Induced Trajectory Synchronization in Biomolecules. AB - Molecular dynamics simulations starting from different initial conditions are commonly used to mimic the behavior of an experimental ensemble. We show in this article that when a Langevin thermostat is used to maintain constant temperature during such simulations, extreme care must be taken when choosing the random number seeds to prevent statistical correlation among the MD trajectories. While recent studies have shown that stochastically thermostatted trajectories evolving within a single potential basin with identical random number seeds tend to synchronize, we show that there is a synchronization effect even for complex, biologically relevant systems. We demonstrate this effect in simulations of alanine trimer and pentamer and in a simulation of a temperature-jump experiment for peptide folding of a 14-residue peptide. Even in replica-exchange simulations, in which the trajectories are at different temperatures, we find partial synchronization occurring when the same random number seed is employed. We explain this by extending the recent derivation of the synchronization effect for two trajectories in a harmonic well to the case in which the trajectories are at two different temperatures. Our results suggest several ways in which mishandling selection of a pseudorandom number generator initial seed can lead to corruption of simulation data. Simulators can fall into this trap in simple situations such as neglecting to specifically indicate different random seeds in either parallel or sequential restart simulations, utilizing a simulation package with a weak pseudorandom number generator, or using an advanced simulation algorithm that has not been programmed to distribute initial seeds. PMID- 26609855 TI - ACEMD: Accelerating Biomolecular Dynamics in the Microsecond Time Scale. AB - The high arithmetic performance and intrinsic parallelism of recent graphical processing units (GPUs) can offer a technological edge for molecular dynamics simulations. ACEMD is a production-class biomolecular dynamics (MD) engine supporting CHARMM and AMBER force fields. Designed specifically for GPUs it is able to achieve supercomputing scale performance of 40 ns/day for all-atom protein systems with over 23 000 atoms. We provide a validation and performance evaluation of the code and run a microsecond-long trajectory for an all-atom molecular system in explicit TIP3P water on a single workstation computer equipped with just 3 GPUs. We believe that microsecond time scale molecular dynamics on cost-effective hardware will have important methodological and scientific implications. PMID- 26609856 TI - Quantum Cluster Equilibrium Theory Applied in Hydrogen Bond Number Studies of Water. 1. Assessment of the Quantum Cluster Equilibrium Model for Liquid Water. AB - Different cluster sets containing only 2-fold coordinated water, 2- and 3-fold coordinated water, and 2-fold, 3-fold, and tetrahedrally coordinated water molecules were investigated by applying second-order Moller-Plesset perturbation theory and density functional theory based on generalized gradient approximation functionals in the framework of the quantum cluster equilibrium theory. We found an improvement of the calculated isobars at low temperatures if tetrahedrally coordinated water molecules were included in the set of 2-fold hydrogen-bonded clusters. This was also reflected in a reduced parameter for the intercluster interaction. If all parameters were kept constant and only the electronic structure methods were varied, large basis set dependencies in the liquid state for the density functional theory results were found. The behavior of the intercluster parameter was also examined for the case that cooperative effects were neglected. The values were 3 times as large as in the calculations including the total electronic structure. Furthermore, these effects are more severe in the tetrahedrally coordinated clusters. Different populations were considered, one weighted by the total number of clusters and one depending on the monomers. PMID- 26609857 TI - Quantum Cluster Equilibrium Theory Applied in Hydrogen Bond Number Studies of Water. 2. Icebergs in a Two-Dimensional Water Continuum? AB - With the aid of the quantum cluster equilibrium method, we calculate thermodynamic properties for a new water cluster set containing 2-fold and additional tetrahedrally hydrogen-bonded water molecules on the basis of accurate correlated electronic structure calculations. The addition of clusters with 4 fold coordinated water molecules leads to an improved thermodynamical description of the liquid phase in comparison to experimental values. The comparison of the obtained isobars from the pure 2-fold cluster set with the mixed cluster set shows improved results for the mixed set. Furthermore, the results of the liquid phase entropy calculation compare excellently with experiment if the mixed cluster set is applied. The calculated populations allow us to determine hydrogen bond numbers, resulting in a temperature-dependent average hydrogen bond number. We observe a decreasing average hydrogen bond number of 2.77 at 274 K to 2.26 at 373 K and a dominance of 75% 2-fold hydrogen-bonded water molecules at room temperature for the mixed cluster set. PMID- 26609858 TI - Unraveling the Catalytic Pathway of Metalloenzyme Farnesyltransferase through QM/MM Computation. AB - The protein farnesyltransferase (FTase) is a Zn(2+)-metalloenzyme that catalyzes the farnesylation reaction, i.e., the transfer of the 15-carbon atom farnesyl group from farnesyl diphosphate (FPP) to a specific cysteine of protein substrates. Oncogenic Ras proteins, which are among the FTase substrates, are observed in about 20-30% of human cancer cells. Thus, FTase represents a target for anticancer drug design. Herein, we present a classical force-field-based and quantum mechanics/molecular mechanics (QM/MM) computational study of the FTase reaction mechanism. Our findings offer a detailed picture of the FTase catalytic pathway, describing structural features and the energetics of its saddle points. A moderate dissociation of the diphosphate group from the FPP is observed during the nucleophilic attack of the zinc-bound thiolate. At the transition state, a resonance structure is observed, which indicates the formation of a metastable carbocation. However, no stable intermediate is found along the reaction pathway. Thus, the reaction occurs via an associative mechanism with dissociative character, in agreement with the mechanism proposed by Fierke et al. ( Biochemistry 2000, 39, 2593-2602 and Biochemistry 2003, 42, 9741-9748 ). Moreover, a fluorine-substituted FPP analogue (CF3-FPP) is used to investigate the inhibitory effect of fluorine, which in turn provides additional agreement with experimental data. PMID- 26609859 TI - Thermochemical Fragment Energy Method for Biomolecules: Application to a Collagen Model Peptide. AB - Herein, we first review different methodologies that have been proposed for computing the quantum mechanical (QM) energy and other molecular properties of large systems through a linear combination of subsystem (fragment) energies, which can be computed using conventional QM packages. Particularly, we emphasize the similarities among the different methods that can be considered as variants of the multibody expansion technique. Nevertheless, on the basis of thermochemical arguments, we propose yet another variant of the fragment energy methods, which could be useful for, and readily applicable to, biomolecules using either QM or hybrid quantum mechanical/molecular mechanics methods. The proposed computational scheme is applied to investigate the stability of a triple-helical collagen model peptide. To better address the actual applicability of the fragment QM method and to properly compare with experimental data, we compute average energies by carrying out single-point fragment QM calculations on structures generated by a classical molecular dynamics simulation. The QM calculations are done using a density functional level of theory combined with an implicit solvent model. Other free-energy terms such as attractive dispersion interactions or thermal contributions are included using molecular mechanics. The importance of correcting both the intermolecular and intramolecular basis set superposition error (BSSE) in the QM calculations is also discussed in detail. On the basis of the favorable comparison of our fragment-based energies with experimental data and former theoretical results, we conclude that the fragment QM energy strategy could be an interesting addition to the multimethod toolbox for biomolecular simulations in order to investigate those situations (e.g., interactions with metal clusters) that are beyond the range of applicability of common molecular mechanics methods. PMID- 26609860 TI - Analyzing the Selectivity and Successiveness of a Two-Electron Capture on a Multiply Disulfide-Linked Protein. AB - Hybrid QM/MM calculations were performed on a circular macropeptide (kalata B1, PDB ID 1NB1) containing three disulfide linkages, to evaluate their respective reactivities toward (gas-phase) electron valence-attachment of one and two electron(s). The three disulfide bonds -CH2-S-S-CH2- were simultaneously described at the MP2/6-31+G**(S),6-31G*(C,H) level of theory, and the remaining of the 29 residues of kalata B1 were described by the CHARMM27 force field. The one-electron addition is favored on the linkage between cysteine residues 1 and 15, Cys(1-15), by ca. 1 eV over the two other disulfide linkages. The decomposition of the overall effect into geometrical and electrostatic contributions evidence (i) the key role of an arginine (R24) and (ii) a weaker geometrical penalty for elongating the nonstructural Cys(1-15) linkage. The addition of a second electron leads to the formation of the dithiolate Cys(1,15), favored by more than 1 eV over other adducts (either dithiolates or diradical dianionic species). This can be traced back to a structural reorganization, with a flip of R24 side chain. Its positively charged extremity points almost equidistantly toward one thiolate -CH2-S(-), hence stabilizing this dianion. PMID- 26609861 TI - Interaction of Benzene with Transition Metal Cations: Theoretical Study of Structures, Energies, and IR Spectra. AB - The cation-pi interactions have been intensively studied. Nevertheless, the interactions of pi systems with heavy transition metals and their accurate conformations are not well understood. Here, we theoretically investigate the structures and binding characteristics of transition metal (TM) cations including novel metal cations (TM(n+) = Cu(+), Ag(+), Au(+), Pd(2+), Pt(2+), and Hg(2+)) interacting with benzene (Bz). For comparison, the alkali metal complex of Na(+) Bz is also included. We employ density functional theory (DFT) and high levels of ab initio theory including Moller-Plesset second-order perturbation (MP2) theory, quadratic CI method with single and double substitutions (QCISD), and the coupled cluster theory with single, double, and perturbative triple excitations (CCSD(T)). Each of the transition metal complexes of benzene exhibits intriguing binding characteristics, different from the typical cation-pi interactions between alkali metal cations and aromatic rings. The complexes of Na(+), Cu(+), and Ag(+) favor the conformation of C6v symmetry with the cation above the benzene centroid (picen). The formation of these complexes is attributed to the electrostatic interaction, while the magnitude of charge transfer has little correlation with the total interaction energy. Because of the TM(n+)<-pi donation, cations Au(+), Pd(2+), Pt(2+), and Hg(2+) prefer the off-center pi conformation (pioff) or the pi coordination to a C atom of the benzene. Although the electrostatic interaction is still important, the TM<-pi donation effect is responsible for the binding site. The TM(n+)-Bz complexes give some characteristic IR peaks. The complexes of Na(+), Cu(+), and Ag(+) give two IR active modes between 800 and 1000 cm(-1),which are inactive in the pure benzene. The complexes of Au(+), Pd(2+), Pt(2+), and Hg(2+) give characteristic peaks for the ring distortion, C-C stretching, and C-H stretching modes as well as significant red-shifts in the CH out-of-plane bending. PMID- 26609862 TI - Curcumin, the main active constituent of turmeric (Curcuma longa L.), induces apoptosis in hepatic stellate cells by modulating the abundance of apoptosis related growth factors. AB - In order to elucidate the mechanism of action of curcumin against hepatic fibrosis, cultured rat hepatic stellate cells (HSC) (HSC-T6) were incubated with curcumin for 24 h, after which apoptosis was measured by flow-cytometry. The protein levels of the pro-apoptotic factors Fas and p53b as well as of the anti apoptotic factor Bcl-2 were monitored by immunocytochemical ABC staining after incubation with curcumin for 24 h. In the case of 20 MUM curcumin, not only was the respective apoptosis index increased, but also the abundance of the pro apoptotic factors Fas and p53 were amplified, whereas that of the anti-apoptotic factor Bcl-2 decreased. All these effects were highly reproducible (P<0.05). Consequently, curcumin has an up-regulating effect on pro-apoptotic factors like Fas and p53 as well as a down-regulating effect of the anti-apoptotic factor Bcl 2, thus inducing apoptosis in HSC. PMID- 26609863 TI - Clinical utility of the (-2)proPSA and evaluation of the evidence: a systematic review. AB - BACKGROUND: Diagnostic studies usually provide important information about the analytical and diagnostic performances. We investigated the clinical utility of ( 2)proPSA in identifying patients with prostate cancer (PCa). METHODS: We performed electronic searches in five databases as well as a list of reference literature. Studies were included if they evaluated the diagnostic accuracy of ( 2)proPSA in men with PSA value ranged from 2.0 to 10 MUg/L. We also analyzed data about total PSA (tPSA), %(-2)proPSa, freePSA (fPSA), its percentage (%fPSA) and the prostate health index (phi). The selection of the studies, the screening of the full texts and the data extraction, as well as the assessment of risk of bias using the QUADAS-2 tool were conducted independently by two authors. Grading the quality of the evidence was carried out according to the GRADE method. The random effects model was used for the meta-analyses. RESULTS: We included 17 studies, including 6912 patients. The pooled sensitivity of (-2)proPSA was 90% and the summary specificity was 13%. The tPSA sensitivity and specificity were 89% and 25%, respectively. Considering (-2)proPSA, 225 men out of 1000 have been identified having PCa true positives (TP). However, 652 persons have been incorrectly identified and undergo biopsy. The majority of studies were judged to carry a moderate risk of bias. Therefore, the overall quality of evidences was deemed to be low. CONCLUSIONS: The (-2)proPSA could be useful to identify men at risk of PCa, but its accuracy still remains uncertain and the level of evidence does not support an improved clinical utility. PMID- 26609864 TI - STORE (Sample Tracking: Organization, Refrigeration and Expansion): a project in a clinical laboratory perspective. PMID- 26609865 TI - Recent advances in siRNA delivery. AB - In the 1990s an unexpected gene-silencing phenomena in plants, the later called RNA interference (RNAi), perplexed scientists. Following the proof of activity in mammalian cells, small interfering RNAs (siRNAs) have quickly crept into biomedical research as a new powerful tool for the potential treatment of different human diseases based on altered gene expression. In the past decades, several promising data from ongoing clinical trials have been reported. However, despite surprising successes in many pre-clinical studies, concrete obstacles still need to be overcome to translate therapeutic siRNAs into clinical reality. Here, we provide an update on the recent advances of RNAi-based therapeutics and highlight novel synthetic platforms for the intracellular delivery of siRNAs. PMID- 26609866 TI - Contemporary measures to reduce the risk of embolic events in patients with atrial fibrillation. AB - Atrial fibrillation is a common arrhythmia with significant risk of embolic events. Patients with atrial fibrillation should undergo a careful assessment using validated risk score calculators to estimate the risk of embolic events and the risk of bleeding. Patients deemed to be at a high risk for arterial thromboembolism should be advised to take an oral anticoagulant with a vitamin K antagonist or a target-specific oral anticoagulant unless contraindicated. These agents significantly reduce the risk of embolic events, but at the expense of a higher risk of bleeding. Antiplatelet agents do not confer the same degree of protection and their use should limited. When antithrombotic treatment is contraindicated, novel approaches such as left atrial appendage occlusion should be considered. PMID- 26609867 TI - Letter to editor: Informed consent in the light of Montgomery. PMID- 26609868 TI - The potential of polymeric film-forming systems as sustained delivery platforms for topical drugs. AB - INTRODUCTION: Dosing regimens requiring multiple daily applications frequently result in poor patient compliance, especially in the treatment of chronic skin diseases. Consequently, development of sustained delivery systems for topical drugs permitting less frequent dosing is of continuing interest for dermatological therapy. AREAS COVERED: This potential of polymeric film-forming systems (FFS), created in situ on the skin, as sustained delivery platforms for topical drug delivery is reviewed. Key formulation parameters that determine delivery efficiency are considered focussing on those that permit a drug reservoir to be established in the upper layers of the skin and/or on the skin surface from which release can be sustained over a prolonged period. The advantageous and superior cosmetic attributes of FFS (compared to conventional semi-solid formulations) that offer significantly improved patient compliance are also addressed. EXPERT OPINION: The promise of polymeric FFS as convenient and aesthetic platforms for sustained topical drug delivery is clear. Manipulation of the formulation allows the delivery profile to be customized and optimized to take advantage of both a rapid, initial input of drug into the skin (likely due to a transient period of supersaturation) and a slower, controlled release over an extended time from the residual film created thereafter. PMID- 26609869 TI - The Technological Transformation of Psychiatric Care- Telepsychiatry Comes of Age. PMID- 26609870 TI - An analysis of reflective writing early in the medical curriculum: The relationship between reflective capacity and academic achievement. AB - OBJECTIVE: To examine the relationship between reflection, gender, residency choice, word count, and academic achievement among medical students. METHODS: A modified version of the Reflection Evaluation for Learners' Enhanced Competencies Tool (REFLECT) was developed and used for this study (Cronbach's alpha of 0.86 with an intraclass correlation coefficient [ICC] of 0.68). This was applied to writing samples about professionalism in gross anatomy from first-year medical students between 2005 and 2011. Four analysts reviewed and scored written reflections independently. Composite reflection scores were compared with gender, residency choice, length of written reflection, NBME(r) Gross Anatomy and Embryology Subject Examination scores, and final gross anatomy course. RESULTS: Total of 319 written reflections were evaluated. Female students who pursued medicine specialties had the highest composite reflection scores (87 [27.2%]). Word count frequently correlated with reflection score (p < 0.0001). Students who performed well on the NBME(r) Gross Anatomy and Embryology Subject Examination tended to achieve high anatomy course grades (p < 0.0001). There was no statistically significant relationship between composite reflection scores and NBME(r) Gross Anatomy and Embryology Subject Examination scores (p = 0.16) or anatomy course grades (p = 0.90). CONCLUSIONS: This study suggests there are likely no correlations between reflective capacity and academic performance on tests of medical knowledge administered early in the medical curriculum. PMID- 26609872 TI - New antiarrhythmic targets in atrial fibrillation. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia in developed countries. AF is associated with increased mortality and morbidity due to thromboembolism, stroke and worsening of pre-existing heart failure. Currently available pharmacological therapies for AF suffer from unsatisfying efficacy and/or are associated with major side effects such as bleeding complications or proarrhythmia. These limitations largely result from the fact that most of the currently available drugs were developed on an empirical basis, without precise knowledge of the molecular mechanisms underlying the arrhythmia. During the last decade substantial progress has been made in understanding the molecular mechanisms contributing to the initiation and maintenance of AF. This knowledge is expected to stimulate the development of safer and more effective drugs. Here, we review new antiarrhythmic drug targets, which have emerged based on this increasing knowledge about the molecular mechanisms of AF. PMID- 26609871 TI - Transfontanellar duplex brain ultrasonography resistive indices as a prognostic tool in neonatal hypoxic-ischemic encephalopathy before and after treatment with therapeutic hypothermia. AB - OBJECTIVE: Prior to therapeutic hypothermia (that is, cooling), transfontanellar duplex brain sonography resistive indices (RI) were studied as a bedside non invasive measures of cerebral hemodynamics in neonates who suffered from hypoxic ischemic encephalopathy (HIE). We compared pre- and post-cooling RI values and examined the relationships between RI values and specific long-term neurodevelopmental outcomes. STUDY DESIGN: Transfontanellar duplex brain sonography, including RI, were obtained for 28 neonates prior to cooling and for 20 neonates following cooling. All RI values were sampled in the anterior cerebral artery at the beginning of each ultrasound study. Neurodevelopmental assessment was conducted between ages 20-32 months with the Mullen Scale of Early Learning. The relationships between pre- and post-cooling RI and cognitive and motor outcomes were studied. RESULT: Neonates with RI values <0.60 prior to and following cooling were more likely to die or have severe neurodevelopmental disability by ages 20-32 months than those with RI>0.60. Lower RI values were associated with specific neurodevelopmental deficits in motor skill attainment. CONCLUSION: Pre- and post-cooling transfontanellar duplex brain sonography RI values may be a useful prognostic tool, in conjunction with other clinical information, for neonates diagnosed with HIE. The results of this study suggest that further study of the prognostic value of RI values for short- and long-term outcomes is warranted. PMID- 26609873 TI - Atrioventricular valvular anomalies and their role in the etiopathogenesis of cardiorespiratory syndrome in farmed common foxes (Vulpes vulpes). AB - BACKGROUND: Cardiorespiratory syndrome of common foxes is associated with a mortality rate ranging from 2.1% to 20%. OBJECTIVE: The aim of this study was to analyze the prevalence of cardiac abnormalities in common foxes (Vulpes vulpes) from Polish farms with a history of cardiorespiratory syndrome. ANIMALS AND METHODS: The prevalence of cardiac abnormalities in common foxes from a Polish farm with a history of cardiorespiratory syndrome was assessed as well as morphological examination of 60 heart specimens from clinically healthy animals. In addition, 38 foxes were examined echocardiographically and subjected to postmortem examination. RESULTS: Atrioventricular valvular abnormalities were found in 57 out of the 98 (58%) analyzed hearts. The abnormalities of the mitral valve documented in more than 20% of the foxes in involved tendinous chords (completely lacking or shortened), papillary muscles and mitral cusps associated with both insufficiency and stenosis of the left atrioventricular orifice. Abnormalities of the tricuspid valve included significant shortening of the tendinous chords and thickening of the valve cusps with the impairment of their mobility. The results of the echocardiographic and postmortem examination were consistent in 79% of the cases. The specimens collected from animals with and without atrioventricular valvular anomalies did not differ significantly in terms of cardiomyocyte width, number of inflammatory cells, adipose tissue content and presence of polychromatic cardiomyocytes. CONCLUSION: Congenital atrioventricular valvular defects may be involved in the etiology of cardiorespiratory syndrome in common foxes, and echocardiography can be used as a measure of stock's health and a criterion for selection for mating. PMID- 26609874 TI - The New Cover for Multivariate Behavioral Research. PMID- 26609875 TI - Iteration of Partially Specified Target Matrices: Applications in Exploratory and Bayesian Confirmatory Factor Analysis. AB - We describe and evaluate a factor rotation algorithm, iterated target rotation (ITR). Whereas target rotation (Browne, 2001) requires a user to specify a target matrix a priori based on theory or prior research, ITR begins with a standard analytic factor rotation (i.e., an empirically informed target) followed by an iterative search procedure to update the target matrix. In Study 1, Monte Carlo simulations were conducted to evaluate the performance of ITR relative to analytic rotations from the Crawford-Ferguson family with population factor structures varying in complexity. Simulation results: (a) suggested that ITR analyses will be particularly useful when evaluating data with complex structures (i.e., multiple cross-loadings) and (b) showed that the rotation method used to define an initial target matrix did not materially affect the accuracy of the various ITRs. In Study 2, we: (a) demonstrated the application of ITR as a way to determine empirically informed priors in a Bayesian confirmatory factor analysis (BCFA; Muthen & Asparouhov, 2012) of a rater-report alexithymia measure (Haviland, Warren, & Riggs, 2000) and (b) highlighted some of the challenges when specifying empirically based priors and assessing item and overall model fit. PMID- 26609876 TI - Comparing Visual and Statistical Analysis in Single-Case Studies Using Published Studies. AB - Little is known about the extent to which interrupted time series analysis (ITSA) can be applied to short, single-case study designs and whether those applications produce results consistent with visual analysis (VA). This article examines the extent to which ITSA can be applied to single-case study designs and compares the results based on two methods: ITSA and VA, using papers published in the Journal of Applied Behavior Analysis in 2010. The study was made possible by the development of software called UnGraph(r), which facilitates the recovery of raw data from the graphs. ITSA was successfully applied to 94% of the examined graphs with the number of observations ranging from 8 to 136. Moderate to high lag-1 autocorrelations (>.50) were found for 46% of the data series. Effect sizes similar to group-level Cohen's d were identified based on the tertile distribution. Effects ranging from 0.00 to 0.99 were classified as small, those ranging from 1.00 to 2.49 as medium, and large effect sizes were defined as 2.50 or greater. Comparison of the conclusions from VA and ITSA had a low level of agreement (Kappa =.14, accounting for the agreement expected by chance). The results demonstrate that ITSA can be broadly implemented in applied behavior analysis research. These two methods should be viewed as complementary and used concurrently. PMID- 26609877 TI - Modeling Cyclical Patterns in Daily College Drinking Data with Many Zeroes. AB - Daily college drinking data often have highly skewed distributions with many zeroes and a rising and falling pattern of use across the week. Alcohol researchers have typically relied on statistical models with dummy variables for either the weekend or all days of the week to handle weekly patterns of use. However, weekend versus weekday categorizations may be too simplistic and saturated dummy variable models too unwieldy, particularly when covariates of weekly patterns are included. In the present study we evaluate the feasibility of cyclical (sine and cosine) covariates in a multilevel hurdle count model for evaluating daily college alcohol use data. Results showed that the cyclical parameterization provided a more parsimonious approach than multiple dummy variables. The number of drinks when drinking had a smoothly rising and falling pattern that was reasonably approximated by cyclical terms, but a saturated set of dummy variables was a better model for the probability of any drinking. Combining cyclical terms and multilevel hurdle models is a useful addition to the data analyst toolkit when modeling longitudinal drinking with high zero counts. However, drinking patterns were not perfectly sinusoidal in the current application, highlighting the need to consider multiple models and carefully evaluate model fit. PMID- 26609878 TI - Detecting Misspecified Multilevel Structural Equation Models with Common Fit Indices: A Monte Carlo Study. AB - This study investigated the sensitivity of common fit indices (i.e., RMSEA, CFI, TLI, SRMR-W, and SRMR-B) for detecting misspecified multilevel SEMs. The design factors for the Monte Carlo study were numbers of groups in between-group models (100, 150, and 300), group size (10, 20, 30, and 60), intra-class correlation (low, medium, and high), and the types of model misspecification (Simple and Complex). The simulation results showed that CFI, TLI, and RMSEA could only identify the misspecification in the within-group model. Additionally, CFI, TLI, and RMSEA were more sensitive to misspecification in pattern coefficients while SRMR-W was more sensitive to misspecification in factor covariance. Moreover, TLI outperformed both CFI and RMSEA in terms of the hit rates of detecting the within group misspecification in factor covariance. On the other hand, SRMR-B was the only fit index sensitive to misspecification in the between-group model and more sensitive to misspecification in factor covariance than misspecification in pattern coefficients. Finally, we found that the influence of ICC on the performance of targeted fit indices was trivial. PMID- 26609879 TI - Simulating Univariate and Multivariate Nonnormal Distributions through the Method of Percentiles. AB - This article derives a standard normal-based power method polynomial transformation for Monte Carlo simulation studies, approximating distributions, and fitting distributions to data based on the method of percentiles. The proposed method is used primarily when (1) conventional (or L) moment-based estimators such as skew (or L-skew) and kurtosis (or L -kurtosis) are unknown or (2) data are unavailable but percentiles are known (e.g., standardized test score reports). The proposed transformation also has the advantage that solutions to polynomial coefficients are available in simple closed form and thus obviates numerical equation solving. A procedure is also described for simulating power method distributions with specified medians, inter-decile ranges, left-right tail weight ratios (skew function), tail-weight factors (kurtosis function), and Spearman correlations. The Monte Carlo results presented in this study indicate that the estimators based on the method of percentiles are substantially superior to their corresponding conventional product-moment estimators in terms of relative bias. It is also shown that the percentile power method can be modified for generating nonnormal distributions with specified Pearson correlations. An illustration shows the applicability of the percentile power method technique to publicly available statistics from the Idaho state educational assessment. PMID- 26609880 TI - Power and Type I Error Control for Univariate Comparisons in Multivariate Two Group Designs. AB - Simulations were conducted to evaluate the statistical power and Type I error control provided by several multiple-comparisons procedures in two-group designs. Stepwise Bonferroni-based procedures, which are known to control the familywise Type I error rate, tended to be more powerful than other methods but did not control the per-family Type I error rate (PFER). It is proposed that more attention should be given to the PFER, particularly with regard to these procedures. Only two methods controlled the PFER: the classical Bonferroni procedure and a modified version of MANOVA-protection. Which of these two procedures was more powerful depended on multiple factors that this article describes in detail and illustrates graphically. It is concluded that which multiple-comparisons procedure is preferable depends on the number of outcome variables, the importance of the PFER, the necessity of confidence intervals, and the extent to which significance in multiple variables is more valuable than significance in one variable. PMID- 26609881 TI - A Different Approach to Dependence Analysis. AB - This article focuses on a statistical tool for dependence analysis in scientific research. Starting from a recent index of concordance for a multiple linear regression model, a coefficient suitable in catching any monotonic dependence relationship between a dependent variable and an independent variable is derived and discussed. Given its interpretation in terms of monotonic dependence, it is called monotonic dependence coefficient (MDC). It is appropriate to all contexts where the dependent variable is quantitative (continuous or discrete) and the independent variable is at least of ordinal nature; tied data are also allowed. MDC's adequacy is validated through Monte Carlo simulations led by taking into account different scenarios of dependence. Finally, an application to real data is provided to stress MDC's capability of detecting dependence relationships between two variables, even if some pieces of information about original data are lost. PMID- 26609883 TI - Antifungal activity of mango peel and seed extracts against clinically pathogenic and food spoilage yeasts. AB - The antioxidant and antifungal (antiyeast) properties of mango (Mangifera indica) peel and seed by-products were investigated. Nine extracts were obtained using three cultivars and two extraction methods. Significant differences between cultivars and extraction methods were detected in their bioactive compounds and antioxidant activity. The antifungal property was determined using agar diffusion and broth micro-dilution assays against 18 yeast species of the genera Candida, Dekkera, Hanseniaspora, Lodderomyces, Metschnikowia, Pichia, Schizosaccharomyces, Saccharomycodes and Zygosaccharomyces. All mango extracts showed antifungal activity. The minimum inhibitory concentration (MIC) and the minimum fungicidal concentration (MFC) values were lower for seed than for peel extracts. MICs and MFCs ranged from values <0.1 to 5 and 5 to >30 mgGAE/mL, respectively. The multivariate analysis showed a relationship between antifungal activity, the capacity to inhibit lipid peroxidation and total phenol content. These properties were associated with high levels of proanthocyanidins, gallates and gallotannins in the extracts. PMID- 26609882 TI - Novel serotonin receptor 2 (5-HT2R) agonists and antagonists: a patent review (2004-2014). AB - INTRODUCTION: Serotonin or 5-hydroxytryptamine (5-HT) is a substance found in plasma, which increases smooth muscle contraction and mediates platelet aggregation. In addition, it is a monoamine neurotransmitter and is implicated in diverse behaviors. The serotonin receptor 2 (5-HT2) subfamily is best known for biased signaling and is strongly expressed mainly in the brain regions postulated to be involved in the modulation of higher cognitive and affective functions. Modulators of the 5-HT2 receptor are currently used to treat a variety of diseases including chronic pain and psychonosema. These properties suggest that 5 HT2 receptors may become an important therapeutic target for the treatment of various pathological conditions. AREAS COVERED: This review highlights the significant progress that has been made in the discovery and development of 5-HT2 receptor agonists and antagonists based on an analysis of the patent literature between January 2004 and December 2014. EXPERT OPINION: Cumulative evidence over the past decade supports the notion that the modulation of 5-HT2 receptors has a positive effect on human cognition and emotion. Therefore, we suggest that new agonists and antagonists may play an important role in the treatment of disorders such as schizophrenia, addiction and obesity. PMID- 26609884 TI - Plantar heel pain and plantar fasciitis. AB - INTRODUCTION: Plantar heel pain, also known as plantar fasciitis, causes soreness or tenderness of the sole of the foot under the heel, which sometimes extends into the medial arch. Pain associated with the condition may cause substantial disability and poor health-related quality of life. The prevalence and prognosis are unclear, but the symptoms seem to resolve over time in most people. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical questions: What are the effects of conservative treatments for plantar heel pain? What are the effects of non-conservative treatments for plantar heel pain? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2013 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). RESULTS: At this update, searching of electronic databases retrieved 162 studies. After deduplication and removal of conference abstracts, 84 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 39 studies and the further review of 45 full articles. Of the 45 full articles evaluated, five systematic reviews and nine RCTs were included at this update. We performed a GRADE evaluation for 30 PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for 12 interventions based on information relating to the effectiveness and safety of corticosteroid injection alone (both short-term and longer-term effects), corticosteroid injections plus local anaesthetic injection (both short-term and longer-term effects), customised foot orthoses, extracorporeal shock wave therapy, heel pads and cups, local anaesthetic injection alone, night splints, stretching exercises, surgery, and taping. PMID- 26609885 TI - Calcium-independent phospholipases A2 in murine osteoblastic cells and their inhibition by bromoenol lactone: impact on arachidonate dynamics and prostaglandin synthesis. AB - CONTEXT: Bromoenol lactone (BEL) is an inhibitor of group VI phospholipases (iPLA2s), but has been shown to have severe side effects. OBJECTIVE: iPLA2 characterization in osteoblasts and effect of BEL on prostaglandin (PG) E2 formation. METHODS: iPLA2 expression: RT-PCR, Western Blotting. PGE2 formation: GC-MS after stimulation, treatment with inhibitors or gene silencing. Arachidonate (AA) reacylation into phospholipids, inhibitor reaction products, PGHS-1 modification proteomic analysis: HR-LC-MS/MS. AA accumulation: (14)C-AA. RESULTS: iPLA2beta and iPLA2gamma were expressed and functionally active. BEL inhibition up to 20 MUM caused AA accumulation and enhanced PGE2 formation, followed by a decrease at higher concentrations. BEL reacted with intracellular cysteine and GSH leading to GSH depletion and oxidative stress. DISCUSSION: Initial PGE2 enhancement after BEL inhibition is due to iPLA2-independent accumulation of AA. GSH depletion caused by high BEL concentrations is responsible for the decrease in PGE2 production. CONCLUSION: BEL must be used with caution in a cellular environment due to conditions of extreme oxidative stress. PMID- 26609886 TI - Design and evaluation of an apta-nano-sensor to detect Acetamiprid in vitro and in silico. AB - Pesticide detection is a main concern of food safety experts. Therefore, it is urgent to design an accurate, rapid, and cheap test. Biosensors that detect pesticide residues could replace current methods, such as HPLC or GC-MC. This research designs a biosensor based on aptamer (Oligonucleotide ss-DNA) in the receptor role, silver nanoparticles (AgNPs) as optical sensors and salt (NaCl) as the aggregative inducer of AgNPs to detect the presence of Acetamiprid. After optimization, .6 MUM aptamer and 100 mM salt were employed. The selectivity and sensitivity of the complex were examined by different pesticides and different Acetamiprid concentrations. To simulate in vitro experimental conditions, bioinformatics software was used as in silico analysis. The results showed the detection of Acetamiprid at the .02 ppm (89.8 nM) level in addition to selectivity. Docking outputs introduced two loops as active sites in aptamer and confirmed aptamer-Acetamiprid bonding. Circular dichroism spectroscopy (CD) confirmed upon Acetamiprid binding, aptamer was folded due to stem-loop formation. Stability of the Apt-Acetamiprid complex in a simulated aqueous media was examined by molecular dynamic studies. PMID- 26609887 TI - A New Symptom, 'Palinendophonia', Associated with Pure Verbal Palinacousis Induced by a Right Inferior Temporal Lesion. AB - We describe the case of a patient with pure verbal palinacousis and perseveration of inner speech after a right inferior temporal lesion. The superior temporal lobe, including the superior temporal sulcus and the interhemispheric connection between the 2 superior temporal lobes, explored by tractography, were preserved. These regions are involved in voice processing, verbal short-term memory and inner speech. It can then be hypothesised that abnormal activity in this network has occurred. Palinacousis and 'palinendophonia', a term proposed for this symptom not previously reported, may be due to common cognitive processes disorders involved in both voice hearing and inner speech. PMID- 26609888 TI - Frequency of Perceived Poststress Symptoms in Inpatients, Outpatients and Healthy Controls: The Role of Perceived Exhaustion and Stress. AB - BACKGROUND: Poststress symptoms occur as a consequence of stress, most commonly during leisure periods such as weekends and vacations. However, the prevalence and the pathological mechanisms of poststress symptoms are poorly understood. METHODS: Here, we compared the frequency of poststress symptoms in healthy controls (n = 984), outpatients (n = 420), and inpatients (n = 101). In outpatients, demographic factors, psychosocial stress, and perceived exhaustion were tested as predictors of poststress symptoms with multivariate regression analysis. Poststress symptoms and perceived exhaustion were assessed using 2 Neuropattern Questionnaires (the NPQ - Patient Questionnaire and the NPQ - Symptom List), and psychosocial stress was evaluated using the Patient Health Questionnaire (PHQ). RESULTS: Poststress symptoms appeared in 2.9% of healthy controls, 20.0% of outpatients, and 34.7% of inpatients. Predictors were educational level, psychosocial stress, and perceived exhaustion. Poststress symptoms differed primarily between exhausted (75.0%) and nonexhausted patients (25.0%). CONCLUSION: Poststress symptoms are rather common in clinical populations, and they are primarily associated with the degree of perceived exhaustion. Preliminary evidence suggests that poststress symptoms are possibly related to depletion of norepinephrine stores, which may facilitate a stratified preventive and therapeutic treatment of these subjects. PMID- 26609889 TI - Irrational Beliefs and Psychological Distress: A Meta-Analysis. AB - BACKGROUND: Since the cognitive revolution of the early 1950s, cognitions have been discussed as central components in the understanding and treatment of mental illnesses. Even though there is an extensive literature on the association between therapy-related cognitions such as irrational beliefs and psychological distress over the past 60 years, there is little meta-analytical knowledge about the nature of this association. METHODS: The relationship between irrational beliefs and distress was examined based on a systematic review that included 100 independent samples, gathered in 83 primary studies, using a random-effect model. The overall effects as well as potential moderators were examined: (a) distress measure, (b) irrational belief measure, (c) irrational belief type, (d) method of assessment of distress, (e) nature of irrational beliefs, (f) time lag between irrational beliefs and distress assessment, (g) nature of stressful events, (h) sample characteristics (i.e. age, gender, income, and educational, marital, occupational and clinical status), (i) developer/validator status of the author(s), and (k) publication year and country. RESULTS: Overall, irrational beliefs were positively associated with various types of distress, such as general distress, anxiety, depression, anger, and guilt (omnibus: r = 0.38). The following variables were significant moderators of the relationship between the intensity of irrational beliefs and the level of distress: irrational belief measure and type, stressful event, age, educational and clinical status, and developer/validator status of the author. CONCLUSIONS: Irrational beliefs and distress are moderately connected to each other; this relationship remains significant even after controlling for several potential covariates. PMID- 26609890 TI - Genetic Associations of Alexithymia in Predicting Interferon-Induced Depression in Chronic Hepatitis C. AB - BACKGROUND: Previous studies have shown that alexithymia is associated with gene polymorphisms that regulate the availability of serotonin (5-HT) in the brain. Since the 5-HT network is involved in interferon (IFN)-induced depression, this paper aimed to investigate the role of alexithymia and the functional gene variants of the 5-HT1A receptor (HTR1A) and the 5-HT transporter (5-HTTLPR) in induction of depression during antiviral treatment. METHODS: The depressive symptoms of 130 consecutive patients with chronic hepatitis C and no current psychopathology were measured during treatment with IFN and ribavirin (6-12 months) and at a 6-month follow-up. At baseline, alexithymia and 2 genotypes (5 HTTLPR and HTR1A) were also assessed. RESULTS: Patients with homozygosity for HTR1A-G and 5-HTTLPR long alleles had significantly higher levels of alexithymia. After controlling for sociodemographic and disease-related factors, alexithymia and HTR1A-G polymorphism, both separately (20-22%) and jointly (14-16%), significantly and independently predicted the development of IFN-induced depression. CONCLUSIONS: Subjects carrying HTR1A-G and 5-HTTLRP double long alleles are more vulnerable to alexithymia. Also patients with a higher level of alexithymia and the HTR1A-G gene variant are more vulnerable to experiencing IFN induced depressive symptoms. The clinical implications of targeting alexithymia and HTR1A receptors as a possible treatment option for mood disorders should be investigated in further studies. PMID- 26609891 TI - Serotonin 7 Receptor Variants Are Not Associated with Response to Second Generation Antipsychotics in Japanese Schizophrenia Patients. AB - BACKGROUND: Individual differences in serotonin 7 receptor (5-HT7R) may result in variable response to antipsychotics with 5-HT7R antagonism. This study investigated the relationship between single nucleotide polymorphisms (SNPs) in the 5-HT7R gene (HTR7) and the efficacy of second-generation antipsychotic drugs with a high affinity for this receptor in Japanese schizophrenia. METHODS: Perospirone or aripiprazole was administered to 100 patients with schizophrenia in a randomized controlled study. All patients were genotyped for three candidate SNPs (rs12412496, rs7916403, and rs1935349). Patient improvement on the Positive and Negative Syndrome Scale (PANSS) total score at 12 weeks was assessed as the primary outcome. PANSS 5-factor scores were investigated as the secondary outcome. RESULTS: Improvement on the PANSS total score and genetic polymorphisms showed no correlation. The rs12412496-rs7916403-rs1935349 A-T-A haplotype was correlated with worse improvement in the cognition score (haplotype frequency: 0.285, p = 0.046, permuted p = 0.043). CONCLUSION: Our results show that HTR7 variants are not related to the overall improvement in schizophrenia symptoms. PMID- 26609892 TI - Dental patients' perceptions and motivation in smoking cessation activities. AB - OBJECTIVE: The aim of the present study was to investigate smokers' perceptions of and motivation for smoking cessation activities in dentistry. MATERIALS AND METHODS PATIENTS: who smoked were consecutively recruited from general as well as specialist dental care clinics in Sweden. After a dental visit the patients completed a questionnaire about self-perceived oral health, smoking habits, motivation, reasons to quit and not to quit smoking, support to quit, smoking cessation activities and questions about smoking asked by dentists and dental hygienists. RESULTS: The sample consisted of 167 adult patients (>= 20 years) who smoked daily. During the last 6 months, 81% of the patients had experienced oral health problems. The most common complaints were discolourations of the teeth, periodontal problems and dry mouth (38%, 36% and 33%, respectively). Improved general health was a major reason to quit smoking (89%). It was also stated that it was important to avoid oral health problems. 71% of the patients preferred to quit by themselves and 16% wanted support from dentistry. High motivation to quit smoking was reported by 20%. Occurrence of periodontitis during the last 6 months was significantly associated with being highly motivated to stop smoking (OR = 3.0, 95% CI = 1.03-8.55). CONCLUSIONS: This study revealed that, although it was important to quit smoking to avoid oral health problems, the patients were not aware that tobacco cessation activities can be performed in dentistry. Periodontal problems seem to be the most motivating factor among the patients who were highly motivated to stop smoking. PMID- 26609893 TI - Effect of calcium chloride on abating inhibition due to volatile fatty acids during the start-up period in anaerobic digestion of municipal solid waste. AB - Biomethanation of municipal solid waste (MSW) is a slow process and the yield of biogas is usually low. The present study was carried out to examine the effect of calcium chloride (CaCl2) on anaerobic digestion of MSW. Three anaerobic digesters with different concentrations of CaCl2, namely sample without additives (Control), sample with 2.5 g/L CaCl2 (R1) and sample with 5 g/L CaCl2 (R2) were studied separately and the significant results are presented. From the experimental results, it was observed that pH decreased with an increase in the dosage of CaCl2. Total solids and volatile solids reduction percentage in digester R2 was considerably lower than Control and R1 digesters. The significant positive correlation with small increments in volatile solids and chemical oxygen demand (COD) reduction were observed with an increase in pH. The cumulative biogas production in all the three digesters (Control, R1 and R2) were observed to be 35.38, 46.46 and 37.56 L, respectively. It was also observed that the volatile fatty acids (VFAs) removal efficiency in digester R1 was the best among all the three digesters. A comparison of the effluent characteristics revealed improvement in the overall performance of the digester R1 amended with 2.5 g/L CaCl2 over the other two digesters. PMID- 26609894 TI - Pathophysiological mechanisms and therapeutic potentials of macrophages in non alcoholic steatohepatitis. AB - INTRODUCTION: Non-alcoholic steatohepatitis (NASH), a hepatic manifestation of metabolic syndrome, is a major cause of morbidity and healthcare burden worldwide. While the molecular pathogenesis of NASH remains unclear and therapeutic options are limited, inflammation is recognized as an essential factor for NASH development. Factors that link NASH to inflammation are macrophages and their secreted cytokines. AREAS COVERED: This review summarizes the current knowledge of macrophage-mediated molecular pathways in NASH to shed insights on potential pharmacotherapeutic applications. EXPERT OPINION: Macrophages are not only known for their role of phagocytosis in innate immunity, but also for both extrinsic and intrinsic regulation of inflammatory functions of many cytokines. Recent advances have revealed the effects of macrophage recruitment and polarization on the development of NASH. We and others have shown that the proliferation of hepatic macrophages and the subsequent production of pro-inflammatory cytokines initiates inflammatory cascades, orchestrates activities of transcription factors involved in lipid metabolism/translocation, and modulates programmed cell death. Together, these findings support the pathophysiological role of macrophages in the pathogenesis of NASH. Thus, evaluating potential therapeutic targets against the infiltration and/or polarization of specific macrophage subtypes is of clinical interest for alleviation of early-stage NASH, with the goal of halting disease progression. PMID- 26609895 TI - Regional variations in pediatric medication exposure: Spatial analysis of poison center utilization in western Pennsylvania. AB - CONTEXT: Medication drug exposures among young children continue to rise despite current poison prevention efforts. These exposures result in increased healthcare utilization and medical costs. New tactics are needed to reduce injuries related to pediatric drug exposures. OBJECTIVE: We aimed to identify cluster patterns in: (1) calls for pediatric medication drug exposures and (2) a subset of calls that resulted in medical evaluation referrals. We identified and evaluated population characteristics associated with cluster patterns. METHODS: We analyzed 26,685 pharmaceutical drug exposures involving children <5 years of age based on calls reported to the Pittsburgh Poison Center from 1 January 2006 to 31 December 2010. We performed spatial statistics to assess for clustering. We used logistic regression to estimate population characteristics associated with clustering. RESULTS: Spatial analysis identified 22 exposure clusters and five referral clusters. Sixty-five percent of 89 ZIP codes in the clusters of drug exposure with healthcare facility (HCF) referral were not identified in the exposure clusters. ZIP codes in the HCF referral clusters were characterized as rural, impoverished, and with high rates of unemployment and school dropouts. DISCUSSION: Our principal findings demonstrate pediatric drug exposures do exist in discrete geographic clusters and with distinct socioeconomic characteristics. CONCLUSION: This study offers a starting point for subsequent investigations into the geographic and social context of pediatric medication drug exposures. This is an important step in revising pediatric poison prevention strategies. PMID- 26609896 TI - Work ability in prostate cancer survivors after radical prostatectomy. AB - OBJECTIVE: The aim of this study was to evaluate work ability (WA) after radical prostatectomy (RP) in prostate cancer survivors, in relation to post-RP urinary leakage (UL) and adjuvant or salvage pelvic radiation therapy (RT) and/or hormone therapy (HT). METHODS: Patients for this cross-sectional study were selected from two surveys on post-RP adverse effects and WA. All participated in the workforce. Using EPIC-50/26, UL was defined as daily use of at least one pad. Data on RT were obtained from the Cancer Registry of Norway. WA, measured by the Work Ability Score (WAS), was categorized into "excellent", "good" or "moderate/poor". Multinomial logistic regression analyses assessed associations between WA and selected variables. p values below 0.05 were considered statistically significant. RESULTS: Of 563 patients, 18% had received post-RP RT and/or HT. Compared to the "excellent" WAS category, such treatment was significantly associated with belonging to the "good" or "moderate/poor" category. Patients with UL (30%) were more than twice as likely to report a "moderate/poor" WAS than those without UL. Age above 65 years, less than 3 years since RP and co-morbidity were additional factors associated with increased risk of reporting a lower WAS. Half of the patients rated their current WA as "very good" with respect to the physical or mental demands of their work. CONCLUSION: Increasing age, UL, co morbidity and time since RP are associated with decreasing post-RP WA. Without specifying the individual therapy, post-RP oncological treatment seems to have an additional negative effect, warranting consideration of patients' work plans when considering post-RP oncological treatment. PMID- 26609897 TI - Response to "Surgical management of abnormally invasive placenta: is decreased blood loss due to participation of gynecologic oncologists?". PMID- 26609898 TI - Fluoride Exposure Effects and Dental Fluorosis in Children in Mexico City. AB - BACKGROUND The objective of the present study was to determine the prevalence and severity of dental fluorosis and to evaluate exposure to fluoridated products in students in the southwest part of the Federal District (Mexico City). MATERIAL AND METHODS Students between 10 and 12 years of age who were born and raised in the study zone were evaluated. The level of dental fluorosis was determined using the modified Dean index (DI) using criteria recommended by the World Health Organization (WHO). A bivariate analysis was performed with the chi2 test, and odds ratios (OR) and 95% confidence intervals (CI) are presented. Logistic regression was performed to evaluate the association between dental fluorosis and the independent variables. RESULTS A total of 239 students were evaluated. Their mean age was 11+/-0.82 years, and there were 122 (51%) males. Overall, dental fluorosis was found in 59% of participants; 29.3% had very mild fluorosis, 20.9% had mild fluorosis, 6.7% had moderate fluorosis, and 2.1% had severe fluorosis. The mean fluorosis score was 0.887+/-0.956. In the final logistic regression model, dental fluorosis was significantly associated with frequency of brushing (OR: 0.444; 95% CI: 0.297-0.666) and with the absence of parental supervision (OR: 0.636; 95% CI: 0.525-0.771). CONCLUSIONS The association found with frequency of brushing and lack of parental supervision may be contributing to the prevalence and severity of dental fluorosis. PMID- 26609899 TI - Developing and Evaluating the Psychometric Properties of the Nurses' Exercise Beliefs Scale. AB - BACKGROUND AND PURPOSE: No instrument exists that measures oncology nurses' exercise beliefs for women with breast cancer experiencing cancer-related fatigue. This article reports on the psychometric evaluation of the Nurses' Exercise Beliefs scale. METHOD: There were 20 items generated for the scale from a review of the literature. An expert panel review achieved content validity of the scale. The scale was administered to 387 registered nurses and the data were analyzed. RESULTS: The scale content validity index (S-CVI) was .85. A 2-factor solution explained 50.4% of the variance in exercise beliefs, supporting construct validity. The factors were exercise benefits beliefs (8 items, alpha = .94) and exercise barriers beliefs (12 items, alpha = .81). CONCLUSIONS: The findings support the subscales as valid and reliable tools. PMID- 26609900 TI - Reliability and Validity of the Psychosocial Distress Questionnaire-Breast Cancer. AB - BACKGROUND AND PURPOSE: To evaluate the psychometric properties of the Psychosocial Distress Questionnaire-Breast Cancer (PDQ-BC) and to compare its referrals with the Distress Thermometer (DT). METHODS: Group 1 (N = 54) and Group 2 (N = 80) completed the PDQ-BC. Group 2 also completed the DT, the Hospital Anxiety and Depression Scale (HADS), and World Health Organization Quality of Life instrument-100 (WHOQOL-100; n = 55). RESULTS: Moderate to high correlations (r >= .44, p < .001) were found between related facets of the PDQ-BC, WHOQOL-100, and DT. The subscales state anxiety and depressive symptoms (PDQ-BC) have a sensitivity of 87.5% and 78.6%, respectively, and a specificity of 81.1% and 73.0%, respectively, compared to the HADS. CONCLUSIONS: The PDQ-BC shows good construct validity, test-retest reliability, and sensitivity to change. The PDQ BC has a satisfactory sensitivity and specificity of the subscales state anxiety and depressive symptoms. PMID- 26609901 TI - Psychometric Properties of the Patient Health Questionnaire-9 in Patients With Heart Failure and Gastrointestinal Symptoms. AB - BACKGROUND AND PURPOSE: Patients who have coexisting medical conditions tend to be more depressed. The purpose of this study was to examine the reliability, validity, and dimensionality of the Patient Health Questionnaire-9 (PHQ-9) in patients with heart failure and gastrointestinal (GI) symptoms. METHODS: The cross-sectional data for this secondary analysis were collected in four studies. Cronbach's alpha was used to examine reliability. Concurrent validity with the Beck Depression Inventory-II (BDI-II) was examined. RESULTS: Cronbach's alpha for the PHQ-9 was .87. Concurrent validity with BDI-II was excellent (r = .78, p < .01). CONCLUSIONS: The evidence from this study supports the reliability and validity of the PHQ-9 as a measure of depression in patients with heart failure and GI symptoms. PMID- 26609902 TI - Reliability and Validity of the Transcultural Self-Efficacy Tool Questionnaire (Greek Version). AB - BACKGROUND AND PURPOSE: This study aimed to investigate the psychometric characteristics of the Transcultural Self-Efficacy Tool (TSET). METHODS: The translated questionnaire was distributed to 250 nurses and 150 student nurses. Internal consistency was determined and convergent validity was examined. The structure of the questionnaire was investigated using factor analysis. RESULTS: The internal consistency coefficient for all subscales was acceptable and more than .70. Cronbach's alpha was .91 for affective and self-awareness subscales and .85 for recognition and advocation. Six factors were revealed with eigenvalues of more than 1 and accounted for 60% of the total variance. CONCLUSIONS: The factorial composition of the TSET continues to be consistent with the underlying theoretical framework and the related literature. The Greek version of TSET was found to possess good reliability and validity. PMID- 26609903 TI - Complexation of U(VI) with benzoic acid at variable temperatures (298-353 K): thermodynamics and crystal structures of U(VI)/benzoate complexes. AB - Thermodynamics of the U(VI) complexation with benzoic acid (HL) was studied by spectrophotometry at varied temperatures (298-353 K) with constant ionic strength (1.05 mol kg(-1) NaClO4). Two U(VI) benzoate complexes, UO2L(+) and UO2(OH)L(aq), were identified and their formation constants determined. The formation of both complexes is endothermic and driven exclusively by entropy. Two types of U(VI)/benzoate complex crystals were synthesized from aqueous solutions at different pH and ligand/metal ratios. Their structures were determined by single crystal X-ray diffractometry. One structure is a 1 : 3 U(VI) benzoate complex (Na[UO2(C7H5O2)3].2H2O), each benzoate holding a bidentate coordination mode to U(VI) in the equatorial plane of UO2(2+). The other is a U(VI) hydroxobenzoate complex with unique MU3-OH bridging ([(UO2)2(C7H5O2)2(MU3-OH)2].4H2O). In the structure, each UO2(2+) ion holds five coordination oxygens in its equatorial plane, two carboxylate oxygens from two benzoate ligands and three oxygens from three MU3-OH groups. PMID- 26609904 TI - Efficacy of Multiple-Talker Phonetic Identification Training in Postlingually Deafened Cochlear Implant Listeners. AB - PURPOSE: This study implemented a pretest-intervention-posttest design to examine whether multiple-talker identification training enhanced phonetic perception of the /ba/-/da/ and /wa/-/ja/ contrasts in adult listeners who were deafened postlingually and have cochlear implants (CIs). METHOD: Nine CI recipients completed 8 hours of identification training using a custom-designed training package. Perception of speech produced by familiar talkers (talkers used during training) and unfamiliar talkers (talkers not used during training) was measured before and after training. Five additional untrained CI recipients completed identical pre- and posttests over the same time course as the trainees to control for procedural learning effects. RESULTS: Perception of the speech contrasts produced by the familiar talkers significantly improved for the trained CI listeners, and effects of perceptual learning transferred to unfamiliar talkers. Such training-induced significant changes were not observed in the control group. CONCLUSION: The data provide initial evidence of the efficacy of the multiple talker identification training paradigm for CI users who were deafened postlingually. This pattern of results is consistent with enhanced phonemic categorization of the trained speech sounds. PMID- 26609906 TI - Unraveling Inter- and Intrachain Electronics in Polythiophene Assemblies Mediated by Coordination Nanospaces. AB - Strong interchain interactions render unsubstituted polythiophene un-fusible, non melting, and insoluble. Therefore, control of the packing structure, which has a profound effect on the optical and electronic properties of the polymer, has never been achieved. Unsubstituted polythiophene was prepared in the one dimensional channels of [La(1,3,5-benzenetrisbenzoate)]n, where polymer chains form unprecedented assembly structures mediated by the host framework. It is noteworthy that the emission and carrier transport properties were drastically changed by varying the number of chains within a particular assembly. The response of the composite to additional guests is also examined as a method to use the composites as low-concentration sensors. Our findings show that the encapsulation of polymer chains in host materials is a facile method for understanding the intrinsic properties of conjugated polymers, along with controlling and enhancing their functions. PMID- 26609905 TI - Identification of pathogenicity-related genes in Fusarium oxysporum f. sp. cepae. AB - Pathogenic isolates of Fusarium oxysporum, distinguished as formae speciales (f. spp.) on the basis of their host specificity, cause crown rots, root rots and vascular wilts on many important crops worldwide. Fusarium oxysporum f. sp. cepae (FOC) is particularly problematic to onion growers worldwide and is increasing in prevalence in the UK. We characterized 31 F. oxysporum isolates collected from UK onions using pathogenicity tests, sequencing of housekeeping genes and identification of effectors. In onion seedling and bulb tests, 21 isolates were pathogenic and 10 were non-pathogenic. The molecular characterization of these isolates, and 21 additional isolates comprising other f. spp. and different Fusarium species, was carried out by sequencing three housekeeping genes. A concatenated tree separated the F. oxysporum isolates into six clades, but did not distinguish between pathogenic and non-pathogenic isolates. Ten putative effectors were identified within FOC, including seven Secreted In Xylem (SIX) genes first reported in F. oxysporum f. sp. lycopersici. Two highly homologous proteins with signal peptides and RxLR motifs (CRX1/CRX2) and a gene with no previously characterized domains (C5) were also identified. The presence/absence of nine of these genes was strongly related to pathogenicity against onion and all were shown to be expressed in planta. Different SIX gene complements were identified in other f. spp., but none were identified in three other Fusarium species from onion. Although the FOC SIX genes had a high level of homology with other f. spp., there were clear differences in sequences which were unique to FOC, whereas CRX1 and C5 genes appear to be largely FOC specific. PMID- 26609907 TI - Secondary organic aerosol formation initiated by alpha-terpineol ozonolysis in indoor air. AB - Secondary organic aerosol (SOA) owing to reactive organic gas (ROG) ozonolysis can be an important indoor particle source. However, SOA formation owing to ozonolysis of alpha-terpineol, which is emitted by consumer product usage and reacts strongly with ozone, has not been systematically quantified. Therefore, we conducted 21 experiments to investigate the SOA formation initiated by alpha terpineol ozonolysis for high (0.84 h-1 ), moderate (0.61 h-1 ), and low (0.36 h 1 ) air exchange rates (AER), which is the frequency with which indoor is replaced by outdoor air. alpha-Terpineol concentrations of 6.39 to 226 ppb were combined with high ozone (~25 ppm) to ensure rapid and complete ozonolysis. No reactants were replenished, so SOA peaked quickly and then decreased due to AER and surface losses, and peak SOA ranged from 2.03 to 281 MUg/m3 at unit density. SOA mass formation was parameterized with the aerosol mass fraction (AMF), a.k.a. the SOA yield, and AMFs ranged from 0.056 to 0.24. The AMFs strongly and positively correlated with reacted alpha-terpineol, whereas they weakly and negatively correlated with higher AERs. One-product, two-product, and volatility basis set (VBS) models were fit to the AMF data. Predictive modeling demonstrated that alpha-terpineol ozonolysis could meaningfully form SOA in indoor air. PMID- 26609908 TI - Influence and analysis of low-dosage steroid therapy in severe aristolochic acid nephropathy patients. AB - AIM: To investigate the effect of low-dosage steroid therapy in patients with severe aristolochic acid nephropathy (AAN). METHODS: Forty-three chronic AAN patients in the Peking Union Medical College Hospital and the First Affiliated Hospital of Xinxiang Medical College were included in this study from November 1998 to October 2013. According to the treatment method, the patients were divided into a steroid group (SG, n = 25) and a control group (CG, n = 18). The serum biochemical indicators at the basement in the two groups exhibited no obvious statistical differences. In comparison with the baseline data, the levels of serum creatinine at 3, 6, 9, and 12 months were analyzed. The blood pressure, haemoglobin, serum biochemical indicators, and the side-effects of steroid application were also observed. Urinary macrophage chemoattractant protein-1 (MCP 1) and transforming growth factor-1 (TGF-1) amounts were measured as well. RESULTS: (i) The serum creatinine content in the CG group was significantly higher than the baseline level during the follow-up(6, 9, and 12 months later), whereas in the SG group it decreased during the 3-6 month period and remained stable within 1 year. (ii) The biochemical indicators, blood pressure, and haemoglobin persisted stable. (iii) The side-effects of low-dosage steroid therapy were not severe and were tolerated by the AAN patients. (4) Urinary MCP-1 and TGF-1 concentrations were positively correlated with serum creatinine and decreased in the SG group. CONCLUSION: Low-dosage steroid therapy reversed or delayed the renal failure progression in severe chronic AAN patients, which may be associated with the suppression of MCP-1 and TGF-beta1 activities. PMID- 26609909 TI - The interleukin-33 receptor ST2 is important for the development of peripheral airway hyperresponsiveness and inflammation in a house dust mite mouse model of asthma. AB - BACKGROUND: Several clinical and experimental studies have implicated IL-33 and its receptor ST2 in the development of asthma. However, the effect of IL-33/ST2 signalling on airway responses and inflammation in allergic asthma is not well established. OBJECTIVE: To investigate the role of IL-33/ST2 signalling in promoting allergen-induced airway hyperresponsiveness (AHR), airway inflammation, antigen-specific IgE production and mast cell activity in a mouse model of asthma. METHODS: ST2-deficient (ST2(-/-)) mice and control BALB/c mice were given house dust mite (HDM) extract over a 6-week period. Forty-eight hours after the final HDM administration, lung function and airway inflammation were evaluated. Airway responsiveness was determined in the central airways and peripheral lung. Cellular infiltration and mast cell protease mMCP-1 levels were quantified in bronchoalveolar lavage fluid (BALF). Recruitment of inflammatory cells and inflammatory cytokine profiles were assessed in pulmonary tissue, and HDM specific IgE was measured in serum. RESULTS: ST2 deficiency diminished HDM induced AHR in the peripheral lung, while AHR in the central airways was unaffected. Inflammatory responses to HDM were also reduced in ST2(-/-) mice as reflected by the lower induction of HDM-specific serum IgE, inhibition of HDM induced eosinophilia and reduced macrophage count in BALF, and a diminished influx of inflammatory cells and reduced goblet cell hyperplasia around the peripheral airways. Furthermore, the levels of the inflammatory cytokines IL 1beta, IL-5, IL-13, IL-33, GM-CSF, thymic stromal lymphopoietin and mast cell protease mMCP-1 were reduced in HDM-treated ST2(-/-) mice compared with wild-type controls. CONCLUSIONS: In addition to promoting Th2 inflammation, we now suggest a role for the IL-33/ST2 pathway for the induction of peripheral inflammation and mucus production that causes AHR in the peripheral lung. This mechanism for inducing AHR at distal parts of the lung may be of specific importance as asthma is considered as a small airway disease. PMID- 26609910 TI - Dendritic cells modulate burn wound healing by enhancing early proliferation. AB - Adequate wound healing is vital for burn patients to reduce the risk of infections and prolonged hospitalization. Dendritic cells (DCs) are antigen presenting cells that release cytokines and are central for the activation of innate and acquired immune responses. Studies have showed their presence in human burn wounds; however, their role in burn wound healing remains to be determined. This study investigated the role of DCs in modulating healing responses within the burn wound. A murine model of full-thickness contact burns was used to study wound healing in the absence of DCs (CD11c promoter-driven diphtheria toxin receptor transgenic mice) and in a DC-rich environment (using fms-like tyrosine kinase-3 ligand, FL- a DC growth factor). Wound closure was significantly delayed in DC-deficient mice and was associated with significant suppression of early cellular proliferation, granulation tissue formation, wound levels of TGFbeta1 and formation of CD31+ vessels in healing wounds. In contrast, DC enhancement significantly accelerated early wound closure, associated with increased and accelerated cellular proliferation, granulation tissue formation, and increased TGFbeta1 levels and CD31+ vessels in healing wounds. We conclude that DCs play an important role in the acceleration of early wound healing events, likely by secreting factors that trigger the proliferation of cells that mediate wound healing. Therefore, pharmacological enhancement of DCs may provide a therapeutic intervention to facilitate healing of burn wounds. PMID- 26609911 TI - Illicit drugs or medicines taken by parachuting. AB - Parachuting (also called bombing) is a method of drug delivery where illicit drugs or medicines are ingested after wrapping the substance. There are little data describing parachuting in the literature. To provide a description of this practice, all cases of parachuting reported to the national addictovigilance network up to 31 December 2014 were identified from spontaneous reports and specific surveillance programs. Cases were described according to the type of substance used, patient age and gender, type of complications, context of use and year of the event. Forty-five cases of parachute use were identified and most (n = 43) occurred after 2011. Patients were mostly men (60%), and mean age was 28.9 years. The context of use, known in 19 cases, was mostly recreational. Complications were present in 24 cases, of which eight were serious. The substance was supposed to be 3,4-methylenedioxymethamphetamine (MDMA) in the majority of cases (64.4%); research chemicals were more involved in the most recent years. The physical form was mainly granular (51.6%). The wrappers were a cigarette paper (nine cases) and in one case plastic package; in the other cases, the term of parachute was used without further details. The reason for use was not explained in the majority of cases; two patients indicated using a parachute for faster effect than with a methadone capsule. Clinicians should be aware of this delivery form as the results suggest that it is common and can involve a great variability of drugs. PMID- 26609912 TI - Solid Polymer Electrolytes Based on Functionalized Tannic Acids from Natural Resources for All-Solid-State Lithium-Ion Batteries. AB - Solid polymer electrolytes (SPEs) for all-solid-state lithium-ion batteries are prepared by simple one-pot polymerization induced by ultraviolet (UV) light using poly(ethylene glycol) methyl ether methacrylate (PEGMA) as an ion-conducting monomeric unit and tannic acid (TA)-based crosslinking agent and plasticizer. The crosslinking agent and plasticizer based on natural resources are obtained from the reaction of TA with glycidyl methacrylate and glycidyl poly(ethylene glycol), respectively. Dimensionally stable free-standing SPE having a large ionic conductivity of 5.6*10(-4) Scm(-1) at room temperature can be obtained by the polymerization of PEGMA into P(PEGMA) with a very small amount (0.1 wt %) of the crosslinking agent and 2.0 wt % of the plasticizer. The ionic conductivity value of SPE with a crosslinked structure is one order of magnitude larger than that of linear P(PEGMA) in the waxy state. PMID- 26609913 TI - Costunolide induces lung adenocarcinoma cell line A549 cells apoptosis through ROS (reactive oxygen species)-mediated endoplasmic reticulum stress. AB - Costunolide is an active sesquiterpene lactone derived from many herbal medicines. It has a broad spectrum of bioactivities, including anti-inflammatory and potential anti-tumor effects. The aims of the present study were to evaluate the inhibitory effects of costunolide on A549 cell growth and to explore the underlying molecular mechanisms. Annexin V-FITC/PI flow cytometry analysis revealed that costunolide induced apoptosis. To study the mechanism, we found that costunolide exposure activated the unfolded protein response (UPR) signaling pathways, as shown by the up-regulation of GRP78 and IRE1alpha and the activation of ASK1 and JNK. Meanwhile, siRNA knockdown of IRE1alpha significantly attenuated costunolide-induced apoptosis and partly restored the mitochondrial membrane potential. ER stress-activated JNK phosphorylated Bcl-2 at Ser70, which changes the anti-apoptotic function of Bcl-2, resulting in mitochondrial dysfunction and leading to mitochondrial activation of apoptosis. Furthermore, costunolide induced ROS generation, while the antioxidant N-acetyl cysteine (NAC) effectively blocked ER stress and apoptosis activation, suggesting that ROS acts as an upstream signaling molecule in triggering ER stress and mitochondrial apoptotic pathways. Taken together, our research demonstrates that costunolide exhibits its anti-tumor activity though inducing apoptosis, which is mediated by ER stress. We further confirm that Bcl-2 is a key molecule connecting the ER stress and mitochondrial pathways. PMID- 26609915 TI - Living donor liver transplantation for intrahepatic arteriovenous fistula with hepatic artery reconstruction using the right gastroepiploic artery. PMID- 26609914 TI - Therapeutic potential of mTOR inhibitors for targeting cancer stem cells. AB - The mammalian target of rapamycin (mTOR) pathway is aberrantly activated in many cancer types. As the intricate network of regulatory mechanisms controlling mTOR activity is uncovered, more refined drugs are designed and tested in clinical trials. While first generation mTOR inhibitors have failed to show clinical efficacy due partly to the feedback relief of oncogenetic circuits, newly developed inhibitors show greater promise as anti-cancer agents. An effective drug must defeat the cancer stem cells (CSCs) while sparing the normal stem cells. Due to its opposing role on normal and malignant stem cells, mTOR lends itself very well as a therapeutic target. Indeed, a preferential inhibitory effect on CSCs has already been shown for some mTOR inhibitors. These results provide a compelling rationale for the clinical development of mTOR-targeted therapies. PMID- 26609916 TI - Light-Controlled Interconversion between a Self-Assembled Triangle and a Rhombicuboctahedral Sphere. AB - Stimuli-responsive structural reorganizations play an important role in biological processes, often in combination with kinetic control scenarios. In supramolecular mimics of such systems, light has been established as the perfect external trigger. Here, we report on the light-driven structural rearrangement of a small, self-assembled Pd3L6 ring based on photochromic dithienylethene (DTE) ligands into a rhombicuboctahedral Pd24L48 sphere measuring about 6.4 nm across. When the wavelength is changed, this interconversion can be fully reversed, as confirmed by NMR and UV/Vis spectroscopy as well as mass spectrometry. The sphere was visualized by AFM, TEM, and GISAXS measurements. Due to dissimilarities in the photoswitch conformations, the interconversion rates between the two assemblies are drastically different in the two directions. PMID- 26609917 TI - LAUNCHING A CAREER IN PSYCHOLOGY WITH ACHIEVEMENT AND ARROGANCE: JAMES McKEEN CATTELL AT THE JOHNS HOPKINS UNIVERSITY, 1882-1883. AB - The scientific career of eminent experimentalist and psychological tester James McKeen Cattell (1860-1944) began at the Johns Hopkins University during the year (1882-1883) he held the university's Fellowship in Philosophy. This article opens by sketching the scope of Cattell's lifetime achievement and then briefly reviews the historical attention that his life and career has attracted during the past few decades. It then outlines the origins and evolution of Cattell's "scientific ideology," traces the course of events that led to his fellowship, reviews his earliest studies at Johns Hopkins, and analyzes in some detail his initial laboratory successes. These laid the groundwork for his later distinguished work as a psychological experimentalist, both in Europe and America. It concludes, however, that even as Cattell's early experimental achievements impressed others, the personal arrogance he exhibited during his year in Baltimore served to alienate him from his colleagues and teachers. Over the long run, this arrogance and his often-antagonistic approach to others continued to color (and even shape) his otherwise distinguished more than 50-year scientific career. PMID- 26609918 TI - Microfluidic Separation of Ethylene and Ethane Using Frustrated Lewis Pairs. AB - Separation of gaseous olefins and paraffins is one of the most important separation processes in the industry. Development of new cost-effective technologies aims at reducing the high energy consumption during the separation process. Here, we took advantage of the reaction of frustrated Lewis pairs (FLPs) with ethylene to achieve reactive extraction of ethylene from ethylene-ethane mixtures. The extraction was studied using a microfluidic platform, which enabled a rapid, high-throughput assessment of reaction conditions to optimize gas separation efficiency. A separation factor of 7.3 was achieved for ethylene from a 1:1 volume ratio mixture of ethylene and ethane, which corresponded to an extracted ethylene purity of 88 %. The results obtained in the microfluidic studies were validated using infrared spectroscopy. This work paves the way for further development of the FLPs and optimization of reaction conditions, thereby maximizing the separation efficiency of olefins from their mixtures with paraffins. PMID- 26609919 TI - External memory aids for memory problems in people with multiple sclerosis: A systematic review. AB - Approximately 40-60% of people with multiple sclerosis (MS) have memory problems, which adversely impact on their everyday functioning. Evidence supports the use of external memory aids in people with stroke and brain injury, and suggests they may reduce everyday memory problems in people with MS. Previous reviews of people with MS have only evaluated randomised trials; therefore this review included other methodologies. The aim was to assess the efficacy of external memory aids for people with MS for improving memory functioning, mood, quality of life, and coping strategies. Seven databases were systematically searched. Intervention studies that involved training in the use of external memory aids, e.g., personal digital assistants, with at least 75% of people with MS, were included. Based on study design, quality was rated with the SCED or PEDro scale. Nine studies involving 540 participants were included. One single case experimental design (mean of 8 on SCED scale) and eight group studies (mean of 5 on PEDro scale) were included. One study reported a significant treatment effect on subjective memory functioning, two on mood, and two on coping strategies. There is insufficient evidence to support or refute the effectiveness of external memory aids for improving memory function in people with MS. PMID- 26609920 TI - A highly sensitive strategy for base excision repair enzyme activity detection based on graphene oxide mediated fluorescence quenching and hybridization chain reaction. AB - A novel fluorescent nanosensor has been developed by combining super fluorescence quenching ability of graphene oxide and hybridization chain reaction amplification, which enables highly sensitive detection of base excision repair enzyme activity with a wide dynamic range from 0.0001 to 100 U mL(-1) and a detection limit of 0.00006 U mL(-1). PMID- 26609921 TI - Incorporation of ZrO2 particles in the oxide layer formed on Mg by anodizing: Influence of electrolyte concentration and current modes. AB - HYPOTHESIS: The objectives of the present study are to ascertain, particle incorporation during the initial stages of microarc oxidation (MAO), feasibility of increasing the level of particle incorporation through manipulation of process variables and, the use of MgO-ZrO2 composite coatings either as a pre-treatment or as a post-treatment for MAO coated Mg. EXPERIMENTS: Anodic oxide coatings were prepared using 0.3M NaOH+15g/l ZrO2 and 3M NaOH+15g/l ZrO2 at 10V under direct current, pulsed current (PC) unipolar and PC bipolar modes. MAO coatings were prepared using 5g/l NaOH+15g/l Na2SiO3 at 250V under direct current mode for 2min. FINDINGS: The study reveals that it is possible to incorporate ZrO2 particles in the anodic oxide layer, suggesting such a possibility during the initial stages of MAO. When the MgO-ZrO2 composite coating is used as a pre treatment, it helps to reduce the size and density of the pores of the MAO coatings and increased the corrosion resistance. When it is used as a post treatment, lamellar shaped Mg(OH)2 with a very high surface area is formed on the surface, which would be beneficial to impart a better bioactivity and to facilitate immobilization of biomolecules. PMID- 26609922 TI - On the phase-field modelling of a miscible liquid/liquid boundary. AB - Mixing of miscible liquids is essential for numerous processes in industry and nature. Mixing, i.e. interpenetration of molecules through the liquid/liquid boundary, occurs via interfacial diffusion. Mixing can also involve externally or internally driven hydrodynamic flows, and can lead to deformation or disintegration of the liquid/liquid boundary. At the moment, the mixing dynamics remains poorly understood. The classical Fick's law, generally accepted for description of the diffusion process, does not explain the experimental observations, in particular, the recent experiments with dissolution of a liquid solute by a liquid solvent within a horizontal capillary (Stevar and Vorobev, 2012). We present the results of the numerical study aimed at development of an advanced model for the dissolution dynamics of liquid/liquid binary mixtures. The model is based on the phase-field (Cahn-Hilliard) approach that is used as a physics-based model for the thermo- and hydrodynamic evolution of binary mixtures. Within this approach, the diffusion flux is defined through the gradient of chemical potential, and, in particular, includes the effect of barodiffusion. The dynamic interfacial stresses at the miscible interface are also taken into account. The simulations showed that such an approach can accurately reproduce the shape of the solute/solvent boundary, and some aspects of the diffusion dynamics. Nevertheless, all experimentally-observed features of the diffusion motion of the solute/solvent boundary, were not reproduced. PMID- 26609923 TI - Solid lipid nanoparticles from amphiphilic calixpyrroles. AB - HYPOTHESIS: Macrocyclic amphiphiles form interesting self-assembling structures, including solid lipid nanoparticles, which have potential applications in drug encapsulation. Aryl-extended calixpyrroles, which act as anion binding hosts, are expected to form solid lipid nanoparticles, even though the alkyl chains have unusual perpendicular geometry with respect to the hydrophilic head group. The preparation conditions and the alkyl chain length should affect the size and stability of the particles. EXPERIMENTS: Solid lipid nanoparticles of two aryl extended calixpyrroles with resorcinol walls and either meso-dodecyl or meso methyl alkyl chains were compared. Ethanolic solutions of the calixpyrroles were mixed with water and the resulting nanoparticle dispersions were studied with dynamic light scattering and nanoparticle tracking analysis. The effect of different calixpyrrole/ethanol/water ratios on particle size was tested. The surface charge of the particles at different pH and NaCl concentration was determined by zeta potential measurements. FINDINGS: The meso-dodecyl calixpyrrole produced small nanoparticles with mean hydrodynamic diameters between 40 and 70nm in 0.86-4.28M ethanol. The particles were stable in solution for several months. Particles prepared from meso-methyl calixpyrrole were larger and less stable. The smallest particles were obtained with low calixpyrrole concentration and calixpyrrole/ethanol ratio. Larger ethanol/water ratio induced broader particle size distributions. Increasing pH aided the stability of the particles due to increased negative surface charge. PMID- 26609924 TI - Thermally activated Cu/Cu2S/ZnO nanoarchitectures with surface-plasmon-enhanced Raman scattering. AB - Hierarchical Cu/Cu2S/ZnO nanoarchitectures were fabricated via an electroplated ZnO nanorod array in the first step, followed by the growth of Cu2S nanostructures for the application of surface-enhanced Raman scattering (SERS) detection. The Cu/Cu2S nanostructures as grown were thermally treated at 150-300 degrees C under a nitrogen atmosphere to improve the crystalline quality, and, unexpectedly, to induce plasmonic Cu nanoshells on the surface of Cu2S. With 4 aminothiophenol (4-ATP) as probing molecules, SERS experiments showed that the thermally treated Cu/Cu2S/ZnO nanostructures exhibit excellent detection performance, so that they can serve as active and cost-effective SERS substrates for ultrasensitive detection. The enhancement is attributed to the coupling between Cu2S and plasmonic Cu, as confirmed by electromagnetic field simulations. This novel hierarchical substrate shows satisfactory reproducibility and a linear dependence of intensity on analyte concentration, revealing an advantage of this method for easily scaled production. PMID- 26609925 TI - Electrochemical energy storage in montmorillonite K10 clay based composite as supercapacitor using ionic liquid electrolyte. AB - Exploring new electrode materials is the key to realize high performance energy storage devices for effective utilization of renewable energy. Natural clays with layered structure and high surface area are prospective materials for electrical double layer capacitors (EDLC). In this work, a novel hybrid composite based on acid-leached montmorillonite (K10), multi-walled carbon nanotube (MWCNT) and manganese dioxide (MnO2) was prepared and its electrochemical properties were investigated by fabricating two-electrode asymmetric supercapacitor cells against activated carbon (AC) using 1.0M tetraethylammonium tetrafluroborate (Et4NBF4) in acetonitrile (AN) as electrolyte. The asymmetric supercapacitors, capable of operating in a wide potential window of 0.0-2.7V, showed a high energy density of 171Whkg(-1) at a power density of ~1.98kWkg(-1). Such high EDLC performance could possibly be linked to the acid-base interaction of K10 through its surface hydroxyl groups with the tetraethylammonium cation [(C2H5)4N(+) or TEA(+)] of the ionic liquid electrolyte. Even at a very high power density of 96.4kWkg(-1), the cells could still deliver an energy density of 91.1Whkg(-1) exhibiting an outstanding rate capability. The present study demonstrates for the first time, the excellent potential of clay-based composites for high power energy storage device applications. PMID- 26609926 TI - A hybrid-assembly approach towards nitrogen-doped graphene aerogel supported cobalt nanoparticles as high performance oxygen reduction electrocatalysts. AB - As a novel electrocatalyst for oxygen reduction reaction (ORR), nitrogen-doped graphene aerogel supported cobalt nanoparticles (Co-NGA) is archived by a hybrid assembly of graphene oxide (GO), o-phthalonitrile and cobalt acetate and the following thermal treatment. The hybrid-assembly process successfully combines the ionic assembly of GO sheets and Co ions with the coordination between o phthalonitrile and Co ions, which can be converted to nitrogen doped carbon and Co nanoparticles in the pyrolysis process under nitrogen flow. Remarkable features of Co-NGA including the macroporous graphene scaffolds, high surface area, and N/Co-doping effect can lead to a high catalytic efficiency for ORR. As the results, the composites pyrolyzed at 600 degrees C (Co-NGA600) shows excellent electrocatalytic activities and kinetics for ORR in basic media, which are comparable with those of Pt/C catalyst, together with superior durability. PMID- 26609927 TI - Photocatalytic CO2 reduction over B4C/C3N4 with internal electric field under visible light irradiation. AB - Boron carbide/graphitic carbon nitride (B4C/g-C3N4) p-n hetero-junction photocatalyst with an internal electric field was synthesized by a facile solvent evaporation method and characterized by field emission scanning electron microscope (FESEM), UV-Vis diffuse reflectance spectra (UV-Vis DRS), photoluminescence spectra (PL), etc. Photocatalytic activity of the composite B4C/g-C3N4 loaded with Pt co-catalyst was evaluated using CO2 conversion to CH4 with H2 as the hydrogen source and reductant under visible light irradiation. The coupling of p-type B4C with n-type g-C3N4 significantly improved the performance of photocatalytic CO2 reduction; with the optimum B4C mass fraction of 1/6, the composite photocatalyst showed approximately 6 and 8 times higher CH4 generation rate than g-C3N4 and B4C, respectively. The enhancement was attributed to efficient photo-excited electron/hole separation due to the formation of internal electric field at the p-B4C/n-C3N4 interface. PMID- 26609928 TI - Photogenerated charges transfer across the interface between NiO and TiO2 nanotube arrays for photocatalytic degradation: A surface photovoltage study. AB - To better understand the behavior of photogenerated charges in the composite photocatalyst interface is beneficial to the designing of effective photocatalyst for photocatalytic reaction. In our work, the separation and transfer process of photogenerated charges in NiO/TiO2 nanotube arrays (NiO/TiO2 NTAs) has been studied by surface photovoltage (SPV) spectroscopy and transient photovoltage (TPV) measurement. Through the experimental results analysis, we find that an interfacial electric field is formed at NiO/TiO2 NTAs interface, which is attributed to the work function difference between NiO and TiO2 NTAs. The photogenerated holes in TiO2 can transfer to the NiO layer along the interface electric field under the ultraviolet irradiation. A large amount of photogenerated holes can be separated effectively and then prolonged the holes lifetime to participate in the photocatalytic oxidation reaction. The above results show that the favorable hole-collecting process of NiO in the surface of TiO2 NTAs is the main factor being responsible for the increase the photocatalytic efficiency. PMID- 26609929 TI - Facile ion-exchange synthesis of mesoporous Bi2S3/ZnS nanoplate with high adsorption capability and photocatalytic activity. AB - Novel Bi2S3/ZnS nanoplates have been successfully prepared by simple reflux and cation exchange reaction between the preformed ZnS spheres and Bi(NO3)3.5H2O. The synthesized Bi2S3/ZnS nanoplates are mesoporous structures, possess a high specific surface area of 101.30m(2)/g and exhibit high adsorption capability and photocatalytic activity for methylene blue (MB) degradation under UV light irradiation. The high adsorption capability and photocatalytic activity can be ascribed to the fact that the formation of Bi2S3/ZnS nanoplates with large specific surface area provides more reactive sites and facilitates the separation of photogenerated electron-hole pairs. The possible formation mechanism of Bi2S3/ZnS nanoplates is proposed based on the time-dependent observation. Moreover, a tentative mechanism for degradation of MB over Bi2S3/ZnS has been proposed involving OH radical and photoinduced holes as the active species, which is confirmed by using methanol or ammonium oxalate as scavengers. This work provides a cost-effective method for large-scale synthesis of composite with controlled architectural morphology and highly promising applications in photocatalysis. PMID- 26609930 TI - Surface engineered gold nanoparticles through highly stable metal-surfactant complexes. AB - Monodispersed Au nanoparticles were synthesized by the reduction of Au decyltrimethylammonium bromide (Au-DTAB), which was easily prepared via the reaction of HAuCl4 and DTAB. This Au-DTAB complex is highly stable in air and moisture, and suitable for large-scale synthesis of uniform-sized Au nanoparticles. The nanoparticles were characterized by transmission electron microscopy, optical absorption spectrometry, X-ray diffraction, and Fourier Transform infrared spectroscopy. The size of Au nanoparticles was controlled in the range of 5-10nm by changing the concentrations of reducing agent and Au precursor. The resulting Au nanoparticles were transferred to the aqueous phase after surface engineering using multidentate polymeric ligands with multiple imidazole functional groups. Polymeric imidazole ligands (PILs) demonstrated enhanced binding stability with the Au surface, and overcame the disadvantage of multidentate thiol ligand systems which have oxidative cross-linking and the formation of disulfide bonding. The colloidal stability of surface engineered Au nanoparticles with PILs was investigated by dynamic light scattering (DLS) characterization. PMID- 26609931 TI - A new designed pi conjugated molecule for stable single walled carbon nanotube dispersion in aqueous medium. AB - A molecule with a pi conjugated backbone built from aromatic thiophene and dialkoxyphenylene units and substituted imidazolium groups (TPO) is designed to obtain ultra-stable single walled carbon nanotube (SWCNT) dispersion in aqueous medium. The proposed mechanism of non-covalent interaction is accompanied by individualization of SWCNT and comprises of dominant nondisruptive pi-pi and cation-pi interaction between them and the TPO conjugated oligomer. The individualization of SWCNT and dispersibility and stability of the ultra-stable suspensions were estimated using high resolution transmission electron microscopy, UV-Visible-NIR absorption spectroscopy, Raman spectroscopy, photoluminescence and zeta potential measurement. Nuclear magnetic resonance data provides direct evidence toward possible cation-pi interaction. PMID- 26609933 TI - Synthesis of hierarchal SAPO-34 nano catalyst with dry gel conversion method in the presence of carbon nanotubes as a hard template. AB - In this study, the silicoaluminophosphate (SAPO) particles were synthesized based on dry gel conversion method using diethyl amine (DEA) as an organic structure directing agent (SDA). Transport pores were introduced into the crystalline structure of the catalyst using carbon nanotubes (CNT) as a hard template. The significance of molar ratio of CNT in the starting gel and the other synthesis parameters such as crystallization time, gel drying temperature and water content added in the crystallization stage, on crystallinity of SAPO-34, crystal phase, particle size and morphology were studied. The products were characterized by XRD, SEM, TEM, BET and EDX. D-optimal experimental design with four numeric factors including gel drying temperature, crystallization time, water/dry gel mass ratio and mole of CNT in the precursor gel each at three levels was implemented to optimize the experimental parameters by analysis of variance (ANOVA). The Fischer test results showed that, all the parameters have significant effect on the crystallinity of the synthesized samples. PMID- 26609932 TI - Doxorubicin-loaded polypeptide nanorods based on electrostatic interactions for cancer therapy. AB - An amphiphilic anionic polypeptide, methoxypolyethylene glycol-poly (glutamic acid) (mPEG-PGA), was synthesized, characterized and evaluated as a nanocarrier for the cationic anticancer drug doxorubicin hydrochloride (DOX.HCl). The complex self-assembled into nanorods in aqueous solutions via electrostatic interactions and exhibited a superior drug loading content (50.8%) and drug loading efficiency (90.2%). The average major axis of the drug-loaded nanorods was approximately 300nm, as determined by transmission electron microscopy. An in vitro release assay showed that drug-loaded nanorods exhibited pH-sensitivity and sustained release. Haemolysis assays demonstrated that the polypeptide was haemocompatible, and the polypeptide drug carrier significantly reduced the haemolysis ratio of DOX.HCl. The pharmacokinetics study showed that DOX-loaded nanorods significantly prolonged the resident time in blood. An in vitro cytotoxicity study and cellular uptake assays demonstrated that the DOX-loaded nanorods resulted in higher cell proliferation inhibition and a higher level of tumour cell uptake in A549 cells than with free DOX.HCl. The prolonged circulation and enhanced antitumor efficacy of DOX-loaded nanorods shows promise for efficient cancer chemotherapy. PMID- 26609934 TI - Interferon but not MxB inhibits foamy retroviruses. AB - Foamy viruses (FV) are retroviruses that are widely distributed in primate and non-primate animal species. We tested here FV with capsids of simian and non simian origin for sensitivity to interferon-beta (IFN-beta). Our data show significant inhibition of FV by IFN-beta early in infection of human HOS and THP 1 but not of HEK293T cells. The post-entry restriction of FV was not mediated by the interferon-induced MxB protein that was recently identified as a capsid interacting restriction factor targeting Human immunodeficiency virus (HIV) before integration. Neither the ectopic expression of MxA or MxB in HEK293T cells nor the lack of MxB expression in CRISPR/CAS MxB THP-1 knockout cells impacted the infection of the tested FV. IFN-beta treated THP-1 and THP-1 KO MxB cells showed the same extend of restriction to FV. Together, the data demonstrate that IFN-beta inhibits FV early in infection and that MxB is not a restriction factor of FV. PMID- 26609935 TI - Protection from genital herpes disease, seroconversion and latent infection in a non-lethal murine genital infection model by immunization with an HSV-2 replication-defective mutant virus. AB - Viral vaccines have traditionally protected against disease, but for viruses that establish latent infection, it is desirable for the vaccine to reduce infection to reduce latent infection and reactivation. While seroconversion has been used in clinical trials of herpes simplex virus (HSV) vaccines to measure protection from infection, this has not been modeled in animal infection systems. To measure the ability of a genital herpes vaccine candidate to protect against various aspects of infection, we established a non-lethal murine model of genital HSV-2 infection, an ELISA assay to measure antibodies specific for infected cell protein 8 (ICP8), and a very sensitive qPCR assay. Using these assays, we observed that immunization with HSV-2 dl5-29 virus reduced disease, viral shedding, seroconversion, and latent infection by the HSV-2 challenge virus. Therefore, it may be feasible to obtain protection against genital disease, seroconversion and latent infection by immunization, even if sterilizing immunity is not achieved. PMID- 26609936 TI - IBDV particles packaged with only segment A dsRNA. AB - Multi-segmented dsRNA viruses have been suggested to utilize cis-acting elements in the plus-strand RNA to accomplish genomic RNA assortment during viral packaging. It is not clear if bi-segmented dsRNA birnavirus uses the same strategy. By applying a reverse genetic technique, we generated IBDV particles packaged with only segment A by co-transfection DF-1 cells of cDNA from segment A and VP1 (without 5' and 3' noncoding region of segment B) supporting random assortment mechanism and indicating the packaging elements of segment B include sequences in the 5' and 3' NCR. However, gfp-containing IBDV could not be generated in the presence of gfp cDNA constructs flanked by 5' and 3' NCR from segment A or segment B. The data suggest additional packaging signals are required for IBDV genomic packaging. The presence of VP1 protein in the IBDV-A particles also suggests the formation of ribonucleoprotein (RNP) complexes might be involved in the assembly of viral particles. PMID- 26609937 TI - Mouse papillomavirus MmuPV1 infects oral mucosa and preferentially targets the base of the tongue. AB - In 2010, a new mouse papillomavirus, MmuPV1, was discovered in a colony of NMRI- Foxn1(nu)/Foxn1(nu) athymic mice in India. This finding was significant because it was the first papillomavirus to be found in a laboratory mouse. In this paper we report successful infections of both dorsal and ventral surfaces of the rostral tongues of outbred athymic nude mice. We also report the observation that the base of the tongue, the area of the tongue often targeted by cancer associated high-risk papillomavirus infections in humans, is especially susceptible to infection. A suitable animal model for the study of oral papillomavirus infections, co-infections, and cancers has long been sought. The work presented here suggests that such a model is now at hand. PMID- 26609938 TI - Alternative RNA splicing of KSHV ORF57 produces two different RNA isoforms. AB - In lytically infected B cells Kaposi sarcoma-associated herpesvirus (KSHV) ORF57 gene encodes two RNA isoforms by alternative splicing of its pre-mRNA, which contains a small, constitutive intron in its 5' half and a large, suboptimal intron in its 3's half. The RNA1 isoform encodes full-length ORF57 and is a major isoform derived from splicing of the constitutive small intron, but retaining the suboptimal large intron as the coding region. A small fraction (<5%) of ORF57 RNA undergoes double splicing to produce a smaller non-coding RNA2 due to lack of a translational termination codon. Both RNAs are cleaved and polyadenylated at the same cleavage site CS83636. The insertion of ORF57 RNA1 into a restriction cutting site in certain mammalian expression vectors activates splicing of the subopitmal intron and produces a truncated ORF57 protein. PMID- 26609939 TI - No SEVI-mediated enhancement of rectal HIV-1 transmission of HIV-1 in two humanized mouse cohorts. AB - Amyloid fibrils from semen-derived peptide (SEVI) enhance HIV-1 infectivity in vitro but the ability of SEVI to mediate enhancement of HIV infection in vivo has not been tested. In this study we used immunodeficient mice reconstituted with human immune systems to test for in vivo enhancement of HIV-1 transmission. This mouse model supports mucosal transmission of HIV-1 via the intrarectal route leading to productive infection. In separate experiments with humanized mouse cohorts reconstituted with two different donor immune systems, high dose HIV-1JR CSF that had been incubated with SEVI amyloid fibrils at physiologically relevant concentrations did not show an increased incidence of infection compared to controls. In addition, SEVI failed to enhance rectal transmission with a reduced concentration of HIV-1. Although we confirmed potent SEVI-mediated enhancement of HIV infectivity in vitro, this model showed no evidence that it plays a role in the much more complex situation of in vivo transmission. PMID- 26609940 TI - Cytisine basicity, solvation, logP, and logD theoretical determination as tool for bioavailability prediction. AB - Cytisine, an alpha4beta2 nicotinic receptor partial agonist, is a plant alkaloid widely used as a smoking cessation agent. Despite long history of use, knowledge on pharmacokinetics of cytisine still demands an extension. This work is aimed at theoretical determination of physicochemical parameters that affect the bioavailability of cytisine. The acidic dissociation constant, Gibbs free energy of solvation in water and n-octanol as well as n-octanol/water partition coefficient and n-octanol/water distribution coefficient of cytisine were calculated as quantities corresponding to its solubility and permeability. Cytisine structure was optimized with several quantum chemical methods-ab initio: HF and MP2, and DFT functionals (B3LYP, B3LYP-D3, CAM-B3LYP, M06-2X, TPSS, VSXC) with 6-311++G(d,p) basis set. Solvation of cytisine in water and n-octanol was determined with the SMD continuum model. It was shown that lipophilicity of cytisine depends on the pH of an environment. Protonated cytisine, the most populated state under acidic conditions, is characterized by enhanced hydrophilicity. Then neutral cytisine, dominating in a basic environment, demonstrates more lipophilic character. It appears that cytisine is very well soluble in the gastrointestinal (GI) tract fluids. Then the distribution of cytisine ought to occur very rapidly. However, permeability of cytisine through the mucous membrane of the GI tract may be limited, leading to the diminished bioavailability. PMID- 26609941 TI - Structural alterations of the language connectome in children with specific language impairment. AB - We evaluated brain white matter pathways associated with language processing in 37 children with specific language impairment aged 6-12 years and 34 controls, matched for age, sex and handedness. Arcuate fascicle (AF), inferior fronto occipital fascicle (IFOF), inferior longitudinal fascicle (ILF) and uncinate fascicle (UF) were identified using magnetic resonance diffusion tensor imaging (DTI). Diffusivity parameters and volume of the tracts were compared between the SLI and control group. Children with SLI showed decreased fractional anisotropy in all investigated tracts, increased mean diffusivity and radial diffusivity component in arcuate fascicle bilaterally, left IFOF and left ILF. Further, bilaterally increased volume of the ILF in children with SLI was found. We confirmed previous findings indicating deficient connectivity of the arcuate fascicle and as a novel finding, demonstrate abnormal development of the ventral language stream in patients with SLI. PMID- 26609942 TI - Sociocultural and identity predictors of body dissatisfaction in ethnically diverse college women. AB - Emerging research suggests that ethnic identity and American identity are associated with mental health in ethnic minorities and European Americans, respectively. Furthermore, although ethnic identity is associated with diminished body dissatisfaction in minority women, the relationship between American identity and body dissatisfaction is unexplored in all ethnic groups. Accordingly, this study examined the relationships among ethnic identity, American identity, thin-ideal internalization, pressures for thinness, and body dissatisfaction in 1018 ethnically diverse college women. Ethnic identity negatively predicted body dissatisfaction for African Americans, and attenuated the relationship between pressures for thinness and body dissatisfaction for African Americans and Asian Americans, but not European Americans or Latina Americans. Results for American identity were inconclusive. Findings suggest that ethnic identity may be a protective factor against eating pathology for Asian American and African American women. PMID- 26609944 TI - An improved RT-IPCR for detection of pyrene and related polycyclic aromatic hydrocarbons. AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous homogeneous chemicals which are well known by carcinogens, mutagens and endocrine disorder. Here, an improved real-time immuno-PCR (RT-IPCR) was developed for detection of pyrene and its homologs in water samples. The PAHs in sample compete with pyrene-modified DNA to bind with monoclonal antibody (McAb) coated on PCR plate. The reporter DNA was exponentially amplified by real-time PCR instrument using Fast Start universal SYBR Green Master (ROX) kit. Only two reaction steps were needed to accomplish the detection. The assay had a good linear range from 5 pmol L(-1) to 5 nmol L(-1) with a detection limit of 3.5 pmol L(-1). For application assay, the average recoveries from tap water, lake water and mineral water were 98.4%, 98.2% and 99.7%, respectively which showed a good correlation (R(2)=0.9906) with those from GC-MS. The results indicated that the improved RT-IPCR seems to be a potential method for simple and ultrasensitive detection of pyrene and some homologues in environment water samples. PMID- 26609943 TI - Immune suppressive mechanisms in the tumor microenvironment. AB - Effective immunotherapy, whether by checkpoint blockade or adoptive cell therapy, is limited in most patients by a key barrier: the immunosuppressive tumor microenvironment. Suppression of tumor-specific T cells is orchestrated by the activity of a variety of stromal myeloid and lymphoid cells. These often display inducible suppressive mechanisms that are triggered by the same anti-tumor inflammatory response that the immunotherapy intends to create. Therefore, a more comprehensive understanding of how the immunosuppressive milieu develops and persists is critical in order to harness the full power of immunotherapy of cancer. PMID- 26609945 TI - Aptamer-based colorimetric detection of proteins using a branched DNA cascade amplification strategy and unmodified gold nanoparticles. AB - A branched DNA amplification strategy was employed to design a colorimetric aptameric biosensor using unmodified gold nanoparticles (AuNPs). First, a programmed DNA dendritic nanostructure was formed using two double-stranded substrate DNAs and two single-stranded auxiliary DNAs as assembly components via a target-assisted cascade amplification reaction, and it was then captured by DNA sensing probe-stabilized AuNPs. The release of sensing probes from AuNPs led to the formation of unstable AuNPs, promoting salt-induced aggregation. By integrating the signal amplification capacity of the branched DNA cascade reaction and unmodified AuNPs as a sensing indicator, this amplified colorimetric sensing strategy allows protein detection with high sensitivity (at the femtomole level) and selectivity. The limit of detection of this approach for VEGF was lower than those of other aptamer-based detection methods. Moreover, this assay provides modification-free and enzyme-free protein detection without sophisticated instrumentation and might be generally applicable to the detection of other protein targets in the future. PMID- 26609946 TI - Release of bio-active dentine extracellular matrix components by histone deacetylase inhibitors (HDACi). AB - AIM: To characterize dentine matrix component (DMC) release and smear layer removal by histone deacetylase inhibitors (HDACis). METHODOLOGY: DMCs were extracted from powdered human dentine over 14 days using three HDACis, valproic acid (VPA), trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) and compared with a control extractant, 10% (w/v) EDTA. Protein compositions of the resultant extracts were analysed by 1D-polyacrylamide gel electrophoresis (1D PAGE), TGF-beta-1 and MMP-9 ELISAs and a high-throughput growth factor antibody array. Dentine discs with a standardized smear layer were prepared from human molars and treated with EDTA (17% w/v), polyacrylic acid (PA) (20% v/v) and the experimental HDACis prior to analysis by scanning electron microscopy. Parametric ELISA data were analysed using one-way anova and Tukey's post hoc test, whilst nonparametric smear layer data were analysed by Kruskal-Wallis test and Mann Whitney U-test (P < 0.05). RESULTS: HDACis did not remove smear layer in the presence or absence of PA pre-treatment (P >= 0.478). 1D-PAGE analysis demonstrated different protein profiles for EDTA and HDACi extracts. All HDACi solutions released TGF-beta-1 although less effectively than EDTA (P < 0.001), whilst MMP-9 was extracted in significantly higher concentration by EDTA and VPA compared with TSA (P < 0.012). Antibody array analysis demonstrated the ability of HDACis to extract a complex cocktail of established/novel growth factors from dentine, albeit significantly less efficiently than EDTA for certain cytokines (TGF-beta-1, PDGF-AA, VEGF-A) and significantly more effectively for others (GDF 15, IGF-1, EGRF-1, NGFR, BDNF, SCF-R). CONCLUSIONS: HDACi release a range of bioactive DMCs that could promote dentine repair processes in vivo; however, they are ineffective at removing smear layer. PMID- 26609947 TI - Fast pyrolysis char - Assessment of alternative uses within the bioliq(r) concept. AB - Experiments with a process development unit for fast pyrolysis of biomass residues of 10kgh(-1) have been performed to quantify the impact of two different product recovery options. Wheat straw, miscanthus and scrap wood have been used as feedstock. A separate recovery of char increases the organic oil yield as compared to a combined recovery of char and organic condensate (OC). Furthermore, it allows for an alternative use of the byproduct char which represents an important product fraction for the high ash biomass residues under consideration. The char produced shows little advantage over its biomass precursor when considered as energy carrier due to its high ash content. Significant value can be added by demineralizing and activating the char. The potential to increase the economic feasibility of fast pyrolysis is shown by an assessment of the bioliq(r) process chain. PMID- 26609948 TI - Sedimentation-induced detachment of magnetite nanoparticles from microalgal flocs. AB - The objective of this study is to develop a simple, one-step approach to separate adsorbed Fe3O4 nanoparticles from microalgal flocs for further downstream processing. Using the wild-type strain of fresh-water algae Chlamydomonas reinhardtii, effective removal of nanoparticles from microalgal flocs by both centrifugal sedimentation (at 1500 or 2000g) and magnetic sedimentation (at 1500 Oe) is demonstrated. At the physiological pH of the solution (i.e., pH 7.0), where the electrostatic force between the nanoparticles and the microalgal cells is strongly attractive, larger separation force was achieved by simply increasing the density and viscosity of the solution to 1.065g/mL and 1.244cP, respectively. The method described here offers significant opportunity for purifying microalgal biomass after nanoparticle-flocculation-based harvesting and decreasing the cost of microalgal biotechnology. This may also find avenues in other applications that apply flocculation, such as algal biofilm formation in photobioreactors and wastewater treatment. PMID- 26609949 TI - Co-composting of poultry manure mixtures amended with biochar - The effect of biochar on temperature and C-CO2 emission. AB - Biochar as an amendment could have an impact on composting dynamics. This study investigated the effect of the addition of biochar (B) to poultry manure (P) mixed with wheat straw (S) (i.e. P:S, P:S+5%B and P:S+10%B) on temperature and carbon dioxide emission. For temperature studies a modified equation for net degree-hour parameter DHnet ( degrees Chday(-1)) was proposed. The modified equation takes into account ambient temperature. The highest daily temperatures DHnet were observed on day 2 and the mixture with the highest addition of biochar (P:S+10%) reached the max temperature. The period of thermophilic temperatures (40 degrees C>) was shorter for mixtures amended with biochar. The addition of biochar increased C-CO2 emission and the total C-CO2 emission were higher about 6.9% and 7.4% for P:S+5%B and P:S+10%B, respectively. PMID- 26609950 TI - Techno-economic assessment of a wood-based biorefinery concept for the production of polymer-grade ethylene, organosolv lignin and fuel. AB - Lignocellulose biorefineries are distinguished by an explicitly integrative, multi-functional concept that transforms biomass into multiple products, using a variety of conversion and separation processes. This study focuses on the technical design and economic evaluation of a lignocellulose biorefinery, that converts 400,000tDM/a (?250MW) of beech wood into chemicals and fuel. A model was simulated with Aspen Plus(r) including the process steps pre-treatment, enzymatic hydrolysis, alcoholic fermentation, dehydration and biogas generation and upgrading. Mass and energy balances showed that 61,600t/a polymer-grade ethylene, 58,520tDM/a organosolv lignin, 38,400t/a biomethane and 90,800tDM/a hydrolysis lignin can be produced with a total energy efficiency of 87.1%. A discounted cash flow analysis indicated that the heat integrated biorefinery concept is not yet profitable. However, the economic results are greatly sensitive regarding various assumptions, in particular in terms of the prices for beech wood, ethylene and organosolv lignin. PMID- 26609951 TI - Patterning with Diffusion Barriers. AB - Notch signaling instructs equivalent cells to form precise differentiation patterns. In this issue of Developmental Cell, Cinquin et al. (2015) characterize diffusion barriers that enhance Notch patterning within the Caenorhabditis elegans gonad. PMID- 26609952 TI - ESCRT Filaments as Spiral Springs. AB - In a recent issue of Cell, Chiaruttini et al. (2015) reveal the mechanical properties of the mysterious spiral filaments formed by the yeast ESCRT-III protein Snf7. The spirals are shown to be springs whose bending drives membrane deformation and perhaps membrane scission. PMID- 26609953 TI - Taking Snapshots of Ciliary Signaling. AB - Although the primary cilium critically influences signaling in development and disease, the organelle's small size and the dynamic nature of signaling events have posed obstacles to dissecting critical mechanisms. Reporting in Developmental Cell, Mick and colleagues (2015) describe cilia-APEX as an approach to provide dynamic "snapshots" of the ciliary proteome. PMID- 26609954 TI - Sperm Motility Requires Wnt/GSK3 Stabilization of Proteins. AB - Inhibition of GSK3 by Wnt signaling stabilizes many cellular proteins, but proof that this effect is independent of beta-catenin-mediated transcription is lacking. Koch, Acebron, and colleagues (2015) now demonstrate that transcriptionally silent mammalian sperm require Wnt signaling via exosomes to prevent protein degradation during their lengthy travels through the epididymis. PMID- 26609955 TI - Keeping Order in Anaphase. AB - The critical components of chromosome segregation machinery are well established, but how they orchestrate the relative order of events during mitosis remains unclear. Kamenz et al. (2015) now report in Molecular Cell quantitative data suggesting competing networks and adaptive thresholds in the control of mitotic exit by the anaphase-promoting complex. PMID- 26609957 TI - Stage-Dependent Axon Transport of Proteasomes Contributes to Axon Development. AB - Axon extension at the growing tip requires elevated local protein supply, with a capability sustainable over long axons in varying environments. The exact mechanisms, however, remain elusive. Here we report that axon-promoting factors elicited a retrograde transport-dependent removal of proteasomes from nascent axon terminals, thereby increasing protein stability at axon tips. Such an effect occurred through phosphorylation of a dynein-interacting proteasome adaptor protein Ecm29. During the transition from immature neurites to nascent axons in cultured hippocampal neurons, live-cell imaging revealed a significant increase of the retrograde axonal transport of fluorescently labeled 20S proteasomes. This retrograde proteasome transport depended on neuron stage and increased with axon lengths. Blockade of retrograde transport caused accumulation of proteasomes, reduction of axon growth, and attenuation of growth-associated Par6 at the axon tip of newly polarized neurons. Our results delineate a regulatory mechanism that controls proteasome abundance via preferential transport required for axon development in newborn neurons. PMID- 26609956 TI - Semi-permeable Diffusion Barriers Enhance Patterning Robustness in the C. elegans Germline. AB - Positional information derived from local morphogen concentration plays an important role in patterning. A key question is how morphogen diffusion and gene expression regulation shape positional information into an appropriate profile with suitably low noise. We address this question using a model system--the C. elegans germline--whose regulatory network has been well characterized genetically but whose spatiotemporal dynamics are poorly understood. We show that diffusion within the germline syncytium is a critical control of stem cell differentiation and that semi-permeable diffusion barriers present at key locations make it possible--in combination with a feedback loop in the germline regulatory network--for mitotic zone size to be robust against spatial noise in Notch signaling. Spatial averaging within compartments defined by diffusion barriers is an advantageous patterning strategy, which attenuates noise while still allowing for sharp transitions between compartments. This strategy could apply to other organs. PMID- 26609958 TI - A bHLH-Based Feedback Loop Restricts Vascular Cell Proliferation in Plants. AB - Control of tissue dimensions in multicellular organisms requires the precise quantitative regulation of mitotic activity. In plants, where cells are immobile, tissue size is achieved through control of both cell division orientation and mitotic rate. The bHLH transcription factor heterodimer formed by target of monopteros5 (TMO5) and lonesome highway (LHW) is a central regulator of vascular width-increasing divisions. An important unanswered question is how its activity is limited to specify vascular tissue dimensions. Here we identify a regulatory network that restricts TMO5/LHW activity. We show that thermospermine synthase ACAULIS5 antagonizes TMO5/LHW activity by promoting the accumulation of SAC51 LIKE (SACL) bHLH transcription factors. SACL proteins heterodimerize with LHW therefore likely competing with TMO5/LHW interactions-prevent activation of TMO5/LHW target genes, and suppress the over-proliferation caused by excess TMO5/LHW activity. These findings connect two thus-far disparate pathways and provide a mechanistic understanding of the quantitative control of vascular tissue growth. PMID- 26609961 TI - Catalytic Enantioselective Nitroso Diels-Alder Reaction. AB - The nitroso Diels-Alder (NDA) reaction is an attractive strategy for the synthesis of 3,6-dihydro-1,2-oxazines and 1-amino-4-hydroxy-2-ene derivatives. Herein we report the Cu(I)-DTBM-Segphos catalyzed asymmetric intermolecular NDA reaction of variously substituted cyclic 1,3-dienes using highly reactive nitroso compounds derived from pyrimidine and pyridazine derivatives. In most of the cases studied, the cycloadducts were obtained in high yields (up to 99%) with very high regio-, diastereo-, and enantioselectivities (up to regioselectivity > 99:1, d.r. > 99:1, and >99% ee). As an application of this methodology, formal syntheses of conduramine A-1 and narciclasine were accomplished. PMID- 26609959 TI - Network Analysis Identifies Mitochondrial Regulation of Epidermal Differentiation by MPZL3 and FDXR. AB - Current gene expression network approaches commonly focus on transcription factors (TFs), biasing network-based discovery efforts away from potentially important non-TF proteins. We developed proximity analysis, a network reconstruction method that uses topological constraints of scale-free, small world biological networks to reconstruct relationships in eukaryotic systems, independent of subcellular localization. Proximity analysis identified MPZL3 as a highly connected hub that is strongly induced during epidermal differentiation. MPZL3 was essential for normal differentiation, acting downstream of p63, ZNF750, KLF4, and RCOR1, each of which bound near the MPZL3 gene and controlled its expression. MPZL3 protein localized to mitochondria, where it interacted with FDXR, which was itself also found to be essential for differentiation. Together, MPZL3 and FDXR increased reactive oxygen species (ROS) to drive epidermal differentiation. ROS-induced differentiation is dependent upon promotion of FDXR enzymatic activity by MPZL3. ROS induction by the MPZL3 and FDXR mitochondrial proteins is therefore essential for epidermal differentiation. PMID- 26609960 TI - Role of Polarized G Protein Signaling in Tracking Pheromone Gradients. AB - Yeast cells track gradients of pheromones to locate mating partners. Intuition suggests that uniform distribution of pheromone receptors over the cell surface would yield optimal gradient sensing. However, yeast cells display polarized receptors. The benefit of such polarization was unknown. During gradient tracking, cell growth is directed by a patch of polarity regulators that wanders around the cortex. Patch movement is sensitive to pheromone dose, with wandering reduced on the up-gradient side of the cell, resulting in net growth in that direction. Mathematical modeling suggests that active receptors and associated G proteins lag behind the polarity patch and act as an effective drag on patch movement. In vivo, the polarity patch is trailed by a G protein-rich domain, and this polarized distribution of G proteins is required to constrain patch wandering. Our findings explain why G protein polarization is beneficial and illuminate a novel mechanism for gradient tracking. PMID- 26609962 TI - Preparing for the primary care clinic: an ambulatory boot camp for internal medicine interns. AB - INTRODUCTION: Internal medicine (IM) interns start continuity clinic with variable ambulatory training. Multiple other specialties have utilized a boot camp style curriculum to improve surgical and procedural skills, but boot camps have not been used to improve interns' ambulatory knowledge and confidence. The authors implemented and assessed the impact of an intern ambulatory boot camp pilot on primary care knowledge, confidence, and curricular satisfaction. METHODS: During July 2014, IM interns attended ambulatory boot camp. It included clinically focused case-based didactic sessions on common ambulatory topics as well as orientation to the clinic and electronic medical records. Interns anonymously completed a 15-question pre-test on topics covered in the boot camp as well as an identical post-test after the boot camp. The interns were surveyed regarding their confidence and satisfaction. RESULTS: Thirty-eight interns participated in the boot camp. Prior to the boot camp, few interns reported confidence managing common outpatient conditions. The average pre-test knowledge score was 46.3%. The average post-test knowledge score significantly improved to 76.1% (p<0.001). All interns reported that the boot camp was good preparation for clinics and 97% felt that the boot camp boosted their confidence. CONCLUSIONS: The ambulatory boot camp pilot improved primary care knowledge, and interns thought it was good preparation for clinic. The ambulatory boot camp was well received and may be an effective way to improve the preparation of interns for primary care clinic. Further assessment of clinical performance and expansion to other programs and specialties should be considered. PMID- 26609963 TI - Relationship between Short-Form Health SF36 Questionnaire and oxygen uptake in healthy workers. AB - BACKGROUND: Physical activity is associated with better health levels, and cardiopulmonary fitness is recognized as one of the best indicators of physical performance, which can be related with some items of quality of life (QoL). The aim of this study was to analyze the relationship between the QoL and cardiorespiratory fitness (VO2max) of healthy workers, measured with the Short Form Health Survey SF36 and incremental cardiopulmonary Test. METHODS: Sample was formed by 250 healthy workers (90 men, mean age 37.25 and 160 female, mean age 37.91). RESULTS: Analyzing the results, VO2's Mean values were higher in men (39.00 mL/kg/min SD 7.56) than in women (29.70 mL/kg/min SD 5.73) with significant differences (P<0.01). We found differences in all dimensions of SF36 indicating that men had higher scores than women, but significant differences between both are present only in physical functioning (PF) (P<0.01). Correlating the values obtained in the domains of Questionnaire SF36 and the Vo2 Max, correlation was significant (positive) in PF (0.276), bodily pain (0.189), general health (0.155), vitality (0.241) and mental health (0.129). Results showed that better cardiorespiratory fitness is related to higher scores in SF36. CONCLUSIONS: These findings suggest that if the values of oxygen uptake in healthy workers are higher, results in SF36 will be better. Therefore it can be assumed that having a good fitness means having a better QoL. PMID- 26609964 TI - Estimation of the neuromuscular fatigue threshold from an incremental cycling test using 1-minute exercise periods. AB - BACKGROUND: The objectives of this study were: 1) to evaluate the method used for estimating the neuromuscular fatigue threshold from surface electromyographic amplitude (the PWCFT test) during a single incremental cycling workout using 1 minute exercise periods, and 2) to investigate the possible associations between PWCFT and metabolic (onset of blood lactate accumulation [OBLA]) and ventilatory (ventilatory threshold [VT] and respiratory compensation point [RCP]) variables. METHODS: Sixteen cyclists performed incremental cycle ergometer rides to exhaustion with bipolar surface sEMG signals recorded from the vastus lateralis. Subsequently, participants performed one constant-workload exercise test at 100% of their PWCFT. RESULTS: During the incremental test, the power output at PWCFT was not correlated with that of OBLA (P>0.05), but it was positively correlated with those of VT and RCP (P<0.05). During the constant-workload test, heart rate and blood lactate increased progressively and significantly (P<0.05), whereas sEMG amplitude remained unchanged (P>0.05). The average duration of the constant workload exercise was 8-9 minutes. CONCLUSIONS: The application of the PWCFT method using 1-min exercise periods could lead to overestimation of the neuromuscular fatigue threshold most likely because this stage duration allows insufficient time for the sEMG response to manifest. PMID- 26609965 TI - Effects of high-impact aerobics vs. low-impact aerobics and strength training in overweight and obese women. AB - BACKGROUND: Regular exercise is one of the factors determining weight reduction and fat loss, and at the same time it is associated with important health benefits. The purpose of this study was to compare the effects of two different modalities of exercise on changes in body composition, physical fitness, and CVR factors in healthy overweight and obese women. METHODS: Thirty-two women were randomly assigned in 2 groups: a high-impact aerobics group (HIA, N.=16) and a low-impact aerobics combined with a strength training program group (LIAS, N.=16). Body weight (BW), body composition, aerobic fitness (AF), speed and agility, vertical-jump distance (VJ), abdominal muscle endurance (AME), the flexibility of the lower back and hamstrings, heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP), total cholesterol (TC), triglyceride (TG), HDL-c, LDL-c, apolipoprotein A-I (Apo A-I) and B (Apo B) were measured at baseline and at the end of the training period. RESULTS: A significant decrease was noted in all anthropometric variables excepting fat-free mass (FFM) which increased in LIAS group (P<0.05). Comparisons between groups noted significant differences in favor of HIA group in BW, fat percentage and FM, and in favor of LIAS group in FFM (P<0.05 for all). DBP, HR, TC, LDL-c, TG, and Apo B significantly decreased, and HDL-c and Apo A-I significantly increased in both groups. No significant modifications were noted in SBP and glucose concentrations. Significant improvements in all physical fitness components were also noted in HIA group (P<0.05), however, only the AF, VJ, AME, and the flexibility were improved in LIAS group (P<0.01). Comparison between groups reported that values related to VJ and AME were higher in LIAS compared to HIA group (P<0.01). CONCLUSIONS: Our findings noted that a 24-week of HIA or LIAS training improved body composition, physical fitness and CVR factors in overweight and obese women. Nevertheless, the use of each training method remains tributary to wished effects. In fact, HIA training method is more effective in body weight reduction and fat loss, however, LIAS training method is more appropriate when the improvement of FFM, aerobic fitness and muscle strength is claimed. PMID- 26609966 TI - Impact of high-intensity and high-volume exercise on short-term perturbations in the circulating fraction of different cell types. AB - BACKGROUND: High-intensity training (HIT) can improve endurance performance and VO2max more effectively than high-volume training (HVT). Hence, the implementation of HIT protocols such as 4x30 s "all-out" and 4x4 min at 90-95% VO2max is currently existent in various sports. However, there is limited awareness of the acute changes in blood cell count following these protocols. Therefore, the purpose of the study was to examine the acute effects on circulating leukocyte differential count (LDC) by comparing the two HIT interventions with a single HVT intervention. METHODS: Twelve healthy triathletes/cyclists (VO2peak: 64.3+/-9.7 mL.kg-1.min-1) participated in the study. Subjects performed: 1) a two-hours low-intensity exercise at an intensity of 55% peak power output (PPO); 2) 4x4 min interval bouts at an intensity of 90 95% PPO; 3) 4x30 s "all-out". Blood samples were taken immediately before exercise (pre) and 0', 30', 60' and 180' postexercise. Biphasic leukocyte enumeration was different between both HIT protocols and nonexistent after high volume exercise. RESULTS: Data revealed significant time and intervention effects for leukocytes, lymphocytes and neutrophils. After 4x30 s lymphocytes were significantly higher 0' postintervention compared to 4x4 min and high-volume exercise. Furthermore, concentrations of leukocytes and neutrophils were significantly higher after the "all-out" protocol compared to 4x4 min at 180' postexercise. CONCLUSIONS: The results suggest that 4x30 s result in larger short term perturbations in the circulating fraction of leukocytes compared to 4x4 min, which might be associated with increased hormonal and metabolic stress responses after 4x30 s. PMID- 26609968 TI - Efficacy of eccentric exercise in lower limb tendinopathies in athletes. AB - Tendinopathies are among the most frequent sport injuries, therefore their correct treatment is a crucial issue in sports medicine practice. In most of the cases, these multifactorial conditions are related to overuse and characterized by activity-induced pain, local tenderness and swelling. Although tendinopathies are common, their treatment is not easy. Currently, it is generally accepted that their management should include early functional exercises. Eccentric exercise (EE) is considered a fundamental therapeutic resource, especially for the treatment of Achilles and patellar tendinopathies. This article focuses on the use of EE for the treatment and prevention of the lower limb tendinopathies, evaluates the existing programs and their efficacy, and reviews the possible mechanisms of the healing process and the action of EE on tendon structure. EE based treatments are useful to improve symptoms and function in lower limb tendinopathies, but more evidence is still required to devise an adequate dose response model and to determine their long-term effects. PMID- 26609967 TI - Androgen receptor CAG and GGN repeat polymorphisms influence performance in boys and girls. AB - BACKGROUND: Shorter CAG and GGN androgen receptor (AR) repeat polymorphisms are associated with stronger androgen signaling, and therefore, could influence lean mass and exercise performance during growth. METHODS: Physical fitness and body composition were measured by standardized procedures and the length of CAG and GGN repeats was determined by PCR and fragment analysis in 152 boys (11.5+/-2.6 years; Tanner <=5) and 116 girls (10.1+/-3.2 years; Tanner <=5). Individuals were grouped as CAG short (CAGS) if harboring repeat lengths of <=21 and CAG long (CAGL) if CAG >21. Moreover, subjects were grouped as GGN short (GGNS) if harboring repeat lengths of <=23 and GGN long (GGNL) if GGN>23. RESULTS: No significant differences in anthropometrics and body composition were observed between either CAGS and CAGL groups and GGNS and GGNL groups. Boys harboring CAGS completed the 300-meter test faster than their CAGL counterparts. Moreover, girls from the GGNL group showed a significant higher VO2max than those in the GGNS group. CONCLUSIONS: In summary, carrying a short allele of the androgen receptor CAG repeat polymorphism is associated to higher anaerobic performance in boys, whereas long alleles of androgen receptor GGN polymorphisms are associated to higher aerobic capacity in girls. PMID- 26609969 TI - Comparison between traditional strength training and complex contrast training on repeated sprint ability and muscle architecture in elite soccer players. AB - BACKGROUND: The purpose of this study was to compare traditional strength training (TST) and complex contrast training (CCT) on the repeated-shuttle-sprint ability (RSSA), the countermovement squat jump (CMJ) height, the one repetition maximum (1RM) at squat on the Smith machine, and on muscle architecture in young, male elite soccer players. METHODS: Twenty-two soccer players (mean age 18.4+/ 0.4 years; mean weight 70.2+/-9.1 kg; mean height 179.9+/-7.5 cm) who belonged to the under-20 age group were randomly assigned into two groups: CCT (N.=10) or TST (N.=12). During the study period, the soccer players trained with CCT through power exercises performed before high-velocity exercises and TST based on a set repetition format through daily, undulatory periodization. RESULTS: After statistical analysis (P<0.05), the results demonstrated that the specific CCT regimen provided a significant improvement in the RSSA percent decrement (moderate effect size), CMJ (large effect size) and 1RM ability (large effect size). However, the TST promoted significant changes in 1RM (large effect size) and a significant increase in the muscle thickness of the vastus intermedius (moderate effect size). CONCLUSIONS: The CCT protocol could be used to improve the RSSA parameters, CMJ and 1RM, and the TST developed dynamic strength and muscle growth. Coaches can choose either CCT or TST protocols according to the needs of their soccer players. PMID- 26609970 TI - The optimal exercise to rest ratios in repeated sprint ability training in youth soccer players. AB - BACKGROUND: The aim of this study was to investigate the applicability of three different exercise to rest ratios in RSA training in youth soccer players, applying those ones already adopted in adult players, when performing three different sprinting modes (straight, shuttle and sprinting with changing of direction). METHODS: Eighteen young trained male soccer players (Height: 1.66+/ 0.07 m; weight: 58.22+/-7.64 kg; BMI 19.37+/-3.42 kg.m-2; age:14 years) participated to the study. In order to compare the different values of the time recorded, a Fatigue Index (FI) was used. Recovery times among trials in the sets were administered according to the 1:5, 1:3; 1:2 exercise to rest ratio, respectively. RESULTS: Significant differences among trials within each set (Repeated Measures Anova; P<0.05) were found. as evidence of fatigue over time. with an average decay of performance of about 4%, but no significant differences were found in FI%, among the three different sprinting modalities when applying the investigated exercise to rest ratios (Factorial Anova; between; P>0.05). CONCLUSIONS: The results of this study confirm that the exercise to rest ratios considered in this study might be suitable to design effective testing protocols and training sessions aimed at the development of the RSA in youth soccer players, keeping the performances in the speed domain (FI%< ~7-8%) but inducing the fatigue processes sought with this kind of training method. PMID- 26609971 TI - A novel apparatus for active leg exercise improves venous flow in the lower extremity. AB - BACKGROUND: Venous thromboembolism is a serious complication associated with major orthopedic surgery to the lower extremities. Although active ankle exercise is recommended, patients with postoperative pain may have difficulty moving their ankles. Therefore, we developed a novel leg exercise apparatus (LEX) to facilitate active ankle movement during the early postoperative period. We describe how LEX facilitates active movement of the leg, and thereby increases venous flow in the lower extremities. METHODS: The femoral venous flow volume and velocity in 8 healthy volunteers (5 men, 3 women; mean age 22.4 years; age range 22-26 years), were measured using duplex ultrasonography. Measurements were repeated 1, 3, 5, and 10 minutes after the completion of 1 minute of active ankle exercise using LEX, and during a 10-minute period of intermittent pneumatic compression (IPC) device use. RESULTS: The flow volume after 1 minute of LEX exercise increased 2.63-fold from baseline; elevated values persisted for 10 minutes. Flow volume at 10 minutes was increased 1.71-fold from baseline. The corresponding values during IPC did not differ from resting values. The mean velocity 1 minute after LEX exercise increased 2.34-fold from baseline; in contrast, mean velocity 1 minute after the start of IPC had decreased 0.90-fold (P=0.009). CONCLUSIONS: A 1-minute period of LEX exercise improved venous flow in the lower extremities, compared with continuous use of IPC. Use of LEX might facilitate improved ankle mobility, and therefore reduced risk of thromboembolism, in postoperative patients. PMID- 26609972 TI - Effect of sport training on forearm bone sites in female handball and soccer players. AB - BACKGROUND: The objective of this study was to evaluate the bone mineral density (BMD) and Z-score of a skeletal region, considered as weight-bearing site in trained handball players (HP), but as non-weight-bearing site in trained soccer players (SP). The bone health status of the same site was also analyzed in an untrained group (CG). METHODS: BMD and Z-score at distal forearm regions (dominant, D; non-dominant, ND) were evaluated in 30 female HP and in 30 female SP, who have been training for 7.7+/-3.8 years, 17 hours per week, as well as in 30 females CG. RESULTS: Playing handball was associated with higher BMD of the skeleton at both measured sites than in CG. Also in comparison with SP, HPs' arms showed a significant increase in BMD. On the other hand, female SP have been reported to exhibit an enhanced ND arm BMD compared with controls. The benefits of exercise appeared to be significantly improved only in SP sub-group who started sport activity before or at menarche. These athletes showed at ND forearm a BMD 4% greater than those SP who started later, reaching a BMD of 11.6% higher than CG, a value similar to the corresponding in HP sub-group. Moreover, their D arm BMD was 7.1% higher compared with CG. CONCLUSIONS: This study indicates that, compared with non-trained subjects, long-term high-impact sport participation is associated with an higher bone health state, especially if the playing careers were started before or at menarche. This effect was observed at level of both forearms in HP, which are considered as weight-bearing sites for this discipline but also on the same skeletal regions of SP, which are not directly loaded by sport-related regular training. PMID- 26609973 TI - Efficient Approach to Reactive Molecular Dynamics with Accurate Forces. AB - Density functional theory is a powerful and efficient method for calculating potential energy surfaces for chemical reactions, but its application to complex systems, such as reactions in enzymes, is often prohibitively expensive, even when high-level theory is applied only to a primary subsystem, such as an active site, and when the remaining system is treated by molecular mechanics. Here we show how the combination of multiconfiguration molecular mechanics with charge response kernels can speed up such calculations by three or more orders of magnitude. The resulting method, called electrostatically embedded multiconfiguration molecular mechanics, is illustrated by calculating the free energy of activation profile for the dehalogenation of 1,2-dichloroethane by haloalkane dehalogenase. This shows how hybrid density functionals or other high level electronic structure methods can now be used efficiently in simulations that require extensive sampling, such as for calculating free energy profiles along a high-barrier reaction coordinate. PMID- 26609974 TI - Dispersion Corrected Atom-Centered Potentials for Phosphorus. AB - Dispersion-corrected atom-centered potentials (DCACPs) for the element phosphorus were generated and tested for the BLYP, BP, and PBE generalized gradient approximations of the exchange-correlation functional. The accuracy and transferability of the DCACPs were tested by evaluating the interaction energy of different weakly bound molecular systems (P2, PH3, and PN dimers). These results were compared to reference CCSD(T) calculations and standard density functional theory (DFT). The DCACP were also tested in the case of condensed phase systems. Specifically, the density and cohesive energies of beta-white and black phosphorus were estimated and compared to available experimental data. Our results show an overall strong improvement both at the qualitative and quantitative level, with respect to uncorrected generalized gradient approximation DFT results for all three functionals. In particular, BLYP corrected results show the maximal transferability, reporting for all systems a deviation from CCSD(T) results of less than 1% in the predicted binding energies. PMID- 26609975 TI - On the Gas-Phase Electronic Chemical Potential of Anions. AB - In the process of evaluating intrinsic electronic chemical potentials and related properties of anions in the gas phase, positive values for this quantity often arise. We herein examine in detail this result in terms of computational grounds. At a low level of theory, this result is often obtained, but its origin is mainly traced to the fact that the LUMO energy level is not really converged. Therefore, this outcome may be an artifact of the calculation. We establish the minimum basis set analysis that is to be performed before the electronic chemical potential of charged electron donors, in the absence of medium (solvent) effects, may be safely calculated to yield physically meaningful results. The implications that this result may have on the phenomenological chemical reactivity theory are discussed in detail, mainly those related to the definition of the electron donating (nucleophilicity) ability of anions in the gas phase. The arguments given are illustrated for a large number of atomic and molecular systems at different levels of theory. PMID- 26609976 TI - Unified Inter- and Intramolecular Dispersion Correction Formula for Generalized Gradient Approximation Density Functional Theory. AB - Density functionals fail to provide a consistent description of weak intra- (i.e., short-range) and inter- (i.e., long-range) molecular interactions arising from nonoverlapping electron densities. An efficient way to correct the long range errors is to add an empirical atom pair wise interaction-correction, inspired by the Lennard-Jones potential (R(-6) dependence). We show that the universal damping function of Tang and Toennies (TT) that includes higher-order correction terms (R(-8) and R(-10) dependent) reduces the intramolecular errors more efficiently, without altering the long-range correction. For general applicability, the TT damping function is augmented by a Fermi damping to prevent corrections at covalent distances. The performance of the new dD10 correction was tested in combination with three nonempirical GGAs (PBE, PBEsol, RGE2) on 64 illustrative reaction energies featuring both intra- and intermolecular interactions. With only two empirical parameters, PBE-dD10 outperforms the computationally more demanding and most recent functionals such as M06-2X or B2PLYP-D (MAD = 3.78 and 1.95 kcal mol(-1), respectively). At the cc-pVTZ level, PBE-dD10 (MAD = 1.24 kcal mol(-1)) considerably reduces common DFT errors successfully balancing intra- (short-range) and inter- (long-range) molecular interactions. While REG2-dD10 performs closely to PBE-dD10 (MAD = 1.48 kcal mol( 1)), the overall MAD of PBEsol-dD10 is again slightly higher (MAD = 1.76 kcal mol(-1)). PMID- 26609977 TI - Activation of Carbon-Hydrogen and Hydrogen-Hydrogen Bonds by Copper-Nitrenes: A Comparison of Density Functional Theory with Single- and Multireference Correlation Consistent Composite Approaches. AB - The kinetics and thermodynamics of copper-mediated nitrene insertion into C-H and H-H bonds (the former of methane) have been studied using several levels of theory: B3LYP/6-311++G(d,p), B97-1/cc-pVTZ, PBE1KCIS/cc-pVTZ, and ccCA (correlation consistent Composite Approach). The results show no significant difference among the DFT methods. All three DFT methods predict the ground state of the copper-nitrene model complex, L'Cu(NH), to be a triplet, while single reference ccCA predicts the singlet to be the ground state. The contributions to the total ccCA energy indicate that the singlet state is favored at the MP2/CBS level of theory, while electron correlation beyond this level (CCSD(T)) favors a triplet state, resulting in a close energetic balance between the two states. A multireference ccCA method is applied to the nitrene active species and supports the assignment of a singlet ground state. In general, the largest difference in the model reaction cycles between DFT and ccCA methods is for processes involving radicals and bond dissociation. PMID- 26609978 TI - What Active Space Adequately Describes Oxygen Activation by a Late Transition Metal? CASPT2 and RASPT2 Applied to Intermediates from the Reaction of O2 with a Cu(I)-alpha-Ketocarboxylate. AB - Multiconfigurational second-order perturbation theory calculations based on a complete active space reference wave function (CASPT2), employing active spaces of increasing size, are well converged at the level of 12 electrons in 12 orbitals for the singlet-triplet state-energy splittings of three supported copper-dioxygen and two supported copper-oxo complexes. Corresponding calculations using the restricted active space approach (RASPT2) offer similar accuracy with a significantly reduced computational overhead provided an inner (2,2) complete active space is included in the overall RAS space in order to account for strong biradical character in most of the compounds. The effects of the different active space choices and the outer RAS space excitations are examined, and conclusions are drawn with respect to the general applicability of the RASPT2 protocol. PMID- 26609979 TI - Universal Theoretical Approach to Extract Anisotropic Spin Hamiltonians. AB - Monometallic Ni(II) and Co(II) complexes with large magnetic anisotropy are studied using correlated wave function based ab initio calculations. Based on the effective Hamiltonian theory, we propose a scheme to extract both the parameters of the zero-field splitting (ZFS) tensor and the magnetic anisotropy axes. Contrarily to the usual theoretical procedure of extraction, the method presented here determines the sign and the magnitude of the ZFS parameters in any circumstances. While the energy levels provide enough information to extract the ZFS parameters in Ni(II) complexes, additional information contained in the wave functions must be used to extract the ZFS parameters of Co(II) complexes. The effective Hamiltonian procedure also enables us to confirm the validity of the standard model Hamiltonian to produce the magnetic anisotropy of monometallic complexes. The calculated ZFS parameters are in good agreement with high-field, high-frequency electron paramagnetic resonance spectroscopy and frequency domain magnetic resonance spectroscopy data. A methodological analysis of the results shows that the ligand-to-metal charge transfer configurations must be introduced in the reference space to obtain quantitative agreement with the experimental estimates of the ZFS parameters. PMID- 26609980 TI - Coupled-Perturbed Scheme for the Calculation of Electronic g-Tensors with Local Hybrid Functionals. AB - A coupled-perturbed Kohn-Sham (CPKS) scheme for calculating second-order magnetic properties has been developed for the case of general occupied-orbital-dependent (OOD) exchange-correlation functionals involving the exact-exchange energy density. The origin of the coupling terms in the functional derivatives of OOD functionals with respect to the orbitals has been thoroughly analyzed, and general expressions for the resulting coupling terms have been obtained. The generalized CPKS scheme thus obtained has been implemented within the MAG-ReSpect code and tested in calculations of electronic g-tensors with local hybrid functionals. Compared to previously tested global hybrids, like B3LYP, thermochemically optimized local hybrids provide only little to moderate improvement for test sets of main-group radicals and paramagnetic transition metal complexes. Closer analyses point to possible areas in which the fundamentally more flexible local hybrids may be improved for the property at hand. PMID- 26609981 TI - Robust Periodic Hartree-Fock Exchange for Large-Scale Simulations Using Gaussian Basis Sets. AB - Hartree-Fock exchange with a truncated Coulomb operator has recently been discussed in the context of periodic plane-waves calculations [Spencer, J.; Alavi, A. Phys. Rev. B: Solid State, 2008, 77, 193110]. In this work, this approach is extended to Gaussian basis sets, leading to a stable and accurate procedure for evaluating Hartree-Fock exchange at the Gamma-point. Furthermore, it has been found that standard hybrid functionals can be transformed into short range functionals without loss of accuracy. The well-defined short-range nature of the truncated exchange operator can naturally be exploited in integral screening procedures and makes this approach interesting for both condensed phase and gas phase systems. The presented Hartree-Fock implementation is massively parallel and scales up to ten thousands of cores. This makes it feasible to perform highly accurate calculations on systems containing thousands of atoms or ten thousands of basis functions. The applicability of this scheme is demonstrated by calculating the cohesive energy of a LiH crystal close to the Hartree-Fock basis set limit and by performing an electronic structure calculation of a complete protein (rubredoxin) in solution with a large and flexible basis set. PMID- 26609982 TI - Toward Understanding the Photochemistry of Photoactive Yellow Protein: A CASPT2/CASSCF and Quantum Theory of Atoms in Molecules Combined Study of a Model Chromophore in Vacuo. AB - Photochemical processes that take place in biological molecules have become an increasingly important research topic for both experimentalists and theoreticians. In this work, we report the reaction mechanism of a model of the photoactive yellow protein (PYP) chromophore in vacuo. The results obtained here, using a strategy based on the simultaneous use of the minimum energy path concept and the quantum theory of atoms in molecules applied to this excited state process, suggest a possible way in which the protein could increase the efficiency of the reaction. The role played by other electronic states of the same and different spin multiplicities in the reaction process is also analyzed, with special emphasis on that played by the lowest-lying triplet state. The possibility of a more complex than expected reaction mechanism is finally discussed, with some suggestions on the possible roles of the protein. PMID- 26609983 TI - Theoretical Determination of the Dissociation Energy of Molecular Hydrogen. AB - The dissociation energy of molecular hydrogen is determined theoretically with a careful estimation of error bars by including nonadiabatic, relativistic, and quantum electrodynamics (QED) corrections. The relativistic and QED corrections were obtained at the adiabatic level of theory by including all contributions of the order alpha(2) and alpha(3) as well as the major (one-loop) alpha(4) term, where alpha is the fine-structure constant. The computed alpha(0), alpha(2), alpha(3), and alpha(4) components of the dissociation energy of the H2 isotopomer are 36 118.7978(2), -0.5319(3), -0.1948(2), and -0.0016(8) cm(-1), respectively, while their sum amounts to 36 118.0695(10) cm(-1), where the total uncertainty includes the estimated size (+/-0.0004 cm(-1)) of the neglected relativistic nonadiabatic/recoil corrections. The obtained theoretical value of the dissociation energy is in excellent agreement with the most recent experimental determination 36 118.0696(4) cm(-1) [J. Liu et al. J. Chem. Phys. 2009, 130, 174 306]. This agreement would have been impossible without inclusion of several subtle QED contributions which have not been considered, thus far, for molecules. A similarly good agreement is observed for the leading vibrational and rotational energy differences. For the D2 molecule we observe, however, a small disagreement between our value 36 748.3633(9) cm(-1) and the experimental result 36 748.343(10) cm(-1) obtained in a somewhat older and less precise experiment [Y. P. Zhang et al. Phys. Rev. Lett. 2004, 92, 203003]. The reason of this discrepancy is not known. PMID- 26609984 TI - Can Induced Orbital Paramagnetism Be Controlled by Strong Magnetic Fields? AB - Magnetic hypersusceptibilities and hypershielding at the nuclei of BH, CH(+), C4H4, and C8H8 molecules in the presence of an external spatially uniform, time independent magnetic field have been investigated accounting for cubic response contributions via Rayleigh-Schrodinger perturbation theory. Numerical estimates have been obtained at the coupled Hartree-Fock and density-functional levels of theory within the conventional common-origin approach, using extended gaugeless basis sets. The fundamental role of electron correlation effects was assessed. Critical values of the applied magnetic field at which transition from paramagnetic to diamagnetic behavior would occur were estimated. It is shown that perturbative methods may successfully be employed to estimate the interaction energy for big cyclic molecules. PMID- 26609985 TI - Assessment of Orbital-Optimized, Spin-Component Scaled Second-Order Many-Body Perturbation Theory for Thermochemistry and Kinetics. AB - An efficient implementation of the orbital-optimized second-order Moller-Plesset perturbation theory (OO-MP2) within the resolution of the identity (RI) approximation is reported. Both conventional MP2 and spin-component scaled (SCS MP2) variants are considered, and an extensive numerical investigation of the accuracy of these approaches is presented. This work is closely related to earlier work of Lochan, R. C.; Head-Gordon, M. J. Chem. Phys. 2007, 126. Orbital optimization is achieved by making the Hylleraas functional together with the energy of the reference determinant stationary with respect to variations of the double excitation amplitudes and the molecular orbital rotation parameters. A simple iterative scheme is proposed that usually leads to convergence within 5-15 iterations. The applicability of the method to larger molecules (up to ~1000-2000 basis functions) is demonstrated. The numerical results show that OO-SCS-MP2 is a major improvement in electronically complicated situations, such as represented by radicals or by transition states where spin contamination often greatly deteriorates the quality of the conventional MP2 and SCS-MP2 methods. The OO-(SCS )MP2 approach reduces the error by a factor of 3-5 relative to the standard (SCS )MP2. For closed-shell main group elements, no significant improvement in the accuracy relative to the already excellent SCS-MP2 method is observed. In addition, the problems of all MP2 variants with 3d transition-metal complexes are not solved by orbital optimization. The close relationship of the OO-MP2 method to the approximate second-order coupled cluster method (CC2) is pointed out. Both methods have comparable computational requirements. Thus, the OO-MP2 method emerges as a very useful tool for computational quantum chemistry. PMID- 26609986 TI - Phase-Dependent Photocatalytic Ability of TiO2: A First-Principles Study. AB - The electronic properties of defected TiO2 were investigated using the first principles calculations based on density functional theory and generalized gradient approximation. Three typical defects, oxygen vacancy, titanium interstitial, and titanium vacancy, were considered in three TiO2 polymorphs, anatase, rutile, and brookite, respectively. Our calculations demonstrated that the defect band is formed by removing an oxygen atom from or inserting an interstitial Ti atom into the TiO2 lattice, which is responsible for the improvement of photocatalytic ability due to the enhanced visible-light absorption. Our calculations further revealed that the defect formation energy increases as following brookite, anatase, and rutile, indicating that defects are easy to be created in brookite TiO2. The relatively high defect density and wide defect band contribute to the better photocatalytic performance of brookite TiO2 in visible light. PMID- 26609987 TI - Hydrogen Interaction in Ti-Doped LiBH4 for Hydrogen Storage: A Density Functional Analysis. AB - Density functional theory studies have been carried out to investigate the energetics and structures of Ti-doped LiBH4 (001), (100), and (010) surfaces. The possibilities of Ti occupying various positions at these surfaces leading to substitution, surface adsorption, and interstitial insertion are examined. Among all possible structures, a Ti atom energetically prefers to occupy interstitial positions involving three or four BH4(-) hydrides and to stay above the top layer of B atoms. The most stable species on the three surfaces have a similar local structure, described as TiB2H8-nBH4 (n = 1, 2), with varying spin states. Molecular orbital analysis for the local structures showed that the structural stability could be attributed to the symmetry-adapted orbital overlap between Ti and "inside" B-H bonds. Furthermore, the hydrogen desorption energies from many positions in these local complex structures were reduced significantly with respect to that from the clean surface. The most favorable hydrogen desorption pathways are found to lead to triplet dehydrogenation products. Therefore, the triplet TiB2H8-BH4 in (001) and TiB2H8-2BH4 in (010) can desorb hydrogen in molecular form, while the quintet TiB2H8-BH4 in (100) must first desorb hydrogen atoms, followed by the formation of a hydrogen molecule in the gas phase. The catalytic effect of Ti doped in LiBH4 has been compared with that in NaAlH4. PMID- 26609988 TI - Electronic Structure and Reactivity of Boron Nitride Nanoribbons with Stone-Wales Defects. AB - Gradient-corrected density functional theory (DFT) computations were performed to investigate the geometry, electronic property, formation energy, and reactivity of Stone-Wales (SW) defects in zigzag-edge and armchair-edge boron nitride nanoribbons (BNNRs). The formation energies of SW defects increase with an increase in the widths of BNNRs and are orientation-dependent. SW defects considerably reduce the band gaps of BNNRs independent of the defect orientations. In addition, the local chemical reactivity of SW defects and edge sites in zigzag-edge and armchair-edge BNNRs was probed with the CH2 cycloaddition reaction. Independent of the nanoribbon types and the SW defect orientations, the reactions at SW defect sites are more exothermic than those at the center of perfect BNNRs, and the newly formed B-B and N-N bonds are the most reactive sites, followed by the 5-7 ring fusions. PMID- 26609989 TI - How Does the Relocation of Internal Water Affect Resonance Raman Spectra of Rhodopsin? An Insight from CASSCF/Amber Calculations. AB - The effect of relocation of the W2 crystallographic water in bovine rhodopsin has been investigated by comparing and analyzing simulated resonance Raman spectra of 1HZX- and 1U19-based quantum mechanics/molecular mechanics (CASSCF/MM) models. The main target is to explore the sensitivity of the simulated resonance Raman spectra to protein cavity change. In particular, we focus on a quantitative investigation of the changes in the vibrational activity of rhodopsin induced by modifications in the protein cavity structure and in the water position. Comparison of the simulated RR spectra of the Rh-1U19 and Rh-1HZX models with the measured spectrum of rhodopsin reveals that the Rh-1U19 model provides a slightly better rhodopsin model consistently with the simulations of the absorption maxima. On the other hand, and irrespective of the comparison with the experimental data, the analysis of two different computational models for the same protein and chromophore makes it possible to investigate and disentangle the relationship between structural features and change in the RR intensities in an unusually detailed way. PMID- 26609991 TI - A General Boundary Potential for Hybrid QM/MM Simulations of Solvated Biomolecular Systems. AB - We present a general boundary potential for the efficient and accurate evaluation of electrostatic interactions in hybrid quantum mechanical/molecular mechanical (QM/MM) approaches called solvated macromolecule boundary potential (SMBP), which is designed for QM/MM calculations with any kind of QM method. The SMBP targets QM/MM single-point energy calculations and geometry optimizations. In the SMBP scheme, the outer solvent and macromolecule region is described by a boundary potential obtained with the use of Poisson-Boltzmann calculations (treating the bulk solvent as a dielectric continuum). In the QM calculations, the SMBP is represented by virtual point charges on a surface enclosing the explicitly treated inner region. These charges and their interactions with the QM density are determined through a self-consistent reaction field procedure. The accuracy of the SMBP is evaluated on three diverse test systems: the intramolecular proton transfer of glycine in water, the hydroxylation reaction in p-hydroxybenzoate hydroxylase, and the spin state energy splittings in the pentacoordinated ferric complex of cytochrome P450cam. In the case of solvated glycine, application of the SMBP turns out to be problematic since analogous QM/MM/SMBP and full QM/MM geometry optimizations lead to different close-lying local minima. In both enzymes, the SMBP performs very well and closely reproduces the results from full QM/MM optimizations of these more rigid test systems. Starting from optimized QM/MM/SMBP structures along a reaction path, one can apply the previously implemented generalized solvent boundary potential (GSBP) to sample over MM phase space in QM/MM free energy calculations within the framework of free energy perturbation theory. This reduces the overall computational costs of sampling by 1 order of magnitude while maintaining good accuracy. The combined use of SMBP and GSBP thus allows for efficient QM/MM free energy studies of enzymes. PMID- 26609990 TI - An Improved Reaction Coordinate for Nucleic Acid Base Flipping Studies. AB - Base flipping is a common strategy utilized by many enzymes to gain access to the functional groups of nucleic acid bases in duplex DNA which are otherwise protected by the DNA backbone and hydrogen bonding with their partner bases. Several X-ray crystallography studies have revealed flipped conformations of nucleotides bound to enzymes. However, little is known about the base-flipping process itself, even less about the role of the enzymes. Computational studies have used umbrella sampling to elicit the free energy profile of the base flipping process using a pseudodihedral angle to represent the reaction coordinate. In this study, we have used an unrestrained trajectory in which a flipped base spontaneously reinserted into the helix in order to evaluate and improve the previously defined pseudodihedral angle. Our modified pseudodihedral angles use a new atom selection to improve the numerical stability of the restraints and also provide better correlation to the extent of flipping observed in simulations. Furthermore, on the basis of the comparison of potential of mean force (PMF) generated using different reaction coordinates, we observed that the shape of a flipping PMF profile is strongly dependent on the definition of the reaction coordinate, even for the same data set. PMID- 26609992 TI - On the Use of low-resolution Data to Improve Structure Prediction of Proteins and Protein Complexes. AB - We present a systematic study of the ability of low-resolution experimental data, when combined with physical/statistical scoring functions, to improve the quality of theoretical structural models of proteins and protein complexes. Particularly, we have analyzed in detail the "extra value" added to the theoretical models by: electrospray mass spectrometry (ESI-MS), small-angle X-ray scattering (SAXS), and hydrodynamic measurements. We found that any low-resolution structural data, even when (as in the case of mass spectrometry) obtained in conditions far from the physiological ones, help to improve the quality of theoretical models, but not all the coarse-grained experimental results are equally rich in information. The best results are always obtained when using SAXS data as experimental constraints, but either hydrodynamics or gas phase CCS data contribute to improving model prediction. The combination of suitable scoring functions and broadly available low-resolution structural data (technically easier to obtain) yields structural models that are notably close to the real structures. PMID- 26609993 TI - Quantum Chemistry on Graphical Processing Units. 2. Direct Self-Consistent-Field (SCF) Implementation. PMID- 26609995 TI - NCICT: a computational solution to estimate organ doses for pediatric and adult patients undergoing CT scans. AB - We developed computational methods and tools to assess organ doses for pediatric and adult patients undergoing computed tomography (CT) examinations. We used the International Commission on Radiological Protection (ICRP) reference pediatric and adult phantoms combined with the Monte Carlo simulation of a reference CT scanner to establish comprehensive organ dose coefficients (DC), organ absorbed dose per unit volumetric CT Dose Index (CTDIvol) (mGy/mGy). We also developed methods to estimate organ doses with tube current modulation techniques and size specific dose estimates. A graphical user interface was designed to obtain user input of patient- and scan-specific parameters, and to calculate and display organ doses. A batch calculation routine was also integrated into the program to automatically calculate organ doses for a large number of patients. We entitled the computer program, National Cancer Institute dosimetry system for CT(NCICT). We compared our dose coefficients with those from CT-Expo, and evaluated the performance of our program using CT patient data. Our pediatric DCs show good agreements of organ dose estimation with those from CT-Expo except for thyroid. Our results support that the adult phantom in CT-Expo seems to represent a pediatric individual between 10 and 15 years rather than an adult. The comparison of CTDIvol values between NCICT and dose pages from 10 selected CT scans shows good agreements less than 12% except for two cases (up to 20%). The organ dose comparison between mean and modulated mAs shows that mean mAs-based calculation significantly overestimates dose (up to 2.4-fold) to the organs in close proximity to lungs in chest and chest-abdomen-pelvis scans. Our program provides more realistic anatomy based on the ICRP reference phantoms, higher age resolution, the most up-to-date bone marrow dosimetry, and several convenient features compared to previous tools. The NCICT will be available for research purpose in the near future. PMID- 26609996 TI - Spin-Unrestricted Calculations of Bare-Edged Nanographenes Using DFT and Many Body Perturbation Theory. AB - The ability of Density Functional Theory to predict the electronic and magnetic properties of semi-infinite graphene with a single bare edge has been probed. In order to improve the accuracy of spin-unrestricted calculations performed with semilocal density functionals, higher-level methods including double hybrid density functionals and many-body perturbation theory have been applied to the polycyclic aromatic hydrocarbons model systems. We show that the antiferromagnetic or ferromagnetic tendencies of the corresponding electronic ground states strongly depend on the choice of the density functional. In addition the relative stability of the armchair and zigzag edges has been investigated, emphasizing the importance of using methods beyond semilocals density functionals. PMID- 26609994 TI - Electrophoretic Deformation of Individual Transfer RNA Molecules Reveals Their Identity. AB - It has been hypothesized that the ribosome gains additional fidelity during protein translation by probing structural differences in tRNA species. We measure the translocation kinetics of different tRNA species through ~3 nm diameter synthetic nanopores. Each tRNA species varies in the time scale with which it is deformed from equilibrium, as in the translocation step of protein translation. Using machine-learning algorithms, we can differentiate among five tRNA species, analyze the ratios of tRNA binary mixtures, and distinguish tRNA isoacceptors. PMID- 26609997 TI - Spatial Decomposition Analysis of the Thermodynamics of Cyclodextrin Complexation. AB - We propose a method of spatial decomposition analysis (SDA) to study the thermodynamics of association in solution, based on three-dimensional molecular theory of solvation. We decompose the solvation thermodynamics quantities into the excluded volume and solvation shell terms and further break them down into partial contributions of the functional groups of the associating species. For illustration, we applied the SDA method to the complexation of beta-cyclodextrin and 1-adamantanecarboxylic acid in water. We calculated the changes in the free energy and in the partial molar volume upon the association and decomposed them into the partial contributions of the functional groups to the excluded volume and solvation shell terms. The SDA shows that the adamantyl group of 1 adamantanecarboxylic acid is responsible for the complexation more than its carboxyl group and that the carboxyl has little contribution to the association process. The SDA results are in good agreement with the observation made in a recent molecular dynamics simulation. The SDA method can reveal a microscopic picture for association processes in solution in a number of areas, including protein stability, and might be a useful tool for rational drug design. PMID- 26609998 TI - Fully Numerical All-Electron Solutions of the Optimized Effective Potential Equation for Diatomic Molecules. AB - We present an approach for fully numerical, all-electron solutions of the optimized effective potential equation within Kohn-Sham density functional theory for diatomic molecules. The approach is based on a real-space, prolate-spheroidal coordinate grid for solving the all-electron Kohn-Sham equations and an iterative scheme for solving the optimized effective potential equation. The accuracy of this method is demonstrated by comparison with previously reported calculations. New fully numerical benchmark results for selected diatomic molecules are provided. PMID- 26609999 TI - Generalization of the New Resonance Theory: Second Quantization Operator, Localization Scheme, and Basis Set. AB - We have recently proposed a method to evaluate the weights of resonance structures embedded in a molecular orbital by utilizing singlet-coupling scheme of an electron pair [J. Phys. Chem. A 2006, 110, 9028]. The method was formulated on the basis of the second quantization, in which a biorthogonal operator related to Mulliken population (MP) was used together with the Boys-Foster (BF) localization scheme. Our method is very easy to use; only a standard localization procedure is required to obtain the resonance weights. In addition, obtained results agreed well with our chemical intuition. In the present Article, the restrictions, namely MP and BF, were removed, and an operator related to Lowdin population (LP) and other various types of localization schemes were employed to examine the generality of the method. We found that computed resonance weights were virtually independent not only on the choice of these combinations but also on basis set. This new finding, the invariant nature in terms of resonance, may suggest that the present approach could be promising for analyzing molecular orbitals. PMID- 26610000 TI - Semiempirical Quantum Chemical PM6 Method Augmented by Dispersion and H-Bonding Correction Terms Reliably Describes Various Types of Noncovalent Complexes. AB - Because of its construction and parametrization for more than 80 elements, the semiempirical quantum chemical PM6 method is superior to other similar methods. Despite its advantages, however, the PM6 method fails for the description of noncovalent interactions, specifically the dispersion energy and H-bonding. Upon inclusion of correction terms for dispersion and H-bonding, the performance of the method was found to be dramatically improved. The former correction included two parameters in the damping function that were parametrized to reproduce the benchmark interaction energies [CCSD(T)/complete basis set (CBS) limit] of the dispersion-bonded complexes from the S22 data set. The latter correction was parametrized on an extended set of H-bonded stabilization energies determined at the MP2/cc-pVTZ level. The resulting PM6-DH method was tested on the S22 data set, for which chemical accuracy (error < 1 kcal/mol) was achieved, and also on the JSCH2005 set, for which significant improvement over the original PM6 method was also obtained. Implementation of analytical gradients allows very efficient geometry optimization, which, for all complexes, provides better agreement with the benchmark data. Excellent results were also achieved for small peptides, and here again, chemical accuracy was obtained (i.e., the error with respect to CCSD(T)/CBS results was smaller than 1 kcal/mol). The performance of the technique was finally demonstrated on extended complexes, namely, the porphine dimer and various graphene models with DNA bases and base pairs, where the PM6-DH stabilization energies agree very well with available benchmark data obtained with DFT-D, SCS-MP2, and MP2.5 methods. The PM6-DH calculations are very efficient and can be routinely applied for systems of up to 1000 atoms. For nonaromatic systems, the use of a linear scaling version of the SCF procedure based on localized orbitals speeds up the method significantly and allows one to investigate systems with several thousand atoms. The method can thus replace force fields, which face basic problems for the description of quantum effects, in many applications. PMID- 26610001 TI - Convergence of the CCSD(T) Correction Term for the Stacked Complex Methyl Adenine Methyl Thymine: Comparison with Lower-Cost Alternatives. AB - We have performed large-scale calculations for the interaction energy of the stacked methyl adenine-methyl thymine complex at the CCSD(T)/aug-ccpVXZ (X = D,T) levels. The results can serve as benchmarks for the evaluation of two methods, MP2.5, introduced recently, and the widely used DeltaCCSD(T) correction defined as the difference between the CCSD(T) and MP2 energies. Our results confirm that the DeltaCCSD(T) correction converges much faster toward the complete basis set (CBS) limit than toward the MP2 or CCSD(T) energies. This justifies approximating the CBS energy by adding the DeltaCCSD(T) correction calculated with a modest basis set to a large basis MP2 energy. The fast convergence of the DeltaCCSD(T) correction is not obvious, as the individual CCSD and (T) contributions converge less rapidly than their sum. The MP2.5 method performs very well for this system, with results very close to CCSD(T). It is conjectured that using a DeltaMP2.5 correction, defined analogously to DeltaCCSD(T), with large basis sets may yield more reliable nonbonded interaction energies than using DeltaCCSD(T) with a smaller basis set. This would result in important computational savings as the MP3 scales computationally much less steep than CCSD(T), although higher than SCS MP2, a similar approximation. PMID- 26610002 TI - Aromaticity of alpha-Oligothiophenes and Equivalent Oligothienoacenes. AB - The aromaticity and the degree of pi-electronic delocalization have been theoretically investigated for alpha,alpha'-linked oligothiophenes containing three and five rings and for their fused analogs oligothienoacenes. By computing magnetic susceptibilities and (1)H NMR shieldings as well as current density maps, it is found that the fused oligomers are more aromatic than the corresponding nonfused partners. The increase of aromaticity with the size of the oligomer-even in the case of quinoidal forms-is also proven. The pi-currents induced by an external magnetic field show that oligothienoacenes behave as single cycles since they present an intense diamagnetic current flowing around the whole molecular perimeter. In contrast, nonfused alpha-oligothiophenes exhibit diamagnetic currents localized over each thiophene ring. For the quinoidal oligomers, local diamagnetic pi vortices appear around CC double bonds, indicating that the pi electrons are rather localized as in conjugated, nonaromatic polyenes. For quinoidal nonathienoacene, it is however found that the electronic circulation around the ethylenic bonds tends to delocalize all over the carbon skeleton, indicating a more effective pi-conjugation and some aromatic character. PMID- 26610003 TI - Multicore Parallelization of Kohn-Sham Theory. AB - A multicore parallelization of Kohn-Sham theory is described, using standard commodity multisocket and multisocket/multicore shared-memory processors. Near linear scaling of the parallel parts of the code was observed up to the maximum of sixteen cores that were available for benchmarking, and an order of magnitude reduction in run time was achieved running using sixteen threads on a quad-socket quad-core Xeon system. The speed-ups achieved using multisocket/multicore processors were competitive with those achieved using numerical accelerator cards. PMID- 26610004 TI - United Atom Lipid Parameters for Combination with the Optimized Potentials for Liquid Simulations All-Atom Force Field. AB - We have developed a new united-atom set of lipid force field parameters for dipalmitoylphosphatidylcholine (DPPC) lipid bilayers that can be combined with the all-atom optimized potentials for liquid simulations (OPLS-AA) protein force field. For this, all torsions have been refitted for a nonbonded 1-4 scale factor of 0.5, which is the standard in OPLS-AA. Improved van der Waals parameters have been obtained for the acyl lipid tails by matching simulation results of bulk pentadecane against recently improved experimental measurements. The charge set has been adjusted from previous lipid force fields to allow for an identical treatment of the alkoxy ester groups. This reduces the amount of parameters required for the model. Simulation of DPPC bilayers in the tension-free NPT ensemble at 50 degrees C gives the correct area per lipid of 62.9 +/- 0.1 A(2), which compares well with the recently refined experimental value of 63.0 A(2). Electron density profiles and deuterium order parameters are similarly well reproduced. The new parameters will allow for improved simulation results in microsecond scale peptide partitioning simulations, which have proved problematic with prior parametrizations. PMID- 26610005 TI - Coarse Graining of Intermolecular Vibrations by a Karhunen-Loeve Transformation of Atomic Displacement Vectors. AB - We have formulated a procedure for evaluating the anisotropic stiffness of a molecular assembly. First, we show how to reduce the dimensions of the matrices that appear in a conventional Hessian analysis of mass-weighted coordination by using a 12-dimensional transverse-rotational basis set for expansion. This treatment yields matrix representations of the intermolecular force and inertial load of the constituent molecules. Next we applied this procedure to 2 aminopyridine dimers and numerically analyzed the low-frequency (~THz region) normal-mode vibrations. By validating the elements of stiffness matrix, this study exemplifies a derivation of the parameters necessary for the normal-mode analysis of a large system like a crystal, without any explicit representation of the potential functions. PMID- 26610006 TI - Many-Body Perturbation Theory Extended to the Quantum Mechanics/Molecular Mechanics Approach: Application to Indole in Water Solution. AB - Optical properties of aromatic chromophores are used to probe complex biological processes, yet how the environment tunes their optical properties is far from being fully understood. Here we present a method to calculate such properties on large-scale systems, like biologically relevant molecules in aqueous solution. Our approach is based on many-body perturbation theory combined with a quantum mechanics/molecular mechanics (QM/MM) approach. We include quasiparticle and excitonic effects for the calculation of optical absorption spectra in a QM/MM scheme. We apply this scheme, together with the well-established TDDFT approach, to indole in water solution. Our calculations show that the solvent induces a red shift in the main spectral peak of indole, in quantitative agreement with the experiments, and they point to the relevance of both the electrostatic and geometrical origin of the shift. PMID- 26610007 TI - A Simple One-Body Approach to the Calculation of the First Electronic Absorption Band of Water. AB - A one-body decomposition approach for investigating the electronic absorption spectra of molecular systems was proposed and applied to water clusters (H2O)N including up to N = 80 water molecules. Two specific aspects of the present implementation are the inclusion of the coupling between excited states and a simplified representation for the N-body Coulombic effects. For smaller clusters, the results based on the one-body decomposition scheme are in good agreement with full EOM-CCSD calculations. Two different regimes can be identified in the electronic absorption profile of larger water clusters. The first low-energy regime is dominated by local excitonic states on the cluster surface, whereas the higher-energy excitations associated with the second one are of delocalized nature. PMID- 26610008 TI - Electronic Energy Transfer in Condensed Phase Studied by a Polarizable QM/MM Model. AB - We present a combined quantum mechanics and molecular mechanics (QM/MM) method to study electronic energy transfer (EET) in condensed phases. The method introduces a quantum mechanically based linear response (LR) scheme to describe both chromophore electronic excitations and electronic couplings, while the environment is described through a classical polarizable force field. Explicit treatment of the solvent electronic polarization is a key aspect of the model, as this allows account of solvent screening effects in the coupling. The method is tested on a model perylene diimide (PDI) dimer in water solution. We find an excellent agreement between the QM/MM method and "exact" supermolecule calculations in which the complete solute-solvent system is described at the QM level. In addition, the estimation of the electronic coupling is shown to be very sensitive to the quality of the parameters used to describe solvent polarization. Finally, we compare ensemble-averaged QM/MM results to the predictions of the PCM LR method, which is based on a continuum dielectric description of the solvent. We find that both continuum and atomistic solvent models behave similarly in homogeneous media such as water. Our findings demonstrate the potential of the method to investigate the role of complex heterogeneous environments, e.g. proteins or nanostructured host materials, on EET. PMID- 26610009 TI - On the Potential Use of Squaraine Derivatives as Photosensitizers in Photodynamic Therapy: A TDDFT and RICC2 Survey. AB - A time-dependent density functional theory (TDDFT) and the second-order approximated coupled-cluster model with the resolution of identity approximation (RICC2) studies are reported here for some classes of squaraine derivatives. These compounds have a sharp electronic band, ranging from the visible to near red part of the spectrum, with an high molar absorption coefficient. These features make them potential photosensitizers in the photodynamic therapy of cancer (PDT), in which a light source, a photosensitizer, and molecular oxygen ((3)O2) are combined to give cytotoxic singlet oxygen ((1)O2) as a final result in a photochemical process. For the examined structures, the introduction of different substituents (electron donating, electron withdrawing, or fused rings) in the parent molecule, in order to give different squaraine derivatives, changes the maximum absorption wavelength (lambdamax) from 620 to 730 nm, giving a near red absorbing photosensitizer that can better penetrate human tissue to damage tumor cells. Theoretical results, obtained from both TDDFT/PBE0 and RICC2, are able to reproduce qualitatively the substitution effect on lambdamax, resulting in a useful tool for testing different structure modifications and, in general, for the molecular design of PDT photosensitizers. Calculated vertical excitation energies (singlet-singlet transitions) generally agree with experimental data within 0.3 eV. The singlet oxygen generation ability of these compounds requires that their triplet energy, for a type II reaction mechanism, should be greater than 0.98 eV. Theoretical triplet energies from the RICC2 method suggests that this requisite is fulfilled for all compounds, though the results are generally overestimated with respect to experiment by 0.7 eV, whereas TDDFT/PBE0 triplet energies, which are underestimated within 0.2 eV in few cases, lie close to the above-mentioned limit and can be considered suitable for PDT applications. PMID- 26610010 TI - Order-Disorder Transition and Phase Separation in the MgB2 Metallic Sublattice Induced by Al Doping. AB - MgB2 is a superconductor constituted by alternating Mg and B planar layers: doping of both the sublattices has been observed experimentally to destroy the outstanding superconductive properties of this simple material. In this study we present the investigation by first principles methods at atomistic scale of the phase separation induced by aluminum doping in the MgB2 lattice. The calculations were performed by Density Functional Theory in generalized gradient approximation and pseudopotentials. Orthorhombic oP36 supercells derived by the primitive hR3 MgB2 cell were built in order to simulate the aluminum-magnesium substitution in the 0-50% composition range. The computational results explained the occurrence of a phase separation in the Mg1-xAlxB2 system. The miscibility gap is predicted to be induced by an order-disorder transition in the metallic sublattice at high Al concentration. Indeed at 1000 K aluminum substitution takes place on random Mg sites for concentration up to 17% of the total metallic sites, whereas at Al content larger than 31% the substitution is energetically more favorable on alternated metallic layers (Mg undoped planes alternate with Mg-Al layers). The formation of this Al-rich phase lead at 50% doping to the formation of the double omega Mg1/2Al1/2B2 ordered lattice. From 17 to 31% the two phases, the disordered Mg1-xAlxB2 (x < 0.17) and the ordered Mg1/2+yAl1/2-yB2 (y < 0.19) lattices, coexist. This phase separation is driven by the balance of the enthalpy and entropy contributions to the Gibbs energy. Present DFT-GGA calculations indicate that this thermodynamically predicted suppression of the Al doping disorder in the metallic sublattice of MgB2 occurs in parallel with the collapse of the superconductive properties of the material. PMID- 26610011 TI - Chemical Detail Force Fields for Mesogenic Molecules. AB - Intra- and intermolecular potential energy surfaces of the 4,4'-di-n-heptyl azoxybenzene molecule have been sampled by ab initio calculations and represented through a force field suitable for classical bulk simulations. The parametrization of the molecular internal flexibility has been performed by a fitting procedure based on single molecule Hessian, gradients and torsional energies, computed using density functional theory. The intermolecular part of the force field has been derived as a pure pair potential, by fitting the dimer potential energy surface sampled by the Fragmentation Reconstruction Method. Preliminary molecular dynamics runs have been performed on systems of 210 and 600 molecules at atmospheric pressure and different temperatures, showing the presence of ordered and isotropic phases. Several properties have been computed, all resulting in a good agreement with the corresponding experimental data. PMID- 26610012 TI - Algorithm for Generating Defective Graphene Sheets. AB - An algorithm is presented for the generation of molecular models of defective graphene fragments, containing a majority of 6-membered rings with a small number of 5- and 7-membered rings as defects. The structures are generated from an initial random array of points in 2D space, which are then subject to Delaunay triangulation. The dual of the triangulation forms a Voronoi tessellation of polygons with a range of ring sizes. An iterative cycle of refinement, involving deletion and addition of points followed by further triangulation, is performed until the user-defined criteria for the number of defects are met. The array of points and connectivities are then converted to a molecular structure and subject to geometry optimization using a standard molecular modeling package to generate final atomic coordinates. On the basis of molecular mechanics with minimization, this automated method can generate structures, which conform to user-supplied criteria and avoid the potential bias associated with the manual building of structures. One application of the algorithm is the generation of structures for the evaluation of the reactivity of different defect sites. Ab initio electronic structure calculations on a representative structure indicate preferential fluorination close to 5-ring defects. PMID- 26610013 TI - Pressure Annealing as a Complement to Temperature Annealing To Find Low-Energy Structures of Oligomeric Molecules. AB - Finding the lowest-energy geometry of a molecule or collection of molecules is a fundamental challenge of modern computational chemistry and is closely related to the more general problem of optimizing a function. Temperature annealing, popularly called simulated annealing, is a powerful and commonly used technique, but it is not well suited to conformational sampling of long, oligomeric molecules. A method is presented herein that incorporates pressure as an optimization parameter to complement temperature annealing, and several tests of its effectiveness are described. Bayesian statistical analysis shows that pressure-temperature annealing confers no advantage in control simulations of Lennard-Jones particles, but it yields lower-energy structures than pure temperature annealing with significant credibility for two model polyethers, monoglyme (CH3OCH2CH2OCH3) and tetraglyme [CH3(OCH2CH2)4OCH3]. PMID- 26610014 TI - Quantum Chemical Benchmark Studies of the Electronic Properties of the Green Fluorescent Protein Chromophore. 1. Electronically Excited and Ionized States of the Anionic Chromophore in the Gas Phase. AB - We present the results of quantum chemical calculations of the electronic properties of the anionic form of the green fluorescent protein chromophore in the gas phase. The vertical detachment energy of the chromophore is found to be 2.4-2.5 eV, which is below the strongly absorbing pipi* state at 2.6 eV. The vertical excitation of the lowest triplet state is around 1.9 eV, which is below the photodetachment continuum. Thus, the lowest bright singlet state is a resonance state embedded in the photodetachment continuum, whereas the lowest triplet state is a regular bound state. Based on our estimation of the vertical detachment energy, we attribute a minor feature in the action spectrum as due to the photodetachment transition. The benchmark results for the bright pipi* state demonstrated that the scaled opposite-spin method yields vertical excitation within 0.1 eV (20 nm) from the experimental maximum at 2.59 eV (479 nm). We also report estimations of the vertical excitation energy obtained with the equation of-motion coupled cluster with the singles and doubles method, a multireference perturbation theory corrected approach MRMP2 as well as the time-dependent density functional theory with range-separated functionals. Expanding the basis set with diffuse functions lowers the pipi* vertical excitation energy by 0.1 eV at the same time revealing a continuum of "ionized" states, which embeds the bright pipi* transition. PMID- 26610015 TI - Quantum Chemical Benchmark Studies of the Electronic Properties of the Green Fluorescent Protein Chromophore: 2. Cis-Trans Isomerization in Water. AB - We present quantum chemical calculations of the properties of the anionic form of the green fluorescent protein (GFP) chromophore that can be directly compared to the results of experimental measurements: the cis-trans isomerization energy profile in water. Calculations of the cis-trans chromophore isomerization pathway in the gas phase and in water reveal a problematic behavior of density functional theory and scaled opposite-spin-MP2 due to the multiconfigurational character of the wave function at twisted geometries. The solvent effects treated with the continuum solvation models, as well as with the water cluster model, are found to be important and can reduce the activation energy by more than 10 kcal/mol. Strong solvent effects are explained by the change in charge localization patterns along the isomerization coordinate. At the equilibrium, the negative charge is almost equally delocalized between the phenyl and imidazolin rings due to the interaction of two resonance structures, whereas at the transition state the charge is localized on the imidazolin moiety. Our best estimate of the barrier obtained in cluster calculations employing the effective fragment potential-based quantum mechanics/molecular mechanics method with the complete active space self-consistent field description of the chromophore augmented by perturbation theory correction and the TIP3P water model is 14.8 kcal/mol, which is in excellent agreement with the experimental value of 15.4 kcal/mol. This result helps to resolve previously reported disagreements between experimental measurements and theoretical estimates. PMID- 26610016 TI - Catalytic Mechanism of Diaminopimelate Epimerase: A QM/MM Investigation. AB - A QM/MM investigation, based on a DFT(B3LYP)//Amber-ff99 potential, has been carried out to elucidate the mechanism of diaminopimelate epimerase. This enzyme catalyzes the reversible stereoconversion of one of the two stereocenters of diaminopimelate and represents a promising target for rational drug design aimed to develop new selective antibacterial therapeutic agents. The QM/MM computations show that the reaction proceeds through a highly asynchronous mechanism where the side-chain of a negatively charged Cys-73 (thiolate) deprotonates the alpha carbon substrate. Simultaneously, the Cys-217 thiolic proton moves toward the same carbon atom on the opposite face, thus determining the configuration inversion. A fingerprint analysis provides a detailed description of the influence of the various residues surrounding the active site and clearly shows the electrostatic nature of the most important contributions to the catalysis. PMID- 26610017 TI - Large Protein Dynamics Described by Hierarchical-Component Mode Synthesis. AB - Protein dynamics has played a pivotal role in understanding the biological function of protein. For investigation of such dynamics, normal-mode analysis (NMA) has been broadly employed with atomistic model and/or coarse-grained models such as elastic network model (ENM). For large protein complexes, NMA with even ENM encounters the expensive computational process such as diagonalization of Hessian (stiffness) matrix. Here, we suggest the hierarchical-component mode synthesis (hCMS), which allows the fast computation of low-frequency normal modes related to conformational change. Specifically, a large protein structure is regarded as a combination of several structural units, for which the eigen-value problem is utilized for obtaining the frequencies and their normal modes for each structural unit, and consequently, such frequencies and normal modes are assembled with geometrical constraint for interface between structural units in order to find the low-frequency normal modes of a large protein complex. It is shown that hCMS is able to provide the normal modes with accuracy, quantitatively comparable to those of original NMA. This implies that hCMS may enable the computationally efficient analysis of large protein dynamics. PMID- 26610018 TI - Structure Prediction of Bis(amino acidato)copper(II) Complexes with a New Force Field for Molecular Modeling. AB - This article presents a new force field whose parameterization was based on experimental crystal data and quantum chemically obtained vacuum structures of a series of copper(II) complexes with aliphatic alpha-amino acids and their N-alkyl derivatives, along with the SPC/E water model. The ability of the new force field to reproduce and predict the structural properties of the copper(II) complexes in the gas phase, in simulated crystalline surroundings, and solvated in water is examined. Molecular dynamics (MD) simulations with the new force field yielded time-average structural coordinates of bis(glycinato)copper(II) [the only one of 25 modeled bis(amino acidato)copper(II) systems with published experimental structural data in aqueous solution at room temperature] within the experimental error values. The study of the cis-trans isomerization of bis(glycinato)copper(II) in aqueous medium at 300 K using the quantum chemical polarized continuum model revealed a small energy difference (5 kJ mol(-1)) between the solvated cis and trans minima, in line with the MD energy estimations. The new force field proved promising in predicting the association of the complexes in aqueous solution and formation of a nucleus of crystallization. PMID- 26610019 TI - Rapid identification of clinical members of Fusarium fujikuroi complex using MALDI-TOF MS. AB - AIM: To develop the matrix-assisted laser desorption ionization mass spectrometry (MALDI-TOF MS) method for identification of Fusarium species within Fusarium fujikuroi complex for use in clinical microbiology laboratories. MATERIALS & METHODS: A total of 24 reference and 60 clinical and environmental isolates belonging to the F. fujikuroi complex were subjected to MALDI-TOF MS identification. Protein extracts of Fusarium isolates were obtained using formic acid extraction. Multilocus sequence analysis was used as a gold standard. RESULTS: The MALDI-TOF MS Biotyper correctly identified 93.6% of the strains down to the species level, while the remaining isolates (6.4%) were identified at the genus level when using scores of >= 2.0 as cut-off values. Correct identification was obtained despite large intraspecific heterogeneities in MALDI-TOF spectra. CONCLUSION: MALDI-TOF MS is a rapid identification tool for the recognition of species within F. fujikuroi complex, provided a database is available. PMID- 26610020 TI - Pheromonicins: an ecologically sound family of bacteriocin-based antibiotics for use in the age of the microbiome. AB - The time is ripe to usher in a new paradigm in infection control and to move beyond our sole reliance on broad-spectrum antibiotics whose use results in extensive collateral damage to our microbiome and, in so doing, exerts significant selective pressures for resistance to emerge. We propose to supplement the existing pharmacy of conventional antibiotics, with a new drug family, the pheromonicins. These bacteriocin-based antimicrobials are stable, nontoxic proteins that possess potent antibacterial activities, and which can be easily and rapidly retargeted against any bacteria desired. Here we discuss colicin Ia, a pore forming bacteriocin, as the base of a novel drug development platform, the pheromonicins. Recent work suggests this versatile drug development platform can be used to generate pheromonicins active against enveloped viruses, fungi and human cancer cells. Pheromonicins provide a less toxic, more ecologically sound alternative to conventional antibiotics, and their use will help limit our sole reliance on broad-spectrum drugs. PMID- 26610022 TI - Cauda equina lymphoma mimicking non-neoplastic hypertrophic neuropathy of the cauda equina: A case report. AB - Spinal cauda equina lymphoma (CEL) is very rare, with only about 14 cases reported in the English medical literature. Magnetic resonance image findings and the gross appearance of CEL at surgery are similar to those of non-neoplastic hypertrophic neuropathy of the cauda equina (HNCE); however, their prognosis and treatment are very different. We report a case of CEL and discuss the differences from non-neoplastic HNCE. PMID- 26610021 TI - Emerging horizons for tick-borne pathogens: from the 'one pathogen-one disease' vision to the pathobiome paradigm. AB - Ticks, as vectors of several notorious zoonotic pathogens, represent an important and increasing threat for human and animal health in Europe. Recent applications of new technology revealed the complexity of the tick microbiome, which may affect its vectorial capacity. Appreciation of these complex systems is expanding our understanding of tick-borne pathogens, leading us to evolve a more integrated view that embraces the 'pathobiome'; the pathogenic agent integrated within its abiotic and biotic environments. In this review, we will explore how this new vision will revolutionize our understanding of tick-borne diseases. We will discuss the implications in terms of future research approaches that will enable us to efficiently prevent and control the threat posed by ticks. PMID- 26610023 TI - Building capacity for education research among clinical educators in the health professions: A BEME (Best Evidence Medical Education) Systematic Review of the outcomes of interventions: BEME Guide No. 34. AB - BACKGROUND/PURPOSE: There is a growing desire for health professions educators to generate high-quality education research; yet, few of them encounter the training to do so. In response, health professions faculties have increasingly been devoting resources to provide members with the skills necessary for education research. The form and impact of these efforts have not been reviewed, though such a synthesis could be useful for practice. The objectives of this systematic review were to (1) identify interventions aimed at building capacity for education research among health professions clinical educators and (2) review the outcomes of these interventions. METHODOLOGY: We developed a systematic review protocol based on our pilot scoping search. This protocol underwent peer review and was prospectively registered with the Best Evidence Medical Education Collaboration. Based on this protocol, we conducted a comprehensive search of health professions' databases and related grey literature. Systematic methods were applied: two independent reviewers completed title screening and full text review for inclusion, data extraction, and methodological quality assessment. Studies were included if they reported outcomes for interventions designed to increase capacity for health professions clinical educators to conduct education research. We conducted a qualitative synthesis of the evidence which included detailed reporting of intervention characteristics and outcomes. RESULTS: Our search returned 14, 149 results, 241 of which were retained after title and abstract screening, and 30 of which met inclusion criteria after full text review. Seven groups of interventions were identified, the most frequent being teaching scholars programs (n = 10), health professions education fellowships (n = 3) or master's programs (n = 4). The most commonly measured outcome was change related to enhanced scholarly outputs (grants, papers, abstracts, and presentations) post-intervention. Unfortunately, most of the included studies lacked detailed description of the intervention and were of low to moderate quality with post-test only design. DISCUSSION/CONCLUSIONS: This review demonstrates that various interventions can have a positive impact on the ability of health professions clinical educators to conduct education research. We note several key elements of the interventions including: (1) protected time, (2) mentorship and/or collaboration, (3) departmental and institutional commitment and leadership, and (4) financial support. Through our analysis we describe the complexities around evaluating clinical educators' health professions research activities and the interventions used to promote education research. While improved study quality would allow more detailed understanding and evaluation of these key features, we are able to provide recommendations for potential strategies for improving participation in and quality of health professions education research based on this analysis. PMID- 26610024 TI - Complete nitrification by Nitrospira bacteria. AB - Nitrification, the oxidation of ammonia via nitrite to nitrate, has always been considered to be a two-step process catalysed by chemolithoautotrophic microorganisms oxidizing either ammonia or nitrite. No known nitrifier carries out both steps, although complete nitrification should be energetically advantageous. This functional separation has puzzled microbiologists for a century. Here we report on the discovery and cultivation of a completely nitrifying bacterium from the genus Nitrospira, a globally distributed group of nitrite oxidizers. The genome of this chemolithoautotrophic organism encodes the pathways both for ammonia and nitrite oxidation, which are concomitantly activated during growth by ammonia oxidation to nitrate. Genes affiliated with the phylogenetically distinct ammonia monooxygenase and hydroxylamine dehydrogenase genes of Nitrospira are present in many environments and were retrieved on Nitrospira-contigs in new metagenomes from engineered systems. These findings fundamentally change our picture of nitrification and point to completely nitrifying Nitrospira as key components of nitrogen-cycling microbial communities. PMID- 26610026 TI - Polymorphism in liver-stage malaria vaccine candidate proteins: immune evasion and implications for vaccine design. AB - The pre-erythrocytic stage of infection by malaria parasites represents a key target for vaccines that aim to eradicate malaria. Two important broad immune evasion strategies that can interfere with vaccine efficacy include the induction of dendritic cell (DC) dysfunction and regulatory T cells (Tregs) by blood-stage malaria parasites, leading to inefficient priming of T cells targeting liver stage infections. The parasite also uses 'surgical strike' strategies, whereby polymorphism in pre-erythrocytic antigens can interfere with host immunity. Specifically, we review how even single amino acid changes in T cell epitopes can lead to loss of binding to major histocompatibility complex (MHC), lack of cross reactivity, or antagonism and immune interference, where simultaneous or sequential stimulation with related variants of the same T cell epitope can cause T cell anergy or the conversion of effector to immunosuppressive T cell phenotypes. PMID- 26610025 TI - Complete nitrification by a single microorganism. AB - Nitrification is a two-step process where ammonia is first oxidized to nitrite by ammonia-oxidizing bacteria and/or archaea, and subsequently to nitrate by nitrite oxidizing bacteria. Already described by Winogradsky in 1890, this division of labour between the two functional groups is a generally accepted characteristic of the biogeochemical nitrogen cycle. Complete oxidation of ammonia to nitrate in one organism (complete ammonia oxidation; comammox) is energetically feasible, and it was postulated that this process could occur under conditions selecting for species with lower growth rates but higher growth yields than canonical ammonia-oxidizing microorganisms. Still, organisms catalysing this process have not yet been discovered. Here we report the enrichment and initial characterization of two Nitrospira species that encode all the enzymes necessary for ammonia oxidation via nitrite to nitrate in their genomes, and indeed completely oxidize ammonium to nitrate to conserve energy. Their ammonia monooxygenase (AMO) enzymes are phylogenetically distinct from currently identified AMOs, rendering recent acquisition by horizontal gene transfer from known ammonia-oxidizing microorganisms unlikely. We also found highly similar amoA sequences (encoding the AMO subunit A) in public sequence databases, which were apparently misclassified as methane monooxygenases. This recognition of a novel amoA sequence group will lead to an improved understanding of the environmental abundance and distribution of ammonia-oxidizing microorganisms. Furthermore, the discovery of the long-sought-after comammox process will change our perception of the nitrogen cycle. PMID- 26610027 TI - Utility of two modified-live virus canine distemper vaccines in wild-caught fishers (Martes pennanti). AB - BACKGROUND: Canine distemper virus (CDV) infects families in the order Carnivora. As a preventive measure, vaccinations against CDV are frequently given to mustelids in captive environments. OBJECTIVES: Our objectives were to compare the utility between two modified-live virus canine distemper vaccines (MLV CDV's), Fervac-D(r) (no longer manufactured) and Galaxy-D(r) (now manufactured by MSD Animal Health as part of a multivalent vaccine), in developing an immune response in wild-caught fishers. ANIMALS AND METHODS: The Pennsylvania Fisher Reintroduction Project (PFRP) used 14 wild-caught fishers during one year of the project to evaluate the utility of vaccinations against CDV as part of any reintroduction project. Fishers were injected subcutaneously in the nape of the neck with their designated vaccine. RESULTS: Fervac-D(r) did not effectively stimulate development of a serologic antibody response, whereas Galaxy-D(r) had adequate seroconversion or rise of titer levels to suggest that the general use of MLV CDV may be suitable in fishers pending further studies. CONCLUSION: We recommend that future studies be conducted, evaluating the use of currently produced vaccines in fishers. Future research should also focus on the length of days required between administration of primary and booster vaccines to achieve sufficient immune response. CLINICAL IMPORTANCE: If only primary doses are required, then hard-release reintroduction projects for fishers could be recommended. If primary and booster vaccines are required then soft-release reintroduction projects should be recommended that include captive management periods, allowing for appropriate vaccination intervals needed to maximize the probability of protection against CDV. PMID- 26610028 TI - Balloon-based pulmonary vein isolation for the treatment of paroxysmal atrial fibrillation (cryoballoon and laserballoon). AB - Electrical isolation of the pulmonary veins still remains one of the major objectives during catheter ablation of atrial fibrillation. In patients with paroxysmal atrial fibrillation, balloon-based technologies hold great promise to simplify the approach to successful pulmonary vein isolation. While the cryoballoon represents the only true 'single-shot' technology, the laserballoon allows real-time endoscopic visualization of the pulmonary vein antrum during energy delivery. Either technology aims at complete electrical isolation, requiring continuous transmural lesion sets encircling the pulmonary veins. Strategies to confirm and to improve upon the efficacy of pulmonary vein isolation are the key to acute and long-term clinical success and will be reviewed in this article. PMID- 26610029 TI - An Evaluation of Weighting Methods Based on Propensity Scores to Reduce Selection Bias in Multilevel Observational Studies. AB - Observational studies of multilevel data to estimate treatment effects must consider both the nonrandom treatment assignment mechanism and the clustered structure of the data. We present an approach for implementation of four propensity score (PS) methods with multilevel data involving creation of weights and three types of weight scaling (normalized, cluster-normalized and effective), followed by estimation of multilevel models with the multilevel pseudo-maximum likelihood estimation method. Using a Monte Carlo simulation study, we found that the multilevel model provided unbiased estimates of the Average Treatment Effect on the Treated (ATT) and its standard error across manipulated conditions and combinations of PS model, PS method, and type of weight scaling. Estimates of between-cluster variances of the ATT were biased, but improved as cluster sizes increased. We provide a step-by-step demonstration of how to combine PS methods and multilevel modeling to estimate treatment effects using multilevel data from the Early Childhood Longitudinal Study-Kindergarten Cohort (ECLS-K). PMID- 26610030 TI - Using Principal Components as Auxiliary Variables in Missing Data Estimation. AB - To deal with missing data that arise due to participant nonresponse or attrition, methodologists have recommended an "inclusive" strategy where a large set of auxiliary variables are used to inform the missing data process. In practice, the set of possible auxiliary variables is often too large. We propose using principal components analysis (PCA) to reduce the number of possible auxiliary variables to a manageable number. A series of Monte Carlo simulations compared the performance of the inclusive strategy with eight auxiliary variables (inclusive approach) to the PCA strategy using just one principal component derived from the eight original variables (PCA approach). We examined the influence of four independent variables: magnitude of correlations, rate of missing data, missing data mechanism, and sample size on parameter bias, root mean squared error, and confidence interval coverage. Results indicate that the PCA approach results in unbiased parameter estimates and potentially more accuracy than the inclusive approach. We conclude that using the PCA strategy to reduce the number of auxiliary variables is an effective and practical way to reap the benefits of the inclusive strategy in the presence of many possible auxiliary variables. PMID- 26610031 TI - Multiple Group Analysis in Multilevel Structural Equation Model Across Level 1 Groups. AB - This article introduces and evaluates a procedure for conducting multiple group analysis in multilevel structural equation model across Level 1 groups (MG1-MSEM; Ryu, 2014). When group membership is at Level 1, multiple group analysis raises two issues that cannot be solved by a simple extension of the standard multiple group analysis in single-level structural equation model. First, the Level 2 data are not independent between Level 1 groups. Second, the standard procedure fails to take into account the dependency between members of different Level 1 groups within the same cluster. The MG1-MSEM approach provides solutions to these problems. In MG1-MSEM, the Level 1 mean structure is necessary to represent the differences between Level 1 groups within clusters. The Level 2 model is the same regardless of Level 1 group membership. A simulation study examined the performance of MUML (Muthen's maximum likelihood) estimation in MG1-MSEM. The MG1 MSEM approach is illustrated for both a multilevel path model and a multilevel factor model using empirical data sets. PMID- 26610032 TI - Bayesian Causal Mediation Analysis for Group Randomized Designs with Homogeneous and Heterogeneous Effects: Simulation and Case Study. AB - A fully Bayesian approach to causal mediation analysis for group-randomized designs is presented. A unique contribution of this article is the combination of Bayesian inferential methods with G-computation to address the problem of heterogeneous treatment or mediator effects. A detailed simulation study shows that this approach has excellent frequentist properties, particularly in the case of small sample sizes with accurate informative priors. The simulation study also demonstrates that the proposed approach can take into account heterogeneous treatment or mediator effects without bias. A case study using data from a school based randomized intervention designed to increase parent social capital leading to improved behavioral and academic outcomes in children is offered to illustrate the Bayesian approach to causal mediation in group-randomized designs. PMID- 26610033 TI - A Multilevel AR(1) Model: Allowing for Inter-Individual Differences in Trait Scores, Inertia, and Innovation Variance. AB - In this article we consider a multilevel first-order autoregressive [AR(1)] model with random intercepts, random autoregression, and random innovation variance (i.e., the level 1 residual variance). Including random innovation variance is an important extension of the multilevel AR(1) model for two reasons. First, between person differences in innovation variance are important from a substantive point of view, in that they capture differences in sensitivity and/or exposure to unmeasured internal and external factors that influence the process. Second, using simulation methods we show that modeling the innovation variance as fixed across individuals, when it should be modeled as a random effect, leads to biased parameter estimates. Additionally, we use simulation methods to compare maximum likelihood estimation to Bayesian estimation of the multilevel AR(1) model and investigate the trade-off between the number of individuals and the number of time points. We provide an empirical illustration by applying the extended multilevel AR(1) model to daily positive affect ratings from 89 married women over the course of 42 consecutive days. PMID- 26610034 TI - A Rigorous Test of the Fit of the Circumplex Model to Big Five Personality Data: Theoretical and Methodological Issues and Two Large Sample Empirical Tests. AB - Our objective was to apply the rigorous test developed by Browne (1992) to determine whether the circumplex model fits Big Five personality data. This test has yet to be applied to personality data. Another objective was to determine whether blended items explained correlations among the Big Five traits. We used two working adult samples, the Eugene-Springfield Community Sample and the Professional Worker Career Experience Survey. Fit to the circumplex was tested via Browne's (1992) procedure. Circumplexes were graphed to identify items with loadings on multiple traits (blended items), and to determine whether removing these items changed five-factor model (FFM) trait intercorrelations. In both samples, the circumplex structure fit the FFM traits well. Each sample had items with dual-factor loadings (8 items in the first sample, 21 in the second). Removing blended items had little effect on construct-level intercorrelations among FFM traits. We conclude that rigorous tests show that the fit of personality data to the circumplex model is good. This finding means the circumplex model is competitive with the factor model in understanding the organization of personality traits. The circumplex structure also provides a theoretically and empirically sound rationale for evaluating intercorrelations among FFM traits. Even after eliminating blended items, FFM personality traits remained correlated. PMID- 26610035 TI - Four Methods for Analyzing Partial Interval Recording Data, with Application to Single-Case Research. AB - Partial interval recording (PIR) is a procedure for collecting measurements during direct observation of behavior. It is used in several areas of educational and psychological research, particularly in connection with single-case research. Measurements collected using partial interval recording suffer from construct invalidity because they are not readily interpretable in terms of the underlying characteristics of the behavior. Using an alternating renewal process model for the behavior under observation, we demonstrate that ignoring the construct invalidity of PIR data can produce misleading inferences, such as inferring that an intervention reduces the prevalence of an undesirable behavior when in fact it has the opposite effect. We then propose four different methods for analyzing PIR summary measurements, each of which can be used to draw inferences about interpretable behavioral parameters. We demonstrate the methods by applying them to data from two single-case studies of problem behavior. PMID- 26610036 TI - Corrigendum. PMID- 26610037 TI - An overview of environmental risk factors in systemic sclerosis. AB - Systemic sclerosis (SSc) is a connective tissue disease with a complex and multifactorial pathogenesis, characterized by excessive collagen deposition and vasculopathy, leading to skin fibrosis and involvement of internal organs. Regarding the aetiology of SSc, our current knowledge is still limited; however, as for other autoimmune syndromes, the disease is probably caused by both endogenous and exogenous factors. Among the exogenous factors, in the past decades, several environmental exposures, including occupational exposure to pollutants, chemicals and hand-arm vibrations as well as infections, silicone and use of drugs, have been suggested to play a role in the development of SSc. The following review analyzes the most recent literature to examine the relationship between environmental exposures and SSc. PMID- 26610038 TI - A new pyrone derivative from an endophytic Aspergillus tubingensis of Lycium ruthenicum. AB - A new pyrone named 6-isovaleryl-4-methoxy-pyran-2-one (1), along with three known pyrone compounds, rubrofusarin B (2), asperpyrones A (3) and campyrone A (4), was isolated from fermentation of Aspergillus tubingensis in Lycium ruthenicum. Their structures were confirmed by spectroscopic techniques, such as IR, NMR and HRESI MS. Compound 2 indicated strong inhibitory activity against Escherichia coli, with MIC value of 1.95 MUg/mL. PMID- 26610039 TI - Effect of high-potency cannabis on corpus callosum microstructure. AB - BACKGROUND: The use of cannabis with higher Delta9-tetrahydrocannabinol content has been associated with greater risk, and earlier onset, of psychosis. However, the effect of cannabis potency on brain morphology has never been explored. Here, we investigated whether cannabis potency and pattern of use are associated with changes in corpus callosum (CC) microstructural organization, in patients with first-episode psychosis (FEP) and individuals without psychosis, cannabis users and non-users. METHOD: The CC of 56 FEP (37 cannabis users) and 43 individuals without psychosis (22 cannabis users) was virtually dissected and segmented using diffusion tensor imaging tractography. The diffusion index of fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity was calculated for each segment. RESULTS: Across the whole sample, users of high potency cannabis had higher total CC MD and higher total CC AD than both low potency users and those who never used (p = 0.005 and p = 0.004, respectively). Daily users also had higher total CC MD and higher total CC AD than both occasional users and those who never used (p = 0.001 and p < 0.001, respectively). However, there was no effect of group (patient/individuals without psychosis) or group x potency interaction for either potency or frequency of use. The within-group analysis showed in fact that the effects of potency and frequency were similar in FEP users and in users without psychosis. CONCLUSIONS: Frequent use of high-potency cannabis is associated with disturbed callosal microstructural organization in individuals with and without psychosis. Since high-potency preparations are now replacing traditional herbal drugs in many European countries, raising awareness about the risks of high-potency cannabis is crucial. PMID- 26610041 TI - Structural variability of C3larvin toxin. Intrinsic dynamics of the alpha/beta fold of the C3-like group of mono-ADP-ribosyltransferase toxins. AB - C3larvin toxin is a new member of the C3 class of the mono-ADP-ribosyltransferase toxin family. The C3 toxins are known to covalently modify small G-proteins, e.g. RhoA, impairing their function, and serving as virulence factors for an offending pathogen. A full-length X-ray structure of C3larvin (2.3 A) revealed that the characteristic mixed alpha/beta fold consists of a central beta-core flanked by two helical regions. Topologically, the protein can be separated into N and C lobes, each formed by a beta-sheet and an alpha-motif, and connected by exposed loops involved in the recognition, binding, and catalysis of the toxin/enzyme, i.e. the ADP-ribosylation turn-turn and phosphate-nicotinamide PN loops. Herein, we provide two new C3larvin X-ray structures and present a systematic study of the toxin dynamics by first analyzing the experimental variability of the X-ray data-set followed by contrasting those results with theoretical predictions based on Elastic Network Models (GNM and ANM). We identify residues that participate in the stability of the N-lobe, putative hinges at loop residues, and energy-favored deformation vectors compatible with conformational changes of the key loops and 3D-subdomains (N/C-lobes), among the X-ray structures. We analyze a larger ensemble of known C3bot1 conformations and conclude that the characteristic 'crab claw' movement may be driven by the main intrinsic modes of motion. Finally, via computational simulations, we identify harmonic and anharmonic fluctuations that might define the C3larvin 'native state.' Implications for docking protocols are derived. PMID- 26610040 TI - Recent developments in antibiotic agents for the treatment of complicated intra abdominal infections. AB - INTRODUCTION: Treatment of complicated intra-abdominal infections (cIAIs) is becoming increasingly difficult because of the widespread emergence of multidrug resistant organisms. AREAS COVERED: In this review, we discuss the effectiveness of several new antibiotics for the treatment of cIAIs, including new beta lactamase inhibitor combinations (BLICs) and tetracycline-class drugs, recently developed aminoglycosides and quinolones, and novel lipoglycopeptides and oxazolidinones. EXPERT OPINION: Of the new BLICs, ceftolozane/tazobactam is associated with adequate clinical cure rates in patients with cIAIs. Currently, two new beta-lactamase inhibitors, namely avibactam and MK-7655, are under development for clinical use in the treatment of cIAIs. Eravacycline, a novel, fully synthetic tetracycline-class drug, has been shown in Phase II and III clinical trials to be more potent than tigecycline against a significant number of multidrug-resistant organisms causing cIAIs. Plazomicin, a next-generation aminoglycoside, is a promising agent for treatment of cIAIs due to multidrug resistant pathogens. Of the recently developed quinolones, delafloxacin and finafloxacin have been shown to be effective against pathogens that survive and multiply in mildly acidic environments, although further clinical studies examining their clinical utility in the treatment of cIAIs are warranted. Oritavancin, a new semisynthetic lipoglycopeptide agent, has been demonstrated to be a potent antibiotic in the treatment of cIAIs due to drug-resistant Gram positive organisms. Several other new antibiotics in development also show promise and will hopefully broaden the possibilities for treatment of complicated intra-abdominal infections due to MDR pathogens. PMID- 26610042 TI - Association between alcohol consumption and rotator cuff tear. AB - BACKGROUND AND PURPOSE: Long-term alcohol intake is associated with various negative effects on capillary microcirculation and tissue perfusion. We hypothesized that alcohol consumption might be a risk factor for both the occurrence and the severity of rotator cuff tears (RCTs). PATIENTS AND METHODS: A case-control study was performed. We studied 249 consecutive patients (139 men and 110 women; mean age 64 (54-78) years) who underwent arthroscopic rotator cuff repair. Tear size was determined intraoperatively. The control group had 356 subjects (186 men and 170 women; mean age 66 (58-82) years) with no RCT. All participants were questioned about their alcohol intake. Participants were divided into: (1) non-drinkers if they consumed less than 0.01 g of ethanol per day, and (2) moderate drinkers and (3) excessive drinkers if women (men) consumed > 24 g (36 g) per day for at least 2 years. RESULTS: Total alcohol consumption, wine consumption, and duration of alcohol intake were higher in both men and women with RCT than in both men and women in the control group. Excessive alcohol consumption was found to be a risk factor for the occurrence of RCT in both sexes (men: OR = 1.7, 95% CI: 1.2-3.9; women: OR = 1.9, 95% CI: 0.94-4.1). Massive tears were associated with a higher intake of alcohol (especially wine) than smaller lesions. INTERPRETATION: Long-term alcohol intake is a significant risk factor for the occurrence and severity of rotator cuff tear in both sexes. PMID- 26610043 TI - Moutan cortex extract exerts protective effects in a rat model of cardiac ischemia/reperfusion. AB - Moutan cortex (MC) is a traditional Chinese medicine with diverse biological effects. The present study was performed to investigate the effects of MC on myocardial ischemia/reperfusion (I/R) in rats and to explore its possible mechanisms. Sprague-Dawley rats were administered MC extract (1.98 g/kg, i.g.) for 14 days and underwent a subsequent open-chest procedure involving 30 min of myocardial ischemia and 60 min of reperfusion. The cardioprotective effect of MC was demonstrated by reduced infarct size and marked improvement in the histopathological examination. The increase in the activity of superoxide dismutase (SOD) and glutathione (GSH) as well as the reduction of malondialdehyde (MDA) indicated that MC effectively promoted the anti-oxidative defense system. Increased anti-oxidative defense was accompanied by decreased release of lactate dehydrogenase (LDH) and creatine kinase (CK). The reduction in TUNEL-positive myocytes demonstrated that MC decreased myocardial apoptosis. The mRNA expression of B cell leukemia-2 (Bcl-2) was upregulated by MC and the ratio of Bcl-2/Bcl-2 associated X protein (Bax) mRNA expression was increased. MC pretreatment decreased the mRNA expression of inducible nitric oxide synthase (iNOS). The data from this study suggest that MC exerted protective effects on acute myocardial I/R injury via anti-oxidative and anti-apoptotic activities. PMID- 26610044 TI - Remodeling of Noncrosslinked Acellular Dermal Matrices in a Rabbit Model of Ventral Hernia Repair. AB - BACKGROUND: Bioprostheses represent a significant advance in the abdominal wall reconstruction since they become degraded until their complete elimination in the recipient organism. This study examines remodeling in the host of three noncrosslinked porcine dermal collagen biomeshes: StratticeTM (St; LifeCell Corp.), XCM Biologic(r) Tissue Matrix (XCM; Synthes CMF) and Protexa(r) (Pr; Deco Med S.R.L.). METHODS: Partial ventral hernia defects created in New Zealand White rabbits were repaired using the biomeshes that were placed in an inlay, preperitoneal position. At 14 and 90 days after implantation, explants were assessed in terms of their host tissue incorporation by morphological studies, collagen gene/protein expression (quantitative real-time PCR/immunofluorescence), macrophage response (immunohistochemistry) and biomechanical strength. RESULTS: There were no cases of mortality or infection. Among our macroscopic findings, the mesh detachment detected in one third of the Pr implants at 90 days was of note. The host tissue response to all the biomeshes was similar at both time points, with a tendency observed for their encapsulation. There were no appreciable signs of mesh degradation. The extent of host tissue infiltration and collagenization was greater for St and Pr than for XCM. Macrophages were observed in zones of inflammation and tissue infiltration inside the mesh. XCM showed a greater macrophage response at 90 days (p < 0.05). Improved tensile strength was observed for St (p < 0.05) over Pr and unrepaired defects. CONCLUSIONS: St showed the best behavior, featuring good collagenization and tensile strength while also inducing a minimal foreign body reaction. PMID- 26610045 TI - The Relationship between Sleep Length and Restorative Sleep in Major Depression: Results from the Danish General Suburban Population Study. PMID- 26610046 TI - Inositide-dependent signaling pathways as new therapeutic targets in myelodysplastic syndromes. AB - INTRODUCTION: Nuclear inositide signaling pathways specifically regulate cell proliferation and differentiation. Interestingly, the modulation of nuclear inositides in hematological malignancies can differentially affect erythropoiesis or myelopoiesis. This is particularly important in patients with myelodysplastic syndromes (MDS), who show both defective erythroid and myeloid differentiation, as well as an increased risk of evolution into acute myeloid leukemia (AML). AREAS COVERED: This review focuses on the structure and function of specific nuclear inositide enzymes, whose impairment could be linked with disease pathogenesis and cancer. The authors, stemming from literature and published data, discuss and describe the role of nuclear inositides, focusing on specific enzymes and demonstrating that targeting these molecules could be important to develop innovative therapeutic approaches, with particular reference to MDS treatment. EXPERT OPINION: Demethylating therapy, alone or in combination with other drugs, is the most common and current therapy for MDS patients. Nuclear inositide signaling molecules have been demonstrated to be important in hematopoietic differentiation and are promising new targets for developing a personalized MDS therapy. Indeed, these enzymes can be ideal targets for drug design and their modulation can have several important downstream effects to regulate MDS pathogenesis and prevent MDS progression to AML. PMID- 26610047 TI - Profiles in drug metabolism and toxicology: Richard Tecwyn Williams (1909-1979). AB - This article pays homage to the life and work of a veritable pioneer in toxicology and drug metabolism, namely a Welshman, Richard Tecwyn Williams, FRS. Professor Williams, or RT as he was known, made major contributions to knowledge about the metabolism and toxicology of drugs and xenobiotics during a scientific career spanning nearly 50 years. Author or coauthor of close to 400 research articles and reviews, including a classic book, entitled Detoxication Mechanisms, Williams and his research school investigated virtually all aspects of drug metabolism, especially conjugations. In particular, the concepts of phase 1 and phase II metabolic pathways were introduced by Williams; the biliary excretion of drugs was extensively studied as were species differences in drug metabolism and detoxication. Besides investigating the metabolism of many pharmaceutical drugs, such as sulfonamides and thalidomide, Williams and his group investigated the disposition and fate in the body of organic pesticides and recreational drugs of abuse, such as amphetamine, methamphetamine and lysergic acid diethylamide (LSD). PMID- 26610048 TI - The Concept of Euthymia. PMID- 26610049 TI - Self-Report Daily Life Activity as a Prognostic Marker of Idiopathic Pulmonary Fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease, leading to substantial physical impairment. The distance walked in 6 min (6MWD) is a measure of exercise tolerance and is of prognostic relevance in IPF. While 6MWD is a punctual measurement which may not be representative, self-reported daily life activity may represent the patients' functional capacity more globally even in less severe affected patients. OBJECTIVES: We evaluated and characterized a simple classification system based on the patients' self-reported daily activity and analyzed if this would add significantly to the prognostic information of the 6MWD alone in IPF patients. METHODS: Daily life activity was assessed in IPF (n = 156) patients with standardized questions and categorized in activity classes (AC I-IV), comprising the less severe impaired in AC I and II. The 6MWD was also assessed. RESULTS: ACs were related to the lung functional impairment and inversely correlated to the 6MWD. Thirty-two patients were in AC I/II, 98 in AC III and 26 patients in AC IV. Thirty-seven (23.7%) patients died during a median follow-up of 14.9 months, comprising 1 patient in AC I/II. In addition, a 6MWD <470 m predicted mortality. Combining AC I/II and a 6MWD >470 m identified a subgroup of patients with favorable outcome. CONCLUSIONS: AC is a novel scoring system which can easily be obtained and correlates with lung functional and physical impairments as well as mortality. Moreover, AC adds prognostic information to the 6MWD. PMID- 26610050 TI - New data analysis in a population study raises the hypothesis that particle size contributes to the pro-asthmatic potential of small pet animal allergens. AB - BACKGROUND: The size of inhaled particles influences where they deposit and theoretically should be important for the development of airway inflammation and responsiveness. Our aim was to assess if sensitization to smaller-sized aeroallergens relates to higher prevalence of treated asthma, increased airway responsiveness, and airway and systemic inflammation. METHODS: Molecular-based IgE antibody determination was done in 467 subjects. Sensitized subjects were grouped based on the particle size of the aeroallergen: (1) Large particles only (mainly pollen); (2) Medium-sized particles (sensitized to mainly mite and mold and possibly to large particles); and 3) Small particles (sensitized to pet allergens and possibly to medium- and/or large-sized particles). Airway responsiveness to methacholine, exhaled nitric oxide (FENO), and serum eosinophil cationic protein (S-ECP) were measured. Asthma and rhinitis were questionnaire assessed. RESULTS: Subjects sensitized to small particles had higher prevalence of treated asthma (35% versus 10%, P < 0.001), higher FENO50 (32 versus 17 ppb, P < 0.001), higher S-ECP (10 versus 7.5 ng/mL, P = 0.04), and increased bronchial responsiveness (dose-response slope, 5.6 versus 7.5, P < 0.001) compared with non atopics. This was consistent after adjusting for potential confounders. Sensitization to only large or to medium and possibly also large aeroallergen particles was not related to any of these outcomes after adjustments. CONCLUSIONS: Sensitization to smaller particles was associated with a higher prevalence of asthma under treatment, higher airway responsiveness, and airway and systemic inflammation. Mapping of IgE sensitization to small particles might help to detect subjects having increased airway and systemic inflammation and bronchial responsiveness, indicating increased risk of developing asthma. PMID- 26610051 TI - Omega-3 Fatty Acids and Age-Related Macular Degeneration. AB - Against a background of considerable epidemiological and other evidence implicating omega-3 fatty acids in the prevention of age-related macular degeneration (AMD), the negative results of the Age-Related Disease Study 2 (AREDS2) were unexpected. The possibility that the design, setting, intake or subjects of AREDS2 may not have permitted the prophylactic potential of omega-3 to be adequately demonstrated is considered. Epidemiological studies had indicated potential preventative effects of omega-3, and an earlier randomised prospective study (NAT2) showed that patients who achieved high red blood cell membrane EPA/DHA (eicosapentaenoic acid/docosahexaenoic acid) levels were significantly protected against AMD compared with those with permanently low EPA/DHA levels. Various methodological differences between these studies are considered. NAT2 included a true placebo group, whereas control subjects in AREDS2 received a nutritional formula already found to be effective in AREDS1, but no placebo for DHA/EPA supplementation. Differences in the handling of non compliant subjects and the formulation of the test formulations are considered. Given these considerations, and other lines of evidence from laboratory and clinical studies, closing the chapter on omega-3 in AMD prevention may be premature. PMID- 26610052 TI - ST waveform analysis versus cardiotocography alone for intrapartum fetal monitoring: a systematic review and meta-analysis of randomized trials. AB - INTRODUCTION: ST waveform analysis was introduced to reduce metabolic acidosis at birth and avoid unnecessary operative deliveries relative to conventional cardiotocography. Our objective was to quantify the efficacy of ST waveform analysis vs. cardiotocography and assess the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation tool. MATERIAL AND METHODS: We identified randomized controlled trials through systematic literature searches and assessed included studies for risk of bias. Meta-analyses were performed, calculating pooled risk ratio or peto odds ratio. We performed post hoc trial sequential analyses for selected outcomes to assess the risk of false-positive results and the need for additional studies. RESULTS: Six randomized controlled trials were included in the meta-analysis. ST waveform analysis was not associated with a reduction in operative deliveries due to fetal distress, but we observed a significantly lower rate of metabolic acidosis (peto odds ratio 0.64; 95% confidence interval 0.46-0.88). Accordingly, 401 women need to be monitored with ST waveform analysis to prevent one case of metabolic acidosis. No statistically significant effects were observed in other fetal or neonatal outcomes, except from fetal blood sampling (risk ratio 0.59; 95% confidence interval 0.45-0.79) and a minor reduction in the number of operative vaginal deliveries for all indications (risk ratio 0.92; 95% confidence interval 0.86-0.99). The quality of the evidence was high to moderate. CONCLUSIONS: Absolute effects of ST waveform analysis were minor, and the clinical significance of the observed reduction in metabolic acidosis is questioned. There is not enough evidence to justify the use of ST waveform analysis in contemporary obstetrics. PMID- 26610053 TI - Hydrogen atom transfer reactions of ferrate(VI) with phenols and hydroquinone. Correlation of rate constants with bond strengths and application of the Marcus cross relation. AB - The oxidation of phenols by HFeO4(-) proceeds via a hydrogen atom transfer (HAT) mechanism, as evidenced by a large deuterium isotope effect and a linear correlation between the log(rate constant) and bond dissociation free energy (BDFE) of phenols. The Marcus cross relation has been applied to predict the rate constant of HAT from hydroquinone to HFeO4(-). PMID- 26610054 TI - Psychometric Properties of the Survey of Workplace Intimidation Instrument. AB - BACKGROUND AND PURPOSE: The purpose of this study was to assess the psychometric properties of the Survey of Workplace Intimidation (SWI), including content and construct validity, factor structure, and internal consistency. METHODS: A cross sectional, descriptive study design was used for this study. The final sample consisted of 237 labor and delivery nurses who completed the SWI and the Practice Environment Scale of the Nursing Work Index (PES-NWI). Cronbach's alpha for the SWI was .930. RESULTS: Content validity was obtained and the scale content validity index (S-CVI) was .943. Convergent validity was calculated by comparing the SWI with the PES-NWI, and the result was .408 (p = .01). A factor analysis explained 61% of the variance and resulted in two factors: prescriber behaviors and nurses' responses to prescribers' behaviors. CONCLUSIONS: The SWI demonstrated acceptable reliability and validity. PMID- 26610055 TI - Identifying and Addressing Sources of Measurement Error in the Norbeck Social Support Questionnaire. AB - BACKGROUND AND PURPOSE: The Norbeck Social Support Questionnaire (NSSQ) provides a rich portrait of one's perceived social support including network size/composition and quality of support. Analyses of quantitative research reports and critiques of the NSSQ revealed non-negligible measurement error. We document evidence of measurement error, report potential sources of this error, and present forthcoming psychometric testing. METHODS: Quantitative evidence of measurement error from the NSSQ literature provided the basis for initial hypotheses concerning sources of error in network nomination and support ratings. We then conducted cognitive interviews to investigate these hypotheses. RESULTS: Cognitive interviews revealed evidence of respondents' miscomprehension and response option bias. CONCLUSIONS: The current nomination process coupled with the lack of a "not applicable" response option and embedded examples in tangible Aid items reduces the accuracy of NSSQ subscores. PMID- 26610056 TI - The Modified-Fetzer Multidimensional Measure of Religiousness and Spirituality: Examination of Construct Validity in Older Black Adults. AB - BACKGROUND AND PURPOSE: Sociocultural explanatory frameworks are increasingly being considered to address causes of health disparities, and attention has been focused on religion among Black Americans and its subsequent influence on health. The purpose of this study was to examine a multidimensional measure of religiousness and spirituality (Modified-Fetzer Multidimensional Measure of Religiousness and Spirituality [M-FMMRS]) in a sample of Black older adults. METHODS: The M-FMMRS was administered to 130 study participants, and confirmatory factor analysis was conducted. RESULTS: Findings did not support the hypothesized factor structure. CONCLUSIONS: Overall, the M-FMMRS is a reliable survey, but the validity needs to be further addressed. Historical documentation, review of data, and participant feedback are used to examine findings. PMID- 26610057 TI - Henoch Schonlein purpura associated with bee sting: case report. AB - Henoch Schonlein purpura (HSP) is a common childhood vasculitis, characterized by a non-thrombocytopenic palpable purpura and systemic features. It can be triggered by conditions like infections and insect bites. We present the case of a six-year-old girl with palpable maculopapular lesions on the lower limbs, itching, mild pain, swelling of feet, limitation of limb mobility, and a history of bee sting. Thigh skin biopsy was performed, with a report of leucocytoclastic vasculitis, and was diagnosed as HSP. She was prescribed bed rest, and was given oral hydration. The patient outcome was favorable and was discharged after five days. This is the fifth report of a HSP case associated with a bee sting with an uncomplicated course, which is in contrast to previous case reports. PMID- 26610058 TI - Rapid evolution of metabolic traits explains thermal adaptation in phytoplankton. AB - Understanding the mechanisms that determine how phytoplankton adapt to warming will substantially improve the realism of models describing ecological and biogeochemical effects of climate change. Here, we quantify the evolution of elevated thermal tolerance in the phytoplankton, Chlorella vulgaris. Initially, population growth was limited at higher temperatures because respiration was more sensitive to temperature than photosynthesis meaning less carbon was available for growth. Tolerance to high temperature evolved after ~ 100 generations via greater down-regulation of respiration relative to photosynthesis. By down regulating respiration, phytoplankton overcame the metabolic constraint imposed by the greater temperature sensitivity of respiration and more efficiently allocated fixed carbon to growth. Rapid evolution of carbon-use efficiency provides a potentially general mechanism for thermal adaptation in phytoplankton and implies that evolutionary responses in phytoplankton will modify biogeochemical cycles and hence food web structure and function under warming. Models of climate futures that ignore adaptation would usefully be revisited. PMID- 26610059 TI - Cost-effectiveness of Ombitasvir/Paritaprevir/Ritonavir, Dasabuvir+Ribavirin for US Post-Liver Transplant Recurrent Genotype 1 HCV. AB - BACKGROUND & AIMS: Orthotopic liver transplant patients with recurrent hepatitis C (HCV) historically have had limited treatment options. Ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin (3D+R) was approved by the FDA in December 2014 for liver transplant recipients with recurrent genotype 1 HCV, in whom it is effective and well-tolerated. METHODS: Using a two-phase Markov model, we analysed the cost-effectiveness of 3D+R in liver transplant recipients, the only HCV treatment with FDA approval in this population. As a sensitivity analysis, we also considered the cost-effectiveness of pegylated interferon plus ribavirin, the only other therapy with data from Phase III trials in this population. Patients were given one of three options: 3D+R for 24 weeks, pegylated interferon and ribavirin for 48 weeks (PR48) or no treatment (NT). Patients were then followed through subsequent disease progression until death. Outcome measures analysed were: lifetime risks of liver morbidity and mortality, treatment costs, non-treatment medical expenditures, and quality-adjusted life years. RESULTS: Treatment with 3D+R was associated with a significantly lower lifetime risk of liver-related morbidity and mortality than treatment with PR48 or NT. 3D+R also was associated with a higher gain in quality-adjusted life years (11.3 compared to 8.25 with NT) and lower discounted overall costs ($423,585 compared to $724,757 with NT). CONCLUSIONS: The use of 3D+R for liver transplant recipients with recurrent HCV is an outcome-improving and cost-effective regimen for this population with limited treatment options and large unmet need. PMID- 26610060 TI - Cystic echinococcosis in South America: systematic review of species and genotypes of Echinococcus granulosus sensu lato in humans and natural domestic hosts. AB - OBJECTIVE: To systematically review publications on Echinococcus granulosus sensu lato species/genotypes reported in domestic intermediate and definitive hosts in South America and in human cases worldwide, taking into account those articles where DNA sequencing was performed; and to analyse the density of each type of livestock that can act as intermediate host, and features of medical importance such as cyst organ location. METHODS: Literature search in numerous databases. We included only articles where samples were genotyped by sequencing since to date it is the most accurate method to unambiguously identify all E. granulosus s. l. genotypes. Also, we report new E. granulosus s. l. samples from Argentina and Uruguay analysed by sequencing of cox1 gene. RESULTS: In South America, five countries have cystic echinococcosis cases for which sequencing data are available: Argentina, Brazil, Chile, Peru and Uruguay, adding up 1534 cases. E. granulosus s. s. (G1) accounts for most of the global burden of human and livestock cases. Also, E. canadensis (G6) plays a significant role in human cystic echinococcosis. Likewise, worldwide analysis of human cases showed that 72.9% are caused by E. granulosus s. s. (G1) and 12.2% and 9.6% by E. canadensis G6 and G7, respectively. CONCLUSIONS: E. granulosus s. s. (G1) accounts for most of the global burden followed by E. canadensis (G6 and G7) in South America and worldwide. This information should be taken into account to suit local cystic echinococcosis control and prevention programmes according to each molecular epidemiological situation. PMID- 26610061 TI - T cell epitope immunotherapy ameliorates allergic responses in a murine model of shrimp allergy. AB - BACKGROUND: Shellfish allergy is one of the most common food hypersensitivities worldwide but allergen-specific immunotherapy for shellfish allergy is not yet available. We believe that T cell peptide-based immunotherapy holds the potential for modulating allergic responses without IgE cross-linking. OBJECTIVE: We sought to identify the immunodominant T cell epitopes of tropomyosin, the major shrimp allergen of Metapenaeus ensis (Met e 1), and to evaluate their therapeutic effects in a Balb/c mouse model of Met e 1 hypersensitivity. METHODS: T cell epitopes of Met e 1 were first identified based on the proliferation and cytokine responses of splenocytes isolated from Met e 1-sensitized Balb/c mice upon stimulation by 18 synthetic peptides that span the full-length Met e 1. The immunodominant T cell peptides identified were then fed orally to Met e 1 sensitized Balb/c mice twice a week for four weeks. Allergic responses, serological antibody levels, intestinal histology and systemic and local cytokine profiles were compared between the treated and the untreated groups. RESULTS: Six major Met e 1 T cell epitopes were identified. Mice treated with the T cell epitope peptide mixture demonstrated an amelioration of systemic allergic symptoms and a significant reduction in Th2-associated antibody and cytokine responses. These benefits were accompanied by a shift to a balanced Th1/Th2 response, induction of IgG2a antibodies possessing in vitro and in vivo blocking activities and the induction of regulatory T cell responses. CONCLUSIONS AND CLINICAL RELEVANCE: T cell epitope-based oral immunotherapy is effective in reducing allergic responses towards shrimp tropomyosin. This is a novel strategy for clinical management of shellfish allergy and is a model for mechanistic studies of oral immunotherapy. PMID- 26610062 TI - Subcutaneous perfusion before and during surgery in obese and nonobese patients. AB - Hypoxia at the surgical site impairs wound healing and oxidative killing of microbes. Surgical site infections are more common in obese patients. We hypothesized that subcutaneous oxygen tension (Psq O2) would decrease substantially in both obese and non-obese patients following induction of anesthesia and after surgical incision. We performed a prospective observational study that enrolled obese and non-obese surgical patients and measured serial Psq O2 before and during surgery. Seven morbidly obese and seven non-obese patients were enrolled. At baseline breathing room air, Psq O2 values were not significantly different (p = 0.66) between obese (6.8 kPa) and non-obese (6.5 kPa) patients. The targeted arterial oxygen tension (40 kPa) was successfully achieved in both groups with an expected significant increase in Psq O2 (obese 16.1 kPa and non-obese 13.4 kPa; p = 0.001). After induction of anesthesia and endotracheal intubation, Psq O2 did not change significantly in either cohort in comparison to levels right before induction (obese 15.5, non-obese 13.5 kPa; p = 0.95), but decreased significantly during surgery (obese 10.1, non-obese 9.3 kPa; p = 0.01). In both morbidly obese and non-obese patients, Psq O2 does not decrease appreciably following induction of anesthesia, but decreases markedly (~33%) after commencement of surgery. Given the theoretical risks associated with low Psq O2 , future research should investigate how Psq O2 can be maintained after surgical incision. PMID- 26610063 TI - Contribution of human-related sources to indoor volatile organic compounds in a university classroom. AB - Although significant progress has been made in understanding the sources and chemistry of indoor volatile organic compounds (VOCs) during the past decades, much is unknown about the role of humans in indoor air chemistry. In the spring of 2014, we conducted continuous measurements of VOCs using a proton transfer reaction mass spectrometer (PTR-MS) in a university classroom. Positive matrix factorization (PMF) of the measured VOCs revealed a 'human influence' component, which likely represented VOCs produced from human breath and ozonolysis of human skin lipids. The concentration of the human influence component increased with the number of occupants and decreased with ventilation rate in a similar way to CO2 , with an average contribution of 40% to the measured daytime VOC concentration. In addition, the human skin lipid ozonolysis products were observed to correlate with CO2 and anticorrelate with O3 , suggesting that reactions on human surfaces may be important sources of indoor VOCs and sinks for indoor O3 . Our study suggests that humans can substantially affect VOC composition and oxidative capacity in indoor environments. PMID- 26610064 TI - Atorvastatin acutely reduces the reactivity to spasmogens in rat aorta: implication of the inhibition of geranylgeranylation and MYPT-1 phosphorylation. AB - Statins are known to display benefits in various diseases independently from their cholesterol lowering properties. In this study, we investigated the acute effects of atorvastatin on vascular reactivity to various spasmogens in isolated rat aorta. The responses to noradrenaline (NA, 10(-8) -10(-4) m), endothelin-1 (ET-1, 10(-10) -10(-7) m), and potassium chloride (KCl, 10-100 mm) were evaluated in aortic rings pretreated with atorvastatin (10(-7) -10(-4) m, 30 min). To verify the mechanism of action, the effects of atorvastatin were studied in the presence of cholesterol precursor, mevalonate (10(-2) m, 45 min), mevalonate derived isoprenoids, namely geranylgeranyl pyrophosphate (GGPP, 5 * 10(-6) m, 30 min) and farnesyl pyrophosphate (FPP, 5 * 10(-6) m, 30 min), and in the absence of endothelium. In parallel, aortic rings were pretreated with the specific inhibitor of Rho kinase, Y-27632 (10(-7) -10(-6) m). Atorvastatin significantly and concentration-dependently reduced the contractions to spasmogens in rat aorta. This acute inhibitory effect was also evident in endothelium-denuded rings. Pretreatment with mevalonate and GGPP, but not with FPP, reversed the inhibitory effect of atorvastatin (10(-4) m) on NA and ET-1 induced contractions. Similar to atorvastatin, pretreatment with Y-27632 inhibited the contractions to NA and KCl in a concentration-dependent manner. Western blot analysis revealed that both atorvastatin (10(-4) m) and Y-27632 (10(-6) m) pretreatment inhibited the phosphorylation of myosin phosphatase target subunit-1 (MYPT-1) triggered by NA, indicating an inhibitory influence on myosin phosphatase. In conclusion, atorvastatin displayed an acute inhibitory effect on vascular contractility evoked by various spasmogens and the inhibitory effect was possibly mediated by the inhibition of mevalonate and GGPP synthesis as well as the prevention of MYPT 1 phosphorylation induced by Rho/Rho kinase. PMID- 26610065 TI - Electrode Build-Up of Reducible Metal Composites toward Achievable Electrochemical Conversion of Carbon Dioxide. AB - At the beginning of the 21st century, our world is faced with a global-warming problem due to the continuous increase in carbon dioxide emission, and thus, the development of novel experimental techniques is needed. The electrochemical conversion of carbon dioxide into high-value organic compounds could be of vital importance to solve this issue. The biggest challenge has always been to develop an electrocatalyst that is chemically active and structurally stable. Herein, previous studies, recent approaches, and current points of view on the electrode structure of metal oxide composites for the advanced electrochemical conversion of carbon dioxide are reviewed. PMID- 26610066 TI - Primary skeletal muscle cells cultured on gelatin bead microcarriers develop structural and biochemical features characteristic of adult skeletal muscle. AB - A primary skeletal muscle cell culture, in which myoblasts derived from newborn rabbit hindlimb muscles grow on gelatin bead microcarriers in suspension and differentiate into myotubes, has been established previously. In the course of differentiation and beginning spontaneous contractions, these multinucleated myotubes do not detach from their support. Here, we describe the development of the primary myotubes with respect to their ultrastructural differentiation. Scanning electron microscopy reveals that myotubes not only grow around the surface of one carrier bead but also attach themselves to neighboring carriers, forming bridges between carriers. Transmission electron microscopy demonstrates highly ordered myofibrils, T-tubules, and sarcoplasmic reticulum. The functionality of the contractile apparatus is evidenced by contractile activity that occurs spontaneously or can be elicited by electrostimulation. Creatine kinase activity increases steadily until day 20 of culture. Regarding the expression of isoforms of myosin heavy chains (MHC), we could demonstrate that from day 16 on, no non-adult MHC isoform mRNAs are present. Instead, on day 28 the myotubes express predominantly adult fast MHCIId/x mRNA and protein. This MHC pattern resembles that of fast muscles of adult rabbits. In contrast, primary myotubes grown on matrigel-covered culture dishes express substantial amounts of non-adult MHC protein even on day 21. To conclude, primary myotubes grown on microcarriers in their later stages exhibit many features of adult skeletal muscle and characteristics of fast type II fibers. Thus, the culture represents an excellent model of adult fast skeletal muscle, for example, when investigating molecular mechanisms of fast-to-slow fiber-type transformation. PMID- 26610067 TI - Lumbar spine endplate fractures: Biomechanical evaluation and clinical considerations through experimental induction of injury. AB - Lumbar endplate fractures were investigated in different experimental scenarios, however the biomechanical effect of segmental alignment was not outlined. The objectives of this study were to quantify effects of spinal orientation on lumbar spine injuries during single-cycle compressive loads and understand lumbar spine endplate injury tolerance. Twenty lumbar motion segments were compressed to failure. Two methods were used in the preparation of the lumbar motion segments. Group 1 (n = 7) preparation maintained pre-test sagittal lordosis, whereas Group 2 (n = 13) specimens had a free-rotational end condition for the cranial vertebra, allowing sagittal rotation of the cranial vertebra to create parallel endplates. Five Group 1 specimens experienced posterior vertebral body fracture prior to endplate fracture, whereas two sustained endplate fracture only. Group 2 specimens sustained isolated endplate fractures. Group 2 fractures occurred at approximately 41% of the axial force required for Group 1 fracture (p < 0.05). Imaging and specimen dissection indicate endplate injury consistently took place within the confines of the endplate boundaries, away from the vertebral periphery. These findings indicate that spinal alignment during compressive loading influences the resulting injury pattern. This investigation identified the specific mechanical conditions under which an endplate breach will take place. Development of endplate injuries has significant clinical implication as previous research identified internal disc disruption (IDD) and degenerative disc disease (DDD) as long-term consequences of the axial load-shift that occurs following a breach of the endplate. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1084-1091, 2016. PMID- 26610068 TI - Outcomes of adult-to-adult living donor liver transplantation in 321 recipients. AB - We conducted a retrospective investigation in order to clarify whether selecting the type of liver graft had an impact on outcomes of adult-to-adult living donor liver transplantation (AALDLT). Data from the medical records of the donors and the recipients of 321 consecutive cases of AALDLT performed between April 2004 and March 2014 were retrospectively analyzed. Our general criteria for selecting the type of liver graft was that a left graft was preferentially selected when the estimated volume of the left graft was >=35% of the standard liver volume of the recipient, and that a right graft was selected only when the estimated remnant liver volume of the donor was >=35% of the total liver volume. In this series, 177 left grafts, 136 right grafts, and 8 posterior grafts were used. The left grafts tended to have 2 or more arteries, whereas the right grafts tended to have 2 or more bile duct orifices. The graft survival curves and the incidences of severe complications were comparable between the AALDLT using right grafts and the AALDLT using left grafts. The preoperative estimation of graft size hardly enabled us to predict severe posttransplant complication. Moreover, small-for size graft syndrome occurred regardless of the estimated graft volumes. Instead, donor age was a significant risk factor for small-for-size graft syndrome. In conclusion, left grafts should be more aggressively used for the sake of donors' safety. The use of hepatic grafts from older donors should be avoided if possible in order to circumvent troublesome posttransplant complications. PMID- 26610069 TI - Gold-Catalyzed C-H Annulation of Anthranils with Alkynes: A Facile, Flexible, and Atom-Economical Synthesis of Unprotected 7-Acylindoles. AB - The gold-catalyzed C-H annulation of anthranil derivatives with alkynes offers a facile, flexible, and atom-economical one-step route to unprotected 7 acylindoles. An intermediate alpha-imino gold carbene, generated by an intermolecular reaction, promotes ortho-aryl C-H functionalization to afford the target products. The transformation proceeds with a broad range of substrates under mild conditions. Moreover, the obtained functionalized indole products represent a versatile platform for the construction of diverse indolyl frameworks. PMID- 26610070 TI - Tailoring the Composition of Bio-oil by Vapor-Phase Removal of Organic Acids. AB - Selective removal of organic acids from biomass pyrolysis vapors was demonstrated. A broad adsorbent range was tested with CaCO3 showing the best selectivity. Extensive material characterization demonstrated that the acid removal occurred through monolayer adsorption on CaCO3. Adsorbent regeneration was achieved by in situ heat treatment of the postreaction adsorbent where the adsorbed acid was converted into a ketone. The mitigation of the loss of other products was achieved by using surface modified CaCO3 materials, resulting in a significant improvement in the selectivity toward organic acid removal. The surface modification appeared to lead to formation of a metal-carboxylate intermediate consisting of both acetate and carbonate groups. Acetate group on the CaCO3 surface resulted in the suppression of side reactions. Generally, a higher acid removal was accompanied with a greater loss of other compounds, which could be tuned by using CaCO3 with different surface modification. PMID- 26610071 TI - "SAFEGUARDING THE INTERESTS OF THE STATE" FROM DEFECTIVE DELINQUENT GIRLS. AB - The 1911 mental classification, "defective delinquent," was created as a temporary legal-medical category in order to identify a peculiar class of delinquent girls in a specific institutional setting. The defective delinquent's alleged slight mental defect, combined with her appearance of normalcy, rendered her a "dangerous" and "incurable" citizen. At the intersection of institutional history and the history of ideas, this article explores the largely overlooked role of borderline mental classifications of near-normalcy in the medicalization of intelligence and criminality during the first third of the twentieth-century United States. Borderline classifications served as mechanisms of control over women's bodies through the criminalization of their minds, and the advent of psychometric tests legitimated and facilitated the spread of this classification beyond its original and intended context. The borderline case of the defective delinquent girl demonstrates the significance of marginal mental classifications to the policing of bodies through the medicalization of intellect. PMID- 26610072 TI - Crossover learning of gestures in two ideomotor apraxia patients: A single case experimental design study. AB - Crossover learning may aid rehabilitation in patients with neurological disorders. Ideomotor apraxia (IMA) is a common sequela of left-brain damage that comprises a deficit in the ability to perform gestures to verbal commands or by imitation. This study elucidated whether crossover learning occurred in two post stroke IMA patients without motor paralysis after gesture training approximately 2 months after stroke onset. We quantitatively analysed the therapeutic intervention history and investigated whether revised action occurred during gesture production. Treatment intervention was to examine how to influence improvement and generalisation of the ability to produce the gesture. This study used an alternating treatments single-subject design, and the intervention method was errorless learning. Results indicated crossover learning in both patients. Qualitative analysis indicated that revised action occurred during the gesture production process in one patient and that there were two types of post-revised action gestures: correct and incorrect gestures. We also discovered that even when a comparably short time had elapsed since stroke onset, generalisation was difficult. Information transfer between the left and right hemispheres of the brain via commissural fibres is important in crossover learning. In conclusion, improvements in gesture-production skill should be made with reference to the left cerebral hemisphere disconnection hypothesis. PMID- 26610073 TI - Twenty-two-item Sino-Nasal Outcome Test in a control population: a cross sectional study and systematic review. AB - BACKGROUND: The 22-item Sino-Nasal Outcome Test (SNOT-22) is a commonly utilized outcome measure for chronic rhinosinusitis (CRS). However, what constitutes a normal score remains poorly defined. The goal of this study was to evaluate SNOT 22 scores in a control population without CRS and perform a systematic review and meta-analysis of "normal" values. METHODS: Ninety-nine subjects without CRS were enrolled, with 95 fully completing the SNOT-22 questionnaire. Multivariable linear regression was used to determine whether demographic factors or medical comorbidities influence SNOT-22 scores in a population without CRS. A systematic literature search was performed, identifying studies that evaluated the SNOT-22 in a non-CRS population and estimates for SNOT-22 values were pooled. RESULTS: Thirty-six males and 59 females were included in the primary analysis with a mean age of 53.4 +/- 17.3 years (range, 18-88 years). The mean SNOT-22 score was 16.4 +/- 15.2. Asthma (p = 0.003) and depression (p = 0.002) were found to be independent predictors of higher SNOT-22 scores. Thirteen articles were identified in the literature search and 1 was provided via author correspondence, with 10 reporting sufficient data to be included in the meta-analysis. Weighted mean SNOT-22 score was 11 +/- 9.4 (n = 1517). Our data differed significantly from published data (mean difference = 5.4; 95% confidence interval [CI], 3.4 to 7.5; p < 0.0001) likely owing to differences in comorbidities. CONCLUSION: SNOT 22 scores vary in non-CRS populations depending upon the group queried. Asthma and depression are associated with higher SNOT-22 scores and should be considered when determining what constitutes a normal value. PMID- 26610074 TI - Peripheral blood gene expression analysis implicates B lymphocyte proliferation and ribosomal S26 transcripts in cognitive dysfunction in people with remitted Major Depression. PMID- 26610075 TI - Harnessing cellular-derived forces in self-assembled microtissues to control the synthesis and alignment of ECM. AB - The alignment and blend of extracellular matrix (ECM) proteins give a tissue its specific mechanical properties as well as its physiological function. Various tissue engineering methods have taken purified ECM proteins and aligned them into gels, sponges and threads. Although, each of these methods has created aligned ECM, they have had many limitations including loss of hierarchal collagen structure and poor mechanical performance. Here, we have developed a new method to control ECM synthesis using self-assembled cells. Cells were seeded into custom designed, scaffold-free, micro-molds with fixed obstacles that harnessed and directed cell-mediated stresses. Cells within the microtissue reacted to self generated tension by aligning, elongating, and synthesizing an ECM whose organization was dictated by the strain field that was set by our micro-mold design. We have shown that through cell selection, we can create tissues with aligned collagen II or aligned elastin. We have also demonstrated that these self assembled microtissues have mechanical properties in the range of natural tissues and that mold design can be used to further tailor these mechanical properties. PMID- 26610076 TI - The influence of the polar head-group of synthetic cationic lipids on the transfection efficiency mediated by niosomes in rat retina and brain. AB - The development of novel non-viral delivery vehicles is essential in the search of more efficient strategies for retina and brain diseases. Herein, optimized niosome formulations prepared by oil-in water (o/w) and film-hydration techniques were characterized in terms of size, PDI, zeta potential, morphology and stability. Three ionizable glycerol-based cationic lipids containing a primary amine group (lipid 1), a triglycine group (lipid 2) and a dimethylamino ethyl pendent group (lipid 3) as polar head-groups were part of such niosomes. Upon the addition of pCMS-EGFP plasmid, nioplexes were obtained at different cationic lipid/DNA ratios (w/w). The resultant nioplexes were further physicochemically characterized and evaluated to condense, release and protect the DNA against enzymatic digestion. In vitro experiments were performed to evaluate transfection efficiency and cell viability in HEK-293, ARPE-19 and PECC cells. Interestingly, niosome formulations based on lipid 3 showed better transfection efficiencies in ARPE-19 and PECC cells than the rest of cationic lipids showed in this study. In vivo experiments in rat retina after intravitreal and subretinal injections together with in rat brain after cerebral cortex administration showed promising transfection efficiencies when niosome formulations based on lipid 3 were used. These results provide new insights for the development of non-viral vectors based on cationic lipids and their applications for efficient delivery of genetic material to the retina and brain. PMID- 26610077 TI - Modeling the community-level effects of male incarceration on the sexual partnerships of men and women. AB - Men who have been incarcerated experience substantial changes in their sexual behavior after release from jail and prison, and high rates of incarceration may change sexual relationship patterns at a community level. Few studies, however, address how rates of incarceration affect community patterns of sexual behavior, and the implications of those patterns for HIV and STD risk. We describe a "proof of principle" computational model that tests whether rates of male incarceration could, in part, explain observed population-level differences in patterns of sexual behavior between communities with high rates of incarceration and those without. This validated agent-based model of sexual partnership among 20-25 year old heterosexual urban residents in the United States uses an algorithm that incarcerates male agents and then releases them back into the agent community. The results from these model experiments suggest that at rates of incarceration similar to those observed for urban African American men, incarceration can cause an increase in the number of partners at the community level. The results suggest that reducing incarceration and creating a more open criminal justice system that supports the maintenance of inmates' relationships to reduce instability of partnerships for men who are incarcerated may have important sexual health and public health implications. Incarceration is one of many social forces that affect sexual decision-making, and incarceration rates may have substantial effects on community-level HIV and STD risks. PMID- 26610078 TI - Dynamic impact of social stratification and social influence on smoking prevalence by gender: An agent-based model. AB - Smoking behavior is tightly related to socioeconomic status and gender, though the dynamic and non-linear association of smoking prevalence across socioeconomic status and gender groups has not been fully examined. With a special focus on gender-bound differences in the susceptibility to social influence of surrounding others' behaviors, we developed an agent-based model to explore how socioeconomic disparity between and within gender groups affects changes in smoking prevalence. Our developed base model reasonably reproduced the actual trend changes by gender groups over the past 5 years in Japan. Counterfactual experiments with the developed model revealed that closing within- and between-gender disparities in socioeconomic status had a limited impact on reducing smoking prevalence. To the contrary, greater socioeconomic disparity facilitated the reduction in prevalence among males, but it impeded that reduction in females. The counterfactual scenario with equalizing gender-bound susceptibility to social influence among women to men's level showed a dramatic reduction in female prevalence without changing the reduction in male prevalence. Simulation results may provide alternative explanation of the growing disparity in smoking prevalence despite improved welfare equality observed in many developed countries, and suggest that redistribution policies may have side effects of widening health gap. Instead, social policy to reduce social pressures to smoking and support interventions to enhance resilience to the pressure targeting the vulnerable population (in this study, women) would be a more effective strategy in combating the tobacco epidemic and closing the health gap. PMID- 26610079 TI - Protocol for quality control in metabolic profiling of biological fluids by U(H)PLC-MS. AB - The process of untargeted metabolic profiling/phenotyping of complex biological matrices, i.e., biological fluids such as blood plasma/serum, saliva, bile, and tissue extracts, provides the analyst with a wide range of challenges. Not the least of these challenges is demonstrating that the acquired data are of "good" quality and provide the basis for more detailed multivariate, and other, statistical analysis necessary to detect, and identify, potential biomarkers that might provide insight into the process under study. Here straightforward and pragmatic "quality control (QC)" procedures are described that allow investigators to monitor the analytical processes employed for global, untargeted, metabolic profiling. The use of this methodology is illustrated with an example from the analysis of human urine where an excel spreadsheet of the preprocessed LC-MS output is provided with embedded macros, calculations and visualization plots that can be used to explore the data. Whilst the use of these procedures is exemplified on human urine samples, this protocol is generally applicable to metabonomic/metabolomic profiling of biofluids, tissue and cell extracts from many sources. PMID- 26610080 TI - Endoscopic radial incision and cutting method for refractory stricture of a rectal anastomosis after surgery. PMID- 26610081 TI - Grasp-to-retract modification of the tulip-bundle technique in forward and retroflexed position for difficult hemostatic therapy in the sigmoid colon. PMID- 26610082 TI - Endoscopic full-thickness resection for suspected residual rectal neuroendocrine tumor and closure of the defect with a new suturing system. PMID- 26610083 TI - Endoscopic ultrasonography-guided ethanol injection as a treatment for ruptured hepatocellular carcinoma in the left hepatic lobe. PMID- 26610084 TI - Fundic gland polyps and duodenal gastric heterotopia - is this an unusual association? PMID- 26610085 TI - Overtube-guided endoscopic extraction of a rectal foreign body: lifting not only the embargo. PMID- 26610086 TI - Extra-anatomical intraduodenal endoscopic-radiologic biliary rendezvous for treatment of iatrogenic complete stenosis of the common bile duct. PMID- 26610087 TI - Vacuum sponge therapy using the pull-through technique via a percutaneous endoscopic gastrostomy to treat iatrogenic duodenal perforation. PMID- 26610088 TI - Delayed massive bleeding caused by an ingested fish bone. PMID- 26610089 TI - A novel approach in benign biliary stricture - balloon dilation combined with cholangioscopy-guided steroid injection. PMID- 26610090 TI - Endoscopic ultrasound-guided biliary drainage with a novel fine-gauge balloon catheter: simplified technique using a coaxial guidewire. PMID- 26610091 TI - A novel method for endoscopic ultrasound-guided pancreatic rendezvous with a microcatheter. PMID- 26610092 TI - Estimating leaf SPAD values of freeze-damaged winter wheat using continuous wavelet analysis. AB - Freeze injury, one of the most destructive agricultural disasters caused by climate, has a significant impact on the growth and production of winter wheat. Chlorophyll content is an important indicator of a plant's growth status. In this study, we analyzed the hyperspectral reflectance of normal and freeze-stressed leaves of winter wheat using a spectro-radiometer in a laboratory. The response of the chlorophyll spectra of plants under freeze stress was analyzed to predict the severity of freeze injury. A continuous wavelet transform (CWT) was conducted in conjunction with a correlation analysis, which generated a correlation scalogram that summarized the correlation between the chlorophyll content (SPAD value) and wavelet power at different wavelengths and decomposition scales. A linear regression model was established to relate the SPAD values and wavelet power coefficients. The results indicated that the most sensitive wavelet feature (region E: 553 nm, scale 5, R(2) = 0.8332) was located near the strong pigment absorption bands, and the model based on this feature could estimate the SPAD value with a high coefficient of determination (R(2) = 0.7444, RMSE = 7.359). The data revealed that the chlorophyll content of leaves under different low temperatures treatments could be accurately estimated using CWT. Also, this emerging spectral analytical approach can be applied to other complex datasets, including a broad range of species, and may be adapted to estimate basic leaf biochemical elements, such as nitrogen, cellulose, and lignin. PMID- 26610093 TI - Bioactivity of MTA Plus, Biodentine and an experimental calcium silicate-based cement on human osteoblast-like cells. AB - AIM: To compare the bioactivity of Biodentine (BIO, Septodont), MTA Plus (MTA P, Avalon) and calcium silicate experimental cement (CSC) with resin (CSCR) associated with zirconium (CSCR ZrO2 ) or niobium (CSCR Nb2 O5 ) oxide as radiopacifiers. METHODOLOGY: According to the relevance of osteoblastic cell response for mineralized tissue repair, human osteoblastic cells (Saos-2) were exposed to test materials and assessed for viability (MTT), cell proliferation, gene expression of alkaline phosphatase (ALP) osteogenic marker by real-time PCR (RT-qPCR), ALP activity assay and alizarin red staining (ARS) to detect mineralization nodule deposition in osteogenic medium. Unexposed cells acted as the control group (C). Statistical analysis was carried out using ANOVA and the Bonferroni post-test (P < 0.05). RESULTS: All tested cements showed dose dependent responses in cell viability (MTT). Exposed cells revealed good viability (80-130% compared to the control group) in the highest dilutions of all types of cement. MTA P, BIO and CSCR ZrO2 significantly increased the velocity of cell proliferation after three days of cell exposure in the wound-healing assay (P < 0.05), which corroborated MTT data. On day 3, the ALP transcript level increased, especially to CSCR Nb2 O5 (P < 0.05). All cements exhibited suitable ALP enzyme activity, highlighting the 7-day period of cell exposure. ARS, CSCR Nb2 O5 , revealed a significant potential to induce mineralization in vitro. CONCLUSIONS: All materials had suitable biocompatibility and bioactivity. The MTA P, BIO and CSCR ZrO2 groups had the highest viability rates and velocity of proliferation whilst the CSCR Nb2 O5 group produced more mineralized nodules. PMID- 26610094 TI - Factors contributing to the development of perceived stigma in people with newly diagnosed epilepsy: A one-year longitudinal study. AB - PURPOSE: We evaluated the course of perceived stigma and the factors associated with perceived stigma over the first year in newly diagnosed people with epilepsy (PWE). METHODS: We recruited newly diagnosed PWE from 12 tertiary hospitals in Korea. The perceived stigma of epilepsy was assessed using the Stigma Scale at baseline and one year later. At the time of diagnosis, demographic, clinical seizure-related, and psychological data were collected. The predictive factors for perceived stigma over one year were analyzed using logistic regression analyses. RESULTS: Two hundred eighteen newly diagnosed PWE were included at baseline, and 153 completed the study. The percentage of participants who felt stigmatized decreased from 30.7% at the time of diagnosis to 17.6% at the end of follow-up. Introverted personality and a high level of anxiety were independent factors contributing to stigma at the time of epilepsy diagnosis. At the one-year follow-up, introverted personality and lower economic status were predictive of the development of perceived stigma. CONCLUSION: Introverted personality was an important factor contributing to the development of perceived stigma at the time of diagnosis and at one year after diagnosis. In addition, a high level of anxiety and a low economic status were independently related to feelings of stigma at baseline and at one year after diagnosis, respectively. There may be a decrease in the perception of stigma over one year in newly diagnosed PWE. PMID- 26610095 TI - Community knowledge of and attitudes toward epilepsy in rural and urban Mukono district, Uganda: A cross-sectional study. AB - INTRODUCTION: The lack of adequate knowledge poses a barrier in the provision of appropriate treatment and care of patients with epilepsy within the community. The purpose of this study was to determine the knowledge of and attitude towards epilepsy and its treatment by community dwellers in Uganda. METHODS: A cross sectional population survey was conducted in urban and rural Mukono district, central Uganda. Adult respondents through multistage stratified sampling were interviewed about selected aspects of epilepsy knowledge, attitudes, and perception using a pretested structured questionnaire. RESULTS: Ninety-one percent of the study respondents had heard or read about epilepsy or knew someone who had epilepsy and had seen someone having a seizure. Thirty-seven percent of the respondents did not know the cause of epilepsy, while 29% cited genetic causes. About seventeen percent of the subjects believed that epilepsy is contagious. Only 5.6% (21/377) of the respondents would take a patient with epilepsy to hospital for treatment. CONCLUSION: Adults in Mukono are very acquainted with epilepsy but have many erroneous beliefs about the condition. Negative attitudes are pervasive within communities in Uganda. The national epilepsy awareness programs need to clarify the purported modes of transmission of epilepsy, available treatment options, and care offered during epileptic seizures during community sensitizations in our settings. PMID- 26610097 TI - Reduction of Cr(VI) to Cr(III) using silicon nanowire arrays under visible light irradiation. AB - We report an efficient visible light-induced reduction of hexavalent chromium Cr(VI) to trivalent Cr(III) by direct illumination of an aqueous solution of potassium dichromate (K2Cr2O7) in the presence of hydrogenated silicon nanowires (H-SiNWs) or silicon nanowires decorated with copper nanoparticles (Cu NPs-SiNWs) as photocatalyst. The SiNW arrays investigated in this study were prepared by chemical etching of crystalline silicon in HF/AgNO3 aqueous solution. The Cu NPs were deposited on SiNW arrays via electroless deposition technique. Visible light irradiation of an aqueous solution of K2Cr2O7 (10(-4)M) in presence of H-SiNWs showed that these substrates were not efficient for Cr(VI) reduction. The reduction efficiency achieved was less than 10% after 120 min irradiation at lambda>420 nm. Addition of organic acids such as citric or adipic acid in the solution accelerated Cr(VI) reduction in a concentration-dependent manner. Interestingly, Cu NPs-SiNWs was found to be a very efficient interface for the reduction of Cr(VI) to Cr(III) in absence of organic acids. Almost a full reduction of Cr(VI) was achieved by direct visible light irradiation for 140 min using this photocatalyst. PMID- 26610098 TI - Insight into the short- and long-term effects of Cu(II) on denitrifying biogranules. AB - This study aimed to investigate the short- and long-term effects of Cu(2+) on the activity and performance of denitrifying bacteria. The short-term effects of various concentrations of Cu(2+) on the denitrifying bacteria were evaluated using batch assays. The specific denitrifying activity (SDA) decreased from 14.3 +/- 2.2 (without Cu(2+)) to 6.1 +/- 0.1 mg N h(-1)g(-1) VSS (100 mg Cu(2+)L(-1)) when Cu(2+) increased from 0 to 100 mg L(-1) with an increment of 10 mg Cu(2+)L( 1). A non-competitive inhibition model was used to calculate the 50% inhibition concentration (IC50) of Cu(2+) on denitrifying sludge (30.6 +/- 2.5 mg L(-1)). Monod and Luong models were applied to investigate the influence of the initial substrate concentration, and the results suggested that the maximum substrate removal rate would be reduced with Cu(2+) supplementation. Pre-exposure to Cu(2+) could lead to an 18.2-46.2% decrease in the SDA and decreasing percentage of the SDA increased with both exposure time and concentration. In the continuous-flow test, Cu(2+) concentration varied from 1 to 75 mg L(-1); however, no clear deterioration was observed in the reactor, and the reactor was kept stable, with the total nitrogen removal efficiency and total organic carbon efficiency greater than 89.0 and 85.0%, respectively. The results demonstrated the short-term inhibition of Cu(2+) upon denitrification, and no notable adversity was observed during the continuous-flow test after long-term acclimation. PMID- 26610096 TI - Roflumilast n-oxide associated with PGE2 prevents the neutrophil elastase-induced production of chemokines by epithelial cells. AB - Neutrophil chemotaxis is involved in the lung inflammatory process in conditions such as chronic obstructive pulmonary disease (COPD). Neutrophil elastase (NE), one of the main proteases produced by neutrophils, has an important role in the inflammatory process via the release of chemokines from airway epithelial cells. It was recently shown that roflumilast N-oxide has therapeutic potential in COPD. The aim of the present study was to investigate roflumilast N-oxide's effect on NE-induced chemokine production and signaling pathways in A549 epithelial cells. A549 cells were incubated with NE for 30min, washed with PBS and then cultured for 2h (for measurement of mRNA expression) and 24h (for chemokine release) or for 5 to 30min (for protein phosphorylation assays). Prior to the addition of NE, cells were also pre-incubated with prostaglandin E2 (PGE2), alone and in combination with roflumilast N-oxide. Addition of NE was associated with elevated chemokine production by A549 cells and induction of the p38alpha pathway. In contrast when combined with PGE2, the roflumilast N-oxide had an additive effect on the inhibition of NE-induced chemokine release and p38alpha and other kinases activation. In conclusion, we demonstrated that NE is able to increase the release of chemokines from epithelial cells via the activation of p38alpha MAP kinase and that roflumilast N-oxide when combined with PGE2 lowers NE-induced kinase activation and chemokine production. PMID- 26610099 TI - The roles of polycarboxylates in Cr(VI)/sulfite reaction system: Involvement of reactive oxygen species and intramolecular electron transfer. AB - In this study, the effects of polycarboxylates on both Cr(VI) reduction and S(IV) consumption in Cr(VI)/S(IV) system was investigated in acidic solution. Under aerobic condition, the productions of reactive oxygen species (ROS), i.e., SO4(-) and OH, have been confirmed in S(IV) reducing Cr(VI) process by using electron spin resonance and fluorescence spectrum techniques, leading to the excess consumption of S(IV). However, when polycarboxylates (oxalic, citric, malic and tartaric acid) were present in Cr(VI)/S(IV) system, the affinity of polycarboxylates to CrSO6(2-) can greatly promote the reduction of Cr(VI) via expanding the coordination of Cr(VI) species from tetrahedron to hexahedron. Besides, as alternatives to S(IV), these polycarboxylates can also act as electron donors for Cr(VI) reduction via intramolecular electron transfer reaction, which is dependent on the energies of the highest occupied molecular orbital of these polycarboxylates. Notably, the variant electron donating capacity of these polycarboxylates resulted in different yield of ROS and therefore the oxidation efficiencies of other pollutants, e.g., rhodamine B and As(III). Generally, this study does not only shed light on the mechanism of S(IV) reducing Cr(VI) process mediated by polycarboxylates, but also provides an escalated, cost-effective and green strategy for the remediation of Cr(VI) using sulfite as a reductant. PMID- 26610100 TI - Guaranteed Discrete Energy Optimization on Large Protein Design Problems. AB - In Computational Protein Design (CPD), assuming a rigid backbone and amino-acid rotamer library, the problem of finding a sequence with an optimal conformation is NP-hard. In this paper, using Dunbrack's rotamer library and Talaris2014 decomposable energy function, we use an exact deterministic method combining branch and bound, arc consistency, and tree-decomposition to provenly identify the global minimum energy sequence-conformation on full-redesign problems, defining search spaces of size up to 10(234). This is achieved on a single core of a standard computing server, requiring a maximum of 66GB RAM. A variant of the algorithm is able to exhaustively enumerate all sequence-conformations within an energy threshold of the optimum. These proven optimal solutions are then used to evaluate the frequencies and amplitudes, in energy and sequence, at which an existing CPD-dedicated simulated annealing implementation may miss the optimum on these full redesign problems. The probability of finding an optimum drops close to 0 very quickly. In the worst case, despite 1,000 repeats, the annealing algorithm remained more than 1 Rosetta unit away from the optimum, leading to design sequences that could differ from the optimal sequence by more than 30% of their amino acids. PMID- 26610101 TI - Static and Dynamical Properties of Liquid Water from First Principles by a Novel Car-Parrinello-like Approach. AB - Using the recently developed Car-Parrinello-like approach to Born-Oppenheimer molecular dynamics ( Kuhne, T. D. ; et al. Phys. Rev. Lett. 2007 , 98 , 066401. ), we assess the accuracy of ab initio molecular dynamics at the semilocal density functional level of theory to describe structural and dynamic properties of liquid water at ambient conditions. We have performed a series of large-scale simulations using a number of parameter-free exchange and correlation functionals, to minimize and investigate the influence of finite size effects as well as statistical errors. We find that finite size effects in structural properties are rather small and, given an extensive sampling, reproducible. On the other hand, the influence of finite size effects on dynamical properties are much larger than generally appreciated. So much so that the infinite size limit is practically out of reach. However, using a finite size scaling procedure, thanks to the greater effectiveness of our new method we can estimate both the thermodynamic value of the diffusion coefficient and the shear viscosity. The hydrogen bond network structure and its kinetics are consistent with the conventional view of tetrahedrally coordinated water. PMID- 26610102 TI - Striking Effects of Hydrodynamic Interactions on the Simulated Diffusion and Folding of Proteins. AB - Successful modeling of the processes of protein folding and aggregation may ultimately require accurate descriptions of proteins' diffusive characteristics, which are expected to be influenced by hydrodynamic effects; a comprehensive study of the diffusion and folding of 11 model proteins with an established simulation model extended to include hydrodynamic interactions between residues has therefore been carried out. Molecular simulations that neglect hydrodynamic interactions are incapable of simultaneously reproducing the expected experimental translational and rotational diffusion coefficients of folded proteins, drastically underestimating both when reasonable hydrodynamic radii are employed. In contrast, simulations that include hydrodynamic interactions produce diffusion coefficients that match very well with the expected experimental values for translation and rotation and also correctly capture the significant decrease in translational diffusion coefficient that accompanies protein unfolding. These effects are reflected in folding simulations of the same proteins: the inclusion of hydrodynamic interactions accelerates folding by 2-3-fold with the rate enhancement for the association of secondary structure elements exhibiting a strong sensitivity on the sequence-distance between the associating elements. PMID- 26610103 TI - Molecular Dynamics Simulations of Solvation and Solvent Reorganization Dynamics in CO2-Expanded Methanol and Acetone. AB - Composition-dependent solvation dynamics around the probe coumarin 153 (C153) have been explored in CO2-expanded methanol and acetone with molecular dynamics (MD) simulations. Solvent response functions are biexponential with two distinct decay time scales: a rapid initial decay (~0.1 ps) and a long relaxation process. Solvation times in both expanded solvent classes are nearly constant at partition compositions up to 80% CO2. The extent of solvation beyond this composition has the greatest tunability and sensitivity to bulk solvent composition. Solvent rotational correlation functions (RCFs) have also been used to explore rotational relaxation. Rotations have a larger range of time scales and are dependent on a number of factors including bulk composition, solvent-solvent interactions, particularly hydrogen bonding, and proximity to C153. The establishment of the solvation structure around a solute in a GXL is clearly a complex process. With respect to the local solvent domain around C153, it was seen to be primarily affected by a nonlinear combination of the rotational and diffusive transport dynamics. PMID- 26610104 TI - Simple, Efficient, and Reliable Computation of Multiple Free Energy Differences from a Single Simulation: A Reference Hamiltonian Parameter Update Scheme for Enveloping Distribution Sampling (EDS). AB - We present an automatic adaptive scheme which allows fast optimization of the reference Hamiltonian parameters in enveloping distribution sampling (EDS). Six different variants of the update scheme have been tested on a condensed phase test system which included the recurrent deletion and creation of complete water molecules in water. All six schemes gave accurate free energy estimates with absolute errors of up to 1 kJ/mol for the worst scheme and up to 0.1 kJ/mol for the best scheme. Configurational sampling is focused on the regions where the end state energy difference distributions intersect, explaining the high accuracy and precision of the free energy estimates. The new update scheme makes the application of EDS to other systems, e.g. in ligand binding studies, easy as no reference state Hamiltonian parameters have to be chosen by the user. The only necessary input are the Hamiltonians of the various end states involved. PMID- 26610105 TI - Fully Automated Incremental Evaluation of MP2 and CCSD(T) Energies: Application to Water Clusters. AB - A fully automated implementation of the incremental scheme for CCSD energies has been extended to treat MP2 and CCSD(T) energies. It is shown in applications on water clusters that the error of the incremental expansion for the total energy is below 1 kcal/mol already at second or third order. It is demonstrated that the approach saves CPU time, RAM, and disk space. Finally it is shown that the calculations can be run in parallel on up to 50 CPUs, without significant loss of computer time. PMID- 26610106 TI - pKa Calculation of Some Biologically Important Carbon Acids - An Assessment of Contemporary Theoretical Procedures. AB - In this study, the aqueous pKa values for 13 neutral, 10 cationic, and 5 anionic carbon acids, including amino acids, peptides, and related species have been calculated using the high level ab initio composite procedure, G3MP2+//BMK, combined with solvation energies that were calculated using the CPCM-(UAKS/UAHF), COSMO-RS, and SM6 continuum models. The pKas were further calculated using three schemes, namely the direct method and the proton exchange method as well as the inclusion of an explicit solvent water molecule. The results of this study indicate that the direct method is unsuitable for computing the pKa of carbon acids, whereas the other two schemes perform significantly better with varying degrees of success, depending on the charge of the carbon acid. Specifically, the combination of the proton exchange scheme and CPCM-UAKS model performed particularly well for neutral species, with mean absolute deviations (MADs) of ~1 pKa unit. The ionic species were more problematic, though the combination of the proton exchange scheme and the SM6 and CPCM-UAKS models performed reasonably well for the cationic and anionic acids, respectively. The inclusion an explicit water molecule generally improved the calculated values for anionic carbon acids. PMID- 26610107 TI - Evaluation of Electronic Coupling in Transition-Metal Systems Using DFT: Application to the Hexa-Aquo Ferric-Ferrous Redox Couple. AB - We present a density-functional theory (DFT) approach, with fractionally occupied orbitals, for studying the prototypical ferric-ferrous electron-transfer (ET) process in liquid water. We use a recently developed ab initio method to calculate the transfer integral (also named electronic-coupling or ET matrix element) between the solvated ions. The computed transfer integral is combined with previous ab initio values of the reorganization energy, within the framework of Marcus' theory, to estimate the rate of the electron self-exchange reaction. The self-interaction correction incorporated (through an appropriate treatment of the electronic correlation effects) into a Hubbard U extension to the DFT scheme leads to a theoretical value of the ET rate relatively close to an experimental estimate from kinetic measurements. The use of fractional occupation numbers (FON) turned out to be crucial for achieving convergence in most self-consistent calculations because of the open-shell d-multiplet electronic structure of each iron ion and the near degeneracy of the redox groups involved. We provide a theoretical justification for the FON approach, which allows a description of the chemical potential and orbital relaxation, and possible extension to other transition-metal redox systems. Accordingly, the methodology developed in this paper, which rests on a suitable combination of Hubbard U correction and a FON approach to DFT, seems to offer a fruitful approach for the quantitative description of ET reactions in biochemical systems. PMID- 26610108 TI - Benchmark Energetic Data in a Model System for Grubbs II Metathesis Catalysis and Their Use for the Development, Assessment, and Validation of Electronic Structure Methods. AB - We present benchmark relative energetics in the catalytic cycle of a model system for Grubbs second-generation olefin metathesis catalysts. The benchmark data were determined by a composite approach based on CCSD(T) calculations, and they were used as a training set to develop a new spin-component-scaled MP2 method optimized for catalysis, which is called SCSC-MP2. The SCSC-MP2 method has improved performance for modeling Grubbs II olefin metathesis catalysts as compared to canonical MP2 or SCS-MP2. We also employed the benchmark data to test 17 WFT methods and 39 density functionals. Among the tested density functionals, M06 is the best performing functional. M06/TZQS gives an MUE of only 1.06 kcal/mol, and it is a much more affordable method than the SCSC-MP2 method or any other correlated WFT methods. The best performing meta-GGA is M06-L, and M06 L/DZQ gives an MUE of 1.77 kcal/mol. PBEh is the best performing hybrid GGA, with an MUE of 3.01 kcal/mol; however, it does not perform well for the larger, real Grubbs II catalyst. B3LYP and many other functionals containing the LYP correlation functional perform poorly, and B3LYP underestimates the stability of stationary points for the cis-pathway of the model system by a large margin. From the assessments, we recommend the M06, M06-L, and MPW1B95 functionals for modeling Grubbs II olefin metathesis catalysts. The local M06-L method is especially efficient for calculations on large systems. PMID- 26610109 TI - Electrostatic Potentials from Self-Consistent Hirshfeld Atomic Charges. AB - It is shown that molecular electrostatic potentials obtained from iterative or self-consistent Hirshfeld atomic point charges agree remarkably well with the ab initio computed electrostatic potentials. The iterative Hirshfeld scheme performs nearly as well as electrostatic potential derived atomic charges, having the advantage of allowing the definition of the atom in the molecule, rather than just yielding charges. The quality of the iterative Hirshfeld charges for computing electrostatic potentials is examined for a large set of molecules and compared to other commonly used techniques for population analysis. PMID- 26610110 TI - Solvatochromic Shifts on Absorption and Fluorescence Bands of N,N Dimethylaniline. AB - A theoretical study of the absorption and fluorescence UV/vis spectra of N,N dimethylaniline in different solvents has been performed, using a method combining quantum mechanics, molecular mechanics, and the mean field approximation. The transitions between the three lowest-lying states have been calculated in vacuum as well as in cyclohexane, tetrahydrofuran, and water. The apparent anomalies experimentally found in water (a blue shift in the absorption bands with respect to the trend in other solvents, and an abnormally high red shift for the fluorescence band) are well reproduced and explained in view of the electronic structure of the solute and the solvent distribution around it. Additional calculations were done with a mixture of cyclohexane and tetrahydrofuran as solvent, which displays a nonlinear solvatochromic shift. Results, although not conclusive, are consistent with experiment and provide a possible explanation for the nonlinear behavior in the solvent mixture. PMID- 26610111 TI - Theoretical Study of Hydrogen Storage in Ca-Coated Fullerenes. AB - First principles calculations based on gradient corrected density functional theory and molecular dynamics simulations of Ca decorated fullerene yield some novel results: (1) C60 fullerene decorated with 32 Ca atoms on each of its 20 hexagonal and 12 pentagonal faces is extremely stable. Unlike transition metal atoms that tend to cluster on a fullerene surface, Ca atoms remain isolated even at high temperatures. (2) C60Ca32 can absorb up to 62 H2 molecules in two layers. The first 30 H2 molecules dissociate and bind atomically on the 60 triangular faces of the fullerene with an average binding energy of 0.45 eV/H, while the remaining 32 H2 molecules bind on the second layer quasi-molecularly with an average binding energy of 0.11 eV/H2. These binding energies are ideal for Ca coated C60 to operate as a hydrogen storage material at near ambient temperatures with fast kinetics. (3) The gravimetric density of this hydrogen storage material can reach 6.2 wt %. Simple model calculations show that this density is the limiting value for higher fullerenes. PMID- 26610112 TI - Charges for Large Scale Binding Free Energy Calculations with the Linear Interaction Energy Method. AB - The linear interaction energy method (LIE), which combines force field based molecular dynamics (MD) simulations and linear response theory, has previously been shown to give fast and reliable estimates of ligand binding free energies, suggesting that this type of technique could be used also in a high-throughput fashion. However, a limiting step in such applications is the assignment of atomic charges for compounds that have not been parametrized within the given force field, in this case OPLS-AA. In order to reach an automatable solution to this problem, we have examined the performance of nine different ab initio and semiempirical charge methods, together with estimates of solvent induced polarization. A test set of ten HIV-1 reverse transcriptase inhibitors was selected, and LIE estimates of their relative binding free energies were calculated using the resulting 23 different charge variants. Over 800 ns of MD simulation show that the LIE method provides excellent estimates with several different charge methods and that the semiempirically derived CM1A charges, in particular, emerge as a fast and reliable alternative for fully automated LIE based virtual screens with the OPLS-AA force field. Our conclusions regarding different charge models are also expected to be valid for other types of force field based binding free energy calculations, such as free energy perturbation and thermodynamic integration simulations. PMID- 26610113 TI - Lennard-Jones Parameters for B3LYP/CHARMM27 QM/MM Modeling of Nucleic Acid Bases. AB - Combined quantum mechanics/molecular mechanics (QM/MM) methods allow computations on chemical events in large molecular systems. Here, we have tested the suitability of the standard CHARMM27 forcefield Lennard-Jones van der Waals (vdW) parameters for the treatment of nucleic acid bases in QM/MM calculations at the B3LYP/6-311+G(d,p)-CHARMM27 level. Alternative parameters were also tested by comparing the QM/MM hydrogen bond lengths and interaction energies with full QM [B3LYP/6-311+G(d,p)] results. The optimization of vdW parameters for nucleic acid bases is challenging because of the likelihood of multiple hydrogen bonds between the nucleic acid base and a water molecule. Two sets of optimized atomic vdW parameters for polar hydrogen, carbonyl carbon, and aromatic nitrogen atoms for nucleic acid bases are reported: base-dependent and base-independent. The results indicate that, for QM/MM investigations of nucleic acids, the standard forcefield vdW parameters may not be appropriate for atoms treated by QM. QM/MM interaction energies calculated with standard CHARMM27 parameters are found to be too large, by around 3 kcal/mol. This is because of overestimation of electrostatic interactions. Interaction energies closer to the full QM results are found using the optimized vdW parameters developed here. The optimized vdW parameters [developed by reference to B3LYP/6-311+G(d,p) results] were also tested at the B3LYP/6-31G(d) QM/MM level and were found to be transferable to the lower level. The optimized parameters also model the interaction energies of charged nucleic acid bases and deprotonation energies reasonably well. PMID- 26610114 TI - Study of the Conformational Dynamics of the Catalytic Loop of WT and G140A/G149A HIV-1 Integrase Core Domain Using Reversible Digitally Filtered Molecular Dynamics. AB - The HIV-1 IN enzyme is one of three crucial virally encoded enzymes (HIV-1 IN, HIV-1 PR, and HIV-1 RT) involved in the life-cycle of the HIV-1 virus, making it an attractive target in the development of drugs against the AIDS virus. The structure and mechanism of the HIV-1 IN enzyme is the least understood of the three enzymes due to the lack of three-dimensional structural information. X-ray cystallographic studies have not yet been able to resolve the full-length structure, and studies have been mainly focused on the catalytic domain. This central domain possesses an important catalytic loop observed to overhang the active site, and experimental studies have shown that its dynamics affects the catalytic activity of mutant HIV-1 IN enzymes. In this study, the enhanced sampling technique, Reversible Digitally Filtered Molecular Dynamics (RDFMD), has been applied to the catalytic domain of the WT and G140A/G149A HIV-1 IN enzymes and has highlighted significant differences between the behavior of the catalytic loop which may explain the decrease of activity observed in experimental studies for this mutant. PMID- 26610115 TI - Conformational Studies of Methyl beta-d-Arabinofuranoside Using the AMBER/GLYCAM Approach. AB - Furanosides are important constituents of a number of glycoconjugates from many microorganisms. The highly flexible nature of these furanosyl moieties is believed to contribute significantly to their role in biological processes. Therefore, an understanding of the conformational preferences of these molecules is an important area of research. As part of a larger program involved in the conformational analysis of mycobacterial oligofuranosides, molecular dynamics simulations on methyl beta-d-arabinofuranoside (3) have been carried out using the AMBER forcefield and the GLYCAM carbohydrate parameter set. This approach was used to predict the rotamer population distribution about the hydroxymethyl group (C4-C5 bond) as well as the ring puckering of this flexible ring system. Comparison of the conformer distributions obtained during the simulation of 3 using the TIP3P water model with those obtained by analysis of (1)H-(1)H coupling constant data indicated that this water model was insufficient to describe the solvation of this system. However, the use of the TIP4P and TIP5P models led to improved agreement with conformer populations obtained from NMR data. PMID- 26610116 TI - Lived experiences of everyday life during curative radiotherapy in patients with non-small-cell lung cancer: A phenomenological study. AB - AIM: To explore and describe the essential meaning of lived experiences of the phenomenon: Everyday life during curative radiotherapy in patients with non-small cell lung cancer (NSCLC). BACKGROUND: Radiotherapy treatment in patients with NSCLC is associated with severe side effects such as fatigue, anxiety, and reduced quality of life. However, little is known about the patients' experience of everyday life during the care trajectory. DESIGN: This study takes a reflective lifeworld approach using an empirical application of phenomenological philosophy described by Dahlberg and colleagues. METHOD: A sample of three patients treated with curative radiotherapy for NSCLC was interviewed 3 weeks after the end of radiotherapy treatment about their experiences of everyday life during their treatment. Data were collected in 2014 and interviews and analysis were conducted within the descriptive phenomenological framework. FINDINGS: The essential meaning structure of the phenomenon studied was described as "Hope for recovery serving as a compass in a changed everyday life," which was a guide for the patients through the radiotherapy treatment to support their efforts in coping with side effects. The constituents of the structure were: Radiotherapy as a life priority, A struggle for acceptance of an altered everyday life, Interpersonal relationships for better or worse, and Meeting the health care system. CONCLUSION: The meaning of hope was essential during radiotherapy treatment and our results suggest that interpersonal relationships can be a prerequisite to the experience of hope. "Hope for recovery serving as a compass in a changed everyday life," furthermore identifies the essentials in the patients' assertive approach to believing in recovery and thereby enabling hope in a serious situation. PMID- 26610117 TI - Keeping up with the caravan of life: Successful aging strategies for Iranian women. AB - BACKGROUND: Because of improving life expectancy in the world in recent times, the focus has shifted to the issue of the quality and nature of life and how to assist successful aging (SA) rather than increasing physical survival and lifespan. SA is a multidimensional, relative, and context-dependent concept with different paths and outcomes. The purpose of this qualitative study was to explore older women's strategies for SA in a specific context. METHODS: Following a grounded theory design approach, we conducted semi-structured individual interviews with 21 women between the ages of 28 and 96 years. We analyzed the data from interviews, written narratives, and field notes using the grounded theory approach. RESULTS: We identified four categories: prevention of threats, internal self-control against threats, coping with threats, and optimizing the passage of time according to opportunity. These described the strategies for SA when encountering with age-related changes. Utilizing these strategies, the women accompanied the caravan of life in the context of threats and opportunities. CONCLUSIONS: The findings suggest that SA is a continuous process in confronting changes related to age. The identified strategies can help to promote SA by familiarizing older women with the threats and opportunities of life and training them in how to use these strategies. PMID- 26610118 TI - Nonmonotonic Recursive Polynomial Expansions for Linear Scaling Calculation of the Density Matrix. AB - As it stands, density matrix purification is a powerful tool for linear scaling electronic structure calculations. The convergence is rapid and depends only weakly on the band gap. However, as will be shown in this letter, there is room for improvements. The key is to allow for nonmonotonicity in the recursive polynomial expansion. On the basis of this idea, new purification schemes are proposed that require only half the number of matrix-matrix multiplications compared to previous schemes. The speedup is essentially independent of the location of the chemical potential and increases with decreasing band gap. PMID- 26610119 TI - Validation of the GROMOS 54A7 Force Field with Respect to beta-Peptide Folding. AB - The recently developed GROMOS 54A7 force field, a modification of the 53A6 force field, is validated by simulating the folding equilibrium of two beta-peptides which show different dominant folds, i.e., a 314-helix and a hairpin, using three different force fields, i.e., GROMOS 45A3, 53A6, and 54A7. The 54A7 force field stabilizes both folds, and the agreement of the simulated NOE atom-atom distances with the experimental NMR data is slightly improved when using the 54A7 force field, while the agreement of the (3)J couplings with experimental results remains essentially unchanged when varying the force field. The 54A7 force field developed to improve the stability of alpha-helical structures in proteins can thus be safely used in simulations of beta-peptides. PMID- 26610120 TI - Boxed Molecular Dynamics: Decorrelation Time Scales and the Kinetic Master Equation. AB - A number of methods proposed in the past few years have been aimed at accelerating the sampling of rare events in molecular dynamics simulations. We recently introduced a method called Boxed Molecular Dynamics (BXD) for accelerating the calculation of thermodynamics and kinetics ( J. Phys. Chem. B 2009 , 113 , 16603 - 16611 ). BXD relies upon confining the system in a series of adjacent "boxes" by inverting the projection of the system velocities along the reaction coordinate. The potential of mean force along the reaction coordinate is obtained from the mean first passage times (MFPTs) for exchange between neighboring boxes, simultaneously providing both kinetics and thermodynamics. In this paper, we investigate BXD in the context of its natural relation to a kinetic master equation and show that the BXD first passage times (FPTs) include different time scales-a fast short time decay due to correlated dynamical motion and slower long time decay arising from phase space diffusion. Correcting the FPTs to remove the fast correlated motion yields accurate thermodynamics and master equation kinetics. We also discuss interrelations between BXD and a recently described Markovian milestoning technique and use a simple application to show that, despite each method producing distinct nonstatistical effects on time scales on the order of dynamical decorrelation, both yield similar long-time kinetics. PMID- 26610121 TI - SHARC: ab Initio Molecular Dynamics with Surface Hopping in the Adiabatic Representation Including Arbitrary Couplings. AB - We present a semiclassical surface-hopping method which is able to treat arbitrary couplings in molecular systems including all degrees of freedom. A reformulation of the standard surface-hopping scheme in terms of a unitary transformation matrix allows for the description of interactions like spin-orbit coupling or transitions induced by laser fields. The accuracy of our method is demonstrated in two systems. The first one, consisting of two model electronic states, validates the semiclassical approach in the presence of an electric field. In the second one, the dynamics in the IBr molecule in the presence of spin-orbit coupling after laser excitation is investigated. Due to an avoided crossing that originates from spin-orbit coupling, IBr dissociates into two channels: I + Br((2)P3/2) and I + Br*((2)P1/2). In both systems, the obtained results are in very good agreement with those calculated from exact quantum dynamical simulations. PMID- 26610122 TI - Path-Integral Calculations of Nuclear Quantum Effects in Model Systems, Small Molecules, and Enzymes via Gradient-Based Forward Corrector Algorithms. AB - A practical approach to treat nuclear quantum mechanical (QM) effects in simulations of condensed phases, such as enzymes, is via Feynman path integral (PI) formulations. Typically, the standard primitive approximation (PA) is employed in enzymatic PI simulations. Nonetheless, these PI simulations are computationally demanding due to the large number of discretizations, or beads, required to obtain converged results. The efficiency of PI simulations may be greatly improved if higher order factorizations of the density matrix operator are employed. Herein, we compare the results of model calculations obtained employing the standard PA, the improved operator of Takahashi and Imada (TI), and several gradient-based forward corrector algorithms due to Chin (CH). The quantum partition function is computed for the harmonic oscillator, Morse, symmetric, and asymmetric double well potentials. These potentials are simple models for nuclear quantum effects, such as zero-point energy and tunneling. It is shown that a unique set of CH parameters may be employed for a variety of systems. Additionally, the nuclear QM effects of a water molecule, treated with density functional theory, are computed. Finally, we derive a practical perturbation expression for efficient computation of isotope effects in chemical systems using the staging algorithm. This new isotope effect approach is tested in conjunction with the PA, TI, and CH methods to compute the equilibrium isotope effect in the Schiff base-oxyanion keto-enol tautomerism in the cofactor pyridoxal-5'-phosphate in the enzyme alanine racemase. The study of the different factorization methods reveals that the higher-order actions converge substantially faster than the PA approach, at a moderate computational cost. PMID- 26610123 TI - Coupled Cluster Theory on Graphics Processing Units I. The Coupled Cluster Doubles Method. AB - The coupled cluster (CC) ansatz is generally recognized as providing one of the best wave function-based descriptions of electronic correlation in small- and medium-sized molecules. The fact that the CC equations with double excitations (CCD) may be expressed as a handful of dense matrix-matrix multiplications makes it an ideal method to be ported to graphics processing units (GPUs). We present our implementation of the spin-free CCD equations in which the entire iterative procedure is evaluated on the GPU. The GPU-accelerated algorithm readily achieves a factor of 4-5 speedup relative to the multithreaded CPU algorithm on same generation hardware. The GPU-accelerated algorithm is approximately 8-12 times faster than Molpro, 17-22 times faster than NWChem, and 21-29 times faster than GAMESS for each CC iteration. Single-precision GPU-accelerated computations are also performed, leading to an additional doubling of performance. Single precision errors in the energy are typically on the order of 10(-6) hartrees and can be improved by about an order of magnitude by performing one additional iteration in double precision. PMID- 26610124 TI - Time-Dependent Density-Functional Description of the (1)La State in Polycyclic Aromatic Hydrocarbons: Charge-Transfer Character in Disguise? AB - The electronic spectrum of alternant polycyclic aromatic hydrocarbons (PAHs) includes two singlet excited states that are often denoted (1)La and (1)Lb. Time dependent density functional theory (TD-DFT) affords reasonable excitation energies for the (1)Lb state in such molecules, but often severely underestimates (1)La excitation energies and fails to reproduce observed trends in the (1)La excitation energy as a function of molecular size. Here, we examine the performance of long-range-corrected (LRC) density functionals for the (1)La and (1)Lb states of various PAHs. With an appropriate choice for the Coulomb attenuation parameter, we find that LRC functionals avoid the severe underestimation of the (1)La excitation energies that afflicts other TD-DFT approaches, while errors in the (1)Lb excitation energies are less sensitive to this parameter. This suggests that the (1)La states of certain PAHs exhibit some sort of charge-separated character, consistent with the description of this state within valence-bond theory, but such character proves difficult to identify a priori. We conclude that TD-DFT calculations in medium-size, conjugated organic molecules may involve significant but hard-to-detect errors. Comparison of LRC and non-LRC results is recommended as a qualitative diagnostic. PMID- 26610125 TI - Artificial Bee Colony Optimization of Capping Potentials for Hybrid Quantum Mechanical/Molecular Mechanical Calculations. AB - We present an algorithmic extension of a numerical optimization scheme for analytic capping potentials for use in mixed quantum-classical (quantum mechanical/molecular mechanical, QM/MM) ab initio calculations. Our goal is to minimize bond-cleavage-induced perturbations in the electronic structure, measured by means of a suitable penalty functional. The optimization algorithm-a variant of the artificial bee colony (ABC) algorithm, which relies on swarm intelligence-couples deterministic (downhill gradient) and stochastic elements to avoid local minimum trapping. The ABC algorithm outperforms the conventional downhill gradient approach, if the penalty hypersurface exhibits wiggles that prevent a straight minimization pathway. We characterize the optimized capping potentials by computing NMR chemical shifts. This approach will increase the accuracy of QM/MM calculations of complex biomolecules. PMID- 26610126 TI - GPU-Based Implementations of the Noniterative Regularized-CCSD(T) Corrections: Applications to Strongly Correlated Systems. AB - The details of the graphical processing unit (GPU) implementation of the most computationally intensive (T)-part of the recently introduced regularized CCSD(T) (Reg-CCSD(T)) method [ Kowalski , K. ; Valiev , M. J. Chem. Phys. 2009 , 131 , 234107 ] for calculating electronic energies of strongly correlated systems are discussed. Parallel tests performed for several molecular systems show very good scalability of the triples part of the Reg-CCSD(T) approach. We also discuss the performance of the Reg-CCSD(T) GPU implementation as a function of the parameters defining the partitioning of the spinorbital domain (tiling structure). The accuracy of the Reg-CCSD(T) method is illustrated on three examples: the methyfluoride molecule, dissociation of dodecane, and open-shell Spiro cation (5,5'(4H,4H')-spirobi[cyclopenta[c]pyrrole] 2,2',6,6'-tetrahydro cation), which is a frequently used model to study electron transfer processes. It is demonstrated that a simple regularization of the cluster amplitudes used in the noniterative corrections accounting for the effect of triply excited configurations significantly improves the accuracies of ground-state energies in the presence of strong quasidegeneracy effects. For methylfluoride, we compare the Reg-CCSD(T) results with the CR-CC(2,3) and CCSDT energies, whereas for Spiro cation we compare Reg-CCSD(T) results with the energies obtained with completely renormalized CCSD(T) method. Performance tests for the Spiro, dodecane, and uracil molecules are also discussed. PMID- 26610127 TI - An Extension of the Hirshfeld Method to Open Shell Systems Using Fractional Occupations. AB - In this work, a new partitioning method is presented which allows one to calculate properties of radicals, in particular, atomic spin populations. The method can be seen as an extension of the Hirshfeld-I method [ Bultinck , P. et al. J. Chem. Phys. 2007 , 126 , 144111 ], in which the atomic weight functions, defining the atoms-in-molecules, are constructed by means of an iterative scheme in which the charges of the atoms-in-molecules are altered but the spin remains fixed. The Hirshfeld-I method is therefore not suitable for the calculation of atomic spin populations of open-shell systems. The new fractional occupation Hirshfeld-I (FOHI) uses an iterative scheme in which both the atomic charge and spin are optimized, resulting in a self-consistent method for the calculation of atomic spin populations. The results obtained with the FOHI method are compared with experimental results obtained using polarized neutron diffraction, thus serving as a validation of the FOHI method as well as the Hirshfeld definition of atoms-in-molecules in general. PMID- 26610128 TI - Molecules-in-Molecules: An Extrapolated Fragment-Based Approach for Accurate Calculations on Large Molecules and Materials. AB - We present a new extrapolated fragment-based approach, termed molecules-in molecules (MIM), for accurate energy calculations on large molecules. In this method, we use a multilevel partitioning approach coupled with electronic structure studies at multiple levels of theory to provide a hierarchical strategy for systematically improving the computed results. In particular, we use a generalized hybrid energy expression, similar in spirit to that in the popular ONIOM methodology, that can be combined easily with any fragmentation procedure. In the current work, we explore a MIM scheme which first partitions a molecule into nonoverlapping fragments and then recombines the interacting fragments to form overlapping subsystems. By including all interactions with a cheaper level of theory, the MIM approach is shown to significantly reduce the errors arising from a single level fragmentation procedure. We report the implementation of energies and gradients and the initial assessment of the MIM method using both biological and materials systems as test cases. PMID- 26610129 TI - Modeling Fast Electron Dynamics with Real-Time Time-Dependent Density Functional Theory: Application to Small Molecules and Chromophores. AB - The response of matter to external fields forms the basis for a vast wealth of fundamental physical processes ranging from light harvesting to nanoscale electron transport. Accurately modeling ultrafast electron dynamics in excited systems thus offers unparalleled insight but requires an inherently nonlinear time-resolved approach. To this end, an efficient and massively parallel real time real-space time-dependent density functional theory (RT-TDDFT) implementation in NWChem is presented. The implementation is first validated against linear-response TDDFT and experimental results for a series of molecules subjected to small electric field perturbations. Second, nonlinear excitation of green fluorescent protein is studied, which shows a blue-shift in the spectrum with increasing perturbation, as well as a saturation in absorption. Next, the charge dynamics of optically excited zinc porphyrin is presented in real time and real space, with relevance to charge injection in photovoltaic devices. Finally, intermolecular excitation in an adenine-thymine base pair is studied using the BNL range separated functional [ Baer , R. ; Neuhauser , D. Phys. Rev. Lett. 2005 , 94 , 043002 ], demonstrating the utility of a real-time approach in capturing charge transfer processes. PMID- 26610130 TI - Computational Mechanistic Studies Addressed to the Transimination Reaction Present in All Pyridoxal 5'-Phosphate-Requiring Enzymes. AB - The pyridoxal-5'-phosphate-dependent enzymes (PLP enzymes) catalyze a myriad of biochemical reactions, being actively involved in the biosynthesis of amino acids and amino acid-derived metabolites as well as in the biosynthetic pathways of amino sugars and in the synthesis or catabolism of neurotransmitters. Although the scope of PLP-catalyzed reactions initially appears to be bewilderingly diverse, there is a simple unifying principle: In the resting state, the cofactor (PLP) is covalently bonded to the amino group of an active site lysine, forming an internal aldimine. Once the amino substrate interacts with the active site, a new Schiff base is generated, commonly referred to as the external aldimine. Only after this step, the mechanistic pathway for each PLP-catalyzed reaction diverges. In this paper, density functional methods have been applied to investigate this common step present in all PLP-dependent enzymes-the transimination reaction. The results indicate that the reaction involves three sequential steps: (i) formation of a tetrahedral intermediate with the active site lysine and the amino substrate bonded to the PLP cofactor; (ii) nondirect proton transfer between the amino substrate and the lysine residue; and (iii) formation of the external aldimine after the dissociation of the lysine residue. The overall reaction is exothermic (-12.0 kcal/mol), and the rate-limiting step is the second one with 12.6 kcal/mol for the activation energy. PMID- 26610131 TI - Efficient Solvation Free Energy Calculations of Amino Acid Analogs by Expanded Ensemble Molecular Simulation. AB - We present an efficient, automated expanded ensemble method to calculate the residual chemical potential or solvation free energy by molecular dynamics simulation. The methodology is validated by computing the residual chemical potential of 13 amino acid analogs in water at 300 K and 1 bar and comparing to reference simulation data. Overall agreement is good, with the methodology of the present study reaching limiting precisions of less than 0.1 kBT in half of the total simulation time of the reference simulation study which utilized Bennett's acceptance ratio method. The apparent difference in the efficiencies is a result of the inherent advantages of the expanded ensemble method, which creates an improved decorrelation of simulation data and improves the sampling of the important regions of the configurational phase space of each subensemble. The present adaptation utilizes histograms of proposed transition energies collected throughout the entire simulation, to make extremely precise calculations of the relative free energy between neighboring subensembles. PMID- 26610132 TI - Conformational Dependence of Isotropic Polarizabilities. AB - We perform a statistical and energetic analysis of atomic polarizabilities obtained with the LoProp approach for all atoms in the avidin tetramer for 70 snapshots from molecular dynamics simulations with seven different biotin analogues, and from the crystal structure of the photosynthetic reaction center (in total 560 698 individual polarizabilities). Dynamic effects give a variation of the polarizabilities of 0.09 A(3) on average. Atoms at different positions in the sequence show a variation of 0.14 A(3) on average, caused by the conformational dependence of the polarizabilities. This variation gives errors of 2 and 1 kJ/mol for relative conformational and ligand-binding induction energies. Averaged elementwise or atom-type polarizabilities give larger errors, e.g., 9 and 7 kJ/mol, respectively, for the relative conformational energies. Therefore, we recommend that polarizabilities should be assigned atomwise (i.e., individual polarizabilities for each atom in all residues), in the same way as for charges. We provide such a set of extensively averaged polarizabilities (xAvPol) for all atoms in avidin and the photosynthetic reaction center, applicable at the B3LYP/aug-cc-pVTZ level, which is converged with respect to the basis-set limit. PMID- 26610133 TI - Vibrational Energy Levels via Finite-Basis Calculations Using a Quasi-Analytic Form of the Kinetic Energy. AB - A variational method for the calculation of low-lying vibrational energy levels of molecules with small amplitude vibrations is presented. The approach is based on the Watson Hamiltonian in rectilinear normal coordinates and characterized by a quasi-analytic integration over the kinetic energy operator (KEO). The KEO beyond the harmonic approximation is represented by a Taylor series in terms of the rectilinear normal coordinates around the equilibrium configuration. This formulation of the KEO enables its extension to arbitrary order until numerical convergence is reached for those states describing small amplitude motions and suitably represented with a rectilinear system of coordinates. A Gauss-Hermite quadrature grid representation of the anharmonic potential is used for all the benchmark examples presented. Results for a set of molecules with linear and nonlinear configurations, i.e., CO2, H2O, and formyl fluoride (HFCO), illustrate the performance of the method and the versatility of our implementation. PMID- 26610134 TI - First Principles Simulations of the Infrared Spectrum of Liquid Water Using Hybrid Density Functionals. AB - We show that first principles hybrid functional (PBE0) simulations of the infrared spectrum of liquid water yields a much better agreement with experimental results than a semilocal functional description; in particular, the quantitative accord with measured stretching and bending bands is very good. Such an improved description stems from two effects: a more accurate account, at the PBE0 level of theory, of the vibrational properties of the monomer and dimer and an underlying structural model for the liquid with a smaller number of hydrogen bonds and oxygen coordination than those obtained with semilocal functionals. The average electronic gap of the liquid is increased by 60% with respect to the PBE value, when computed at the PBE0 level of theory, and is in fair agreement with experimental results. PMID- 26610135 TI - Combination of RISM and Cheminformatics for Efficient Predictions of Hydration Free Energy of Polyfragment Molecules: Application to a Set of Organic Pollutants. AB - Here, we discuss a new method for predicting the hydration free energy (HFE) of organic pollutants and illustrate the efficiency of the method on a set of 220 chlorinated aromatic hydrocarbons. The new model is computationally inexpensive, with one HFE calculation taking less than a minute on a PC. The method is based on a combination of a molecular integral equations theory, one-dimensional reference interaction site model (1D RISM), with the cheminformatics approach. We correct HFEs obtained by the 1D RISM with a set of empirical corrections. The corrections are associated with the partial molar volume and structural descriptors of the molecules. We show that the introduced corrections can significantly improve the quality of the 1D RISM HFE predictions obtained by the partial wave free energy expression [ Ten-no , S. J. Chem. Phys. 2001 , 115 , 3724 ] and the Kovalenko-Hirata closure [ Kovalenko , A. ; Hirata , F. J. Chem. Phys. 1999 , 110 , 10095 ]. We also show that the quality of the model can be further improved by the reparametrization using QM-derived partial charges instead of the originally used OPLS-AA partial charges. The final model gives good results for polychlorinated benzenes (the mean and standard deviation of the error are 0.02 and 0.36 kcal/mol, correspondingly). At the same time, the model gives somewhat worse results for polychlorobiphenyls (PCBs) with a systematic bias of -0.72 kcal/mol but a small standard deviation equal to 0.55 kcal/mol. We note that the error remains the same for the whole set of PCBs, whereas errors of HFEs predicted with continuum solvation models (data were taken from Phillips , K. L. et al. Environ. Sci. Technol. 2008 , 42 , 8412 ) increase significantly for higher chlorinated PCB congeners. In conclusion, we discuss potential future applications of the model and several avenues for its further improvement. PMID- 26610136 TI - Using Theory to Reconcile Experiment: The Structural and Thermodynamic Basis of Ligand Recognition by Phenylethanolamine N-Methyltransferase (PNMT). AB - A fundamental challenge in computational drug design is the availability of reliable and validated experimental binding and structural data against which theoretical calculations can be compared. In this work a combination of molecular dynamics (MD) simulations and free energy calculations has been used to analyze the structural and thermodynamic basis of ligand recognition by phenylethanolamine N-methyltransferase (PNMT) in an attempt to resolve uncertainties in the available binding and structural data. PNMT catalyzes the conversion of norepinephrine into epinephrine (adrenaline), and inhibitors of PNMT are of potential therapeutic importance in Alzheimer's and Parkinson's disease. Excellent agreement between the calculated and recently revised relative binding free energies to human PNMT was obtained with the average deviation between the calculated and the experimentally determined values being only 0.8 kJ/mol. In this case, the variation in the experimental data over time is much greater than the uncertainties in the theoretical estimates. The calculations have also enabled the refinement of structure-activity relationships in this system, to understand the basis of enantiomeric selectivity of substitution at position three of tetrahydroisoquinoline and to identify the role of specific structural waters. Finally, the calculations suggest that the preferred binding mode of trans-(1S,2S)-2-amino-1-tetralol is similar to that of its epimer cis (1R,2S)-2-amino-1-tetralol and that the ligand does not adopt the novel binding mode proposed in the pdb entry 2AN5 . The work demonstrates how MD simulations and free energy calculations can be used to resolve uncertainties in experimental binding affinities, binding modes, and other aspects related to X-ray refinement and computational drug design. PMID- 26610137 TI - On the Calculation of the Dielectric Permittivity and Relaxation of Molecular Models in the Liquid Phase. AB - Methodology to compute the relative static dielectric permittivity and dielectric relaxation time of molecular liquids is reviewed and explicit formulas are given for the external field method in the case of simulations using a spherical cutoff, in which the background dielectric permittivity (epsiloncs) can be larger than one, in combination with a Poisson-Boltzmann reaction-field approximation for long-range electrostatic interactions. The external field method is simple to implement and computationally efficient. It is particularly suitable for polarizable molecular models with zero permanent dipole moment and for coarse grained molecular models with epsiloncs > 1. The dielectric permittivities and relaxation times of water (H2O), dimethylsulfoxide (DMSO), methanol (MeOH), and chloroform (CHCl3), which range from 2 to 80 and from 5 ps to 50 ps, respectively, were calculated as an illustration. PMID- 26610138 TI - Small Molecules in C60 and C70: Which Complexes Could Be Stabilized? AB - The recent syntheses of complexes involving some small molecules in opened fullerenes and those of hydrogen molecule(s) in C60 and C70 are accompanied in the literature by numerous computations for endohedral fullerene complexes which cope with the problem of the stability of these complexes. In this contribution, stabilization energies of endohedral complexes of C60 and C70 with H2, N2, CO, HCN, H2O, H2S, NH3, CH4, CO2, C2H2, H2CO, and CH3OH guests have been estimated using symmetry-adapted perturbation theory, which, contrary to the standard DFT and some other approaches, correctly describes the dispersion contribution of the host-guest interactions. On the basis of these calculations, the endohedral complexes with all these guests were found stable in the larger fullerene, while the C60 cage was found too small to host the latter four molecules. Except for H2 and H2CO, a stabilization effect for most guests in the C60 cage is about 30 kJ/mol. For H2 and H2O guests, a typical supramolecular effect is observed; namely, the stabilization in the smaller cage is equal to or larger than that in the larger C70 host. Except for the water molecule where the induction interaction plays a non-negligible role, in all complexes the main stabilization effect comes from the dispersion interaction. The information on the stability of hypothetical endohedral fullerene complexes and physical factors contributing to it can be of importance in designing future experiments contributing to their applications. PMID- 26610139 TI - Free Energy Landscapes of Alanine Dipeptide in Explicit Water Reproduced by the Force-Switching Wolf Method. AB - Precise and rapid calculation of long-range interactions is of crucial importance for molecular dynamics (MD) and Monte Carlo simulations. Instead of the Ewald method or its high speed variant, PME, we applied our novel method, called the force-switching Wolf method, to computation of the free energy landscapes of a short peptide in explicit water. Wolf and co-workers showed that long-range electrostatic energy under a periodic boundary condition can be well reproduced even by truncating the contribution from the distant charges, when the charge neutrality is taken into account. We recently applied the procedure proposed by Wolf and co-workers to a mathematically consistent MD theory by means of a force switching scheme, and we show that the total electrostatic energy for sodium chloride liquid was well conserved and stable during the MD simulation with the force-switching Wolf method. Our current results for an aqueous peptide solution with a series of canonical and multicanonical molecular dynamics simulations show that the force-switching Wolf method is not only in good accordance with the energies and forces calculated by the conventional PME method but also properly reproduces the solvation and the free energy landscapes of the peptide at 300 K. PMID- 26610140 TI - Quantum Chemical Modeling of Enzymatic Reactions: The Case of Decarboxylation. AB - We present a systematic study of the decarboxylation step of the enzyme aspartate decarboxylase with the purpose of assessing the quantum chemical cluster approach for modeling this important class of decarboxylase enzymes. Active site models ranging in size from 27 to 220 atoms are designed, and the barrier and reaction energy of this step are evaluated. To model the enzyme surrounding, homogeneous polarizable medium techniques are used with several dielectric constants. The main conclusion is that when the active site model reaches a certain size, the solvation effects from the surroundings saturate. Similar results have previously been obtained from systematic studies of other classes of enzymes, suggesting that they are of a quite general nature. PMID- 26610141 TI - Impact of Thermostats on Folding and Aggregation Properties of Peptides Using the Optimized Potential for Efficient Structure Prediction Coarse-Grained Model. AB - The simulation of amyloid fibril formation is impossible if one takes into account all chemical details of the amino acids and their detailed interactions with the solvent. We investigate the folding and aggregation of two model peptides using the optimized potential for efficient structure prediction (OPEP) coarse-grained model and replica exchange molecular dynamics (REMD) simulations coupled with either the Langevin or the Berendsen thermostat. For both the monomer of blocked penta-alanine and the trimer of the 25-35 fragment of the Alzheimer's amyloid beta protein, we find little variations in the equilibrium structures and heat capacity curves using the two thermostats. Despite this high similarity, we detect significant differences in the populations of the dominant conformations at low temperatures, whereas the configurational distributions remain the same in proximity of the melting temperature. Abeta25-35 trimers at 300 K have an averaged beta-sheet content of 12% and are primarily characterized by fully disordered peptides or a small curved two-stranded beta-sheet stabilized by a disordered peptide. In addition, OPEP molecular dynamics simulations of Abeta25-35 hexamers at 300 K with a small curved six-stranded antiparallel beta sheet do not show any extension of the beta-sheet content. These data support the idea that the mechanism of Abeta25-35 amyloid formation does not result from a high fraction of extended beta-sheet-rich trimers and hexamers. PMID- 26610142 TI - Interplay of Correlation and Relativistic Effects in Correlated Calculations on Transition-Metal Complexes: The (Cu2O2)(2+) Core Revisited. AB - Owing to the availability of large-scale computing facilities and the development of efficient new algorithms, wave function-based ab initio calculations are becoming more common in bioinorganic chemistry. In principle they offer a systematic route toward high accuracy. However, these calculations are by no means trivial. In this contribution we address some pertinent points through a systematic theoretical study for the equilibrium between the peroxo- and bis-(MU oxo) isomers of the [{Cu(C2H8N2)}2O2](2+) complex. While this system is often regarded as a prototypical multireference case, we treat it with the single reference local-pair natural orbital coupled cluster method and reiterate that the multireference character in this system is very limited. A set of intermediate structures, for the interconversion between the two isomers, is calculated through a relaxed surface scan thus allowing the calculation of an energetic profile that cleanly connects the bis-(MU-oxo) and side-on peroxo minima on the ground-state potential energy surface. Only at the highest level of theory involving complete basis set extrapolation, triple excitation contributions as well as relativistic and solvent effects, the bis-(MU-oxo) isomer is found to be slightly more stable than the peroxo structure. This is in agreement with the experimental findings. The effects of basis set, triples excitation, relativity, and solvent contribution have all been analyzed in detail. Finally, the ab initio results are compared with density functional calculations using various functionals. It is demonstrated that the largest part of the discrepancies of the results reported in the literature are due to an inconsistent handling of relativistic effects, which are large in both ab initio and density functional theory calculations. PMID- 26610143 TI - Role of the Axial Base in the Modulation of the Cob(I)alamin Electronic Properties: Insight from QM/MM, DFT, and CASSCF Calculations. AB - Quantum chemical computations are used to study the electronic and structural properties of the cob(I)alamin intermediate of the cobalamin-dependent methionine synthase (MetH). QM(DFT)/MM calculations on the methylcobalamin (MeCbl) binding domain of MetH reveal that the transfer of the methyl group to the substrate is associated with the displacement of the histidine axial base (His759). The axial base oscillates between a His-on form in the Me-cob(III)lamin:MetH resting state, where the Co-N(His759) distance is 2.27 A, and a His-off form in the cob(I)alamin:MetH intermediate (2.78 A). Furthermore, QM/MM and gas phase DFT calculations based on an unrestricted formalism show that the cob(I)alamin intermediate exhibits a complex electronic structure, intermediate between the Co(I) and Co(II)-radical corrin states. To understand this complexity, the electronic structure of Im...[Cob(I)alamin] is investigated using multireference CASSCF/QDPT2 calculations on gas phase models where the axial histidine is modeled by imidazole (Im). It is found that the correlated ground state wave function consists of a closed-shell Co(I) (d(8)) configuration and a diradical contribution, which can be described as a Co(II) (d(7))-radical corrin (pi*)(1) configuration. Moreover, the contribution of these two configurations depends on the Co-NIm distance. At short Co-NIm distances (<2.5 A), the dominant electronic configuration is the diradical state, while for longer distances it is the closed shell state. The implications of this finding are discussed in the context of the methyl transfer reaction between the Me-H4folate substrate and cob(I)alamin. PMID- 26610144 TI - Secondary Structure Assignment of Amyloid-beta Peptide Using Chemical Shifts. AB - The distinct conformational dependence of chemical shifts caused by alpha-helices and beta-sheets renders NMR chemical shift analysis a powerful tool for the structural determination of proteins. However, the time scale of NMR experiments can make a secondary structure assignment of highly flexible peptides or proteins, which may be converting between conformational substates, problematic. For instance the amyloid-beta monomer, according to NMR chemical shifts, adopts a predominately random coil structure in aqueous solution (with <3% alpha-helical content). Molecular dynamics simulations, on the other hand, suggest that alpha helical content can be significant (10-25%). In this paper, we explore the possible reasons for this discrepancy and show that the different results from experiments and theory are not necessarily mutually exclusive but may reflect a general problem of secondary structure assignment of conformationally flexible biomolecules. PMID- 26610145 TI - Local currents in a 2D topological insulator. AB - Symmetry protected edge states in 2D topological insulators are interesting both from the fundamental point of view as well as from the point of view of potential applications in nanoelectronics as perfectly conducting 1D channels and functional elements of circuits. Here using a simple tight-binding model and the Landauer-Buttiker formalism we explore local current distributions in a 2D topological insulator focusing on effects of non-magnetic impurities and vacancies as well as finite size effects. For an isolated edge state, we show that the local conductance decays into the bulk in an oscillatory fashion as explained by the complex band structure of the bulk topological insulator. We demonstrate that although the net conductance of the edge state is topologically protected, impurity scattering leads to intricate local current patterns. In the case of vacancies we observe vortex currents of certain chirality, originating from the scattering of current-carrying electrons into states localized at the edges of hollow regions. For finite size strips of a topological insulator we predict the formation of an oscillatory band gap in the spectrum of the edge states, the emergence of Friedel oscillations caused by an open channel for backscattering from an impurity and antiresonances in conductance when the Fermi energy matches the energy of the localized state created by an impurity. PMID- 26610146 TI - Disruption and eradication of P. aeruginosa biofilms using nitric oxide-releasing chitosan oligosaccharides. AB - Biofilm disruption and eradication were investigated as a function of nitric oxide- (NO) releasing chitosan oligosaccharide dose and the results compared with control (i.e., non-NO-releasing) chitosan oligosaccharides and tobramycin. Quantification of biofilm expansion/contraction and multiple-particle tracking microrheology were used to assess the structural integrity of the biofilm before and after antibacterial treatment. While tobramycin had no effect on the physical properties of the biofilm, NO-releasing chitosan oligosaccharides exhibited dose dependent behavior with biofilm degradation. Control chitosan oligosaccharides increased biofilm elasticity, indicating that the scaffold may mitigate the biofilm disrupting power of nitric oxide somewhat. The results from this study indicate that nitric oxide-releasing chitosan oligosaccharides act as dual-action therapeutics capable of eradicating and physically disrupting P. aeruginosa biofilms. PMID- 26610147 TI - Student-selected components in neurosurgery. AB - Student-selected components (SSCs) are protected periods of time in the undergraduate medical curriculum which allow students to explore an area of medicine they are interested in. They are particularly valuable in exposing students to smaller specialties like neurosurgery, which are often sparsely covered in the rest of the undergraduate curriculum. Moreover, they provide opportunities for students interested in pursuing a career in neurosurgery to increase their likelihood of being successful in specialty training applications. In this article, we summarise our department's experience of hosting SSCs. Furthermore, we have set out to establish a series of achievable objectives over the course of a typical SSC in neurosurgery. This includes the possibility of participation in research and audit, which, if well planned, can be rewarding for both the student and the host unit. SSCs are an effective means of exposing medical students to neurosurgery and provide a multitude of opportunities for enhancing clinical competencies and career development. PMID- 26610148 TI - Cost-analysis model of colonoscopy preparation using split-dose reduced-volume oral sulfate solution (OSS) and polyethylene glycol with electrolytes solution (PEG-ELS). AB - OBJECTIVE: The study aimed to (1) develop a cost model for colonoscopy preparation among patients referred for colonoscopy using split-dose reduced volume oral sulfate solution (OSS) and generic polyethylene glycol with electrolytes solution (PEG-ELS), (2) examine cost savings associated with OSS vs PEG-ELS, and (3) assess the robustness of the cost model. METHODS: Efficacy of each agent was based on the results of a 541-patient clinical trial comparing OSS to PEG-ELS. Cleansing agent and colonoscopy procedure costs were calculated from OptumHealth Reporting & Insights claims data for 2010-Q12013. In the model, patients' colonoscopies were tracked over a 25 or 35 year time period until the patients reached age 75. The difference per patient per year (PPPY) in total cleansing agent and colonoscopy procedure costs over the time horizon between the OSS and PEG-ELS cohort was calculated. One-way sensitivity analyses were conducted to test the robustness of the cost model. RESULTS: The model showed lower cost for OSS patients over the time horizon. Total PPPY costs were $280.34 for the OSS cohort and $296.36 for the PEG-ELS cohort, resulting in a cost saving of $16.01 PPPY for the OSS cohort. This was due primarily to OSS patients having fewer colonoscopies (OSS: 0.158 vs PEG-ELS: 0.170 PPPY). Over the time horizon, cost savings of $4 763 335 were observed among 10, 000 OSS patients. Cost savings switched from OSS to PEG-ELS cohort in four cases: (1) base-case cost of a completed colonoscopy decreased by 75%, (2) base-case cost of OSS increased to over $143 per usage, (3) all non-completers were lost to follow-up, and (4) OSS bowel preparation quality dropped below PEG-ELS to 70%. CONCLUSIONS: From a payer's perspective, the model showed that the use of OSS as the cleansing agent resulted in potential cost savings compared with PEG-ELS. Cost savings under OSS remained under various sensitivity analyses. PMID- 26610149 TI - MicroRNA-10a Influences Osteoblast Differentiation and Angiogenesis by Regulating beta-Catenin Expression. AB - BACKGROUND/AIMS: Elucidation of the molecular mechanisms governing osteoblast differentiation and angiogenesis are of great importance for improving the treatment of bone-related diseases. In this study, we examined the role of microRNA (miR)-10a in the differentiation of MC3T3-E1 cells and pro angiogenic activity of mouse umbilical vein endothelial cells (MUVECs). METHODS: The murine pre-osteoblast cell line MC3T3-E1 and MUVECs were used in the experiment. After transfected with miR-10a mimics or inhibitors, with or without LiCl pretreatment, the miR-10a, ALP, Runx2, Osx, OC and Dlx5 expression were assessed by RT-PCR. MC3T3-E1 cells were cultured with BMP2 to differentiate into bone cells, osteogenic differentiation of MC3T3-E1 cells were detected by ALP and ARS staining. Cell viability were analyzed by MTT and the protein expression of beta catenin, LEF1, cyclinD1, MMP2, and VEGF were detected by Western blotting; VEGF and VE-cadherin release were assessed by ELISA, and the migration of MUVECs, as well as tube formation were also detected. RESULTS: MiR-10a expression was obviously down-regulated during osteogenic differentiation. Overexpression of miR 10a inhibited osteogenic differentiation of MC3T3-E1 cells, effectively decreasing MUVECs proliferation, migration, VEGF expression, VE-cadherin concentrations, and tube formation in vitro, whereas miR-10a silence enhanced those processes. Further mechanism assays demonstrated that overexpression of miR 10a reduced the beta-catenin at both protein and transcription level, while pretreatment with Wnt signaling activator Licl partially attenuated the suppression effects of miR-10a overexpression on osteoblast differentiation and angiogenesis. CONCLUSION: Our findings imply that miR-10a plays a suppressive role in osteoblast differentiation of MC3T3-E1 cells and pro angiogenic activity of MUVECs by regulating the beta-catenin expression, representing a novel and potential therapeutic target for the treatment of bone regeneration-related diseases. PMID- 26610150 TI - Communities of teaching practice in the workplace: Evaluation of a faculty development programme. AB - BACKGROUND: The focus of faculty development (FD) has recently shifted from individual and formal learning to formal and informal learning by a team of teachers in the workplace where the teaching is actually effected. This study aimed to evaluate the impact of a faculty development programme on teachers' educational workplace environment. METHODS: We invited 23 teachers, who had successfully completed a University Teaching Qualification (UTQ) programme, to evaluate the faculty development programme and participate in focus group discussions. This UTQ programme spanned one year and covered 185 hours of formal and informal learning and training activities and formal coaching. RESULTS: After having obtained their UTQ, teachers reported that coaching enhances reflection and feedback, to participate more frequently in educational networks, which enhances consultation among teachers, increased awareness of organizational educational policies and more confidence in fulfilling educational tasks and activities. CONCLUSION: The evaluation of the UTQ programme demonstrated to enhance the development of a community of teachers at the workplace who share a passion for education and provide each other with support and feedback, which triggered a change in culture enhancing improvement of education. However, this did not hold for all teachers. Inhibiting factors hold sway, such as a prevailing commitment to research over education in some departments and a lack of interest in education by some department chairs. PMID- 26610151 TI - Armored kinorhynch-like scalidophoran animals from the early Cambrian. AB - Morphology-based phylogenetic analyses support the monophyly of the Scalidophora (Kinorhyncha, Loricifera, Priapulida) and Nematoida (Nematoda, Nematomorpha), together constituting the monophyletic Cycloneuralia that is the sister group of the Panarthropoda. Kinorhynchs are unique among living cycloneuralians in having a segmented body with repeated cuticular plates, longitudinal muscles, dorsoventral muscles, and ganglia. Molecular clock estimates suggest that kinorhynchs may have diverged in the Ediacaran Period. Remarkably, no kinorhynch fossils have been discovered, in sharp contrast to priapulids and loriciferans that are represented by numerous Cambrian fossils. Here we describe several early Cambrian (~535 million years old) kinorhynch-like fossils, including the new species Eokinorhynchus rarus and two unnamed but related forms. E. rarus has characteristic scalidophoran features, including an introvert with pentaradially arranged hollow scalids. Its trunk bears at least 20 annuli each consisting of numerous small rectangular plates, and is armored with five pairs of large and bilaterally placed sclerites. Its trunk annuli are reminiscent of the epidermis segments of kinorhynchs. A phylogenetic analysis resolves E. rarus as a stem group kinorhynch. Thus, the fossil record confirms that all three scalidophoran phyla diverged no later than the Cambrian Period. PMID- 26610152 TI - Is asthma prevalence still increasing? AB - Increased awareness of asthma in society and altered diagnostic practices makes evaluation of data on prevalence change difficult. In most parts of the world the asthma prevalence seems to still be increasing. The increase is associated with urbanization and has been documented particularly among children and teenagers in urban areas of middle- and low-level income countries. Use of validated questionnaires has enabled comparisons of studies. Among adults there are few studies based on representative samples of the general population which allow evaluation of time trends of prevalence. This review focuses mainly on studies of asthma prevalence and symptoms among adults. Parallel with increased urbanization, we can assume that the increase in asthma prevalence in most areas of the world will continue. However, in Australia and North-West Europe studies performed, particularly among children and adolescents, indicate that the increase in asthma prevalence may now be leveling off. PMID- 26610153 TI - The use of electromyography interference pattern analysis to determine muscle force of the deep digital flexor muscle in healthy and laminitic horses. AB - BACKGROUND: In equine laminitis, the deep digital flexor muscle (DDFM) appears to have increased muscle force, but evidence-based confirmation is lacking. OBJECTIVES: The purpose of this study was to test if the DDFM of laminitic equines has an increased muscle force detectable by needle electromyography interference pattern analysis (IPA). ANIMALS AND METHODS: The control group included six Royal Dutch Sport horses, three Shetland ponies and one Welsh pony [10 healthy, sound adults weighing 411 +/- 217 kg (mean +/- SD) and aged 10 +/- 5 years]. The laminitic group included three Royal Dutch Sport horses, one Friesian, one Haflinger, one Icelandic horse, one Welsh pony, one miniature Appaloosa and six Shetland ponies (14 adults, weight 310 +/- 178 kg, aged 13 +/- 6 years) with acute/chronic laminitis. The electromyography IPA measurements included firing rate, turns/second (T), amplitude/turn (M) and M/T ratio. Statistical analysis used a general linear model with outcomes transformed to geometric means. RESULTS: The firing rate of the total laminitic group was higher than the total control group. This difference was smaller for the ponies compared to the horses; in the horses, the geometric mean difference of the laminitic group was 1.73 [geometric 95% confidence interval (CI) 1.29-2.32], and in the ponies this value was 1.09 (geometric 95% CI 0.82-1.45). CONCLUSION AND CLINICAL RELEVANCE: In human medicine, an increased firing rate is characteristic of increased muscle force. Thus, the increased firing rate of the DDFM in the context of laminitis suggests an elevated muscle force. However, this seems to be only a partial effect as in this study, the unchanged turns/second and amplitude/turn failed to prove the recruitment of larger motor units with larger amplitude motor unit potentials in laminitic equids. PMID- 26610154 TI - Using Score Equating and Measurement Invariance to Examine the Flynn Effect in the Wechsler Adult Intelligence Scale. AB - The Flynn effect (FE; i.e., increase in mean IQ scores over time) is commonly viewed as reflecting population shifts in intelligence, despite the fact that most FE studies have not investigated the assumption of score comparability. Consequently, the extent to which these mean differences in IQ scores reflect population shifts in cognitive abilities versus changes in the instruments used to measure these abilities is unclear. In this study, we used modern psychometric tools to examine the FE. First, we equated raw scores for each common subtest to be on the same scale across instruments. This enabled the combination of scores from all three instruments into one of 13 age groups before converting raw scores into Z scores. Second, using age-based standardized scores for standardization samples, we examined measurement invariance across the second (revised), third, and fourth editions of the Wechsler Adult Intelligence Scale. Results indicate that while scores were equivalent across the third and fourth editions, they were not equivalent across the second and third editions. Results suggest that there is some evidence for an increase in intelligence, but also call into question many published FE findings as presuming the instruments' scores are invariant when this assumption is not warranted. PMID- 26610155 TI - A Heterogeneous Growth Curve Model for Nonnormal Data. AB - The heterogeneous growth curve model (HGM; Klein & Muthen, 2006 ) is a method for modeling heterogeneity of growth rates with a heteroscedastic residual structure for the slope factor. It has been developed as an extension of a conventional growth curve model and a complementary tool to growth curve mixture models. In this article, a robust version of the heterogeneous growth curve model (HGM-R) is presented that extends the original HGM with a mixture model to allow for an unbiased parameter estimation under the condition of nonnormal data. In two simulation studies, the performance of the method is examined under the condition of nonnormality and a misspecified heteroscedastic residual structure. The results of the simulation studies suggest an unbiased estimation of the heterogeneity by the HGM-R when sample size was large enough and a good approximation of the heteroscedastic residual structure even when the functional form of the heteroscedasticity was misspecified. The practical application of the approach is demonstrated for a data set from HIV-infected patients. PMID- 26610156 TI - Testing Group Mean Differences of Latent Variables in Multilevel Data Using Multiple-Group Multilevel CFA and Multilevel MIMIC Modeling. AB - Considering that group comparisons are common in social science, we examined two latent group mean testing methods when groups of interest were either at the between or within level of multilevel data: multiple-group multilevel confirmatory factor analysis (MG ML CFA) and multilevel multiple-indicators multiple-causes modeling (ML MIMIC). The performance of these methods were investigated through three Monte Carlo studies. In Studies 1 and 2, either factor variances or residual variances were manipulated to be heterogeneous between groups. In Study 3, which focused on within-level multiple-group analysis, six different model specifications were considered depending on how to model the intra-class group correlation (i.e., correlation between random effect factors for groups within cluster). The results of simulations generally supported the adequacy of MG ML CFA and ML MIMIC for multiple-group analysis with multilevel data. The two methods did not show any notable difference in the latent group mean testing across three studies. Finally, a demonstration with real data and guidelines in selecting an appropriate approach to multilevel multiple-group analysis are provided. PMID- 26610157 TI - Implications of Item Keying and Item Valence for the Investigation of Construct Dimensionality. AB - Factor analysis and nomological network analysis are commonly used as complementary procedures in the investigation of the dimensionality of constructs (e.g., self-esteem, job satisfaction). Although it has been demonstrated that factor analyses are often biased toward a two-dimensional solution for measures including regular- and reverse-keyed items, less attention has been paid to the implications for nomological network analyses. We propose, and demonstrate empirically in two studies, that item keying is confounded with item valence (i.e., favorability of item content), and that item valence can bias the results of both factor analysis and nomological network analysis toward a two-dimensional interpretation. We also demonstrate that the valence effect is related to, but distinguishable from, social desirability response bias. We caution that the practice of excluding reverse-keyed items to achieve unidimensionality can lead to distortion in correlations among constructs, and we offer alternative remedies to the valence problem. PMID- 26610158 TI - Persistent atrial fibrillation ablation: conventional versus driver-guided strategy. AB - While pulmonary vein isolation for paroxysmal atrial fibrillation (AF) is highly effective, catheter ablation for persistent AF remains a challenge with varying clinical success reported. Several ablation techniques have been proposed to target persistent AF, with the additional ablation of complex fractionated electrograms and linear lesions shown to provide incremental success to pulmonary vein isolation alone. Recently, several studies have suggested the presence of localized drivers (re-entrant or focal) in AF. By targeting these drivers, clinical outcomes may be maintained while minimizing the extent of ablation. This article will focus on the conventional stepwise ablation approach for persistent AF versus driver-guided ablation with the use of newer mapping technologies. PMID- 26610159 TI - Pharmacological effects of berberine and its derivatives: a patent update. AB - INTRODUCTION: A number of plant-derived agents are used in many therapeutic areas. Berberine, an important protoberberine alkaloid, is present in a number of medicinal plants that have been widely used in traditional Chinese medicine for hundreds of years. Modern research has shown that berberine and its derivatives display several pharmacological effects through various mechanisms. AREAS COVERED: This review discusses recent and mostly Chinese patents that report the synthesis of berberine, berberine derivatives and berberine salts, and methods of preparation for formulations (traditional Chinese medicine) containing herbal components rich in berberine, along with their applications. The review covers several therapeutic effects of berberine, its derivatives and pharmaceutical formulations against cancer, obesity, diabetes, inflammation, atherosclerosis, Alzheimer's disease, rheumatoid arthritis and cardiovascular diseases. In addition, the mechanisms underlying the pharmacological effects are discussed. EXPERT OPINION: Modification of the functional groups of berberine has a significant effect on the pharmacological activity. However, studies on altering the atoms and size of the berberine skeleton are rare. Thus, it may be beneficial to initiate a drug development program focused on inserting heterocyclic rings of different sizes into berberine. Furthermore, structural modification to improve the safety, efficacy and selectivity is necessary to promote the use of berberine based drugs in clinical settings. PMID- 26610160 TI - Internet-supported versus face-to-face cognitive behavior therapy for depression. AB - Major depression and depressive symptoms are highly prevalent and there is a need for different forms of psychological treatments that can be delivered from a distance at a low cost. In the present review the authors contrast face-to-face and Internet-delivered cognitive behavior therapy (ICBT) for depression. A total of five studies are reviewed in which guided ICBT was directly compared against face-to-face CBT. Meta-analytic summary statistics were calculated for the five studies involving a total of 429 participants. The average effect size difference was Hedge's g = 0.12 (95% CI: -0.06-0.30) in the direction of favoring guided ICBT. The small difference in effect has no implication for clinical practice. The overall empirical status of clinician-guided ICBT for depression is commented on and future challenges are highlighted. Among these are developing treatments for patients with more severe and long-standing depression and for children, adolescents and the elderly. Also, there is a need to investigate mechanisms of change. PMID- 26610161 TI - Two new triterpenoid glycosides from the stems of Camellia oleifera Abel. AB - Two new oleanane-type triterpenoid glycosides, 3-O-beta-D-xylopyranosyl-(1->2) alpha-L-arabinopyranosyl-(1->3)-[beta-D-glucuronopyranosyl-(1->2)]-beta-D glucuronopyranosyl-22alpha-angeloyloxyolean-12-ene-15alpha,16alpha,28-triol(1) and 3-O-beta-D-xylopyranosyl-(1->2)-alpha-L-arabinopyranosyl-(1->3)-[beta-D glucuronopyranosyl-(1->2)]-beta-D-glucuronopyranosyl-21beta-acetyl-22alpha angeloyloxyolean-12-ene-16alpha,28-diol (2) were isolated from the stems of Camellia oleifera Abel. Their structures were elucidated by means of spectroscopic methods and chemical evidence. The cytotoxic activities of compounds 1-2 were evaluated against five human tumour cell lines (HCT-8, BGC 823, A5049, and A2780). Compounds 1-2 showed cytotoxic activity against five human cancer cell lines, with IC50 values ranging from 3.15 to 7.32 MUM. PMID- 26610162 TI - Adenocarcinoma arising from heterotopic gastric mucosa in the cervical esophagus and upper thoracic esophagus: two case reports and literature review. AB - Primary adenocarcinoma arising from heterotopic gastric mucosa (HGM) is rare and the clinicopathological characteristics are not well known. We present two cases of esophageal adenocarcinoma arising from HGM with a review of a case series. Case 1 was a 78-year-old woman who underwent a periodic medical examination without complaining of any symptoms. Preoperative evaluation suggested esophageal adenocarcinoma arising from the HGM. The patient was treated with endoscopic submucosal dissection. Definitive pathological diagnosis confirmed adenocarcinoma arising from the HGM. Case 2 was a 70-year-old man who underwent a medical examination after complaining of dysphagia. Preoperative diagnosis suggested esophageal adenocarcinoma; however, its origin was unclear. The patient was treated with surgical resection. Definitive pathological diagnosis revealed adenocarcinoma arising from the HGM. In this article, the authors report the clinicopathological features of esophageal adenocarcinoma arising from HGM that were collected from a literature review and our cases. PMID- 26610163 TI - A computational study on role of 6-(hydroxymethyl)-3-[3,4,5-trihydroxy-6-[(3,4,5 trihydroxyoxan-2-yl)oxymethyl]oxan-2-yl]oxyoxane-2,4,5-triol in the regulation of blood glucose level. AB - 6-(hydroxymethyl)-3-[3,4,5-trihydroxy-6-[(3,4,5-trihydroxyoxan-2 yl)oxymethyl]oxan-2-yl]oxyoxane-2,4,5-triol (SID 242078875) was isolated from the fruits of Syzygium densiflorum Wall. ex Wight & Arn (Myrtaceae), which has been traditionally used in the treatment of diabetes by the tribes of The Nilgiris, Tamil Nadu, India. In this study, reverse pharmacophore mapping approach and text based database search identified the dipeptidyl peptidase-IV, protein-tyrosine phosphatase 1B, phosphoenolpyruvate carboxykinase, glycogen synthase kinase-3beta and glucokinase as potential targets of SID 242078875 in diabetes management. Further, molecular docking was performed to predict the binding pose of SID 242078875 in the active site region of the target protein. In addition, dynamic behaviour and stability of protein-ligand complexes were observed for a period of 50 ns through molecular dynamics simulation. PMID- 26610164 TI - A proposed set of metrics for standardized outcome reporting in the management of low back pain. PMID- 26610165 TI - Trait predictors of placebo responses in itch. AB - This study investigated trait predictors of placebo responses in the context of inflammatory skin reactions. This was a randomized, cross-over, experimental study using a deceptive placebo protocol. A healthy sample of volunteers (N = 48) completed online personality measures, then attended two laboratory sessions in which short-term inflammatory skin reactions were induced. One was a control session and the other the 'treatment' session in which a placebo cream was administered with the suggestion of a reduced skin reaction. A placebo response was defined as smaller skin reactions in control vs. treatment sessions. The traits ego resiliency and neuroticism were selected as possible predictors of placebo responses. Traits were selected in consideration of the two-faceted transactional model of placebo responsiveness and in light of empirical and psychometric considerations ego resiliency emerged as a consistent predictor of placebo responses in itch (p < .05). This is the first study to identify trait predictors of placebo responses in inflammatory skin reactions. Ego resiliency may typify greater placebo responsiveness; however, this may only be in certain contexts. Matching treatment approaches to bio-behavioural response tendencies may be useful clinically if the placebo component of traditional treatments can be enhanced. PMID- 26610166 TI - Short-term oxycodone treatment does not affect electrogenic ion transport in isolated mucosa from the human rectosigmoid colon. AB - OBJECTIVE: Opioid therapy is associated with altered secretion and motility of the gut. The relative contribution of decreased secretion to the development of opioid-induced constipation remains unknown. MATERIALS AND METHODS: Twenty-five healthy males were treated with oxycodone for 5 d in a placebo-controlled, randomised cross-over design. Gastrointestinal adverse effects were assessed with validated questionnaires (bowel function index and gastrointestinal symptom rating scale). Rectosigmoid mucosal biopsies were taken at baseline and on day 5 during both treatments and mounted in Ussing chambers. Electrogenic ion transport parameters (short circuit current (SCC) and slope conductance) were measured after addition of secretagogues (prostaglandin E2 (PGE2) (6 MUm), theophylline (400 MUm)), and an inhibitor (ouabain (200 MUm)). Additionally, morphine (50 MUm) was added to investigate the direct opioid effect on colonic mucosa. RESULTS: Questionnaires showed pronounced bowel symptoms, including constipation during oxycodone treatment (eight-fold increase in bowel function index score from day 1 to day 5 (p < 0.001) while no significant change occurred during placebo treatment (p = 0.47). Basal SCC and slope conductance did not differ between treatments (all p > 0.05) and application with PGE2, theophylline, and ouabain yielded comparable results on all examinations (all p > 0.05). Morphine application consistently did not evoke a change in ion transport. CONCLUSION: Compared to placebo, epithelial electrogenic ion transport is not altered in mucosal biopsies from the rectosigmoid colon following 5-d oxycodone treatment. The secretory mechanisms in isolated mucosa appear to play a negligible role in the development of opioid-induced constipation. PMID- 26610167 TI - A Randomized Controlled Clinical Trial of Dialogical Exposure Therapy versus Cognitive Processing Therapy for Adult Outpatients Suffering from PTSD after Type I Trauma in Adulthood. AB - BACKGROUND: Although there are effective treatments for posttraumatic stress disorder (PTSD), there is little research on treatments with non-cognitive behavioural backgrounds, such as gestalt therapy. We tested an integrative gestalt-derived intervention, dialogical exposure therapy (DET), against an established cognitive-behavioural treatment (cognitive processing therapy, CPT) for possible differential effects in terms of symptomatic outcome and drop-out rates. METHODS: We randomized 141 treatment-seeking individuals with a diagnosis of PTSD to receive either DET or CPT. Therapy length in both treatments was flexible with a maximum duration of 24 sessions. RESULTS: Dropout rates were 12.2% in DET and 14.9% in CPT. Patients in both conditions achieved significant and large reductions in PTSD symptoms (Impact of Event Scale - Revised; Hedges' g = 1.14 for DET and d = 1.57 for CPT) which were largely stable at the 6-month follow-up. At the posttreatment assessment, CPT performed statistically better than DET on symptom and cognition measures. For several outcome measures, younger patients profited better from CPT than older ones, while there was no age effect for DET. CONCLUSIONS: Our results indicate that DET merits further research and may be an alternative to established treatments for PTSD. It remains to be seen whether DET confers advantages in areas of functioning beyond PTSD symptoms. PMID- 26610168 TI - Genetic polymorphisms analysis of drug-metabolizing enzyme CYP2C9 in the Uyghur population. AB - Genetic variations in cytochrome P450 2C9 are known to contribute to interindividual and interethnic variability in response to clinical drugs, but little is known about the genetic variation of CYP2C9 in the Uyghur population. We directly sequenced the whole CYP2C9 gene in 96 unrelated, healthy Uyghur from Xinjiang Uygur Autonomous Region of China and screened for genetic variants in the promoter, exons, introns and 3'-UTR. Thirty five previously reported alleles and six genotypes were detected in this study. The allele frequencies of CYP2C9*1, *2, *11, *12, *29 and *33 were 89.58, 7.81, 0.52, 0.52, 1.04 and 0.52%, respectively. We detected one non-synonymous novel variant at position 329 from Arg to Cys and this mutation is predicted to be intolerant by SIFT. Our results provide basic information about CYP2C9 alleles in Uyghur, which may help to optimize pharmacotherapy effectiveness by providing personalized medicine to this ethnic group. PMID- 26610169 TI - Systematic review of antenatal dietary and lifestyle interventions in women with a normal body mass index. AB - INTRODUCTION: Women who commence pregnancy with a normal body mass index (BMI) are at the greatest risk of excessive gestational weight gain, impacting on infant birthweight, pregnancy-related complications and postpartum weight retention. Our aim was to review systematically the effect of antenatal dietary and lifestyle interventions in pregnant women with a normal BMI on maternal and infant outcomes. MATERIAL AND METHODS: We searched the Cochrane Controlled Trials Register, PubMed, Medline, and the Australian and International Clinical Trials Registry with the date of the last search in July 2015. We included all published, unpublished and ongoing randomized trials recruiting women of a normal BMI, comparing dietary and/or lifestyle interventions with standard antenatal care. RESULTS: Twelve randomized controlled trials were identified, involving a total of 2713 pregnant women, with five studies reporting clinical data for 714 women with a normal BMI. Women who received a dietary and lifestyle intervention were less likely to experience gestational weight gain [four studies, 446 women; mean difference -1.25 kg; 95% confidence interval (CI) -2.39 to -0.11], weight gain above the Institute of Medicine guidelines (four studies, 446 women; risk ratio 0.66; 95% CI 0.53-0.83) and hypertension (two studies; 243 women; risk ratio 0.34; 95% CI 0.13-0.91). There were no statistically significant differences in the occurrence of gestational diabetes, cesarean section or birthweight greater than 4 kg. CONCLUSIONS: While providing an antenatal dietary and lifestyle intervention for pregnant women of normal BMI appears to reduce gestational weight gain, the review was limited by the relatively small available sample size. Further well-designed randomized controlled trials are required. PMID- 26610171 TI - LabDisk with complete reagent prestorage for sample-to-answer nucleic acid based detection of respiratory pathogens verified with influenza A H3N2 virus. AB - Portable point-of-care devices for pathogen detection require easy, minimal and user-friendly handling steps and need to have the same diagnostic performance compared to centralized laboratories. In this work we present a fully automated sample-to-answer detection of influenza A H3N2 virus in a centrifugal LabDisk with complete prestorage of reagents. Thus, the initial supply of the sample remains the only manual handling step. The self-contained LabDisk automates by centrifugal microfluidics all necessary process chains for PCR-based pathogen detection: pathogen lysis, magnetic bead based nucleic acid extraction, aliquoting of the eluate into 8 reaction cavities, and real-time reverse transcription polymerase chain reaction (RT-PCR). Prestored reagents comprise air dried specific primers and fluorescence probes, lyophilized RT-PCR mastermix and stick-packaged liquid reagents for nucleic acid extraction. Employing two different release frequencies for the stick-packaged liquid reagents enables on demand release of highly wetting extraction buffers, such as sequential release of lysis and binding buffer. Microfluidic process-flow was successful in 54 out of 55 tested LabDisks. We demonstrate successful detection of the respiratory pathogen influenza A H3N2 virus in a total of 18 LabDisks with sample concentrations down to 2.39 * 10(4) viral RNA copies per ml, which is in the range of clinical relevance. Furthermore, we detected RNA bacteriophage MS2 acting as internal control in 3 LabDisks with a sample concentration down to 75 plaque forming units (pfu) per ml. All experiments were applied in a 2 kg portable, laptop controlled point-of-care device. The turnaround time of the complete analysis from sample-to-answer was less than 3.5 hours. PMID- 26610172 TI - Group Drumming Modulates Cytokine Response in Mental Health Services Users: A Preliminary Study. PMID- 26610173 TI - The Use of Autologous Schwann Cells to Supplement Sciatic Nerve Repair With a Large Gap: First in Human Experience. AB - Insufficient donor nerve graft material in peripheral nerve surgery remains an obstacle for successful long-distance regeneration. Schwann cells (SCs) can be isolated from adult mammalian peripheral nerve biopsies and can be grown in culture and retain their capacity to enhance peripheral nerve regeneration within tubular repair strategies in multiple animal models. Human Schwann cells (hSCs) can be isolated, expanded in number, and retain their ability to promote regeneration and myelinate axons, but have never been tested in a clinical case of peripheral nerve injury. A sural nerve biopsy and peripheral nerve tissue from the traumatized sciatic nerve stumps was obtained after Food and Drug Administration (FDA) and Institutional Review Board (IRB) approval as well as patient consent. The SCs were isolated after enzymatic digestion of the nerve and expanded with the use of heregulin beta1 (0.1 ug/ml) and forskolin (15 mM). After two passages the Schwann cell isolates were combined with sural nerve grafts to repair a large sciatic nerve defect (7.5 cm) after a traumatic nerve injury. The sural nerve and the traumatized sciatic nerve ends both served as an excellent source of purified (90% and 97%, respectively) hSCs. Using ultrasound and magnetic resonance imaging (MRI) we were able to determine continuity of the nerve graft repair and the absence of tumor formation. The patient had evidence of proximal sensory recovery and definitive motor recovery distal to the repair in the distribution of the tibial and common peroneal nerve. The patient did experience an improvement in her pain scores over time. The goals of this approach were to determine the safety and clinical feasibility of implementing a new cellular repair strategy. In summary, this approach represents a novel strategy in the treatment of peripheral nerve injury and represents the first reported use of autologous cultured SCs after human peripheral nerve injury. PMID- 26610174 TI - Comparative transcriptomic analyses of Zymoseptoria tritici strains show complex lifestyle transitions and intraspecific variability in transcription profiles. AB - Zymoseptoria tritici causes Septoria tritici blotch (STB) on wheat. The disease interaction is characterized by clearly defined temporal phases of infection, ultimately resulting in the death of host tissue. Zymoseptoria tritici is a highly polymorphic species with significant intraspecific variation in virulence profiles. We generated a deep transcriptomic sequencing dataset spanning the entire time course of an infection using a previously uncharacterized, highly virulent Z. tritici strain isolated from a Swiss wheat field. We found that seven clusters of gene transcription profiles explained the progression of the infection. The earliest highly up-regulated genes included chloroperoxidases, which may help the fungus cope with plant defences. The onset of necrotrophy was characterized by a concerted up-regulation of proteases, plant cell wall degrading enzymes and lipases. Functions related to nutrition and growth characterized late necrotrophy and the transition to saprotrophic growth on dead plant tissue. We found that the peak up-regulation of genes essential for mating coincided with the necrotrophic phase. We performed an intraspecies comparative transcriptomics analysis using a comparable time course infection experiment of the genome reference isolate IPO323. Major components of the fungal infection transcriptome were conserved between the two strains. However, individual small, secreted proteins, proteases and cell wall-degrading enzymes showed strongly differentiated transcriptional profiles between isolates. Our analyses illustrate that successful STB infections involve complex transcriptomic remodelling to up regulate distinct gene functions. Heterogeneity in transcriptomes among isolates may explain some of the considerable variation in virulence and host specialization found within the species. PMID- 26610175 TI - Geoepidemiology of hepatocellular carcinoma in the island of Crete, Greece. A possible role of pesticides. AB - BACKGROUND & AIMS: Geoepidemiological data of hepatocellular carcinoma (HCC) are lacking. Crete has a genetically homogeneous population and is suitable for studies to identify a possible contribution of environmental factors in HCC. METHODS: Databases for HCC (316 cases), hepatitis B virus (HBV) (633) and hepatitis C virus (HCV) (392), constructed over the past 20 years in our Unit, were used. Data included place of birth and place of residence for the last 15 years. Hellenic Statistical Authority provided population statistics from 1980 to 2014. Time-spatial methods were applied in Gis-ArcMap 10 software. Spatial autocorrelation tests (Moran's index) detected differences between the spatial distribution to place of residence. Spatial density maps were created. Kriging Interpolation was applied, to produce prediction maps of HCC. RESULTS: Hepatitis C virus appears in areas of high prevalence while HBV is uniformly distributed. HCC is more prevalent in Eastern Crete. A spatial autocorrelation between HCC and either HCV (Moran's I = 0.88, P < 0.001) or HBV (I = 0.84, P < 0.02) was found as expected. However, there is a discrepancy in the South East of Crete, where a higher prevalence of HCC than expected was observed. This is an area where extensive use of pesticides in large green houses is practiced. CONCLUSIONS: Hepatocellular carcinoma is associated with the dispersion of HCV and HBVs. In an area with widespread use of pesticides, a higher than expected spatial distribution of HCC was detected. PMID- 26610176 TI - Cost-optimization in the treatment of multidrug resistant tuberculosis in Nigeria. AB - OBJECTIVE: To compare the cost of facility-based MDR TB care (F) to home-based care (H) from the perspective of the Nigerian national health system. METHODS: We assessed the expected costs of the two MDR TB treatment approaches using a decision-analytic model with a follow-up of 6 months. MDR TB treatment outcomes were obtained from a systematic review of randomised clinical trials. The outcomes of interest included treatment success, treatment failure, treatment default and mortality and did not vary significantly between the two alternatives. Treatment costs included the cost of the following: drug therapy (F, H), hospital stay (F), nurse care (F, H), physician care (F), nursing facility (F) and transport to the healthcare provider (H). Finally, we estimated the potential cost savings associated with home-based treatment for all patients starting MDR TB treatment in Nigeria. RESULTS: The average expected total treatment cost for a Nigerian patient treated for MDR TB was estimated at US2095 for facility - based care and 1535 for home-based care, a potential saving of 25%. One of the major drivers of this difference is significantly more intensive, and therefore more costly, nursing care in hospitals. In 2013, a total of 426 patients were initiated on facility-based MDR TB treatment in Nigeria. Thus, the potential savings through home-based care are US$ 223 204 per year. CONCLUSION: In Nigeria, treatment of MDR TB using home-based care is expected to result in similar patient outcomes at markedly reduced public health costs as facility based care. PMID- 26610177 TI - [SQUIRE 2.0 (Standards for QUality Improvement Reporting Excellence): Revised publication guidelines from a detailed consensus process]. AB - Since the publication of Standards for Quality Improvement Reporting Excellence (SQUIRE 1.0) guidelines in 2008, the science of the field has advanced considerably. In this manuscript, we describe the development of SQUIRE 2.0 and its key components. We undertook the revision between 2012 and 2015 using (1) semi-structured interviews and focus groups to evaluate SQUIRE 1.0 plus feedback from an international steering group, (2) two face-to-face consensus meetings to develop interim drafts, and (3) pilot testing with authors and a public comment period. SQUIRE 2.0 emphasizes the reporting of three key components of systematic efforts to improve the quality, value, and safety of healthcare: the use of formal and informal theory in planning, implementing, and evaluating improvement work; the context in which the work is done; and the study of the intervention(s). SQUIRE 2.0 is intended for reporting the range of methods used to improve healthcare, recognizing that they can be complex and multi dimensional. It provides common ground to share these discoveries in the scholarly literature (www.squire-statement.org). PMID- 26610178 TI - Clinical predictors of diagnostic testing utility in the initial evaluation of chronic kidney disease. AB - AIM: No evidence-based approach to the evaluation of CKD has been established. We sought to identify clinical criteria to guide a rational diagnostic approach for the initial evaluation of CKD. METHODS: We conducted a retrospective cohort study of 1487 patients presenting for initial evaluation of CKD over 3 years (1/2010 1/2013) to academic nephrology clinics. We utilized the electronic medical record to determine tests ordered, abnormal results and testing that affected diagnosis and/or management. Diagnostic and management yield of testing was defined as the percentage of tests that affected diagnosis and/or management. High yield for a given test was defined as an increased likelihood of the test affecting diagnosis and/or management. RESULTS: We identified clinical criteria predictive of high yield for paraprotein-related testing (one of the following: history of monoclonal disease, high risk of CKD progression, hypercalcemia or haemoglobin < 10.6), and clinical criteria predictive of high yield for glomerulonephritis testing (one of the following: abnormal urine sediment, 3+ or greater hematuria or proteinuria > 500 mg/gm). A prior history of hydronephrosis and renal artery stenosis was predictive of high yield of abnormal renal ultrasound. Higher yield of testing was associated with higher risk progression categories for ANA, SPEP, urine sediment, calcium, PTH, haemoglobin, iron and ferritin. We estimate that initial CKD evaluation costs range from $28 to $109 million/year in US-Medicare expenditure. CONCLUSION: Numerous tests without significant clinical utility are obtained in initial CKD evaluation. Identifying criteria that can guide diagnostic testing may lead to a more informed and cost-effective approach to evaluation. PMID- 26610179 TI - Characterizing the bacterial communities in retail stores in the United States. AB - The microorganisms present in retail environments have not been studied in detail despite the fact that these environments represent a potentially important location for exposure. In this study, HVAC filter dust samples in 13 US retail stores were collected and analyzed via pyrosequencing to characterize the indoor bacterial communities and to explore potential relationships between these communities and building and environmental parameters. Although retail stores contained a diverse bacterial community of 788 unique genera, over half of the nearly 118K sequences were attributed to the Proteobacteria phylum. Streptophyta, Bacillus, Corynebacterium, Pseudomonas, and Acinetobacter were the most prevalent genera detected. The recovered indoor airborne microbial community was statistically associated with both human oral and skin microbiota, indicating occupants are important contributors, despite a relatively low occupant density per unit volume in retail stores. Bacteria generally associated with outdoor environments were present in the indoor communities with no obvious association with air exchange rate, even when considering relative abundance. No significant association was observed between the indoor bacterial community recovered and store location, store type, or season. However, predictive functional gene profiling showed significant associations between the indoor community and season. The microbiome recovered from multiple samples collected months apart from the same building varied significantly indicating that caution is warranted when trying to characterize the bacterial community with a single sampling event. PMID- 26610180 TI - Antecedents of inflammation biomarkers in preterm newborns on days 21 and 28. AB - AIM: Most studies of systemic inflammation in very preterm newborns focus on assessments made during the first two weeks. The purpose of this study was to identify some of the antecedents of systemic inflammation evident during postnatal weeks three and four. METHODS: We measured the protein concentrations in blood spots collected on postnatal days 21 (N = 176) and 28 (N = 157) from infants born before the 28th week of gestation and sought correlates of measurements in the top quartile. Odds ratios of elevated concentrations were calculated for the most obvious correlates. RESULTS: Infants born for maternal and foetal indications were more likely than their peers to have top quartile concentrations of IL-beta, IL-8, TNF-alpha and ICAM-1 on both days 21 and 28. Similarly, infants whose birthweight Z-score was <-2 or between -1 and -2 were also more likely than their peers to have elevated concentrations of these proteins. CONCLUSION: Markers of systemic inflammation in the very preterm newborn during the third and fourth postnatal weeks are most strongly associated with maternal and foetal indications for (very preterm) delivery and their common correlate/consequence, foetal growth restriction. PMID- 26610181 TI - Personality and complex brain networks: The role of openness to experience in default network efficiency. AB - The brain's default network (DN) has been a topic of considerable empirical interest. In fMRI research, DN activity is associated with spontaneous and self generated cognition, such as mind-wandering, episodic memory retrieval, future thinking, mental simulation, theory of mind reasoning, and creative cognition. Despite large literatures on developmental and disease-related influences on the DN, surprisingly little is known about the factors that impact normal variation in DN functioning. Using structural equation modeling and graph theoretical analysis of resting-state fMRI data, we provide evidence that Openness to Experience-a normally distributed personality trait reflecting a tendency to engage in imaginative, creative, and abstract cognitive processes-underlies efficiency of information processing within the DN. Across two studies, Openness predicted the global efficiency of a functional network comprised of DN nodes and corresponding edges. In Study 2, Openness remained a robust predictor-even after controlling for intelligence, age, gender, and other personality variables explaining 18% of the variance in DN functioning. These findings point to a biological basis of Openness to Experience, and suggest that normally distributed personality traits affect the intrinsic architecture of large-scale brain systems. Hum Brain Mapp 37:773-779, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26610182 TI - Ex vivo evaluation of 4 different viscoelastic assays for detecting moderate to severe coagulopathy during liver transplantation. AB - Prolonged prothrombin time (PT) and its ratio are routinely used for the assessment of candidates for liver transplantation (LT), but intraoperative coagulation management of transfusion is hindered by its long turnaround time. Abnormal reaction time (R time) on thromboelastography (TEG) or clotting time (CT) of rotational thromboelastometry (ROTEM) are presumably an alternative, but there is a paucity of clinical data on abnormal R time/CT values compared to PT during LT. After receiving institutional review board approval and informed consent, we obtained blood samples from 36 LT patients for international normalized ratio (INR), factor (F) X level, and viscoelastic tests (EXTEM/INTEM and kaolin/rapid TEG) at baseline and 30 minutes after graft reperfusion. Receiver operating characteristic (ROC) curves were calculated for INR > 1.5 and viscoelastic R time/CT thresholds to assess the ability to diagnose FX deficiency at the moderate (<50%) or severe (<35%) level. The FX deficiency data were calculated using cutoff values of INR (>1.5) and abnormal R time/CT for TEG and ROTEM. Tissue factor (TF)-activated INR and EXTEM-CT performed well in diagnosing FX below 50%, but rapid TEG with combined TF and kaolin activators failed. Improved performance of INTEM-CT in diagnosing FX below 35% underlies multifactorial deficiency involving both intrinsic and common pathways. In conclusion, the differences among different viscoelastic tests and clinical situations should be carefully considered when they are used to guide transfusion during LT. PMID- 26610183 TI - Effect of radial shock wave therapy for carpal tunnel syndrome: A prospective randomized, double-blind, placebo-controlled trial. AB - Three recent studies demonstrated the positive effect of extracorporeal shock wave therapy (ESWT) for treating carpal tunnel syndrome (CTS). However, none have entirely proved the effects of ESWT on CTS because all studies had a small sample size and lacked a placebo-controlled design. Moreover, radial ESWT (rESWT) has not been used to treat CTS. We conducted a prospective randomized, controlled, double-blinded study to assess the effect of rESWT for treating CTS. Thirty-four enrolled patients (40 wrists) were randomized into intervention and control groups (20 wrists in each). Participants in the intervention group underwent three sessions of rESWT with nightly splinting, whereas those in the control group underwent sham rESWT with nightly splinting. The primary outcome was visual analog scale (VAS), whereas the secondary outcomes included the Boston Carpal Tunnel Syndrome Questionnaire (BCTQ), cross-sectional area (CSA) of the median nerve, sensory nerve conduction velocity of the median nerve, and finger pinch strength. Evaluations were performed before treatment and at 1, 4, 8, and 12 weeks after the third rESWT session. A significantly greater improvement in the VAS, BCTQ scores, and CSA of the median nerve was noted in the intervention group throughout the study as compared to the control group (except for BCTQ severity at week 12 and CSA at weeks 1 and 4) (p < 0.05). This is the first study to assess rESWT in a randomized placebo-controlled trial and demonstrate that rESWT is a safe and effective method for relieving pain and disability in patients with CTS. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:977-984, 2016. PMID- 26610184 TI - Adjuvants Based on Hybrid Antibiotics Overcome Resistance in Pseudomonas aeruginosa and Enhance Fluoroquinolone Efficacy. AB - The use of adjuvants that rescue antibiotics against multidrug-resistant (MDR) pathogens is a promising combination strategy for overcoming bacterial resistance. While the combination of beta-lactam antibiotics and beta-lactamase inhibitors has been successful in restoring antibacterial efficacy in MDR bacteria, the use of adjuvants to restore fluoroquinolone efficacy in MDR Gram negative pathogens has been challenging. We describe tobramycin-ciprofloxacin hybrid adjuvants that rescue the activity of fluoroquinolone antibiotics against MDR and extremely drug-resistant Pseudomonas aeruginosa isolates in vitro and enhance fluoroquinolone efficacy in vivo. Structure-activity studies reveal that the presence of both tobramycin and ciprofloxacin, which are separated by a C12 tether, is critical for the function of the adjuvant. Mechanistic studies indicate that the antibacterial modes of ciprofloxacin are retained while the role of tobramycin is limited to destabilization of the outer membrane in the hybrid. PMID- 26610185 TI - Anthraquinone-Based Polymer as Cathode in Rechargeable Magnesium Batteries. AB - Mg batteries are a promising battery technology that could lead to safer and significantly less expensive non-aqueous batteries with energy densities comparable or even better than state-of-the-art Li-ion batteries. Although the first prototype Mg battery using stable Mo6S8 as cathode was introduced over fifteen years ago, major challenges remain to be solved. In particular, the design of high energy cathode materials and the development of non-corrosive electrolytes with high oxidative stability are issues that need to be tackled. Herein, we present a new, general, and robust approach towards achieving stable cycling of Mg batteries. The core of our approach is the use of stable polymer cathode and Mg powder anode coupled with non-nucleophilic electrolytes. Our systems exhibit an excellent rate capability and significant improvement in electrochemical stability. PMID- 26610186 TI - The impact of an inverse climate-isotope relationship in soil water on the oxygen isotope composition of Larix gmelinii in Siberia. AB - Stable oxygen isotope ratios (delta(18) O) in trees from high latitude ecosystems are valuable sources of information for recent and past environmental changes, but the interpretation is hampered by the complex hydrology of forests growing under permafrost conditions, where only a shallow layer of soil thaws in summer. We investigated larch trees (Larix gmelinii) at two sites with contrasting soil conditions in Siberia and determined delta(18) O of water from different soil depths, roots, twigs, and needles as well as delta(18) O of soluble carbohydrates regularly over two growing seasons. A comparison of results from the 2 yrs revealed an unexpected 'inverse' climate-isotope relationship, as dry and warm summer conditions resulted in lower soil and root delta(18) O values. This was due to a stronger uptake of isotopically depleted water pools originating from melted permafrost or previous winter snow. We developed a conceptual framework that considers the dependence of soil water profiles on climatic conditions for explaining delta(18) O in needle water, needle soluble carbohydrates and stem cellulose. The negative feedback of drought conditions on the source isotope value could explain decreasing tree-ring delta(18) O trends in a warming climate and is likely relevant in many ecosystems, where a soil isotope gradient with depth is observed. PMID- 26610187 TI - Male partner experiences of females with an acquired brain injury: An interpretative phenomenological analysis. AB - Acquired brain injury (ABI) not only has an impact on the survivor, but also on the partner and personal relationships as a whole. The present study aimed to investigate the male partner experience of living with a female with an ABI; exploring role change, intimacy and future expectations. Semi-structured interviews were conducted with six male partners of five females with a subarachnoid haemorrhage and one female with a traumatic brain injury. Interviews were transcribed verbatim and analysed in depth using Interpretative Phenomenological Analysis (IPA). Four main themes captured the male partner's lived experience; "Entering the unknown world of ABI", "Imprisoned by the ABI", "Compassion without self-compassion", and "Holding on to hope". The accounts uncovered the male partner's journey following ABI; the unpredictability, sorrow, frustration, and finally acceptance and commitment to their partner. They identified the limited support available for partners following ABI; the sense of feeling forgotten by services and the need for information and support in the acute stages. Rehabilitation needs to take a systemic and longer-term focus, supporting both the survivor and their partner through the journey of ABI. PMID- 26610189 TI - Unusual chemistries in fungal meroterpenoid biosynthesis. AB - Meroterpenoids are polyketide and terpenoid hybrid natural products with remarkable biological activities. Recent progress in fungal meroterpenoid biosynthesis has revealed several unusual enzyme reactions and novel enzymes, including unique terpene cyclization reactions by a novel family of membrane bound terpene cyclases and post-cyclization modification reactions by oxygenases, such as non-heme iron-dependent dioxygenases, flavin adenine dinucleotide dependent monooxygenases, and cytochrome P450 monooxygenases. They contribute to the structural diversification and increase in complexity of fungal meroterpenoids. Structure-function studies of these enzymes provide strategies for engineering the biosynthetic machinery to create novel molecular scaffolds for drug discovery. PMID- 26610188 TI - LumeNEXT: A Practical Method to Pattern Luminal Structures in ECM Gels. AB - In vitro biomimetic modeling of physio-logical structures bridges the gap between 2D in vitro culture and animal models. Lumens (tubular structures) are ubiquitous in vivo, being present in blood vessels, mammary ducts, and the lymphatic system. A method 'LumeNEXT' is presented here that allows the fabrication of 3D embedded lumens where size, structure, distance, and configuration can be controlled using standard poly-dimethylsiloxane micromolding methods. PMID- 26610190 TI - An examination of the prospective impact of bulimic symptoms and dietary restraint on life hassles and social support. AB - BACKGROUND: The stress generation hypothesis posits that individuals with psychopathology engage in maladaptive behaviors that create stress. Although extensively researched in the depression literature, few studies have investigated whether the stress generation hypothesis applies to eating disorders. This study examined whether bulimic symptoms and dietary restraint predict future life hassles and low social support among undergraduate students. METHODS: Three hundred seventy-four undergraduate students participated in this two-part prospective study through a secure online system. They completed questionnaires assessing depressive symptoms, bulimic symptoms, dietary restraint, life hassles, and social support. RESULTS: Regression analyses revealed that baseline bulimic symptoms predicted greater life hassles but not lower social support one month later, after statistically controlling for baseline measures. Baseline dietary restraint did not predict future life hassles or social support. LIMITATIONS: Limitations include use of self-report measures, suboptimal response rates at the follow-up assessment, and use of a non-clinical sample with primarily White participants. CONCLUSIONS: These results provide preliminary support for the stress generation hypothesis in relation to bulimic symptoms. Individuals with bulimic symptoms may generate stressors similar to those experiencing depressive symptoms. Our findings suggest that emphasizing stress management in the treatment of individuals with bulimic symptoms could potentially improve treatment outcomes. PMID- 26610191 TI - Structure-function relationships in human cytochrome c: The role of tyrosine 67. AB - Spectroscopic and functional properties of human cytochrome c and its Tyr67 residue mutants (i.e., Tyr67His and Tyr67Arg) have been investigated. In the case of the Tyr67His mutant, we have observed only a very limited structural alteration of the heme pocket and of the Omega-loop involving, among others, the residue Met80 and its bond with the heme iron. Conversely, in the Tyr67Arg mutant the Fe-Met80 bond is cleaved; consequently, a much more extensive structural alteration of the Omega-loop can be envisaged. The structural, and thus the functional modifications, of the Tyr67Arg mutant are present in both the ferric [Fe(III)] and the ferrous [Fe(II)] forms, indicating that the structural changes are independent of the heme iron oxidation state, depending instead on the type of substituting residue. Furthermore, a significant peroxidase activity is evident for the Tyr67Arg mutant, highlighting the role of Arg as a basic, positively charged residue at pH7.0, located in the heme distal pocket, which may act as an acid to cleave the O-O bond in H2O2. As a whole, our results indicate that a delicate equilibrium is associated with the spatial arrangement of the Omega-loop. Clearly, Arg, but not His, is able to stabilize and polarize the negative charge on the Fe(III)-OOH complex during the formation of Compound I, with important consequences on cytochrome peroxidation activity and its role in the apoptotic process, which is somewhat different in yeast and mammals. PMID- 26610192 TI - Removal of pharmaceuticals from secondary effluents by an electro-peroxone process. AB - This study compared the removal of pharmaceuticals from secondary effluents of wastewater treatment plants (WWTPs) by conventional ozonation and the electro peroxone (E-peroxone) process, which involves electrochemically generating H2O2 in-situ from O2 in sparged O2 and O3 gas mixture (i.e., ozone generator effluent) during ozonation. Several pharmaceuticals with kO3 ranging from <0.1 to 6.8 * 10(5) M(-1) s(-1) were spiked into four secondary effluents collected from different WWTPs, and then treated by ozonation and the E-peroxone process. Results show that both processes can rapidly remove ozone reactive pharmaceuticals (diclofenac and gemfibrozil), while the E-peroxone process can considerably accelerate the removal of ozone-refractory pharmaceuticals (e.g., ibuprofen and clofibric acid) via indirect oxidation with OH generated from the reaction of sparged O3 with electro-generated H2O2. Compared with ozonation, the E-peroxone process enhanced the removal kinetics of ozone-refractory pharmaceuticals in the four secondary effluents by ~40-170%, and the enhancement was more pronounced in secondary effluents that had relatively lower effluent organic matter (EfOM). Due to its higher efficiency for removing ozone-refractory pharmaceuticals, the E-peroxone process reduced the reaction time and electrical energy consumption required to remove >=90% of all spiked pharmaceuticals from the secondary effluents as compared to ozonation. These results indicate that the E-peroxone process may provide a simple and effective way to improve existing ozonation system for pharmaceutical removal from secondary effluents. PMID- 26610193 TI - Characterization of organic precursors for chlorinous odor before and after ozonation by a fractionation technique. AB - To identify the primary fraction of dissolved organic matter (DOM) responsible for chlorinous odor, waters treated by the conventional treatment (i.e., coagulation, flocculation, sedimentation and rapid sand filtration (RSF)) and ozonation were characterized by a fractionation technique prior to chlorination. Furthermore, chlorinous odor strengths originated from organic fractions were compared with that resulted from trichloramine (NCl3). Odor strengths and trichloramine concentrations were determined by the triangle sensory test and head space-GC/MS, respectively. The major DOM fraction for outlet water of RSF was hydrophobic acid (HoA), whereas the hydrophilic acid (HiA) fraction was dominant in the ozonated water. For a fixed DOC level (1 mgC/L), the base (Bas) or hydrophilic base (HiB) fraction was found to be the major organic precursor of chlorinous odor for the effluent of RSF. Even the mass percentages of DOM fractions in RSF water were considered, Bas was the major DOM fractions responsible for chlorinous odor. For ozonated water, two major precursors of chlorinous odor were HiA and hydrophilic neutral (HiN) fractions. Furthermore, the influence of trichloramine on chlorinous odor intensity for ozonated water should not be negligible. Under variation of seasonal organic contents, changes in precursors of chlorinous odor were observed. PMID- 26610194 TI - Impact of socio-economic growth on desalination in the US. AB - In 2013, around 1336 desalination plants in the United States (US) provided purified water mainly to municipalities, the industry sector and for power generation. In 2013 alone, ~200 million m(3) of water were desalinated; the amount that could satisfy annual municipal water consumption of more than 1.5 million people in the US. Desalination has proven to be a reliable water supply source in many countries around the world, with the total global desalination capacity of ~60 million m(3)/day in 2013. Desalination has been used to mitigate water scarcity and lessen the pressure on water resources. Currently, data and information about desalination are still limited, while extensive socio-economic analyses are missing. This paper presents an econometric model to fill this gap. It evaluates the impact of selected socio-economic variables on desalination development in the US in the time span 1970-2013. The results show that the GDP and population growth have significantly impacted the desalination sector over the analyzed time period. The insights into the economics of desalination provided with this paper can be used to further evaluate cost-effectiveness of desalination both in the US and in other countries around the world. PMID- 26610195 TI - Synthesis and photocatalytic activity of TiO2 nanowires in the degradation of p aminobenzoic acid: A comparative study with a commercial catalyst. AB - The photocatalytic degradation of p-aminobenzoic acid was studied using TiO2 nanowires as the catalyst synthesized through a hydrothermal procedure. The as synthesized TiO2 nanowires were fully characterized by SEM, TEM, XRD and Raman with a very high surface area of 512 m(2) g(-1). The photocatalytic degradation of p-aminobenzoic acid was carried out under 180 min of constant radiation and the results were compared with P25 as commercial catalyst. Optimal experimental conditions were determined for TiO2 nanowires with a catalyst dosage of 1.0 g L( 1) under acidic conditions with a 20 MUM p-aminobenzoic acid solution obtaining 95% of degradation. Under similar experimental conditions comparative studies were performed obtaining 98% of degradation when P25 is employed. In both systems, a pseudo first order reaction was found to provide the best correlations, with constant rates of 2.0 * 10(-2) min(-1) and 2.4 * 10(-2) min( 1) for TiO2 nanowires and P25, respectively. PMID- 26610196 TI - Development and testing of a new framework for rapidly assessing legal and managerial protection afforded by marine protected areas: Mediterranean Sea case study. AB - AIM: The Convention on Biological Diversity (CBD) states the need to effectively conserve at least 10% of coastal and marine areas of particular importance for biodiversity by 2020. Here, a new indicator-based methodological framework to assess biodiversity protection afforded by marine protected areas' (MPA) was developed as a quick surrogate for MPAs' potential conservation effectiveness: the Marine Protected Area Protection Assessment Framework (MaPAF). The MaPAF consists of a limited number of headline indicators that are integrated in two indexes: Legal protection and Management effort, which eventually integrate in the overall MPA Protection super-index. The MaPAF was then tested in the Mediterranean MPA network as a case study. Spatial analyses were performed at three meaningful scales: the whole Mediterranean Sea, Mediterranean ecoregions and countries. The results of this study suggest that: 1) The MaPAF can serve as a useful tool for consistent, adaptive, quick and cost-effective MPA effectiveness assessments of MPAs and MPA networks in virtually any marine region, as the headline indicators used are commonly compiled and easy to retrieve; 2) The MaPAF proved usable and potentially relevant in the Mediterranean Sea where most indicators in the framework can be publicly accessed through the MAPAMED database and are planned to be regularly updated; 3) Protection afforded by MPAs is low across the whole Mediterranean, with only few MPAs having relatively high legal and managerial protection; and 4) Most Mediterranean countries need to devote substantially more work to improve MPA effectiveness mainly through increased management effort. PMID- 26610197 TI - Insights into neurosensory toxicity of mercury in fish eyes stemming from tissue burdens, oxidative stress and synaptic transmission profiles. AB - This study aims to contribute to fill a knowledge gap related with Hg effects in fish eyes. As a pioneering strategy, Hg bioaccumulation in eye wall of the wild grey mullet (Liza aurata) was assessed, together with oxidative stress and synaptic transmission profiles. This approach was complemented by the characterisation of environmental contamination (both in water and sediment). Sampling was conducted in winter and summer in two sites of a Portuguese coastal lagoon (Aveiro lagoon): Largo do Laranjo (LAR) - located in an Hg contaminated/confined area; Sao Jacinto (SJ) - closer to the lagoon inlet and selected as reference site. Levels of total Hg (tHg), inorganic Hg (iHg) and methylmercury (MeHg) in eye wall were higher at LAR than SJ, both in winter and summer, reflecting the environmental contamination patterns. Moreover, fish caught at LAR in winter showed a significant decrease of catalase and superoxide dismutase activities, in line with the occurrence of peroxidative damage. A different spatial pattern was recorded in summer, being characterised by the increment of glutathione peroxidase and glutathione reductase activities at LAR, as well as total glutathione content, preventing the occurrence of lipid peroxidation. Also in summer, a significant decrease of acetylcholinesterase activity was recorded in fish eyes at LAR, pointed out Hg as an anticholinergic agent. Besides Hg, water salinity had probably an indirect effect on spatial and winter-summer variation patterns of AChE. Current data pointed out that Hg (in iHg and MeHg forms) could exert ocular toxicity both by the promotion of oxidative stress and by the interference with neurotransmission processes. PMID- 26610198 TI - Management of pregnancy associated breast cancer with chemotherapy in a developing country. AB - CONTEXT: Although breast cancer is a common cancer, Pregnancy associated breast cancer is uncommon. Adjuvant chemotherapy administered intrapartum has been resolved to be safe from the second trimester. OBJECTIVE: To review cases of pregnancy associated breast cancer managed with adjuvant intrapartum chemotherapy. PATIENTS AND METHOD: Gravid patients diagnosed with breast cancer had chemotherapy administered by a slow infusion protocol at 3 weekly interval from the second trimester till 4 weeks to expected date of delivery. Obstetric scans were done to monitor fetal growth and development. Requisite surgery was carried out intrapartum and postpartum. RESULTS: There were three cases of pregnancy associated breast cancer Age range 32-33 years, mean 32.5 years. Two cases presented in the second trimester while one presented in the third trimester. The second case had overt metastatic disease and was grave in respiratory distress. Histology showed invasive lobular carcinoma in two cases and extensive intraductal carcinoma with invasive component in the third. Immunohistochemistry showed triple negative in the first case and hormone positive in the third case. Wide local excision was done for a 3cm lump in the first case and mastectomy postpartum in the third case. but had no surgery. Doxorubicin and cyclophosphamide was administered three weekly from the second trimester up to 32 weeks and continued postpartum. Taxanes was administered afterwards. The grave clinical state of the second case was markedly improved with the first cycle of chemotherapy instituted. All cases had spontaneous vaginal delivery with good apgar scores. Children had normal developmental milestones. First case with breast conservation is clinically disease free, the second case demised postpartum from disease progression while the third had a mastectomy and is on cue for radiotherapy. CONCLUSION: Adjuvant intrapartum chemotherapy had a successful outcome with birth of normal babies with normal developmental milestones in our miniseries. PMID- 26610199 TI - Bilateral Idiopathic Adrenal Hyperplasia: Genetics and Beyond. AB - Bilateral adrenal hyperplasia currently accounts for up to 2 thirds of cases of primary aldosteronism. As such, it represents a major opportunity for targeted medical management as opposed to unilateral surgically correctable forms of the disease. Although the majority of cases of primary aldosteronism are sporadic, bilateral adrenal hyperplasia may occur in the context of familial hyperaldosteronism where it is associated with specific germline mutations. Over the past 5 years, impressive progress has been made in our understanding of the genetic basis underlying primary aldosteronism, allowing us to identify and characterize new familial forms of the disease and to understand the mechanisms involved in the formation of aldosterone producing adenoma. In contrast, our knowledge of the genetic contribution to the development of bilateral adrenal hyperplasia, and in a larger context, to renin and aldosterone levels in the general population, is still poor. This review summarizes our current knowledge on the genetics of bilateral adrenal hyperplasia and addresses some open questions to be addressed by future research. In particular, genome-wide association studies in large populations may provide clues to understanding the genetic susceptibility underlying the development of primary aldosteronism. PMID- 26610200 TI - Toenails as an alternative source material for the extraction of DNA from decomposed human remains. AB - The DNA identification of decomposed human remains for coronial investigations at the Victorian Institute of Forensic Medicine routinely requires the retrieval and processing of a bone sample obtained from the deceased. Bone is a difficult sample type to work with as it requires surgical removal from the deceased, refrigerated storage, and additional processing steps prior to DNA analysis in comparison to other samples types such as buccal swabs or blood stains. In an attempt to overcome the issues posed by bone, a DNA extraction method utilising toenails as an alternate source material was optimised and trialled. Two DNA extraction methods were optimised for digestion of toenail material, with the method utilising the QIAGEN DNA Investigator Kit selected for a casework trial. Single source DNA profiles, matching those of the conventional samples taken, were obtained for toenail samples collected from 28 of 30 coronial cases available for this study. Of these, 26 toenail samples produced full profiles. Although the overall DNA profile quality from the toenails was less than that of the conventional sample, the profiles from toenails met the reporting requirements for identification. Based on the results obtained, the Victorian Institute of Forensic Medicine will be implementing toenails as the primary sample type for collection from decomposed remains when blood is not a suitable sample type. PMID- 26610201 TI - Mechanisms of mechanosensing - mechanosensitive channels, function and re engineering. AB - Sensing and responding to mechanical stimuli is an ancient behavior and ubiquitous to all forms of life. One of its players 'mechanosensitive ion channels' are involved in processes from osmosensing in bacteria to pain in humans. However, the mechanism of mechanosensing is yet to be elucidated. This review describes recent developments in the understanding of a bacterial mechanosensitive channel. Force from the lipid principle of mechanosensation, new methods to understand protein-lipid interactions, the role of water in the gating, the use of engineered mechanosensitive channels in the understanding of the gating mechanism and application of the accumulated knowledge in the field of drug delivery, drug design and sensor technologies are discussed. PMID- 26610202 TI - Cholestasis-induced adaptive remodeling of interlobular bile ducts. AB - Cholestasis is a common complication in liver diseases that triggers a proliferative response of the biliary tree. Bile duct ligation (BDL) is a frequently used model of cholestasis in rodents. To determine which changes occur in the three-dimensional (3D) architecture of the interlobular bile duct during cholestasis, we used 3D confocal imaging, surface reconstructions, and automated image quantification covering a period up to 28 days after BDL. We show a highly reproducible sequence of interlobular duct remodeling, where cholangiocyte proliferation initially causes corrugation of the luminal duct surface, leading to an approximately five-fold increase in surface area. This is analogous to the function of villi in the intestine or sulci in the brain, where an expansion of area is achieved within a restricted volume. The increase in surface area is further enhanced by duct branching, branch elongation, and loop formation through self-joining, whereby an initially relatively sparse mesh surrounding the portal vein becomes five-fold denser through elongation, corrugation, and ramification. The number of connections between the bile duct and the lobular bile canalicular network by the canals of Hering decreases proportionally to the increase in bile duct length, suggesting that no novel connections are established. The diameter of the interlobular bile duct remains constant after BDL, a response that is qualitatively distinct from that of large bile ducts, which tend to enlarge their diameters. Therefore, volume enhancement is only due to net elongation of the ducts. Because curvature and tortuosity of the bile duct are unaltered, this enlargement of the biliary tree is caused by branching and not by convolution. CONCLUSION: BDL causes adaptive remodeling that aims at optimizing the intraluminal surface area by way of corrugation and branching. PMID- 26610203 TI - Elevated levels of ZAC1 disrupt neurogenesis and promote rapid in vivo reprogramming. AB - The zinc finger transcription factor Zac1 is expressed in dividing progenitors of the nervous system with expression levels negatively controlled by genomic imprinting. To explore the consequences of elevated ZAC1 levels during neurogenesis we overexpressed it in the developing CNS. Increased levels of ZAC1 rapidly promoted upregulation of CDK inhibitors P57 and P27 followed by cell cycle exit. Surprisingly this was accompanied by stalled neuronal differentiation. Genome wide expression analysis of cortical cells overexpressing Zac1 revealed a decrease in neuronal gene expression and an increased expression of imprinted genes, factors regulating mesoderm formation as well as features of differentiated muscle. In addition, we observed a rapid induction of several genes regulating pluripotency. Taken together, our data suggests that expression levels of Zac1 need to be kept under strict control to avoid premature cell cycle exit, disrupted neurogenesis and aberrant expression of non-neuronal genes including pluripotency associated factors. PMID- 26610204 TI - Maternal depression across the first years of life compromises child psychosocial adjustment; relations to child HPA-axis functioning. AB - Maternal depression across the first years of life negatively impacts children's development. One pathway of vulnerability may involve functioning of the hypothalamic-pituitary-adrenal (HPA) axis. We utilize a community cohort of 1983 women with no comorbid risk repeatedly assessed for depression from birth to six years to form two groups; chronically depressed (N=40) and non-depressed (N=91) women. At six years, mother and child underwent psychiatric diagnosis, child salivary cortisol (CT) was assessed three times during a home-visit, mother-child interaction was videotaped, and child empathy was coded from behavioral paradigms. Latent Growth curve Model using Structural Equation Modeling (SEM) estimated the links between maternal depression and mother's negative parenting and three child outcomes; psychopathology, social withdrawal, and empathy as related to child CT baseline and variability. Depressed mothers displayed more negative parenting and their children showed more Axis-I psychopathology and social withdrawal. SEM analysis revealed that maternal depression was associated with reduced CT variability, which predicted higher child psychopathology and social withdrawal. Whereas all children exhibited similar initial levels of CT, children of controls reduced CT levels over time while children of depressed mothers maintained high, non-flexible levels. Mother negativity was related to lower initial CT levels, which predicted decreased empathy. Findings suggest that chronic maternal depression may compromise children's social-emotional adjustment by diminishing HPA-system flexibility as well as limiting the mother's capacity to provide attuned and predictable caregiving. PMID- 26610205 TI - Theoretical Characterization of the Spectral Density of the Water-Soluble Chlorophyll-Binding Protein from Combined Quantum Mechanics/Molecular Mechanics Molecular Dynamics Simulations. AB - Over the past decade, both experimentalists and theorists have worked to develop methods to describe pigment-protein coupling in photosynthetic light-harvesting complexes in order to understand the molecular basis of quantum coherence effects observed in photosynthesis. Here we present an improved strategy based on the combination of quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations and excited-state calculations to predict the spectral density of electronic-vibrational coupling. We study the water-soluble chlorophyll binding protein (WSCP) reconstituted with Chl a or Chl b pigments as the system of interest and compare our work with data obtained by Pieper and co-workers from differential fluorescence line-narrowing spectra (Pieper et al. J. Phys. Chem. B 2011, 115 (14), 4042-4052). Our results demonstrate that the use of QM/MM MD simulations where the nuclear positions are still propagated at the classical level leads to a striking improvement of the predicted spectral densities in the middle- and high-frequency regions, where they nearly reach quantitative accuracy. This demonstrates that the so-called "geometry mismatch" problem related to the use of low-quality structures in QM calculations, not the quantum features of pigments high-frequency motions, causes the failure of previous studies relying on similar protocols. Thus, this work paves the way toward quantitative predictions of pigment-protein coupling and the comprehension of quantum coherence effects in photosynthesis. PMID- 26610206 TI - A novel cyclic helix B peptide inhibits dendritic cell maturation during amelioration of acute kidney graft rejection through Jak-2/STAT3/SOCS1. AB - We recently synthesized a novel proteolysis-resistant cyclic helix B peptide (CHBP) that exhibits promising renoprotective effects. Dendritic cells (DCs) play an activation role in acute rejection (AR). Thus, the present study was designed to investigate the effects of CHBP on DCs in a rat renal transplantation model. The left kidney was harvested from male Lewis rats and then transplanted into male Wistar rats with or without CHBP treatment. Five successive treatment doses of CHBP after transplantation significantly ameliorated AR with lower histological injury, apoptosis and CD4(+) and CD8(+) T-cell infiltration in renal allografts. CHBP reduced IFN-gamma and IL-1beta levels but increased IL-4 and IL 10 levels in the serum. The number of mature DCs was significantly decreased in renal allografts treated with CHBP. In addition, incubating DCs with CHBP in vitro led to reduction in TNF-alpha, IFN-gamma, IL-1beta and IL-12 levels and increase of IL-10 expression at the protein level in the supernatant. Mechanistically, CHBP inhibited TLR activation-induced DC maturation by increasing SOCS1 expression through Jak-2/STAT3 signaling. In conclusion, CHBP suppresses renal allograft AR by inhibiting the maturation of DCs via Jak 2/STAT3/SOCS1 signaling, suggesting that CHBP may be an potential therapeutic drug for treating renal AR. PMID- 26610207 TI - Elevated alpha-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson's patient-derived induced pluripotent stem cells. AB - We have assessed the impact of alpha-synuclein overexpression on the differentiation potential and phenotypic signatures of two neural-committed induced pluripotent stem cell lines derived from a Parkinson's disease patient with a triplication of the human SNCA genomic locus. In parallel, comparative studies were performed on two control lines derived from healthy individuals and lines generated from the patient iPS-derived neuroprogenitor lines infected with a lentivirus incorporating a small hairpin RNA to knock down the SNCA mRNA. The SNCA triplication lines exhibited a reduced capacity to differentiate into dopaminergic or GABAergic neurons and decreased neurite outgrowth and lower neuronal activity compared with control cultures. This delayed maturation phenotype was confirmed by gene expression profiling, which revealed a significant reduction in mRNA for genes implicated in neuronal differentiation such as delta-like homolog 1 (DLK1), gamma-aminobutyric acid type B receptor subunit 2 (GABABR2), nuclear receptor related 1 protein (NURR1), G-protein regulated inward-rectifier potassium channel 2 (GIRK-2) and tyrosine hydroxylase (TH). The differentiated patient cells also demonstrated increased autophagic flux when stressed with chloroquine. We conclude that a two-fold overexpression of alpha-synuclein caused by a triplication of the SNCA gene is sufficient to impair the differentiation of neuronal progenitor cells, a finding with implications for adult neurogenesis and Parkinson's disease progression, particularly in the context of bioenergetic dysfunction. PMID- 26610208 TI - In non-transformed cells Bak activates upon loss of anti-apoptotic Bcl-XL and Mcl 1 but in the absence of active BH3-only proteins. AB - Mitochondrial apoptosis is controlled by proteins of the B-cell lymphoma 2 (Bcl 2) family. Pro-apoptotic members of this family, known as BH3-only proteins, initiate activation of the effectors Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak), which is counteracted by anti-apoptotic family members. How the interactions of Bcl-2 proteins regulate cell death is still not entirely clear. Here, we show that in the absence of extrinsic apoptotic stimuli Bak activates without detectable contribution from BH3-only proteins, and cell survival depends on anti-apoptotic Bcl-2 molecules. All anti apoptotic Bcl-2 proteins were targeted via RNA interference alone or in combinations of two in primary human fibroblasts. Simultaneous targeting of B cell lymphoma-extra large and myeloid cell leukemia sequence 1 led to apoptosis in several cell types. Apoptosis depended on Bak whereas Bax was dispensable. Activator BH3-only proteins were not required for apoptosis induction as apoptosis was unaltered in the absence of all BH3-only proteins known to activate Bax or Bak directly, Bcl-2-interacting mediator of cell death, BH3-interacting domain death agonist and p53-upregulated modulator of apoptosis. These findings argue for auto-activation of Bak in the absence of anti-apoptotic Bcl-2 proteins and provide evidence of profound differences in the activation of Bax and Bak. PMID- 26610209 TI - P2X7 receptor activity regulation: the role of CD44 proteoglycan GAG chains. PMID- 26610211 TI - Theoretical Modeling on the Reaction Mechanism of p-Nitrophenylmethylphosphate Alkaline Hydrolysis and its Kinetic Isotope Effects. AB - We have studied the alkaline hydrolysis of p-nitrophenylmethylphosphate (p-NPmP) in aqueous solution by means of polarizable continuum models and by hybrid quantum-mechanical/molecular-mechanical (QM/MM) methods. The theoretical predictions of kinetic isotope effects (KIEs) are in very good agreement with the experimental data, confirming a concerted asynchronous molecular mechanism. In addition, comparison of high level DFT theory with semiempirical AM1/d Hamiltonian has allowed checking the reliability of the later to be used in modeling very large molecular models containing phosphorus atoms. PMID- 26610210 TI - MicroRNA-22 inhibits tumor growth and metastasis in gastric cancer by directly targeting MMP14 and Snail. AB - MicroRNAs (miRNAs) deregulation is frequent in human gastric cancers (GCs), but the role of specific miRNAs involved in this disease remains elusive. MiR-22 was previously reported to act as tumor suppressors or oncogenes in diverse cancers. However, their accurate expression, function and mechanism in GC are largely unclear. Here, we found that the expression of miR-22 was significantly reduced in clinical GC tissues compared with paired adjacent normal tissues, and was significantly correlated with a more aggressive phenotype of GC in patients, and miR-22 low expression correlated with poor overall survival. The introduction of miR-22 markedly suppressed GC cell growth, migration and invasion, and inhibition of miR-22 promoted GC cell proliferation, migration and invasion in vitro. We further demonstrated that miR-22 acted as tumor suppressors through targeting extracellular matrix (ECM) remodeling member matrix metalloproteinase 14 (MMP14) and epithelial-to-mesenchymal transition (EMT) inducer Snail in GC. Moreover, ectopic expression of MMP14 or Snail restored inhibitory effects of miR-22 on cell migration and invasion in GC cells, and a negative relationship between the miR-22 expression and MMP14 or Snail mRNA levels was observed in GC. Finally, overexpression of miR-22 suppressed tumor growth, peritoneal dissemination and pulmonary metastasis in vivo. Taken together, we identified that miR-22 is a potent tumor suppressor in GC. MiR-22 downregulation promotes GC invasion and metastasis by upregulating MMP14 and Snail, and then inducing ECM remodeling and EMT. These findings provide a better understanding of the development and progression of GC and may be an important implication for future therapy of the GC. PMID- 26610212 TI - Computational Investigation of Wave Packet Scattering in the Complex Plane: Propagation on a Grid. AB - The time-dependent scattering of a wave packet from a Gaussian barrier is investigated computationally in the complex z-plane. The initial wave packet and the potential energy are obtained through analytic continuation from functions specified on the real-axis. The wave packet is then propagated on the two dimensional grid. For a low initial wave packet energy, the time evolution is followed by plotting the following functions: |psi(z,t)|, real(psi(z,t)), and the quantum momentum function (QMF), p(z,t). In the reflected packet, an important role is played by ripples (quasi-nodes) forming above the real axis. As these quasi-nodes move down across the real axis, they are 'detected' as 'interference oscillations' in the density. In contrast, the component of the packet below the real axis makes a significant contribution to the transmitted packet. Vector maps of the QMF show hyperbolic flow around quasi-nodes and counterclockwise circular flow around transient stagnation points, where the QMF vanishes. However, when the Polya vector field (defined by P(z,t) = p*(z,t)) is plotted, circular counterclockwise flow is obtained near the quasi-nodes. The real and imaginary parts of the quantum action function S(z,t) are plotted and the vorticity, defined by the curl of the Polya field, is used to pinpoint regions of nonanalyticity in the QMF. PMID- 26610213 TI - Computational Investigation of Wave Packet Scattering in the Complex Plane: Dynamics of Exact Quantum Trajectories. AB - In two previous studies, the time-dependent scattering of a wave packet from a Gaussian barrier was investigated computationally in the complex z-plane. One of these involved the 'direct' propagation of the wave packet in the complex space, and the other used numerical analytic continuation techniques to generate the dynamics in the complex plane from the wave function computed on the real-axis. In the current study, the dynamics of exact quantum trajectories are analyzed for the same barrier scattering problem. Thousands of quantum trajectories were launched from positions near the center of the initial wave packet. These trajectories were computed by integrating equations-of-motion involving the quantum momentum function, which was obtained from the time-dependent wave function and its derivative. In order to analyze the dynamics, many trajectories were plotted on space-time diagrams. Particular emphasis was placed upon trajectories undergoing reflection in the barrier region. Some groups of strongly correlated trajectories form long-lived highly organized patterns, including helical wrappings around a series of stagnation filaments. These curves alternate with quasi-nodes where the amplitude of the wave function reaches low values. In addition, other trajectories for short times follow hyperbolic paths as they propagate near vorticity tubes surrounding these quasi-nodes. PMID- 26610214 TI - Tunneling Dynamics in a Double-Well Model of an H Transfer Reaction. AB - We study the role that tunneling can play in the reaction dynamics of H atom transfer. The small mass of the H atom offers it another, nonclassical route, from reactants to products, tunneling through an activation barrier. In this work, we carefully define the portion of a reaction rate constant that is caused by tunneling in such reactions. We do this by decomposing an initial H atom wavepacket into above and below the barrier components. We show that for a very particular decomposition, the quantum dynamics of the system can be separated into two events: tunneling and above-the-barrier product production. We show for such decomposition it is possible to determine a rate constant because of tunneling alone. Finally, we demonstrate that from a single experimental observable, the overall decay of reactant concentration, one can extract structural and dynamical information about the H atom transfer reaction. PMID- 26610215 TI - Investigating the Conformational Preferences of Transforming Growth Factor-beta Isoforms using Targeted Molecular Dynamics Simulations. AB - We study the conformational preferences and mechanical properties of two isoforms of the cytokine transforming growth factor-beta (-beta1 and -beta3) with atomistic detail and including the effects of explicit water. Targeted molecular dynamics simulations are used to perturb experimental "closed" conformations of both proteins into an "open" conformation, thus far only observed crystallographically for one of the two isoforms. The artificial restraints imposed by the protocol are later released, allowing the two covalently bound units of each homodimer to relax. Homology models of the two proteins are also constructed using the other as a template; models that are later subjected to the same process of perturbation into the open conformation and relaxation. On release, both simulations of transforming growth factor-beta1 show a tendency to snap back toward the closed conformation, while those of transforming growth factor-beta3 remain open for the remainder of the simulation, apparently consistent with measurements from a variety of experimental sources. Duplication of the simulations affords confidence that this observation reflects a genuine effect of the sequence, as opposed to an artifact of the conformations selected at the outset. The study provides a previously unseen level of detail, describing the structural and dynamic behavior of these proteins in solution, and brings us a step closer to understanding the complex relationship between sequence, structure, and signaling in this family of cytokines. PMID- 26610216 TI - Gaussian Basis Set and Planewave Relativistic Spin-Orbit Methods in NWChem. AB - Relativistic spin-orbit density functional theory (DFT) methods have been implemented in the molecular Gaussian DFT and pseudopotential planewave DFT modules of the NWChem electronic-structure program. The Gaussian basis set implementation is based upon the zeroth-order regular approximation (ZORA) while the planewave implementation uses spin-orbit pseudopotentials that are directly generated from the atomic Dirac-Kohn-Sham wave functions or atomic ZORA-Kohn-Sham wave functions. Compared to solving the full Dirac equation these methods are computationally efficient but robust enough for a realistic description of relativistic effects such as spin-orbit splitting, molecular orbital hybridization, and core effects. Both methods have been applied to a variety of small molecules, including I2, IF, HI, Br2, Bi2, AuH, and Au2, using various exchange-correlation functionals. Our results are in good agreement with experiment and previously reported calculations. PMID- 26610217 TI - Auxiliary Basis Sets for Density-Fitted MP2 Calculations: Correlation-Consistent Basis Sets for the 4d Elements. AB - Auxiliary basis sets for use in density fitting second-order Moller-Plesset perturbation theory and other correlated ab initio methods have been developed for the 4d transition metal elements Y-Tc and Rh-Pd (sets for Ru, Ag, and Cd are already available), to be used in conjunction with the correlation consistent basis sets with pseudopotentials cc-pVnZ-PP and aug-cc-pVnZ-PP. Correlation energy calculations for a test set of small- to medium-sized transition metal complexes encompassing a variety of oxidation states show that the error in using these auxiliary basis sets is around 3-4 orders of magnitude smaller than the error due to orbital basis set size. The effect of truncating the auxiliary basis sets to remove higher angular momentum functions is also considered. PMID- 26610218 TI - A Scheme for the Evaluation of Electron Delocalization and Conjugation Efficiency in Linearly pi-Conjugated Systems. AB - In this study, we present a scheme for the evaluation of electron delocalization and conjugation efficiency in lineraly pi-conjugated systems. The scheme, based on the natural bond orbital theory, allows monitoring the evolution of electron delocalization along an extended conjugation path as well as its response to chemical modification. The scheme presented is evaluated and illustrated by means of a computational investigation of pi-conjugation in all-trans polyacetylene [PA; H(-CH?CH)n-H], polydiacetylene [PDA, H(-C=C-CH?CH)n-H], and polytriacetylene [PTA, H(-C=C-CH?CH-C=C)n-H] with up to 180 carbon atoms, all related by the number of ethynyl units incorporated in the chain. We are able to show that for short oligomers the incorporation of ethynyl spacers into the PA chain increases the pi-delocalization energy, but, on the other hand, reduces the efficiency with which pi-electron delocalization is promoted along the backbone. This explains the generally shorter effective conjugation lengths observed for the properties of the polyeneynes (PDA and PTA) relative to the polyenes (PA). It will also be shown that the reduced conjugation efficiency, within the NBO-based model presented in this work, can be related to the orbital interaction pattern along the pi-conjugated chain. We will show that the orbital interaction energy pattern is characteristic for the type and the length of the backbone and may therefore serve as a descriptor for linearly pi-conjugated chains. PMID- 26610219 TI - Comprehensive Energy Analysis for Various Types of pi-Interaction. AB - We have investigated various types of pi-interactions, where one of the interacting pi-systems is represented by an aromatic benzene molecule. The system includes Rg-pi, CH-pi, pi-pi(D), pi-pi(T), H-pi(T), pi(+)-pi(D), pi(+)-pi(T), H(+)-pi(T), pi(+2)-pi(D), M(+)-pi, and M(+2)-pi complexes, where Rg denotes a rare gas or noble atom, M denotes a metal, and D/T indicates displaced-stacked/T shaped structure. The microsolvation effect is also considered. We note that the interaction between a cationic pi system and a neutral pi system (pication-pi interaction) is so far ambiguously considered as either pi-pi or cation-pi interaction. In terms of total binding energy, the pication-pi interaction is weaker than the cation-pi interaction, but much stronger than the pi-pi interaction. When the hydrophilic (N-H)(+) or (C-H)(+) group in a singly charged pi(+) system (as in protonated histidine, arginine, pyridine, or dimethyl imidazolium) interacts with a pi-system, the complex favors a T-shaped form [pi(+)-pi(T) complex]. However, in the presence of polar solvating molecules or counteranions, these species interact with the (N-H)(+)/(C-H)(+) group, while the pi(+) system interacts with the neutral aromatic ring. Then, the displaced stacked form [pi(+)-pi(D) complex] is favored or otherwise nearly isoenergetic to the pi(+)-pi(T) form. The pi(+)-pi systems are stabilized mainly by both dispersion and electrostatic energies. Ternary diagrams using either attractive energy components or both attractive and repulsive energy components show that the pi(+)-pi(D) complexes have more contribution from dispersion energy but less contribution from induction energy than the pi(+)-pi(T) complexes, while both complexes have similar percentage contributions from electrostatic and exchange energy components. In particular, the pi(+)-pi(D) complexes are found to be distinctly different from the pi-pi complexes and the non-pi organic or metallic cation-pi complexes. PMID- 26610220 TI - Molecular Mechanics Force Field for Octahedral Organometallic Compounds with Inclusion of the Trans Influence. AB - Efficient calculation of the properties of metal-containing complexes relevant to catalysis is of major interest for better characterizing and optimizing the catalysts. For this, a new force field, called VALBOND-TRANS here, is proposed. It is based on the existing VALBOND force field of Landis and co-workers, extended by adding terms that account for electronic effects such as the trans influence of ligands on bond lengths and relative energies. Parameters and results for model octahedral complexes of Ru, Os, Rh, and Ir are determined and discussed. The model is then applied to the study of reactive intermediates involved in asymmetric hydrogenation catalyzed by iridium complexes with chiral phosphinooxazolines (PHOX) ligands. The new force field explores and capitalizes on the separation of electronic and steric effects on the stability of different diastereomers and reproduces DFT results which are consistent with experimental observations. PMID- 26610221 TI - Fully Integrated Approach to Compute Vibrationally Resolved Optical Spectra: From Small Molecules to Macrosystems. AB - A general and effective time-independent approach to compute vibrationally resolved electronic spectra from first principles has been integrated into the Gaussian computational chemistry package. This computational tool offers a simple and easy-to-use way to compute theoretical spectra starting from geometry optimization and frequency calculations for each electronic state. It is shown that in such a way it is straightforward to combine calculation of Franck-Condon integrals with any electronic computational model. The given examples illustrate the calculation of absorption and emission spectra, all in the UV-vis region, of various systems from small molecules to large ones, in gas as well as in condensed phases. The computational models applied range from fully quantum mechanical descriptions to discrete/continuum quantum mechanical/molecular mechanical/polarizable continuum models. PMID- 26610222 TI - Benchmarks for Electronically Excited States: A Comparison of Noniterative and Iterative Triples Corrections in Linear Response Coupled Cluster Methods: CCSDR(3) versus CC3. AB - CCSDR(3) calculations of vertical excitation energies are reported for a set of 24 molecules and 121 excited valence singlet states from a recently published benchmark of organic molecules. The same geometries (MP2/6-31G*) and basis set (TZVP) were employed as in our previous linear response CC2, CCSD, and CC3 calculations. The CCSDR(3) results are compared against the CCSD and CC3 results. Statistical evaluation of all CCSDR(3) excitation energies gives mean absolute deviations of 0.09 eV from CC3 and 0.30 eV from CCSD. For excited states, which are dominated by single excitations, the absolute mean deviation from CC3 is reduced to 0.02 eV and the maximum deviation is 0.09 eV. CCSDR(3) is thus a very cost-effective accurate alternative to CC3. PMID- 26610223 TI - Franck-Condon Simulations including Anharmonicity of the A(1)A''-X(1)A' Absorption and Single Vibronic Level Emission Spectra of HSiCl and DSiCl. AB - RCCSD(T) and/or CASSCF/MRCI calculations have been carried out on the X(1)A' and A(1)A'' states of HSiCl employing basis sets of up to the aug-cc-pV5Z quality. Contributions from core correlation and extrapolation to the complete basis set limit were included in determining the computed equilibrium geometrical parameters and relative electronic energy of these two states of HSiCl. Franck Condon factors which include allowance for anharmonicity and Duschinsky rotation between these two states of HSiCl and DSiCl were calculated employing RCCSD(T) and CASSCF/MRCI potential energy functions, and were used to simulate the A(1)A'' <- X(1)A' absorption and A(1)A'' -> X(1)A' single vibronic level (SVL) emission spectra of HSiCl and DSiCl. Simulated absorption and experimental LIF spectra, and simulated and observed A(1)A''(0,0,0) -> X(1)A' SVL emission spectra, of HSiCl and DSiCl are in very good agreement. However, agreement between simulated and observed A(1)A''(0,1,0) -> X(1)A' and A(1)A''(0,2,1) -> X(1)A' SVL emission spectra of DSiCl is not as good. Preliminary calculations on low-lying excited states of HSiCl suggest that vibronic interaction between low-lying vibrational levels of the A(1)A'' state and highly excited vibrational levels of the a(3)A'' is possible. Such vibronic interaction may change the character of the low-lying vibrational levels of the A(1)A'' state, which would lead to perturbation in the SVL emission spectra from these vibrational levels. PMID- 26610224 TI - Topological Analysis of the Interactions between Organic Molecules and Co(Ni)MoS Catalytic Active Phases. AB - The adsorption modes of toluene, 2,3-dimethylbut-1-ene, and 2-methylthiophene on the edges of Co(Ni)MoS nanocrystallites has been investigated with the ELF topological approach of chemical bonding. The chemisorbed modes are characterized by the formation of bonding basins linking the substrate to the catalytic sites. The electronic rearrangements within the substrate are discussed. It is shown that a unique electronic descriptor, namely the metallic atomic basin contribution to the substrate ELF basins, provides a sizable correlation with the interaction energy. PMID- 26610225 TI - Valence-Bond Order (VBO): A New Approach to Modeling Reactive Potential Energy Surfaces for Complex Systems, Materials, and Nanoparticles. AB - The extension of molecular mechanics to reactive systems, metals, and covalently bonded clusters with variable coordination numbers requires new functional forms beyond those popular for organic chemistry and biomolecules. Here we present a new scheme for reactive molecular mechanics, which is denoted as the valence-bond order model, for approximating reactive potential energy surfaces in large molecules, clusters, nanoparticles, solids, and other condensed-phase materials, especially those containing metals. The model is motivated by a moment approximation to tight binding molecular orbital theory, and we test how well one can approximate potential energy surfaces with a very simple functional form involving only interatomic distances with no explicit dependence on bond angles or dihedral angles. For large systems the computational requirements scale linearly with system size, and no diagonalizations or iterations are required; thus the method is well suited to large-scale simulations. The method is illustrated here by developing a force field for particles and solids composed of aluminum and hydrogen. The parameters were optimized against both interaction energies and relative interaction energies. The method performs well for pure aluminum clusters, nanoparticles, and bulk lattices and reasonably well for pure hydrogen clusters; the mean unsigned error per atom for the aluminum-hydrogen clusters is 0.1 eV/atom. PMID- 26610226 TI - Toward an Accurate Density-Functional Tight-Binding Description of Zinc Containing Compounds. AB - An extended self-consistent charge density-functional tight-binding (SCC-DFTB) parametrization for Zn-X (X = H, C, N, O, S, and Zn) interactions has been derived. The performance of this new parametrization has been validated by calculating the structural and energetic properties of zinc solid phases such as bulk Zn, ZnO, and ZnS; ZnO surfaces and nanostructures; adsorption of small species (H, CO2, and NH3) on ZnO surfaces; and zinc-containing complexes mimicking the biological environment. Our results show that the derived parameters are universal and fully transferable, describing all the above mentioned systems with accuracies comparable to those of first-principles DFT results. PMID- 26610227 TI - Lipid Models for United-Atom Molecular Dynamics Simulations of Proteins. AB - United-atom force fields for molecular dynamics (MD) simulations provide a higher computational efficiency, especially in lipid membrane simulations, with little sacrifice in accuracy, when compared to all-atom force fields. Excellent united atom lipid models are available, but in combination with depreciated protein force fields. In this work, a united-atom model of the lipid 1,2-dipalmitoyl-sn glycero-3-phosphocholine has been built with standard parameters of the force field GROMOS96 53a6 that reproduces the experimental area per lipid of a lipid bilayer within 3% accuracy to a value of 0.623 +/- 0.011 nm(2) without the assumption of a constant surface area or the inclusion of surface pressure. In addition, the lateral self-diffusion constant and deuterium order parameters of the acyl chains are in agreement with experimental data. Furthermore, models for 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1-palmitoyl-2-oleoyl-sn glycero-3-phosphocholine (POPC), and 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphoglycerol (POPG) result in areas per lipid of 0.625 nm(2) (DMPC), 0.693 nm(2) (POPC), and 0.700 nm(2) (POPG) from 40 ns MD simulations. Experimental lateral self-diffusion coefficients are reproduced satisfactorily by the simulation. The lipid models can form the basis for molecular dynamics simulations of membrane proteins with current and future versions of united-atom protein force fields. PMID- 26610228 TI - Graph Measures Reveal Fine Structure of Complexes Forming in Multiparticle Simulations. AB - Modern simulation techniques are beginning to be used to study the dynamic assembly and disassembly of multiprotein systems. In these many-particle simulations it can be very tedious to monitor the formation of specific structures such as fully assembled protein complexes or virus capsids above a background of monomers and partial complexes. However, such analyses can be performed conveniently when the spatial configuration is mapped onto a dynamically updated interaction graph. On the example of Monte Carlo simulations of spherical particles with either isotropic or directed mutual attractions, we demonstrate that this combined strategy allows for an efficient and also detailed analysis of complex formation in many-particle systems. PMID- 26610229 TI - Protein Influence on Electronic Spectra Modeled by Multipoles and Polarizabilities. AB - We have developed automatic methods to calculate multipoles and anisotropic polarizabilities for all atoms and bond centers in a protein and to include such a model in the calculation of electronic properties at any level of quantum mechanical theory. This approach is applied for the calculation of the electronic spectra of retinal in rhodopsin at the CASPT2//CASSCF level (second-order multiconfigurational perturbation theory) for the wild-type protein, as well as two mutants and isorhodopsin in QM/MM structures based on two crystal structures. We also perform a detailed investigation of the importance and distance dependence of the multipoles and the polarizabilities for both the absolute and the relative absorption energies. It is shown that the model of the surrounding protein strongly influences the spectrum and that different models give widely different results. For example, the Amber 1994 and 2003 force fields give excitation energies that differ by up to 16 kJ/mol. For accurate excitation energies, multipoles up to quadrupoles and anisotropic polarizabilities are needed. However, interactions with residues more than 10 A from the chromophore can be treated with a standard polarizable force field without any dipoles or quadrupoles. PMID- 26610230 TI - Bound Ligand Conformer Revealed by Flexible Structure Alignment in Absence of Crystal Structures: Indirect Drug Design Probed for HIV-1 Protease Inhibitors. AB - In the absence of structural knowledge on the target protein, the bound ligand conformer (BLC) can be constructed approximately by an indirect drug-design approach that uses a set of ligands binding to the same target. Once the bound ligand conformer (BLC) is known, different strategies of drug design can be pursued. The indirect drug-design approach of the present study is based on the assumption that a set of ligands with chemically different architecture binding to the same target protein carry hidden information of their corresponding true BLCs. It is shown how this information can be extracted by pairwise flexible structure alignment (FSA) using molecular dynamics (MD) simulations with attractive intermolecular interactions that derive from the molecular similarity of the ligands and allow the ligands to adopt the same space. The FSA approach is performed with a newly designed module overlap in the experimental CHARMM-29a1, which soon will become publicly available. Combining the conformations obtained from FSA of different ligand pairs yields consensus ligand conformers (CLCs) that should be similar to the BLCs. This procedure was validated on HIV-1 protease (HIV-P), where at present 44 crystal structures with bound ligands of sufficiently diverse chemical composition are available. The FSA approach identifies four different clusters of HIV-P BLCs. These clusters are consistent with the H-bond patterns of the ligands bound to HIV-P in the crystal structures exhibiting four different binding modes. The cluster-specific CLCs are indeed very similar (rmsd ~ 2 A) to the corresponding BLCs from the crystal structure, demonstrating the feasibility of the present approach. PMID- 26610232 TI - Bicelles and Other Membrane Mimics: Comparison of Structure, Properties, and Dynamics from MD Simulations. AB - The increased interest in studying membrane proteins has led to the development of new membrane mimics such as bicelles and nanodiscs. However, only limited knowledge is available of how these membrane mimics are affected by embedded proteins and how well they mimic a lipid bilayer. Herein, we present molecular dynamics simulations to elucidate structural and dynamic properties of small bicelles and compare them to a large alignable bicelle, a small nanodisc, and a lipid bilayer. Properties such as lipid packing and properties related to embedding both an alpha-helical peptide and a transmembrane protein are investigated. The small bicelles are found to be very dynamic and mainly assume a prolate shape substantiating that small bicelles cannot be regarded as well defined disclike structures. However, addition of a peptide results in an increased tendency to form disc-shaped bicelles. The small bicelles and the nanodiscs show increased peptide solvation and difference in peptide orientation compared to embedding in a bilayer. The large bicelle imitated a bilayer well with respect to both curvature and peptide solvation, although peripheral binding of short tailed lipids to the embedded proteins is observed, which could hinder ligand binding or multimer formation. PMID- 26610233 TI - The effect of vacancies on the optical properties of AuAl2. AB - AuAl2 is an intermetallic compound with a vivid purple colour attributable to a bulk plasmon energy in the visible part of the spectrum. However, the colour of as-deposited thin films is not as strong and only develops upon annealing. Density functional theory calculations of the dielectric function are presented for a variety of vacancy types and concentrations. The results support the view that the effect of annealing on colour is correlated with a reduction in concentration of Al vacancies. The effect of vacancies on the optical properties can be understood as arising from the complex interplay between interband transitions around the Fermi level and the plasmon energy. PMID- 26610234 TI - A numerical solution of the mechanical bidomain model. AB - INTRODUCTION: The mechanical bidomain model predicts forces on integrin proteins in the membrane. It has been solved analytically for idealized examples, but a numerical algorithm is needed to address realistic problems. METHODS: The bidomain equations are approximated using finite differences. An ischemic region is modeled as a circular area having no active tension, surrounded by normal tissue. RESULTS: The membrane force is large in the ischemic border zone, but is small elsewhere. Strain is distributed widely throughout the ischemic region and surrounding tissue. CONCLUSION: This calculation provides a testable prediction for the mechanism of mechanotransduction and remodeling in cardiac tissue. PMID- 26610235 TI - Incidence of pituitary dysfunction following traumatic brain injury: A prospective study from a regional neurosurgical centre. AB - Patients with traumatic brain injury (TBI) may develop pituitary dysfunction. Although, there is now increasing awareness of and investigations into such post traumatic hypopituitarism (PTHP), the exact prevalence and incidence remain uncertain. Here, we aim to identify the incidence of PTHP in a selected population of TBI patients deemed at risk of PTHP at a regional neurosurgical centre in the UK. A total of 105 patients have been assessed in two cohorts: (i) 58 patients in serial cohort and (ii) 47 patients in cross-sectional late cohort. We found that in serial cohort, 10.3% (6/58) of TBI patients had abnormalities of the pituitary-adrenal axis in the acute phase (Day 0-7 post injury). In comparison, in cross-sectional late cohort, 21.3% (10/47) of the patients developed dysfunction in at least one of their pituitary axes at 6 months or more post-TBI, with hypogonadotrophic hypogonadism being the most common. Twenty-two patients from these two cohorts had their growth hormone assessment at 12 months or more post-TBI and 9.1% (2/22) were found to have growth hormone deficiency. Our results suggest that PTHP is a common condition amongst sufferers of TBI, and appropriate measures should be taken to detect and manage it. PMID- 26610236 TI - Pregnancy outcomes after cerclage placement in nulliparous women with a short cervix on transvaginal ultrasonography. AB - OBJECTIVE: Little is known about pregnancy outcomes associated with a short cervix and cerclage placement in nulliparous women. METHODS: An electronic query of our ultrasound database was used to identify patients whose cervical length measured < 25 mm between 16-24 weeks of gestation. Any nulliparous women, with no prior pregnancy lasting beyond 13 weeks 6 d gestational age, were included in the analysis. The primary outcome was the interval of time from the diagnosis of a short cervix (<25 mm) to the time of delivery. RESULTS: Our query identified 70 patients for analysis. The interval of time from diagnosis of a short cervix to delivery was observed to be 85 d (12.1 weeks) in the cerclage group and 116 d (16.6 weeks) in the expectantly managed group (p = 0.02). In those women receiving a cerclage, there was a statistically significant risk of spontaneous preterm birth <32 weeks gestational age (R.R. 6.7 [95% CI 1.45-30.6]). CONCLUSIONS: The impact of a short cervix is largely unknown in patients with an uncomplicated obstetrical history. Our investigation would suggest that in this subset of patients, cerclage would not be beneficial in preventing preterm delivery. PMID- 26610240 TI - Peaches Preceded Humans: Fossil Evidence from SW China. AB - Peach (Prunus persica, Rosaceae) is an extremely popular tree fruit worldwide, with an annual production near 20 million tons. Peach is widely thought to have origins in China, but its evolutionary history is largely unknown. The oldest evidence for the peach has been Chinese archaeological records dating to 8000 7000 BP. Here, we report eight fossil peach endocarps from late Pliocene strata of Kunming City, Yunnan, southwestern China. The fossils are identical to modern peach endocarps, including size comparable to smaller modern varieties, a single seed, a deep dorsal groove, and presence of deep pits and furrows. These fossils show that China has been a critical region for peach evolution since long before human presence, much less agriculture. Peaches evolved their modern morphology under natural selection, presumably involving large, frugivorous mammals such as primates. Much later, peach size and variety increased through domestication and breeding. PMID- 26610241 TI - Investigating the link between smoke-free legislation and stillbirths. AB - Despite considerable recent progress in tobacco control, smoking and second-hand smoke exposure continue to pose a major health threat to adults, children, and (unborn) babies. There is increasing evidence that implementation of smoke-free legislation, through reducing smoking and smoke exposure, has the potential to improve population health. In this editorial we focus on the research on smoke free legislation in relation to stillbirths, summarizing the findings to-date, reflecting on methodological issues that need to be considered when interpreting this evidence base, and highlighting some key next steps to further strengthen the evidence in order to inform evidence-based policy making. PMID- 26610246 TI - Long Non-Coding RNA MEG3 Inhibits Cell Proliferation and Induces Apoptosis in Prostate Cancer. AB - BACKGROUND/AIMS: Long non-coding RNAs (lncRNAs) play important roles in diverse biological processes, such as cell growth, apoptosis and migration. Although downregulation of lncRNA maternally expressed gene 3 (MEG3) has been identified in several cancers, little is known about its role in prostate cancer progression. The aim of this study was to detect MEG3 expression in clinical prostate cancer tissues, investigate its biological functions in the development of prostate cancer and the underlying mechanism. METHODS: MEG3 expression levels were detected by qRT-PCR in both tumor tissues and adjacent non-tumor tissues from 21 prostate cancer patients. The effects of MEG3 on PC3 and DU145 cells were assessed by MTT assay, colony formation assay, western blot and flow cytometry. Transfected PC3 cells were transplanted into nude mice, and the tumor growth curves were determined. RESULTS: MEG3 decreased significantly in prostate cancer tissues relative to adjacent normal tissues. MEG3 inhibited intrinsic cell survival pathway in vitro and in vivo by reducing the protein expression of Bcl 2, enhancing Bax and activating caspase 3. We further demonstrated that MEG3 inhibited the expression of cell cycle regulatory protein Cyclin D1 and induced cell cycle arrest in G0/G1 phase. CONCLUSIONS: Our study presents an important role of MEG3 in the molecular etiology of prostate cancer and implicates the potential application of MEG3 in prostate cancer therapy. PMID- 26610247 TI - Using Lasso for Predictor Selection and to Assuage Overfitting: A Method Long Overlooked in Behavioral Sciences. AB - Ordinary least squares and stepwise selection are widespread in behavioral science research; however, these methods are well known to encounter overfitting problems such that R(2) and regression coefficients may be inflated while standard errors and p values may be deflated, ultimately reducing both the parsimony of the model and the generalizability of conclusions. More optimal methods for selecting predictors and estimating regression coefficients such as regularization methods (e.g., Lasso) have existed for decades, are widely implemented in other disciplines, and are available in mainstream software, yet, these methods are essentially invisible in the behavioral science literature while the use of sub optimal methods continues to proliferate. This paper discusses potential issues with standard statistical models, provides an introduction to regularization with specific details on both Lasso and its related predecessor ridge regression, provides an example analysis and code for running a Lasso analysis in R and SAS, and discusses limitations and related methods. PMID- 26610248 TI - A Comparison of Imputation Strategies for Ordinal Missing Data on Likert Scale Variables. AB - This article compares a variety of imputation strategies for ordinal missing data on Likert scale variables (number of categories = 2, 3, 5, or 7) in recovering reliability coefficients, mean scale scores, and regression coefficients of predicting one scale score from another. The examined strategies include imputing using normal data models with naive rounding/without rounding, using latent variable models, and using categorical data models such as discriminant analysis and binary logistic regression (for dichotomous data only), multinomial and proportional odds logistic regression (for polytomous data only). The result suggests that both the normal model approach without rounding and the latent variable model approach perform well for either dichotomous or polytomous data regardless of sample size, missing data proportion, and asymmetry of item distributions. The discriminant analysis approach also performs well for dichotomous data. Naively rounding normal imputations or using logistic regression models to impute ordinal data are not recommended as they can potentially lead to substantial bias in all or some of the parameters. PMID- 26610249 TI - Addressing Item-Level Missing Data: A Comparison of Proration and Full Information Maximum Likelihood Estimation. AB - Often when participants have missing scores on one or more of the items comprising a scale, researchers compute prorated scale scores by averaging the available items. Methodologists have cautioned that proration may make strict assumptions about the mean and covariance structures of the items comprising the scale (Schafer & Graham, 2002 ; Graham, 2009 ; Enders, 2010 ). We investigated proration empirically and found that it resulted in bias even under a missing completely at random (MCAR) mechanism. To encourage researchers to forgo proration, we describe a full information maximum likelihood (FIML) approach to item-level missing data handling that mitigates the loss in power due to missing scale scores and utilizes the available item-level data without altering the substantive analysis. Specifically, we propose treating the scale score as missing whenever one or more of the items are missing and incorporating items as auxiliary variables. Our simulations suggest that item-level missing data handling drastically increases power relative to scale-level missing data handling. These results have important practical implications, especially when recruiting more participants is prohibitively difficult or expensive. Finally, we illustrate the proposed method with data from an online chronic pain management program. PMID- 26610250 TI - How Do Propensity Score Methods Measure Up in the Presence of Measurement Error? A Monte Carlo Study. AB - Considering that the absence of measurement error in research is a rare phenomenon and its effects can be dramatic, we examine the impact of measurement error on propensity score (PS) analysis used to minimize selection bias in behavioral and social observational studies. A Monte Carlo study was conducted to explore the effects of measurement error on the treatment effect and balance estimates in PS analysis across seven different PS conditioning methods. In general, the results indicate that even low levels of measurement error in the covariates lead to substantial bias in estimates of treatment effects and concomitant reduction in confidence interval coverage across all methods of conditioning on the PS. PMID- 26610251 TI - Correcting Too Much or Too Little? The Performance of Three Chi-Square Corrections. AB - This simulation study investigates the performance of three test statistics, T1, T2, and T3, used to evaluate structural equation model fit under non normal data conditions. T1 is the well-known mean-adjusted statistic of Satorra and Bentler. T2 is the mean-and-variance adjusted statistic of Sattertwaithe type where the degrees of freedom is manipulated. T3 is a recently proposed version of T2 that does not manipulate degrees of freedom. Discrepancies between these statistics and their nominal chi-square distribution in terms of errors of Type I and Type II are investigated. All statistics are shown to be sensitive to increasing kurtosis in the data, with Type I error rates often far off the nominal level. Under excess kurtosis true models are generally over-rejected by T1 and under rejected by T2 and T3, which have similar performance in all conditions. Under misspecification there is a loss of power with increasing kurtosis, especially for T2 and T3. The coefficient of variation of the nonzero eigenvalues of a certain matrix is shown to be a reliable indicator for the adequacy of these statistics. PMID- 26610252 TI - Models for the Detection of Deviations from the Expected Processing Strategy in Completing the Items of Cognitive Measures. AB - This paper presents confirmatory factor models with fixed factor loadings that enable the identification of deviations from the expected processing strategy. The instructions usually define the expected processing strategy to a considerable degree. Simplification is a deviation from instructions that is likely to occur in complex cognitive measures. Since simplification impairs the validity of the measure, its identification is important. Models representing simplicity and instruction-based processing strategies were considered in investigating the data of 345 participants obtained by a working memory measure in order to find out whether and how the use of these strategies influences model data fit. As expected, the consideration of simplicity strategies improved the model-data fit achieved for the instruction-based strategy. PMID- 26610253 TI - Extending the Debate Between Spearman and Wilson 1929: When do Single Variables Optimally Reproduce the Common Part of the Observed Covariances? AB - The covariances of observed variables reproduced from conventional factor score predictors are generally not the same as the covariances reproduced from the common factors. We sought to find a factor score predictor that optimally reproduces the common part of the observed covariances. It was found algebraically that-under some conditions-the single observed variable with highest loading on a factor reproduces the non-diagonal elements of the observed covariance matrix more exactly than the conventional factor score predictors. This finding is linked to Spearman's and Wilson's 1929 debate on the use of single variables as factor score predictors. A population-based and a sample based simulation study confirmed the algebraic result that taking a single variable can outperform conventional factor score predictors in reproducing the non-diagonal covariances when the nonzero loading size and the number of nonzero loadings per factor are small. The results indicated that a weighted aggregation of variables does not necessarily lead to an improvement of the score over the variable with the highest loading. PMID- 26610254 TI - Techniques to improve and confirm pulmonary vein isolation. AB - Atrial fibrillation is the most common acquired arrhythmia and is increasing in frequency as the population ages. Treatment for atrial fibrillation ranges from minimal intervention to complex catheter ablations. The strategy used to treat atrial fibrillation largely rests on the extent of symptoms in an individual patient. This review will focus on ablation for atrial fibrillation and efforts to improve the success of the procedure. PMID- 26610255 TI - Membrane lipids as therapeutic targets for Parkinson's disease: a possible link between Lewy pathology and membrane lipids. AB - INTRODUCTION: Pathologically, Parkinson's disease (PD) is characterized by nigral cell loss and Lewy pathology in the remaining neurons. Whereas the motor symptoms of PD show a marked response to dopamine replacement therapy, many of the non motor symptoms are resistant to treatment. This suggests that in addition to nigral cell loss, widespread Lewy pathology in the nervous system is associated with the manifestations of PD. Areas covered: Although the mechanism of Lewy body formation remains largely unknown, it is becoming clear that changes in the behavior of alpha-synuclein are critical in this process. alpha-Synuclein behaves differently depending on the lipid composition of membranes with which it interacts; therefore, one can postulate that the altered lipid composition of neuronal membranes may lead to Lewy pathology. The lipid composition of cellular membranes is consistently altered in the brains of patients with PD, and Lewy pathology is a common feature of several human lipidoses with mutations in enzymes that affect membrane lipids. This further supports the concept that alterations in the membrane lipids of neurons are central to Lewy pathology. Expert opinion: This concept provides a new platform to establish models for the development of novel treatments for PD. PMID- 26610256 TI - An evaluation of entecavir for the treatment of chronic hepatitis B infection in adults. AB - Entecavir is a nucleoside analogue of 2'-deoxyguanosine whose intracellular triphosphate form inhibits replication of the hepatitis B virus. Entecavir is recommended as a first-line monotherapy option for nucleos(t)ide-naive patients with HBeAg-positive or -negative chronic hepatitis B infection. Entecavir has a three-step mechanism of action: It maintains viral suppression with a greater than 90% chance of undetectable hepatitis B virus DNA during continuous therapy, improves liver histology, and reduces the risk of liver failure or hepatocellular carcinoma development. The safety profile of long-term entecavir therapy is favorable; however, its optimal treatment duration is unknown. Entecavir monotherapy is not a rescue option for patients with lamivudine/adefovir resistance or baseline lamivudine-resistant mutants; rather, combination treatment is recommended for patients with lamivudine/adefovir resistance. PMID- 26610257 TI - Toward the understanding of the molecular basis for the inhibition of COX-1 and COX-2 by phenolic compounds present in Uruguayan propolis and grape pomace. AB - Propolis and grape pomace have significant amounts of phenols which can take part in anti-inflammatory mechanisms. As the cyclooxygenases 1 and 2 (COX-1 and COX-2) are involved in said mechanisms, the possibility for a selective inhibition of COX-2 was analyzed in vitro and in silico. Propolis and grape pomace from Uruguayan species were collected, extracted in hydroalcoholic mixture and analyzed. Based on phenols previously identified, and taking as reference the crystallographic structures of COX-1 and COX-2 in complex with the commercial drug Celecoxib, a molecular docking procedure was devised to adjust 123 phenolic molecular models at the enzyme-binding sites. The most important results of this work are that the extracts have an overall inhibition activity very similar in COX-1 and COX-2, i.e. they do not possess selective inhibition activity for COX 2. Nevertheless, 10 compounds of the phenolic database turned out to be more selective and 94 phenols resulted with similar selectivity than Celecoxib, an outcome that accounts for the overall experimental inhibition measures. Binding site environment observations showed increased polarity in COX-2 as compared with COX-1, suggesting that polarity is the key for selectivity. Accordingly, the screening of molecular contacts pointed to the residues: Arg106, Gln178, Leu338, Ser339, Tyr341, Tyr371, Arg499, Ala502, Val509, and Ser516, which would explain, at the atomic level, the anti-inflammatory effect of the phenolic compounds. Among them, Gln178 and Arg499 appear to be essential for the selective inhibition of COX-2. PMID- 26610258 TI - Treatment of prosthetic joint infections due to Propionibacterium. PMID- 26610259 TI - Attitude toward the out-patient cardiac rehabilitation program and facilitators for maintenance of exercise behavior. AB - OBJECTIVE: This study examined the attitudes of Chinese patients with coronary heart disease (CHD) toward the outpatient cardiac rehabilitation program (OCRP), as well as their exercise behavior, intention, maintenance and related factors. METHOD: A qualitative descriptive study design was used, and 22 CHD patients were recruited in Hong Kong in 2014. In-depth interviews and content analyses were conducted. The tripartite model of attitudes was adopted as research framework. RESULT: Two themes were identified: (1) informant attitude (perception, affection, and practice) toward the OCRP and (2) Exercise Behavior - intention, maintenance and its related factors. Most informants showed positive perception and affection regarding the outpatient rehabilitation program, leading to regular practice of exercise in the program and at home. Peer, group dynamic, social support and Chinese culture influences on exercise behavior may serve as major facilitators to maintain exercise behavior. CONCLUSION: Positive attitude toward the OCRP enhanced the participation rate, whereas peer and social support from the family and workplace were useful to improve the maintenance of exercise behavior. Overall, this study provides insights into strategic planning for the OCRP and continual support for CHD patients in the community. PMID- 26610260 TI - The effects of preconception interventions on improving reproductive health and pregnancy outcomes in primary care: A systematic review. AB - BACKGROUND: Reproductive health and pregnancy outcomes may be improved if the reproductive risk assessment is moved from the antenatal to the preconception period. Primary care has been highlighted as an ideal setting to offer preconception assessment, yet the effectiveness in this setting is still unclear. OBJECTIVES: To evaluate the effectiveness of preconception interventions on improving reproductive health and pregnancy outcomes in primary care. METHODS: MEDLINE, CINAHL, EMBASE and PsycINFO databases were searched from July 1999 to the end of July 2015. Only interventional studies with a comparator were included, analysed and appraised systematically, taking into consideration the similarities and differences of the participants, the nature of interventions and settings. RESULTS: Eight randomized controlled trials were eligible. Preconception interventions involved multifactorial or single reproductive health risk assessment, education and counselling and the intensity ranged from brief, involving a single session within a day to intensive, involving more than one session over several weeks. Five studies recruited women planning a pregnancy. Four studies involved multifactorial risks interventions; two were brief and the others were intensive. Four studies involved single risk intervention, addressing folate or alcohol. There was some evidence that both multifactorial and single risk interventions improved maternal knowledge; self-efficacy and health locus of control; and risk behaviour, irrespective of whether brief or intensive. There was no evidence to support reduced adverse pregnancy outcomes. One study reported no undue anxiety. The quality of the studies was moderate to poor. CONCLUSION: The evidence from eligible studies is limited to inform future practice in primary care. Nevertheless, this review has highlighted that women who received preconception education and counselling were more likely to have improved knowledge, self-efficacy and health locus of control and risk behaviour. More studies are needed to evaluate the effects on adverse pregnancy outcomes. PMID- 26610261 TI - A comprehensive study of novel microcapsules incorporating gliclazide and a permeation enhancing bile acid: hypoglycemic effect in an animal model of Type-1 diabetes. AB - CONTEXT: Gliclazide (G) is a commonly prescribed drug for Type 2 diabetes (T2D). In a recent study, we found that when G was combined with a primary bile acid, and gavaged to an animal model of Type 1 diabetes (T1D), it exerted a hypoglycemic effect. We hypothesized this to be due to metabolic activation of the primary bile acid into a secondary or a tertiary bile acid, which enhanced G solubility and absorption. The tertiary bile acid, taurocholic acid (TCA), has shown strong permeation-enhancing effects in vivo. Thus, we aimed to design, characterize, and test microcapsules incorporating G and TCA in an animal model of T1D. METHODS: Microcapsules were prepared using the polymer sodium alginate (SA). G-SA microcapsules (control) and G-TCA-SA microcapsules (test) were extensively examined (in-vitro) at different pH and temperatures. The microcapsules were gavaged to diabetic rats, and blood glucose and G concentrations in serum were examined. Ex-vivo studies were also performed using a muscle cell line (C2C12), and cell viability and glucose intake post-treatment were examined. RESULTS: G-TCA-SA microcapsules showed good stability, uniformity, and thermal and chemical excipient compatibilities. TCA did not change the size or the shape of the microcapsules, but it enhanced their mechanical resistance and reduced their swelling properties. G-TCA-SA enhanced the viability of C2C12 cells over 24 hours, and exerted a hypoglycemic effect in alloxan-induced type-1 diabetic rats. CONCLUSIONS: The incorporation of TCA into G-microcapsules resulted in functionally improved microcapsules with a positive effect on cell viability and glycemic control in Type-1 diabetic animals. PMID- 26610262 TI - Cardiovascular medication after cancer at a young age in Finland: A nationwide registry linkage study. AB - Despite improved survival rates, childhood and young adult (YA) cancer survivors face elevated risks for life-threatening morbidities, especially cardiovascular complications. Our nationwide Finnish registry study investigated the purchases of cardiovascular medication from 1993 to 2011 in patients diagnosed with cancer aged below 35 years (N = 8,197) between 1993 and 2004 compared to siblings (N = 29,974) via linkage to the drug purchase registry. The cumulative incidence for purchasing cardiovascular medications was higher in childhood and YA cancer patients compared to siblings with a rising trend over time. After childhood cancer, the highest hazard ratio (HR) was found for purchasing anticoagulants (HR 19.8, 95% CI 8.5-45.9). The HRs for any cardiovascular medication (HR 7.2, 95% CI 5.1-10.1) and cardiac medication (HR 4.8, 95% CI 3.3-6.9) were markedly elevated after childhood cancer as well. Regarding YA cancer patients, the respective HRs were 2.5 (95% CI 2.0-3.2) for anticoagulants, HR 1.7 (95% CI 1.5-1.9) for any cardiovascular medication and HR 1.5 (95% CI 1.3-1.7) for cardiac medication. Among cancer patients, highest HRs for cardiovascular medication were observed after childhood acute lymphoblastic leukemia (ALL) and bone tumors (HR 10.2, 95% CI 6.8-15.5 and HR 7.4, 95% CI 4.0-13.7) and YA ALL and acute myeloid leukemia (HR 5.1, 95% CI 3.5-7.1 and HR 2.8, 95% CI 1.8-4.0). Our study demonstrated increased HRs for purchasing cardiovascular medication after early-onset cancer compared to siblings reflecting elevated cardiovascular morbidity. Thus, the implementation of long-term cardiovascular disease screening is imperative to prevent, detect and adequately treat cardiovascular late effects after cancer at a young age. PMID- 26610263 TI - Digital droplet PCR on disk. AB - Existing systems for digital droplet PCR (ddPCR) either suffer from low integration or are difficult to introduce to mass fabrication. Here we present an integrated system that is compatible to mass fabrication and combines emulsification, PCR, and fluorescence readout in a single chamber within a disposable cartridge (disk). Droplets are generated by injecting the sample into fluorinated oil via centrifugal step emulsification. The resulting emulsion is aligned in the PCR and readout zone by capillary action. During thermocycling, gas bubbles generated by degassing are removed by capillary driven transport through tapered regions in the PCR chamber. Thereby, the positioning of the emulsion within the readout zone of the PCR chamber is ensured at any time and no bubbles are present during readout. Manual handling of the disk solely requires pipetting of oil and PCR mix into the inlet structures, placing the disk into the thermocycler and subsequently into a microarray scanner. The functionality of the ddPCR process chain is demonstrated by quantitative detection of the cystic fibrosis causing mutation p.Phe508del, which is of interest for non-invasive prenatal testing (NIPT). The mutation was detected in a concentration range spanning four orders of magnitude. We envision that this work will lay the base for the development of highly integrated sample-to-digital-answer PCR systems that can be employed in routine clinical diagnosis. PMID- 26610264 TI - White Matter Plasticity Induced by Psychoeducation in Bipolar Patients: A Controlled Diffusion Tensor Imaging Study. PMID- 26610265 TI - Differential Functional Connectivity Correlates of Cerebrospinal Fluid Biomarkers in Dementia of the Alzheimer's Type. AB - BACKGROUND: Alzheimer's disease (AD) is characterized by two cardinal pathologies, which have different topological distributions. The differential anatomical distributions of these pathologies raise the possibility that they exert differential effects on brain networks. OBJECTIVES: To investigate whether cerebrospinal fluid (CSF) biomarkers of the cardinal pathologies have differential relationships with functional connectivity networks in patients with dementia of the Alzheimer's type (DAT). METHODS: Thirty-nine participants underwent CSF sampling and resting-state functional magnetic resonance imaging. Functional connectivity networks were computed for each participant. CSF biomarker levels of p-tau and amyloid-beta (Abeta) were regressed onto these networks to identify subnetworks associated with each biomarker. RESULTS: A subnetwork associated with tau-related pathology was identified with its hub in the right anterior entorhinal cortex. A separate subnetwork associated with Abeta with its hub in the right dorsal anterior cingulate cortex was identified. CONCLUSION: These results demonstrate the differential effects of AD biomarkers on functional connectivity networks, supporting a possible division of labour between the cardinal pathologies. PMID- 26610266 TI - A light sensitive self-assembled nanogel as a tecton for protein patterning materials. AB - A self-assembled nanogel is constructed from light-sensitive cholesteryl pullulan (Ls-CHP) by using photo-labile ortho-nitrobenzyl (o-NB) units. The nanogel-based film is obtained by evaporation of an Ls-CHP nanogel solution. Exposure of the resulting nanogel-based film to light with a mask resulted in a patterned film that can encapsulate FITC-insulin. PMID- 26610268 TI - Dual RNA-seq reveals Meloidogyne graminicola transcriptome and candidate effectors during the interaction with rice plants. AB - Root-knot nematodes secrete proteinaceous effectors into plant tissues to facilitate infection by suppressing host defences and reprogramming the host metabolism to their benefit. Meloidogyne graminicola is a major pest of rice (Oryza sativa) in Asia and Latin America, causing important crop losses. The goal of this study was to identify M. graminicola pathogenicity genes expressed during the plant-nematode interaction. Using the dual RNA-sequencing (RNA-seq) strategy, we generated transcriptomic data of M. graminicola samples covering the pre parasitic J2 stage and five parasitic stages in rice plants, from the parasitic J2 to the adult female. In the absence of a reference genome, a de novo M. graminicola transcriptome of 66 396 contigs was obtained from those reads that were not mapped on the rice genome. Gene expression profiling across the M. graminicola life cycle revealed key genes involved in nematode development and provided insights into the genes putatively associated with parasitism. The development of a 'secreted protein prediction' pipeline revealed a typical set of proteins secreted by nematodes, as well as a large number of cysteine-rich proteins and putative nuclear proteins. Combined with expression data, this pipeline enabled the identification of 15 putative effector genes, including two homologues of well-characterized effectors from cyst nematodes (CLE-like and VAP1) and a metallothionein. The localization of gene expression was assessed by in situ hybridization for a subset of candidates. All of these data represent important molecular resources for the elucidation of M. graminicola biology and for the selection of potential targets for the development of novel control strategies for this nematode species. PMID- 26610269 TI - Digital Image Analysis to Assess Quantity and Morphological Quality of Isolated Pancreatic Islets. AB - Quantity and quality assessment of human pancreatic islets are essential processes to define a safe and potent quality product used for clinical transplantation. The conventional method of manual assessment has been used in the field for longer than two decades. The high degree of variability in product quantity and lack of archival imaging records of the product for verification are two major disadvantages of using the manual method for quantity and quality assessment of human pancreatic islets. Investigators have developed promising new methods for technical improvement. In this study, we briefly review the published methods and highlight the advantages of digital imaging analysis (DIA) when compared to the manual method. The application of DIA reduces measurement variability and increases the precision of islet equivalent (IEQ) determination for batch analysis. It produces images that can be archived for retrospective analysis and validation, and the data can be transmitted electronically for off site analysis. These features are important for quality pancreatic islet assessment and are consistent with FDA requirements of current good manufacturing practice for clinical islet transplantation. PMID- 26610270 TI - Biliary complications after living donor hepatectomy: A first report from India. AB - Biliary complications after donor hepatectomy can result in significant morbidity. We herein present our experience of donor hepatectomy, highlighting surgical techniques that prevent complications. Data were reviewed from a prospectively maintained database of all donors who underwent hepatectomy from April 2011 to April 2015. Standard operative technique as described was followed in all patients. Biliary complications and morbidity were recorded and stratified as per Clavien-Dindo classification. Results were compared with published literature. During the study period, 160 donors underwent hepatectomy. The majority of the graft types were right hemiliver without the middle hepatic vein (71.9%). Major complications (grade III and above) occurred in 5.6% of the donors. There was no donor mortality. Only 1 out of the 160 donors (0.6%) has had a grade III biliary complication requiring endoscopic retrograde cholangiography and papillotomy. There were 3 grade II biliary complications, all occurring after left lateral sectionectomy, necessitating prolonged retention of the intra abdominal drain. The median duration of hospital stay was 11 days (range, 5-67 days), and the duration of follow-up was 16 months (range, 3-52 months). There was no loss to follow-up, and no donor required readmission or outpatient procedures for any biliary complication. In conclusion, with careful donor selection and a standardized surgical technique, biliary complications can be minimized. Liver Transplantation 22 607-614 2016 AASLD. PMID- 26610271 TI - Health status and disease burden of unaccompanied asylum-seeking adolescents in Bielefeld, Germany: cross-sectional pilot study. AB - OBJECTIVE: This exploratory pilot study aimed to investigate the physical and mental disease burden of unaccompanied asylum-seeking adolescents arriving in Bielefeld, a medium-size city in Germany. METHODS: A cross-sectional survey with purposive sampling of 102 unaccompanied asylum-seeking adolescents aged 12-18 years was performed. Information on general health status, selected infectious and non-communicable diseases, iron deficiency anaemia and mental illness was collected during routine check-up medical examinations upon arrival in Bielefeld, Germany. The data were analysed using descriptive statistics. RESULTS: The analysis revealed a complex disease burden with a high prevalence of infections (58.8%), mental illness (13.7%) and iron deficiency anaemia (17.6%) and a very low prevalence of non-communicable diseases (<2.0%). One in five of the refugees were infected with parasites. Whilst sub-Saharan Africans showed the highest prevalence of infections (86.7%), including highest prevalences of parasites (46.7%), West Asians had the highest prevalence of mental disorders (20.0%). Overall, the disease burden in females was higher. CONCLUSION: A thorough medical and psychological screening after arrival is highly recommended to reduce the individual disease burden and the risk of infection for others. This promotes good physical and mental health, which is needed for successful integration into the receiving society. Barriers to health service access for unaccompanied asylum seeking adolescents need to be lowered to allow need-specific health care and prevention. PMID- 26610272 TI - Measuring the Therapeutic Relationship in Internet-Based Interventions. PMID- 26610274 TI - Diet inequality prevails among consumers interested and knowledgeable in nutrition. AB - BACKGROUND: Previous studies have demonstrated a correlation between diet cost and adherence to nutritional recommendations among consumers in general. This has adverse effects on diet and health inequality. It could be hypothesized that consumers knowledgeable in nutrition escape this correlation. OBJECTIVE: Investigate whether the previously observed relationship between diet cost and nutritional quality prevails among consumers with an above-average interest in and knowledge of nutrition. DESIGN: Full open diet registrations of 330 students taking a basic university-level course in nutrition over a total of 780 days. RESULTS: The consumers with the highest daily average diet cost differ from the lowest cost quartile: The diets had higher micronutrient density, more fruits and vegetables, and lower energy density. The highest cost daily diet quartile had a significantly higher energy adjusted intake of the micronutrients that were on average consumed below the recommendation (vitamin D, folate, and iron for women). On the other hand, alcohol intake was significantly higher among the high diet cost group. The highest diet cost respondents consumed more fish, meat, coffee, and spreads, whereas the lowest diet cost respondents had a higher consumption of cereals, bread, jam, sausage, and milk. CONCLUSIONS: Dietary differences prevail even in the above-average interested and knowledgeable group. The respondents did not use their higher level of knowledge to break this commonly observed relationship. This suggests that an increased minimum level of knowledge in nutrition may not by itself eliminate dietary inequality. PMID- 26610273 TI - Evolution of a protein folding nucleus. AB - The folding nucleus (FN) is a cryptic element within protein primary structure that enables an efficient folding pathway and is the postulated heritable element in the evolution of protein architecture; however, almost nothing is known regarding how the FN structurally changes as complex protein architecture evolves from simpler peptide motifs. We report characterization of the FN of a designed purely symmetric beta-trefoil protein by phi-value analysis. We compare the structure and folding properties of key foldable intermediates along the evolutionary trajectory of the beta-trefoil. The results show structural acquisition of the FN during gene fusion events, incorporating novel turn structure created by gene fusion. Furthermore, the FN is adjusted by circular permutation in response to destabilizing functional mutation. FN plasticity by way of circular permutation is made possible by the intrinsic C3 cyclic symmetry of the beta-trefoil architecture, identifying a possible selective advantage that helps explain the prevalence of cyclic structural symmetry in the proteome. PMID- 26610275 TI - Comparing dietary macronutrient composition and food sources between native and diasporic Ghanaian adults. AB - BACKGROUND: Dietary acculturation may contribute to the increased burden of non communicable diseases (NCDs) in diasporic populations of African ancestry. OBJECTIVE: To assess nutritional composition and the contribution that traditional foods make to the diets of native and UK-dwelling Ghanaian adults. DESIGN: An observational study of Ghanaian adults living in Accra (n=26) and London (n=57) was undertaken. Three-day food records were translated to nutrient data using culturally sensitive methods and comparisons were made for energy, macronutrients, and dietary fibre between cohorts. The contribution of traditional foods to dietary intake was measured and the foods contributing to each nutrient were identified. RESULTS: Compared to native Ghanaians, UK Ghanaians derived a significantly higher proportion of energy from protein (16.9+/-3.9 vs. 14.1+/-2.8%, p=0.001), fat (29.9+/-7.9 vs. 24.4+/-8.5%, p=0.005), and saturated fat (8.5+/-3.4 vs. 5.8+/-3.7%, p<0.001) and a significantly lower energy from carbohydrate (52.2+/-7.7 vs. 61.5+/-9.3%, p<0.001). Dietary fibre intake was significantly higher in the UK-Ghanaian diet compared to the native Ghanaian diet (8.3+/-3.1 vs. 6.7+/-2.2 g/1,000 kcal, p=0.007). There was significantly less energy, macronutrients, and fibre derived from traditional foods post-migration. Non-traditional foods including breakfast cereals, wholemeal bread, and processed meats made a greater contribution to nutrient intake post-migration. CONCLUSIONS: Our findings show the migrant Ghanaian diet is characterised by significantly higher intakes of fat, saturated fat, and protein and significantly lower intakes of carbohydrate; a macronutrient profile which may promote increased risk of NCDs amongst UK-Ghanaians. These differences in the nutrient profile are likely to be modulated by the consumption of 'Western' foods observed in migrant communities. PMID- 26610276 TI - The role of uric acid in chronic kidney disease patients. AB - AIM: Chronic kidney disease (CKD) is always associated with hyperuricaemia. However, the studies evaluating the clinical implications of hyperuricaemia have shown conflicting results in these patients. METHODS: A retrospective observational study was conducted in 2408 stage 3-5 CKD patients. Instead of one baseline uric acid (UA) level, the averaged level of the two consecutive measurements for each participant was used as the predictor for the outcomes of the study, which included mortality, renal outcomes, and hospitalization risk. A multivariate Cox proportional hazards model and logistic regression model were performed to determine the independent risk factor. RESULTS: The mean UA level was 0.46 +/- 0.106 mmol/L. Of the 2408 patients, there were 563 (23.3%) deaths, 143 (5.9%) cardiovascular deaths, 652 (27%) subjects commencing renal replacement therapy (RRT), 664 (27.5%) subjects with rapid renal progression, 1937 (58%) patients requiring hospitalization and 404 (16.7%) patients with CVD hospitalization during a mean follow-up of approximately 3.03 years. After multivariate adjustments, a 1-mg/dL increase in uric acid level was associated with a hazard ratio (HR) of 1.26 for RRT (P = 0.002), an odds ratio (OR) of 1.27 for rapid renal progression (P = 0.001), an HR of 1.19 for all-cause hospitalization (P < 0.001), and an HR of 1.12 for cardiovascular disease (CVD) hospitalization (P = 0.02), but not significantly with all-cause mortality and cardiovascular death at the end of follow-up. CONCLUSIONS: In stage 3-5 CKD patients, hyperuricaemia was associated with a higher risk of renal replacement therapy, rapid renal progression and hospitalization for all causes or CVD, but not with all-cause mortality or cardiovascular mortality. PMID- 26610277 TI - Electroluminescence of Giant Stretchability. AB - A new type of electroluminescent device achieves giant stretchability by integrating electronic and ionic components. The device uses phosphor powders as electroluminescent materials, and hydrogels as stretchable and transparent ionic conductors. Subject to cyclic voltage, the phosphor powders luminesce, but the ionic conductors do not electrolyze. The device produces constant luminance when stretched up to an area strain of 1500%. PMID- 26610278 TI - Is epidural steroid injection effective for degenerative lumbar spinal stenosis? AB - There are several nonsurgical alternatives to treat radicular pain in degenerative lumbar spinal stenosis. Epidural steroid injections have been used for several decades, but the different studies have shown variable effects. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified nine systematic reviews including seven pertinent randomized controlled trials. We concluded epidural steroid injection probably leads to little or no effect on reducing radicular pain of spinal stenosis. PMID- 26610279 TI - Lipid Diffusion in Supported Lipid Bilayers: A Comparison between Line-Scanning Fluorescence Correlation Spectroscopy and Single-Particle Tracking. AB - Diffusion in lipid membranes is an essential component of many cellular process and fluorescence a method of choice to study membrane dynamics. The goal of this work was to directly compare two common fluorescence methods, line-scanning fluorescence correlation spectroscopy and single-particle tracking, to observe the diffusion of a fluorescent lipophilic dye, DiD, in a complex five-component mitochondria-like solid-supported lipid bilayer. We measured diffusion coefficients of DFCS ~ 3 um2 * s-1 and DSPT ~ 2 um2 * s-1, respectively. These comparable, yet statistically different values are used to highlight the main message of the paper, namely that the two considered methods give access to distinctly different dynamic ranges: D sup or approximatively 1um2 * s-1 for FCS and D inf or approximatively 5 um2 s-1 for SPT (with standard imaging conditions). In the context of membrane diffusion, this means that FCS allows studying lipid diffusion in fluid membranes, as well as the diffusion of loosely bound proteins hovering above the membrane. SPT, on the other hand, is ideal to study the motions of membrane-inserted proteins, especially those presenting different conformations, but only allows studying lipid diffusion in relatively viscous membranes, such as supported lipid bilayers and cell membranes. PMID- 26610280 TI - Is Travel Time to Colonoscopy Associated With Late-Stage Colorectal Cancer Among Medicare Beneficiaries in Iowa? AB - BACKGROUND: Colorectal cancer (CRC) screening has been shown to decrease the incidence of late-stage colorectal cancer, yet a substantial proportion of Americans do not receive screening. Those in rural areas may face barriers to colonoscopy services based on travel time, and previous studies have demonstrated lower screening among rural residents. Our purpose was to assess factors associated with late-stage CRC, and specifically to determine if longer travel time to colonoscopy was associated with late-stage CRC among an insured population in Iowa. METHODS: SEER-Medicare data were used to identify individuals ages 65 to 84 years old diagnosed with CRC in Iowa from 2002 to 2009. The distance between the centroid of the ZIP code of residence and the ZIP code of colonoscopy was computed for each individual who had continuous Medicare fee-for service coverage for a 3- to 4-month period prior to diagnosis, and a professional claim for colonoscopy within that time frame. Demographic characteristics and travel times were compared between those diagnosed with early versus late-stage CRC. Also, demographic differences between those who had colonoscopy claims identified within 3-4 months prior to diagnosis (81%) were compared to patients with no colonoscopy claims identified (19%). RESULTS: A total of 5,792 subjects met inclusion criteria; 31% were diagnosed with early stage versus 69% with late-stage CRC. Those divorced or widowed (vs married) were more likely to be diagnosed with late-stage CRC (OR: 1.20, 95% CI: 1.06-1.37). Travel time was not associated with diagnosis of late-stage CRC. DISCUSSION: Among a Medicare-insured population, there was no relationship between travel time to colonoscopy and disease stage at diagnosis. It is likely that factors other than distance to colonoscopy present more pertinent barriers to screening in this insured population. Additional research should be done to determine reasons for nonadherence to screening among those with access to CRC screening services, given that over two-thirds of these insured individuals were diagnosed with late-stage CRC. PMID- 26610281 TI - Tuning Thiophene-Based Phenothiazines for Stable Photocatalytic Hydrogen Production. AB - Dibranched donor-(pi-acceptor)2 dyes, where phenothiazine is the donor core, cyanoacrylic acid is the acceptor/anchoring group, and pi is represented by mono- and poly-cyclic simple and fused thiophene derivatives, were tested as photosensitizers in the photocatalytic production of H2 , in combination with a Pt/TiO2 catalyst. The optical and electrochemical properties of the dyes were investigated, showing that careful design of the thiophene-based pi spacer afforded enhanced optical properties. In the H2 production over 20 h, the new thiophene-based sensitizers revealed improved stability after longer irradiation times and enhanced performances, in terms of H2 production rates and light-to fuel efficiencies, after an initial activation period, which were for the first time associated with enhanced stability under photocatalytic production of H2 and the absence of critical dye degradation. PMID- 26610282 TI - Nonparametric covariate adjustment in estimating hazard ratios. AB - In randomized clinical trials with time-to-event outcomes, the hazard ratio is commonly used to quantify the treatment effect relative to a control. The Cox regression model is commonly used to adjust for relevant covariates to obtain more accurate estimates of the hazard ratio between treatment groups. However, it is well known that the treatment hazard ratio based on a covariate-adjusted Cox regression model is conditional on the specific covariates and differs from the unconditional hazard ratio that is an average across the population. Therefore, covariate-adjusted Cox models cannot be used when the unconditional inference is desired. In addition, the covariate-adjusted Cox model requires the relatively strong assumption of proportional hazards for each covariate. To overcome these challenges, a nonparametric randomization-based analysis of covariance method was proposed to estimate the covariate-adjusted hazard ratios for multivariate time to-event outcomes. However, empirical evaluations of the performance (power and type I error rate) of the method have not been studied. Although the method is derived for multivariate situations, for most registration trials, the primary endpoint is a univariate outcome. Therefore, this approach is applied to univariate outcomes, and performance is evaluated through a simulation study in this paper. Stratified analysis is also investigated. As an illustration of the method, we also apply the covariate-adjusted and unadjusted analyses to an oncology trial. PMID- 26610283 TI - The right temporoparietal junction in attention and social interaction: A transcranial magnetic stimulation study. AB - The right temporoparietal junction (rTPJ) has been associated with the ability to reorient attention to unexpected stimuli and the capacity to understand others' mental states (theory of mind [ToM]/false belief). Using activation likelihood estimation meta-analysis we previously unraveled that the anterior rTPJ is involved in both, reorienting of attention and ToM, possibly indicating a more general role in attention shifting. Here, we used neuronavigated transcranial magnetic stimulation to directly probe the role of the rTPJ across attentional reorienting and false belief. Task performance in a visual cueing paradigm and false belief cartoon task was investigated after application of continuous theta burst stimulation (cTBS) over anterior rTPJ (versus vertex, for control). We found that attentional reorienting was significantly impaired after rTPJ cTBS compared with control. For the false belief task, error rates in trials demanding a shift in mental state significantly increased. Of note, a significant positive correlation indicated a close relation between the stimulation effect on attentional reorienting and false belief trials. Our findings extend previous neuroimaging evidence by indicating an essential overarching role of the anterior rTPJ for both cognitive functions, reorienting of attention and ToM. Hum Brain Mapp 37:796-807, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26610284 TI - Joint analysis of IVD herniation and degeneration by rat caudal needle puncture model. AB - Intervertebral disc (IVD) degeneration is responsible for various spine pathologies and present clinical treatments are insufficient. Concurrently, the mechanisms behind IVD degeneration are still not completely understood, so as to allow development of efficient tissue engineering approaches. A model of rat IVD degeneration directly coupled to herniation is here proposed in a pilot study. Disc injury is induced by needle puncture, using two different needles gauges: a low caliber 25-G needle and a high caliber 21-G needle. Histological, biochemical, and radiographic degeneration was evaluated at 2 and 6 weeks post injury. We show that the larger caliber needle results in a more extended histological and radiographic degeneration within the IVD, compared to the smaller one. TUNEL quantification indicates also increased cell death in the 21-G group. Analyses of collagen type I (Picrosirius red staining), collagen type II (immunofluorescence), and GAG content (Blyscan assay) indicate that degeneration features spontaneously recover from 2 to 6 weeks, for both needle types. Moreover, we show the occurrence of hernia proportional to the needle gauge. The number of CD68+ macrophages present, as well as cell apoptosis within the herniated tissue are both proportional to hernia volume. Moreover, hernias formed after lesion tend to spontaneously diminish in volume after 6 weeks. Finally, MMP3 is increased in the hernia in the 21-G group at 2 weeks. This model, by uniquely combining IVD degeneration and IVD herniation in the same animal, may help to understand mechanisms behind IVD pathophysiology, such as hernia formation and spontaneous regression. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:258-268, 2017. PMID- 26610285 TI - Remarkable Dependence of the Final Charge Separation Efficiency on the Donor Acceptor Interaction in Photoinduced Electron Transfer. AB - The unprecedented dependence of final charge separation efficiency as a function of donor-acceptor interaction in covalently-linked molecules with a rectilinear rigid oligo-p-xylene bridge has been observed. Optimization of the donor-acceptor electronic coupling remarkably inhibits the undesirable rapid decay of the singlet charge-separated state to the ground state, yielding the final long lived, triplet charge-separated state with circa 100% efficiency. This finding is extremely useful for the rational design of artificial photosynthesis and organic photovoltaic cells toward efficient solar energy conversion. PMID- 26610286 TI - Estrogenic activity and nutrient losses in surface runoff after winter manure application to small watersheds. AB - Confined Animal Feeding Operations generate large amounts of wastes that are land applied to provide nutrients for crop production and return organic matter to the soil. Production practices and storage limitations often necessitate that wastes be applied to frozen and snow-covered soil. Use of application setbacks have reduced concerns related to nutrient losses in surface runoff from manure, but the estrogenic activity of runoff under these conditions has not been evaluated. Therefore, we measured and sampled surface runoff when manure was applied in the winter at a rate to meet crop N needs and measured estradiol equivalents (E2Eqs) using E-Screen. In year one, six small watersheds used to produce corn were evaluated, treatments: 2 no-manure controls, 2 liquid swine manure with 30-m setbacks, and 2 turkey litter with 30-m setbacks. In addition, beef manure was applied to six frozen plots of forage. For years 2 and 3, applications were repeated on the swine manure watersheds and one control watershed. E2Eqs and nutrient concentrations generally peaked in the first runoff event after application. The highest measured E2Eq (5.6 ng L(-1)) was in the first event after swine manure application and was less than the 8.9 ng L(-1) Lowest Observable Effect Concentration (LOEC) for aquatic species and well below the concentrations measured in other studies using ELISAs to measure hormone concentrations. No runoff occurred from plots planted with forage, indicating low risk for environmental impact, and therefore plots were discontinued from study. In years 2 and 3, estrogenic activity never exceeded the Predicted No Effect Concentrations for E2 of 2 ng L(-1). When post-application runoff contained high estrogenic activity, strong correlations (R(2) 0.86 to 0.96) of E2Eq to Ca(2+), Mg(2+), and K(+) concentrations were observed, indicating under some condition these cations might be useful surrogates for E2Eq measurements. PMID- 26610287 TI - Potential impact on food safety and food security from persistent organic pollutants in top soil improvers on Mediterranean pasture. AB - The organic carbon of biosolids from civil wastewater treatment plants binds persistent organic pollutants (POPs), such as polychlorodibenzo -dioxins and furans (PCDD/Fs), dioxin and non-dioxin -like polychlorobiphenyls (DL and NDL PCBs), polybrominated diphenyl ethers (PBDEs), and perfluorooctane sulfonic acid (PFOS). The use of such biosolids, derived digestates and composts as top soil improvers (TSIs) may transfer POPs into the food chain. We evaluated the potential carry-over of main bioavailable congeners from amended soil-to-milk of extensive farmed sheep. Such estimates were compared with regulatory limits (food security) and human intakes (food safety). The prediction model was based on farming practices, flocks soil intake, POPs toxicokinetics, and dairy products intake in children, of the Mediterranean area. TSI contamination ranged between 0.20-113 ng WHO-TEQ/kg dry matter for PCDD/Fs and DL-PCBs (N = 56), 3.40-616 MUg/kg for ?6 NDL-PCBs (N = 38), 0.06-17.2 and 0.12-22.3 MUg/kg for BDE no. 47 and no. 99, 0.872-89.50 MUg/kg for PFOS (N = 27). For a 360 g/head/day soil intake of a sheep with an average milk yield of 2.0 kg at 6.5% of fat percentage, estimated soil quality standards supporting milk safety and security were 0.75 and 4.0 ng WHO-TEQ/kg for PCDD/Fs and DL-PCBs, and 3.75 and 29.2 MUg/kg for ?6 NDL-PCBs, respectively. The possibility to use low-contaminated TSIs to maximize agriculture benefits and if the case, to progressively mitigate highly contaminated soils is discussed. PMID- 26610288 TI - AsHSP17, a creeping bentgrass small heat shock protein modulates plant photosynthesis and ABA-dependent and independent signalling to attenuate plant response to abiotic stress. AB - Heat shock proteins (HSPs) are molecular chaperones that accumulate in response to heat and other abiotic stressors. Small HSPs (sHSPs) belong to the most ubiquitous HSP subgroup with molecular weights ranging from 12 to 42 kDa. We have cloned a new sHSP gene, AsHSP17 from creeping bentgrass (Agrostis stolonifera) and studied its role in plant response to environmental stress. AsHSP17 encodes a protein of 17 kDa. Its expression was strongly induced by heat in both leaf and root tissues, and by salt and abscisic acid (ABA) in roots. Transgenic Arabidopsis plants constitutively expressing AsHSP17 exhibited enhanced sensitivity to heat and salt stress accompanied by reduced leaf chlorophyll content and decreased photosynthesis under both normal and stressed conditions compared to wild type. Overexpression of AsHSP17 also led to hypersensitivity to exogenous ABA and salinity during germination and post-germinative growth. Gene expression analysis indicated that AsHSP17 modulates expression of photosynthesis related genes and regulates ABA biosynthesis, metabolism and ABA signalling as well as ABA-independent stress signalling. Our results suggest that AsHSP17 may function as a protein chaperone to negatively regulate plant responses to adverse environmental stresses through modulating photosynthesis and ABA-dependent and independent signalling pathways. PMID- 26610289 TI - Magnetic resonance imaging and computer tomography of brain lesions in water buffaloes and cattle stunned with handguns or captive bolts. AB - Owing to the demand for genuine mozzarella, some 330 water buffaloes are being slaughtered every year in Switzerland albeit a stunning procedure meeting animal welfare and occupational safety requirements remains to be established. To provide a basis for improvements, we sized anatomical specifics in water buffaloes and cattle and we assessed brain lesions after stunning with captive bolts or handguns by diagnostic imaging. In water buffaloes and cattle, the median distance from the frontal skin surface to the inner bone table was 74.0mm (56.0-100.0mm) vs 36.6mm (29.3-44.3mm) and from skin to the thalamus 144.8mm (117.1-172.0mm) vs 102.0 (101.0-121.0mm), respectively. Consequently, customary captive bolt stunners may be inadequate. Free bullets are potentially suitable for stunning buffaloes but involve occupational safety hazards. The results of the present study shall be used to develop a device allowing effective and safe stunning of water buffaloes. PMID- 26610290 TI - Effect of hot water treatment of beef trimmings on processing characteristics and eating quality of ground beef. AB - The effect of hot water treatment of beef trimmings on the processing characteristics, shelf-life and consumer acceptability of ground beef was evaluated. Hot water treatment (85 degrees C for 40s) substantially enhanced the microbial quality of trimmings during refrigerated storage and this was independent of the fat level of the trimmings. Treatment had no effect on the oxidative stability of trimmings stored up to 7days, ground beef displayed in a retail cabinet for up to 3days, and had minimal effect on textural properties. Instrumental results demonstrate that ground beef from hot water treated trimmings was slightly lighter and tended to have less red color compared to non treated beef. These color differences did not impact the consumer acceptance of raw patties, and in addition, hot water treatment did not significantly affect the consumer acceptability of cooked patty attributes. PMID- 26610291 TI - Global health and domestic policy - What motivated the development of the German Global Health Strategy? AB - In 2013, the German government published its national Global Health Strategy, outlining principles and focal topics for German engagement in global health. We asked the question of why Germany has decided to establish a national policy framework for global health at this point in time, and how the development process has taken place. The ultimate goal of this study was to achieve better insights into the respective health and foreign policy processes at the national level. This article reports on the results of semi-structured interviews with those actors that were responsible for initiating and drafting the German Global Health Strategy (GGHS). Our study shows that a series of external developments, stakeholders, and advocacy efforts created an environment conducive to the creation of the strategic document. In addition, a number of internal considerations, struggles, and capacities played a decisive role during the development phase of the GGHS. Understanding these factors better can not only provide substantial insights into global health related policy processes in Germany, but also contribute to the general discourse on the role of the nation state in global health governance. PMID- 26610292 TI - Presence of an epigenetic signature of prenatal cigarette smoke exposure in childhood. AB - Prenatal exposure to tobacco smoke has lifelong health consequences. Epigenetic signatures such as differences in DNA methylation (DNAm) may be a biomarker of exposure and, further, might have functional significance for how in utero tobacco exposure may influence disease risk. Differences in infant DNAm associated with maternal smoking during pregnancy have been identified. Here we assessed whether these infant DNAm patterns are detectible in early childhood, whether they are specific to smoking, and whether childhood DNAm can classify prenatal smoke exposure status. Using the Infinium 450K array, we measured methylation at 26 CpG loci that were previously associated with prenatal smoking in infant cord blood from 572 children, aged 3-5, with differing prenatal exposure to cigarette smoke in the Study to Explore Early Development (SEED). Striking concordance was found between the pattern of prenatal smoking associated DNAm among preschool aged children in SEED and those observed at birth in other studies. These DNAm changes appear to be tobacco-specific. Support vector machine classification models and 10-fold cross-validation were applied to show classification accuracy for childhood DNAm at these 26 sites as a biomarker of prenatal smoking exposure. Classification models showed prenatal exposure to smoking can be assigned with 81% accuracy using childhood DNAm patterns at these 26 loci. These findings support the potential for blood-derived DNAm measurements to serve as biomarkers for prenatal exposure. PMID- 26610294 TI - Climate change and fetal health: The impacts of exposure to extreme temperatures in New York City. AB - BACKGROUND: Climate change is projected to increase the frequency, intensity, and duration of heat waves while reducing cold extremes, yet few studies have examined the relationship between temperature and fetal health. OBJECTIVES: We estimate the impacts of extreme temperatures on birth weight and gestational age in Manhattan, a borough in New York City, and explore differences by socioeconomic status (SES). METHODS: We combine average daily temperature from 1985 to 2010 with birth certificate data in Manhattan for the same time period. We then generate 33 downscaled climate model time series to project impacts on fetal health. RESULTS: We find exposure to an extra day where average temperature <25 degrees F and >85 degrees F during pregnancy is associated with a 1.8 and 1.7 g (respectively) reduction in birth weight, but the impact varies by SES, particularly for extreme heat, where teen mothers seem most vulnerable. We find no meaningful, significant effect on gestational age. Using projections of temperature from these climate models, we project average net reductions in birth weight in the 2070-2099 period of 4.6g in the business-as-usual scenario. CONCLUSIONS: Results suggest that increasing heat events from climate change could adversely impact birth weight and vary by SES. PMID- 26610293 TI - Urinary polycyclic aromatic hydrocarbons and measures of oxidative stress, inflammation and renal function in adolescents: NHANES 2003-2008. AB - OBJECTIVE: Recent evidence has suggested that polycyclic aromatic hydrocarbons (PAHs) may contribute to cardiometabolic and kidney dysfunction by increasing oxidative stress, but little is known about impacts in childhood. STUDY DESIGN: We performed cross-sectional analyses of 660 adolescents aged 12-19 years in the 2003-2008 National Health and Nutrition Examination Survey (NHANES), using levels of 10 monohydroxylated urinary PAH metabolites as our exposure. Our primary outcomes of interest were biomarkers of oxidative stress and renal function, including estimated glomerular filtration rate (eGFR), urinary albumin to creatinine ratio (ACR), insulin resistance, and serum uric acid, gamma glutamyl transferase (GGT) and C-reactive protein (CRP). RESULTS: We observed statistically significant associations between PAH metabolites and levels of serum GGT, CRP, uric acid and eGFR. Each 100% increase in 2-hydroxyphenanthrene was related to a 3.36% increase in uric acid (95% CI: 0.338-6.372; p=0.032), a 3.86% increase in GGT (95% CI: 1.361-6.362; p=0.005) and a 16.78% increase in CRP (95% CI: 1.848-31.689; p=0.029). Each 100% increase in 4-hydroxyphenanthrene was associated with a 6.18% increase in GGT (95% CI: 4.064-8.301; p<0.001) and a 13.66% increase in CRP (95% CI: 2.764-24.564; p=0.017). Each 100% increase in 9 hydroxyfluorene was associated with a 2.58% increase in GGT (95% CI: 0.389-4776; p=0.024). Each 100% increase in 3-hydroxyphenanthrene was associated with a 2.66% decrease in eGFR (95% CI: -4.979 to -0.331; p=0.028). CONCLUSIONS: Urinary PAH metabolites were associated with serum uric acid, GGT and CRP, suggesting possible impacts on cardiometabolic and kidney function in adolescents. Prospective work is needed to investigate the potential long-term health consequences of these findings. PMID- 26610295 TI - Exogenous nitrate attenuates nitrite toxicity to anaerobic ammonium oxidizing (anammox) bacteria. AB - Anaerobic ammonium oxidizing bacteria (anammox) can be severely inhibited by one of its main substrates, nitrite (NO2(-)). At present, there is limited information on the processes by which anammox bacteria are able to tolerate toxic NO2(-). Intracellular consumption or electrochemically driven (transmembrane proton motive force) NO2(-) export are considered the main mechanisms of NO2(-) detoxification. In this work, we evaluated the potential of exogenous nitrate (NO3(-)) on relieving NO2(-) toxicity, putatively facilitated by NarK, a NO3( )/NO2(-) transporter encoded in the anammox genome. The relative contribution of NO3(-) to NO2(-) detoxification was found to be pH dependent. Exposure of anammox cells to NO2(-) in absence of their electron donating substrate, ammonium (NH4(+)), causes NO2(-) stress. At pH 6.7 and 7.0, the activity of NO2(-) stressed cells was respectively 0 and 27% of the non-stressed control activity (NO2(-) and NH4(+) fed simultaneously). Exogenous NO3(-) addition caused the recovery to 42% and 80% of the control activity at pH 6.7 and 7.0, respectively. The recovery of the activity of NO2(-) stressed cells improved with increasing NO3(-) concentration, the maximum recovery being achieved at 0.85 mM. The NO3(-) pre-incubation time is less significant at pH 7.0 than at pH 6.7 due to a more severe NO2(-) toxicity at lower pH. Additionally, NO3(-) caused almost complete attenuation of NO2(-) toxicity in cells exposed to the proton gradient disruptor carbonyl cyanide m-chlorophenyl hydrazone at pH 7.5, providing evidence that the NO3(-) attenuation is independent of the proton motive force. The absence of a measurable NO3(-) consumption (or NO3(-) dependent N2 production) during the batch tests leaves NO3(-) dependent active transport of NO2(-) as the only plausible explanation for the relief of NO2(-) inhibition. We suggest that anammox cells can use a secondary transport system facilitated by exogenous NO3( ) to alleviate NO2(-) toxicity. PMID- 26610296 TI - Comparative studies on the effects of seawater acidification caused by CO2 and HCl enrichment on physiological changes in Mytilus edulis. AB - The present medium term (21 d) study was performed to evaluate the effects of HCl or CO2-induced acidified seawater (pH 7.7, 7.1 or 6.5; control: pH 8.1) on the physiological responses of the blue mussel, Mytilus edulis, at different levels of biological organization. The results demonstrate that: (1) either HCl or CO2 enrichment had significant impacts on physiological changes in M. edulis: the mortality increased while condition index (CI) decreased steadily as the pH decreased, those indexes indicate the metabolic activities (e.g. filtering rate, oxygen consumption rate, etc.) underwent similar changes; moreover, the decrease of calcification rate and carbonic anhydrase activity indicate that the carbon sink ability of the mussels was significantly affected. We hypothesize that acidification induced intracellular energy crisis and a decrease in enzyme activities could be a potential explanation for our findings. (2) Comparatively, CO2 enrichment had more severe effects on mortality but caused less stress to the metabolic and carbon sink indexes than HCl adjustment at the same pH level. Apoptosis caused by the 'intracellular acidification' in the CO2 group and difference in cytoplasmic Ca(2+) concentration between two groups are suggested to be responsible for these results. (3) An integrated biomarker response (IBR) was set up on the basis of the estimated indexes; it was determined that the IBR decreased steadily with the decrease of pH, and a positive relationship was observed between them, inferring that the IBR might be a potential biological monitoring method in evaluating the effects of seawater acidification. PMID- 26610297 TI - Occurrence of 13 veterinary drugs in animal manure-amended soils in Eastern China. AB - The occurrence of 13 veterinary drugs were studied in soil fertilized with animal manures in Eastern China. The 69 soil samples were obtained from twenty-three vegetable fields in 2009 and analysed for selected veterinary drugs by HPLC-MS/MS at soil depths of 0-20, 20-40 and 40-60 cm, and two additional samples were re analysed from an earlier study from November 2011. Results showed that animal wastes, especially those from poultry farms, were one of pollution sources of veterinary drugs in soil. The detection frequency of veterinary drugs in soil was 83%, 91% and 87% in the three soil depths, respectively. The detection rates for the five classes of drugs in soils followed the rank order cyromazine > tetracyclines > sulfonamides > fluoroquinolones > florfenicol. Veterinary drugs were detected in soil layers at 20-40 and 40-60 cm depth to a greater extent than at 0-20 cm depth. The results of the same point in years 2009 and 2011 indicated that veterinary drugs accumulate easily and persist in the deeper soil. In addition, residue levels of veterinary drugs in soil were related to the animal species the manure was derived from. Overall, the predominance of tetracyclines in sampled soils underscored the need to regulate their veterinary use in order to improve the management and treatment of associated releases. PMID- 26610298 TI - Observation of emerging per- and polyfluoroalkyl substances (PFASs) in Greenland marine mammals. AB - The present pilot study examined emerging per- and polyfluoroalkyl substances (PFASs), i.e., a suite of short chain perfluoroalkyl acids (PFAAs), PFAA precursors and replacement chemicals, and legacy PFASs (long chain length PFAAs) in livers from ringed seals, polar bears and, for the first time, killer whales from East Greenland collected in 2012-2013. Among the emerging PFASs, perfluorobutanesulfonic acid (PFBS) and F-53B (a chlorinated polyfluorinated ether sulfonic acid) were detected in Arctic wildlife, albeit at concentrations approximately four orders of magnitude lower compared to perfluorooctanesulfonic acid (PFOS). PFOS was positively correlated with F-53B, but not PFBS in all three species. A total of 17 PFASs were detected in killer whales, including in a mother-fetus pair, demonstrating maternal transfer. ?PFAS concentrations in killer whales (269 +/- 90 ng/g) were comparable to concentrations found in ringed seals (138 +/- 7 ng/g), however, an order of magnitude lower compared to concentrations found in polar bear livers (2336 +/- 263 ng/g). Patterns of long chain PFAAs in killer whales differed from the pattern in ringed seals and polar bears. Of the monitored PFAA precursors, only perfluorooctanesulfonamide (FOSA) was detected in all three species, and FOSA/PFOS ratios and isomer patterns indicated that killer whales have a potential lower metabolic capacity to degrade FOSA compared to polar bears and ringed seals. PMID- 26610299 TI - Contribution of heavy metals to toxicity of coal combustion related fine particulate matter (PM2.5) in Caenorhabditis elegans with wild-type or susceptible genetic background. AB - Contribution of chemical components in coal combustion related fine particulate matter (PM2.5) to its toxicity is largely unclear. We focused on heavy metals in PM2.5 to investigate their contribution to toxicity formation in Caenorhabditis elegans. Among 8 heavy metals examined (Fe, Zn, Pb, As, Cd, Cr, Cu, and Ni), Pb, Cr, and Cu potentially contributed to PM2.5 toxicity in wild-type nematodes. Combinational exposure to any two of these three heavy metals caused higher toxicity than exposure to Pb, Cr, or Cu alone. Toxicity from the combinational exposure to Pb, Cr, and Cu at the examined concentrations was higher than exposure to PM2.5 (100 mg/L). Moreover, mutation of sod-2 or sod-3 gene encoding Mn-SOD increased susceptibility in nematodes exposed to Fe, Zn, or Ni, although Fe, Zn, or Ni at the examined concentration did not lead to toxicity in wild-type nematodes. Our results highlight the potential contribution of heavy metals to PM2.5 toxicity in environmental organisms. PMID- 26610300 TI - Dual role of arginine metabolism in establishing pathogenesis. AB - Arginine is an integral part of host defense when invading pathogens are encountered. The arginine metabolite nitric oxide (NO) confers antimicrobial properties, whereas the metabolite ornithine is utilized for polyamine synthesis. Polyamines are crucial to tissue repair and anti-inflammatory responses. iNOS/arginase balance can determine Th1/Th2 response. Furthermore, the host arginine pool and its metabolites are utilized as energy sources by various pathogens. Apart from its role as an immune modulator, recent studies have also highlighted the therapeutic effects of arginine. This article sheds light upon the roles of arginine metabolism during pathological conditions and its therapeutic potential. PMID- 26610301 TI - A naturalistic examination of social comparisons and disordered eating thoughts, urges, and behaviors in college women. AB - OBJECTIVE: We examined the effects of body, eating, and exercise social comparisons on prospective disordered eating thoughts and urges (i.e., restriction thoughts, exercise thoughts, vomiting thoughts, binge eating urges) and behaviors (i.e., restriction attempts, exercising for weight/shape reasons, vomiting, binge eating) among college women using ecological momentary assessment (EMA). METHOD: Participants were 232 college women who completed a 2-week EMA protocol, in which they used their personal electronic devices to answer questions three times per day. Generalized estimating equation models were used to assess body, eating, and exercise comparisons as predictors of disordered eating thoughts, urges, and behaviors at the next report, adjusting for body dissatisfaction, negative affect, and the disordered eating thought/urge/behavior at the prior report, as well as body mass index. RESULTS: Body comparisons prospectively predicted more intense levels of certain disordered eating thoughts (i.e., thoughts about restriction and exercise). Eating comparisons prospectively predicted an increased likelihood of subsequent engagement in all disordered eating behaviors examined except vomiting. Exercise comparisons prospectively predicted less-intense thoughts about exercise and an increased likelihood of subsequent vomiting. DISCUSSION: Social comparisons are associated with later disordered eating thoughts and behaviors in the natural environment and may need to be specifically targeted in eating disorder prevention and intervention efforts. Targeting body comparisons may be helpful in terms of reducing disordered eating thoughts, but eating and exercise comparisons are also important and may need to be addressed in order to decrease engagement in actual disordered eating behaviors. PMID- 26610303 TI - Genetic diversity of 38 insertion-deletion polymorphisms in Jewish populations. AB - Population genetic data of 38 non-coding biallelic autosomal indels are reported for 466 individuals, representing six populations with Jewish ancestry (Ashkenazim, Mizrahim, Sephardim, North African, Chuetas and Braganca crypto Jews). Intra-population diversity and forensic parameters values showed that this set of indels was highly informative for forensic applications in the Jewish populations studied. Genetic distance analysis demonstrated that this set of markers efficiently separates populations from different continents, but does not seem effective for molecular anthropology studies in Mediterranean region. Finally, it is important to highlight that although the genetic distances between Jewish populations were small, significant differences were observed for Chuetas and Braganca Jews, and therefore, specific databases must be used for these populations. PMID- 26610304 TI - Review: Interpretation of drug presence in the hair of children. AB - Hair analyses for drugs of abuse are being increasingly used in both clinical and forensic toxicology, including cases involving children exposed to a drug using environment. A review was conducted of peer-reviewed publications reporting hair concentrations of drugs in children published in the English language. Fifty-two publications were aggregated into three categories: results published on the newborn where hair was sampled at, or shortly after, birth that reflected in utero exposure and/or short-term exposure from the mother's breast milk, and publications in which children were either believed to have been exposed passively from drugs of abuse through their environment or by active exposure from accidental ingestion or deliberate administration by a caregiver. There was limited data for comparison of all three exposure routes. On average, cocaine, codeine, 6-AM and morphine showed higher concentrations in hair from in utero exposure compared to children exposed passively; however, there was considerable overlap in concentrations. Methamphetamine showed no significant difference between passive and in utero exposure, although there was only one study reporting hair concentrations from in utero exposure. There was no difference in concentrations for those cases exposed passively or actively for codeine and methadone. There was insufficient data for other drugs and other comparisons. Comparison data was confounded by the variability in extraction techniques employed as well as a variety of washing techniques, including studies that did not employ any decontamination technique. These data further illustrate the difficulties in interpreting hair concentrations in isolation of relevant contextual data, particularly in children. PMID- 26610302 TI - The genetic associations of acute anterior uveitis and their overlap with the genetics of ankylosing spondylitis. AB - Acute anterior uveitis (AAU) involves inflammation of the iris and ciliary body of the eye. It occurs both in isolation and as a complication of ankylosing spondylitis (AS). It is strongly associated with HLA-B*27, but previous studies have suggested that further genetic factors may confer additional risk. We sought to investigate this using the Illumina Exomechip microarray, to compare 1504 cases with AS and AAU, 1805 with AS but no AAU and 21 133 healthy controls. We also used a heterogeneity test to test the differences in effect size between AS with AAU and AS without AAU. In the analysis comparing AS+AAU+ cases versus controls, HLA-B*27 and HLA-A*02:01 were significantly associated with the presence of AAU (P<10(-300) and P=6 * 10(-8), respectively). Secondary independent association with PSORS1C3 (P=4.7 * 10(-5)) and TAP2 (P=1.1 * 10(-5)) were observed in the major histocompatibility complex. There was a new suggestive association with a low-frequency variant at zinc-finger protein 154 in the AS without AAU versus control analysis (zinc-finger protein 154 (ZNF154), P=2.2 * 10(-6)). Heterogeneity testing showed that rs30187 in ERAP1 has a larger effect on AAU compared with that in AS alone. These findings also suggest that variants in ERAP1 have a differential impact on the risk of AAU when compared with AS, and hence the genetic risk for AAU differs from AS. PMID- 26610306 TI - The ketogenic diet in two paediatric patients with refractory myoclonic status epilepticus. AB - AIM: We describe two patients with refractory myoclonic status epilepticus treated with the ketogenic diet. METHODS: Between May 1, 2014 and January 1, 2015, two patients who met the diagnostic criteria for refractory myoclonic status epilepticus, seen at our department, were placed on the ketogenic diet and followed for a minimum of six months. RESULTS: One patient with myoclonic epilepsy of unknown aetiology had a 75-90% seizure reduction, and the other with progressive encephalopathy associated with myoclonic epilepsy had a 50% seizure reduction. Both patients retained good tolerability for the diet. At the last control, one patient had isolated myoclonias and EEG showed occasional generalized spike-and-polyspike waves; the patient is now successfully attending kindergarten. The quality of life of the second patient improved significantly. In both cases, the number of antiepileptic drugs was reduced. CONCLUSION: The ketogenic diet is an effective and well-tolerated treatment option for patients with refractory myoclonic status epilepticus and should be considered earlier in the course of treatment. PMID- 26610307 TI - Dietary resistant dextrins positively modulate fecal and cecal microbiota composition in young rats. AB - The objective of the present study was to demonstrate the effect of dietary resistant dextrins, as potential prebiotics, on the intestinal microflora of young rats. Enzyme-resistant dextrin, prepared by heating of potato starch in the presence of hydrochloric (0.1% dsb) and tartaric (40% dsb) acid at 130oC for 2 h (CA-dextrin). The experiment was performed on 24 Wistar male rats at 3-wk of age, divided by analogues in three experimental groups (control, starch and dextrin). Analyses determined the overall bacterial counts and the counts of Lactobacillus, Bifidobacterium, Bacteroides and Clostridium strains within the feces and cecal contents of rats using fluorescence in situ hybridization method. CA-dextrin had no effect on primary growth indicators (body weight, body weight gain, dietary consumption) or the mass of the small intestine and the cecum, but dextrins caused a reduction in pH and the concentration of ammonia within the cecal contents. That supplementation of diet with resistant dextrins had a positive effect on composition of intestinal microflora in rats. It increased the counts of Bifidobacterium and Lactobacillus strains both in the feces and in the cecum. Moreover, it reduced the counts of Clostridium and Bacteroides strains. These results may suggest that resistant dextrins exerted a prebiotic-like effect in the large intestine. PMID- 26610308 TI - The microbiological, histological, immunological and molecular determinants of Helicobacter pylori infection in guinea pigs as a convenient animal model to study pathogenicity of these bacteria and the infection dependent immune response of the host. AB - Helicobacter pylori is an etiological agent of chronic gastritis, gastric and duodenal ulcers and gastric cancers. The use of an appropriate animal model for experimental studies on the pathogenesis of H. pylori infections is necessary due to the chronic character of such infections and difficulties in identifying their early stage in humans. The aim of this study was to develop a guinea pig model of H. pylori infection and identify its microbiological, histological, serological and molecular determinants. Guinea pigs were inoculated per os with H. pylori strains: CCUG 17874 or ATCC 700312, both producing vacuolating cytotoxin A (VacA) and cytotoxin associated gene A (CagA) protein, suspended in Brucella broth with fetal calf serum (FCS) and Skirrow supplement of antibiotics. To determine H. pylori colonization, 7 and 28 days after the challenge, a panel of diagnostic methods was used. It included culturing of microorganisms from the gastric tissue, histopathological analysis of gastric sections, stained by Mayer,s haematoxylin and eosin to assess inflammatory response, by Giemsa as well as Warthin-Starry silver staining to visualise Helicobacter-like organisms (HLO) and with anti-Ki-67 antigen to assess epithelial cell proliferation. H. pylori infection was also confirmed by polymerase chain reactions (PCR) for detection in gastric tissue of ureC and cagA genes and by serological assessment of H. pylori antigens in faeces. This study showed the usefulness of microbiological, histological, immunological and molecular methods for the detection of persistent H. pylori infections in guinea pigs, which could be an appropriate model for studying H. pylori pathogenesis and the related immune response against these microbes. PMID- 26610309 TI - PCR and real-time PCR assays to detect fungi of Alternaria alternata species. AB - Fungi of the Alternaria genus are mostly associated with allergic diseases. However, with a growing number of immunocompromised patients, these fungi, with A. alternata being the most prevalent one, are increasingly recognized as etiological agents of infections (phaeohyphomycoses) in humans. Nowadays, identification of Alternaria spp. requires their pure culture and is solely based on morphological criteria. Clinically, Alternaria infections may be indistinguishable from other fungal diseases. Therefore, a diagnostic result is often delayed or even not achieved at all. In this paper we present easy to perform and interpret PCR and real-time PCR assays enabling detection of A. alternata species. On the basis of alignment of beta-tubulin gene sequences, A. alternata-specific primers were designed. DNA from fungal isolates, extracted in a two-step procedure, were used in PCR and real-time PCR assays followed by electrophoresis or melting temperature analysis, respectively. The assays specificity was confirmed, since positive results were obtained for all A. alternata isolates, and no positive results were obtained neither for other molds, dermatophytes, yeast-like fungi, nor human DNA. The assays developed here enable fast and unambiguous identification of A. alternata pathogens. PMID- 26610310 TI - Influence of the silver nanoparticles on microbial community in different environments. AB - The aim of this study was to assess the influence of silver nanoparticles (AgNPs) on the number and diversity of microbial community in different environments (soil extract, water, sewage), and to determine whether the environment inhibits or accelerates the influence of AgNPs on moulds. AgNPs (45 ppm) present in the environment decreased bacterial (91%) and fungal (33-85%) numbers, and eliminated some strains, e.g., Alternaria alternata and Cryptococcus laurentii. Based on the biomass growth of Aspergillus niger and Penicillium chrysogenum in a medium with AgNPs and the environmental samples, it was noticed that environment can enhance (soil extract) or inhibit (sewage) antifungal activity of AgNPs. PMID- 26610311 TI - The sequence diversity and expression among genes of the folic acid biosynthesis pathway in industrial Saccharomyces strains. AB - Folic acid is an important vitamin in human nutrition and its deficiency in pregnant women's diets results in neural tube defects and other neurological damage to the fetus. Additionally, DNA synthesis, cell division and intestinal absorption are inhibited in case of adults. Since this discovery, governments and health organizations worldwide have made recommendations concerning folic acid supplementation of food for women planning to become pregnant. In many countries this has led to the introduction of fortifications, where synthetic folic acid is added to flour. It is known that Saccharomyces strains (brewing and bakers' yeast) are one of the main producers of folic acid and they can be used as a natural source of this vitamin. Proper selection of the most efficient strains may enhance the folate content in bread, fermented vegetables, dairy products and beer by 100% and may be used in the food industry. The objective of this study was to select the optimal producing yeast strain by determining the differences in nucleotide sequences in the FOL2, FOL3 and DFR1 genes of folic acid biosynthesis pathway. The Multitemperature Single Strand Conformation Polymorphism (MSSCP) method and further nucleotide sequencing for selected strains were applied to indicate SNPs in selected gene fragments. The RT qPCR technique was also applied to examine relative expression of the FOL3 gene. Furthermore, this is the first time ever that industrial yeast strains were analysed regarding genes of the folic acid biosynthesis pathway. It was observed that a correlation exists between the folic acid amount produced by industrial yeast strains and changes in the nucleotide sequence of adequate genes. The most significant changes occur in the DFR1 gene, mostly in the first part, which causes major protein structure modifications in KKP 232, KKP 222 and KKP 277 strains. Our study shows that the large amount of SNP contributes to impairment of the selected enzymes and S. cerevisiae and S. pastorianus produce reduced amounts of the investigated metabolite. The results obtained here yield a list of genetically stable yeast strains which can be implemented as a starter culture in the food industry. PMID- 26610312 TI - DYT6 Dystonia: A Neuropathological Study. AB - BACKGROUND: Mutations in the thanatos-associated protein domain containing apoptosis-associated protein 1 gene (THAP1) are responsible for adult-onset isolated dystonia (DYT6). However, no neuropathological studies of genetically proven DYT6 cases have been previously reported. OBJECTIVE: We report the first detailed neuropathological investigation carried out on two DYT6 brains. METHODS: Genetic screening for THAP1 gene mutations using standard Sanger polymerase chain reaction sequencing identified 2 cases, 1 with a known pathogenic mutation and the other with a novel mutation. A detailed neuropathological assessment of the cases was performed. RESULTS: Both DYT6 cases showed no significant neurodegeneration and no specific disease-related pathology. CONCLUSIONS: No neuropathological features that could be defined as hallmark features of DYT6 dystonia were identified. Our study supports the notion that in isolated dystonia, there is no significant neurodegeneration or morphological lesions that can be identified using routine methods. PMID- 26610313 TI - Cocaine Use Disorder Treated with Specific Cognitive Behavioral Therapy and Adjunctive Propranolol. PMID- 26610314 TI - Sensitivity to Social Exclusion in Major Depressive Disorder Predicts Therapeutic Outcome after Inpatient Treatment. PMID- 26610315 TI - The New Conceptualization of Alzheimer's Disease under the Microscope of Influential Definitions of Disease. AB - BACKGROUND: According to its new conceptualization, Alzheimer's disease (AD) has preclinical and symptomatic phases, and biomarker abnormality justifies the diagnosis of the disease. METHODS: The conceptual validity of AD is assessed on the basis of the disease definitions of T. Szasz, R.E. Kendell and J.G. Scadding, C. Boorse, K.W.M. Fulford and J.C. Wakefield, as well as of the DSM-5 classification system. RESULTS: The new AD conceptualization could fit the Szaszian disease definition, provided that AD biomarkers reflected the pathological hallmarks of a singular disease, but it seems that they do not. Moreover, preclinical AD does not yield a biological disadvantage, being a central criterion for justifying the presence of a disease according to the disease definition of Scadding and Kendell. In addition, it remains unclear whether abnormality of biomarkers in elderly people embodies a statistical deviation from normal ageing and a pathological characteristic. Furthermore, not all stages of AD are related to experiences of failure of intentional doing, which is the criterion of the disease definition of Fulford, whilst the Wakefieldian harmful dysfunction and the DSM-5 mental disorder criteria are fulfilled only in the symptomatic phases of the disease course. DISCUSSION: Our analytical endeavours unveiled weak sides and the fuzzy boundaries of the new conceptualization of AD. Future refinements of the criteria should address them so that the validity of the AD concept is increased. PMID- 26610321 TI - Clinicopathological characterization and genomic sequence differences observed in a highly virulent fowl Aviadenovirus serotype 4. AB - Highly virulent fowl aviadenoviruses (genus: Aviadenovirus) represent a significant risk in poultry farming that may contribute to increased mortality rates and may adversely affect the growth performance of poultry flocks. In this study, we performed the clinicopathological characterization of a FAdV strain SHP95 isolated from a commercial farm and its whole genome sequencing. The study revealed that the isolated strain is a highly virulent serotype 4 FAdV that can cause 100% mortality in day-old specific pathogen free (SPF) chickens with a dose of 2.5 * 10(5) TCID50. At a lower viral dose (1.5 * 10(4) TCID50), the infection in day-old SPF chickens caused 40% mortality and lesions characteristic for Hepatitis-hydropericardium syndrome (HHS). The viral strain was detectable by real time PCR in chicken organs, including the lymphoid organs until day 28 after infection. The whole genome assembly of strain SHP95 revealed a size of 45,641 bp, which encodes for 42 viral open reading frame (ORF). The comparative analysis in the genome shows 98.1% similarity between strain SHP95 and other FAdV-4 genomes reported. The major differences in the genome sequence between pathogenic and non-pathogenic fowl Adenovirus were identified in the right arm of the genome. PMID- 26610316 TI - Psychological distress and its effect on tuberculosis treatment outcomes in Ethiopia. AB - BACKGROUND: Psychological distress is the major comorbidity among tuberculosis (TB) patients. However, its magnitude, associated factors, and effect on treatment outcome have not been adequately studied in low-income countries. OBJECTIVE: This study aimed to determine the magnitude of psychological distress and its effect on treatment outcome among TB patients on treatment. DESIGN: A follow-up study was conducted in Addis Ababa, Ethiopia, from May to December 2014. Patients (N=330) diagnosed with all types of TB who had been on treatment for 1-2 months were enrolled consecutively from 15 randomly selected health centers and one TB specialized hospital. Data on sociodemographic variables and economic status were collected using a structured questionnaire. The presence of psychological distress was assessed at baseline (within 1-2 months after treatment initiation) and end point (6 months after treatment initiation) using the 10-item Kessler (K-10) scale. Alcohol use and tobacco smoking history were assessed using WHO Alcohol Use Disorder Identification Test and Australian Smoking Assessment Checklist, respectively. The current WHO TB treatment outcome definition was used to differentiate the end result of each patient at completion of the treatment. RESULTS: The overall psychological distress was 67.6% at 1-2 months and 48.5% at 6 months after treatment initiation. Multiple logistic regression analysis revealed that past TB treatment history [adjusted odds ratio (AOR): 3.76; 95% confidence interval (CI): 1.67-8.45], being on anti-TB and anti HIV treatments (AOR: 5.35; 95% CI: 1.83-15.65), being unmarried (AOR: 4.29; 95% CI: 2.45-7.53), having alcohol use disorder (AOR: 2.95; 95% CI: 1.25-6.99), and having low economic status (AOR: 4.41; 95% CI: 2.44-7.97) were significantly associated with psychological distress at baseline. However, at 6 months after treatment initiation, only being a multidrug-resistant tuberculosis (MDR-TB) patient (AOR: 3.02; 95% CI: 1.17-7.75) and having low economic status (AOR: 3.75; 95% CI: 2.08-6.74) were able to predict psychological distress significantly. Past TB treatment history (AOR: 2.13; 95% CI: 1.10-4.12), employment status (AOR: 2.06; 95% CI: 1.06-7.00), and existence of psychological distress symptoms at 6 months after treatment initiation (AOR: 2.87; 95% CI: 1.05-7.81) were found to be associated with treatment outcome. CONCLUSIONS: The overall magnitude of psychological distress was high across the follow-up period; this was more pronounced at baseline. At baseline, past TB treatment history, being on anti-TB and anti-HIV treatments, being unmarried, and having symptoms of alcohol use disorder were associated with psychological distress. However, both at baseline and end point, low economic status was associated with psychological distress. Screening and treatment of psychological distress among TB patients across the whole treatment period is needed, and focusing more on patients who have been economically deprived, previously treated for TB, and on MDR-TB treatment are important. PMID- 26610323 TI - The prognostic value of sleep patterns in disorders of consciousness in the sub acute phase. AB - OBJECTIVE: This study aimed to evaluate, through polysomnographic analysis, the prognostic value of sleep patterns, compared to other prognostic factors, in patients with disorders of consciousness (DOCs) in the sub-acute phase. METHODS: Twenty-seven patients underwent 24-h polysomnography and clinical evaluation 3.5 +/- 2 months after brain injury. Their clinical outcome was assessed 18.5 +/- 9.9 months later. Polysomnographic recordings were evaluated using visual and quantitative indexes. A general linear model was applied to identify features able to predict clinical outcome. Clinical status at follow-up was analysed as a function of the baseline clinical status, the interval between brain injury and follow-up evaluation, patient age and gender, the aetiology of the injury, the lesion site, and visual and quantitative sleep indexes. RESULTS: A better clinical outcome was predicted by a visual index indicating the presence of sleep integrity (p=0.0006), a better baseline clinical status (p=0.014), and younger age (p=0.031). Addition of the quantitative sleep index strengthened the prediction. CONCLUSIONS: More structured sleep emerged as a valuable predictor of a positive clinical outcome in sub-acute DOC patients, even stronger than established predictors (e.g. age and baseline clinical condition). SIGNIFICANCE: Both visual and quantitative sleep evaluation could be helpful in predicting clinical outcome in sub-acute DOCs. PMID- 26610324 TI - Non-invasive measurement of baroreflex during Valsalva maneuver: Evaluation of alpha and beta-adrenergic components. AB - OBJECTIVE: To evaluate alpha and beta components of adrenergic baroreflex sensitivity (BRSa) in Valsalva maneuver (VM). METHODS: BRSa was studied in 89 healthy subjects aged 30+/-13 [16-75] years. Subjects were divided into three groups per blood pressure (BP) patterns associated with relatively balanced or increased alpha-adrenergic modulation: (1) BAR (n=43) - Balanced Autonomic Response with a BP dip below baseline in late phase II (IIL) and recovery in phase IV; (2) SAR (n=16) - Suppressed Autonomic Response with a non-dipping BP; and (3) AAR (n=30) - Augmented Autonomic Response with a BP recovery in phase IIL. Discrete (alpha and beta) BRSa formulae were produced using alpha- or beta adrenergic phases: alpha-BRSa (phase IIL) and beta-BRSa (phase IV), respectively. Discrete BRSa were studied to determine potential correlations to BRSa1 (validated BRSa evaluation) and evaluated for reliability. RESULTS: Patterns with higher alpha-adrenergic influence showed correlation between alpha-BRSa and BRSa1 (AAR: r=0.447, p<0.05; SAR: r=0.774, p<0.01). BAR showed correlation between beta BRSa and BRSa1 (r=-0.566, p<0.01), and alpha- and beta-adrenergic coefficients (r=-0.381, p<0.05). Discrete BRSa were more reliable than BRSa1 (n=33; p<0.05). CONCLUSIONS: Discrete BRSa are reproducible and correlated with BRSa1. SIGNIFICANCE: If validated, discrete BRSa may differentiate physiologic variances and vague dysautonomia. PMID- 26610325 TI - Psychometric Properties of the Spanish Adaptation of the Health Care Communication Questionnaire (HCCQ). AB - This study's aim is to adapt the Health Care Communication Questionnaire in a Spanish sample, and then test the psychometric properties of the adapted instrument. To do so, the questionnaire was adapted for the Spanish context and then applied in a pilot study as well as a final study. The final sample consisted of 200 patients at Morales Meseguer Hospital in Murcia, Spain. The results show that this adaptation's psychometric properties were similar to those of the original questionnaire. As for item analysis, all items obtained discriminant indices > .30. Confirmatory factor analysis revealed the same structure as that of the original questionnaire (chi2/df = 1.345; CFI = .983; IFI = .983; TLI = .977; RMSEA = .042), with indices reflecting adequate goodness of fit. Also, results from the analysis of each dimension's internal consistency had coefficients between .71 and .86. We conclude that the Spanish version of the HCCQ has adequate psychometric properties, is useful, and will serve its purpose in the context in which it will be used. PMID- 26610326 TI - Generation of genome-edited mouse epiblast stem cells via a detour through ES cell-chimeras. AB - Conventionally, mouse epiblast stem cells (EpiSCs) are derived directly from the epiblast or ectoderm germ layer of the post-implantation embryo. Self-renewing and multipotent EpiSC-like stem cells can also be derived by the conversion of embryonic stem cells (ESCs) via the provision of culture conditions that enable the maintenance of the EpiSCs. Here, we outline an experimental procedure for deriving EpiSCs from post-implantation chimeric embryos that are generated using genome-edited ESCs. This strategy enables the production of EpiSCs where (i) no genetically modified animals or ESCs are available, (ii) the impact of the genetic modification on post-implantation development, which may influence the property of the EpiSCs, is requisite knowledge for using the EpiSC for a specific investigation, and (iii) multiple editing of the genome is desirable to modify the biological attributes of the EpiSCs for studying, for example, the gene network activity on the trajectory of lineage differentiation and tissue morphogenesis. PMID- 26610327 TI - Mesenchymal-epithelial interaction techniques. AB - This paper reviews the importance of mesenchymal-epithelial interactions in development and gives detailed technical protocols for investigating these interactions. Successful analysis of mesenchymal-epithelial interactions requires knowing the ages in which embryonic, neonatal and adult organs can be separated into mesenchymal and epithelial tissues. Methods for separation of mesenchymal and epithelial tissues and preparation of tissue recombinants are described. PMID- 26610328 TI - Sequential Single Shot X-ray Photon Correlation Spectroscopy at the SACLA Free Electron Laser. AB - Hard X-ray free electron lasers allow for the first time to access dynamics of condensed matter samples ranging from femtoseconds to several hundred seconds. In particular, the exceptional large transverse coherence of the X-ray pulses and the high time-averaged flux promises to reach time and length scales that have not been accessible up to now with storage ring based sources. However, due to the fluctuations originating from the stochastic nature of the self-amplified spontaneous emission (SASE) process the application of well established techniques such as X-ray photon correlation spectroscopy (XPCS) is challenging. Here we demonstrate a single-shot based sequential XPCS study on a colloidal suspension with a relaxation time comparable to the SACLA free-electron laser pulse repetition rate. High quality correlation functions could be extracted without any indications for sample damage. This opens the way for systematic sequential XPCS experiments at FEL sources. PMID- 26610329 TI - Mesorhizobium calcicola sp. nov., Mesorhizobium waitakense sp. nov., Mesorhizobium sophorae sp. nov., Mesorhizobium newzealandense sp. nov. and Mesorhizobium kowhaii sp. nov. isolated from Sophora root nodules. AB - In total, 31 strains of Gram-stain-negative, rod-shaped bacteria were isolated from Sophora root nodules and authenticated as rhizobia on this host. Based on 16S rRNA gene phylogeny, they were shown to belong to the genus Mesorhizobium, with the representative strains ICMP 19560T, ICMP 19523T, ICMP 19535T, ICMP 19545T and ICMP 19512T being related most closely to Mesorhizobium sangaii SCAU7T (99.9-99.6 % similarity), Mesorhizobium cantuariense ICMP 19515T (99.7-99.6 %) and Mesorhizobium ciceri UMP-CA7T (99.7-99.5 %). Additionally, the novel strains formed distinct groups based on housekeeping gene sequence analysis and were closely related to Mesorhizobium waimense ICMP 19557T (93.5-94.9, 92.5-95.6 and 94.2-96.0 %), M. cantuariense ICMP 19515T (93.1-97.7, 93.5-95.4 and 94.8-96.8 %) and M. ciceri UMP-CA7T (93.2-97.2, 94.6-96.8 and 95.5-97.3 %) for glnII, recA and rpoB, respectively. Chemotaxonomic data supported the assignment of the strains to the genus Mesorhizobium, and DNA-DNA hybridizations, matrix-assisted laser desorption/ionization time-of-flight MS analysis, enterobacterial repetitive intergenic consensus PCR, physiological and biochemical tests allowed the genotypic and phenotypic differentiation from their nearest neighbouring species. Therefore, these strains represent five novel species for which the names Mesorhizobium calcicola sp. nov. (type strain ICMP 19560T = LMG 28224T = HAMBI 3609T), Mesorhizobium waitakense sp. nov. (type strain ICMP 19523T = LMG 28227T = HAMBI 3605T), Mesorhizobium sophorae sp. nov. (type strain ICMP 19535T = LMG 28223T = HAMBI 3606T), Mesorhizobium newzealandense sp. nov. (type strain ICMP 19545T = LMG 28226T = HAMBI 3607T) and Mesorhizobium kowhaii sp. nov. (type strain ICMP 19512T = LMG 28222T = HAMBI 3603T) are proposed. PMID- 26610330 TI - Hoverfly locomotor activity is resilient to external influence and intrinsic factors. AB - Hoverflies are found across the globe, with approximately 6000 species described worldwide. Many hoverflies are being used in agriculture and some are emerging as model species for laboratory experiments. As such it is valuable to know more about their activity. Like many other dipteran flies, Eristalis hoverflies have been suggested to be strongly diurnal, but this is based on qualitative visualization by human observers. To quantify how hoverfly activity depends on internal and external factors, we here utilize a locomotor activity monitoring system. We show that Eristalis hoverflies are active during the entire light period when exposed to a 12 h light:12 h dark cycle, with a lower activity if exposed to light during the night. We show that the hoverflies' locomotor activity is stable over their lifetime and that it does not depend on the diet provided. Surprisingly, we find no difference in activity between males and females, but the activity is significantly affected by the sex of an accompanying conspecific. Finally, we show that female hoverflies are more resilient to starvation than males. In summary, Eristalis hoverflies are resilient to a range of internal and external factors, supporting their use in long-term laboratory experiments. PMID- 26610331 TI - Sex steroid profiles and pair-maintenance behavior of captive wild-caught zebra finches (Taeniopygia guttata). AB - Here, we studied the life-long monogamous zebra finch, to examine the relationship between circulating sex steroid profiles and pair-maintenance behavior in pairs of wild-caught zebra finches (paired in the laboratory for >1 month). We used liquid chromatography-tandem mass spectrometry to examine a total of eight androgens and progestins [pregnenolone, progesterone, dehydroepiandrosterone (DHEA), androstenediol, pregnan-3,17-diol-20-one, androsterone, androstanediol, and testosterone]. In the plasma, only pregnenolone, progesterone, DHEA, and testosterone were above the limit of quantification. Sex steroid profiles were similar between males and females, with only circulating progesterone levels significantly different between the sexes (female > male). Circulating pregnenolone levels were high in both sexes, suggesting that pregnenolone might serve as a circulating prohormone for local steroid synthesis in zebra finches. Furthermore, circulating testosterone levels were extremely low in both sexes. Additionally, we found no correlations between circulating steroid levels and pair-maintenance behavior. Taken together, our data raise several interesting questions about the neuroendocrinology of zebra finches. PMID- 26610332 TI - Structure of distress call: implication for specificity and activation of dopaminergic system. AB - We conducted a set of playback experiments aimed at understanding whether distress-call structure in the greater short-nosed fruit bat Cynopterus sphinx is specific in encoding information relating to stress that attracts conspecifics. We tested the specificity by playing their distress call and its modified version at a foraging site for free-ranging bats, as well as under captive conditions involving either a small group or individuals. In a separate playback experiment, bats showed a significantly greater response when the natural call as opposed to a modified call was played back to captive as well as free-ranging bats at the foraging site. Under captive conditions, bats showed less of a response to the playback of distress calls when in a group than when alone. We subsequently found that tyrosine hydroxylase (TH) and its transcription factor-nuclear receptor related factor 1 (Nurr-1); and the dopamine transporter (DAT) and its receptor (D1DR) were elevated significantly in the amygdala of bats both emitting and responding to a distress call, but not in the case of bats responding to the modified call. These results suggest that distress-call structure encodes information on the state of stress that is capable of being conveyed to conspecifics. PMID- 26610334 TI - Heat stress related dairy cow mortality during heat waves and control periods in rural Southern Ontario from 2010-2012. AB - BACKGROUND: Heat stress is a physiological response to extreme environmental heat such as heat waves. Heat stress can result in mortality in dairy cows when extreme heat is both rapidly changing and has a long duration. As a result of climate change, heat waves, which are defined as 3 days of temperatures of 32 degrees C or above, are an increasingly frequent extreme weather phenomenon in Southern Ontario. Heat waves are increasing the risk for on-farm dairy cow mortality in Southern Ontario. Heat stress indices (HSIs) are generally based on temperature and humidity and provide a relative measure of discomfort which can be used to predict increased risk of on-farm dairy cow mortality. In what follows, the heat stress distribution was described over space and presented with maps. Similarly, on-farm mortality was described and mapped. The goal of this study was to demonstrate that heat waves and related HSI increases during 2010 2012 were associated with increased on-farm dairy cow mortality in Southern Ontario. Mortality records and farm locations for all farms registered in the CanWest Dairy Herd Improvement Program in Southern Ontario were retrieved for 3 heat waves and 6 three-day control periods from 2010 to 2012. A random sample of controls (2:1) was taken from the data set to create a risk-based hybrid design. On-farm heat stress was estimated using data from 37 weather stations and subsequently interpolated across Southern Ontario by geostatistical kriging. A Poisson regression model was applied to assess the on-farm mortality in relation to varying levels of the HSI. RESULTS: For every one unit increase in HSI the on farm mortality rate across Southern Ontario increases by 1.03 times (CI95% (IRR) = (1.025,1.035); p = <= 0.001). With a typical 8.6 unit increase in HSI from a control period to a heat wave, mortality rates are predicted to increase by 1.27 times. CONCLUSIONS: Southern Ontario was affected by heat waves, as demonstrated by high levels of heat stress and increased on-farm mortality. Farmers should be aware of these risks, and informed of appropriate methods to mitigate such risks. PMID- 26610333 TI - Effectiveness and safety of misoprostol distributed to antenatal women to prevent postpartum haemorrhage after child-births: a stepped-wedge cluster-randomized trial. AB - BACKGROUND: Oral misoprostol, administered by trained health-workers is effective and safe for preventing postpartum haemorrhage (PPH). There is interest in expanding administration of misoprostol by non-health workers, including task shifting to pregnant women themselves. However, the use of misoprostol for preventing PPH in home-births remains controversial, due to the limited evidence to support self-administration or leaving it in the hands of non-health workers. This study aimed to determine if antenatally distributing misoprostol to pregnant women to self-administer at home birth reduces PPH. METHODS: Between February 2013 and March 2014, we conducted a stepped-wedge cluster-randomized trial in six health facilities in Central Uganda. Women at 28+ weeks of gestation attending antenatal care were eligible. Women in the control-arm received the standard-of care; while the intervention-arm were offered 600 mcg of misoprostol to swallow immediately after birth of baby, when oxytocin was not available. The primary outcome (PPH) was a drop in postpartum maternal haemoglobin (Hb) by >= 2 g/dl, lower than the prenatal Hb. Analysis was by intention-to-treat at the cluster level and we used a paired t-tests to assess whether the mean difference between the control and intervention groups was statistically significant. RESULTS: 97% (2466/2545) of eligible women consented to participate; 1430 and 1036 in the control and intervention arms respectively. Two thousand fifty-seven of the participants were successfully followed up and 271 (13.2%) delivered outside a health facility. There was no significant difference between the study group in number of women who received a uterotonic at birth (control 80.4% vs intervention 91.4%, mean difference = -11.0%, 95% confidence interval [CI] -25.7% to 3.6%, p = 0.11). No woman took misoprostol before their baby's birth. Shivering and fever were 14.9% in the control arm compared to 22.2% in the intervention arm (mean difference = -7.2%, 95% CI -11.1% to -3.7%), p = 0.005). There was a slight, but non-significant, reduction in the percentage of women with Hb drop >= 2g/dl from 18.5% in the control arm to 11.4% in the intervention arm (mean difference = 7.1%, 95% CI -3.1% to 17.3%, p = 0.14). Similarly, there was no significant difference between the groups in the primary outcome in the women who delivered at home (control 9.6% vs intervention 14.5%, mean difference -4.9; 95% CI -12.7 to 2.9), p = 0.17). CONCLUSION: This study was unable to detect a significant reduction in PPH following the antenatal distribution of misoprostol. The study was registered with Pan-African Clinical Trials Network ( PACTR201303000459148, on 19/11/2012). PMID- 26610335 TI - Leucocyte-derived extracellular trap formation significantly contributes to Haemonchus contortus larval entrapment. AB - BACKGROUND: Polymorphonuclear neutrophil (PMN) and eosinophil extracellular trap (ETs) formation has recently been described as an important host effector mechanism against invading pathogens. So far, scarce evidence on metazoan triggered ET formation has been published. We here describe for the first time Haemonchus contortus-triggered ETs being released by bovine PMN and ovine eosinophils in response to ensheathed and exsheathed third stage larvae (L3). METHODS: The visualization of ETs was achieved by SEM analysis. The identification of classical ETs components was performed via fluorescence microscopy analysis. The effect of larval exsheathment and parasite integrity on ET formation was evaluated via Pico Green(r)- fluorescence intensities. ETs formation under acidic conditions was assessed by using media of different pH ranges. Parasite entrapment was evaluated microscopically after co-culture of PMN and L3. ET inhibition experiments were performed using inhibitors against NADPH oxidase, NE and MPO. Eosinophil-derived ETs were estimated via fluorescence microscopy analysis. RESULTS: L3 significantly induced PMN-mediated ETs and significant parasite entrapment through ETs structures was rapidly observed after 60 min of PMN and L3 co-culture. Co-localization studies of PMN-derived extracellular DNA with histones (H3), neutrophil elastase (NE) and myeloperoxidase (MPO) in parasite-entrapping structures confirmed the classical characteristics of ETs. Haemonchus contortus-triggered ETs were significantly diminished by NADPH oxidase-, NE- and MPO-inhibition. Interestingly, different forms of ETs, i.e. aggregated (aggETs), spread (sprETs) and diffused (diffETs) ETs, were induced by L3. AggETs and sprETs firmly ensnared larvae in a time dependent manner. Significantly stronger aggETs reactions were detected upon exposure of PMN to ensheathed larvae than to exsheathed ones. Low pH conditions as are present in the abomasum did not block ETosis and led to a moderate decrease of ETs. Eosinophil-ETs were identified extruding DNA via fluorescence staining. CONCLUSION: We postulate that ETs may limit the establishment of H. contortus within the definitive host by immobilizing the larvae and hampering them from migrating into the site of infection. Consequently, H. contortus mediated ET formation might have an impact on the outcome of the disease. Finally, besides PMN-triggered ETs, we here present first indications of ETs being released by eosinophils upon H. contortus L3 exposure. PMID- 26610336 TI - Detection of signature volatiles for cariogenic microorganisms. AB - The development of a breath test by the identification of volatile organic compounds (VOCs) emitted by cariogenic bacteria is a promising approach for caries risk assessment and early caries detection. The aim of the present study was to investigate the volatile profiles of three major cariogenic bacteria and to assess whether the obtained signatures were species-specific. Therefore, the headspaces above cultures of Streptococcus mutans, Lactobacillus salivarius and Propionibacterium acidifaciens were analysed after 24 and 48 h of cultivation using gas chromatography and mass spectrometry. A volatile database was queried for the obtained VOC profiles. Sixty-four compounds were detected within the analysed culture headspaces and were absent (36) or at least only present in minor amounts (28) in the control headspace. For S. mutans 18, for L. salivarius three and for P. acidifaciens five compounds were found to be unique signature VOCs. Database matching revealed that the identified signatures of all bacteria were unique. Furthermore, 13 of the 64 detected substances have not been previously reported to be emitted by bacteria or fungi. Specific VOC signatures were found in all the investigated bacteria cultures. The obtained results encourage further research to investigate the transferability to in vivo conditions towards the development of a breath test. PMID- 26610337 TI - Microbial biofilms associated with intravascular catheter-related bloodstream infections in adult intensive care patients. AB - Catheter-related bloodstream infection (CRBSI) is one of the most serious complications in hospitalised patients, leading to increased hospitalisation, intensive care admissions, extensive antibiotic treatment and mortality. A greater understanding of these bacterial infections is needed to improve the prevention and the management of CRBSIs. We describe here the systematic culture independent evaluation of intravascular catheter (IVC) bacteriology. Twelve IVCs (6 central venous catheters and 6 arterial catheters) were collected from 6 patients. By using traditional culture methods, 3 patients were diagnosed with catheter colonisation including 1 patient who also had CRBSI, and 3 had no colonisation. From a total of 839,539 high-quality sequence reads from high throughput sequencing, 8 microbial phyla and 76 diverse microbial genera were detected. All IVCs examined in this study were colonised with complex microbial communities including "non-colonised IVCs," as defined using traditional culture methods. Two main community types were observed: Enterobacteriaceae spp., dominant in patients without colonisation or CRBSI; and Staphylococcus spp., dominant in patients with colonisation and CRBSI. More diverse pathogens and a higher microbial diversity were present in patients with IVC colonisation and CRBSI. Community composition did not appear to be affected by patients' antibiotic treatment or IVC type. Characterisation of these communities is the first step in elucidating roles of these pathogens in disease progression, and to ultimately facilitate the improved prevention, refined diagnosis and management of CRBSI. PMID- 26610338 TI - Clinical presentation of infective endocarditis caused by different groups of non beta haemolytic streptococci. AB - Streptococci are common causes of infective endocarditis (IE) and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has provided a practical tool for their species determination. We aimed to investigate if particular groups of non-beta heamolytic streptococci were associated with IE or to specific presentations thereof. The Swedish Registry of Infective Endocarditis was used to identify cases of IE caused by streptococci and a local database to identify cases of streptococcal bacteremia. The bacteria were grouped using MALDI-TOF MS and the clinical characteristics of IE caused by different groups were compared. We identified a group of 201 streptococcal IE isolates: 18 isolates belonged to the anginosus, 19 to the bovis, 140 to the mitis, 17 to the mutans, and seven to the salivarius groups. The mitis and mutans groups were significantly more common and the anginosus group less common among IE cases as compared to all cause bacteremia. Patients infected with the bovis group isolates were older, had more cardiac devices, and had more commonly prosthetic valve IE compared to IE caused by streptococci of the other groups. Twenty-one percent of patients needed surgery, and in-hospital mortality was 8% with no significant differences between the groups. Grouping of non-beta haemolytic streptococci using MALDI-TOF MS can provide a basis for decision making in streptococcal bacteremia. IE caused by bovis group isolates have clinical characteristics distinguishing them from IE caused by other groups of Streptococcus. PMID- 26610339 TI - Diagnosis of spacer-associated infection using quantitative cultures from sonicated antibiotics-loaded spacers: implications for the clinical outcome. AB - Recent studies showed that a positive microbiological result from sonication of the PMMA spacer was associated with poor outcome of patients, but no quantitative analysis has yet been performed. For this purpose, a prospective analysis of 50 spacers (46 patients) was performed. All spacers were processed according to a previously described protocol, including centrifugation and quantitative culture. Clinical data and outcome were also analysed. A statistical relationship between the results of the cultures and the outcome of the patient was assessed. Sixteen patients were diagnosed with spacer-associated infection. Thirteen out of 50 spacers gave a positive culture. Nine of 13 presented with growth of an organism not isolated in the first-stage cultures, and in 7 out of 13 the organisms count was high (>10,000 CFU/ml). We have detected a significant statistical relationship between poor outcome and positive cultures, high colony counts, isolation of different organisms, positive periprosthetic cultures and spacer associated infection. The detection in a sonicated, antibiotic-loaded PMMA spacer of organisms other than those isolated in the first surgical samples or high colony counts of any organisms is diagnostic with regard to spacer-associated infection. PMID- 26610341 TI - [Overcoming treatment resistance in chronic depression : The role of inpatient psychotherapy]. AB - BACKGROUND: Chronic depression poses a particular challenge for the psychiatric and psychotherapeutic care system. Owing to high rates of psychiatric comorbidities and multiple pharmacological and psychotherapeutic treatment resistance, novel treatment strategies are urgently required. AIM: In this article, we describe the clinical characteristics of chronic and treatment resistant depression and review the pharmacological and psychotherapeutic treatment options currently available. We focus on the Cognitive Behavioral Analysis System of Psychotherapy (CBASP), the first specific psychotherapy approach to chronic depression. Finally, we discuss the role of psychotherapeutic inpatient programs and stepped care concepts in chronic and treatment-resistant depression. PMID- 26610340 TI - Assessment of microscopic and molecular tools for the diagnosis and follow-up of cryptosporidiosis in patients at risk. AB - Cryptosporidiosis is an important though underreported public health concern. Molecular tools might be helpful in improving its diagnosis. In this study, ZR Fecal DNA MiniPrepTM Kit (ZR) and NucliSens(r) easyMAG(r) (EM) were compared using four Cryptosporidium-seeded feces and 29 Cryptosporidium-positive stools. Thereafter, ZR was selected for prospective evaluation of Cryptosporidium detection by 18S rDNA and LAXER quantitative PCR (qPCR) in 69 stools from 56 patients after Cryptosporidium detection by glycerin, modified Ziehl-Neelsen (ZN) and auramine-phenol (AP) stainings. The combination of any of the two extraction methods with 18S qPCR yielded adequate detection of Cryptosporidium in seeded stools, but the ZR kit showed the best performance. All 29 Cryptosporidium positive samples were positive with 18S qPCR, after both ZR and EM extraction. However, false-negative results were found with LAXER qPCR or nested PCR. Cryptosporidiosis was diagnosed in 7/56 patients. All the microscopic methods enabled the initial diagnosis, but Cryptosporidium was detected in 12, 13, and 14 samples from these seven patients after glycerin, ZN, and AP staining respectively. Among these samples, 14 and 12 were positive with 18S and LAXER qPCR respectively. In two patients, Cryptosporidium DNA loads were found to be correlated with clinical evolution. Although little known, glycerin is a sensitive method for the initial detection of Cryptosporidium. When combined with 18S qPCR, ZR extraction, which had not been evaluated so far for Cryptosporidium, was an accurate tool for detecting Cryptosporidium and estimating the oocyst shedding in the course of infection. PMID- 26610342 TI - [Patient-centered care. Improvement of communication between university medical centers and general practitioners for patients in neuro-oncology]. AB - INTRODUCTION: Communication between university medical centers and general practitioners (GP) is becoming increasingly more important in supportive patient care. A survey among GPs was performed with the primary objective to assess their opinion on current workflow and communication between GPs and the university medical center. METHODS: The GPs were asked to score (grades 1-6) their opinion on the current interdisciplinary workflow in the care of patients with brain tumors, thereby rating communication between a university medical center in general and the neuro-oncology outpatient center in particular. RESULTS: Questionnaires were sent to1000 GPs and the response rate was 15 %. The mean scored evaluation of the university medical center in general was 2.62 and of the neuro-oncological outpatient clinic 2.28 (range 1-6). The most often mentioned issues to be improved were easier/early telephone information (44 %) and a constantly available contact person (49 %). Interestingly, > 60 % of the GPs indicated they would support web-based tumor boards for interdisciplinary and palliative neuro-oncological care. CONCLUSION: As interdisciplinary care for neuro-oncology patients is an essential part of therapy, improvement of communication between GPs and university medical centers is indispensable. Integrating currently available electronic platforms under data protection aspects into neuro-oncological palliative care could be an interesting tool in order to establish healthcare networks and could find acceptance with GPs. PMID- 26610343 TI - [Flexibilization of sectoral borders? Con]. PMID- 26610345 TI - Continuous succinic acid production from xylose by Actinobacillus succinogenes. AB - Continuous, anaerobic fermentations of D-xylose were performed by Actinobacillus succinogenes 130Z in a custom, biofilm reactor at dilution rates of 0.05, 0.10 and 0.30 h(-1). Succinic acid yields on xylose (0.55-0.68 g g(-1)), titres (10.9 29.4 g L(-1)) and productivities (1.5-3.4 g L(-1) h(-1)) were lower than those of a previous study on glucose, but product ratios (succinic acid/acetic acid = 3.0 5.0 g g(-1)) and carbohydrate consumption rates were similar. Also, mass balance closures on xylose were up to 18.2 % lower than those on glucose. A modified HPLC method revealed pyruvic acid excretion at appreciable concentrations (1.2-1.9 g L(-1)) which improved the mass balance closure by up to 16.8 %. Furthermore, redox balances based on the accounted xylose consumed and the excreted metabolites, indicated an overproduction of reducing power. The oxidative pentose phosphate pathway was shown to be a plausible source of the additional reducing power. PMID- 26610344 TI - Cross-continental comparison of the association between the physical environment and active transportation in children: a systematic review. AB - BACKGROUND: The purpose of this systematic review was to determine the relationship between a wide range of physical environmental characteristics and different contexts of active transportation in 6- to 12-year-old children across different continents. METHODS: A systematic search was conducted in six databases (Pubmed, Web of Science, Cinahl, SportDiscus, TRIS and Cochrane) resulting in 65 papers, eligible for inclusion. The investigated physical environmental variables were grouped into six categories: walkability, accessibility, walk/cycle facilities, aesthetics, safety, recreation facilities. RESULTS: The majority of the studies were conducted in North America (n = 35), Europe (n = 17) and Australia (n = 11). Active transportation to school (walking or cycling) was positively associated with walkability. Walking to school was positively associated with walkability, density and accessibility. Evidence for a possible association was found for traffic safety and all forms of active transportation to school. No convincing evidence was found for associations between the physical environment and active transportation during leisure. General safety and traffic safety were associated with active transportation to school in North America and Australia but not associated with active transportation to school in Europe. CONCLUSIONS: The physical environment was mainly associated with active transportation to school. Continent specific associations were found, indicating that safety measures were most important in relation to active commuting to school in North America and Australia. There is a need for longitudinal studies and studies conducted in Asia, Africa and South-America and studies focusing specifically on active transportation during leisure. PMID- 26610346 TI - Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis. AB - BACKGROUND: Tamoxifen (TAM) is an important cancer therapeutic and an experimental tool for effecting genetic recombination using the inducible Cre-Lox technique. Despite its widespread use in the clinic and laboratory, we know little about its effects on the nervous system. This is of significant concern because TAM, via unknown mechanisms, induces cognitive impairment in humans. A hallmark of cellular stress is induction of Activating Transcription Factor 3 (Atf3), and so to determine whether TAM induces cellular stress in the adult nervous system, we generated a knock-in mouse in which Atf3 promoter activity drives transcription of TAM-dependent Cre recombinase (Cre-ERT2); when crossed with tdtomato reporter mice, Atf3 induction results in robust and permanent genetic labeling of cells in which it is up-regulated even transiently. RESULTS: We found that granular neurons of the olfactory bulb and dentate gyrus, vascular cells and ependymal cells throughout the brain, and peripheral sensory neurons expressed tdtomato in response to TAM treatment. We also show that TAM induced Atf3 up-regulation through inhibition of cholesterol epoxide hydrolase (ChEH): reporter expression was mitigated by delivery in vitamin E-rich wheat germ oil (vitamin E depletes ChEH substrates), and was partially mimicked by a ChEH specific inhibitor. CONCLUSIONS: This work demonstrates that TAM stresses cells of the adult central and peripheral nervous systems and highlights concerns about clinical and experimental use of TAM. We propose TAM administration in vitamin E rich vehicles such as wheat germ oil as a simple remedy. PMID- 26610347 TI - What Can We Expect from Value-Based Funding of Medicines? A Retrospective Study. AB - OBJECTIVE: Deciding on public funding for pharmaceuticals on the basis of value for money is now widespread. We suggest that evidence-based assessment of value has restricted the availability of medicines in Australia in a way that reflects the relative bargaining power of government and the pharmaceutical industry. We propose a simple informal game-theoretic model of bargaining between the funding agency and industry and test its predictions using a logistic multiple regression model of past funding decisions made by the Pharmaceutical Benefits Advisory Committee in Australia. METHOD: The model estimates the probability of a drug being recommended for subsidy as a function of incremental cost per quality adjusted life-year (QALY), as well as other drug and market characteristics. Data are major submissions or resubmissions from 1993 to 2009 where there was a claim of superiority and evidence of a difference in quality of life. Independent variables measure the incremental cost per QALY, the cost to the public budget, the strength and quality of the clinical and economic evidence, need as measured by severity of illness and the availability of alternative treatments, whether or not a resubmission, and newspaper reports as a measure of public pressure. We report the odds ratio for each variable and calculate the ratio of the marginal effect of each variable to the marginal effect of the cost per QALY as a measure of the revealed willingness to pay for each of the variables that influence the decision. RESULTS: The results are consistent with a bargaining model where a 10,000 Australian dollar ($A) fall in value (increase in cost per QALY) reduces the average probability of public funding from 37 to 33% (95% CI 34-32). If the condition is life threatening or the drug has no active comparator, then the odds of a positive recommendation are 3.18 (95% CI 1.00-10.11) and 2.14 (95% CI 0.95 4.83) greater, equivalent to a $A33,000 and a $A21,000 increase in value (fall in cost per QALY). If both conditions are met, the odds are increased by 4.41 (95% CI 1.28-15.24) times, equivalent to an increase in value of $A46,000. Funding is more likely as time elapses and price falls, but we did not find clear evidence that public or corporate pressure influences decisions. CONCLUSION: Evidence from Australia suggests that the determinants of public funding and pricing decisions for medicines reflect the relative bargaining power of government and drug companies. Value for money depends on the quality of evidence, timing, patient need, perceived benefit and opportunity cost; these factors reflect the potential gains from striking a bargain and the risk of loss from not doing so. PMID- 26610348 TI - Relationships between Genetic Variations of PNPLA3, TM6SF2 and Histological Features of Nonalcoholic Fatty Liver Disease in Japan. AB - BACKGROUND/AIMS: It is important to determine the noninvasive parameters of histological features in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the value of genetic variations as surrogate markers of histological features. METHODS: The parameters that affected the histological features of NAFLD were investigated in 211 Japanese patients with biopsy-proven NAFLD. The relationships between genetic variations in PNPLA3 rs738409 or TM6SF2 rs58542926 and histological features were analyzed. Furthermore, the impact of genetic variations that affected the pathological criteria for the diagnosis of nonalcoholic steatohepatitis (NASH) (Matteoni classification and NAFLD activity score) was evaluated. RESULTS: The fibrosis stage of PNPLA3 GG was significantly more progressive than that of CG by multiple comparisons. Multivariate analysis identified PNPLA3 genotypes as predictors of fibrosis of stage 2 or more, but the impact tended to decrease at stage 3 or greater. There were no significant differences among the histological features of the three genotypes of TM6SF2. PNPLA3 genotypes partly affected the definition of NASH by the NAFLD activity score, but TM6SF2 genotypes did not affect the definition of NASH. CONCLUSIONS: In Japanese patients with biopsy-proven NAFLD, PNPLA3 genotypes may partly affect histological features, including stage of fibrosis, but the TM6SF2 genotype does not affect histological features. PMID- 26610349 TI - Auditory dominance in motor-sensory temporal recalibration. AB - Perception of synchrony between one's own action (e.g. a finger tap) and the sensory feedback thereof (e.g. a flash or click) can be shifted after exposure to an induced delay (temporal recalibration effect, TRE). It remains elusive, however, whether the same mechanism underlies motor-visual (MV) and motor auditory (MA) TRE. We examined this by measuring crosstalk between MV- and MA delayed feedbacks. During an exposure phase, participants pressed a mouse at a constant pace while receiving visual or auditory feedback that was either delayed (+150 ms) or subjectively synchronous (+50 ms). During a post-test, participants then tried to tap in sync with visual or auditory pacers. TRE manifested itself as a compensatory shift in the tap-pacer asynchrony (a larger anticipation error after exposure to delayed feedback). In experiment 1, MA and MV feedback were either both synchronous (MV-sync and MA-sync) or both delayed (MV-delay and MA delay), whereas in experiment 2, different delays were mixed across alternating trials (MV-sync and MA-delay or MV-delay and MA-sync). Exposure to consistent delays induced equally large TREs for auditory and visual pacers with similar build-up courses. However, with mixed delays, we found that synchronized sounds erased MV-TRE, but synchronized flashes did not erase MA-TRE. These results suggest that similar mechanisms underlie MA- and MV-TRE, but that auditory feedback is more potent than visual feedback to induce a rearrangement of motor sensory timing. PMID- 26610350 TI - 3D structured illumination microscopy of mammalian embryos and spermatozoa. AB - BACKGROUND: Super-resolution fluorescence microscopy performed via 3D structured illumination microscopy (3D-SIM) is well established on flat, adherent cells. However, blastomeres of mammalian embryos are non-adherent, round and large. Scanning whole mount mammalian embryos with 3D-SIM is prone to failure due to the movement during scanning and the large distance to the cover glass. RESULTS: Here we present a highly detailed protocol that allows performing 3D-SIM on blastomeres of mammalian embryos with an image quality comparable to scans in adherent cells. This protocol was successfully tested on mouse, rabbit and cattle embryos and on rabbit spermatozoa. CONCLUSIONS: Our protocol provides detailed instructions on embryo staining, blastomere isolation, blastomere attachment, embedding, correct oil predictions, scanning conditions, and oil correction choices after the first scan. Finally, the most common problems are documented and solutions are suggested. To our knowledge, this protocol presents for the first time a highly detailed and practical way to perform 3D-SIM on mammalian embryos and spermatozoa. PMID- 26610352 TI - Breathless in Iraq. PMID- 26610351 TI - Quality-of-life outcomes and unmet needs between ileal conduit and orthotopic ileal neobladder after radical cystectomy in a Chinese population: a 2-to-1 matched-pair analysis. AB - BACKGROUND: Health-related quality-of-life (HRQoL) is an important consideration after radical cystectomy (RC). Lack of effective ways to assess HRQoL after RC and unawareness of disease-specific problems related to ileal conduit (IC) and orthotopic ileal neobladder (OIN) are serious problems. The present study was to evaluate and compare morbidity and HRQoL between IC and OIN after RC, and examine their unmet needs in the two groups. METHODS: A retrospective analysis was made of 294 patients treated with RC in our hospital between 2007 and 2013. Matched pair analysis was used to determine the patients of IC and OIN groups. Patient HRQoL between IC and OIN groups was assessed using the bladder-specific bladder cancer index (BCI) and European Organization for Research and Treatment of Cancer Body Image scale (BIS) questionnaires. Unmet information of patients undergoing these two urinary diversions was recorded through individual interviews. RESULTS: Of the 117 included patients, 39 patients were treated with OIN and the other 78 matched patients with IC as controls for matched pair analysis. There was no significant difference in baseline characteristics between the two groups. OIN patients showed significantly better BIS scores in terms of HRQoL outcomes after RC at a short-term (<1 year) follow-up level, but there was no significant difference at a long-term (>1 year) follow-up level between the two groups. Interestingly, urinary bother (UB) and urinary function (UF) were poor in OIN patients at the one-year follow-up level, but there was no significant difference in UB between the two groups at the long term follow-up level. Unmet needs analysis showed that OIN patients had a more positive attitude towards treatment and participated in physical and social activities more positively, although they may have more urine leakage problems. CONCLUSIONS: The mean BIS score in OIN group patients was significantly better than that in IC group patients at the one year follow-up level, but there was no significant difference at the long-term follow-up level. Due attention should be paid to some particular unmet needs in individual patients in managing the two UD modalities. PMID- 26610353 TI - Regional neuromuscular regulation within human rectus femoris muscle during gait in young and elderly men. AB - Recently, we demonstrated region-specific electromyography (EMG) responses along the rectus femoris (RF) muscle during gait in healthy young men (Watanabe et al., 2014b). For the RF muscle, regional EMG response should be tested to characterize neuromuscular control and/or to assess its dysfunction and/or pathology during gait. We aimed to identify spatial distribution of EMG pattern within the RF muscle in elderly during gait. Seven young men (age: 20.4+/-1.0 years) and 8 elderly men (age: 73.8+/-5.9 years) walked on treadmill with three different speed: slow (preferred -1km/h), preferred, and fast (preferred +1km/h). The spatial distribution of surface EMG was tested by central locus activation (CLA), which is calculated from 18 surface electrodes along the longitudinal line of the muscle. CLA were not different between the groups for slow and preferred gait speed (p>0.05) during a gait cycle. In fast gait speed, CLA at 80% of a gait cycle (swing phase) for the elderly were significantly located at more distal site than the young group (p<0.05) (13.0+/-2.1cm and 10.2+/-2.2cm from most proximal electrodes for the elderly and young). This difference in CLA reflected a significantly lower EMG activity at the proximal regions in the elderly group (p<0.05). These results suggest the elderly manifest characteristic regional EMG responses within the RF muscle for leg swing movement of fast speed gait. PMID- 26610354 TI - A Video-Based Module for Teaching Communication Skills to Otolaryngology Residents. AB - OBJECTIVE: To determine whether instructional videos modeling examples of "good" and "bad" patient communication skills are useful as an educational tool for improving resident-patient communication. DESIGN: Retrospective study in which resident participants in the module gave survey responses indicating perceived utility of the exercise. SETTING: Tertiary academic medical center. PARTICIPANTS: A total of 11 otolaryngology trainees from postgraduate year 1-5 who attended the course over 2 separate sessions and provided feedback on the benefits of the module. RESULTS: All 11 residents attended both sessions. Of 22 total survey responses, 21 found that the videos were "realistic and engaging" and were a true representation of commonly encountered clinical scenarios. Residents identified multiple themes and behaviors distinguishing "good" vs "bad" communication with patients and felt they could incorporate these into daily practice. A perceived weakness was the lack of opportunity for "role playing" with a video-based module as opposed to standardized patients. CONCLUSIONS: Instructional videos, when realistic, are useful for modeling effective patient communication skills for residents. By watching the videos, residents are able to identify specific techniques they can incorporate into their daily practice. PMID- 26610355 TI - Coaching Non-technical Skills Improves Surgical Residents' Performance in a Simulated Operating Room. AB - OBJECTIVE: To investigate the effect of coaching on non-technical skills and performance during laparoscopic cholecystectomy in a simulated operating room (OR). BACKGROUND: Non-technical skills (situation awareness, decision making, teamwork, and leadership) underpin technical ability and are critical to the success of operations and the safety of patients in the OR. The rate of developing assessment tools in this area has outpaced development of workable interventions to improve non-technical skills in surgical training and beyond. METHOD: A randomized trial was conducted with senior surgical residents (n = 16). Participants were randomized to receive either non-technical skills coaching (intervention) or to self-reflect (control) after each of 5 simulated operations. Coaching was based on the Non-Technical Skills For Surgeons (NOTSS) behavior observation system. Surgeon-coaches trained in this method coached participants in the intervention group for 10 minutes after each simulation. Primary outcome measure was non-technical skills, assessed from video by a surgeon using the NOTSS system. Secondary outcomes were time to call for help during bleeding, operative time, and path length of laparoscopic instruments. RESULTS: Non technical skills improved in the intervention group from scenario 1 to scenario 5 compared with those in the control group (p = 0.04). The intervention group was faster to call for help when faced with unstoppable bleeding in the final scenario (no. 5; p = 0.03). CONCLUSIONS: Coaching improved residents' non technical skills in the simulated OR compared with those in the control group. Important next steps are to implement non-technical skills coaching in the real OR and assess effect on clinically important process measures and patient outcomes. PMID- 26610356 TI - Beta Test of Web-Based Virtual Patient Decision-Making Exercises for Residents Demonstrates Discriminant Validity and Learning. AB - INTRODUCTION: Correct clinical decision-making is a key competency of surgical trainees. The purpose of this study was to assess validity and effect on resident decision-making accuracy of web-based virtual patient case scenarios in general surgery training. MATERIAL AND METHODS: During the 2013-2014 academic year, the use of web-based virtual patient scenarios for teaching and assessment of resident critical thinking and decision-making was assessed in 2 urban university based residency programs. In all, 71 residents (PGY [postgraduate year] 1 = 21, PGY2 = 11, PGY3 = 14, PGY4 = 13, and PGY5 = 12) took the cases over the course of the academic year. Cases were made available to the residents online 1 week before a scheduled debriefing conference with a faculty facilitator and were completed by residents individually on their own schedule. At the completion of each case attempt, residents were given a computer-generated score and feedback. Residents were allowed to repeat the cases before the debriefing if they wished. Cases were required to be completed by 48 hours before the conference, at which time a faculty report was computer generated that measured group and individual performance and identified the frequency of errors in decision-making. This report was reviewed with the residents in the faculty debriefing, and teaching focused on the knowledge gaps identified in the reports. RESULTS: The mean percentage of assigned cases completed by categorical residents was 85.7%. Mean score (maximum possible = 100) on the cases increased by resident year (PGY1 = 45.3, PGY2 = 49.3, PGY3 = 53.6, PGY4 = 57.5, and PGY5 = 61.8), a 25% increase between PGY1 and PGY5 (p < 0.001 by analysis of variance). In all, 45 (63%) residents chose to repeat at least 1 case before the debriefing. The number of repetitions of individuals on the same case varied from a minimum of 1 to a maximum of 5. On repeated cases, mean scores rose (attempt 1 = 22.6, attempt 2 = 69.3, attempt 3 = 72.1, attempt 4 = 77.5, attempt 5 = 100, p < 0.0001 by analysis of variance). Paired t tests on case repetition using each resident as his-her own control showed that scores rose by 46 points between attempt 1 and attempt 2 (p < 0.001). CONCLUSIONS: (1) In a beta test of web-based scenarios that teach and assess clinical decision-making, resident scores improved by 25% from PGY 1 to PGY5 in a stepwise and statistically significant manner, suggesting that such exercises could serve as milestones for competency assessment. Additional studies are needed to acquire evidence for other forms of validity. (2) Repetition of cases after feedback led to highly significant increases in performance, suggesting that requiring repeated training to reach defined levels of competence is practical. PMID- 26610357 TI - Is a Single-Item Operative Performance Rating Sufficient? AB - OBJECTIVE: A valid measure of resident operative performance ability requires direct observation and accurate rating of multiple resident performances under the normal range of operating conditions. The challenge is to create an operative performance rating (OPR) system that: is easy to use, encourages completion of many ratings immediately after performances and minimally disrupts supervising surgeons' work days. The purpose of this study was to determine whether a score based on a single-item overall OPR provides a valid and stable appraisal of resident operative performances. DESIGN: A retrospective comparison of a single item OPR with a gold-standard rating based on multiple procedure-specific and general OPR items. SETTING: Data were collected in the general surgery residency program at Southern Illinois University from 2001 through 2012. PARTICIPANTS: Assessments of 1033 operative performances (3 common procedures, 2 laparoscopic, and 1 open) by general surgery residents were collected. OPRs based on single item overall performance scale scores were compared with gold-standard ratings for the same performances. RESULTS: Differences in performance scores using the 2 scales averaged 0.02 points (5-point scale). Correlations of the single-item and gold-standard scale scores averaged 0.95. Based on generalizability analyses of laparoscopic cholecystectomy ratings, each instrument required 5 observations to achieve reliabilities of 0.80 and 11 observations to achieve reliabilities of 0.90. Only 4.4% of single-item ratings misclassified the performance when compared with the gold-standard rating and all misclassifications were near misses. For 80% of misclassified ratings, single-item ratings were lower. CONCLUSIONS: Single-item operative performance measures produced ratings that were virtually identical to gold-standard scale ratings. Misclassifications occurred infrequently and were minor in magnitude. Ratings using the single-item scale: take less time to complete, should increase the sample of procedures rated, and encourage attending surgeons to complete ratings immediately after observing performances. Face-to-face and written comments and suggestions should continue to be used to provide the granular feedback residents need to improve subsequent performances. PMID- 26610358 TI - A Milestone-Based Evaluation System-The Cure for Grade Inflation? AB - PURPOSE: Controversy exists over the optimal use of the Milestones in the process of resident evaluation and feedback. We sought to evaluate the performance of a Milestones-based feedback system in comparison to a traditional model. METHODS: The traditional evaluation system (TES) consisted of a generic 16-item survey using a 5-point Likert scale ranging from 1 to 5, and a free-text comments section. The Milestones-based evaluation system (MBES) was launched in July 2014, ranging from 0 to 4. Individual milestones were mapped to rotations based on resident educational goals by postgraduate year (PGY). The MBES consisted of a survey with a maximum of 7 items, followed by a free-text comment section. Within each evaluation system, an overall composite score was calculated for each categorical general surgical resident. To scale the 2 systems for comparison, TES scores were adjusted downward by 1 point. Descriptive statistics were performed. Univariate analysis was performed with the Wilcoxon signed-rank test. A test for trend across PGY was used for the MBES only. RESULTS: In the traditional system, the median score was 3.66 (range: 3.2-4.0). There was no meaningful difference in the median score by PGY. In the new system, the median score was 2.69 (range: 1.5 3.7, p < 0.01). The median score differed across PGY and increased by PGY of training (p < 0.01). There was an increase in differences between median scores by PGY. CONCLUSIONS: On using the milestones to facilitate faculty evaluation of resident knowledge and skill, there was a trend in increasing score by PGY of training. In the MBES, scores could be used to better discriminate resident skill and knowledge levels and resulted in improved differentiation in scoring by PGY. The use of the milestones as a basis for evaluation enabled the program to provide more meaningful feedback to residents and represents an improvement in surgical education. PMID- 26610359 TI - [Localized salt-dependent aquagenic urticaria: A case report]. AB - BACKGROUND: Aquagenic urticaria is a rare but well-known form of physical urticaria mainly affecting young women. It is characterised by the appearance of erythematous and pruritic plaques a few minutes after initial contact with water and irrespective of temperature. The physiopathology of this condition remains poorly understood. Herein, we report a case of localised aquagenic urticaria occurring solely on contact with seawater. PATIENTS AND METHODS: A 32-year-old woman reported onset of erythematous and pruritic plaques, confined to the neck and lower part of the face, several minutes after the start of bathing in seawater. Skin tests were carried out by applying wet compresses soaked in seawater (37 degrees C for 30 min) to the areas in which the skin reaction usually occurred. A control test using a compress soaked in fresh water was carried out under identical conditions. An urticaria reaction was noted in the areas in contact with seawater, but no reaction was seen in the areas coming into contact with fresh water. Antihistamines taken on the days of bathing proved ineffective. DISCUSSION: A number of similar cases have been reported in the literature, enabling the characterisation of this particular form of aquagenic urticaria and allowing its principal characteristics to be defined. It appears to be dependent solely on the salt content of the water. It is reported by young women while bathing in seawater. The urticaria plaques show a predilection for the neck and lower part of the face, as in our case, as well as the shoulders on occasion. The efficacy of antihistamines is inconsistent. The prevalence of this as yet poorly known entity is doubtless underreported. PMID- 26610360 TI - [McCune-Albright syndrome revealed by Blaschko-linear cafe-au-lait spots on the back]. AB - BACKGROUND: McCune-Albright syndrome is a rare sporadic disease defined by the triad of cafe-au-lait spots, fibrous dysplasia of bone and endocrine disorder. Diagnosis is classically confirmed by the presence of bone lesions or precocious puberty. We report a case of McCune-Albright syndrome diagnosed solely on the basis of the cutaneous signs. PATIENTS AND METHODS: A four-year-old girl was seen in our clinic due to the presence of congenital cafe-au-lait spots on her back. These macules were irregular, with jagged borders, and were disposed in a broad band on the left shoulder and in the lumbar region, in a Blaschko-linear pattern. McCune-Albright syndrome was immediately suspected, despite the absence of other signs of the disease. Genetic assessment carried out a year and a half later confirmed the diagnosis, with arginine substitution at position 201 of Gs alpha protein. The child was still asymptomatic. Regular radiographic and endocrine assessments remained normal for three years until the sudden appearance at the age of seven years of precocious puberty and radiographic evidence of fibrous dysplasia of the right hand. DISCUSSION: Cafe-au-lait spots are very common in the general population. An underlying genetic disorder should only be sought when such spots are multiple. However, in the case of McCune-Albright syndrome, it is the irregular borders and the Blaschko-linear arrangement of the spots in broad irregular bands that are pathognomonic, reflecting as they do the genetic mosaicism characteristic of this disease. PMID- 26610361 TI - [Furuncular myiasis caused by Dermatobia hominis. Fortuitous diagnosis on extemporaneous macroscopic analysis of an excised cutaneous nodule]. AB - BACKGROUND: Furuncular myiasis is a parasitic disease caused by the development of human botfly larva in the skin. It affects people living in tropical countries and travelers returning from these countries and concerns a number of medical specialties. One form of treatment involves surgical extraction of the parasites. PATIENTS AND METHODS: We report the case of a 47-year-old man returning from Guyana presenting two furuncle-like nodules of the skin on the right buttock and on the right shoulder blade. Extemporaneous intraoperative macroscopic examination of the buttock nodule resulted in diagnosis of myiasis caused by the human botfly, Dermatobia hominis. DISCUSSION: The diagnosis of furuncular myiasis is made primarily on clinical grounds and should be suspected on observation of an abscess in subjects returning from a tropical region. It is consequently rare to find D. hominis in biopsy specimens. In the present case, macroscopic examination showed an extremely rare image of the edge of the intact larva in a longitudinal cut, which to our knowledge has never been published to date. PMID- 26610362 TI - [Genital lichen sclerosus in boys]. PMID- 26610363 TI - A high performance, visible to mid-infrared photodetector based on graphene nanoribbons passivated with HfO2. AB - Graphene has drawn tremendous attention as a promising candidate for electronic and optoelectronic applications owing to its extraordinary properties, such as broadband absorption and ultrahigh mobility. Nevertheless, the absence of a bandgap makes graphene unfavorable for digital electronic or photonic applications. Although patterning graphene into nanostructures with the quantum confinement effect is able to open a bandgap, devices based on these graphene nanostructures generally suffer from low carrier mobility and scattering losses. In this paper, we demonstrated that encapsulation of an atomic layer deposited high-quality HfO2 film will greatly enhance the carrier mobility and decrease the scattering losses of graphene nanoribbons, because this high-k dielectric layer weakens carrier coulombic interactions. In addition, a photodetector based on HfO2 layer capped graphene nanoribbons can cover broadband wavelengths from visible to mid-infrared at room temperature, exhibiting ~10 times higher responsivity than the one without a HfO2 layer in the visible regime and ~8 times higher responsivity in the mid-infrared regime. The method employed here could be potentially used as a general approach to improve the performance of graphene nanostructures for electronic and optoelectronic applications. PMID- 26610364 TI - Progesterone supplements do not reduce risk of recurrent miscarriage, study shows. PMID- 26610366 TI - Evaluation of the long-term imprecision of the Capillarys 2 Flex Piercing(r) with serial differences in patient Hemoblogin A1c data: A comparison with two common immunoassays. AB - Since HbA1c became a diagnostic criterion for type 2 diabetes, assays measuring this analyte were required to be analytically stronger. Although precision of Sebia Capillarys 2 Flex Piercing(r) was previously evaluated with standard methods and material, we wanted to document the long-term performance of this analyzer in two different centers. DESIGN AND METHODS: In this study, we evaluated, with a non-conventional methodology, the analytical precision of the Sebia Capillarys 2 Flex Piercing(r) using HbA1c patient data and compared it with two different common commercial immunoassays. RESULTS: CV of 1.33% and 1.32% was obtained in the two centers for the electrophoretic technique compared to 2.66% and 3.92% for the Roche Cobas Integra 800(r) and Beckman Synchron DxC(r) immunoassays technique respectively. CONCLUSIONS: Our results show that capillary electrophoresis is more robust than the 2 immunoassays tested for long-term precision and even exceeds minimal requirements recommended. PMID- 26610365 TI - Choosy Wolves? Heterozygote Advantage But No Evidence of MHC-Based Disassortative Mating. AB - A variety of nonrandom mate choice strategies, including disassortative mating, are used by vertebrate species to avoid inbreeding, maintain heterozygosity and increase fitness. Disassortative mating may be mediated by the major histocompatibility complex (MHC), an important gene cluster controlling immune responses to pathogens. We investigated the patterns of mate choice in 26 wild living breeding pairs of gray wolf (Canis lupus) that were identified through noninvasive genetic methods and genotyped at 3 MHC class II and 12 autosomal microsatellite (STR) loci. We tested for deviations from random mating and evaluated the covariance of genetic variables at functional and STR markers with fitness proxies deduced from pedigree reconstructions. Results did not show evidences of MHC-based disassortative mating. Rather we found a higher peptide similarity between mates at MHC loci as compared with random expectations. Fitness values were positively correlated with heterozygosity of the breeders at both MHC and STR loci, whereas they decreased with relatedness at STRs. These findings may indicate fitness advantages for breeders that, while avoiding highly related mates, are more similar at the MHC and have high levels of heterozygosity overall. Such a pattern of MHC-assortative mating may reflect local coadaptation of the breeders, while a reduction in genetic diversity may be balanced by heterozygote advantages. PMID- 26610367 TI - [Rethinking clinical research in surgical oncology. From comic opera to quality control]. AB - The evidence base for the effectiveness of surgical interventions is relatively poor and data from large, randomized prospective studies are rare with often a poor quality. Many efforts have been made to increase the number of high quality randomized trials in surgery and theoretical proposals have been put forward to improve the situation, but practical implementation of these proposals is seriously lacking. The consequences of this policy are not trivial; with very few patients included in surgical oncology trials, this represents wasted opportunity for advances in cancer treatment. In this review, we cover the difficulties inherent to clinical research in surgical oncology, such as quality control, equipoise, accrual, and funding and promote alternative designs to the randomized controlled trial. Although the classic randomized controlled trial has a valid but limited place in surgical oncology, other prospective designs need to be promoted as a new deal. This new deal not only implicates surgeons but also journal editors, tender jury, as well as regulatory bodies to cover legal gaps currently surrounding surgical innovation. PMID- 26610368 TI - Biogeochemical gradients above a coal tar DNAPL. AB - Naturally occurring distribution and attenuation processes can keep hydrocarbon emissions from dense non aqueous phase liquids (DNAPL) into the adjacent groundwater at a minimum. In a historically coal tar DNAPL-impacted site, the de facto absence of a plume sparked investigations regarding the character of natural attenuation and DNAPL resolubilization processes at the site. Steep vertical gradients of polycyclic aromatic hydrocarbons, microbial community composition, secondary water quality and redox-parameters were found to occur between the DNAPL-proximal and shallow waters. While methanogenic and mixed electron acceptor conditions prevailed close to the DNAPL, aerobic conditions and very low dissolved contaminant concentrations were identified in three meters vertical distance from the phase. Comprehensive two-dimensional gas chromatography-mass spectrometry (GC*GC-MS) proved to be an efficient tool to characterize the behavior of the present complex contaminant mixture. Medium to low bioavailability of ferric iron and manganese oxides of aquifer samples was detected via incubation with Shewanella alga and evidence for iron and manganese reduction was collected. In contrast, 16S rDNA phylogenetic analysis revealed the absence of common iron reducing bacteria. Aerobic hydrocarbon degraders were abundant in shallow horizons, while nitrate reducers were dominating in deeper aquifer regions, in addition to a low relative abundance of methanogenic archaea. Partial Least Squares - Canonical Correspondence Analysis (PLS-CCA) suggested that nitrate and oxygen concentrations had the greatest impact on aquifer community structure in on- and offsite wells, which had a similarly high biodiversity (H' and Chao1). Overall, slow hydrocarbon dissolution from the DNAPL appears to dominate natural attenuation processes. This site may serve as a model for developing legal and technical strategies for the treatment of DNAPL-impacted sites where contaminant plumes are absent or shrinking. PMID- 26610369 TI - Spiked environmental matrix for use as a reference material for gamma-ray spectrometry: Production and homogeneity test. AB - The application of a spiking method for reference material production and its utilisation for a food matrix is presented. The raw rice powder was tested by means of gamma-ray spectrometry and spiked with a (137)Cs solution. The spiked material was mixed and tested for homogeneity. The future use of the rice powder reference material after the entire characterisation cycle will be for gamma-ray spectrometry method validation. PMID- 26610371 TI - Assessing the Validity of Automated Webcrawlers as Data Collection Tools to Investigate Online Child Sexual Exploitation. AB - The distribution of child sexual exploitation (CE) material has been aided by the growth of the Internet. The graphic nature and prevalence of the material has made researching and combating difficult. Although used to study online CE distribution, automated data collection tools (e.g., webcrawlers) have yet to be shown effective at targeting only relevant data. Using CE-related image and keyword criteria, we compare networks starting from CE websites to those from similar non-CE sexuality websites and dissimilar sports websites. Our results provide evidence that (a) webcrawlers have the potential to provide valid CE data, if the appropriate criterion is selected; (b) CE distribution is still heavily image-based suggesting images as an effective criterion; (c) CE-seeded networks are more hub-based and differ from non-CE-seeded networks on several website characteristics. Recommendations for improvements to reliable criteria selection are discussed. PMID- 26610372 TI - Three-dimensional hydrodynamic focusing microfluidic emitter: a strategy to inhibit sample ion expansion in nanoelectrospray ionization. AB - A microfluidic emitter based on three-dimensional hydrodynamic focusing was developed to generate a wrapped charged aerosol plume, in which the distribution of the sample ion in the nanoelectrospray could be regulated. Deposition patterns of the wrapped spray from the proposed three-dimensional hydrodynamic focusing nanoelectrospray emitter (3D HFNE) were collected under different conditions to ensure the wrapped configuration. Moreover, sample ion intensities as well as their ratios to a focusing background ion were studied as a function of different displacements from the center of the wrapped electrospray to confirm the inhibition of ion expansion. Furthermore, the proposed 3D HFNE indicated improved sensitivities compared with a reported nanoelectropray emitter as well as its commercial ESI counterpart, and this demonstrated its capacity for determining samples with low concentrations and infusion rates. In addition, the proposed 3D HFNE was compatible with various sample flow compositions (from 100% methanol to 100% water) and a broad infusion rate range (from 10 nL min(-1) to 15 MUL min( 1)). Finally, its stability and durability were indicated to be acceptable for various determinations. Therefore, the 3D HFNE is a potential option to achieve on-line nanoelectrospray MS determinations using microfluidics with conventional mass spectrometers, considering its low cost and user-friendly properties. PMID- 26610370 TI - Progenitor cell niches in the human pancreatic duct system and associated pancreatic duct glands: an anatomical and immunophenotyping study. AB - Pancreatic duct glands (PDGs) are tubule-alveolar glands associated with the pancreatic duct system and can be considered the anatomical counterpart of peribiliary glands (PBGs) found within the biliary tree. Recently, we demonstrated that endodermal precursor niches exist fetally and postnatally and are composed functionally of stem cells and progenitors within PBGs and of committed progenitors within PDGs. Here we have characterized more extensively the anatomy of human PDGs as novel niches containing cells with multiple phenotypes of committed progenitors. Human pancreata (n = 15) were obtained from cadaveric adult donors. Specimens were processed for histology, immunohistochemistry and immunofluorescence. PDGs were found in the walls of larger pancreatic ducts (diameters > 300 MUm) and constituted nearly 4% of the duct wall area. All of the cells identified were negative for nuclear expression of Oct4, a pluripotency gene, and so are presumably committed progenitors and not stem cells. In the main pancreatic duct and in large interlobular ducts, Sox9(+) cells represented 5-30% of the cells within PDGs and were located primarily at the bottom of PDGs, whereas rare and scattered Sox9(+) cells were present within the surface epithelium. The expression of PCNA, a marker of cell proliferation, paralleled the distribution of Sox9 expression. Sox9(+) PDG cells proved to be Pdx1(+) /Ngn3(+/-) /Oct4A(-) . Nearly 10% of PDG cells were positive for insulin or glucagon. Intercalated ducts contained Sox9(+) /Pdx1(+) /Ngn3(+) cells, a phenotype that is presumptive of committed endocrine progenitors. Some intercalated ducts appeared in continuity with clusters of insulin-positive cells organized in small pancreatic islet-like structures. In summary, PDGs represent niches of a population of Sox9(+) cells exhibiting a pattern of phenotypic traits implicating a radial axis of maturation from the bottoms of the PDGs to the surface of pancreatic ducts. Our results complete the anatomical background that links biliary and pancreatic tracts and could have important implications for the common patho-physiology of biliary tract and pancreas. PMID- 26610373 TI - Mutations in WNT9B are associated with Mayer-Rokitansky-Kuster-Hauser syndrome. AB - Mayer-Rokitansky-Kuster-Hauser syndrome (MRKHS) is a well-known malformation pattern of the Mullerian ducts (MDs) characterized by congenital absence of the uterus and vagina. To date, most cases remain unexplained at molecular level. As female Wnt9b-/- mice show a MRKHS-like phenotype, WNT9B has emerged as a promising candidate gene for this disease. We performed retrospective sequence analyses of WNT9B in 226 female patients with disorders of the MDs, including 109 patients with MRKHS, as well as in 135 controls. One nonsense mutation and five likely pathogenic missense mutations were detected in WNT9B. Five of these mutations were found in cases with MRKHS accounting for 4.6% of the patients with this phenotype. No pathogenic mutations were detected in the control group (p = 0.017). Interestingly, all of the MRKHS patients with a WNT9B mutation were classified as MRKHS type 1, representing 8.5% of the cases from this subgroup. In previous studies, two of the patients with a WNT9B mutation were found to carry either an additional deletion of LHX1 or a missense mutation in TBX6. We conclude that mutations in WNT9B were frequently associated with MRKHS in our cohort and some cases may be explained by a digenic disease model. PMID- 26610374 TI - Direct observation of titanium-centered octahedra in titanium-antimony-tellurium phase-change material. AB - Phase-change memory based on Ti0.4Sb2Te3 material has one order of magnitude faster Set speed and as low as one-fifth of the Reset energy compared with the conventional Ge2Sb2Te5 based device. However, the phase-transition mechanism of the Ti0.4Sb2Te3 material remains inconclusive due to the lack of direct experimental evidence. Here we report a direct atom-by-atom chemical identification of titanium-centered octahedra in crystalline Ti0.4Sb2Te3 material with a state-of-the-art atomic mapping technology. Further, by using soft X-ray absorption spectroscopy and density function theory simulations, we identify in amorphous Ti0.4Sb2Te3 the titanium atoms preferably maintain the octahedral configuration. Our work may pave the way to more thorough understanding and tailoring of the nature of the Ti-Sb-Te material, for promoting the development of dynamic random access memory-like phase-change memory as an emerging storage class memory to reform current memory hierarchy. PMID- 26610375 TI - ECG monitoring: One step closer to the modernization of the delivery room. PMID- 26610376 TI - Stent thrombosis after primary percutaneous coronary intervention in comatose survivors of out-of-hospital cardiac arrest: Are the new P2Y12 inhibitors really more effective than clopidogrel? AB - AIM: High rates of stent thrombosis (ST) have been reported in patients with out of-hospital cardiac arrest (OHCA) who require a primary percutaneous coronary intervention (PCI). The aim of this study was to assess risk factors of ST in this population with a special focus on antiplatelet therapy administered during the acute phase. MATERIALS AND METHODS: We conducted a retrospective observational study in patients treated with primary PCI after OHCA between 2011 and 2013 in our center. All consecutive patients were treated with mild therapeutic hypothermia and dual antiplatelet therapy after primary angioplasty. RESULTS: A total of 101 consecutive patients were included in the present analysis. Mean age was 61.3 +/- 12.7 years and 75% of patients had an initial ventricular fibrillation. All patients received aspirin before PCI. P2Y12 inhibitors were administered after PCI and included clopidogrel (47.5%), prasugrel (21.8%) or ticagrelor (29.7%). The survival rate at discharge was 44.5%. We identified 11 cases (10.9%) of definite or probable ST (clopidogrel (n=2), prasugrel (n=4) and ticagrelor (n=5)) occurring at a median of 2 days after PCI. No specific predictors were found to be significantly associated with ST. New P2Y12 inhibitors were associated with more ST compared to clopidogrel (17.3% vs. 4.2%; respectively, p=0.05). ST was associated with a decreased left ventricular ejection fraction (p=0.007) and with a trend toward a higher mortality compared to patients without ST (82% vs. 52%, p=0.06). CONCLUSION: The incidence of ST in OHCA survivors is high and associated with poor clinical outcome. The use of new oral P2Y12 inhibitors does not appear to be associated with a reduction in ST compared to clopidogrel. PMID- 26610377 TI - Comparison of complications secondary to cardiopulmonary resuscitation between out-of-hospital cardiac arrest and in-hospital cardiac arrest. AB - OBJECTIVE: The aim of this study was to assess whether there was a significant difference in the complications of cardiopulmonary resuscitation (CPR) between out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA) survivors using multidetector computed tomography (MDCT). SUBJECTS AND METHODS: We performed a retrospective analysis of prospective registry data. We enrolled both OHCA and IHCA patients who underwent successful CPR. We classified chest injuries secondary to chest compression into rib fractures, sternum fractures, and uncommon complications such as lung contusions and extrathoracic complications. We compared these complications according to CPR locations. We also analysed risk factors for CPR complications using multiple regression analysis and classification and regression tree analysis. RESULTS: During the study period, a total of 148 patients were included in the primary analysis. Rib fractures were detected more in OHCA survivors than in IHCA survivors (74 patients (83.2%) vs. 37 patients (62.7%), p=0.05), and frequency of multiple rib fractures was higher in OHCA survivors than IHCA survivors (69 patients (77.5%) vs. 34 patients (57.6%), p=0.01). Although other complications were not significantly different between the groups, there was a trend for OHCA survivors to sustain more serious and direct high-energy related complications. Older age, longer CPR, and OHCA were significantly associated with incidence of rib fractures, multiple rib fractures, and number of rib fractures. CONCLUSIONS: Rib fractures were more likely to occur in OHCA survivors, and serious complications tended to occur more often in OHCA compared to IHCA survivors. PMID- 26610378 TI - The Role of Curcumin Administration in Patients with Major Depressive Disorder: Mini Meta-Analysis of Clinical Trials. AB - Major depression is a common, recurrent, and chronic disease that negatively affects the quality of life and increases the risk of mortality. Several studies have demonstrated that curcumin, the yellow-pigmented substance of the turmeric, possesses antidepressant properties. The aim of this review is to meta analytically assess the antidepressant effect of curcumin in patients with major depressive disorders. We extensively searched the literature until August 2015. The random-effect model was used to calculate the pooled standardized difference of means (SMD). Subgroup analyses were also performed to examine the effect of different study characteristics on the overall model. Six clinical trials met the inclusion criteria. Overall, curcumin administration showed a significantly higher reduction in depression symptoms [SMD = -0.34; 95% confidence interval (CI) = -0.56, -0.13; p = 0.002]. Subgroup analyses showed that curcumin had the highest effect when given to middle-aged patients (SMD = -0.36; 95% CI = -0.59; 0.13; p = 0.002), for longer duration of administration (SMD = -0.40; 95% CI = 0.64, -0.16; p = 0.001), and at higher doses (SMD = -0.36; 95% CI = -0.59, -0.13; p = 0.002). The administration of new formulation of curcumin (BCM-95) had non significantly higher effect on depression as compared with the conventional curcumin-piperine formula. We conclude that there is supporting evidence that curcumin administration reduces depressive symptoms in patients with major depression. PMID- 26610380 TI - Phosphorylation of JNK Increases in the Cortex of Rat Subjected to Diabetic Cerebral Ischemia. AB - Previous studies have demonstrated that the c-Jun N-terminal kinase (JNK) pathway plays an important role in inducing neuronal apoptosis following cerebral ischemic injury. JNK signaling pathway in activated during cerebral ischemic injury. It participates in ischemia-induced neuronal apoptosis. However, whether JNK signaling is involved in the process of neuronal apoptosis of diabetes induced cerebral ischemia is largely unknown. This study was undertaken to evaluate the influence of cerebral ischemia-reperfusion injury on phosphorylation of JNK in diabetic rats. Twenty-four adult streptozotocin induced diabetic and 24 adult non-diabetic rats were randomly subjected to 15 min of forebrain ischemia followed by reperfusion for 0, 1, 3, and 6 h. Sixteen sham-operated diabetic and non-diabetic rats were used as controls. Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL). Protein expression of phospho-JNK was examined by immunohistochemistry and Western blot. The numbers of TUNEL-positive cells and phospho-JNK protein expression in the cerebral cortices after 1, 3 and 6 h reperfusion was significantly higher in diabetic rats compared to non-diabetic animals subjected to ischemia and reperfusion (p < 0.05). Western blot analysis showed significantly higher phospho JNK protein expression in the cerebral cortices of the diabetic rats after 1 and 3 h reperfusion than that was presented in non-diabetic animals subjected to ischemia and reperfusion (p < 0.05). These findings suggest that increased phosphorylation of JNK may be associated with diabetes-enhanced ischemic brain damage. PMID- 26610381 TI - 2,8-Decadiene-1,10-Diol Inhibits Lipopolysaccharide-Induced Inflammatory Responses Through Inactivation of Mitogen-Activated Protein Kinase and Nuclear Factor-kappaB Signaling Pathway. AB - Amomum tsao-ko (A. tsao-ko) has been used as a traditional medicine for the treatment of infectious and digestive disorders. In the present study, we report the anti-inflammatory activity and molecular mechanism of 2,8-decadiene-1,10-diol (DDO) isolated from the extract of A. tsao-ko in lipopolysaccharide-stimulated RAW 264.7 cells. DDO treatment inhibited the production of nitric oxide and prostaglandin E2 by downregulating inducible nitric oxide synthase and cyclooxygenase-2 expression, respectively. Moreover, DDO suppressed the production of pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha. These inhibitory effects of DDO on the expression of inflammatory proteins were found to be mediated through the inactivation of mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase, c-Jun-N terminal kinase and p38(MAPK), and inhibition of nuclear factor-kappaB (NF kappaB) pathways including degradation of inhibitor of kappaB-alpha and nuclear localization of NF-kappaB. Taken together, these findings demonstrate the pharmacological roles and molecular mechanisms of DDO in regulating inflammatory responses, and suggest further evaluation and development of DDO as a potent therapeutic agent for the treatment of inflammatory disorders. PMID- 26610382 TI - Quantitative Gene Expression by Recurrence Score in ER-Positive Breast Cancer, by Age. AB - INTRODUCTION: Breast cancer in young women (<50 years) has been associated with an increased risk of recurrence and decreased survival compared with patients older than 50. The objective of this analysis was to determine, from a large database of patients with early-stage breast cancer, if the Recurrence Score((r)) result (Oncotype DX((r)), Genomic Health, Inc, Redwood City, CA, USA) provided clinically meaningful differences in predicted risk of recurrence in younger compared with older-patients. METHODS: Tumor samples from patients with estrogen receptor (ER)-positive breast cancers that were successfully processed in the Genomic Health central lab between June 2004 and December 2013 for Recurrence Score and quantitative gene expression of ER, progesterone receptor (PR), and Her/2neu, were included. Descriptive statistics were used to describe the distribution of scores by age group: <40, 40-49, 50-59, 60-69, and >=70 years, nodal status, and histologic subtype. RESULTS: Specimens from 394,031 patients [3.3% (n = 13,029) aged <40 years; 15.6% (n = 61,643) aged >=70 years] were included; 81.6% of patients had invasive ductal carcinoma. Nodal status was specified for 362,001 patients (87.0% negative). Median Recurrence Score results were similar across risk groups. Low (<18)- and high (>=31)- risk Recurrence Score results were seen in 58.5% and 8.5% of patients, respectively. A greater proportion of patients aged <40 (14.1%) than >=70 (8.8%) years had a high-risk score. ER expression increased as a function of age and PR single-gene and invasion gene group expression were similar across age groups. CONCLUSION: These data indicate that in patients with ER-positive breast cancer, age alone does not reflect the underlying individual tumor biology, suggesting that the Recurrence Score result may add potentially useful information for personalized treatment decisions. FUNDING: Genomic Health, Inc. PMID- 26610383 TI - A Prospective Comparison of the 21-Gene Recurrence Score and the PAM50-Based Prosigna in Estrogen Receptor-Positive Early-Stage Breast Cancer. AB - INTRODUCTION: The 21-gene Recurrence Score((r)) assay (Oncotype DX((r)), Genomic Health, Inc.) is a validated predictor of recurrence risk/chemotherapy benefit in patients with estrogen receptor-positive (ER+) early-stage breast cancer treated with endocrine therapy. The Prosigna((r)) assay (NanoString Technologies Inc.) is a validated prognosticator in postmenopausal patients with low-risk ER+ early stage breast cancer treated with endocrine therapy. The assays were analytically/clinically developed and validated differently. This study focused on comparing recurrence risk estimates as determined by these assays and is the first blinded comparison of these assays on matched patient samples. METHODS: Sequential breast cancer specimens from postmenopausal, node-negative, ER+ patients treated at the Marin General Hospital were analyzed: first by the 21 gene assay then by the Prosigna assay in an independent lab blinded to the Recurrence Score results. RESULTS: The final analysis included 52 patients. Correlation between the Recurrence Score and the Prosigna assay results was poor (r = 0.08). Agreement between risk classifications based on these assays was 54%; 4/7 of patients classified as high risk by the Prosigna assay had low Recurrence Score results. Two tumors with high Recurrence Score results had low ER expression (close to positivity threshold); both of which had a low/intermediate Prosigna assay result. The Prosigna assay classified 73.1% and 23.1% of samples as luminal A and luminal B, respectively. A range of Recurrence Score results was observed within the subtypes; 83% of luminal B samples had a low Recurrence Score result. CONCLUSION: Consistent with prior comparisons between the 21-gene and other genomic assays, our study demonstrated substantial differences in the way patients are risk stratified, suggesting that the different assays are not interchangeable. FUNDING: Genomic Health, Inc. PMID- 26610384 TI - Evaluation of Effectiveness and Safety of High-Dose Daptomycin: Results from Patients Included in the European Cubicin((r)) Outcomes Registry and Experience. AB - INTRODUCTION: Daptomycin, a rapid concentration-dependent bactericidal antibiotic, is approved at a dose of 4 mg/kg/day for the treatment of complicated skin and soft tissue infections (cSSTI) and at a dose of 6 mg/kg/day for the treatment of Staphylococcus aureus right-sided infective endocarditis (RIE) and bacteremia associated with cSSTI and RIE. Studies have reported the successful use of high-dose daptomycin (>6 mg/kg/day) in patients with difficult-to-treat infections. The present analysis evaluated the effectiveness and safety of high doses (>6 mg/kg/day) of daptomycin for the treatment of different Gram-positive infections. METHODS: European Cubicin((r)) Outcomes Registry and Experience (EU CORE) is a non-interventional, multicenter, retrospective, patient registry designed to collect real-world data from patients treated with daptomycin between 2006 and 2012. Clinical outcomes were assessed at the end of daptomycin treatment for three dose groups: <=6, >6 to <8, and >=8 mg/kg/day. Safety was assessed for up to 30 days post-daptomycin treatment. RESULTS: Of the 6075 patients enrolled in EU-CORE, 4892 patients received daptomycin doses <=6 mg/kg/day, while 1097 patients received high doses (>6 mg/kg/day). The primary infections with the largest proportion of patients treated with a high dose (>6 mg/kg/day) were osteomyelitis (37.1%), foreign body/prosthetic infection (31.6%), and endocarditis (27.6%). S. aureus was identified in 42.9% of patients with positive cultures treated with either <=6 or >6 mg/kg/day. The overall clinical success rate was 82.0% (899/1097) with high doses (>6 mg/kg/day) and 80.3% (3928/4890) with doses <=6 mg/kg/day. Numerically higher clinical success rate was observed for endocarditis and foreign body/prosthetic infection, as well as for coagulase negative staphylococcal and enterococcal infections, with high-dose daptomycin treatment. There were no new or unexpected safety findings at doses >6 mg/kg/day. CONCLUSION: These results suggested that daptomycin at doses >6 mg/kg/day was effective and well tolerated. High-dose daptomycin is a potential therapeutic option in patients with difficult-to-treat Gram-positive infections. FUNDING: This study was funded by Novartis Pharma AG. PMID- 26610385 TI - Early identification of adverse drug reactions from search log data. AB - The timely and accurate identification of adverse drug reactions (ADRs) following drug approval is a persistent and serious public health challenge. Aggregated data drawn from anonymized logs of Web searchers has been shown to be a useful source of evidence for detecting ADRs. However, prior studies have been based on the analysis of established ADRs, the existence of which may already be known publically. Awareness of these ADRs can inject existing knowledge about the known ADRs into online content and online behavior, and thus raise questions about the ability of the behavioral log-based methods to detect new ADRs. In contrast to previous studies, we investigate the use of search logs for the early detection of known ADRs. We use a large set of recently labeled ADRs and negative controls to evaluate the ability of search logs to accurately detect ADRs in advance of their publication. We leverage the Internet Archive to estimate when evidence of an ADR first appeared in the public domain and adjust the index date in a backdated analysis. Our results demonstrate how search logs can be used to detect new ADRs, the central challenge in pharmacovigilance. PMID- 26610386 TI - Reduced activity in functional networks during reward processing is modulated by abstinence in cocaine addicts. AB - Cocaine addiction is characterized by alterations in motivational and cognitive processes. Recent studies have shown that some alterations present in cocaine users may be related to the activity of large functional networks. The aim of this study was to investigate how these functional networks are modulated by non drug rewarding stimuli in cocaine-dependent individuals. Twenty abstinent cocaine dependent and 21 healthy matched male controls viewed erotic and neutral pictures while undergoing a functional magnetic resonance imaging scan. Group independent component analysis was then performed in order to investigate how functional networks were modulated by reward in cocaine addicts. The results showed that cocaine addicts, compared with healthy controls, displayed diminished modulation of the left frontoparietal network in response to erotic pictures, specifically when they were unpredicted. Additionally, a positive correlation between the length of cocaine abstinence and the modulation of the left frontoparietal network by unpredicted erotic images was found. In agreement with current addiction models, our results suggest that cocaine addiction contributes to reduce sensitivity to rewarding stimuli and that abstinence may mitigate this effect. PMID- 26610379 TI - In Vivo NMR Studies of the Brain with Hereditary or Acquired Metabolic Disorders. AB - Metabolic disorders, whether hereditary or acquired, affect the brain, and abnormalities of the brain are related to cellular integrity; particularly in regard to neurons and astrocytes as well as interactions between them. Metabolic disturbances lead to alterations in cellular function as well as microscopic and macroscopic structural changes in the brain with diabetes, the most typical example of metabolic disorders, and a number of hereditary metabolic disorders. Alternatively, cellular dysfunction and degeneration of the brain lead to metabolic disturbances in hereditary neurological disorders with neurodegeneration. Nuclear magnetic resonance (NMR) techniques allow us to assess a range of pathophysiological changes of the brain in vivo. For example, magnetic resonance spectroscopy detects alterations in brain metabolism and energetics. Physiological magnetic resonance imaging (MRI) detects accompanying changes in cerebral blood flow related to neurovascular coupling. Diffusion and T1/T2 weighted MRI detect microscopic and macroscopic changes of the brain structure. This review summarizes current NMR findings of functional, physiological and biochemical alterations within a number of hereditary and acquired metabolic disorders in both animal models and humans. The global view of the impact of these metabolic disorders on the brain may be useful in identifying the unique and/or general patterns of abnormalities in the living brain related to the pathophysiology of the diseases, and identifying future fields of inquiry. PMID- 26610388 TI - Neuronal network activity in the hippocampus of tau transgenic (Tg4510) mice. AB - Development of neurofibrillary tangles in Alzheimer's disease correlates with neuronal loss and dementia. Transgenic Tg4510 mice model the tauopathy of the disease, with these mice exhibiting progressive, region-specific neuronal loss, and behavioral deficits. In the present study, neuronal network activity in the hippocampus of 7-month-old Tg4510 mice was investigated and compared with age matched wild-type (WT) mice. Multisite field potentials were recorded using 16 site silicon probes, inserted across the hippocampus in urethane anesthetized mice. The hippocampal network theta oscillation was evaluated in these mice by stimulating the brainstem nucleus pontis oralis. Subsequently, population spikes in the dentate gyrus were identified in response to perforant path stimulation, and long-term potentiation was elicited by theta burst stimulation. Tg4510 mice showed dramatically reduced dentate gyrus population spike amplitude; however, the magnitude of theta burst stimulation-induced long-term potentiation was identical in WT and transgenic mice. WT and Tg4510 mice showed identical increase in frequency to nucleus pontis oralis stimulation, whereas absolute theta power was severely reduced in the Tg4510 animals. Because total signal power over the entire frequency band range was reduced, there was no difference in relative theta power between WT and Tg4510 mice. These presently described electrophysiological findings can be directly attributed to the drastic reduction of pyramidal/granule neurons in Tg4510 mice, which could be the main contributing factor to their impaired behavior and cognitive function. However, the remaining synapses and neuronal circuitry seem to function properly in these assays. PMID- 26610387 TI - Initiation of calorie restriction in middle-aged male rats attenuates aging related motoric decline and bradykinesia without increased striatal dopamine. AB - Aging-related bradykinesia affects ~ 15% of those reaching age 65 and 50% of those reaching their 80s. Given this high risk and lack of pharmacologic therapeutics, noninvasive lifestyle strategies should be identified to diminish its risk and identify the neurobiological targets to reduce aging-related bradykinesia. Early-life, long-term calorie restriction (CR) attenuates aging related bradykinesia in rodents. Here, we addressed whether CR initiation at middle age could attenuate aging-related bradykinesia and motoric decline measured as rotarod performance. A 30% CR regimen was implemented for 6 months duration in 12-month-old male Brown-Norway Fischer 344 F1 hybrid rats after establishing individual baseline locomotor activities. Locomotor capacity was assessed every 6 weeks thereafter. The ad libitum group exhibited predictably decreased locomotor activity, except movement speed, out to 18 months of age. In contrast, in the CR group, movement number and horizontal activity did not decrease during the 6-month trial, and aging-related decline in rotarod performance was attenuated. The response to CR was influenced by baseline locomotor activity. The lower the locomotor activity level at baseline, the greater the response to CR. Rats in the lower 50th percentile surpassed their baseline level of activity, whereas rats in the top 50th percentile decreased at 6 weeks and then returned to baseline by 12 weeks of CR. We hypothesized that nigrostriatal dopamine tissue content would be greater in the CR group and observed a modest increase only in substantia nigra with no group differences in striatum, nucleus accumbens, or ventral tegmental area. These results indicate that initiation of CR at middle age may reduce aging-related bradykinesia, and, furthermore, subjects with below average locomotor activity may increase baseline activity. Sustaining nigral dopamine neurotransmission may be one component of preserving locomotor capabilities during aging. PMID- 26610389 TI - Mobile application as a prenatal education and engagement tool: A randomized controlled pilot. AB - OBJECTIVES: Research has shown that mobile applications provide a powerful alternative to traditional paper diaries; however, little data exists in comparing apps to the traditional mode of paper as a patient education and engagement tool in the clinical setting. This study was designed to compare the effectiveness of a mobile app versus a spiral-notebook guide throughout prenatal care. METHODS: This randomized (n=173) controlled pilot was conducted at an East Coast community hospital. Chi-square and repeated-measures analysis of variance was used to test intervention effects in the sample of 127 pregnant mothers who completed their prenatal care in the healthcare system. RESULTS: Patients who were distributed the mobile application used the tool to record information about pregnancy more frequently (p=.04) and developed greater patient activation (p=.02) than patients who were distributed notebooks. No difference was detected on interpersonal clinical communication. CONCLUSION: A mobile application successfully activated a patient population in which self-management is a critical factor. PRACTICE IMPLICATIONS: This study shows that mobile apps can prompt greater use and result in more activated patients. Findings may be translated to other patient populations who receive recurring care for chronic disease. PMID- 26610390 TI - Development, pilot testing and psychometric validation of a short version of the coronary artery disease education questionnaire: The CADE-Q SV. AB - OBJECTIVE: To develop, pilot test and psychometrically validate a shorter version of the coronary artery disease education questionnaire (CADE-Q), called CADE-Q SV. METHODS: Based on previous versions of the CADE-Q, cardiac rehabilitation (CR) experts developed 20 items divided into 5 knowledge domains to comprise the first version of the CADE-Q SV. To establish content validity, they were reviewed by an expert panel (N=12). Refined items were pilot-tested in 20 patients, in which clarity was provided. A final version was generated and psychometrically tested in 132CR patients. Test-retest reliability was assessed via the intraclass correlation coefficient (ICC), the internal consistency using Cronbach's alpha, and criterion validity with regard to patients' education and duration in CR. RESULTS: All ICC coefficients meet the minimum recommended standard. All domains were considered internally consistent (alpha>0.7). Criterion validity was supported by significant differences in mean scores by educational level (p<0.01) and duration in CR (p<0.05). Knowledge about exercise and nutrition was higher than knowledge about medical condition. CONCLUSION: The CADE-Q SV was demonstrated to have good reliability and validity. PRACTICE IMPLICATIONS: This is a short, quick and appropriate tool for application in clinical and research settings, assessing patients' knowledge during CR and as part of education programming. PMID- 26610391 TI - Modifying beliefs about back pain: A pilot study among healthcare professionals. AB - OBJECTIVES: This study aimed to explore whether a preventive intervention based on the non-injury model and the biopsychosocial model of back pain succeeded in shifting beliefs toward less negative representations and in decreasing fear avoidance beliefs related to back pain. METHODS: One hundred and one healthcare professionals took part in a 10-h educational program held over 2 consecutive days, based on the key messages of the "Back Book." Baseline values were measured 6 weeks before the intervention and when it started. Follow-up was performed at the end of the intervention and six months later. RESULTS: No significant changes were observed between baseline values and values measured at the beginning of the intervention, but participants' beliefs about LBP changed significantly after the program. The benefit remained at 6 months follow-up. CONCLUSION: A prevention program based on the non-injury and bio-psychosocial models of LBP, introducing empowerment and problem-solving strategies, significantly reduced fear-avoidance and negative beliefs about LBP. The change was clinically relevant and thus could decrease direct and indirect healthcare costs. PMID- 26610393 TI - Co-administration of morphine and gabapentin leads to dose dependent synergistic effects in a rat model of postoperative pain. AB - Despite much evidence that combination of morphine and gabapentin can be beneficial for managing postoperative pain, the nature of the pharmacological interaction of the two drugs remains unclear. The aim of this study was to assess the interaction of morphine and gabapentin in range of different dose combinations and investigate whether co-administration leads to synergistic effects in a preclinical model of postoperative pain. The pharmacodynamic effects of morphine (1, 3 and 7mg/kg), gabapentin (10, 30 and 100mg/kg) or their combination (9 combinations in total) were evaluated in the rat plantar incision model using an electronic von Frey device. The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on Loewe additivity response surface analyses. The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects in a preclinical model of postoperative pain. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response ranged between 26 and 58% for the synergistic doses. The finding of dose-dependent synergistic effects highlights that choosing the right dose-dose combination is of importance in postoperative pain therapy. Our results indicate benefit of high doses of gabapentin as adjuvant to morphine. If these findings translate to humans, they might have important implications for the treatment of pain in postoperative patients. PMID- 26610394 TI - Functionalized alkynyl-chlorogermanes: hydrometallation, Ge-Cl bond activation, Ge-H bond formation and chlorine-tert-butyl exchange via a transient germyl cation. AB - Treatment of alkynyl-arylchlorogermanes ArylnGe(Cl)(C[triple bond, length as m dash]C-(t)Bu)3-n (n = 1, 2) with HM(t)Bu2 (M = Al, Ga) yielded mixed Al or Ga alkenyl-alkynylchlorogermanes via hydrometallation reactions. Intramolecular interactions between the Lewis-basic Cl atoms and the Lewis-acidic Al or Ga atoms afforded MCGeCl heterocycles. The endocyclic M-Cl distances were significantly lengthened compared to the starting compounds and indicated Ge-Cl bond activation. Dual hydrometallation succeeded only with HGa(t)Bu2. One Ga atom of the product was involved in a Ga-Cl bond, while the second one had an interaction to a C-H bond of a phenyl group. In two cases treatment of chlorogermanes with two equivalents of HAl(t)Bu2 resulted in hydroalumination of one alkynyl group and formation of unprecedented Ge-H functionalized germanes, Aryl-Ge(H)(C[triple bond, length as m-dash]C-(t)Bu)[C(Al(t)Bu2)[double bond, length as m-dash]C(H) (t)Bu] (Aryl = mesityl, triisopropylphenyl). The Al atoms of these compounds interacted with the alpha-C atoms of the alkynyl groups. Ph(Cl)Ge(C[triple bond, length as m-dash]C-(t)Bu)[C(Al(t)Bu2}[double bond, length as m-dash]C(H)-(t)Bu] reacted in an unusual Cl/(t)Bu exchange to yield the tert-butylgermane Ph((t)Bu)Ge(C[triple bond, length as m-dash]C-(t)Bu)[C{Al((t)Bu)(Cl)}[double bond, length as m-dash]C(H)-(t)Bu]. Quantum chemical calculations suggested the formation of a germyl cation as a transient intermediate. PMID- 26610392 TI - Functional analysis of the 11q23.3 glioma susceptibility locus implicates PHLDB1 and DDX6 in glioma susceptibility. AB - Glioma is the most common malignant primary brain tumor and is associated with poor prognosis. Genetic factors contributing to glioma risk have recently been investigated through genome-wide association studies (GWAS), implicating seven independent glioma risk loci in six chromosomal regions. Here, we performed an in depth functional analysis of the risk locus proximal to the PHLDB1 gene on 11q23.3. We retrieved all SNPs in linkage disequilibrium (r(2) >= 0.2) with the glioma-associated SNP (rs498872) and performed a comprehensive bioinformatics and experimental functional analysis for the region. After testing candidate SNPs for allele-specific activity in a luciferase-based enhancer scanning assay, we established a subset of 10 functional SNPs in the promoters of PHLDB1 and DDX6, and in a putative enhancer element. Chromatin conformation capture (3C) identified a physical interaction between the enhancer element containing a functional SNP (rs73001406) and the promoter of the DDX6 gene. Knockdown experiments in cell culture and 3D assays to evaluate the role of PHLDB1 and DDX6 suggest that both genes may contribute to the phenotype. These studies reveal the functional landscape of the 11q23.3 glioma susceptibility locus and identify a network of functional SNPs in regulatory elements and two target genes as a possible mechanism driving glioma risk association. PMID- 26610395 TI - Relevance of saddle-splay elasticity in complex nematic geometries. AB - We demonstrate the relevance of saddle-splay elasticity in nematic liquid crystalline fluids in the context of complex surface anchoring conditions and the complex geometrical confinement. Specifically, nematic cells with patterns of surface anchoring and colloidal knots are shown as examples where saddle-splay free energy contribution can have a notable role which originates from nonhomogeneous surface anchoring and the varying surface curvature. Patterned nematic cells are shown to exhibit various (meta)stable configurations of nematic field, with relative (meta)stability depending on the saddle-splay. We show that for high enough values of saddle-splay elastic constant K24 a previously unstable conformation can be stabilised, more generally indicating that the saddle-splay can reverse or change the (meta)stability of various nematic structures affecting their phase diagrams. Furthermore, we investigate saddle-splay elasticity in the geometry of highly curved boundaries - the colloidal particle knots in nematic - where the local curvature of the particles induces complex spatial variations of the saddle-splay contributions. Finally, a nematic order parameter tensor based saddle-splay invariant is shown, which allows for the direct calculation of saddle-splay free energy from the Q-tensor, a possibility very relevant for multiple mesoscopic modelling approaches, such as Landau-de Gennes free energy modelling. PMID- 26610396 TI - In vitro metabolism of the cyanotoxin cylindrospermopsin in HepaRG cells and liver tissue fractions. AB - No evidence for phase I metabolites of the cyanotoxin cylindrospermopsin (CYN) was given using HepaRG cells and different liver tissue fractions when studying metabolic conversion. Although the application of ketoconazole, a CYP3A4 inhibitor, led to a decreased cytotoxicity of CYN, no metabolites were detected applying high resolution mass spectrometry. Quantification of non-modified CYN led to recovery rates of almost 100%. Consequently, reduction of CYN toxicity in the presence of metabolism inhibiting agents must be attributed to alternative pathways. PMID- 26610397 TI - Increased inflammation in rheumatoid arthritis patients living where farm soils contain high levels of copper. AB - BACKGROUND/PURPOSE: Heavy metal pollution in farm soils is a problem in some parts of Taiwan. Copper can be a factor associated with increased disease activities of rheumatoid arthritis (RA). Thus, the aim of this study was to investigate whether copper pollution in farm soils is associated with worsened RA. METHODS: Clinical parameters from 122 RA patients were collected from a medical center in central Taiwan. Levels of heavy metals in the blood were measured using inductively coupled plasma mass spectrometry. Levels of copper in farm soils were retrieved from a national survey. These data were analyzed to find the factors related to RA disease activities. RESULTS: RA patients living where farm soils contained high levels of copper had increased white blood cell counts, erythrocyte sedimentation rate, and disease activity score 28, compared with patients living where copper levels were low. Among the nine types of heavy metal measured in the study, blood levels of copper and nickel correlated with erythrocyte sedimentation rate. CONCLUSION: Our cross-sectional data suggest a correlation between RA disease activity and the level of copper at township farm soils samples. Further longitudinal studies using more rigorous methodologies are warranted to examine whether this correlation is causal. PMID- 26610398 TI - Activation of NLRP3 inflammasome in human neutrophils by Helicobacter pylori infection. AB - TLRs and NLRs participate in the immune system recognition of Helicobacter pylori. However, little is known about the mechanisms leading to inflammasome activation by H. pylori and if NLRs in neutrophils are involved in the process. We studied how NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome components are involved in IL-1beta maturation in human neutrophils in response to the infection and if they are dependent on T4SS (type IV secretion system) and TLRs. Human neutrophils were cultured and infected with the 26695 or the VirD4- H. pylori strains; the IL-1beta concentration was analyzed by ELISA, and we also evaluated the activation of TLRs 2 and 4. The infection of neutrophils with both strains of H. pylori induced production of IL-1beta and expression of the NLRP3 inflammasome components such as apoptosis-associated speck-like protein with CARD domain and NLRP3 protein. The infection also increased the activity of caspase-1, which is required for the maturation of IL 1beta. Our study shows, for the first time, that H. pylori infection induces the expression and activation of components of NLRP3 inflammasomes in human neutrophils and that the activation is independent of a functional T4SS and TLR2 and TLR4. PMID- 26610399 TI - Motives for Vulvar Surgery of Women with Lichen Sclerosus. AB - INTRODUCTION: Women with lichen sclerosus (LS) may experience (superficial) dyspareunia or the inability to have vaginal intercourse due to painful fissures and narrowing of the vaginal introitus. A surgical procedure may contribute to the relief of these sexual pain problems. It is unknown what motives women have to undergo surgery in order to regain the ability to have sexual intercourse. Such knowledge can offer important insights that are indispensable when discussing the option of vulvar surgery with patients with LS and might prevent potential patient dissatisfaction. This study's purpose is to examine why women with LS decide to undergo vulvar surgery in order to restore intercourse. METHODS: Nineteen women with anogenital LS participated in audiotaped qualitative individual interviews, in which their motives for undergoing vulvar surgery to restore intercourse were explored retrospectively. Interview data were analyzed using the constant comparative method. RESULTS: Three main motives for wanting to undergo surgery in order to restore intercourse were found. These were the desire to be a "normal" woman, the desire to sexually satisfy the male partner, and the desire to regain the experience of intimacy and sexual enjoyment. Another reason for surgery was to reduce daily life LS symptoms. The sexual pain complaints prevented the women from living up to their norms about heterosexuality and gender roles. Being unable to have intercourse led women to feel inadequate as a woman and as a sexual partner. CONCLUSIONS: Women with LS may opt for surgery to restore their identity as a "normal" woman and sexual partner, to regain the experience of coital intimacy, and to be less bothered by LS symptoms in daily life. The present findings point to the importance of a thorough couple-based sexual history in which women's motives for and expectations of vulvar surgery will be explored in order to facilitate a good decision and to increase treatment satisfaction. PMID- 26610400 TI - Dendrimer porphyrin-coated gold nanoshells for the synergistic combination of photodynamic and photothermal therapy. AB - A dendrimer porphyrin (DP)-coated gold nanoshell (AuNS-DP) was prepared for the synergistic combination of photodyanmic and photothermal therapy. The resultant AuNS-DP successfully exhibited the generation of reactive oxygen species (ROS) as well as photothermal effect for the simultaneous application of photodynamic therapy (PDT) and photothermal therapy (PTT). PMID- 26610402 TI - Risk of diabetes in combined metabolic abnormalities and body mass index categories. AB - AIM: The present study was designed to estimate the progression rates from combination of normal weight, overweight, obesity, and number of metabolic abnormalities (MA) to type 2 diabetes (T2D) in a non-diabetic high risk population in Isfahan, Iran. METHODS: A total of 1869 non-diabetic first-degree relatives (FDR) of patients with T2D 30-70 years old were examined and followed for a mean (SD) of 7.3 (2.2) years for T2D incidence. At baseline and through follow-up, participants underwent a standard 75-g 2-h oral glucose tolerance test. RESULTS: The metabolically healthy overweight and obese at baseline were associated with incidence of T2D, independently of age and gender. Any one MA increased the risk of developing T2D among normal weight, overweight and obese individuals. Those with normal weight and >=3 MA were over 20 times (odds ratios (OR) 20.21; 95% confidence intervals (CI) 2.4, 170.4) and those with overweight and >=3 MA 22.5 times (OR 22.5; 95% CI 3.0, 167.0) and obese with >=3 MA were 25.4 times (OR 25.4; 95% CI 3.4, 187) more likely to develop T2D than those with normal weight and without MA. Compared with participants without MA, obese individuals with concomitant MA were not significantly more likely to progress to T2D. CONCLUSION: Our data provide further evidence that normal weight, overweight and obese individuals with MA had a higher risk of incident T2D than normal weight individuals without MA. PMID- 26610401 TI - Bioavailability and metabolism of benzyl glucosinolate in humans consuming Indian cress (Tropaeolum majus L.). AB - SCOPE: Benzyl isothiocyanate (BITC), which occurs in Brassicales, has demonstrated chemopreventive potency and cancer treatment properties in cell and animal studies. However, fate of BITC in human body is not comprehensively studied. Therefore, the present human intervention study investigates the metabolism of the glucosinolate (GSL) glucotropaeolin and its corresponding BITC metabolites. Analyzing BITC metabolites in plasma and urine should reveal insights about resorption, metabolism, and excretion. METHODS AND RESULTS: Fifteen healthy men were randomly recruited for a cross-over study and consumed 10 g freeze-dried Indian cress as a liquid preparation containing 1000 MUmol glucotropaeolin. Blood and urine samples were taken at several time points and investigated by LC-ESI-MS/MS after sample preparation using SPE. Plasma contained high levels of BITC-glutathione (BITC-GSH), BITC-cysteinylglycine (BITC-CysGly), and BITC-N-acetyl-L-cysteine (BITC-NAC) 1-5 h after ingestion, with BITC-CysGly appearing as the main metabolite. Compared to human plasma, the main urinary metabolites were BITC-NAC and BITC-Cys, determined 4-6 h after ingestion. CONCLUSION: This study confirms that consumption of Indian cress increases the concentration of BITC metabolites in human plasma and urine. The outcome of this human intervention study supports clinical research dealing with GSL-containing innovative food products or pharmaceutical preparations. PMID- 26610403 TI - Which is responsible for cardiac autonomic dysfunction in non-diabetic patients with metabolic syndrome: Prediabetes or the syndrome itself? AB - AIMS: Cardiac autonomic dysfunction (CAD) is associated with both prediabetes and metabolic syndrome (MS). Heart rate variability (HRV) and heart rate turbulence (HRT) are reliable 24-h Holter-ECG findings of cardiac autonomic function. This study aimed to investigate the relation between MS and its components and CAD using HRV and HRT. MATERIALS AND METHODS: The study included 80 non-diabetic patients with MS and 70 control subjects. All study population and the patients with MS were further analyzed for each diagnostic component of MS to investigate which criteria impaired HRV and HRT. RESULTS: HRV and HRT parameters were disturbed in patients in the MS group. While impairment in HRV and HRT was significantly related to the presence of the fasting plasma glucose (FPG) criterion, there were no differences between groups in terms of the other 4 MS criteria. Moreover, FPG level was significantly correlated with SDNN (r=-0.352, p<0.001), SDNN index (r=-0.423, p<0.001), SDANN (r=-0.301, p<0.001), RMSSD (r= 0.237, p<0.001), pNN50 (r=-0.237, p<0.001), turbulence onset (TO) (r=0.365, p<0.001) and turbulence slope (TS) (r=-0.365, p<0.001). Among the MS diagnostic criteria, only FPG level was an independent determinant of all HRV and HRT parameters. CONCLUSIONS: This study confirms the relation between MS and CAD. Increased FPG alone appears to be responsible for the mentioned findings among the 5 diagnostic criteria. Accordingly, CAD may be the result of prediabetes, not MS in patients with MS. PMID- 26610404 TI - Diabetes knowledge, attitude and practice (KAP) study among Iranian in-patients with type-2 diabetes: A cross-sectional study. AB - AIM: Recent studies highlight barriers of diabetes educational programs in Iran and also present some successful experiences carried out for improving the knowledge, attitude, and practice (KAP) of type-2 diabetic patients. Hence, evaluation of patients' KAP seems to be needed. We designed a multicenter study evaluating level of KAP in type-2 diabetic patients in the capital city of Tehran and identifying variables that affect this KAP level. METHODS: This multicenter analytical cross-sectional study was approved by Shahid Beheshti University of Medical Sciences Ethics Committee. Questionnaires were designed for evaluation of diabetes-related KAP in patients. After validating the questionnaires by endocrinologists, test-retest method was used for questionnaire reliability by checking in 15 diabetic patients. Two hundred type-2 diabetic patients admitted to 4 hospitals of Tehran filled out the questionnaires. Using SPSS software, the level of KAP and its confounders were evaluated in patients. RESULTS: Two hundred type-2 diabetic patients with the mean age of 60.17 years were evaluated (106 male and 94 female). The mean diabetes duration was 13.06 years. The levels of patients' good knowledge, attitude, and practice were 61.41%, 50.44% and 52.23%, respectively. Age, treatment methods, DM duration, and existence of diabetic retinopathy had significant correlations with KAP level. CONCLUSIONS: The results of this study showed that recent educational programs in Iran improved KAP level. Patients' KAP increases as their condition worsens/progresses. Hence education should be considered as a priority for newly diagnosed patients and those with lower KAP levels before occurrence of diabetes complications. PMID- 26610405 TI - Stabilization and Transfer of the Transient [Mes*P4](-) Butterfly Anion Using BPh3. AB - The transient bicyclo[1.1.0]tetraphosphabutane anion, generated from white phosphorus (P4) and Mes*Li (Mes*=2,4,6-tBu3C6H2), can be trapped by BPh3 in THF. This Lewis acid stabilized anion can be used as an [RP4](-) transfer agent, reacting cleanly with neutral Lewis acids (B(C6F5)3, BH3, and W(CO)5) to afford unique singly and doubly coordinated butterfly anions, and with the trityl cation to form a neutral, nonsymmetrical, all-carbon-substituted P4 derivative. This reaction path enables a simple, stepwise functionalization of white phosphorus. PMID- 26610406 TI - Freshwater biota and rising pCO2? AB - Rising atmospheric carbon dioxide (CO2) has caused a suite of environmental issues, however, little is known about how the partial pressure of CO2 (pCO2) in freshwater will be affected by climate change. Freshwater pCO2 varies across systems and is controlled by a diverse array of factors, making it difficult to make predictions about future levels of pCO2. Recent evidence suggests that increasing levels of atmospheric CO2 may directly increase freshwater pCO2 levels in lakes, but rising atmospheric CO2 may also indirectly impact freshwater pCO2 levels in a variety of systems by affecting other contributing factors such as soil respiration, terrestrial productivity and climate regimes. Although future freshwater pCO2 levels remain uncertain, studies have considered the potential impacts of changes to pCO2 levels on freshwater biota. Studies to date have focused on impacts of elevated pCO2 on plankton and macrophytes, and have shown that phytoplankton nutritional quality is reduced, plankton community structure is altered, photosynthesis rates increase and macrophyte distribution shifts with increasing pCO2. However, a number of key knowledge gaps remain and gaining a better understanding of how freshwater pCO2 levels are regulated and how these levels may impact biota, will be important for predicting future responses to climate change. PMID- 26610407 TI - First Detection of Ehrlichia canis in Cerebrospinal Fluid From a Nonthrombocytopenic Dog with Meningoencephalitis By Broad-Range PCR. PMID- 26610408 TI - Prognostic significance of histological therapeutic effect in preoperative chemotherapy for breast cancer. AB - To establish a prognostic prediction system, we examined the relationships between prognosis and histological therapeutic effect or ypTNM classification in 258 breast cancer patients who received neoadjuvant chemotherapy. The case distribution according to therapeutic effect was nine patients (3.5%) with Grade 0, 169 (65.5%) with Grade 1, 58 (22.5%) with Grade 2, and 22 (8.5%) with Grade 3. The 5-year overall survival (OS) rate by therapeutic effect was 56% in Grade 0, 81% in Grade 1, 87% in Grade 2, and 96% in Grade 3. The higher the therapeutic effect the better the prognosis, with a significant difference among the groups (P = 0.008). The case distribution according to ypTNM classification was 20 patients (7.8%) with Stage 0, 83 (32.2%) with Stage I, 77 (29.8%) with Stage II, and 78 (30.2%) with Stage III. The 5-year OS rate by ypTNM classification was 95% in Stage 0, 94% in Stage I, 89% in Stage II, and 59% in Stage III. While prognosis was mostly comparable in Stages 0 and I, in the other stages it became significantly worse as residual cancer increased (P < 0.001). The prognosis of breast cancer patients with neoadjuvant chemotherapy can be predicted by histological therapeutic effect and staging classification of residual cancer. PMID- 26610409 TI - 'Arm-based' parameterization for network meta-analysis. AB - We present an alternative to the contrast-based parameterization used in a number of publications for network meta-analysis. This alternative "arm-based" parameterization offers a number of advantages: it allows for a "long" normalized data structure that remains constant regardless of the number of comparators; it can be used to directly incorporate individual patient data into the analysis; the incorporation of multi-arm trials is straightforward and avoids the need to generate a multivariate distribution describing treatment effects; there is a direct mapping between the parameterization and the analysis script in languages such as WinBUGS and finally, the arm-based parameterization allows simple extension to treatment-specific random treatment effect variances. We validated the parameterization using a published smoking cessation dataset. Network meta analysis using arm- and contrast-based parameterizations produced comparable results (with means and standard deviations being within +/- 0.01) for both fixed and random effects models. We recommend that analysts consider using arm-based parameterization when carrying out network meta-analyses. (c) 2015 The Authors Research Synthesis Methods Published by John Wiley & Sons Ltd. PMID- 26610410 TI - Hepatic glucose metabolism in 2015: Nutrient and hormone-sensing-dependent regulation. PMID- 26610411 TI - Metabolism: One step forward for exercise. PMID- 26610412 TI - Diabetes: Enterovirus dysregulates islet miRNAs. PMID- 26610413 TI - Nutrition: Glycaemic response variation suggests value of personalized diets. PMID- 26610415 TI - Split protein biosensor assays in molecular pharmacological studies. AB - Cellular signalling is commonly mediated through dynamic protein-protein interactions (PPIs). When pivotal PPIs are deregulated, cellular signalling can be altered; it is therefore attractive to monitor regulated PPIs to understand their role in health and disease. Genetically encoded biosensors that rely on protein fragment complementation have made it feasible to monitor PPIs in living cells precisely and robustly. In particular, split protein biosensors using fluorescent proteins or luciferases are frequently applied. Further, split TEV and split ubiquitin biosensor platforms flexibly allow using readouts of choice, including transcriptional barcode reporters that are amenable to multiplexed high throughput formats and next-generation sequencing. Combining these technologies will enable assessing drug target activities and cellular response profiles in parallel, thereby opening up new avenues in drug discovery. PMID- 26610414 TI - New therapeutic agents for acromegaly. AB - The currently available somatostatin receptor ligands (SRLs) and growth hormone (GH) antagonists are used to control levels of GH and insulin-like growth factor 1 (IGF-1) in patients with acromegaly. However, these therapies are limited by wide variations in efficacy, associated adverse effects and the need for frequent injections. A phase III trial of oral octreotide capsules demonstrated that this treatment can safely sustain suppressed levels of GH and IGF-1 and reduce the severity of symptoms in patients with acromegaly previously controlled by injectable SRL therapy, with the added benefit of no injection-site reactions. Phase I and phase II trials of the pan-selective SRL DG3173, the liquid crystal octreotide depot CAM2029 and an antisense oligonucleotide directed against the GH receptor have shown that these agents can be used to achieve biochemical suppression in acromegaly and have favourable safety profiles. This Review outlines the need for new therapeutic agents for patients with acromegaly, reviews clinical trial data of investigational agents and considers how these therapies might best be integrated into clinical practice. PMID- 26610416 TI - Assessment of cognitive safety in clinical drug development. AB - Cognitive impairment is increasingly recognised as an important potential adverse effect of medication. However, many drug development programmes do not incorporate sensitive cognitive measurements. Here, we review the rationale for cognitive safety assessment, and explain several basic methodological principles for measuring cognition during clinical drug development, including study design and statistical analysis, from Phase I through to postmarketing. The crucial issue of how cognition should be assessed is emphasized, especially the sensitivity of measurement. We also consider how best to interpret the magnitude of any identified effects, including comparison with benchmarks. We conclude by discussing strategies for the effective communication of cognitive risks. PMID- 26610417 TI - Drug regulators and ethics: which GCP issues are also ethical issues? AB - Within the European Union (EU), good clinical practice (GCP) provides an ethical mandate to regulators; however, it is unclear what the content of that mandate is. By looking at the correspondence between GCP and ethical imperatives, we identify that the mandate is within the following: principles; benefit-risk ratio; scientific validity; results publication; informed consent; respect for participants; and special populations. There are also cases when regulations were ethical but were not pairable to an imperative, and when the former were stricter than the latter. Hence, we suggest closer cooperation between ethics committees and regulators to ensure that future versions of ethics guidelines cover the ethically relevant regulations that were not directly pairable to any imperative, and cooperation between GCP legislative bodies and ethics guideline-making bodies to resolve the discordant areas. PMID- 26610418 TI - Prevention of Influenza in Children. AB - Influenza infects 5% to 20% of school-age children annually. Although universal influenza vaccine is recommended for children and adults 6 months of age and older, uptake is below national targets. Influenza immunization of the child and the family is the key to decreasing annual disease burden. Antiviral therapy is an important treatment strategy for children and adults, especially those who are at high risk of complications from influenza, irrespective of immunization status or whether illness onset is greater than 48 hours. Although antiviral therapy may also be used for pre-exposure and postexposure prophylaxis, it should not replace immunization as a preventive strategy when immunization is feasible. PMID- 26610419 TI - The Challenge of Global Poliomyelitis Eradication. AB - In the United States during the 1950's, polio was on the forefront of every provider and caregiver's mind. Today, most providers in the United States have never seen a case. The Global Polio Eradication Initiative (GPEI), which began in 1988 has reduced the number of cases by over 99%. The world is closer to achieving global eradication of polio than ever before but as long as poliovirus circulates anywhere in the world, every country is vulnerable. The global community can support the polio eradication effort through continued vaccination, surveillance, enforcing travel regulations and contributing financial support, partnerships and advocacy. PMID- 26610420 TI - The Changing Epidemiology of Meningococcal Disease. AB - The incidence of meningococcal disease is at an historic low in the United States, but prevention remains a priority because of the devastating outcomes and risk for outbreaks. Available vaccines are recommended routinely for persons at increased risk for disease to protect against all major serogroups of Neisseria meningitidis circulating in the United States. Although vaccination has virtually eliminated serogroup A meningococcal outbreaks from the Meningitis Belt of Africa and reduced the incidence of serogroup C disease worldwide, eradication of N meningitidis will unlikely be achieved by currently available vaccines because of the continued carriage and transmission of nonencapsulated organisms. PMID- 26610422 TI - The Expanded Impact of Human Papillomavirus Vaccine. AB - Human papilloma virus (HPV) infection is the most common sexually transmitted infection in the United States. Some infections will result in anogenital warts and anogenital or oropharyngeal cancers. Preventing HPV infection is a public health priority to reduce cancer and HPV-associated complications. Prevention through vaccination is the most cost-effective and lifesaving intervention to decrease the burden of HPV-related cancers and other HPV-associated diseases. It is critical for pediatricians to make a strong recommendation for early and timely vaccination and completion of the 3-dose series. The goal of early vaccination is to immunize before first exposure to HPV virus. PMID- 26610421 TI - Pneumococcal Disease in the Era of Pneumococcal Conjugate Vaccine. AB - Universal immunization of infants and toddlers with pneumococcal conjugate vaccines over the last 15 years has dramatically altered the landscape of pneumococcal disease. Decreases in invasive pneumococcal disease, all-cause pneumonia, empyema, mastoiditis, acute otitis media, and complicated otitis media have been reported from multiple countries in which universal immunization has been implemented. Children with comorbid conditions have higher rates of pneumococcal disease and increased case fatality rates compared with otherwise healthy children, and protection for the most vulnerable pediatric patients will require new strategies to address the underlying host susceptibility and the expanded spectrum of serotypes observed. PMID- 26610423 TI - Measles 50 Years After Use of Measles Vaccine. AB - In response to severe measles, the first measles vaccine was licensed in the United States in 1963. Widespread use of measles vaccines for more than 50 years has significantly reduced global measles morbidity and mortality. However, measles virus continues to circulate, causing infection, illness, and an estimated 400 deaths worldwide each day. Measles is preventable by vaccine, and humans are the only reservoir. Clinicians should promote and provide on-time vaccination for all patients and keep measles in their differential diagnosis of febrile rash illness for rapid case detection, confirmation of measles infection, isolation, treatment, and appropriate public health response. PMID- 26610424 TI - Approach to Immunization for the Traveling Child. AB - Children are traveling to regions of the world that could pose a risk of acquiring diseases such as malaria, dermatosis, and infectious diarrhea. Most of these can be prevented by modifying high-risk behaviors or through the use of medications. Many of these same regions are endemic with diseases that are preventable through vaccination. Clinicians must be able to effectively prepare their pediatric-age travelers for international travel. Preventive education, prophylactic and self-treating medications, and vaccinations are all important components of this preparation. Familiarity with the use of travel vaccines is imperative. PMID- 26610425 TI - Pediatric Infectious Diseases, Part 2. PMID- 26610426 TI - Three-Dimensional Porous Iron Vanadate Nanowire Arrays as a High-Performance Lithium-Ion Battery. AB - Development of three-dimensional nanoarchitectures on current collectors has emerged as an effective strategy for enhancing rate capability and cycling stability of the electrodes. Herein, a new type of three-dimensional porous iron vanadate (Fe0.12V2O5) nanowire arrays on a Ti foil has been synthesized by a hydrothermal method. The as-prepared Fe0.12V2O5 nanowires are about 30 nm in diameter and several micrometers in length. The effect of reaction time on the resulting morphology is investigated and the mechanism for the nanowire formation is proposed. As an electrode material used in lithium-ion batteries, the unique configuration of the Fe0.12V2O5 nanowire arrays presents enhanced capacitance, satisfying rate capability and good cycling stability, as evaluated by cyclic voltammetry and galvanostatic discharge-charge cycling. It delivers a high discharge capacity of 293 mAh.g(-1) at 2.0-3.6 V or 382.2 mAh.g(-1) at 1.0-4.0 V after 50 cycles at 30 mA.g(-1). PMID- 26610427 TI - White matter alterations in narcolepsy patients with cataplexy: tract-based spatial statistics. AB - Functional imaging studies and voxel-based morphometry analysis of brain magnetic resonance imaging showed abnormalities in the hypothalamus-thalamus-orbitofrontal pathway, demonstrating altered hypocretin pathway in narcolepsy. Those distinct morphometric changes account for problems in wake-sleep control, attention and memory. It also raised the necessity to evaluate white matter changes. To investigate brain white matter alterations in drug-naive narcolepsy patients with cataplexy and to explore relationships between white matter changes and patient clinical characteristics, drug-naive narcolepsy patients with cataplexy (n = 22) and healthy age- and gender-matched controls (n = 26) were studied. Fractional anisotropy and mean diffusivity images were obtained from whole-brain diffusion tensor imaging, and tract-based spatial statistics were used to localize white matter abnormalities. Compared with controls, patients showed significant decreases in fractional anisotropy of white matter of the bilateral anterior cingulate, fronto-orbital area, frontal lobe, anterior limb of the internal capsule and corpus callosum, as well as the left anterior and medial thalamus. Patients and controls showed no differences in mean diffusivity. Among patients, mean diffusivity values of white matter in the bilateral superior frontal gyri, bilateral fronto-orbital gyri and right superior parietal gyrus were positively correlated with depressive mood. This tract-based spatial statistics study demonstrated that drug-naive patients with narcolepsy had reduced fractional anisotropy of white matter in multiple brain areas and significant relationship between increased mean diffusivity of white matter in frontal/cingulate and depression. It suggests the widespread disruption of white matter integrity and prevalent brain degeneration of frontal lobes according to a depressive symptom in narcolepsy. PMID- 26610428 TI - pH-susceptibility of HLA-DO tunes DO/DM ratios to regulate HLA-DM catalytic activity. AB - The peptide-exchange catalyst, HLA-DM, and its inhibitor, HLA-DO control endosomal generation of peptide/class II major histocompatibility protein (MHC II) complexes; these complexes traffic to the cell surface for inspection by CD4+ T cells. Some evidence suggests that pH influences DO regulation of DM function, but pH also affects the stability of polymorphic MHC-II proteins, spontaneous peptide loading, DM/MHC-II interactions and DM catalytic activity, imposing challenges on approaches to determine pH effects on DM-DO function and their mechanistic basis. Using optimized biochemical methods, we dissected pH dependence of spontaneous and DM-DO-mediated class II peptide exchange and identified an MHC-II allele-independent relationship between pH, DO/DM ratio and efficient peptide exchange. We demonstrate that active, free DM is generated from DM-DO complexes at late endosomal/lysosomal pH due to irreversible, acid-promoted DO destruction rather than DO/DM molecular dissociation. Any soluble DM that remains in complex with DO stays inert. pH-exposure of DM-DO in cell lysates corroborates such a pH-regulated mechanism, suggesting acid-activated generation of functional DM in DO-expressing cells. PMID- 26610429 TI - Neutral alpha-1,4-glucosidase and fructose levels contribute to discriminating obstructive and nonobstructive azoospermia in Chinese men with azoospermia. AB - Nowadays, whether neutral alpha-1,4-glucosidase (NAG) and fructose levels are contributed to discriminating obstructive and nonobstructive azoospermia in Chinese azoospermic patients remains unclear. In this study, we retrospectively analysed the levels of NAG and fructose in 229 patients with obstructive azoospermia and 415 patients with nonobstructive azoospermia from three different medical central. Results indicated that NAG and fructose levels in patients with nonobstructive azoospermia were significantly higher compared with those with obstructive azoospermia (P < 0.05). According to the reference value of NAG and fructose defined by the World Health Organization (WHO, 2010), decreased level of NAG was observed in 77.3% of patients with obstructive azoospermia, which was significantly higher than those with nonobstructive azoospermia (55.2%, P < 0.0001). Low level of fructose was observed in 48.0% of patients with obstructive azoospermia, which is also obviously higher than those with nonobstructive azoospermia (31.8%, P < 0.0001). Moreover, the decrease of both NAG and fructose was only recorded in 3.7% of patients with SCO syndrome, 5.0% of patients with severe hypospermatogenesis and 18.2% of patients with maturation arrest. Therefore, our results indicated that NAG and fructose levels are contributed to discriminating obstructive and nonobstructive azoospermia in Chinese patients based on the histological types of testes. PMID- 26610430 TI - Increased sexual desire with exogenous testosterone administration in men with obstructive sleep apnea: a randomized placebo-controlled study. AB - Testosterone (T) deficiency, sexual dysfunction, obesity and obstructive sleep apnea (OSA) are common and often coexist. T prescriptions have increased worldwide during the last decade, including to those with undiagnosed or untreated OSA. The effect of T administration on sexual function, neurocognitive performance and quality of life in these men is poorly defined. The aim of this study was to examine the impact of T administration on sexual function, quality of life and neurocognitive performance in obese men with OSA. We also secondarily examined whether baseline T might modify the effects of T treatment by dichotomizing on baseline T levels pre-specified at 8, 11 and 13 nmol/L. This was a randomized placebo-controlled study in which 67 obese men with OSA (mean age 49 +/- 1.3 years) were randomized to receive intramuscular injections of either 1000 mg T undecanoate or placebo at baseline, week 6 and week 12. All participants were concurrently enrolled in a weight loss program. General and sleep-related quality of life, neurocognitive performance and subjective sexual function were assessed before and 6, 12 and 18 weeks after therapy. T compared to placebo increased sexual desire (p = 0.004) in all men, irrespective of baseline T levels. There were no differences in erectile function, frequency of sexual attempts, orgasmic ability, general or sleep-related quality of life or neurocognitive function (all p = NS). In those with baseline T levels below 8 nmol/L, T increased vitality (p = 0.004), and reduced reports of feeling down (p = 0.002) and nervousness (p = 0.03). Our findings show that 18 weeks of T therapy increased sexual desire in obese men with OSA independently of baseline T levels whereas improvements in quality of life were evident only in those with T levels below 8 nmol/L. These small improvements would need to be balanced against potentially more serious adverse effects of T therapy on breathing. PMID- 26610431 TI - Quantitative immunoenzymatic detection of viral encephalopathy and retinopathy virus (betanodavirus) in sea bass Dicentrarchus labrax. AB - Viral encephalopathy and retinopathy disease caused by betanodavirus, genus of the family Nodaviridae, affects marine, wild and farmed species including sea bass, one of the most important farmed species in Europe. This work describes a reliable and sensitive indirect ELISA assay to detect betanodavirus in biological samples using a polyclonal antiserum (pAb 283) against the 283/I09 virus strain, the most common red-spotted grouper nervous necrosis virus (RGNNV) genotype in the Mediterranean area, and a capture-based ELISA using a monoclonal antibody (mAb 4C3) specific to a common epitope present on the capsid protein. Using adsorbed, purified VERv preparation, the detection limit of indirect ELISA was 2 MUg mL(-1) (3 * 10(5) TCID50 per mL), whereas for capture-based ELISA, the sensitivity for the antigen in solution was 17 MUg mL(-1) (35 * 10(5) TCID50 per mL). The capture-based ELISA was employed to detect VERv in brain homogenates of in vivo infected sea bass and resulted positive in 22 of 32 samples, some of these with a high viral load estimates (about 1.1 * 10(8) TCID50 per mL). The ELISA system we propose may be helpful in investigations where coupling of viral content in fish tissues with the presence of circulating VERv-specific IgM is required, or for use in samples where PCR is difficult to perform. PMID- 26610432 TI - Pseudomonas aeruginosa facilitates Campylobacter jejuni growth in biofilms under oxic flow conditions. AB - We investigated the growth of Campylobacter jejuni in biofilms with Pseudomonas aeruginosa under oxic flow conditions. We observed the growth of C. jejuni in mono-culture, deposited on pre-established P. aeruginosa biofilms, and co inoculated with P. aeruginosa. In mono-culture, C. jejuni was unable to form biofilms. However, deposited C. jejuni continuously grew on pre-established P. aeruginosa biofilms for a period of 3 days. The growth of scattered C. jejuni clusters was strictly limited to the P. aeruginosa biofilm surface, and no intergrowth was observed. Co-culturing of C. jejuni and P. aeruginosa also enabled the growth of both organisms in biofilms, with C. jejuni clusters developing on the surface of the P. aeruginosa biofilm. Dissolved oxygen (DO) measurements in the medium showed that P. aeruginosa biofilms depleted the effluent DO from 9.0 to 0.5 mg L(-1) 24 hours after inoculation. The localized microaerophilic environment generated by P. aeruginosa promoted the persistence and growth of C. jejuni. Our findings show that P. aeruginosa not only prolongs the survival of C. jejuni under oxic conditions, but also enables the growth of C. jejuni on the surface of P. aeruginosa biofilms. PMID- 26610433 TI - Microbiota is an essential element for mice to initiate a protective immunity against Vaccinia virus. AB - The gastrointestinal tract of vertebrates harbors one of the most complex ecosystems known in microbial ecology and this indigenous microbiota almost always has a profound influence on host-parasite relationships, which can enhance or reduce the pathology of the infection. In this context, the impact of the microbiota during the infection of several viral groups remains poorly studied, including the family Poxviridae. Vaccinia virus (VACV) is a member of this family and is the causative agent of bovine vaccinia, responsible for outbreaks that affect bovines and humans. To determine the influence of the microbiota in the development of the disease caused by VACV, a comparative study using a murine model was performed. Germ-free and conventional, 6- to 7-week-old Swiss NIH mice were infected by tail scarification and intranasally with VACV. Moreover, immunosuppression and microbiota reposition were performed, to establish the interactions among the host's immune system, microbiota and VACV. The data demonstrate that the microbiota is essential for the effective immune response of mice against VACV in intranasal inoculation and to control the virus at the primary site of infection. Furthermore, this study is the first to show that Swiss conventional mice are refractory to the intranasal infection of VACV. PMID- 26610434 TI - Isolation and identification of Pseudomonas syringae facilitated by a PCR targeting the whole P. syringae group. AB - We present a reliable PCR-based method to avoid the biases related to identification based on the conventional phenotypes currently used in the identification of Pseudomonas syringae sensu lato, a ubiquitous environmental bacterium including plant pathogens. We identified a DNA target suitable for this purpose by applying a comparative genomic pipeline to Pseudomonas genomes. We designed primers and developed PCR conditions that led to a clean and strong PCR product from 97% of the 185 strains of P. syringae strains tested and gave a clear negative result for the 31 non-P. syringae strains tested. The sensitivity of standard PCR was determined with pure strains to be 10(6) bacteria mL(-1) or 0.4 ng of DNA MUL(-1). Sensitivity could be improved with the touchdown method. The new PCR-assisted isolation of P. syringae was efficient when deployed on an environmental sample of river water as compared to the isolation based on phenotypes. This innovation eliminates the need for extensive expertise in isolating P. syringae colonies, was simpler, faster and very reliable. It will facilitate discovery of more diversity of P. syringae and research on emergence, dispersion and evolution to understand the varied functions of this environmental bacterium. PMID- 26610436 TI - New Sulphated Flavonoids from Wissadula periplocifolia (L.) C. Presl (Malvaceae). AB - Wissadula periplocifolia (L.) C. Presl (Malvaceae) is commonly used in Brazil to treat bee stings and as an antiseptic. The antioxidant properties of its extracts have been previously demonstrated, thus justifying a phytochemical investigation for its bioactive phenolic constituents. This has yielded five new sulphated flavonoids: 8-O-sulphate isoscutellarein (yannin) (1a); 4'-O-methyl-7-O-sulphate isoscutellarein (beltraonin) (1b); 7-O-sulphate acacetin (wissadulin) (2a); 4'-O methyl-8-O-sulphate isoscutellarein (caicoine) (2b) and 3'-O-methyl-8-O-sulphate hypolaetin (pedroin) (3b) along with the known flavonoids 7,4'-di-O-methyl-8-O sulphate isoscutellarein (4), acacetin, apigenin, isoscutellarein, 4'-O-methyl isoscutellarein, 7,4'-di-O-methylisoscutellarein, astragalin and tiliroside. The compounds were isolated by column chromatography and identified by NMR (1H, 13C, HMQC, HMBC and COSY) and LC-HRMS. A cell based assay was carried out to evaluate the preliminary cytotoxic properties of the flavonoids against UVW glioma and PC 3M prostate cancer cells as well as non-tumour cell lines. The obtained results showed that acacetin, tiliroside, a mixture of acacetin+apigenin and the sulphated flavonoids 2a+2b exhibited inhibitory activity against at least one of the cell lines tested. Among the tested flavonoids acacetin and tiliroside showed lower IC50 values, presenting promising antitumor effects. PMID- 26610437 TI - Recent Advances in Developing Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylases and Their Therapeutic Implications. AB - Hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs) are members of the 2 oxoglutarate dependent non-heme iron dioxygenases. Due to their physiological roles in regulation of HIF-1alpha stability, many efforts have been focused on searching for selective PHD inhibitors to control HIF-1alpha levels for therapeutic applications. In this review, we first describe the structure of PHD2 as a molecular basis for structure-based drug design (SBDD) and various experimental methods developed for measuring PHD activity. We further discuss the current status of the development of PHD inhibitors enabled by combining SBDD approaches with high-throughput screening. Finally, we highlight the clinical implications of small molecule PHD inhibitors. PMID- 26610438 TI - Ardipusilloside-I Metabolites from Human Intestinal Bacteria and Their Antitumor Activity. AB - Ardipusilloside-I (ADS-I) is a triterpenoid saponin extracted from Ardisia pusilla DC, and has been demonstrated to have potent antitumor activity. However, ADS-I metabolism in humans has not been investigated. In this study, we studied the biotransformation of ADS-I in human intestinal bacteria, and examined the in vitro antitumor activity of the major metabolites. Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was used to detect ADS-I biotransformation products, and their chemical structures were identified by high performance liquid chromatography-nuclear magnetic resonance (HPLC-NMR). The antitumor activity of the major metabolites was determined by the MTT assay. Here, we show that main reaction seen in the metabolism of ADS-I in human intestinal bacteria was deglycosylation, which produced a total of four metabolites. The structures of the two major metabolites M1 and M2 were confirmed by using NMR. MTT assay showed that ADS-I metabolites M1 and M2 have the same levels of inhibitory activities as ADS-I in cultured SMMC-7721 cells and MCF-7 cells. In conclusion, this study demonstrates deglycosylation as a primary pathway of ADS-I metabolism in human intestinal bacteria, and suggests that the pharmacological activity of ADS-I may be mediated, at least in part, by its metabolites. PMID- 26610439 TI - Immobilization of Metal Hexacyanoferrate Ion-Exchangers for the Synthesis of Metal Ion Sorbents--A Mini-Review. AB - Metal hexacyanoferrates are very efficient sorbents for the recovery of alkali and base metal ions (including radionuclides such as Cs). Generally produced by the direct reaction of metal salts with potassium hexacyanoferrate (the precursors), they are characterized by ion-exchange and structural properties that make then particularly selective for Cs(I), Rb(I) and Tl(I) recovery (based on their hydrated ionic radius consistent with the size of the ion-exchanger cage), though they can bind also base metals. The major drawback of these materials is associated to their nanometer or micrometer size that makes them difficult to recover in large-size continuous systems. For this reason many techniques have been designed for immobilizing these ion-exchangers in suitable matrices that can be organic (mainly polymers and biopolymers) or inorganic (mineral supports), carbon-based matrices. This immobilization may proceed by in situ synthesis or by entrapment/encapsulation. This mini-review reports some examples of hybrid materials synthesized for the immobilization of metal hexacyanoferrate, the different conditionings of these composite materials and, briefly, the parameters to take into account for their optimal design and facilitated use. PMID- 26610440 TI - Ursolic Acid--A Pentacyclic Triterpenoid with a Wide Spectrum of Pharmacological Activities. AB - Ursolic acid (UA) is a natural terpene compound exhibiting many pharmaceutical properties. In this review the current state of knowledge about the health promoting properties of this widespread, biologically active compound, as well as information about its occurrence and biosynthesis are presented. Particular attention has been paid to the application of ursolic acid as an anti-cancer agent; it is worth noticing that clinical tests suggesting the possibility of practical use of UA have already been conducted. Amongst other pharmacological properties of UA one can mention protective effect on lungs, kidneys, liver and brain, anti-inflammatory properties, anabolic effects on skeletal muscles and the ability to suppress bone density loss leading to osteoporosis. Ursolic acid also exhibits anti-microbial features against numerous strains of bacteria, HIV and HCV viruses and Plasmodium protozoa causing malaria. PMID- 26610441 TI - New Diethyl Ammonium Salt of Thiobarbituric Acid Derivative: Synthesis, Molecular Structure Investigations and Docking Studies. AB - The synthesis of the new diethyl ammonium salt of diethylammonium(E)-5-(1,5-bis(4 fluorophenyl)-3-oxopent-4-en-1-yl)-1,3-diethyl-4,6-dioxo-2 thioxohexaydropyrimidin-5-ide 3 via a regioselective Michael addition of N,N diethylthiobarbituric acid 1 to dienone 2 is described. In 3, the carboanion of the thiobarbituric moiety is stabilized by the strong intramolecular electron delocalization with the adjacent carbonyl groups and so the reaction proceeds without any cyclization. The molecular structure investigations of 3 were determined by single-crystal X-ray diffraction as well as DFT computations. The theoretically calculated (DFT/B3LYP) geometry agrees well with the crystallographic data. The effect of fluorine replacement by chlorine atoms on the molecular structure aspects were investigated using DFT methods. Calculated electronic spectra showed a bathochromic shift of the pi-pi* transition when fluorine is replaced by chlorine. Charge decomposition analyses were performed to study possible interaction between the different fragments in the studied systems. Molecular docking simulations examining the inhibitory nature of the compound show an anti-diabetic activity with Pa (probability of activity) value of 0.229. PMID- 26610442 TI - Cyclovirobuxine D Inhibits Cell Proliferation and Induces Mitochondria-Mediated Apoptosis in Human Gastric Cancer Cells. AB - Gastric cancer is one of the most common malignant cancers, with high death rates, poor prognosis and limited treatment methods. Cyclovirobuxine D (CVB-D) is the main active component of the traditional Chinese medicine Buxus microphylla. In the present study, we test the effects of CVB-D on gastric cancer cells and the underlying mechanisms of action. CVB-D reduced cell viability and colony formation ability of MGC-803 and MKN28 cells in a time- and concentration dependent manner. Flow cytometry showed that cell cycle of CVB-D treated cells was arrested at the S-phase. CVB-D also induced apoptosis in MGC-803 and MKN28 cells, especially early stage apoptosis. Furthermore, mitochondria membrane potential (Deltapsim) was reduced and apoptosis-related proteins, cleaved Caspase 3 and Bax/Bcl-2, were up-regulated in CVB-D-treated MGC-803 and MKN28 cells. Taken together, our studies found that CVB-D plays important roles in inhibition of gastric tumorigenesis via arresting cell cycle and inducing mitochondria mediated apoptosis, suggesting the potential application of CVB-D in gastric cancer therapy. PMID- 26610444 TI - Solvatochromic and Single Crystal Studies of Two Neutral Triarylmethane Dyes with a Quinone Methide Structure. AB - The crystal structure of two neutral triarylmethane dyes with a p-quinone methide core was determined by X-ray diffraction analysis. The spectroscopic characteristics of both compounds in 23 solvents with different polarities or hydrogen-bonding donor (HBD) abilities has been studied as a function of three solvatochromic parameters (ET(30), pi* and alpha). Both compounds 1 and 2 showed a pronounced bathochromic shift of the main absorption band on increasing solvent polarity and HBD ability. The correlation is better for compound 2 than for compound 1. The stronger effect and better correlation was observed for compound 2 with the increment of the solvent HBD ability (alpha parameter). PMID- 26610443 TI - The Effect of Low Monotonic Doses of Zearalenone on Selected Reproductive Tissues in Pre-Pubertal Female Dogs--A Review. AB - The growing interest in toxic substances combined with advancements in biological sciences has shed a new light on the problem of mycotoxins contaminating feeds and foods. An interdisciplinary approach was developed by identifying dose response relationships in key research concepts, including the low dose theory of estrogen-like compounds, hormesis, NOAEL dose, compensatory response and/or food tolerance, and effects of exposure to undesirable substances. The above considerations increased the researchers' interest in risk evaluation, namely: (i) clinical symptoms associated with long-term, daily exposure to low doses of a toxic compound; and (ii) dysfunctions at cellular or tissue level that do not produce clinical symptoms. Research advancements facilitate the extrapolation of results and promote the use of novel tools for evaluating the risk of exposure, for example exposure to zearalenone in pre-pubertal female dogs. The arguments presented in this paper suggest that low doses of zearalenone in commercial feeds stimulate metabolic processes and increase weight gains. Those processes are accompanied by lower proliferation rates in the ovaries, neoangiogenesis and vasodilation in the ovaries and the uterus, changes in the steroid hormone profile, and changes in the activity of hydroxysteroid dehydrogenases. All of the above changes result from exogenous hyperestrogenizm. PMID- 26610445 TI - Cinidium officinale and its Bioactive Compound, Butylidenephthalide, Inhibit Laser-Induced Choroidal Neovascularization in a Rat Model. AB - Choroidal neovascularization (CNV) is a common pathology in age-related macular degeneration. In this study, we evaluated in a rat model the effect of an extract of Cinidium officinale Makino and its bioactive compound, butylidenephthalide, on laser-induced CNV. Experimental CNV was induced in Long-Evans rats by laser photocoagulation. C. officinale extract (COE) and butylidenephthalide was intraperitoneally injected once per day for ten days after laser photocoagulation. Choroidal flat mounts were prepared to measure CNV areas and macrophage infiltration. We used a protein array to evaluate the expression levels of angiogenic factors. The CNV area and macrophage infiltration in COE treated rats were significantly lower than in vehicle-treated rats. COE decreased the expression levels of IGFBP-1, MCP-1, PAI-1, and VEGF. Additionally, butylidenephthalide also inhibited the laser-induced CNV formation and macrophage infiltration and down-regulated the expression of IGFBP-1, MCP-1 and VEGF. These results suggest that COE exerts anti-angiogenic effects on laser-induced CNV by inhibiting the expression of IGFBP-1, MCP-1, and VEGF, indicating that anti angiogenic activities of COE may be in part due to its bioactive compound, butylidenephthalide. PMID- 26610446 TI - An Efficient and Recyclable Nanoparticle-Supported Cobalt Catalyst for Quinoxaline Synthesis. AB - The syntheses of quinoxalines derived from 1,2-diamine and 1,2-dicarbonyl compounds under mild reaction conditions was carried out using a nanoparticle supported cobalt catalyst. The supported nanocatalyst exhibited excellent activity and stability and it could be reused for at least ten times without any loss of activity. No cobalt contamination could be detected in the products by AAS measurements, pointing to the excellent activity and stability of the Co nanomaterial. PMID- 26610447 TI - Condensation of Diacetyl with Alkyl Amines: Synthesis and Reactivity of p Iminobenzoquinones and p-Diiminobenzoquinones. AB - Condensation reactions between diacetyl and alpha-branched primary alkylamines under mild and neutral conditions provided a mixture of 2,5 dimethylbenzoquinone(alkylimines), 2,5-dimethylbenzoquinone(bis-alkyldiimines), and N,N'-dialkyl-2,5-dimethylbenzene-1,4-diamines, which were efficiently separated as pure products by column chromatography. Both 2,5 dimethylbenzoquinone(alkylimines) and 2,5-dimethylbenzoquinone(bis-alkyldiimines) underwent an interchange of the alkylimino group when treated with anilines, followed by reductive aromatization, to provide diarylamines and 1,4 dianilinobenzenes, respectively. Evaluation was also made of the reactivity and selectivity of these compounds in the presence of anilines, thiophenols and alkylhalides. PMID- 26610448 TI - Current Research on Antiepileptic Compounds. AB - Epilepsy affects about 1% of the world's population. Due to the fact all antiepileptic drugs (AEDs) have some undesirable side effects and about 30% of epileptic patients are not seizure-free with the existing AEDs, there is still an urgent need for the development of more effective and safer AEDs. Based on our research work on antiepileptic compounds and other references in recent years, this review covers the reported work on antiepileptic compounds which are classified according to their structures. This review summarized 244 significant anticonvulsant compounds which are classified by functional groups according to the animal model data, although there are some limitations in the data. This review highlights the properties of new compounds endowed with promising antiepileptic properties, which may be proven to be more effective and selective, and possibly free of unwanted side effects. The reviewed compounds represent an interesting possibility to overcome refractory seizures and to reduce the percentage of patients with a poor response to drug therapy. PMID- 26610449 TI - DNA Catalysis: The Chemical Repertoire of DNAzymes. AB - Deoxyribozymes or DNAzymes are single-stranded catalytic DNA molecules that are obtained by combinatorial in vitro selection methods. Initially conceived to function as gene silencing agents, the scope of DNAzymes has rapidly expanded into diverse fields, including biosensing, diagnostics, logic gate operations, and the development of novel synthetic and biological tools. In this review, an overview of all the different chemical reactions catalyzed by DNAzymes is given with an emphasis on RNA cleavage and the use of non-nucleosidic substrates. The use of modified nucleoside triphosphates (dN*TPs) to expand the chemical space to be explored in selection experiments and ultimately to generate DNAzymes with an expanded chemical repertoire is also highlighted. PMID- 26610450 TI - A 7-Deazaadenosylaziridine Cofactor for Sequence-Specific Labeling of DNA by the DNA Cytosine-C5 Methyltransferase M.HhaI. AB - DNA methyltransferases (MTases) catalyze the transfer of the activated methyl group of the cofactor S-adenosyl-l-methionine (AdoMet or SAM) to the exocyclic amino groups of adenine or cytosine or the C5 ring atom of cytosine within specific DNA sequences. The DNA adenine-N6 MTase from Thermus aquaticus (M.TaqI) is also capable of coupling synthetic N-adenosylaziridine cofactor analogues to its target adenine within the double-stranded 5'-TCGA-3' sequence. This M.TaqI mediated coupling reaction was exploited to sequence-specifically deliver fluorophores and biotin to DNA using N-adenosylaziridine derivatives carrying reporter groups at the 8-position of the adenine ring. However, these 8-modified aziridine cofactors were poor substrates for the DNA cytosine-C5 MTase from Haemophilus haemolyticus (M.HhaI). Based on the crystal structure of M.HhaI in complex with a duplex oligodeoxynucleotide and the cofactor product, we synthesized a stable 7-deazaadenosylaziridine derivative with a biotin group attached to the 7-position via a flexible linker. This 7-modified aziridine cofactor can be efficiently used by M.HhaI for the direct, quantitative and sequence-specific delivery of biotin to the second cytosine within 5'-GCGC-3' sequences in short duplex oligodeoxynucleotides and plasmid DNA. In addition, we demonstrate that biotinylation by M.HhaI depends on the methylation status of the target cytosine and, thus, could provide a method for cytosine-C5 DNA methylation detection in mammalian DNA. PMID- 26610452 TI - Identification of RNA Oligonucleotides Binding to Several Proteins from Potential G-Quadruplex Forming Regions in Transcribed Pre-mRNA. AB - G-quadruplexes (G4s) are noncanonical DNA/RNA structures formed by guanine-rich sequences. Recently, G4s have been found not only in aptamers but also in the genomic DNA and transcribed RNA. In this study, we identified new RNA oligonucleotides working as aptamers by focusing on G4-forming RNAs located within the pre-mRNA. We showed that the G4 in the 5' UTR and first intron of VEGFA bound to the protein encoded in VEGFA gene, VEGF165, with high affinity. Moreover, G4-forming RNAs located within the PDGFA and the PDGFB introns bound to PDGF-AA and PDGF-BB, respectively, indicating that G4 in the pre-mRNA could be an aptamer. It had been reported that the putative G4-forming RNA sequences are located in some parts of most genes, thus our strategy for aptamer identification could be applicable to other proteins. It has been reported that some G4-forming RNAs in 5' UTRs are involved in translation control; however, G4-forming excised intronic RNA function has not been revealed previously. Therefore, these findings could not only contribute to the identification of RNA aptamers but also provide new insights into the biological functioning of G4-forming RNAs located within intronic RNA sequences. PMID- 26610451 TI - Two New Cyototoxic Cardenolides from the Whole Plants of Adonis multiflora Nishikawa & Koki Ito. AB - A phytochemical investigation of the whole plants of Adonis multiflora Nishikawa & Koki Ito. resulted in the isolation and identification of two new cardenolides- adonioside A (1) and adonioside B (6)--as well as four known cardenolides: tupichinolide (2) oleandrine (3), cryptostigmin II (4), and cymarin (5). Their structures were elucidated on the basis of NMR, MS, and IR spectroscopic analyses. Compounds 1, 2, 5, and 6 showed significant cytotoxicity against six human cancer cell lines (HCT-116, HepG2, HeLa, SK-OV-3, and SK-MEL-5, and SK-BR 3). PMID- 26610453 TI - Phytochelators Intended for Clinical Use in Iron Overload, Other Diseases of Iron Imbalance and Free Radical Pathology. AB - Iron chelating drugs are primarily and widely used in the treatment of transfusional iron overload in thalassaemia and similar conditions. Recent in vivo and clinical studies have also shown that chelators, and in particular deferiprone, can be used effectively in many conditions involving free radical damage and pathology including neurodegenerative, renal, hepatic, cardiac conditions and cancer. Many classes of phytochelators (Greek: phyto (phiupsilontauomicron)-plant, chele (chietalambdaeta)-claw of the crab) with differing chelating properties, including plant polyphenols resembling chelating drugs, can be developed for clinical use. The phytochelators mimosine and tropolone have been identified to be orally active and effective in animal models for the treatment of iron overload and maltol for the treatment of iron deficiency anaemia. Many critical parameters are required for the development of phytochelators for clinical use including the characterization of the therapeutic targets, ADMET, identification of the therapeutic index and risk/benefit assessment by comparison to existing therapies. Phytochelators can be developed and used as main, alternative or adjuvant therapies including combination therapies with synthetic chelators for synergistic and or complimentary therapeutic effects. The development of phytochelators is a challenging area for the introduction of new pharmaceuticals which can be used in many diseases and also in ageing. The commercial and other considerations for such development have great advantages in comparison to synthetic drugs and could also benefit millions of patients in developing countries. PMID- 26610454 TI - Synthesis of Tertiary and Quaternary Amine Derivatives from Wood Resin as Chiral NMR Solvating Agents. AB - Chiral tertiary and quaternary amine solvating agents for NMR spectroscopy were synthesized from the wood resin derivative (+)-dehydroabietylamine (2). The resolution of enantiomers of model compounds [Mosher's acid (3) and its n-Bu4N salt (4)] (guests) by (+)-dehydroabietyl-N,N-dimethylmethanamine (5) and its ten different ammonium salts (hosts) was studied. The best results with 3 were obtained using 5 while with 4 the best enantiomeric resolution was obtained using (+)-dehydroabietyl-N,N-dimethylmethanaminium bis(trifluoromethane-sulfonimide) (6). The compounds 5 and 6 showed a 1:1 complexation behaviour between the host and guest. The capability of 5 and 6 to recognize the enantiomers of various alpha-substituted carboxylic acids and their n-Bu4N salts in enantiomeric excess (ee) determinations was demonstrated. A modification of the RES-TOCSY NMR pulse sequence is described, allowing the enhancement of enantiomeric discrimination when the resolution of multiplets is insufficient. PMID- 26610455 TI - Quaternary Alkylammonium Conjugates of Steroids: Synthesis, Molecular Structure, and Biological Studies. AB - The methods of synthesis as well as physical, spectroscopic (1H-NMR, 13C-NMR, and FT-IR, ESI-MS), and biological properties of quaternary and dimeric quaternary alkylammonium conjugates of steroids are presented. The results were contrasted with theoretical calculations (PM5 methods) and potential pharmacological properties (PASS). Alkylammonium sterols exhibit a broad spectrum of antimicrobial activity comparable to squalamine. PMID- 26610456 TI - Ultrasound-Assisted Extraction, Antioxidant and Anticancer Activities of the Polysaccharides from Rhynchosia minima Root. AB - Box-Behnken design (BBD), one of the most common response surface methodology (RSM) methods, was used to optimize the experimental conditions for ultrasound assisted extraction of polysaccharides from Rhynchosia minima root (PRM). The antioxidant abilities and anticancer activity of purified polysaccharide fractions were also measured. The results showed that optimal extraction parameters were as follows: ultrasound exposure time, 21 min; ratio of water to material, 46 mL/g; ultrasound extraction temperature, 63 degrees C. Under these conditions, the maximum yield of PRM was 16.95%+/-0.07%. Furthermore, the main monosaccharides of purified fractions were Ara and Gal. PRM3 and PRM5 exhibited remarkable DPPH radical scavenging activities and reducing power in vitro. PRM3 showed strong inhibitory activities on the growth of MCF-7 cells in vitro. The above results indicate that polysaccharides from R. minima root have the potential to be developed as natural antioxidants and anticancer ingredients for the food and pharmaceutical industries. PMID- 26610458 TI - Synthesis, Crystal Structure, Absolute Configuration and Antitumor Activity of the Enantiomers of 5-Bromo-2-chloro-N-(1-phenylethyl)pyridine-3-sulfonamide. AB - Pyridinesulfonamide is an important fragment which has a wide range of applications in novel drugs. R- and S-isomers of 5-bromo-2-chloro-N-(1 phenylethyl)pyridine-3-sulfonamide have been synthesized, and the stereostructures have been researched. Single crystals of both compounds were obtained for X-ray analysis, and the absolute configurations (ACs) have been further confirmed by electronic circular dichroism (ECD), optical rotation (OR) and quantum chemical calculations. The crystal structures and calculated geometries were extremely similar, which permitted a comparison of the relative reliabilities of ACs obtained by ECD analyses and theoretical simulation. In addition, the effect of stereochemistry on the PI3Kalpha kinase and anticancer activity were investigated. Compounds 10a and 10b inhibit the activity of PI3Kalpha kinase with IC50 values of 1.08 and 2.69 MUM, respectively. Furthermore, molecular docking was performed to analyze the binding modes of R- and S-isomers. PMID- 26610457 TI - New Flavones, a 2-(2-Phenylethyl)-4H-chromen-4-one Derivative, and Anti Inflammatory Constituents from the Stem Barks of Aquilaria sinensis. AB - In the current study, two new flavones, 4'-O-geranyltricin (1) and 3'-O geranylpolloin (2), and a new 2-(2-phenylethyl)-4H-chromen-4-one derivative, 7 hydroxyl-6-methoxy-2-(2-phenylethyl)chromone (3), have been isolated from the stem barks of A. sinensis, together with 21 known compounds 4-24. The structures of new compounds 1-3 were determined through spectroscopic and MS analyses. Compounds 2, 3, 5, 6, and 8-10 exhibited inhibition (IC50<=12.51 MUM) of superoxide anion generation by human neutrophils in response to formyl-L methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fMLP/CB). Compounds 3, 6, 8, 10, and 19 inhibited fMLP/CB-induced elastase release with IC50 values<=15.25 MUM. This investigation reveals bioactive isolates (especially 2, 3, 5, 6, 8, 9, 10, and 19) could be further developed as potential candidates for the treatment or prevention of various inflammatory diseases. PMID- 26610459 TI - Clones of FeSOD, MDHAR, DHAR Genes from White Clover and Gene Expression Analysis of ROS-Scavenging Enzymes during Abiotic Stress and Hormone Treatments. AB - Increased transcriptional levels of genes encoding antioxidant enzymes play important protective roles in coping with excessive accumulation of reactive oxygen species (ROS) in plants exposed to various abiotic stresses. To fully elucidate different evolutions and functions of ROS-scavenging enzymatic genes, we isolated iron superoxide dismutase (FeSOD), dehydroascorbate reductase (DHAR) and monodehydroascorbate reductase (MDHAR) from white clover for the first time and subsequently tested dynamic expression profiles of these genes together with previously identified other antioxidant enzyme genes including copper zinc superoxide dismutase (Cu/ZnSOD), manganese superoxide dismutase (MnSOD), glutathione reductase (GR), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX) in response to cold, drought, salinity, cadmium stress and exogenous abscisic acid (ABA) or spermidine (Spd) treatment. The cloned fragments of FeSOD, DHAR and MDHAR genes were 630, 471 and 669 bp nucleotide sequences encoding 210, 157 and 223 amino acids, respectively. Phylogenetic analysis indicated that both amino acid and nucleotide sequences of these three genes are highly conservative. In addition, the analysis of genes expression showed the transcription of GR, POD, MDHAR, DHAR and Cu/ZnSOD were rapidly activated with relatively high abundance during cold stress. Differently, CAT, APX, FeSOD, Cu/ZnSOD and MnSOD exhibited more abundant transcripts compared to others under drought stress. Under salt stress, CAT was induced preferentially (3-12 h) compared to GR which was induced later (12-72 h). Cadmium stress mainly up regulated Cu/ZnSOD, DHAR and MDHAR. Interestingly, most of genes expression induced by ABA or Spd happened prior to various abiotic stresses. The particular expression patterns and different response time of these genes indicated that white clover differentially activates genes encoding antioxidant enzymes to mitigate the damage of ROS during various environmental stresses. PMID- 26610460 TI - Carapanolides T-X from Carapa guianensis (Andiroba) Seeds. AB - Two new mexicanolide-type limonoids, carapanolides T-U (1-2), and three new phragmalin-type limonoids, carapanolides V-X (3-5), were isolated from the seeds of Carapa guianensis (andiroba). Their structures were determined on the basis of 1D- and 2D-NMR spectroscopy. PMID- 26610461 TI - Pyranocoumarins from Root Extracts of Peucedanum praeruptorum Dunn with Multidrug Resistance Reversal and Anti-Inflammatory Activities. AB - In the search for novel herbal-based anticancer agents, we isolated a new angular type pyranocoumarin, (+)-cis-(3'S,4'S)-3'-angeloyl-4'-tigloylkhellactone (1) along with 12 pyranocoumarins (2-13), two furanocoumarins (14, 15), and a polyacetylene (16) were isolated from the roots of Peucedanum praeruptorum using chromatographic separation methods. The structures of the compounds were determined using spectroscopic analysis with nuclear magnetic resonance (NMR) and high-resolution-electrospray ionization-mass spectrometry (HR-ESI-MS). The multidrug-resistance (MDR) reversal and anti-inflammatory effects of all the isolated compounds were evaluated in human sarcoma MES-SA/Dx5 and lipopolysaccharide (LPS)-induced RAW 264.7 cells. Among the 16 tested compounds, two (2 and 16) downregulated nitric oxide (NO) production and five (1, 7, 8, 11, and 13) inhibited the efflux of drugs by MDR protein, indicating the reversal of MDR. Therefore, these compounds may be potential candidates for the development of effective agents against MDR forms of cancer. PMID- 26610462 TI - DNA Aptamers in the Diagnosis and Treatment of Human Diseases. AB - Aptamers have a promising role in the field of life science and have been extensively researched for application as analytical tools, therapeutic agents and as vehicles for targeted drug delivery. Compared with RNA aptamers, DNA aptamers have inherent advantages in stability and facility of generation and synthesis. To better understand the specific potential of DNA aptamers, an overview of the progress in the generation and application of DNA aptamers in human disease diagnosis and therapy are presented in this review. Special attention is given to researches that are relatively close to practical application. DNA aptamers are expected to have great potential in the diagnosis and treatment of human diseases. PMID- 26610463 TI - Algae Undaria pinnatifida Protects Hypothalamic Neurons against Endoplasmic Reticulum Stress through Akt/mTOR Signaling. AB - Increased endoplasmic reticulum (ER) stress is known to be one of the causes of hypothalamic neuronal damage, as well as a cause of metabolic disorders such as obesity and diabetes. Recent evidence has suggested that Undaria pinnatifida (UP), an edible brown algae, has antioxidant activity. However, the neuroprotective effect of UP has yet to be examined. In this study, to investigate the neuroprotective effect of UP on ER stress-induced neuronal damage in mouse hypothalamic neurons, mice immortal hypothalamic neurons (GT1-7) were incubated with extract of UP. ER stress was induced by treating with tunicamycin. Tunicamycin induced apoptotic cell death was compared with the vehicle treatment through excessive ER stress. However UP protected GT1-7 cells from cell death, occurring after treatment with tunicamycin by reducing ER stress. Treatment with UP resulted in reduced increment of ATF6 and CHOP, and recovered the decrease of phosphorylation of Akt/mTOR by tunicamycin and the increment of autophagy. These results show that UP protects GT1-7 cells from ER stress induced cell death through the Akt/mTOR pathway. The current study suggests that UP may have a beneficial effect on cerebral neuronal degeneration in metabolic diseases with elevated ER stress. PMID- 26610464 TI - Development and Evaluation of Liquid and Solid Self-Emulsifying Drug Delivery Systems for Atorvastatin. AB - The objective of this work was to design and characterize liquid and solid self emulsifying drug delivery systems (SEDDS) for poorly soluble atorvastatin. To optimize the composition of liquid atorvastatin-SEDDS, solubility tests, pseudoternary phase diagrams, emulsification studies and other in vitro examinations (thermodynamic stability, droplet size and zeta potential analysis) were performed. Due to the disadvantages of liquid SEDDS (few choices for dosage forms, low stability and portability during the manufacturing process), attempts were also made to obtain solid SEDDS. Solid SEDDS were successfully obtained using the spray drying technique from two optimized liquid formulations, CF3 and OF2. Despite liquid SEDDS formulation, CF3 was characterized by lower turbidity, higher percentage transmittance and better self-emulsifying properties, and based on the in vitro dissolution study it can be concluded that better solubilization properties were exhibited by solid formulation OF2. Overall, the studies demonstrated the possibility of formulating liquid and solid SEEDS as promising carriers of atorvastatin. SEDDS, with their unique solubilization properties, provide the opportunity to deliver lipophilic drugs to the gastrointestinal tract in a solubilized state, avoiding dissolution-a restricting factor in absorption rate of BCS Class 2 drugs, including atorvastatin. PMID- 26610465 TI - Synthesis and Fungicidal Activities of (Z/E)-3,7-Dimethyl-2,6-octadienamide and Its 6,7-Epoxy Analogues. AB - In order to find new lead compounds with high fungicidal activity, (Z/E)-3,7 dimethyl-2,6-octadienoic acids were synthesized via selective two-step oxidation using the commercially available geraniol/nerol as raw materials. Twenty-eight different (Z/E)-3,7-dimethyl-2,6-octadienamide derivatives were prepared by reactions of (Z/E)-carboxylic acid with various aromatic and aliphatic amines, followed by oxidation of peroxyacetic acid to afford their 6,7-epoxy analogues. All of the compounds were characterized by HR-ESI-MS and 1H-NMR spectral data. The preliminary bioassays showed that some of these compounds exhibited good fungicidal activities against Rhizoctonia solani (R. solani) at a concentration of 50 ug/mL. For example, 5C, 5I and 6b had 94.0%, 93.4% and 91.5% inhibition rates against R. solani, respectively. Compound 5f displayed EC50 values of 4.3 and 9.7 uM against Fusahum graminearum and R. Solani, respectively. PMID- 26610466 TI - Optical and Electrical Properties of TTF-MPcs (M = Cu, Zn) Interfaces for Optoelectronic Applications. AB - Sandwich structures were fabricated by a vacuum deposition method using MPc (M = Cu, Zn), with a Tetrathiafulvalene (TTF) derivative, and Indium Tin Oxide (ITO) and aluminum electrodes. The structure and morphology of the deposited films were studied by IR spectroscopy, scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS). The absorption spectra of TTF derivative-MPc (M = Cu, Zn) thin films deposited at room temperature were recorded in the spectral range 200-1000 nm. The optical band gap of the thin films was determined from the (alphahnu)(1/2) vs. hnu plot. The direct-current (DC) electrical properties of the glass/ITO/TTFderiv-MPc (M = Cu, Zn)/Al structures were also investigated. Changes in conductivity of the derivative-TTF-enriched Pc compounds suggest the formation of alternative paths for carrier conduction. At low voltages, forward current density obeys an ohmic I-V relationship; at higher voltages, conduction is mostly due to a space-charge-limited conduction (SCLC) mechanism. PMID- 26610467 TI - Application of Wnt Pathway Inhibitor Delivering Scaffold for Inhibiting Fibrosis in Urethra Strictures: In Vitro and in Vivo Study. AB - OBJECTIVE: To evaluate the mechanical property and biocompatibility of the Wnt pathway inhibitor (ICG-001) delivering collagen/poly(L-lactide-co-caprolactone) (P(LLA-CL)) scaffold for urethroplasty, and also the feasibility of inhibiting the extracellular matrix (ECM) expression in vitro and in vivo. METHODS: ICG-001 (1 mg (2 mM)) was loaded into a (P(LLA-CL)) scaffold with the co-axial electrospinning technique. The characteristics of the mechanical property and drug release fashion of scaffolds were tested with a mechanical testing machine (Instron) and high-performance liquid chromatography (HPLC). Rabbit bladder epithelial cells and the dermal fibroblasts were isolated by enzymatic digestion method. (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay) and scanning electron microscopy (SEM) were used to evaluate the viability and proliferation of the cells on the scaffolds. Fibrolasts treated with TGF beta1 and ICG-001 released medium from scaffolds were used to evaluate the anti fibrosis effect through immunofluorescence, real time PCR and western blot. Urethrography and histology were used to evaluate the efficacy of urethral implantation. RESULTS: The scaffold delivering ICG-001 was fabricated, the fiber diameter and mechanical strength of scaffolds with inhibitor were comparable with the non-drug scaffold. The SEM and MTT assay showed no toxic effect of ICG-001 to the proliferation of epithelial cells on the collagen/P(LLA-CL) scaffold with ICG 001. After treatment with culture medium released from the drug-delivering scaffold, the expression of Collagen type 1, 3 and fibronectin of fibroblasts could be inhibited significantly at the mRNA and protein levels. In the results of urethrography, urethral strictures and fistulas were found in the rabbits treated with non-ICG-001 delivering scaffolds, but all the rabbits treated with ICG-001-delivering scaffolds showed wide caliber in urethras. Histology results showed less collagen but more smooth muscle and thicker epithelium in urethras repaired with ICG-001 delivering scaffolds. CONCLUSION: After loading with the Wnt signal pathway inhibitor ICG-001, the Collagen/P(LLA-CL) scaffold could facilitate a decrease in the ECM deposition of fibroblasts. The ICG-001 delivering Collagen/P(LLA-CL) nanofibrous scaffold seeded with epithelial cells has the potential to be a promising substitute material for urethroplasty. Longer follow-up study in larger animals is needed in the future. PMID- 26610469 TI - The Role of Porphyrin-Free-Base in the Electronic Structures and Related Properties of N-Fused Carbazole-Zinc Porphyrin Dye Sensitizers. AB - Dye sensitizers can significantly affect power conversion efficiency of dye sensitized solar cells (DSSCs). Porphyrin-based dyes are promising sensitizers due to their performances in DSSCs. Here, based upon a N-fused carbazole-zinc porphyrin-free-base porphyrin triad containing an ethynyl-linkage (coded as DTBC), the novel porphyrin dyes named DTBC-MP and DTBC-TP were designed by varying the porphyrin-free-base units in the pi conjugation of DTBC in order to study the effect of porphyrin-free-base in the modification of electronic structures and related properties. The calculated results indicate that, the extension of the conjugate bridge with the porphyrin-free-base unit results in elevation of the highest occupied molecular orbital (HOMO) energies, decrease of the lowest unoccupied molecular orbital (LUMO) energies, reduction of the HOMO LUMO gap, red-shift of the absorption bands, and enhancement of the absorbance. The free energy changes demonstrate that introducing more porphyrin-free-base units in the conjugate bridge induces a faster rate of electron injection. The transition properties and molecular orbital characters suggest that the different transition properties might lead to a different electron injection mechanism. In terms of electronic structure, absorption spectra, light harvesting capability, and free energy changes, the designed DTBC-TP is a promising candidate dye sensitizer for DSSCs. PMID- 26610470 TI - Safety Profile of TiO2-Based Photocatalytic Nanofabrics for Indoor Formaldehyde Degradation. AB - Anatase TiO2 nanoparticles (TNPs) are synthesized using the sol-gel method and loaded onto the surface of polyester-cotton (65/35) fabrics. The nanofabrics degrade formaldehyde at an efficiency of 77% in eight hours with visible light irradiation or 97% with UV light. The loaded TNPs display very little release from nanofabrics (~0.0%) during a standard fastness to rubbing test. Assuming TNPs may fall off nanofabrics during their life cycles, we also examine the possible toxicity of TNPs to human cells. We found that up to a concentration of 220 MUg/mL, they do not affect viability of human acute monocytic leukemia cell line THP-1 macrophages and human liver and kidney cells. PMID- 26610468 TI - Multi-Functional Macromers for Hydrogel Design in Biomedical Engineering and Regenerative Medicine. AB - Contemporary biomaterials are expected to provide tailored mechanical, biological and structural cues to encapsulated or invading cells in regenerative applications. In addition, the degradative properties of the material also have to be adjustable to the desired application. Oligo- or polymeric building blocks that can be further cross-linked into hydrogel networks, here addressed as macromers, appear as the prime option to assemble gels with the necessary degrees of freedom in the adjustment of the mentioned key parameters. Recent developments in the design of multi-functional macromers with two or more chemically different types of functionalities are summarized and discussed in this review illustrating recent trends in the development of advanced hydrogel building blocks for regenerative applications. PMID- 26610471 TI - Biodistribution, Stability, and Blood Distribution of the Cell Penetrating Peptide Maurocalcine in Mice. AB - Maurocalcine (MCa) is the first natural cell penetrating peptide to be discovered in animal venom. In addition to the fact that it represents a potent vector for the cell penetration of structurally diverse therapeutic compounds, MCa also displays several distinguishing features that make it a potential peptide of choice for clinical and biotechnological applications. The aim of the present study was to gain new information about the properties of MCa in vivo in order to delineate the future potential applications of this vector. For this purpose, two analogues of this peptide with (Tyr-MCa) and without (Lin-Tyr-MCa) disulfide bridges were synthesized, radiolabeled with (125)I, and their in vitro stabilities were first evaluated in mouse blood. The results indicated that (125)I-Tyr-MCa was stable in vitro and that the disulfide bridges conferred a competitive advantage for the stability of peptide. Following in vivo injection in mice, (125)I-Tyr-MCa targeted peripheral organs with interesting quantitative differences and the main route of peptide elimination was renal. PMID- 26610472 TI - Metabolite Profile of Cervicovaginal Fluids from Early Pregnancy Is Not Predictive of Spontaneous Preterm Birth. AB - In our study, we used a mass spectrometry-based metabolomic approach to search for biomarkers that may act as early indicators of spontaneous preterm birth (sPTB). Samples were selected as a nested case-control study from the Screening for Pregnancy Endpoints (SCOPE) biobank in Auckland, New Zealand. Cervicovaginal swabs were collected at 20 weeks from women who were originally assessed as being at low risk of sPTB. Samples were analysed using gas chromatography-mass spectrometry (GC-MS). Despite the low amount of biomass (16-23 mg), 112 compounds were detected. Statistical analysis showed no significant correlations with sPTB. Comparison of reported infection and plasma inflammatory markers from early pregnancy showed two inflammatory markers were correlated with reported infection, but no correlation with any compounds in the metabolite profile was observed. We hypothesise that the lack of biomarkers of sPTB in the cervicovaginal fluid metabolome is simply because it lacks such markers in early pregnancy. We propose alternative biofluids be investigated for markers of sPTB. Our results lead us to call for greater scrutiny of previously published metabolomic data relating to biomarkers of sPTB in cervicovaginal fluids, as the use of small, high risk, or late pregnancy cohorts may identify metabolite biomarkers that are irrelevant for predicting risk in normal populations. PMID- 26610473 TI - Inhibitory Effect of Gardenoside on Free Fatty Acid-Induced Steatosis in HepG2 Hepatocytes. AB - Gardenoside is one of the most important effective extractions of a herb for its hepatoprotective properties. The aim of this study was to address the mechanism of Gardenoside on HepG2 cellular steatosis induced by free fatty acids (FFAs). The model of HepG2 steatosis was duplicated by oleic and palmitic acid at the proportion of 2:1 (FFAs mixture) for 24 h, then lipid toxicity was induced. 3 (4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were used to detect cell viability and Oil Red O staining method was used to judge the lipid accumulation respectively. Inflammatory cytokines TNF-alpha, IL-1beta, IL-6 and intracellular NFkappaB were measured after 24 h. The steatosis was significantly decreased after Gardenoside treatment without cytotoxicity. TNF-alpha, IL-1beta, IL-6 were modulated to HepG2 cells by treatment of Gardenoside. In the meantime, the activation of NFkappaB was inhibited by Gardenoside. Gardenoside has a protective effect on FFA-induced cellular steatosis in HepG2 cells which indicates that Gardenoside might be a potential therapeutic herb against NASH by suppressed supernatant inflammatory cytokine production and intracellular NFkB activity. PMID- 26610474 TI - Resveratrol Protects against Helicobacter pylori-Associated Gastritis by Combating Oxidative Stress. AB - Helicobacter pylori (H. pylori)-induced oxidative stress has been shown to play a very important role in the inflammation of the gastric mucosa and increases the risk of developing gastric cancer. Resveratrol has many biological functions and activities, including antioxidant and anti-inflammatory effect. The purpose of this study was to probe whether resveratrol inhibits H. pylori-induced gastric inflammation and to elucidate the underlying mechanisms of any effect in mice. A mouse model of H. pylori infection was established via oral inoculation with H. pylori. After one week, mice were administered resveratrol (100 mg/kg body weight/day) orally for six weeks. The mRNA and protein levels of iNOS and IL-8 were assessed using RT-PCR, Western blot and ELISA. The expression levels of IkappaBalpha and phosphorylated IkappaBalpha (which embodies the level and activation of NF-kappaB), Heme Oxygenase-1 (HO-1; a potent antioxidant enzyme) and nuclear factor-erythroid 2 related factor 2 (Nrf2) were determined using Western blot, and lipid peroxide (LPO) level and myeloperoxidase (MPO) activity were examined using an MPO colorimetric activity assay, thiobarbituric acid reaction, and histological-grade using HE staining of the gastric mucosa. The results showed that resveratrol improved the histological infiltration score and decreased LPO level and MPO activity in the gastric mucosa. Resveratrol down regulated the H. pylori-induced mRNA transcription and protein expression levels of IL-8 and iNOS, suppressed H. pylori-induced phosphorylation of IkappaBalpha, and increased the levels of HO-1 and Nrf2. In conclusion, resveratrol treatment exerted significant effects against oxidative stress and inflammation in H. pylori-infected mucosa through the suppression of IL-8, iNOS, and NF-kappaB, and moreover through the activation of the Nrf2/HO-1 pathway. PMID- 26610475 TI - Redox Roles of Reactive Oxygen Species in Cardiovascular Diseases. AB - Cardiovascular disease (CVD), a major cause of mortality in the world, has been extensively studied over the past decade. However, the exact mechanism underlying its pathogenesis has not been fully elucidated. Reactive oxygen species (ROS) play a pivotal role in the progression of CVD. Particularly, ROS are commonly engaged in developing typical characteristics of atherosclerosis, one of the dominant CVDs. This review will discuss the involvement of ROS in atherosclerosis, specifically their effect on inflammation, disturbed blood flow and arterial wall remodeling. Pharmacological interventions target ROS in order to alleviate oxidative stress and CVD symptoms, yet results are varied due to the paradoxical role of ROS in CVD. Lack of effectiveness in clinical trials suggests that understanding the exact role of ROS in the pathophysiology of CVD and developing novel treatments, such as antioxidant gene therapy and nanotechnology related antioxidant delivery, could provide a therapeutic advance in treating CVDs. While genetic therapies focusing on specific antioxidant expression seem promising in CVD treatments, multiple technological challenges exist precluding its immediate clinical applications. PMID- 26610476 TI - Epigenetic Repression of miR-218 Promotes Esophageal Carcinogenesis by Targeting ROBO1. AB - miR-218, consisting of miR-218-1 at 4p15.31 and miR-218-2 at 5q35.1, was significantly decreased in esophageal squamous cell carcinoma (ESCC) in our previous study. The aim of this study was to determine whether aberrant methylation is associated with miR-218 repression. Bisulfite sequencing analysis (BSP), methylation specific PCR (MSP), and 5-aza-2'-deoxycytidine treatment assay were applied to determine the methyaltion status of miR-218 in cells and clinical samples. In vitro assays were performed to explore the role of miR-218. Results showed that miR-218-1 was significantly CpG hypermethylated in tumor tissues (81%, 34/42) compared with paired non-tumor tissues (33%, 14/42) (p < 0.05). However, no statistical difference was found in miR-218-2. Accordingly, expression of miR-218 was negatively correlated with miR-218-1 methylation status (p < 0.05). After demethylation treatment by 5-aza-2'-deoxycytidine, there was a 2.53- and 2.40-fold increase of miR-218 expression in EC109 and EC9706, respectively. miR-218 suppressed cell proliferation and arrested cells at G1 phase by targeting 3' untranslated region (3'UTR) of roundabout guidance receptor 1 (ROBO1). A negative correlation was found between miR-218 and ROBO1 mRNA expression in clinical samples. In conclusion, our results support that aberrant CpG hypermethylation at least partly accounts for miR-218 silencing in ESCC, which impairs its tumor-suppressive function. PMID- 26610478 TI - Production of Two Novel Methoxy-Isoflavones from Biotransformation of 8 Hydroxydaidzein by Recombinant Escherichia coli Expressing O-Methyltransferase SpOMT2884 from Streptomyces peucetius. AB - Biotransformation of 8-hydroxydaidzein by recombinant Escherichia coli expressing O-methyltransferase (OMT) SpOMT2884 from Streptomyces peucetius was investigated. Two metabolites were isolated and identified as 7,4'-dihydroxy-8-methoxy isoflavone (1) and 8,4'-dihydroxy-7-methoxy-isoflavone (2), based on mass, 1H nuclear magnetic resonance (NMR) and 13C-NMR spectrophotometric analysis. The maximum production yields of compound (1) and (2) in a 5-L fermenter were 9.3 mg/L and 6.0 mg/L, respectively. The two methoxy-isoflavones showed dose dependent inhibitory effects on melanogenesis in cultured B16 melanoma cells under non-toxic conditions. Among the effects, compound (1) decreased melanogenesis to 63.5% of the control at 25 MUM. This is the first report on the 8-O-methylation activity of OMT toward isoflavones. In addition, the present study also first identified compound (1) with potent melanogenesis inhibitory activity. PMID- 26610477 TI - Molecular, Cellular and Functional Effects of Radiation-Induced Brain Injury: A Review. AB - Radiation therapy is the most effective non-surgical treatment of primary brain tumors and metastases. Preclinical studies have provided valuable insights into pathogenesis of radiation-induced injury to the central nervous system. Radiation induced brain injury can damage neuronal, glial and vascular compartments of the brain and may lead to molecular, cellular and functional changes. Given its central role in memory and adult neurogenesis, the majority of studies have focused on the hippocampus. These findings suggested that hippocampal avoidance in cranial radiotherapy prevents radiation-induced cognitive impairment of patients. However, multiple rodent studies have shown that this problem is more complex. As the radiation-induced cognitive impairment reflects hippocampal and non-hippocampal compartments, it is of critical importance to investigate molecular, cellular and functional modifications in various brain regions as well as their integration at clinically relevant doses and schedules. We here provide a literature overview, including our previously published results, in order to support the translation of preclinical findings to clinical practice, and improve the physical and mental status of patients with brain tumors. PMID- 26610479 TI - Noncoding RNA Expression Aberration Is Associated with Cancer Progression and Is a Potential Biomarker in Esophageal Squamous Cell Carcinoma. AB - Esophageal cancer is one of the most common cancers worldwide. Esophageal squamous cell carcinoma (ESCC) is the major histological type of esophageal cancer in Eastern Asian countries. Several types of noncoding RNAs (ncRNAs) function as key epigenetic regulators of gene expression and are implicated in various physiological processes. Unambiguous evidence indicates that dysregulation of ncRNAs is deeply implicated in carcinogenesis, cancer progression and metastases of various cancers, including ESCC. The current review summarizes recent findings on the ncRNA-mediated mechanisms underlying the characteristic behaviors of ESCC that will help support the development of biomarkers and the design of novel therapeutic strategies. PMID- 26610480 TI - Tuning the Phosphoryl Donor Specificity of Dihydroxyacetone Kinase from ATP to Inorganic Polyphosphate. An Insight from Computational Studies. AB - Dihydroxyacetone (DHA) kinase from Citrobacter freundii provides an easy entry for the preparation of DHA phosphate; a very important C3 building block in nature. To modify the phosphoryl donor specificity of this enzyme from ATP to inorganic polyphosphate (poly-P); a directed evolution program has been initiated. In the first cycle of evolution, the native enzyme was subjected to one round of error-prone PCR (EP-PCR) followed directly (without selection) by a round of DNA shuffling. Although the wild-type DHAK did not show activity with poly-P, after screening, sixteen mutant clones showed an activity with poly phosphate as phosphoryl donor statistically significant. The most active mutant presented a single mutation (Glu526Lys) located in a flexible loop near of the active center. Interestingly, our theoretical studies, based on molecular dynamics simulations and hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) optimizations, suggest that this mutation has an effect on the binding of the poly-P favoring a more adequate position in the active center for the reaction to take place. PMID- 26610481 TI - Establishment and Comparison of Two Different Diagnostic Platforms for Detection of DENV1 NS1 Protein. AB - Dengue virus (DENV) infection is currently at pandemic levels, with populations in tropical and subtropical regions at greatest risk of infection. Early diagnosis and management remain the cornerstone for good clinical outcomes, thus efficient and accurate diagnostic technology in the early stage of the disease is urgently needed. Serotype-specific monoclonal antibodies (mAbs) against the DENV1 nonstructural protein 1 (NS1), DA12-4, DA13-2, and DA15-3, which were recently generated using the hybridoma technique, are suitable for use in diagnostic platforms. Immunofluorescence assay (IFA), enzyme-linked immunosorbent assay (ELISA) and Western blot analysis further confirmed the serotype specificity of these three monoclonal antibodies. The ELISA-based diagnostic platform was established using the combination of two highly sensitive mAbs (DA15-3 and DB20 6). The same combination was also used for the flow cytometry-based diagnostic platform. We report here the detection limits of flow cytometry-based and ELISA based diagnostic platforms using these mAbs to be 0.1 and 1 ng/mL, respectively. The collected clinical patient serum samples were also assayed by these two serotyping diagnostic platforms. The sensitivity and specificity for detecting NS1 protein of DENV1 are 90% and 96%, respectively. The accuracy of our platform for testing clinical samples is more advanced than that of the two commercial NS1 diagnostic platforms. In conclusion, our platforms are suitable for the early detection of NS1 protein in DENV1 infected patients. PMID- 26610483 TI - Nucleotide-Induced Conformational Changes in Escherichia coli DnaA Protein Are Required for Bacterial ORC to Pre-RC Conversion at the Chromosomal Origin. AB - DnaA oligomerizes when bound to origins of chromosomal replication. Structural analysis of a truncated form of DnaA from Aquifex aeolicus has provided insight into crucial conformational differences within the AAA+ domain that are specific to the ATP- versus ADP- bound form of DnaA. In this study molecular docking of ATP and ADP onto Escherichia coli DnaA, modeled on the crystal structure of Aquifex aeolicus DnaA, reveals changes in the orientation of amino acid residues within or near the vicinity of the nucleotide-binding pocket. Upon limited proteolysis with trypsin or chymotrypsin ADP-DnaA, but not ATP-DnaA generated relatively stable proteolytic fragments of various sizes. Examined sites of limited protease susceptibility that differ between ATP-DnaA and ADP-DnaA largely reside in the amino terminal half of DnaA. The concentration of adenine nucleotide needed to induce conformational changes, as detected by these protease susceptibilities of DnaA, coincides with the conversion of an inactive bacterial origin recognition complex (bORC) to a replication efficient pre-replication complex (pre-RC) at the E. coli chromosomal origin of replication (oriC). PMID- 26610482 TI - Gap Junctional Blockade Stochastically Induces Different Species-Specific Head Anatomies in Genetically Wild-Type Girardia dorotocephala Flatworms. AB - The shape of an animal body plan is constructed from protein components encoded by the genome. However, bioelectric networks composed of many cell types have their own intrinsic dynamics, and can drive distinct morphological outcomes during embryogenesis and regeneration. Planarian flatworms are a popular system for exploring body plan patterning due to their regenerative capacity, but despite considerable molecular information regarding stem cell differentiation and basic axial patterning, very little is known about how distinct head shapes are produced. Here, we show that after decapitation in G. dorotocephala, a transient perturbation of physiological connectivity among cells (using the gap junction blocker octanol) can result in regenerated heads with quite different shapes, stochastically matching other known species of planaria (S. mediterranea, D. japonica, and P. felina). We use morphometric analysis to quantify the ability of physiological network perturbations to induce different species-specific head shapes from the same genome. Moreover, we present a computational agent-based model of cell and physical dynamics during regeneration that quantitatively reproduces the observed shape changes. Morphological alterations induced in a genomically wild-type G. dorotocephala during regeneration include not only the shape of the head but also the morphology of the brain, the characteristic distribution of adult stem cells (neoblasts), and the bioelectric gradients of resting potential within the anterior tissues. Interestingly, the shape change is not permanent; after regeneration is complete, intact animals remodel back to G. dorotocephala-appropriate head shape within several weeks in a secondary phase of remodeling following initial complete regeneration. We present a conceptual model to guide future work to delineate the molecular mechanisms by which bioelectric networks stochastically select among a small set of discrete head morphologies. Taken together, these data and analyses shed light on important physiological modifiers of morphological information in dictating species-specific shape, and reveal them to be a novel instructive input into head patterning in regenerating planaria. PMID- 26610484 TI - The kin17 Protein in Murine Melanoma Cells. AB - kin17 has been described as a protein involved in the processes of DNA replication initiation, DNA recombination, and DNA repair. kin17 has been studied as a potential molecular marker of breast cancer. This work reports the detection and localization of this protein in the murine melanoma cell line B16F10-Nex2 and in two derived subclones with different metastatic potential, B16-8HR and B16 10CR. Nuclear and chromatin-associated protein fractions were analyzed, and kin17 was detected in all fractions, with an elevated concentration observed in the chromatin-associated fraction of the clone with low metastatic potential, suggesting that the kin17 expression level could be a marker of melanoma. PMID- 26610485 TI - CREB Negatively Regulates IGF2R Gene Expression and Downstream Pathways to Inhibit Hypoxia-Induced H9c2 Cardiomyoblast Cell Death. AB - During hypoxia, gene expression is altered by various transcription factors. Insulin-like growth factor-II (IGF2) is known to be induced by hypoxia, which binds to IGF2 receptor IGF2R that acts like a G protein-coupled receptor, might cause pathological hypertrophy or activation of the mitochondria-mediated apoptosis pathway. Cyclic adenosine monophosphate (cAMP) responsive element binding protein (CREB) is central to second messenger-regulated transcription and plays a critical role in the cardiomyocyte survival pathway. In this study, we found that IGF2R level was enhanced in H9c2 cardiomyoblasts exposed to hypoxia in a time-dependent manner but was down-regulated by CREB expression. The over expression of CREB in H9c2 cardiomyoblasts suppressed the induction of hypoxia induced IGF2R expression levels and reduced cell apoptosis. Gel shift assay results further indicated that CREB binds to the promoter sequence of IGF2R. With a luciferase assay method, we further observed that CREB represses IGF2R promoter activity. These results suggest that CREB plays an important role in the inhibition of IGF2R expression by binding to the IGF2R promoter and further suppresses H9c2 cardiomyoblast cell apoptosis induced by IGF2R signaling under hypoxic conditions. PMID- 26610486 TI - Molecular Cloning, Promoter Analysis and Expression Profiles of the sox3 Gene in Japanese Flounder, Paralichthys olivaceus. AB - Sox3, which belongs to the SoxB1 subgroup, plays major roles in neural and gonadal development. In the present study, Japanese flounder Paralichthys olivaceus sox3 gene (Posox3) and its promoter sequence were isolated and characterized. The deduced PoSox3 protein contained 298 amino acids with a characteristic HMG-box domain. Alignment and phylogenetic analyses indicated that PoSox3 shares highly identical sequence with Sox3 homologues from different species. The promoter region of Posox3 has many potential transcription factor (TF) binding sites. The expression profiles of Posox3 in different developmental stages and diverse adult tissues were analyzed by quantitative real-time RT-PCR (qRT-PCR). Posox3 mRNA was maternally inherited, and maintained at a considerably high expression level between the blastula stage and the hatching stage during embryonic development. Posox3 was abundantly expressed in the adult brain and showed sexually dimorphic expression pattern. In situ hybridization (ISH) was carried out to investigate the cellular distribution of Posox3 in the ovary, and results showed the uniform distribution of Posox3 throughout the cytoplasm of oogonia and stage I-III oocytes. These results indicate that Posox3 has potentially vital roles in embryonic and neural development and may be involved in the oogenesis process. Our work provides a fundamental understanding of the structure and potential functions of Sox3 in Paralichthys olivaceus. PMID- 26610487 TI - MiR542-3p Regulates the Epithelial-Mesenchymal Transition by Directly Targeting BMP7 in NRK52e. AB - Accumulating evidence demonstrated that miRNAs are highly involved in kidney fibrosis and Epithelial-Eesenchymal Transition (EMT), however, the mechanisms of miRNAs in kidney fibrosis are poorly understood. In this work, we identified that miR542-3p could promote EMT through down-regulating bone morphogenetic protein 7 (BMP7) expression by targeting BMP7 3'UTR. Firstly, real-time PCR results showed that miR542-3p was significantly up-regulated in kidney fibrosis in vitro and in vivo. Moreover, Western blot results demonstrated that miR542-3p may promote EMT in the NRK52e cell line. In addition, we confirmed that BMP7, which played a crucial role in anti-kidney fibrosis and suppressed the progression of EMT, was a target of miR542-3p through Dual-Luciferase reporter assay, as did Western blot analysis. The effects of miR542-3p on regulating EMT could also be suppressed by transiently overexpressing BMP7 in NRK52e cells. Taken together, miR542-3p may be a critical mediator of the induction of EMT via directly targeting BMP7. PMID- 26610488 TI - The Deubiquitinase USP17 Regulates the Stability and Nuclear Function of IL-33. AB - IL-33 is a new member of the IL-1 family cytokines, which is expressed by different types of immune cells and non-immune cells. IL-33 is constitutively expressed in the nucleus, where it can act as a transcriptional regulator. So far, no direct target for nuclear IL-33 has been identified, and the regulation of IL-33 nuclear function remains largely unclear. Here, we report that the transcription of type 2 inflammatory cytokine IL-13 is positively regulated by nuclear IL-33. IL-33 can directly bind to the conserved non-coding sequence (CNS) before the translation initiation site in the IL13 gene locus. Moreover, IL-33 nuclear function and stability are regulated by the enzyme ubiquitin-specific protease 17 (USP17) through deubiquitination of IL-33 both at the K48 and at the K63 sites. Our data suggest that IL13 gene transcription can be directly activated by nuclear IL-33, which is negatively regulated by the deubiquitinase USP17. PMID- 26610489 TI - Effects of Monotypic and Binary Mixtures of Metal Oxide Nanoparticles on Microbial Growth in Sandy Soil Collected from Artificial Recharge Sites. AB - The potential effects of monotypic and binary metal oxide nanoparticles (NPs, ZnO, NiO, Co3O4 and TiO2) on microbial growth were evaluated in sandy soil collected from artificial recharge sites. Microbial growth was assessed based on adenosine triphosphate (ATP) content, dehydrogenase activity (DHA), and viable cell counts (VCC). Microbial growth based on ATP content and VCC showed considerable differences depending on NP type and concentration, whereas DHA did not significantly change. In general, ZnO NPs showed the strongest effect on microbial growth in all measurements, showing an EC50 value of 10.9 mg/L for ATP content. The ranking (EC50) of NPs based on their effect on microbial growth assessed by ATP content and VCC was ZnO > Co3O4 > NiO > TiO2. Upon exposure to binary NP mixtures, synergistic and additive modes of action were observed for ATP content and VCC, respectively. The ranges of observed (P(O)) and expected (P(E)) activity were 83%-92% and 78%-82% of the control (p-value 0.0010) based on ATP content and 78%-95% and 72%-94% of the control (p-value 0.8813) based on VCC under the tested conditions, respectively. The results indicate that the effects of NP mixtures on microbial growth in the sandy soil matrix were as great, or greater, than those of single NPs. Therefore, understanding the effects of single NPs and NP mixtures is essential for proper ecological risk assessment. Additionally, these findings demonstrate that the evaluation of NP effects may be profoundly influenced by the method of microbial growth measurement. PMID- 26610490 TI - Henrin A: A New Anti-HIV Ent-Kaurane Diterpene from Pteris henryi. AB - Henrin A (1), a new ent-kaurane diterpene, was isolated from the leaves of Pteris henryi. The chemical structure was elucidated by analysis of the spectroscopic data including one-dimensional (1D) and two-dimensional (2D) NMR spectra, and was further confirmed by X-ray crystallographic analysis. The compound was evaluated for its biological activities against a panel of cancer cell lines, dental bacterial biofilm formation, and HIV. It displayed anti-HIV potential with an IC50 value of 9.1 uM (SI = 12.2). PMID- 26610491 TI - A Refractive Index Sensor Based on a Metal-Insulator-Metal Waveguide-Coupled Ring Resonator. AB - A refractive index sensor composed of two straight metal-insulator-metal waveguides and a ring resonator is presented. One end of each straight waveguide is sealed and the other end acts as port. The transmission spectrum and magnetic field distribution of this sensor structure are simulated using finite-difference time-domain method (FDTD). The results show that an asymmetric line shape is observed in the transmission spectrum, and that the transmission spectrum shows a filter-like behavior. The quality factor and sensitivity are taken to characterize its sensing performance and filter properties. How structural parameters affect the sensing performance and filter properties is also studied. PMID- 26610492 TI - An Inductorless Self-Controlled Rectifier for Piezoelectric Energy Harvesting. AB - This paper presents a high-efficiency inductorless self-controlled rectifier for piezoelectric energy harvesting. High efficiency is achieved by discharging the piezoelectric device (PD) capacitance each time the current produced by the PD changes polarity. This is achieved automatically without the use of delay lines, thereby making the proposed circuit compatible with any type of PD. In addition, the proposed rectifier alleviates the need for an inductor, making it suitable for on-chip integration. Reported experimental results show that the proposed rectifier can harvest up to 3.9 times more energy than a full wave bridge rectifier. PMID- 26610493 TI - Toward Higher-Order Mass Detection: Influence of an Adsorbate's Rotational Inertia and Eccentricity on the Resonant Response of a Bernoulli-Euler Cantilever Beam. AB - In this paper a new theoretical model is derived, the results of which permit a detailed examination of how the resonant characteristics of a cantilever are influenced by a particle (adsorbate) attached at an arbitrary position along the beam's length. Unlike most previous work, the particle need not be small in mass or dimension relative to the beam, and the adsorbate's geometric characteristics are incorporated into the model via its rotational inertia and eccentricity relative to the beam axis. For the special case in which the adsorbate's (translational) mass is indeed small, an analytical solution is obtained for the particle-induced resonant frequency shift of an arbitrary flexural mode, including the effects of rotational inertia and eccentricity. This solution is shown to possess the exact first-order behavior in the normalized particle mass and represents a generalization of analytical solutions derived by others in earlier studies. The results suggest the potential for "higher-order" nanobeam based mass detection methods by which the multi-mode frequency response reflects not only the adsorbate's mass but also important geometric data related to its size, shape, or orientation (i.e., the mass distribution), thus resulting in more highly discriminatory techniques for discrete-mass sensing. PMID- 26610494 TI - An Electrochemical Quartz Crystal Microbalance Multisensor System Based on Phthalocyanine Nanostructured Films: Discrimination of Musts. AB - An array of electrochemical quartz crystal electrodes (EQCM) modified with nanostructured films based on phthalocyanines was developed and used to discriminate musts prepared from different varieties of grapes. Nanostructured films of iron, nickel and copper phthalocyanines were deposited on Pt/quartz crystals through the Layer by Layer technique by alternating layers of the corresponding phthalocyanine and poly-allylamine hydrochloride. Simultaneous electrochemical and mass measurements were used to study the mass changes accompanying the oxidation of electroactive species present in must samples obtained from six Spanish varieties of grapes (Juan Garcia, Prieto Picudo, Mencia Regadio, Cabernet Sauvignon, Garnacha and Tempranillo). The mass and voltammetric outputs were processed using three-way models. Parallel Factor Analysis (PARAFAC) was successfully used to discriminate the must samples according to their variety. Multi-way partial least squares (N-PLS) evidenced the correlations existing between the voltammetric data and the polyphenolic content measured by chemical methods. Similarly, N-PLS showed a correlation between mass outputs and parameters related to the sugar content. These results demonstrated that electronic tongues based on arrays of EQCM sensors can offer advantages over arrays of mass or voltammetric sensors used separately. PMID- 26610495 TI - A Passive Testing Approach for Protocols in Wireless Sensor Networks. AB - Smart systems are today increasingly developed with the number of wireless sensor devices drastically increasing. They are implemented within several contexts throughout our environment. Thus, sensed data transported in ubiquitous systems are important, and the way to carry them must be efficient and reliable. For that purpose, several routing protocols have been proposed for wireless sensor networks (WSN). However, one stage that is often neglected before their deployment is the conformance testing process, a crucial and challenging step. Compared to active testing techniques commonly used in wired networks, passive approaches are more suitable to the WSN environment. While some works propose to specify the protocol with state models or to analyze them with simulators and emulators, we here propose a logic-based approach for formally specifying some functional requirements of a novel WSN routing protocol. We provide an algorithm to evaluate these properties on collected protocol execution traces. Further, we demonstrate the efficiency and suitability of our approach by its application into common WSN functional properties, as well as specific ones designed from our own routing protocol. We provide relevant testing verdicts through a real indoor testbed and the implementation of our protocol. Furthermore, the flexibility, genericity and practicability of our approach have been proven by the experimental results. PMID- 26610496 TI - A Wireless Sensor Network-Based Approach with Decision Support for Monitoring Lake Water Quality. AB - Online monitoring and water quality analysis of lakes are urgently needed. A feasible and effective approach is to use a Wireless Sensor Network (WSN). Lake water environments, like other real world environments, present many changing and unpredictable situations. To ensure flexibility in such an environment, the WSN node has to be prepared to deal with varying situations. This paper presents a WSN self-configuration approach for lake water quality monitoring. The approach is based on the integration of a semantic framework, where a reasoner can make decisions on the configuration of WSN services. We present a WSN ontology and the relevant water quality monitoring context information, which considers its suitability in a pervasive computing environment. We also propose a rule-based reasoning engine that is used to conduct decision support through reasoning techniques and context-awareness. To evaluate the approach, we conduct usability experiments and performance benchmarks. PMID- 26610497 TI - Concept Design for a 1-Lead Wearable/Implantable ECG Front-End: Power Management. AB - Power supply quality and stability are critical for wearable and implantable biomedical applications. For this reason we have designed a reconfigurable switched-capacitor DC-DC converter that, aside from having an extremely small footprint (with an active on-chip area of only 0.04 mm2), uses a novel output voltage control method based upon a combination of adaptive gain and discrete frequency scaling control schemes. This novel DC-DC converter achieves a measured output voltage range of 1.0 to 2.2 V with power delivery up to 7.5 mW with 75% efficiency. In this paper, we present the use of this converter as a power supply for a concept design of a wearable (15 mm * 15 mm) 1-lead ECG front-end sensor device that simultaneously harvests power and communicates with external receivers when exposed to a suitable RF field. Due to voltage range limitations of the fabrication process of the current prototype chip, we focus our analysis solely on the power supply of the ECG front-end whose design is also detailed in this paper. Measurement results show not just that the power supplied is regulated, clean and does not infringe upon the ECG bandwidth, but that there is negligible difference between signals acquired using standard linear power supplies and when the power is regulated by our power management chip. PMID- 26610498 TI - Pothole Detection System Using a Black-box Camera. AB - Aging roads and poor road-maintenance systems result a large number of potholes, whose numbers increase over time. Potholes jeopardize road safety and transportation efficiency. Moreover, they are often a contributing factor to car accidents. To address the problems associated with potholes, the locations and size of potholes must be determined quickly. Sophisticated road-maintenance strategies can be developed using a pothole database, which requires a specific pothole-detection system that can collect pothole information at low cost and over a wide area. However, pothole repair has long relied on manual detection efforts. Recent automatic detection systems, such as those based on vibrations or laser scanning, are insufficient to detect potholes correctly and inexpensively owing to the unstable detection of vibration-based methods and high costs of laser scanning-based methods. Thus, in this paper, we introduce a new pothole detection system using a commercial black-box camera. The proposed system detects potholes over a wide area and at low cost. We have developed a novel pothole detection algorithm specifically designed to work with the embedded computing environments of black-box cameras. Experimental results are presented with our proposed system, showing that potholes can be detected accurately in real-time. PMID- 26610499 TI - Multi-Layer Approach for the Detection of Selective Forwarding Attacks. AB - Security breaches are a major threat in wireless sensor networks (WSNs). WSNs are increasingly used due to their broad range of important applications in both military and civilian domains. WSNs are prone to several types of security attacks. Sensor nodes have limited capacities and are often deployed in dangerous locations; therefore, they are vulnerable to different types of attacks, including wormhole, sinkhole, and selective forwarding attacks. Security attacks are classified as data traffic and routing attacks. These security attacks could affect the most significant applications of WSNs, namely, military surveillance, traffic monitoring, and healthcare. Therefore, there are different approaches to detecting security attacks on the network layer in WSNs. Reliability, energy efficiency, and scalability are strong constraints on sensor nodes that affect the security of WSNs. Because sensor nodes have limited capabilities in most of these areas, selective forwarding attacks cannot be easily detected in networks. In this paper, we propose an approach to selective forwarding detection (SFD). The approach has three layers: MAC pool IDs, rule-based processing, and anomaly detection. It maintains the safety of data transmission between a source node and base station while detecting selective forwarding attacks. Furthermore, the approach is reliable, energy efficient, and scalable. PMID- 26610500 TI - An Analytic Model for the Success Rate of a Robotic Actuator System in Hitting Random Targets. AB - Autonomous robotic systems are increasingly being used in a wide range of applications such as precision agriculture, medicine, and the military. These systems have common features which often includes an action by an "actuator" interacting with a target. While simulations and measurements exist for the success rate of hitting targets by some systems, there is a dearth of analytic models which can give insight into, and guidance on optimization, of new robotic systems. The present paper develops a simple model for estimation of the success rate for hitting random targets from a moving platform. The model has two main dimensionless parameters: the ratio of actuator spacing to target diameter; and the ratio of platform distance moved (between actuator "firings") to the target diameter. It is found that regions of parameter space having specified high success are described by simple equations, providing guidance on design. The role of a "cost function" is introduced which, when minimized, provides optimization of design, operating, and risk mitigation costs. PMID- 26610501 TI - Early Fault Diagnosis of Bearings Using an Improved Spectral Kurtosis by Maximum Correlated Kurtosis Deconvolution. AB - The early fault characteristics of rolling element bearings carried by vibration signals are quite weak because the signals are generally masked by heavy background noise. To extract the weak fault characteristics of bearings from the signals, an improved spectral kurtosis (SK) method is proposed based on maximum correlated kurtosis deconvolution (MCKD). The proposed method combines the ability of MCKD in indicating the periodic fault transients and the ability of SK in locating these transients in the frequency domain. A simulation signal overwhelmed by heavy noise is used to demonstrate the effectiveness of the proposed method. The results show that MCKD is beneficial to clarify the periodic impulse components of the bearing signals, and the method is able to detect the resonant frequency band of the signal and extract its fault characteristic frequency. Through analyzing actual vibration signals collected from wind turbines and hot strip rolling mills, we confirm that by using the proposed method, it is possible to extract fault characteristics and diagnose early faults of rolling element bearings. Based on the comparisons with the SK method, it is verified that the proposed method is more suitable to diagnose early faults of rolling element bearings. PMID- 26610502 TI - Molecular Electronic Angular Motion Transducer Broad Band Self-Noise. AB - Modern molecular electronic transfer (MET) angular motion sensors combine high technical characteristics with low cost. Self-noise is one of the key characteristics which determine applications for MET sensors. However, until the present there has not been a model describing the sensor noise in the complete operating frequency range. The present work reports the results of an experimental study of the self-noise level of such sensors in the frequency range of 0.01-200 Hz. Based on the experimental data, a theoretical model is developed. According to the model, self-noise is conditioned by thermal hydrodynamic fluctuations of the operating fluid flow in the frequency range of 0.01-2 Hz. At the frequency range of 2-100 Hz, the noise power spectral density has a specific inversely proportional dependence of the power spectral density on the frequency that could be attributed to convective processes. In the high frequency range of 100-200 Hz, the noise is conditioned by the voltage noise of the electronics module input stage operational amplifiers and is heavily reliant to the sensor electrical impedance. The presented results allow a deeper understanding of the molecular electronic sensor noise nature to suggest the ways to reduce it. PMID- 26610503 TI - Feature Selection and Predictors of Falls with Foot Force Sensors Using KNN-Based Algorithms. AB - The aging process may lead to the degradation of lower extremity function in the elderly population, which can restrict their daily quality of life and gradually increase the fall risk. We aimed to determine whether objective measures of physical function could predict subsequent falls. Ground reaction force (GRF) data, which was quantified by sample entropy, was collected by foot force sensors. Thirty eight subjects (23 fallers and 15 non-fallers) participated in functional movement tests, including walking and sit-to-stand (STS). A feature selection algorithm was used to select relevant features to classify the elderly into two groups: at risk and not at risk of falling down, for three KNN-based classifiers: local mean-based k-nearest neighbor (LMKNN), pseudo nearest neighbor (PNN), local mean pseudo nearest neighbor (LMPNN) classification. We compared classification performances, and achieved the best results with LMPNN, with sensitivity, specificity and accuracy all 100%. Moreover, a subset of GRFs was significantly different between the two groups via Wilcoxon rank sum test, which is compatible with the classification results. This method could potentially be used by non-experts to monitor balance and the risk of falling down in the elderly population. PMID- 26610504 TI - Liver Cancer Detection by a Simple, Inexpensive and Effective Immunosensor with Zinc Oxide Nanoparticles. AB - Regular monitoring of blood alpha-fetoprotein (AFP) and/or carcino-embryonic antigen (CEA) levels is important for the routine screening of liver cancer. However, AFP and CEA have a much lower specificity than des-gamma carboxyprothrombin (DCP) to detect liver cancer. Therefore, the study reported here was designed, to develop a screen-printed DCP immunosensor incorporating zinc oxide nanoparticles, for accurate determination of DCP. The designed immunosensor shows low detection limits for the detection of DCP: 0.440 ng/mL (based on impedance measurement), 0.081 ng/mL (based on real part of impedance measurement) and 0.078 ng/mL (based on imaginary part of impedance measurement), within the range of 3.125 ng/mL to 2000 ng/mL. In addition, there was little interference to DCP determination by molecules such as Na+, K+, Ca(2+), Cl(-), glucose, urea, and uric acid. It is therefore concluded that the DCP immunosensor developed and reported here is simple, inexpensive and effective, and shows promise in the rapid screening of early-stage liver cancer at home with a point of-care approach. PMID- 26610505 TI - NiCu Alloy Nanoparticle-Loaded Carbon Nanofibers for Phenolic Biosensor Applications. AB - NiCu alloy nanoparticle-loaded carbon nanofibers (NiCuCNFs) were fabricated by a combination of electrospinning and carbonization methods. A series of characterizations, including SEM, TEM and XRD, were employed to study the NiCuCNFs. The as-prepared NiCuCNFs were then mixed with laccase (Lac) and Nafion to form a novel biosensor. NiCuCNFs successfully achieved the direct electron transfer of Lac. Cyclic voltammetry and linear sweep voltammetry were used to study the electrochemical properties of the biosensor. The finally prepared biosensor showed favorable electrocatalytic effects toward hydroquinone. The detection limit was 90 nM (S/N = 3), the sensitivity was 1.5 uA uM(-1), the detection linear range was 4 * 10(-7)-2.37 * 10(-6) M. In addition, this biosensor exhibited satisfactory repeatability, reproducibility, anti interference properties and stability. Besides, the sensor achieved the detection of hydroquinone in lake water. PMID- 26610506 TI - Study on Miniaturized UHF Antennas for Partial Discharge Detection in High Voltage Electrical Equipment. AB - Detecting partial discharge (PD) is an effective way to evaluate the condition of high-voltage electrical equipment insulation. The UHF detection method has attracted attention due to its high sensitivity, strong interference resistance, and ability to locate PDs. In this paper, a miniaturized equiangular spiral antenna (ESA) for UHF detection that uses a printed circuit board is proposed. I shaped, L-shaped, and C-shaped microstrip baluns were designed to match the impedance between the ESA and coaxial cable and were verified by a vector network analyzer. For comparison, three other types of UHF antenna were also designed: A microstrip patch antenna, a microstrip slot antenna, and a printed dipole antenna. Their antenna factors were calibrated in a uniform electric field of different frequencies modulated in a gigahertz transverse electromagnetic cell. We performed comparison experiments on PD signal detection using an artificial defect model based on the international IEC 60270 standard. We also conducted time-delay test experiments on the ESA sensor to locate a PD source. It was found that the proposed ESA sensor meets PD signal detection requirements. The sensor's compact size makes it suitable for internal installation in high-voltage electrical equipment. PMID- 26610507 TI - Robust Diagnosis Method Based on Parameter Estimation for an Interturn Short Circuit Fault in Multipole PMSM under High-Speed Operation. AB - This paper proposes a diagnosis method for a multipole permanent magnet synchronous motor (PMSM) under an interturn short circuit fault. Previous works in this area have suffered from the uncertainties of the PMSM parameters, which can lead to misdiagnosis. The proposed method estimates the q-axis inductance (Lq) of the faulty PMSM to solve this problem. The proposed method also estimates the faulty phase and the value of G, which serves as an index of the severity of the fault. The q-axis current is used to estimate the faulty phase, the values of G and Lq. For this reason, two open-loop observers and an optimization method based on a particle-swarm are implemented. The q-axis current of a healthy PMSM is estimated by the open-loop observer with the parameters of a healthy PMSM. The Lq estimation significantly compensates for the estimation errors in high-speed operation. The experimental results demonstrate that the proposed method can estimate the faulty phase, G, and Lq besides exhibiting robustness against parameter uncertainties. PMID- 26610508 TI - Wireless Low-Power Integrated Basal-Body-Temperature Detection Systems Using Teeth Antennas in the MedRadio Band. AB - This study proposes using wireless low power thermal sensors for basal-body temperature detection using frequency modulated telemetry devices. A long-term monitoring sensor requires low-power circuits including a sampling circuit and oscillator. Moreover, temperature compensated technologies are necessary because the modulated frequency might have additional frequency deviations caused by the varying temperature. The temperature compensated oscillator is composed of a ring oscillator and a controlled-steering current source with temperature compensation, so the output frequency of the oscillator does not drift with temperature variations. The chip is fabricated in a standard Taiwan Semiconductor Manufacturing Company (TSMC) 0.18-MUm complementary metal oxide semiconductor (CMOS) process, and the chip area is 0.9 mm2. The power consumption of the sampling amplifier is 128 uW. The power consumption of the voltage controlled oscillator (VCO) core is less than 40 uW, and the output is -3.04 dBm with a buffer stage. The output voltage of the bandgap reference circuit is 1 V. For temperature measurements, the maximum error is 0.18 degrees C with a standard deviation of +/-0.061 degrees C, which is superior to the required specification of 0.1 degrees C. PMID- 26610509 TI - TF4SM: A Framework for Developing Traceability Solutions in Small Manufacturing Companies. AB - Nowadays, manufacturing processes have become highly complex. Besides, more and more, governmental institutions require companies to implement systems to trace a product's life (especially for foods, clinical materials or similar items). In this paper, we propose a new framework, based on cyber-physical systems, for developing traceability systems in small manufacturing companies (which because of their size cannot implement other commercial products). We propose a general theoretical framework, study the requirements of these companies in relation to traceability systems, propose a reference architecture based on both previous elements and build the first minimum functional prototype, to compare our solution to a traditional tag-based traceability system. Results show that our system reduces the number of inefficiencies and reaction time. PMID- 26610510 TI - Detection of Lettuce Discoloration Using Hyperspectral Reflectance Imaging. AB - Rapid visible/near-infrared (VNIR) hyperspectral imaging methods, employing both a single waveband algorithm and multi-spectral algorithms, were developed in order to discrimination between sound and discolored lettuce. Reflectance spectra for sound and discolored lettuce surfaces were extracted from hyperspectral reflectance images obtained in the 400-1000 nm wavelength range. The optimal wavebands for discriminating between discolored and sound lettuce surfaces were determined using one-way analysis of variance. Multi-spectral imaging algorithms developed using ratio and subtraction functions resulted in enhanced classification accuracy of above 99.9% for discolored and sound areas on both adaxial and abaxial lettuce surfaces. Ratio imaging (RI) and subtraction imaging (SI) algorithms at wavelengths of 552/701 nm and 557-701 nm, respectively, exhibited better classification performances compared to results obtained for all possible two-waveband combinations. These results suggest that hyperspectral reflectance imaging techniques can potentially be used to discriminate between discolored and sound fresh-cut lettuce. PMID- 26610511 TI - A Real-Time Monitoring System of Industry Carbon Monoxide Based on Wireless Sensor Networks. AB - Carbon monoxide (CO) burns or explodes at over-standard concentration. Hence, in this paper, a Wifi-based, real-time monitoring of a CO system is proposed for application in the construction industry, in which a sensor measuring node is designed by low-frequency modulation method to acquire CO concentration reliably, and a digital filtering method is adopted for noise filtering. According to the triangulation, the Wifi network is constructed to transmit information and determine the position of nodes. The measured data are displayed on a computer or smart phone by a graphical interface. The experiment shows that the monitoring system obtains excellent accuracy and stability in long-term continuous monitoring. PMID- 26610512 TI - Automated Negotiation for Resource Assignment in Wireless Surveillance Sensor Networks. AB - Due to the low cost of CMOS IP-based cameras, wireless surveillance sensor networks have emerged as a new application of sensor networks able to monitor public or private areas or even country borders. Since these networks are bandwidth intensive and the radioelectric spectrum is limited, especially in unlicensed bands, it is mandatory to assign frequency channels in a smart manner. In this work, we propose the application of automated negotiation techniques for frequency assignment. Results show that these techniques are very suitable for the problem, being able to obtain the best solutions among the techniques with which we have compared them. PMID- 26610513 TI - Automated Low-Cost Smartphone-Based Lateral Flow Saliva Test Reader for Drugs-of Abuse Detection. AB - Lateral flow assay tests are nowadays becoming powerful, low-cost diagnostic tools. Obtaining a result is usually subject to visual interpretation of colored areas on the test by a human operator, introducing subjectivity and the possibility of errors in the extraction of the results. While automated test readers providing a result-consistent solution are widely available, they usually lack portability. In this paper, we present a smartphone-based automated reader for drug-of-abuse lateral flow assay tests, consisting of an inexpensive light box and a smartphone device. Test images captured with the smartphone camera are processed in the device using computer vision and machine learning techniques to perform automatic extraction of the results. A deep validation of the system has been carried out showing the high accuracy of the system. The proposed approach, applicable to any line-based or color-based lateral flow test in the market, effectively reduces the manufacturing costs of the reader and makes it portable and massively available while providing accurate, reliable results. PMID- 26610514 TI - Vision Sensor-Based Road Detection for Field Robot Navigation. AB - Road detection is an essential component of field robot navigation systems. Vision sensors play an important role in road detection for their great potential in environmental perception. In this paper, we propose a hierarchical vision sensor-based method for robust road detection in challenging road scenes. More specifically, for a given road image captured by an on-board vision sensor, we introduce a multiple population genetic algorithm (MPGA)-based approach for efficient road vanishing point detection. Superpixel-level seeds are then selected in an unsupervised way using a clustering strategy. Then, according to the GrowCut framework, the seeds proliferate and iteratively try to occupy their neighbors. After convergence, the initial road segment is obtained. Finally, in order to achieve a globally-consistent road segment, the initial road segment is refined using the conditional random field (CRF) framework, which integrates high level information into road detection. We perform several experiments to evaluate the common performance, scale sensitivity and noise sensitivity of the proposed method. The experimental results demonstrate that the proposed method exhibits high robustness compared to the state of the art. PMID- 26610515 TI - Particle Fabrication Using Inkjet Printing onto Hydrophobic Surfaces for Optimization and Calibration of Trace Contraband Detection Sensors. AB - A method has been developed to fabricate patterned arrays of micrometer-sized monodisperse solid particles of ammonium nitrate on hydrophobic silicon surfaces using inkjet printing. The method relies on dispensing one or more microdrops of a concentrated aqueous ammonium nitrate solution from a drop-on-demand (DOD) inkjet printer at specific locations on a silicon substrate rendered hydrophobic by a perfluorodecytrichlorosilane monolayer coating. The deposited liquid droplets form into the shape of a spherical shaped cap; during the evaporation process, a deposited liquid droplet maintains this geometry until it forms a solid micrometer sized particle. Arrays of solid particles are obtained by sequential translation of the printer stage. The use of DOD inkjet printing for fabrication of discrete particle arrays allows for precise control of particle characteristics (mass, diameter and height), as well as the particle number and spatial distribution on the substrate. The final mass of an individual particle is precisely determined by using gravimetric measurement of the average mass of solution ejected per microdrop. The primary application of this method is fabrication of test materials for the evaluation of spatially-resolved optical and mass spectrometry based sensors used for detecting particle residues of contraband materials, such as explosives or narcotics. PMID- 26610516 TI - Influence of Culture Media on Microbial Fingerprints Using Raman Spectroscopy. AB - Raman spectroscopy has a broad range of applications across numerous scientific fields, including microbiology. Our work here monitors the influence of culture media on the Raman spectra of clinically important microorganisms (Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis and Candida albicans). Choosing an adequate medium may enhance the reproducibility of the method as well as simplifying the data processing and the evaluation. We tested four different media per organism depending on the nutritional requirements and clinical usage directly on a Petri dish. Some of the media have a significant influence on the microbial fingerprint (Roosvelt-Park Institute Medium, CHROMagar) and should not be used for the acquisition of Raman spectra. It was found that the most suitable medium for microbiological experiments regarding these organisms was Mueller Hinton agar. PMID- 26610517 TI - Study and Test of a New Bundle-Structure Riser Stress Monitoring Sensor Based on FBG. AB - To meet the requirements of riser safety monitoring in offshore oil fields, a new Fiber Bragg Grating (FBG)-based bundle-structure riser stress monitoring sensor has been developed. In cooperation with many departments, a 49-day marine test in water depths of 1365 m and 1252 m was completed on the "HYSY-981" ocean oil drilling platform. No welding and pasting were used when the sensor was installed on risers. Therefore, the installation is convenient, reliable and harmless to risers. The continuous, reasonable, time-consistent data obtained indicates that the sensor worked normally under water. In all detailed working conditions, the test results show that the sensor can do well in reflecting stresses and bending moments both in and in magnitude. The measured maximum stress is 132.7 MPa, which is below the allowable stress. In drilling and testing conditions, the average riser stress was 86.6 MPa, which is within the range of the China National Offshore Oil Corporation (CNOOC) mechanical simulation results. PMID- 26610518 TI - The Indoor Localization and Tracking Estimation Method of Mobile Targets in Three Dimensional Wireless Sensor Networks. AB - Indoor localization is a significant research area in wireless sensor networks (WSNs). Generally, the nodes of WSNs are deployed in the same plane, i.e., the floor, as the target to be positioned, which causes the sensing signal to be influenced or even blocked by unpredictable obstacles, like furniture. However, a 3D system, like Cricket, can reduce the negative impact of obstacles to the maximum extent and guarantee the sensing signal transmission by using the line of sight (LOS). However, most of the traditional localization methods are not available for the new deployment mode. In this paper, we propose the self localization of beacons method based on the Cayley-Menger determinant, which can determine the positions of beacons stuck in the ceiling; and differential sensitivity analysis (DSA) is also applied to eliminate measurement errors in measurement data fusion. Then, the calibration of beacons scheme is proposed to further refine the locations of beacons by the mobile robot. According to the robot's motion model based on dead reckoning, which is the process of determining one's current position, we employ the Hinfinity filter and the strong tracking filter (STF) to calibrate the rough locations, respectively. Lastly, the optimal node selection scheme based on geometric dilution precision (GDOP) is presented here, which is able to pick the group of beacons with the minimum GDOP from all of the beacons. Then, we propose the GDOP-based weighting estimation method (GWEM) to associate redundant information with the position of the target. To verify the proposed methods in the paper, we design and conduct a simulation and an experiment in an indoor setting. Compared to EKF and the Hinfinity filter, the adopted STF method can more effectively calibrate the locations of beacons; GWEM can provide centimeter-level precision in 3D environments by using the combination of beacons that minimizes GDOP. PMID- 26610519 TI - Tunable Microfluidic Devices for Hydrodynamic Fractionation of Cells and Beads: A Review. AB - The adjustable microfluidic devices that have been developed for hydrodynamic based fractionation of beads and cells are important for fast performance tunability through interaction of mechanical properties of particles in fluid flow and mechanically flexible microstructures. In this review, the research works reported on fabrication and testing of the tunable elastomeric microfluidic devices for applications such as separation, filtration, isolation, and trapping of single or bulk of microbeads or cells are discussed. Such microfluidic systems for rapid performance alteration are classified in two groups of bulk deformation of microdevices using external mechanical forces, and local deformation of microstructures using flexible membrane by pneumatic pressure. The main advantage of membrane-based tunable systems has been addressed to be the high capability of integration with other microdevice components. The stretchable devices based on bulk deformation of microstructures have in common advantage of simplicity in design and fabrication process. PMID- 26610520 TI - SSL: Signal Similarity-Based Localization for Ocean Sensor Networks. AB - Nowadays, wireless sensor networks are often deployed on the sea surface for ocean scientific monitoring. One of the important challenges is to localize the nodes' positions. Existing localization schemes can be roughly divided into two types: range-based and range-free. The range-based localization approaches heavily depend on extra hardware capabilities, while range-free ones often suffer from poor accuracy and low scalability, far from the practical ocean monitoring applications. In response to the above limitations, this paper proposes a novel signal similarity-based localization (SSL) technology, which localizes the nodes' positions by fully utilizing the similarity of received signal strength and the open-air characteristics of the sea surface. In the localization process, we first estimate the relative distance between neighboring nodes through comparing the similarity of received signal strength and then calculate the relative distance for non-neighboring nodes with the shortest path algorithm. After that, the nodes' relative relation map of the whole network can be obtained. Given at least three anchors, the physical locations of nodes can be finally determined based on the multi-dimensional scaling (MDS) technology. The design is evaluated by two types of ocean experiments: a zonal network and a non-regular network using 28 nodes. Results show that the proposed design improves the localization accuracy compared to typical connectivity-based approaches and also confirm its effectiveness for large-scale ocean sensor networks. PMID- 26610521 TI - A Modified Rife Algorithm for Off-Grid DOA Estimation Based on Sparse Representations. AB - In this paper we address the problem of off-grid direction of arrival (DOA) estimation based on sparse representations in the situation of multiple measurement vectors (MMV). A novel sparse DOA estimation method which changes MMV problem to SMV is proposed. This method uses sparse representations based on weighted eigenvectors (SRBWEV) to deal with the MMV problem. MMV problem can be changed to single measurement vector (SMV) problem by using the linear combination of eigenvectors of array covariance matrix in signal subspace as a new SMV for sparse solution calculation. So the complexity of this proposed algorithm is smaller than other DOA estimation algorithms of MMV. Meanwhile, it can overcome the limitation of the conventional sparsity-based DOA estimation approaches that the unknown directions belong to a predefined discrete angular grid, so it can further improve the DOA estimation accuracy. The modified Rife algorithm for DOA estimation (MRife-DOA) is simulated based on SRBWEV algorithm. In this proposed algorithm, the largest and sub-largest inner products between the measurement vector or its residual and the atoms in the dictionary are utilized to further modify DOA estimation according to the principle of Rife algorithm and the basic idea of coarse-to-fine estimation. Finally, simulation experiments show that the proposed algorithm is effective and can reduce the DOA estimation error caused by grid effect with lower complexity. PMID- 26610522 TI - UAVs Task and Motion Planning in the Presence of Obstacles and Prioritized Targets. AB - The intertwined task assignment and motion planning problem of assigning a team of fixed-winged unmanned aerial vehicles to a set of prioritized targets in an environment with obstacles is addressed. It is assumed that the targets' locations and initial priorities are determined using a network of unattended ground sensors used to detect potential threats at restricted zones. The targets are characterized by a time-varying level of importance, and timing constraints must be fulfilled before a vehicle is allowed to visit a specific target. It is assumed that the vehicles are carrying body-fixed sensors and, thus, are required to approach a designated target while flying straight and level. The fixed-winged aerial vehicles are modeled as Dubins vehicles, i.e., having a constant speed and a minimum turning radius constraint. The investigated integrated problem of task assignment and motion planning is posed in the form of a decision tree, and two search algorithms are proposed: an exhaustive algorithm that improves over run time and provides the minimum cost solution, encoded in the tree, and a greedy algorithm that provides a quick feasible solution. To satisfy the target's visitation timing constraint, a path elongation motion planning algorithm amidst obstacles is provided. Using simulations, the performance of the algorithms is compared, evaluated and exemplified. PMID- 26610523 TI - Therapeutic Potential of Interferon-gamma and Its Antagonists in Autoinflammation: Lessons from Murine Models of Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome. AB - Interferon-gamma (IFN-gamma) affects immune responses in a complex fashion. Its immunostimulatory actions, such as macrophage activation and induction of T helper 1-type responsiveness, are widely acknowledged, however, as documented by a large body of literature, IFN-gamma has also the potential to temper inflammatory processes via other pathways. In autoimmune and autoinflammatory disorders, IFN-gamma can either play a disease-enforcing role or act as protective agent, depending on the nature of the disease. In animal models of any particular autoimmune disease, certain changes in the induction procedure can reverse the net outcome of introduction or ablation of IFN-gamma. Here, we review the role of endogenous IFN-gamma in inflammatory disorders and related murine models, with a focus on systemic juvenile idiopathic arthritis (sJIA) and macrophage activation syndrome (MAS). In particular, we discuss our recent findings in a mouse model of sJIA, in which endogenous IFN-gamma acts as a regulatory agent, and compare with results from mouse models of MAS. Also, we elaborate on the complexity in the activity of IFN-gamma and the resulting difficulty of predicting its value or that of its antagonists as treatment option. PMID- 26610525 TI - The Type I IFN-Induced miRNA, miR-21. AB - The interferon (IFN) family of cytokines not only has antiviral properties at various steps in the viral replication cycle, but also anticancer activity through multiple pathways that include inhibiting cell proliferation, regulating cellular responses to inducers of apoptosis and modulating angiogenesis and the immune system. IFNs are known to induce their biological activity through the induction of protein encoding IFN-stimulated genes. However, recent studies have established that IFNs also induce the expression of microRNAs (miRNAs), which are small endogenous non-coding RNAs that suppress gene expression at the post transcriptional level. MiRNAs play critical roles in tumorigenesis and have been implicated to act as either oncogenes or tumor suppressors in various human cancers. Therefore, IFN-induced miRNAs play an important role, not only in the host response to innate immune response to cancer, but also in the tumorigenic process itself. Furthermore, IFN-induced miRNAs may participate in and/or orchestrate antiviral defense in certain viral infections. In this review, we describe our recent studies on the induction of miR-21 by type I IFN, the role of the STAT3 and NFkappaB signaling pathways in IFN-induced miR-21 expression, the role of miR-21 in different cancers and the role of miR-21 in regulating the antiviral response. PMID- 26610524 TI - Control of Biofilms with the Fatty Acid Signaling Molecule cis-2-Decenoic Acid. AB - Biofilms are complex communities of microorganisms in organized structures attached to surfaces. Importantly, biofilms are a major cause of bacterial infections in humans, and remain one of the most significant challenges to modern medical practice. Unfortunately, conventional therapies have shown to be inadequate in the treatment of most chronic biofilm infections based on the extraordinary innate tolerance of biofilms to antibiotics. Antagonists of quorum sensing signaling molecules have been used as means to control biofilms. QS and other cell-cell communication molecules are able to revert biofilm tolerance, prevent biofilm formation and disrupt fully developed biofilms, albeit with restricted effectiveness. Recently however, it has been demonstrated that Pseudomonas aeruginosa produces a small messenger molecule cis-2-decenoic acid (cis-DA) that shows significant promise as an effective adjunctive to antimicrobial treatment of biofilms. This molecule is responsible for induction of the native biofilm dispersion response in a range of Gram-negative and Gram positive bacteria and in yeast, and has been shown to reverse persistence, increase microbial metabolic activity and significantly enhance the cidal effects of conventional antimicrobial agents. In this manuscript, the use of cis-2 decenoic acid as a novel agent for biofilm control is discussed. Stimulating the biofilm dispersion response as a novel antimicrobial strategy holds significant promise for enhanced treatment of infections and in the prevention of biofilm formation. PMID- 26610526 TI - Salternamide A Suppresses Hypoxia-Induced Accumulation of HIF-1alpha and Induces Apoptosis in Human Colorectal Cancer Cells. AB - Hypoxia inducible factor-1alpha (HIF-1alpha) is an essential regulator of the cellular response to low oxygen concentrations, activating a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1alpha is overexpressed in various cancers and therefore represents a considerable chemotherapeutic target. Salternamide A (SA), a novel small molecule that is isolated from a halophilic Streptomyces sp., is a potent cytotoxic agent against a variety of human cancer cell lines. However, the mechanisms by which SA inhibits tumor growth remain to be elucidated. In the present study, we demonstrate that SA efficiently inhibits the hypoxia-induced accumulation of HIF 1alpha in a time- and concentration-dependent manner in various human cancer cells. In addition, SA suppresses the upstream signaling of HIF-1alpha, such as PI3K/Akt/mTOR, p42/p44 MAPK, and STAT3 signaling under hypoxic conditions. Furthermore, we found that SA induces cell death by stimulating G2/M cell cycle arrest and apoptosis in human colorectal cancer cells. Taken together, SA was identified as a novel small molecule HIF-1alpha inhibitor from marine natural products and is potentially a leading candidate in the development of anticancer agents. PMID- 26610528 TI - Phorbaketal A, Isolated from the Marine Sponge Phorbas sp., Exerts Its Anti Inflammatory Effects via NF-kappaB Inhibition and Heme Oxygenase-1 Activation in Lipopolysaccharide-Stimulated Macrophages. AB - Marine sponges harbor a range of biologically active compounds. Phorbaketal A is a tricyclic sesterterpenoid isolated from the marine sponge Phorbas sp.; however, little is known about its biological activities and associated molecular mechanisms. In this study, we examined the anti-inflammatory effects and underlying molecular mechanism of phorbaketal A in lipopolysaccharide (LPS) stimulated RAW 264.7 macrophages. We found that phorbaketal A significantly inhibited the LPS-induced production of nitric oxide (NO), but not prostaglandin E2, in RAW 264.7 cells. Further, phorbaketal A suppressed the expression of inducible NO synthase at both the mRNA and protein levels. In addition, phorbaketal A reduced the LPS-induced production of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and monocyte chemotactic protein-1. Treatment with phorbaketal A inhibited the transcriptional activity of nuclear factor-kappaB (NF-kappaB), a crucial signaling molecule in inflammation. Moreover, phorbaketal A up-regulated the expression of heme oxygenase-1 (HO-1) in LPS-stimulated RAW 264.7 cells. These data suggest that phorbaketal A, isolated from the marine sponge Phorbas sp., inhibits the production of inflammatory mediators via down-regulation of the NF-kappaB pathway and up-regulation of the HO-1 pathway. PMID- 26610527 TI - Omega-3 Fatty Acids and Skeletal Muscle Health. AB - Skeletal muscle is a plastic tissue capable of adapting and mal-adapting to physical activity and diet. The response of skeletal muscle to adaptive stimuli, such as exercise, can be modified by the prior nutritional status of the muscle. The influence of nutrition on skeletal muscle has the potential to substantially impact physical function and whole body metabolism. Animal and cell based models show that omega-3 fatty acids, in particular those of marine origin, can influence skeletal muscle metabolism. Furthermore, recent human studies demonstrate that omega-3 fatty acids of marine origin can influence the exercise and nutritional response of skeletal muscle. These studies show that the prior omega-3 status influences not only the metabolic response of muscle to nutrition, but also the functional response to a period of exercise training. Omega-3 fatty acids of marine origin therefore have the potential to alter the trajectory of a number of human diseases including the physical decline associated with aging. We explore the potential molecular mechanisms by which omega-3 fatty acids may act in skeletal muscle, considering the n-3/n-6 ratio, inflammation and lipidomic remodelling as possible mechanisms of action. Finally, we suggest some avenues for further research to clarify how omega-3 fatty acids may be exerting their biological action in skeletal muscle. PMID- 26610529 TI - Interactions between Carotenoids from Marine Bacteria and Other Micronutrients: Impact on Stability and Antioxidant Activity. AB - Recently isolated spore-forming pigmented marine bacteria Bacillus indicus HU36 are sources of oxygenated carotenoids with original structures (about fifteen distinct yellow and orange pigments with acylated d-glucosyl groups). In this study, we evaluated the stability (sensitivity to iron-induced autoxidation) and antioxidant activity (inhibition of iron-induced lipid peroxidation) of combinations of bacterial HU36 carotenoids with the bacterial vitamin menaquinone MQ-7 and with phenolic antioxidants (vitamin E, chlorogenic acid, rutin). Unexpectedly, MQ-7 strongly improves the ability of HU36 carotenoids to inhibit Fe(II)-induced lipid peroxidation, although MQ-7 was not consumed in the medium. We propose that their interaction modifies the carotenoid antioxidant mechanism(s), possibly by allowing carotenoids to scavenge the initiating radicals. For comparison, beta-carotene and lycopene in combination were shown to exhibit a slightly higher stability toward iron-induced autoxidation, as well as an additive antioxidant activity as compared to the carotenoids, individually. HU36 carotenoids and phenolic antioxidants displayed synergistic activities in the inhibition of linoleic acid peroxidation induced by heme iron, but not by free iron. Synergism could arise from antioxidants interacting via electron transfer through the porphyrin nucleus of heme iron. Overall, combining antioxidants acting via complementary mechanisms could be the key for optimizing the activity of this bacterial carotenoid cocktail. PMID- 26610530 TI - Characterization of a Newly Isolated Marine Fungus Aspergillus dimorphicus for Optimized Production of the Anti-Tumor Agent Wentilactones. AB - The potential anti-tumor agent wentilactones were produced by a newly isolated marine fungus Aspergillus dimorphicus. This fungus was derived from deep-sea sediment and identified by polyphasic approach, combining phenotypic, molecular, and extrolite profiles. However, wentilactone production was detected only under static cultures with very low yields. In order to improve wentilactone production, culture conditions were optimized using the response surface methodology. Under the optimal static fermentation conditions, the experimental values were closely consistent with the prediction model. The yields of wentilactone A and B were increased about 11-fold to 13.4 and 6.5 mg/L, respectively. The result was further verified by fermentation scale-up for wentilactone production. Moreover, some small-molecule elicitors were found to have capacity of stimulating wentilactone production. To our knowledge, this is first report of optimized production of tetranorlabdane diterpenoids by a deep sea derived marine fungus. The present study might be valuable for efficient production of wentilactones and fundamental investigation of the anti-tumor mechanism of norditerpenoids. PMID- 26610531 TI - Prevalence of Diabetes and Impaired Fasting Glucose in Hypertensive Adults in Rural China: Far from Leveling-Off. AB - In recent years data from many investigations has shown a leveling-off trend in diabetes incidence. In order to explain the diabetes epidemic in rural China during the past ten years, we conducted a survey from July 2012 to August 2013. Data from comprehensive questionnaires, physical examinations, and blood tests were obtained from 5919 residents with hypertension, aged >= 35 years. Diabetes and impaired fasting glucose (IFG) were defined according to the American Diabetes Association (ADA) criteria. The overall prevalence of diabetes and IFG were 15.3% (13.6% in men, 16.8% in women) and 40.7% (44.1% in men, 34.7% in women) in the hypertensive rural Chinese population. The prevalence of previously diagnosed diabetes was 6.5% (4.6% in men, 8.4% in women). The prevalence of undiagnosed diabetes was 8.7% (9.0% in men, 8.5% in women). Multivariate logistic regression revealed that increasing age, drinking, overweight or obesity, systolic blood pressure, low HDL-C, high total cholesterol and triglycerides increased the risk of diabetes (p < 0.05). Diabetes is thus still prevalent in rural areas of China and is manifesting an accelerating trend. It remains an important public health problem in China, especially in rural areas and routine assessment for the early detection and treatment of diabetes should be emphasized. PMID- 26610533 TI - Predicting the Incidence of Human Cataract through Retinal Imaging Technology. AB - With the progress of science, technology and medicine, the proportion of elderly people in society has gradually increased over the years. Thus, the medical care and health issues of this population have drawn increasing attention. In particular, among the common medical problems of the elderly, the occurrence of cataracts has been widely observed. In this study, we developed retinal imaging technology by establishing a human eye module with ray tracing. Periodic hole arrays with different degrees were constructed on the anterior surface of the lens to emulate the eyesight decline caused by cataracts. Then, we successfully predicted the incidence of cataracts among people with myopia ranging from -3.0 D to -9.0 D. Results show that periodic hole arrays cause severe eyesight decline when they are centralized in the visual center. However, the wide distribution of these arrays on the anterior surface of the lens would not significantly affect one's eyesight. PMID- 26610532 TI - Pooling Bio-Specimens in the Presence of Measurement Error and Non-Linearity in Dose-Response: Simulation Study in the Context of a Birth Cohort Investigating Risk Factors for Autism Spectrum Disorders. AB - We sought to determine the potential effects of pooling on power, false positive rate (FPR), and bias of the estimated associations between hypothetical environmental exposures and dichotomous autism spectrum disorders (ASD) status. Simulated birth cohorts in which ASD outcome was assumed to have been ascertained with uncertainty were created. We investigated the impact on the power of the analysis (using logistic regression) to detect true associations with exposure (X1) and the FPR for a non-causal correlate of exposure (X2, r = 0.7) for a dichotomized ASD measure when the pool size, sample size, degree of measurement error variance in exposure, strength of the true association, and shape of the exposure-response curve varied. We found that there was minimal change (bias) in the measures of association for the main effect (X1). There is some loss of power but there is less chance of detecting a false positive result for pooled compared to individual level models. The number of pools had more effect on the power and FPR than the overall sample size. This study supports the use of pooling to reduce laboratory costs while maintaining statistical efficiency in scenarios similar to the simulated prospective risk-enriched ASD cohort. PMID- 26610534 TI - Prolonged Sitting is Associated with Attenuated Heart Rate Variability during Sleep in Blue-Collar Workers. AB - Prolonged sitting is associated with increased risk for cardiovascular diseases and mortality. However, research into the physiological determinants underlying this relationship is still in its infancy. The aim of the study was to determine the extent to which occupational and leisure-time sitting are associated with nocturnal heart rate variability (HRV) in blue-collar workers. The study included 138 blue-collar workers (mean age 45.5 (SD 9.4) years). Sitting-time was measured objectively for four days using tri-axial accelerometers (Actigraph GT3X+) worn on the thigh and trunk. During the same period, a heart rate monitor (Actiheart) was used to sample R-R intervals from the electrocardiogram. Time and frequency domain indices of HRV were only derived during nighttime sleep, and used as markers of cardiac autonomic modulation. Regression analyses with multiple adjustments (age, gender, body mass index, smoking, job-seniority, physical work load, influence at work, and moderate-to-vigorous physical activity) were used to investigate the association between sitting time and nocturnal HRV. We found that occupational sitting-time was negatively associated (p < 0.05) with time and frequency domain HRV indices. Sitting-time explained up to 6% of the variance in HRV, independent of the covariates. Leisure-time sitting was not significantly associated with any HRV indices (p > 0.05). In conclusion, objectively measured occupational sitting-time was associated with reduced nocturnal HRV in blue collar workers. This indicates an attenuated cardiac autonomic regulation with increasing sitting-time at work regardless of moderate-to-vigorous physical activity. The implications of this association for cardiovascular disease risk warrant further investigation via long-term prospective studies and intervention studies. PMID- 26610535 TI - Harm Reduction as "Continuum Care" in Alcohol Abuse Disorder. AB - Alcohol abuse is one of the most important risk factors for health and is a major cause of death and morbidity. Despite this, only about one-tenth of individuals with alcohol abuse disorders receive therapeutic intervention and specific rehabilitation. Among the various dichotomies that limit an effective approach to the problem of alcohol use disorder treatment, one of the most prominent is integrated treatment versus harm reduction. For years, these two divergent strategies have been considered to be opposite poles of different philosophies of intervention. One is bound to the search for methods that aim to lead the subject to complete abstinence; the other prioritizes a progressive decline in substance use, with maximum reduction in the damage that is correlated with curtailing that use. Reduction of alcohol intake does not require any particular setting, but does require close collaboration between the general practitioner, specialized services for addiction, alcohology services and psychiatry. In patients who reach that target, significant savings in terms of health and social costs can be achieved. Harm reduction is a desirable target, even from an economic point of view. At the present state of neuroscientific knowledge, it is possible to go one step further in the logic that led to the integration of psychosocial and pharmacological approaches, by attempting to remove the shadows of social judgment that, at present, are aiming for a course of treatment that is directed towards absolute abstention. PMID- 26610536 TI - Factors Associated with Suicidal Ideation and Suicide Attempt among School-Going Urban Adolescents in Peru. AB - The study examines the prevalence of suicidal ideation and suicide attempt, and associated factors among school-going urban adolescents in Peru. A cross sectional survey was conducted in a sample of 916 secondary school adolescents in 2014. A structured questionnaire adapted from Global School-based Student Health Survey was used to obtain information. Data were analyzed using logistic regression models at 5% level of significance. Overall, 26.3% reported having suicidal ideation, and 17.5% reported having attempted suicide during the past 12 months. Multivariate logistic regression analysis showed that female sex, being in a fight, being insulted, being attacked, perceived unhappiness, smoking and sexual intercourse initiation were significantly associated with increased risk of suicidal ideation, while female sex, being in a fight, being insulted, being attacked, perceived unhappiness, alcohol and illicit drug use were related to suicide attempt. The prevalence of suicidal ideation and suicide attempts observed in the survey area is relatively high. Female adolescents are particularly vulnerable to report suicidal ideation and suicide attempt. Interventions that address the issue of violence against adolescents, fighting with peers, health risk behaviors particularly initiation of smoking, alcohol and illicit drug use and encourage supportive role of parents may reduce the risk of suicidal behaviors. PMID- 26610537 TI - The Association between Health Behaviours and Academic Performance in Canadian Elementary School Students: A Cross-Sectional Study. AB - BACKGROUND: Establishing early healthy eating and physical activity behaviours is critical in supporting children's long-term health and well-being. The objective of the current paper was to examine the association between health behaviours and academic performance in elementary school students in a school board in Nova Scotia, Canada. METHODS: Our population-based study included students in grades 4 6 across 18 schools in a rural school board. Diet and physical activity were assessed through validated instruments. Academic performance measures were obtained from the school board for Mathematics and English Language Arts (ELA). Associations between health behaviours and academic performance were assessed using multilevel logistic regression. RESULTS: Students with unhealthy lifestyle behaviours were more likely to have poor academic performance for both ELA and Mathematics compared to students with healthy lifestyle behaviours; associations were statistically significant for diet quality, physical activity, sugar sweetened beverage consumption for ELA; and breakfast skipping, not being physically active at morning recess, and not being physically active after school for Mathematics. The effects of diet and physical activity were independent of each other and there was no interaction between the two exposures. CONCLUSIONS: Our findings suggest that support for healthy behaviours may help to improve academic outcomes of students. PMID- 26610538 TI - Workplace Violence and Job Performance among Community Healthcare Workers in China: The Mediator Role of Quality of Life. AB - OBJECTIVE: To explore the impact of workplace violence on job performance and quality of life of community healthcare workers in China, especially the relationship of these three variables. METHODS: From December 2013 to April 2014, a total of 1404 healthcare workers were recruited by using the random cluster sampling method from Community Health Centers in Guangzhou and Shenzhen. The workplace violence scale, the job performance scale and the quality of life scale (SF-36) were self-administered. The structural equation model constructed by Amos 17.0 was employed to assess the relationship among these variables. RESULTS: Our study found that 51.64% of the respondents had an experience of workplace violence. It was found that both job performance and quality of life had a negative correlation with workplace violence. A positive association was identified between job performance and quality of life. The path analysis showed the total effect (beta = -0.243) of workplace violence on job performance consisted of a direct effect (beta = -0.113) and an indirect effect (beta = 0.130), which was mediated by quality of life. CONCLUSIONS: Workplace violence among community healthcare workers is prevalent in China. The workplace violence had negative effects on the job performance and quality of life of CHCs' workers. The study suggests that improvement in the quality of life may lead to an effective reduction of the damages in job performance caused by workplace violence. PMID- 26610539 TI - Air Pollution Exposure and Physical Activity in China: Current Knowledge, Public Health Implications, and Future Research Needs. AB - Deteriorating air quality in China has created global public health concerns in regard to health and health-related behaviors. Although emerging environmental regulations address ambient air pollution in China, the level of enforcement and long-term impact of these measures remain unknown. Exposure to air pollution has been shown to lead to multiple adverse health outcomes, including increased rates of heart disease and mortality. However, a lesser-known but increasingly significant concern is the relationship between air pollution and its effects on outdoor exercise. This is especially important in China, which has a culturally rooted lifestyle that encourages participation in outdoor physical activity. This article evaluates the intersection of air pollution and outdoor exercise and provides a discussion of issues related to its public health impact in China, where efforts to promote a healthy lifestyle may be adversely affected by the ambient air pollution that has accompanied rapid economic development and urbanization. PMID- 26610540 TI - The Effects of the Urban Built Environment on Mental Health: A Cohort Study in a Large Northern Italian City. AB - Mental health (MH) has a relevant burden on the health of populations. Common MH disorders (anxiety and non-psychotic depression) are well associated to socioeconomic individual and neighborhood characteristics, but little is known about the influence of urban structure. We analyzed among a Turin (Northwest Italy) urban population the association at area level of different urban structure characteristics (density, accessibility by public transport, accessibility to services, green and public spaces) and consumption of antidepressants. Estimates were adjusted by individual socio-demographic variables (education, housing tenure, employment) and contextual social environment (SE) variables (social and physical disorder, crime rates). Data was extracted from the Turin Longitudinal Study (TLS)-a census-based cohort study following up prospectively the mortality and morbidity of the population. As expected, individual characteristics show the strongest association with antidepressant drug consumption, while among built environment (BE) indicators accessibility by public transport and urban density only are associated to MH, being slightly protective factors. Results from this study, in agreement with previous literature, suggest that BE has a stronger effect on MH for people who spend more time in the neighborhood. Therefore, this research suggests that good accessibility to public transport, as well as a dense urban structure (versus sprawl), could contribute to reduced risk of depression, especially for women and elderly, by increasing opportunities to move around and have an active social life. PMID- 26610541 TI - An Examination of Electronic Cigarette Content on Social Media: Analysis of E Cigarette Flavor Content on Reddit. AB - In recent years, the emerging electronic cigarette (e-cigarette) marketplace has shown great development prospects all over the world. Reddit, one of the most popular forums in the world, has a very large user group and thus great influence. This study aims to gain a systematic understanding of e-cigarette flavors based on data collected from Reddit. Flavor popularity, mixing, characteristics, trends, and brands are analyzed. Fruit flavors were mentioned the most (n = 15,720) among all the posts and were among the most popular flavors (n = 2902) used in mixed blends. Strawberry and vanilla flavors were the most popular for e-juice mixing. The number of posts discussing e-cigarette flavors has increased sharply since 2014. Mt. Baker Vapor and Hangen were the most popular brands discussed among users. Information posted on Reddit about e cigarette flavors reflected consumers' interest in a variety of flavors. Our findings suggest that Reddit could be used for data mining and analysis of e cigarette-related content. Understanding how e-cigarette consumers' view and utilize flavors within their vaping experience and how producers and marketers use social media to promote flavors and sell products could provide valuable information for regulatory decision-makers. PMID- 26610542 TI - Unintentional Injuries and Psychosocial Correlates among in-School Adolescents in Malaysia. AB - The study aimed to provide estimates of the prevalence and psychosocial correlates of unintentional injury among school-going adolescents in Malaysia. Cross-sectional data from the Global School-Based Health Survey (GSHS) included 21,699 students (predominantly <=13 to >=17 years) that were selected by a two stage cluster sample design to represent all secondary school students in Forms 1 to 5. The percentage of school children reporting one or more serious injuries in the past year was 34.9%, 42.1% of boys and 27.8% of girls. The two major causes of the most serious injury were "fall" (9.9%) and motor vehicle accident or being hit by a motor vehicle (5.4%), and the most frequent type of injury sustained was cut, puncture, or stab wound (6.2%) and a broken bone or dislocated joint (4.2%). In multivariable logistic regression analysis, sociodemographic factors (being male and low socioeconomic status), substance use (tobacco and cannabis use), frequent soft drink consumption, attending physical education classes three or more times a week, other risky behavior (truancy, ever having had sex, being bullied), psychological distress, and lack of parental or guardian bonding were associated with annual injury prevalence. Several factors were identified, which could be included in injury prevention promotion programs among secondary school children. PMID- 26610543 TI - Radon Exposure Assessment and Relative Effective Dose Estimation to Inhabitants of Puglia Region, South Italy. AB - Indoor radon concentrations were measured in dwellings of the Puglia region in Southern Italy using LR-115 passive detectors. The results show that the radon concentrations varied from 15 +/- 2 to 2166 +/- 133 Bq/m3 with a geometric mean of 114 Bq/m3 and a geometric standard deviation of 2.3. An analysis on the factors affecting radon concentration such as age of the dwellings, floors, and stories, was performed. The mean effective dose to inhabitants has been calculated and found to be 8.2 mSv/y. Finally, for estimation of cancer risks, the lifetime risk and lung cancer cases per years per million have been calculated. PMID- 26610545 TI - Conformational Ensemble of the Poliovirus 3CD Precursor Observed by MD Simulations and Confirmed by SAXS: A Strategy to Expand the Viral Proteome? AB - The genomes of RNA viruses are relatively small. To overcome the small-size limitation, RNA viruses assign distinct functions to the processed viral proteins and their precursors. This is exemplified by poliovirus 3CD protein. 3C protein is a protease and RNA-binding protein. 3D protein is an RNA-dependent RNA polymerase (RdRp). 3CD exhibits unique protease and RNA-binding activities relative to 3C and is devoid of RdRp activity. The origin of these differences is unclear, since crystal structure of 3CD revealed "beads-on-a-string" structure with no significant structural differences compared to the fully processed proteins. We performed molecular dynamics (MD) simulations on 3CD to investigate its conformational dynamics. A compact conformation of 3CD was observed that was substantially different from that shown crystallographically. This new conformation explained the unique properties of 3CD relative to the individual proteins. Interestingly, simulations of mutant 3CD showed altered interface. Additionally, accelerated MD simulations uncovered a conformational ensemble of 3CD. When we elucidated the 3CD conformations in solution using small-angle X-ray scattering (SAXS) experiments a range of conformations from extended to compact was revealed, validating the MD simulations. The existence of conformational ensemble of 3CD could be viewed as a way to expand the poliovirus proteome, an observation that may extend to other viruses. PMID- 26610544 TI - Fluorescent Protein Approaches in Alpha Herpesvirus Research. AB - In the nearly two decades since the popularization of green fluorescent protein (GFP), fluorescent protein-based methodologies have revolutionized molecular and cell biology, allowing us to literally see biological processes as never before. Naturally, this revolution has extended to virology in general, and to the study of alpha herpesviruses in particular. In this review, we provide a compendium of reported fluorescent protein fusions to herpes simplex virus 1 (HSV-1) and pseudorabies virus (PRV) structural proteins, discuss the underappreciated challenges of fluorescent protein-based approaches in the context of a replicating virus, and describe general strategies and best practices for creating new fluorescent fusions. We compare fluorescent protein methods to alternative approaches, and review two instructive examples of the caveats associated with fluorescent protein fusions, including describing several improved fluorescent capsid fusions in PRV. Finally, we present our future perspectives on the types of powerful experiments these tools now offer. PMID- 26610546 TI - Genetic and Phylogenetic Characterization of Tataguine and Witwatersrand Viruses and Other Orthobunyaviruses of the Anopheles A, Capim, Guama, Koongol, Mapputta, Tete, and Turlock Serogroups. AB - The family Bunyaviridae has more than 530 members that are distributed among five genera or remain to be classified. The genus Orthobunyavirus is the most diverse bunyaviral genus with more than 220 viruses that have been assigned to more than 18 serogroups based on serological cross-reactions and limited molecular biological characterization. Sequence information for all three orthobunyaviral genome segments is only available for viruses belonging to the Bunyamwera, Bwamba/Pongola, California encephalitis, Gamboa, Group C, Mapputta, Nyando, and Simbu serogroups. Here we present coding-complete sequences for all three genome segments of 15 orthobunyaviruses belonging to the Anopheles A, Capim, Guama, Kongool, Tete, and Turlock serogroups, and of two unclassified bunyaviruses previously not known to be orthobunyaviruses (Tataguine and Witwatersrand viruses). Using those sequence data, we established the most comprehensive phylogeny of the Orthobunyavirus genus to date, now covering 15 serogroups. Our results emphasize the high genetic diversity of orthobunyaviruses and reveal that the presence of the small nonstructural protein (NSs)-encoding open reading frame is not as common in orthobunyavirus genomes as previously thought. PMID- 26610548 TI - Enterovirus D68 Infection. AB - First described in 1962 in children hospitalized for pneumonia and bronchiolitis, the Enterovirus D68 (EV-D68) is an emergent viral pathogen. Since its discovery, during the long period of surveillance up to 2005, EV-D68 was reported only as a cause of sporadic outbreaks. In recent years, many reports from different countries have described an increasing number of patients with respiratory diseases due to EV-D68 associated with relevant clinical severity. In particular, an unexpectedly high number of children have been hospitalized for severe respiratory disease due to EV-D68, requiring intensive care such as intubation and mechanical ventilation. Moreover, EV-D68 has been associated with acute flaccid paralysis and cranial nerve dysfunction in children, which has caused concerns in the community. As no specific antiviral therapy is available, treatment is mainly supportive. Moreover, because no vaccines are available, conventional infection control measures (i.e., standard, for contacts and droplets) in both community and healthcare settings are recommended. However, further studies are required to fully understand the real importance of this virus. Prompt diagnosis and continued surveillance of EV-D68 infections are essential to managing and preventing new outbreaks. Moreover, if the association between EV-D68 and severe diseases will be confirmed, the development of adequate preventive and therapeutic approaches are a priority. PMID- 26610547 TI - Oncolytic Adenovirus: Strategies and Insights for Vector Design and Immuno Oncolytic Applications. AB - Adenoviruses (Ad) are commonly used both experimentally and clinically, including oncolytic virotherapy applications. In the clinical area, efficacy is frequently hampered by the high rates of neutralizing immunity, estimated as high as 90% in some populations that promote vector clearance and limit bioavailability for tumor targeting following systemic delivery. Active tumor targeting is also hampered by the ubiquitous nature of the Ad5 receptor, hCAR, as well as the lack of highly tumor-selective targeting ligands and suitable targeting strategies. Furthermore, significant off-target interactions between the viral vector and cellular and proteinaceous components of the bloodstream have been documented that promote uptake into non-target cells and determine dose-limiting toxicities. Novel strategies are therefore needed to overcome the obstacles that prevent efficacious Ad deployment for wider clinical applications. The use of less seroprevalent Ad serotypes, non-human serotypes, capsid pseudotyping, chemical shielding and genetic masking by heterologous peptide incorporation are all potential strategies to achieve efficient vector escape from humoral immune recognition. Conversely, selective vector arming with immunostimulatory agents can be utilized to enhance their oncolytic potential by activation of cancer specific immune responses against the malignant tissues. This review presents recent advantages and pitfalls occurring in the field of adenoviral oncolytic therapies. PMID- 26610550 TI - Coxsackievirus B4 Can Infect Human Peripheral Blood-Derived Macrophages. AB - Beyond acute infections, group B coxsackieviruses (CVB) are also reported to play a role in the development of chronic diseases, like type 1 diabetes. The viral pathogenesis mainly relies on the interplay between the viruses and innate immune response in genetically-susceptible individuals. We investigated the interaction between CVB4 and macrophages considered as major players in immune response. Monocyte-derived macrophages (MDM) generated with either M-CSF or GM-CSF were inoculated with CVB4, and infection, inflammation, viral replication and persistence were assessed. M-CSF-induced MDM, but not GM-CSF-induced MDM, can be infected by CVB4. In addition, enhancing serum was not needed to infect MDM in contrast with parental monocytes. The expression of viral receptor (CAR) mRNA was similar in both M-CSF and GM-CSF MDM. CVB4 induced high levels of pro inflammatory cytokines (IL-6 and TNFalpha) in both MDM populations. CVB4 effectively replicated and persisted in M-CSF MDM, but IFNalpha was produced in the early phase of infection only. Our results demonstrate that CVB4 can replicate and persist in MDM. Further investigations are required to determine whether the interaction between the virus and MDM plays a role in the pathogenesis of CVB-induced chronic diseases. PMID- 26610549 TI - Neurotropic Enterovirus Infections in the Central Nervous System. AB - Enteroviruses are a group of positive-sense single stranded viruses that belong to the Picornaviridae family. Most enteroviruses infect humans from the gastrointestinal tract and cause mild symptoms. However, several enteroviruses can invade the central nervous system (CNS) and result in various neurological symptoms that are correlated to mortality associated with enteroviral infections. In recent years, large outbreaks of enteroviruses occurred worldwide. Therefore, these neurotropic enteroviruses have been deemed as re-emerging pathogens. Although these viruses are becoming large threats to public health, our understanding of these viruses, especially for non-polio enteroviruses, is limited. In this article, we review recent advances in the trafficking of these pathogens from the peripheral to the central nervous system, compare their cell tropism, and discuss the effects of viral infections in their host neuronal cells. PMID- 26610551 TI - Recent Advances in BLV Research. AB - Different animal models have been proposed to investigate the mechanisms of Human T-lymphotropic Virus (HTLV)-induced pathogenesis: rats, transgenic and NOD SCID/gammacnull (NOG) mice, rabbits, squirrel monkeys, baboons and macaques. These systems indeed provide useful information but have intrinsic limitations such as lack of disease relevance, species specificity or inadequate immune response. Another strategy based on a comparative virology approach is to characterize a related pathogen and to speculate on possible shared mechanisms. In this perspective, bovine leukemia virus (BLV), another member of the deltaretrovirus genus, is evolutionary related to HTLV-1. BLV induces lymphoproliferative disorders in ruminants providing useful information on the mechanisms of viral persistence, genetic determinants of pathogenesis and potential novel therapies. PMID- 26610552 TI - An Evolutionarily Young Polar Bear (Ursus maritimus) Endogenous Retrovirus Identified from Next Generation Sequence Data. AB - Transcriptome analysis of polar bear (Ursus maritimus) tissues identified sequences with similarity to Porcine Endogenous Retroviruses (PERV). Based on these sequences, four proviral copies and 15 solo long terminal repeats (LTRs) of a newly described endogenous retrovirus were characterized from the polar bear draft genome sequence. Closely related sequences were identified by PCR analysis of brown bear (Ursus arctos) and black bear (Ursus americanus) but were absent in non-Ursinae bear species. The virus was therefore designated UrsusERV. Two distinct groups of LTRs were observed including a recombinant ERV that contained one LTR belonging to each group indicating that genomic invasions by at least two UrsusERV variants have recently occurred. Age estimates based on proviral LTR divergence and conservation of integration sites among ursids suggest the viral group is only a few million years old. The youngest provirus was polar bear specific, had intact open reading frames (ORFs) and could potentially encode functional proteins. Phylogenetic analyses of UrsusERV consensus protein sequences suggest that it is part of a pig, gibbon and koala retrovirus clade. The young age estimates and lineage specificity of the virus suggests UrsusERV is a recent cross species transmission from an unknown reservoir and places the viral group among the youngest of ERVs identified in mammals. PMID- 26610553 TI - Multiple Poliovirus Proteins Repress Cytoplasmic RNA Granules. AB - We have previously shown that poliovirus (PV) infection induces stress granule (SG) formation early in infection and then inhibits the formation of SG and disperses processing bodies (PBs) by the mid-phase of infection. Loss of SG was linked to cleavage of G3BP1 by viral 3C proteinase (3C(pro)), however dispersal of PBs was not strongly linked to cleavage of specific factors by viral proteinases, suggesting other viral proteins may play roles in inhibition of SG or PB formation. Here we have screened all viral proteins for roles in inducing or inhibiting the formation of RNA granules by creating fusions with mCherry and expressing them individually in cells. Expression of viral proteins separately revealed that the capsid region P1, 2A(pro), 3A, 3C(pro), the protease precursor 3CD and 3D polymerase all affect RNA granules to varying extents, whereas 2BC does not. 2A(pro), which cleaves eIF4GI, induced SGs as expected, and entered novel foci containing the SG nucleating protein G3BP1. Of the two forms of G3BP, only G3BP1 is cleaved by a virus proteinase, 3C(pro), whereas G3BP2 is not cleaved by 3C(pro) or 2A(pro). Surprisingly, 3CD, which contains proteinase activity, differentially repressed PBs but not SGs. Further, both 2A(pro) and 3C(pro) expression dispersed PBs, however molecular targets were different since PB dispersal due to 2A(pro) and heat shock protein (Hsp)90 inhibition but not 3C(pro), could be rescued by application of oxidative stress to cells. The data indicate that PV repression of SGs and PBs is multifactorial, though protease function is dominant. PMID- 26610554 TI - Silencing of a Germin-Like Protein Gene (CchGLP) in Geminivirus-Resistant Pepper (Capsicum chinense Jacq.) BG-3821 Increases Susceptibility to Single and Mixed Infections by Geminiviruses PHYVV and PepGMV. AB - Germin-like proteins (GLPs) are encoded by a family of genes found in all plants, and in terms of function, the GLPs are implicated in the response of plants to biotic and abiotic stresses. CchGLP is a gene encoding a GLP identified in a geminivirus-resistant Capsicum chinense Jacq accession named BG-3821, and it is important in geminivirus resistance when transferred to susceptible tobacco in transgenic experiments. To characterize the role of this GLP in geminivirus resistance in the original accession from which this gene was identified, this work aimed at demonstrating the possible role of CchGLP in resistance to geminiviruses in Capsicum chinense Jacq. BG-3821. Virus-induced gene silencing studies using a geminiviral vector based in PHYVV component A, displaying that silencing of CchGLP in accession BG-3821, increased susceptibility to geminivirus single and mixed infections. These results suggested that CchGLP is an important factor for geminivirus resistance in C. chinense BG-3821 accession. PMID- 26610555 TI - Alignment of Short Reads: A Crucial Step for Application of Next-Generation Sequencing Data in Precision Medicine. AB - Precision medicine or personalized medicine has been proposed as a modernized and promising medical strategy. Genetic variants of patients are the key information for implementation of precision medicine. Next-generation sequencing (NGS) is an emerging technology for deciphering genetic variants. Alignment of raw reads to a reference genome is one of the key steps in NGS data analysis. Many algorithms have been developed for alignment of short read sequences since 2008. Users have to make a decision on which alignment algorithm to use in their studies. Selection of the right alignment algorithm determines not only the alignment algorithm but also the set of suitable parameters to be used by the algorithm. Understanding these algorithms helps in selecting the appropriate alignment algorithm for different applications in precision medicine. Here, we review current available algorithms and their major strategies such as seed-and-extend and q-gram filter. We also discuss the challenges in current alignment algorithms, including alignment in multiple repeated regions, long reads alignment and alignment facilitated with known genetic variants. PMID- 26610556 TI - Inconsistency of Association between Coffee Consumption and Cognitive Function in Adults and Elderly in a Cross-Sectional Study (ELSA-Brasil). AB - BACKGROUND: Coffee is one of the most consumed beverages worldwide and the effect on cognition appears to be task specific and vary by age. METHOD: In cohort of 14,563 public service workers (35-74 years old) we assessed coffee consumption habits and examined cognitive function using standardized neuropsychological test battery. By linear regression and generalize linear regression with logarithmic link and gamma distribution we investigated the relation of coffee consumption (never/almost never, <=1 cup/day, 2-3 cups/day, >=3 cups/day) in the last 12 months to performance on specific domains of cognition for adults and elderly separately. RESULTS: Among elderly, after adjustments, coffee consumption was associated only with an increase in the mean words remembered on learning, recall, and word recognition tests when comparing the 2-3 cups/day to never/almost never category (arithmetic mean ratio (AMR): 1.03; 95% Confidence Interval (CI): 1.00 to 1.07), and to an increase in the mean words pronounced in semantic verbal fluency test when comparing the >=3 cups/day to never/almost never category (difference of the mean: 1.23; 95% CI: 0.16 to 2.29). However, coffee consumption was not associated with any cognitive function tests in adults and also was not associated with the phonemic verbal fluency test and trail making test B in elderly. CONCLUSIONS: RESULTS suggest that coffee consumption might be slightly beneficial to memory in elderly but lacks a dose response relationship. Longitudinal analyses are needed to investigate possible, even if subtle, positive effects of coffee drinking on specific cognitive domains in elderly. PMID- 26610557 TI - Nutrient Composition of Retail Samples of Australian Beef Sausages. AB - Some nutrient data for beef sausages in Australia's food composition table, NUTTAB 2010, is over 25 years old and may no longer reflect the composition of this popular food. To update this, 41 retail samples of fresh beef sausages were purchased in Melbourne, Australia, in May 2015. Each purchase was analysed, uncooked, for moisture, protein and fat. Sausages were then grouped by fat content into one of three composites and analysed for a wide range of nutrients, before and after dry heat cooking, the most popular sausage cooking method. Fat content in raw sausages averaged 14.9 g/100 g, 30% lower than NUTTAB values, varying from 7.3 to 22.6 g/100 g. This indicates it is possible to formulate leaner sausages that meet consumer expectations and may qualify for certain nutrition labelling statements. Under current Australian labelling requirements, two low fat sausages contain sufficient protein, B12, niacin, phosphorus and zinc to qualify as a good source of these nutrients and sufficient iron, selenium and vitamin A to qualify as a source of these. Sodium levels are higher than fresh beef, ranging from 680 to 840 mg/100 g. These data will be used to update NUTTAB and support product labelling and consumer education. PMID- 26610558 TI - Cognitive Performance and Mood Following Ingestion of a Theacrine-Containing Dietary Supplement, Caffeine, or Placebo by Young Men and Women. AB - Theacrine is a purine alkaloid found primarily in the leaves of the Camellia Kucha plant and is now included within dietary supplements. To compare the effects of a theacrine-containing dietary supplement with caffeine and placebo on energy and mood, as well as objective measures of cognitive performance, heart rate, and blood pressure, 10 healthy men (20.8 +/- 0.7 years) and 10 healthy women (22.2 +/- 1.1 years) ingested the dietary supplement TheaTrim (Purus Labs; containing a branded form of theacrine (TeacrineTM) and caffeine (150 mg)), caffeine only (150 mg), or a placebo on three different days, separated by approximately one week. Before, and for up to 4 h following, ingestion of the assigned condition, subjects completed a subjective assessment of energy and mood, as well as tests of cognitive performance (trail making test (TMT), digit symbol substitution test (DSST)), and reaction time. Heart rate and blood pressure were measured. No condition or interaction effects were noted for TMT, DSST, or reaction time, despite a trend for improvement in selected variables with both TheaTrim and caffeine treatment. Condition effects or trends were noted for subjective feelings, with values for attentive, alert, focused, and energetic higher for TheaTrim than for placebo and caffeine, while values for lethargic and groggy were lower for TheaTrim than for placebo and caffeine. Heart rate and blood pressure were largely unaffected by treatment. These data indicate that TheaTrim treatment does not result in a statistically significant improvement in cognitive performance but may favorably impact multiple subjective feelings related to energy and mood. PMID- 26610559 TI - Intakes of Calcium and Phosphorus and Calculated Calcium-to-Phosphorus Ratios of Older Adults: NHANES 2005-2006 Data. AB - BACKGROUND: High intakes of dietary phosphorus (P), relative to calcium (Ca) intake, are associated with a lower calcium:phosphorus ratio (Ca:P) ratio which potentially has adverse health effects, including arterial calcification, bone loss, and death. A substantial percentage of older adults (50 to 70 and 71 plus years) who have a higher risk of fracture rate than younger adults typically have low intakes of dietary Ca that are dominated by higher intakes of dietary P from natural and fortified foods, and lower Ca:P ratios than desirable. OBJECTIVE: This investigation was undertaken to examine Ca and P intakes and the resulting Ca:P ratios (by mass) across gender and older adult age groups, using data from the National Health and Nutrition Examination Survey (NHANES) 2005-2006. DESIGN: NHANES data are based on a cross-sectional sample of the non-institutionalized United States (US) population within various regions. This sample is selected to be representative of the entire US population at all ages. National Cancer Institute (NCI) methods and SAS survey procedures were used for analyses. Ca:P ratios were calculated using total Ca from both foods and supplements, whereas P intakes were calculated from food composition values and supplements. The amounts of P additives in processed foods are not available. RESULTS: Mean Ca and P intakes demonstrated lower intakes of Ca and higher intakes of P compared to current Recommended Dietary Allowances (RDAs). The Ca:P ratios in older male and female adults were influenced by both low-Ca and high-P dietary consumption patterns. CONCLUSIONS: Both low total Ca intakes and high P amounts contribute to lower Ca:P ratios, i.e., ~0.7:1.0, in the consumption patterns of older adults than is recommended by the RDAs, i.e., ~1.5:1.0. Whether Ca:P ratios lower than recommended contribute to increased risk of bone loss, arterial calcification, and all-cause mortality cannot be inferred from these data. Additional amounts of chemical P additives in the food supply may actually reduce even further the Ca:P ratios of older adults of both genders, but, without P additive data from the food industry, calculation of more precise ratios from NHANES 2005-2006 data is not possible. PMID- 26610560 TI - Tomato (Lycopersicon esculentum) Supplementation Induces Changes in Cardiac miRNA Expression, Reduces Oxidative Stress and Left Ventricular Mass, and Improves Diastolic Function. AB - The aim of this study was to evaluate the effects of tomato supplementation on the normal rat heart and the role of oxidative stress in this scenario. Male Wistar rats were assigned to two groups: a control group (C; n = 16), in which animals received a control diet + 0.5 mL of corn oil/kg body weight/day, and a tomato group (T; n = 16), in which animals received a control diet supplemented with tomato +0.5 mL of corn oil/kg body weight/day. After three months, morphological, functional, and biochemical analyses were performed. Animals supplemented with tomato had a smaller left atrium diameter and myocyte cross sectional area (CSA) compared to the control group (C group: 474 (415-539); T group: 273 (258-297) um2; p = 0.004). Diastolic function was improved in rats supplemented with tomato. In addition, lipid hydroperoxide was lower (C group: 267 +/- 46.7; T group: 219 +/- 23.0 nmol/g; p = 0.039) in the myocardium of rats supplemented with tomato. Tomato intake was also associated with up-regulation of miR-107 and miR-486 and down-regulation of miR-350 and miR-872. In conclusion, tomato supplementation induces changes in miRNA expression and reduces oxidative stress. In addition, these alterations may be responsible for CSA reduction and diastolic function improvement. PMID- 26610561 TI - Resveratrol as a Bioenhancer to Improve Anti-Inflammatory Activities of Apigenin. AB - The aim of this study was to improve the anti-inflammatory activities of apigenin through co-treatment with resveratrol as a bioenhancer of apigenin. RAW 264.7 cells pretreated with hepatic metabolites formed by the co-metabolism of apigenin and resveratrol (ARMs) in HepG2 cells were stimulated with lipopolysaccharide (LPS). ARMs prominently inhibited (p < 0.05) the production of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin (IL)-1beta, IL-6 and TNF-alpha. Otherwise no such activity was observed by hepatic metabolites of apigenin alone (AMs). ARMs also effectively suppressed protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Co-administration of apigenin (50 mg/kg) and resveratrol (25 mg/kg) also showed a significant reduction of carrageenan-induced paw edema in mice (61.20% to 23.81%). Co-administration of apigenin and resveratrol led to a 2.39 fold increase in plasma apigenin levels compared to administration of apigenin alone, suggesting that co-administration of resveratrol could increase bioavailability of apigenin. When the action of resveratrol on the main apigenin metabolizing enzymes, UDP glucuronosyltransferases (UGTs), was investigated, resveratrol mainly inhibited the formation of apigenin glucuronides by UGT1A9 in a non-competitive manner with a Ki value of 7.782 MUM. These results suggested that resveratrol helps apigenin to bypass hepatic metabolism and maintain apigenin's anti-inflammatory activities in the body. PMID- 26610562 TI - Antidepressant Use is Associated with Increased Energy Intake and Similar Levels of Physical Activity. AB - Antidepressants have been associated with weight gain, but the causes are unclear. The aims of this study were to assess the association of antidepressant use with energy intake, macronutrient diet composition, and physical activity. We used data on medication use, energy intake, diet composition, and physical activity for 3073 eligible adults from the 2005-2006 National Health and Nutrition Examination Survey (NHANES). Potential confounding variables, including depression symptoms, were included in the models assessing energy intake, physical activity, and sedentary behavior. Antidepressant users reported consuming an additional (mean +/- S.E.) 215 +/- 73 kcal/day compared to non-users (p = 0.01). There were no differences in percent calories from sugar, fat, or alcohol between the two groups. Antidepressant users had similar frequencies of walking or biking, engaging in muscle-strengthening activities, and engaging in moderate or vigorous physical activity. Antidepressant users were more likely to use a computer for >=2 h/day (OR 1.77; 95% CI: 1.09-2.90), but TV watching was similar between the two groups. These results suggest increased energy intake and sedentary behavior may contribute to weight gain associated with antidepressant use. Focusing on limiting food intake and sedentary behaviors may be important in mitigating the weight gain associated with antidepressant use. PMID- 26610563 TI - Increasing Awareness and Use of Iodised Salt in a Marginalised Community Setting in North-West Pakistan. AB - Iodine deficiency is still prevalent in parts of Pakistan, despite the introduction of a national Iodine Deficiency Disorder Control Programme in 1994. The purpose of this study was to gain an understanding of the knowledge, attitudes and practice regarding the use of iodised salt in a brick kiln community, and to use this information to design an intervention to increase its consumption. A cross-sectional survey was used to assess the use of iodised salt and focus group discussions explored the attitudes and barriers to its use. Thematically analysed transcripts informed the design of a 4-month intervention. Iodised salt sales and urine iodine concentration (UIC) were monitored to assess the effectiveness of the intervention. At baseline, 2.6% of households reported use of iodised salt and barriers included its higher cost and belief about a negative impact on reproduction. During the intervention, sales of salt labelled as iodised increased by 45%, however this was not reflected in an increase in UIC. This study highlighted the positive impact of education and awareness raising on iodised salt consumption in a hard to reach, marginalised community. However, issues regarding adequate iodisation by local producers and appropriate storage also need to be urgently addressed at a provincial level. PMID- 26610564 TI - Rice and Bean Targets for Biofortification Combined with High Carotenoid Content Crops Regulate Transcriptional Mechanisms Increasing Iron Bioavailability. AB - Iron deficiency affects thousands of people worldwide. Biofortification of staple food crops aims to support the reduction of this deficiency. This study evaluates the effect of combinations of common beans and rice, targets for biofortification, with high carotenoid content crops on the iron bioavailability, protein gene expression, and antioxidant effect. Iron bioavailability was measured by the depletion/repletion method. Seven groups were tested (n = 7): Pontal bean (PB); rice + Pontal bean (R + BP); Pontal bean + sweet potato (PB + SP); Pontal bean + pumpkin (PB + P); Pontal bean + rice + sweet potato (PB + R + P); Pontal bean + rice + sweet potato (PB + R + SP); positive control (Ferrous Sulfate). The evaluations included: hemoglobin gain, hemoglobin regeneration efficiency (HRE), gene expression of divalente metal transporter 1 (DMT-1), duodenal citocromo B (DcytB), ferroportin, hephaestin, transferrin and ferritin and total plasma antioxidant capacity (TAC). The test groups, except the PB, showed higher HRE (p < 0.05) than the control. Gene expression of DMT-1, DcytB and ferroportin increased (p < 0.05) in the groups fed with high content carotenoid crops (sweet potato or pumpkin). The PB group presented lower (p < 0.05) TAC than the other groups. The combination of rice and common beans, and those with high carotenoid content crops increased protein gene expression, increasing the iron bioavailability and antioxidant capacity. PMID- 26610565 TI - Dietary Protein Intake in Dutch Elderly People: A Focus on Protein Sources. AB - INTRODUCTION: Sufficient high quality dietary protein intake is required to prevent or treat sarcopenia in elderly people. Therefore, the intake of specific protein sources as well as their timing of intake are important to improve dietary protein intake in elderly people. OBJECTIVES: to assess the consumption of protein sources as well as the distribution of protein sources over the day in community-dwelling, frail and institutionalized elderly people. METHODS: Habitual dietary intake was evaluated using 2- and 3-day food records collected from various studies involving 739 community-dwelling, 321 frail and 219 institutionalized elderly people. RESULTS: Daily protein intake averaged 71 +/- 18 g/day in community-dwelling, 71 +/- 20 g/day in frail and 58 +/- 16 g/day in institutionalized elderly people and accounted for 16% +/- 3%, 16% +/- 3% and 17% +/- 3% of their energy intake, respectively. Dietary protein intake ranged from 10 to 12 g at breakfast, 15 to 23 g at lunch and 24 to 31 g at dinner contributing together over 80% of daily protein intake. The majority of dietary protein consumed originated from animal sources (>=60%) with meat and dairy as dominant sources. Thus, 40% of the protein intake in community-dwelling, 37% in frail and 29% in institutionalized elderly originated from plant based protein sources with bread as the principle source. Plant based proteins contributed for >50% of protein intake at breakfast and between 34% and 37% at lunch, with bread as the main source. During dinner, >70% of the protein intake originated from animal protein, with meat as the dominant source. CONCLUSION: Daily protein intake in these older populations is mainly (>80%) provided by the three main meals, with most protein consumed during dinner. More than 60% of daily protein intake consumed is of animal origin, with plant based protein sources representing nearly 40% of total protein consumed. During dinner, >70% of the protein intake originated from animal protein, while during breakfast and lunch a large proportion of protein is derived from plant based protein sources. PMID- 26610566 TI - The Family-Home Nutrition Environment and Dietary Intake in Rural Children. AB - Obesity and food insecurity rates are higher among rural compared to non-rural populations. Little is known, however, about how family-home environments influence childhood obesity-related behaviors, particularly in rural settings. This study examined associations between the family-home nutrition (FN) environment, food insecurity, and dietary intake (fruits, vegetables, whole grains, dairy, protein foods, and added sugars) in rural elementary school-age children (grades K-5/6; n = 102). Parents/caregivers completed surveys on FN, food insecurity, and the Block Kids Food Screener (BKFS). Body mass index (BMI, kg/m2) was calculated from measured height and weight. Approximately 33% of children were classified as overweight/obese and 28% of families were at-risk for food insecurity. Multivariable linear regression analyses examined associations between dietary intakes with FN and food insecurity. More favorable FN scores were associated with lower added sugar intake (B = -1.38, p = 0.04) and higher vegetable (B = 0.15, p < 0.001), fruit (B = 0.71, p = 0.01), and dairy (B = 0.31, p < 0.001) intakes. No significant associations were found between food insecurity and dietary intake. Given the association between higher FN scores and more favorable dietary intake, promoting healthy FN environments among rural children is warranted. PMID- 26610567 TI - Optimization of Sample Preparation for the Identification and Quantification of Saxitoxin in Proficiency Test Mussel Sample using Liquid Chromatography-Tandem Mass Spectrometry. AB - Saxitoxin (STX) and some selected paralytic shellfish poisoning (PSP) analogues in mussel samples were identified and quantified with liquid chromatography tandem mass spectrometry (LC-MS/MS). Sample extraction and purification methods of mussel sample were optimized for LC-MS/MS analysis. The developed method was applied to the analysis of the homogenized mussel samples in the proficiency test (PT) within the EQuATox project (Establishment of Quality Assurance for the Detection of Biological Toxins of Potential Bioterrorism Risk). Ten laboratories from eight countries participated in the STX PT. Identification of PSP toxins in naturally contaminated mussel samples was performed by comparison of product ion spectra and retention times with those of reference standards. The quantitative results were obtained with LC-MS/MS by spiking reference standards in toxic mussel extracts. The results were within the z-score of +/-1 when compared to the results measured with the official AOAC (Association of Official Analytical Chemists) method 2005.06, pre-column oxidation high-performance liquid chromatography with fluorescence detection (HPLC-FLD). PMID- 26610568 TI - Recommended Mass Spectrometry-Based Strategies to Identify Ricin-Containing Samples. AB - Ricin is a protein toxin produced by the castor bean plant (Ricinus communis) together with a related protein known as R. communis agglutinin (RCA120). Mass spectrometric (MS) assays have the capacity to unambiguously identify ricin and to detect ricin's activity in samples with complex matrices. These qualitative and quantitative assays enable detection and differentiation of ricin from the less toxic RCA120 through determination of the amino acid sequence of the protein in question, and active ricin can be monitored by MS as the release of adenine from the depurination of a nucleic acid substrate. In this work, we describe the application of MS-based methods to detect, differentiate and quantify ricin and RCA120 in nine blinded samples supplied as part of the EQuATox proficiency test. Overall, MS-based assays successfully identified all samples containing ricin or RCA120 with the exception of the sample spiked with the lowest concentration (0.414 ng/mL). In fact, mass spectrometry was the most successful method for differentiation of ricin and RCA120 based on amino acid determination. Mass spectrometric methods were also successful at ranking the functional activities of the samples, successfully yielding semi-quantitative results. These results indicate that MS-based assays are excellent techniques to detect, differentiate, and quantify ricin and RCA120 in complex matrices. PMID- 26610569 TI - Botulinum Neurotoxins: Qualitative and Quantitative Analysis Using the Mouse Phrenic Nerve Hemidiaphragm Assay (MPN). AB - The historical method for the detection of botulinum neurotoxin (BoNT) is represented by the mouse bioassay (MBA) measuring the animal survival rate. Since the endpoint of the MBA is the death of the mice due to paralysis of the respiratory muscle, an ex vivo animal replacement method, called mouse phrenic nerve (MPN) assay, employs the isolated N. phrenicus-hemidiaphragm tissue. Here, BoNT causes a dose-dependent characteristic decrease of the contraction amplitude of the indirectly stimulated muscle. Within the EQuATox BoNT proficiency 13 test samples were analysed using the MPN assay by serial dilution to a bath concentration resulting in a paralysis time within the range of calibration curves generated with BoNT/A, B and E standards, respectively. For serotype identification the diluted samples were pre-incubated with polyclonal anti BoNT/A, B or E antitoxin or a combination of each. All 13 samples were qualitatively correctly identified thereby delivering superior results compared to single in vitro methods like LFA, ELISA and LC-MS/MS. Having characterized the BoNT serotype, the final bath concentrations were calculated using the calibration curves and then multiplied by the respective dilution factor to obtain the sample concentration. Depending on the source of the BoNT standards used, the quantitation of ten BoNT/A containing samples delivered a mean z-score of 7 and of three BoNT/B or BoNT/E containing samples z-scores <2, respectively. PMID- 26610570 TI - Diet and Pancreatic Cancer Prevention. AB - Pancreatic cancer is without any doubt the malignancy with the poorest prognosis and the lowest survival rate. This highly aggressive disease is rarely diagnosed at an early stage and difficult to treat due to its resistance to radiotherapy and chemotherapy. Therefore, there is an urgent need to clarify the causes responsible for pancreatic cancer and to identify preventive strategies to reduce its incidence in the population. Some circumstances, such as smoking habits, being overweight and diabetes, have been identified as potentially predisposing factors to pancreatic cancer, suggesting that diet might play a role. A diet low in fat and sugars, together with a healthy lifestyle, regular exercise, weight reduction and not smoking, may contribute to prevent pancreatic cancer and many other cancer types. In addition, increasing evidence suggests that some food may have chemo preventive properties. Indeed, a high dietary intake of fresh fruit and vegetables has been shown to reduce the risk of developing pancreatic cancer, and recent epidemiological studies have associated nut consumption with a protective effect against it. Therefore, diet could have an impact on the development of pancreatic cancer and further investigations are needed to assess the potential chemo preventive role of specific foods against this disease. This review summarizes the key evidence for the role of dietary habits and their effect on pancreatic cancer and focuses on possible mechanisms for the association between diet and risk of pancreatic cancer. PMID- 26610571 TI - Optimizing Management of Patients with Adult T Cell Leukemia-Lymphoma. AB - Adult T cell leukemia-lymphoma is a rare disease with a high mortality rate, and is challenging for the clinician. Early allogeneic stem cell transplant can confer durable remission. As novel therapeutic agents become available to treat T cell malignancies, it is increasingly important that medical oncologists, hematologists, and hematopathologists recognize and accurately diagnose adult T cell leukemia-lymphoma. There is no uniform standard of treatment of adult T cell leukemia-lymphoma, and clinical trials remain critical to improving outcomes. Here we present one management approach based on the recent advances in treatment for adult T cell leukemia-lymphoma patients. PMID- 26610572 TI - Haplotypes and Sequence Variation in the Ovine Adiponectin Gene (ADIPOQ). AB - The adiponectin gene (ADIPOQ) plays an important role in energy homeostasis. In this study five separate regions (regions 1 to 5) of ovine ADIPOQ were analysed using PCR-SSCP. Four different PCR-SSCP patterns (A1-D1, A2-D2) were detected in region-1 and region-2, respectively, with seven and six SNPs being revealed. In region-3, three different patterns (A3-C3) and three SNPs were observed. Two patterns (A4-B4, A5-B5) and two and one SNPs were observed in region-4 and region 5, respectively. In total, nineteen SNPs were detected, with five of them in the coding region and two (c.46T/C and c.515G/A) putatively resulting in amino acid changes (p.Tyr16His and p.Lys172Arg). In region-1, -2 and -3 of 316 sheep from eight New Zealand breeds, variants A1, A2 and A3 were the most common, although variant frequencies differed in the eight breeds. Across region-1 and region-3, nine haplotypes were identified and haplotypes A1-A3, A1-C3, B1-A3 and B1-C3 were most common. These results indicate that the ADIPOQ gene is polymorphic and suggest that further analysis is required to see if the variation in the gene is associated with animal production traits. PMID- 26610573 TI - The Experience of Caregivers Living with Cancer Patients: A Systematic Review and Meta-Synthesis. AB - The objectives of this meta-synthesis were to: (1) explore the experience of caregivers who were caring for cancer patients, including their perceptions and responses to the situation; and (2) describe the context and the phenomena relevant to the experience. Five databases were used: CINAHL, MEDLINE, Academic Search, Science Direct, and a Thai database known as the Thai Library Integrated System (ThaiLIS). Three sets of the context of the experience and the phenomena relevant to the experience were described. The contexts were (1) having a hard time dealing with emotional devastation; (2) knowing that the caregiving job was laborious; and (3) knowing that I was not alone. The phenomenon showed the progress of the caregivers' thoughts and actions. A general phenomenon of the experience-balancing my emotion-applied to most of the caregivers; whereas, more specific phenomenon-keeping life as normal as possible and lifting life above the illness-were experienced by a lesser number of the caregivers. This review added a more thorough explanation of the issues involved in caregiving for cancer patients. A more comprehensive description of the experience of caregiving was described. The findings of this review can be used to guide clinical practice and policy formation in cancer patient care. PMID- 26610575 TI - Evaluation of Cyantraniliprole and Other Commercial Fly Baits under Laboratory and Field Conditions. AB - Laboratory and field trials were performed to evaluate the attractiveness and efficacy of commercial baits (cyantraniliprole; methomyl + (Z)-9-tricosene; dinotefuran + (Z)-9-tricosene; imidacloprid granular + (Z)-9-tricosene; and imidacloprid liquid + (Z)-9-tricosene). In choice tests; flies were most attracted to cyantraniliprole bait > dinotefuran + (Z)-9 > methomyl + (Z)-9 bait > imidacloprid granular + (Z)-9 bait > imidacloprid liquid + (Z)-9 bait. Significant degradation in bait efficacy was observed after two weeks of aging excluding imidacloprid granular; which began to degrade in field conditions after one week. Cyantraniliprole; the new fly bait active ingredient in Zyrox((r)); had the longest time to knockdown in the laboratory tests; but on susceptible flies; achieved 95%-100% knockdown within an hour of exposure. Zyrox((r)) was resistant to weathering for a week; and was more attractive to flies in the field when compared to methomyl + (Z)-9 bait. PMID- 26610574 TI - Sex, Race, and Age Differences in Observed Years of Life, Healthy Life, and Able Life among Older Adults in The Cardiovascular Health Study. AB - OBJECTIVE: Longevity fails to account for health and functional status during aging. We sought to quantify differences in years of total life, years of healthy life, and years of able life among groups defined by age, sex, and race. DESIGN: Primary analysis of a cohort study. SETTING: 18 years of annual evaluations in four U.S. communities. PARTICIPANTS: 5888 men and women aged 65 and older. MEASUREMENTS: Years of life were calculated as the time from enrollment to death or 18 years. Years of total, healthy, and able life were determined from self report during annual or semi-annual contacts. Cumulative years were summed across each of the age and sex groups. RESULTS: White women had the best outcomes for all three measures, followed by white men, non-white women, and non-white men. For example, at the mean age of 73, a white female participant could expect 12.9 years of life, 8.9 of healthy life and 9.5 of able life, while a non-white female could expect 12.6, 7.0, and 8.0 years, respectively. A white male could expect 11.2, 8.1, and 8.9 years of life, healthy life, and able life, and a non-white male 10.3, 6.2, and 7.9 years. Regardless of starting age, individuals of the same race and sex groups spent similar amounts (not proportions) of time in an unhealthy or unable state. CONCLUSION: Gender had a greater effect on longevity than did race, but race had a greater effect on years spent healthy or able. The mean number of years spent in an unable or sick state was surprisingly independent of the lifespan. PMID- 26610576 TI - Full Genomic Characterization of a Saffold Virus Isolated in Peru. AB - While studying respiratory infections of unknown etiology we detected Saffold virus in an oropharyngeal swab collected from a two-year-old female suffering from diarrhea and respiratory illness. The full viral genome recovered by deep sequencing showed 98% identity to a previously described Saffold strain isolated in Japan. Phylogenetic analysis confirmed the Peruvian Saffold strain belongs to genotype 3 and is most closely related to strains that have circulated in Asia. This is the first documented case report of Saffold virus in Peru and the only complete genomic characterization of a Saffold-3 isolate from the Americas. PMID- 26610577 TI - A Comparison of Diets Supplemented with a Feed Additive Containing Organic Acids, Cinnamaldehyde and a Permeabilizing Complex, or Zinc Oxide, on Post-Weaning Diarrhoea, Selected Bacterial Populations, Blood Measures and Performance in Weaned Pigs Experimentally Infected with Enterotoxigenic E. coli. AB - The effects of feeding a diet supplemented with zinc oxide (ZnO) or a blend of organic acids, cinnamaldehyde and a permeabilizing complex (OACP) on post-weaning diarrhoea (PWD) and performance in pigs infected with enterotoxigenic E. coli (ETEC) were examined. Additionally, changes in selected bacterial populations and blood measures were assessed. A total of 72 pigs weaned at 22 d of age and weighing 7.2 +/- 1.02 kg (mean +/- SEM) was used. Treatments were: base diet (no antimicrobial compounds); base diet + 3 g ZnO/kg; base diet + 1.5 g OACP/kg. Dietary treatments started on the day of weaning and were fed ad libitum for 3 weeks. All pigs were infected with an F4 ETEC on d 4, 5 and 6 after weaning. The incidence of PWD was lower in pigs fed ZnO ( p = 0.026). Overall, pigs fed ZnO grew faster ( p = 0.013) and ate more ( p = 0.004) than the base diet-fed pigs, with OACP-fed pigs performing the same ( p > 0.05) as both the ZnO- and base diet fed pigs. Feed conversion ratio was similar for all diets ( p > 0.05). The percentage of E. coli with F4 fimbriae was affected a day by treatment interaction ( p = 0.037), with more E. coli with F4 fimbriae found in pigs fed ZnO on d 11 ( p = 0.011) compared to base diet-fed pigs. Only significant time effects ( p < 0.05) occurred for blood measures. Under the conditions of this study, inclusion of OACP gave statistically similar production responses to pigs fed ZnO, however pigs fed ZnO had less PWD compared to OACP- and the base diet fed pigs. PMID- 26610578 TI - Social Licking in Pregnant Dairy Heifers. AB - Housing affects social behaviors, such as competition, but little work has addressed affiliative behaviors. This study compared social licking (SL) in pregnant heifers housed indoors (in a free-stall barn) versus outdoors (on pasture), and relationships with competition, feeding and physical proximity to others. Six heifer groups were observed during two six-hour-periods in both treatments. The total number of social events (SL and agonistic interactions) was four times higher when heifers were housed indoors compared to pasture (546 +/- 43 vs. 128 +/- 7 events/group; P < 0.05). SL as a ratio of the total number of social events was similar in the two treatments (12% vs . 8% of interactions, free-stall and pasture, respectively; P > 0.05). Housing did not affect how the SL bout was initiated and terminated, the duration, the body part licked and behavior preceding licking ( P > 0.05). Animals in close proximity showed higher rates of SL ( P < 0.0001) but not agonistic interactions ( P > 0.05). A previous agonistic event did not predict occurrence or the role of heifers in the following licking event. The higher stocking density indoors likely resulted in increased social interactions. PMID- 26610579 TI - Dietary Lecithin Supplementation Can Improve the Quality of the M. Longissimus thoracis. AB - Forty crossbred (Large White * Landrace * Duroc) female pigs (16.4 kg +/- 0.94 kg) were used to investigate the effect of dietary lecithin supplementation on growth performance and pork quality. Pigs were randomly allocated to a commercial diet containing either 0, 3, 15 or 75 g lecithin/kg of feed during the grower and finisher growth phase. Pork from pigs consuming the diets containing 15 g and 75 g lecithin/kg had lower hardness ( P < 0.001) and chewiness ( P < 0.01) values compared to the controls. Dietary lecithin supplementation at 75 g/kg significantly increased ( P < 0.05) the linoleic acid and reduced ( P < 0.05) the myristic acid levels of pork compared to the control and the 3 g/kg and 15 g/kg lecithin supplemented treatments. Pigs fed the 75 g/kg lecithin supplemented diet had lower plasma cholesterol ( P < 0.05) at slaughter compared to pigs fed the control diet and the 3 g/kg and 15 g/kg lecithin supplemented treatments. These data indicate that dietary lecithin supplementation has the potential to improve the quality attributes of pork from female pigs. PMID- 26610580 TI - Influence of the Ionic Liquid Type on the Gel Polymer Electrolytes Properties. AB - Gel Polymer Electrolytes (GPEs) composed by ZnTf2 salt, poly(vinylidene fluoride co-hexafluoropropylene) (PVdF-HFP), and different ionic liquids are synthesized using n-methyl-2-pyrrolidone (NMP) as solvent. Three different imidazolium-based ionic liquids containing diverse cations and anions have been explored. Structural and electrical properties of the GPEs varying the ZnTf2 concentration are analyzed by ATR-FTIR, DSC, TG, and cyclic voltammetry. Free salt IL-GPEs present distinct behavior because they are influenced by the different IL cations and anions composition. However, inclusion of ZnTf2 salt inside the polymers provide GPEs with very similar characteristics, pointing out that ionic transport properties are principally caused by Zn(2+) and triflate movement. Whatever the IL used, the presence of NMP solvent inside the polymer's matrix turns out to be a key factor for improving the Zn(2+) transport inside the GPE due to the interaction between Zn(2+) cations and carbonyl groups of the NMP. High values of ionic conductivity, low activation energy values, and good voltammetric reversibility obtained regardless of the ionic liquid used enable these GPEs to be applied in Zn batteries. Capacities of 110-120 mAh.g(-1) have been obtained for Zn/IL-GPE/MnO2 batteries discharged at -1 mA.cm(-2). PMID- 26610581 TI - Application of Membrane Crystallization for Minerals' Recovery from Produced Water. AB - Produced water represents the largest wastewater stream from oil and gas production. Generally, its high salinity level restricts the treatment options. Membrane crystallization (MCr) is an emerging membrane process with the capability to extract simultaneously fresh water and valuable components from various streams. In the current study, the potential of MCr for produced water treatment and salt recovery was demonstrated. The experiments were carried out in lab scale and semi-pilot scale. The effect of thermal and hydrodynamic conditions on process performance and crystal characteristics were explored. Energy dispersive X-ray (EDX) and X-ray diffraction (XRD) analyses confirmed that the recovered crystals are sodium chloride with very high purity (>99.9%), also indicated by the cubic structure observed by microscopy and SEM (scanning electron microscopy) analysis. It was demonstrated experimentally that at recovery factor of 37%, 16.4 kg NaCl per cubic meter of produced water can be recovered. Anti-scaling surface morphological features of membranes were also identified. In general, the study provides a new perspective of isolation of valuable constituents from produced water that, otherwise, is considered as a nuisance. PMID- 26610582 TI - Selectivity of Direct Methanol Fuel Cell Membranes. AB - Sulfonic acid-functionalized polymer electrolyte membranes alternative to Nafion((r)) were developed. These were hydrocarbon systems, such as blend sulfonated polyetheretherketone (s-PEEK), new generation perfluorosulfonic acid (PFSA) systems, and composite zirconium phosphate-PFSA polymers. The membranes varied in terms of composition, equivalent weight, thickness, and filler and were investigated with regard to their methanol permeation characteristics and proton conductivity for application in direct methanol fuel cells. The behavior of the membrane electrode assemblies (MEA) was investigated in fuel cell with the aim to individuate a correlation between membrane characteristics and their performance in a direct methanol fuel cell (DMFC). The power density of the DMFC at 60 degrees C increased according to a square root-like function of the membrane selectivity. This was defined as the reciprocal of the product between area specific resistance and crossover. The power density achieved at 60 degrees C for the most promising s-PEEK-based membrane-electrode assembly (MEA) was higher than the benchmark Nafion((r)) 115-based MEA (77 mW.cm(-2) vs. 64 mW.cm(-2)). This result was due to a lower methanol crossover (47 mA.cm(-2) equivalent current density for s-PEEK vs. 120 mA.cm(-2) for Nafion((r)) 115 at 60 degrees C as recorded at OCV with 2 M methanol) and a suitable area specific resistance (0.15 Ohm cm2 for s-PEEK vs. 0.22 Ohm cm2 for Nafion((r)) 115). PMID- 26610583 TI - Recent Advances in Electrochemical Biosensors Based on Fullerene-C60 Nano Structured Platforms. AB - Nanotechnology is becoming increasingly important in the field of (bio)sensors. The performance and sensitivity of biosensors is greatly improved with the integration of nanomaterials into their construction. Since its first discovery, fullerene-C60 has been the object of extensive research. Its unique and favorable characteristics of easy chemical modification, conductivity, and electrochemical properties has led to its tremendous use in (bio)sensor applications. This paper provides a concise review of advances in fullerene-C60 research and its use as a nanomaterial for the development of biosensors. We examine the research work reported in the literature on the synthesis, functionalization, approaches to nanostructuring electrodes with fullerene, and outline some of the exciting applications in the field of (bio)sensing. PMID- 26610584 TI - Alcohol and Apoptosis: Friends or Foes? AB - Alcohol abuse causes 79,000 deaths stemming from severe organ damage in the United States every year. Clinical manifestations of long-term alcohol abuse on the cardiac muscle include defective contractility with the development of dilated cardiomyopathy and low-output heart failure; which has poor prognosis with less than 25% survival for more than three years. In contrast, low alcohol consumption has been associated with reduced risk of cardiovascular disease, however the mechanism of this phenomenon remains elusive. The aim of this study was to determine the significance of apoptosis as a mediating factor in cardiac function following chronic high alcohol versus low alcohol exposure. Adult rats were provided 5 mM (low alcohol), 100 mM (high alcohol) or pair-fed non-alcohol controls for 4-5 months. The hearts were dissected, sectioned and stained with cresyl violet or immunohistochemically for caspase-3, a putative marker for apoptosis. Cardiomyocytes were isolated to determine the effects of alcohol exposure on cell contraction and relaxation. High alcohol animals displayed a marked thinning of the left ventricular wall combined with elevated caspase-3 activity and decreased contractility. In contrast, low alcohol was associated with increased contractility and decreased apoptosis suggesting an overall protective mechanism induced by low levels of alcohol exposure. PMID- 26610587 TI - In Vivo Acute on Chronic Ethanol Effects in Liver: A Mouse Model Exhibiting Exacerbated Injury, Altered Metabolic and Epigenetic Responses. AB - Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57/BL6 mice fed ethanol in liquid diet (4%) for four weeks followed by binge ethanol (intragastric administration, 3.5 g/kg body weight, three doses, 12h apart). Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9), dually modified phosphoacetylated histone H3 (H3AcK9/PS10), and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10) and H3 ser 28 (H3S28) increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute/binge ethanol induced acceleration of alcoholic liver disease. PMID- 26610586 TI - The Potential Role of the Proteases Cathepsin D and Cathepsin L in the Progression and Metastasis of Epithelial Ovarian Cancer. AB - Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies and has a poor prognosis due to relatively unspecific early symptoms, and thus often advanced stage, metastasized cancer at presentation. Metastasis of EOC occurs primarily through the transcoelomic route whereby exfoliated tumor cells disseminate within the abdominal cavity, particularly to the omentum. Primary and metastatic tumor growth requires a pool of proangiogenic factors in the microenvironment which propagate new vasculature in the growing cancer. Recent evidence suggests that proangiogenic factors other than the widely known, potent angiogenic factor vascular endothelial growth factor may mediate growth and metastasis of ovarian cancer. In this review we examine the role of some of these alternative factors, specifically cathepsin D and cathepsin L. PMID- 26610585 TI - DNA Damage Signalling and Repair Inhibitors: The Long-Sought-After Achilles' Heel of Cancer. AB - For decades, radiotherapy and chemotherapy were the two only approaches exploiting DNA repair processes to fight against cancer. Nowadays, cancer therapeutics can be a major challenge when it comes to seeking personalized targeted medicine that is both effective and selective to the malignancy. Over the last decade, the discovery of new targeted therapies against DNA damage signalling and repair has offered the possibility of therapeutic improvements in oncology. In this review, we summarize the current knowledge of DNA damage signalling and repair inhibitors, their molecular and cellular effects, and future therapeutic use. PMID- 26610588 TI - High Intrinsic Aerobic Capacity Protects against Ethanol-Induced Hepatic Injury and Metabolic Dysfunction: Study Using High Capacity Runner Rat Model. AB - Rats artificially selected over several generations for high intrinsic endurance/aerobic capacity resulting in high capacity runners (HCR) has been developed to study the links between high aerobic fitness and protection from metabolic diseases (Wisloff et al., Science, 2005). We have previously shown that the HCR strain have elevated hepatic mitochondrial content and oxidative capacity. In this study, we tested if the elevated hepatic mitochondrial content in the HCR rat would provide "metabolic protection" from chronic ethanol-induced hepatic steatosis and injury. The Leiber-Decarli liquid diet with ethanol (7% v/v; HCR-E) and without (HCR-C) was given to HCR rats (n = 8 per group) from 14 to 20 weeks of age that were weight matched and pair-fed to assure isocaloric intake. Hepatic triglyceride (TG) content and macro- and microvesicular steatosis were significantly greater in HCR-E compared with HCR-C (p < 0.05). In addition, hepatic superoxide dismutase activity and glutathione levels were significantly (p < 0.05) reduced in the HCR-E rats. This hepatic phenotype also was associated with reduced total hepatic fatty acid oxidation (p = 0.03) and beta-hydroxyacyl CoA dehydrogenase activity (p = 0.01), and reductions in microsomal triglyceride transfer protein and apoB-100 protein content (p = 0.01) in HCR-E animals. However, despite these documented hepatic alterations, ethanol ingestion failed to induce significant hepatic liver injury, including no changes in hepatic inflammation, or serum alanine amino transferase (ALTs), free fatty acids (FFAs), triglycerides (TGs), insulin, or glucose. High intrinsic aerobic fitness did not reduce ethanol-induced hepatic steatosis, but protected against ethanol-induced hepatic injury and systemic metabolic dysfunction in a high aerobic capacity rat model. PMID- 26610590 TI - The Hinge Region of Bovine Zona Pellucida Glycoprotein ZP3 Is Involved in the Formation of the Sperm-Binding Active ZP3/ZP4 Complex. AB - The zona pellucida (ZP) surrounds the mammalian oocyte and mediates species selective sperm-oocyte interactions. Bovine ZP consists of glycoproteins ZP2, ZP3, and ZP4. Neither ZP3 nor ZP4 alone shows inhibitory activity for the binding of sperm to the ZP; however, this activity is seen with the ZP3/ZP4 heterocomplex. Here, we constructed a series of bovine ZP3 mutants to identify the ZP4-binding site on ZP3. Each ZP3 mutant was co-expressed with ZP4 using a baculovirus-Sf9 cell expression system and examined for interaction with ZP4 as well as inhibitory activity for sperm-ZP binding. N-terminal fragment Arg-32 to Arg-160 of ZP3 interacted with ZP4 and inhibited sperm-ZP binding, whereas fragment Arg-32 to Thr-155 showed much weaker interaction with ZP4. Mutation of N glycosylated Asn-146 to Asp in the N-terminal fragment Arg-32 to Glu-178 of ZP3 did not interrupt the interaction of this fragment with ZP4, but it did reduce the inhibitory activity of the complex for sperm-ZP binding. In contrast, mutation of N-glycosylated Asn-124 to Asp did not significantly reduce the activity. Taken together, these results suggest that one of the ZP4 binding sites exists in the flexible hinge region of ZP3 and that the N-glycosylation in this region is involved in the sperm binding. PMID- 26610591 TI - Probing protein interactions in living mammalian cells on a microtubule bench. AB - Microtubules are MUm-long cylinders of about 25 nm in diameter which are present in the cytoplasm of eukaryotic cells. Here, we have developed a new method which uses these cylindrical structures as platforms to detect protein interactions in cells. The principle is simple: a protein of interest used as bait is brought to microtubules by fusing it to Tau, a microtubule-associated protein. The presence of a protein prey on microtubules then reveals an interaction between bait and prey. This method requires only a conventional optical microscope and straightforward fluorescence image analysis for detection and quantification of protein interactions. To test the reliability of this detection scheme, we used it to probe the interactions among three mRNA-binding proteins in both fixed and living cells and compared the results to those obtained by pull-down assays. We also tested whether the molecular interactions of Cx43, a membrane protein, can be investigated with this system. Altogether, the results indicate that microtubules can be used as platforms to detect protein interactions in mammalian cells, which should provide a basis for investigating pathogenic protein interactions involved in human diseases. PMID- 26610592 TI - The Effect of Body Mass Index on Fluoroscopic Time and Radiation Dose During Sacroiliac Joint Injections. AB - BACKGROUND: Sacroiliac joint (SIJ) injections are commonly performed under fluoroscopic guidance. Radiation exposure to patients and providers has not been comprehensively studied, particularly the effect of body mass index (BMI). OBJECTIVE: To identify whether patients with a larger BMI require longer fluoroscopy time or a larger radiation dose during performance of an SIJ injection. DESIGN: Retrospective study of an academic institution database. SETTING: Academic outpatient musculoskeletal clinic. PATIENTS: All patients who underwent SIJ injections during a 10-year period. MAIN OUTCOME MEASUREMENTS: Machine-reported fluoroscopic time and machine-reported radiation dose. A Bonferroni correction was implemented with P <= .01 as statistically significant. RESULTS: A total of 453 SIJ injections were performed in 359 patients. No statistically significant differences in fluoroscopy time were found between patients with BMI scores identified as normal, overweight, and obese (P = .054). However, the radiation doses were significantly greater for patients with higher BMI scores (chi(2) [2, n = 441] = 62.4, P < .001); the median (interquartile range) doses were 1210 (839), 1671 (1240), and 2090 (2170) mGy-cm(2) for normal weight, overweight, and obese patients, respectively. Although longer needles were used more often in obese patients (chi(2) [2, n = 452] = 31.5, P < .001), fluoroscopy time was not associated with needle length (P = .162). No relationships were identified between fluoroscopy time and first-time (as opposed to repeat) injection (P = .123), trainee involvement (chi(2) [1, n = 698] = 3.9, P = .049), or age (P = .337). CONCLUSIONS: Patients with an elevated BMI score who are undergoing SIJ injection receive an increased radiation dose despite equivalent fluoroscopic time. This finding suggests that the increased dose is likely due to x-ray output from the fluoroscope traversing a greater tissue mass, as opposed to the physician requiring more fluoroscopic images for proper needle placement. Fortunately, the increased radiation dose delivered to patients with a larger BMI score likely has negligible effects. PMID- 26610589 TI - Role of microRNAs in Alcohol-Induced Multi-Organ Injury. AB - Alcohol consumption and its abuse is a major health problem resulting in significant healthcare cost in the United States. Chronic alcoholism results in damage to most of the vital organs in the human body. Among the alcohol-induced injuries, alcoholic liver disease is one of the most prevalent in the United States. Remarkably, ethanol alters expression of a wide variety of microRNAs that can regulate alcohol-induced complications or dysfunctions. In this review, we will discuss the role of microRNAs in alcoholic pancreatitis, alcohol-induced liver damage, intestinal epithelial barrier dysfunction, and brain damage including altered hippocampus structure and function, and neuronal loss, alcoholic cardiomyopathy, and muscle damage. Further, we have reviewed the role of altered microRNAs in the circulation, teratogenic effects of alcohol, and during maternal or paternal alcohol consumption. PMID- 26610593 TI - Ginger-derived nanoparticles protect against alcohol-induced liver damage. AB - Daily exposure of humans to nanoparticles from edible plants is inevitable, but significant advances are required to determine whether edible plant nanoparticles are beneficial to our health. Additionally, strategies are needed to elucidate the molecular mechanisms underlying any beneficial effects. Here, as a proof of concept, we used a mouse model to show that orally given nanoparticles isolated from ginger extracts using a sucrose gradient centrifugation procedure resulted in protecting mice against alcohol-induced liver damage. The ginger-derived nanoparticle (GDN)-mediated activation of nuclear factor erythroid 2-related factor 2 (Nrf2) led to the expression of a group of liver detoxifying/antioxidant genes and inhibited the production of reactive oxygen species, which partially contributes to the liver protection. Using lipid knock-out and knock-in strategies, we further identified that shogaol in the GDN plays a role in the induction of Nrf2 in a TLR4/TRIF-dependent manner. Given the critical role of Nrf2 in modulating numerous cellular processes, including hepatocyte homeostasis, drug metabolism, antioxidant defenses, and cell-cycle progression of liver, this finding not only opens up a new avenue for investigating GDN as a means to protect against the development of liver-related diseases such as alcohol-induced liver damage but sheds light on studying the cellular and molecular mechanisms underlying interspecies communication in the liver via edible plant-derived nanoparticles. PMID- 26610594 TI - Differences in initial treatment modality for end-stage renal disease among glomerulonephritis subtypes in the USA. AB - BACKGROUND: Kidney transplantation is the preferred treatment for end-stage renal disease (ESRD), while peritoneal dialysis affords certain benefits over hemodialysis. Distributions and determinants of first ESRD treatment modality have not been compared across glomerulonephritis (GN) subtypes. METHODS: We identified all adult (18-75 years) patients with ESRD attributed to any of six GN subtypes [focal segmental glomerulosclerosis (FSGS), IgA nephropathy (IgAN), membranous nephropathy (MN), membranoproliferative GN (MPGN), lupus nephritis (LN) and vasculitis] who were first registered in the US Renal Data System (USRDS) between 1996 and 2011. We used multinomial logistic regression--adjusting for temporal, geographic, demographic, socioeconomic and comorbid factors--to determine odds ratios (ORs) with 95% confidence intervals (CIs) for transplantation versus hemodialysis, and for peritoneal dialysis versus hemodialysis, comparing other GN subtypes to IgAN. RESULTS: Among the 75 278 patients studied, patients with comparator GN subtypes were significantly less likely than those with IgAN to receive either transplantation or peritoneal dialysis. After adjusting for potentially confounding covariates, patients with comparator primary GN subtypes (FSGS, MN, MPGN) were at least as likely to receive transplantation [FSGS OR 0.98 (95% CI 0.93-1.15), MN OR 1.19 (95% CI 1.01 1.39), MPGN OR 1.08 (95% CI 0.93-1.26)] or peritoneal dialysis [FSGS OR 1.05 (95% CI 0.98-1.12), MN OR 1.30 (95% CI 1.18-1.43), MPGN OR 0.95 (95% CI 0.85-1.06)] as patients with IgAN. Conversely, patients with the secondary GN subtypes LN and vasculitis remained significantly less likely to receive either modality [transplantation OR 0.49 (95% CI 0.43-0.56) for LN and 0.27 (95% CI 0.22-0.34) for vasculitis, peritoneal dialysis OR 0.76 (95% CI 0.70-0.82) for LN and 0.54 (95% CI 0.48-0.60) for vasculitis]. CONCLUSIONS: Significant differences in ESRD treatment practice patterns are apparent among GN subtypes. To ensure equitable care for all patients, regardless of GN subtype, reasons for observed disparities should be elucidated and-if appropriate-eliminated. PMID- 26610595 TI - Increased risk of glomerular hyperfiltration in subjects with impaired glucose tolerance and newly diagnosed diabetes. AB - BACKGROUND: Glomerular hyperfiltration is closely related to diabetes and may lead to subsequent nephropathy, but the association between glomerular hyperfiltration and prediabetic state is unclear. We examined the relationship of different glycemic statuses, including normal glucose tolerance (NGT), isolated impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and newly diagnosed diabetes (NDD), with glomerular hyperfiltration. METHODS: This study included 12 833 subjects >=20 years of age without a history of renal disease, cancer, moderate/severe anemia or diabetes and taking medications for hypertension, diabetes, hyperlipidemia or cardiovascular disease from National Cheng Kung University Hospital between January 2000 and August 2009. Hyperfiltration was defined as an estimated GFR (eGFR) above the age- and gender specific 95th percentile for apparently healthy subjects, while hypofiltration was defined as an eGFR below the 5th percentile. eGFR was assessed using the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS: After further excluding hypofiltration and adjusting for available confounders, fasting plasma glucose (FPG), 2-hour postload glucose (2hPG), 2hPG-FPG (fluctuating blood glucose), HbA1c (average blood glucose), NDD and IGT but not isolated IFG were significantly associated with increased eGFR and a higher risk of hyperfiltration {NDD: odds ratio [OR] 1.97 [95% confidence interval (CI), 1.48-2.64], P < 0.001; IGT: OR 1.34 (95% CI 1.07-1.66), P = 0.009}. CONCLUSIONS: High glucose states increase hyperfiltration risk. In addition to newly diagnosed diabetes, excessively high GFR also deserves attention in subjects with IGT. PMID- 26610596 TI - One hundred ABO-incompatible kidney transplantations between 2004 and 2014: a single-centre experience. AB - BACKGROUND: ABO-incompatible kidney transplantation (ABOi KTx) expands the living donor transplantation options. However, long-term outcome data, especially in comparison with ABO-compatible kidney transplantation (ABOc KTx), remain limited. Since the first ABOi KTx in Germany on 1 April 2004 at our centre, we have followed 100 ABOi KTx over up to 10 years. METHODS: One hundred ABOi KTx and 248 ABOc KTx from 1 April 2004 until 28 October 2014 were analysed in this observational, single-centre study. Three ABOi KTx and 141 ABOc KTx were excluded because of cyclosporine A-based immunosuppression, and 1 ABOc KTx was lost to follow-up. RESULTS: Median estimated 10-year patient and graft survival in ABOi KTx was 99 and 94%, respectively, and surpassed ABOc-KTx patient and graft survival of 80 and 88%, respectively. The incidence rate of antibody-mediated rejections was 10 and 8%, and that of T-cell-mediated rejections was 17 and 20% in ABOi KTx and ABOc KTx, respectively. Infectious and malignant complications in ABOi KTx were not more common than in ABOc KTx. However, postoperative lymphoceles occurred more frequently in ABOi KTx. Subgroup analysis of ABOi-KTx patients revealed that patients with high-titre isohaemagglutinins before transplantation had equal long-term results compared with low-titre isohaemagglutinin patients. CONCLUSION: Taken together, long-term outcome of ABOi KTx is not inferior to ABOc KTx. Incidences of rejection episodes, infectious complications and malignancies are not increased, despite the more vigorous immunosuppression in ABOi KTx. Our data provide further evidence that ABOi KTx with living donation is a safe, successful and reasonable option to reduce the organ shortage. PMID- 26610597 TI - Acetylation of asymmetric and symmetric dimethylarginine: an undercharacterized pathway of metabolism of endogenous methylarginines. AB - BACKGROUND: Increased levels of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are associated with cardiovascular and renal diseases. We and others have shown that both ADMA and SDMA can be Nalpha-acetylated to form asymmetric and symmetric Nalpha-acetyldimethylarginine (Ac-ADMA and Ac-SDMA). The current study further investigated this undercharacterized metabolic pathway. METHODS: ADMA and SDMA were infused in C57/BL6 mice for 3 days using osmotic minipumps. Half of the mice underwent bilateral nephrectomy 24 h before completion of the infusion. Plasma and tissue levels of Ac-ADMA and Ac-SDMA were detected by liquid chromatography-tandem mass spectrometry. RESULTS: ADMA and SDMA infusion resulted in a 3.6-fold increase in plasma Ac-ADMA and a 21-fold increase in plasma Ac-SDMA levels, respectively. Plasma Ac-ADMA and Ac-SDMA levels were dramatically increased after bilateral nephrectomy. The highest baseline tissue concentrations of Ac-ADMA and Ac-SDMA in wild-type mice were detected in the liver, kidney, small intestine, pancreas and spleen. Incubation of the tissue lysates with ADMA and SDMA resulted in increased levels of the corresponding Nalpha-acetylated products only in the liver, kidney and small intestine. CONCLUSIONS: Our results show that overload of ADMA or SDMA leads to an increase in plasma Ac-ADMA and Ac-SDMA levels. This observation is consistent with the hypothesis that Ac-ADMA and Ac-SDMA are formed directly from ADMA and SDMA in vivo. The increase in plasma Ac-ADMA and Ac-SDMA concentrations after bilateral nephrectomy suggests that both compounds are predominantly eliminated via the kidneys. We demonstrated that acetylation of ADMA and SDMA occurs primarily in the liver, kidney and small intestine. PMID- 26610598 TI - A pilot randomized controlled trial of pioglitazone for the treatment of poorly controlled asthma in obesity. AB - BACKGROUND: Obese asthmatics tend to have poorly controlled asthma, and resistance to standard asthma controller medications. The purpose of this study was to determine the efficacy of pioglitazone, an anti-diabetic medication which can alter circulating adipokines and have direct effects on asthmatic inflammation, in the treatment of asthma in obesity. METHODS: A two-center, 12 week, randomized, placebo-controlled, double-blinded trial. Treatments were randomly assigned with concealment of allocation. The primary outcome was difference in change in airway reactivity between participants assigned to pioglitazone versus placebo at 12 weeks. RESULTS: Twenty-three participants were randomized to treatment, 19 completed the study. Median airway reactivity, measured by PC20 to methacholine was 1.99 (IQR 3.08) and 1.60 (5.91) mg/ml in placebo and pioglitazone group at baseline, and 2.37 (15.22) and 5.08 (7.42) mg/ml after 12 weeks, p = 0.38. There was no difference in exhaled nitric oxide, asthma control or lung function between treatment groups over the 12 week trial. Participants assigned to pioglitazone gained a significant amount more weight than those assigned to placebo (pioglitazone group mean weight 113.6, CI 94.5 132.7 kg at randomization and 115.9, CI 96.9-135.1 at 12 weeks; placebo mean weight 127.5, CI 108.4 - 146.6 kg at randomization and 124.5, CI 105.4 - 143.6 kg at 12 weeks; p = 0.04). CONCLUSIONS: This pilot study suggests limited efficacy for pioglitazone in the treatment of poorly controlled asthma in obesity, and also the potential for harm, given the weight gain in those assigned to active treatment, and the association between increased weight and worse outcomes in asthma. TRIAL REGISTRATION: Clinicaltrials.gov (NCT00634036). PMID- 26610599 TI - Vitamin D deficiency and dyslipidemia in early pregnancy. AB - BACKGROUND: Vitamin D deficiency is a common nutritional issue and dietary supplementation in the general population, including pregnant women, is generally advised. Appropriately high levels of vitamin D are expected to play a role in containing the glycemic and atherogenic profiles observed in pregnancy. However, the relation between vitamin D status and the lipid metabolic profile in Saudi women, who are known to suffer from chronic vitamin D deficiency and high incidence of obesity and type II DM, during the course of pregnancy is not known. METHODS: In this study, we analyzed the relation between serum vitamin D level and various serum metabolic markers among Saudi women (n = 515) in their first trimester of pregnancy (11.2 +/- 3.4 weeks). Coefficients of Pearson correlation and Spearman rank correlation were calculated for Gaussian and non-Gaussian variables, respectively. Serum vitamin D status was defined as (in nmol/L): deficient (<25), insufficient (25-50); sufficient (50-75) and desirable (>75). RESULTS: Results indicated that vitamin D status was sufficient in only 3.5% of the study participants and insufficient and deficient in 26.2% and 68.0% of participants, respectively. Serum vitamin D values in the overall study population correlated positively with serum levels of total cholesterol (R = 0.172; p < 0.01), triglycerides (R = 0.184; p < 0.01) and corrected calcium (R = 0.141; p < 0.05). In the subgroup of vitamin D deficient subjects (n = 350), log serum vitamin D values correlated with serum triglycerides (R = 0.23; p = 0.002) and cholesterol (R = 0.26; p = 0.001). CONCLUSIONS: The positive correlations between serum vitamin D and the atherogenic factors such as total cholesterol and triglycerides indicate a pro-atherogenic metabolic status in vitamin D deficient expectant mothers. This may represent an adaptation to the high metabolic demands of pregnancy. PMID- 26610600 TI - Clinically early-stage CSPalpha mutation carrier exhibits remarkable terminal stage neuronal pathology with minimal evidence of synaptic loss. AB - Autosomal dominant adult-onset neuronal ceroid lipofuscinosis (AD-ANCL) is a multisystem disease caused by mutations in the DNAJC5 gene. DNAJC5 encodes Cysteine String Protein-alpha (CSPalpha), a putative synaptic protein. AD-ANCL has been traditionally considered a lysosomal storage disease based on the intracellular accumulation of ceroid material. Here, we report for the first time the pathological findings of a patient in a clinically early stage of disease, which exhibits the typical neuronal intracellular ceroid accumulation and incipient neuroinflammation but no signs of brain atrophy, neurodegeneration or massive synaptic loss. Interestingly, we found minimal or no apparent reductions in CSPalpha or synaptophysin in the neuropil. In contrast, brain homogenates from terminal AD-ANCL patients exhibit significant reductions in SNARE-complex forming presynaptic protein levels, including a significant reduction in CSPalpha and SNAP-25. Frozen samples for the biochemical analyses of synaptic proteins were not available for the early stage AD-ANLC patient. These results suggest that the degeneration seen in the patients with AD-ANCL reported here might be a consequence of both the early effects of CSPalpha mutations at the cellular soma, most likely lysosome function, and subsequent neuronal loss and synaptic dysfunction. PMID- 26610601 TI - A novel quantification method for the total demethylation potential of aquatic sample extracts from Bohai Bay using the EGFP reporter gene. AB - BACKGROUND: The demethylation potential of environmental pollutants is possibly an innate part of their comprehensive health risk. This paper develops a novel method called TDQ to quantify the demethylation epigenetic toxicity, termed the 5 AZA-CdR demethylation toxic equivalency, of aquatic samples from the heavily polluted Bohai Bay using Hep G2 cell lines transiently transfected with the pEGFP C3 plasmid containing a methylated promoter of the EGFP reporter gene inserted artificially in vitro. RESULTS: If the aquatic sample extract has strong total demethylation potential to the promoter, its methylation level will decrease, and increased green fluorescence will be observed under microscopy after TDQ co incubation. The 5-AZA-CdR was selected as a representative demethylation agent to validate the principle of the TDQ method on three levels: significant dose response relationships between the concentration of 5-AZA-CdR and the methylation level of promoters, mRNA expression level of the EGFP gene, and the fluorescence intensity of EGFP proteins. Twenty extracts from aquatic samples are successfully quantified with the TDQ test. Eight of them return meaningful results ranging from 0.00004 to 0.20053 MUM 5-AZA-CdR toxicity equivalents. CONCLUSIONS: The TDQ method is a reliable and rapid assay for the quantification of the DNA demethylation potential of aquatic sample extracts, which may shed light on the safety evaluation of food material. PMID- 26610603 TI - Environmental and anthropogenic factors affecting the probability of occurrence of Oncomegas wageneri (Cestoda: Trypanorhyncha) in the southern Gulf of Mexico. AB - BACKGROUND: Understanding the environmental and anthropogenic factors influencing the probability of occurrence of the marine parasitic species is fundamental for determining the circumstances under which they can act as bioindicators of environmental impact. The aim of this study was to determine whether physicochemical variables, polyaromatic hydrocarbons or sewage discharge affect the probability of occurrence of the larval cestode Oncomegas wageneri, which infects the shoal flounder, Syacium gunteri, in the southern Gulf of Mexico. METHODS: The study area included 162 sampling sites in the southern Gulf of Mexico and covered 288,205 km(2), where the benthic sediments, water and the shoal flounder individuals were collected. We used the boosted generalised additive models (boosted GAM) and the MaxEnt to examine the potential statistical relationships between the environmental variables (nutrients, contaminants and physicochemical variables from the water and sediments) and the probability of the occurrence of this parasite. The models were calibrated using all of the sampling sites (full area) with and without parasite occurrences (n = 162) and a polygon area that included sampling sites with a depth of 1500 m or less (n = 134). RESULTS: Oncomegas wageneri occurred at 29/162 sampling sites. The boosted GAM for the full area and the polygon area accurately predicted the probability of the occurrence of O. wageneri in the study area. By contrast, poor probabilities of occurrence were obtained with the MaxEnt models for the same areas. The variables with the highest frequencies of appearance in the models (proxies for the explained variability) were the polyaromatic hydrocarbons of high molecular weight (PAHH, 95 %), followed by a combination of nutrients, spatial variables and polyaromatic hydrocarbons of low molecular weight (PAHL, 5 %). CONCLUSIONS: The contribution of the PAHH to the variability was explained by the fact that these compounds, together with N and P, are carried by rivers that discharge into the ocean, which enhances the growth of hydrocarbonoclastic bacteria and the productivity and number of the intermediate hosts. Our results suggest that sites with PAHL/PAHH ratio values up to 1.89 promote transmission based on the high values of the prevalence of O. wageneri in the study area. In contrast, PAHL/PAHH ratio values >= 1.90 can be considered harmful for the transmission stages of O. wageneri and its hosts (copepods, shrimps and shoal flounders). Overall, the results indicate that the PAHHs affect the probability of occurrence of this helminth parasite in the southern Gulf of Mexico. PMID- 26610604 TI - The associations of illness perceptions and self-efficacy with psychological well being of patients in preparation for joint replacement surgery. AB - Patient well-being on referral to surgery likely affects their surgical experience yet few studies examine pre-surgical correlates of well-being. Guided by the Common Sense Model of Self-Regulation and Social Cognitive theory, this study examined whether illness and emotional representations, general and domain self-efficacy were associated with pre-surgical well-being. The pre-surgical assessment of a three-wave prospective study is reported. Fifty-four hip and knee replacements patients (mean age = 69.33; SD = 8.57) were recruited in the pre surgery educational clinic at a UK general hospital. Patients completed a questionnaire-pack including the Revised Illness Perceptions Questionnaire, the General Self-Efficacy Scale, the Self-Efficacy for Rehabilitation Outcome Scale, the Falls-Efficacy Scale, and the Short Form of Psychological Well-Being Index. Multiple hierarchical regression analyses showed that above and beyond demographic and clinical characteristics, negative emotional representations were associated with lower psychological well-being while strong general self-efficacy beliefs were positively related to psychological well-being. Independent of demographic and clinical characteristics, joint replacement patients' psychological well-being was associated with their cognitions and emotional reactions to their condition before surgery. Early interventions could potentially target these modifiable factors to improve pre-surgical well-being in this group of patients, with potential for additional post-surgical benefit. PMID- 26610605 TI - Social Skills Questionnaire for Argentinean College Students (SSQ-U) Development and Validation. AB - In this paper we present a new instrument called Social Skills Questionnaire for Argentinean College Students (SSQ-U). Based on the adapted version of the Social Skills Inventory - Del Prette (SSI-Del Prette) (Olaz, Medrano, Greco, & Del Prette, 2009), we wrote new items for the scale, and carried out psychometric analysis to assess the validity and reliability of the instrument. In the first study, we collected evidence based on test content through expert judges who evaluated the quality and the relevance of the items. In the second and third studies, we provided validity evidence based on the internal structure of the instrument using exploratory (n = 1067) and confirmatory (n = 661) factor analysis. Results suggested a five-factor structure consistent with the dimensions of social skills, as proposed by Kelly (2002). The fit indexes corresponding to the obtained model were adequate, and composite reliability coefficients of each factor were excellent (above .75). Finally, in the fourth study, we provided evidence of convergent and discriminant validity. The obtained results allow us to conclude that the SSQ-U is the first valid and reliable instrument for measuring social skills in Argentinean college students. PMID- 26610602 TI - Pressuromodulation at the cell membrane as the basis for small molecule hormone and peptide regulation of cellular and nuclear function. AB - Building on recent knowledge that the specificity of the biological interactions of small molecule hydrophiles and lipophiles across microvascular and epithelial barriers, and with cells, can be predicted on the basis of their conserved biophysical properties, and the knowledge that biological peptides are cell membrane impermeant, it has been further discussed herein that cellular, and thus, nuclear function, are primarily regulated by small molecule hormone and peptide/factor interactions at the cell membrane (CM) receptors. The means of regulating cellular, and thus, nuclear function, are the various forms of CM Pressuromodulation that exist, which include Direct CM Receptor-Mediated Stabilizing Pressuromodulation, sub-classified as Direct CM Receptor-Mediated Stabilizing Shift Pressuromodulation (Single, Dual or Tri) or Direct CM Receptor Mediated Stabilizing Shift Pressuromodulation (Single, Dual or Tri) cum External Cationomodulation (>=3+ -> 1+); which are with respect to acute CM receptor stabilizing effects of small biomolecule hormones, growth factors or cytokines, and also include Indirect CM- or CM Receptor-Mediated Pressuromodulation, sub classified as Indirect 1ary CM-Mediated Shift Pressuromodulation (Perturbomodulation), Indirect 2ary CM Receptor-Mediated Shift Pressuromodulation (Tri or Quad Receptor Internal Pseudo-Cationomodulation: SS 1+), Indirect 3ary CM Receptor-Mediated Shift Pressuromodulation (Single or Dual Receptor Endocytic External Cationomodulation: 2+) or Indirect (Pseudo) 3ary CM Receptor-Mediated Shift Pressuromodulation (Receptor Endocytic Hydroxylocarbonyloetheroylomodulation: 0), which are with respect to sub-acute CM receptor-stabilizing effects of small biomolecules, growth factors or cytokines. As a generalization, all forms of CM pressuromodulation decrease CM and nuclear membrane (NM) compliance (whole cell compliance), due to pressuromodulation of the intracellular microtubule network and increases the exocytosis of pre synthesized vesicular endogolgi peptides and small molecules as well as nuclear to-rough endoplasmic reticulum membrane proteins to the CM, with the potential to simultaneously increase the NM-associated chromatin DNA transcription of higher molecular weight protein forms, secretory and CM-destined, mitochondrial and nuclear, including the highest molecular weight nuclear proteins, Ki67 (359 kDa) and Separase (230 kDa), with the latter leading to mitogenesis and cell division; while, in the case of growth factors or cytokines with external cationomodulation capability, CM Receptor External Cationomodulation of CM receptors (>=3+ -> 1+) results in cationic extracellular interaction (>=3+) with extracellular matrix heparan sulfates (>=3+ -> 1+) concomitant with lamellopodesis and cell migration. It can be surmised that the modulation of cellular, and nuclear, function is mostly a reactive process, governed, primarily, by small molecule hormone and peptide interactions at the cell membrane, with CM receptors and the CM itself. These insights taken together, provide valuable translationally applicable knowledge. PMID- 26610606 TI - Fabrication of homobifunctional crosslinker stabilized collagen for biomedical application. AB - Collagen biopolymer has found widespread application in the field of tissue engineering owing to its excellent tissue compatibility and negligible immunogenicity. Mechanical strength and enzymatic degradation of the collagen necessitates the physical and chemical strength enhancement. One such attempt deals with the understanding of crosslinking behaviour of EGS (ethylene glycol bis (succinic acid N-hydroxysuccinimide ester)) with collagen to improve the physico-chemical properties. The incorporation of a crosslinker during fibril formation enhanced the thermal and mechanical stability of collagen. EGS crosslinked collagen films exhibited higher denaturation temperature (T d) and the residue left after thermogravimetric analysis was about 16 +/- 5.2%. Mechanical properties determined by uniaxial tensile tests showed a threefold increase in tensile strength and Young's modulus at higher concentration (100 MUM). Water uptake capacity reduced up to a moderate extent upon crosslinking which is essential for the transport of nutrients to the cells. Cell viability was found to be 100% upon treatment with 100 MUM EGS whereas only 30% viability could be observed with glutaraldehyde. Rheological studies of crosslinked collagen showed an increase in shear stress and shear viscosity at 37 degrees C. Crosslinking with EGS resulted in the formation of a uniform fibrillar network. Trinitrobenzene sulfonate (TNBS) assay confirmed that EGS crosslinked collagen by forming a covalent interaction with epsilon-amino acids of collagen. The homobifunctional crosslinker used in this study enhanced the effectiveness of collagen as a biomaterial for biomedical application. PMID- 26610607 TI - Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion. AB - Endocrine therapies target the activation of the oestrogen receptor alpha (ERalpha) via distinct mechanisms, but it is not clear whether breast cancer cells can adapt to treatment using drug-specific mechanisms. Here we demonstrate that resistance emerges via drug-specific epigenetic reprogramming. Resistant cells display a spectrum of phenotypical changes with invasive phenotypes evolving in lines resistant to the aromatase inhibitor (AI). Orthogonal genomics analysis of reprogrammed regulatory regions identifies individual drug-induced epigenetic states involving large topologically associating domains (TADs) and the activation of super-enhancers. AI-resistant cells activate endogenous cholesterol biosynthesis (CB) through stable epigenetic activation in vitro and in vivo. Mechanistically, CB sparks the constitutive activation of oestrogen receptors alpha (ERalpha) in AI-resistant cells, partly via the biosynthesis of 27-hydroxycholesterol. By targeting CB using statins, ERalpha binding is reduced and cell invasion is prevented. Epigenomic-led stratification can predict resistance to AI in a subset of ERalpha-positive patients. PMID- 26610609 TI - Distinct colicin M-like bacteriocin-immunity pairs in Burkholderia. AB - The Escherichia coli bacteriocin colicin M (ColM) acts via degradation of the cell wall precursor lipid II in target cells. ColM producers avoid self inhibition by a periplasmic immunity protein anchored in the inner membrane. In this study, we identified colM-like bacteriocin genes in genomes of several beta proteobacterial strains belonging to the Burkholderia cepacia complex (Bcc) and the Burkholderia pseudomallei group. Two selected Burkholderia ambifaria proteins, designated burkhocins M1 and M2, were produced recombinantly and showed antagonistic activity against Bcc strains. In their considerably sequence diverged catalytic domain, a conserved aspartate residue equally proved pivotal for cytotoxicity. Immunity to M-type burkhocins is conferred upon susceptible strains by heterologous expression of a cognate gene located either upstream or downstream of the toxin gene. These genes lack homology with currently known ColM immunity genes and encode inner membrane-associated proteins of two distinct types, differing in predicted transmembrane topology and moiety exposed to the periplasm. The addition of burkhocins to the bacteriocin complement of Burkholderia reveals a wider phylogenetic distribution of ColM-like bacteriotoxins, beyond the gamma-proteobacterial genera Escherichia, Pectobacterium and Pseudomonas, and illuminates the diversified nature of immunity-providing proteins. PMID- 26610610 TI - Determining the area of influence of depression cone in the vicinity of lignite mine by means of triangle method and LANDSAT TM/ETM+ satellite images. AB - Problems with lowering of water table are common all over the world. Intensive pumping of water from aquifers for consumption, irrigation, industrial or mining purposes often causes groundwater depletion and results in the formation of cone of depression. This can severely decrease water pressure, even over vast areas, and can create severe problems such as degradation of agriculture or natural environment sometimes depriving people and animals of water supply. In this paper, the authors present a method for determining the area of influence of a groundwater depression cone resulting from prolonged drainage, by means of satellite images in optical, near infrared and thermal infrared bands from TM sensor (Thematic Mapper) and ETM+ sensor (Enhanced Thematic Mapper +) placed on Landsat 5 and Landsat 7 satellites. The research area was Szczercowska Valley (Pol. Kotlina Szczercowska), Central Poland, located within a range of influence of a groundwater drainage system of the lignite coal mine in Belchatow. It is the biggest lignite coal mine in Poland and one of the largest in Europe exerting an enormous impact on the environment. The main method of satellite data analysis for determining soil moisture, was the so-called triangle method. This method, based on TVDI (Temperature Vegetation Dryness Index) was supported by additional spatial analysis including ordinary kriging used in order to combine fragmentary information obtained from areas covered by meadows. The results obtained are encouraging and confirm the usefulness of the triangle method not only for soil moisture determination but also for assessment of the temporal and spatial changes in the area influenced by the groundwater depression cone. The range of impact of the groundwater depression cone determined by means of above-described remote sensing analysis shows good agreement with that determined by ground measurements. The developed satellite method is much faster and cheaper than in situ measurements, and allows for systematic monitoring of the vast area in the vicinity of Belchatow lignite mine. Besides, this method could be useful as a helper in in-situ measurement allowing a significant reduction of the number of in-situ measurements by performing them only within problematic areas. Hence, the triangle method can be used as an effective supplement to field measurements. Although the research area is located in Poland, in the vicinity of lignite mine, the method of observation of depression cones provided in this study is universal and effective, and therefore could also be useful to an international audience. PMID- 26610608 TI - Function of desiccate in gustatory sensilla of drosophila melanogaster. AB - Desiccate (Desi), initially discovered as a gene expressing in the epidermis of Drosophila larvae for protection from desiccation stress, was recently found to be robustly expressed in the adult labellum; however, the function, as well as precise expression sites, was unknown. Here, we found that Desi is expressed in two different types of non-neuronal cells of the labellum, the epidermis and thecogen accessory cells. Labellar Desi expression was significantly elevated under arid conditions, accompanied by an increase in water ingestion by adults. Desi overexpression also promoted water ingestion. In contrast, a knockdown of Desi expression reduced feeding as well as water ingestion due to a drastic decrease in the gustatory sensillar sensitivity for all tested tastants. These results indicate that Desi helps protect insects from desiccation damage by not only preventing dehydration through the integument but also accelerating water ingestion via elevated taste sensitivities of the sensilla. PMID- 26610611 TI - Intestinal barrier dysfunction and increased COX-2 gene expression in the gut of elderly rats with acute pancreatitis. AB - BACKGROUND/OBJECTIVES: The clinical course of acute pancreatitis can vary from mild to severe. In its most severe manifestation, acute pancreatitis is associated with an exacerbated systemic inflammatory response and high mortality rates. The severe form of acute pancreatitis is more frequent in elderly patients than in young patients, but the mechanisms underlying this difference are still under investigation. METHODS: Rats were divided into two groups as follows: Group 1, young rats; and Group 2, old rats. Acute pancreatitis group was induced by a retrograde injection of a sodium taurocholate solution into the biliopancreatic duct. Using this model of acute pancreatic injury, we designed a study to investigate possible differences in microbial translocation and characteristics of the intestinal barrier between elderly and young rats. RESULTS: There was a significantly higher number of bacterial colonies in the pancreas of elderly rats compared with young rats following pancreas injury, which was associated with a more severe local intestinal inflammatory response that included elevated gene expression of COX-2 and a decreased gene expression of tight junction proteins. CONCLUSIONS: We conclude that intestinal damage during acute pancreatitis is exacerbated in elderly rats compared with young rats and that COX-2 inhibition could be a potential therapeutic target to offer tailored treatment for acute pancreatitis in the elderly. PMID- 26610612 TI - Real-Time Mass Spectrometry Monitoring of Oak Wood Toasting: Elucidating Aroma Development Relevant to Oak-aged Wine Quality. AB - We introduce a real-time method to monitor the evolution of oak aromas during the oak toasting process. French and American oak wood boards were toasted in an oven at three different temperatures, while the process-gas was continuously transferred to the inlet of a proton-transfer-reaction time-of-flight mass spectrometer for online monitoring. Oak wood aroma compounds important for their sensory contribution to oak-aged wine were tentatively identified based on soft ionization and molecular mass. The time-intensity profiles revealed toasting process dynamics illustrating in real-time how different compounds evolve from the oak wood during toasting. Sufficient sensitivity was achieved to observe spikes in volatile concentrations related to cracking phenomena on the oak wood surface. The polysaccharide-derived compounds exhibited similar profiles; whilst for lignin-derived compounds eugenol formation differed from that of vanillin and guaiacol at lower toasting temperatures. Significant generation of oak lactone from precursors was evident at 225 (o)C. Statistical processing of the real-time aroma data showed similarities and differences between individual oak boards and oak wood sourced from the different origins. This study enriches our understanding of the oak toasting process and demonstrates a new analytical approach for research on wood volatiles. PMID- 26610613 TI - The 8th International Conference on Counter-current Chromatography held at Brunel University, London, UK, July 23-25, 2014. AB - The 8th International Conference on Counter-current Chromatography (CCC2014) was held at Brunel University London from July 23rd to 25th, 2014. It has been 14 years since Brunel hosted the first International Conference on CCC (CCC2000) at the beginning of the millennium and therefore, it was a good opportunity to review the progress of this emerging technology and particularly the impact it is having with industry today. PMID- 26610614 TI - Structural characterization and discrimination of Chinese medicinal materials with multiple botanical origins based on metabolite profiling and chemometrics analysis: Clematidis Radix et Rhizoma as a case study. AB - Traditional Chinese medicines (TCMs)-based products are becoming more and more popular over the world. To ensure the safety and efficacy, authentication of Chinese medicinal materials has been an important issue, especially for that with multiple botanical origins (one-to-multiple). Taking Clematidis Radix et Rhizoma (CRR) as a case study, we herein developed an integrated platform based on metabolite profiling and chemometrics analysis to characterize, classify, and predict the "one-to-multiple" herbs. Firstly, the predominant constituents, triterpenoid saponins, in three Clematis CRR were rapid characterized by a novel UPLC-QTOF/MS-based strategy, and a total of 49 triterpenoid saponins were identified. Secondly, metabolite profiling was performed by UPLC-QTOF/MS, and 4623 variables were extracted and aligned as dataset. Thirdly, by using pattern recognition analysis, a clear separation of the three Clematis CRR was achieved as well as a total number of 28 variables were screened as the valuable variables for discrimination. By matching with identified saponins, these 28 variables were corresponding to 10 saponins which were identified as marker compounds. Fourthly, based on the relative intensity of the marker compounds-related variables, genetic algorithm optimized support vector machines (GA-SVM) was employed to predict the species of CRR samples. The obtained model showed excellent prediction performance with a prediction accuracy of 100%. Finally, a heatmap visualization was employed for clarifying the distribution of identified saponins, which could be useful for phytochemotaxonomy study of Clematis herbs. These results indicated that our proposed platform was a powerful tool for chemical profiling and discrimination of herbs with multiple botanical origins, providing promising perspectives in tracking the formulation processes of TCMs products. PMID- 26610615 TI - Systematic identification of shikonins and shikonofurans in medicinal Zicao species using ultra-high performance liquid chromatography quadrupole time of flight tandem mass spectrometry combined with a data mining strategy. AB - Shikonin, shikonofuran and their derivatives are the main bioactive components of Zicao, a traditional Chinese herbal medicine prepared with the dried roots of Lithospermum erythrorhizon, Arnebia euchroma or Arnebia guttata. However, approaches on the systematic discovery and identification of shikonins and shikonofurans, especially unknown ones, are still not available. To address this issue, the gas-phase CID-fragmentation routes for the shikonins and shikonofurans were established by using ESI-QTOF-MS in the negative ion mode and low-energy collision induced dissociation tandem mass spectrometry (CID-MS/MS) in this study using seventeen standards. As a result, diagnostic product ions for rapid discovery and classification of shikonins and shikonofurans were determined. In addition, various mobile phase compositions and UHPLC elution programs were evaluated to achieve optimal separation efficiency and detection response of these types of analytes. Based on these findings, an integral approach using UHPLC-ESI-QTOF-MS and CID-MS/MS analyses together with a novel two steps data mining strategy was developed for systematic analysis of shikonins and shikonofurans in complex samples. Consequently, 58 compounds including 32 novel ones were efficiently discovered and identified from the crude extract of Zicao. Moreover, comparative analyses of the 58 chemical components in three Zicao species including Lithospermum erythrorhizon, Arnebia euchroma and Arnebia guttata samples were conducted using the established analytical method, which can be instructive for future utilization of Zicao and its related medicinal products. PMID- 26610617 TI - Foreword. PMID- 26610616 TI - Investigation into the phenomena affecting the retention behavior of basic analytes in chaotropic chromatography: Joint effects of the most relevant chromatographic factors and analytes' molecular properties. AB - The aim of this study was to systematically investigate the phenomena affecting the retention behavior of structurally diverse basic drugs in ion-interaction chromatographic systems with chaotropic additives. To this end, the influence of three factors was studied: pH value of the aqueous phase, concentration of sodium hexafluorophosphate, and content of acetonitrile in the mobile phase. Mobile phase pH was found to affect the thermodynamic equilibria in the studied system beyond its effects on the analytes' ionization state. Specifically, increasing pH from 2 to 4 led to longer retention times, even with analytes which remain completely protonated. An explanation for this phenomenon was sought by studying the adsorption behavior of acetonitrile and chaotropic additive onto stationary phase. It was shown that the magnitude of the developed surface potential, which significantly affects retention - increases with pH, and that this can be attributed to the larger surface excess of acetonitrile. To study how analytes' structural properties influence their retention, quantitative structure-retention modeling was performed next. A support vector machine regression model was developed, relating mobile phase constituents and structural descriptors with retention data. While the ETA_EtaP_B_RC and XlogP can be considered as molecular descriptors which describe factors affecting retention in any RP-HPLC system, TDB9p and RDF45p are molecular descriptors which account for spatial arrangement of polarizable atoms and they can clearly relate to analytes' behavior on the stationary phase surface, where the electrostatic potential develops. Complementarity of analytes' structure with that of the electric double layer can be seen as a key factor influencing their retention behavior. Structural diversity of analytes and good predictive capabilities over a range of experimental conditions make the established model a useful tool in predicting retention behavior in the studied chromatographic system. PMID- 26610618 TI - Screening of inhibitors of glycogen synthase kinase-3beta from traditional Chinese medicines using enzyme-immobilized magnetic beads combined with high performance liquid chromatography. AB - Glycogen synthase kinase-3beta (GSK-3beta) was immobilized on magnetic beads (MBs) by affinity method for the first time. The enzyme-immobilized MBs were coupled with high-performance liquid chromatography-ultraviolet (HPLC-UV) technique to establish a cost-effective and reliable method for screening of inhibitors of GSK-3beta. A peptide substrate of GSK-3beta containing a tyrosine residue was employed since it can be sensitively detected by UV detector at 214nm. The substrate and its phosphorylated product were separated by baseline within 10min. The enzyme activity was determined by the quantification of peak area of the product. Parameters including enzyme immobilization, enzyme reaction and the performance of immobilized-enzyme were investigated. The immobilized enzyme can be reused for 10 times and remain stable for 4 days at 4 degrees C. The inhibitory activities of extracts of 15 traditional Chinese medicines (TCMs) were screened. As a result, three of them including Euonymus fortunei, Amygdalus communis and Garcinia xanthochymus were found possessing high inhibitory activities (inhibition rate >90%). From G. xanthochymus, a new inhibitor of GSK 3beta, fukugetin, was discovered with an IC50 value of 3.18+/-0.07MUM. Enzyme kinetics and molecular docking experiments further revealed the inhibitory mechanism, indicating fukugetin was a non-ATP competitive inhibitor interacting with the phosphate recognizing substrate binding site of GSK-3beta. PMID- 26610619 TI - Perioperative Medicine: The Value Proposition for Anesthesia?: A UK Perspective on Delivering Value from Anesthesiology. AB - Perioperative medicine describes the practice of patient centered, multidisciplinary, and integrated medical care of patients from the moment of contemplation of surgery until full recovery. The value proposition for perioperative medicine rests on defining benefits that outweigh the costs of change. This article discusses the concept of value in the context of healthcare and highlights a number of reasons for relative market failure. Five key opportunities for adding value in the perioperative journey are suggested: collaborative decision-making, lifestyle modification before surgery, standardization of in-hospital perioperative care, achieving full recovery after surgery, and the use of data for quality improvement. PMID- 26610620 TI - Demonstrating Value: A Case Study of Enhanced Recovery. AB - An enhanced recovery after surgery strategy will be increasingly adopted in the era of value-based care. The various elements in each enhanced recovery after surgery protocol are likely to add value to the overall patient surgical journey. Although the evidence varies considerably based on type of surgery and patient group, the team-based approach of care should be universally applied to patient care. This article provides an overview of up-to-date techniques and methodology for enhanced recovery, including an overview of value-based care, delivery, and the evidence base supporting enhanced recovery after surgery. PMID- 26610621 TI - Value from the Patients' and Payers' Perspectives. AB - Health care costs continue to increase, and the approach of countries and insurers is to focus on the value of the care delivered. Value is a function of quality in relation to costs. The perspective of the individual measuring value is important. Calculation of costs may include return to work if the employer's perspective is taken. The patients' perspectives include out-of-pocket expenses and work lost for both patients and potentially caregivers. The authors provide one example in the area of sleep apnea in which the anesthesiologist can provide value uniquely by being part of the team making the diagnosis. PMID- 26610622 TI - "What Have We Done for Us Lately?"--Defining Performance and Value at the Individual Clinician Level. AB - Consolidation in anesthesiology practice and the rest of health care creates pressure to improve the product offered by anesthesia professionals. Anesthesia professionals must offer more than a reliable stream of anesthetized, operated, and recovered patients to remain competitive. By pooling resources and application of leadership effort, large departments and group practices can conduct individual-level value assessments of clinicians. Individual clinicians can be incentivized to improve their personal value proposition. By creating an interlocking program of ongoing assessment, career development coaching and opportunities, as well as compensation, departments and group practices can return value to individual clinicians by curating and accelerating their career and capability development. PMID- 26610623 TI - Performance Measurement to Demonstrate Value. AB - Anesthesiologists are obligated to demonstrate the value of the care they provide. The Centers for Medicare and Medicaid Services has multiple performance based payment programs to drive high-value care and motivate integrated care for surgical patients and hospitalized patients. These programs rely on diverse arrays of performance measures and complex reporting rules. Among all specialties, anesthesiology has tremendous potential to effect wide-ranging change on diverse measures. Performance measures deserve scrutiny by anesthesiologists as tools to improve care, the means by which payment is determined, and as a means to demonstrate the value of care to surgeons, hospitals, and patients. PMID- 26610624 TI - Optimizing Operating Room Scheduling. AB - This article reviews the management of an operating room (OR) schedule and use of the schedule to add value to an organization. We review the methodology of an OR block schedule, daily OR schedule management, and post anesthesia care unit patient flow. We discuss the importance of a well-managed OR schedule to ensure smooth patient care, not only in the OR, but throughout the entire hospital. PMID- 26610625 TI - Lean Strategies in the Operating Room. AB - Lean strategies can be readily applied to health care in general and operating rooms specifically. The emphasis is on the patient as the customer, respect and engagement of all providers, and leadership from management. The strategy of lean is to use continuous improvement to eliminate waste from the care process, leaving only value-added activities. This iterative process progressively adds the steps of identifying the 7 common forms of waste (transportation, inventory, motion, waiting, overproduction, overprocessing, and defects), 5S (sort, simplify, sweep, standardize, sustain), visual controls, just-in-time processing, level-loaded work, and built-in quality to achieve the highest quality of patient care. PMID- 26610626 TI - Providing Value in Ambulatory Anesthesia in 2015. AB - Ambulatory anesthesia's popularity continues to increase and techniques continue to adapt to the needs of patients. Alterations in existing medications are promising. Postoperative nausea and vomiting, pain, obstructive sleep apnea, and chronic comorbidities are concerns in ambulatory settings. Regional anesthesia has multiple advantages over general anesthesia. The implementation of the Affordable Health Care Act specifically affects ambulatory settings as the demand and need for patients to undergo screening procedures with anesthesia. The question remains what the best strategy is to meet the needs of our future patients while preserving economic feasibility within an already strained health care system. PMID- 26610627 TI - Acute Pain Management/Regional Anesthesia. AB - Effective and efficient acute pain management strategies have the potential to improve medical outcomes, enhance patient satisfaction, and reduce costs. Pain management records are having an increasing influence on patient choice of health care providers and will affect future financial reimbursement. Dedicated acute pain and regional anesthesia services are invaluable in improving acute pain management. In addition, nonpharmacologic and alternative therapies, as well as information technology, should be viewed as complimentary to traditional pharmacologic treatments commonly used in the management of acute pain. The use of innovative technologies to improve acute pain management may be worthwhile for health care institutions. PMID- 26610628 TI - Examining Health Care Costs: Opportunities to Provide Value in the Intensive Care Unit. AB - As health care costs threaten the economic stability of American society, increasing pressures to focus on value-based health care have led to the development of protocols for fast-track cardiac surgery and for delirium management. Critical care services can be led by anesthesiologists with the goal of improving ICU outcomes and at the same time decreasing the rising cost of ICU medicine. PMID- 26610629 TI - Perioperative Surgical Home: Perspective II. AB - Healthcare delivery and payment systems in the United States must continue to be reformed to address currently untenably increasing healthcare expenditures, while increasing the quality of care. The Perioperative Surgical Home is a highly patient-centered approach to care, focusing on the standardization, coordination, transitions, and value of care, throughout the perioperative continuum, including after hospital discharge. To increase the value of surgical care, any Perioperative Surgical Home model must translate, implement, and sustain improvements in quality, safety, and satisfaction, plus cost reduction strategies, throughout the perioperative continuum. Healthcare informatics, analytics, decision support, and practice change are central to this effort. PMID- 26610630 TI - The Pain Medical Home: A Patient-Centered Medical Home Model of Care for Patients with Chronic Pain. AB - Chronic pain affects an estimated 100 million people a year in the United States and costs society anywhere from $560 to $635 billion annually. The patient centered medical home and the patient-centered medical home-neighbor models of care have been advocated to improve patient outcomes. These models of care advocate improved coordination of care within the primary care and specialty care setting. The authors present the patient-centered medical home model of care and suggest how this model of care might be used to improve patient outcomes for patients with chronic pain. PMID- 26610631 TI - Value--The Current Cure for Health Care's Ailments? PMID- 26610633 TI - Time for pharmacists to accept their role in community pharmacy: Pakistani perspective. PMID- 26610632 TI - Aristaless-Like Homeobox protein 1 (ALX1) variant associated with craniofacial structure and frontonasal dysplasia in Burmese cats. AB - Frontonasal dysplasia (FND) can have severe presentations that are medically and socially debilitating. Several genes are implicated in FND conditions, including Aristaless-Like Homeobox 1 (ALX1), which is associated with FND3. Breeds of cats are selected and bred for extremes in craniofacial morphologies. In particular, a lineage of Burmese cats with severe brachycephyla is extremely popular and is termed Contemporary Burmese. Genetic studies demonstrated that the brachycephyla of the Contemporary Burmese is a simple co-dominant trait, however, the homozygous cats have a severe craniofacial defect that is incompatible with life. The craniofacial defect of the Burmese was genetically analyzed over a 20 year period, using various genetic analysis techniques. Family-based linkage analysis localized the trait to cat chromosome B4. Genome-wide association studies and other genetic analyses of SNP data refined a critical region. Sequence analysis identified a 12bp in frame deletion in ALX1, c.496delCTCTCAGGACTG, which is 100% concordant with the craniofacial defect and not found in cats not related to the Contemporary Burmese. PMID- 26610634 TI - Variation of plate fixation for mandibular advancement with intraoral vertical ramus osteotomy using endoscopically assisted intraoral rigid or semi-rigid internal fixation: Case series study: Postoperative condylar seating control for mandibular advancement. AB - The purpose of the present study was to evaluate the safety and efficacy associated with mandibular advancement by intraoral vertical ramus osteotomy (IVRO) with endoscopically assisted intraoral rigid or semi-rigid internal fixation. The study sample included all patients who had undergone an mandibular advancement by IVRO procedure with endoscopically assisted intraoral plate fixation from September 2008 to May 2012. An mandibular advancement by IVRO with endoscopically assisted intraoral rigid or semi-rigid internal fixation was used for mandibular advancement. The patients were analyzed prospectively, with more than 2 years of follow-up, and were evaluated in terms of functional results, postoperative complications, and skeletal stability. A total of 14 patients (bilateral, 7 patients with class II; unilateral, 7 patients with asymmetry) were included in the present study. The average degree of mandibular advancement was 5.5 +/- 1.9 mm (range, 3-9 mm). Both the occlusal relationship and facial appearance in all patients were significantly improved by the surgical orthodontic treatment, with no major harmful clinical symptoms. In addition, one screw semi-rigid fixation could control postoperative passive condylar seating. This study showed that mandibular advancement by IVRO with endoscopically assisted, intraoral semi-rigid internal fixation offers a promising treatment alternative for patients with skeletal class II malocclusion or facial asymmetry. PMID- 26610635 TI - Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders. AB - As a group, we met to discuss the current challenges for creating meaningful patient-specific in vitro models to study brain disorders. Although the convergence of findings between laboratories and patient cohorts provided us confidence and optimism that hiPSC-based platforms will inform future drug discovery efforts, a number of critical technical challenges remain. This opinion piece outlines our collective views on the current state of hiPSC-based disease modeling and discusses what we see to be the critical objectives that must be addressed collectively as a field. PMID- 26610636 TI - Sarcopenia in cases of chronic and acute illness. A mini-review. AB - BACKGROUND: Loss of muscle mass and muscle weakness are often found in cases of acute or chronic illness in elderly patients. Sarcopenia is a risk factor for complications and higher mortality. Based on an exact diagnosis and knowledge of the risk factors for developing sarcopenia, it is now possible to improve the prognosis by providing effective treatment options. METHODS: This review was carried out based on a PubMed search in the period from 1998 to 2015 using original articles and reviews and posting the terms "sarcopenia", "elderly" and "acute illness". CONCLUSION: Given the evidence from the current literature, in the case of acute illness it is feasible to identify patients at risk, diagnose sarcopenia and prescribe a multidimensional treatment program to prevent or treat sarcopenia even in the bustling environment of geriatric wards or institutions. PMID- 26610637 TI - Photobiomodulation and eccentric exercise for Achilles tendinopathy: a randomized controlled trial. AB - BACKGROUND: The common regime of eccentric exercise in use for Achilles tendinopathy is somewhat arduous and compliance issues can arise. This is the first study to investigate the effectiveness of a regime of fewer exercise sessions combined with photobiomodulation for the treatment of Achilles tendinopathy. METHODS: A double blind randomized controlled trial and intention to-treat analysis were performed. Eighty participants, 18-65 years with Achilles tendinopathy and symptoms for longer than 3 months, were included in the trial. Participants randomized into one of four groups; 1 (Placebo + Ex Regime 1) or 2 (Laser + Ex Regime 1) or 3 (Placebo + Ex Regime 2) or 4 (Laser + Ex Regime 2). The primary outcome measure was the Victorian Institute of Sports Assessment Achilles (VISA-A) questionnaire. Outcomes were collected at baseline, week 4 and week 12. RESULTS: Sixteen participants were lost to follow-up at 12 weeks, 4 of which due to adverse reactions. As per intention to treat, missing data were imputed, 80 participants were included in the final analysis. For VISA-A at 12 weeks, group 4 achieved significant gains over the other 3 groups: group 1 (18.5 [9.1, 27.9]), group 2 (10.4 [1.5, 19.2]), group 3 (11.3 [3.0, 19.6]). There was a moderate effect size in favour of exercise twice per week (7.2 [-1.8, 16.2], ES .7). CONCLUSIONS: Twice-daily exercise sessions are not necessary as equivalent results can be obtained with two exercise sessions per week. The addition of photobiomodulation as adjunct to exercise can bring added benefit. PMID- 26610638 TI - Indirect comparisons of the efficacy of biological agents in patients with psoriatic arthritis with an inadequate response to traditional disease-modifying anti-rheumatic drugs or to non-steroidal anti-inflammatory drugs: A meta analysis. AB - BACKGROUND: While the efficacy of biologic agents for the treatment of psoriatic arthritis (PsA) has been well demonstrated in randomized controlled trials (RCTs), the data on their relative efficacy is limited. This meta-analysis is aimed at assessing the comparative efficacy of these agents in patients who had persistently active disease despite traditional non-steroidal anti-inflammatory drugs (NSAIDs)/disease-modifying anti-rheumatic drugs (DMARDs), or who could not tolerate NSAIDs/DMARDs. METHODS: RCTs examining the efficacy of biologic agents in patients with PsA who experienced inadequate response or intolerance of traditional DMARDs or NSAIDs were identified. If more than one RCT were available for a given biologic agent, the pooled risk ratio (RR) and 95% confidence interval (CI) of attaining a 20% improvement according to American College of Rheumatology criteria (ACR20) response across trials were calculated. The pooled risk ratios for each biologic agent were then compared using the indirect comparison technique. RESULTS: A total of 12 RCTs were identified and included in the data analyses. We found that patients who received older TNF inhibitors (etanercept, infliximab, adalimumab, and golimumab) had a statistically significantly higher chance of achieving ACR20 response compared with apremilast, ustekinumab, and certolizumab. The likelihood of achieving ACR20 response among secukinumab users (at the dose of 150 mg and 300 mg weekly) was also higher compared with apremilast, ustekinumab, and certolizumab, though the relative risk did not always reach statistical significance. CONCLUSIONS: Our study demonstrates that patients with PsA who experience inadequate response or intolerance of traditional DMARDs or NSAIDs have a higher probability of achieving the ACR20 response with older TNF inhibitors and secukinumab. PMID- 26610639 TI - Hunting down factor VIII in the immunopeptidome. AB - Major histocompatibility complex class II (MHCII)-restricted peptide presentation is crucial for the selection and subsequent proliferation of antigen specific CD4+ T cells. While selection of antigen-specific CD4+ T cells is beneficial in the context of vaccination, emergence of antigen CD4+ T cells following administration of therapeutic proteins like factor VIII (FVIII) is not desirable. The mechanism of uptake, processing and presentation of FVIII by antigen presenting cells (APCs) has been the subject of intense study over the past 10 years. Multiple receptors have been implicated in the uptake of FVIII by APCs. A crucial determinant directing its entry in APCs resides in the C1 domain of FVIII. Until recently, our knowledge on the repertoire of FVIII derived presented on MHCII was limited. Peptide sequences on FVIII recognized by CD4+ T cells have been identified using MHCII tetramers as well as by directly monitoring peptide induced proliferation of CD4+ T cells. More recently, the repertoire of naturally presented peptides derived from FVIII has been identified by pulsing of immature dendritic cells with FVIII. In a complementary approach HLA-DRB1(*)15 transgenic mice were used to identify HLA-DRB1(*)15 restricted CD4+ T cells reactive towards human FVIII. In this review we summarize our current knowledge on FVIII derived peptides that are presented on MHCII and discuss the relevance of these findings for the etiology of inhibitor development in patients with hemophilia A. PMID- 26610640 TI - Erythropoietin preconditioning improves clinical and histologic outcome in an acute spinal cord ischemia and reperfusion rabbit model. AB - OBJECTIVE: This study examined effects and functional outcome of recombinant human erythropoietin (rhEPO) and carbamylated erythropoietin fusion protein (cEPO FC) preconditioning in a rabbit model for spinal cord ischemia and resulting paraplegia. This model was chosen because only a small surgical effect is needed to cause paraplegia in rabbits, which facilitates postoperative observation of animals. METHODS: Anesthetized but spontaneously breathing New Zealand White rabbits randomly received cEPO-FC (50 MUg/kg; n = 8), rhEPO (5000 IU/kg; n = 10), or vehicle (control; n = 10) 30 minutes before and after infrarenal aortic clamping. Ideal clamping time of 22 minutes was identified from preceding clamping tests (15-25 minutes). Postoperative observation time was 96 hours. Spinal cord function was assessed by neurologic evaluation of hind limb motor function every 12 hours using a modified Tarlov score. Spinal cord tissue damage was evaluated after 96 hours using hematoxylin and eosin, elastica van Gieson, Nissl, Masson-Goldner, and hemosiderin staining. Plasma levels of cell senescence markers stathmin, chitinase 1/3, elongation factor 1-alpha were determined. RESULTS: Rabbits that received rhEPO showed significant improvement of spontaneous lower limb movements until 36 hours of reperfusion and improved histologic scores upon examination of the lumbar spinal cord compared with the control group. In contrast, cEPO-FC treatment showed comparable outcome to the control group concerning movements of the lower limbs and histology. Senescence markers were elevated in the control group, but not in the treatment groups, except for chitinase 3 in the rhEPO group. Only stathmin showed no significant effect. Markers for senescence might increase after acute ischemic injury. Attenuation of senescence markers might not come alone from improvement of the spinal cord. CONCLUSIONS: Preconditioning with rhEPO attenuates ischemia/reperfusion injury of the spinal cord, whereas the carbamylated derivative (cEPO-FC) showed no positive effect on spinal cord function. PMID- 26610641 TI - Outcomes of arterial resection during pancreatectomy for tumor. AB - OBJECTIVE: Arterial resection (AR) during pancreatic tumor resection is controversial. We examined the safety and efficacy of AR during pancreatectomy. METHODS: We used a prospective institutional database that includes 6522 patients who underwent pancreatectomy from 1970 to 2014; 35 had AR. We performed a 2:1 propensity match for patients without and with AR on the basis of preoperative patient and tumor variables. We then compared operative and postoperative outcomes between matched groups. RESULTS: AR included 18 hepatic, 8 celiac, 3 splenic, 3 middle colic, 2 superior mesenteric, and 1 left renal artery. There were 20 primary, 4 vein, and 2 graft reconstructions; 11 were emergent and 24 elective. Before matching, patients with AR were younger (58 +/- 2 vs 63 +/- 0.2 years old; P = .05), more likely to be of black race (26% vs 9%; P = .003), to have received preoperative chemotherapy (17% vs 2%; P < .001), have a later stage and larger tumor (4 +/- 0.8 vs 3 +/- 0.04 cm; P = .05), more resections that included removal of all macroscopic disease, but microscopic residual tumor remained (31% vs 14%; P = .02), greater blood loss (1285 +/- 276 vs 822 +/- 16 mL; P = .02), and more frequent cardiac complications (11% vs 4%; P = .03) compared with patients without AR. After propensity matching, baseline patient characteristics were similar between groups. For perioperative outcomes, the groups did not differ in surgical time, blood loss, length of stay, or complications including anastomotic leaks, bleeding, cardiac, infectious complications, or liver infarct or failure (all; P = not significant). Patency was 97% at a mean follow-up of 510 +/- 184 days with 1 hepatic artery AR thrombosis. Long-term outcomes were significantly different: patients with AR had a lower rate of local tumor recurrence (20% vs 47%; P = .007) but also lower 1 year (50% vs 87%; P = .002) and median survival (22 +/- 18 vs 49 +/- 7 months; P = .002). CONCLUSIONS: AR during pancreatectomy is safe and not associated with increased complications. Although it significantly reduces the risk of local tumor recurrence, AR is associated with worse survival compared with patients who do not undergo AR. PMID- 26610642 TI - Discussion. PMID- 26610644 TI - Discussion. PMID- 26610643 TI - Carotid angiographic characteristics in the CREST trial were major contributors to periprocedural stroke and death differences between carotid artery stenting and carotid endarterectomy. AB - OBJECTIVE: The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) demonstrated a higher periprocedural stroke and death (S+D) rate among patients randomized to carotid artery stenting (CAS) than to carotid endarterectomy (CEA). Herein, we seek factors that affect the CAS-CEA treatment differences and potentially to identify a subgroup of patients for whom CAS and CEA have equivalent periprocedural S+D risk. METHODS: Patient and arterial characteristics were assessed as effect modifiers of the CAS-CEA treatment difference in 2502 patients by the addition of factor-by-treatment interaction terms to a logistic regression model. RESULTS: Lesion length and lesions that were contiguous or were sequential and noncontiguous extending remote from the bulb were identified as influencing the CAS-to-CEA S+D treatment difference. For those with longer lesion length (>=12.85 mm), the risk of CAS was higher than that of CEA (odds ratio [OR], 3.42; 95% confidence interval [CI], 1.19-9.78). Among patients with sequential or remote lesions extending beyond the bulb, the risk for S+D was higher for CAS relative to CEA (OR, 9.01; 95% CI, 1.20-67.8). For the 37% of patients with lesions that were both short and contiguous, the odds of S+D in those treated with CAS was nonsignificantly 28% lower than for CEA (OR, 0.72; 95% CI, 0.21-2.46). CONCLUSIONS: The higher S+D risk for those treated with CAS appears to be largely isolated to those with longer lesion length and/or those with sequential and remote lesions. In the absence of those lesion characteristics, CAS appears to be as safe as CEA with regard to periprocedural risk of S+D. PMID- 26610645 TI - Treatment of sac expansion after endovascular aneurysm repair with obliterating endoaneurysmorrhaphy and stent graft preservation. AB - BACKGROUND: Persistent type II endoleaks (T2Ls) with sac enlargement after endovascular abdominal aortic aneurysm repair are still of concern in view of the potential for rupture. Current treatments (embolization and stent graft [SG] explantation) are associated with lack of efficacy or high perioperative morbidity and mortality. This study evaluated an alternative technique that combines sacotomy, ligation of patent back-bleeding vessels, and SG preservation for T2L or unspecified endoleak repair. METHODS: This multicenter study in France included 28 patients (27 men; median age, 78 years). Twenty-one patients (75%) had a bifurcated SG (including 3 fenestrated SGs) and seven (25%) had an aortouni iliac SG (2 for ruptured aneurysm). Unsuccessful embolization had been performed in 10 patients (36%). Four patients (14%) presented sac enlargement with no endoleak visible on computed tomography. The origin of the endoleak remained unspecified in three patients 3 (11%). The median diameter of the aneurysmal sac was 78 mm (vs 55 mm at the time of endovascular abdominal aortic aneurysm repair) after a median follow-up of 24 months. RESULTS: A transperitoneal approach was used in 21 patients (75%) and a retroperitoneal approach was used in seven (25%). A guidewire was placed in the supraceliac aorta in 14 patients, and an occlusion balloon was temporarily inflated in six. Aortic cross-clamping was performed in five patients. T2Ls were identified in 26 patients, and associated with a distal type I endoleak in 1 patient, a type III endoleak in 3, and a type IV endoleak in 1. Two patients presented with endotension. All the endoleaks were treated successfully, with a mean operating time of 120 minutes and a mean blood loss of 450 mL. One SG was explanted 12 days after the procedure because of early infection. One patient died during SG explantation for an aortoduodenal fistula 26 months after the endoaneurysmorrhaphy. During a median follow-up of 24 months, the control computed tomography scan showed shrinkage of the aneurysmal sac with stable diameters in all patients. No missed T2Ls, no recurrence of T2L, and no SG migration or disjunction was observed. CONCLUSIONS: Obliterating endoaneurysmorrhaphy with SG preservation can be considered as an alternative to SG removal in cases of persistent T2L responsible for aneurysmal sac enlargement after embolization failure. By avoiding extensive dissection for surgical aortic cross-clamping, minimizing hemodynamic changes, and reducing blood loss and operating time, this procedure can be performed even in patients initially considered unfit for surgery. PMID- 26610646 TI - Discussion. PMID- 26610647 TI - Aortic anatomic severity grade correlates with resource utilization. AB - BACKGROUND: Potential cost effectiveness of endovascular aneurysm repair (EVAR) compared with open aortic repair (OAR) is offset by the use of intraoperative adjuncts (components) or late reinterventions. Anatomic severity grade (ASG) can be used preoperatively to assess abdominal aortic aneurysms, and provide a quantitative measure of anatomic complexity. The hypothesis of this study is that ASG is directly related to the use of intraoperative adjuncts and cost of aortic repair. METHODS: Patients who undergo elective OAR and EVAR for abdominal aortic aneurysms were identified over a consecutive 3-year period. ASG scores were calculated manually using three-dimensional reconstruction software by two blinded reviewers. Statistical analysis of cost data was performed using a log transformation. Regression analyses, with a continuous or dichotomous outcome, used a generalized estimating equations approach with the sandwich estimator, being robust with respect to deviations from model assumptions. RESULTS: One hundred forty patients were identified for analysis, n = 33 OAR and n = 107 EVAR. The mean total cost (+/- standard deviation) for OAR was per thousand (k) $38.3 +/- 49.3, length of stay (LOS) 13.5 +/- 14.2 days, ASG score 18.13 +/- 3.78; for EVAR, mean total cost was k $24.7 +/- 13.0 (P = .016), LOS 3.0 +/- 4.4 days (P = .012), ASG score 15.9 +/- 4.13 (P = .010). In patients who underwent EVAR, 25.2% required intraoperative adjuncts, and analysis of this group revealed a mean total cost of k $31.5 +/- 15.9, ASG score 18.48 +/- 3.72, and LOS 3.9 +/- 4.5, which were significantly greater compared with cases without adjunctive procedures. An ASG score of >=15 correlated with an increased propensity for requirement of intraoperative adjuncts; odds ratio, 5.75 (95% confidence interval, 1.82-18.19). ASG >15 was also associated with chronic kidney disease, end stage renal disease, hypertension, female sex, increased cost, and use of adjunctive procedures. CONCLUSIONS: Complex aneurysm anatomy correlates with increased total cost and need for adjunctive procedures during EVAR. Preoperative assessment with ASG scores can delineate patients at greater risk for increased resource use. Patient comorbid factors are associated with anatomic complexity defined according to ASG. A critical examination of the relationship between anatomic complexity and finances is required within the context of aggressive endovascular treatment strategies and shifts toward value-based reimbursement. PMID- 26610648 TI - Predictors of hospital readmissions after lower extremity amputations in Canada. AB - OBJECTIVE: To describe the factors associated with early (<=30 days) and late (31 365 days) hospital readmissions after lower extremity amputations in Canada. METHODS: A retrospective cohort study was carried out for all Canadian adults who underwent elective lower extremity amputations in the years 2006 to 2008 for nontraumatic indications. Patients were identified from the Canadian Institute for Health Information's Discharge Abstract Database, which includes all hospital admissions across Canada, with the exception of the Province of Quebec. RESULTS: During the study period, 3823 patients underwent lower limb amputations (major amputations = 95%) and 2116 were readmitted at least once (55.4%). Of those patients, 1112 (29.1%) were readmitted within 30 days (mean = 5.0 +/- 8.3 days after discharge) and 1004 (26.3%) were readmitted between 31 and 365 days (mean = 151.4 +/- 95.9 days after discharge). Stump complications accounted for 13% and 10% of early and late readmissions, respectively. Stump revision surgery was performed in 301 readmitted patients (7.9%). Predictors of early readmission included amputation by a vascular surgeon (odds ratio, 1.6; 95% confidence interval, 1.3-1.9), female sex (odds ratio, 1.2; 95% confidence interval, 1.1 1.5), and a short (<7 day) admission (odds ratio, 1.7; 95% confidence interval, 1.4-2.1). Predictors of late readmission included a longer (>=7 days) admission (odds ratio, 1.5; 95% confidence interval, 1.2-1.8), discharge to a long-term care facility (odds ratio, 3.3; 95% confidence interval, 2.7-3.9), and home discharge with community support (odds ratio, 2.3; 95% confidence interval, 1.8 2.9). CONCLUSIONS: Half of patients who underwent lower extremity amputations were readmitted to the hospital within 1 year. Markers of patient dependence (long hospitalization, discharge to long-term care facility) predict late readmission. PMID- 26610649 TI - Occurrence of "never events" after major open vascular surgery procedures. AB - OBJECTIVE: "Never events" refers to harmful hospital-acquired conditions that the Centers for Medicare and Medicaid Services identified in 2008 as largely preventable and that would no longer be reimbursed. Our goal was to identify the incidence, predictive factors, temporal trend, and associated consequences of never events after major open vascular surgery procedures. METHODS: The Nationwide Inpatient Sample (NIS) (2003-2011) was queried to identify never events applicable to vascular surgery patients, including air embolism, catheter based urinary tract infections (UTIs), stage 3 and 4 pressure ulcers, falls/trauma, blood incompatibility, vascular catheter infections, complications of poor glucose control, retained foreign objects, and wrong-site surgery. We specifically evaluated open abdominal aortic aneurysm repair, carotid endarterectomy, and lower extremity bypass/femoral endarterectomy. Multivariable logistic regression was used to predict never events based on preoperative variables. Multivariable logistic and gamma regression models were used to study mortality, hospital length of stay (LOS), and charges. RESULTS: Never events were identified in 774 of 267,734 patients. The distribution of never events were falls/trauma (59%), pressure ulcers (19%), catheter-based UTI (9%), vascular catheter infection (6%), complications of poor glucose control (5%), and retained objects (4%). Rates of falls and catheter-based UTIs have increased since 2008. Multivariable predictors of any never event included lower extremity bypass, abdominal aortic aneurysm, weight loss, nonelective admission, paralysis, repair, congestive heart failure, altered mental status, renal failure, weekend admission, diabetes, female gender, and age. Race, insurance, hospital type, income level, geography, July to September admission, and other comorbidities were not predictive. After risk factor adjustment, never events were associated with increased perioperative mortality (odds ratio, 2.7; 95% confidence interval [CI], 1.5-34.8; P < .001), LOS (means ratio, 1.9; 95% CI, 1.7-2.0; P < .001), and total charges (means ratio, 1.7; 95% CI, 1.6-1.8; P < .001). CONCLUSIONS: Never events after major vascular surgery are associated with a number of perioperative factors and are predictive of increased charges, LOS, and mortality. Falls and catheter-based UTIs have increased in frequency since the Centers for Medicare and Medicaid Services announced that it would no longer reimburse for these complications. This study establishes baseline never event rates in the vascular surgery patient population and identifies high-risk patients to target for quality improvement. PMID- 26610650 TI - Clinical-Pathological Conference Series from the Medical University of Graz: Case No 156: 82-year-old woman with chronic diarrhea and weight loss of 20 kilograms. PMID- 26610651 TI - Individual differences in the attentional blink: Evidence from the amplitude of low-frequency fluctuations in non-blinkers and blinkers. AB - The attentional blink (AB) is a deficit in reporting the second target (T2) when it is presented within 500ms of the first target (T1) as part of a rapid serial visual presentation (RSVP). Despite the considerable number of imaging studies having investigated the neural correlates of the AB, differences in the spontaneous neural activity of non-blinkers and blinkers remain unclear. In the present study, we investigated this issue using the RSVP task in 43 participants. The results revealed that the amplitude of low-frequency fluctuations (ALFF) in occipitotemporal regions and the cerebellum region was higher in blinkers than in non-blinkers. In contrast, the ALFF in frontoparietal regions was higher in non blinkers than in blinkers. These findings suggest that the AB is due to an overinvestment of attentional resources in distractors as well as a weakness of attentional control in targets. PMID- 26610652 TI - Relationship of high leptin levels with an adverse lipid and insulin profile in 6 8 year-old children in Spain. AB - BACKGROUND AND AIMS: Leptin, an adipokine elevated in obesity, may be related to an adverse cardiovascular risk profile in childhood. However, evidence for this relationship in pre-pubertal children is scarce. We aimed to analyze the relationship between leptin levels and lipid and insulin profiles in Spanish children. METHODS AND RESULTS: Our population-based sample included 389 males and 369 females aged 6-8 years. Lipid levels were determined by standard methods, insulin by radioimmunoassay and leptin by sandwich ELISA. Leptin levels were higher in girls (8.6 ng/ml) than boys (4.7 ng/ml) (p < 0.001). Leptin increased from ages 6 to 8 in girls, but remained steady in boys. In both sexes, leptin increased significantly (p < 0.001) across weight category from normal weight to obese. Children in the highest tertile of leptin concentration showed significantly (p < 0.01) lower levels of HDL-cholesterol (HDL-C) and apolipoprotein-AI (apo-AI) and significantly higher triglyceride (TG) levels than children in lower tertiles. However, in linear regression analysis, after adjustment for body mass index (BMI), leptin only accounted for 1.5% of the variance of HDL-C in boys, and 2.6% of the variance of apo-AI in girls. Leptin was strongly and positively correlated with insulin and HOMA. Upon regression analysis, leptin contributed to over 20% of the variability in insulin and HOMA, independent of BMI. CONCLUSION: Leptin levels show sex differences in pre pubertal children. In this age group, leptin levels are strongly related to insulin, and affect lipid profile -namely HDL-C, apo-AI and TG- particularly when leptin levels are high. PMID- 26610653 TI - Healthy eating and survival among elderly men with and without cardiovascular metabolic diseases. AB - BACKGROUND AND AIMS: The strength of the associations of dietary scores with cardiovascular disease (CVD) and all-cause mortality in elderly vary considerably between a priori scores. To assess whether healthy eating lowers the risk of CVD and all-cause mortality among elderly men. METHODS AND RESULTS: The Zutphen Elderly Study (age 65-84 years) was divided into men with (n = 210) and without (n = 616) cardiovascular-metabolic diseases at baseline in 1985. Diet was assessed with the cross-check dietary history method. We created the "Dutch Healthy Nutrient and Food Score" (DHNaFS) and the "Dutch Undesirable Nutrient and Food Score" (DUNaFS). Associations of the scores with CVD and all-cause mortality were assessed using multivariable Cox regression models. Associations of scores with life years gained used general linear models. During a median follow-up of 10.6 years (IQR 5.8-15.9) 806 participants died, of whom 359 from CVD. In all men, diet scores did not predict death. Among men with cardiovascular-metabolic diseases, DHNaFS was associated with lower CVD (HR: 0.57; 95% CI: 0.35-0.93) and all-cause mortality risk (HR: 0.64; 95% CI: 0.44-0.94) comparing the highest vs. the lowest score tertiles. Men with cardiovascular-metabolic diseases in the highest vs. the lowest tertile of the DHNaFS lived approximately 2.5 years longer. The DHNaFS was not associated with CVD and all-cause mortality in men without cardiovascular-metabolic diseases. The DUNaFS was not associated with any of the outcomes. CONCLUSION: A high quality diet was associated with a 40% lower mortality risk and 2.5 years longer life expectancy in elderly men with, but not without, cardiovascular-metabolic diseases. PMID- 26610654 TI - Novel remodeling of the mouse heart mitochondrial proteome in response to acute insulin stimulation. AB - BACKGROUND AND AIM: Mitochondrial dysfunction contributes to the pathophysiology of diabetic cardiomyopathy. The aim of this study was to investigate the acute changes in the mitochondrial proteome in response to insulin stimulation. METHODS AND RESULTS: Cardiac mitochondria from C57BL/6 mice after insulin stimulation were analyzed using two-dimensional fluorescence difference gel electrophoresis. MALDI-TOF MS/MS was utilized to identify differences. Two enzymes involved in metabolism and four structural proteins were identified. Succinyl-CoA ligase [ADP forming] subunit beta was identified as one of the differentially regulated proteins. Upon insulin stimulation, a relatively more acidic isoform of this protein was increased by 53% and its functional activity was decreased by ~32%. CONCLUSIONS: This proteomic remodeling in response to insulin stimulation may play an important role in the normal and diabetic heart. PMID- 26610655 TI - Readiness for practice change: Evaluation of a tool for the Australian midwifery context. AB - BACKGROUND: Midwifery is a research-informed profession with a mandated requirement to utilise latest best evidence. It is now recognised, however, that the introduction of new evidence into practice is complicated and uncertain. Growing awareness of this fact has led to the establishment of a new discipline, Implementation Science (IS), which is focused on developing ways to expedite the timely movement of evidence into practice. To date though, the wider midwifery profession has yet to make use of IS change-facilitation tools and methods. AIM: The aim of this study was to determine the fitness for use in midwifery of one established IS tool: the UK NHS Spread & Adoption tool, which is designed to enable clinicians to assess their organisational context for change readiness. METHODS: A qualitative descriptive methodology was used for this study, which was set in two Australian states. Focus groups were used to collect data. The sample comprised ten Australian change-leader midwifery teams who had led evidence-based practice change initiatives in the previous 12 months. FINDINGS: Three themes emerged from the data which together convey that although poor internet access was problematic for some, and some of the language was found to be inappropriate, the tool was ultimately viewed as very useful for helping the implementation of practice change in midwifery settings. CONCLUSIONS: This study provides valuable information about the broad suitability of the tested tool for Australian midwifery settings. Further research is required to evaluate a revised version. PMID- 26610657 TI - Analysis of Multicontrast Carotid Plaque MR Imaging. AB - Plaque imaging by MR imaging provides a wealth of information on the characteristics of individual plaque that may reveal vulnerability to rupture, likelihood of progression, or optimal treatment strategy. T1-weighted and T2 weighted images among other options reveal plaque morphology and composition. Dynamic contrast-enhanced-MR imaging reveals plaque activity. To extract this information, image processing tools are needed. Numerous approaches for analyzing such images have been developed, validated against histologic gold standards, and used in clinical studies. These efforts are summarized in this article. PMID- 26610656 TI - Three-Dimensional Carotid Plaque MR Imaging. AB - There has been significant progress made in 3-dimensional (3D) carotid plaque MR imaging techniques in recent years. Three-dimensional plaque imaging clearly represents the future in clinical use. With effective flow-suppression techniques, choices of different contrast weighting acquisitions, and time efficient imaging approaches, 3D plaque imaging offers flexible imaging plane and view angle analysis, large coverage, multivascular beds capability, and even can be used in fast screening. PMID- 26610658 TI - Incorporating Carotid Plaque Imaging into Routine Clinical Carotid Magnetic Resonance Angiography. AB - The incorporation of a short, easy-to-acquire and simple to read sequence to visualize the vessel wall and detect intraplaque hemorrhage (IPH) is achievable now. Demonstration of IPH may be helpful in primary or secondary prevention of neuroischemic events, assessment prior to carotid intervention and the general definition of an individual's vascular phenotype. The addition of an IPH detecting vessel wall sequence only adds 5 to 6 minutes to a standard carotid MRI examination making clinical translation feasible and achievable. PMID- 26610659 TI - FDG PET/CT Imaging of Carotid Atherosclerosis. AB - Atherosclerosis is a complex inflammatory process and an integral component of myocardial infarction and stroke. Atherosclerotic plaques can be detected using ultrasonography, myocardial perfusion imaging, coronary angiography, multidetector computed tomography (CT), and MR imaging. These modalities assess the luminal encroachment of the plaques or the structural features. Imaging plaque biology in concert with plaque structure may provide important insights. PET scanning using (18)F fluorodeoxyglucose. ((18)F FDG-PET) is commonly combined with CT scanning to characterize oncological processes. This review examines the role of (18)F FDG-PET/CT imaging in the characterization of atherosclerotic plaque biology. PMID- 26610660 TI - Utility of Combining PET and MR Imaging of Carotid Plaque. AB - By harnessing the versatility and soft tissue imaging capabilities of MR imaging alongside the unmatched sensitivity and biomolecular flexibility of PET, the potential to provide detailed multiparametric plaque characterization in the carotid arteries is clear. The ability to acquire simultaneous, and dynamic multimodal data is perhaps PET/MR's greatest strength that will be of major interest to researchers investigating carotid and coronary atherosclerosis alike. This review summarizes the current status of dedicated hybrid PET/MR imaging; to crystallize the rationale for and advantages of this technique with respect to carotid atherosclerosis; and to discuss current limitations, challenges, and future directions. PMID- 26610661 TI - Three-Dimensional Ultrasound of Carotid Plaque. AB - Measurement of plaque burden is different from measurement of carotid intima media thickness (IMT). Carotid total plaque area is a stronger predictor of cardiovascular risk than IMT, and in contrast to progression of IMT, which does not predict cardiovascular events, progression of total plaque area and total plaque volume strongly predict cardiovascular events. Measurement of plaque burden is useful in genetic research, and in evaluation of new therapies for atherosclerosis. Perhaps more importantly, it can be used for management of patients. A strategy called "treating arteries instead of treating risk factors" markedly reduces risk among patients with asymptomatic carotid stenosis. PMID- 26610662 TI - The Use of Contrast-enhanced Ultrasonography for Imaging of Carotid Atherosclerotic Plaques: Current Evidence, Future Directions. AB - Contrast-enhanced ultrasonography (CEUS) is a rapidly evolving modality for imaging carotid artery disease and systemic atherosclerosis. CEUS coupled with diagnostic ultrasonography predicts the degree of carotid artery stenosis and is comparable with computed tomography and magnetic resonance angiography. This article reviews the literature on the evolving role of CEUS for the identification and characterization of carotid plaques with an emphasis on detection of intra-plaque neovascularization and related high-risk morphologic features notably present in symptomatic patients. CEUS carotid imaging may play a prominent additive role in risk stratifying patients and serve as a powerful tool for monitoring therapeutic interventions. PMID- 26610663 TI - Detection of Vulnerable Plaque in Patients with Cryptogenic Stroke. AB - In up to 40% of ischemic stroke cases the etiology remains unknown. A substantial proportion of these patients has non- or only mildly stenosing carotid artery plaques not fulfilling common criteria for large artery stroke, but beeing suspicious for arterio-arteriell embolism. Several imaging techniques allow the non-invasive analysis of plaque features. Nevertheless, carotid MRI might be best suited to assess the key features of vulnerable plaques. This review article discusses potential causes of cryptogenic stroke, the role of plaque imaging in non-stenosing plaques and the association of vulnerable plaques and specific plaque features with stroke risk and stroke recurrence. PMID- 26610664 TI - Plaque Assessment in the Management of Patients with Asymptomatic Carotid Stenosis. AB - The continued occurrence of stroke despite advances in medical therapy for asymptomatic carotid stenosis (ACS) strongly indicates that individual response to medical therapy may vary widely. This article reviews the literature that identifies MR imaging and ultrasound plaque features which are seen in patients at increased risk of future cardiovascular events. Imaging can identify plaque phenotype that is the most amendable to intensive medical therapy. There is also good evidence that plaque imaging can measure the individual response to medical therapy and the lack of response identifies a high-risk group of ACS patients. PMID- 26610665 TI - Low-Grade Carotid Stenosis: Implications of MR Imaging. AB - Although treatment guidelines are well established for symptomatic patients with greater than 69% carotid stenosis on catheter angiography, optimal management of lower degrees of stenosis remain unclear. Vessel wall MR imaging of the carotid arteries has proved helpful in the evaluation of plaque burden and vulnerable plaque characteristics, and in stratifying risk in low-grade carotid stenosis. This article discusses the pathophysiology and imaging of atherosclerotic plaques resulting in low-grade carotid stenosis, and the corresponding stroke risk and association with plaque elsewhere in the cardiovascular system. PMID- 26610666 TI - Unusual Cerebral Emboli. AB - The heart and the carotid arteries are the most common sites of origin of embolic disease to the brain. Clots arising from these locations are the most common types of brain emboli. Less common cerebral emboli include air, fat, calcium, infected vegetations, and tumor cells as well as emboli originating in the venous system. Although infarcts can be the final result of any type of embolism, described herein are the ancillary and sometimes unique imaging features of less common types of cerebral emboli that may allow for a specific diagnosis to be made or at least suspected in many patients. PMID- 26610667 TI - Plaque Imaging to Decide on Optimal Treatment: Medical Versus Carotid Endarterectomy Versus Carotid Artery Stenting. AB - Many of the current guidelines for the management of carotid atherosclerosis are based on clinical trial findings published more than 2 decades ago. The lack of plaque information in clinical decision making represents a major shortcoming and highlights the need for contemporary trials based on characteristics of the atherosclerotic lesion itself, rather than luminal stenosis alone. This article summarizes the major dilemmas clinicians face in current practice, and discusses the rationale and evidence that plaque imaging may help to address these challenges and optimize the clinical management of carotid artery disease in the future. PMID- 26610669 TI - Foreword. Plaque Imaging. PMID- 26610668 TI - Clinical Perspective of Carotid Plaque Imaging. AB - At present, patients with carotid disease are selected for invasive recanalization therapies mainly based on the degree of luminal narrowing and the presence or absence of recent ischemic symptoms. A more sophisticated risk model takes into account other clinical variables, such as age, sex, and the type of recent symptoms, as well as presence of ulcerated plaque. A growing body of evidence shows that noninvasive imaging of the carotid plaque by various methods reliably identifies structural correlates of plaque vulnerability, which are associated with an increased risk of cerebrovascular events. PMID- 26610670 TI - Preface. Carotid Plaque Imaging Comes of Age. PMID- 26610671 TI - Stressful Life Events Prior to Depression Onset and the Cortisol Response to Stress in Youth with First Onset Versus Recurrent Depression. AB - The strongest proximal predictors of depression onset in adolescence are stressful life events (SLEs). Changes in the hypothalamic-pituitary-adrenal (HPA) axis response to stress are theorized to mediate the etiological effect of SLEs on depression onset. The goal of the current study was to examine differences in the cortisol response to a laboratory-induced stressor between youth with versus without at least one SLE in the etiologically-central 3-month period prior to depression onset. One hundred adolescents (24 first-onset depression, 18 recurrent depression, and 58 non-depressed controls) had five salivary cortisol samples collected over the course of the Trier Social Stress Test (TSST). SLEs were assessed using a rigorous contextual interview and rating system. Among those with an SLE, youth on their first onset of depression had a flatter cortisol reactivity slope relative to non-depressed adolescents, and youth on a recurrent episode of depression had a steeper recovery slope relative to first onsets and non-depressed adolescents. In contrast, no between-group differences were found among those with no SLE prior to onset. These results suggest that differences in the HPA axis response pattern may represent a neurobiological mechanism that distinguishes depressed and non-depressed groups but only for adolescents whose depression is precipitated by SLEs. Further, this neurobiological mechanism may play a different role in the very first episode of depression than it does in recurrent episodes. PMID- 26610673 TI - Multiple vertebral metastasis with fluid-fluid level from a pleomorphic lobular breast carcinoma. PMID- 26610672 TI - Annular puncture with tumor necrosis factor-alpha injection enhances painful behavior with disc degeneration in vivo. AB - BACKGROUND CONTEXT: Painfulintervertebral disc degeneration is extremely common and costly. Effective treatments are lacking because the nature of discogenic pain is complex with limited capacity to distinguish painful conditions from age related changes in the spine. Hypothesized sources of discogenic pain include chronic inflammation, neurovascular ingrowth, and structural disruption. PURPOSE: This study aimed to investigate inflammation, pro-neurovascular growth factors, and structural disruption as sources of painful disc degeneration STUDY DESIGN/SETTING: This study used an in vivo study to address these hypothesized mechanisms with anterior intradiscal injections of tumor necrosis factor-alpha (TNFalpha), pro-neurovascular growth factors: nerve growth factor and vascular endothelial growth factor (NGF and VEGF), and saline with additional sham surgery and naive controls. Depth of annular puncture was also evaluated for its effects on structural and painful degeneration. METHODS: Rat lumbar discs were punctured (shallow or deeper puncture) and intradiscally injected with saline, TNFalpha, or NGF and VEGF. Structural disc degeneration was assessed using X-ray, magnetic resonance imaging (MRI), and histology. The rat painful condition was evaluated using Von Frey hyperalgesia measurements, and substance P immunostaining in dorsal root ganglion (DRG) was performed to determine the source of pain. RESULTS: Saline injection increased painful responses with degenerative changes in disc height, MRI intensity, and morphologies of disc structure and cell. TNFalpha and NGF/VEGF accelerated painful behavior, and TNFalpha-injected animals had increased substance P in DRGs. Deeper punctures led to more severe disc degeneration. Multiple regression analysis showed that the painful behavior was correlated with disc height loss. CONCLUSIONS: We concluded that rate and severity of structural disc degeneration was associated with the amount of annular disruption and puncture depth. The painful behavior was associated with disc height loss and discal inflammatory state, whereas pro-inflammatory cytokines might play a more important role in the level of pain, which might have resulted from enhanced DRG sensitization. These in vivo painful disc degeneration models with different severities of structural changes may be useful for investigating discogenic pain mechanisms and for screening therapies, although interpretations must note the differences between all surgically induced animal models and the human condition. PMID- 26610674 TI - A Case of Bifid Phallus and Bladder Neck Incompetence: Is This a Variant of Epispadias or Hypospadias? AB - Diphallia or duplication of the penis is an extremely rare congenital anomaly. Based on the presence of one or two corpora cavernosa in each of the penises, diphallia is classified into two major groups: bifid phallus and true diphallia. Because true diphallia associated with various anomalies is dominant in published studies, little is known about bifid phallus or isolated cases. Here we present a 9-month-old boy with an isolated bifid phallus. After successful reconstruction of the penis and urethra, urinary incontinence became apparent. To the best of our knowledge, this is the first case of complete bifid phallus associated with bladder neck incompetence. PMID- 26610675 TI - The Biochemical and Pathological Correlates of Successful Semen Cryopreservation From Patients With Testicular Cancer: A Single Tertiary Center Experience. AB - OBJECTIVE: To determine the predictors for success with regard to semen cryopreservation and good semen quality of patients with testicular cancer. MATERIALS AND METHODS: A total of 50 men (aged 16-36 years) with testicular cancer, referred for semen cryopreservation prior to gonadotoxic treatment, were included. Age, alpha fetal protein (alpha-FP), beta human chorionic gonadotropin, lactate dehydrogenase, clinical staging, tumor volume, and pathological reports were evaluated as correlates of successful semen cryopreservation and good semen quality. RESULTS: The overall success rate was 52%. alpha-FP (4113.1 ng/mL vs 81.2 ng/mL) and tumor volume (77.7 mL vs 25.5 mL) were significantly higher in the failure group as compared to the success group. The seminoma to nonseminomatous germ cell tumor ratio was lower in the failure group as compared to the success group (9/17 vs 3/21). There was nearly a significant difference (P = .066). The optimal cutoff value for alpha-FP > 1000 ng/mL showed the highest Youden index (0.689) and resulted in a sensitivity of 0.625 and specificity of 1.0 for predicting poor outcome. In terms of multivariate analysis, the alpha-FP (P = .013), tumor volume (P = .047), and alpha-FP > 1000 ng/mL (P = .010) were significantly associated with poor semen quality and failure to preserve semen. Sperm quality was found to be higher in the seminoma versus the nonseminomatous germ cell tumor patients in: sperm concentration (21.5 million/mL vs 11.8 million/mL, P < .027). Furthermore, tumor volume is correlated to alpha-FP (P = .018) and is weakly correlated to lactate dehydrogenase (P = .067) CONCLUSION: Elevated alpha-FP and tumor volume are independently poor factors for semen quality and semen cryopreservation. In clinical use, alpha-FP is a noninvasive tool to predict the success of semen cryopreservation and patients with alpha-FP > 1000 ng/mL should be informed of the higher risk of poor semen quality and semen cryopreservation concerns. PMID- 26610676 TI - Prostate Artery Embolization (PAE) in the Management of Refractory Hematuria of Prostatic Origin Secondary to Iatrogenic Urological Trauma: A Safe and Effective Technique. AB - INTRODUCTION: Incidence of refractory hematuria of prostatic origin (RHPO) is extremely rare, with an iatrogenic etiology even rarer. When conservative methods fail to control bleeding, more invasive surgical methods are needed. In this article we describe our experience with prostatic artery embolization (PAE) as a minimally invasive alternative treatment option in patients with RHPO secondary to iatrogenic urologic trauma. TECHNICAL CONSIDERATIONS: Three patients presented with RHPO. The etiologies were transurethral resection of prostate surgery, Foley catheter removal with a supratherapeutic international normalized ratio and self traumatic Foley catheter removal respectively. Stepwise management with conservative and medical methods failed to control bleeding. Under local anesthesia and moderate sedation, bilateral PAE was performed via a right common femoral artery access and using cone beam computed tomography. An embolic mixture containing 300-500 um Embosphere(r) Microspheres (Biosphere Medical, Rockland, MA) was injected under fluoroscopic guidance until stasis was achieved. PAE using the described technique was a technical and clinical success in all three patients. Hematuria resolved within a period of 24 hours. There were no intra- or periprocedural complications. CONCLUSION: PAE offers a reasonable option in treatment of RHPO, regardless of the cause and may be attempted prior to surgical techniques or sometimes in conjunction. Being minimally invasive and performed under local anesthesia, PAE is especially useful when excessive bleeding prevents adequate visualization of a bleeding source during cystoscopy and in the elderly age group with several comorbidities. An added advantage is the prostatic parenchymal ischemia leading to significant prostate volume reduction and alleviation of the obstructive symptoms. PMID- 26610677 TI - Two new cases of serine deficiency disorders treated with l-serine. AB - OBJECTIVE AND PATIENTS: We report on two new cases of serine deficiency due respectively to 3-phosphoglycerate dehydrogenase (PHGDH) deficiency (Patient 1) and phosphoserine aminotransferase (PSAT1) deficiency (Patient 2), presenting with congenital microcephaly (<3rd centile at birth) and encephalopathy with spasticity. Patient 1 had also intractable seizures. A treatment with oral l serine was started at age 4.5 years and 3 months respectively. RESULTS: Serine levels were low in plasma and CSF relative to the reference population, for which we confirm recently redefined intervals based on a larger number of samples. l Serine treatment led in patient 1 to a significant reduction of seizures after one week of treatment and decrease of electroencephalographic abnormalities within one year. In patient 2 treatment with l-serine led to an improvement of spasticity. However for both patients, l-serine failed to improve substantially head circumference (HC) and neurocognitive development. In a couple related to patient's 2 family, dosage of serine was performed on fetal cord blood when the fetus presented severe microcephaly, showing reduced serine levels at 30 weeks of pregnancy. CONCLUSIONS: l-Serine treatment in patients with 2 different serine synthesis defects, led to a significant reduction of seizures and an improvement of spasticity, but failed to improve substantially neurocognitive impairment. Therefore, CSF and plasma serine levels should be measured in all cases of severe microcephaly at birth to screen for serine deficiency, as prompt treatment with l serine may significantly impact the outcome of the disease. Reduced serine levels in fetal cord blood may also be diagnostic as early as 30 weeks of pregnancy. PMID- 26610678 TI - Fibrillin-1 microfibrils influence adult bone marrow hematopoiesis. AB - We have recently demonstrated that fibrillin-1 assemblies regulate the fate of skeletal stem cells (aka, mesenchymal stem cells [MSCs]) by modulating TGFbeta activity within the microenvironment of adult bone marrow niches. Since MSCs can also influence hematopoietic stem cell (HSC) activities, here we investigated adult hematopoiesis in mice with Cre-mediated inactivation of the fibrillin-1 (Fbn1) gene in the mesenchyme of the forming limbs (Fbn1(Prx1-/-) mice). Analyses of 3-month-old Fbn1(Prx1-/-) mice revealed a statistically significant increase of circulating red blood cells, which a differentiation assay correlated with augmented erythropoiesis. This finding, together with evidence of fibrillin-1 deposition in erythroblastic niches, supported the notion that this extracellular matrix protein normally restricts differentiation of erythroid progenitors. Whereas flow cytometry measurements identified a decreased HSC frequency in mutant relative to wild type mice, no appreciable differences were noted with regard to the relative abundance and differentiation potential of myeloid progenitor cells. Together these findings implied that fibrillin-1 normally promotes HSC expansion but does not influence cell lineage commitment. Since local TGFbeta hyperactivity has been associated with abnormal osteogenesis in Fbn1(Prx1-/-) mice, 1-month-old mutant and wild type animals were systemically treated for 8weeks with either a pan-TGF-beta-neutralizing antibody or an antibody of the same IgG1 isotype. The distinct outcomes of these pharmacological interventions strongly suggest that fibrillin-1 differentially modulates TGFbeta activity in HSC vs. erythroid niches. PMID- 26610679 TI - [Mobile IT: Possibilities and barriers of mHealth]. AB - The increasing availability of mobile devices and corresponding applications, both for providers and patients, often leads to speculation that mHealth, as the combination of mobile devices and health services is often called, would revolutionize the use of information technology (IT) in healthcare. On the other hand users, providers and operators providing such solutions are often confronted with completely new challenges. This article assesses the options and potential of mHealth and also takes a critical look at potential obstacles. As this field is very broad this critical analysis is illustrated by means of three exemplary application areas: mHealth in radiology, the influence of mHealth on research and mHealth as an enabler of new services, always with examples from other countries.The use of mHealth in radiology currently often develops empirically from existing applications in a relatively unstructured way and benefiting from the dynamic development of mobile technology. The possibilities range from viewing images at the bedside via mobile accessibility of radiologists up to teleradiology. In research there is a huge potential in solutions that actively involve patients with their own mobile devices but the field of data protection is still perceived in Germany as problematic so that only a few research institutions are actively addressing these options. The concept of mHealth allows physicians, hospitals and other service providers to invent entirely new services and a start-up scene is beginning to be established with business models becoming successful particularly with exchanges at the interface with established suppliers. PMID- 26610681 TI - [Combined PET-MRI of the abdomen]. AB - The first fully integrated combined positron emission tomography-magnetic resonance imaging (PET-MRI) scanners have been clinically available since 2010. Large prospective studies regarding indications and diagnostic accuracy of this new modality are not yet available; however, preliminary studies have shown a higher diagnostic accuracy and confidence compared to PET-computed tomography (PET-CT) in regions where MRI is known to be superior to CT, such as the liver. The benefit of MRI in accurate lesion characterization and the additional value of diffusion-weighted imaging (DWI) as a complementary functional modality by means of the apparent diffusion coefficient (ADC) is apparent in entities with low tracer uptake (e.g. due to small size) and a decreased or absent accumulation pattern on PET. PMID- 26610682 TI - [Physiology made visible]. PMID- 26610680 TI - [Functional MR imaging of the liver]. AB - The diagnostics of diffuse liver disease traditionally rely on liver biopsies and histopathological analysis of tissue specimens. However, a liver biopsy is invasive and carries some non-negligible risks, especially for patients with decreased liver function and those requiring repeated follow-up examinations. Over the last decades, magnetic resonance imaging (MRI) has developed into a valuable tool for the non-invasive characterization of focal liver lesions and diseases of the bile ducts. Recently, several MRI methods have been developed and clinically evaluated that also allow the diagnostics and staging of diffuse liver diseases, e.g. non-alcoholic fatty liver disease, hepatitis, hepatic fibrosis, liver cirrhosis, hemochromatosis and hemosiderosis. The sequelae of diffuse liver diseases, such as a decreased liver functional reserve or portal hypertension, can also be detected and quantified by modern MRI methods. This article provides the reader with the basic principles of functional MRI of the liver and discusses the importance in a clinical context. PMID- 26610683 TI - [Gynecological tumors of the true pelvis: Radiological diagnosis for pelvic tumors made simple]. AB - Tumors of the reproductive organs are among the most common female tumors. Computed tomography (CT) and magnetic resonance imaging (MRI) are used for establishing the differential diagnosis, for staging and increasingly for treatment stratification. Sonography is the first line imaging modality for assessing benign and malignant tumors of the uterus as well as ovarian and adnexal lesions. In sonographically indeterminate masses MRI is used for clarification as it allows not only a prediction of the dignity but also in most cases a specific diagnosis. The MRI examination is also superior to CT in the assessment of tumors resembling benign pelvic lesions. Whereas MRI has become established as the modality of choice for local staging and treatment planning in cancers of the uterine cervix and endometrial cancer, CT is used for staging of ovarian cancer due to the propensity for peritoneal spread outside the pelvis at the time of initial diagnosis. PMID- 26610684 TI - Heme Iron Release from Alginate Beads at In Vitro Simulated Gastrointestinal Conditions. AB - Heme iron (Fe) release from alginate beads at in vitro simulated gastrointestinal conditions for potential use as oral heme Fe supplement was studied. Five beads at different ratios of sodium alginate (SA)-to-spray-dried bovine blood cells (SDBC) with weight ratios of 1:1.25, 1:2.5, 1:5, 1:10, and 1:15 (w/w) were prepared. Release characteristics of these beads were investigated at in vitro simulated gastrointestinal conditions. Release media pH strongly influenced the controlled Fe release from the beads. The heme Fe-beads in simulated gastric fluid (pH 2) remained in a shrinkage state and Fe release was low: 25.8, 21.1, 11.6, 12.1, and 12.0 % for 1:1.25, 1:2.5, 1:5, 1:10, and 1:15 ratios, respectively. Proportion and amount of Fe released by 1:1.25 and 1:2.5 ratios was higher than the other ratios. The heme Fe-beads swelled and dissociated in simulated intestinal fluid (pH 6), releasing three-fourths of the Fe in 200 min. The morphology studies showed that Fe release followed formation of pores in the alginate matrix, generating erosion of the beads and complete disintegration after 75 and 200 min of gastric and intestinal incubation, respectively. These results indicate that heme Fe-beads may be useful for oral delivery of heme Fe supplement. PMID- 26610685 TI - ICP-OES and Micronucleus Test to Evaluate Heavy Metal Contamination in Commercially Available Brazilian Herbal Teas. AB - Increased tea consumption in combination with intensive pesticide use is generating heavy metal contaminations amongst Brazilian tea consumers, causing health concerns. Inductively coupled plasma optical emission spectrometry (ICP OES) was applied to quantify minerals and heavy metals such as aluminum, barium, cadmium, lead, cobalt, copper, chromium, tin, manganese, molybdenum, nickel, selenium, silver, thallium, vanadium and zinc in Brazilian chamomile, lemongrass, fennel and yerba mate teas. Teas, purchased in local supermarkets, were prepared using infusion and acid digestion. Higher concentrations of Al were present in all samples. In the digested samples, the Al mean concentration was 2.41 MUg g( 1) (sd = 0.72) for fennel and 33.42 MUg g(-1) (sd = 17.18) for chamomile, whilst the sample C for chamomile tea presented the highest concentration with 51.62 MUg g(-1) (sd = 9.17). The safety relation in decreasing order is fennel, lemongrass, chamomile and yerba mate. Chemometric analyses demonstrated a strong correlation between the elements Cd and Pb in the samples. Yerba mate had the highest amount of metal (100 mg kg(-1)), being the subject of a micronucleus test assay for cytotoxicity. The metals found in Yerba mate did not present cytotoxicity/mutagenicity using the micronucleus test. The inorganic contaminants in teas should have their impact carefully monitored. PMID- 26610686 TI - Rickettsial retinitis-an Indian perspective. AB - BACKGROUND: Though rickettsiosis is common in India, there is paucity of rickettsial retinitis (RR) reports from India. Moreover, rickettsial sub-types and their association with retinitis have not been studied. We are reporting a case series of presumed RR with their course of the disease, visual outcome, and association with rickettsial sub-type based on Weil-Felix test. FINDINGS: This is a retrospective study of 19 eyes of 10 patients presented to a single institution. Cases diagnosed with presumed RR were identified from our database from March 2006 to October 2014 and studied retrospectively for patient's demography, clinical presentation, and treatment. Patients with history of fever, retinitis, and a positive Weil-Felix test and a negative chikungunya and dengue serology were diagnosed as presumed rickettsial uveitis. One patient was diagnosed to have epidemic typhus, and four were diagnosed to have Indian tick typhus. Nine patients had bilateral presentation. One patient had history of dog tick bite, and four patients had skin rashes. All the patients presented between 2 and 4 weeks after a fever. CONCLUSIONS: Retinitis on posterior pole with recent history of fever with or without skin rash and a positive Weil-Felix test may suggest a rickettsial etiology. Its ocular manifestation could be an immune response to recent systemic rickettsial infection. Indian tick typhus and epidemic typhus could be the common sub-types seen in our population. Although it has aggressive presentation, it has a good visual prognosis. PMID- 26610687 TI - Discrete choice experiments of pharmacy services: a systematic review. AB - Background Two previous systematic reviews have summarised the application of discrete choice experiments to value preferences for pharmacy services. These reviews identified a total of twelve studies and described how discrete choice experiments have been used to value pharmacy services but did not describe or discuss the application of methods used in the design or analysis. Aims (1) To update the most recent systematic review and critically appraise current discrete choice experiments of pharmacy services in line with published reporting criteria and; (2) To provide an overview of key methodological developments in the design and analysis of discrete choice experiments. Methods The review used a comprehensive strategy to identify eligible studies (published between 1990 and 2015) by searching electronic databases for key terms related to discrete choice and best-worst scaling (BWS) experiments. All healthcare choice experiments were then hand-searched for key terms relating to pharmacy. Data were extracted using a published checklist. Results A total of 17 discrete choice experiments eliciting preferences for pharmacy services were identified for inclusion in the review. No BWS studies were identified. The studies elicited preferences from a variety of populations (pharmacists, patients, students) for a range of pharmacy services. Most studies were from a United Kingdom setting, although examples from Europe, Australia and North America were also identified. Discrete choice experiments for pharmacy services tended to include more attributes than non pharmacy choice experiments. Few studies reported the use of qualitative research methods in the design and interpretation of the experiments (n = 9) or use of new methods of analysis to identify and quantify preference and scale heterogeneity (n = 4). No studies reported the use of Bayesian methods in their experimental design. Conclusion Incorporating more sophisticated methods in the design of pharmacy-related discrete choice experiments could help researchers produce more efficient experiments which are better suited to valuing complex pharmacy services. Pharmacy-related discrete choice experiments could also benefit from more sophisticated analytical techniques such as investigations into scale and preference heterogeneity. Employing these sophisticated methods for both design and analysis could extend the usefulness of discrete choice experiments to inform health and pharmacy policy. PMID- 26610688 TI - Age-related changes in the fracture resistance of male Fischer F344 rat bone. AB - In addition to the loss in bone volume that occurs with age, there is a decline in material properties. To test new therapies or diagnostic tools that target such properties as material strength and toughness, a pre-clinical model of aging would be useful in which changes in bone are similar to those that occur with aging in humans. Toward that end, we hypothesized that similar to human bone, the estimated toughness and material strength of cortical bone at the apparent-level decreases with age in the male Fischer F344 rat. In addition, we tested whether the known decline in trabecular architecture in rats translated to an age-related decrease in vertebra (VB) strength and whether non-X-ray techniques could quantify tissue changes at micron and sub-micron length scales. Bones were harvested from 6-, 12-, and 24-month (mo.) old rats (n=12 per age). Despite a loss in trabecular bone with age, VB compressive strength was similar among the age groups. Similarly, whole-bone strength (peak force) in bending was maintained (femur) or increased (radius) with aging. There was though an age-related decrease in post-yield toughness (radius) and bending strength (femur). The ability to resist crack initiation was actually higher for the 12-mo. and 24-mo. than for 6-mo. rats (notch femur), but the estimated work to propagate the crack was less for the aged bone. For the femur diaphysis region, porosity increased while bound water decreased with age. For the radius diaphysis, there was an age related increase in non-enzymatic and mature enzymatic collagen crosslinks. Raman spectroscopy analysis of embedded cross-sections of the tibia mid-shaft detected an increase in carbonate subsitution with advanced aging for both inner and outer tissue. PMID- 26610690 TI - Control of growth factor binding and release in bisphosphonate functionalized hydrogels guides rapid differentiation of precursor cells in vitro. AB - An in situ cross-linkable hyaluronan hydrogel functionalized with bisphosphonate (BP) groups allows tunable release of bone morphogenetic protein-2 (BMP-2) determined by the amount of BP groups. The high affinity of matrix-anchored BP groups towards BMP-2 permits guided differentiation of entrapped progenitor cells in 3-D cultures. PMID- 26610689 TI - Severity of DSS-induced colitis is reduced in Ido1-deficient mice with down regulation of TLR-MyD88-NF-kB transcriptional networks. AB - Indoleamine 2,3 -dioxygenase 1 (IDO1) catalyzes L-tryptophan to kynurenine in the first and rate-limiting step of tryptophan metabolism. IDO1 is expressed widely throughout the body, with especially high expression in colonic intestinal tissues. To examine the role of IDO1 in the colon, transcriptome analysis was performed in both Ido1(-/-) and Ido1(+/+) mice. Gene set enrichment analysis identified the Inflammatory Response as the most significant category modulated by the absence of IDO1. This observation prompted us to further investigate the function of IDO1 in the development of tissue inflammation. By using DSS-induced experimental colitis mice models, we found that the disease in Ido1(-/-) mice was less severe than in Ido1(+/+) mice. Pharmacological inhibition of IDO1 by L-1MT attenuated the severity of DSS-colitis as well. Transcriptome analyses revealed that pathways involving TLR and NF-kB signaling were significantly down-regulated by the absence of IDO1. Furthermore, dramatic changes in TLR and NF-kB signaling resulted in substantial changes in the expression of many inflammatory cytokines and chemokines. Numbers of inflammatory cells in colon and peripheral blood were reduced in IDO1 deficiency. These findings suggest that IDO1 plays important roles in producing inflammatory responses and modulating transcriptional networks during the development of colitis. PMID- 26610692 TI - Rare earth anthracenedicarboxylate metal-organic frameworks: slow relaxation of magnetization of Nd(3+), Gd(3+), Dy(3+), Er(3+) and Yb(3+) based materials. AB - We have synthesized a new family of metal-organic-frameworks (MOFs) based on a 9,10-anthracenedicarboxylate linker. We report the formation of lanthanide-based MOFs using soft solvothermal routes with dimethylformamide as a solvent. These materials display intense photoluminescence properties in the solid state at room temperature. What is more interesting is, some of them exhibit slow relaxation of magnetization with activation barriers of 22.9, 15.4, 52.7, 13.0 and 16.2 K for Nd(3+), Gd(3+), Dy(3+), Er(3+) and Yb(3+), respectively. To the best of our knowledge, Nd(3+) and Yb(3+) materials are the first examples of 3D- and 2D-MOFs, respectively, that show slow relaxation of magnetization. PMID- 26610691 TI - Chitosan microspheres with an extracellular matrix-mimicking nanofibrous structure as cell-carrier building blocks for bottom-up cartilage tissue engineering. AB - Scaffolds for tissue engineering (TE) which closely mimic the physicochemical properties of the natural extracellular matrix (ECM) have been proven to advantageously favor cell attachment, proliferation, migration and new tissue formation. Recently, as a valuable alternative, a bottom-up TE approach utilizing cell-loaded micrometer-scale modular components as building blocks to reconstruct a new tissue in vitro or in vivo has been proved to demonstrate a number of desirable advantages compared with the traditional bulk scaffold based top-down TE approach. Nevertheless, micro-components with an ECM-mimicking nanofibrous structure are still very scarce and highly desirable. Chitosan (CS), an accessible natural polymer, has demonstrated appealing intrinsic properties and promising application potential for TE, especially the cartilage tissue regeneration. According to this background, we report here the fabrication of chitosan microspheres with an ECM-mimicking nanofibrous structure for the first time based on a physical gelation process. By combining this physical fabrication procedure with microfluidic technology, uniform CS microspheres (CMS) with controlled nanofibrous microstructure and tunable sizes can be facilely obtained. Especially, no potentially toxic or denaturizing chemical crosslinking agent was introduced into the products. Notably, in vitro chondrocyte culture tests revealed that enhanced cell attachment and proliferation were realized, and a macroscopic 3D geometrically shaped cartilage-like composite can be easily constructed with the nanofibrous CMS (NCMS) and chondrocytes, which demonstrate significant application potential of NCMS as the bottom-up cell-carrier components for cartilage tissue engineering. PMID- 26610693 TI - The effect of adsorption kinetics on the rate of surfactant-enhanced spreading. AB - A comparison of the kinetics of spreading of aqueous solutions of two different surfactants on an identical substrate and their short time adsorption kinetics at the water/air interface has shown that the surfactant which adsorbs slower provides a higher spreading rate. This observation indicates that Marangoni flow should be an important part of the spreading mechanism enabling surfactant solutions to spread much faster than pure liquids with comparable viscosities and surface tensions. PMID- 26610694 TI - PORTUGUESE RECOMMENDATIONS FOR THE USE OF BIOLOGICAL THERAPIES IN PATIENTS WITH PSORIATIC ARTHRITIS--2015 UPDATE. AB - OBJECTIVE: To update recommendations for the treatment of psoriatic arthritis with biological therapies, endorsed by the Portuguese Society of Rheumatology (SPR). METHODS: These treatment recommendations were formulated by Portuguese rheumatologists based on literature evidence and consensus opinion. At a national meeting the 16 recommendations included in this document were discussed and updated. The level of agreement among Portuguese Rheumatologists was assessed using an online survey. A draft of the full text of the recommendations was then circulated and suggestions were incorporated. A final version was again circulated before publication. RESULTS: A consensus was achieved regarding the initiation, assessment of response and switching biological therapies in patients with psoriatic arthritis (PsA). Specific recommendations were developed for several disease domains: peripheral arthritis, axial disease, enthesitis and dactylitis. CONCLUSION: These recommendations may be used for guidance in deciding which patients with PsA should be treated with biological therapies. They cover a rapidly evolving area of therapeutic intervention. As more evidence becomes available and more biological therapies are licensed, these recommendations will have to be updated. PMID- 26610695 TI - Fatty acid profiles of milk and Minas frescal cheese from lactating grazed cows supplemented with peanut cake. AB - Milk and Minas frescal cheese were evaluated from crossbred Holstein * Gir cows that were fed diets enriched with 0, 33, 66 and 100% inclusion levels of palm kernel cake in a concentrated supplement in replace of soybean meal. Eight crossbred lactating cows were distributed (four animals * four treatments * four periods) in the experimental design of double 4 * 4 Latin squares. The capric (C : 10, P = 0.0270), undecylic (C : 11, P = 0.0134), and lauric (C : 12, P = 0.0342) saturated fatty acid concentrations and CLA (C18 : 2c9t11, P = 0.0164) of the milk fat decreased linearly with an increasing percentage of peanut cake in the diet. The increased peanut cake content (100%) in the diet was associated with a linear decrease in C : 10 (P = 0.0447), C : 12 (P = 0.0002), mirystic (C : 14, P 0.05) ratios were not influenced by the different peanut cake levels. The inclusion of up to 100% peanut cake as a substitution for soybean meal in the concentrate of grazing lactating cows resulted in changes in the nutritional quality of their milk products, as indicated by the increase in polyunsaturated fatty acids and the decrease of saturated fatty acids (lauric, myristic, and palmitic). PMID- 26610696 TI - Assessment of acquired capability for suicide in clinical practice. AB - The Interpersonal Psychological Theory of suicide proposes that the interaction between Thwarted Belongingness, Perceived Burdensomeness, and Acquired Capability for Suicide (ACS) predicts proximal risk of death by suicide. Instruments to assess all three constructs are available. However, research on the validity of one of them, the acquired capability for suicide scale (ACSS), has been limited, especially in terms of its clinical relevance. This study aimed to explore the utility of the different versions of the ACSS in clinical assessment. Three versions of the scale were investigated, the full 20-item version, a 7-item version and a single item version representing self-perceived capability for suicide. In a sample of patients recruited from a clinic specialising in the treatment of suicidality and in a community sample, all versions of the ACSS were found to show reasonable levels of reliability and to correlate as expected with reports of suicidal ideation, self-harm, and attempted suicide. The item assessing self-perceived acquired capacity for suicide showed highest correlations with all levels of suicidal behaviour. However, no version of the ACSS on its own showed a capacity to indicate suicide attempts in the combined sample. It is concluded that the versions of the scale have construct validity, but their clinical utility is limited. An assessment using a single item on self perceived ACS outperforms the full and shortened versions of ACSS in clinical settings and can be recommended with caution for clinicians interested in assessing this characteristic. PMID- 26610697 TI - Prophylactic antibiotics for manual removal of retained placenta during vaginal birth: a systematic review of observational studies and meta-analysis. AB - BACKGROUND: Manual removal of the placenta is an invasive obstetric procedure commonly used for the management of retained placenta. However, it is unclear whether antibiotic prophylaxis is beneficial in preventing infectious morbidity. We conducted a systematic review to determine the efficacy and safety of routine use of antibiotics for preventing adverse maternal outcomes related to manual placenta removal following vaginal birth. METHODS: A detailed search of MEDLINE, EMBASE, Cochrane library and the CINAHL databases was conducted for non randomized studies involving women undergoing manual placenta delivery after vaginal births and where antibiotic prophylaxis use was compared with no treatment or placebo to prevent maternal infection. Search terms including 'delivery, obstetric', 'placenta, retained', 'anti-infective agents', and 'chemoprevention' were used. RESULTS: Of the 407 citations that resulted after elimination of duplicates, 81 full texts were potentially eligible after independent assessment of the title and abstracts. Independent review of the full texts identified three eligible cohort studies which were retrospective in design. These studies contained data on two of the pre-specified outcomes, endometritis and puerperal fever. Other secondary outcomes such as perineal infection and/or any infection, hospital stay duration, sepsis, hemorrhage >1000 ml or hospital readmissions were not reported on excluding puerperal fever. A meta-analysis showed no significant reduction in the incidence of endometritis (odds ratio [OR] 0.84, 95% confidence interval [CI] 0.38 to 1.85, three studies, 567 women) and puerperal fever (OR 0.99, 95% CI 0.38 to 2.27, one study, 302 women). CONCLUSIONS: There is currently no evidence to suggest beneficial effects for routine antibiotic use in women undergoing manual placental removal following vaginal birth. In appropriate settings, further research is required to determine whether a policy of routine antibiotic prophylaxis for the procedure should be maintained or discouraged. PMID- 26610698 TI - Do I Know What I'm Doing? Cognitive Dissonance and Action Identification Theory. AB - Our main purpose was to explore hypotheses derived from the Identification of Action Theory in a particular situation that is, a dissonant situation. Thus, we varied the identification (low versus high-level) of a problematic behavior (to stop speaking for 24 hours) in the forced compliance paradigm. Two modes of dissonance reduction were presented: cognitive rationalization (classical attitude-change) and behavioral rationalization (target behavior: to stop speaking for 48 hours). As predicted, the results showed that high-level identity of action leads to cognitive rationalization whereas low-level identity leads to behavioural rationalization. Thus, participants identifying the problematic behavior at a low-level were more inclined to accept the target behavior, compared with participants identifying their problematic behavior at a higher level. These results are of particular interest for understanding the extent to which the understanding of the discrepant act interferes with the cognitive processes of dissonance reduction. PMID- 26610699 TI - Erratum: Coherence in the presence of absorption and heating in a molecule interferometer. PMID- 26610701 TI - Breast MRI after mammography detects additional aggressive cancers, study shows. PMID- 26610700 TI - Systems analysis of methylerythritol-phosphate pathway flux in E. coli: insights into the role of oxidative stress and the validity of lycopene as an isoprenoid reporter metabolite. AB - BACKGROUND: High-throughput screening methods assume that the output measured is representative of changes in metabolic flux toward the desired product and is not affected by secondary phenotypes. However, metabolic engineering can result in unintended phenotypes that may go unnoticed in initial screening. The red pigment lycopene, a carotenoid with antioxidant properties, has been used as a reporter of isoprenoid pathway flux in metabolic engineering for over a decade. Lycopene production is known to vary between wild-type Escherichia coli hosts, but the reasons behind this variation have never been fully elucidated. RESULTS: In an examination of six E. coli strains we observed that strains also differ in their capacity for increased lycopene production in response to metabolic engineering. A combination of genetic complementation, quantitative SWATH proteomics, and biochemical analysis in closely-related strains was used to examine the mechanistic reasons for variation in lycopene accumulation. This study revealed that rpoS, a gene previously identified in lycopene production association studies, exerts its effect on lycopene accumulation not through modulation of pathway flux, but through alteration of cellular oxidative status. Specifically, absence of rpoS results in increased accumulation of reactive oxygen species during late log and stationary phases. This change in cellular redox has no effect on isoprenoid pathway flux, despite the presence of oxygen-sensitive iron sulphur cluster enzymes and the heavy redox requirements of the methylerythritol phosphate pathway. Instead, decreased cellular lycopene in the DeltarpoS strain is caused by degradation of lycopene in the presence of excess reactive oxygen species. CONCLUSIONS: Our results demonstrate that lycopene is not a reliable indicator of isoprenoid pathway flux in the presence of oxidative stress, and suggest that caution should be exercised when using lycopene as a screening tool in genome-wide metabolic engineering studies. More extensive use of systems biology for strain analysis will help elucidate such unpredictable side-effects in metabolic engineering projects. PMID- 26610703 TI - Parallel simulations for QUAntifying RElaxation magnetic resonance constants (SQUAREMR): an example towards accurate MOLLI T1 measurements. AB - BACKGROUND: T1 mapping is widely used today in CMR, however, it underestimates true T1 values and its measurement error is influenced by several acquisition parameters. The purpose of this study was the extraction of accurate T1 data through the utilization of comprehensive, parallel Simulations for QUAntifying RElaxation Magnetic Resonance constants (SQUAREMR) of the MOLLI pulse sequence on a large population of spins with physiologically relevant tissue relaxation constants. METHODS: A CMR protocol consisting of different MOLLI schemes was performed on phantoms and healthy human volunteers. For every MOLLI experiment, the identical pulse sequence was simulated for a large range of physiological combinations of relaxation constants, resulting in a database of all possible outcomes. The unknown relaxation constants were then determined by finding the simulated signals in the database that produced the least squared difference to the measured signal intensities. RESULTS: SQUAREMR demonstrated improvement of accuracy in phantom studies and consistent mean T1 values and consistent variance across the different MOLLI schemes in humans. This was true even for tissues with long T1s and MOLLI schemes with no pause between modified-Look-Locker experiments. CONCLUSIONS: SQUAREMR enables quantification of T1 data obtained by existing clinical pulse sequences. SQUAREMR allows for correction of quantitative CMR data that have already been acquired whereas it is expected that SQUAREMR may improve data consistency and advance quantitative MR across imaging centers, vendors and experimental configurations. While this study is focused on a MOLLI based T1-mapping technique, it could however be extended in other types of quantitative MRI throughout the body. PMID- 26610704 TI - Vogesella facilis sp. nov., isolated from a freshwater river, and emended description of the genus Vogesella. AB - A bacterial strain, designated TTM-24T, was isolated from a freshwater river in Taiwan and characterized using a polyphasic taxonomic approach. Cells of strain TTM-24T were Gram-stain-negative, facultatively anaerobic, poly-beta hydroxybutyrate-accumulating, motile by a single polar flagellum, rod-shaped, with rods surrounded by a thick capsule and forming white-coloured colonies. Growth occurred at 15-37 degrees C (optimum, 25 degrees C), at pH 6.0-8.0 (optimum, pH 7.0) and with 0-1 % NaCl (optimum, 0.5 %). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain TTM-24T belonged to the genus Vogesella and was most closely related to 'Vogesella amnigena' Npb-02 with sequence similarity of 97.1 %. Strain TTM-24T contained summed feature 3 (comprising C16 : 1 omega7c and/or C16 : 1 omega6c) and C16 : 0 as the major fatty acids. The major respiratory quinone was Q-8. The polar lipid profile consisted of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, an uncharacterized aminophospholipid and two uncharacterized phospholipids. The genomic DNA G+C content of strain TTM-24T was 67.4 mol%. The DNA-DNA hybridization value for strain TTM-24T with 'V. amnigena' Npb-02 was less than 45 %. On the basis of the phylogenetic inference and phenotypic data, strain TTM-24T should be classified as a novel species, for which the name Vogesella facilis sp. nov. is proposed. The type strain is TTM-24T ( = BCRC 80912T = KCTC 42742T = LMG 29003T). PMID- 26610702 TI - Multimodal targeted high relaxivity thermosensitive liposome for in vivo imaging. AB - Liposomes are spherical, self-closed structures formed by lipid bilayers that can encapsulate drugs and/or imaging agents in their hydrophilic core or within their membrane moiety, making them suitable delivery vehicles. We have synthesized a new liposome containing gadolinium-DOTA lipid bilayer, as a targeting multimodal molecular imaging agent for magnetic resonance and optical imaging. We showed that this liposome has a much higher molar relaxivities r1 and r2 compared to a more conventional liposome containing gadolinium-DTPA-BSA lipid. By incorporating both gadolinium and rhodamine in the lipid bilayer as well as biotin on its surface, we used this agent for multimodal imaging and targeting of tumors through the strong biotin-streptavidin interaction. Since this new liposome is thermosensitive, it can be used for ultrasound-mediated drug delivery at specific sites, such as tumors, and can be guided by magnetic resonance imaging. PMID- 26610705 TI - Aminopeptidase T of M29 Family Acts as A Novel Intracellular Virulence Factor for Listeria monocytogenes Infection. AB - The foodborne pathogen Listeria monocytogenes employs a number of virulence determinants including metalloproteases to infect hosts. Here for the first time, we identified an M29 family aminopeptidase T (encoded by lmo1603) from L. monocytogenes that possesses a typical feature to catalyze the cleavage of amino acids from peptide substrates, with a preference for arginine. The purified recombinant Lmo1603 was activated by Fe(3+), Zn(2+) and Mn(2+), but strongly stimulated by Co(2+), indicating that Lmo1603 is a cobalt-dependent aminopeptidase. Single mutation at any of the Glu216, Glu281, His308, Tyr315, His327, and Asp329 completely abolished the enzymatic activity of Lmo1603. More importantly, we showed that Lmo1603 was mainly involved in Listeria infection, but not required for growth in rich laboratory medium and minimal defined medium. Disruption of Lmo1603 resulted in almost complete attenuation of Listeria virulence in a mouse infection model. In addition, we demonstrated that Lmo1603 was mainly localized in the bacterial cytosol and required for invasion and survival inside human epithelial cells and murine macrophages. We conclude that Lmo1603 encodes a functional aminopeptidase T of M29 family, which acts as a novel intracellular virulence factor essential in the successful establishment of L. monocytogenes infections in a mouse model. PMID- 26610706 TI - Construction of a high-density mutant library in soybean and development of a mutant retrieval method using amplicon sequencing. AB - BACKGROUND: Functions of most genes predicted in the soybean genome have not been clarified. A mutant library with a high mutation density would be helpful for functional studies and for identification of novel alleles useful for breeding. Development of cost-effective and high-throughput protocols using next generation sequencing (NGS) technologies is expected to simplify the retrieval of mutants with mutations in genes of interest. RESULTS: To increase the mutation density, seeds of the Japanese elite soybean cultivar Enrei were treated with the chemical mutagen ethyl methanesulfonate (EMS); M2 seeds produced by M1 plants were treated with EMS once again. The resultant library, which consisted of DNA and seeds from 1536 plants, revealed large morphological and physiological variations. Based on whole-genome re-sequencing analysis of 12 mutant lines, the average number of base changes was 12,796 per line. On average, 691 and 35 per line were missense and nonsense mutations, respectively. Two screening strategies for high resolution melting (HRM) analysis and indexed amplicon sequencing were designed to retrieve the mutants; the mutations were confirmed by Sanger sequencing as the final step. In comparison with HRM screening of several genes, indexed amplicon sequencing allows one to scan a longer sequence range and skip screening steps and to know the sequence information of mutation because it uses systematic DNA pooling and the index of NGS reads, which simplifies the discovery of mutants with amino acid substitutions. CONCLUSIONS: A soybean mutant library with a high mutation density was developed. A high mutation density (1 mutation/74 kb) was achieved by repeating the EMS treatment. The mutation density of our library is sufficiently high to obtain a plant in which a gene is nonsense mutated. Thus, our mutant library and the indexed amplicon sequencing will be useful for functional studies of soybean genes and have a potential to yield useful mutant alleles for soybean breeding. PMID- 26610708 TI - Staphylococcus epidermidis: metabolic adaptation and biofilm formation in response to different oxygen concentrations. AB - Staphylococcus epidermidis has become a major health hazard. It is necessary to study its metabolism and hopefully uncover therapeutic targets. Cultivating S. epidermidis at increasing oxygen concentration [O2] enhanced growth, while inhibiting biofilm formation. Respiratory oxidoreductases were differentially expressed, probably to prevent reactive oxygen species formation. Under aerobiosis, S. epidermidis expressed high oxidoreductase activities, including glycerol-3-phosphate dehydrogenase, pyruvate dehydrogenase, ethanol dehydrogenase and succinate dehydrogenase, as well as cytochromes bo and aa3; while little tendency to form biofilms was observed. Under microaerobiosis, pyruvate dehydrogenase and ethanol dehydrogenase decreased while glycerol-3-phosphate dehydrogenase and succinate dehydrogenase nearly disappeared; cytochrome bo was present; anaerobic nitrate reductase activity was observed; biofilm formation increased slightly. Under anaerobiosis, biofilms grew; low ethanol dehydrogenase, pyruvate dehydrogenase and cytochrome bo were still present; nitrate dehydrogenase was the main terminal electron acceptor. KCN inhibited the aerobic respiratory chain and increased biofilm formation. In contrast, methylamine inhibited both nitrate reductase and biofilm formation. The correlation between the expression and/or activity or redox enzymes and biofilm-formation activities suggests that these are possible therapeutic targets to erradicate S. epidermidis. PMID- 26610707 TI - Evaluation of efficacy, safety, pain perception and health-related quality of life of percutaneous ethanol injection as first-line treatment in symptomatic thyroid cysts. AB - BACKGROUND: To evaluate the efficacy, safety, pain perception and health-related quality of life (QoL) of percutaneous ethanol injection treatment (PEIT) as an alternative to thyroid surgery in symptomatic thyroid cysts. METHODS: Thirty consecutive patients (46 +/- 10 years; 82% women) with symptomatic benign thyroid cysts relapsed after drainage were included. In all cases, cytology prior to treatment, maximum cyst diameter and volume were determined. PEIT was conducted using the established procedure, and the volume of fluid removed and pain perceived by the patient were assessed. In each procedure, the volume of alcohol instilled was <2 ml. After follow-up, final cyst diameter and volume were determined and the persistence of symptoms and QoL were assessed by a questionnaire (SF-36). RESULTS: Mean symptom duration was 10 +/- 20 months. A single session of PEIT was required to complete the procedure in 45% of patients, two in 31% and three in 13%. Mean initial maximum cyst diameter was 3.5 +/- 1.0 cm and mean extracted liquid volume 61 +/- 36 ml. During PEIT, 39% of patients experienced virtually no pain, 43% mild pain and 17% moderate pain. No complications of PEIT were observed. After 12.1 +/- 1.4 months of follow-up, cysts were reduced more than 70% in volume in 86.3% of patients, more than 80% in 61.9% and more than 90% in 42%. On the health-related QoL SF-36 questionnaire, patient scores 6 months post-PEIT did not differ significantly from those of the healthy Spanish population. With respect to cosmetic complaints or local symptoms of compression, PEIT-treated patients presented an initial score of 22 +/- 8 and 13 +/- 5 after treatment (p < 0.05). CONCLUSIONS: In our experience, percutaneous ethanol injection has prove to be an effective, safe and well-tolerated first line treatment of symptomatic thyroid cysts. PMID- 26610709 TI - A community-wide school health project for the promotion of smoke-free homes. AB - BACKGROUND: A community-wide school health project for the promotion of smoke free homes was launched in June 2010 with the aim of promoting the benefits of smoke-free homes to all school-aged children (aged 6-18), and indirectly to their parents and family members. The 1-year project included health talks on a smoke free life; the distribution of educational leaflets; slogan and visual art competitions; and a health fair held in June 2011. Two sets of questionnaires were developed to solicit a resolution and action from the participants regarding the establishment of a smoke-free home, and their decision to stay smoke-free. This is a paper to report on the activities of this project, the attempts to reach out to school-aged children, and their indications of agreement with, support for, and commitment to promoting smoke-free homes. RESULTS: The project reached an estimated 12,800 school-aged children in Hong Kong. A large proportion of those received educational leaflets (69.6-88.2 %). Of those who participated in the health fair, 69.7-87.6 % agreed to promote the concept of smoke-free homes to friends and family. More primary than secondary students pledged to not take up smoking (90.8 vs 85.8 %). About 82 % of those who had experimented with smoking pledged to stop. A small proportion of them reported already having established a smoke-free policy at home (14.9 %), placed a 'No Smoking' sign at home (16.4 %), informed visitors of their smoke-free policy at home (12.9 %), and asked visitors to dispose of lit cigarettes before entering their home (15.9 %). DISCUSSION: This community-wide school health project on the benefits of smoke free homes reached a large number of students, and indirectly to family members, and home visitors. Public health efforts of this kind should be continued to reach younger generations and the general public. PMID- 26610710 TI - Alzheimer disease. Could anti-amyloid-beta immunotherapy do more harm than good? PMID- 26610711 TI - 18-FDG PET/ CT Scan in the Diagnosis and Follow-up of Chronic Q fever Aortic Valve Endocarditis. AB - Chronic Q fever endocarditis is a rare but important infection associated with risk of morbidity and mortality. Echocardiography rarely visualises the vegetative lesion. We describe the first Australian report of chronic Q fever aortic valve endocarditis confirmed with the use of 18 -FDG PET/ CT scan. Following valvular replacement, the patient had ongoing high serological titres despite active treatment and he was managed with yearly serial PET/ CT scan to confirm the absence of active infection. The utility of serial PET /CT scan imaging as a follow-up management strategy has not been described in the literature previously and should be investigated further. PMID- 26610712 TI - Are Results of 4-D Ultrasound Angiography Examinations Dependent on the Doppler Technology Applied? Comparison of Results Obtained from an In Vivo Model. AB - We aimed to evaluate the agreement of results obtained by 4-D spatio-temporal image correlation (STIC) angiography with two options of Doppler technology (power Doppler [PD] and high-definition flow [HDF]) from an ovary as an in vivo model. Thirty-eight ovaries were recorded by trans-vaginal ultrasound examination in the first part of the menstrual cycle. Two STIC sequences (4-D HDF and 4-D PD) were stored. Volumetric pulsatility index, volumetric resistance index and volumetric systolic/diastolic index for each of these sequences were calculated, and their mean values were compared and correlated. Agreement between 4-D HDF and 4-D PD was assessed using the intra-class correlation coefficient. Intra-class correlation coefficients for all three indices were high, but 95% confidence intervals and limits of agreement were wide. We conclude that both 4-D power Doppler and 4-D high-definition flow may be used for calculating volumetric pulsatility index, volumetric resistance index and volumetric systolic/diastolic index from a STIC sequence, at least in ovaries used as an in vivo model. However, values obtained by both methods cannot be used interchangeably. PMID- 26610713 TI - Liver Function Assessment Using Parenchyma-Specific Contrast-Enhanced Ultrasonography. AB - The aim of this study was to assess hepatic functional reserve by analyzing the hepatic parenchyma enhancement curve of parenchyma-specific contrast-enhanced ultrasonography (CEUS). Fifty-two patients with cirrhosis who underwent CEUS and indocyanine green tests (ICG) because of a focal liver lesion were enrolled. We evaluated the hemodynamic-related parameters of the time-intensity curve and compared these findings with the ICG retention rate at 15 min (ICG R15). The correlation between the time from peak to one half (s) and ICG R15 was statistically significant and was relatively proportional to the ICG R15. A cut off value of 149 s was determined for the time from peak to one half for abnormal ICG R15 (>14). The sensitivity and specificity were 85.7% and 92.3%, respectively, for the detection of abnormal ICG R15. In conclusion, the time from peak to one half of the time-intensity curve of parenchyma-specific CEUS of the liver can be a useful parameter to predict the hepatic reserve in liver cirrhosis. PMID- 26610714 TI - Enhanced Homing of CXCR-4 Modified Bone Marrow-Derived Mesenchymal Stem Cells to Acute Kidney Injury Tissues by Micro-Bubble-Mediated Ultrasound Exposure. AB - Although the curative effects of bone marrow stromal cells (BMSCs) for acute kidney injury (AKI) have been recognized, their in vivo reparative capability is limited by the low levels of targeted homing and retention of intravenous injected cells. Stromal cell-derived factor-1 (SDF-1) plays an important role in stem cell homing and retention through interaction with its specific functional receptor, CXCR4, which is presumably related to the poor homing in AKI therapy. However, most of the functional CXCR4 chemokine receptors are lost upon in vitro culturing. Ultrasound-targeted micro-bubble destruction (UTMD) has become one of the most promising strategies for the targeted delivery of drugs and genes. To improve BMSC homing to AKI kidneys, we isolated and cultured rat BMSCs to third passage and enhanced CXCR-4 transfection efficiency in vitro by applying UTMD and polyethylenimine. Transwell migration assay showed that the migration ability of CXCR4-modified BMSCs was nine-fold higher than controls. Then, mercuric chloride induced AKI rats were injected with transfected BMSCs through their tail veins. We showed that enhanced homing and retention of BMSCs were observed in the CXCR-4 modified group compared with other groups at 1, 2 and 3 d post-treatment. Collectively, our data indicated that UTMD was an effective method to increase BMSCs' engraftment to AKI kidney tissues by increasing CXCR-4 expression. PMID- 26610715 TI - Orbital-dependent Electron-Hole Interaction in Graphene and Associated Multi Layer Structures. AB - We develop an orbital-dependent potential to describe electron-hole interaction in materials with structural 2D character, i.e. quasi-2D materials. The modulated orbital-dependent potentials are also constructed with non-local screening, multi layer screening, and finite gap due to the coupling with substrates. We apply the excitonic Hamiltonian in coordinate-space with developed effective electron-hole interacting potentials to compute excitons' binding strength at M (pi band) and Gamma (sigma band) points in graphene and its associated multi-layer forms. The orbital-dependent potential provides a range-separated property for regulating both long- and short-range interactions. This accounts for the existence of the resonant pi exciton in single- and bi-layer graphenes. The remarkable strong electron-hole interaction in sigma orbitals plays a decisive role in the existence of sigma exciton in graphene stack at room temperature. The interplay between gap-opening and screening from substrates shed a light on the weak dependence of sigma exciton binding energy on the thickness of graphene stacks. Moreover, the analysis of non-hydrogenic exciton spectrum in quasi-2D systems clearly demonstrates the remarkable comparable contribution of orbital dependent potential with respect to non-local screening process. The understanding of orbital-dependent potential developed in this work is potentially applicable for a wide range of materials with low dimension. PMID- 26610716 TI - Do as I do, not as I say: Actions speak louder than words in preschoolers learning from others. AB - To date, no research has examined children's imitative abilities in the context of learning self-regulatory strategies from adults-especially when there is a conflict between communicative intent and later behavior. A sample of 84 4- and 5 year-olds performed a delay-of-gratification task after observing an adult perform the same task. Across four between-participants conditions, the model either did or did not state her intention to complete the task (positive vs. negative communication), modeled self-regulatory strategies, and then either did or did not complete the task successfully (positive vs. negative outcome). Children in the positive outcome conditions were more likely to imitate the novel strategies and successfully wait in both familiar and unfamiliar self-regulation tasks irrespective of the model's communicated intent. We discuss implications for practice and interventions. PMID- 26610717 TI - Polypyrrole coating on poly-(lactide/glycolide)-beta-tricalcium phosphate screws enhances new bone formation in rabbits. AB - Polypyrrole (PPy) has gained interest as an implant material due to its multifunctional properties and its high compatibility with several cell and tissue types. For the first time, the biocompatibility and osteointegration of PPy coating, incorporated with chondroitin sulfate (CS), were studied in vivo by implanting PPy-coated bioabsorbable bone fixation composite screws of poly (lactide/glycolide) copolymer (PLGA) and beta-tricalcium phosphate (TCP) into New Zealand white rabbits. Uncoated bioabsorbable polymer composite screws and commercially available stainless steel cortical screws were used as reference implants. The rabbits were euthanized 12 and 26 weeks after the implantation. The systemic effects were evaluated from food and water consumption, body weight, body temperature, clinical signs, blood samples, internal organ weights, and histological examination. Local effects were studied from bone tissue and surrounding soft tissue histology. New bone formation was evaluated by micro computed tomography, tetracycline labeling and torsion tests. Torsion tests were performed in order to capture the peak value of the torsion force during the course of the screw's loosening. The coated screws induced significantly more bone formation than the uncoated screws. In addition, none of the implants induced any systemic or local toxicity. The results suggest that PPy is biocompatible with bone tissue and is a potential coating for enhancing osteointegration in orthopedic implants. PMID- 26610718 TI - Hesperetin attenuates ventilator-induced acute lung injury through inhibition of NF-kappaB-mediated inflammation. AB - Hesperetin, a major bioflavonoid in sweet oranges and lemons, has been reported to have anti-inflammatory properties. However, the effect of hesperetin on ventilator-induced acute lung injury has not been studied. In present study, we investigated the protective effect of hesperetin on ventilator-induced acute lung injury in rats. Rats were orally administered hesperetin (10, 20, or 40mg/kg) two hour before acute lung injury was induced by mechanical ventilation. Rats were then randomly divided into six groups: the lung protective ventilation group (n=20, LV group), injurious ventilation group (n=20, HV group), vehicle-treated injurious ventilation group (n=20, LV+vehicle group), hesperetin (10mg/kg) treated acute lung injury group (n=20, HV+Hsp (10mg)), hesperetin (20mg/kg) treated acute lung injury group (n=20, HV+Hsp (20mg)), and hesperetin (40mg/kg) treated acute lung injury group (n=20, HV+Hsp (40mg)). The lung tissues and bronchoalveolar lavage fluid were isolated for subsequent measurements. Treatment with hesperetin dramatically improved the histology of lung tissue, and reduced the wet/dry ratio, myeloperoxidase activity, protein concentration, and production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-1beta, and MIP-2 in the bronchoalveolar lavage fluid of rats with ventilator-induced acute lung injury. Additionally, our study indicated that this protective effect of hesperetin results from its ability to increase the expression of peroxisome proliferator-activated receptor (PPAR)-gamma and inhibit the activation of the nuclear factor (NF)-kappaB pathway. These results suggest that hesperetin may be a potential novel therapeutic candidate for protection against ventilator-induced acute lung injury. PMID- 26610719 TI - Geographic Variation in the Use of Diagnostic Testing of Patients with Newly Diagnosed Open-Angle Glaucoma. AB - PURPOSE: To determine the extent of geographic variation in the proportion of patients with newly diagnosed open-angle glaucoma (OAG) undergoing visual field (VF) testing, fundus photography (FP), and other ocular imaging (OOI) among patients residing in different US communities. DESIGN: Retrospective, longitudinal cohort study. PARTICIPANTS: All enrollees with newly diagnosed OAG enrolled in a managed care network between 2001 and 2014. METHODS: We identified all persons in the plan with incident OAG residing in 201 communities across the United States. All communities contributed >=20 enrollees. The proportion of enrollees undergoing >=1 VF test, FP, OOI, and no testing of any type in the 2 years after first OAG diagnosis was determined for each community, and comparisons were made to assess the extent of variation in use of diagnostic testing among patients residing in the different communities. MAIN OUTCOME MEASURES: Receipt of VF testing, FP, OOI, or none of these tests in the 2 years after initial OAG diagnosis. RESULTS: Of the 56675 enrollees with newly diagnosed OAG, the mean proportion of patients undergoing VF testing within 2 years of initial diagnosis was 74%+/-7%, ranging from as low as 51% in Rochester, Minnesota, to as high as 95% in Lancaster, Pennsylvania. The mean proportion undergoing OOI was 63%+/-10% and varied from 34% in Palm Springs/Rancho Mira, California, to 85% in Charleston, South Carolina. The mean proportion receiving FP was 26%+/-10% and ranged from as low as 3% in Fresno, California, to as high as 57% in Harlingen, Texas. The proportion undergoing no glaucoma testing ranged from 0% in Binghamton, New York, to as high as 35% in 2 other communities. CONCLUSIONS: In many US communities, a high proportion of patients are undergoing testing according to established practice guidelines. However, in several communities, less than 60% of patients with newly diagnosed OAG are undergoing VF testing in the 2 years after initial OAG diagnosis, and in a few communities >1 in 4 patients have no record of glaucoma diagnostic testing of any type. Additional research is needed to understand factors driving this variation in practice patterns and its impact on patient outcomes. PMID- 26610720 TI - Long-term Natural History of Dry Eye Disease from the Patient's Perspective. AB - PURPOSE: To describe the natural history of dry eye disease (DED), which chronically affects millions of people in the United States. DESIGN: This study is based on the Women's Health Study and Physicians' Health Studies, and uses questionnaires and medical records. PARTICIPANTS: A total of 398 men and 386 women who reported a diagnosis of DED and responded to a questionnaire about change in disease since diagnosis. METHODS: Three subscales were developed using factor analysis of questionnaire responses: ocular surface symptoms, vision related symptoms, and social impact. We examined correlates of worsening on each subscale, obtained medical records from a subset of 261 study participants, and examined changes in clinical signs of DED over time. MAIN OUTCOME MEASURES: Worsening in ocular surface symptoms, vision-related symptoms, and social impact plus clinical signs. RESULTS: The average duration of DED of 10.5 years (standard deviation, 9.5 years). Worsening was reported by 24% for ocular surface symptoms, 29% for vision-related symptoms, and 10% for social impact. Factors associated with worsening on at least 2 of 3 subscales included a previous report of severe DED symptoms (odds ratio [OR], 2.17 for ocular surface symptoms; OR, 2.35 for vision-related symptoms), spending >$20 per month on DED treatments (OR, 1.80 for ocular surface symptoms; OR, 1.99 for vision-related symptoms), history of blepharitis or meibomian gland dysfunction (MGD) (OR, 1.57 for vision-related symptoms; OR, 2.12 for social impact), and use of systemic beta-blockers (OR, 1.62 for ocular surface symptoms; OR, 1.84 for vision-related symptoms; OR, 1.86 for the social impact of DED). Presence of corneal staining based on review of medical records was associated with use of level 2 or higher DED treatments (OR, 1.54; confidence interval [CI], 1.01-2.36), a previous report of severe DED symptoms (OR, 1.79; CI, 1.07-3.00), having a tear break-up test performed (OR, 2.73; CI, 1.72-4.36), and having blepharitis or MGD (OR, 0.59; CI, 0.35-0.98). CONCLUSIONS: A proportion of patients with DED experience worsening over time, tending to report with more severe symptoms earlier in the disease. Forthcoming data on the natural history of DED from prospective studies should help clarify some of the limitations of this retrospective study. PMID- 26610721 TI - Gender as a Moderator of the Relation Between Age Cohort and Three-Dimensional Wisdom in Iranian Culture. AB - This study examined whether gender moderated the association between age cohort and the cognitive, reflective, and compassionate dimensions of wisdom, using an Iranian sample of 439 adults from three age cohorts: young (18-34), middle-aged (35-54), and older (55 and above). Results indicated that the interaction effect between gender and age cohort was significant for three-dimensional wisdom and all three wisdom dimensions. Compared with younger women and older men, older women tended to have less education and to score lower on the cognitive wisdom dimension, but they had similar average scores as older men on the compassionate wisdom dimension. Overall, the association between age and wisdom was only positive for men, due mainly to the positive relation between age and the reflective and compassionate wisdom dimensions for men after adjusting for education. The results are interpreted with reference to generation gaps, socialization of men versus women, and life experiences and opportunities. PMID- 26610722 TI - Gender, Race, and Age: The Content of Compound Stereotypes Across the Life Span. AB - While stereotypes about gender, race, and age (particularly old age) have been studied independently, few have examined the content of compound stereotypes that consider the intersection of gender, race, and age. Using a within-subjects design, we examined stereotypes as a function of target gender (male, female), race (Black, White), and age across the life span (adolescent, young adult, middle-aged, young-old, and old-old). Participants rated 20 target groups on 10 attributes representative of either an agentic (e.g., ambitious) or communal (e.g., considerate) orientation. Participants were presented only with categorical information (e.g., Black, 85-year-old, males), and ordering of categorical information and target groups was counterbalanced across participants. We hypothesized differential effects of target gender and race as a function of age. Multivariate analyses of variance on each attribute revealed significant main effects that supported traditional stereotype research, but significant interactions revealed a more complicated picture. Overall, results showed that while gender stereotypes about agency and communion generally hold up across the life span, they are more applicable to White than Black targets. Results also supported the notion that we hold unique stereotypes based on multiple social categories rather than simply perceiving one social category as more salient than another, which was best exemplified in the case of Black female targets that were less likely to be perceived in gender stereotypic ways across the life span. We suggest stereotype research needs to shift to accommodate for the complexity and diversity of real people. PMID- 26610723 TI - DNA induced sequestration of a bioactive cationic fluorophore from the lipid environment: A spectroscopic investigation. AB - The effect of calf-thymus DNA (ctDNA) on the lipid bound probe, formed by the cationic phenazinium dye phenosafranin (PSF) and the anionic lipid dimyristoyl-L alpha-phosphatidylglycerol (DMPG), has been unearthed exploiting various spectroscopic techniques. Steady state and time-resolved fluorometric studies and measurements of circular dichroism and DNA helix melting temperature reveal that in the presence of DNA the probe is dislodged from the lipid environment and gets intercalated within the DNA helix. The work qualitatively illustrates that the anionic lipid can be used as a potential nanocarrier for delivering the cationic drugs to the most relevant biomacromolecular target, DNA. PMID- 26610724 TI - A Direct Neurokinin B Projection from the Arcuate Nucleus Regulates Magnocellular Vasopressin Cells of the Supraoptic Nucleus. AB - Central administration of neurokinin B (NKB) agonists stimulates immediate early gene expression in the hypothalamus and increases the secretion of vasopressin from the posterior pituitary through a mechanism that depends on the activation of neurokinin receptor 3 receptors (NK3R). The present study reports that, in the rat, immunoreactivity for NK3R is expressed in magnocellular vasopressin and oxytocin neurones in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus, and that NKB immunoreactivity is expressed in fibres in close juxtaposition with vasopressin neurones at both of these sites. Retrograde tracing in the rat shows that some NKB-expressing neurones in the arcuate nucleus project to the SON and, in mice, using an anterograde tracing approach, it is found that kisspeptin-expressing neurones of the arcuate nucleus, which are known to co-express NKB, project to the SON and PVN. Finally, i.c.v. injection of the NK3R agonist senktide is shown to potently increase the electrical activity of vasopressin neurones in the SON in vivo with no significant effect detected on oxytocin neurones. The results suggest that NKB containing neurones in the arcuate nucleus regulate the secretion of vasopressin from magnocellular neurones in rodents, and the possible significance of this is discussed. PMID- 26610725 TI - Validity and test-retest reliability of Children's Hand-use Experience Questionnaire in children with unilateral cerebral palsy. AB - AIM: To investigate the validity of the internet-based version of the Children's Hand-use Experience Questionnaire (CHEQ) by testing the new four-category rating scale, internal structure, and test-retest reliability. METHOD: Data were collected for 242 children with unilateral cerebral palsy (CP) (137 males and 105 females; mean age 9y 10mo, SD 3y 5mo, range 6-18y). Twenty children from the study sample (mean age 11y 8mo, SD 3y 10mo) participated in a retest within 7 to 14 days. Validity was tested by Rasch analysis based on a rating scale model and test-retest reliability by Kappa analysis and intraclass correlation coefficient (ICC). RESULTS: The four-category rating scale was within recommended criteria for rating scale structure. One item was removed because of misfit. CHEQ showed good scale structure according to the criteria. The effective operational range was >90% for two of the CHEQ scales. Test-retest reliability for the three CHEQ scales was: grasp efficacy, ICC=0.91; time taken, ICC=0.88; and feeling bothered, ICC=0.91. INTERPRETATION: The internet-based CHEQ with a four-category rating scale is valid and reliable for use in children with unilateral CP. Further studies are needed to investigate the validity of the internet-based version of CHEQ for children with upper limb reduction deficiency or obstetric brachial plexus palsy and the validity of the recommended improvements to the current version. PMID- 26610726 TI - Suicidal ideation in early to middle adolescence: sex-specific trajectories and predictors. AB - BACKGROUND: The present study examined developmental trajectories of suicidal ideation (SI) and predictors of the course of SI across early to middle adolescence in a sample of 521 children utilizing a prospective longitudinal design. METHOD: A baseline assessment including structured interviews and parent- and adolescent-reported measures was conducted at age 11-12 years, with follow-up assessments occurring 6, 12, 18, and 36 months later. RESULTS: Group-based trajectory analyses revealed three groups of individuals, one group that remained at low ideation scores throughout the time period examined, another group with moderate ideation scores and a minority of children who had fluctuating SI. Sex differences in SI trajectories were revealed with the highest SI scores at age 12 for boys. For boys in this group, high ideation followed by a steady decline in the slope over time. SI in girls demonstrated a quadratic function increasing from age 12 to 13, and decreasing from age 14 to 15. Factors that predicted SI group membership were identified. Depression, externalizing problems, family and friend support discriminated SI trajectories for both boys and girls. History of a suicide attempt was associated with moderate- and high-declining ideation groups for boys, and moderate and high ideation group for girls. CONCLUSIONS: Assessment of SI in adolescents should occur in early adolescents, particularly around the time of school transitions. PMID- 26610727 TI - Ethanol affects limbic and striatal presynaptic glutamatergic and DNA methylation gene expression in outbred rats exposed to early-life stress. AB - Alcohol use disorder is the outcome of both genetic and environmental influences and their interaction via epigenetic mechanisms. The neurotransmitter glutamate is an important regulator of reward circuits and implicated in adaptive changes induced by ethanol intake. The present study aimed at investigating corticolimbic and corticostriatal genetic signatures focusing on the glutamatergic phenotype in relation to early-life stress (ELS) and consequent adult ethanol consumption. A rodent maternal separation model was employed to mimic ELS, and a free-choice paradigm was used to assess ethanol intake in adulthood. Gene expression levels of the Vesicular Glutamate Transporters (Vglut) 1, 2 and 3, as well as two key regulators of DNA methylation, DNA (cytosine-5)-methyltransferase 1 (Dnmt1) and methyl-CpG-binding protein 2 (Mecp2), were analyzed. Brain regions of interest were the ventral tegmental area (VTA), nucleus accumbens (Acb), medial prefrontal cortex (mPFC) and dorsal striatum (dStr), all involved in mediating aspects of ethanol reward. Region-specific Vglut, Dnmt1 and Mecp2 expression patterns were observed. ELS was associated with down-regulated expression of Vglut2 in the VTA and mPFC. Rats exposed to ELS were more sensitive to ethanol-induced changes in Vglut expression in the VTA, Acb, and dStr and in Dnmt1 and Mecp2 expression in the striatal regions. These findings suggest long-term glutamatergic and DNA methylation neuroadaptations as a consequence of ELS, and show an association between voluntary drinking in non-preferring, non-dependent, rodents and different Vglut, Dnmt1 and Mecp2 expression depending on early-life history. PMID- 26610729 TI - Dietary regulation of adiponectin by direct and indirect lipid activators of nuclear hormone receptors. AB - Adiponectin is an adipokine mainly secreted by adipocytes that presents antidiabetic, anti-inflammatory, and antiatherogenic functions. Therefore, modulation of adiponectin expression represents a promising target for prevention or treatment of several diseases including insulin resistance and type II diabetes. Pharmacological agents such as the nuclear hormone receptor synthetic agonists like peroxisome proliferator activated receptor gamma agonists are of particular interest in therapeutic strategies due to their ability to increase the plasma adiponectin concentration. Nutritional approaches are also of particular interest, especially in primary prevention, since some active compounds of our diet (notably vitamins, carotenoids, or other essential nutrients) are direct or indirect lipid-activators of nuclear hormone receptors and are modifiers of adiponectin expression and secretion. The aim of the present review is to summarize current knowledge about the nutritional regulation of adiponectin by derivatives of active compounds naturally present in the diet acting as indirect or direct activators of nuclear hormone receptors. PMID- 26610730 TI - Outcomes of endovascular treatment of basilar artery occlusion in the stent retriever era: a systematic review and meta-analysis. AB - BACKGROUND: Stent retriever thrombectomy has recently been found to be effective for anterior circulation strokes, but its efficacy for basilar artery occlusion (BAO) is unclear. OBJECTIVE: To carry out a systematic review and meta-analysis to analyze the available evidence for the use of stent retrievers for BAO. METHODS: Two independent reviewers searched six databases for studies reporting outcomes following endovascular treatment for BAO. RESULTS: A total of 17 articles (6 prospective and 11 retrospective) were included. The weighted mean age of patients was 67 years (range 59-82) and 59% were male. Thrombolytic drugs were administered intravenously and intra-arterially in 46% (range 0-88%) and 38% (range 0-90%) of patients, respectively. Weighted pooled estimates of successful recanalization (TICI 2b-3) and good outcome (modified Rankin Scale <=2) were 80.0% (95% CI 70.7% to 88.0%; I2=80.28%; p<0.001) and 42.8% (95% CI 34.0% to 51.8%; I2=61.83%; p=0.002), respectively. Pooled mortality was 29.4% (95% CI 23.9% to 35.3%; I2=37.01%; p=0.087). Incidence of procedure-related complications and symptomatic hemorrhage was 10.0% (95% CI 3.7% to 18.3%; I2=61.05%; p=0.017) and 6.8% (95% CI 3.5% to 10.8%; I2=37.99%; p=0.08), respectively. CONCLUSIONS: Stent retriever thrombectomy achieves a high rate of recanalization and functional independence while being relatively safe for patients with BAO. Future prospective studies with long-term follow-up are warranted. PMID- 26610731 TI - Effect of hemodynamics on outcome of subtotally occluded paraclinoid aneurysms after stent-assisted coil embolization. AB - BACKGROUND: Endovascular treatment of paraclinoid aneurysms is preferred in clinical practice. Flow alterations caused by stents and coils may affect treatment outcome. OBJECTIVE: To assess hemodynamic changes following stent assisted coil embolization (SACE) in subtotally embolized paraclinoid aneurysms with residual necks that were predisposed to recanalization. METHODS: We studied 27 paraclinoid aneurysms (seven recanalized and 20 stable) treated with coils and Enterprise stents. Computational fluid dynamic simulations were performed on patient-specific aneurysm geometries using virtual stenting and porous media technology. RESULTS: After stent placement in 27 cases, aneurysm flow velocity decreased significantly, the reduction gradually increasing from the neck plane (11.9%), to the residual neck (12.3%), to the aneurysm dome (16.3%). Subsequent coil embolization was performed after stent placement and the hemodynamic factors decreased further and significantly at all aneurysm regions except the neck plane. In a comparison of recanalized and stable cases, univariate analysis showed no significant differences in any parameter before treatment. After stent assisted coiling, only the reduction in area-averaged velocity at the neck plane differed significantly between recanalized (8.1%) and stable cases (20.5%) (p=0.016). CONCLUSIONS: Aneurysm flow velocity can be significantly decreased by stent placement and coil embolization. However, hemodynamics at the aneurysm neck plane is less sensitive to coils. Significant reduction in flow velocity at the neck plane may be an important factor in preventing recanalization of paraclinoid aneurysms after subtotal SACE. PMID- 26610732 TI - Biological Investigations of (+)-Danicalipin A Enabled Through Synthesis. AB - A total synthesis of the chlorosulfolipid (+)-danicalipin A has been accomplished in 12 steps and 4.4% overall yield. The efficient and scalable synthesis enabled in-depth investigations of the lipid's biological properties, in particular cytotoxicity towards various mammalian cell lines. Furthermore, the ability of (+)-danicalipin A to increase the uptake of fluorophores into bacteria and mammalian cells was demonstrated, indicating it may enhance membrane permeability. By comparing (+)-danicalipin A with racemic 1,14-docosane disulfate, and the diol precursor of (+)-danicalipin A, we have shown that both chlorine and sulfate functionalities are necessary for biological activity. PMID- 26610733 TI - A study of the suppression of body odour in elderly subjects by anti-fungal agents. AB - OBJECTIVE: The suppression of body odour following the use of shampoos or soaps containing the anti-fungal agent miconazole nitrate (MCZ) has been recognized anecdotally. To determine whether MCZ could play a role in the suppression of body odour through inhibiting squalene oxidation. METHODS: A prospective study recruited 54 elderly subjects residing in a nursing facility who needed bathing assistance. Subjects bathed with three types of body soap over a 6-week study period (regular soap, sample soap (soap containing MCZ), control soap; 2 weeks per type of soap). Body odour was evaluated based on olfactory assessment of the subjects and their clothing. The subjects and the examiners were blinded to the type of soap (sample or control) being used during the study. An analysis using GC/MS was also carried out to identify the volatile compounds associated with body odour. RESULTS: Suppression of unpleasant body odour of the neck and axilla was reported in subjects who used the sample soap. Three common volatile compounds were detected from the T-shirts worn by the subjects: 2-ethylbutanal, 6 methyl-5-hepten-2-one, and geranylacetone. The occurrence of these compounds was reduced using the sample soap. CONCLUSION: Our findings suggest that MCZ could play a role in the suppression of body odour. PMID- 26610734 TI - Sex differences in relationships between habitat use and reproductive performance in Soay sheep (Ovis aries). AB - The role of habitat use in generating individual variation in fitness has rarely been examined empirically in natural populations of long-lived mammals, particularly for both sexes simultaneously. This is the case despite the increase in studies attempting to understand evolutionary change in such populations. Using data from the St. Kilda Soay sheep population, we quantified the association between lifetime reproductive performance (lifetime breeding and reproductive success) and the proportion of the home range covered by a key grass species, H. lanatus, for 490 females and 304 males. Increased H. lanatus cover was associated only with increased female lifetime reproductive success, but increased lifetime breeding success for both sexes, arising through increased male longevity and increased female fecundity. This work suggests that improved understanding of the causes and consequences of fitness differences will likely require us to better account for habitat-derived individual variation, and to do so for the sexes appropriately. PMID- 26610736 TI - Beneficial effects of aminoguanidine on radiotherapy-induced kidney and testis injury. AB - This experimental study was designed to investigate both protective and therapeutic effects of aminoguanidine (AG), on radiotherapy (RT)-induced oxidative stress in kidney and testis. Forty rats were divided into five groups equally as follows: (i) control, (ii) RT, (iii) AG, (iv) AG+RT and (v) RT+AG group. Histopathological findings and biochemical evaluations, including tissue malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione (GSH), total oxidant status (TOS), total antioxidant capacity, oxidative stress index (OSI), blood urea nitrogen (BUN), serum creatinine (Cr) and testosterone levels, were determined. MDA, TOS and OSI were significantly higher in RT-treated groups, whereas SOD, CAT, GPX and GSH were significantly lower in these groups when compared with the control rats in the kidney and testis tissue. AG treatment significantly decreased MDA, TOS and OSI levels and increased SOD, CAT, GPX and GSH levels, when compared to the RT treated groups in both kidney and testis tissue. BUN and Cr levels did not change among the groups, whereas testosterone levels were found as reduced in the RT treated rats. AG treatment significantly augmented these hazardous effects of RT on testis tissue. According to our results, AG has beneficial effects against RT induced kidney and testis injury. PMID- 26610735 TI - Genetic Variation in Toll-Interacting Protein Is Associated With Leprosy Susceptibility and Cutaneous Expression of Interleukin 1 Receptor Antagonist. AB - Leprosy is a chronic disease characterized by skin and peripheral nerve pathology and immune responses that fail to control Mycobacterium leprae. Toll-interacting protein (TOLLIP) regulates Toll-like receptor (TLR) and interleukin 1 receptor (IL-1R) signaling against mycobacteria. We analyzed messenger RNA (mRNA) expression of candidate immune genes in skin biopsy specimens from 85 individuals with leprosy. TOLLIP mRNA was highly and specifically correlated with IL-1R antagonist (IL-1Ra). In a case-control gene-association study with 477 cases and 1021 controls in Nepal, TOLLIP single-nucleotide polymorphism rs3793964 TT genotype was associated with increased susceptibility to leprosy (recessive, P = 1.4 * 10(-3)) and with increased skin expression of TOLLIP and IL-1Ra. Stimulation of TOLLIP-deficient monocytes with M. leprae produced significantly less IL-1Ra (P < .001), compared with control. These data suggest that M. leprae upregulates IL-1Ra by a TOLLIP-dependent mechanism. Inhibition of TOLLIP may decrease an individual's susceptibility to leprosy and offer a novel therapeutic target for IL-1-dependent diseases. PMID- 26610737 TI - Elevated sL1-CAM levels in BALF and serum of IPF patients. AB - BACKGROUND AND OBJECTIVE: IPF is a form of interstitial pneumonia of unknown origin that has a poor prognosis for which current treatments are limited. Recent studies have shown that EMT plays a role in IPF and tumour metastasis. L1-CAM has also been linked to EMT during tumour development and tumour metastasis. Our aim was to determine prospectively the level of L1-CAM in IPF patients. METHODS: Forty consecutive Chinese patients (with IPF, 16; LC, 12; and CC, 12), but no apparent lung or other organ's diseases were enrolled. Soluble L1-CAM (sL1-CAM), TGF-beta1, PDGF, gamma-INF levels in BALF and serum sL1-CAM were measured using ELISA. RESULTS: BALF sL1-CAM levels of IPF, LC and CC patients were 10.87 +/- 0.88 ng/mL, 6.34 +/- 0.67 ng/mL and 5.43 +/- 0.65 ng/mL, respectively. BALF sL1 CAM concentration of IPF patients was significantly higher than that in LC and in CC patients. Besides, serum sL1-CAM levels in patients with IPF, LC and CC were 9.60 +/- 1.41 ng/mL, 9.82 +/- 0.72 ng/mL and 5.41 +/- 1.07 ng/mL, respectively. The serum sL1-CAM levels in patients with IPF and LC were significantly higher than those in patients with CC (P < 0.001, respectively). CONCLUSIONS: The concentrations of sL1-CAM both in BALF and in serum of patients with IPF are markedly increased compared with controls. This indicates that L1-CAM might be involved in the pathogenesis of IPF as well as that of LC. PMID- 26610738 TI - The emergence and stability of attention deficit hyperactivity disorder in boys with fragile X syndrome. AB - BACKGROUND: Children with fragile X syndrome (FXS) are at high risk for developing a range of behavioural disorders, including attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). However, very few studies have investigated the comorbid profile of FXS and ADHD and the possible dissociation from the FXS and ASD profile. The present study examined the relationship of childhood temperament characteristics of the Surgency facet (activity level, impulsivity, approach, shyness, and smiling and laughter) and the severity of ADHD and ASD features at two measurement time points in childhood, preschool (ages 3-4) and at school entry (ages 5-6). METHODS: The study consisted of males with FXS measured at each time point (preschool and school entry), as well as comparison of typically developing (TD) boys at the preschool measurement time point. Parent reported measures of temperament and behavioural symptoms were collected at each time point. Multiple regression analyses were used to analyse obtained data. RESULTS: Elevated activity level scores are associated with ADHD scores at preschool age and elevated shyness and decreased smiling and laughter are strongly associated with ADHD scores upon school entry. Impulsivity emerges as a strong indicator of elevated ADHD scores around school age, but even preschool impulsivity scores demonstrate some predictive value for higher ADHD scores later in school. Finally, no Surgency characteristic was significantly related to ASD scores at any age. CONCLUSIONS: Impulsivity serves as an indicator of elevated ADHD symptoms across development periods in boys with FXS, while activity level is just indicative of higher ADHD scores at the preschool age. The Surgency facet of temperament at either age does not predict strong relationships of comorbid pathologies of ADHD and ASD in FXS. However, Surgency characteristics may serve as informative discriminative factors when studying behavioural outcomes in boys with FXS. PMID- 26610740 TI - Do Personality Traits Predict Functional Impairment and Quality of Life in Adult ADHD? A Controlled Study. AB - OBJECTIVE: To examine the association of personality traits and characteristics on quality of life and functioning in adults with ADHD. METHOD: Participants were adults with (n = 206) and without ADHD (n = 123) who completed the Temperament and Character Inventory (TCI), the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), and the Social Adjustment Scale-Self-Report (SAS-SR). Participants also provided information on academic, motor vehicle operation, legal, social, familial, and occupational functioning. Outcomes were examined using stepwise linear regression, logistic regression (for binary outcomes), and negative binomial regression (for count outcomes) controlling for ADHD symptoms, psychiatric comorbidity, and executive dysfunction. RESULTS: Adults with ADHD significantly differed from controls across nearly all TCI personality domains. On average, adults with ADHD endorsed more novelty seeking, harm avoidance, and self-transcendence, and less reward dependence, persistence, self-directedness, and cooperativeness. Personality traits and characteristics, especially self directedness, significantly predicted functional impairments even after controlling for ADHD symptoms, executive function deficits, and current psychiatric comorbidities. CONCLUSION: In adults with ADHD, personality traits exert unique associations on quality of life and functional impairment across major life domains, beyond the relations expected of and associated with ADHD symptoms and other associated psychiatric conditions and cognitive vulnerabilities. Addressing personality traits in adults with ADHD may lead to improvements in quality of life and reductions in functional impairment. PMID- 26610739 TI - New models for describing outliers in meta-analysis. AB - An unobserved random effect is often used to describe the between-study variation that is apparent in meta-analysis datasets. A normally distributed random effect is conventionally used for this purpose. When outliers or other unusual estimates are included in the analysis, the use of alternative random effect distributions has previously been proposed. Instead of adopting the usual hierarchical approach to modelling between-study variation, and so directly modelling the study specific true underling effects, we propose two new marginal distributions for modelling heterogeneous datasets. These two distributions are suggested because numerical integration is not needed to evaluate the likelihood. This makes the computation required when fitting our models much more robust. The properties of the new distributions are described, and the methodology is exemplified by fitting models to four datasets. (c) 2015 The Authors. Research Synthesis Methods published by John Wiley & Sons, Ltd. PMID- 26610741 TI - ADHD and Psychiatric Comorbidity: Functional Outcomes in a School-Based Sample of Children. AB - OBJECTIVE: Investigate the prevalence and impact of psychiatric comorbidities in community-based samples of schoolchildren with/without ADHD. METHOD: Teachers and parents screened children in South Carolina (SC; n = 4,604) and Oklahoma (OK; n = 12,626) for ADHD. Parents of high-screen and selected low-screen children received diagnostic interviews (SC: n = 479; OK: n = 577). RESULTS: Psychiatric disorders were increased among children with ADHD and were associated with low academic performance. Conduct disorder/oppositional defiant disorder (CD/ODD) were associated with grade retention (ODD/CD + ADHD: odds ratio [OR] = 3.0; confidence interval [CI] = [1.5, 5.9]; ODD/CD without ADHD: OR = 4.0; CI = [1.7, 9.7]). School discipline/police involvement was associated with ADHD alone (OR = 3.2; CI = [1.5, 6.8]), ADHD + CD/ODD (OR = 14.1, CI = [7.3, 27.1]), ADHD + anxiety/depression (OR = 4.8, CI = [1.6, 14.8]), and CD/ODD alone (OR = 2.8, CI = [1.2, 6.4]). Children with ADHD + anxiety/depression had tenfold risk for poor academic performance (OR = 10.8; CI = [2.4, 49.1]) compared to children with ADHD alone. This should be interpreted with caution due to the wide confidence interval. CONCLUSION: Most children with ADHD have psychiatric comorbidities, which worsens functional outcomes. The pattern of outcomes varies by type of comorbidity. PMID- 26610742 TI - Internet Activities During Leisure: A Comparison Between Adolescents With ADHD and Adolescents From the General Population. AB - OBJECTIVE: Adolescents' leisure activities are increasingly focusing on Internet activities, and today, these coexist with traditional leisure activities such as sport and meeting friends. The purpose of the present study was to investigate leisure activities, particularly Internet activities, among boys and girls with ADHD, and compare these with boys and girls from the general population. The objective was also to explore how traditional leisure activities and Internet activities interrelate among adolescents with ADHD. METHOD: Adolescents with ADHD ( n = 102) were compared with adolescents from the general population on leisure activities and Internet use. RESULTS: Leisure activities among adolescents with ADHD tended to focus on Internet activities, particularly online games. Internet activities were broadening leisure activities among adolescents with ADHD, rather than being a substitute for traditional leisure activities. CONCLUSION: Internet activities may provide adolescents with ADHD accessible means of social interaction. PMID- 26610743 TI - Correlation of cervical cytology with high-risk HPV molecular diagnosis, genotypes, and histopathology--A four year study from the UAE. AB - BACKGROUND: Cervical cancer is one of the most common cancers among women in the world and in the Middle East. Its prevention and screening strategies assume great importance especially in view of the ability to identify the illness at an early stage and disrupt its progression toward neoplasia. Cervical cancer screening program of our center in UAE as well as this study is oriented in this direction. METHODS: Cervical cytology data encompassing 4 years (2011-2014) was compiled and analyzed for 14,950 cases to assess the abnormal smear reporting pattern, correlation with biopsy histopathology, HPV high-risk screening data, and HPV genotype prevalence among patients with abnormal smear test, as well as in relation to the respective nationalities of patients. RESULTS: Abnormal smear rates as well as HPV high-risk positivity correlated well with established data. Cytology-histology correlation was good. HPV high-risk type 16 was the commonest, type 18 which is the second common type worldwide was less frequently detected, several other high risk subtypes such as 51, 31 as well as rare types such as 66, 56, and 59 were detected in a significant number of patients. CONCLUSION: Assessment of cervical cytology reporting pattern, correlation of cervical cytology with HPV molecular diagnosis, and biopsy histopathology is a useful way to audit our work and a good quality control practice. Higher prevalence of HPV HR types such as type 51, 31 as well as 66, 56, and 59 found in the present as well as many similar other studies apart from the commonest subtype 16 may imply necessity for development of more targeted and multivalent anti-HPV vaccines for protection of women in our region. HPV genotypes correlation with the nationalities of patients is useful from an epidemiological standpoint to plan preventive strategies. PMID- 26610745 TI - TRAP-induced platelet aggregation is enhanced in cardiovascular patients receiving dabigatran. AB - BACKGROUND/OBJECTIVES: Novel (or non-vitamin K antagonist) oral anti-coagulants (NOACs) are antagonists of coagulation factors (F) Xa (rivaroxaban) or IIa (dabigatran), and their non-inferiority compared with vitamin K antagonists has been demonstrated in patients with non-valvular atrial fibrillation. However, it is still not fully understood if and how dabigatran and rivaroxaban impact platelet function. This observational study aimed to assess platelet function in patients receiving dabigatran or rivaroxaban. METHODS/RESULTS: This was a single centre, observational study quantifying platelet aggregation in 90 patients treated with NOACs by multiple electrode aggregometry. The thrombin receptor activating peptide (TRAP)-induced platelet aggregation was significantly higher in 35 patients receiving dabigatran (d) compared with control (c) patients (d 108+/-31 vs. c 85+/-30arbitrary units [AU]*min, p<0.001). Patients receiving rivaroxaban (r) showed no differences compared with the control group (r 88+/-32 vs. c 85+/-30AU*min, p=0.335). In intraindividual time courses of 16 patients, a significantly higher aggregation was found after the administration of dabigatran (before vs. after; 83+/-29 vs. 100+/-31AU*min, p=0.009). CONCLUSION: In this observational study, the TRAP-induced platelet aggregation was enhanced in cardiovascular patients receiving dabigatran. This might be explained by a change in the expression profile of thrombin receptors on the surface of platelets. Rivaroxaban had no influence on platelet aggregation. PMID- 26610744 TI - The predictive role of the Bova risk score in acute normotensive pulmonary embolism: A retrospective analysis on a real life cohort. PMID- 26610746 TI - Safety of antithrombotic drugs in patients with atrial fibrillation and non-end stage chronic kidney disease: Meta-analysis and systematic review. AB - OBJECTIVE: To evaluate the safety of antithrombotic drugs used in patients with both atrial fibrillation (AF) and non-end-stage chronic kidney disease (NECKD). METHODS: A search was performed for studies on major bleeding outcomes in patients with concurrent AF and NECKD using Medline and Cochrane databases on 19th February, 2015. Fixed- or random-effects meta-analysis was adopted for evaluating pooled effect sizes according to whether heterogeneity existed. RESULTS: Twelve articles were included for analysis. Three studies evaluated AF patients who took warfarin vs. placebo/antiplatelet drugs in the presence of NECKD. No significant difference in major bleeding risk was observed according to the pooled analysis using the random-effects model (RR: 1.05, 95% CI: 0.74-1.36). The risk of a composite of major bleeding outcomes was reduced by 19% in patients randomized to direct oral anticoagulants (DOACs) compared to dose-adjusted warfarin from pooled data of three randomized controlled trials with regard to AF and NECKD (RR: 0.81, 95% CI: 0.75-0.88). This superiority of DOACs to warfarin maintained until the renal function was severely impaired. CONCLUSIONS: In patients with AF and NECKD, no significant increase in the incidence of major bleeding outcomes was observed in warfarin use compared with placebo/antiplatelet drugs. DOACs reduced the risk of major bleeding by 19% compared to warfarin and further data-exploration indicated that the risk did not increase as renal function deteriorated during the renal status of mild to moderate impairment. PMID- 26610747 TI - Increased risk of venous thromboembolism in patients with brain tumors: A systematic review and meta-analysis. AB - BACKGROUND: Currently published studies investigating the association between brain tumors and venous thromboembolism (VTE) risk have yielded inconsistent findings. To provide a more precise estimate for this association, we firstly performed a meta-analysis by pooling all currently available data. METHODS: Pooled relative risks (RRs) with 95% confidence intervals (95% CIs) were calculated by use of STATA 12.0 software. All eligible studies were identified by a comprehensive literature search in databases of PubMed, Embase, Web of Science, and Google scholar. RESULTS: According to the inclusion criteria, 9 independent studies were finally included into this study. Individuals with brain tumors were at an increased risk of VTE (RR=1.66, 95% CI 1.31-2.12, P<0.001), particularly those undergoing surgery (RR=1.68, 95% CI 1.44-1.98, P<0.001). Stratified analysis by type of tumor showed that the risk of VTE was significantly associated with glioma (RR=1.68, 95% CI 1.44-1.98, P<0.001), high-grade glioma (RR=1.70, 95% CI 1.29-2.23, P<0.001), and glioblastoma multiforme (RR=1.74, 95% CI 1.43-2.12, P<0.001). CONCLUSIONS: The present meta-analysis suggests increased risk of VTE in patients with brain tumors, particularly those undergoing surgery. PMID- 26610748 TI - Percutaneous management of periprocedural cardiac perforation during left atrial appendage closure. PMID- 26610749 TI - Localized Gene Expression Analysis during Sprouting Angiogenesis in Mouse Embryoid Bodies Using a Double Barrel Carbon Probe. AB - The mouse embryonic stem (ES) cell-derived angiogenesis model is widely used as a 3D model, reproducing cell-cell interactions in the living body. Previously, many methods to analyze localized cellular function, including in situ hybridization and laser capture microdissection, have been reported. In this study, we achieved a collection of localized cells from the angiogenesis model in hydrogel. The gene expression profiles of the endothelial cells derived from mouse ES cells were evaluated. First, we collected localized cells from the live tissue model embedded in hydrogel using the double barrel carbon probe (DBCP) and quantified mRNA expression. Second, we found that vascular marker genes were expressed at a much higher level in sprouting vessels than in the central core of the embryoid body because the cells in sprouting vessels might significantly differentiate into endothelial linages, including tip/stalk cells. Third, the gene expression levels tended to be different between the top and middle regions in the sprouting vessel due to the difference in the degree of differentiation in these regions. At the top region of the vessel, both the tip and stalk cells were present. The cells in the middle region became more mature. Collectively, these results show that DBCP is very useful for analyzing localized gene expression in cells collected from 3D live tissues embedded in hydrogel. This technique can be applied to comprehensive gene expression analyses in the medical field. PMID- 26610750 TI - Right paraesophageal lymph node metastasis. PMID- 26610751 TI - Nitric oxide-repressed Forkhead factor FoxE1 expression is involved in the inhibition of TSH-induced thyroid peroxidase levels. AB - Thyroid peroxidase (TPO) is essential for thyroid hormone synthesis mediating the covalent incorporation of iodine into tyrosine residues of thyroglobulin process known as organification. Thyroid-stimulating hormone (TSH) via cAMP signaling is the main hormonal regulator of TPO gene expression. In thyroid cells, TSH stimulated nitric oxide (NO) production inhibits TSH-induced thyroid-specific gene expression, suggesting a potential autocrine role of NO in modulating thyroid function. Indeed, NO donors downregulate TSH-induced iodide accumulation and organification in thyroid cells. Here, using FRTL-5 thyroid cells as model, we obtained insights into the molecular mechanism underlying the inhibitory effects of NO on iodide organification. We demonstrated that NO donors inhibited TSH-stimulated TPO expression by inducing a cyclic guanosine monophosphate dependent protein kinase-mediated transcriptional repression of the TPO gene. Moreover, we characterized the FoxE1 binding site Z as mediator of the NO inhibited TPO expression. Mechanistically, we demonstrated that NO decreases TSH induced FoxE1 expression, thus repressing the transcripcional activation of TPO gene. Taken together, we provide novel evidence reinforcing the inhibitory role of NO on thyroid cell function, an observation of potential pathophysiological relevance associated with human thyroid pathologies that come along with changes in the NO production. PMID- 26610752 TI - TRAF2 mediates JNK and STAT3 activation in response to IL-1beta and IFNgamma and facilitates apoptotic death of insulin-producing beta-cells. AB - Interleukin-1beta (IL-1beta) and interferon-gamma (IFNgamma) contribute to type 1 diabetes (T1D) by inducing beta-cell death. Tumor necrosis factor (TNF) receptor associated factor (TRAF) proteins are adaptors that transduce signaling from a variety of membrane receptors including cytokine receptors. We show here that IL 1beta and IFNgamma upregulate the expression of TRAF2 in insulin-producing INS-1E cells and isolated rat pancreatic islets. siRNA-mediated knockdown (KD) of TRAF2 in INS-1E cells reduced IL-1beta-induced phosphorylation of JNK1/2, but not of p38 or ERK1/2 mitogen-activated protein kinases. TRAF2 KD did not modulate NFkappaB activation by cytokines, but reduced cytokine-induced inducible nitric oxide synthase (iNOS) promotor activity and expression. We further observed that IFNgamma-stimulated phosphorylation of STAT3 required TRAF2. KD of TRAF2 or STAT3 reduced cytokine-induced caspase 3/7 activation, but, intriguingly, potentiated cytokine-mediated loss of plasma membrane integrity and augmented the number of propidium iodide-positive cells. Finally, we found that TRAF2 KD increased cytokine-induced production of reactive oxygen species (ROS). In summary, our data suggest that TRAF2 is an important mediator of IL-1beta and IFNgamma signaling in pancreatic beta-cells. PMID- 26610753 TI - Immunophenotypical characterization and influence on liver homeostasis of depleting and repopulating hepatic macrophages in rats injected with clodronate. AB - Hepatic macrophages (including Kupffer cells) play a crucial role in the homeostasis and act as mediators of inflammatory response in the liver. Hepatic macrophages were depleted in male F344 rats by a single intravenous injection of liposomal clodronate (CLD; 50mg/kg body weight), and immunophenotypical characteristics of depleting and repopulating macrophages were analyzed by different antibodies specific for macrophages. CD163(+) Kupffer cells were almost completely depleted on post-injection (PI) days 1-12. Macrophages reacting to CD68, Iba-1, and Gal-3 were drastically reduced in number on PI day 1 and then recovered gradually until PI day 12. MHC class II(+) and CD204(+) macrophages were moderately decreased during the observation period. Although hepatic macrophages detectable by different antibodies were reduced in varying degrees, Kupffer cells were the most susceptible to CLD. Liver situation influenced by depleted hepatic macrophages was also investigated. No marked histological changes were seen in the liver, but the proliferating activity of hepatocytes was significantly increased, supported by changes of gene profiles relating to cell proliferation on microarray analysis on PI day 1; the values of AST and ALT were significantly elevated; macrophage induction/activation factors (such as MCP-1, CSF-1, IL-6 and IL-4) were increased exclusively on PI day 1, whereas anti inflammatory factors such as IL-10 and TGF-beta1 remained significantly decreased after macrophage depletion. The present study confirmed importance of hepatic macrophages in liver homeostasis. The condition of hepatic macrophages should be taken into consideration when chemicals capable of inhibiting macrophage functions are evaluated. PMID- 26610754 TI - Changes in plasma concentrations of corticosterone and its precursors after ketoconazole administration in rats: An application of simultaneous measurement of multiple steroids using LC-MS/MS. AB - The adrenal gland is the most common toxicological target in the endocrine system, and inhibition of adrenal steroidogenesis by drugs can be fatal in humans. However, methods to evaluate the drug effect are limited. Recently, simultaneous measurement of multiple steroids, including precursors, has become possible. Here, we evaluated the usefulness of this simultaneous measurement for the evaluation of drug effects on adrenal steroidogenesis in vivo. For this purpose, we measured plasma concentrations of adrenal steroids in rats dosed with ketoconazole, a known inhibitor of adrenal steroidogenesis, and examined its relationship with the changes in histopathology and mRNA expression of steroidogenic enzymes in the adrenal gland. Ketoconazole (150mg/kg/day) was orally administered to male rats for 7 days. The adrenal weight was high, and the zona fasciculata/reticularis were hypertrophic with an accumulation of lipid droplets. mRNA expression of CYP11A1, a rate-limiting enzyme in adrenal steroidogenesis, was slightly high in the adrenal gland. Plasma concentration of deoxycorticosterone was markedly high, while there were no significant changes in that of corticosterone, progesterone, or pregnenolone. The changes in the adrenal gland and plasma concentration of steroids were thought to reflect inhibited metabolism of deoxycorticosterone to corticosterone through inhibition of CYP11B1, and compensatory reaction for the inhibition. The compensatory reaction was thought to have masked decrease of corticosterone. These results suggest that simultaneous measurement of multiple steroids can enable sensitive evaluation of drug effects on adrenal steroidogenesis in vivo, while providing insight into the underlying mechanism of the effect. PMID- 26610755 TI - Visual and refractive outcomes of small incision lenticule extraction for the correction of myopia: 1-year follow-up. AB - OBJECTIVE: To assess the 1 year clinical outcomes of small incision lenticule extraction (SMILE) for the correction of myopia and myopic astigmatism using a 500 kHz femtosecond laser system. METHODS: This prospective study evaluated 52 eyes of 39 consecutive patients (31.8+/-6.9 years, mean age+/-SD) with spherical equivalents of -4.11+/-1.73 D (range, -1.25 to -8.25 D) who underwent SMILE for myopia and myopic astigmatism. Preoperatively, 1 week, and 1, 3, 6 and 12 months postoperatively, we assessed the safety, efficacy, predictability, stability, corneal endothelial cell loss and the adverse events of the surgery. RESULTS: The logarithm of the minimal angle of resolution (logMAR) uncorrected distance visual acuity and LogMAR corrected distance visual acuity were -0.16+/-0.11 and -0.22+/ 0.07, respectively, 1 year postoperatively. At 1 year, all eyes were within+/-0.5 D of the targeted correction. Manifest refraction changes of -0.05+/-0.32 D occurred from 1 week to 1 year postoperatively (p=0.20, Wilcoxon signed-rank test). The endothelial cell density was not significantly changed from 2804+/-267 cells/mm(2) preoperatively to 2743+/-308 cells/mm(2) 1 year postoperatively (p=0.12). No vision-threatening complications occurred during the observation period. CONCLUSIONS: SMILE performed well in the correction of myopia and myopic astigmatism, and no significant change in endothelial cell density or any other serious complications occurred throughout the 1-year follow-up period, suggesting its viability as a surgical option for the treatment of such eyes. PMID- 26610756 TI - Obesity in pregnancy: infant health service utilisation and costs on the NHS. AB - OBJECTIVE: To estimate the direct healthcare cost of infants born to overweight or obese mothers to the National Health Service in the UK. DESIGN: Retrospective prevalence-based study. SETTING: Combined linked anonymised electronic data sets on a cohort of mother-child pairs enrolled on the Growing Up in Wales: Environments for Healthy Living (EHL) study. Infants were categorised according to maternal early-pregnancy body mass index (BMI): healthy weight mother (18.5<=BMI<25 kg/m(2); n=342), overweight mother (25<=BMI<=29.9 kg/m(2); n=157) and obese mother (BMI>=30; n=110). PARTICIPANTS: 609 singleton pregnancies with available health service records and an antenatal maternal BMI. PRIMARY OUTCOME MEASURE: Total health service utilisation and direct healthcare costs for providing these services in the year 2012-2013. Costs are calculated as cost of the infant (no maternal costs considered) and are related to health service usage from birth to age 1 year. RESULTS: A strong association existed between healthcare usage cost and BMI (p<0.001). Mean total costs were 72% higher among children born to obese mothers (rate ratio (RR) 1.72, 95% CI 1.71 to 1.73) compared with infants born to healthy weight mothers. Higher costings were attributed to a significantly greater number (RR 1.39, 95% CI 1.04 to 1.84) and duration (RR 1.55, 95% CI 1.37 to 1.74) of inpatient visits and a higher number of general practitioner visits (RR 1.10, 95% CI 1.03 to 1.16). Total mean additional resource cost was estimated at L65.13 for infants born to overweight mothers and L1138.11 for infants born to obese mothers, when compared with infants of healthy weight mothers. CONCLUSIONS: Increasingly infants born to mothers with high BMIs consume additional health service resources in the first year of life; this was apparent across inpatient and general practitioner services. Considering both maternal and infant health service use, interventions that cost less than L2310 per person in reducing obesity early pregnancy could be cost-effective. PMID- 26610757 TI - Social epidemiology of excess weight and central adiposity in older Indians: analysis of Study on global AGEing and adult health (SAGE). AB - OBJECTIVES: We aimed to estimate the prevalence of overweight and obesity, represented by extra body weight and abdominal circumference, among older Indians; and to characterise the social pattern of obesity and measure the magnitude of hypertension attributable to it. SETTING: A nationally representative sample of older Indians was selected from 6 Indian states, including Rajasthan, Uttar Pradesh, West Bengal, Assam, Maharashtra and Karnataka, as a part of the multicountry Study on global AGEing and adult health (SAGE). PARTICIPANTS: Indians aged 50 years or more (n=7273) were included in the first wave of the SAGE (2010), which we used in our study. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measures included excess weight (EW), defined by body mass index (BMI) >25 kg/m(2), and central adiposity (CA), defined by waist circumference >90 cm for men and >80 cm for women. The secondary outcome included hypertension, defined by systolic blood pressure >139 or diastolic blood pressure >79 mm Hg, or by those receiving antihypertensive medications. RESULTS: 14% of older Indians possessed EW, whereas 35% possessed CA; 50.9% of the wealthier third and 27.7% of the poorer two-thirds have CA; the proportions being 69.1% and 46.2%, respectively, in older women. Mostly wealth (adjusted OR for CA: 4.36 (3.23 to 5.95) and EW: 4.39 (3.49 to 5.53)), but also urban residence, privileged caste, higher education, white-collared occupation and female gender, were important determinants. One of 17 older Indians overall and 1 of 18 in the poorer 70% suffered from CA-driven hypertension, independent of BMI. CONCLUSIONS: The problem of CA and its allied diseases is already substantial and expected to rise across all socioeconomic strata of older Indians, though currently, CA affects the privileged more than the underprivileged, in later life. Population based promotion of appropriate lifestyles, with special emphasis on women, is required to counteract prosperity-driven obesity before it becomes too entrenched and expensive to uproot. PMID- 26610758 TI - Beyond height and weight: a programme of school nurse assessed skinfold measurements from white British and South Asian origin children aged 4-5 years within the Born in Bradford cohort study. AB - OBJECTIVE: To describe the feasibility, reliability and additional information gained from collecting additional body fatness measures (beyond height and weight) from UK reception year children. DESIGN: Prospective cohort study. SETTING: Bradford, UK. PARTICIPANTS: 2458 reception year children participating in the Born in Bradford (BiB) cohort study. MAIN OUTCOME MEASURES: The feasibility and reliability of subscapular and triceps skinfold measurements and differences in adiposity between ethnic groups. RESULTS: Of those children who were matched to their school, 91% had a subscapular skinfold measurement and 92% had a triceps skinfold measurement recorded. Reliability was generally over 90% for all measurers and both measurements. Pakistani children were slightly taller but weighed less and had lower triceps skinfold thickness (mean difference -1.8 mm, 95% CI -2.1 to -1.4 mm) but higher subscapular (mean difference 0.1 mm, 95% CI -0.1 to 0.4 mm) than white British children. CONCLUSIONS: We have shown that it is feasible for school nurses to collect skinfold measurements in a similar way to the height and weight measurements collected from reception year children for the National Child Measurement Programme (NCMP), and that these measurements are reliable. It is important for healthcare practice to acknowledge ethnic specific risk and these additional measurements can provide important information to examine population-level risk in populations with large proportions of South Asian children. PMID- 26610760 TI - Correction. PMID- 26610759 TI - Role of development partners in Maternal, Newborn and Child Health (MNCH) programming in post-reform times: a qualitative study from Pakistan. AB - OBJECTIVES: Despite certain reforms undertaken in Pakistan to reorient its health system, the health-related millennium goals lagged behind many neighbouring and regional countries. This study was conducted to understand the implications of government reforms including the devolution on the National Maternal Newborn and Child Health (MNCH) programme; and to determine donors' and development partners' current and prospective role in the post-reform scenario. SETTING: The donor agencies based in the federal capital Islamabad, as well as the federal and provincial government offices involved in the financing, design, oversight and implementation of various MNCH initiatives in Pakistan, were included in the sample. PARTICIPANTS: A descriptive qualitative study based on individual in depth interviews with representatives from donor agencies and government offices (8 each) involved in programmes directly related to the MNCH sector. RESULTS: The reforms are denounced as deficient in terms of detailed planning and operationalisation of the vertical programmes including that for MNCH. The government had to face coordination challenges with the provinces, which has affected donor engagement and funding mechanisms to a great deal. Investment in MNCH, population and nutrition has been the topmost priority of development partners in Pakistan. Their contributions towards health systems also include assistance in developing and implementing provincial health sector strategies, establishment of Health Sector Reform Units and investments in service delivery, research and advocacy. CONCLUSIONS: Any health sector reform must be complemented by a roll-out strategy, including robust support to the provincial health systems and to their capacity building. Development partners must align and coordinate their strategies with provinces to stabilise the MNCH programme in Pakistan. More coordination between the different tiers of the government and the donors could streamline MNCH partnership in post-reform times. PMID- 26610761 TI - Safety culture perceptions of pharmacists in Malaysian hospitals and health clinics: a multicentre assessment using the Safety Attitudes Questionnaire. AB - OBJECTIVE: To assess the safety attitudes of pharmacists, provide a profile of their domains of safety attitude and correlate their attitudes with self-reported rates of medication errors. DESIGN: A cross-sectional study utilising the Safety Attitudes Questionnaire (SAQ). SETTING: 3 public hospitals and 27 health clinics. PARTICIPANTS: 117 pharmacists. MAIN OUTCOME MEASURES: Safety culture mean scores, variation in scores across working units and between hospitals versus health clinics, predictors of safety culture, and medication errors and their correlation. RESULTS: Response rate was 83.6% (117 valid questionnaires returned). Stress recognition (73.0+/-20.4) and working condition (54.8+/-17.4) received the highest and lowest mean scores, respectively. Pharmacists exhibited positive attitudes towards: stress recognition (58.1%), job satisfaction (46.2%), teamwork climate (38.5%), safety climate (33.3%), perception of management (29.9%) and working condition (15.4%). With the exception of stress recognition, those who worked in health clinics scored higher than those in hospitals (p<0.05) and higher scores (overall score as well as score for each domain except for stress recognition) correlated negatively with reported number of medication errors. Conversely, those working in hospital (versus health clinic) were 8.9 times more likely (p<0.01) to report a medication error (OR 8.9, CI 3.08 to 25.7). As stress recognition increased, the number of medication errors reported increased (p=0.023). Years of work experience (p=0.017) influenced the number of medication errors reported. For every additional year of work experience, pharmacists were 0.87 times less likely to report a medication error (OR 0.87, CI 0.78 to 0.98). CONCLUSIONS: A minority (20.5%) of the pharmacists working in hospitals and health clinics was in agreement with the overall SAQ questions and scales. Pharmacists in outpatient and ambulatory units and those in health clinics had better perceptions of safety culture. As perceptions improved, the number of medication errors reported decreased. Group-specific interventions that target specific domains are necessary to improve the safety culture. PMID- 26610762 TI - Where children and adolescents drown in Queensland: a population-based study. AB - OBJECTIVE: This retrospective population-based study examined drowning location by the site of immersion for both fatal and non-fatal drowning events in Queensland. Drowning location is not routinely collected, and this study used data linkage to identify drowning sites. The resulting enhanced quality data quantify drowning incidence for specific locations by geographic region, age group and by severity for the first time. DESIGN: Linked data were accessed from the continuum of care (prehospital, emergency, hospital admission and death data) on fatal and non-fatal drowning episodes in children aged 0-19 years in Queensland for the years 2002-2008 inclusive. RESULTS: Drowning locations ranked in order of overall incidence were pools, inland water, coastal water, baths and other man-made water hazards. Swimming pools produced the highest incidence rates (7.31/100,000) for overall drowning events and were more often privately owned pools and in affluent neighbourhoods. Toddlers 0-4 years were most at risk around pools (23.94/100,000), and static water bodies such as dams and buckets-the fatality ratios were highest at these 2 locations for this age group. Children 5 14 years incurred the lowest incidence rates regardless of drowning location. Adolescents 15-19 years were more frequently involved in a drowning incident on the coast shoreline, followed by inland dynamic water bodies. CONCLUSIONS: Linked data have resulted in the most comprehensive data collection on drowning location and severity to date for children in the state of Queensland. Most mortality and morbidity could have been prevented by improving water safety through engaged supervision around pools and bath time, and a heightened awareness of buckets and man-made water hazards around the farm home for young children. These data provide a different approach to inform prevention strategies. PMID- 26610763 TI - Effects of placebos without deception compared with no treatment: protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Placebos have long provided a robust control for evaluating active pharmacological preparations, but frequently demonstrate a variable therapeutic effect when delivered in double-blinded placebo-controlled trials. Delivery of placebos as treatment alone has been considered unethical, as it has been thought that deception is essential for their effect. However, recent evidence suggests that clinical benefit can be derived from placebos delivered without deception (unblinded/open-label) manner. Here, we present a protocol for the first systematic review and meta-analysis of studies of the effects of non-deceptive placebos compared with no treatment. METHODS AND ANALYSIS: This protocol will compare the effect of placebos delivered non-deceptively to no treatment. It will also assess the methods of delivery used for non-deceptive placebos. Studies will be sought through relevant database searches and will include those within disease settings and those among healthy controls. To be included, trials must include both non-deceptive (open-label) placebo and no treatment groups. All data extraction and analysis will be conducted by two independent reviewers. The analysis will evaluate any differences in outcome measures between the non deceptive placebo and no treatment groups. Outcome measures will be the clinically-relevant outcomes detailed in the primary papers. The delivery methods, such as verbal instructions, which may provide positive expectations and outcomes, of non-deceptive placebos will also be assessed. Each study will be comprehensively assessed for bias. Subgroup analyses will identify any discrepancies among heterogeneous data. ETHICS AND DISSEMINATION: This review does not require ethical approval. The completed review will be widely disseminated by publication and social media where appropriate. This protocol has been registered on PROSPERO (2015:CRD42015023347). PMID- 26610764 TI - Effects of birth weight and growth on childhood wheezing disorders: findings from the Born in Bradford Cohort. AB - OBJECTIVES: To examine the effects of birth weight and childhood growth on childhood wheezing disorders. We hypothesised that low birth weight and fast growth during early age would increase the risk of wheezing disorders. SETTING: Observational secondary analysis of data from the Born in Bradford cohort. PARTICIPANTS: All children who were born at the Bradford Royal Infirmary hospital between March 2007 and December 2010 were eligible for the study. A total of 13,734 and 1598 children participated in the analyses of the effects of birth weight and growth on wheezing disorders, respectively. PRIMARY AND SECONDARY OUTCOME MEASURES: Wheezing disorders diagnosis (diagnosed as asthma or had wheezing symptom) during the ages of 0-7 years were the primary outcome measures. Diagnosis of asthma and occurrence of wheezing during the same period were secondary outcome measures. Birth weight was classified as normal (2.5-4.0 kg), low (<2.5 kg) and high (>4.0 kg). Growth mixture models were used to drive growth pattern outcomes which were classified as 'normal', 'fast' and 'slow' growth based on their velocities between birth and 36 months. RESULTS: The adjusted relative risks (RRs) of wheezing disorders diagnosis for the low and high birthweight children were 1.29 (95% CI 1.12 to 1.50; p=0.001) and 0.91 (95% CI 0.79 to 1.04; p=0.17), respectively. The adjusted RRs of wheezing disorders diagnosis were 1.30 (95% CI 0.56 to 3.06; p=0.54) and 0.60 (95% CI 0.16 to 2.18; p=0.44), respectively, for the 'fast' and 'slow' growth as compared with the 'normal' growth. CONCLUSIONS: Low birth weight is associated with an increased risk of wheezing disorders; however, there is a weak evidence that suggests high birthweight children have a reduced risk in this birth cohort. Low birth weight coupled with a slower growth until 3 months and a sharp growth between 3 and 12 months has an increased risk of wheezing disorders diagnosis. PMID- 26610765 TI - Association between perception of fault for the crash and function, return to work and health status 1 year after road traffic injury: a registry-based cohort study. AB - OBJECTIVES: To establish the association between the patient's perception of fault for the crash and 12-month outcomes after non-fatal road traffic injury. SETTING: Two adult major trauma centres, one regional trauma centre and one metropolitan trauma centre in Victoria, Australia. PARTICIPANTS: 2605 adult, orthopaedic trauma patients covered by the state's no-fault third party insurer for road traffic injury, injured between September 2010 and February 2014. OUTCOME MEASURES: EQ-5D-3L, return to work and functional recovery (Glasgow Outcome Scale-Extended score of upper good recovery) at 12 months postinjury. RESULTS: After adjusting for key confounders, the adjusted relative risk (ARR) of a functional recovery (0.57, 95% CI 0.46 to 0.69) and return to work (0.92, 95% CI 0.86 to 0.99) were lower for the not at fault compared to the at fault group. The ARR of reporting problems on EQ-5D items was 1.20-1.35 times higher in the not at fault group. CONCLUSIONS: Patients who were not at fault, or denied being at fault despite a police report of fault, experienced poorer outcomes than the at fault group. Attributing fault to others was associated with poorer outcomes. Interventions to improve coping, or to resolve negative feelings from the crash, could facilitate better outcomes in the future. PMID- 26610766 TI - Cross-sectional imaging of thoracic and abdominal complications of cerebrospinal fluid shunt catheters. AB - This study aims to review the imaging findings of distal (thoracic and abdominal) complications related to ventriculo-peritoneal (VP), ventriculo-pleural (VPL), and ventriculo-atrial (VA) cerebrospinal fluid (CSF) shunt catheter placement. Institution review board-approved single-center study of patients with thoracic and abdominal CSF catheter-related complications on cross-sectional imaging examinations over a 14-year period was performed. Clinical presentation, patient demographics, prior medical history, and subsequent surgical treatment were recorded. The presence or absence of CSF catheter-related infection and/or acute hydrocephalus on cross-sectional imaging was also recorded. There were 81 distal CSF catheter-related complications identified on 47 thoracic or abdominal imaging examinations in 30 patients (age 5-80 years, mean 39.3 years), most often on CT (CT = 42, MRI = 1, US = 4). Complications included 38 intraperitoneal and 11 extraperitoneal fluid collections. Extraperitoneal collections included nine abdominal wall subcutaneous (SC) pseudocysts associated with shunt migration and obesity, an intrapleural pseudocyst, and a breast pseudocyst. There were also two large VPL-related pleural effusions, a fractured catheter in the SC tissues, and a large VA shunt thrombus within the right atrium. Ten patients (33.3 %) had culture-positive infection from CSF or shunt catheter samples. Ten patients (33.3 %) had features of temporally related acute or worsening hydrocephalus on neuroimaging. In four of these patients, the detection of thoracic and abdominal complications on CT preceded and predicted the findings of acute hydrocephalus on cranial imaging. Thoracic and abdominal complications of CSF shunts, as can be identified on CT, include shunt infection and/or obstruction, may be both multiple and recurrent, and may be predictive of concurrent acute intracranial problems. PMID- 26610767 TI - Vaccination of chemotherapy patients--effect of guideline implementation. AB - PURPOSE: Despite substantial morbidity and mortality of influenza and pneumococcal infections in cancer patients treated with chemotherapy, vaccination against both illnesses is infrequent. We evaluated the impact of implementation of clinical guidelines on vaccination of chemotherapy patients treated in our institute. METHODS: We performed a prospective audit before (2012) and after (2013-2014) the introduction of immunisation guidelines for chemotherapy patients in a UK tertiary cancer centre. RESULTS: Guideline implementation was associated with a significant increase in the rate of pneumococcal vaccination compared to the 2012 baseline (47 vs. 25 %, P = 0.0018), though this was not sustained the following year (34 %, P = 0.13, vs. baseline). Influenza vaccine coverage was high (~ 70 %) throughout. There was a marked disparity between patients aged <= 65 and those >65 years in the rate of pneumococcal vaccination in both 2013 and 2014 (38 vs. 68 % and 17 vs. 53 %, respectively, both P < 0.001), and, to a lesser extent, in the rate of influenza vaccination in the same period (64 vs. 82 %, P < 0.1, and 63 vs. 85 %, P = 0.009, respectively). CONCLUSIONS: The implementation of clinical vaccine guidelines was associated with a significant increase in pneumococcal vaccination, though continued effort appears required to deliver persistent improvement. Initiatives to increase vaccination uptake in patients aged <= 65 are merited. PMID- 26610768 TI - Feelings, perceptions, and expectations of patients during the process of oral cancer diagnosis. AB - PURPOSE: Communication barriers during the process of cancer diagnosis can adversely affect how patients understand their health, and understanding patient's perceptions and expectations can favor adherence to professional recommendations and their prognosis. This study aimed to describe the sociodemographic characteristics, perceptions, expectations, and psychological symptoms of patients during the process of oral cancer diagnosis. METHODS: Patients were assessed at two time points: pre-biopsy (T0) and post-diagnosis (T1). At T0, 49 patients answered a sociodemographic, perceived social support, lifestyle questionnaire and inventories (anxiety-State-Trait Anxiety Inventory (STAI-S/T), depression-Beck Depression Inventory (BDI), risk drinkers-Alcohol Use Disorders Identification Test (AUDIT)). They also were interviewed concerning their perceptions, feelings, and expectations. At T1, the 29 patients diagnosed with oral cancer were reassessed for anxiety (STAI-E) and depression symptoms. An interview investigated the same aspects at T0. RESULTS: Patient mean age was 59 years old (+/-13.7) and 73.5 % were men. At T0, depression symptoms were more frequent among cancer patients (83.3 %) than those without the disease (p < 0.05), with a prevalence of 36.7 %. Patients presented anxiety (40.8 %) and alcohol abuse behavior (32.6 %). Associations between characteristics and categories at T0 showed that patients with lower income and living with a partner reported negative feelings (p < 0.05) more frequently, together with negative expectations concerning the diagnosis among older patients (p < 0.05) and those with depressive symptoms (p < 0.05). At T1, negative feelings were more frequently reported among patients with anxiety (p < 0.01) and depression symptoms (p < 0.05). CONCLUSION: Professional support and care regarding the psychological aspects and characteristics of patients is required during the diagnosis process in order to promote patient adhesion and favorable prognosis. PMID- 26610769 TI - [Chronic diarrhoea: Definition, classification and diagnosis]. AB - Chronic diarrhoea is a common presenting symptom in both primary care medicine and in specialized gastroenterology clinics. It is estimated that >5% of the population has chronic diarrhoea and nearly 40% of these patients are older than 60 years. Clinicians often need to select the best diagnostic approach to these patients and choose between the multiple diagnostic tests available. In 2014 the Catalan Society of Gastroenterology formed a working group with the main objective of creating diagnostic algorithms based on clinical practice and to evaluate diagnostic tests and the scientific evidence available for their use. The GRADE system was used to classify scientific evidence and strength of recommendations. The consensus document contains 28 recommendations and 6 diagnostic algorithms. The document also describes criteria for referral from primary to specialized care. PMID- 26610770 TI - [Early transjugular intrahepatic portosystemic shunt: When, how and in whom?]. AB - Early TIPS is basically a new application of an old concept. This intervention used to be a useful rescue therapy when other interventions failed but has now become a primary intervention in patients with variceal bleeding and risk factors for poor prognosis. This technique has also been proven to control bleeding and has a definite survival advantage at 6 weeks and 1 year over standard therapy with vasoactive drugs and endoscopy, without increasing the rate of adverse events. In well-trained hands and with appropriate candidate selection, early TIPS is a safe, life-saving and evidenced-based procedure. PMID- 26610771 TI - Management of Thyroid Nodular Disease: Current Cytopathology Classifications and Genetic Testing. AB - Preoperative diagnosis and operative planning for patients with thyroid nodules has improved over the last decade. The Bethesda criteria for cytopathologic classification of thyroid nodule aspirate has enhanced communication between pathologists and clinicians. Multiple genetic tests, including molecular markers and the Afirma gene expression classifier, have been developed and validated. The tests, along with clinical and radiologic information, are most useful in the setting of indeterminate cytology. The development of an updated diagnostic and treatment algorithm incorporating all available tests will help standardize the management of patients with nodular thyroid disease and reduce variation and inefficiencies in care. PMID- 26610772 TI - Surgical Management of Lymph Node Compartments in Papillary Thyroid Cancer. AB - Although papillary thyroid cancer (PTC) commonly metastasizes to cervical lymph nodes, prophylactic central neck dissection is controversial. The primary treatment for lymph node metastases is surgical resection. Patients diagnosed with PTC should be assessed preoperatively by cervical ultrasound to evaluate central and lateral neck lymph node compartments. Sonographically suspicious lymph nodes in the lateral neck should be biopsied for cytology or thyroglobulin levels. Any compartment (central or lateral) that has definitive proof of nodal metastases should be formally dissected at the time of thyroidectomy. PMID- 26610773 TI - Current Guidelines for Postoperative Treatment and Follow-Up of Well Differentiated Thyroid Cancer. AB - Well-differentiated thyroid cancer is increasing in incidence but the disease specific mortality remains very low. The only effective adjuvant treatment is radioactive iodine ablation. Guidelines regarding the use and dosage of radioactive iodine depend on pathologic features of the primary and metastatic tumor that define risk. Long-term treatment includes thyroid-stimulating hormone suppression and surveillance with serum thyroglobulin and radiologic assessment for nodal recurrence. PMID- 26610775 TI - Asymptomatic Primary Hyperparathyroidism: Diagnostic Pitfalls and Surgical Intervention. AB - Primary hyperparathyroidism (PHPT) is a common disease, with a prevalence as high as 1 in 400 women and 1 in 1000 men, and most are asymptomatic. Patients with PHPT have hypercalcemia with inappropriately normal levels of parathyroid hormone. Parathyroidectomy is the only curative therapy, and the procedure has become more common and more safe. Among asymptomatic patients, parathyroidectomy halts the progression of disease, improves quality of life, and may decrease risk of fracture and adverse cardiovascular outcomes. Thus, surgery should be considered in all patients with asymptomatic PHPT who have minimal perioperative risk and sufficient life expectancy, regardless of chronologic age. PMID- 26610774 TI - Outpatient Thyroidectomy: Is it Safe? AB - Outpatient thyroid surgery is controversial because of concerns over life threatening cervical hematoma. Despite this concern, outpatient thyroidectomy is becoming increasingly common, especially among high-volume endocrine surgeons. Multiple studies have now demonstrated that careful patient selection combined with surgeon experience can result in successful and safe surgery without a full inpatient admission. This article reviews the data on safety and outcomes for outpatient thyroidectomy and discusses several techniques used to minimize risk to patients. PMID- 26610776 TI - Intraoperative Parathyroid Hormone Monitoring: Optimal Utilization. AB - Intraoperative parathyroid hormone (IOPTH) monitoring is a highly accurate surgical adjunct used to determine the extent of surgery in the setting of primary hyperparathyroidism. It is the successful interpretation of changes in PTH levels that is essential for using this technique in a way to optimize cure. Thus, it is imperative that the surgeon has an understanding of PTH dynamics and carefully chooses the appropriate IOPTH protocol and interpretation criteria that will best predict operative success, minimize unnecessary bilateral exploration, decrease the likelihood of resecting parathyroid glands that are not hypersecreting, and prevent recurrence. PMID- 26610777 TI - Minimally Invasive Parathyroidectomy Versus Bilateral Neck Exploration for Primary Hyperparathyroidism. AB - Primary hyperparathyroidism is a disease that is caused by excess parathyroid hormone (PTH) secretion from 1 or more of the parathyroid glands. Surgery is the only cure. Traditional surgical management consists of a 4-gland cervical exploration. Development of imaging specific to identification of parathyroid glands and application of the rapid PTH assay to operative management have made more minimal exploration possible. There are distinct advantages and disadvantages of minimally invasive parathyroidectomy (MIP) and bilateral neck exploration (BNE). The advantages of MIP seem to outweigh those of BNE, and MIP has replaced BNE as the operation of choice by many surgeons. PMID- 26610778 TI - Pheochromocytoma and Paraganglioma: Diagnosis, Genetics, and Treatment. AB - This article highlights the epidemiology and pathophysiology of pheochromocytomas and paragangliomas. The current management of pheochromocytoma and paragangliomas, including utilization and interpretation of biochemical testing, preoperative imaging, and genetic screening are discussed. Furthermore, perioperative surgical management, outcomes, and recommended follow-up are reviewed. PMID- 26610779 TI - Minimally Invasive Adrenalectomy. AB - Minimally invasive adrenalectomy has become the gold standard for removal of benign adrenal tumors. The imaging characteristics, biochemical evaluation, and patient selection for laparoscopic transabdominal and posterior retroperitoneoscopic approaches are discussed with details of surgical technique for both procedures. PMID- 26610780 TI - Surgical Management of Adrenocortical Carcinoma: An Evidence-Based Approach. AB - Adrenocortical carcinoma frequently presents with sequelae of steroid precursor overproduction and has a proclivity for aggressive local growth, early metastasis, and recurrence. En bloc surgical resection with negative margins is the cornerstone of therapy for localized disease, and re-resection has a role in selected recurrent cases. Presence of occult micrometastatic disease at the time of presentation is confirmed by frequent distant failure after apparent negative margin resection. Data for many aspects of therapy are limited or nonexistent. This review critically considers existing evidence with a particular focus on surgical management. PMID- 26610782 TI - Minimally Invasive Techniques for Resection of Pancreatic Neuroendocrine Tumors. AB - Surgical resection remains the treatment of choice for primary pancreatic neuroendocrine tumors (PNETs), because it is associated with increased survival. Minimally invasive procedures are a safe modality for the surgical treatment of PNETs. In malignant PNETs, laparoscopy is not associated with a compromise in terms of oncologic resection, and provides the benefits of decreased postoperative pain, better cosmetic results, shorter hospital stay, and a shorter postoperative recovery period. Further prospective, multicenter, randomized trials are required for the analysis of these minimally invasive surgical techniques for the treatment of PNETs and their comparison with traditional open pancreatic surgery. PMID- 26610783 TI - Treatment of Neuroendocrine Liver Metastases. AB - Neuroendocrine tumors are rare and slow-growing malignancies that commonly metastasize to the liver, resulting hormonal syndromes and death from liver failure. Surgical consultation and liver debulking are key components in management. Traditional surgical resection guidelines do not apply to these tumors as with other cancers. Surgical resection has shown survival benefit even in the event of an incomplete resection. Ablation may be used as an adjunct to resection or in patients who are not candidates for resection. Asymptomatic patients with high-volume disease do as well with intra-arterial therapy as with surgery. PMID- 26610781 TI - Biochemical Diagnosis and Preoperative Imaging of Gastroenteropancreatic Neuroendocrine Tumors. AB - Neuroendocrine tumors are a group of neoplasms that can arise in a variety of locations throughout the body and often metastasize early. A patient's only chance for cure is surgical removal of the primary tumor and all associated metastases, although even when surgical cure is unlikely, patients can benefit from surgical debulking. A thorough preoperative workup will often require multiple clinical tests and imaging studies to locate the primary tumor, delineate the extent of the disease, and assess tumor functionality. This review discusses the biomarkers important for the diagnosis of these tumors and the imaging modalities needed. PMID- 26610784 TI - Foreword. PMID- 26610785 TI - Advances in Endocrine Surgery. PMID- 26610786 TI - Parental exposure to the herbicide diuron results in oxidative DNA damage to germinal cells of the Pacific oyster Crassostrea gigas. AB - Chemical pollution by pesticides has been identified as a possible contributing factor to the massive mortality outbreaks observed in Crassostrea gigas for several years. A previous study demonstrated the vertical transmission of DNA damage by subjecting oyster genitors to the herbicide diuron at environmental concentrations during gametogenesis. This trans-generational effect occurs through damage to genitor-exposed gametes, as measured by the comet-assay. The presence of DNA damage in gametes could be linked to the formation of DNA damage in other germ cells. In order to explore this question, the levels and cell distribution of the oxidized base lesion 8-oxodGuo were studied in the gonads of exposed genitors. High-performance liquid chromatography coupled with UV and electrochemical detection analysis showed an increase in 8-oxodGuo levels in both male and female gonads after exposure to diuron. Immunohistochemistry analysis showed the presence of 8-oxodGuo at all stages of male germ cells, from early to mature stages. Conversely, the oxidized base was only present in early germ cell stages in female gonads. These results indicate that male and female genitors underwent oxidative stress following exposure to diuron, resulting in DNA oxidation in both early germ cells and gametes, such as spermatozoa, which could explain the transmission of diuron-induced DNA damage to offspring. Furthermore, immunostaining of early germ cells seems indicates that damages caused by exposure to diuron on germ line not only affect the current sexual cycle but also could affect future gametogenesis. PMID- 26610787 TI - The epsilon glutathione S-transferases contribute to the malathion resistance in the oriental fruit fly, Bactrocera dorsalis (Hendel). AB - Epsilon glutathione S-transferases (eGSTs) play important roles in xenobiotics detoxification and insecticides resistance in insects. However, the molecular mechanisms of eGSTs-mediated insecticide resistance remain largely unknown in the Bactrocera dorsalis (Hendel), one of the most notorious pests in the world. Here, we investigated the roles of eight GST genes which belonged to epsilon class (BdGSTe1, BdGSTe2, BdGSTe3, BdGSTe4, BdGSTe5, BdGSTe6, BdGSTe7 and BdGSTe9) in conferring malathion resistance in B. dorsalis. Adult developmental stage-, sex- and tissue-specific expression patterns of the eight eGST genes were analyzed via quantitative reverse transcription PCR. The results showed that BdGSTe2, BdGSTe3, BdGSTe4 and BdGSTe9 were abundant in the midgut, fat body and Malpighian tubules. Notably, BdGSTe2, BdGSTe4 and BdGSTe9 were significantly overexpressed in a malathion-resistant (MR) strain of B. dorsalis compared to the malathion susceptible (MS) strain. Functional expression and cytotoxicity assays showed significantly higher malathion detoxification capabilities in BdGSTe2-, BdGSTe3-, BdGSTe4- and BdGSTe9-expressing Sf9 cells compared to the parental and green fluorescent protein (GFP)-expressing Sf9 cells. Moreover, malathion susceptibility in MS adults was increased 30%, 14%, and 33% when BdGSTe2, BdGSTe3 and BdGSTe4 mRNA levels were repressed by RNA interference (RNAi)-mediated knockdown, respectively. Taken together, overexpression of the isoforms of eGSTs, including BdGSTe2, BdGSTe4, and particularly, BdGSTe9 plays an important role in the malathion resistant development in B. dorsalis. PMID- 26610788 TI - Amblyopic children read more slowly than controls under natural, binocular reading conditions. AB - BACKGROUND: Recent evidence suggests that amblyopia results in fixation instability and atypical saccades. Reading is a vision-reliant ability that requires sequential eye movements, including forward and regressive saccades. This study investigated reading and associated eye movements in school-age amblyopic children. METHODS: Amblyopic children with strabismus and/or anisometropia (n = 29) were compared to nonamblyopic children treated for strabismus (n = 23) and normal control children (n = 21). While fitted with the ReadAlyzer, an eye movement recording system, children silently read a grade level paragraph of text during binocular viewing. Reading rate, number of forward and regressive saccades per 100 words, and fixation duration were determined. Comprehension was evaluated with a 10-item quiz; only data from children with at least 80% correct responses were included. RESULTS: Amblyopic children read more slowly and had more saccades compared with nonamblyopic children with treated strabismus and normal controls. Fixation duration did not differ significantly for amblyopic children versus normal controls. Treated strabismic children without amblyopia did not differ significantly from normal controls on any reading measure. Amblyopic eye visual acuity was not correlated with any reading measure. CONCLUSIONS: Amblyopia was associated with slower reading speed in school-age children. Treatment for monocular amblyopia visual acuity impairment could improve reading speed and efficiency. PMID- 26610789 TI - Molecular association of adsorbed water with lignocellulosic materials examined by micro-FTIR spectroscopy. AB - For lignocellulosic materials, water adsorption is extremely important for its product performance. For gaining a deeper understanding of moisture adsorption mechanisms, the molecular interactions between adsorbed water and a typical lignocellulosic material (i.e., wood) were studied using in-situ microscopic Fourier transform infrared (micro-FTIR) spectroscopy and a specially designed sample cell. The spectral shifts of 1733 cm(-1), 1604 cm(-1) and 1236 cm(-1) and different spectra between the moist and dry spectra indicated that carbonyl CO and CO groups preferred to combine with water molecules to form hydrogen bonds. From component band analysis of the spectral range of 2900-3700 cm(-1), three peaks at 3178 cm(-1), 3514 cm(-1) and 3602 cm(-1) were identified and assigned to strongly, moderately and weakly hydrogen-bonded water molecules, respectively. According to the variation trend of these hydrogen-bonded water molecules, three sections were divided for the adsorption process. Furthermore, the molecular structure of water absorbed by hydrophilic groups of wood in each section was demonstrated. PMID- 26610790 TI - Associations of vitamin D status and vitamin D-related polymorphisms with sex hormones in older men. AB - OBJECTIVE: Evidence regarding relationships of serum 25-hydroxyvitamin D (25(OH)D) with sex hormones and gonadotropin concentrations remains inconsistent. Polymorphisms in vitamin D-related genes may underly these relationships. Our aim was to examine the relationship of vitamin D status and polymorphisms in vitamin D-related genes with sex hormone and gonadotropin levels. DESIGN AND MEASUREMENTS: We analysed data from the Longitudinal Aging Study Amsterdam, an ongoing population-based cohort study of older Dutch individuals (65-89 years). We included data of men with measurements of serum 25-hydroxyvitamin D (25(OH)D) (n=643) and determination of vitamin D-related gene polymorphisms (n=459). 25(OH)D concentrations were classified into four categories: <25, 25-50, 50-75 and >75nmol/L. Outcome measures were total testosterone, calculated bioavailable and free fraction testosterone, SHBG, estradiol, LH and FSH concentrations. Hypogonadism was defined as a total testosterone level <8.0nmol/L. RESULTS: Serum 25(OH)D was positively associated with total and bioavailable testosterone levels. After adjustments for confounders, men with serum 25(OH)D less than 25 (n=56), 25-50 (n=199) and 50-75nmol/L (n=240) had lower total testosterone levels compared to men with serum 25(OH)D higher than 75nmol/L (n=148) (beta (95% confidence interval): -2.1 (-3.7 to -0.4nmol/L), -0.8 (-1.9 to 0.4nmol/L) and 1.4 (-2.4 to -0.3nmol/L), respectively). For bioavailable testosterone the association was significant only for men with serum 25(OH)D less than 25nmol/L ( 0.8 (-1.4 to -0.1nmol/L)) compared to men with serum 25(OH)D >75nmol/L. Serum 25(OH)D was not related to SHBG, estradiol or gonadotropin levels. Hypogonadism (n=29) was not associated with lower serum 25(OH)D. No significant differences were found in hormone levels between the different genotypes of the vitamin D related gene polymorphisms. Also, the polymorphisms did not modify the relationships of serum 25(OH)D with sex hormones or gonadotropins. CONCLUSION: Vitamin D status is positively associated with testosterone levels. No association was found between vitamin D-related gene polymorphisms and hormone levels. PMID- 26610792 TI - [Short-term outcomes of the GeSRU Academics research network]. PMID- 26610791 TI - A stochastic model of input effectiveness during irregular gamma rhythms. AB - Gamma-band synchronization has been linked to attention and communication between brain regions, yet the underlying dynamical mechanisms are still unclear. How does the timing and amplitude of inputs to cells that generate an endogenously noisy gamma rhythm affect the network activity and rhythm? How does such "communication through coherence" (CTC) survive in the face of rhythm and input variability? We present a stochastic modelling approach to this question that yields a very fast computation of the effectiveness of inputs to cells involved in gamma rhythms. Our work is partly motivated by recent optogenetic experiments (Cardin et al. Nature, 459(7247), 663-667 2009) that tested the gamma phase dependence of network responses by first stabilizing the rhythm with periodic light pulses to the interneurons (I). Our computationally efficient model E-I network of stochastic two-state neurons exhibits finite-size fluctuations. Using the Hilbert transform and Kuramoto index, we study how the stochastic phase of its gamma rhythm is entrained by external pulses. We then compute how this rhythmic inhibition controls the effectiveness of external input onto pyramidal (E) cells, and how variability shapes the window of firing opportunity. For transferring the time variations of an external input to the E cells, we find a tradeoff between the phase selectivity and depth of rate modulation. We also show that the CTC is sensitive to the jitter in the arrival times of spikes to the E cells, and to the degree of I-cell entrainment. We further find that CTC can occur even if the underlying deterministic system does not oscillate; quasicycle type rhythms induced by the finite-size noise retain the basic CTC properties. Finally a resonance analysis confirms the relative importance of the I cell pacing for rhythm generation. Analysis of whole network behaviour, including computations of synchrony, phase and shifts in excitatory-inhibitory balance, can be further sped up by orders of magnitude using two coupled stochastic differential equations, one for each population. Our work thus yields a fast tool to numerically and analytically investigate CTC in a noisy context. It shows that CTC can be quite vulnerable to rhythm and input variability, which both decrease phase preference. PMID- 26610793 TI - Laparoscopic gastrojejunostomy for superior mesenteric artery syndrome in a patient with Parkinson's disease. AB - INTRODUCTION: Superior mesenteric artery syndrome is rare cause of intestinal obstruction. We report an unusual case of a patient with Parkinson's disease who developed superior mesenteric artery syndrome and discuss her management including laparoscopic gastrojejunostomy and Roux-en-Y anastomosis. CASE PRESENTATION: A 78-year-old patient with advanced Parkinson's disease presented with significant malnutrition, vomiting and post-prandial abdominal pain. Computed tomography confirmed duodenal compression by the superior mesenteric artery. We hypothesised this was likely triggered by extreme weight loss associated with advanced Parkinson's disease. As the patient failed to improve with conservative measures, laparoscopic gastrojejunostomy and Roux-en-Y anastomosis was successfully performed without complications and the patient discharged on day 7. CONCLUSION: Successful treatment was achieved due to early recognition of the consequences of chronic illness and addressing malnutrition. From this experience, we propose that laparoscopic gastric bypass is a safe and minimally invasive effective treatment option for superior mesenteric artery syndrome. PMID- 26610794 TI - The effect of hemoperfusion on patients with toxic encephalopathy induced by silkworm chrysalis ingestion. AB - This study aims to determine therapeutic effect of hemoperfusion on patients with acute toxic encephalopathy induced by silkworm chrysalis ingestion. Three patients who developed toxic encephalopathy after chrysalis ingestion were analysed. Two patients lost their consciousness, while two patients had typical extrapyramidal tremor symptoms. Further neurological examination revealed various degrees of muscle strength impairment in these patients. All of them received treatments of omeprazole (40 mg/day), furosemide (one dose of 20 mg), vitamin C (2.0 g/day), calcium gluconate (2.0 g/day) and rehydration with glucose and sodium chloride (1500 ml/day). In addition, they received hemoperfusion treatment for 1.5 h. All patients recovered well after hemoperfusion. Two patients with loss of consciousness significantly recovered at 45 min and 65 min after hemoperfusion, respectively. All tremor symptoms were completely resolved in these patients at 30 min, 50 min, and 70 min following treatment, respectively. After the hemoperfusion treatment, encephalopathy symptoms of two patients had completely disappeared. All patients were followed up for one month and did not report any abnormalities. Our study indicates that hemoperfusion could be a useful and efficient treatment strategy for patients with acute encephalopathy after silkworm chrysalis ingestion. Larger clinical trials with longer follow-up are warranted to confirm the clinical benefit of hemoperfusion. PMID- 26610795 TI - The manufacture of blood plasma products in Scotland: a brief history. AB - A number of essential clinical products are derived from human blood plasma, including immunoglobulin products for the treatment of infections and disorders of immunity; albumin for protein and fluid replacement and coagulation factors for the treatment of haemophilia and other disorders of haemostasis. For many years, these protein pharmaceuticals were manufactured by the Scottish National Blood Transfusion Service (SNBTS) at its Scottish Protein Fractionation Centre (PFC) in Edinburgh, a contribution which ended with the closure of the PFC in 2008. The origins and development of plasma fractionation in Scotland are summarised in this article, as well as issues which contributed to the closure of the PFC. PMID- 26610796 TI - In-patient hospital mortality patterns by day of the week: an analysis of admissions to a regional renal unit. AB - BACKGROUND AND AIMS: Higher mortality rates have been reported for patients admitted at a weekend compared to a weekday. Our aim was to assess in-patient mortality patterns by day of the week, in a tertiary renal unit. METHOD AND RESULTS: Mortality related to day of admission and day of death was analysed over a two-year period at Glasgow Western Infirmary renal unit. Typical caseload was also assessed over two random four-week periods. As a proportion of admissions, 30-day mortality was 46/540 (8.5%) on a weekend day compared with a weekday 107/2013 (5.3%) (RR1.60, p = 0.005). Thirty-day mortality rate was 46/208 = 0.22 deaths/weekend day of admission compared with 107/523 = 0.20 deaths/weekday of admission (incident rate ratio = 1.08, p = 0.67). There was no significant increased risk of death on a weekend day compared to a weekday (RR1.23, p = 0.23). A higher proportion of weekend admissions were from other hospitals. Acute kidney injury and haemodialysis patients formed a higher percentage of admissions. CONCLUSION: Admission day mortality expressed as a death rate/day does not differ between weekend/weekday admissions. Admission day mortality expressed as a proportion of total admissions was significantly higher at weekends. This suggests admission case-mix/workload differs at weekends with fewer 'well' patients admitted. In-patient mortality patterns are complex and any conclusions made should take into account case mix and workload. PMID- 26610797 TI - Autologous blood clot embolisation in posttraumatic high-flow priapism. AB - Non-ischemic, high-flow priapism is defined as the state of painless and permanent erection of the penis which generally develops by perineal trauma. Selective transarterial embolisation is one of the treatment options. We present an 18-year-old men who had complaints of painless and permanent erection after a blunt perineal trauma. Colour Doppler ultrasound revealed a pseudoaneurysm and fistula at the left cavernosal artery. Hence autologous blood clot injection was performed to embolise the pseudoaneurysm. Due to the recanalization on the postprocedural seventh day, second embolisation was performed. One month after the second procedure, colour Doppler ultrasound revealed a 50% shrink but mild refilling in the pseudoaneurysm, whereas complete thrombus formation was observed on follow-up imaging. His priapism had fully recovered and erectile functions were totally normal at the six months and one year follow up. Autologous blood clot embolisation seems as a safe and successful treatment. PMID- 26610798 TI - KRAS Exon 2 Mutations as Prognostic Indicators in Advanced Colorectal Cancer in Clinical Practice: A Mono-Institutional Study. AB - BACKGROUND: Kirsten-Ras (KRAS) mutations are widely accepted negative predictive factors for anti-EGFR therapies in metastatic colorectal cancer (mCRC), while their prognostic significance is still under discussion. OBJECTIVE: This mono institutional retrospective study aims to investigate the real-life impact of exon 2 codon 12 and 13 mutations in mCRC. METHODS: All mCRC patients treated at our institution between 2008 and 2014 carrying KRAS exon 2 mutations were included. The primary endpoint was to determine any significant difference in overall survival (OS) between codon 12 and 13 mutations. Secondary endpoints included progression-free survival (PFS), OS in both populations according to antiangiogenic treatment, and OS in liver-limited disease (LLD). RESULTS: Of 620 mCRC patients, 218 carried KRAS exon 2 mutations (35.1%): 162 (26.1%) at codon 12 and 56 (9.0 %) at codon 13. Median OS results were similar: 32.0 months (codon 12) and 31.0 months (codon 13). PFS was also comparable, reaching 10.8 months in both populations. The addition of bevacizumab to chemotherapy conferred a trend toward survival advantage in codon 12 but not codon 13 mutation (p = 0.058). A high proportion of LLD patients underwent hepatic surgery with radical purpose (62.3%): in these patients, median OS has not yet been reached, while OS in non LLD patients was 30.2 months. CONCLUSIONS: No difference in OS between KRAS codon 12/13 mutated disease was found. This analysis showed a very prolonged OS for KRAS-mutated patients, even when LLD patients were excluded; OS of our real-life series favorably compares with OS of all-RAS wild-type patients in recent randomized studies. PMID- 26610799 TI - Display of phytase on the cell surface of Saccharomyces cerevisiae to degrade phytate phosphorus and improve bioethanol production. AB - Currently, development of biofuels as an alternative fuel has gained much attention due to resource and environmental challenges. Bioethanol is one of most important and dominant biofuels, and production using corn or cassava as raw materials has become a prominent technology. However, phytate contained in the raw material not only decreases the efficiency of ethanol production, but also leads to an increase in the discharge of phosphorus, thus impacting on the environment. In this study, to decrease phytate and its phosphorus content in an ethanol fermentation process, Saccharomyces cerevisiae was engineered through a surface-displaying system utilizing the C-terminal half of the yeast alpha agglutinin protein. The recombinant yeast strain, PHY, was constructed by successfully displaying phytase on the surface of cells, and enzyme activity reached 6.4 U/g wet biomass weight. Ethanol productions using various strains were compared, and the results demonstrated that the specific growth rate and average fermentation rate of the PHY strain were higher 20 and 18 %, respectively, compared to the control strain S. cerevisiae CICIMY0086, in a 5-L bioreactor process by simultaneous saccharification and fermentation. More importantly, the phytate phosphorus concentration decreased by 89.8 % and free phosphorus concentration increased by 142.9 % in dry vinasse compared to the control in a 5-L bioreactor. In summary, we constructed a recombinant S. cerevisiae strain displaying phytase on the cell surface, which could improve ethanol production performance and effectively reduce the discharge of phosphorus. The strain reported here represents a useful novel engineering platform for developing an environment-friendly system for bioethanol production from a corn substrate. PMID- 26610800 TI - Identification of the phd gene cluster responsible for phenylpropanoid utilization in Corynebacterium glutamicum. AB - Phenylpropanoids as abundant, lignin-derived compounds represent sustainable feedstocks for biotechnological production processes. We found that the biotechnologically important soil bacterium Corynebacterium glutamicum is able to grow on phenylpropanoids such as p-coumaric acid, ferulic acid, caffeic acid, and 3-(4-hydroxyphenyl)propionic acid as sole carbon and energy sources. Global gene expression analyses identified a gene cluster (cg0340-cg0341 and cg0344-cg0347), which showed increased transcription levels in response to phenylpropanoids. The gene cg0340 (designated phdT) encodes for a putative transporter protein, whereas cg0341 and cg0344-cg0347 (phdA-E) encode enzymes involved in the beta-oxidation of phenylpropanoids. The phd gene cluster is transcriptionally controlled by a MarR-type repressor encoded by cg0343 (phdR). Cultivation experiments conducted with C. glutamicum strains carrying single-gene deletions showed that loss of phdA, phdB, phdC, or phdE abolished growth of C. glutamicum with all phenylpropanoid substrates tested. The deletion of phdD (encoding for putative acyl-CoA dehydrogenase) additionally abolished growth with the alpha,beta saturated phenylpropanoid 3-(4-hydroxyphenyl)propionic acid. However, the observed growth defect of all constructed single-gene deletion strains could be abolished through plasmid-borne expression of the respective genes. These results and the intracellular accumulation of pathway intermediates determined via LC-ESI MS/MS in single-gene deletion mutants showed that the phd gene cluster encodes for a CoA-dependent, beta-oxidative deacetylation pathway, which is essential for the utilization of phenylpropanoids in C. glutamicum. PMID- 26610801 TI - Phenol degradation by halophilic fungal isolate JS4 and evaluation of its tolerance of heavy metals. AB - Phenol is one of the most common pollutants in many kinds of industrial wastewater, some of which are in high salinity, resulting in more difficulties of biodegradation. In this work, a halophilic strain capable of utilizing phenol as sole source of carbon and energy in both hypersaline and no-salt media was isolated and identified as genus Debaryomyces. The optimization of environmental parameters including phenol concentration, pH, dissolved oxygen as well as salinity was carried out and tolerance of heavy metals by the strain was evaluated. The strain Debaryomyces sp. was able to grow in culture when initial phenol concentration, pH, agitation and salinity were at wide ranges (0-1200 mg L(-1), 4.0-10.0, 50-200 rpm, 0 %-15 %, respectively). High removal efficiency was hardly affected in the presence of 5 mM of Zn (II) and Mn (II). Under optimal conditions (pH 6.0, 200 rpm, 1 % of salinity without heavy metals), 500 mg L(-1) of phenol could be completely degraded within 32 h. The high removal efficiency of phenol by the strain with significant variations of process parameters might contribute to the bioremediation of phenol-polluted environments under hypersaline or no-salt conditions. PMID- 26610802 TI - Effects of plant downtime on the microbial community composition in the highly saline brine of a geothermal plant in the North German Basin. AB - The microbial biocenosis in highly saline fluids produced from the cold well of a deep geothermal heat store located in the North German Basin was characterized during regular plant operation and immediately after plant downtime phases. Genetic fingerprinting revealed the dominance of sulfate-reducing bacteria (SRB) and fermentative Halanaerobiaceae during regular plant operation, whereas after shutdown phases, sequences of sulfur-oxidizing bacteria (SOB) were also detected. The detection of SOB indicated oxygen ingress into the well during the downtime phase. High 16S ribosomal RNA (rRNA) and dsrA gene copy numbers at the beginning of the restart process showed an enrichment of bacteria, SRB, and SOB during stagnant conditions consistent with higher concentrations of dissolved organic carbon (DOC), sulfate, and hydrogen sulfide in the produced fluids. The interaction of SRB and SOB during plant downtimes might have enhanced the corrosion processes occurring in the well. It was shown that scale content of fluids was significantly increased after stagnant phases. Moreover, the sulfur isotopic signature of the mineral scales indicated microbial influence on scale formation. PMID- 26610803 TI - Lactobacillus plantarum CCFM639 alleviates aluminium toxicity. AB - Aluminium (Al) is the most abundant metal in the earth's crust. Al exposure can cause a variety of adverse physiological effects in humans and animals. Our aim was to demonstrate that specific probiotic bacteria can play a special physiologically functional role in protection against Al toxicity in mice. Thirty strains of lactic acid bacteria (LAB) were tested for their aluminium-binding ability, aluminium tolerance, their antioxidative capacity, and their ability to survive the exposure to artificial gastrointestinal (GI) juices. Lactobacillus plantarum CCFM639 was selected for animal experiments because of its excellent performance in vitro. Forty mice were divided into four groups: control, Al only, Al plus CCFM639, and Al plus deferiprone (DFP). CCFM639 was administered at 10(9) CFU once daily for 10 days, followed by a single oral dose of aluminium chloride hexahydrate at 5.14 mg aluminium (LD50) for each mouse. The results showed that CCFM639 treatment led to a significant reduction in the mortality rates with corresponding decrease in intestinal aluminium absorption and in accumulation of aluminium in the tissues and amelioration of hepatic histopathological damage. This probiotic treatment also resulted in alleviation of hepatic, renal, and cerebral oxidative stress. The treatment of L. plantarum CCFM639 has potential as a therapeutic dietary strategy against acute aluminium toxicity. PMID- 26610804 TI - Preparation and characterization of a novel variant of human tumor necrosis factor-related apoptosis-inducing ligand from the rhesus monkey, Macaca mulatta. AB - Human tumor necrosis factor-related apoptosis-inducing ligand (hTRAIL) and its variants are attractive antitumor drug candidates. The predicted amino acid sequence of the functional extracellular domain of Macaca mulatta TRAIL (mmTRAIL) was found to differ from that of hTRAIL at four positions. In this study, the gene encoding mmTRAIL was cloned and recombinantly expressed in Escherichia coli at a yield of approximately 20-30 mg/L, which was two times higher than that of hTRAIL. SDS-PAGE showed that denatured mmTRAIL and hTRAIL had similar molecular weights. However, size-exclusion chromatography and dynamic light scattering (DLS) analysis demonstrated that the molecular size of native mmTRAIL was smaller than that of native hTRAIL. Cooling solutions of these proteins from room temperature to 0 degrees C induced considerable precipitation of hTRAIL but not of mmTRAIL, indicating that mmTRAIL was more soluble than hTRAIL at low temperatures. Additionally, mmTRAIL was more resistant than hTRAIL to N bromosuccinimide (NBS)-induced precipitation. Although mmTRAIL and hTRAIL showed comparable nanomolar affinities for human death receptors, the dissociation rate of the mmTRAIL-receptor complex was slower than that of the hTRAIL-receptor complex, suggesting that the mmTRAIL-receptor complex was more stable. Moreover, mmTRAIL induced caspase-dependent apoptosis in human tumor cells with an IC50 that was two to three times lower than that of hTRAIL. However, in vivo evaluation demonstrated that mmTRAIL or hTRAIL led to a similar level of tumor suppression in mice bearing COLO205 xenografts. Nevertheless, the advantage of its better solubility should promote the production and further use of mmTRAIL in cancer biotherapy. PMID- 26610805 TI - Calcium fluoride nanoparticles induced suppression of Streptococcus mutans biofilm: an in vitro and in vivo approach. AB - Biofilm formation on the tooth surface is the root cause of dental caries and periodontal diseases. Streptococcus mutans is known to produce biofilm which is one of the primary causes of dental caries. Acid production and acid tolerance along with exopolysaccharide (EPS) formation are major virulence factors of S. mutans biofilm. In the current study, calcium fluoride nanoparticles (CaF2-NPs) were evaluated for their effect on the biofilm forming ability of S. mutans in vivo and in vitro. The in vitro studies revealed 89 % and 90 % reduction in biofilm formation and EPS production, respectively. Moreover, acid production and acid tolerance abilities of S. mutans were also reduced considerably in the presence of CaF2-NPs. Confocal laser scanning microscopy and transmission electron microscopy images were in accordance with the other results indicating inhibition of biofilm without affecting bacterial viability. The qRT-PCR gene expression analysis showed significant downregulation of various virulence genes (vicR, gtfC, ftf, spaP, comDE) associated with biofilm formation. Furthermore, CaF2-NPs were found to substantially decrease the caries in treated rat groups as compared to the untreated groups in in vivo studies. Scanning electron micrographs of rat's teeth further validated our results. These findings suggest that the CaF2-NPs may be used as a potential antibiofilm applicant against S. mutans and may be applied as a topical agent to reduce dental caries. PMID- 26610806 TI - Systematic optimization of fed-batch simultaneous saccharification and fermentation at high-solid loading based on enzymatic hydrolysis and dynamic metabolic modeling of Saccharomyces cerevisiae. AB - An integrative simultaneous saccharification and fermentation (SSF) modeling is a useful guiding tool for rapid process optimization to meet the techno-economic requirement of industrial-scale lignocellulosic ethanol production. In this work, we have developed the SSF model composing of a metabolic network of a Saccharomyces cerevisiae cell associated with fermentation kinetics and enzyme hydrolysis model to quantitatively capture dynamic responses of yeast cell growth and fermentation during SSF. By using model-based design of feeding profiles for substrate and yeast cell in the fed-batch SSF process, an efficient ethanol production with high titer of up to 65 g/L and high yield of 85 % of theoretical yield was accomplished. The ethanol titer and productivity was increased by 47 and 41 %, correspondingly, in optimized fed-batch SSF as compared to batch process. The developed integrative SSF model is, therefore, considered as a promising approach for systematic design of economical and sustainable SSF bioprocessing of lignocellulose. PMID- 26610807 TI - Ubiquitous anaerobic ammonium oxidation in inland waters of China: an overlooked nitrous oxide mitigation process. AB - Denitrification has long been regarded as the only pathway for terrestrial nitrogen (N) loss to the atmosphere. Here we demonstrate that large-scale anaerobic ammonium oxidation (anammox), an overlooked N loss process alternative to denitrification which bypasses nitrous oxide (N2O), is ubiquitous in inland waters of China and contributes significantly to N loss. Anammox rates in aquatic systems show different levels (1.0-975.9 MUmol N m(-2) h(-1), n = 256) with hotspots occurring at oxic-anoxic interfaces and harboring distinct biogeochemical and biogeographical features. Extrapolation of these results to the China-national level shows that anammox could contribute about 2.0 Tg N yr( 1), which equals averagely 11.4% of the total N loss from China's inland waters. Our results indicate that a significant amount of the nitrogen lost from inland waters bypasses denitrification, which is important for constructing more accurate climate models and may significantly reduce potential N2O emission risk at a large scale. PMID- 26610808 TI - Composite hydrogels of polyacrylamide and crosslinked pH-responsive micrometer sized hollow particles. AB - Whilst hydrogels and hollow particles both continue to attract much attention in the literature there are few examples of hydrogel composites containing hollow particles. Here, we study composite polyacrylamide (PAAm) hydrogels containing micrometer-sized pH-responsive shell-crosslinked hollow particles (abbreviated as HPXL) based on poly(methylmethacrylate-co-methacrylic acid) functionalised with glycidyl methacrylate (GMA). The HPXL particles were prepared using our scaleable emulsion template method and inclusion of GMA was found to promote spherical hollow particle formation. The pendant vinyl groups from GMA enabled shell crosslinked hollow particles to be prepared prior to formation of the PAAm/HPXL composite gels. The morphologies of the particles and composite gels were studied by optical microscopy, confocal laser scanning microscopy and scanning electron microscopy. Dynamic rheology measurements for the composite gels showed that the modulus variation with HPXL concentration could be described by a percolation model with a HPXL percolation threshold concentration of 4.4 wt% and a scaling exponent of 2.6. The composite gels were pH-responsive and largely maintained their mechanical properties over the pH range 4.0 to 8.0. Because the composite gels had tuneable mechanical properties (with modulus values up to 530 kPa) and were pH-responsive they are potential candidates for future wound healing or membrane applications. PMID- 26610809 TI - A meta-analysis of the impact of pre-existing and new-onset atrial fibrillation on clinical outcomes in patients undergoing transcatheter aortic valve implantation. AB - AIMS: Little is known about the prognostic role of pre-existing atrial fibrillation (AF) and new-onset AF (NOAF) in transcatheter aortic valve implantation (TAVI). Therefore, the aim of this meta-analysis was to compare the short- and long-term clinical outcomes of patients undergoing TAVI with and without pre-existing and new-onset AF. METHODS AND RESULTS: Twenty-six studies, enrolling 14,078 patients undergoing TAVI, of whom 33.4% had pre-existing AF and 17.5% had NOAF, were analysed for early and long-term all-cause mortality, cardiovascular mortality and cerebrovascular events (CVE). In patients with pre existing AF, 30-day all-cause mortality was similar to patients in sinus rhythm (SR). Conversely, long-term all-cause and cardiovascular mortality were significantly greater in pre-existing AF patients than in patients with SR (20 studies; 8,743 patients; HR: 1.68; p<0.00001, and three studies; 1,138 patients; HR: 2.07; p=0.01, respectively). Pre-existing AF was not a predictor of CVE at long-term follow-up. NOAF patients showed similar short- and long-term all-cause mortality when compared to patients in SR, whereas they experienced a significantly higher incidence of CVE at short-term follow-up (six studies; 2,025 patients; HR: 2.86; p<0.00001). A non-significant increase in the incidence of CVE was observed at long-term follow-up. CONCLUSIONS: Pre-existing AF is a predictor of all-cause mortality in patients undergoing TAVI. NOAF is related to the occurrence of CVE at short-term follow-up. Similarly to surgical aortic valve replacement (SAVR), the optimal management and risk stratification of these patients should be further investigated. PMID- 26610811 TI - Inkjet-printed all solid-state electrochromic devices based on NiO/WO3 nanoparticle complementary electrodes. AB - Nanostructured thin films are important in the fields of energy conversion and storage. In particular, multi-layered nanostructured films play an important role as a part of the energy system for energy saving applications in buildings. Inkjet printing is a low-cost and attractive technology for patterning and deposition of multi-layered nanostructured materials on various substrates. However, it requires the development of a suitable ink formulation with optimum viscosity, surface tension and evaporation rate for various materials. In this study, a versatile ink formulation was successfully developed to prepare NiO and WO3 nanostructured films with strong adhesion to ITO coated glass using inkjet printing for energy saving electrochromic applications. We achieved a high performance electrochromic electrode, producing porous and continuous electrochromic films without aggregation. The NiO film with 9 printed layers exhibits an optical modulation of 64.2% at 550 nm and a coloration efficiency (CE) of 136.7 cm(2) C(-1). An inkjet-printed complementary all solid-state device was assembled, delivering a larger optical modulation of 75.4% at 633 nm and a higher CE of 131.9 cm(2) C(-1) among all solid-state devices. The enhanced contrast is due to the printed NiO film that not only performs as an ion storage layer, but also as a complementary electrochromic layer. PMID- 26610813 TI - A supramolecular H-bond driven light switch sensor for small anions. AB - A cationic iridium complex with a 2,2'-bibenzimidazole ligand can act as a luminescent sensor for various anions. Strong H-bond supported ion pair bonding with an electron accepting dinitro-benzoate anion switches the luminescence "off". The luminescence of the sensor is switched back "on" when benzoate is replaced by competing H-bonded small anions, therefore leading to an enhanced sensitivity of the sensor system. PMID- 26610812 TI - The Beneficial Impact of Antidepressant Drugs on Prenatal Stress-Evoked Malfunction of the Insulin-Like Growth Factor-1 (IGF-1) Protein Family in the Olfactory Bulbs of Adult Rats. AB - Insulin-like growth factor-1 (IGF-1) promotes the growth, differentiation, and survival of both neurons and glial cells, and it is believed to exert antidepressant-like activity. Thus, disturbances in the IGF-1 system could be responsible for the course of depression. To date, there have been no papers showing the impact of chronic antidepressant treatment on the IGF-1 network in the olfactory bulb (OB) in an animal model of depression. Prenatal stress was used as model of depression. Twenty-four 3-month-old male offspring of control and stressed mothers were subjected to behavioral testing (forced swim test). The mRNA expression of IGF-1 and IGF-1 receptor (IGF-1R) and the protein level of IGF 1 and its phosphorylation, as well as the concentrations of IGF-binding proteins (IGFBP-2, -4, -3, and -6), were measured in OBs before and after chronic imipramine, fluoxetine, or tianeptine administration. Adult rats exposed prenatally to stressful stimuli displayed not only depression-like behavior but also decreased IGF-1 expression, dysregulation in the IGFBP network, and diminished mRNA expression, as well as IGF-1R phosphorylation, in the OB. The administration of antidepressants normalized most of the changes in the IGF-1 system of the OB evoked by prenatal stress. These results suggested a beneficial effect of chronic antidepressant drug treatment in the alleviation of IGF-1 family malfunction in OBs in an animal model of depression. PMID- 26610810 TI - Epigenetic regulation of ID4 in the determination of the BRCAness phenotype in breast cancer. AB - BRCAness breast tumors represent a group of sporadic tumors characterized by a reduction in BRCA1 gene expression. As BRCA1 is involved in double-strand breaks (DSBs) repair, dysfunctional BRCA pathway could make a tumor sensitive to DNA damaging drugs (e.g., platinum agents). Thus, accurately identifying BRCAness could contribute to therapeutic decision making in patients harboring these tumors. The purpose of this study was to identify if BRCAness tumors present a characteristic methylation profile and/or were related to specific clinico pathological features. BRCAness was measured by MLPA in 63 breast tumors; methylation status of 98 CpG sites within 84 cancer-related genes was analyzed by MS-MLPA. Protein and mRNA expressions of the selected genes were measured by quantitative real-time PCR and Western Blot. BRCAness was associated with younger age, higher nuclear pleomorphism, and triple-negative (TN) status. Epigenetically, we found that the strongest predictors for BRCAness tumors were the methylations of MLH1 and PAX5 plus the unmethylations of CCND2 and ID4. We determined that ID4 unmethylation correlated with the expression levels of both its mRNA and protein. We observed an inverse relation between the expressions of ID4 and BRCA1. To the best of our knowledge, this is the first report suggesting an epigenetic regulation of ID4 in BRCAness tumors. Our findings give new information of BRCAness etiology and encourage future studies on potential drug targets for BRCAness breast tumors. PMID- 26610814 TI - Under-treatment of elderly patients with ovarian cancer: a population based study. AB - BACKGROUND: Ovarian cancer is the fourth most common cancer among women in France, and mainly affects the elderly. The primary objective of this study was to compare treatment of ovarian cancer according to age. METHODS: All patients with invasive cancer (n=1151) diagnosed between 1997 and 2011 in the Herault Department of southern France were included. Demographic data (age, area of residence), cancer characteristics (stage, histology, grade) and treatment modality (type, period and location of treatment) were analysed. Univariate and multivariate logistic regression was used to compare treatment by age. RESULTS: Ovarian cancer was less treated in elderly compared to younger patients, regardless of the type of treatment. This difference was more pronounced for chemotherapy, and was maximal for surgery followed by chemotherapy (odds ratio (OR) for surgery for patients aged >70 vs those aged <70 years=0.47 [0.24-0.91], OR for chemotherapy, age>70 vs <70=0.30 [0.16-0.55] and OR for surgery plus chemotherapy, age>70 vs <70=0.14 [0.08-0.28]). This effect of age was independent of other variables, including stage and grade. The probability of receiving standard treatment, in accordance with recommendations, was reduced by 50% in elderly patients compared to their younger counterparts. Overall and net survival of elderly patients with standard treatment was similar to those of younger patients treated outside standard treatment. CONCLUSIONS: Elderly women with ovarian cancer were therapeutically disadvantaged compared to younger women. Further studies including co morbidities are necessary to refine these results and to improve therapeutic management of elderly patients with ovarian cancer. PMID- 26610815 TI - Free radicals and related reactive species as mediators of tissue injury and disease: implications for Health. AB - A radical is any molecule that contains one or more unpaired electrons. Radicals are normal products of many metabolic pathways. Some exist in a controlled (caged) form as they perform essential functions. Others exist in a free form and interact with various tissue components. Such interactions can cause both acute and chronic dysfunction, but can also provide essential control of redox regulated signaling pathways. The potential roles of endogenous or xenobiotic derived free radicals in several human pathologies have stimulated extensive research linking the toxicity of numerous xenobiotics and disease processes to a free radical mechanism. In recent years, improvements in analytical methodologies, as well as the realization that subtle effects induced by free radicals and oxidants are important in modulating cellular signaling, have greatly improved our understanding of the roles of these reactive species in toxic mechanisms and disease processes. However, because free radical-mediated changes are pervasive, and a consequence as well as a cause of injury, whether such species are a major cause of tissue injury and human disease remains unclear. This concern is supported by the fact that the bulk of antioxidant defenses are enzymatic and the findings of numerous studies showing that exogenously administered small molecule antioxidants are unable to affect the course of most toxicities and diseases purported to have a free radical mechanism. This review discusses cellular sources of various radical species and their reactions with vital cellular constituents, and provides examples of selected disease processes that may have a free radical component. PMID- 26610816 TI - Erratum. PMID- 26610817 TI - Erratum: Autophagy and endosomal trafficking inhibition by Vibrio cholerae MARTX toxin phosphatidylinositol-3-phosphate-specific phospholipase A1 activity. PMID- 26610818 TI - Presynaptic and postsynaptic regulation of muscle contractions in the ascarid nematode Ascaris suum: a target for drug action. AB - The aim of this study was to determine the role in contractions of postsynaptic nicotinic acetylcholine (nACh) and gamma-aminobutyric acid (GABA) receptors, in the bag region of Ascaris suum muscle cells, as well as the role of synaptic receptors between interneurons and motor neurons in the dorsal and ventral nerve cord. We have measured the isometric contractions of isolated segments of A. suum, with or without the nerve cord (dorsal or ventral). Contractions were caused by increasing concentrations of ACh or by electrical field stimulation (EFS). Based on our results, the presence of the nerve cord is essential for the contractile effects of ACh. The EC50 value of ACh for innervated muscle strips was 10.88 MUm. Unlike intact (innervated) preparations, there was no contraction of the muscle flaps when the nerve cord was mechanically removed. Furthermore, continuous EFS produced stable contractions of innervated muscle strips, but they are not sensitive to mecamylamine (100 MUm). However, GABA (30 MUm) significantly inhibited the EFS-induced contractions. EFS with the same characteristics did not cause muscle contractions of denervated muscle strips, but EFS with a wider pulse induced the increasing of tone and irregular contractions. These contractions were completely insensitive to the effect of GABA. The EC50 for ACh did not differ between the dorsal and ventral segments (9.83 MUm and 9.45 MUm), while GABA exhibited features of competitive and non-competitive antagonists, regardless of whether it acted on the dorsal or ventral segments of A. suum. It is obvious that drugs will be more effective if they act on both the synaptic and extrasynaptic nACh and GABA receptors. PMID- 26610819 TI - Billions with oral disease: A global health crisis--a call to action. PMID- 26610820 TI - Scaling and root planing. PMID- 26610821 TI - More about scaling and root planing. PMID- 26610822 TI - Laser use in scaling and root planing. PMID- 26610823 TI - Authors' response. PMID- 26610824 TI - Local anesthetics in pregnancy. PMID- 26610825 TI - Authors' response. PMID- 26610826 TI - More on local anesthetics in pregnancy. PMID- 26610827 TI - Authors' response. PMID- 26610828 TI - Authors' response. PMID- 26610829 TI - E-cigarettes. PMID- 26610830 TI - Addressing dentistry's "busyness problem". PMID- 26610831 TI - More on the "busyness problem". PMID- 26610833 TI - Mobile health application for remote oral cancer surveillance. AB - BACKGROUND: To determine the effectiveness of a mobile phone-based remote oral cancer surveillance program (Oncogrid) connecting primary care dental practitioners and frontline health care workers (FHW) with oral cancer specialists. METHODS: The study population (N = 3,440) included a targeted cohort (n = 2,000) and an opportunistic cohort (n = 1,440) screened by FHW and dental professionals, respectively. The authors compared the screening efficacy in both groups, with specialist diagnosis considered the reference standard. The outcomes measured were lesion detection and capture of interpretable images of the oral cavity. RESULTS: In the targeted cohort, among 51 of 81 (61%) interpretable images, 23 of 51 (45%) of the lesions were confirmed by specialists, while the opportunistic cohort showed 100% concordance with the specialists (106 of 106). Sixty-two of 129 (48%) of the recommended patients underwent biopsy; 1 of 23 (4%) were in the targeted cohort, and 61 of 106 (57%) were in the opportunistic cohort. Ninety percent of the lesions were confirmed to be malignant or potentially malignant. CONCLUSIONS: The mobile health-based approach adopted in this study aided remote early detection of oral cancer by primary care dental practitioners in a resource-constrained setting. Further optimization of this program is required to adopt the system for FHW. Evaluation of its efficacy in a larger population is also warranted. PRACTICAL IMPLICATIONS: The increased efficiency of early detection by dentists, when assisted by a remote mobile health-based approach, is a step toward a more effective oral cancer screening program. PMID- 26610832 TI - Dental disease patterns in methamphetamine users: Findings in a large urban sample. AB - BACKGROUND: The authors used a large community sample of methamphetamine (MA) users to verify the patterns and severity of dental disease and establish a hierarchy of caries susceptibility by tooth type and tooth surface. METHODS: Using a stratified sampling approach, 571 MA users received comprehensive oral examinations and psychosocial assessments. Three calibrated dentists characterized dental and periodontal disease by using National Health and Nutrition Examination Survey protocols. The authors also collected data on substance use history and other attributes linked to dental disease. RESULTS: On all dental outcome measures, MA users evidenced high dental and periodontal disease, with older (>= 30 years) and moderate or heavy MA users disproportionately affected. Women had higher rates of tooth loss and caries, as well as a greater prevalence of anterior caries. Current cigarette smokers were more likely to manifest 5 or more anterior surfaces with untreated caries and 3 or more teeth with root caries. Nearly 3% were edentulous, and a significant percentage (40%) indicated embarrassment with their dental appearance. CONCLUSIONS: MA users have high rates of dental and periodontal disease and manifest a dose-response relationship, with greater levels of MA use associated with higher rates of dental disease. Women and current cigarette smokers are affected disproportionately. The intraoral patterns and hierarchy of caries susceptibility in MA users are distinctive. PRACTICAL IMPLICATIONS: The prevalence and patterns of dental and periodontal disease could be used to alert dentists to possible covert MA use and to plan treatment. Concerns about dental appearance have potential as triggers for behavioral interventions. PMID- 26610835 TI - Correlation of flexural strength of coupons versus strength of crowns fabricated with different zirconia materials with and without aging. AB - BACKGROUND: The purpose of this study was to determine the presence of a correlation between flexural strength and simulated crown strength; a correlation between crown strength and mode of fracture; an effect of aging on the flexural strength; and an effect of aging on the crown strength. METHODS: Two hundred forty zirconia specimens were fabricated with 2 different designs, fully contoured crown shape specimens (n = 120) and rectangular coupons (n = 120), to provide 10 specimens each of 6 brands of zirconia (Lava Plus High Translucency [3M ESPE], Argen HT [Argen Corp], Zirlux [Ardent], BruxZir [Glidewell Laboratories], ZenoStar [Wieland Dental], and DDBioZX(2) [Dental Direkt]). One half of each sample type was given a severe, simulated low-temperature aging treatment. The coupons were tested by 3-point flexural strength, and crowns were tested after luting to metallic abutments using resin cement. Statistical significance was evaluated by 2-factor analysis of variance (P = .05). RESULTS: Aging increased the mean (standard deviation [SD]) flexural strength for the following groups: Argen HT (995 [140] megapascals versus 677 [121] MPa before aging), Zirlux (939 [101] MPa versus 826 [169] MPa before aging), and ZenoStar (954 [81] MPa versus 764 [77] MPa before aging). There were statistical differences for the mean (SD) crown strengths for the following aged crowns: DDBioZX(2) had higher magnitudes (9,755 [1,095] MPa) than ZenoStar (8,864 [976] MPa), whereas Lava Plus High Translucency crowns had higher magnitudes (9,871 [942] MPa) than ZenoStar (8,864 [976] MPa). There was no effect of aging on the crown strength. There were statistical differences in the mode of fracture for the zirconia crowns between the following groups: nonaged and aged BruxZir (P = .014), nonaged and aged ZenoStar (P = .0226), and nonaged and aged Lava Plus High Translucency (P < .0001). There was no correlation between flexural strength and crown strength. CONCLUSIONS: There was no direct correlation between ranking of flexural strength and crown strength in the range of properties exhibited by these dental zirconias. PRACTICAL IMPLICATIONS: Flexural strength does not predict simulated clinical strengths for crowns. PMID- 26610834 TI - Repair or replacement of restorations: A prospective cohort study by dentists in The National Dental Practice-Based Research Network. AB - BACKGROUND: A prospective cohort study that included dentists in The National Dental Practice-Based Research Network was conducted to quantify 12-month failures of restorations that were repaired or replaced at baseline. The study tested the hypothesis that no significant differences exist in failure percentages between repaired and replaced restorations after 12 months. It also tested the hypothesis that certain dentist, patient, and restoration characteristics are significantly associated with the incidence of restoration failure. METHODS: Dentists recorded data for 50 or more consecutive defective restorations. The restorations that were either repaired or replaced were recalled after 12 months and characterized for developing defects. RESULTS: Dentists (N = 195) recorded data on 5,889 restorations; 378 restorations required additional treatment (74 repaired, 171 replaced, 84 teeth received endodontic treatment, and 49 were extracted). Multivariable logistic regression analysis indicated that additional treatment was more likely to occur if the original restoration had been repaired (7%) compared with replaced (5%) (odds ratio [OR], 1.6; P < .001; 95% confidence interval [CI], 1.2-2.1), if a molar was restored (7%) compared with premolars or anterior teeth (5% and 6%, respectively) (OR, 1.4; P = .010; 95% CI, 1.1-1.7), and if the primary reason was a fracture (8%) compared with other reasons (6%) (OR, 1.3; P = .033; 95% CI, 1.1-1.6). CONCLUSIONS: An additional treatment was more likely to occur within the first year if the original restoration had been repaired (7%) compared with being replaced (5%). However, repaired restorations were less likely to need an aggressive treatment (replacement, endodontic treatment, or extraction) than replaced restorations. PRACTICAL IMPLICATIONS: One year after repair or replacement of a defective restoration, the failure rate was low. However, repaired restorations were less likely to need an aggressive treatment than replaced restorations. PMID- 26610836 TI - Simple indicators for projecting short-term dental market fluctuations. AB - BACKGROUND: There have been fluctuations over time in dental care expenditures in the United States. This project aims to develop simple indicators that are easily available to people and that can be useful to predict short-term market fluctuations. METHODS: The authors analyzed data concerning 30 variables for the period of 1980 through 2012 for correlations with dental care expenditures during that period, looking for factors that historically moved in a highly correlated manner, either positively or negatively, with dental care expenditures. The authors lagged the factors to determine their potential predictive value for dental care expenditures. RESULTS: Personal consumption expenditures and gross domestic product emerged as valid leading indicators for predicting short-term dental market fluctuations. CONCLUSION: Two simple measures that are easily available to dentists and others can serve as indicators of short-term fluctuations in the dental marketplace. Their validity as indicators can, and should, be monitored regularly. PRACTICAL IMPLICATIONS: These indicators can be of significant value for practitioners in being alerted to potential market changes and planning to accommodate these changes. Combined, these factors can tell what changes are coming and when they have arrived. PMID- 26610837 TI - A practical approach to evidence-based dentistry: X: How to avoid being misled by clinical studies' results in dentistry. AB - BACKGROUND AND OVERVIEW: Clinicians using evidence to inform decisions on a daily basis have access to a number of tools to help them judge the importance of discriminating studies conducted using suboptimal methods from more rigorous ones. Many checklists have been developed to facilitate and guide clinicians to identify and critically appraise clinical studies. However, only limited guidance is available addressing how clinicians can identify misleading claims from those that can be supported reliably by study results. PRACTICAL IMPLICATIONS: In this final article of a series of 10, the authors provide key concepts that clinicians can use to help them avoid using biased inferences or statements that are "too good to be true." PMID- 26610838 TI - The evolution of thinking about temporomandibular pain. PMID- 26610839 TI - Short-term oral antibiotics may be as effective as the standard course of penicillin for children with acute streptococcal pharyngitis. PMID- 26610840 TI - Ethical obligations when concerned about the work of another dentist. PMID- 26610841 TI - For the patient. Targeting bad breath. PMID- 26610842 TI - Same data, different structures: diastereoisomers with substantially identical NMR data from nature. AB - Fusarins G1/G2 (1/2) and G3/G4 (3/4), two sets of interesting examples of diastereoisomers with substantially identical NMR data, were discovered from natural products. The reason was discussed and the generally applicable determinant conditions were proposed. The minimum interval for stereoclusters to be entirely segregated was also discussed. PMID- 26610843 TI - Supplemental vibrational force does not reduce pain experience during initial alignment with fixed orthodontic appliances: a multicenter randomized clinical trial. AB - This prospective randomized trial investigated the effect of supplemental vibrational force on orthodontic pain during alignment with fixed-appliances. Eighty-one subjects < 20 years-old undergoing extraction-based fixed-appliance treatment were randomly allocated to supplementary (20-minutes/day) use of an intra-oral vibrational device (AcceleDent((r))) (n = 29); an identical non functional (sham) device (n = 25) or fixed-appliances only (n = 27). Each subject recorded pain intensity (using a 100-mm visual-analogue scale) and intake of oral analgesia in a questionnaire, following appliance-placement (T1) and first adjustment (T2) for 1-week (immediately-after, 4, 24, 72-hours and at 1-week). Mean maximum-pain for the total sample was 72.96 mm [SD 21.59; 95%CI 68.19-77.74 mm] with no significant differences among groups (P = 0.282). Subjects taking analgesics reported slightly higher maximum-pain although this was not significant (P = 0.170). The effect of intervention was independent of analgesia (P = 0.883). At T1 and T2, a statistically and clinically significant increase in mean pain was seen at 4 and 24-hours, declining at 72-hours and becoming insignificant at 1-week. For mean alignment-rate, pain-intensity and use of analgesics, no significant differences existed between groups (P > 0.003). The only significant predictor for mean pain was time. Use of an AcceleDent vibrational device had no significant effect on orthodontic pain or analgesia consumption during initial alignment with fixed appliances. PMID- 26610844 TI - Summary of anti-malarial prophylactic efficacy of tafenoquine from three placebo controlled studies of residents of malaria-endemic countries. AB - BACKGROUND: Tafenoquine is a long half-life primaquine analog being developed for malaria prophylaxis. The US Army recently performed a unified analysis of efficacy in preparation for a regulatory submission, utilizing legacy data from three placebo-controlled studies conducted in the late 1990s and early 2000s. The subjects were residents of Africa who were naturally exposed to Plasmodium falciparum for 12-26 weeks. METHODS: The prophylactic efficacy of tafenoquine and mefloquine (included in some studies as a comparator) was calculated using incidence density among subjects who had completed the three-day loading doses of study drug, had at least one maintenance dose and had at least one blood smear assessed during the prophylactic period. The three placebo-controlled studies were analysed separately and then in two pooled analyses: one for tafenoquine versus placebo (three studies) and one for tafenoquine and mefloquine versus placebo (two studies). RESULTS: The pooled protective efficacy (PE) of a tafenoquine regimen with three daily loading doses plus weekly maintenance at 200 mg for 10 weeks or longer (referred to as 200-mg weekly hereafter) relative to placebo in three placebo-controlled studies was 93.1 % [95 % confidence interval (CI) 89.1-95.6 %; total N = 492]. The pooled PEs of regimens of tafenoquine 200 mg weekly and mefloquine 250-mg weekly relative to placebo in two placebo controlled studies (total N = 519) were 93.5 % (95 % CI 88.6-96.2 %) and 94.5 % (95 % CI 88.7-97.3 %), respectively. Three daily loading plus weekly maintenance doses of 50- and 100-mg, but not 25-mg, exhibited similar PEs. The PEs of tafenoquine regimens of a three-day loading dose at 400-mg with and without follow-up weekly maintenance doses at 400-mg were 93.7 % (95 % CI 85.4-97.3 %) and 81.0 % (95 % CI 66.8-89.1 %), respectively. CONCLUSIONS: Tafenoquine provided the same level of prophylactic efficacy as mefloquine in residents of Africa. These data support the prophylactic efficacy of tafenoquine and mefloquine that has already been demonstrated in the intended malaria naive population. PMID- 26610846 TI - BMA welcomes government's U turn on Acas talks ahead of planned strike. PMID- 26610845 TI - Association of Retinoid X Receptor Alpha Gene Polymorphism with Clinical Course of Chronic Glomerulonephritis. AB - BACKGROUND Vitamin D (VD), VD binding protein, VD receptor (VDR), and retinoids are involved in pathogenesis of chronic glomerulonephritis (ChGN). We aimed to compare distribution of VD pathway gene polymorphisms in ChGN patients showing glomerular filtration rate (GFR) category 1-3, GFR category 5D, and healthy controls in order to elucidate the role of VD-related polymorphisms in the course of ChGN. MATERIAL AND METHODS GFR category 1-3 ChGN patients (n=195), GFR category 5D ChGN patients (n=178), and controls (n=751) underwent testing for polymorphisms of genes encoding VD binding protein (GC, rs2298849, rs7041, rs1155563), VDR (VDR, rs2228570, rs1544410), and retinoid X receptor alpha (RXRA, rs10776909, rs10881578, rs749759). RESULTS Among GFR 1-3 subjects possessing TT genotype of RXRA rs10776909, 75% of patients had nephrotic syndrome, and 37.5% had glomerular hyperfiltration defined as GFR >140 ml/min/1.73 m2, and, consequently, serum creatinine was lower in these patients compared to the remaining subjects (0.67+/-0.26 vs. 0.94+/-0.34, P=0.014). In GFR category 5D ChGN patients, frequencies of RXRA rs10776909 allele T (25% vs. 19%) and CT+TT (46% vs. 34%) were higher compared to frequencies of respective variants in controls (Ptrend=0.004, Pgenotype=0.008). CONCLUSIONS RXRA rs10776909 allele T is specifically involved in the pathogenesis of ChGN. This risk allele may be also associated with worse clinical course of ChGN. PMID- 26610847 TI - Impulsive Driving: Definition and Measurement Using the I-Driving Scale (IDS). AB - Impulsivity has been widely studied in the context of traffic. The trait is believed to be the root of some accidents, along with other variables like aggression and anger. The present research objective is to develop a new scale - the I-Driving Scale (IDS) - to evaluate and measure the construct of impulsivity in specific driving situations. To that end, two studies were conducted, with 162 and 107 participants, respectively. In both studies, participants were recruited via their social networks, and answered anonymously. In addition to the IDS, they completed the Use the Vehicle to Express Anger subscale of the Driving Anger Expression Inventory (DAX), the Driving Anger Scale (DAS), and the Barratt Impulsivity Scale (BIS11), and also provided demographic information. The final scale had 11 items falling into two factors: impatience, and aggressiveness/abruptness. The results show a high consistency (alphaT = .81, alphaI = .70, and alphaA = .85 in the first study; alphaT = .83, alphaI = .80, and alphaA = .88 in the second study). Statistical results of Exploratory Factor Analysis in the first sample indicated goodness of fit to a two-factor model (RMSR = .057, GFI = .98). The second study confirmed that factorial structure (chi2/df = 80.50/43 = 1.87, RMSEA = .088, CFI = .94, TLI = .92). Correlations with other measures indicated the Impatience subscale is associated with different expressions of anger behind the wheel, and directly correlated with the loss of driver's license points. Furthermore, the Aggressiveness or Abruptness subscale was associated with more mechanical aspects, and correlated inversely with age. PMID- 26610848 TI - High Efficiency Organic/Silicon-Nanowire Hybrid Solar Cells: Significance of Strong Inversion Layer. AB - Organic/silicon nanowires (SiNWs) hybrid solar cells have recently been recognized as one of potentially low-cost candidates for photovoltaic application. Here, we have controllably prepared a series of uniform silicon nanowires (SiNWs) with various diameters on silicon substrate by metal-assisted chemical etching followed by thermal oxidization, and then fabricated the organic/SiNWs hybrid solar cells with poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate) ( PEDOT: PSS). It is found that the reflective index of SiNWs layer for sunlight depends on the filling ratio of SiNWs. Compared to the SiNWs with the lowest reflectivity (LR-SiNWs), the solar cell based on the SiNWs with low filling ratio (LF-SiNWs) has a higher open-circuit voltage and fill factor. The capacitance-voltage measurements have clarified that the built-in potential barrier at the LF-SiNWs/ PEDOT: PSS interface is much larger than that at the LR-SiNWs/PEDOT one, which yields a strong inversion layer generating near the silicon surface. The formation of inversion layer can effectively suppress the carrier recombination, reducing the leakage current of solar cell, and meanwhile transfer the LF-SiNWs/ PEDOT: PSS device into a p-n junction. As a result, a highest efficiency of 13.11% is achieved for the LF-SiNWs/ PEDOT: PSS solar cell. These results pave a way to the fabrication of high efficiency organic/SiNWs hybrid solar cells. PMID- 26610849 TI - Retraction Note: Chronic neuroinflammation and cognitive impairment following transient global cerebral ischemia: role of fractalkine/CX3CR1 signaling. AB - This article [1] has been retracted by the Editors-in-Chief. Based on the report of an inquiry conducted by Wayne State University and additional analysis conducted by the Office of Research Integrity (ORI) [2], the ORI informed the journal that the first author Dr Teresita L. Briones engaged in research misconduct by falsifying and/or fabricating data by falsely reporting the results of Western blot experiments, and that data reported in Figures 2A and 2C in [1] were duplicated, reused and falsely relabelled, and claimed to represent different experiments. We have not been able to contact any of the authors. PMID- 26610850 TI - Small-scale pig farmers' behavior, silent release of African swine fever virus and consequences for disease spread. AB - The expanding distribution of African swine fever (ASF) is threatening the pig industry worldwide. Most outbreaks occur in backyard and small-scale herds, where poor farmers often attempt to limit the disease's economic consequences by the emergency sale of their pigs. The risk of African swine fever virus (ASFV) release via this emergency sale was investigated. Simulation modeling was used to study ASFV transmission in backyard and small-scale farms as well as the emergency sale of pigs, and the potential impact of improving farmers and traders' clinical diagnosis ability-its timeliness and/or accuracy-was assessed. The risk of ASFV release was shown to be high, and improving farmers' clinical diagnosis ability does not appear sufficient to effectively reduce this risk. Estimates obtained also showed that the distribution of herd size within the backyard and small-scale sectors influences the relative contribution of these farms to the risk of release of infected pigs. These findings can inform surveillance and control programs. PMID- 26610851 TI - Deferrisoma palaeochoriense sp. nov., a thermophilic, iron(III)-reducing bacterium from a shallow-water hydrothermal vent in the Mediterranean Sea. AB - A novel thermophilic, anaerobic, mixotrophic bacterium, designated strain MAG PB1T, was isolated from a shallow-water hydrothermal vent system in Palaeochori Bay off the coast of the island of Milos, Greece. The cells were Gram-negative, rugose, short rods, approximately 1.0 MUm long and 0.5 MUm wide. Strain MAG-PB1T grew at 30-70 degrees C (optimum 60 degrees C), 0-50 g NaCl l- 1 (optimum 15-20 g l- 1) and pH 5.5-8.0 (optimum pH 6.0). Generation time under optimal conditions was 2.5 h. Optimal growth occurred under chemolithoautotrophic conditions with H2 as the energy source and CO2 as the carbon source. Fe(III), Mn(IV), arsenate and selenate were used as electron acceptors. Peptone, tryptone, Casamino acids, sucrose, yeast extract, d-fructose, alpha-d-glucose and ( - )-d-arabinose also served as electron donors. No growth occurred in the presence of lactate or formate. The G+C content of the genomic DNA was 66.7 mol%. Phylogenetic analysis of the 16S rRNA gene sequence indicated that this organism is closely related to Deferrisoma camini, the first species of a recently described genus in the Deltaproteobacteria. Based on the 16S rRNA gene phylogenetic analysis and on physiological, biochemical and structural characteristics, the strain was found to represent a novel species, for which the name Deferrisoma palaeochoriense sp. nov. is proposed. The type strain is MAG-PB1T ( = JCM 30394T = DSM 29363T). PMID- 26610852 TI - Transcriptome profiling reveals that feeding wild zooplankton to larval Atlantic cod (Gadus morhua) influences suites of genes involved in oxidation-reduction, mitosis, and selenium homeostasis. AB - BACKGROUND: Larval nutrition and growth are key issues for wild and cultured cod. While it was shown previously that larval cod fed wild zooplankton grow faster than those fed only rotifers, the mechanisms involved in this enhanced growth are not completely understood. We used microarrays to identify larval cod transcripts that respond to feeding with small amounts of wild zooplankton (5-10 % of live prey items). The larval transcriptome was compared between 3 treatment groups [fed rotifers (RA), rotifers with protein hydrolysate (RA-PH), or rotifers with zooplankton (RA-Zoo)] at 9-10 mm length [26-30 days post-hatch (dph)] to identify a robust suite of zooplankton-responsive genes (i.e. differentially expressed between RA-Zoo and both other groups). RESULTS: The microarray experiment identified 147 significantly up-regulated and 156 significantly down-regulated features in RA-Zoo compared with both RA and RA-PH. Gene ontology terms overrepresented in the RA-Zoo responsive gene set included "response to selenium ion" and several related to cell division and oxidation-reduction. Ten selenoprotein-encoding genes, and 2 genes involved in thyroid hormone generation, were up-regulated in RA-Zoo compared with both other groups. Hierarchical clustering of RA-Zoo responsive genes involved in oxidation-reduction and selenium homeostasis demonstrated that only the zooplankton treatment had a considerable and consistent impact on the expression of these genes. Fourteen microarray-identified genes were selected for QPCR involving 9-13 mm larvae, and 13 of these were validated as differentially expressed between RA-Zoo and both other groups at ~9 mm. In contrast, in age-matched (34-35 dph; ~11 mm RA and RA PH, ~13 mm RA-Zoo) and size-matched (~13 mm) older larvae, only 2 and 3 genes, respectively, showed the same direction of RA-Zoo-responsive change as in ~9 mm larvae. CONCLUSIONS: The modulation of genes involved in selenium binding, redox homeostasis, and thyroid hormone generation in ~9 mm RA-Zoo larvae in this study may be in response to the relatively high levels of selenium, iodine, and LC-PUFA (potentially causing oxidative stress) in zooplankton. Nonetheless, only a subset of zooplankton-responsive genes in ~9 mm larvae remained so in older larvae, suggesting that the observed transcriptome changes are largely involved in initiating the period of growth enhancement. PMID- 26610853 TI - Palliative sedation: more data and fewer opinions. PMID- 26610854 TI - Effect of continuous deep sedation on survival in patients with advanced cancer (J-Proval): a propensity score-weighted analysis of a prospective cohort study. AB - BACKGROUND: Continuous deep sedation (CDS) before death is a form of palliative sedation therapy that has become a focus of strong debate, especially with respect to whether it shortens survival. We aimed to examine whether CDS shortens patient survival using the propensity score-weighting method, and to explore the effect of artificial hydration during CDS on survival. METHODS: This study was a secondary analysis of a large multicentre prospective cohort study that recruited and followed up patients between Sept 3, 2012, and April 30, 2014, from 58 palliative care institutions across Japan, including hospital palliative care settings, inpatient palliative care units, and home-based palliative care services. Adult patients (aged >= 20 years) with advanced cancer who received care through the participating palliative care services were eligible for this secondary analysis. Patients with missing data for outcome variables or who lived for more than 180 days were excluded. We compared survival after enrolment between patients who did and did not receive CDS. We used a propensity score weighting method to control for patient characteristics, disease status, and symptom burden at enrolment. FINDINGS: Of 2426 enrolled patients with advanced cancer, we excluded 289 (12%) for living longer than 180 days and 310 (13%) with missing data, leaving an analysis population of 1827 patients. 269 (15%) of 1827 patients received CDS. Unweighted median survival was 27 days (95% CI 22-30) in the CDS group and 26 days (24-27) in the no CDS group (median difference -1 day [95% CI -5 to 4]; HR 0.92 [95% CI 0.81-1.05]; log-rank p=0.20). After propensity score weighting, these values were 22 days (95% CI 21-24) and 26 days (24-27), respectively (median difference -1 day [95% CI -6 to 4]; HR 1.01 [95% CI 0.87 1.17]; log-rank p=0.91). Age (p(interaction)=0.67), sex (p(interaction)=0.26), performance status (p(interaction)=0.90), and volume of artificial hydration (p(interaction)=0.14) did not have an effect modification on the association between sedation and survival, although care setting did have a significant effect modification (p(interaction)=0.021). INTERPRETATION: CDS does not seem to be associated with a measurable shortening of life in patients with advanced cancer cared for by specialised palliative care services, and could be considered a viable option for palliative care in this setting. FUNDING: Japanese National Cancer Center Research and Development Fund. PMID- 26610855 TI - Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion from a Meckel diverticulum neuroendocrine tumor: case report. AB - BACKGROUND: Ectopic production of adrenocorticotropic hormone (ACTH) by neuroendocrine tumours (NET) is a rare condition, occult presentations often hampering the diagnosis. Although NET are relatively frequent in the ileon and Meckel diverticulum, we describe the first Cushing's syndrome due to ectopic adrenocorticotropic syndrome (CS-EAS) arising from a Meckel diverticulum. CASE PRESENTATION: A 44-year-old man was admitted with recent onset of diabetes, myopathy, edema and hypokalemic metabolic alkalosis consistent with Cushing's syndrome. Both basal and dynamic laboratory evaluation suggested CS-EAS. Laboratory testing also showed high serum levels of chromogranin A (CgA) and urinary 5-hydroxyindoleacetic acid (5HIAA). Pituitary and neck/thorax/abdomen/pelvis imaging proved to be normal, while somatostatin analogue ((99m)Tc-HYNIC-TOC) scintigraphy revealed increased focalized ileum uptake on the right iliac fossa. Pre-operative ketoconazole and sandostatin treatment controlled the hypercortisolism within a month. Pathological analysis of the resected submucosal 1.8 cm tumour of the Meckel diverticulum and a metastatic local lymph node confirmed a well differentiated neuroendocrine tumour (grade I), whereas immunohistochemistry was positive for ACTH, chromogranin A and synaptophysin. Post-operative clinical and biochemical resolution of Cushing's syndrome was followed by normalization of both CgA and 5HIAA, which were maintained at the 6 month follow-up. CONCLUSION: The identification, characterization and follow-up of this rare cause of ectopic ACTH secretion is important in order to assess the long-term prognostic and management. PMID- 26610856 TI - Parathyroid adenoma causing spontaneous cervical hematoma: two case reports. AB - BACKGROUND: Although spontaneous rupture of a cervical parathyroid adenoma with extracapsular hemorrhage is rare, it may cause cervical and mediastinal hematoma, leading to potentially fatal consequences. CASE PRESENTATION: The first case was a 76-year-old Asian female who presented with pharyngeal discomfort and anterior chest ecchymosis. Endoscopic investigation showed submucosal hemorrhage in the pharynx and larynx. The second case was a 62-year-old Asian male who presented with anterior chest ecchymosis and suspected of a ruptured blood vessel. Both cases were diagnosed parathyroid adenoma with extracapsular bleeding by hypercalcemia, high levels of intact parathyroid hormone and presence of a nodule behind the thyroid. Both cases were treated with excision of tumor 7 months after initial presentation. After surgery, serum calcium and parathyroid hormone levels had decreased to normal level in both cases. CONCLUSION: Extracapsular bleeding of a parathyroid adenoma should be considered in the differential diagnosis of non-traumatic neck hematoma. PMID- 26610857 TI - Preoperative Pelvic Floor Muscle Exercise and Postprostatectomy Incontinence: A Systematic Review and Meta-analysis. AB - CONTEXT: Preoperative pelvic floor muscle exercise (PFME) is often prescribed to reduce the severity of postprostatectomy incontinence. OBJECTIVE: Systematic review and meta-analysis of evidence regarding the effect of preoperative PFME on postoperative urinary incontinence following radical prostatectomy. EVIDENCE ACQUISITION: A systematic search was performed of the Cochrane Library, Medline, Embase, and all potential articles from references in relevant articles on 4 October 2014. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Identified reports were critically appraised for quality and relevance. Only studies of preoperative PFME compared with no preoperative PFME were included. EVIDENCE SYNTHESIS: Eleven studies were included based on the selection criteria. The total number of patients included in the final analysis was 739. In seven studies, sufficient quantitative data on postoperative incontinence were available for meta-analysis. At 1 mo, there was no difference in continence rates between the groups (odds ratio [OR]: 0.68; 95% confidence interval [CI], 0.45-1.03). At 3 mo, there was 36% improvement in the preoperative PFME group (OR: 0.64; 95% CI, 0.47-0.88). At 6 mo, there was no difference between groups (OR: 0.60; 95% CI, 0.32-1.15). When examining quality of life measures, four of seven studies demonstrated significant improvement in the preoperative PFME group at 3 mo, and two of these studies demonstrated significant differences at 6 mo. CONCLUSIONS: Preoperative PFME improves postoperative urinary incontinence after radical prostatectomy at 3 mo but not at 6 mo, suggesting it improves early continence but not long-term continence rates. PATIENT SUMMARY: We reviewed all evidence for preoperative pelvic floor muscle exercise (PFME) in treating urinary incontinence following radical prostatectomy. We found evidence to suggest that preoperative PFME improves early continence rates but not long-term continence rates. PMID- 26610858 TI - Androgen Deprivation Therapy (ADT) Plus Docetaxel Versus ADT Alone in Metastatic Non castrate Prostate Cancer: Impact of Metastatic Burden and Long-term Survival Analysis of the Randomized Phase 3 GETUG-AFU15 Trial. AB - BACKGROUND: The role of chemotherapy in metastatic non castrate prostate cancer (mNCPC) is debated. Survival benefits of docetaxel (D) added to androgen deprivation therapy (ADT) were shown in the CHAARTED trial in patients with metastatic high-volume disease (HVD). OBJECTIVE: To assess the impact of metastatic burden and to update overall survival (OS) data of the GETUG-AFU15 study. DESIGN, SETTING, AND PARTICIPANTS: Randomized phase 3 trial of ADT plus D versus ADT alone in 385 mNCPC patients; median follow-up of 7 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary end point was OS. Secondary end points were biochemical progression-free survival (bPFS) and radiographic progression-free survival (rPFS). Retrospective analysis was by tumor volume. RESULTS AND LIMITATIONS: After a median follow-up of 83.9 mo, median OS in the overall population was 62.1 mo (95% confidence interval [CI], 49.5-73.7) and 48.6 mo (95% CI, 40.9-60.6) for ADT plus D and ADT arms, respectively (hazard ratio [HR]: 0.88 [95% CI, 0.68-1.14]; p=0.3). Median OS in ADT plus D and ADT arms, respectively, was for HVD patients: 39.8 mo (95% CI, 28.0-53.4) versus 35.1 mo (95% CI, 29.9-43.6) (HR: 0.78 [95% CI, 0.56-1.09]; p=0.14), for low-volume disease (LVD) patients; median was not reached (NR; 95% CI, 69.5-NR) and 83.4 mo (95% CI, 61.8-NR) (HR: 1.02 [95% CI, 0.67-1.55]; p=0.9). For upfront metastatic patients, OS was 52.6 mo (95% CI, 43.3-66.8) and 41.5 mo (95% CI, 36.3-54.5), respectively (HR: 0.93 [95% CI, 0.69-1.25]; p=0.6). The bPFS (HR: 0.73 [95% CI, 0.56-0.94]; p=0.014) and rPFS (HR: 0.75 [95% CI, 0.58-0.97]; p=0.030) were significantly longer in the ADT plus D arm. Limitations included the retrospective analysis of metastatic extent and the lack of statistical power to detect a significant difference in subgroups. CONCLUSIONS: The post hoc analyses of the GETUG-AFU15 study demonstrated a nonsignificant 20% reduction in the risk of death in the HVD subgroup. Patients with LVD had no survival improvement with early D. PATIENT SUMMARY: In this study, docetaxel added to castration did not improve survival in patients with metastatic hormone-sensitive prostate cancer, partly due to methodological issues. However, early chemotherapy should be discussed with all patients, given the data of three randomized trials including GETUG-AFU15. PMID- 26610859 TI - Web-based symptom screening in cystic fibrosis patients: A feasibility study. AB - BACKGROUND: Cystic fibrosis (CF) causes high illness burden. Screening may identify patients who could potentially benefit from interventions for symptoms or other sources of distress. We evaluated the feasibility of a web-based system for routine monitoring. METHODS: Adult CF patients enrolled in a study of palliative care service delivery completed web-based assessments every 30 days on global distress, physical and psychological symptom distress, and the perceived benefits of discussing advance care planning (ACP) with CF clinicians. Feasibility was assessed by the rate of survey completion, survey reminders, and missed surveys during a 9-month rolling enrollment period. RESULTS: Of 74 participants (47.3% women, 94.4% white), 36.7% had comorbid diabetes, and 56.9% had an FEV1% predicted score of 40-69. In total, patients completed 456 (80.6%) of 566 surveys every 30 days over the assessment period. Sixty-five (87.8%) completed 405 (79.7%) of 508 surveys online and 9 (12.2%) completed 51 (88.0%) of 58 surveys using a combination of online, telephone, and mail-based methods. Many surveys were completed without reminders (online: 261 [64.4%] of 405; combined methods: 29 [56.9%] of 51), with 166 (36.4%) surveys requiring 1 or more reminders. Further, 23.0% (17) of patients noted elevated global distress; 20.3% (15) endorsed physical symptom distress, 12.2% (9) had psychological distress, and 58.1% (43) reported that discussing ACP would be beneficial. CONCLUSIONS: Repeated web-based screening for symptom distress and ACP preferences is feasible in adult CF patients. Future studies should assess the system's generalizability and staff resources when implementing reminders and non-web methods of completion. PMID- 26610860 TI - A longitudinal analysis of chronic MRSA and Pseudomonas aeruginosa co-infection in cystic fibrosis: A single-center study. AB - BACKGROUND: Few studies have examined the association between chronic methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PA) co infection and health outcomes despite evidence that these pathogens alone contribute to higher morbidity and mortality in cystic fibrosis (CF). This study examines outcomes among CF patients with chronic MRSA and PA co-infection compared with patients with either or neither of these organisms. METHODS: CF patients attending the care center in Atlanta, GA from 2007-2013 comprised the study cohort. Chronic co-infection was defined as >50% PA+ cultures and >50% MRSA+ cultures and modeled as time-varying. The rate of decline in lung function (FEV1) and the rate of IV treatments were the main outcomes. RESULTS: Among all patients (N=354), chronic co-infection was associated with a significantly more rapid rate of FEV1 decline compared with patients with chronic PA alone [adjusted difference: -0.60% predicted/year (-1.13, -0.08)] and chronic MRSA alone [adjusted difference: -0.89% predicted/year (-1.56, -0.22)]. Rate of IV treatments was significantly higher among patients with chronic co-infection compared with patients with chronic PA alone [adjusted IRR: 1.24 (1.01, 1.52)] and chronic MRSA alone [adjusted IRR: 1.34 (1.03, 1.74)]. CONCLUSIONS: Data from the Atlanta Care Center suggest that chronic MRSA and PA co-infection may be associated with increased rate of lung function decline and rate of intravenous antibiotics compared with patients with either pathogen alone. PMID- 26610861 TI - Self-renewal of human embryonic stem cells on defined synthetic electrospun nanofibers. AB - Human embryonic stem cells (hESCs) are conventionally expanded and maintained in vitro on biological substrates. Synthetic electrospun polymer nanofibers have the potential to act as non-biological substrates in the culture of hESCs. Three synthetic, FDA approved polymers: poly-E-caprolactone (PCL), poly-L-lactic acid (PLLA) and poly lactic-co-glycolic acid (PLGA) were electrospun as nanofibers (random or aligned conformations) on glass coverslips and their supportive role in hESC culture examined. Clonogenicity experiments demonstrated that nanofibrous scaffolds (PCL aligned and random, PLLA aligned and PLGA aligned) supported hESC adhesion and expansion. A significantly greater number of colonies were observed on PCL-aligned nanofibrous scaffolds in comparison to PLLA-aligned and PLGA aligned substrates (p < 0.05). hESC colonies were significantly larger on PCL aligned nanofibrous substrates when compared to other polymer substrates (p < 0.05-0.001), where fiber diameter played a pivotal role in support of hESC clonogenicity (on PCL). Retention of pluripotentiality was confirmed by expression of Alkaline phosphatase, OCT-3/4 and Nanog expression on PCL scaffolds and the expression of transcripts representative of mesoderm (ACTC1), ectoderm (SOX1) and endoderm (AFP) during subsequent spontaneous in vitro differentiation. These results demonstrate the potential of nanofibers as xeno-free scaffolds supportive of hESC adhesion, self-renewal and differentiation in in vitro culture conditions. PMID- 26610862 TI - Low density lipoprotein receptor-related protein 1 mediated endocytosis of beta1 integrin influences cell adhesion and cell migration. AB - The low density lipoprotein receptor-related protein 1 (LRP1) has been shown to interact with beta1-integrin and regulate its surface expression. LRP1 knock-out cells exhibit altered cytoskeleton organization and decreased cell migration. Here we demonstrate coupled endocytosis of LRP1 and beta1-integrin and the involvement of the intracellular NPxY2 motif of LRP1 in this process. Mouse embryonic fibroblasts harboring a knock in replacement of the NPxY2 motif of LRP1 by a multiple alanine cassette (AAxA) showed elevated surface expression of beta1 integrin and decreased beta1-integrin internalization rates. As a consequence, cell spreading was altered and adhesion rates were increased in our cell model. Cells formed more focal adhesion complexes, whereby in vitro cell migration rates were decreased. Similar results could be observed in a corresponding mouse model, the C57Bl6 LRP1 NPxYxxL knock in mice, therefore, the biochemistry of cellular adhesion was altered in primary cortical neurons. In vivo cell migration experiments demonstrated a disturbance of neuroblast cell migration along the rostral migratory stream. In summary, our results indicate that LRP1 interacts with beta1-integrin mediating integrin internalization and thus correlates with downstream signaling of beta1-integrin such as focal adhesion dynamics. Consequently, the disturbance of this interaction resulted in a dysfunction in in vivo and in vitro cell adhesion and cell migration. PMID- 26610863 TI - Engineering macrophages to control the inflammatory response and angiogenesis. AB - Macrophage (MPhi) dysregulation is increasingly becoming recognized as a risk factor for a number of inflammatory complications including atherosclerosis, cancer, and the host response elicited by biomedical devices. It is still unclear what roles the pro-inflammatory (M1) MPhi and pro-healing (M2) MPhi phenotypes play during the healing process. However, it has been shown that a local overabundance of M1 MPhis can potentially lead to a chronically inflamed state of the tissue; while a local over-exuberant M2 MPhi response can lead to tissue fibrosis and even promote tumorigenesis. These notions strengthen the argument that the tight temporal regulation of this phenotype balance is necessary to promote inflammatory resolution that leads to tissue homeostasis. In this study, we have engineered pro-inflammatory MPhis, MPhi-cTLR4 cells, which can be activated to a M1-like MPhi phenotype with a small molecule, the chemical inducer of dimerization (CID) drug. The MPhi-cTLR4 cells when activated with the CID drug, express increased levels of TNFalpha, IL-6, and iNOS. Activated MPhi-cTLR4 cells stay stimulated for at least 48h; once the CID drug is withdrawn, the MPhi cTLR4 cells return to baseline state within 18h. Further, in vitro CID-activated MPhi-cTLR4 cells induce upregulation of VCAM-1 and ICAM-1 on endothelial cells (EC) in a TNFalpha-dependent manner. With the ability to specifically modulate the MF-cTLR4 cells with the presence or absence of a small molecule, we now have the tool necessary to observe a primarily M1 MF response during inflammation. By isolating this phase of the wound healing response, it may be possible to determine conditions for ideal healing. PMID- 26610864 TI - Noise-assisted energy transport in electrical oscillator networks with off diagonal dynamical disorder. AB - Noise is generally thought as detrimental for energy transport in coupled oscillator networks. However, it has been shown that for certain coherently evolving systems, the presence of noise can enhance, somehow unexpectedly, their transport efficiency; a phenomenon called environment-assisted quantum transport (ENAQT) or dephasing-assisted transport. Here, we report on the experimental observation of such effect in a network of coupled electrical oscillators. We demonstrate that by introducing stochastic fluctuations in one of the couplings of the network, a relative enhancement in the energy transport efficiency of 22.5 +/- 3.6% can be observed. PMID- 26610865 TI - Clinical experience of infective endocarditis complicated by acute cerebrovascular accidents. AB - BACKGROUND/OBJECTIVE: To evaluate the clinical results of patients with infective endocarditis (IE) complicated by acute cerebrovascular accidents (CVAs). METHODS: A total of 44 patients with IE complicated by CVA at admission were retrospectively analyzed in a single medical institute from 2005 to 2011. At the time of admission, 18 patients were diagnosed with hemorrhagic stroke, and 26 patients were diagnosed with ischemic stroke. Fifteen patients received surgical intervention during hospitalization. RESULTS: The hospital mortality rate was 38.9% for the hemorrhagic stroke group and 42.3% for the ischemic stroke group (p = 0.821). The mortality rate was 33.3% for the surgical group and 44.8% for the nonsurgical group (p = 0.531). At 30 days of hospitalization, 45.8% of the patients experienced an adverse event (defined as death due to organ failure, restroke, cardiogenic shock, or septic shock during the treatment period), and the attrition rate was 1.5% per day. Surgery performed after the adverse events increased mortality (80.0%) compared with surgery performed on patients with no adverse events (10.0%; p = 0.017). A Cox regression analysis revealed that creatinine > 2 mg/dL, diabetes, and staphylococcal infection were the risk factors of the adverse events. CONCLUSION: Early surgical intervention for IE with ischemic stroke may prevent adverse events, particularly in patients with impaired renal function, diabetes, or staphylococcal infection. A delay in operation of > 30 days is recommended after hemorrhagic stroke. PMID- 26610866 TI - The tomato HD-Zip I transcription factor SlHZ24 modulates ascorbate accumulation through positive regulation of the D-mannose/L-galactose pathway. AB - Ascorbate (AsA) is an antioxidant that can scavenge the reactive oxygen species (ROS) produced when plants encounter stressful conditions. Here, it was revealed by a yeast one-hybrid assay that a tomato (Solanum lycopersicum) HD-Zip I family transcription factor, SlHZ24, binds to the promoter of an AsA biosynthetic gene encoding GDP-D-mannose pyrophosphorylase 3 (SlGMP3). Both the transient expression system and electrophoretic mobility shift assay (EMSA) showed that SlHZ24 binds to a regulatory cis-element in the SlGMP3 promoter, and further overexpression of SlHZ24 in transgenic tomato lines resulted in increased AsA levels. In contrast, suppressing expression of the gene using RNA interference (RNAi) had the opposite effect. These data suggest that SlHZ24 can positively regulate the accumulation of AsA, and in support of this it was shown that SlGMP3 expression increased in the SlHZ24-overexpressing lines and declined in SlHZ24 RNAi lines. SlHZ24 also affected the expression of other genes in the D-mannose/L galactose pathway, such as genes encoding GDP-mannose-3',5'-epimerase 2 (SlGME2), GDP-L-galactose phosphorylase (SlGGP) and SlGMP4. The EMSA indicated that SlHZ24 bound to the promoters of SlGME2 and SlGGP, suggesting multi-targeted regulation of AsA biosynthesis. Finally, SlHZ24-overexpressing plants showed less sensitivity to oxidative stress; we therefore conclude that SlHZ24 promotes AsA biosynthesis, which in turn enhances oxidative stress tolerance. PMID- 26610867 TI - Risky bicycling behavior among youth with and without attention-deficit hyperactivity disorder. AB - BACKGROUND: Injury risk from car-bicycle collisions is particularly high among youth with attention-deficit hyperactivity disorder (ADHD). Here, we capitalized on advances in virtual environment technology to safely and systematically examine road-crossing behavior among child cyclists with and without ADHD. METHODS: Sixty-three youth (26 with ADHD, 37 non-ADHD controls) ages 10-14 years crossed 12 intersections with continuous cross-traffic while riding a high fidelity bicycling simulator. Traffic density (i.e., temporal gaps between vehicles) was manipulated to examine the impact of varying traffic density on behavioral indices of road crossing, including gap selection, timing of entry into the roadway, time to spare when exiting the roadway, and close calls with oncoming cars. In addition, parents filled out questionnaires assessing their child's ADHD symptomatology, temperamental characteristics, bicycling experience, and injury history. RESULTS: ADHD youth largely chose the same size gaps as non ADHD youth, although ADHD youth were more likely to select smaller gap sizes following exposure to high-density traffic. In addition, youth with ADHD demonstrated poorer movement timing when entering the intersection, resulting in less time to spare when exiting the roadway. Hyperactivity-impulsivity symptoms were specifically associated with selection of smaller gaps, whereas timing deficits were specifically associated with inattention and inhibitory control. CONCLUSION: Findings highlight two related yet potentially dissociable mechanisms that may influence injury risk among youth with ADHD and provide a foundation for development of injury prevention strategies. PMID- 26610868 TI - Do research studies in the UK reporting child neurodevelopment adjust for the variability of assessors: a systematic review. AB - AIM: Neurodevelopment is a key outcome for many childhood trials and observational studies. Clinically important decisions may rest on finding relatively small differences in neurodevelopment between groups receiving complex and costly interventions. Our purpose was to determine whether studies which measure neurodevelopment report the numbers, training, and auditing of assessors and, for multiple assessor studies, whether the results were adjusted and if so by which method? METHOD: Electronic searches were conducted using Medline, Embase, Cinahl, PsycINFO, and the Cochrane Library. A study was eligible if it reported neurodevelopmental outcome in children resident in the UK, less than or equal to 18 years and was published between 2000 and 2015. Trials and observational studies were included. RESULTS: Three hundred and seven full papers were reviewed: 52% of papers did not report the number of assessors used; 21% used a single assessor; and 27% used multiple assessors. Thirty-five per cent mentioned that assessors were trained in the use of the neurodevelopmental tool; 13% of assessors were audited; and only 1% of studies adjusted statistically for the number of assessors. INTERPRETATION: At the very least, the quality of reporting the use of assessors in these research publications is poor, while at worst, the variability of assessors may mask the true relationship between an intervention/observation and neurodevelopmental outcome. PMID- 26610869 TI - Granzyme B Deficiency Protects against Angiotensin II-Induced Cardiac Fibrosis. AB - Cardiac fibrosis is observed across diverse etiologies of heart failure. Granzyme B (GzmB) is a serine protease involved in cell-mediated cytotoxicity in conjunction with the pore-forming protein, perforin. Recent evidence suggests that GzmB also contributes to matrix remodeling and fibrosis through an extracellular, perforin-independent process. However, the role of GzmB in the onset and progression of cardiac fibrosis remains elusive. The present study investigated the role of GzmB in the pathogenesis of cardiac fibrosis. GzmB was elevated in fibrotic human hearts and in angiotensin II-induced murine cardiac fibrosis. Genetic deficiency of GzmB reduced angiotensin II-induced cardiac hypertrophy and fibrosis, independently of perforin. GzmB deficiency also reduced microhemorrhage, inflammation, and fibroblast accumulation in vivo. In vitro, GzmB cleaved the endothelial junction protein, vascular endothelial (VE) cadherin, resulting in the disruption of endothelial barrier function. Together, these results suggest a perforin-independent, extracellular role for GzmB in the pathogenesis of cardiac fibrosis. PMID- 26610870 TI - MiR-29-mediated elastin down-regulation contributes to inorganic phosphorus induced osteoblastic differentiation in vascular smooth muscle cells. AB - Vascular calcification increases the risk of cardiovascular mortality. We previously reported that expression of elastin decreases with progression of inorganic phosphorus (Pi)-induced vascular smooth muscle cell (VSMC) calcification. However, the regulatory mechanisms of elastin mRNA expression during vascular calcification remain unclear. MicroRNA-29 family members (miR 29a, b and c) are reported to mediate elastin mRNA expression. Therefore, we aimed to determine the effect of miR-29 on elastin expression and Pi-induced vascular calcification. Calcification of human VSMCs was induced by Pi and evaluated measuring calcium deposition. Pi stimulation promoted Ca deposition and suppressed elastin expression in VSMCs. Knockdown of elastin expression by shRNA also promoted Pi-induced VSMC calcification. Elastin pre-mRNA measurements indicated that Pi stimulation suppressed elastin expression without changing transcriptional activity. Conversely, Pi stimulation increased miR-29a and miR 29b expression. Inhibition of miR-29 recovered elastin expression and suppressed calcification in Pi-treated VSMCs. Furthermore, over-expression of miR-29b promoted Pi-induced VSMC calcification. RT-qPCR analysis showed knockdown of elastin expression in VSMCs induced expression of osteoblast-related genes, similar to Pi stimulation, and recovery of elastin expression by miR-29 inhibition reduced their expression. Our study shows that miR-29-mediated suppression of elastin expression in VSMCs plays a pivotal role in osteoblastic differentiation leading to vascular calcification. PMID- 26610871 TI - Photoluminescence Architectures for Disease Diagnosis: From Graphene to Thin Layer Transition Metal Dichalcogenides and Oxides. AB - Ever since the discovery of graphene, increasing efforts have been devoted to the use of this stellar material as well as the development of other graphene-like materials such as thin-layer transition metal dichalcogenides and oxides (TMD/Os) for a variety of applications. Because of their large surface area and unique optical properties, these two-dimensional materials with a size ranging from the micro- to the nanoscale have been employed as the substrate to construct photoluminescence architectures for disease diagnosis as well as theranostics. These architectures are built through the simple self-assembly of labeled biomolecular probes with the substrate material, leading to signal quenching. Upon the specific interaction of the architecture with a target biomarker, the signal can be spontaneously restored in a reversible manner. Meanwhile, by co loading therapeutic agents and employing the inherent photo-thermal properties of the material substrates, a combined disease imaging and therapy (theranostics) can be achieved. This review highlights the latest advances in the construction and application of graphene and TMD/O based thin-layer material composites for single-target and multiplexed detection of a variety of biomarkers and theranostics. These versatile material architectures, owing to their ease in preparation, low cost and flexibility in functionalization, provide promising tools for both basic biochemical research and clinical applications. PMID- 26610872 TI - Psychological Treatment Trials for Hypoactive Sexual Desire Disorder: A Sexual Medicine Critique and Perspective. AB - INTRODUCTION: Publications claim efficacy for treatment of hypoactive sexual desire disorder (HSDD) in women with cognitive behavior therapy (CBT) and mindfulness meditation training (MMT). However, no review has evaluated the evidence for these therapies from the rigorous perspective of sexual medicine. AIMS: The aim of this study was to evaluate the published controlled trials of CBT and MMT for disorders of sexual desire from the perspective of sexual medicine standards of control paradigms, risk/benefit ratios, and clinical significance. METHODS: MEDLINE was reviewed from the last 10 years. Evaluated study quality via 10 metrics and efficacy as mean change, and proportion of responders and remitters. RESULTS: Three controlled trials support CBT and two controlled trials support MMT. The reports of the trials each lacked several scientific requirements: a hierarchy of endpoints with a planned primary endpoint, sufficient information on the intervention to reproduce it, randomization, adequate control, accepted measures of benefits and harms, compliance data, and/or outcomes of clinical relevance. CONCLUSIONS: Psychological treatments for HSDD are not yet supported by adequate clinical trials. The current scientific and regulatory standards for drug treatment trials should also be applicable to psychological treatment trials. PMID- 26610873 TI - Comparative Cognitive Profile of Second-Generation Antidepressants in Elderly Nursing Home Residents With Depression. AB - BACKGROUND: Past literature suggests that the use of second-generation antidepressants improves cognition in depressed elderly patients. OBJECTIVE: This study assessed the comparative cognitive profile of commonly used second generation antidepressant classes in elderly residents with depression. METHODS: A multiple propensity score adjusted retrospective cohort study was conducted using 2007-2010 Medicare Part D claims and Minimum Data Set (MDS). Elderly nursing home residents (65 years or older) with depression using a new prescription of selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and tetracyclics constituted the study cohort. The outcome of interest was cognition, measured using the MDS Cognition Scale. Cognition was measured at each quarterly assessment after antidepressant initiation for a maximum of 1 year. The propensity score-adjusted repeated-measures mixed model was used to evaluate the comparative profile of SSRIs, SNRIs, and tetracyclics with respect to cognition. RESULTS: The study cohort comprised 1518 elderly nursing home residents. Of these, 1081 received SSRIs (71.21%), 320 received tetracyclics (21.08%), and 117 received SNRIs (7.71%). The propensity score-adjusted repeated-measures mixed model did not show any statistically significant difference in cognition with the use of SSRIs (beta = -0.14; 95% CI = -0.53, 0.25) or tetracyclics (beta = -0.36; 95% CI = -0.80, 0.08) when compared with SNRIs, after controlling for other factors. CONCLUSIONS: The cognitive effect of SSRIs, SNRIs, and tetracyclics was similar in elderly nursing home residents with depression. Further studies are needed to evaluate the long-term cognitive effects of second-generation antidepressants in this vulnerable population. PMID- 26610874 TI - Gastrointestinal Bleeding in Patients With Atrial Fibrillation Treated With Rivaroxaban or Warfarin: ROCKET AF Trial. AB - BACKGROUND: Gastrointestinal (GI) bleeding is a common complication of oral anticoagulation. OBJECTIVES: This study evaluated GI bleeding in patients who received at least 1 dose of the study drug in the on-treatment arm of the ROCKET AF (Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial. METHODS: The primary outcome was adjudicated GI bleeding reported from first to last drug dose + 2 days. Multivariable modeling was performed with pre specified candidate predictors. RESULTS: Of 14,236 patients, 684 experienced GI bleeding during follow-up. These patients were older (median age 75 years vs. 73 years) and less often female. GI bleeding events occurred in the upper GI tract (48%), lower GI tract (23%), and rectum (29%) without differences between treatment arms. There was a significantly higher rate of major or nonmajor clinical GI bleeding in rivaroxaban- versus warfarin-treated patients (3.61 events/100 patient-years vs. 2.60 events/100 patient-years; hazard ratio: 1.42; 95% confidence interval: 1.22 to 1.66). Severe GI bleeding rates were similar between treatment arms (0.47 events/100 patient-years vs. 0.41 events/100 patient years; p = 0.39; 0.01 events/100 patient-years vs. 0.04 events/100 patient-years; p = 0.15, respectively), and fatal GI bleeding events were rare (0.01 events/100 patient-years vs. 0.04 events/100 patient-years; 1 fatal events vs. 5 fatal events total). Independent clinical factors most strongly associated with GI bleeding were baseline anemia, history of GI bleeding, and long-term aspirin use. CONCLUSIONS: In the ROCKET AF trial, rivaroxaban increased GI bleeding compared with warfarin. The absolute fatality rate from GI bleeding was low and similar in both treatment arms. Our results further illustrate the need for minimizing modifiable risk factors for GI bleeding in patients on oral anticoagulation. PMID- 26610875 TI - Matching the NOAC to the Patient: Remember the Modifiable Bleeding Risk Factors. PMID- 26610876 TI - Bioprosthetic Valve Thrombosis Versus Structural Failure: Clinical and Echocardiographic Predictors. AB - BACKGROUND: Bioprosthetic valve thrombosis (BPVT) is considered uncommon; this may be related to the fact that it is often unrecognized. Recent data suggest that BPVT responds to vitamin K antagonists, emphasizing the need for reliable diagnosis. OBJECTIVES: This study sought to determine the diagnostic features of BPVT and to formulate a diagnostic model for BPVT. METHODS: Cases of BPVT occurring between 1997 and 2013 were identified from the Mayo Clinic pathology database. Patients with BPVT were matched 1:2 for age, sex, and prosthesis position with patients whose valves were explanted for structural failure. We formulated a diagnostic model for BPVT using multivariate linear logistic regression and receiver operating characteristic. RESULTS: Among 397 consecutive cases of explanted bioprostheses, there were 46 cases of BPVT (11.6%; aortic 29, mitral 9, tricuspid 7, pulmonary 1), mean age was 63 years, and 68% were male. Thirty (65%) cases occurred >12 months post-implantation; median bioprosthetic valve longevity was 24 months (cases) versus 108 months (controls) (p < 0.001). Independent predictors of BPVT were >50% increase in mean echo-Doppler gradient from baseline within 5 years (odds ratio [OR]: 12.7), paroxysmal atrial fibrillation (OR: 5.19), subtherapeutic international normalized ratio (OR: 7.37), increased cusp thickness (OR: 12.2), and abnormal cusp mobility (OR: 6.94). Presence of all 5 diagnostic features was predictive of BPVT with 76% sensitivity, 93% specificity, 85% positive predictive value, and 89% negative predictive value (p < 0.001). CONCLUSIONS: BPVT is not uncommon and can occur several years after surgery. A combination of clinical and echocardiographic features can reliably diagnose BPVT. PMID- 26610877 TI - Thrombosis of Bioprosthetic Valves: Can We Afford to Ignore It? PMID- 26610878 TI - Diagnosis, Prognosis, and Therapy of Transthyretin Amyloidosis. AB - Transthyretin amyloidosis is a fatal disorder that is characterized primarily by progressive neuropathy and cardiomyopathy. It occurs in both a mutant form (with autosomal dominant inheritance) and a wild-type form (with predominant cardiac involvement). This article guides clinicians as to when the disease should be suspected, describes the appropriate diagnostic evaluation for those with known or suspected amyloidosis, and reviews the interventions currently available for affected patients. PMID- 26610879 TI - Hypercholesterolemia Abolishes High-Density Lipoprotein-Related Cardioprotective Effects in the Setting of Myocardial Infarction. PMID- 26610880 TI - Understanding the Mechanism of T-Wave Inversion in Athletes May Be Key to Best Management. PMID- 26610881 TI - Reply: Understanding the Mechanism of T-Wave Inversion in Athletes May Be Key to Best Management. PMID- 26610882 TI - Speckle-Tracking Echocardiography-Derived Longitudinal Dysfunction: A Novel Starting Point of the Hypertensive Patient's Journey Toward Heart Failure. PMID- 26610883 TI - Reply: Speckle-Tracking Echocardiography-Derived Longitudinal Dysfunction: A Novel Starting Point of the Hypertensive Patient's Journey Toward Heart Failure. PMID- 26610884 TI - Copper(I)-Catalyzed Interrupted Click Reaction: Synthesis of Diverse 5-Hetero Functionalized Triazoles. AB - The 5-heterofunctionalized triazoles are important scaffolds in bioactive compounds, but current click reactions (CuAAC) cannot produce these core structures. A copper(I)-catalyzed interrupted click reaction to access diverse 5 functionalized triazoles is reported. Various 5-amino-, thio-, and selenotriazoles were readily assembled in one step in high yields. The reaction proceeds under mild conditions with complete regioselectivity. It also features a broad substrate scope and good functional group compatibility. PMID- 26610885 TI - UV-blocking potential of oils and juices. AB - OBJECTIVE: Sunscreens are commonly used to protect the body from damage caused by UV light. Some components of organic sunscreens have been shown to pass through the skin during wear which could raise toxicity concerns for these compounds. This study explores the potential for oils and fruit and vegetable juices to be substitutes for these compounds. METHODS: The absorptivity of various oils (canola oil, citronella oil, coconut oil, olive oil, soya bean oil, vitamin E, as well as aloe vera) and fruit and vegetable juices (acerola, beet, grape, orange carrot, purple carrot and raspberry) was measured in vitro. The mean absorptivity was compared with FDA-approved UV absorbers to gauge the potential of the natural products. The most promising candidates were incorporated into formulations, and the UV transmittance of a 20-MUm-thick film of the formulation was measured. The formulations were also imaged by light microscopy and scanning electron microscopy. RESULTS: The absorptivity of oils was at least two orders of magnitude lower compared to the commercial UV blockers. The fruit juice powders were more effective at UV blocking but still showed an order of magnitude lower absorptivity compared to commercial UV blockers. CONCLUSION: The UV blocking from most natural oils is insufficient to obtain a significant UV protection. Formulations containing 50wt% purple carrot showed good UV-blocking capabilities and represent a promising ingredient for sunscreen and cosmetic applications. PMID- 26610886 TI - An autopsied case of unclassifiable sporadic four-repeat tauopathy presenting with parkinsonism and speech disturbances. AB - A 48-year-old Japanese woman experienced slow-onset parkinsonism and speech disturbances. Neurological examinations revealed rigidity in the trunk and extremities, bradykinesia and postural instability, although cognitive impairments and psychiatric symptoms were not apparent in the early disease stage. Neuroimaging revealed progressive bilateral frontotemporal lobe atrophy with cerebral blood flow hypoperfusion. No apparent signs of lower motor neuron involvement were observed, such as fasciculation or electromyogram findings. She eventually reached the akinetic mutism state, and gastrostomy and tracheotomy were performed at 4 years after onset. A clinical diagnosis of progressive supranuclear palsy was made prior to her death, which occurred 6 years after onset. Post mortem examinations revealed that the brain weighed 1200 g and showed atrophy of the frontotemporal lobe and brainstem. Severe neuron loss and gliosis were observed in the frontotemporal lobe. The superior and middle frontal gyri were the most severely affected and showed spongiform changes in the superficial layer. The globus pallidus, subthalamic nucleus, cerebellar dentate nucleus, substantia nigra and inferior olivary nucleus also showed neuronal loss with gliosis. Using hyperphosphorylated tau (AT-8) immunostaining, pretangle-like neurons, numerous short threads and glial tau pathology were extensively observed. Using Gallyas-Braak silver staining, thin and short threads were also extensively observed, but considerably fewer than those observed by AT-8 immunostaining. Neither astrocytic plaques nor tuft-shaped astrocytes were observed. Examination by immunoelectron microscopy showed straight fibrils approximately 15 nm in diameter in the neuronal cytoplasmic inclusions in the cerebral cortex and in the fibrillary structures in the cerebral white matter. Western blot analysis of sarkosyl-insoluble tau revealed predominantly four repeat tau and a banding pattern similar to that seen in progressive supranuclear palsy. No pathogenic mutations were found during the gene analysis of microtubule associated protein tau. After completing our comprehensive investigation, we diagnosed this patient with unclassifiable four-repeat tauopathy. PMID- 26610887 TI - Accumulation of basement membrane components in oral epithelial lesions. PMID- 26610888 TI - Joseph R. Gusfield, 1923-2015. PMID- 26610889 TI - Concise Asymmetric Construction of C2 -symmetric 1,9-Diarylnonanoids Using a Hypervalent Silicon Complex: Total Synthesis of (-)-Ericanone. AB - By using a phosphine oxide-catalyzed enantioselective double aldol reaction, we achieved the concise construction of C2 -symmetric 1,9-diarylnonanoids, enabling the synthesis of (-)-ericanone from p-hydroxybenzaldehyde in 6 steps with 65 % overall yield. The enantioselective double aldol reaction is useful for establishing C2 -symmetric 1,9-diaryl-3,7-dihydroxy-5-nonanones with a single operation. Furthermore, the use of o-nosyl-protected p-hydroxybenzaldehyde and a 4,4'-disubstituted BINAP dioxide catalyst dramatically improved the reactivity and selectivity in the double aldol reaction, enabling the total synthesis of (-) ericanone with high yield and with excellent enantiopurity. PMID- 26610890 TI - Mucin-type O-glycosylation is controlled by short- and long-range glycopeptide substrate recognition that varies among members of the polypeptide GalNAc transferase family. AB - A large family of UDP-GalNAc:polypeptide GalNAc transferases (ppGalNAc-Ts) initiates and defines sites of mucin-type Ser/Thr-O-GalNAc glycosylation. Family members have been classified into peptide- and glycopeptide-preferring subfamilies, although both families possess variable activities against glycopeptide substrates. All but one isoform contains a C-terminal carbohydrate binding lectin domain whose roles in modulating glycopeptide specificity is just being understood. We have previously shown for several peptide-preferring isoforms that the presence of a remote Thr-O-GalNAc, 6-17 residues from a Ser/Thr acceptor site, may enhance overall catalytic activity in an N- or C-terminal direction. This enhancement varies with isoform and is attributed to Thr-O-GalNAc interactions at the lectin domain. We now report on the glycopeptide substrate utilization of a series of glycopeptide (human-ppGalNAc-T4, T7, T10, T12 and fly PGANT7) and peptide-preferring transferases (T2, T3 and T5) by exploiting a series of random glycopeptide substrates designed to probe the functions of their catalytic and lectin domains. Glycosylation was observed at the -3, -1 and +1 residues relative to a neighboring Thr-O-GalNAc, depending on isoform, which we attribute to specific Thr-O-GalNAc binding at the catalytic domain. Additionally, these glycopeptide-preferring isoforms show remote lectin domain-assisted Thr-O GalNAc enhancements that vary from modest to none. We conclude that the glycopeptide specificity of the glycopeptide-preferring isoforms predominantly resides in their catalytic domain but may be further modulated by remote lectin domain interactions. These studies further demonstrate that both domains of the ppGalNAc-Ts have specialized and unique functions that work in concert to control and order mucin-type O-glycosylation. PMID- 26610892 TI - Therapeutic Outcomes and Prognostic Factors in Childhood Absence Epilepsy. AB - BACKGROUND AND PURPOSE: Childhood absence epilepsy (CAE) is one of the most common types of pediatric epilepsy. It is generally treated with ethosuximide (ESM), valproic acid (VPA), or lamotrigine (LTG), but the efficacy and adverse effects of these drugs remain controversial. This study compared initial therapy treatment outcomes, including VPA-LTG combination, and assessed clinical factors that may predict treatment response and prognosis. METHODS: Sixty-seven patients with typical CAE were retrospectively enrolled at the Korea University Medical Center. We reviewed patients' clinical characteristics, including age of seizure onset, seizure-free interval, duration of seizure-free period, freedom from treatment failure, breakthrough seizures frequency, and electroencephalogram (EEG) findings. RESULTS: The age at seizure onset was 7.9+/-2.7 years (mean+/ SD), and follow-up duration was 4.4+/-3.7 years. Initially, 22 children were treated with ESM (32.8%), 23 with VPA (34.3%), 14 with LTG (20.9%), and 8 with VPA-LTG combination (11.9%). After 48 months of therapy, the rate of freedom from treatment failure was significantly higher for the VPA-LTG combination therapy than in the three monotherapy groups (p=0.012). The treatment dose administrated in the VPA-LTG combination group was less than that in the VPA and LTG monotherapy groups. The shorter interval to loss of 3-Hz spike-and-wave complexes and the presence of occipital intermittent rhythmic delta activity on EEG were significant factors predicting good treatment response. CONCLUSIONS: This study showed that low-dose VPA-LTG combination therapy has a good efficacy and fewer side effects than other treatments, and it should thus be considered as a firstline therapy in absence epilepsy. PMID- 26610891 TI - Functional analysis of N-linking oligosaccharyl transferase enzymes encoded by deep-sea vent proteobacteria. AB - Bacterial N-linking oligosaccharyl transferases (OTase enzymes) transfer lipid linked glycans to selected proteins in the periplasm and were first described in the intestinal pathogen Campylobacter jejuni, a member of the epsilon proteobacteria-subdivision of bacteria. More recently, orthologues from other epsilon-proteobacterial Campylobacter and Helicobacter species and a delta proteobacterium, Desulfovibrio desulfuricans, have been described, suggesting that these two subdivisions of bacteria may be a source of further N-linked protein glycosylation systems. Whole-genome sequencing of both epsilon- and delta proteobacteria from deep-sea vent habitats, a rich source of species from these subdivisions, revealed putative ORFs encoding OTase enzymes and associated adjacent glycosyltransferases similar to the C. jejuni N-linked glycosylation locus. We expressed putative OTase ORFs from the deep-sea vent species Nitratiruptor tergarcus, Sulfurovum lithotrophicum and Deferribacter desulfuricans in Escherichia coli and showed that they were able to functionally complement the C. jejuni OTase, CjPglB. The enzymes were shown to possess relaxed glycan specificity, transferring diverse glycan structures and demonstrated different glycosylation sequon specificities. Additionally, a permissive D. desulfuricans acceptor protein was identified, and we provide evidence that the N linked glycan synthesized by N. tergarcus and S. lithotrophicum contains an acetylated sugar at the reducing end. This work demonstrates that deep-sea vent bacteria encode functional N-glycosylation machineries and are a potential source of biotechnologically important OTase enzymes. PMID- 26610893 TI - Dermatological Manifestations of Postural Tachycardia Syndrome Are Common and Diverse. AB - BACKGROUND AND PURPOSE: Postural tachycardia syndrome (POTS) is a syndrome of orthostatic intolerance in the setting of excessive tachycardia with orthostatic challenge, and these symptoms are relieved when recumbent. Apart from symptoms of orthostatic intolerance, there are many other comorbid conditions such as chronic headache, fibromyalgia, gastrointestinal disorders, and sleep disturbances. Dermatological manifestations of POTS are also common and range widely from livedo reticularis to Raynaud's phenomenon. METHODS: Questionnaires were distributed to 26 patients with POTS who presented to the neurology clinic. They were asked to report on various characteristics of dermatological symptoms, with their answers recorded on a Likert rating scale. Symptoms were considered positive if patients answered with "strongly agree" or "agree", and negative if they answered with "neutral", "strongly disagree", or "disagree". RESULTS: The most commonly reported symptom was rash (77%). Raynaud's phenomenon was reported by over half of the patients, and about a quarter of patients reported livedo reticularis. The rash was most commonly found on the arms, legs, and trunk. Some patients reported that the rash could spread, and was likely to be pruritic or painful. Very few reported worsening of symptoms on standing. CONCLUSIONS: The results suggest that dermatological manifestations in POTS vary but are highly prevalent, and are therefore of important diagnostic and therapeutic significance for physicians and patients alike to gain a better understanding thereof. Further research exploring the underlying pathophysiology, incidence, and treatment strategies is necessary. PMID- 26610894 TI - Clinical Trials of Adult Stem Cell Therapy in Patients with Ischemic Stroke. AB - Stem cell therapy is considered a potential regenerative strategy for patients with neurologic deficits. Studies involving animal models of ischemic stroke have shown that stem cells transplanted into the brain can lead to functional improvement. With current advances in the understanding regarding the effects of introducing stem cells and their mechanisms of action, several clinical trials of stem cell therapy have been conducted in patients with stroke since 2005, including studies using mesenchymal stem cells, bone marrow mononuclear cells, and neural stem/progenitor cells. In addition, several clinical trials of the use of adult stem cells to treat ischemic stroke are ongoing. This review presents the status of our understanding of adult stem cells and results from clinical trials, and introduces ongoing clinical studies of adult stem cell therapy in the field of stroke. PMID- 26610895 TI - Tissue microarray-based study of hepatocellular carcinoma validating SPIB as potential clinical prognostic marker. AB - Currently, the prognostic significance of SPIB protein overexpression in human hepatocellular carcinoma (HCC) is unclear. The aim of the present study was to investigate the level of SPIB expression in human HCC in order to determine possible correlations between SPIB expression and clinicopathological findings. The expression of SPIB proteins was detected using immunohistochemical staining in commercial multiple-tissue microarrays as a means of examining expression profiles in patients. Using online biomarker validation tool SurvExpress, we focused on the correlation between SPIB overexpression and survival as well as relapse-free survival (RFS). Results show that SPIB protein expression levels were significantly higher in colon, liver, and stomach tumors than in non-tumor tissues (p<0.05). SPIB overexpression in patients with HCC was also significantly higher than that of the normal samples (p<0.001). Among patients with liver disease, SPIB protein expression levels differ significantly according to the stage of liver disease, specifically between stages I, II, and III of HCC (p<0.05). SPIB expression was also shown to be significantly correlated with age (p=0.046) and histological grade (p=0.027). Furthermore, the SurvExpress analysis suggested that high SPIB and KI-67 mRNA expression were significantly associated with the poor survival of patients with HCC (p<0.05). Our results indicate that cross-talk in the expression of SPIB and KI-67 may be associated with poor prognosis and may potentially serve as a clinical prognostic indicator of HCC. This is the first time that such an association has been reported. PMID- 26610896 TI - Mechanisms of Very Long Abortive Transcript Release during Promoter Escape. AB - A phage T5 N25 promoter variant, DG203, undergoes the escape transition at the +16 to +19 positions after transcription initiation. By specifically examining the abortive activity of the initial transcribing complex at position +19 (ITC19), we observe the production of both GreB-sensitive and GreB-resistant VLAT19. This suggests that ITC19, which is perched on the brink of escape, is highly unstable and can achieve stabilization through either backtracking or forward translocation. Of the forward-tracked fraction, only a small percentage escapes normally (followed by stepwise elongation) to produce full-length RNA; the rest presumably hypertranslocates to release GreB-resistant VLATs. VLAT formation is dependent not only on consensus -35/-10 promoters with 17 bp spacing but also on sequence characteristics of the spacer DNA. Analysis of DG203 promoter variants containing different spacer sequences reveals that AT-rich spacers intrinsically elevate the level of VLAT formation. The AT-rich spacer of DG203 joined to the -10 box presents an UP element sequence capable of interacting with the polymerase alpha subunit C-terminal domain (alphaCTD) during the escape transition, which in turn enhances VLAT release. Utilization of the spacer/-10 region UP element by alphaCTD subunits requires a 10-15 bp hypertranslocation. We document the physical occurrence of hyper forward translocation using ExoIII footprinting analysis. PMID- 26610897 TI - Influenza-Associated Excess Mortality in South Korea. AB - INTRODUCTION: It is important to determine the health impact of influenza in order to calibrate public health measures. The objective of this study was to estimate excess mortality associated with influenza in Korea in 2003-2013. METHODS: The authors constructed multiple linear regression models in 2014 with weekly mortality rates stratified by age, region, and cause of death against weekly surveillance data on influenza virus collected in 2003-2013. Excess mortality rates were estimated using the difference between predicted mortality rates from the fitted model versus predicted mortality rates with the influenza covariate for each strain set to 0. RESULTS: During the study period, influenza was associated with an average of 2,900 excess deaths per year. The impact of influenza on mortality was significantly higher in older people; the overall all cause excess annual mortality rate per 100,000 people was 5.97 (95% CI=4.89, 7.19), whereas it was 46.98 (95% CI=36.40, 55.82) for adults aged >=65 years. It also greatly varied from year to year, ranging from 2.04 in 2009-2010 to 18.76 in 2011-2012. CONCLUSIONS: The impact of influenza on mortality in Korea is substantial, particularly among the elderly and the rural population. More comprehensive studies may be needed to estimate the full impact of influenza. PMID- 26610901 TI - Acute cholecystitis in a situs inversus totalis patient. PMID- 26610898 TI - Surgery is associated with ventricular enlargement as well as cognitive and functional decline. AB - INTRODUCTION: In preclinical studies, surgery/anesthesia contribute to cognitive decline and enhance neuropathologic changes underlying Alzheimer's disease (AD). Nevertheless, the link between surgery, anesthesia, apolipoprotein E epsilon4 (APOE epsilon4), and AD remains unclear. METHODS: We performed a retrospective cohort analysis of two prospective longitudinal aging studies. Mixed-effects statistical models were used to assess the relationship between surgical/anesthetic exposure, the APOE genotype, and rate of change in measures of cognition, function, and brain volumes. RESULTS: The surgical group (n = 182) experienced a more rapid rate of deterioration compared with the nonsurgical group (n = 345) in several cognitive, functional, and brain magnetic resonance imaging measures. Furthermore, there was a significant synergistic effect of anesthesia/surgery exposure and presence of the APOE epsilon4 allele in the decline of multiple cognitive and functional measures. DISCUSSION: These data provide insight into the role of surgical exposure as a risk factor for cognitive and functional decline in older adults. PMID- 26610902 TI - Uncommon HLA alleles identified by hemizygous ultra-high Sanger sequencing: haplotype associations and reconsideration of their assignment in the Common and Well-Documented catalogue. AB - Although the number of HLA alleles still increases, many of them have been reported being uncommon. This is partly due to lack of full length gene sequencing, especially for those alleles belonging to an allele ambiguity in which the first discovered allele has been assigned as the most frequent one. As members of the working group on Common and Well Documented (CWD) alleles and since we implemented full length group-specific sequencing as standard method routinely, we have investigated the presence of presumably rare alleles in our collection of HLA typing data. We identified 50 alleles, that were not previously encountered as Common or Well Documented. Sixteen of them should be added to the CWD catalogue, since we encountered them in 5 or more unrelated individuals. Another 11 could be added, based upon our results and the data present in the IMGT database and the rare allele section of the allele frequencies database. Furthermore, tight associations were observed between several different alleles even at the level of synonymous and non-coding sequences. In addition, in several cases the uncommon allele was found to be more frequent than its common counterpart. PMID- 26610903 TI - Transgenic n-3 PUFAs enrichment leads to weight loss via modulating neuropeptides in hypothalamus. AB - Body weight is related to fat mass, which is associated with obesity. Our study explored the effect of fat-1 gene on body weight in fat-1 transgenic mice. In present study, we observed that the weight/length ratio of fat-1 transgenic mice was lower than that of wild-type mice. The serum levels of triglycerides (TG), cholesterol (CT), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and blood glucose (BG) in fat-1 transgenic mice were all decreased. The weights of peri-bowels fat, perirenal fat and peri testicular fat in fat-1 transgenic mice were reduced. We hypothesized that increase of n-3 PUFAs might alter the expression of hypothalamic neuropeptide genes and lead to loss of body weight in fat-1 transgenic mice. Therefore, we measured mRNA levels of appetite neuropeptides, Neuropeptide Y (NPY), Agouti related peptides (AgRP), Proopiomelanocortin (POMC), Cocaine and amphetamine regulated transcript (CART), ghrelin and nesfatin-1 in hypothalamus by real-time PCR. Compared with wild-type mice, the mRNA levels of CART, POMC and ghrelin were higher, while the mRNA levels of NPY, AgRP and nesfatin-1 were lower in fat-1 transgenic mice. The results indicate that fat-1 gene or n-3 PUFAs participates in regulation of body weight, and the mechanism of this phenomenon involves the expression of appetite neuropeptides and lipoproteins in fat-1 transgenic mice. PMID- 26610904 TI - Overexpression of alpha-synuclein simultaneously increases glutamate NMDA receptor phosphorylation and reduces glucocerebrosidase activity. AB - Progressive accumulation of alpha-synuclein (alpha-syn)-containing protein aggregates throughout the nervous system is a pathological hallmark of Parkinson's disease (PD). The mechanisms whereby alpha-syn exerts neurodegeneration remain to be fully understood. Here we show that overexpression of alpha-syn in transgenic mice leads to increased phosphorylation of glutamate NMDA receptor (NMDAR) subunits NR1 and NR2B in substantia nigra and striatum as well as reduced glucocerebrosidase (GCase) levels. Similarly, molecular studies performed in mouse N2A cells stably overexpressing human alpha-syn ((alpha syn)N2A) showed that phosphorylation states of the same NMDAR subunits were increased, whereas GCase levels and lysosomal GCase activity were reduced. (alpha syn)N2A cells showed an increased sensitivity to neurotoxicity towards 6 hydroxydopamine and NMDA. However, wildtype N2A, but not (alpha-syn)N2A cells, showed a further reduction in viability when co-incubated with 6-hydroxydopamine and the lysosomal inhibitors NH4Cl and leupeptin, suggesting that alpha-syn per se perturbs lysosomal functions. NMDA treatment reduced lysosomal GCase activity to the same extent in (alpha-syn)N2A cells as in wildtype N2A cells, indicating that the alpha-syn-dependent difference in NMDA neurotoxicity is unrelated to an altered GCase activity. Nevertheless, these data provide molecular evidence that overexpression of alpha-syn simultaneously induces two potential neurotoxic hits by increasing glutamate NMDA receptor phosphorylation, consistent with increased NMDA receptors functionality, and reducing GCase activity. PMID- 26610905 TI - Extracellular levels of ATP and acetylcholine during lithium-pilocarpine induced status epilepticus in rats. AB - Acetylcholine (ACh) and ATP are rapidly acting neurotransmitters with a putative role in epileptic seizures. In the present study we investigated extracellular concentrations of both neurotransmitters in parallel by microdialysis in rat hippocampus. We found that infusion of neostigmine increases, while calcium-free perfusion and infusion of tetrodotoxin (TTX) decreases, ACh levels. Calcium-free perfusion also decreased ATP levels which were, however, not affected by neostigmine or TTX. During status epilepticus, ACh levels were increased threefold but returned to baseline after the termination of seizures by diazepam. ATP levels were unchanged during status epilepticus but a several-fold increase was seen when AOPCP, an inhibitor of 5'-endonucleotidase, was infused. The results demonstrate an increase of ATP levels during epileptic seizures which, however, was not of neuronal origin. PMID- 26610906 TI - Aging in Place of Vulnerable Older Adults: Person-Environment Fit Perspective. AB - Based on the premise that the experience of aging in place is different for vulnerable subgroups of older adults compared with less vulnerable subgroups, we focus on low-income older adults as a vulnerable subgroup and senior housing as an alternative to a conventional, private home environment. Using the 2008 and 2010 waves of the Health Retirement Study, regression models determined the impact of person-environment (P-E) fit between poverty status and residence in senior housing on self-rated health. Consistent with the environmental docility hypothesis, findings show that, among low-income individuals, the supportive environment of senior housing plays a pronounced compensating role and may be a key to successful adaptation in aging. As the first research effort to empirically demonstrate the positive health effects of senior housing among socioeconomically vulnerable elders, our findings provide a much-needed theoretical and practical underpinning for policy-making efforts regarding vulnerable elders. PMID- 26610907 TI - Social Engagement After Nursing Home Admission: Racial and Ethnic Disparities and Risk Factors. AB - Older adults admitted to nursing homes (NHs) are at risk for low social engagement, which has associations with medical, psychological, and social well being. Minorities may be at a disadvantage for social engagement because of their racial or ethnic group identity. This study assessed whether there were racial/ethnic disparities in social engagement among older adults ( N = 15,927) at 1 year after their NH admission using multi-level predictors. No racial or ethnic-based disparities in social engagement were found; hence, an analysis of risk factors at NH admission that predicted low social engagement at 1 year for all residents was conducted. Significant risk factors for low social engagement were low social engagement at admission, deficits in activities in daily living and cognition, problems with vision and communication, and residing in an NH in an urban community. Results highlight the importance of initiating interventions to increase social engagement at the time of NH admission. PMID- 26610908 TI - Urinary excretion of the water channel aquaporin 2 correlated with the pharmacological effect of tolvaptan in cirrhotic patients with ascites. AB - BACKGROUND: The water channel aquaporin 2 (AQP2) at the apical membrane of renal collecting duct cells mediates water reabsorption. The expression of AQP2 at the apical membrane is tightly regulated by vasopressin and was quantitated by measurement of the urinary form by a recently developed ELISA. Tolvaptan, an antagonist of vasopressin type 2 receptor, inhibits water reabsorption in cirrhosis. The aim of this study was to determine the correlation between the pharmacological effect of tolvaptan and the dynamics of urinary AQP2 levels. METHODS: Tolvaptan was administered to 41 cirrhotic patients with ascites unresponsive to standard diuretic therapy. Urinary excretion of AQP2 and urinary osmolarity were measured at the baseline and at 4, 8, and 24 h after administration of tolvaptan. RESULTS: At the baseline, urinary AQP2/creatinine ratios were significantly higher in cirrhotic patients with ascites than in healthy controls (P < 0.0001). After administration of tolvaptan, urinary AQP2/creatinine ratios decreased by 45.0 % at 4 h and 77.0 % at 8 h. Similarly, urinary osmolarity decreased by 42.0 % at 4 h and 41.5 % at 8 h. Urinary AQP2 levels and urinary osmolarity significantly correlated at the baseline and at all time points after tolvaptan administration. The degree of the decrease in urinary AQP2 levels and degree of the decrease in urinary osmolarity correlated significantly at 4 h (r = 0.452, P = 0.009) and 8 h (r = 0.384, P = 0.030) after tolvaptan administration. CONCLUSIONS: These results indicate that the vasopressin-AQP2 system plays a major role in fluid retention in cirrhosis and that the pharmacological effect of tolvaptan to inhibit water reabsorption can be monitored by measurement of the dynamics of urinary AQP2 levels. PMID- 26610910 TI - Integrating Activities of Laminins that Drive Basement Membrane Assembly and Function. AB - Studies on extracellular matrix proteins, cells, and genetically modified animals have converged to reveal mechanisms of basement membrane self-assembly as mediated by gamma1 subunit-containing laminins, the focus of this chapter. The basic model is as follows: A member of the laminin family adheres to a competent cell surface and typically polymerizes followed by laminin binding to the extracellular adaptor proteins nidogen, perlecan, and agrin. Assembly is completed by the linking of nidogen and heparan sulfates to type IV collagen, allowing it to form a second stabilizing network polymer. The assembled matrix provides structural support, anchoring the extracellular matrix to the cytoskeleton, and acts as a signaling platform. Heterogeneity of function is created in part by the isoforms of laminin that vary in their ability to polymerize and to interact with integrins, dystroglycan, and other receptors. Mutations in laminin subunits, affecting expression or LN domain-specific functions, are a cause of human diseases that include those of muscle, nerve, brain, and kidney. PMID- 26610909 TI - Incidental diffuse low-grade gliomas: from early detection to preventive neuro oncological surgery. AB - Although a large amount of data supports early surgical resection for symptomatic diffuse low-grade glioma, the therapeutic strategy is still a matter of debate regarding incidentally discovered diffuse low-grade glioma. Indeed, early and "preventive" surgery has recently been proposed in asymptomatic patients with silent diffuse low-grade glioma with better outcomes. The present review discusses the importance of an early diagnosis and of a preventive surgical treatment to improve the outcomes of incidental diffuse low-grade glioma and suggests the possible relevance of a tailored screening policy. PMID- 26610911 TI - Laminin-alpha2 Chain-Deficient Congenital Muscular Dystrophy: Pathophysiology and Development of Treatment. AB - Laminin-211 is a major constituent of the skeletal muscle basement membrane. It stabilizes skeletal muscle and influences signal transduction events from the myomatrix to the muscle cell. Mutations in the gene encoding the alpha2 chain of laminin-211 lead to congenital muscular dystrophy type 1A (MDC1A), a life threatening disease characterized by severe hypotonia, progressive muscle weakness, and joint contractures. Common complications include severely impaired motor ability, respiratory failure, and feeding difficulties. Several adequate animal models for laminin-alpha2 chain deficiency exist and analyses of different MDC1A mouse models have led to a significant improvement in our understanding of MDC1A pathogenesis. Importantly, the animal models have been indispensable tools for the preclinical development of new therapeutic approaches for laminin-alpha2 chain deficiency, highlighting a number of important disease driving mechanisms that can be targeted by pharmacological approaches. In this chapter, I will describe laminin-211 and discuss the cellular and molecular pathophysiology of MDC1A as well as progression toward development of treatment. PMID- 26610912 TI - Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. AB - Basement membranes are highly specialized extracellular matrices. Once considered inert scaffolds, basement membranes are now viewed as dynamic and versatile environments that modulate cellular behaviors to regulate tissue development, function, and repair. Increasing evidence suggests that, in addition to providing structural support to neighboring cells, basement membranes serve as reservoirs of growth factors that direct and fine-tune cellular functions. Type IV collagens are a major component of all basement membranes. They evolved along with the earliest multicellular organisms and have been integrated into diverse fundamental biological processes as time and evolution shaped the animal kingdom. The roles of basement membranes in humans are as complex and diverse as their distributions and molecular composition. As a result, basement membrane defects result in multisystem disorders with ambiguous and overlapping boundaries that likely reflect the simultaneous interplay and integration of multiple cellular pathways and processes. Consequently, there will be no single treatment for basement membrane disorders, and therapies are likely to be as varied as the phenotypes. Understanding tissue-specific pathology and the underlying molecular mechanism is the present challenge; personalized medicine will rely upon understanding how a given mutation impacts diverse cellular functions. PMID- 26610913 TI - Epidermal Basement Membrane in Health and Disease. AB - Skin, as the organ protecting the individual from environmental aggressions, constantly meets external insults and is dependent on mechanical toughness for its preserved function. Accordingly, the epidermal basement membrane (BM) zone has adapted to enforce tissue integrity. It harbors anchoring structures created through unique organization of common BM components and expression of proteins exclusive to the epidermal BM zone. Evidence for the importance of its correct assembly and the nonredundancy of its components for skin integrity is apparent from the multiple skin blistering disorders caused by mutations in genes coding for proteins associated with the epidermal BM and from autoimmune disorders in which autoantibodies target these molecules. However, it has become clear that these proteins not only provide mechanical support but are also critically involved in tissue homeostasis, repair, and regeneration. In this chapter, we provide an overview of the unique organization and components of the epidermal BM. A special focus will be given to its function during regeneration, and in inherited and acquired diseases. PMID- 26610914 TI - Applying Proteomics to Investigate Extracellular Matrix in Health and Disease. AB - The molecular composition of basement membranes (BMs) has traditionally been investigated by candidate-based approaches leading to the identification of key structural components as described in previous chapters. Laminins, collagen IV, nidogens, perlecan, and type XV/XVIII collagen are integral to BMs with isoforms showing tissue specificity. More recently the application of mass spectrometry (MS)-based proteomics has led to the discovery of many more structural and regulatory components of BMs and more broadly, extracellular matrix (ECM). These investigations have revealed tissue-specific signatures of between 100 and 150 ECM components, demonstrating the complexity of the extracellular niche. In addition to providing a structural scaffold for cells, ECM is a dynamic extracellular environment capable of regulating the physical properties of tissues. Global investigations of ECM with proteomics in turn enable systems level analyses and when applied to health and disease states these investigations provide insights into pathways regulating matrix dysregulation. This chapter focuses on the methods used to extract ECM and on the analysis of its composition using MS-based proteomics, and it provides examples of how these approaches have been used to investigate health and disease states. PMID- 26610915 TI - Molecular Basis of Laminin-Integrin Interactions. AB - Laminins are composed of three polypeptide chains, designated as alpha, beta, and gamma. The C-terminal region of laminin heterotrimers, containing coiled-coil regions, short tails, and laminin globular (LG) domains, is necessary and sufficient for binding to integrins, which are the major laminin receptor class. Laminin recognition by integrins critically requires the alpha chain LG domains and a glutamic acid residue of the gamma chain at the third position from the C terminus. Furthermore, the C-terminal region of the beta chain contains a short amino acid sequence that modulates laminin affinity for integrins. Thus, all three of the laminin chains act cooperatively to facilitate integrin binding. Mammals possess 5 alpha (alpha1-5), 3 beta (beta1-3), and 3 gamma (gamma1-3) chains, combinations of which give rise to 16 distinct laminin isoforms. Each isoform is expressed in a tissue-specific and developmental stage-specific manner, exerting its functions through binding of integrins. In this review, we detail the current knowledge surrounding the molecular basis and physiological relevance of specific interactions between laminins and integrins, and describe the mechanisms underlying laminin action through integrins. PMID- 26610917 TI - The Basement Membrane Proteoglycans Perlecan and Agrin: Something Old, Something New. AB - Several members of the proteoglycan family are integral components of basement membranes; other proteoglycan family members interact with or bind to molecular residents of the basement membrane. Proteoglycans are polyfunctional molecules, for they derive their inherent bioactivity from the amino acid motifs embedded in the core protein structure as well as the glycosaminoglycan (GAG) chains that are covalently attached to the core protein. The presence of the covalently attached GAG chains significantly expands the "partnering" potential of proteoglycans, permitting them to interact with a broad spectrum of targets, including growth factors, cytokines, chemokines, and morphogens. Thus proteoglycans in the basement membrane are poised to exert diverse effects on the cells intimately associated with basement membranes. PMID- 26610916 TI - Cell Receptor-Basement Membrane Interactions in Health and Disease: A Kidney Centric View. AB - Cell-extracellular matrix (ECM) interactions are essential for tissue development, homeostasis, and response to injury. Basement membranes (BMs) are specialized ECMs that separate epithelial or endothelial cells from stromal components and interact with cells via cellular receptors, including integrins and discoidin domain receptors. Disruption of cell-BM interactions due to either injury or genetic defects in either the ECM components or cellular receptors often lead to irreversible tissue injury and loss of organ function. Animal models that lack specific BM components or receptors either globally or in selective tissues have been used to help with our understanding of the molecular mechanisms whereby cell-BM interactions regulate organ function in physiological and pathological conditions. We review recently published works on animal models that explore how cell-BM interactions regulate kidney homeostasis in both health and disease. PMID- 26610920 TI - Preface. PMID- 26610918 TI - Building from the Ground up: Basement Membranes in Drosophila Development. AB - Basement membranes (BMs) are sheetlike extracellular matrices found at the basal surfaces of epithelial tissues. The structural and functional diversity of these matrices within the body endows them with the ability to affect multiple aspects of cell behavior and communication; for this reason, BMs are integral to many developmental processes. The power of Drosophila genetics, as applied to the BM, has yielded substantial insight into how these matrices influence development. Here, we explore three facets of BM biology to which Drosophila research has made particularly important contributions. First, we discuss how newly synthesized BM proteins are secreted to and assembled exclusively on basal epithelial surfaces. Next, we examine how regulation of the structural properties of the BM mechanically supports and guides tissue morphogenesis. Finally, we explore how BMs influence development through the modulation of several major signaling pathways. PMID- 26610919 TI - Basement Membranes in the Worm: A Dynamic Scaffolding that Instructs Cellular Behaviors and Shapes Tissues. AB - The nematode worm Caenorhabditis elegans has all the major basement membrane proteins found in vertebrates, usually with a smaller gene family encoding each component. With its powerful forward genetics, optical clarity, simple tissue organization, and the capability to functionally tag most basement membrane components with fluorescent proteins, C. elegans has facilitated novel insights into the assembly and function of basement membranes. Although basement membranes are generally thought of as static structures, studies in C. elegans have revealed their active properties and essential functions in tissue formation and maintenance. Here, we review discoveries from C. elegans development that highlight dynamic aspects of basement membrane assembly, function, and regulation during organ growth, tissue polarity, cell migration, cell invasion, and tissue attachment. These studies have helped transform our view of basement membranes from static support structures to dynamic scaffoldings that play broad roles in regulating tissue organization and cellular behavior that are essential for development and have important implications in human diseases. PMID- 26610922 TI - Involvement of autophagy upregulation in 3,4-methylenedioxymethamphetamine ('ecstasy')-induced serotonergic neurotoxicity. AB - It has been suggested that autophagy plays pathogenetic roles in cerebral ischemia, brain trauma, and neurodegenerative disorders. 3,4 Methylenedioxymethamphetamine (MDMA or ecstasy) is an illicit drug that causes long-term serotonergic neurotoxicity in the brain. Apoptosis and necrosis have been implicated in MDMA-induced neurotoxicity, but the role of autophagy in MDMA elicited serotonergic toxicity has not been investigated. The present study aimed to examine the contribution of autophagy to neurotoxicity in serotonergic neurons in in vitro and in vivo animal models challenged with MDMA. Here, we demonstrated that in cultured rat serotonergic neurons, MDMA exposure induced LC3B-densely stained autophagosome formation, accompanying by a decrease in neurite outgrowth. Autophagy inhibitor 3-methyladenine (3-MA) significantly attenuated MDMA-induced autophagosome accumulation, and ameliorated MDMA-triggered serotonergic neurite damage and neuron death. In contrast, enhanced autophagy flux by rapamycin or impaired autophagosome clearance by bafilomycin A1 led to more autophagosome accumulation in serotonergic neurons and aggravated neurite degeneration. In addition, MDMA-induced autophagy activation in cultured serotonergic neurons might be mediated by serotonin transporter (SERT). In an in vivo animal model administered MDMA, neuroimaging showed that 3-MA protected the serotonin system against MDMA-induced downregulation of SERT evaluated by animal-PET with 4 [(18)F]-ADAM, a SERT radioligand. Taken together, our results demonstrated that MDMA triggers upregulation of autophagy in serotonergic neurons, which appears to be detrimental to neuronal growth. PMID- 26610921 TI - Neurotoxicity of traffic-related air pollution. AB - The central nervous system is emerging as an important target for adverse health effects of air pollution, where it may contribute to neurodevelopmental and neurodegenerative disorders. Air pollution comprises several components, including particulate matter (PM) and ultrafine particulate matter (UFPM), gases, organic compounds, and metals. An important source of ambient PM and UFPM is represented by traffic-related air pollution, primarily diesel exhaust (DE). Human epidemiological studies and controlled animal studies have shown that exposure to air pollution, and to traffic-related air pollution or DE in particular, may lead to neurotoxicity. In particular, air pollution is emerging as a possible etiological factor in neurodevelopmental (e.g. autism spectrum disorders) and neurodegenerative (e.g. Alzheimer's disease) disorders. The most prominent effects caused by air pollution in both humans and animals are oxidative stress and neuro-inflammation. Studies in mice acutely exposed to DE (250-300MUg/m3 for 6h) have shown microglia activation, increased lipid peroxidation, and neuro-inflammation in various brain regions, particularly the hippocampus and the olfactory bulb. An impairment of adult neurogenesis was also found. In most cases, the effects of DE were more pronounced in male mice, possibly because of lower antioxidant abilities due to lower expression of paraoxonase 2. PMID- 26610923 TI - Methylmercury upregulates RE-1 silencing transcription factor (REST) in SH-SY5Y cells and mouse cerebellum. AB - Methylmercury (MeHg) is a highly neurotoxic compound that, in adequate doses, can cause damage to the brain, including developmental defects and in severe cases cell death. The RE-1-silencing transcription factor (REST) has been found to be involved in the neurotoxic effects of environmental pollutants such as polychlorinated biphenyls (PCBs). In this study, we investigated the effects of MeHg treatment on REST expression and its role in MeHg-induced neurotoxicity in neuroblastoma SH-SY5Y cells. We found that MeHg exposure caused a dose- and time- dependent apoptotic cell death, as evidenced by the appearance of apoptotic hallmarks including caspase-3 processing and annexin V uptake. Moreover, MeHg increased REST gene and gene product expression. MeHg-induced apoptotic cell death was completely abolished by REST knockdown. Interestingly, MeHg (1MUM/24h) increased the expression of REST Corepressor (Co-REST) and its binding with REST whereas the other REST cofactor mammalian SIN3 homolog A transcription regulator (mSin3A) was not modified. In addition, we demonstrated that the acetylation of histone protein H4 was reduced after MeHg treatment and was critical for MeHg induced apoptosis. Accordingly, the pan-histone deacetylase inhibitor trichostatin-A (TSA) prevented MeHg-induced histone protein H4 deacetylation, thereby reverting MeHg-induced neurotoxic effect. Male mice subcutaneously injected with 10mg/kg of MeHg for 10 days showed an increase in REST expression in the granule cell layer of the cerebellum together with a decrease in histone H4 acetylation. Collectively, we demonstrated that methylmercury exposure can cause neurotoxicity by activating REST gene expression and H4 deacetylation. PMID- 26610924 TI - Reaction kinetics of dual setting alpha-tricalcium phosphate cements. AB - Addition of ductile polymers to calcium-deficient hydroxyapatite (CDHA)-forming bone cements based on alpha-tricalcium phosphate (alpha-TCP) is a promising approach to improve the mechanical performance of alpha-TCP cements and extend their application to load-bearing defects, which is else impeded by the brittleness of the hardened cement. One suitable polymer is poly-(2 hydroxyethylmethacrylate) (p-HEMA), which forms during cement setting by radical polymerisation of the monomer. In this study the hydration kinetics and the mechanical performance of alpha-TCP cements modified with addition of different HEMA concentrations (0-50 wt% in the cement liquid) was investigated by quantitative in situ XRD and four-point bending tests. Morphology of CDHA crystals was monitored by scanning electron microscopy. The hydration of alpha TCP to CDHA was increasingly impeded and the visible crystal size of CDHA increasingly reduced with increasing HEMA concentration. Modification of the cements by adding 50 wt% HEMA to the cement liquid changed the brittle performance of the hardened cement to a pseudoplastic behaviour, reduced the flexural modulus and increased the work of fracture, while lower HEMA concentrations had no significant effect on these parameters. In such a composite, the extent of CDHA formation was considerably reduced (34.0 +/- 1.8 wt% CDHA with 50 % HEMA compared to 54.1 +/- 2.4 wt% CDHA in the reference formed after 48 h), while the general reaction kinetics were not changed. In conclusion, while the extent of CDHA formation was decreased, the mechanical properties were noticeably improved by addition of HEMA. Hence, alpha-TCP/HEMA composites might be suitable for application in some load-bearing defects and have adequate properties for mechanical treatment after implantation, like insertion of screws. PMID- 26610925 TI - Evaluation of the effects of nano-TiO2 on bioactivity and mechanical properties of nano bioglass-P3HB composite scaffold for bone tissue engineering. AB - To emulate bone structure, porous composite scaffold with suitable mechanical properties should be designed. In this research the effects of nano-titania (nTiO2) on the bioactivity and mechanical properties of nano-bioglass-poly-3 hydroxybutyrate (nBG/P3HB)-composite scaffold were evaluated. First, nBG powder was prepared by melting method of pure raw materials at a temperature of 1400 degrees C and then the porous ceramic scaffold of nBG/nTiO2 with 30 wt% of nBG containing different weight ratios of nTiO2 (3, 6, and 9 wt% of nTiO2 with grain size of 35-37 nm) was prepared by using polyurethane sponge replication method. Then the scaffolds were coated with P3HB in order to increase the scaffold's mechanical properties. Mechanical strength and modulus of scaffolds were improved by adding nTiO2 to nBG scaffold and adding P3HB to nBG/nTiO2 composite scaffold. The results of the compressive strength and porosity tests showed that the best scaffold is 30 wt% of nBG with 6 wt% of nTiO2 composite scaffold immersed for 30 s in P3HB with 79.5-80 % of porosity in 200-600 MUm, with a compressive strength of 0.15 MPa and a compressive modulus of 30 MPa, which is a good candidate for bone tissue engineering. To evaluate the bioactivity of the scaffold, the simulated body fluid (SBF) solution was used. The best scaffold with 30 wt% of nBG, 6 wt% of P3HB and 6 wt% of nTiO2 was immersed in SBF for 4 weeks at an incubation temperature of 37 degrees C. The bioactivity of the scaffolds was characterized by AAS, SEM, EDXA and XRD. The results of bioactivity showed that bone-like apatite layer formed well at scaffold surface and adding nTiO2 to nBG/P3HB composite scaffold helped increase the bioactivity rate. PMID- 26610926 TI - Modification of resin modified glass ionomer cement by addition of bioactive glass nanoparticles. AB - In the present study, sol-gel derived nanoparticle calcium silicate bioactive glass was added to the resin-modified light cure glass-ionomer cement to assess the influence of additional bioactive glass nanoparticles on the mechanical and biological properties of resin-modified glass-ionomer cement. The fabricated bioactive glass nanoparticles added resin-modified glass-ionomer cements (GICs) were immersed in the phosphate buffer solution for 28 days to mimic real condition for the mechanical properties. Resin-modified GICs containing 3, 5 and 10 % bioactive glass nanoparticles improved the flexural strength compared to the resin-modified glass-ionomer cement and the samples containing 15 and 20 % bioactive glass nanoparticles before and after immersing in the phosphate buffer solution. Characterization of the samples successfully expressed the cause of the critical condition for mechanical properties. Cell study clarified that resin modified glass-ionomer cement with high concentrations of bioactive glass nanoparticles has higher cell viability and better cell morphology compare to control groups. The results for mechanical properties and toxicity approved that the considering in selection of an optimum condition would have been a more satisfying conclusion for this study. PMID- 26610927 TI - Application of albumin-based nanoparticles in the management of cancer. AB - Over the past three decades, tremendous progress has been made in cancer prevention and treatment. Despite these advances, a substantial number of cancer cases experience early recurrence and metastases. Thus, the better management of cancer, especially developing more effective drugs for combating cancer cells, is an arduous task. Albumin-based nanoparticles are emerging as a promising approach to replace the traditional way of carrying therapeutic drugs to a tumor site. In this review, we describe the basic knowledge on albumin-based nanoparticles, recent progress of using albumin-based nanoparticles in the diagnosis and treatment of cancer, and the application of nanoparticle albumin bound (Nab) paclitaxel for the treatment of lung, breast and pancreatic cancer. Last but not least, we try to discuss future goals and perspectives in the field of drug delivery research, thereby facilitating the antitumor activity. PMID- 26610928 TI - Influences of the steam sterilization on the properties of calcium phosphate porous bioceramics. AB - The influences of steam sterilization on the physicochemical properties of calcium phosphate (Ca-P) porous bioceramics, including beta-tricalcium phosphate (beta-TCP), biphasic calcium phosphate (BCP) and hydroxyapatite (HA) are investigated. After being steam sterilized in an autoclave (121 degrees C for 40 min), the porous bioceramics are dried and characterized. The steam sterilization has no obvious effects on the phase composition, thermal stability, pH value and dissolubility of beta-TCP porous bioceramic, but changes its morphology and mechanical strength. Meanwhile, the steam sterilization leads to the significant changes of the morphology, phase composition, pH value and dissolubility of BCP porous bioceramic. The increase of dissolubility and mechanical strength, the decrease of pH value of the immersed solution and partial oriented growth of crystals are also observed in HA porous bioceramic after steam sterilization. These results indicate that the steam sterilization can result in different influences on the physicochemical properties of beta-TCP, BCP and HA porous bioceramics, thus the application of the steam sterilization on the three kinds of Ca-P porous bioceramics should be considered carefully based on the above changed properties. PMID- 26610929 TI - Bacterial adhesion on biomedical surfaces covered by yttria stabilized zirconia. AB - The aim of this study was to compare the bacterial adhesion of Staphylococcus spp. on Ti-6Al-4V with respect to Ti-6Al-V modified alloys with a set of Cubic yttria stabilized zirconia (YSZ) and Ag-YSZ nanocomposite films. Silver is well known to have a natural biocidal character and its presence in the surface predicted to enhance the antimicrobial properties of biomedical surfaces. Microbial adhesion tests were performed using collection strains and twelve clinical strains of Staphylococcus aureus and Staphylococcus epidermidis. The adherence study was performed using a previously published protocol by Kinnari et al. Both collection strains and clinical isolates have shown lower bacterial adhesion to materials modified with respect to the alloy Ti-6Al-4V and the modification with silver reduced the bacterial adhesion for most of all the strains studied. Moreover the percentage of dead bacteria have been evaluated, demonstrating increased proportion of dead bacteria for the modified surfaces. Nanocrystalline silver dissolves releasing both Ag(+) and Ag(0) whereas other silver sources release only Ag(+). We can conclude that YSZ with nanocrystalline silver coating may lead to diminished postoperative infections and to increased corrosion and scratch resistance of YSZ incorporating alloys Ti-6Al-4V. PMID- 26610930 TI - One-step fabrication of inorganic/organic hybrid microspheres with tunable surface texture for controlled drug release application. AB - In this paper, we report one-step fabrication of poly(lactide-co-glycolic acid)/titanium oxide (PLGA/TiO2) hybrid microspheres with tunable surface texture via droplet-based microfluidics. Surface texture of microspheres can be continuously tuned by changing the mass ratio between titanium tetraisopropoxide (TTIP) and PLGA in the dispersed phase. The fast hydrolysis of TTIP on the droplet surface can generate a thin shell membrane, resulting in a wrinkled surface after extraction of organic solvent. In vitro drug release monitoring of tanshinone IIA-loaded PLGA/TiO2 hybrid microsphere reveals that surface texture can affect the drug release rate to a large extent without sacrificing the drug encapsulation efficiency. Our finding might benefit the sustained drug delivery where variable drug release rate and high drug encapsulation efficiency are both required. PMID- 26610932 TI - Erratum to: Impaired mitochondrial oxidative phosphorylation and supercomplex assembly in rectus abdominis muscle of diabetic obese individuals. PMID- 26610931 TI - The association of bound aldehyde content with bioprosthetic tissue calcification. AB - The rapid progression of mineralization seen in glutaraldehyde-treated valves has prompted a wide variety of secondary treatments aimed at mitigating dystrophic calcification. We tested the hypothesis that aldehyde residuals bound to bioprosthetic tissue is a significant promoter of calcification. We developed a novel assay to measure residual aldehyde functional groups and assessed aldehyde content in three different groups: glutaraldehyde-fixed tissue (Glut-only), Edwards ThermaFixTM treated tissue and Edwards RESILIATM tissue. The amount of tissue calcification in these same groups was assessed in vivo using a well established rabbit model, in which tissue samples were implanted intramuscularly for 60 days. The aldehyde content of the Glut-only, ThermaFixTM treated and RESILIATM tissues were 225.7 +/- 31.5, 101.9 +/- 79.7 and 32.5 +/- 48.4 nmol/g, respectively. The differences among all three groups were highly significant (p < 0.001, Student's unpaired t test). The median (interquartile range) calcium content of the Glut-only, ThermaFixTM treated and RESILIATM tissues were 227.4 (221.8-243.6), 101.0 (23.05-169.6), and 10.1 (0.28-51.7) MUg/mg. The differences among all three groups were highly significant (p < 0.001, Mann-Whitney U test). The results indicated that our novel assay was able to reliably measure aldehyde content in bovine pericardial tissue. Furthermore, there appeared to be a close association between aldehyde content and tissue calcium content. The processing of bioprosthetic valves to reduce their aldehyde content may offer a significant advantage in terms of reducing the potential for long-term calcification in human implants. PMID- 26610934 TI - Slowing Menthol's Progress: Differential Impact of a Tobacco Tax Increase on Cigarette Sales. AB - OBJECTIVES: The proportion of smokers who use menthol cigarettes has increased nationally since 2004, while use of non-menthol cigarettes is declining, suggesting that menthol may be undermining the effectiveness of population level tobacco control efforts. In 2013 Minnesota passed a $1.75 cigarette tax increase. We investigated whether sales of menthol and non-menthol cigarettes were differentially affected by the price increase. METHODS: Cigarette sales data from convenience stores in the Minneapolis, Minnesota, metro area from January 2012, through May 2015, were obtained. Proportion of sales accounted for by menthol cigarettes was analyzed with segmented regression. RESULTS: Before the price increase, menthol cigarettes gained 2.21% (1.17, 3.12) of market share annually. Following the price increase, the trend slowed to 0.26% (-0.78, 1.56) annually. The slope before the price increase was significantly positive; the slope following the price increase did not significantly differ from zero. CONCLUSIONS: Sales of menthol cigarettes declined less rapidly than non-menthol cigarettes before the price increase. Sales of menthol and non-menthol cigarettes declined at more comparable rates after the price increase. Increasing the price of tobacco may help ensure declines in consumption are more evenly distributed across menthol and non-menthol cigarettes. IMPLICATIONS: Using sales data, we found that a trend of increasing market share for menthol cigarettes was significantly reduced by a $1.75 cigarette price increase. These results suggest that cigarette price increases, a core tobacco control policy, may have a greater effect on menthol smokers than non-menthol smokers. PMID- 26610935 TI - Preference for Flavored Noncombustible Nicotine Products Among Smokers Motivated to Switch From Cigarettes. PMID- 26610933 TI - Non-Antarctic notothenioids: Past phylogenetic history and contemporary phylogeographic implications in the face of environmental changes. AB - The non-Antarctic Notothenioidei families, Bovichtidae, Pseudaphritidae and Eleginopsidae, diverged early from the main notothenioid lineage. They are important in clarifying the early evolutionary processes that triggered notothenioid evolution in the Antarctic. The early-diverged group represents 8% of all notothenioid species and never established themselves on the Antarctic shelf. Most attention has been paid to the Antarctic notothenioids and their limited physiological tolerance to climate change and increased temperatures. In this review, we discuss key life history traits that are characteristic of the non-Antarctic early-diverged notothenioid taxa as well as the genetic resources and population differentiation information available for this group. We emphasise the population fitness and dynamics of these species and indicate how resource management and conservation of the group can be strengthened through an integrative approach. Both Antarctic waters and the non-Antarctic regions face rapid temperature rises combined with strong anthropogenic exploitation. While it is expected that early-diverged notothenioid species may have physiological advantages over high Antarctic species, it is difficult to predict how climate changes might alter the geographic range, behaviour, phenology and ultimately genetic variability of these species. It is possible, however, that their high degree of endemism and dependence on local environmental specificities to complete their life cycles might enhance their vulnerability. PMID- 26610936 TI - Socioeconomic Inequalities in Secondhand Smoke Exposure at Home and at Work in 15 Low- and Middle-Income Countries. AB - INTRODUCTION: In high-income countries, secondhand smoke (SHS) exposure is higher among disadvantaged groups. We examine socioeconomic inequalities in SHS exposure at home and at workplace in 15 low- and middle-income countries (LMICs). METHODS: Secondary analyses of cross-sectional data from 15 LMICs participating in Global Adult Tobacco Survey (participants >= 15 years; 2008-2011) were used. Country specific analyses using regression-based methods were used to estimate the magnitude of socioeconomic inequalities in SHS exposure: (1) Relative Index of Inequality and (2) Slope Index of Inequality. RESULTS: SHS exposure at home ranged from 17.4% in Mexico to 73.1% in Vietnam; exposure at workplace ranged from 16.9% in Uruguay to 65.8% in Bangladesh. In India, Bangladesh, Thailand, Malaysia, Philippines, Vietnam, Uruguay, Poland, Turkey, Ukraine, and Egypt, SHS exposure at home reduced with increasing wealth (Relative Index of Inequality range: 1.13 [95% confidence interval [CI] 1.04-1.22] in Turkey to 3.31 [95% CI 2.91-3.77] in Thailand; Slope Index of Inequality range: 0.06 [95% CI 0.02-0.11] in Turkey to 0.43 [95% CI 0.38-0.48] in Philippines). In these 11 countries, and in China, SHS exposure at home reduced with increasing education. In India, Bangladesh, Thailand, and Philippines, SHS exposure at workplace reduced with increasing wealth. In India, Bangladesh, Thailand, Philippines, Vietnam, Poland, Russian Federation, Turkey, Ukraine, and Egypt, SHS exposure at workplace reduced with increasing education. CONCLUSION: SHS exposure at homes is higher among the socioeconomically disadvantaged in the majority of LMICs studied; at workplaces, exposure is higher among the less educated. Pro-equity tobacco control interventions alongside targeted efforts in these groups are recommended to reduce inequalities in SHS exposure. IMPLICATIONS: SHS exposure is higher among the socioeconomically disadvantaged groups in high-income countries. Comprehensive smoke-free policies are pro-equity for certain health outcomes that are strongly influenced by SHS exposure. Using nationally representative Global Adult Tobacco Survey (2008-2011) data from 15 LMICs, we studied socioeconomic inequalities in SHS exposure at homes and at workplaces. The study showed that in most LMICs, SHS exposure at homes is higher among the poor and the less educated. At workplaces, SHS exposure is higher among the less educated groups. Accelerating implementation of pro-equity tobacco control interventions and strengthening of efforts targeted at the socioeconomically disadvantaged groups are needed to reduce inequalities in SHS exposure in LMICs. PMID- 26610937 TI - A Two-Wave Observational Study of Compliance With Youth Access and Tobacco Advertising Provisions of the Cigarettes and Other Tobacco Products Act in India. AB - INTRODUCTION: The Indian Cigarettes and Other Tobacco Products Act prohibits youths' access to tobacco products at points-of-sale and near educational institutions, requires signage stating these restrictions in these venues, and bans outdoor advertisements. This observational study examined compliance with these provisions, changes in compliance over 1 year, and factors associated with compliance. METHODS: Data were collected in 2012 and 2013 from points-of-sale (n = 555 in 2012, n = 718 in 2013), educational institutions (n = 277 in 2012, n = 276 in 2013), and neighborhoods (n = 104 in 2012, n = 125 in 2013) in 25 urban and rural towns in five states. Compliance across years was compared using chi square tests. Multilevel regression equations assessed factors associated with compliance at Wave 2 and change in compliance from Wave 1 to Wave 2. RESULTS: Most points-of-sale had no/low compliance, with little change over time (58% to 63%, P = .108). The proportion of educational institutions observing just 1-2 provisions increased (39% to 52%, P = .002). Most neighborhoods complied with the advertisement ban at both waves (91% to 96%, P = .172). In the multilevel analysis, point-of-sale compliance increased in small cities; compliance decreased at points-of-sale and increased at institutions in mid-sized cities. Changes in point-of-sale compliance were due to compliance with access restrictions and signage requirements; changes in educational institution compliance were due to compliance with the sales ban. CONCLUSIONS: Compliance with provisions regarding the sale and display of tobacco products is moderate, while compliance with the advertisement ban remains high in these five Indian states. Greater enforcement will further reduce youths' exposure to tobacco products. IMPLICATIONS: The study adds to the literature on compliance and changes in compliance with policy to prohibit youth access to tobacco products in India, a country that has large geographic disparities in youth smoking prevalence. The findings highlight several important areas on which efforts can focus to improve compliance among points-of-sale, educations institutions, and neighborhoods to limit youths' exposure and access to tobacco products. Rural areas and large cities in particular need more concerted efforts. PMID- 26610938 TI - Noise-Induced Hearing Loss: Permanent Versus Temporary Threshold Shifts and the Effects of Hair Cell Versus Neuronal Degeneration. AB - For decades, research on permanent noise-induced hearing loss has concentrated on the death of sensory hair cells and the associated threshold elevations. Recent work has shown that cochlear neurons are actually more vulnerable to noise, and even after exposures causing only temporary threshold elevation and no loss of hair cells, there is a rapid and irreversible loss of synaptic connections between cochlear neurons and hair cells followed by a slow degeneration of cochlear nerve cell bodies and central axons. Although this noise-induced neuropathy does not affect the audiogram, it likely reduces performance on more complex auditory tasks such as speech discrimination in noise. PMID- 26610939 TI - Modeled and Measured Underwater Sound Isopleths and Implications for Marine Mammal Mitigation in Alaska. AB - Before operating air guns in Alaska, industry is usually required to model underwater sound isopleths, some of which have implications for the mitigation and monitoring of potential marine mammal impacts. Field measurements are often required to confirm or revise model predictions. We compared modeled and measured air gun sound isopleths from 2006 to 2012 and found poor agreement. Natural variability in the marine environment, application of precautionary correction factors, and data interpretation in the generation of circular isopleths all contributed to the observed poor agreement. A broader understanding of the realities of modeled and measured underwater sound isopleths will contribute to improved mitigation practices. PMID- 26610940 TI - Peer-Reviewed Studies on the Effects of Anthropogenic Noise on Marine Invertebrates: From Scallop Larvae to Giant Squid. AB - Marine invertebrates at the base of oceanic trophic webs play important ecological and economical roles supporting worldwide fisheries worth millions. There is an increasing concern about the effects of anthropogenic noise on marine fauna but little is known about its effects on invertebrates. Here the current peer-reviewed literature on this subject is reviewed, dealing with different ontogenetic stages and taxa. These studies show that the noise effects on marine invertebrates range from apparently null to behavioral/physiological responses to mortalities. They emphasize the need to consider potential interactions of human activities using intense sound sources with the conservation and fisheries of local invertebrate stocks. PMID- 26610941 TI - Sources of Underwater Sound and Their Characterization. AB - Because of the history of sonar and sonar engineering, the concept of "source level" is widely used to characterize anthropogenic sound sources, but is it useful for sources other than sonar transmitters? The concept and applicability of source level are reviewed for sonar, air guns, explosions, ships, and pile drivers. International efforts toward the harmonization of the terminology for underwater sound and measurement procedures for underwater sound sources are summarized, with particular attention to the initiatives of the International Organization for Standardization. PMID- 26610942 TI - Assessment of Marine Mammal Impact Zones for Use of Military Sonar in the Baltic Sea. AB - Military sonars are known to have caused cetaceans to strand. Navies in shallow seas use different frequencies and sonar pulses, commonly frequencies between 25 and 100 kHz, compared with most studied NATO sonar systems that have been evaluated for their environmental impact. These frequencies match the frequencies of best hearing in the harbor porpoises and seals resident in the Baltic Sea. This study uses published temporary and permanent threshold shifts, measured behavioral response thresholds, technical specifications of a sonar system, and environmental parameters affecting sound propagation common for the Baltic Sea to estimate the impact zones for harbor porpoises and seals. PMID- 26610943 TI - Contribution to the Understanding of Particle Motion Perception in Marine Invertebrates. AB - Marine invertebrates potentially represent a group of species whose ecology may be influenced by artificial noise. Exposure to anthropogenic sound sources could have a direct consequence on the functionality and sensitivity of their sensory organs, the statocysts, which are responsible for their equilibrium and movements in the water column. The availability of novel laser Doppler vibrometer techniques has recently opened the possibility of measuring whole body (distance, velocity, and acceleration) vibration as a direct stimulus eliciting statocyst response, offering the scientific community a new level of understanding of the marine invertebrate hearing mechanism. PMID- 26610944 TI - Functional Morphology and Symmetry in the Odontocete Ear Complex. AB - Odontocete ear complexes or tympanoperiotic complexes (TPCs) were compared for asymmetry. Left and right TPCs were collected from one long-beaked common dolphin (Delphinus capensis) and one Amazon River dolphin (Inia geoffrensis). Asymmetry was assessed by volumetric comparisons of left and right TPCs and by visual comparison of superimposed models of the right TPC to a reflected mirror image of the left TPC. Kolmogorov-Smirnov tests were performed to compare the resonant frequencies of the TPCs as calculated by vibrational analysis. All analyses found slight differences between TPCs from the same specimen in contrast to the directional asymmetry in the nasal region of odontocete skulls. PMID- 26610945 TI - A Low-Cost Open-Source Acoustic Recorder for Bioacoustics Research. AB - Acoustic recorders are the primary tool used in marine bioacoustics; however, available devices are either expensive or lack self-calibration capabilities that are critical for high-quality measurements. Moreover, the software used in proprietary designs can be inflexible and may involve unknown processing steps. To address this, we have designed a miniature low-cost yet high-performance acoustic recorder that features open-source hardware and software. Circuitry is included for self-calibration, making it possible to evaluate device performance in situ. Our intention is that the design will develop in conjunction with the needs of the bioacoustics community. PMID- 26610946 TI - Assessment of Impulsive and Continuous Low-Frequency Noise in Irish Waters. AB - As part of the European Union Marine Strategy Framework Directive (MSFD), member states are required to address noise pollution in the marine environment under Descriptor 11. This study aimed to provide a practical desk-based application of Descriptor 11 assessment, focusing on the main contributors of ocean noise pollution in Irish waters, seismic surveying and shipping. To highlight specific geographical areas subject to elevated levels of noise pollution, the proportion of days over a calendar year that seismic air guns were operational was calculated and the vessel density per 50-km(2) grids was determined across Ireland's exclusive economic zone (EEZ). Additionally, cetacean sighting data were used to determine the degree of spatial overlap between areas of elevated noise pollution and areas of cetacean abundance. PMID- 26610947 TI - Is the Venice Lagoon Noisy? First Passive Listening Monitoring of the Venice Lagoon: Possible Effects on the Typical Fish Community. AB - Three passive listening surveys have been carried out in two of the three Venice lagoon tide inlets and inside the Venice island. The spectral content and the intensity level of the underwater noise as well as the presence or absence of Sciaena umbra and the distribution of its different sound patterns have been investigated in all the recording sites. The passive listening proved to be successful in detecting S. umbra drumming sounds in both Venice lagoon tide inlets. Our results indicate that the spectral content and the level of underwater noise pollution in the Venice lagoon could affect fish acoustic communication. PMID- 26610948 TI - Effect of Pile-Driving Sounds on the Survival of Larval Fish. AB - Concern exists about the potential effects of pile-driving sounds on fish, but evidence is limited, especially for fish larvae. A device was developed to expose larvae to accurately reproduced pile-driving sounds. Controlled exposure experiments were carried out to examine the lethal effects in common sole larvae. No significant effects were observed at zero-to-peak pressure levels up to 210 dB re 1 MUPa(2) and cumulative sound exposure levels up to 206 dB re 1 MUPa(2).s, which is well above the US interim criteria for nonauditory tissue damage in fish. Experiments are presently being carried out for European sea bass and herring larvae. PMID- 26610949 TI - Challenge of Using Passive Acoustic Monitoring in High-Energy Environments: UK Tidal Environments and Other Case Studies. AB - The use of passive acoustic monitoring (PAM) around marine developments is commonplace. A buffer-based PAM system (e.g., C-POD) is a cost-effective method for assessing cetacean acoustic presence. Devices have been deployed by Sea Mammal Research Unit (SMRU) Marine around the United Kingdom, allowing an examination of the performance of C-PODs with respect to background noise, tilt angle, and environmental factors. C-PODs were found to often only monitor for a few seconds of each minute, resulting in significant loss of monitoring time. Issues were likely driven by environmental and deployment factors. The practical limitations of buffer-based PAM systems in high-energy/noisy environments are indicated here. PMID- 26610950 TI - Hearing Mechanisms and Noise Metrics Related to Auditory Masking in Bottlenose Dolphins (Tursiops truncatus). AB - Odontocete cetaceans are acoustic specialists that depend on sound to hunt, forage, navigate, detect predators, and communicate. Auditory masking from natural and anthropogenic sound sources may adversely affect these fitness related capabilities. The ability to detect a tone in a broad range of natural, anthropogenic, and synthesized noise was tested with bottlenose dolphins using a psychophysical, band-widening procedure. Diverging masking patterns were found for noise bandwidths greater than the width of an auditory filter. Despite different noise types having equal-pressure spectral-density levels (95 dB re 1 MUPa(2)/Hz), masked detection threshold differences were as large as 22 dB. Consecutive experiments indicated that noise types with increased levels of amplitude modulation resulted in comodulation masking release due to within channel and across-channel auditory mechanisms. The degree to which noise types were comodulated (comodulation index) was assessed by calculating the magnitude squared coherence between the temporal envelope from an auditory filter centered on the signal and temporal envelopes from flanking filters. Statistical models indicate that masked thresholds in a variety of noise types, at a variety of levels, can be explained with metrics related to the comodulation index in addition to the pressure spectral-density level of noise. This study suggests that predicting auditory masking from ocean noise sources depends on both spectral and temporal properties of the noise. PMID- 26610951 TI - Effects of Hatchery Rearing on the Structure and Function of Salmonid Mechanosensory Systems. AB - This paper reviews recent studies on the effects of hatchery rearing on the auditory and lateral line systems of salmonid fishes. Major conclusions are that (1) hatchery-reared juveniles exhibit abnormal lateral line morphology (relative to wild-origin conspecifics), suggesting that the hatchery environment affects lateral line structure, perhaps due to differences in the hydrodynamic conditions of hatcheries versus natural rearing environments, and (2) hatchery-reared salmonids have a high proportion of abnormal otoliths, a condition associated with reduced auditory sensitivity and suggestive of inner ear dysfunction. PMID- 26610952 TI - Effects of Impulsive Pile-Driving Exposure on Fishes. AB - Six species of fishes were tested under aquatic far-field, plane-wave acoustic conditions to answer several key questions regarding the effects of exposure to impulsive pile driving. The issues addressed included which sound levels lead to the onset of barotrauma injuries, how these levels differ between fishes with different types of swim bladders, the recovery from barotrauma injuries, and the potential effects exposure might have on the auditory system. The results demonstrate that the current interim criteria for pile-driving sound exposures are 20 dB or more below the actual sound levels that result in the onset of physiological effects on fishes. PMID- 26610953 TI - Review of the Effects of Offshore Seismic Surveys in Cetaceans: Are Mass Strandings a Possibility? AB - Displacement of cetaceans is commonly reported during offshore seismic surveys. Speculation concerning possible links between seismic survey noise and cetacean strandings is available for a dozen events but without convincing causal evidence. This lack of evidence should not be considered conclusive but rather as reflecting the absence of a comprehensive analysis of the circumstances. Current mitigation guidelines are inadequate for long-range effects such as displacements and the potential for strandings. This review presents the available information for ten documented strandings that were possibly linked to seismic surveys and recommends initial measures and actions to further evaluate this potential link. PMID- 26610954 TI - Addressing Challenges in Studies of Behavioral Responses of Whales to Noise. AB - Studying the behavioral response of whales to noise presents numerous challenges. In addition to the characteristics of the noise exposure, many factors may affect the response and these must be measured and accounted for in the analysis. An adequate sample size that includes matching controls is crucial if meaningful results are to be obtained. Field work is thus complicated, logistically difficult, and expensive. This paper discusses some of the challenges and how they are being met in a large-scale multiplatform project in which humpback whales are exposed to the noise of seismic air guns. PMID- 26610955 TI - Measurements of Operational Wind Turbine Noise in UK Waters. AB - The effects of wind farm operational noise have not been addressed to the same extent as their construction methods such as piling and drilling of the foundations despite their long operational lifetimes compared with weeks of construction. The results of five postconstruction underwater sound-monitoring surveys on wind farms located throughout the waters of the British Isles are discussed. These wind farms consist of differing turbine power outputs, from 3 to 3.6 MW, and differing numbers of turbines. This work presents an overview of the results obtained and discusses both the levels and frequency components of the sound in several metrics. PMID- 26610956 TI - A Bioenergetics Approach to Understanding the Population Consequences of Disturbance: Elephant Seals as a Model System. AB - Using long-term empirical data, we developed a complete population consequences of acoustic disturbance (PCAD) model and application for northern elephant seals. We assumed that the animals would not successfully forage while in a 100-km diameter disturbance region within their foraging and transit paths. The decrease in lipid gain due to exposure was then translated to changes in birth rate and pup survival. Given their large foraging range, elephant seals were resilient to such a disturbance, showing no population-level effects. However, similar track analysis showed that given their more coastal nature, California sea lions were within a 25-km-diameter region of disturbance more often. PMID- 26610957 TI - Singing Fish in an Ocean of Noise: Effects of Boat Noise on the Plainfin Midshipman (Porichthys notatus) in a Natural Ecosystem. AB - When it comes to hearing and vocal communication in fishes, the plainfin midshipman (Porichthys notatus) is perhaps best understood. However, distinctly lacking are studies investigating communication of P. notatus in its natural ecosystems and the effects of noise on wild fish populations. Here, an exploratory look into both is discussed. By monitoring a population of wild P. notatus off British Columbia, Canada, call patterns were distinguished, the function of communicative sounds was identified, and midshipman vocalizations in agonistic encounters with natural predators were evaluated. A preliminary investigation into the effects of boat noise on wild midshipman is also described. PMID- 26610958 TI - Detection of Complex Sounds in Quiet Conditions by Seals and Sea Lions. AB - To test how accurately baseline audiometric data predict detection of complex stimuli, absolute detection thresholds for frequency-modulated (FM), amplitude modulated (AM), and harmonic stimuli were obtained for one Phoca vitulina (harbor seal) and one Zalophus californianus (California sea lion) at frequencies spanning the functional range of hearing. These thresholds were then compared with a priori predictions based on the tonal audiograms of these subjects. Predicted thresholds were accurate for most FM signals and for AM signals for the California sea lion. Predictions were unreliable for harmonic signals for both species and for AM signals for the harbor seal. PMID- 26610959 TI - Offshore Dredger Sounds: Source Levels, Sound Maps, and Risk Assessment. AB - The underwater sound produced during construction of the Port of Rotterdam harbor extension (Maasvlakte 2) was measured, with emphasis on the contribution of the trailing suction hopper dredgers during their various activities: dredging, transport, and discharge of sediment. Measured source levels of the dredgers, estimated source levels of other shipping, and time-dependent position data from a vessel-tracking system were used as input for a propagation model to generate dynamic sound maps. Various scenarios were studied to assess the risk of possible effects of the sound from dredging activities on marine fauna, specifically on porpoises, seals, and fish. PMID- 26610960 TI - Effects of Offshore Wind Farms on the Early Life Stages of Dicentrarchus labrax. AB - Anthropogenically generated underwater noise in the marine environment is ubiquitous, comprising both intense impulse and continuous noise. The installation of offshore wind farms across the North Sea has triggered a range of ecological questions regarding the impact of anthropogenically produced underwater noise on marine wildlife. Our interest is on the impact on the "passive drifters," i.e., the early life stages of fish that form the basis of fish populations and are an important prey for pelagic predators. This study deals with the impact of pile driving and operational noise generated at offshore wind farms on Dicentrarchus labrax (sea bass) larvae. PMID- 26610961 TI - The European Marine Strategy: Noise Monitoring in European Marine Waters from 2014. AB - The European Marine Strategy Framework Directive requires European member states to develop strategies for their marine waters leading to programs of measures that achieve or maintain good environmental status (GES) in all European seas by 2020. An essential step toward reaching GES is the establishment of monitoring programs, enabling the state of marine waters to be assessed on a regular basis. A register for impulsive noise-generating activities would enable assessment of their cumulative impacts on wide temporal and spatial scales; monitoring of ambient noise would provide essential insight into current levels and any trend in European waters. PMID- 26610962 TI - Potential Population Consequences of Active Sonar Disturbance in Atlantic Herring: Estimating the Maximum Risk. AB - Effects of noise on fish populations may be predicted by the population consequence of acoustic disturbance (PCAD) model. We have predicted the potential risk of population disturbance when the highest sound exposure level (SEL) at which adult herring do not respond to naval sonar (SEL(0)) is exceeded. When the population density is low (feeding), the risk is low even at high sonar source levels and long-duration exercises (>24 h). With densely packed populations (overwintering), a sonar exercise might expose the entire population to levels >SEL(0) within a 24-h exercise period. However, the disturbance will be short and the response threshold used here is highly conservative. It is therefore unlikely that naval sonar will significantly impact the herring population. PMID- 26610963 TI - Fulfilling EU Laws to Ensure Marine Mammal Protection During Marine Renewable Construction Operations in Scotland. AB - Large-scale offshore renewable energy infrastructure construction in Scottish waters is anticipated in coming decades. An approach being pursued, with a view to preventing short-range marine mammal injury, is the introduction of additional noise sources to intentionally disturb and displace animals from renewable sites over the construction period. To date, no full and transparent consideration has been given to the long-term cost benefits of noise reduction compared with noise inducing mitigation techniques. It has yet to be determined if the introduction of additional noise is consistent with the objectives of the EU Habitats Directive and the Marine Strategy Framework Directive. PMID- 26610964 TI - Expert Elicitation Methods in Quantifying the Consequences of Acoustic Disturbance from Offshore Renewable Energy Developments. AB - There are many developments for offshore renewable energy around the United Kingdom whose installation typically produces large amounts of far-reaching noise, potentially disturbing many marine mammals. The potential to affect the favorable conservation status of many species means extensive environmental impact assessment requirements for the licensing of such installation activities. Quantification of such complex risk problems is difficult and much of the key information is not readily available. Expert elicitation methods can be employed in such pressing cases. We describe the methodology used in an expert elicitation study conducted in the United Kingdom for combining expert opinions based on statistical distributions and copula-like methods. PMID- 26610965 TI - Masking Experiments in Humans and Birds Using Anthropogenic Noises. AB - This study investigated the masking of pure tones by anthropogenic noises in humans and birds. Bird experiments were conducted in the laboratory using operant conditioning and psychophysical procedures but with anthropogenic noises rather than white noise. Humans were tested using equivalent psychophysical procedures in the field with ambient background noise. Results show that for both humans and birds published critical ratios can be used to predict the masking thresholds for pure tones by these complex noises. Thus, the species' critical ratio can be used to estimate the effect of anthropogenic environmental noises on the perception of communication and other biologically relevant sounds. PMID- 26610967 TI - Soundscapes and Larval Settlement: Larval Bivalve Responses to Habitat-Associated Underwater Sounds. AB - We quantified the effects of habitat-associated sounds on the settlement response of two species of bivalves with contrasting habitat preferences: (1) Crassostrea virginicia (oyster), which prefers to settle on other oysters, and (2) Mercenaria mercenaria (clam), which settles on unstructured habitats. Oyster larval settlement in the laboratory was significantly higher when exposed to oyster reef sound compared with either off-reef or no-sound treatments. Clam larval settlement did not vary according to sound treatments. Similar to laboratory results, field experiments showed that oyster larval settlement in "larval housings" suspended above oyster reefs was significantly higher compared with off reef sites. PMID- 26610966 TI - Documenting and Assessing Dolphin Calls and Ambient and Anthropogenic Noise Levels via PAM and a SPL Meter. AB - Song Meter SM2M marine recorders were deployed to document dolphin calls and ambient and anthropogenic noise. Recordings from Bimini were split into 2-h segments; no segment was without dolphin calls. At Dolphin Encounters, average noise levels ranged from 110 to 125 dB; the highest source level was 147.98 dB re 1 MUPa at 1 m. Average ambient-noise levels documented at 4 sites in Guam were below 118 dB re 1 MUPa at 1 m. These data were compared with values from a custom built sound pressure level (SPL) meter and confirm that the SM2M recorder is a useful tool for assessing animal calls and ambient and anthropogenic noise levels. PMID- 26610968 TI - Characterizing Marine Soundscapes. AB - The study of marine soundscapes is becoming widespread and the amount of data collected is increasing rapidly. Data owners (typically academia, industry, government, and defense) are negotiating data sharing and generating potential for data syntheses, comparative studies, analyses of trends, and large-scale and long-term acoustic ecology research. A problem is the lack of standards and commonly agreed protocols for the recording of marine soundscapes, data analysis, and reporting that make a synthesis and comparison of results difficult. We provide a brief overview of the components in a marine soundscape, the hard- and software tools for recording and analyzing marine soundscapes, and common reporting formats. PMID- 26610969 TI - Pile-Driving Noise Impairs Antipredator Behavior of the European Sea Bass Dicentrarchus labrax. AB - In an increasingly industrialized world, man-made noise is changing the underwater acoustic environment. The effects of anthropogenic noise on marine ecosystems are not yet fully understood despite important implications for science and policy, in particular with respect to investment in offshore renewable energy. In this study, a traditional looming-stimulus experimental setup was used to investigate the acute effects of pile-driving noise on the antipredator response of European sea bass (Dicentrarchus labrax). Playback of pile-driving noise was found to impair significantly the startle response of individuals, which potentially translates to an increased likelihood of being captured by predators in natural conditions. PMID- 26610970 TI - Using Reaction Time and Equal Latency Contours to Derive Auditory Weighting Functions in Sea Lions and Dolphins. AB - Subjective loudness measurements are used to create equal-loudness contours and auditory weighting functions for human noise-mitigation criteria; however, comparable direct measurements of subjective loudness with animal subjects are difficult to conduct. In this study, simple reaction time to pure tones was measured as a proxy for subjective loudness in a Tursiops truncatus and Zalophus californianus. Contours fit to equal reaction-time curves were then used to estimate the shapes of auditory weighting functions. PMID- 26610971 TI - Does Primary Productivity Turn Up the Volume? Exploring the Relationship Between Chlorophyll a and the Soundscape of Coral Reefs in the Pacific. AB - Chlorophyll is the basis for ecosystem productivity in most marine environments. We report on an ongoing effort to examine whether ambient sounds are tied to chlorophyll levels. We hypothesized that an increase in food-web available energy will be distributed across trophic levels, eventually reaching sound-producing animals and increasing acoustic levels. To test our hypothesis, we compared reef environments to explore links between soundscapes and chlorophyll a concentrations. The study sites resided in disparate oceanographic regimes that experienced substantially different oceanographic conditions. We anticipated that the results would show differing patterns of primary productivity between sites and therefore would be reflected in the soundscapes. PMID- 26610972 TI - Expert Elicitation of Population-Level Effects of Disturbance. AB - Expert elicitation is a rigorous method for synthesizing expert knowledge to inform decision making and is reliable and practical when field data are limited. We evaluated the feasibility of applying expert elicitation to estimate population-level effects of disturbance on marine mammals. Diverse experts estimated parameters related to mortality and sublethal injury of North Atlantic right whales (Eubalaena glacialis). We are now eliciting expert knowledge on the movement of right whales among geographic regions to parameterize a spatial model of health. Expert elicitation complements methods such as simulation models or extrapolations from other species, sometimes with greater accuracy and less uncertainty. PMID- 26610973 TI - Current Status of Development of Methods to Assess Effects of Cumulative or Aggregated Underwater Sounds on Marine Mammals. AB - There are no standards for assessment of the cumulative effects of underwater sound. Quantitative assessments typically consider a single source, whereas qualitative assessments may include multiple sources but rarely identify response variables. As a step toward understanding the cumulative effects of underwater sound, we assessed the aggregated sounds of multiple sources received by migrating bowhead whales (Balaena mysticetus). The quantitative method models the sound field from multiple sources and simulates movement of a population through it. The qualitative method uses experts to assess the responses of individuals and populations to sound sources and identify the potential mechanisms. These methods increase the transparency of assessments. PMID- 26610974 TI - Seismic Survey Footprints in Irish Waters: A Starting Point for Effective Mitigation. AB - The noise footprint of a given activity is defined as the area where the noise from the activity spreads into the ocean at levels above the existing statistical ambient noise. The noise footprints of seismic surveys in Irish waters from 2,000 to 2,011 have been estimated using Quonops, a global ocean noise prediction service. Noise footprints are converted into sound exposure levels to evaluate the cumulative risks toward high-, mid-, and low-frequency marine mammals. The results demonstrate large variability in risk areas as a function of existing ambient-noise levels, season, survey location, and characteristics of the survey. PMID- 26610975 TI - Stochastic Modeling of Behavioral Response to Anthropogenic Sounds. AB - The effect of anthropogenic sounds on marine wildlife is typically assessed by convolving the spatial, temporal, and spectral properties of a modeled sound field with a representation of animal distribution within the field. Both components benefit from stochastic modeling techniques based on field observations. Recent studies have also highlighted the effect of context on the probability and severity of the animal behavioral response to sound. This paper extends the stochastic approach to three modeling scenarios, including key contextual variables in aversion from a given level of sound and as a means of evaluating the effectiveness of passive acoustic monitoring. PMID- 26610976 TI - Underwater Sound Levels at a Wave Energy Device Testing Facility in Falmouth Bay, UK. AB - Passive acoustic monitoring devices were deployed at FaBTest in Falmouth Bay, UK, a marine renewable energy device testing facility during trials of a wave energy device. The area supports considerable commercial shipping and recreational boating along with diverse marine fauna. Noise monitoring occurred during (1) a baseline period, (2) installation activity, (3) the device in situ with inactive power status, and (4) the device in situ with active power status. This paper discusses the preliminary findings of the sound recording at FabTest during these different activity periods of a wave energy device trial. PMID- 26610977 TI - Predicting Anthropogenic Noise Contributions to US Waters. AB - To increase understanding of the potential effects of chronic underwater noise in US waters, the National Oceanic and Atmospheric Administration (NOAA) organized two working groups in 2011, collectively called "CetSound," to develop tools to map the density and distribution of cetaceans (CetMap) and predict the contribution of human activities to underwater noise (SoundMap). The SoundMap effort utilized data on density, distribution, acoustic signatures of dominant noise sources, and environmental descriptors to map estimated temporal, spatial, and spectral contributions to background noise. These predicted soundscapes are an initial step toward assessing chronic anthropogenic noise impacts on the ocean's varied acoustic habitats and the animals utilizing them. PMID- 26610978 TI - Auditory Sensitivity and Masking Profiles for the Sea Otter (Enhydra lutris). AB - Sea otters are threatened marine mammals that may be negatively impacted by human generated coastal noise, yet information about sound reception in this species is surprisingly scarce. We investigated amphibious hearing in sea otters by obtaining the first measurements of absolute sensitivity and critical masking ratios. Auditory thresholds were measured in air and underwater from 0.125 to 40 kHz. Critical ratios derived from aerial masked thresholds from 0.25 to 22.6 kHz were also obtained. These data indicate that although sea otters can detect underwater sounds, their hearing appears to be primarily air adapted and not specialized for detecting signals in background noise. PMID- 26610979 TI - Are Masking-Based Models of Risk Useful? AB - As our understanding of directly observable effects from anthropogenic sound exposure has improved, concern about "unobservable" effects such as stress and masking have received greater attention. Equal energy models of masking such as power spectrum models have the appeal of simplicity, but do they offer biologically realistic assessments of the risk of masking? Data relevant to masking such as critical ratios, critical bandwidths, temporal resolution, and directional resolution along with what is known about general mammalian antimasking mechanisms all argue for a much more complicated view of masking when making decisions about the risk of masking inherent in a given anthropogenic sound exposure scenario. PMID- 26610980 TI - "Large" Tank Acoustics: How Big Is Big Enough? AB - In this paper, we discuss the issues encountered when trying to perform hearing experiments in water-filled tanks that are several meters in lateral extent, typically large in terms of the size of the animals under study but not necessarily so with respect to the wavelengths of interest. This paper presents measurements of pressure and particle motion fields in these "large" tanks. The observed characteristics and complexities are discussed in reference to their potential impact on the planning and interpretation of hearing experiments. PMID- 26610981 TI - High-Resolution Analysis of Seismic Air Gun Impulses and Their Reverberant Field as Contributors to an Acoustic Environment. AB - In September and October 2011, a seismic survey took place in Baffin Bay, Western Greenland, in close proximity to a marine protected area (MPA). As part of the mitigation effort, five bottom-mounted marine acoustic recording units (MARUs) collected data that were used for the purpose of measuring temporal and spectral features from each impulsive event, providing a high-resolution record of seismic reverberation persistent after the direct impulse. Results were compared with ambient-noise levels as computed after the seismic survey to evidence that as a consequence of a series of repeating seismic impulses, sustained elevated levels create the potential for masking. PMID- 26610982 TI - Underwater Sound Propagation Modeling Methods for Predicting Marine Animal Exposure. AB - The offshore exploration and production (E&P) industry requires comprehensive and accurate ocean acoustic models for determining the exposure of marine life to the high levels of sound used in seismic surveys and other E&P activities. This paper reviews the types of acoustic models most useful for predicting the propagation of undersea noise sources and describes current exposure models. The severe problems caused by model sensitivity to the uncertainty in the environment are highlighted to support the conclusion that it is vital that risk assessments include transmission loss estimates with statistical measures of confidence. PMID- 26610983 TI - Investigating the Effect of Tones and Frequency Sweeps on the Collective Behavior of Penned Herring (Clupea harengus). AB - We experimentally played back tones and sweeps to captive herring (Clupea harengus) in a net pen and measured the collective response of a large and a small group of fish using a camera, echo sounder, and multibeam sonar. The playbacks ranged in frequency from 160 to 500 Hz and 131 to 147 dB re 1 MUPa in received sound pressure level. Herring behavior was scored by a team that blindly evaluated the observations. Overall, the responses were modest. Stronger reactions were observed at higher source levels, lower frequencies, and smaller school sizes, but there was no effect on signal rise time. PMID- 26610984 TI - The Challenges of Analyzing Behavioral Response Study Data: An Overview of the MOCHA (Multi-study OCean Acoustics Human Effects Analysis) Project. AB - This paper describes the MOCHA project which aims to develop novel approaches for the analysis of data collected during Behavioral Response Studies (BRSs). BRSs are experiments aimed at directly quantifying the effects of controlled dosages of natural or anthropogenic stimuli (typically sound) on marine mammal behavior. These experiments typically result in low sample size, relative to variability, and so we are looking at a number of studies in combination to maximize the gain from each one. We describe a suite of analytical tools applied to BRS data on beaked whales, including a simulation study aimed at informing future experimental design. PMID- 26610985 TI - National Oceanic and Atmospheric Administration's Cetacean and Sound Mapping Effort: Continuing Forward with an Integrated Ocean Noise Strategy. AB - To help manage chronic and cumulative impacts of human activities on marine mammals, the National Oceanic and Atmospheric Administration (NOAA) convened two working groups, the Underwater Sound Field Mapping Working Group (SoundMap) and the Cetacean Density and Distribution Mapping Working Group (CetMap), with overarching effort of both groups referred to as CetSound, which (1) mapped the predicted contribution of human sound sources to ocean noise and (2) provided region/time/species-specific cetacean density and distribution maps. Mapping products were presented at a symposium where future priorities were identified, including institutionalization/integration of the CetSound effort within NOAA wide goals and programs, creation of forums and mechanisms for external input and funding, and expanded outreach/education. NOAA is subsequently developing an ocean noise strategy to articulate noise conservation goals and further identify science and management actions needed to support them. PMID- 26610986 TI - Understanding the Population Consequences of Acoustic Disturbance for Marine Mammals. AB - Loud anthropogenic underwater noise, such as that associated with sonar operations, pile driving, or seismic surveys, can cause behavioral and physiological disturbance to many animals that may affect their survival or ability to breed. However, no formal framework for assessing the population-level consequences of this disturbance is currently available. We describe an interim version of a framework developed by a working group on the population consequences of disturbance, funded by the US Office of Naval Research through the University of California, that can be used to assess the effects of offshore renewable energy developments on marine mammal populations. PMID- 26610987 TI - Multiple-Pulse Sounds and Seals: Results of a Harbor Seal (Phoca vitulina) Telemetry Study During Wind Farm Construction. AB - Offshore construction and survey techniques can produce pulsed sounds with a high sound pressure level. In coastal waters, the areas in which they are produced are often also used by seals, potentially resulting in auditory damage or behavioral avoidance. Here, we describe a study on harbor seals during a wind farm installation off southeast England. The study used GPS/global system for mobile communication tags on 23 harbor seals that provided distribution and activity data; the closest range of individual seals to piling varied from 6.65 to 46.1 km. Furthermore, the maximum predicted received levels (RLs) at individual seals varied between 146.9 and 169.4 dB re 1 MUPa peak to peak. PMID- 26610988 TI - Developing Sound Exposure Criteria for Fishes. AB - In assessing the impact of aquatic developments, it is important to evaluate whether accompanying underwater sounds might have adverse effects on fishes. Risk assessment can then be used to evaluate new and existing technologies for effective prevention, control, or mitigation of impacts. It is necessary to know the levels of sound that may cause potential harm to different species from different sources as well as those levels that are likely to be of no consequence. The development and use of impact criteria are still at an early stage for fishes. PMID- 26610989 TI - Calibration and Characterization of Autonomous Recorders Used in the Measurement of Underwater Noise. AB - The use of autonomous recorders is motivated by the need to monitor underwater noise, such as in response to the requirements of the European Union Marine Strategy Framework Directive. The performance of these systems is a crucial factor governing the quality of the measured data, providing traceability for future underwater noise-monitoring programs aimed at the protection of the marine environment from anthropogenic noise. In this paper, a discussion is presented of measurement methodologies for the key acoustic performance characteristics of the recorders, including self-noise, dynamic range, and the absolute sensitivity as a function of frequency of the hydrophone and recorder system. PMID- 26610990 TI - Intrinsic Directional Information of Ground Roll Waves. AB - Ground roll waves traveling across the seabed provide extra information, their direction of rotation, compared with plane waves in fluids or solids. Idealized Rayleigh waves are "retrograde" in that their horizontal particle motion opposes the direction of travel of the wave when the interface is raised. A single point measurement near the seabed can determine this rotation. In water, there are associated evanescent pressure waves that are largely confined to the bottom, likely to affect fish and other creatures near the seabed during pile driving. The directional information may prove key to the lifestyle of such creatures. PMID- 26610992 TI - Playback Experiments for Noise Exposure. AB - Playbacks are a useful tool for conducting well-controlled and replicated experiments on the effects of anthropogenic noise, particularly for repeated exposures. However, playbacks are unlikely to fully reproduce original sources of anthropogenic noise. Here we examined the sound pressure and particle acceleration of boat noise playbacks in a field experiment and reveal that although there remain recognized limitations, the signal-to-noise ratios of boat playbacks to ambient noise do not exceed those of a real boat. The experimental setup tested is therefore of value for use in experiments on the effects of repeated exposure of aquatic animals to boat noise. PMID- 26610991 TI - A Permanent Soundscape Monitoring System for the Care of Animals in Aquaria. AB - Sound pressure levels in facilities that house acoustically sensitive animals should be monitored on a regular basis as a standard component of animal care. Monitoring of noise levels in the pools housing Lagenorhynchus obliquidens (Pacific white-sided dolphins) at the Vancouver Aquarium during regular operations revealed average sound pressure levels (SPLs) across all frequency bins of 91.9 (range 87.0-104.5) dB re 1 MUPa Root Mean Square (RMS). Sustained pressure levels were highest during cleaning, where ambient noise levels increased approximately 25 dB re 1 MUPa RMS. PMID- 26610993 TI - Natural Variation in Stress Hormones, Comparisons Across Matrices, and Impacts Resulting from Induced Stress in the Bottlenose Dolphin. AB - Knowledge regarding stress hormones and how they vary in response to seasonality, gender, age, and reproductive status for any marine mammal is limited. Furthermore, stress hormones may be measured in more than one matrix (e.g., feces, blood, blubber), but the relationships between levels of a given hormone across these matrices are unknown, further complicating the interpretations of hormones measured in samples collected from wild animals. A study is underway to address these issues in a population of bottlenose dolphins trained for voluntary participation in sample collections from different matrices and across season and time of day. PMID- 26610994 TI - Risk Functions of Dolphins and Sea Lions Exposed to Sonar Signals. AB - Acoustic dose-response functions have been recommended as a means of predicting behavioral impacts on marine mammals from anthropogenic noise exposure. Thirty bottlenose dolphins and fifteen sea lions participated in a controlled exposure study to explore dose-response relationships to the received level of a simulated sonar signal. Both species showed an increase in the probability of response and in the severity of response with increased received levels. Differences in species sensitivity were noted in habituation and the impact of age on responsiveness. PMID- 26610995 TI - Residency of Reef Fish During Pile Driving Within a Shallow Pierside Environment. AB - The potential effects of pile driving on fish populations and commercial fisheries have received significant attention given the prevalence of construction occurring in coastal habitats throughout the world. In this study, we used acoustic telemetry to assess the movement and survival of free-ranging reef fish in Port Canaveral, FL, in response to 35 days of pile driving at an existing wharf complex. The site fidelity and behavior of 15 sheepshead (Archosargus probatocephalus) and 10 gray snapper (Lutjanus griseus) were determined before, during, and after pile driving. No obvious signs of mortality or injury to tagged fish were evident from the data. There was a significant decline in the residency index for mangrove snapper at the construction wharf after pile driving compared with the baseline, although this may be influenced by natural movements of this species in the study area rather than a direct response to pile driving. PMID- 26610996 TI - Hidden Markov Models Capture Behavioral Responses to Suction-Cup Tag Deployment: A Functional State Approach to Behavioral Context. AB - The biological consequences of behavioral responses to anthropogenic noise depend on context. We explore the links between individual motivation, condition, and external constraints in a concept model and illustrate the use of motivational behavioral states as a means to quantify the biologically relevant effects of tagging. Behavioral states were estimated from multiple streams of data in a hidden Markov model and used to test the change in foraging effort and the change in energetic success or cost given the effort. The presence of a tag boat elicited a short-term reduction in time spent in foraging states but not for proxies for success or cost within foraging states. PMID- 26610997 TI - A Change in the Use of Regulatory Criteria for Assessing Potential Impacts of Sound on Fishes. AB - The National Marine Fisheries Service (NMFS) currently uses interim criteria developed on the US West Coast to assess the potential onset of peak and cumulative effects of noise on fishes. Analyses performed for this project provided adequate support for the NMFS to use the peak criterion (i.e., area ensonified by 206 dB re 1 MUPa peak sound pressure level [SPL(peak)]) for estimating the incidental take of Hudson River sturgeon. Application of the peak criterion (rather than the cumulative criterion) could have implications for future construction projects because estimates of take using SPL(peak) will generally be considerably lower than estimates of take based on the cumulative sound exposure level. PMID- 26610998 TI - In-Air and Underwater Hearing in the Great Cormorant (Phalacrocorax carbo sinensis). AB - Hearing thresholds of a great cormorant (Phalacrocorax carbo) were measured in air and under water using psychophysics. The lowest thresholds were at 2 kHz (45 dB re 20 MUPa root-mean-square [rms] in air and 79 dB re 1 MUPa rms in water). Auditory brainstem response measurements on one anesthetized bird in air indicated an audiogram with a shape that resembled the one achieved by psychophysics. This study suggests that cormorants have rather poor in-air hearing abilities compared with other similar-size birds. The hearing capabilities in water are better than what would have been expected for a purely in-air adapted ear. PMID- 26610999 TI - Stress Response and Habituation to Motorboat Noise in Two Coastal Fish Species in the Bothnian Sea. AB - The effect of motorboat noise on stress responsiveness in Eurasian perch and roach was tested in field enclosure experiments. Perch showed elevated cortisol levels after one 30-min noise exposure but not when exposed to noise repeatedly for 11 days. Roach had higher cortisol levels when exposed to noise than without noise when short- and long-term experiments were pooled. Both species had more cortisol in enclosures with mixed species compared with single-species enclosures. Both species also had higher cortisol levels in the short-term compared with the long-term experiment. Thus, a stress effect of motorboat noise may decrease with time due to habituation. PMID- 26611000 TI - Cumulative Effects of Exposure to Continuous and Intermittent Sounds on Temporary Hearing Threshold Shifts Induced in a Harbor Porpoise (Phocoena phocoena). AB - The effects of exposure to continuous and intermittent anthropogenic sounds on temporary hearing threshold shifts (TTSs) in a harbor porpoise were investigated by testing hearing before and after exposure to 1- to 2-kHz downsweeps of 1 s, without harmonics, presented as paired-intermittent and continuous-exposure combinations with identical cumulative sound exposure levels (SEL(cum)). Exposure to intermittent sounds resulted in lower TTSs than exposure to continuous sounds with the same SEL(cum). Therefore, the hearing of marine mammals is at less risk from intermittent anthropogenic noises than from continuous ones at the same received sound pressure level and duration. PMID- 26611001 TI - Great Ears: Low-Frequency Sensitivity Correlates in Land and Marine Leviathans. AB - Like elephants, baleen whales produce low-frequency (LF) and even infrasonic (IF) signals, suggesting they may be particularly susceptible to underwater anthropogenic sound impacts. Analyses of computerized tomography scans and histologies of the ears in five baleen whale and two elephant species revealed that LF thresholds correlate with basilar membrane thickness/width and cochlear radii ratios. These factors are consistent with high-mass, low-stiffness membranes and broad spiral curvatures, suggesting that Mysticeti and Proboscidea evolved common inner ear adaptations over similar time scales for processing IF/LF sounds despite operating in different media. PMID- 26611002 TI - What We Can Learn from Artificial Lateral Line Sensor Arrays. AB - The lateral line system of fish is important for many behaviors, including spatial orientation, prey detection, intraspecific communication, and entraining. With aid of the lateral line, fish perceive minute water motions. The smallest sensory unit of the lateral line is the neuromast, which occurs freestanding on the skin and in fluid-filled canals. We have built artificial lateral line canal systems that can be used to measure spatiotemporal flow patterns. Those patterns can, for instance, be used to distinguish between different environments and upstream objects. PMID- 26611003 TI - Protection of Marine Mammals. AB - Within the European Defense Agency (EDA), the Protection of Marine Mammals (PoMM) project, a comprehensive common marine mammal database essential for risk mitigation tools, was established. The database, built on an extensive dataset collection with the focus on areas of operational interest for European navies, consists of annual and seasonal distribution and density maps, random and systematic sightings, an encyclopedia providing knowledge on the characteristics of 126 marine mammal species, data on marine mammal protection areas, and audio information including numerous examples of various vocalizations. Special investigations on marine mammal acoustics were carried out to improve the detection and classification capabilities. PMID- 26611004 TI - Avoidance of Pile-Driving Noise by Hudson River Sturgeon During Construction of the New NY Bridge at Tappan Zee. AB - Sturgeon movements were monitored during a pile-driving operation. Fewer sturgeon were detected during pile driving and remained for a shorter time than during silent control periods. Moreover, the short time spent by sturgeon near pile driving suggests that they were unlikely to have reached the criterion of 187 dB re 1 MUPa(2).s cumulative sound exposure level. These results suggest that sturgeon are likely to avoid impact pile driving and not remain long enough to experience physiological effects, thus providing empirical evidence that the 206 dB re 1 MUPa peak sound pressure level is the appropriate criterion for assessing the impacts of pile-driving noise on sturgeon. PMID- 26611005 TI - Methods for Predicting Potential Impacts of Pile-Driving Noise on Endangered Sturgeon During Bridge Construction. AB - The potential impacts of pile-driving noise on Hudson River sturgeon during construction of the New NY Bridge were predicted. Abundance data for shortnose and Atlantic sturgeon derived from fisheries sampling were combined with data about the spatial extent of pile-driving noise. This approach was used to calculate the number of sturgeon that could occur within sound level isopleths exceeding peak and cumulative noise criteria used by the National Marine Fisheries Service to determine the incidental take of sturgeon. The number of sturgeon subject to the potential onset of physiological effects during pile driving was predicted to be 35-41 fish for each species. PMID- 26611006 TI - Automatic Classification of Marine Mammals with Speaker Classification Methods. AB - We present an automatic acoustic classifier for marine mammals based on human speaker classification methods as an element of a passive acoustic monitoring (PAM) tool. This work is part of the Protection of Marine Mammals (PoMM) project under the framework of the European Defense Agency (EDA) and joined by the Research Department for Underwater Acoustics and Geophysics (FWG), Bundeswehr Technical Centre (WTD 71) and Kiel University. The automatic classification should support sonar operators in the risk mitigation process before and during sonar exercises with a reliable automatic classification result. PMID- 26611007 TI - Directional Hearing and Head-Related Transfer Function in Odontocete Cetaceans. AB - The head-related transfer function (HRTF) is an important descriptor of spatial sound field reception by the listener. In this study, we computed the HRTF of the common dolphin Delphinus delphis. The received sound pressure level at various locations within the acoustic fats of the internal pinna near the surface of the tympanoperiotic complex (TPC) was calculated for planar incident waves directed toward the animal. The relative amplitude of the received pressure versus the incident pressure was the representation of the HRTF from the point of view of the animal. It is of interest that (1) different locations on the surface of the TPC resulted in different HRTFs, (2) the HRTFs for the left and right ears were slightly asymmetric, and (3) the locations of the peaks of the HRTF depended on the frequency of the incident wave. PMID- 26611008 TI - Controlled Sonar Exposure Experiments on Cetaceans in Norwegian Waters: Overview of the 3S-Project. AB - In mitigating the risk of sonar operations, the behavioral response of cetaceans is one of the major knowledge gaps that needs to be addressed. The 3S-Project has conducted a number of controlled exposure experiments with a realistic sonar source in Norwegian waters from 2006 to 2013. In total, the following six target species have been studied: killer, long-finned pilot, sperm, humpback, minke, and northern bottlenose whales. A total of 38 controlled sonar exposures have been conducted on these species. Responses from controlled and repeated exposure runs have been recorded using acoustic and visual observations as well as with electronic tags on the target animal. So far, the first dose-response curves as well as an overview of the scored severity of responses have been revealed. In this paper, an overview is presented of the approach for the study, including the results so far as well as the current status of the ongoing analysis. PMID- 26611009 TI - SOFAR: A New Sound-Acquisition Software Package for Underwater Noise Monitoring. AB - When monitoring underwater noise, the recording of in situ environmental parameters is a vital supplement to the recording of ambient noise or offshore anthropogenic activities. Although there are some software packages available that have the capability of recording sound at different sample rates using a variety of tools, the set-up configuration and all important environmental conditions recording still rely on the operator. SOFAR, a new sound-acquisition software package, was designed and created to provide an intuitive and streamlined process of recording data along with all the necessary metrics that play a vital role in the data analysis and assessment. PMID- 26611010 TI - Passive Underwater Noise Attenuation Using Large Encapsulated Air Bubbles. AB - Measurements demonstrating low-frequency underwater sound attenuation using arrays of large, tethered, stationary encapsulated bubbles to surround a sound source were compared with various effective medium models for the acoustic dispersion relationship in bubbly liquids. Good agreement was observed between measurements for the large bubbles (on the order of 10 cm) at frequencies below 1 kHz and a model originally intended to describe the acoustic behavior of ultrasound contrast agents. The primary goal is to use the model for designing encapsulated-bubble-based underwater noise abatement systems and to reduce uncertainty in system performance. PMID- 26611011 TI - Measurement of Underwater Operational Noise Emitted by Wave and Tidal Stream Energy Devices. AB - The increasing international growth in the development of marine and freshwater wave and tidal energy harvesting systems has been followed by a growing requirement to understand any associated underwater impact. Radiated noise generated during operation is dependent on the device's physical properties, the sound-propagation environment, and the device's operational state. Physical properties may include size, distribution in the water column, and mechanics/hydrodynamics. The sound-propagation environment may be influenced by water depth, bathymetry, sediment type, and water column acoustic properties, and operational state may be influenced by tidal cycle and wave height among others This paper discusses some of the challenges for measurement of noise characteristics from these devices as well as a case study of the measurement of radiated noise from a full-scale wave energy converter. PMID- 26611012 TI - Likely Age-Related Hearing Loss (Presbycusis) in a Stranded Indo-Pacific Humpback Dolphin (Sousa chinensis). AB - The hearing of a stranded Indo-Pacific humpback dolphin (Sousa chinensis) in Zhuhai, China, was measured. The age of this animal was estimated to be ~40 years. The animal's hearing was measured using a noninvasive auditory evoked potential (AEP) method. The results showed that the high-frequency hearing cutoff frequency of the studied dolphin was ~30-40 kHz lower than that of a conspecific younger individual ~13 year old. The lower high-frequency hearing range in the older dolphin was explained as a likely result of age-related hearing loss (presbycusis). PMID- 26611014 TI - Soundscapes and Larval Settlement: Characterizing the Stimulus from a Larval Perspective. AB - There is growing evidence that underwater sounds serve as a cue for the larvae of marine organisms to locate suitable settlement habitats; however, the relevant spatiotemporal scales of variability in habitat-related sounds and how this variation scales with larval settlement processes remain largely uncharacterized, particularly in estuarine habitats. Here, we provide an overview of the approaches we have developed to characterize an estuarine soundscape as it relates to larval processes, and a conceptual framework is provided for how habitat-related sounds may influence larval settlement, using oyster reef soundscapes as an example. PMID- 26611013 TI - Impacts of Underwater Noise on Marine Vertebrates: Project Introduction and First Results. AB - The project conducts application-oriented research on impacts of underwater noise on marine vertebrates in the North and Baltic Seas. In distinct subprojects, the hearing sensitivity of harbor porpoises and gray seals as well as the acoustic tolerance limit of harbor porpoises to impulsive noise from pile driving and stress reactions caused by anthropogenic noise is investigated. Animals are equipped with DTAGs capable of recording the actual surrounding noise field of free-swimming harbor porpoises and seals. Acoustic noise mapping including porpoise detectors in the Natura 2000 sites of the North and Baltic Seas will help to fully understand current noise impacts. PMID- 26611015 TI - Does Vessel Noise Affect Oyster Toadfish Calling Rates? AB - The question we addressed in this study is whether oyster toadfish respond to vessel disturbances by calling less when vessels with lower frequency spectra are present in a sound recording and afterward. Long-term data recorders were deployed at the Neuse (high vessel-noise site) and Pamlico (low vessel-noise site) Rivers. There were many fewer toadfish detections at the high vessel-noise site than the low-noise station. Calling rates were lower in the high-boat traffic area, suggesting that toadfish cannot call over loud vessel noise, reducing the overall calling rate, and may have to call more often when vessels are not present. PMID- 26611016 TI - Comparison of PAM Systems for Acoustic Monitoring and Further Risk Mitigation Application. AB - We present results of the SIRENA 2011 research cruises conducted by the NATO Undersea Research Centre (NURC) and joined by the Research Department for Underwater Acoustics and Geophysics (FWG), Bundeswehr Technical Centre (WTD 71) and the Universities of Kiel and Pavia. The cruises were carried out in the Ligurian Sea. The main aim of the FWG was to test and evaluate the newly developed towed hydrophone array as a passive acoustic monitoring (PAM) tool for risk mitigation applications. The system was compared with the PAM equipment used by the other participating institutions. Recorded sounds were used to improve an automatic acoustic classifier for marine mammals, and validated acoustic detections by observers were compared with the results of the classifier. PMID- 26611017 TI - Cardiorespiratory Responses to Acoustic Noise in Belugas. AB - To date, most research on the adverse effects of anthropogenic noise on marine mammals has focused on auditory and behavioral responses. Other responses have received little attention and are often ignored. In this study, the effect of acoustic noise on heart rate was examined in captive belugas. The data suggest that (1) heart rate can be used as a measure of physiological response (including stress) to noise in belugas and other cetaceans, (2) cardiac response is influenced by parameters of noise and adaptation to repeated exposure, and (3) cetacean calves are more vulnerable to the adverse effect of noise than adults. PMID- 26611018 TI - Acoustic Communication in Fishes and Potential Effects of Noise. AB - Many soniferous fishes such as cods and groupers are commercially important. Sounds are produced during courtship and spawning, and there is the potential for aquatic noise to interfere with critical behaviors and affect populations. There are few data on the response of wild populations of sound-producing fishes to acoustic noise. New motion and sound exposure fish tags could be used to assess the behavioral responses of large numbers of fish to noise exposure. Many factors, such as fishing mortality and environmental variability in prey supply, could also affect populations and potentially interact with the behavioral responses to noise. PMID- 26611019 TI - Evaluation of Three Sensor Types for Particle Motion Measurement. AB - All fish sense acoustic particle motion; some species also sense pressure. Concern over the effects of anthropogenic sounds is increasing the need to monitor acoustic particle motion. Particle motion can be measured directly using vector sensors or calculated from pressure gradients. This article compares three devices that measure particle motion: a three-axis accelerometer, a three-axis velocity sensor, and two 4-element hydrophone arrays. A series of sounds (constant-wave tones, white noise, and Ricker wavelets) were played from a fixed position projector. The particle motion of sounds from imploding light bulbs was also measured. PMID- 26611020 TI - Regional Variations and Trends in Ambient Noise: Examples from Australian Waters. AB - Studies of ambient noise south of Australia show higher levels at low frequencies in the deep water off the continental shelf compared with locations on the shelf. The difference arises because of differences in transmission loss. Marine animals would experience significantly different noise levels and directionality in the two regions and while crossing the boundary, provide positional information. Opportunities for long-range, low-frequency communication by animals would be significantly limited by the higher background noise in the open ocean. Measures of long-term sea noise trends highlight the influence of biological sources and the importance of local sound transmission regimens. PMID- 26611021 TI - Spatial Patterns of Inshore Marine Soundscapes. AB - Passive acoustic monitoring was employed to investigate spatial patterns of soundscapes within a marine reserve. High energy level broadband snaps dominated nearly all habitat soundscapes. Snaps, the principal acoustic feature of soundscapes, were primarily responsible for the observed spatial patterns, and soundscapes appeared to retain a level of compositional and configurational stability. In the presence of high-level broadband snaps, soundscape composition was more influenced by geographic location than habitat type. Future research should focus on investigating the spatial patterns of soundscapes across a wider range of coastal and offshore seascapes containing a variety of distinct ecosystems and habitats. PMID- 26611022 TI - Soundscape and Noise Exposure Monitoring in a Marine Protected Area Using Shipping Data and Time-Lapse Footage. AB - We review recent work that developed new techniques for underwater noise assessment that integrate acoustic monitoring with automatic identification system (AIS) shipping data and time-lapse video, meteorological, and tidal data. Two sites were studied within the Moray Firth Special Area of Conservation (SAC) for bottlenose dolphins, where increased shipping traffic is expected from construction of offshore wind farms outside the SAC. Noise exposure varied markedly between the sites, and natural and anthropogenic contributions were characterized using multiple data sources. At one site, AIS-operating vessels accounted for total cumulative sound exposure (0.1-10 kHz), suggesting that noise modeling using the AIS would be feasible. PMID- 26611023 TI - Global Trends in Ocean Noise. AB - This ongoing work provides information about sound level trends from three ocean regions to compare with those of the North Pacific to determine whether increasing sound levels are a global phenomenon. Here the term soundscape is used to describe a measured physical property that can be selectively decomposed by frequency and sound level is used to provide insight relating to conditions ranging from the quietest conditions (sound floor) to the most extreme acoustic events. Acoustic time series from the Indian, South Atlantic, and Equatorial Pacific Oceans were used to quantify the rate and direction of low-frequency change over the past decade. PMID- 26611024 TI - Pile-Driving Pressure and Particle Velocity at the Seabed: Quantifying Effects on Crustaceans and Groundfish. AB - We modeled the effects of pile driving on crustaceans, groundfish, and other animals near the seafloor. Three different waves were investigated, including the compressional wave, shear wave, and interface wave. A finite element (FE) technique was employed in and around the pile, whereas a parabolic equation (PE) code was used to predict propagation at long ranges from the pile. Pressure, particle displacement, and particle velocity are presented as a function of range at the seafloor for a shallow-water environment near Rhode Island. We discuss the potential effects on animals near the seafloor. PMID- 26611025 TI - Measuring Hearing in Wild Beluga Whales. AB - We measured the hearing abilities of seven wild beluga whales (Delphinapterus leucas) during a collection-and-release experiment in Bristol Bay, AK. Here we summarize the methods and initial data from one animal and discuss the implications of this experiment. Audiograms were collected from 4 to 150 kHz. The animal with the lowest threshold heard best at 80 kHz and demonstrated overall good hearing from 22 to 110 kHz. The robustness of the methodology and data suggest that the auditory evoked potential audiograms can be incorporated into future collection-and-release health assessments. Such methods may provide high quality results for multiple animals, facilitating population-level audiograms and hearing measures in new species. PMID- 26611026 TI - Auditory Discrimination of Natural and High-Pass Filtered Bark Vocalizations in a California Sea Lion (Zalophus californianus). AB - A California sea lion performed a psychophysical auditory discrimination task with a set of six stimuli: three barks recorded from conspecific males and high pass filtered versions of the barks that removed the majority of energy at fundamental frequencies. Discrimination performance and subject reaction times (RTs) suggested that the vocalizations were all perceived as fairly dissimilar. This preliminary study hints that low-frequency components are a salient part of the California sea lion bark despite elevation of this species' aerial hearing thresholds and the potential for elevated environmental noise levels at frequencies below 1 kHz. PMID- 26611027 TI - Hearing Sensation Changes When a Warning Predicts a Loud Sound in the False Killer Whale (Pseudorca crassidens). AB - Stranded whales and dolphins have sometimes been associated with loud anthropogenic sounds. Echolocating whales produce very loud sounds themselves and have developed the ability to protect their hearing from their own signals. A false killer whale's hearing sensitivity was measured when a faint warning sound was given just before the presentation of an increase in intensity to 170 dB. If the warning occurred within 1-9 s, as opposed to 20-40 s, the whale showed a 13 dB reduction in hearing sensitivity. Warning sounds before loud pulses may help mitigate the effects of loud anthropogenic sounds on wild animals. PMID- 26611028 TI - Does Masking Matter? Shipping Noise and Fish Vocalizations. AB - Shipping creates large near-field background noises at levels similar to or higher than fish vocalizations and in the same critical bandwidths. This noise has the potential to "mask" biologically important signals and prevent fish from hearing them; any interference with the detection and recognition of sounds may impact fish survival. The Lombard effect, whereby vocalizations are altered to reduce or exclude masking effects, is an adaptation that has been observed in mammals and birds. Research is needed to establish whether the Lombard effect occurs in fish to gain a better understanding of the implications of noise pollution on fish populations. PMID- 26611029 TI - Noise Mitigation During Pile Driving Efficiently Reduces Disturbance of Marine Mammals. AB - Acoustic monitoring of harbor porpoises (Phocoena phocoena L., 1758) indicated a strongly reduced disturbance by noise emitted by pile driving for offshore wind turbine foundations insulated by a big bubble curtain (BBC). This newly developed noise mitigation system was tested during construction of the offshore wind farm Borkum West II (North Sea). Because porpoise activity strongly corresponded to the sound level, operation of the new system under its most suitable configuration reduced the porpoise disturbance area by ~90%. Hence, for the first time, a positive effect of a noise mitigation system during offshore pile driving on an affected marine mammal species could be demonstrated. PMID- 26611030 TI - Noise Impact on European Sea Bass Behavior: Temporal Structure Matters. AB - Anthropogenic sounds come in different forms, varying not only in amplitude and frequency spectrum but also in temporal structure. Although fish are sensitive to the temporal characteristics of sound, little is known about how their behavior is affected by anthropogenic sounds of different temporal patterns. We investigated this question using groups of Dicentrarchus labrax (European sea bass) in an outdoor basin. Our data revealed that the temporal pattern of sound exposure is important in noise impact assessments. PMID- 26611031 TI - Does Noise From Shipping and Boat Traffic Affect Predator Vigilance in the European Common Hermit Crab? AB - The effect of noise on predator vigilance in Pagurus bernhardus was explored in this study. Latency of the first response, emergence time, and response type were measured from hermit crabs during continuous and variable vessel noise and two controls. The mean (+/-SE) response latency was longer for the noise treatments (continuous, 18.19 +/- 2.78 s; variable, 11.39 +/- 1.48 s) than for the controls (ambient, 7.21 +/- 0.82 s; silent, 6.66 +/- 0.95 s). Response type and emergence time were not significantly affected but were more variable during the noise treatments than during the controls. Noisy conditions may increase predation risk, suggesting potential fitness consequences for invertebrates. PMID- 26611033 TI - Sound Transmission Validation and Sensitivity Studies in Numerical Models. AB - In 1974, Norris and Harvey published an experimental study of sound transmission into the head of the bottlenose dolphin. We used this rare source of data to validate our Vibroacoustic Toolkit, an array of numerical modeling simulation tools. Norris and Harvey provided measurements of received sound pressure in various locations within the dolphin's head from a sound source that was moved around the outside of the head. Our toolkit was used to predict the curves of pressure with the best-guess input data (material properties, transducer and hydrophone locations, and geometry of the animal's head). In addition, we performed a series of sensitivity analyses (SAs). SA is concerned with understanding how input changes to the model influence the outputs. SA can enhance understanding of a complex model by finding and analyzing unexpected model behavior, discriminating which inputs have a dominant effect on particular outputs, exploring how inputs combine to affect outputs, and gaining insight as to what additional information improves the model's ability to predict. Even when a computational model does not adequately reproduce the behavior of a physical system, its sensitivities may be useful for developing inferences about key features of the physical system. Our findings may become a valuable source of information for modeling the interactions between sound and anatomy. PMID- 26611032 TI - The Use of Deep Water Berths and the Effect of Noise on Bottlenose Dolphins in the Shannon Estuary cSAC. AB - The Shannon Estuary on the west coast of Ireland is one of Europe's premier deepwater berths catering for ships up to 200,000 deadweight tonnage. It is also Ireland's only designated candidate special area of conservation for bottlenose dolphins under the EU Habitats Directive. Long-term static acoustic monitoring was carried out at a number of intensive shipping sites. In 2012, noise monitoring took place over a 6-month period (at 1 site) as part of Ireland's requirements under the Marine Strategy Framework Directive (MSFD). This is the first assessment of the potential effect of vessel traffic on the behavior of this discrete dolphin population. PMID- 26611034 TI - Patterns of Occurrence and Marine Mammal Acoustic Behavior in Relation to Navy Sonar Activity Off Jacksonville, Florida. AB - Passive acoustic data collected from marine autonomous recording units deployed off Jacksonville, FL (from 13 September to 8 October 2009 and 3 December 2009 to 8 January 2010), were analyzed for detection of cetaceans and Navy sonar. Cetaceans detected included Balaenoptera acutorostrata, Eubalaena glacialis, B. borealis, Physeter macrocephalus, blackfish, and delphinids. E. glacialis were detected at shallow and, somewhat unexpectedly, deep sites. P. macrocephalus were characterized by a strong diel pattern. B. acutorostrata showed the strongest relationship between sonar activity and vocal behavior. These results provide a preliminary assessment of cetacean occurrence off Jacksonville and new insights on vocal responses to sonar. PMID- 26611035 TI - Hearing in Whales and Dolphins: Relevance and Limitations. AB - Understanding the hearing of marine mammals has been a priority to quantify and mitigate the impact of anthropogenic sound on these apex predators. Yet our knowledge of cetacean hearing is still limited to a few dozen species, therefore compromising any attempt to design adaptive management strategies. The use of auditory evoked potentials allows scientists to rapidly and noninvasively obtain the hearing data of species rarely available in captivity. Unfortunately, many practical and ethical reasons still limit the availability of large whales, thus restricting the possibility to effectively ensure that anthropogenic sounds have minimum effects on these species. The example of a recent Blainville's beaked whale (Mesoplodon densirostris) audiogram collected after a stranding indicated, for instance, very specialized hearing between 40 and 50 kHz, which corresponded to the frequency-modulated upsweep signals used by this species during echolocation. The methods used during a stranding event are presented along with the major difficulties that have slowed down the scientific community in measuring the audition of large whales and the potential value in obtaining such results when successful. PMID- 26611037 TI - Renewables, Shipping, and Protected Species: A Vanishing Opportunity for Effective Marine Spatial Planning? AB - Anthropogenic noise is a by-product from human activity that impacts protected species and is increasingly being considered in environmental management decisions. Offshore energy development presents a navigational hazard to existing shipping, making the locations of these two sources of noise mutually exclusive. This fact means that licensing decisions are stepping into the realm of coastal and marine spatial planning (CMSP). To be effective, conservation measures must also be considered in the CMSP process to mitigate potential cumulative adverse effects associated with resource development, particularly with multiuse conflicts. Thus managers should consider shipping lane relocation to make environmentally optimal decisions. PMID- 26611036 TI - Humans, Fish, and Whales: How Right Whales Modify Calling Behavior in Response to Shifting Background Noise Conditions. AB - This study investigates the role of behavioral plasticity in the variation of sound production of southern right whales (Eubalaena australis) in response to changes in the ambient background noise conditions. Data were collected from southern right whales in Brazilian waters in October and November 2011. The goal of this study was to quantify differences in right whale vocalizations recorded in low background noise as a control, fish chorus noise, and vessel noise. Variation in call parameters were detected among the three background noise conditions and have implications for future studies of noise effects on whale sound production. PMID- 26611038 TI - Are the 1/3-Octave Band 63- and 125-Hz Noise Levels Predictive of Vessel Activity? The Case in the Cres-Losinj Archipelago (Northern Adriatic Sea, Croatia). AB - A 3-years sea ambient-noise (SAN) monitoring was carried out in the Cres-Losinj Archipelago (Croatia), where a bottlenose dolphin population is threatened by unregulated nautical tourism. A total of 540 5-min SAN samples were collected and analyzed in an Indicator 11.2.1 (Marine Strategy Framework Directive) perspective. The 1/3-octave band center frequencies of 63 and 125 Hz (re 1 MUPa.rms) proved to be predictive of local predominant ship type over time. However, the noisiest band level was centered on 200 Hz. We therefore suggest measuring a wider frequency band than those requested in Indicator 11.2.1. PMID- 26611039 TI - The Good, The Bad, and The Distant: Soundscape Cues for Larval Fish. AB - Coral reef noise is an important navigation cue for settling reef fish larvae and can thus potentially affect reef population dynamics. Recent evidence has shown that fish are able to discriminate between the soundscapes of different types of habitat (e.g., mangrove and reef). In this study, we investigated whether discernible acoustic differences were present between sites within the same coral reef system. Differences in sound intensity and transient content were found between sites, but site-dependent temporal variation was also present. We discuss the implications of these findings for settling fish larvae. PMID- 26611040 TI - Terrestrial Soundscapes: Status of Ecological Research in Natural and Human Dominated Landscapes. AB - Soundscape ecological research in terrestrial systems is relatively new. In this paper, I present a brief summary of the origins of this research area, describe research questions related to several research thrusts that are ongoing, summarize several soundscape projects that exist and how these relate to the research thrusts, and briefly describe the work of a global network of scientists, musicians, and engineers that are attempting to move this new field forward. PMID- 26611041 TI - Effects of Underwater Turbine Noise on Crab Larval Metamorphosis. AB - The development of marine tidal turbines has advanced at a rapid rate over the last decade but with little detailed understanding of the potential noise impacts on invertebrates. Previous research has shown that underwater reef noise plays an important role in mediating metamorphosis in many larval crabs and fishes. New research suggests that underwater estuarine noise may also mediate metamorphosis in estuarine crab larvae and that the noise emitted from underwater tidal and sea based wind turbines may significantly influence larval metamorphosis in estuarine crabs. PMID- 26611042 TI - Temporary Threshold Shifts in Naive and Experienced Belugas: Can Dampening of the Effects of Fatiguing Sounds Be Learned? AB - In belugas (Delphinapterus leucas), substantial (10-15 dB) differences in temporary threshold shifts (TTSs) were observed between the first and subsequent experimental sessions in the same subjects. In the first session (naive subject state), the TTSs produced by exposure to fatiguing noises were larger than the TTSs produced in subsequent sessions (experienced subject state). After one to two sessions, the TTSs stabilized. The baseline hearing thresholds did not differ between the naive and experienced states. One possible explanation for this effect is that the animals learned to dampen their hearing during exposure to fatiguing noises and thus mitigate the impact of those noises. PMID- 26611044 TI - Effects of Seismic Air Guns on Pallid Sturgeon and Paddlefish. AB - Pallid sturgeon and paddlefish were placed at different distances from a seismic air gun array to determine the potential effects on mortality and nonauditory body tissues from the sound from a single shot. Fish were held 7 days postexposure and then necropsied. No fish died immediately after sound exposure or over the postexposure period. Statistical analysis of injuries showed no differences between the experimental and control animals in either type or severity of injuries. There was also no difference in injuries between fish exposed closest to the source compared with those exposed furthest from the source. PMID- 26611043 TI - Pile Driving at the New Bridge at Tappan Zee: Potential Environmental Impacts. AB - A new bridge will be constructed to replace the aging Tappan Zee Bridge over the Hudson River in New York. Construction will potentially result in hydroacoustic impacts to the local fish fauna. As a consequence, a substantial environmental impact analysis had to be conducted to obtain construction permits. This paper describes the process of environmental analysis and some of the results of the studies that led up to the final permitting. The process included modeling of pile-driving acoustics, analysis of river ambient noise, analysis of test piling, and observations on fish behavior during these tests. PMID- 26611045 TI - A Summary Comparison of Active Acoustic Detections and Visual Observations of Marine Mammals in the Canadian Beaufort Sea. AB - Fisheries sonar was used to determine the applicability of active acoustic monitoring (AAM) for marine mammal detection in the Canadian Beaufort Sea. During 170 h of simultaneous observation by marine mammal observers and active acoustic observation, 119 Balaena mysticetus (bowheads) and 4 Delphinapterus leucas (belugas) were visually sighted, while 59 acoustic signals of bowheads were detected by AAM operators. Observations and detection of seals were also recorded. Comparative results indicate that commercially available active acoustic systems can detect seals at distances up to 500 m and large baleen whales at distances up to 2 km. PMID- 26611046 TI - Use of Preoperation Acoustic Modeling Combined with Real-Time Sound Level Monitoring to Mitigate Behavioral Effects of Seismic Surveys. AB - Underwater acoustic modeling is often used to estimate the injury radius around a seismic exploration source; only occasionally has it been applied to the mitigation of behavioral effects, where the safety boundary may extend to many kilometers. Such a mitigation strategy requires precise estimation of the sound field for many source locations and likely entails field validation over the course of the operation to ensure that mitigation regions are accurate. This article reviews the enactment of such an approach for a seismic survey off Sakhalin Island and examines how similar principles may be applied to other surveys under suitable conditions. PMID- 26611047 TI - Potential Competitive Dynamics of Acoustic Ecology. AB - The top predators in coastal marine ecosystems, such as whales, dolphins, seabirds, and large predatory fishes (including sharks), may compete with each other to exploit food aggregations. Finding these patchy food sources and being first to a food patch could provide a significant competitive advantage. Our hypothesis is that food patches have specific sound signatures that marine predators could detect and that acoustic sources and animal sensory capabilities may contribute to competition dynamics. Preliminary analysis shows that diving gannets have a distinct spectral signature between 80 and 200 Hz, which falls within the hearing sensitivity of large pelagic fishes. Therefore, we suggest that diving birds may contribute to the sound signatures of food aggregations, linking competition dynamics both above and below the water surface. PMID- 26611048 TI - Beyond a Simple Effect: Variable and Changing Responses to Anthropogenic Noise. AB - A growing number of experimental studies have demonstrated that exposure to anthropogenic noise can affect the behavior and physiology of a variety of aquatic organisms. However, work in other fields suggests that responses are likely to differ between species, individuals, and situations and across time. We suggest that issues such as interspecific and intrapopulation variation, context dependency, repeated exposure and prior experience, and recovery and compensation need to be considered if we are to gain a full understanding of the impacts of this global pollutant. PMID- 26611049 TI - Underwater Sound Propagation from Marine Pile Driving. AB - Pile driving occurs in a variety of nearshore environments that typically have very shallow-water depths. The propagation of pile-driving sound in water is complex, where sound is directly radiated from the pile as well as through the ground substrate. Piles driven in the ground near water bodies can produce considerable underwater sound energy. This paper presents examples of sound propagation through shallow-water environments. Some of these examples illustrate the substantial variation in sound amplitude over time that can be critical to understand when computing an acoustic-based safety zone for aquatic species. PMID- 26611050 TI - Effects of Sound on the Behavior of Wild, Unrestrained Fish Schools. AB - To assess and manage the impact of man-made sounds on fish, we need information on how behavior is affected. Here, wild unrestrained pelagic fish schools were observed under quiet conditions using sonar. Fish were exposed to synthetic piling sounds at different levels using custom-built sound projectors, and behavioral changes were examined. In some cases, the depth of schools changed after noise playback; full dispersal of schools was also evident. The methods we developed for examining the behavior of unrestrained fish to sound exposure have proved successful and may allow further testing of the relationship between responsiveness and sound level. PMID- 26611051 TI - Sensitivity of Crustaceans to Substrate-Borne Vibration. AB - There is increasing interest in the responsiveness of crustaceans to vibrations, especially in the context of marine developments where techniques such as pile driving create strong vibrations that are readily transmitted through the seabed. Experiments were undertaken under controlled conditions to investigate the sensitivity of unconditioned crustaceans to substrate-borne vibration. The subjects were exposed to a range of frequencies and amplitudes using the staircase method of presentation to determine the thresholds of response. Behavior varied according to the strength of the stimuli and included bursts of movement and rapid bouts of movement. PMID- 26611052 TI - Parvulescu Revisited: Small Tank Acoustics for Bioacousticians. AB - Researchers often perform hearing studies on fish in small tanks. The acoustic field in such a tank is considerably different from the acoustic field that occurs in the animal's natural environment. The significance of these differences is magnified by the nature of the fish's auditory system where either acoustic pressure (a scalar), acoustic particle velocity (a vector), or both may serve as the stimulus. It is essential for the underwater acoustician to understand the acoustics of small tanks to be able to carry out valid auditory research in the laboratory and to properly compare and interpret the results of others. PMID- 26611053 TI - Assessing the Underwater Ship Noise Levels in the North Tyrrhenian Sea. AB - The purpose of this research was to assess the anthropic underwater noise caused by ships within the Cetacean Sanctuary, a wide area in the North Tyrrhenian Sea. Noise from low-frequency continuous sounds has been investigated within the 1/3 octave bands centered at 63 and 125 Hz. All the information about noise sources and sound attenuation have been organized in a database; a tool automatically extracts useful information from it and feeds a ray-tracing model to estimate noise levels. The results show average levels generally over the 100 dB re 1 MUPa value. PMID- 26611054 TI - Radiated Sound of a High-Speed Water-Jet-Propelled Transportation Vessel. AB - The radiated noise from a high-speed water-jet-propelled catamaran was measured for catamaran speeds of 12, 24, and 37 kn. The radiated noise increased with catamaran speed, although the shape of the noise spectrum was similar for all speeds and measuring hydrophone depth. The spectra peaked at ~200 Hz and dropped off continuously at higher frequencies. The radiated noise was 10-20 dB lower than noise from propeller-driven ships at comparable speeds. The combination of low radiated noise and high speed could be a factor in the detection and avoidance of water-jet-propelled ships by baleen whales. PMID- 26611055 TI - Impact of Anthropogenic Noise on Aquatic Animals: From Single Species to Community-Level Effects. AB - Anthropogenic noise underwater is on the rise and may affect aquatic animals of marine and freshwater ecosystems. Many recent studies concern some sort of impact assessment of a single species. Few studies addressed the noise impact on species interactions underwater, whereas there are some studies that address community level impact but only on land in air. Key processes such as predator-prey or competitor interactions may be affected by the masking of auditory cues, noise related disturbance, or attentional interference. Noise-associated changes in these interactions can cause shifts in species abundance and modify communities, leading to fundamental ecosystem changes. To gain further insight into the mechanism and generality of earlier findings, we investigated the impact on both a predator and a prey species in captivity, zebrafish (Danio rerio) preying on waterfleas (Daphnia magna). PMID- 26611056 TI - Identifying Variations in Baseline Behavior of Killer Whales (Orcinus orca) to Contextualize Their Responses to Anthropogenic Noise. AB - Determining the baseline behavior of a whale requires understanding natural variations occurring due to environmental context, such as changes in prey behavior. Killer whales feeding on herring consistently encircle herring schools; however, depth of feeding differs from near the surface in winter to deeper than 10 m in spring and summer. These variations in feeding depth are probably due to the depth of the prey and the balance between the costs and benefits of bringing schools of herring to the surface. Such variation in baseline behavior may incur different energetic costs and consequently change the motivation of whales to avoid a feeding area. Here, we discuss these variations in feeding behavior in the context of exposure to noise and interpret observed responses to simulated navy sonar signals. PMID- 26611057 TI - A Brief Review of Cephalopod Behavioral Responses to Sound. AB - Sound is a widely available cue in aquatic environments and is used by many marine animals for vital behaviors. Most research has focused on marine vertebrates. Relatively little is known about sound detection in marine invertebrates despite their abundance and importance in marine environments. Cephalopods are a key taxon in many ecosystems, but their behavioral interactions relative to acoustic stimuli have seldom been studied. Here we review current knowledge regarding (1) the frequency ranges and sound levels that generate behavioral responses and (2) the types of behavioral responses and their biological relevance. PMID- 26611058 TI - Effects of Model Formulation on Estimates of Health in Individual Right Whales (Eubalaena glacialis). AB - Right whales are vulnerable to many sources of anthropogenic disturbance including ship strikes, entanglement with fishing gear, and anthropogenic noise. The effect of these factors on individual health is unclear. A statistical model using photographic evidence of health was recently built to infer the true or hidden health of individual right whales. However, two important prior assumptions about the role of missing data and unexplained variance on the estimates were not previously assessed. Here we tested these factors by varying prior assumptions and model formulation. We found sensitivity to each assumption and used the output to make guidelines on future model formulation. PMID- 26611059 TI - Auditory Effects of Multiple Impulses from a Seismic Air Gun on Bottlenose Dolphins (Tursiops truncatus). AB - Auditory thresholds were measured in three bottlenose dolphins before and after exposure to ten impulses from a seismic air gun. Thresholds were measured using behavioral and electrophysiological methods to determine the amount of temporary threshold shift induced. The results suggest that the potential for seismic surveys using air guns to cause auditory effects on dolphins may be lower than previously predicted; however, two of the three dolphins exhibited "anticipatory" behavioral changes at the highest exposure condition that suggested they were attempting to mitigate the effects of the exposures. PMID- 26611060 TI - Communicating the Issue of Underwater Noise Pollution: The Deaf as a Fish Project. AB - Aquatic noise pollution is largely ignored by the lay public. How experts communicate this issue is critical to move public opinion. In 2010, the Cassa di Risparmio di Gorizia (CaRiGO) bank sponsored the Deaf as a Fish project that included local underwater noise monitoring, a boat census, a pamphlet for nonexperts, and some seminars and public meetings. This project allowed us to raise interest in this issue. Using accurate and understandable language in a light-humored setting goes far toward cultivating trust from a public audience that can be intimidated or suspicious of complicated scientific messaging. PMID- 26611061 TI - Mapping Underwater Sound in the Dutch Part of the North Sea. AB - The European Union requires member states to achieve or maintain good environmental status for their marine territorial waters and explicitly mentions potentially adverse effects of underwater sound. In this study, we focused on producing maps of underwater sound from various natural and anthropogenic origins in the Dutch North Sea. The source properties and sound propagation are simulated by mathematical methods. These maps could be used to assess and predict large scale effects on behavior and distribution of underwater marine life and therefore become a valuable tool in assessing and managing the impact of underwater sound on marine life. PMID- 26611062 TI - Passive Acoustic Monitoring of the Environmental Impact of Oil Exploration on Marine Mammals in the Gulf of Mexico. AB - The Gulf of Mexico is a region densely populated by marine mammals that must adapt to living in a highly active industrial environment. This paper presents a new approach to quantifying the anthropogenic impact on the marine mammal population. The results for sperm and beaked whales of a case study of regional population dynamics trends after the Deepwater Horizon oil spill, derived from passive acoustic-monitoring data gathered before and after the spill in the vicinity of the accident, are presented. PMID- 26611063 TI - BIAS: A Regional Management of Underwater Sound in the Baltic Sea. AB - Management of the impact of underwater sound is an emerging concern worldwide. Several countries are in the process of implementing regulatory legislations. In Europe, the Marine Strategy Framework Directive was launched in 2008. This framework addresses noise impacts and the recommendation is to deal with it on a regional level. The Baltic Sea is a semienclosed area with nine states bordering the sea. The number of ships is one of the highest in Europe. Furthermore, the number of ships is estimated to double by 2030. Undoubtedly, due to the unbound character of noise, an efficient management of sound in the Baltic Sea must be done on a regional scale. In line with the European Union directive, the Baltic Sea Information on the Acoustic Soundscape (BIAS) project was established to implement Descriptor 11 of the Marine Strategy Framework Directive in the Baltic Sea region. BIAS will develop tools, standards, and methodologies that will allow for cross-border handling of data and results, measure sound in 40 locations for 1 year, establish a seasonal soundscape map by combining measured sound with advanced three-dimensional modeling, and, finally, establish standards for measuring continuous sound. Results from the first phase of BIAS are presented here, with an emphasis on standards and soundscape mapping as well as the challenges related to regional handling. PMID- 26611064 TI - Psychoacoustic Studies of Spotted (Phoca largha) and Ringed (Pusa hispida) Seals. AB - Human development of the marine environment raises questions regarding the potential adverse effects of anthropogenic noise on marine mammals. For species that live in remote Arctic regions, recent and expanding human intrusions may pose a particular threat. Northern seals are poorly studied relative to their temperate counterparts and little is known of their acoustic ecology or behavior. Given this scarcity of relevant data, studies of hearing in Arctic seals are essential to characterize their auditory capabilities and to inform management decisions. This paper describes ongoing psychoacoustic studies that are examining aspects of hearing in two ice seal species. PMID- 26611065 TI - A Seaway Acoustic Observatory in Action: The St. Lawrence Seaway. AB - A setup for measuring spectral source levels (SSLs) of ships transiting along a seaway, the traffic density and shipping noise, is presented. The results feed shipping-noise modeling that reproduces the actual in situ observations to map shipping-noise variability over space and time for investigating its effects on aquatic organisms. The ship's SSL databank allows sorting the different contributors to total shipping noise for assisting in exploring mitigation approaches (e.g., fleet composition, rerouting). Such an acoustic observatory was deployed since November 2012 for a complete annual cycle of measurements in the deep downstream part of the St. Lawrence Seaway. PMID- 26611066 TI - Small-Boat Noise Impacts Natural Settlement Behavior of Coral Reef Fish Larvae. AB - After a pelagic larval phase, settlement-stage coral reef fish must locate a suitable reef habitat for juvenile life. Reef noise, produced by resident fish and invertebrates, provides an important cue for orientation and habitat selection during this process, which must often occur in environments impacted by anthropogenic noise. We adapted an established field-based protocol to test whether recorded boat noise influenced the settlement behavior of reef fish. Fewer fish settled to patch reefs broadcasting boat + reef noise compared with reef noise alone. This study suggests that boat noise, now a common feature of many reefs, can compromise critical settlement behavior of reef fishes. PMID- 26611067 TI - Auditory Evoked Potential Audiograms Compared with Behavioral Audiograms in Aquatic Animals. AB - Auditory evoked potentials (AEPs) have become popular for estimating hearing thresholds and audiograms. What is the utility of these measurements? How do AEP audiograms compare with behavioral audiograms? In general, AEP measurements for fishes and marine mammals often underestimate behavioral thresholds, but comparisons are especially complicated when the AEP and behavioral measures are obtained under different acoustic conditions. There is no single representative relationship between AEP and behavioral audiograms and these audiograms should not be considered equivalent. We suggest that the most valuable comparisons are those made by the same researcher using similar acoustic conditions for both measurements. PMID- 26611068 TI - Aiming for Progress in Understanding Underwater Noise Impact on Fish: Complementary Need for Indoor and Outdoor Studies. AB - Anthropogenic noise can be detrimental to aquatic life through physical harm and behavioral impact. Physical harm to fish only occurs very close to typically brief but high-power sources. Behavioral impact occurs at more moderate levels and is spatially and temporally much more widespread. More studies are needed to get a better understanding of the behavioral impact on fish. Indoor and outdoor studies vary in their acoustic and behavioral validity and in the amount of experimental control. Although each approach has its limitations, scientific progress and applied insights will depend on the exploitation of their complementary potential. PMID- 26611069 TI - Relationship Between Hair Cell Loss and Hearing Loss in Fishes. AB - Exposure to intense sound or ototoxic chemicals can damage the auditory hair cells of vertebrates, resulting in hearing loss. Although the relationship between such hair cell damage and auditory function is fairly established for terrestrial vertebrates, there are limited data available to understand this relationship in fishes. Although investigators have measured either the morphological damage of the inner ear or the functional deficits in the hearing of fishes, very few have directly measured both in an attempt to find a relationship between the two. Those studies that have examined both auditory hair cell damage in the inner ear and the resulting hearing loss in fishes are reviewed here. In general, there is a significant linear relationship between the number of hair cells lost and the severity of hearing threshold shifts, although this varies between species and different hair cell-damaging stimuli. After trauma to the fish ear, auditory hair cells are able to regenerate to control level densities. With this regeneration also comes a restoration of hearing. Thus there is also a significant relationship between hair cell recovery and hearing recovery in fishes. PMID- 26611070 TI - Characterization of the Sounds Produced by Temperate and Tropical Sea Urchins During Feeding (Diadematidae and Echinometridae). AB - Despite the abundance and ecological importance of sea urchins in eastern Australia, it is not known how they may contribute to ambient noise. The sounds of feeding of two temperate and two tropical species were recorded in captivity. Most sound was produced between 2.3 and 9.2 kHz, but there were differences between species and substrate types. PMID- 26611071 TI - Acoustic Response to Playback of Pile-Driving Sounds by Snapping Shrimp. AB - There is concern about the effects of noise from impact pile driving as this constructional technique becomes increasingly widespread in coastal areas. The habitats of most marine invertebrate species are likely to overlap with the areas of human activities along the coast and be affected by the increased levels of noise produced. This paper investigates the acoustic response of chorusing snapping shrimp to different sound pressure levels. A significant increase in the snap number and snap amplitude was recorded during the playback of piling noise, suggesting that noise exposure affected the acoustic behavior of these animals. PMID- 26611072 TI - Development of a Finite-Difference Time Domain (FDTD) Model for Propagation of Transient Sounds in Very Shallow Water. AB - This finite-difference time domain (FDTD) model for sound propagation in very shallow water uses pressure and velocity grids with both 3-dimensional Cartesian and 2-dimensional cylindrical implementations. Parameters, including water and sediment properties, can vary in each dimension. Steady-state and transient signals from discrete and distributed sources, such as the surface of a vibrating pile, can be used. The cylindrical implementation uses less computation but requires axial symmetry. The Cartesian implementation allows asymmetry. FDTD calculations compare well with those of a split-step parabolic equation. Applications include modeling the propagation of individual fish sounds, fish aggregation sounds, and distributed sources. PMID- 26611073 TI - Vessel Noise Promotes Hull Fouling. AB - Fouling of submerged vessel hulls due to the rapid settlement of algae and invertebrates is a longstanding and costly problem. It is widely thought that the presence of extensive vacant surfaces on vessel hulls is responsible for the rapid attachment and growth of biofouling. We investigated whether noise from vessels in port could also be involved in promoting the settlement and growth of common biofouling organisms on vessel hulls. Three important biofouling species exhibited significantly faster development and settlement and better survival when exposed to vessel noise compared with control species. The extent of these responses appeared to vary in relation to the intensity of the vessel noise and may help to explain differences in biofouling observed on vessel hulls. PMID- 26611074 TI - Potential Uses of Anthropogenic Noise as a Source of Information in Animal Sensory and Communication Systems. AB - Although current research on the impact of anthropogenic noise has focused on the detrimental effects, there is a range of ways by which animals could benefit from increased noise levels. Here we discuss two potential uses of anthropogenic noise. First, local variations in the ambient-noise field could be used to perceive objects and navigate within an environment. Second, introduced sound cues could be used as a signal for prey detection or orientation and navigation. Although the disadvantages of noise pollution will likely outweigh any positive effects, it is important to acknowledge that such changes may benefit some species. PMID- 26611075 TI - Active Acoustic Monitoring of Aquatic Life. AB - Active acoustic monitoring (AAM) can be used to study the behavioral response of marine life and to mitigate harm during high-danger anthropogenic activities. This has been done in fish studies for many decades, and there are now case studies in which AAM has been used for marine mammal monitoring as well. This includes monitoring where the ranges, AAM frequency of operation, and species are such that the AAM operation is completely outside the hearing range of the animals. However, it also includes AAM operations within the hearing range of marine life, although this does not necessarily that imply AAM is not a suitable tool. It is just not always possible to have a sufficient detection and tracking range and operate at a frequency outside the marine life hearing range. Likely, the best and most important application of AAM is when the anthropogenic activity to be conducted is temporary and presents a clear danger to aquatic life. PMID- 26611076 TI - Is Sound Exposure Level a Convenient Metric to Characterize Fatiguing Sounds? A Study in Beluga Whales. AB - Both the level and duration of fatiguing sounds influence temporary threshold shifts (TTSs) in odontocetes. These two parameters were combined into a sound exposure level (SEL). In the beluga whale Delphinapterus leucas, TTSs were investigated at various sound pressure level (SPL)-to-duration ratios at a specific SEL. At low SPL-to-duration ratios, the dependence was positive: shorter high-level sounds produced greater TTSs than long low-level sounds of the same SEL. At high SPL-to-duration ratios, the dependence was negative: long low-level sounds produced greater TTSs than short high-level sounds of the same SEL. Thus, the validity of SEL as a metric for fatiguing sound efficiency is limited. PMID- 26611077 TI - Frequency Tuning of Hearing in the Beluga Whale. AB - Data on frequency tuning in odontocetes are contradictory: different authors have reported filter qualities from 2 to almost 50. In this study, frequency tuning was measured in a beluga whale (Delphinapterus leucas) using a rippled-noise test stimulus in conjunction with the auditory evoked potential (AEP) technique. The response to ripple reversions was considered to indicate resolvability of the ripple pattern. The limit of ripple-pattern resolution ranged from 20 to 32 ripples per octave (rpo). A model of interaction of the ripple spectrum with frequency-tuned filters suggests that this resolution limit requires a filter quality of 29-46. PMID- 26611078 TI - How Might We Assess and Manage the Effects of Underwater Noise on Populations of Marine Animals? AB - The European Union Marine Strategy Framework Directive (MSFD) aims to achieve good environmental status (GES) in European seas by 2020. One of the features of GES is that underwater sound should not adversely affect the marine environment. Direct injury of marine life may occur, but a more pervasive effect is likely to be through the cumulative indirect effects on behavior. Assessing the significance of these effects on an ecosystem scale is difficult. If subsequent management of these effects is required, complex and challenging international decisions will be required. PMID- 26611079 TI - Anthropogenic Noise and Physiological Stress in Wildlife. AB - The ecological impacts of increasing levels of anthropogenic noise in marine and freshwater systems are of growing public interest. Recent emphasis on the physiological approaches to identifying the impacts of noise has led to increased recognition that anthropogenic noise is an environmental stressor. We briefly review the research on noise-induced physiological stress. Additionally, we summarize findings from a controlled playback experiment that explored the relationship between traffic noise and physiological stress in anurans (frogs and toads), an aquatic group that relies on acoustic communication for survival and reproduction. PMID- 26611080 TI - Harp Seals Do Not Increase Their Call Frequencies When It Gets Noisier. AB - Some species avoid low-frequency masking by shifting their calls to higher frequencies. We addressed the hypothesis that Pagophilus groenlandicus (harp seals) will make more high-frequency underwater calls to avoid low-frequency conspecific masking as calling rates increase. The spectral shapes at high and low calling rates were compared (after equalizing the broadband amplitudes). There were no significant differences between the spectral shapes. Pagophilus groenlandicus do not alter the proportions of low- and high-frequency calls as it gets noisier. This suggests that they may not shift their calling frequencies when encountering low-frequency, broadband anthropogenic noise. PMID- 26611081 TI - Measuring In-Air and Underwater Hearing in Seabirds. AB - Electrophysiological methods were used to measure the in-air hearing of 10 species of seabirds. There are currently no measures of the underwater hearing abilities of diving birds. In preparation for constructing a behavioral audiogram both in-air and underwater hearing, several species of diving ducks were raised. Because there is a considerable amount of literature on bird hearing in air, the technical setup and training methods were modeled on similar studies, with modifications to address the nature of the underwater sound field and the difficulty of the task for the birds. PMID- 26611082 TI - WODA Technical Guidance on Underwater Sound from Dredging. AB - The World Organization of Dredging Associations (WODA) has identified underwater sound as an environmental issue that needs further consideration. A WODA Expert Group on Underwater Sound (WEGUS) prepared a guidance paper in 2013 on dredging sound, including a summary of potential impacts on aquatic biota and advice on underwater sound monitoring procedures. The paper follows a risk-based approach and provides guidance for standardization of acoustic terminology and methods for data collection and analysis. Furthermore, the literature on dredging-related sounds and the effects of dredging sounds on marine life is surveyed and guidance on the management of dredging-related sound risks is provided. PMID- 26611083 TI - Noise Exposure Criteria for Harbor Porpoises. AB - Despite a major research effort, no generally accepted exposure limits are available for harbor porpoises. Recent studies of the temporary threshold shift (TTS) in porpoises indicate that the sound exposure levels (SELs) required to induce low levels of TTS depend on stimulus frequency and roughly parallel the shape of the audiogram. A number of studies on behavioral avoidance reactions (negative phonotaxis) to pingers, seal scarers, and pile driving show a similar dependence on stimulus frequency. Both TTS and behavioral data suggest that weighting sound pressure levels with a filter function resembling the inverted audiogram would be appropriate. PMID- 26611084 TI - Review of Offshore Wind Farm Impact Monitoring and Mitigation with Regard to Marine Mammals. AB - Monitoring and mitigation reports from 19 UK and 9 other European Union (EU) offshore wind farm (OWF) developments were reviewed, providing a synthesis of the evidence associated with the observed environmental impact on marine mammals. UK licensing conditions were largely concerned with mitigation measures reducing the risk of physical and auditory injury from pile driving. At the other EU sites, impact monitoring was conducted along with mitigation measures. Noise-mitigation measures were developed and tested in UK and German waters in German government financed projects. We highlight some of the review's findings and lessons learned with regard to noise impact on marine mammals. PMID- 26611085 TI - Discovery of Sound in the Sea: Resources for Educators, Students, the Public, and Policymakers. AB - There is increasing concern about the effects of underwater sound on marine life. However, the science of sound is challenging. The Discovery of Sound in the Sea (DOSITS) Web site ( http://www.dosits.org ) was designed to provide comprehensive scientific information on underwater sound for the public and educational and media professionals. It covers the physical science of underwater sound and its use by people and marine animals for a range of tasks. Celebrating 10 years of online resources, DOSITS continues to develop new material and improvements, providing the best resource for the most up-to-date information on underwater sound and its potential effects. PMID- 26611086 TI - Effects of Previous Acoustic Experience on Behavioral Responses to Experimental Sound Stimuli and Implications for Research. AB - Ambient noise differs considerably between habitats. Increased ambient noise can affect the physiology and behavior in a variety of taxa. Previous acoustic experience can modify behavior and potentially affect research conclusions in natural and laboratory environments. Acoustic conditions should thus be accounted for, especially in experiments involving experimental sound stimuli. Methods sections should contain acoustic specifications, and a consensus should be achieved over which measurements to include for comparability between researchers. Further investigation of how previous and repeated exposure to sound affects behavior and research conclusions is needed to improve our knowledge of acoustic long-term effects in animal welfare and conservation. PMID- 26611087 TI - Assessing the Effectiveness of Ramp-Up During Sonar Operations Using Exposure Models. AB - Ramp-up procedures are used to mitigate the impact of sound on marine mammals. Sound exposure models combined with observations of marine mammals responding to sound can be used to assess the effectiveness of ramp-up procedures. We found that ramp-up procedures before full-level sonar operations can reduce the risk of hearing threshold shifts with marine mammals, but their effectiveness depends strongly on the responsiveness of the animals. In this paper, we investigated the effect of sonar parameters (source level, pulse-repetition time, ship speed) on sound exposure by using a simple analytical model and highlight the mechanisms that limit the effectiveness of ramp-up procedures. PMID- 26611088 TI - Mapping the Acoustic Soundscape off Vancouver Island Using the NEPTUNE Canada Ocean Observatory. AB - NEPTUNE Canada is a cabled ocean observatory system containing five nodes located in the northeast Pacific Ocean. Using passive acoustic data recorded at two nodes (Folger Passage Deep and Barkley Canyon Axis) between June 2010 and May 2011, we sought to quantify the levels of vessel traffic and the occurrence of biological sounds to determine the potential impact of anthropogenic sound in masking acoustic communication. The results from a comparison of the relative amplitude and occurrence of low-frequency biotic sounds to broadband sounds resulting from vessel traffic are presented. Additional contributions to the marine soundscape from self-generated instrument noise are discussed. PMID- 26611089 TI - Behavioral Response of Reef Fish and Green Sea Turtles to Midfrequency Sonar. AB - There is growing concern over the potential effects of high-intensity sonar on wild fish populations and commercial fisheries. Acoustic telemetry was employed to measure the movements of free-ranging reef fish and sea turtles in Port Canaveral, FL, in response to routine submarine sonar testing. Twenty-five sheepshead (Archosargus probatocephalus), 28 gray snapper (Lutjanus griseus), and 29 green sea turtles (Chelonia mydas) were tagged, with movements monitored for a period of up to 4 months using an array of passive acoustic receivers. Baseline residency was examined for fish and sea turtles before, during, and after the test event. No mortality of tagged fish or sea turtles was evident from the sonar test event. There was a significant increase in the daily residency index for both sheepshead and gray snapper at the testing wharf subsequent to the event. No broad-scale movement from the study site was observed during or immediately after the test. PMID- 26611090 TI - Underwater Equal-Latency Contours of a Harbor Porpoise (Phocoena phocoena) for Tonal Signals Between 0.5 and 125 kHz. AB - Loudness perception can be studied based on the assumption that sounds of equal loudness elicit equal reaction time (RT; or "response latency"). We measured the underwater RTs of a harbor porpoise to narrowband frequency-modulated sounds and constructed six equal-latency contours. The contours paralleled the audiogram at low sensation levels (high RTs). At high-sensation levels, contours flattened between 0.5 and 31.5 kHz but dropped substantially (RTs shortened) beyond those frequencies. This study suggests that equal-latency-based frequency weighting can emulate noise perception in porpoises for low and middle frequencies but that the RT-loudness correlation is relatively weak for very high frequencies. PMID- 26611091 TI - Underwater Hearing in Turtles. AB - The hearing of turtles is poorly understood compared with the other reptiles. Although the mechanism of transduction of sound into a neural signal via hair cells has been described in detail, the rest of the auditory system is largely a black box. What is known is that turtles have higher hearing thresholds than other reptiles, with best frequencies around 500 Hz. They also have lower underwater hearing thresholds than those in air, owing to resonance of the middle ear cavity. Further studies demonstrated that all families of turtles and tortoises share a common middle ear cavity morphology, with scaling best suited to underwater hearing. This supports an aquatic origin of the group. Because turtles hear best under water, it is important to examine their vulnerability to anthropogenic noise. However, the lack of basic data makes such experiments difficult because only a few species of turtles have published audiograms. There are also almost no behavioral data available (understandable due to training difficulties). Finally, few studies show what kinds of sounds are behaviorally relevant. One notable paper revealed that the Australian snake-necked turtle (Chelodina oblonga) has a vocal repertoire in air, at the interface, and under water. Findings like these suggest that there is more to the turtle aquatic auditory scene than previously thought. PMID- 26611092 TI - Quantitative Measures of Anthropogenic Noise on Harbor Porpoises: Testing the Reliability of Acoustic Tag Recordings. AB - In recent years, several sound and movement recording tags have been developed to sample the acoustic field experienced by cetaceans and their reactions to it. However, little is known about how tag placement and an animal's orientation in the sound field affect the reliability of on-animal recordings as proxies for actual exposure. Here, we quantify sound exposure levels recorded with a DTAG-3 tag on a captive harbor porpoise exposed to vessel noise in a controlled acoustic environment. Results show that flow noise is limiting onboard noise recordings, whereas no evidence of body shading has been found for frequencies of 2-20 kHz. PMID- 26611093 TI - Development of a Model to Assess Masking Potential for Marine Mammals by the Use of Air Guns in Antarctic Waters. AB - We estimated the long-range effects of air gun array noise on marine mammal communication ranges in the Southern Ocean. Air gun impulses are subject to significant distortion during propagation, potentially resulting in a quasi continuous sound. Propagation modeling to estimate the received waveform was conducted. A leaky integrator was used as a hearing model to assess communication masking in three species due to intermittent/continuous air gun sounds. Air gun noise is most probably changing from impulse to continuous noise between 1,000 and 2,000 km from the source, leading to a reduced communication range for, e.g., blue and fin whales up to 2,000 km from the source. PMID- 26611094 TI - Review of Low-Level Bioacoustic Behavior in Wild Cetaceans: Conservation Implications of Possible Sleeping Behavior. AB - Shallow, low-activity, low-biosonar parabolic-shaped dives were observed in biologging data from tagged harbor porpoises in Danish waters and identified as potential sleeping behavior. This behavioral state merits consideration in assessing the context for noise exposure and passive acoustic monitoring studies. Similar dives have also been reported for other cetacean species. The existence of low-level bioacoustic dives that may represent that sleeping has implications for the mitigation of not only noise exposure but also of bycatch as well as legal repercussions given the protected status of sleeping, as a part of resting, under many legislative regimes. PMID- 26611095 TI - Noise-Dependent Fish Distribution in Kelp Beds. AB - The marine marbled rockfish Sebastiscus marmoratus is dependent on kelp beds and rocks for survival and reproduction. We found that sound production and hearing sensitivity in S. marmoratus are closely matched in the frequency domain. We also found that the juvenile rockfish prefers the habitat of the larger macroalgae Sargassum horueri rather than the habitat containing the smaller algae Ulva pertusa where the adult rockfish prefers to live. Our underwater noise recording data from these two habitats indicate that their spectra of the background noise have different values. The results suggest that the acoustic cues may be critical for pelagic larvae when selecting the preferential habitat in which to settle. PMID- 26611096 TI - Summary Report Panel 1: The Need for Protocols and Standards in Research on Underwater Noise Impacts on Marine Life. AB - As concern about anthropogenic noise and its impacts on marine fauna is increasing around the globe, data are being compared across populations, species, noise sources, geographic regions, and time. However, much of the raw and processed data are not comparable due to differences in measurement methodology, analysis and reporting, and a lack of metadata. Common protocols and more formal, international standards are needed to ensure the effectiveness of research, conservation, regulation and practice, and unambiguous communication of information and ideas. Developing standards takes time and effort, is largely driven by a few expert volunteers, and would benefit from stakeholders' contribution and support. PMID- 26611097 TI - Summary Report Panel 2: Regulatory Issues. AB - The Effects of Noise on Aquatic Life 2013 Conference convened four panels to discuss specific topics related to the effects of anthropogenic noise on aquatic ecosystems. The second of these four panels, the Regulatory Issues Panel, brought together several different perspectives: representatives of agencies responsible for regulating activities that introduce anthropogenic noise into aquatic ecosystems: representatives of the regulated industries, agencies, and consultancies that advise regulators and regulated industries; and nongovernmental organizations and other stakeholders with an interest in anthropogenic noise. The goal of the panel was to help develop a more productive relationship between these groups. PMID- 26611098 TI - Summary Report Panel 3: Gap Analysis from the Perspective of Animal Biology: Results of the Panel Discussion from the Third International Conference on the Effects of Noise on Aquatic Life. AB - There is little disagreement among regulators, scientists, and other interested parties as to the complexity surrounding our understanding of the potential and realized impacts of anthropogenic noise on marine life. Given the challenges of research in an aquatic environment, the breadth of species of interest and the range of human-made noise-producing activities, it is difficult at best to identify the most important science needs that improve our understanding and ultimately regulation of the issue. PMID- 26611099 TI - Summary Report Panel 4: Communication and Interpretation: Presenting Information to the General Public. AB - Complex scientific information is often difficult to communicate to nonscience audiences who may not have the foundational knowledge to understand the content. Scientists are called on with increasing frequency to share the results of their research for the purposes of education, outreach, and popular media stories. These three spheres of activity, represented in Fig. 1, are geared toward different but complementary goals. PMID- 26611100 TI - [Measles, mumps, and rubella vaccine. Resurgence of measles in Europe]. AB - Measles is a rash illness of moderate severity and high risk of serious complications, with recovery in several weeks. It is a viral disease caused by one of the most infectious and contagious pathogens that exists, whose only known reservoir is human. In 1998, the European Region of the WHO set a target of eliminating measles by 2010. This goal has not been achieved. Furthermore, it has been observed the resurgence of the disease in some parts of Europe. We review the disease and its vaccines as well as the epidemiological and social factors that have so far prevented the total control of the disease. PMID- 26611101 TI - [Nocardia veterana bacteraemia after a lung infection in a patient with acute myeloid leukaemia]. PMID- 26611105 TI - Geometric order parameters derived from the Voronoi tessellation show signatures of the jamming transition. AB - A jammed packing of frictionless spheres at zero temperature is perfectly specified by the network of contact forces from which mechanical properties can be derived. However, we can alternatively consider a packing as a geometric structure, characterized by a Voronoi tessellation which encodes the local environment around each particle. We find that this local environment characterizes systems both above and below jamming and changes markedly at the transition. A variety of order parameters derived from this tessellation carry signatures of the jamming transition, complete with scaling exponents. Furthermore, we define a real space geometric correlation function which also displays a signature of jamming. Taken together, these results demonstrate the validity and usefulness of a purely geometric approach to jamming. PMID- 26611104 TI - Coactivator-Dependent Oscillation of Chromatin Accessibility Dictates Circadian Gene Amplitude via REV-ERB Loading. AB - A central mechanism for controlling circadian gene amplitude remains elusive. We present evidence for a "facilitated repression (FR)" model that functions as an amplitude rheostat for circadian gene oscillation. We demonstrate that ROR and/or BMAL1 promote global chromatin decondensation during the activation phase of the circadian cycle to actively facilitate REV-ERB loading for repression of circadian gene expression. Mechanistically, we found that SRC-2 dictates global circadian chromatin remodeling through spatial and temporal recruitment of PBAF members of the SWI/SNF complex to facilitate loading of REV-ERB in the hepatic genome. Mathematical modeling highlights how the FR model sustains proper circadian rhythm despite fluctuations of REV-ERB levels. Our study not only reveals a mechanism for active communication between the positive and negative limbs of the circadian transcriptional loop but also establishes the concept that clock transcription factor binding dynamics is perhaps a central tenet for fine tuning circadian rhythm. PMID- 26611103 TI - HIV alters neuronal mitochondrial fission/fusion in the brain during HIV associated neurocognitive disorders. AB - HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of HIV patients, and therapies to combat HAND progression are urgently needed. HIV proteins are released from infected cells and cause neuronal damage, possibly through mitochondrial abnormalities. Altered mitochondrial fission and fusion is implicated in several neurodegenerative disorders. Here, we hypothesized that mitochondrial fission/fusion may be dysregulated in neurons during HAND. We have identified decreased mitochondrial fission protein (dynamin 1-like; DNM1L) in frontal cortex tissues of HAND donors, along with enlarged and elongated mitochondria localized to the soma of damaged neurons. Similar pathology was observed in the brains of GFAP-gp120 tg mice. In vitro, recombinant gp120 decreased total and active DNM1L levels, reduced the level of Mitotracker staining, and increased extracellular acidification rate (ECAR) in primary neurons. DNM1L knockdown enhanced the effects of gp120 as measured by reduced Mitotracker signal in the treated cells. Interestingly, overexpression of DNM1L increased the level of Mitotracker staining in primary rat neurons and reduced neuroinflammation and neurodegeneration in the GFAP-gp120-tg mice. These data suggest that mitochondrial biogenesis dynamics are shifted towards mitochondrial fusion in brains of HAND patients and this may be due to gp120-induced reduction in DNM1L activity. Promoting mitochondrial fission during HIV infection of the CNS may restore mitochondrial biogenesis and prevent neurodegeneration. PMID- 26611102 TI - Does PGC1alpha/FNDC5/BDNF Elicit the Beneficial Effects of Exercise on Neurodegenerative Disorders? AB - Neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases have high prevalence among the elderly. Many strategies have been established to alleviate the symptoms experienced by affected individuals. Recent studies have shown that exercise helps patients with neurological disorders to regain lost physical abilities. PGC1alpha/FNDC5/BDNF has emerged recently as a critical pathway for neuroprotection. PGC1alpha is a highly conserved co activator of transcription factors that preserves and protects neurons against destruction. PGC1alpha regulates FNDC5 and its processed and secreted peptide Irisin, which has been proposed to play a critical role in energy expenditure and to promote neural differentiation of mouse embryonic stem cells. FNDC5 may also increase the expression of the neurotrophic factor BDNF, a neuroprotective agent, in the hippocampus. BDNF is secreted from hippocampus, amygdala, cerebral cortex and hypothalamus neurons and initiates intracellular signaling pathways through TrkB receptors. These pathways have positive feedback on CREB activities and lead to enhancement in PGC1alpha expression in neurons. Therefore, FNDC5 could behave as a key regulator in neuronal survival and development. This review presents recent findings on the PGC1alpha/FNDC5/BDNF pathway and its role in neuroprotection, and discusses the controversial promise of irisin as a mediator of the positive benefits of exercise. PMID- 26611108 TI - Abstracts from the UC Davis Transgenic Animal Research Conference X (TARC X) : Tahoe City, CA, USA, August 9-12, 2015. PMID- 26611106 TI - Therapeutic window of globular adiponectin against cerebral ischemia in diabetic mice: the role of dynamic alteration of adiponectin/adiponectin receptor expression. AB - Recent studies have demonstrated that adiponectin (APN) attenuates cerebral ischemic/reperfusion via globular adiponectin (gAD). However, the therapeutic role of gAD in cerebral ischemic injury in type 1 diabetes mellitus (T1DM) remains unclear. Our results showed that gAD improved neurological scores and reduced the infarct volumes in the 8-week T1DM (T1DM-8W) mice, but not in the 2 week T1DM (T1DM-2W) mice. Moreover, the ischemic penumbra APN levels increased and peaked in T1DM-2W mice, and reduced to normal in T1DM-8W mice, while the APN receptor 1 (AdipoR1) expression change was the opposite. Administration of rosiglitazone in T1DM-2W mice up-regulated the expression of AdipoR1 and restored the neuroprotection of gAD, while intracerebroventricular injection of AdipoR1 small interfering RNA (siRNA) in T1DM-8W mice reversed it. Furthermore, the expression of p-PERK, p-IRE1 and GRP78 were increased whereas the expressions of CHOP and cleaved caspase-12 as well as the number of apoptotic neurons were decreased after gAD treatment in T1DM-8W mice. These beneficial effects of gAD were reversed by pretreatment with AdipoR1 siRNA. These results demonstrated a dynamic dysfunction of APN/AdipoR1 accompanying T1DM progression. Interventions bolstering AdipoR1 expression during early stages and gAD supplementation during advanced stages may potentially reduce the cerebral ischemic injury in diabetic patients. PMID- 26611107 TI - 18F-FDG PET/CT in the diagnosis of prosthetic valve endocarditis. AB - Recent studies have shown promising results using (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) in the diagnosis of prosthetic valve endocarditis (PVE). However, previous studies did not include negative controls. The aim of this study was to compare (18)F-FDG uptake around prosthetic aortic valves in patients with and without PVE and to determine the diagnostic performance of (18)F-FDG PET/CT in the diagnosis of PVE. (18)F-FDG PET/CT examinations in patients with a prosthetic aortic valve performed 2008-2014 were retrieved. Eight patients with a final diagnosis of definite PVE were included in the analysis of the diagnostic performance of (18)F FDG PET/CT. Examinations performed on suspicion of malignancy in patients without PVE (n = 19) were used as negative controls. Visual and semi-quantitative analysis was performed. Maximal standardized uptake value (SUVmax) in the valve area was measured and SUVratio was calculated by dividing valve SUVmax by SUVmax in the descending aorta. The sensitivity was 75 %, specificity 84 %, positive likelihood ratio [LR(+)] 4.8 and negative likelihood ratio [LR(-)] 0.3 on visual analysis. Both SUVmax and SUVratio were significantly higher in PVE patients [5.8 (IQR 3.5-6.5) and 2.4 (IQR 1.7-3.0)] compared to non-PVE patients [3.2 (IQR 2.8 3.8) and 1.5 (IQR 1.3-1.6)] (p < 0.001). ROC-curve analysis of SUVratio yielded an area under the curve of 0.90 (95 % CI 0.74-1.0). (18)F-FDG-uptake around non infected aortic prosthetic valves was low. The level of (18)F-FDG-uptake in the prosthetic valve area showed a good diagnostic performance in the diagnosis of PVE. PMID- 26611109 TI - Creating nanoporosity in silver nanocolumns by direct exposure to radio-frequency air plasma. AB - Nanoporous materials are of great importance for a broad range of applications including catalysis, optical sensors and water filtration. Although several approaches already exist for the creation of nanoporous materials, the race for the development of versatile methods, more suitable for the nanoelectronics industry, is still ongoing. In this communication we report for the first time on the possibility of generating nanoporosity in silver nanocolumns using a dry approach based on the oxidation of silver by direct exposure to a commercially available radio-frequency air plasma. The silver nanocolumns are created by glancing angle deposition using magnetron sputtering of a silver target in pure argon plasma. We show that upon exposure to the rf air plasma, the nanocolumns transform from solid silver into nanoporous silver oxide. We further show that by tuning the plasma pressure and the exposure duration, the oxidation process can be finely adjusted allowing for precisely controlling the morphology and the nanoporosity of the silver oxide nanocolumns. The generation of porosity within the silver nanocolumns is explained according to a cracking-induced oxidation mechanism based on two repeated events occurring alternately during the oxidation process: (i) oxidation of silver upon exposure to the air plasma and (ii) generation of nanocracks and blisters within the oxide layer due to the high internal stress generated within the material during oxidation. PMID- 26611110 TI - The role of multidetector CT in local staging and evaluation of retroperitoneal surgical margin involvement in colon cancer. AB - PURPOSE: We aimed to evaluate preoperative T and N staging and retroperitoneal surgical margin (RSM) involvement in colon cancer using multidetector computed tomography (MDCT). METHODS: In this retrospective study, preoperative MDCTs of 141 patients with colon adenocarcinoma were evaluated in terms of T and N staging and retroperitoneal surgical margin involvement by two observers. Results were compared with histopathology. RESULTS: In determining extramural invasion, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of MDCT were 81%, 50%, 95%, 26%, and 81% for observer 1 and 87%, 75%, 97%, 27%, and 84% for observer 2, respectively. Moderate interobserver agreement was observed (K=0.425). In determining T stage of the tumor, accuracy of MDCT was 55% for observer 1 and 51% for observer 2. In the detection of lymph node metastasis, sensitivity, specificity, PPV, NPV, and accuracy of MDCT were 84%, 46%, 60%, 74% and 64% for observer 1 and 84%, 56%, 65%, 78%, and 70% for observer 2, respectively. Interobserver agreement was substantial (K=0.650). RSM was involved in six cases (4.7%). When only retroperitoneal colon segments were considered, 1.6% of subjects demonstrated RSM involvement. Four of the six RSM-positive tumors were located on sigmoid colon and one tumor was on transverse colon and caecum. Considering all colon tumors, in the detection of RSM involvement, sensitivity and specificity of MDCT were 33% and 81% for observer 1 and 50% and 80% for observer 2. Interobserver agreement was moderate (K=0.518). CONCLUSION: MDCT is a promising technique with moderate interobserver agreement in detection of extramural invasion, lymph node metastases, and RSM involvement in colon carcinomas. PMID- 26611111 TI - Radiofrequency ablation for lung tumors: outcomes, effects on survival, and prognostic factors. AB - PURPOSE: We aimed to evaluate the survival benefit achieved with radiofrequency (RF) ablation of primary and metastatic lung tumors and determine significant prognostic factors for recurrence-free survival. METHODS: Forty-nine patients with lung cancer (10 primary and 39 metastatic) underwent computed tomography guided percutaneous RF ablation between June 2005 and October 2013. A total of 112 tumors (101 metastatic and 11 primary non-small cell lung cancer) were treated with RF ablation. Tumor diameter ranged from 0.6 to 4 cm (median 1.5 cm). Effectiveness of treatment, complications, and survival were analyzed. RESULTS: Primary success rate was 79.5% and local tumor progression occurred in 23 tumors. Among tumors showing progression, 10 were re-treated with RF ablation and secondary success rate was 87.5%. One-, two-, and three-year overall survival rates of 10 patients with primary lung cancer were 100%, 86%, and 43%, respectively. One-, two-, three-, four-, and five-year overall survival rates for 39 patients with metastatic lung tumors were 90%, 73%, 59%, 55%, and 38%, respectively. One-, two-, three-, and four-year overall survival rates for 16 patients with colorectal pulmonary metastases were 94%, 80%, 68%, and 23%, respectively. Complications occurred in 30 sessions (24.6%). Pneumothorax occurred in 19 sessions with seven requiring image-guided percutaneous chest tube drainage. Tumor status (solitary or multiple) and presence of extrapulmonary metastasis at initial RF ablation were significant prognostic factors in terms of recurrence-free survival. CONCLUSION: RF ablation is a safe and effective treatment with a survival benefit for selected patients with primary and secondary lung tumors. PMID- 26611112 TI - Updated Lagrangian finite element formulations of various biological soft tissue non-linear material models: a comprehensive procedure and review. AB - Simplified material models are commonly used in computational simulation of biological soft tissue as an approximation of the complicated material response and to minimize computational resources. However, the simulation of complex loadings, such as long-duration tissue swelling, necessitates complex models that are not easy to formulate. This paper strives to offer the updated Lagrangian formulation comprehensive procedure of various non-linear material models for the application of finite element analysis of biological soft tissues including a definition of the Cauchy stress and the spatial tangential stiffness. The relationships between water content, osmotic pressure, ionic concentration and the pore pressure stress of the tissue are discussed with the merits of these models and their applications. PMID- 26611113 TI - Nitric oxide, prostaglandins and angiotensin II in the regulation of renal medullary blood flow during volume expansion. AB - Regulation of medullary blood flow (MBF) is essential in maintaining renal function and blood pressure. However, it is unknown whether outer MBF (OMBF) and papillary blood flow (PBF) are regulated independently when extracellular volume (ECV) is enhanced. The aim of this study was to determine whether OMBF and PBF are differently regulated and whether there is an interaction between nitric oxide (NO), prostaglandins (PGs) and angiotensin II (Ang II) in regulating OMBF and PBF when ECV is enhanced. To achieve these goals, OMBF and PBF were measured by laser-Doppler in volume-expanded rats treated with a cyclooxygenase inhibitor (meclofenamate, 3 mg/kg) and/or a NO synthesis inhibitor (L-nitro-arginine methyl ester (L-NAME), 3 MUg/kg/min) and/or Ang II (10 ng/kg/min). OMBF was unchanged by NO or PGs synthesis inhibition but decreased by 36 % (P < 0.05) when L-NAME and meclofenamate were infused simultaneously. PBF was similarly reduced by L-NAME (12 %), meclofenamate (17 %) or L-NAME + meclofenamate (19 %). Ang II did not modify OMBF, but it led to a similar decrease (P < 0.05) in OMBF when it was administered to rats with reduced NO (32 %), PGs (36 %) or NO and PGs (37 %) synthesis. In contrast, the fall in PBF induced by Ang II (12 %) was enhanced (P < 0.05) by the simultaneous PGs (30 %) or PGs and NO (31 %) synthesis inhibition but not in L-NAME-treated rats (20 %). This study presents novel findings suggesting that blood flows to the outer medulla and renal papilla are differently regulated and showing that there is a complex interaction between NO, PGs and Ang II in regulating OMBF and PBF when ECV is enhanced. PMID- 26611114 TI - Inhibition of IRF3 expression reduces TGF-beta1-induced proliferation of hepatic stellate cells. AB - Therapeutic management of liver fibrosis remains an unresolved clinical problem. Activation of hepatic stellate cell (HSC) is a pivotal event in the progression of liver fibrosis. Recent reports have showed that inhibition of activated HSC proliferation contributes to the reversal of liver fibrosis. Interferon regulatory factor 3 (IRF3), one member of the interferon regulatory factor (IRF) family, is recently proven to be a critical modulator in cardiac fibrosis. And accumulating evidence demonstrated that IRF3 plays a crucial role in liver diseases, such as hepatic steatosis, liver inflammation, and alcoholic liver injury. However, the understanding of the function of IRF3 in liver fibrosis remains limited. Our results identified the role of IRF3 in regulating human HSC (LX-2 cell) cell proliferation and apoptosis. The present study indicated that the expression of IRF3 was significantly increased in HSCs in response to TGF beta1 stimulation. Moreover, a stable and unlimited source of human HSC, the LX-2 cell line, transfected with IRF3-siRNA significantly decreases the expression level of type I collagen (Col1a1) and alpha-smooth muscle actin (alpha-SMA) in activated LX-2 cells. On the contrary, overexpression of IRF3 gives rise to an upregulation of Col1a1 and alpha-SMA in LX-2 cells, and further promoted HSC proliferation. Moreover, the inhibition of IRF3 significantly suppressed TGF beta1-induced HSC proliferation and increased its apoptosis. Of note, the present study indicated IRF3 may regulate LX-2 cell proliferation by via AKT signaling pathway. In summary, these observations suggest IRF3 may function as a novel regulator to modulate TGF-beta1-induced LX-2 proliferation, at least in part, via AKT signaling pathway. PMID- 26611115 TI - Increased risk of sudden sensorineural hearing loss in patients with depressive disorders: population-based cohort study. AB - OBJECTIVES: To evaluate the incidence rates and risk of sudden sensorineural hearing loss among patients with depressive disorders. METHOD: Data for 27 547 patients with newly diagnosed depressive disorders and 27 547 subjects without depressive disorders between 2001 and 2008 were yielded from the Taiwan National Health Insurance Research Database. Sudden sensorineural hearing loss incidence at the end of 2011 was determined. Cumulative incidence and adjusted hazard ratio were computed. RESULTS: Sudden sensorineural hearing loss incidence was 1.45 times higher in the depressive disorders group compared to the non-depressive disorders group (p = 0.0041), with an adjusted hazard ratio of 1.460. A significant increased risk of developing sudden sensorineural hearing loss was noted in patients with diabetes mellitus, chronic kidney disease and hyperlipidaemia (p < 0.05). CONCLUSION: The results suggest an increased risk of developing sudden sensorineural hearing loss in patients with depressive disorders. Co-morbidities such as diabetes mellitus, chronic kidney disease and hyperlipidaemia significantly aggravated the risk. Depressive disorders might be considered a risk factor for sudden sensorineural hearing loss. It remains to be seen whether control of depressive disorders can decrease the incidence of sudden sensorineural hearing loss in patients with depressive disorders. PMID- 26611116 TI - Intense parenting: a qualitative study detailing the experiences of parenting children with complex care needs. AB - BACKGROUND: Increased numbers of children with chronic illnesses and/or disabilities who have complex care needs are living at home. Along with the transfer of care to the home setting, parents assume the primary responsibility of their child's complex care needs. Accordingly, it becomes even more important to understand the evolving roles and challenges faced by parents of children with complex care needs in order to better support them. The aim of this paper is to present research findings that add to our understanding of the roles parents assume in parenting their children with complex care needs. METHODS: To arrive at a detailed and accurate understanding of families' perspectives and experiences, the qualitative research design of ethnography was used. In total, 68 parents from 40 families were recruited. Data collection strategies included ethnographic methods of interviewing and photovoice. Several levels of analysis generated a sociocultural theme with subthemes representing how parents experienced raising children with complex care needs within the context of their life situations. RESULTS: Intense parenting as the overarching theme refers to the extra efforts parents had to commit to in raising their children with complex care needs. Parenting was described as labour-intensive, requiring a readiness to provide care at any time. This left parents with minimal time for addressing any needs and tasks not associated with caring for their child. The main theme is supported by four sub-themes: 1) the good parent; 2) more than a nurse; 3) there's just not enough; 4) it takes a toll on the health of parents. CONCLUSIONS: Overall, parents of children with complex care needs take on more roles as well as work more intensely at these roles than parents of healthy children. This, in turn, has led to the need for additional supports and resources for parents. However, to date, parents of children with complex care needs are still lacking adequate services and supports necessary to help them in their role of intense parenting. The findings sensitize professionals to the issues confronted by parents caring for children with complex care needs. Implications for further research and clinical practice are discussed. PMID- 26611118 TI - Xenobiotic conjugation with phosphate - a metabolic rarity. AB - 1. Although not unknown, the conjugation of a xenobiotic with phosphate appears a rarity amongst the routes available for foreign compound metabolism. This is especially true in mammals and may be somewhat surprising as conjugation with sulphate, a seemingly similar moiety, is commonplace. 2. Information from the literature, where xenobiotic phosphate conjugates have been described or suggested, has been collated and presented in this article. By bringing together this diverse material, hopefully interest will be generated in this unusual xenobiotic reaction, and perhaps further research undertaken to better understand and delineate the reasons for its relative absence from the xenobiotic scene. PMID- 26611117 TI - Identification of candidate genes for prostate cancer-risk SNPs utilizing a normal prostate tissue eQTL data set. AB - Multiple studies have identified loci associated with the risk of developing prostate cancer but the associated genes are not well studied. Here we create a normal prostate tissue-specific eQTL data set and apply this data set to previously identified prostate cancer (PrCa)-risk SNPs in an effort to identify candidate target genes. The eQTL data set is constructed by the genotyping and RNA sequencing of 471 samples. We focus on 146 PrCa-risk SNPs, including all SNPs in linkage disequilibrium with each risk SNP, resulting in 100 unique risk intervals. We analyse cis-acting associations where the transcript is located within 2 Mb (+/-1 Mb) of the risk SNP interval. Of all SNP-gene combinations tested, 41.7% of SNPs demonstrate a significant eQTL signal after adjustment for sample histology and 14 expression principal component covariates. Of the 100 PrCa-risk intervals, 51 have a significant eQTL signal and these are associated with 88 genes. This study provides a rich resource to study biological mechanisms underlying genetic risk to PrCa. PMID- 26611119 TI - Field evaluation of the effectiveness of three industrial by-products as organic amendments for phytostabilization of a Pb/Zn mine tailings. AB - Although the potential of industrial by-products as organic amendments for phytostabilization has long been recognized, most of the previous studies addressing this issue have been laboratory-based. In this study, a field trial was conducted to evaluate the effectiveness of three industrial by-products [sweet sorghum vinasse (SSV), medicinal herb residues (MHR) and spent mushroom compost (SMC)] as organic amendments for phytostabilization of abandoned Pb/Zn mine tailings. Our results showed the following: (i) when compared to the control tailings, the mean concentrations of diethylene-triamine-pentaacetic acid (DTPA) extractable Cd, Cu, Pb and Zn in SSV, MHR and SMC treatments decreased by 20.8 28.0%, 41.6-49.1%, 17.7-22.7% and 9.5-14.7%, respectively; (ii) the mean values of organic C, ammonium-N and available P in SSV, MHR and SMC treatments increased by 1.7-2.8, 10.8-14.9 and 3.9-5.1 times as compared with the mine tailings; and (iii) the addition of SSV, MHR and SMC significantly enhanced soil respiration and microbial biomass being 1.5-1.8 and 1.3-1.6 fold higher than those in the control tailings. There were no significant differences in soil biochemical properties among the plots amended with these by-products, suggesting that they were almost equally effective in improving the biochemical conditions of the tailings. In addition, the application of these amendments promoted seed germination, seedling growth, and consequently increased the vegetation cover and its biomass. Moreover, concentrations of Cd, Cu, Pb and Zn in above-ground parts of the plants were below the toxicity limit levels for animals. The results obtained in this field study confirmed that the three organic-rich industrial by products could be used as amendments for phytostabilization of some types of mine tailings. PMID- 26611120 TI - Usefulness of Nutraceuticals (Armolipid Plus) Versus Ezetimibe and Combination in Statin-Intolerant Patients With Dyslipidemia With Coronary Heart Disease. AB - Statins are extensively used to treat dyslipidemia, but, because of their low tolerability profile, they are discontinued in a significant proportion of patients. Ezetimibe and nutraceuticals have been introduced as alternative therapies and have proved to be effective and well tolerated. A single-blind, single-center, randomized, prospective, and parallel group trial comparing a combination of nutraceuticals (red yeast rice, policosanol, berberine, folic acid, coenzyme Q10 and astaxanthin), called Armolipid Plus, and ezetimibe for 3 months in terms of efficacy and tolerability. Patients who did not achieve their therapeutic target (low-density lipoprotein cholesterol <100 mg/dl) could add the alternative treatment on top of randomized treatment for another 12 months: 100 patients who are dyslipidemic with ischemic heart disease treated with percutaneous coronary intervention were enrolled (ezetimibe n = 50, nutraceutical n = 50). Efficacy (lipid profile) and tolerability (adverse events, transaminases, and creatine kinase) were assessed after 3 and 12 months. After 3 months, 14 patients in the nutraceutical group achieved their therapeutic target, whereas none of the patients in the ezetimibe group did. At 1-year follow-up, 58 patients (72.5%) of the combined therapy group (n = 86) and 14 (100%) of the nutraceutical group reached the therapeutic goal. No patients experienced important undesirable effects. In conclusion, nutraceuticals alone or in combination with ezetimibe are well tolerated and improve the lipid profile in statin-intolerant patients with coronary heart disease. Further studies are needed to assess long-term effects of nutraceuticals on mortality. PMID- 26611121 TI - Medical Therapy and Coronary Revascularization for Patients With Stable Coronary Artery Disease and Unclassified Appropriateness Score. AB - Although the appropriate use criteria incorporate common clinical scenarios for coronary revascularization, a significant proportion of patients with stable coronary artery disease (CAD) cannot be assigned an appropriateness score. Our objective was to characterize these patients and to evaluate whether coronary revascularization is associated with improved outcomes. A population-based cohort of patients aged >=66 years, who underwent cardiac catheterization in Ontario, Canada, were included. Clinical characteristics were compared between patients with and without an appropriateness score. Clinical outcomes between coronary revascularization and medical therapy in patients with unclassified appropriateness score were compared using the inverse probability of treatment weighted propensity method for confounder adjustment. Of the 19,228 patients with stable CAD, 11.2% (2,153 patients) were not assigned to an appropriateness score, mostly (92.9%) because of a lack of ischemic evaluation or a noninterpretable test. These patients were older, had higher rate of severe angina, and had more medical co-morbidities compared to patients with an appropriateness score. The 2 year rate of death or myocardial infarction in patients with unclassified appropriateness score was 15.3% in the revascularization group versus 20.7% in the medical therapy group. After propensity weighting, revascularization was associated with significantly lower hazard ratio (0.70; 95% confidence interval 0.61 to 0.79) for death or myocardial infarction compared with medical therapy. In conclusion, in patients aged >=66 years with stable CAD and unclassified appropriateness score, revascularization is associated with improved outcomes. PMID- 26611122 TI - Frequent Atrial Premature Complexes and Their Association With Risk of Atrial Fibrillation. AB - Identification of precursors of atrial fibrillation (AF) may lead to early detection and prevent associated morbidity and mortality. This study aimed to examine the association between frequent atrial premature complexes (APCs) and incidence of AF. For this retrospective cohort study, we analyzed Holter recordings obtained from 2000 to 2010 of 1,357 veterans free of AF at baseline. All pertinent data in electronic medical records were reviewed to ascertain baseline characteristics. Holter groups with frequent (>=100/day) and infrequent (<100/day) APCs were compared for development of new AF over a median follow-up of 7.5 years. Multivariate Cox regression analyses were performed before and after propensity score matching. Mean age was 64 years with 93% men. Mean body mass index, hemoglobin A1C, low-density lipoprotein, left atrial size, and heart rate were 31.24 kg/m(2), 6.42%, 107.92 mg/dl, 4.26 cm, and 73 beats/min, respectively. AF was noted in 21.8% of patients with frequent APCs compared to 5.6% of those with infrequent APCs. After adjusting for demographics, medication use, co-morbidities, and laboratory and echocardiographic findings, multivariate Cox regression analyses confirmed frequent APCs to be independently associated with higher incidence of AF (hazard ratio [HR] 2.97, 95% confidence interval [CI] 1.85 to 4.80; p <0.001). In propensity-matched groups, this association remained significant (HR 2.87, 95% CI 1.65 to 4.98; p <0.001). Additionally, atrial couplets (>=50/day), atrial bigeminy (>=50/day), frequent runs of >=3 APCs (>=20 runs/day), and longer runs (>=10 beats/run) were significantly associated with AF (HR 3.11, 3.67, 2.94, and 1.73, respectively, all p <0.05). In conclusion, frequent APCs (>=100/day) are associated with greater risk of AF. PMID- 26611123 TI - Infective Endocarditis Involving the Pulmonary Valve. AB - Pulmonary valve (PV) infective endocarditis (IE) is a rare entity, accounting for 1.5% to 2% of cases of IE. Published data are limited to a few case series and reports. We sought to review the Mayo Clinic experience and describe clinical, echocardiographic, and microbiologic features. We included all patients aged >=18 years seen from 2000 to 2014 who had a diagnosis of native PV IE and unequivocal echocardiographic involvement of the PV. Nine patients with PV IE were identified. Isolated PV IE was present in 7 (78%) of 9 cases. The median age was 59 years and 22% were women. Three patients had congenital heart disease, 2 had central venous catheters, and 3 had cardiovascular implantable electronic devices. Five patients (56%) received chronic immunosuppressive therapy. Enterococcus faecalis and viridans group streptococci were the most common pathogens, isolated in 22% of cases each. Transthoracic echocardiogram (TTE) and transesophageal echocardiogram (TEE) were done in 6 and 7 patients, respectively. Four patients underwent both procedures. TTE was diagnostic in all cases, but TEE failed to detect PV involvement in 1 patient. Median follow-up was 1.8 years. Five patients (56%) underwent PV replacement. There were no operative deaths. One patient had sudden death during follow-up, unrelated to his PV IE episode. Our results suggest that PV IE is rare but carries significant morbidity. TTE and TEE provide complementary information with TEE providing better visualization of other cardiac structures. Our findings of a high prevalence of immunosuppressive therapy and cardiovascular implantable electronic devices have not been previously reported and deserve further investigation. PMID- 26611124 TI - Impact of Funding Source on Clinical Trial Results Including Cardiovascular Outcome Trials. AB - Previous authors have suggested a higher likelihood for industry-sponsored (IS) studies to have positive outcomes than non-IS studies, though the influence of publication bias was believed to be a likely confounder. We attempted to control for the latter using a prepublication database to compare the primary outcome of recent trials based on sponsorship. We used the "advanced search" feature in the clinicaltrials.gov website to identify recently completed phase III studies involving the implementation of a pharmaceutical agent or device for which primary data were available. Studies were categorized as either National Institutes of Health (NIH) sponsored or IS. Results were labeled "favorable" if the results favored the intervention under investigation or "unfavorable" if the intervention fared worse than standard medical treatment. We also performed an independent literature search to identify the cardiovascular trials as a case example and again categorized them into IS versus NIH sponsored. A total of 226 studies sponsored by NIH were found. When these were compared with the latest 226 IS studies, it was found that IS studies were almost 4 times more likely to report a positive outcome (odds ratio [OR] 3.90, 95% confidence interval [CI] 2.6087 to 5.9680, p <0.0001). As a case example of a specialty, we also identified 25 NIH-sponsored and 215 IS cardiovascular trials, with most focusing on hypertension therapy (31.6%) and anticoagulation (17.9%). IS studies were 7 times more likely to report favorable outcomes (OR 7.54, 95% CI 2.19 to 25.94, p = 0.0014). They were also considerably less likely to report unfavorable outcomes (OR 0.11, 95% CI 0.04 to 0.26, p <0.0001). In conclusion, the outcomes of large clinical studies especially cardiovascular differ considerably on the basis of their funding source, and publication bias appears to have limited influence on these findings. PMID- 26611126 TI - High-affinity sequence-selective DNA binding by iridium(III) polypyridyl organometallopeptides. AB - We demonstrate the application of solid-phase peptide synthesis methods for the straightforward assembly of polynuclear Ir(III) organometallopeptides, and show that their oligoarginine derivatives exhibit high DNA binding affinity, sequence selectivity, and high cytotoxicity towards a set of cancer cell lines. PMID- 26611125 TI - VASP, zyxin and TES are tension-dependent members of Focal Adherens Junctions independent of the alpha-catenin-vinculin module. AB - Mechanical forces are integrated at cadherin-based adhesion complexes to regulate morphology and strength of cell-cell junctions and organization of associated F actin. A central mechanosensor at the cadherin complex is alpha-catenin, whose stretching recruits vinculin to regulate adhesion strength. The identity of the F actin regulating signals that are also activated by mechanical forces at cadherin based junctions has remained elusive. Here we identify the actin-regulators VASP, zyxin and TES as members of punctate, tensile cadherin-based junctions called Focal Adherens Junctions (FAJ) and show that they display mechanosensitive recruitment similar to that of vinculin. However, this recruitment is not altered by destroying or over-activating the alpha-catenin/vinculin module. Structured Illumination Microscopy (SIM) indicates that these tension sensitive proteins concentrate at locations within FAJs that are distinct from the core cadherin complex proteins. Furthermore, localization studies using mutated versions of VASP and zyxin indicate that these two proteins require binding to each other in order to localize to the FAJs. We conclude that there are multiple force sensitive modules present at the FAJ that are activated at distinct locations along the cadherin-F-actin axis and regulate specific aspects of junction dynamics. PMID- 26611127 TI - CELEBRATING THE 75TH ANNIVERSARY OF THE AMERICAN JOURNAL OF PSYCHOANALYSIS. PMID- 26611128 TI - In these pages... THE INTERTWINING OF EXTERNAL AND INTERNAL EVENTS IN THE CHANGING WORLD. PMID- 26611129 TI - INDIAN CASTE SYSTEM: HISTORICAL AND PSYCHOANALYTIC VIEWS. AB - This paper elucidates the historical origins and transformations of India's caste system. Surveying the complex developments over many centuries, it points out that three positions have been taken in this regard. One suggests that the caste one is born into can be transcended within one's lifetime by performing good deeds. The other declares caste to be immutable forever. And, the third says that one can be reborn into a higher caste if one lives a virtuous life. Moving on to the sociopolitical realm, the paper notes how these positions have been used and exploited. The paper then attempts to anchor the existence and purpose of the Hindu caste system in Freud's ideas about group psychology and Klein's proposals of splitting and projective identification. The paper also deploys the large group psychology concepts of Volkan and the culturally nuanced psychoanalytic anthropology of Roland and Kakar. It concludes with delineating some ameliorative strategies for this tragic problem in the otherwise robust democratic society of India. PMID- 26611130 TI - CYPRUS TURKISH FAIRY TALES: GLIMPSE OF A HARMONIOUS PAST. AB - On the island of Cyprus, believed to be the birthplace of Aphrodite, the Muslim minority (settled there following the Ottoman conquest of the island in 1571) and Orthodox Christians (the native majority) lived together in peace for hundreds of years. However, as a result of ethnic conflict in the late 1950s, the Muslim Cypriot Turks established their own political state in the north of the island in 1974, and Cyprus was divided into northern Turkish and southern Greek sections. This paper attempts to examine historical, religious, cultural and psychological aspects of the relationship between these two large groups, prior to recent conflicts, by studying fairy tales told by Turkish Cypriots about a hundred years ago. It is hoped that this paper will encourage similar studies of other communities where different large-group identities live side by side, and that such studies may support their peaceful co-existence. PMID- 26611131 TI - COMMUNISM AND THE TRAUMA OF ITS COLLAPSE REVISITED. AB - This paper focuses on the intertwinement of society and the psyche as a consequence of 70 years of Communist rule and the trauma of its collapse in the 90's. The trauma had profound effects on the psyche. An empirical study that was carried out in 1996/1997, which compared the personality structure of adolescents from Russia and Austria, and a research dialogue in 1999, has been re-evaluated in the light of current political events. One aim that we had was to find out whether we could discover characteristic personality features, resulting from the Communist totalitarian society in Russia, as well as from the trauma of its collapse. This led to the development of the concepts of the "impersonal self" and the "denial mode". The Russians seemed to be frozen in a protective shell with "flat" affects. They were anxious, conflict avoidant, and somewhat lost. Ideas about missing adolescence and the importance of privacy are discussed. Society was shown to not only have intruded into the individual psyche, but also into the members of the intercultural research team in the form of projective identification. The importance of the interaction between society and the individual as a basic psychoanalytic concept dating back to Freud is elaborated. Finally, considerations pertaining to mental health and democracy are presented. PMID- 26611132 TI - FEMALE SEXUALITY, NATIONALISM AND LARGE GROUP IDENTITY. AB - Nationalist movements are emerging today everywhere in the world. Many of them display a high level of aggression and a negative attitude toward sexuality and especially female sexuality. Along with this, erotic fiction with a sadomasochistic orientation has achieved great success and has hundreds of millions of readers in the world. This collective fantasy allows some integration of aggression in sexual life while questioning liberal morality and its equality in gender roles and conservative morality and its idea of control over passion. Both phenomena may represent different responses to the appearance of a new female sexuality threatening the social structure we know. PMID- 26611133 TI - IDENTITY FORMATION DIFFICULTIES IN IMMIGRANT ADOLESCENTS: THREE CASES FROM GERMANY. AB - Adolescence is a period of instability caused by biological changes and restructuring of the personality. An immigration background renders the process of identity formation even more difficult or fragile, with an additional burden coming from persecution and harassment. Three case studies of mentally disturbed adolescents with different immigration backgrounds illustrate the problems in diagnosis and psychotherapy. All three cases share a common feature--the particular influence of the native country on the psychic disorder of the adolescent, be it a suitable target of narcissistic self-aggrandizement, a reactivated metaphor of the past or a deposited conflict. I point out and discuss the danger of diagnostic colonization and activation of perpetrator-victim constellations--such as the Nazi past in the present. Offering a transcultural transitional space as a container yields a therapeutic approach to the different worlds of these borderland adolescents. PMID- 26611139 TI - Internet Abuse Risk Factors among Spanish Adolescents. AB - Empirical evidence has revealed various factors that contribute to the development and maintenance of Internet abuse. The aim of this paper was to analyze, on a sample of Spanish adolescents, the relationship between Internet abuse and: (1) Personal and interpersonal risk factors, including social skills in both virtual and real-life contexts; (2) Drug use. A total of 814 high school students aged between 13 and 17 participated in this study, and were divided into two groups: Internet Abusers (IA = 173) and Non-Internet Abusers (NIA = 641). Questionnaires were used to analyze Internet and drug use/abuse, as well as social skills, in virtual and real contexts. Various interpersonal risk factors (family and group of friends) were also assessed. IA showed a more severe pattern of Internet and drug use, as well as poorer social skills in both contexts. Moreover, their groups of friends appeared more likely to become involved in risky situations related to Internet and drug abuse. Both IA and NIA showed more adaptive social skills in the virtual context than in the real one. There is a need for further research to build on these findings, with a view to designing specific preventive programs that promote responsible Internet use. PMID- 26611140 TI - Synthesis of ZnO nanosheet arrays with exposed (100) facets for gas sensing applications. AB - ZnO nanosheet (NS) arrays have been synthesized by a facile ultrathin liquid layer electrodeposition method. The ion concentration and electrode potential play important roles in the formation of ZnO NS arrays. Studies on the structural information indicate that the NSs are exposed with (100) facets. The results of Raman and PL spectra indicate that there existed a large amount of oxygen vacancies in the NSs. The gas sensing performances of the ZnO NS arrays are investigated: the ZnO NS arrays exhibited high gas selectivity and quick response/recovery for detecting NO2 at a low working temperature. High binding energies between NO2 molecules and exposed ZnO(100) facets lead to large surface reconstructions, which is responsible for the intrinsic NO2 sensing properties. In addition, the highly exposed surface and a large amount of oxygen vacancies existing in the NSs also make a great contribution to the gas sensing performance. PMID- 26611141 TI - A paper and plastic device for the combined isothermal amplification and lateral flow detection of Plasmodium DNA. AB - BACKGROUND: Isothermal amplification techniques are emerging as a promising method for malaria diagnosis since they are capable of detecting extremely low concentrations of parasite target while mitigating the need for infrastructure and training required by other nucleic acid based tests. Recombinase polymerase amplification (RPA) is promising for further development since it operates in a short time frame (<30 min) and produces a product that can be visually detected on a lateral flow dipstick. A self-sealing paper and plastic system that performs both the amplification and detection of a malaria DNA sequence is presented. METHODS: Primers were designed using the NCBI nBLAST tools and screened using gel electrophoresis. Paper and plastic devices were prototyped using commercial design software and parts were cut using a laser cutter and assembled by hand. Synthetic copies of the Plasmodium 18S gene were spiked into solution and used as targets for the RPA reaction. To test the performance of the device the same samples spiked with synthetic target were run in parallel both in the paper and plastic devices and using conventional bench top methods. RESULTS: Novel RPA primers were developed that bind to sequences present in the four species of Plasmodium which infect humans. The paper and plastic devices were found to be capable of detecting as few as 5 copies/uL of synthetic Plasmodium DNA (50 copies total), comparable to the same reaction run on the bench top. The devices produce visual results in an hour, cost approximately $1, and are self-contained once the device is sealed. CONCLUSIONS: The device was capable of carrying out the RPA reaction and detecting meaningful amounts of synthetic Plasmodium DNA in a self sealing and self-contained device. This device may be a step towards making nucleic acid tests more accessible for malaria detection. PMID- 26611142 TI - Additive Manufacturing of a Microbial Fuel Cell--A detailed study. AB - In contemporary society we observe an everlasting permeation of electron devices, smartphones, portable computing tools. The tiniest living organisms on Earth could become the key to address this challenge: energy generation by bacterial processes from renewable stocks/waste through devices such as microbial fuel cells (MFCs). However, the application of this solution was limited by a moderately low efficiency. We explored the limits, if any, of additive manufacturing (AM) technology to fabricate a fully AM-based powering device, exploiting low density, open porosities able to host the microbes, systems easy to fuel continuously and to run safely. We obtained an optimal energy recovery close to 3 kWh m(-3) per day that can power sensors and low-power appliances, allowing data processing and transmission from remote/harsh environments. PMID- 26611143 TI - Post-traumatic stress disorder. PMID- 26611144 TI - Robot-based assessment of motor and proprioceptive function identifies biomarkers for prediction of functional independence measures. AB - BACKGROUND: Neurological impairments following stroke impact the ability of individuals to perform daily activities, although the relative impact of individual impairments is not always clear. Recovery of sensorimotor function following stroke can vary widely, from complete recovery to modest or minimal improvements, across individuals. An important question is whether one can predict the amount of recovery based on initial examination of the individual. Robotic technologies are now being used to quantify a range of behavioral capabilities of individuals post-stroke, providing a rich set of biomarkers of sensory and motor dysfunction. The objective of the present study is to use mathematical models to identify which biomarkers best predict the ability of subjects with stroke to perform daily activities before and after rehabilitation. METHODS: The Functional Independence Measure (FIM) was quantified approximately 2 weeks and three months post-stroke in 61 ischemic and 24 hemorrhagic subjects with stroke. At 2 weeks post-stroke, subjects also completed clinical assessments and robotic assessments of sensory and motor function. A computational search algorithm, known as Fast Orthogonal Search, was used to identify the robotic and clinical biomarkers that best estimated Functional Independence Measures. RESULTS: Clinical and robot-based biomarkers were statistically similar at predicting FIM scores at 2 weeks (r = 0.817 vs. 0.774, respectively) and 3 months (r = 0.643 vs. 0.685, respectively). Importantly, robot-based biomarkers highlighted that parameters related to proprioception were influential for predicting FIM scores at 2 weeks, whereas biomarkers related to bimanual motor function were influential for predicting FIM scores at 3 months. CONCLUSIONS: The present study provides a proof of principle on the use of robot-based biomarkers of sensory and motor dysfunction to estimate present and future FIM scores. The addition of other behavioral tasks will likely increase the accuracy of these predictions, and potentially help guide rehabilitation strategies to maximize functional recovery. PMID- 26611145 TI - Paludisphaera borealis gen. nov., sp. nov., a hydrolytic planctomycete from northern wetlands, and proposal of Isosphaeraceae fam. nov. AB - Two isolates of aerobic, budding, pink-pigmented bacteria, designated strains PX4T and PT1, were isolated from a boreal Sphagnum peat bog and a forested tundra wetland. Cells of these strains were non-motile spheres that occurred singly or in short chains. Novel isolates were capable of growth at pH values between 3.5 and 6.5 (optimum at pH 5.0-5.5) and at temperatures between 6 and 30 degrees C (optimum at 15-25 degrees C). Most sugars and a number of polysaccharides including pectin, xylan, lichenin and Phytagel were used as growth substrates. The major fatty acids were C16 : 0, C18 : 1omega9 and C18 : 0; the major polar lipids were phosphocholine and trimethylornithine. The quinone was menaquinone-6, and the G+C content of the DNA was 66 mol%. Strains PX4T and PT1 were members of the order Planctomycetales and displayed 93-94 % 16S rRNA gene sequence similarity to Aquisphaera giovannonii, 91-92 % to species of the genus Singulisphaera and 90-91 % to Isosphaera pallida. The two novel strains, however, differed from members of these genera by cell morphology, substrate utilization pattern and a number of physiological characteristics. Based on these data, the novel isolates should be considered as representing a novel genus and species of planctomycetes, for which the name Paludisphaera borealis gen. nov., sp. nov., is proposed. The type strain is PX4T ( = DSM 28747T = VKM B-2904T). We also suggest the establishment of a novel family, Isosphaeraceae fam. nov., to accommodate stalk-free planctomycetes with spherical cells, which can be assembled in short chains, long filaments or shapeless aggregates. This family includes the genera Isosphaera, Aquisphaera, Singulisphaera and Paludisphaera. PMID- 26611146 TI - Identification and analysis of divergent immune gene families within the Tasmanian devil genome. AB - BACKGROUND: The Tasmanian devil (Sarcophilus harrisii) is being threatened with extinction in the wild by a disease known as devil facial tumour disease (DFTD). In order to prevent the spread of this disease a thorough understanding of the Tasmanian devil immune system and its response to the disease is required. In 2011 and 2012 two genome sequencing projects of the Tasmania devil were released. This has provided us with the raw data required to begin to investigate the Tasmanian devil immunome in depth. In this study we characterise immune gene families of the Tasmanian devil. We focus on immunoglobulins, T cell receptors and cytokine families. RESULTS: We identify and describe 119 cytokines including 40 interleukins, 39 chemokines, 8 interferons, 18 tumour necrosis family cytokines and 14 additional cytokines. Constant regions for immunoglobulins and T cell receptors were also identified. The repertoire of genes in these families was similar to the opossum, however devil specific duplications were seen and orthologs to eutherian genes not previously identified in any marsupial were also identified. CONCLUSIONS: By using multiple data sources as well as targeted search methods, highly divergent genes across the Tasmanian devil immune system were identified and characterised. This understanding will allow for the development of devil specific assays and reagents and allow for future studies into the immune response of the Tasmanian devil immune system to DFTD. PMID- 26611148 TI - Petrologic Characteristics of the Lunar Surface. AB - Petrologic analysis of the lunar surface is critical for determining lunar formation and evolution. Here, we report the first global petrologic map that includes the five most important lunar lithological units: the Ferroan Anorthositic (FAN) Unit, the Magnesian Suite (MS) Unit, the Alkali Suite (AS) Unit, the KREEP Basalt (KB) Unit and the Mare Basalt (MB) Unit. Based on the petrologic map and focusing on four long-debated and important issues related to lunar formation and evolution, we draw the following conclusions from the new insights into the global distribution of the five petrologic units: (1) there may be no petrogenetic relationship between MS rocks and KB; (2) there may be no petrogenetic link between MS and AS rocks; (3) the exposure of the KREEP component on the lunar surface is likely not a result of MB volcanism but is instead mainly associated with the combined action of plutonic intrusion, KREEP volcanism and celestial collision; (4) the impact size of the South Pole-Aitken basin is constrained, i.e., the basin has been excavated through the whole crust to exhume a vast majority of lower-crustal material and a very limited mantle components to the lunar surface. PMID- 26611147 TI - Exploring end of life priorities in Saudi males: usefulness of Q-methodology. AB - BACKGROUND: Quality end-of-life care depends on understanding patients' end-of life choices. Individuals and cultures may hold end-of-life priorities at different hierarchy. Forced ranking rather than independent rating, and by-person factor analysis rather than averaging may reveal otherwise masked typologies. METHODS: We explored Saudi males' forced-ranked, end-of-life priorities and dis priorities. Respondents (n = 120) rank-ordered 47 opinion statements on end-of life care following a 9-category symmetrical distribution. Statements' scores were analyzed by averaging analysis and factor analysis (Q-methodology). RESULTS: Respondents' mean age was 32.1 years (range, 18-65); 52% reported average religiosity, 88 and 83% >= very good health and life-quality, respectively, and 100% >= high school education. Averaging analysis revealed that the extreme five end-of-life priorities were to, be at peace with God, be able to say the statement of faith, maintain dignity, resolve conflicts, and have religious death rituals respected, respectively. The extreme five dis-priorities were to, die in the hospital, not receive intensive care if in coma, die at peak of life, be informed about impending death by family/friends rather than doctor, and keep medical status confidential from family/friends, respectively. Q-methodology classified 67% of respondents into five highly transcendent opinion types. Type-I (rituals-averse, family-caring, monitoring-coping, life-quality-concerned) and Type-V (rituals-apt, family-centered, neutral-coping, life-quantity-concerned) reported the lowest and highest religiosity, respectively. Type-II (rituals-apt, family-dependent, monitoring-coping, life-quantity-concerned) and Type-III (rituals-silent, self/family-neutral, avoidance-coping, life-quality & quantity concerned) reported the best and worst life-quality, respectively. Type-I respondents were the oldest with the lowest general health, in contrast to Type IV (rituals-apt, self-centered, monitoring-coping, life-quality/quantity neutral). Of the extreme 14 priorities/dis-priorities for the five types, 29, 14, 14, 50, and 36%, respectively, were not among the extreme 20 priorities/dis priorities identified by averaging analysis for the entire cohort. CONCLUSIONS: 1) Transcendence was the extreme end-of-life priority, and dying in the hospital was the extreme dis-priority. 2) Quality of life was conceptualized differently with less emphasize on its physiological aspects. 3) Disclosure of terminal illness to family/close friends was preferred as long it is through the patient. 4) Q-methodology identified five types of constellations of end-of-life priorities and dis-priorities that may be related to respondents' demographics and are partially masked by averaging analysis. PMID- 26611149 TI - Measurement of abdominal circumference in preterm infants. AB - BACKGROUND: Body weight, length and head and thoracic circumference are routinely measured in obstetric and neonatal departments. Reference values for these measurements have been established for the neonatal population. Neonatal abdominal circumference is not routinely measured, and no reference values for this measurement have been determined. To evaluate the increase in abdominal circumference in newborns with abdominal pathology such as necrotizing enterocolitis, information about normal abdominal circumference in healthy neonates shortly after birth is needed. The aim of this study was to determine the correlation between abdominal circumference and birth weight by measuring the abdominal circumference of premature neonates soon after birth. METHODS: Abdominal circumference was measured within 30 min of birth in 220 neonates born between 23 and 35 weeks' gestation. RESULTS: There was no statistically significant difference in abdominal circumference between boys and girls in the study population. A specific formula for estimating normal abdominal circumference was developed: y = 0.0053x + 14.83 (y = abdominal circumference in cm; x = body weight in g; 0.0053 = regression coefficient; 14.83 = regression constant). CONCLUSION: A positive linear correlation between abdominal circumference and birth weight was found in infants at birth. The correlation can be summarized as a linear regression equation. Further studies are needed to investigate possible factors associated with abdominal circumference in fed versus unfed preterm infants. PMID- 26611150 TI - Polychromatic polarization microscope: bringing colors to a colorless world. AB - Interference of two combined white light beams produces Newton colors if one of the beams is retarded relative to the other by from 400 nm to 2000 nm. In this case the corresponding interfering spectral components are added as two scalars at the beam combination. If the retardance is below 400 nm the two-beam interference produces grey shades only. The interference colors are widely used for analyzing birefringent samples in mineralogy. However, many of biological structures have retardance <100 nm. Therefore, cells and tissues under a regular polarization microscope are seen as grey image, which contrast disappears at certain orientations. Here we are proposing for the first time using vector interference of polarized light in which the full spectrum colors are created at retardance of several nanometers, with the hue determined by orientation of the birefringent structure. The previously colorless birefringent images of organelles, cells, and tissues become vividly colored. This approach can open up new possibilities for the study of biological specimens with weak birefringent structures, diagnosing various diseases, imaging low birefringent crystals, and creating new methods for controlling colors of the light beam. PMID- 26611151 TI - The relative biological effectiveness of out-of-field dose. AB - PURPOSE: using simulations and models derived from existing literature, this work investigates relative biological effectiveness (RBE) for out-of-field radiation and attempts to quantify the relative magnitudes of different contributing phenomena (spectral, bystander, and low dose hypersensitivity effects). Specific attention is paid to external beam radiotherapy treatments for prostate cancer. MATERIALS AND METHODS: using different biological models that account for spectral, bystander, and low dose hypersensitivity effects, the RBE was calculated for different points moving radially out from isocentre for a typical single arc VMAT prostate case. The RBE was found by taking the ratio of the equivalent dose with the physical dose. Equivalent doses were calculated by determining what physical dose would be necessary to produce the same overall biological effect as that predicted using the different biological models. RESULTS: spectral effects changed the RBE out-of-field less than 2%, whereas response models incorporating low dose hypersensitivity and bystander effects resulted in a much more profound change of the RBE for out-of-field doses. The bystander effect had the largest RBE for points located just outside the edge of the primary radiation beam in the cranial caudal (z-direction) compared to low dose hypersensitivity and spectral effects. In the coplanar direction, bystander effect played the largest role in enhancing the RBE for points up to 8.75 cm from isocentre. CONCLUSIONS: spectral, bystander, and low dose hypersensitivity effects can all increase the RBE for out-of-field radiation doses. In most cases, bystander effects seem to play the largest role followed by low dose hypersensitivity. Spectral effects were unlikely to be of any clinical significance. Bystander, low dose hypersensitivity, and spectral effect increased the RBE much more in the cranial caudal direction (z-direction) compared with the coplanar directions. PMID- 26611152 TI - Hypercarotinemia after bariatric surgery. PMID- 26611153 TI - [Diagnosis and treatment of iron deficiency, with or without anemia, before and after bariatric surgery]. AB - Bariatric surgery (BS) is an increasingly used therapeutic option for severe obesity which allows patients to achieve sustained weight loss over time and resolution or improvement in most associated pathological conditions. Major mid- and long-term complications of BS include iron deficiency and iron-deficient anemia, which may occur in up to 50% of cases and significantly impair patient quality of life. These changes may be present before surgery. The aim of this review was to prepare schemes for diagnosis and treatment of iron deficiency and iron-deficient anemia before and after bariatric surgery. PMID- 26611155 TI - Genetic and environmental contributions to perfectionism and its common factors. AB - The aims of this study: (1) To evaluate the relative contributions of genetics and environment to perfectionism and it's two constructs: self-oriented, and socially prescribed perfectionism. (2) To clarify genetic and environmental common origins of both personal and social components. METHODS: Participants were 258 pairs of adolescent Spanish twins. Socially prescribed and self-oriented perfectionism were assessed using the perfectionism subscale of the Eating Disorder Inventory. STATISTICS: univariate and bivariate twin models, according to sex. Results; Heritability of self-oriented perfectionism was 23% in boys and 30% in girls, and of socially prescribed perfectionism 39% in boys and 42% in girls. Bivariate analysis suggested a common genetic and environmental pathway model. The genetic correlation between both perfectionisms was 0.981 in boys and 0.704 in girls. The non-shared environmental correlation was 0.254 in boys and 0.259 in girls. Conclusions; genetic influences on perfectionism are moderate during adolescence. Our results point toward a shared genetic component underlying both kind of perfectionism. These findings generate doubts about the hypothesis of a leading role of genetics in the pathogenesis of Self-oriented perfectionism and of environment in socially prescribed. The high genetic correlation seems to indicate that self-oriented and socially prescribed are the same dimension of perfectionism. PMID- 26611154 TI - HSC Aging and Senescent Immune Remodeling. AB - Aging-associated changes in the function of the immune system are referred to as senescent immune remodeling (SIR). Here we review the current understanding on the cellular and molecular mechanisms underlying SIR. We focus on aging associated changes in T and B cells, and discuss recent evidence supporting the notion that aging of the hematopoietic stem cell (HSC) compartment directly contributes to SIR due to aging-associated alterations in stem cell differentiation. We conclude by outlining strategies to attenuate SIR, including approaches to rejuvenate HSCs, which may open new avenues for targeting SIR in the clinic. PMID- 26611156 TI - Lexical and sub-lexical reading skills and their correlation to clinical symptoms in young Chinese patients with schizophrenia. AB - Patients with schizophrenia often experience severe reading deficits such as oral reading and reading comprehension deficits. However, it is not known whether different types of lexical or sub-lexical components in reading are also impaired. In order to address this issue, the present study had 22 young Chinese patients with schizophrenia and 22 young Chinese normal controls undergo a battery of reading tests, which specifically measures lexical and sub-lexical components of reading in Chinese. The schizophrenic group further underwent Brief Psychiatric Rating Scale (BPRS) in order to ascertain the severity of patients' clinical symptoms. The results showed that compared to the controls, (1) the schizophrenic patients performed significantly poorly in orthographic processing, orthography-phonology mapping, and orthography-semantic mapping tests and further that (2) their performances in orthographic processing, and orthography-semantic mapping skill tests negatively correlated with the BPRS score. Note however that their ability to access their mental lexicon was intact. There is thus a clear need for studies with a larger sample-size and neurobiological measures which would lead to our better understanding of the behavioral as well as the neural relationships between schizophrenic patients, and their reading processing impairments, thus developing effective reading intervention programs for the schizophrenic patients. PMID- 26611157 TI - Protein profiles in cortical and nuclear regions of aged human donor lenses: A confocal Raman microspectroscopic and imaging study. AB - A combination of Raman spectroscopy, imaging, hierarchical cluster analysis (HCA) and peak ratio analysis was used to analyze protein profiles in the superficial cortex (SC), deep cortex (DC) and nucleus of old human lenses with cortical, nuclear and mixed cataracts. No consistent differences were observed in protein spectra and after cluster analysis between the three locations irrespective of the presence or absence of cortical opacities and/or coloration. A sharp increase (~15%-~33%) in protein content from SC to DC, normal for human lenses, was found in 7 lenses. In 4 lenses, characterized by the absence of cortical opacities, the SC has a protein content of ~35%. A significant increase in the disulfide-to protein ratio is found only in the SC of the 7 cortical cataracts. No changes were found in sulfhydryl-to-protein ratio. The relative contents of alpha-helices and beta-sheets increase from SC to nucleus. beta-Sheets are more common in the SC of lenses with cortical cataract. The absence of significant and consistent changes in protein profiles between nucleus and cortex even in cases of severe coloration is not favoring the prevailing concept that ubiquitous protein oxidation is a key factor for age related nuclear (ARN) cataracts. The observations favor the idea that multilamellar bodies or protein aggregates at very low volume densities are responsible for the rise in Mie light scatter as a main cause of ARN cataracts leaving the short-range-order of the fiber cytoplasm largely intact. The absence of significant changes in the protein spectra of the deep cortical opacities, milky white as a result of the presence of vesicle-like features, indicate they are packed with relatively undisturbed crystallins. PMID- 26611158 TI - Germostatin resistance locus 1 encodes a PHD finger protein involved in auxin mediated seed dormancy and germination. AB - Seed dormancy and germination are important physiological processes during the life cycle of a seed plant. Recently, auxin has been characterized as a positive regulator that functions during seed dormancy and as a negative regulator during germination. Through chemical genetic screenings, we have identified a small molecule, germostatin (GS), which effectively inhibits seed germination in Arabidopsis. GSR1 (germostatin resistance locus 1) encodes a tandem plant homeodomain (PHD) finger protein, identified by screening GS-resistant mutants. Certain PHD fingers of GSR1 are capable of binding unmethylated H3K4, which has been reported as an epigenetic mark of gene transcriptional repression. Biochemical studies show that GSR1 physically interacts with the transcriptional repressor ARF16 and attenuates the intensity of interaction of IAA17/ARF16 by directly interacting with IAA17 to release ARF16. Further results show that axr3 1, arf10 arf16 are hyposensitive to GS, and gsr1 not only resists auxin-mediated inhibition of seed germination but also displays decreased dormancy. We therefore propose that GSR1 may form a co-repressor with ARF16 to regulate seed germination. Besides promoting auxin biosynthesis via upregulating expression of YUCCA1, GS also enhances auxin responses by inducing degradation of DIotaIota VENUS and upregulating expression of DR5-GFP. In summary, we identified GSR1 as a member of the auxin-mediated seed germination genetic network, and GS, a small non-auxin molecule that specifically acts on auxin-mediated seed germination. PMID- 26611161 TI - Isolation of a furan fatty acid from Hevea brasiliensis latex employing the combined use of pH-zone-refining and conventional countercurrent chromatography. AB - Furan fatty acids are valuable and bioactive minor fatty acids that usually contribute <0.1% to the fatty acid content of food samples. Their biological role still remains unclear as authentic furan fatty acid standards are not readily available and thorough experimental studies verifying the relevance of furan fatty acids are thus virtually impossible. An efficient protocol for the isolation of the furan fatty acid 9-(3-methyl-5-pentylfuran-2-yl)-nonanoic acid from hydrolyzed and centrifuged latex of Hevea brasiliensis was developed using countercurrent chromatography. A first run using pH-zone-refining countercurrent chromatography provided 48.4 mg of 9-(3-methyl-5-pentylfuran-2-yl)-nonanoic acid from 210 mg latex extract in a purity of 95%. The purity was increased to 99% by means of one second run in conventional countercurrent chromatography mode. The Structure and purity of 9-(3-methyl-5-pentylfuran-2-yl)-nonanoic acid were determined by gas chromatography coupled to mass spectrometry and (1)H and (13)C NMR spectroscopy. PMID- 26611159 TI - Ictal onset patterns of local field potentials, high frequency oscillations, and unit activity in human mesial temporal lobe epilepsy. AB - OBJECTIVE: To characterize local field potentials, high frequency oscillations, and single unit firing patterns in microelectrode recordings of human limbic onset seizures. METHODS: Wide bandwidth local field potential recordings were acquired from microelectrodes implanted in mesial temporal structures during spontaneous seizures from six patients with mesial temporal lobe epilepsy. RESULTS: In the seizure onset zone, distinct epileptiform discharges were evident in the local field potential prior to the time of seizure onset in the intracranial EEG. In all three seizures with hypersynchronous (HYP) seizure onset, fast ripples with incrementally increasing power accompanied epileptiform discharges during the transition to the ictal state (p < 0.01). In a single low voltage fast (LVF) onset seizure a triad of evolving HYP LFP discharges, increased single unit activity, and fast ripples of incrementally increasing power were identified ~20 s prior to seizure onset (p < 0.01). In addition, incrementally increasing fast ripples occurred after seizure onset just prior to the transition to LVF activity (p < 0.01). HYP onset was associated with an increase in fast ripple and ripple rate (p < 0.05) and commonly each HYP discharge had a superimposed ripple followed by a fast ripple. Putative excitatory and inhibitory single units could be distinguished during limbic seizure onset, and heterogeneous shifts in firing rate were observed during LVF activity. SIGNIFICANCE: Epileptiform activity is detected by microelectrodes before it is detected by depth macroelectrodes, and the one clinically identified LVF ictal onset was a HYP onset at the local level. Patterns of incrementally increasing fast ripple power are consistent with observations in rats with experimental hippocampal epilepsy, suggesting that limbic seizures arise when small clusters of synchronously bursting neurons increase in size, coalesce, and reach a critical mass for propagation. PMID- 26611163 TI - Editorial. PMID- 26611162 TI - International patterns of the public awareness of aphasia. AB - BACKGROUND: It has been suggested that public awareness of aphasia is vital for extending services, research support, social inclusion and targeted raising of awareness. Earlier studies show that knowledge of aphasia varies across a range of variables, but is very low compared with other conditions. AIMS: To report a series of surveys of public awareness of aphasia from six countries, the largest study conducted this far. METHODS & PROCEDURES: Surveys were conducted in Argentina (N = 800), Canada (N = 831), Croatia (N = 400), Greece (N = 800), Norway (N = 251) and Slovenia (N = 400) using the same methodology requesting information on age, sex and occupation, asking whether respondents had heard of aphasia and where they had heard of it. Respondents were tested on their levels of knowledge of aphasia. OUTCOMES & RESULTS: Results revealed low levels of awareness of aphasia in countries surveyed with marked variability that appeared to interact with occupation, country, age and sex. We surveyed 3483 respondents (mean age = 43.16; SD = 17.68). Between 60% (Croatia) and 16% (Slovenia) said they had heard of aphasia (37.1% overall), but those with actual knowledge ranged from 13.9% (Norway) to 1.0% (Argentina). The combined mean of those with basic knowledge was 9.2%. Those who had heard of aphasia were younger; and females had higher levels of awareness. We also found associations between socio-economic status and awareness. Those working in health, social and educational spheres had the highest levels. Respondents mainly heard about aphasia through the media and work or personal contact with aphasia. CONCLUSIONS & IMPLICATIONS: Levels of awareness are low everywhere in absolute terms, and relative to the awareness of other conditions, with significant variability between countries, sex and socio economic status. We examine how surveys can be utilized to plan ways to increase understanding and discuss the comparison of awareness of aphasia with other conditions. PMID- 26611164 TI - Streptococcus thermophilus, an emerging and promising tool for heterologous expression: Advantages and future trends. AB - Streptococcus thermophilus is the second most used bacterium in dairy industry. It is daily consumed by millions of people through the worldwide consumption of yogurts, cheeses and fermented milks. S. thermophilus presents many features that make it a good candidate for the production of heterologous proteins. First, its ability to be naturally transformable allows obtaining swiftly and easily recombinant strains using various genetic tools available. Second, its Generally Recognised As Safe status and its ability to produce beneficial molecules or to liberate bioactive peptides from milk proteins open up the way for the development of new functional foods to maintain health and well-being of consumers. Finally, its ability to survive the intestinal passage and to be metabolically active in gastrointestinal tract allows considering S. thermophilus as a potential tool for delivering various biological molecules to the gastrointestinal tract. The aim of this review is therefore to take stock of various genetic tools which can be employed in S. thermophilus to produce heterologous proteins and to highlight the advantages and future trends of use of this bacterium as a heterologous expression host. PMID- 26611165 TI - Exopolysaccharides produced by Oenococcus oeni: From genomic and phenotypic analysis to technological valorization. AB - Oenococcus oeni (O. oeni), which is the main species that drives malolactic fermentation (FML), an essential step for wine microbial stabilization and quality improvement, is known to produce exopolysaccharides (EPS). Depending on the strain, these EPS can be soluble, remain attached to the cell or both. In the present study, fourteen strains were examined for eps gene content and EPS production capacities. Cell-linked and soluble heteropolysaccharides made of glucose, galactose and rhamnose, soluble beta-glucan, and soluble dextran or levan were found, depending on the strain. The protective potential of either cell-linked heteropolysaccharides or dextrans produced was then studied during freeze drying of the bacterial strains. PMID- 26611166 TI - Use of the dynamic gastro-intestinal model TIM to explore the survival of the yogurt bacterium Streptococcus thermophilus and the metabolic activities induced in the simulated human gut. AB - Streptococcus thermophilus, a lactic acid bacterium used to produce yogurts and cheeses is more and more considered for its potential probiotic properties. This implies that additional information should be obtained regarding its survival and metabolic activity in the human Gastro-Intestinal Tract (GIT). In this study, we screened 30 S. thermophilus strains for urease, small heat shock protein, and amino-acid decarboxylase functions which may play a role in survival in the upper part of the GIT. The survival kinetics of 4 strains was investigated using the TIM, a physiologically relevant in vitro dynamic gastric and small intestinal model. The three strains LMD9, PB18O and EBLST20 showed significantly higher survival than CNRZ21 in all digestive compartments of the TIM, which may be related to the presence of urease and heat shock protein functions. When LMD9 bacterial cells were delivered in a fermented milk formula, a significant improvement of survival in the TIM was observed compared to non-fermented milk. With the RIVET (Recombinase In Vivo Expression Technology) method applied to the LMD9 strain, a promoter located upstream of hisS, responsible for the histidyl transfer RNA synthesis, was found to be specifically activated in the artificial stomach. The data generated on S. thermophilus survival and its adaptation capacities to the digestive tract are essential to establish a list of biomarkers useful for the selection of probiotic strains. PMID- 26611167 TI - Survival of cheese-ripening microorganisms in a dynamic simulator of the gastrointestinal tract. AB - A mixture of nine microorganisms (six bacteria and three yeasts) from the microflora of surface-ripened cheeses were subjected to in vitro digestive stress in a three-compartment "dynamic gastrointestinal digester" (DIDGI). We studied the microorganisms (i) grown separately in culture medium only (ii) grown separately in culture medium and then mixed, (iii) grown separately in culture medium and then included in a rennet gel and (iv) grown together in smear-ripened cheese. The yeasts Geotrichum candidum, Kluyveromyces lactis and Debaryomyces hansenii, were strongly resistant to the whole DIDGI process (with a drop in viable cell counts of less than <1 log CFU mL(-1)) and there were no significant differences between lab cultures and cheese-grown cultures. Ripening bacteria such as Hafnia alvei survived gastric stress less well when grown in cheese (with no viable cells after 90 min of exposure of the cheese matrix, compared with 6 CFU mL(-1) in lab cultures). The ability of Corynebacterium casei and Staphylococcus equorum to withstand digestive stress was similar for cheese and pure culture conditions. When grow in a cheese matrix, Brevibacterium aurantiacum and Arthrobacter arilaitensis were clearly more sensitive to the overall digestive process than when grown in pure cultures. Lactococcus lactis displayed poorer survival in gastric and duodenal compartments when it had been grown in cheese. In vivo experiments in BALB/c mice agreed with the DIDGI experiments and confirmed the latter's reliability. PMID- 26611168 TI - Sourdough microbial community dynamics: An analysis during French organic bread making processes. AB - Natural sourdoughs are commonly used in bread-making processes, especially for organic bread. Despite its role in bread flavor and dough rise, the stability of the sourdough microbial community during and between bread-making processes is debated. We investigated the dynamics of lactic acid bacteria (LAB) and yeast communities in traditional organic sourdoughs of five French bakeries during the bread-making process and several months apart using classical and molecular microbiology techniques. Sourdoughs were sampled at four steps of the bread making process with repetition. The analysis of microbial density over 68 sourdough/dough samples revealed that both LAB and yeast counts changed along the bread-making process and between bread-making runs. The species composition was less variable. A total of six LAB and nine yeast species was identified from 520 and 1675 isolates, respectively. The dominant LAB species was Lactobacillus sanfranciscensis, found for all bakeries and each bread-making run. The dominant yeast species changed only once between bread-making processes but differed between bakeries. They mostly belonged to the Kazachstania clade. Overall, this study highlights the change of population density within the bread-making process and between bread-making runs and the relative stability of the sourdough species community during bread-making process. PMID- 26611170 TI - Immunomodulation properties of multi-species fermented milks. AB - Dairy propionibacteria (PAB) are used as a ripening starter in combination with Lactic acid bacteria (LAB) for dairy products such as Swiss-type cheese. LAB and PAB have also been studied for their probiotic properties but little is still known about their individual and/or synergistic beneficial effects within dairy matrices. In the context of a rising incidence of Inflammatory Bowel Diseases, it has become crucial to evaluate the immunomodulatory potential of bacteria ingested in large numbers via dairy products. We therefore selected different strains and combinations of technological LAB and PAB. We determined their immunomodulatory potential by IL-10 and IL-12 induction, in human peripheral blood mononuclear cells, on either single or mixed cultures, grown on laboratory medium or directly in milk. Milk was fermented with selected anti-inflammatory strains of LAB or PAB/LAB mixed cultures and the resulting bacterial fractions were also evaluated for these properties, together with starter viability and optimum technological aspects. The most promising fermented milks were evaluated in the context of TNBS- or DSS-induced colitis in mice. The improvement in inflammatory parameters evidenced an alleviation of colitis symptoms as a result of fermented milk consumption. This effect was clearly strain-dependent and modulated by growth within a fermented dairy product. These findings offer new tools and perspectives for the development of immunomodulatory fermented dairy products for targeted populations. PMID- 26611169 TI - Biofilms of Lactobacillus plantarum and Lactobacillus fermentum: Effect on stress responses, antagonistic effects on pathogen growth and immunomodulatory properties. AB - Few studies have extensively investigated probiotic functions associated with biofilms. Here, we show that strains of Lactobacillus plantarum and Lactobacillus fermentum are able to grow as biofilm on abiotic surfaces, but the biomass density differs between strains. We performed microtiter plate biofilm assays under growth conditions mimicking to the gastrointestinal environment. Osmolarity and low concentrations of bile significantly enhanced Lactobacillus spatial organization. Two L. plantarum strains were able to form biofilms under high concentrations of bile and mucus. We used the agar well-diffusion method to show that supernatants from all Lactobacillus except the NA4 isolate produced food pathogen inhibitory molecules in biofilm. Moreover, TNF-alpha production by LPS activated human monocytoid cells was suppressed by supernatants from Lactobacillus cultivated as biofilms but not by planktonic culture supernatants. However, only L. fermentum NA4 showed anti-inflammatory effects in zebrafish embryos fed with probiotic bacteria, as assessed by cytokine transcript level (TNF-alpha, IL-1beta and IL-10). We conclude that the biofilm mode of life is associated with beneficial probiotic properties of lactobacilli, in a strain dependent manner. Those results suggest that characterization of isolate phenotype in the biofilm state could be additional valuable information for the selection of probiotic strains. PMID- 26611171 TI - Inhibition mechanism of Listeria monocytogenes by a bioprotective bacteria Lactococcus piscium CNCM I-4031. AB - Listeria monocytogenes is a pathogenic Gram positive bacterium and the etiologic agent of listeriosis, a severe food-borne disease. Lactococcus piscium CNCM I 4031 has the capacity to prevent the growth of L. monocytogenes in contaminated peeled and cooked shrimp. To investigate the inhibititory mechanism, a chemically defined medium (MSMA) based on shrimp composition and reproducing the inhibition observed in shrimp was developed. In co-culture at 26 degrees C, L. monocytogenes was reduced by 3-4 log CFU g(-1) after 24 h. We have demonstrated that the inhibition was not due to secretion of extracellular antimicrobial compounds as bacteriocins, organic acids and hydrogen peroxide. Global metabolomic fingerprints of these strains in pure culture were assessed by liquid chromatography coupled with high resolution mass spectrometry. Consumption of glucose, amino-acids, vitamins, nitrogen bases, iron and magnesium was measured and competition for some molecules could be hypothesized. However, after 24 h of co-culture, when inhibition of L. monocytogenes occurred, supplementation of the medium with these compounds did not restore its growth. The inhibition was observed in co-culture but not in diffusion chamber when species were separated by a filter membrane. Taken together, these data indicate that the inhibition mechanism of L. monocytogenes by L. piscium is cell-to-cell contact-dependent. PMID- 26611172 TI - Templated Atom-Precise Galvanic Synthesis and Structure Elucidation of a [Ag24Au(SR)18](-) Nanocluster. AB - Synthesis of atom-precise alloy nanoclusters with uniform composition is challenging when the alloying atoms are similar in size (for example, Ag and Au). A galvanic exchange strategy has been devised to produce a compositionally uniform [Ag24Au(SR)18](-) cluster (SR: thiolate) using a pure [Ag25(SR)18](-) cluster as a template. Conversely, the direct synthesis of Ag24Au cluster leads to a mixture of [Ag(25-x)Au(x)(SR)18](-), x=1-8. Mass spectrometry and crystallography of [Ag24Au(SR)18](-) reveal the presence of the Au heteroatom at the Ag25 center, forming Ag24Au. The successful exchange of the central Ag of Ag25 with Au causes perturbations in the Ag25 crystal structure, which are reflected in the absorption, luminescence, and ambient stability of the particle. These properties are compared with those of Ag25 and Ag24Pd clusters with same ligand and structural framework, providing new insights into the modulation of cluster properties with dopants at the single-atom level. PMID- 26611173 TI - Editorial Comment from Dr Aizawa to Propiverine increases urethral wall catecholamine levels and bladder leak point pressure in rats. PMID- 26611174 TI - Effect of cosmetic matrices on the release and odour profiles of the supercritical CO2 extract of Origanum majorana L. AB - OBJECTIVE: In this study, the effect of different cosmetic matrices on the release profile and odour intensity of the fragrance O. majorana was investigated for the first time. METHODS: The fragrance compounds of O. majorana were extracted by supercritical fluid extraction using carbon dioxide (SFE-CO2 ) at 40 degrees C and two operating pressures (8.5 and 10 MPa), and their chemical profiles were assessed by gas chromatography with flame ionization detector coupled with mass spectrometry (GC-FID/MS). Lastly, the fragrance compounds were incorporated into three cosmetic matrices (glycerine, dipropylene glycol and skin lotion) to assess their release and odour profiles over time using dynamic headspace (DHS)/GC-FID/MS and Odour Value concept, respectively. RESULTS: The SFE CO2 enabled recovering extracts with the pleasant scent of the living plant, and the increment of pressure induced an increase on the extraction yield. GC-FID/MS analyses revealed that oxygen-containing monoterpenes was the principal group of components identified in both SFE-CO2 extracts. The fragrance compounds were more retained in dipropylene glycol, and the major deviations from the original odour intensity (control) were observed in the presence of dipropylene glycol and skin lotion. CONCLUSION: The hydrophilic character of the cosmetic matrices strongly influenced the release of the fragrance compounds, thus affecting the odour profile of the studied mixtures. PMID- 26611178 TI - Context, patterns and practices: lessons in adaptation from environmental design and planning. PMID- 26611176 TI - Clinical predictors of hospital admission in acute lower respiratory tract infection in 2 months to 2-year-old children. AB - BACKGROUND AND OBJECTIVE: Acute lower respiratory tract infections (ALRI) are a common cause of paediatric emergency visits in young children. We studied risk factors for hospitalization and developed a clinical score for predicting hospitalization among 2 months to 2-year-old children with ALRI. METHODS: We conducted this prospective cohort study in the paediatric emergency department of a tertiary-care teaching hospital in India. Consecutive children, aged 2 months to 2 years with ALRI were enrolled from 15 December 2011 to 14 December 2012. A total of 26 a priori identified, putative risk factors were studied among enrolled children. We determined independent predictors of hospital admission (primary outcome) through multi-variable logistic regression analysis and assimilated them into a clinical risk score using regression coefficients. RESULTS: A total of 240 children (130 admissions) with ALRI were enrolled. Eleven clinical risk factors, which displayed association with hospital admission on univariate analysis (P < 0.1), were entered into multi-variable logistic regression analysis. Five factors retained independent association and were incorporated in a predictive score for hospitalization: tachypnoea (score of 5), chest retractions (score of 3), temperature > 37.8 degrees C (score of 3), SpO2 < 92% at room air (score of 4), GCS < 15 (score of 6). Area under the receiver operator characteristic curve was 0.80 (95% CI: 0.75-0.85, P < 0.001). CONCLUSION: Five clinical risk factors-tachypnoea, chest retractions, fever > 37.8 degrees C, SpO2 < 92% and GCS < 15-independently predicted hospital admission in infants with ALRI. A novel clinical score predicting hospital admission is presented. PMID- 26611179 TI - Patterns, trends and thinking 'inside' the box in medical education. PMID- 26611180 TI - The quandary of the sacred vagina: exploring the value of gynaecological teaching associates. PMID- 26611181 TI - So what's the problem? Reflection and reflexivity as agents of change. PMID- 26611175 TI - Host and disease factors are associated with cognitive function in European HIV infected adults prior to initiation of antiretroviral therapy. AB - OBJECTIVES: Deficits in cognitive function remain prevalent in HIV-infected individuals. The aim of this European multicentre study was to assess factors associated with cognitive function in antiretroviral therapy (ART)-naive HIV infected subjects at the time of enrolment in the NEAT 001/Agence Nationale de Recherche sur le SIDA (ANRS) 143 study. METHODS: Prior to starting ART, seven cognitive tests exploring domains including episodic memory, verbal fluency, executive function and psychomotor speed were administered with scores standardized to z-score using the study population sample mean and standard deviation. The primary measure was overall z-score average (NPZ). We assessed associations between baseline factors and test results using multivariable regression models. RESULTS: Of 283 subjects with baseline cognitive assessments, 90% were male and 12% of black ethnicity. Median (interquartile range) age, years of education, years of known HIV infection, baseline CD4 count and baseline HIV RNA were 39 (31, 47) years, 13 (11, 17) years, 1 (0, 4) years, 344 (279, 410) cells/MUL and 4.74 (4.28, 5.14) log10 HIV-1 RNA copies/mL, respectively. Forty per cent were current smokers. Factors significantly associated with poorer overall cognitive performance in multivariable models included older age, shorter duration of education, black ethnicity, lower height, and lower plasma HIV RNA. CONCLUSIONS: In this large, European-wide, ART-naive population with relatively preserved immunity and early HIV infection, cognitive function scores at the time of ART initiation were associated with demographic and HIV-disease factors. PMID- 26611182 TI - Workplace affordances to increase learner engagement in the clinical workplace. PMID- 26611183 TI - When I say ... excellent. PMID- 26611184 TI - Exploring patterns and pattern languages of medical education. AB - CONTEXT: The practices and concepts of medical education are often treated as global constants even though they can take many forms depending on the contexts in which they are realised. This represents challenges in presenting and appraising medical education research, as well as in translating practices and concepts between different contexts. This paper explores the problem and seeks to respond to its challenges. METHODS: This paper explores the application of architectural theorist Christopher Alexander's work on patterns and pattern languages to medical education. The authors review the underlying concepts of patterns and pattern language, they consider the development of pattern languages in medical education, they suggest possible applications of pattern languages for medical education and they discuss the implications of such use. Examples are drawn from across the field of medical education. RESULTS: The authors argue that the deliberate and systematic use of patterns and pattern languages in describing medical educational activities, systems and contexts can help us to make sense of the world, and the pattern languages of medical education have the potential to advance understanding and scholarship in medical education, to drive innovation and to enable critical engagement with many of the underlying issues in this field. PMID- 26611185 TI - The effectiveness of gynaecological teaching associates in teaching pelvic examination: a systematic review and meta-analysis. AB - CONTEXT: An increasing number of graduating students are unable to competently and confidently perform a pelvic examination. Gynaecology teaching associates (GTAs) teach technical and communication skills and offer immediate feedback. The objective was to perform a systematic literature review to assess whether teaching pelvic examinations using real women who are trained to give instructions on technique and feedback improves the competence, confidence and communication skills of trainees when compared with traditional teaching methods. METHODS: MEDLINE, EMBASE, the Cochrane Library, CINAHL and the ISRCTN Register of Clinical Trials were searched using selected terminology. No language restrictions were applied. The selection criteria were randomised clinical trials (RCTs) and controlled studies that investigated the use of GTAs to teach students or health-related professionals the pelvic examination. Data evaluating study outcomes, along with methodological details, were extracted in duplicate. The outcomes measured were: self-reported confidence, assessed competence and assessed communication skills. The standard mean difference (SMD) was derived for each study where possible and heterogeneity across studies was quantified using the I(2) statistic. In the presence of substantial variation, the data were pooled using a random effects model. RESULTS: Eleven studies with 856 participants were included: five RCTs and six observational studies. GTA training improved competence compared with other teaching methods and the finding of enhanced competence was consistent when the pooled analysis was restricted to RCTs. Communication skills were also improved with GTA teaching, but to a lesser degree, whereas no effect on student confidence was observed. Statistical heterogeneity was present for all outcomes when data were pooled. CONCLUSION: Our findings suggest that GTA-based teaching of pelvic examination is associated with improvement in the competence and communication skills of trainees. However, further larger-scale studies with standardised relevant educational outcomes are needed to confirm these findings. PMID- 26611186 TI - 'You become a man in a man's world': is there discursive space for women in surgery? AB - CONTEXT: The UK set a target of 20% of the surgical consultant workforce to be represented by women by 2009; in 2012, it remains 7%. Studies have attributed this shortfall to the nature of careers in surgery and differing career aspirations among women. OBJECTIVES: Rather than exploring barriers to participation, this study aims to explore the self-narratives of those women who do undertake surgical careers and who do come to see themselves as surgeons. METHODS: The study comprises 15 individual interviews with women in surgical careers, from those aspiring to be surgeons, to senior and retired surgeons. Data were explored using discourse analysis with a priori themes derived from the literature on women in surgery and Holland et al.'s theoretical framework of Figured Worlds. RESULTS: Discourses of being a surgeon and discourses of being a woman, existed in competition. Female surgeons figured surgery as a career requiring 100% dedication, as they did motherhood, although the demands of the two roles differed and consequently the roles were not discursively compatible. Many related powerfully negative experiences in which their gender had marked them out as 'other' within surgery. Women described how they were expected to show masculine traits as surgeons and the ways to consequently become legitimate in the surgical world as a 'woman surgeon'. They found creative ways to articulate how women in general, and feminine qualities in particular, enhanced surgery. Finally, some women engaged in identity work, termed 'world making', - the creative orchestration of discourses of surgeonhood and motherhood to be mutually sustaining. CONCLUSIONS: There is little discursive space in which to be both a successful woman and a successful surgeon. Those who combine these roles must either be innovative in refiguring what it means to be a woman or what it means to be a surgeon, or they must author a new space for themselves, a powerful discursive process termed 'world making'. PMID- 26611187 TI - Clinical participation of medical students in three contemporary training models. AB - OBJECTIVES: As community settings are being used increasingly in undergraduate medical programmes, this study aimed to explore and compare the clinical experiences of students in hospital-based and community-based training programmes. It measured students' clinical participation and compared the perspectives of Year 3 medical students in three different models of clinical education: a tertiary hospital block programme; a community hybrid programme, and a rural longitudinal integrated clerkship (LIC) programme. METHODS: The study used a mixed methodology approach to examine the clinical experiences of students through the analysis of logbooks and semi-structured student interviews. This involved the quantitative analysis of 88 logbook weeks, data from which were triangulated through the analysis of 101 individual interviews using grounded theory. RESULTS: A total of 35 students across the three different clinical training models participated in the study. The results demonstrate significant differences among the three models in students' clinical participation and suggest that community settings provide more opportunities to students for meaningful engagement in patient care activities. CONCLUSIONS: Consistent wider and more direct access to patients for students, as found in the community-based model, provides a pathway for engaging students in the learning processes, and a step towards making them aware of their learning needs and knowledge. Interviews provide evidence that authentic clinical activities can be enhanced through structured systems of supervision and through the provision of authentic roles for students in clinical teams. PMID- 26611188 TI - Diagnostic reasoning and underlying knowledge of students with preclinical patient contacts in PBL. AB - CONTEXT: Medical experts have access to elaborate and integrated knowledge networks consisting of biomedical and clinical knowledge. These coherent knowledge networks enable them to generate more accurate diagnoses in a shorter time. However, students' knowledge networks are less organised and students have difficulties linking theory and practice and transferring acquired knowledge. Therefore we wanted to explore the development and transfer of knowledge of third year preclinical students on a problem-based learning (PBL) course with real patient contacts. METHODS: Before and after a 10-week PBL course with real patients, third-year medical students were asked to think out loud while diagnosing four types of paper patient problems (two course cases and two transfer cases), and explain the underlying pathophysiological mechanisms of the patient features. Diagnostic accuracy and time needed to think through the cases were measured. The think-aloud protocols were transcribed verbatim and different types of knowledge were coded and quantitatively analysed. The written pathophysiological explanations were translated into networks of concepts. Both the concepts and the links between concepts in students' networks were compared to model networks. RESULTS: Over the course diagnostic accuracy increased, case processing time decreased, and students used less biomedical and clinical knowledge during diagnostic reasoning. The quality of the pathophysiological explanations increased: the students used more concepts, especially more model concepts, and they used fewer wrong concepts and links. The findings differed across course and transfer cases. The effects were generally less strong for transfer cases. CONCLUSIONS: Students' improved diagnostic accuracy and the improved quality of their knowledge networks suggest that integration of biomedical and clinical knowledge took place during a 10-week course. The differences between course and transfer cases demonstrate that transfer is complex and time-consuming. We therefore suggest offering students many varied patient contacts with the same underlying pathophysiological mechanism and encouraging students to link biomedical and clinical knowledge. PMID- 26611189 TI - Don't look at my wheelchair! The plasticity of longlasting prejudice. AB - CONTEXT: Scientific research has consistently shown that prejudicial behaviour may contribute to discrimination and disparities in social groups. However, little is known about whether and how implicit assumptions and direct contact modulate the interaction and quality of professional interventions in education and health contexts. OBJECTIVES: This study was designed to examine implicit and explicit attitudes towards wheelchair users. METHODS: We investigated implicit and explicit attitudes towards wheelchair users in three different groups: patients with traumatic spinal cord injury (SCI); health professionals with intense contact with wheelchair users, and healthy participants without personal contact with wheelchair users. To assess the short-term plasticity of prejudices, we used a valid intervention that aims to change implicit attitudes through brief direct contact with a patient who uses a wheelchair in an ecologically valid real life interaction. RESULTS: We found that: (i) wheelchair users with SCI held positive explicit but negative implicit attitudes towards their novel in-group; (ii) the amount of experience with wheelchair users affected implicit attitudes among health professionals, and (iii) interacting with a patient with SCI who contradicts prejudices modulated implicit negative bias towards wheelchair users in healthy participants. CONCLUSIONS: The use of a wheelchair immediately and profoundly affects how a person is perceived. However, our findings highlight the dynamic nature of perceptions of social identity, which are not only sensitive to personal beliefs, but also highly permeable to intergroup interactions. Having direct contact with people with disabilities might foster positive attitudes in multidisciplinary health care teams. Such interventions could be integrated into medical education programmes to successfully prevent or reduce hidden biases in a new generation of health professionals and to increase the general acceptance of disability in patients. PMID- 26611190 TI - Dimensions, discourses and differences: trainees conceptualising health care leadership and followership. AB - CONTEXT: As doctors in all specialties are expected to undertake leadership within health care organisations, leadership development has become an inherent part of medical education. Whereas the leadership literature within medical education remains mostly focused on individual, hierarchical leadership, contemporary theory posits leadership as a group process, which should be distributed across all levels of health care organisation. This gap between theory and practice indicates that there is a need to understand what leadership and followership mean to medical trainees working in today's interprofessional health care workplace. METHODS: Epistemologically grounded in social constructionism, this research involved 19 individual and 11 group interviews with 65 UK medical trainees across all stages of training and a range of specialties. Semi-structured interviewing techniques were employed to capture medical trainees' conceptualisations of leadership and followership. Interviews were audiotaped, transcribed verbatim and analysed using thematic framework analysis to identify leadership and followership dimensions which were subsequently mapped onto leadership discourses found in the literature. RESULTS: Although diversity existed in terms of medical trainees' understandings of leadership and followership, unsophisticated conceptualisations focusing on individual behaviours, hierarchy and personality were commonplace in trainees' understandings. This indicated the dominance of an individualist discourse. Patterns in understandings across all stages of training and specialties, and whether definitions were solicited or unsolicited, illustrated that context heavily influenced trainees' conceptualisations of leadership and followership. CONCLUSIONS: Our findings suggest that UK trainees typically hold traditional understandings of leadership and followership, which are clearly influenced by the organisational structures in which they work. Although education may change these understandings to some extent, changes in leadership practices to reflect contemporary theory are unlikely to be sustained if leadership experiences in the workplace continue to be based on individualist models. PMID- 26611191 TI - Linking quality of care and training costs: cost-effectiveness in health professions education. AB - OBJECTIVE: To provide a model for conducting cost-effectiveness analyses in medical education. The model was based on a randomised trial examining the effects of training midwives to perform cervical length measurement (CLM) as compared with obstetricians on patients' waiting times. (CLM), as compared with obstetricians. METHODS: The model included four steps: (i) gathering data on training outcomes, (ii) assessing total costs and effects, (iii) calculating the incremental cost-effectiveness ratio (ICER) and (iv) estimating cost effectiveness probability for different willingness to pay (WTP) values. To provide a model example, we conducted a randomised cost-effectiveness trial. Midwives were randomised to CLM training (midwife-performed CLMs) or no training (initial management by midwife, and CLM performed by obstetrician). Intervention group participants underwent simulation-based and clinical training until they were proficient. During the following 6 months, waiting times from arrival to admission or discharge were recorded for women who presented with symptoms of pre term labour. Outcomes for women managed by intervention and control-group participants were compared. These data were then used for the remaining steps of the cost-effectiveness model. RESULTS: Intervention-group participants needed a mean 268.2 (95% confidence interval [CI], 140.2-392.2) minutes of simulator training and a mean 7.3 (95% CI, 4.4-10.3) supervised scans to attain proficiency. Women who were scanned by intervention-group participants had significantly reduced waiting time compared with those managed by the control group (n = 65; mean difference, 36.6 [95% CI 7.3-65.8] minutes; p = 0.008), which corresponded to an ICER of 0.45 EUR minute(-1) . For WTP values less than EUR 0.26 minute(-1) , obstetrician-performed CLM was the most cost-effective strategy, whereas midwife-performed CLM was cost-effective for WTP values above EUR 0.73 minute(-1) . CONCLUSION: Cost-effectiveness models can be used to link quality of care to training costs. The example used in the present study demonstrated that different training strategies could be recommended as the most cost-effective depending on administrators' willingness to pay per unit of the outcome variable. PMID- 26611192 TI - Comments on 'Shame, guilt, and the medical learner'. PMID- 26611194 TI - What do we know about the application of the Mental Capacity Act (2005) in healthcare practice regarding decision-making for frail and older people? A systematic literature review. AB - In England and Wales, decision-making in cases of uncertain mental capacity is regulated by the Mental Capacity Act 2005. The Act provides a legal framework for decision-making for adults (16 and over) who are shown to lack capacity and where best interest decisions need to be made on their behalf. Frail older people with cognitive impairments represent a growing demographic sector across England and Wales for whom the protective principles of the Act have great relevance, as they become increasingly dependent on the care of others. However, while the Act articulates core principles, applying the Act in everyday healthcare contexts raises challenges for care providers in terms of interpretation and application. This paper presents a review of the published evidence documenting the use of the Act in healthcare practice, with particular reference to frail older people. Our aim was to identify, review and critically evaluate published empirical studies concerned with the implementation and application of the Act in healthcare settings. A systematic approach was undertaken with pre-determined exclusion and inclusion criteria applied across five electronic bibliographic databases combined with a manual search of specific journals. This review reports on 38 empirical sources which met the inclusion criteria published between 2005 and 2013. From the 38 sources, three descriptive themes were identified: knowledge and understanding, implementation and tensions in applying the Act, and alternative perspectives of the Act. There is a need for improved knowledge and conceptualisation to enable successful incorporation of the Act into everyday care provision. Inconsistencies in the application of the Act are apparent across a variety of care settings. This review suggest staff need more opportunities to engage, learn and implement the Act, in order for it to have greater resonance to their individual practice and ultimately benefit patient care. PMID- 26611195 TI - Silver-Catalyzed Allylation of Ketones and Intramolecular Cyclization through Carbene Intermediates from Cyclopropenes Under Ambient Conditions. AB - Tandem C-C bond formation was achieved through silver-catalyzed ring-opening of cyclopropenes via carbene intermediates. The reaction of cyclopropenes in the presence of a silver catalyst gave indene derivatives under ambient conditions. In contrast, the insertion of organozinc reagents to silver carbene or allylic cation intermediates afforded allylmetal intermediates for the tandem allylation of carbonyl compounds. PMID- 26611196 TI - The Janus Face of the X Ligand in the Copper-Catalyzed Azide-Alkyne Cycloaddition. AB - To understand the effect of the anion (X) in the copper-catalyzed azide-alkyne cycloaddition (CuAAC) catalytic process, the kinetic profiles of the successive steps of the catalytic cycle have been studied by performing stoichiometric reactions using copper complexes LCuX in which L is a cyclic (alkyl)(amino)carbene (CAAC) ligand and X = OTf, Cl, OAc, OPh, or OtBu. Basic ligands favor the metalation step but disfavor the formation of the catalytically active sigma,pi-bis(copper) acetylide, whereas non-nucleophilic ligands favor the latter but slowly promote the former. We show that acetate is a good compromise, and in addition, it is very efficient in the proto-demetalation step. PMID- 26611198 TI - [Implementation of an oncological care program in a multidisciplinary clinic]. AB - INTRODUCTION: A working group has highlighted guidelines in thoracic oncology in Europe without study of their implementation, due to a lack of data. METHODS: The records of 354 untreated lung cancer patients seen between January 2009 and December 2012 were reviewed. Any new treatment should have been proposed by a multidisciplinary consultation (MDC) in accordance with an oncology care program (OCP) based on the European Lung Cancer Working Party guidelines. RESULTS: For the 354 patients, there were 636 MDC (332, 176, 81 and 47 in 1st, 2nd, 3rd and subsequent lines). For the first line, the MDC rate was 88%, in accordance with the OCP, and 75% of treatments were in agreement with the guidelines. For the 2nd and 3rd lines, the rates were 93% and 92% respectively (MDC), 90 and 89% (OCP), 55 and 63% (guidelines). In the first line, the main causes of non-compliance with the OCP were patient's refusal or doctor's choice and with guidelines a lack of adequate recommendations for specific situations such as comorbidities or the appearance of new treatments. CONCLUSION: The vast majority of patients are the subject of a MDC with a high rate of application of OCP. Guidelines should be updated regularly to incorporate new treatments. PMID- 26611197 TI - Adaptive servo-ventilation: How does it fit into the treatment of central sleep apnoea syndrome? Expert opinions. AB - The preliminary results of the SERVE-HF study have led to the release of safety information with subsequent contraindication to the use of adaptive servo ventilation (ASV) for the treatment of central sleep apnoeas in patients with chronic symptomatic systolic heart failure with left ventricular ejection fraction (LVEF) <= 45%. The aim of this article is to review these results, and to provide more detailed arguments based on data from the literature advocating the continued use of ASV in different indications, including heart failure with preserved LVEF, complex sleep apnoea syndrome, opioid-induced central sleep apnea syndrome, idiopathic central SAS, and central SAS due to a stroke. Based on these findings, we propose to set up registers dedicated to patients in whom ASV has been stopped and in the context of the next setting up of ASV in these specific indications to ensure patient safety and allow reasoned decisions on the use of ASV. PMID- 26611199 TI - Optimal imaging protocol for measuring dynamic expiratory collapse of the central airways. AB - AIM: To compare measurements of expiratory collapse obtained using multidetector computed tomography (MDCT) of the central airways on routine axial and multiplanar reformatted (MPR) images. MATERIALS AND METHODS: Fifty volunteers with normal pulmonary function and no smoking history were imaged using a 64 MDCT system (40 mAs, 120 kVp, 0.625 mm collimation) with spirometric monitoring at end inspiration and during forced expiration. Measurements of the trachea, right main (RMB) and left main bronchus (LMB) were obtained on axial and MPR images. Inspiratory and dynamic-expiratory cross-sectional area (CSA) measurements were used to calculate the mean percentage expiratory collapse (%Collapse). A paired t test was used to assess within-subject differences and a Bland-Altman plot was used to assess agreement between the methods. RESULTS: Among 24 men and 26 women (mean age+/-standard deviation 50+/-15 years), CSA values were significantly greater on axial than MPR images (all p<0.001); however, the mean difference in %Collapse values for axial versus MPR were small: trachea ~1% (55 +/-19 versus 56+/-18, p=0.338); LMB identical (60+/-20 versus 60+/-17 p=0.856); and, RMB 4% (62 +/-19 versus 66+/-19 p<0.001). On average, creation of MPR required 12 minutes of additional time per case (range=10-15 min). CONCLUSION: Differences in mean %Collapse for axial versus MPR images were small and unlikely to influence clinical management. This finding suggests that MPR may not be indicated for routine assessment of central airway collapse. PMID- 26611200 TI - Assessment of influenza vaccine effectiveness in a sentinel surveillance network 2010-13, United States. AB - BACKGROUND: Influenza vaccines are now widely used to reduce the burden of annual epidemics of influenza virus infections. Influenza vaccine effectiveness (VE) is monitored annually to determine VE against each season's circulating influenza strains in different groups such as children, adults and the elderly. Few prospective surveillance programs are available to evaluate influenza VE against medically attended illness for patients of all ages in the United States. METHODS: We conducted surveillance of patients with acute respiratory illnesses in 101 clinics across the US during three consecutive influenza seasons. We analyzed laboratory testing results for influenza virus, self-reported vaccine history, and patient characteristics, defining cases as patients who tested positive for influenza virus and controls as patients who tested negative for influenza virus. Comparison of influenza vaccination coverage among cases versus controls, adjusted for potential confounders, was used to estimate VE as one minus the adjusted odds ratio multiplied by 100%. RESULTS: We included 10,650 patients during three influenza seasons from August 2010 through December 2013, and estimated influenza VE in children 6m-5y of age (58%; 95% CI: 49%-66%), children 6-17y (45%; 95% CI: 34%-53%), adults 18-49y (36%; 95% CI: 24%, 46%), and adults >=50y (34%, 95% CI: 13%, 51%). VE was higher against influenza A(H1N1) compared to A(H3N2) and B. CONCLUSIONS: Our estimates of moderate influenza VE confirm the important role of vaccination in protecting against medically attended influenza virus infection. PMID- 26611201 TI - Neutralizing antibody and functional mapping of Bacillus anthracis protective antigen-The first step toward a rationally designed anthrax vaccine. AB - Anthrax is defined by the Centers for Disease Control and Prevention as a Category A pathogen for its potential use as a bioweapon. Current prevention treatments include Anthrax Vaccine Adsorbed (AVA). AVA is an undefined formulation of Bacillus anthracis culture supernatant adsorbed to aluminum hydroxide. It has an onerous vaccination schedule, is slow and cumbersome to produce and is slightly reactogenic. Next-generation vaccines are focused on producing recombinant forms of anthrax toxin in a well-defined formulation but these vaccines have been shown to lose potency as they are stored. In addition, studies have shown that a proportion of the antibody response against these vaccines is focused on non-functional, non-neutralizing regions of the anthrax toxin while some essential functional regions are shielded from eliciting an antibody response. Rational vaccinology is a developing field that focuses on designing vaccine antigens based on structural information provided by neutralizing antibody epitope mapping, crystal structure analysis, and functional mapping through amino acid mutations. This information provides an opportunity to design antigens that target only functionally important and conserved regions of a pathogen in order to make a more optimal vaccine product. This review provides an overview of the literature related to functional and neutralizing antibody epitope mapping of the Protective Antigen (PA) component of anthrax toxin. PMID- 26611202 TI - Attenuation mechanism of virulent infectious bronchitis virus strain with QX genotype by continuous passage in chicken embryos. AB - The virulent isolate SDZB0808 of QX-type infectious bronchitis virus (IBV) was continuously passaged in chicken embryos for 110 generations. The safety and immune efficacy of the 110th generation of IBVs (P110) were evaluated. Damage was not found in the appearance of the 3-day-old specific-pathogen-free (SPF) chicks immunized with 10(4.5) EID50 (median embryo infective dose) of P110 by intranasal and ocular administration. At 14 d after the vaccination with 10(4.5) EID50 of P110, all the 3-day-old SPF chicks were immune from the attack of the homologous virulent strain SDZB0808 and the heterologous virulent strain SDIB821/2012. The whole genome sequencing of SDZB0808 of different generations (P1-P110) indicated that the replicase 1a sequences of P60-P110 all lost a length of 30bp in the same region. Specific primers were designed according to the differences in the genomes of P1-P110. SYBR Green I real-time quantitative PCR was adopted to analyze the proportion of the viruses with 30bp deletion in P60, P100, and P110. Results showed that with the passage in chicken embryos, the proportion of the viruses with 30bp deletion gradually increased. Almost 100% of the viruses in the P110 had 30bp deletion in the replicase 1a sequence. Therefore, the attenuation of IBV's virulence may be the outcome of directional screening in the chicken embryos. This work confirmed the high safety and immune efficacy of P110 in SPF chickens. Thus, P110 can serve as an attenuated IBV vaccine candidate. PMID- 26611203 TI - Rotavirus - Global research density equalizing mapping and gender analysis. AB - BACKGROUND: Rotaviruses are the leading reason for dehydration and severe diarrheal disease and in infants and young children worldwide. An increasing number of related publications cause a crucial challenge to determine the relevant scientific output. Therefore, scientometric analyses are helpful to evaluate quantity as well as quality of the worldwide research activities on Rotavirus. Up to now, no in-depth global scientometric analysis relating to Rotavirus publications has been carried out. This study used scientometric tools and the method of density equalizing mapping to visualize the differences of the worldwide research effort referring to Rotavirus. The aim of the study was to compare scientific output geographically and over time by using an in-depth data analysis and New quality and quantity indices in science (NewQIS) tools. Furthermore, a gender analysis was part of the data interpretation. METHODS: We retrieved all Rotavirus-related articles, which were published on "Rotavirus" during the time period from 1900 to 2013, from the Web of Science by a defined search term. These items were analyzed regarding quantitative and qualitative aspects, and visualized with the help of bibliometric methods and the technique of density equalizing mapping to show the differences of the worldwide research efforts. This work aimed to extend the current NewQIS platform. RESULTS: The 5906 Rotavirus associated articles were published in 138 countries from 1900 to 2013. The USA authored 2037 articles that equaled 34.5% of all published items followed by Japan with 576 articles and the United Kingdom - as the most productive representative of the European countries - with 495 articles. Furthermore, the USA established the most cooperations with other countries and was found to be in the center of an international collaborative network. We performed a gender analysis of authors per country (threshold was set at a publishing output of more than 100 articles by more than 50 authors whose names could be identified in more than 50% of cases) showed a domination of female scientists in Brazil, while in all other countries, male scientists predominate. Relating the number of publications to the population of a country (Q1) and compared to the GPD (Q2), we found that European and African countries as well as Australia and New Zealand - not the USA - were among the top ranked nations. CONCLUSION: Regarding rotavirus related scientific output, the USA was the overall leading nation when qualitative and qualitative aspects were taken into account. In contrast to these classical scientometric variables, indices such as Q1 and Q2 enable comparability between countries with unequal conditions and scientific infrastructures helping to differentiate publishing quality and quantity in a more relevant way. Also, it was deduced that counties with a high rotavirus-associated child mortality, like the Democratic Republic of Congo, should be integrated into the collaborative efforts more intensively. PMID- 26611204 TI - The interactive role of CB(1) and GABA(B) receptors in hippocampal synaptic plasticity in rats. AB - Long-term potentiation (LTP) of synaptic transmission is a cellular process underlying learning and memory. Cannabinoids are known to be powerful modulators of this kind of synaptic plasticity. Changes in GABAergic inhibition have also been shown to affect synaptic plasticity in the hippocampus. GABA receptor type B (GABAB) and cannabinoid receptor type 1 (CB1) exhibit overlapping anatomical localization in some brain areas including the hippocampus. CB1 and GABAB are also localized to the same cells and share a common signaling pathway in some brain areas. In this study, we examined the hippocampal effects of co administrating AM251 and CGP55845, which are CB1 and GABAB antagonists, respectively, on LTP induction in the dentate gyrus (DG) of rats. LTP in the hippocampal area was induced by high-frequency stimulation (HFS) of the perforant path. Our results showed that HFS coupled with administration of the CB1 antagonist increased both the population spike (PS) amplitude and field excitatory post-synaptic potential (fEPSP). Conversely, the GABAB antagonist decreased these parameters along with decreased LTP induction. We also demonstrated that the co-administration of CB1 and GABAB antagonists had different effects on the PS amplitude and fEPSP slope. It is likely that GABAB receptor antagonists modulate cannabinoid outputs that cause a decrease in synaptic plastisity, while in the simultaneous consumption of two antagonists, CB1 antagonists can alter the release of GABA which in turn results in enhancement of LTP induction. These findings suggest that there are functional interactions between the CB1 and GABAB receptor in the hippocampus. PMID- 26611205 TI - Pre-treatment neutrophil-to-lymphocyte ratio predicts prognosis in patients with locoregionally advanced laryngeal carcinoma treated with chemoradiotherapy. AB - OBJECTIVE: The aim of this study was to investigate the effect of neutrophil-to lymphocyte ratio on the prognosis of patients with locoregionally advanced laryngeal carcinoma treated with chemoradiotherapy. METHODS: One hundred and twenty-five patients with locoregionally advanced laryngeal carcinoma (cT3-4 N0 3M0) treated with chemoradiotherapy were reviewed retrospectively. Chemoradiotherapy comprised external beam radiotherapy to the larynx (70 Gy) with three cycles of cisplatin at 3 week intervals. The survival rate was calculated using the Kaplan-Meier method, and a multivariate analysis was used to identify significant factors associated with prognosis, using a Cox proportional hazards model. RESULTS: During the median (range) follow-up of 45 months, the median neutrophil-to-lymphocyte ratio was 3.02. The high neutrophil-to-lymphocyte ratio group (neutrophil-to-lymphocyte ratio > 3.0) contained 69 patients and the low neutrophil-to-lymphocyte ratio group (neutrophil-to-lymphocyte ratio < 3.0) contained 46 patients. The low neutrophil-to-lymphocyte ratio group patients had a significantly higher chemoradiotherapeutic disease control rate (86.96 vs. 69.57%, P = 0.031). Forty-six patients had a low neutrophil-to-lymphocyte ratio (<3.0) before chemoradiotherapy and their progression-free survival and 75% overall survival were significantly better than that of the high neutrophil-to lymphocyte ratio patients (P = 0.015, P = 0.045). Multivariate analysis showed that neutrophil-to-lymphocyte ratio and N stage were independent prognostic indicators for progression-free survival (with a hazard ratio of 1.79, P = 0.003 and a hazard ratio of 1.28, P = 0.034) and overall survival (with a hazard ratio of 1.51, P = 0.029 and a hazard ratio of 1.21, P = 0.043), respectively. CONCLUSION: Pre-treatment neutrophil-to-lymphocyte ratio is a useful prognostic marker in patients with locoregionally advanced laryngeal carcinoma treated with chemoradiotherapy. PMID- 26611206 TI - Characterization of apela, a novel endogenous ligand of apelin receptor, in the adult heart. AB - The G protein-coupled apelin receptor regulates important processes of the cardiovascular homeostasis, including cardiac development, cardiac contractility, and vascular tone. Most recently, a novel endogenous peptide ligand for the apelin receptor was identified in zebrafish, and it was named apela/elabela/toddler. The peptide was originally considered as an exclusively embryonic regulator, and so far its function in the adult organism remains elusive. We show here that apela is predominantly expressed in the non cardiomyocyte fraction in the adult rodent heart. We also provide evidence that apela binds to apelin receptors in the heart. Using isolated adult rat hearts, we demonstrate, that just like the fellow receptor agonist apelin, apela increases cardiac contractility and induces coronary vasodilation already in the nanomolar level. The inotropic effect, as revealed by Western blot analysis, is accompanied by a significant increase in extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. Pharmacological inhibition of ERK1/2 activation markedly attenuates the apela-induced inotropy. Analysis of samples from infarcted mouse hearts showed that expression of both apela and apelin receptor is induced in failing mouse hearts and correlate with left ventricular ejection fraction. Hence, we conclude that apela is present in the adult heart, is upregulated in post-infarction cardiac remodeling, and increases cardiac contractility in an ERK1/2-dependent manner. PMID- 26611209 TI - Prevention of adenosine A2A receptor activation diminishes beat-to-beat alternation in human atrial myocytes. AB - Atrial fibrillation (AF) has been associated with increased spontaneous calcium release from the sarcoplasmic reticulum and linked to increased adenosine A2A receptor (A2AR) expression and activation. Here we tested whether this may favor atrial arrhythmogenesis by promoting beat-to-beat alternation and irregularity. Patch-clamp and confocal calcium imaging was used to measure the beat-to-beat response of the calcium current and transient in human atrial myocytes. Responses were classified as uniform, alternating or irregular and stimulation of Gs protein coupled receptors decreased the frequency where a uniform response could be maintained from 1.0 +/- 0.1 to 0.6 +/- 0.1 Hz; p < 0.01 for beta-adrenergic receptors and from 1.4 +/- 0.1 to 0.5 +/- 0.1 Hz; p < 0.05 for A2ARs. The latter was linked to increased spontaneous calcium release and after-depolarizations. Moreover, A2AR activation increased the fraction of non-uniformly responding cells in HL-1 myocyte cultures from 19 +/- 3 to 51 +/- 9 %; p < 0.02, and electrical mapping in perfused porcine atria revealed that adenosine induced electrical alternans at longer cycle lengths, doubled the fraction of electrodes showing alternation, and increased the amplitude of alternations. Importantly, protein kinase A inhibition increased the highest frequency where uniform responses could be maintained from 0.84 +/- 0.12 to 1.86 +/- 0.11 Hz; p < 0.001 and prevention of A2AR-activation with exogenous adenosine deaminase selectively increased the threshold from 0.8 +/- 0.1 to 1.2 +/- 0.1 Hz; p = 0.001 in myocytes from patients with AF. In conclusion, A2AR-activation promotes beat-to-beat irregularities in the calcium transient in human atrial myocytes, and prevention of A2AR activation may be a novel means to maintain uniform beat-to-beat responses at higher beating frequencies in patients with atrial fibrillation. PMID- 26611208 TI - Persistent increases in Ca(2+) influx through Cav1.2 shortens action potential and causes Ca(2+) overload-induced afterdepolarizations and arrhythmias. AB - Persistent elevation of Ca(2+) influx due to prolongation of the action potential (AP), chronic activation of the beta-adrenergic system and molecular remodeling occurs in stressed and diseased hearts. Increases in Ca(2+) influx are usually linked to prolonged myocyte action potentials and arrhythmias. However, the contribution of chronic enhancement of Cav1.2 activity on cardiac electrical remodeling and arrhythmogenicity has not been completely defined and is the subject of this study. Chronically increased Cav1.2 activity was produced with a cardiac specific, inducible double transgenic (DTG) mouse system overexpressing the beta2a subunit of Cav (Cavbeta2a). DTG myocytes had increased L-type Ca(2+) current (ICa-L), myocyte shortening, and Ca(2+) transients. DTG mice had enhanced cardiac performance, but died suddenly and prematurely. Telemetric electrocardiograms revealed shortened QT intervals in DTG mice. The action potential duration (APD) was shortened in DTG myocytes due to significant increases of potassium currents and channel abundance. However, shortened AP in DTG myocytes did not fully limit excess Ca(2+) influx and increased the peak and tail ICa-L. Enhanced ICa promoted sarcoplasmic reticulum (SR) Ca(2+) overload, diastolic Ca(2+) sparks and waves, and increased NCX activity, causing increased occurrence of early and delayed afterdepolarizations (EADs and DADs) that may contribute to premature ventricular beats and ventricular tachycardia. AV blocks that could be related to fibrosis of the AV node were also observed. Our study suggests that increasing ICa-L does not necessarily result in AP prolongation but causes SR Ca(2+) overload and fibrosis of AV node and myocardium to induce cellular arrhythmogenicity, arrhythmias, and conduction abnormalities. PMID- 26611210 TI - A minimal fate-selection switch. AB - To preserve fitness in unpredictable, fluctuating environments, a range of biological systems probabilistically generate variant phenotypes--a process often referred to as 'bet-hedging', after the financial practice of diversifying assets to minimize risk in volatile markets. The molecular mechanisms enabling bet hedging have remained elusive. Here, we review how HIV makes a bet-hedging decision between active replication and proviral latency, a long-lived dormant state that is the chief barrier to an HIV cure. The discovery of a virus-encoded bet-hedging circuit in HIV revealed an ancient evolutionary role for latency and identified core regulatory principles, such as feedback and stochastic 'noise', that enable cell-fate decisions. These core principles were later extended to fate selection in stem cells and cancer, exposed new therapeutic targets for HIV, and led to a potentially broad strategy of using 'noise modulation' to redirect cell fate. PMID- 26611207 TI - Emerging role of liver X receptors in cardiac pathophysiology and heart failure. AB - Liver X receptors (LXRs) are master regulators of metabolism and have been studied for their pharmacological potential in vascular and metabolic disease. Besides their established role in metabolic homeostasis and disease, there is mounting evidence to suggest that LXRs may exert direct beneficial effects in the heart. Here, we aim to provide a conceptual framework to explain the broad mode of action of LXRs and how LXR signaling may be an important local and systemic target for the treatment of heart failure. We discuss the potential role of LXRs in systemic conditions associated with heart failure, such as hypertension, diabetes, and renal and vascular disease. Further, we expound on recent data that implicate a direct role for LXR activation in the heart, for its impact on cardiomyocyte damage and loss due to ischemia, and effects on cardiac hypertrophy, fibrosis, and myocardial metabolism. Taken together, the accumulating evidence supports the notion that LXRs may represent a novel therapeutic target for the treatment of heart failure. PMID- 26611212 TI - A 17-Year-Old Female With Respiratory Depression as a Result of Opioid Overdose. PMID- 26611213 TI - Stroke: Part 2. PMID- 26611214 TI - Defensive Medicine. PMID- 26611215 TI - Articles That May Change Your Practice: Prehospital Blood Products. PMID- 26611217 TI - Lessons from a Legend: James "Red Duke". PMID- 26611218 TI - Carbon Monoxide Exposure in Norwegian Rescue Helicopters. AB - OBJECTIVE: Exposure to exhaust fumes from combustion engines can lead to carbon monoxide (CO) poisoning. Sea King Rescue helicopter crews are frequently subjected to engine exhaust. This study investigates the extent of CO exposure and potential for intoxication for flight crews during standard operational training procedures. METHODS: Over a 2-week period, rescue helicopter flight crews were monitored for exposure to exhaust fumes and clinical symptoms of CO intoxication by means of a written survey and measurements of carboxyhemoglobin saturation (SpCO) with a handheld pulse CO oximeter (RAD-57; Masimo, Irvine, CA). Normal ranges for SpCO were defined as <= 4%. RESULTS: Sixty-nine completed surveys and 138 SpCO measurements of 37 crewmembers were included in the study. Sixty-four percent (n = 44) experienced subjective exposure to engine exhaust during training. Clinical symptoms were reported in 8.6% (n = 6) and included exhaustion (n = 4), headache (n = 1), and nausea (n = 1). Twenty-nine percent (n = 20) showed postflight SpCO levels outside the normal range (>= 4%). The maximum postflight SpCO level among all measurements was 7%. CONCLUSION: Exposure to engine fumes is common, even more so during open cargo door operations. However, clinical symptoms are infrequent and mild. Toxic SpCO levels were not reached in this study, but approximately one third of postflight SpCO levels were outside the normal range. PMID- 26611219 TI - Prehospital Helicopter Air Ambulances Part 1: Access, Protocols, and Utilization. AB - OBJECTIVE: In the prehospital setting, helicopter air ambulances (HAAs) are used to bring advanced care to patients and reduce time to definitive care. Research related to emergency medical service (EMS) professionals' access to medical helicopters, protocols for HAA use, and prevalence of HAA transport for different patient types is sparse. Our first objective was to describe EMS professionals' access to HAA and the prevalence of written protocols regarding their use. Next, we looked at HAA use for specific patient types (trauma, nontraumatic chest pain, stroke, and pediatric). METHODS: We conducted a census survey of nationally certified EMS professionals. Descriptive analyses were performed. RESULTS: There were 15,366 responses. Over 90% of nationally certified EMS professionals had access to at least 1 HAA service. Of these, 86% had the authority to request a medical helicopter, and two thirds reported having written HAA protocols. Although HAAs were used mostly for trauma patients, EMS professionals also used these resources for nontrauma transports of patients with time-sensitive conditions. CONCLUSION: Most nationally certified EMS professionals had access to a medical helicopter service and used these resources mainly for trauma patients. About one third reported they did not have or were unsure if their agency had written protocols for HAA use. PMID- 26611220 TI - Prehospital Helicopter Air Ambulances Part 2: Utilization Criteria and Training. AB - OBJECTIVES: The decision to request a helicopter air ambulance (HAA) is critical and complex. Emergency medical service (EMS) professionals must know how to appropriately and safely use HAA resources. We sought to describe important criteria for using HAA and the prevalence of HAA-related training among EMS professionals. Then, we identified characteristics associated with receiving training. METHODS: We sent an electronic questionnaire to all nationally certified EMS professionals. We performed descriptive analyses and multivariable logistic regression modeling. RESULTS: We received 15,366 responses. Nearly all respondents reported that time to nearest trauma center and mechanism of injury were important in their last decision to use a HAA. About two thirds received HAA safety training (66.7%), whereas 69.0% received HAA utilization training within the past 24 months. Nearly three fourths (74.2%) received training in at least 1 HAA-related topic. Providers working at advanced life support levels, fire-based services, agencies providing 911 response, or in rural communities had greater odds of having received HAA training, whereas women, members of minority ethic/racial groups, and those with higher weekly call volumes had decreased odds. CONCLUSION: Although their decision-making criteria appear to include the major factors recommended within current evidence-based guidelines, many nationally certified EMS professionals had not received recent HAA training. PMID- 26611221 TI - Association Between Difficult Airway Predictors and Failed Prehosptial Endotracheal Intubation. AB - OBJECTIVE: Difficult airway predictors (DAPs) are associated with failure of endotracheal intubation (ETI) in the emergency department (ED). The purpose of this study was to determine if DAPs are associated with failure of prehospital ETI. METHODS: This retrospective study compared the prevalence of DAPs in cases of failed prehospital ETI successfully intubated in the ED (FPH/SED) with cases with no prehospital attempt that were successfully intubated in the ED on the first attempt by a physician using direct laryngoscopy (NPH/SED). All cases were transported by ground or air to an academic, level-1 trauma center. RESULTS: A total of 1377 ED ETIs were performed; 161 FPH/SED and 530 NPH/SED were identified. The odds ratios with 95% confidence intervals (CIs) of finding DAPs in the FPH/SED group compared with the NPH/SED group was blood = 5.80 (95% CI, 3.89-8.63), vomit = 2.01 (95% CI, 1.25-3.21), short neck = 2.67 (95% CI, 1.39 5.03), neck immobility = 2.52 (95% CI, 1.72-3.67), airway edema = 10.52 (95% CI, 4.15-29.92), facial trauma = 4.64 (95% CI, 2.91-7.39), and large tongue = 3.08 (95% CI, 1.75-5.40). When grouped by the number of DAPs per case (0, 1, 2, 3, or >= 4), the odds of multiple DAPs in cases of FPH/SED compared with NPH/SED ranged from 2.89 (95% CI, 1.71-4.90) with 1 DAP to 24.55 (95% CI, 10.60-56.90) with >= 4 DAPs. CONCLUSION: Cases of FPH/SED have more DAPs than NPH/SEDs. PMID- 26611223 TI - A Ketamine Protocol and Intubation Rates for Psychiatric Air Medical Retrieval. AB - OBJECTIVE: The air medical transfer of psychiatric patients with acute agitation is a regular requirement in only a few countries, with ours (Australia) being one of them. The optimal strategy has yet to be well described, ranging from physical restraints to general anesthesia with endotracheal intubation. In an Australian air medical service, Royal Flying Doctor Service (Queensland Section) rates of endotracheal intubation required for patient management were retrospectively compared before and after implementation of a ketamine sedation protocol for this patient population. METHODS: A systematic retrospective review was performed using 9 years of data included in the Royal Flying Doctor Service (Queensland Section) electronic database (2004-2013). Coding for mental health as the primary diagnosis and intubation were the search criteria. RESULTS: A total of 1,478 patients were transferred during the study period, with 44 requiring intubation. This equates to intubation rates of 3.5% before protocol use compared with 2.3% after protocol implementation. CONCLUSION: In an Australian air medical service, the implementation of a ketamine sedation protocol for the management of the acutely agitated patient requiring air transfer has reduced the number of intubations in this patient group. PMID- 26611222 TI - Stroke and Helicopter Emergency Medical Service Transports: An Analysis of 25,332 Patients. AB - OBJECTIVE: Helicopter emergency medical services (HEMS) are effective in time sensitive illnesses, including stroke. Intravenous tissue plasminogen activator is beneficial for ischemic stroke within 4.5 hours of onset. This study analyzed the largest repository of US HEMS electronic medical record data characterizing demographic and logistical trends during stroke center accreditation. This study developed a methodology to aggregate, analyze, and report data from multiple providers. METHODS: This is a descriptive study of aggregate, deidentified data from 67 US providers from 2004 to 2011. Retrospective data including age, ethnicity, total transport time, mission type, and locality were analyzed. The effect of primary stroke center (PSC) designation was assessed for 2011. RESULTS: A total of 25,332 patients were transported for "stroke." Stroke increased from 1.4% to 3.9% during the study. Ninety-six percent of transports arrived at definitive care within 2 hours. Seventy-two percent of transports were "interfacility," and 58% were from "rural" or "super-rural" localities. Seventy nine percent of 2011 transports were to PSCs. Ethnicity and age were significant barriers to transport to PSCs (P < .001). CONCLUSIONS: HEMS has increased access to stroke care for super-rural, rural, and urban communities offering timely transport within the treatment window if symptoms are recognized within 2.5 hours of onset. This study created a methodology for future multicenter aggregate data studies. PMID- 26611224 TI - Assessment of Paramedic Ultrasound Curricula: A Systematic Review. AB - OBJECTIVE: Prehospital ultrasound is being applied in the field. The purpose of this systematic review is to describe evidence pertaining to ultrasound curricula for paramedics specifically, including content, duration, setting, design, evaluation, and application. METHODS: Electronic searches of MEDLINE, Embase, CINAHL, and the Cochrane Center Register of Controlled Trials were conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Primary literature describing acute care ultrasound curricula for paramedics were included. Two authors independently extracted data and assessed quality using 2 validated tools. RESULTS: Twelve studies with 187 paramedics were included. Curricula duration varied, with effective curricula teaching focused assessment with sonography for trauma (FAST) in 6 to 8 hours and pleural ultrasound in 25 minutes. FAST, pleural, and fracture-detection ultrasound are being applied in the field by paramedics; however, no literature exists describing application to detect cardiac standstill. Curricula combined didactic and hands-on components including simulation and evaluated competency using sensitivity and specificity of paramedic-performed ultrasound. CONCLUSIONS: Paramedic ultrasound curricula in FAST and pleural ultrasound is feasible and time effective with successful application. Although fracture detection ultrasound is being used by the special operations forces, no comprehensive curriculum was described. Curricula designed to detect cardiac standstill have been too short, and successful application by paramedics has not been shown. PMID- 26611225 TI - Improved Oxygenation After Transport in Patients With Hypoxemic Respiratory Failure. AB - OBJECTIVE: The purpose of this study is to measure the rate and magnitude of changes in oxygenation that occur in patients with hypoxemic respiratory failure after transport by a critical care transport team. METHODS: We performed a retrospective review of 239 transports of patients with hypoxemic respiratory failure requiring a fraction of inspired oxygen (Fio2) > 50% transported from October 2009 to December 2012 from referring hospitals to 3 tertiary care hospitals. We analyzed the change the ratio of the partial pressure of oxygen in the blood to FiO2 from the sending to the receiving hospital as well as the percentage saturation of oxygen (Spo2) before, after, and en route. RESULTS: The mean change in the Pao2/Fio2 ratio from the sending to the receiving hospital was an increase of 27.62 (95% confidence interval [CI], 15.84-39.40; P = .0003). The mean change in Pao2 was an increase of 27.85 mm Hg (CI, 17.49-38.22; P < .0001). The mean Spo2 was not significantly changed at -0.12 (CI, - 1.69 to 1.45, P = .9). Despite improvement in the Pao2/Fio2 ratio and a stable Spo2 on arrival, 28.1% of patients desaturated to Spo2 < 90% in transport. CONCLUSION: In patients with hypoxemic respiratory failure, Pao2/Fio2 and Pao2 increased after transport by a critical care transport team despite 28.1% of patients desaturating with hypoxemia in transit. PMID- 26611226 TI - Performance of a one-step quantitative duplex RT-PCR for detection of rotavirus A and noroviruses GII during two periods of high viral circulation. AB - Rotavirus A (RVA) and noroviruses (NoV) are the major viral agents of acute gastroenteritis (AGE) worldwide. In the present study, we aimed to evaluate the performance of a one-step duplex quantitative RT-PCR (dRT-qPCR) assay, established for detection and quantification of RVA and NoV genogroup II (GII) using a single DNA standard curve (SC), as well as to investigate the association between fecal viral load and optical density (OD) values, and viruses' genotyping. The results obtained by dRT-qPCR in 530 fecal samples from AGE cases were compared with methods employed for the diagnosis of those viruses as follows: enzyme immunoassay (EIA) and polyacrylamide gel electrophoresis (PAGE) for RVA; and qualitative PCR for NoV. By using dRT-qPCR, we detected RVA and NoV in 353 (66%), increasing the positivity rate by 22.5% for RVA and 11.5% NoV, comparing the number of positive samples. RVA and NoV GII were detected in a range of 5.17 * 10(3) to 6.56 * 10(9) and 3.76 * 10(3) to 9.13 * 10(10) genome copies per gram of feces, respectively. We observed a significant direct correlation between genome copies values and optical density, using dRT-qPCR and EIA assays, respectively (Spearman rho=0.41; p<0.0001). Viruses characterization demonstrated a predominance of NoV GII.4 Sidney 2012 variant during October 2013 to February 2014, followed by the emergence of RVA genotype G12P[8] in 2014. The established assay using a single SC provides an early feedback concerning detection and quantification, with the advantage of detecting simultaneously RVA and NoV GII, reducing time and reagent costs. PMID- 26611227 TI - RT-PCR and sequence analysis of the full-length fusion protein of Canine Distemper Virus from domestic dogs. AB - During 2007-2014, 84 out of 236 (35.6%) samples from domestic dogs submitted to our laboratory for diagnostic purposes were positive for Canine Distemper Virus (CDV), as analyzed by RT-PCR amplification of a fragment of the nucleoprotein gene. Fifty-nine of them (70.2%) were from dogs that had been vaccinated against CDV. The full-length gene encoding the Fusion (F) protein of fifteen isolates was sequenced and compared with that of those of other CDVs, including wild-type and vaccine strains. Phylogenetic analysis using the F gene full-length sequences grouped all the Argentinean CDV strains in the SA2 clade. Sequence identity with the Onderstepoort vaccine strain was 89.0-90.6%, and the highest divergence was found in the 135 amino acids corresponding to the F protein signal-peptide, Fsp (64.4-66.7% identity). In contrast, this region was highly conserved among the local strains (94.1-100% identity). One extra putative N-glycosylation site was identified in the F gene of CDV Argentinean strains with respect to the vaccine strain. The present report is the first to analyze full-length F protein sequences of CDV strains circulating in Argentina, and contributes to the knowledge of molecular epidemiology of CDV, which may help in understanding future disease outbreaks. PMID- 26611228 TI - Consistent viral DNA quantification after prolonged storage at ambient temperature. AB - Long-term storage of biological specimens at low temperatures is costly and impractical in resource limited settings, where the disease burden of chronic viral infections is highest, and the need for research greatest. We examined the necessity of cold storage by comparing the quantity of HHV-8 DNA recovered from swab samples before and after 9-11 months of storage at temperatures of -20 degrees C, 4 degrees C and 37 degrees C. Quantitative levels of HHV-8 DNA remained consistent for laboratory or mucosal swab samples regardless of storage temperature. Freezer storage is determined to be not necessary for mucosal samples destined for HHV-8 DNA quantification. PMID- 26611229 TI - Rapid and sensitive detection of porcine torovirus by a reverse transcription loop-mediated isothermal amplification assay (RT-LAMP). AB - Porcine torovirus (PToV) is associated with swine gastroenteritis, but its pathogenesis is uncertain because there is limited information regarding PToV due to its difficulty to adapt in vitro. This study has developed a rapid one-step reverse transcription loop-mediated isothermal amplification (RT-LAMP) method for the detection of PToV. A set of four primers specific to six regions within the PToV's highly conserved fragment of the M gene was designed for use with the RT LAMP assay. The RT-LAMP assay was sensitive with a detection limit of 1 * 10(1)copies/MUL, which was 100-fold higher than reverse-transcription PCR. No cross-reaction was observed with other similar viruses. A total of 175 clinical specimens were collected from the Sichuan province, and PToV was detected by the established RT-LAMP assay with a positive rate of 39.2% (69/175). This study developed the first rapid, sensitive, simple, cost-effective and accurate method for the detection of PToV. The results show that the RT-LAMP assay is highly feasible in clinical settings. PMID- 26611230 TI - Microspheres of carboxymethyl chitosan, sodium alginate and collagen for a novel hemostatic in vitro study. AB - To develop biocompatible composite microspheres for novel hemostatic use, we designed and prepared a novel biomaterial, composite microspheres consisting of carboxymethyl chitosan, sodium alginate, and collagen (CSCM). The ultra-structure of CSCM was investigated by scanning electron microscopy assay. In hemostatic function experiment, it was found that CSCM could facilitate platelet adherence, platelet aggregation, and platelet activation in vitro. Besides, the maximum swelling of CSCM submerged in PBS for 50 min was over 300% of that exhibited by commercial hemostatic compound microporous polysaccharide haemostatic powder (CMPHP). In addition, CSCM exhibited good biodegradability and non-cytotoxicity. These results demonstrated that CSCM may be useful in platelet plug formation, and this study would provide important information for further research on hemostasis experiment in vivo. PMID- 26611231 TI - A unique monoclonal antibody for therapeutic use against chronic hepatitis B: not all antibodies are created equal. PMID- 26611232 TI - Screening for gastric cancer in Western countries. PMID- 26611233 TI - Sarcopenia as a predictor of major hepatectomy complications: a little addition. PMID- 26611234 TI - Postoperative permanent pressure alopecia. AB - A 49-year-old Chinese female underwent elective laparoscopic assisted Whipple's surgery lasting 12 h. This was complicated by postoperative pressure alopecia at the occipital area of the scalp. Pressure-induced hair loss after general anaesthesia is uncommon and typically temporary, but may be disconcerting to the patient. We report this case of postoperative permanent pressure alopecia due to its rarity in the anaesthesia/local literature, and review the risk factors for its development. PMID- 26611235 TI - Waxing and Waning Congenital Diaphragmatic Hernia of Morgagni: A Diagnostic Conundrum. PMID- 26611236 TI - The relation of PTSD symptoms to migraine and headache-related disability among substance dependent inpatients. AB - Despite emerging evidence for the comorbidity of posttraumatic stress disorder (PTSD) and migraine, few studies have examined the relation of PTSD and migraine, particularly among clinical populations at-risk for both conditions (e.g., substance-dependent patients). This study examined the role of PTSD symptoms in migraine and headache-related disability within a sample of 153 substance dependent inpatients (37.25% female, Mean age 36.46). PTSD symptoms predicted both migraine and headache-related disability above and beyond gender, depression and anxiety symptoms, the experience of a Criterion A traumatic event, and current alcohol use disorder. Findings highlight the strong association between migraine and PTSD symptoms in a unique population at risk for both conditions. PMID- 26611237 TI - Impact of road environment on drivers' behaviors in dilemma zone: Application of agent-based simulation. AB - At a signalized intersection, there exists an area where drivers become indecisive as to either stop their car or proceed through when the traffic signal turns yellow. This point, called a dilemma zone, has remained a safety concern for drivers due to the great possibility of a rear-end or right-angle crash occurring. In order to reduce the risk of car crashes at the dilemma zone, Institute of Transportation Engineers (ITE) recommended a dilemma zone model. The model, however, fails to provide precise calculations on the decision of drivers because it disregards the supplemental roadway information, such as whether a red light camera is present. Hence, the goal of this study was to incorporate such roadway environmental factors into a more realistic driver decision-making model for the dilemma zone. A driving simulator was used to determine the influence of roadway conditions on decision-making of real drivers. Following data collection, each driver's decision outcomes were implemented in an Agent-Based Simulation (ABS) so as to analyze behaviors under realistic road environments. The experimental results revealed that the proposed dilemma zone model was able to accurately predict the decisions of drivers. Specifically, the model confirmed the findings from the driving simulator study that the changes in the roadway environment reduced the number of red light violations at an intersection. PMID- 26611238 TI - Where is the mechanism we have lost in mapping? PMID- 26611239 TI - The precise timing of tachycardia entrainment is determined by the postpacing interval, the tachycardia cycle length, and the pacing rate: Theoretical insights and practical applications. AB - BACKGROUND: Previous observations have reported that the number of pacing stimuli required to entrain a tachycardia varies on the basis of arrhythmia type and location, but a quantitative formulation of the number needed to entrain (NNE) that unifies these observations has not been characterized. OBJECTIVE: We sought to investigate the relationship between the number of pacing stimulations, the tachycardia cycle length (TCL), the overdrive pacing cycle length (PCL), and the postpacing interval (PPI) to accurately estimate the timing of tachycardia entrainment. METHODS: First, we detailed a mathematical derivation unifying electrophysiological parameters with empirical confirmation in 2 patients undergoing catheter ablation of typical atrial flutter. Second, we validated our formula in 44 patients who underwent various catheter ablation procedures. For accuracy, we corrected for rate-related changes in conduction velocity. RESULTS: We derived the equations NNE = |(PPI - TCL)/(TCL - PCL)| + 1 and Tachycardia advancement = (NNE - 1) * (TCL - PCL) - (PPI - TCL), which state that the NNE and the amount of tachycardia advancement on the first resetting stimulation are determined using regularly measured intracardiac parameters. In the retrospective cohort, the observed PPI - TCL highly correlated with the predicted PPI - TCL (mean difference 5.8 ms; r = 0.97; P < .001), calculated as PPI - TCL = (NNE - 1) * (TCL - PCL) - tachycardia advancement. CONCLUSION: The number of pacing stimulations required to entrain a reentrant tachycardia is predictable at any PCL after correcting for cycle length-dependent changes in conduction velocity. This relationship unifies established empirically derived diagnostic and mapping criteria for supraventricular tachycardia and ventricular tachycardia. This relationship may help elucidate when antitachycardia pacing episodes are ineffective or proarrhythmic and could potentially serve as a theoretical basis to customize antitachycardia pacing settings for improved safety and effectiveness. PMID- 26611240 TI - [Effectiveness of a programme based on a virtual reality game for cognitive enhancement in schizophrenia]. AB - OBJECTIVE: To evaluate the effectiveness of a programme based on a virtual reality game to improve cognitive domains in patients with schizophrenia. METHOD: A randomized controlled trial was conducted in 40 patients with schizophrenia, 20 in the experimental group and 20 in the control group. The experimental group received 10 sessions with Nintendo Wii((r)) for 5 weeks, 50 minutes/session, 2 days/week in addition to conventional treatment. The control group received conventional treatment only. RESULTS: Statistically significant differences in the T-Score were found in 5 of the 6 cognitive domains assessed: processing speed (F=12.04, p=0.001), attention/vigilance (F=12.75, p=0.001), working memory (F=18.86, p <0.01), verbal learning (F=7.6, p=0.009), visual learning (F=3.6, p=0.064), and reasoning and problem solving (F=11.08, p=0.002). CONCLUSIONS: Participation in virtual reality interventions aimed at cognitive training have great potential for significant gains in different cognitive domains assessed in patients with schizophrenia. PMID- 26611241 TI - Erratum to: Classification and Clustering on Microarray Data for Gene Functional Prediction Using R. PMID- 26611242 TI - Homeostatic regulation of trace mineral transport by ubiquitination of membrane transporters. AB - Post-translational modification is a critical mechanism by which trace mineral transporters rapidly adapt to their environment to homeostatically regulate ion transport. Recently, a novel pathway was described whereby iron stimulates the ubiquitination and proteasomal degradation of the trace mineral transporter ZIP14. Discovery of this pathway suggests the proteasome as a potential therapeutic target for regulation of iron storage. Moreover, these findings contribute to a theoretical framework that can be applied to other ubiquitinated trace mineral transporters. This review will detail the current state of knowledge regarding the ubiquitination of trace mineral transporters, focusing on iron and zinc transporters, and the potential utility of post-translational modification of trace mineral transporters in the treatment of disease. PMID- 26611243 TI - Glottic Cancer: A Metamorphosing Disease. AB - OBJECTIVE: Conventional wisdom is that the overwhelming majority of glottic cancer patients have a smoking history. However, in recent years observations suggested that an increasing number of glottic cancer patients had never been smokers. Therefore, an investigation was done examining the incidence of having a smoking history in a recent cohort of glottic cancer patients. METHOD: Retrospective review of 100 patients with glottic cancer to determine those reporting never having smoked. RESULTS: Thirty-one of 100 did not have a smoking history. Clinical observations of those cases revealed that the disease morphology tended to be exophytic, papillary, and very vascular, often resembling recurrent respiratory papillomatosis (RRP). Remarkably, 2 of 31 were initially treated elsewhere assuming they had RRP and underwent 5 cidofovir injections. Both presented with advanced cancer, and the disease growth markedly accelerated coincident with the injections. CONCLUSIONS: Observations herein provide new insights that glottic cancer may be an evolving disease in which smoking is less exclusive, not unlike HPV-induced pharynx cancer. Similar to RRP, the angiogenic papillary disease morphology is well suited for voice-preserving angiolytic KTP laser treatment. Given the resemblance of some glottic cancers to RRP, great care should be taken when using cidofovir for papillary glottic neoplasms. PMID- 26611244 TI - A Controlled, Randomized Clinical Study on the Impact of Treatment on Antral Mucociliary Clearance: Uncinectomy Versus Balloon Sinuplasty. AB - OBJECTIVES: To find out the effect of minimal invasive sinus surgery and balloon sinuplasty on mucociliary clearance and compare different methods of measuring mucociliary clearance. METHODS: Twenty-nine patients with chronic rhinosinusitis were randomized in 2 operative groups (uncinectomy or balloon sinuplasty). Before and 6 months after the treatment, patients filled out a quality of life questionnaire (Sino Nasal Outcome Test-22 [SNOT-22]), and mucociliary clearance was measured with endoscope and gamma camera after 0.03 ml of saccharine, methylene-blue dye, and human albumin labeled with Tc99m was introduced to the bottom of maxillary sinuses. RESULTS: In uncinectomy group, SNOT-22 score decreased, but treatment had no effect on mucociliary clearance. Based on saccharine test, smoking was associated with worse mucociliary clearance (r = 0.618, P < .05). Methylene blue test results associated with saccharine test (r = 0.434, P < .05) and Tc99m-labeled tracer technique (r = 0.261, P = .039) separately. CONCLUSION: Treatment positively affects patients' quality of life; however, it has no effect on mucociliary clearance. There was a statistically significant correlation between the Tc99m-labeled tracer technique and the methylene blue technique. The saccharine technique was even less accurate, but it can be useful in clinical practice because it is a quick, easy, and safe technique. PMID- 26611245 TI - Oxymetazoline Applied Topically to the Nasal Mucosa Decreases Trans-Mucosal Nitrous Oxide Exchange for the Middle Ear. AB - OBJECTIVE: Determine if the middle ear (ME) trans-mucosal nitrous oxide (N2O) gas exchange rate can be pharmacologically modulated by the nasal application of a vasoconstrictor. METHODS: In a randomized, double-blind, crossover study, 20 adults received a nasal spray challenge containing either oxymetazoline or saline (placebo). At each session, subjects were fitted with a non-rebreathing mask and breathed room air for 20 minutes, 50% N2O:50% O2 for 20 minutes, and 100% O2 for 10 minutes. Throughout, heart rate, blood pressure (BP), and blood O2 saturation were monitored, and bilateral ME pressure was recorded by tympanometry every minute. The primary outcome measure was the slope of the ME pressure-time function for the experimental period, a direct measure of the transMEM N2O exchange constant. The effects of treatment, session, and period on the measured vital signs and of treatment, session, disease history, and ear on the ME pressure-time slopes were evaluated for statistical significance using repeated measures ANOVAs. RESULTS: The analysis documented a significant effect of period on O2 saturation (N2O > room air, P = .03) and of treatment on blood pressure (oxymetazoline > placebo, P < .02) and the ME pressure-time slope (placebo > oxymetazoline, P = .05). CONCLUSION: The exchange rate across the ME mucosa of inert gases can be decreased by topical treatment of the nasal mucosa with oxymetazoline. PMID- 26611246 TI - High-Grade Neuroendocrine Carcinoma of the Larynx: The Mayo Clinic Experience. AB - OBJECTIVE: To report a single institutional series of high-grade neuroendocrine carcinoma of the larynx (NCL), a very rare yet aggressive tumor. To review the management of NCL, including discussion of clinical behavior, treatment outcome, and prognosis. METHOD: A retrospective chart review of high-grade laryngeal neuroendocrine carcinomas at a single institution, including small- and large cell neuroendocrine carcinomas. A total of 8 patients with high-grade NCL treated at our institution from 1992 to 2014 were identified. RESULTS: The median age at diagnosis was 65.5 years (range, 43-80). Five patients were male. Two patients had a known smoking history. Primary tumor location was supraglottic in 7 patients and glottic in 1 patient. Primary treatment consisted of surgery alone (3 patients), radiotherapy alone (1 patient), combination of chemotherapy and radiotherapy (1 patient), and surgery followed by postoperative chemoradiotherapy (3 patients). Locoregional recurrence followed by distant metastasis occurred in 6 patients. Median overall survival was 44.0 months (95% CI, 3-62.0). CONCLUSION: High-grade NCL is a rare diagnosis. Compared to well- and moderately differentiated NCL, high-grade NCL has a far more aggressive clinical course and associated with a worse prognosis. To our knowledge, this is the largest series of patients with high-grade NCL treated at a single institution. Prompt diagnosis and multimodality therapy including elective neck dissection may improve survival. PMID- 26611247 TI - Adrenal and thyroid metachronous metastases from renal cell carcinoma. PMID- 26611248 TI - Lessons learned from cardiovascular outcome clinical trials with dipeptidyl peptidase 4 (DPP-4) inhibitors. AB - Previous trials of glucose-lowering strategies in subjects with type 2 diabetes have demonstrated a beneficial effect of intensive glycemic control on microvascular complications but failed to show a clear benefit on cardiovascular complications. The findings of meta-analyses of rosiglitazone trials suggesting that rosiglitazone might increase the risk of myocardial infarction have cast doubt on the cardiovascular safety of glucose-lowering drugs. In 2008, the US Food and Drug Administration has implemented rigorous criteria to approve new glucose-lowering drugs, requiring proof of cardiovascular safety. These regulatory requirements have led to a considerable increase in the number of cardiovascular outcome trials in type 2 diabetes to ensure that newer glucose lowering drugs are not associated with increased cardiovascular risk. Incretin based therapies including dipeptidyl peptidase 4 (DPP-4) inhibitors, and injectable glucagon-like peptide 1 (GLP-1) receptor agonists are novel treatment options for patients with inadequate glucose control. Although DPP-4 inhibitors have shown neutral effects on risk factors for cardiovascular diseases, it remains unclear whether treatment with these new glucose-lowering agents might be associated with a reduction in cardiovascular events. The results of the three cardiovascular outcome trials comparing DPP-4 inhibitors treatment to placebo in addition to other glucose-lowering drugs have been published. All the three DPP-4 inhibitor cardiovascular outcome trials have shown non-inferiority with regard to cardiovascular safety, compared with placebo, when added to usual care. In this review, we summarize cardiovascular outcome trials of DPP-4 inhibitors, and provide an overview of these trials and their limitations. PMID- 26611249 TI - Challenges in the clinical development of new antiepileptic drugs. AB - Despite the current availability in the market of over two dozen antiepileptic drugs (AEDs), about one third of people with epilepsy fail to achieve complete freedom from seizures with existing medications. Moreover, currently available AEDs have significant limitations in terms of safety, tolerability and propensity to cause or be a target for clinically important adverse drug interactions. A review of the evidence shows that there are many misperceptions about the viability of investing into new therapies for epilepsy. In fact, there are clear incentives to develop newer and more efficacious medications. Developing truly innovative drugs requires a shift in the paradigms for drug discovery, which is already taking place by building on greatly expanded knowledge about the mechanisms involved in epileptogenesis, seizure generation, seizure spread and development of co-morbidities. AED development can also benefit by a review of the methodology currently applied in clinical AED development, in order to address a number of ethical and scientific concerns. As discussed in this article, many processes of clinical drug development, from proof-of-concept studies to ambitious programs aimed at demonstrating antiepileptogenesis and disease-modification, can be facilitated by a greater integration of preclinical and clinical science, and by application of knowledge acquired during decades of controlled epilepsy trials. PMID- 26611250 TI - [Training in patient safety in medical and nursing schools]. AB - OBJECTIVE: To compare the information on patient safety received by students of medicine and nursing. METHOD: Cross-sectional study was conducted using a convenience sample of medical and nursing students of 3 Universities. The Latin Patient Safety Student Information and a test of 5 questions with 5 options were used. A sample of 79 students in each group was enrolled to detect differences of .3 units (bilateral estimation), considering 80% statistical power and 95% confidence interval. RESULTS: A total of 144 students replied (74 nursing and 70 medicine students). Nursing students achieved higher scores in the communication with patients factor (3.8 vs 3.2, P<.001) and proactive attitude to identify risks for patient safety (4.3 vs 3.8, P<.001). Medical students were more aware of the inevitability of adverse events (2.3 vs 3.1, P<.001). Ten (7%) students had only one fault in the test, and only one (1%) answered all questions correctly. CONCLUSIONS: The training in patient safety should be improved both in nursing and medicine, although nursing students receive more information. PMID- 26611251 TI - "Passing on the Fire" to Communicate High-quality Scientific Knowledge for Biomedicine and Health Care. PMID- 26611252 TI - Erratum to: "Youden's Index and the Likelihood Ratio Positive in Diagnostic Testing". PMID- 26611253 TI - Enhanced Charge Separation and FRET at Heterojunctions between Semiconductor Nanoparticles and Conducting Polymer Nanofibers for Efficient Solar Light Harvesting. AB - Energy harvesting from solar light employing nanostructured materials offer an economic way to resolve energy and environmental issues. We have developed an efficient light harvesting heterostructure based on poly(diphenylbutadiyne) (PDPB) nanofibers and ZnO nanoparticles (NPs) via a solution phase synthetic route. ZnO NPs (~20 nm) were homogeneously loaded onto the PDPB nanofibers as evident from several analytical and spectroscopic techniques. The photoinduced electron transfer from PDPB nanofibers to ZnO NPs has been confirmed by steady state and picosecond-resolved photoluminescence studies. The co-sensitization for multiple photon harvesting (with different energies) at the heterojunction has been achieved via a systematic extension of conjugation from monomeric to polymeric diphenyl butadiyne moiety in the proximity of the ZnO NPs. On the other hand, energy transfer from the surface defects of ZnO NPs (~5 nm) to PDPB nanofibers through Forster Resonance Energy Transfer (FRET) confirms the close proximity with molecular resolution. The manifestation of efficient charge separation has been realized with ~5 fold increase in photocatalytic degradation of organic pollutants in comparison to polymer nanofibers counterpart under visible light irradiation. Our results provide a novel approach for the development of nanoheterojunctions for efficient light harvesting which will be helpful in designing future solar devices. PMID- 26611254 TI - In Response to: "Battery-powered bone drill: caution needed in densely blastic lesions". PMID- 26611256 TI - Roll-to-roll printed silver nanowires for increased stability of flexible ITO free organic solar cell modules. AB - We report the use of roll-to-roll printed silver nanowire networks as front electrodes for fully roll-to-roll processed flexible indium-tin-oxide (ITO) free OPV modules. We prepared devices with two types of back electrodes, a simple PEDOT: PSS back electrode and a PEDOT: PSS back electrode with a printed silver grid in order to simultaneously explore the influence of the back electrode structure on the operational stability of the modules that did not include any UV protection. We subjected the devices to stability testing under a number of protocols recommended by the international summit on OPV stability (ISOS). We explored accelerated ISOS-D-2, ISOS-D-3, ISOS-L-2, ISOS-L-3, ISOS-O-1 and ISOS-O 2 testing protocols and compared the performance to previous reports employing the same testing protocols on devices with PEDOT: PSS instead of the silver nanowires in the front electrode. We find significantly increased operational stability across all ISOS testing protocols over the course of the study and conclude that replacement of PEDOT: PSS in the front electrode with silver nanowires increase operational stability by up to 1000%. The duration of the tests were in the range of 140-360 days. The comparison of front and back electrode stability in this study shows that the modules with silver nanowire front electrodes together with a composite back electrode comprising PEDOT: PSS and a silver grid present the best operational stability. PMID- 26611255 TI - Measuring physiological and pathological femoral anteversion using a biplanar low dose X-ray system: validity, reliability, and discriminative ability in cerebral palsy. AB - OBJECTIVE: The aims of this study were to evaluate the concurrent validity and reliability of a low-dose biplanar X-ray system (Ld-BPR) for the measurement of femoral anteversion (FA) by comparing Ld-BPR-based three-dimensional measures with CT-scan-based measures and to assess the discriminative ability of this method in children with cerebral palsy. MATERIALS AND METHODS: Fifty dry femora were scanned using both a CT scan and the Ld-BPR system. Ten femora were artificially modified to mimic a range of anteversion from -30 degrees to +60 degrees and scanned by both modalities. FA was quantified using the images from both modalities and statistically compared for concurrent validity. Intra- and inter-observer reliability of the Ld-BPR system was also determined. Further, Ld BPR data from 16 hemiplegic and 22 diplegic children were analyzed for its discriminative ability. RESULTS: The concurrent validity between the Ld-BPR and CT-scan measures was excellent (R (2) = 0.83-0.84) and no significant differences were found. The intra- and inter-trial reliability were excellent (ICCs = 0.98 and 0.97) with limits of agreement of (-2.28 degrees ; +2.65 degrees ) and (-2.76 degrees ; +3.38 degrees ) respectively. Further, no significant effects of angle or method were found in the sample of modified femora. Ld-BPR measures for FA were significantly different between healthy and impaired femora. CONCLUSIONS: The excellent concurrent validity with the CT scan modality, the excellent reliability, and the ability to discriminate pathological conditions evaluated by this study make this radiological method suitable for a validated use across hospitals and research institutes. PMID- 26611257 TI - Imaging features of Burkitt lymphoma in pediatric patients. AB - Burkitt lymphoma is an aggressive and rapidly growing tumor that is curable and highly sensitive to chemotherapy. It can affect almost every tissue in the body, producing various clinical presentations and imaging appearances, according to the predilection of the different subtypes for certain sites. Awareness of its diagnostically specific imaging appearances plays an important role in rapid detection and treatment. In this pictorial review, we aimed to identify the most common imaging features of Burkitt lymphoma in pediatric patients. PMID- 26611259 TI - Preliminary study on analysis and removal of wax from a Carrara marble statue. AB - This preliminary study has mainly focused on the wax identification by nuclear magnetic resonance (NMR) and removal. Wax is used for many purposes in the field of art as protective coatings on wooden, stone or metal objects. From the comparison of the spectra H NMR and in particular with the correspondence of the resonance peaks of the samples taken from the statue and beeswax and paraffin, we can conclude that the wax applied on the statue surface is beeswax. From our data, it can be concluded that, to remove the beeswax, from any stone support, the more effective solvent is the mixture of cyclohexane/ethyl acetate. The removal percentages ranged from 19 to 99%. Lower percentages of removal have been observed in the case of yellow marble, probably because of its high porosity. We can affirm that, this solvent mixture can be employed in real art objects using cotton swabs to remove protective wax. PMID- 26611258 TI - Increased x-ray attenuation in malignant vs. benign mediastinal nodes in an orthotopic model of lung cancer. AB - PURPOSE: Staging of lung cancer is typically performed with fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT); however, false positive PET scans can occur due to inflammatory disease. The CT scan is used for anatomic registration and attenuation correction. Herein, we evaluated x-ray attenuation (XRA) within nodes on CT and correlated this with the presence of malignancy in an orthotopic lung cancer model in rats. METHODS: 1*106 NCI-H460 cells were injected transthoracically in six National Institutes of Health nude rats and six animals served as controls. After two weeks, animals were sacrificed; lymph nodes were extracted and scanned with a micro-CT to determine their XRA prior to histologic analysis. RESULTS: Median CT density in malignant lymph nodes (n=20) was significantly higher than benign lymph nodes (n=12; P = 0.018). Short-axis diameter of metastatic lymph nodes was significantly different than benign nodes (3.4 mm vs. 2.4 mm; P = 0.025). Area under the curve for malignancy was higher for density-based lymph node analysis compared with size measurements (0.87 vs. 0.7). CONCLUSION: XRA of metastatic mediastinal lymph nodes is significantly higher than benign nodes in this lung cancer model. This suggests that information on nodal density may be useful when used in combination with the results of FDG-PET in determining the likelihood of malignant adenopathy. PMID- 26611260 TI - Smartphone speech-to-text applications for communication with profoundly deaf patients. AB - OBJECTIVE: Visual communication aids, such as handwriting or typing, are often used to communicate with deaf patients in the clinic. This study aimed to establish the feasibility of communicating through smartphone speech recognition software compared with writing or typing. METHOD: Thirty doctors and medical students were timed writing, typing and dictating a standard set of six sentences appropriate for a post-operative consultation, and the results were assessed for accuracy and legibility. RESULTS: The mean time for smartphone dictation (17.8 seconds, 95 per cent confidence interval = 17.0-18.7) was significantly faster than writing (59.2 seconds, 95 per cent confidence interval = 56.6-61.7) or typing (44 seconds, 95 per cent confidence interval = 41.0-47.1) (p < 0.001). Speech recognition was slightly less accurate, but accuracy increased with time spent dictating. CONCLUSION: Smartphone dictation is a feasible alternative to typing and handwriting. Slow speech may improve accuracy. Early clinical experience has been promising. PMID- 26611262 TI - Genetic diversity in South African Nguni cattle ecotypes based on microsatellite markers. AB - The Nguni cattle breed is a landrace breed adapted to different ecological regions of South Africa. A number of ecotypes are recognised based on phenotype within the breed, but it is not known if they are genetically distinct. In this study, molecular characterisation was performed on Makhathini (MAK), Pedi (PED), Shangaan (SHA) and Venda (VEN) Nguni cattle ecotypes. Two Nguni cattle populations, not kept as separate ecotypes, from the University of Fort Hare (UFH) and Agricultural Research Council Loskop South farm (LOS) were also included. Genotypic data was generated for 189 unrelated Nguni cattle selected based on pedigree records using 22 microsatellite markers. The expected heterozygosity values varied from 69 % (UFH) to 72 % (PED) with a mean number of alleles ranging from 6.0 to 6.9. The F ST estimate demonstrated that 4.8 % of the total genetic variation was due to the genetic differentiation between the populations and 92.2 % accounted for differences within the populations. The genetic distances and structure analysis revealed the closest relationship between MAK, PEDI and SHA ecotypes, followed by SHA and VEN. The UFH population clustered with the MAK ecotype, indicating that they are more genetically similar, while the LOS cattle grouped as a distinct cluster. Results suggest that the genetic differentiation between the PED and SHA ecotypes is low and can be regarded as one ecotype based on limited genetic differences. The results of this study can be applied as a point of reference for further genetic studies towards conservation of Nguni cattle ecotypes. PMID- 26611263 TI - 2015 Multiple Sclerosis Experts Summit. PMID- 26611261 TI - Abeta-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by synapse loss due to mechanisms that remain poorly understood. We show that the neural cell adhesion molecule 2 (NCAM2) is enriched in synapses in the human hippocampus. This enrichment is abolished in the hippocampus of AD patients and in brains of mice overexpressing the human amyloid-beta (Abeta) precursor protein carrying the pathogenic Swedish mutation. Abeta binds to NCAM2 at the cell surface of cultured hippocampal neurons and induces removal of NCAM2 from synapses. In AD hippocampus, cleavage of the membrane proximal external region of NCAM2 is increased and soluble extracellular fragments of NCAM2 (NCAM2-ED) accumulate. Knockdown of NCAM2 expression or incubation with NCAM2-ED induces disassembly of GluR1-containing glutamatergic synapses in cultured hippocampal neurons. Abeta-dependent disassembly of GluR1-containing synapses is inhibited in neurons overexpressing a cleavage-resistant mutant of NCAM2. Our data indicate that Abeta-dependent disruption of NCAM2 functions in AD hippocampus contributes to synapse loss. PMID- 26611264 TI - Prevalence of multiple sclerosis symptoms across lifespan: data from the NARCOMS Registry. AB - The North American Research Committee on Multiple Sclerosis is a voluntary patient registry with more than 38,000 registrants as of 2015. In a recent collaborative project, longitudinal data on patient-perceived impairment in 11 domains commonly affected by multiple sclerosis were examined and tabulated as a function of disease duration. The patterns of disability accumulation differed by domain. Certain symptoms (sensory, fatigue) were particularly prevalent early in the disease. Other symptoms (mobility, hand function, fatigue, bowel/bladder dysfunction, spasticity) were progressively more common with longer disease duration. Some symptoms (vision, cognition, sensory, pain, depression) were relatively common early on in multiple sclerosis, but did not appear to be more frequent with longer disease duration. Ongoing research includes studies of the impact of disease-modifying therapy and symptomatic treatment on patient perceived impairment over the disease course. PMID- 26611265 TI - Multiple sclerosis and infections. AB - The intersection between infections and multiple sclerosis (MS) is complex and bidirectional. Numerous infectious agents have been posited to play a role in the initiation of MS, while emerging evidence suggests a potential relationship between established MS and the gut microbiome. As both systemic and CNS infections are major complications of MS, the clinical manifestations and evolving epidemiology of these infections over the lifespan of the MS patient are examined in this review. Data from animal models and human studies are discussed. PMID- 26611266 TI - Advances in the management of multiple sclerosis symptoms: pathophysiology and assessment of spasticity in multiple sclerosis. AB - Spasticity is a prevalent and troublesome symptom for people with multiple sclerosis (MS). Common instruments to measure MS spasticity include the clinician rated (modified) Ashworth scale and the patient-rated 0-10 spasticity Numerical Rating Scale (NRS). Current opinion is that measurement of MS spasticity should incorporate the patient's perspective. Other instruments to assess spasticity associated symptoms such as the Penn spasms frequency scale, sleep quality NRS and pain NRS can assist in tracking MS spasticity evolution and inform management choices. Worsening spasticity reduces patient autonomy, impacts negatively on quality of life and increases health resource utilization and costs. Despite the wide range of issues associated with MS spasticity, undertreatment is common and standard treatment options (physiotherapy and classical oral therapies) often fail to provide adequate symptomatic control. PMID- 26611267 TI - Advances in the management of MS symptoms: real-life evidence. AB - Once the efficacy and tolerability of a new intervention have been demonstrated in clinical trials under ideal experimental conditions, observational studies within approved label conditions are performed to determine its effectiveness in real-world use and expand the safety/tolerability data. Several large observational studies have been conducted of Sativex((r)) (THC:CBD) oromucosal spray as add-on therapy for moderate-to-severe treatment-resistant multiple sclerosis (MS) spasticity. Studies performed to date with a focus on tolerability have confirmed the absence of abuse, misuse, addiction and lack of impairment of cognition or driving ability. Open-label studies performed to date with a focus on effectiveness have indicated that about one-half to two-thirds of patients initiated on THC:CBD oromucosal spray continue to derive benefit after 3 months' treatment at a mean dosage of 5-7 sprays/day. PMID- 26611268 TI - Advances in the management of MS symptoms: recently proposed clinical management algorithms. AB - Guidelines from both the German and Spanish Neurology Societies for managing patients with multiple sclerosis (MS) spasticity emphasize the importance of setting clear objectives and use evidence levels and grades to support their recommendations. Swedish guidelines for MS spasticity also reflect the need to establish treatment aims and recommend use of validated scales to measure symptom changes. Treatment of generalized MS spasticity, beyond physiotherapy, tends to begin with baclofen, tizanidine and/or diazepam, adding Sativex (THC:CBD) oromucosal spray for moderate-to-severe cases. The European Federation of Neurological Societies/European Academy of Neurology Taskforce on Spasticity in Multiple Sclerosis is currently reviewing the literature supporting the pharmacological treatment of MS spasticity and aims to publish recommendations in the near future to guide clinicians in their treatment choices. PMID- 26611269 TI - What is new in MS spasticity research? Poster session highlights. AB - Each year at the Experts Summit, recent relevant research in the field of multiple sclerosis spasticity is featured in the poster sessions. Highlights of the 2015 poster session are presented. PMID- 26611270 TI - Country break-out session highlights. AB - Individuals with multiple sclerosis (MS) spasticity present a wide range of symptoms and disability levels that are frequently challenging to manage. At the MS Experts Summit 2015, five country breakout sessions were conducted in parallel, and mainly in the native language, to examine various aspects about the management of treatment-resistant MS spasticity. Topics covered included video documentation of MS spasticity management (Germany), use of cannabinoid medicines in daily practice (Italy), multidisciplinary approach to MS spasticity care (France), titration and adherence to treatments for MS spasticity (Spain) and management of MS symptoms (Norway/Rest of World). For the benefit of all attendees, session highlights were collated and presented in a Plenary Session which is summarized herein. PMID- 26611271 TI - Multiple sclerosis and family planning. PMID- 26611272 TI - Cognitive assessment in MS. PMID- 26611273 TI - MS tracking: basic and new tools/exergaming. PMID- 26611274 TI - Physician-patient communication skills: e-tools. PMID- 26611275 TI - Pooling real-world multiple sclerosis patient data on a European level: a true story of success. AB - Patient-based evidence is becoming increasingly important in budget-restricted healthcare systems as the information can help influence the direction of funds towards interventions that provide the most relevant outcomes for people living with a chronic disease. The European Multiple Sclerosis Platform (EMSP) is an umbrella organization for national multiple sclerosis (MS) patients' associations in Europe which represents the interests of >700,000 MS patients, their families and caregivers. EMSP aims to ensure the delivery of high-quality equitable treatment for persons with MS across Europe. EMSP is involved in numerous projects and activities that encompass its vision and mission. The European Network of MS Registries project has provided proof of concept that high quality MS data from previously unconnected sources can be integrated to inform research and improve patient outcomes. PMID- 26611276 TI - Effects of pH and dissolved oxygen on the photodegradation of 17alpha ethynylestradiol in dissolved humic acid solution. AB - To probe the mechanisms responsible for pH and dissolved oxygen (DO) affecting the photodegradation of 17alpha-ethynylestradiol (EE2) in dissolved humic acid (HA) solution, EE2 aqueous solutions with pH values ranging from 3.0 to 11.0 and different DO conditions were irradiated by using a 300 W mercury lamp equipped with 290 nm light cutoff filters. In 5.0 mg L(-1) HA solutions (pH 8.0), EE2 was degraded at a rate of 0.0739 h(-1) which was about 4-fold faster than that in Milli-Q water. The degradation of EE2 was mainly caused by the oxidation of photogenerated reactive species (RS), and the contribution of direct photodegradation to EE2 degradation was always lower than 27%. Both the direct and indirect photodegradation of EE2 were closely dependent on the EE2 initial concentration, pH value and DO concentration. The photodegradation rate of EE2 decreased with increased initial concentration of EE2 due to the limitation of photon flux. With pH and DO increasing, the degradation rate of EE2 increased significantly due to the increase in the yields of excited EE2 and RS. Among the photogenerated RS, HO and (3)HA* were determined to be the key contributors, and their global contribution to EE2 photodegradation was about 50%. Although HA could generate more (1)O2 than HO, the contribution of (1)O2 to EE2 degradation was lower than 13% due to its low reactivity towards EE2. This study could enlarge our knowledge on the photochemical behaviors of steroid estrogens in natural sunlit waters. PMID- 26611277 TI - Special Issue with Review Articles from the 18th Annual Meeting of the Society for Behavioral Neuroendocrinology in Sydney, Australia in August 2014. PMID- 26611278 TI - Breast Cancer Knowledge Among Male High School Students in Saudi Arabia. AB - Breast cancer (BC) accounts for 24 % of all women cancer cases diagnosed in Saudi Arabia each year. Awareness is extremely important in combating this disease. This study was undertaken to assess male high school students' response to BC. This cross-sectional survey was performed on male high school students across schools in Jeddah. A questionnaire gathered data on respondent demographics, beliefs about BC, BC risk factors, early screening methods, and role of men in BC. Statistical analysis was done using SPSS 20. A total of 824 students participated, with an average age of 17.0 years. There was more than 50 % agreement that early detection of BC enhances the chances of recovery, that BC is treatable, and that clinical breast examination and breastfeeding provide protection from BC. Around half the survey population thought that BC was fatal and contagious. Fewer than 50 % thought that BC was inherited and related to smoking, consumption of contraceptive pills, repeated exposure to radiation, obesity, and wearing a bra and that breast tumors were all malignant and spread to different parts of the body. Others knew that mammograms should be performed periodically. A high percentage persuaded their relatives to have mammograms and provided them with psychological support. Knowledge of BC among male high school students in Saudi Arabia is still limited, and, therefore, programs and activities need to be established to increase awareness among high school students. PMID- 26611279 TI - Bones hold the key to DNA virus history and epidemiology. AB - DNA in human skeletal remains represents an important historical source of host genomic information and potentially of infecting viruses. However, little is known about viral persistence in bone. We searched ca. 70-year-old long bones of putative Finnish casualties from World War II for parvovirus B19 (B19V) DNA, and found a remarkable prevalence of 45%. The viral sequences were exclusively of genotypes 2 (n = 41), which disappeared from circulation in 1970's, or genotype 3 (n = 2), which has never been reported in Northern Europe. Based on mitochondrial and Y-chromosome profiling, the two individuals carrying B19V genotype 3 were likely from the Soviet Red Army. The most recent common ancestor for all genotypes was estimated at early 1800s. This work demonstrates the forms of B19V that circulated in the first half of the 20(th) century and provides the first evidence of the suitability of bone for exploration of DNA viruses. PMID- 26611281 TI - Soft nanotubes acting as confinement effecters and chirality inducers for achiral polythiophenes. AB - Depending on their nanochannel sizes, soft nanotubes were able to not only control the conformation and aggregation state of encapsulated achiral polythiophene boronic acids but also induce chirality in the polythiophene chains that exhibit chiral recognition abilities for D, L-sugars. PMID- 26611282 TI - Green shoots or sleight of hand? PMID- 26611280 TI - Pharmacological interventions for challenging behaviour in children with intellectual disabilities: a systematic review and meta-analysis. AB - BACKGROUND: Psychotropic medications are frequently used to treat challenging behaviour in children with intellectual disabilities, despite a lack of evidence for their efficacy. This systematic review and meta-analysis aimed to determine the safety and efficacy of pharmacological interventions for challenging behaviour among children with intellectual disabilities. METHODS: Electronic databases were searched and supplemented with a hand search of reference lists and trial registries. Randomised controlled trials of pharmacological interventions for challenging behaviour among children with intellectual disabilities were included. Data were analysed using meta-analysis or described narratively if meta-analysis was not possible. For quality assessment, the Cochrane Risk of Bias tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach were used. RESULTS: Fourteen studies including 912 participants met inclusion criteria. Antipsychotic medication reduced challenging behaviour among children with intellectual disabilities in the short-term (SMD = -1.09, p < 0.001 for risperidone; SMD = -0.64, p <0.001 for aripiprazole). However, there were significant side-effects including elevated prolactin levels (SMD = 3.22, p < 0.001) and weight gain (SMD = 0.82, p < 0.001). Evidence was inconclusive regarding the effectiveness of anticonvulsants and antioxidants for reducing challenging behaviour. The quality of all evidence was low and there were no long term follow up studies. CONCLUSIONS: Antipsychotic medications appear to be effective for reducing challenging behaviour in the short-term among children with intellectual disabilities, but they carry a risk of significant side effects. Findings from this review must be interpreted with caution as studies were typically of low quality and most outcomes were based on a small number of studies. Further long-term, high-quality research is needed to determine the effectiveness and safety of psychotropic medication for reducing challenging behaviour. PMID- 26611283 TI - Case reports: Plastic canal? PMID- 26611284 TI - Infection control: Removing the sensation. PMID- 26611285 TI - Smoking cessation: Out with the new and in with the old? PMID- 26611286 TI - Guidance: Lost in translation. PMID- 26611287 TI - Dental education: What are we going to do about it? PMID- 26611288 TI - Recognising the early stages of dementia through oral health. PMID- 26611291 TI - NHS England appoints Deputy Chief Dental Officers. PMID- 26611292 TI - Platform announces recommendations for EU-wide action on oral health. PMID- 26611293 TI - Dentists best in Britain at handling customer phone calls. PMID- 26611294 TI - BDA to GDC: Stop hoarding registrants' money. PMID- 26611295 TI - Dangers of swallowing dental instruments. PMID- 26611298 TI - Her Majesty The Queen to attend official ceremony for new Birmingham Dental Hospital and School of Dentistry. PMID- 26611299 TI - And finally... PMID- 26611300 TI - When David met Sara Part 2. PMID- 26611301 TI - A three dimensional view of stereopsis in dentistry. AB - Stereopsis and its role in dental practice has been a topic of debate in recent editions of this Journal. These discussions are particularly timely as they come at a point when virtual reality simulators are becoming increasingly popular in the education of tomorrow's dentists. The aim of this article is to discuss the lack of robust empirical evidence to ascertain the relationship (if any) between stereopsis and dentistry and to build a case for the need for further research to build a strong evidence base on the topic. PMID- 26611302 TI - Assessing root canal fillings on a radiograph--an overview. AB - This article will discuss why a root filling that appears satisfactory on a radiograph may fail, and why one which appears unsatisfactory on a radiograph may succeed. In doing so, this article will also discuss the criteria of endodontic success and failure and its implications on the decision to retreat. PMID- 26611303 TI - Patient attendance at a UK dental hospital emergency clinic. AB - A questionnaire survey was performed within a dental emergency clinic at a London teaching hospital to determine patients' reasons for attendance and satisfaction with their care. Questionnaires were distributed to all patients registering for the dental emergency clinic over a four week period. A total of 1,058 questionnaires were returned, with an average satisfaction score of 9.3/10. The majority of patients (58%) reported symptomatic dental attendance. Common reasons for irregular attendance were lack of perceived 'need' for care and concerns about cost of care. Patients with irregular attendance were significantly more likely to report their past dental care had been affected by cost than regular attenders. Fifty-one percent of all respondents had tried to make an appointment with a dentist prior to attending the emergency clinic, and 21% of patients with a GDP reporting difficulty accessing urgent care at their practice. Forty-nine percent of patients attending the emergency clinic were referred to oral surgery clinics. Overall, this survey revealed high levels of satisfaction with care in this dental emergency clinic. Patients' reasons for attendance at the clinic can be considered in terms of 'push' and 'pull' factors, deterring them from primary dental care and drawing them into secondary/tertiary care environments. PMID- 26611308 TI - Understanding emotionally relevant situations in primary dental practice. 3. Emerging narratives. AB - BACKGROUND AND AIMS: Dentists experience considerable occupational stress. Stressful clinical situations can provoke high levels of negative emotions, and situations which are associated with positive emotions tend to be overlooked by practitioners. Reflection regarding difficult situations is encouraged to facilitate learning. Cognitive behavioural therapy (CBT) formulations may be applied to situations appraised both positively and negatively. Analysis and interpretation of the dentist's coping behaviour and the consequent outcomes facilitate learning and reflection upon individual interactions with patients. METHOD: Twenty primary care dental practitioners in the greater Lincoln area participated in a semi-structured interview which explored their stressful and positive clinical experiences. Some of the episodes were analysed to create CBT formulations. RESULTS AND DISCUSSION: CBT formulations are presented and the learning points highlighted by this structured presentation are discussed. In particular, it is suggested that this structured reconstruction of events, which highlights dentists' emotions, responses and the transactional effects of coping responses, might well facilitate objective reflective learning either individually or as part of peer to peer support. It should facilitate dentists' emotional processing of events and may thus contribute to stress reduction. CONCLUSION: CBT formulations of positive and negative dental scenarios may be constructed. It is proposed that this is a useful technique to foster reflection and learning in clinical situations and should lead to improved communication skills and shared decision-making, resulting in fewer complaints and thereby reduced stress. It should also improve dentists' emotional processing. PMID- 26611309 TI - Explaining diet as a risk factor for periodontal disease in primary dental care. AB - AIMS AND OBJECTIVES: An audit was carried out to assess the delivery of dietary advice in general dental practice for patients diagnosed with chronic/aggressive periodontitis, with the objective of finding ways to deliver dietary advice and improve patient education on a potentially important modifiable risk factor. METHODOLOGY: Following a retrospective pilot sample, an initial sample of 50 patients (of dentists, a dental therapist and dental hygienist) was selected. The delivery of dietary advice and the method by which it was given was recorded as part of the data set. A semi-structured interview was also completed to discuss various aspects of delivering dietary advice. A staff meeting was carried out following the first cycle to raise awareness and inform on the link between diet and periodontal disease. Following this a second cycle was carried out to complete the audit cycle and the results were analysed. RESULTS: It was evident that following the first cycle dietary advice was not being given with respect to periodontal prevention. While the standard set was not met following re-audit there was significant improvement in the delivery of dietary advice as well as different ways to deliver the information. The feedback from the semi-structured interview suggested various obstacles in delivering dietary advice including lack of knowledge at first and also overloading patients with too much information initially. CONCLUSION: Using the entire dental team can be an effective way of educating our patients on risk factors for periodontal disease. It is important to note that this audit focused on clinicians delivering the advice and future direction should consider patient compliance and uptake of information. PMID- 26611310 TI - Characteristics of patients attending for cognitive behavioural therapy at one UK specialist unit for dental phobia and outcomes of treatment. AB - AIM: To describe the characteristics of patients attending a psychologist-led cognitive behavioural therapy (CBT) service for individuals with dental phobia and the outcomes of treatment. METHOD: Analysis of routinely collected assessment and outcome data from 130 patients attending a single secondary service providing CBT for dental phobia. FINDINGS: The patients comprised 99 women and 31 men, with an average age of 39.9 years (SD 14.8). Approximately 77% of the patients scored at levels suggestive of dental phobia on the Modified Dental Anxiety Scale (MDAS). Fear of dental injections and the dental drill were the most common high scoring items on the MDAS. Ninety four percent of patients reported one or more impacts of their mouth, teeth and gums on their life using the OHIP-14. A minority of patients had co-morbid psychological conditions - 36.9% had high levels of general anxiety and 12.3% had clinically significant levels of depression. Suicidal ideation was reported by 12% of patients and four (3%) reported recent intent to commit suicide. Of all patients referred 79% went on to have dental treatment without sedation and 6% had their dental treatment under sedation. The average number of CBT appointments required before a patient received dental treatment without sedation was five. CONCLUSIONS: CBT offers an effective technique for helping dentally anxious patients receive treatment without sedation. Those interested in running such services should be cognizant of the moderately high level of co-morbid psychological conditions in this group. PMID- 26611320 TI - Longitudinal Study of Cognitive Variables in Women with Schizophrenia: 31-Year Follow-Up Study. AB - OBJECTIVE: To longitudinally analyze the course of cognitive dimensions in schizophrenic women over a period of 31 years. METHOD: Accidental sampling. Developmental longitudinal design. Diagnosis according to the ICD-10. Thirty institutionalized women were evaluated using the WAIS on three separate occasions (in 1981, 1997, and 2012). The data were analyzed using a repeated measures split plot method. RESULTS: Patients scored one to two standard deviations below the average on the WAIS. At all three evaluation times, they scored consistently, significantly worse on Performance IQ scales than on Verbal IQ in the following sequence: Processing Speed (PS) < Perceptual Organization (PO) < Working Memory (WM) < Verbal Comprehension (VC). Longitudinally, there was a significant, linear average trend that was stable between the first and second assessments, with a significant drop in scores at the third evaluation on Performance IQ (eta2 = .586) and Verbal IQ scales (eta2 = .299). The same trend was observed in PS (eta2 = .655) and WM (eta2 = .438), while PO decreased across the three evaluations (eta2 = .509) and no difference in VC was found (eta2 = .126). CONCLUSION: Patients with schizophrenia presented with a low cognitive level. Longitudinally, they had a stable, differential profile of WAIS factors until late life, when performance dropped significantly. PMID- 26611321 TI - Deciphering conformational transitions of proteins by small angle X-ray scattering and normal mode analysis. AB - Structural flexibility and conformational rearrangements are often related to important functions of biological macromolecules, but the experimental characterization of such transitions with high-resolution techniques is challenging. At a lower resolution, small angle X-ray scattering (SAXS) can be used to obtain information on biomolecular shapes and transitions in solution. Here, we present SREFLEX, a hybrid modeling approach that uses normal mode analysis (NMA) to explore the conformational space of high-resolution models and refine the structure guided by the agreement with the experimental SAXS data. The method starts from a given conformation of the protein (which does not agree with the SAXS data). The structure is partitioned into pseudo-domains either using structural classification databases or automatically from the protein dynamics as predicted by the NMA. The algorithm proceeds hierarchically employing NMA to first probe large rearrangements and progresses into smaller and more localized movements. At the large rearrangements stage the pseudo-domains stay as rigid bodies allowing one to avoid structural disruptions inherent to the earlier NMA based algorithms. To validate the approach, we compiled a representative benchmark set of 88 conformational states known experimentally at high resolution. The performance of the algorithm is demonstrated in the simulated data on the benchmark set and also in a number of experimental examples. SREFLEX is included into the ATSAS program package freely available to the academic users, both for download and in the on-line mode. PMID- 26611323 TI - Photogenerated Intrinsic Free Carriers in Small-molecule Organic Semiconductors Visualized by Ultrafast Spectroscopy. AB - Confirmation of direct photogeneration of intrinsic delocalized free carriers in small-molecule organic semiconductors has been a long-sought but unsolved issue, which is of fundamental significance to its application in photo-electric devices. Although the excitonic description of photoexcitation in these materials has been widely accepted, this concept is challenged by recently reported phenomena. Here we report observation of direct delocalized free carrier generation upon interband photoexcitation in highly crystalline zinc phthalocyanine films prepared by the weak epitaxy growth method using ultrafast spectroscopy. Transient absorption spectra spanning the visible to mid-infrared region revealed the existence of short-lived free electrons and holes with a diffusion length estimated to cross at least 11 molecules along the pi-pi stacking direction that subsequently localize to form charge transfer excitons. The interband transition was evidenced by ultraviolet-visible absorption, photoluminescence and electroluminescence spectroscopy. Our results suggest that delocalized free carriers photogeneration can also be achieved in organic semiconductors when the molecules are packed properly. PMID- 26611322 TI - Genetic-deletion of Cyclooxygenase-2 Downstream Prostacyclin Synthase Suppresses Inflammatory Reactions but Facilitates Carcinogenesis, unlike Deletion of Microsomal Prostaglandin E Synthase-1. AB - Prostacyclin synthase (PGIS) and microsomal prostaglandin E synthase-1 (mPGES-1) are prostaglandin (PG) terminal synthases that function downstream of inducible cyclooxygenase (COX)-2 in the PGI2 and PGE2 biosynthetic pathways, respectively. mPGES-1 has been shown to be involved in various COX-2-related diseases such as inflammatory diseases and cancers, but it is not yet known how PGIS is involved in these COX-2-related diseases. Here, to clarify the pathophysiological role of PGIS, we investigated the phenotypes of PGIS and mPGES-1 individual knockout (KO) or double KO (DKO) mice. The results indicate that a thioglycollate-induced exudation of leukocytes into the peritoneal cavity was suppressed by the genetic deletion of PGIS. In the PGIS KO mice, lipopolysaccharide-primed pain nociception (as assessed by the acetic acid-induced writhing reaction) was also reduced. Both of these reactions were suppressed more effectively in the PGIS/mPGES-1 DKO mice than in the PGIS KO mice. On the other hand, unlike mPGES-1 deficiency (which suppressed azoxymethane-induced colon carcinogenesis), PGIS deficiency up regulated both aberrant crypt foci formation at the early stage of carcinogenesis and polyp formation at the late stage. These results indicate that PGIS and mPGES 1 cooperatively exacerbate inflammatory reactions but have opposing effects on carcinogenesis, and that PGIS-derived PGI2 has anti-carcinogenic effects. PMID- 26611324 TI - Dispensing and determinants of non-adherence to treatment for non complicated malaria caused by Plasmodium vivax and Plasmodium falciparum in high-risk municipalities in the Brazilian Amazon. AB - BACKGROUND: In Brazil, 99.7 % of malaria cases occur in the Amazon region. Although the number of cases is decreasing, the country accounted for almost 60 % of cases in the Americas Region, in 2013. Novel approaches for malaria treatment open the possibility of eliminating the disease, but suboptimal dispensing and lack of adherence influence treatment outcomes. The aim of this paper is to show the results on dispensing practices, non-adherence and determinants of non adherence to treatment of non-complicated malaria. METHODS: The study was conducted in six high-risk municipalities with Plasmodium vivax and Plasmodium falciparum transmission in the Brazilian Amazon and based on the theoretical framework of the Mafalda Project, which included investigation of dispensing and adherence. The World Health Organization Rapid Evaluation Method has been used to estimate sample size. Individuals over 15 years of age with malaria were approached at health facilities and invited to participate through informed consent. Data was collected in chart review forms focusing on diagnosis, Plasmodium type, prescribing, and dispensing (kind, quantity, labelling and procedures). Follow-up household interviews complemented data collection at health facility. Non-adherence was measured during the implementation phase, by self-reports and pill-counts. Analysis was descriptive and statistical tests were carried out. Determinants of non-adherence and quality of dispensing were assessed according to the literature. RESULTS: The study involved 165 patients. Dispensing was done according to the national guidelines. Labelling was adequate for P. vivax but inadequate for P. falciparum medicines. Non-adherent patients were 12.1 % according to self-reports and 21.8 % according to pill-counts. Results point to greater non-adherence among all P. falciparum patients and among malaria non-naive patients. More patients informed understanding adverse effects than 'how to use' anti-malarials. CONCLUSIONS: Non-adherent patients were mostly those with a P. falciparum diagnosis and those in their second or more malaria episode. New taxonomies and concepts on adherence stress the importance of focusing on the individual patient. Interventions targeted to and tailored for malaria patients must be addressed by health policy and implemented by managers and clinicians. PMID- 26611325 TI - Assembly of the MHC I peptide-loading complex determined by a conserved ionic lock-switch. AB - Salt bridges in lipid bilayers play a decisive role in the dynamic assembly and downstream signaling of the natural killer and T-cell receptors. Here, we describe the identification of an inter-subunit salt bridge in the membrane within yet another key component of the immune system, the peptide-loading complex (PLC). The PLC regulates cell surface presentation of self-antigens and antigenic peptides via molecules of the major histocompatibility complex class I. We demonstrate that a single salt bridge in the membrane between the transporter associated with antigen processing TAP and the MHC I-specific chaperone tapasin is essential for the assembly of the PLC and for efficient MHC I antigen presentation. Molecular modeling and all-atom molecular dynamics simulations suggest an ionic lock-switch mechanism for the binding of TAP to tapasin, in which an unfavorable uncompensated charge in the ER-membrane is prevented through complex formation. Our findings not only deepen the understanding of the interaction network within the PLC, but also provide evidence for a general interaction principle of dynamic multiprotein membrane complexes in immunity. PMID- 26611326 TI - Combined genetic variants of human cytomegalovirus envelope glycoproteins as congenital infection markers. AB - BACKGROUND: Human cytomegalovirus (HCMV) is still considered to be the main viral cause of birth defects and long-term neurological and sensory sequelae following congenital infection. Several Authors sustain a key role of HCMV envelope glycoproteins, such as gB, gN and gO - mainly involved in cell targeting, viral penetration and spread - as putative virulence factors. The genes coding for these glycoproteins possess hypervariable regions, resulting in a number of genetic variants in circulating clinical strains. Considering that the genetic polymorphisms underlying the specific differences between gB, gN and gO genotypes can influence the ability of HCMV to preferentially target specific host cells, it is very likely that they play an important role in defining HCMV infection outcome. In the present study, we analysed HCMV gB, gN and gO gene polymorphisms in viral strains isolated from paediatric patients with congenital or post-natal infection, to investigate whether specific genetic variants may be associated with congenital infection. METHODS: The restriction fragment polymorphisms of genes coding for HCMV gB (UL55), gN (UL73) and gO (UL74) were investigated by analysing viral DNA extracted from 40 urine samples of as many paediatric patients with congenital or post-natal HCMV infection. Randomly selected samples were subjected to DNA sequencing and phylogenetic analysis. Statistical analysis was performed using Fisher's exact test to assess the significance of single and combined glycoprotein genotypes frequency distribution. Statistical significance was considered at a P <0.05. RESULTS: While gB genomic variants were quite homogeneously represented in both paediatric groups, the gN4 genotype significantly prevailed in congenitally infected children (89.5 %) vs post natally infected children (47.6 %), with a predominance of the gN4c variant (47.4 %). A similar trend was observed for gO3 (52.6 % vs 19 %). Concerning genotypes association, a statistically significant (P = 0.037) gN4-gO3 combination was found specifically in the congenitally infected group. CONCLUSIONS: The results indicate that the gN4 (mostly the gN4c variant) and gO3 combined genotypes could provide useful markers of congenital infection and represent suitable candidate molecules for prophylactic vaccine preparations. PMID- 26611328 TI - Ultrasound elastography assessment of bone/soft tissue interface. AB - We report on the use of elastographic imaging techniques to assess the bone/soft tissue interface, a region that has not been previously investigated but may provide important information about fracture and bone healing. The performance of axial strain elastograms and axial shear strain elastograms at the bone/soft tissue interface was studied ex vivo on intact and fractured canine and ovine tibias. Selected ex vivo results were corroborated on intact sheep tibias in vivo. The elastography results were statistically analyzed using elastographic image quality tools. The results of this study demonstrate distinct patterns in the distribution of the normalized local axial strains and axial shear strains at the bone/soft tissue interface with respect to the background soft tissue. They also show that the relative strength and distribution of the elastographic parameters change in the presence of a fracture and depend on the degree of misalignment between the fracture fragments. Thus, elastographic imaging modalities might be used in the future to obtain information regarding the integrity of bones and to assess the severity of fractures, alignment of bone fragments as well as to follow bone healing. PMID- 26611327 TI - Collaborative cross mice in a genetic association study reveal new candidate genes for bone microarchitecture. AB - BACKGROUND: The microstructure of trabecular bone is a composite trait governed by a complex interaction of multiple genetic determinants. Identifying these genetic factors should significantly improve our ability to predict of osteoporosis and its associated risks. Genetic mapping using collaborative cross mice (CC), a genetically diverse recombinant inbred mouse reference panel, offers a powerful tool to identify causal loci at a resolution under one mega base pairs, with a relatively small cohort size. Here, we utilized 31 CC lines (160 mice of both sexes in total) to perform genome-wide haplotype mapping across 77,808 single-nucleotide polymorphisms (SNPs). Haplotype scans were refined by imputation with the catalogue of sequence variation segregating in the CC to suggest potential candidate genes. Trabecular traits were obtained following microtomographic analysis, performed on 10-MUm resolution scans of the femoral distal metaphysis. We measured the trabecular bone volume fraction (BV/TV), number (Tb.N), thickness (Tb.Th), and connectivity density (Conn.D). RESULTS: Heritability of these traits ranged from 0.6 to 0.7. In addition there was a significant (P < 0.01) sex effect in all traits except Tb.Th. Our haplotype scans yielded six quantitative trait loci (QTL) at 1 % false discovery rate; BV/TV and Tb.Th produced two proximal loci each, on chromosome 2 and 7, respectively, and Tb.N and Conn.D yielded one locus on chromosomes 8 and 14, respectively. We identified candidate genes with previously-reported functions in bone biology, and implicated unexpected genes whose function in bone biology has yet to be assigned. Based on the literature, among the genes that ranked particularly high in our analyses (P < 10(-6)) and which have a validated causal role in skeletal biology, are Avp, Oxt, B2m (associated with BV/TV), Cnot7 (with Tb.N), Pcsk6, Rgma (with Tb.Th), Rb1, and Cpb2 (with Conn.D). Other candidate genes strongly suggested by our analyses are Sgcz, Fgf20 (associated with Tb.N), and Chd2 (with Tb.Th). CONCLUSION: We have demonstrated for the first time genome-wide significant association between several genetic loci and trabecular microstructural parameters for genes with previously reported experimental observations, as well as proposing a role for new candidate genes with no previously characterized skeletal function. PMID- 26611329 TI - Jaminaea phylloscopi sp. nov. (Microstromatales), a basidiomycetous yeast isolated from migratory birds in the Mediterranean basin. AB - During a survey of yeasts vectored by migratory birds in the Mediterranean basin, isolations from the cloacae of members of the order Passeriformes collected in Ustica (Italy) were performed. Based on phylogenetic analysis of the D1/D2 domain of the 26S rRNA gene and the internal transcribed spacer ITS1-5.8S rRNA gene-ITS2 region, five yeast isolates clustered in a new lineage within the Microstromatales clade. The DNA sequences of these isolates differed from those of their closest relatives, Jaminaea angkorensis and Jaminaea lanaiensis, by 20 and 25 nt substitutions in the D1/D2 domain and 119 and 131 nt substitutions in the complete ITS region, respectively. In addition, the five isolates showed phenotypic characteristics not observed in their closest relatives, such as the ability to grow at 44 degrees C and at pH 2.5, which suggests a possible adaptation to the bird gastrointestinal tract. On the basis of the isolation source, phenotypic features and molecular strain typing carried out with randomly amplified polymorphic DNA (RAPD)-PCR and mini-satellite-primed (MSP)-PCR analysis, the five isolates were characterized as five distinct strains of a novel species formally described as Jaminaea phylloscopi sp. nov., with 551B6T ( = PYCC 6783T = CBS 14087T) as the type strain. The Mycobank accession number is MB811984. PMID- 26611330 TI - Hirschsprung's disease: A bridge for science and surgery. AB - BACKGROUND/PURPOSE: Understanding the true nature of the disease provided the basis for appropriate surgery for Hirschsprung's disease some 60 years ago. Nevertheless, surgical outcome remains unsatisfactory. Advances in diagnosis and treatment will depend on the elucidation of the pathogenesis and disease heterogeneity. METHODS: This lecture outlines the author's attempt in the past 30 years to bridge some of the gaps of knowledge in Hirschsprung's disease. RESULTS: Studies of human fetal gut and aganglionic gut gave insight into the complexity of the human enteric nervous system, but the more fruitful studies came from genetic studies in which disease-causing genes were discovered, and the importance of noncoding mutations conferring disease susceptibility was unraveled. Animal models and pluripotent stem cell studies allowed elucidation of the interacting gene-cell-microenvironment signaling pathways for neural crest proliferation, migration, and differentiation. CONCLUSION: Hirschsprung's disease has been a bridge for science and surgery. An integrative approach could provide breakthroughs in the diagnosis and treatment strategies of this complex condition, leading to improved outcome. PMID- 26611331 TI - Laparoscopic harvesting of omental pedicle flap for cerebral revascularization in children with moyamoya disease. AB - INTRODUCTION: An abundance of angiogenic and immunologic factors makes the omentum an ideal tissue for reconstruction and revascularization of a variety of extraperitoneal wounds and defects. Omental harvesting was historically performed through a large laparotomy and subcutaneous tunneling to the site of disease. Several complications of the open procedure including abdominal wound infection, fascial dehiscence, ventral hernia, and postoperative ileus have been described. The use of laparoscopy to harvest the omentum has the potential to reduce such complications. We describe the surgical technique and outcomes of a series of patients undergoing laparoscopic pedicled omental flap mobilization for cerebral revascularization in moyamoya disease. METHODS: A retrospective chart review of all patients undergoing laparoscopic omental cerebral transposition for moyamoya disease between 2011 and 2014 was performed. Clinical indication, surgical technique, operative times, complications, and outcomes at follow-up were reviewed. RESULTS: A total of 7 children underwent the procedure. The general surgery team performed laparoscopic omental mobilization, extraperitonealization, and subcutaneous tunneling, while the neurosurgical team performed craniotomy and cerebral application of the graft. The patients were followed postoperatively with clinic visits and angiography. There was one intraoperative complication (colon injury) and one postoperative complication (intermittent omental hernia at fascial defect for pedicle). All patients had partial to complete symptomatic resolution and demonstrated adequate intracranial revascularization on angiography. CONCLUSION: Laparoscopic omental pedicle flap mobilization and subcutaneous transposition is feasible in children who require salvage cerebral revascularization for moyamoya disease. The procedure should be considered for other conditions requiring extraperitoneal revascularization. PMID- 26611332 TI - Single-incision laparoscopic versus conventional laparoscopic surgery for Hirschsprung's disease: A comparison of medium-term outcomes. AB - INTRODUCTION: This study aims to report medium-term outcomes of single-incision laparoscopic surgery (SILS) and compare its results with conventional laparoscopic surgery (CLS). PATIENTS AND METHODS: Seventy-five patients with Hirschsprung's disease (HD) underwent operations from January 2009 to December 2012 in our institution (SILS, n=40; CLS, n=35). SILS procedure is similar to CLS, but uses a single, 1.5-cm horizontal skin incision in the umbilicus for laparoscopic access. Operative characteristics and medium-term outcomes were assessed. RESULTS: On average, patients in the SILS group had shorter operative times (mean+/-standard deviation, 226+/-69.4min) than those in the CLS group (268.9+/-83.6min) (P=0.01). Fourteen cases (35%) in the SILS group and ten cases (28.6%) in the CLS group had extended HD. Medium-term outcomes did not significantly differ between the groups, and the SILS group had better cosmetic results. CONCLUSIONS: SILS could be safely performed in HD patients with good medium-term outcomes. Although SILS and CLS procedures had similar medium-term outcomes, SILS has advantages such as better cosmetic results and shorter operative times. PMID- 26611333 TI - Medical training and public health budgets will be cut, Osborne confirms. PMID- 26611334 TI - Self-medication with steroids in inflammatory bowel disease. AB - BACKGROUND: The self-prescribing rates of corticosteroids in inflammatory bowel disease (IBD) patients treated with biologicals are unknown. AIM: To investigate the frequency and modalities of self-medication with steroids in adult IBD patients. METHODS: Patients with IBD who attended Nancy University Hospital between November 2012 and May 2013 were included in the study. Patients were interviewed using an 11 item questionnaire. RESULTS: 100 patients participated in the survey. In total 15 patients (15%) had already used corticosteroids without medical prescription since their IBD diagnosis and 4 patients of them (27%) used steroids as self-medication while on anti-TNF treatment. The mean total duration of corticosteroid treatment was 24 days (range 1.5-105). In total 4 patients (27%) used corticosteroids more than 10 times without medical prescription (range 1-20). The two main reasons were the need for quick relief of symptoms (n=6) and the unwillingness to consult a physician (n=3). CONCLUSION: A relatively high proportion of patients with IBD use corticosteroids without medical prescription. Due to their side effects, self-medication may include 'steroid dependency' as it may reflect uncontrolled disease. As steroids have significant side effects and patients may have active disease it is important to counsel patients and to monitor their self-prescribing patterns in IBD patients. PMID- 26611335 TI - Risk of hepatocellular carcinoma in relation to ABO blood type. AB - BACKGROUND: Mortality and incidence rates of hepatocellular carcinoma (HCC) parallel the geographical distribution of hepatitis B and C viruses among the general population, however genetic factors modulate individual cancer risk. AIMS: ABO blood type, as a genetic marker, has previously been associated with the risk of several malignancies; we aimed to evaluate whether an association exists with HCC. METHODS: This is a retrospective case-control study based on ABO distribution in 194 patients with HCC, compared with 215 decompensated cirrhotics without HCC listed for liver transplantation, and 90,322 healthy blood donors. RESULTS: In patients with HCC, prevalence of blood type O was 35%, vs. 44% in cirrhotics (OR: 0.67, 95% CI 0.45-0.99; p=0.046) and 45% in blood donors (OR: 0.65, 95% CI 0.48-0.88; p=0.004). CONCLUSIONS: ABO blood type non-O is associated with higher risk of hepatocellular carcinoma, compared to cirrhotics without HCC and healthy subjects. PMID- 26611336 TI - Challenges in Antimalarial Drug Treatment for Vivax Malaria Control. AB - Plasmodium vivax is the most widespread human malaria parasite, but has received much less attention than Plasmodium falciparum during the past 50 years of research. Plasmodium vivax was historically seen as causing only benign disease, but this view has recently changed, with increased recognition of the burden of vivax malaria, as well as numerous case reports of severe malaria or death caused by this parasite. The complexity of P. vivax biology is characteristic of specific features of the parasite, and recent years have seen major progress in our understanding of this complexity. In this review, we analyze the latest advances in the field, describing the constraints that the unique features of P. vivax place on drug treatments aimed at controlling or eliminating it. PMID- 26611337 TI - New Approaches to Biological Pacemakers: Links to Sinoatrial Node Development. AB - Irreversible degeneration of the cardiac conduction system is a common disease that can cause activity intolerance, fainting, and death. While electronic pacemakers provide effective treatment, alternative approaches are needed when long-term indwelling hardware is undesirable. Biological pacemakers comprise electrically active cells that functionally integrate with the heart. Recent findings on cardiac pacemaker cells (PCs) within the sinoatrial node (SAN), along with developments in stem cell technology, have opened a new era in biological pacing. Recent experiments that have derived PC-like cells from non-PCs have brought the field closer than ever before to biological pacemakers that can faithfully recapitulate SAN activity. In this review, I discuss these approaches in the context of SAN biology and address the potential for clinical translation. PMID- 26611338 TI - Hyaluronate lyase activity of Streptococcus suis serotype 2 and modulatory effects of hyaluronic acid on the bacterium's virulence properties. AB - BACKGROUND: Streptococcus suis serotype 2 is a major swine pathogen and zoonotic agent worldwide causing mainly meningitis and septicemia. Hyaluronate lyases are enzymes that degrade hyaluronic acid, a major constituent of animal tissues, and have been reported as virulence factors in various bacterial species. Since the hyaluronate lyase of S. suis has been considered ambiguously as a virulence factor, we screened 50 isolates from the three major clonal complexes found in North America (sequence type [ST] 1, ST25, and ST28) known to differ in their degree of virulence in order to link the presence or absence of this activity with the degree of virulence. Moreover, the effect of exogenous hyaluronic acid on S. suis virulence factor gene expression and the pro-inflammatory response of brain macrovascular endothelial cells (BMEC) was also investigated. RESULTS: We found that all but one ST1 isolates (high virulence) were devoid of hyaluronate lyase activity whereas all ST25 (intermediate virulence) and ST28 (low virulence) isolates possessed the activity. A 2 bp insertion was responsible for the lack of activity in ST1 strains. Since the most virulent isolates did not degrade hyaluronic acid, this tissue component may be found during the infectious process. Therefore, we investigated its effect on S. suis and host cells. Hyaluronic acid was found to modulate S. suis adhesion to BMEC, to increase S. suis virulence factor expression, and to enhance pro-inflammatory cytokine secretion by BMEC. CONCLUSIONS: These findings suggest that S. suis hyaluronate lyase does not represent a critical virulence factor in its active form. However, exogenous hyaluronic acid that is likely to interact with S. suis and host cells during the course of infection appears to modulate several virulence determinants of the bacterium, in addition to promote inflammation. PMID- 26611339 TI - Tympanostomy tube placement in awake, unrestrained pediatric patients: A prospective, multicenter study. AB - OBJECTIVES: Tympanostomy tube (tube) placement is the most common pediatric otolaryngologic surgery in the United States. Most surgeries are performed in an operating-room setting under general anesthesia due to the lack of tolerable and reliable local anesthesia methods suitable for pediatric patients, and concerns regarding myringotomy procedures in a mobile child. This study evaluated the safety and efficacy of an iontophoresis system (IPS) to achieve local anesthesia in combination with a tube delivery system (TDS) for tube placement in pediatric patients in an office setting. METHODS: A prospective, single-arm study was conducted at 9 otolaryngology sites in the United States. Participants included pediatric patients aged 6 months to less than 22 years requiring tube placement. Patients were prepared for the procedure using behavioral support techniques and tube placement was attempted under local anesthesia using the IPS in conjunction with the TDS. No physical restraints were allowed and no anxiolytics, analgesics, or sedatives were permitted. Safety was assessed through the occurrence of adverse events and success rates for tube placement under local anesthesia were determined. Tolerability of the procedure was evaluated using the 5-point Wong Baker FACES Pain Rating Scale and parental satisfaction was assessed using a postoperative survey. RESULTS: Seventy patients (127 ears) were enrolled in the study [mean (SD) age=7.0 (3.9) years]. No serious adverse events occurred in the 70 enrolled patients. Tube placement using the TDS was successful in 96.6% (114/118) of attempted ears. A single TDS was required in 105 ears, while more than 1 device was required in 9 ears. Of the 70 patients enrolled in study, 63 (90.0%) successfully received tubes in all indicated ears during their in-office visit. The mean (SD) change in pain score from pre-anesthesia to post-surgery was +0.9 (1.8). Favorable ratings for overall satisfaction with the in-office procedure were obtained from 96.9% (63/65) of respondents. Tube retention at 2 weeks was 99.1%. As only 15 patients were enrolled who were 3 years old or younger, the ability to generalize these results to younger patients is limited. CONCLUSIONS: In this study, use of the IPS and TDS technologies enabled safe, reliable, and tolerable placement of tubes in awake, unrestrained pediatric patients. PMID- 26611340 TI - Prevalence of hearing loss among primary school children in Mbarara, Uganda. AB - INTRODUCTION: Hearing loss in children is a common entity worldwide. We examined the prevalence and etiology of hearing loss among primary school children in Mbarara, Uganda. METHODS: Cross-sectional study in primary school children aged 5 14 was performed to determine the prevalence of hearing loss. Ugandan primary school children were screened for disabling hearing loss (threshold >30dB) and confirmatory audiometry was performed on those who failed the screening. RESULTS: There were 639 children screened. Thirty-five (5.5%) of children screened failed and were referred for further testing. Two children were lost to follow-up. The percentage of children with true hearing loss was 3.1%. CONCLUSIONS: The incidence of failed hearing screening and hearing loss in Mbarara, Uganda is similar to other populations. Hearing loss is a significant problem in Uganda and efforts should be made for primary, secondary, and tertiary prevention of hearing loss. PMID- 26611341 TI - Head and neck teratomas in children--A series of 23 cases at Great Ormond Street Hospital. AB - OBJECTIVE: Head and neck teratomas are rare and malignant change is rarer still. This is a report detailing all of the teratomas treated by the ear, nose and throat or craniofacial teams over the last 28 years at our institution. Examining the common presenting and radiological features as well as our success rates compared to the current literature. METHOD: A retrospective review of all cases presenting to our institution with a head and neck teratoma were analysed. Data regarding the following characteristics were collected: antenatal history, clinical features, biological serum makers, radiological and pathological characteristics. Surgical treatment, rates of reoccurrence and the degree of post operative follow up were also analysed. RESULTS: 23 cases in total were included: 8 cervical, 6 nasopharyngeal, 5 thyroid, 2 thymus, 2 temporal. One had malignant change. The majority of children presented at birth with respiratory distress, 5 cases were picked up antenatally and one case presented at 10 years of age. All were treated surgically; with complete excision in 20 patients. No clinical recurrence occurred but further surgery was performed for radiologically suspected residual disease in one case. DISCUSSION: This is the largest detailed case series in literature in regard to head and neck teratomas. Illustrating that this is frequently a benign disease process disease in the head and neck region and has an excellent long term prognosis following surgery. In the situation of incomplete resection careful meticulous follow up with radiological imaging and a multidisciplinary team approach is a safe and viable alternative. PMID- 26611342 TI - Auditory neuropathy spectrum disorder in hypomyelinating leukodystrophy--A case study. PMID- 26611343 TI - Video-otoscopy in children and patient-centered care: A randomized, controlled study. AB - OBJECTIVES: Medicine today is moving towards patient centered care and patient empowerment. This enhances patient autonomy, allows shared decision making and increases satisfaction. Current technology enables the caregiver to share visual data with the patients, making them more active participants in a medical encounter. It has been shown that higher patient satisfaction rate has a positive effect on outcome and patient compliance. Otoscopic examination is one of the most common procedures performed in the pediatric population. Video-otoscopy uses endoscopic technology to project the image of the tympanic membrane onto a monitor visible to both the physician and the patient. The objective of this study is to assess whether video-otoscopy used in a pediatric emergency department can improve patient-centeredness and parental satisfaction with treatment. METHODS: A randomized, controlled study comparing video-otoscopy with conventional otoscopy was performed. Patients were randomized into 2 groups. In one, ear examination was performed by video-otoscopy and in the other by conventional otoscopy. Following examination, parents in both groups were asked to fill a questionnaire regarding their satisfaction with the otoscopic examination and the patient-centeredness of the encounter. RESULTS: 60 children were recruited and were randomized into two groups: 30 in the video-otoscopy group and 30 in the conventional otoscopy group. Parental satisfaction was significantly higher in the video-otoscopy group. The level of patient centeredness was significantly higher in the video-otoscopy group. There was a positive correlation between patient-centeredness and parental satisfaction in both groups, with a significantly higher correlation in the video-otoscopy group. CONCLUSIONS: Video-otoscopy was found to encourage patient-centered care and increase parental satisfaction with otoscopy. There is a significantly higher positive correlation between patient-centeredness and parental satisfaction when video-otoscopy is used. PMID- 26611344 TI - Characterization of ClpS2, an essential adaptor protein for the cyanobacterium Synechococcus elongatus. AB - The adaptor protein ClpS associates to the Clp protease and promotes degradation of N-end rule substrates in eubacteria and in algal/plant chloroplasts. Cyanobacteria are unusual in having two distinct ClpS paralogs. Although ClpSl is typical of bacterial ClpS, ClpS2 differs in crucial ways. ClpS2 in Synechococcus elongatus is a relatively low-abundant, soluble protein essential for phototrophic growth. Like ClpSl, ClpS2 binds to the ClpCP3/R protease to block alpha-casein degradation and promote that of N-end rule substrates in vitro. However, their substrate specificity differs, with ClpSl recognizing destabilizing Phe and Tyr residues at the substrate N-terminus whereas ClpS2 recognizes Leu. Overall, ClpS2 appears to have independently evolved in cyanobacteria to degrade a particular group of proteins, whose turnover is vital for cell viability. PMID- 26611345 TI - Calcium ions inhibit reduction of heme a in bovine cytochrome c oxidase. AB - The effect of Ca(2+) on the rate of heme a reduction by dithionite and hexaammineruthenium (RuAm) was studied in the cyanide-complexed bovine cytochrome oxidase (CcO). The rate of heme a reduction is proportional to RuAm concentration below 300 MUM with kv of 0.53*10(6) M(-1) s(-1). Ca(2+) inhibits the rate of heme a reduction by dithionite by ~25%. As the reaction speeds up with increased concentrations of RuAm, the inhibition by Ca(2+) disappears. The inhibition of heme a reduction may contribute to recently described partial inhibition of CcO by Ca(2+) in the enzymatic assays. The inhibitory effect of Ca(2+) on heme a reduction indicates that ET through heme a may be coupled to proton movement in the exit part of the proton channel H. PMID- 26611346 TI - Mass spectrometry cancer data classification using wavelets and genetic algorithm. AB - This paper introduces a hybrid feature extraction method applied to mass spectrometry (MS) data for cancer classification. Haar wavelets are employed to transform MS data into orthogonal wavelet coefficients. The most prominent discriminant wavelets are then selected by genetic algorithm (GA) to form feature sets. The combination of wavelets and GA yields highly distinct feature sets that serve as inputs to classification algorithms. Experimental results show the robustness and significant dominance of the wavelet-GA against competitive methods. The proposed method therefore can be applied to cancer classification models that are useful as real clinical decision support systems for medical practitioners. PMID- 26611347 TI - Insights into the behavioral difference of water in the presence of GM1. AB - Studies on the structure and dynamics of interfacial water, emphasizing on the properties of water near the surface of biomolecules, are well reported, but there is a lack of evidence on the behavior of water near a comparatively rough surface containing molecules with a bulky head group like GM1. In this report we comparatively analyze the structure and dynamics of water as a function of distance from the lipid head group in GM1 containing lipid bilayers, with the lipid bilayers where GM1 is not present. This approach effectively demonstrates the behavioral difference and hence delayed convergence from bound water to bulk water in the presence of GM1 compared to a relatively smooth surface. PMID- 26611348 TI - Cancer and metabolism: Why should we care? PMID- 26611349 TI - A pre-modern and post-modern perspective of epigenetic inheritance. PMID- 26611351 TI - Molecular insights into the function of the viral RNA silencing suppressor HCPro. AB - Potyviral helper component proteinase (HCPro) is a well-characterized suppressor of antiviral RNA silencing, but its mechanism of action is not yet fully understood. In this study, we used affinity purification coupled with mass spectrometry to identify binding partners of HCPro in potyvirus-infected plant cells. This approach led to identification of various HCPro interactors, including two key enzymes of the methionine cycle, S-adenosyl-L-methionine synthase and S-adenosyl-L-homocysteine hydrolase. This finding, together with the results of enzymatic activity and gene knockdown experiments, suggests a mechanism in which HCPro complexes containing viral and host proteins act to suppress antiviral RNA silencing through local disruption of the methionine cycle. Another group of HCPro interactors identified in this study comprised ribosomal proteins. Immunoaffinity purification of ribosomes demonstrated that HCPro is associated with ribosomes in virus-infected cells. Furthermore, we show that HCPro and ARGONAUTE1 (AGO1), the core component of the RNA-induced silencing complex (RISC), interact with each other and are both associated with ribosomes in planta. These results, together with the fact that AGO1 association with ribosomes is a hallmark of RISC-mediated translational repression, suggest a second mechanism of HCPro action, whereby ribosome-associated multiprotein complexes containing HCPro relieve viral RNA translational repression through interaction with AGO1. PMID- 26611350 TI - Reprogramming the tumor microenvironment to enhance adoptive cellular therapy. AB - The frontiers of cancer immunotherapy are extending in terms of both the range of cancer types that can potentially be targeted and the types of therapeutics that are in clinical development. The use of adoptive cellular therapy (ACT) and its derivative, chimeric antigen receptor (CAR) T cells, is currently limited to hematological malignancies and immunogenic cancers such as melanoma and renal cell carcinoma. Although ACT utilizing ex vivo expanded tumor-infiltrating lymphocytes (TIL) or engineered CAR/TCR T cells have undergone clinical trials for other solid cancers, their efficacy to date has been limited. This may be due, in part, to the immunosuppressive nature of the tumor microenvironment. The development of novel combination approaches which target the immunosuppressive network engineered by tumors has raised the possibility of using ACT for a broader range of cancers. This review summarizes the potential of such strategies and outlines the clinical relevance of these observations. PMID- 26611353 TI - De novo DNM1 mutations in two cases of epileptic encephalopathy. AB - Dynamin 1 (DNM1) is a large guanosine triphosphatase involved in clathrin mediated endocytosis. In recent studies, de novo mutations in DNM1 have been identified in five individuals with epileptic encephalopathy. In this study, we report two patients with early onset epileptic encephalopathy possessing de novo DNM1 mutations. Using whole exome sequencing, we detected the novel mutation c.127G>A (p.Gly43Ser) in a patient with Lennox-Gastaut syndrome, and a recurrent mutation c.709C>T (p.Arg237Trp) in a patient with West syndrome. Structural consideration of DNM1 mutations revealed that both mutations would destabilize the G domain structure and impair nucleotide binding, dimer formation, and/or GTPase activity of the G domain. These and previous cases of DNM1 mutations were reviewed to verify the phenotypic spectrum. The main clinical features of DNM1 mutations include intractable seizures, intellectual disability, developmental delay, and hypotonia. Most cases showed development delay before the onset of seizures. A patient carrying p.Arg237Trp in this report showed a different developmental status from that of a previously reported case, together with characteristic extrapyramidal movement. PMID- 26611352 TI - Fast-scan cyclic voltammetry demonstrates that L-DOPA produces dose-dependent, regionally selective bimodal effects on striatal dopamine kinetics in vivo. AB - Parkinson's disease (PD) is a debilitating condition that is caused by a relatively specific degeneration of dopaminergic (DAergic) neurons of the substantia nigra pars compacta. L-DOPA was introduced as a viable treatment option for PD over 40 years ago and still remains the most common and effective therapy for PD. Though the effects of L-DOPA to augment striatal DA production are well known, little is actually known about how L-DOPA alters the kinetics of DA neurotransmission that contribute to its beneficial and adverse effects. In this study, we examined the effects of L-DOPA administration (50 mg/kg carbidopa + 0, 100, and 250 mg/kg L-DOPA) on regional electrically stimulated DA response kinetics using fast-scan cyclic voltammetry in anesthetized rats. We demonstrate that L-DOPA enhances DA release in both the dorsal striatum (D-STR) and nucleus accumbens (NAc), but surprisingly causes a delayed inhibition of release in the D STR. In both regions, L-DOPA progressively attenuated reuptake kinetics, predominantly through a decrease in Vmax . These findings have important implications on understanding the pharmacodynamics of L-DOPA, which may be informative for understanding its therapeutic effects and also common side effects like L-DOPA-induced dyskinesias (LID). L-DOPA is commonly used to treat Parkinsonian symptoms, but little is known about how it affects presynaptic DA neurotransmission. Using in vivo fast-scan cyclic voltammetry, we show L-DOPA inhibits DA reuptake in a region-specific and dose-dependent manner, and L-DOPA has paradoxical effects on release. These findings may be important when considering mechanisms for L-DOPA's therapeutic benefits and adverse side effects. PMID- 26611354 TI - Magnetic "Molecular Oligomers" Based on Decametallic Supertetrahedra: A Giant Mn49 Cuboctahedron and its Mn25Na4 Fragment. AB - Two nanosized Mn49 and Mn25Na4 clusters based on analogues of the high-spin (S=22) [Mn(III)6Mn(II)4(MU4-O)4](18+) supertetrahedral core are reported. Mn49 and Mn25Na4 complexes consist of eight and four decametallic supertetrahedral subunits, respectively, display high virtual symmetry (O(h)), and are unique examples of clusters based on a large number of tightly linked high nuclearity magnetic units. The complexes also have large spin ground-state values (Mn49: S=61/2; Mn25Na4: S=51/2) with the Mn49 cluster displaying single-molecule magnet (SMM) behavior and being the second largest reported homometallic SMM. PMID- 26611355 TI - Application of Linear and Branched Poly(Ethylene Glycol)-Poly(Lactide) Block Copolymers for the Preparation of Films and Solution Electrospun Meshes. AB - Poly(ethylene glycol)-poly(lactide) (PEG-PLA) block copolymers are processed to solvent cast films and solution electrospun meshes. The effect of polymer composition, architecture, and number of anchoring points for the plasticizer on swelling, degradation, and mechanical properties of these films and meshes is investigated as potential barrier device for the prevention of peritoneal adhesions. As a result, adequate properties are achieved for the massive films with a longer retention of the plasticizer PEG for star-shaped block copolymers than for the linear triblock copolymers and consequently more endurable mechanical properties during degradation. For electrospun meshes fabricated using the same polymers, similar trends are observed, but with an earlier start of fragmentation and lower tensile strengths. To overcome the poor mechanical strengths and an occurring shrinkage during incubation, which may impair the coverage of the wound, further adaptions of the meshes and the fabrication process are necessary. PMID- 26611356 TI - Combined Implantation of a Penile Prosthesis and Adjustable Continence Therapy ProACT in Patients with Erectile Dysfunction and Urinary Incontinence after Radical Prostatectomy: Results of a Prospective Pilot Study. AB - INTRODUCTION: The treatment of postradical prostatectomy erectile dysfunction (post-RP-ED) and stress urinary incontinence (post-RP-SUI) may require the combined implantation of a penile prosthesis and incontinence surgery. However, there is a lack of consensus regarding which incontinence surgery should be associated with a penile implant. AIMS: To evaluate the combined implantation of a penile prosthesis and the adjustable continence therapy ProACT in patients with post-RP-ED and post-RP-SUI. METHODS: We implanted the ProACT device and a penile prosthesis synchronously (n = 6) and asynchronously (n = 4) in 10 patients with moderate post-RP-SUI and severe post-RP-ED. We evaluated the effects on urinary incontinence using the ICIQ and PGI-I scores and pad use. We evaluated the effect on sexual function using the EHS and Global Assessment Questionnaire (GAQ), and we evaluated satisfaction with the penile prosthesis on a 5-point scale. Postoperative pain associated with each procedure was evaluated by a numeric rating scale. RESULTS: No cases of urinary retention or prosthesis infection were observed. Postoperative pain was mainly related to penile prosthesis implantation. After a mean follow-up of 22.7 +/- 20.9 months (range: 6-53), significant improvements of the ICIQ score (15.3 +/- 3.7 vs. 4.7 +/- 2.3, P < 0.001) and pad use per day (2.8 +/- 1.2 vs. 0.3 +/- 0.5, P < 0.001) were observed compared with baseline. According to the PGI-I questionnaire, eight patients described a very much improved (n = 6) or much improved (n = 2) urinary condition. All patients declared an EHS = 4 with the use of penile prosthesis; all patients were very satisfied (n = 6) or satisfied (n = 4) with their penile prosthesis. All patients answered the GAQ positively. CONCLUSION: The combined implantation of a Pro-ACT device and penile prosthesis represents a feasible therapeutic option in patients with post-RP-SUI and post-RP-ED. The absence of postoperative pain associated with the ProACT procedure may represent the main interest in this therapy. PMID- 26611357 TI - Percutaneous compressive bone tie for reduction of condylar phalangeal fractures. PMID- 26611359 TI - Autoubiquitination of TRIM26 links TBK1 to NEMO in RLR-mediated innate antiviral immune response. AB - The transcription factors IRF3 and NF-kappaB are required for the expression of many genes involved in antiviral innate immune response, including type I interferons (IFNs) and proinflammatory cytokines. It is well established that TBK1 is an essential kinase engaged downstream of multiple pattern-recognition receptors (PRRs) to mediate IRF3 phosphorylation and activation, whereas the precise mechanisms of TBK1 activation have not been fully elucidated yet. Here, we identified tripartite motif 26 (TRIM26) as an important regulator for RNA virus-triggered innate immune response. Knockdown of TRIM26 impaired virus triggered IRF3, NF-kappaB activation, IFN-beta induction, and cellular antiviral response. TRIM26 was physically associated with TBK1 independent of viral infection. As an E3 ligase, TRIM26 underwent autoubiquitination upon viral infection. Ubiquitinated TRIM26 subsequently associated with NEMO, thus bridging TBK1-NEMO interaction, which is critical for the recruitment of TBK1 to the VISA signalsome and activation of TBK1. Our findings suggest that TRIM26 is an important regulator of innate immune responses against RNA viruses, which functions by bridging TBK1 to NEMO and mediating the activation of TBK1. PMID- 26611358 TI - The quest for precision in transanal total mesorectal excision. AB - Transanal total mesorectal excision (TME) is an emerging minimally invasive approach to rectal cancer, with encouraging preliminary results. However, the new surgical anatomy of the bottom-up approach complicates surgical understanding and increases the risks of inadvertent injuries to crucial anatomical structures, including nerves. Key elements to improve the safety and stimulate interest in such a complex technique might be robotics and image guidance, to enhance the level of precision. In this editorial, some of the technologies that could be used for precision TME are outlined, in light of the experience of our Institute for Image-Guided Surgery. PMID- 26611360 TI - [Managing complications in invasive electrophysiology]. PMID- 26611362 TI - Do particular design features assist people with aphasia to comprehend text? An exploratory study. AB - BACKGROUND: Much of the evidence underlying guidelines for producing accessible information for people with aphasia focuses on client preference for particular design features. There is limited evidence regarding the effects of these features on comprehension. AIMS: To examine the effects of specific design features on text comprehension. It was hypothesized that font style, letter case and supporting images would all have a significant impact on people with aphasias' ability to comprehend text. METHODS & PROCEDURES: Participants (N = 9) read 35 paragraphs and selected the most appropriate word or phrase from a choice of four to finish the final sentence. Reading comprehension was assessed in three conditions: font style, letter case and text with a supporting image. One-way analyses of variance (ANOVAs) with Bonferroni post-hoc tests were used to test the effect of each design feature on reading comprehension. OUTCOMES & RESULTS: People with aphasia comprehended significantly more written information when presented in sans-serif font than in a serif style (p = .01) and when presented in lower case than in upper case (p = .03). The inclusion of a single supporting image to illustrate a paragraph of text did not have a significant effect on comprehension. CONCLUSIONS & IMPLICATIONS: This research supports the premise that font style and letter case have a significant effect on text comprehension, but that illustrating a paragraph of text with a single image may not significantly improve comprehension when text is written at a low readability level. Although it is critical to produce accessible information, improving comprehension is only one rationale for modified text presentation and therefore these results must be viewed in the context of other recommendations. PMID- 26611361 TI - The Impact of Stigma and Social Support on Development of Post-traumatic Growth Among Persons Living with HIV. AB - Given high rates of trauma in people living with HIV (PLH) and the health benefits of posttraumatic growth (PTG), understanding how to foster PTG in PLH exposed to trauma could be of interest to clinical psychologists working with this population. The current study examined factors theoretically related to development of PTG in PLH, namely HIV-related stigma, disclosure of HIV status, and emotional support. A sample of 334 HIV-positive adults answered a battery of self-report questionnaires. HIV-related stigma, disclosure to sexual partners, and emotional support were significant predictors of PTG: stigma was associated with lower PTG, whereas disclosure and emotional support were associated with higher PTG. Disclosure and emotional support remained significantly associated with PTG in the model including demographic factors and stigma. These findings highlight the need for development of interventions that can aid PLH in disclosing their HIV status to sexual partners and increasing available social support. PMID- 26611363 TI - Correction of a mobile posttraumatic kyphosis in the thoracolumbar spine with a combined posterior-anterior approach. PMID- 26611364 TI - Morphological studies of cartilage endplates in subaxial cervical region. AB - PURPOSE: The aim of this study was to provide morphological data of endplates for the redesign of cervical artificial disc for use in the middle and lower cervical spine (C3-C7). METHODS: Reformatted CT scans of 73 individuals were analysed. The shapes of superior endplates (SEPs) and inferior endplates (IEPs) were classified as either flat or arced. The curvature radius of the IEP and sagittal disc angle were measured in the mid-sagittal plane. The maximum transverse diameter (MTD) of the SEPs and IEP was measured in the coronal plane. RESULTS: The majority of SEPs were flat (79.5 % at C7 and 91.8-95.9 % at C3-C6). Almost all (98.6-100 %) IEPs were arced. The curvature radius has a gradually increasing trend from C3 to C6 (P < 0.05, mean 29.26 mm). There were significant differences at C3-C7 in the average sagittal disc angles (5.80 degrees , 6.92 degrees , 7.51 degrees , and 8.82 degrees , respectively; P < 0.05; mean 7.26 degrees ), the average MTDs of the SEPs (13.64, 14.42, 15.03, and 16.74 mm, respectively, P < 0.05; mean 14.96 mm) and the average MTD of the IEPs (16.77, 17.67, 19.15, and 21.66 mm, respectively; P < 0.05; mean 18.81 mm). CONCLUSION: The majority of SEPs were flat, while almost all IEPs were curved. The curvature radius of IEPs has a gradually increasing trend from C3 to C6. The average sagittal disc angles, MTDs of the SEPs and IEPs significantly increased from C3 to C7. Based on the above, the current cervical artificial disc design does not sufficiently match the morphology of cervical endplates (CEPs). This mismatch may lead to some postoperative complications of cervical disc arthroplasty. PMID- 26611365 TI - Melatonin administration induced reactivation in the seminal gland of the soay rams during non-breeding season: An ultrastructural and morphometrical study. AB - Fifteen adult Soay rams were used in this experiment. Eight animals were given subcutaneous implants containing melatonin, while the other seven animals were used as control. After 11 weeks, the rams were killed and the seminal vesicles were examined by light and electron microscope. In contrast to the control grouped animals, the melatonin treated rams showed morphological, morphometrical, and ultrastructural changes as a result of reactivation of the glandular tissues of the seminal glands. The ratio of interstitial connective tissues to glandular tissues was reduced in the treated group. Melatonin induced an evident significant increase in number and height of principal cells that showed signs of increased secretory activity; apical cytoplasmic protrusions became well developed and covering the inner surface of the glandular end-pieces, also, the basal cells were significantly increased in number. The main cytological alteration in the principal cells of the seminal vesicles in treated animals was prominent increase in the concentrically arranged membranes of sER, secretory vacuoles and glycogen granules and appearance of numerous lysosomes and multivesicular bodies. Interstitial Cajal- like cells were significantly increased in number and formed a network around the epithelium and between smooth muscle cells in the treated group. The main components of these cells were mitochondria, rER, sER, and many caveolae. The cytological alterations were accompanied by subepithelial and intraepithelial nonmyelinated nerve terminals in the treated animals. The results support the view that melatonin activates and increases the secretory activity of seminal gland in sheep. PMID- 26611366 TI - Influence of Oxynitrided Surface in the Production of a Less Susceptible Titanium Surface to Skin-Borne Bacterial Adhesion. AB - There is a growing quest for an ideal biomaterial that shows appropriate cellular response and is not susceptible to microbial adhesion. In this study, commercial grade II titanium was submitted to RF/DC plasma surface modification at 2.2 mbar, using gas mixtures of argon, nitrogen, and oxygen at proportions 4:1:2 and 4:1:3. The surfaces were physically and chemically characterized. In order to evaluate bacterial response, the surfaces were exposed to Staphylococcus epidermidis. Oxynitrided samples, although having a higher roughness as compared with untreated samples, exhibited lower bacterial growth. This observation is probably due to the formation of different crystalline phases of nitrides and oxides caused by plasma treatment. The surface with highest contact angle and highest surface tension showed lower bacterial adhesion. These results were confirmed by scanning electron microscopy. The role of nitrogen in reducing bacterial adhesion is clear when this material is compared with untreated titanium, on which only an oxide film is present. PMID- 26611367 TI - Nanosilver and Nano Zero-Valent Iron Exposure Affects Nutrient Exchange Across the Sediment-Water Interface. AB - To examine how nanoparticles influence biogeochemical cycles in streams, we studied the acute impact of nanosilver (nAg) and nanoparticulate zero-valent iron (nZVI) exposure on nutrient and oxygen exchange across the sediment-water interface of two streams (agricultural canal and wetland) that differed in their water quality and sediment characteristics. At the agricultural site, nAg increased oxygen consumption and decreased N2 flux rates from that observed in control incubations. nZVI caused sediment-water systems from both streams to go hypoxic within 1.5 h of exposure. N2 flux rates were at least an order of magnitude higher in nZVI treatments as compared to control. Water column nitrate and nitrite concentrations were not impacted by nZVI exposure but total dissolved phosphorus concentrations were higher in cores treated with nZVI. nAg and nZVI exposure to surface water ecosystems can disrupt ecological function across the sediment-water interface. PMID- 26611368 TI - Groundwater Molybdenum from Emerging Industries in Taiwan. AB - This study determined the influence of emerging industries development on molybdenum (Mo) groundwater contamination. A total of 537 groundwater samples were collected for Mo determination, including 295 samples from potentially contaminated areas of 3 industrial parks in Taiwan and 242 samples from non potentially contaminated areas during 2008-2014. Most of the high Mo samples are located downstream from a thin film transistor-liquid crystal display (TFT-LCD) panel factory. Mean groundwater Mo concentrations from potentially contaminated areas (0.0058 mg/L) were significantly higher (p < 0.05) than those from non potentially contaminated areas (0.0022 mg/L). The highest Mo wastewater concentrations in the effluent from the optoelectronics industry and following wastewater batch treatment were 0.788 and 0.0326 mg/L, respectively. This indicates that wastewater containing Mo is a possible source of both groundwater and surface water contamination. Nine samples of groundwater exceed the World Health Organization's suggested drinking water guideline of 0.07 mg/L. A non carcinogenic risk assessment for Mo in adults and children using the Mo concentration of 0.07 mg/L yielded risks of 0.546 and 0.215, respectively. These results indicate the importance of the development of a national drinking water quality standard for Mo in Taiwan to ensure safe groundwater for use. According to the human health risk calculation, the groundwater Mo standard is suggested as 0.07 mg/L. Reduction the discharge of Mo-contaminated wastewater from factories in the industrial parks is also the important task in the future. PMID- 26611369 TI - Evaluation of Inhibition Efficiency for the Detection of Captan, 2,3,7,8 Tetrachlorodibenzodioxin, Pentachlorophenol and Carbosulfan in Water: An Electrochemical Approach. AB - A novel bio-analytical method has been devised based on the change in catalytic activity of acetylcholinesterase (AChE) enzyme induced by captan, carbosulfan, 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and pentachlorophenol (PCP) for the investigation of inhibition efficiency and sensitivity using Pt/ZnO/AChE/Chitosan bioelectrode. The inhibition curves of captan, carbosulfan, TCDD and PCP were similar to Michaelis-Menten curve. TCDD held the minimum inhibitor Michaelis Menten constant ([Formula: see text]) value (10.2 nM) in comparison with PCP (10.9 nM), carbosulfan (14.5 nM) and captan (7.9 * 10(3) nM). The maximum inhibition of AChE enzyme by captan was about 100 %, which was much higher than that of TCDD (72.7 %), PCP (68.1 %) and carbosulfan (47.7 %). The calculated theoretical sensitivity was in the order of TCDD > PCP > carbosulfan > captan. Comparing with TCDD (35.3 %), PCP (47.8 %) and carbosulfan (20.9 %), only the inhibition efficiency of captan (55.0 %) was the maximum. The developed bioelectrode exhibited high recovery and low relative standard deviation in local tap water samples. PMID- 26611370 TI - Cylindroxanthones A-C, three new xanthones and their cytotoxicity from the stem bark of Garcinia cylindrocarpa. AB - Three new xanthones, cylindroxanthones A-C (1-3), were isolated from the stem bark of Garcinia cylindrocarpa. The structures were established on the basis of spectroscopic analysis. The molecular structure of 1 was unequivocally confirmed by single-crystal X-ray diffraction analysis. These three xanthones were evaluated regarding their cytotoxicity against KB, HeLa S-3, HT-29, MCF-7, and Hep G2 cancer cell lines. Compound 1 exhibited good cytotoxicity against KB cell with IC50 value of 2.36 MUM. PMID- 26611371 TI - New clerodane diterpenoids from Croton crassifolius. AB - Two new clerodane diterpenoids (1-2), one new clerodane diterpenoid alkaloid (3), as well as thirteen known compounds were isolated from Croton crassifolius. The structures of new compounds were established by a combination of spectroscopic methods, including HRMS, (1)H NMR, (13)C NMR, (1)H (1)H COSY, HSQC, HMBC, NOESY and X-ray crystallographic analysis. Compound 3 is firstly reported as the clerodane-type diterpenoid alkaloid in natural products. All of the compounds were evaluated for in vitro cytotoxic activities against CT26.WT cell using the MTT method. PMID- 26611372 TI - Untargeted Metabolic Profiling of Winery-Derived Biomass Waste Degradation by Penicillium chrysogenum. AB - Winery-derived biomass waste was degraded by Penicillium chrysogenum under solid state fermentation over 8 days in a (2)H2O-supplemented medium. Multivariate statistical analysis of the gas chromatography-mass spectrometry (GC-MS) data resulted in the identification of 94 significant metabolites, within 28 different metabolic pathways. The majority of biomass sugars were utilized by day 4 to yield products such as sugars, fatty acids, isoprenoids, and amino acids. The fungus was observed to metabolize xylose to xylitol, an intermediate of ethanol production. However, enzyme inhibition and autolysis were observed from day 6, indicating 5 days as the optimal time for fermentation. P. chrysogenum displayed metabolism of pentoses (to alcohols) and degraded tannins and lignins, properties that are lacking in other biomass-degrading ascomycetes. Rapid fermentation (3-5 days) may not only increase the pentose metabolizing efficiency but also increase the yield of medicinally important metabolites, such as syringate. PMID- 26611373 TI - Are Oral and Maxillofacial Surgery Residents Trained Adequately in Alloplastic Total Temporomandibular Joint Replacement? AB - PURPOSE: To assess the current level of experience and training that oral and maxillofacial surgery (OMS) residents receive in alloplastic temporomandibular joint (TMJ) total joint replacement (TJR) at OMS training programs in the United States. MATERIALS AND METHODS: A questionnaire was developed using REDCap (Chicago, IL), and an on-line link was emailed to the program directors of all 101 OMS training programs in the United States accredited by the Commission on Dental Accreditation. The questionnaire included 20 questions related to the program's alloplastic TMJ TJR curriculum and clinical experience. In addition, a Likert scale was used to assess the respondents' opinions on resident training and the future of alloplastic TMJ TJR education and its clinical effect and usage. RESULTS: The study sample included 53 respondents (52.5%). Of the 53 responding OMS programs, 94% provide TMJ TJR didactic lectures presented by OMS faculty. The alloplastic TMJ TJR procedures averaged 0 to 6 annually per program; however, 25% of the programs reported more than 10 cases annually. Infection and continued pain were reported as the most common reasons for alloplastic TMJ TJR device replacement. CONCLUSIONS: It appears that adequate didactic and clinical training is being provided to OMS residents in alloplastic TMJ TJR during their training. Additional studies might elucidate the actual geographic distribution of OMS surgeons who perform alloplastic TMJ TJR procedures. PMID- 26611374 TI - Applications of Cone-Beam Computed Tomography in Oral and Maxillofacial Surgery: An Overview of Published Indications and Clinical Usage in United States Academic Centers and Oral and Maxillofacial Surgery Practices. AB - PURPOSE: The American Association of Oral and Maxillofacial Surgeons appointed a task force to study the indications, safety, and clinical practice patterns of cone-beam computed tomography (CBCT) in oral and maxillofacial surgery (OMS). The charge was to review the published applications of CBCT in OMS, identify the current position of academic thought leaders in the field, and research the adoption and usage of the technology at the clinical practitioner level. MATERIALS AND METHODS: This study reviewed the CBCT world literature and summarized published indications for the modality. A nationwide survey of academic thought leaders and practicing oral and maxillofacial surgeons was compiled to determine how the modality is currently being used and adopted by institutions and practices. RESULTS: This report summarizes published applications of CBCT that have been vetted by the academic and practicing OMS community to define current indications. The parameters of patient safety, radiation exposure, accreditation, and legal issues are reviewed. An overview of third-party adoption of CBCT is presented. CONCLUSION: CBCT is displacing 2 dimensional imaging in the published literature, academia, and private practice. Best practices support reading the entire scan volume with a written report defining results, patient exposure, and field of view. Issues of patient safety, ALARA ("as low as reasonably achievable"), accreditation, and the legal and regulatory environment are reviewed. Third-party patterns for reimbursements vary widely and seem to lack consistency. There is much confusion within the provider community about indications, authorizations, and payment policies. The current medical and dental indications for CBCT in the clinical practice of OMS are reviewed and an industry guideline is proposed. These guidelines offer a clear way of differentiating consensus medical indications and common dental uses for clinicians. This matrix should bring a predictable logic to third-party authorizations, billing, and predictable payments for this emerging technology in OMS. PMID- 26611375 TI - Applications of 3-Dimensional Printing in Facial Plastic Surgery. PMID- 26611376 TI - Neutron Beam Radiation Therapy: An Overview of Treatment and Oral Complications When Treating Salivary Gland Malignancies. AB - PURPOSE: There is limited information in the literature regarding the oral complications of neutron radiotherapy, with an associated lack of guidelines for their management. The purpose of this study was to review the indications, dosing, prognosis, and oral complications of neutron radiotherapy for salivary gland malignancies. MATERIALS AND METHODS: This is a retrospective case series of patients with salivary gland malignancies treated with neutron radiotherapy by the Radiation Oncology Department at the University of Washington from 1997 to 2006. Variables included patient demographics, tumor staging and characteristics, operative treatment, final diagnosis, operative and pathologic findings (ie, perineural invasion, lymph node involvement, and skull base invasion), dosing, complications, and locoregional control and survival rates. Data were extracted from patients' charts and by telephone for follow-up and quality-of-life information. RESULTS: The sample was composed of 140 patients (49% men, 51% women) with a mean age of 53 years (standard deviation, 15 yr). Adenoid cystic carcinoma of the submandibular gland was the most common tumor type and location. Post-treatment trismus occurred in 56%. Acute mucositis and xerostomia occurred in approximately 88 and 89% of patients, respectively. Osteoradionecrosis was reported in 5.7% of patients. The 6-year survival rate was 58% and the 6-year locoregional control was 72%. The current standard neutron dose for head and neck tumors is 1.15 neutron Gray (nGy) 4 times per week for 4 weeks (total, 18.4 nGy), which is an equivalent amount of radiation as the standard 60 to 70 Gy given for 6 to 7 weeks with conventional photon radiation. CONCLUSION: The 6-year overall survival of 58% found in this study compares favorably to the survival rate reported in the literature for traditional photon radiation treatment of advanced salivary gland tumors. The dental profession should be educated regarding neutron radiotherapy and its indications, dosing methods, and oral complications. PMID- 26611377 TI - A rational approach to single, dual and triple therapy in COPD. AB - The complexity of COPD treatment has increased over the last 5 years mainly because of the proliferation of drugs and delivery devices. In this paper, we will focus on currently available therapy used for maintaining patient well-being rather than acute relief of symptoms. We propose a series of principles for rational therapy, and following a review of how currently available treatments perform in isolation and when compared with each other, we suggest an approach to aid the rational selection of the most appropriate treatment based on current evidence. PMID- 26611378 TI - Erythrocyte and platelet proteomics in hematological disorders. AB - Erythrocytes undergo ineffective erythropoesis, hemolysis, and premature eryptosis in sickle cell disease and thalassemia. Abnormal hemoglobin variants associated with hemoglobinopathy lead to vesiculation, membrane instability, and loss of membrane asymmetry with exposal of phosphatidylserine. This potentiates thrombin generation resulting in activation of the coagulation cascade responsible for subclinical phenotypes. Platelet activation also results in the release of microparticles, which express and transfer functional receptors from platelet membrane, playing key roles in vascular reactivity and activation of intracellular signaling pathways. Over the last decade, proteomics had proven to be an important field of research in studies of blood and blood diseases. Blood cells and its fluidic components have been proven to be easy systems for studying differential expressions of proteins in hematological diseases encompassing hemoglobinopathies, different types of anemias, myeloproliferative disorders, and coagulopathies. Proteomic studies of erythrocytes and platelets reported from several groups have highlighted various factors that intersect the signaling networks in these anucleate systems. In this review, we have elaborated on the current scenario of anucleate blood cell proteomes in normal and diseased individuals and the cross-talk between the two major constituent cell types of circulating blood. PMID- 26611379 TI - CHILD syndrome with minimal limb abnormalities. PMID- 26611380 TI - HIV, highly active antiretroviral therapy and the heart: a cellular to epidemiological review. AB - The advent of potent highly active antiretroviral therapy (HAART) for persons infected with HIV-1 has led to a "new" chronic disease with complications including cardiovascular disease (CVD). CVD is a significant cause of morbidity and mortality in persons with HIV infection. In addition to traditional risk factors such as smoking, hypertension, insulin resistance and dyslipidaemia, infection with HIV is an independent risk factor for CVD. This review summarizes: (1) the vascular and nonvascular cardiac manifestations of HIV infection; (2) cardiometabolic effects of HAART; (3) atherosclerotic cardiovascular disease (ASCVD) risk assessment, prevention and treatment in persons with HIV-1 infection. PMID- 26611381 TI - Impact of bronchoalveolar lavage multiplex polymerase chain reaction on microbiological yield and therapeutic decisions in severe pneumonia in intensive care unit. AB - PURPOSE: The purpose of the study is to evaluate the impact of adding bronchoalveolar lavage multiplex polymerase chain reaction (M-PCR) to conventional cultures (CC) on microbiological yield and therapeutic decisions in adult intensive care unit patients with pneumonia and severe sepsis or septic shock. MATERIAL AND METHODS: In this retrospective case-control study, bronchoalveolar lavage cultures were taken for control (58 patients, 58 admissions) and study arms (57 patients, 58 admissions). Bronchoalveolar lavage M PCR was sent simultaneously for the latter. RESULTS: A total of 267 microorganisms were identified (M-PCR alone, 211; CC alone, 15; both, 41) in the study arm vs 64 in controls. Concordance between M-PCR and culture was complete in 32 (55.17%), partial in 4 (6.9%), and discordant in 22 (37.93%) including 17 with positive M-PCR but negative CC. Time to antibiotic therapy modification was significantly less (P < .001) in M-PCR group compared to controls (32.40 +/- 14.41 vs 41.74 +/- 45.61 hours). There was no significant difference in index episode resolution (48.3% vs 50%; P = 1), intensive care unit mortality (57.4% vs 51.2%; P = .67), and hospital mortality (59.6% vs 61.5%; P = 1) in study and control arms, respectively, despite more septic shock patients in the study arm (89.7% vs 75.9%; P = .05). CONCLUSION: Bronchoalveolar lavage M-PCR with culture leads to higher microbiological yield and earlier modification of antibiotics compared to conventional culture. PMID- 26611383 TI - Pain and Hand Function. AB - Pain is a unique somatosensory perception that can dramatically affect our ability to function. It is also a necessary perception, without which we would do irreparable damage to ourselves. In this article, the authors assess the impact of pain on function of the hand. Pain can be categorized into acute pain, chronic pain, and neuropathic pain. Hand function and objective measurements of hand function are analyzed as well as the impact of different types of pain on each of these areas. PMID- 26611382 TI - Risk factors for mortality despite early protocolized resuscitation for severe sepsis and septic shock in the emergency department. AB - PURPOSE: The purpose was to identify risk factors associated with in-hospital mortality among emergency department (ED) patients with severe sepsis and septic shock managed with early protocolized resuscitation. METHODS: This was a retrospective, observational cohort study in an academic, tertiary care ED. We enrolled 411 adult patients with severe sepsis and lactate >=4.0 mmol/L (n = 203) or septic shock (n = 208) who received protocolized resuscitation from 2005 to 2009. Emergency department variables, microbial cultures, and in-hospital outcomes were obtained from the medical record. Multivariable regression was used to identify factors independently associated with in-hospital mortality. RESULTS: Mean age was 59.5 +/- 16.3 years; 57% were male. Mean lactate was 4.8 mmol/L (3.5 6.7), 54% had positive cultures, and 27% received vasopressors in the ED. One hundred and five (26%) patients died in-hospital. Age, active cancer, do-not resuscitate status on ED arrival, lack of fever, hypoglycemia, and intubation were independently associated with increased in-hospital mortality. Lactate clearance and diabetes were associated with a decreased risk of in-hospital death. CONCLUSIONS: We identified a number of factors that were associated with in-hospital mortality among ED patients with severe sepsis or septic shock despite treatment with early protocolized resuscitation. These findings provide insights into aspects of early sepsis care that can be targets for future intervention. PMID- 26611384 TI - Self-Report Measures of Hand Pain Intensity: Current Evidence and Recommendations. AB - Successful management of problems related to the hands and upper extremities begins with a comprehensive assessment of the pain experience and related factors. Pain intensity is the domain most commonly assessed, and pain relief is often the primary goal of treatment. Because pain is a private and subjective experience, self-report is considered the gold standard of pain measurement. This article describes and discusses the strengths and weaknesses of the most commonly used self-report scales used to measure hand pain intensity, and gives recommendations to help clinicians select from among the various options for measuring the intensity of hand pain. PMID- 26611385 TI - Pain Examination and Diagnosis. AB - Pain is a clinical challenge to health care providers who care for hand disorders. Pathologic pain that prevents recovery leads to dissatisfaction for both patients and providers. Despite pain being common, the root cause is often difficult to diagnose. This article reviews the examination and diagnostic tools that are helpful in identifying pathologic and neuropathic pain. This article provides tools to speed recognition of these processes to allow earlier intervention and better patient outcomes. PMID- 26611386 TI - Factors Associated with Greater Pain Intensity. AB - The intensity of pain reported for a given nociception is highly variable. Variation in pain intensity is best accounted for by stress, distress, and ineffective coping strategies. Among orthopedic surgery patients, greater intake of opioids is associated with greater pain intensity and decreased satisfaction with pain control, no matter the pathophysiology or nociception. The single most effective pain reliever is self-efficacy (the sense that one can manage and that everything will be okay). PMID- 26611387 TI - Pain Psychology and Pain Catastrophizing in the Perioperative Setting: A Review of Impacts, Interventions, and Unmet Needs. AB - This article provides a brief overview of the literature on perioperative pain psychology in terms of relevant factors and treatments. Where possible, the content emphasizes hand surgery or hand trauma populations, although this literature is notably limited, as well as the relevant musculoskeletal surgery literature. In addition, gaps in understanding and patient care are identified and discussed. PMID- 26611389 TI - Pharmacologic Management of Upper Extremity Chronic Nerve Pain. AB - The treatment of pain is a complex process that requires a team approach. This article provides an overview of the pharmaceutical treatments available. It gives providers treating upper extremity disorders more tools to treat their patients with chronic pain. Another goal is to improve hand providers' understanding of the medications their pain colleagues prescribe in shared patients. Pharmaceuticals are an important component in the treatment of chronic pain and opioids are often not a good solution. Knowing what other medications are available can improve the care for these challenging patients. PMID- 26611390 TI - Hand Therapy Treatment. AB - Clinical pain is multifactorial. It is not simply the consequences of a "switching on" of the pain system in the periphery, but also excitability of central nociceptive areas. For pain management to be successful in treating the upper extremity both the peripheral and central symptoms must be targeted. The patient education process must ensure that patients understand their symptoms and treatment program. This article discusses recent advancements in the neuroscience of pain that impact evolving strategies to identify and treat the pain mechanisms. PMID- 26611391 TI - Surgical Treatment of Upper Extremity Pain. AB - If the patient with hand pain remains without significant relief and without recovery of function after appropriate pharmaceutical and physical modality treatments, it is appropriate to consider a surgical approach to the pain. Categories of pain amenable to a surgical approach are pain caused by nerve compression, pain caused by a neuroma, and joint pain of neural origin. Compressed nerve should be decompressed and depending on the intraoperative findings a neurolysis also should be performed. Painful neuroma must be resected to stop the pain generator. For a painful joint, the biomechanics of that joint must first be stable before denervation. PMID- 26611388 TI - New Concepts in Complex Regional Pain Syndrome. AB - Despite the severe pain and disability associated with complex regional pain syndrome (CRPS), the lack of understanding of the pathophysiological mechanisms supporting this enigmatic condition prevents the rational design of new therapies, a situation that is frustrating to both the physician and the patient. The review highlights some of the mechanisms thought to be involved in the pathophysiology of CRPS in preclinical models and CRPS patients, with the ultimate goal that understanding these mechanisms will lead to the design of efficacious, mechanism-based treatments available to the clinic. PMID- 26611392 TI - The Proper Use of Neurostimulation for Hand Pain. AB - Upper extremity neuropathic pain states greatly impact patient functionality and quality of life, despite appropriate surgical intervention. This article focuses on the advanced therapies that may improve pain care, including advanced treatment strategies that are available. The article also surveys therapies on the immediate horizon, such as spinal cord stimulation, peripheral nerve stimulation, and dorsal root ganglion spinal cord stimulation. As these therapies evolve, so too will their placement within the pain care algorithm grounded by a foundation of evidence to improve patient safety and management of patients with difficult neuropathic pain. PMID- 26611393 TI - Future Directions for Pain Management: Lessons from the Institute of Medicine Pain Report and the National Pain Strategy. AB - According to the Institute of Medicine Relieving Pain in America Report and the soon to be released National Pain Strategy, pain affects over 100 million Americans and costs our country in over $500 billion per year. We have a greater appreciation for the complex nature of pain and that it can develop into a disease in itself. As such, we need more efforts on prevention of chronic pain and for interdisciplinary approaches. For precision pain medicine to be successful, we need to link learning health systems with pain biomarkers (eg, genomics, proteomics, patient reported outcomes, brain markers) and its treatment. PMID- 26611394 TI - Pain Management. PMID- 26611395 TI - Effect of a hepatitis B virus inhibitor, NZ-4, on capsid formation. AB - During the hepatitis B virus (HBV) life cycle, nucleocapsid assembly is essential for HBV replication. Both RNA reverse transcription and DNA replication occur within the HBV nucleocapsid. HBV nucleocapsid is consisted of core protein (HBcAg), whose carboxy-terminal domain (CTD) contains an Arg-rich domain (ARD). The ARD of HBcAg does contribute to the encapsidation of pregenomic RNA (pgRNA). Previously, we reported a small-molecule, NZ-4, which dramatically reduced the HBV DNA level in an in vitro cell setting. Here, we explore the possible mechanisms by which NZ-4 inhibits HBV function. As an HBV inhibitor, NZ-4 leads to the formation of genome-free capsids, including a new population of capsid that runs faster on agarose gels. NZ-4's activity was dependent on the presence of the ARD I, containing at least one positively charged amino acid. NZ-4 might provide a new option for further development of HBV therapeutics for the treatment of chronic hepatitis B. PMID- 26611396 TI - Curcumin and Boswellia serrata gum resin extract inhibit chikungunya and vesicular stomatitis virus infections in vitro. AB - Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes chikungunya fever and has infected millions of people mainly in developing countries. The associated disease is characterized by rash, high fever, and severe arthritis that can persist for years. CHIKV has adapted to Aedes albopictus, which also inhabits temperate regions including Europe and the United States of America. CHIKV has recently caused large outbreaks in Latin America. No treatment or licensed CHIKV vaccine exists. Traditional medicines are known to have anti-viral effects; therefore, we examined whether curcumin or Boswellia serrata gum resin extract have antiviral activity against CHIKV. Both compounds blocked entry of CHIKV Env-pseudotyped lentiviral vectors and inhibited CHIKV infection in vitro. In addition, vesicular stomatitis virus vector particles and viral infections were also inhibited to the same extent, indicating a broad antiviral activity. Although the bioavailability of these compounds is rather poor, they might be used as a lead structure to develop more effective antiviral drugs or might be used topically to prevent CHIKV spread in the skin after mosquito bites. PMID- 26611397 TI - Test-retest reliability of effective connectivity in the face perception network. AB - Computational approaches have great potential for moving neuroscience toward mechanistic models of the functional integration among brain regions. Dynamic causal modeling (DCM) offers a promising framework for inferring the effective connectivity among brain regions and thus unraveling the neural mechanisms of both normal cognitive function and psychiatric disorders. While the benefit of such approaches depends heavily on their reliability, systematic analyses of the within-subject stability are rare. Here, we present a thorough investigation of the test-retest reliability of an fMRI paradigm for DCM analysis dedicated to unraveling intra- and interhemispheric integration among the core regions of the face perception network. First, we examined the reliability of face-specific BOLD activity in 25 healthy volunteers, who performed a face perception paradigm in two separate sessions. We found good to excellent reliability of BOLD activity within the DCM-relevant regions. Second, we assessed the stability of effective connectivity among these regions by analyzing the reliability of Bayesian model selection and model parameter estimation in DCM. Reliability was excellent for the negative free energy and good for model parameter estimation, when restricting the analysis to parameters with substantial effect sizes. Third, even when the experiment was shortened, reliability of BOLD activity and DCM results dropped only slightly as a function of the length of the experiment. This suggests that the face perception paradigm presented here provides reliable estimates for both conventional activation and effective connectivity measures. We conclude this paper with an outlook on potential clinical applications of the paradigm for studying psychiatric disorders. Hum Brain Mapp 37:730-744, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26611398 TI - Sample preparation for thermo-gravimetric determination and thermo-gravimetric characterization of refuse derived fuel. AB - Thermo-gravimetric analysis (TGA) is a useful method for characterizing fuels. In the past it has been applied to the study of refuse derived fuel (RDF) and related materials. However, the heterogeneity of RDF makes the preparation of small representative samples very difficult and this difficulty has limited the effectiveness of TGA for characterization of RDF. A TGA method was applied to a variety of materials prepared from a commercially available RDF using a variety of procedures. Applicability of TGA method to the determination of the renewable content of RDF was considered. Cryogenic ball milling was found to be an effective means of preparing RDF samples for TGA. When combined with an effective sample preparation, TGA could be used as an alternative method for assessing the renewable content of RDF. PMID- 26611399 TI - Effect of C/N ratio and salinity on power generation in compost microbial fuel cells. AB - In this work, compost Microbial Fuel Cells (cMFCs) were used to generate electricity from a mix of fruit and vegetable wastes, and soil with different C/N ratios and salinities. Experiments were carried out in 500mL cMFCs equipped with carbon felt anodes and manganese dioxide cathodes. The cMFCs were loaded with fresh compost and operated at 20-23 degrees C for up to 97days. The low C/N ratio (C/N 24) had a greater power production with a maximum power density of 5.29mW/m(2) (71.43mW/m(3)), indicating a more favorable condition for microbial growth. High-saline cMFCs produced lower power, suggesting that their level of salinity (10g/L of NaCl) inhibited electricigenic microorganisms. The closed circuit cMFC showed an improved degradation of organic matter by 6% to 8% compared to the control MFC operated in an open circuit mode (no external resistor attached). PMID- 26611400 TI - Metal concentrations in lime stabilised, thermally dried and anaerobically digested sewage sludges. AB - Cognisant of the negative debate and public sentiment about the land application of treated sewage sludges ('biosolids'), it is important to characterise such wastes beyond current regulated parameters. Concerns may be warranted, as many priority metal pollutants may be present in biosolids. This study represents the first time that extensive use was made of a handheld X-ray fluorescence (XRF) analyser to characterise metals in sludges, having undergone treatment by thermal drying, lime stabilisation, or anaerobic digestion, in 16 wastewater treatment plants (WWTPs) in Ireland. The concentrations of metals, expressed as mgkg(-1) dry solids (DS), which are currently regulated in the European Union, ranged from 11 (cadmium, anaerobically digested (AD) biosolids) to 1273mgkg(-1) (zinc, AD biosolids), and with the exception of lead in one WWTP (which had a concentration of 3696mgkg(-1)), all metals were within EU regulatory limits. Two potentially hazardous metals, antimony (Sb) and tin (Sn), for which no legislation currently exists, were much higher than their baseline concentrations in soils (17 20mgSbkg(-1) and 23-55mgSnkg(-1)), meaning that potentially large amounts of these elements may be applied to the soil without regulation. This study recommends that the regulations governing the values for metal concentrations in sludges for reuse in agriculture are extended to include Sb and Sn. PMID- 26611402 TI - Rapid fabrication of ZnO nanorod arrays with controlled spacing by micelle templated solvothermal growth. AB - We present a facile method for the synthesis of nanorod arrays over large areas with fine control over the average rod-rod spacing. Block copolymer micelles are used to template solvothermal synthesis of ZnO nanorods by preferentially enabling reactant diffusion through the micelle cores to an underlying seed layer. The distance between nanorod centers is defined by the micelle number density which is in turn controlled by the molecular weight of the block copolymer, and the block copolymer concentration in a templating film. We demonstrate the ability to control the resulting nanorod number density from ~100 MUm(-2) down to ~10 MUm(-2) with high fidelity. Correspondingly, the distance between nanorod surfaces was varied from ~60 nm to 230 nm. The method developed here provides a viable approach for rapidly fabricating large-area nanostructured electrodes comprised of nanorod arrays with controlled geometries. The ability to tailor nanorod spacing over a broad range suggests applications in photovoltaics and sensors based on optical resonances can be readily addressed. PMID- 26611401 TI - Performance of a plastic-wrapped composting system for biosecure emergency disposal of disease-related swine mortalities. AB - A passively-ventilated plastic-wrapped composting system initially developed for biosecure disposal of poultry mortalities caused by avian influenza was adapted and tested to assess its potential as an emergency disposal option for disease related swine mortalities. Fresh air was supplied through perforated plastic tubing routed through the base of the compost pile. The combined air inlet and top vent area is ?~1% of the gas exchange surface of a conventional uncovered windrow. Parameters evaluated included: (1) spatial and temporal variations in matrix moisture content (m.c.), leachate production, and matrix O2 concentrations; (2) extent of soft tissue decomposition; and (3) internal temperature and the success rate in achieving USEPA time/temperature (T) criteria for pathogen reduction. Six envelope materials (wood shavings, corn silage, ground cornstalks, ground oat straw, ground soybean straw, or ground alfalfa hay) and two initial m.c.'s (15-30% w.b. for materials stored indoors, and 45-65% w.b. to simulate materials exposed to precipitation) were tested to determine their effect on performance parameters (1-3). Results of triple-replicated field trials showed that the composting system did not accumulate moisture despite the 150kg carcass water load (65% of 225kg total carcass mass) released during decomposition. Mean compost m.c. in the carcass layer declined by ~7 percentage points during 8-week trials, and a leachate accumulation was rare. Matrix O2 concentrations for all materials other than silage were ?10% using the equivalent of 2m inlet/vent spacing. In silage O2 dropped below 5% in some cases even when 0.5m inlet/vent spacing was used. Eight week soft tissue decomposition ranged from 87% in cornstalks to 72% in silage. Success rates for achievement of USEPA Class B time/temperature criteria ranged from 91% for silage to 33-57% for other materials. Companion laboratory biodegradation studies suggest that Class B success rates can be improved by slightly increasing envelope material m.c. Moistening initially dry (15% m.c.) envelope materials to 35% m.c. nearly doubled their heat production potential, boosting it to levels ?silage. The 'contradictory' silage test results showing high temperatures paired with slow soft tissue degradation are likely due to this material's high density, low gas permeability and low water vapor loss. While slow decomposition typically suggests low microbial activity and heat production, it does not rule out high internal temperatures if the heat produced is conserved. Occasional short-term odor releases during the first 2weeks of composting were associated with top-to bottom gas flow which is contrary to the typical bottom-to-top flow typically observed in conventional compost piles. In cases where biosecurity concerns are paramount, results of this study show the plastic-wrapped passively-ventilated composting method to have good potential for above-ground swine mortality disposal. PMID- 26611403 TI - Thyroid Solid Cell Nests: Usefulness of Cytokeratin 5/6? : Cytokeratin 5/6 in Thyroid Cell Nests. PMID- 26611404 TI - Study on chemical analysis, antioxidant and in vitro antifungal activities of essential oil from wild Vitex agnus-castus L. seeds growing in area of Argan Tree of Morocco against clinical strains of Candida responsible for nosocomial infections. AB - OBJECTIVE: To study the composition, the antioxidant activity and the in vitro antifungal action anti-Candida species of essential oils extracted from seeds of Vite xagnus-castus L. MATERIALS AND METHOD: The essential oils were extracted using Clevenger-type apparatus and analyzed by gas chromatography/mass spectrometry (GC/MS). The antioxidant activity was analyzed using the DPPH free radical-scavenging method. Susceptibility tests for Candida albicans (12), C. dubliniensis (1), C. glabrata (3), C. krusei (3), C. parapsilosis (6), C. lusitaniae (1), C. famata (1) and C. tropicalis (3) were expressed as inhibition zone by the disc-diffusion method and as minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) by the broth macrodilution method, compared to amphotricin B and fluconazol as standard drugs. RESULTS: Major components were: 1,8-cineole (19.61%), sabinene (14.57%), alpha-pinene (9.76%), beta-farnesene (6.04%), beta-caryophyllene oxide (5.83%) and beta-caryophyllene (5.02%). A low antioxidant activity was found (IC50=1.072mg/ml), but it can be exploited. V. agnus-castus seeds essential oils disosed a 35-58mm zone of inhibition (mean: 49mm) against all 30 isolates tested. In broth macrodilution method, all the tested Candida species were susceptible to the essential oils and this activity was concentration-dependent. MIC values varied from 0.13 to 2.13mg/ml V. agnus-castus seeds essential oils. CONCLUSION: Results of this study indicated that the oils of plant origin could be used as potential anti-Candida species causative agents of nosocomial infections. These oils exhibited a noticeable antifungal activity against the selected fungi. The natural antifungal substances are inexpensive and have fewer side effects, they may represent alternative therapies for candidiasis. PMID- 26611405 TI - Strong Geometrical Effects in Submillimeter Selective Area Growth and Light Extraction of GaN Light Emitting Diodes on Sapphire. AB - Advanced semiconductor devices often utilize structural and geometrical effects to tailor their characteristics and improve their performance. We report here detailed understanding of such geometrical effects in the epitaxial selective area growth of GaN on sapphire substrates and utilize them to enhance light extraction from GaN light emitting diodes. Systematic size and spacing effects were performed side-by-side on a single 2" sapphire substrate to minimize experimental sampling errors for a set of 144 pattern arrays with circular mask opening windows in SiO2. We show that the mask opening diameter leads to as much as 4 times increase in the thickness of the grown layers for 20 MUm spacings and that spacing effects can lead to as much as 3 times increase in thickness for a 350 MUm dot diameter. We observed that the facet evolution in comparison with extracted Ga adatom diffusion lengths directly influences the vertical and lateral overgrowth rates and can be controlled with pattern geometry. Such control over the facet development led to 2.5 times stronger electroluminescence characteristics from well-faceted GaN/InGaN multiple quantum well LEDs compared to non-faceted structures. PMID- 26611406 TI - Sources of Experimental Variation in 2-D Maps: The Importance of Experimental Design in Gel-Based Proteomics. AB - The success of proteomic studies employing 2-D maps largely depends on the way surveys and experiments have been organized and performed. Planning gel-based proteomic experiments involves the selection of equipment, methodology, treatments, types and number of samples, experimental layout, and methods for data analysis. A good experimental design will maximize the output of the experiment while taking into account the biological and technical resources available. In this chapter we provide guidelines to assist proteomics researchers in all these choices and help them to design quantitative 2-DE experiments. PMID- 26611407 TI - Decoding 2-D Maps by Autocovariance Function. AB - This chapter describes a mathematical approach based on the study of the 2-D autocovariance function (2-D ACVF) useful for decoding the complex signals resulting from the separation of protein mixtures. The method allows to obtain fundamental analytical information hidden in 2-D PAGE maps by spot overlapping, such as the number of proteins present in the sample and the mean standard deviation of the spots, describing the separation performance. In addition, it is possible to identify ordered patterns potentially present in spot positions, which can be related to the chemical composition of the protein mixture, such as post-translational modifications.The procedure was validated on computer simulated maps and successfully applied to reference maps obtained from literature sources. PMID- 26611408 TI - Two-Dimensional Gel Electrophoresis Image Analysis via Dedicated Software Packages. AB - Analyzing two-dimensional gel electrophoretic images is supported by a number of freely and commercially available software. Although the respective program is highly specific, all the programs follow certain standardized algorithms. General steps are: (1) detecting and separating individual spots, (2) subtracting background, (3) creating a reference gel and (4) matching the spots to the reference gel, (5) modifying the reference gel, (6) normalizing the gel measurements for comparison, (7) calibrating for isoelectric point and molecular weight markers, and moreover, (8) constructing a database containing the measurement results and (9) comparing data by statistical and bioinformatic methods. PMID- 26611409 TI - Comparative Evaluation of Software Features and Performances. AB - Analysis of two-dimensional gel images is a crucial step for the determination of changes in the protein expression, but at present, it still represents one of the bottlenecks in 2-DE studies. Over the years, different commercial and academic software packages have been developed for the analysis of 2-DE images. Each of these shows different advantageous characteristics in terms of quality of analysis. In this chapter, the characteristics of the different commercial software packages are compared in order to evaluate their main features and performances. PMID- 26611410 TI - Image Pretreatment Tools I: Algorithms for Map Denoising and Background Subtraction Methods. AB - One of the critical steps in two-dimensional electrophoresis (2-DE) image pre processing is the denoising, that might aggressively affect either spot detection or pixel-based methods. The Median Modified Wiener Filter (MMWF), a new nonlinear adaptive spatial filter, resulted to be a good denoising approach to use in practice with 2-DE. MMWF is suitable for global denoising, and contemporary for the removal of spikes and Gaussian noise, being its best setting invariant on the type of noise. The second critical step rises because of the fact that 2-DE gel images may contain high levels of background, generated by the laboratory experimental procedures, that must be subtracted for accurate measurements of the proteomic optical density signals. Here we discuss an efficient mathematical method for background estimation, that is suitable to work even before the 2-DE image spot detection, and it is based on the 3D mathematical morphology (3DMM) theory. PMID- 26611411 TI - Image Pretreatment Tools II: Normalization Techniques for 2-DE and 2-D DIGE. AB - Gel electrophoresis is usually applied to identify different protein expression profiles in biological samples (e.g., control vs. pathological, control vs. treated). Information about the effect to be investigated (a pathology, a drug, a ripening effect, etc.) is however generally confounded with experimental variability that is quite large in 2-DE and may arise from small variations in the sample preparation, reagents, sample loading, electrophoretic conditions, staining and image acquisition. Obtaining valid quantitative estimates of protein abundances in each map, before the differential analysis, is therefore fundamental to provide robust candidate biomarkers. Normalization procedures are applied to reduce experimental noise and make the images comparable, improving the accuracy of differential analysis. Certainly, they may deeply influence the final results, and to this respect they have to be applied with care. Here, the most widespread normalization procedures are described both for what regards the applications to 2-DE and 2D Difference Gel-electrophoresis (2-D DIGE) maps. PMID- 26611412 TI - Spot Matching of 2-DE Images Using Distance, Intensity, and Pattern Information. AB - The analysis of a large number of two-dimensional gel electrophoresis (2-DE) images requires developing automatic methods. In such analyses, spot matching plays a fundamental role, in particular for the identification of proteins. We describe a simple and accurate method which allows to automatically and accurately match spots in 2-DE images. The method consists of simultaneously exploiting the distance between the spots, their intensity, and the pattern formed by their spatial configuration. PMID- 26611413 TI - Algorithms for Warping of 2-D PAGE Maps. AB - Software-based image analysis of 2-D PAGE maps is an important step for the investigation of proteome. Warping algorithms, which are employed to register spots among gels, are able to overcome the difficulties due to the low reproducibility of this analytical technique. Over the years, the research of new matching and warping mathematical methods has allowed the development of several routine applications of easy-to-use software. This chapter describes common and basic spatial transformations used for the alignment of protein spots present in different gel maps; some recently new approaches are also presented. PMID- 26611414 TI - 2-DE Gel Analysis: The Spot Detection. AB - The abundance of different proteins on a 2-DE gel is reflected by the shape, size, and intensity of the corresponding spots. Protein quantitation requires the conversion of an analog gel image into digital data, resulting into a catalog of individual spots listed as x, y positions, shape parameters, and quantitative values. So, it is possible to carry out objective comparisons of equivalent spots on different gels, determining whether a particular protein is more or less abundant in one sample compared with another. Unfortunately, spots on protein gels are not uniform in shape, size, or density, and detection, quantitation, and comparison can be challenging without intervention. Once a processed image is available, a number of different algorithms can be applied to detect and quantitate individual spots. PMID- 26611415 TI - GENOCOP Algorithm and Hierarchical Grid Transformation for Image Warping of Two Dimensional Gel Electrophoretic Maps. AB - Hierarchical grid transformation is a powerful hierarchical approach to 2-D map warping, able to model both global and local deformations. The algorithm can be stopped when a desired degree of accuracy in the images alignment is obtained. The deformed image is warped and aligned to the target image using a grid where the number of nodes increases in each step of the algorithm. The numerical optimization of the position of the nodes of the grid can be efficiently solved by genetic algorithms, ensuring the achievement of the optimal position of the nodes with a low computational cost with respect to other methods. Here, the optimization of the position of the nodes is carried out by GENOCOP (genetic algorithm for numerical optimization of constrained problems), refined by the following conjugate gradient optimization step. The modeling of the warped space is then achieved by a spline model where some constraints are introduced in the choice of the nodes that are moved. The whole procedure can be intended as an evolutionary method that models the deformation of the gel map at different levels of detail. PMID- 26611416 TI - Detection and Quantification of Protein Spots by Pinnacle. AB - Accurate spot detection and quantification is a challenging task that must be performed effectively in order to properly extract the proteomic information from two-dimensional (2-D) gel electrophoresis images. In Morris et al., Bioinformatics 24:529-536, 2008, we introduced Pinnacle, an automatic, fast, effective noncommercial package for spot detection and quantification for 2-D gel images, and subsequently we have developed a freely available gui-based interface for applying the method to a set of gels. In this chapter, we overview Pinnacle, and in a step-by-step manner we describe how to use the software to obtain spot lists and quantifications, to be used for comparative proteomic analysis. PMID- 26611417 TI - A Novel Gaussian Extrapolation Approach for 2-D Gel Electrophoresis Saturated Protein Spots. AB - Analysis of images obtained from two-dimensional gel electrophoresis (2-D GE) is a topic of utmost importance in bioinformatics research, since commercial and academic software currently available have proven to be neither completely effective nor fully automatic, often requiring manual revision and refinement of computer generated matches. In this chapter, we present an effective technique for the detection and the reconstruction of over-saturated protein spots. Firstly, the algorithm reveals overexposed areas, where spots may be truncated, and plateau regions caused by smeared and overlapping spots. Next, it reconstructs the correct distribution of pixel values in these overexposed areas and plateau regions, using a two-dimensional least-squares fitting based on a generalized Gaussian distribution. Pixel correction in saturated and smeared spots allows more accurate proteins quantification, providing more reliable image analysis results. The method is validated for processing highly exposed 2-D GE images, comparing reconstructed spots with the corresponding non-saturated image. The results demonstrate that the algorithm enables correct spot quantification. PMID- 26611418 TI - Multiple Testing and Pattern Recognition in 2-DE Proteomics. AB - After separation through two-dimensional gel electrophoresis (2-DE), several hundreds of individual protein abundances can be quantified in a cell population or sample tissue. However, gel-based proteomics has the reputation of being a slow and cumbersome art. But art is not dead! While 2-DE may no longer be the tool of choice in high-throughput differential proteomics, it is still very effective to identify and quantify protein species caused by genetic variations, alternative splicing, and/or PTMs. This chapter reviews some typical statistical exploratory and confirmatory tools available and suggests case-specific guidelines for (1) the discovery of potentially interesting protein spots, and (2) the further characterization of protein families and their possible PTMs. PMID- 26611419 TI - Chemometric Multivariate Tools for Candidate Biomarker Identification: LDA, PLS DA, SIMCA, Ranking-PCA. AB - 2-D gel electrophoresis usually provides complex maps characterized by a low reproducibility: this hampers the use of spot volume data for the identification of reliable biomarkers. Under these circumstances, effective and robust methods for the comparison and classification of 2-D maps are fundamental for the identification of an exhaustive panel of candidate biomarkers. Multivariate methods are the most suitable since they take into consideration the relationships between the variables, i.e., effects of synergy and antagonism between the spots. Here the most common multivariate methods used in spot volume datasets analysis are presented. The methods are applied on a sample dataset to prove their effectiveness. PMID- 26611420 TI - The Use of Legendre and Zernike Moment Functions for the Comparison of 2-D PAGE Maps. AB - The comparison of 2-D maps is not trivial, the main difficulties being the high complexity of the sample and the large experimental variability characterizing 2 D gel electrophoresis. The comparison of maps from control and treated samples is usually performed by specific software, providing the so-called spot volume dataset where each spot of a specific map is matched to its analogous in other maps, and they are described by their optical density, which is supposed to be related to the underlying protein amount. Here, a different approach is presented, based on the direct comparison of 2-D map images: each map is decomposed in terms of moment functions, successively applying the multivariate tools usually adopted in image analysis problems. The moments calculated are then treated with multivariate classification techniques. Here, two types of moment functions are presented (Legendre and Zernike moments), while linear discriminant analysis and partial least squares discriminant analysis are exploited as classification tools to provide the classification of the samples. The procedure is applied to a sample dataset to prove its effectiveness. PMID- 26611421 TI - Nonlinear Dimensionality Reduction by Minimum Curvilinearity for Unsupervised Discovery of Patterns in Multidimensional Proteomic Data. AB - Dimensionality reduction is largely and successfully employed for the visualization and discrimination of patterns, hidden in multidimensional proteomics datasets. Principal component analysis (PCA), which is the preferred approach for linear dimensionality reduction, may present serious limitations, in particular when samples are nonlinearly related, as often occurs in several two dimensional electrophoresis (2-DE) datasets. An aggravating factor is that PCA robustness is impaired when the number of samples is small in comparison to the number of proteomic features, and this is the case in high-dimensional proteomic datasets, including 2-DE ones. Here, we describe the use of a nonlinear unsupervised learning machine for dimensionality reduction called minimum curvilinear embedding (MCE) that was successfully applied to different biological samples datasets. In particular, we provide an example where we directly compare MCE performance with that of PCA in disclosing neuropathic pain patterns, hidden in a multidimensional proteomic dataset. PMID- 26611422 TI - Differential Analysis of 2-D Maps by Pixel-Based Approaches. AB - Two approaches to the analysis of 2-D maps are available: the first one involves a step of spot detection on each gel image; the second one is based instead on the direct differential analysis of 2-D map images, following a pixel-based procedure. Both approaches strongly depend on the proper alignment of the gel images, but the pixel-based approach allows to solve important drawbacks of the spot-volume procedure, i.e., the problem of missing data and of overlapping spots. However, this approach is quite computationally intensive and requires the use of algorithms able to separate the information (i.e., spot-related information) from the background. Here, the most recent pixel-based approaches are described. PMID- 26611423 TI - Drug-induced sleep-endoscopy in children's sleep related breathing disorders. AB - INTRODUCTION: Drug-induced sedation endoscopy is a valid tool to assess site obstruction of the upper airway responsible for children's obstructive Sleep Apnea The aim is to show the experience of an ENT department with Drug-induced sedation endoscopy in children selected for sleep apnea surgery METHODS: Includes 56 cases between 2 and 12 years old (mean age: 59,13+/-27,29 months) presenting at the Otorhinolaryngology consultation clinic with snoring and apnea. Prior polysomnography had been practiced and mean AHI was 6,32+/-8,71. The distribution of cases was 10 persistent sleep apnea (17.85%), 15 clinical disproportion (26.78%) and 31 conventional (55.35%). All sleep endoscopies were performed in the operating room and Chan classification was used to assess the areas of collapse. RESULTS: In cases of residual disease the most affected regions were the side walls of the oropharynx (70%) and turbinate (70%) and the most frequently applied surgery was total tonsillectomy followed by second tongue tonsil reduction and turbinate radiofrequency. In clinical cases of desproportion, the most affected regions were the oropharyngeal side walls (93.3%) and adenoids (66.6%). The most frequently applied surgery in this group was adenoidectomy and radiofrequency tonsillotomy. CONCLUSION: Drug-induced sedation endoscopy is a technique that can be incorporated easily into medical practice, mostly in children with residual sleep apnea syndrome or those suspected to have some cause other than adenotonsillar hypertrophy. PMID- 26611424 TI - Relationship between video head impulse test (vHIT) and caloric test in patients with vestibular neuritis. AB - INTRODUCTION AND OBJECTIVES: The caloric test is the gold standard for the loss of vestibular function diagnosis. The Video Head Impulse Test (vHIT) assesses the same reflex by using a video- assisted examination of the impulsive maneuver. We intend to compare the variation of results of the vHIT and the caloric test in patients with vestibular neuritis with respect to their initial condition at two different moments of their evolution and to check the level of correlation between them and with that of the DHI test METHODS: We explored 20 patients with neuritis by using both vHIT and the caloric test on the same day. We assessed the correlation between these two tests and with the DHI test for each patient at two different moments of their evolution. RESULTS: We calculated gain asymmetry and compared it with the canal paresis, but we found neither a linear correlation between them, nor a correlation between the DHI test or improvement of these two other tests. We conclude that the covert saccades maintain a similar speed whilst present in the VHIT, but the overts diminish their speed over time. CONCLUSIONS: The VHIT and the caloric test show different responses of the vestibulo-ocular reflex, because they stimulate different frequencies of this reflex. No correlation was found between the VHIT, the caloric test and the DHI test. The tests appear to complement one another. PMID- 26611425 TI - Pilot prospective evaluation of (18)F-FPPRGD2 PET/CT in patients with cervical and ovarian cancer. AB - PURPOSE: We report the effect of antiangiogenic therapy on the biodistribution of (18)F-FPPRGD2 (a surrogate biomarker of integrin alphavbeta3 expression), and the potential of (18)F-FPPRGD2 to predict the prognosis in patients with cervical cancer and ovarian cancer in this clinical scenario. METHODS: Data from six women, age range 30 - 59 years (mean +/- SD 44.0 +/- 12.5 years), who had undergone a (18)F-FPPRGD2 PET/CT scan and bevacizumab-containing therapy were prospectively collected and analyzed. We compared baseline (18)F-FPPRGD2 and (18)F-FDG uptake in the lesions and tumor-to-background (T/B) ratios. The maximum and mean (18)F-FPPRGD2 standardized uptake values (SUVmax and SUVmean) were recorded for 13 normal organs, as well as in all the identified malignant lesions on the pretreatment scan and the 1-week post-treatment scan. We also measured changes in (18)F-FPPRGD2 uptake from before to 1 week after treatment, and compared them to the changes in (18)F-FDG uptake from before to 6 weeks after treatment. Treatment outcomes were correlated with these changes. RESULTS: The uptake in lesions and T/B ratio of (18)F-FPPRGD2 were lower than those of (18)F FDG (SUVmax 3.7 +/- 1.3 vs. 6.0 +/- 1.8, P < 0.001; SUVmean 2.6 +/- 0.7 vs. 4.2 +/- 1.3, P < 0.001; T/B ratio based on SUVmax 2.4 +/- 1.0 vs. 2.6 +/- 1.0, P < 0.04; T/B ratio based on SUVmean 1.9 +/- 0.6 vs. 2.4 +/- 1.0, P < 0.003). One patient did not return for the follow-up scan and in another patient no lesions were identified on the pretreatment scan. (18)F-FPPRGD2 uptake in lesions in the remaining four patients had significantly changed 1 week after treatment (SUVmean 3.3 +/- 1.0 vs. 2.7 +/- 1.0, P < 0.001), while uptake in all normal tissues analyzed was not affected by treatment. One patient with clinical disease progression had a decrease in lesional (18)F-FPPRGD2 SUVmean of 1.6 % and in (18)F-FDG SUVmean of 9.4 %. Two patients with a clinical complete response to treatment had decreases in lesional (18)F-FPPRGD2 SUVmean of 25.2 % and 25.0 % and in (18)F-FDG SUVmean of 6.1 % and 71.8 %. One patient with a clinical partial response had a decrease in lesional (18)F-FPPRGD2 SUVmean of 7.9 % and in (18)F FDG SUVmean of 76.4 %. CONCLUSION: This pilot study showed that (18)F-FPPRGD2 and (18)F-FDG provide independent information about the biology of ovarian and cervical cancers. Bevacizumab-containing therapy does not affect (18)F-FPPRGD2 uptake in normal organs, but does result in statistically significant changes in lesions. In addition, (18)F-FPPRGD2 may have potential for early prediction of response to such treatments. These preliminary findings have to be confirmed in larger studies. PMID- 26611426 TI - Diagnostic performance of FDG PET/CT for surveillance in asymptomatic gastric cancer patients after curative surgical resection. AB - PURPOSE: The present study evaluated the diagnostic performance of 2-[(18)F] fluoro-2-deoxy-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) for surveillance in asymptomatic gastric cancer patients after curative surgical resection. METHODS: We retrospectively recruited 190 gastric cancer patients (115 early gastric cancer patients and 75 advanced gastric cancer patients) who underwent 1-year (91 patients) or 2-year (99 patients) postoperative FDG PET/CT surveillance, along with a routine follow-up program, after curative surgical resection. All enrolled patients were asymptomatic and showed no recurrence on follow-up examinations performed before PET/CT surveillance. All PET/CT images were visually assessed and all abnormal findings on follow-up examinations including FDG PET/CT were confirmed with histopathological diagnosis or clinical follow-up. RESULTS: During follow-up, 19 patients (10.0 %) developed recurrence. FDG PET/CT showed abnormal findings in 37 patients (19.5 %). Among them, 16 patients (8.4 %) were diagnosed as cancer recurrence. Of 153 patients without abnormal findings on PET/CT, three patients were false-negative and diagnosed as recurrence on other follow-up examinations. The sensitivity, specificity, positive predictive value, and negative predictive value of FDG PET/CT were 84.2 %, 87.7 %, 43.2 %, and 98.0 %, respectively. Among 115 early gastric cancer patients, PET/CT detected recurrence in four patients (3.5 %) and one patient with local recurrence. Among 75 advanced gastric cancer patients, PET/CT detected recurrence in 12 patients (16.0 %), excluding two patients experiencing peritoneal recurrence. In addition, FDG PET/CT detected secondary primary cancer in six (3.2 %) out of all the patients. CONCLUSIONS: Post-operative FDG PET/CT surveillance showed good diagnostic ability for detecting recurrence in gastric cancer patients. FDG PET/CT could be a useful follow-up modality for gastric cancer patients, especially those with advanced gastric cancer. However, further careful evaluation is needed because of false positive findings on PET/CT. PMID- 26611427 TI - Peptide receptor radionuclide therapy with (177)Lu-DOTATATE in advanced bronchial carcinoids: prognostic role of thyroid transcription factor 1 and (18)F-FDG PET. AB - PURPOSE: Typical and atypical carcinoids (TC and AC) represent 20 - 25 % of all neuroendocrine tumours. No standard therapeutic approach is available for patients with advanced disease. The aim of this phase II study was to investigate the efficacy and safety of peptide receptor radionuclide therapy with (177)Lu DOTATATE (Lu-PRRT) and the role of thyroid transcription factor 1 (TTF-1) and (18)F-FDG PET as prognostic factors in patients with advanced TC or AC. METHODS: A total of 34 consecutive patients with radiologically documented progressive disease were treated with Lu-PRRT at a therapeutic cumulative activity of 18.5 or 27.8 GBq in four or five cycles according to the patient's kidney function and bone marrow reserve. Information on TTF-1 was available in all patients. FDG PET studies prior to Lu-PRRT were available in 29 patients. RESULTS: The median follow-up was 29 months (range 7 - 69 months). The disease control rate (DCR) in patients with TC was 80 %: 6 % complete response, 27 % partial response and 47 % stable disease. The median progression-free survival (mPFS) was 20.1 months (95 % CI 11.8 - 26.8 months). Stable disease was achieved in 47 % of patients with AC with a mPFS of 15.7 months (95 % CI 10.6 - 25.9 months). No major acute or delayed toxicity occurred in either group or with either cumulative activity. mPFS in patients with TTF-1-negative TC was 26.3 months (95 % CI 12.9 - 45.2 months), but in patients with TTF-1-positive TC mPFS was 7.2 months (4.2 - 14.0 months; p = 0.0009). FDG PET was negative in 13 patients (10 TC and 3 AC) and positive in 16 patients (4 TC and 12 AC). The mPFS in the FDG PET-negative group was 26.4 months (95 % CI 14.2 - 48.9 months) and 15.3 months (11.7 - 31.1 months) in the FDG PET-positive group. CONCLUSION: Lu-PRRT showed antitumour activity in terms of DCR and PFS and proved safe, even in patients with a higher risk of side effects. TTF-1 would appear to be a prognostic factor. FDG PET positivity in bronchial carcinoids is a hallmark of aggressive tumour and is more frequent in patients with AC than in those with TC. PMID- 26611428 TI - [Aortic inflammatory lesions in Behcet's disease]. AB - The arterial lesions affect about 10% of patients with Behcet's disease (BD). Aortic inflammatory involvement includes predominantly aortic aneurysmal lesions affecting most often the abdominal aorta. They account for the severity of the disease and are a leading cause of death when they hit the aorta or pulmonary arteries. Within the arterial lesions of BD, aortic involvement is, with femoral lesions, the most common site involved (18-28% of patients with vascular disease). Unlike other large vessels vasculitis (i.e. giant cell arteritis and Takayasu's arteritis) diffuse aortitis is observed in less than 5% of patients with BD. Aortic lesions of BD may be asymptomatic (systematic imaging or occasionally associated with other vascular event) or be revealed by the occurrence of abdominal, thoracic or lumbar pain, or an aortic valve insufficiency. Fever is frequently associated. Increase in acute phase reactants is common in these patients. Histological analysis may show infiltration by lymphocytes, neutrophils and plasma cells in the media and adventitia and a proliferation of the vasa vasorum in the media as well as a fibroblastic proliferation. In the later phase, a fibrous thickening of the media and adventitia is observed as well as a proliferation and thickening of the vasa vasorum. The therapeutic management should always include a medical treatment for the control of inflammation (corticosteroids, immunosuppressive drugs and/or biotherapy) and often an endovascular or surgical treatment if the aneurysm is threatening. The choice between endovascular or surgical treatment is considered case by case, depending on the experience of the team, anatomical conditions and of the clinical presentation. In this review, we provide a detailed and updated review of the literature to describe the aortic inflammatory damage associated with Behcet's disease. PMID- 26611429 TI - [Association of lymphoma and granulomatosis: A case series]. AB - PURPOSE: The sarcoidosis-lymphoma syndrome is a recognised entity. However, the presence of granulomas in patients with a haematological disease should not lead too easily to a diagnosis of sarcoidosis. The presence of granulomatous lesions during the follow-up of these patients raises diagnostic and therapeutic issues. METHODS: We included 25 patients followed by the department of haematology in a French hospital (Centre Leon-Berard). These patients presented with granulomatous lesions. Patients with a history of sarcoidosis were excluded. We report the type of haematological disease, the time of onset of the granulomatous disease compared to that of lymphoma, associated symptoms, aetiology and outcome. Patients were divided into three groups according to the time of onset of the granulomatous lesions. RESULTS: Granulomatous lesions appeared before the haematological disease in 4 cases, was concomitant in 8 cases and appeared later in 13 remaining cases. The two main subtypes of lymphoma encountered were: diffuse large cell lymphoma (36%) and Hodgkin's lymphoma (28%). Granulomatous lesions were related to the progression of the hematological disease in 11 cases, to sarcoidosis in 4 cases, to infection in 3 cases, to drug allergy in one case, to inflammatory bowel disease in one case, to granuloma annulare in one case and was isolated in 4 cases (no identified etiology). In the group where granulomas appeared after the haematological disease, mean SUV was 11 for the haematological disease versus 6.4 for granulomas. CONCLUSION: Granulomatous diseases in lymphomas can be due to various aetiologies: infection, reaction to the haematological disease, or systemic sarcoidosis. It is an important challenge for clinicians, who can miss the diagnosis of lymphoma and or conclude to a treatment failure or a relapse. Computed tomography scan (CT-scan) or (18)F-deoxyglucose positron emission tomography scan can help establish a diagnosis but do not replace biopsy. PMID- 26611430 TI - [Revisiting the scope of extrahepatic manifestations of hepatitis C virus infection]. PMID- 26611431 TI - Balancing Early Aggression Against Risk of Progression in Multiple Sclerosis. AB - Multiple sclerosis is a chronic demyelinating disease characterized by focal and diffuse inflammation of the central nervous system resulting in significant physical and cognitive disabilities. Disease-modifying therapies targeting the dysfunctional immune response are most effective in the first few years after disease onset, indicating that there is a limited time window for therapy to influence the disease course. No evidence of disease activity is emerging as a new standard for treatment response and may be associated with improved long-term disability outcomes. An aggressive management strategy, including earlier use of more potent immunomodulatory agents and close monitoring of the clinical and radiologic response to treatment, is recommended to minimize early brain volume loss and slow the progression of physical and cognitive impairments in patients with relapsing-remitting multiple sclerosis. PMID- 26611432 TI - Single molecule approaches for quantifying transcription and degradation rates in intact mammalian tissues. AB - A key challenge in mammalian biology is to understand how rates of transcription and mRNA degradation jointly shape cellular gene expression. Powerful techniques have been developed for measuring these rates either genome-wide or at the single molecule level, however these techniques are not applicable to assessment of cells within their native tissue microenvironment. Here we describe a technique based on single molecule Fluorescence in-situ Hybridization (smFISH) to measure transcription and degradation rates in intact mammalian tissues. The technique is based on dual-color libraries targeting the introns and exons of the genes of interest, enabling visualization and quantification of both nascent and mature mRNA. We present a software, TransQuant, that facilitates quantifying these rates from smFISH images. Our approach enables assessment of both transcription and degradation rates of any gene of interest while controlling for the inherent heterogeneity of intact tissues. PMID- 26611433 TI - Design and participant characteristics for a randomized effectiveness trial of an intensive lifestyle intervention to reduce cardiovascular risk in adults with type 2 diabetes: The I-D-HEALTH study. AB - Intervening in Diabetes with Healthy Eating, Activity and Linkages To Healthcare (I-D-HEALTH) is a community-based randomized trial evaluating the effectiveness of a group-based adaption of the Look AHEAD intensive lifestyle intervention. Most potentially eligible patients were identified through electronic medical record queries or referral to a diabetes resource hub. Trial enrollees had a usual source of primary care, elevated body mass index (BMI) and type 2 diabetes. I-D-HEALTH participants were randomized to either standard care alone or standard care plus free-of-charge access to a group-based lifestyle intervention (GLI) offered by the YMCA. GLI participation was encouraged, but not required, for the latter group. The primary outcome is percent weight change over 6, 12 and 24months. Secondary outcomes include direct intervention costs and direct medical and non-medical expenditures, as well as changes in systolic blood pressure, hemoglobin A1c and cholesterol. Among 331 I-D-HEALTH participants, 167 were randomized to standard care and 164 to GLI. The mean age (+/-standard deviation) in each group was 57.1years (+/-12.2) and 57.6years (+/-10.5), respectively. Mean BMI was 34.9kg/m(2) (+/-7.3) among standard care participants and 36.2kg/m(2) (+/ 7.8) among GLI participants. In both groups, approximately one third of participants were non-Hispanic Whites. We detected no significant differences between groups in mean systolic blood pressure, hemoglobin A1c or total cholesterol (P >0.05 for all characteristics above). The I-D-HEALTH study enrolled a diverse sample of adults with diabetes and offers a unique opportunity to evaluate the effectiveness of offering a community-based intensive lifestyle intervention. PMID- 26611434 TI - Slowing the progression of age-related hearing loss: Rationale and study design of the ASPIRIN in HEARING, retinal vessels imaging and neurocognition in older generations (ASPREE-HEARING) trial. AB - BACKGROUND: Age-related hearing loss (ARHL) is a leading cause of disability in the elderly. Low-grade inflammation and microvessel pathology may be responsible for initiating or exacerbating some of the hearing loss associated with aging. A growing body of evidence demonstrates an association of hearing loss with cognitive decline. A shared etiological pathway may include a role of inflammation, alongside vascular determinants. The ASPREE-HEARING study aims to determine whether low-dose aspirin decreases the progression of ARHL, and if so, whether this decrease in progression is also associated with retinal microvascular changes and/or greater preservation of cognitive function. DESIGN AND METHODS: A three year double-blind, randomized controlled trial of oral 100mg enteric-coated aspirin or matching placebo, enrolling 1262 Australians aged >=70years with normal cognitive function and no overt cardiovascular disease. The primary outcome is the change in mean pure tone average hearing threshold (decibels) in the better ear, over a 3-year period. Secondary outcomes consist of changes in retinal microvascular indicators, and changes in cognitive function. Participants are recruited from a larger trial, ASPirin in Reducing Events in the Elderly (ASPREE), which is designed to assess whether daily low dose aspirin will extend disability-free life. DISCUSSION: ASPREE-HEARING will determine whether aspirin slows development or progression of ARHL, and will interrogate the relationship between inflammatory and microvascular mechanisms that may underlie the effects of aspirin on ARHL. This study will improve understanding of the patterns of comorbidity with, and the relationships between, aging and ARHL, alongside modeling the impacts of ARHL. PMID- 26611436 TI - A new secoiridoid glycoside from the fruits of Cornus officinalis (Cornaceae). AB - A new secoiridoid glycoside, 7beta-O-dimethyl butanedioate morroniside (1) was isolated from the fruits of Cornus officinalis (Cornaceae) along with the known compound, caffeoyltartaric acid dimethyl ester (2) which was isolated from the family Cornaceae for the first time. Their structures were elucidated by physical and spectroscopic data analysis, including 1D and 2D NMR, ESI-MS and CD experiments. PMID- 26611435 TI - Embedding clinical interventions into observational studies. AB - Novel approaches to observational studies and clinical trials could improve the cost-effectiveness and speed of translation of research. Hybrid designs that combine elements of clinical trials with observational registries or cohort studies should be considered as part of a long-term strategy to transform clinical trials and epidemiology, adapting to the opportunities of big data and the challenges of constrained budgets. Important considerations include study aims, timing, breadth and depth of the existing infrastructure that can be leveraged, participant burden, likely participation rate and available sample size in the cohort, required sample size for the trial, and investigator expertise. Community engagement and stakeholder (including study participants) support are essential for these efforts to succeed. PMID- 26611437 TI - Boron nitride colloidal solutions, ultralight aerogels and freestanding membranes through one-step exfoliation and functionalization. AB - Manufacturing of aerogels and membranes from hexagonal boron nitride (h-BN) is much more difficult than from graphene or graphene oxides because of the poor dispersibility of h-BN in water, which limits its exfoliation and preparation of colloidal solutions. Here, a simple, one-step mechano-chemical process to exfoliate and functionalize h-BN into highly water-dispersible, few-layer h-BN containing amino groups is presented. The colloidal solutions of few-layer h-BN can have unprecedentedly high concentrations, up to 30 mg ml(-1), and are stable for up to several months. They can be used to produce ultralight aerogels with a density of 1.4 mg cm(-3), which is ~1,500 times less than bulk h-BN, and freestanding membranes simply by cryodrying and filtration, respectively. The material shows strong blue light emission under ultraviolet excitation, in both dispersed and dry state. PMID- 26611439 TI - Predictive Neuromuscular Fatigue of the Lower Extremity Utilizing Computer Modeling. AB - This paper studies the modeling of lower extremity muscle forces and their correlation to neuromuscular fatigue. Two analytical fatigue models were combined with a musculoskeletal model to estimate the effects of hamstrings fatigue on lower extremity muscle forces during a side step cut. One of the fatigue models (Tang) used subject-specific knee flexor muscle fatigue and recovery data while the second model (Xia) used previously established fatigue and recovery parameters. Both fatigue models were able to predict hamstrings fatigue within 20% of the experimental data, with the semimembranosus and semitendinosus muscles demonstrating the largest (11%) and smallest (1%) differences, respectively. In addition, various hamstrings fatigue levels (10-90%) on lower extremity muscle force production were assessed using one of the analytical fatigue models. As hamstrings fatigue levels increased, the quadriceps muscle forces decreased by 21% (p < 0.01), while gastrocnemius muscle forces increased by 36% (p < 0.01). The results of this study validate the use of two analytical fatigue models in determining the effects of neuromuscular fatigue during a side step cut, and therefore, this model can be used to assess fatigue effects on risk of lower extremity injury during athletic maneuvers. Understanding the effects of fatigue on muscle force production may provide insight on muscle group compensations that may lead to altered lower extremity motion patterns as seen in noncontact anterior cruciate ligament (ACL) injuries. PMID- 26611438 TI - The Association Between Online Health Information-Seeking Behaviors and Health Behaviors Among Hispanics in New York City: A Community-Based Cross-Sectional Study. AB - BACKGROUND: Hispanics are the fastest-growing minority group in the United States and they suffer from a disproportionate burden of chronic diseases. Studies have shown that online health information has the potential to affect health behaviors and influence management of chronic disease for a significant proportion of the population, but little research has focused on Hispanics. OBJECTIVE: The specific aim of this descriptive, cross-sectional study was to examine the association between online health information-seeking behaviors and health behaviors (physical activity, fruit and vegetable consumption, alcohol use, and hypertension medication adherence) among Hispanics. METHODS: Data were collected from a convenience sample (N=2680) of Hispanics living in northern Manhattan by bilingual community health workers in a face-to-face interview and analyzed using linear and ordinal logistic regression. Variable selection and statistical analyses were guided by the Integrative Model of eHealth Use. RESULTS: Only 7.38% (198/2680) of the sample reported online health information-seeking behaviors. Levels of moderate physical activity and fruit, vegetable, and alcohol consumption were low. Among individuals taking hypertension medication (n=825), adherence was reported as high by approximately one-third (30.9%, 255/825) of the sample. Controlling for demographic, situational, and literacy variables, online health information-seeking behaviors were significantly associated with fruit (beta=0.35, 95% CI 0.08-0.62, P=.01) and vegetable (beta=0.36, 95% CI 0.06-0.65, P=.02) consumption and physical activity (beta=3.73, 95% CI 1.99-5.46, P<.001), but not alcohol consumption or hypertension medication adherence. In the regression models, literacy factors, which were used as control variables, were associated with 3 health behaviors: social networking site membership (used to measure one dimension of computer literacy) was associated with fruit consumption (beta=0.23, 95% CI 0.05-0.42, P=.02), health literacy was associated with alcohol consumption (beta=0.44, 95% CI 0.24-0.63, P<.001), and hypertension medication adherence (beta=-0.32, 95% CI -0.62 to -0.03, P=.03). Models explained only a small amount of the variance in health behaviors. CONCLUSIONS: Given the promising, although modest, associations between online health information seeking behaviors and some health behaviors, efforts are needed to improve Hispanics' ability to access and understand health information and to enhance the availability of online health information that is suitable in terms of language, readability level, and cultural relevance. PMID- 26611440 TI - Genome-wide comparative chromosome maps of Arvicola amphibius, Dicrostonyx torquatus, and Myodes rutilus. AB - The subfamily Arvicolinae consists of a great number of species with highly diversified karyotypes. In spite of the wide use of arvicolines in biological and medicine studies, the data on their karyotype structures are limited. Here, we made a set of painting probes from flow-sorted chromosomes of a male Palearctic collared lemming (Dicrostonyx torquatus, DTO). Together with the sets of painting probes made previously from the field vole (Microtus agrestis, MAG) and golden hamster (Mesocricetus auratus, MAU), we carried out a reciprocal chromosome painting between these three species. The three sets of probes were further hybridized onto the chromosomes of the Eurasian water vole (Arvicola amphibius) and northern red-backed vole (Myodes rutilus). We defined the diploid chromosome number in D. torquatus karyotype as 2n = 45 + Bs and showed that the system of sex chromosomes is X1X2Y1. The probes developed here provide a genomic tool-kit, which will help to investigate the evolutionary biology of the Arvicolinae rodents. Our results show that the syntenic association MAG1/17 is present not only in Arvicolinae but also in some species of Cricetinae; and thus, should not be considered as a cytogenetic signature for Arvicolinae. Although cytogenetic signature markers for the genera have not yet been found, our data provides insight into the likely ancestral karyotype of Arvicolinae. We conclude that the karyotypes of modern voles could have evolved from a common ancestral arvicoline karyotype (AAK) with 2n = 56 mainly by centric fusions and fissions. PMID- 26611441 TI - Molecular and pathogenicity characterization of Gallid herpesvirus 2 newly isolated in China from 2009 to 2013. AB - During the course of our continuous surveillance of Gallid herpesvirus 2 (GaHV 2), 44 isolates were obtained from GaHV-2-positive chickens of different flocks in China from 2009 to 2013. The meq gene, considered as a major GaHV-2 oncogene, was sequenced and was found to contain an open reading frame of 1020 nucleotides encoding a 339 amino acid (aa) polypeptide in all isolates. Compared with the GaHV-2 GA strain, the meq genes in 15.9 % (7/44) of the isolates analyzed in this study contained an aa substitution mutation at position 88 (A to T) of which is the first report. The main characteristics of Chinese GaHV-2 isolates meq genes included the substitutions K77E, D80Y, V115A, T139A, P176R, and P217A, and the aa substitution frequency at positions 139 and 176 showed an increase. To test the pathogenicity of the isolates, a pathogenicity study and a vaccination-challenge test were performed on three selected isolates (ZY/1203, WC/1203, and WC/1110) and reference strain GA. The results showed that the three isolates induced gross Marek's disease (MD) lesions in 95.0-100 % cases, which was a higher rate than that obtained for strain GA (82.4 %). Three isolates induced mortality in 10-21.1 % of specific-pathogen-free chickens, which was similar to results with strain GA (23.5 %). The commercially available CVI988 vaccine induced lower protective indices (PIs) against ZY/1203 (82.4) and WC/1110 (83.3) as compared to those against WC/1203 (100) and GA (100). These results showed an evolving trend in the meq genes of the isolates; three isolates exhibited higher morbidity as compared to the reference strain and the vaccine induced lower PIs against two isolates as compared to that against the reference strain. PMID- 26611442 TI - Identification and genetic analysis of H3N8 subtype influenza viruses isolated from domestic pigeons in Central China. AB - A novel strain of H3N8 influenza virus was isolated from domestic pigeons during the avian influenza virus (AIV) surveillance in wet markets in Anhui, China, during 2013. The virus was characterized by whole-genome sequencing with subsequent genetic comparison and phylogenetic analysis. Phylogenetic analysis revealed that the NA gene of AIV mapped to the North American lineage, and the remaining seven genes belong to a Eurasian lineage. These findings indicated that this H3N8 virus is a novel nature reassortant virus. Comparison of the hemagglutinin amino acid sequences indicated 9 substitutions. One substitution caused the loss of a potential glycosylation site, and six substitutions were not previously observed in avian H3 isolates. Q226 and T228 at the receptor binding sites suggested that Anhui-08 preferentially binds to a-2,3-linked sialic acid receptors, and the cleavage site sequence showed a low pathogenic feature. Animal experiments further confirmed that A/pigeon/Anhui/08/2013 (H3N8) is low or in pigeons. The results improve our understanding of these viruses as they evolve and also provide important information to aid ongoing risk assessment analyses because these zoonotic influenza viruses continue to circulate and adapt to new hosts. PMID- 26611443 TI - Microencapsulation of probiotics in hydrogel particles: enhancing Lactococcus lactis subsp. cremoris LM0230 viability using calcium alginate beads. AB - Probiotics are beneficial microbes often added to food products to enhance the health and wellness of consumers. A major limitation to producing efficacious functional foods containing probiotic cells is their tendency to lose viability during storage and gastrointestinal transit. In this study, the impact of encapsulating probiotics within food-grade hydrogel particles to mitigate sensitivity to environmental stresses was examined. Confocal fluorescence microscopy confirmed that Lactococcus lactis were trapped within calcium alginate beads formed by dripping a probiotic-alginate mixture into a calcium solution. Encapsulation improved the viability of the probiotics during aerobic storage: after seven days, less than a two-log reduction was observed in encapsulated cells stored at room temperature, demonstrating that a high concentration of cells survived relative to non-encapsulated bacteria. These hydrogel beads may have applications for improving the stability and efficacy of probiotics in functional foods. PMID- 26611445 TI - The cost-effective synthesis of furan- and thienyl-based microporous polyaminals for adsorption of gases and organic vapors. AB - This work reveals that furfural and 2-thenaldehyde can readily react with melamine via "one-step" polycondensation to yield hyper-cross-linked sulfur-, nitrogen- and oxygen-rich microporous polyaminals with promising applications in adsorption of gases and toxic organic vapors. PMID- 26611453 TI - Addressing Resident and Fellow Mental Health and Well-Being: What Can You Do in Your Department? PMID- 26611444 TI - omega-Tbo-IT1-New Inhibitor of Insect Calcium Channels Isolated from Spider Venom. AB - Novel disulfide-containing polypeptide toxin was discovered in the venom of the Tibellus oblongus spider. We report on isolation, spatial structure determination and electrophysiological characterization of this 41-residue toxin, called omega Tbo-IT1. It has an insect-toxic effect with LD50 19 MUg/g in experiments on house fly Musca domestica larvae and with LD50 20 MUg/g on juvenile Gromphadorhina portentosa cockroaches. Electrophysiological experiments revealed a reversible inhibition of evoked excitatory postsynaptic currents in blow fly Calliphora vicina neuromuscular junctions, while parameters of spontaneous ones were not affected. The inhibition was concentration dependent, with IC50 value 40 +/- 10 nM and Hill coefficient 3.4 +/- 0.3. The toxin did not affect frog neuromuscular junctions or glutamatergic and GABAergic transmission in rat brains. Ca(2+) currents in Calliphora vicina muscle were not inhibited, whereas in Periplaneta americana cockroach neurons at least one type of voltage gated Ca(2+) current was inhibited by omega-Tbo-IT1. Thus, the toxin apparently acts as an inhibitor of presynaptic insect Ca(2+) channels. Spatial structure analysis of the recombinant omega-Tbo-IT1 by NMR spectroscopy in aqueous solution revealed that the toxin comprises the conventional ICK fold containing an extended beta-hairpin loop and short beta-hairpin loop which are capable of making "scissors-like mutual motions". PMID- 26611454 TI - 50 Years Ago in The Journal of Pediatrics: Immunosuppressive Therapy in Persistent Hypocomplementemic Glomerulonephritis and Lupus Nephritis. PMID- 26611455 TI - 50 Years Ago in The Journal of Pediatrics: Bacterial Endocarditis in Infants and Children. PMID- 26611456 TI - 50 Years Ago in The Journal of Pediatrics: Hydrocephalus. PMID- 26611457 TI - 50 Years Ago in The Journal of Pediatrics: Cardiac Arrhythmias in Normal Newborn Infants. PMID- 26611458 TI - The Economic Burden of Child Maltreatment in High Income Countries. PMID- 26611459 TI - The ATM-BID pathway plays a critical role in the DNA damage response by regulating mitochondria metabolism. PMID- 26611460 TI - Chronic lymphocytic leukemia: looking into the dark side of the genome. PMID- 26611461 TI - Deciding to Cooperate in Northern Ghana: Trust as an Evolutionary Constraint Across Cultural Diversity. AB - The upper-east and northern regions of Ghana offers a unique opportunity to study the influence of evolutionary social dynamics in making cooperation possible, despite cultural differences. These regions are occupied by several distinct ethnic groups, in interaction, such as the Kussasi, Mamprusi, Bimoba, Konkomba, and Fulani. We will report our fieldwork related to how cooperation takes places there, both within each group and among people from the different groups. Methods included personal networks of cooperation (ego networks), interviews and analysis of group contexts. The most important result is that, while each ethnic group may differ in terms of family and clan structure, a similar pattern can be found in all of them, of cooperation structured around small groups of trust-based close relationships. The study suggests that habitual decisions about cooperation are not strategic or self-interested, but instead are based on unconscious processes sustained by the emotional bonds of trust. These kind of emotional bonds are claimed to be relevant from an evolutionary point of view. PMID- 26611462 TI - Efficacy of Concurrent Chemotherapy for Intermediate Risk NPC in the Intensity Modulated Radiotherapy Era: a Propensity-Matched Analysis. AB - This study is to evaluate the efficacy of additional concurrent chemotherapy for intermediate risk (stage II and T3N0M0) NPC patients treated with intensity modulated radiotherapy (IMRT).440 patients with intermediate risk NPC were studied retrospectively, including 128 patients treated with IMRT alone [radiotherapy group (RT group)] and 312 paitents treated with IMRT plus concurrent chemotherapy [chemoradiotherapy group (CRT group)]. Propensity score matching was carried out to create RT and CRT cohorts equally matched for host and tumor factor. Significantly more severe acute toxicities were observed in the CRT group than in the RT group. Multivariate analyses of 440 patients failed to demonstrate concurrent chemotherapy as an independent prognostic factor for FFS, LR-FFS, and D-FFS. Between the well-matched RT cohort and the CRT cohort, no significant difference was demonstrated in all survival endpoints (FFS: 92.8% versus 91.2%, P = 0.801; LR-FFS: 95.2% versus 94.4%, P = 0.755; D-FFS: 96.4% versus 96.3%, P = 0.803; OS: 98.2% versus 98.9%, P = 0.276). Our results demonstrated that for patients with intermediate risk NPC treated with IMRT, additional concurrent chemotherapy did not provide any significant survival benefit but significantly more severe acute toxicities. However, prospective randomized trials are warranted for the ultimate confirm of our findings. PMID- 26611463 TI - High levels of isotope elimination improve precision and allow individual-based measurements of metabolic rates in animals using the doubly labeled water method. AB - Doubly labeled water (DLW) can be used to measure energy expenditure in free ranging animals, but questions have been raised about its accuracy in different species or contexts. We investigated whether differences in the extent of isotope elimination affects the precision and accuracy of the DLW method, which can vary according to the experimental design or metabolic rate of the species. Estimated total energy expenditure by the DLW method (TEEdlw) was compared with actual total energy expenditure simultaneously measured via respirometry (TEEresp) in streaked shearwaters Calonectris leucomelas, a pelagic seabird. Subjects were divided into three groups with different experimental conditions: at rest on the ground for 24 h (Group A) or for 48 h (Group B), and at rest on the water for 24 h (Group C). TEEdlw in Group A matched TEEresp, whereas there was an overestimation of TEEdlw in both Groups B and C compared with TEEresp. However, compared with Group A, TEEdlw in Groups B and C had reduced the isotopic analytical variability and thus higher precision. The best regression model (TEEdlw = 1.37 TEEresp - 14.12) showed a high correlation (R(2) = 0.82) between TEEdlw and TEEresp and allows a correction factor for field metabolic rates in streaked shearwaters. Our results demonstrate that the commonly made assumption that the DLW method is not appropriate for individual-based estimates may be incorrect in certain circumstances. Although a correction factor may be necessary when using the DLW method to estimate metabolic rate, greater levels of isotope eliminations provides DLW estimates with high precision, which can adequately represent relative individual estimates. Nevertheless, the DLW method, should be used with caution when characterizing interspecies difference of energy expenditures. PMID- 26611464 TI - Effects of muscle relaxation on sustained contraction of ipsilateral remote muscle. AB - The objective of this study was to clarify the temporal change of muscle activity during relaxation of ipsilateral remote muscles. While participants maintained a constant right wrist extensor isometric force, they dorsiflexed the ipsilateral ankle from resting position or relaxed from dorsiflexed position in response to an audio signal. The wrist extensor force magnitude increased in the 0-400 msec period after the onset of foot contraction compared to that of the resting condition (P < 0.05). On the other hand, wrist extensor force magnitude and electromyographic (EMG) activity decreased in the 0-400 msec period after the onset of ankle dorsiflexion compared to that of the resting condition (P < 0.05). Our findings suggest that foot muscle relaxation induces temporal reduction in hand muscle EMG activity and force magnitude. PMID- 26611465 TI - Pericolactines A-C, a New Class of Diterpenoid Alkaloids with Unusual Tetracyclic Skeleton. AB - Fusicoccane diterpenoids usually possess a fused 5-8-5 tricyclic ring system, which are biogenetically generated from geranylgeranyl diphosphate (GGDP). In our report, three novel diterpenoid alkaloids with fusicoccane skeleton, pericolactines A-C (1-3), were isolated from Periconia sp.. Their structures with absolute configurations were determined by spectroscopic analyses and quantum chemical ECD calculation. Pericolactines A-C (1-3) are a new class of diterpenoid alkaloids with an unusual fused 5-5-8-5 tetracyclic ring system, which derive from a geranylgeranyl diphosphate (GGDP) and serine conjugated biosynthesis. They belong to the atypical diterpenoid alkaloids. PMID- 26611466 TI - Validity and Reliability of GraphClick and DataThief III for Data Extraction. AB - Researchers frequently rely on meta-analyses of prior research studies to efficiently evaluate a broad spectrum of results on a particular topic. In the realm of single-subject experimental designs (SSEDs), meta-analyses have a particular cachet: retaining the rigor of single-subject designs with the added robustness of replication to more fully determine the strength of a given approach or intervention. Until recently, researchers wishing to undertake meta analytic research themselves have had limited options for synthesizing the intervention effects of a collection of studies. Researchers consistently use two software programs, DataThief III and GraphClick, to conduct meta-analytic work using SSEDs. The purpose of this study was to evaluate and compare the validity and reliability of the results yielded by each of these programs when evaluating the results of multiple research studies on the Good Behavior Game, a classroom based intervention that has been in practice since 1969. Study findings suggest that both GraphClick and DataThief III provide valid methods of data extraction. In addition, both programs allow for reliable extraction of data between raters and between software programs. Limitations and directions for future research are explored. PMID- 26611467 TI - Preliminary Evaluation of the Values Tracker: A Two-Item Measure of Engagement in Valued Activities in Those With Chronic Pain. AB - Engagement in valued activities is an important outcome, particularly in treatments that aim to enhance quality of life in those with chronic conditions. The present study describes the initial evaluation of the Values Tracker (VT), a two-item measure of values engagement, in 302 treatment-seeking adults with chronic pain. Hierarchical regression analyses were conducted to examine the utility of the VT in the statistical prediction of pain-related functioning, after controlling for demographic variables, pain intensity, and pain-related distress. Across analyses, pain intensity accounted for significant variance (range DeltaR2 = .06-.09) with pain-related distress adding additional unique variance (range DeltaR2 = .07-.19). The VT accounted for additional unique variance (range DeltaR2 = .02-.17) for all variables with the exception of physical disability. These findings provide initial support for the utility of the VT in those with chronic pain. Given the VT's brevity, it may be particularly useful for tracking changes in engagement in values across sessions. PMID- 26611468 TI - Monitoring patients on chronic treatment with antidepressants between 2003 and 2011: analysis of factors associated with compliance. AB - BACKGROUND: Clinical practice guidelines consider the use of antidepressants as one of the standard treatments for anxiety disorders, due to the significant improvements obtained in quality of life and functional disability. In addition, in patients who have not achieved a favorable response after 3 months of psychotherapy, antidepressants are recommended as part of a combined treatment approach. This combination with psychotropic drugs and psychotherapy appears to be indicated from baseline in patients with moderate, severe or recurrent depression. In the last decade, antidepressant prescription rates in general practice have increased between 4 and 10 times. Depression presents high rates of relapse and recurrence. Treatment is often interrupted prematurely, leading to increases in both relapse rates and health care costs. Few studies have analysed the chronic use of antidepressant drugs and long-term adherence. OBJECTIVE: To evaluate compliance with antidepressant treatment between 2003 and 2011 and to explore the associated factors. METHODS: Retrospective cohort study of antidepressant dispensing. SETTING: Health Region of Lleida between 2003 and 2011. PARTICIPANTS: Patients with chronic prescription of antidepressants (ATC code NO6A) during 2003 were followed up until December 2011. The sample comprised 3684 subjects. MAIN MEASURES: The compliance rate was calculated on the basis of the number of units withdrawn from the pharmacy and the theoretical number of units required according to the scheduled duration of treatment: compliance was defined in cases with scores greater than or equal to 80%. RESULTS: 12.5% of patients received chronic antidepressant treatment for at least 4 years. Mean age was 54 years, and 73.2% of patients were female. Almost a third (32.4%) presented anxiety disorders and 26.5% mood disorders. The overall compliance rate was 22% (28% in patients with depression, and 21% in patients with anxiety). According to gender, compliance rates were 21.4% for males and 22.4% for females. Compliance was more likely in patients with polypharmacy. CONCLUSIONS: One in 4 patients complied with treatment. Factors associated with better compliance were polypharmacy and diagnosis of depressive or mixed anxiety-depressive disorder. PMID- 26611469 TI - Ultrasonography of thyroid nodules: a pictorial review. AB - Thyroid nodules are a common occurrence in the general population, and these incidental thyroid nodules are often referred for ultrasound (US) evaluation. US provides a safe and fast method of examination. It is sensitive for the detection of thyroid nodules, and suspicious features can be used to guide further investigation/management decisions. However, given the financial burden on the health service and unnecessary anxiety for patients, it is unrealistic to biopsy every thyroid nodule to confirm diagnosis. The British Thyroid Association (BTA) has recently produced a US classification (U1-U5) of thyroid nodules to facilitate the decision-making process regarding the need to perform fine-needle aspiration cytology (FNAC) for suspicious cases. In this pictorial review, we provide a complete series of sonographic images to illustrate benign and malignant features of thyroid nodules according to the U1-5 classification. Specifically, we highlight morphologic characteristic of the nodule, including its echo signal in relation to its consistency, nodular size, number and contour. Additional diagnostic features such as halo, colloid, calcification and vascular patterns are also discussed in detail. The aim is to assist radiologists and clinicians in recognising sonographic patterns of benign, suspicious and malignant nodules based on U1-5 criteria, and in planning for further investigations. MAIN MESSAGES: * Ultrasound is sensitive in identifying suspicious features, which require aspiration. * Whether nodules require aspiration should be based on sonographic features and clinical findings. * U1-5 classification of sonographic findings can help determine whether aspiration is necessary. PMID- 26611470 TI - Computational fluid dynamics simulations of blood flow regularized by 3D phase contrast MRI. AB - BACKGROUND: Phase contrast magnetic resonance imaging (PC-MRI) is used clinically for quantitative assessment of cardiovascular flow and function, as it is capable of providing directly-measured 3D velocity maps. Alternatively, vascular flow can be estimated from model-based computation fluid dynamics (CFD) calculations. CFD provides arbitrarily high resolution, but its accuracy hinges on model assumptions, while velocity fields measured with PC-MRI generally do not satisfy the equations of fluid dynamics, provide limited resolution, and suffer from partial volume effects. The purpose of this study is to develop a proof-of concept numerical procedure for constructing a simulated flow field that is influenced by both direct PC-MRI measurements and a fluid physics model, thereby taking advantage of both the accuracy of PC-MRI and the high spatial resolution of CFD. The use of the proposed approach in regularizing 3D flow fields is evaluated. METHODS: The proposed algorithm incorporates both a Newtonian fluid physics model and a linear PC-MRI signal model. The model equations are solved numerically using a modified CFD algorithm. The numerical solution corresponds to the optimal solution of a generalized Tikhonov regularization, which provides a flow field that satisfies the flow physics equations, while being close enough to the measured PC-MRI velocity profile. The feasibility of the proposed approach is demonstrated on data from the carotid bifurcation of one healthy volunteer, and also from a pulsatile carotid flow phantom. RESULTS: The proposed solver produces flow fields that are in better agreement with direct PC-MRI measurements than CFD alone, and converges faster, while closely satisfying the fluid dynamics equations. For the implementation that provided the best results, the signal-to error ratio (with respect to the PC-MRI measurements) in the phantom experiment was 6.56 dB higher than that of conventional CFD; in the in vivo experiment, it was 2.15 dB higher. CONCLUSIONS: The proposed approach allows partial or complete measurements to be incorporated into a modified CFD solver, for improving the accuracy of the resulting flow fields estimates. This can be used for reducing scan time, increasing the spatial resolution, and/or denoising the PC-MRI measurements. PMID- 26611471 TI - Concomitant gain of 1q21 and MYC translocation define a poor prognostic subgroup of hyperdiploid multiple myeloma. PMID- 26611472 TI - Polymorphism in TGFB1 is associated with worse non-relapse mortality and overall survival after stem cell transplantation with unrelated donors. AB - Transforming growth factor beta-1, encoded by the TGFB1 gene, is a cytokine that plays a central role in many physiological and pathogenic processes. We have sequenced TGFB1 regulatory region and assigned allelic genotypes in a large cohort of hematopoietic stem cell transplantation patients and donors. In this study, we analyzed 522 unrelated donor-patient pairs and examined the combined effect of all the common polymorphisms in this genomic region. In univariate analysis, we found that patients carrying a specific allele, 'p001', showed significantly reduced overall survival (5-year overall survival 30.7% for p001/p001 patients vs. 41.6% others; P=0.032) and increased non-relapse mortality (1-year non-relapse mortality: 39.0% vs. 25.4%; P=0.039) after transplantation. In multivariate analysis, the presence of a p001/p001 genotype in patients was confirmed as an independent factor for reduced overall survival [hazard ratio=1.53 (1.04-2.24); P=0.031], and increased non-relapse mortality [hazard ratio=1.73 (1.06-2.83); P=0.030]. In functional experiments we found a trend towards a higher percentage of surface transforming growth factor beta-1-positive regulatory T cells after activation when the cells had a p001 allele (P=0.07). Higher or lower production of transforming growth factor beta-1 in the inflammatory context of hematopoietic stem cell transplantation may influence the development of complications in these patients. Findings indicate that TGFB1 genotype could potentially be of use as a prognostic factor in hematopoietic stem cell transplantation risk assessment algorithms. PMID- 26611473 TI - The addition of rituximab to fludarabine and cyclophosphamide chemotherapy results in a significant improvement in overall survival in patients with newly diagnosed mantle cell lymphoma: results of a randomized UK National Cancer Research Institute trial. AB - Mantle cell lymphoma is an incurable and generally aggressive lymphoma that is more common in elderly patients. Whilst a number of different chemotherapeutic regimens are active in this disease, there is no established gold standard therapy. Rituximab has been used widely to good effect in B-cell malignancies but there is no evidence that it improves outcomes when added to chemotherapy in this disease. We performed a randomized, open-label, multicenter study looking at the addition of rituximab to the standard chemotherapy regimen of fludarabine and cyclophosphamide in patients with newly diagnosed mantle cell lymphoma. A total of 370 patients were randomized. With a median follow up of six years, rituximab improved the median progression-free survival from 14.9 to 29.8 months (P<0.001) and overall survival from 37.0 to 44.5 months (P=0.005). This equates to absolute differences of 9.0% and 22.1% for overall and progression-free survival, respectively, at two years. Overall response rates were similar, but complete response rates were significantly higher in the rituximab arm: 52.7% vs. 39.9% (P=0.014). There was no clinically significant additional toxicity observed with the addition of rituximab. Overall, approximately 18% of patients died of non lymphomatous causes, most commonly infections. The addition of rituximab to fludarabine and cyclophosphamide chemotherapy significantly improves outcomes in patients with mantle cell lymphoma. However, these regimens have significant late toxicity and should be used with caution. This trial has been registered (ISRCTN81133184 and clinicaltrials.gov:00641095) and is supported by the UK National Cancer Research Network. PMID- 26611475 TI - Time-dependent effects of clinical predictors in unrelated hematopoietic stem cell transplantation. AB - Hematopoietic stem cell transplantation is a multifactorial process. Some of the predictors exhibit time-dependent effects. We present a systematic analysis and description of selected clinical predictors influencing outcome in a time dependent manner based on an analysis of registry data from the German Registry for Stem Cell Transplantation. A total of 14,951 patients with acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome and non-Hodgkin lymphoma transplanted with peripheral blood stem cells or bone marrow grafts were included. Multivariate Cox regression models were tested for time-dependent effects within each diagnosis group. Predictors not satisfying the proportional hazards assumption were modeled in a time-dependent manner, extending the Cox regression models. Similar patterns occurred in all diagnosis groups. Patients with a poor Karnofsky performance score (<80) had a high risk for early mortality until day 139 following transplantation (HR 2.42, CI: 2.19-2.68; P<0.001) compared to patients with a good Karnofsky performance score (80-100). Afterwards the risk reduced to HR 1.43, CI: 1.25-1.63; P<0.001. A lower mortality risk was found for patients after conditioning treatment with reduced intensity until day 120 post transplant (HR: 0.81 CI: 0.75-0.88; P<0.001). After this, a slightly higher risk could be shown for these patients. Similarly, patients who had received a PBSC graft exhibited a significantly lower mortality risk until day 388 post transplantation (HR 0.79, CI: 0.73-0.85; P<0.001), reversing to a significantly higher risk afterwards (HR 1.23, CI: 1.08-1.40; P=0.002). Integrating time dependency in regression models allows a more accurate description and quantification of clinical predictors to be made, which may help in risk assessment and patient counseling. PMID- 26611474 TI - A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis. AB - Thymic stromal lymphopoietin (TSLP) stimulates in-vitro proliferation of human fetal B-cell precursors. However, its in-vivo role during normal human B lymphopoiesis is unknown. Genetic alterations that cause overexpression of its receptor component, cytokine receptor-like factor 2 (CRLF2), lead to high-risk B cell acute lymphoblastic leukemia implicating this signaling pathway in leukemogenesis. We show that mouse thymic stromal lymphopoietin does not stimulate the downstream pathways (JAK/STAT5 and PI3K/AKT/mTOR) activated by the human cytokine in primary high-risk leukemia with overexpression of the receptor component. Thus, the utility of classic patient-derived xenografts for in-vivo studies of this pathway is limited. We engineered xenograft mice to produce human thymic stromal lymphopoietin (+T mice) by injection with stromal cells transduced to express the cytokine. Control (-T) mice were produced using stroma transduced with control vector. Normal levels of human thymic stromal lymphopoietin were achieved in sera of +T mice, but were undetectable in -T mice. Patient-derived xenografts generated from +T as compared to -T mice showed a 3-6-fold increase in normal human B-cell precursors that was maintained through later stages of B-cell development. Gene expression profiles in high-risk B-cell acute lymphoblastic leukemia expanded in +T mice indicate increased mTOR pathway activation and are more similar to the original patient sample than those from -T mice. +T/-T xenografts provide a novel pre-clinical model for understanding this pathway in B lymphopoiesis and identifying treatments for high-risk B-cell acute lymphoblastic leukemia with overexpression of cytokine-like factor receptor 2. PMID- 26611476 TI - A patient with odynophagia and unusual endoscopic findings. AB - The case describes a 50-year-old woman presenting with a severe painful dysphagia to solids, impacting on her nutritional intake. She had a history of pemphigus vulgaris maintained in remission with azathioprine, with no evidence of active oral or cutaneous disease at the time of presentation. Endoscopy and histology from the distal oesophagus revealed oesophageal involvement of pemphigus vulgaris. This is a relatively rare clinical form of the disease, with only 58 cases reported worldwide. Patients with pemphigus vulgaris are also prone to infective or steroid-induced gastritis, which present in the same way. Early endoscopic evaluation is therefore essential to distinguish between oesophageal involvement of pemphigus vulgaris and other pathologies, which warrant significant differences in management. PMID- 26611477 TI - Generalised reversible encephalopathy syndrome: a variant of posterior reversible encephalopathy syndrome (PRES). AB - Posterior reversible encephalopathy syndrome (PRES) is a clinical-radiological syndrome characterised by headache, visual disturbance, seizures and altered consciousness. Radiological findings show hyperintense T2-lesions on MRI, predominantly located in the subcortical white matter of the posterior occipital and parietal lobes. We report the case of a 74-year-old woman with adenocarcinoma of the gastric cardia who developed severe neurological signs and symptoms. MRI of the brain showed atypical generalised hyperintense lesions on T2 and fluid attenuated inversion recovery sequences. Under symptomatic treatment, the radiological changes as well as neurological signs and symptoms improved. Several potential risk factors for PRES, such as hypertensive crisis, blood transfusions, infection and cancer, were identified in our patient, whereby perhaps the coexistence of these risk factors led to the unusual radiological and clinical manifestation of a generalised PRES variant. PMID- 26611478 TI - Acute compartment syndrome risk in fracture fixation with regional blocks. AB - Acute compartment syndrome is a surgical emergency that most commonly occurs after trauma or reperfusion after prolonged arterial occlusion. It is caused by a build-up of blood and oedema fluid within a closed muscle compartment, and can be limb and life-threatening. It is therefore imperative that a prompt diagnosis is made. The risk of developing this condition is <1% in patients with distal radius fractures and 4-5% in those with tibial diaphyseal fractures. Pain management is an important aspect of treatment following any fracture. Regional anaesthesia can be used during surgical fixation of the fracture and has the potential to reduce the need for specialist postoperative care and analgesia, as well as to shorten the length of hospitalisation. With this case report, we hope to highlight the potential risk of masking symptoms of compartment syndrome while using regional blocks, as this can cause a delay in diagnosis and treatment, leading to associated complications. PMID- 26611479 TI - Metastatic pancreatic cancer: abdominal pain in a 22-year-old woman. AB - Pancreatic cancer remains fourth among cancer-related deaths. Its diagnosis is often missed, owing to its vague abdominal symptoms, leading to a diagnosis of stage IV pancreatic cancer. FOLFIRINOX chemotherapy was administered to the patient in this report, resulting in significant improvement based on tests of biological markers as well as radiographic resolution of the metastatic disease. A keen awareness of this condition along with appropriate diagnostic tests can allow for an earlier diagnosis and may impact its high mortality. PMID- 26611480 TI - Correction. PMID- 26611481 TI - Bardet-Biedl syndrome: multiple fingers with multiple defects! AB - Bardet-Biedl syndrome (BBS) is a rare congenital ciliopathy characterised by rod cone dystrophy, postaxial polydactyly, central obesity, mental retardation, hypogonadism and renal dysfunction. A 45-year-old Indian man presented with New York Heart Association class 2 dyspnoea of 3 months duration. He was blind since childhood. He was obese, cyanosed, and had clubbing and polydactyly. Systemic examination revealed presence of wide and fixed split second heart sound with systolic murmur in the left parasternal area. Work up unmasked the presence of secondary polycythaemia, atypical retinitis pigmentosa and partial atrioventricular defect. He was diagnosed to have BBS based on clinical and radiological features. This case is interesting for its rarity and also for the peculiarity of its cardiovascular association. Polydactyly with a suspicious clinical background is the clue and by itself warrants the clinician to search for occult anomalies. Clinicians must be aware of this syndrome, for which an early diagnosis and a multidisciplinary approach will significantly improve mortality and morbidity in patients. PMID- 26611482 TI - The first report of a previously undescribed EBV-negative NK-cell lymphoma of the GI tract presenting as chronic diarrhoea with eosinophilia. AB - A 74-year-old man presented with a 2-month history of watery diarrhoea. His complete blood count showed lymphopaenia and marked eosinophilia. Investigations for common infectious causes including Clostridium difficile toxin, stool culture, ova and parasites were negative. Endoscopy revealed extensive colitis and a CT of the abdomen identified numerous large abdominal lymph nodes suspicious for lymphoma. Multiple tissue samples were obtained; colon, mesenteric lymph node and bone marrow biopsy, as well as pleural fluid from a rapidly developing effusion, confirmed the presence of metastatic lymphoma with an immunophenotype most consistent with an aggressive variant of Epstein-Barr virus (EBV)-negative natural killer (NK)-cell lymphoma. The patient's clinical condition rapidly deteriorated and he died shortly following diagnosis. To the best of our knowledge, this is the first case report of a primary gastrointestinal EBV-negative NK-cell lymphoma, and its clinical presentation highlights the importance of a broad differential in the management of chronic diarrhoea. PMID- 26611483 TI - Longitudinally extensive transverse myelitis with anti-NMDA receptor antibodies during a systemic lupus erythematosus flare-up. AB - Transverse myelitis (TM) with systemic lupus erythematosus (SLE) has been linked to the presence of autoantibodies (eg, antiaquaporin 4 (AQP4) and anticardiolipin (aCL)) and SLE-induced secondary vasculitis, but the aetiology remains incompletely understood. A 48-year-old Japanese man with a 6-year history of poorly controlled SLE had stopped glucocorticoid therapy 1 year before admission. 3 days before admission, he developed flaccid paraplegia. Spinal MRI showed a longitudinally hyperintense T2 grey matter lesion from the level of Th4 to the conus medullaris, which was considered longitudinally extensive TM (LETM). We administered steroid pulse therapy (methyl-prednisolone 1000 mg/day) for 3 days and prednisolone 50 mg/day. The patient's flaccid paralysis gradually improved. We concluded that the patient's TM was caused by SLE flare-up, even though we could not completely rule out antiphospholipid syndrome. SLE myelitis is relatively rare and many aetiologies are possible for TM in SLE. PMID- 26611484 TI - Miliaria crystallina: relevance in patients with hemato-oncological febrile neutropenia. PMID- 26611485 TI - Ventricular fibrillation after elective surgery in an adolescent with long QT syndrome. AB - Congenital long QT syndrome (LQTS) is a potentially lethal but highly treatable channelopathy. Along with multiple risk reduction measures, a recommendation for left sympathetic cardiac denervation therapy and/or implantable cardioverter defibrillator is made for higher risk patients. Despite its relatively common incidence in paediatric patients, there are no formal recommendations regarding perioperative management and discharge criteria for LQTS patients undergoing ambulatory surgery. This report describes a 17-year-old girl, diagnosed with congenital LQTS at 9 years of age, who had an episode of ventricular fibrillation the day after elective ear, nose and throat surgery. Despite several risk factors, she had a same-day dismissal, was not adequately monitored postoperatively and her cardiologists were not notified of her procedure. For the high-risk LQTS patient, we recommend monitoring of perioperative electrolytes and rhythm, postoperative ECG, adequate beta-blockade therapy, avoidance of particular pharmacological agents, consideration of overnight observation and communication with the patient's cardiologist prior to procedure, and at discharge. PMID- 26611486 TI - Proteus endocarditis in an intravenous drug user. AB - Infective endocarditis (IE) is a life-threatening condition with adverse consequences and increased mortality, despite improvements in treatment options. Diagnosed patients usually require a prolonged course of antibiotics, with up to 40-50% requiring surgery during initial hospital admission. We report a case of a 42-year-old intravenous drug user who presented feeling generally unwell, with lethargy, rigours, confusion and a painful swollen right leg. He was subsequently diagnosed with Proteus mirabilis endocarditis (fulfilling modified Duke criteria for possible IE) and deep vein thrombosis (DVT). He was successfully treated with single antibiotic therapy without needing surgical intervention or requiring anticoagulation for his DVT. Proteus endocarditis is extremely uncommon, with a limited number of case reports available in the literature. This case illustrates how blood cultures are invaluable in the diagnosis of IE, especially that due to unusual microorganisms. Our case also highlights how single antibiotic therapy can be effective in treating Proteus endocarditis. PMID- 26611487 TI - Dysphagia to liver failure. PMID- 26611488 TI - Abdominal actinomycosis mimicking acute appendicitis. AB - A 52-year-old Hispanic woman presented to the emergency department, reporting worsening sharp lower right quadrant abdominal pain for 3 days. CT of the abdomen and pelvis showed evidence of inflammation in the peritoneal soft tissues adjacent to an enlarged and thick-walled appendix, an appendicolith, no abscess formation and a slightly thickened caecum consistent with acute appendicitis. During laparoscopic appendectomy, the caecum was noted to be firm, raising suspicion of malignancy. Surgical oncology team was consulted and open laparotomy with right hemicolectomy was performed. Pathology reported that the ileocaecal mass was not a malignancy but was, rather, actinomycosis. The patient was discharged after 10 days of intravenous antibiotics in the hospital, with the diagnosis of abdominal actinomycosis. Although the original clinical and radiological findings in this case were highly suggestive of acute appendicitis, abdominal actinomycosis should be in the differential for right lower quadrant pain as it may be treated non-operatively. PMID- 26611490 TI - Experimental pencil beam kernels derivation for 3D dose calculation in flattening filter free modulated fields. AB - This paper presents a method to obtain the pencil-beam kernels that characterize a megavoltage photon beam generated in a flattening filter free (FFF) linear accelerator (linac) by deconvolution from experimental measurements at different depths. The formalism is applied to perform independent dose calculations in modulated fields. In our previous work a formalism was developed for ideal flat fluences exiting the linac's head. That framework could not deal with spatially varying energy fluences, so any deviation from the ideal flat fluence was treated as a perturbation. The present work addresses the necessity of implementing an exact analysis where any spatially varying fluence can be used such as those encountered in FFF beams. A major improvement introduced here is to handle the actual fluence in the deconvolution procedure. We studied the uncertainties associated to the kernel derivation with this method. Several Kodak EDR2 radiographic films were irradiated with a 10 MV FFF photon beam from two linacs from different vendors, at the depths of 5, 10, 15, and 20cm in polystyrene (RW3 water-equivalent phantom, PTW Freiburg, Germany). The irradiation field was a 50mm diameter circular field, collimated with a lead block. The 3D kernel for a FFF beam was obtained by deconvolution using the Hankel transform. A correction on the low dose part of the kernel was performed to reproduce accurately the experimental output factors. Error uncertainty in the kernel derivation procedure was estimated to be within 0.2%. Eighteen modulated fields used clinically in different treatment localizations were irradiated at four measurement depths (total of fifty-four film measurements). Comparison through the gamma-index to their corresponding calculated absolute dose distributions showed a number of passing points (3%, 3mm) mostly above 99%. This new procedure is more reliable and robust than the previous one. Its ability to perform accurate independent dose calculations was demonstrated. PMID- 26611489 TI - Impaired ATP6V0A2 expression contributes to Golgi dispersion and glycosylation changes in senescent cells. AB - Many genes and signaling pathways have been found to be involved in cellular senescence program. In the present study, we have identified 16 senescence associated genes by differential proteomic analysis of the normal human diploid fibroblast cell line, TIG-1, and focused on ATP6V0A2. The aim of this study is to clarify the role of ATP6V0A2, the causal gene for ARCL2, a syndrome of abnormal glycosylation and impaired Golgi trafficking, in cellular senescence program. Here we showed that ATP6V0A2 is critical for cellular senescence; impaired expression of ATP6V0A2 disperses the Golgi structure and triggers senescence, suggesting that ATP6V0A2 mediates these processes. FITC-lectin staining and glycoblotting revealed significantly different glycosylation structures in presenescent (young) and senescent (old) TIG-1 cells; reducing ATP6V0A2 expression in young TIG-1 cells yielded structures similar to those in old TIG-1 cells. Our results suggest that senescence-associated impaired expression of ATP6V0A2 triggers changes in Golgi structure and glycosylation in old TIG-1 cells, which demonstrates a role of ATP6V0A2 in cellular senescence program. PMID- 26611491 TI - Upside-Down. PMID- 26611492 TI - Importance of tumor size as a prognostic factor after partial liver resection for solitary hepatocellular carcinoma: Implications on the current AJCC staging system. AB - BACKGROUND: Presently, the impact of tumors size as a prognostic factor after curative liver resection (LR) for solitary hepatocellular carcinoma (HCC) remains controversial. This study was performed to determine the prognostic factors of patients undergoing LR for solitary HCC with special emphasis on the importance of tumor size. METHODS: Between 2000 and 2013, 560 patients underwent curative LR for solitary primary HCC which met the study criteria. RESULTS: One-hundred and seventy-eight patients underwent major hepatectomies and the overall in-hospital mortality was 2.0%. There were 282 patients (50.4%) with liver cirrhosis. The 5 year overall survival (OS) was 64% and recurrence free survival (RFS) was 50%, respectively. Multivariate analyses demonstrated that cirrhosis, microvascular invasion and size were independent predictors of RFS and cirrhosis, microvascular invasion and age were independent prognostic factors of OS. Subset analysis demonstrated that tumor size was a prognostic factor for solitary HCC with microvascular invasion (AJCC T2) but not solitary HCC without microvascular invasion (AJCC T1). CONCLUSIONS: Size, microvascular invasion, and cirrhosis are independent prognostic factors of RFS for solitary HCC after LR. Tumor size is an important prognostic factor in T2 but not T1 solitary tumors. These findings suggest that the current AJCC TNM staging system may need to be revised. PMID- 26611493 TI - Prognostic indices in stereotactic radiotherapy of brain metastases of non-small cell lung cancer. AB - BACKGROUND: Our purpose was to analyze the long-term clinical outcome and to identify prognostic factors after Linac-based stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) on patients with brain metastases (BM) from non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We performed a retrospective analysis of survival on 90 patients who underwent SRS or FSRT of intracranial NSCLC metastases between 04/2004 and 05/2014 that had not undergone prior surgery or whole brain radiotherapy (WBRT) for BM. Follow-up data was analyzed until May 2015. Potential prognostic factors were examined in univariable and multivariable analyses. The Golden Grading System (GGS), the disease-specific graded prognostic assessment (DS-GPA), the RADES II prognostic index as well as the NSCLC-specific index proposed by Rades et al. in 2013 (NSCLC RADES) were calculated and their predictive values were tested in univariable analysis. RESULTS: The median follow-up time of the surviving patients was 14 months. The overall survival (OS) rate was 51 % after 6 months and 29.9 % after 12 months. Statistically significant factors of better OS after univariable analysis were lower International Union Against Cancer (UICC) stage at first diagnosis, histology of adenocarcinoma, prior surgery of the primary tumor and lower total BM volume. After multivariable analysis adenocarcinoma histology remained a significant factor; higher Karnofsky Performance Score (KPS) and the presence of extracranial metastases (ECM) were also significant. The RADES II and the NSCLC-RADES indices were significant predictors of OS. However, the NSCLC RADES failed to differentiate between intermediate- and low-risk patients. The DS GPA and GGS were not statistically significant predictors of survival in univariable analysis. CONCLUSION: The ideal prognostic index has not been defined yet. We believe that more specific indices will be developed in the future. Our results indicate that the histologic subtype of NSCLC could add to the prognostic value of specialized future indices. The RADES II index had the highest predictive value in the examined patient cohort. PMID- 26611494 TI - Effects of Expanded California Health Coverage on Hospitals: Implications for ACA Medicaid Expansions. AB - OBJECTIVE: To assess the effects on hospitals of early California actions to expand insurance coverage for low-income uninsured adults after passage of the Affordable Care Act. DATA SOURCES/STUDY SETTING: Data from the California Office of Statewide Health Planning and Development and the California Department of Health were merged with U.S. census data for 294 short-term general hospitals during the period 2009-2012. STUDY DESIGN: A difference-in-difference analysis was conducted with hospitals in counties that did not implement insurance expansions used as a comparison group. Variables examined included payer mix, costs of unreimbursed care, and hospital operating margin. Sensitivity analyses were conducted as well as a triple difference analysis. Effects were estimated for hospitals overall and by ownership type. PRINCIPAL FINDINGS: California insurance expansions primarily benefited for-profit hospitals, with these facilities experiencing significant decreases in self-pay patients, increases in county-covered patients, and reductions in charity care. Most models yielded no significant change in payer mix and conflicting changes in unreimbursed care for nonprofit hospitals. CONCLUSIONS: California hospitals that treated the most uninsured prior to insurance expansions did not as a group experience substantial benefit in terms of reduced uninsured burden or better financial performance after program expansions occurred. PMID- 26611495 TI - A pioneer protein is part of a large complex involved in trans-splicing of a group II intron in the chloroplast of Chlamydomonas reinhardtii. AB - Splicing of organellar introns requires the activity of numerous nucleus-encoded factors. In the chloroplast of Chlamydomonas reinhardtii, maturation of psaA mRNA encoding photosystem I subunit A involves two steps of trans-splicing. The exons, located on three separate transcripts, are flanked by sequences that fold to form the conserved structures of two group II introns. A fourth transcript contributes to assembly of the first intron, which is thus tripartite. The raa7 mutant (RNA maturation of psaA 7) is deficient in trans-splicing of the second intron of psaA, and may be rescued by transforming the chloroplast genome with an intron less version of psaA. Using mapped-based cloning, we identify the RAA7 locus, which encodes a pioneer protein with no previously known protein domain or motif. The Raa7 protein, which is not associated with membranes, localizes to the chloroplast. Raa7 is a component of a large complex and co-sediments in sucrose gradients with the previously described splicing factors Raa1 and Raa2. Based on tandem affinity purification of Raa7 and mass spectrometry, Raa1 and Raa2 were identified as interacting partners of Raa7. Yeast two-hybrid experiments indicate that the interaction of Raa7 with Raa1 and Raa2 may be direct. We conclude that Raa7 is a component of a multimeric complex that is required for trans-splicing of the second intron of psaA. The characterization of this psaA trans-splicing complex is also of interest from an evolutionary perspective because the nuclear spliceosomal introns are thought to derive from group II introns, with which they show mechanistic and structural similarity. PMID- 26611497 TI - Radial bisection of words and lines in right-brain-damaged patients with spatial neglect. AB - The bisection of lines positioned radially (with the two ends of the line close and far, with respect to the participant's body) has been less investigated than that of lines placed horizontally (with their two ends left and right, with respect to the body's midsagittal plane). In horizontal bisection, patients with left neglect typically show a rightward bias for both lines and words, greater with longer stimuli. As for radial bisection, available data indicate that neurologically unimpaired participants make a distal error, while results from right-brain-damaged patients with left spatial neglect are contradictory. We investigated the bisection of radially oriented words, with the prediction that, during bisection, linguistic material would be recoded to its canonical left-to right format in reading, with the performance of neglect patients being similar to that for horizontal words. Thirteen right-brain-damaged patients (seven with left spatial neglect) and fourteen healthy controls were asked to manually bisect 40 radial and 40 horizontal words (5-10 letters), and 80 lines, 40 radial and 40 horizontal, of comparable length. Right-brain-damaged patients with spatial neglect exhibited a proximal bias in the bisection of short radial words, with the proximal part corresponding to the final right part of horizontally oriented words. This proximal error was not found in patients without neglect and healthy controls. For bisection, short radial words may be recoded to the canonical orthographic horizontal format, unveiling the impact of left neglect on radially oriented stimuli. PMID- 26611496 TI - Ligand-Promoted Borylation of C(sp(3))-H Bonds with Palladium(II) Catalysts. AB - A quinoline-based ligand effectively promotes the palladium-catalyzed borylation of C(sp(3))-H bonds. Primary beta-C(sp(3))-H bonds in carboxylic acid derivatives as well as secondary C(sp(3))-H bonds in a variety of carbocyclic rings, including cyclopropanes, cyclobutanes, cyclopentanes, cyclohexanes, and cycloheptanes, can thus be borylated. This directed borylation method complements existing iridium(I)- and rhodium(I)-catalyzed C-H borylation reactions in terms of scope and operational conditions. PMID- 26611498 TI - Women's intentions to use fertility preservation to prevent age-related fertility decline. AB - The optimal age to cryopreserve oocytes for later use is before 36 years. Current users are on average 38 years old. In this cross-sectional study an online survey was constructed about the factors associated with the intentions of childless women aged 28-35 years to use fertility preservation (FP). Questions were derived from the Theory of Planned Behaviour (attitudes and subjective norms regarding FP and perceived behaviour control to do FP) and the Health Belief Model (perceived susceptibility of infertility, perceived severity of childlessness, barriers and benefits of FP and cue to use FP). Also addressed were parenthood goals, fertility knowledge and intentions to use FP within 2 years. The data were analysed using structural equation modelling. The Health Belief Model showed a good fit to the data (chi(2) [14, n = 257] = 13.63, P = 0.477; CFI = 1.000: RMSEA = 00, 90% CI [0.00-0.06]). Higher intentions to use FP were associated with feeling susceptible to infertility, considering FP useful to achieve parenthood, perceiving the implications of infertility as severe, expecting to have children at a later age and having fewer ethical concerns. This suggests an increase of fertility awareness is necessary for the optimal use of FP. PMID- 26611499 TI - Increasing fertility knowledge and awareness by tailored education: a randomized controlled trial. AB - Women of reproductive age have insufficient fertility knowledge and awareness. Reproductive lifespan and assisted reproduction are the primary areas in which awareness is lacking. Relatively simple interventions can be used to increase knowledge among university students; however, no intervention has been tested to date in a population with more varied education levels. The aim of this study was to evaluate which intervention most improved fertility knowledge in women attending a fertility centre for oocyte donation. A randomized controlled trial was conducted with three intervention groups: tailored, untailored and control. A questionnaire was administered on the day of the first consultation, and again at the oocyte retrieval. Two hundred and one women were enrolled and completed the pre-test, 109 started the cycle and 90 completed the post-test. The effect of the intervention was measured as the difference between the groups in their score from the pre-test to the post test. Only the tailored group showed a significant increase (+2.5; 95% CI [1.8, 3.3]; P = 0.001). Information relating to a woman's most fertile age and limits for childbearing were the most useful. Tailored oral education, therefore, increases fertility knowledge in young women, particularly in relation to their fertility lifespan. PMID- 26611500 TI - The effect of protein supplement concentration in embryo transfer medium on clinical outcome of IVF/ICSI cycles: a prospective, randomized clinical trial. AB - The aim of this prospective, randomized clinical trial (RCT) was to evaluate whether the supplemental protein concentration in embryo transfer (ET) medium affects the clinical outcomes in IVF-ET. A total of 750 patients undergoing IVF ET who met the inclusion criteria were randomly divided into three groups, according to the concentration of synthetic serum substitute (SSS) in ET medium as follows: 10% (Group A), 20% (Group B) and 50% (Group C). The patient characteristics and embryology data were all similar among the groups. The rates of implantation, clinical pregnancy and live birth were compared. Clinical pregnancy (44.61%, 48.79% and 45.49%), multiple pregnancy (24.18%, 28.71% and 25.0%), implantation (28.21%, 30.68% and 29.86%) and live birth (41.67%, 43.96% and 41.70%) rates in the three groups (A, B and C, respectively) showed no significant differences. This RCT demonstrates that supplemental protein concentration in the ET medium does not affect the treatment outcomes in IVF-ET. There was no statistical evidence to support the hypothesis that supplemental protein concentration in the ET medium influences treatment outcomes in IVF-ET. PMID- 26611501 TI - Obesity and psychological wellbeing in patients undergoing fertility treatment. AB - Obesity negatively affects reproductive functioning and psychological wellbeing. Distress experienced by infertile women with elevated body mass index (BMI) was investigated. Infertile women (n = 403) were stratified according to World Health Organization (2000) BMI categories (normal, overweight and obese) and infertility category (polycystic ovary syndrome [PCOS] or non-PCOS). Participants anonymously completed a Demographics Questionnaire, International Physical Activity Questionnaire, Depression, Anxiety and Stress Scale, Positive and Negative Affect Schedule, Rosenberg Self Esteem Scale, Fertility Problem Inventory, Clinical Perfectionism Questionnaire and the Eating Disorder Examination Questionnaire. Women in the obese BMI group were no more psychologically vulnerable to general mood (depression, anxiety and stress) or fertility-specific distress than normal or overweight BMI women. Independent of their PCOS status, obese women reported more frequent episodes of binge eating, shape concerns and low self-esteem symptoms associated with disordered eating. Women with PCOS had elevated shape concerns and anxiety independent of their BMI category compared with women who did not have PCOS. Obese infertile women presenting with the characteristics of binge eating, low self-esteem and body shape concerns may represent a vulnerable subgroup that could benefit from accessing targeted psychological interventions as do women with PCOS who have body shape concerns. PMID- 26611502 TI - A Supramolecular Gel Approach to Minimize the Neural Cell Damage during Cryopreservation Process. AB - The storage method for living cells is one of the major challenges in cell-based applications. Here, a novel supramolecular gel cryopreservation system (BDTC gel system) is introduced, which can observably increase the neural cell viability during cryopreservation process because this system can (1) confine the ice crystal growth in the porous of BDTC gel system, (2) decrease the amount of ice crystallization and cryopreservation system's freezing point, and (3) reduce the change rates of cell volumes and osmotic shock. In addition, thermoreversible BDTC supramolecular gel is easy to be removed after thawing so it does not hinder the adherence, growth, and proliferation of cells. The results of functionality assessments indicate that BDTC gel system can minimize the neural cell damage during cryopreservation process. This method will be potentially applied in cryopreservation of other cell types, tissues, or organs and will benefit cell therapy, tissue engineering, and organs transplantation. PMID- 26611503 TI - Allogeneic MSC persistence may not be necessary for a beneficial effect in burn wound healing. PMID- 26611504 TI - The Biology of Pulmonary Metastasis. AB - The process of metastasis relies on a series of stochastic and sequential steps, with selective pressure exerted on a large number of genetically volatile cancer cells to produce a very small fraction of tumor cells with the ability to navigate the transition from primary tumor cell to end-organ metastasis. This process is intricately determined by cell-microenvironment interactions, the mechanistic understanding of which is steadily increasing. The continued elucidation of pathways that govern these interactions offers potential therapeutic options to patients with advanced disease. PMID- 26611505 TI - Preoperative Evaluation and Indications for Pulmonary Metastasectomy. AB - Most patients with pulmonary metastases will not be candidates for pulmonary metastasectomy. Preoperative evaluation determines whether a patient is both fit enough for surgery and has disease that is actually resectable. Both components are necessary for patients who undergo resection with curative intent. In general, to be considered for pulmonary metastasectomy, patients must fit the following criteria: the primary disease site and any extrathoracic disease are both controlled; complete resection of pulmonary involvement is achievable with adequate pulmonary reserve; and there are no effective medical therapies. PMID- 26611506 TI - Open Surgical Approaches for Pulmonary Metastasectomy. AB - Surgeons differ in the approach to resection of pulmonary metastases from nonpulmonary primary malignancies, with some favoring procedures that minimize trauma to the patient, and others performing open procedures with the goal of maximizing likelihood of resection of all detectable sites of disease. This article reviews how pulmonary metastasectomy emerged as a therapy for metastatic disease. Discussed is how surgical approaches used for this procedure have evolved, the available literature addressing whether open procedures lead to more complete resections, and if so whether resection by open procedures increases the likelihood of cure following resection. The technical aspects of the various thoracotomy techniques are also reviewed. PMID- 26611507 TI - Ablative Approaches for Pulmonary Metastases. AB - Pulmonary metastases are common in patients with cancer for which surgery is considered a standard approach in appropriately selected patients. A number of patients are not candidates for surgery due to a medical comorbidities or the extent of surgery required. For these patients, noninvasive or minimally invasive approaches to ablate pulmonary metastases are potential treatment strategies. This article summarizes the rationale and outcomes for non-surgical treatment approaches, including radiotherapy, radiofrequency and microwave ablation, for pulmonary metastases. PMID- 26611508 TI - Lymphadenectomy During Pulmonary Metastasectomy. AB - Pulmonary metastasectomy continues to be an effective approach to prolong survival in appropriately selected patients. The incidence of lymphatic spread is more common than previously recognized, with an estimate of 20% to 25% across multiple tumor types. The presence of metastatically involved lymph nodes adversely affects survival. What remains unclear is whether N1 vs N2, or the number of stations involved affects survival differently. The role of surgery for pulmonary metastasectomy in the patient with nodal metastases will likely expand with ongoing improvements in targeted and immunotherapies. PMID- 26611509 TI - Results of Pulmonary Resection: Colorectal Carcinoma. AB - Whether pulmonary metastasectomy improves survival in patients with metastatic colorectal cancer is controversial. Wedge resection is the most common form of surgical intervention. When anatomic resection is required, segmentectomy may be preferable to lobectomy for preservation of lung parenchyma. Each intervention to remove metastatic pulmonary parenchymal disease should consider future disease recurrence. Nonoperative modalities, such as radiofrequency ablation, cryoablation, and microwave ablation, are becoming more popular regarding parenchymal preservation. The future may embrace complex risk-profile analysis including molecular markers, nomograms to predict survival, and hybrid treatment approaches. Minimally invasive surgical techniques are used with increased frequency, making reoperative metastasectomy less tedious. PMID- 26611510 TI - Results of Pulmonary Resection: Sarcoma and Germ Cell Tumors. AB - Pulmonary metastasis occurs in as many as 88% and 80% of stage IV patients with sarcoma and germ cell tumors, respectively. Pulmonary metastatectomy may be the only means of rendering a patient disease free. Sublobar resection (wedge or segmentectomy), lobectomy, and pneumonectomy achieve complete resection. Bilateral disease can be resected via staged thoracoscopy/thoracotomy, median sternotomy, or clamshell thoracotomy. Multiple resections and re-resections have resulted in improved survival. Five-year survival rates as high as 35% to 52% for sarcoma and 80% for germ cell tumor can be realized. PMID- 26611512 TI - Immunotherapy for Resected Pulmonary Metastases. AB - Micrometastatic disease following pulmonary metastasectomy is an ideal setting to test adjuvant immunotherapy, as the efficacy of immunotherapy in experimental models is greatest with the smallest tumor burdens. Although there is not a standard-of-care adjuvant immunotherapy for resected pulmonary metastases, there have been several studies using cytokines and other immunostimulatory molecules in conjunction with metastasectomies in patients with melanoma, renal cell carcinoma, sarcoma, and colorectal cancer, which have provided preliminary data that such adjuvant therapy is feasible and safe and may be useful in the future, following more rigorous testing, as routine therapy to prevent recurrences. PMID- 26611511 TI - Isolated Lung Perfusion for Pulmonary Metastases. AB - Isolated lung perfusion (ILP) is a surgical technique developed to treat pulmonary metastases. During ILP, high-dose chemotherapy is delivered into the pulmonary vasculature, minimizing systemic exposure and delivering the chemotherapeutic agent directly to the lung. ILP has been studied extensively in a variety of animal models and in humans in phase I trials. The most frequently studied chemotherapeutic agents used in ILP are doxorubicin, 5-flurodeoxyuridine, tumor necrosis factor-alpha, paclitaxel, melphalan, gemcitabine, and cisplatin. Phase I clinical trials with ILP have shown that ILP can be safely performed in humans but with mixed clinical results and poor long-term survival. PMID- 26611513 TI - Is Surgery Warranted for Oligometastatic Disease? AB - The development of metastases after curative treatment can be seen as a failure. A common justification for the removal of metastases is that the knowledge that they are there may cause psychological distress, a real symptom that may be relieved by their removal. Although it is a commonly used justification for metastasectomy, the authors are unaware of any studies confirming or quantifying the health gain. This article strongly challenges the belief in clinical effectiveness and demonstrates that it is supported neither by a sound biological rationale nor by any good evidence. Reasons are suggested why this unfounded belief has become so prevalent. PMID- 26611514 TI - Thoracoscopic Management of Pulmonary Metastases. AB - In appropriately selected patients, resection of pulmonary metastases from various primary tumors can lead to improved survival. Metastasectomy has traditionally been performed by open thoracotomy; however, thoracoscopic resection offers the important benefits of a less invasive approach with more expeditious recovery. Concerns regarding missed lesions during thoracoscopy have not been realized in analyses of survival and may be offset by a policy of repeat metastasectomy for pulmonary recurrences. Despite the relative paucity of prospective trials, the preponderance of data supports the use of video-assisted thoracic surgery for pulmonary metastasectomy, which represents our preferred strategy for these patients. PMID- 26611515 TI - Results of Pulmonary Resection: Other Epithelial Malignancies. AB - This article summarizes the interdisciplinary work, survival, prognostic factors, and prognostic groups for lung metastases from breast cancer and renal cell cancer. Furthermore, the prevalence of lymph node metastases and the importance of a systematic lymph node dissection in metastasectomy of breast cancer and renal cell cancer for a true R0 resection are discussed. PMID- 26611516 TI - Thoracoscopic Lung Suffusion. AB - The lung is a common site of metastatic disease, which may be the only measurable malignancy in some patients. Unfortunately, because of the invasiveness of previous techniques and the fragility of these target organs, many attempts at regional lung therapies have not become that popular. Accordingly, a method for thoracoscopic vascular control to enable permeation of the lung with agents was developed and termed suffusion to distinguish it from earlier methods. This article describes the preclinical work supporting lung suffusion and our early human experience. PMID- 26611517 TI - Modern Management of Pulmonary Metastases. PMID- 26611518 TI - Investigation of the Characteristics of HeartWare HVAD and Thoratec HeartMate II Under Steady and Pulsatile Flow Conditions. AB - The aim of this study was to elucidate the dynamic characteristics of the Thoratec HeartMate II (HMII) and the HeartWare HVAD (HVAD) left ventricular assist devices (LVADs) under clinically representative in vitro operating conditions. The performance of the two LVADs were compared in a normothermic, human blood-filled mock circulation model under conditions of steady (nonpulsatile) flow and under simulated physiologic conditions. These experiments were repeated using 5% dextrose in order to determine its suitability as a blood analog. Under steady flow conditions, for the HMII, approximately linear inverse LVAD differential pressure (H) versus flow (Q) relationships were observed with good correspondence between the results of blood and 5% dextrose under all conditions except at a pump speed of 9000 rpm. For the HVAD, the corresponding relationships were inverse curvilinear and with good correspondence between the blood-derived and 5% dextrose-derived relationships in the flow rate range of 2-6 L/min and at pump speeds up to 3000 rpm. Under pulsatile operating conditions, for each LVAD operating at a particular pump speed, an counterclockwise loop was inscribed in the HQ domain during a simulated cardiac cycle (HQ loop); this showed that there was a variable phase relationship between LVAD differential pressure and LVAD flow. For both the HMII and HVAD, increasing pump speed was associated with a right-hand and upward shift of the HQ loop and simulation of impairment of left ventricular function was associated with a decrease in loop area. During clinical use, not only does the pressure differential across the LVAD and its flow rate vary continuously, but their phase relationship is variable. This behavior is inadequately described by the widely accepted representation of a plot of pressure differential versus flow derived under steady conditions. We conclude that the dynamic HQ loop is a more meaningful representation of clinical operating conditions than the widely accepted steady flow HQ curve. PMID- 26611520 TI - Burn and anchor: a novel food impaction retrieval technique. PMID- 26611521 TI - Single-operator cholangioscopy-guided holmium laser lithotripsy: the new-age "rescue" lithotripsy. PMID- 26611522 TI - Morphological analysis of the hagfish heart. I. The ventricle, the arterial connection and the ventral aorta. AB - We have studied the heart in three species of hagfish: Myxine glutinosa, Eptatretus stoutii, and Eptatretus cirrhatus and report about the morphology of the ventricle, the arterial connection and the ventral aorta. On the whole, the hagfish heart lacks outflow tract components, the ventricle and atrium adopt a dorso-caudal rather than a ventro-dorsal relationship, and the sinus venosus opens into the left side of the atrium. This may indicate a "defective" cardiac looping during embryogenesis. The ventral aorta is elongated in M. glutinosa and E. stoutii but sac-like in E. cirrhatus. The ventricles are entirely trabeculated. The myocytes show a low myofibrillar content and junctional complexes formed by fascia adherens and desmosomes. Gap junctions could not be demonstrated. Myocardial cells in M. glutinosa contain numerous lipid droplets. These droplets are less numerous in E. stoutii and practically absent in E. cirrhatus, suggesting different metabolic requirements. Other cell types present in the ventricle are chromaffin cells and granular leukocytes that contain rod shaped granules. The ventricle-aorta connection is guarded by a bicuspid valve with left and right, pocket-like leaflets. The leaflets extend from the cranial end of the ventricle into the aorta but the junction is asymmetrical. This junction contains a ganglion-like structure in E. cirrhatus. The ventral aorta shows endothelial, media, and adventitial layers. The media contains smooth muscle cells surrounded by dense bands formed by tightly-packed extracellular filaments. In addition, a short number of elastic fibers are observed in M. glutinosa and E. stoutii. Cellular and extracellular elements are more loosely organized in the aorta of E. cirrhatus. The collagenous adventitia contains ganglion-like cells in the three species. In the absence of nerves, chromaffin and ganglion-like cells may control the activity of the myocardium and that of the aortic smooth muscle cells, respectively. PMID- 26611523 TI - Human challenge trials in vaccine development: Strasbourg, September 29 - October 1, 2014. AB - An international workshop to discuss the role of Human Challenge Trials (HCT) in vaccine development was held in Strasbourg, France from 29 September to 1 October 2015. In addition to scientific presentations, several panel discussions focused on key questions and proposed recommendations, including the acknowledgement that HCT have proven to be useful tools to explore vaccine targets, identify immune correlates of protection, and evaluate clinical efficacy, and when appropriate they should be continued and encouraged. In some cases, a HCT may be the only feasible way to move forward with development of an investigational product. HCT must be strongly scientifically justified, because the need for a given investigational objective must be always balanced against the risks a HCT may pose, understanding that an infectious organism will be given to the study participants. It should be noted that numerous HCT have been successfully performed, safely and ethically, to the benefit of vaccine development and public health. This workshop report highlights the scientific presentations, discussions by the panelists and attendees, and twenty recommendations that emerged as considerations for future development of international guidance on the role of HCT in vaccine development and licensure. PMID- 26611524 TI - Bacaryolanes A-C, Rare Bacterial Caryolanes from a Mangrove Endophyte. AB - Caryolanes are known as typical plant-derived sesquiterpenes. Here we describe the isolation and full structure elucidation of three caryolanes, bacaryolane A-C (1-3), that are produced by a bacterial endophyte (Streptomyces sp. JMRC:ST027706) of the mangrove plant Bruguiera gymnorrhiza. By 2D NMR, analysis of the first X-ray crystallographic data of a caryolane (bacaryolane C), CD spectroscopy, and comparison with data for plant-derived caryolanes, we rigorously established the absolute configuration of the bacaryolanes and related compounds from bacteria. Bacterial caryolanes appear as the mirror images of typical plant caryolanes. Apparently plant and bacteria harbor stereodivergent biosynthetic pathways, which may be used as metabolic signatures. The discovery of plant-like volatile terpenes in endophytes not only is an important addition to the bacterial terpenome but may also point to complex molecular interactions in the plant-microbe association. PMID- 26611525 TI - The protective effect of different airway humidification liquids to lung after tracheotomy in traumatic brain injury: The role of pulmonary surfactant protein-A (SP-A). AB - The purpose of this study was to establish a rat model of a brain injury with tracheotomy and compared the wetting effects of different airway humidification liquids, afterward, the best airway humidification liquid was selected for the clinical trial, thus providing a theoretical basis for selecting a proper airway humidification liquid in a clinical setting. Rats were divided into a sham group, group A (0.9% NaCl), group B (0.45% NaCl), group C (0.9% NaCl+ambroxol) and group D (0.9% NaCl+Pulmicort). An established rat model of traumatic brain injury with tracheotomy was used. Brain tissue samples were taken to determine water content, while lung tissue samples were taken to determine wet/dry weight ratio (W/D), histological changes and expression levels of SP-A mRNA and SP-A protein. 30 patients with brain injury and tracheotomy were selected and divided into two groups based on the airway humidification liquid instilled in the trachea tube, 0.45% NaCl and 0.9% NaCl+ambroxol. Blood was then extracted from the patients to measure the levels of SP-A, interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha). The difference between group C and other groups in lung W/D and expression levels of SP-A mRNA and SP-A protein was significant (P<0.05). In comparison, the histological changes showed that the lung tissue damage was smallest in group C compared to the three other groups. Aspect of patients, 0.45% NaCl group and 0.9% NaCl+ambroxol group were significantly different in the levels of SP-A, IL-6, IL-8 and TNF-alpha (P<0.01). In the present study, 0.9% NaCl+ambroxol promote the synthesis and secretion of pulmonary surfactant, and has anti-inflammatory and antioxidant effects, which inhibit the release of inflammatory factors and cytokines, making it an ideal airway humidification liquid. PMID- 26611526 TI - Molecular characterization of the lgals1 gene in large scale loach Paramisgurnus dabryanus. AB - Galectins constitute a group of lectins with binding specificity for beta galactoside sugars. Galectin-1 is a prototype galectin and the multifunctionality of mammalian galectin-1s is well-known, but only a few of fish galectin-1s have been identified. In this study, we obtained the full-length cDNA and genomic sequence of the galectin-1 gene (designated as Pdlgals1) from large scale loach (Paramisgurnus dabryanus), performed phylogenetic analysis, and characterized the expression pattern and the transcriptional activity of its 5' flanking region. The Pdlgals1 gene contains 4 exons that encode a peptide of 132 amino acids with all the galectin signature motifs. Phylogenetic analysis and sequence alignment indicated that Pdlgals1 is a homologue of human LGALS1. RT-PCR and whole-mount in situ hybridization revealed that Pdlgals1 is mainly expressed in the skin, muscle, intestine and cavum oropharyngeum. Transcriptional activity assays demonstrated that the basal promoter of Pdlgals1 is located in a region from 500bp to its transcriptional start site. Potential binding sites for transcription factors including C/EBP, AP-1, GATA, Oct-1, deltaEF1, NF-kappaB, c Myb, SP-1, AP-2, AML-1alpha, and AP-4 were identified in the basal promoter, suggesting that these factors are associated with the regulation of Pdlgals1. These results provided clues for further investigation of galectin-1 functions in loaches. PMID- 26611527 TI - Characterization of the complete mitochondrial genome of tea tussock moth, Euproctis pseudoconspersa (Lepidoptera: Lymantriidae) and its phylogenetic implications. AB - In present work, we described the mitochondrial genome (mitogenome) of the tea tussock moth Euproctis pseudoconspersa (Lepidoptera: Lymantriidae). The complete mitogenome of E. pseudoconspersa is a circular genome 15,461 bp in size. It contains 37 genes and an A+T-rich region usually presented in lepidopteran mitogenomes, which genes share a lot of features with other known lepidopteran mitogenomes. Nucleotide composition of A+T in this mitogenome is 79.92%, and the AT skew is slightly positive. Both codon distribution and relative synonymous codon usage of the 13 protein-coding genes (PCGs) are consistent with those published lepidopteran sequences. All tRNA genes have typical cloverleaf secondary structures, except for the tRNA(Ser(AGN)), in which the dihydrouridine (DHU) arm is simplified down to a loop. The A+T-rich region of E. pseudoconspersa mitogenome possess the motif 'ATAGA' and poly-T stretch as the formerly identified conserved elements of Lepidoptera mitogenomes. The phylogenetic relationships were reconstructed by using maximum likelihood (ML) and Bayesian inference (BI) methods based on nucleotide sequences of 13 PCGs of 38 moths. The results were very consistent with the traditional relationships within Noctuoidea from morphological data, and showed that Lymantriidae is more closely related to Erebidae than to Noctuidae. PMID- 26611528 TI - Let-7b promotes alpaca hair growth via transcriptional repression of TGFbetaR I. AB - The young male alpaca ear and the back skins were used to investigate the effect of transforming growth factor receptor-beta I (TGFbetaR I) on alpaca hair follicles and hair growth. The expression level and location of TGFbetaR I in alpaca ear and dorsal skin were detected through real-time quantitative PCR (RT PCR) and paraffin section immunohistochemical technique (ICC-P). The results shown TGFbetaR I was lower expression in back skin compared to ear skin and the mean density of the positive reaction in ear skin was significantly higher than back skin. The targeted relationship with let-7b was detected using the dual luciferase reporter vector of TGFbetaR I, which showed a significant target relationship between let-7b and TGFbetaR I. After transfection with let-7b eukaryotic expression vector, the relative mRNA expression of TGFbetaR I in alpaca skin fibroblasts did not differ, while the relative protein level was significantly decreased. In summary, a higher TGFbetaR I expression level in the ear skin suggests that TGFbetaR I may inhibit coat hair elongation. Further studies showed TGFbetaR I protein was downregulated by let-7b through transcriptional repression. PMID- 26611530 TI - Identification and molecular characterization of nitric oxide synthase (NOS) gene in the intertidal copepod Tigriopus japonicus. AB - In copepods, no information has been reported on the structure or molecular characterization of the nitric oxide synthase (NOS) gene. In the intertidal copepod Tigriopus japonicus, we identified a NOS gene that is involved in immune responses of vertebrates and invertebrates. In silico analyses revealed that nitric oxide (NO) synthase domains, such as the oxygenase and reductase domains, are highly conserved in the T. japonicus NOS gene. The T. japonicus NOS gene was highly transcribed in the nauplii stages, implying that it plays a role in protecting the host during the early developmental stages. To examine the involvement of the T. japonicus NOS gene in the innate immune response, the copepods were exposed to lipopolysaccharide (LPS) and two Vibrio sp. After exposure to different concentrations of LPS and Vibrio sp., T. japonicus NOS transcription was significantly increased over time in a dose-dependent manner, and the NO/nitrite concentration increased as well. Taken together, our findings suggest that T. japonicus NOS transcription is induced in response to an immune challenge as part of the conserved innate immunity. PMID- 26611529 TI - The cytoplasmic peptide:N-glycanase (NGLY1) - Structure, expression and cellular functions. AB - NGLY1/Ngly1 is a cytosolic peptide:N-glycanase, i.e. de-N-glycosylating enzyme acting on N-glycoproteins in mammals, generating free, unconjugated N-glycans and deglycosylated peptides in which the N-glycosylated asparagine residues are converted to aspartates. This enzyme is known to be involved in the quality control system for the newly synthesized glycoproteins in the endoplasmic reticulum (ER). In this system, misfolded (glyco)proteins are retrotranslocated to the cytosol, where the 26S proteasomes play a central role in degrading the proteins: a process referred to as ER-associated degradation or ERAD in short. PNGase-mediated deglycosylation is believed to facilitate the efficient degradation of some misfolded glycoproteins. Human patients harboring mutations of NGLY1 gene (NGLY1-deficiency) have recently been discovered, clearly indicating the functional importance of this enzyme. This review summarizes the current state of our knowledge on NGLY1 and its gene product in mammalian cells. PMID- 26611531 TI - A novel framework for inferring condition-specific TF and miRNA co-regulation of protein-protein interactions. AB - Recent studies have shown that transcription factors (TFs) and microRNAs (miRNAs), while independently regulate their downstream targets, collaborate with each other to regulate gene expression. However, their synergistic roles in protein-protein interactions (PPIs) remain mostly unknown. In this paper, we present a novel framework (called CoRePPI) for inferring TF and miRNA co regulation of PPIs. Particularly, CoRePPI is aimed at discovering the co regulation specific to a condition of interest, by using heterogeneous data, including miRNA and messenger RNA (mRNA) expression profiles, putative miRNA targets, TF targets and PPIs. CoRePPI firstly finds the network motifs indicating the co-regulation of PPIs by TFs and miRNAs in tumor and normal conditions separately. Then by identifying the differential motifs found in one condition but not in the other, it builds the networks consisting of TFs, miRNAs and their co-regulated PPIs specific to different conditions respectively. To validate CoRePPI, we apply it to the Pan-Cancer dataset which includes the expression profiles of 12 cancer types from TCGA. Through network topology analysis, we found that the tumor and normal CoRePPI networks are scale-free. Furthermore, the results of differential and intersected network analysis between the tumor and normal CoRePPI networks suggest that only a small fraction of the regulatory relationships between TFs and miRNAs are conserved in both conditions but they co regulate different downstream PPIs in tumor and normal conditions; and in different conditions the majority of the regulatory relationships between TFs and miRNAs are different although they may regulate the same PPIs in their respective conditions. The CoRePPI sub-networks constructed for the three types of cancers (breast cancer, lung cancer and ovarian cancer) are all scale-free, and the intersection of these CoRePPI sub-networks can be utilized as the biomarker CoRePPI sub-network of the three types of cancers. The PPI enrichment analyses of the tumor and normal CoRePPI networks suggest that the co-regulating TFs and miRNAs are significantly associated with the specific biological processes, diseases and pathways. In addition, comparing with the two non-condition-specific approaches, the tumor CoRePPI network is found to have the most enriched cancer related PPIs. Altogether, the results uncover the combined regulatory patterns of TFs and miRNAs on the PPIs, and may provide new insights for research in cancer associated TFs and miRNAs. PMID- 26611532 TI - Analysis of the complete mitochondrial genome of the Zhedong White goose and characterization of NUMTs: Reveal domestication history of goose in China and Euro. AB - To understand the phyletic evolution of geese, the complete mitogenome of the Zhedong goose was sequenced for the first time. It is composed of 37 genes and 1 control region, and the structure and arrangement of all genes sequenced are identical to those of other goose breeds. We confirmed the accuracy of the mitogenome sequence through RT-PCR and found numts from amplification in genomic DNA. Comparisons of the phylogenetic trees and sequences of geese that were suggested a clade of Chinese geese, except the Yili goose, were classified in the Euro clade. Several breed-specific mutations and Chinese breed-specific mutations were found. Our results suggest that Chinese geese evolved from the swan goose, splitting from their common ancestors at different times, which was consistent with studies before. Furthermore, numts in most genes of Zhedong goose clustered with European geese in the phylogenetic tree, suggesting that the haplotypes in the Euro clade might be more ancient. However, the mitogenome of the swan goose shows distinctive evolutionary positions in some genes, which suggest its unclear relationship with Chinese geese and European geese. The current study added to the understanding of the evolution of geese and provided evidence that the typing of numts is an encouraging way for the evolutionary study of geese and the mitochondrial genomes of geese deserve further investigation. PMID- 26611534 TI - Paenibacillus etheri sp. nov., able to grow on media supplemented with methyl tert-butyl ether (MTBE) and isolated from hydrocarbon-contaminated soil. AB - A bacterial strain, designated SH7T, was isolated from the hydrocarbon contaminated soil of a pilot plant (Granada, Spain). The strain was selected for its capacity to grow in media supplemented with methyl tert-butyl ether (MTBE) as sole energy and carbon source. Strain SH7T was a Gram-stain-positive, facultatively anaerobic, spore-forming, rod-shaped bacterium. Phylogenetic analysis using 16S rRNA gene sequences showed that strain SH7T belongs to a cluster comprising species of the genus Paenibacillus and was closely related to Paenibacillus borealis KK19T (97 % 16S rRNA gene sequence similarity) and Paenibacillus odorifer TOD45T (98 %). DNA-DNA hybridization tests showed low relatedness of strain SH7T with the type strains of Paenibacillus borealis (16.9 +/- 1.5 %) and Paenibacillus odorifer (16.6 +/- 2.1 %). The cell wall of strain SH7T contained meso-diaminopimelic acid. The predominant respiratory quinone was MK-7, and anteiso-C15 : 0 (32.9 %) and C16 : 0 (29.0 %) were the predominant cellular fatty acids. Phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol and three unknown aminophospholipids were the major phospholipids. The DNA G+C content was 44.3 mol%. Data obtained in this study indicate that strain SH7T represents a novel species of the genus Paenibacillus, for which the name Paenibacillus etheri sp. nov. is proposed. The type strain is SH7T ( = CECT 8558T = DSM 29760T). PMID- 26611533 TI - Multimodular type I polyketide synthases in algae evolve by module duplications and displacement of AT domains in trans. AB - BACKGROUND: Polyketide synthase (PKS) catalyzes the biosynthesis of polyketides, which are structurally and functionally diverse natural products in microorganisms and plants. Here, we have analyzed available full genome sequences of microscopic and macroscopic algae for the presence of type I PKS genes. RESULTS: Type I PKS genes are present in 15 of 32 analyzed algal species. In chlorophytes, large proteins in the MDa range are predicted in most sequenced species, and PKSs with free-standing acyltransferase domains (trans-AT PKSs) predominate. In a phylogenetic tree, PKS sequences from different algal phyla form clades that are distinct from PKSs from other organisms such as non photosynthetic protists or cyanobacteria. However, intermixing is observed in some cases, for example polyunsaturated fatty acid (PUFA) and glycolipid synthases of various origins. Close relationships between type I PKS modules from different species or between modules within the same multimodular enzyme were identified, suggesting module duplications during evolution of algal PKSs. In contrast to type I PKSs, nonribosomal peptide synthetases (NRPSs) are relatively rare in algae (occurrence in 7 of 32 species). CONCLUSIONS: Our phylogenetic analysis of type I PKSs in algae supports an evolutionary scenario whereby integrated AT domains were displaced to yield trans-AT PKSs. Together with module duplications, the displacement of AT domains may constitute a major mechanism of PKS evolution in algae. This study advances our understanding of the diversity of eukaryotic PKSs and their evolutionary trajectories. PMID- 26611535 TI - Extracellular volume expansion and the preservation of residual renal function in Korean peritoneal dialysis patients: a long-term follow up study. AB - INTRODUCTION: In chronic peritoneal dialysis patients, preservation of residual renal function (RRF) is a major determinant of patient survival, and maintaining sufficient intravascular volume has been hypothesized to be beneficial for the preservation of RRF. The present study aimed to test this hypothesis using multifrequency bioimpedence analyzer (MFBIA), in Korean peritoneal dialysis patients. METHODS: A total of 129 patients were enrolled in this study. The baseline MFBIA was checked, and the patients were divided into the following two groups: group 1, extracellular water per total body water (ECW/TBW) < median, group 2, ECW/TBW > median. We followed up the patients, and then we analyzed the changes in the urine output (UO) and the solute clearance (weekly uKt/V) in each group. Data associated with patient and technical survivor were collected by medical chart review. The volume measurement was made using Inbody S20 equipment (Biospace, Seoul, Korea). We excluded the anuric patients at baseline. RESULT: The median value of ECW/TBW was 0.396. The mean patient age was 49.74 +/- 10.01 years, and 62.1 % of the patients were male; most of the patients were on continuous ambulatory peritoneal dialysis (89.1 %). The mean dialysis vintage was 26.20 +/- 28.71 months. All of the patients were prescribed hypertensive medication, and 48.5 % of the patients had diabetes. After 25.47 +/- 6.86 months of follow up, DeltaUO and Deltaweekly Kt/V were not significantly different in the two groups as follows: DeltaUO (-236.07 +/- 185.15 in group 1 vs -212.21 +/- 381.14 in group 2, p = 0.756); Delta weekly Kt/v (-0.23 +/- 0.43 in group 1 vs 0.29 +/- 0.49 in group 2, p = 0.461). The patient and technical survivor rate was inferior in the group 2, and in the multivariable analysis, initial hypervolemia was an independent factor that predicts both of the patient mortality [HR 1.001 (1.001-1.086), p = 0.047] and the technical failure [HR 1.024 (1.001-1.048), p = 0.042]. CONCLUSIONS: Extracellular volume expansion, measured by MFBIA, does not help preserve residual renal function, and is harmful for the technical and patient survival in Korean peritoneal dialysis patients. PMID- 26611536 TI - Comparison of innate immune responses towards rhinovirus infection of primary nasal and bronchial epithelial cells. AB - BACKGROUND AND OBJECTIVE: Rhinoviruses (RV) replicate in both upper and lower airway epithelial cells. We evaluated the possibility of using nasal epithelial cells (NEC) as surrogate of bronchial epithelial cells (BEC) for RV pathogenesis cell culture studies. METHODS: We used primary paired NEC and BEC cultures established from healthy subjects and compared the replication of RV belonging to the major (RV16) and minor (RV1B) group, and the cellular antiviral and proinflammatory cytokine responses towards these viruses. We related antiviral and pro-inflammatory responses of NEC isolated from CF and COPD patients with those of BEC. RESULTS: RV16 replication and major group surface receptor (ICAM-1) expression were higher in healthy NEC compared with BEC (P < 0.05); RV1B replication and minor group surface receptor (LDLR) expression were similar. Healthy NEC and BEC produced similar levels of IFN-beta and IFN-lambda2/3 upon RV infection or after simulation with poly(IC). IL-8 production was similar between healthy NEC and BEC. IL-6 release at baseline (P < 0.01) and upon infection with RV16 (P < 0.05) and poly(IC) stimulation (P < 0.05) was higher in NEC. RV1B viral load in NEC was related to RV1B viral load in BEC (r = 0.49, P = 0.01). There was a good correlation of IFN levels between NEC and BEC (r = 0.66, P = 0.0004 after RV1B infection). IL-8 production in NEC was related to IL-8 production in BEC (r = 0.48, P = 0.02 after RV1B infection). CONCLUSION: NEC are a suitable alternative cellular system to BEC to study the pathophysiology of RV infections and particularly to investigate IFN responses induced by RV infection. PMID- 26611537 TI - Survey of physicochemical characteristics and microbial contamination in selected food locally vended in Morogoro Municipality, Tanzania. AB - BACKGROUND: Raw milk, raw fruit juice and raw fish are enriched with essential nutrients for human diet but are prone to microbial contamination along the value chain. This cross sectional study was conducted to assess physicochemical characteristics and microbial quality of raw milk, fruit juice and fish from food vendors in Morogoro Municipality, Tanzania. The physicochemical assessment of food samples was done by smell, colour, presence of debris, turbidity, consistence, pH and clot on alcohol test. Hygiene of food containers, personnel and the vending environment was also assessed. Qualitative and quantitative microbial assessment of food was done using standard laboratory protocols as described by Tanzania Bureau of Standards and International Systems of Standards. RESULTS: Raw milk sold in Morogoro was of poor quality since was adulterated with water, contained sediments and clotted on alcohol test. Up to 63 % of the milk samples were contaminated with Escherichia coli and 60 % had higher total viable count (TVC) than the recommended values. Raw fruit juice was stored in dirty containers and sold under unhygienic environment. Seventy-three percent of juice samples had TVC beyond the recommendations while E. coli contamination rate was 63.3 %. The raw fish samples had started spoiling as depicted through sensory evaluation. E. coli contamination rate was 55 % and that of Campylobacter jejuni was 0.5 %. The mean TVC of raw fish was 8.1 (Log cfu/g) and 96.2 % of the fish samples had TVC beyond the recommended limits of 5.0 Log cfu/g. CONCLUSIONS: The physicochemical characteristics of food vended in Morogoro Municipality were of poor quality. The food had high bacterial contaminations. This situation poses health risks to the public and losses to food vendors due to spoilage. Stakeholders in food value chain should be educated on safe production and good hygienic practices. Routine quality and safety assessment of locally vended food, inspection of selling premises and regular health check-up of the personnel involved in food vending industry should be instituted. PMID- 26611538 TI - Primary surgery as a frontline treatment for synchronous metastatic gastrointestinal stromal tumors: an analysis of the Kinki GIST registry. AB - PURPOSE: To investigate the outcomes of a combined treatment regimen comprising primary surgery and tyrosine kinase inhibitor (TKI) therapy for synchronous metastatic gastrointestinal stromal tumors (GIST). METHODS: We analyzed retrospectively 14 cases of synchronous metastatic GIST from the Kinki GIST registry between 2003 and 2007. RESULTS: The primary tumor was located in the stomach, small intestine, and rectum in seven, six, and one patients, respectively. Metastatic tumors developed in the liver, peritoneum, other sites, and multiple organs in three, six, two, and three patients, respectively. The R0 resection rate was 42.9 % and the 5-year overall survival rate was 69.3 %. There was no significant difference in the 5-year overall survival rate between patients who underwent R0/R1 and those who underwent R2 resection (71.4 vs. 68.6 %). There was a strong correlation between survival time from diagnosis and the duration of imatinib therapy (Pearson's correlation coefficient, 0.86; p < 0.001). CONCLUSIONS: Although the role of surgery in the treatment of synchronous metastatic GIST is still unclear, primary surgery as the sole frontline treatment may not have a survival benefit: Continuous TKI therapy is more important for prolonging survival. PMID- 26611539 TI - Brazilian green propolis water extract up-regulates the early expression level of HO-1 and accelerates Nrf2 after UVA irradiation. AB - BACKGROUND: Exposure to ultraviolet A (UVA) irradiation is the major cause of human skin aging. Suppression of UVA irradiation-induced skin fibroblast cell damage protects the skin against aging. An oxidative stress response transcription factor nuclear factor-(erythroid-derived 2)-related factor 2 (Nrf2) has an important role as a cytoprotective system against oxidative stress in the human skin and other organs. Propolis has been commonly used as a traditional medicine since ancient times. The water extract of propolis (WEP) mainly contains caffeoylquinic acids. In our previous study, we reported that WEP and its major constituents protected immortalized human skin fibroblast cells (NB1-RGB) against UVA irradiation-induced cell death. In this study, we examined the mechanism of WEP-mediated skin protection and the possible involvement of Nrf2/antioxidant response element (ARE) pathways. METHODS: Brazilian green propolis was used in the present study (Minas Gerais State, Brazil), Baccharis dracunculifolia is its main source. The Baccharis propolis was extracted with water at 50 degrees C to yield water extract. The NB1-RGB cell cultures were incubated for 23 h. After replenishing the medium, WEP or its constituents were added to the cell cultures. After 1 h, the cells were exposed to 10 J/cm(2) of UVA light (365 nm UVA light source, CL-1000 L UV Closslinkers, Ultraviolet Products Ltd., Cambridge, UK). Heme oxygenase-1 (HO-1) expression levels in NB1-RGB cells were evaluated using western blotting. Nrf2 nuclear translocation changes in NB1-RGB cells were indicated using immunostaining. RESULTS: We demonstrated that WEP pretreatment up regulated HO-1 expression level after UVA irradiation at earlier time points than vehicle pretreatment did, and three main constituents of WEP showed similar effects. Furthermore, WEP pretreatment also accelerated Nrf2 nuclear translocation after UVA irradiation. CONCLUSIONS: Our findings indicated that WEP acts as an early inducer of HO-1 and rapid activator of Nrf2 to protect against UVA-induced oxidative stress. PMID- 26611540 TI - From Campers to Counselors: a Resource for Prospective Genetic Counseling Students. AB - When thinking about the future of the genetic counseling field, one place to start is with prospective genetic counseling graduate school applicants. Although resources and mentorship opportunities exist for genetic counselors entering the field, the process of deciding on a career, applying to graduate programs, and being admitted can be daunting. As members of the profession, we should take responsibility for ensuring that individuals have the information and resources necessary to make an educated decision about whether genetic counseling is the correct path for them and to take the initial steps along this path. In this article, we present our Genetic Counseling Boot Camp as a model for other genetic counselors to use in developing their own local programs. This type of program can benefit prospective genetic counselors as they begin their professional journeys and can also provide value for the organizers and presenters who are already seasoned in the field. PMID- 26611541 TI - [Not Available]. PMID- 26611542 TI - Alkanes from Bioderived Furans by using Metal Triflates and Palladium-Catalyzed Hydrodeoxygenation of Cyclic Ethers. AB - Using a metal triflate and Pd/C as catalysts, alkanes were prepared from bioderived furans in a one-pot hydrodeoxygenation (HDO) process. During the reaction, the metal triflate plays a crucial role in the ring-opening HDO of furan compounds. The entire reaction process has goes through two major phases: at low temperatures, saturation of the exocyclic double bond and furan ring are catalyzed by Pd/C; at high temperatures, the HDO of saturated furan compounds is catalyzed by the metal triflate. The reaction mechanism was verified by analyzing the changes of the intermediates during the reaction. In addition, different metal triflates, solvents, and catalyst recycling were also investigated. PMID- 26611543 TI - Two thirds of families in Maharashtra's "free" health scheme pay for treatment. PMID- 26611545 TI - The relationship between arterial stiffness and the lifestyle habits of female athletes after retiring from competitive sports: a prospective study. AB - This study investigated the relationship between changes in arterial stiffness and the lifestyle habits of endurance athletes after retiring from competition. The subjects were 10 female university endurance athletes. We used formPWV/ABI(r) as an index for arterial stiffness and measured brachial-ankle pulse-wave velocity (baPWV) directly before subjects retired (0Y) and at 2 years after retirement (2Y). Furthermore, to investigate the relationship between arterial stiffness and lifestyle habits 2 years later, Lifecorder (r) PLUS was used to measure physical activity levels, hours of sleep were surveyed using a questionnaire, and a food intake survey was conducted using Excel Eiyoukun Food Frequency Questionnaire Based on Food Group, FFQg Ver. 3.5. We found that baPWV increased significantly from 0Y to 2Y (P<0.05). Furthermore, negative correlations were observed between 2Y baPWV and step count as the physical activity index (r = -0.653, P<0.05) and moderate physical activity (r = -0.663, P<0.05). With regard to lifestyle habits that affected the amount of increase in baPWV from 0Y to 2Y (DeltabaPWV), negative correlations were noted between the step count (r = -0.690, P<0.05) and total physical activity (r = -0.657, P<0.05). However, no significant correlations were observed between 2Y baPWV and DeltabaPWV with food intake or hours of sleep. The results of this study suggested that physical activity was a lifestyle habit that inhibited an increase in arterial stiffness after retirement from competition and that having a high step count or engaging in physical activity for long periods of time in particular was useful in this regard. PMID- 26611544 TI - Single-particle cryo-electron microscopy of macromolecular complexes. AB - Recent technological breakthroughs in image acquisition have enabled single particle cryo-electron microscopy (cryo-EM) to achieve near-atomic resolution structural information for biological complexes. The improvements in image quality coupled with powerful computational methods for sorting distinct particle populations now also allow the determination of compositional and conformational ensembles, thereby providing key insights into macromolecular function. However, the inherent instability and dynamic nature of biological assemblies remain a tremendous challenge that often requires tailored approaches for successful implementation of the methodology. Here, we briefly describe the fundamentals of single-particle cryo-EM with an emphasis on covering the breadth of techniques and approaches, including low- and high-resolution methods, aiming to illustrate specific steps that are crucial for obtaining structural information by this method. PMID- 26611546 TI - Identification of genome-wide selection signatures in the Limousin beef cattle breed. AB - The study is aimed at identifying selection footprints within the genome of Limousin cattle. With the use of Extended Haplotype Homozygosity test, supplemented with correction for variation in recombination rates across the genome, we created map of selection footprints and detected 173 significant (p < 0.01) core haplotypes being potentially under positive selection. Within these regions, a number of candidate genes associated inter alia with skeletal muscle growth (GDF15, BMP7, BMP4 and TGFB3) or postmortem proteolysis and meat maturation (CAPN1 and CAPN5) were annotated. Noticeable clusters of selection footprints were detected on chromosomes 1, 4, 8 and 14, which are known to carry several quantitative trait loci for growth traits and meat quality. The study provides information about the genes and metabolic pathways potentially modified under the influence of directional selection, aimed at improving beef production characteristics in Limousin cattle. PMID- 26611547 TI - The History of Cortisone Discovery and Development. AB - Philip Hench, Edward Kendall, and Tadeus Reichstein received the Nobel Prize in medicine and physiology in 1950 for their "investigations of the hormones of the adrenal cortex." Hench and Kendall took compound E from the laboratory to the clinic to the Nobel Prize in a span of 2 years. This article examines the paths that led to the day when the first rheumatoid arthritis patient received cortisone, and from there to the 1950 Nobel Prize ceremony. The aftermath of this achievement is also discussed. Although there have been significant advances in corticosteroid preparations and use since 1950, the side effects remain daunting. PMID- 26611549 TI - Glucocorticoids and Rheumatoid Arthritis. AB - Glucocorticoids (GCs) were discovered in the 1940s and were administered for the first time to patients with rheumatoid arthritis in 1948. However, side effects were subsequently reported. In the last 7 decades, the mechanisms of action for both therapeutic properties and side effects have been elucidated. Mechanisms for minimizing side effects were also developed. GCs are the most frequently used class of drugs in the treatment of rheumatoid arthritis because of their efficacy in relieving symptoms and their low cost. A review of clinical applications, side effects, and drug interactions is presented. PMID- 26611548 TI - Corticosteroids: Mechanisms of Action in Health and Disease. AB - Glucocorticoids are primary stress hormones that regulate a variety of physiologic processes and are essential for life. The actions of glucocorticoids are predominantly mediated through the classic glucocorticoid receptor (GR). GRs are expressed throughout the body, but there is considerable heterogeneity in glucocorticoid sensitivity and biologic responses across tissues. The conventional belief that glucocorticoids act through a single GR protein has changed dramatically with the discovery of a diverse collection of receptor isoforms. This article provides an overview of the molecular mechanisms that regulate glucocorticoid actions, highlights the dynamic nature of hormone signaling, and discusses the molecular properties of the GR isoforms. PMID- 26611550 TI - Corticosteroids in Lupus. AB - Corticosteroids are the mainstay of treatment of systemic lupus erythematosus, with most patients receiving them at some point in the course of their disease. Corticosteroid use is associated with significant side effects, including infections, hypertension, hyperglycemia, osteoporosis, avascular necrosis, myopathy, cataracts, and glaucoma. Dosing regimens are based on limited data, with the goal of adequately controlling inflammatory symptoms while minimizing steroid exposure in order to reduce adverse effects. PMID- 26611551 TI - Corticosteroids in Lupus Nephritis and Central Nervous System Lupus. AB - Corticosteroids are a mainstay of therapy for severe organ-threatening systemic lupus erythematosus. Lupus nephritis and central nervous system (CNS) lupus remain two of the most debilitating and potentially life-threatening manifestations of lupus. The dose and duration of corticosteroids required for control of lupus nephritis and CNS lupus have never been tested in a randomized trial design, so current recommendations are based on observation and expert opinion. As more targeted individualized therapeutic approaches are developed for lupus nephritis and CNS lupus, reliance on long-term corticosteroids will decrease, as will the long-term damage and early mortality associated with their use. PMID- 26611552 TI - Glucocorticoids for Management of Polymyalgia Rheumatica and Giant Cell Arteritis. AB - Diagnosis of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) is based on typical clinical, histologic, and laboratory features. Ultrasonographic imaging in PMR with assessment especially of subdeltoid bursitis can aid in diagnosis and in following response to treatment. In GCA, diagnosis and disease activity are supported with ultrasonographic, MRI, or [(18)F]fluorodeoxyglucose PET evaluation of large vessels. Glucocorticoids are the primary therapy for PMR and GCA. Methotrexate may be used in patients at high risk for glucocorticoid adverse effects and patients with frequent relapse or needing protracted therapy. Other therapeutic approaches including interleukin 6 antagonists are under evaluation. PMID- 26611553 TI - Corticosteroids in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. AB - Glucocorticoids (GCs) have been the cornerstone of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) therapy since their advent in the 1950s. There is considerable variation in their use, both with respect to dose and duration. Given considerable treatment-related morbidity and mortality, refining the role of GCs is becoming increasingly important. This article discusses the current role of GCs in various phases of AAV treatment, including remission induction, maintenance therapy, treatment of relapses, and the use of local GCs. It discusses current controversies relating to GC use as well as research efforts that seek to reduce GC toxicity in AAV. PMID- 26611555 TI - Corticosteroids in Sarcoidosis. AB - Corticosteroids are the drug of choice for the treatment of sarcoidosis. Because the natural course of sarcoidosis may be self-limiting and/or cause no long-term harm, treatment is not mandatory. Corticosteroids are usually effective for all forms of sarcoidosis, and they work quickly. However, because of the potential toxicities of corticosteroids, alternative medications often need to be considered. Efforts should be made to minimize the corticosteroid dose while keeping the risk of toxicity as low as possible. This article outlines the indications for corticosteroid therapy for sarcoidosis, discusses various dosing regimens, and suggests when alternative corticosteroid agents should be considered. PMID- 26611554 TI - Corticosteroids in Myositis and Scleroderma. AB - Idiopathic inflammatory myopathies (IIMs) involve inflammation of the muscles and are classified by the patterns of presentation and immunohistopathologic features on skin and muscle biopsy into 4 categories: dermatomyositis, polymyositis, inclusion body myositis, and immune-mediated necrotizing myopathy. Systemic corticosteroid (CS) treatment is the standard of care for IIM with muscle and organ involvement. The extracutaneous features of systemic sclerosis are frequently treated with CS; however, high doses have been associated with scleroderma renal crisis in high-risk patients. Although CS can be effective first-line agents, their significant side effect profile encourages concomitant treatment with other immunosuppressive medications to enable timely tapering. PMID- 26611556 TI - Corticosteroids for Pain of Spinal Origin: Epidural and Intraarticular Administration. AB - Targeted interventional delivery of corticosteroids remains a mainstay of treatment for spinal pain syndromes because this approach has a wider therapeutic index than other approaches. The best evidence for analgesic efficacy is in subacute radicular syndromes associated with new-onset or recurrent lumbar radiculitis. Complications often relate to drug delivery technique as much as actions of the steroid itself and require careful consideration and vigilance by the administering physician. Considerable uncertainty persists concerning which patients with chronic pain are most likely to benefit from corticosteroid injections. Matching this treatment option with specific spinal pain syndromes remains a major challenge. PMID- 26611558 TI - Glucocorticoid-induced Osteoporosis. AB - Glucocorticoid-induced osteoporosis (GIOP) is one of the most common and serious adverse effects associated with glucocorticoid use. This article highlights GIOP pathophysiology, epidemiologic associations, effective treatment, and lifestyle modifications that can reduce fracture risk for long-term glucocorticoid users and additionally emphasizes the importance of early intervention. PMID- 26611559 TI - Corticosteroids. PMID- 26611557 TI - Infection Risk and Safety of Corticosteroid Use. AB - Corticosteroids are frequently used to treat rheumatic diseases. Their use comes with several well-established risks, including osteoporosis, avascular necrosis, glaucoma, and diabetes. The risk of infection is of utmost concern and is well documented, although randomized controlled trials of short-term and lower-dose steroids have generally shown little or no increased risk. Observational studies from the real world, however, have consistently shown dose-dependent increases in risk for serious infections as well as certain opportunistic infections. In patients who begin chronic steroid therapy, vaccination and screening strategies should be used in an attempt to mitigate this risk. PMID- 26611560 TI - Corticosteroids: Friends and Foes. PMID- 26611561 TI - Interaction between handling induced stress and anxiolytic effects of ethanol in zebrafish: A behavioral and neurochemical analysis. AB - Stress is often considered an important factor in the development of alcohol addiction. In rodents, various types of stressors have been shown to potentiate the effects of alcohol on behavioral responses, and to increase consumption of this substance. However, few have investigated the interaction between stress and alcohol in zebrafish. In the current study we present a repeated handling stress paradigm we developed for zebrafish, and examine whether stress alters alcohol induced behavioral and neurochemical responses. Our results show that repeated handling of zebrafish conducted for 2 consecutive days is sufficient to increase anxiety-like behavioral responses quantified 24h post-stressor. Repeatedly handled zebrafish also exhibited a reduction in the levels of serotonin's metabolite, 5-hydroxyindole acetic acid (quantified by high precision liquid chromatography) compared to unhandled controls. A 60-min acute exposure to 1% ethanol was found to significantly increase locomotor activity and decrease anxiety-like behavioral responses in stressed zebrafish but not in controls. Furthermore, unhandled control zebrafish exhibited a significant increase in whole-brain dopamine levels following exposure to ethanol but the increase was not observed in repeatedly handled fish. Our findings suggest that ethanol induced locomotor activity and anxiolysis is potentiated by handling stress and may be partially mediated by changes in dopaminergic and serotonergic activity. Overall, we demonstrate the validity of our repeated handling stressor paradigm for zebrafish, which can be used to investigate the interaction between stress and ethanol. PMID- 26611562 TI - Exposure to an enriched environment up to middle age allows preservation of spatial memory capabilities in old age. AB - In rats, some cognitive capabilities, like spatial learning and memory, are preserved from age-related decline by whole adult life enriched environment (EE) exposure. However, to which extent late EE contributes to such maintenance remains to be investigated. Here we assessed the impact of late housing condition (e.g., from the age of 18 months) on spatial learning and memory of aged rats (24 months) previously exposed or unexposed to EE from young adulthood. The results showed that late EE was not required for spatial memory maintenance in aged rats previously housed in EE. In contrast, late EE mitigates spatial memory deficit in aged rats previously unexposed to EE. These outcomes suggest that EE exposure up to middle age provides a "reserve"-like advantage which supports an enduring preservation of spatial capabilities in old age. PMID- 26611563 TI - Single pellet grasping following cervical spinal cord injury in adult rat using an automated full-time training robot. AB - Task specific motor training is a common form of rehabilitation therapy in individuals with spinal cord injury (SCI). The single pellet grasping (SPG) task is a skilled forelimb motor task used to evaluate recovery of forelimb function in rodent models of SCI. The task requires animals to obtain food pellets located on a shelf beyond a slit at the front of an enclosure. Manually training and testing rats in the SPG task requires extensive time and often yields results with high outcome variability and small therapeutic windows (i.e., the difference between pre- and post-SCI success rates). Recent advances in automated SPG training using automated pellet presentation (APP) systems allow rats to train ad libitum 24h a day, 7 days a week. APP trained rats have improved success rates, require less researcher time, and have lower outcome variability compared to manually trained rats. However, it is unclear whether APP trained rats can perform the SPG task using the APP system after SCI. Here we show that rats with cervical SCI can successfully perform the SPG task using the APP system. We found that SCI rats with APP training performed significantly more attempts, had slightly lower and less variable final score success rates, and larger therapeutic windows than SCI rats with manual training. These results demonstrate that APP training has clear advantages over manual training for evaluating reaching performance of SCI rats and represents a new tool for investigating rehabilitative motor training following CNS injury. PMID- 26611564 TI - Cholinergic deafferentation of the hippocampus causes non-temporally graded retrograde amnesia in an odor discrimination task. AB - Dementia of the Alzheimer's type (DAT) is a neurodegenerative disorder marked by loss of hippocampal cholinergic tone and significant memory impairments, specifically for memories acquired prior to disease onset. The nature of this relationship, however, remains debated. The current study used the string pulling task to evaluate the temporal effects of odor discrimination learning in animals with selective cholinergic lesions to determine the role of the septohippocampal cholinergic system in mnemonic function. Rats with 192-IgG-Saporin lesions to the medial septum had a higher number of correct responses in the reversal training when compared to sham rats, suggesting an inability to retrieve the previously learned discrimination; however, no temporal gradient was observed. Furthermore, there were no group differences when learning a novel odor discrimination, demonstrating the ability for all rats to form new memories. These results establish a role for the cholinergic medial septum projections in long-term memory retrieval. The current study provides a behavioral assessment technique to investigate factors that influence mnemonic deficits associated with rodent models of DAT. PMID- 26611566 TI - Fabrication of a novel dual mode cholesterol biosensor using titanium dioxide nanowire bridged 3D graphene nanostacks. AB - Herein, we fabricated a novel electrochemical-photoelectrochemical (PEC) dual mode cholesterol biosensor based on graphene (G) sheets interconnected-graphene embedded titanium nanowires (TiO2(G)-NWs) 3D nanostacks (designated as G/Ti(G) 3DNS) by exploiting the beneficial characteristics of G and TiO2-NWs to achieve good selectivity and high sensitivity for cholesterol detection. The G/Ti(G) 3DNS was fabricated by the reaction between functionalized G and TiO2(G)-NWs. Cholesterol oxidase (ChOx) was subsequently immobilized in to G/Ti(G) 3DNS using chitosan (CS) as the binder and the dual mode G/Ti(G) 3DNS/CS/ChOx biosensor was fabricated. The electro-optical properties of the G/Ti(G) 3DNS/CS/ChOx bioelectrode were characterized by cyclic voltammetry and UV-vis diffuse reflection spectroscopy. The cyclic voltammetry of immobilized ChOx showed a pair of well-defined redox peaks indicating direct electron transfer (DET) of ChOx. The amperometric reduction peak current (at -0.05V) linearly increased with increase in cholesterol concentration. The G/Ti(G) 3DNS/CS/ChOx bioelectrode was selective to cholesterol with a remarkable sensitivity (3.82MUA/cm(2)mM) and a lower detection limit (6MUM). Also, G/Ti(G) 3DNS/CS/ChOx functioned as photoelectrode and exhibited selective detection of cholesterol under a low bias voltage and light irradiation. Kinetic parameters, reproducibility, repeatability, storage stability and effect of temperature and pH were evaluated. We envisage that G/Ti(G) 3DNS with its prospective characteristics, would be a promising material for wide range of biosensing applications. PMID- 26611565 TI - Detection of aberrant hippocampal mossy fiber connections: Ex vivo mesoscale diffusion MRI and microtractography with histological validation in a patient with uncontrolled temporal lobe epilepsy. AB - Understanding the neurobiology and functional connectivity of hippocampal structures is essential for improving the treatment of mesial temporal lobe epilepsy. At the macroscale, in vivo MRI often reveals hippocampal atrophy and decreased fractional anisotropy, whereas at the microscopic scale, there frequently is evidence of neuronal loss and gliosis. Mossy fiber sprouting in the dentate gyrus (DG), with evidence of glutamatergic synapses in the stratum moleculare (SM) putatively originating from granule cell neurons, may also be observed. This aberrant connection between the DG and SM could produce a reverberant excitatory circuit. However, this hypothesis cannot easily be evaluated using macroscopic or microscopic techniques. We here demonstrate that the ex vivo mesoscopic MRI of surgically excised hippocampi can bridge the explanatory and analytical gap between the macro- and microscopic scale. Specifically, diffusion- and T2 -weighted MRI can be integrated to visualize a cytoarchitecture that is akin to immunohistochemistry. An appropriate spatial resolution to discern individual cell layers can then be established. Processing of diffusion tensor images using tractography detects extra- and intrahippocampal connections, hence providing a unique systems view of the hippocampus and its connected regions. Here, this approach suggests that there is indeed an aberrant connection between the DG and SM, supporting the sprouting hypothesis of a reverberant excitatory network. Mesoscopic ex vivo MR imaging hence provides an exciting new avenue to study hippocampi from treatment-resistant patients and allows exploration of existing hypotheses, as well as the development of new treatment strategies based on these novel insights. Hum Brain Mapp 37:780-795, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26611567 TI - Detection and quantitative analysis of two independent binding modes of a small ligand responsible for DC-SIGN clustering. AB - DC-SIGN (dendritic cell-specific ICAM-3 grabbing non-integrin) is a C-type lectin receptor (CLR) present, mainly in dendritic cells (DCs), as one of the major pattern recognition receptors (PRRs). This receptor has a relevant role in viral infection processes. Recent approaches aiming to block DC-SIGN have been presented as attractive anti-HIV strategies. DC-SIGN binds mannose or fucose containing carbohydrates from viral proteins such as the HIV envelope glycoprotein gp120. We have previously demonstrated that multivalent dendrons bearing multiple copies of glycomimetic ligands were able to inhibit DC-SIGN dependent HIV infection in cervical explant models. Optimization of glycomimetic ligands requires detailed characterization and analysis of their binding modes because they notably influence binding affinities. In a previous study we characterized the binding mode of DC-SIGN with ligand 1, which shows a single binding mode as demonstrated by NMR and X-ray crystallography. In this work we report the binding studies of DC-SIGN with pseudotrisaccharide 2, which has a larger affinity. Their binding was analysed by TR-NOESY and STD NMR experiments, combined with the CORCEMA-ST protocol and molecular modelling. These studies demonstrate that in solution the complex cannot be explained by a single binding mode. We describe the ensemble of ligand bound modes that best fit the experimental data and explain the higher inhibition values found for ligand 2. PMID- 26611569 TI - [Evaluation of postoperative symptoms after GreenlightTM photovaporization of the prostate through a dedicated questionnaire]. AB - AIMS: To evaluate postoperative symptoms after GreenlightTM photovaporisation of the prostate (PVP), through a dedicated questionnaire. METHODS: A retrospective study has been conducted between 2008 and 2014. The questionnaire had 5 sections about pain while voiding, hematuria, urgency, incontinence and urinary stream, and was filled at one-month postoperative. The main outcome criterion was pain while voiding. Descriptive statistical analyses were done to identify predictive factors for pain while voiding. RESULTS: Out of 169 patients, 22% had no pain while voiding, 37% had moderate pain, 30% acceptable pain and 11% intense pain. Patients with pain were significantly older, (P=0.012), had more urgency (P=0.01) and more often hematuria (P=0.0001). Only 7% of patients had no symptoms of urgency, and urgency was painful or bothering in 57% of cases. Hematuria was frequent, with clots in 21% of cases. Ninety three percent felt improvement of urinary stream. CONCLUSIONS: Systematic evaluation of symptoms through a dedicated questionnaire one month after PVP has shown that 41% of patients felt pain while voiding, 57% had urgency and 39% significant hematuria. These results should encourage a more accurate patient information and further studies to better understand postoperative healing after PVP. PMID- 26611570 TI - Sentinel Lymph Node Biopsy in Malignant Eyelid Tumor: Hybrid Single Photon Emission Computed Tomography/Computed Tomography and Dual Dye Technique. PMID- 26611568 TI - Accelerated apoptotic death and in vivo turnover of erythrocytes in mice lacking functional mitogen- and stress-activated kinase MSK1/2. AB - The mitogen- and stress-activated kinase MSK1/2 plays a decisive role in apoptosis. In analogy to apoptosis of nucleated cells, suicidal erythrocyte death called eryptosis is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine (PS) externalization. Here, we explored whether MSK1/2 participates in the regulation of eryptosis. To this end, erythrocytes were isolated from mice lacking functional MSK1/2 (msk(-/-)) and corresponding wild-type mice (msk(+/+)). Blood count, hematocrit, hemoglobin concentration and mean erythrocyte volume were similar in both msk(-/-) and msk(+/+) mice, but reticulocyte count was significantly increased in msk(-/-) mice. Cell membrane PS exposure was similar in untreated msk(-/-) and msk(+/+) erythrocytes, but was enhanced by pathophysiological cell stressors ex vivo such as hyperosmotic shock or energy depletion to significantly higher levels in msk(-/-) erythrocytes than in msk(+/+) erythrocytes. Cell shrinkage following hyperosmotic shock and energy depletion, as well as hemolysis following decrease of extracellular osmolarity was more pronounced in msk(-/-) erythrocytes. The in vivo clearance of autologously-infused CFSE-labeled erythrocytes from circulating blood was faster in msk(-/-) mice. The spleens from msk(-/-) mice contained a significantly greater number of PS-exposing erythrocytes than spleens from msk(+/+) mice. The present observations point to accelerated eryptosis and subsequent clearance of erythrocytes leading to enhanced erythrocyte turnover in MSK1/2-deficient mice. PMID- 26611571 TI - Study the effects of saffron on depression and lipid profiles: A double blind comparative study. AB - Depression is a one of the most prevalent psychiatric disorder. Despite several pharmacological treatments, still treating depression is a challenge. Herbal medicine that is better culturally accepted may play an important role in treatment of depression. In this double blind placebo controlled clinical trial, 40 patients that were suffering from major depression according to DSM-IV criteria were randomly allocated to take either fluoxetine and saffron (20 patients) or fluoxetine and placebo (20 patients). The patients of the two groups were evaluated with Beck depression scale at the beginning of the study and after four weeks. Lipid profile (total Triglyceride (TG) level, total cholesterol level, low density lipoprotein (LDL) level and high density lipoprotein (HDL) level) of the patients also was measured at the beginning and end of the trial. 30 patients (19 in saffron group and 11 in placebo group) completed the study. The two groups improved significantly in depression severity at the end of the study without significant difference (P: 0.560). The lipid profile of the two groups did not change significantly. Our study did not demonstrate antidepressive effects for saffron. We did not observe any lipid lowering effect in saffron group too. Of note is that our study is preliminary and larger studies with more patients and longer duration are needed to prove our results. CLINICAL TRIAL REGISTRATION NUMBER: IRCT 2013110915334. PMID- 26611572 TI - The Multidisciplinary Management of Cancer in Daily Clinical Practice: Towards a Community Hospital Comprehensive Cancer Center. PMID- 26611573 TI - Barriers to support for new graduated nurses in clinical settings: A qualitative study. AB - BACKGROUND: New graduated nurses often find the transition to registered nurse a traumatic experience and studies suggest that within some countries this process is inadequately supported. The reasons for this inadequacy remain unclear. OBJECTIVES: The current study was conducted to identify barriers impeding the provision of support to new graduated nurses in clinical settings within Iran. METHODS AND PARTICIPANTS: This is a qualitative study conducted through unstructured and semi-structured interviews with 18 licensed nurses (experienced nurses) recruited through purposive sampling. Data were collected at various hospital centers in Iran. All interviews were recorded and transcribed and analysis was completed through the use of content analysis. RESULTS: Barriers to support new graduated nurses included a lack of support-seeking behaviors, management weaknesses, ineffective communication, personal characteristics, and cultural barriers. CONCLUSIONS: Understanding the problems and barriers likely to prevent goal attainment is an important step toward reaching those goals. The present study provides a greater and more focused understanding of the barriers impeding the support of new graduated nurses within clinical settings. These barriers mainly include deficiencies in the organizational structure, management, and personal characteristics of colleagues and new graduated nurses. This study will have been a successful undertaking if it can help resolve these barriers. PMID- 26611574 TI - Nursing education research in Finland--A review of doctoral dissertations. AB - OBJECTIVES: The aim of this literature review was to describe the focus of nursing education research in Finnish doctoral dissertations in the field of nursing and caring sciences between the years 1979-2014. In addition, the characteristics (methods, study informants and reporting of validity, reliability, and research ethics) of the dissertations were described. METHODS AND DATA: A literature review was carried out. Altogether 51 Finnish doctoral dissertations of nursing and caring sciences focusing on nursing education research were included in the final analysis. The dissertations were published in 1990-2014. The data were analyzed by content analysis both deductively and inductively. RESULTS: Finnish nursing education research was focused on four main areas: structural factors in nursing education, nurse teacherhood, teaching activities, and learning and learning outcomes in nursing education. The most central focus was learning in nursing education whereas nurse teacherhood and structural factors in nursing education were studied the least. Students were the predominant study informant group while nurse staff including nurse mentors were next and nurse educators only the third. Surveys and interviews were the most common data collection methods. In the findings there were a lot of similarities with international nursing education research. CONCLUSIONS: Finnish nursing education research has been relatively student-centered yet studies focusing on the education of other nursing-based professions are rare. Future research about nurse teacherhood, curricula and structural factors in nursing education is recommended also. In addition, nursing education research should focus on the central phenomena of nursing education and working life. All in all, more nursing education research is needed. Nursing education dissertations cover only 12.3% of all the dissertations of nursing and caring sciences in Finland. PMID- 26611575 TI - Introduction to Viral Vectors and Other Delivery Methods for Gene Therapy of the Nervous System. AB - The use of gene therapy in neuroscience research has become common place in many laboratories across the world. However, contrary to common belief, the practical application of viral or non-viral gene therapy is not as straightforward as it may seem. All too often investigators see their experiments fail due to low quality third-party vectors or due to a lack of knowledge regarding the proper use of these tools. For example, researchers often find themselves performing experiments using the wrong methodology (e.g., using the wrong type of vector or mishandling the vector to the point where the efficacy is significantly reduced) resulting in experiments that potentially fail to accurately answer a hypothesis, or the generation of irreproducible data. Thus, it is important for investigators that seek to utilize gene therapy approaches to gain a basic understanding of how to apply this technology. This includes understanding how to appropriately design and execute an experiment, understanding various delivery vehicles (e.g., what virus to use), delivery methods (e.g., systemic versus intracranial injections), what expression system to use, and the time course involved with a particular expression system. This chapter is intended to present an overview of this fundamental knowledge, providing the researcher with a decision tree upon which to build their gene therapy experiment. PMID- 26611577 TI - Expression of Multiple Functional RNAs or Proteins from One Viral Vector. AB - In this chapter, we will cover the available design choices for enabling expression of two functional protein or RNA sequences from a single viral vector. Such vectors are very useful in the neuroscience-related field of neuronal control and modulation, e.g., using optogenetics or DREADDs, but are also desirable in applications of CRISPR/Cas9 in situ genome editing and more refined therapeutic approaches. Each approach to achieving this combined expression has its own strengths and limitations, which makes them more or less suitable for different applications. In this chapter, we describe the available alternatives and provide tips on how they can be implemented. PMID- 26611576 TI - Delivering Transgenic DNA Exceeding the Carrying Capacity of AAV Vectors. AB - Gene delivery using recombinant adeno-associated virus (rAAV) has emerged to the forefront demonstrating safe and effective phenotypic correction of diverse diseases including hemophilia B and Leber's congenital amaurosis. In addition to rAAV's high efficiency of transduction and the capacity for long-term transgene expression, the safety profile of rAAV remains unsoiled in humans with no deleterious vector-related consequences observed thus far. Despite these favorable attributes, rAAV vectors have a major disadvantage preventing widespread therapeutic applications; as the AAV capsid is the smallest described to date, it cannot package "large" genomes. Currently, the packaging capacity of rAAV has yet to be definitively defined but is approximately 5 kb, which has served as a limitation for large gene transfer. There are two main approaches that have been developed to overcome this limitation, split AAV vectors, and fragment AAV (fAAV) genome reassembly (Hirsch et al., Mol Ther 18(1):6-8, 2010). Split rAAV vector applications were developed based upon the finding that rAAV genomes naturally concatemerize in the cell post-transduction and are substrates for enhanced homologous recombination (HR) (Hirsch et al., Mol Ther 18(1):6-8, 2010; Duan et al., J Virol 73(1):161-169, 1999; Duan et al., J Virol 72(11):8568 8577, 1998; Duan et al., Mol Ther 4(4):383-391, 2001; Halbert et al., Nat Biotechnol 20(7):697-701, 2002). This method involves "splitting" the large transgene into two separate vectors and upon co-transduction, intracellular large gene reconstruction via vector genome concatemerization occurs via HR or nonhomologous end joining (NHEJ). Within the split rAAV approaches there currently exist three strategies: overlapping, trans-splicing, and hybrid trans splicing (Duan et al., Mol Ther 4(4):383-391, 2001; Halbert et al., Nat Biotechnol 20(7):697-701, 2002; Ghosh et al., Mol Ther 16(1):124-130, 2008; Ghosh et al., Mol Ther 15(4):750-755, 2007). The other major strategy for AAV-mediated large gene delivery is the use of fragment AAV (fAAV) (Dong et al., Mol Ther 18(1):87-92, 2010; Hirsch et al., Mol Ther 21(12):2205-2216, 2013; Lai et al., Mol Ther 18(1):75-79, 2010; Wu et al., Mol Ther 18(1):80-86, 2010). This strategy developed following the observation that the attempted encapsidation of transgenic cassettes exceeding the packaging capacity of the AAV capsid results in the packaging of heterogeneous single-strand genome fragments (<5 kb) of both polarities (Dong et al., Mol Ther 18(1):87-92, 2010; Hirsch et al., Mol Ther 21(12):2205-2216, 2013; Lai et al., Mol Ther 18(1):75-79, 2010; Wu et al., Mol Ther 18(1):80-86, 2010). After transduction by multiple fAAV particles, the genome fragments can undergo opposite strand annealing, followed by host-mediated DNA synthesis to reconstruct the intended oversized genome within the cell. Although, there appears to be growing debate as to the most efficient method of rAAV-mediated large gene delivery, it remains possible that additional factors including the target tissue and the transgenomic sequence factor into the selection of a particular approach for a specific application (Duan et al., Mol Ther 4(4):383-391, 2001; Ghosh et al., Mol Ther 16(1):124-130, 2008; Hirsch et al., Mol Ther 21(12):2205-2216, 2013; Trapani et al., EMBO Mol Med 6(2):194-211, 2014; Ghosh et al., Hum Gene Ther 22(1):77-83, 2011). Herein we discuss the design, production, and verification of the leading rAAV large gene delivery strategies. PMID- 26611578 TI - Regulated Gene Therapy. AB - Gene therapy represents a promising approach for the treatment of monogenic and multifactorial neurological disorders. It can be used to replace a missing gene and mutated gene or downregulate a causal gene. Despite the versatility of gene therapy, one of the main limitations lies in the irreversibility of the process: once delivered to target cells, the gene of interest is constitutively expressed and cannot be removed. Therefore, efficient, safe and long-term gene modification requires a system allowing fine control of transgene expression.Different systems have been developed over the past decades to regulate transgene expression after in vivo delivery, either at transcriptional or post-translational levels. The purpose of this chapter is to give an overview on current regulatory system used in the context of gene therapy for neurological disorders. Systems using external regulation of transgenes using antibiotics are commonly used to control either gene expression using tetracycline-controlled transcription or protein levels using destabilizing domain technology. Alternatively, specific promoters of genes that are regulated by disease mechanisms, increasing expression as the disease progresses or decreasing expression as disease regresses, are also examined. Overall, this chapter discusses advantages and drawbacks of current molecular methods for regulated gene therapy in the central nervous system. PMID- 26611579 TI - Design of shRNA and miRNA for Delivery to the CNS. AB - Neurologic diseases tend to target various areas of the central nervous system (CNS) and can therefore result in paralysis, dementia, and death. Neurodegenerative diseases distinguish themselves from other diseases by affecting nerve cells, which unlike many other cells in our body cannot regenerate when severely injured. The discovery of RNA interference (RNAi) has enabled scientist to design new therapeutic approaches based on specific gene silencing rather than the canonical gene therapy through gene augmentation. Two types of molecules can be used for viral vector-mediated gene silencing: short hairpin RNAs (shRNAs) and artificial microRNAs (miRNAs) that have the ability to enter the RNAi pathway. Although both shRNAs and miRNAs can be used to silence genes, they enter the RNAi pathway at different points. Unlike shRNAs, miRNAs require an additional cleavage step inside the nucleus before being exported to the cytoplasm. These molecules can then be incorporated into the RNA-induced silencing complex (RISC) which utilizes sequence complementarity to recognize target mRNAs and activate either translational repression, in the case of partial complementarity, or induce mRNA cleavage in the case of complete complementarity. Elevated amounts of shRNAs, which are commonly driven by strong polymerase III promoters, can cause saturation of the endogenous RNAi machinery due to competition between endogenous and artificial molecules. Switching to a DNA polymerase II promoter is an alternative to reduce shRNA production, thereby reducing toxicity. Even though the molecules are designed to target specific mRNAs there may be off-target effects due to nonspecific binding that must be accounted for during the design process. In this chapter we discuss the design and in vitro screening of shRNAs and artificial miRNAs. PMID- 26611580 TI - Tissue-Specific Promoters in the CNS. AB - This chapter outlines some general principles of transcriptional targeting approaches using viral vectors in the central nervous system. Transcriptional targeting is first discussed in the context of vector tropism and appropriate delivery. Then, some of our own attempts to restrict expression of therapeutic factors to distinct brain cell populations are discussed, followed by a detailed description of the setscrews that are available for these experiments. A critical discussion of current stumbling blocks and necessary developments to achieve clinical applicability of advanced targeted vector systems is provided. PMID- 26611581 TI - Small-Scale Recombinant Adeno-Associated Virus Purification. AB - Recombinant adeno-associated virus (rAAV) vectors have become increasingly popular in research and clinical trials due to their efficient gene transfer and long-term expression in tissues including brain. In addition, rAAV has demonstrated an impressive safety profile in gene therapy trials. The emergence of rAAV serotypes with different cell tropisms and distribution properties has allowed scientists to tailor serotypes to specific experimental needs. AAV does not have a cytopathic effect; therefore, purification methods require extraction of the viral vector from the cell. This involves gradient ultracentrifugation of the cellular extract sometimes followed by chromatography. This chapter describes a small-scale production method for rAAV purification from ten to twenty 15 cm plates of human embryonic kidney-derived 293B cells (HEK 293) cells that can yield approximately 300 MUl of a 5 * 10(12) to 1 * 10(13) genome copies/ml viral preparation final concentration. PMID- 26611582 TI - Lentivirus Production and Purification. AB - Lentiviral (LV) vectors offer unique advantages over other gene delivery systems, namely the ability to integrate transgenes into the genome of both dividing and nondividing cells. Detailed herein is a simple protocol for the production LV vectors, describing the triple transfection of an LV transfer vector and LV helper plasmids into HEK-293 cells, and the subsequent purification of virions from the cellular media. The current protocol is versatile, and can be easily modified to fit the specific needs of the researcher in order to produce relatively high-titer LV vectors which can be used to transduce a wide variety of cells both in vitro and in vivo. PMID- 26611583 TI - Viral Vector Production: Adenovirus. AB - Adenoviral vectors have proven to be valuable resources in the development of novel therapies aimed at targeting pathological conditions of the central nervous system, including Alzheimer's disease and neoplastic brain lesions. Not only can some genetically engineered adenoviral vectors achieve remarkably efficient and specific gene delivery to target cells, but they also may act as anticancer agents by selectively replicating within cancer cells.Due to the great interest in using adenoviral vectors for various purposes, the need for a comprehensive protocol for viral vector production is especially apparent. Here, we describe the process of generating an adenoviral vector in its entirety, including the more complex process of adenoviral fiber modification to restrict viral tropism in order to achieve more efficient and specific gene delivery. PMID- 26611585 TI - Altering Tropism of rAAV by Directed Evolution. AB - Directed evolution represents an attractive approach to derive AAV capsid variants capable of selectively infect specific tissue or cell targets. It involves the generation of an initial library of high complexity followed by cycles of selection during which the library is progressively enriched for target specific variants. Each selection cycle consists of the following: reconstitution of complete AAV genomes within plasmid molecules; production of virions for which each particular capsid variant is matched with the particular capsid gene encoding it; recovery of capsid gene sequences from target tissue after systemic administration. Prevalent variants are then analyzed and evaluated. PMID- 26611586 TI - Altering Entry Site Preference of Lentiviral Vectors into Neuronal Cells by Pseudotyping with Envelope Glycoproteins. AB - A lentiviral vector system provides a powerful strategy for gene therapy trials against a variety of neurological and neurodegenerative disorders. Pseudotyping of lentiviral vectors with different envelope glycoproteins not only confers the neurotropism to the vectors, but also alters the preference of sites of vector entry into neuronal cells. One major group of lentiviral vectors is a pseudotype with vesicular stomatitis virus glycoprotein (VSV-G) that enters preferentially cell body areas (somata/dendrites) of neurons and transduces them. Another group contains lentiviral vectors pseudotyped with fusion envelope glycoproteins composed of different sets of rabies virus glycoprotein and VSV-G segments that enter predominantly axon terminals of neurons and are transported through axons retrogradely to their cell bodies, resulting in enhanced retrograde gene transfer. This retrograde gene transfer takes a considerable advantage of delivering the transgene into neuronal cell bodies situated in regions distant from the injection site of the vectors. The rational use of these two vector groups characterized by different entry mechanisms will further extend the strategy for gene therapy of neurological and neurodegenerative disorders. PMID- 26611587 TI - Directed Evolution of Adenoviruses. AB - The ability to evolve viruses in cell culture in the face of selective pressure is an invaluable method to elucidate the molecular mechanisms of synthetic or natural antivirals, expand tropism, or alter virulence. Recently, mutations to the human adenovirus polymerase that reduce replicative fidelity were described, and we have incorporated one of these mutations into the pol gene of a conditionally replicating human adenovirus serotype 5 (HAdV-5)-based vector (Uil et al., Nucleic Acids Res 39:e30, 2011; Myers et al., J Virol 87:6047-6050, 2013). Here, we describe methods to evolve this virus (HAdV-5.polF421Y) under selective pressure from antivirals to identify their mechanisms of action. PMID- 26611584 TI - Controlling AAV Tropism in the Nervous System with Natural and Engineered Capsids. AB - More than one hundred naturally occurring variants of adeno-associated virus (AAV) have been identified, and this library has been further expanded by an array of techniques for modification of the viral capsid. AAV capsid variants possess unique antigenic profiles and demonstrate distinct cellular tropisms driven by differences in receptor binding. AAV capsids can be chemically modified to alter tropism, can be produced as hybrid vectors that combine the properties of multiple serotypes, and can carry peptide insertions that introduce novel receptor-binding activity. Furthermore, directed evolution of shuffled genome libraries can identify engineered variants with unique properties, and rational modification of the viral capsid can alter tropism, reduce blockage by neutralizing antibodies, or enhance transduction efficiency. This large number of AAV variants and engineered capsids provides a varied toolkit for gene delivery to the CNS and retina, with specialized vectors available for many applications, but selecting a capsid variant from the array of available vectors can be difficult. This chapter describes the unique properties of a range of AAV variants and engineered capsids, and provides a guide for selecting the appropriate vector for specific applications in the CNS and retina. PMID- 26611588 TI - Intraparenchymal Stereotaxic Delivery of rAAV and Special Considerations in Vector Handling. AB - Stereotaxic surgery enables precise and consistent microinjections to discrete neural nuclei. Using stereotaxic surgery to deliver viral vectors is a powerful tool that provides the ability to manipulate gene expression in specific regions, or even specific cell types in the brain. Here, we describe the proper handling and stereotaxic delivery of recombinant adeno-associated virus to various neuroanatomical structures of the rodent brain. PMID- 26611589 TI - MRI-Guided Delivery of Viral Vectors. AB - Gene therapy has emerged as a potential avenue of treatment for many neurological disorders. Technological advances in imaging techniques allow for the monitoring of real-time infusions into the brain of rodents, nonhuman primates, and humans. Here, we discuss the use of magnetic resonance imaging (MRI) as a tool in the delivery of adeno-associated viral (AAV) particles into brain of nonhuman primates. PMID- 26611590 TI - Systemic Gene Therapy for Targeting the CNS. AB - Systemic gene delivery is useful for modeling and treatment of a body-wide disease. Recently, it has been shown that certain agents, when delivered systemically, can efficiently target the central nervous system. This technique has been used to model and treat rodent models of neurological disease with unprecedented success. Here, we describe intravenous delivery in neonate and adult mice. These techniques are easily learned and have minimal equipment requirements. PMID- 26611591 TI - Widespread Neuronal Transduction of the Rodent CNS via Neonatal Viral Injection. AB - The rapid pace of neuroscience research demands equally efficient and flexible methods for genetically manipulating and visualizing selected neurons within the rodent brain. The use of viral vectors for gene delivery saves the time and cost of traditional germline transgenesis and offers the versatility of readily available reagents that can be easily customized to meet individual experimental needs. Here, we present a protocol for widespread neuronal transduction based on intraventricular viral injection of the neonatal mouse brain. Injections can be done either free-hand or assisted by a stereotaxic device to produce lifelong expression of virally delivered transgenes. PMID- 26611592 TI - AAV-Mediated Gene Transfer to Dorsal Root Ganglion. AB - Transferring genetic molecules into the peripheral sensory nervous system to manipulate nociceptive pathophysiology is a powerful approach for experimental modulation of sensory signaling and potentially for translation into therapy for chronic pain. This can be efficiently achieved by the use of recombinant adeno associated virus (rAAV) in conjunction with nociceptor-specific regulatory transgene cassettes. Among different routes of delivery, direct injection into the dorsal root ganglia (DRGs) offers the most efficient AAV-mediated gene transfer selectively into the peripheral sensory nervous system. Here, we briefly discuss the advantages and applications of intraganglionic microinjection, and then provide a detailed approach for DRG injection, including a list of the necessary materials and description of a method for performing DRG microinjection experiments. We also discuss our experience with several adeno-associated virus (AAV) options for in vivo transgene expression in DRG neurons. PMID- 26611593 TI - Gene Therapy of the Peripheral Nervous System: The Enteric Nervous System. AB - The enteric nervous system (ENS) is a complex network of ganglia embedded in the walls of the gastrointestinal (GI) tract. The highly integrated enteric neural network can act independently of sympathetic and parasympathetic innervation to control all aspects of GI function. Due to the central role the ENS plays in GI physiology, the ability to manipulate genetic expression within the ENS is an invaluable tool for both research and clinical applications. Here, we describe a method for gene delivery to the ENS using direct injections of adeno-associated virus (AAV) into the gut wall. This method is able to achieve transgene expression in both neurons and glia located in discrete areas of the ENS. PMID- 26611594 TI - Gene Therapy of the Peripheral Nervous System: Celiac Ganglia. AB - Gene therapy has played an integral role in advancing our understanding of the central nervous system. However, gene therapy techniques have yet to be widely utilized in the peripheral nervous system. Critical targets for gene therapy within the PNS are the neurons in sympathetic ganglia, which are the final pathway to end organs. Thus they are the most specific targets for organ-specific neuron modification. This presents challenges because neurons are not viscerotopically organized within the ganglia and therefore cannot be targeted by their location. However, organ-specific neurons have been identified in sympathetic ganglia of some species and this offers an opportunity for targeting and transducing neurons by way of their target. In fact, alterations in sympathetic neurons have had pathological effects, and transducing organ-specific sympathetic neurons offer an exciting opportunity to selectively modify sympathetic pathology. In this chapter, we describe a method to virally transduce the celiac ganglion (CG), a prevertebral sympathetic ganglion that innervates abdominal organs, with AAV serotypes 1 and 6; thereby, providing a potential avenue to modulate specific subsets of neurons within the celiac ganglion. PMID- 26611595 TI - Convection Enhanced Delivery of Recombinant Adeno-associated Virus into the Mouse Brain. AB - Recombinant adeno-associated virus (rAAV) has become an extremely useful tool for the study of gene over expression or knockdown in the central nervous system of experimental animals. One disadvantage of intracranial injections of rAAV vectors into the brain parenchyma has been restricted distribution to relatively small volumes of the brain. Convection enhanced delivery (CED) is a method for delivery of clinically relevant amounts of therapeutic agents to large areas of the brain in a direct intracranial injection procedure. CED uses bulk flow to increase the hydrostatic pressure and thus improve volume distribution. The CED method has shown robust gene transfer and increased distribution within the CNS and can be successfully used for different serotypes of rAAV for increased transduction of the mouse CNS. This chapter details the surgical injection of rAAV by CED into a mouse brain. PMID- 26611596 TI - Nonviral Gene Therapy of the Nervous System: Electroporation. AB - Electroporation has been widely used to efficiently transfer foreign genes into the mammalian central nervous system (CNS), and thus plays an important role in gene therapeutic studies on some brain disorders. A lot of work concerning electroporation is focused on gene transfer into rodent brains. This technique involves an injection of nucleic acids into the brain ventricle or specific area and then applying appropriate electrical field to the injected area. Here, we briefly introduced the advantages and the basic procedures of gene transfer into the rodent brain using electroporation. Better understanding of electroporation in rodent brain may further facilitate gene therapeutic studies on brain disorders. PMID- 26611597 TI - Non-Viral, Lipid-Mediated DNA and mRNA Gene Therapy of the Central Nervous System (CNS): Chemical-Based Transfection. AB - Appropriate gene delivery systems are essential for successful gene therapy in clinical medicine. Cationic lipid-mediated delivery is an alternative to viral vector-mediated gene delivery. Lipid-mediated delivery of DNA or mRNA is usually more rapid than viral-mediated delivery, offers a larger payload, and has a nearly zero risk of incorporation. Lipid-mediated delivery of DNA or RNA is therefore preferable to viral DNA delivery in those clinical applications that do not require long-term expression for chronic conditions. Delivery of RNA may be preferable to non-viral DNA delivery in some clinical applications, because transit across the nuclear membrane is not necessary and onset of expression with RNA is therefore even faster than with DNA, although both are faster than most viral vectors. Here, we describe techniques for cationic lipid-mediated delivery of nucleic acids encoding reporter genes in a variety of cell lines. We describe optimized formulations and transfection procedures that we previously assessed by bioluminescence and flow cytometry. RNA transfection demonstrates increased efficiency relative to DNA transfection in non-dividing cells. Delivery of mRNA results in onset of expression within 1 h after transfection and a peak in expression 5-7 h after transfection. Duration of expression in eukaryotic cells after mRNA transcript delivery depends on multiple factors, including transcript stability, protein turnover, and cell type. Delivery of DNA results in onset of expression within 5 h after transfection, a peak in expression 24-48 h after transfection, and a return to baseline that can be as long as several weeks after transfection. In vitro results are consistent with our in vivo delivery results, techniques for which are described as well. RNA delivery is suitable for short term transient gene expression due to its rapid onset, short duration of expression and greater efficiency, particularly in non-dividing cells, while the longer duration and the higher mean levels of expression per cell that are ultimately obtained following DNA delivery confirm a continuing role for DNA gene delivery in clinical applications that require longer term transient gene expression. PMID- 26611598 TI - Ex Vivo Gene Therapy Using Human Mesenchymal Stem Cells to Deliver Growth Factors in the Skeletal Muscle of a Familial ALS Rat Model. AB - Therapeutic protein and molecule delivery to target sites by transplanted human stem cells holds great promise for ex vivo gene therapy. Our group has demonstrated the therapeutic benefits of ex vivo gene therapy targeting the skeletal muscles in a transgenic rat model of familial amyotrophic lateral sclerosis (ALS). We used human mesenchymal stem cells (hMSCs) and genetically modified them to release neuroprotective growth factors such as glial cell line derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF). Intramuscular growth factor delivery via hMSCs can enhance neuromuscular innervation and motor neuron survival in a rat model of ALS (SOD1(G93A) transgenic rats). Here, we describe the protocol of ex vivo delivery of growth factors via lentiviral vector-mediated genetic modification of hMSCs and hMSC transplantation into the skeletal muscle of a familial ALS rat model. PMID- 26611600 TI - Viral Vector-Based Modeling of Neurodegenerative Disorders: Parkinson's Disease. AB - Gene therapy methods are increasingly used to model Parkinson's disease (PD) in animals in an effort to test experimental therapeutics within a more relevant context to disease pathophysiology and neuropathology. We have detailed several criteria that are critical or advantageous to accurately modeling PD in a murine model or in a nonhuman primate. Using these criteria, we then evaluate approaches made to model PD using viral vectors to date, including both adeno-associated viruses and lentiviruses. Lastly, we comment on the consideration of aging as a critical factor for modeling PD. PMID- 26611601 TI - Gene Therapy-Based Modeling of Neurodegenerative Disorders: Huntington's Disease. AB - Huntington's disease is a fatal neurodegenerative disease characterized by impairments in motor control, and cognitive and psychiatric disturbances. In this chapter, viral vector-mediated approaches used in modeling the key neuropathological features of the disease including the production of abnormal intracellular protein aggregates, neuronal dysfunction and degeneration and motor impairments in rodents are described. PMID- 26611602 TI - Gene Therapy for the Treatment of Neurological Disorders: Amyotrophic Lateral Sclerosis. AB - Gene therapy is a powerful tool for treating diseases, including neurological disorder such at amyotrophic lateral sclerosis. When delivered to the CNS, gene therapy vectors can provide prosurvival signals to neurons, knock down the expression of toxic proteins, or restore lost function. How to best deliver this type of therapeutic depends on the nature of the disease and the expected function of the transgene. Here we describe a method for parenchymal injection into rodent models, allowing for localized delivery of gene therapy vectors and other therapeutic molecules. This technique has been a robust mechanism for proof of-principle experiments. PMID- 26611599 TI - Gene Therapy Models of Alzheimer's Disease and Other Dementias. AB - Dementias are among the most common neurological disorders, and Alzheimer's disease (AD) is the most common cause of dementia worldwide. AD remains a looming health crisis despite great efforts to learn the mechanisms surrounding the neuron dysfunction and neurodegeneration that accompanies AD primarily in the medial temporal lobe. In addition to AD, a group of diseases known as frontotemporal dementias (FTDs) are degenerative diseases involving atrophy and degeneration in the frontal and temporal lobe regions. Importantly, AD and a number of FTDs are collectively known as tauopathies due to the abundant accumulation of pathological tau inclusions in the brain. The precise role tau plays in disease pathogenesis remains an area of strong research focus. A critical component to effectively study any human disease is the availability of models that recapitulate key features of the disease. Accordingly, a number of animal models are currently being pursued to fill the current gaps in our knowledge of the causes of dementias and to develop effective therapeutics. Recent developments in gene therapy-based approaches, particularly in recombinant adeno-associated viruses (rAAVs), have provided new tools to study AD and other related neurodegenerative disorders. Additionally, gene therapy approaches have emerged as an intriguing possibility for treating these diseases in humans. This chapter explores the current state of rAAV models of AD and other dementias, discuss recent efforts to improve these models, and describe current and future possibilities in the use of rAAVs and other viruses in treatments of disease. PMID- 26611603 TI - Stereotaxic Surgical Targeting of the Nonhuman Primate Caudate and Putamen: Gene Therapy for Huntington's Disease. AB - Stereotaxic surgery is an invaluable tool to deliver a variety of gene therapy constructs to the nonhuman primate caudate and putamen in preclinical studies for the genetic, neurodegenerative disorder, Huntington's disease (HD). Here we describe in detail how to perform this technique beginning with a pre-surgical magnetic resonance imaging scan to determine surgical coordinates followed by the stereotaxic surgical injection technique. In addition, we include methodology of a full necropsy including brain and peripheral tissue removal and a standard immunohistochemical technique to visualize the injected gene therapy agent. PMID- 26611606 TI - AAV2-Neurturin for Parkinson's Disease: What Lessons Have We Learned? AB - The dream that trophic factors could be effectively delivered and potently forestall and reverse the symptoms of Parkinson's disease (PD) has yet to be realized. Research in this area has been active for 20 years, but after much work, the prospects for utilizing trophic factors in the treatment of PD are currently dim. Millions of dollars have been spent, numerous academic, foundation, and government resources have been invested, and hundreds of patient research volunteers have contributed their time and hope to this effort without a therapeutic breakthrough. As a scientist who has journeyed these events from the beginning and participated in many of the decisions that navigated this field, I consider it important for the movement disorder scientific community to reflect on the evolution of thought and to participate in the dialog over whether the investments were worthwhile.The most studied group of trophic factor for PD is the glial cell derived family of ligands, of which glial cell derived neurotrophic factor (GDNF) and neurturin are members, and are the best studied. I trace the development of these factors chronologically with commentary on the key decision-making points. Before we collectively invest further, I offer this scientific reflection on the past and offer my own view on the next steps of research in the field of neurotrophins as potential therapeutic agents in PD. PMID- 26611605 TI - Gene Therapy for the Treatment of Neurological Disorders: Central Nervous System Neoplasms. AB - Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults with a median survival of 16.2-21.2 months post diagnosis (Stupp et al., N Engl J Med 352(10): 987-996, 2005). Because of its location, complete surgical resection is impossible; additionally because GBM is also resistant to chemotherapeutic and radiotherapy approaches, development of novel therapies is urgently needed. In this chapter we describe the development of preclinical animal models and a conditionally cytotoxic and immune-stimulatory gene therapy strategy that successfully causes tumor regression in several rodent GBM models. PMID- 26611607 TI - The accuracy and timeliness of neuraminidase inhibitor dispensing data for predicting laboratory-confirmed influenza. AB - Neuraminidase inhibitor (NI) dispensing has emerged as a possible automated data source for influenza surveillance. We aimed to evaluate its timeliness, correlation, and predictive accuracy in relation to influenza activity in Quebec, Canada, 2010-2013. Our secondary objective was to use the same metrics to compare NI dispensing to visits for influenza-like illness (ILI) in emergency departments (EDs). Provincial weekly counts of positive influenza laboratory tests were used as a reference measure for the level of influenza circulation. We applied ARIMA models to account for serial correlation. We computed cross-correlations to measure the strengths of association and lead-lag relationships between NI dispensing, ILI ED visits, and our reference indicator. Finally, using an ARIMA model, we evaluated the ability of NI dispensing and ILI ED visits to predict laboratory-confirmed influenza. NI dispensing was significantly correlated (R = 0.68) with influenza activity with no lag. The maximal correlation of ILI ED visits was not as strong (R = 0.50). Both NI dispensing and ILI ED visits were significant predictors of laboratory-confirmed influenza in a multivariable model; predictive potential was greatest when NI counts were lagged to precede laboratory surveillance by 2 weeks. We conclude that NI dispensing data provides timely and valuable information for influenza surveillance. PMID- 26611604 TI - Gene Therapy for the Treatment of Neurological Disorders: Metabolic Disorders. AB - Metabolic disorders comprise a large group of heterogeneous diseases ranging from very prevalent diseases such as diabetes mellitus to rare genetic disorders like Canavan Disease. Whether either of these diseases is amendable by gene therapy depends to a large degree on the knowledge of their pathomechanism, availability of the therapeutic gene, vector selection, and availability of suitable animal models. In this book chapter, we review three metabolic disorders of the central nervous system (CNS; Canavan Disease, Niemann-Pick disease and Phenylketonuria) to give examples for primary and secondary metabolic disorders of the brain and the attempts that have been made to use adeno-associated virus (AAV) based gene therapy for treatment. Finally, we highlight commonalities and obstacles in the development of gene therapy for metabolic disorders of the CNS exemplified by those three diseases. PMID- 26611608 TI - Expression, purification and guanine nucleotide binding characterization of Arabidopsis RabE1d13-185 GTPase. AB - Arabidopsis RabE1d subclass plays important plant-specific functions in plant growth and development, response to ethylene and defence to plant pathogen, besides their basic cellular role in membrane trafficking. In this study, we present the expression, purification, and characterization of the recombinant core domain of AtRabE1d13-185. AtRabE1d13-185 was successfully expressed in Escherichia coli and purified via two-step nickel affinity chromatography followed by gel filtration, and identified single band in SDS-PAGE. The resultant protein was functionally active, as determined by interaction with guanine nucleotide by a fluorescence-based assay. The intrinsic tryptophan of AtRabE1d13 185 showed fluorescence resonance energy transfer (FRET) effect upon forming complex with fluorescent methylanthraniloyl (mant)-GDP, but quenched when binding with non-labelled guanine nucleotide. The association rate of mantGDP with AtRabE1d13-185 was determined to be 3.48 * 10(7) s(-1) M(-1). The dissociation rates of GDP and mantGDP from the complex with AtRabE1d13-185 were similar. The koff values were determined to be 4.02 * 10(-4) s(-1) based on the FRET effect for the AtRabE1d13-185:GDP and 5.41 * 10(-4) s(-1) for mantGDP excited directly. PMID- 26611609 TI - Development of monoclonal antibodies and immunochromatographic lateral flow device for rapid test of alanine aminotransferase isoenzyme 1. AB - BACKGROUND: Alanine aminotransferase (ALT) has been used as a sensitive marker for liver injury in people and in preclinical toxicity studies. But measurement of ALT isoenzymes, ALT1 and ALT2, was reported to be of more diagnostic value. The aim of this study is to develop an ideal pair of anti-ALT1 monoclonal antibodies (MAbs) of high specificity and affinity, and subsequently prepare a Immunochromatographic lateral flow device (LFD) for rapid test of ALT1 in human serums. METHODS: The complete coding sequence of ALT1 gene (1500 bp) was cloned from human hepatoma G2 cells (HepG2) and inserted into the expression vector pET 32a(+). ALT1 recombinant protein was routinely prepared by E. coli BL21 (DE3) expression and Ni(2+) affinity purification. Balb/c mice were immunized with purified ALT1 and the splenocytes were fused with Sp2/0 myeloma cells. The positive clones, verified by indirect enzyme-linked immunosorbent assay (ELISA) using purified ALT1, were subcloned to single clones by limiting dilution process. A MAb pair was selected from the obtained MAbs according the sandwich ELISA pairing results and then used for lateral flow device (LFD) production. After evaluation of the sensitivity and specificity, the LFD strips were employed to test human serum samples with known ALT activity levels. RESULTS: ALT1 recombinant protein was expectedly prepared by expression and purification. A total of 8 stable clones that produced antibodies specifically recognizing ALT1 protein were developed. After sandwich ELISA pairing, an ideal pair of anti-ALT1 MAbs, designated as BD7 and DG3, were selected and proved to be of high specificity, titer and affinity. Based on the MAb pair, LFD strips specifically for ALT1 rapid test were subsequently prepared. The detection threshold of the LFD strips was 12 U/L. No cross reaction was found. CONCLUSIONS: The ALT1 LFD with high sensitivity and specificity was successfully developed. It is valuable for testing ALT1 protein in human sera and can be a beneficial complement for traditional ALT test. PMID- 26611610 TI - Expression, subcellular localization, and enzyme activity of a recombinant human extra-cellular superoxide dismutase in tobacco (Nicotiana benthamiana L.). AB - Human extracellular superoxide dismutase (hEC-SOD) is an enzyme that scavenges reactive oxygen species (ROS). Because of its antioxidant activity, hEC-SOD has been used as a therapeutic protein to treat skin disease and arthritis in mammalian systems. In this study, codon-optimized hEC-SOD was expressed in tobacco (Nicotiana benthamiana L.) via a plant-based transient protein expression system. Plant expression binary vectors containing full-length hEC-SOD (f-hEC SOD) and modified hEC-SOD (m-hEC-SOD), in which the signal peptide and heparin binding domain were deleted, were constructed for the cytosolic-, endoplasmic reticulum (ER)-, and chloroplast-localizations in tobacco leaf mesophyll cells. The results demonstrated that f-hEC-SOD was more efficiently expressed in the cytosolic fractions than in the ER or chloroplasts of tobacco cells. Our data further indicated that differently localized f-hEC-SOD and m-hEC-SOD displayed SOD enzyme activities, suggesting that the hEC-SODs expressed by plants may be functionally active. The f-hEC-SOD was expressed up to 3.8% of the total leaf soluble protein and the expression yield was calculated to be 313.7 MUg f-hEC-SOD per g fresh weight of leaf. Overall, our results reveal that it was possible to express catalytically active hEC-SODs by means of a transient plant expression system in tobacco leaf cells. PMID- 26611611 TI - High level expression of organophosphorus hydrolase in Pichia pastoris by multicopy ophcM assembly. AB - The residues of organophosphorus pesticides bring serious impact on the environmental safety and people's health. Biodegradation of organophosphorus pesticides is recognized as an ideal method. An organophosphorus hydrolase (OPHCM) from Pseudomonas pseudoalcaligenes was synthesized and expressed in Pichia pastoris. The yield reached approximately 470 mg/l after a 6-d induction in shake flasks. To improve the enzyme production, we describe a novel approach to express OPHCM efficiently with a biobrick assembly method in vitro. Four recombinant plasmids containing 1-4 copies of ophcM-expressing cassettes were constructed and transformed into P. pastoris. Increasing the copy number of ophcM gene enhanced the expression level of OPHCM. The maximum yield and specific activity in P. pastoris harboring two-copy tandem ophcM-expressing cassettes reached 610 mg/l after a 6-d induction in shake flasks and 7.8 g/l in high density fermentation with specific activity of 13.7 U/mg. The optimum pH and temperature of the recombinant OPHCM activity were 11.0 and 50 degrees C, respectively. In addition, the enzyme activity of recombinant OPHCM enhanced 57.6% and 30.1% in the presence of 1 mM Cd(2+) and 5% glycerol, respectively. The high expression and good properties of recombinant OPHCM provide an effective solution to solve the pollution of organophosphorus pesticides in the environment. Moreover, the approach for generating multicopy gene expressing vectors here will benefit the study for enhancing the expression level of genes of interest. PMID- 26611612 TI - Overexpression and characterization of a novel endo-beta-1,3(4)-glucanase from thermophilic fungus Humicola insolens Y1. AB - A novel endo-beta-1,3(4)-glucanase gene, cel16A, was cloned from the fungus Humicola insolens Y1. The 988-bp full-length gene encoded a 286-residue polypeptide consisting of a putative signal peptide of 20 residues and a catalytic domain belonging to glycosyl hydrolase family 16. It was successfully overexpressed in Pichia pastoris GS115. The purified recombinant Cel16A exhibited highest specific activity toward barley beta-glucan, followed by lichenan and laminarin, but not toward CMC-Na, birchwood xylan, Avicel and filter paper, indicating that Cel16A is an endo-beta-1,3(4)-glucanases. Recombinant Cel16A had a pH optimum at 5.5 and a temperature optimum at 55 degrees C with a specific activity of 693 U/mg toward barley beta-glucan. It exhibited good stability over pH 5.0-9.0 and at temperatures up to 50 degrees C, retaining over 80% maximum activity. The Km and Vmax values of Cel16A for barley beta-glucan were 0.91 mg ml 1 and 1530 MUmol min-1.mg-1, respectively. All these favorable enzymatic properties of Cel16A make it a good candidate for applications in various industries. PMID- 26611614 TI - Intimate Partner Violence Victimization in the Cyber and Real World: Examining the Extent of Cyber Aggression Experiences and Its Association With In-Person Dating Violence. AB - This study explores the extent of cyber aggression victimization in intimate relationships and its co-occurrence with in-person experiences of psychological, physical, and sexual partner violence. Data were collected from 540 college students who reported being in a dating relationship in the past 12 months. Participants were asked to complete an online questionnaire that included measures assessing intimate partner victimization experiences in differing social contexts (through socially interactive technology and in face-to-face encounters). Findings indicated that intimate partner cyber aggression victimization is not uncommon, as nearly three quarters of respondents reported having experienced some form of it in the past year. Multivariate analyses also indicate that such aggression may be part of a larger violence nexus given its relation to in-person psychological, physical, and sexual partner violence victimization experiences. In light of these findings, it is recommended that longitudinal research encompassing multiple violence victimization experiences in varying social contexts is completed to determine whether online experiences foreshadow offline ones and, if so, consider interaction effects on outcomes as well as potential intervention strategies to reduce harm associated with such negative experiences. PMID- 26611613 TI - Case-Mix Variables and Predictors for Outcomes of Laparoscopic Hysterectomy: A Systematic Review. AB - The assessment of surgical quality is complex, and an adequate case-mix correction is missing in currently applied quality indicators. The purpose of this study is to give an overview of all studies mentioning statistically significant associations between patient characteristics and surgical outcomes for laparoscopic hysterectomy (LH). Additionally, we identified a set of potential case-mix characteristics for LH. This systematic review was conducted according to the Meta-Analysis of Observational Studies in Epidemiology guidelines. We searched PubMed and EMBASE from January 1, 2000 to August 1, 2015. All articles describing statistically significant associations between patient characteristics and adverse outcomes of LH for benign indications were included. Primary outcomes were blood loss, operative time, conversion, and complications. The methodologic quality of the included studies was assessed using the Newcastle Ottawa Quality Assessment Scale. The included articles were summed per predictor and surgical outcome. Three sets of case-mix characteristics were determined, stratified by different levels of evidence. Eighty-five of 1549 identified studies were considered eligible. Uterine weight and body mass index (BMI) were the most mentioned predictors (described, respectively, 83 and 45 times) in high quality studies. For longer operative time and higher blood loss, uterine weight >= 250 to 300 g and >=500 g and BMI >= 30 kg/m(2) dominated as predictors. Previous operations, adhesions, and higher age were also considered as predictors for longer operative time. For complications and conversions, the patient characteristics varied widely, and uterine weight, BMI, previous operations, adhesions, and age predominated. Studies of high methodologic quality indicated uterine weight and BMI as relevant case-mix characteristics for all surgical outcomes. For future development of quality indicators of LH and to compare surgical outcomes adequately, a case-mix correction is suggested for at least uterine weight and BMI. A potential case-mix correction for adhesions and previous operations can be considered. For both surgeons and patients it is valuable to be aware of potential factors predicting adverse outcomes and to anticipate this. Finally, to benchmark clinical outcomes at an international level, it is of the utmost importance to introduce uniform outcome definitions. PMID- 26611615 TI - Measuring the Tangible Fear of Heterosexist Violence. AB - Fear of crime (FoC) has dominated the political landscape over the last 20 years, with many crime policy developments during this period linked not to actual experiences of violence but to the fear of victimization. Fear of crime studies, in most cases, are conducted with populations that have only a passing, mediated knowledge of crime victimization. The research discussed in this article, in contrast, considers the impact of FoC with a highly victimized community, and establishes psychometric testing to validate an instrument to measure the impact of that fear ( Fear of Heterosexism Scale [ FoHS]). If FoC is related to experiences of crime as the existing research suggests, then victims of heterosexist prejudice, discrimination, and/or violence would be more likely to fear such incidents in the future. It was also predicted that participants who concealed their sexual and/or gender identity and had lower levels of social connectedness would experience higher levels of fear. The findings highlight the importance of contextual factors in FoH, and identify the critical roles that disclosure and social connectedness play in ameliorating the damaging effects of heterosexist victimization. PMID- 26611616 TI - Intimate Partner Violence and Animal Abuse in an Immigrant-Rich Sample of Mother Child Dyads Recruited From Domestic Violence Programs. AB - We examined rates of animal abuse in pet-owning families experiencing intimate partner violence (IPV). We also examined whether higher levels of IPV (as measured by subscales from the Conflict Tactics Scales) predicted increased risk for partner-perpetrated animal abuse. Our sample included 291 mother-child dyads, where the mothers sought services from domestic violence agencies. Nearly half the sample is comprised of Mexican immigrants. Mothers reported that 11.7% of partners threatened to harm a pet and 26.1% actually harmed a pet, the latter of which represents a lower rate than in similar studies. When examining animal abuse by "Hispanic status," follow-up analyses revealed significant omnibus differences between groups, in that non-Hispanic U.S.-born partners (mostly White) displayed higher rates of harming pets (41%) than either U.S.-born or Mexican-born Hispanic groups (27% and 12.5%, respectively). Differences in rates for only threatening (but not harming) pets were not significant, possibly due to a small number of partners ( n = 32) in this group. When examining whether partners' IPV predicted only threatening to harm pets, no IPV subscale variables (Physical Assault, Psychological Aggression, Injury, or Sexual Coercion) were significant after controlling for income, education, and Hispanic status. When examining actual harm to pets, more Psychological Aggression and less Physical Assault significantly predicted slightly higher risk of harm. However, Mexican born partners had nearly 4 times lower risk of harming a pet. Overall, these results suggest that Hispanic men who are perpetrators of IPV are less likely to harm pets than non-Hispanic perpetrators of IPV, particularly if Mexican-born. Considering that the United States has a significant proportion of Mexican immigrants, it may be worthwhile to explore the topics of IPV and animal abuse within this group. PMID- 26611617 TI - Thymus catharinae Camarda essential oil: beta-cyclodextrin inclusion complexes, evaluation of antimicrobial activity. AB - An efficient antimicrobial activity was evidenced in a complex beta-cyclodextrin essential oil of Thymus catharinae Camarda (carvacrol chemotype). The release of carvacrol with respect to the antimicrobial activity was calculated as function of time. The betaCD-complex of the bioactive agent was obtained by a simple, efficient and non-expensive method without purification of the carvacrol chemotype essential oil. According to the starting stoichiometry of beta cyclodextrin with respect to carvacrol, two inclusion complexes were produced, 1:1 and 2:1, respectively. The results demonstrate that, although the antimicrobial activity of the essential oil of T. catharinae Camarda is remarkable but acts too quickly in some types of application, its inclusion in a bio-matrix allows a slower release and improves its effectiveness. PMID- 26611618 TI - Frequent HLA class I alterations in human prostate cancer: molecular mechanisms and clinical relevance. AB - Reduced expression of HLA class I is an important immune escape mechanism from cytotoxic T cells described in various types of malignancy. It often correlates with poor prognosis and resistance to therapy. However, current knowledge about the frequency, underlying molecular mechanisms, and prognostic value of HLA class I and II alterations in prostate cancer (PC) is limited. Immunohistochemical analysis demonstrated that 88 % of the 42 studied cryopreserved prostate tumors have at least one type of HLA alteration as compared to adjacent normal prostate epithelium or benign hyperplasia. Total loss of HLA-I expression found in 50 % of tumors showed an association with increased incidence of tumor relapse, perineural invasion, and high D'Amico risk. The remaining HLA-I-positive tumors demonstrated locus and allelic losses detected in 26 and 12 % of samples, respectively. Loss of heterozygosity at chromosome 6 was detected in 32 % of the studied tumors. Molecular analysis revealed a reduced expression of B2M, TAP2, tapasin and NLRC5 mRNA in microdissected HLA-I-negative tumors. Analysis of twelve previously unreported cell lines derived from neoplastic and normal epithelium of cancerous prostate revealed different types of HLA-I aberration, ranging from locus and/or allelic downregulation to a total absence of HLA-I expression. The high incidence of HLA-I loss observed in PC, caused by both regulatory and structural defects, is associated with more aggressive disease development and may pose a real threat to patient health by increasing cancer progression and resistance to T-cell-based immunotherapy. PMID- 26611619 TI - Magnetic moments induce strong phonon renormalization in FeSi. AB - The interactions of electronic, spin and lattice degrees of freedom in solids result in complex phase diagrams, new emergent phenomena and technical applications. While electron-phonon coupling is well understood, and interactions between spin and electronic excitations are intensely investigated, only little is known about the dynamic interactions between spin and lattice excitations. Noncentrosymmetric FeSi is known to undergo with increasing temperature a crossover from insulating to metallic behaviour with concomitant magnetic fluctuations, and exhibits strongly temperature-dependent phonon energies. Here we show by detailed inelastic neutron-scattering measurements and ab initio calculations that the phonon renormalization in FeSi is linked to its unconventional magnetic properties. Electronic states mediating conventional electron-phonon coupling are only activated in the presence of strong magnetic fluctuations. Furthermore, phonons entailing strongly varying Fe-Fe distances are damped via dynamic coupling to the temperature-induced magnetic moments, highlighting FeSi as a material with direct spin-phonon coupling and multiple interaction paths. PMID- 26611620 TI - Resident Use of Text Messaging for Patient Care: Ease of Use or Breach of Privacy? AB - BACKGROUND: Short message service (SMS) text messaging is an efficient form of communication and pervasive in health care, but may not securely protect patient information. It is unclear if resident providers are aware of the security concerns of SMS text messaging when communicating about patient care. OBJECTIVE: We sought to compare residents' preferences for SMS text messaging compared with other forms of in-hospital communication when considering security versus ease of use. METHODS: This study was a cross-sectional multi-institutional survey of internal medicine residents. Residents ranked different communication modalities based on efficiency, ease of use, and security using a Likert scale. Communication options included telephone, email, hospital paging, and SMS text messaging. Respondents also reported whether they had received confidential patient identifiers through any of these modalities. RESULTS: SMS text messaging was preferred by 71.7% (94/131) of respondents because of its efficiency and by 79.8% (103/129) of respondents because of its ease of use. For security, 82.5% (104/126) of respondents preferred the hospital paging system, whereas only 20.6% (26/126) of respondents preferred SMS text messaging for secure communication. In all, 70.9% (93/131) of respondents reported having received patient identifiers (first and/or last name), 81.7% (107/131) reported receiving patient initials, and 50.4% (66/131) reported receiving a patient's medical record number through SMS text messages. CONCLUSIONS: Residents prefer in-hospital communication through SMS text messaging because of its ease of use and efficiency. Despite security concerns, the majority of residents reported receiving confidential patient information through SMS text messaging. For providers, it is possible that the benefits of improved in-hospital communication with SMS text messaging and the presumed improvement in the coordination and delivery of patient care outweigh security concerns they may have. The tension between the security and convenience of SMS text messaging may represent an educational opportunity to ensure the compliance of mobile technology in the health care setting. PMID- 26611621 TI - Dose-related effects of ferric citrate supplementation on endoplasmic reticular stress responses and insulin signalling pathways in streptozotocin-nicotinamide induced diabetes. AB - Diabetic patients are at high risk of developing anemia; however, pharmacological doses of iron supplementation may vary greatly depending on diabetes-related complications. The aim of this study was to investigate the dose-dependent effect of iron on glucose disposal with a special focus on endoplasmic reticular (ER) stress, iron metabolism, and insulin signalling pathways. Diabetes was induced in overnight fasted rats by intraperitoneal (i.p.) injections of 40 mg kg(-1) streptozotocin (STZ) and 100 mg kg(-1) nicotinamide. Diabetic rats were fed a standard diet (36.7 mg ferric iron per kg diet) or pharmacological doses of ferric citrate (0.5, 1, 2, and 3 g ferric iron per kg diet). Ferric citrate supplementation showed a dose-related effect on hepatic ER stress responses and total iron levels, which were associated with increased hepcidin and decreased ferroportin expressions. Iron-fed rats had increased sizes of their pancreatic islets and hyperinsulinemia compared to rats fed a standard diet. A western blot analysis revealed that iron feeding decreased total insulin receptor substrate 1 (IRS1), phosphorylated IRS1ser307, and AS160 but increased phosphorylated GSK 3beta. Iron supplementation inhibited the nuclear translocation of AKT but promoted FOXO1 translocation to nuclei. Ferric citrate supplementation showed a dose-related effect on ER stress responses, hepatic iron, and the insulin signaling pathway. Adverse effects were more evident at high iron doses (>1 g ferric iron per kg diet), which is equivalent to a 60 kg human male consuming >500 mg elemental iron per day. PMID- 26611623 TI - Spontaneous self-assembly and disassembly of colloidal gold nanoparticles induced by tetrakis(hydroxymethyl) phosphonium chloride. AB - Upon reacting with tetrakis(hydroxymethyl) phosphonium chloride, 15 nm citrate gold nanoparticles rapidly assemble into linear chains, followed by slowly disassembling into monodisperse components. This work highlights the first example of (31)P NMR on gold particles of this size and suggests that the phosphonium is oxidized on-particle, contributing to particle disassembly. PMID- 26611622 TI - Lactic Acid Bacteria Protects Caenorhabditis elegans from Toxicity of Graphene Oxide by Maintaining Normal Intestinal Permeability under different Genetic Backgrounds. AB - Lactic acid bacteria (LAB) is safe and useful for food and feed fermentation. We employed Caenorhabditis elegans to investigate the possible beneficial effect of LAB (Lactobacillus bulgaricus) pretreatment against toxicity of graphene oxide (GO) and the underlying mechanisms. LAB prevented GO toxicity on the functions of both primary and secondary targeted organs in wild-type nematodes. LAB blocked translocation of GO into secondary targeted organs through intestinal barrier by maintaining normal intestinal permeability in wild-type nematodes. Moreover, LAB prevented GO damage on the functions of both primary and secondary targeted organs in exposed nematodes with mutations of susceptible genes (sod-2, sod-3, gas-1, and aak-2) to GO toxicity by sustaining normal intestinal permeability. LAB also sustained the normal defecation behavior in both wild-type nematodes and nematodes with mutations of susceptible genes. Therefore, the beneficial role of LAB against GO toxicity under different genetic backgrounds may be due to the combinational effects on intestinal permeability and defecation behavior. Moreover, the beneficial effects of LAB against GO toxicity was dependent on the function of ACS-22, homologous to mammalian FATP4 to mammalian FATP4. Our study provides highlight on establishment of pharmacological strategy to protect intestinal barrier from toxicity of GO. PMID- 26611624 TI - Annual review of selected scientific literature: Report of the Committee on Scientific Investigation of the American Academy of Restorative Dentistry. PMID- 26611625 TI - Disease Burden Among Individuals with Severe Mental Illness in a Community Setting. AB - This study examines the prevalence of comorbid physical health conditions within a community sample of individuals with severe mental illness (SMI), compares them to a matched national sample without SMI, and identifies which comorbidities create the greatest disease burden for those with SMI. Self-reported health status, co-morbid medical conditions and perceived disease burden were collected from 203 adults with SMI. Prevalence of chronic health conditions was compared to a propensity-matched sample without SMI from the National Comorbidity Survey Replication (NCS-R). Compared to NCS-R sample without SMI, our sample with SMI had a higher prevalence of seven out of nine categories of chronic health conditions. Chronic pain and headaches, as well as the number of chronic conditions, were associated with increased disease burden for individuals with SMI. Further investigation of possible interventions, including effective pain management, is needed to improve the health status of this population. PMID- 26611626 TI - Growth stage-based modulation in physiological and biochemical attributes of two genetically diverse wheat (Triticum aestivum L.) cultivars grown in salinized hydroponic culture. AB - Hydroponic experiment was conducted to appraise variation in the salt tolerance potential of two wheat cultivars (salt tolerant, S-24, and moderately salt sensitive, MH-97) at different growth stages. These two wheat cultivars are not genetically related as evident from randomized polymorphic DNA analysis (random amplified polymorphic DNA (RAPD)) which revealed 28% genetic diversity. Salinity stress caused a marked reduction in grain yield of both wheat cultivars. However, cv. S-24 was superior to cv. MH-97 in maintaining grain yield under saline stress. Furthermore, salinity caused a significant variation in different physiological attributes measured at different growth stages. Salt stress caused considerable reduction in different water relation attributes of wheat plants. A significant reduction in leaf water, osmotic, and turgor potentials was recorded in both wheat cultivars at different growth stages. Maximal reduction in leaf water potential was recorded at the reproductive stage in both wheat cultivars. In contrast, maximal turgor potential was observed at the boot stage. Salt induced adverse effects of salinity on different water relation attributes were more prominent in cv. MH-97 as compared to those in cv. S-24. Salt stress caused a substantial decrease in glycine betaine and alpha tocopherols. These biochemical attributes exhibited significant salt-induced variation at different growth stages in both wheat cultivars. For example, maximal accumulation of glycine betaine was evident at the early growth stages (vegetative and boot). However, cv. S-24 showed higher accumulation of this organic osmolyte, and this could be the reason for maintenance of higher turgor than that of cv. MH-97 under stress conditions. Salt stress significantly increased the endogenous levels of toxic ions (Na(+) and Cl(-)) and decreased essential cations (K(+) and Ca(2+)) in both wheat cultivars at different growth stages. Furthermore, K(+)/Na(+) and Ca(2+)/Na(+) ratios decreased markedly due to salt stress in both wheat cultivars at different growth stages, and this salt-induced reduction was more prominent in cv. MH-97. Moreover, higher K(+)/Na(+) and Ca(2+)/Na(+) ratios were recorded at early growth stages in both wheat cultivars. It can be inferred from the results that wheat plants are more prone to adverse effects of salinity stress at early growth stages than that at the reproductive stage. PMID- 26611627 TI - Assessment of dioxin-like activity in PM10 air samples from an industrial location in Algeria, using the DRE-CALUX bioassay. AB - When compared to the European guidelines, PM10 (particulate matter up to 10-MUm size) concentrations in Algeria are often exceeding the maximum limits, and in general, no information exists on the compounds bound on its surface. The objective of this study was to measure the dioxin-like activity of polychlorinated dibenzodioxines and dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (PCBs) in the PM10 fraction at the Sour El Ghozlane cement plant in Algeria. PM10 samples (n = 23) were taken between 24 March and 15 April 2013, using a medium volume sampler and 47-mm PTFE filters. The 24-h samples were dried to determine the PM10 content and afterward extracted, cleaned up, and analyzed with the dioxin-responsive element-chemical-activated luciferase gene expression (DRE-CALUX) bioassay. Our results showed that the measured bioanalytical equivalents (BEQs) were similar to those in other international industrial sites worldwide. The PCDD/Fs and dioxin-like PCBs (dl-PCBs) were positively correlated (rho = 0.6, p = 0.002), indicating that they have similar sources. Furthermore, samples from March showed higher PCDD/F and dl-PCB BEQs and humidity but lower temperatures compared to samples from April, while there was no difference in the PM10 concentrations between the two months. These results reveal that PM10 alone is not a good proxy and that meteorological conditions are an important factor in assessing dioxin-like pollution in the atmosphere. It seems that, at present, there is no health hazard through direct airborne human exposure to dioxin-like pollutants in PM10 from this site. However, it is important to monitor these POPs for a longer period of time and also to gain more insight in their distribution between the particulate and gas phase in relation to meteorological conditions. PMID- 26611628 TI - The presence of cadmium in the intertidal environments of a moderately impacted coastal lagoon in western Portugal (Obidos Lagoon)--spatial and seasonal evaluations. AB - A seasonal environmental monitoring program was carried out (winter 2009 to summer 2010) to evaluate the spatial and seasonal cadmium concentrations in the intertidal environments of the Obidos Lagoon (Portugal). Also, some environmental parameters were monitored at each sampling station. Both the water and the sediment samples were contaminated, although to different degrees. In general, cadmium contamination appears to be mostly focused on the inner areas of the lagoon, namely, in Barrosa's arm, which receives a small tributary contaminated by agro-industrial activities. Only cadmium concentration in sediment showed to be significantly influenced by seasons. Some environmental parameters presented spatial and temporal heterogeneity which influenced, to some extent, cadmium bioavailability. The results of this study allow a better understanding of the environmental quality of this ecosystem regarding cadmium contamination and may assist in the definition of future coastal management measures specifically targeted to trace metal contamination and pollution monitoring. PMID- 26611629 TI - Post-treatment of anaerobic reactor effluent using coagulation/oxidation followed by double filtration. AB - This study evaluates the efficacy of a sanitary sewage treatment system, proposing post-treatment of the effluent generated by the upflow anaerobic sludge blanket UASB reactor, through a Fenton coagulation/oxidation ((ferric chloride (FC) or ferrous sulfate (FS) and peracetic acid (PAA)), followed by a double filtration system, composed of a gravel ascending drainage filter and a sand descending filter. Following the assessment of treatability, the system efficiency was evaluated using physicochemical and microbiological parameters. In all treatments performed in the pilot unit, total suspended solids (TSS) were completely removed, leading to a decrease in turbidity greater than 90% and close to 100% removal of total phosphorous. In the FC and PAA combination, the effluent was oxygenated prior to filtration, enabling a more significant removal of biochemical oxygen demand (BOD), which characterizes aerobic degradation even in a quick sand filter. The treatments carried out in the presence of the PAA oxidizing agent showed a more significant bleaching of the effluent. Concerning the microbiological parameters, the simultaneous use of PAA and FC contributed to the partial inactivation of the assessed microorganisms. A 65% recovery of the effluent was obtained with the proposed treatment system, considering the volume employed in filter backwashing. PMID- 26611630 TI - Nanoscale zerovalent iron-mediated degradation of DDT in soil. AB - Nanoscale zerovalent iron (nZVI)-mediated degradation of 1,1,1-trichloro-2,2 bis(p-chlorophenyl)ethane (DDT) was investigated in a spiked soil under different conditions (iron sources, iron dosage, soil moisture, temperature, and soil types) and DDT-contaminated field. The degradation efficiency of p,p'-DDT by nZVI and nZVI coated with sodium oleate (SO-nZVI) was much higher than that by nZVI coated with polyimide (PI-nZVI). The rapid degradation of p,p'-DDT by nZVI only occurred in flooded soil. The degradation half-life of p,p'-DDT decreased significantly from 58.3 to 27.6 h with nZVI dosage from 0.5 to 2.0% and from 46.5 to 32.0 h with temperature from 15 to 35 degrees C. The degradation efficiency of p,p'-DDT by nZVI differed in Jinhua (JH), Jiaxing (JX), Xiaoshan (XS), Huajiachi (HJC), and Heilongjiang (HLJ) soils. A good correlation was found between the degradation half-life of p,p'-DDT and multiple soil properties. The probable nZVI-mediated degradation pathway of p,p'-DDT in soil was proposed as DDT -> DDD/DDE -> DDNS -> DDOH based on the metabolites identified by GC-MS. The in situ degradation efficiency of residual DDTs in a contaminated field was profoundly enhanced by the addition of nZVI as compared to the control. It is concluded that nZVI might be an efficient agent for the remediation of DDT contaminated soil under anaerobic environment. PMID- 26611631 TI - Red cabbage yield, heavy metal content, water use and soil chemical characteristics under wastewater irrigation. AB - The objective of this 2-year field study was to evaluate the effects of drip irrigation with urban wastewaters reclaimed using primary (filtration) and secondary (filtration and aeration) processes on red cabbage growth and fresh yield, heavy metal content, water use and efficiency and soil chemical properties. Filtered wastewater (WW1), filtered and aerated wastewater (WW2), freshwater and filtered wastewater mix (1:1 by volume) (WW3) and freshwater (FW) were investigated as irrigation water treatments. Crop evapotranspiration decreased significantly, while water use efficiency increased under wastewater treatments compared to FW. WW1 treatment had the lowest value (474.2 mm), while FW treatments had the highest value (556.7 mm). The highest water use efficiency was found in the WW1 treatment as 8.41 kg m(-3), and there was a twofold increase with regard to the FW. Wastewater irrigation increased soil fertility and therefore red cabbage yield. WW2 treatment produced the highest total fresh yield (40.02 Mg ha(-1)). However, wastewater irrigation increased the heavy metal content in crops and soil. Cd content in red cabbage heads was above the safe limit, and WW1 treatment had the highest value (0.168 mg kg(-1)). WW3 treatment among wastewater treatments is less risky in terms of soil and crop heavy metal pollution and faecal coliform contamination. Therefore, WW3 wastewater irrigation for red cabbage could be recommended for higher yield and water efficiency with regard to freshwater irrigation. PMID- 26611632 TI - Prediction models for transfer of arsenic from soil to corn grain (Zea mays L.). AB - In this study, the transfer of arsenic (As) from soil to corn grain was investigated in 18 soils collected from throughout China. The soils were treated with three concentrations of As and the transfer characteristics were investigated in the corn grain cultivar Zhengdan 958 in a greenhouse experiment. Through stepwise multiple-linear regression analysis, prediction models were developed combining the As bioconcentration factor (BCF) of Zhengdan 958 and soil pH, organic matter (OM) content, and cation exchange capacity (CEC). The possibility of applying the Zhengdan 958 model to other cultivars was tested through a cross-cultivar extrapolation approach. The results showed that the As concentration in corn grain was positively correlated with soil pH. When the prediction model was applied to non-model cultivars, the ratio ranges between the predicted and measured BCF values were within a twofold interval between predicted and measured values. The ratios were close to a 1:1 relationship between predicted and measured values. It was also found that the prediction model (Log [BCF]=0.064 pH-2.297) could effectively reduce the measured BCF variability for all non-model corn cultivars. The novel model is firstly developed for As concentration in crop grain from soil, which will be very useful for understanding the As risk in soil environment. PMID- 26611633 TI - Regulating riparian forests for aquatic productivity in the Pacific Northwest, USA: addressing a paradox. AB - Forested riparian buffers isolate streams from the influence of harvesting operations that can lead to water temperature increases. Only forest cover between the sun and stream limits stream warming, but that cover also reduces in stream photosynthesis, aquatic insect production, and fish productivity. Water temperature increases that occur as streams flow through canopy openings decrease rapidly downstream, in as little as 150 m. Limiting management options in riparian forests restricts maintenance and optimization of various buffer contributions to beneficial uses, including forest products, fish, and their food supply. Some riparian disturbance, especially along cold streams, appears to benefit fish productivity. Options for enhancing environmental investments in buffers should include flexibility in application of water quality standards to address the general biological needs of fish and temporary nature of clearing induced warming. Local prescriptions for optimizing riparian buffers and practices that address long-term habitat needs deserve attention. Options and incentives are needed to entice landowners to actively manage for desirable riparian forest conditions. PMID- 26611634 TI - The Hippo pathway effectors YAP and TAZ promote cell growth by modulating amino acid signaling to mTORC1. AB - YAP and TAZ are transcriptional co-activators and function as the major effectors of the Hippo tumor suppressor pathway, which controls cell growth, tissue homeostasis, and organ size. Here we show that YAP/TAZ play an essential role in amino acid-induced mTORC1 activation, particularly under nutrient-limiting conditions. Mechanistically, YAP/TAZ act via the TEAD transcription factors to induce expression of the high-affinity leucine transporter LAT1, which is a heterodimeric complex of SLC7A5 and SLC3A2. Deletion of YAP/TAZ abolishes expression of LAT1 and reduces leucine uptake. Re-expression of SLC7A5 in YAP/TAZ knockout cells restores leucine uptake and mTORC1 activation. Moreover, SLC7A5 knockout cells phenocopies YAP/TAZ knockout cells which exhibit defective mTORC1 activation in response to amino acids. We further demonstrate that YAP/TAZ act through SLC7A5 to provide cells with a competitive growth advantage. Our study provides molecular insight into the mechanism of YAP/TAZ target genes in cell growth regulation. PMID- 26611637 TI - Determination of Mean Inner Potential and Inelastic Mean Free Path of ZnTe Using Off-Axis Electron Holography and Dynamical Effects Affecting Phase Determination. AB - The mean inner potential (MIP) and inelastic mean free path (IMFP) of undoped ZnTe are determined using a combination of off-axis electron holography and convergent beam electron diffraction. The ZnTe MIP is measured to be 13.7+/-0.6 V, agreeing with previously reported simulations, and the IMFP at 200 keV is determined to be 46+/-2 nm for a collection angle of 0.75 mrad. Dynamical effects affecting holographic phase imaging as a function of incident beam direction for several common semiconductors are systematically studied and compared using Bloch wave simulations. These simulation results emphasize the need for careful choice of specimen orientation when carrying out quantitative electron holography studies in order to avoid erroneous phase measurements. PMID- 26611636 TI - Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. AB - Inflammasome is an intracellular signaling complex of the innate immune system. Activation of inflammasomes promotes the secretion of interleukin 1beta (IL 1beta) and IL-18 and triggers pyroptosis. Caspase-1 and -11 (or -4/5 in human) in the canonical and non-canonical inflammasome pathways, respectively, are crucial for inflammasome-mediated inflammatory responses. Here we report that gasdermin D (GSDMD) is another crucial component of inflammasomes. We discovered the presence of GSDMD protein in nigericin-induced NLRP3 inflammasomes by a quantitative mass spectrometry-based analysis. Gene deletion of GSDMD demonstrated that GSDMD is required for pyroptosis and for the secretion but not proteolytic maturation of IL-1beta in both canonical and non-canonical inflammasome responses. It was known that GSDMD is a substrate of caspase-1 and we showed its cleavage at the predicted site during inflammasome activation and that this cleavage was required for pyroptosis and IL-1beta secretion. Expression of the N-terminal proteolytic fragment of GSDMD can trigger cell death and N-terminal modification such as tagging with Flag sequence disrupted the function of GSDMD. We also found that pro-caspase-1 is capable of processing GSDMD and ASC is not essential for GSDMD to function. Further analyses of LPS plus nigericin- or Salmonella typhimurium treated macrophage cell lines and primary cells showed that apoptosis became apparent in Gsdmd(-/-) cells, indicating a suppression of apoptosis by pyroptosis. The induction of apoptosis required NLRP3 or other inflammasome receptors and ASC, and caspase-1 may partially contribute to the activation of apoptotic caspases in Gsdmd(-/-) cells. These data provide new insights into the molecular mechanisms of pyroptosis and reveal an unexpected interplay between apoptosis and pyroptosis. PMID- 26611635 TI - PslG, a self-produced glycosyl hydrolase, triggers biofilm disassembly by disrupting exopolysaccharide matrix. AB - Biofilms are surface-associated communities of microorganism embedded in extracellular matrix. Exopolysaccharide is a critical component in the extracellular matrix that maintains biofilm architecture and protects resident biofilm bacteria from antimicrobials and host immune attack. However, self produced factors that target the matrix exopolysaccharides, are still poorly understood. Here, we show that PslG, a protein involved in the synthesis of a key biofilm matrix exopolysaccharide Psl in Pseudomonas aeruginosa, prevents biofilm formation and disassembles existing biofilms within minutes at nanomolar concentrations when supplied exogenously. The crystal structure of PslG indicates the typical features of an endoglycosidase. PslG mainly disrupts the Psl matrix to disperse bacteria from biofilms. PslG treatment markedly enhances biofilm sensitivity to antibiotics and macrophage cells, resulting in improved biofilm clearance in a mouse implant infection model. Furthermore, PslG shows biofilm inhibition and disassembly activity against a wide range of Pseudomonas species, indicating its great potential in combating biofilm-related complications. PMID- 26611638 TI - Density functional study on the hole doping of single-layer SnS2 with metal element X (X = Li, Mg, and Al). AB - The effects of metal element X-doping on the electronic and optical properties of single-layer SnS2 were investigated using density functional theory. The results show that the doping is energetically more favorable under S-rich conditions than under Sn-rich conditions. For Li and Mg doping, there is the existence of ionic bonding between the dopants and adjacent S atoms, and the systems exhibit magnetic ground states. However, covalent bonding character is observed in Al doped single-layer SnS2, and the system exhibits non-magnetic ground states. The optical properties show that the optical absorptions are anisotropic for all doping cases. The X doping not only results in a red shift of the absorption edges, but also enhances the effective utilization in the near-infrared light region. Additionally, Li-doped single-layer SnS2 is active for overall water splitting under visible light radiation whereas Mg and Al-doped SnS2 are only suitable for oxygen evolution. PMID- 26611639 TI - Structural modifications due to interface chemistry at metal-nitride interfaces. AB - Based on accurate first principles density functional theory (DFT) calculations, an unusual phenomenon of interfacial structural modifications, due to the interface chemistry influence is identified at two metal-nitride interfaces with strong metal-nitrogen affinity, Al/TiN {111} and Al/VN {111} interfaces. It is shown that at such interfaces, a faulted stacking structure is energetically preferred on the Al side of the interface. And both intrinsic and extrinsic stacking fault energies in the vicinity Al layers are negligibly small. However, such phenomenon does not occur in Pt/TiN and Pt/VN interfaces because of the weak Pt-N affinity. Corresponding to structural energies of metal-nitride interfaces, the linear elasticity analysis predicts characteristics of interfacial misfit dislocations at metal-nitride interfaces. PMID- 26611641 TI - A dose calculation algorithm with correction for proton-nucleus interactions in non-water materials for proton radiotherapy treatment planning. AB - In treatment planning for proton radiotherapy, the dose measured in water is applied to the patient dose calculation with density scaling by stopping power ratio [Formula: see text]. Since the body tissues are chemically different from water, this approximation may cause dose calculation errors, especially due to differences in nuclear interactions. We proposed and validated an algorithm for correcting these errors. The dose in water is decomposed into three constituents according to the physical interactions of protons in water: the dose from primary protons continuously slowing down by electromagnetic interactions, the dose from protons scattered by elastic and/or inelastic interactions, and the dose resulting from nonelastic interactions. The proportions of the three dose constituents differ between body tissues and water. We determine correction factors for the proportion of dose constituents with Monte Carlo simulations in various standard body tissues, and formulated them as functions of their [Formula: see text] for patient dose calculation. The influence of nuclear interactions on dose was assessed by comparing the Monte Carlo simulated dose and the uncorrected dose in common phantom materials. The influence around the Bragg peak amounted to -6% for polytetrafluoroethylene and 0.3% for polyethylene. The validity of the correction method was confirmed by comparing the simulated and corrected doses in the materials. The deviation was below 0.8% for all materials. The accuracy of the correction factors derived with Monte Carlo simulations was separately verified through irradiation experiments with a 235 MeV proton beam using common phantom materials. The corrected doses agreed with the measurements within 0.4% for all materials except graphite. The influence on tumor dose was assessed in a prostate case. The dose reduction in the tumor was below 0.5%. Our results verify that this algorithm is practical and accurate for proton radiotherapy treatment planning, and will also be useful in rapidly determining fluence correction factors for non-water phantom dosimetry. PMID- 26611640 TI - Increased diversity of egg-associated bacteria on brown trout (Salmo trutta) at elevated temperatures. AB - The taxonomic composition of egg-associated microbial communities can play a crucial role in the development of fish embryos. In response, hosts increasingly influence the composition of their associated microbial communities during embryogenesis, as concluded from recent field studies and laboratory experiments. However, little is known about the taxonomic composition and the diversity of egg associated microbial communities within ecosystems; e.g., river networks. We sampled late embryonic stages of naturally spawned brown trout at nine locations within two different river networks and applied 16S rRNA pyrosequencing to describe their bacterial communities. We found no evidence for a significant isolation-by-distance effect on the composition of bacterial communities, and no association between neutral genetic divergence of fish host (based on 11 microsatellites) and phylogenetic distances of the composition of their associated bacterial communities. We characterized core bacterial communities on brown trout eggs and compared them to corresponding water samples with regard to bacterial composition and its presumptive function. Bacterial diversity was positively correlated with water temperature at the spawning locations. We discuss this finding in the context of the increased water temperatures that have been recorded during the last 25 years in the study area. PMID- 26611642 TI - CACNA1C risk variant affects facial emotion recognition in healthy individuals. AB - Recognition and correct interpretation of facial emotion is essential for social interaction and communication. Previous studies have shown that impairments in this cognitive domain are common features of several psychiatric disorders. Recent association studies identified CACNA1C as one of the most promising genetic risk factors for psychiatric disorders and previous evidence suggests that the most replicated risk variant in CACNA1C (rs1006737) is affecting emotion recognition and processing. However, studies investigating the influence of rs1006737 on this intermediate phenotype in healthy subjects at the behavioral level are largely missing to date. Here, we applied the "Reading the Mind in the Eyes" test, a facial emotion recognition paradigm in a cohort of 92 healthy individuals to address this question. Whereas accuracy was not affected by genotype, CACNA1C rs1006737 risk-allele carries (AA/AG) showed significantly slower mean response times compared to individuals homozygous for the G-allele, indicating that healthy risk-allele carriers require more information to correctly identify a facial emotion. Our study is the first to provide evidence for an impairing behavioral effect of the CACNA1C risk variant rs1006737 on facial emotion recognition in healthy individuals and adds to the growing number of studies pointing towards CACNA1C as affecting intermediate phenotypes of psychiatric disorders. PMID- 26611643 TI - Differential increase in prevalence estimates of inadequate sleep among black and white Americans. AB - BACKGROUND: The National Health Interview Survey (NHIS) was used to ascertain whether increases in inadequate sleep differentially affected black and white Americans. We tested the hypothesis that prevalence estimates of inadequate sleep were consistently greater among blacks, and that temporal changes have affected these two strata differentially. METHODS: NHIS is an ongoing cross-sectional study of non-institutionalized US adults (>=18 years) providing socio demographic, health risk, and medical factors. Sleep duration was coded as very short sleep [VSS] (<5 h), short sleep [SS] (5-6 h), or long sleep [LS] (>8 h), referenced to 7-8 h sleepers. Analyses adjusted for NHIS' complex sampling design using SAS-callable SUDAAN. RESULTS: Among whites, the prevalence of VSS increased by 53% (1.5% to 2.3%) from 1977 to 2009 and the prevalence of SS increased by 32% (19.3% to 25.4 %); prevalence of LS decreased by 30% (11.2% to 7.8%). Among blacks, the prevalence of VSS increased by 21% (3.3% to 4.0%) and the prevalence of SS increased by 37% (24.6 % to 33.7%); prevalence of LS decreased by 42% (16.1% to 9.4%). Adjusted multinomial regression analysis showed that odds of reporting inadequate sleep for whites were: VSS (OR = 1.40, 95% CI = 1.13-1.74, p < 0.001), SS (OR = 1.34, 95 % CI = 1.25-1.44, p < 0.001), and LS (OR = 0.94, 95% CI = 0.85-1.05, NS). For blacks, estimates were: VSS (OR = 0.83, 95% CI = 0.60 1.40, NS), SS (OR = 1.21, 95% CI = 1.05-1.50, p < 0.001), and LS (OR = 0.84, 95% CI = 0.64-1.08, NS). CONCLUSIONS: Blacks and whites are characteristically different regarding the prevalence of inadequate sleep over the years. Temporal changes in estimates of inadequate sleep seem dependent upon individuals' race/ethnicity. PMID- 26611645 TI - Anti-tumor angiogenesis effect of a new compound: B-9-3 through interference with VEGFR2 signaling. AB - B-9-3, a derivative of harmine, was first synthesized in our laboratory. We have reported that B-9-3 has an anti-proliferative effect against human lung cancer cells via induction of apoptosis and inhibition of cell migration. In the present study, we first studied that the anti-tumor angiogenesis effect and the molecular mechanism of B-9-3-induced tumor vascular degrade and mortify in lung cancer. In vitro, the results showed that B-9-3 selectively inhibited the proliferation of endothelial cells IC50 = 6.16 MUg/ml) and vascular fibroblasts (IC50 = 12.59 MUg/ml) and induced regression of tumor cells of the following: Lewis lung carcinoma (LLC), Mouse fore-stomach carcinoma (MFC), Human ovarian cancer (SK-OV 3), and prostate cancer (22RV1). Moreover, B-9-3 could significantly increase the apoptosis rate (80.95 %) of vascular endothelial cells, while inhibiting migration of endothelial cells, capillary tube formation of endothelial cells, neovascularization of the rat thoracic aorta ring, and the angiogenesis of chick chorioallantoic membrane (CAM) predominantly through blocking VEGFR2 signaling pathway. In vivo, we investigated the anti-tumor rate and the signal transduction mechanism of B-9-3 by LCC-bearing C57BL/6 mice. The data showed that the tumor inhibition ratio of high dose (20 mg/kg) of B-9-3 was 72.9 %, and quantification of CD34 marker indicated a marked reduction in the number of neovessels after B-9 3 treatment as compared with control group (66.87 %). Remarkably, using IHC and q RT-PCR, we found that downregulation of the expression of VEGFR2, VEGF-A, and TGFbeta1 in tumor confers enhancement to the angiogenesis effect of B-9-3. These data suggest that the angiogenesis inhibitor B-9-3 selectively induces apoptosis of endothelial cells, in part through disruption of VEGF-A/VEGFR2 signaling. PMID- 26611644 TI - Expression of chemokine receptor CXCR4 is closely correlated with clinical outcome in human nasopharyngeal carcinoma. AB - The CXC chemokine receptor 4 (CXCR4) has been reported to be involved in the development and progression of nasopharyngeal carcinoma (NPC). However, the role of CXCR4 in clinical outcome and prognosis of NPC patients remains controversial. In the present study, we investigated and reviewed the expression of CXCR4 in NPC tissues and then analyzed the definitive role of CXCR4 in clinical outcome and prognosis. Here, we found that the expression level of CXCR4 was significantly higher in NPC cancer specimens (61/98) than that in paired non-tumor tissues (p < 0.001). Together with our pathological analysis, statistic analysis revealed that CXCR4 expression was indeed closely correlated with UICC stage (p = 0.000), N stage (p = 0.019), and metastasis (p = 0.000). Most importantly, the systematic review combined with our survival and multivariate analysis that revealed high expression of CXCR4 was obviously associated with poor overall survival (OS) (p = 0.000) and progression-free survival (PFS) (p = 0.000) and can act as an independent prognostic factor in NPC patients. In conclusion, this study suggests that CXCR4 is highly activated and expressed in the development of NPC and may be recommended as an indicator in the diagnosis of NPC. Thus, targeting of CXCR4 gene or protein could be used as a potential therapy for NPC. PMID- 26611646 TI - Downregulation of long noncoding RNA NONHSAT037832 in papillary thyroid carcinoma and its clinical significance. AB - Long noncoding RNA (lncRNA) is a kind of RNA that is longer than 200 nucleotides with limited or no protein-coding potential. Studies have proved that lncRNAs play important regulatory roles in gene expression and contribute to oncogenesis and cancer metastasis. However, the expression level of lncRNAs and their clinicopathologic significance in papillary thyroid carcinoma (PTC) have not been well studied. In this study, we investigated the expression level of a novel lncRNA NONHSAT037832 in PTC and paired noncancerous thyroid tissues as well as some cell lines by quantitative real-time polymerase chain reaction. The association between the expression level of NONHSAT037832 and clinicopathologic characteristics of patients with PTC was further analyzed. Three receiver operating characteristic curves (ROCs) were established to evaluate the diagnostic value of NONHSAT037832. The results suggested that the expression level of NONHSAT037832 was significantly decreased in PTC compared with paired noncancerous tissues (P < 0.01). And, NONHSAT037832 was also significantly downregulated in two PTC cell lines (K1 and IHH-4) compared to normal thyroid follicular epithelial cell line Nthy-ori 3-1 (P < 0.01). Downregulated NONHSAT037832 was significantly associated with lymph node metastasis (P = 0.015) and tumor size (P = 0.032). The ROCs revealed that NONHSAT037832 had a high diagnostic value for differentiating between PTC and noncancerous diseases as well as identifying PTC with lymph node metastasis and larger tumors (>=3 cm). The area under curve was up to 0.897 (95%CI = 0.852-0.942, P = 0.000), 0.641 (95%CI = 0.519-0.762, P = 0.033), and 0.702 (95%CI = 0.567-0.827, P = 0.008), respectively. This study indicated that NONHSAT037832 might serve as a potential biomarker of PTC. PMID- 26611647 TI - Decreased expression of BRCA1-associated protein 1 predicts unfavorable survival in gastric adenocarcinoma. AB - BRCA1-associated protein 1 (BAP1) has been reported as a novel tumor suppressor, while in gastric adenocarcinoma, the function of this protein was still await to be uncovered. Based on a large group of patients with gastric adenocarcinoma, our study aimed to have a further understanding about the correlation of BAP1 expression and patients' clinical outcomes. We performed quantitative PCR and Western blot to examine BAP1 expression in 38 cases of gastric adenocarcinoma samples and adjacent non-cancerous tissues. Immunochemistry was used to evaluate BAP1 expression in a large cohort of 474 paraffin-embedded specimens. The clinical and prognostic significance of BAP1 expression was statistically analyzed. Postoperative survival between groups was using Kaplan-Meier analysis. BAP1 was overexpressed in paracancerous normal mucosa compared with gastric cancer. Decreased BAP1 expression was associated with higher histologic grade (P = 0.044), tumor infiltration (P < 0.001), metastasis status (P = 0.023), and TNM stage (P < 0.001). Patients with low expression of BAP1 had shorter overall survival compared with those with high expression (P < 0.001). Patients' survival in stage N0 could be stratified by the expression of BAP1. Multivariate analysis showed that in gastric adenocarcinoma, BAP1 expressing level was an independent prognostic factor (RR = 0.575, P < 0.001). Decreased expression of BAP1 suggests pessimistic prognosis for gastric adenocarcinoma patients. Further studies are warranted. PMID- 26611649 TI - A high-density microelectrode-tissue-microelectrode sandwich platform for application of retinal circuit study. AB - BACKGROUND: Microelectrode array (MEA) devices are frequently used in neural circuit studies, especially in retinal prosthesis. For a high throughput stimulation and recording paradigm, it is desirable to obtain the responses of multiple surface RGCs initiated from the electrical signals delivered to multiple photoreceptor cells. This can be achieved by an high density MEA-tissue-MEA (MTM) sandwich configuration. However, the retina is one of the most metabolically active tissues, consumes oxygen as rapidly as the brain. The major concern of the MTM configuration is the supply of oxygen. METHODS: We aimed to develop a high density MTM sandwich platform which consists of stacks of a stimulation MEA, retinal tissue and a recording MEA. Retina is a metabolically active tissue and the firing rate is very sensitive to oxygen level. We designed, simulated and microfabricated porous high density MEAs and an adjustable perfusion system that electrical signals can be delivered to and recorded from the clipped retinal tissue. RESULTS: The porous high-density MEAs linked with stimulation or recording devices within a perfusion system were manufactured and the MTM platform was assembled with a retina slice inside. The firing rate remained constant between 25 and 55 min before dramatically declined, indicating that within certain period of time (e.g. 30 min after habituation), the retina condition was kept by sufficient oxygen supply via the perfusion holes in the MEAs provided by the double perfusion system. CONCLUSIONS: MTM sandwich structure is an efficient platform to study the retinal neural circuit. The material and arrangement of high density microelectrodes with porous design make this MEA appropriate for sub-retina prosthesis. Finding ways to prolong the recording time and reduce the signal-to-noise ratio are important to improve our MTM prototype. PMID- 26611650 TI - Trust and Reflection in Primary Care Practice Redesign. AB - OBJECTIVE: To test a conceptual model of relationships, reflection, sensemaking, and learning in primary care practices transitioning to patient-centered medical homes (PCMH). DATA SOURCES/STUDY SETTING: Primary data were collected as part of the American Academy of Family Physicians' National Demonstration Project of the PCMH. STUDY DESIGN: We conducted a cross-sectional survey of clinicians and staff from 36 family medicine practices across the United States. Surveys measured seven characteristics of practice relationships (trust, diversity, mindfulness, heedful interrelation, respectful interaction, social/task relatedness, and rich and lean communication) and three organizational attributes (reflection, sensemaking, and learning) of practices. DATA COLLECTION/EXTRACTION METHODS: We surveyed 396 clinicians and practice staff. We performed a multigroup path analysis of the data. Parameter estimates were calculated using a Bayesian estimation method. PRINCIPAL FINDINGS: Trust and reflection were important in explaining the characteristics of practice relationships and their associations with sensemaking and learning. The strongest associations between relationships, sensemaking, and learning were found under conditions of high trust and reflection. The weakest associations were found under conditions of low trust and reflection. CONCLUSIONS: Trust and reflection appear to play a key role in moderating relationships, sensemaking, and learning in practices undergoing practice redesign. PMID- 26611651 TI - Genomic and evolutionary inferences between American and global strains of porcine epidemic diarrhea virus. AB - Porcine epidemic diarrhea virus (PEDV) has caused severe economic losses both recently in the United States (US) and historically throughout Europe and Asia. Traditionally, analysis of the spike gene has been used to determine phylogenetic relationships between PEDV strains. We determined the complete genomes of 93 PEDV field samples from US swine and analyzed the data in conjunction with complete genome sequences available from GenBank (n=126) to determine the most variable genomic areas. Our results indicate high levels of variation within the ORF1 and spike regions while the C-terminal domains of structural genes were highly conserved. Analysis of the Receptor Binding Domains in the spike gene revealed a limited number of amino acid substitutions in US strains compared to Asian strains. Phylogenetic analysis of the complete genome sequence data revealed high rates of recombination, resulting in differing evolutionary patterns in phylogenies inferred for the spike region versus whole genomes. These finding suggest that significant genetic events outside of the spike region have contributed to the evolution of PEDV. PMID- 26611648 TI - The immunobiology of myeloid-derived suppressor cells in cancer. AB - The tumor microenvironment is a complex and heterogeneous milieu in which multiple interactions occur between tumor and host cells. Immunosuppressive cells which are present in this microenvironment, such as regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), play an important role in tumor progression, via down-regulation of antitumor responses. MDSCs represent a heterogeneous group of cells originated from the myeloid lineage that are in the immature state. These cells markedly accumulate under pathologic conditions, such as cancer, infection, and inflammation, and use various mechanisms to inhibit both adaptive and innate immune responses. These immunosuppressive mechanisms include deprivation of T cells from essential amino acids, induction of oxidative stress, interference with viability and trafficking of T cells, induction of immunosuppressive cells, and finally polarizing immunity toward a tumor-promoting type 2 phenotype. In addition to suppression of antitumor immune responses, MDSCs can also enhance the tumor metastasis and angiogenesis. Previous studies have shown that increased frequency of MDSCs is related to the tumor progression. Moreover, various drugs that directly target these cells or reverse their suppressive activity can improve antitumor immune responses as well as increase the efficacy of immunotherapeutic intervention. In this review, we will first discuss on the immunobiology of MDSCs in an attempt to find the role of these cells in tumor progression and then discuss about therapeutic approaches to target these cells. PMID- 26611652 TI - Characterization and evolution of porcine deltacoronavirus in the United States. AB - Porcine deltacoronavirus (PDCoV) was identified in multiple states across the United States (US) in 2014. In this study, we investigate the presence of PDCoV in diagnostic samples, which were further categorized by case identification (ID), and the association between occurrence, age, specimen and location between March and September 2014. Approximately, 7% of the case IDs submitted from the US were positive for PDCoV. Specimens were categorized into eight groups, and the univariate analysis indicated that oral fluids had 1.89 times higher odds of detecting PDCoV compared to feces. While the 43-56 day age group had the highest percentage of PDCoV positives (8.4%), the univariate analysis indicated no significant differences between age groups. However, multivariable analysis for age adjusted by specimen indicated the >147 day age group had 59% lower odds than suckling pigs of being positive for PDCoV. The percentage of PDCoV in diagnostic samples decreased to <1% in September 2014. In addition, 19 complete PDCoV genomes were sequenced, and Bayesian analysis was conducted to estimate the emergence of the US clade. The evolutionary rate of the PDCoV genome is estimated to be 3.8*10(-4) substitutions/site/year (2.3*10(-4)-5.4*10(-4), 95% HPD). Our results indicate that oral fluids continue to be a valuable specimen to monitor swineherd health, and PDCoV has been circulating in the US prior to 2014. PMID- 26611653 TI - Association of polymorphisms in translesion synthesis genes with prognosis of advanced non-small-cell lung cancer patients treated with platinum-based chemotherapy. AB - BACKGROUND AND OBJECTIVES: Translesion synthesis (TLS) polymerases enable cells to bypass or overcome DNA damage during DNA replication and contributes to genomic instability and cancer. Inhibition of the expression of TLS genes enhances the sensitivity of cancer cells to cisplatin. This study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) in the TLS genes and clinical outcome of advanced non-small-cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. METHODS: A total of 16 SNPs were genotyped and analyzed in 302 advanced NSCLC patients (discovery set), and the results were further validated in additional 428 NSCLC patients (validation set). RESULTS: Analyses revealed significant associations of two SNPs, rs3213801 and rs3792136, with overall survival, with the lowest combined P values of 0.003 and 0.016, respectively. These effects also remained in stratification analyses by clinical variables. Furthermore, the number of risk genotypes of the two SNPs showed a cumulative effect on overall survival (P = 0.03). CONCLUSIONS: Genetic polymorphisms in the TLS genes might serve as potential predictive biomarkers of prognosis of advanced NSCLC patients treated with platinum-based chemotherapy. PMID- 26611654 TI - A highly specific microRNA-mediated mechanism silences LTR retrotransposons of strawberry. AB - Small RNAs are involved in a plethora of functions in plant genomes. In general, transcriptional gene silencing is mediated by 24-nucleotide siRNAs and is required for maintaining transposable elements in a silenced state. However, microRNAs are not commonly associated with transposon silencing. In this study, we performed small RNA transcriptome and degradome analyses of the Rosaceae model plant Fragaria vesca (the woodland strawberry) at the genome-wide level, and identified miRNA families and their targets. We report a highly specific mechanism of LTR retrotransposon silencing mediated by an abundant, ubiquitously expressed miRNA (fve-miR1511) generated from a single locus. This miRNA specifically targets LTR retroelements, silencing them post-transcriptionally by perfectly pairing to the highly conserved primer binding site for methionyl initiator tRNA that is essential for reverse transcription. We investigated the possible origins of this miRNA, and present evidence that the pre-miR1511 hairpin structure probably derived from a locus coding for tRNA(iM) (et) through a single microinversion event. Our study shows that this miRNA targets retrotransposons specifically and constitutively, and contributes to features such as genome stability, size and architecture in a far more direct way than previously thought. PMID- 26611655 TI - Usefulness of Rajka & Langeland Eczema Severity Score in Clinical Practice. AB - Simple, validated eczema severity scores are required for the evaluation of interventions. The Rajka & Langeland (R&L) scale is based on 3 domains (extent, course, and intensity); however, its validity is not yet confirmed. The aim of this study was to investigate the quality aspects of the R&L scale in clinical practice. In the first part of the study, experts and consumers judged the content validity of the scale. The second part of the study was performed with 87 children during a 4-month eczema school. Construct validity, internal consistency, sensitivity to change, time consumption and health-related quality of life variables were investigated. The content of the R&L scale was considered valid by 45 panellists. Inter- and intra-observer reliability was very good. Divergent construct validity was adequate, while convergent construct validity and internal consistency were inadequate. The R&L scale was able to define a significant improvement in eczema during the eczema school. The time required for completing the R&L assessment was significantly shorter than for objective Severity Scoring of Atopic Dermatitis (SCORAD). The R&L scale is a simple, fast, valid, reliable and sensitive tool for scoring of atopic dermatitis in everyday clinical practice. PMID- 26611657 TI - High Reactivity of Strained Seven-Membered-Ring trans-Alkenes. AB - trans-Oxasilacycloheptenes are highly reactive strained alkenes. Competition reactions showed that these seven-membered ring trans-alkenes underwent [4+2] cycloaddition reactions faster than a trans-cyclooctene. They also reacted with quinones and dimethyl acetylenedicarboxylate to form adducts with high diastereoselectivity. Kinetic studies showed that ring strain increases nucleophilicity by approximately 10(9). PMID- 26611656 TI - Dosimetric analysis of the alopecia preventing effect of hippocampus sparing whole brain radiation therapy. AB - BACKGROUND: Whole brain radiation therapy (WBRT) is widely used for the treatment of brain metastases. Cognitive decline and alopecia are recognized adverse effects of WBRT. Recently hippocampus sparing whole brain radiation therapy (HS WBRT) has been shown to reduce the incidence of memory loss. In this study, we found that multi-field intensity modulated radiation therapy (IMRT), with strict constraints to the brain parenchyma and to the hippocampus, reduces follicular scalp dose and prevents alopecia. METHODS: Suitable patients befitting the inclusion criteria of the RTOG 0933 trial received Hippocampus sparing whole brain radiation. On follow up, they were noticed to have full scalp hair preservation. 5 mm thickness of follicle bearing scalp in the radiation field was outlined in the planning CT scans. Conventional opposed lateral WBRT radiation fields were applied to these patient-specific image sets and planned with the same nominal dose of 30 Gy in 10 fractions. The mean and maximum dose to follicle bearing skin and Dose Volume Histogram (DVH) data were analyzed for conventional and HS-WBRT. Paired t-test was used to compare the means. RESULTS: All six patients had fully preserved scalp hair and remained clinically cognitively intact 1-3 months after HS-WBRT. Compared to conventional WBRT, in addition to the intended sparing of the Hippocampus, HS-WBRT delivered significantly lower mean dose (22.42 cGy vs. 16.33 cGy, p < 0.0001), V24 (9 cc vs. 44 cc, p < 0.0000) and V30 (9 cc vs. 0.096 cc, p = 0.0106) to follicle hair bearing scalp and prevented alopecia. There were no recurrences in the Hippocampus area. CONCLUSIONS: HS-WBRT, with an 11-field set up as described, while attempting to conserve hippocampus radiation and maintain radiation dose to brain inadvertently spares follicle-bearing scalp and prevents alopecia. PMID- 26611658 TI - Refining the head and neck cancer referral guidelines: a two-centre analysis of 4715 referrals. AB - OBJECTIVES: To identify the set of referral criteria that will offer optimal diagnostic efficacy in patients suspected to have head and neck cancer (HNC) in the primary care setting. DESIGN: Statistical analysis of referral criteria and outcomes. SETTING: Two tertiary care cancer centres in the United Kingdom. PARTICIPANTS: 4715 patients who were referred via the fast-track system with a suspected HNC between 2007 and 2010. MAIN OUTCOME MEASURES: Parameters of diagnostic efficacy, multivariate regression model to calculate estimated probability of HNC and area under the receiver operating characteristic curve (AUROC). RESULTS: The majority of referring symptoms had a positive predictive value higher than the 3% cut-off point stated to be significant for HNC detection in the 2015 NICE recommendations. Nevertheless, our multivariate analysis identified nine symptoms to be linked with HNC. Of these, only four are included in the latest NICE guidelines. The best fit predictive model for this data set included the following symptoms: hoarseness >3 weeks, dysphagia >3 weeks, odynophagia, unexplained neck mass, oral swelling >3 weeks, oral ulcer >3 weeks, prolonged otalgia with normal otoscopy, the presence of blood in mouth with concurrent sensation of lump in throat and the presence of otalgia with concurrent lump in throat sensation. Intermittent hoarseness and sensation of lump in throat were negatively associated with HNC. The AUROC demonstrated that our model had a higher predictive value (0.77) compared to those generated using the NICE 2005 (0.69) and 2015 (0.68) referral criteria (P < 0.0001). An online risk calculator based on this study is available at http://www.orlhealth.com/risk calculator.html. CONCLUSIONS: This study presents a significantly refined version of referral guidelines which demonstrate greater diagnostic efficacy than the current NICE guidelines. We recommend that further iterative refinements of referral criteria be considered when referring patients with suspected HNC. PMID- 26611659 TI - B cells as multi-functional players during Mycobacterium tuberculosis infection and disease. AB - Immunity to tuberculosis is still understood to be driven and maintained by T cell derived immune responses. With a steady influx of data, it is becoming clear that B cells, the mediators of humoral immunity, have the capacity to function in roles not previously appreciated within the traditional B cell dogma. In this review we aim to discuss B cells, from its generation through to its functioning as effectors in both the innate and adaptive immune response, within the tuberculosis domain. PMID- 26611660 TI - Development of Non-Cell Adhesive Vascular Grafts Using Supramolecular Building Blocks. AB - Cell-free approaches to in situ tissue engineering require materials that are mechanically stable and are able to control cell-adhesive behavior upon implantation. Here, the development of mechanically stable grafts with non-cell adhesive properties via a mix-and-match approach using ureido-pyrimidinone (UPy) modified supramolecular polymers is reported. Cell adhesion is prevented in vitro through mixing of end-functionalized or chain-extended UPy-polycaprolactone (UPy PCL or CE-UPy-PCL, respectively) with end-functionalized UPy-poly(ethylene glycol) (UPy-PEG) at a ratio of 90:10. Further characterization reveals intimate mixing behavior of UPy-PCL with UPy-PEG, but poor mechanical properties, whereas CE-UPy-PCL scaffolds are mechanically stable. As a proof-of-concept for the use of non-cell adhesive supramolecular materials in vivo, electrospun vascular scaffolds are applied in an aortic interposition rat model, showing reduced cell infiltration in the presence of only 10% of UPy-PEG. Together, these results provide the first steps toward advanced supramolecular biomaterials for in situ vascular tissue engineering with control over selective cell capturing. PMID- 26611661 TI - Novel approach to target cancer stem cells for therapy. AB - Even though lots of efforts have been made to find different strategies for cancer treatments, currently available therapeutic approaches are chemotherapy, radiation and surgery or combination of these. These treatments prolonged the survival of patients but did not assure complete cure of the disease. Recent scientific evidences suggest that cancer stem cells (CSC) are responsible for recurrence, resistance and existence of this disease even after various therapeutic treatments. Therefore, we hypothesize that the best approach is to target CSCs along with cancer cells for complete remission of the disease. Before targeting these cells, studying their morphological, proliferation, behavioral aspects, physico-chemical interaction and characterizations are very important. For therapeutic approach the differentiation capacity of these cells to cancer cells with or without drugs is critical. To study basic parameters; the best approach would be aseptic sorting of CSCs from cancer cells based on specific cell surface markers by flowcytometer or magnetic cell sorter. The sorted cells have to be grown in culture conditions and treat with optimum concentrations of drugs to target CSC and cancer cell to find appropriate potential combination. PMID- 26611662 TI - Profiles in Comparative Endocrinology: Kazuyoshi Tsutsui. PMID- 26611663 TI - Efficacy and implementation of an Internet psychoeducational program for teens with type 1 diabetes. AB - OBJECTIVE: The purpose of the study was to evaluate the participation and preliminary efficacy of an Internet psychoeducational program (Teens.Connect) shown to be efficacious under controlled conditions compared with an open-access diabetes website for youth (Planet D) on the primary outcomes of A1C and quality of life (QoL), and secondary outcomes of psychosocial and behavioral factors. RESEARCH DESIGN AND METHODS: Teens with type 1 diabetes (n = 124, 11-14 yr) from two clinical sites were randomly prescribed one of the programs and completed baseline, 3-month and 6-month data. A1C was obtained from clinic records. Participation data included number of log ins, posts to the discussion board, and lessons completed (Teens.Connect only). Descriptive and mixed model analyses were used. RESULTS: Eighty-five percent (85%) of consented teens registered for their prescribed program. Satisfaction and log ins were similar between groups (satisfaction ranged 3.3-3.5/5; mean log ins = 14/teen). Posts to the discussion forum were higher in Planet D (mean = 28 vs. 19). Participation in the Teens.Connect lessons was low, with only 69% of teens completing any lesson. After 6 months there were no significant differences in A1C, QoL or secondary outcomes between groups. Teens in the Teens.Connect group reported lower perceived stress over time (p < 0.01). CONCLUSIONS: Teens do not actively participate in an Internet psychoeducational program when they do not have frequent reminders, which may have contributed to a lack of treatment effect. Teens have many competing demands. Strategic implementation that includes targeted reminders and family support may be necessary to assure participation and improvement in health outcomes. PMID- 26611665 TI - Time-Dependent Density Functional Theory Study of Low-Lying Absorption and Fluorescence Band Shapes for Phenylene-Containing Oligoacenes. AB - Low-lying band shapes of absorption and fluorescence spectra for a member of a newly synthesized family of phenylene-containing oligoacenes (POA 6) reported in J. Am. Chem. Soc. 2012 , 134 , 15351 are studied theoretically with two different approaches with TIPS-anthracene as a comparison. Underlying photophysics and exciton-phonon interactions in both molecules are investigated in details with the aid of the time-dependent density functional theory and multimode Brownian oscillator model. The first two low-lying excited-states of POA 6 were found to exhibit excitation characteristics spanning entire conjugated backbone despite the presence of antiaromatic phenylene section. Absorption and fluorescence spectra calculated from both time-dependent density functional theory and multimode Brownian oscillator model are shown to reach good agreement with experimental ones. The coupling between phonon modes and optical transitions is generally weak as suggested by the multimode Brownian oscillator model. Broader peaks of POA 6 spectra are found to relate to stronger coupling between low frequency phonon modes such as backbone twisting (with frequency <300 cm(-1)) and optical transitions. Furthermore, POA 6 exhibits weaker exciton-phonon coupling for the phonon modes above 1000 cm(-1) compared to TIPS-anthracene owing to extended conjugated backbone. A significant coupling between an in-plane breathing mode localized around the antiaromatic phenylene segment with frequency at 1687 cm(-1) and optical transitions for the first two excited-states of POA 6 is also observed. PMID- 26611664 TI - The Coagulative Profile of Cyanotic Children Undergoing Cardiac Surgery: The Role of Whole Blood Preoperative Thromboelastometry on Postoperative Transfusion Requirement. AB - The objective of this study is to evaluate the preoperative coagulation pattern and its association to postoperative blood products transfusion in children with congenital heart disease (CHD), focusing on cyanotic patients (oxygen saturation, SATO 2 < 85%). From January to August 2014, preoperative standard coagulation tests and rotational thromboelastometry assays were performed on 81 pediatric patients (<16 years old) who underwent surgery for CHD with the aid of cardiopulmonary bypass. Sixty patients (74%) were acyanotic and 21 (26%) cyanotic. Mean age at time of surgery was 7.9 months (interquartile range 2.9 43.6 months). Cyanotic patients had a significantly higher hematocrit (P < 0.001), a reduced prothrombin activity (PT) (P = 0.01) level, and a lower platelet count (P = 0.02) than acyanotic patients. An inverse linear association was found between patient's SATO2 and clot formation time (CFT) (INTEM, P = 0.001, and EXTEM, P < 0.0001). A direct linear association was found between patient's SATO2 and maximum clot firmness (MCF) (INTEM, P = 0.04, and EXTEM, P = 0.05). Preoperative cyanosis was also associated with a lower median MCF in FIBTEM (P = 0.02). Cyanotic patients required more frequent postoperative transfusions of fibrinogen (7/21 patients, 33% vs. 4/60 patients, 6.7%, P = 0.01) and fresh frozen plasma (14/21, 67% vs. 25/60, 42%, P = 0.08). Patients with a lower presurgery PT and platelet count subsequently required more fibrinogen transfusion P = 0.02 and P = 0.003, respectively); the same goes for patients with a longer CFT (INTEM, P = 0.01 and EXTEM, P = 0.03) and a reduced MCF (INTEM, P = 0.02 and FIBTEM, P = 0.01) as well. Cyanotic patients showed significant preoperative coagulation anomalies and required a higher postoperative fibrinogen supplementation. The preoperative MCF FIBTEM has become an important factor in our postoperative thromboelastometry-guided transfusion protocols. PMID- 26611666 TI - Barriers to administering non-oral formulations in a paediatric population: A semi-structured interview study. AB - There is a paucity of research exploring barriers to non-oral medicines administration in paediatric patients; however, these undoubtedly influence medicines adherence. Studies conducted with healthcare professionals have identified various issues with the administration and acceptance of non-oral medicines and devices (Venables et al., 2012; Walsh et al., 2015). EMA (2014) guidelines specify that formulation teams should demonstrate 'acceptability' of paediatric formulations when developing pharmaceutical formulations. Semi structured interviews exploring barriers to administering non-oral medicines were conducted with young persons and the parents/legal guardians of children (0-17 years) with chronic conditions at the University Hospital of Coventry and Warwickshire, UK. 90 children prescribed a total of 148 non-oral medicines were recruited to the study; 88 barriers to administering non-oral medicines were reported. The most commonly reported barriers were: poor acceptance of face mask/difficulties with spacer for inhaled formulations (38% of reports); disliking parenteral/preferring alternative formulations (38% of reports); greasy texture of topical preparations; difficulty with administering an ocular ointment and the large dose volume of a nasal preparation. Formulation teams should consider the use of child-friendly, age-appropriate designs to improve usability and acceptance, thus medicines adherence. These findings should be used to inform future development of non-oral formulations and devices, suitable in terms of safety, efficacy and acceptability to paediatric patients. PMID- 26611667 TI - Letter to the Editor. PMID- 26611668 TI - Transdermal delivery of heparin: Physical enhancement techniques. AB - Thromboembolic complications are the most common preventable cause of mortality and morbidity in trauma patients. Thrombosis is also the common cause of ischemic heart disease (acute coronary syndrome), stroke, and venous thromboembolism. Heparin, as a potent anticoagulant, has been used in clinical practice for more than five decades and remains the major medicine for the prevention and treatment of venous thromboembolism. However it binds to the endothelium and has a high affinity for plasma proteins resulting in a short half-life and unpredictable bioavailability. Transdermal drug delivery can address the problems of short half life and unpredictable bioavailability. Other advantages of transdermal drug delivery include convenience, improved patient compliance, prompt termination of dosing and avoidance of the first-pass effect. This review focuses on different approaches used for transdermal delivery of heparin. PMID- 26611669 TI - Evaluation of critical formulation parameters in design and differentiation of self-microemulsifying drug delivery systems (SMEDDSs) for oral delivery of aciclovir. AB - The study investigated the influence of formulation parameters for design of self microemulsifying drug delivery systems (SMEDDSs) comprising oil (medium chain triglycerides) (10%), surfactant (Labrasol((r)), polysorbate 20, or Kolliphor((r)) RH40), cosurfactant (Plurol((r)) Oleique CC 497) (q.s. ad 100%), and cosolvent (glycerol or macrogol 400) (20% or 30%), and evaluate their potential as carriers for oral delivery of a poorly permeable antivirotic aciclovir (acyclovir). The drug loading capacity of the prepared formulations ranged from 0.18-31.66 mg/ml. Among a total of 60 formulations, three formulations meet the limits for average droplet size (Z-ave) and polydispersity index (PdI) that have been set for SMEDDSs (Z-ave<=100nm, PdI<0.250) upon spontaneous dispersion in 0.1M HCl and phosphate buffer pH 7.2. SMEDDSs with the highest aciclovir loading capacity (24.06 mg/ml and 21.12 mg/ml) provided the in vitro drug release rates of 0.325 mg cm(-2)min(-1) and 0.323 mg cm(-2)min(-1), respectively, and significantly enhanced drug permeability in the parallel artificial membrane permeability assay (PAMPA), in comparison with the pure drug substance. The results revealed that development of SMEDDSs with enhanced drug loading capacity and oral delivery potential, required optimization of hydrophilic ingredients, in terms of size of hydrophilic moiety of the surfactant, surfactant-to-cosurfactant mass ratio (Km), and log P of the cosolvent. PMID- 26611670 TI - Enhanced solubility and antibacterial activity of lipophilic fluoro-substituted N benzoyl-2-aminobenzothiazoles by complexation with beta-cyclodextrins. AB - Some lipophilic fluoro-substituted N-benzoyl-2-aminobenzothiazole antibacterial agents have been evaluated for their activity in the presence of cyclodextrins (CDs) containing aqueous solutions where CDs are adopted as solubilizing excipients for improving the poor water solubility of these compounds. For such purpose both the natural beta-CD and one of FDA/EMA approved CDs for parenteral use (i.e. HP-beta-CD) have been employed. The solubility rank order observed was accounted for by thermal analysis (Differential Scanning Calorimetry) and FT-IR spectroscopy. The most promising compound was subjected to further NMR spectroscopic studies and molecular modelling simulations to verify the interactions between the guest molecule and the CD cavity. The assessment of the antibacterial activity of such compounds against selected Gram positive and Gram negative bacterial strains clearly showed that their antimicrobial effectiveness may, quite in all instances, be positively affected by complexation with beta-CD and HP-beta-CD. These results, which are in some ways in contrast with those already reported in the literature, are herein discussed on the basis of plausible mechanisms. Moreover, this investigation also reveals that the described methodology of complexing both lipophilic and hydrophilic antimicrobial agents with CDs may be an useful approach to enhance their effectiveness as well as a promising strategy to overcome even the microbial resistance problem. PMID- 26611672 TI - RORgammat inhibitors suppress T(H)17 responses in inflammatory arthritis and inflammatory bowel disease. PMID- 26611673 TI - Correction notice for TNF-R on mast cells regulate airway responses to Mycoplasma pneumoniae. PMID- 26611674 TI - Effect of fibre-reinforced composite on the fracture resistance of endodontically treated teeth. AB - The aim of this study is to evaluate the fracture resistance of root-filled teeth restored with fibre-reinforced composite (everX posterior). Fifty mandibular molars were divided into five groups (n = 10). Group 1: no treatment was applied (intact teeth). Group 2-5: canals were prepared and root filled. Group 2: no coronal restoration was placed. Group 3: teeth were coronally restored with composite. Group 4: composite restorations were performed following polyethylene fibre insertion at the cavity base. Group 5: composite resin placed over everX posterior. After thermocycling (5-55 degrees C, 5000*), fracture resistance was measured. Mean force load for each sample was recorded in Newtons (N). Results were statistically analysed with one-way analysis of variance and post hoc Tukey's tests. The mean force required to fracture samples and standard deviations are as follows: group 1: 2859.5 +/- 551.27 N, group 2: 318.97 +/- 108.67 N, group 3: 1489.5 +/- 505.04 N, group 4: 1958.3 +/- 362.94 N, group 5: 2550.7 +/- 586.1 N. everX posterior (group 5) was higher than groups 2, 3 and 4 (P < 0.05). There were no significant differences between everX posterior and intact teeth (P > 0.05). Placing fibre-reinforced composite under composite increased the fracture strength of root-filled teeth to the level of intact teeth. PMID- 26611676 TI - Marimicrobium arenosum gen. nov., sp. nov., a moderately halophilic bacterium isolated from sea sand. AB - A Gram-stain-negative, non-pigmented, non-spore-forming, non-motile, strictly aerobic bacterial strain, designated CAU 1038T, was isolated from a sea sand sample in Modo, Republic of Korea, and its taxonomic position was examined using a polyphasic approach. Cells of strain CAU 1038T grew optimally at 30 degrees C, pH 7.5 in 2 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain CAU 1038T formed a distinct lineage within the class Gammaproteobacteria as a separate deep branch, with 95.2 % or lower sequence similarity to representatives of the genera Haliea, Halioglobus and Chromatocurvus, and 92.3 % or lower with Luminiphilus, Pseudohaliea and Congregibacter. The major cellular fatty acids of strain CAU 1038T were C16 : 0, C16 : 1omega7c and C18 : 1omega7c. The polar lipid pattern of the isolate consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, an unidentified aminolipid and two unidentified lipids. The strain contained lipoquinone (Q-8) as the sole respiratory quinone. The G+C content of the genomic DNA was 65 mol%. On the basis of phenotypic and chemotaxonomic data, and phylogenetic inference, strain CAU 1038T represents a novel species of a new genus in the family Halieaceae, for which the name Marimicrobium arenosum gen. nov., sp. nov. is proposed. The type strain of the type species is CAU 1038T ( = KCTC 42300T = NBRC 110727T). PMID- 26611675 TI - Genome-wide expression profiles of Pyropia haitanensis in response to osmotic stress by using deep sequencing technology. AB - BACKGROUND: Pyropia haitanensis is an economically important marine crop grown in harsh intertidal habitats of southern China; it is also an excellent model system for studying mechanisms of stress tolerance. To understand the molecular mechanisms underlying osmotic tolerance and adaptation to intertidal environments, a comprehensive analysis of genome-wide gene expression profiles in response to dehydration and rehydration in Py. haitanensis was undertaken using digital gene expression profile (DGE) approaches combined with de novo transcriptome sequencing. RESULTS: RNA-sequencing of the pooled RNA samples from different developmental phases and stress treatments was performed, which generated a total of 47.7 million clean reads. These reads were de novo assembled into 28,536 unigenes (>= 200 bp), of which 18,217 unigenes (63.83 %) were annotated in at least one reference database. DGE analysis was performed on four treatments (two biological replicates per treatment), which included moderate dehydration, severe dehydration, rehydration, and normal conditions. The number of raw reads per sample ranged from 12.47 to 15.79 million, with an average of 14.69 million reads per sample. After quality filtering, the number of clean reads per sample ranged from 11.83 to 15.04 million. All distinct sequencing reads were annotated using the transcriptome of Py. haitanensis as reference. A total of 1,681 unigenes showed significant differential expression between moderate dehydration and normal conditions, in which 977 genes were upregulated, and 704 genes were downregulated. Between severe dehydration and normal conditions, 1,993 unigenes showed significantly altered expression, which included both upregulated (1,219) and downregulated genes (774). In addition, 1,086 differentially expressed genes were detected between rehydration and normal conditions, of which 720 genes were upregulated and 366 unigenes were downregulated. Most gene expression patterns in response to dehydration differed from that of rehydration, except for the synthesis of unsaturated fatty acids, several transcription factor families, and molecular chaperones that have been collectively implicated in the processes of dehydration and rehydration in Py. haitanensis. CONCLUSIONS: Taken together, these data provide a global high resolution analysis of gene expression changes during osmotic stress that could potentially serve as a key resource for understanding the biology of osmotic acclimation in intertidal red seaweed. PMID- 26611677 TI - Achieving hip fracture surgery within 36 hours: an investigation of risk factors to surgical delay and recommendations for practice. AB - BACKGROUND: The UK hip fracture best practice tariff (BPT) aims to deliver hip fracture surgery within 36 h of admission. Ensuring that delays are reserved for conditions which compromise survival, but are responsive to medical optimisation, would help to achieve this target. We aimed to identify medical risk factors of surgical delay, and assess their impact on mortality. MATERIALS AND METHODS: Prospectively collected patient data was obtained from the National Hip Fracture Database (NHFD). Medical determinants of surgical delay were identified and analysed using a multivariate regression analysis. The mortality risk associated with each factor contributing to surgical delay was then calculated. RESULTS: A total 1361 patients underwent hip fracture surgery, of which 537 patients (39.5 %) received surgery within 36 h of admission. Following multivariate analyses, only hyponatraemia was deduced to be a significant risk factor for delay RR = 1.24 (95 % CI 1.06-1.44). However, following a validated propensity score matching process, a Pearson chi-square test failed to demonstrate a statistical difference in mortality incidence between the hypo- and normonatraemic patients [chi (2) (1, N = 512) = 0.10, p = 0.757]. CONCLUSIONS: Hip fracture surgery should not be delayed in the presence of non-severe and isolated hyponatraemia. Instead, surgical delay may only be warranted in the presence of medical conditions which contribute to mortality and are optimisable. LEVEL OF EVIDENCE: III. PMID- 26611678 TI - Hetropolyacid-Catalyzed Oxidation of Glycerol into Lactic Acid under Mild Base Free Conditions. AB - Lactic acid (LA) is a versatile platform molecule owing to the opportunity to transform this compound into useful chemicals and materials. Therefore, efficient production of LA based on inexpensive renewable feedstocks is of utmost importance for insuring its market availability. Herein, we report the efficient conversion of glycerol into LA catalyzed by heteropolyacids (HPAs) under mild base-free conditions. The catalytic performance of molecular HPAs appears to correlate with their redox potential and Bronsted acidity. Namely, H3 PMo(12)O(40) (HPMo) exhibits the best selectivity towards LA (90 %) with 88 % conversion of glycerol. Loading of HPMo onto a carbon support (HPMo/C) further improves LA productivity resulting in 94 % selectivity at 98 % conversion under optimized reaction conditions. The reaction takes place through the formation of dihydroxyacetone/glyceraldehyde and pyruvaldehyde as intermediates. No leaching of HPMo was observed under the applied reaction conditions and HPMo/C could be recycled 5 times without significant loss of activity. PMID- 26611679 TI - Short-time weight-bearing capacity assessment for non-ambulatory patients with subacute stroke: reliability and discriminative power. AB - BACKGROUND: Weight-bearing capacity (WBC) on the hemiparetic leg is crucial for independent walking, and is thus an important outcome to monitor after a stroke. A specific and practical assessment in non-ambulatory patients is not available. This is of importance considering the increasing administration of high intensive gait training for the severely impaired stroke population. The aim was to develop a fast and easy-to-perform assessment for WBC on a foot pressure plate to be used in clinical routine. METHODS: WBC was assessed in the frontal plane in 30 non ambulatory patients with subacute stroke and 10 healthy controls under 3 conditions: static, dynamic, and rhythmic. Force-time curves for the hemiparetic leg (patients with stroke) and the non-dominant leg (healthy controls) were normalised as a percentage of body weight (%BW), and the means analysed over 60, 30, and 15 s (static) and the mean of the peak values for 15, 10, 5, 4, and 3 repetition trials (dynamic, rhythmic). The data were tested for discriminative power and reliability. Dynamic and rhythmic tests could discriminate between patients with stroke and healthy controls over all periods (15, 10, 5, 4, and 3 repetitions) (p < 0.001), but not the static test (60 s, p = 0.639; 30 s, p = 0.708; 15 s, p = 0.685). Excellent relative intra-session [intra-class correlation (ICC) >0.829] and inter-session reliability (ICC = 0.740) were found for 3 repetitions in the dynamic test with acceptable absolute reliability [standard error of measurement (SEM) <5 %BW, minimal detectable difference (MDD) <12.4 %BW] and no within- or between-test differences (trial 1, p = 0.792; trial 2, p = 0.067; between trials, p = 0.102). CONCLUSIONS: Three dynamic repetitions of loading the hemiparetic leg are sufficient to assess WBC in non-ambulatory patients with subacute stroke. This is an important finding regarding the implementation of a fast and easy-to-perform assessment for routine clinical usage in patients with limited standing ability. PMID- 26611680 TI - Visual processing in migraine. AB - Background Migraine is a common neurological condition that often involves differences in visual processing. These sensory processing differences provide important information about the underlying causes of the condition, and for the development of treatments. Review of psychophysical literature Psychophysical experiments have shown consistent impairments in contrast sensitivity, orientation acuity, and the perception of global form and motion. They have also established that the addition of task-irrelevant visual noise has a greater effect, and that surround suppression, masking and adaptation are all stronger in migraine. Theoretical signal processing model We propose utilising an established model of visual processing, based on signal processing theory, to account for the behavioural differences seen in migraine. This has the advantage of precision and clarity, and generating clear, falsifiable predictions. Conclusion Increased effects of noise and differences in excitation and inhibition can account for the differences in migraine visual perception. Consolidating existing research and creating a unified, defined theoretical account is needed to better understand the disorder. PMID- 26611681 TI - Spontaneous extracranial hemorrhagic phenomena in primary headache disorders: A systematic review of published cases. AB - Background Head pain is a cardinal feature of primary headache disorders (PHDs) and is often accompanied by autonomic and vasomotor symptoms and/or signs. Spontaneous extracranial hemorrhagic phenomena (SEHP), including epistaxis, ecchymosis, and hematohidrosis (a disorder of bleeding through sweat glands), are poorly characterized features of PHDs. Aim To critically appraise the association between SEHP and PHDs by systematically reviewing and pooling all reports of SEHP associated with headaches. Methods Advanced searches using the PubMed/MEDLINE, Web of Science, Cochrane Library, Google Scholar, and ResearchGate databases were carried out for clinical studies by combining the terms "headache AND ecchymosis", "headache AND epistaxis", and "headache AND hematohidrosis" spanning all medical literature prior to October 10, 2015. Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology guidelines were applied. Results A total of 105 cases of SEHP associated with PHDs (83% migraine and 17% trigeminal autonomic cephalgias) were identified (median age 27 years, male to female ratio 1:2.3); 63% had epistaxis, 33% ecchymosis, and 4% hematohidrosis. Eighty-three percent of studies applied the International Classification of Headache Disorders diagnostic criteria. Eighty percent of the reported headaches were episodic and 20% were chronic. Twenty-four percent of studies reported recurrent episodes of SEHP. Conclusions Our results suggest that SEHP may be rare features of PHDs. Future studies would benefit from the systematic characterization of these phenomena. PMID- 26611682 TI - Late onset aura may herald cerebral amyloid angiopathy: A case report. AB - BACKGROUND: Although migraine usually begins in the early decades of life, late onset of migraine with aura is occasionally observed and can occur without headache, causing confusion in the differential diagnosis. CASE REPORT: A 72-year old man presented with recurrent episodes of visual aura lasting for 20 minutes. These episodes had started at 57 years of age and were only once accompanied by a severe headache. Magnetic resonance imaging revealed changes in the periventricular white matter, left occipital haemorrhage and subcortical haemosiderin deposits, compatible with cerebral amyloid angiopathy. Previous treatment with antiplatelet drugs was discontinued. His episodes of visual aura stopped on treatment with lamotrigine and add-on treatment with verapamil. CONCLUSION: In patients with a late onset of migraine aura, doctors must consider other under-recognized causes of transient neurological symptoms, such as cerebral amyloid angiopathy. Blood-sensitive magnetic resonance imaging sequences are the best tool for the early detection of an underlying pathology and therefore treatment with antiplatelet/anticoagulant drugs should be avoided as this may increase the risk of haemorrhage. PMID- 26611683 TI - SUNCT syndrome: A cohort of 15 Portuguese patients. AB - BACKGROUND: In this paper, we describe a cohort of patients with short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), a rare trigeminal autonomic headache, managed in the outpatient clinic of a tertiary hospital. METHODS: Patients were identified through review of individual records between January 1, 2008 and June 30, 2014. RESULTS: Fifteen patients were identified (eight males:seven females), with mean age at onset of 49.7 years, mean number of attacks per day of 7.5 and mean attack duration of 54.6 seconds. Pain was mostly orbital, periorbital or temporal. Cranial autonomic signs/symptoms were universally present; one patient reported ipsilateral epistaxis. Two symptomatic cases were identified and treated surgically. Most patients responded to lamotrigine, one to topiramate and another to eslicarbazepine. CONCLUSION: Our case series is among the largest reported, with findings similar to others already published, but the first to report epistaxis during SUNCT attack and response to eslicarbazepine. PMID- 26611684 TI - The effect of symmetrical and asymmetrical hearing impairment on music quality perception. AB - The purpose of this study was to investigate the effect of symmetrical, asymmetrical and unilateral hearing impairment on music quality perception. Six validated music pieces in the categories of classical music, folk music and pop music were used to assess music quality in terms of its 'pleasantness', 'naturalness', 'fullness', 'roughness' and 'sharpness'. 58 participants with sensorineural hearing loss [20 with unilateral hearing loss (UHL), 20 with bilateral symmetrical hearing loss (BSHL) and 18 with bilateral asymmetrical hearing loss (BAHL)] and 29 normal hearing (NH) subjects participated in the present study. Hearing impaired (HI) participants had greater difficulty in overall music quality perception than NH participants. Participants with BSHL rated music pleasantness and naturalness to be higher than participants with BAHL. Moreover, the hearing thresholds of the better ears from BSHL and BAHL participants as well as the hearing thresholds of the worse ears from BSHL participants were negatively correlated to the pleasantness and naturalness perception. HI participants rated the familiar music pieces higher than unfamiliar music pieces in the three music categories. Music quality perception in participants with hearing impairment appeared to be affected by symmetry of hearing loss, degree of hearing loss and music familiarity when they were assessed using the music quality rating test (MQRT). This indicates that binaural symmetrical hearing is important to achieve a high level of music quality perception in HI listeners. This emphasizes the importance of provision of bilateral hearing assistive devices for people with asymmetrical hearing impairment. PMID- 26611685 TI - The changing epidemiological and complications profile of chronic suppurative otitis media in a developing country after two decades. AB - To evaluate the shift in epidemiological and complication profiles of chronic suppurative otitis media (CSOM) over two decades in a resource-limited economy. A retrospective analysis of the prevalence of CSOM and its complications in tertiary health institution a over a period of 2 years were compared between 203 cases seen in 2009 and December 2010 (present era); and 343 cases seen in 1990 and 1991 (previous era). Data were collected on the demographic characteristics of the patients, age of onset of otorrhoea, the disease type, laterality and complications of CSOM. The prevalence of CSOM significantly reduced from 9 % in the previous era to 5.1 % in the present era (P < 0.0001). The mean age of the recent group was 27.6 +/- 19.3 years, and was 21.6 +/- 18.2 years in the previous group. (P = 0.009). Although both group had peak age prevalence at 11-20 years, recent group saw more significant adult population >20 years of age (P <= 0.001). More significant cases of cholesteatoma were documented in the recent group (3.4 %) than previous era (0.9 %) (P = 0.02). Although no significant change was noted regarding the rates of complication of CSOM in the two eras (P = 0.18), there was a notable shift toward predominant extracranial pattern of complication in the recent group (P = 0.04). The prevalence of CSOM has shown a significant reduction after two decades and it appears that there has been a shift in the epidemiology of CSOM towards a predominantly adult population in the recent years. Despite an overall reduction in the incidence of intracranial complications of CSOM in our series, its complication rates have not changed remarkably after 20 years. PMID- 26611686 TI - The teaching of neurosurgery in UK medical schools: a message from British medical students. AB - BACKGROUND: A great variability exists in the clinical exposure of neurosurgery across all academic years in UK medical schools, although the effects of this on knowledge level and confidence in referring cases appropriately to specialists have not been reported. METHODS: A cross-sectional study was carried out involving students in years 1-5 across nine British medical schools. An electronic questionnaire was sent out which consisted of questions concerning the teaching of the subject; and questions assessing the knowledge of basic neurosurgery through mini clinical scenarios testing which specialty should receive a referral. RESULTS: Of 417 participants, 60 were excluded due to incomplete participation. Senior years outperformed students in junior years for correctly answered questions on five neurosurgical scenarios (mean score: years 1 3 (184/357) = 3.33/5, years 4-5 (173/357) = 3.79/5, p < 0.05). Participants in years 1-5 with prior clinical exposure in neurosurgery scored higher than participants who had no exposure (mean score: exposed (247/357) = 4.21/5, not exposed (110/357) = 3 . 50/5, p < 0.05). Sixty-one percent prefer receiving neurosurgical teaching via increased exposure to operations. Students in years 4 5 with exposure in both classroom and operating theatre scored higher than students with classroom-only experience (mean classroom (69/131) = 3.62/5, mean classroom and operating theatre (62/131) = 4.21/5, p < 0.05); 33.3 % of final year students reported difficulty in identifying patients that require neurosurgical referral. CONCLUSIONS: Students with exposure to an operating theatre outperformed those students exposed to just classroom teaching. Students indicated an increased preference for teaching through the operating theatre scene. One in three final-year medical students had difficulty identifying the need for a neurosurgical referral.If neurosurgical teaching were further enhanced at medical school, it could lead to increased confidence and efficiency in junior year doctors when facing the neurosurgical referral process. Increased exposure to clinical neurosurgery may significantly improve the ability of future doctors to tackle neurosurgical scenarios. PMID- 26611688 TI - Tolosa-Hunt Syndrome: Another legitimate target for radiosurgery? PMID- 26611689 TI - Gamma Knife radiosurgery in steroid-intolerant Tolosa-Hunt syndrome: case report. AB - Tolosa-Hunt syndrome is a rare cause of painful ophthalmoplegia due to idiopathic chronic granulomatous inflammation in the cavernous sinus. Usually clinical manifestations are well controlled by corticosteroid therapy, but steroid dependency or resistance is common. We report a case of marked improvement of Tolosa-Hunt syndrome without symptom relapse after Gamma Knife radiosurgery in a patient with steroid intolerance. PMID- 26611690 TI - Different clinical course of pallidal deep brain stimulation for phasic- and tonic-type cervical dystonia. AB - BACKGROUND: Dystonia has been treated well using deep brain stimulation at the globus pallidus internus (GPi DBS). Dystonia can be categorized as two basic types of movement, phasic-type and tonic-type. Cervical dystonia is the most common type of focal dystonia, and sequential differences in clinical outcomes between phasic-type and tonic-type cervical dystonia have not been reported. METHODS: This study included a retrospective cohort of 30 patients with primary cervical dystonia who underwent GPi DBS. Age, disease duration, dystonia direction, movement types, employment status, relevant life events, and neuropsychological examinations were analyzed with respect to clinical outcomes following GPi DBS. RESULTS: The only significant factor affecting clinical outcomes was movement type (phasic or tonic). Sequential changes in clinical outcomes showed significant differences between phasic- and tonic-type cervical dystonia. A delayed benefit was found in both phasic- and tonic-type dystonia. CONCLUSIONS: The clinical outcome of phasic-type cervical dystonia is more favorable than that of tonic-type cervical dystonia following GPi DBS. PMID- 26611691 TI - High prevalence of pharmacologically induced platelet dysfunction in the acute setting of brain injury. AB - BACKGROUND: The management of patients with traumatic brain injury (TBI), primary intracerebral hemorrhage (pICH) and primary subarachnoid hemorrhage (pSAH) remains a highly demanding challenge in critical care medicine. Antithrombotic agents are one of the most relevant risk factors for poor outcome. However, in the acute setting of brain injury, information on preexisting medication might not be available. This group of patients is insufficiently characterized regarding pharmacologically induced platelet impairment. METHODS: We retrospectively analyzed consecutive patients with TBI, pICH and pSAH admitted to our department with unknown preexisting medication. The impact of acetylsalicylic acid and ADP-receptor antagonists on platelet function was tested via the Multiplate analyzer. Patients' characteristics, management and the influence of platelet impairment on outcome were evaluated. RESULTS: Within 25 months 103 patients with TBI (61), pICH (32) or pSAH (10) and unknown antithrombotic medication were admitted to our department. In 54 (52.4 %) of the patients reduced platelet function was detected, mainly caused by acetylsalicylic acid. In the TBI group, 30 patients (49.2 %) were identified, while Multiplate analysis detected platelet dysfunction in 19 (59.4 %) subjects in the pICH group and 5 in the pSAH group (50 %). In multivariable analysis the pathological Multiplate result was not associated with worse outcome; however, in our cohort 47 (87 %) patients received hemostatic therapy following detection of impaired platelet function. CONCLUSION: Our results demonstrate the high frequency of pharmacologically impaired platelet function in patients with unknown preexisting medication. Early assessment of platelet function is an important tool to allow optimized treatment in these patients. PMID- 26611693 TI - Does night shift, stress or both make us dumber? PMID- 26611692 TI - "Men's health--a little in the shadow": a formative evaluation of medical curriculum enhancement with men's health teaching and learning. AB - BACKGROUND: Enhancing a medical school curriculum with new men's health teaching and learning requires an understanding of the local capacity and the facilitators and barriers to implementing new content, and an approach that accommodates the systemic and cultural differences between medical schools. METHODS: A formative evaluation was undertaken to determine the perspectives of key informants (academics, curriculum developers) from four Australian medical schools about the strategies needed to enhance their curriculum with men's health teaching and learning. Through semi-structured questioning with 17 key informants, interviewees also described the contextual barriers and facilitators to incorporating new topic areas into existing curriculum. Interviews were recorded with consent, transcribed verbatim, and analysed by two researchers to identify key themes. RESULTS: Interviewees were enthusiastic about incorporating men's health content through a men's health curriculum framework but highlighted the need for systems to assist in identifying gaps in their current curriculum where the men's health topics could be integrated. The student experience was identified as a key driver for men's health teaching and learning. Furthermore, core men's health clinical outcomes needed to be defined and topic areas vertically integrated across the curricula. This would ensure that students were appropriately equipped with the skills and knowledge for subsequent clinical practice in a range of geographical settings. Interviewees consistently suggested that the best implementation strategy is to have someone 'on the ground' to work directly with medical school staff and champion the men's health discipline. Providing mechanisms for sharing knowledge and resources across medical schools was highlighted to facilitate implementation, particularly for those medical schools with limited men's health teaching resources. CONCLUSIONS: Despite the unanimous support for men's health teaching and learning, the evaluation highlighted that the student experience must be recognised as paramount when integrating new topic areas into an already packed curriculum. A community of practice, where medical schools share relevant resources and knowledge, could help to ensure a commonality of student experience with respect to men's health learning in medical schools across different geographical settings and with different levels of resourcing. Such an approach could also be adapted to other areas of curriculum enhancement. PMID- 26611694 TI - A Comparative Analysis of Oral Health on the Santo Domingo Pueblo Reservation. AB - The study was done to compare oral health data from a tribe in a relatively accessible location between Santa Fe and Albuquerque, New Mexico to national American Indian data and broader US data sets. Participants (N = 399) were recruited via random sampling of housing units. Dental health measures included DMFT/dmft and dental sealants. Comparisons were made using data from large-scale oral health surveillance studies. There was no difference in oral health for 3-5 year olds compared to a recent study of AI/AN preschool children. Compared to the general US population, Santo Domingo Pueblo children and adults showed higher prevalence of untreated decay. Children ages 5-19 had higher rates of sealant retention on permanent teeth, and adults showed lower prevalence of complete tooth retention. The children ages 5-19 and 12-19 with at least one sealant have significantly lower DMFT and less untreated decay than those without sealants. However, the percentage of children with and without sealants who had untreated decay was still more than two times higher than the general US population. Oral health of American Indian children and adults in Santo Domingo Pueblo was worse compared to the general US population but similar to previous results reported for the same Indian Health Service Area even though their location is less isolated than many other tribes. PMID- 26611695 TI - Hypertension Prevalence, Awareness, Treatment, and Control: Should 24-Hour Ambulatory Blood Pressure Monitoring be the Tool of Choice? AB - We aimed to examine hypertension prevalence, awareness, treatment and control in a community sample and investigate the impact of using 24 hour ABPM. Office blood pressure (BP) was taken from the electronic health record. Study BP was measured by standardised methods. Participants were invited to undergo ABPM. Hypertension was defined by accepted thresholds or anti-hypertensive use. Standardised questions assessed awareness and treatment. Control was defined as anti hypertensive use with BP below normal threshold. There were 931 (45%) participants with office BP, study BP and ABPM. By study BP, hypertension prevalence was 60%, awareness 59%, 60% were treated and 46% controlled. By daytime ABPM threshold, prevalence was 61%, awareness 59%, 59% were treated and 54% controlled. ABPM reclassified 13.5% from normotensive to hypertensive and 14.5% from hypertensive to normotensive. ABPM may not hugely impact population hypertension prevalence but at an individual level it reduces misclassification and facilitates more appropriate management. PMID- 26611696 TI - Bell's Palsy. AB - Bell's palsy is unilateral, acute onset facial paralysis that is a common condition. One in every 65 people experiences Bell's palsy in the course of their lifetime. The majority of patients afflicted with this idiopathic disorder recover facial function. Initial treatment involves oral corticosteroids, possible antiviral drugs, and protection of the eye from desiccation. A small subset of patients may be left with incomplete recovery, synkinesis, facial contracture, or hemifacial spasm. A combination of medical and surgical treatment options exist to treat the long-term sequelae of Bell's palsy. PMID- 26611697 TI - Botulinum Toxin in the Treatment of Facial Paralysis. AB - This article reviews the current literature supporting the use of botulinum toxin in producing symmetric facial features and reducing unwanted, involuntary movements. Methods, protocols, and adverse events are discussed. Additionally, the authors suggest that using botulinum toxin A therapy in postparalytic facial synkinesis can provide long-term results when used in conjunction with other treatment modalities. PMID- 26611698 TI - Management of the Eye in Facial Paralysis. AB - The preoperative assessment of the eye in facial paralysis is a critical component of surgical management. The degree of facial nerve paralysis, lacrimal secretion, corneal sensation, and lower eyelid position must be assessed accurately. Upper eyelid loading procedures are standard management of lagophthalmos. Lower eyelid tightening repositions the lower eyelid and helps maintain the aqueous tear film. Eyelid reanimation allows an aesthetic symmetry with blinking and restores protective functions vital to ocular preservation. Patients often have multiple nervous deficits, including corneal anesthesia. Other procedures include tarsorrhaphy, spring implantation, and temporalis muscle transposition; associated complications have rendered them nearly obsolete. PMID- 26611699 TI - Static Facial Slings: Approaches to Rehabilitation of the Paralyzed Face. AB - Facial paralysis results from a variety of different causes. Patients with facial paralysis have cosmetic and functional defects that significantly affect quality of life. Surgical intervention has the potential to help improve cosmetic and functional outcomes. The 2 main categories of surgical rehabilitation are static and dynamic surgical procedures. Static rehabilitation of the midface is typically performed using autologous tissue grafts, allografts, synthetic grafts, permanent suspension sutures, and a novel technique using percutaneous suture based slings. PMID- 26611700 TI - Temporalis Muscle Tendon Unit Transfer for Smile Restoration After Facial Paralysis. AB - Temporalis muscle tendon unit (MTU) transfer may be used as a single-stage procedure for dynamic reanimation of the paralyzed face. Principles and biomechanics of muscle function and tendon transposition are essential in optimizing outcome. Critical steps and pearls for success include minimizing scarring, maintaining glide plains, mobilizing adequate tendon length, insertion of MTU at ideal tension based on intraoperative dynamic tension-excursion relationship, and insertion of tendon as close to the lip margin as possible. Because muscles adapt to tension, load, and task changes by altering their sarcomere arrangement and muscle fiber composition, physiotherapy should be initiated to use the repurposed temporalis MTU for smile restoration. PMID- 26611701 TI - The Gracilis Free Flap. AB - The gracilis free flap is the ideal modality of emotive and spontaneous facial reanimation in patients with a viable contralateral facial nerve. A 2-stage procedure with a cross-face nerve graft followed by gracilis free flap inset is advocated. In this article, the anatomy of the gracilis muscle, alternative neural sources (including the masseteric nerve), and technical aspects of the procedure are discussed. The literature regarding outcomes and complications is reviewed. PMID- 26611702 TI - The Sternohyoid Flap for Facial Reanimation. AB - This article discusses the use of the sternohyoid muscle for facial reanimation. The report outlines the rationale for use, the technical aspects of flap harvest, and early clinical outcomes. The utility of the flap and its comparative attributes relative to the gracilis flap are discussed. PMID- 26611703 TI - Neural Reanimation Advances and New Technologies. AB - Facial paralysis can have a profound effect on the patient from both an aesthetic and functional point of view. Just as there are numerous etiologies of facial paresis, there are as many therapeutic options and variations of these options. The purpose of this article was to review the most current surgical options for neural reanimation of a damaged facial nerve, including recent advances in nerve repair, conduit technology, and nerve transfers, as well as emerging technology in translational research with biomedical engineering and tissue engineering. PMID- 26611704 TI - Facial Paralysis: State of the Art. PMID- 26611705 TI - The doctor will move in with you now. PMID- 26611706 TI - Perception of Non-Vibrato Sung Tones: A Pilot Study. AB - OBJECTIVES/HYPOTHESIS: Singers are often asked to sing with a non-vibrato production. The term non-vibrato is problematic in that it is not possible for a human to sing a tone without fundamental frequency variation. Whether a singer achieves a quality of tone that is perceived as non-vibrato is an aurally subjective matter. The specific aim of this study was to determine when a tone is perceived as non-vibrato by a population of singers, voice teachers, choir directors, and speech pathologists. Using voice samples that exhibit a variety of vibrato rates and extents, the investigators sought to determine (1) if there is a threshold for the perception of non-vibrato tone with regard to vibrato extent; (2) if vibrato rate, given similar vibrato extent, does affect the perceptual threshold of non-vibrato tone; and (3) if there are differences in the perceptual threshold of non-vibrato tone across the different professions of the research subjects. STUDY DESIGN: Survey. METHODS: Participants responded to an online survey featuring 40 randomized samples of soprano voices singing [alpha] with a variety of vibrato rates and extents. Some samples were repeated to test subject response reliability. RESULTS AND CONCLUSIONS: Results indicate that a perceptual threshold exists with regard to vibrato extent. However, vibrato rate significantly affected where this extent threshold occurred for the participants. Vibrato extent and rate work together to affect perception of non-vibrato tone. Significant differences were not found across the different groups. PMID- 26611707 TI - Triboelectric-Potential-Regulated Charge Transport Through p-n Junctions for Area Scalable Conversion of Mechanical Energy. AB - Regulation of charge-transport direction is realized through the coupling of triboelectrification, electrostatic induction, and semiconducting properties for area-scalable conversion of mechanical energy. The output current from each unit triboelectric generator can always constructively add up due to the unidirectional flow of electrons. This work proposes a practical and general route to area-scalable applications of the triboelectric generator and other energy-harvesting techniques. PMID- 26611708 TI - Financial Analysis of Behavioral Health Services in a Pediatric Endocrinology Clinic. AB - OBJECTIVE: This article addresses a current need in psychological practice by describing a financially feasible model that moves toward integrated care of behavioral health services in a pediatric endocrinology clinic. METHODS: Financial information (costs and revenue associated with behavioral health services) for the clinic, over an 18-month period (July 2012 to December 2013), was obtained through the hospital's financial department. The clinic meets one half day per week. RESULTS: Over the 18-month period, the behavioral health services generated a net gain of $3661.45 in the favor of the clinic. We determined that the psychologist and clinical psychology residents needed to see a total of four patients per half-day clinic for the clinic to "break-even." CONCLUSIONS: We describe one financially feasible way of integrating behavioral health services into a pediatric endocrinology clinic in the hope that this will be generalizable to other medical settings. PMID- 26611709 TI - Human disorders of peroxisome metabolism and biogenesis. AB - Peroxisomes are dynamic organelles that play an essential role in a variety of cellular catabolic and anabolic metabolic pathways, including fatty acid alpha- and beta-oxidation, and plasmalogen and bile acid synthesis. Defects in genes encoding peroxisomal proteins can result in a large variety of peroxisomal disorders either affecting specific metabolic pathways, i.e., the single peroxisomal enzyme deficiencies, or causing a generalized defect in function and assembly of peroxisomes, i.e., peroxisome biogenesis disorders. In this review, we discuss the clinical, biochemical, and genetic aspects of all human peroxisomal disorders currently known. PMID- 26611711 TI - Differentiating unipolar and bipolar depression by alterations in large-scale brain networks. AB - BACKGROUND: Misdiagnosing bipolar depression can lead to very deleterious consequences of mistreatment. Although depressive symptoms may be similarly expressed in unipolar and bipolar disorder, changes in specific brain networks could be very distinct, being therefore informative markers for the differential diagnosis. We aimed to characterize specific alterations in candidate large-scale networks (frontoparietal, cingulo-opercular, and default mode) in symptomatic unipolar and bipolar patients using resting state fMRI, a cognitively low demanding paradigm ideal to investigate patients. METHODS: Networks were selected after independent component analysis, compared across 40 patients acutely depressed (20 unipolar, 20 bipolar), and 20 controls well-matched for age, gender, and education levels, and alterations were correlated to clinical parameters. RESULTS: Despite comparable symptoms, patient groups were robustly differentiated by large-scale network alterations. Differences were driven in bipolar patients by increased functional connectivity in the frontoparietal network, a central executive and externally-oriented network. Conversely, unipolar patients presented increased functional connectivity in the default mode network, an introspective and self-referential network, as much as reduced connectivity of the cingulo-opercular network to default mode regions, a network involved in detecting the need to switch between internally and externally oriented demands. These findings were mostly unaffected by current medication, comorbidity, and structural changes. Moreover, network alterations in unipolar patients were significantly correlated to the number of depressive episodes. CONCLUSION: Unipolar and bipolar groups displaying similar symptomatology could be clearly distinguished by characteristic changes in large-scale networks, encouraging further investigation of network fingerprints for clinical use. Hum Brain Mapp 37:808-818, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26611710 TI - The protein arginine methyltransferase PRMT6 inhibits HIV-1 Tat nucleolar retention. AB - The human immunodeficiency virus (HIV)-1 transactivator protein Tat is known to play a key role in HIV infection, integrally related to its role in the host cell nucleus/nucleolus. Here we show for the first time that Tat localisation can be modulated by specific methylation, whereby overexpression of active but not catalytically inactive PRMT6 methyltransferase specifically leads to exclusion of Tat from the nucleolus. An R52/53A mutated Tat derivative does not show this redistribution, implying that R52/53, within Tat's nuclear/nucleolar localisation signal, are the targets of PRMT6 activity. Analysis using fluorescence recovery after photobleaching indicate that Tat nucleolar accumulation is largely through binding to nucleolar components, with methylation of Tat by PRMT6 preventing this. To our knowledge, this is the first report of specific protein methylation inhibiting nucleolar retention. PMID- 26611712 TI - Rawal's catalyst as an effective stimulant for the highly asymmetric Michael addition of beta-keto esters to functionally rich nitro-olefins. AB - A general approach to asymmetric synthesis of highly substituted dihydroquinolines was achieved through neighboring ortho-amino group engaged sequential Michael/amination/dehydration reactions on (E)-2-(2 nitrovinyl)anilines with cyclic and acyclic beta-keto esters in the presence of a catalytic amount of Rawal's quinidine-NH-benzyl squaramide followed by TFA. PMID- 26611713 TI - Sulfonation of raloxifene in HEK293 cells overexpressing SULT1A3: Involvement of breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance-associated protein 4 (MRP4/ABCC4) in excretion of sulfate metabolites. AB - Excretion of sulfate metabolites is an essential process in disposition of raloxifene via the sulfonation pathway. However, the transporters responsible for excretion of raloxifene sulfates remain undefined. Here, sulfonation of raloxifene and excretion of its sulfate metabolites were investigated using SULT1A3-overexpressing HEK293 cells (or SULT293 cells) with significant expression of BCRP and MRP4. SULT293 cell lysate catalyzed the sulfonation of raloxifene at both 6-OH and 4'-OH groups, generating raloxifene-6-sulfate (R-6-S) and raloxifene-4'-sulfate (R-4'-S), respectively. Sulfate formation followed the Michaelis-Menten kinetics (Km = 0.49 MUM and Vmax = 5.79 pmol/min/mg for R-6-S; Km = 0.33 MUM and Vmax = 1.25 pmol/min/mg for R-4'-S). As expected, the recombinant SULT1A3 enzyme showed a high similarity in raloxifene sulfonation profiles with the lysate preparation. Ko143, a selective inhibitor of BCRP, significantly decreased the excretion rates of raloxifene sulfates (maximal 66.1%) while increasing the intracellular sulfates (maximal 282%). As a result, the apparent efflux clearance (CLef,app, representing the efflux efficiency of raloxifene sulfates) was substantially reduced (maximal 85.6%). Likewise, the pan MRP inhibitor MK-571 significantly deceased the excretion rates (maximal 69.6%) and CLef,app values (maximal 96.0%) of raloxifene sulfates while increasing the intracellular sulfates (maximal 667%). Further, the short-hairpin RNA (shRNA) targeting BCRP significantly reduced (maximal 35.0%) sulfate excretion. Use of BCRP shRNA also caused significant decreases (maximal 52.5%) in the CLef,app values. Silencing of MRP4 by shRNA led to a substantial alteration in sulfate disposition (i.e., 28.6-37.8% reductions in sulfate excretion, 30.5-59.3% elevations in intracellular sulfates, and 44.8-47.7% deceases in CLef,app values). In conclusion, two sulfate metabolites R-6-S and R-4'-S were generated from raloxifene in SULT293 cells. Cellular excretion of the raloxifene sulfates was mainly mediated by BCRP and MRP4. PMID- 26611714 TI - Association of SCNN1A Single Nucleotide Polymorphisms with neonatal respiratory distress syndrome. AB - Increasing evidence has demonstrated that lung fluid absorption disorders might be an important cause of neonatal respiratory distress syndrome (RDS) by influencing gas exchange or surfactant function. The SCNN1A gene, which encodes the alpha-ENaC, might predispose infants to RDS. To explore whether the single nucleotide polymorphisms (SNPs) of SCNN1A are associated with RDS, we conducted a case-control study to investigate the RDS-associated loci in Han Chinese infants. Seven target SNPs were selected from the SCNN1A gene and were genotyped using the improved multiplex ligase detection reaction (iMLDR). In the total sample, only rs4149570 was associated with NRDS; this association was further confirmed in logistic regression analysis after adjusting for birth weight, gestational age and sex. In the subgroup of infants whose gestational age was 37 weeks and older, in addition to rs4149570, rs7956915 also showed a significant association with RDS. Interestingly, these associations were only observed in term infants. No significant association was observed between the target SNPs and the risk of RDS in preterm infants. We report for the first time that the rs4149570 and rs7956915 polymorphisms of SCNN1A might play important roles in the susceptibility to RDS, particularly in term infants. PMID- 26611715 TI - Proximal row carpectomy in total arthrodesis of the rheumatoid wrist. AB - BACKGROUND: Advanced proximal carpal row damage is common in rheumatoid arthritis (RA). Proximal row carpectomy (PRC) simplifies total wrist arthrodesis, obviating the need for an iliac bone graft. In theory, PRC also improves the chances of healing, as fusion of a single joint space is needed for the procedure to be successful. Potential effects of the loss of carpal height related to PRC are unknown. HYPOTHESIS: We hypothesised that PRC performed concomitantly with total wrist arthrodesis in patients with RA produces good clinical and radiological outcomes, without inducing loss of strength or digital deformities. MATERIAL AND METHODS: In 38 total arthrodeses of rheumatoid wrists, a clinical evaluation was performed, including a visual analogue scale (VAS) pain score, the Patient-Rated Wrist Evaluation (PRWE), grip strength, digital deformities, and patient satisfaction. A standard radiographic workup was obtained to assess healing and carpal height indices. RESULTS: After a mean follow-up of 50 months, the mean VAS pain score was 0.4 (range: 0-7), the mean PRWE score was 21 (range: 0-80.5), and grip strength as a percentage of the contralateral limb was 76%. The healing rate was 92% (35/38 wrists), and 34 (90%) patients reported being satisfied or very satisfied. No effects of carpal height loss on clinical or radiographic parameters was detected. DISCUSSION: Total wrist arthrodesis combined with PRC provides reliable and reproducible benefits. This study found no evidence of adverse effects related to the loss of carpal height. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 26611716 TI - May one-stage exchange for Candida albicans peri-prosthetic infection be successful? AB - Fungal infection of a total joint arthroplasty has a low incidence but is generally considered as more difficult to cure than bacterial infection. As for bacterial infection, two-stage exchange is considered as the gold standard of treatment. We report two cases of one-stage total joint exchange for fungal peri prosthetic infection with Candida albicans, where the responsible pathogens was only identified on intraoperative samples. This situation can be considered as a one-stage exchange for fungal peri-prosthetic infection without preoperative identification of the responsible organism, which is considered as having a poor prognosis. Both cases were free of infection after two years. One-stage revision has several potential advantages over two-stage revision, including shorter hospital stay and rehabilitation, no interim period with significant functional impairment, shorter antibiotic treatment, better functional outcome and probably lower costs. We suggest that one-stage revision for C. albicans peri-prosthetic infection may be successful even without preoperative fungal identification. LEVEL OF EVIDENCE: Level IV-Historical cases. PMID- 26611717 TI - From novice to master surgeon: improving feedback with a descriptive approach to intraoperative assessment. AB - BACKGROUND: A developmental and descriptive approach to assessing trainee intraoperative performance was explored. METHODS: Semistructured interviews with 20 surgeon educators were recorded, transcribed, deidentified, and analyzed using a grounded theory approach to identify emergent themes. Two researchers independently coded the transcripts. Emergent themes were also compared to existing theories of skill acquisition. RESULTS: Surgeon educators characterized intraoperative surgical performance as an integrated practice of multiple skill categories and included anticipating, planning for contingencies, monitoring progress, self-efficacy, and "working knowledge." Comments concerning progression through stages, broadly characterized as "technician," "anatomist," "anticipator," "strategist," and "executive," formed a narrative about each stage of development. CONCLUSIONS: The developmental trajectory with narrative, descriptive profiles of surgeons working toward mastery provide a standardized vocabulary for communicating feedback, while fostering reflection on trainee progress. Viewing surgical performance as integrated practice rather than the conglomerate of isolated skills enhances authentic assessment. PMID- 26611718 TI - Metabolic response to omega-3 fatty acid supplementation in patients with diabetic nephropathy: A randomized, double-blind, placebo-controlled trial. AB - BACKGROUND & AIMS: This study was carried out to evaluate the effects of omega-3 fatty acid administration on markers of insulin resistance, lipid concentrations, biomarkers of inflammation and oxidative stress in patients with diabetic nephropathy (DN). METHODS: This parallel randomized double-blind placebo controlled clinical trial was performed among 60 patients with DN. Patients were randomly allocated into two groups to receive either 1000 mg/day omega-3 fatty acid from flaxseed oil (n = 30) or placebo (n = 30) for 12 weeks. Fasting blood samples were taken at the onset of the study and 12 weeks after supplementation to assess glycaemic status, lipid concentrations, biomarkers of inflammation and oxidative stress. RESULTS: After 12 weeks of treatment, patients who consumed omega-3 fatty acid supplements compared with the placebo had significantly decreased serum insulin levels (-39.6 +/- 10.8 vs. -7.2 +/- 8.4 pmol/L, P = 0.001), homeostasis model of assessment-estimated b cell function (HOMA-B) (-30.2 +/- 11.2 vs. -1.5 +/- 6.8, P = 0.03) and improved quantitative insulin sensitivity check index (QUICKI) (+0.01 +/- 0.004 vs. +0.002 +/- 0.004, P = 0.03). Additionally, compared with the placebo, omega-3 fatty acid administration led to a significant reduction in serum triglycerides (-19.8 +/- 8.8 vs. +12.6 +/ 10.2 mg/dL, P = 0.01) and VLDL-cholesterol concentrations (-4.0 +/- 1.8 vs. +2.5 +/- 2.0 mg/dL, P = 0.01). Supplementation with omega-3 fatty acid had no significant effects on other lipid subfractions, biomarkers of inflammation and oxidative stress compared with the placebo. In addition, within-group differences revealed significant reductions in serum insulin (P = 0.001), HOMA-IR (P = 0.004), HOMA-B (P = 0.01), serum triglycerides (P = 0.03), VLDL- (P = 0.03), total- (P < 0.001), LDL- (P = 0.002), total-/HDL-cholesterol ratio (P = 0.001), blood urea nitrogen (P = 0.04), and significant increases in QUICKI (P = 0.001) and nitric oxide (P = 0.005) and total antioxidant capacity concentrations (P = 0.02) in the omega-3 fatty acid group. CONCLUSIONS: Our findings indicated that omega-3 fatty acid administration for 12 weeks among DN patients had favorable effects on insulin levels, HOMA-B, QUICKI, serum triglycerides and VLDL cholesterol; however, it did not influence biomarkers of inflammation and oxidative stress. PMID- 26611720 TI - Multifunctional role of beta-1, 3 glucan binding protein purified from the haemocytes of blue swimmer crab Portunus pelagicus and in vitro antibacterial activity of its reaction product. AB - beta-1, 3 glucan binding protein (beta-GBP) was isolated from the haemocytes of blue swimmer crab, Portunus pelagicus and purified by laminarin coupled Sephadex G-100 affinity column chromatography. The purified beta-GBP has the molecular mass of 100 kDa, confirmed by SDS-PAGE. The X-ray diffraction analysis of purified beta-GBP indicates the crystalline nature of the protein and also the presence of single peak confirming the existence of beta-glucan molecule. The results of agglutination assay showed that the purified beta-GBP had the ability to agglutinate with yeast cell, Saccharomyces cerevisiae and mammalian erythrocytes. beta-GBP can agglutinate with yeast cells at the concentration of 50 MUg/ml. The phagocytic and encapsulation activity of purified beta-GBP from P. pelagicus was determined with yeast cell S. cerevisiae and sepharose bead suspension respectively. This reveals that, beta-GBP have the ability to detect the pathogen associated molecular patterns (PAMP) found on the surface of fungi and bacteria. The recognition of invading foreign substances and in the involvement of functional activities induces the activation of prophenoloxidase. This revealed that beta-GBP play a major role in the innate immune system of crustaceans by stimulating the prophenoloxidase system. Moreover, it was obvious to note that beta-GBP reaction product exhibited antibacterial and antibiofilm activity against Gram positive and Gram negative bacteria. This study concludes the functional aspects of beta-GBP purified from P. pelagicus and its vital role in the stimulation of prophenoloxidase cascade during the pathogenic infection. PMID- 26611721 TI - Histological changes and antioxidant enzyme activity in signal crayfish (Pacifastacus leniusculus) associated with sub-acute peracetic acid exposure. AB - Peracetic acid (PAA) is a powerful disinfectant recently adopted as a therapeutic agent in aquaculture. A concentration of 10 mg L(-1) PAA effectively suppresses zoospores of Aphanomyces astaci, the agent of crayfish plague. To aid in establishing safe therapeutic guideline, the effects of PAA on treated crayfish were investigated through assessment of histological changes and oxidative damage. Adult female signal crayfish Pacifastacus leniusculus (n = 135) were exposed to 2 mg L(-1) and 10 mg L(-1) of PAA for 7 days followed by a 7 day recovery period in clean water. Superoxide dismutase activity was significantly lower in gill and hepatopancreas after three days exposure to 10 mg L(1) PAA than in the group treated with 2 mg L(-1) PAA and a control in only clean water. Catalase activity in gill and hepatopancreas remained unaffected by both exposures. Glutathione reductase was significantly decreased in gill of 10 mg L( 1) PAA treated crayfish and increased in group exposed to 2 mg L(-1) compared to control after 7 days exposure. Antioxidant enzyme activity in exposed groups returned to control values after recovery period. Gill, hepatopancreas, and antennal gland showed slight damage in crayfish treated with 2 mg L(-1) of PAA compared to the control group. The extent and frequency of histological alterations were more pronounced in animals exposed to 10 mg L(-1). The gill was the most affected organ, infiltrated by granular hemocytes and displaying malformations of lamella tips and disorganization of epithelial cells. After a 7 day recovery period, the infiltrating cells in affected tissues of the exposed crayfish began to return to normal levels. Results suggested that the given concentrations could be applied to signal crayfish against crayfish plague agent in aquaculture; however, further studies are required for safe use. PMID- 26611719 TI - A neuroscience perspective on sexual risk behavior in adolescence and emerging adulthood. AB - Late adolescence and emerging adulthood (specifically ages 15-24) represent a period of heightened sexual risk taking resulting in the greatest annual rates of sexually transmitted infections and unplanned pregnancies in the US population. Ongoing efforts to prevent such negative consequences are likely to benefit from a deepening of our understanding of biological mechanisms through which sexual risk taking emerges and biases decision making during this critical window. Here we present a neuroscience framework from which a mechanistic examination of sexual risk taking can be advanced. Specifically, we adapt the neurodevelopmental triadic model, which outlines how motivated behavior is governed by three systems: approach, avoidance, and regulation, to sexual decision making and subsequent risk behavior. We further propose a testable hypothesis of the triadic model, wherein relatively decreased threat-related amygdala reactivity and increased reward-related ventral striatum reactivity leads to sexual risk taking, which is particularly exaggerated during adolescence and young adulthood when there is an overexpression of dopaminergic neurons coupled with immature top-down prefrontal cortex regulation. We conclude by discussing how future research based on our adapted triadic model can inform ongoing efforts to improve intervention and prevention efforts. PMID- 26611722 TI - Mapping of brain lipid binding protein (Blbp) in the brain of adult zebrafish, co expression with aromatase B and links with proliferation. AB - Adult fish exhibit a strong neurogenic capacity due to the persistence of radial glial cells. In zebrafish, radial glial cells display well-established markers such as the estrogen-synthesizing enzyme (AroB) and the brain lipid binding protein (Blbp), which is known to strongly bind omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA). While Blpb is mainly described in the telencephalon of adult zebrafish, its expression in the remaining regions of the brain is poorly documented. The present study was designed to further investigate Blbp expression in the brain, its co-expression with AroB, and its link with radial glial cells proliferation in zebrafish. We generated a complete and detailed mapping of Blbp expression in the whole brain and show its complete co expression with AroB, except in some tectal and hypothalamic regions. By performing PCNA and Blbp immunohistochemistry on cyp19a1b-GFP (AroB-GFP) fish, we also demonstrated preferential Blbp expression in proliferative radial glial cells in almost all regions studied. To our knowledge, this is the first complete and detailed mapping of Blbp-expressing cells showing strong association between Blbp and radial glial cell proliferation in the adult brain of fish. Given that zebrafish is now recognized models for studying neurogenesis and brain repair, our data provide detailed characterization of Blbp in the entire brain and open up a broad field of research investigating the role of omega-3 polyunsaturated fatty acids in neural stem cell activity in fish. PMID- 26611724 TI - Characterizing entanglement of an artificial atom and a cavity cat state with Bell's inequality. AB - The Schrodinger's cat thought experiment highlights the counterintuitive concept of entanglement in macroscopically distinguishable systems. The hallmark of entanglement is the detection of strong correlations between systems, most starkly demonstrated by the violation of a Bell inequality. No violation of a Bell inequality has been observed for a system entangled with a superposition of coherent states, known as a cat state. Here we use the Clauser-Horne-Shimony-Holt formulation of a Bell test to characterize entanglement between an artificial atom and a cat state, or a Bell-cat. Using superconducting circuits with high fidelity measurements and real-time feedback, we detect correlations that surpass the classical maximum of the Bell inequality. We investigate the influence of decoherence with states up to 16 photons in size and characterize the system by introducing joint Wigner tomography. Such techniques demonstrate that information stored in superpositions of coherent states can be extracted efficiently, a crucial requirement for quantum computing with resonators. PMID- 26611723 TI - Evolving landscape in the management of transthyretin amyloidosis. AB - Transthyretin (TTR) amyloidosis (ATTR amyloidosis) is a multisystemic, multigenotypic disease resulting from deposition of insoluble ATTR amyloid fibrils in various organs and tissues. Although considered rare, the prevalence of this serious disease is likely underestimated because symptoms can be non specific and diagnosis largely relies on amyloid detection in tissue biopsies. Treatment is guided by which tissues/organs are involved, although therapeutic options are limited for patients with late-stage disease. Indeed, enthusiasm for liver transplantation for familial ATTR amyloidosis with polyneuropathy was dampened by poor outcomes among patients with significant neurological deficits or cardiac involvement. Hence, there remains an unmet medical need for new therapies. The TTR stabilizers tafamidis and diflunisal slow disease progression in some patients with ATTR amyloidosis with polyneuropathy, and the postulated synergistic effect of doxycycline and tauroursodeoxycholic acid on dissolution of amyloid is under investigation. Another therapeutic approach is to reduce production of the amyloidogenic protein, TTR. Plasma TTR concentration can be significantly reduced with ISIS-TTR(Rx), an investigational antisense oligonucleotide-based drug, or with patisiran and revusiran, which are investigational RNA interference-based therapeutics that target the liver. The evolving treatment landscape for ATTR amyloidosis brings hope for further improvements in clinical outcomes for patients with this debilitating disease. PMID- 26611725 TI - Assessment of the potential of a high frequency acoustomicrofluidic nebulisation platform for inhaled stem cell therapy. AB - Despite the promise of stem cell therapy for lung therapeutics and repair, there are few viable means for directly delivering stem cells to locally target the respiratory airways via inhalation. This is not surprising given the significant challenges in aerosolising stem cells, particularly given their susceptibility to damage under the large stresses involved in the nebulisation process. Here, we present promising results using a microfluidic acoustic nebulisation platform that is not only low cost and portable, but also its high MHz order frequencies are effective for preserving the structural and functional integrity of mesenchymal stem cells (MSCs) during the nebulisation process. This is verified through an assessment of the viability, structure, metabolic activity, proliferation ability and genetic makeup of the nebulised MSCs using a variety of assays, including cell viability staining, flow cytometry, reverse transcription and quantitative polymerase chain reaction, and immunophenotyping, thus demonstrating the platform as a promising method for efficient pulmonary stem cell delivery. PMID- 26611726 TI - Coexistence of Scattering Enhancement and Suppression by Plasmonic Cavity Modes in Loaded Dimer Gap-Antennas. AB - Plasmonic nanoantenna is of promising applications in optical sensing and detection, enhancement of optical nonlinear effect, surface optical spectroscopy, photoemission, etc. Here we show that in a carefully-designed dimer gap-antenna made by two metallic nanorods, the longitudinal plasmon antenna mode (AM) of bonding dipoles can compete with the transverse plasmonic cavity modes (CMs), yielding dramatically enhanced or suppressed scattering efficiency, depending on the CMs symmetry characteristics. More specifically, it is demonstrated that an appropriately loaded gap layer enables substantial excitation of toroidal moment and its strong interaction with the AM dipole moment, resulting in Fano- or electromagnetically induced transparency (EIT)-like profile in the scattering spectrum. However, for CMs with nonzero azimuthal number, the spectrum features a cumulative signature of the respective AM and CM resonances. We supply both detailed near-field and far-field analysis, showing that the modal overlap and phase relationship between the fundamental moments of different order play a crucial role. Finally, we show that the resonance bands of the AM and CMs can be tuned by adjusting the geometry parameters and the permittivity of the load. Our results may be useful in plasmonic cloaking, spin-polarized directional light emission, ultra-sensitive optical sensing, and plasmon-mediated photoluminescence. PMID- 26611727 TI - Three-dimensional in vivo difference between native acetabular version and acetabular component version influences iliopsoas impingement after total hip arthroplasty. AB - PURPOSE: The potential influence of acetabular component orientation on iliopsoas impingement in total hip arthroplasty (THA) has not been previously quantified. The aim of the present study was to utilize pre- and post-operative CT-based 3D models to quantify iliopsoas impingement on acetabular components, and to identify any potential factors associated with iliopsoas impingement. METHODS: Iliopsoas muscle was modelled from pre-operative CT scans and transferred to the post-operative 3D models in 19 THAs. The volume and the area of the overlap between iliopsoas muscle and acetabular cup (iliopsoas volume & area) was measured on axial and sagittal images. Most protruded lengths of cup uncovered by acetabular bone were measured on axial sagittal scan of CT scans. Version of acetabulum, acetabular cup, and the difference between the two (version difference) were also measured with cup inclination and size. Linear regression analysis was performed to identify any factor influencing iliopsoas impingement. RESULTS: Iliopsoas impingement volume and area were 100.6 +/- 226.1 (range, 0.0 663.9) mm3 and 52.6 +/- 102.0 (0.0-342.3) mm3, respectively. The protruded lengths on axial and sagittal view were 6.9 +/- 5.3 (0.0-16.0) and 2.1 +/- 2.7 (0.0-8.0). Linear regression model showed that version difference was significantly related to the iliopsoas impingement volume and area (beta = 0.709, p = 0.041 for volume, and beta = -0.684, p = 0.047 for area). CONCLUSIONS: The results of this study demonstrate that iliopsoas impingement on acetabular components was influenced by the version difference between pre-operative acetabular bone and acetabular component rather than the magnitude of post operative cup version alone. PMID- 26611728 TI - Incidence of heterotopic ossification in direct anterior vs posterior approach to total hip arthroplasty: a retrospective radiographic review. AB - PURPOSE: To investigate the prevalence of heterotopic ossification following direct anterior approach total hip arthroplasty compared to posterior approach, performed by a single surgeon at one institution METHODS: All primary THAs performed by the senior author (JEL) over a 70-month period were reviewed, including 235 DAA and 120 posterior THAs. Brooker's system was used to grade HO at a minimum of six months follow-up. RESULTS: Patients undergoing DAA were less likely to develop clinically significant HO compared to posterior THA (p = 0.04). The overall incidence of HO following DAA THA was 24.3 % (3 % grade 3 and 0 % grade 4), and following posterior THA was 27.5 % (4.2 % grade 3 and 3.3 % grade 4). CONCLUSIONS: Lower rates of clinically significant (Brooker grade 3 and 4) HO were observed in DAA THA than in posterior approach THA. This data may be instructive when approaching THA candidates with conditions that predispose them to HO. PMID- 26611730 TI - Unprecedented copper-mediated oxidative demethylation of propionamides via bidentate-chelation assistance. AB - A copper-mediated directed demethylation of propionamides has been developed. This reaction proceeds predominantly at the alpha-methyl groups of aliphatic amides with high efficiency and provides a unique tool for the direct cleavage of unactivated C(sp(3))-C(sp(3)) bonds. The directing groups can be smoothly removed to afford the corresponding alkyl carboxylic acids. PMID- 26611729 TI - What are the risk factors for post-operative infection after hip hemiarthroplasty? Systematic review of literature. AB - BACKGROUND: Femoral neck fractures are frequent in the elderly population and lead to high morbidity and mortality. Hemiarthroplasty is an established surgical procedure for displaced intracapsular femoral neck fractures. Post-operative infection is frequent and is potentially devastating for the patient and the healthcare services. The goal of this study was to identify the risk factors of infection after hemiarthroplasty and help adapt our surgical practice. METHODS: A systematic review of the literature was performed in July 2015 by two authors using the MedLine, PubMed and Cochrane databases. We used the MeSH keywords "hip hemiarthroplasty" AND "infection" to identify risk factors and methods of prevention for surgical site infection after hemiarthroplasty. Following the search, two authors independently performed the first stage based on titles and abstracts. RESULTS: Thirty-seven articles were selected. Review and analysis of the references was performed to find other articles of interest. Thirteen articles were selected to analyse. According to literature, the surgical site infection (SSI) rate after hip hemiarthroplasty (HHA) is between 1.7 and 7.3 %. Pre-operative comorbidities (obesity, liver disease, advanced age), operative conditions (junior surgeon, uncemented stems, time of surgery) and post-operative management (length of hospitalisation, haematoma, prolonged wound drainage and two urinary catheterisations) were identified as risk factors of surgical site infection. Authors describe conditions to decrease the incidence of these complications and underline the importance of "a specialised hip team" that provides fast care and helps decrease the duration of hospitalisation. CONCLUSIONS: Careful patient management for hemiarthroplasty is vital and may decrease the incidence of surgical site infection, which is associated with high morbidity and high procedure cost. Our review suggests that there are specific correctable risk factors for SSIs after HHA. Being able to identify these risk factors leads to better care because of SSI prevention in patients undergoing HHAs after femoral neck fractures. To improve the outcomes, some methods of prevention of surgical site infection are available: before, during and after the operation. STUDY DESIGN: Review of literature. LEVEL OF EVIDENCE: IV. PMID- 26611731 TI - Increased Sympathetic Renal Innervation in Hemodialysis Patients Is the Anatomical Substrate of Sympathetic Hyperactivity in End-Stage Renal Disease. AB - BACKGROUND: Renal denervation represents an emerging treatment for resistant hypertension in patients with end-stage renal disease, but data about the anatomic substrate of this treatment are lacking. Therefore, the aim of this study was to investigate the morphological basis of sympathetic hyperactivity in the setting of hemodialysis patients to identify an anatomical substrate that could warrant the use of this new therapeutic approach. METHODS AND RESULTS: The distribution of sympathetic nerves was evaluated in the adventitia of 38 renal arteries that were collected at autopsy or during surgery from 25 patients: 9 with end-stage renal disease on dialysis (DIAL group) and 16 age-matched control nondialysis patients (CTRL group). Patients in the DIAL group showed a significant increase in nerve density in the internal area of the peri adventitial tissue (within the first 0.5 mm of the beginning of the adventitia) compared with the CTRL group (4.01+/-0.30 versus 2.87+/-0.28*mm(2), P=0.01). Regardless of dialysis, hypertensive patients with signs of severe arteriolar damage had a greater number of nerve endings in the most internal adventitia, and this number was significantly higher than in patients without hypertensive arteriolar damage (3.90+/-0.36 versus 2.87+/-0.41*mm(2), P=0.04), showing a correlation with hypertensive arteriolar damage rather than with hypertensive clinical history. CONCLUSIONS: The findings from this study provide a morphological basis underlying sympathetic hyperactivity in patients with end stage renal disease and might offer useful information to improve the use of renal denervation in this group of patients. PMID- 26611732 TI - Placental telomere length and risk of placental abruption. AB - OBJECTIVE: To investigate the associations of placental telomere length with placental abruption (PA) risk and interactions between placental telomere length and placental mitochondrial DNA (mtDNA) copy number on PA risk. MATERIALS AND METHODS: Relative telomere length and mtDNA copy number in placental samples collected from 105 cases and 73 controls were measured in two batches using qRT PCR. Mean differences in relative telomere length between PA cases and controls were examined. After creating batch-specific median cutoffs for relative telomere length (84.92 and 102.53) and mtDNA copy number (2.32 and 1.42), interaction between the two variables was examined using stratified logistic regression models. RESULTS: Adjusted mean difference in relative telomere length between PA cases and controls was -0.07 (p > 0.05). Among participants with low mtDNA copy number, participants with short relative telomere length had a 3.07-fold higher odds (95% CI: 1.13-8.38) of PA as compared with participants with long relative telomere length (the reference group). Among participants with high mtDNA copy number, participants with short relative telomere length had a 0.71-fold lower odds (95% CI: 0.28-1.83) of PA as compared with the reference group (interaction p values = 0.03). CONCLUSION: Findings suggest complex relationships between placental telomere length, mtDNA copy number and PA risk which warrant further larger studies. PMID- 26611733 TI - Thermally activated long range electron transport in living biofilms. AB - Microbial biofilms grown utilizing electrodes as metabolic electron acceptors or donors are a new class of biomaterials with distinct electronic properties. Here we report that electron transport through living electrode-grown Geobacter sulfurreducens biofilms is a thermally activated process with incoherent redox conductivity. The temperature dependency of this process is consistent with electron-transfer reactions involving hemes of c-type cytochromes known to play important roles in G. sulfurreducens extracellular electron transport. While incoherent redox conductivity is ubiquitous in biological systems at molecular length scales, it is unprecedented over distances it appears to occur through living G. sulfurreducens biofilms, which can exceed 100 microns in thickness. PMID- 26611734 TI - The cell cultures and the use of haemocytes from marine molluscs for ecotoxicology assessment. AB - Among aquatic organisms suitable for biological monitoring, molluscs occupy a prominent place due to their wide geographic distribution, their abundance and accessibility in the field as well as in aquaculture. Molluscs reflect the degree of environmental contamination and are the most useful bioindicator tools. The study of modulation of immune system or immunomodulation in marine molluscs has become one of the privileged ways for evaluating the physiological effects of environmental factors. Physiological responses of molluscs to environmental stresses could be mediated by haemocytes. These cells are continually exposed to the external environment due to the open circulatory system of molluscs and are affected by pollutants. In fact, several studies showed the effects of different environmental contaminants on haemocyte functions (viability, phagocytosis, ROS production) as well as on proteins involved in cytoskeletal structure maintenance using the in vitro approaches. In ecotoxicology, in vitro approach is an alternative to animal testing due to the reduced use of experimental animals, low cost and rapid performance. Although several studies showed the importance of using in vitro cell models to determine the effects of different environmental contaminants on haemocyte parameters in marine molluscs, a few reviews highlight these effects. The main purpose of this paper is to summarize the recent data on the effect of some xenobiotics on haemocyte parameters in some mollusc species and then suggest future research prospects. PMID- 26611735 TI - Phospholipase D2 promotes degradation of hypoxia-inducible factor-1alpha independent of lipase activity. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) is a key transcriptional mediator that coordinates the expression of various genes involved in tumorigenesis in response to changes in oxygen tension. The stability of HIF-1alpha protein is determined by oxygen-dependent prolyl hydroxylation, which is required for binding of the von Hippel-Lindau protein (VHL), the recognition component of an E3 ubiquitin ligase that targets HIF-1alpha for ubiquitination and degradation. Here, we demonstrate that PLD2 protein itself interacts with HIF-1alpha, prolyl hydroxylase (PHD) and VHL to promote degradation of HIF-1alpha via the proteasomal pathway independent of lipase activity. PLD2 increases PHD2-mediated hydroxylation of HIF-1alpha by increasing the interaction of HIF-1alpha with PHD2. Moreover, PLD2 promotes VHL-dependent HIF-1alpha degradation by accelerating the association between VHL and HIF-1alpha. The interaction of the pleckstrin homology domain of PLD2 with HIF-1alpha also promoted degradation of HIF-1alpha and decreased expression of its target genes. These results indicate that PLD2 negatively regulates the stability of HIF-1alpha through the dynamic assembly of HIF-1alpha, PHD2 and VHL. PMID- 26611736 TI - A meta-analysis of neonatal health outcomes from oocyte donation. AB - Donated oocytes are a treatment modality for female infertility which is also associated with increased risks of preeclampsia. Subsequently it is important to evaluate if there is concomitant increased risks for adverse neonatal events in donated oocyte neonates. A structured search of the literature using PubMed, EMBASE and Cochrane Reviews was performed to investigate the perinatal health outcomes of offspring conceived from donor oocytes compared with autologous oocytes. Meta-analysis was performed on comparable outcomes data. Twenty-eight studies were eligible and included in the review, and of these, 23 were included in a meta-analysis. Donor oocyte neonates are at increased risk of being born with low birth weight (<2500 g) [risk ratio (RR): 1.18, 95% confidence interval (CI): 1.14-1.22, P-value (P)<0.00001], very low birth weight (<1500 g) (RR: 1.24, CI: 1.15-1.35, P<0.00001), preterm (<37 weeks) (RR: 1.26, CI: 1.23-1.30, P<0.00001), of lower gestational age (mean difference -0.3 weeks, CI: -0.35 weeks to -0.25 weeks, P<0.00001), and preterm with low birth weight (RR: 1.24, CI: 1.19 1.29, P<0.00001), when compared with autologous oocyte neonates. Conversely, low birth weight outcomes were improved in term donor oocyte neonates (RR: 0.86, CI: 0.8-0.93, P=0.0003). These negative outcomes remained significant when controlling for multiple deliveries. The donor oocyte risk rates are higher than those found in general ART outcomes, are important considerations for the counselling of infertile patients and may also influence the long term health of the offspring. PMID- 26611737 TI - A Label-Free Photoluminescence Genosensor Using Nanostructured Magnesium Oxide for Cholera Detection. AB - Nanomaterial-based photoluminescence (PL) diagnostic devices offer fast and highly sensitive detection of pesticides, DNA, and toxic agents. Here we report a label-free PL genosensor for sensitive detection of Vibrio cholerae that is based on a DNA hybridization strategy utilizing nanostructured magnesium oxide (nMgO; size >30 nm) particles. The morphology and size of the synthesized nMgO were determined by transmission electron microscopic (TEM) studies. The probe DNA (pDNA) was conjugated with nMgO and characterized by X-ray photoelectron and Fourier transform infrared spectroscopic techniques. The target complementary genomic DNA (cDNA) isolated from clinical samples of V. cholerae was subjected to DNA hybridization studies using the pDNA-nMgO complex and detection of the cDNA was accomplished by measuring changes in PL intensity. The PL peak intensity measured at 700 nm (red emission) increases with the increase in cDNA concentration. A linear range of response in the developed PL genosensor was observed from 100 to 500 ng/MUL with a sensitivity of 1.306 emi/ng, detection limit of 3.133 ng/MUL and a regression coefficient (R(2)) of 0.987. These results show that this ultrasensitive PL genosensor has the potential for applications in the clinical diagnosis of cholera. PMID- 26611738 TI - Cytochrome b5 reductase, a plasma membrane redox enzyme, protects neuronal cells against metabolic and oxidative stress through maintaining redox state and bioenergetics. AB - The plasma membrane redox system (PMRS) containing NADH-dependent reductases is known to be involved in the maintenance of redox state and bioenergetics. Neuronal cells are very vulnerable to oxidative stress and altered energy metabolism linked to mitochondrial dysfunction. However, the role of the PMRS in these pathways is far from clear. In this study, in order to investigate how cytochrome b5 reductase (b5R), one of the PM redox enzymes, regulates cellular response under stressed conditions, human neuroblastoma cells transfected with b5R were used for viability and mitochondrial functional assays. Cells transfected with b5R exhibited significantly higher levels of the NAD(+)/NADH ratio, consistent with increased levels of b5R activity. Overexpression of b5R made cells more resistant to H2O2 (oxidative stress), 2-deoxyglucose (metabolic stress), rotenone and antimycin A (energetic stress), and lactacystin (proteotoxic stress), but did not protect cells against H2O2 and serum withdrawal. Overexpression of b5R induced higher mitochondrial functions such as ATP production rate, oxygen consumption rate, and activities of complexes I and II, without formation of further reactive oxygen species, consistent with lower levels of oxidative/nitrative damage and resistance to apoptotic cell death. In conclusion, higher NAD(+)/NADH ratio and consequent more efficient mitochondrial functions are induced by the PMRS, enabling them to maintain redox state and energy metabolism under conditions of some energetic stresses. This suggests that b5R can be a target for therapeutic intervention for aging and neurodegenerative diseases. PMID- 26611739 TI - Hybrid QM/MM study of FMO complex with polarized protein-specific charge. AB - The Fenna-Matthews-Olson (FMO) light-harvesting complex is now one of the primary model systems for the study of excitation energy transfer (EET). However, the mechanism of the EET in this system is still controversial. In this work, molecular dynamics simulations and the electrostatic-embedding quantum mechanics/molecular-mechanics single-point calculations have been employed to predict the energy transfer pathways utilizing the polarized protein-specific charge (PPC), which provides a more realistic description of Coulomb interaction potential in the protein than conventional mean-field charge scheme. The recently discovered eighth pigment has also been included in this study. Comparing with the conventional mean-field charges, more stable structures of FMO complex were found under PPC scheme during molecular dynamic simulation. Based on the electronic structure calculations, an exciton model was constructed to consider the couplings during excitation. The results show that pigments 3 and 4 dominate the lowest exciton levels whereas the highest exciton level are mainly constituted of pigments 1 and 6. This observation agrees well with the assumption based on the spatial distribution of the pigments. Moreover, the obtained spectral density in this study gives a reliable description of the diverse local environment embedding each pigment. PMID- 26611741 TI - Constraints on natural global atmospheric CO2 fluxes from 1860 to 2010 using a simplified explicit forward model. AB - Land-use changes until the beginning of the 20(th) century made the terrestrial biosphere a net source of atmospheric carbon. Later, burning of fossil fuel surpassed land use changes as the major anthropogenic source of carbon. The terrestrial biosphere is at present suggested to be a carbon sink, but the distribution of excess anthropogenic carbon to the ocean and biosphere sinks is highly uncertain. Our modeling suggest that land-use changes can be tracked quite well by the carbon isotopes until mid-20(th) century, whereas burning of fossil fuel dominates the present-day observed changes in the isotope signature. The modeling indicates that the global carbon isotope fractionation has not changed significantly during the last 150 years. Furthermore, increased uptake of carbon by the ocean and increasing temperatures does not yet appear to have resulted in increasing the global gross ocean-to-atmosphere carbon fluxes. This may however change in the future when the excess carbon will emerge in the ocean upwelling zones, possibly reducing the net-uptake of carbon compared to the present-day ocean. PMID- 26611740 TI - Volumetric CT with sparse detector arrays (and application to Si-strip photon counters). AB - Novel x-ray medical imaging sensors, such as photon counting detectors (PCDs) and large area CCD and CMOS cameras can involve irregular and/or sparse sampling of the detector plane. Application of such detectors to CT involves undersampling that is markedly different from the commonly considered case of sparse angular sampling. This work investigates volumetric sampling in CT systems incorporating sparsely sampled detectors with axial and helical scan orbits and evaluates performance of model-based image reconstruction (MBIR) with spatially varying regularization in mitigating artifacts due to sparse detector sampling. Volumetric metrics of sampling density and uniformity were introduced. Penalized likelihood MBIR with a spatially varying penalty that homogenized resolution by accounting for variations in local sampling density (i.e. detector gaps) was evaluated. The proposed methodology was tested in simulations and on an imaging bench based on a Si-strip PCD (total area 5 cm * 25 cm) consisting of an arrangement of line sensors separated by gaps of up to 2.5 mm. The bench was equipped with translation/rotation stages allowing a variety of scanning trajectories, ranging from a simple axial acquisition to helical scans with variable pitch. Statistical (spherical clutter) and anthropomorphic (hand) phantoms were considered. Image quality was compared to that obtained with a conventional uniform penalty in terms of structural similarity index (SSIM), image uniformity, spatial resolution, contrast, and noise. Scan trajectories with intermediate helical width (~10 mm longitudinal distance per 360 degrees rotation) demonstrated optimal tradeoff between the average sampling density and the homogeneity of sampling throughout the volume. For a scan trajectory with 10.8 mm helical width, the spatially varying penalty resulted in significant visual reduction of sampling artifacts, confirmed by a 10% reduction in minimum SSIM (from 0.88 to 0.8) and a 40% reduction in the dispersion of SSIM in the volume compared to the constant penalty (both penalties applied at optimal regularization strength). Images of the spherical clutter and wrist phantoms confirmed the advantages of the spatially varying penalty, showing a 25% improvement in image uniformity and 1.8 * higher CNR (at matched spatial resolution) compared to the constant penalty. The studies elucidate the relationship between sampling in the detector plane, acquisition orbit, sampling of the reconstructed volume, and the resulting image quality. They also demonstrate the benefit of spatially varying regularization in MBIR for scenarios with irregular sampling patterns. Such findings are important and integral to the incorporation of a sparsely sampled Si-strip PCD in CT imaging. PMID- 26611742 TI - Adoption of pleurectomy and decortication for malignant mesothelioma leads to similar survival as extrapleural pneumonectomy. AB - OBJECTIVE: We changed our surgical approach to malignant pleural mesothelioma (MPM) in August 2011 and adopted pleurectomy and decortication (PD) instead of extrapleural pneumonectomy (EPP). In this study, we analyzed our perioperative and survival results during the 2 periods. METHODS: All patients who underwent surgical intervention for MPM during 2003-2014 were included. Data were retrospectively analyzed from a prospective database. Before August 2011, patients underwent evaluation for EPP and adjuvant chemoradiation (group 1). After August 2011, patients were evaluated for PD and adjuvant chemotherapy and/or radiation (group 2). Demographic characteristics, surgical technique, histology, side, completeness of resection, and types of treatments were recorded. Statistics was performed using Student t test, chi(2) tests, uni- and multivariate regression, and Kaplan-Meier survival analysis. RESULTS: The same surgical team operated on 130 patients. Median age was 55.7 years (range, 26-80 years) and 76 were men. EPP and extended PD was performed in 72 patients. Ninety day mortality was 10%. Median survival was 17.8 months with a 5-year survival rate of 14%. Uni- and multivariate analyses showed that epithelioid histology, stage N0, and trimodality treatment were associated with better survival (P = .039, P = .012, and P < .001, respectively). Demographic variables and overall survival (15.6 vs 19.6 months, respectively) were similar between the groups, whereas nonepithelioid histology, use of preoperative chemotherapy, and incomplete resections were more frequent in group 2 (P < .001, P < .001, and P = .006, respectively). Follow-up was shorter in group 2 (22.5 +/- 20.6 vs 16.4 +/- 10.9 months; P < .001). CONCLUSIONS: Adoption of PD as the main surgical approach is not associated with survival disadvantage in the surgical treatment of MPM. PMID- 26611743 TI - The devil is in the details. PMID- 26611744 TI - Decision making in acute DeBakey I aortic dissection: Balancing extensive arch reconstruction versus mortality. PMID- 26611745 TI - Something borrowed, something blue: A gift for the bride with everything, including an ectopic parathyroid adenoma. PMID- 26611746 TI - Too many nodules: Can we do better than computed tomography screening for lung cancer? PMID- 26611747 TI - Characterizing the angiogenic activity of patients with single ventricle physiology and aortopulmonary collateral vessels. AB - OBJECTIVES: Patients with single ventricle congenital heart disease often form aortopulmonary collateral vessels via an unclear mechanism. To gain insights into the pathogenesis of aortopulmonary collateral vessels, we correlated angiogenic factor levels with in vitro activity and angiographic aortopulmonary collateral assessment and examined whether patients with single ventricle physiology have increased angiogenic factors that can stimulate endothelial cell sprouting in vitro. METHODS: In patients with single ventricle physiology (n = 27) and biventricular acyanotic control patients (n = 21), hypoxia-inducible angiogenic factor levels were measured in femoral venous and arterial plasma at cardiac catheterization. To assess plasma angiogenic activity, we used a 3-dimensional in vitro cell sprouting assay that recapitulates angiogenic sprouting. Aortopulmonary collateral angiograms were graded using a 4-point scale. RESULTS: Compared with controls, patients with single ventricle physiology had increased vascular endothelial growth factor (artery: 58.7 +/- 1.2 pg/mL vs 35.3 +/- 1.1 pg/mL, P < .01; vein: 34.8 +/- 1.1 pg/mL vs 21 +/- 1.2 pg/mL, P < .03), stromal derived factor 1-alpha (artery: 1901.6 +/- 1.1 pg/mL vs 1542.6 +/- 1.1 pg/mL, P < .03; vein: 2092.8 pg/mL +/- 1.1 vs 1752.9 +/- 1.1 pg/mL, P < .02), and increased arterial soluble fms-like tyrosine kinase-1, a regulatory vascular endothelial growth factor receptor (612.3 +/- 1.2 pg/mL vs 243.1 +/- 1.2 pg/mL, P < .003). Plasma factors and sprout formation correlated poorly with aortopulmonary collateral severity. CONCLUSIONS: We are the first to correlate plasma angiogenic factor levels with angiography and in vitro angiogenic activity in patients with single ventricle disease with aortopulmonary collaterals. Patients with single ventricle disease have increased stromal-derived factor 1-alpha and soluble fms like tyrosine kinase-1, and their roles in aortopulmonary collateral formation require further investigation. Plasma factors and angiogenic activity correlate poorly with aortopulmonary collateral severity in patients with single ventricles, suggesting complex mechanisms of angiogenesis. PMID- 26611748 TI - Active clearance of chest drainage catheters reduces retained blood. AB - OBJECTIVE: Chest tubes are used to clear blood from around the heart and lungs after heart surgery, but they can be obstructed by a blood clot, leading to retained blood syndrome (RBS). We sought to examine the frequency of RBS and associated morbidity, and to determine the influence of a preventative active chest tube clearance (ATC) protocol on these outcomes. METHODS: A multidisciplinary team developed a simple protocol to institute ATC to preventatively clear chest tubes of clot during the first 24 hours after heart surgery. An extensive educational in-service was performed before universal implementation (phase 1). We retrospectively compared data collected prospectively from 1849 patients before universal implementation (phase 0) with data from 256 patients collected prospectively after universal implementation (phase 2), and then used propensity matching for outcomes assessment. RESULTS: In propensity-matched patients, 19.9% of patients had interventions for RBS (phase 0). After the implementation of ATC (phase 2), the percent of patients with interventions for RBS was reduced to 11.3%, representing a 43% reduction in RBS (P = .0087). These patients had a 33% reduced incidence of postoperative atrial fibrillation from 30% (78 out of 256) in phase 0 to 20% (52 out of 256) in phase 2. (P = .013). CONCLUSIONS: ATC is associated with a reduced need for interventions for RBS and postoperative atrial fibrillation. Our findings underscore the importance of maintaining chest tube patency in the early hours after cardiac surgery. PMID- 26611749 TI - Pleurectomy decortication for mesothelioma: The procedure of choice when possible. PMID- 26611751 TI - Why few older adults participate in complex motor skills: a qualitative study of older adults' perceptions of difficulty and challenge. AB - BACKGROUND: Maintaining neuromotor fitness across the life course is imperative. It can reduce falls in older individuals and improve/maintain physical and cognitive functioning. Complex motor skills (CMS) are involved in many physical activities (e.g., ball games, dance), which can improve neuromotor fitness. However, few older adults participate in CMS. This study aimed to understand how older adults perceive the degree of difficulty and challenge, using Gentile's taxonomy of motor skills as a framework. METHODS: Six focus groups (FGs) were conducted with older adults (aged 61-92 years; N = 36) using a semi-structured question guide, to explore older adults' perceptions of difficulty and challenges associated with physical activity types. FGs were conducted in three villages and community groups in Sydney, Australia. Verbatim transcripts were coded inductively following a grounded theory approach to analysis to discover categories and concepts based on participants' views. RESULTS: Older adults perceived physical effort and pace as influencing difficulty where as challenging activities were not found to hinder older adults' willingness to participate. Other challenges in performing activities were attributed to: skill level, environment conditions (e.g., pool versus ocean swimming) and variations influencing complexity. Social and interpersonal issues, such as embarrassment, rapport with instructors, prior experience/ familiarity, in addition to physical effort, were other central features of older adults' perceptions of physical activities. Themes that appeared to increase the likelihood of participation in CMS were: age appropriate modification; enjoyment; social aspects; past experience; and having experienced instructors. CONCLUSIONS: This study offers recommendations for increasing participation in CMS. Modifying activities to suit ability and age and increasing exposure during the life span may help maintain participation into old age. Gentile's taxonomy provides an appropriate framework for classifying activities as simple or complex, which were recognised by participants on a descriptive level. Existing and new sports, which have been modified for old age, should be made available to older adults. Within the motor learning literature, the focus on older adults is limited. If activity complexity translates to improved cognitive abilities as well as improved individual neuromotor performance, the challenge of modifying activities to suit older adults' preferences needs to be addressed. PMID- 26611750 TI - Does grafting coronary arteries with only moderate stenosis affect long-term mortality? AB - OBJECTIVE: Stenting coronary arteries with non-ischemia-producing moderate stenosis leads to worse outcomes than leaving them unstented. We sought to determine whether grafting coronary arteries with angiographically moderate stenosis is associated with worse long-term survival than leaving them ungrafted. METHODS: From 1972 to 2011, 55,567 patients underwent primary isolated coronary artery bypass grafting (CABG); 8531 had a single coronary artery with moderate (50%-69%) stenosis, bypassed in 6598 (77%) and not bypassed in 1933 (23%). These arteries were grafted with internal thoracic arteries (ITAs) in 1806 patients (27%) and with saphenous veins (SVs) in 4625 (70%). Mean follow-up for all-cause mortality was 13.0 +/- 9.7 years. RESULTS: Survival was similar for patients with and without a graft to the moderately stenosed coronary artery (P = .3): 97%, 76%, 43%, and 18% at 1, 10, 20, and 30 years among patients receiving no graft; 97%, 74%, 41%, and 18% among those receiving an SV graft; and 98%, 82%, 51%, and 23% among those receiving an ITA graft. After adjusting for patient characteristics, SV grafting versus nongrafting of moderately stenosed coronary arteries was associated with similar long-term mortality (P = .2), whereas ITA grafting was associated with 22% lower long-term mortality (hazard ratio 0.78; 68% confidence interval 0.75-0.82; P < .0001). CONCLUSIONS: Grafting coronary arteries with angiographically moderate stenosis is not harmful. Instead, ITA grafting of such coronary arteries is associated with lower long-term mortality. Thus, after placing the first ITA to the left anterior descending, the second ITA should be placed to the second most important coronary artery, even if it is moderately stenosed. PMID- 26611752 TI - Efficacy of doxorubicin-transferrin conjugate in apoptosis induction in human leukemia cells through reactive oxygen species generation. AB - BACKGROUND: Doxorubicin (DOX) is a small molecular cytotoxic agent that can be transferred efficiently to cancer cells by nanocarriers. This anthracycline antibiotic serves as an effective anti-neoplastic drug against both hematological and solid malignancies. Here, we set out to assess the capacity of a novel doxorubicin - transferrin conjugate (DOX-TRF) to provoke apoptosis in human normal and leukemia cells through free radicals produced via a redox cycle of doxorubicin (DOX) when released from its conjugate. METHODS: After DOX-TRF exposure, we determined the time-course of apoptotic and necrotic events, the generation of reactive oxygen species (ROS), changes in mitochondrial membrane potential, as well as alterations in cytochrome c levels and intracellular calcium concentrations in human leukemia-derived cell lines (CCRF-CEM, K562 and its doxorubicin-resistant derivative K562/DOX) and normal peripheral blood derived mononuclear cells (PBMC). RESULTS: We found that DOX-TRF can induce apoptosis in all leukemia-derived cell lines tested, which was associated with morphological changes and decreases in mitochondrial membrane potential. In comparison to free DOX treated cells, we observed a time-dependency between a higher level of ROS generation and a higher drop in mitochondrial membrane potential, particularly in the doxorubicin-resistant cell line. In addition, we found that the apoptotic cell death induced by DOX-TRF was directly associated with a release of cytochrome c from the mitochondria and an increase in intracellular calcium level in all human leukemia-derived cell lines tested. CONCLUSIONS: Our data indicate that DOX-TRF is considerably more cytotoxic to human leukemia cells than free DOX. In addition, we show that DOX-TRF can effectively produce free radicals, which are directly involved in apoptosis induction. PMID- 26611753 TI - A ternary complex comprising FAK, PTPalpha and IP3 receptor 1 functionally engages focal adhesions and the endoplasmic reticulum to mediate IL-1-induced Ca2+ signalling in fibroblasts. AB - Ca(2+) release is tightly sequestered in eukaryotic cells to enable fine spatio temporal control of signalling but how Ca(2+) release from the endoplasmic reticulum (ER) is linked to cell adhesions is not defined. We examined the spatial restriction of Ca(2+) release through the inositol 1,4,5-triphosphate receptor 1 (IP3R1) in response to interleukin-1 (IL-1) and the functions of the adhesion-associated proteins, focal adhesion kinase (FAK) and protein tyrosine phosphatase-alpha (PTPalpha). In cultured fibroblasts IL-1 treatment promoted co localization of PTPalpha and FAK with the ER and increased association of IP3R1 with PTPalpha and FAK at focal adhesions (FAs). GST pull-down assays of purified proteins demonstrated that PTPalpha and FAK directly interacted with IP3R1. These interactions depended on the focal adhesion-targeting (FAT) and band4.1-ezrin radixin-moesin (FERM) domains of FAK. PTPalpha was required for the association of IP3R1 with Src, which mediated IP3R1 phosphorylation and consequently ER Ca(2+) release. Collectively, these data indicate that PTPalpha and FAK, which are enriched in FAs, interact with IP3R1 at adjacent ER sites to spatially sequester IL-1-induced Ca(2+) signalling. PMID- 26611754 TI - Nurse-Led Programs to Facilitate Enrollment to Children's Oncology Group Cancer Control Trials. AB - The progress made over the past 50 years in disease-directed clinical trials has significantly increased cure rates for children and adolescents with cancer. The Children's Oncology Group (COG) is now conducting more studies that emphasize improving quality of life for young people with cancer. These types of clinical trials are classified as cancer control (CCL) studies by the National Cancer Institute and require different resources and approaches to facilitate adequate accrual and implementation at COG institutions. Several COG institutions that had previously experienced problems with low accruals to CCL trials have successfully implemented local nursing leadership for these types of studies. Successful models of nurses as institutional leaders and "champions" of CCL trials are described. PMID- 26611755 TI - Hydroxyurea in Pediatric Patients With Sickle Cell Disease: What Nurses Need to Know. AB - Sickle cell disease (SCD) is an inherited disorder in which sickled red blood cells occlude the small vessels of the body, reducing oxygen delivery to tissues and ultimately negatively affecting many of the body's major organs. Hydroxyurea has proven beneficial in the treatment of SCD and prevention of disease-related complications. The 2014 guidelines put forth by the National Heart, Lung, and Blood Institute recommend hydroxyurea treatment in infants 9 months and older, children, and adolescents with SCD-SS or SCD-Sbeta(0) thalassemia regardless of clinical severity. This is a change from the 2002 guidelines in which hydroxyurea was recommended for adolescents and children with SCD-SS or SCD-Sbeta(0) thalassemia with frequent episodes of pain, a history of acute chest syndrome, severe and symptomatic anemia or other severe vaso-occlusive events. Nurses play a critical role in working with patients and families to provide education, guidance, and support to improve compliance to mitigate the long-term effects of SCD. PMID- 26611756 TI - Factors Affecting Health-Related Quality of Life in Children Undergoing Curative Treatment for Cancer: A Review of the Literature. AB - BACKGROUND: Health-related quality of life (HRQoL) is an important measure to evaluate a child's reported treatment experience. Although there are numerous studies of HRQoL in children undergoing curative cancer treatment, there is limited literature on factors that influence this. OBJECTIVE: To review published studies that describe the HRQoL and associated factors in children undergoing curative cancer treatment. METHOD: Full-text publications in English from January 2005 to March 2013 were searched in PubMed, PsychINFO, and CINAHL for children <=18 years of age undergoing curative cancer treatment. HRQoL-associated factors were categorized as cancer diagnosis, treatment, child, family, and community. RESULTS: Twenty-six studies met the inclusion criteria. The most frequently used generic and cancer-specific instruments were PedsQL (Pediatric Quality of Life Inventory) Generic and PedsQL Cancer, respectively. Cancer diagnosis and treatment were the most frequently identified variables; fewer studies measured family and community domains. Gender, treatment intensity, type of cancer treatments, time in treatment, and cancer diagnosis were correlated with HRQoL. CONCLUSION: Our study highlights the need to develop interventions based on diagnosis and treatment regimen to improve the HRQoL in children undergoing curative cancer treatment. PMID- 26611757 TI - Monoclonal antibodies specific to heat-treated porcine blood. AB - BACKGROUND: Porcine blood is potentially being utilized in food as a binder, gelling agent, emulsifier or colorant. However, for certain communities, the usage of animal blood in food is strictly prohibited owing to religious concerns and health reasons. This study reports the development of monoclonal antibodies (MAbs) against heat-treated soluble proteins (HSPs) of autoclaved porcine blood; characterization of MAbs against blood, non-blood and plasma from different animal species using qualitative indirect non-competitive enzyme-linked immunosorbent assay (ELISA); and immunoblotting of antigenic components in HSPs of porcine blood. RESULTS: Fifteen MAbs are specific to heat-treated and raw porcine blood and not cross-reacted with other animal blood and non-blood proteins (meat and non-meat). Twelve MAbs are specific to porcine plasma, while three MAbs specific to porcine plasma are cross-reacted with chicken plasma. Immunoblotting revealed antigenic protein bands (~60, ~85-100 and ~250 kDa) in porcine blood and plasma recognized by the MAbs. CONCLUSION: Selection of MAbs that recognized 60 kDa HSPs of porcine blood and plasma as novel monoclonal antibodies would be useful for detection of porcine plasma in processed food using the immunoassay method. (c) 2015 Society of Chemical Industry. PMID- 26611758 TI - Purification and characterization of a new beta-lactamase OXA-205 from Pseudomonas aeruginosa. AB - BACKGROUND: We have identified a novel class 1 integron (1503 bp), named In671 in a clinical Pseudomonas aeruginosa isolate. Integron sequence analysis revealed two gene cassettes, one coding for a new OXA-type beta-lactamase designated as OXA-205 and the other coding for the aadB gene that is responsible for aminoglycoside resistance. The 266 amino acid sequence of OXA-205 revealed that this beta-lactamase belongs to the Ambler class D showing highest sequence homology to the OXA-2 sub-lineage. Our objective was to purify and characterize beta-lactamase OXA-205. METHODS: Escherichia coli cells were transformed with a plasmid containing cloned bla OXA-205 gene from P. aeruginosa. Purification of overproduced OXA-205 consisted of a single ion-exchange chromatography step. SDS PAGE and isoelectric focusing were performed to determine the molecular mass and pI, respectively. Size-exclusion chromatography was undertaken to determine the OXA-205 oligomerization state. Substrate hydrolysis reactions were employed to assess enzyme kinetic parameters. RESULTS: Purification of OXA-205 yielded the enzyme with >95 % purity (as verified by SDS-PAGE). Approximate yield of the protein was estimated to be 20 mg per liter of culture. OXA-205 had a pI at 8.1, molecular mass of 26 kDa and a monomeric native structure. Kinetic analysis revealed that OXA-205 hydrolyzed narrow spectrum substrates, including ampicillin, carbenicillin, oxacillin, penicillin G, cefazolin and cefuroxime. Additionally, we observed a substrate inhibition profile towards carbenicillin and oxacillin, but not with ampicillin or penicillin G. Our results also show that OXA-205 conferred unusually high (among class D beta-lactamases) resistance towards inhibition by NaCl. CONCLUSIONS: OXA-205 can be considered a narrow spectrum monomeric beta-lactamase that demonstrates unusually high resistance profile towards inhibition by NaCl. PMID- 26611759 TI - The 'bother' of obstructed defecation. AB - OBJECTIVE: To examine the relationship of visual analog scale (VAS) 'bother' scores for obstructed defecation (OD) with demographic data, physical examination and sonographic findings of the posterior compartment. METHODS: All patients seen at a urogynecology clinic between January and October 2013 were included. Patients were diagnosed with OD if they had any of the following: incomplete bowel emptying, straining with bowel movement or need for digitation. Patients used a VAS to rate OD bother on a scale of 0-10 (0, no bother; 10, worst imaginable bother). For each patient, a comprehensive history was obtained, the International Continence Society Pelvic Organ Prolapse Quantification was performed and four-dimensional translabial ultrasound volumes were recorded on maximal Valsalva maneuver. Linear and multiple regression models were used to correlate bother VAS scores with demographic, clinical and sonographic findings. RESULTS: Among 265 patients included in the analysis, 61% had OD symptoms with a mean VAS bother score of 5.6. OD bother scores were associated with a history of previous prolapse surgery (P = 0.0001), previous hysterectomy (P = 0.0006), descent of the posterior compartment (Bp; P = 0.004) and hiatal dimensions (Pb and Gh + Pb; P = 0.006 and P = 0.004). OD bother was associated with the following sonographic findings: true rectocele (P = 0.01), depth of rectocele (P = 0.04), descent of rectal ampulla (P = 0.02), enterocele (P = 0.03) and rectal intussusception (P < 0.0001). CONCLUSIONS: VAS bother scores are associated with both clinical and sonographic measures of posterior compartment descent. Rectal intussusception was most likely to result in highly bothersome symptoms of OD. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26611760 TI - Perventricular device closure of a doubly committed juxtaarterial ventricular septal defect through a left parasternal approach: midterm follow-up results. AB - BACKGROUND: It is infeasible to occlude a doubly committed juxtaarterial ventricular septal defect (DCVSD) percutaneously. The previous perventricular device closure technique was performed through an inferior median sternotomy approach. The purpose of this study is to evaluate the feasibility, safety and efficacy of perventricular device closure of DCVSDs through a left parasternal approach. METHODS: Sixty-two patients, with the DCVSD of less than 6 mm in diameter, were enrolled in this study. The pericardial space was approached through a left parasternal mini-incision without entering into the pleural space. Two parallel pursestring sutures were placed on the right ventricular outflow tract for puncture. Under transesophageal echocardiographic guidance, a new delivery sheath loaded with the device was inserted into the right ventricle and advanced through the defect into the left ventricle. The device, connected with a device stay suture, was deployed subsequently. RESULTS: Successful device closure of the defects was achieved in 58/62 patients (94 %). The DCVSD failed to close in 4 (6 %) patients due to device-related aortic regurgitation and device migration. The mean DCVSD diameter was 3.4 +/- 1.0 mm (range, 2.0 to 6.0 mm). The implanted device size was 5.2 +/- 1.3 mm (range, 4 to 8 mm). Forty-four out of 58 patients (76 %) was implanted with an eccentric occluder. The mean intracardiac manipulation time was 14 +/- 13 min (range, 2 to 60 min). The procedure time was 66 +/- 15 min (range, 42 to 98 min). During the follow-up period of 180 to 1860 (median 880) days, new mild pulmonary regurgitation occurred in 2 patients. No other device-related complications were found. The complete closure rate was 95 % at discharge, 98 % at 1-, 6- and 12-month, 96 % at 2-year, and 100 % at 3-year follow-up. CONCLUSIONS: Perventricular device closure of a DCVSD through a left parasternal approach is feasible, safe, and efficacious in selected patients. This minimally invasive technique permits easy defect crossing and accurate device positioning. PMID- 26611761 TI - Matrix Metalloproteinases and Their Inhibitors in Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) is characterised by irreversible airflow limitation associated with chronic inflammation. Matrix metalloproteinases (MMPs) are proteolytic enzymes that contribute to the inflammatory response in COPD and degrade extracellular matrix components. Their enzymatic activity is inhibited by a four-member family of tissue inhibitors of metalloproteinases (TIMPs). In COPD, the MMP/TIMP network, mainly MMP-9, has been repeatedly observed to be dysregulated at both the local (lung) and systemic levels. Here, we review the findings reported in numerous cross-sectional studies with our primary focus on longitudinal observations in human COPD studies. The data from longitudinal prospective studies on the MMP/TIMP network may lead to the introduction of novel prognostic biomarkers into clinical management of COPD. We address the relationship between the systemic and local lung MMP/TIMP network in COPD patients and briefly describe the involvement of microRNAs. Finally, the role of the MMP/TIMP network in COPD treatment is discussed. PMID- 26611763 TI - Intraductal papillary mucinous neoplasm involving pancreaticobiliary maljunction and an aberrant pancreatic duct draining into the stomach: A case report and review of the literature. AB - Intraductal papillary mucinous neoplasms (IPMN) are characterized by the growth of epithelial components with mucin production in the main pancreatic duct, or a large branch. We report a case of intraductal papillary mucinous carcinoma (IPMC) of the pancreatic head, complicated by pancreaticobiliary maljunction (PBM) and an aberrant pancreatic duct draining into the stomach. A 50-year-old man with malaise and jaundice was found to have a mass in the pancreatic head at a local hospital. He was clinically diagnosed with IPMC with invasion to the stomach and duodenum after extensive endoscopic and radiological evaluation and a pancreaticoduodenectomy was performed. Histologically, most of the lesion exhibited proliferation of atypical glands, with irregular papillary and villoglandular structures lined by mucinous columnar epithelium, which extended intraepithelially along the dilated pancreatic duct wall. Tumor cells spread into the duodenal wall formed mucous nodules. The pancreatic ducts of this lesion uniquely showed two malformations; PBM, and an aberrant pancreatic duct opening to the gastric wall. This case was rare in the sense that IPMC extended into such unique structures. We report a case of IPMC with rare localization. The pathogenesis of this type of tumor in an abnormal pancreatic duct will be discussed. PMID- 26611764 TI - Highlights from Gastro Update Europe: Budapest, June 12-13, 2015. PMID- 26611765 TI - Quadruple therapy versus standard triple therapy for eradication of Helicobacter pylori in Kuwait. AB - BACKGROUND AND STUDY AIMS: Chronic infection caused by Helicobacter pylori (H. pylori) is associated with chronic gastritis, peptic ulcer disease, and gastric cancer. Eradication of H. pylori reduces morbidity of chronic gastritis and incidence of gastric cancer in high-risk population. We aimed at testing the efficacy of clarithromycin-based triple therapy and bismuth-based quadruple therapy for eradicating H. pylori in patients with chronic gastritis in Kuwait. PATIENTS AND METHODS: A total of 218 dyspeptic patients from different countries who were proved to have chronic gastritis by endoscopy and gastric biopsy were enroled. All of them were naive to H. pylori eradication therapy. They were randomised into two groups: group A, received triple therapy (omeprazole, amoxicillin, and clarithromycin) for 10days; and group B, received quadruple therapy (omeprazole, bismuth subcitrate potassium, tetracycline, and metronidazole) for 10days. All patients were tested for eradication of H. pylori by carbon-13 urea breath test 4weeks after treatment. RESULTS: Total response rate of eradication therapy in both groups was 77.5% (n=169). However, group B (n=100) had a higher eradication rate (88%) than group A (n=118) (68.6%). H. pylori eradication rate was significantly higher in males (84.2%) than females (70.2%) in both groups (p<0.01). There were no differences in eradication rates with regard to median age or nationality. CONCLUSION: Bismuth-based quadruple therapy is more effective as a first-line therapy than clarithromycin-based triple therapy for eradicating H. pylori in patients with H. pylori-related chronic gastritis in Kuwait. PMID- 26611762 TI - Neurotrophic Factors and Their Potential Applications in Tissue Regeneration. AB - Neurotrophic factors are growth factors that can nourish neurons and promote neuron survival and regeneration. They have been studied as potential drug candidates for treating neurodegenerative diseases. Since their identification, there are more and more evidences to indicate that neurotrophic factors are also expressed in non-neuronal tissues and regulate the survival, anti-inflammation, proliferation and differentiation in these tissues. This mini review summarizes the characteristics of the neurotrophic factors and their potential clinical applications in the regeneration of neuronal and non-neuronal tissues. PMID- 26611766 TI - Network regularised Cox regression and multiplex network models to predict disease comorbidities and survival of cancer. AB - In cancer genomics, gene expression levels provide important molecular signatures for all types of cancer, and this could be very useful for predicting the survival of cancer patients. However, the main challenge of gene expression data analysis is high dimensionality, and microarray is characterised by few number of samples with large number of genes. To overcome this problem, a variety of penalised Cox proportional hazard models have been proposed. We introduce a novel network regularised Cox proportional hazard model and a novel multiplex network model to measure the disease comorbidities and to predict survival of the cancer patient. Our methods are applied to analyse seven microarray cancer gene expression datasets: breast cancer, ovarian cancer, lung cancer, liver cancer, renal cancer and osteosarcoma. Firstly, we applied a principal component analysis to reduce the dimensionality of original gene expression data. Secondly, we applied a network regularised Cox regression model on the reduced gene expression datasets. By using normalised mutual information method and multiplex network model, we predict the comorbidities for the liver cancer based on the integration of diverse set of omics and clinical data, and we find the diseasome associations (disease-gene association) among different cancers based on the identified common significant genes. Finally, we evaluated the precision of the approach with respect to the accuracy of survival prediction using ROC curves. We report that colon cancer, liver cancer and renal cancer share the CXCL5 gene, and breast cancer, ovarian cancer and renal cancer share the CCND2 gene. Our methods are useful to predict survival of the patient and disease comorbidities more accurately and helpful for improvement of the care of patients with comorbidity. Software in Matlab and R is available on our GitHub page: https://github.com/ssnhcom/NetworkRegularisedCox.git. PMID- 26611767 TI - Two-Phase Electrospinning to Incorporate Polyelectrolyte Complexes and Growth Factors into Electrospun Chitosan Nanofibers. AB - Growth factors are potent signaling proteins for tissue engineering, but they are susceptible to loss of activity when exposed to solvents used for polymer processing. This work explores preservation of fibroblast growth factor-2 (FGF-2) activity in chitosan nanofibers using two-phase electrospinning via a compound coaxial needle and from a water-in-oil emulsion FGF-2 in aqueous poly(vinyl alcohol) is added on either the inside (A/O) or the outside (O/A) of an organic chitosan phase, using the compound needle. FGF-2 is further stabilized by complexation to heparin-based nanoparticles. The emulsion method does not result in detectable incorporation of FGF-2. The A/O fibers incorporate the highest amount of FGF-2. Nanoparticle-stabilized FGF-2 in A/O nanofibers is most active toward bone-marrow stromal cells. PMID- 26611768 TI - Dual-Targeting Nanovesicles for In Situ Intracellular Imaging of and Discrimination between Wild-type and Mutant p53. AB - p53 is a tumor-suppressor protein related to the cell cycle and programmed cell apoptosis. Herein, dual-targeting nanovesicles are designed for in situ imaging of intracellular wild-type p53 (WTp53) and mutant p53 (MUp53). Nanovesicle encapsulated plasmonic gold nanoparticles (AuNPs) were functionalized with consensus DNA duplexes, and a fluorescein isothiocyanate (FITC)-marked anti-MUp53 antibody was conjugated to the nanovesicle surface. After entering the cytoplasm, the released AuNPs aggregated through recognition of WTp53 and the double stranded DNA. The color changes of AuNPs were observed using dark-field microscopy, which showed the intracellular WTp53 distribution. The MUp53 location was detected though the immunological recognition between FITC-labeled anti-MUp53 and MUp53. Thus, a one-step incubation method for the in situ imaging of intracellular WTp53 and MUp53 was obtained; this was used to monitor the p53 level under a drug treatment. PMID- 26611769 TI - Increased risk of A(H1N1)pdm09 influenza infection in UK pig industry workers compared to a general population cohort. AB - BACKGROUND: Pigs are mixing vessels for influenza viral reassortment, but the extent of influenza transmission between swine and humans is not well understood. OBJECTIVES: To assess whether occupational exposure to pigs is a risk factor for human infection with human and swine-adapted influenza viruses. METHODS: UK pig industry workers were frequency-matched on age, region, sampling month, and gender with a community-based comparison group from the Flu Watch study. HI assays quantified antibodies for swine and human A(H1) and A(H3) influenza viruses (titres >= 40 considered seropositive and indicative of infection). Virus specific associations between seropositivity and occupational pig exposure were examined using multivariable regression models adjusted for vaccination. Pigs on the same farms were also tested for seropositivity. RESULTS: Forty-two percent of pigs were seropositive to A(H1N1)pdm09. Pig industry workers showed evidence of increased odds of A(H1N1)pdm09 seropositivity compared to the comparison group, albeit with wide confidence intervals (CIs), adjusted odds ratio after accounting for possible cross-reactivity with other swine A(H1) viruses (aOR) 25.3, 95% CI (1.4-536.3), P = 0.028. CONCLUSION: The results indicate that A(H1N1)pdm09 virus was common in UK pigs during the pandemic and subsequent period of human A(H1N1)pdm09 circulation, and occupational exposure to pigs was a risk factor for human infection. Influenza immunisation of pig industry workers may reduce transmission and the potential for virus reassortment. PMID- 26611770 TI - Sparsity-weighted outlier FLOODing (OFLOOD) method: Efficient rare event sampling method using sparsity of distribution. AB - As an extension of the Outlier FLOODing (OFLOOD) method [Harada et al., J. Comput. Chem. 2015, 36, 763], the sparsity of the outliers defined by a hierarchical clustering algorithm, FlexDice, was considered to achieve an efficient conformational search as sparsity-weighted "OFLOOD." In OFLOOD, FlexDice detects areas of sparse distribution as outliers. The outliers are regarded as candidates that have high potential to promote conformational transitions and are employed as initial structures for conformational resampling by restarting molecular dynamics simulations. When detecting outliers, FlexDice defines a rank in the hierarchy for each outlier, which relates to sparsity in the distribution. In this study, we define a lower rank (first ranked), a medium rank (second ranked), and the highest rank (third ranked) outliers, respectively. For instance, the first-ranked outliers are located in a given conformational space away from the clusters (highly sparse distribution), whereas those with the third-ranked outliers are nearby the clusters (a moderately sparse distribution). To achieve the conformational search efficiently, resampling from the outliers with a given rank is performed. As demonstrations, this method was applied to several model systems: Alanine dipeptide, Met-enkephalin, Trp-cage, T4 lysozyme, and glutamine binding protein. In each demonstration, the present method successfully reproduced transitions among metastable states. In particular, the first-ranked OFLOOD highly accelerated the exploration of conformational space by expanding the edges. In contrast, the third-ranked OFLOOD reproduced local transitions among neighboring metastable states intensively. For quantitatively evaluations of sampled snapshots, free energy calculations were performed with a combination of umbrella samplings, providing rigorous landscapes of the biomolecules. PMID- 26611772 TI - In Defense of Theory. AB - Formal theories of mental representation have receded from the importance they had in the early days of cognitive science. I argue that such theories are crucial in any mental domain, not just for their own sake, but to guide experimental inquiry, as well as to integrate the domain into the mind as a whole. To illustrate the criteria of adequacy for theories of mental representation, I compare two theoretical approaches to language: classical generative grammar (Chomsky, 1965, 1981, 1995) and the parallel architecture (Jackendoff, 1997, 2002). The grounds for comparison include (a) the internal coherence of the theory across phonology, syntax, and semantics; (b) the relation of language to other mental faculties; (c) the relationship between grammar and lexicon; (d) relevance to theories of language processing; and (e) the possibility of languages with little or no syntax. PMID- 26611773 TI - Time of insemination relative to reaching activity threshold is associated with pregnancy risk when using sex-sorted semen for lactating Jersey cows. AB - The objective of this observational experiment was to determine the association between the interval from reaching activity threshold (AT) to artificial insemination (AI) with sex-sorted semen and the probability of pregnancy. Jersey cows (n = 678) from a commercial dairy herd were fitted with heat-rumination long distance collars (SCR Ltd., Netanya, Israel) at approximately 42 +/- 7 days postpartum. Cows were presynchronized with three injections of PGF2alpha given 14 days apart starting on Day 39 +/- 3 postpartum. Cows in estrus, based on tail paint removal, after 50 +/- 3 days postpartum were inseminated by one of three technicians with semen from one of six sires. Cows were examined for pregnancy at 31 +/- 3 and 66 +/- 3 days after insemination. Only cows inseminated in estrus and examined for pregnancy at 31 +/- 3 days after AI were used in the experiment (n = 419). A subsample of cows (n = 35) were examined by ultrasound every 8 hours after reaching AT to estimate the interval from reaching AT and ovulation. The mean (+/- standard error of the mean) interval from reaching AT to AI was 16.9 +/ 0.5 hours, whereas the interval from peak activity to AI was 9.8 +/- 0.5 hours. The length of high activity among cows diagnosed in estrus was 17.3 +/- 0.3 hours. The mean interval from reaching AT to ovulation was 25.7 +/- 1.2 hours. There was a quadratic effect of the interval between reaching AT and AI on probabilities of pregnancy at 31 +/- 3 (P = 0.07) and 66 +/- 3 (P = 0.15) days after AI. Pregnancy per AI at 66 +/- 3 days after AI was higher for cows inseminated between 23 and 41 hours after the onset of estrus (<= 3 hours = 20.0%, 4-12 hours = 27.1%, 13-22 hours = 39.1%, 23-41 hours = 45.6%, and >= 42 = 40.0%). Insemination of lactating Jersey cows with sex-sorted semen closer to expected ovulation yielded the highest probability of pregnancy. PMID- 26611771 TI - The use of multiphase nonlinear mixed models to define and quantify long-term changes in serum prostate-specific antigen: data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. AB - PURPOSE: To test the hypothesis that the pattern of prostate-specific antigen (PSA) change in men diagnosed with high-risk prostate cancer (PrCA) differs from the pattern evident in men diagnosed with low-risk PrCA or those with no evidence of PrCA. METHODS: A retrospective cohort study from which PSA measures were taken before PrCA diagnosis from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Data were fitted using a nonlinear regression model to estimate the adjusted absolute and relative (%) change of PSA. RESULTS: Data on 20,888 men with an average age of 61.61 years were included in the analysis. Of these, the 324 (1.55%) diagnosed with high-risk PrCA had a steeper and earlier transition into an exponential pattern of PSA change than the 1368 men diagnosed with low risk cancer. At 1 year before diagnosis and/or exit, the average absolute PSA rates were 0.05 ng/mL/year (0.05-0.05), 0.59 (0.52-0.66), and 2.60 (2.11-3.09) for men with no evidence of PrCA, men with low-risk PrCA and those with high-risk PrCA, respectively. CONCLUSIONS: The pattern of PSA change with time was significantly different for men who develop high-risk PrCA from those diagnosed with low-risk PrCA. Further research is required to validate this method and its utilization in PrCA screening. PMID- 26611775 TI - Thromboelastography in the Management of Coagulopathy Associated With Ebola Virus Disease. AB - Here, we describe the first use of thromboelastography (TEG) in the management of 2 cases of Ebola virus disease. Early in their illness, both patients had evidence of a consumptive coagulopathy. As this resolved, TEG demonstrated that both developed a marked hypercoagulable state, which was treated with low molecular-weight heparin. PMID- 26611774 TI - Robust Reconstitution of Tuberculosis-Specific Polyfunctional CD4+ T-Cell Responses and Rising Systemic Interleukin 6 in Paradoxical Tuberculosis Associated Immune Reconstitution Inflammatory Syndrome. AB - BACKGROUND: The immunopathogenesis of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains unclear. We determined the association between pathogen-specific T-cell responses and development of paradoxical TB-IRIS on antiretroviral therapy (ART). METHODS: This study was nested within a prospective cohort study of HIV-infected patients with active pulmonary tuberculosis and baseline CD4 counts <=125 cells/uL initiating ART. T cell immune activation (CD38, HLA-DR, and PD-1 expression), phenotype, and polyfunctional pathogen-specific cellular immune responses prior to and 4 weeks after ART initiation were determined by flow cytometry. Patients with TB-IRIS were compared to non-IRIS controls using chi(2) and rank-sum tests and logistic regression. RESULTS: TB-IRIS patients and controls had similar CD4 counts, levels of T-cell-associated immune activation, frequencies of T-cell memory subsets, and frequencies of interferon gamma (IFN-gamma(+))/interleukin 2 (IL-2(+))/tumor necrosis factor alpha (TNF-alpha(+)) CD4(+) T-cells prior to ART initiation. After ART initiation, cellular immune activation and T-cell subsets also were similar in TB-IRIS patients and controls. In contrast, TB-IRIS patients had significantly greater early increases in the frequency of tuberculosis-specific polyfunctional IFN-gamma(+)/IL-2(+)/TNF-alpha(+) CD4(+) T-cells on ART (P = .02); each quartile increase in the percentage of these cells was independently associated with a 2.8-fold increased risk of TB-IRIS (95% confidence interval, 1.1 to 7.5-fold). In a secondary analysis, patients with TB-IRIS had rapid, concomitant increases in tuberculosis-specific adaptive immune responses and interleukin 6 (IL-6) levels, whereas controls with similarly rapid increases in cellular immune function had IL-6 levels that tended to decrease on ART. CONCLUSIONS: Rapid expansion of tuberculosis-specific polyfunctional CD4(+) T cell responses, likely linked to increases in IL-6, is associated with development of paradoxical TB-IRIS. PMID- 26611776 TI - Emergency Department Screening for Hepatitis C Virus: Geographic Reach and Spatial Clustering in Central Alabama. AB - Hepatitis C virus (HCV) infection is a growing problem, disproportionately affecting those born between 1945 and 1965. Here, we demonstrate the wide geographic reach and surveillance potential of emergency department-based screening and identify areas of elevated HCV infection in central Alabama that were socioeconomically disadvantaged compared with surrounding communities. PMID- 26611777 TI - A Randomized Clinical Trial of Single-Dose Versus Weekly Dalbavancin for Treatment of Acute Bacterial Skin and Skin Structure Infection. AB - BACKGROUND: Acute bacterial skin and skin structure infections (ABSSSIs) are a cause of significant morbidity and therapy can be a burden to the healthcare system. New antibiotics that simplify treatment and avoid hospitalization are needed. This study compared the safety and efficacy of a single intravenous infusion of 1500 mg of dalbavancin to the 2-dose regimen. METHODS: This study was a randomized, double-blind trial in patients aged >18 years with ABSSSIs. Patients were randomized to dalbavancin 1500 mg either as a single intravenous (IV) infusion or 1000 mg IV on day 1 followed 1 week later by 500 mg IV. The primary endpoint was a >=20% reduction in the area of erythema at 48-72 hours in the intent-to-treat population. Noninferiority was to be declared if the lower limit of the 95% confidence interval (CI) on the difference in the outcomes was greater than -10%. Clinical outcome was also assessed at days 14 and 28. RESULTS: Six hundred ninety-eight patients were randomized. Demographic characteristics were similar on each regimen, although there were more patients with methicillin resistant Staphylococcus aureus (MRSA) at baseline on the 2-dose regimen (36/210 [17.1%] vs 61/220 [27.7%]). Dalbavancin delivered as a single dose was noninferior to a 2-dose regimen (81.4% vs 84.2%; difference, -2.9% [95% CI, -8.5% to 2.8%]). Clinical outcomes were also similar at day 14 (84.0% vs 84.8%), day 28 (84.5% vs 85.1%), and day 14 in clinically evaluable patients with MRSA in a baseline culture (92.9% vs 95.3%) in the single- and 2-dose regimens, respectively. Treatment-emergent adverse events occurred in 20.1% of the single dose patients and 19.9% on the 2-dose regimen. CONCLUSIONS: A single 1500-mg infusion of dalbavancin is noninferior to a 2-dose regimen, has a similar safety profile, and removes logistical constraints related to delivery of the second dose. CLINICAL TRIALS REGISTRATION: NCT02127970. PMID- 26611779 TI - Drug-Drug Interactions With Novel All Oral Interferon-Free Antiviral Agents in a Large Real-World Cohort. AB - BACKGROUND: With the approval of direct-acting antivirals (DAAs), the management of drug-drug interactions (DDIs) has become an important challenge while treating individuals with hepatitis C. To date, the potential of causing DDIs for the recently approved DAAs has not been systematically investigated. We aimed to assess the clinical significance of DDI between the regular outpatient medications and DAA therapies in a large real-world cohort. METHODS: Overall, 261 hepatitis C virus monoinfected patients who were selected for DAA therapy at 2 intervals between 2011 and 2014 were asked about their regular outpatient medications. The potential for DDIs between all these drugs and sofosbuvir/ribavirin, ledipasvir/sofosbuvir, sofosbuvir/daclatasvir, sofosbuvir/simeprevir, ombitasvir/paritaprevir/ritonavir +/- dasabuvir as well as boceprevir and telaprevir triple therapy was assessed using www.hep druginteractions.org and the relevant prescribing information. RESULTS: The 261 patients took a median number of 2 drugs (range 0-15); 20% of patients did not take any medication. Sofosbuvir/ribavirin had the lowest risk to cause a potentially significant DDI (9.6%). In contrast, for ombitasvir/paritaprevir/ritonavir +/- dasabuvir potentially significant DDIs could be expected in 66.3% of the patients. Significant DDIs for sofosbuvir/simeprevir would be expected in 31.4%, for sofosbuvir/daclatasvir in 36.8%, and for sofosbuvir/ledipasvir in 40.2%. Proton pump inhibitors, thyroid hormones, and dihydropyridine derivatives were frequently used and presented a risk of interacting with the antiviral regimen. CONCLUSIONS: A significant number of patients are at risk for DDIs if treated with the recently approved DAA regimens. A careful evaluation of potential DDI is essential to prevent adverse effects or unnecessary risk of treatment failure. PMID- 26611778 TI - The Emergence of Zoonotic Onchocerca lupi Infection in the United States--A Case Series. AB - This case-series describes the 6 human infections with Onchocerca lupi, a parasite known to infect cats and dogs, that have been identified in the United States since 2013. Unlike cases reported outside the country, the American patients have not had subconjunctival nodules but have manifested more invasive disease (eg, spinal, orbital, and subdermal nodules). Diagnosis remains challenging in the absence of a serologic test. Treatment should be guided by what is done for Onchocerca volvulus as there are no data for O. lupi. Available evidence suggests that there may be transmission in southwestern United States, but the risk of transmission to humans is not known. Research is needed to better define the burden of disease in the United States and develop appropriately targeted prevention strategies. PMID- 26611780 TI - Prevention of Infectious Mastitis by Oral Administration of Lactobacillus salivarius PS2 During Late Pregnancy. AB - BACKGROUND: Previous studies have shown that oral administration of lactobacilli can be an efficient approach to treat lactational infectious mastitis. In this trial, we have evaluated the potential of Lactobacillus salivarius PS2 to prevent this condition when orally administered during late pregnancy to women who had experienced infectious mastitis after previous pregnancies. METHODS: In this study, 108 pregnant women were randomly assigned to one of 2 groups. Those in the probiotic group (n = 55) ingested daily 9 log10 colony-forming units of L. salivarius PS2 from approximately week 30 of pregnancy until delivery, whereas those in the placebo group (n = 53) received a placebo. The occurrence of mastitis was evaluated during the first 3 months after delivery. RESULTS: Globally, 44 of 108 women (41%) developed mastitis; however, the percentage of women with mastitis in the probiotic group (25% [n = 14]) was significantly lower than in the control group (57% [n = 30]). When mastitis occurred, the milk bacterial counts in the probiotic group were significantly lower than those obtained in the placebo group. CONCLUSIONS: Oral administration of L. salivarius PS2 during late pregnancy appears to be an efficient method to prevent infectious mastitis in a susceptible population. CLINICAL TRIALS REGISTRATION: NCT01505361. PMID- 26611781 TI - New Diagnostic Techniques Highlight the Need for Negative Controls. PMID- 26611782 TI - Home Screening for Bacterial Vaginosis to Prevent Sexually Transmitted Diseases. AB - BACKGROUND: Longitudinal studies have consistently found a significant association between bacterial vaginosis (BV) and acquisition of sexually transmitted diseases. However, there are limited prospective data to confirm these findings. METHODS: We conducted a prospective, randomized, open-label trial of home screening and treatment of young women with asymptomatic BV who were also at high risk for sexually transmitted diseases. These women were screened every 2 months for 12 months and randomized to treatment with oral metronidazole 500 mg twice daily for 7 days or observation alone. The primary outcome was the incidence of gonorrhea and/or chlamydia. RESULTS: A total of 1365 subjects were enrolled in the study across 10 sites. Adherence with mailing specimens obtained at home was excellent in both groups (84%-88%). The incidence of gonorrhea and/or chlamydia was 19.1 per 100 person-years (95% confidence interval, 15.1-22.1) for the treatment group and 18.5 per 100 person-years (15.1-22.8) for the observation arm, a difference that was not statistically significant. CONCLUSIONS: Young women were very amenable to home screening for BV, gonorrhea, and chlamydia. Treatment of asymptomatic BV with 1 week of oral metronidazole did not decrease the incidence of gonorrhea and/or chlamydia. CLINICAL TRIALS REGISTRATION: NCT00667368. PMID- 26611783 TI - Cognitive deficits in bipolar disorder: from acute episode to remission. AB - Considerable evidence demonstrates that neuropsychological deficits are prevalent in bipolar disorder during both acute episodes and euthymia. However, it is less clear whether these cognitive disturbances are state- or trait-related. We here present the first longitudinal study employing a within-subject pre- and post testing examining acutely admitted bipolar patients (BP) in depression or mania and during euthymia, aiming to identify cognitive performance from acute illness to remission. Cognitive performance was measured during acute episodes and repeated after at least 3 months of remission. To do so, 55 BP (35 depressed, 20 hypo-/manic) and 55 healthy controls (HC) were tested with a neuropsychological test battery (attention, working memory, verbal memory, executive functioning). The results showed global impairments in acutely ill BP compared to HC: depressed patients showed a characteristic psychomotor slowing, while manic patients had severe deficits in executive functioning. Twenty-nine remitted BP could be measured in the follow-up (dropout rate 48 %), whose cognitive functions partially recovered, whereas working memory and verbal memory were still impaired. However, we found that subthreshold depressive symptoms and persisting sleep disturbances in euthymic BP were associated with reduced speed, deficits in attention and verbal memory, while working memory was correlated with psychotic symptoms (lifetime). This result indicates working memory as trait related for a subgroup of BP with psychotic symptoms. In contrast, attention and verbal memory are negatively influenced by state factors like residual symptoms, which should be more considered as possible confounders in the search of cognitive endophenotypes in remitted BP. PMID- 26611784 TI - Association of RBP4 genetic variants with childhood obesity and cardiovascular risk factors. AB - BACKGROUND: Recent data suggest that retinol-binding protein 4 (RBP4) gene variants could be associated with a risk of obesity and its co-morbidities, such as metabolic syndrome, which increases the risk of developing type 2 diabetes mellitus and cardiovascular disease. OBJECTIVES: The present study examined the potential association of RBP4 single nucleotide polymorphisms (SNPs) with childhood obesity and its metabolic complications. METHODS: Four RBP4 SNPs, rs3758538 (3944A>C), rs3758539 (4406G>A), rs12265684 (12177G>C) and rs34571439 (14684T>G), were genotyped in a population of 180 Spanish Caucasian children (97 obese and 83 normal-weight children). Association of RBP4 SNPs with obesity, metabolic risk factors (blood pressure, triglycerides, high-density lipoprotein cholesterol, insulin resistance) and markers of vascular inflammation, such as high-sensitive C-reactive protein (hs-CRP), was tested. RESULTS: We found SNP rs3758538 to be associated with obesity (p = 0.007). Specifically, each copy of the minor allele C was associated with an increased risk of obesity, by more than twofold, in respect of being homozygous for the major allele A (odds ratio = 2.4; 95% confidence interval = 1.2-4.8). The rs3758538 and rs34571439 RBP4 SNPs correlated with plasma RBP4 levels. The SNPs rs12265684 and rs34571439 correlated with plasma triglyceride levels. The rs34571439 was also associated to hs-CRP levels. Marginal association of RBP4 SNPs with plasma high-density lipoprotein levels (rs34571439), blood pressure (rs12265684) and insulin resistance (rs3758539) was also observed. CONCLUSIONS: These findings suggest that childhood obesity may be associated with variations in RBP4 gene. The presence of selective SNPs in the RBP4 gene may account for metabolic complications. PMID- 26611785 TI - Sense of coherence does not moderate the relationship between the perceived impact of stress on health and self-rated health in adults with congenital heart disease. AB - BACKGROUND: Adults with congenital heart disease seem to be more distressed than their healthy counterparts, which might render them even more susceptible to developing detrimental health outcomes. Previous research has confirmed the relationship between the perceived impact of stress on health and self-rated health. However, it remains unknown whether sense of coherence, a person's capacity to cope with stressors, moderates this relationship. AIM: This cross sectional study aims to explore: the relationship between demographic and clinical characteristics, sense of coherence, and the perceived impact of stress on health; the relationship between the perceived impact of stress on health and self-rated health; and the moderating effect of sense of coherence in a sample of adults with congenital heart disease. METHODS: Patients were recruited from the database of congenital and structural cardiology of a university hospital. The analytic sample included 255 patients (median age 35 years; 50% men). Data were obtained using self-report questionnaires and through medical record view. Univariate analyses and multiple regression analysis were conducted. RESULTS: The perceived impact of stress on health was negatively associated with sense of coherence (P<0.01), but there was no significant association with demographic or clinical characteristics. The perceived impact of stress on health and self-rated health were negatively associated (P<0.001), but sense of coherence did not moderate this relationship. CONCLUSIONS: Our findings support the need for further research on the perceived impact of stress on health. Such insights can be valuable for developing interventions aimed at reducing the negative health consequences of stress in patients with congenital heart disease. PMID- 26611786 TI - Student learning in interprofessional practice-based environments: what does theory say? AB - Student learning in interprofessional practice-based environments has garnered significant attention in the last decade, and is reflected in a corresponding increase in published literature on the topic. We review the current empirical literature with specific attention to the theoretical frameworks that have been used to illustrate how and why student learning occurs in interprofessional practice-based environments. Our findings show there are relatively few theoretical-based studies available to guide educators and researchers alike. We recommend a more considered and consistent use of theory and suggest that professional identity and socio-cultural frameworks offer promising avenues for advancing understandings of student learning and professional identity development within interprofessional practice-based environments. PMID- 26611788 TI - Postpancreatectomy Hemorrhage After Pancreatic Surgery in Patients Receiving Anticoagulation or Antiplatelet Agents. AB - Background Postpancreatectomy hemorrhage (PPH) is a serious complication after pancreatic surgery. In this study, we evaluated PPH and thromboembolic complications after pancreatic surgery in patients with perioperative antithrombotic treatment. Methods Medical records of patients undergoing pancreatic surgery were reviewed retrospectively. Patients receiving thromboprophylaxis were given either bridging therapy with unfractionated heparin or continued on aspirin as perioperative antithrombotic treatment according to clinical indications and published recommendations. The International Study Group of Pancreatic Surgery definition of PPH was used. Risk factors associated with PPH were assessed by multivariate analysis. Results Thirty-four of 158 patients received perioperative antithrombotic treatment; this group had a significantly higher PPH rate (29.4% vs 6.5%, P = .001) and mortality (11.8% vs 2.4%, P = .039) than patients not receiving thromboprophylaxis. Multivariate analysis revealed that perioperative antithrombotic treatment was the only independent risk factor for PPH after pancreatic surgery (odds ratio 4.77; 95% CI 1.61-14.15; P = .005). Conclusions Perioperative antithrombotic treatment is an independent risk factor for PPH in patients undergoing pancreatic surgery, although this treatment effectively prevents postoperative thromboembolic events. PMID- 26611787 TI - Immunosenescence of the CD8(+) T cell compartment is associated with HIV infection, but only weakly reflects age-related processes of adipose tissue, metabolism, and muscle in antiretroviral therapy-treated HIV-infected patients and controls. AB - BACKGROUND: Despite effective antiretroviral therapy (ART), HIV-infected patients exhibit systemic inflammation, early onset of age-related diseases, and features of immunosenescence. The role of inflammation in the development of age-related diseases is widely recognized. However, the role of immunosenescence is not well established. Studying immunosenescence in HIV-infection could give insight into its role in ageing processes. In this cross-sectional study, we aimed to investigate whether ART-treated HIV-infected patients exhibit immunosenescence; and whether immunosenescence is associated with age-related processes of inflammation, metabolism, adipose tissue, and muscle. T cell immunosenescence and exhaustion were assessed by flow cytometry analysis of CD8 (+) cells from 43 ART treated HIV-infected patients (HIV(+)) and ten Controls using markers of differentiation: CD27/CD28; maturation: CD27/CD45RA; senescence: killer cell lectin-like receptor G1 (KLRG1); and exhaustion: programmed death-1 (PD-1). Relationships between CD8 (+) T cell immunosenescence, exhaustion, and age related processes were assessed using linear regressions. RESULTS: HIV-infection was strongly associated with more highly differentiated and mature CD8 (+) T cell phenotypes. PD-1 and KLRG1 expression did not differ between HIV(+) and Controls, but depended on differentiation and maturation stages of the cells. CD8 (+) T cell maturation was associated with age. KLRG1 expression was associated with age, metabolic syndrome, visceral adipose tissue, and high muscle mass. PD-1 expression was not associated with age-related parameters. CONCLUSIONS: HIV infection strongly affected CD8 (+) T cell differentiation and maturation, whereas age-related processes were only weakly associated with immune parameters. Our findings suggest that, in contrast to inflammation, immunosenescence appears to be highly dependent on HIV-infection and is only to a small extent associated with age-related parameters in well-treated HIV-infection. PMID- 26611789 TI - Surgical Treatment of Diverticulitis: Hand-Assisted Laparoscopic Resection Is Predominantly Used for Complex Cases and Is Associated With Increased Postoperative Complications and Prolonged Hospitalization. AB - Introduction Laparoscopic (LAP) colectomy is now the "gold" standard for diverticulitis; the role of hand-assisted LAP (HAL) and Open methods today is unclear. This study assessed the elective use of these methods for diverticulitis. Methods A retrospective review of demographic, comorbidity (Carlson Comorbidity Index [CCI]), resection type, and short-term outcomes was carried out. Results There were 125 (44.5%) LAP, 125 (44.5%) HAL, and 31 (11%) Open cases (overall N = 281). The mean age, body mass index, and percentage of high-risk patients (CCI score >2) of the HAL group were greater (P < .05) than the LAP group (vs Open, P = ns). The Open group's mean age and percent with CCI >2 was greater when compared with the LAP group (P < .05). More Open (P < .05) and HAL patients had complex disease (Open, 63%; HAL, 40%, LAP, 22%) and were diverted (Open, 35%; HAL, 10%; LAP, 3%). Time to bowel movement was not different; however, there was a stepwise increase in median length of stay (LOS; days) from the LAP (5 days) to HAL (6 days) to Open group (7 days) (P < .05 for all). The LAP complication rate (22.4%) was lower (P < .05) than the HAL (42.4%) or Open groups' (45.2%) rates. The LAP surgical site infection rate (5.6%) was lower (P < .05) than the HAL (12.8%) or Open groups (19.6%). Conclusion The HAL and Open groups had more high risk, complex disease, diverted, and older patients than the LAP group; likewise, the overall complication rate and LOS was higher in the HAL and Open groups. Use of HAL methods likely contributed to the high minimally invasive surgery utilization rate (89%). PMID- 26611791 TI - Confluentibacter lentus gen. nov., sp. nov., isolated from the junction between the ocean and a freshwater lake. AB - A Gram-stain-negative, non-flagellated, non-gliding, aerobic and rod-shaped bacterium, designated HJM-3T, was isolated from the place where the ocean and a freshwater lake meet at Hwajinpo on the East Sea, South Korea, and subjected to a polyphasic taxonomic study. The novel strain grew optimally at 30-35 degrees C, at pH 7.0-7.5 and in the presence of 1.0-2.0 % (w/v) NaCl. A neighbour-joining phylogenetic tree based on 16S rRNA gene sequences showed that strain HJM-3T clustered with the type strain of Yeosuana aromativorans and the proposed type strain of Mariniflexile ostreae. Strain HJM-3T exhibited the highest 16S rRNA gene sequence similarity values (each 95.1 %) to these representative strains of Y. aromativorans and M. ostreae, and sequence similarities of less than 94.9 % to the type strains of other recognized species. Strain HJM-3T contained menaquinone 6 as the predominant isoprenoid quinone, and iso-C15 : 0, iso-C15 : 1 G and iso C17 : 0 3-OH as the major fatty acids. The major polar lipids detected in strain HJM-3T were phosphatidylethanolamine and one unidentified lipid. The DNA G+C content of strain HJM-3T was 34.7 mol%. The fatty acid and polar lipid profiles and DNA G+C content of strain HJM-3T could be distinguished from those of the phylogenetically related taxa. On the basis of the phylogenetic, chemotaxonomic and other phenotypic properties, strain HJM-3T is considered to represent a novel genus and species within the family Flavobacteriaceae, for which the name Confluentibacter lentus gen. nov., sp. nov., is proposed. The type strain is HJM 3T ( = KCTC 42777T = NBRC 111588T). PMID- 26611790 TI - A population pharmacokinetic model for R- and S-citalopram and desmethylcitalopram in Alzheimer's disease patients with agitation. AB - The citalopram for Alzheimer's disease trial evaluated citalopram for the management for agitation in Alzheimer's disease patients. Sparse data was available from this elderly patient population. A nonlinear mixed effects population pharmacokinetic modeling approach was used to describe the pharmacokinetics of R- and S-citalopram and their primary metabolite (desmethylcitalopram). A structural model with 4 compartments (one compartment/compound) with linear oral absorption and elimination described the data adequately. Overall, the model showed that clearance of the R-enantiomer was slower than the clearance of the S-enantiomer. Without accounting for any patient specific covariates, the population estimate of the metabolic clearance of citalopram was 8.6 (R-citalopram) and 14 L/h (S-citalopram). The population estimate of the clearance of desmethylcitalopram was 23.8 (R-Dcit) and 38.5 L/h (S-Dcit). Several patient-specific covariates were found to have a significant effect on the pharmacokinetics of R,S-citalopram and desmethylcitalopram. A significant difference in the metabolic clearance of R-citalopram between males and females (13 vs 9.05 L/h) was identified in this analysis. Both R- and S citalopram metabolic clearance decreased with age. Additionally, consistent with literature reports S-citalopram metabolic clearance increased with increasing body weight and was significantly influenced by CYPC19 genotype, with a difference of 5.8 L/h between extensive/rapid and intermediate/poor metabolizers. R,S-desmethylcitalopram clearance increased with increasing body weight. This model may allow for the opportunity to delineate the effect of R- and S citalopram on pharmacodynamics outcomes related to the management of agitation in Alzheimer's disease. PMID- 26611792 TI - The time horizon matters: results of an exploratory study varying the timeframe in time trade-off and standard gamble utility elicitation. AB - INTRODUCTION: The purpose of this study was to examine whether the time horizon of time trade-off (TTO) and standard gamble (SG) utility assessment influences utility scores and discrimination between health states. METHODS: In two phases, UK general population participants rated three osteoarthritis health states in TTO and SG procedures with two time horizons: (1) 10-year and (2) a time horizon derived from self-reported additional life expectancy (ALE). The two time horizons were compared in terms of mean utilities and discrimination among health states. RESULTS: In Phase 1, the 10-year tasks were completed by 80 participants, 35 of whom also completed utility assessment with the ALE. In Phase 2, all 101 participants completed procedures with both time horizons. Utility scores tended to be lower with the ALE than the 10-year, a difference that was statistically significant for two health states with SG in Phase 1 (P < 0.05), two health states with TTO in Phase 2 (P < 0.01), and one health state with SG in Phase 2 (P < 0.001). In Phase 1, rates of discrimination between mild and moderate osteoarthritis health states were significantly higher with the ALE than the 10 year (TTO: P = 0.03; SG: P = 0.001). This pattern of discrimination was similar in Phase 2. DISCUSSION: Results suggest that the time horizon could influence utility scores and discrimination among health states. When designing utility evaluations, researchers should carefully consider the time horizon so that the value of health states is accurately represented in cost-utility models. PMID- 26611793 TI - Is higher nursing home quality more costly? AB - Widespread issues regarding quality in nursing homes call for an improved understanding of the relationship with costs. This relationship may differ in European countries, where care is mainly delivered by nonprofit providers. In accordance with the economic theory of production, we estimate a total cost function for nursing home services using data from 45 nursing homes in Switzerland between 2006 and 2010. Quality is measured by means of clinical indicators regarding process and outcome derived from the minimum data set. We consider both composite and single quality indicators. Contrary to most previous studies, we use panel data and control for omitted variables bias. This allows us to capture features specific to nursing homes that may explain differences in structural quality or cost levels. Additional analysis is provided to address simultaneity bias using an instrumental variable approach. We find evidence that poor levels of quality regarding outcome, as measured by the prevalence of severe pain and weight loss, lead to higher costs. This may have important implications for the design of payment schemes for nursing homes. PMID- 26611794 TI - Mandarin Chinese vowel-plus-tone identification in noise: Effects of language experience. AB - Several studies found better English vowel identification in English multi-talker babble (MTB) and temporally-modulated (TM) noise, but not in quiet condition for native Chinese listeners in the US (CNU) with the US residency of 1-3 years than native Chinese listeners in China (CNC) with no residency history in English speaking countries. Two possible explanations were proposed: (1) CNU listeners used temporal dips of noise more efficiently than CNC listeners; and (2) CNU listeners had less informational masking of MTB than their CNC peers. The current study explored whether the difference in noise processing between CNU and CNC listeners was also presented for their native speech perception. Chinese vowel plus-tone identifications were measured for CNU and CNC in quiet, stationary and TM noise, babble-modulated noise, and MTB. The identification scores of CNU listeners were significantly higher than CNC listeners in most noisy backgrounds, whereas both groups had the same performance in quiet. Moreover, compared with CNC listeners, CNU listeners gained greater masking releases from the temporal modulation in TM noise at low SNRs, whereas no significant difference was found in informational masking between the two groups. In conclusion, the native English experience may improve native Chinese listeners' capacity to use temporal glimpses in TM noise, possibly depending on the modulation frequency and depth, while it may not improve their ability to resist the informational masking of babble when perceiving their native speech. PMID- 26611795 TI - Expanded endothelial progenitor cells mitigate lung injury in septic mice. AB - Endothelial progenitor cells (EPCs) improve survival and reduce organ failure in cecal ligation and puncture-induced sepsis; however, expanded EPCs may represent an even better approach for vascular repair. To date, no study has compared the effects of non-expanded EPCs (EPC-NEXP) with those of expanded EPCs (EPC-EXP) and mesenchymal stromal cells of human (MSC-HUMAN) and mouse (MSC-MICE) origin in experimental sepsis. One day after cecal ligation and puncture sepsis induction, BALB/c mice were randomized to receive saline, EPC-EXP, EPC-NEXP, MSC-HUMAN or MSC-MICE (1 * 10(5)) intravenously. EPC-EXP, EPC-NEXP, MSC-HUMAN, and MSC-MICE displayed differences in phenotypic characterization. On days 1 and 3, cecal ligation and puncture mice showed decreased survival rate, and increased elastance, diffuse alveolar damage, and levels of interleukin (IL)-1beta, IL-6, IL-10, tumor necrosis factor-alpha, vascular endothelial growth factor, and platelet-derived growth factor in lung tissue. EPC-EXP and MSC-HUMAN had reduced elastance, diffuse alveolar damage, and platelet-derived growth factor compared to no-cell treatment. Tumor necrosis factor-alpha levels decreased in the EPC EXP, MSC-HUMAN, and MSC-MICE groups. IL-1beta levels decreased in the EPC-EXP group, while IL-10 decreased in the MSC-MICE. IL-6 levels decreased both in the EPC-EXP and MSC-MICE groups. Vascular endothelial growth factor levels were reduced regardless of therapy. In conclusion, EPC-EXP and MSC-HUMAN yielded better lung function and reduced histologic damage in septic mice. PMID- 26611797 TI - Human error largely to blame for MSF hospital attack, US investigators say. PMID- 26611796 TI - Normal human CD4(+) helper T cells express Kv1.1 voltage-gated K(+) channels, and selective Kv1.1 block in T cells induces by itself robust TNFalpha production and secretion and activation of the NFkappaB non-canonical pathway. AB - TNFalpha is a very potent and pleiotropic pro-inflammatory cytokine, essential to the immune system for eradicating cancer and microorganisms, and to the nervous system, for brain development and ongoing function. Yet, excess and/or chronic TNFalpha secretion causes massive tissue damage in autoimmune, inflammatory and neurological diseases and injuries. Therefore, many patients with autoimmune/inflammatory diseases receive anti-TNFalpha medications. TNFalpha is secreted primarily by CD4(+) T cells, macrophages, monocytes, neutrophils and NK cells, mainly after immune stimulation. Yet, the cause for the pathologically high and chronic TNFalpha secretion is unknown. Can blocking of a particular ion channel in T cells induce by itself TNFalpha secretion? Such phenomenon was never revealed or even hypothesized. In this interdisciplinary study we discovered that: (1) normal human T cells express Kv1.1 voltage-gated potassium channel mRNA, and the Kv1.1 membrane-anchored protein channel; (2) Kv1.1 is expressed in most CD4(+)CD3(+) helper T cells (mean CD4(+)CD3(+)Kv1.1(+) T cells of 7 healthy subjects: 53.09 +/- 22.17 %), but not in CD8(+)CD3(+) cytotoxic T cells (mean CD8(+)CD3(+)Kv1.1(+) T cells: 4.12 +/- 3.04 %); (3) electrophysiological whole cell recordings in normal human T cells revealed Kv currents; (4) Dendrotoxin-K (DTX-K), a highly selective Kv1.1 blocker derived from snake toxin, increases the rate of rise and decay of Kv currents in both resting and activated T cells, without affecting the peak current; (5) DTX-K by itself induces robust TNFalpha production and secretion by normal human T cells, without elevating IFNgamma, IL 4 and IL-10; (6) intact Ca(2+) channels are required for DTX-induced TNFalpha secretion; (7) selective anti-Kv1.1 antibodies also induce by themselves TNFalpha secretion; (8) DTX-K activates NFkappaB in normal human T cells via the unique non-canonical-pathway; (9) injection of Kv1.1-blocked human T cells to SCID mice, causes recruitment of resident mouse cells into the liver, alike reported after TNFalpha injection into the brain. Based on our discoveries we speculate that abnormally blocked Kv1.1 in T cells (and other immune cells?), due to either anti Kv1.1 autoimmune antibodies, or Kv1.1-blocking toxins alike DTX-K, or Kv1.1 blocking genetic mutations, may be responsible for the chronic/excessive TNFalpha in autoimmune/inflammatory diseases. Independently, we also hypothesize that selective block of Kv1.1 in CD4(+) T cells of patients with cancer or chronic infectious diseases could be therapeutic, since it may: a. augment beneficial secretion and delivery of TNFalpha to the disease-affected sites; b. induce recruitment and extravasation of curative immune cells and factors; c. improve accessibility of drugs to the brain and few peripheral organs thanks to TNFalpha induced increased permeability of organ's barriers. PMID- 26611798 TI - Health Insurance Expansion and Treatment of Pancreatic Cancer: Does Increased Access Lead to Improved Care? AB - BACKGROUND: Pancreatic cancer is increasingly common and poised to become the second leading cause of cancer deaths by the year 2020. Surgical resection is the only chance for cure, yet significant disparities in resection rates exist by insurance status. The 2006 Massachusetts health care reform serves as natural experiment to evaluate the unknown impact of health insurance expansion on treatment of pancreatic cancer. STUDY DESIGN: Using the Agency for Healthcare Research and Quality's State Inpatient Databases, this cohort study examines nonelderly, adult patients with no insurance, private coverage, or government subsidized insurance plans, who were admitted with pancreatic cancer in Massachusetts and 3 control states. The primary end point was change in pancreatic resection rates. Difference-in-difference models were used to show the impact of Massachusetts health care reform on resection rates for pancreatic cancer, controlling for confounding factors and secular trends. RESULTS: Before the Massachusetts reform, government-subsidized and self-pay patients had significantly lower rates of resection than privately insured patients. The 2006 Massachusetts health reform was associated with a 15% increased rate of admission with pancreatic cancer (p = 0.043) and a 67% increased rate of surgical resection (p = 0.043) compared with control states. Measured disparities in likelihood of resection by insurance status decreased in Massachusetts and remained unchanged in control states. CONCLUSIONS: The 2006 Massachusetts health care reform was associated with increased resection rates for pancreatic cancer compared with control states. Our findings provide hopeful evidence that increased insurance coverage can help improve equity in pancreatic cancer treatment. Additional studies are needed to evaluate the longevity of these findings and generalizability in other states. PMID- 26611799 TI - Patient-Reported Outcomes Accurately Measure the Value of an Enhanced Recovery Program in Liver Surgery. AB - BACKGROUND: Enhanced recovery (ER) pathways have become increasingly integrated into surgical practice. Studies that compare ER and traditional pathways often focus on outcomes confined to inpatient hospitalization and rarely assess a patient's functional recovery. The aim of this study was to compare functional outcomes for patients treated on an Enhanced Recovery in Liver Surgery (ERLS) pathway vs a traditional pathway. STUDY DESIGN: One hundred and eighteen hepatectomy patients rated symptom severity and life interference using the validated MD Anderson Symptom Inventory preoperatively and postoperatively at every outpatient visit until 31 days after surgery. The ERLS protocol included patient education, narcotic-sparing anesthesia and analgesia, diet advancement, restrictive fluid administration, early ambulation, and avoidance of drains and tubes. RESULTS: Seventy-five ERLS pathway patients were clinically comparable with 43 patients simultaneously treated on a traditional pathway. The ERLS patients reported lower immediate postoperative pain scores and experienced fewer complications and decreased length of stay. As measured by symptom burden on life interference, ERLS patients were more likely to return to baseline functional status in a shorter time interval. The only independent predictor of faster return to baseline interference levels was treatment on an ERLS pathway (p = 0.021; odds ratio = 2.62). In addition, ERLS pathway patients were more likely to return to intended oncologic therapy (95% vs 87%) at a shorter time interval compared to patients on the traditional pathway (44.7 vs 60.2 days). CONCLUSIONS: In oncologic liver surgery, enhanced recovery's primary mechanism of action is reduction in life interference by postoperative surgical symptoms, allowing patients to return sooner to normal function and adjuvant cancer therapies. PMID- 26611800 TI - Stenting and Curative Resection: In Reply to Falk. PMID- 26611801 TI - Stenting in the Neoadjuvant Setting. PMID- 26611802 TI - Feasibility of Angiotensin Inhibition for Obese Trauma Patients. PMID- 26611803 TI - Angiotensin Inhibition Warrants Focused Investigation: In Reply to Fujita. PMID- 26611805 TI - Comparison of two live Bacillus species as feed additives for improving in vitro fermentation of cereal straws. AB - This study was performed in a 2 * 4 factorial arrangement to explore and compare the effects of inclusion of two live Bacillus additives (B. licheniformis and B. subtilis) at four doses (0, 0.25 * 10(7), 0.50 * 10(7) and 0.75 * 10(7) colony forming units (cfu)) on in vitro gas production kinetics, fiber degradation, methane production and ruminal fermentation characteristics of maize stover and rice straw by mixed rumen microorganisms in dairy cows. The pH, concentrations of ammonia nitrogen (NH3-N) and isovalerate were increased (P < 0.05), while the methane (CH4) production, ratio of acetate to propionate, and total volatile fatty acids (TVFA) concentration were decreased (P < 0.05) by the supplementation of B. licheniformis compared with that of B. subtilis. Adding B. licheniformis and B. subtilis raised (P < 0.05) or numerically raised the maximum gas production, while decreasing (P < 0.05) or numerically lowering pH and concentrations of most volatile fatty acids. The addition of B. licheniformis increased (P < 0.05) the NH3-N concentration but reduced CH4 production and ratio of acetate to propionate (P < 0.05), while the NH3 -N concentration was decreased (P < 0.05), and the CH4 production and ratio of acetate to propionate were increased by that of B. subtilis compared to the control. Results obtained in this research suggest that B. licheniformis would be preferred as a live Bacillus additive in comparison with B. subtilis, and its optimal dose should be 0.25 * 10(7) cfu/500 mg substrates. PMID- 26611807 TI - AuPt Alloy on TiO2: A Selective and Durable Catalyst for L-Sorbose Oxidation to 2 Keto-Gulonic Acid. AB - Pt nanoparticles were prepared by a sol immobilization route, deposited on supports with different acid/base properties (MgO, activated carbon, TiO2 , Al2O3, H-Mordenite), and tested in the selective oxidation of sorbose to 2-keto gulonic acid (2-KGUA), an important precursor for vitamin C. In general, as the basicity of the support increased, a higher catalytic activity occurred. However, in most cases, a strong deactivation was observed. The best selectivity to 2-KGUA was observed with acidic supports (TiO2 and H-Mordenite) that were able to minimize the formation of C1/C2 products. We also demonstrated that, by alloying Pt to Au, it is possible to enhance significantly the selectivity of Pt-based catalysts. Moreover, the AuPt catalyst, unlike monometallic Pt, showed good stability in recycling because of the prevention of metal leaching during the reaction. PMID- 26611806 TI - The use of microbial-earthworm ecofilters for wastewater treatment with special attention to influencing factors in performance: A review. AB - With the unique advantages of lower operational and maintenance cost, the use of microbial-earthworm ecofilters (MEEs) for the wastewater treatment has been increasing rapidly in the recent years. This paper provided an overview of the research activities on the use of MEEs for removing pollutants from various wastewater throughout the world. However, the long-term effective treatment performance and sustainable operation of this system still remain a challenge since the treatment performance would be affected by design parameters, operational conditions, and environmental factors. In order to promote the treatment performance, therefore, this paper also provided and summarized the influencing factors of pollutants removal in MEEs. The design parameters and operational conditions of MEEs include earthworm species and load, filter media type, hydraulic loading rate, nutrient load, packing bed height, chemical factors and temperature. Lastly, this review highlighted the further research on these issues to improve performance and sustainability of MEEs. PMID- 26611808 TI - Mechanisms of long-term weight regain in patients undergoing sleeve gastrectomy. AB - OBJECTIVES: Weight regain after bariatric surgery may be associated with behavioral, metabolic, or mechanical factors alone or in combination. The aim of this study was to investigate which factors are related to weight regain in the long-term after sleeve gastrectomy (SG). METHODS: A retrospective case-control study with 40 patients undergoing SG (32 women, 8 men; age 42.9 +/- 10.7 y; preoperative body mass index 35 +/- 2.8 kg/m(2)), was performed. Patients were grouped according percentile->50% (cases) or <50% (controls)-of weight regain (%WR cutoff: 25% of weight loss). Weight history, anthropometry, glucose, insulin, homeostasis model assessment-estimated insulin resistance (HOMA-IR), thyroid-stimulating hormone, resting energy expenditure, body composition, dietary survey, psychological test, and physical activity were recorded. Residual gastric capacity was estimated using a radiologic method. RESULTS (MEDIAN [P25 P75]): The evaluation was conducted 38.5 mo (34-41 mo) after SG. Percent weight regain ranged from 2.7% to 129.2% (25.4% [13-37.1]). Patients in the higher %WR group had a greater residual gastric volume (252.7 +/- 108.4 versus 148.5 +/- 25.3; P < 0.05) and the estimated volume was significantly correlated with %WR (r = 0.673; P = 0.023). Significantly higher body mass index (P = 0.001), resting energy expenditure (P = 0.04), fasting insulin (P = 0.01), and HOMA-IR (P = 0.02) were observed in the higher %WR group. A higher fat intake and a trend toward higher total energy intake were observed in the group with greater %WR. Clinical or borderline levels of anxiety were more frequently observed in the higher %WR group (70% versus 30%; P = 0.01). CONCLUSIONS: Results from the present study demonstrated that the most important factor associated with long-term weight regain after SG was residual gastric volume. Additional prospective studies with larger numbers of patients are necessary to confirm our results. PMID- 26611810 TI - Synthesis of 3-substituted isoindolin-1-ones via a tandem desilylation, cross coupling, hydroamidation sequence under aqueous phase-transfer conditions. AB - A simple and expedient method for the synthesis of 3-methylene-isoindolin-1-ones 4 under aqueous phase-transfer conditions has been developed. Starting from 2 iodobenzamides 1 and (silyl)alkynes, the products are obtained in high yields and short reaction times (30 min) with the use of inexpensive CuCl/PPh3 catalyst system in the presence of n-Bu4NBr (TBAB) as a phase-transfer agent. Terminal alkynes are conveniently "unmasked" upon in situ desilylation under the reaction conditions. Alkynes possessing heterocyclic moieties were also found as amenable substrates. Furthermore, a one-pot process starting from 2-iodobenzamides 1, aryl halides (bromides or iodides) and trimethylsilylacetylene (TMSA) as a convenient acetylene surrogate was also shown to be feasible under Pd/Cu catalysis. PMID- 26611811 TI - Landscape effects on the abundance and larval diet of the polyphagous pest Helicoverpa armigera in cotton fields in North Benin. AB - BACKGROUND: The noctuid Helicoverpa armigera is one of the key cotton pests in the Old World. One possible pest regulation method may be the management of host crop in the landscapes. For polyphagous pests such as H. armigera, crop diversity and rotations can offer sequential and alternate resources that may enhance abundance. We explore the impact of landscape composition and host crop diversity on the abundance and natal host plant use of H. armigera in northern Benin. RESULTS: Host plant diversity at the largest scale examined (500 m diameter) was positively correlated with H. armigera abundance. Host plant diversity and the cover of tomato crops were the most important variables in relation to high abundance of H. armigera. Host plant (cotton, maize, tomato, sorghum) proportions and C3 versus C4 plants did not consistently correlate positively with H. armigera abundance. Moth proportion derived from cotton-fed larvae was low, 15% in 2011 and 11% in 2012, and not significantly related to H. armigera abundance. CONCLUSION: Cotton crop cover was not significantly related to H. armigera abundance and may be considered as a sink crop. Landscape composition and sequential availability of host plants should be considered as keys factors for further studies on H. armigera regulation. (c) 2015 Society of Chemical Industry. PMID- 26611809 TI - Clinical and epidemiological features of leishmaniasis in northwestern-Argentina through a retrospective analysis of recent cases. AB - Leishmaniasis is a parasitic disease caused by hemoflagellates of the genus Leishmania and is transmitted to humans by the bite of infected phlebotomine sandflies. Depending on the Leishmania species, the disease has different clinical forms including cutaneous, mucocutaneous, and visceral manifestations. Previous studies performed in endemic zones of northwestern-Argentina, during epidemic outbreaks, have been important for detecting patients suffering from the acute phase of the disease, but have not given a complete representation of the clinical and epidemiological features in the region. Furthermore, due to the resurgence of leishmaniasis worldwide and in particular the large increase of international tourism to the region, it seems pertinent to update the current epidemiological and clinical profile of leishmaniasis in northwestern-Argentina. Here we present a retrospective analysis of 95 Leishmania positive cases, presenting between 2000 and 2014. Patients were derived from hospitals and diagnosed in our lab at the University of Salta, located in a non-endemic area in Salta, Argentina. We detected numerous extensive mucocutaneous cases (34/95, 35.8%) distinct from mucosal affected patients, some instances originating in locations with no previously reported human cases. Additionally patients suffering from concomitant diseases, besides leishmaniasis, were assessed. These included Chagas disease, syphilis, deep mycoses, tuberculosis, toxoplasmosis and intestinal parasitosis. This study updates the clinical and epidemiological features of leishmaniasis in northwestern-Argentina, and discusses the implications and management strategy for patients who acquire the disease in this region. PMID- 26611812 TI - Use of the cobas 4800 system for the rapid detection of toxigenic Clostridium difficile and methicillin-resistant Staphylococcus aureus. AB - The new cobas(r) Cdiff and cobas(r) MRSA/SA tests were compared with conventional methods for the rapid detection of toxigenic Clostridium difficile and methicillin-resistant Staphylococcus aureus. The final concordance between cobas Cdiff Test and GDH/toxin gene screening was 97.62% and between cobas MRSA/SA Test and chromogenic culture, 91.30%, respectively. PMID- 26611813 TI - Numerical simulation of the nonlinear ultrasonic pressure wave propagation in a cavitating bubbly liquid inside a sonochemical reactor. AB - We investigate the acoustic wave propagation in bubbly liquid inside a pilot sonochemical reactor which aims to produce antibacterial medical textile fabrics by coating the textile with ZnO or CuO nanoparticles. Computational models on acoustic propagation are developed in order to aid the design procedures. The acoustic pressure wave propagation in the sonoreactor is simulated by solving the Helmholtz equation using a meshless numerical method. The paper implements both the state-of-the-art linear model and a nonlinear wave propagation model recently introduced by Louisnard (2012), and presents a novel iterative solution procedure for the nonlinear propagation model which can be implemented using any numerical method and/or programming tool. Comparative results regarding both the linear and the nonlinear wave propagation are shown. Effects of bubble size distribution and bubble volume fraction on the acoustic wave propagation are discussed in detail. The simulations demonstrate that the nonlinear model successfully captures the realistic spatial distribution of the cavitation zones and the associated acoustic pressure amplitudes. PMID- 26611814 TI - Fast synthesize ZnO quantum dots via ultrasonic method. AB - Green emission ZnO quantum dots were synthesized by an ultrasonic sol-gel method. The ZnO quantum dots were synthesized in various ultrasonic temperature and time. Photoluminescence properties of these ZnO quantum dots were measured. Time resolved photoluminescence decay spectra were also taken to discover the change of defects amount during the reaction. Both ultrasonic temperature and time could affect the type and amount of defects in ZnO quantum dots. Total defects of ZnO quantum dots decreased with the increasing of ultrasonic temperature and time. The dangling bonds defects disappeared faster than the optical defects. Types of optical defects first changed from oxygen interstitial defects to oxygen vacancy and zinc interstitial defects. Then transformed back to oxygen interstitial defects again. The sizes of ZnO quantum dots would be controlled by both ultrasonic temperature and time as well. That is, with the increasing of ultrasonic temperature and time, the sizes of ZnO quantum dots first decreased then increased. Moreover, concentrated raw materials solution brought larger sizes and more optical defects of ZnO quantum dots. PMID- 26611816 TI - ERRATUM. PMID- 26611817 TI - Interplay of Exciton Coupling and Large-Amplitude Motions in the Vibrational Circular Dichroism Spectrum of Dehydroquinidine. AB - A detailed analysis of the computed structure, energies, vibrational absorption (VA) and circular dichroism (VCD) spectra of 30 low-energy conformers of dehydroquinidine reveals the existence of families of pseudo-conformers, the structures of which differ mostly in the orientation of a single O-H bond. The pseudo-conformers in a family are separated by very small energy barriers (i.e., 1.0 kcal mol(-1) or smaller) and have very different VCD spectra. First, we demonstrate the unreliable character of the Boltzmann factors predicted with DFT. Then, we show that the large differences observed between the VCD spectra of the pseudo-conformers in a family are caused by large-amplitude motions involving the O-H bond, which trigger the appearance/disappearance of strong VCD exciton coupling bands in the fingerprint region. This interplay between exciton coupling and large-amplitude-motion phenomena demonstrates that when dealing with flexible molecules with polar bonds, vibrational averaging of VCD spectra should not be neglected. In this regard, the dehydroquinidine molecule considered here is expected to be a typical example and not the exception to the rule. PMID- 26611815 TI - Synthetic pheromones and plant volatiles alter the expression of chemosensory genes in Spodoptera exigua. AB - Pheromone and plant odorants are important for insect mating, foraging food sources and oviposition. To understand the molecular mechanisms regulating pheromone and odorant signaling, we employed qRT-PCR to study the circadian rhythms of ABP, OBP, PBP, and OR gene expression in the beet armyworm, Spodoptera exigua and their responses after a pre-exposure to sex pheromone compounds or plant volatiles. The neuronal responses of male S. exigua to 20 chemical compounds were recorded at three specific time periods using the electroantennogram. The results showed a circadian rhythm in the expression profiles of some chemosensory genes in the antennae similar to their behavioral rhythm. The expression profiles of OR3, OR6, OR11, OR13, OR16, OR18, Orco, ABP2, OBP1, OBP7, and PBP1, and EAG responses to chemical compounds, as well as their circadian rhythm were significantly affected after exposure to synthetic sex pheromones and plant volatiles. These findings provide the first evidence that the gene expression of chemosensory genes and olfactory sensitivity to sex pheromones are affected by pre-exposing insects to pheromone compounds and plant volatiles. It helps to understand the molecular mechanisms underlying pheromone activity, and the application of sex pheromones and plant volatiles in mating disruption or mass trapping. PMID- 26611820 TI - An Unusual Case of Tricuspid Regurgitation. PMID- 26611821 TI - Trends, Predictors, and Outcomes of Stroke After Surgical Aortic Valve Replacement in the United States. AB - BACKGROUND: Postoperative stroke is a devastating complication after aortic valve replacement (AVR). Our objective was to use a large national database to identify the incidence of and risk factors for stroke after AVR, as well as to determine incremental mortality, resource use, and cost of stroke. METHODS: We identified 360,437 patients who underwent isolated surgical AVR between 1998 and 2011 from the National Inpatient Sample (NIH) database. Mean age was 66 +/- 32 years. Multivariable regression and propensity matching were used to identify risk factors and the effect of stroke on outcomes. Patients were stratified according to the Elixhauser comorbidity score (ECS) into low- (0-5), medium- (6-15), and high-risk (16+) categories. RESULTS: Stroke after AVR occurred in 5,092 (1.45%) patients. The incidence of stroke declined from 1.69% in 1999 to 0.94% in 2011 (p < 0.001). Increasing age and higher comorbidities were the main predictors of stroke (each p < 0.001). The highest-volume centers (>200 AVRs/y) had the lowest rate of stroke (1.2%). After multivariable adjustment, high-volume centers had lower odds of stroke in medium-risk (odds ratio [OR], 0.59; 95% confidence interval [CI], 0.37-0.94) and high-risk patients (OR, 0.39; 95% CI, 0.22-0.68) compared with the lowest-volume centers. For low-risk patients, volume was not associated with stroke. Patients who experienced stroke were hospitalized for 4 days longer, had an average of $10,496 higher costs, and had 2.74 (95% CI, 1.97 3.80) times higher odds of in-hospital mortality compared with those who did not experience stroke (all p < 0.001). CONCLUSIONS: The incidence of stroke after AVR has decreased but remains a significant cause of morbidity in medium- and high risk patients. Superior outcomes can be achieved in medium- to high-risk patients at high-volume centers. PMID- 26611822 TI - Prenatal interventions for congenital diaphragmatic hernia for improving outcomes. AB - BACKGROUND: Congenital diaphragmatic hernia (CDH), is an uncommon but severe condition in which there is a developmental defect in the fetal diaphragm, resulting in liver and bowel migrating to the chest cavity and impairing lung development and function for the neonate. This condition can be diagnosed during pregnancy and as such, is potentially amenable to in-utero prenatal intervention. Neonatal surgical repair is possible, but even with early surgical repair and improving neonatal management, neonatal morbidity and mortality is high. Prenatal interventions described to date have included maternal antenatal corticosteroid administration and fetal tracheal occlusion, with both methods aiming to improve lung growth and maturity. However surgical procedures have potential maternal complications, as the uterus and amniotic sac are breached in order to gain access to the fetus. OBJECTIVES: To compare the effects of prenatal versus postnatal interventions for CDH on perinatal mortality and morbidity, longer-term infant outcomes and maternal morbidity, and to compare the effects of different prenatal interventions with each other. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2015) and reference lists of retrieved studies. SELECTION CRITERIA: All published (including those published in abstract form), unpublished, and ongoing randomised controlled trials comparing prenatal and postnatal interventions for fetuses with CDH. Quasi RCTs were eligible for inclusion but none were identified. Trials using a cross over design are not eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors evaluated trials for inclusion and methodological quality without consideration of their results according to the stated eligibility criteria and extracted data independently. Data were checked for accuracy. MAIN RESULTS: We identified 11 studies for potential inclusion. Of those, we included three studies involving 97 women. Two additional studies are ongoing.Two trials examined in-utero fetal tracheal occlusion with standard (postnatal) care in fetuses with severe diaphragmatic hernia. Whilst the trials utilised fetal interventions that were similar, there were important differences in how access was gained to the fetus and in the timing and mode of delivery. Therefore, we did not combine these trials in meta-analysis and the results are examined in separate comparisons. One trial examined the effect of antenatal corticosteroids versus placebo. Overall, the methodological quality of the trials was variable and no data were available for a number of this review's secondary outcomes. In utero fetal occlusion by maternal laparotomy versus standard postnatal management (one trial, 24 women)For the primary infant outcome (perinatal mortality), there were no data suitable for inclusion in the analysis. There was no difference between groups in terms of long-term infant survival (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.66 to 1.69). In-utero fetal occlusion by minimally invasive fetoscopy versus standard postnatal management (one trial, 41 women)The primary infant outcome (perinatal mortality) was not reported. Minimally invasive fetoscopy was associated with a small reduction in the mean gestational age at birth (mean difference (MD) -1.80 weeks, 95% CI -3.13 to -0.47), but there was no clear difference in the risk of preterm birth before 37 weeks (RR 1.75, 95% CI 0.78 to 3.92). Long-term infant survival (three to six months) (RR 10.50, 95% CI 1.48 to 74.71) was increased with the intervention when compared with standard management, and there was a corresponding reduction in pulmonary hypertension (RR 0.58, 95% CI 0.36 to 0.93) associated with the intervention. There was no difference between groups in terms of preterm ruptured membranes (< 37 weeks) (RR 1.47, 95% CI 0.56 to 3.88) or maternal infectious morbidity (RR 3.14, 95% CI 0.14 to 72.92), and there were no maternal blood transfusions. Antenatal corticosteroids versus placebo (one trial, 32 women)We also included one trial (involving 32 women) examining the effect of antenatal corticosteroids versus placebo. There was no clear difference in the incidence of perinatal mortality (our primary infant outcome) between the group of women who received antenatal corticosteroids and the placebo control (RR 1.24, 95% CI 0.50 to 3.08). Data (mean only) were reported for two of our secondary outcomes (mechanical ventilation and days of hospital admission) but standard deviations (SDs) were not provided. For the purposes of this review and to permit further analysis we have estimated the SDs based on the reported P values reported in the trial report, although our estimation does assume that the SD is the same in both the intervention and control groups. There were no differences between the antenatal corticosteroid group and the placebo control in terms of days of mechanical ventilation (MD 18.00 days, 95% CI -14.77 to 50.77) or days of hospital admission (MD 17.00 days, 95% CI -13.93 to 47.93) . AUTHORS' CONCLUSIONS: There is currently insufficient evidence to recommend in-utero intervention for fetuses with CDH as a part of routine clinical practice. We identified three small studies, with only one study adequately reporting on the primary outcome of this review - perinatal mortality, and there were few data pertaining to many of this review's secondary outcomes.WIth regard to the administration of antenatal corticosteroids, there remains a gap in current research, and a large multicentre trial with adequate statistical power should be undertaken to answer this unresolved question. More studies are needed to further examine the effect of in utero fetal tracheal occlusion on important neonatal outcomes and long-term infant survival and health. Long-term follow-up is of particular importance, and should include morbidity and mortality measures. Further studies should examine the benefits of an in-utero intervention on subgroups with moderate and severe congenital diaphragmatic hernia. Indeed, there are three ongoing studies, being conducted by European, North and South American fetal medicine centres, which will contribute to this gap. Ongoing research and any implementation into clinical practice should include standardisation of the procedure, inclusion criteria and long-term childhood follow-up. PMID- 26611823 TI - Prevalence and subtype distribution of Blastocystis in healthy individuals in Sharjah, United Arab Emirates. AB - Blastocystis is estimated to be one of the most common parasites of the intestinal tract of humans, comprising multiple subtypes (ST). Meanwhile, the distribution of Blastocystis ST in many communities and countries remains unknown. In the present work, we aimed to identify the prevalence of Blastocystis and the ST distribution in human stool samples collected from healthy expatriates from different geographical regions and residing in Sharjah, United Arabian Emirates (UAE). A total of 133 samples were screened and subtyped using partial small subunit ribosomal RNA gene sequencing. Fifty-nine (44.4%) samples were identified as positive. Among these, 39 were successfully sequenced and subtyped. The ST distribution was as follows: ST3, 58.9% (23/39); ST1, 28.2% (11/39); and ST2, 7.6% (3/39). No correlation between geographic origin and infection (chi(2)=11.006; P=0.528) nor gender and infection (chi(2)=1.264; P=0.261) was observed. The data were compared with those available for other Middle Eastern and North African neighboring countries. This study is the first to provide data concerning the prevalence of Blastocystis and the frequency of various STs in the UAE, confirming the absence of ST4 and the commonness of ST1, ST2, and ST3 in this geographical region. PMID- 26611824 TI - Characterization of GII.4 noroviruses circulating among children with acute gastroenteritis in Pune, India: 2005-2013. AB - Genogroup II genotype 4 noroviruses (GII.4 NoVs), an important cause of sporadic childhood gastroenteritis worldwide, undergo continuous evolution leading to the periodic emergence of novel variants. The present study was undertaken for surveillance of GII.4 NoVs and identification and characterization of GII.4 variants circulating among children with sporadic gastroenteritis in Pune, India during 2005-2013. Among the 12 GII genotypes detected in the study, GII.4 was predominant. Sequencing and phylogenetic analysis of ORF2 (major capsid protein VP1 gene) of the GII.4 NoVs revealed circulation of seven GII.4 variants, Hunter_2004 (2005-2007), Yerseke_2006a (2006), DenHaag_2006b (2007), Osaka_2007 (2007-2009), Apeldoorn_2007 (2008), New Orleans_2009 (2008-2012) and Sydney_2012 (2013), with the Pune strains grouping with the contemporary global reference strains. The Hunter_2004, Osaka_2007 and New Orleans_2009 variants showed prolonged circulation, with the Hunter_2004 and New Orleans_2009 variants differentiating into temporally separated sub-clusters. Analysis of VP1 sequences and predicted structures of the GII.4 variants identified variant specific amino acid positions, particularly in and near (within 8A( degrees )) the epitopes A-E, displaying differences in the sequence and physicochemical characteristics of the different variants. Comparison with the reference strains of each of the GII.4 variants revealed up to 11 amino acid substitutions at the variant specific positions in the GII.4 strains from Pune. Amino acid variations were also noted among the strains of the same GII.4 variant in Pune. The strains of different sub clusters identified in the Hunter_2004 and New Orleans_2009 variants showed differences in sequence and physicochemical properties of either or all of the epitopes A, C and E. The study thus describes the temporal variations and diversity of the GII.4 strains in Pune and emphasizes continuous monitoring and analysis of the GII.4 variants. PMID- 26611825 TI - Correlation of phylogenetic clade diversification and in vitro infectivity differences among Cosmopolitan genotype strains of Chikungunya virus. AB - Cosmopolitan genotypes of Chikungunya virus caused the large-scale febrile disease outbreaks in the last decade in Asian and African continents. Molecular analyses of these strains had revealed significant genetic diversification and occurrence of novel mosquito-adaptive mutations. In the present study we looked into whether the genetic diversification has implications in the infectivity phenotype. A detailed sequence and phylogenetic analyses of these virus strains of Indian Ocean lineage from Kerala, South India from the years 2008 to 2013 identified three distinct genetic clades (I, II and III), which had presence of clade-specific amino acid changes. The E2 envelope protein of the strains from the years 2012 to 2013 had a K252Q or a novel K252H change. This site is reported to affect mosquito cell infectivity. Most of these strains also had the E2 G82R mutation, a mutation previously identified to increase mammalian cell infectivity, and a novel mutation E2 N72S. Positive selection was identified in four sites in the envelope proteins (E1 K211E, A226V and V291I; E2 K252Q/H). In infectivity analysis, we found that strains from clade III had enhanced cytopathogenicity in HEK293 and Vero cells than by strains representing other two clades. These two strains formed smaller sized plaques and had distinctly higher viral protein expression, infectious virus production and apoptosis induction in HEK293 cells. They had novel mutations R171Q in the nsP1; I539S in nsP2; N409T in nsP3; and N72S in E2. Our study identifies a correlation between phylogenetic clade diversification and differences in mammalian cell infectivity phenotype among Cosmopolitan genotype CHIKV strains. PMID- 26611826 TI - Identification and functional characterization of the putative polysaccharide biosynthesis protein (CapD) of Enterococcus faecium U0317. AB - Most bacterial species produce capsular polysaccharides that contribute to disease pathogenesis through evasion of the host innate immune system and are also involved in inhibiting leukocyte killing. In the present study, we identified a gene in Enterococcus faecium U0317 with homologies to the polysaccharide biosynthesis protein CapD that is made up of 336 amino acids and putatively catalyzes N-linked glycosylation. A capD deletion mutant was constructed and complemented by homologous recombination that was confirmed by PCR and sequencing. The mutant revealed different growth behavior and morphological changes compared to wild-type by scanning electron microscopy, also the capD mutant showed a strong hydrophobicity and that was reversed in the reconstituted mutant. For further characterization and functional analyses, in vitro cell culture and in-vivo a mouse infection models were used. Antibodies directed against alpha lipotechoic acid (alphaLTA) and the peptidyl-prolyl cis trans isomerase (alphaPpiC), effectively mediated the opsonophagocytic killing in the capD knock-out mutant, while this activity was not observed in the wild-type and reconstituted mutant. By comparison more than 2-fold decrease was seen in mutant colonization and adherence to both T24 and Caco2 cells. However, a significant higher bacterial colonization was observed in capD mutant during bacteremia in the animal model, while virulence in a mouse UTI (urinary tract infection) model, there were no obvious differences. Further studies are needed to elucidate the function of capsular polysaccharide synthesis gene clusters and its involvement in the disease pathogenesis with the aim to develop targeted therapies to treat multidrug-resistant E. faecium infections. PMID- 26611827 TI - Not all the infected develop the disease - A "Lotus and Cactus" model. AB - The immunogenetic dictum "not all the infected develop the disease" can best be explained by a "Lotus and Cactus" model. Lotuses grow in ponds and cacti in deserts: analogously, we can say that tubercle patient's lung (genetic makeup) functions as an ideal 'broth' for Mycobacterium tuberculosis (M.tb) germs to grow, but not the lungs of an endemic control. HLA association studies from Europe to Asia since 1983 till date, have shown a persistent HLA DR2 (15) association. Further, HLA DR2 and non-DR2 endemic controls showed disparate patterns of immune responses and gene expressions. The host and pathogen MHC diversities, Th1-Th2 paradigm and cytokine circuits all may play a crucial role in TB susceptibility. It is possible to decipher the protective immunity by controlling the known confounders - epidemiological, demographic, socio biological and also host and pathogen diversities. This has become significant with our understanding on the 'out of Africa' migration and neolithic co dispersal of M.tb with modern human. Divergence and expansion of various MHCs (eg HLA-DRB1*15, HLA-B*57) and non-MHC alleles in various continents might be responsible for the skewed transmission and distribution of the infectious diseases around the globe. The 'Lotus and Cactus' model proposed here exemplifies this. A holistic genetic epidemiology approach employing modern tools is the need of the hour to better understand infectious disease susceptibility. PMID- 26611828 TI - Analysis of deaths between 2007 and 2012 of patients with cancer of the head and neck on a surgical ward at a regional centre and in an independent hospice. AB - Providing the best care for patients dying from cancer of the head and neck is crucial, and their complex, unpredictable needs, particularly at the end of life, mean that they are likely to die in institutional care. To evaluate the care given at the end of life we retrospectively reviewed the case notes of patients who died between 2007 and 2012 in a regional head and neck unit and a specialist palliative care unit (hospice). Deaths were categorised as sudden (rapid or unanticipated) or expected (gradual or anticipated). A total of 105 patients died, of whom 29 were excluded from analysis because records were missing. Of the remaining 76, 63 died in the head and neck unit and 13 in the hospice. Patients who died the hospice were younger (mean (SD) age 63.7 (11.0) years) than those who died in hospital (mean (SD) age 70.6 (11.9) years). Most had stage III or IV disease (head and neck unit 45/57, 79%, hospice 9/13, 69%). Death was sudden in 33 (43%) and expected in 43 (57%). Haemorrhage was the commonest cause of sudden death (n=13) and carcinomatosis (n=17) the commonest cause of expected death. Specialists in palliative care had been involved in the care of 13 patients who died suddenly (39%) and 34 whose deaths were expected (79%). The family was present at the time of death (or was aware of it) in 30 who died suddenly (91%) and in 40 (93%) whose deaths were expected. In patients with cancer of the head and neck death can be sudden because of unpredictable complications, and everyone should be aware of this. PMID- 26611829 TI - Mental health trajectories from adolescence to adulthood: Language disorder and other childhood and adolescent risk factors. AB - Longitudinal research on mental health development beyond adolescence among nonclinical populations is lacking. This study reports on psychiatric disorder trajectories from late adolescence to young adulthood in relation to childhood and adolescent risk factors. Participants were recruited for a prospective longitudinal study tracing a community sample of 5-year-old children with communication disorders and a matched control cohort to age 31. Psychiatric disorders were measured at ages 19, 25, and 31. Known predictors of psychopathology and two school-related factors specifically associated with language disorder (LD) were measured by self-reports and semistructured interviews. The LD cohort was uniquely characterized by a significantly decreasing disorder trajectory in early adulthood. Special education was associated with differential disorder trajectories between LD and control cohorts, whereas maltreatment history, specific learning disorder, family structure, and maternal psychological distress were associated with consistent trajectories between cohorts. From late adolescence to young adulthood, childhood LD was characterized by a developmentally limited course of psychiatric disorder; maltreatment was consistently characterized by an elevated risk of psychiatric disorder regardless of LD history, whereas special education was associated with significantly decreasing risk of psychiatric disorder only in the presence of LD. PMID- 26611831 TI - Characterization of Ambra1 in asexual cycle of a non-vertebrate chordate, the colonial tunicate Botryllus schlosseri, and phylogenetic analysis of the protein group in Bilateria. AB - Ambra1 is a positive regulator of autophagy, a lysosome-mediated degradative process involved both in physiological and pathological conditions. Nowadays, Ambra1 has been characterized only in mammals and zebrafish. Through bioinformatics searches and targeted cloning, we report the identification of the complete Ambra1 transcript in a non-vertebrate chordate, the tunicate Botryllus schlosseri. Tunicata is the sister group of Vertebrata and the only chordate group possessing species that reproduce also by blastogenesis (asexual reproduction). B. schlosseri Ambra1 deduced amino acid sequence is shorter than vertebrate homologues but still contains the typical WD40 domain. qPCR analyses revealed that the level of B. schlosseri Ambra1 transcription is temporally regulated along the colonial blastogenetic cycle. By means of similarity searches we identified Wdr5 and Katnb1 as proteins evolutionarily associated to Ambra1. Phylogenetic analyses on Bilateria indicate that: (i) Wdr5 is the most related to Ambra1, so that they may derive from an ancestral gene, (ii) Ambra1 forms a group of ancient genes evolved before the radiation of the taxon, (iii) these orthologous Ambra1 share the two conserved WD40/YVTN repeat-like-containing domains, and (iv) they are characterized by ancient duplications of WD40 repeats within the N-terminal domain. PMID- 26611830 TI - Anti-Ebola therapies based on monoclonal antibodies: current state and challenges ahead. AB - The 2014 Ebola outbreak, the largest recorded, took us largely unprepared, with no available vaccine or specific treatment. In this context, the World Health Organization declared that the humanitarian use of experimental therapies against Ebola Virus (EBOV) is ethical. In particular, an experimental treatment consisting of a cocktail of three monoclonal antibodies (mAbs) produced in tobacco plants and specifically directed to the EBOV glycoprotein (GP) was tested in humans, apparently with good results. Several mAbs with high affinity to the GP have been described. This review discusses our current knowledge on this topic. Particular emphasis is devoted to those mAbs that have been assayed in animal models or humans as possible therapies against Ebola. Engineering aspects and challenges for the production of anti-Ebola mAbs are also briefly discussed; current platforms for the design and production of full-length mAbs are cumbersome and costly. PMID- 26611832 TI - Association of Single-Nucleotide Polymorphism in ANK1 with Late-Onset Alzheimer's Disease in Han Chinese. AB - Recently, two CpG sites in ankyrin 1 (ANK1) gene were identified to be hypermethylated and associated with Alzheimer's disease (AD)-related neuropathology in two large independent studies. Genetic variations are indicated to be involved in DNA methylation, especially when the associated single nucleotide polymorphisms (SNPs) are located adjacent to the CpG site. Accordingly, ANK1 polymorphisms might contribute to late-onset AD (LOAD) risk. One polymorphism rs515071 was identified to be a potential risk factor for type 2 diabetes (T2D). As shared genetic background was found underlying T2D and AD, we postulate that rs515071 polymorphism may be associated with late-onset AD (LOAD) risk and assessed the association in 982 LOAD patients and 1346 sex- and age matched healthy controls. Our results showed that minor allele A of rs515071 significantly increased LOAD risk in the APOE epsilon4 (+) subgroup (genotype P = 0.015, allele P = 0.020). After adjusting for age and gender, the association remained significant under the dominant model (OR = 1.809, 95 % confidence interval (CI) = 1.186-2.757, P = 0.006). In conclusion, our findings demonstrate that rs515071 in ANK1 is a novel genetic risk for LOAD susceptibility in Han Chinese. PMID- 26611833 TI - Enriched Endogenous Omega-3 Polyunsaturated Fatty Acids Protect Cortical Neurons from Experimental Ischemic Injury. AB - Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert therapeutic potential in a variety of neurological disorders, including ischemic stroke. However, the underlying mechanisms still lack investigation. Here, we report that cultured cortical neurons isolated from fat-1 mice with high endogenous n-3 PUFAs were tolerant to oxygen-glucose deprivation/reperfusion (OGD/R) injury. Fat-1 neurons exhibited significantly attenuated reactive oxygen species (ROS) activation induced by OGD/R injury, upregulated antiapoptotic proteins Bcl-2 and Bcl-xL, and reduced cleaved caspase-3. Exogenous administration of docosahexaenoic acid (DHA), a major component of the n-3 PUFA family, resulted in similar protective effects on cultured cortex neurons. We further verified the protective effects of n-3 PUFAs in vivo, using a mini ischemic model with a reproducible cortical infarct and manifest function deficits by occlusion of the distal branch of the middle cerebral artery with focused femtosecond laser pulses. The Fat-1 animals showed decreased ROS expression and higher level of glutathione in the injured brain, associated with improved functional recovery. We therefore provide evidence that n-3 PUFAs exert their protective effects against ischemic injury both in vitro and in vivo, partly through inhibiting ROS activation. PMID- 26611834 TI - Ferulic Acid Protects Against Lead Acetate-Induced Inhibition of Neurite Outgrowth by Upregulating HO-1 in PC12 Cells: Involvement of ERK1/2-Nrf2 Pathway. AB - Prenatal lead exposure is associated with poor intellectual development in children. However, there are few breakthroughs in therapeutic intervention of developmental lead neurotoxicity. The aim of this study is to evaluate the hypothesis that ferulic acid-mediated promotion of neurite outgrowth following lead exposure might mainly result from its antioxidant capability by extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Exposure of PC12 cells to lead acetate inhibits neurite outgrowth and causes oxidative stress as measured by ROS, LPO, GSH/GSSG, and NAD+/NADH. FA treatment significantly, although not completely, protected the cells against lead acetate-induced neurite outgrowth inhibition. The effects of FA could be blocked by PD98059, zinc protoporphyrin (Zn-PP), and Nrf2 shRNA. In addition, FA induced heme oxygenase 1 (HO-1) gene expression, enhanced antioxidant response element (ARE) promoter activity, promoted ERK1/2 phosphorylation, and Nrf2 translocation in PC12 cells exposed to lead acetate. ERK1/2 locate upstream of Nrf2 and regulate Nrf2-dependent HO-1 expression in antioxidative effects of FA. Our results suggest that FA is a promising candidate for treatment of developmental lead neurotoxicity. These promising findings warrant future investigation evaluating the FA-mediated potentiation of neurite outgrowth following lead exposure in vivo. PMID- 26611835 TI - Meta-analysis of the Association between Alzheimer Disease and Variants in GAB2, PICALM, and SORL1. AB - The genetic variants play a crucial role in the pathogenesis of Alzheimer's disease (AD), while the relationships of specific single nucleotide polymorphisms (SNPs) with AD are still controversial. We performed the meta-analysis to obtain a more precise estimation of whether growth factor receptor-bound protein associated binding protein 2 (GAB2), phosphatidylinositol binding clathrin assembly protein (PICALM), and sortilin-related receptor (SORL1) variants are associated with AD. Databases including PubMed, Embase, and Cochrane Library were searched to find relevant studies. Cochran's Q-statistic and I 2 were used to assess the heterogeneity among the included studies. Odds ratios (OR) and 95 % confidence intervals (95 % CIs) were conducted to evaluate the association between the SNP and the susceptibility to AD. Publication bias was estimated by funnel plots. All of the statistical analyses were implemented using R Version 3.2.1 software. A total of 35 case-control studies involving 15 SNPs were included. There was no significant association between SNPs of GAB2 rs2373115 (G > T) and PICALM rs541458 (C > T) and AD. The allele T of rs3851179 in PICALM was associated with a 13 % increase in the risk of AD. Seven SNPs on SORL1 were significantly associated with AD. Four SNPs, including rs1010159*T, rs641120*A, rs668387*T, and rs689021*A, were associated with a decreased risk of AD, while the other three SNPs, including rs12285364*T, rs2070045*G, and rs2282649*T, were all associated with an increased risk of AD. The results of the present study suggested that multiple gene variants were associated with AD. The SNP of rs3851179 (PICALM), rs12285364 (SORL1), rs2070045 (SORL1), and rs2282649 (SORL1) was associated with an increased risk of AD, whereas SORL1 rs1010159, rs641120, rs668387, and rs689021 were associated with a decreased risk of AD. PMID- 26611837 TI - Semi-reciprocal polarization maintaining fibre coupler with distinctive transmission characteristics. AB - Optical couplers are very important devices in optical communication systems and optical sensor systems. Several types of optical couplers with different materials or different transmission characteristics have been reported. Here we propose a semi-reciprocal polarization maintaining fibre coupler with unique transmission characteristics, which is distinct from conventional polarization maintaining fibre couplers and polarization beam splitters, and investigate the characteristics of the coupler theoretically and experimentally. The experimental results show that for circularly and elliptically polarized input light, the proposed coupler will act both as an in-line polariser and a conventional polarization maintaining fibre coupler. The output polarization extinction ratio of the transmission arm is 31.79 dB at a centre wavelength of 841 nm. For linearly polarized input light, the coupler will merely act as a conventional 3 dB polarization maintaining fibre coupler. The unique features of the proposed coupler enables the removal of polarisers from optical sensor systems and coherent optical communication systems, and reduces the insertion loss and production cost of the optical path. Therefore there is wide application for this device in optical sensor systems and optical communication systems. PMID- 26611836 TI - The NLRP3 inflammasome is critically involved in the development of bronchopulmonary dysplasia. AB - The pathogenesis of bronchopulmonary dysplasia (BPD), a devastating lung disease in preterm infants, includes inflammation, the mechanisms of which are not fully characterized. Here we report that the activation of the NLRP3 inflammasome is associated with the development of BPD. Hyperoxia-exposed neonatal mice have increased caspase-1 activation, IL1beta and inflammation, and decreased alveolarization. Nlrp3(-/-) mice have no caspase-1 activity, no IL1beta, no inflammatory response and undergo normal alveolarization. Treatment of hyperoxia exposed mice with either IL1 receptor antagonist to block IL1beta or glyburide to block the Nlrp3 inflammasome results in decreased inflammation and increased alveolarization. Ventilated preterm baboons show activation of the NLRP3 inflammasome with increased IL1beta:IL1ra ratio. The IL1beta:IL1ra ratio in tracheal aspirates from preterm infants with respiratory failure is predictive of the development of BPD. We conclude that early activation of the NLRP3 inflammasome is a key mechanism in the development of BPD, and represents a novel therapeutic target for BPD. PMID- 26611839 TI - Pd-catalyzed gem-difluoroallylation of arylboronic acids with gamma,gamma difluoroallylic acetates. AB - A highly regio- and stereo-selective palladium-catalyzed gem-difluoroallylation of arylboronic acids with gamma,gamma-difluoroallylic acetates has been described. The method allows the synthesis of a variety of gem-difluoroallylated arenes with a tosyloxy group on the C=C double bond, thus providing a good opportunity for down-stream transformations. PMID- 26611840 TI - Preliminary investigation of methylation status of microRNA-124a in spinal cords of rat fetuses with congenital spina bifida. AB - OBJECTIVE: We investigated the expression of microRNA-124a and its methylation status in the spinal cords of rats with congenital spina bifida versus rats with normal fetuses. METHODS: Real-time quantitative reverse transcription-polymerase chain reaction was used to compare the expression of microRNA-124a in the spinal cords of 42 rats with all-trans retinoic acid induced congenital spina bifida and 42 rats with normal fetuses. The DNA methylation status in the promoter region of miRNA-124a was detected using methylation specific-PCR. RESULTS: Compared with rats with normal fetuses, expression of microRNA-124a was significantly decreased in rats with congenital spina bifida fetuses. The percentages of spinal cords with DNA hypermethylation in the microRNA-124a promoter were 81% and 14% in the congenital spina bifida and normal control groups, respectively. The difference was statistically significant. Further apoptosis testing revealed increased apoptosis cell numbers in the congenital spina bifida samples. Meanwhile, the phosphorylated mitogen-activated protein kinase protein expression level dramatically decreased in the congenital spina bifida samples. CONCLUSION: Aberrant DNA methylation was responsible for down-regulation of microRNA-124a by regulating the mitogen-activated protein kinase pathway, suggesting that microRNA 124a is a potential diagnostic biomarker in congenital spina bifida. PMID- 26611838 TI - A second-generation expression system for tyrosine-sulfated proteins and its application in crop protection. AB - Posttranslational modification (PTM) of proteins and peptides is important for diverse biological processes in plants and animals. The paucity of heterologous expression systems for PTMs and the technical challenges associated with chemical synthesis of these modified proteins has limited detailed molecular characterization and therapeutic applications. Here we describe an optimized system for expression of tyrosine-sulfated proteins in Escherichia coli and its application in a bio-based crop protection strategy in rice. PMID- 26611841 TI - Surgery for sight: outcomes of congenital and developmental cataracts operated in Durban, South Africa. AB - PURPOSE: To study the visual outcomes of congenital and developmental cataract surgery and determine variables for presentation for pediatric cataract surgery in KwaZulu Natal province of South Africa. METHODS: Care-givers of children presenting with cataract to a quaternary centre were asked when they first detected the condition. The reasons for delay between detection and surgery were studied. The children underwent a comprehensive eye examination and then appropriate surgery. They were prospectively followed up for 3 months and visual acuity and stereopsis were noted. Delay in presentation for surgery and visual outcomes were co-related with demographic and clinical factors. RESULTS: Eighty three non-traumatic cataract surgeries in 50 children were studied. Twenty-six (52%) were males, mean age was 3 years 10 months (SD 3yrs 4 months). The mean delay between identification and surgery was 20.7 months (SD 18 months). Twenty six (52%) children had >15 months interval between diagnosis and surgery. Only mother's occupation was significantly associated with delay (P=0.017). Post surgery 17/69 (24.7%) had visual acuity >=6/18, 20/69 (29.0%) had vision between 6/24-6/60, whereas 32/69 (46.3%) had visual acuity <=6/60. The final vision was associated with age (P=0.031), delay between diagnosis and surgery (P<0.001), type of surgery (P=0.046) and preoperative vision (P<0.001). CONCLUSION: Although the children's vision improved substantially, a longer follow-up and amblyopia treatment would be necessary to optimize the visual outcome, which depended on age and preoperative vision. Health promotion activities aimed at mothers are important in improving visual outcomes. PMID- 26611842 TI - 'Toy' laser macular burns in children: 12-month update. AB - PURPOSE: There is increasing evidence that high-powered hand-held laser devices cause retinal injury. We present 12-month follow-up data for three patients that we previously reported with such retinal injuries. METHODS: A retrospective case series of three children with maculopathy secondary to exposure to high-power hand-held laser devices. All children underwent clinical examination and spectral domain optical coherence tomography (SD-OCT) at presentation and follow-up. Fundus-controlled microperimetry was also undertaken 12-19 months after exposure. RESULTS: Three children sustained macular injury after exposure to a high-powered hand-held laser. Acutely, they presented with a 'vitelliform-like' maculopathy with reduced vision. Over the course of follow-up, the best corrected Snellen acuity in all three patients improved to 'normal' levels (range 6/6-6/9). Long term deficits in foveal retinal sensitivity were identified in two patients using fundus-controlled microperimetry. SD-OCT imaging showed persistent disruption of the foveal outer photoreceptor layers in all three children. CONCLUSION: Although visual acuity improved over time, deficits in microperimetry and SD-OCT persisted. All three children had retinal pigment epithelium changes, requiring follow-up for longer-term sequelae of laser injuries such as expansion of retinal atrophy and development of choroidal neovascular membranes. PMID- 26611843 TI - Comment on: 'Direct ophthalmoscopy should be taught to undergraduate medical students'. PMID- 26611844 TI - Direct ophthalmoscopy should be taught to undergraduate medical students. PMID- 26611845 TI - Surgical challenges and outcomes of rhegmatogenous retinal detachment in albinism. AB - PURPOSE: To report the outcomes and surgical difficulties during rhegmatogenous retinal detachment (RRD) repair in patients with albinism. METHODS: Retrospective analysis of 10 eyes of 9 patients with albinism that underwent RRD repair was performed. Collected data included demographic details, preoperative examination details, surgical procedure, surgical difficulties, anatomical, and visual outcomes. Outcome measures were retinal reattachment and visual acuity at the last follow-up. RESULTS: Mean preoperative best-corrected visual acuity (BCVA) was logMAR (Logarithm of the Minimum Angle of Resolution) 2.15 (range 0.9-3.0) with preoperative localization of causative break in six eyes. One eye had proliferative vitreoretinopathy grade C1 preoperatively. Four eyes underwent scleral buckling (SB) and six underwent 20G pars plana vitrectomy (PPV) with silicone oil injection. Intraoperative complication as iatrogenic retinal break occurred in four eyes. For retinopexy during vitrectomy, endolaser delivery was possible in three out of six eyes, whereas three eyes had cryopexy. The mean follow-up was 12 months in SB group (range 1-12; median 12 months) and 5.33 months (range 1-12; median 3 months) in PPV group. Among vitrectomized eye, two eyes had recurrence at 3 months with oil in situ. Rest of the eyes had attached retina at last follow-up. Mean BCVA at last follow-up was logMAR -1.46 (range 0.7 2.0) with mean improvement of -0.57 logMAR. CONCLUSIONS: Identification of break, induction of posterior vitreous detachment, and endolaser delivery may be difficult during RRD repair in patients with albinism. The incidence of PVR appeared less in these eyes. Both SB and PPV were efficacious and appear to be good surgical techniques for use in this patient population. PMID- 26611847 TI - Response to: 'Direct ophthalmoscopy should be taught to undergraduate medical students'. PMID- 26611846 TI - A view on glaucoma--are we seeing it clearly? AB - Successful clinical management of glaucoma should not simply be about control of intraocular pressure, but must equate to correct decisions about intensifying treatment when patients are at risk of developing 'visual disability'. Yet little is known about what visual field defects, at different stages of glaucoma, specifically affect patients' abilities to perform everyday visual tasks. One way to do this is to measure patient performance in tasks in a lab setting. Another way is to ask patients themselves. The latter can be revealing and demystify views about how patients perceive the world. This short commentary highlights some of the current research in this area. PMID- 26611848 TI - Caregiver perceptions about the impact of caring for patients with wet age related macular degeneration. AB - PURPOSE: Caregivers of older persons with eye disease, namely age-related macular degeneration (AMD), have been reported to have a higher than expected distress. Very few studies have explored caregiver perceptions as to what is important when providing care. The aim of this study was to explore the perceptions of caregivers of persons with neovascular AMD in relation to the most important aspects of caring, as described in extended answers to self-administered survey questions. METHODS: A cross-sectional, self-administered survey of 643 caregivers of people with neovascular AMD, comprising 27 closed-response questions and 2 open ended questions. The latter were analysed as part of this study utilising and 'inductive' Grounded Theory approach. RESULTS: Six-hundred and forty-three caregiver responses to 2 open ended questions were analysed using an inductive approach and sorted into thematic networks. Three discrete categories arose: The Impact of Caring; Injections and Information and Activities of Daily Living. CONCLUSIONS: Most caregivers were family caregivers and were found to be compassionate and self-sacrificing. They accepted additional responsibility whilst providing an encouraging environment for their care recipient. As a result, they experience distress and consider their own needs as secondary. Very few seek or receive respite and this added burden can have a negative impact upon the relationship between caregiver and care recipient. PMID- 26611850 TI - Direct ophthalmoscopy should be taught within the context of its limitations. PMID- 26611851 TI - Extinction of myeloproliferative neoplasm by acquisition of a lymphoid disease: JAK2 (V617F) and JAK2 exon 12 allele burden disappearance during the follow-up of two patients. PMID- 26611849 TI - Dexamethasone implant in diabetic macular edema in real-life situations. AB - PURPOSE: To report outcome of eyes with recalcitrant and naive eyes with diabetic macular edema (DME) treated with intravitreal dexamethasone implants (Ozurdex) injection. METHODS: Retrospective multicenter data analysis of eyes with DME treated with Ozurdex implant and with minimum follow-up of at least one year after the first implant. Data collected included demographic details, history of presenting illness, past treatment history, clinical examination details including visual acuity at presentation, and follow-up with imaging and treatment details. Paired sample t-test was used to measure mean differences between pre- and post-implant values obtained at baseline and last follow-up. RESULTS: A total of 79 eyes (62 subjects) were included. Sixty-four eyes had been previously treated; 15 eyes were naive. Among the previously treated eyes, mean interval between first Ozurdex injection and any previous treatment was 7.69+/-8.2 months. In naive eyes, the visual acuity improved from baseline 0.58+/-0.25 to 0.44+/ 0.33 logMAR at last follow-up (P=0.05). In eyes that had been previously treated, the improvement was from 0.65+/-0.34 at baseline to 0.48+/-0.35 logMAR (P=0.01). Mean treatment-free interval was 6.5+/-4.5 months. Nine eyes were steroid responder with controlled intraocular pressure (IOP), none showed any spike in IOP during the follow-up period. CONCLUSIONS: Ozurdex implant could be a good alternative for recalcitrant as well as naive eyes with DME. The visual gain after initial implant injection was fairly maintained, with additional treatment usually after 6 months in naive eyes. Ozurdex appeared safe even in steroid responders with good control of IOP with antiglaucoma medications. PMID- 26611852 TI - Pain management trend of vaso-occulsive crisis (VOC) at a community hospital emergency department (ED) for patients with sickle cell disease. AB - Pain management at the emergency department (ED) for vaso-occulsive crisis (VOC) for patients with sickle cell disease has not been optimum, with a long delay in giving the initial analgesic. We conducted a retrospective survey over a 7-year period to determine our ED's timing in giving pain medication to patients with VOC as a quality improvement project. We compared different periods, children vs adults, and the influence of gender in the analgesic administration timing. This is a retrospective chart review of three different periods: (1) years 2007-2008, (2) years 2011-2012, and (3) year 2013. We extracted relevant information from ED records. Data were analyzed using Student t test, chi-square analysis, and the Kruskal-Wallis test. There was a progressive improvement in the time interval to the 1st analgesic over these three periods. Children received analgesics more quickly than adults in all periods. Male adult patients received pain medication faster than female adult patients, although initial pain scores were higher in female than in male patients. Progressively fewer pediatric patients utilized ED over these three periods, but no difference for adult patients was observed. The proportion of pediatric patients admitted to the hospital increased with each period. The progressive decrease in both the number of patients and the number of visits to the ED by children suggested that the collective number of VOC in children has decreased, possibly secondary to the dissemination of hydroxyurea use. We failed to observe the same trend in adult patients. The need for IV access, and ordering laboratory tests or imaging studies tends to delay analgesic administration. Delay in administration of the first analgesic was more pronounced for female adult patients than male adult patients in spite of their higher pain score. Health care providers working in ED should make conscious efforts to respect pain in women as well as pain in men. Though not proven from this study, we believe that a significantly wider use of hydroxyurea by adult patients most likely would reduce their utilization of ED for the purpose of relief of pain, and further pediatric hematologists may be better positioned to increase hydroxyurea adherence by young adult patients, since they have had established rapport with them before transitioning to adult care. PMID- 26611853 TI - Ferritin as an early marker of graft rejection after allogeneic hematopoietic stem cell transplantation in pediatric patients. AB - Diagnosis of adverse events following hematopoietic stem cell transplantation (HSCT) is mainly assigned to clinical symptoms or biopsies and thus rather unspecific and/or invasive. Studies indicate a distinct role of serum ferritin in HSCT and its correlation with adverse events such as graft-versus-host disease (GvHD), veno-occlusive disease (VOD), or infections. However, published data on the relevance of ferritin as a prognostic marker for post-transplant adverse events is rare, especially in pediatric patients. The present study analyzes ferritin plasma concentrations of 138 pediatric patients after HSCT between 2007 and 2010 including the control group (n = 21). Given the initial results regarding ferritin as a significant predictor for acute graft rejection after allogeneic HSCT in 9 of the 138 pediatric patients, serum ferritin of all pediatric patients (n = 27) who experienced graft rejection between 2007 and 2014 was analyzed. In addition, laboratory parameters including C-reactive protein (CRP), lactate dehydrogenase (LDH), fibrinogen, and D-dimer as possible differentiation markers for graft rejection were determined. In 24 (88.9 %) of the 27 pediatric patients with graft rejection, a significant increase of ferritin levels was observed 1 to 7 days prior to (P < 0.0001) and at the time of graft rejection (P < 0.0001). Moreover, there was an increase of D-dimer, CRP, LDH, and fibrinogen 1-7 days before graft rejection. Ferritin increased significantly at time of VOD (P = 0.0067), at time of intestinal (P < 0.0001) and skin GvHD (P < 0.0001), and at time of sepsis (P = 0.0005) and bacteremia (P = 0.0029). Ferritin might serve as a readily available identification marker for differentiation and identification of adverse events after HSCT in combination with other laboratory markers. PMID- 26611854 TI - Increased efficacy of intermediate-dose cytarabine + G-CSF compared to DHAP + G CSF for stem cell mobilization in patients with lymphoma: an analysis by the polish lymphoma research group. AB - Salvage regimens, like DHAP (dexamethasone, cytarabine, and cisplatin) are frequently used for stem cell mobilization in lymphoma. The aim of this study was to compare the efficacy of DHAP + G-CSF with intermediate-dose cytarabine (ID AraC) + G-CSF, recently proposed as an alternative schedule. Consecutive patients with Hodgkin's or non-Hodgkin lymphoma who had received at least 2 lines of chemotherapy, mobilized with either DHAP (n = 51) or ID-AraC (n = 50) + G-CSF were included in the analysis. AraC was administered at the dose of 400 mg/m [1] bid intravenously for 2 days followed by filgrastim starting from day 5. In the AraC group, 96 % of patients collected at least 2 * 10 [2] CD34(+) cells/kg compared to 71 % in the DHAP group (p = 0.0006). The CD34(+) cell yield was 9.3 (0-30.3) * 10 [2]/kg vs. 5.6 (0-24.8) * 10 [2]/kg, respectively (p = 0.006). A single apheresis was sufficient to achieve the threshold number of CD34(+) cells in 82 % of the cases after AraC compared to 45 % after DHAP (p = 0.001). We conclude that stem cell mobilization using ID-AraC is associated with a significantly higher efficacy than DHAP, allowing for collection of the transplant material in almost all patients with lymphoma. Our observation suggests that ID-AraC + G-CSF may be a preferable mobilization regimen in this setting. PMID- 26611855 TI - Single MoO3 nanoribbon waveguides: good building blocks as elements and interconnects for nanophotonic applications. AB - Exploring new nanowaveguide materials and structures is of great scientific interest and technological significance for optical and photonic applications. In this work, high-quality single-crystal MoO3 nanoribbons (NRs) are synthesized and used for optical guiding. External light sources are efficiently launched into the single MoO3 NRs using silica fiber tapers. It is found that single MoO3 NRs are as good nanowaveguides with loss optical losses (typically less than 0.1 dB/MUm) and broadband optical guiding in the visible/near-infrared region. Single MoO3 NRs have good Raman gains that are comparable to those of semiconductor nanowaveguides, but the second harmonic generation efficiencies are about 4 orders less than those of semiconductor nanowaveguides. And also no any third order nonlinear optical effects are observed at high pump power. A hybrid Fabry Perot cavity containing an active CdSe nanowire and a passive MoO3 NR is also demonstrated, and the ability of coupling light from other active nanostructures and fluorescent liquid solutions has been further demonstrated. These optical properties make single MoO3 NRs attractive building blocks as elements and interconnects in miniaturized photonic circuitries and devices. PMID- 26611856 TI - Switching operation and degradation of resistive random access memory composed of tungsten oxide and copper investigated using in-situ TEM. AB - In-situ transmission electron microscopy (in-situ TEM) was performed to investigate the switching operation of a resistive random access memory (ReRAM) made of copper, tungsten oxide and titanium nitride (Cu/WOx/TiN). In the first Set (Forming) operation to initialize the device, precipitation appeared inside the WOx layer. It was presumed that a Cu conducting filament was formed, lowering the resistance (on-state). The Reset operation induced a higher resistance (the off-state). No change in the microstructure was identified in the TEM images. Only when an additional Reset current was applied after switching to the off state could erasure of the filament be seen (over-Reset). Therefore, it was concluded that structural change relating to the resistance switch was localized in a very small area around the filament. With repeated switching operations and increasing operational current, the WOx/electrode interfaces became indistinct. At the same time, the resistance of the off-state gradually decreased. This is thought to be caused by Cu condensation at the interfaces because of leakage current through the area other than through the filament. This will lead to device degradation through mechanisms such as endurance failure. This is the first accelerated aging test of ReRAM achieved using in-situ TEM. PMID- 26611857 TI - Heartbeat: Altmetrics and Cardiovascular Risk Factor Studies. PMID- 26611858 TI - EUS to the Rescue: Endoscopic Ultrasound-Guided Transgastric Cholecystostomy in Acute Cholecystitis. PMID- 26611859 TI - The Impact of Gallbladder Status on Biliary Complications After the Endoscopic Removal of Choledocholithiasis. AB - BACKGROUND: Endoscopic sphincterotomy (EST) with stone extraction is the standard management for choledocholithiasis. However, the necessity for subsequent management of gallstone to prevent the biliary complications remained controversial and few data were evaluated for the impact of status of gallbladder on recurrent biliary complications. We retrospectively investigated the relationship between the status of gallbladder and the occurrence of biliary complications after endoscopic removal of choledocholithiasis. METHODS: Between January 1998 and December 2008, we enrolled 453 patients with intact gallbladder who underwent EST for choledocholithiasis and allocated into two groups: calculous gallbladder (n = 256) and acalculous gallbladder (n = 197). By reviewing patients' medical records, we compared the occurrence of biliary complications according to the presence or absence of gallstone in GB in situ. RESULTS: In total, biliary complications occurred in 83 patients (18.3 %) during the follow-up period. Calculous GB group had higher rate of overall complications (22.7 vs. 12.7 %; p = 0.007) and GB-associated complications (11.3 vs. 2.5 %; p = 0.001) than acalculous GB group. On the multivariate analysis, only the presence of gallstone was shown to be significant risk factor for overall biliary complication (OR 2.029; 95 % CI 1.209-3.405; p = 0.007) and GB-associated complications (OR 5.077; 95 % CI 1.917-13.446; p = 0.001). Mean event-free period was shorter in calculous GB group than acalculous GB group for overall complications (1774 vs. 2159 days; p = 0.012) and GB-associated complication (2153 vs. 2591 days; p = 0.001). CONCLUSIONS: Prophylactic cholecystectomy may not be necessary to prevent biliary complication in patients with acalculous gallbladder after endoscopic removal of pigment stones from bile duct. PMID- 26611861 TI - Validation of nuclear models in Geant4 using the dose distribution of a 177 MeV proton pencil beam. AB - A proton pencil beam is associated with a surrounding low-dose envelope, originating from nuclear interactions. It is important for treatment planning systems to accurately model this envelope when performing dose calculations for pencil beam scanning treatments, and Monte Carlo (MC) codes are commonly used for this purpose. This work aims to validate the nuclear models employed by the Geant4 MC code, by comparing the simulated absolute dose distribution to a recent experiment of a 177 MeV proton pencil beam stopping in water. Striking agreement is observed over five orders of magnitude, with both the shape and normalisation well modelled. The normalisations of two depth dose curves are lower than experiment, though this could be explained by an experimental positioning error. The Geant4 neutron production model is also verified in the distal region. The entrance dose is poorly modelled, suggesting an unaccounted upstream source of low-energy protons. Recommendations are given for a follow-up experiment which could resolve these issues. PMID- 26611860 TI - Premature Birth and Large for Gestational Age Are Associated with Risk of Barrett's Esophagus in Adults. AB - BACKGROUND: Birth characteristics, including weight and gestational age, may be associated with risk of Barrett's esophagus (BE), the only known precursor for esophageal adenocarcinoma; however, data are limited. AIMS: To examine associations between various birth characteristics and BE, and whether these associations are mediated by known risk factors for BE. METHODS: Data were obtained from a cross-sectional study among eligible Veterans Affairs patients scheduled for an upper endoscopy, and a sample identified from primary care clinics. Participants underwent an esophagogastroduodenoscopy and completed a survey that captured information on sociodemographic and clinical factors, as well as birth information. We compared 263 patients with histologically confirmed BE to 1416 controls without BE on endoscopy. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated using multivariate logistic regression. RESULTS: Premature birth was independently associated with risk of BE after adjusted by age, sex, race, and other birth characteristics (OR 3.28, 95 % CI 1.22-8.79). On the other hand, large for gestational age was inversely associated with risk of BE (OR 0.46, 95 % CI 0.21-0.98). These effects were stronger for patients with long-segment BE than with short-segment BE. The associations were not mediated by gastroesophageal reflux disease symptoms, use of proton pump inhibitors, Helicobacter Pylori infection, waist-hip-ratio, height or the presence of hiatus hernia. CONCLUSIONS: Premature birth and large for gestational age may be associated with risk of BE in adults. These associations do not appear to be mediated through known risk factors for BE; however, additional studies are required to confirm our findings. PMID- 26611862 TI - Massilia violacea sp. nov., isolated from riverbank soil. AB - A bacterial strain designated CAVIOT was isolated during the course of a study of culturable bacteria in a riverbank soil sample from Tlaxcala, Mexico. The strain was subjected to a polyphasic taxonomic characterization. Strain CAVIOT was aerobic, Gram-stain-negative, non-spore-forming and rod-shaped. Colonies grown on R2A agar at 28 degrees C were pale violet, mucoid, rounded, smooth and glossy. The strain was motile and catalase- and oxidase-positive, and maximum growth temperature was 35 degrees C. Strain CAVIOT was classified within the genus Massilia as its 16S rRNA gene sequence was closely related to those of Massilia umbonata LP01T (97.5 % similarity), Massilia dura 16T (97.2 %) and Massilia plicata 76T (97.1 %). The predominant respiratory quinone was Q8. The major fatty acids were summed feature 3 (C16 : 1omega7c/C16 : 1omega6c), C16 : 0 and summed feature 8 (C18 : 1omega7c/C18 : 1omega6c). The predominant polar lipids were phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol and an unknown phospholipid. The DNA G+C content was 65.0 mol% (Tm). DNA-DNA hybridization results showed values below 25 % with respect to the type strains of the closest related species. Therefore, strain CAVIOT can be differentiated from previously described species of the genus Massilia and represents a novel species, for which the name Massilia violacea sp. nov. is proposed. The type strain is CAVIOT ( = CECT 8897T = LMG 28941T). PMID- 26611863 TI - Interannual and cyclone-driven variability in phytoplankton communities of a tropical coastal lagoon. AB - One of the main challenges in phytoplankton ecology is to understand their variability at different spatiotemporal scales. We investigated the interannual and cyclone-derived variability in phytoplankton communities of Chilika, the largest tropical coastal lagoon in Asia and the underlying mechanisms in relation to environmental forcing. Between July 2012 and June 2013, Cyanophyta were most prolific in freshwater northern region of the lagoon. A category-5 very severe cyclonic storm (VSCS) Phailin struck the lagoon on 12th October 2013 and introduced additional variability into the hydrology and phytoplankton communities. Freshwater Cyanophyta further expanded their territory and occupied the northern as well as central region of the lagoon. Satellite remote sensing imagery revealed that the phytoplankton biomass did not change much due to high turbidity prevailing in the lagoon after Phailin. Modeling analysis of species salinity relationship identified specific responses of phytoplankton taxa to the different salinity regime of lagoon. PMID- 26611864 TI - Characterization of an Injury Induced Population of Muscle-Derived Stem Cell-Like Cells. AB - We recently discovered a novel population of stem cells from the injured murine skeletal muscle. These injury induced muscle-derived stem cell-like cells (iMuSCs) are partially reprogrammed from differentiated myogenic cells and display a pluripotent-like state. The iMuSCs exhibit stem cell properties including the ability to differentiate into multiple lineages, such as neurogenic and myogenic differentiations; they also display a superior migration capacity that demonstrating a strong ability of muscle engraftment in vivo. IMuSCs express several pluripotent and myogenic stem cell markers; have the capability to form embryoid bodies and teratomas, and can differentiate into all three germ layers. Moreover, blastocyst microinjection showed that the iMuSCs contributed to chimeric embryos but could not complete germline transmission. Our results indicate that the iMuSCs are in a partially reprogrammed state of pluripotency, which are generated by the microenvironment of injured skeletal muscle. PMID- 26611865 TI - Chinese adaptation of Emotion Regulation Questionnaire for Children and Adolescents (ERQ-CCA): A psychometric evaluation in Chinese children. AB - This study validated a Chinese adaptation of the Emotion Regulation Questionnaire for Children and Adolescents (ERQ-CCA), a self-report instrument that evaluates two emotion regulation (ER) strategies, based on the process model of ER. The ERQ CCA was evaluated using a sample of 1381 Chinese children aged between 7 and 12 years. The internal consistencies of the two factors indicated adequate reliability. Confirmatory factor analysis (CFA) revealed good support as the structure proved to be identical with that of the original instrument. Multigroup CFA supported an invariant factor solution of the ERQ-CCA across several demographic variations (gender, age, registered permanent residence and migrant status) in different groups. Test-retest correlations over a 2-month period were calculated using a subsample of children (N = 70). Convergent validity was evaluated in relation to the model dimensions of the ERQ-CCA, Chinese version of the Children's Depression Inventory, and Chinese version of the Eysenck Personality Questionnaire for Children and Adolescents. Results indicated that the ERQ-CCA has generally satisfactory reliability and validity in investigating the use of two ER strategies during the middle childhood developmental period. PMID- 26611866 TI - Ginsenoside Rb1 rescues anxiety-like responses in a rat model of post-traumatic stress disorder. AB - Single prolonged stress (SPS), a rat model of post-traumatic stress disorder (PTSD), induces alterations in the hypothalamic-pituitary-adrenal axis. Korean red ginseng, whose major active component is ginsenoside Rb1 (GRb1), is one of the widely used traditional anxiolytics. However, the efficacy of GRb1 in alleviating PTSD-associated anxiety-like abnormalities has not been investigated. The present study used several behavioral tests to examine the effects of GRb1 on symptoms of anxiety in rats after SPS exposure and on the central noradrenergic system. Male Sprague-Dawley rats received GRb1 (10 or 30 mg/kg, i.p., once daily) during 14 days of SPS. Daily GRb1 (30 mg/kg) administration significantly increased the number and duration of open-arm visits in the elevated plus maze (EPM) test, reduced the anxiety index, increased the risk assessment, reduced grooming behaviors in the EPM test, and increased the total number of line crossings of an open field after SPS. The higher dose of GRb1 also blocked SPS induced decreases in hypothalamic neuropeptide Y expression, increases in locus coeruleus tyrosine hydroxylase expression, and decreases in hippocampal mRNA expression of brain-derived neurotrophic factor. These findings suggest that GRb1 has anxiolytic-like effects on both behavioral and biochemical symptoms similar to those observed in patients with PTSD. PMID- 26611867 TI - Color, sensory and physicochemical attributes of beef burger made using meat from young bulls fed levels of licuri cake. AB - BACKGROUND: Licuri cake is a biodiesel byproduct and has been tested as an alternative feed additive for use in cattle production. This study analyzed the color, sensory and chemical attributes of burger meat from bovines. Thirty-two young Nellore bulls were used, housed in individual pens and distributed in a randomized experimental design with four treatments: no addition or the addition of 7, 14 or 21% (w/w) licuri cake in the dry matter of the diet. RESULTS: Interactions between the licuri cake level and the physicochemical variables (P > 0.05) were observed. Additionally, an interaction was observed between the licuri cake level and the burger beef color parameter lightness index (L*) (P = 0.0305). The L* value was positively and linearly correlated with the proportion of licuri cake in the diet of young bulls. The level of inclusion of licuri cake did not affect (P > 0.05) the sensory characteristics; the variables were graded between 6 and 7, indicating good overall acceptance. CONCLUSION: Up to 21% (w/w) licuri cake can be included in the diet of young bulls without negatively impacting on beef burger quality. (c) 2015 Society of Chemical Industry. PMID- 26611868 TI - Mortality trends among migrant groups living in Amsterdam. AB - BACKGROUND: The main aim of this paper is to see to what extent mortality patterns between migrants living in the Netherlands converge. This might be an indicator of health and health care acculturation. METHODS: This is an observational study on the basis of standard mortality registration data collected between 1996 and 2007. Eight ethnic groups living in Amsterdam are examined to see if mortality converges or diverges over time. Trends in mortality are studied using Poisson regression. The life expectancy between groups is compared for three time periods. RESULTS: The data showed that for males and females the life expectancy and death rates improved between 1996-1999 and 2004 2007. Most ethnic groups, both males and females, followed this positive trend. For most indicators the ethnic groups converged in terms of mortality. The data also shows the healthy migrant effect with those in Amsterdam from Dutch origin having a relatively high mortality and low life expectancy. DISCUSSION: In this paper the "healthy migrant effect" can be clearly observed. An important cause is the emigration of the original and relatively affluent and healthy Dutch population to suburban areas. Mortality trends tend to converge between ethnic groups during the period 1997-2000 and 2004-2007. The data presented here shows further that trends in mortality and life expectancy which apply to all ethnic groups are much more powerful as this convergence. One wonders if bridging the mortality gap between groups is of much benefit for minority groups, or that minority groups would benefit more from an overall decrease in mortality. CONCLUSION: Mortality trends that apply to all groups tend to be much stronger compared with trends for individual groups. This shows that dynamics affecting all groups similarly have a considerably stronger effect on mortality outcomes in various ethnic groups compared with possible convergence. PMID- 26611869 TI - First-trimester screening for trisomies 18 and 13, triploidy and Turner syndrome by detailed early anomaly scan. AB - OBJECTIVE: To examine the performance of first-trimester ultrasound screening for trisomies 18 and 13, triploidy and Turner syndrome based on fetal nuchal translucency thickness (NT), additional fetal ultrasound markers including anatomy of the nasal bone (NB), blood flow across the tricuspid valve (TV) and through the ductus venosus (DV) and a detailed fetal anomaly scan at 11-13 weeks' gestation. METHODS: This was a retrospective case-matched study involving pregnant women at 11-13 weeks' gestation. The study population consisted of fetuses with trisomy 18, trisomy 13, triploidy or Turner syndrome. For each fetus with an abnormal karyotype, 50 randomly selected euploid fetuses were added to the study population. In all cases, the crown-rump length and NT were measured. In addition NB, TV flow and DV flow were examined. The summed risk for trisomies 21, 18 and 13 was computed based on: first, maternal age (MA); second, MA and fetal NT; third, MA, NT and one of the markers NB, TV flow or DV flow; fourth, MA, NT and all these markers combined; fifth, MA, NT and fetal anomalies; and, finally, MA, NT, all markers and fetal anomalies. RESULTS: The study population consisted of 4550 euploid and 91 aneuploid fetuses. Median NT was 1.8 mm in euploid fetuses and 4.8, 6.8, 1.8 and 10.0 mm in fetuses with trisomy 18, trisomy 13, triploidy and Turner syndrome, respectively. The NB, TV flow and DV flow were abnormal in 48 (1.1%), 34 (0.7%) and 99 (2.2%) euploid fetuses, respectively, and in 42 (46.2%), 31 (34.1%) and 62 (68.1%) aneuploid fetuses, respectively. At least one defect was found in 60 (1.3%) euploid and in 76 (83.5%) aneuploid fetuses. For a false-positive rate of 3%, the detection rate for screening based on MA and fetal NT was 75.8%. It increased to 84.6-86.8% when including one of the additional ultrasound markers and it was 90.1% when all three markers were included. When screening was based on MA, fetal NT and a detailed anomaly scan, the detection rate was 94.5% and increased to 95.6% with the addition of NB, TV flow and DV flow. CONCLUSION: A detailed anomaly scan at 11-13 weeks' gestation can identify about 95% of fetuses with trisomy 18, trisomy 13, triploidy and Turner syndrome. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26611870 TI - Non-invasive molecular imaging of inflammatory macrophages in allograft rejection. AB - BACKGROUND: Macrophages represent a critical cell type in host defense, development and homeostasis. The ability to image non-invasively pro-inflammatory macrophage infiltrate into a transplanted organ may provide an additional tool for the monitoring of the immune response of the recipient against the donor graft. We therefore decided to image in vivo sialoadhesin (Sn, Siglec 1 or CD169) using anti-Sn mAb (SER-4) directly radiolabelled with (99m)Tc pertechnetate. METHODS: We used a heterotopic heart transplantation model where allogeneic or syngeneic heart grafts were transplanted into the abdomen of recipients. In vivo nanosingle-photon emission computed tomography (SPECT/CT) imaging was performed 7 days post transplantation followed by biodistribution and histology. RESULTS: In wild-type mice, the majority of (99m)Tc-SER-4 monoclonal antibody cleared from the blood with a half-life of 167 min and was located predominantly on Sn(+) tissues in the spleen, liver and bone marrow. The biodistribution in the transplantation experiments confirmed data derived from the non-invasive SPECT/CT images, with significantly higher levels of (99m)Tc-SER-4 observed in allogeneic grafts (9.4 (+/-2.7) %ID/g) compared to syngeneic grafts (4.3 (+/-10.3) %ID/g) (p = 0.0022) or in mice which received allogeneic grafts injected with (99m)Tc-IgG isotype control (5.9 (+/-0.6) %ID/g) (p = 0.0185). The transplanted heart to blood ratio was also significantly higher in recipients with allogeneic grafts receiving (99m)Tc-SER-4 as compared to recipients with syngeneic grafts (p = 0.000004) or recipients with allogeneic grafts receiving (99m)Tc-IgG isotype (p = 0.000002). CONCLUSIONS: Here, we demonstrate that imaging of Sn(+) macrophages in inflammation may provide an important additional and non-invasive tool for the monitoring of the pathophysiology of cellular immunity in a transplant model. PMID- 26611871 TI - Current Controversies With Recent Cholesterol Treatment Guidelines. AB - Several guidelines and expert recommendations have been published recently regarding the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD) risk. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend a drastic paradigm change in the treatment of cholesterol where treatment, based on level of cardiovascular risk, is based around using a fixed statin intensity therapy. This approach is endorsed by the American Diabetes Association. However, recommendations by the National Lipid Association (NLA) consist of the traditional approach of titrating therapy to achieve patient-specific lipoprotein targets. Despite the differences in overall approaches, the use of statin therapy as the cornerstone of treatment to reduce risk of cardiovascular events in at risk patients is a strong common theme. Clinicians should be aware of these differences, as they represent controversies with the overall treatment of ASCVD risk. Additional controversies related to the treatment of patients with ASCVD risk pertain to the role of nonstatin drugs and approaches to managing side effects. These topics are reviewed within this article and discuss implications for patient care. PMID- 26611872 TI - Concurrent and aerobic exercise training promote similar benefits in body composition and metabolic profiles in obese adolescents. AB - BACKGROUND: The prevalence of obesity in pediatric population is increasing at an accelerated rate in many countries, and has become a major public health concern. Physical activity, particularly exercise training, remains to be a cornerstone of pediatric obesity interventions. The purpose of our current randomized intervention trial was to compare the effects of two types of training matched for training volume, aerobic and concurrent, on body composition and metabolic profile in obese adolescents. Thus the aim of the study was compare the effects of two types of training matched for training volume, aerobic and concurrent, on body composition and metabolic profile in obese adolescents. METHODS: 32 obese adolescents participated in two randomized training groups, concurrent or aerobic, for 20 weeks (50 mins x 3 per week, supervised), and were compared to a 16-subject control group. We measured the percentage body fat (%BF, primary outcome), fat-free mass, percentage of android fat by dual energy x-ray absorptiometry, and others metabolic profiles at baseline and after interventions, and compared them between groups using the Intent-to-treat design. RESULTS: In 20 weeks, both exercise training groups significantly reduced %BF by 2.9-3.6% as compare to no change in the control group (p = 0.042). There were also positive changes in lipid levels in exercise groups. No noticeable changes were found between aerobic and concurrent training groups. CONCLUSIONS: The benefits of exercise in reducing body fat and metabolic risk profiles can be achieved by performing either type of training in obese adolescents. TRIAL REGISTRATION: REGISTRATION NUMBER: RBR-4HN597. PMID- 26611873 TI - Mobile phone applications in management of enuresis: The good, the bad, and the unreliable! AB - INTRODUCTION: The proliferation of medical-type applications or 'apps' on smartphones is a typical example of the impact technology has had on medical practice. Maintaining a bladder diary is a recommended part of evaluating the effect of interventions for patients suffering from enuresis. Traditional pen-and paper bladder diaries have poor completion rates, inconsistent patterns in data entry, and are deficient in validation. Electronic bladder diaries have been proposed to overcome these obstacles. With increasing numbers of smartphone apps available to the general public, it is important to distinguish well-designed apps for childhood enuresis. PURPOSE: To identify, evaluate, and rank all available mobile-phone apps for the management of childhood enuresis. METHODS: On August 21, 2014, a search was conducted on iTunes, Android Play Store, and BlackBerry World for smartphone apps using the following search terms: bladder, bedwetting, bladder diary, enuresis, incontinence, and wetting. Apps that did not have a bladder diary function and that were unrelated to the investigation, follow-up, and treatment of childhood enuresis were excluded. Apps were rated by a paediatric urology consultant, fellow, registrar, and resident medical officer using standardised criteria including: design; ease of use; languages; quality of instructions; security; accordance with ICCS definition of enuresis; and ability to store histories; record bowel habits; transfer data to other devices; and print data. RESULTS: Across all three search platforms, a total of 1041 apps were identified. Only 24 were included and reviewed based on exclusion criteria. Average ratings for apps ranged from 10 to 30.75 out of 50 based on standardised criteria. DISCUSSION: Smartphone apps are playing an increasingly significant role in the management of enuresis in place of pen-and-paper bladder diaries. Apps available to the general public vary in quality and it can be difficult for patients to identify one appropriate for use. We found apps with higher ratings consistently had engaging interfaces, were easy to use, and defined the primary purpose clearly. Lower ratings and performance often was caused by poor quality of experience through "freezing"/"crashing." CONCLUSION: Bladder diary apps can eliminate disadvantages of pen-and-paper diaries in the management of enuresis. Currently, apps available vary in quality. The three best-rated apps currently available are My Dryness Tracker, Bedwetting Tracker, and HapPee Time. There is room for medical associations to collaborate with developers for further app development. PMID- 26611874 TI - Reassessment of the Necessity of the Proton Gantry: Analysis of Beam Orientations From 4332 Treatments at the Massachusetts General Hospital Proton Center Over the Past 10 Years. AB - PURPOSE: To retrospectively analyze the beam approaches used in gantry-based proton treatments, and to reassess the practical advantages of the gantry, compared with beam approaches that are achievable without a gantry, in the context of present-day technology. METHODS AND MATERIALS: We reviewed the proton therapy plans of 4332 patients treated on gantries at our hospital, delivered by the double scattering technique (n=4228) and, more recently, pencil beam scanning (PBS) (n=104). Beam approaches, relative to the patient frame, were analyzed individually to identify cases that could be treated without a gantry. Three treatment configurations were considered, with the patient in lying position, sitting position, or both. The FIXED geometry includes a fixed horizontal portal. The BEND geometry enables a limited vertical inflection of the beam by up to 20 degrees . The MOVE geometry allows for flexibility of the patient head and body setup. RESULTS: The percentage of patients with head and neck tumors that could be treated without a gantry using double scattering was 44% in FIXED, 70% in 20 degrees BEND, and 100% in 90 degrees MOVE. For torso regions, 99% of patients could be treated in 20 degrees BEND. Of 104 PBS treatments, all but 1 could be reproduced with FIXED geometry. The only exception would require a 10 degrees BEND capability. Note here that the PBS treatments were applied to select anatomic sites, including only 2 patients with skull-base tumors. CONCLUSIONS: The majority of practical beam approaches can be realized with gantry-less delivery, aided by limited beam bending and patient movements. Practical limitations of the MOVE geometry, and treatments requiring a combination of lying and sitting positions, may lower the percentage of head and neck patients who could be treated without a gantry. Further investigation into planning, immobilization, and imaging is needed to remove the practical limitations and to facilitate proton treatment without a gantry. PMID- 26611875 TI - Initial Report of a Prospective Dosimetric and Clinical Feasibility Trial Demonstrates the Potential of Protons to Increase the Therapeutic Ratio in Breast Cancer Compared With Photons. AB - PURPOSE: To compare dosimetric endpoints between proton therapy (PT) and conventional radiation and determine the feasibility of PT for regional nodal irradiation (RNI) in women with breast cancer. METHODS AND MATERIALS: From 2012 to 2014, 18 women (stage IIA-IIIB) requiring RNI prospectively enrolled on a pilot study. Median age was 51.8 years (range, 42-73 years). The cohort included breast-conserving therapy (BCT) and mastectomy patients and right- and left-sided cancers. Treatment targets and organs at risk were delineated on computed tomography scans, and PT and conventional plans were developed. Toxicity was prospectively recorded using Common Terminology Criteria for Adverse Events version 4.0. A Wilcoxon signed-rank sum test compared the dose-volume parameters. The primary endpoint was a reduction in cardiac V5. RESULTS: Median follow-up was 20 months (range, 2-31 months). For all patients, the PT plan better met the dosimetric goals and was used for treatment. Proton therapy alone was used for 10 patients (9 postmastectomy, 1 after BCT) and combined proton-photon in 8 (6 BCT, 2 postmastectomy with immediate expander reconstruction). Proton therapy improved coverage of level 2 axilla (P=.0005). Adequate coverage of internal mammary nodes was consistently achieved with PT (median D95, 50.3 Gy; range, 46.6-52.1 Gy) but not with conventional radiation therapy (median D95, 48.2 Gy; range, 40.8-55 Gy; P=.0005). Median cardiac V5 was 0.6% with PT and 16.3% with conventional radiation (P<.0001). Median ipsilateral lung V5 and V20 were improved with PT (median V5 35.3% vs 60.5% [P<.0001]; and median V20, 21.6% vs 35.5% [P<.0001]). Grade 3 dermatitis developed in 4 patients (22%), which was the only grade 3 toxicity. No grade 4+ toxicities developed. CONCLUSION: Proton therapy for RNI after mastectomy or BCT significantly improves cardiac dose, especially for left sided patients, and lung V5 and V20 in all patients without excessive acute toxicity. Proton therapy simultaneously improves target coverage for the internal mammary nodes and level 2 axilla, which may positively impact long-term survival in breast cancer patients. PMID- 26611878 TI - Paclitaxel-Loaded beta-Cyclodextrin-Modified Poly(Acrylic Acid) Nanoparticles through Multivalent Inclusion for Anticancer Therapy. AB - A nanoassembled drug delivery system for anticancer treatment, formed by the host guest interactions between paclitaxel (PTX) and beta-cyclodextrin (beta-CD) modified poly(acrylic acid) (PCDAA), is successfully prepared. After such design, the aqueous solubility of PTX is greatly increased from 0.34 to 36.02 MUg mL(-1), and the obtained PCDAA-PTX nanoparticles (PCDAA-PTX NPs) exhibit a sustained PTX release behavior in vitro. In vitro cytotoxicity finds that PCDAA-PTX NPs can accumulate significantly in tumor cells and remain the pharmacological activity of PTX. The in vivo real-time biodistribution of PCDAA-PTX NPs is investigated using near-infrared fluorescence imaging, indicating that the PCDAA-PTX NPs can effectively target to the tumor site by the enhanced permeability and retention effect in H22 tumor-bearing mice. Through in vivo antitumor examination, PCDAA PTX NPs exhibit superior efficacy in impeding the tumor growth compared to the commercially available Taxol(r). PMID- 26611879 TI - [Liver and intestinal transplant in paediatric population]. AB - Our organizational model allows an annual 1,000 liver transplants. Pediatric liver transplantation constitutes 5% of such activity and provides, in children with severe, progressive and irreversible liver disease, a 1 year-survival of 90% and more than 80% after 15 years of follow-up. The main indication is biliary atresia followed by metabolic liver disease and acute liver failure. Around half of the procedures are performed in children under two years and 25-30% in the first year of life. The waiting list remains at around 35 patients, with an average of 100 patients enrolled annually and 60 of them finally transplanted after an average of 136.3 days on the waiting list. The prioritization of the candidates uses the PELD as an objective tool for decision-making. However, the progressive aging of donors, with a profile increasingly different from the requirements of the pediatric patients included in the waiting list, requires strategies such as living donor liver transplantation and the split liver transplantation, to increase the probability of transplant while reducing both time and mortality on the waiting list at the same time. Pediatric intestinal transplantation registers a low indication but involves strict requirements that outline a very uncommon donor in our country which, together with the absence of alternatives that outweigh the impact of these difficulties, penalizes the chances of transplant for these patients. PMID- 26611877 TI - Ascending aortic aneurysm repair and surgical ablation for atrial fibrillation. AB - BACKGROUND: Although surgical ablation of atrial fibrillation is commonly performed during concomitant coronary or valve surgery, it is still only performed in a fraction these cases when indicated, and less often in patients undergoing aneurysm surgery. We describe our experience in patients undergoing ascending aneurysm repair and concomitant atrial fibrillation ablation. METHODS: From January 2004 until November 2011, 40 patients underwent ascending aneurysm repair and atrial fibrillation ablation at our institution and were retrospectively analyzed. RESULTS: Average age was 67.6 years (43-85). Root replacement was performed in 23 (57.5 %) and arch replacement with circulatory arrest in 18 (45 %). At an average of 41.8 months, 81 % of patients were in sinus rhythm. Operative survival was 100 %, with 1 and 5 year survival of 97.5 and 93.1 %, respectively. Kaplan-Meier analysis revealed improved overall survival in patients with rhythm success (log-rank test p = 0.037). CONCLUSIONS: Aortic aneurysm repair with concomitant atrial fibrillation ablation is safe and efficacious despite the requirement for an already extensive procedure with rhythm success rates similar to those quoted in the setting of other procedures. Successful restoration of sinus rhythm improves long term survival and should be considered in patients presenting with aortic aneurysm and atrial fibrillation. PMID- 26611876 TI - Mitophagy programs: mechanisms and physiological implications of mitochondrial targeting by autophagy. AB - Mitochondria are an essential source of ATP for cellular function, but when damaged, mitochondria generate a plethora of stress signals, which lead to cellular dysfunction and eventually programmed cell death. Thus, a major component of maintaining cellular homeostasis is the recognition and removal of dysfunctional mitochondria through autophagy-mediated degradation, i.e., mitophagy. Mitophagy further constitutes a developmental program, and undergoes a high degree of crosstalk with apoptosis. Reduced mitochondrial quality control is linked to disease pathogenesis, suggesting the importance of process elucidation as a clinical target. Recent work has revealed multiple mitophagy programs that operate independently or undergo crosstalk, and require modulated autophagy receptor activities at outer membranes of mitochondria. Here, we review these mitophagy programs, focusing on pathway mechanisms which recognize and target mitochondria for sequestration by autophagosomes, as well as mechanisms controlling pathway activities. Furthermore, we provide an introduction to the currently available methods for detecting mitophagy. PMID- 26611880 TI - [Probiotic associations in the prevention of necrotising enterocolitis and the reduction of late-onset sepsis and neonatal mortality in preterm infants under 1,500g: A systematic review]. AB - INTRODUCTION AND OBJECTIVE: Necrotising enterocolitis (NEC) is one of the most common and serious acquired bowel diseases a premature newborn can face. This meta-analysis was performed comparing different probiotic mixtures to ascertain their benefits as a routine tool for preventing necrotising enterocolitis and reducing late-onset sepsis and mortality in premature neonates of less than 1500g. MATERIAL AND METHODS: A systematic review of randomised controlled trials, between January 1980 and March 2014, on MEDLINE, the Cochrane Central Register of Controlled Trials, together with EMBASE, was carried out. Studies with infants <1500g or <34 weeks were selected, discarding those with Jadad scores lower than 4. RESULTS: 9 studies were selected for further investigation, pooling a total of 3521 newborns. Probiotics were found to reduce the NEC incidence (RR 0.39; 95%CI: 0.26-0.57) and mortality (RR 0.70; 95%CI: 0.52-0.93), with no difference to placebo regarding late-onset sepsis (RR 0.91; 95%CI: 0.78-1.06). Finally, when analysing the different strands, the use of a 2-probiotic combination (Lactobacillus acidophilus with Bifidobacterium bifidum) proved to be statistically significant in reducing all-cause mortality when compared to other probiotic combinations (RR 0.32; 95%CI: 0.15-0.66, NNT 20; 95%CI: 12-50). CONCLUSIONS: Probiotics are a beneficial tool in the prevention of NEC and mortality in preterm neonates. Moreover, the combination of 2 probiotics (Lactobacillus acidophilus with Bifidobacterium bifidum) seems to produce the greatest benefits. However, due to the differences in probiotic components and administration, it would be wise to perform a randomised controlled trial comparing different probiotic mixtures. PMID- 26611881 TI - Defining A-Kinase Anchoring Protein (AKAP) Specificity for the Protein Kinase A Subunit RI (PKA-RI). AB - A-Kinase anchoring proteins (AKAPs) act as spatial and temporal regulators of protein kinase A (PKA) by localizing PKA along with multiple proteins into discrete signaling complexes. AKAPs interact with the PKA holoenzyme through an alpha-helix that docks into a groove formed on the dimerization/docking domain of PKA-R in an isoform-dependent fashion. In an effort to understand isoform selectivity at the molecular level, a library of protein-protein interaction (PPI) disruptors was designed to systematically probe the significance of an aromatic residue on the AKAP docking sequence for RI selectivity. The stapled peptide library was designed based on a high affinity, RI-selective disruptor of AKAP binding, RI-STAD-2. Phe, Trp and Leu were all found to maintain RI selectivity, whereas multiple intermediate-sized hydrophobic substitutions at this position either resulted in loss of isoform selectivity (Ile) or a reversal of selectivity (Val). As a limited number of RI-selective sequences are currently known, this study aids in our understanding of isoform selectivity and establishing parameters for discovering additional RI-selective AKAPs. PMID- 26611882 TI - Sodium-glucose cotransporter 2 inhibitors and diabetic ketoacidosis. PMID- 26611883 TI - Covered Stents and Coil Embolization for Treatment of Postpancreatectomy Arterial Hemorrhage. AB - PURPOSE: To evaluate the efficacy and clinical outcomes associated with stent graft placement and coil embolization for postpancreatectomy arterial hemorrhage (PPAH). MATERIALS AND METHODS: Retrospective review of 38 stent-graft and/or embolization procedures in 28 patients (23 men; mean age, 65.1 y) for PPAH between 2007 and 2014 was performed. Time of bleeding, source of hemorrhage, intervention and devices used, repeat intervention rate, time to recurrent bleeding, complications, and 30-day mortality were assessed. Independent risk factors for recurrent bleeding and 30-day mortality were identified. RESULTS: Median onset of hemorrhage was at 39 days (mean, 27.9 d; range, 5-182 d). Covered stents were used in 65.7% of interventions, coil embolization in 23.6%, stent assisted embolization in 5.2%, and stent-graft angioplasty in 2.6%. A total of 28 stent-grafts were placed, of which 19 were self-expandable and nine were balloon mounted. Mean stent-graft diameter was 6.6 mm (range, 5-10 mm). Recurrent bleeding occurred following 26.3% of interventions in seven patients at a mean interval of 22 days. The site of recurrent bleeding was new in 80% of cases. There was no significant difference in recurrent bleeding rate in early-onset (< 30 d; n = 22) versus late-onset PPAH (> 30 d; n = 6; P > .05). No ischemic hepatic or bowel complications were identified. The 30-day mortality rate was 7.1% (n = 2) and was significantly higher in patients with initial PPAH at >= 39 days (n = 5; P = .007). CONCLUSIONS: Covered stents and coil embolization are effective for managing PPAH and maintaining distal organ perfusion to minimize morbidity and mortality. Recurrent bleeding is common and most often occurs from new sites of vascular injury rather than previously treated ones. PMID- 26611884 TI - Uncertainty and variability in models of the cardiac action potential: Can we build trustworthy models? AB - Cardiac electrophysiology models have been developed for over 50years, and now include detailed descriptions of individual ion currents and sub-cellular calcium handling. It is commonly accepted that there are many uncertainties in these systems, with quantities such as ion channel kinetics or expression levels being difficult to measure or variable between samples. Until recently, the original approach of describing model parameters using single values has been retained, and consequently the majority of mathematical models in use today provide point predictions, with no associated uncertainty. In recent years, statistical techniques have been developed and applied in many scientific areas to capture uncertainties in the quantities that determine model behaviour, and to provide a distribution of predictions which accounts for this uncertainty. In this paper we discuss this concept, which is termed uncertainty quantification, and consider how it might be applied to cardiac electrophysiology models. We present two case studies in which probability distributions, instead of individual numbers, are inferred from data to describe quantities such as maximal current densities. Then we show how these probabilistic representations of model parameters enable probabilities to be placed on predicted behaviours. We demonstrate how changes in these probability distributions across data sets offer insight into which currents cause beat-to-beat variability in canine APs. We conclude with a discussion of the challenges that this approach entails, and how it provides opportunities to improve our understanding of electrophysiology. PMID- 26611885 TI - Not low hanging but still sweet: Metabolic proteomes in cardiovascular disease. AB - The application of proteomics in biology and medicine has reached a moment of truth. The demand of biologists for transformative insights into how cells work, plus the mandate of basic science research to ultimately impact clinical medicine, crystallize as a test on the rigor and reproducibility of any 'omics measurement. Studies like that by Boylston et al. indicate that proteomics can pass that test. PMID- 26611886 TI - Parkin-dependent mitophagy in the heart. AB - Mitochondria can undergo autophagic elimination for differing reasons, e.g. as part of a cell-wide macroautophagic response, as part of mitochondrial turnover during metabolic remodeling, or in the case of selective mitophagic destruction of dysfunctional mitochondria, during mitochondrial quality control. Multiple mechanistically distinct pathways converge upon, and activate, mitochondrial autophagy. Here, the evidence supporting a role for the prototypical mitochondrial quality control pathway, PINK1-Parkin mediated mitophagy, in cardiac homeostasis and heart disease is reviewed. Contrary to popular wisdom based on findings from non-cardiac systems, current data do not support a major role for Parkin-mediated mitophagy as a mechanism for constitutive mitochondrial housekeeping, and instead suggest that this pathway primarily functions in adult hearts as an inducible cardiac stress-response mechanism. Recent findings have also uncovered an unsuspected role for Parkin-mediated mitochondrial turnover in the normal perinatal transformation of myocardial metabolism. PMID- 26611887 TI - [Experiences of adolescents seropositive for HIV/AIDS: a qualitative study]. AB - OBJECTIVE: Explore the meanings attributed by young individuals about "living as an adolescent with HIV" in a group of patients that acquired the infection at birth and the elements involved with the adherence to antiretroviral treatment. METHODS: Qualitative study, involving 20 subjects (aged 13-20 years), followed at services specialized in the treatment of pediatric Aids in Sao Paulo, Brazil. Semi-structured interviews were carried out of which script consisted of questions about their personal histories, experiences and difficulties they must face while living with HIV/Aids. RESULTS: Being "normal" and "different" were central issues voiced by the participants. However, a normal life situation is guaranteed by being responsible with one's health, the condition that the diagnosis be kept secret and concerns about HIV transmission and dissemination to a sexual partner. The answers about treatment show that adherence is a dynamic process and involves moments of greater or lesser interest in relation to care for one's health. The adolescents have plans and projects and although HIV is considered a stressor, positive perspectives for the future prevailed. CONCLUSIONS: To live as an adolescent with HIV involves subtle dimensions that need to be recognized and legitimized by professionals who follow the trajectory of these young individuals. It is necessary to allow a space in which the adolescents can reflect and find support regarding issues related to the construction of their sexuality and care of one's own body. PMID- 26611888 TI - [Cerebral blood flow assessment of preterm infants during respiratory therapy with the expiratory flow increase technique]. AB - OBJECTIVE: To assess the impact of respiratory therapy with the expiratory flow increase technique on cerebral hemodynamics of premature newborns. METHODS: This is an intervention study, which included 40 preterm infants (<=34 weeks) aged 8 15 days of life, clinically stable in ambient air or oxygen catheter use. Children with heart defects, diagnosis of brain lesion and/or those using vasoactive drugs were excluded. Ultrasonographic assessments with transcranial Doppler flowmetry were performed before, during and after the increase in expiratory flow session, which lasted 5minutes. Cerebral blood flow velocity and resistance and pulsatility indices in the pericallosal artery were assessed. RESULTS: Respiratory physical therapy did not significantly alter flow velocity at the systolic peak (p=0.50), the end diastolic flow velocity (p=0.17), the mean flow velocity (p=0.07), the resistance index (p=0.41) and the pulsatility index (p=0.67) over time. CONCLUSIONS: The expiratory flow increase technique did not affect cerebral blood flow in clinically-stable preterm infants. PMID- 26611889 TI - [Atypical presentation of intra-abdominal extralobar pulmonary sequestration detected in prenatal care: a case report]. AB - OBJECTIVE: To describe an unusual clinical presentation of intra-abdominal extralobar pulmonary sequestration in a 2-year, 9 month-old patient and assess diagnostic and treatment aspects of this pathology. CASE DESCRIPTION: An undefined intra-abdominal mass was identified in the right adrenal region in a male fetus. Postnatal evaluation with ultrasound images, computed tomography, magnetic resonance imaging and laboratory testing was insufficient to determine the nature of the lesion. After two years, laparoscopic resection of the mass and histopathological examination of the surgical specimen allowed to establish the diagnosis of intra-abdominal extralobar pulmonary sequestration. COMMENTS: This malformation can be monitored clinically; however, surgical excision is often performed, probably due to the impossibility of attaining diagnosis with non invasive methods, such as in the present case, in which the lesion appeared in an unusual position for intra-abdominal extralobar pulmonary sequestration. Therefore, the surgical approach seems to be the key to attain the diagnosis and establish the conduct for this type of congenital malformation. PMID- 26611890 TI - Vitamin D status in youth with type 1 and type 2 diabetes enrolled in the Pediatric Diabetes Consortium (PDC) is not worse than in youth without diabetes. AB - OBJECTIVE: To describe vitamin D levels and prevalence of vitamin D sufficiency, insufficiency and deficiency in a large, ethnically/racially diverse population of youth with type 1 diabetes (T1D) and type 2 diabetes (T2D) in comparison to national data and examine the associations between clinical/demographic factors and vitamin D levels. METHODS: 25-hydroxy vitamin D (25OHD) levels were measured in 215 youth with T1D and 326 youth with T2D enrolled in the Pediatric Diabetes Consortium (PDC). These levels were compared with those of youth of the same age without diabetes from the 2005-2006 NHANES Survey. RESULTS: Vitamin D deficiency (<21 ng/mL) was present in 36% of PDC participants, and insufficiency (21-29 ng/mL) was present in an additional 34%. About 36% of age-matched youth in the NHANES Survey were vitamin D deficient and an additional 41% were insufficient. Deficiency or insufficiency varied by race/ethnicity, being highest in African Americans (86%), intermediate in Hispanics (77%), and lowest in non-Hispanic whites (47%). Lower 25OHD levels were observed in African-American and Hispanic youth, during fall and winter, and at sites in the northern United States (all p values < 0.001). Youth with T2D had significantly lower 25OHD levels than youth with T1D (p < 0.001), but this difference was largely eliminated after adjusting for race/ethnicity and socio-economic status. CONCLUSIONS: Vitamin D deficiency/insufficiency is present in a substantial proportion of youth with diabetes, particularly minorities, but the prevalence appears similar to that in youth without diabetes. Further studies are needed to examine whether youth with diabetes would benefit from vitamin D supplementation. PMID- 26611891 TI - A new model for non-typeable Haemophilus influenzae middle ear infection in the Junbo mutant mouse. AB - Acute otitis media, inflammation of the middle ear, is the most common bacterial infection in children and, as a consequence, is the most common reason for antimicrobial prescription to this age group. There is currently no effective vaccine for the principal pathogen involved, non-typeable Haemophilus influenzae (NTHi). The most frequently used and widely accepted experimental animal model of middle ear infection is in chinchillas, but mice and gerbils have also been used. We have established a robust model of middle ear infection by NTHi in the Junbo mouse, a mutant mouse line that spontaneously develops chronic middle ear inflammation in specific pathogen-free conditions. The heterozygote Junbo mouse (Jbo/+) bears a mutation in a gene (Evi1, also known as Mecom) that plays a role in host innate immune regulation; pre-existing middle ear inflammation promotes NTHi middle ear infection. A single intranasal inoculation with NTHi produces high rates (up to 90%) of middle ear infection and bacterial titres (10(4)-10(5) colony-forming units/ul) in bulla fluids. Bacteria are cleared from the majority of middle ears between day 21 and 35 post-inoculation but remain in approximately 20% of middle ears at least up to day 56 post-infection. The expression of Toll like receptor-dependent response cytokine genes is elevated in the middle ear of the Jbo/+ mouse following NTHi infection. The translational potential of the Junbo model for studying antimicrobial intervention regimens was shown using a 3 day course of azithromycin to clear NTHi infection, and its potential use in vaccine development studies was shown by demonstrating protection in mice immunized with killed homologous, but not heterologous, NTHi bacteria. PMID- 26611892 TI - Finger skin temperatures in 8- to 11-year-old children: determinants including physical characteristics and seasonal variation. The Physical Activity and Nutrition in Children (PANIC) Study. AB - PURPOSE: The fingertip skin temperature (FST) reflects skin blood flow, and FST measurement has been suggested for the investigation of vascular responses. As a limitation, the multifactorial nature and the seasonal variation in measured values have been earlier described in adults but not in children. In the present study, we identify the modifiers of FST in a population sample of Finnish children. METHODS: FST was measured in children (age range 8-11 years, n = 432) with infrared thermometer, and its possible determinants including the subjects' physical characteristics and seasonal variables, such as daylight time and outdoor temperature, were identified. RESULTS: In univariate regression models, FST was dependent on the sex, age and anthropometric characteristics of the children with the higher body fat content-related variables and a lower surface area-to-mass ratio as strongest single modifiers of FST. There was interaction between sex and puberty with FST. In addition, FST was directly related to daylight time and outdoor temperature although the children had stayed inside for at least 2 h before the measurements. The FST values were lowest in the winter and highest in the summer. In multivariate regression model, main determinants of FST were a higher body fat percentage (standardized regression coefficient beta = 0.472; p < 0.001), male sex (beta = 0.291; p < 0.001) and longer daylight time (0.226; p < 0.001). CONCLUSIONS: Altogether, complex effects of body composition and sex with the confounding effect of seasonal variation may complicate the use of FST as a tool to study the vascular function in children. PMID- 26611893 TI - Evaluating the effect of a proposed logistics fee cap on pharmaceuticals in South Africa--a pre and post analysis. AB - BACKGROUND: South Africa has proposed the implementation of a maximum logistics fee paid by pharmaceutical manufacturers to wholesalers and distributors. However very little knowledge exists of the effects, unintended or otherwise, of the implementation of these proposed regulations, which are required to guide further policy development and implementation. The objectives of this study was to therefore evaluate the effects of the proposed logistics fee cap on different pharmaceuticals and different dosage forms, as well as to observe the logistics fee contribution to the Single Exit Price. METHODS: Private sector medicine prices were sourced from the South African Medicine Price Registry as at 20 December 2013. For each medicine the maximum logistics fee was calculated based on the 2012 proposed government guidelines. The logistics fee as a percentage of the final Single Exit Price was calculated, as part of the analysis of results. RESULTS: Out of the 47 medicines in the overall sample from the current study, only 16 medicines showed a decrease in the Single Exit Price with the application of the maximum logistics fee cap. CONCLUSION: This study reveals the need for greater transparency of the mark ups along the distribution chain as well as further research with regards to the costing of logistics fees of similar pharmaceuticals. PMID- 26611894 TI - Acute Onset of Anemia After IV Immunoglobulin. PMID- 26611895 TI - Neuroprotective effects of Cerebrolysin in triple repeat Tau transgenic model of Pick's disease and fronto-temporal tauopathies. AB - BACKGROUND: Tauopathies are a group of neurodegenerative disorders with accumulation of three-repeat (3R) or four-repeat (4R) Tau. While 3R tau is found in Pick's disease and Alzheimer's disease (AD), 4R tau is more abundant in corticobasal degeneration, progressive supranuclear palsy, and AD. We have previously shown that CerebrolysinTM (CBL), a neuropeptide mixture with neurotrophic effects, ameliorates the pathology in amyloid precursor protein transgenic (tg) mouse model of AD and 4R tau, however it is unclear if CBL ameliorates the deficits and neuropathology in the mouse model of Pick's disease over expressing 3R tau. RESULTS: Mice expressing 3R tau (L266V and G272V mutations) under the mThy-1 promoter were treated with CBL in two separate groups, the first was 3 months old (treated for 3 months, IP) and the second was 6 months old (treated for 3 months, IP) at the start of the treatment. We found that although the levels of total 3R tau were unchanged, CBL reduced the levels of hyper-phosphorylated tau in both groups of mice. This was accompanied by reduced neurodegenerative pathology in the neocortex and hippocampus in both groups and by improvements in the behavioral deficits in the nest-building test and water maze in the 3-6 month group. CONCLUSION: Taken together these results support the notion that CBL may be beneficial in other taupathy models by reducing the levels of aberrantly phosphorylated tau. PMID- 26611896 TI - Reliability of classification for post-traumatic ankle osteoarthritis. AB - PURPOSE: The purpose of this study was to identify the most reliable classification system for clinical outcome studies to categorize post-traumatic fracture-osteoarthritis. METHODS: A total of 118 orthopaedic surgeons and residents-gathered in the Ankle Platform Study Collaborative Science of Variation Group-evaluated 128 anteroposterior and lateral radiographs of patients after a bi- or trimalleolar ankle fracture on a Web-based platform in order to rate post traumatic osteoarthritis according to the classification systems coined by (1) van Dijk, (2) Kellgren, and (3) Takakura. Reliability was evaluated with the use of the Siegel and Castellan's multirater kappa measure. Differences between classification systems were compared using the two-sample Z-test. RESULTS: Interobserver agreement of surgeons who participated in the survey was fair for the van Dijk osteoarthritis scale (k = 0.24), and poor for the Takakura (k = 0.19) and the Kellgren systems (k = 0.18) according to the categorical rating of Landis and Koch. This difference in one categorical rating was found to be significant (p < 0.001, CI 0.046-0.053) with the high numbers of observers and cases available. CONCLUSIONS: This study documents fair interobserver agreement for the van Dijk osteoarthritis scale, and poor interobserver agreement for the Takakura and Kellgren osteoarthritis classification systems. Because of the low interobserver agreement for the van Dijk, Kellgren, and Takakura classification systems, those systems cannot be used for clinical decision-making. LEVEL OF EVIDENCE: Development of diagnostic criteria on basis of consecutive patients, Level II. PMID- 26611897 TI - Physical examination tests and imaging studies based on arthroscopic assessment of the long head of biceps tendon are invalid. AB - PURPOSE: The aim of this study was to evaluate whether glenohumeral arthroscopy is an appropriate gold standard for the diagnosis of long head of biceps (LHB) tendon pathology. The objectives were to evaluate whether the length of tendon that can be seen at arthroscopy allows visualisation of areas of predilection of pathology and also to determine the rates of missed diagnoses at arthroscopy when compared to an open approach. METHODS: A systematic review of cadaveric and clinical studies was performed. The search strategy was applied to MEDLINE, PubMed and Google Scholar databases. All relevant articles were included. Critical appraisal of clinical studies was performed using a validated quality assessment scale. RESULTS: Five articles were identified for inclusion in the review. This included both clinical and cadaveric studies. The overall population comprised 18 cadaveric specimens and 575 patients. Out of the five included studies, three reported the length of LHB tendon visualised during arthroscopy and four reported the rate of missed LHB diagnosis. Cadaveric studies showed that the use of a hook probe allowed arthroscopic visualisation of between 34 and 48 % of the overall length of the LHB. In the clinical series, the rate of missed diagnoses at arthroscopy when compared to open exploration ranged between 33 and 49 %. CONCLUSIONS: Arthroscopy allows visualisation of only a small part of the extra-articular LHB tendon. This leads to a high rate of missed pathology in the distal part of the tendon. Published figures for sensitivities and specificities of common physical examination and imaging tests for LHB pathology that are based on arthroscopy as the gold standard are therefore invalid. In clinical practice, it is important to note that a "negative" arthroscopic assessment does not exclude a lesion of the LHB tendon as this technique does not allow visualisation of common sites of distal pathology. LEVEL OF EVIDENCE: IV. PMID- 26611898 TI - Early functional outcome after lateral UKA is sensitive to postoperative lower limb alignment. AB - PURPOSE: The predictive role of patient-specific characteristics and radiographic parameters on medial unicompartmental knee arthroplasty (UKA) outcomes is well known, but knowledge of these predictors is lacking in lateral UKA. Therefore, purpose of this study was to assess the predictive role of these parameters on short-term functional outcomes of lateral UKA. METHODS: In this retrospective cohort study, Western Ontario and McMaster Universities Arthritis Index scores were collected at 2-year follow-up (median 2.2 years, range 2.0-4.0 years) in 39 patients who underwent lateral UKA. Patient-specific characteristics included age, BMI and gender, while radiographic parameters included osteoarthritis severity of all three compartments and both preoperative and postoperative hip knee-ankle alignment. RESULTS: BMI, gender, age and preoperative valgus alignment were not correlated with functional outcomes, while postoperative valgus alignment was correlated with functional outcomes (0.561; p = 0.001). Postoperative valgus of 3 degrees -7 degrees was correlated with better outcomes than more neutral (-2 degrees to 3 degrees valgus) alignment (96.7 vs. 85.6; p = 0.011). Postoperative alignment was a predictor when corrected for patient specific characteristics (regression coefficient 4.1; p < 0.001) and radiological parameters (regression coefficient 3.8; p = 0.002). CONCLUSIONS: Postoperative valgus alignment of 3 degrees -7 degrees was correlated with the best short-term functional outcomes in lateral UKA surgery, while patient-specific parameters and preoperative alignment were not correlated with functional outcomes. Based on these findings, a surgeon should aim for valgus alignment of 3 degrees -7 degrees when performing lateral UKA surgery for optimal functional outcomes. LEVEL OF EVIDENCE: Prognostic study, Level II. PMID- 26611899 TI - Infection recurrence factors in one- and two-stage total knee prosthesis exchanges. AB - PURPOSE: Revision of infected total knee replacements (TKR) is usually delayed for a period in which the joint space is filled with an antibiotic-loaded acrylic spacer. In contrast, one-stage re-implantation supposes immediate re implantation. Formal comparisons between the two methods are scarce. A retrospective multi-centre study was conducted to investigate the effects of surgery type (one-stage vs. two-stage) on cure rates. It was hypothesised that this parameter would not influence the results. METHOD: All infected TKR, treated consecutively between 2005 and 2010 by senior surgeons working in six referral hospitals, were included retrospectively. Two hundred and eighty-five patients, undergoing one-stage or two-stage TKR, with more than 2-year follow-up (clinical and radiological) were eligible for data collection and analysis. Of them, 108 underwent one-stage and 177 received two-stage TKR. Failure was defined as infection recurrence or persistence of the same or unknown pathogens. Factors linked with infection recurrence were analysed by uni- and multi-variate logistic regression with random intercept. RESULTS: Factors associated with infection recurrence were fistulae (odds ratio (OR) 3.4 [1.2-10.2], p = 0.03), infection by gram-negative bacteria (OR 3.3 [1.0-10.6], p = 0.05), and two-stage surgery with static spacers (OR 4.4 [1.1-17.9], p = 0.04). Gender and type of surgery interacted (p = 0.05). In men (133 patients), type of surgery showed no significant linkage with infection recurrence. In women (152 patients), two-stage surgery with static spacers was associated independently with infection recurrence (OR 5.9 [1.5-23.6], p = 0.01). Among patients without infection recurrence, International Knee Society scores were similar between those undergoing one-stage or two-stage exchanges. CONCLUSION: Two-stage procedures offered less benefit to female patients. It suggests that one-stage procedures are preferable, because they offer greater comfort without increasing the risk of recurrence. Routine one-stage procedures may be a reasonable option in the treatment of infected TKR. LEVEL OF EVIDENCE: III. PMID- 26611900 TI - Does pre-operative sampling predict intra-operative cultures and antibiotic sensitivities in knee replacements revised for infection?: a study using the NJR dataset. AB - PURPOSE: This study examined a cohort of primary knee arthroplasties revised for peri-prosthetic infection to (1) determine whether the microorganisms isolated by sampling (up to 6 months pre-operatively) are representative of the microorganisms encountered at the time of knee revision, (2) determine whether the antibiotic sensitivity profiles of matching organisms correlate and (3) determine whether the proportion of organism and antibiotic sensitivity matches is influenced by the type of infection, timing of sample collection and the type of microorganism isolated. METHODS: From the National Joint Registry database for England and Wales, a consecutive series of primary knee arthroplasties performed between 2003 and 2014 that went on to have a revision for peri-prosthetic infection were identified. Each case was then linked to a national microbiology database held by Public Health England. Following data linkage, intra-operative and pre-operative cultures were identified and compared in a group of 75 patients. RESULTS: Pre-operative genus matched intra-operative genus in 56 of 75 cases (75 %). Of those 56, the corresponding antimicrobial sensitivities matched in 37 (66 % of cases). Overall, 37 of 75 cases (49 %) matched for both microorganism and antimicrobial sensitivity. The proportion of matches was highest in the pure Staphylococcal genus infections (genus match 88 %, sensitivity match 62 %, genus and sensitivity match 55 %) and lowest in those patients with mixed organism infections (genus match 29 %, sensitivity match 14 %). CONCLUSION: Pre-operative joint sampling obtained by either aspiration or tissue biopsy is advocated in cases where peri-prosthetic infection is suspected and provides the only means of determining infecting organism prior to revision. Overall, only half of all pre-operative cultures matched completely the findings of intra-operative samples in terms of both the microorganism(s) encountered and their corresponding antimicrobial sensitivity profile. Clinicians should be vigilant regarding the possibility of the patient acquiring further microorganisms or the development of new antibiotic resistance by the time of revision, especially in historic pre-operative cultures. Broad spectrum antibiotic therapies should therefore be employed until final microorganisms and antimicrobial sensitivities are confirmed from intra-operative samples. LEVEL OF EVIDENCE: IV. PMID- 26611901 TI - Analgesic efficacy and quadriceps strength of adductor canal block versus femoral nerve block following total knee arthroplasty. AB - PURPOSE: Femoral nerve blocks (FNBs) provide effective analgesia after total knee arthroplasty, but have been associated with quadriceps weakness. Adductor canal block (ACB) is a promising alternative option that delivers a primarily sensory blockade. The aim of this study was to determine whether ACB provides superior quadriceps strength and similar pain control than FNB. METHODS: A systematic search of PubMed, the Cochrane Library, EMBASE and Web of Science was conducted without publication data or language restriction. Comparative studies comparing ACB with FNB were included. Two authors independently assessed data extraction and quality of the studies. RESULTS: Nine studies with 639 patients were identified. Results of meta-analysis showed that compared with FNB, ACB preserved quadriceps muscle strength better than FNB [MD24h = 1.14, 95 % CI (0.38, 1.91), p < 0.01; MD48h = 0.40, 95 % CI (0.16, 0.64), p < 0.01], while there were no significant differences in pain score during rest at 24 h [SMD = - 0.04, 95 % CI (-0.17, 0.26); n.s] or 48 h [SMD = - 0.10, 95 % CI (-0.27, 0.08); n.s], pain score during activity at 24 h [SMD = 0.13, 95 % CI (-0.36, 0.62); n.s] or 48 h [SMD = - 0.13, 95 % CI (-0.37, 0.12); n.s], opioid consumption at 24 h [SMD = - 0.01, 95 % CI (-1.68, 1.66); n.s] or 48 h [SMD = - 0.92, 95 % CI (-6.86, 5.01); n.s], length of hospital stay [MD = 0.05, 95 % CI (-0.91, 1.00); n.s] and nausea or vomiting [RR = 1.17, 95 % CI (0.62, 2.20); n.s] between ACB and FNB. CONCLUSIONS: ACB preserved the strength of quadriceps more than FNB and achieves similar analgesic effects in post-operative pain. LEVEL OF EVIDENCE: Level III. PMID- 26611902 TI - Five-year experience of cementless Oxford unicompartmental knee replacement. AB - PURPOSE: Cementless unicompartmental knee replacement (UKR) was introduced to address some of the problems that can occur following cemented UKR. The aim of this study was to report the 5-year experience of the first 512 medial cementless Oxford UKR implanted by two surgeons for the recommended indications. METHODS: The first consecutive 512 cementless Phase 3 Oxford UKRs implanted by two surgeons for the recommended indications between June 2004 and October 2013 were prospectively identified and followed up independently. All the procedures were carried out through a minimally invasive approach without eversion or dislocation of the patella. Patients were assessed clinically pre-operatively and at 1, 2, 5, 7 and 10 years after surgery with functional outcome scores and radiographs. RESULTS: There were eight reoperations of which six were revisions giving a 5 year survival of 98 % (95 % CI 94-100 %). At a mean follow-up of 3.4 years (1.0 10.2), the mean OKS was 43 (SD 7), AKSS (objective) was 81 (SD 13), and AKSS (functional) was 86 (SD 17). The first 120 cases had a minimum follow-up of 5 years (mean 5.9; range 5-10.2). In these patients, the mean OKS was 41 (SD 8), AKSS (objective) was 81 (SD 14), and AKSS (functional) was 82 (SD 18). There were no femoral radiolucencies and no complete tibial radiolucencies. 11 % of tibial components had partial radiolucent lines; the remaining 89 % had no radiolucencies. CONCLUSION: The clinical results are as good as or better than those previously reported for cemented fixation. The radiographic results are better with secure bony attachment to the implants in every case. LEVEL OF EVIDENCE: IV. PMID- 26611903 TI - Radiographic femoral bicondylar width predicts anterior cruciate ligament insertion site sizes. AB - PURPOSE: The purpose of this study was to determine whether radiographic femoral bicondylar width predicts intra-operative anterior cruciate ligament (ACL) insertion site sizes. METHODS: Seventy-three consecutive patients (39 males and 34 females; mean age 25.2 years +/- 10.2) who underwent anatomic ACL reconstruction were retrospectively reviewed. Femoral condyle width was measured using a pre-operative anteroposterior (AP) radiograph of the operative knee. Lines were drawn through the anatomic axis of the femur, as well as perpendicularly through the condyles. Bicondylar width was measured as the maximum width across both the medial and lateral femoral condyles utilizing this perpendicular line. The ACL insertion site lengths (in the AP direction) of both the tibia and the femur were measured intra-operatively using a commercially available arthroscopic ruler. RESULTS: The average bicondylar width was significantly smaller for females compared to males (p < 0.05). The average tibial and femoral insertion site sizes were significantly smaller for females compared to males (p < 0.05). Regression analysis predicted tibial (r 2 = 0.88) and femoral (r 2 = 0.90) insertion site sizes based on femoral bicondylar width measurements. CONCLUSION: A simple radiographic measurement of femoral bicondylar width can predict intra-operative tibial and femoral insertion site sizes, which has the potential to assist surgeons in performing individualized ACL reconstruction in cases where MRI scan is unavailable. LEVEL OF EVIDENCE: IV. PMID- 26611904 TI - Correlations of magnetic resonance imaging findings with clinical symptom severity and prognosis of frozen shoulder. AB - PURPOSE: To evaluate the correlation between indirect magnetic resonance (MR) arthrographic imaging findings and the clinical symptoms and prognosis of patients with frozen shoulder. METHODS: Indirect MR arthrography was performed for 52 patients with primary frozen shoulder (mean age 55.1 +/- 9.0 years) and 52 individuals without frozen shoulder (mean age 53.1 +/- 10.7 years); capsular thickening and enhancement of the axillary recess as well as soft tissue thickening of the rotator interval were evaluated. Clinical symptom severity was assessed using the Visual Analogue Scale for Pain (VAS Pain), simple shoulder test (SST), Constant score, American Shoulder and Elbow Surgeons (ASES) score, and range of motion (ROM). At 6-month follow-up, we evaluated whether MR arthrography findings correlated with the clinical symptoms and prognosis. RESULTS: Capsular thickening and enhancement of the axillary recess as well as soft tissue thickening of the rotator interval were significantly greater in the patient group than in the controls (p < 0.001). Capsular thickening of the axillary recess did not correlate with clinical symptoms or ROM (n.s.); however, capsular enhancement correlated with clinical symptom severity according to VAS Pain (p = 0.005), SST (p = 0.046), and ASES scores (p = 0.009). Soft tissue thickening of the rotator interval did not correlate with clinical symptom severity, but was associated with external rotation limitation (p = 0.002). However, none of the parameters correlated with clinical symptoms at 6-month follow-up. CONCLUSIONS: Indirect MR arthrography provided ancillary findings, especially with capsular enhancement, for evaluating clinical symptom severity of frozen shoulder, but did not reflect the prognosis. MR findings in frozen shoulder should not replace clinical judgments regarding further prognosis and treatment decisions. LEVEL OF EVIDENCE: IV. PMID- 26611905 TI - Effect of Religiosity on Voice. AB - The aim of this study was to examine the relationship between religiosity and phonatory behavior. A total of 186 participants participated in a survey that included four sections: demographic data, extent of religiosity, history of dysphonia, phonatory behavior and laryngeal manipulation, in addition to the Voice Handicap Index (VHI-10). There was no significant association between the prevalence of phonatory symptoms and any of the religiosity questions. There was no significant association between phonatory behavior, history of laryngeal manipulation and any of the religiosity questions. There was also no significant association between the score of the Voice Handicap Index and any of the five religiosity questions. There is no association between religiosity and prevalence of phonatory disturbances, phonotraumatic behavior and/or history of laryngeal manipulation. PMID- 26611906 TI - Stability of murine scrapie strain 87V after passage in sheep and comparison with the CH1641 ovine strain. AB - Breed- and prion protein (PRNP) genotype-related disease phenotype variability has been observed in sheep infected with the 87V murine scrapie strain. Therefore, the stability of this strain was tested by inoculating sheep-derived 87V brain material back into VM mice. As some sheep-adapted 87V disease phenotypes were reminiscent of CH1641 scrapie, transgenic mice (Tg338) expressing ovine prion protein (PrP) were inoculated with the same sheep-derived 87V sources and with CH1641. Although at first passage in VM mice the sheep-derived 87V sources showed some divergence from the murine 87V control, all the characteristics of murine 87V infection were recovered at second passage from all sheep sources. These included 100 % attack rates and indistinguishable survival times, lesion profiles, immunohistochemical features of disease-associated PrP accumulation in the brain and PrP biochemical properties. All sheep-derived 87V sources, as well as CH1641, were transmitted to Tg338 mice with identical clinical, pathological, immunohistochemical and biochemical features. While this might potentially indicate that sheep-adapted 87V and CH1641 are the same strain, profound divergences were evident, as murine 87V was unable to infect Tg338 mice but was lethal for VM mice, while the reverse was true for CH1641. These combined data suggest that: (i) murine 87V is stable and retains its properties after passage in sheep; (ii) it can be isolated from sheep showing a CH1641-like or a more conventional scrapie phenotype; and (iii) sheep-adapted 87V scrapie, with conventional or CH1641-like phenotype, is biologically distinct from experimental CH1641 scrapie, despite the fact that they behave identically in a single transgenic mouse line. PMID- 26611908 TI - Estimation of passive and active properties in the human heart using 3D tagged MRI. AB - Advances in medical imaging and image processing are paving the way for personalised cardiac biomechanical modelling. Models provide the capacity to relate kinematics to dynamics and-through patient-specific modelling-derived material parameters to underlying cardiac muscle pathologies. However, for clinical utility to be achieved, model-based analyses mandate robust model selection and parameterisation. In this paper, we introduce a patient-specific biomechanical model for the left ventricle aiming to balance model fidelity with parameter identifiability. Using non-invasive data and common clinical surrogates, we illustrate unique identifiability of passive and active parameters over the full cardiac cycle. Identifiability and accuracy of the estimates in the presence of controlled noise are verified with a number of in silico datasets. Unique parametrisation is then obtained for three datasets acquired in vivo. The model predictions show good agreement with the data extracted from the images providing a pipeline for personalised biomechanical analysis. PMID- 26611909 TI - Immunogenicity and antigenic relationships among spike proteins of porcine epidemic diarrhea virus subtypes G1 and G2. AB - Porcine epidemic diarrhea virus (PEDV) is a coronavirus that infects cells lining the small intestine of swine, resulting in vomiting, diarrhea, and dehydration. The amino acid sequence of the spike (S) protein, which is the principal target recognized by host immune cells, has multiple mutations that distinguish the two PEDV genotypes, G1 and G2. To determine whether these mutations lead to changes in antigenicity, as suggested by the failure of PEDV vaccines in China, we first optimized the codons of typical S genes of the CV777 vaccine strain (G1 subtype) and LNCT2 strain (G2 subtype) and expressed the recombinant full-length sequence of the S protein in a eukaryotic expression system. The IgG antibody levels of serum from mice immunized with purified S protein were markedly high. Antigenicity was compared by detection of polyclonal antibodies (PAbs) against the virus and S protein using an enzyme-linked immunosorbent assay (ELISA), an indirect immunofluorescence assay (IFA), and a serum cross-neutralization (SN) assay. Reactivity with the PAbs revealed significant cross-reactivity between the two PEDV subtypes, although there was a twofold difference in the antigenic responses based on PAb titers in the ELISA and IFA. Consistent with the variation in the S gene sequences, the SN titer suggested differences in the neutralization activity of the S protein between the two subtypes, which could explain the antigenic variation between the PEDV subtypes G1 and G2. PMID- 26611907 TI - The role of viral infections in exacerbations of chronic obstructive pulmonary disease and asthma. AB - Asthma and chronic obstructive pulmonary disease (COPD) are major causes of global morbidity and mortality worldwide. The clinical course of both asthma and COPD are punctuated by the occurrence of exacerbations, acute events characterized by increased symptoms and airflow obstruction. Exacerbations contribute most of the morbidity, mortality and excess healthcare costs associated with both asthma and COPD. COPD and asthma exacerbations are frequently associated with respiratory virus infections and this has led to an intense research focus into the mechanisms of virus-induced exacerbations over the past decade. Current therapies are effective in reducing chronic symptoms but are less effective in preventing exacerbations, particularly in COPD. Understanding the mechanisms of virus-induced exacerbation will lead to the development of new targeted therapies that can reduce the burden of virus-induced exacerbations. In this review we discuss current knowledge of virus-induced exacerbations of asthma and COPD with a particular focus on mechanisms, human studies, virus-bacteria interactions and therapeutic advances. PMID- 26611912 TI - Secondhand smoke and incidence of dental caries in deciduous teeth among children in Japan: population based retrospective cohort study. PMID- 26611910 TI - A report on the outbreak of Zika virus on Easter Island, South Pacific, 2014. AB - Zika virus (ZIKV) is an emerging mosquito-borne flavivirus circulating in Asia and Africa. In 2013, a large outbreak was reported on the archipelago of French Polynesia. In this study, we report the detection and molecular characterization of Zika virus for the first time in Chile from an outbreak among the inhabitants of Easter Island. A total of 89 samples from patients suspected of having ZIKV infection were collected between the period from January to May, 2014. Molecular diagnosis of the virus was performed by RT-PCR followed by the sequencing of the region containing the NS5 gene. A comparison of the viral nucleic acid sequence with those of other strains of ZIKA virus was performed using the MEGA software. Fifty-one samples were found positive for ZIKV by RT-PCR analysis. Further analysis of the NS5 gene revealed that the ZIKV strains identified in Easter Island were most closely related to those found in French Polynesia (99.8 to 99.9% nt and 100% aa sequence identity). These results strongly suggest that the transmission pathway leading to the introduction of Zika virus on Easter Island has its origin in French Polynesia. PMID- 26611911 TI - Molecular diversity of turncurtoviruses in Iran. AB - Turnip curly top virus (TCTV) is the only member of the newly established genus Turncurtovirus (family Geminiviridae). As part of an ongoing study to identify additional plant hosts and the diversity of turncurtoviruses, between 2012 and 2014, we sampled symptomatic turnip plants and other crops in the provinces Fars and Khorasan Razavi (southern and northeastern Iran, respectively). Infection by turncurtoviruses was tested by PCR and/or rolling-circle amplification (RCA) coupled with restriction enzyme digests. Turncurtoviruses were identified in turnip as well as seven other field crops, including eggplant, basil, radish, lettuce, sugar beet, red beet and spinach. Full turncurtovirus genomes were recovered from 25 of these samples, leading to the identification of TCTV and a new putative turncurtovirus, turnip leaf roll virus (TLRV; 13 isolates), which shares <80% genome-wide pairwise identity with TCTV. Agroinoculation of plants with an infectious clone of TLRV demonstrated that this virus could infect several plant hosts under greenhouse conditions and could be transmitted by the leafhopper Circulifer haematoceps (Mulsant and Rey, 1855) from agroinoculated to healthy plants. PMID- 26611913 TI - Cryopreservation of equine mesenchymal stem cells in 95% autologous serum and 5% DMSO does not alter post-thaw growth or morphology in vitro compared to fetal bovine serum or allogeneic serum at 20 or 95% and DMSO at 10 or 5. AB - INTRODUCTION: Equine superficial digital flexor tendon injury is a well-accepted model of human tendon injury and is routinely treated with local injections of autologous mesenchymal stem cells (MSCs). Identification of a clinically safe medium for short-term cryopreservation of MSCs prior to cell implantation would streamline laboratory and clinical procedures for autologous regenerative therapies. Veterinary experience with short-term (MSCs prepared after the injury has occurred) cryopreserved MSCs in naturally occurring injury in the horse will be of value to human practitioners. METHODS: Equine bone marrow derived MSCs were cryopreserved in 6 different solutions consisting of 20% serum, 10% DMSO and 70% media or 95% serum and 5% DMSO. Serum was autologous serum, commercially available pooled equine serum or fetal bovine serum (FBS). Cell survival, morphology and growth kinetics were assessed by total cell number, measurement of growth kinetics, colony-forming-unit-assay and morphology of MSCs after monolayer culture post-thaw. RESULTS: There were no significant differences in post-thaw viability, total cell number, morphology scores or growth kinetics among the 6 solutions. Post thaw viabilities from each group ranged from 80-90%. In all solutions, there were significantly fewer MSCs and the majority (99%) of MSCs remained in the original generation 24 hours post-thaw. Seventy two hours post thaw, the majority of MSCs (50%) were proliferating in the fourth generation. Mean colony count in the CFU-F assay ranged from 72 to 115 colonies. CONCLUSIONS: Each of the serum sources could be used for short-term cryopreservation of equine bone marrow derived MSCs. Prior to clinical use, clinicians may prefer autologous serum and a lower concentration of DMSO. PMID- 26611914 TI - The role of the seven crude drug components in the sleep-promoting effect of Yokukansan. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Yokukansan is a traditional Japanese "Kampo" medicine derived from Yi-Gan San in traditional Chinese medicine. Many studies have been published on its effects and mechanisms. In this study, we focused on the sleep-promoting effects of Yokukansan. AIM OF THE STUDY: Yokukansan composes of seven crude drugs: Uncaria Hook, Bupleurm Root, Cnidium Rhizome, Japanese Angelica Root, Poria Sclerotium, Atractylodes Lancea Rhizome, and Glycyrrhiza. Although each has distinctive effects in isolation, they combine to work as a sleep aid in the Yokukansan formula. We examined the roles of the seven crude drug components in the sleep-promoting effect of Yokukansan. MATERIAL AND METHODS: In this study, we used an easy in vivo assay method which we developed previously to screen sleeping substances using thermography. This assay method focuses on the decrease in skin temperature of mice during sleep inducement. RESULTS: By administering the crude drug components of Yokukansan one at a time, it was possible to separate them into two groups: those that caused a decrease in body temperature (Uncaria Hook, Bupleurm Root, Cnidium rhizome, and Japanese Angelica root) and those that did not (Poria Sclerotium, Atractylodes Lancea Rhizome, and Glycyrrhiza). Accordingly, it was thought that the crude drugs causing a drop in body temperature were responsible for promoting sleep, while those in the other group would have no such effect in isolation. To investigate whether the crude drugs that did not cause a decrease in body temperature might be unnecessary for the sleep-promoting effect of Yokukansan, a number of decoctions were prepared using only six of the seven crude drug components, excluding a different crude drug in each case. Results showed that when any of the three components (Poria Sclerotium, Atractylodes Lancea Rhizome, or Glycyrrhiza) of Yokukansan that had no effect on body temperature in isolation were removed from Yokukansan, the resulting extract no longer had any of Yokukansan's sleep-promoting effects. This result suggested that these three crude drug components were involved indirectly in the activity of Yokukansan, by supporting other crude drugs. The interactions of the three supporting crude drugs were then examined further. As a result, a combination of Poria Sclerotium, Atractylodes Lancea Rhizome, and Glycyrrhiza was found to cause a decrease in body temperature, even though none of the three crude drugs had this effect in isolation. When an extract prepared by infusing the three crude drugs together was tested alongside extracts made by infusing the three crude drugs separately, the latter showed no effect and there were differences between the two in constituent analysis by HPLC. These results indicate that some reactions may occur during extraction. CONCLUSIONS: Results of this study show that all crude drug components of Yokukansan contribute to its sleep-promoting effects. This is the first report to show the role of the seven clude drug components in the sleep inducing effects of Yokukansan. PMID- 26611916 TI - Eco-friendly Energy Storage System: Seawater and Ionic Liquid Electrolyte. AB - As existing battery technologies struggle to meet the requirements for widespread use in the field of large-scale energy storage, novel concepts are urgently needed concerning batteries that have high energy densities, low costs, and high levels of safety. Here, a novel eco-friendly energy storage system (ESS) using seawater and an ionic liquid is proposed for the first time; this represents an intermediate system between a battery and a fuel cell, and is accordingly referred to as a hybrid rechargeable cell. Compared to conventional organic electrolytes, the ionic liquid electrolyte significantly enhances the cycle performance of the seawater hybrid rechargeable system, acting as a very stable interface layer between the Sn-C (Na storage) anode and the NASICON (Na3 Zr2 Si2 PO12) ceramic solid electrolyte, making this system extremely promising for cost efficient and environmentally friendly large-scale energy storage. PMID- 26611915 TI - Endogenous CRF in rat large intestine mediates motor and secretory responses to stress. AB - BACKGROUND: Corticotropin-releasing factor (CRF) mediates our body's overall responses to stress. The role of central CRF in stress-stimulated colonic motility is well characterized. We hypothesized that transient perturbation in expression of enteric CRF is sufficient to change stress-induced colonic motor and secretory responses. METHODS: Sprague-Dawley rats (adult, male) were subjected to 1-h partial restraint stress (PRS) and euthanized at 0, 4, 8, and 24 h. CRF mRNA and peptide levels in the colon were quantified by real-time RT-PCR, enzyme immuno-assay and immunohistochemistry. Double-stranded RNA (dsRNA) designed to target CRF (dsCRF) was injected into the colonic wall to attain RNA interference-mediated inhibition of CRF mRNA expression. DsRNA for beta-globin was used as a control (dsControl). Four days after dsRNA injection, rats were subjected to 1-h PRS. Fecal output was measured. Ussing chamber techniques were used to assess colonic mucosal ion secretion and transepithelial tissue conductance. KEY RESULTS: Exposure to PRS elevated CRF expression and increased CRF release in the rat colon. Injection of dsCRF inhibited basal CRF expression and prevented the PRS-induced increase in CRF expression, whereas CRF expression in dsControl-injected colons remained high after PRS. In rats treated with dsControl, PRS caused a significant increase in fecal pellet output, colonic baseline ion secretion, and transepithelial tissue conductance. Inhibition of CRF expression in the colon prevented PRS-induced increase in fecal output, baseline ion secretion, and transepithelial tissue conductance. CONCLUSIONS & INFERENCES: These results provide direct evidence that transient perturbation in peripherally expressed CRF prevents colonic responses to stress. PMID- 26611917 TI - Population-based birth defects data in the United States, 2008 to 2012: Presentation of state-specific data and descriptive brief on variability of prevalence. PMID- 26611918 TI - Enkephalin analogues with N-phenyl-N-(piperidin-2-ylmethyl)propionamide derivatives: Synthesis and biological evaluations. AB - N-Phenyl-N-(piperidin-2-ylmethyl)propionamide based bivalent ligands are unexplored for the design of opioid based ligands. Two series of hybrid molecules bearing N-phenyl-N-(piperidin-2-ylmethyl)propionamide derived small molecules conjugated with an enkephalin analogues with and without a linker (beta-alanine) were designed and synthesized. Both bivalent ligand series exhibited remarkable binding affinities from nanomolar to subnanomolar range at both MU and delta opioid receptors and displayed potent agonist activities as well. The replacement of Tyr with Dmt and introduction of a linker between the small molecule and enkephalin analogue resulted in highly potent ligands. Both series of ligands showed excellent binding affinities at both MU (0.6-0.9nM) and delta (0.2-1.2nM) opioid receptors respectively. Similarly, these bivalent ligands exhibited potent agonist activities in both MVD and GPI assays. Ligand 17 was evaluated for in vivo antinociceptive activity in non-injured rats following spinal administration. Ligand 17 was not significantly effective in alleviating acute pain. The most likely explanations for this low intrinsic efficacy in vivo despite high in vitro binding affinity, moderate in vitro activity are (i) low potency suggesting that higher doses are needed; (ii) differences in experimental design (i.e. non-neuronal, high receptor density for in vitro preparations versus CNS site of action in vitro); (iii) pharmacodynamics (i.e. engaging signalling pathways); (iv) pharmacokinetics (i.e. metabolic stability). In summary, our data suggest that further optimisation of this compound 17 is required to enhance intrinsic antinociceptive efficacy. PMID- 26611919 TI - Cross metathesis with hydroxamate and benzamide BOC-protected alkenes to access HDAC inhibitors and their biological evaluation highlighted intrinsic activity of BOC-protected dihydroxamates. AB - Conditions for the metathesis of alkenes in the convergent synthesis of HDAC inhibitors have been improved by continuous catalyst flow injection in the reaction media. Intermediate and target compounds obtained were tested for their ability to induce HDAC inhibition and tubulin acetylation, revealing the key role of the tert-butyloxycarbonyl (BOC) group for more HDAC6 selectivity. Molecular modelling added rationale for this BOC effect. PMID- 26611920 TI - Optimization of allosteric MEK inhibitors. Part 2: Taming the sulfamide group balances compound distribution properties. AB - Recently, we had identified an unexplored pocket adjacent to the known binding site of allosteric MEK inhibitors which allowed us to design highly potent and in vivo efficacious novel inhibitors. We now report that our initial preclinical candidate, featuring a phenoxy side chain with a sulfamide capping group, displayed human carbonic anhydrase off-target activity and species-dependent blood cell accumulation, which prevented us from advancing this candidate further. Since this sulfamide MEK inhibitor displayed an exceptionally favorable PK profile with low brain penetration potential despite being highly oral bioavailable, we elected to keep the sulfamide capping group intact while taming its unwanted off-target activity by optimizing the structural surroundings. Introduction of a neighboring fluorine atom or installation of a methylene linker reduced hCA potency sufficiently, at the cost of MEK target potency. Switching to a higher fluorinated central core reinstated high MEK potency, leading to two new preclinical candidates with long half-lives, high bioavailabilities, low brain penetration potential and convincing efficacy in a K-Ras-mutated A549 xenograft model. PMID- 26611921 TI - Updates in Perioperative Care: Ideas from the Human Field. AB - The article focuses mainly on appropriate patient preparation for an anesthetic episode. Special attention is given to evaluate the environmental situation for optimal adjustment to reduce stress before the anesthetic event. During the anesthetic event, special attention must be paid regarding monitoring and, evaluating the patient during and after the anesthetic episode. PMID- 26611922 TI - Update on Surgical Principles and Equipment. AB - The diversity implicit in exotic animal surgery requires a tailored approach to optimize successful outcomes. Outlined is information on patient preparation, instrumentation, hemostatic techniques, and magnification as it pertains to the exotic animal. Application of topical antiseptic solutions and judicious removal of pelage and feathers will decrease bacterial load during patient preparation. The use of specific barrier protection ensures proper aseptic technique and enables optimal patient monitoring. Magnification combined with a focal light source enhances visual acuity, allowing for better use of delicate instrumentation and identification of anatomic structures. PMID- 26611923 TI - Principles of Wound Management and Wound Healing in Exotic Pets. AB - The care of wounds in exotic animal species can be a challenging endeavor. Special considerations must be made in regard to the animal's temperament and behavior, unique anatomy and small size, and tendency toward secondary stress related health problems. It is important to assess the entire patient with adequate systemic evaluation and consideration of proper nutrition and husbandry, which could ultimately affect wound healing. This article summarizes the general phases of wound healing, factors that affect healing, and principles of wound management. Emphasis is placed on novel methods of treating wounds and species differences in wound management and healing. PMID- 26611924 TI - Fish Surgery: Presurgical Preparation and Common Surgical Procedures. AB - Fish surgical procedures are commonplace in aquaria, zoos, laboratory facilities, and pet clinical practice. To incorporate fish surgery into a clinical setting, an understanding of anatomic differences between mammals and fish, bath anesthetics, and recirculating anesthesia techniques must be developed; a system or different size systems to accommodate anesthesia and surgery of particular species of concern at an institution or practice constructed; and familiar mammalian surgical principles applied with some adaptations. Common surgical procedures in fish include coeliotomy for intracoelomic mass removal, reproductive procedures, gastrointestinal foreign body removal, radiotransmitter placement, and integumentary mass excision. PMID- 26611925 TI - Surgery in Amphibians. AB - Amphibian surgery has been especially described in research. Since the last decade, interest for captive amphibians has increased, so have the indications for surgical intervention. Clinicians should not hesitate to advocate such manipulations. Amphibian surgeries have no overwhelming obstacles. These patients heal well and tolerate blood loss more than higher vertebrates. Most procedures described in reptiles (mostly lizards) can be undertaken in most amphibians if equipment can be matched to the patients' size. In general, the most difficult aspect would be the provision of adequate anesthesia. PMID- 26611926 TI - Reptile Soft Tissue Surgery. AB - The surgical approach to reptiles can be challenging. Reptiles have unique physiologic, anatomic, and pathologic differences. This may result in frustrating surgical experiences. However, recent investigations provided novel, less invasive, surgical techniques. The purpose of this review was to describe the technical aspects behind soft tissue surgical techniques that have been used in reptiles, so as to provide a general guideline for veterinarians working with reptiles. PMID- 26611927 TI - Avian Soft Tissue Surgery. AB - Basic surgical instrumentation for avian soft tissue surgery includes soft tissue retractors, microsurgical instrumentation, surgical loupes, and head-mounted lights. Hemostasis is fundamental during the surgical procedures. The indications, approach, and complications associated with soft tissue surgeries of the integumentary (digit constriction repair, feather cyst excision, cranial wound repair, sternal wound repair, uropygial gland excision), gastrointestinal (ingluviotomy, crop biopsy, crop burn repair, celiotomy, coelomic hernia and pseudohernia repair, proventriculotomy, ventriculotomy, enterotomy, intestinal resection and anastomosis, cloacoplasty, cloacopexy), respiratory (rhinolith removal, sinusotomy, tracheotomy, tracheal resection and anastomosis, tracheostomy, pneumonectomy) and reproductive (ovocentesis, ovariectomy, salpingohysterectomy, cesarean section, orchidectomy, vasectomy, phallectomy) systems are reviewed. PMID- 26611928 TI - Rabbit Soft Tissue Surgery. AB - This article summarizes the available information on different soft tissue surgical procedures in rabbits, based on the literature and the authors' experiences, emphasizing the differences between rabbits and the more familiar dogs and cats. The major surgical principles in rabbits are discussed, and common surgical procedures, such as abdominal exploration, gastrotomy, enterotomy, liver lobectomy, nephrectomy, cystotomy, cystectomy, ovariohysterectomy, ovariectomy, orchidectomy, are described. PMID- 26611929 TI - Surgical Management of Ear Diseases in Rabbits. AB - Otitis externa and media are frequently diagnosed disorders in rabbits and are particularly common in lop-eared breeds because of the specific anatomy of the ear canal. Medical management for otitis externa and media often provides only a temporary improvement in clinical signs. Surgery by means of partial or total ear canal ablation (PECA or TECA) combined with lateral bulla osteotomy (LBO) represents a feasible approach that is well tolerated and provides a good clinical outcome. Short-term complications associated with PECA/TECA-LBO include facial nerve paralysis and vestibular disease. PMID- 26611930 TI - Small Mammals: Common Surgical Procedures of Rodents, Ferrets, Hedgehogs, and Sugar Gliders. AB - Small mammal surgical procedures are a part of clinical veterinary practice and are performed with regularity. Anesthetic and analgesic techniques are important components of any successful small mammal surgical procedure. Many basic surgical principles used in dogs and cats can be directly applied to small mammals, but tissues tend to be smaller and thinner, and hemostasis is critical with small patients due to risk of death with minimal blood loss. Common surgical procedures in small mammals include integumentary mass and abscess excision, reproductive procedures, gastrointestinal foreign body removal, urolith removal, prolapsed tissues associated with the gastrointestinal tract, intra-abdominal mass excision, and hepatic surgery. PMID- 26611931 TI - Eye Removal Surgeries in Exotic Pets. AB - This article covers considerations and techniques of eye removal surgeries in exotic pets. After issues including surgical indications, anesthesia, patient preparation, and instrumentation are explored, surgical techniques are described. Enucleation/exenteration and modified evisceration are discussed, with species specific nuances of small mammals, birds, reptiles, snakes, amphibians, and fish highlighted. PMID- 26611932 TI - Exotic Mammal Laparoscopy. AB - Laparoscopy is an evolving field in veterinary medicine, and there is an increased interest in using laparoscopic techniques in nondomestic mammals, including zoo animals, wildlife, and exotic pets. The aim of this article is to summarize the approach to laparoscopic procedures, including instrumentation, patient selection and preparation, and surgical approaches, and to review the current literature on laparoscopy in exotic mammals. PMID- 26611933 TI - Soft Tissue Surgery. PMID- 26611934 TI - Prognostic effect of estimated glomerular filtration rate in patients with cardiogenic shock or cardiac arrest undergoing percutaneous veno-arterial extracorporeal membrane oxygenation. AB - BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) can improve survival in patients with cardiogenic shock or cardiac arrest. We investigated the association between initial renal function and clinical outcome in patients undergoing VA-ECMO for cardiogenic shock and cardiac arrest. METHODS: This was a single-center, retrospective cohort study of 287 patients who underwent ECMO at our hospital from January 2005 to December 2014. We excluded 70 patients with non-cardiogenic events. The remaining 217 patients were divided into 2 groups according to initial estimated glomerular filtration rate (eGFR): Initial high eGFR (non-renal failure: non-RF) group: eGFR>=60ml/min/1.73m2 (n=73) and initial low eGFR (RF) group: eGFR<60ml/min/1.73m2 (n=144). Clinical outcome was defined as all-cause death at 30 days after extracorporeal life support. RESULTS: VA-ECMO was begun in 87% of patients for cardiac arrest. The non-RF group was significantly younger (51.6 vs. 62.6 years), had lower body mass index (22.8 vs. 24.7kg/m2), lower blood urea nitrogen (14.4 vs. 23.9mg/dl), and lower K (4.0 vs. 4.5mEq/l, all p<0.05) than the RF group. Incidence of all-cause death at 30 days was significantly lower in the non-RF than RF group (49% vs. 76%, p<0.0001). Initial low eGFR was an independent predictor of mortality after adjustment for multiple cofounders (OR: 4.08, 95% CI: 1.77-9.42, p<0.001). Kaplan Meier curve showed better outcome in the non-RF versus RF group (p=0.0009). CONCLUSION: An initial low eGFR may predict worse clinical outcome in patients undergoing VA-ECMO for cardiogenic shock and cardiac arrest. PMID- 26611935 TI - Author's reply. PMID- 26611936 TI - Advanced interatrial block predicts clinical recurrence of atrial fibrillation after catheter ablation. AB - BACKGROUND: It has been demonstrated that advanced interatrial block (IAB) is associated with an increased risk of atrial fibrillation (AF); however, the impact of advanced IAB on recurrence of paroxysmal AF after catheter ablation is not clear. METHODS: 204 consecutive patients with paroxysmal AF who underwent index circumferential pulmonary vein (PV) isolation were prospectively enrolled. In all patients, a resting electrocardiogram in sinus rhythm was evaluated for the presence of advanced IAB, defined as a P-wave duration >120ms and biphasic (+/-) morphology in the inferior leads. Advanced IAB was detected in 20.1% of patients. AF recurrence was defined as the occurrence of confirmed atrial tachyarrhythmia lasting more than 30s beyond 3 months after the catheter ablation in the absence of any antiarrhythmic treatment. RESULTS: During the mean follow up period of 13.9+/-6.2 months (range, 3-27 months), 62 patients (30.4%) developed recurrence of AF. The recurrence rate was higher in patients with advanced IAB than those without advanced IAB (46.3% vs. 26.4%, p=0.006). Cox regression analysis with adjustment for age, P-wave duration, CHADS2 score, and PV isolation identified advanced IAB (hazard ratio, 2.111; 95% confidence interval, 1.034-4.308; p=0.040) and left atrial diameter (hazard ratio, 1.051; 95% confidence interval, 1.004-1.100; p=0.034) as two independent predictors of recurrence of AF. CONCLUSIONS: Patients with advanced IAB were at an increased risk of AF recurrence after catheter ablation. PMID- 26611937 TI - Left atrial remodeling, early repolarization pattern, and inflammatory cytokines in professional soccer players. AB - OBJECTIVES: Although regular physical exercise clearly reduces cardiovascular morbidity risk, long-term endurance sports practice has been recognized as a risk factor for atrial fibrillation (AF). However, the mechanisms how endurance sports can lead to AF are not yet clear. The aim of our present study was to investigate the influence of long-term endurance training on vagal tone, atrial size, and inflammatory profile in professional elite soccer players. METHODS: A total of 25 professional major league soccer players (mean age 24+/-4 years) and 20 sedentary controls (mean age 26+/-3 years) were included in the study and consecutively examined. All subjects underwent a sports cardiology check-up with physical examination, electrocardiography, echocardiography, exercise testing on a bicycle ergometer, and laboratory analysis [standard laboratory and cytokine profile: interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, IL-8, IL-10]. RESULTS: Athletes were divided into two groups according to presence or absence of an early repolarization (ER) pattern, defined as a ST-segment elevation at the J point (STE) >=0.1mm in 2 leads. Athletes with an ER pattern showed significantly lower heart rate and an increased E/e' ratio compared to athletes without an ER pattern. STE significantly correlated with E/e' ratio as well as with left atrial (LA) volume. The pro-inflammatory cytokines IL-6, IL-8, TNF-alpha as well as the anti-inflammatory cytokine IL-10 were significantly elevated in all soccer players. However, athletes with an ER pattern had significantly higher IL-6 plasma levels than athletes without ER pattern. Furthermore, athletes with "high" level IL-6 had significantly larger LA volumes than players with "low" level IL 6. CONCLUSIONS: Athletes with an ER pattern had significantly higher E/e' ratios, reflecting higher atrial filling pressures, higher LA volume, and higher IL-6 plasma levels. All these factors may contribute to atrial remodeling over time and thus increase the risk of AF in long-term endurance sports. PMID- 26611938 TI - The effect of RO3201195 and a pyrazolyl ketone P38 MAPK inhibitor library on the proliferation of Werner syndrome cells. AB - Microwave-assisted synthesis of the pyrazolyl ketone p38 MAPK inhibitor RO3201195 in 7 steps and 15% overall yield, and the comparison of its effect upon the proliferation of Werner Syndrome cells with a library of pyrazolyl ketones, strengthens the evidence that p38 MAPK inhibition plays a critical role in modulating premature cellular senescence in this progeroid syndrome and the reversal of accelerated ageing observed in vitro on treatment with SB203580. PMID- 26611939 TI - Hydrogel-based biosensors and sensing devices for drug delivery. AB - In the past 15years drug delivery devices have received added attention, not only as passive systems of drug delivery that respond to the needs of the health care provider or the patient but have an added advantage or an added characteristic of being triggered by an external process of recognition of a cause, a disease or an analyte that leads to a triggering mechanism for specific drug delivery. In this review, we will examine some of the pioneering work in this field, and speak on the use of biodegradable, environmentally-responsive hydrogels as sensing components in novel microscale devices. PMID- 26611940 TI - Large Ferrierite Crystals as Models for Catalyst Deactivation during Skeletal Isomerisation of Oleic Acid: Evidence for Pore Mouth Catalysis. AB - Large zeolite crystals of ferrierite have been used to study the deactivation, at the single particle level, of the alkyl isomerisation catalysis of oleic acid and elaidic acid by a combination of visible micro-spectroscopy and fluorescence microscopy (both polarised wide-field and confocal modes). The large crystals did show the desired activity, albeit only traces of the isomerisation product were obtained and low conversions were achieved compared to commercial ferrierite powders. This limited activity is in line with their lower external non-basal surface area, supporting the hypothesis of pore mouth catalysis. Further evidence for the latter comes from visible micro-spectroscopy, which shows that the accumulation of aromatic species is limited to the crystal edges, while fluorescence microscopy strongly suggests the presence of polyenylic carbocations. Light polarisation associated with the spatial resolution of fluorescence microscopy reveals that these carbonaceous deposits are aligned only in the larger 10-MR channels of ferrierite at all crystal edges. The reaction is hence further limited to these specific pore mouths. PMID- 26611941 TI - Delayed brachial artery dilation response and increased resting blood flow velocity in young children with mild sleep-disordered breathing. AB - AIM: This study aimed to evaluate whether the vascular dysfunction perceived in adults with sleep-disordered breathing (SDB) was also evident in children with snoring referred for evaluation of clinically suspected SDB. OBJECTIVES: This study compared flow-mediated dilatation (FMD), measured at the brachial artery, at rest and during hyperaemic stress between children who snore [n = 23; mean standard deviation (SD) age = 7.51 (1.3) years] and healthy, non-snoring children [n = 11; age = 8.0 (1.3) years]. METHODS: Children with suspected obstructive sleep apnoea (OSA) and healthy non-snoring controls underwent overnight polysomnography (PSG). Using standard techniques, non-invasive FMD and brachial arterial blood flow velocity during rest and hyperaemia were subsequently measured by ultrasound imaging MEASUREMENTS: Resting and hyperaemic velocity time integral (area under the curve of mean systolic velocity * ejection time), maximal dilation response (highest percentage difference from baseline diameter) and the time taken to reach maximal dilation were calculated. RESULTS: Children awaiting adenotonsillectomy compared to healthy non-snoring control children had higher velocity time integrals at rest (14 +/- 3 m vs. 20 +/- 8 m, p < 0.01) and during hyperaemic stress (56 +/- 6m vs. 63 +/- 13m, p < 0.01) despite having only mild SDB on polysomnographic assessment. Lower nadir oxygen saturation values during non-rapid eye movement sleep were negatively associated with higher resting (r = -0.58, p <0.001) and hyperaemic (r = -0.36, p < 0.05) velocity time integrals. Maximal FMD dilatation response was not significantly different between snoring and non-snoring groups, but the estimated time to reach maximal dilation was significantly delayed in children who snored (60.7 +/- 28.4 vs. 39.2 +/- 13.2 s, p < 0.05). CONCLUSIONS: Children with mild SDB showed increased blood flow velocity at rest and during hyperaemic stress suggesting altered cardiovascular and haemodynamic function. The delay in time to maximal vessel dilatation in children who snored also suggests possible reduced vascular compliance in response to hyperaemic sheer stress. Mild SDB appears to alter the peripheral vascular response in young children. The long-term vascular implications of these changes in the growing child are unknown and warrant further investigation. PMID- 26611942 TI - Characterisation of sleep disturbances in postural orthostatic tachycardia syndrome: a polysomnography-based study. AB - BACKGROUND AND AIM: Postural orthostatic tachycardia syndrome (PoTS) has been frequently associated with sleep disturbances but objective sleep data are lacking. In addition, although regional autonomic denervation has been described, less is known about autonomic nervous activity overnight in these patients. PATIENTS/METHODS: A full polysomnography and heart rate variability were performed on 37 patients diagnosed with PoTS . In addition, a multiple sleep latency test (MSLT) was conducted on a subgroup of patients with excessive daytime sleepiness. RESULTS: The polysomnographic data did not show major pathological findings except the percentage spent in rapid eye movement (REM) sleep which was slightly reduced at 18.4%. The MSLT did not confirm excessive daytime sleepiness as median mean sleep latency was 14.4 min (11.8-17.5). When comparing patients with and without subjective daytime sleepiness, it was found that the latter had a reduced parasympathetic activation at night as expressed by the average high frequency [6936.5 ms(2) (6028.2-8675.5) vs. 4689.5 (3922.7 7685.2) p < 0.05]. CONCLUSION: Patients with PoTS do not exhibit polysomnographic findings consistent with relevant sleep pathologies nor objective daytime sleepiness. Subjective daytime sleepiness is associated with enhanced activation of the parasympathetic nervous system. PMID- 26611943 TI - Updated clinical evidence of Chinese herbal medicine for insomnia: a systematic review and meta-analysis of randomized controlled trials. AB - This systematic review is to evaluate the efficacy and safety of Chinese herbal medicine (CHM) for people with insomnia. Randomized controlled trials (RCTs) investigating oral CHM alone or in combination with conventional therapies for primary insomnia were identified by searching English and Chinese publications and databases of clinical trial registration. Risk of bias was assessed according to the Cochrane Handbook 5.1. Meta-analysis was conducted using RevMan 5.2.4. Seventy-nine trials (7886 participants) were finally included in the review, and 76 were included in the meta-analysis. Twenty-seven trials reported the methods of random sequence generation, and five of them used the allocation concealment. Blinding of participants and personnel were used in 10 studies. The main meta analysis showed that CHM alone was more effective than placebo by reducing scores of Pittsburgh Sleep Quality Index (mean difference, MD: -3.06, 95% confidence interval, CI: -5.14 to -0.98, I(2) = 97%) and benzodiazepine drugs (BZDs) (MD: 1.94, 95% CI: -2.45 to -1.43, I(2) = 96%). The effect was also seen when CHM was combined with BZDs compared with placebo plus BZDs (MD: -1.88, 95% CI: -2.78 to 0.97, I(2) = 0%) or cognitive and behavioral therapy (MD: -3.80, 95% CI: -4.91 to -2.68, I(2) = 68%) alone. There was no significant difference between CHM and placebo regarding the frequency of adverse events (relative risk, RR: 1.65, 95% CI: 0.67-4.10, I(2) = 0). Overall, oral CHM used as a monotherapy or as an adjunct to conventional therapies appears safe, and it may improve subjective sleep in people with insomnia. However, the typical effect of CHM for insomnia cannot be determined due to heterogeneity. Further study focusing on individual CHM formula for insomnia is needed. The development of a comparable placebo is also needed to improve the successful blinding in RCTs. PMID- 26611944 TI - Relationship between short sleep duration and cardiovascular risk factors in a multi-ethnic cohort - the helius study. AB - BACKGROUND AND AIM: The aim of this study was to investigate the association between short sleep duration and cardiovascular disease (CVD) risk factors including hypertension, diabetes, obesity and lipid profile among various ethnic groups (South Asian Surinamese, African Surinamese, Ghanaians, Turks, Moroccans and the Dutch) living in the Netherlands. The contribution of social economic status (SES) and lifestyle factors were also examined to this association. METHOD: A total of 12,805 participants (aged 18-70 years) from the multi-ethnic Healthy Life in an Urban Setting (HELIUS) cohort. Short sleep duration was defined as <7 h/night. The association between short sleep and CVD risk factors, along with the contribution of SES and lifestyle factors, was assessed using prevalence ratios (PRs). RESULTS: Short sleep was significantly associated with obesity in four out of six ethnic groups, with the socio-demographic-adjusted PR of 1.45 (95% CI, 1.07-1.95) in the Dutch, 1.21 (1.01-1.44) in South Asian Surinamese, 1.25 (1.09-1.43) in African Surinamese and 1.16 (1.04-1.29) in Turks. Short sleep was significantly associated with diabetes in African Surinamese (1.45, 1.14-1.84), Turks (1.59, 1.26-2.02) and Moroccans (1.29, 1.02-1.63). By contrast, the associations between other cardiovascular risk factors and short sleep were not significant in most ethnic groups, with the exception of the association with hypertension in the Dutch and Turks, and dyslipidaemia in South Asian Surinamese (reduced high-density lipoprotein cholesterol and triglyceride) and Moroccans (raised total cholesterol). SES and lifestyle factors contributed little to the observed associations. CONCLUSION: The findings indicate that short sleep is associated with obesity and diabetes in most ethnic groups. The associations for other risk factors vary between ethnic groups. Further studies are warranted to establish the potential factors that might lead to the observed differences across populations. PMID- 26611946 TI - Missing links. PMID- 26611945 TI - Habitual sleep variability, mediated by nutrition intake, is associated with abdominal obesity in adolescents. AB - OBJECTIVE: To investigate habitual sleep duration (HSD) and habitual sleep variability (HSV) in relation to abdominal obesity and nutrient intake as mediating factors in adolescents. METHODS: We analyzed data from 305 adolescents who participated in the Penn State Child Cohort follow-up examination. An actigraphy device was used for seven consecutive nights to calculate HSD and HSV. Abdominal obesity was assessed by dual-energy x-ray absorptiometry. The Youth/Adolescent Food Frequency Questionnaire was used to obtain daily total caloric, protein, fat, and carbohydrates intakes. Linear regression models were used to associate HSD and HSV with abdominal obesity and to qualitatively identify mediating factors. The mediating effect was quantitatively estimated by mediation models. RESULTS: After adjusting for major covariates and HSD, higher HSV was significantly associated with abdominal obesity measures. For example, with 1-hour increase in HSV, android/gynoid fat ratio and visceral fat area increased by 0.02 cm(2) (standard error = 0.01, p = 0.03) and 6.86 cm(2) (standard error = 2.82, p = 0.02), respectively. HSD was not associated with abdominal obesity in HSV-adjusted models. Total caloric, fat, and carbohydrate intakes were significant mediating factors. For instance, 20% of the association between HSV and visceral fat can be attributed to carbohydrate intake. CONCLUSIONS: Higher HSV, not HSD, is significantly associated with abdominal obesity, which can be partially explained by increased caloric intake, especially from carbohydrate, in adolescents. This study suggests that more attention should be paid to establish and maintain regular sleep patterns in adolescents. PMID- 26611947 TI - Supine sleep and obstructive sleep apnea syndrome in Parkinson's disease. AB - OBJECTIVE: Supine sleep is associated with increased obstructive sleep apnea. People with Parkinson's disease (PD) complain about difficulties turning around in bed. The relationship between supine sleep and sleep-disordered breathing has never been explored in people with Parkinson's disease. METHODS: Fifteen consecutive people with PD with severe Obstructive Sleep Apnea Syndrome (OSAS) were compared to: (1) 15 age-matched, gender-matched, body mass index-matched and Unified Parkinson's Disease Rating Scale-III score-matched people with PD without sleep-disordered breathing; (2) 11 age-matched and gender-matched people with severe obstructive sleep apnea syndrome (OSAS) alone; and (3) 11 age-matched and gender-matched healthy controls. Outcomes were: number of position changes during the night and per hour of sleep, and the percentage of sleep time spent in supine. RESULTS: People with PD and severe OSAS spent most of their sleep time in the supine position (93 +/- 11%); while people with PD without OSAS (61 +/- 24%, p <0.001), people with isolated, severe OSAS (50 +/- 28%, p <0.001), and the controls (40 +/- 21, p <0.001) spent significantly less time on their back. People with PD and severe OSAS changed their position in bed per hour of sleep (0.4 +/- 0.5) less frequently than those with PD without OSAS (1.1 +/- 0.8, p = 0.002), those with isolated OSAS (1.2 +/- 1.0, p = 0.006) and the controls (1.5 +/- 0.5, p <0.001). CONCLUSION: PD and severe OSAS are associated with a major reduction in the number of position changes and an increased supine sleep position during the night. For people with PD, alleviating the difficulties of turning around in bed might reduce the supine sleep position and improve sleep disordered breathing. PMID- 26611948 TI - Neuroimaging-evident lesional pathology associated with REM sleep behavior disorder. AB - BACKGROUND/RATIONALE: Rapid eye movement (REM) sleep behavior disorder (RBD) is a potentially injurious parasomnia characterized by dream enactment behavior and polysomnographic REM sleep without atonia (RSWA). Recently, RBD not only has been shown to be strongly associated with synucleinopathy neurodegeneration but has also been rarely reported to be associated with structural lesions involving the brainstem or limbic system. The aim of this study was to describe the clinical, neuroimaging, and outcome characteristics in a case series of patients with lesional RBD. METHODS: This is a retrospective case series from a tertiary care referral center. RESULTS: A total of 10 patients with lesional RBD were identified. Seven (70%) were men, with an average age of sleep symptom onset of 53.7 +/- 17.0 years. Structural pathology evident on neuroimaging included four extraaxial (three meningiomas and one basilar fusiform aneurysm with brainstem compression) and six intraaxial (encephalomalacia, multiple sclerosis, vasculitis, autoimmune limbic encephalitis, and leukodystrophy) lesions. No patient developed parkinsonian features or cognitive impairment suggestive of synucleinopathy over an average of 45.4 +/- 35.2 months of follow-up. CONCLUSIONS: RBD is rarely associated with non-synuclein structural lesions affecting the pons, medulla, or limbic system. The spectrum of lesional RBD comprises tumors, aneurysms, leukodystrophy, and autoimmune/inflammatory/demyelinating brain lesions. PMID- 26611949 TI - A prospective study of total sleep duration and incident metabolic syndrome: the ARIRANG study. AB - BACKGROUND AND OBJECTIVE: Chronic sleep deprivation is increasingly common in industrialized societies. Recent data have revealed that chronic sleep deprivation is associated with negative health outcome. While prospective studies lack the predictive value of sleep duration to identify individuals at high risk of new-onset metabolic syndrome, total sleep duration may play a role in the development of metabolic abnormalities. This study investigates the association between total sleep duration and the incidence of metabolic syndrome in a population-based longitudinal study. RESEARCH DESIGN AND METHODS: At baseline, a prospective cohort study was conducted with 2579 adults without metabolic syndrome aged between 40 and 70 years. Based on a self-reported questionnaire, the participants in this study were investigated between 2005-2008 (baseline) and 2008-2011 (follow-up) and were categorized according to their total sleep duration (<6 h, 6-7.9 h, 8-9.9 h, >=10 h). Metabolic syndrome was defined according to the recent harmonized definition. RESULTS: During an average of 2.6 years of follow-up, 558 (21.6%) subjects developed metabolic syndrome. In multivariable adjusted models, the odds ratio (95% confidence interval (CI)) for incident metabolic syndrome comparing the 6 to 7.9 h to the <6 h of total sleep duration was 1.41 (1.06-1.88). The corresponding odds ratios (95% CI) for high waist circumference, low high-density lipoprotein (HDL) cholesterol, high triglycerides, high blood pressure, and high blood glucose were 1.30 (0.98-1.69), 0.75 (0.56-0.97), 0.82 (0.60-1.11), 1.56 (1.19-2.03), and 1.31 (0.96-1.79), respectively. CONCLUSION: Short sleep duration is an independent risk factor for incident metabolic syndrome in a population-based longitudinal study. PMID- 26611950 TI - The diagnostic value of power spectra analysis of the sleep electroencephalography in narcoleptic patients. AB - OBJECTIVE: Manifestations of narcolepsy with cataplexy (NC) include disturbed nocturnal sleep - hereunder sleep-wake instability, decreased latency to rapid eye movement (REM) sleep, and dissociated REM sleep events. In this study, we characterized the electroencephalography (EEG) of various sleep stages in NC versus controls. METHODS: EEG power spectral density (PSD) was computed in 136 NC patients and 510 sex- and age-matched controls. Features reflecting differences in PSD curves were computed. A Lasso-regularized regression model was used to find an optimal feature subset, which was validated on 19 NC patients and 708 non NC patients from a sleep clinic. Reproducible features were analyzed using receiver operating characteristic (ROC) curves. RESULTS: Thirteen features were selected based on the training dataset. Three were applicable in the validation dataset, indicating that NC patients show (1) increased alpha power in REM sleep, (2) decreased sigma power in wakefulness, and (3) decreased delta power in stage N1 versus wakefulness. Sensitivity of these features ranged from 4% to 10% with specificity around 98%, and it did not vary substantially with and without treatment. CONCLUSIONS: EEG spectral analysis of REM sleep, wake, and differences between N1 and wakefulness contain diagnostic features of NC. These traits may represent sleepiness and dissociated REM sleep in patients with NC. However, the features are not sufficient for differentiating NC from controls, and further analysis is needed to completely evaluate the diagnostic potential of these features. PMID- 26611951 TI - Restless legs syndrome in Egyptian medical students using a validated Arabic version of the Restless Legs Syndrome Rating Scale. AB - OBJECTIVE: Restless legs syndrome (RLS) is a common movement disorder that has a variable prevalence and impact reported from different countries and specific populations. The current study validated an Arabic version of the International Restless Legs Syndrome Study Group (IRLSSG) rating scale (IRLS) and investigated the prevalence and impact of RLS in medical students at Ain Shams University in Cairo. METHODS: Translation of IRLS was done according to standard recognized guidelines provided by the publisher. A total of 389 medical students (217 female and 172 male) participated in the study and answered four questions to detect RLS as proposed by the IRLSSG. Subjects who answered positively the first three questions were recruited for face-to-face interview to exclude RLS mimics and to answer the IRLS. RESULTS: A total of 46 subjects (11.8%; 27 female and 19 male) met the four criteria for RLS. Of these, 39 subjects (10%) had idiopathic RLS. Five subjects (1.3%) and two subjects (0.5%) reported association with history of anemia and diabetes mellitus respectively. Their mean total IRLS score was 16.33 +/- 5.3, with moderate severity (11.62 +/- 3.9) and low impact (3.1 +/- 1.8). The prevalence of individuals who had two or more episodes of RLS of at least moderate severity per week was 5.9%. CONCLUSION: In this specific population of Egyptian medical students, a within-average prevalence of RLS was found with low impact on quality of life similar to worldwide reported populations. RLS sufferers were of high prevalence among this cohort. The Arabic version of IRLS is reliable and valid for further research in Arabic countries. PMID- 26611953 TI - Larval development of Culex quinquefasciatus in water with low to moderate. AB - Population growth and urbanization have increased the potential habitats, and consequently the abundance of Culex quinquefasciatus, the southern house mosquito, a vector of West Nile Virus in urban areas. Water quality is critical in larval habitat distribution and in providing microbial food resources for larvae. A mesocosm experiment was designed to demonstrate which specific components of water chemistry are conducive to larval Culex mosquitoes. Dose response relationships between larval development and NO3 , NH4 , and PO4 concentrations in stream water were developed through this experiment to describe the isolated effects of each nutrient on pre-adult development. The emergence pattern of Culex mosquitoes was found to be strongly related to certain nutrients, and results showed that breeding sites with higher PO4 or NO3 concentrations had higher larval survival rates. High NO3 concentrations favor the development of male mosquitoes and suppress the development of female mosquitoes, but those adult females that do emerge develop faster in containers with high NO3 levels compared to the reference group. The addition of PO4 in the absence of nitrogen sources to the larval habitat slowed larval development, however, it took fewer days for larvae to reach the pupal stage in containers with combinations of NO3 and PO4 or NH4 and PO4 nutrients. Results from this study may bolster efforts to control WNV in urban landscapes by exploring water quality conditions of Culex larval habitats that produce adult mosquitoes. PMID- 26611952 TI - Shift work disorder, depression, and anxiety in the transition to rotating shifts: the role of sleep reactivity. AB - AIM: The aim of this study is to investigate premorbid sleep reactivity as a vulnerability to incident shift work disorder (SWD), and related changes in depression as well as anxiety following a transition to a rotating shifts work schedule. METHODS: This is a longitudinal study with two waves of data collection. The community-based sample included normal sleeping non-shift workers (N = 96; 62.5% female; 47.9 +/- 13.3 years) without a lifetime history of insomnia or baseline excessive daytime sleepiness who transitioned to rotating shift work one year later. Participants reported demographic characteristics, trait sleep reactivity on the Ford Insomnia Response to Stress Test, depression symptoms on the Quick Inventory of Depression Symptomatology, and anxiety symptoms on the Beck Anxiety Inventory. SWD was determined based on significant sleep disturbance and/or excessive sleepiness in the context of working in a rotating-shift schedule. RESULTS: Analyses revealed that the odds were over five times greater for highly sleep-reactive individuals to develop SWD after transitioning to rotating shifts (OR = 5.59, p = 0.04). Nearly 90% of participants who suffered from SWD were accurately identified as high risk at one year before disease onset. Furthermore, individuals who developed SWD reported greater increases in symptoms of depression and anxiety. Finally, analyses revealed significant indirect effects wherein high sleep reactivity increased risk for SWD, which led to greater severity of anxiety and depression symptoms. CONCLUSIONS: The Ford Insomnia Response to Stress Test (FIRST) accurately identifies a focused target population in which the premorbid psychobiological processes complicit in SWD onset and progression, as well as shift work-related depression and anxiety changes, can be better investigated, thus improving future preventative efforts. PMID- 26611954 TI - Local prevalence and transmission of avian malaria in the Alakai Plateau of Kauai, Hawaii, U.S.A. AB - Avian malaria is among the most important threats to native Hawaiian forest birds. It is caused by the parasite Plasmodium relictum and is transmitted by the introduced mosquito vector Culex quinquefasciatus. Temperature increases and precipitation declines due to climate change over the last decade may be responsible for the observed recent expansion in the range and prevalence of avian malaria on the Alakai Plateau, Kauai Island. To examine the hypothesis that conditions are now favorable for transmission of malaria on the Plateau, mosquitoes were sampled with CO2 and Reiter oviposition traps at three sites (Kawaikoi, Halepa'akai, and Koke'e) on several occasions between October, 2013 and April, 2014. P. relictum infection was assessed by PCR or dissection under a microscope. We also surveyed mosquito larvae along Halepa'akai and Kawaikoi streams. We observed that Cx. quinquefasciatus is well established on the Alakai Plateau, as mosquitoes were caught on all field trips, except in April at Halepa'akai, and larvae were found throughout the year. We observed differences in adult abundance among sites and microhabitats (stream vs ridge lines). PMID- 26611955 TI - Tadpoles of three common anuran species from Thailand do not prey on mosquito larvae. AB - Tadpoles are often considered to be predators of mosquito larvae and are therefore beneficial for the control of certain disease vectors. Nevertheless, only a few species have actually been recorded to prey on mosquito larvae. The mosquito larvae predation rates of tadpoles of three common Thai anuran species (Bufo melanostictus, Kaloula pulchra and Hylarana raniceps) were experimentally tested. Tadpoles in varying developmental stages were used to assess a size/age effect on the predation rate. In addition, different instars of Culex quinquefasciatus were used in order to assess a prey size effect on the predation rates. All three species failed to show any evidence of mosquito larvae predation. Neither small nor large tadpoles fed on mosquito larvae. Prey size also did not affect predation. Although tadpoles do not feed on mosquito larvae, there may be other direct or indirect inter-specific interactions that adversely impact the development of larvae in shared habitats with tadpoles. PMID- 26611956 TI - Prevalence of Rickettsia and Bartonella species in Spanish cats and their fleas. AB - The aim of this study was to determine the prevalence of Bartonella henselae, Rickettsia felis, and Rickettsia typhi in fleas and companion cats (serum and claws) and to assess their presence as a function of host, host habitat, and level of parasitism. Eighty-nine serum and claw samples and 90 flea pools were collected. Cat sera were assayed by IFA for Bartonella henselae and Rickettssia species IgG antibodies. Conventional PCRs were performed on DNA extracted from nails and fleas collected from cats. A large portion (55.8%) of the feline population sampled was exposed to at least one of the three tested vector-borne pathogens. Seroreactivity to B. henselae was found in 50% of the feline studied population, and to R. felis in 16.3%. R. typhi antibodies were not found in any cat. No Bartonella sp. DNA was amplified from the claws. Flea samples from 41 cats (46%) showed molecular evidence for at least one pathogen; our study demonstrated a prevalence rate of 43.3 % of Rickettsia sp and 4.4% of Bartonella sp. in the studied flea population. None of the risk factors studied (cat's features, host habitat, and level of parasitation) was associated with either the serology or the PCR results for Bartonella sp. and Rickettsia sp.. Flea associated infectious agents are common in cats and fleas and support the recommendation that stringent flea control should be maintained on cats. PMID- 26611958 TI - Simulation of climate-tick-host-landscape interactions: Effects of shifts in the seasonality of host population fluctuations on tick densities. AB - Tick vector systems are comprised of complex climate-tick-host-landscape interactions that are difficult to identify and estimate from empirical observations alone. We developed a spatially-explicit, individual-based model, parameterized to represent ecological conditions typical of the south-central United States, to examine effects of shifts in the seasonal occurrence of fluctuations of host densities on tick densities. Simulated shifts in the seasonal occurrence of periods of high and low host densities affected both the magnitude of unfed tick densities and the seasonality of tick development. When shifting the seasonal densities of all size classes of hosts (small, medium, and large) synchronously, densities of nymphs were affected more by smaller shifts away from the baseline host seasonality than were densities of larval and adult life stages. When shifting the seasonal densities of only a single size-class of hosts while holding other size classes at their baseline levels, densities of larval, nymph, and adult life stages responded differently. Shifting seasonal densities of any single host-class earlier resulted in a greater increase in adult tick density than when seasonal densities of all host classes were shifted earlier simultaneously. The mean densities of tick life stages associated with shifts in host densities resulted from system-level interactions of host availability with tick phenology. For example, shifting the seasonality of all hosts ten weeks earlier resulted in an approximately 30% increase in the relative degree of temporal co-occurrence of actively host-seeking ticks and hosts compared to baseline, whereas shifting the seasonality of all hosts ten weeks later resulted in an approximately 70% decrease compared to baseline. Differences among scenarios in the overall presence of active host-seeking ticks in the system were due primarily to the degree of co-occurrence of periods of high densities of unfed ticks and periods of high densities of hosts. PMID- 26611957 TI - Identification of Aedes albopictus larval index thresholds in the transmission of dengue in Guangzhou, China. AB - Entomological indices have been used to quantitatively express vector density, but the threshold of larval indices of Aedes albopictus in dengue epidemics is still undefined. We conducted a case-control study to identify the thresholds of Aedes albopictus larval indices in dengue epidemics. Two unit levels of analysis were used: district and street. The discriminative power of the indices was assessed by receiver operating characteristic (ROC) curves. The association between the entomologic indices and dengue transmission was further explored by a logistic regression model. At the district level, there was no significant difference in the Breteau index (BI) between districts that reported cases and those did not (t=0.164, p>0.05), but the Container index (CI) did show a significant difference (t=2.028, p<0.01). The AUC (Area Under the Curve) of BI, CI, and prediction value were 0.540, 0.630, and 0.533, respectively. Predicting at the street level, the AUC of BI, CI, and prediction values were 0.684, 0.660, and 0.685, respectively, and 0.861, 0.827, and 0.867 for outbreaks. BI=5.1, CI=5.4, or prediction value =0.491were suggested to control the epidemic efficiently with the fewest resources, where BI=4.0, CI=5.1, or PRE =0.483 were suggested to achieve effectiveness. PMID- 26611959 TI - Oviposition substrate in Asian tiger mosquito surveillance: Do the sizes matter? AB - Ovitraps are regarded as a reliable system to monitor Aedes albopictus dynamics. However, the dimensions of the oviposition substrate are not standardized, and no studies have investigated which should be the most effective sizes. In this study, the effect of paddle sizes in tiger mosquito egg collection was evaluated. Egg count and density on the wide surfaces and margins of different-sized oviposition substrates have been evaluated in two studies (A and B). In study A, a total of 29,995 Ae. albopictus eggs was counted in 250 classic oviposition substrates. Eggs were found on both wide surfaces (53.1%) and margins (46.9%). Egg density was significantly larger in margins compared to wide surfaces. Overall in study B, 983 Ae. albopictus eggs were collected. According to paddle sizes, 51.8% of eggs were on large and 48.2% on small paddles. Mean egg density of wide surfaces was significantly larger in small paddles (0.25 eggs/cm(2) ) compared to large paddles (0.06 eggs/cm(2) ). Results indicate that wider oviposition substrates do not mean larger number of Ae. albopictus eggs. Indeed, on paddles four times thinner than others, the number of eggs counted was not statistically different. These findings suggest that small paddles may be routinely employed in ovitraps, thus allowing savings of materials and money. PMID- 26611960 TI - Detection of Rickettsia and Anaplasma from hard ticks in Thailand. AB - We collected a total of 169 adult hard ticks and 120 nymphs from under the leaves of plants located along tourist nature trails in ten localities. The results present data examining the vector competence of ticks of different genera and the presence of Rickettsia and Anaplasma species. The ticks belonged to three genera, Amblyomma, Dermacentor, and Haemaphysalis, comprising 11 species. Rickettsia bacteria were detected at three collection sites, while Anaplasma bacteria were detected at only one site. Phylogenetic analysis revealed new rickettsia genotypes from Thailand that were closely related to Rickettsia tamurae, Rickettsia monacensis, and Rickettsia montana. This study was also the first to show that Anaplasma bacteria are found in Haemaphysalis shimoga ticks and are closely related evolutionarily to Anaplasma bovis. These results provide additional information for the geographical distribution of tick species and tick borne bacteria in Thailand and can therefore be applied for ecotourism management. PMID- 26611961 TI - Larval habitats of sand flies in rural areas of southern Brazil. AB - We report the results of an investigation of natural larval sand fly habitats in the Recanto Marista, Doutor Camargo municipality, Parana state, Brazil, from May, 2010 to August, 2012. We used Alencar emergence traps (AT), experimental traps (ET), and soil samples incubated in a biochemical oxygen demand incubator. Eight sand flies were collected with ATs. One specimen was collected with an ET and 21 were collected in soil samples. The collected species were Brumptomyia brumpti, Micropygomyia ferreirana, Migonemyia bursiformis, Migonemyia migonei, Nyssomyia neivai, Nyssomyia whitmani, and Pintomyia pessoai. The laval habitats of sand flies were located in the Recanto Marista, especially between tree roots, but the number of adults that emerged in the traps and soil samples was small despite the high density of sand flies that has been recorded in the Recanto Marista. PMID- 26611962 TI - Determining meteorological drivers of salt marsh mosquito peaks in tropical northern Australia. AB - In northern Australia the northern salt marsh mosquito Aedes vigilax is a vector of Ross River virus and is an appreciable pest. A coastal wetland adjacent to Darwin's residential suburbs offers a favorable habitat for Ae. vigilax, and despite vigilant mosquito control efforts, peaks of Ae. vigilax occur in excess of 500/trap/night some months. To improve mosquito control for disease and nuisance biting to nearby residential areas, we sought to investigate meteorological drivers associated with these Ae. vigilax peaks. We fitted a cross sectional logistic regression model to weekly counts of female Ae. vigilax mosquitoes collected between July, 1998 and June, 2009 against variables, tide, rainfall, month, year, and larval control. Aedes vigilax peaks were associated with rainfall during the months September to November compared with January, when adjusted for larval control and tide. To maximize mosquito control efficiency, larval control should continue to be implemented after high tides and with increased emphasis on extensive larval hatches triggered by rainfall between September and November each year. This study reiterates the importance of monitoring and evaluating service delivery programs. Using statistical modelling, service providers can obtain solutions to operational problems using routinely collected data. These methods may be applicable in mosquito surveillance or control programs in other areas. PMID- 26611963 TI - Natural vertical transmission of dengue viruses in Aedes aegypti in selected sites in Cebu City, Philippines. AB - We attempted to determine the vertical transmission of dengue virus (DENV) in Aedes aegypti in selected sites in Cebu City, Philippines. Mosquito sub-adults were collected monthly from households and the field during the wet-dry-wet season from November, 2011 to July, 2012 and were laboratory-reared to adults. Viral RNA extracts in mosquitoes were assayed by hemi-nested RT-PCR. Results showed that 62 (36.26%; n=679) out of 171 mosquito pools (n=2,871) were DENV+. The minimum infection rate (MIR) of DENV ranged from 0 in wet months to 48.22/1,000 mosquitoes in April, 2012 (mid-dry). DENVs were detected in larvae, pupae, and male and female adults, with DENV-4, DENV-3, and DENV-1, in that rank of prevalence. DENV-1 co-infected with either DENV-3 or -4 or with both in April, 2012; DENV-3 and -4 were present in both seasons. More DENV+ mosquitoes were collected from households than in field premises (p<0.001) and in the dry than in the wet season (p<0.05), with significant interaction (p<0.05) between sites and premises but no interaction between sites and seasons (p>0.05). By Generalized Linear Mixed models, the type of premises nested in sites and monthly total rainfall were significant predictors of monthly dengue cases (p<0.05) and not MIR, season, temperature, and relative humidity. Surveillance of DENV prevalence in Ae. aegypti and detecting their natural foci in the dry season provide an early warning signal of dengue outbreak. PMID- 26611964 TI - Intraspecific variation in desiccation survival time of Aedes aegypti (L.) mosquito eggs of Australian origin. AB - Aedes aegypti (L.) mosquitoes preferentially oviposit in natural and artificial receptacles where their eggs are able to withstand drying as water levels fluctuate. Desiccation-resistant eggs also increase the potential for establishment in non-native habitats while providing logistical impediments to control programs. Viability and mean survival times of eggs stored under three dryness conditions for up to 367 days were investigated among three field-derived colonies of Australian Ae. aegypti to understand variation in desiccation survival. Further investigations compared egg survival between an established colony and its wild counterpart. Our results confirmed that Ae. aegypti eggs can withstand desiccation for extended periods of time with approximately 2-15% egg viability recorded after one year and viability remaining above 88% under all conditions through 56 days. Intraspecific variations in egg survival times were recorded, suggesting local adaptation while each of the colonies demonstrated a consistent preference for higher humidity. Egg volume varied between the populations, suggesting a relationship between egg volume and survival time, with the marginally larger eggs (Charters Towers and Innisfail) having greater desiccation resistance over the range of conditions. The strong survivorship of Charters Towers eggs in dry, warm conditions demonstrates the adaptive significance of a desiccation-resistant egg. PMID- 26611965 TI - Comparative efficacy of existing surveillance tools for Aedes aegypti in Western Kenya. AB - All traditional surveillance techniques for Aedes aegypti have been developed for the cosmopolitan domestic subspecies Ae. aegypti aegypti, and not the sylvatic subspecies, Ae. aegypti formosus. The predominant form in Western Kenya is Ae. aegypti formosus that is rarely associated with human habitations but is linked to transmission of sylvatic dengue virus strains. We compared five surveillance methods for their effectiveness in sampling Ae. aegypti formosus with the goal of determining a sustainable surveillance strategy in Kenya. The methods included larval and pupal surveys, oviposition trapping, BG-Sentinel trapping, resting boxes, and backpack aspirations. Larval and pupal surveys collected the highest number of Ae. aegypti formosus (51.3%), followed by oviposition traps (45.7%), BG Sentinel traps (3.0%), and zero collected with either backpack aspiration or resting box collections. No Ae. aegypti formosus larvae or pupae were found indoors. The results indicate that oviposition traps and outdoor larval and pupal surveys were better surveillance methods for Ae. aegypti formosus in Western Kenya. PMID- 26611966 TI - Culicoides (Diptera: Ceratopogonidae) and livestock in the Netherlands: comparing host preference and attack rates on a Shetland pony, a dairy cow, and a sheep. AB - Culicoides (Diptera: Ceratopogonidae) host preferences and attack rates were quantified in early summer at a dairy farm in the Netherlands using livestock tethered at pasture. Midges were aspirated hourly over seven consecutive hours (17:00-23:00) from a dairy cow, a Shetland pony, and a sheep and correspondingly yielded seventeen, thirteen, and nine species. Of the 14,181 midges obtained, approximately 95% belonged to the C. obsoletus complex, C. dewulfi, C. chiopterus, and C. punctatus that together include all proven or potential vectors for arboviral diseases in livestock in northwestern Europe. On average, 7.6 and 3.5 times more Culicoides were collected, respectively, from the cow and the Shetland pony than from the sheep. In descending order of abundance, the C. obsoletus complex, C. dewulfi, and C. chiopterus dominated attacks on all three hosts, whereas C. punctatus and C. pulicaris favored only the two larger hosts. Irrespective of the host species involved, the three body regions attracted the same component species, C. chiopterus favoring the legs, C. punctatus and C. achrayi the belly, and the C. obsoletus complex, C. dewulfi, and C. pulicaris the head, back, and flanks. That known and potential vectors for animal diseases feed indiscriminately on a broad range of mammal hosts means that all major livestock species, including equines, are rendered susceptible to one or more Culicoides borne pathogens. PMID- 26611967 TI - The effects of plant essential oils on escape response and mortality rate of Aedes aegypti and Anopheles minimus. AB - The High Throughput Screening System (HITSS) has been applied in insecticide behavioral response studies with various mosquito species. In general, chemical or natural compounds can produce a range of insect responses: contact irritancy, spatial repellency, knock-down, and toxicity. This study characterized these actions in essential oils derived from citronella, hairy basil, catnip, and vetiver in comparison to DEET and picaridin against Aedes aegypti and Anopheles minimus mosquito populations. Results indicated the two mosquito species exhibited significantly different (P<0.05) contact irritant escape responses between treatment and control for all tested compound concentrations, except with the minimum dose of picaridin (P>0.05) against Ae. aegypti. Spatial repellency responses were elicited in both mosquito species when exposed to all compounds, but the strength of the repellent response was dependent on compound and concentration. Data show that higher test concentrations had greatest toxic effects on both mosquito populations, but vetiver had no toxic effect on Ae. aegypti and picaridin did not elicit toxicity in either Ae. aegypti or An. minimus at any test concentration. Ultimately, this study demonstrates the ability of the HITSS assay to guide selection of effective plant essential oils for repelling, irritating, and killing mosquitoes. PMID- 26611968 TI - Coexistence of Bartonella henselae and B. clarridgeiae in populations of cats and their fleas in Guatemala. AB - Cats and their fleas collected in Guatemala were investigated for the presence of Bartonella infections. Bartonella bacteria were cultured from 8.2% (13/159) of cats, and all cultures were identified as B. henselae. Molecular analysis allowed detection of Bartonella DNA in 33.8% (48/142) of cats and in 22.4% (34/152) of cat fleas using gltA, nuoG, and 16S-23S internal transcribed spacer targets. Two Bartonella species, B. henselae and B. clarridgeiae, were identified in cats and cat fleas by molecular analysis, with B. henselae being more common than B. clarridgeiae in the cats (68.1%; 32/47 vs 31.9%; 15/47). The nuoG was found to be less sensitive for detecting B. clarridgeiae compared with other molecular targets and could detect only two of the 15 B. clarridgeiae-infected cats. No significant differences were observed for prevalence between male and female cats and between different age groups. No evident association was observed between the presence of Bartonella species in cats and in their fleas. PMID- 26611969 TI - Comparing the effect of modeled climatic variables on the distribution of African horse sickness in South Africa and Namibia. AB - Africa horse sickness (AHS) is a lethal disease of horses with a seasonal occurrence that is influenced by environmental conditions that favor the development of Culicoides midges (Diptera: Ceratopogonidae). This study compared and evaluated the relationship of various modeled climatic variables with the distribution and abundance of AHS in South Africa and Namibia. A comprehensive literature review of the historical AHS reported data collected from the Windhoek archives as well as annual reports from the Directorate of Veterinary services in Namibia were conducted. South African AHS reported data were collected from the South African Department of Agriculture, Forestry, and Fisheries. Daily climatic data were extracted for the time period 1993-2011 from the ERA-interim re analysis dataset. The principal component analysis of the complete dataset indicated a significant statistical difference between Namibia and South Africa for the various climate variables and the outbreaks of AHS. The most influential parameters in the distribution of AHS included humidity, precipitation, evaporation, and minimum temperature. In South Africa, temperature had the most significant effect on the outbreaks of AHS, whereas in Namibia, humidity and precipitation were the main drivers. The maximum AHS cases in South Africa occurred at temperatures of 20-22 degrees C and relative humidity between 50 70%. Furthermore, anthropogenic effects must be taken into account when trying to understand the distribution of AHS. PMID- 26611970 TI - Spatial relations among environmental factors and phlebotomine sand fly populations (Diptera: Psychodidae) in central and southern Morocco. AB - Phlebotomine sand flies (Diptera: Psychodidae, Phlebotominae) are of considerable public health importance because of their ability to transmit several human parasites, mainly as vectors of Leishmania spp. Over the past decade, the epidemiological situation of cutaneous leishmaniasis (CL) has significantly increased with its geographic expansion to previously free areas and the emergence of overlapping foci of cutaneous leishmaniasis and visceral leishmaniasis (VL) in several provinces of Morocco. A total of 15,313 specimens was collected during this entomological survey. The genera Phlebotomus (57.38%) and Sergentomyia (42.62%) were identified. Sergentomyia minuta (22.01%) was the most prevalent species, followed by S. fallax (18.21%), Phlebotomus perniciosus (14.35%), P. papatasi (14.06%), P. sergenti (12.85%), P. longicuspis (10.74%), P. ariasi (2.68%), S. dreyfussi (1.53%), P. alexandri (1.31%), P. bergeroti (1.14%), S. christophersi (0.62%), S. africana (0.25%), P. chabaudi (0.14%), P. chadlii (0.05%), and P. kazeruni (0.04%). We aimed to determine current distribution of leishmaniases vectors, their ecological characteristics, and the significance of the predominant species at any bioclimate stage, altitude range, and soil texture in terms of the risk of leishmaniasis transmission. PMID- 26611971 TI - Association of vectors and environmental conditions during the emergence of Peruvian horse sickness orbivirus and Yunnan orbivirus in northern Peru. AB - Since 1983, cases of diseased donkeys and horses with symptoms similar to those produced by alphaviruses were identified in two departments in northern Peru; however serological testing ruled out the presence of those viruses and attempts to isolate an agent were also unproductive. In 1997, also in northern Peru, two new orbiviruses were discovered, each recognized as a causative agent of neurological diseases in livestock and domestic animals and, at the same time, mosquitoes were found to be infected with these viruses. Peruvian horse sickness virus (PHSV) was isolated from pools of culicid mosquitoes, Aedes serratus and Psorophora ferox, and Yunnan virus (YUOV) was isolated from Aedes scapularis in the subtropical jungle (upper jungle) located on the slope between the east side of the Andes and the Amazonian basin in the Department of San Martin. Both viruses later were recovered from mosquitoes collected above the slope between the west side of the Andes and the coast (Department of Piura) in humid subtropical areas associated with the Piura River basin. In this region, PHSV was isolated from Anopheles albimanus and YUOV was isolated from Ae. scapularis. We discuss the ecology of vector mosquitoes during the outbreaks in the areas where these mosquitoes were found. PMID- 26611972 TI - Seasonal patterns of horse fly richness and abundance in the Pampa biome of southern Brazil. AB - Fluctuations in seasonal patterns of horse fly populations were examined in rainforests of tropical South America, where the climate is seasonal. These patterns were evaluated with robust analytical models rather than identifying the main factors that influenced the fluctuations. We examined the seasonality of populations of horse flies in fields and lowland areas of the Pampa biome of southern Brazil with generalized linear models. We also investigated the diversity of these flies and the sampling effort of Malaise traps in this biome over two years. All of the 29 species had clear seasonality with regard to occurrence and abundance, but only seven species were identified as being influenced by temperature and humidity. The sampling was sufficient and the estimated diversity was 10% more than observed. Seasonal trends were synchronized across species and the populations were most abundant between September and March and nearly zero in other months. While previous studies demonstrated that seasonal patterns in population fluctuations are correlated with climatic conditions in horse fly assemblages in South America rainforests, we show a clear effect of each factor on richness and abundance and the seasonality in the prevalence of horse fly assemblages in localities of the Pampa biome. PMID- 26611973 TI - Performance of light-emitting diode traps for collecting sand flies in entomological surveys in Argentina. AB - The performance of two light-emitting diode traps with white and black light for capturing phlebotomine sand flies, developed by the Argentinean Leishmaniasis Research Network (REDILA-WL and REDILA-BL traps), were compared with the traditional CDC incandescent light trap. Entomological data were obtained from six sand fly surveys conducted in Argentina in different environments. Data analyses were conducted for the presence and the abundance of Lutzomyia longipalpis, Migonemyia migonei, and Nyssomyia whitmani (106 sites). No differences were found in presence/absence among the three types of traps for all sand fly species (p>0.05). The collection mean of Lu. longipalpis from the REDILA BL didn't differ from the CDC trap means, nor were differences seen between the REDILA-WL and the CDC trap collection means (p>0.05), but collections were larger from the REDILA-BL trap compared to the REDILA-WL trap (p<0.05). For Mg. migonei and Ny. whitmani, no differences were found among the three types of traps in the number of individuals captured (p>0.05). These results suggest that both REDILA traps could be used as an alternative capture tool to the original CDC trap for surveillance of these species, and that the REDILA-BL will also allow a comparable estimation of the abundance of these flies to the CDC light trap captures. In addition, the REDILA-BL has better performance than the REDILA-WL, at least for Lu. longipalpis. PMID- 26611974 TI - Infestation of arboreal nests of coatis by triatomine species, vectors of Trypanosoma cruzi, in a large Neotropical wetland. AB - The coati (Nasua nasua, Carnivora) is a medium-sized mammal common in the Pantanal of Brazil. Unlike most mammals, coatis construct arboreal nests used for resting and reproduction. In this region, the coati is an important host of Trypanosoma cruzi, the causative agent of Chagas disease. There are two possible routes through coatis can be infected by T. cruzi: the oral route or the vectorial route. However, the relative importance of each of these routes in the infection of coatis and its role in the sylvatic cycle of the parasite are unknown. Our objectives were to investigate: (i) whether coati nests were infested by triatomine bugs, (ii) what species were frequent in the nests, (iii) whether the triatomines in nests were infected by T. cruzi, and (iv) what were the food resources of these triatomines. Eight of the 24 nests sampled were infested with triatomines, a total of 37 specimens of at least two species (Rhodnius stali and Triatoma sordida). In one nest, R. stali and T. sordida co occurred and both fed on multiple resources, including coatis. This is the first report of triatomines occurring in arboreal nests of coatis. The co-occurrence of two different genera of triatomine vectors and coatis within the limited space of the coati nests provide multiple opportunities for the exchange of the protozoan parasite through both the vectorial and oral transmission routes. PMID- 26611976 TI - Prevalence of parasitism and adult survival time of Aedes albifasciatus (Diptera: Culicidae) parasitized by Strelkovimermis spiculatus (Nematoda: Mermithidae). AB - We described the carryover of Strelkovimermis spiculatus (Poinar and Camino) (Nematoda: Mermithidae) from mosquito larvae, the primary site of maturation, to adults. We analyzed the survival time of male and female Aedes albifasciatus (Macquart) (Diptera: Culicidae) parasitized by S. spiculatus, the time of emergence of nematodes from adult mosquitoes, and the state of parasitism in the same mosquito cohorts during the immature stages. Mosquito larvae with single and multiple parasitism (up to 11 parasites) were observed. The mortality of mosquito larvae and adults was produced in all cases where at least one mermithid emerged. The mortality of S. spiculatus showed an increasing trend in mosquito larvae with larger numbers of nematodes and was higher in larvae parasitized by eight or more nematodes. Maximum survival of parasitized adult females of Ae. albifasciatus was 38 days, while non-parasitized adult males and females survived 39 and 41 days, respectively. Strelkovimermis spiculatus mortality was observed in Ae. albifasciatus larvae with single or multiple parasitisms. The spread of mermithid parasitism in adult mosquito populations is discussed. PMID- 26611975 TI - Avian Plasmodium infection in field-collected mosquitoes during 2012-2013 in Tarlac, Philippines. AB - Global warming threatens to increase the spread and prevalence of mosquito transmitted diseases. Certain pathogens may be carried by migratory birds and transmitted to local mosquito populations. Mosquitoes were collected in the northern Philippines during bird migration seasons to detect avian malaria parasites as well as for the identification of potential vector species and the estimation of infections among local mosquito populations. We used the nested PCR to detect the avian malaria species. Culex vishnui (47.6%) was the most abundant species collected and Cx. tritaeniorhynchus (13.8%) was the second most abundant. Avian Plasmodium parasites were found in eight mosquito species, for which the infection rates were between 0.5% and 6.2%. The six Plasmodium genetic lineages found in this study included P. juxtanucleare -GALLUS02, Tacy7 (Donana04), CXBIT01, Plasmodium species LIN2 New Zealand, and two unclassified lineages. The potential mosquito vectors for avian Plasmodium parasites in the Philippines were Cq. crassipes, Cx. fuscocephala, Cx. quinquefasciatus, Cx. sitiens, Cx. vishnui, and Ma. Uniformis; two major genetic lineages, P. juxtanucleare and Tacy7, were identified. PMID- 26611977 TI - Updated checklist of the mosquitoes (Diptera: Culicidae) of Belgium. AB - Most information about the systematics and bioecology of Belgian mosquitoes dates back from before 1950, and only scattered information was produced during the last decades. In this paper we review and update the list of mosquito species recorded in Belgium, from first report (1908) to 2015. Six genera and 31 species were recorded so far, including 28 autochthonous species and three invasive alien species recently recorded in Belgium: Aedes albopictus (Skuse 1894), Ae. japonicus japonicus (Theobald 1901), and Ae. koreicus (Edwards 1917). The six genera are Anopheles (five species), Aedes (sixteen species), Coquillettidia (one species), Culex (four species), Culiseta (four species), and Orthopodomyia (one species). PMID- 26611978 TI - New records of Aedes aegypti at the southern limit of its distribution in Buenos Aires province, Argentina. PMID- 26611979 TI - First report of the main vector of visceral leishmaniasis in America, Lutzomyia longipalpis (Lutz, Neiva, 1912) (Diptera: Psychodidae: Phlebotominae), in southern Minas Gerais State, Brazil. PMID- 26611980 TI - Nucleotide sequence differentiation of Argentine isolates of the mosquito parasitic nematode Strelkovimermis spiculatus (Nematoda: Mermithidae). PMID- 26611981 TI - Natural infection of Evandromyia lenti (Mangabeira) (Diptera: Psychodidae) by Psychodiella chagasi (Adler & Mayrink) (Apicomplexa: Lecudinidae). PMID- 26611982 TI - Rickettsia rickettsii and Rickettsia felis infection in Rhipicephalus sanguineus ticks and Ctenocephalides felis fleas co-existing in a small city in Yucatan, Mexico. PMID- 26611983 TI - Dissolved oxygen levels affect the survival and developmental period of the mosquito Culex pipiens. PMID- 26611984 TI - Reflections of a Vaccinologist: Lessons Learned About What We Can Do to Improve Trust in Vaccines and Vaccine Programsa. AB - Public trust can be improved by learning from past mistakes, by establishing a standing forum for review of new concerns as they arise, and by maintaining a robust vaccine safety system. Developing standard guidelines for reporting causality assessment in case reports would help educate physicians and prevent future unnecessary concerns based on false assumptions of causal relationships. PMID- 26611985 TI - Evaluation of thermal formation and air ventilation inside footwear during gait: The role of gait and fitting. AB - Comfort is an important concept in footwear design. The microclimate inside footwear contributes to the perception of thermal comfort. To investigate the effect of ventilation on microclimate formation inside footwear, experiments with subjects were conducted at four gait speeds with three different footwear sizes. Skin temperature, metabolism, and body mass were measured at approximately 25 degrees C and 50% relative humidity, with no solar radiation and a calm wind. The footwear occupancy and ventilation rate were also estimated, with the latter determined using the tracer gas method. The experimental results revealed that foot movement, metabolism, evaporation, radiation, convection, and ventilation were the main factors influencing the energy balance for temperature formation on the surface of the foot. The cooling effect of ventilation on the arch temperature was observed during gait. The significance of the amount of air space and ventilation on the improvement in the thermal comfort of footwear was clarified. PMID- 26611986 TI - The ability of UK offshore workers of different body size and shape to egress through a restricted window space. AB - 404 male offshore workers aged 41.4 +/- 10.7 y underwent 3D body scanning and an egress task simulating the smallest helicopter window emergency exit size. The 198 who failed were older (P < 0.01), taller (P < 0.05) and heavier (P < 0.0001) than the 206 who passed. Using all extracted dimensions from the scans, binary logistic regression identified a model (refined using backward elimination) which predicted egress outcome with 75.2% accuracy. Using only weight, bideltoid breadth and maximum chest depth, the model achieved ~70% accuracy. When anatomical dimensions categorise individuals for small window egress, 25% or more will be misclassified, with false positives (those predicted to fail, but pass) slightly outnumbering false negatives (those predicted to pass, but fail), highlighting the limitations of a predictive approach which treats the body as a rigid object. Differences in flexibility and technique may explain these observations, which may be important considerations for future research. PMID- 26611987 TI - Beyond safety outcomes: An investigation of the impact of safety climate on job satisfaction, employee engagement and turnover using social exchange theory as the theoretical framework. AB - Safety climate, a measure of the degree to which safety is perceived by employees to be a priority in their company, is often implicated as a key factor in the promotion of injury-reducing behavior and safe work environments. Using social exchange theory as a theoretical basis, this study hypothesized that safety climate would be related to employees' job satisfaction, engagement, and turnover rate, highlighting the beneficial effects of safety climate beyond typical safety outcomes. Survey data were collected from 6207 truck drivers from two U.S. trucking companies. The objective turnover rate was collected one year after the survey data collection. Results showed that employees' safety climate perceptions were linked to employees' level of job satisfaction, engagement, and objective turnover rate, thus supporting the application of social exchange theory. Job satisfaction was also a significant mediator between safety climate and the two human resource outcomes (i.e., employee engagement and turnover rate). This study is among the first to assess the impact of safety climate beyond safety outcomes among lone workers (using truck drivers as an exemplar). PMID- 26611988 TI - Reflecting on Jens Rasmussen's legacy (2) behind and beyond, a 'constructivist turn'. AB - This article is the second part of a study on the legacy of Jens Rasmussen. The first article, subtitled 'A Strong Program for a Hard Problem', looks back on his 30 years of scientific contribution, from 1969 to 2000. This second article explores and investigates some of the intellectual roots which influenced his thinking, using them as a basis to understand some limits and move forward. Indeed, historically oriented studies such as this one are not only tributes to researchers, but a way to differentiate and contrast our present situation with the past in order to integrate contemporary trends, be they theoretical or empirical, or oriented towards research and new models. In the first section of this article, I offer a synthesis of the background covered in the previous article, but I use a tree here as a graphical complement. Branches of the tree show the many fruitful directions opened by Jens Rasmussen, directions which inspired many researchers. In the second part, I address what I believe to be behind this wealth of engineering legacy: cybernetics. I contend that cybernetics has had a profound influence on his thinking and provided him key principles for his inspiring and successful models. To develop the tree image, one might say that cybernetics is the trunk of the tree. Finally, in the third part, I take the opportunity to explore the relevance of extending and sensitising his program to constructivist discourses. After an introduction to this discourse, identifying four types of constructivisms (cognitive, social, epistemological and anthropological), I characterise this move as a 'constructivist turn'. PMID- 26611989 TI - Action slips during whole-body vibration. AB - Helicopter aircrew members engage in highly demanding cognitive tasks in an environment subject to whole-body vibration (WBV). Sometimes their actions may not be according to plan (e.g. action slips and lapses). This study used a Sustained Attention to Response Task (SART) to examine whether action slips were more frequent during exposure to WBV. Nineteen participants performed the SART in two blocks. In the WBV block participants were exposed to 17 Hz vertical WBV, which is typical of larger helicopter working environments. In the No-WBV block there was no WBV. There were more responses to the rare no-go digit 3 (i.e. action slips) in the WBV block, and participants responded faster in the WBV block. These results suggest that WBV influences response inhibition, and can induce impulsive responding. WBV may increase the likelihood of action slips, mainly due to failure of response inhibition. PMID- 26611990 TI - Normal Venous Phase Documented during Angiography in Patients with Spinal Vascular Malformations: Incidence and Clinical Implications. AB - BACKGROUND AND PURPOSE: A key angiographic sign observed in patients with spinal vascular malformations is the absence of a normal venous phase. While this finding alone is often believed to rule out a lesion impacting the perimedullary venous drainage, the observation of a venous phase in several patients with vascular malformations led us to reconsider the validity of that sign. MATERIALS AND METHODS: Eighty-one patients with 6 spinal arteriovenous malformations, 16 perimedullary arteriovenous fistulas, 61 spinal epidural or dural AVFs, and 1 paravertebral AVF (2 patients had multiple lesions) were reviewed. The venous phase was defined as normal, absent, or indeterminate. The venous phase timing was analyzed in patients with spinal dural or epidural AVFs. RESULTS: The existence of a venous phase could not be determined for technical reasons in 23 patients. A venous phase was documented in 25 of 58 patients (43%), including 16 of 49 vascular malformations (40.0%) with perimedullary venous drainage. Twelve of the 30 patients (40.0%) with dural or epidural AVFs had a normal venous phase, appearing, on average, 10.1 seconds and best visualized 15.0 seconds after opacification of the artery of Adamkiewicz. CONCLUSIONS: A normal venous phase was observed in 43% of patients with spinal vascular malformations, and within an acceptable delay (<18 seconds) in 40% of slow-flow AVFs. While it remains an important angiographic sign, the observation of a normal venous phase cannot be used to exclude the presence of a vascular malformation or justify interrupting a diagnostic spinal angiogram. PMID- 26611991 TI - Pipeline Embolization Device in the Treatment of Recurrent Previously Stented Cerebral Aneurysms. AB - BACKGROUND AND PURPOSE: The use of the Pipeline Embolization Device in the management of recurrent previously stented cerebral aneurysms is controversial. The aim of this study was to evaluate the efficacy and safety of the Pipeline Embolization Device in the treatment of recurrent, previously stented aneurysms. MATERIALS AND METHODS: Twenty-one patients with previously stented recurrent aneurysms who later underwent Pipeline Embolization Device placement (group 1) were retrospectively identified and compared with 63 patients who had treatment with the Pipeline Embolization Device with no prior stent placement (group 2). Occlusion at the latest follow-up angiogram, recurrence and retreatment rates, clinical outcome, complications, and morbidity and mortality observed after treatment with the Pipeline Embolization Device were analyzed. RESULTS: Patient characteristics were similar between the 2 groups. The mean time from stent placement to recurrence was 25 months. Pipeline Embolization Device treatment resulted in complete aneurysm occlusion in 55.6% of patients in group 1 versus 80.4% of patients in group 2 (P = .036). The retreatment rate in group 1 was 11.1% versus 7.1% in group 2 (P = .62). The rate of good clinical outcome at the latest follow-up in group 1 was 81% versus 93.2% in group 2 (P = .1). Complications were observed in 14.3% of patients in group 1 and 9.5% of patients in group 2 (P = .684). CONCLUSIONS: The use of the Pipeline Embolization Device in the management of previously stented aneurysms is less effective than the use of this device in nonstented aneurysms. Prior stent placement can worsen the safety and efficacy profile of this device. PMID- 26611992 TI - Risk Factors for Growth of Intracranial Aneurysms: A Systematic Review and Meta Analysis. AB - BACKGROUND AND PURPOSE: Understanding risk factors for intracranial aneurysm growth is important for patient management. We performed a meta-analysis examining risk factors for intracranial aneurysm growth in longitudinal studies and examined the association between aneurysm growth and rupture. MATERIALS AND METHODS: We searched the literature for longitudinal studies of patients with unruptured aneurysms. We examined the associations of demographics, multiple aneurysms, prior subarachnoid hemorrhage, family history of aneurysm or subarachnoid hemorrhage, smoking, and hypertension; and aneurysm shape, size, and location with aneurysm growth. We studied the association between aneurysm growth and rupture. A meta-analysis was performed by using a random-effects model by using summary statistics from included studies. RESULTS: Twenty-one studies including 3954 patients with 4990 aneurysms with 13,294 aneurysm-years of follow up were included. The overall proportion of growing aneurysms was 3.0% per aneurysm-year (95% CI, 2.0%-4.0%). Patient risk factors for growth included age older than 50 years (3.8% per year versus 0.9% per year, P < .01), female sex (3.2% per year versus 1.3% per year, P < .01), and smoking history (5.5% per year versus 3.5% per year, P < .01). Characteristics associated with higher growth rates included cavernous carotid artery location (14.4% per year), nonsaccular shape (14.7% per year versus 5.2% per year for saccular, P < .01), and aneurysm size (P < .01). Aneurysm growth was associated with a rupture rate of 3.1% per year compared with 0.1% per year for stable aneurysms (P < .01). CONCLUSIONS: Observational evidence provided multiple clinical and anatomic risk factors for aneurysm growth, including age older than 50 years, female sex, smoking history, and nonsaccular shape. These findings should be considered when counseling patients regarding the natural history of unruptured intracranial aneurysms. PMID- 26611993 TI - CT-Fluoroscopic Cervical Transforaminal Epidural Steroid Injections: Extraforaminal Needle Tip Position Decreases Risk of Intravascular Injection. AB - BACKGROUND AND PURPOSE: Cervical transforaminal epidural steroid injections are commonly performed for temporary pain relief or diagnostic presurgical planning in patients with cervical radiculopathy. Intravascular injection of steroids during the procedure can potentially result in cord infarct, stroke, and even death. CT-fluoroscopy allows excellent anatomic resolution and precise needle positioning. This study sought to determine the safest needle tip position during CT-guided cervical transforaminal epidural steroid injection as determined by the incidence of intravascular injection. MATERIALS AND METHODS: We retrospectively evaluated procedural imaging for consecutive single-site CT-fluoroscopic cervical transforaminal epidural steroid injection performed during a 13-month period. Intravascular injections were identified and classified by volume, procedure phase, vessel type, and needle tip position relative to the targeted neural foramen. ANOVA, Wilcoxon, or Pearson chi(2) testing was used to assess differences among groups as appropriate. RESULTS: Intravascular injections occurred in 49/201 (24%) procedures. Of the intravascular injections, 13/49 (27%) were large, 10/49 (20%) were small, and 26/49 (53%) were trace volume. Sixteen of 49 (33%) intravascular injections occurred with a trial contrast dose; 27/49 (55%), with a steroid/analgesic cocktail; and 6/49 (12%), with both. Twenty-seven of 49 (55%) intravascular injections were likely venous, 22/49 (45%) were indeterminate, and none were likely arterial. The intravascular injection rate was significantly lower (P < .001) for the extraforaminal needle position (8/82, 10%) compared with junctional (27/88, 31%) and foraminal (14/31, 45%) needle tip positions. CONCLUSIONS: An extraforaminal needle position for CT-guided cervical transforaminal epidural steroid injection decreases the risk of intravascular injection and therefore may be safer than other needle tip positions. PMID- 26611994 TI - A Spiral Spin-Echo MR Imaging Technique for Improved Flow Artifact Suppression in T1-Weighted Postcontrast Brain Imaging: A Comparison with Cartesian Turbo Spin Echo. AB - BACKGROUND AND PURPOSE: A challenge with the T1-weighted postcontrast Cartesian spin-echo and turbo spin-echo brain MR imaging is the presence of flow artifacts. Our aim was to develop a rapid 2D spiral spin-echo sequence for T1-weighted MR imaging with minimal flow artifacts and to compare it with a conventional Cartesian 2D turbo spin-echo sequence. MATERIALS AND METHODS: T1-weighted brain imaging was performed in 24 pediatric patients. After the administration of intravenous gadolinium contrast agent, a reference Cartesian TSE sequence with a scanning time of 2 minutes 30 seconds was performed, followed by the proposed spiral spin-echo sequence with a scanning time of 1 minutes 18 seconds, with similar spatial resolution and volumetric coverage. The results were reviewed independently and blindly by 3 neuroradiologists. Scores from a 3-point scale were assigned in 3 categories: flow artifact reduction, subjective preference, and lesion conspicuity, if any. The Wilcoxon signed rank test was performed to evaluate the reviewer scores. The t test was used to evaluate the SNR. The Fleiss kappa coefficient was calculated to examine interreader agreement. RESULTS: In 23 cases, spiral spin-echo was scored over Cartesian TSE in flow artifact reduction (P < .001). In 21 cases, spiral spin-echo was rated superior in subjective preference (P < .001). Ten patients were identified with lesions, and no statistically significant difference in lesion conspicuity was observed between the 2 sequences. There was no statistically significant difference in SNR between the 2 techniques. The Fleiss kappa coefficient was 0.79 (95% confidence interval, 0.65-0.93). CONCLUSIONS: The proposed spiral spin-echo pulse sequence provides postcontrast images with minimal flow artifacts at a faster scanning time than its Cartesian TSE counterpart. PMID- 26611995 TI - TICI and Age: What's the Score? AB - BACKGROUND AND PURPOSE: Previous studies have suggested that advanced age predicts worse outcome following mechanical thrombectomy. We assessed outcomes from 2 recent large prospective studies to determine the association among TICI, age, and outcome. MATERIALS AND METHODS: Data from the Solitaire FR Thrombectomy for Acute Revascularization (STAR) trial, an international multicenter prospective single-arm thrombectomy study and the Solitaire arm of the Solitaire FR With the Intention For Thrombectomy (SWIFT) trial were pooled. TICI was determined by core laboratory review. Good outcome was defined as an mRS score of 0-2 at 90 days. We analyzed the association among clinical outcome, successful versus-unsuccessful reperfusion (TICI 2b-3 versus TICI 0-2a), and age (dichotomized across the median). RESULTS: Two hundred sixty-nine of 291 patients treated with Solitaire in the STAR and SWIFT data bases for whom TICI and 90-day outcome data were available were included. The median age was 70 years (interquartile range, 60-76 years) with an age range of 25-88 years. The mean age of patients 70 years of age or younger was 59 years, and it was 77 years for patients older than 70 years. There was no significant difference between baseline NIHSS scores or procedure time metrics. Hemorrhage and device-related complications were more common in the younger age group but did not reach statistical significance. In absolute terms, the rate of good outcome was higher in the younger population (64% versus 44%, P < .001). However, the magnitude of benefit from successful reperfusion was higher in the 70 years of age and older group (OR, 4.82; 95% CI, 1.32-17.63 versus OR 7.32; 95% CI, 1.73-30.99). CONCLUSIONS: Successful reperfusion is the strongest predictor of good outcome following mechanical thrombectomy, and the magnitude of benefit is highest in the patient population older than 70 years of age. PMID- 26611996 TI - Basal Ganglia Iron in Patients with Multiple Sclerosis Measured with 7T Quantitative Susceptibility Mapping Correlates with Inhibitory Control. AB - BACKGROUND AND PURPOSE: T2 hypointensity in the basal ganglia of patients with MS has been associated with clinical progression and cognitive decline. Our objectives were the following: 1) to compare signal in T2WI, R2 (ie, 1/T2), and R2* (ie, 1/T2*) relaxation rates and quantitative susceptibility mapping; and 2) to investigate the associations among MR imaging, clinical scores, and cognitive measures of inhibitory control linked to basal ganglia functioning. MATERIALS AND METHODS: Twenty-nine patients with MS underwent a battery of neuropsychological tests including the Flanker and Stroop tasks. 7T MR imaging included 3D gradient echo and single-echo multishot spin-echo EPI. Quantitative susceptibility mapping images were calculated by using a Wiener filter deconvolution algorithm. T2WI signal was normalized to CSF. R2 and R2* were calculated by log-linear regression. Average MR imaging metrics for the globus pallidus, putamen, and caudate were computed from manually traced ROIs including the largest central part of each structure. RESULTS: Marked spatial variation was consistently visualized on quantitative susceptibility mapping and T2/T2*WI within each basal ganglia structure. MR imaging metrics correlated with each other for each basal ganglia structure individually. Notably, caudate and putamen quantitative susceptibility mapping metrics were similar, but the putamen R2 was larger than the caudate R2. This finding suggests that tissue features contribute differently to R2 and quantitative susceptibility mapping. Caudate and anterior putamen quantitative susceptibility mapping correlated with the Flanker but not Stroop measures; R2 did not correlate with inhibitory control measures. Putamen quantitative susceptibility mapping and caudate and putamen R2 correlated with the Expanded Disability Status Scale. CONCLUSIONS: Our study showed that quantitative susceptibility mapping and R2 may be complementary indicators for basal ganglia tissue changes in MS. Our findings are consistent with the hypothesis that decreased performance of basal ganglia-reliant tasks involving inhibitory control is associated with increased quantitative susceptibility mapping. PMID- 26611997 TI - Neurophysiological effects of needle trauma and intraneural injection in a porcine model: a pilot study. AB - BACKGROUND: Neurophysiological data are lacking in the research of nerve injury during regional anaesthesia. The aim of this pilot study was to establish a large animal model in order to test the hypothesis that needle trauma alone or in combination with intraneural injection would result in measurable nerve injury. METHODS: The experimental set-up was elaborated in four pre-test animals. In the remaining animals (n = 11), 22 sciatic nerves were randomly assigned to one of four groups: needle trauma (n = 5) generated by ultrasound-guided forced needle advancement; intraneural injection of 2.5 ml saline (n = 6); intraneural injection of 5 ml saline (n = 6); extraneural injection of 5 ml saline (n = 5) as control group. Compound muscle action potential (CMAP) amplitudes as well as latencies were taken as outcome parameter and monitored over 180 min. Sonographic assessments were performed simultaneously. RESULTS: Following needle trauma and intraneural injection, CMAP amplitudes declined significantly over 180 min (P < 0.001). The control group showed no electrophysiological alterations. At 60 min, decreases in amplitude were significant after needle trauma (P = 0.04) and intraneural injection of 2.5 ml (P = 0.045), and highly significant after injection of 5 ml (P = 0.006) when compared to controls. Sustained nerve swelling was observed after intraneural injection, but not after needle trauma and perineural injection. CONCLUSIONS: Isolated mechanical trauma caused by forced needle advancement alone or in combination with intraneural injection of saline was followed by a significant decline in CMAP amplitudes indicating conduction block due to disruption of myelin or axon loss (pseudo-conduction block). PMID- 26611998 TI - Cardiac magnetic resonance imaging to assess the impact of maternal habitus on cardiac remodeling during pregnancy. AB - BACKGROUND: It is well known that the maternal cardiovascular system undergoes profound alterations throughout pregnancy. Interest in understanding these changes has led investigators to use evolving and increasingly sophisticated techniques to study these changes, most recently with 2-dimensional echocardiography. Despite its clinical utility, echocardiography has limitations, and cardiac magnetic resonance imaging (CMRI) has become increasingly used for evaluation of cardiac structure and function. OBJECTIVE: We used CMRI to evaluate cardiac remodeling according to maternal habitus throughout pregnancy and postpartum. STUDY DESIGN: This was a prospective, observational study of nulliparous women aged 18-30 years, without preexisting medical conditions, conducted from October 2012 through December 2014. Women were classified according to prepregnancy body mass index (BMI) as either normal (BMI 18.5-24.9 kg/m(2)) or overweight (BMI 25-35 kg/m(2)). All women underwent CMRI during 5 epochs throughout gestation: 12-16 weeks, 26-30 weeks, 32-36 weeks, at delivery, and 3 months' postpartum. Using left ventricular mass (LVM) as a marker of cardiac remodeling, the 2 cohorts were compared. RESULTS: There were 14 normal weight (BMI 22.2 +/- 1.3) and 9 overweight (BMI 29.1 +/- 2.0) women who participated in the study. Beginning at 26-30 weeks and continuing to delivery, LVM of both normal-weight and overweight women was significantly increased compared with the respective first-trimester studies for each cohort (P < .001). LVM of both cohorts returned to their index values by 3 months' postpartum. The geometric ratio of LVM to left ventricular end-diastolic volume was calculated, and both normal-weight and overweight women demonstrated concentric remodeling throughout gestation, however this resolved by 12 weeks' postpartum. CONCLUSION: There is substantial cardiac remodeling during pregnancy with significant increases in LVM that are proportional to maternal size. Left ventricular geometric remodeling was concentric in both normal-weight and overweight women. All changes in cardiac remodeling resolved by 3 months' postpartum. PMID- 26611999 TI - Analysis of mitochondrial structure and function in the Drosophila larval musculature. AB - Mitochondria are dynamic organelles that change their architecture in normal physiological conditions. Mutations in genes that control mitochondrial fission or fusion, such as dynamin-related protein (Drp1), Mitofusins 1 (Mfn1) and 2 (Mfn2), and Optic atrophy 1 (Opa1), result in neuropathies or neurodegenerative diseases. It is increasingly clear that altered mitochondrial dynamics also underlie the pathology of other degenerative diseases, including Parkinson's disease (PD). Thus, understanding mitochondrial distribution, shape, and dynamics in all cell types is a prerequisite for developing and defining treatment regimens that may differentially affect tissues. The majority of Drosophila genes implicated in mitochondrial dynamics have been studied in the adult indirect flight muscle (IFM). Here, we discuss the utility of Drosophila third instar larvae (L3) as an alternative model to analyze and quantify mitochondrial behaviors. Advantages include large muscle cell size, a stereotyped arrangement of mitochondria that is conserved in mammalian muscles, and the ability to analyze muscle-specific gene function in mutants that are lethal prior to adult stages. In particular, we highlight methods for sample preparation and analysis of mitochondrial morphological features. PMID- 26612000 TI - African American and White women's perceptions of weight gain, physical activity, and nutrition during pregnancy. AB - OBJECTIVE: To describe African American and White women's perceptions of weight gain, physical activity, and nutrition during pregnancy and to explore differences in perceptions by race. DESIGN: Qualitative interview study. SETTING: Two Ob/Gyn clinics in South Carolina, USA. PARTICIPANTS: Thirty pregnant women (15 African American, 15 White) between 20 and 30 weeks gestation, equally represented across pre-pregnancy BMI categories (10 normal weight, 10 overweight, and 10 obese). FINDINGS: White women more frequently described intentions to meet weight gain, physical activity, and dietary guidelines in pregnancy than African American women. African American women were more concerned with inadequate weight gain while White women more commonly expressed concerns about excessive weight gain. More White women discussed the importance of physical activity for weight management. Regardless of race, few women described risks of excessive weight gain or benefits of physical activity as it relates to the baby's health. The primary cited barrier of healthy eating was the high cost of fresh produce. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Several knowledge gaps as well as race differences were identified in women's perceptions and intentions toward weight gain, physical activity, and nutrition during pregnancy. Future interventions should seek to educate women about common misperceptions. It may be necessary to culturally tailor gestational weight gain interventions to optimise health outcomes. PMID- 26612001 TI - Infant feeding and maternal guilt: The application of a feminist phenomenological framework to guide clinician practices in breast feeding promotion. PMID- 26612002 TI - The mitotic regulator Hec1 is a critical modulator of prostate cancer through the long non-coding RNA BX647187 in vitro. AB - Hec1 (highly expressed in cancer) is a member of a conserved Ndc80 (nuclear division cycle 80) complex that regulates mitotic processes. Its overexpression is seen in various tumours and is associated with cancer progression. However, its expression pattern and role inhuman prostate cancer (PCa) still not clear. The aim of our study is to investigate the expression and functional role of Hec1 in human PCa. Hec1 expression was measured in 10 pairs of PCa cancerous and non cancerous tissue samples by quantitative real-time (qRT)-PCR. The effects of Hec1 on PCa cells were studied by RNAi approach. Apoptosis and cell cycle were analysed by flow cytometry. Cells viability was evaluated using cell counting Kit 8. Cyclin B1-Cdc2 (cell division cycle 2) activity was measured by ELISA assay. Long non-coding (Lnc)RNAs regulated by Hec1 were gained from bioinformatics analysis. The role of LncRNA BX647187, regulated by Hec1, was finally characterized in PCa cells by siRNA. Our results showed that Hec1 mRNA and protein were significantly overexpressed in Human PCa tissues and several PCa cell lines. Silencing Hec1 markedly suppressed proliferation, promoted apoptosis and induced cell-cycle arrest in G2/M-phase in PCa cells. Through bioinformatics analysis and knockdown Hec1 in PCa cells, we found LncRNA BX647187 was positively regulated by Hec1. We further demonstrated that suppression of BX647187 in PCa cells significantly reduced cell proliferation and promoted apoptosis. Thus, we conclude that Hec1 is consistently overexpressed in human PCa and Hec1 is closely linked with human PCa progression through the meditator LncRNA BX647187. Our studies may contribute to understand the molecular mechanism of PCa pathogenesis and clinical therapy. PMID- 26612003 TI - A case of chemical scalp burns after hair highlights: experimental evidence of oxidative injuries. AB - Hair highlights are quite common procedures carried out in hair salons by using a mixture of a lightening powder containing persulfates with a suspension containing hydrogen peroxide: a representative case of chemical scalp burns is described as a consequence of this treatment. The aim of the paper is to demonstrate the strict relationship between the scalp damage and the commercial products used in a case of hair highlighting. The results of some chemical analyses have been reported, showing, in particular, that the chemical reactivity of the mixture changes in the time, thus strongly suggesting that the procedure for the application of the mixture is critical for the occurrence of possible accidents. The presence in the powder of chemical compounds bearing aliphatic chains as surfactants explains the appearance of dramatic symptoms after days due to a slow dissolution of the oxidant compounds in the stratum corneum of skin with no effect in reducing injury of palliative treatments. Safety suggestions and recommendations for producers and workers are also included. PMID- 26612004 TI - Children of the postwar years: A two-generational multilevel risk assessment of child psychopathology in northern Uganda. AB - In postconflict settings risk factors at multiple levels of the social ecology, including community, family, and relationship factors, potentially affect children's mental health. In addition, intergenerational risk factors such as guardians' history of childhood family violence, war exposure, and psychopathology may contribute to children's psychopathological symptoms. In this study, we aimed to identify risk constellations that predict child internalizing and externalizing behavior problems, depression, and posttraumatic stress symptoms in the postconflict setting of northern Uganda. In a cross-sectional epidemiological study, 513 second-grade students and their female guardians were interviewed using standardized clinical questionnaires. A higher exposure to traumatic events, more witnessed or experienced violence within the family, and lower child-reported care from female guardians independently predicted psychopathological symptoms in children. While controlling for intergenerational risk factors in female guardians, serial mediation modeling revealed that the effect of trauma exposure on children's psychopathological symptoms was partially mediated by higher exposure to family violence and lower child-perceived care from female guardians. The mediation appeared to be stronger for children's depression symptoms and internalizing and externalizing behavior problems than for posttraumatic stress symptoms. The current findings support the need for targeted interventions at the individual and family system levels that are matched to children's psychopathological symptoms. PMID- 26612005 TI - Docking and molecular dynamics studies of peripheral site ligand-oximes as reactivators of sarin-inhibited human acetylcholinesterase. AB - In the present work, we performed docking and molecular dynamics simulations studies on two groups of long-tailored oximes designed as peripheral site binders of acetylcholinesterase (AChE) and potential penetrators on the blood brain barrier. Our studies permitted to determine how the tails anchor in the peripheral site of sarin-inhibited human AChE, and which aminoacids are important to their stabilization. Also the energy values obtained in the docking studies corroborated quite well with the experimental results obtained before for these oximes. PMID- 26612006 TI - Microbiological diagnosis of Eggerthella lenta blood culture isolates in a Swedish tertiary hospital: Rapid identification and antimicrobial susceptibility profile. AB - Eggerthella lenta is a Gram-positive anaerobic bacillus. Improved diagnostics and increased awareness of rare pathogens have revealed its potential to cause serious invasive infections. In this study, 18 clinical E. lenta isolates derived from positive blood cultures were included. Underlying problems of the patients were in the majority of cases related to the gastrointestinal tract. The performance of two MALDI-TOF MS systems, i.e. Bruker and Vitek MS, in identification of E. lenta was analyzed. In addition, the minimal inhibitory concentrations for clinically relevant antimicrobial agents were determined by routine procedures using E-test. 17 of the 18 E. lenta isolates investigated in this study were correctly identified to species level by the Bruker MS system, while the Vitek MS system identified all 18 isolates. Antimicrobial sensitivity towards the tested agents was in general good. However, high resistance rates were observed for penicillin G and piperacillin-tazobactam based on EUCAST breakpoints. PMID- 26612007 TI - A case of bacteremia caused by Dialister pneumosintes and Slackia exigua in a patient with periapical abscess. AB - Dialister pneumosintes and Slackia exigua are both obligatory anaerobe and known to be associated with periodontal diseases and other oral infection. We report a case of blood stream infection caused by D. pneumosintes and S. exigua. This occurred in a 78-year-old female patient that presented with general weakness and fever. We revealed that she had a periapical abscess. The blood culture was positive for D. pneumosintes and S. exigua; however, identifying them was challenging. Ultimately, 16S rRNA sequencing was used to identify the organisms. The patient recovered after being treated with ceftriaxone and clindamycin. To the best of our knowledge, this is the first report of bacteremia caused by mixed infection of D. pneumosintes and S. exigua. PMID- 26612009 TI - Extreme events in multilayer, interdependent complex networks and control. AB - We investigate the emergence of extreme events in interdependent networks. We introduce an inter-layer traffic resource competing mechanism to account for the limited capacity associated with distinct network layers. A striking finding is that, when the number of network layers and/or the overlap among the layers are increased, extreme events can emerge in a cascading manner on a global scale. Asymptotically, there are two stable absorption states: a state free of extreme events and a state of full of extreme events, and the transition between them is abrupt. Our results indicate that internal interactions in the multiplex system can yield qualitatively distinct phenomena associated with extreme events that do not occur for independent network layers. An implication is that, e.g., public resource competitions among different service providers can lead to a higher resource requirement than naively expected. We derive an analytical theory to understand the emergence of global-scale extreme events based on the concept of effective betweenness. We also articulate a cost-effective control scheme through increasing the capacity of very few hubs to suppress the cascading process of extreme events so as to protect the entire multi-layer infrastructure against global-scale breakdown. PMID- 26612008 TI - Universal mechanisms of sound production and control in birds and mammals. AB - As animals vocalize, their vocal organ transforms motor commands into vocalizations for social communication. In birds, the physical mechanisms by which vocalizations are produced and controlled remain unresolved because of the extreme difficulty in obtaining in vivo measurements. Here, we introduce an ex vivo preparation of the avian vocal organ that allows simultaneous high-speed imaging, muscle stimulation and kinematic and acoustic analyses to reveal the mechanisms of vocal production in birds across a wide range of taxa. Remarkably, we show that all species tested employ the myoelastic-aerodynamic (MEAD) mechanism, the same mechanism used to produce human speech. Furthermore, we show substantial redundancy in the control of key vocal parameters ex vivo, suggesting that in vivo vocalizations may also not be specified by unique motor commands. We propose that such motor redundancy can aid vocal learning and is common to MEAD sound production across birds and mammals, including humans. PMID- 26612010 TI - Differential effects of metal ions on TCDD-induced cytotoxicity and cytochrome P4501A1 gene expression in a zebrafish liver (ZFL) cell-line. AB - Trace metal ions and trace organic compounds are common co-contaminants in the environment that pose risks to human health. We evaluated the effects of four metal ions (As(3+), Cu(2+), Hg(2+), and Zn(2+)) on 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD) induced cytotoxicity and the expression of the cytochrome P4501A1 gene (cyp1a1) in the zebrafish liver (ZFL) cell line. A metal accumulation study showed that Cu and Zn did not accumulate in ZFL cells. However, As and Hg did accumulate, which resulted in the inhibition of TCDD-mediated induction of cyp1a1 mRNA and protein expression, and 7-ethoxyresorufin O-deethylase activity. A luciferase assay showed that both As(3+) and Hg(2+) inhibited the TCDD-induced activity of gene constructs containing either synthetic 3XRE or a distal cyp1a1 promoter region, implying that the decreased levels of TCDD-induced cyp1a1 were due to transcriptional effects. A proteomic study showed that the toxic effects of As(3+) might be due to changes in cellular metabolic processes, the cellular stimulation response and the cellular redox state in ZFL cells. PMID- 26612011 TI - Platinum nanoparticles encapsulated metal-organic frameworks for the electrochemical detection of telomerase activity. AB - A simple and rapid electrochemical sensor is constructed for the detection of telomerase activity based on the electrocatalysis of platinum nanoparticle (Pt NP) encapsulated metal-organic frameworks (MOFs), which are synthesized by one pot encapsulation of Pt NPs into prototypal MOFs, UiO-66-NH2. Integrating with the efficient electrocatalysis of Pt@MOFs towards NaBH4 oxidation, this biosensor shows the wide dynamic correlation of telomerase activity from 5 * 10(2) to 10(7) HeLa cells mL(-1) and the telomerase activity in a single HeLa cell was calculated to be 2.0 * 10(-11) IU, providing a powerful platform for detecting telomerase activity. PMID- 26612012 TI - Obituary. PMID- 26612013 TI - Tenofovir rescue therapy in chronic hepatitis B patients who failed previous nucleoside analogue treatment. AB - BACKGROUND: Tenofovir (TDF) is considered as the first line therapy for chronic hepatitis B. This study presents the results of TDF monotherapy in patients who failed previous nucleoside analogue treatment. METHODS: The study included 29 patients treated with TDF 245 mg once daily for 18 months after lamivudine monotherapy (LAM arm: n = 15) or sequential therapy with lamivudine and entecavir (LAM -> ETV arm: n = 14). The previous antiviral therapy was discontinued due to lack of efficacy. All patients had HBV DNA between 2.1 and 8.23 log10 IU/ml and 15 were HBeAg-positive, while 45% of patients had increased ALT activity. Undetectable HBV DNA (<20 IU/ml) at months 3, 6, 12 and 18 was the primary endpoint in the study, while HBeAg/HBsAg loss/seroconversion and ALT normalisation were secondary endpoints. RESULTS: Primary nonresponse to TDF was not observed. HBV DNA was undetectable in 80, 80, 80 and 93% in LAM arm and 50, 71, 86 and 86% in LAM -> ETV arm patients, at 3, 6, 12 and 18 months of TDF therapy, respectively. One patient achieved anti-HBeAg seroconversion. 86.5% of patients had normal ALT activity at the end of the study. The baseline HBV DNA load, HBeAg status and the length of the duration of TDF therapy appeared significantly associated with the response to the therapy. HBV DNA clearance occurred faster in HBeAg-negative patients than in those positive for HBeAg. CONCLUSIONS: TDF is an effective antiviral medication in patients with previous exposure to LAM or LAM and ETV. Final proportion of patients who achieved undetectable HBV DNA and had normal ALT activity in both arms, was similar. PMID- 26612015 TI - Medical School Training for the Surgeon. AB - This review outlines the current state of undergraduate medical education for the surgeon in training, and highlights ongoing efforts to improve the preparation of graduating students entering surgical residency. Possible models for improved integration of specialty specific training in medical school are explored, and future directions in undergraduate surgical education are considered in the context of ongoing curricular initiatives in medical schools within North America. PMID- 26612014 TI - High adherence to all-oral directly acting antiviral HCV therapy among an inner city patient population in a phase 2a study. AB - BACKGROUND: As treatment for chronic hepatitis C (HCV) virus has evolved to all oral, interferon-free directly acting antiviral (DAA) therapy, the impact of these improvements on patient adherence has not been described. METHODS: Medication adherence was measured in 60 HCV, genotype-1, treatment-naive participants enrolled in a phase 2a clinical trial at the National Institutes of Health and community clinics. Participants received either ledipasvir/sofosbuvir (LDV/SOF) (90 mg/400 mg) (one pill) daily for 12 weeks, LDV/SOF + GS-9451 (80 mg/day) (two pills) daily for 6 weeks, or LDV/SOF + GS-9669 (500 mg twice daily; three pills, two in the morning, one in the evening) for 6 weeks. Adherence was measured using medication event monitoring system (MEMS) caps, pill counts and patient report. RESULTS: Overall adherence to DAAs was high. Adherence declined over the course of the 12-week treatment (p = 0.04). While controlled psychiatric disease or symptoms of depression did not influence adherence, recent drug use was a risk factor for non-adherence to 12-week (p = 0.01), but not 6-week regimens. Adherence as measured by MEMS was lower than by patient report. CONCLUSIONS: Adherence to short courses of DAA therapy with 1-3 pills a day was excellent in an urban population with multiple risk factors for non-adherence. PMID- 26612016 TI - Assessment of Competence: The Accreditation Council for Graduate Medical Education/Residency Review Committee Perspective. AB - Competency is an individual trait. As an agency that accredits programs and institutions, the Accreditation Council for Graduate Medical Education (ACGME) does not define or access competency. However, in the past 15 years the ACGME has promulgated several initiatives to aid programs in the assessment of the competence of their residents and fellows. Those initiatives include the Outcomes Project (which codified the competencies), the Milestones, and the Clinical Learning Environment Review Program. In the near future, the ACGME will implement an initiative by which programs can develop and study the results of competency based residency curricula. PMID- 26612017 TI - Transition from Training to Surgical Practice. AB - Surgical training graduates require a period of adjustment as they transform from trainees to experienced surgeons. Making a smooth transition is important for patient safety and new surgeon success. A subset of current graduates does not feel confident to enter directly into practice. Residency design with curriculum refocus, credentialing to encourage graded responsibility, and increased operative exposure is necessary. Onboarding programs should include formal mentoring, career counseling, proctoring by senior surgeons, and objective review of outcomes. The ACS developed a one-year TTP program to provide independent decision-making, operative autonomy, mentoring by senior surgeons, and practice management experience. PMID- 26612018 TI - Alternative Considerations for Surgical Training and Funding. AB - Since the late 1880s surgical residency programs have existed in forms that are similar to our current models. Many important variations have been introduced over time. On aggregate this system has worked remarkably well; though as economic, demographic, and cultural changes continue to evolve, one must wonder if we were to change our models how might we do that and what reasoning could we use. This article's focus is to take a stratospheric view of what could be done, particularly in the United States, rather than characterize what happens in other countries with other health economic systems. PMID- 26612019 TI - Fellowship Training: Need and Contributions. AB - Surgical subspecialties are now well established, and many surgery residents pursue fellowship training for various reasons. Fellowships can bridge the gaps found in many residency programs by providing graduating residents with opportunities to master surgical skills, gain confidence and progressive autonomy, and receive further mentorship. The experience also eases the transition to independent practice by allowing surgeons to tailor their training to coincide with personal interests and future practice goals. It is unlikely that the number of surgery residents pursuing fellowship training will decrease, so it is important to provide the infrastructure, oversight, and opportunities to meet their needs. PMID- 26612020 TI - Surgical Residency Training at a University-Based Academic Medical Center. AB - The past two decades have been witness to some of the most dynamic changes that have occurred in surgical education in all of its history. Political policies, social revolution, and the competing priorities of a new generation of surgical trainees are defining the needs of modern training paradigms. Although the university-based academic program's tripartite mission of clinical service, research, and education has remained steadfast, the mechanisms for achieving success in this mission necessitate adaptation and innovation. The resource-rich learning environment and the unique challenges that face university-based programs contribute to its ability to generate the future leaders of the surgical workforce. PMID- 26612021 TI - Evolving Educational Techniques in Surgical Training. AB - Training competent and professional surgeons efficiently and effectively requires innovation and modernization of educational methods. Today's medical learner is quite adept at using multiple platforms to gain information, providing surgical educators with numerous innovative avenues to promote learning. With the growth of technology, and the restriction of work hours in surgical education, there has been an increase in use of simulation, including virtual reality, robotics, telemedicine, and gaming. The use of simulation has shifted the learning of basic surgical skills to the laboratory, reserving limited time in the operating room for the acquisition of complex surgical skills". PMID- 26612022 TI - The Impaired Surgeon. AB - Impaired physicians are unable to manage professional activities safely. Impairment can be the result of physical or mental disorders, but impaired physicians commonly refers to those suffering from substance use disorders. These disorders are at least as common in physicians as they are in the general population, and physician health programs have been established in each state to provide expeditious and detailed evaluation, referral to treatment facilities, and post-treatment monitoring to ensure compliance. These programs protect participants against sanctions and safeguard patients. The prognosis for participants is excellent, with more than 70% able to practice medicine at 5 years. PMID- 26612023 TI - Workforce Needs and Demands in Surgery. AB - The health care environment in the United States is witnessing major changes. The Halstedian model has produced surgeons who joined the workforce for over a century. While the Halstedian model will continue to be of benefit, we need to be proactive and develop innovative models of graduate medical education that meet the needs of the 21st century. The history of graduate medical education is punctuated by surgical leaders that made great contributions. The time is ripe again for the surgical community to develop innovative models of graduate medical education that will continue to sustain the surgical workforce of the future. PMID- 26612024 TI - Education and Training to Address Specific Needs During the Career Progression of Surgeons. AB - Surgeons have specific education and training needs as they enter practice, progress through the core period of active practice, and then as they wind down their clinical work before retirement. These transitions and the career progression process, combined with the dynamic health care environment, present specific opportunities for innovative education and training based on practice based learning and improvement, and continuous professional development methods. Cutting-edge technologies, blended models, simulation, mentoring, preceptoring, and integrated approaches can play critical roles in supporting surgeons as they provide the best surgical care throughout various phases of their careers. PMID- 26612025 TI - The Aging Surgeon: Implications for the Workforce, the Surgeon, and the Patient. AB - Surgeons suffer from the same physiologic impairments common to all people with advancing age. These impairments not only affect the surgeon but also the patients under their care. This article delineates the epidemiologic context of the graying population of surgeons and the cognitive and physiologic changes that occur as the result of aging, the consequence of which is that greater experience does not necessarily equate with better clinical outcomes. This work also addresses potential methods for the ongoing evaluation of the aging surgeon and how elder surgeons may be best used as they reach the conclusion of their career. PMID- 26612026 TI - Forks in the Road: The Assessment of Surgeons from the American Board of Surgery Perspective. AB - Surgical learning starts in medical school and continues through retirement. Assessment of knowledge and skills across a variety of arenas at each stage is an obligation of the profession in its duty to the public. The American Board of Surgery is engaged in standardization and assessment to a greater or lesser degree at each stage of surgical learning. PMID- 26612027 TI - Residency Surgical Training at an Independent Academic Medical Center. AB - Independent academic medical centers have been training surgeons for more than a century; this environment is distinct from university or military programs. There are several advantages to training at a community program, including a supportive learning environment with camaraderie between residents and faculty, early and broad operative experience, and improved graduate confidence. Community programs also face challenges, such as resident recruitment and faculty engagement. With the workforce needs for general surgeons, independent training programs will continue to play an integral role. PMID- 26612028 TI - Foreword. PMID- 26612029 TI - Development of a Surgeon. PMID- 26612030 TI - Theoretical studies of energetics and binding isotope effects of binding a triazole-based inhibitor to HIV-1 reverse transcriptase. AB - Understanding of protein-ligand interactions is crucial for rational drug design. Binding isotope effects, BIEs, can provide intimate details of specific interactions between individual atoms of an inhibitor and the binding pocket. We have applied multi-scale QM/MM simulations to evaluate binding energetics of a novel triazole-based non-nucleoside inhibitor of HIV-1 reverse transcriptase and to calculate associated BIEs. The binding sites can be distinguished based on the (18)O-BIE. PMID- 26612032 TI - Measuring Phonon Mean Free Path Distributions by Probing Quasiballistic Phonon Transport in Grating Nanostructures. AB - Heat conduction in semiconductors and dielectrics depends upon their phonon mean free paths that describe the average travelling distance between two consecutive phonon scattering events. Nondiffusive phonon transport is being exploited to extract phonon mean free path distributions. Here, we describe an implementation of a nanoscale thermal conductivity spectroscopy technique that allows for the study of mean free path distributions in optically absorbing materials with relatively simple fabrication and a straightforward analysis scheme. We pattern 1D metallic grating of various line widths but fixed gap size on sample surfaces. The metal lines serve as both heaters and thermometers in time-domain thermoreflectance measurements and simultaneously act as wire-grid polarizers that protect the underlying substrate from direct optical excitation and heating. We demonstrate the viability of this technique by studying length-dependent thermal conductivities of silicon at various temperatures. The thermal conductivities measured with different metal line widths are analyzed using suppression functions calculated from the Boltzmann transport equation to extract the phonon mean free path distributions with no calibration required. This table top ultrafast thermal transport spectroscopy technique enables the study of mean free path spectra in a wide range of technologically important materials. PMID- 26612033 TI - Isolation and Comparative Genomic Analysis of T1-Like Shigella Bacteriophage pSf 2. AB - The increasing prevalence of antibiotic-resistant Shigella sp. emphasizes that alternatives to conventional antibiotics are needed. Siphoviridae bacteriophage (phage), pSf-2, infecting S. flexneri ATCC((r)) 12022 was isolated from Geolpocheon stream in Korea. Morphological analysis by transmission electron microscopy revealed that pSf-2 has a head of about 57 +/- 4 nm in diameter with a long tail of 136 +/- 3 nm in length and 15 +/- 2 nm in width. One-step growth analysis revealed that pSf-2 has latent period of 30 min and burst size of 16 PFU/infected cell. The DNA genome of pSf-2 is composed of 50,109 bp with a G+C content of 45.44 %. The genome encodes 83 putative ORFs, 19 putative promoters, and 23 transcriptional terminator regions. Genome sequence analysis of pSf-2 and comparative analysis with the homologous T1-like Shigella phages, Shfl1 and pSf 1, revealed that pSf-2 is a novel T1-like Shigella phage. These results showed that pSf-2 might have a high potential as a biocontrol agent to control shigellosis. Also, the genomic information may lead to further understanding of phage biodiversity, especially T1-like phages. PMID- 26612031 TI - Epidemiology study of HBV genotypes and antiviral drug resistance in multi-ethnic regions from Western China. AB - Hepatitis B virus (HBV) infection is a critical global health issue and moderately epidemic in Western China, but HBV molecular epidemiology characteristics are still limited. We conducted this study to investigate HBV genotypes and antiviral resistant mutations in this multi-ethnic area. A total of 1316 HBV patients were recruited from four ethnic groups from 2011 to 2013. Genotypes and resistant mutations were determined by Sanger sequencing. Four genotypes (B, C, D and C/D) were identified. Genotype B and C were common in Han population, while genotype D was predominant in Uygurs. Genotype C was the major genotype in both Tibetans and Yis, and recombinant C/D was found in Tibetans only. Lamivudine resistance was common in all populations, especially in Hans with prevalence of 42.8%. Entecavir resistance was barely observed regardless of ethnicity. Genotype C isolates had higher rates of rtA181T/V than genotype B (13.5% vs. 5.1%, P < 0.001), in accordance with higher prevalence of resistance to adefovir (20.0% vs. 9.5%, P < 0.001). While incidence of resistant mutations to other drugs and clinical factors showed no difference among different genotypes. HBV genotypes and resistance-conferring mutations had different geographic and demographic distributions in Western China, which provided molecular epidemiology data for clinical management. PMID- 26612034 TI - Effect of Gamma Radiation on Zinc Tolerance Efficiency of Aspergillus terreus Thorn. AB - The present study emphasizes the potential of gamma radiation in enhancing zinc tolerance of Aspergillus terreus. Gamma-exposed A. terreus could tolerate 1.13 times more Zn, reflecting higher growth (in terms of CFU) under Zn stress and enhanced Zn removal efficacies than their unirradiated counterparts. Radiation induced upregulation of antioxidative system (SOD, CAT, GSH and MT) of A. terreus is responsible for radiation-induced enhancement of Zn tolerance. FTIR spectra reveals the involvement of functional groups in Zn biosorption; SEM study divulges the structural changes due to metal and gamma exposure and SEM-EDX depicts the Zn uptake by A. terreus (both in gamma-exposed and unexposed conditions). This work sheds light toward utilizing low doses of ionizing radiation for making more metal-tolerant fungi and the possible mechanisms adopted by A. terreus for being more metallo-resistant. PMID- 26612035 TI - An unusual case of enoxaparin induced thrombocytopenia in intensive care unit. AB - OBJECTIVES: To present a case of heparin induced thrombocytopenia in a patient treated with enoxaparin. METHODS: A case of heparin-induced thrombocytopenia was examinated with a detailed platelet count analysis over the time and with detection of platelets antibodies. RESULTS: The detection of platelet antobodies and the recovery of platelet count after cessation of enoxaparin strongly support the diagnosis of heparin-induced thrombocytopenia (HIT). CONCLUSION: HIT is a severe side effects of heparin administration. It is more frequent in patients treated with unfractionated heparin however can also be induced by low molecular weight heparin. Guideline suggests the cessation of heparin administration and the treatment of patients with fondaparinux. KEY WORDS: Enoxaparin, Heparin induced thrombocytopenia, Thrombocytopenia. PMID- 26612036 TI - Conservation and Role of Electrostatics in Thymidylate Synthase. AB - Conservation of function across families of orthologous enzymes is generally accompanied by conservation of their active site electrostatic potentials. To study the electrostatic conservation in the highly conserved essential enzyme, thymidylate synthase (TS), we conducted a systematic species-based comparison of the electrostatic potential in the vicinity of its active site. Whereas the electrostatics of the active site of TS are generally well conserved, the TSs from minimal organisms do not conform to the overall trend. Since the genomes of minimal organisms have a high thymidine content compared to other organisms, the observation of non-conserved electrostatics was surprising. Analysis of the symbiotic relationship between minimal organisms and their hosts, and the genetic completeness of the thymidine synthesis pathway suggested that TS from the minimal organism Wigglesworthia glossinidia (W.g.b.) must be active. Four residues in the vicinity of the active site of Escherichia coli TS were mutated individually and simultaneously to mimic the electrostatics of W.g.b TS. The measured activities of the E. coli TS mutants imply that conservation of electrostatics in the region of the active site is important for the activity of TS, and suggest that the W.g.b. TS has the minimal activity necessary to support replication of its reduced genome. PMID- 26612037 TI - Gender differences in personal values of national and local Italian politicians, activists and voters. AB - Theorists of politics of presence postulate that women elected to political office would still hold values similar to ordinary women and therefore represent them better than male politicians. Gender differences in personal values, which underline and give coherence to core political values, have been found among voters: males score higher on self-enhancement values (power and achievement) and females higher on self-transcendence values (universalism and benevolence). Our study aims to explore if gender differences in personal values are still present among activists, local and national politicians. We administer a shortened version of the Portrait Values Questionnaire to 233 Italian national politicians (46% females), 425 local politicians (56% females), 626 political activists (44% females), and 3249 ordinary citizens (49% females). Our results confirm only partially politics of presence theory: females at all levels of political involvement score higher in self-transcendent values that emphasise concern for the welfare of others, but no significant gender differences emerge for self enhancement, which favour the pursuit of self-interest. Our findings support ethical struggles for more balanced gender representation: a higher proportion of women in politics could strengthen the political representation of self transcendence values. PMID- 26612038 TI - Effect of different drying technologies on drying characteristics and quality of red pepper (Capsicum frutescens L.): a comparative study. AB - BACKGROUND: Hot air drying and sun drying are traditional drying technologies widely used in the drying of agricultural products for a long time, but usually recognized as time-consuming or producing lower-quality products. Infrared drying is a rather effective drying technology that has advantages over traditional drying technologies. Thus, in order to investigate the application of infrared drying in the dehydration of red pepper, the drying characteristics and quality of infrared-dried red pepper were compared with those of sun-dried and hot air dried red pepper. RESULTS: The infrared drying technology significantly enhanced the drying rate when compared with hot air drying and sun drying. Temperature was the most important factor affecting the moisture transfer during the process of infrared drying as well as hot air drying. Effective moisture diffusivity (Deff ) values of infrared drying ranged from 1.58 * 10(-9) to 3.78 * 10(-9) m(2) s(-1) . The Ea values of infrared drying and hot air drying were 42.67 and 44.48 kJ mol( 1) respectively. Infrared drying and hot air drying produced color loss to a similar extent. Relatively higher crispness values were observed for infrared dried samples. CONCLUSION: Sun drying produced dried red pepper with the best color when compared with hot air drying and infrared drying. Meanwhile, infrared drying markedly improved the drying rate at the same drying temperature level of hot air drying, and the products obtained had relatively better quality with higher crispness values. (c) 2015 Society of Chemical Industry. PMID- 26612039 TI - Comamonas piscis sp. nov., isolated from the intestine of a Korean rockfish, Sebastes schlegelii. AB - A novel Gram-stain-negative, obligately aerobic, non-motile and coccus-shaped bacterium, designated strain CN1T, was isolated from the intestine of a Korean rockfish, Sebastes schlegelii. The optimum growth condition for strain CN1T was 25 degrees C, pH 7 and 0-1 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain CN1T was in the genus Comamonas and that the nearest type strain was Comamonas koreensis YH12T with 98.65 % 16S rRNA gene sequence similarity. The primary cellular fatty acids of strain CN1T were summed feature 3 (comprised of C16 : 1omega7c and/or C16 : 1omega6c), C16 : 0 and summed feature 8 (comprised of C18 : 1omega6c and/or C18 : 1omega7c). The predominant isoprenoid quinone was ubiquinone Q-8. The polar lipids were phosphatidylglycerol, phosphatidylethanolamine, an unidentified lipid, an unidentified phospholipid and two aminophospholipids. The DNA G+C content was 65.5 mol%. The phenotypic, phylogenetic and genotypic analyses indicated that strain CN1T represents a novel species of the genus Comamonas, for which the name Comamonas piscis sp. nov. is proposed. The type strain is CN1T ( = KACC 18403T = JCM 30718T). PMID- 26612040 TI - Procedure-related complications of open vs endoscopic fetal surgery for treatment of spina bifida in an era of intrauterine myelomeningocele repair: systematic review and meta-analysis. AB - OBJECTIVE: To assess and compare the rate of procedure-related complications after intrauterine treatment of spina bifida by endoscopic surgery and by open fetal surgery. METHODS: Systematic literature searches in PubMed and SCOPUS databases were performed on 20 September 2015 to identify randomized controlled trials and observational studies on treatment of human spina bifida by endoscopic or open fetal surgery techniques. Only studies with >= 10 cases that were published in or after 2000 were included in the meta-analysis in order to reduce the risk of bias. Primary outcomes (complete dehiscence, focal dehiscence and/or markedly thin hysterotomy scar; preterm delivery < 34 weeks; mean gestational age at delivery) and secondary outcomes (oligohydramnios, prelabor rupture of membranes, placental abruption, chorioamnionitis and perinatal death) were assessed for both techniques. Precision of the estimated proportions was evaluated with 95% CIs. Inconsistency was assessed using the I(2) statistic. RESULTS: The search identified 1080 records that were examined based on title and abstract, of which 28 full-text articles were examined completely for eligibility. Nine records were excluded because cases were also described in other studies, leaving 19 records for analysis. When comparing endoscopic vs open fetal surgery, the rate of complete dehiscence, focal dehiscence and/or markedly thin hysterotomy scar was, respectively, 1% (95% CI, 0-4%) vs 26% (95% CI, 12 42%); preterm delivery < 34 weeks was 80% (95% CI, 41-100%) vs 45% (95% CI, 38 53%); oligohydramnios was 39% (95% CI, 9-75%) vs 14% (95% CI, 7-24%); prelabor rupture of membranes was 67% (95% CI, 12-100%) vs 38% (95% CI, 26-50%); and perinatal death was 14% (95% CI, 1-38%) vs 5% (95% CI, 3-8%). CONCLUSION: Open fetal surgery for spina bifida seems to show lower rates of procedure-related complications than does endoscopic surgery, but the rate of hysterotomy scar complications is high after open surgery. Because of the low quality of evidence, the conclusions should be interpreted with caution. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26612042 TI - On signaling pathways: hematopoietic stem cell specification from hemogenic endothelium. AB - Hematopoietic stem cells (HSCs) are specified and generated during the embryonic development and have remarkable potential to replenish the full set of blood cell lineages. Researchers have long been interested in clarifying the molecular events involved in HSC specification. Many studies have reported the development of methods for generating functional hematopoietic cells from pluripotent stem cells (PSCs-embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs)) for decades. However, the generation of HSCs with robust long-term repopulation potential remains a swingeing challenge, of which a major factor contributing to this failure is the difficulty to define the intraembryonic signals related to the specification of HSCs. Since HSCs directly derive from hemogenic endothelium, in this review, we summarize both in vivo and in vitro studies on conserved signaling pathways that control the specification of HSCs from hemogenic endothelial cells. PMID- 26612041 TI - Formaldehyde scavengers function as novel antigen retrieval agents. AB - Antigen retrieval agents improve the detection of formaldehyde-fixed proteins, but how they work is not well understood. We demonstrate that formaldehyde scavenging represents a key characteristic associated with effective antigen retrieval; under controlled temperature and pH conditions, scavenging improves the typical antigen retrieval process through reversal of formaldehyde-protein adduct formation. This approach provides a rational framework for the identification and development of more effective antigen retrieval agents. PMID- 26612043 TI - Molecular pathogenesis of lymphomas of mucosa-associated lymphoid tissue--from (auto)antigen driven selection to the activation of NF-kappaB signaling. AB - Lymphomas of mucosa-associated lymphoid tissue (MALT) are typically present at sites such as the stomach, lung or urinary tract, where lymphoid tissues scatter in mucosa lamina propria, intra- or sub-epithelial cells. The infection of certain pathogens, such as Helicobacter pylori, Chlamydophila psittaci, Borrelia burgdorferi, hepatitis C virus, or certain autoantigens cause these sites to generate a germinal center called the "acquired lymphoid tissue". The molecular pathogenesis of MALT lymphoma is a multi-step process. Receptor signaling, such as the contact stimulation of B cell receptors and CD4 positive T cells mediated by CD40/CD40-ligand and T helper cell type 2 cytokines like interleukin-4, contributes to tumor cell proliferation. A number of genetic alterations have been identified in MALT lymphoma, and among them are important translocations, such as t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21) and t(3;14)(p13;q32). Fusion proteins generated by these translocations share the same NF-kappaB signaling pathway, which is activated by the caspase activation and recruitment domain containing molecules of the membrane associated guanylate kinase family, B cell lymphoma-10 and MALT1 (CBM) protein complex. They act downstream of cell surface receptors, such as B cell receptors, T cell receptors, B cell activating factors and Toll-like receptors, and participate in the biological process of MALT lymphoma. The discovery of therapeutic drugs that exclusively inhibit the antigen receptor signaling pathway will be beneficial for the treatment of B cell lymphomas in the future. PMID- 26612045 TI - Giardia infection in foreign visitors to Cuba. PMID- 26612044 TI - Provider costs for prevention and treatment of cardiovascular and related conditions in low- and middle-income countries: a systematic review. AB - BACKGROUND: The burden of cardiovascular disease (CVD) and CVD risk conditions is rapidly increasing in low- and middle-income countries, where health systems are generally ill-equipped to manage chronic disease. Policy makers need an understanding of the magnitude and drivers of the costs of cardiovascular disease related conditions to make decisions on how to allocate limited health resources. METHODS: We undertook a systematic review of the published literature on provider incurred costs of treatment for cardiovascular diseases and risk conditions in low- and middle-income countries. Total costs of treatment were inflated to 2012 US dollars for comparability across geographic settings and time periods. RESULTS: This systematic review identified 60 articles and 143 unit costs for the following conditions: ischemic heart disease, non-ischemic heart diseases, stroke, heart failure, hypertension, diabetes, and chronic kidney disease. Cost data were most readily available in middle-income countries, especially China, India, Brazil, and South Africa. The most common conditions with cost studies were acute ischemic heart disease, type 2 diabetes mellitus, stroke, and hypertension. CONCLUSIONS: Emerging economies are currently providing a base of cost evidence for NCD treatment that may prove useful to policy-makers in low income countries. Initial steps to publicly finance disease interventions should take account of costs. The gaps and limitations in the current literature include a lack of standardized reporting as well as sparse evidence from low-income countries. PMID- 26612046 TI - A drink to die for: Arak and methanol poisoning in Indonesia. PMID- 26612047 TI - No fever, no malaria ? A diagnostic challenge in an immunocompromised patient. AB - We describe the case of an immunosuppressed women with proven malaria tropicana. Fever was not reported with this patient. We conclude that the concept of using fever as a primary surrogate indicator for the presence of malaria should be used with caution in patients with complex immunosuppression. PMID- 26612048 TI - Serum uric acid levels in patients with infections of central nervous system. AB - The lower levels of serum uric acid (UA) correlated with meningitis have been reported. However, comparison of UA levels among different kinds of infections of central nervous system (CNS) and changes of UA levels before and after treatment are unknown. Our study aimed to investigate the antioxidant status of serum UA in five common types of CNS infections. We retrospectively evaluated serum UA levels of 399 patients with different types of CNS infections including viral meningitis or meningoencephalitis (VM), brain cysticercosis (BC), tuberculous meningitis or meningoencephalitis (TM), cryptococcus meningitis or meningoencephalitis (CM) and bacterial meningitis or meningoencephalitis (BM), and 119 healthy controls. The changes of serum UA were examined and analyzed. The serum levels of UA in patients with CNS infections were significantly lower than those in normal subjects and among in TM, CM and BM groups were apparently lower when compared with VM and BC groups; otherwise, after effective therapy, serum UA levels were obviously higher than before. Our findings showed that patients with CNS infections had lower serum UA levels, which was independent of the classification and the serum UA levels increased obviously after valid treatment, the variation of UA levels might be considered as an indicator of clinical curative effect in patients with CNS infections. PMID- 26612049 TI - Adiponectin is associated with poor prognosis in carcinoma patients: evidence from a meta-analysis. AB - BACKGROUND: Studies have come to conflicting conclusions about whether adiponectin (APN) expression is associated with cancer prognosis. To help resolve this question, we meta-analyzed the available evidence. METHODS: PubMed, EMBASE, the Cochrane Library, the Chinese Biological Medical Database and the Chinese National Knowledge Infrastructure Database were systematically searched to identify all eligible studies examining APN expression and prognosis for patients with any type of cancer. Pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) related to overall survival (OS) or disease-free survival (DFS) were calculated. RESULTS: Ten studies involving 999 patients were meta-analyzed. Analysis across all patients revealed no significant association between high/positive APN expression and DFS, but they did show a significant association between high/positive APN expression and OS (HR 1.51, 95 %CI 1.21 to 1.89). Subgroup analysis showed that high/positive APN expression in non-Asians was significantly associated with both DFS (HR 1.36, 95% CI 1.03 to 1.80) and OS (HR 1.53, 95 %CI 1.20 to 1.96), but no such associations were observed in Asians. In addition, high/positive APN expression was significantly associated with OS across all patients with hepatocellular carcinoma (HR 1.89, 95 %CI 1.20 to 2.98). CONCLUSIONS: The available evidence suggests that high/positive APN expression is associated with poor prognosis for patients with various carcinomas, especially for non-Asian cancer patients and for all patients with hepatocellular carcinoma. These findings should be confirmed and extended in large, well-designed studies. PMID- 26612051 TI - Identification of information types and sources by the public for promoting awareness of Middle East respiratory syndrome coronavirus in Saudi Arabia. AB - Middle East Respiratory Syndrome (MERS) is a viral respiratory disease of serious consequences caused by MERS Coronavirus (MERS-CoV). Saudi communities still lack awareness of available protective measures to prevent the transmission of the virus. It is necessary to explore the current information-seeking strategies and preferences for communication tools among the Saudi population to promote dissemination of accurate information. Guided by McGuire's Input-Output Persuasion Model and focusing on input variables (receiver characteristics, sources, message, channel and destination), we explored the current information seeking strategies and preferences for different communication tools among residents of Riyadh (n = 658). Preferred and sought-after information sources on MERS. Most participants in the sample were female (61.7%), and the majority (98.2%) had internet access at home. The internet was the most commonly used source of information (39.5%) and the most endorsed channel for a MERS awareness campaign. Physicians were the preferred source of information (45.6%), followed by other health care providers (31.3%). In univariate multinomial logistic regression models, males and individuals aged <=27 years were more likely to seek information from the internet than from physicians. Residents of southern and western Riyadh preferred physicians as a credible source of information over the Ministry of Health. The results of this survey provide valuable information on how to reach this population and for understanding how to launch an effective MERS risk communication campaign in a Saudi population. PMID- 26612050 TI - Association of parental health literacy with oral health of Navajo Nation preschoolers. AB - Health literacy is 'the capacity to obtain, process and understand basic health information and services needed to make appropriate health decisions'. Although numerous studies show a link between health literacy and clinical outcomes, little research has examined the association of health literacy with oral health. No large-scale studies have assessed these relationships among American Indians, a population at risk for limited health literacy and oral health problems. This analysis was conducted as part of a clinical trial aimed at reducing dental decay among preschoolers in the Navajo Nation Head Start program. Using baseline data for 1016 parent-child dyads, we examined the association of parental health literacy with parents' oral health knowledge, attitudes, and behavior, as well as indicators of parental and pediatric oral health. More limited health literacy was associated with lower levels of oral health knowledge, more negative oral health attitudes, and lower levels of adherence to recommended oral health behavior. Parents with more limited health literacy also had significantly worse oral health status (OHS) and reported their children to have significantly worse oral health-related quality of life. These results highlight the importance of oral health promotion interventions that are sensitive to the needs of participants with limited health literacy. PMID- 26612052 TI - Diagnostic accuracy of silica clotting time method for lupus anticoagulant in a clinical population with various symptoms of antiphospholipid syndrome. AB - INTRODUCTION: Correct interpretation of lupus anticoagulant (LA) tests is crucial for diagnosis of antiphospholipid syndrome (APS). This study assessed diagnostic accuracy of the SCT method in a clinical population with various symptoms of APS. MATERIAL AND METHODS: Altogether 60 APS patients were consecutively recruited from a relevant clinical population. All cases had stable positivity of at least one of the reference tests (two other LA methods; anticardiolipin- and anti-beta2 glycoprotein-I antibodies). Controls (n = 62) with negative reference tests were also consecutively recruited from the same clinical population. RESULTS AND CONCLUSIONS: Receiver operator characteristic (ROC) analysis for the SCT test to identify the APS cases showed area under the curve of 0.82 (95% CI 0.75-0.90). The positive cut-off defined by a non-parametric method (99 percentile in a healthy population) had specificity of 92%, but low sensitivity of 53%. The optimal cut-off corresponded to the 97.5 percentile (67% sensitivity and 92% specificity). Combined sensitivity of the positive diluted Russell Viper Venom time (dRVVT) and SCT tests was 73%, while specificity remained 92%. The sensitivity of the SCT method varied in different clinical subgroups and was highest in patients with rheumatic diseases and in patients with triple positivity of three reference methods. PMID- 26612053 TI - Combined pulmonary endarterectomy and balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension. AB - BACKGROUND: Pulmonary endarterectomy (PEA) is a curative treatment option for more than 60% of patients with chronic thromboembolic pulmonary hypertension (CTEPH). For selected inoperable patients, interventional balloon pulmonary angioplasty (BPA) has recently been established in addition to medical treatment. This approach disrupts scar tissue occluding the pulmonary arteries, leading to an improvement in parenchymal perfusion. CTEPH is occasionally heterogeneous, with operable disease on one side but peripheral, inoperable changes on the contralateral side. Performing unilateral PEA (on the operable side only) in these patients may lead to a worse hemodynamic outcome and increased mortality compared with patients who that can be surgically corrected bilaterally. We sought to determine the feasibility, safety, and benefits of BPA applied to the contralateral lung in several patients with predominantly unilateral disease that was amenable to treatment by PEA. METHODS: Standard unilateral PEA in deep hypothermic circulatory arrest was performed in 3 CTEPH patients with poor pulmonary hemodynamics, and inoperability of the contralateral pulmonary artery obstructions was confirmed. The inoperable side was treated by BPA. The intervention was performed during the rewarming phase of cardiopulmonary bypass. RESULTS: A dramatic improvement in pulmonary hemodynamics, with a mean reduction in pulmonary vascular resistance of 842 dyne . sec/cm(5), was achieved in all patients. World Health Organization Functional Class was also significantly improved at the midterm follow-up. CONCLUSIONS: The combination of surgical PEA and interventional BPA is a new treatment option for highly selected high-risk CTEPH patients. A multidisciplinary CTEPH expert team is a basic pre-requisite for this complex concept. PMID- 26612054 TI - Development of de novo aortic valve incompetence in patients with the continuous flow HeartWare ventricular assist device. AB - BACKGROUND: In this study we investigated the development of aortic incompetence (AI) and change in aortic root and left ventricular dimensions after implantation of the continuous-flow HeartWare ventricular assist device (HVAD) in our adult patient cohort. METHODS: A retrospective analysis of serial echocardiograms was performed on patients implanted with an HVAD between July 2009 and July 2013. Data from echocardiograms performed before and at 1 and 2 years (+/-3 months) were analyzed. Patients with native aortic valves (AoVs) with no previous intervention and HVAD in situ for >=6 months were included. RESULTS: A total of 73 HVADs in 71 patients with a mean duration of support of 624 +/- 359 days were included in our study. One patient developed moderate AI at 1 year (1.9%). Mild or greater AI was more likely in those with a closed or intermittently opening AoV at 1 year (p = 0.005). Aortic annulus dimensions increased significantly at 1 and 2 years, regardless of extent of AI. At 2 years, in those with mild or worse AI, the sinuses of Valsalva were also larger (p = 0.002). Left ventricular end diastolic dimension (LVEDD) was significantly reduced in those with no or trace AI at 1 and 2 years (p = 0.012 and p = 0.008, respectively), but remained unchanged in those with AI at both time-points. CONCLUSIONS: The development of more than mild AI is rare in HVAD patients at our center. When encountered, it is more common with a closed AoV. Dilation of the aortic annulus, and root dilation in those with mild or more AI, is seen with HVAD support over time. PMID- 26612055 TI - Early initiation of mTOR inhibitors in children with heart transplantation: A propensity-based registry analysis. PMID- 26612057 TI - [Cardiovascular assessment and management prior to non-cardiac surgery. Comment on the new 2014 ESC/ESA guidelines]. AB - In 2014 the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA) published an update of the guidelines on "non-cardiac surgery: cardiovascular assessment and management". Epidemiological data underline the relevance of these guidelines: a total of 5.7 million surgical procedures are performed per year in patients with increased cardiac risk and approximately 167,000 cardiac complications occur per year in Europe of which 19,000 are life-threatening. This new version of the guidelines highlights the patient characteristics, such as functional capacity and comorbidities and procedure-specific aspects for perioperative risk stratification. Decision-making for preoperative stress tests and coronary angiography has been simplified, procedure-specific risks have been revised and the role of multidisciplinary teamwork for high risk procedures is emphasized. A standardized stepwise approach on how to stratify patient-specific and procedure-associated risks has been established. For the first time, the guidelines recommend perioperative regimens on dual antiplatelet therapy and the new oral anticoagulants (NOAC). PMID- 26612056 TI - Establishing a low-expression renalase gene model in cardiac tissue of Sprague Dawley rats. AB - BACKGROUND: Renalase is a novel secretory amino oxidase expressed in the kidney and heart. To study the protective mechanism of renalase in local heart tissue, we established a low-expression renalase model with lentivirus (LV)-mediated RNA interference technology. MATERIALS AND METHODS: Three renalase-targeting oligonucleotides were designed after analyzing the mRNA of renalase. LV particles were prepared with LV expression systems (using the Trono 3 plasmid component system), after which LV-RNLS-shRNAs and LV-NC-shRNA were transfected into H9C2 cells in different cell culture plates. The optimal oligonucleotide was screened by real-time PCR and Western blot. These techniques were also used to detect renalase gene expression in the heart tissue. RESULTS: In the cell screening experiment, the efficacy of the inhibition of renalase mRNA expression was 93.7 % and that of renalase protein expression was 83.1 % in H9C2 cells. When the oligonucleotide was injected into the pericardial cavities of the SD rats on the 10th day, it inhibited 63.9 % of the expression of renalase protein in the heart tissue. CONCLUSION: LV-RNLS-RNAi (19813-1) can be used to establish an optimal renalase low-expression model for further research on the renalase system. PMID- 26612058 TI - Interventional approaches to mitral regurgitation. What's in the pipeline? AB - Mitral regurgitation (MR) is the most prevalent valvular heart disease in the Western world. Surgical repair is the gold standard for the treatment of degenerative MR in low-risk patients. Given the rising number of patients with functional MR and higher operative risk due to relevant comorbidities and increasing age, interventional approaches to repair or replace diseased mitral valves are on the rise. However, the complex anatomy and physiology of the mitral valve and its adjacent valve apparatus bear major challenges. To date, only the MitraClip device has been used in a large number of patients; however, several other devices and systems specifically targeted at different underlying pathologies of MR are currently under development. In addition to valve repair, the first steps toward mitral valve replacement have been taken. The present article reviews the current state of the art of interventional approaches to mitral valve disease and its future perspectives. PMID- 26612059 TI - Brief report: Past, present, emergent and future identities of young inmates. AB - This study aims to investigate how young inmates integrate temporal and contextual elements of identity and what is the role of education in identity integration. Twenty-six young inmates were interviewed. Thematic analysis revealed that inmates integrated the elements of four time identities using different mechanisms to deal with each identity: (a) Past identity (before imprisonment) is defined by cumulative risk factors, where detachment from family, society, and institutions prevails; (b) present identity is characterized by the engagement in prison's educational activities; (c) emergent identity (until their release) is characterized by their requests for a proper education and training and their commitment to acquire qualifications; (d) future identity (after their release) is characterized by the investment on future aims for personal growth, family, education/work and community. Inmates used the non formal educational program, which was offered in prison, as a vehicle towards positive identity contemplation. PMID- 26612060 TI - Superconductivity in Potassium-Doped Metallic Polymorphs of MoS2. AB - Superconducting layered transition metal dichalcogenides (TMDs) stand out among other superconductors due to the tunable nature of the superconducting transition, coexistence with other collective electronic excitations (charge density waves), and strong intrinsic spin-orbit coupling. Molybdenum disulfide (MoS2) is the most studied representative of this family of materials, especially since the recent demonstration of the possibility to tune its critical temperature, Tc, by electric-field doping. However, just one of its polymorphs, band-insulator 2H-MoS2, has so far been explored for its potential to host superconductivity. We have investigated the possibility to induce superconductivity in metallic polytypes, 1T- and 1T'-MoS2, by potassium (K) intercalation. We demonstrate that at doping levels significantly higher than that required to induce superconductivity in 2H-MoS2, both 1T and 1T' phases become superconducting with Tc = 2.8 and 4.6 K, respectively. Unusually, K intercalation in this case is responsible both for the structural and superconducting phase transitions. By adding new members to the family of superconducting TMDs, our findings open the way to further manipulate and enhance the electronic properties of these technologically important materials. PMID- 26612061 TI - Seeking Extremes in Molecular Design: To What Extent May Two "Non-Bonded" Hydrogen Atoms be Squeezed in a Hydrocarbon? AB - A series of novel and possibly synthetically accessible rigid hydrocarbon structures is computationally introduced, maintaining ultrashort non-bonded hydrogen-hydrogen (H???H) contacts smaller than 1.2 A. These are the shortest non bonded H???H contacts reported to date, bypassing previous world records of both experimentally observed, 1.56 A, and computationally derived, 1.4 A, H???H contacts in any stable molecular structure. PMID- 26612062 TI - Lower rates of hypoglycemia during maintenance treatment with insulin degludec/insulin aspart versus biphasic insulin aspart 30: a combined analysis of two Phase 3a studies in type 2 diabetes. AB - BACKGROUND: Insulin degludec/insulin aspart (IDegAsp) is a soluble coformulation of the basal analog insulin degludec and the rapid-acting prandial insulin aspart in a single injection. The present combined analysis of two Phase 3a trials compared the incidence of hypoglycemia in participants treated twice daily with IDegAsp or biphasic insulin aspart 30 (BIAsp 30). METHODS: Hypoglycemia data were analyzed from two similarly designed randomized controlled open-label treat-to target Phase 3a clinical trials of adults with type 2 diabetes (T2D). Participants were treated twice daily with IDegAsp or BIAsp 30, with breakfast and their main evening meal. RESULTS: Over 26 weeks, the rates of overall confirmed, nocturnal confirmed and severe hypoglycemic events were 19%, 57%, and 39% lower, respectively, with IDegAsp (n = 504) than BIAsp 30 (n = 364); estimated rate ratios were 0.81 (95% confidence interval [CI] 0.67, 0.98; P = 0.0341), 0.43 (95% CI 0.31, 0.59; P = 0.0001), and 0.61 (95% CI 0.26, 1.45; P = NS). The between-treatment differences were more pronounced during the maintenance period (>=16 weeks); compared with BIAsp 30, rates of overall confirmed, nocturnal confirmed and severe hypoglycemic events with IDegAsp were 0.69 (95% CI 0.55, 0.87; -31%; P = 0.0015); 0.38 (95% CI 0.25, 0.58; -62%; P < 0.0001), and 0.16 (95% CI 0.04, 0.59; -84%; P = 0.0061), respectively. CONCLUSIONS: Compared with BIAsp 30 twice daily, IDegAsp twice daily provided similar improvements in glycemic control with a lower risk of hypoglycemia, particularly nocturnal hypoglycemia, in subjects with T2D previously treated with insulin. PMID- 26612063 TI - Synthesis of Novel Cellulose Carbamates Possessing Terminal Amino Groups and Their Bioactivity. AB - Cellulose phenyl carbonates are an excellent platform to synthesize a broad variety of soluble and functional cellulose carbamates. In this study, the synthesis of cellulose carbamates with terminal amino groups, namely omega aminoethylcellulose- and omega-aminoethyl-p-aminobenzyl-cellulose carbamate, is discussed. The products are well soluble and their structures can be clearly described by NMR spectroscopy. The cellulose carbamates exhibit a bactericide and fungicide activity in vitro. The omega-aminoethylcellulose carbamate possesses a strong activity against Candida albicans and Staphylococcus aureus (IC50 of 0.02 mg mL(-1) and 0.05 mg mL(-1)). The antimicrobial activity and cytotoxicity can be improved by p-amino-benzylamine (ABA) as an additional substituent. The mixed cellulose carbamate exhibits a high biocompatibility (LC50 of 3.18 mg mL(-1)) and forms films on cotton and PES, which exhibit a strong activity against S. aureus and Klebsiella pneumoniae. PMID- 26612064 TI - Introduction: Female fertility preservation: innovations and questions. AB - Oocyte and ovarian tissue cryopreservation represents one of the most important advances in the field of reproductive medicine and biology. Preserving a woman's potential for becoming a genetic mother is now possible for numerous diseases that could impair female fertility either by themselves or as a result of their treatments. However, female fertility preservation is still at the pioneering level and is thus often considered an experimental treatment either from a technical standpoint or in the clinical situation in which it is discussed. As a consequence, many ethics issues are raised with fertility preservation treatment in infants, adolescents, and young women. PMID- 26612065 TI - Isoform-specific regulation of transforming growth factor-beta mRNA expression in macrophages in response to adrenoceptor stimulation. AB - Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine responsible for both immune regulation and tissue repair. Although TGF-beta consists of TGF-beta1, -beta2, and -beta3 in mammals, isoform-selective transcriptional regulation is less well documented in myeloid linage cells such as macrophages. In the present study, the effect of the stress-related catecholamine adrenaline on the expression of TGF-beta isoforms in RAW264.7 macrophages and murine bone marrow-derived macrophages was examined. Treatment with adrenaline markedly increased the mRNA expression of TGF-beta3 but not of TGF-beta1 and -beta2. Agonist and antagonist studies indicated that adrenaline induced TGF-beta3 mRNA expression is mediated via beta2 -adrenoceptor. Protein kinase A (PKA) inhibitor H89 was found to block an increase in adrenoceptor mediated TGF-beta3 mRNA expression. The membrane-permeable cAMP analog 8-Br-cAMP increased the mRNA expression of TGF-beta3 but not of TGF-beta1 and -beta2. Thus, the beta2 -adrenoceptor-mediated cAMP-PKA pathway appears to enhance TGF-beta3 mRNA expression in macrophages. Adrenoceptor-mediated TGF-beta3 expression by macrophages may influence immune regulation and tissue repair in conditions of stress, during which the sympathetic-nervous system releases catecholamines. PMID- 26612066 TI - Dynamic coupling of photoacclimation and photoinhibition in a model of microalgae growth. AB - The development of mathematical models that can predict photosynthetic productivity of microalgae under transient conditions is crucial for enhancing large-scale industrial culturing systems. Particularly important in outdoor culture systems, where the light irradiance varies greatly, are the processes of photoinhibition and photoacclimation, which can affect photoproduction significantly. The former is caused by an excess of light and occurs on a fast time scale of minutes, whereas the latter results from the adjustment of the light harvesting capacity to the incoming irradiance and takes place on a slow time scale of days. In this paper, we develop a dynamic model of microalgae growth that simultaneously accounts for the processes of photoinhibition and photoacclimation, thereby spanning multiple time scales. The properties of the model are analyzed in connection to PI-response curves, under a quasi steady state assumption for the slow processes and by neglecting the fast dynamics. For validation purposes, the model is calibrated and compared against multiple experimental data sets from the literature for several species. The results show that the model can describe the difference in photosynthetic unit acclimation strategies between Dunaliella tertiolecta (n-strategy) and Skeletonema costatum (s-strategy). PMID- 26612067 TI - Anion Recognition in Water: Recent Advances from a Supramolecular and Macromolecular Perspective. AB - The recognition of anions in water remains a key challenge in modern supramolecular chemistry, and is essential if proposed applications in biological, medical, and environmental arenas that typically require aqueous conditions are to be achieved. However, synthetic anion receptors that operate in water have, in general, been the exception rather than the norm to date. Nevertheless, a significant step change towards routinely conducting anion recognition in water has been achieved in the past few years, and this Review highlights these approaches, with particular focus on controlling and using the hydrophobic effect, as well as more exotic interactions such as C-H hydrogen bonding and halogen bonding. We also look beyond the field of small-molecule recognition into the macromolecular domain, covering recent advances in anion recognition based on biomolecules, polymers, and nanoparticles. PMID- 26612068 TI - Feasibility and safety of continuous retrograde administration of Del Nido cardioplegia: a case series. AB - BACKGROUND: Del Nido (DN) cardioplegia, a calcium-free, hyperkalemic solution containing lidocaine and magnesium has been developed to help reduce intracellular calcium influx and the resulting myocyte damage in the immediate postischemic period following cardiac arrest. DN cardioplegia has been used for pediatric cardiac surgery but its use in complex reoperative surgery has not been studied. We specifically report the outcomes of patients undergoing reoperative cardiac surgery after previous coronary artery bypass grafting with a patent internal mammary artery (IMA). METHODS: Patients undergoing reoperative cardiac surgery with prior coronary bypass grafting surgery were studied between 2010 and 2013. Fourteen patients were identified who required continued retrograde cardioplegia administration. In all cases, an initial antegrade dose was given, followed by continuous retrograde administration. Demographics, co-morbidities, intra-operative variables including cardioplegia volumes, post-operative complications, and patient outcomes were collected. RESULTS: The mean age of all patients was 73.3+/-6.7 years, and 93 % were male. Aortic cross clamp time and cardiopulmonary bypass times were 81+/-35 and 151+/-79 mins, respectively. Antegrade, retrograde and total cardioplegia doses were 1101+/-398, 3096+/-3185 and 4367+/-3751 ml, respectively. An average of 0.93+/-0.92 inotropes and 1.50+/ 0.76 pressors were used on ICU admission after surgery. ICU and total hospital lengths of stay were 5.5+/-7.4 and 9.6+/-8.0 days, respectively. Complications occurred in two patients (14 %) (pneumonia and prolonged mechanical ventilation) and new arrhythmias occurred in five patients (36 %) (four new-onset atrial fibrillation and one pulseless electrical activity requiring 2 min of chest compression). No perioperative myocardial infarctions were noted based on electrocardiograms and cardiac serum markers. Postoperatively, left ventricular function was preserved in all patients whereas two patients (14 %) had mild decrease in right ventricular function as assessed by echocardiography. No mortality was observed. CONCLUSION: Del Nido cardioplegia solution provides acceptable myocardial protection for cardiac surgery that requires continuous retrograde cardioplegia administration. DN cardioplegia's administration in a continuous retrograde fashion with a patent IMA is believed to provide adequate myocardial protection while avoiding injuring the IMA through dissection and clamping. PMID- 26612069 TI - Uncovering novel loci for mesocotyl elongation and shoot length in indica rice through genome-wide association mapping. AB - MAIN CONCLUSION: Totally, 23 loci were detected, and 383 candidate genes were identified, and four of these candidate genes, Os01g0392100, Os04g0630000, Os01g0904700 and Os07g0615000, were regarded as promising targets. Direct-seeding cultivation is becoming popular in rice (Oryza sativa L.)-planting countries because it is labor- and time-efficient. However, low seedling establishment and slow seedling emergence have restricted the application and popularity of the technique. Mesocotyl elongation and shoot length are two important traits that can enhance rice seedling emergence. A single nucleotide polymorphism (SNP) is a genome sequence variation caused by a single base within a population, and SNPs evenly distributed throughout the genomes of plant species. In this study, a genome-wide association study (GWAS), based on 4136 SNPs, was performed using a compressed mixed linear model that accounted for population structure and relative kinship to detect novel loci for the two traits. Totally, 23 loci were identified, including five loci located known QTLs region. For the mesocotyl elongation, 17 major loci were identified, explaining ~19.31 % of the phenotypic variation. For the shoot length, six major loci were detected, explaining ~ 39.79 % of the phenotypic variation. In total, 383 candidate genes were included in a 200-kb genomic region (+/- 100 kb of each locus). Additionally, 32 SNPs were identified in 30 candidate genes. Relative expression level analyses indicated that four candidate genes containing SNP variations, Os01g0392100, Os04g0630000, Os01g0904700 and Os07g0615000, represented promising targets. Finally, eight elite accessions with long mesocotyl and shoot lengths were chosen as breeding donors for further rice direct-seeding variety modifications. PMID- 26612071 TI - 'Cognitive biases plus': covert subverters of healthcare evidence. PMID- 26612070 TI - Functional testing of a PF02458 homologue of putative rice arabinoxylan feruloyl transferase genes in Brachypodium distachyon. AB - MAIN CONCLUSION: We show that changing the expression of a putative feruloyl transferase gene belonging to the BAHD acyl-transferase family alters the levels of cell wall esterified ferulates and diferulates in Brachypodium distachyon cell walls. While the potential of grass cell walls for biofuel production has been realized, the technology for lignocellulosic biomass conversion for the production of ethanol is still inefficient because of structural mechanisms that plants have evolved to make the cell wall recalcitrant to enzymatic attack. One of these mechanisms in grasses involves the esterification of arabinoxylans in the cell wall with ferulic acid via an ester linkage to arabinose side chains on xylans. These ferulates undergo oxidative coupling reactions to form ferulate dimers, thus crosslinking polysaccharides. Arabinoxylan feruloylation is an important factor that determines cell wall recalcitrance because it directly cross-links xylans and because ferulates act as nucleating sites for the formation of lignin and for the linkage of lignin to the xylan/cellulose network. Here we report on the effects of changing the expression of Bradi2g43520 (BdAT1), a homologue of the rice feruloyl transferase gene Os01g42880 belonging to the Pfam PF02458 family, in Brachypodium distachyon. Down regulation in several independent RNAi::BdAT1 lines, resulted in up to a 35 % reduction of ferulate levels in both leaves and stems compared to control plants, over 2-3 generations of selfing. In contrast, overexpression of putative BdAT1 resulted in an increase of up to 58 and 47 % of ferulate levels in leaves and stems, respectively, compared to control plants and analyzed over 2-3 generations of selfing. These findings suggest that Bradi2g43520 may be a good candidate for feruloylation of AX in Brachypodium. PMID- 26612072 TI - Accuracy of an autocalibrated pulse contour analysis in cardiac surgery patients: a bi-center clinical trial. AB - BACKGROUND: Less-invasive and easy to install monitoring systems for continuous estimation of cardiac index (CI) have gained increasing interest, especially in cardiac surgery patients who often exhibit abrupt haemodynamic changes. The aim of the present study was to compare the accuracy of CI by a new semi-invasive monitoring system with transpulmonary thermodilution before and after cardiopulmonary bypass (CPB). METHODS: Sixty-five patients (41 Germany, 24 Spain) scheduled for elective coronary surgery were studied before and after CPB, respectively. Measurements included CI obtained by transpulmonary thermodilution (CITPTD) and autocalibrated semi-invasive pulse contour analysis (CIPFX). Percentage changes of CI were also calculated. RESULTS: There was only a poor correlation between CITPTD and CIPFX both before (r (2) = 0.34, p < 0.0001) and after (r (2) = 0.31, p < 0.0001) CPB, with a percentage error (PE) of 62 and 49 %, respectively. Four quadrant plots revealed a concordance rate over 90 % indicating an acceptable correlation of trends between CITPTD and CIPFX before (concordance: 93 %) and after (concordance: 94 %) CPB. In contrast, polar plot analysis showed poor trending before and an acceptable trending ability of changes in CI after CPB. CONCLUSIONS: Semi-invasive CI by autocalibrated pulse contour analysis showed a poor ability to estimate CI compared with transpulmonary thermodilution. Furthermore, the new semi-invasive device revealed an acceptable trending ability for haemodynamic changes only after CPB. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02312505 Date: 12.03.2012. PMID- 26612073 TI - Diabetes enhances oxidative stress-induced TRPM2 channel activity and its control by N-acetylcysteine in rat dorsal root ganglion and brain. AB - N-acetylcysteine (NAC) is a sulfhydryl donor antioxidant that contributes to the regeneration of glutathione (GSH) and also scavengers via a direct reaction with free oxygen radicals. Recently, we observed a modulatory role of NAC on GSH depleted dorsal root ganglion (DRG) cells in rats. NAC may have a protective role on oxidative stress and calcium influx through regulation of the TRPM2 channel in diabetic neurons. Therefore, we investigated the effects of NAC on DRG TRPM2 channel currents and brain oxidative stress in streptozotocin (STZ)-induced diabetic rats. Thirty-six rats divided into four groups: control, STZ, NAC and STZ + NAC. Diabetes was induced in the STZ and STZ + NAC groups by intraperitoneal STZ (65 mg/kg) administration. After the induction of diabetes, rats in the NAC and STZ + NAC groups received NAC (150 mg/kg) via gastric gavage. After 2 weeks, DRG neurons and the brain cortex were freshly isolated from rats. In whole-cell patch clamp experiments, TRPM2 currents in the DRG following diabetes induction with STZ were gated by H2O2. TRPM2 channel current densities in the DRG and lipid peroxidation levels in the DRG and brain were higher in the STZ groups than in controls; however, brain GSH, GSH peroxidase (GSH-Px), vitamin C and vitamin E concentrations and DRG GSH-Px activity were decreased by diabetes. STZ + H2O2-induced TRPM2 gating was totally inhibited by NAC and partially inhibited by N-(p-amylcinnamoyl) anthranilic acid (ACA) and 2 aminoethyl diphenylborinate (2-APB). GSH-Px activity and lipid peroxidation levels were also attenuated by NAC treatment. In conclusion, we observed a modulatory role of NAC on oxidative stress and Ca(2+) entry through the TRPM2 channel in the diabetic DRG and brain. Since excessive oxidative stress and overload Ca(2+) entry are common features of neuropathic pain, our findings are relevant to the etiology and treatment of pain neuropathology in DRG neurons. PMID- 26612074 TI - Marek's disease virus undergoes complete morphogenesis after reactivation in a T lymphoblastoid cell line transformed by recombinant fluorescent marker virus. AB - T-lymphocytes are central targets of Marek's disease, a major chicken disease induced by the oncogenic alphaherpesvirus Marek's disease virus (MDV). T lymphocyte infection is also associated with immunosuppression and virus latency. To decipher viral morphogenesis in T-lymphocytes, we used the recombinant vRB-1B 47EGFP marker virus to generate a new lymphoblastoid cell line, 3867K, that exhibited typical properties of other MDV-transformed chicken cell lines in term of cell markers, reactivation rate and infectivity. Examination of reactivating EGFP-positive 3867K cells by transmission electron microscopy revealed the presence of most types of herpesvirus particles inside the cells but no extracellular ones. Quantification of virion types indicated only 5% cytoplasmic particles, with 0.5% being mature. This study demonstrated that MDV morphogenesis is complete upon reactivation in T-lymphocytes, albeit with poor efficiency, with a defect in the exit of virions from the nucleus and secondary envelopment, as occurs in infected fibroblasts. PMID- 26612075 TI - Colon wall motility: comparison of novel quantitative semi-automatic measurements using cine MRI. AB - BACKGROUND: Recently, cine magnetic resonance imaging (MRI) has shown promise for visualizing movement of the colonic wall, although assessment of data has been subjective and observer dependent. This study aimed to develop an objective and semi-automatic imaging metric of ascending colonic wall movement, using image registration techniques. METHODS: Cine balanced turbo field echo MRI images of ascending colonic motility were acquired over 2 min from 23 healthy volunteers (HVs) at baseline and following two different macrogol stimulus drinks (11 HVs drank 1 L and 12 HVs drank 2 L). Motility metrics derived from large scale geometric and small scale pixel movement parameters following image registration were developed using the post ingestion data and compared to observer grading of wall motion. Inter and intra-observer variability in the highest correlating metric was assessed using Bland-Altman analysis calculated from two separate observations on a subset of data. KEY RESULTS: All the metrics tested showed significant correlation with the observer rating scores. Line analysis (LA) produced the highest correlation coefficient of 0.74 (95% CI: 0.55-0.86), p < 0.001 (Spearman Rho). Bland-Altman analysis of the inter- and intra-observer variability for the LA metric, showed almost zero bias and small limits of agreement between observations (-0.039 to 0.052 intra-observer and -0.051 to 0.054 inter-observer, range of measurement 0-0.353). CONCLUSIONS & INFERENCES: The LA index of colonic motility derived from cine MRI registered data provides a quick, accurate and non-invasive method to detect wall motion within the ascending colon following a colonic stimulus in the form of a macrogol drink. PMID- 26612077 TI - Segmentation of fat in MRI using a preparatory pair of rectangular RF pulses of opposite direction. AB - A radiofrequency (RF) pulse-based MRI method is introduced as a novel fat (or water) segmentation method that, unlike the mostly used Dixon's method, does not depend on the echo times. A pair of rectangular RF pulses of opposite direction, when the duration of its rectangular pulse and the off-resonance of its carrier frequency are set to specific values, is proposed as a preparatory RF pulse to be used for the quantitative fat segmentation. The optimal duration of its rectangular pulse and its specific off-resonance were first determined theoretically. Then, such pair of rectangular pulses of opposite direction (PROD pulse) was applied in imaging a few phantoms and volunteers. During the imaging experiments, MRI images were dynamically acquired with the PROD pulse while its carrier frequency was varied in a predefined off-resonance range. By analyzing the dynamically acquired signal changes, the theoretical properties of the PROD pulse were confirmed and the utility of the PROD pulse for the fat segmentation was verified. All MRI scans were performed in a clinical 3T system. The PROD pulse, if the duration of each rectangular pulse was set to 1.66ms and its carrier frequency was set to a specific off-resonance (e.g. +/-223.5Hz, or 670.5Hz) in 3T, was effective in optimally modulating MRI signals to be used for the fat-water segmentation. Therefore, the PROD pulse can successfully be used as a preparatory RF pulse in MRI to achieve effective fat (or water) segmentation in MRI. PMID- 26612076 TI - Separation of parallel encoded complex-valued slices (SPECS) from a single complex-valued aliased coil image. AB - PURPOSE: Achieving a reduction in scan time with minimal inter-slice signal leakage is one of the significant obstacles in parallel MR imaging. In fMRI, multiband-imaging techniques accelerate data acquisition by simultaneously magnetizing the spatial frequency spectrum of multiple slices. The SPECS model eliminates the consequential inter-slice signal leakage from the slice unaliasing, while maintaining an optimal reduction in scan time and activation statistics in fMRI studies. MATERIALS AND METHODS: When the combined k-space array is inverse Fourier reconstructed, the resulting aliased image is separated into the un-aliased slices through a least squares estimator. Without the additional spatial information from a phased array of receiver coils, slice separation in SPECS is accomplished with acquired aliased images in shifted FOV aliasing pattern, and a bootstrapping approach of incorporating reference calibration images in an orthogonal Hadamard pattern. RESULT: The aliased slices are effectively separated with minimal expense to the spatial and temporal resolution. Functional activation is observed in the motor cortex, as the number of aliased slices is increased, in a bilateral finger tapping fMRI experiment. CONCLUSION: The SPECS model incorporates calibration reference images together with coefficients of orthogonal polynomials into an un-aliasing estimator to achieve separated images, with virtually no residual artifacts and functional activation detection in separated images. PMID- 26612078 TI - Optimizing accuracy and precision of micro-coil localization in active-MR tracking. AB - OBJECTIVE: To examine whether a centroid peak detection algorithm and micro transmit tracking improve the accuracy and precision of active-MR tracking when combined with previously published strategies of Hadamard Multiplexing and Phase field Dithering. MATERIALS AND METHODS: The dipole magnetic field of a solenoid tracking coil was modeled and MR spin excitation using both a uniform body coil and the tracking coil was simulated for 5329 orientations of the solenoid coil with respect to B0. A lumenless micro-coil was built onto a rotation platform and MR-tracking accuracy and precision were experimentally assessed for 576 orientations within a 1.5-T MRI scanner. Peak identification strategies (i.e. maximum pixel detection and the centroid pixel method) and transmit modes (body transmit and micro-transmit tracking) were employed and localization accuracy was assessed for each orientation in both simulation and experimentation. RESULTS: The simultaneous use of the centroid pixel method, micro-transmit tracking, Phase field Dithering, and Hadamard Multiplexing resulted in high MR tracking accuracy and precision: 0.52+/-0.41 mm and 0.34 mm respectively. Furthermore, all four methods combined offered a tracking error less than the size of the micro-coil, despite the lack of a signal source within the micro-coil. CONCLUSIONS: Micro transmit tracking and the centroid pixel method improve MR tracking accuracy and precision when combined with Phase-field Dithering and Hadamard Multiplexing compared to using Phase-field Dithering and Hadamard Multiplexing alone. PMID- 26612079 TI - ASAP (Automatic Software for ASL Processing): A toolbox for processing Arterial Spin Labeling images. AB - The method of Arterial Spin Labeling (ASL) has experienced a significant rise in its application to functional imaging, since it is the only technique capable of measuring blood perfusion in a truly non-invasive manner. Currently, there are no commercial packages for processing ASL data and there is no recognized standard for normalizing ASL data to a common frame of reference. This work describes a new Automated Software for ASL Processing (ASAP) that can automatically process several ASL datasets. ASAP includes functions for all stages of image pre processing: quantification, skull-stripping, co-registration, partial volume correction and normalization. To assess the applicability and validity of the toolbox, this work shows its application in the study of hypoperfusion in a sample of healthy subjects at risk of progressing to Alzheimer's disease. ASAP requires limited user intervention, minimizing the possibility of random and systematic errors, and produces cerebral blood flow maps that are ready for statistical group analysis. The software is easy to operate and results in excellent quality of spatial normalization. The results found in this evaluation study are consistent with previous studies that find decreased perfusion in Alzheimer's patients in similar regions and demonstrate the applicability of ASAP. PMID- 26612080 TI - Prevalence and distribution of anomalies of permanent dentition in 9584 Japanese high school students. AB - This study investigated the prevalence and distribution of anomalies of permanent dentition in the current Japanese population by examining an unbiased sample. We conducted a survey of dental anomalies by mass dental screening at eight high schools in 2012. Participants were all students with permanent dentition. Dental anomalies were classified as hypodontia, supernumerary teeth, peg-shaped teeth, fused teeth, and talon cusps. Students with one or more dental anomalies on oral examination were given a differential diagnosis by three specialists. The final sample comprised 9584 participants (5062 boys, 4522 girls). Hypodontia was present in 372 students (3.88 %) with no significant sex difference (191 boys, 181 girls). Frequent sites were the right or left mandibular second premolar, right or left maxillary second premolar, and right or left maxillary lateral incisor. Supernumerary teeth were observed in three boys (0.06 %) and one girl (0.02 %). Peg-shaped teeth were observed in 74 students (0.77 %; 27 boys, 47 girls), differing significantly between sexes; they were most prevalent among maxillary lateral incisors. Of affected students, 18 students (0.19 %) also had hypodontia (3 boys, 15 girls). Fused teeth were present in two boys (0.04 %) and three girls (0.07 %) (gemination in one boy and fusion in the remaining four students). Sites were limited to maxillary and mandibular central and lateral incisors. Talon cusps were observed in two boys (0.04 %) and four girls (0.09 %). The present survey of a large unbiased sample can be considered to reflect the prevalence and distribution of anomalies of permanent dentition in the current Japanese population. PMID- 26612081 TI - Silver Nanowire Top Electrodes in Flexible Perovskite Solar Cells using Titanium Metal as Substrate. AB - Flexible perovskite solar cells (FPSCs) have various applications such as wearable electronic textiles and portable devices. In this work, we demonstrate FPSCs on a titanium metal substrate employing solution-processed silver nanowires (Ag NWs) as the top electrode. The Ag NW electrodes were deposited on top of the spiro-MeOTAD hole transport layer by a carefully controlled spray-coating method at moderate temperatures. The power conversion efficiency (PCE) reached 7.45 % under AM 1.5 100 mW cm(-2) illumination. Moreover, the efficiency for titanium based FPSCs decreased only slightly (by 2.6 % of the initial value) after the devices were bent 100 times. With this and other advances, fully solution-based indium-free flexible photovoltaics, advantageous in terms of price and processing, have the potential to be scaled into commercial production. PMID- 26612082 TI - Hormonal receptor status, Ki-67 and HER2 expression: Prognostic value in the recurrence of ductal carcinoma in situ of the breast? AB - PURPOSE: Local recurrence is considered a major concern in patients diagnosed with ductal carcinoma in situ (DCIS), as its invasive occurrence is associated with high rates of distant disease and mortality. This study aims to assess the possible correlation of hormonal receptor status, Ki-67 and HER2 expression with recurrence rates in women with DCIS, taking also into account the potential prognostic effects of grade and age at diagnosis. METHODS: 230 consecutive patients with DCIS were included in this study. Invasive and non-invasive recurrence events were recorded, as a total. Clinicopathological information, as well as PR positivity, ER positivity, HER2 positivity and ki-67 expression were analyzed. Multivariable Cox regression analysis was performed, examining the risk factors for recurrence. RESULTS: Recurrence was noted in 17.8% of cases; the median follow-up was 44 months. Higher grade (adjusted HR = 1.72, 95%CI: 1.06 2.78), age at diagnosis (adjusted HR = 0.60, 95%CI: 0.43-0.83), Ki-67 expression (adjusted HR = 1.78, 95%CI: 1.11-2.88), and type of administered treatment were independently associated with increased recurrence rates. Recurrence rates were not significantly associated with ER, PR status or HER2 expression. CONCLUSION: In addition to high grade, administered treatment and younger age at diagnosis, high Ki-67 expression seems to be independently associated with increased likelihood of recurrence in patients with DCIS. Future studies with additional molecular markers seem necessary to further improve the identification of high risk patients for DCIS recurrence. PMID- 26612083 TI - Nipple sparing mastectomy: Surgical and oncological outcomes from a national multicentric registry with 913 patients (1006 cases) over a six year period. AB - BACKGROUND: Nipple sparing mastectomy is deemed surgically and oncologically safe based on a long lasting literature data from reviews of single institution series. This study aims at evaluating surgical and oncological outcomes of NSM on a large multi-institutional scale, by means of the Italian National registry. METHODS: In July 2011 a panel of Italian specialists agreed upon and designed a National database of NSM. Centers with at least 150 cancers per year and following the National follow-up schedule guidelines could participate inserting any NSM case performed, retrospectively and prospectively from that moment on. In March 2015 analysis of data was accomplished. Dataset for this study consists of cases performed in the period between January 1st 2009 and December 31st 2014. RESULTS: 913 Women were included in the analysis, for a total of 1006 procedures. Prophylactic mastectomies were 124 (12.3%). MRI utilization increased over time. NSM failure rate, with NAC removal for any reason was 11.5%. NAC necrosis rate was 4.8%. Larger skin-flap necrosis rate was 2.3%. Major surgical complications rate was 4.4%. Oncological outcomes were calculated among primitive EBC cases only: locoregional recurrences rate was 2.9%, NAC recurrence 0.7%. Systemic recurrence rate was 1.0%. Five deaths (0.7%) were registered. CONCLUSIONS: More than 10% of NSM procedures are prophylactic mastectomies. MRI is gaining more importance over time. Surgical and oncological results show that NSM is effective. This National multicentric analysis enables a comparison of results with no geographical differences and a "safe" state of the art of NSM in Italy. PMID- 26612084 TI - Enhancing effect of phenotype mutational robustness on adaptation in Escherichia coli. AB - Theoretical and computational studies predict a positive role for widespread phenotype resistance to genetic mutation, or "phenotype mutational robustness," in enhancing adaptation to novel environments through the accumulation of cryptic genetic variation. However, this has not been verified through experimental evolution in biological systems at the level of whole organisms. In a short-term evolution experiment of about 250 generations, we studied the adaptive performances of independently evolving populations of the bacterium Escherichia coli in two new nutritional environments, represented by minimal media with either lactate or glycerol as the sole carbon source. At the start of the experiments, all populations expressed identical phenotype, while differing for the amount of cryptic genetic variation, artificially produced by mutagenesis. We found that cryptic genetic variation can promote significantly faster adaptation to a new nutritional environment in E. coli. The scale of this effect varies between the two environments, and correlates with an estimation of the phenotype robustness of the ability to grow in a given medium, based on survival rate after mutagenesis in the same medium. PMID- 26612086 TI - Pay in the NHS: who earns what? PMID- 26612085 TI - Antioxidant and anti-inflammatory effects of intravenously injected adipose derived mesenchymal stem cells in dogs with acute spinal cord injury. AB - INTRODUCTION: Mesenchymal stem cells can potentially be used in therapy for spinal cord injury (SCI). Methylprednisolone sodium succinate (MPSS) has been used as a scavenging agent in acute SCI treatment, but its use no longer recommended. This study aimed to identify ways to reduce the usage and risk of high doses of glucocorticoid steroids, and determine whether AD-MSCs could be used as an early alternative treatment modality for acute SCI. METHODS: Sixteen adult beagle dogs with SCI were assigned to four treatment groups: control, MPSS, AD-MSCs, and AD-MSCs + MPSS. Additionally, one dog was used to evaluate the distribution of AD-MSCs in the body after injection. AD-MSCs (1 * 10(7) cells) were injected intravenously once a day for 3 days beginning at 6 hours post-SCI. MPSS was also injected intravenously according to the standard protocol for acute SCI. A revised Tarlov scale was used to evaluate hindlimb functional recovery. The levels of markers for oxidative metabolism (3-nitrotyrosine, 4 hydroxynonenal, and protein carbonyl) and inflammation (cyclooxygenase-2, interleukin-6, and tumor necrosis factor-alpha) were also measured. RESULTS: At 7 days post-treatment, hindlimb movement had improved in the AD-MSCs and AD-MSCs + MPSS groups; however, subjects in the groups treated with MPSS exhibited gastrointestinal hemorrhages. Hematoxylin and eosin staining revealed fewer hemorrhages and lesser microglial infiltration in the AD-MSCs group. The green fluorescent protein-expressing AD-MSCs were clearly detected in the lung, spleen, and injured spinal cord; however, these cells were not detected in the liver and un-injured spinal cord. Levels of 3-nitrotyrosine were decreased in the MPSS and AD-MSCs + MPSS groups; 4-hydroxynenonal and cyclooxygenase-2 levels were decreased in all treatment groups; and interleukin-6, tumor necrosis factor alpha, and phosphorylated-signal transducer and activator transcription 3 levels were decreased in the AD-MSCs and AD-MSCs + MPSS groups. CONCLUSION: Our results suggest that early intravenous injection of AD-MSCs after acute SCI may prevent further damage through enhancement of antioxidative and anti-inflammatory mechanisms, without inducing adverse effects. Additionally, this treatment could also be used as an alternative intravenous treatment modality for acute SCI. PMID- 26612087 TI - Precentral and inferior prefrontal hypoactivation during facial emotion recognition in patients with schizophrenia: A functional near-infrared spectroscopy study. AB - Although patients with schizophrenia demonstrate abnormal processing of emotional face recognition, the neural substrates underlying this process remain unclear. We previously showed abnormal fronto-temporal function during facial expression of emotions, and cognitive inhibition in patients with schizophrenia using functional near-infrared spectroscopy (fNIRS). The aim of the current study was to use fNIRS to identify which brain regions involved in recognizing emotional faces are impaired in patients with schizophrenia, and to determine the neural substrates underlying the response to emotional facial expressions per se, and to facial expressions with cognitive inhibition. We recruited 19 patients with schizophrenia and 19 healthy controls, statistically matched on age, sex, and premorbid IQ. Brain function was measured by fNIRS during emotional face assessment and face identification tasks. Patients with schizophrenia showed lower activation of the right precentral and inferior frontal areas during the emotional face task compared to controls. Further, patients with schizophrenia were slower and less accurate in completing tasks compared to healthy participants. Decreasing performance was associated with increasing severity of the disease. Our present and prior studies suggest that the impaired behavioral performance in schizophrenia is associated with different mechanisms for processing emotional facial expressions versus facial expressions combined with cognitive inhibition. PMID- 26612088 TI - Gold-catalyzed cyclization and cycloisomerization of yne-tethered ynamide: the significance of a masked enol-equivalent of an amide. AB - This perspective briefly describes the conceptual manifestation of a Bronsted acid promoted Au-catalyzed cyclization of yne-tethered ynamides for the construction of novel N-heterocycles. A hetero-atom assisted intramolecular 6 endo-dig cyclization of a transient ketene N,O-acetal (a masked enol-ether of an amide), generated from an ambivalent ynamide through the attack of p-TsOH, with a Au-activated yne-motif creates dihydropyridinones and benzo[f]dihydroisoquinolones. The Au(I)-catalyzed cycloisomerization of an alkyne tethered ketene N,N-acetal to manufacture unusual cyclobutene-fused azepine scaffolds is also highlighted. PMID- 26612090 TI - Inhibition of Atherosclerosis Progression, Intimal Hyperplasia, and Oxidative Stress by Simvastatin and Ivabradine May Reduce Thoracic Aorta's Stiffness in Hypercholesterolemic Rabbits. AB - AIMS: This study aims to evaluate atherosclerosis, oxidative stress, and arterial stiffness attenuation by simvastatin and ivabradine in hyperlipidemic rabbits. METHODS AND RESULTS: Forty rabbits were randomly divided into 4 groups: atherogenic diet (group C), atherogenic diet plus simvastatin (group S), atherogenic diet plus ivabradine (group I), and atherogenic diet plus simvastatin and ivabradine (group S + I). After 9 weeks, rabbits were euthanized and descending aortas excised for mechanical testing. Atherogenic diet induced the development of significant atherosclerotic lesions in group C animals but in none of groups S, I, and S + I. RAM-11 and HHF-35-positive cells were significantly reduced in groups S, I, and S + I compared with group C (P < .001). A significant neointimal hyperplasia and intima-media ratio reduction was demonstrated in groups S (P = .015 and P < .001), I (P = .021 and P < .001), and S + I (P = .019 and P < .001) compared with group C. Protein nitrotyrosine levels were significantly decreased in group S compared with group C (P = .009), and reactive oxygen species levels were decreased in group I compared with group C (P = .011). Aortic stiffness was significantly reduced in groups S, I, and S + I compared with group C (P = .003, P = .011, and P = .029). CONCLUSION: Simvastatin and ivabradine significantly inhibited intimal hyperplasia and oxidative stress contributing to aortic stiffness reduction in hyperlipidemic rabbits. PMID- 26612089 TI - Stability of food neophobia from infancy through early childhood. AB - The purpose of the present study was to examine whether rejection of novel foods during infancy predicted child behavioral and parent-reported neophobia at 4.5 years of age. Data for the present study were drawn from a longitudinal study following individuals (n = 82) from infancy through early childhood. At 6 and 12 months of age, the infants tasted a novel food (green beans, hummus, or cottage cheese) and their reactions were coded for rejection of the food (i.e. crying, force outs, or refusals). The children returned to the laboratory at 4.5 years of age and participated in a behavioral neophobia task where they were offered three novel foods (lychee, nori, and haw jelly) and the number of novel foods they tasted was recorded. Mothers also reported their own and their children's levels of food neophobia. Regression analyses revealed that rejection of novel foods at 6 months interacted with maternal neophobia to predict parent-rated child neophobia. Infants who exhibited low levels of rejection at 6 months showed higher levels of parent-rated neophobia when their mothers also showed high compared to low levels of neophobia. At 12 months of age, however, infants who exhibited high levels of rejection tended to have high levels of parent-rated neophobia regardless of their mothers' levels of neophobia. These results provide preliminary evidence that rejection of novel foods during infancy does predict neophobia during early childhood, but the results vary depending on when rejection of new foods is measured. PMID- 26612091 TI - Approaches to Improving Cardiac Structure and Function During and After an Acute Myocardial Infarction: Acute and Chronic Phases. AB - While progress has been made in improving survival following myocardial infarction, this injury remains a major source of mortality and morbidity despite modern reperfusion therapy. While one approach has been to develop therapies to reduce lethal myocardial cell reperfusion injury, this concept has not translated to the clinics, and several recent negative clinical trials raise the question of whether reperfusion injury is important in humans undergoing reperfusion for acute ST segment elevation myocardial infarction. Therapy aimed at reducing myocardial cell death while the myocytes are still ischemic is more likely to further reduce myocardial infarct size. Developing new therapies to further reduce left ventricular remodeling after the acute event is another approach to preserving structure and function of the heart after infarction. Such therapy may include chronic administration of pharmacologic agents and/or therapies developed from the field of regenerative cardiology, including cellular or non-cellular materials such as extracellular matrix. The optimal therapy will be to administer agents that both reduce myocardial infarct size in the acute phase of infarction as well as reduce adverse left ventricular remodeling during the chronic or healing phase of myocardial infarction. Such a dual approach will help optimize the preservation of both cardiac structure and function. PMID- 26612092 TI - Native Chemical Ligation to Minimize Aspartimide Formation during Chemical Synthesis of Small LDLa Protein. AB - The inhibition of the G protein-coupled receptor, relaxin family peptide receptor 1 (RXFP1), by a small LDLa protein may be a potential approach for prostate cancer treatment. However, it is a significant challenge to chemically produce the 41-residue and three-disulfide cross-bridged LDLa module which is highly prone to aspartimide formation due to the presence of several aspartic acid residues. Known palliative measures, including addition of HOBt to piperidine for N(alpha) -deprotection, failed to completely overcome this side reaction. For this reason, an elegant native chemical ligation approach was employed in which two segments were assembled for generating the linear LDLa protein. Acquisition of correct folding was achieved by using either a regioselective disulfide bond formation or global oxidation strategies. The final synthetic LDLa protein obtained was characterized by NMR spectroscopic structural analysis after chelation with a Ca(2+) ion and confirmed to be equivalent to the same protein obtained by recombinant DNA production. PMID- 26612093 TI - A clinical evaluation of efficacy and safety of cefepime monotherapy versus piperacillin-tazobactam in patients of paediatric age group with febrile neutropenia in a tertiary care centre of north India. AB - OBJECTIVE: To evaluate clinically the efficacy and safety in northern India of cefepime monotherapy versus piperacillin-tazobactam in patients of paediatric age group with febrile neutropenia. MATERIAL AND METHODS: Children aged <=18 years admitted febrile with chemotherapy-induced neutropenia were randomised into two groups comprising 20 cases in each group viz. CEF (receiving cefepime only) and PIP-TAZO (receiving piperacillin-tazobactam). Based on clinical and laboratory tests, patients were classified into: microbiologically documented infections (MDI); clinically documented infections (CDI); and unexplained fever (UF). They were assessed for clinical signs and symptoms as well as laboratory parameters at the time of enrolment and subsequently on days 3 and 7. RESULTS: Incidence of MDI, CDI and UF were 22.5%, 47.5% and 30%, respectively. The mean duration of neutropenia (in days) was 5.45 +/- 2.1 in the PIP-TAZO group and 5.5 +/- 1.5 in the CEF group (P = 0.305). The success rate defined as clearing infection effectively and improvement of neutropenia was comparable (P = 0.705). There was a mortality rate of 20% in the PIP-TAZO group as compared to 10% in the CEF group. CONCLUSION: We conclude that cefepime monotherapy and piperacillin tazobactam are equally efficacious and safe in treating patients with febrile neutropenia. Empirical monotherapy with cefepime would prevent an unnecessary extra economic burden as well as avoiding the serious adverse or toxic effects of multi-drug regimes, especially in low- and middle-income countries. PMID- 26612094 TI - Staphylococcal brain abscess associated with maternal breast abscess in young infants. PMID- 26612095 TI - The Presence of Phage Orthologous Genes in Helicobacter pylori Correlates with the Presence of the Virulence Factors CagA and VacA. AB - BACKGROUND: The bacterium Helicobacter pylori is associated with ulcers and the development of gastric cancer. Several genes, including cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA), are associated with increased gastric cancer risk. Some strains of H. pylori also contain sequences related to bacteriophage phiHP33; however, the significance of these phage-related sequences remains unknown. MATERIALS AND METHODS: We assessed the extent to which phiHP33 related sequences are present in 335 H. pylori strains using homology searches then mapped shared genes between phiHP33 and H. pylori strains onto an existing phylogeny. RESULTS: One hundred and twenty-one H. pylori strains contain phage orthologous sequences, and the presence of the phage-related sequences correlates with the presence of CagA and VacA. Mapping of the phage orthologs onto a phylogeny of H. pylori is consistent with the hypothesis that these genes were acquired by horizontal gene transfer. CONCLUSIONS: phiHP33 phage orthologous sequences might be of significance in understanding virulence of different H. pylori strains. PMID- 26612096 TI - Dependence of radiation dose on the behavioral patterns among school children: a retrospective analysis 18 to 20 months following the 2011 Fukushima nuclear incident in Japan. AB - After radioactive incidents, the exposure risk in daily activities among children is a major public concern. However, there are limited methods available for evaluation of this risk, which is essential to future health risk management. To this end, this study assessed the relationship between behavioral patterns of school children and radiation exposure for a period of 18-20 months following the 2011 Fukushima nuclear incident. The assessed population comprised 520 school children from Minamisoma city, located 20 km north of the nuclear plant. Data for the doses were obtained using individual dosimeters and from results of a behavior survey administered by the City Office. The mean value of the doses in the study period was 0.34 mSv, with a standard deviation of 0.14 mSv, indicating an annual dose of ~1.36 mSv, which includes doses from natural sources. Our results showed that behavior with respect to outdoor activities had no statistically significant relationship to the dose. A 0.1 MUSv/h increase in the air dose rate at home was associated with a 10% increase in the dose; however, a 0.01 MUSv/h increase in the air dose rate on the school grounds was associated with a 2% increase in the dose. This study indicates that the air contamination levels at the places where children spend most of their day are the significant predictors of the dose, as opposed to the levels at those outdoor locations in which short periods of time spent. PMID- 26612097 TI - A minichaperone-based fusion system for producing insoluble proteins in soluble stable forms. AB - We have developed a fusion system for reliable production of insoluble hydrophobic proteins in soluble stable forms. A carrier is thermophilic minichaperone, GroEL apical domain (GrAD), a 15 kDa monomer able to bind diverse protein substrates. The Met-less variant of GrAD has been made for further convenient use of Met-specific CNBr chemical cleavage, if desired. The Met-less GrAD retained stability and solubility of the original protein. Target polypeptides can be fused to either C-terminus or N-terminus of GrAD. The system has been tested with two unrelated insoluble proteins fused to the C-terminus of GrAD. One of the proteins was also fused to GrAD N-terminus. The fusions formed inclusion bodies at 25 degrees C and above and were partly soluble only at lower expression temperatures. Most importantly, however, after denaturation in urea, all fusions without exception were completely renatured in soluble stable forms that safely survived freezing-thawing as well as lyophilization. All fusions for both tested target proteins retained solubility at high concentrations for days. Functional analysis revealed that a target protein may retain functionality in the fusion. Convenience features include potential thermostability of GrAD fusions, capacity for chemical and enzymatic cleavage of a target and His6 tag for purification. PMID- 26612099 TI - Safety studies on intravenous infusion of a potent angiogenesis inhibitor: taurocholate-conjugated low molecular weight heparin derivative LHT7 in preclinical models. AB - CONTEXT: As a class of angiogenesis inhibitors, heparin conjugates have shown significant effectiveness in several studies. OBJECTIVES: The purpose of our current study is to evaluate the effectiveness and safety of infusing the conjugate of low molecular weight heparin and taurocholate (LHT7), which has been developed as a potent angiogenesis inhibitor. METHODS: To evaluate its safety, the method of intravenous infusion was compared with its i.v. bolus administration. Intravenous infusion was administered at a rate of 400 MUl/min/kg of body weight for 30 min. Pharmacokinetic (PK) analysis, organ accumulation, and plasma concentration profiles of LHT7 were measured. The anticancer effect of LHT7 was evaluated in murine and human xenograft models, and preclinical studies were performed in SD rats and beagle dogs. RESULTS: The results of the PK studies showed reduced organ accumulation in mice and the AUC(0-96 h) (area under the curve) was increased up to 1485 +/- 125 h * MUg/ml. The efficacy, at dose 1 mg/kg/2 d was higher for i.v. infusion than for i.v. bolus administration in both murine and human cancer models. The preclinical studies showed the safety dose of LHT7 is less than 20 mg/kg in SD rats and in the next safety analysis in beagle dogs showed that there were no organ-specific adverse effects in higher doses, such as, 12 mg/kg. LHT7 showed sustained effects with minimized adverse events when administered through i.v. infusion. CONCLUSIONS: LHT7 (i.v. infusion) could be safely used for further clinical development as a multi-targeting anti angiogenic agent. PMID- 26612100 TI - Efficacy and safety of intravenous fentanyl administered by ambulance personnel. AB - BACKGROUND: Management of pain in the pre-hospital setting is often inadequate. In 2011, ambulance personnel were authorized to administer intravenous fentanyl in the Central Denmark Region. The aim of this study was to evaluate the efficacy and safety of intravenous fentanyl administered by ambulance personnel. METHODS: Pre-hospital medical charts from 2348 adults treated with intravenous fentanyl by ambulance personnel during a 6-month period were reviewed. The primary outcome was the change in pain intensity on a numeric rating scale (NRS) from before fentanyl treatment to hospital arrival. Secondary outcomes included the number of patients with reduction in pain intensity during transport (NRS >= 2), the number of patients with NRS > 3 at hospital arrival, and potential fentanyl-related side effects. RESULTS: Fentanyl reduced pain from before treatment (8, IQR 7-9) to hospital arrival (4, IQR 3-6) (NRS reduction: 3, IQR 2-5; P = 0.001), 79.3% of all patients had a reduction in > 2 on the NRS during transport, and 58.4% of patients experienced pain at hospital arrival (NRS > 3). Twenty-one patients (0.9%) had oxygen saturation < 90%. A decrease in Glasgow Coma Scale was seen in 31 patients (1.3%) and hypotension observed in 71 patients (3.0%). CONCLUSION: Intravenous fentanyl caused clinically meaningful pain reduction in most patients and was safe in the hands of ambulance personnel. Many patients had moderate to severe pain at hospital arrival. As the protocol allowed higher doses of fentanyl, feedback on effect and safety should be part of continuous education of ambulance personnel. PMID- 26612098 TI - Planning and reporting of quality-of-life outcomes in cancer trials. PMID- 26612101 TI - Altered activation of the diaphragm in late-onset Pompe disease. AB - Pompe disease is an inherited neuromuscular disorder that affects respiratory function and leads to dependence on external ventilatory support. We studied the activation of the diaphragm using bilateral phrenic magnetic stimulation and hypothesized that diaphragm compound muscle action potential (CMAP) amplitude and evoked transdiaphragmatic pressure (Twitch PDI) would correlate to disease severity. Eight patients with late onset Pompe disease (LOPD, aged 14-48 years) and four healthy control subjects completed the tests. Maximal Twitch PDI responses were progressively reduced in patients with LOPD compared to control subjects (1.4-17.1cm H2O, p<0.001) and correlated to voluntary functional tests (p<0.05). Additionally, CMAP amplitude (mA) was lower in the patients who used nighttime or fulltime ventilatory support, when compared to controls and patients who used no ventilatory support (p<0.005). However, the normalized (%peak) Twitch PDI and CMAP responses were similar between patients and controls. This suggests a loss of functional phrenic motor units in patients, with normal recruitment of remaining motor units. PMID- 26612102 TI - Structural changes upon peroxynitrite-mediated nitration of peroxiredoxin 2; nitrated Prx2 resembles its disulfide-oxidized form. AB - Peroxiredoxins are cys-based peroxidases that function in peroxide detoxification and H2O2-induced signaling. Human Prx2 is a typical 2-Cys Prx arranged as pentamers of head-to-tail homodimers. During the catalytic mechanism, the active site cysteine (CP) cycles between reduced, sulfenic and disulfide state involving conformational as well as oligomeric changes. Several post-translational modifications were shown to affect Prx activity, in particular CP overoxidation which leads to inactivation. We have recently reported that nitration of Prx2, a post-translational modification on non-catalytic tyrosines, unexpectedly increases its peroxidase activity and resistance to overoxidation. To elucidate the cross-talk between this post-translational modification and the enzyme catalysis, we investigated the structural changes of Prx2 after nitration. Analytical ultracentrifugation, UV absorption, circular dichroism, steady-state and time-resolved fluorescence were used to connect catalytically relevant redox changes with tyrosine nitration. Our results show that the reduced nitrated Prx2 structurally resembles the disulfide-oxidized native form of the enzyme favoring a locally unfolded conformation that facilitates disulfide formation. These results provide structural basis for the kinetic analysis previously reported, the observed increase in activity and the resistance to overoxidation of the peroxynitrite-treated enzyme. PMID- 26612103 TI - Biochemistry and regulation of the protein arginine methyltransferases (PRMTs). AB - Many key cellular processes can be regulated by the seemingly simple addition of one, or two, methyl groups to arginine residues by the nine known mammalian protein arginine methyltransferases (PRMTs). The impact that arginine methylation has on cellular well-being is highlighted by the ever growing evidence linking PRMT dysregulation to disease states, which has marked the PRMTs as prominent pharmacological targets. This review is meant to orient the reader with respect to the structural features of the PRMTs that account for catalytic activity, as well as provide a framework for understanding how these enzymes are regulated. An overview of what we understand about substrate recognition and binding is provided. Control of product specificity and enzyme processivity are introduced as necessary but flexible features of the PRMTs. Precise control of PRMT activity is a critical component to eukaryotic cell health, especially given that an arginine demethylase has not been identified. We therefore conclude the review with a comprehensive discussion of how protein arginine methylation is regulated. PMID- 26612104 TI - Cardiac and Non-Cardiac Abnormalities in Heterotaxy Syndrome. AB - Thoraco-abdominal viscera have unique morphological asymmetry, unlike the body's external organs. Heterotaxy syndrome is a disorder in which there is a loss of normal left to right asymmetry of thoraco-abdominal viscera and their naturally proscribed spatial relationship. It has multiple anatomical alterations, culminating into physiological and hemodynamic consequences. It is divided into two groups on the basis of morphology of the two atrial appendages. These subgroups are - 1) Isomerism of right atrial appendage (asplenia syndrome); 2) Isomerism of left atrial appendage (polysplenia syndrome); Patients from group I, usually have severe cardiac malformations and present early. They may have duct dependent lesions and eventually may undergo Fontan surgery. However, extracardiac anomalies are more common in group II. All the patients must be evaluated in detail to rule out anomalies like gut-malrotation. Patients must be provided with special care for their susceptibility to infection due to absence of spleen or presence of splenic malfunction. Majority of these patients may have genetic link and may present in families. Hence, genetic evaluation is necessary before assuming long term outcome. PMID- 26612105 TI - Satisfying the Einstein-Podolsky-Rosen criterion with massive particles. AB - In 1935, Einstein, Podolsky and Rosen (EPR) questioned the completeness of quantum mechanics by devising a quantum state of two massive particles with maximally correlated space and momentum coordinates. The EPR criterion qualifies such continuous-variable entangled states, where a measurement of one subsystem seemingly allows for a prediction of the second subsystem beyond the Heisenberg uncertainty relation. Up to now, continuous-variable EPR correlations have only been created with photons, while the demonstration of such strongly correlated states with massive particles is still outstanding. Here we report on the creation of an EPR-correlated two-mode squeezed state in an ultracold atomic ensemble. The state shows an EPR entanglement parameter of 0.18(3), which is 2.4 s.d. below the threshold 1/4 of the EPR criterion. We also present a full tomographic reconstruction of the underlying many-particle quantum state. The state presents a resource for tests of quantum nonlocality and a wide variety of applications in the field of continuous-variable quantum information and metrology. PMID- 26612106 TI - American Society of Hypertension position paper: central blood pressure waveforms in health and disease. AB - A number of devices are available which noninvasively estimate central aortic blood pressure using a variety of approaches such as tonometry or oscillometry. In this position paper, we discuss how the central pressure waveform is generated and measured, how central pressure waveforms appear in health and disease, the predictive value of central blood pressure measurements, the effects of interventions on waveforms, and areas of future need in this field of clinical and research endeavor. PMID- 26612107 TI - Control and Manipulation of Nano Cracks Mimicking Optical Wave. AB - Generally, a fracture is considered as an uncontrollable thus useless phenomenon due to its highly random nature. The aim of this study is to investigate highly ordered cracks such as oscillatory cracks and to manipulate via elaborate control of mechanical properties of the cracking medium including thickness, geometry, and elastic mismatch. Specific thin film with micro-sized notches was fabricated on a silicon based substrate in order to controllably generate self-propagating cracks in large area. Interestingly, various nano-cracks behaved similar to optical wave including refraction, total internal reflection and evanescent wave. This novel phenomena of controlled cracking was used to fabricate sophisticated nano/micro patterns in large area which cannot be obtained even with conventional nanofabrication methods. We also have showed that the cracks are directly implementable into a nano/micro-channel application since the cracks naturally have a form of channel-like shape. PMID- 26612108 TI - A comparative modeling and molecular docking study on Mycobacterium tuberculosis targets involved in peptidoglycan biosynthesis. AB - An alarming rise of multidrug-resistant Mycobacterium tuberculosis strains and the continuous high global morbidity of tuberculosis have reinvigorated the need to identify novel targets to combat the disease. The enzymes that catalyze the biosynthesis of peptidoglycan in M. tuberculosis are essential and noteworthy therapeutic targets. In this study, the biochemical function and homology modeling of MurI, MurG, MraY, DapE, DapA, Alr, and Ddl enzymes of the CDC1551 M. tuberculosis strain involved in the biosynthesis of peptidoglycan cell wall are reported. Generation of the 3D structures was achieved with Modeller 9.13. To assess the structural quality of the obtained homology modeled targets, the models were validated using PROCHECK, PDBsum, QMEAN, and ERRAT scores. Molecular dynamics simulations were performed to calculate root mean square deviation (RMSD) and radius of gyration (Rg) of MurI and MurG target proteins and their corresponding templates. For further model validation, RMSD and Rg for selected targets/templates were investigated to compare the close proximity of their dynamic behavior in terms of protein stability and average distances. To identify the potential binding mode required for molecular docking, binding site information of all modeled targets was obtained using two prediction algorithms. A docking study was performed for MurI to determine the potential mode of interaction between the inhibitor and the active site residues. This study presents the first accounts of the 3D structural information for the selected M. tuberculosis targets involved in peptidoglycan biosynthesis. PMID- 26612109 TI - Chemo-enzymatic Baeyer-Villiger oxidation of 4-methylcyclohexanone via kinetic resolution of racemic carboxylic acids: direct access to enantioenriched lactone. AB - A new method for the asymmetric chemo-enzymatic Baeyer-Villiger oxidation of prochiral 4-methylcyclohexanone to (R)-4-methylcaprolactone in the presence of (+/-)-4-methyloctanoic acid, Candida Antarctica lipase B and 30% aq. H2O2 has been developed. A mechanism for the asymmetric induction based on kinetic resolution of racemic carboxylic acids is proposed. PMID- 26612110 TI - Evolutionary suicide through a non-catastrophic bifurcation: adaptive dynamics of pathogens with frequency-dependent transmission. AB - Evolutionary suicide is a riveting phenomenon in which adaptive evolution drives a viable population to extinction. Gyllenberg and Parvinen (Bull Math Biol 63(5):981-993, 2001) showed that, in a wide class of deterministic population models, a discontinuous transition to extinction is a necessary condition for evolutionary suicide. An implicit assumption of their proof is that the invasion fitness of a rare strategy is well-defined also in the extinction state of the population. Epidemic models with frequency-dependent incidence, which are often used to model the spread of sexually transmitted infections or the dynamics of infectious diseases within herds, violate this assumption. In these models, evolutionary suicide can occur through a non-catastrophic bifurcation whereby pathogen adaptation leads to a continuous decline of host (and consequently pathogen) population size to zero. Evolutionary suicide of pathogens with frequency-dependent transmission can occur in two ways, with pathogen strains evolving either higher or lower virulence. PMID- 26612111 TI - Can ferroelectric polarization explain the high performance of hybrid halide perovskite solar cells? AB - The power conversion efficiency of photovoltaic cells based on the use of hybrid halide perovskites, CH3NH3PbX3 (X = Cl, Br, I), now exceeds 20%. Recently, it was suggested that this high performance originates from the presence of ferroelectricity in the perovskite, which is hypothesized to lower charge recombination in the device. Here, we investigate and quantify the influence of mesoscale ferroelectric polarization on the device performance of perovskite solar cells. We implement a 3D drift diffusion model to describe the solar cell operation. To account for the mesoscale ferroelectricity, we incorporate domains defined by polarization strength, P, in 3D space, forming different polarization landscapes or microstructures. Study of microstructures with highly-ordered polarized domains shows that charge transport and recombination in the solar cell depends significantly on the polarization landscape viz. the orientation of domain boundaries and the size of domains. In the case of the microstructure with random correlated polarization, a realistic scenario, we find indication of the existence of channels for efficient charge transport in the device which leads to lowering of charge recombination, as evidenced by the high fill factor (FF). However, the high open-circuit voltage (VOC), which is typical of high performance perovskite solar cells, is unlikely to be explained by the presence of ferroelectric polarization in the perovskite. PMID- 26612112 TI - Tuneable endogenous mammalian target complementation via multiplexed plasmid based recombineering. AB - Understanding the quantitative functional consequences of human disease mutations requires silencing of endogenous genes and expression of mutants at close to physiological levels. Changing protein levels above or below these levels is also important for system perturbation and modelling. Fast design optimization demands flexible interchangeable cassettes for endogenous gene silencing and tuneable expression. Here, we introduce 'TEMTAC', a multigene recombineering and delivery system for simultaneous siRNA-based knockdown and regulated mutant (or other variant) expression with different dynamic ranges. We show its applicability by confirming known phenotypic effects for selected mutations for BRAF, HRAS, and SHP2. PMID- 26612113 TI - Identifying the temperamental roots of children's patterns of security in the interparental relationship. AB - Guided by emotional security theory, this study examined the temperamental precursors of distinctive profiles of children's responses to interparental conflict. Participants included 243 children (M = 4.6 years) and their parents across two annual measurement occasions. Temperamental constructs of frustration proneness, approach, positive affect, activity level, and effortful control were assessed through multiple methods, informants, and contexts. Behavioral observations of children's responses to interparental conflict at each wave yielded four profiles: secure (i.e., efficiently address direct threat), mobilizing (i.e., vigilance to potential threat and social opportunities), dominant (i.e., directly defeat threat), and demobilizing (i.e., reduce salience as a target of hostility). Results supported hypotheses on the distinct constellations of temperament in predicting subsequent change in the four security profiles. PMID- 26612114 TI - White bread enriched with polyphenol extracts shows no effect on glycemic response or satiety, yet may increase postprandial insulin economy in healthy participants. AB - Extracts from different plant sources have been shown to modify starch digestion from carbohydrate-rich foods and lower resulting glycemia. It was hypothesized that extracts rich in polyphenols, added to white bread, would improve the glycemic response and insulin response and increase satiety in healthy participants. An in vitro dose-response analysis was performed to determine the optimal dose of a variety of extracts (baobab fruit extract, green tea extract, grape seed extract, and resveratrol) for reducing rapidly digestible starch in white bread. The 2 extracts with the greatest sugar reducing potential were then used for the human study in which 13 volunteers (9 female and 4 male) were recruited for a crossover trial of 3 different meals. On separate days, participants consumed a control white bread, white bread with green tea extract (0.4%), and white bread with baobab fruit extract (1.88%). Glycemic response, insulin response, and satiety were measured 3 hours postprandially. Although enriched breads did not reduce glycemic response or hunger, white bread with added baobab fruit extract significantly (P < .05) reduced the total (0-180 minutes) and segmental insulin area under the curve at 0 to 90, 0 to 120, and 0 to 150 minutes, and therefore reduced the amount of insulin needed for a given blood glucose response. This preliminary research suggests that there is potential for baobab fruit extract added into white bread to improve insulin economy in healthy adults. PMID- 26612115 TI - Recurrence of Ovarian Endometrioma in Adolescents after Conservative, Laparoscopic Cyst Enucleation. AB - STUDY OBJECTIVE: To evaluate the cumulative recurrence rate of endometriomas after a laparoscopic endometriotic cyst enucleation in adolescents and to find the factors associated with recurrence. DESIGN: A multicenter retrospective cohort study. SETTING: Three university hospitals. PARTICIPANTS: One hundred five patients surgically treated with laparoscopic enucleation of endometriotic cysts younger than 20 years of age were selected. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Endometrioma recurrence was considered when transvaginal or transrectal sonography indicated a cystic mass with a diameter of 20 mm or greater. Recurrence rate of endometrioma and median time to recurrence were evaluated. RESULTS: In total, 105 patients were followed for 47.3 (+/-44.3) months (range, 3 161 months). Seventeen patients (16.2%) experienced recurrence after the first line surgery and 8 patients (7%) underwent a second surgery. The median time to recurrence was 53.0 (+/-8.5) months (range, 8-111 months). Using Kaplan-Meier method, the cumulative recurrence rates of endometrioma per patient at 24, 36, 60, and 96 months after the first-line surgery were 6.4%, 10%, 19.9% and 30.9%, respectively. Surgical characteristics, such as the diameter of the cyst, revised American Society for Reproductive Medicine stage, unilateral or bilateral involvement, and coexistence of deep endometriosis were not associated with recurrence in this age group. CONCLUSION: Although the short-term recurrence rate in adolescents after first-line surgery is relatively low, the recurrence rate appears to be higher according to the follow-up duration. Long-term and continuous follow-up is needed for patients who have undergone surgical treatment for endometriosis in the adolescent period. PMID- 26612116 TI - Knowledge of Human Papillomavirus and Acceptability to Vaccinate in Adolescents and Young Adults of the Moroccan Population. AB - STUDY OBJECTIVE: Human papillomavirus (HPV) infection is estimated to play an etiologic role in 99.7% of cervical cancer. Vaccines can prevent up to 70% of the cervical cancer caused by HPV 16 and 18. The present study was designed to define the knowledge of HPV and HPV vaccine acceptability among Moroccan youth. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: A nationwide anonymous questionnaire with a sample of 688 adolescents (12-17 years) and 356 young adults (18-30 years) was organized, that asked about HPV, origin of cervical cancer, Papanicolaou (Pap) test, and acceptability of HPV vaccine. Data were analyzed using univariate and multivariate logistic regression methods. RESULTS: Overall, a low frequency (213/1044 = 20%) of HPV knowledge was observed among the studied population. A multivariate model analysis showed that age, educational level, and knowledge of the Pap test remained significantly associated factors with HPV knowledge. Additionally, only 27% (282/1044) of participants were willing to accept HPV vaccination. Highest acceptability was observed among young adults compared with adolescents (166/356 = 46.6% vs 116/688 = 16.9%). Sixty-two percent (103/165) of male participants accepted the HPV vaccine compared with only 20.4% (179/879) of female participants. Educational level, type of school, and knowledge of the Pap test were associated factors with HPV vaccine acceptability in a multivariate model analysis. CONCLUSION: The present study showed a low level of HPV knowledge and HPV vaccine acceptability among Moroccan youth. Promotion of activities and sensitization are required to maximize public awareness in the future. This objective can be achieved with the use of media, active efforts by health care providers, and introduction of sexual education in school programs. PMID- 26612117 TI - Using Individualized Learning Plans to Facilitate Learner-Centered Teaching. AB - Individualized learning plans (ILPs) are helpful tools that can facilitate learner-centered education and can be used with all levels of learners. We introduce the concept of ILPs, the rationale for their use in pediatric and adolescent gynecology education, and review the challenges that learners might face in creating ILPs, and describes how educators can support learners during this process. PMID- 26612118 TI - Treatment of Acute Abnormal Uterine Bleeding in Adolescents: What Are Providers Doing in Various Specialties? AB - STUDY OBJECTIVE: The purpose of this study was to assess whether variability exists in the management of acute abnormal uterine bleeding (AUB) in adolescents between pediatric Emergency Department (ED) physicians, pediatric gynecologists, and adolescent medicine specialists. DESIGN: Retrospective chart review. SETTING: Tertiary care medical center ED. PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: We included girls aged 9-22 years who presented from July 2008 to June 2014 with the complaint of acute AUB. Patients were identified using the International Classification of Diseases, ninth revision codes for heavy menstrual bleeding, AUB, and irregular menses. Exclusion criteria included pregnancy and current use of hormonal therapy. One hundred fifty patients were included. RESULTS: Among those evaluated, 61% (n = 92) were prescribed hormonal medication to stop their bleeding by providers from the ED, Adolescent Medicine, or Pediatric Gynecology. ED physicians prescribed mostly single-dose and multidose taper combined oral contraceptive pills (85%; n = 24), compared with Adolescent Medicine (54%, n = 7), and Gynecology (28%, n = 13). Pediatric gynecologists were more likely than ED physicians to treat patients with norethindrone acetate, either alone or in combination with a single dose combined oral contraceptive pill (61%, n = 33 vs 7%, n = 2; P < .001). CONCLUSION: Variations in treatment strategies for adolescents who present with acute AUB exist among pediatric specialties, which reflects a lack of standardized care for adolescents. Prospective evaluation of the shortest interval to cessation of bleeding, side effects, and patient satisfaction are valuable next steps. PMID- 26612119 TI - Radiographic signs of gastrointestinal perforation in children: A pictorial review. AB - Plain abdominal radiographs remain an important aid for clinicians in the diagnosis of gastrointestinal perforation, especially in neonates and very sick children where clinical features of peritonitis may not be as prominent. Suggestive radiographic features are not always very obvious, especially when taken in the supine position and may lead to delayed or missed diagnosis. Through a pictorial review of plain radiographs, this article highlights a number of documented features of gastrointestinal perforation on X-ray in the paediatric setting, which increases the accuracy of diagnosis. PMID- 26612120 TI - Masterly inactivity in infantile haemangioma: Does it still hold relevance? AB - BACKGROUND: Haemangiomas are a source of concern to the parents. It has long been advised to plan a conservative management and counsel the attendants in various literatures owing to the spontaneous regression in these cases. We tried to find out the role of conservative management in our setup. The objective of this study was to assess the effect of conservative management in infantile haemangiomas. MATERIALS AND METHODS: This was a retrospective study from January 2001 to December 2012 including infants with haemangioma in low risk locations. Patients were evaluated at periodic intervals for regression and complications. Interventions done were surgical excision/ cauterisation in cases presenting with complications in the form of bleed or severe ulceration or in residual lesion not responding to the conservative management. RESULTS: A total of 104 cases were included. Mean age of the cases at presentation was 32 weeks (range: 6-48 weeks). Mean follow-up was 48 months (range: 9-68 months). Average lesion size at the time of presentation was 4.2 +/- 0.5 cm 2 and the average lesion size at last presentation was 1.8 +/- 0.5 cm 2 . A total of 28 cases presented with complications as bleed, ulceration. These cases were located at extremities and were managed by excision in 13 cases and cauterisation in 15 cases. 13 cases presented with rapid proliferation. Thus, 41 (39.4%) cases presented with complications or rapid progression. Complete regression was seen in 49 cases and remaining 14 (22.2%) cases had some residual lesion. CONCLUSIONS: Conservative management should be offered only to very small lesions located at concealed sites. Lesions located at extremities and exposed sites should not be considered for conservative management. PMID- 26612121 TI - Wilms' tumour: Determinants of prognosis in an African setting. AB - BACKGROUND: The few studies available in the literature on Wilms' tumour (WT) from sub-Saharan Africa have reported a dismal outcome for children with the tumour. This study evaluated the risk factors that have been correlated with outcome in the literature and compare these with outcome among our patients. MATERIALS AND METHODS: Cases of histologically confirmed WT between 2009 and 2013 in a tertiary hospital in Northwestern Nigeria were evaluated for gender, age, laterality, symptoms, duration before presentation, stage at presentation, histologic subtype and p53 mutation. These were then correlated with outcome. RESULTS: Totally, 30 cases of WT were diagnosed with mean age of 4.8 +/- 1.9 years; and male:female ratio of 2:1. No statistically significant relationship with outcome was found for gender (P = 0.138) or histologic subtype (P = 0.671). The most significant variables which positively influenced the outcome were presentation at earlier stages (P = 0.007) and completion of therapy (P = 0.0007). p53 mutation was seen in 3 (16.7%) of 18 cases and was not associated with a poor outcome (P = 0.089). However, 2 of the 3 cases presented in Stage IV and none of them survived the 1 st year. CONCLUSION: This study shows that even though p53 mutation was associated with a more aggressive phenotype, the most significant determinants of a good outcome among patients in a developing country like ours is non-blastemal dominant histologic subtype, early stage at presentation and completion of therapy. PMID- 26612123 TI - Traumatic chest injury in children: A single thoracic surgeon's experience in two Nigerian tertiary hospitals. AB - BACKGROUND: This study was to determine the extent and outcome of childhood chest injury in Nigeria, and to compare results with that of other literatures. PATIENTS AND METHODS: A Prospective study of all children under 18 years of age with chest trauma in two tertiary hospitals in Southern Nigeria from January 2012 to December 2014 was reviewed. The aetiology, type, associated injury, mechanism, treatment and outcome were evaluated. The patients were followed up in the clinic. The data were analysed using SPSS version 20.0 with a significant P < 0.05. RESULTS: Thirty-one patients (12.1%) under 18 years of age of 256 chest trauma patients were managed in the thoracic units. The mean age was 9.78 +/- 6.77 years and 27 (87.1%) were male. The aetiology in 13 was from falls, 10 from automobile crashes, 3 from gunshots, 4 from stabbing and 1 from abuse. The highest peak of chest injury was on Saturday of the week and April of the year. The pleural collections are as follows: 15 (71.4%) was haemothorax, 4 (19.1%) pneumothorax, 2 (9.5%) haemopneumothorax and 18 patients had lung contusion in combination or alone with the pleural collections. Seven patients who presented >12-h versus 2 who presented <12-h and 6 of children between 0 and 9 years versus 3 at 10-18 years of age had empyema thoracis (P value not significant). One death was recorded. CONCLUSION: Chest trauma in children is still not common, and blunt chest injury from falls and automobile accidents are more common than penetrating chest injury. Treatment with tube thoracostomy is the major management modality with empyema thoracis as the most common complication. PMID- 26612122 TI - Laparoscopic-assisted vaginal pull-through: A new approach for congenital adrenal hyperplasia patients with high urogenital sinus. AB - BACKGROUND: To open vaginal cavity to the pelvic floor is part of surgical treatment for urogenital sinus (UGS) in girls with congenital adrenal hyperplasia (CAH). For high UGS, this operative procedure can be challenging and may jeopardise urinary continence. Combined perineal and laparoscopic approaches could be useful to minimise perineal dissection and to facilitate the vaginal lowering. PATIENTS AND METHODS: We report the procedure of a laparoscopic assisted vaginal pull-through for supra-sphincteric UGS in a 5-year-old girl with CAH. Laparoscopic dissection of the vagina from the posterior wall of the bladder and urethra, division of the confluence and vaginal pull-through to the perineum are described. DISCUSSION: The technique is derived from laparoscopic-assisted treatment for high ano-rectal malformations. Compared with current procedures for treatment for high UGS, laparoscopic-assisted approach allows mobilising vagina with minimal dissection of perineum and complete preservation of urethra. Another major advantage is to provide a direct vision for dissection of the space between rectum and urethra prior to vaginal pull-through. CONCLUSION: Laparoscopic assisted vaginal pull-through appears to be an interesting approach for high UGS in CAH patients, reducing dissection and risk of urinary incontinence. This new approach needs to be strengthened by other cases. PMID- 26612124 TI - Oesophageal atresia: Diagnosis and prognosis in Dakar, Senegal. AB - BACKGROUND: Oesophageal atresia is a neonatal emergency surgery whose prognosis has improved significantly in industrialised countries in recent decades. In sub Saharan Africa, this malformation is still responsible for a high morbidity and mortality. The objective of this study was to analyse the diagnostic difficulties and its impact on the prognosis of this malformation in our work environment. PATIENTS AND METHODS: We conducted a retrospective study over 4 years on 49 patients diagnosed with esophageal atresia in the 2 Paediatric Surgery Departments in Dakar. RESULTS: The average age was 4 days (0-10 days), 50% of them had a severe pneumonopathy. The average time of surgical management was 27 h (6-96 h). In the series, we noted 10 preoperative deaths. The average age at surgery was 5.7 days with a range of 1-18 days. The surgery mortality rate is 28 patients (72%) including 4 late deaths. CONCLUSION: The causes of death were mainly sepsis, cardiac decompensation and anastomotic leaks. PMID- 26612125 TI - A conservative approach in a child with haematuria after accidental rectal impalement trauma. AB - We present a case of an 11-year-old boy with haematuria after traumatic rectal insertion of a sharp metal stick. It demonstrates that an expectative management with close observation can be considered in patients with rectal impalement trauma presenting with haematuria and stable vital parameters without significant injury on abdominal ultrasound. PMID- 26612126 TI - Visceral basidiobolomycosis: An overlooked infection in immunocompetent children. AB - Visceral basidiobolomycosis is an unusual fungal infection of viscera caused by saprophyte Basidiobolus ranarum. It is very rare in healthy children and poses a diagnostic challenge due to the non-specific clinical presentation and the absence of predisposing factors. We report a case of gastrointestinal basidiobolomycosis in a 4-year-old healthy girl who presented with a short history of abdominal pain, bleeding per rectum, fever, and weight loss. The diagnosis was based on high eosinophilic count, classical histopathology findings of fungal hyphae (the Splendore-Hoeppli phenomenon), and positive fungal culture from a tissue biopsy. Fungal infection was successfully eradicated with a combined approach of surgical resection of the infected tissue and a well monitored course of antifungal therapy. The atypical clinical presentation, diagnostic techniques, and the role of surgery in the management of a rare and lethal fungal disease in an immunocompetent child are discussed. PMID- 26612127 TI - Laparoscopic suture repair of idiopathic gastric perforation in Duchenne muscular dystrophy. AB - We report herein an adolescent case of Duchenne muscular dystrophy (DMD) with idiopathic gastric perforation, in which emergency surgical repair was performed laparoscopically. A 14-year-old nonambulatory boy with DMD was brought to our emergency department with sudden onset of severe abdominal pain and distention. Plain radiograph and computed tomography confirmed the presence of free intraperitoneal air and intrapelvic effusion. The patient elected to undergo laparoscopic inspection with 4 trocars, revealing a focal perforation, 3-4 cm in diameter, on the upper gastric body near the diaphragm. The stomach was also found to have a thin wall without evidence of peptic ulcer disease or other abnormalities. An interrupted suture was placed using 4-0 PDS. The abdomen was extensively irrigated, and multiple J-Vac drains were left in situ. Total operation time was 90 min, and no intraoperative complications were encountered. Enteral feeding through a nasogastric tube was started on postoperative day 7. The postoperative course has been uneventful as of the 12-month follow-up. Pediatric surgeons should be aware of the increased risk of gastric perforation associated with DMD, and that laparoscopic repair can be safely performed even in emergency settings. PMID- 26612128 TI - Acute gastric volvulus and congenital diaphragmatic hernia, case report and review. AB - Congenital diaphragmatic hernia (CDH) is the result of the incomplete fusion and closure of the pleuroperitoneal canal during the fetal development. CDH is usually diagnosed prenatally but, if undiagnosed, the clinical presentation ranges from asymptomatic children to serious respiratory or gastrointestinal symptoms. Acute gastric volvulus associated with CDH is a rare surgical emergency in children. We report two cases of acute gastric volvulus associated with CDH and review the literature. PMID- 26612130 TI - Wilms' tumour and chemotherapeutic access. PMID- 26612129 TI - Congenital mesenteric hernia in neonates: Still a dilemma. AB - Congenital transmesenteric hernia in neonates is a rare cause of intestinal obstruction with devastating outcomes and still remains a challenge to diagnose pre-operatively. Patients are often managed with emergency surgical exploration and may need bowel resection. We present 2 neonates with small bowel obstruction secondary to strangulated transmesenteric hernia through a congenital defect in the small bowel mesentery, which were managed successfully. We have also reviewed the literature about congenital transmesenteric hernia in neonates. PMID- 26612131 TI - Childhood non-accidental traumatic brain injuries. PMID- 26612132 TI - Massive purulent pericarditis in HIV-infected children. PMID- 26612133 TI - Increased risks between Interleukin-10 gene polymorphisms and haplotype and head and neck cancer: a meta-analysis. AB - Molecular epidemiological research suggests that interleukin-10 (IL-10) polymorphisms may be associated with an increased risk of head and neck cancer (HNC), but results remain controversial. To derive a more precise evaluation, we performed a meta-analysis focused on genetic polymorphisms of IL-10. PubMed, Embase, CNKI and Wanfang databases were searched for studies that examined the relationship between IL-10 polymorphisms or haplotypes and HNC risk. The odds ratio (OR) and 95% confidence interval (CI) were applied to assess the relationship strength. Publication bias, sensitivity and cumulative analyses were conducted to measure the robustness of our findings. Overall, nine related studies involving 2,258 patients and 2,887 control samples were analyzed. Significant associations between the IL-10-1082A > G polymorphism and HNC risk were observed (G vs. A: OR = 1.56, 95% CI = 1.27-1.92, P < 0.01, I(2) = 69.4%; AG vs. AA: OR = 1.64, 95% CI = 1.32-2.05, P < 0.01, I(2) = 55.6%; GG vs. AA: OR = 2.24, 95% CI = 1.69-2.97, P < 0.01, I(2) = 38.5%; AG + GG vs. AA: OR = 1.70, 95% CI = 1.36-2.14, P = 0.02, I(2) = 61.8%; GG vs. AA + AG: OR = 1.89, 95% CI = 1.23 2.90, P = 0.01, I(2) = 46.3%) in the total population, as well as in subgroup analysis. Moreover, increased HNC risks were also associated with the IL-10 -819T > C polymorphism and the GCC haplotype. In conclusion, our meta-analyses suggest that IL-10 polymorphisms, specifically the -1082A > G polymorphism, may be associated with increased risk of HNC development. PMID- 26612134 TI - LY2603618, a selective CHK1 inhibitor, enhances the anti-tumor effect of gemcitabine in xenograft tumor models. AB - Pharmacological inhibition of CHK1 in the absence of p53 functionality leads to abrogation of the S and G2/M DNA damage checkpoints. We report the preclinical therapeutic activity of LY2603618 (CHK1 inhibitor) at inhibiting CHK1 activation by gemcitabine and enhancing in vivo efficacy. The in vivo biochemical effects of CHK1 inhibition in the absence or presence of DNA damage were measured in human tumor xenograft models. Colon, lung and pancreatic xenografts models were treated with gemcitabine, LY2603618, or gemcitabine plus LY2603618. Gemcitabine treatment alone induced a significant increase in CHK1 autophosphorylation over untreated tumors. Co-administration of LY2603618 with gemcitabine showed a clear inhibition of CHK1 autophosphorylation for at least 24 h. Combining LY2603618 with gemcitabine resulted in an increase in H2AX serine 139 phosphorylation, indicating a corresponding increase in damaged DNA in the tumors. LY2603618 abrogated the S-phase DNA damage checkpoint in Calu-6 xenograft tumors treated with gemcitabine but did not significantly alter the G2/M checkpoint. Combining gemcitabine with LY2603618 resulted in a significant increase in tumor growth inhibition in Calu-6, HT-29 and PAXF 1869 xenografts over gemcitabine treatment alone. The best combination efficacy occurred when LY2603618 was given 24 h following dosing with gemcitabine. LY2603618 worked effectively to remove the S phase DNA damage checkpoint and increase the DNA damage and the antitumor activity of gemcitabine treatment. PMID- 26612135 TI - Patient-reported quality of life after primary major joint arthroplasty: a prospective comparison of hip and knee arthroplasty. AB - BACKGROUND: To investigate and compare the impact of primary hip (THA) and knee (TKA) arthroplasty on quality of life in patients with osteoarthritis, to determine patients' satisfaction with total joint arthroplasty, and to detect the effect of patients' demographic and clinical characteristics on outcome. METHODS: Three hundred seventy eight (378) patients with hip (174) and knee (204) osteoarthritis undergoing total joint arthroplasty (174 THA-204 TKA) were assessed pre- and post-operatively (6 weeks, 3, 6, and 12 months) using the Western Ontario and McMaster Osteoarthritis Index (WOMAC) and Centre for Epidemiological Studies Depression Scale (CES-D10). The patients' satisfaction with the results of total joint arthroplasty was also assessed. Differences were analyzed using general linear model for repeated measures. RESULTS: The one-year response rate was 97 % for THA and 90 % for TKA. WOMAC and CES-D10 scores improved significantly after one year for both THA and TKA (P < 0.0001). The improvement in WOMAC total score was significantly greater for TKA patients (P < 0.0001 at 12 months). WOMAC pain and stiffness improved earlier for THA (6 weeks), while TKA had equivalent improvements at 3 and 6 months respectively. Both THA/TKA displayed significant improvement of WOMAC function at 3 months but TKA had greater improvement. Age, body mass index, residence, education and social support were not significant predictors of quality of life after total joint arthroplasty. One year postoperatively 88 % of patients were satisfied. CONCLUSIONS: WOMAC and CES-D10 improved significantly one year postoperatively. Although pain and stiffness improved earlier in THA, functional improvement was inferior in THA compared to TKA. PMID- 26612136 TI - Lachnotalea glycerini gen. nov., sp. nov., an anaerobe isolated from a nanofiltration unit treating anoxic groundwater. AB - A strictly anaerobic bacterium, strain DLD10T, was isolated from a biofilm that developed on a nanofiltration membrane treating anoxic groundwater using glycerol as substrate. Cells were straight to slightly curved rods 0.2-0.5 MUm in diameter and 1-3 MUm in length, non-motile and non-spore-forming. The optimum temperature and pH for growth were 30 degrees C and pH 7.0. Strain DLD10T was able to grow in the presence of 0.03-4.5 % (w/v) NaCl. Substrates utilized by strain DLD10T included glycerol and various carbohydrates (glucose, sucrose, fructose, mannose, arabinose, pectin, starch, xylan), which were mainly converted to ethanol, acetate, H2 and formate. Thiosulphate, sulphur and Fe(III) were used as electron acceptors, but sulphate, fumarate and nitrate were not. The predominant membrane fatty acids were C16 : 0, iso-C17 : 1 and C17 : 1omega8c. The DNA G+C content was 36.4 mol%. Strain DLD10T belongs to the family Lachnospiraceae and is distantly related to Clostridium populeti DSM 5832T, Hespellia porcina DSM 15481T and Robinsoniella peoriensis CCUG 48729T (93 % 16S rRNA gene sequence similarity). Physiological characteristics and phylogenetic analysis indicated that strain DLD10T is a representative of a novel species of a new genus, for which the name Lachnotalea glycerini gen. nov., sp. nov. is proposed. The type strain of Lachnotalea glycerini is DLD10T ( = DSM 28816T = JCM 30818T). PMID- 26612137 TI - Special issue on emerging technologies for the management of diabetes mellitus. PMID- 26612138 TI - A novel algorithm for analyzing drug-drug interactions from MEDLINE literature. AB - Drug-drug interaction (DDI) is becoming a serious clinical safety issue as the use of multiple medications becomes more common. Searching the MEDLINE database for journal articles related to DDI produces over 330,000 results. It is impossible to read and summarize these references manually. As the volume of biomedical reference in the MEDLINE database continues to expand at a rapid pace, automatic identification of DDIs from literature is becoming increasingly important. In this article, we present a random-sampling-based statistical algorithm to identify possible DDIs and the underlying mechanism from the substances field of MEDLINE records. The substances terms are essentially carriers of compound (including protein) information in a MEDLINE record. Four case studies on warfarin, ibuprofen, furosemide and sertraline implied that our method was able to rank possible DDIs with high accuracy (90.0% for warfarin, 83.3% for ibuprofen, 70.0% for furosemide and 100% for sertraline in the top 10% of a list of compounds ranked by p-value). A social network analysis of substance terms was also performed to construct networks between proteins and drug pairs to elucidate how the two drugs could interact. PMID- 26612139 TI - Diabetes mellitus and venous thromboembolism: A systematic review and meta analysis. AB - Diabetes mellitus (DM) may be a risk factor for venous thromboembolism (VTE) but results are inconsistent. AIM: We conducted a systematic review and meta-analysis of epidemiologic studies to quantify the association between DM and VTE. METHODS AND RESULTS: We included studies identified in PubMed, Web of Science, and CINAHL through 07/31/2014. We identified 19 studies that met our selection criteria. We pooled RRs using a random-effects model: the pooled RR for the association of DM with VTE was 1.10 (95% CI: 0.94-1.29). Between-study heterogeneity was explored with a forest plot, funnel plot, meta-regression, and a stratified analysis. Between-study heterogeneity was observed and not explained by study design, method of DM assessment, or degree of adjustment for confounding. Sensitivity analyses omitted one study at a time to assess the influence of any single study on the pooled estimate. These analyses indicated that one large study was highly influential; when this study was excluded, the pooled estimate increased and just reached statistical significance: 1.16 (95% CI: 1.01-1.34). CONCLUSIONS: This meta-analysis suggests either no association or a modest positive one between DM and VTE in the general population. DM is unlikely to play a major role in VTE development. PMID- 26612140 TI - Preregistration nursing students' perspectives on the learning, teaching and application of bioscience knowledge within practice. AB - AIMS AND OBJECTIVES: This paper aims to explore student nurses' experiences of bioscience learning, teaching and application within the practice setting. It draws upon the social learning theory of communities of practice to consider the issues raised. BACKGROUND: The teaching of bioscience within many nursing curricula has shifted from traditional to more integrated approaches. Student nurses recognise bioscience as a valuable component of their studies, but many find it challenging. The focus of previous research in this area has often focussed on bioscience learning in theoretical rather than practice settings. DESIGN: A phenomenological study. METHODS: Data were collected via focus group or interview with a total of seven students across two campuses in a Scottish university. Participants were offered the opportunity to share their experiences at both the end of year one and year two of their studies. A thematic analysis was undertaken independently then jointly by the authors. RESULTS: The findings suggest that although participants recognise the value of bioscience within practice settings, they found that opportunities for learning were often limited. Bioscience-related learning, teaching and application was perceived to have been given less legitimacy by the practice setting than other aspects of placement activity. To enhance bioscience approaches participants expressed a desire for more structured and integrated approaches within both practice and university along with further peer learning opportunities. CONCLUSIONS: Students recognise that bioscience knowledge is important in relation to the provision of safe and effective care. They request greater structure and consistency in relation to the learning, teaching and application of this topic during their placements. RELEVANCE TO CLINICAL PRACTICE: Those with a stake in educating nurses within clinical settings may find the views of student nurses on the topic of bioscience learning useful when planning and facilitating placement experiences. PMID- 26612141 TI - Resonant energy transfer between patterned InGaN/GaN quantum wells and CdSe/ZnS quantum dots. AB - We explore an easy method for preparation of a hybrid device of a photonic crystal InGaN/GaN quantum well (QW) and colloidal quantum dots using conventional photolithography. It is demonstrated from electroluminescence spectra that Forster resonance energy transfer takes place efficiently between the photonic crystal InGaN/GaN QW and CdSe/ZnS colloidal quantum dots. From the photoluminescence decay of the InGaN/GaN QW, the largest Forster resonance energy transfer efficiency between the photonic crystal GaN quantum well and colloidal quantum dots is measured as 88% and the corresponding Forster-resonance-energy transfer fraction reached 42%. An easy approach is explored to realize a highly efficient electrically driven colloidal quantum dot device using the Forster resonance-energy-transfer mechanism. PMID- 26612142 TI - Development of an immunochromatographic test strip for simultaneous qualitative and quantitative detection of ochratoxin A and zearalenone in cereal. AB - BACKGROUND: Ochratoxin A (OTA) and zearalenone (ZEN) are natural products of filamentous fungi that are harmful to humans and animals exposed to them even in extremely low concentration. The immunochromatographic test strip has become a popular diagnostic tool for detecting analytes. Its major advantages are that results can be obtained within 5-10 min, all needed reagents are included in the strip and it can be used to detect OTA and ZEN contamination in spots. In this study a colloidal gold-based immunochromatographic test strip of competitive format was developed for the rapid simultaneous qualitative and quantitative detection of OTA and ZEN in corn and other cereals. RESULTS: The test strip results with the naked eye showed that the sensitivities were 6 ug kg(-1) OTA and 20 ug kg(-1) ZEN in cereal, while those with a TSR3000 membrane strip reader showed that the IC50 values of OTA and ZEN were 1.7905 and 4.3514 ng mL(-1) and the lower detection limit (LDL) values were 0.7697 and 1.2000 ug kg(-1) respectively. These results were confirmed by high-performance liquid chromatography. CONCLUSION: The immunochromatographic test strip developed in this study could be used for the rapid simultaneous, qualitative and quantitative screening of OTA and ZEN in corn samples. (c) 2015 Society of Chemical Industry. PMID- 26612143 TI - Outcomes of ventricular assist device implantation in children and young adults: the Melbourne experience. AB - BACKGROUND: We evaluated our experience with ventricular assist device (VAD) implantation in children and young adults. METHODS: A total of 64 patients underwent VAD implantation in two centres. The mean age was 15 +/- 7.2 years. Thirty-five (55%) patients were under 18 years of age. Devices implanted included the Thoratec Paracorporeal in 30 (47%) patients, Berlin Heart EXCOR in 11 (17%) and VentrAssist in 14 (22%). The diagnosis was cardiomyopathy in 53, congenital heart disease in 11, and graft failure in four patients. RESULTS: There were 10 (16%) in-hospital deaths. Mortality was higher in patients <18 years of age (26% compared with 3.4% for those >=18 years, P = 0.02). The use of extracorporeal membrane oxygenation prior to VAD implantation was associated with higher mortality (P = 0.006). Seventeen (27%) patients experienced stroke. Nine patients (14%) required change of VAD because of thrombosis. Transplantation was performed in 44 patients after a mean of 131 +/- 141 days on VAD, 11 patients died without transplantation and three patients currently await transplantation. The VAD was explanted in six patients because of recovery. Overall survival from VAD implantation was 69% and 61% at 5 and 10 years, respectively. The 5-year post transplant survival for those bridged with VAD support was 91% and was comparable with a cohort of patients who did not receive a pre-transplant VAD. CONCLUSIONS: Children requiring pre-transplant VAD support have a higher mortality and morbidity compared with young adults. Survival after heart transplantation those supported with VADs was similar to patients of similar age who did not require pre-transplant support. PMID- 26612144 TI - Streptomyces lactacystinicus sp. nov. and Streptomyces cyslabdanicus sp. nov., producing lactacystin and cyslabdan, respectively. AB - Correction to: The Journal of Antibiotics (2015) 68, 322-327; doi:10.1038/ja.2014.162; published online 10 December 2014. The authors of the above article noticed following error in the publication of this paper. In the Abstract and the "Description of Streptomyces lactacystinicus sp. nov." sub section under the Results and Discussion section, DSM number for strain OM-6519T was wrong. It should have been read OM-6519T (=NBRC 110082T, DSM 42136T). Authors apologize for this mistake. PMID- 26612145 TI - Teaching Bioethics in India. PMID- 26612146 TI - Neonatal Vitamin A Supplementation for Improving Infant Survival:Hope or hype? PMID- 26612147 TI - Multiskills training of medical doctors in India: Experience from Rajasthan. AB - BACKGROUND: The Government of India has been conducting multiskills training programmes to address the shortage of specialized human resources in gynaecology and anaesthesia for maternal and child healthcare. There has been little evaluation of the operation of these programmes, though several years have passed since their introduction. METHODS: We did a cross-sectional study to assess some aspects of the multiskills training programmes in gynaecology and anaesthesia, and the utilization of human resources trained under this scheme in Rajasthan. The analysis was primarily based on a review of records of postings of doctors obtained from the Department of Health and Family Welfare, Government of Rajasthan. Information was also obtained through qualitative interviews with 122 doctors from 14 districts of the state, irrespective of their training status. RESULTS: In 2012, a total of 302 anaesthetists and 480 gynaecologists were posted in various public health facilities in Rajasthan. Of these, 128 (42%) anaesthetists and 69 (14.4%) gynaecologists had received multiskills training. However, only 57% of trained doctors were posted at health facilities for which they were trained. The acceptance of multiskills training among doctors was found to be low. CONCLUSION: Posting and deployment of personnel who had received multiskills training was often inappropriate, leading to suboptimal utilization of the skills acquired during such training and suboptimal delivery of public health services. Accreditation of the multiskills training programmes by regulatory bodies such as the Medical Council of India may improve the acceptance of such training among MBBS doctors and their colleagues. There is a need to review multiskills training programmes. PMID- 26612148 TI - Health issues of sanitation workers in a town in Karnataka: Findings from a lay health-monitoring study. AB - BACKGROUND: Official estimates are not available for mortality or morbidity among sanitation workers (including manual scavengers) in India. Little is known about their health issues and health-seeking behaviour in the context of their occupational hazards (work practices and exposures). We attempted to understand the nature of health problems of sanitation workers using a lay epidemiological process. METHODS: A community-based organization working in Chitradurga town in Karnataka for the development of sanitation workers recorded the health problems of workers and their treatment-seeking practices every month using a health monitoring tool. We used a lay epidemiological approach to identify occupational health problems and deficiencies in healthcare access through the narrative of workers' perceptions of their illness. Descriptive analysis was done to map the occupational health status, healthcareseeking practices and the social support mechanisms in place. RESULTS: Injuries and chest pain were the most commonly reported illnesses. Most workers continued to work without appropriate treatment as they ignored their illness, and did not want to miss their wages or lose their job. Self-medication was common. Intake of alcohol was prevalent to cope with the inhuman task of cleaning filthy sewage, and as a modality to forget their health problems. The pattern of illnesses reported during monthly monitoring was also reported as long-standing illnesses. Health and safety mechanisms at workplace did not exist and were not mandated by regulatory bodies. CONCLUSION: Health and safety of sanitation workers has been inadequately addressed in public health research. Sanitation work lacks specific protective regulatory guidelines to address health hazards unlike other hazardous occupations. PMID- 26612149 TI - Cowden syndrome with Lhermitte- Duclos disease presenting as ataxia. AB - Cowden syndrome or multiple hamartoma syndrome is a rare genodermatosis of autosomal dominant inheritance characterized by multiple hamartomatous lesions of ectodermal, mesodermal and endodermal origin. A 45-year-old man presented to us with a history of dural arteriovenous fistula and intracerebral bleed in the past with gradually progressive difficulty in walking. Magnetic resonance imaging (MRI) of the brain showed a heterogeneous lesion in the cerebellum which was diagnosed as adult Lhermitte-Duclos disease which is considered a component of Cowden syndrome. On examination we found florid skin and mucosal manifestations of Cowden syndrome. A family history of thyroid malignancy was also present. Using the Cleveland Clinic web calculator, the patient had an 82% chance of having a phosphatase and tensin homologue (PTEN) mutation. PMID- 26612150 TI - Cardiopulmonary resuscitation (CPR) in out-ofhospital cardiac arrest: Man or machine? PMID- 26612151 TI - Proton pump inhibitors and bleeding ulcers. PMID- 26612152 TI - Challenges in scaling up successful public health interventions: Lessons learnt from resistance to a nationwide roll-out of the weekly iron-folic acid supplementation programme for adolescents in India. PMID- 26612153 TI - Tobacco control in India: A case for the Health-in-All Policy approach. PMID- 26612154 TI - Sickle cell anaemia: The need for new approaches in management. AB - Sickle cell anaemia is an important genetic disorder in India and is associated with considerable morbidity and mortality. Over 100 000 people are affected by this disorder and 10%-40% of the 85 million tribal population carries this gene. Conventional management and therapy with hydroxyurea provides symptomatic relief. A search for an anti-sickling agent has so far proved unsuccessful. However, improving upon existing compounds; looking for newer products using modern tools of bioinformatics, monoclonal antibody and aptamer technology; and evaluating medicines from ethno-pharmacology are promising approaches in managing this disease. PMID- 26612155 TI - Manjunath. PMID- 26612156 TI - Lieutenant General (Retd) Anand Mohan Ahuja. PMID- 26612158 TI - Letter from Glasgow. PMID- 26612164 TI - Journal-reading habits of undergraduate medical students. PMID- 26612165 TI - Clerkship in paediatrics to enhance competency among undergraduates: An experience. PMID- 26612166 TI - Malignant hyperthermia in a young adolescent in Singapore. PMID- 26612167 TI - Authors' reply. PMID- 26612168 TI - A rare case of lymphatic filariasis from Sikkim. PMID- 26612169 TI - Courvoisier sign. PMID- 26612176 TI - In vitro follicle growth supports human oocyte meiotic maturation. AB - In vitro follicle growth is a potential approach to preserve fertility for young women who are facing a risk of premature ovarian failure (POF) caused by radiation or chemotherapy. Our two-step follicle culture strategy recapitulated the dynamic human follicle growth environment in vitro. Follicles developed from the preantral to antral stage, and, for the first time, produced meiotically competent metaphase II (MII) oocytes after in vitro maturation (IVM). PMID- 26612177 TI - In-vitro cytotoxicity assessment of carbon-nanodot-conjugated Fe-aminoclay (CD FeAC) and its bio-imaging applications. AB - We have investigated the cytotoxic assay of Fe-aminoclay (FeAC) nanoparticles (NPs) and simultaneous imaging in HeLa cells by photoluminescent carbon nanodots (CD) conjugation. Non-cytotoxic, photostable, and CD NPs are conjugated with cationic FeAC NPs where CD NPs play a role in bio-imaging and FeAC NPs act as a substrate for CD conjugation and help to uptake of NPs into cancer cells due to positively charged surface of FeAC NPs in physiological media. As increase of CD FeAC NPs loading in HeLa cell in vitro, it showed slight cytotoxicity at 1000 MUg/mL but no cytotoxicity for normal cells up to concentration of 1000 MUg/mL confirmed by two 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and neutral red (NR) assays, with further observations by 4',6-diamidino-2 phenylindole (DAPI) stained confocal microscopy images, possessing that CD-FeAC NPs can be used as potential drug delivery platforms in cancer cells with simultaneous imaging. Graphical abstract CD conjugation with organo-building blocks of delaminated FeAC NPs. PMID- 26612179 TI - Percutaneous cholecystostomy is safe and effective option for acute calculous cholecystitis in select group of high-risk patients. AB - PURPOSE: In high-risk patients with acute calculous cholecystitis (ACC), percutaneous cholecystostomy (PC) can serve as a bridging option to cholecystectomy [laparoscopic cholecystectomy (LC)] or as definitive treatment. The purpose of this study was to identify predictors of the need for permanent PC. METHODS: Data from 257 PCs performed for ACC (mean age 67.3 +/- 14) was collected for a 10-year period. Demographic and clinical characteristics at initial admission, co-morbidities were analyzed. Patients who underwent interval LC were defined as the surgery group (SG; n = 163, 63.4 %) and the remaining patients as the non-SG (NSG; n = 94, 36.6 %). RESULTS: Patients in the SG were significantly younger and had a shorter length of hospital stay (p < 0.01). The rate of coronary artery disease (CAD; 63.2 vs. 20.2 %), chronic renal failure (14.9 vs. 6.1 %), and the mean number of co-morbidities (2.2 vs. 1.4) were significantly higher in the NSG. Sepsis at admission was more common in the NSG (19.1 vs. 4.9 %, p < 0.001). 56 patients (34.4 %) in the SG and 24 patients (25.5 %) in the NSG developed tube-related complications. In hospital mortality was similar between the groups. Multivariate analysis showed that age >=75, increased alkaline phosphatase (ALK-P), history of CAD, were predictors of PC as a definite treatment in this high-risk group of patients with ACC. CONCLUSIONS: High operative risk due to older age and CAD preclude LC in more than one-third of patients following PC especially presenting with sepsis and elevated ALK-P. This study suggests that PC could be a safe treatment option in this select group of high-risk patients. PMID- 26612180 TI - Impact of the Cincinnati Aligning Forces for Quality Multi-Payer Patient Centered Medical Home Pilot on Health Care Quality, Utilization, and Costs. AB - To evaluate the potential for a patient-centered medical home initiative to reduce utilization and cost while improving quality, we examined a natural experiment involving 11 primary care practices in Cincinnati, Ohio, that participated in the Aligning Forces for Quality Multi-Payer Patient Centered Medical Home pilot. Our research design involved difference-in-difference analyses, comparing changes in utilization, costs, and quality between patients attributed to pilot practices compared with those attributed to a matched comparison cohort after 2 years of active engagement by the practices. The Cincinnati pilot was associated with a reduction of ambulatory care-sensitive emergency department visits of approximately 0.7 per 1,000 member months or approximately 22.6% (p = .01). While there was a reduction in total costs of care of $7,679 per 1,000 member months, the difference did not reach statistical significance. After 2 years of the pilot, lipid testing in diabetics had increased by 2.7 percentage points (a 3.3% improvement; p < .0001). Patient centered medical homes have the potential to improve the quality of care and reduce emergency department use but expectations for cost control in a relatively short time horizon and absent other changes may be unrealistic. PMID- 26612181 TI - Does antenatal education reduce fear of childbirth? AB - AIM: The aim of this study was to determine the effect of antenatal education on fear of childbirth, acceptance of pregnancy and identification with motherhood role. BACKGROUND: There is insufficient evidence pertaining to the effect of antenatal education on fear of childbirth, acceptance of pregnancy and identification with motherhood role. INTRODUCTION: The purpose of antenatal education is to help couples make the right decisions during delivery. Through antenatal education, couples prepare themselves for delivery. METHODS: This is a quasi-experimental and prospective study that employs a pre- and post-education model. In total, 192 pregnant women (education group, n = 69 and control group, n = 123) participated in the study. Data were collected using the pregnancy identification form: the Prenatal Self-Evaluation Questionnaire and a version of the Wijma Delivery Expectancy/Experience Questionnaire. RESULTS: Prior to participating in the study, the education group and control group had similar levels of acceptance of pregnancy and identification with motherhood role, whereas a significant difference was found in their fear of childbirth levels. When surveyed again after receiving education, the two groups' levels of acceptance of pregnancy and fear of childbirth were found to be significantly different. However, they had similar levels of identification with the motherhood role. CONCLUSION: Antenatal education appears to increase the acceptance of pregnancy, does not affect the identification with motherhood role and reduces the fear of childbirth. IMPLICATIONS FOR NURSING AND HEALTH POLICY: A systematic antenatal education programme, as part of routine antenatal care services, would help reduce the rate of interventional labour and facilitate pregnant women's conscious participation in the act of labour by reducing their fear of childbirth. PMID- 26612182 TI - How can we quantify impacts of contaminants in marine ecosystems? The ICON project. AB - An international workshop on marine integrated contaminant monitoring (ICON) was organised to test a framework on integrated environmental assessment and simultaneously assess the status of selected European marine areas. Biota and sediment were sampled in selected estuarine, inshore and offshore locations encompassing marine habitats from Iceland to the Spanish Mediterranean. The outcome of the ICON project is reported in this special issue as method-oriented papers addressing chemical analyses, PAH metabolites, oxidative stress, biotransformation, lysosomal membrane stability, genotoxicity, disease in fish, and sediment assessment, as well as papers assessing specific areas. This paper provides a background and introduction to the ICON project, by reviewing how effects of contaminants on marine organisms can be monitored and by describing strategies that have been employed to monitor and assess such effects. Through the ICON project we have demonstrated the use of an integrating framework and gleaned more knowledge than ever before in any single field campaign about the impacts contaminants may have in European marine areas. PMID- 26612183 TI - Assessment of curing behavior of light-activated dental composites using intensity correlation based multiple reference optical coherence tomography. AB - BACKGROUND AND OBJECTIVES: Monitoring the curing kinetics of light-activated resin is a key area of research. These resins are used in restorative applications and particularly in dental applications. They can undergo volumetric shrinkage due to poor control of the depth dependent curing process, modulated by the intensity and duration of the curing light source. This often results in the formation of marginal gaps, causing pain and damage to the restoration site. In this study, we demonstrate the capabilities of a correlation method applied using a multiple references optical coherence tomography (MR-OCT) architecture to monitor the curing of the resin. STUDY DESIGN/MATERIALS AND METHODS: A MR-OCT system is used in this study to monitor the curing of the resin. The system operates at the center wavelength of 1310 nm with an A-scan rate of 1200 A-scans per second. The axial and lateral resolution of the system is ~13 MUm and ~27 MUm. The method to determine the intensity correlation between adjacent B-frames is based on the Pearson correlation coefficient for a region of interest. Calculating the correlation coefficient for multiple B-frames related to the first B-frame at regular spaced time points, shows for a noncured resin a reduction of the correlation coefficient over time due to Brownian motion. The time constant of the reduction of the correlation value is a measure for the progress of the polymerization during LED light irradiation of the resin. The proposed approach is potentially a low-cost, powerful and unique optical imaging modality for measuring the curing behavior of dental resin and other resins, coatings, and adhesives in medical and industrial applications. RESULTS: To demonstrate the proposed method to monitor the curing process, a light-activated resin composite from GRADIA DIRECT ANTERIOR (GC Corporation, Japan) is studied. The curing time of resin was measured and monitored as a function of depth. The correlation coefficient method is highly sensitive to Brownian motion. The process of curing results in a change in intensity as measured by the MR-OCT signal and hence can be monitored using this method. CONCLUSIONS: These results show that MR-OCT has the potential to measure the curing time and monitor the curing process as a function of depth. Moreover, MR-OCT as a product has potential to be compact, low-cost and to fit into a smartphone. Using such a device for monitoring the curing of the resin will be suitable for dentists in stationary and mobile clinical settings. PMID- 26612184 TI - A White Lesion in the Stomach. PMID- 26612185 TI - A Woman With Chronic Postprandial Abdominal Pain and Vomiting. PMID- 26612186 TI - A 9-Month-Old Presenting With Rectal Prolapse. PMID- 26612187 TI - A Rare Cause of Obscure Gastrointestinal Bleeding. PMID- 26612188 TI - Effects of pH during liquid storage of goat semen on sperm viability and fertilizing potential. AB - A specific problem in goat semen preservation is the detrimental effect of seminal plasma on sperm viability in extenders containing yolk or milk. Thus, the use of chemically defined extenders will have obvious advantages. Although previous studies indicate that the initial pH of an extender is crucial to sustain high sperm motility, changes in extender pH during long-term semen storage have not been observed. Monitoring extender pH at different times of semen storage and modeling its variation according to nonlinear models is thus important for protocol optimization for long-term liquid semen preservation. The present results showed that during long-term liquid storage of goat semen, both sperm motility and semen pH decreased gradually, and a strong correlation was observed between the two. Whereas increasing the initial extender pH from 6.04 to 6.25 or storage with stabilized pH improved, storage with artificially lowered pH impaired sperm motility. Extender renewal improved sperm motility by maintaining a stable pH. Sperm coating with chicken (Gallus gallus) egg yolk improved motility by increasing tolerance to pH decline. A new extender (n-mZAP) with a higher buffering capacity was formulated, and n-mZAP maintained higher sperm motility, membrane integrity and acrosome intactness than the currently used mZAP extender did. Goat semen liquid-stored for 12 d in n-mZAP produced pregnancy and kidding rates similar to those obtained with freshly collected semen following artificial insemination. In conclusion, maintenance of a stable pH during liquid semen storage dramatically improved sperm viability and fertilizing potential. PMID- 26612189 TI - The Need Associated with Diabetes Primary Care and the Impact of Referral to a Specialist-Centered Multidisciplinary Diabetes Program (the NADIR Study). AB - OBJECTIVE: The impact of specialist care on glycemia and cardiovascular risk factors in patients with diabetes is uncertain. This observational cohort study investigated metabolic risk factors in patients referred to LMC Diabetes & Endocrinology for diabetes management. METHODS: The cohort included 306 consecutive patients with diabetes referred to LMC in Ontario between January and June 2010. Sources of prereferral data included consultation notes, records from primary care physicians and the Ontario Lab Information System. Postreferral data were obtained from LMC's patients' records. RESULTS: The mean duration of diabetes before referral was 11 years, and the mean baseline glycated hemoglobin (A1C) level was 8.8%. Among patients with uncontrolled A1C levels at baseline, 73% had had no A1C values <=7% for up to 6 years before referral. Following referral, mean A1C levels decreased to 7.8% at 6 and 12 months (both p<0.001 vs. baseline). Attendance at diabetes education programs improved from 28% to 67% postreferral, and attendees achieved significantly greater A1C reductions than nonattendees (mean 1.1% vs. 0.7%, respectively). Mean low-density lipoprotein levels declined from 2.3 mmol/L at referral to 1.8 mmol/L at 12 months (p<0.05). Mean blood pressure was similar, at 128/75 before and 129/75 mm Hg after referral; however, following referral, blood pressure improved from 143/89 to 134/80 (p<0.001) in patients with previously uncontrolled blood pressure. Use of guideline-recommended medications increased significantly following referral. CONCLUSION: Referral to specialist care should be considered early in the course of diabetes in order to optimize management of glycemia and cardiovascular risk factors. PMID- 26612190 TI - Biofunctionalized Hydrogel Microscaffolds Promote 3D Hepatic Sheet Morphology. AB - Development of artificial tissues providing the proper geometrical, mechanical, and environmental cues for cells is highly coveted in the field of tissue engineering. Recently, microfabrication strategies in combination with other chemistries have been utilized to capture the architectural complexity of intricate organs, such as the liver, in in vitro platforms. Here it is shown that a biofunctionalized poly (ethylene glycol) (PEG) hydrogel scaffold, fabricated using a sphere-template, facilitates hepatic sheet formation that follows the microscale patterns of the scaffold surface. The design takes advantage of the excellent diffusion properties of porous, uniform 3D hydrogel platforms, and the enhanced-cell-extracellular matrix interaction with the display of conjugated collagen type I, which in turn elicits favorable Huh-7.5 response. Collectively, the experimental findings and corresponding simulations demonstrate the importance of biofunctionalized porous scaffolds and indicate that the microscaffold shows promise in liver tissue engineering applications and provides distinct advantages over current cell sheet and hepatocyte spheroid technologies. PMID- 26612191 TI - A user's guide to local perforator flap reconstruction in a post-conflict setting. PMID- 26612192 TI - Serum levels of renin, angiotensin-converting enzyme and angiotensin II in patients treated by surgical excision, propranolol and captopril for problematic proliferating infantile haemangioma. AB - The role of the renin-angiotensin system (RAS) in the biology of infantile haemangioma (IH) and its accelerated involution induced by beta-blockers was first proposed in 2010. This led to the first clinical trial in 2012 using low dose captopril, an angiotensin-converting enzyme (ACE) inhibitor, demonstrating a similar response in these tumours. This study aimed to compare serial serum levels of the components of the RAS in patients before and after surgical excision, propranolol or captopril treatment for problematic proliferating IH. Patients with problematic proliferating IH underwent measurements of serum levels of plasma renin activity (PRA), ACE and angiotensin II (ATII) before, and 1-2 and 6 months following surgical excision, propranolol or captopril treatment. This study included 27 patients undergoing surgical excision (n = 8), propranolol (n = 11) and captopril (n = 8) treatment. Treatment with either surgical excision or propranolol resulted in significant decrease in the mean levels of PRA. Surgical excision or captopril treatment led to significant decline in the mean levels of ATII. All three treatment modalities had no significant effect on the mean levels of ACE. This study demonstrates the effect of surgical excision, propranolol and captopril treatment in lowering the levels of PRA and ATII, but not ACE, supporting a mechanistic role for the RAS in the biology of IH. PMID- 26612193 TI - Sneddon's syndrome with optic disc macroaneurysm and macular edema successfully treated with subtenon steroid injection. PMID- 26612194 TI - Sedative load, carious teeth and infection in the periodontium among community dwelling older people. AB - OBJECTIVE: To study the relation of sedative load to carious teeth and periodontal pocketing - indication of infectious periodontal disease - among older people. MATERIALS AND METHODS: This cross-sectional study was based on a subpopulation of 158 community-dwelling, dentate, non-smoking, 75-year-old or older people from the Oral Health Geriatric Multidisciplinary Strategy study. The data were collected by interviews and clinical oral examinations during 2004 2005. Sedative load was measured by means of the sedative load model, and Poisson multivariate regression models were used to estimate relative risk (RR) with 95% confidence intervals (CI). RESULTS: Participants with a sedative load of either 1 2 (n = 31) or >=3 (n = 12) had an increased likelihood of having carious teeth (RR: 1.8, CI: 1.2-2.6 and RR: 2.4, CI: 1.4-4.1, respectively) compared to participants without a sedative load. There was an inverse association between sedative load and the number of teeth with periodontal pockets. CONCLUSIONS: Presence of dental caries was associated with the use of drugs with sedative properties. The use of drugs with sedative properties was not associated with the presence of periodontal pockets. PMID- 26612195 TI - Poly(N-isopropylacrylamide) Phase Diagrams: Fifty Years of Research. AB - In 1968, Heskins and Guillet published the first systematic study of the phase diagram of poly(N-isopropylacrylamide) (PNIPAM), at the time a "young polymer" first synthesized in 1956. Since then, PNIPAM became the leading member of the growing families of thermoresponsive polymers and of stimuli-responsive, "smart" polymers in general. Its thermal response is unanimously attributed to its phase behavior. Yet, in spite of 50 years of research, a coherent quantitative picture remains elusive. In this Review we survey the reported phase diagrams, discuss the differences and comment on theoretical ideas regarding their possible origins. We aim to alert the PNIPAM community to open questions in this reputably mature domain. PMID- 26612196 TI - Oncologic Outcomes of Kidney Sparing Surgery versus Radical Nephroureterectomy for the Elective Treatment of Clinically Organ Confined Upper Tract Urothelial Carcinoma of the Distal Ureter. AB - PURPOSE: We compared the oncologic outcomes of radical nephroureterectomy, distal ureterectomy and endoscopic surgery for elective treatment of clinically organ confined upper tract urothelial carcinoma of the distal ureter. MATERIALS AND METHODS: From a multi-institutional collaborative database we identified 304 patients with unifocal, clinically organ confined urothelial carcinoma of the distal ureter and bilateral functional kidneys. Rates of overall, cancer specific, local recurrence-free and intravesical recurrence-free survival according to surgery type were compared using Kaplan-Meier statistics. Univariable and multivariable Cox regression analyses were performed to assess the adjusted outcomes of radical nephroureterectomy, distal ureterectomy and endoscopic surgery. RESULTS: Overall 128 (42.1%), 134 (44.1%) and 42 patients (13.8%) were treated with radical nephroureterectomy, distal ureterectomy and endoscopic surgery, respectively. Although rates of overall, cancer specific and intravesical recurrence-free survival were equivalent among the 3 surgical procedures, 5-year local recurrence-free survival was lower for endoscopic surgery (35.7%) than for nephroureterectomy (95.0%, p <0.001) or ureterectomy (85.5%, p = 0.01) with no significant difference between nephroureterectomy and distal ureterectomy. On multivariable analyses only endoscopic surgery was an independent predictor of decreased local recurrence-free survival compared to nephroureterectomy (HR 1.27, p = 0.001) or distal ureterectomy (HR 1.14, p = 0.01). Distal ureterectomy and endoscopic surgery did not significantly correlate to cancer specific or intravesical recurrence-free survival. However, when adjustment was made for ASA((r)) (American Society of Anesthesiologists((r))) score, distal ureterectomy (HR 0.80, p = 0.01) and endoscopic surgery (HR 0.84, p = 0.02) were independent predictors of increased overall survival, although no significant difference was found between them. CONCLUSIONS: Because of better oncologic outcomes, distal ureterectomy could be considered the elective first line treatment of clinically organ confined urothelial carcinoma of the distal ureter. PMID- 26612197 TI - Update on the Diagnosis and Management of Renal Angiomyolipoma. AB - PURPOSE: Advances in minimally invasive therapies and novel targeted chemotherapeutics have provided a breadth of options for the management of renal masses. Management of renal angiomyolipoma has not been reviewed in a comprehensive fashion in more than a decade. We provide an updated review of the current diagnosis and management strategies for renal angiomyolipoma. MATERIALS AND METHODS: We conducted a PubMed((r)) search of all available literature for renal or kidney angiomyolipoma. Further sources were identified in the reference lists of identified articles. We specifically reviewed case series of partial nephrectomy, selective arterial embolization and ablative therapies as well as trials of mTOR inhibitors for angiomyolipoma from 1999 to 2014. RESULTS: Renal angiomyolipoma is an uncommon benign renal tumor. Although associated with tuberous sclerosis complex, these tumors occur sporadically. Risk of life threatening hemorrhage is the main clinical concern. Due to the fat content, angiomyolipomas are generally readily identifiable on computerized tomography and magnetic resonance imaging. However, fat poor angiomyolipoma can present a diagnostic challenge. Novel research suggests that various strategies using magnetic resonance imaging, including chemical shift magnetic resonance imaging, have the potential to differentiate fat poor angiomyolipoma from renal cell carcinoma. Active surveillance is the accepted management for small asymptomatic masses. Generally, symptomatic masses and masses greater than 4 cm should be treated. However, other relative indications may apply. Options for treatment have traditionally included radical and partial nephrectomy, selective arterial embolization and ablative therapies, including cryoablation and radio frequency ablation, all of which we review and update. We also review recent advances in the medical treatment of patients with tuberous sclerosis complex associated angiomyolipomas with mTOR inhibitors. Specifically trials of everolimus for patients with tuberous sclerosis complex suggest that this agent may be safe and effective in treating angiomyolipoma tumor burden. A schema for the suggested management of renal angiomyolipoma is provided. CONCLUSIONS: Appropriately selected cases of renal angiomyolipoma can be managed by active surveillance. For those patients requiring treatment nephron sparing approaches, including partial nephrectomy and selective arterial embolization, are preferred options. For those with tuberous sclerosis complex mTOR inhibitors may represent a viable approach to control tumor burden while conserving renal parenchyma. PMID- 26612199 TI - Combined inhibition of complement and CD14 improved outcome in porcine polymicrobial sepsis. AB - INTRODUCTION: Sepsis is an exaggerated and dysfunctional immune response to infection. Activation of innate immunity recognition systems including complement and the Toll-like receptor family initiate this disproportionate inflammatory response. The aim of this study was to explore the effect of combined inhibition of the complement component C5 and the Toll-like receptor co-factor CD14 on survival, hemodynamic parameters and systemic inflammation including complement activation in a clinically relevant porcine model of polymicrobial sepsis. METHODS: Norwegian landrace piglets (4 +/- 0.5 kg) were blindly randomized to a treatment group (n = 12) receiving the C5 inhibitor coversin (OmCI) and anti-CD14 or to a positive control group (n = 12) receiving saline. Under anesthesia, sepsis was induced by a 2 cm cecal incision and the piglets were monitored in standard intensive care for 8 hours. Three sham piglets had a laparotomy without cecal incision or treatment. Complement activation was measured as sC5b-9 using enzyme immunoassay. Cytokines were measured with multiplex technology. RESULTS: Combined C5 and CD14 inhibition significantly improved survival (p = 0.03). Nine piglets survived in the treatment group and four in the control group. The treatment group had significantly lower pulmonary artery pressure (p = 0.04) and ratio of pulmonary artery pressure to systemic artery pressure (p < 0.001). Plasma sC5b-9 levels were significantly lower in the treatment group (p < 0.001) and correlated significantly with mortality (p = 0.006). IL-8 and IL-10 were significantly (p < 0.05) lower in the treatment group. CONCLUSIONS: Combined inhibition of C5 and CD14 significantly improved survival, hemodynamic parameters and inflammation in a blinded, randomized trial of porcine polymicrobial sepsis. PMID- 26612200 TI - Collaboration in implicit memory: evidence from word-fragment completion and category exemplar generation. AB - Recent studies have begun to investigate the effects of collaboration on explicit tests such as free recall, cued recall, and recognition. In contrast, little is known about the impact of this variable on implicit memory. To bridge this gap, the present study compared the performance of nominal and collaborative groups in two implicit memory tasks-word-fragment completion (WFCT) and category exemplar generation (CEGT). Both the disruption-of-individual-retrieval-strategies and the retrieval blocking hypotheses predicted no significant negative effects of collaboration on repetition priming; in contrast, the retrieval inhibition hypothesis predicted lower priming in collaborative than in nominal groups in both tasks. The results supported the former hypotheses, because priming scores in the WFCT and the CEGT did not differ between collaborative and individual groups. Interestingly; however, a significant collaborative inhibition was obtained in the CEGT (but not in the WFCT) when considering the raw proportions of studied and unstudied exemplars generated. The latter finding might indicate that the performance of collaborative groups can be significantly impaired by the disruption of within-category order resulting from the exposure to the exemplars generated by other group members, even when participants do not explicitly attempt to retrieve the stimuli presented at encoding. PMID- 26612201 TI - More attentional focusing through binaural beats: evidence from the global-local task. AB - A recent study showed that binaural beats have an impact on the efficiency of allocating attention over time. We were interested to see whether this impact affects attentional focusing or, even further, the top-down control over irrelevant information. Healthy adults listened to gamma-frequency (40 Hz) binaural beats, which are assumed to increase attentional concentration, or a constant tone of 340 Hz (control condition) for 3 min before and during a global local task. While the size of the congruency effect (indicating the failure to suppress task-irrelevant information) was unaffected by the binaural beats, the global-precedence effect (reflecting attentional focusing) was considerably smaller after gamma-frequency binaural beats than after the control condition. Our findings suggest that high-frequency binaural beats bias the individual attentional processing style towards a reduced spotlight of attention. PMID- 26612202 TI - Functional characterization of a human POU1F1 mutation associated with isolated growth hormone deficiency: a novel etiology for IGHD. AB - POU1F1, a pituitary-specific POU-homeo domain transcription factor, plays an essential role in the specification of the somatotroph, lactotroph and thyrotroph lineages and in the activation of GH1, PRL and TSHbeta transcription. Individuals with mutations in POU1F1 present with combined deficiency of GH, PRL and TSH. Here, we identified a heterozygous missense mutation with evidence of pathogenicity, at the POU1F1 locus, in a large family in which an isolated growth hormone deficiency segregates as an autosomal dominant trait. The corresponding p.Pro76Leu mutation maps to a conserved site within the POU1F1 transactivation domain. Bandshift assays revealed that the mutation alters wild-type POU1F1 binding to cognate sites within the hGH-LCR and hGH1 promoter, but not to sites within the PRL promoter, and it selectively increases binding affinity to sites within the hGH-LCR. Co-immunoprecipitation studies reveal that this substitution enhances interactions of POU1F1 with three of its cofactors, PITX1, LHX3a and ELK1, and that residue 76 plays a critical role in these interactions. The insertion of the mutation at the mouse Pou1f1 locus results in a dramatic loss of protein expression despite normal mRNA concentrations. Mice heterozygous for the p.Pro76Leu mutation were phenotypically normal while homozygotes demonstrated a dwarf phenotype. Overall, this study unveils the involvement of POU1F1 in dominantly inherited isolated GH deficiency and demonstrates a significant impact of the Pro76Leu mutation on DNA-binding activities, alterations in transactivating functions and interactions with cofactors. Our data further highlight difficulties in modeling human genetic disorders in the mouse despite apparent conservation of gene expression pathways and physiologic functions. PMID- 26612203 TI - Disruption of polycystin-L causes hippocampal and thalamocortical hyperexcitability. AB - Epilepsy or seizure disorder is among the least understood chronic medical conditions affecting over 65 million people worldwide. Here, we show that disruption of the polycystic kidney disease 2-like 1 (Pkd2l1 or Pkdl), encoding polycystin-L (PCL), a non-selective cation channel, increases neuronal excitability and the susceptibility to pentylenetetrazol-induced seizure in mice. PCL interacts with beta2-adrenergic receptor (beta2AR) and co-localizes with beta2AR on the primary cilia of neurons in the brain. Pkdl deficiency leads to the loss of beta2AR on neuronal cilia, which is accompanied with a remarkable reduction in cAMP levels in the central nervous system (CNS). The reduction of cAMP levels is associated with a reduction in the activation of cAMP response element-binding protein, but not the activation of Ca(2+)/calmodulin-dependent protein kinase II, Akt or mitogen-activated protein kinases. Our data, thus, indicate for the first time that a ciliary protein complex is required for the control of neuronal excitability in the CNS. PMID- 26612204 TI - Who and when should we screen for prostate cancer? Interviews with key opinion leaders. AB - Prostate cancer screening using prostate-specific antigen (PSA) is highly controversial. In this Q & A, Guest Editors for BMC Medicine's 'Spotlight on Prostate Cancer' article collection, Sigrid Carlsson and Andrew Vickers, invite some of the world's key opinion leaders to discuss who, and when, to screen for prostate cancer. In response to the points of view from the invited experts, the Guest Editors summarize the experts' views and give their own personal opinions on PSA screening. PMID- 26612205 TI - Comparison of medical costs generated by IBS patients in primary and secondary care in the Netherlands. AB - BACKGROUND: Irritable Bowel Syndrome (IBS) is a functional somatic syndrome characterized by patterns of persistent bodily complaints for which a thorough diagnostic workup does not reveal adequate explanatory structural pathology. Detailed insight into disease-specific health-care costs is critical because it co-determines the societal impact of the disease, enables the assessment of cost effectiveness of existing and new treatments, and facilitates choices in treatment policy. In the present study the aim was, to compare the costs and magnitude of healthcare consumption for patients diagnosed with Irritable Bowel Syndrome (IBS) in primary and secondary care, compare these costs with the average health care expenditure for patients without IBS and describe these costs in further detail. METHODS: Reimbursement data for patients diagnosed with IBS by a general practitioner (GP) or specialist between 2006 and 2009 were extracted from a healthcare insurance company and compared to an age and gender matched control group of patients without IBS. Using a case-control design, direct medical costs for GP consultations, specialist care and medication prescriptions were calculated. RESULTS: Data of 326 primary care and 9274 secondary care IBS patients were included in the analysis. For primary care patients, the mean total annual health care costs for the three years after diagnosis compared to the three years before diagnosis, increased with 486 Euro after IBS was diagnosed, whereas for secondary care patients, these costs increased with 2328 Euro. Total health care costs remained higher in the three years after the initial diagnosis when the patient is treated in secondary care, compared to primary care. This increase was significant for hospital specialist costs and medications, but not for GP contacts. For controls, there was no significant difference in mean total annual health costs in the three years before and the three years after the diagnosis and also no significant difference in cost increases between both primary- and secondary-care control patients. CONCLUSION: Total healthcare costs per patient substantially increase after a diagnosis of IBS and IBS related costs are significantly higher when patients are treated in secondary-care compared to primary-care. IBS patients should be treated in primary-care where possible, not only because guidelines recommend this from a quality of care viewpoint, but also to optimize use of health care resources. Referral should be restricted to those patients with alarm symptoms, with ill-matching symptoms, or other cases of diagnostic uncertainty. PMID- 26612206 TI - Acute lumbosacral nerve stimulation does not affect anorectal motor function in a rodent model. AB - BACKGROUND: Sacral nerve stimulation has become a first line treatment for fecal incontinence, however, its effect on the motor function of the anorectum is uncertain. The aim of this study was to apply acute lumbosacral nerve stimulation in an animal model and to determine its effect on the external and internal anal sphincter forces, the rectoanal inhibitory and excitatory reflexes, and the slow wave frequency of the internal anal sphincter. METHODS: Lumbosacral nerve stimulation was applied to 16 nulliparous female rats. A novel in vivo preparation was designed to allow simultaneous monitoring of external and internal anal sphincter forces. The effect of rectal distension on the two anal sphincters was also studied. KEY RESULTS: Lumbosacral nerve stimulation delivered at either S1 or L6 in rodents did not affect sphincter forces, rectoanal reflexes or slow wave frequency of anal canal smooth muscle. CONCLUSIONS & INFERENCES: The absence of effect on the motor pathways of continence suggests that the mechanism of action is predominantly on sensory feedback mechanisms from the anorectum, thereby increasing cortical awareness of the pelvic floor. PMID- 26612207 TI - Technique of extraperitoneal uterosacral ligament suspension for apical suspension. AB - AIM OF THE VIDEO/INTRODUCTION: Vaginal vault prolapse can occur alone or in combination with anterior or posterior compartment prolapse. Apical prolapse has shown a strong correlation with anterior wall prolapse and a moderate correlation with posterior wall prolapse. The McCall culdoplasty uses the extraperitoneal vaginal approach to support the vault at the time of hysterectomy. Sacrospinous fixation and ileococcygeus suspension with or without mesh have also been used for the treatment of vaginal vault prolapse. The uterosacral ligaments can also be used to re-suspend the vaginal vault using the extraperitoneal or transperitoneal approach. With the extraperitoneal approach, the peritoneal sac, which can be difficult to access at times, especially when there are dense pelvic adhesions, does not need to be opened. The extraperitoneal approach also carries a lower risk of ureteric injury, as the ureters and the bladder can be retracted from the field using a Breisky-Navratil retractor. METHODS: This video, which documents the surgical treatment of a woman with a complete vaginal eversion and grade 3 pelvic organ prolapse (POP), was recorded in a live workshop during the 2015 Urogynaecology and Reconstructive Pelvic Surgery Conference, held in Chennai, India, in January 2015. It is aimed at educating interested surgeons in the technique of extraperitoneal uterosacral suspension. CONCLUSIONS: This video demonstrates the extraperitoneal approach to uterosacral ligament suspension for apical support in women with vaginal vault prolapse. PMID- 26612209 TI - Aqueous Modification of Nano- and Microfibrillar Cellulose with a Click Synthon. AB - The modification of cellulose as a renewable resource has received wide attention in research and industry. A major problem regarding chemical modification, including heating and drying, is related to hornification that causes pore-system collapse and results in decreased reactivity and changes in the 3D structure of the material. A mild and green approach for the modification of different never dried and thus wet cellulose substrates (pulp, nanostructured celluloses, and viscose fibers) by an alkoxysilane-azide in water is presented. A kinetic study of the silanization reaction demonstrates that alkoxy-trans-silanization of the cellulose surface is accomplished in water as a suspension medium within a few hours at room temperature. The resulting, azido-equipped celluloses are widely applicable precursor materials for subsequent functionalization by so-called click chemistry, for example, with a fluorescent Rhodamine derivative as a representative reagent. Successful covalent bonding was shown by GPC and a model reaction. The 3D structure of the materials remained intact, as was inter alia visualized by optical and fluorescence microscopy. PMID- 26612208 TI - Learning, memory and synaptic plasticity in hippocampus in rats exposed to sevoflurane. AB - PURPOSE: Developmental exposure to volatile anesthetics has been associated with cognitive deficits at adulthood. Rodent studies have revealed impairments in performance in learning tasks involving the hippocampus. However, how the duration of anesthesia exposure impact on hippocampal synaptic plasticity, learning, and memory is as yet not fully elucidated. METHODS: On postnatal day 7(P7), rat pups were divided into 3 groups: control group (n=30), 3% sevoflurane treatment for 1h (Sev 1h group, n=30) and 3% sevoflurane treatment for 6h (Sev 6h group, n=28). Following anesthesia, synaptic vesicle-associated proteins and dendrite spine density and synapse ultrastructure were measured using western blotting, Golgi staining, and transmission electron microscopy (TEM) on P21. In addition, the effects of sevoflurane treatment on long-term potentiation (LTP) and long-term depression (LTD), two molecular correlates of memory, were studied in CA1 subfields of the hippocampus, using electrophysiological recordings of field potentials in hippocampal slices on P35-42. Rats' neurocognitive performance was assessed at 2 months of age, using the Morris water maze and novel-object recognition tasks. RESULTS: Our results showed that neonatal exposure to 3% sevoflurane for 6h results in reduced spine density of apical dendrites along with elevated expression of synaptic vesicle-associated proteins (SNAP-25 and syntaxin), and synaptic ultrastructure damage in the hippocampus. The electrophysiological evidence indicated that hippocampal LTP, but not LTD, was inhibited and that learning and memory performance were impaired in two behavioral tasks in the Sev 6h group. In contrast, lesser structural and functional damage in the hippocampus was observed in the Sev 1h group. CONCLUSION: Our data showed that 6-h exposure of the developing brain to 3% sevoflurane could result in synaptic plasticity impairment in the hippocampus and spatial and nonspatial hippocampal-dependent learning and memory deficits. In contrast, shorter-duration exposure (1h) results in less damage. These results provide further evidences that duration of anesthesia exposure could have differential effects on neuronal plasticity and neurocognitive performance. PMID- 26612210 TI - Identification of novel rabbit hemorrhagic disease virus B-cell epitopes and their interaction with host histo-blood group antigens. AB - Rabbit haemorrhagic disease, caused by rabbit hemorrhagic disease virus (RHDV), results in the death of millions of adult rabbits worldwide, with a mortality rate that exceeds 90%. The sole capsid protein, VP60, is divided into shell (S) and protruding (P) domains, and the more exposed P domain likely contains determinants for cell attachment and antigenic diversity. Nine mAbs against VP60 were screened and identified. To map antigenic epitopes, a set of partially overlapping and consecutive truncated proteins spanning VP60 were expressed. The minimal determinants of the linear B-cell epitopes of VP60 in the P domain, N(326)PISQV(331), D(338)MSFV(342) and K(562)STLVFNL(569), were recognized by one (5H3), four (1B8, 3D11, 4C2 and 4G2) and four mAbs (1D4, 3F7, 5G2 and 6B2), respectively. Sequence alignment showed epitope D(338)MSFV(342) was conserved among all RHDV isolates. Epitopes N(326)PISQV(331) and K(562)STLVFNL(569) were highly conserved among RHDV G1-G6 and variable in RHDV2 strains. Previous studies demonstrated that native viral particles and virus-like particles (VLPs) of RHDV specifically bound to synthetic blood group H type 2 oligosaccharides. We established an oligosaccharide-based assay to analyse the binding of VP60 and epitopes to histo-blood group antigens (HBGAs). Results showed VP60 and its epitopes (aa 326-331 and 338-342) in the P2 subdomain could significantly bind to blood group H type 2. Furthermore, mAbs 1B8 and 5H3 could block RHDV VLP binding to synthetic H type 2. Collectively, these two epitopes might play a key role in the antigenic structure of VP60 and interaction of RHDV and HBGA. PMID- 26612212 TI - Autophagy Mediates Tumor Suppression via Cellular Senescence. AB - Autophagy not only constitutes a robust barrier against malignant transformation at the cell-intrinsic level, but also contributes to the organismal control of potentially oncogenic cells. Recent data provide molecular insights into the mechanisms whereby oncogene hyperactivation induces autophagy to establish a permanent proliferative arrest commonly known as cellular senescence. PMID- 26612213 TI - From the New Editor-in-Chief. PMID- 26612211 TI - miR-124 interacts with the Notch1 signalling pathway and has therapeutic potential against gastric cancer. AB - Aberrant Notch signalling plays an important role in cancer progression. However, little is known about the interaction between miRNA and the Notch signalling pathway and its role in gastric cancer (GC). In this study, we found that miR-124 was down-regulated in GC compared with adjacent normal tissue. Forced expression of miR-124 inhibited GC cell growth, migration and invasion, and induced cell cycle arrest. miR-124 negatively regulated Notch1 signalling by targeting JAG1. miR-124 levels were also shown to be inversely correlated with JAG1 expression in GC. Furthermore, we found that the overexpression of the intracellular domain of Notch1 repressed miR-124 expression, promoted GC cell growth, migration and invasion. Conversely, blocking Notch1 using a gamma-secretase inhibitor up regulated miR-124 expression, inhibited GC cell growth, migration and invasion. In conclusion, our data demonstrates a regulatory feedback loop between miR-124 and Notch1 signalling in GC cells, suggesting that the miR-124/Notch axis may be a potential therapeutic target against GC. PMID- 26612214 TI - Morphologic Updates in Prostate Pathology. AB - In the past several years, modifications have been made to the original Gleason system with resultant therapeutic and prognostic implications. Several morphologic variants of prostatic adenocarcinoma have also been described. Prostate pathology has also evolved over the years with the discovery and utility of new immunohistochemical stains. The topics discussed in this update include the Gleason grading system, prognostic grade grouping, variants of prostatic adenocarcinoma, and the application of immunohistochemistry to prostate pathology. PMID- 26612215 TI - Molecular Updates in Prostate Cancer. AB - A wide array of molecular markers and genomic signatures, reviewed in this article, may soon be used as adjuncts to currently established screening strategies, prognostic parameters, and early detection markers. Markers of genetic susceptibility to PCA, recurrent epigenetic and genetic alterations, including ETS gene fusions, PTEN alterations, and urine-based early detection marker PCA3, are discussed. Impact of recent genome-wide assessment on our understanding of key pathways of PCA development and progression and their potential clinical implications are highlighted. PMID- 26612216 TI - Active Surveillance: Pathologic and Clinical Variables Associated with Outcome. AB - Over the past 10 years, active surveillance has emerged as a primary management option for men diagnosed with low-risk prostate cancer. Given the morbidity associated with curative treatment, active surveillance maintains quality of life for men whose disease may never become symptomatic. In order to confidently and safely offer this approach to as many patients as possible, improved metrics are needed to fully assess risk. While pathologic and clinical variables currently help determine whether active surveillance is a reasonable approach, emerging biomarkers and imaging technologies demonstrate promise for more precise identification of ideal candidates. PMID- 26612217 TI - Adult Renal Cell Carcinoma: A Review of Established Entities from Morphology to Molecular Genetics. AB - According to the current World Health Organization (WHO), renal cell carcinomas (RCCs) that primarily affect adults are classified into 8 major subtypes. Additional emerging entities in renal neoplasia have also been recently recognized and these are discussed in further detail by Mehra et al (Emerging Entities in Renal Neoplasia, Surgical Pathology Clinics, 2015, Volume 8, Issue 4). In most cases, the diagnosis of a RCC subtype can be based on morphologic criteria, but in some circumstances the use of ancillary studies can aid in the diagnosis. This review discusses the morphologic, genetic, and molecular findings in RCCs previously recognized by the WHO, and provides clues to distinction from each other and some of the newer subtypes of RCC. As prognosis and therapeutic options vary for the different subtypes of RCC, accurate pathologic distinction is critical for patient care. PMID- 26612218 TI - Emerging Entities in Renal Neoplasia. AB - This article reviews emerging entities in renal epithelial neoplasia, including tubulocystic carcinoma, clear-cell-papillary renal cell carcinoma (RCC), thyroid like follicular RCC, ALK-related RCC, translocation RCC, acquired cystic disease related RCC, succinate dehydrogenase-deficient RCC, and hereditary leiomyomatosis RCC syndrome-associated RCC. Many of these rarer subtypes of RCC were recently studied in more depth and are included in the upcoming version of the World Health Organization classification of tumors. Emphasis is placed on common gross and morphologic features, differential diagnoses, use of ancillary studies for making accurate diagnoses, molecular alterations, and predicted biologic behavior based on previous studies. PMID- 26612219 TI - Diagnosis of Renal Cell Carcinoma: A Clinician's Perspective. AB - Renal cell carcinoma (RCC) is a heterogeneous disease. A rigorous diagnostic assessment by a pathologist with close communication with the clinician provides more accurate prognostication and informed treatment decisions. In the localized setting, an accurate prognostic assessment directs patients to potential adjuvant clinical trials. For patients with advanced disease, the pathologic assessment may have a direct impact on the systemic therapy algorithm. Additionally, it provides the basis for continuous efforts in biomarker development. In rare histologic subtypes, the interaction between clinicians and pathologists provides an opportunity to offer patients specific clinical trials. Molecular characterization platforms may identify targets for therapeutic intervention. PMID- 26612220 TI - Morphologic and Molecular Characteristics of Bladder Cancer. AB - Bladder cancer is the fourth most common cancer in men, and is associated with significant morbidity and mortality. Pathologic evaluation of urothelial cancers relies predominantly on histomorphologic features but can be aided in a small subset of cases by immunohistochemical analyses. Distinction of papillary versus flat lesions, low-grade versus high-grade cytology, and histologic variants and the presence or absence of invasive tumor is important for proper clinical management. Advances in the molecular alterations associated with the various subtypes of urothelial carcinoma have been made but such studies are ongoing. PMID- 26612221 TI - Diagnosis of Bladder Carcinoma: A Clinician's Perspective. AB - In 2014, more than 74,000 new cases and 15,000 deaths from bladder cancer were estimated to occur. The most reliable prognostic factors for survival are pathologic stage and histologic grade. Accordingly, a good understanding of the pathologic features of these cancers is essential to guide optimal clinical treatment, which requires a multidisciplinary team of pathologists, urologists, radiation oncologists, and medical oncologists. This review highlights several clinical scenarios in which detailed pathologic evaluation and accurate reporting impact clinical management. PMID- 26612222 TI - Tumors of the Testis: Morphologic Features and Molecular Alterations. AB - This article reviews the most frequently encountered tumor of the testis; pure and mixed malignant testicular germ cell tumors (TGCT), with emphasis on adult (postpubertal) TGCTs and their differential diagnoses. We additionally review TGCT in the postchemotherapy setting, and findings to be integrated into the surgical pathology report, including staging of testicular tumors and other problematic issues. The clinical features, gross pathologic findings, key histologic features, common differential diagnoses, the use of immunohistochemistry, and molecular alterations in TGCTs are discussed. PMID- 26612223 TI - Diagnosis and Treatment of Testicular Cancer: A Clinician's Perspective. AB - Testicular germ cell tumors (GCTs) include seminoma and nonseminoma. Chance of cure is excellent for clinical stage I disease regardless of whether adjuvant treatment or a surveillance strategy with treatment only for those who relapse is used. Risk of recurrence is greater in nonseminoma with evidence of lymphovascular invasion, but most can be salvaged with chemotherapy and survival rates remain high. This article outlines key pathologic and clinical considerations in clinical stage I seminoma, nonseminoma, advanced disease, and assessment of cancer of unknown primary as a potential GCT. PMID- 26612224 TI - Adrenal Tumors in Adults. AB - Although most adrenal tumors are not diagnostic dilemmas, there are cases that are challenging. This may be due to the tissue provided, for example fragmented tissue received in the setting of morcellation, or it may be due to inherently challenging histology, such as in cases with equivocal features of malignancy. Additionally, much has been learned about the molecular alterations of adrenal tumors, especially pheochromocytomas. Many of these alterations represent germline mutations with significant clinical implications for patients and their families. The aim of this review is to provide an overview of the most common adrenal tumors in adults so that pathologists can tackle these interesting tumors. PMID- 26612225 TI - Adrenocortical Carcinoma: A Clinician's Perspective. AB - Within the category of orphan diseases and rare malignancies, adrenocortical carcinoma (ACC) represents an aggressive entity with high mortality and morbidity. While localized tumors which are diagnosed early can be cured with surgical intervention, there are prognostic factors which predict for micrometastases and consequent recurrent and advanced disease. In such cases, mitotane and cytotoxic chemotherapy have been utilized with a modest degree of benefit. The poor prognosis of recurrent and advanced ACC has underscored the interest in nuanced characterization of ACC cases to guide the personalized use of immunotherapeutic and novel targeted therapies. PMID- 26612226 TI - Updates in Benign Lesions of the Genitourinary Tract. AB - The genitourinary tract is a common site for new cancer diagnosis, particularly for men. Therefore, cancer-containing specimens are very common in surgical pathology practice. However, many benign neoplasms and nonneoplastic, reactive, and inflammatory processes in the genitourinary tract may mimic or cause differential diagnostic challenges with malignancies. Emerging clinicopathologic, immunohistochemical, and molecular characteristics have shed light on the pathogenesis and differential diagnosis of these lesions. This review addresses differential diagnostic challenges related to benign genitourinary tract lesions in the kidney, urinary bladder, prostate, and testis, with emphasis on recent advances in knowledge and areas most common in diagnostic practice. PMID- 26612227 TI - Preface. PMID- 26612228 TI - Raman spectroscopy towards clinical application: drug monitoring and pathogen identification. AB - Raman spectroscopy is a label-free method that measures quickly and contactlessly, providing detailed information from the sample, and has proved to be an ideal tool for medical and life science research. In this review, recent advances of the technique towards drug monitoring and pathogen identification by the Jena Research Groups are reviewed. Surface-enhanced Raman spectroscopy (SERS) and ultraviolet resonance Raman spectroscopy in hollow-core optical fibres enable the detection of drugs at low concentrations as shown for the metabolites of the immunosuppressive drug 6-mercaptopurine as well as antimalarial agents. Furthermore, Raman spectroscopy can be used to characterise pathogenic bacteria in infectious diseases directly from body fluids, making time-consuming cultivation processes dispensable. Using the example of urinary tract infection, it is shown how bacteria can be identified from patients' urine samples within <1 h. The methods cover both single-cell analysis and dielectrophoretic capturing of bacteria in suspension. The latter method could also be used for fast (<3.5 h) identification of antibiotic resistance as shown exemplarily for vancomycin resistant enterococci. PMID- 26612229 TI - The challenge of Clostridium difficile infection: Overview of clinical manifestations, diagnostic tools and therapeutic options. AB - The most important infectious cause of antibiotic-associated diarrhoea and colitis is Clostridium difficile, which is a Gram-positive, anaerobic, spore forming, toxin-producing bacillus. In this overview we will discuss the diagnostic and therapeutic management of patients presenting with suspected or proven C. difficile infection (CDI). The clinical spectrum varies from asymptomatic C. difficile carriers to fulminant colitis with multi-organ failure. The onset of symptoms is usually within 2 weeks after initiation of antibiotic treatment. Diagnosis is based on the combination of clinical symptoms and either a positive stool test for C. difficile toxins or endoscopic or histological findings of pseudomembranous colitis. There is no indication for treatment of asymptomatic carriers, but patients with proven CDI should be treated. Treatment consists of cessation of the provoking antibiotic treatment, secondary prevention by infection control strategies, and treatment with metronidazole or vancomycin. Treatment of recurring CDI, severe infection, the need for surgery, and novel alternative potential treatment strategies will be discussed. The concurrent increase in multiresistant colonisation and increasing numbers of asymptomatic carriers of C. difficile will lead to an increase of the situation in which patients with severe infections, treated with broad-spectrum antibiotics, will develop concurrent severe CDI. We will discuss possible therapy strategies for these patients. PMID- 26612230 TI - Regiocontrolled synthesis of (hetero)aryl and alkenyl dehydropyrrolidines, dehydropiperidines and azepenes by Ru-catalyzed, heteroatom-directed alpha-C-H activation/cross-coupling of cyclic enamides with boronic acids. AB - The synthesis of alpha-aryl and alkenyl pyrrolidine-, piperidine-, and azepane derivatives, through the intermediacy of cyclic enamides is described. The desired outcome is achieved through ruthenium-catalyzed, site-selective sp(2) C-H activation/cross-coupling with aryl and alkenyl boronic acids. The regioselectivity (alpha-sp(2)vs. alpha-sp(3)vs. beta-sp(2) C-H functionalization) is governed by the rate differences between sp(2) and sp(3) C-H activation and the necessity for chelation between the ruthenium metal and the carbonyl directing group. PMID- 26612231 TI - Investigation of antitumor potential of Ni(II) complexes with tridentate PNO acylhydrazones of 2-(diphenylphosphino)benzaldehyde and monodentate pseudohalides. AB - Square-planar azido Ni(II) complex with condensation product of 2 (diphenylphosphino)benzaldehyde and Girard's T reagent was synthesized and its crystal structure was determined. Cytotoxic activity of the azido complex and previously synthesized isothiocyanato, cyanato and chlorido Ni(II) complexes with this ligand was examined on six tumor cell lines (HeLa, A549, K562, MDA-MB-453, MDA-MB-361 and LS-174) and two normal cell line (MRC-5 and BEAS-2B). All the investigated nickel(II) complexes were cytotoxic against all tumor cell lines. The newly synthesized azido complex showed selectivity to HeLa and A549 tumor cell lines compared to the normal cells (for A549 IC50 was similar to that of cisplatin). Azido complex interferes with cell cycle phase distribution of A549 and HeLa cells and possesses nuclease activity towards supercoiled DNA. The observed selectivity of the azido complex for some tumor cell lines can be connected with its strong DNA damaging activity. PMID- 26612233 TI - Bailliere's best practice rheumatology edition on work and MSDs. PMID- 26612232 TI - Supporting systematic reviews using LDA-based document representations. AB - BACKGROUND: Identifying relevant studies for inclusion in a systematic review (i.e. screening) is a complex, laborious and expensive task. Recently, a number of studies has shown that the use of machine learning and text mining methods to automatically identify relevant studies has the potential to drastically decrease the workload involved in the screening phase. The vast majority of these machine learning methods exploit the same underlying principle, i.e. a study is modelled as a bag-of-words (BOW). METHODS: We explore the use of topic modelling methods to derive a more informative representation of studies. We apply Latent Dirichlet allocation (LDA), an unsupervised topic modelling approach, to automatically identify topics in a collection of studies. We then represent each study as a distribution of LDA topics. Additionally, we enrich topics derived using LDA with multi-word terms identified by using an automatic term recognition (ATR) tool. For evaluation purposes, we carry out automatic identification of relevant studies using support vector machine (SVM)-based classifiers that employ both our novel topic-based representation and the BOW representation. RESULTS: Our results show that the SVM classifier is able to identify a greater number of relevant studies when using the LDA representation than the BOW representation. These observations hold for two systematic reviews of the clinical domain and three reviews of the social science domain. CONCLUSIONS: A topic-based feature representation of documents outperforms the BOW representation when applied to the task of automatic citation screening. The proposed term-enriched topics are more informative and less ambiguous to systematic reviewers. PMID- 26612234 TI - The management of musculoskeletal disorders in the workplace. AB - Musculoskeletal disorders are a major cause of suffering and disability among working-age adults. Although working in ergonomically unsound jobs may lead to the development of certain musculoskeletal disorders, it is increasingly recognised that well-designed work is generally good for health and individuals with musculoskeletal disorders generally benefit from working. This chapter explores how health-care professionals should assess patients' fitness for work, what factors should be considered and how the results should be communicated and to whom. Of necessity, this chapter describes current United Kingdom (UK) schemes and systems. Nevertheless, the principles described can be extended to most countries but the reader is advised to familiarise themselves with the detail of the equivalent national services in their own practice. The new UK Fit for Work service is explained together with advice on how best to use a fit note to optimise patients' short- and long-term health. We detail what benefits are available to those who are unable to work because of poor health and how health professionals can achieve an optimum balance between supporting those who are genuinely unfit to work through benefits from a welfare state and encouraging and facilitating those who can earn an independent living to do so. PMID- 26612235 TI - Economic impact of musculoskeletal disorders (MSDs) on work in Europe. AB - Musculoskeletal disorders (MSDs) are the leading cause of work disability, sickness absence from work, 'presenteeism' and loss of productivity across all the European Union (EU) member states. It is estimated that the total cost of lost productivity attributable to MSDs among people of working age in the EU could be as high as 2% of gross domestic product (GDP). This paper examines the available evidence on the economic burden of MSDs on work across Europe and highlights areas of policy, clinical and employment practice which might improve work outcomes for individuals and families and reduce the economic and social costs of MSDs. PMID- 26612236 TI - Psychological and psychosocial determinants of musculoskeletal pain and associated disability. AB - Although much attention has been given to the physical determinants of common musculoskeletal complaints such as back and arm pain, research points to a stronger influence of psychological factors. Multiple studies have implicated poor mental health and somatisation (a tendency to worry about the common somatic symptoms) in the incidence and chronicity of musculoskeletal pain and associated disability. Also important are adverse beliefs about the prognosis of such disorders, and about the role of physical activity in their development and persistence. Differences in societal beliefs may have contributed to major variation in the prevalence of disabling musculoskeletal pain that has been observed between countries and in the same countries over time. Psychosocial aspects of work have also been linked with musculoskeletal pain, although relative risks have generally been smaller. There is a need to take account of psychological factors in the clinical management of patients with back, neck and arm pain. PMID- 26612237 TI - Ageing, musculoskeletal health and work. AB - Changing demographics mean that many patients with soft tissue rheumatism, osteoarthritis, inflammatory arthritis, large joint prostheses and age-related co morbidities are seeking to work beyond the traditional retirement age. In this chapter, we review the evidence on musculoskeletal health and work at older ages. We conclude that musculoskeletal problems are common in older workers and have a substantial impact on their work capacity. Factors that influence their job retention are described, together with approaches that may extend working life. Many gaps in evidence were found, notably on the health risks and benefits of continued work in affected patients and on which interventions work best. The roles of physicians and managers are also considered. PMID- 26612238 TI - Shoulder disorders and occupation. AB - Shoulder pain is very common, and it causes substantial morbidity. Standardised classification systems based upon presumed patho-anatomical origins have proved poorly reproducible and hampered epidemiological research. Despite this, there is evidence that exposure to combinations of physical workplace strains such as overhead working, heavy lifting and forceful work as well as working in an awkward posture increases the risk of shoulder disorders. Psychosocial risk factors are also associated. There is currently little evidence to suggest that either primary prevention or treatment strategies in the workplace are very effective, and more research is required, particularly around the cost effectiveness of different strategies. PMID- 26612239 TI - Rheumatic effects of vibration at work. AB - Occupational exposures to vibration come in many guises, and they are very common at a population level. It follows that an important minority of working-aged patients seen by medical services will have been exposed to this hazard of employment. Vibration can cause human health effects, which may manifest in the patients that rheumatologists see. In this chapter, we identify the health effects of relevance to them, and review their epidemiology, pathophysiology, clinical presentation, differential diagnosis and vocational and clinical management. On either side of this, we describe the nature and assessment of the hazard, the scale and common patterns of exposure to vibration in the community and the legal basis for controlling health risks, and we comment on the role of health surveillance in detecting early adverse effects and what can be done to prevent the rheumatic effects of vibration at work. PMID- 26612240 TI - Carpal tunnel syndrome and work. AB - Carpal tunnel syndrome (CTS) is the most common peripheral nerve entrapment syndrome, and it frequently presents in working-aged adults. Its mild form causes 'nuisance' symptoms including dysaesthesia and nocturnal waking. At its most severe, CTS can significantly impair motor function and weaken pinch grip. This review discusses the anatomy of the carpal tunnel and the clinical presentation of the syndrome as well as the classification and diagnosis of the condition. CTS has a profile of well-established risk factors including individual factors and predisposing co-morbidities, which are briefly discussed. There is a growing body of evidence for an association between CTS and various occupational factors, which is also explored. Management of CTS, conservative and surgical, is described. Finally, the issue of safe return to work post carpal tunnel release surgery and the lack of evidence-based guidelines are discussed. PMID- 26612241 TI - Knee pain, knee injury, knee osteoarthritis & work. AB - Symptomatic knee osteoarthritis (OA) can be viewed as the end result of a molecular cascade which ensues after certain triggers occur and ultimately results in irreversible damage to the articular cartilage. The clinical phenotype that knee OA can produce is variable and often difficult to accurately predict. This is further complicated by the often poor relationship between radiographic OA and knee pain. As a consequence, it can be difficult to compare studies that use different definitions of OA. However, the literature suggests that while there are multiple causes of knee OA, two have attracted particular attention over recent years; occupation related knee OA and OA subsequent to previous knee injury. The evidence of a relationship, and the strength of this association, is discussed in this chapter. PMID- 26612243 TI - Back pain: Prevention and management in the workplace. AB - Despite all the efforts in studying work-related risk factors for low back pain (LBP), interventions targeting these risk factors to prevent LBP have no proven cost-effectiveness. Even with adequate implementation strategies for these interventions on group level, these did not result in the reduction of incident LBP. Physical exercise, however, does have a primary preventive effect on LBP. For secondary prevention, it seems that there are more opportunities to cost effectively intervene in reducing the risk of long-term sickness absence due to LBP. Starting at the earliest moment possible with proper assessment of risk factors for long-term sickness absence related to the individual, the underlying mechanisms of the LBP, and also factors related to the workplace by a well trained clinician, may increase the potential of effective return to work (RTW) management. More research on how to overcome barriers in the uptake of these effective interventions in relation to policy-specific environments, and with regard to proper financing of RTW management is necessary. PMID- 26612242 TI - HIP osteoarthritis and work. AB - Epidemiological evidence points strongly to a hazard of hip osteoarthritis from heavy manual work. Harmful exposures may be reduced by the elimination or redesign of processes and the use of mechanical aids. Reducing obesity might help to protect workers whose need to perform heavy lifting cannot be eliminated. Particularly high relative risks have been reported in farmers, and hip osteoarthritis is a prescribed occupational disease in the UK for long-term employees in agriculture. Even where it is not attributable to employment, hip osteoarthritis impacts importantly on the capacity to work. Factors that may influence work participation include the severity of disease, the physical demands of the job, age and the size of the employer. Published research does not provide a strong guide to the timing of return to work following hip arthroplasty for osteoarthritis, and it is unclear whether patients should avoid heavy manual tasks in their future employment. PMID- 26612244 TI - Rheumatoid arthritis and work: The impact of rheumatoid arthritis on absenteeism and presenteeism. AB - For patients with rheumatoid arthritis (RA), being in paid work is very important, and it increases self-esteem and financial independence. Although the management of RA has changed in the last 15 years to early aggressive treatment and the introduction of biologic treatments, many patients still have to take sick leave or even stop working because of their RA (i.e., absenteeism). For those remaining in paid work, patients may experience problems due to RA resulting in productivity loss while at work (i.e., presenteeism). The costs attributed to absenteeism and presenteeism (i.e., indirect costs) have been estimated to be very high, and they even exceed direct costs. However, there is no consensus on how to calculate these costs. This manuscript examines the relationship between the use of biologic therapy and absenteeism, with a focus on sick leave, and on presenteeism, and it provides an overview of indirect costs of absenteeism and presenteeism in those treated with biologic therapies. PMID- 26612245 TI - The impact of ankylosing spondylitis/axial spondyloarthritis on work productivity. AB - Ankylosing spondylitis (AS) is a chronic inflammatory condition that has a significant impact on the quality of life and work productivity. New classification criteria have enabled earlier diagnosis of this condition. However, work productivity is an important issue that is still often overlooked during clinical assessments and consultations. This article focusses on the relationship between axial spondyloarthritis (axial SpA) and work productivity. It summarises the impact of this condition on work productivity, and it highlights the tools available to assess this. It also highlights the increasing role and potential of employers, health professionals and new treatments for enhancing work productivity for people with this condition. PMID- 26612246 TI - Women find safety planning more useful than referrals in a maternal and child health IPV intervention. PMID- 26612247 TI - Handwashing and nail clipping reduce risk of intestinal parasite infection in school-age children. PMID- 26612248 TI - The statistical sins of Jeremy Hunt. PMID- 26612249 TI - The Contemporary Role of Masked Continuous Glucose Monitoring in a Real-Time World. AB - Real-time continuous glucose monitoring (RT-CGM) has, in the span of just a few years, established an essential role in the contemporary management of type 1 diabetes. Nonetheless, masked CGM retains an important place in the management of diabetes including assisting with hypoglycemia detection and avoidance, optimizing glycemic control, and acting as a teaching tool for people living with diabetes. PMID- 26612250 TI - Relevance of Helicobacter pylori vacA 3'-end Region Polymorphism to Gastric Cancer. AB - BACKGROUND: Helicobacter pylori vacA genotypes play an important role in the pathogenesis of severe gastrointestinal disease. MATERIALS AND METHODS: We identified a novel polymorphic site in the 3'-end region of H. pylori vacA gene, denoted by c1/-c2 (c1: with deletion of 15 bp), and examined associations of this and the previous four sites as well as cagA status with gastroduodenal diseases, in a total of 217 Iranian H. pylori isolates. Histopathologic evaluations were performed and patients with gastric cancer (GC) were further classified based on the anatomic site of tumor, including cardia and noncardia GC, and the histopathologic type of tumor, including intestinal- and diffuse-type GC. RESULTS: The vacA m1, i1, d1, c1, and cagA genotypes were significantly associated with an increased risk of GC, the odds ratio (95% confidence interval) was 4.29 (2.03-9.08), 6.11 (2.63-14.19), 3.18 (1.49-6.76), 15.13 (5.86-39.01), and 2.59 (1.09-6.12), respectively. The vacA c1 genotype had an increased age- and sex-adjusted risk for GC by the multiple logistic regression analysis; the OR was 38.32 (95% CI, 6.60-222.29). This association was independent of and larger than the associations of the m-, i-, and d-type of vacA or cagA status with GC. No significant correlation was found between s1, whether independently or in combination, and the risk of GC or peptic ulcer disease (PUD). The vacA i1 and cagA genotypes were linked to an increased risk of PUD; the OR (95% CI) was 2.80 (1.45-5.40) and 2.62 (1.23-5.61), respectively. The presence of both the vacA i1 and cagA genotypes further increased the risk of PUD; the OR was 5.20 (95% CI, 1.92-14.03). CONCLUSION: The H. pylori vacA c1 genotype might therefore be one of the strongest risk predictors of GC in male patients aged >=55 in Iran. PMID- 26612251 TI - Recent advances in anticoagulant drug delivery. AB - INTRODUCTION: Anticoagulants have been prescribed to patients to prevent deep vein thrombosis or pulmonary embolism. However, because of several problems in anticoagulant therapy, much attention has been directed at developing an ideal anticoagulant, and numerous attempts have been made to develop new anticoagulant delivery systems in recent years. AREAS COVERED: This review discusses the challenges associated with the recent development of anticoagulants and their delivery systems. Various delivery methods have been developed to improve the use of anticoagulants. Recent advances in anticoagulant delivery and antidote development are also discussed in the context of their current progression states. EXPERT OPINION: There have been many different approaches to developing the delivery system of anticoagulants. One approach has been to expand the use of new oral agents and develop their antidotes. Reducing the size of heparins to use smaller heparins for delivery, and developing oral or topical heparins are also some of the approaches used. Various physical formulations or chemical modifications are other ways that have enhanced the therapeutic potential of anticoagulant agents. On the whole, recent advances have contributed to increasing the efficacy and safety of anticoagulant clinically and have benefited the field of anticoagulant delivery. PMID- 26612252 TI - Impact of oxygen sources on performance of the Ventrain((r)) ventilation device in an in vitro set-up. AB - BACKGROUND: The Ventrain((r)) (Dolphys Medical, Eindhoven, The Netherlands) is a disposable handheld ventilation device allowing active inspiration and expiration through a transtracheal catheter. This study investigated Ventrain((r)) 's performance when used with different clinical oxygen sources in an in vitro set up. METHODS: Three anesthesia oxygen sources (wall-mounted flowmeter, respirator oxygen outlet port, and anesthesia ventilator circuit) were used at gas flow rates of 6, 9, 12, and 15 l/min. First, the sources' driving pressures (DP), the insufflation pressure (IP), and the flow at the catheter tip were measured using a gas flow analyzer. Tidal volumes (VT) delivered by the Ventrain((r)) were assessed by the ASL5000 test lung (respiratory rate: 15 min(-1), I:E = 1:1, compliance: 100 ml/cmH2O, resistance: 3.06 cmH2O/l/s). RESULTS: VT ranged from 82 to 483 ml for inspiration and 82 to 419 ml for expiration. Measured IP, flow, and VT were less dependent on the set gas flow rate but more on the source's DP. With rising DP the IP, the flow at the catheter tip and consequently VT increased. At an approximate target I:E ratio of 1:1, the ratio of inspiratory to expiratory VT increased with higher DP and gas flow rates. CONCLUSION: The oxygen sources resulted in clinically different IP, flows, and VT delivered by the Ventrain((r)) at given gas flow rates. This needs to be considered in a clinical emergency situation. Integrating an adjustable pressure valve into Ventrain((r)) to allow regulation of the lowest necessary IP would make its use safer. PMID- 26612253 TI - Stack Heterotrimeric G Proteins and MAPK Cascades on a RACK. AB - Heterotrimeric G proteins are molecular switches that relay intracellular signaling in eukaryotes. Recent studies in plant immunity provide a link between heterotrimeric G proteins and an MAPK cascade via the RACK1 scaffolding proteins. Research also points to a potential regulation of G proteins by cell surface receptors. PMID- 26612254 TI - Detection of amyloid-beta fibrils using the DNA-intercalating dye YOYO-1: Binding mode and fibril formation kinetics. AB - Identification of the chemical and biological properties of amyloid fibrils is important for understanding their roles in human diseases and to clarify the mechanisms that govern their formation. In pursuit of these goals, small molecule fluorescent dyes have received increasing attention as probes of amyloid conformations. In this study, we report on the ability of YOYO-1, a homodimeric derivative of oxazole yellow, to detect fibrils formed by the Alzheimer's disease related Abeta(1-42) peptide. We find that YOYO-1 binds to Abeta(1-42) fibrils with the long axes of its oxazole yellow moieties parallel to the fibril axis, resulting in a 200x emission enhancement; a result that shows that YOYO-1 is a sensitive amyloid probe. Further, YOYO-1 exhibits characteristic absorption shifts upon binding to the Abeta(1-42) fibrils that we attribute to a self stacking to non-stacking transition in its homodimer configuration; herein we show how this phenomenon can be exploited to estimate the degree of dye binding. Furthermore, we show that YOYO-1 can be used to monitor the kinetics of amyloid formation reactions. Taken together, our results show that YOYO-1 is a sensitive amyloid probe that can operate with both absorption and fluorescence read-outs, and this suggests that this commercially available dye could become a useful complement to thioflavin-T for in vitro amyloid-sensing applications. PMID- 26612255 TI - Arabidopsis Toxicos en Levadura 78 (AtATL78) mediates ABA-dependent ROS signaling in response to drought stress. AB - Plants have developed a variety of complicated responses to cope with drought, one of the most challenging environmental stresses. As a quick response, plants rapidly inhibit stomatal opening under the control of abscisic acid (ABA) signaling pathway, in order to preserve water. Here, we report that Arabidopsis Toxicos en Levadura (ATL), a RING-type E3 ubiquitin ligase, mediates the ABA dependent stomatal closure. In contrast to wild-type plants, the stomatal closure was fully impaired in atatl78 mutant plants even in the presence of exogenous ABA and reactive oxygen species (ROS). Besides, under high concentrations of Ca(2+), a down-stream signaling molecule of ABA signaling pathway, atatl78 mutant plants successfully closed the pores. Furthermore, AtATL78 protein indirectly associated with catalases and the deficiency of AtATL78 led the reduction of catalase activity and H2O2, implying the function of AtATL78 in the modulation of ROS activity. Based on these results, we suggest that AtATL78 possibly plays a role in promoting ROS-mediated ABA signaling pathway during drought stress. PMID- 26612256 TI - Crystal structure of the GTPase domain and the bundle signalling element of dynamin in the GDP state. AB - Dynamin is the prototype of a family of large multi-domain GTPases. The 100 kDa protein is a key player in clathrin-mediated endocytosis, where it cleaves off vesicles from membranes using the energy from GTP hydrolysis. We have solved the high resolution crystal structure of a fusion protein of the GTPase domain and the bundle signalling element (BSE) of dynamin 1 liganded with GDP. The structure provides a hitherto missing snapshot of the GDP state of the hydrolytic cycle of dynamin and reveals how the switch I region moves away from the active site after GTP hydrolysis and release of inorganic phosphate. Comparing our structure of the GDP state with the known structures of the GTP state, the transition state and the nucleotide-free state of dynamin 1 we describe the structural changes through the hydrolytic cycle. PMID- 26612257 TI - miR-543 promotes gastric cancer cell proliferation by targeting SIRT1. AB - SIRT1, a class III histone deacetylase, exerts inhibitory effects on tumorigenesis and is downregulated in gastric cancer. However, the role of microRNAs in the regulation of SIRT1 in gastric cancer is still largely unknown. Here, we identified miR-543 as a predicted upstream regulator of SIRT1 using 3 different bioinformatics databases. Mimics of miR-543 significantly inhibited the expression of SIRT1, whereas an inhibitor of miR-543 increased SIRT1 expression. MiR-543 directly targeted the 3'-UTR of SIRT1, and both of the two binding sites contributed to the inhibitory effects. In gastric epithelium-derived cell lines, miR-543 promoted cell proliferation and cell cycle progression, and overexpression of SIRT1 rescued the above effects of miR-543. The inhibitory effects of miR-543 on SIRT1 were also validated using clinical gastric cancer samples. Moreover, we found that miR-543 expression was positively associated with tumor size, clinical grade, TNM stage and lymph node metastasis in gastric cancer patients. Our results identify a new regulatory mechanism of miR-543 on SIRT1 expression in gastric cancer, and raise the possibility that the miR 543/SIRT1 pathway may serve as a potential target for the treatment of gastric cancer. PMID- 26612258 TI - Genome-wide identification and expression profiling analysis of trihelix gene family in tomato. AB - The trihelix family, classified as GT factors due to their binding specificity for GT elements, constitutes a plant-specific transcription factor family with a conserved trihelix DNA binding domain. In the present study, the comprehensive analysis of 36 putative GT factors was performed in tomato. SlGT members can be classified into six subgroups (GT-1, GT-2, SH4, SIP1, GT-gamma and GT-delta). Expression analysis of SlGT gene transcripts showed the distinct expression patterns of SlGT genes in various tomato organs. All the SlGT genes were regulated in response to various abiotic stresses and hormone treatments by the quantitative real-time PCR (qRT-PCR) analysis. Several SlGT genes, including SlGT 27 and SlGT-34, were highly regulated by multiple abiotic stresses and phytohormone treatments. Taken together, our results presented here would be providing a useful platform for molecular clone and functional identification of SlGT genes in tomato. PMID- 26612259 TI - Development of human neutralizing antibody to ADAMTS4 (aggrecanase-1) and ADAMTS5 (aggrecanase-2). AB - ADAMTS4 (aggrecanase-1) and ADAMTS5 (aggrecanase-2), members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family, are considered to play a key role in aggrecan degradation of articular cartilage in human osteoarthritis. Here, we developed a neutralizing antibody to these aggrecanases by screening human combinatorial antibody library. Among the five candidate antibodies, one antibody was immunoreactive with both ADAMTS4 and ADAMTS5, showing no or negligible cross-reactivity with 10 different related metalloproteinases of the ADAMTS, ADAM (a disintegrin and metalloproteinase) and MMP (matrix metalloproteinase) gene families. This antibody almost completely and partially inhibited aggrecanase activity of ADAMTS4 and ADAMTS5, respectively. It also suppressed the aggrecanase activity derived from interleukin-1-stimulated osteoarthritic chondrocytes. These data demonstrate that the antibody is specific to ADAMTS4 and ADAMTS5 and inhibits their aggrecanase activity at molecular and cellular levels, and suggest that this antibody may be useful for treatment of pathological conditions such as osteoarthritis. PMID- 26612260 TI - He Loves Me Not. PMID- 26612261 TI - Lungs and subcutaneous metastases from a solitary fibrous tumour of the pancreas. AB - Solitary fibrous tumour is an uncommon mesenchymal neoplasm previously thought to only originate from the pleura; it is seen only rarely in an extra-pleural location. We report the first case of pancreatic solitary fibrous tumour in an 87 year-old woman that has metastasized to the lungs and subcutaneous tissue. We have identified a solitary mass excised from the groin region, which is positive for CD34 and vimentic marker with high proliferative rate, nuclear atypia and cellular necrosis. Imaging studies confirmed a slow-growing solitary mass in the uncinate lobe of the pancreas with evidence of lung metastasis. PMID- 26612262 TI - Evaluation of (99m)Tc-TRODAT-1 SPECT in the diagnosis of Parkinson's disease versus other progressive movement disorders. AB - OBJECTIVE: Parkinson disease (PD), parkinsonian syndromes (PS) and essential tremor (ET) are different types of movement disorders which share some symptoms resulting in a difficulty of certain diagnosis. This study was conducted to determine the value of (99m)Tc-TRODAT-1 scan to differentiate PD from ET and other PS cases. METHODS: Totally, 75 patients were studied including 29 PD, 6 possible PD, 22 ET and 18 PS cases. A dual-head SPECT-CT was used to perform basal ganglia (BG) imaging following administration of (99m)Tc-TRODAT-1. The BG uptake values were normalized to whole brain and occipital activity. All patients were followed for 2-22 months to reach a certain diagnosis. RESULTS: Patients with ET and drug-induced parkinsonism show significantly higher normalized BG uptake as compared to the other subgroups; however, no significant difference was noted between PD and PS patients. The sensitivity and specificity of the findings for the differentiation between patients with the disease associated versus not associated with BG dysfunction were 80 and 83.3%, respectively. A predictive positive value of 82.6% was obtained using an additive scaling index defined as asymmetry and unevenness of uptake in putamen and/or caudate contralateral to the dominant side of current symptoms. CONCLUSIONS: (99m)Tc-TRODAT-1 scan is an appropriate method to differentiate PD or PS versus ET. A combination of scan pattern including asymmetry of BG uptake and unevenness of activity in caudate and putamen along with the side of dominant symptoms may be valuable for the differentiation of Parkinson's disease from the other parkinsonian syndromes. PMID- 26612263 TI - Infection-induced type I interferons activate CD11b on B-1 cells for subsequent lymph node accumulation. AB - Innate-like B-1a lymphocytes rapidly redistribute to regional mediastinal lymph nodes (MedLNs) during influenza infection to generate protective IgM. Here we demonstrate that influenza infection-induced type I interferons directly stimulate body cavity B-1 cells and are a necessary signal required for B-1 cell accumulation in MedLNs. Vascular mimetic flow chamber studies show that type I interferons increase ligand-mediated B-1 cell adhesion under shear stress by inducing high-affinity conformation shifts of surface-expressed integrins. In vivo trafficking experiments identify CD11b as the non-redundant, interferon activated integrin required for B-1 cell accumulation in MedLNs. Thus, CD11b on B 1 cells senses infection-induced innate signals and facilitates their rapid sequester into secondary lymphoid tissues, thereby regulating the accumulation of polyreactive IgM producers at sites of infection. PMID- 26612264 TI - Psychological and physiological correlates of childhood obesity in Taiwan. AB - Evidence of associations between psychopathology and obesity in childhood remains inconsistent, and most studies have been conducted in Western countries. This study investigated psychological and physiological correlates of obesity in a community sample of children in Taiwan. In total, 302 children (157 overweight/obese and 145 healthy-weight children) were selected from first- and fourth-grade schoolchildren in eight elementary schools in 2009. These children participated in a comprehensive health examination, including a physical examination, blood sample analysis, and questionnaire administration. We found that regarding physiological characteristics, compared with the healthy-weight children, the overweight/obese children had significantly higher values for body fat estimated using the bioelectrical impedance method (p < 0.001), systolic blood pressure (p < 0.001), and diastolic blood pressure (p = 0.001); lower values for high-density lipoprotein (p < 0.001); and worse values for glutamic pyruvic transaminase (p < 0.001), triglycerides (p < 0.001), and fasting blood glucose (p = 0.049). In logistic models adjusted for parental and child traits and physiological characteristics, children's overweight/obesity was significantly associated with lower self-concept (odds ratio [OR] = 0.96, 95% confidence interval [CI] = 0.93-0.99) and less disruptive behavior (OR = 0.96, 95% CI = 0.92-0.99). Less disruptive behavior and the lack of a higher prevalence of anxiety and depression in childhood obesity appear to be a unique pattern in Taiwan that warrants further investigation. PMID- 26612265 TI - Atomic/molecular layer deposition: a direct gas-phase route to crystalline metal organic framework thin films. AB - Atomic/molecular layer deposition offers us an elegant way of fabricating crystalline copper(ii)terephthalate metal-organic framework (MOF) thin films on various substrate surfaces. The films are grown from two gaseous precursors with a digital atomic/molecular level control for the film thickness under relatively mild conditions in a simple and fast one-step process. PMID- 26612266 TI - Evaluation and validation of a multi-residue method based on biochip technology for the simultaneous screening of six families of antibiotics in muscle and aquaculture products. AB - The Evidence InvestigatorTM system (Randox, UK) is a biochip and semi-automated system. The microarray kit II (AM II) is capable of detecting several compounds belonging to different families of antibiotics: quinolones, ceftiofur, thiamphenicol, streptomycin, tylosin and tetracyclines. The performance of this innovative system was evaluated for the detection of antibiotic residues in new matrices, in muscle of different animal species and in aquaculture products. The method was validated according to the European Decision No. EC/2002/657 and the European guideline for the validation of screening methods, which represents a complete initial validation. The false-positive rate was equal to 0% in muscle and in aquaculture products. The detection capabilities CCbeta for 12 validated antibiotics (enrofloxacin, difloxacin, ceftiofur, desfuroyl ceftiofur cysteine disulfide, thiamphenicol, florfenicol, tylosin, tilmicosin, streptomycin, dihydrostreptomycin, tetracycline, doxycycline) were all lower than the respective maximum residue limits (MRLs) in muscle from different animal origins (bovine, ovine, porcine, poultry). No cross-reactions were observed with other antibiotics, neither with the six detected families nor with other families of antibiotics. The AM II kit could be applied to aquaculture products but with higher detection capabilities from those in muscle. The detection capabilities CCbeta in aquaculture products were respectively at 0.25, 0.10 and 0.5 of the respective MRL in aquaculture products for enrofloxacin, tylosin and oxytetracycline. The performance of the AM II kit has been compared with other screening methods and with the performance characteristics previously determined in honey. PMID- 26612267 TI - Electrocaloric effect in ferroelectric nanowires from atomistic simulations. AB - Electrocaloric effect is presently under active investigation owing to both the recent discoveries of giant electrocaloric effects and its potential for solid state cooling applications. We use first-principles-based direct simulations to predict the electrocaloric temperature change in ferroelectric ultrathin nanowires. Our findings suggest that in nanowires with axial polarization direction the maximum electrocaloric response is reduced when compared to bulk, while the room temperature electrocaloric properties can be enhanced by tuning the ferroelectric transition temperature. The potential of ferroelectric nanowires for electrocaloric cooling applications is discussed. PMID- 26612268 TI - Single molecule detection with graphene and other two-dimensional materials: nanopores and beyond. AB - Graphene and other two dimensional (2D) materials are currently integrated into nanoscaled devices that may - one day - sequence genomes. The challenge to solve is conceptually straightforward: cut a sheet out of a 2D material and use the edge of the sheet to scan an unfolded biomolecule from head to tail. As the scan proceeds - and because 2D materials are atomically thin - the information provided by the edge might be used to identify different segments - ideally single nucleotides - in the biomolecular strand. So far, the most efficient approach was to drill a nano-sized pore in the sheet and use this pore as a channel to guide and detect individual molecules by measuring the electrochemical ionic current. Nanoscaled gaps between two electrodes in 2D materials recently emerged as powerful alternatives to nanopores. This article reviews the current status and prospects of integrating 2D materials in nanopores, nanogaps and similar devices for single molecule biosensing applications. We discuss the pros and cons, the challenges, and the latest achievements in the field. To achieve high-throughput sequencing with 2D materials, interdisciplinary research is essential. PMID- 26612269 TI - Protective role of glycerol against benzene stress: insights from the Pseudomonas putida proteome. AB - Chemical activities of hydrophobic substances can determine the windows of environmental conditions over which microbial systems function and the metabolic inhibition of microorganisms by benzene and other hydrophobes can, paradoxically, be reduced by compounds that protect against cellular water stress (Bhaganna et al. in Microb Biotechnol 3:701-716, 2010; Cray et al. in Curr Opin Biotechnol 33:228-259, 2015a). We hypothesized that this protective effect operates at the macromolecule structure-function level and is facilitated, in part at least, by genome-mediated adaptations. Based on proteome profiling of the soil bacterium Pseudomonas putida, we present evidence that (1) benzene induces a chaotrope stress response, whereas (2) cells cultured in media supplemented with benzene plus glycerol were protected against chaotrope stress. Chaotrope-stress response proteins, such as those involved in lipid and compatible-solute metabolism and removal of reactive oxygen species, were increased by up to 15-fold in benzene stressed cells relative to those of control cultures (no benzene added). By contrast, cells grown in the presence of benzene + glycerol, even though the latter grew more slowly, exhibited only a weak chaotrope-stress response. These findings provide evidence to support the hypothesis that hydrophobic substances induce a chaotropicity-mediated water stress, that cells respond via genome mediated adaptations, and that glycerol protects the cell's macromolecular systems. We discuss the possibility of using compatible solutes to mitigate hydrocarbon-induced stresses in lignocellulosic biofuel fermentations and for industrial and environmental applications. PMID- 26612270 TI - Regulation of bacterial gene expression by ribosome stalling and rescuing. AB - Ribosome is responsible for protein synthesis and is able to monitor the sequence and structure of the nascent peptide. Such ability plays an important role in determining overall gene expression profile of the bacteria through ribosome stalling and rescuing. In this review, we briefly summarize our current understanding of the regulation of gene expression through ribosome stalling and rescuing in bacteria, as well as mechanisms that modulate ribosome activity. Understanding the mechanisms of how bacteria modulate ribosome activity will provide not only fundamental insights into bacterial gene regulation, but also new candidate targets for the development of novel antimicrobial agents. PMID- 26612271 TI - Encapsulation of cosmetic active ingredients for topical application--a review. AB - Microencapsulation is finding increasing applications in cosmetics and personal care markets. This article provides an overall discussion on encapsulation of cosmetically active ingredients and encapsulation techniques for cosmetic and personal care products for topical applications. Some of the challenges are identified and critical aspects and future perspectives are addressed. Many cosmetics and personal care products contain biologically active substances that require encapsulation for increased stability of the active materials. The topical and transdermal delivery of active cosmetic ingredients requires effective, controlled and safe means of reaching the target site within the skin. Preservation of the active ingredients is also essential during formulation, storage and application of the final cosmetic product. Microencapsulation offers an ideal and unique carrier system for cosmetic active ingredients, as it has the potential to respond to all these requirements. The encapsulated agent can be released by several mechanisms, such as mechanical action, heat, diffusion, pH, biodegradation and dissolution. The selection of the encapsulation technique and shell material depends on the final application of the product, considering physical and chemical stability, concentration, required particle size, release mechanism and manufacturing costs. PMID- 26612273 TI - Within the Bounds: The Role of Relocation on Intimate Partner Violence Help Seeking for Immigrant and Native Women With Histories of Homelessness. AB - Our study examines the effects of abused women's relocation and recentness to an area on informal and formal help-seeking, and how access to personal and social resources affect these relationships. Secondary data analysis was conducted using a sample of 572 women with histories of abuse and homelessness who were interviewed at shelters in the state of Florida. Findings from nested linear regressions demonstrate that relocation affects formal help-seeking while recentness to an area affects informal help-seeking. Access to personal resources also predicts women's use of both informal and formal resources. Implications for intimate partner violence help-seeking are discussed. PMID- 26612272 TI - Trajectories of internalizing and externalizing symptoms among adults with autism spectrum disorders. AB - Individuals with autism spectrum disorder (ASD) experience higher rates of psychopathology than their typically developing peers or peers with other intellectual or developmental disabilities. Little is known about the developmental course of psychiatric symptoms such as internalizing and externalizing behaviors in this population. Individual characteristics and aspects of the family environment may explain variability in outcomes for adults with ASD. The present study extends our current understanding of psychopathology among individuals with ASD by examining group-based trajectories of internalizing and externalizing symptoms in adulthood. Overall, the results showed that symptoms became less severe over time. Distinct patterns of change in psychopathology were observed and associated with differential profiles of psychotropic medication use, comorbid mental health diagnoses, and residential placement. The likelihood of following each developmental trajectory was estimated based on characteristics of the adults with ASD (gender, adaptive behavior, and autistic symptoms) and maternal expressed emotion (criticism and warmth). Maternal criticism and warmth were identified as key risk and protective factors, respectively, with important implications for future research and intervention for individuals with ASD. PMID- 26612274 TI - Measuring Physical Violence and Rape Against Somali Women Using the Neighborhood Method. AB - This study was conducted to estimate prevalence of gender-based violence (GBV) among female Somalis in Ethiopian refugee camps and host communities, compare prevalence in camps and communities, and compare prevalence in flight and in camp. Systematic random sampling was used to select households in Awbare camp (n = 85), Awbare town (n = 76), and Kebribeyah camp (n = 83). GBV was common and overwhelmingly domestic. Prevalence was higher in Awbare town than Kebribeyah camp. Women were at increased risk of GBV in camp compared with in flight. The domestic nature of GBV in humanitarian settings requires attention. Assumptions about violence in humanitarian settings should be further tested. PMID- 26612275 TI - Negotiating Peril: The Lived Experience of Rural, Low-Income Women Exposed to IPV During Pregnancy and Postpartum. AB - This qualitative study of 10 rural women examines their lived experience of intimate partner violence during pregnancy and the first 2 postpartum years. In depth interviews occurred during pregnancy and 4 times postpartum. A Heideggerian approach revealed "negotiating peril" as the overarching theme; sub-themes were unstable environment, adaptive calibration, primacy of motherhood, and numb acceptance. Some incremental shifts in severity of abusive situations were observed. Results elucidate the ambivalence with which these women view institutions that are designed to help them. Findings highlight factors that may explain why interventions designed to help often do not appear efficacious in facilitating complete termination of an abusive situation. PMID- 26612276 TI - Latinos With Chronic Kidney Failure Treated by Dialysis: Understanding Their Palliative Care Perspectives. PMID- 26612277 TI - Proliferative Glomerulonephritis With Monoclonal IgG1kappa Deposits in a Hepatitis C Virus-Positive Patient. AB - Hepatitis C virus infection is associated with several glomerular diseases, most commonly cryoglobulinemic glomerulonephritis, which is typically secondary to type II mixed cryoglobulinemia. We present a patient with hepatitis C virus infection and cryoglobulinemic glomerulonephritis secondary to type I (monoclonal) cryoglobulinemia that is likely related to a concurrent hepatitis C virus infection-associated lymphoproliferative disorder. We list the differential diagnosis of cryoglobulinemic glomerulonephritis. Additionally, the case draws attention to the possibility that, rarely, even clinically undetectable "occult" B-cell lymphoproliferative disorders may result in significant kidney disease. PMID- 26612278 TI - Misclassification of Obesity by Body Mass Index Among Patients Receiving Hemodialysis. PMID- 26612279 TI - Hand Ischemia in a Patient With an Arteriovenous Fistula. AB - An ischemic digit causes significant morbidity due to its associated discomfort and potential for tissue necrosis. Historically, when this phenomenon was peripheral to an ipsilateral arteriovenous access in a hemodialysis patient, it was called "steal syndrome" and was usually treated with access ligation, resulting in loss of the access. We present a dialysis patient with hand pain due to ischemia that was referred for access ligation. Instead, a minimally invasive banding procedure was performed that resulted in access salvage and resolution of symptoms. We present images and a discussion of the diagnosis and treatment of distal hypoperfusion ischemia syndrome in this Imaging Teaching Case. PMID- 26612281 TI - Haploidentical Peripheral Blood Stem Cell Transplantation with Post Transplantation Cyclophosphamide in Children with Advanced Acute Leukemia with Fludarabine-, Busulfan-, and Melphalan-Based Conditioning. AB - Post-transplantation cyclophosphamide (PTCY) therapy has made haploidentical transplantation a global reality in adults, but the literature is largely silent on the feasibility of this approach in children. We conducted a prospective study of 20 patients (median age, 12 years; range, 2-20 years) with advanced acute leukemia to evaluate the feasibility of PTCY-based haploidentical peripheral blood stem cell (PBSC) transplantation in children. The conditioning regimen comprised fludarabine, i.v. busulfan, and melphalan (Flu-Bu-Mel). PTCY on days +3 and +4 was followed by mycophenolate mofetil for 14-21 days and cyclosporine for 60 days. Thirteen patients (65%) had refractory or relapsed myelogenous leukemia, and the remainder had high-risk lymphoblastic leukemia. Prompt engraftment was noted at a median of 14 days, with full donor chimerism by day +28. The cumulative incidence of acute and chronic graft-versus-host disease was 35% and 5%, respectively. Nonrelapse mortality at 1 year was 20%. The incidence of disease progression was 25.7%. The actuarial overall survival at 2 years was 64.3% (95% confidence interval, 53.4%-75.2%). Our data suggest that Flu-Bu-Mel based conditioning followed by PTCY-based haploidentical PBSC transplantation with reduced duration of immunosuppression is feasible in pediatric patients with advanced leukemia. PMID- 26612280 TI - Functional Dependence and Mortality in the International Dialysis Outcomes and Practice Patterns Study (DOPPS). AB - BACKGROUND: Patients receiving long-term dialysis have among the highest mortality and hospitalization rates. In the nonrenal literature, functional dependence is recognized as a contributor to subsequent disability, recurrent hospitalization, and increased mortality. A higher burden of functional dependence with progressive worsening of kidney function has been observed in several studies, suggesting that functional dependence may contribute to both morbidity and mortality in dialysis patients. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 7,226 hemodialysis patients from 12 countries in the DOPPS (Dialysis Outcomes and Practice Patterns Study) phase 4 (2009-2011) with self-reported data for functional status. PREDICTOR: Patients' ability to perform 13 basic and instrumental activities of daily living was summarized to create an overall functional status score (range, 1.25 [most dependent] to 13 [functionally independent]). OUTCOME: Cox regression was used to estimate the association between functional status and all-cause mortality, adjusting for several demographic and clinical risk factors for mortality. Median follow-up was 17.2 months. RESULTS: The proportion of patients who could perform each activity of daily living task without assistance ranged from 97% (eating) to 47% (doing housework). 36% of patients could perform all 13 tasks without assistance (functional status = 13), and 14% of patients had high functional dependence (functional status < 8). Functionally independent patients were younger and had many indicators of better health status, including higher quality of life. Compared with functionally independent patients, the adjusted HR for mortality was 2.37 (95% CI, 1.92-2.94) for patients with functional status < 8. LIMITATIONS: Possible nonresponse bias and residual confounding. CONCLUSIONS: We found a high burden of functional dependence across all age groups and across all DOPPS countries. When adjusting for several known mortality risk factors, including age, access type, cachexia, and multimorbidity, functional dependence was a strong consistent predictor of mortality. PMID- 26612282 TI - Add-on Protective Effect of Pentoxifylline in Advanced Chronic Kidney Disease Treated with Renin-Angiotensin-Aldosterone System Blockade - A Nationwide Database Analysis. AB - A combination therapy of pentoxifylline with an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) decreased proteinuria or glomerular filtration rate decline in early chronic kidney disease (CKD). Whether adding pentoxifylline to ACEI/ARB provides additional benefits on outcome is unclear in CKD stage 5 patients who have not yet received dialysis (CKD 5 ND). A prospective cohort study was conducted based on the Taiwan National Health Insurance Research Database. From January 1, 2000 to June 30, 2009, we enrolled 14,117 CKD 5 ND with serum creatinine levels >6 mg/dL and hematocrit levels <28% and who have been treated with ACEI/ARB. All patients were divided into pentoxifylline users and nonusers. Patient follow-up took place until dialysis, death before initiation of dialysis or December 31, 2009. Finally, 9,867 patients (69.9%) required long-term dialysis and 2,805 (19.9%) died before dialysis. After propensity score-matching, use of pentoxifylline was associated with a lower risk for long-term dialysis or death in ACEI/ARB users (HR, 0.94; 95% CI, 0.90-0.99) or ARB users (HR, 0.91; 95% CI, 0.85-0.97). In conclusion, pentoxifylline exhibited a protective effect in reducing the risk for the composite outcome of long-term dialysis or death in ACEI/ARB treated CKD 5 ND. PMID- 26612283 TI - Serum Bilirubin and 6-min Walk Distance as Prognostic Predictors for Inoperable Chronic Thromboembolic Pulmonary Hypertension: A Prospective Cohort Study. AB - BACKGROUND: Inoperable chronic thromboembolic pulmonary hypertension (CTEPH) is a severe clinical syndrome characterized by right cardiac failure and possibly subsequent liver dysfunction. However, whether serum markers of liver dysfunction can predict prognosis in inoperable CTEPH patients has not been determined. Our study aimed to evaluate the potential role of liver function markers (such as serum levels of transaminase, bilirubin, and gamma-glutamyl transpeptidase [GGT]) combined with 6-min walk test in the prediction of prognosis in patients with inoperable CTEPH. METHODS: From June 2005 to May 2013, 77 consecutive patients with inoperable CTEPH without confounding co-morbidities were recruited for this prospective cohort study. Baseline clinical characteristics and 6-min walk distance (6MWD) results were collected. Serum biomarkers of liver function, including levels of aspartate aminotransferase, alanine aminotransferase, GGT, uric acid, and serum bilirubin, were also determined at enrollment. All-cause mortality was recorded during the follow-up period. RESULTS: During the follow up, 22 patients (29%) died. Cox regression analyses demonstrated that increased serum concentration of total bilirubin (hazard ratio [HR] = 7.755, P < 0.001), elevated N-terminal of the prohormone brain natriuretic peptide (HR = 1.001, P = 0.001), decreased 6MWD (HR = 0.990, P < 0.001), increased central venous pressure (HR = 1.074, P = 0.040), and higher pulmonary vascular resistance (HR = 1.001, P = 0.018) were associated with an increased risk of mortality. Serum concentrations of total bilirubin (HR = 4.755, P = 0.007) and 6MWD (HR = 0.994, P = 0.017) were independent prognostic predictors for CTEPH patients. Patients with hyperbilirubinemia (>=23.7 MUmol/L) had markedly worse survival than those with normobilirubinemia. CONCLUSION: Elevated serum bilirubin and decreased 6MWD are potential predictors for poor prognosis in inoperable CTEPH. PMID- 26612284 TI - Clinical Characteristics and Prognosis of Peri-strut Low-intensity Area Detected by Optical Coherence Tomography. AB - BACKGROUND: Peri-strut low-intensity area (PLIA) is a typical image pattern of neointima detected by optical coherence tomography (OCT) after stent implantation. However, few studies evaluated the predictors and prognosis of the PLIA; therefore, we aimed to explore the genesis and prognosis of PLIA detected by OCT in this study. METHODS: Patients presenting neointimal hyperplasia documented by OCT reexamination after percutaneous coronary intervention were prospectively included from 2009 to 2011. Peri-strut intensity was analyzed and classified into two patterns: Low-intensity and high-intensity. Clinical characteristics were analyzed to assess their contribution to peri-strut intensity patterns. Follow-up were performed in patients who did not receive revascularization during OCT reexamination, and the prognosis of the patients was evaluated. RESULTS: There were 128 patients underwent OCT reexamination after stent implantation included in the study. PLIA was detected in 22 (17.2%) patients. The incidence of PLIA was positively correlated with serum triglyceride (odds ratio [OR]: 2.11, 95% confidence interval [CI]: 1.14-3.90, P = 0.017), low density lipoprotein (OR: 2.61, 95% CI: 1.22-5.66, P = 0.015), history of cerebrovascular disease (OR: 101.11, 95% CI: 6.54-1562.13, P < 0.001), and initial clinical presentation of acute coronary syndrome (ACS, OR: 18.77, 95% CI: 2.73-128.83, P = 0.003) while negatively correlated with stent implantation time (OR: 0.57, 95% CI: 0.33-0.98, P = 0.043). The median follow-up was longer than 3.8 years. Major adverse cardiovascular events (MACEs) occurred in 7 (7.3%) patients while showed no correlation with PLIA. A total of 17 (17.7%) patients experienced unstable angina (UA) and showed significant correlation with PLIA (hazard ratio: 6.16, 95% CI: 1.25-30.33, P = 0.025). CONCLUSIONS: PLIA detected by OCT was positively correlated with higher serum lipid level, history of cerebrovascular disease and initial presentation of ACS, and negatively correlated with stent implantation time. Patients with PLIA were more likely to have UA than those with high-intensity while no significant difference was found in MACEs. PMID- 26612285 TI - Lack of Efficacy of Ulinastatin Therapy During Cardiopulmonary Bypass Surgery. AB - BACKGROUND: It was believed that inflammatory response induced by cardiopulmonary bypass (CPB) was blamed for complications after cardiac surgery. To improve the outcome, many pharmacological interventions have been applied to attenuate inflammatory response during CPB. The objective of this study was to investigate the effect of ulinastatin (urinary trypsin inhibitor [UTI]) on outcome after CPB surgery. METHODS: Totally, 208 patients undergoing elective valves replacement between November 2013 and September 2014 were divided into Group U (n = 70) and Group C (n = 138) based on they received UTI or not. Categorical variables were compared between groups using Fisher's exact test, and continuous variables using unpaired Student's t-test or Mann-Whitney U-test. One-way analysis of variance and Dunnett's or Tukey's tests were used to compare values at different time points within the same group. The risk of outcomes was estimated and adjusted by multivariable logistic regression, propensity scoring, and mixed-effect models for all measured variables. RESULTS: Both the serious complications in total, including death, acute lung injury, acute respiratory distress syndrome and acute kidney injury, and the other complications, including hemodialysis, infection, re incubation, and tracheotomy were similar between the two groups (P > 0.05). After adjusted by multivariable logistic regression and the propensity score, UTI still cannot be found any benefit to improve any outcomes after cardiac surgery. Also, no statistical differences with regard to duration of postoperative mechanical ventilation, the length of Intensive Care Unit and hospital stays (P > 0.05). CONCLUSION: UTI did not improve postoperative outcomes in our patients after cardiopulmonary bypass surgery. PMID- 26612286 TI - Dexmedetomidine-midazolam versus Sufentanil-midazolam for Awake Fiberoptic Nasotracheal Intubation: A Randomized Double-blind Study. AB - BACKGROUND: Awake fiberoptic intubation (AFOI) is usually performed in the management of the predicted difficult airway. The aim of this study was to evaluate the feasibility of dexmedetomidine with midazolam (DM) and sufentanil with midazolam (SM) for sedation for awake fiberoptic nasotracheal intubation. METHODS: Fifty patients with limited mouth opening scheduled for AFOI were randomly assigned to two groups (n = 25 per group) by a computer-generated randomization schedule. All subjects received midazolam 0.02 mg/kg as premedication and airway topical anesthesia with a modified "spray-as-you-go" technique. Group DM received dexmedetomidine at a loading dose of 0.5 MUg/kg over 10 min followed by a continuous infusion of 0.25 MUg.kg-1.h-1, whereas Group SM received sufentanil at a loading dose of 0.2 MUg/kg over 10 min followed by a continuous infusion of 0.1 MUg.kg-1.h-1. As necessary, since the end of the administration of the loading dose of the study drug, an additional dose of midazolam 0.5 mg at 2-min intervals was given to achieve a modified Observers' Assessment of Alertness/Sedation of 2-3. The quality of intubation conditions and adverse events were observed. RESULTS: The scores of ease of the AFOI procedure, patient's reaction during AFOI, coughing severity, tolerance after intubation, recall of the procedure and discomfort during the procedure were comparable in both groups (z = 0.572, 0.664, 1.297, 0.467, 0.895, and 0.188, respectively, P > 0.05). Hypoxic episodes similarly occurred in the two groups, but the first partial pressure of end-tidal CO2after intubation was higher in Group SM than that in Group DM (45.2 +/- 4.2 mmHg vs. 42.2 +/- 4.3 mmHg, t = 2.495, P < 0.05). CONCLUSIONS: Both dexmedetomidine and sufentanil are effective as an adjuvant for AFOI under airway topical anesthesia combined with midazolam sedation, but respiratory depression is still a potential risk in the sufentanil regimen. PMID- 26612287 TI - Clinicopathological Characteristics and Prognosis of Colorectal Cancer in Chinese Adolescent Patients. AB - BACKGROUND: Colorectal adenocarcinoma rarely occurred in adolescent. Clinical feature and prognosis of this population are not clear until now. In addition, DNA mismatch repair (MMR) status may relate to the early disease occurrence. The present study aimed to perform a retrospective analysis of adolescent patients with colorectal cancer, including clinicopathological characteristics and prognosis. METHODS: The medical records of 11,503 patients diagnosed as colorectal cancer in Cancer Hospital, Chinese Academy of Medical Sciences from January 1999 to December 2009 were retrospectively reviewed. Finally, 19 patients who were between 10 and 20 years old were selected as the study group. We summarized the clinicopathological characteristics, analyzed the association with prognosis and assessed the expression of MMR protein by immunohistochemical method. RESULTS: The most common primary site was the right colon in 7 patients. Ten patients had Stage III colorectal cancer, 5 patients had Stage IV disease. Signet ring cell carcinoma was the most frequent pathological type (7/19). Deficient MMR was identified in 2 patients. The 5-year survival rate and median survival time were 23.2% and 26 months. Distant metastasis was identified as an independent prognostic factor (P = 0.02). CONCLUSIONS: Colorectal cancer in Chinese adolescents was very rare. The chinese adolecents with colorectal cancer were frequently diagnosed in the right colon, as Stage III/IV disease with signet ring cell carcinoma. The prognosis was relatively poor. PMID- 26612288 TI - Blunt Dissection: A Solution to Prevent Bile Duct Injury in Laparoscopic Cholecystectomy. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) has been a standard operation and replaced the open cholecystectomy (OC) rapidly because the technique resulted in less pain, smaller incision, and faster recovery. This study was to evaluate the value of blunt dissection in preventing bile duct injury (BDI) in laparoscopic cholecystectomy (LC). METHODS: From 2003 to 2015, LC was performed on 21,497 patients, 7470 males and 14,027 females, age 50.3 years (14-84 years). The Calot's triangle was bluntly dissected and each duct in Calot's triangle was identified before transecting the cystic duct. RESULTS: Two hundred and thirty nine patients (1.1%) were converted to open procedures. The postoperative hospital stay was 2.1 (0-158) days, and cases (46%) had hospitalization days of 1 day or less, and 92.8% had hospitalization days of 3 days or less; BDI was occurred in 20 cases (0.09%) including 6 cases of common BDI, 2 cases of common hepatic duct injury, 1 case of right hepatic duct injury, 1 case of accessory right hepatic duct, 1 case of aberrant BDI 1 case of biliary stricture, 1 case of biliary duct perforation, 3 cases of hemobilia, and 4 cases of bile leakage. CONCLUSION: Exposing Calot's triangle by blunt dissection in laparoscopic cholecystectomy could prevent intraoperative BDI. PMID- 26612289 TI - Depression of the Thoracolumbar Posterior Vertebral Body on the Estimation of Cement Leakage in Vertebroplasty and Kyphoplasty Operations. AB - BACKGROUND: The cross-section of thoracolumbar vertebral body is kidney-shaped with depressed posterior boundary. The anterior wall of the vertebral canal is separated from the posterior wall of the vertebral body on the lateral X-ray image. This study was designed to determine the sagittal distance between the anterior border of the vertebral canal and the posterior border of the vertebral body (DBCV) and to analyze the potential role of DBCV in the estimation of cement leakage during percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP). METHODS: We retrospectively recruited 233 patients who had osteoporotic vertebral compression fractures and were treated with PVP or PKP. Computed tomography images of T11-L2 normal vertebrae were measured to obtain DBCV. The distance from cement to the posterior wall of the vertebral body (DCPW) of thoracolumbar vertebrae was measured from C-arm images. The selected vertebrae were divided into two groups according to DCPW, with the fracture levels, fracture grades and leakage rates of the two groups compared. A relative operating characteristic (ROC) curve was applied to determine whether the DCPW difference can be used to estimate the degree of cement leakage. The data were processed by statistical software SPSS version 21.0 using independent sample t test and Chi-square tests. RESULTS: The maximum DBCV was 6.40 mm and the average DBCV was 3.74 +/- 0.95 mm. DBCV appeared to be longer in males than in females, but the difference was not statistically significant. The average DCPW of type-B leakage vertebrae (2.59 +/- 1.20 mm) was shorter than that of other vertebrae (7.83 +/- 2.38 mm, P < 0.001). The leakage rate of group DCPW <=6.40 mm was lower than that of group DCPW >6.40 mm for type-C and type-S, but much higher for type B. ROC curve revealed that DCPW only has a predictive value for type-B leakage (area under the curve: 0.98, 95% confidence interval: 0.95-0.99, P < 0.001), and when the cut-off value was 4.05 mm, the diagnostic sensitivity and the specificity were 94.87% and 93.02%, respectively. CONCLUSIONS: Depression of the thoracolumbar posterior vertebral body may be informative for the estimation of cement location on C-arm images. To reduce type-B leakage, DCPW should be made longer than DBCV on C-arm images for safety during PVP or PKP. PMID- 26612290 TI - Comparison of Clinical Outcome of Autograft and Allograft Reconstruction for Anterior Cruciate Ligament Tears. AB - BACKGROUND: Hamstring (HS) autograft and bone-patellar tendon-bone allograft are the most common choice for reconstruction of anterior cruciate ligament (ACL). There was a little report about the clinical outcome and difference of arthroscopic ACL reconstruction using allograft and autograft. This study aimed to compare the clinical outcome of autograft and allograft reconstruction for ACL tears. METHODS: A total of 106 patients who underwent surgery because of ACL tear were included in this study. The patients were randomly divided into two groups, including 53 patients in each group. The patients in group I underwent standard ACL reconstruction with HS tendon autografts, while others in group II underwent reconstruction with bone-patellar tendon-bone allograft. All the patients were followed up and analyzed; the mean follow-up was 81 months (range: 28-86 months). Clinical outcomes were evaluated using the International Knee Documentation Committee (IKDC), Lysholm scores, physical instability tests, and patient satisfaction questionnaires. The complication rates of both groups were compared. Tibial and femoral tunnel widening were assessed using lateral and anteroposterior radiographs. RESULTS: At the end of follow-up, no significant differences were found between the groups in terms of IKDC, Lysholm scores, physical instability tests, patient satisfaction questionnaires, and incidences of arthrofibrosis. Tibial and femoral tunnel widening was less in the HS tendon autografts. This difference was more significant on the tibial side. CONCLUSIONS: In the repair of ACL tears, allograft reconstruction is as effective as the autograft reconstruction, but the allograft can lead to more tunnel widening evidently in the tibial tunnel, particularly. PMID- 26612291 TI - Pregnancy Outcomes of In Vitro Fertilization with or without Ovarian Hyperstimulation Syndrome: A Retrospective Cohort Study in Chinese Patients. AB - BACKGROUND: The effect of ovarian hyperstimulation syndrome (OHSS) on pregnancy outcomes of in vitro fertilization (IVF) patients is still ambiguous. This study aimed to analyze pregnancy outcomes of IVF with or without OHSS in Chinese patients. METHODS: A retrospective cohort study was undertaken to compare pregnancy outcomes between 190 women with OHSS and 197 women without OHSS. We examined the rates of clinical pregnancy, multiple pregnancies, miscarriage, live birth, preterm delivery, preterm birth before 34 weeks' gestation, cesarean delivery, low birth weight (LBW), and small-for-gestational age (SGA) between the two groups. Odds ratios (OR s) and 95% confidence intervals (CI s) of measure of clinical pregnancy were also analyzed. RESULTS: The clinical pregnancy rate of OHSS patients was significantly higher than that of non-OHSS patients (91.8% vs. 43.5%, P < 0.001). After controlling for drug protocol and causes of infertility, the adjusted OR s of moderate OHSS and severe/critical OHSS for clinical pregnancy were 4.65 (95% CI, 1.86-11.61) and 5.83 (95% CI, 3.45-9.86), respectively. There were no significant differences in rates of multiple pregnancy (4.0% vs. 3.7%) and miscarriage (16.1% vs. 17.5%) between the two groups. With regard to ongoing clinical pregnancy, we also found no significant differences in the rates of live birth (82.1% vs. 78.8%), preterm delivery (20.9% vs. 17.5%), preterm birth before 34 weeks' gestation (8.6% vs. 7.9%), cesarean delivery (84.9% vs. 66.3%), LBW (30.2% vs. 23.5%), and SGA (21.9% vs. 17.6%) between the two groups. CONCLUSION: OHSS, which occurs in the luteal phase or early pregnancy in IVF patients and represents abnormal transient hemodynamics, does not exert any obviously adverse effect on the subsequent pregnancy. PMID- 26612292 TI - Factors Associated with Effectiveness of Treatment and Reproductive Outcomes in Patients with Thin Endometrium Undergoing Estrogen Treatment. AB - BACKGROUND: Thin endometrium is associated with poor reproductive outcomes; estrogen treatment can increase endometrial thickness (EMT). The aim of this retrospective cohort study was to investigate the factors influencing the effectiveness of estrogen treatment and reproductive outcomes after the treatment in patients with thin endometrium. METHODS: Relevant clinical data of 101 patients with thin endometrium who had undergone estrogen treatment were collected. Possible factors influencing the effectiveness of treatment were analyzed retrospectively by logistic regression analysis. Eighty-seven infertile women without thin endometrium who had undergone assisted reproduction served as controls. The cases and controls were matched for age, assisted reproduction method, and number of embryos transferred. Reproductive outcomes of study and control groups were compared using Student's t-test and the Chi-square test. RESULTS: At the end of estrogen treatment, EMT was >=8 mm in 93/101 patients (92.1%). Effectiveness of treatment was significantly associated with maximal pretreatment EMT (P = 0.017) and treatment duration (P = 0.004). The outcomes of assisted reproduction were similar in patients whose treatment was successful in increasing EMT to >=8 mm and the control group. The rate of clinical pregnancy in patients was associated with the number of good-quality embryos transferred in both fresh (P = 0.005) and frozen-thawed (P = 0.000) embryo transfer cycles. CONCLUSIONS: Thinner EMT before estrogen treatment requires longer treatment duration and predicts poorer treatment outcomes. The effectiveness of treatment depends on the duration of estrogen administration. Assisted reproductive outcomes of patients whose treatment is successful (i.e., achieves an EMT >=8 mm) are similar to those of controls. The quality of embryos transferred is an important predictor of assisted reproductive outcomes in patients treated successfully with exogenous estrogen. PMID- 26612294 TI - Comparative Study of Three Commonly Used Methods for Hospital Efficiency Analysis in Beijing Tertiary Public Hospitals, China. AB - BACKGROUND: Tertiary hospitals serve as the medical service center within the region and play an important role in the medical and health service system. They are also the key targets of public hospital reform in the new era in China. Through the reform of health system, the public hospital efficiency has changed remarkably. Therefore, this study aimed to provide some advice for efficiency assessment of public hospitals in China by comparing and analyzing the consistency of results obtained by three commonly used methods for examining hospital efficiency, that is, ratio analysis (RA), stochastic frontier analysis (SFA), and data envelopment analysis (DEA). METHODS: The theoretical basis, operational processes, and the application status of RA, SFA, and DEA were learned through literature analysis. Then, the empirical analysis was conducted based on measured data from 51 tertiary public hospitals in Beijing from 2009 to 2011. RESULTS: The average values of hospital efficiency calculated by SFA with index screening and principal component analysis (PCA) results and those calculated by DEA with index screening results were relatively stable. The efficiency of specialized hospitals was higher than that of general hospitals and that of traditional Chinese medicine hospitals. The results obtained by SFA with index screening results and the results obtained by SFA with PCA results showed a relatively high correlation (r-value in 2009, 2010, and 2011 were 0.869, 0.753, and 0.842, respectively, P < 0.01). The correlation between results obtained by DEA with index screening results and PCA results and results obtained by other methods showed statistical significance, but the correlation between results obtained by DEA with index screening results and PCA results was lower than that between results obtained by SFA with index screening results and PCA results. CONCLUSIONS: RA is not suitable for multi-index evaluation of hospital efficiency. In the given conditions, SFA is a stable efficiency analysis method. In the evaluation of hospital efficiency, DEA combined with PCA should be adopted with caution due to its poor stability. PMID- 26612293 TI - Abnormal Degree Centrality of Bilateral Putamen and Left Superior Frontal Gyrus in Schizophrenia with Auditory Hallucinations: A Resting-state Functional Magnetic Resonance Imaging Study. AB - BACKGROUND: Dysconnectivity hypothesis of schizophrenia has been increasingly emphasized. Recent researches showed that this dysconnectivity might be related to occurrence of auditory hallucination (AH). However, there is still no consistent conclusion. This study aimed to explore intrinsic dysconnectivity pattern of whole-brain functional networks at voxel level in schizophrenic with AH. METHODS: Auditory hallucinated patients group (n = 42 APG), no hallucinated patients group (n = 42 NPG) and normal controls (n = 84 NCs) were analyzed by resting-state functional magnetic resonance imaging. The functional connectivity metrics index (degree centrality [DC]) across the entire brain networks was calculated and evaluated among three groups. RESULTS: DC decreased in the bilateral putamen and increased in the left superior frontal gyrus in all the patients. However, in APG, the changes of DC were more obvious compared with NPG. Symptomology scores were negatively correlated with the DC of bilateral putamen in all patients. AH score of APG positively correlated with the DC in left superior frontal gyrus but negatively correlated with the DC in bilateral putamen. CONCLUSION: Our findings corroborated that schizophrenia was characterized by functional dysconnectivity, and the abnormal DC in bilateral putamen and left superior frontal gyrus might be crucial in the occurrence of AH. PMID- 26612295 TI - Proteomic Analysis of the Uterosacral Ligament in Postmenopausal Women with and without Pelvic Organ Prolapse. AB - BACKGROUND: Pelvic organ prolapse (POP) is a major health problem in adult women that involves many factors. No proteomic analysis has been conducted exclusively in POP patients. This study aimed to identify the differential expression of proteins that may be involved in POP by proteomic analysis. METHODS: Samples of the uterosacral ligament (USL) were collected from five POP patients and five non POP patients matched according to age, parity, and menopausal status and analyzed using two-dimensional electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify the mRNA expression of proteins that showed differential expression in the proteomic analyses. RESULTS: Proteins differentially expressed between POP and non-POP patients were detected. Eight proteins that were down-regulated in the POP group were identified by MALDI-TOF-MS. These proteins included electron transfer flavoprotein, apolipoprotein A-I, actin, transgelin, cofilin-1, cyclophilin A, myosin, and galectin-1, and their expression was verified by qRT-PCR. CONCLUSION: Using comparative proteomics, we identified eight differentially expressed proteins (including four cytoskeleton proteins and three proteins related to apoptosis) in the USL that may be involved in apoptosis associated with the tissue effects in POP pathophysiology. PMID- 26612296 TI - Effect of Hyperbaric Oxygen on the Growth of Intracranial Glioma in Rats. AB - BACKGROUND: Numerous studies have confirmed that hyperbaric oxygen (HBO) in combination with radiotherapy or chemotherapy may increase the efficacy of radiotherapy or chemotherapy in patients with glioma. However, whether HBO therapy alone may inhibit or promote the growth of malignant tumors remains controversial. This study aimed to investigate the effect of HBO on the growth of glioma in rats, and the impact of HBO on the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-alpha (HIF-1alpha), angiogenesis, and apoptosis of glioma cells. METHODS: Male Sprague-Dawley rats were treated with or without HBO after glioma cell inoculation and followed for up to 16 days postinoculation. Rats were randomized to receive bilateral forelimb function tests (n = 20 per group) and head magnetic resonance imaging (n = 5 per group). Differences between HBO and control groups were tested using 2-sample independent t-tests and changes over time within treatment groups were analyzed using a repeated measurement analysis of variance with Bonferroni correction. The effect of HBO on the expression of VEGF, HIF-1alpha, von Willebrand factor, angiogenesis, and tumor cell apoptosis were also examined (n = 5 per group). RESULTS: Forelimb function scores were reduced in both HBO-treated and control groups. HBO-treated rats had significantly larger tumor volume and more water in the cerebellum compared with control rats. The intratumoral expression of VEGF was significantly higher in HBO-treated rats compared with control rats (23.2% vs. 13.3%, P = 0.002). HIF-1alpha was significantly increased in HBO-treated rats compared with controls in the expression of both intratumoral (72.7% vs. 54.9%, P = 0.001) and peritumoral (2.6% vs. 1.9%, P = 0.003) cells. The intratumoral microvessel density (MVD) was significantly higher in the HBO group (15.6 vessels/field vs. 4.4 vessels/field, P < 0.001), and the peritumoral MVD was not significantly different between the two groups (P > 0.05). Apoptosis was significantly lower in HBO-treated rats compared with controls (44.4% vs. 82.8% for intratumoral; 10.1% vs. 77.5% for peritumoral, both P < 0.001). CONCLUSIONS: The current results demonstrate that HBO alone may promote tumor growth, and is therefore not suitable to treat patients with gliomas with neurological deficits or disorders with HBO alone. If HBO must be used as a mean of rehabilitation, it is recommended that HBO should be combined with radiotherapy or chemotherapy. PMID- 26612297 TI - Effects of Altered Intra-abdominal Pressure on the Upper Airway Collapsibility in a Porcine Model. AB - BACKGROUND: Obstructive sleep apnea is strongly associated with obesity, particularly abdominal obesity common in centrally obese males. Previous studies have demonstrated that intra-abdominal pressure (IAP) is increased in morbid obesity, and tracheal traction forces may influence pharyngeal airway collapsibility. This study aimed to investigate that whether IAP plays a role in the mechanism of upper airway (UA) collapsibility via IAP-related caudal tracheal traction. METHODS: An abdominal wall lifting (AWL) system and graded CO2pneumoperitoneum pressure was applied to four supine, anesthetized Guizhou miniature pigs and its effects on tracheal displacement (TD) and airflow dynamics of UA were studied. Individual run data in 3 min obtained before and after AWL and obtained before and after graded pneumoperitoneum pressure were analyzed. Differences between baseline and AWL/graded pneumoperitoneum pressure data of each pig were examined using a Student's t-test or analysis of variance. RESULTS: Application of AWL resulted in decreased IAP and significant caudal TD. The average displacement amplitude was 0.44 mm (P < 0.001). There were three subjects showed increased tidal volume (TV) (P < 0.01) and peak inspiratory airflow (P < 0.01); however, the change of flow limitation inspiratory UA resistance (Rua) was not significant. Experimental increased IAP by pneumoperitoneum resulted in significant cranial TD. The average displacement amplitude was 1.07 mm (P < 0.001) when IAP was 25 cmH2O compared to baseline. There were three subjects showed reduced Rua while the TV increased (P < 0.01). There was one subject had decreased TV and elevated Rua (P < 0.001). CONCLUSIONS: Decreased IAP significantly increased caudal TD, and elevated IAP significantly increased cranial TD. However, the mechanism of UA collapsibility appears primarily mediated by changes in lung volume rather than tracheal traction effect. TV plays an independent role in the mechanism of UA collapsibility. PMID- 26612298 TI - Exenatide Reduces Tumor Necrosis Factor-alpha-induced Apoptosis in Cardiomyocytes by Alleviating Mitochondrial Dysfunction. AB - BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) plays an important role in progressive contractile dysfunction in several cardiac diseases. The cytotoxic effects of TNF-alpha are suggested to be partly mediated by reactive oxygen species (ROS)- and mitochondria-dependent apoptosis. Glucagon-like peptide-1 (GLP 1) or its analogue exhibits protective effects on the cardiovascular system. The objective of the study was to assess the effects of exenatide, a GLP-1 analogue, on oxidative stress, and apoptosis in TNF-alpha-treated cardiomyocytes in vitro. METHODS: Isolated neonatal rat cardiomyocytes were divided into three groups: Control group, with cells cultured in normal conditions without intervention; TNF alpha group, with cells incubated with TNF-alpha (40 ng/ml) for 6, 12, or 24 h without pretreatment with exenatide; and exenatide group, with cells pretreated with exenatide (100 nmol/L) 30 mins before TNF-alpha (40 ng/ml) stimulation. We evaluated apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and flow cytometry, measured ROS production and mitochondrial membrane potential (MMP) by specific the fluorescent probes, and assessed the levels of proteins by Western blotting for all the groups. RESULTS: Exenatide pretreatment significantly reduced cardiomyocyte apoptosis as measured by flow cytometry and TUNEL assay at 12 h and 24 h. Also, exenatide inhibited excessive ROS production and maintained MMP. Furthermore, declined cytochrome-c release and cleaved caspase-3 expression and increased bcl-2 expression with concomitantly decreased Bax activation were observed in exenatide-pretreated cultures. CONCLUSION: These results suggested that exenatide exerts a protective effect on cardiomyocytes, preventing TNF-alpha-induced apoptosis; the anti apoptotic effects may be associated with protection of mitochondrial function. PMID- 26612299 TI - Adjuvant Efficacy of Nutrition Support During Pulmonary Tuberculosis Treating Course: Systematic Review and Meta-analysis. AB - BACKGROUND: Malnutrition and tuberculosis (TB) tend to interact with each other. TB may lead to nutrition deficiencies that will conversely delay recovery by depressing immune functions. Nutrition support can promote recovery in the subject being treated for TB. The aim of this study was to evaluate the effectiveness of nutrition support on promoting the recovery of adult pulmonary TB patients with anti-TB drug therapy. METHODS: English database of the Cochrane Controlled Trials Register, PubMed, EMBASE, and Chinese database of CBM, CNKI, VIP, and WANFANG were searched. Randomized controlled trials comparing nutrition support (given for more than 2 weeks) with no nutrition intervention, nutrition advice only, or placebo-control for TB patients being anti-TB treated were included. Two reviewers conducted data extraction, assessed the quality of the studies independently, and any discrepancies were solved by the third reviewer. Data were entered and analyzed by RevMan 5.2 software, and meta-analysis was done using risk ratios (RR s) for dichotomous variables and mean differences (MDs) for continuous variables with 95% confidence intervals (CI s). RESULTS: A total of 19 studies (3681 participants) were included. In nutritional support for TB patients, pooled RR and its 95% CI of sputum smears- or culture-negative conversion rate and chest X-ray (CXR) absorption rate were 1.10 (1.04, 1.17) and 1.22 (1.08, 1.39), respectively, the pooled MD and its 95% CI of body mass index (BMI) and time of sputum smears or culture negativity were 0.59 (0.16, 1.2) and - 5.42 (-7.93, -2.92), respectively, compared with the control group. The differences in outcomes of CXR zone affected, TB score, serum albumin, and hemoglobin were not statistically significant (P = 0.76, 0.24, 0.28, and 0.20, respectively) between the intervention group and the control group. No systemic adverse events were recorded. CONCLUSIONS: During anti-TB course, nutrition support may be helpful in treatment of TB patients by improving both sputum smears- or culture-negative conversion rate and BMI, shortening the time of sputum conversion negative. Whether it can improve the final clinical effect, there still needs high-level quality studies to confirm in the future. PMID- 26612300 TI - High-resolution Magnetic Resonance Imaging of Moyamoya Disease. AB - OBJECTIVE: To introduce the imaging characteristics of moyamoya disease (MMD) using high-resolution magnetic resonance imaging (HR-MRI) and to discuss the role of HR-MRI in differentiating MMD from other intracranial artery diseases, especially intracranial atherosclerotic disease (ICAD). DATA SOURCES: This review was based on the data in articles published between 2005 and 2015, which were obtained from PubMed. The keywords included HR-MRI, MMD, ICAD, and intracranial artery diseases. STUDY SELECTION: Articles related to HR-MRI for MMD or other intracranial artery diseases were selected for review. RESULTS: There are differences between the characteristic patterns of HR-MRI in MMD and ICAD. MMD is associated with inward remodeling, smaller outer diameters, concentric occlusive lesions and homogeneous signal intensity, while ICAD is more likely to be associated with outward remodeling, normal outer diameters, eccentric occlusive lesions, and heterogeneous signal intensity. Other intracranial artery diseases, such as dissection and vasculitis, also have distinctive characteristics in HR MRI. HR-MRI may become a useful tool for the differential diagnosis of MMD in the future. CONCLUSIONS: HR-MRI of MMD provides a more in-depth understanding of MMD, and it is helpful in evaluating pathological changes in the vessel wall and in differentiating MMD from other intracranial artery steno-occlusive diseases, particularly ICAD. PMID- 26612301 TI - Status on Heart Transplantation in China. PMID- 26612302 TI - A Study on Neonatal Tolerance Against Graves' Disease in BALB/c Mice. PMID- 26612303 TI - Hydrogen sulfide inhibits transforming growth factor beta-1 induced bronchial epithelial-mesenchymal transition. PMID- 26612304 TI - Sudden Deaths Among Chinese Physicians. PMID- 26612305 TI - Multi-Colitis Cystica Profunda: A Case Report. PMID- 26612306 TI - Lymphoma without Lymphadenopathy. PMID- 26612307 TI - Ramsay Hunt Syndrome Complicated by Brainstem Encephalitis in Varicella-zoster Virus Infection. PMID- 26612308 TI - Superior Mesenteric Artery Syndrome in a 20-year-old Athletic Female with Abdominal Pain. PMID- 26612309 TI - Paraparesis in Coarctation of Aorta: Diagnosis in Disguise. PMID- 26612310 TI - Retraction: MreBCD Associated Cytoskeleton is Required for Proper Segregation of the Chromosomal Terminus during the Division Cycle of Escherichia Coli. PMID- 26612311 TI - Complete Fracture of a Chimney Stent in the Left Common Carotid Artery after Thoracic Endovascular Aortic Repair for Thoracic Aneurysm. PMID- 26612312 TI - Fractional Flow Reserve-Guided Lesion or Patient Management? PMID- 26612313 TI - Treatment of a mouse model of ankylosing spondylitis with exogenous sclerostin has no effect on disease progression. AB - BACKGROUND: No treatment to date is available which specifically targets bone formation in ankylosing spondylitis (AS). Several recent studies have shown that sclerostin (SOST), a Wnt inhibitor specific to osteocytes and chondrocytes, is down-regulated in AS patients. This suggests Wnt signalling may be upregulated, and application of exogenous recombinant SOST (rSOST) may inhibit Wnt signalling and slow pathological bone formation. METHODS: The proteoglycan-induced spondylitis (PGISp) mouse model in which we have previously demonstrated downregulated SOST expression, was used for this study. Mice were injected with 2.5 ug rSOST/day for a period of 8 weeks following induction of disease. Axial skeleton disease development was assessed by histology and skeletal changes examined using DEXA. RESULTS: rSOST treatment had no effect on peripheral or axial disease development, bone density or disease severity. Injected rSOST was stable over 8 h and residual levels were evident 24 h after injection, resulting in a cumulative increase in SOST serum levels over the treatment time course. Immunohistochemical examination of SOST levels within the joints in non-rSOST treated PGISp mice showed a significant decrease in the percentage of positive osteocytes in the unaffected joints compared to the affected joints, while no difference was seen in rSOST treated mice. This suggests that rSOST treatment increases the number of SOST-positive osteocytes in unaffected joints but not affected joints, despite having no impact on the number of joints affected by disease. CONCLUSIONS: Although not disease-modifying, rSOST treatment did appear to regulate SOST levels in the joints suggesting biological activity. Further dose response studies are required and SOST may require modifications to improve its bone targeting ability in order to affect tissue formation to a meaningful level in this model. PMID- 26612314 TI - Rapid clearance of circulating tumor DNA during treatment with AZD9291 of a lung cancer patient presenting the resistance EGFR T790M mutation. PMID- 26612315 TI - Money rules the world. PMID- 26612316 TI - Hymenobacter monticola sp. nov., isolated from mountain soil. AB - A Gram-reaction-negative, aerobic, non-motile, red-pigmented and rod-shaped bacterium, designated XF-6RT, was isolated from mountain soil in the Sichuan province of China. Phylogenetic trees based on 16S rRNA gene sequence analysis showed that XF-6RT belonged to the genus Hymenobacter. The greatest 16S rRNA gene sequence similarities of strain XF-6RT were with Hymenobacter soli PB17T (96.4 %) and Hymenobacter saemangeumensis GSR0100T (95.8 %). Summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), iso-C15 : 0, C16 : 1omega5c and anteiso-C15 : 0 were the major fatty acids (>10 %). The only menaquinone was menaquinone-7. The major polar lipids were phosphatidylethanolamine, four aminolipids, four phosphoaminolipids and three lipids. The DNA G+C content was 62 mol%. On the basis of the polyphasic taxonomic analysis, strain XF-6RT is considered to represent a novel species of the genus Hymenobacter, for which the name Hymenobacter monticola sp. nov. is proposed. The type strain is XF-6RT ( = KCTC 42733T = CCTCC AB 2015206T). PMID- 26612317 TI - Topological phase transition in quasi-one dimensional organic conductors. AB - We explore topological phase transition, which involves the energy spectra of field-induced spin-density-wave (FISDW) states in quasi-one dimensional (Q1D) organic conductors, using an extended Su-Schrieffer-Heeger (SSH) model. We show that, in presence of half magnetic-flux FISDW state, the system exhibits topologically nontrivial phases, which can be characterized by a nonzero Chern number. The nontrivial evolution of the bulk bands with chemical potential in a topological phase transition is discussed. We show that the system can have a similar phase diagram which is discussed in the Haldane's model. We suggest that the topological feature should be tested experimentally in this organic system. These studies enrich the theoretical research on topologically nontrivial phases in the Q1D lattice system as compared to the Haldane topological phase appearing in the two-dimensional lattices. PMID- 26612318 TI - Chemical and genetic characterization of Phlomis species and wild hybrids in Crete. AB - The genus Phlomis is represented in the island of Crete (Greece, Eastern Mediterranean) by three species Phlomis cretica C. Presl., Phlomis fruticosa L., the island endemic Phlomis lanata Willd. and three hybrids Phlomis x cytherea Rech.f. (P. cretica x P. fruticosa), Phlomis x commixta Rech.f. (P. cretica x P. lanata) and Phlomis x sieberi Vierh. (P. fruticosa x P. lanata). This work describes (a) the profile of hybrids and parental species concerning their volatile compounds, (b) the suitability of ribosomal nuclear (ITS region), chloroplast (trnH-psbA), and AFLP markers to identify hybrids and (c) their competence to characterize the different chemotypes of both hybrids and their parental species. The cluster analysis and PCA constructed from chemical data (volatile oils) suggest that there are three groups of taxa. Group IA includes P. cretica and P. fruticosa, group IB includes P. x cytherea, whereas group II consists of P. x commixta, P. x sieberi and P. lanata. Volatile compounds detected only in the hybrids P. x sieberi and P. x commixta correspond to the 3% of the total compounds, value that is much higher in P. x cytherea (21%). Neighbor-joining, statistical parsimony analysis and the observations drawn from ribotypes spectrum of ITS markers divided Phlomis species in two groups, P. lanata and the complex P. cretica/P. fruticosa. In contrast to the ITS region, the plastid DNA marker follows a geographically related pattern. Neighbor-Net, PCA and Bayesian assignment analysis performed for AFLP markers separated the genotypes into three groups corresponding to populations of P. cretica, P. fruticosa, and P. lanata, respectively, while populations of P. x commixta, P. x cytherea, and P. x sieberi presented admixed ancestry. Most of the P. x cytherea samples were identified as F1 hybrids by Bayesian assignment test, while those of P. x commixta and P. x sieberi were identified as F2 hybrids. Overall, high chemical differentiation is revealed in one of the three hybrids, which is likely related with niche variation. Moreover, molecular markers show potential to identify Phlomis taxa. PMID- 26612319 TI - Effect of auricular acupressure for postpartum insomnia: an uncontrolled clinical trial. AB - AIMS AND OBJECTIVES: This study examined the effects of auricular acupressure therapy on women with postpartum insomnia. BACKGROUND: Postpartum women generally have poor sleep quality because of frequent night-time breastfeeding during the first month after giving birth. DESIGN: A one-group pretest/post-test quasi experiment was conducted. METHODS: A convenience sampling method was used to recruit participants at a postpartum centre (doing-the-month centre) in Northern Taiwan, from January 2014-July 2014. Thirty women with postpartum insomnia received auricular acupressure therapy on one auricular point (Shenmen point pressing) four times a day for 14 days. The Chinese version of the Pittsburgh Sleep Quality Index was used to assess sleep quality before and after the 14-day treatment. RESULTS: After the 14-day auricular acupressure treatment, the Pittsburgh Sleep Quality Index total scores of the women decreased from 8.7 (pretest) to 5.57 (post-test, 36% reduction). Scores on the subscales of the Pittsburgh Sleep Quality Index, including sleep quality, sleep latency, sleep duration and sleep disturbance, also statistically improved (p < 0.05). CONCLUSIONS: Hormone changes and frequent breastfeeding were identified as characteristics that may exacerbate poor sleep quality of postpartum women, for whom the auricular acupressure intervention may effectively improve sleep quality. RELEVANCE TO CLINICAL PRACTICE: Auricular acupressure can be an alternative complementary therapy to aid postpartum women with insomnia in improving sleep quality. PMID- 26612320 TI - Laying open (deroofing) and curettage of sinus as treatment of pilonidal disease: a systematic review and meta-analysis. AB - BACKGROUND: Laying open (deroofing, not excision) and curettage of the sinus is a minimally invasive procedure to treat pilonidal disease. A consensus on its efficacy and outcomes has not been reached. We reviewed and meta-analysed the efficacy of this procedure. METHODS: PubMed, Medline, Scopus, Ovid, Cochrane central register of controlled trials (CENTRAL) and Google scholar databases were searched. All studies describing laying open (not excision) of sinus with curettage of the tract to treat pilonidal disease (simple and complicated) were included. The primary outcome parameter was recurrence and the secondary outcome parameters were complication rate, operating time, return to work and healing time. RESULTS: A total of 1194 studies were screened. Out of these, 13 studies were finally included for the analysis. The analysis (n = 1445) demonstrated a net proportion meta-analysis (random effect) pooled rate of 4.47% (95% CI = 0.029 0.063) for recurrence, 1.44% (95% CI = 0.005-0.028) for complications, 34.59 min (95% CI = 13.58-55.61) for operating time, 21-72 days for healing time and 8.4 days (95% CI = 5.23-11.72) for return to work. The procedure was possible under local anaesthesia in seven out of 13 studies. CONCLUSIONS: The meta-analysis demonstrates that laying open (deroofing) and curettage has distinct advantages. These are high success rate, possible in all types of pilonidal disease (simple and complex), low complication rate, short operating time and early return to normal routine and work. This procedure can be conveniently under local anaesthesia as an outpatient procedure. PMID- 26612321 TI - A prospective phase II study of magnetic resonance imaging guided hematopoietical bone marrow-sparing intensity-modulated radiotherapy with concurrent chemotherapy for rectal cancer. AB - PURPOSE: To reduce acute hematologic toxicity (HT) in rectal cancer patients treated with neoadjuvant concurrent chemoradiotherapy by sparing the hematopoietical bone marrow (BM) indentified by magnetic resonance (MR). MATERIALS AND METHODS: A total of 35 staged II/III rectal cancer patients were prospectively enrolled. MR images of pelvis were fused with the simulating CT images. Active BM indentified by MR was contoured as an organ at risk in the treatment plan. The neoadjuvant treatment regimen consisted of 50 Gy of radiation delivered in 25 fractions, 5 days per week, with concurrent daily capecitabine (1650 mg/m(2)/day, twice daily during RT course) and weekly oxiliplatin 50 mg/m(2)/qw. Multivariable linear regression model is used to test correlation between HT and dose-volume of BM. RESULTS: Thirty-one patients (88.6%) had stage T3-4 disease, and 30 patients (85.7%) had node-positive disease. The median age of cohort was 55 years (range 28-73 years). Only 9 (25.7%), 6 (17.1%), 1 (2.9%) and 1 (2.9%) experienced acute Grade 2-4 leukopenia, neutropenia, anemia and thrombocytopenia, respectively. Multivariable linear regression revealed increased BM-V5 was significantly associated with decreased WBC nadirs (p = 0.005), decreased ANC nadirs (p = 0.002), and decreased PLT nadirs (p = 0.017). No dose-volume parameters of BM were found to be related with decreased Hb. CONCLUSIONS: The irradiated volume of pelvic BM identified by MR is associated with HT in rectal cancer patients undergoing neoadjuvant concurrent chemoradiotherapy. PMID- 26612322 TI - Spectral CT imaging of intranodular hemorrhage in cases with challenging benign thyroid nodules. AB - While conventional ultrasound and laboratory testing can differentiate most thyroid conditions and malignancies, spectral dual-energy computed tomography (DECT) provides molecular data potentially useful in differential diagnosis of small, complex, and partially obscured hemorrhaged nodules with recent bleeding. To demonstrate that Gemstone Spectral Imaging (GSI) analysis of DECT data differentiates challenging benign thyroid nodule conditions in patients with intranodular hemorrhages. A retrospective study was conducted of 30 intranodular hemorrhage patients from 2010 to 2013, including 18 that underwent surgery and provided thyroid tissues for prospective histological analysis. Iodine and water content were determined in patient CT scans and ex vivo tissue specimen scans by reconstruction of raw CT data at 65 keV (optimal contrast). Slope of spectral curve (lambda HU), effective atomic number (Z eff), and final pathological diagnosis were recorded. Iodine content, water content, Z eff, and lambda HU significantly varied by region (intranodular hemorrhage, solid thyroid nodule, and adjacent margins) in patients and tissue specimens (P < 0.05). Intranodular hemorrhage exhibited elevated water concentrations (~1100 mg/mL), suggesting a practical threshold of 1075 mg/mL for differentiating intra-plaque hemorrhage and solid nodular regions. Spectral CT provided diagnostic information in 14 thyroid adenomas and four goiters (histologically confirmed in donor specimens), and eight thyroid adenomas and four nodular goiters based on clinical diagnosis. Diagnostically useful regional characteristic of intranodular hemorrhage in the thyroid was visualized via spectral CT employing material decomposition, potentially yielding additional molecular data about complex lesion characteristics no apparent in conventional imaging or laboratory methods. PMID- 26612324 TI - Silicon as a potential anode material for Li-ion batteries: where size, geometry and structure matter. AB - Silicon has attracted huge attention in the last decade because it has a theoretical capacity ~10 times that of graphite. However, the practical application of Si is hindered by three major challenges: large volume expansion during cycling (~300%), low electrical conductivity, and instability of the SEI layer caused by repeated volume changes of the Si material. Significant research efforts have been devoted to addressing these challenges, and significant breakthroughs have been made particularly in the last two years (2014 and 2015). In this review, we have focused on the principles of Si material design, novel synthesis methods to achieve such structural designs, and the synthesis-structure performance relationships to enhance the properties of Si anodes. To provide a systematic overview of the Si material design strategies, we have grouped the design strategies into several categories: (i) particle-based structures (containing nanoparticles, solid core-shell structures, hollow core-shell structures, and yolk-shell structures), (ii) porous Si designs, (iii) nanowires, nanotubes and nanofibers, (iv) Si-based composites, and (v) unusual designs. Finally, our personal perspectives on outlook are offered with an aim to stimulate further discussion and ideas on the rational design of durable and high performance Si anodes for the next generation Li-ion batteries in the near future. PMID- 26612323 TI - Utilizing gemstone spectral CT imaging to evaluate the therapeutic efficacy of radiofrequency ablation in lung cancer. AB - PURPOSE: To evaluate the therapeutic efficacy of radiofrequency ablation (RFA), quantitative water-based, and iodine-based images of gemstone spectral computed tomography (CT) were analyzed. PATIENTS AND METHODS: 30 patients underwent lung RFAs from March 2012 to March 2013. Through enhanced chest scans, we obtained the tumor size values by conventional CT images, and quantitatively analyzed the densities of iodine and water in lung tumors from water-based and iodine-based material decomposition images. RESULTS: Tumors in 22 cases increased in size after RFA while there was no detectable change in the remaining 8 cases. Through water-based material decomposition images, the water content in the tumors increased from (1014.76 +/- 6.83 mg/mL) to (1022.71 +/- 10.16 mg/mL) after RFA, and this difference was significant (t = -2.329, p < 0.05). Through iodine-based material decomposition images, the iodine content in the tumors was 2.49 +/- 0.74 mg/mL before RFA. The tumors were mostly or completely necrotized after RFA and the iodine content in the area of necrosis reduced to 0.45 +/- 0.29 mg/m (t = 11.072, p = 0.000). CONCLUSION: By comparing the tumor size, water content and iodine content before and after RFA, we can visualize the morphology and metabolic states of the tumors and evaluate the therapeutic efficiency. PMID- 26612325 TI - The LysM receptor-like kinase SlLYK10 regulates the arbuscular mycorrhizal symbiosis in tomato. AB - Most plants have the ability to establish a symbiosis with arbuscular mycorrhizal (AM) fungi, which allows better plant nutrition. A plant signaling pathway, called the common symbiosis signaling pathway (CSSP), is essential for the establishment of both AM and root nodule symbioses. The CSSP is activated by microbial signals. Plant receptor(s) for AM fungal signals required for the activation of the CSSP and initial fungal penetration are currently unknown. We set up conditions to use virus-induced gene silencing (VIGS) in Solanum lycopersicum to study the genes potentially involved in AM. We show that the lysin motif receptor-like kinase SlLYK10, whose orthologs in legumes are essential for nodulation, but not for AM, and SlCCaMK, a component of the CSSP, are required for penetration of the AM fungus Rhizophagus irregularis into the roots of young tomato plants. Our results support the hypothesis that the SILYK10 ancestral gene originally played a role in AM and underwent duplication and neofunctionalization for a role in nodulation in legumes. Moreover, we conclude that VIGS is an efficient method for fast screening of genes playing major roles in AM. PMID- 26612327 TI - [Pharmaconutrition in intensive and perioperative care]. AB - The review article covers specific methods of artificial nutrition in current advances in intensive care. This area of care is somewhat specific, and indications for pharmaconutrients are different from classical artificial nutrition. The pharmaconutrients of amino acid and polyenoic fatty acid groups are described. The components of nutritional pharmacology, based on exceedingly high doses of pure nutritional substrates, are a useful and safe means of modifying selected mechanisms, such as fluidocoagulation, inflammatory reactions or vasomotorics. PMID- 26612326 TI - In Vivo Voltage-Sensitive Dye Imaging of Subcortical Brain Function. AB - The whisker system of rodents is an excellent model to study peripherally evoked neural activity in the brain. Discrete neural modules represent each whisker in the somatosensory cortex ("barrels"), thalamus ("barreloids"), and brain stem ("barrelettes"). Stimulation of a single whisker evokes neural activity sequentially in its corresponding barrelette, barreloid, and barrel. Conventional optical imaging of functional activation in the brain is limited to surface structures such as the cerebral cortex. To access subcortical structures and image sensory-evoked neural activity, we designed a needle-based optical system using gradient-index (GRIN) rod lens. We performed voltage-sensitive dye imaging (VSDi) with GRIN rod lens to visualize neural activity evoked in the thalamic barreloids by deflection of whiskers in vivo. We stimulated several whiskers together to determine the sensitivity of our approach in differentiating between different barreloid responses. We also carried out stimulation of different whiskers at different times. Finally, we used muscimol in the barrel cortex to silence the corticothalamic inputs while imaging in the thalamus. Our results show that it is possible to obtain functional maps of the sensory periphery in deep brain structures such as the thalamic barreloids. Our approach can be broadly applicable to functional imaging of other core brain structures. PMID- 26612328 TI - [New psychoactive substances and their prevalence in the Czech Republic]. AB - Recently, there is a global growing concern over the new (mainly synthetic) psychoactive substances, known as legal highs, research chemicals or bath salts. They are represented by various chemical groups imitating "old" illicit drugs with stimulant, euphoric, hallucinogenic or sedative effects. In the Czech Republic, the peak of their use and supply was observed at the beginning of 2011, when new psychoactive substances were available in smart shops known locally as Amsterdam shops - in that time mainly synthetic cathinones and also synthetic cannabinoids were present. After legislative change that placed tens of new substances under the control of criminal law in April 2011, new psychoactive substances are available at Internet and their use is (after short and media driven boom in early 2011) rather limited and decreasing. Though, the use of new synthetic stimulants was recently reported locally among problem (injecting) drug users; new very potent synthetic opioids represent potential threat of further expansion in this users subgroup. PMID- 26612329 TI - [Ultrasound elastography and its use in the head and neck imaging]. AB - Ultrasound elastography (sonoelastography, USE) is a relatively new, rapidly evolving area of imaging that measures elasticity of tissues. Its development started in the last decade of the 20th century and was accelerated after devices allowing real-time imaging and quantification (shear wave elastography, SWE) became broadly available for clinical practise. First results suggest that combination of sonoelastography and conventional ultrasound gives more precise results than ultrasound alone in certain areas. In head and neck imaging, just a few mostly pilot studies have been published till January 2014. This article summarizes available information about sonoelastography and current view on USE imaging in otorhinolaryngology. PMID- 26612330 TI - Medical consequences of Chernobyl with focus on the endocrine system: Part 1. AB - In the last 70 years, atomic disasters have occurred several times. The nuclear power plant accident at Chernobyl in 1986 in North-Central Ukraine was a unique experience in population exposures to radiation by all ages, and ongoing studies have brought a large amount of information on effects of radiation on human organism. Concerning the deteriorating global security situation and the strong rhetoric of some of the world leaders, the knowledge on the biological effects of ionizing radiation and the preventive measures designed to decrease the detrimental effects of radiation gains a new dimension, and involves all of us. This review focuses on the long-term effects of Chernobyl catastrophe especially on the endocrine system in children and in adults, and includes a summary of preventive measures in case of an atomic disaster. PMID- 26612331 TI - [The Cryopre-servation: history and the ethical issue of storing embryos]. AB - This review article deals with the technique which is called cryopreservation. Text describes the principle of this method, history and ethical problems in assisted reproduction. PMID- 26612332 TI - [Serum concentration and tubular resorption of sodium and chloride in patients with chronic renal disease]. AB - Tubular transport of sodium (TNa+) and chloride (TCl-) is decreased in patients with chronic kidney disease. The decrease of TCl- is relatively lower than that of TNa+. These changes of tubular transport of Na+ and Cl- participate on the development of acid base disturbance in patients with chronic kidney disease and with their glomerular filtration rate lower than 0.5 ml/s/1.73 m2. PMID- 26612333 TI - [Trajectory of anaesthesiology and intensive medicine--history, presence and prospects]. AB - Anaesthesia has been practised in a very simple way in ancient ages already, nevertheless its real progress started during last 50 years, supported with recent neurophysiological achievements, technical development, digital evaluation and telemedicine. Since the end of the 20th century close relations exist with CPR and with contemporary complex features of perioperative medicine. They form fundamental pillars for modern surgery encl. intensive medicine and care. Changing demography and efficient support of vital functions in intensive medicine create new phenomena and postulates: safety, chronic critical illness, long-term mechanical ventilation, palliative intensive care, patients preferences for own active end of life. Vital and global importance of anaesthesia equal to surgery has been accepted for the first time in their global history during the meeting of World Health Assembly (WHA) in the year 2015. Brief survey of development and trends in anaesthesiology and intensive medicine in our country completes the historical text. PMID- 26612334 TI - [Wisdom of the World Medical Association (to one forgotten anniversary)]. AB - BACKGROUND: The idea to found an international medical organization was born in July 1945 at the informal conference of doctors from several countries which was held in London. This date represents the very beginning of The World Medical Association. We can therefore celebrate its 70th anniversary and above all to congratulate WMA for keeping the true wisdom of medical ethics and therefore also the integrity of the medical profession to this day. In any medical decision the best interest of individual patient should be considered first. PMID- 26612335 TI - Anatomical Society core regional anatomy syllabus for undergraduate medicine: the Delphi process. AB - A modified Delphi method was employed to seek consensus when revising the UK and Ireland's core syllabus for regional anatomy in undergraduate medicine. A Delphi panel was constructed involving 'expert' (individuals with at least 5 years' experience in teaching medical students anatomy at the level required for graduation). The panel (n = 39) was selected and nominated by members of Council and/or the Education Committee of the Anatomical Society and included a range of specialists including surgeons, radiologists and anatomists. The experts were asked in two stages to 'accept', 'reject' or 'modify' (first stage only) each learning outcome. A third stage, which was not part of the Delphi method, then allowed the original authors of the syllabus to make changes either to correct any anatomical errors or to make minor syntax changes. From the original syllabus of 182 learning outcomes, removing the neuroanatomy component (163), 23 learning outcomes (15%) remained unchanged, seven learning outcomes were removed and two new learning outcomes added. The remaining 133 learning outcomes were modified. All learning outcomes on the new core syllabus achieved over 90% acceptance by the panel. PMID- 26612336 TI - Comparing the measurement equivalence of EQ-5D-5L across different modes of administration. AB - BACKGROUND: Interest in collecting Patient Reported Outcomes using electronic methods such as mobile phones has increased in recent years. However there is debate about the level of measurement equivalence between the traditional paper and newer electronic modes. Information about the acceptability of the electronic versions to respondents is also required. The aim of this study is to compare the equivalence of delivering a widely used generic measure of health status (EQ-5D 5L) across two administration modes (paper and mobile phone). METHODS: Respondents from a research cohort of people in South Yorkshire were identified, and randomly allocated to one of two administration modes (paper vs. mobile phone) based on stratifications for age and gender (and across a range of self reported health conditions). A parallel group design was used where each respondent only completed EQ-5D-5L using one of the modes. In total, 70 respondents completed the measure in the mobile phone arm, and 66 completed the standard paper version. Follow up usability questions were also included to assess the acceptability of the mobile version of EQ-5D-5L. Measurement equivalence was compared at the dimension, utility score and visual analogue scale level using chi square analysis and ANOVA, and by comparing mean differences to an estimated minimally important difference value. RESULTS: Response rates were higher in the mobile arm. The mean EQ-5D-5L utility and VAS scores, and the frequency of respondents endorsing individual EQ-5D-5L dimension response levels did not significantly differ across the administration modes. The majority of the mobile arm agreed that the mobile version of EQ-5D-5L was easy to complete, and that the phone was easy to use, and that they would complete mobile health measures again. CONCLUSIONS: Completing health status measures such as EQ 5D using mobile phones produces equivalent results to more traditional methods, but with added benefits (for example lessening the burden of data entry). Respondents are positive towards completing questionnaires using these methods. The results provide evidence that electronic measures are valid for use to collect data in a range of settings including clinical trials, routine care, and in health diary settings. PMID- 26612337 TI - Signal intensity alteration in the infrapatellar fat pad at baseline for the prediction of knee symptoms and structure in older adults: a cohort study. AB - OBJECTIVE: To describe the associations between infrapatellar fat pad (IPFP) signal intensity alteration at baseline and knee symptoms and structural changes in older adults. METHODS: A total of 874 subjects (mean 62.1 years, 50.1% female) selected randomly from local community were studied at baseline and 770 were followed up (only 357 had MRI at follow-up) over 2.6 years. T1-weighted or T2 weighted fat suppressed MRI was used to assess IPFP signal intensity alteration (0-3), cartilage volume, cartilage defects and bone marrow lesions (BMLs) at baseline and 2.6 years later. Knee pain was assessed by self-administered Western Ontario and McMaster Osteoarthritis Index questionnaire. Radiographic osteoarthritis (OA) was assessed. RESULTS: In cross-sectional analyses, IPFP signal intensity alteration was significantly and positively associated with total knee pain as well as knee cartilage defects, BMLs and knee radiographic OA and negatively associated with patellar cartilage volume after adjustment for age, sex, body mass index and/or radiographic OA. Longitudinally, baseline signal intensity alteration within IPFP was significantly and positively associated with increases in knee pain when going upstairs/downstairs as well as increases in tibiofemoral cartilage defects and BMLs, and negatively associated with change in lateral tibial cartilage volume in multivariable analyses. CONCLUSIONS: IPFP signal intensity alteration at baseline was associated with knee structural abnormalities and clinical symptoms cross-sectionally and longitudinally in older adults, suggesting that it may serve as an important imaging biomarker in knee OA. PMID- 26612339 TI - Elucidating the burden of recurrent and chronic digital ulcers in systemic sclerosis: long-term results from the DUO Registry. AB - OBJECTIVES: Digital ulcers (DUs) occur in up to half of patients with systemic sclerosis (SSc) and may lead to infection, gangrene and amputation with functional disability and reduced quality of life. This study has elucidated the burden of SSc-associated DUs through identification of four patient categories based on the pattern of DU recurrence over a 2-year observation period. METHODS: Patients with SSc-associated DUs enrolled in the Digital Ulcers Outcome Registry between 1 April 2008 and 19 November 2013, and with >=2 years of observation and >=3 follow-up visits during the observation period were analysed. Incident DU associated complications were recorded during follow-up. Work and daily activity impairment were measured using a functional assessment questionnaire completed by patients after the observation period. Potential factors that could predict incident complications were identified in patients with chronic DUs. RESULTS: From 1459 patients, four DU occurrence categories were identified: 33.2% no-DU; 9.4% episodic; 46.2% recurrent; 11.2% chronic. During the observation period, patients from the chronic category had the highest rate of incident complications, highest work impairment and greatest need for help compared with the other categories. Independent factors associated with incident complications included gastrointestinal manifestations (OR 3.73, p=0.03) and previous soft tissue infection (OR 5.86, p=0.01). CONCLUSIONS: This proposed novel categorisation of patients with SSc-associated DUs based on the occurrence of DUs over time may help to identify patients in the clinic with a heavier DU burden who could benefit from more complex management to improve their functioning and quality of life. PMID- 26612338 TI - Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. AB - OBJECTIVES: Rheumatoid arthritis (RA)-specific anti-citrullinated protein/peptide antibodies (ACPAs) appear before disease onset and are associated with bone destruction. We aimed to dissect the role of ACPAs in osteoclast (OC) activation and to identify key cellular mediators in this process. METHODS: Polyclonal ACPA were isolated from the synovial fluid (SF) and peripheral blood of patients with RA. Monoclonal ACPAs were isolated from single SF B-cells of patients with RA. OCs were developed from blood cell precursors with or without ACPAs. We analysed expression of citrullinated targets and peptidylarginine deiminases (PAD) enzymes by immunohistochemistry and cell supernatants by cytometric bead array. The effect of an anti-interleukin (IL)-8 neutralising antibody and a pan-PAD inhibitor was tested in the OC cultures. Monoclonal ACPAs were injected into mice and bone structure was analysed by micro-CT before and after CXCR1/2 blocking with reparixin. RESULTS: Protein citrullination by PADs is essential for OC differentiation. Polyclonal ACPAs enhance OC differentiation through a PAD dependent IL-8-mediated autocrine loop that is completely abolished by IL-8 neutralisation. Some, but not all, human monoclonal ACPAs derived from single SF B-cells of patients with RA and exhibiting distinct epitope specificities promote OC differentiation in cell cultures. Transfer of the monoclonal ACPAs into mice induced bone loss that was completely reversed by the IL-8 antagonist reparixin. CONCLUSIONS: We provide novel insights into the key role of citrullination and PAD enzymes during OC differentiation and ACPA-induced OC activation. Our findings suggest that IL8-dependent OC activation may constitute an early event in the initiation of the joint specific inflammation in ACPA-positive RA. PMID- 26612340 TI - Glucocorticoid-induced leucine zipper (GILZ) inhibits B cell activation in systemic lupus erythematosus. AB - OBJECTIVES: Systemic lupus erythematosus (SLE) is a serious multisystem autoimmune disease, mediated by disrupted B cell quiescence and typically treated with glucocorticoids. We studied whether B cells in SLE are regulated by the glucocorticoid-induced leucine zipper (GILZ) protein, an endogenous mediator of anti-inflammatory effects of glucocorticoids. METHODS: We conducted a study of GILZ expression in blood mononuclear cells of patients with SLE, performed in vitro analyses of GILZ function in mouse and human B cells, assessed the contributions of GILZ to autoimmunity in mice, and used the nitrophenol coupled to keyhole limpet haemocyanin model of immunisation in mice. RESULTS: Reduced B cell GILZ was observed in patients with SLE and lupus-prone mice, and impaired induction of GILZ in patients with SLE receiving glucocorticoids was associated with increased disease activity. GILZ was downregulated in naive B cells upon stimulation in vitro and in germinal centre B cells, which contained less enrichment of H3K4me3 at the GILZ promoter compared with naive and memory B cells. Mice lacking GILZ spontaneously developed lupus-like autoimmunity, and GILZ deficiency resulted in excessive B cell responses to T-dependent stimulation. Accordingly, loss of GILZ in naive B cells allowed upregulation of multiple genes that promote the germinal centre B cell phenotype, including lupus susceptibility genes and genes involved in cell survival and proliferation. Finally, treatment of human B cells with a cell-permeable GILZ fusion protein potently suppressed their responsiveness to T-dependent stimuli. CONCLUSIONS: Our findings demonstrated that GILZ is a non-redundant regulator of B cell activity, with important potential clinical implications in SLE. PMID- 26612341 TI - Laser-assisted delivery of vitamin C, vitamin E, and ferulic acid formula serum decreases fractional laser postoperative recovery by increased beta fibroblast growth factor expression. AB - BACKGROUND AND OBJECTIVE: Laser-assisted drug delivery is an emerging technology to achieve greater penetration by existing topical medications to reach desired targets in the tissue. The objective of this research was to study whether laser assisted delivery of Vitamin C, E, and Ferulic immediately postoperatively of fractional ablative laser could improve wound healing. Secondary objectives were to evaluate the potential molecular markers involved in this wound-healing process. STUDY DESIGN/MATERIAL AND METHODS: A double blinded, prospective, single center, randomized split face trial of Vitamin C, E, and Ferulic topical formula #740019 to decrease postoperative recovery time in fractional ablative laser resurfacing for photo damage. Fifteen healthy men and women of ages 30-55 years were treated with the Vitamin C, E, and Ferulic acid serum to one side of face and vehicle to the other side of face, within 2 minutes immediately after fractional ablative CO2 laser surgery and daily during the healing process. Patients were evaluated daily on days 1-7 using photographs, patient questionnaires, and molecular evaluation. RESULTS: Clinically, postoperative Vitamin C, E, and Ferulic delivery resulted in decreased edema versus vehicle on postoperative day 7 and decreased erythema versus vehicle on postoperative days 3 and 5. Molecularly, the expression of basic fibroblast growth factor (bFGF) was significantly increased at day 5 on the lesion treated with Vitamin C, E, and Ferulic acid serum compared to vehicle control on the other side. CONCLUSION: This is first study to show that Vitamin C, E, and Ferulic acid correlate with more rapid wound healing post-fractional ablative laser. Elevated bFGF could be involved in the Vitamin C, E, and Ferulic acid-induced rapid wound healing. PMID- 26612342 TI - Abnormal uterine artery remodelling in the stroke prone spontaneously hypertensive rat. AB - INTRODUCTION: The stroke prone spontaneously hypertensive rat (SHRSP) is an established model of human cardiovascular risk. We sought to characterise the uteroplacental vascular response to pregnancy in this model and determine whether this is affected by the pre-existing maternal hypertension. METHODS: Doppler ultrasound and myography were utilised to assess uterine artery functional and structural changes pre-pregnancy and at gestational day 18 in SHRSP (untreated and nifedipine treated) and in the normotensive Wistar-Kyoto (WKY) rat. Maternal adaptations to pregnancy were also assessed along with histology and expression of genes involved in oxidative stress in the placenta. RESULTS: SHRSP uterine arteries had a pulsatile blood flow and were significantly smaller (70906 +/- 3903 MUm(2) vs. 95656 +/- 8524 MUm(2) cross-sectional area; p < 0.01), had a significant increase in contractile response (57.3 +/- 10.5 kPa vs 27.7 +/- 1.9 kPa; p < 0.01) and exhibited impaired endothelium-dependent vasorelaxation (58.0 +/- 5.9% vs 13.9 +/- 4.6%; p < 0.01) compared to WKY. Despite significant blood pressure lowering, nifedipine did not improve uterine artery remodelling, function or blood flow in SHRSP. Maternal plasma sFLT-1/PlGF ratio (5.3 +/- 0.3 vs 4.6 +/- 0.1; p < 0.01) and the urinary albumin/creatinine ratio (1.9 +/- 0.2 vs 0.6 +/- 0.1; p < 0.01) was increased in SHRSP vs WKY. The SHRSP placenta had a significant reduction in glycogen cell content and an increase in Hif1alpha, Sod1 and Vegf. DISCUSSION: We conclude that the SHRSP exhibits a number of promising characteristics as a model of spontaneous deficient uteroplacental remodelling that adversely affect pregnancy outcome, independent of pre-existing hypertension. PMID- 26612344 TI - Abstracts for the 36th Congress of the Spanish Society of Pharmacology, 16-18 September 2015, Valencia, Spain. PMID- 26612343 TI - Maternal microchimerism in health and disease. AB - Circulating maternal cells transfer to the fetus during pregnancy, where they may integrate with the fetal immune and organ systems, creating a state of maternal microchimerism (MMc). MMc can persist throughout the child's life, and it has been implicated in the triggering or perpetuation of chronic inflammatory autoimmune diseases, in the context of specific major histocompatibility genes. Correlative data in humans have now been tested in animal model systems. Results suggest that maternal-fetal tolerance may have health implications far beyond the time of pregnancy and into the child's life. PMID- 26612345 TI - Tensions Between Science and Intuition Across the Lifespan. AB - The scientific knowledge needed to engage with policy issues like climate change, vaccination, and stem cell research often conflicts with our intuitive theories of the world. How resilient are our intuitive theories in the face of contradictory scientific knowledge? Here, we present evidence that intuitive theories in 10 domains of knowledge-astronomy, evolution, fractions, genetics, germs, matter, mechanics, physiology, thermodynamics, and waves-persist more than four decades beyond the acquisition of a mutually exclusive scientific theory. Participants (104 younger adults, Mage = 19.6, and 48 older adults, Mage = 65.1) were asked to verify two types of scientific statements as quickly as possible: those that are consistent with intuition (e.g., "the moon revolves around the Earth") and those that involve the same conceptual relations but are inconsistent with intuition (e.g., "the Earth revolves around the sun"). Older adults were as accurate as younger adults at verifying both types of statements, but the lag in response times between intuition-consistent and intuition inconsistent statements was significantly larger for older adults than for younger adults. This lag persisted even among professional scientists. Overall, these results suggest that the scientific literacy needed to engage with topics of global importance may be constrained by patterns of reasoning that emerge in childhood but persist long thereafter. PMID- 26612346 TI - Toe resurfacing with a thin thoracodorsal artery perforator flap. AB - BACKGROUND: In toe reconstruction, amputation procedures are much more common than salvage procedures. However, toe resurfacing, rather than amputation, provides superior functional and aesthetic results. In this study, we report the clinical outcomes of toe resurfacing using a thin thoracodorsal artery perforator flap. PATIENTS AND METHODS: Between January 2004 and June 2013, a total of 15 patients underwent toe resurfacing using thoracodorsal artery perforator flaps. Thin flaps were harvested by discarding the deep adipose layer. Twelve cases involved a great toe defect, three, a second toe defect, three, a third toe defect, and one, a fourth toe defect. Patient ages ranged from 19 to 82 years (mean, 42.9 years). The mechanism of injury varied, including crushing injury, degloving injury, and diabetic foot infection. RESULTS: The size of thoracodorsal artery perforator flap ranged from 4 * 3 to 20 * 8 cm2 and the thickness of the flap ranged from 4 to 9 mm (mean, 6.5 mm). All flap survived completely without complications. The mean follow-up period was 18.8 months (range, 12-60 months). Only one patient with rheumatoid arthritis had mild gait disturbance. All patients were satisfied with the aesthetic and functional results. CONCLUSION: Toe resurfacing with thin thoracodorsal artery perforator flaps appears to be a safer and more reliable option than amputation for preserving their function. (c) 2015 Wiley Periodicals, Inc. Microsurgery 37:312-318, 2017. PMID- 26612347 TI - Synthesis of D-Desosamine and Analogs by Rapid Assembly of 3-Amino Sugars. AB - D-Desosamine is synthesized in 4 steps from methyl vinyl ketone and sodium nitrite. The key step in this chromatography-free synthesis is the coupling of (R)-4-nitro-2-butanol and glyoxal (trimeric form) mediated by cesium carbonate, which affords in crystalline form 3-nitro-3,4,6-trideoxy-alpha-D-glucose, a nitro sugar stereochemically homologous to D-desosamine. This strategy has enabled the syntheses of an array of analogous 3-nitro sugars. In each case the 3-nitro sugars are obtained in pure form by crystallization. PMID- 26612348 TI - Role of eukaryotic translation initiation factors 3a in hypoxia-induced right ventricular remodeling of rats. AB - AIM: Eukaryotic translation initiation factors 3a (eIF3a) is involved in regulating cell cycle, cell division, growth and differentiation. Previous studies suggest a role of eIF3a on fibrosis disease and cellular proliferation and differentiation of fibroblasts. The present study aims to investigate the role of eIF3a on hypoxia-induced right ventricular (RV) remodeling and underlying mechanism. MAIN METHODS: RV remodeling was induced by hypoxia (10% O2, 3 weeks) in rats. Primary cardiac fibroblasts were cultured in vitro and their proliferation was investigated by MTS and EdU incorporation method. eIF3a knockdown was conducted by eIF3a siRNA. The expression/level of TGF-beta1, eIF3a, p27 and alpha-SMA, collagen-I, collagen-III, ANP and BNP were analyzed by ELISA, real-time PCR or Western blot. KEY FINDINGS: The expression of eIF3a was obviously increased in right ventricle of RV remodeling rats accompanied by up regulation of alpha-SMA and collagens. In cultured cardiac fibroblasts, application of exogenous TGF-beta1-induced cellular proliferation and differentiation concomitantly with up-regulation of eIF3a expression and down regulation of p27 expression. The effects of TGF-beta1-induced proliferation and up-regulation of alpha-SMA and collagen in cardiac fibroblasts were abolished by eIF3a siRNA. eIF3a siRNA reversed TGF-beta1 induced down-regulation of p27 expression. SIGNIFICANCE: The eIF3a plays a crucial role in hypoxia-induced RV remodeling by regulating TGF-beta1-induced proliferation and differentiation of cardiac fibroblasts, which is mediated via eIF3a/p27 pathway. PMID- 26612349 TI - Effects of Hypericum perforatum extract and its main bioactive compounds on the cytotoxicity and expression of CYP1A2 and CYP2D6 in hepatic cells. AB - AIMS: Hypericum perforatum (H. perforatum) is one of the most used medicinal plants. However, it has been associated with relevant interactions with several drugs. This situation is probably mediated by cytochrome P450 enzymes (CYP450), namely the 1A2 (CYP1A2) and 2D6 (CYP2D6) isoforms This study aims to assess the cytotoxic and CYP1A2 and CYP2D6 inductive and/or inhibitory effects of a H. perforatum extract and its main bioactive components in hepatic cell lines. MAIN METHODS: A MTT proliferation assay was performed in WRL-68, HepG2 and HepaRG cells after exposition to different concentrations of H. perforatum extract, hypericin and hyperforin for 24 and 72 h. Then, a real-time PCR analysis was accomplished after incubating the cells with these products evaluating the relative CYP1A2 and CYP2D6 expression. KEY FINDINGS: These products have relevant cytotoxicity at a 10 MUM concentration and it was also demonstrated for the first time that H. perforatum can lead to a significant CYP1A2 and CYP2D6 induction in all cell lines. Moreover, hypericin seems to induce CYP1A2 in HepG2 cells and to inhibit its expression in HepaRG cells while hyperforin induced CYP1A2 in HepG2 and in WRL-68 cells. Additionally, hypericin and hyperforin induce CYP2D6 in HepG2 cells but inhibits its expression in HepaRG and in WRL-68 cells. SIGNIFICANCE: This study not only evidenced that H. perforatum extract and two of its bioactive components can have toxic effects in hepatic cell lines but also emphasized the potential risk of the consumption of H. perforatum with CYP1A2- and CYP2D6-metabolized drugs. PMID- 26612350 TI - Pre-administration of BAX-inhibiting peptides decrease the loss of the nigral dopaminergic neurons in rats. AB - AIMS: In this study, we investigated the effects of Bax-inhibiting peptide (Bip) V5, an anti-apoptosis membrane-permeable peptide, on the 6-hydroxydopamine (6 OHDA) induced Parkinson's disease (PD) model rats. MATERIALS AND METHODS: Rats were randomly divided into five groups: Control, 6-OHDA only, Vehicle+6-OHDA, zVAD+6-OHDA, and V5+6-OHDA, that rats were preadministrated with different reagents before 6-OHDA administration. KEY FINDINGS: The result showed that intrastriatal preadministration of Bip-V5 significantly decreased the amphetamine induced rotation of the 6-OHDA model rats and the loss of the nigral dopaminergic (DA) neurons. Moreover, Bip-V5 intrastriatal preadministration not only significantly decreased the expression of activated caspase 9 and activated caspase 3 but also decreased the enhanced expression of AIF and its nuclear translocation in the SNpc. The results in our study provide the first experimental evidence that both caspase-dependent and AIF-dependent apoptosis pathways are involved in the loss of the nigral DA neurons caused by intrastriatal administration of 6-OHDA, and intrastriatal preadministration of Bip-V5 can inhibit the above two apoptosis pathways to protect the nigral DA neurons. SIGNIFICANCE: Our results provide a new idea that Bax-inhibiting peptide may be a promising preventive or therapeutic method for PD. PMID- 26612351 TI - Coated platelet assay: a feasible approach to a complicated science. PMID- 26612353 TI - Multi-laboratory validation of SkinEthic HCE test method for testing serious eye damage/eye irritation using liquid chemicals. AB - A prospective multicentric study of the reconstructed human corneal epithelial tissue-based in vitro test method (SkinEthicTM HCE) was conducted to evaluate its usefulness to identify chemicals as either not classified for serious eye damage/eye irritation (No Cat.) or as classified (Cat. 1/Cat. 2) within UN GHS. The aim of this study was to demonstrate the transferability and reproducibility of the SkinEthicTM HCE EITL protocol for liquids and define its predictive capacity. Briefly, 60 chemicals were three times tested (double blinded) in 3 laboratories and 45 additional chemicals were tested three times in one laboratory. Good within laboratory reproducibility was achieved of at least 88.3% (53/60) and 92.4% (97/105) for the extended data set. Furthermore, the overall concordance between the laboratories was 93.3% (56/60). The accuracy of the SkinEthicTM HCE EITL for the extended dataset, based on bootstrap resampling, was 84.4% (95% CI: 81.9% to 87.6%) with a sensitivity of 99.0% (95% CI: 96.4% to 100%) and specificity of 68.5% (95% CI: 64.0% to 74.0%), thereby meeting all acceptance criteria for predictive capacity. This efficient transferable and reproducible assay is a promising tool to be integrated within a battery of assays to perform an eye irritation risk assessment. PMID- 26612352 TI - Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock? AB - Severe systemic inflammatory response to infection results in severe sepsis and septic shock, which are the leading causes of death in critically ill patients. Septic shock is characterised by refractory hypotension and is typically managed by fluid resuscitation and administration of catecholamine vasopressors such as norepinephrine. Vasopressin can also be administered to raise mean arterial pressure or decrease the norepinephrine dose. Endogenous norepinephrine and vasopressin are synthesised by the copper-containing enzymes dopamine beta hydroxylase and peptidylglycine alpha-amidating monooxygenase, respectively. Both of these enzymes require ascorbate as a cofactor for optimal activity. Patients with severe sepsis present with hypovitaminosis C, and pre-clinical and clinical studies have indicated that administration of high-dose ascorbate decreases the levels of pro-inflammatory biomarkers, attenuates organ dysfunction and improves haemodynamic parameters. It is conceivable that administration of ascorbate to septic patients with hypovitaminosis C could improve endogenous vasopressor synthesis and thus ameliorate the requirement for exogenously administered vasopressors. Ascorbate-dependent vasopressor synthesis represents a currently underexplored biochemical mechanism by which ascorbate could act as an adjuvant therapy for severe sepsis and septic shock. PMID- 26612354 TI - Inhibition of ATP synthesis by fenbufen and its conjugated metabolites in rat liver mitochondria. AB - Fenbufen is an arylpropionic acid derivative belonging to the group of non steroidal anti-inflammatory drugs (NSAIDs). Even though fenbufen is considered a safe drug, some adverse reactions including hepatic events have been reported. To investigate whether mitochondrial damage could be involved in the drug induced liver injury (DILI) by fenbufen, the inhibitory effect of fenbufen and its conjugated metabolites on oxidative phosphorylation (ATP synthesis) in rat liver mitochondria was investigated. Fenbufen glucuronide (F-GlcA), fenbufen-N-acetyl cysteine-thioester (F-NAC) and fenbufen-S-glutathione thioester (F-SG) were found to be more potent inhibitors compared to parent fenbufen (F), whereas fenbufen-O carnitine (F-carn), fenbufen-glycine (F-gly) and fenbufen-N-acetyl lysine amide (F-NAL) were less potent compared to fenbufen. Fenbufen-CoA thioester (F-CoA) was equally potent as fenbufen in inhibiting ATP synthesis. Fenbufen showed time and concentration dependent inhibition of ATP synthesis with Kinact of 4.4 min(-1) and KI of 0.88 MUM and Kinact/KI ratio of 5.01 min(-1) MUM(-1). Data show that fenbufen did not act through opening MPT pore, nor did incubation of mitochondria with reduced GSH and fenbufen show any protective effect on fenbufen mediated inhibition of oxidative phosphorylation. Inclusion of NADPH in mitochondrial preparations with fenbufen did not modulate the inhibitory effects, suggesting no role of CYP mediated oxidative metabolites on the ATP synthesis in isolated mitochondria. The results from the present experiments provide evidence that fenbufen and its metabolites could be involved in mitochondrial toxicity through inhibition of ATP synthesis. PMID- 26612355 TI - Dose-dependent DNA adduct formation by cinnamaldehyde and other food-borne alpha,beta-unsaturated aldehydes predicted by physiologically based in silico modelling. AB - Genotoxicity of alpha,beta-unsaturated aldehydes shown in vitro raises a concern for the use of the aldehydes as food flavourings, while at low dose exposures the formation of DNA adducts may be prevented by detoxification. Unlike many alpha,beta-unsaturated aldehydes for which in vivo data are absent, cinnamaldehyde was shown to be not genotoxic or carcinogenic in vivo. The present study aimed at comparing dose-dependent DNA adduct formation by cinnamaldehyde and 18 acyclic food-borne alpha,beta-unsaturated aldehydes using physiologically based kinetic/dynamic (PBK/D) modelling. In rats, cinnamaldehyde was predicted to induce higher DNA adducts levels than 6 out of the 18 alpha,beta-unsaturated aldehydes, indicating that these 6 aldehydes may also test negative in vivo. At the highest cinnamaldehyde dose that tested negative in vivo, cinnamaldehyde was predicted to form at least three orders of magnitude higher levels of DNA adducts than the 18 aldehydes at their respective estimated daily intake. These results suggest that for all the 18 alpha,beta-unsaturated aldehydes DNA adduct formation at doses relevant for human dietary exposure may not raise a concern. The present study illustrates a possible use of physiologically based in silico modelling to facilitate a science-based comparison and read-across on the possible risks posed by DNA reactive agents. PMID- 26612356 TI - Nanoformulated copper/zinc superoxide dismutase reduces adipose inflammation in obesity. AB - OBJECTIVE: An intimate association exists between oxidative stress and inflammation. Because adipose tissue (AT) inflammation is intricately linked to metabolic disorders, it was hypothesized that reducing oxidative stress would be effective in ameliorating AT inflammation in obesity. METHODS: Wild-type mice were fed a high-fat diet (HF) for 8 weeks followed by a 2-week treatment with nanoformulated copper/zinc superoxide dismutase (NanoSOD). The mice were divided into: 1) chow diet, 2) HF, and 3) HF + NanoSOD. RESULTS: The HF + NanoSOD-treated mice showed a significant decrease in plasma and liver triglycerides when compared with HF-fed mice. Interestingly, NanoSOD reduced the expression of macrophage and inflammatory markers in visceral AT (VAT) and stromal cells derived from VAT. Moreover, the activation of proinflammatory signaling pathways, in particular, the extracellular signal-regulated kinases, was blunted in VAT on NanoSOD treatment. However, markers of oxidative stress were not altered significantly in the HF + NanoSOD group in the experimental conditions. Pretreatment of either macrophages or adipocytes significantly reduced the inflammatory response invoked in an in vitro coculture system, further supporting the role of NanoSOD in inhibiting obesity-linked inflammation. CONCLUSIONS: This data suggest that NanoSOD is effective not only in reducing AT macrophage accumulation and AT inflammation but also in promoting triglyceride metabolism in obesity. PMID- 26612357 TI - Preliminary study of differentiating smears from cancerous and non-cancerous nasopharyngeal tissue using confocal Raman spectroscopy. AB - PURPOSE: Current practice for diagnosing nasopharyngeal carcinoma (NPC) is based on invasive tissue biopsy. This study aims to explore the feasibility of using Raman spectroscopy to differentiate cancerous and non-cancerous nasopharyngeal tissue smears, expecting to realize minimal invasive diagnosis using smears from in vivo mucosa tissue by Raman spectroscopy. METHODS: Biopsy tissue smears were acquired from 74 patients with pathologically diagnosed nasopharyngeal diseases and measured using confocal Raman spectroscopy. RESULTS: Both fingerprint region and high wavenumber Raman spectra were acquired with distinguish features. Multivariate statistical analysis was used to differentiate cancerous and non cancerous groups, achieving a diagnostic sensitivity of 87.2 and specificity of 85.7 % for differentiating NPC from nasopharyngeal non-cancerous smears. CONCLUSIONS: This work indicates that the method has a unique advantage in microanalysis for tissue smears which may provide a promising minimal invasive (or noninvasive) diagnosing tool for cancer diagnosis. PMID- 26612358 TI - Genome-wide association study reveals a locus for nasal carriage of Staphylococcus aureus in Danish crossbred pigs. AB - BACKGROUND: Staphylococcus aureus is an important human opportunistic pathogen residing on skin and mucosae of healthy people. Pigs have been identified as a source of human colonization and infection with methicillin-resistant Staphylococcus aureus (MRSA) and novel measures are needed to control zoonotic transmission. A recent longitudinal study indicated that a minority of pigs characterized by high nasal load and stable carriage may be responsible for the maintenance of S. aureus within farms. The primary objective of the present study was to detect genetic loci associated with nasal carriage of S. aureus in Danish crossbred pigs (Danish Landrace/Yorkshire/Duroc). RESULTS: Fifty-six persistent carriers and 65 non-carriers selected from 15 farms surveyed in the previous longitudinal study were genotyped using Illumina's Porcine SNP60 beadchip. In addition, spa typing was performed on 126 S. aureus isolates from 37 pigs to investigate possible relationships between host and S. aureus genotypes. A single SNP (MARC0099960) on chromosome 12 was found to be associated with nasal carriage of S. aureus at a genome-wide level after permutation testing (p = 0.0497) whereas the association of a neighboring SNP was found to be borderline (p = 0.114). Typing of S. aureus isolates led to detection of 11 spa types belonging to the three main S. aureus clonal complexes (CC) previously described in pigs (CC9, CC30 and CC398). Individual carriers often harbored multiple S. aureus genotypes and the host-pathogen interaction seems to be independent of S. aureus genotype. CONCLUSION: Our results suggest it may be possible to select pigs genetically resistant to S. aureus nasal colonization as a tool to control transmission of livestock-associated MRSA to humans. PMID- 26612359 TI - iPSC-derived human cardiac progenitor cells improve ventricular remodelling via angiogenesis and interstitial networking of infarcted myocardium. AB - We investigate the effects of myocardial transplantation of human induced pluripotent stem cell (iPSC)-derived progenitors and cardiomyocytes into acutely infarcted myocardium in severe combined immune deficiency mice. A total of 2 * 10(5) progenitors, cardiomyocytes or cell-free saline were injected into peri infarcted anterior free wall. Sham-operated animals received no injection. Myocardial function was assessed at 2-week and 4-week post-infarction by using echocardiography and pressure-volume catheterization. Early myocardial remodelling was observed at 2-week with echocardiography derived stroke volume (SV) in saline (20.45 +/- 7.36 MUl, P < 0.05) and cardiomyocyte (19.52 +/- 3.97 MUl, P < 0.05) groups, but not in progenitor group (25.65 +/- 3.61 MUl), significantly deteriorated as compared to sham control group (28.41 +/- 4.41 MUl). Consistently, pressure-volume haemodynamic measurements showed worsening chamber dilation in saline (EDV: 23.24 +/- 5.01 MUl, P < 0.05; ESV: 17.08 +/- 5.82 MUl, P < 0.05) and cardiomyocyte (EDV: 26.45 +/- 5.69 MUl, P < 0.05; ESV: 18.03 +/- 6.58 MUl, P < 0.05) groups by 4-week post-infarction as compared to control (EDV: 15.26 +/- 2.96 MUl; ESV: 8.41 +/- 2.94 MUl). In contrast, cardiac progenitors (EDV: 20.09 +/- 7.76 MUl; ESV: 13.98 +/- 6.74 MUl) persistently protected chamber geometry against negative cardiac remodelling. Similarly, as compared to sham control (54.64 +/- 11.37%), LV ejection fraction was preserved in progenitor group from 2-(38.68 +/- 7.34%) to 4-week (39.56 +/- 13.26%) while cardiomyocyte (36.52 +/- 11.39%, P < 0.05) and saline (35.34 +/- 11.86%, P < 0.05) groups deteriorated early at 2-week. Improvements of myocardial function in the progenitor group corresponded to increased vascularization (16.12 +/- 1.49/mm(2) to 25.48 +/- 2.08/mm(2) myocardial tissue, P < 0.05) and coincided with augmented networking of cardiac telocytes in the interstitial space of infarcted zone. PMID- 26612360 TI - The patient's perception of a delirium: A qualitative research in a Belgian intensive care unit. AB - OBJECTIVES: This research aims to describe the intensive care patients' perception of a delirium. RESEARCH METHODOLOGY: A hermeneutic qualitative research was designed using semi-structured interviews. Adult patients admitted between December 2011 and April 2012 to the intensive care unit of a Belgian public hospital, scoring positive for delirium at least once, were eligible for this study. At least 48hours after the last positive score for delirium, the patients could be interviewed. Data saturation was achieved after 30 patients. RESULTS: Several patients spontaneously indicated the recollection of the delirium, whereas others needed a few questions or needed the specificity of the syndrome to be pointed out. The analysis of the qualitative data resulted in four major themes: (1) contact and communication, (2) feelings, (3) sleep and time and (4) implication of the delirious episode. CONCLUSION: Interviewees recollected a vivid delirium with unrealistic scenes. The study delivered a first understanding of patients' perceptions during a delirium. This qualitative research tried to image the patients' perceptions providing nurses, physicians, other health-care workers as well as patients and their family with a better insight into the syndrome. Targeted interventions may be developed to relieve the burden of the syndrome. PMID- 26612361 TI - Hemoptysis due to fungus ball after tuberculosis: A series of 21 cases treated with hemostatic radiotherapy. AB - BACKGROUND: In patients who are not amenable to surgical resection (cavernostomy), it is difficult to achieve palliation of hemoptysis from pulmonary aspergilloma. There are only 9 cases with a short follow-up that have reported the use of radiotherapy for hemoptysis in this scenario. METHODS: A retrospective series of 21 patients with chronic necrotizing pulmonary aspergillosis were treated with radiotherapy (20 Gray) from 1990 to 2002. The outcome measures were the period from tuberculosis treatment to the onset of hemoptysis, hemoptysis resolution rate, change in Zubrod performance status after 30 days of the completion of radiotherapy, local failure-free survival, and overall survival. RESULTS: The median time between tuberculosis treatment and the onset of hemoptysis due to aspergilloma was 9 years. After radiotherapy, general status improved and the hemoptysis resolved in all patients. During the follow-up period, 4 failures occurred, with a 5-year local failure-free survival rate of 82 % and a 5-year overall survival rate of 59 %. Of these failures, 2 patients died due to recurrence of the hemoptysis, and 2 were rescued (using cavernostomy and reirradiation). The presence of chronic obstructive pulmonary disease (COPD) (p = 0.021) and female gender (p = 0.032) were negatively associated with overall survival. None of the variables was related to local control. CONCLUSIONS: Based on these long-term data, radiotherapy is a potential option for controlling bleeding due to fungus balls. Female patients and COPD were associated with lower survival. PMID- 26612362 TI - Highlight report: toxicology of copper. PMID- 26612363 TI - Bayesian integrated testing strategy (ITS) for skin sensitization potency assessment: a decision support system for quantitative weight of evidence and adaptive testing strategy. AB - The presented Bayesian network Integrated Testing Strategy (ITS-3) for skin sensitization potency assessment is a decision support system for a risk assessor that provides quantitative weight of evidence, leading to a mechanistically interpretable potency hypothesis, and formulates adaptive testing strategy for a chemical. The system was constructed with an aim to improve precision and accuracy for predicting LLNA potency beyond ITS-2 (Jaworska et al., J Appl Toxicol 33(11):1353-1364, 2013) by improving representation of chemistry and biology. Among novel elements are corrections for bioavailability both in vivo and in vitro as well as consideration of the individual assays' applicability domains in the prediction process. In ITS-3 structure, three validated alternative assays, DPRA, KeratinoSens and h-CLAT, represent first three key events of the adverse outcome pathway for skin sensitization. The skin sensitization potency prediction is provided as a probability distribution over four potency classes. The probability distribution is converted to Bayes factors to: 1) remove prediction bias introduced by the training set potency distribution and 2) express uncertainty in a quantitative manner, allowing transparent and consistent criteria to accept a prediction. The novel ITS-3 database includes 207 chemicals with a full set of in vivo and in vitro data. The accuracy for predicting LLNA outcomes on the external test set (n = 60) was as follows: hazard (two classes)-100 %, GHS potency classification (three classes)-96 %, potency (four classes)-89 %. This work demonstrates that skin sensitization potency prediction based on data from three key events, and often less, is possible, reliable over broad chemical classes and ready for practical applications. PMID- 26612365 TI - Highlight report: quality control for genome-wide expression data: how to identify sample mix-up. PMID- 26612364 TI - Catalytic efficiencies of directly evolved phosphotriesterase variants with structurally different organophosphorus compounds in vitro. AB - The nearly 200,000 fatalities following exposure to organophosphorus (OP) pesticides each year and the omnipresent danger of a terroristic attack with OP nerve agents emphasize the demand for the development of effective OP antidotes. Standard treatments for intoxicated patients with a combination of atropine and an oxime are limited in their efficacy. Thus, research focuses on developing catalytic bioscavengers as an alternative approach using OP-hydrolyzing enzymes such as Brevundimonas diminuta phosphotriesterase (PTE). Recently, a PTE mutant dubbed C23 was engineered, exhibiting reversed stereoselectivity and high catalytic efficiency (k cat/K M) for the hydrolysis of the toxic enantiomers of VX, CVX, and VR. Additionally, C23's ability to prevent systemic toxicity of VX using a low protein dose has been shown in vivo. In this study, the catalytic efficiencies of V-agent hydrolysis by two newly selected PTE variants were determined. Moreover, in order to establish trends in sequence-activity relationships along the pathway of PTE's laboratory evolution, we examined k cat/K M values of several variants with a number of V-type and G-type nerve agents as well as with different OP pesticides. Although none of the new PTE variants exhibited k cat/K M values >107 M-1 min-1 with V-type nerve agents, which is required for effective prophylaxis, they were improved with VR relative to previously evolved variants. The new variants detoxify a broad spectrum of OPs and provide insight into OP hydrolysis and sequence-activity relationships. PMID- 26612366 TI - Highlight report: overview of hepatoprotective compounds. PMID- 26612368 TI - Evaluation and Management of Acne. AB - Acne is a common complaint in the primary care clinics. It has not only physical implications but also psychological. This article discusses the epidemiology, pathophysiology, and criteria for making the diagnosis. It also discusses endocrine disorders that may be the cause of acne. Treatment and management are discussed by subtype. Acne mechanica or sports-related acne is also discussed. PMID- 26612367 TI - High-throughput imaging-based nephrotoxicity prediction for xenobiotics with diverse chemical structures. AB - The kidney is a major target for xenobiotics, which include drugs, industrial chemicals, environmental toxicants and other compounds. Accurate methods for screening large numbers of potentially nephrotoxic xenobiotics with diverse chemical structures are currently not available. Here, we describe an approach for nephrotoxicity prediction that combines high-throughput imaging of cultured human renal proximal tubular cells (PTCs), quantitative phenotypic profiling, and machine learning methods. We automatically quantified 129 image-based phenotypic features, and identified chromatin and cytoskeletal features that can predict the human in vivo PTC toxicity of 44 reference compounds with ~82 % (primary PTCs) or 89 % (immortalized PTCs) test balanced accuracies. Surprisingly, our results also revealed that a DNA damage response is commonly induced by different PTC toxicants that have diverse chemical structures and injury mechanisms. Together, our results show that human nephrotoxicity can be predicted with high efficiency and accuracy by combining cell-based and computational methods that are suitable for automation. PMID- 26612369 TI - Urticaria and Allergy-Mediated Conditions. AB - Urticaria is a common condition that involves pruritic, raised skin wheals. Although urticaria is a benign, self-limiting condition, it may cause frustration for patients, often because of its chronicity and its tendency to recur. It can also be a life-threatening allergic reaction. Diagnosis is made clinically. It affects 20% of the general population. The first-line treatment for nonremitting cases includes H-1anti-histamines. However, other therapies may be employed. Other allergy-mediated skin conditions include angioedema, contact dermatitis, and atopic dermatitis. Diagnosis is clinical, and management focuses on prevention, avoiding triggers, and treating the itching and inflammation that accompany these conditions. PMID- 26612370 TI - Bacterial Skin Infections. AB - Skin and soft tissue infections account for 0.5% of outpatient visits to primary care. Skin and soft tissue infections can usually be managed in an outpatient setting. However, there are certain circumstances as discussed in this article that require more urgent care or inpatient management. Primary care providers should be able to diagnose, manage, and provide appropriate follow-up care for these frequently seen skin infections. This article provides family physicians with a comprehensive review of the assessment and management of common bacterial skin infections. PMID- 26612371 TI - Superficial Fungal Infections. AB - Superficial fungal infections grow in dark and moist areas and invade various parts of the body. These infections are easily treatable in immunocompetent individuals. In immunosuppressed individuals, the presentation can be quite severe, requiring use of more potent antifungal agents. The treatment for these conditions consists of topical antifungal agents, creams, and oral systemic medications. The use of prednisone can alter the appearance of superficial fungal infections, making them difficult to diagnose. It is important for primary care providers to become adept at understanding the epidemiology, transmission, clinical presentation, diagnosis techniques, and treatment options available. PMID- 26612372 TI - Viral Skin Diseases. AB - In the vast world of skin diseases, viral skin disorders account for a significant percentage. Most viral skin diseases present with an exanthem (skin rash) and, oftentimes, an accompanying enanthem (lesions involving the mucosal membrane). In this article, the various viral skin diseases are explored, including viral childhood exanthems (measles, rubella, erythema infectiosum, and roseola), herpes viruses (herpes simplex virus, varicella zoster virus, Kaposi sarcoma herpes virus, viral zoonotic infections [orf, monkeypox, ebola, smallpox]), and several other viral skin diseases, such as human papilloma virus, hand, foot, and mouth disease, molluscum contagiosum, and Gianotti-Crosti syndrome. PMID- 26612373 TI - Evaluation and Management of the Hair Loss Patient in the Primary Care Setting. AB - Alopecias represent a heterogeneous group of disorders with different etiologies, presentations, and treatment options. The evaluation of the hair loss patient includes a comprehensive clinical history and physical examination; appropriate laboratory testing; and if indicated, a scalp biopsy. Treatment methods vary depending on the type of alopecia, and include watchful waiting, topical and systemic formulations, surgery, and treatment of any underlying or associated conditions. Referral to a dermatologist is helpful in diagnostically challenging and difficult to treat cases. Alopecia can cause emotional, mental, and social distress to patients. Early diagnosis and timely institution of appropriate treatment are helpful and comforting to those affected by this disease. PMID- 26612374 TI - Sunburn, Thermal, and Chemical Injuries to the Skin. AB - Sunburn, thermal, and chemical injuries to the skin are common in the United States and worldwide. Initial management is determined by type and extent of injury with special care to early management of airway, breathing, and circulation. Fluid management has typically been guided by the Parkland formula, whereas some experts now question this. Each type of skin injury has its own pathophysiology and resultant complications. All primary care physicians should have at least a basic knowledge of management of acute and chronic skin injuries. PMID- 26612375 TI - Dermatologic Manifestations of Systemic Diseases. AB - Dermatologic complaints are encountered frequently by the primary care provider. Patients often are required as well as want to see their primary care provider before referral to a specialist. Therefore, primary care providers must be skilled in a variety of topics including dermatology. Certain dermatologic manifestations are associated with, or indicative of, systemic diseases. Primary care providers must be knowledgeable in diagnosis, evaluation, and treatment of dermatologic conditions, as well as when to appropriately refer. This article reviews common dermatologic manifestations of systemic diseases. PMID- 26612376 TI - Pressure and Friction Injuries in Primary Care. AB - Pressure and friction injuries are common throughout the lifespan. A detailed history of the onset and progression of friction and pressure injuries is key to aiding clinicians in determining the underlying mechanism behind the development of the injury. Modifying or removing the forces that are creating pressure or friction is the key to both prevention and healing of these injuries. Proper care of pressure and friction injuries to the skin is important to prevent the development of infection. Patient education on positioning and ergonomics can help to prevent recurrence of pressure and friction injuries. PMID- 26612377 TI - Skin Cancer. AB - Skin cancer accounts for most malignancies across the globe. They are primarily divided into melanoma and nonmelanoma skin malignancies. Nonmelanoma skin cancer includes basal cell carcinoma and squamous cell carcinoma. Fair skin and chronic ultraviolet B exposure are the most important risk factors. Primary prevention is achieved by avoiding sun exposure and tanning beds. PMID- 26612378 TI - Parasitic Skin Infections for Primary Care Physicians. AB - The 2 epidermal parasitic skin infections most commonly encountered by primary care physicians in developed countries are scabies and pediculosis. Pediculosis can be further subdivided into pediculosis capitis, corporis, and pubis. This article presents a summary of information and a review of the literature on clinical findings, diagnosis, and treatment of these commonly encountered parasitic skin infestations. PMID- 26612379 TI - Nail Deformities and Injuries. AB - A variety of nail deformities commonly presents in the primary care office. An understanding of nail anatomy coupled with inspection of the nails at routine office visits can reveal undetected disorders. Some problems are benign, and treatment should be attempted by the primary care provider, such as onychomycosis, paronychia, or ingrown toenails. For conditions such as benign melanonychia, longitudinal ridges, isolated Beau lines, and onycholysis, clinicians may offer reassurance to patients who are concerned about the change in their nails. For deformities such as early pterygium or clubbing, a thorough evaluation and referral to an appropriate specialist may be warranted. PMID- 26612380 TI - Pattern Recognition. Foreword. PMID- 26612381 TI - Beyond Superficial: Primary Care Dermatology. PMID- 26612382 TI - Child organ trafficking: global reality and inadequate international response. AB - In organ transplantation, the demand for human organs has grown far faster than the supply of organs. This has opened the door for illegal organ trade and trafficking including from children. Organized crime groups and individual organ brokers exploit the situation and, as a result, black markets are becoming more numerous and organized organ trafficking is expanding worldwide. While underprivileged and vulnerable men and women in developing countries are a major source of trafficked organs, and may themselves be trafficked for the purpose of illegal organ removal and trade, children are at especial risk of exploitation. With the confirmed cases of children being trafficked for their organs, child organ trafficking, which once called a "modern urban legend", is a sad reality in today's world. By presenting a global picture of child organ trafficking, this paper emphasizes that child organ trafficking is no longer a myth but a reality which has to be addressed. It argues that the international efforts against organ trafficking and trafficking in human beings for organ removal have failed to address child organ trafficking adequately. This chapter suggests that more orchestrated international collaboration as well as development of preventive measure and legally binding documents are needed to fight child organ trafficking and to support its victims. PMID- 26612383 TI - Evaluation of brain SERT occupancy by resveratrol against MDMA-induced neurobiological and behavioral changes in rats: A 4-[18F]-ADAM/small-animal PET study. AB - The misuse of 3,4-methylenedioxymethamphetamine (MDMA) has drawn a growing concern worldwide for its psychophysiological impacts on humans. MDMA abusers are often accompanied by long-term serotonergic neurotoxicity, which is associated with reduced density of cerebral serotonin transporters (SERT) and depressive disorders. Resveratrol (RSV) is a natural polyphenolic phytoalexin that has been known for its antidepressant and neuroprotective effects. However, biological targets of RSV as well as its neuroprotective effects against MDMA remained largely unknown. In this study, we examined binding potency of RSV and MDMA to SERT using small-animal positron emission tomography (PET) with the SERT radioligand, N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4 [(18)F]-ADAM) and investigated the protection of RSV against the acute and long term adverse effects of MDMA. We found that RSV exhibit binding potentials to SERT in vivo in a dose-dependent manner with variation among brain regions. When the MDMA-treated rats (10mg/kg, s.c.) were co-injected with RSV (20mg/kg, i.p.) twice daily for 4 consecutive days, MDMA-induced acute elevation in plasma corticosterone was significantly reduced. Further, 4-[(18)F]-ADAM PET imaging revealed that RSV protected against the MDMA-induced decrease in SERT availability in the midbrain and the thalamus 2 weeks following the co-treatment. The PET data were comparable to the observation from the forced swim test that RSV sufficiently ameliorated the depressive-like behaviors of the MDMA-treated rats. Together, these findings suggest that RSV is a potential antidepressant and may confer protection against neurobiological and behavioral changes induced by MDMA. PMID- 26612384 TI - Replication of the association between CHRNA4 rs1044396 and harm avoidance in a large population-based sample. AB - Harm avoidance is a personality trait characterized by excessive worrying and fear of uncertainty, which has repeatedly been related to anxiety disorders. Converging lines of research in rodents and humans point towards an involvement of the nicotinic cholinergic system in the modulation of anxiety. Most notably, the rs1044396 polymorphism in the CHRNA4 gene, which codes for the alpha4 subunit of the nicotinic acetylcholine receptor, has been linked to negative emotionality traits including harm avoidance in a recent study. Against this background, we investigated the association between harm avoidance and the rs1044396 polymorphism using data from N=1673 healthy subjects, which were collected in the context of the German multi-centre study 'Genetics of Nicotine Dependence and Neurobiological Phenotypes'. Homozygous carriers of the C-allele showed significantly higher levels of harm avoidance than homozygous T-allele carriers, with heterozygous subjects exhibiting intermediate scores. The effect was neither modulated by age or gender nor by smoking status. By replicating previous findings in a large population-based sample for the first time, the present study adds to the growing evidence suggesting an involvement of nicotinic cholinergic mechanism in anxiety and negative emotionality, which may pose an effective target for medical treatment. PMID- 26612385 TI - Sleep Restriction Enhances the Daily Rhythm of Circulating Levels of Endocannabinoid 2-Arachidonoylglycerol. AB - STUDY OBJECTIVES: Increasing evidence from laboratory and epidemiologic studies indicates that insufficient sleep may be a risk factor for obesity. Sleep curtailment results in stimulation of hunger and food intake that exceeds the energy cost of extended wakefulness, suggesting the involvement of reward mechanisms. The current study tested the hypothesis that sleep restriction is associated with activation of the endocannabinoid (eCB) system, a key component of hedonic pathways involved in modulating appetite and food intake. METHODS: In a randomized crossover study comparing 4 nights of normal (8.5 h) versus restricted sleep (4.5 h) in healthy young adults, we examined the 24-h profiles of circulating concentrations of the endocannabinoid 2-arachidonoylglycerol (2 AG) and its structural analog 2-oleoylglycerol (2-OG). We concomitantly assessed hunger, appetite, and food intake under controlled conditions. RESULTS: A robust daily variation of 2-AG concentrations with a nadir around the middle of the sleep/overnight fast, followed by a continuous increase culminating in the early afternoon, was evident under both sleep conditions but sleep restriction resulted in an amplification of this rhythm with delayed and extended maximum values. Concentrations of 2-OG followed a similar pattern, but with a lesser amplitude. When sleep deprived, participants reported increases in hunger and appetite concomitant with the afternoon elevation of 2-AG concentrations, and were less able to inhibit intake of palatable snacks. CONCLUSIONS: Our findings suggest that activation of the eCB system may be involved in excessive food intake in a state of sleep debt and contribute to the increased risk of obesity associated with insufficient sleep. COMMENTARY: A commentary on this article appears in this issue on page 495. PMID- 26612386 TI - Upper Airway Collapsibility (Pcrit) and Pharyngeal Dilator Muscle Activity are Sleep Stage Dependent. AB - STUDY OBJECTIVES: An anatomically narrow/highly collapsible upper airway is the main cause of obstructive sleep apnea (OSA). Upper airway muscle activity contributes to airway patency and, like apnea severity, can be sleep stage dependent. Conversely, existing data derived from a small number of participants suggest that upper airway collapsibility, measured by the passive pharyngeal critical closing pressure (Pcrit) technique, is not sleep stage dependent. This study aimed to determine the effect of sleep stage on Pcrit and upper airway muscle activity in a larger cohort than previously tested. METHODS: Pcrit and/or muscle data were obtained from 72 adults aged 20-64 y with and without OSA.Pcrit was determined via transient reductions in continuous positive airway pressure (CPAP) during N2, slow wave sleep (SWS) and rapid eye movement (REM) sleep. Genioglossus and tensor palatini muscle activities were measured: (1) awake with and without CPAP, (2) during stable sleep on CPAP, and (3) in response to the CPAP reductions used to quantify Pcrit. RESULTS: Pcrit was 4.9 +/- 1.4 cmH2O higher (more collapsible) during REM versus SWS (P = 0.012), 2.3 +/- 0.6 cmH2O higher during REM versus N2 (P < 0.001), and 1.6 +/- 0.7 cmH2O higher in N2 versus SWS (P = 0.048). Muscle activity decreased from wakefulness to sleep and from SWS to N2 to REM sleep for genioglossus but not for tensor palatini. Pharyngeal muscle activity increased by ~50% by breath 5 following CPAP reductions. CONCLUSIONS: Upper airway collapsibility measured via the Pcrit technique and genioglossus muscle activity vary with sleep stage. These findings should be taken into account when performing and interpreting "passive" Pcrit measurements. PMID- 26612387 TI - Insomnia Symptoms Are Not Associated with Dyslipidemia: A Population-Based Study. AB - STUDY OBJECTIVES: The purpose of this study was to examine whether or not insomnia symptoms were associated with measured dyslipidemia. METHODS: This was a population-based multiyear cross-sectional study, using data from 2005-2008 United States National Health and Nutrition Examination Surveys. Survey participants ages 20 y and older self-reported the frequency of difficulty falling asleep, prolonged nocturnal awakening, and undesired early morning awakening over the preceding month. One-time venipuncture was performed and a low density lipoprotein cholesterol (LDL-C) of >= 160 mg/ dL, triglycerides of >= 200 mg/dL, and a high-density lipoprotein cholesterol (HDL-C) of < 40 mg/dL denoted dyslipidemia. Descriptive statistics and multiple logistic regression were used. RESULTS: Data on LDL-C, triglycerides, and HDL-C was available for 4,635, 4,757, and 9,798 individuals, respectively. There were no significant associations between having any insomnia symptom at least five times in the past month and high LDL-C (odds ratio [OR] 1.20, 95% confidence interval [CI] 0.92-1.55) or low HDL-C (OR 0.92, 95% CI 0.82-1.04) in unadjusted analyses, or with high triglycerides after adjusting for covariates (OR 1.03, 95% CI 0.78-1.37). Recipients of sleeping pills who also had insomnia symptoms had significantly increased adjusted odds of elevated LDL-C (OR 2.18, 95% CI 1.14-4.15). CONCLUSIONS: Insomnia symptoms were generally not associated with dyslipidemia, but receipt of sleeping pills in the setting of insomnia was associated with elevated LDL-C. Further research is needed to confirm a possible link between sleeping pill use and dyslipidemia and to delineate if an association with atherosclerosis exists with specific types of sleeping pills or with all sedative medications more broadly. PMID- 26612388 TI - Suppression of Sleep Spindle Rhythmogenesis in Mice with Deletion of CaV3.2 and CaV3.3 T-type Ca(2+) Channels. AB - STUDY OBJECTIVES: Low-threshold voltage-gated T-type Ca(2+) channels (T-channels or CaV3 channels) sustain oscillatory discharges of thalamocortical (TC) and nucleus Reticularis thalami (nRt) cells. The CaV3.3 subtype dominates nRt rhythmic bursting and mediates a substantial fraction of spindle power in the NREM sleep EEG. CaV3.2 channels are also found in nRt, but whether these contribute to nRt-dependent spindle generation is unexplored. We investigated thalamic rhythmogenesis in mice lacking this subtype in isolation (CaV3.2KO mice) or in concomitance with CaV3.3 deletion (CaV3.double-knockout (DKO) mice). METHODS: We examined discharge characteristics of thalamic cells and intrathalamic evoked synaptic transmission in brain slices from wild-type, CaV3.2KO and CaV3.DKO mice through patch-clamp recordings. The sleep profile of freely behaving CaV3.2KO and CaV3.DKO mice was assessed by polysomnographic recordings. RESULTS: CaV3.2 channel deficiency left nRt discharge properties largely unaltered, but additional deletion of CaV3.3 channels fully abolished low threshold whole-cell Ca(2+) currents and bursting, and suppressed burst-mediated inhibitory responses in TC cells. CaV3.DKO mice had more fragmented sleep, with shorter NREM sleep episodes and more frequent microarousals. The NREM sleep EEG power spectrum displayed a relative suppression of the sigma frequency band (10 15 Hz), which was accompanied by an increase in the delta band (1-4 Hz). CONCLUSIONS: Consistent with previous findings, CaV3.3 channels dominate nRt rhythmogenesis, but the lack of CaV3.2 channels further aggravates neuronal, synaptic, and EEG deficits. Therefore, CaV3.2 channels can boost intrathalamic synaptic transmission, and might play a modulatory role adjusting the relative presence of NREM sleep EEG rhythms. PMID- 26612389 TI - Mild Airflow Limitation during N2 Sleep Increases K-complex Frequency and Slows Electroencephalographic Activity. AB - STUDY OBJECTIVES: To determine the effects of mild airflow limitation on K complex frequency and morphology and electroencephalogram (EEG) spectral power. METHODS: Transient reductions in continuous positive airway pressure (CPAP) during stable N2 sleep were performed to induce mild airflow limitation in 20 patients with obstructive sleep apnea (OSA) and 10 healthy controls aged 44 +/- 13 y. EEG at C3 and airflow were measured in 1-min windows to quantify K-complex properties and EEG spectral power immediately before and during transient reductions in CPAP. The frequency and morphology (amplitude and latency of P200, N550 and N900 components) of K-complexes and EEG spectral power were compared between conditions. RESULTS: During mild airflow limitation (18% reduction in peak inspiratory airflow from baseline, 0.38 +/- 0.11 versus 0.31 +/- 0.1 L/sec) insufficient to cause American Academy of Sleep Medicine-defined cortical arousal, K-complex frequency (9.5 +/- 4.5 versus 13.7 +/- 6.4 per min, P < 0.01), N550 amplitude (25 +/- 3 versus 27 +/- 3 MUV, P < 0.01) and EEG spectral power (delta: 147 +/- 48 versus 230 +/- 99 MUV(2), P < 0.01 and theta bands: 31 +/- 14 versus 34 +/- 13 MUV(2), P < 0.01) significantly increased whereas beta band power decreased (14 +/- 5 versus 11 +/- 4 MUV(2), P < 0.01) compared to the preceding non flow-limited period on CPAP. K-complex frequency, morphology, and timing did not differ between patients and controls. CONCLUSION: Mild airflow limitation increases K-complex frequency, N550 amplitude, and spectral power of delta and theta bands. In addition to providing mechanistic insight into the role of mild airflow limitation on K-complex characteristics and EEG activity, these findings may have important implications for respiratory conditions in which airflow limitation during sleep is common (e.g., snoring and OSA). PMID- 26612391 TI - Prevalence of Obstructive Sleep Apnea in Children with Down Syndrome. AB - STUDY OBJECTIVES: To evaluate the prevalence of obstructive sleep apnea (OSA) in a large cohort of children with Down syndrome (DS), and to investigate which patient- related factors correlate with disease severity. METHODS: We performed a retrospective, cross-sectional study in children with DS referred for full overnight polysomnography in a tertiary care center. RESULTS: Polysomnographic data are available for 122 children (70 boys), age 5.0 y (2.8-10.5), and body mass index (BMI) z-score 0.7 (-0.3 to 1.7). The overall prevalence of OSA was 66.4%. In almost half of these children severe OSA was diagnosed (obstructive AHI [oAHI] >= 10/h). In children with parental reports of snoring or witnessed apneas (group A), OSA was significantly more common (75.7%) than in those without these symptoms (group B) 53.8% (P = 0.019). Children in group A had more severe OSA, oAHI 5.7/h (1.7-13.8) compared to those in group B 2.2/h (0.8-8.0) (P = 0.018). A significant inverse correlation between age and oAHI (P = 0.028) was found. Sex and BMI z-score were not significantly correlated to oAHI. CONCLUSIONS: Based upon full night polysomnography, an overall 66.4% prevalence of OSA was found in children with Down syndrome. Even in those with a negative history for OSA, the prevalence was 53.8%. Younger age was associated with more severe disease. PMID- 26612390 TI - EphA4 is Involved in Sleep Regulation but Not in the Electrophysiological Response to Sleep Deprivation. AB - STUDY OBJECTIVES: Optimal sleep is ensured by the interaction of circadian and homeostatic processes. Although synaptic plasticity seems to contribute to both processes, the specific players involved are not well understood. The EphA4 tyrosine kinase receptor is a cell adhesion protein regulating synaptic plasticity. We investigated the role of EphA4 in sleep regulation using electrocorticography in mice lacking EphA4 and gene expression measurements. METHODS: EphA4 knockout (KO) mice, Clock(Delta19/Delta19) mutant mice and littermates, C57BL/6J and CD-1 mice, and Sprague-Dawley rats were studied under a 12 h light: 12 h dark cycle, under undisturbed conditions or 6 h sleep deprivation (SLD), and submitted to a 48 h electrophysiological recording and/or brain sampling at different time of day. RESULTS: EphA4 KO mice showed less rapid eye movement sleep (REMS), enhanced duration of individual bouts of wakefulness and nonrapid eye movement sleep (NREMS) during the light period, and a blunted daily rhythm of NREMS sigma activity. The NREMS delta activity response to SLD was unchanged in EphA4 KO mice. However, SLD increased EphA4 expression in the thalamic/hypothalamic region in C57BL/6J mice. We further show the presence of E boxes in the promoter region of EphA4, a lower expression of EphA4 in Clock mutant mice, a rhythmic expression of EphA4 ligands in several brain areas, expression of EphA4 in the suprachiasmatic nuclei of the hypothalamus (SCN), and finally an unchanged number of cells expressing Vip, Grp and Avp in the SCN of EphA4 KO mice. CONCLUSIONS: Our results suggest that EphA4 is involved in circadian sleep regulation. PMID- 26612392 TI - Cognitive Performance, Sleepiness, and Mood in Partially Sleep Deprived Adolescents: The Need for Sleep Study. AB - STUDY OBJECTIVES: To investigate the effects of sleep restriction (7 nights of 5 h time in bed [TIB]) on cognitive performance, subjective sleepiness, and mood in adolescents. METHODS: A parallel-group design was adopted in the Need for Sleep Study. Fifty-six healthy adolescents (25 males, age = 15-19 y) who studied in top high schools and were not habitual short sleepers were randomly assigned to Sleep Restriction (SR) or Control groups. Participants underwent a 2-w protocol consisting of 3 baseline nights (TIB = 9 h), 7 nights of sleep opportunity manipulation (TIB = 5 h for the SR and 9 h for the control groups), and 3 nights of recovery sleep (TIB = 9 h) at a boarding school. A cognitive test battery was administered three times each day. RESULTS: During the manipulation period, the SR group demonstrated incremental deterioration in sustained attention, working memory and executive function, increase in subjective sleepiness, and decrease in positive mood. Subjective sleepiness and sustained attention did not return to baseline levels even after 2 recovery nights. In contrast, the control group maintained baseline levels of cognitive performance, subjective sleepiness, and mood throughout the study. Incremental improvement in speed of processing, as a result of repeated testing and learning, was observed in the control group but was attenuated in the sleep-restricted participants, who, despite two recovery sleep episodes, continued to perform worse than the control participants. CONCLUSIONS: A week of partial sleep deprivation impairs a wide range of cognitive functions, subjective alertness, and mood even in high-performing high school adolescents. Some measures do not recover fully even after 2 nights of recovery sleep. COMMENTARY: A commentary on this article appears in this issue on page 497. PMID- 26612394 TI - Dorsal hippocampal NMDA receptors mediate the interactive effects of arachidonylcyclopropylamide and MDMA/ecstasy on memory retrieval in rats. AB - A combination of cannabis and ecstasy may change the cognitive functions more than either drug alone. The present study was designed to investigate the possible involvement of dorsal hippocampal NMDA receptors in the interactive effects of arachidonylcyclopropylamide (ACPA) and ecstasy/MDMA on memory retrieval. Adult male Wistar rats were cannulated into the CA1 regions of the dorsal hippocampus (intra-CA1) and memory retrieval was examined using the step through type of passive avoidance task. Intra-CA1 microinjection of a selective CB1 receptor agonist, ACPA (0.5-4ng/rat) immediately before the testing phase (pre-test), but not after the training phase (post-training), impaired memory retrieval. In addition, pre-test intra-CA1 microinjection of MDMA (0.5-1MUg/rat) dose-dependently decreased step-through latency, indicating an amnesic effect of the drug by itself. Interestingly, pre-test microinjection of a higher dose of MDMA into the CA1 regions significantly improved ACPA-induced memory impairment. Moreover, pre-test intra-CA1 microinjection of a selective NMDA receptor antagonist, D-AP5 (1 and 2MUg/rat) inhibited the reversal effect of MDMA on the impairment of memory retrieval induced by ACPA. Pre-test intra-CA1 microinjection of the same doses of D-AP5 had no effect on memory retrieval alone. These findings suggest that ACPA or MDMA consumption can induce memory retrieval impairment, while their co-administration improves this amnesic effect through interacting with hippocampal glutamatergic-NMDA receptor mechanism. Thus, it seems that the tendency to abuse cannabis with ecstasy may be for avoiding cognitive dysfunction. PMID- 26612396 TI - Core-Shell Al-Polytetrafluoroethylene (PTFE) Configurations to Enhance Reaction Kinetics and Energy Performance for Nanoenergetic Materials. AB - The energy performance of solid energetic materials (Al, Mg, etc.) is typically restricted by a natural passivation layer and the diffusion-limited kinetics between the oxidizer and the metal. In this work, we use polytetrafluoroethylene (PTFE) as the fluorine carrier and the shielding layer to construct a new type of nano-Al based fuels. The PTFE shell not only prevents nano-Al layers from oxidation, but also assists in enhancing the reaction kinetics, greatly improving the stability and reactivity of fuels. An in situ chemical vapor deposition combined with the electrical explosion of wires (EEW) method is used to fabricate core-shell nanostructures. Studies show that by controlling the stoichiometric ratio of the precursors, the morphology of the PTFE shell and the energy performance can be easily tuned. The resultant composites exhibit superior energy output characters than that of their physically mixed Al/PTFE counterparts. This synthetic strategy might provide a general approach to prepare other high-energy fuels (Mg, Si). PMID- 26612395 TI - Prevalence of pathogenic bacteria in Ixodes ricinus ticks in Central Bohemia. AB - Bacteria associated with the tick Ixodes ricinus were assessed in specimens unattached or attached to the skin of cats, dogs and humans, collected in the Czech Republic. The bacteria were detected by PCR in 97 of 142 pooled samples including 204 ticks, i.e. 1-7 ticks per sample, collected at the same time from one host. A fragment of the bacterial 16S rRNA gene was amplified, cloned and sequenced from 32 randomly selected samples. The most frequent sequences were those related to Candidatus Midichloria midichlori (71% of cloned sequences), followed by Diplorickettsia (13%), Spiroplasma (3%), Rickettsia (3%), Pasteurella (3%), Morganella (3%), Pseudomonas (2%), Bacillus (1%), Methylobacterium (1%) and Phyllobacterium (1%). The phylogenetic analysis of Spiroplasma 16S rRNA gene sequences showed two groups related to Spiroplasma eriocheiris and Spiroplasma melliferum, respectively. Using group-specific primers, the following potentially pathogenic bacteria were detected: Borellia (in 20% of the 142 samples), Rickettsia (12%), Spiroplasma (5%), Diplorickettsia (5%) and Anaplasma (2%). In total, 68% of I. ricinus samples (97/142) contained detectable bacteria and 13% contained two or more putative pathogenic groups. The prevalence of tick-borne bacteria was similar to the observations in other European countries. PMID- 26612397 TI - Did we learn something new on pemphigoid autoimmune blistering diseases? PMID- 26612398 TI - Healing of localized gingival recessions treated with a coronally advanced flap alone or combined with an enamel matrix derivative and a porcine acellular dermal matrix: a preclinical study. AB - OBJECTIVE: This study aimed to evaluate the effects of a porcine acellular dermal matrix (PADM) with or without an enamel matrix derivative (EMD) on gingival recession defects treated with a coronally advanced flap (CAF) in dogs. MATERIALS AND METHODS: Miller class II gingival recession defects (5 mm wide and 7 mm deep) were surgically created on the labial side of bilateral maxillary canines in 12 dogs. After 8 weeks of plaque accumulation, the 24 chronic defects were randomly assigned to one of the following 4 treatments: CAF, CAF with PADM (CAF/PADM), CAF with EMD (CAF/EMD), and CAF with EMD and PADM (CAF/EMD/PADM). The animals were sacrificed 10 weeks after surgery for histologic evaluation. RESULTS: In all groups, root coverage was obtained to a varying degree. PADM was well incorporated in gingival connective tissue in the CAF/PADM and in the CAF/EMD/PADM groups. The height of newly formed bone was significantly greater in the CAF/EMD/PADM group than in the CAF and CAF/PADM groups. New cementum with periodontal ligament-like tissue was predominantly found in the CAF/EMD and CAF/EMD/PADM groups. The CAF/EMD/PADM group showed the greatest amount of new cementum among the groups examined, although the difference was not statistically significant. CONCLUSION: Within the limitations of the present study, it can be concluded that CAF/EMD/PADM treatment may promote periodontal regeneration in gingival recession defects. CLINICAL RELEVANCE: The present results suggest that the combination of EMD and PADM in conjunction with CAF may represent a promising approach for treating single Miller class II gingival recessions. PMID- 26612399 TI - Non-thermal atmospheric pressure plasma increased mRNA expression of growth factors in human gingival fibroblasts. AB - OBJECTIVES: The aim of this in vitro study was to investigate the effects of a non-thermal atmospheric pressure plasma jet (NTAPPJ) on the cellular activity of human gingival fibroblasts (HGF) for possible non-surgical application of it during gingival wound healing. MATERIALS AND METHODS: HGF cells were exposed with NTAPPJ for 1, 2, and 4 min and were investigated for cellular attachment, cell viability, morphology of attached cells, proliferation rate, and messenger ribonucleic acid (mRNA) expression of various growth factors. Also, scavengers for chemicals produced by NTAPPJ were used to identify the chemical species responsible for the effects. RESULTS: There was no significant change in the number of HGF cells attached or their proliferation following NTAPPJ exposure. Also, high cell viability resulted from exposure of all of HGF cells to NTAPPJ for 1, 2, and 4 min. However, cells were more stretched while the mRNA expressions of transforming growth factor and vascular endothelial growth factor were significantly increased following NTAPPJ exposure. Additionally, the scavenger test showed that nitric oxide is likely to be the chemical responsible for an increase of cellular activity. CONCLUSION: The results demonstrated that the NTAPPJ increased mRNA expressions of growth factors in human gingival fibroblasts. CLINICAL RELEVANCE: Application of NTAPPJ would be useful in gingival wound healing in clinics though additional studies confirming the effects would be needed. PMID- 26612400 TI - Apical filling characteristics of carrier-based techniques vs. single cone technique in curved root canals. AB - OBJECTIVES: In this in vitro study, we assessed filling characteristics (adaptation, homogeneity, sealer percentage, position of the carrier) of warm and cold obturation methods in curved root canals. MATERIALS AND METHODS: A reciprocating method was used to prepare 90 curved roots (25 degrees average curvature) to an apical size of 25.08. They were then obturated with either (A) Guttafusion (VDW, Munich, Germany), (B) Thermafil (Maillefer, Ballaigues, Switzerland) or (C) single cone technique using 25.08 gutta-percha (VDW) and sealer (2Seal easymix) (n = 30 each group). Five sections in 1-mm steps were obtained from each root, beginning 1 mm short of the apex. The percentage of voids in contact with root canal walls (PVO), the proportion of voids per area (PVA) and the percentage of sealer per area (PSA) were measured. RESULTS: Little to no differences between Guttafusion and Thermafil were seen in curved root canals with respect to adaptation and homogeneity in the apical region. Both methods showed significantly better adaptation and homogeneity than the single cone technique. The proportion of sealer was significantly greater when roots were obturated with Guttafusion than with Thermafil, but both warm obturation techniques had significantly smaller sealer areas than the single cone technique. CONCLUSIONS: Compared to the single cone technique, a more favourable root canal filling with less sealer could be expected from both warm obturation techniques in curved root canals. CLINICAL RELEVANCE: The easier-to-handle Guttafusion leads to comparable results as Thermafil in curved root canals. PMID- 26612401 TI - Microbial adhesion on novel yttria-stabilized tetragonal zirconia (Y-TZP) implant surfaces with nitrogen-doped hydrogenated amorphous carbon (a-C:H:N) coatings. AB - OBJECTIVES: Biomaterial surfaces are at high risk for initial microbial colonization, persistence, and concomitant infection. The rationale of this study was to assess the initial adhesion on novel implant surfaces of Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans upon incubation. MATERIALS AND METHODS: The tested samples were 3 mol% yttria-stabilized tetragonal zirconia polycrystal (3Y-TZP) samples with nitrogen-doped hydrogenated amorphous carbon (a-C:H:N) coating (A) and 3Y-TZP samples coated with ceria-stabilized zirconia-based (Ce-TZP) composite and a C:H:N (B). Uncoated 3Y-TZP samples (C) and bovine enamel slabs (BES) served as controls. Once the surface was characterized, the adherent microorganisms were quantified by estimating the colony-forming units (CFUs). Microbial vitality was assessed by live/dead staining, and microbial-biomaterial surface topography was visualized by scanning electron microscopy (SEM). RESULTS: Overall, A and B presented the lowest CFU values for all microorganisms, while C sheltered significantly less E. faecalis, P. aeruginosa, and C. albicans than BES. Compared to the controls, B demonstrated the lowest vitality values for E. coli (54.12 %) and C. albicans (67.99 %). Interestingly, A (29.24 %) exhibited higher eradication rates for S. aureus than B (13.95 %). CONCLUSIONS: Within the limitations of this study, a-C:H:N-coated 3Y-TZP surfaces tended to harbor less initially adherent microorganisms and selectively interfered with their vitality. CLINICAL RELEVANCE: This could enable further investigation of the new multi functional zirconia surfaces to confirm their favorable antimicrobial properties in vivo. PMID- 26612402 TI - Prevalence of self-reported jaw pain in Germany: two cross-sectional surveys of the general German population. AB - OBJECTIVES: This study evaluated the prevalence of jaw pain as a local, regional, or widespread pain condition and its association with psychosocial variables in a large representative group of the general population from all regions in Germany. METHODS: In two representative samples consisting of 2524 and 2515 subjects, respectively, the 7-day and 3-month pain prevalences were measured by using the Regional Pain Scale (RPS). Somatic symptom burden (somatization) and pain-related depression were assessed with the Patient Health Questionnaire and the Somatic Symptom Scale, respectively. Binary logistic regression was chosen to calculate the associations between demographic and psychological clinical predictor variables with jaw pain. RESULTS: The 7-day jaw pain prevalence was 4.0 % (95 % CI = 3.2-4.8). Of the subjects with jaw pain, only 9 % had local pain (1 pain site), while the remaining 91 % reported regional pain (2-5 pain sites), or widespread pain (6-19 pain sites). The 3-month prevalence of generally present jaw pain was 0.9 % (95 % CI = 0.6-1.0). Regional or widespread pain was present in 82 % of the participants. Jaw pain was predicted by somatic symptom burden (past 7 days, OR = 1.15 [95 % CI = 1.09-1.22]; past 3 months, OR = 1.13 [95 % CI = 1.02-1.25]), but not by depression. CONCLUSIONS: Most individuals with jaw pain have additional pain in other anatomical regions. They might also exhibit a greater risk for pain-associated somatic symptom burden. CLINICAL RELEVANCE: Assessment of pain distribution in the whole body and the use of a psychometric screening questionnaire for somatic symptom burden are recommended for individuals presenting with jaw pain in a clinical setting. PMID- 26612403 TI - Synthesis and characterization of CaO-loaded electrospun matrices for bone tissue engineering. AB - OBJECTIVES: This study aims to synthesize and characterize biodegradable polymer based matrices loaded with CaO nanoparticles for osteomyelitis treatment and bone tissue engineering. MATERIALS AND METHODS: Poly(epsilon-caprolactone) (PCL) and PCL/gelatin (1:1, w/w) solutions containing CaO nanoparticles were electrospun into fibrous matrices. Scanning (SEM) and transmission (TEM) electron microscopy, Fourier transformed infrared (FTIR), energy dispersive X-ray spectroscopy (EDS), contact angle (CA), tensile testing, and antibacterial activity (agar diffusion assay) against Staphylococcus aureus were performed. Osteoprecursor cell (MC3T3 E1) response (i.e., viability and alkaline phosphatase expression/ALP) and infiltration into the matrices were evaluated. RESULTS: CaO nanoparticles were successfully incorporated into the fibers, with the median fiber diameter decreasing after CaO incorporation. The CA decreased with the addition of CaO, and the presence of gelatin made the matrix very hydrophilic (CA = 0 degrees ). Increasing CaO concentrations progressively reduced the mechanical properties (p <= 0.030). CaO-loaded matrices did not display consistent antibacterial activity. MC3T3-E1 cell viability demonstrated the highest levels for CaO-loaded matrices containing gelatin after 7 days in culture. An increased ALP expression was consistently seen for PCL/CaO matrices when compared to PCL and gelatin containing counterparts. CONCLUSIONS: Despite inconsistent antibacterial activity, CaO nanoparticles can be effectively loaded into PCL or PCL/gelatin fibers without negatively affecting the overall performance of the matrices. More importantly, CaO incorporation enhanced cell viability as well as differentiation capacity, as demonstrated by an increased ALP expression. CLINICAL SIGNIFICANCE: CaO-loaded electrospun matrices show potential for applications in bone tissue engineering. PMID- 26612405 TI - Perioperative extracorporeal membrane oxygenation bridging in patients undergoing pulmonary endarterectomy. AB - OBJECTIVES: Chronic thromboembolic pulmonary hypertension is the only curable form of pulmonary arterial hypertension. Pulmonary endarterectomy (PEA) has been established as the treatment of choice in these patients producing very satisfying results. Some patients develop severe cardiorespiratory decompensation before PEA or during weaning from cardiopulmonary bypass. This might be due to acute reperfusion oedema and/or right ventricular failure caused by residual hypertension. Extracorporeal membrane oxygenation (ECMO) support has been established as a bridging therapy in cardiorespiratory failure. At our department, we used peripheral veno-arterial ECMO in patients deteriorating before PEA and in patients where weaning from cardiopulmonary bypass was not possible. METHODS: We conducted a retrospective analysis of all the patients undergoing PEA who needed pre- and/or postoperative veno-arterial ECMO support. Outcomes including survival, morbidity and haemodynamic improvement were compared between patients surviving and non-surviving after ECMO support. Further, we analysed survival and risk factors of patients requiring ECMO versus patients without ECMO support. RESULTS: Between January 2001 and March 2013, a total of 161 patients underwent PEA at our institution. Thirty-one patients (19.3%) required support with peripheral veno-arterial ECMO, either both, pre- and postoperatively (n = 2), or only postoperatively (n = 29). Twenty-eight patients received ECMO directly in the theatre and 1 patient received ECMO at the ICU after successful weaning from cardiopulmonary bypass after PEA. Twenty-eight patients (90.3%) were successfully weaned from ECMO and 20 patients left the hospital alive giving a salvage rate of 64.5%. For those not requiring ECMO support, in-house mortality was 3.1% (n = 4). In the 3 patients where weaning from ECMO was not possible, lung transplantation was performed as a rescue therapy. Long-term survival in the patients requiring ECMO who survived was worse than survival in the non-ECMO patient group. The only significant risk factor for the use of ECMO was a pulmonary vascular resistance higher than 1000 dynes cm s( 5). CONCLUSIONS: Pre- and postoperative ECMO bridging in patients undergoing PEA is a feasible option to stabilize patients in a critical pre- and/or postoperative situation and to improve outcome in these patients who would otherwise probably not survive the procedure. PMID- 26612406 TI - Is an adjunctive subvalvular repair during mitral annuloplasty for secondary mitral regurgitation effective in preventing recurrent regurgitation? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: Is an adjunctive subvalvular repair during mitral annuloplasty for secondary mitral regurgitation effective in preventing recurrent regurgitation? Altogether, 353 studies were found using the reported search, of which 9 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. The best evidence regarding adjunctive subvalvular repair during mitral annuloplasty for secondary mitral regurgitation was from retrospective analyses. The studies reported outcomes of mitral valve repair (MVr) with annuloplasty alone (ring MVr) versus adjunctive papillary muscle approximation (PMA; n = 3), papillary muscle relocation (PMR; n = 3), secondary chordal cutting (n = 2) and PMA + PMR (n = 1). All but one study included concomitant coronary artery bypass grafting, whereas additional ventriculoplasty was performed in three studies. Follow-up ranged from 1 month to 5 years. The performance of PMA was associated with a lower mitral regurgitation (MR) grade when combined with ventriculoplasty in one study, whereas a greater improvement in left ventricular end-diastolic diameter and left ventricular ejection fraction at follow-up was observed with PMA alone in a separate study. Three studies of ring + PMR reported a reduction in >= 2+ recurrent MR, whereas two studies also observed a greater reduction in left ventricular end-diastolic diameter. The two studies on secondary chordal cutting reported a lower MR grade, lower recurrence of >= 2+ MR and a greater left ventricular ejection fraction at follow-up. Combining PMA + PMR + ventriculoplasty significantly reduced left ventricular end-systolic volume index at short-term follow-up in one study. Finally, none of the studies reported a significant difference in operative mortality between ring MVr (0-13%) versus ring MVr + subvalvular repair (0-15%). We conclude that an adjunctive subvalvular repair performed at the time of mitral annuloplasty for secondary MR can be safely performed, improves the durability of valve repair and enhances left ventricular reverse remodelling. PMID- 26612404 TI - Clinical parameter of odontoma with special emphasis on treatment of impacted teeth-a retrospective multicentre study and literature review. AB - OBJECTIVES: Odontoma-separated into complex (CxOD) and compound (CpOD) subtypes represents the most frequent odontogenic malformation. Retention of permanent teeth is a common symptom. Therefore, in a series of odontomas, an analysis of the management of retained teeth was conducted. MATERIALS AND METHODS: In a retrospective multicenter study of two University Medical Centers and one private praxis in Germany, demographic and clinical data regarding odontomas from 01/2000 03/2015 were obtained. In particular, the influence of operative therapy on the dentition and on the treatment of impacted teeth was analyzed. RESULTS: Forty five patients with 15 CxOD and 30 CpOD were included. Initial symptoms were delayed eruption of permanent teeth (n = 11), pain (n = 4), and swellings (n = 2); 28 cases were discovered by incidence, all of them via panoramic radiographs. The mandible/maxilla ratio was about 1:0.55 (29/16). Thirty-five out of 45 odontomas were in close proximity of at least one tooth (n = 16 at molars). A total of 14 teeth were extracted (CxOD: n = 5; CpOD: n = 9). Extractions had to be conducted more often in older patients (mean age 39.8 vs. 25.6 years). Of the non-extracted teeth, 8 teeth were displaced and retained. Of those, 4 teeth were aligned in the dental arch via orthodontic help and 2 teeth erupted spontaneously after operation during the follow-up period. In all cases, no relapse was seen. CONCLUSION: Odontomas can cause displacement as well as malformation and resorption of the adjacent teeth. CLINICAL RELEVANCE: Mostly, removal of odontomas is conducted. Extirpation of odontoma can allow for normal tooth eruption, often rendering extractions avoidable. Orthodontic alignment, though sometimes challenging, is a reasonable therapeutic option. These findings underline the value of the panoramic radiograph in preventive dentistry in younger patients. PMID- 26612407 TI - Efficacy of 10-day Sitafloxacin-Containing Third-Line Rescue Therapies for Helicobacter pylori Strains Containing the gyrA Mutation. AB - BACKGROUND AND AIM: Sitafloxacin-containing Helicobacter pylori eradication therapy is a promising third-line therapeutic approach, but there is no previous studies between gyrA mutation status of H. pylori strains and the efficacy of 10 day sitafloxacin-containing regimens. Here, we assessed the efficacy of 2 different 10-day sitafloxacin-containing rescue regimens. METHODS: Patients who failed first- and second-line eradication therapies were enrolled. The minimum inhibitory concentrations (MICs) of sitafloxacin, amoxicillin, and metronidazole and the gyrA mutation status of the H. pylori strains were determined before treatment. The patients were randomized to receive a 10-day triple therapy containing either esomeprazole (20 mg, b.i.d.), amoxicillin (500 mg, q.i.d.), and sitafloxacin (100 mg, b.i.d.) (EAS regimen) or esomeprazole (20 mg, b.i.d.), metronidazole (250 mg, b.i.d.), and sitafloxacin (100 mg, b.i.d.) (EMS regimen). Eradication rates were evaluated by the [13C] urea breath test or the H. pylori stool antigen test. RESULTS: All patients with gyrA mutation-negative strains (24 in EAS and 16 in EMS) showed successful eradication, irrespective of the regimen they received. In patients with gyrA mutation-positive strains, we found eradication rates of 70.3% (26/37) and 66.7% (26/39) in the EAS and EMS groups in per-protocol population, respectively (p = .81). According to logistic regression analyses, the MICs of sitafloxacin, which were strongly associated with gyrA mutation status, were independently associated with successful eradication in both groups. This study was registered in the UMIN Clinical Trials Registry as UMIN000006483. CONCLUSION: There is no significant difference in the eradication rates between EAS and EMS, regardless of the gyrA mutation status of the H. pylori strains. GyrA mutation status was an important factor in predicting successful eradication with sitafloxacin-containing rescue therapies. PMID- 26612409 TI - Host Range Specificity of Scymnus camptodromus (Coleoptera: Coccinellidae), A Predator of Hemlock Woolly Adelgid (Hemiptera: Adelgidae). AB - Scymnus (Neopullus) camptodromus Yu and Liu (Coleoptera: Coccinellidae) was brought to the United States from China as a potential biological control agent for hemlock woolly adelgid (Adelges tsugae Annand) (Hemiptera: Adelgidae). Scymnus camptodromus phenology is closely synchronized with that of A. tsugae and has several characteristics of a promising biological control agent. As a prerequisite to field release, S. camptodromus was evaluated for potential nontarget impacts. In host range studies, the predator was given the choice of sympatric adelgid and nonadelgid prey items. Nontarget testing showed that S. camptodromus will feed to some degree on other adelgid species, but highly prefers A. tsugae. We also evaluated larval development of S. camptodromus on pine bark adelgid (Pineus strobi (Hartig)) (Hemiptera: Adelgidae) and larch adelgid (Adelges laricis Vallot) (Hemiptera: Adelgidae); a small proportion of predator larvae was able to develop to adulthood on P. strobi or A. laricis alone. Scymnus camptodromus showed no interest in feeding on woolly alder aphid (Paraprociphilus tessellatus Fitch) (Hemiptera: Aphididae) or woolly apple aphid (Eriosoma lanigerum (Hausmann)) (Hemiptera: Aphididae), and minimal interest in cotton aphid (Aphis gossypii Glover) (Hemiptera: Aphididae) in choice and no choice experiments. Scymnus camptodromus females did not oviposit on any host material other than A. tsugae-infested hemlock. Under the circumstances of the study, S. camptodromus appears to be a specific predator of A. tsugae, with minimal risk to nontarget species. Although the predator can develop on P. strobi, the likelihood that S. camptodromus would oviposit on pine hosts of this adelgid is small. PMID- 26612408 TI - Male breast carcinoma: radiotherapy contributed to favorable local control in two cases and related literature review. AB - Male breast carcinoma (MBC) is rarely encountered in clinical practice. Due to its paucity, our knowledge of MBC only rely on small or single-institutional studies and sporadic cases. The current guidelines for MBC are extrapolated from its female counterparts Rudlowski (Breast Care (Basel) 3(3):183-189, 2008). Nowadays, MBC is actively studied and viewed as a potentially different entity on the aspects of etiology, biological behavior and prognosis. Thus, special treatment strategy guidelines should be established for MBC. Additionally, advance in the systemic chemotherapy and hormonal therapy also contribute to the local control. The indication of radiotherapy need to be clarified and over treatment should be avoided. Here we present two cases of MBC in which radiotherapy help to sustain a satisfactory disease free survival. Our cases will provide valuable experience for identifying the role of radiotherapy in MBC. PMID- 26612410 TI - Sixty seconds on . . . ADHD. PMID- 26612411 TI - Opportunities and challenges in using human hepatocytes in cytochromes P450 induction assays. AB - INTRODUCTION: Identification of inducers of xenobiotic-metabolizing cytochromes P450 (CYP) is of topical interest. The issue mainly concerns three sectors: (i) preclinical testing of drug candidates and testing existing drugs and their combinations; (ii) food safety applications with regard to additives, contaminants, and adulterants; (iii) environmental applications, comprising detection and identification of endocrine disruptors. AREAS COVERED: A literature search was performed using the PubMed database, covering state-of-the-art of human hepatocyte (HH) culture use, and their exploitation for the identification of P450 inducers. A list of CYP inducers identified by HHs is provided. EXPERT OPINION: Primary cultures of HHs had long been considered as a gold standard for induction assays of xenobiotic-metabolizing enzymes. Owing to several shortcomings of HHs, alternative approaches such as immortalization of HHs, use of cell lines, generation of clonal cell lines from HHs, use of induced pluripotent stem (iPS) cells, cells from humanized animals, etc., were employed. While yielding particular advantage, overall, alternatives to HHs still remain an avenue for discrete applications or technical situations. Thus, HHs remain the most suitable model for complex CYP induction studies. The summary may be effectively expressed by strength/weakness/opportunity/threats analysis. PMID- 26612413 TI - Strontium (Sr) and silver (Ag) loaded nanotubular structures with combined osteoinductive and antimicrobial activities. AB - Two frequent problems are associated with the titanium surfaces of bone/dental implants: lack of native tissue integration and associated infection. These problems have prompted a significant body of research regarding the modification of these surfaces. The present study describes a hydrothermal treatment for the fabrication of strontium (Sr) and silver (Ag) loaded nanotubular structures with different tube diameters on titanium surfaces. The Sr loading from a Sr(OH)2 solution was regulated by the size of the inner diameter of the titanium nanotubes (NT) (30nm or 80nm, formed at 10V or 40V, respectively). The quantity of Ag was adjusted by immersing the samples in 1.5 or 2.0M AgNO3 solutions. Sr and Ag were released in a controllable and prolonged matter from the NT-Ag.Sr samples, with negligible cytotoxicity. Prominent antibacterial activity was observed due to the release of Ag. Sr incorporation enhanced the initial cell adhesion, migration, and proliferation of preosteoblast MC3T3-E1 cells. Sr release also up-regulated the expression of osteogenic genes and induced mineralization, as suggested by the presence of more mineralized calcium nodules in cells cultured on NT-Ag.Sr surfaces. In vivo experiments showed that the Sr loaded samples accelerated the formation of new bone in both osteoporosis and bone defect models, as confirmed by X-ray, Micro-CT evaluation, and histomorphometric analysis of rats implanted with NT-Ag.Sr samples. The antibacterial activity and outstanding osteogenic properties of NT-Ag.Sr samples highlight their excellent potential for use in clinical applications. STATEMENT OF SIGNIFICANCE: Two frequent problems associated with Ti surfaces, widely used in orthopedic and dental arenas, are their lack of native tissue integration and risk of infection. We describe a novel approach for the fabrication of strontium (Sr) and silver (Ag) loaded nanotubular structures on titanium surfaces. A relevant aspect of this work is the demonstration of long-lasting and controllable Ag release, leading to excellent antibacterial and anti-adherent properties against methicillin-resistant Staphylococcus aureus (MRSA), and Gram negative bacteria such as Escherichia coli. The extended release of Sr accelerates the filling of bone defects by improving the repair of damaged cortical bone and increasing trabecular bone microarchitecture. Our results highlight the potential of Sr and Ag loaded nanotubular structures for use in clinical applications. PMID- 26612412 TI - A Three-Way Interaction among Maternal and Fetal Variants Contributing to Congenital Heart Defects. AB - Congenital heart defects (CHDs) develop through a complex interplay between genetic variants, epigenetic modifications, and maternal environmental exposures. Genetic studies of CHDs have commonly tested single genetic variants for association with CHDs. Less attention has been given to complex gene-by-gene and gene-by-environment interactions. In this study, we applied a recently developed likelihood-ratio Mann-Whitney (LRMW) method to detect joint actions among maternal variants, fetal variants, and maternal environmental exposures, allowing for high-order statistical interactions. All subjects are participants from the National Birth Defect Prevention Study, including 623 mother-offspring pairs with CHD-affected pregnancies and 875 mother-offspring pairs with unaffected pregnancies. Each individual has 872 single nucleotide polymorphisms encoding for critical enzymes in the homocysteine, folate, and trans-sulfuration pathways. By using the LRMW method, three variants (fetal rs625879, maternal rs2169650, and maternal rs8177441) were identified with a joint association to CHD risk (nominal P-value = 1.13e-07). These three variants are located within genes BHMT2, GSTP1, and GPX3, respectively. Further examination indicated that maternal SNP rs2169650 may interact with both fetal SNP rs625879 and maternal SNP rs8177441. Our findings suggest that the risk of CHD may be influenced by both the intragenerational interaction within the maternal genome and the intergenerational interaction between maternal and fetal genomes. PMID- 26612414 TI - Release of zirconia nanoparticles at the metal stem-bone cement interface in implant loosening of total hip replacements. AB - In a previous failure analysis performed on femoral components of cemented total hip replacements, we determined high volumes of abraded bone cement. Here, we describe the topography of the polished surface of polymethyl methacrylate (PMMA) bone cement containing zirconia radiopacifier, analyzed by scanning electron microscopy and vertical scanning interferometry. Zirconia spikes protruded about 300nm from the PMMA matrix, with pits of former crystal deposition measuring about 400nm in depth. We deduced that the characteristically mulberry-shaped agglomerates of zirconia crystals are ground and truncated into flat surfaces and finally torn out of the PMMA matrix. Additionally, evaluation of in vitro PMMA-on PMMA articulation confirmed that crystal agglomerations of zirconia were exposed to grain pullout, fatigue, and abrasion. In great quantities, micron-sized PMMA wear and zirconia nanoparticles accumulate in the cement-bone interface and capsular tissues, thereby contributing to osteolysis. Dissemination of nanoparticles to distant lymph nodes and organs of storage has been reported. As sufficient information is lacking, foreign body reactions to accumulated nanosized zirconia in places of long-term storage should be investigated. STATEMENT OF SIGNIFICANCE: The production of wear particles of PMMA bone cement in the interface to joint replacement devices, presents a local challenge. The presence of zirconia particles results in frustrated digestion attempts by macrophages, liberation of inflammatory mediators, and necrosis leading to aseptic inflammation and osteolyses. Attempts to minimize wear of articulating joints reduced the attention to the deterioration of cement cuffs. We therefore investigated polished surfaces of retrieved cuffs to demonstrate their morphology and to measure surface roughness. Industrially admixed agglomerates of the radiopacifier are abraded to micron and nano-meter sized particles. The dissemination of zirconia particles in the reticulo-endothelial system to storage organs is a possible burden. Research to replace the actual contrast media by non particulate material deserves more attention. PMID- 26612415 TI - Preservation of human limbal epithelial progenitor cells on carbodiimide cross linked amniotic membrane via integrin-linked kinase-mediated Wnt activation. AB - The Wnt pathway is a major signaling pathway that regulates corneal epithelial stem cells. However, little is known about how the ultrastructure of the limbal epithelial basement membrane (EBM) affects Wnt activity. Due to its enhanced matrix stability, the cross-linked amniotic membrane (AM) has gained increasing interest in the field of regenerative medicine. For the first time, we used EDC/NHS cross-linked denuded AM (CLDAM) as a simulated EBM substrate to investigate this mechanism. Human limbal epithelial (HLE) cells were cultured on dishes (HLE/dish), denuded AM (HLE/DAM) or CLDAM (HLE/CLDAM). Compared with HLE/dish or HLE/DAM cultures, HLE/CLDAM cultures showed greater BrdU retention and colony formation efficiency and expressed higher levels of p63, ABCG2, integrin beta1, and integrin-linked kinase (ILK). Nuclear beta-catenin and TCF-4 levels were higher in HLE/CLDAM cultures compared with HLE cells cultured on collagen IV, laminin, Matrigel, or DAM. Silencing of ILK in HLE/CLDAM cultures resulted in decreased levels of nuclear beta-catenin, TCF-4 and deltaNp63alpha, whereas cytokeratin 12 expression increased. Over-expression of ILK in HLE/dish cultures had the opposite effects. Accordingly, we proposed that the CLDAM matrix, with its higher rigidity and rougher ultrastructure, better preserved HLE progenitor cells in vitro, possibly by activating integrin beta1/ILK, which indirectly activated Wnt/beta-catenin and subsequently deltaNp63alpha. Crosstalk between the integrin beta1/ILK and Wnt/beta-catenin pathways appears to play a crucial role in limbal progenitor cell survival on EBM. STATEMENT OF SIGNIFICANCE: We demonstrated the superior capability of carbodiimide cross linked denuded amniotic membrane (CLDAM) than natural DAM to preserve limbo corneal epithelial progenitor cells in vitro, then we used CLDAM as a simulated epithelial basement membrane (EBM) to study how EBM maintains limbal epithelial stem cells (LESCs). We found that integrin-linked kinase (ILK) is an important mediator that transfers survival signals detected by integrin beta1 to the Wnt/beta-catenin pathway, which in turn up-regulates deltaNp63alpha, a master gene that regulates LESC function. The rougher surface of the limbal EBM suggests that the surface complexity of the LESC niche may be important in regulating LESC function, which is triggered by the recognition of topographic cues by integrin beta1, followed by activation of the ILK/Wnt/beta-catenin/p63 cascade. PMID- 26612416 TI - Co-delivery of Se nanoparticles and pooled SiRNAs for overcoming drug resistance mediated by P-glycoprotein and class III beta-tubulin in drug-resistant breast cancers. AB - Drug resistance mediated by P-glycoprotein (P-gp) and class III beta-tubulin (beta-tubulin III) is a major barrier in microtubule-targeting cancer chemotherapy. In this study, layered double hydroxide nanoparticles (LDHs) were employed to simultaneously deliver selenium (Se) and pooled small interfering RNAs (siRNAs) to achieve therapeutic efficacy. LDH-supported Se nanoparticles (Se@LDH) were compacted with siRNAs (anti-P-gp and anti-beta-tubulin III) via electrostatic interactions, which could protect siRNA from degradation. Se@LDH showed excellent abilities to deliver siRNA into cells, including enhancing siRNA internalization, and promoting siRNA escape from endosomes. siRNA transfection experiments further confirmed a higher gene silencing efficiency of Se@LDH than LDH. Interestingly, we found Se@LDH may be a microtubule (MT) stabilizing agent which could inhibit cell proliferation by blocking cell cycle at G2/M phase, disrupting normal mitotic spindle formation and inducing cell apoptosis. When complexed with different specific siRNAs, Se@LDH/siRNA nanoparticles, especially the Se@LDH-pooled siRNAs, exhibit an efficient gene-silencing effect that significantly downregulate the expression of P-gp and beta-tubulin III. Moreover, Se@LDH-pooled siRNAs could induce cell apoptosis, change cell morphology and increase cellular ROS levels through change the expression of Bcl-2/Bax, activation of caspase-3, PI3K/AKT/mTOR and MAPK/ERK pathways. These results suggested that co-delivery of Se and pooled siRNAs may be a promising strategy for overcoming the drug resistance mediated by P-gp and beta-tubulin III in drug resistant breast cancers. PMID- 26612418 TI - Use of nanoscale mechanical stimulation for control and manipulation of cell behaviour. AB - The ability to control cell behaviour, cell fate and simulate reliable tissue models in vitro remains a significant challenge yet is crucial for various applications of high throughput screening e.g. drug discovery. Mechanotransduction (the ability of cells to convert mechanical forces in their environment to biochemical signalling) represents an alternative mechanism to attain this control with such studies developing techniques to reproducibly control the mechanical environment in techniques which have potential to be scaled. In this review, the use of techniques such as finite element modelling and precision interferometric measurement are examined to provide context for a novel technique based on nanoscale vibration, also known as "nanokicking". Studies have shown this stimulus to alter cellular responses in both endothelial and mesenchymal stem cells (MSCs), particularly in increased proliferation rate and induced osteogenesis respectively. Endothelial cell lines were exposed to nanoscale vibration amplitudes across a frequency range of 1-100 Hz, and MSCs primarily at 1 kHz. This technique provides significant potential benefits over existing technologies, as cellular responses can be initiated without the use of expensive engineering techniques and/or chemical induction factors. Due to the reproducible and scalable nature of the apparatus it is conceivable that nanokicking could be used for controlling cell behaviour within a wide array of high throughput procedures in the research environment, within drug discovery, and for clinical/therapeutic applications. STATEMENT OF SIGNIFICANCE: The results discussed within this article summarise the potential benefits of using nanoscale vibration protocols for controlling cell behaviour. There is a significant need for reliable tissue models within the clinical and pharma industries, and the control of cell behaviour and stem cell differentiation would be highly beneficial. The full potential of this method of controlling cell behaviour has not yet been realised. PMID- 26612417 TI - Inhibition of COX1/2 alters the host response and reduces ECM scaffold mediated constructive tissue remodeling in a rodent model of skeletal muscle injury. AB - Extracellular matrix (ECM) has been used as a biologic scaffold material to both reinforce the surgical repair of soft tissue and serve as an inductive template to promote a constructive tissue remodeling response. Success of such an approach is dependent on macrophage-mediated degradation and remodeling of the biologic scaffold. Macrophage phenotype during these processes is a predictive factor of the eventual remodeling outcome. ECM scaffolds have been shown to promote an anti inflammatory or M2-like macrophage phenotype in vitro that includes secretion of downstream products of cycolooxygenases 1 and 2 (COX1/2). The present study investigated the effect of a common COX1/2 inhibitor (Aspirin) on macrophage phenotype and tissue remodeling in a rodent model of ECM scaffold treated skeletal muscle injury. Inhibition of COX1/2 reduced the constructive remodeling response by hindering myogenesis and collagen deposition in the defect area. The inhibited response was correlated with a reduction in M2-like macrophages in the defect area. The effects of Aspirin on macrophage phenotype were corroborated using an established in vitro macrophage model which showed a reduction in both ECM induced prostaglandin secretion and expression of a marker of M2-like macrophages (CD206). These results raise questions regarding the common peri surgical administration of COX1/2 inhibitors when biologic scaffold materials are used to facilitate muscle repair/regeneration. STATEMENT OF SIGNIFICANCE: COX1/2 inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely administered post-surgically for analgesic purposes. While COX1/2 inhibitors are important in pain management, they have also been shown to delay or diminish the healing process, which calls to question their clinical use for treating musculotendinous injuries. The present study aimed to investigate the influence of a common NSAID, Aspirin, on the constructive remodeling response mediated by an ECM scaffold (UBM) in a rat skeletal muscle injury model. The COX1/2 inhibitor, Aspirin, was found to mitigate the ECM scaffold-mediated constructive remodeling response both in an in vitro co-culture system and an in vivo rat model of skeletal muscle injury. The results presented herein provide data showing that NSAIDs may significantly alter tissue remodeling outcomes when a biomaterial is used in a regenerative medicine/tissue engineering application. Thus, the decision to prescribe NSAIDs to manage the symptoms of inflammation post-ECM scaffold implantation should be carefully considered. PMID- 26612419 TI - Interaction of a small molecule Natura-alpha and STAT3-SH2 domain to block Y705 phosphorylation and inhibit lupus nephritis. AB - A small molecule, Natura-alpha, a clinical stage investigational new drug for certain inflammatory diseases, has been evaluated for drug interaction with STAT3 and inhibiting systemic lupus erythematosus (SLE). Studies have revealed that it selectively inhibits STAT3-Y705 phosphorylation and, suppresses pro-inflammatory cytokines, stimulates anti-inflammatory cytokine IL-10, thereby skewing T cell differentiation from the Th1/Th17 lineages toward the Treg lineage. The potential binding of the drug to STAT3 protein has been investigated with a computational modeling and docking simulation using X-ray crystal structure of the STAT3beta homodimer. Natura-alpha was shown to directly bind to SH2 domain of STAT3 and forms H-bonds with amino acids Glu594 and Arg609. The phosphorylation of Y705 was prevented and making the formation of STAT3 homodimer impossible, thereby blocking STAT3 activation. The in vivo efficacy of Natura-alpha in SLE was evaluated in a bioassay with NZB/W female mice. Mice at week 19 were given orally Natura-alpha at 25 or 75 mg/kg, once a day, 5 days per week for 29 weeks. Mice were monitored weekly until 52 weeks of age. Both dosages were effective to reduce proteinuria and significantly improved animal survival rate. The renal functions were preserved with glomerular lesions reversed, which paralleled with decreased C3 deposit. The numbers of kidney cells stained with phosphorylated STAT3-Y705 remarkably decreased, demonstrating blocking of Y-705 phosphorylation by the treatment. Since NZB/W mice develop nephritis which resembles SLE in men, the data strongly suggests that Natura-alpha may be a potential effective therapeutic agent for lupus. PMID- 26612420 TI - Effect of Home-Based Complementary Food Fortification on Prevalence of Anemia Among Infants and Young Children Aged 6 to 23 Months in Poor Rural Regions of China. AB - Following the 2008 Wenchuan earthquake, the Chinese government instituted an infant and young and child nutrition program that included promotion of in-home fortification of complementary food with ying yang bao (YYB), a soy-based powder containing iron, 2.5 mg as iron-EDTA and 5 mg as ferrous fumarate, and other micronutrients. Ying yang bao was provided to participating families in 8 poor rural counties in Sichuan, Shaanxi, and Gansu provinces by the Ministry of Health. We assessed hemoglobin levels among infants and young children (IYC) aged 6 to 23 months at baseline in May 2010 (n = 1290) and during follow-up in November 2010 (n = 1142), May 2011 (n = 1118), and November 2011 (n = 1040), using the Hemocue method. Interviewers collected basic demographic information and child feeding practices from the children's caretakers. Altitude-adjusted hemoglobin level averaged 10.8 g/dL, and total anemia prevalence was 49.5% at baseline. Average hemoglobin was 11.3 g/dL at 6 months, 11.6 g/dL at 12 months, and 11.7 g/dL at 18 months after introduction of YYB. Moderate anemia (hemoglobin: 70-99 g/dL) decreased from 20.3% at baseline to 7.5%, 5.8%, and 7.3% after 6, 12, and 18 months of home fortification, respectively (P < .001), whereas mild anemia (hemoglobin: 100-110 g/dL) decreased from 29.0% to 16.7%, 18.1%, and 15.4%, respectively (P < .001). Among infants aged 6 to 23 months, 95% had regularly been fed YYB during the observation period. Regression analysis showed that the duration of YYB consumption and number of sachets consumed per week correlated positively with hemoglobin levels and negatively with anemia rates. Home food fortification with YYB is feasible and effective for nutrition promotion among IYC in high-risk regions of China. PMID- 26612421 TI - A Blinded, Cluster-Randomized, Placebo-Controlled School FeedingTrial in Burundi Using Rice Fortified With Iron, Zinc, Thiamine, and Folic Acid. AB - BACKGROUND: Iron-deficiency anemia is a major public health problem among school aged children in sub-Saharan Africa. OBJECTIVE: To evaluate the effectiveness of micronutrient-fortified rice to increase hemoglobin (Hb) concentration and reduce the prevalence of anemia among schoolchildren. METHODS: Nine hundred four schoolchildren participated in this cluster-randomized trial during a 7-month intervention period. The study was conducted in 12 primary schools in rural Burundi. Hemoglobin, socioeconomic status, febrile illness, and dietary diversity were measured at baseline and follow-up. The changes in Hb concentration and anemia status were analyzed using linear and logistic mixed models, respectively. The micronutrient formulation contained an iron-to-zinc molar ratio of approximately 2.2. RESULTS: There was no significant difference in Hb concentration between the intervention and control groups (beta = .09 g/dL; 95% confidence interval: -0.21 to 0.38) following the 7-month intervention. Nearly half the children reported having a fever within 2 weeks prior to baseline or follow-up. Children with febrile illness preceding follow-up were less than half as likely to show improvement in anemia status (odds ratio = 0.47, P < .001), with an average 0.56 g/dL smaller improvement in Hb at follow-up (P < .001). CONCLUSION: The high prevalence of fever and low iron-to-zinc molar ratio of the Ultra Rice formulation may have contributed to the lack of improvement in Hb. Alternatively, the detected anemia may not have been due to nutrient deficiencies. Anemia interventions in Burundi should implement multiple strategies to eliminate both iron deficiency and infectious causes of anemia. PMID- 26612423 TI - Convergence of microbial assimilations of soil carbon, nitrogen, phosphorus, and sulfur in terrestrial ecosystems. AB - How soil microbes assimilate carbon-C, nitrogen-N, phosphorus-P, and sulfur-S is fundamental for understanding nutrient cycling in terrestrial ecosystems. We compiled a global database of C, N, P, and S concentrations in soils and microbes and developed relationships between them by using a power function model. The C:N:P:S was estimated to be 287:17:1:0.8 for soils, and 42:6:1:0.4 for microbes. We found a convergence of the relationships between elements in soils and in soil microbial biomass across C, N, P, and S. The element concentrations in soil microbial biomass follow a homeostatic regulation curve with soil element concentrations across C, N, P and S, implying a unifying mechanism of microbial assimilating soil elements. This correlation explains the well-constrained C:N:P:S stoichiometry with a slightly larger variation in soils than in microbial biomass. Meanwhile, it is estimated that the minimum requirements of soil elements for soil microbes are 0.8 mmol C Kg(-1) dry soil, 0.1 mmol N Kg(-1) dry soil, 0.1 mmol P Kg(-1) dry soil, and 0.1 mmol S Kg(-1) dry soil, respectively. These findings provide a mathematical explanation of element imbalance in soils and soil microbial biomass, and offer insights for incorporating microbial contribution to nutrient cycling into Earth system models. PMID- 26612424 TI - Double head-to-tail direct arylation as a viable strategy towards the synthesis of the aza-analog of dihydrocyclopenta[hi]aceanthrylene--an intriguing antiaromatic heterocycle. AB - The first case of double head-to-tail direct arylation of aromatic compounds and the unusual photophysical properties of the resulting 2,2a(1,5)b(1,7) tetraazacyclopenta[hi]aceanthrylene are reported. This molecule, comprising of two imidazo[1,2-a]pyridine units, is antiaromatic due to the changes in the efficiency of pi-electron ring current and it belongs to a class of seldom encountered compounds with a dark lowest electronically excited singlet state. PMID- 26612422 TI - Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors. AB - The type 1 cannabinoid receptor (CB1) modulates numerous neurobehavioral processes and is therefore explored as a target for the treatment of several mental and neurological diseases. However, previous studies have investigated CB1 by targeting it globally, regardless of its two main neuronal localizations on glutamatergic and GABAergic neurons. In the context of cocaine addiction this lack of selectivity is critical since glutamatergic and GABAergic neuronal transmission is involved in different aspects of the disease. To determine whether CB1 exerts different control on cocaine seeking according to its two main neuronal localizations, we used mutant mice with deleted CB1 in cortical glutamatergic neurons (Glu-CB1) or in forebrain GABAergic neurons (GABA-CB1). In Glu-CB1, gene deletion concerns the dorsal telencephalon, including neocortex, paleocortex, archicortex, hippocampal formation and the cortical portions of the amygdala. In GABA-CB1, it concerns several cortical and non-cortical areas including the dorsal striatum, nucleus accumbens, thalamic, and hypothalamic nuclei. We tested complementary components of cocaine self-administration, separating the influence of primary and conditioned effects. Mechanisms underlying each phenotype were explored using in vivo microdialysis and ex vivo electrophysiology. We show that CB1 expression in forebrain GABAergic neurons controls mouse sensitivity to cocaine, while CB1 expression in cortical glutamatergic neurons controls associative learning processes. In accordance, in the nucleus accumbens, GABA-CB1 receptors control cocaine-induced dopamine release and Glu-CB1 receptors control AMPAR/NMDAR ratio; a marker of synaptic plasticity. Our findings demonstrate a critical distinction of the altered balance of Glu-CB1 and GABA-CB1 activity that could participate in the vulnerability to cocaine abuse and addiction. Moreover, these novel insights advance our understanding of CB1 neuropathophysiology. PMID- 26612425 TI - High coagulation factor VIII and von Willebrand factor in patients with lymphoma and leukemia. AB - The risk of venous thromboembolism is increased in patients with lymphoma and leukemia; however, little is known about the potential underlying hereditary or acquired thrombophilia. We prospectively analyzed procoagulant markers and gene mutations in patients with lymphoma (n = 35) and leukemia (n = 10) at diagnosis and over the course of treatment. Global coagulation tests were normal in all patients, as were antithrombin and protein S. Activated protein C resistance caused by the factor V Leiden mutation was found in four patients, one patient had the G20210A mutation of the prothrombin gene, and one patient had protein C deficiency. The most striking findings were sustained very high levels of factor VIII (>150 %) in 30 patients (68 %), which correlated with high von Willebrand factor. An acute phase response in these patients was ruled out by absence of fever and normal IL-6 and -alpha. Elevated factor VIII is an independent thrombophilic risk factor and may play an etiologic role in thromboembolic complications in patients with malignant lymphoma. Since high von Willebrand factor is most likely caused by endothelial cell injury, an additional, unknown pathophysiological association with malignant lymphoma and acute leukemia is possible. PMID- 26612426 TI - Ethics of tobacco harm reduction from a liberal perspective. AB - Mixed evidence on the possible harms, benefits and usage patterns of electronic nicotine delivery systems (ENDS, or 'e-cigarettes'), has led to vigorous and ongoing debates on the issue. The ethical trade-off often represented is that, though smokers should be permitted access to ENDS as a less harmful alternative to smoking, this comes at the expense of non-smokers and children who may experiment with ENDS, become addicted to them, or experience health issues from long-term exposure to passive ENDS vapour. Lacking from many debates is a balanced analysis based on sound ethical reasoning, so this paper aims to examine the issue from a liberal perspective. More specifically, focus is on how ENDS policy can help to promote freedom in a broader sense, with 'freedom' considered as originating from having options and the necessary information and ability to autonomously choose between these options. PMID- 26612427 TI - Pigment epithelium-derived factor regulation by human chorionic gonadotropin in granulosa cells. AB - Human chorionic gonadotropin (hCG) is a known trigger of ovarian hyperstimulation syndrome (OHSS), a potentially life-threatening complication of assisted reproduction. Administration of hCG results in the release of vascular endothelial growth factor (VEGF) from the ovary. We have previously shown that expression of pigment epithelium-derived factor (PEDF) in granulosa cell line is regulated by hCG, reciprocally to VEGF, and that the PEDF-VEGF balance is impaired in OHSS. Our aim was to explore the signaling network by which hCG downregulates the expression of PEDF mRNA and protein in granulosa cells. We applied specific chemical inhibitors and stimuli to human primary granulosa cells and rat granulosa cell line. We found that PKA and protein kinase C, as well as EGFR, ERK1/2 and PI3K, participate in the signaling network. The finding that hCG induced PEDF downregulation and VEGF upregulation are mediated by similar signaling cascades emphasizes the delicate regulation of ovarian angiogenesis. PMID- 26612429 TI - Pharmacokinetics of meloxicam in adult goats: a comparative study of subcutaneous, oral and intravenous administration. AB - AIMS: To determine the plasma disposition of meloxicam in goats following S/C, oral or I/V administration at a single dose of 0.5 mg/kg bodyweight. METHODS: Five healthy Saanen goats, aged 12-14 months and weighing 35-40 kg, were used for a three phase cross-over design with a 10-day washout period, with meloxicam administered I/V, then orally and S/C. Heparinised blood samples (5 mL) were collected from all animals prior to drug administration (0 hours) and subsequently up to 96 hours. Concentrations of meloxicam in plasma were measured using high performance liquid chromatography. Concentration-time curves were fitted and pharmacokinetic parameters were estimated for each administration group. RESULTS: Subcutaneous administration of meloxicam exhibited unique plasma distribution characteristics that differed from oral and I/V administration. Mean peak plasma concentrations were greater (1.91 (SD 0.39) vs. 0.71 (SD 0.17) ug/mL) and the time to reach them shorter (3.20 (SD 1.64) vs. 14.33 (SD 2.19) hours) following S/C compared with oral administration (p<0.05). The terminal half-life was longer (15.16 (SD 4.74) vs. 10.69 (SD 1.49) hours) and the MRT was shorter (15.67 (SD 2.37) vs. 24.33 (SD 3.12) hours) following S/C than oral administration (p<0.05), but bioavailability was similar (98.24 (SD 9.62) vs. 96.49 (SD 10.71)%). CONCLUSION AND CLINICAL RELEVANCE: Subcutaneous administration of meloxicam resulted in long-term presence of drug at high concentration in goat plasma. This unique plasma disposition characteristic may offer an advantage in some clinical cases towards potentially improving the treatment efficacy in goats. PMID- 26612428 TI - Tandem Spinach Array for mRNA Imaging in Living Bacterial Cells. AB - Live cell RNA imaging using genetically encoded fluorescent labels is an important tool for monitoring RNA activities. A recently reported RNA aptamer fluorogen system, the Spinach, in which an RNA aptamer binds and induces the fluorescence of a GFP-like 3,5-difluoro-4-hydroxybenzylidene imidazolinone (DFHBI) ligand, can be readily tagged to the RNA of interest. Although the aptamer-fluorogen system is sufficient for imaging highly abundant non-coding RNAs (tRNAs, rRNAs, etc.), it performs poorly for mRNA imaging due to low brightness. In addition, whether the aptamer-fluorogen system may perturb the native RNA characteristics has not been systematically characterized at the levels of RNA transcription, translation and degradation. To increase the brightness of these aptamer-fluorogen systems, we constructed and tested tandem arrays containing multiple Spinach aptamers (8-64 aptamer repeats). Such arrays enhanced the brightness of the tagged mRNA molecules by up to ~17 fold in living cells. Strong laser excitation with pulsed illumination further increased the imaging sensitivity of Spinach array-tagged RNAs. Moreover, transcriptional fusion to the Spinach array did not affect mRNA transcription, translation or degradation, indicating that aptamer arrays might be a generalizable labeling method for high-performance and low-perturbation live cell RNA imaging. PMID- 26612430 TI - Developing and understanding biofluid vibrational spectroscopy: a critical review. AB - Vibrational spectroscopy can provide rapid, label-free, and objective analysis for the clinical domain. Spectroscopic analysis of biofluids such as blood components (e.g. serum and plasma) and others in the proximity of the diseased tissue or cell (e.g. bile, urine, and sputum) offers non-invasive diagnostic/monitoring possibilities for future healthcare that are capable of rapid diagnosis of diseases via specific spectral markers or signatures. Biofluids offer an ideal diagnostic medium due to their ease and low cost of collection and daily use in clinical biology. Due to the low risk and invasiveness of their collection they are widely welcomed by patients as a diagnostic medium. This review underscores recent research within the field of biofluid spectroscopy and its use in myriad pathologies such as cancer and infectious diseases. It highlights current progresses, advents, and pitfalls within the field and discusses future spectroscopic clinical potentials for diagnostics. The requirements and issues surrounding clinical translation are also considered. PMID- 26612431 TI - Diagnosis of functional ischemia in a right coronary artery with anomalous aortic origin. AB - Anomalous aortic origin of coronary artery (AAOCA) is rare but critical for the association with sudden cardiac death. In detecting the origin of AAOCA, coronary CT angiography is more accurate than invasive coronary angiography, but only with anatomical evaluation. A novel technology FFRCT, which is noninvasively computed by coronary CT image, can evaluate functional ischemia of coronary artery even without atherosclerotic plaque and has potential for innovation in AAOCA. PMID- 26612434 TI - Familial influences on the full range of variability in attention and activity levels during adolescence: A longitudinal twin study. AB - To investigate familial influences on the full range of variability in attention and activity across adolescence, we collected maternal ratings of 339 twin pairs at ages 12, 14, and 16, and estimated the transmitted and new familial influences on attention and activity as measured by the Strengths and Weaknesses of Attention-Deficit/Hyperactivity Disorder Symptoms and Normal Behavior Scale. Familial influences were substantial for both traits across adolescence: genetic influences accounted for 54%-73% (attention) and 31%-73% (activity) of the total variance, and shared environmental influences accounted for 0%-22% of the attention variance and 13%-57% of the activity variance. The longitudinal stability of individual differences in attention and activity was largely accounted for by familial influences transmitted from previous ages. Innovations over adolescence were also partially attributable to familial influences. Studying the full range of variability in attention and activity may facilitate our understanding of attention-deficit/hyperactivity disorder's etiology and intervention. PMID- 26612435 TI - TGFbeta3 (TGFB3) polymorphism is associated with male infertility. AB - Factors affecting the blood-testis barrier function may be involved in testicular damage and male infertility. Two cytokines play an important role in the barrier regulation, namely transforming growth factor beta 3 (TGF-beta3) and tumor necrosis factor (TNF-alpha). The aim of this study was to investigate the potential association between TGF-beta3 (TGFB3) and TNF-alpha (TNF) gene polymorphisms and male infertility. A total of 846 subjects, 423 diagnosed with male infertility and 423 fertile men were enrolled. TGFB3 (rs2268626:T > C, rs3917158:C > T, rs2284792:A > G, rs2268625:T > C, rs3917187:C > T) and TNF (rs1800629:-308G > A) gene polymorphisms were genotyped. No association between TNF genotype and infertility was observed. As for TGFB3, the genotypes distribution was similar in infertile and fertile men. However, rs2284792 minor allele frequency was significantly higher among infertile subjects. Heterozygous rs2284792 AG genotype was associated with increased odds for infertility [OR = 1.40 (95% CI 1.05-1.86), p = 0.021] and similar results were observed for G allele carrier status [OR = 1.40 (95% CI 1.06-1.84), p = 0.017]. Heterozygosity in TGFB3 rs3917158 was also associated with the infertility [OR = 1.37 (95% CI 1.01-1.87), p = 0.041]. The TGFB3 variant genotypes were associated with lower spermatozoa motility parameters in fertile men. The results indicate that variants in TGFB3 gene may be associated with male infertility. However, the findings require further replication and validation. PMID- 26612437 TI - Editorial: Health Gaps. PMID- 26612436 TI - Polymorphisms of the eNOS gene are associated with disease activity in rheumatoid arthritis. AB - Nitric oxide (NO) is a mediator in autoimmune responses and thus involved in the pathogenesis of a variety of rheumatic diseases. Genetic factors that influence the expression of the enzyme endothelial nitric oxide synthase (eNOS) that catalyzes NO synthesis are important for the control of NO level and consequently its activity. We have analyzed three functionally relevant polymorphisms of eNOS gene: T-786C, G894T and VNTR (4a/b), to investigate whether they are predisposing factors in pathogenesis of RA in Serbian population and to evaluate their role in clinical manifestations of RA. We performed genotyping of 196 patients with RA and the control group of 132 healthy individuals from Serbian population, using PCR and polymerase chain reaction-restriction fragment length polymorphism methods. Disease activity was prospectively assessed using number of tender joints, number of swollen joints and 28-joints disease activity score (DAS28). There were no differences between the patients and control groups in the genotypes and alleles frequencies of the three analyzed SNPs. Our results showed statistically significant differences in all three analyzed parameters of disease severity between 786TT/786CT and 786CC genotypes and between 894GG/894GT and 894TT genotypes. In the case of 4a/b polymorphism, carriers of minor allele had significantly lower DAS28 values. In conclusion, our results do not support the implication of analyzed eNOS gene polymorphisms in susceptibility to RA but associate them with the disease activity and give assumption that minor alleles are indicators of better clinical course. PMID- 26612438 TI - Improvements in breast cancer recurrence. PMID- 26612439 TI - Journey through the clinics - The experience of a woman with BRCA2. AB - Being told that you carry the gene abnormality for breast cancer is hard enough, then being told that you need surgery that will render you menopausal at a young age makes life even harder. Trying to navigate through the NHS, the genetics service, the gynaecology clinics, the gynaecology surgery, primary care services and finally menopause clinics has highlighted the need for cohesive and consistent advice for such women. This woman reports on her personal, generally positive, experience of this journey. PMID- 26612440 TI - Practice observed. PMID- 26612441 TI - [Jean-Louis-Paul Denuce (1824-1889): A forgotten pioneer of plastic surgery]. AB - The authors propose to define as main characterization of plastic reconstructive surgery the conceptual thinking that leads to a rational choice of an operative treatment. Conceptual thinking in plastic surgery started halfway the nineteenth century with the first schematic representations of the operative procedures available at that time, in which Von Ammon and Baumgarten, Szymanowski and Denuce played a prominent role. These four authors and their works are presented with special attention for the less known of them, Jean-Paul Denuce, surgeon in Bordeaux. PMID- 26612442 TI - Calcium-sensing receptor, proinflammatory cytokines and calcium homeostasis. AB - The calcium-sensing receptor (CaSR) expressed in the parathyroid gland and the kidney tubule acts as the calciostat and orchestrates blood calcium homeostasis by modulating production and release of parathyroid hormone (PTH) and active vitamin D that influence Ca(2+) fluxes across the bone, kidney and intestine. Here we consider the role of the CaSR as a responder to proinflammatory cytokines released as part of the innate immune response to tissue injury and inflammation with resetting of the calciostat on the one hand and as a promoter and mediator of the initial inflammatory response on the other. The importance of the CaSR in systemic calcium homeostasis is exemplified by the fact that inactivating and activating mutations in the gene result in hypercalcemia and hypocalcemia, respectively. Proinflammatory cytokines interleukin-1beta and interleukin-6 upregulate CaSR expression in parathyroid and kidney and do this through defined response elements in the CASR gene promoters. This results in decreased serum PTH and 1,25-dihydroxyvitamin D and calcium levels. This is likely to underlie the hypocalcemia that commonly occurs in critically ill patients, those with burn injury and sepsis, for example. The level of calcium in extracellular fluid bathing necrotic cells is often elevated and acts as a chemokine to attract monocytes/macrophages that express the CaSR to sites of tissue injury. Elevated levels of calcium acting via the CaSR can function as a danger signal that stimulates assembly of myeloid cell cytosolic multiprotein inflammasomes resulting in maturation of the proinflammatory cytokine IL-1beta by caspase-1. Thus the CaSR is both promoter of and responder to the inflammation. PMID- 26612443 TI - Percutaneous computed tomography-guided lung biopsy of solitary nodular ground glass opacity. AB - OBJECTIVE: To evaluate the diagnostic performance and safety of percutaneous lung biopsy under computed tomography (CT)-fluoroscopic guidance for ground-glass opacity (GGO) lesions. MATERIALS AND METHODS: Thirty-eight patients received core biopsy utilizing an automated cutting needle and were evaluated histologically. RESULTS: Five patients had a bronchioloalveolar carcinoma, 3 patients had adenocarcinomas, 18 patients had pulmonary alveoli epithelial dysplasia, 1 patient had a large number of lymphocytes, and 11 patients had a small amount of fibrous connective tissue. Twenty-three lesions (23/38, 60.5%) were located in the upper lobes while 15 lesions (15/38, 39.5%) were located in the lower lobes. Twenty-five lesions (25/38, 65.8%) were located in the right lung while 13 lesions (13/38, 34.2%) were located in the left lung. Three patients had pneumothorax, appeared on CT images performed immediately after the biopsy. Four patients had mild parenchymal hemorrhage along the needle tract or within the lesion. No patient required additional therapy such as a blood transfusion, endotracheal intubation, or chest tube placement after the biopsy. None of the patients had serious complications. CONCLUSION: Percutaneous CT-guided aspiration can be useful and safe diagnostic procedures for evaluating GGO nodules and a guidance to make a clinical decision for further patient management. PMID- 26612444 TI - Contribution of ultrasound-guided fine-needle aspiration cell blocks of metastatic supraclavicular lymph nodes to the diagnosis of lung cancer. AB - PURPOSES: Routine smears of fine-needle aspiration (FNA) specimens of supraclavicular lymph nodes with ultrasound (US) real-time guidance have proven useful in lung cancer staging, but the clinical value of additional information from cell-block of FNA samples has been little researched. This study mainly focused on the contribution of cell block analysis to the diagnosis and staging in lung cancer. MATERIALS AND METHODS: Clinical data about 211 lung cancer patients with supraclavicular lymph node enlargement admitted to ultrasonography in the Zhejiang Cancer Hospital and recommended a needle biopsy under US-guided, the adequacy of the specimens for preparing cell blocks was acquireded, and the additional immunohistochemistry or genetic information provided from cell block analysis was examined. RESULTS: In 211 lung cancer patients referred for US guided FNA (median age 61.8 +/- 10.0 years, range 30-88) 279 aspirations were performed. Conventional smears could be obtained from 185 aspirates (66.3%) and contained 176 (95.1%) diagnostic smears. Cell blocks could be obtained from 94 aspirates (33.7%) and contained diagnostic material in 88 (93.6%) aspirates. Above all, cell blocks also made epithelial growth factor receptor gene mutation analysis in 17 patients with FNA samples, and the positive rate was 70.6%. Overall, cell blocks provided clinically significant information for 51 of the 211 patients participating in the study (24.2%). CONCLUSION: Cell-block samples from US-guided FNA is a promising, relatively noninvasive technique to provide additional information in lung cancer diagnosis. Analysis of cell blocks allows for genetic analysis of the patients with supraclavicular lymph nodes metastasis. PMID- 26612445 TI - Effect of capilliposide for induction apoptosis in human nasopharyngeal cancer CNE-2 cells through up-regulating PUMA expression. AB - OBJECTIVE: To observe the apoptosis of capilliposide against human nasopharyngeal cancer CNE-2 cells and to study its primary mechanisms. MATERIALS AND METHODS: Vectors pSilencer-PUMA-small interfering RNA (siRNA) were constructed to transcribe functional siRNA specially targeting PUMA. The interfering plasmids were used to transfect CNE-2 cells with lipofectamine 2000 transfection reagent. PUMA messenger RNA (mRNA) expression levels were analyzed by polymerase chain reaction. The proliferation of CNE-2 cells was detected using MTT colorimetry. Annexin V/propidium iodide double staining was applied to detect the apoptosis rate of CNE-2 cells. The protein levels of p53, PUMA, and Bax were detected using Western blot analysis. RESULTS: Recombinant siRNA expression vector targeting PUMA was constructed. MTT assays showed capilliposide inhibited the proliferation of CNE-2 cells in a concentration-dependent manner. The inhibition was strengthened along with increased concentrations. Apoptosis detected by flow cytometry in control group, drug group, siRNA group, and drug combined siRNA group was 9.3 +/- 2.3%, 31.4 +/- 5.6%, 12.3 +/- 4.1%, and 13.2 +/- 3.7%, respectively. After pretreated by capilliposide, PUMA protein was upregulated, and BAX was distributed to mitochondria in CNE-2 cells using Western blot analysis, but this effect can be interrupted by PUMA-siRNA. CONCLUSIONS: Capilliposide could induce the apoptosis of CNE-2 cells, which might be related with the increasing in PUMA-Bax pathway. PMID- 26612446 TI - Combined use of radioiodine therapy and radiofrequency ablation in treating postsurgical thyroid remnant of differentiated thyroid carcinoma. AB - PURPOSE: To determine whether postoperative radioiodine (RAI) combined with radiofrequency ablation (RFA) is an effective, safe, and feasible method for elimination of excessive postsurgical thyroid remnant for differentiated thyroid carcinoma (DTC). MATERIALS AND METHODS: We took a prospective study and treated 12 DTC patients (4 males, 8 females, age 20-78 years) who underwent thyroidectomy for RFA followed by 131 I ablation. The pretreatment requires iodine-free diet and thyroid hormone withdrawal for 3-4 week. All the patients showed the level of serum thyroid-stimulating hormone (TSH) <30 mU/L, and obvious thyroid remnant in 99m Technetium (99m Tc) imaging. Serum TSH level was determined 1 day before RFA and on days 1, 7, 14 after RFA, and 99m Tc imaging was performed on day 14 after RFA. Subsequently, the patients were given an oral dosage of 3700 MBq 131 I for remnant ablation, and posttreatment whole body scan was performed on day 5 after ablation. Efficacy evaluation was done 4-6 months after treatment. The changes of variants before and after RFA were analyzed using Wilcoxon signed rank sum test. RESULTS: Serum TSH was <30 MUIU/ml (mean value 10.27 +/- 6.16 MUIU/ml) before RFA, and increased to more than 30 MUIU/ml (34.73 +/- 3.93 MUIU/ml) 2 weeks later (P = 0.002, Wilcoxon rank sum test). The 99m Tc uptake ratio on day 14 postRFA was (0.31 +/- 0.12)%, which is significantly lower than before RFA (0.80 +/- 0.16)% (P = 0.002, Wilcoxon rank sum test). The success rate of thyroid remnant ablation was 91.7% (11/12), which was assessed 4-6 months after treatment. All patients reported neck discomfort and some are self-limiting, with no hoarseness, choking, or radiation thyroiditis symptoms. Five patients had puncture area pain, among which one patient had neck edema, which was relieved after prednisone treatment. CONCLUSION: Combined use of RAI therapy and radiofrequency ablation in treating excessive postsurgical thyroid remnant of DTC can be an effective approach and avoids re-operation. Long-term efficacy monitoring would further determine its feasibility. PMID- 26612447 TI - Two different endoscopic long intestinal tube placements for small bowel obstruction: Transnasal ultrathin endoscopy versus conventional endoscopy. AB - AIM: To investigate and compare the effect on small bowel obstruction (SBO) of a long intestinal tube inserted by two different endoscopic placements which are transnasal ultrathin endoscopy and conventional endoscopy. PATIENTS AND METHODS: Twenty-nine patients who had been diagnosed as suffering from SBO underwent long tube insertion placed by transnasal ultrathin endoscopy were included as subjects. Thirty-two patients who had undergone insertion of a long tube placed by conventional endoscopy were included as controls. The success rate of intubation of the small bowel, the time required for the procedure, and complications were compared between the subjects and controls. RESULTS: The success rate of intubation was 100% (29/29) in subjects and 93.8% (30/32) in controls, without a significant difference (P = 0.493). There are 2 failed cases that the procedure was attempted near 60 min in 2 patients who had performed Billroth II anastomosis before, and the intestinal tube could not be inserted into efferent loops of jejunum in controls. The mean time required for the procedure was 15.3 min in subjects and 22.9 min in controls, respectively, and with a significant difference (P < 0.001). Epistaxis occurred in both groups, and 2 cases encountered bleeding of the gastrointestinal tract in controls. CONCLUSION: Long tube insertion facilitated by transnasal ultrathin endoscopy takes shorter time and has a higher success rate compared with the procedure conducted with the help of conventional endoscopy. It is safe and useful to insert a long intestinal tube assisted by transnasal ultrathin endoscopy for the decompression of small bowel. PMID- 26612448 TI - Two endoscopic submucosal dissection procedures for stripping huge segment of the gastric mucosa to treat early gastric signet ring cell carcinoma. AB - AIM: To introduce the method of stripping of early gastric signet ring cell carcinioma by two ESD procedures. METHODS: A lesion of early gastric signet ring cell carcinoma in an elderly was removed by two consecutive ESD procedures. The pathology was analyzed and the patient was followed-up. RESULTS: The lesion removed by first ESD procedure, which was 10 cm in diameter, has tumor tissue on its edge, and the second lesion which was 5 cm in diameter had an edge without tumor. There was no metastasis or recurrence during 24-month follow-up. CONCLUSION: We first described the method using two consecutive ESD procedures in man with gastric signet ring cell carcinoma, and the procedure was proved to be safe and efficient. PMID- 26612449 TI - Comparison of conventional laparoscopy and robotic radical hysterectomy for early stage cervical cancer: A meta-analysis. AB - BACKGROUND: Cervical cancer continues to be a global burden for women, with >500,000 cases and 275,000 deaths reported annually. Resources-rich countries have seen a dramatic reduction in the prevalence of invasive cervical cancer due to widely accessed radical hysterectomy (RH). We aimed to compare initial surgical outcomes and complication rates of conventional laparoscopic RH (LRH) and robotic RH (RRH) for treating cervical cancer through a systematic meta analysis. METHODS: PubMed, EMBASE, and the Cochrane Library databases were systematically searched for all relevant studies. Data were abstracted independently. A meta-analysis was performed to compare intra- and post-operative outcomes for the two techniques. RESULTS: A total of 12 clinical trials were identified. Meta-analysis showed that although LRH and RRH were similar in terms of operating time, the length of hospital stay, and a number of pelvic lymph nodes resected, RRH presented less blood loss and overwhelming advantage against LRH with the respect of complications. CONCLUSION: RRH may be a reliable technique for treating early cervical cancer. Available evidence suggests that it is better than LRH for postoperative recovery, while the two techniques involve similar surgical outcomes and share the same limits in clinical practice. PMID- 26612450 TI - The comparison of anesthesia effect of lung surgery through video-assisted thoracic surgery: A meta-analysis. AB - OBJECTIVE: The epidural anesthesia and general anesthesia are the most commonly used in lung surgery through video-assisted thoracic surgery (VATS). Each of these methods has their advantages and disadvantages, so the aim of this meta analysis is to identify which anesthesia is more conducive to lung surgery under VATS and rehabilitation of patients. MATERIALS AND METHODS: The Cochrane Library Database (Issue 12, 2013), PubMed (1966-2015), and China National Knowledge Infrastructure (1950-2015) were searched without language restrictions. Meta analyses were conducted using Review Manager 5.2 software (The Cochrane Collaboration, Software Update, Oxford). We calculated odds ratio (OR) and its confidence interval (95% CI) to estimate the difference between epidural anesthesia and general anesthesia through finishing of the collected data. RESULTS: Due to our search results, 7 studies were included in our study. Studies among them show that different contents of these articles are not all the same about research direction. Our findings suggested that epidural anesthesia had more advantages than general anesthesia for operative time (mean difference = - 23.85, 95% CI: - 29.67-- 18.03, P = 0.0001). More than that, epidural anesthesia showed a good surgical outcome on postoperative hospital stay (mean difference = 0.43, 95% CI: - 0.85-- 0.01, P = 0.04) than general anesthesia. But we found that there were no different on numbers of people with complications (OR = 0.45, 95% CI: 0.23-0.89, P = 0.97) and headache occurrence (OR = 2.69, 95% CI: 0.62 11.70, P = 0.91) between epidural anesthesia and general anesthesia. CONCLUSION: These results indicated that epidural anesthesia can save operating time and postoperative hospital stay time. But epidural anesthesia and general anesthesia have the same effect on complications. PMID- 26612451 TI - Evaluation of melanoma antigen gene A3 expression in drug resistance of epidermal growth factor receptor-tyrosine kinase inhibitors in advanced nonsmall cell lung cancer treatment. AB - OBJECTIVE: To investigate the correlation between melanoma antigen gene A3 (MAGE A3) expression and progression-free survival (PFS) of nonsmall cell lung cancer (NSCLC) patients with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs) therapy, aiming to provide a basis for research and treatment of EGFR TKIs resistance. RESEARCH AND METHODS: Retrospective analysis is conducted of PFS of 359 NSCLC patients who have been tested positive for EGFR, and experienced drug resistance during oral treatment of icotinib. MAGE-A3 expression is tested using immunology and histology chemistry methods, and T790M and c-MeT expression are tested using mutation-enriched polymerase chain reaction. RESULTS: (1) MAGE A3 expression in targeted treatment of NSCLC patients shows a positive rate of 33.98%. The comparative difference between MAGE-A3 expression and T790M, c-MeT and other resistance genes was not statistically significant (P > 0.05). (2) MAGE A3 expression was higher in patients with NSCLC targeted therapy of primary drug resistance of positive rate than acquired resistance; meanwhile the expression level differences in three modes of acquired resistance are statistically significant (P < 0.05). (3) PFS of MAGE-A3 positive expression in the targeted treatment of acquired drug resistance in patients with NSCLC is shorter than the PFS of MAGE-A3 negative expression (P = 0.01); the comparative PFS differences in the three kinds of acquired drug resistance pattern have statistical significance (P = 0.02). (4) PFS and levels of MAGE-A3 expression in NSCLC patients with the three modes of acquired resistance are negatively correlated (P < 0.01), and MAGE A3 expression has no correlation with age, gender, pathological type or PS score (P > 0.05). CONCLUSION: MAGE-A3 expression in EGFR-TKIs target therapy in NSCLC patient suggests that there might be EGFR-TKIs drug resistance, and the higher the level of expression, the shorter the time of acquired drug resistance. PMID- 26612452 TI - Clinical analysis of 64 patients with lung-cancer-associated hypercalcemia. AB - OBJECTIVE: This study investigated the factors influencing survival time of patients with lung-cancer-associated hypercalcemia. DATA AND METHODS: A total of 64 pathologically confirmed patients with Stage IV lung-cancer-associated hypercalcemia were enrolled from Beijing Hospitals between August 2010 and July 2015. Clinical materials included patients' gender, age, pathological type, highest albumin-corrected calcium level, serum alkaline phosphatase level, creatinine clearance rate, organ (bone, liver, brain, and adrenal gland) metastasis, number of distal metastatic sites, and survival time after diagnosis of hypercalcemia. Univariate and multivariate analyses were performed to screen the risk factors affecting patients' survival. RESULTS: Albumin-corrected calcium levels of the 64 patients ranged from 2.56 to 4.57 mmol/L, and the median value was 2.76 mmol/L. Survival time after diagnosis of hypercalcemia varied from 1 to 1340 days, and the median survival time was 104 days. Univariate analysis showed that gender, age (>60-year-old), albumin-corrected calcium levels, elevation of alkaline phosphatases, brain metastasis, and number of distal metastatic sites were predictors for poor survival (P = 0.026, P = 0.022, P < 0.001, P = 0.043, P = 0.041, P = 0.003). In Cox proportional hazard model analysis, corrected hypercalcemia levels and alkaline phosphatase levels were determined to be risk factors affecting patients' survival time (hazard ratio [HR] = 6.828, P = 0.000; HR = 1.957, P = 0.026). CONCLUSIONS: Patients with Stage IV lung-cancer associated moderate and severe hypercalcemia exhibited shorter survival time and poor prognosis. After correction, moderate and severe elevations of hypercalcemia and abnormal elevation of alkaline phosphatase levels were shown to be significant factors shortening patients' survival time. PMID- 26612453 TI - Pancreatic neuroendocrine carcinoma diagnosed using endoscopic ultrasound-guided fine needle aspiration: A case report and literature review. AB - Pancreatic neuroendocrine carcinoma (NEC) is a rare pancreatic neoplasm. In this study, we report the case of a 67-year-old male who was admitted with epigastric pain, which began during the previous week. The planar imaging of the magnetic resonance imaging sequence detected oval shapes in the neck and tail of the pancreas. Endoscopic ultrasonography showed low-echo lumps at these sites. Endoscopic ultrasound-guided fine needle aspiration was performed on the pancreatic masses. Pathology results indicated that the tissue taken from the pancreas was consistent with small cell NEC. We also review the current published literature on pancreatic NEC. PMID- 26612454 TI - An Integrative Literature Review of Patient Turnover in Inpatient Hospital Settings. AB - High patient turnover can result in fragmentation of nursing care. It can also increase nursing workload and thus impede the ability of nurses to provide safe and high-quality care. We reviewed 20 studies that examined patient turnover in relation to nursing workload, staffing, and patient outcomes as well as interventions in inpatient hospital settings. The studies consistently addressed the importance of accounting for patient turnover when estimating nurse staffing needs. They also showed that patient turnover varied by time, day, and unit type. Researchers found that higher patient turnover was associated with adverse events; however, further research on this topic is needed because evidence on the effect of patient turnover on patient outcomes is not yet strong and conclusive. We suggest that researchers and administrators need to pay more attention to patterns and levels of patient turnover and implement managerial strategies to reduce nursing workload and improve patient outcomes. PMID- 26612455 TI - The molecular events behind ferulic acid mediated modulation of IL-6 expression in LPS-activated Raw 264.7 cells. AB - Identification of new antioxidant and anti-inflammatory bioactive molecules is an important tool for selecting effective formulations for the treatment of inflammation. The mouse macrophage cell line RAW 264.7, lipopolysaccharide (LPS) activated, is associated with an inflammation response. Activated macrophages produce reactive oxygen species (ROS), nitric oxide (NO) and inflammatory cytokines such as IL-6, TNF-alpha and IL-10. In the present study we have showed that pre-treatment with Ferulic Acid (FA) reduces NO accumulation in the culture medium of LPS-induced macrophage cells. Moreover, real-time experiments have revealed that FA has an inhibitory effect at the transcriptional level on the expression of some inflammatory mediators such as IL-6, TNF-alpha and iNOS and an activation effect on the expression of some antioxidant molecules such as Metallothioneins (MT-1, MT-2). Importantly, we have found that FA reduced the translocation of NF-E2-related factor 2 (Nrf2) and nuclear transcription factor kappaB (NF-kappaB) into the nuclei through a reduction of the expression of phosphorylated IKK and consequently inhibited IL-6 and NF-kappaB promoter activity in a luciferase assay. Our data clearly suggest that FA anti inflammatory effects are mainly mediated through IKK/NF-kappaB signalling pathway. Therefore, FA could represent a new natural drug extremely useful to improve anti-inflammatory treatment. PMID- 26612456 TI - Cultured enterocytes internalise bacteria across their basolateral surface for, pathogen-inhibitable, trafficking to the apical compartment. AB - In vitro- and in vivo-polarised absorptive epithelia (enterocytes) are considered to be non-phagocytic towards bacteria with invasive pathogenic strains relying on virulence factors to 'force' entry. Here, we report a serendipitous discovery that questions these beliefs. Thus, we uncover in well-established models of human small (Caco-2; TC-7) and large (T84) intestinal enterocytes a polarization dependent mechanism that can transfer millions of bacteria from the basal to apical compartment. Antibiotic-protection assays, confocal imaging and drug inhibitor data are consistent with a transcellular route in which internalized, basolateral-membrane enclosed bacteria are trafficked to and across the apical surface. Basal-to-apical transport of non-pathogenic bacteria (and inert beads) challenged the idea of pathogens relying on virulence factors to force entry. Indeed, studies with Salmonella demonstrated that it's entry-forcing virulence factor (SPI-I) was not required to enter via the basolateral surface but to promote another virulence-associated event (intra-enterocyte accumulation). PMID- 26612457 TI - Hardcore smoking after comprehensive smoke-free legislation and health warnings on cigarette packets in Hong Kong. AB - OBJECTIVE: To examine if there were changes in the proportion of hardcore smokers and factors associated with hardcore smoking before and after implementation of smoke-free legislation, and warning labels on cigarette packets in Hong Kong in January 2007. STUDY DESIGN: Repeated cross-sectional surveys of the general population in Hong Kong. METHODS: Data from all daily smokers aged >= 15 years in the population-based Thematic Household Surveys from 2005 (n = 3740) and 2008 (n = 2958) were used to estimate the prevalence of hardcore smokers before and after implementation of smoke-free legislation. A logistic regression model was used to identify the factors associated with hardcore smoking, and to examine if there were any changes in their associations with the likelihood of hardcore smoking after implementation of smoke-free legislation. RESULTS: The proportion of hardcore smokers among current daily smokers increased significantly from 22.5% [95% confidence interval (CI) 21.1-23.8%] in 2005 to 28.3% (95% CI 26.7-29.9%) in 2008. Change in the strength of the association of hardcore smoking with three factors was observed. The strength of the association between hardcore smoking and 'necessity in social functions' [odds ratio (OR) 0.54, 95% CI 0.31-0.95) and 'necessity for killing time' (OR 0.56, 95% CI 0.36-0.89) decreased, while the association between hardcore smoking and 'necessity as refreshment' increased (OR 3.02, 95% CI 1.43-6.39) after implementation of smoke-free legislation and warning labels on cigarette packets. 'Smoking had become a habit' was the factor associated most strongly with hardcore smoking (OR 4.88, 95% CI 4.02-5.93). CONCLUSIONS: The proportion of hardcore smokers remained stable in Hong Kong from 2005 to 2008. While the implementation of the two tobacco control measures may have provided an environment to reduce social smoking in hardcore smokers, addiction appeared to be the most important factor associated with hardcore smoking. More effective and tailor-made cessation services that target this group of smokers are needed. PMID- 26612458 TI - Misuse of 'over-the-counter' codeine analgesics: does formulation play a role? PMID- 26612459 TI - Low back pain patients in Sweden, Denmark and the UK share similar characteristics and outcomes: a cross-national comparison of prospective cohort studies. AB - BACKGROUND: Low back pain (LBP) is the world's leading cause of disability and yet poorly understood. Cross-national comparisons may motivate hypotheses about outcomes being condition-specific or related to cultural differences and can inform whether observations from one country may be generalised to another. This analysis of data from three cohort studies explored whether characteristics and outcomes differed between LBP patients visiting chiropractors in Sweden, Denmark and the UK. METHODS: LBP patients completed a baseline questionnaire and were followed up after 3, 5, 12 and 26 weeks. Outcomes were LBP intensity (0-10 scales) and LBP frequency (0-7 days the previous week). Cohort differences were tested in mixed models accounting for repeated measures. It was investigated if any differences were explained by different baseline characteristics, and interaction terms between baseline factors and nations tested if strength of prognostic factors differed across countries. RESULTS: The study sample consisted of 262, 947 and 453 patients from Sweden, Denmark and the UK respectively. Patient characteristics were largely similar across cohorts although some statistically significant differences were observed. The clinical course followed almost identical patterns across nations and small observed differences were not present after adjusting for baseline factors. The associations of LBP intensity and episode duration with outcome differed in strength between countries. CONCLUSIONS: Chiropractic patients with low back pain had similar characteristics and clinical course across three Northern European countries. It is unlikely that culture have substantially different impacts on the course of LBP in these countries and the results support knowledge transfer between the investigated countries. PMID- 26612460 TI - Alternative migratory locust phenotypes are associated with differences in the expression of genes encoding the methylation machinery. AB - Despite the importance of locust density-dependent polyphenism as a model system for understanding phenotypic plasticity, there is still much to be learnt about its underlying molecular control. Here we describe the first investigation into the expression of genes encoding the DNA methylation machinery in the migratory locust (Locusta migratoria). We show that the alternative solitarious and gregarious phenotypic states induced by different locust rearing densities are associated with significant differences in the expression of the target genes DNA methyltransferase 1, DNA methyltransferase 2 and methyl-CpG-binding domain protein 2/3. This variation was most pronounced in the embryos of solitarious vs. gregarious mothers. We mapped the embryonic methylation profiles of several intragenic regions and a Long Interspersed Nuclear Element (LINE), each of which is known to be differentially expressed between alternative locust phenotypes or has been directly implicated in phase change. LmI and three genes, adenyl cyclase associated binding protein 2, choline kinase alpha-like and henna, were methylated. Our results set the stage for future studies investigating the specific role of DNA methylation in the maternal transfer of migratory locust phase polyphenism. PMID- 26612461 TI - Eco-evolutionary feedbacks between private and public goods: evidence from toxic algal blooms. AB - The importance of 'eco-evolutionary feedbacks' in natural systems is currently unclear. Here, we advance a general hypothesis for a particular class of eco evolutionary feedbacks with potentially large, long-lasting impacts in complex ecosystems. These eco-evolutionary feedbacks involve traits that mediate important interactions with abiotic and biotic features of the environment and a self-driven reversal of selection as the ecological impact of the trait varies between private (small scale) and public (large scale). Toxic algal blooms may involve such eco-evolutionary feedbacks due to the emergence of public goods. We review evidence that toxin production by microalgae may yield 'privatised' benefits for individual cells or colonies under pre- and early-bloom conditions; however, the large-scale, ecosystem-level effects of toxicity associated with bloom states yield benefits that are necessarily 'public'. Theory predicts that the replacement of private with public goods may reverse selection for toxicity in the absence of higher level selection. Indeed, blooms often harbor significant genetic and functional diversity: bloom populations may undergo genetic differentiation over a scale of days, and even genetically similar lineages may vary widely in toxic potential. Intriguingly, these observations find parallels in terrestrial communities, suggesting that toxic blooms may serve as useful models for eco-evolutionary dynamics in nature. Eco-evolutionary feedbacks involving the emergence of a public good may shed new light on the potential for interactions between ecology and evolution to influence the structure and function of entire ecosystems. PMID- 26612462 TI - Bacillus oceani sp. nov., isolated from seawater. AB - Two Gram-staining-positive, endospore-forming, rod-shaped bacterial strains, designated strain SW109T and strain W006, were isolated from a seawater sample collected from the Indian Ocean. The strains were strictly aerobic, catalase- and oxidase-positive and motile by peritrichous flagella. The predominant cellular fatty acids (>10 %) were anteiso-C15 : 0, iso-C15 : 0 and iso-C14 : 0. The major menaquinone was menaquinone-7 (MK-7) and the major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. The genomic DNA G+C content of strain SW109T and strain W006 was 46.3 and 46.1 mol%, respectively. Phylogenetic analyses based on 16S rRNA gene sequences indicated that the two strains represented a novel member of the genus Bacillus, showing the highest similarity with Bacillus halodurans LMG 7121T and Bacillus okuhidensis DSM 13666T (96.4 and 96.2 % sequence similarity, respectively). On the basis of phylogenetic inference and phenotypic characteristics, it is proposed that the two strains represent a novel species of the genus Bacillus, for which the name Bacillus oceani sp. nov. is proposed. The type strain is SW109T ( = CGMCC 1.12347T = DSM 100579T). PMID- 26612464 TI - Transcriptome-derived evidence supports recent polyploidization and a major phylogeographic division in Trithuria submersa (Hydatellaceae, Nymphaeales). AB - Relatively little is known about species-level genetic diversity in flowering plants outside the eudicots and monocots, and it is often unclear how to interpret genetic patterns in lineages with whole-genome duplications. We addressed these issues in a polyploid representative of Hydatellaceae, part of the water-lily order Nymphaeales. We examined a transcriptome of Trithuria submersa for evidence of recent whole-genome duplication, and applied transcriptome-derived microsatellite (expressed-sequence tag simple-sequence repeat (EST-SSR)) primers to survey genetic variation in populations across its range in mainland Australia. A transcriptome-based Ks plot revealed at least one recent polyploidization event, consistent with fixed heterozygous genotypes representing underlying sets of homeologous loci. A strong genetic division coincides with a trans-Nullarbor biogeographic boundary. Patterns of 'allelic' variation (no more than two variants per EST-SSR genotype) and recently published chromosomal evidence are consistent with the predicted polyploidization event and substantial homozygosity underlying fixed heterozygote SSR genotypes, which in turn reflect a selfing mating system. The Nullarbor Plain is a barrier to gene flow between two deep lineages of T. submersa that may represent cryptic species. The markers developed here should also be useful for further disentangling species relationships, and provide a first step towards future genomic studies in Trithuria. PMID- 26612463 TI - Integrated analysis of the genomic instability of PTEN in clinically insignificant and significant prostate cancer. AB - Patients with clinically insignificant prostate cancer remain a major over treated population. PTEN loss is one of the most recurrent alterations in prostate cancer associated with an aggressive phenotype, however, the occurrence of PTEN loss in insignificant prostate cancer has not been reported and its role in the separation of insignificant from significant prostate cancer is unclear. An integrated analysis of PTEN loss was, therefore, performed for structural variations, point mutations and protein expression in clinically insignificant (48 cases) and significant (76 cases) prostate cancers treated by radical prostatectomy. Whole-genome mate pair sequencing was performed on tumor cells isolated by laser capture microdissection to characterize PTEN structural alterations. Fluorescence in situ hybridization probes were constructed from the sequencing data to detect the spectrum of these PTEN alterations. PTEN loss by mate pair sequencing and fluorescence in situ hybridization occurred in 2% of insignificant, 13% of large volume Gleason score 6, and 46% of Gleason score 7 and higher cancers. In Gleason score 7 cancers with PTEN loss, PTEN alterations were detected in both Gleason pattern 3 and 4 in 57% of cases by mate pair sequencing, 75% by in situ hybridization and 86% by immunohistochemistry. PTEN loss by sequencing was strongly associated with TMPRSS2-ERG fusion, biochemical recurrence, PTEN loss by in situ hybridization and protein loss by immunohistochemistry. The complex nature of PTEN rearrangements was unveiled by sequencing, detailing the heterogeneous events leading to homozygous loss of PTEN. PTEN point mutation was present in 5% of clinically significant tumors and not in insignificant cancer or high-grade prostatic intraepithelial neoplasia. PTEN loss is infrequent in clinically insignificant prostate cancer, and is associated with higher grade tumors. Detection of PTEN loss in Gleason score 6 cancer in a needle biopsy specimen indicates a higher likelihood of clinically significant prostate cancer. PMID- 26612465 TI - Utility of Translocator Protein (18 kDa) as a Molecular Imaging Biomarker to Monitor the Progression of Liver Fibrosis. AB - Hepatic fibrosis is the wound healing response to chronic hepatic injury caused by various factors. In this study, we aimed to evaluate the utility of translocator protein (18 kDa) (TSPO) as a molecular imaging biomarker for monitoring the progression of hepatic fibrosis to cirrhosis. Model rats were induced by carbon tetrachloride (CCl4), and liver fibrosis was assessed. Positron emission tomography (PET) with N-benzyl-N-methyl-2-[7,8-dihydro-7-(2 [(18)F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]-acetamide ([(18)F]FEDAC), a radioprobe specific for TSPO, was used for noninvasive visualisation in vivo. PET scanning, immunohistochemical staining, ex vivo autoradiography, and quantitative reverse-transcription polymerase chain reaction were performed to elucidate the relationships among radioactivity uptake, TSPO levels, and cellular sources enriching TSPO expression in damaged livers. PET showed that uptake of radioactivity in livers increased significantly after 2, 4, 6, and 8 weeks of CCl4 treatment. Immunohistochemistry demonstrated that TSPO was mainly expressed in macrophages and hepatic stellate cells (HSCs). TSPO-expressing macrophages and HSCs increased with the progression of liver fibrosis. Interestingly, the distribution of radioactivity from [(18)F]FEDAC was well correlated with TSPO expression, and TSPO mRNA levels increased with the severity of liver damage. TSPO was a useful molecular imaging biomarker and could be used to track the progression of hepatic fibrosis to cirrhosis with PET. PMID- 26612466 TI - Standard-b-value vs low-b-value DWI for differentiation of benign and malignant vertebral fractures: a meta-analysis. AB - OBJECTIVE: To determine the comparative diagnostic performance of standard-b value (>=500 mm(2)) vs low-b-value (<500s mm(-2)) diffusion-weighted imaging (DWI) for discriminating malignant from benign vertebral compression fractures. METHODS: 12 studies with a total of 350 malignant and 312 benign vertebral fractures were included. RESULTS: The apparent diffusion coefficient (ADC) value of benign vertebral compression fractures was lower than that of malignant vertebral compression fractures (SMD = 1.81, 95% CI 0.98 to 2.64 Z = 4.27, p < 0.05). ADC value difference was more pronounced in the group of low-b-value DWI (SMD = 2.31, 95% CI 1.02 to 3.60 Z = 3.51, p < 0.05) than in the group of standard-b-value DWI (SMD = 1.38, 95% CI 0.18 to 2.59 Z = 2.25, p < 0.05). Ethnicity stratified analysis demonstrated higher ADC values in benign vertebral compression fractures in comparison to malignant tissues in both the Asian and Caucasian subgroups (Asians: SMD = 2.400, 95%CI 1.45 to approximately 3.35, p<0.05; Caucasians: SMD = 0.592, 95 % CI -0.848 to approximately 2.032, p < 0.05). And the ADC value difference was more pronounced in the Asian subgroup. CONCLUSION: ADC value appears to be a reliable method to differentiate benign from malignant fractures. Low-b-value DWI was more a valuable parameter than standard-b-value DWI for discriminating malignant from benign vertebral compression fractures. And the diffusion characteristics of the benign vertebral fractures such as osteoporosis, trauma and infection have rarely been investigated separately. ADVANCES IN KNOWLEDGE: The use of low-b-value DWI for differentiation of benign and malignant vertebral fractures is recommended. PMID- 26612467 TI - X-ray phase contrast tomography; proof of principle for post-mortem imaging. AB - OBJECTIVE: To demonstrate the feasibility of using X-ray phase-contrast tomography to assess internal organs in a post-mortem piglet model, as a possible non-invasive imaging autopsy technique. METHODS: Tomographic images of a new-born piglet were obtained using a free-space propagation X-ray phase-contrast imaging setup at a synchrotron (European Synchrotron Radiation Facility, Grenoble, France). A monochromatic X-ray beam (52 keV) was used in combination with a detector pixel size of 46 * 46 um(2). A phase-retrieval algorithm was applied to all projections, which were then reconstructed into tomograms using the filtered back projection algorithm. Images were assessed for diagnostic quality. RESULTS: Images obtained with the free-space propagation setup presented high soft-tissue contrast and sufficient resolution for resolving organ structure. All of the main body organs (heart, lungs, kidneys, liver and intestines) were easily identified and adequately visualized. In addition, grey/white matter differentiation in the cerebellum while still contained within the skull was shown. CONCLUSION: The feasibility of using X-ray phase-contrast tomography as a post-mortem imaging technique in an animal model has been demonstrated. Future studies will focus on translating this experiment to a laboratory-based setup. ADVANCES IN KNOWLEDGE: Appropriate image processing and analysis enable the simultaneous visualization of both soft- and hard-tissue structures in X-ray phase-contrast images of a complex, thick sample. PMID- 26612468 TI - The role of emergency radiology in spinal trauma. AB - Spinal trauma is very frequent injury with different severity and prognosis varying from asymptomatic condition to temporary neurological dysfunction, focal deficit or fatal event. The major causes of spinal trauma are high- and low energy fall, traffic accident, sport and blunt impact. The radiologist has a role of great responsibility to establish the presence or absence of lesions, to define the characteristics, to assess the prognostic influence and therefore treatment. Imaging has an important role in the management of spinal trauma. The aim of this paper was to describe: incidence and type of vertebral fracture; imaging indication and guidelines for cervical trauma; imaging indication and guidelines for thoracolumbar trauma; multidetector CT indication for trauma spine; MRI indication and protocol for trauma spine. PMID- 26612469 TI - Controllable Growth of the Graphene from Millimeter-Sized Monolayer to Multilayer on Cu by Chemical Vapor Deposition. AB - As is well established, mastery to precise control of the layer number, stacking order of graphene, and the size of single-crystal monolayer graphene is very important for both fundamental interest and practical applications. In this report, millimeter-sized single-crystal monolayer graphene has been synthesized to multilayer graphene on Cu by chemical vapor deposition. The relationship of the growth process between monolayer graphene and multilayer graphene is investigated carefully. Besides the general multilayer graphene with Bernal stacking order, parts of multilayer graphene with non-Bernal stacking order were modulated under optimized growth conditions. The oxide nanoparticle on the Cu surface derived from annealing has been found to play the key role in nucleation. In addition, the hydrogen concentration impacts significantly on the layer number and shape of the graphene. Moreover, a possible mechanism was proposed to understand the growth process discussed above, which may provide an instruction to graphene growth on Cu by chemical vapor deposition. PMID- 26612471 TI - [Modern laboratory diagnostic workup in dermatology]. PMID- 26612470 TI - Primary mucinous cystadenocarcinoma of the renal pelvis misdiagnosed as ureteropelvic junction stenosis with renal pelvis stone: a case report and literature review. AB - BACKGROUND: Primary mucinous adenocarcinoma of the renal pelvis is extremely rare, with only ~100 cases reported till now. Its presumed pathogenesis includes glandular metaplasia of the urothelium of the calyces and the pelvis and malignant transformation of the metaplasia. Unfortunately, it has no characteristic symptoms or radiological features. We report a case of primary mucinous adenocarcinoma of the renal pelvis misdiagnosed as ureteropelvic junction stenosis with a renal pelvis stone. CASE PRESENTATION: A 50-year-old man presented with discomfort in his right flank after a fall. A physical examination was normal except mild costovertebral angle tenderness on the right side. The results of most laboratory tests were within normal limits. Plain radiography of the kidneys, ureter, and urinary bladder showed a large radio-opaque mass in the right kidney. Abdominal computed tomography showed a hyperdense mass with 2.62 * 5.70 cm size in the right renal pelvis and severe hydronephrosis and cortical thinning. Diuretic-enhanced 99mTc DTPA renal scanning showed that the relative function of the right versus the left kidney was 20 versus 80 %. On the basis of the imaging findings, kidney dysfunction due to ureteropelvic junction stenosis with a large stone was initially diagnosed. However, the drained urine volume was almost zero, and gelatinous material was aspirated when percutaneous nephrostomy was performed for decompression of hydronephrosis. Although the cytopathology of gelatinous material was negative for malignancy, we could not rule out other disease, such as hidden malignancies of the kidney. We therefore performed radical nephrectomy, and pathological examination of the kidney uncovered a mucinous cystadenocarcinoma in the renal pelvis. A bone scan and positron emission tomography showed no evidence of other malignancies, metastasis, or remnant cancer. The patient has been well, without evidence of tumour recurrence or metastasis, for 20 months after surgery. CONCLUSIONS: Primary mucinous adenocarcinomas of the renal pelvis are extremely rare, and most are diagnosed via post-operative analysis of resected specimens. Although preoperative diagnosis is difficult, urologists should consider the possibility of primary mucinous adenocarcinoma in patients with severe hydronephrosis accompanied by renal stones and chronic inflammation. PMID- 26612472 TI - [Molecular diagnosis of autoimmune dermatoses]. AB - Bullous autoimmune diseases are organ-specific disorders characterized by an autoantibody-mediated blistering of skin and mucous membranes. The detection of tissue-bound and serum autoantibodies is prerequisite for the diagnosis of autoimmune blistering diseases. The individual entities of this group may be difficult to differentiate on clinical grounds alone. An accurate diagnosis is however important for prognosis and therapy. A preliminary diagnostic step includes direct and indirect immunofluorescence microscopy, which provide information about the binding pattern and isotype of autoantibodies and allow the diagnosis of the autoimmune blistering disease. Subsequent characterization of the molecular specificity of autoantibodies is necessary for the exact classification of autoimmune bullous dermatoses. The quantitative measurement of autoantibodies against structural proteins of the skin may be often used to assess disease severity at follow-up. PMID- 26612474 TI - Non-specific abdominal pain in childhood. PMID- 26612473 TI - Complicated Intra-Abdominal Infections: The Old Antimicrobials and the New Players. AB - Complicated intra-abdominal infections (cIAIs) are an important cause of morbidity and mortality worldwide. They are diagnosed when the initial abdominal organ infection has spread into the peritoneal space. Successful treatment relies on adequate source control and appropriate empiric antimicrobial therapy. Inappropriate antimicrobial therapy may result in poor patient outcomes and increases in healthcare costs. Current guidelines recommend several single and combination antimicrobial regimens; however, empiric antimicrobial treatment has been complicated by the increasing rates of resistant organisms, especially the extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. Additionally, the overuse of carbapenems to combat these resistant pathogens has contributed to the rise of carbapenemase-producing microorganisms, especially Klebsiella pneumoniae. This increasing resistance has prompted the development of novel antimicrobials like ceftazidime-avibactam and ceftolozane-tazobactam, whose activity extends to ESBL-producing microorganisms. Furthermore, the optimal duration of antimicrobial therapy is still unknown, and further research is necessary to find a definitive answer. This review will focus on antimicrobial therapies recommended by the current guidelines, the individual properties of these agents, appropriate duration of therapy, recent clinical trials, and place in therapy of the antimicrobial agents recently approved for the treatment of cIAIs. PMID- 26612475 TI - Dynamic locking plate vs. simple cannulated screws for nondisplaced intracapsular hip fracture: A comparative study. AB - INTRODUCTION: Intracapsular hip fractures (ICHF) are a common cause of morbidity and mortality and pose a great economic burden on the health care systems. Appropriate surgical treatment requires balancing optimal outcomes with the cost of treatment to the health care system. While in elderly patients with displaced ICHF arthroplasty became the standard of care, the internal fixation method for conserving the femoral head in younger patients or in nondisplaced ICHF is still in debate. We compared a dynamic locking plate with the standard cancellous cannulated screws (CCS) for treatment of nondisplaced ICHF. METHODS: All patients treated with internal fixation for nondisplaced ICHF between July 2009 and December 2012 at our level one trauma center were included in this study. Patients treated with Targon FN (Aesculap) implants and CCS (Synthes) were compared. Charts were reviewed for demographics, intraoperative data and peri/post operative complications retrospectively. Radiographical analysis, pain (VAS), quality of life (SF12) and function (MHHS) data were prospectively gathered. RESULTS: One hundred and fifteen non-displaced ICHFs were treated with internal fixation, 81 with CCS and 34 with Targon FN implant; the mean follow-up was 19 and 28 months, respectively. Group fracture characteristics (Garden/Powel classification), and demographics, excluding age, were not significantly different. Post-operative revision rates of the Targon FN and CCS groups, perioperative complications were not statistically different (p>0.05). Quality of life (SF-12), function (Modified Harris Hip Score) and Visual Analogue Scale (VAS) pain scores were not statistical different. CONCLUSIONS: Complication rates and clinical outcomes for the treatment of nondisplaced ICHF with Targon FN and SCC showed no significant differences. Based on this evidence in consideration of the substantial cost differential between the Targon FN and SCC we suggest SCC for treatment of nondisplaced ICHF. LEVEL OF EVIDENCE: III. PMID- 26612476 TI - A three-year follow-up on injuries sustained by cruise ship passengers and crew treated at the Orthopaedic and Traumatology Department at Dubrovnik County Hospital. AB - Dubrovnik is one of the most popular destinations in the world for cruise ships. Several cruise ship passengers and crew members who have suffered different injuries have been treated at our department. This was a retrospective study to analyse injuries that occurred to crew members and passengers on cruise ships that docked in Dubrovnik over a three-year period from December 2010 to December 2013. During this period, a total of 370 patients suffered trauma that needed medical treatment. A total of 119 of these patients required hospitalisation and received medical help based on the nature of the trauma they suffered. The remaining 251 patients were treated at our outpatient clinic. Female patients in this study were exposed to osteoporotic trauma. Male patients presented mostly with injuries sustained during physical activities or because of the nature of their job on board. The leading cause of trauma accidents in the present study was falls on the same level. PMID- 26612477 TI - Reducing damage to the periosteal capillary network caused by internal fixation plating: An experimental study. AB - BACKGROUND: The importance of the periosteum in fracture healing is well-known. Preserving periosteal vascularisation is essential during internal plate fixation of fractures. METHODS: This was an experimental randomised, controlled animal study on nine sheep. Standard dynamic compression plate (DCP) and four different newly designed reefed plates, with different plate-bone contact surface areas and different reef directions, were fixated on to the tibia or radius. After two weeks the plates were removed and the underlying periosteum was analysed. Blood vessels were marked by immunohistochemical staining (CD31 and CD34), microphotographs were taken and blood vessels counted to calculate blood vessel density. RESULTS: Median blood vessel density beneath the standard plate was significantly lower than in the intact periosteum (18.0 vs 27.7mm(3)/cm(3)). Blood vessel density in the periosteum beneath plates with reefs was significantly increased compared with the intact periosteum, and was highest beneath the plate with the lowest bone-plate contact area and crosswise reefs (51.5mm(3)/cm(3)), followed by plates with transverse, oblique and longitudinal reefs, respectively. The direction of the reefs did not have much influence on the periosteal capillary network. Lower contact surface area seems to be the main factor that increases blood vessel density beneath the plates. CONCLUSIONS: The results show that plates with lower contact surface area stimulate angiogenesis in the underlying periosteum, which results in much higher blood vessel density compared with standard DCP. A randomised clinical trial is needed to prove the clinical relevance of these findings. PMID- 26612478 TI - Microcirculatory alterations during haemorrhagic shock and after resuscitation in a paediatric animal model. AB - BACKGROUND: Haemorrhagic shock is frequent in paediatric trauma patients and after cardiac surgery, especially after cardiopulmonary bypass. It has demonstrated to be related to bad outcome. OBJECTIVES: To evaluate changes on microcirculatory parameters during haemorrhagic shock and resuscitation in a paediatric animal model. To determine correlation between microcirculatory parameters and other variables routinely used in the monitoring of haemorrhagic shock. METHODS: Experimental study on 17 Maryland pigs. Thirty minutes after haemorrhagic shock induction by controlled bleed animals were randomly assigned to three treatment groups receiving 0.9% normal saline, 5% albumin with 3% hypertonic saline, or 5% albumin with 3% hypertonic saline plus a bolus of terlipressin. Changes on microcirculation (perfused vessel density (PVD), microvascular blood flow (MFI) and heterogeneity index (HI)) were evaluated and compared with changes on macrocirculation and tisular perfusion parameters. RESULTS: Shock altered microcirculation: PVD decreased from 13.5 to 12.3 mm mm( 2) (p=0.05), MFI decreased from 2.7 to 1.9 (p<0.001) and HI increased from 0.2 to 0.5 (p<0.001). After treatment, microcirculatory parameters returned to baseline (PVD 13.6 mm mm(-2) (p<0.05), MFI 2.6 (p<0.001) and HI 0.3 (p<0.05)). Microcirculatory parameters showed moderate correlation with other parameters of tissue perfusion. There were no differences between treatments. CONCLUSIONS: Haemorrhagic shock causes important microcirculatory alterations, which are reversed after treatment. Microcirculation should be assessed during haemorrhagic shock providing additional information to guide resuscitation. PMID- 26612479 TI - Response of patients with indolent systemic mastocytosis to tamoxifen citrate. AB - We examined whether tamoxifen citrate at 20mg/day for 1 year had a beneficial effect on laboratory findings, bone marrow mastocytosis, common clinical symptoms, or quality-of-life assessment for 5 women and 2 men with indolent systemic mastocytosis. Tamoxifen was well tolerated. We found significant reductions in the platelet count, serum alkaline phosphatase, and 24-h urinary excretion of N-methylhistamine and significant increases in serum lactate dehydrogenase and (excluding 2 patients taking aspirin) in 24-h urinary excretion of 11beta-prostaglandin F2alpha. Overall, no change occurred in percent involvement of bone marrow by mastocytosis. Symptom scores were mild and did not change during the treatment. The 36-Item Short Form Health Survey scores for quality of life physical and mental components showed no marked changes. Tamoxifen, an older, nonhematotoxic medication, has limited activity in systemic mastocytosis at the dosage used in this study. PMID- 26612480 TI - Phase II study of everolimus in refractory testicular germ cell tumors. AB - BACKGROUND: Testicular germ cell tumors (TGCTs) represent a highly curable disease; however, a small proportion of patients develop disease recurrence. Loss of the tumor-suppressor gene phosphatase and tensin homolog marks the transition from intratubular germ cell neoplasia to invasive GCT and is correlated with disease progression. Inactivation of phosphatase and tensin homolog is associated with deregulation of the PI3K/Akt pathway and increased mammalian target of rapamycin signaling. This study aimed to determine the efficacy and toxicity of a mammalian target of rapamycin inhibitor, everolimus, in patients with refractory TGCTs. METHODS: From December 2011 to February 2015, 15 patients with refractory GCTs were enrolled in the phase II study. All patients were pretreated with at least 2 cisplatin-based therapies; 4 tumors (26.7%) were absolutely refractory to cisplatin and 9 patients (60.0%) had visceral nonpulmonary metastases. Everolimus was administered at a dose of 10mg daily until progression or unacceptable toxicity. The primary end point was the objective response rate, according to Response Evaluation Criteria in Solid Tumors. RESULTS: No objective response was observed, but 6 patients (40.0%) achieved 12-week progression-free survival. During a median follow-up period of 3.6 months (range: 1-35.1mo), all patients experienced disease progression and 11 patients (80.0%) died. Median progression free survival was 1.7 months (95% CI: 1.1-4.0mo) and median overall survival was 3.6 months (95% CI: 2.0-11.0mo). CONCLUSIONS: This study failed to achieve its primary end point and our data suggest limited efficacy of everolimus against unselected heavily pretreated refractory TGCTs. CONDENSED ABSTRACT: Everolimus showed limited efficacy in unselected heavily pretreated refractory TGCTs. Prolonged disease stabilization could be achieved in selected patients. PMID- 26612481 TI - Current standards of care and future directions for "high-risk" pediatric renal tumors: Anaplastic Wilms tumor and Rhabdoid tumor. AB - 'High risk' renal tumors of childhood generally includes anaplastic Wilms tumor, rhabdoid tumor, and metastatic renal sarcomas and carcinomas. In this review, the epidemiology, biology, treatment and prognosis of anaplastic Wilms tumor and rhabdoid tumor are presented. Future directions related to management of such cancers are discussed, with insights provided into possible clinical trials in development that consider integration of novel targeted therapies. PMID- 26612482 TI - Rehabilitation Interventions for Older Individuals With Cognitive Impairment Post Hip Fracture: A Systematic Review. AB - PURPOSE: Currently, most rehabilitation services for individuals who sustain a hip fracture are not designed to meet the complex needs of those who also have cognitive impairment. The goal of this review was to identify current best practices for rehabilitation in long-term care settings and approaches to optimize outcomes among individuals with dementia and other cognitive impairments post-hip fracture. PROCEDURES: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement was used to guide the review. Five electronic databases, including PubMed, EMBASE, CINAHL (EBSCO), Medline (EBSCO), and PsycINFO (EBSCO), were searched for intervention studies published in English language journals. Studies were eligible if they focused on rehabilitation interventions post-hip fracture among older individuals (>= 65 years) with cognitive impairment who were living in or transferred to long-term care or postacute/rehabilitation settings post-hip fracture. Studies were excluded if they did not enroll individuals with cognitive impairment, the study was descriptive without any intervention content, or the intervention components were only medication, surgical approach or medical treatment. MAIN FINDINGS: A total of 4478 records were identified, 1915 of which were duplicative, 2563 were relevant based on title, and after careful review 7 studies were included. Two included studies were randomized controlled trials, one was a single group pre- and post-test, one a descriptive comparison between those with and without cognitive impairment, one a case controlled matched trial, one a nonequivalent groups trial, and one a case report. The interventions varied between manipulating the type and amount of exercise or testing multifactorial issues including environmental interventions and the use of an interdisciplinary team to address psychosocial factors, medication management, use of assistive devices, and specific preferences or concerns of the individuals. CONCLUSIONS: The evidence summarized in this review suggests that it is feasible to implement rehabilitation programs focused on individuals with cognitive impairment in postacute care settings. Moreover, there was evidence to suggest that intensive rehabilitation and exercise activities are beneficial, although innovative approaches may be needed to engage individuals with cognitive impairment. PMID- 26612483 TI - Investigating the Challenges and Opportunities in Home Care to Facilitate Effective Information Technology Adoption. AB - BACKGROUND: As home care utilization increases, information technology (IT) becomes a critical tool for providing quality home care. However, most home health agencies (HHAs) in the United States are in a position to adopt and leverage IT solutions in budget-constrained settings, where it is crucial to address important and pressing challenges and opportunities for achieving effectiveness in IT adoption. OBJECTIVES: (1) Explore HHAs' challenges and opportunities related to delivering home care as well as performing administrative functions and conducting business, (2) learn about current IT implementation levels and activities in home care, and (3) make recommendations to facilitate efforts and initiatives designed for adopting IT in home care effectively. METHODS: Semistructured interviews were conducted to elicit rich contextual information from the participants recruited from 13 local HHAs in one of the states in the United States. Established systems analysis techniques were used to ask questions during the interviews. Framework, a qualitative research method, was used to analyze the qualitative data obtained from the interviews. RESULTS: Coordinating clinical and administrative workflows was an important challenge. Inadequate access to patients' medical history and difficulties with medication reconciliation detracted from the quality of care. Hiring, training, scheduling, and retaining qualified personnel constituted another important challenge. Training and educating patients, caregivers, and families hold important opportunities for improving the quality of care. All except one HHA adopted electronic health records (EHR) but many continued to struggle considerably in their day-to-day functions. Health information exchange (HIE) seems to be the most needed technology. Telehealth solutions were perceived to be promising but their added value and financial viability in the long run were questioned. CONCLUSIONS: The recommendations for effective IT adoption include keeping a quality improvement focus, keeping a holistic organizational perspective, considering potential information exchange problems, addressing education and training needs, experimentation with telehealth if resources permit, considering organization size, and reducing lengthy procedures and excessive documentation requirements. The relevant stakeholders, such as home care professionals, IT vendors, and policy makers, should consider the recommendations from this study to facilitate success in future IT efforts and initiatives in home care. PMID- 26612484 TI - Cardiovascular Outcomes of Dipeptidyl Peptidase-4 Inhibitors in Elderly Patients With Type 2 Diabetes: A Nationwide Study. AB - OBJECTIVES: The elderly (aged >=65 years) population with type 2 diabetes (T2D) is growing substantially, but evidence for associations between the use of dipeptidyl peptidase-4 inhibitors (DPP-4is), novel incretin-based antidiabetic drugs, and clinical hard endpoints in this group remains inconclusive. We aimed to assess the safety and cardiovascular effects of DPP-4i use in a nationally representative sample of elderly adults with T2D. DESIGN, SETTING, AND PARTICIPANTS: We conducted a nationwide, observational, propensity score-matched study using Taiwan's National Health Insurance Research Database. Of a total of 414,213 patients aged >=65 years with T2D, 58,485 patients receiving initial DPP 4i prescriptions between March 1, 2009, and June 31, 2013, were included. Each DPP-4i user was matched with a nonuser control using propensity scores. The endpoints were all-cause mortality and major adverse cardiovascular events (MACEs), including ischemic stroke and myocardial infarction. Potential adverse effects of hospitalization for heart failure and hypoglycemia were also evaluated. RESULTS: Compared with the matched control cohort, the risks of all cause mortality (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.52-0.56), MACEs (HR 0.79, 95% CI 0.75-0.83), myocardial infarction (HR 0.79, 95% CI 0.72 0.87), and ischemic stroke (HR 0.79, 95% CI 0.75-0.84) were lower in the DPP-4i cohort. DPP-4i use did not affect the risks of hospitalization for heart failure and hypoglycemia. Stratified analyses produced consistent results across age, sex, and comorbidity subgroups. CONCLUSIONS: Prescription of DPP-4is was associated with reduced risks of all-cause mortality and MACEs in patients aged >=65 years with T2D. PMID- 26612485 TI - Intron retention in mRNA: No longer nonsense: Known and putative roles of intron retention in normal and disease biology. AB - Until recently, retention of introns in mature mRNAs has been regarded as a consequence of mis-splicing. Intron-retaining transcripts are thought to be non functional because they are readily degraded by nonsense-mediated decay. However, recent advances in next-generation sequencing technologies have enabled the detection of numerous transcripts that retain introns. As we review herein, intron-retaining mRNAs play an essential conserved role in normal physiology and an emergent role in diverse diseases. Intron retention should no longer be overlooked as a key mechanism that independently reduces gene expression in normal biology. Exploring its contribution to the development and/or maintenance of diseases is of increasing importance. PMID- 26612487 TI - Abstracts of CSPR 2015, 18-21 August 2015, China. PMID- 26612486 TI - Comparison of the Kyoto Scale of Psychological Development 2001 with the parent rated Kinder Infant Development Scale (KIDS). AB - OBJECTIVE: The purpose of the study was to extend our understanding of the Kyoto Scale of Psychological Development (KSPD) by comparison with a parent-rated scale, the Kinder Infant Development Scale (KIDS). METHODS: The participants of this study were 229 children aged 0-4, who were referred to the Developmental Evaluation Center of the National Center for Child Health and Development, due to a suspected developmental disorder/delay. The participants were divided into subgroups, depending on age and overall DQ. For each group separately, correlation analyses were conducted between the Developmental Quotient (DQ) of each KSPD domain and DQ of each KIDS subscale. RESULTS: For high DQ group, in all ages, the KSPD Postural-Motor (P-M) domain DQ demonstrated a high correlation with the KIDS Physical-Motor DQ, and at young ages, it was also found to be moderately or strongly associated with the KIDS Manipulation DQ. For high DQ group, the KSPD Cognitive-Adaptive (C-A) domain DQ was most consistently related to the KIDS Manipulation DQ, and was also moderately correlated with the KIDS Physical-Motor DQ, Receptive Language DQ, Social Relationship with Adults DQ, Discipline DQ, and Feeding DQ, depending on age. For high DQ group, the KSPD Language-Social (L-S) DQ most consistently showed a moderate or high correlation with the KIDS Receptive Language DQ and the Manipulation DQ, and also related to Physical-Motor DQ, Expressive Language DQ, Language Conception DQ, Social Relationship with Adults DQ, and Social Relationship with Children DQ for some age groups. The low DQ group demonstrated stronger relationships on many of the pairs of the DQ of a KSPD subdomain and the DQ of a KIDS subscale, regardless of the type of subdomains and subscales. CONCLUSIONS: For high DQ group, the KSPD P M domain was consistently related to parent-reported physical/motor development, the C-A domain primarily reflected a child's fine motor skills and his/her ability to understand and follow verbal instructions provided by adults, while the L-S domain was associated with parent-reported language ability. For low DQ group, the effect of global delay increased overall correlations between each domain and subscale. Further studies are necessary to replicate the findings in a larger sample including typical children. PMID- 26612488 TI - Association of overhydration and cardiac dysfunction in patients have chronic kidney disease but not yet dialysis. AB - BACKGROUND/AIM: Fluid overload and cardiac dysfunction is well established in hemodialysis patients. But in predialysis chronic kidney disease, the association of fluid overload and cardiac dysfunction is relatively unknown. In this study, we aimed to investigate the relationship between fluid overload and cardiac dysfunction in predialysis chronic kidney disease patients. METHOD: We enrolled 107 consecutive patients in our study. Fluid overload was assessed via body composition monitor. Patients were dichotomized according to the fluid overload status. The patients with FO < 1.1L were determined as normovolemic and those with FO >= 1.1L as hypervolemic according to the previously reported physiologic model. Left atrial volume index (LAVI), left ventricular end-diastolic-end systolic index (LVEDVI, LVESVI), E/e', LVMI and global longitudinal left ventricular left ventricular strain (GLS-%) were evaluated in each patient as markers of cardiac dysfunction. Arterial stiffness was also assessed by Mobil-O Graph((r)) 24h pulse wave analysis monitor and pWV values were recorded. RESULTS: Fifty-five patients were normovolemic and 52 patients were hypervolemic. LAVI, LVMI, LDEDVI, LVEDSVI, E/e' were increased in hypervolemic patients. Also in hypervolemic patients pulse wave velocity was increased and GLS was decreased. Multivariate analysis showed that FO was independently associated with GLS which is the most specific echo-parameter for left ventricular dysfunction. CONCLUSION: FO was independently associated with cardiac dysfunction in patients with chronic kidney disease not ongoing dialysis. Effective treatment of hypervolemia may be important in these patients to avoid further cardiac damage. PMID- 26612489 TI - DASACT: A decision aiding software for axiomatic consensus theory. AB - There have been various attempts, solutions, and approaches towards constructing an appropriate consensus tree based on a given set of phylogenetic trees. However, for practitioners, it is not always clear, for a given data set, which of these would create the most relevant consensus tree. In this paper, we introduce an open-source software called DASACT (Decision Aiding Software for Axiomatic Consensus Theory) created to assist practitioners on choosing the most appropriate consensus function. It is based on an exhaustive evaluation of axiomatic properties and consensus functions, which define the knowledge space as a concept lattice. Using a selection of axiomatic properties provided by the user, it is able to aid the user in choosing the most suitable function. DASACT is freely available at http://www.cs.unic.ac.cy/florent/software.htm. PMID- 26612490 TI - Personality, Parasites, Political Attitudes, and Cooperation: A Model of How Infection Prevalence Influences Openness and Social Group Formation. AB - What is the origin of individual differences in ideology and personality? According to the parasite stress hypothesis, the structure of a society and the values of individuals within it are both influenced by the prevalence of infectious disease within the society's geographical region. High levels of infection threat are associated with more ethnocentric and collectivist social structures and greater adherence to social norms, as well as with socially conservative political ideology and less open but more conscientious personalities. Here we use an agent-based model to explore a specific opportunities-parasites trade-off (OPTO) hypothesis, according to which utility maximizing agents place themselves at an optimal point on a trade-off between (a) the gains that may be achieved through accessing the resources of geographically or socially distant out-group members through openness to out-group interaction, and (b) the losses arising due to consequently increased risks of exotic infection to which immunity has not been developed. We examine the evolution of cooperation and the formation of social groups within social networks, and we show that the groups that spontaneously form exhibit greater local rather than global cooperative networks when levels of infection are high. It is suggested that the OPTO model offers a first step toward understanding the specific mechanisms through which environmental conditions may influence cognition, ideology, personality, and social organization. PMID- 26612491 TI - Novel splittable N-Tx/2N-Rx transceiver phased array to optimize both signal-to noise ratio and transmit efficiency at 9.4T. AB - PURPOSE: The goal of this study was to optimize signal-to-noise ratio (SNR) and parallel receive (Rx) performance of ultrahigh field (UHF) (>=7T) transceiver arrays without compromising their transmit (Tx) efficiency. UHF transceiver head phased arrays with a tight fit improve Tx efficiency in comparison with Tx-only arrays, which are usually larger so that Rx-only arrays can fit inside. However, having >=16 elements inside a head transceiver array presents decoupling problems. Furthermore, the available number of Tx channels is limited. METHODS: A prototype of a splittable transceiver phased array was constructed. The array consisted of four flat surface Tx loops positioned in two rows. Each loop could be split into two smaller overlapped Rx loops during reception. RESULTS: Experimental data demonstrated that both SNR and parallel reception performance improved substantially by doubling the number of Rx elements from four to eight. CONCLUSION: As a proof of concept, we developed and constructed a novel splittable transceiver phased array that allows doubling of the number of Rx elements while keeping both Tx and Rx elements at the same distance from the subject. Both Tx and Rx performance can be optimized at the same time using this method. Magn Reson Med 76:1621-1628, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26612492 TI - Resources for the design of CRISPR gene editing experiments. AB - CRISPR-based approaches have quickly become a favored method to perturb genes to uncover their functions. Here, we review the key considerations in the design of genome editing experiments, and survey the tools and resources currently available to assist users of this technology. PMID- 26612494 TI - Microglial dysfunction connects depression and Alzheimer's disease. AB - Alzheimer's disease (AD) and major depressive disorder (MDD) are highly prevalent neuropsychiatric conditions with intriguing epidemiological overlaps. Depressed patients are at increased risk of developing late-onset AD, and around one in four AD patients are co-diagnosed with MDD. Microglia are the main cellular effectors of innate immunity in the brain, and their activation is central to neuroinflammation - a ubiquitous process in brain pathology, thought to be a causal factor of both AD and MDD. Microglia serve several physiological functions, including roles in synaptic plasticity and neurogenesis, which may be disrupted in neuroinflammation. Following early work on the 'sickness behavior' of humans and other animals, microglia-derived inflammatory cytokines have been shown to produce depressive-like symptoms when administered exogenously or released in response to infection. MDD patients consistently show increased circulating levels of pro-inflammatory cytokines, and anti-inflammatory drugs show promise for treating depression. Activated microglia are abundant in the AD brain, and concentrate around senile plaques, hallmark lesions composed of aggregated amyloid-beta peptide (Abeta). The Abeta burden in affected brains is regulated largely by microglial clearance, and the complex activation state of microglia may be crucial for AD progression. Intriguingly, recent reports have linked soluble Abeta oligomers, toxins that accumulate in AD brains and are thought to cause memory impairment, to increased brain cytokine production and depressive-like behavior in mice. Here, we review recent findings supporting the inflammatory hypotheses of AD and MDD, focusing on microglia as a common player and therapeutic target linking these devastating disorders. PMID- 26612493 TI - Facilitating the implementation of pharmacokinetic-guided dosing of prophylaxis in haemophilia care by discrete choice experiment. AB - INTRODUCTION: Patients', parents' and providers' preferences with regard to medical innovations may have a major impact on their implementation. AIM: To evaluate barriers and facilitators for individualized pharmacokinetic (PK)-guided dosing of prophylaxis in haemophilia patients, parents of young patients, and treating professionals by discrete choice experiment (DCE) questionnaire. PATIENTS/METHODS: The study population consisted of patients with haemophilia currently or previously on prophylactic treatment with factor concentrate (n = 114), parents of patients aged 12-18 years (n = 19) and haemophilia professionals (n = 91). DCE data analysis was performed, taking preference heterogeneity into account. RESULTS: Overall, patients and parents, and especially professionals were inclined to opt for PK-guided dosing of prophylaxis. In addition, if bleeding was consequently reduced, more frequent infusions were acceptable. However, daily dosing remained an important barrier for all involved. 'Reduction of costs for society' was a facilitator for implementation in all groups. CONCLUSIONS: To achieve implementation of individualized PK-guided dosing of prophylaxis in haemophilia, reduction of bleeding risk and reduction of costs for society should be actively discussed as they are motivating for implementation; daily dosing is still reported to be a barrier for all groups. The knowledge of these preferences will enlarge support for this innovation, and aid in the drafting of implementable guidelines and information brochures for patients, parents and professionals. PMID- 26612495 TI - Identification of a warm-temperature acclimation-associated 65-kDa protein encoded by a temperature- and infection-responsive gene in the Kumgang fat minnow Rhynchocypris kumgangensis. AB - Water temperature is one of the most important factors in fish physiology; thus, it is important to identify genes that respond to changes in water temperature. In this study, we identified a warm- temperature acclimation-associated 65-kDa protein (Wap65) in the Kumgang fat minnow Rhynchocypris kumgangensis, a small, cold-freshwater fish species endemic to Korea. Kumgang fat minnow Wap65-1 (kmWap65-1) was cloned using polymerase chain reaction (PCR)-based strategies, and was found to be highly homologous with teleost Wap65-1 and mammalian hemopexin, a heme-binding protein that transfers plasma heme into hepatocytes. kmWap65-1 mRNA was expressed mainly in the liver and its expression levels were significantly increased by both short- and long-term exposure to high temperature, which was evaluated by real-time quantitative PCR. Furthermore, the expression levels of kmWap65-1 were highly elevated by exposure to bacterial lipopolysaccharide. These results indicate that kmWap65-1 expression is associated with environmental stresses such as increases in water temperature and bacterial infection. J. Exp. Zool. 325A:65-74, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26612496 TI - P2Y12 antagonist attenuates eosinophilic inflammation and airway hyperresponsiveness in a mouse model of asthma. AB - Leukotriene E4 (LTE4) that plays a key role in airway inflammation is expressed on platelets and eosinophils. We investigated whether blocking of the P2Y12 receptor can suppress eosinophilic inflammation in a mouse model of asthma because platelets and eosinophils share this receptor to be activated. BALB/c mice were sensitized by intraperitoneal injection of ovalbumin (OVA), followed by OVA nebulization. On each challenge day, clopidogrel, a P2Y12 antagonist was administered 30 min. before each challenge. Forty-eight hours after the last OVA challenge, mice were assessed for airway hyperresponsiveness (AHR), cell composition and cytokine levels, including chemokine ligand 5 (CCL5), in bronchoalveolar lavage (BAL) fluid. EOL cells were treated with LTE4, with or without clopidogrel treatment, and intracellular and extracellular eosinophil cationic protein (ECP) expressions were measured to find the inhibiting function of P2Y12 antagonist on eosinophilic activation. The levels of P2Y12 expression were increased markedly in the lung homogenates of OVA-sensitized and -challenged mice after platelet depletion. Administration of clopidogrel decreased AHR and the number of airway inflammatory cells, including eosinophils, in BAL fluid following OVA challenge. These results were associated with decreased levels of Th2 cytokines and CCL5. Histological examination showed that inflammatory cells as well as mucus-containing goblet cells were reduced in clopidogrel-administered mice compared to vehicle-treated mice. Clopidogrel inhibited extracellular ECP secretion after LTE4 stimulation in EOL-1 cells. Clopidogrel could prevent development of AHR and airway inflammation in a mouse model of asthma. P2Y12 can be a novel therapeutic target to the suppression of eosinophils in asthma. PMID- 26612497 TI - Fern-synthesized nanoparticles in the fight against malaria: LC/MS analysis of Pteridium aquilinum leaf extract and biosynthesis of silver nanoparticles with high mosquitocidal and antiplasmodial activity. AB - Malaria remains a major public health problem due to the emergence and spread of Plasmodium falciparum strains resistant to chloroquine. There is an urgent need to investigate new and effective sources of antimalarial drugs. This research proposed a novel method of fern-mediated synthesis of silver nanoparticles (AgNP) using a cheap plant extract of Pteridium aquilinum, acting as a reducing and capping agent. AgNP were characterized by UV-vis spectrophotometry, Fourier transform infrared (FTIR) spectroscopy, energy-dispersive X-ray spectroscopy (EDX), and X-ray diffraction (XRD). Phytochemical analysis of P. aquilinum leaf extract revealed the presence of phenols, alkaloids, tannins, flavonoids, proteins, carbohydrates, saponins, glycosides, steroids, and triterpenoids. LC/MS analysis identified at least 19 compounds, namely pterosin, hydroquinone, hydroxy acetophenone, hydroxy-cinnamic acid, 5, 7-dihydroxy-4-methyl coumarin, trans cinnamic acid, apiole, quercetin 3-glucoside, hydroxy-L-proline, hypaphorine, khellol glucoside, umbelliferose, violaxanthin, ergotamine tartrate, palmatine chloride, deacylgymnemic acid, methyl laurate, and palmitoyl acetate. In DPPH scavenging assays, the IC50 value of the P. aquilinum leaf extract was 10.04 MUg/ml, while IC50 of BHT and rutin were 7.93 and 6.35 MUg/ml. In mosquitocidal assays, LC50 of P. aquilinum leaf extract against Anopheles stephensi larvae and pupae were 220.44 ppm (larva I), 254.12 ppm (II), 302.32 ppm (III), 395.12 ppm (IV), and 502.20 ppm (pupa). LC50 of P. aquilinum-synthesized AgNP were 7.48 ppm (I), 10.68 ppm (II), 13.77 ppm (III), 18.45 ppm (IV), and 31.51 ppm (pupa). In the field, the application of P. aquilinum extract and AgNP (10 * LC50) led to 100 % larval reduction after 72 h. Both the P. aquilinum extract and AgNP reduced longevity and fecundity of An. stephensi adults. Smoke toxicity experiments conducted against An. stephensi adults showed that P. aquilinum leaf-, stem-, and root-based coils evoked mortality rates comparable to the permethrin-based positive control (57, 50, 41, and 49 %, respectively). Furthermore, the antiplasmodial activity of P. aquilinum leaf extract and green-synthesized AgNP was evaluated against CQ-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of P. falciparum. IC50 of P. aquilinum were 62.04 MUg/ml (CQ-s) and 71.16 MUg/ml (CQ r); P. aquilinum-synthesized AgNP achieved IC50 of 78.12 MUg/ml (CQ-s) and 88.34 MUg/ml (CQ-r). Overall, our results highlighted that fern-synthesized AgNP could be candidated as a new tool against chloroquine-resistant P. falciparum and different developmental instars of its primary vector An. stephensi. Further research on nanosynthesis routed by the LC/MS-identified constituents is ongoing. PMID- 26612498 TI - First molecular evidence of the simultaneous human infection with two species of Echinococcus granulosus sensu lato: Echinococcus granulosus sensu stricto and Echinococcus canadensis. AB - Cystic echinococcosis is a widespread zoonotic parasitic disease especially in Tunisia which is one of the most endemic countries in the Mediterranean area. The etiological agent, Echinococcus granulosus sensu lato, implies dogs and other canids as definitive hosts and different herbivore species as intermediate hosts. Human contamination occurs during the consumption of parasite eggs passed in the environment through canid feces. Hydatid cysts coming from a child operated for multiple echinococcosis were collected and analyzed in order to genotype and to obtain some epidemiological molecular information. Three targets, ribosomal DNA ITS1 fragment, NADH dehydrogenase subunit 1 (nad1), and mitochondrial cytochrome c oxydase subunit 1 (CO1) genes, were amplified and analyzed by RFLP and sequencing approach. This study presents the first worldwide report in human of a simultaneous infection with Echinococcus granulosus sensu stricto (genotype G1) and Echinococcus canadensis (genotype G6) species. This is also the first report of the presence of E. canadensis in the Tunisian population which argues in favor of a greater importance of this species in human infestation in Tunisia than previously believed. PMID- 26612499 TI - Symbiosis within Symbiosis: Evolving Nitrogen-Fixing Legume Symbionts. AB - Bacterial accessory genes are genomic symbionts with an evolutionary history and future that is different from that of their hosts. Packages of accessory genes move from strain to strain and confer important adaptations, such as interaction with eukaryotes. The ability to fix nitrogen with legumes is a remarkable example of a complex trait spread by horizontal transfer of a few key symbiotic genes, converting soil bacteria into legume symbionts. Rhizobia belong to hundreds of species restricted to a dozen genera of the Alphaproteobacteria and Betaproteobacteria, suggesting infrequent successful transfer between genera but frequent successful transfer within genera. Here we review the genetic and environmental conditions and selective forces that have shaped evolution of this complex symbiotic trait. PMID- 26612501 TI - Evaluating the reproductive ability of breeding rams in North-Eastern Spain using clinical examination of the body and external genitalia. AB - BACKGROUND: Predicting the ability of rams to detect, mate and fertilise ewes in oestrus accurately is certainly difficult; however, tests based on clinical examinations have been performed to assess the overall potential capacity of rams to serve and impregnate ewes. Clinical examinations for breeding soundness evaluation were carried out in 897 Rasa Aragonesa (RA) rams from 35 flocks in North-Eastern (NE) Spain. Clinical examinations of head, trunk, limbs and genitals were performed in each ram. Blood samples were collected for a serological study of Brucella ovis. The sheep owners were surveyed regarding the characteristics of the flock, rams' health history and the management of rams. The clinical alterations found were classified according to severity (mild or severe). Rams were classified as suitable (without lesions or with only mild lesions) or unsuitable (with severe lesions) for breeding depending on the results of the clinical examinations. RESULTS: The results showed that 60.6 % of rams presented some type of alteration (mild: 43.3 %; severe: 17.3 %) in various body parts (genitalia: 31.6 %; head and trunk: 37.2 %; limbs: 15.5 %), and that 16.7 % of rams were classified as unsuitable breeders. The most common genital alterations were ulcerative posthitis (18.7 %) followed by testicular lesions (5.3 %). The highest prevalence of unsuitable breeders was found in the category of adult and aged rams (13.8 % and 37.4 %, respectively) and in the category of emaciated rams (33.3 %). All rams examined were seronegative to Brucella ovis. The mean percentage of rams in flocks was 2.8 % (min: 1.6 %; max: 4.6 %); nevertheless, this percentage dropped to 2.5 % (min: 1.4 %; max: 3.7 %) and 2.1 % (min: 0.3 %; max: 3.5 %) when only suitable or effective (suitable mature) rams were considered. CONCLUSION: Thus, it is concluded that there are fewer effective rams in farms than farmers realise. Frequent clinical examination of males is recommended in order to identify potentially infertile rams. PMID- 26612500 TI - Household Transmission of Influenza Virus. AB - Human influenza viruses cause regular epidemics and occasional pandemics with a substantial public health burden. Household transmission studies have provided valuable information on the dynamics of influenza transmission. We reviewed published studies and found that once one household member is infected with influenza, the risk of infection in a household contact can be up to 38%, and the delay between onset in index and secondary cases is around 3 days. Younger age was associated with higher susceptibility. In the future, household transmission studies will provide information on transmission dynamics, including the correlation of virus shedding and symptoms with transmission, and the correlation of new measures of immunity with protection against infection. PMID- 26612502 TI - Influence of Plasmodium gametocyte carriage on the prevalence of fever, splenomegaly and cardiovascular parameters in children less than 15 years in the Mount Cameroon area: cross sectional study. AB - BACKGROUND: Cardiovascular parameters can be impaired by repeated infections with P. falciparum. This study aimed at investigating the influence of gametocyte carriage on; the prevalence of fever and splenomegaly, blood pressure, heart rate and haematological indices in children <15 years, in the Mount Cameroon area. METHODS: A cross-sectional study was carried out, from February to July 2013. A child with axillary body temperature >=37.5 degrees C was considered febrile and splenomegaly was investigated by palpation. Systolic and diastolic blood pressures as well as heart rate were assessed by non-invasive methods. Malaria parasites were detected and density assessed from Giemsa-stained thin and thick blood films. An auto haematology analyser was used to obtain complete blood count values such as haemoglobin (Hb), haematocrit (Hct), red blood cell (RBC) and white blood cell (WBC) counts, mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCHC), and mean corpuscular haemoglobin (MCH). Univariate analyses were used to examine influence of gametocyte carriage on fever and splenomegaly while, multiple linear regression models were used to evaluate influence of independent variables on the dependent variables. RESULTS: Of a total of 454 children examined, malaria parasitaemia, fever, splenomegaly and gametocyte carriage were detected in 36.6, 21.6, 14.3 and 7.3 % of them respectively. Children who were asexual parasite and gametocyte positive (ASP + Gam Pos) had significantly highest (P = 0.03, P = 0.002) prevalence of fever and splenomegaly (39.4 %, 33.3 %) respectively than their aparasitaemic (AP) and asexual parasite positive (ASP Pos) equivalents (19.0 %, 10.9 % and 22.8 %, 16.9 % respectively). The presence of asexual malaria parasitaemia significantly influenced the MCV (P = 0.03), MCH (P = 0.03) and heart beats /min (0.03) while gametocytaemia significantly influenced the Hb (P < 0.001), Hct (P < 0.001), RBC (P < 0.001) and systolic blood pressure (P < 0.05). CONCLUSION: Gametocyte carriage significantly influenced the prevalence of fever, splenomegaly and some cardiovascular indices. In effect, children concurrently having asexual parasitaemia and gametocytes had significantly lower, Hct, Hb levels, RBC and platelet counts and systolic blood pressure. PMID- 26612503 TI - The mechanisms associated with the development of hypertension after exposure to lead, mercury species or their mixtures differs with the metal and the mixture ratio. AB - Hypertension is considered to be the most important risk factor for the development of cardiovascular diseases. Beside life-style risk factors, exposure to lead and mercury species are increasingly discussed as potential risk factors. Although there are a few previous studies, the underlying mechanism by which exposure to lead and mercury disturb blood pressure regulation is not currently understood. Potential mechanisms are oxidative stress production, kidney damage and activation of the renin-angiotensin system (RAS), all of which can interact to cause dysregulation of blood pressure. Male rats (Wistar) were exposed to lead, inorganic mercury, methylmercury or two mixtures of all three metals for four weeks through the drinking water. The two mixture ratios were based on ratios of known reference values or environmental exposure from the literature. To investigate the potential mechanism of actions, blood pressure was measured after four weeks and compared to plasma nitrotyrosine or reduced/oxidized glutathione levels in liver as markers for oxidative stress. Plasma renin and angiotensin II levels were used as markers for RAS activation. Finally, kidney function and injury were assessed via urinary and plasma creatinine levels, creatinine clearance and urinary kidney-injury molecule (KIM-1). While exposure to lead by itself increased oxidative stress and kidney damage along with blood pressure, inorganic mercury did not affect blood pressure or any end-point examined. Conversely, methylmercury instead increased RAS activation along with blood pressure. Surprisingly, when administered as mixtures, lead no longer increased oxidative stress or altered kidney function. Moreover, the mixture based on an environmental ratio no longer had an effect on blood pressure, while the reference value ratio still retained an increase in blood pressure. Based on our results, the prominent mechanism of action associated with the development of hypertension seems to be oxidative stress and kidney damage for lead, while increased RAS activation links methylmercury to hypertension, but these mechanisms along with hypertension disappear when metals are present in some mixtures. PMID- 26612504 TI - Lung deposition and clearance of microparticle and nanoparticle C60 fullerene aggregates in B6C3F1 mice and Wistar Han rats following nose-only inhalation for 13 weeks. AB - C60 fullerenes (C60) are spherical structures consisting of 60 carbon atoms that are generated via combustion from both natural and anthropogenic sources. C60 are also synthesized intentionally for industrial applications. Individual C60 structures have an approximate diameter of 1nm; however, C60 readily forms aggregates and typically exist as larger particles that range from nanometers to micrometers in diameter. In this report, lung and extrapulmonary tissue deposition and lung clearance of C60 nanoparticles (nano-C60, 50nm) and microparticles (micro-C60, 1MUm) were examined in Wistar Han rats and B6C3F1/N mice after nose-only inhalation for 90 days. Exposure concentrations were 0.5 and 2mg/m(3) (nano-C60) and 2, 15, and 30mg/m(3) (micro-C60). For both C60 particle sizes, the C60 lung burden increased proportionally to exposure concentration. The C60 lung burden was greater in both species at all time points following exposure to nano-C60 particle exposure compared to micro-C60 exposure at the common exposure concentration 2mg/m(3). The calculated C60 particle lung retention half-times were similar for both nano-C60 and micro-C60 exposure at 2mg/m(3) in male mice (15-16 days). In contrast, in male rats, the half-time of C60 particles following nano-C60 exposure (61 days) was roughly twice as long as the half-time following micro-C60 exposure (27 days) at the same exposure concentration (2mg/m(3)) and was similar to the clearance following micro-C60 exposure at higher exposure concentrations (15 and 30mg/m(3)). C60 was detected in bronchial lymph nodes but the burden was not quantified due to the high variability in the data. C60 concentrations were below the experimental limit of quantitation (ELOQ) in liver, spleen, blood, brain and kidney tissues. These tissue burden data provide information for comparison between nanometer and micrometer sized C60 particle exposure and will aid in the interpretation of toxicity data. PMID- 26612505 TI - Reactivity measurement in estimation of benzoquinone and benzoquinone derivatives' allergenicity. AB - Benzoquinone (BQ) and benzoquinone derivatives (BQD) are used in the production of dyes and cosmetics. While BQ, an extreme skin sensitizer, is an electrophile known to covalently modify proteins via Michael Addition (MA) reaction whilst halogen substituted BQD undergo nucleophilic vinylic substitution (SNV) mechanism onto amine and thiol moieties on proteins, the allergenic effects of adding substituents on BQ have not been reported. The effects of inserting substituents on the BQ ring has not been studied in animal assays. However, mandated reduction/elimination of animals used in cosmetics testing in Europe has led to an increased need for alternatives for the prediction of skin sensitization potential. Electron withdrawing and electron donating substituents on BQ were assessed for effects on BQ reactivity toward nitrobenzene thiol (NBT). The NBT binding studies demonstrated that addition of EWG to BQ as exemplified by the chlorine substituted BQDs increased reactivity while addition of EDG as in the methyl substituted BQDs reduced reactivity. BQ and BQD skin allerginicity was evaluated in the murine local lymph node assay (LLNA). BQD with electron withdrawing groups had the highest chemical potency followed by unsubstituted BQ and the least potent were the BQD with electron donating groups. The BQD results demonstrate the impact of inductive effects on both BQ reactivity and allergenicity, and suggest the potential utility of chemical reactivity data for electrophilic allergen identification and potency ranking. PMID- 26612506 TI - Longitudinal trends and subgroup analysis in publication patterns for preclinical data of newly approved drugs. AB - Having observed a large variation in the number and type of original preclinical publications for newly registered drugs, we have explored whether longitudinal trends and/or factors specific for certain drugs or their manufacturers may explain such variation. Our analysis is based on 1954 articles related to 170 newly approved drugs. The number of preclinical publications per compound declined from a median of 10.5 in 1991 to 3 in 2011. A similar trend was observed for the number of in vivo studies in general, but not in the subset of in vivo studies in animal models of disease. The percentage of compounds with studies using isolated human cells or cell lines almost doubled over time from 37 to 72%. Number of publications did not exhibit major differences between compounds intended for human versus veterinary use, therapeutic areas, small molecules versus biologicals, or innovator versus follow-up compounds; however, some companies may publish fewer studies per compound than others. However, there were qualitative differences in the types of models being used depending on the therapeutic area; specifically, compounds for use in oncology very often used isolated cells and cell lines, often from human origin. We conclude that the large variation in number and type of reported preclinical data is not easily explained. We propose that pharmaceutical companies should consistently provide a comprehensive documentation of the preclinical data they generate as part of their development programs in the public domain to enable a better understanding of the drugs they intend to market. PMID- 26612507 TI - Preclinical research strategies for newly approved drugs as reflected in early publication patterns. AB - The present study aimed to explore early publication patterns (i.e. up to 1 year after obtaining regulatory approval) for newly registered drugs. From the website of the US Food and Drug Administration, all newly approved drugs for 6 calendar years between 1991 and 2011 were identified. Non-clinical original publications for these compounds were retrieved from PubMed and their abstracts analysed for type of study and reported data. This yielded 170 compounds for which 1954 original non-clinical publications were identified, i.e. a median/mean of 5/11.5 publications per compound; however, number of publications per compound varied widely (0-90) and this variation exhibited a non-Gaussian distribution. The earliest non-clinical publication typically was published less than 5 years before regulatory approval and more than 5 years after filing of the primary patent, but some compounds exhibited notable deviations from this pattern. Publications most often reported on efficacy related to the target indication and on potential future indications, with fewer studies addressing mechanisms of action, potency, selectivity, pharmacokinetics and toxic effects. For most compounds, data at the cellular and in vivo level were published, with fewer reports on effects on isolated tissues and even fewer at the molecular level. The preferred species for cellular studies was human, whereas for in vivo studies, it was rats and mice. In 75 % of cases, the lead author of the publication came from an academic institution, and most studies were published in classic pharmacology journals. We conclude that number, timing and scope of early non-clinical publications on newly approved drugs exhibit major variance. Factors potentially associated with such variance are explored in a companion paper. PMID- 26612508 TI - Development of Hybrid BiOClx Br1-x -Embedded Alumina Films and Their Application as Highly Efficient Visible-Light-Driven Photocatalytic Reactors. AB - A highly stable 75 wt % BiOClx Br1-x -loaded alumina composite film has been developed for the fabrication of glass-based photoreactors. A very simple approach has been adopted that does not involve the use of a special instrument and can be applied to all types of substrates irrespective to their size and shape. The structure and morphology of the films were well characterized by XRD, SEM, TEM, N2 -sorption, IR, Raman, and UV/Vis diffuse reflectance spectroscopy. BiOClx Br1-x microspheres (1-3 MUm) with closely packed thin nanoplates (width ~10 nm) were integrated within alumina to develop a hybrid film. The photocatalytic capacity of the films was evaluated for the decomposition of Rhodamine B (RhB) and naphthalene under visible-light irradiation. The composite films showed a remarkable photocatalytic activity and stability and have been reused for several cycles without any deterioration of their original activity. PMID- 26612509 TI - Association of Sleep Disordered Breathing with Wake-Up Acute Ischemic Stroke: A Full Polysomnographic Study. AB - STUDY OBJECTIVES: Sleep disordered breathing (SDB) is a frequent comorbidity in stroke patients. SDB is one of the independent risk factors for ischemic stroke. Conversely, stroke may contribute to SDB onset or aggravate premorbid SDB. Multiple mechanisms underlying SDB might be responsible for the development of stroke. The aim of this study was to compare polysomnographic, clinical, and laboratory characteristics of wake-up (WUS) and non-wake-up acute ischemic strokes (NWUS). METHODS: We prospectively enrolled 88 patients with acute ischemic stroke. Clinical characteristics of the population were recorded on admission, and blood samples were obtained in the fasting condition following morning. SDB was assessed using standard overnight polysomnography in the acute phase of the stroke. RESULTS: WUS were present in 16 patients (18.2%), and NWUS in 72 patients (81.8%). In WUS compared to NWUS, we observed significantly higher values of apnea-hypopnea index (24.8 vs. 7.6, p = 0.007), desaturation index ([DI] 26.9 vs. 8.8, p = 0.005), arousal index (22.6 vs. 13.1, p = 0.035), diastolic blood pressure (91.6 mm Hg vs. 85.2 mm Hg, p = 0.039), triglyceride levels ([TG] 1.9 mmol/L vs. 1.2 mmol/L, p = 0.049), and significantly lower levels of D-dimer (0.4 MUg/L vs. 0.7 MUg/L, p = 0.035). DI (CI: 1.003-1.054, p = 0.031) and TG (CI: 1.002-1.877, p = 0.049) were the only independent variables significantly associated with WUS in binary logistic regression model. CONCLUSIONS: Although the design of our study does not prove the causal relationship between SDB and WUS, higher severity of SDB parameters in WUS supports this hypothesis. COMMENTARY: A commentary on this article appears in this issue on page 467. PMID- 26612510 TI - Effect of Sleep State and Position on Obstructive Respiratory Events Distribution in Adolescent Children. AB - STUDY OBJECTIVES: This study aimed to examine the effect of sleep state (rapid eye movement [REM] versus non-rapid eye movement [NREM]) and position (supine versus non-supine position) on obstructive respiratory events distribution in adolescent population (ages 12 to 18 y). METHODS: This was a retrospective study that included 150 subjects between the ages of 12 to 18 y with an apnea-hypopnea index (AHI) > 1/h. Subjects using REM sleep-suppressant medications and subjects with history of genetic anomalies or craniofacial syndromes were excluded. RESULTS: The median age was 14 y with interquartile range (IQR) of 13 to 16 y, 56% of patients were males and the median body mass index (BMI) z-score was 2.35 (IQR: 1.71-2.59) with 77.3% of patients fulfilling obesity criteria. Respiratory obstructive events were more common in REM sleep. The median REM obstructive AHI (OAHI) was 8.9 events per hour (IQR: 2.74-22.8), whereas the median NREM OAHI was 3.2 events per hour (IQR: 1.44-8.29; p < 0.001). African American adolescents had more REM obstructive events with median REM OAHI of 13.2 events per hour (IQR: 4.88-30.6), which was significantly higher than median REM OAHI of 4.94 (IQR: 2.05-11.36; p = 0.004) in white adolescents. Obstructive events were more common in supine position with higher median supine OAHI of 6.55 (IQR: 4-17.73) when compared to median non-supine OAHI of 2.94 (IQR: 1-6.54; p < 0.001). CONCLUSIONS: This study shows that sleep related obstructive respiratory events in the adolescents (12 to 18 y of age) occur predominantly in REM sleep and in supine position. PMID- 26612511 TI - A Three-Item Instrument for Measuring Daytime Sleepiness: The Observation and Interview Based Diurnal Sleepiness Inventory (ODSI). AB - STUDY OBJECTIVES: We aimed to develop a new three-item assessment tool for daytime sleepiness in older adults, the Observation and interview-based Diurnal Sleepiness Inventory (ODSI) and determine its validity, internal consistency, test-retest reliability, and optimal cutoff score. METHODS: A total of 133 elderly subjects including 73 patients with obstructive sleep apnea (OSA) (mean age, 79 y) and 60 controls (mean age, 80 y) were consecutively enrolled and answered all questionnaires. The ODSI questionnaire was validated using the Epworth Sleepiness Scale considered as a gold standard. Reliability, validity, and cut-points were tested. RESULTS: The ODSI has acceptable validity, internal consistency, and test-retest reliability properties. The ODSI has internal consistency and a reliability coefficient (Pearson rho) of 0.70 for its three items, which suggests strong reliability. The estimated sensitivity and specificity were 0.842 with 95% confidence interval [0.624; 0.945] and 0.851 [0.761; 0.911], respectively. The consistency of summated scale scores during test and retest sessions was high (r = 0.970, 95% bootstrap confidence interval [0.898; 0.991]). Receiver operating characteristic analysis suggests that a cut point of 6 is effective for identifying older adults with excessive levels of daytime sleepiness. CONCLUSIONS: The ODSI is a brief, valid, easy-to-administer three-item assessment that can screen for excessive daytime sleepiness among elderly patients with OSA. PMID- 26612512 TI - IGF-1 Levels are Inversely Associated With Metabolic Syndrome in Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: This study examined insulin-like growth factor-1 (IGF-1) production and its association with the metabolic syndrome (MS) in men with obstructive sleep apnea (OSA). METHODS: In total, 47 overweight and obese men who had been referred for suspected OSA underwent polysomnography and were classified based on the apnea-hypopnea index (AHI) into three groups: no OSA, < 5 events/h (n = 11); mild OSA, >= 5 to < 15 events/h (n = 8); and moderate-severe OSA, >= 15 events/h (n = 28). The assessment of the somatotropic axis function included IGF 1 measurement. MS was diagnosed according to the National Cholesterol Education Program guidelines. RESULTS: IGF-1 level in the moderate-severe OSA group was lower than in the no-OSA group (156.8 +/- 54.3 MUg/L versus 225.5 +/- 80.5 MUg/L; p = 0.013). IGF-1 level was negatively correlated with body mass index, waist circumference (WC), AHI, and sleep duration with oxygen (O2) saturation < 90% and positively correlated with the average and minimum O2 saturation (p = 0.027). In a multivariable linear regression, considering WC and minimum O2 saturation as independent variables, only the minimum O2 saturation was a predictor of low IGF 1 levels. The proportions of patients with MS were different between the three groups (18.2% in no OSA; 25% in mild OSA, and 57.1% in moderate-severe OSA; p = 0.047). Furthermore, in the lowest tertile of IGF-1 value, 66.7% of patients were affected by MS (p = 0.049). Hemoglobin (Hb)A1c correlated negatively with the minimum O2 saturation and IGF-1 levels. However, in multivariable linear regression only IGF-1 levels were a predictor of HbA1c levels. CONCLUSION: The occurrence of OSA is associated with a reduction in IGF-1 levels. IGF-1 alterations in OSA also seem to be associated with a higher prevalence of MS. PMID- 26612514 TI - Hepatoma derived growth factor (HDGF) dynamics in ovarian cancer cells. AB - As a leading cause of cancer death among women, identification of pathophysiologically-relevant biomarkers for ovarian cancer is important. The heparin binding, hepatoma-derived growth factor (HDGF) is overexpressed in ovarian cancer cell lines and may have prognostic value, but the mechanism by which this predominantly nuclear protein is secreted or functions is unknown. In this study, we focused on the circumstances under which HDGF is released by cells and the functional relevance of extracellular HDGF in the context of ovarian cancer. Immunofluorescence imaging showed nuclear localization of HDGF in ovarian cells, but unlike what is reported for other cell types, HDGF was minimally secreted into the media. However, HDGF was passively released by necrotic and late apoptotic cells. Extracellular HDGF was functionally relevant as it stimulated phosphorylation of ERK 1/2 and P38 in both non-cancer and ovarian cancer cells, and enhanced cellular migration. Overall, our study uncovers a novel function of HDGF as a messenger of cellular condition (alarmin) which in turn modulates cellular function-aspects that could be used as a biomarker for ovarian cancer. PMID- 26612513 TI - Pre-diagnostic Sleep Duration and Sleep Quality in Relation to Subsequent Cancer Survival. AB - STUDY OBJECTIVES: Poor sleep quality and short sleep duration have been associated with elevated risk for several cancer types; however, the relationship between sleep and cancer outcomes has not been well characterized. We assessed the association between pre-diagnostic sleep attributes and subsequent cancer survival within the Women's Health Initiative (WHI). METHODS: We identified WHI participants in whom a first primary invasive cancer had been diagnosed during follow-up (n = 21,230). Participants provided information on sleep characteristics at enrollment. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between these pre diagnostic sleep characteristics and cancer-specific survival for all cancers combined and separately for common cancers. Analyses were adjusted for age, study arm, cancer site, marital status, income, smoking, physical activity, and time to diagnosis. RESULTS: No individual pre-diagnostic sleep characteristics were found to be significantly associated with cancer survival in analyses of all cancer sites combined; however, women who reported short sleep duration (<= 6 h sleep/night) combined with frequent snoring (>= 5 nights/w experienced significantly poorer cancer-specific survival than those who reported 7-8 h of sleep/night and no snoring (HR = 1.32, 95% CI: 1.14-1.54). Short sleep duration (HR = 1.46, 95% CI: 1.07-1.99) and frequent snoring (HR = 1.34, 95% CI: 0.98 1.85) were each associated with poorer breast cancer survival; those reporting short sleep combined with frequent snoring combined had substantially poorer breast cancer survival than those reporting neither (HR = 2.14, 95% CI: 1.47 3.13). CONCLUSIONS: Short sleep duration combined with frequent snoring reported prior to cancer diagnosis may influence subsequent cancer survival, particularly breast cancer survival. PMID- 26612515 TI - Hp-normogram (normo-graham) for Assessing the Outcome of H. pylori Therapy: Effect of Resistance, Duration, and CYP2C19 Genotype. AB - There have been hundreds of H. pylori eradication trials and yet doubt remains regarding the best regimen for any situation. With most regimens, treatment failure is the result of resistance to one component (e.g., clarithromycin). Thus, if one knows the treatment success with two groups (all with susceptible and with all with resistant infections), one can construct a normogram that provides a reliable estimate of the outcome at any prevalence of resistance. The same data can be used to estimate the prevalence of resistance in any clinical trial, the effects duration of therapy, and effects of any procedures to improve outcome (e.g., increasing the proton-pump inhibitor dose, the duration of therapy, etc.). Because the Hp-normo-graham can reliably predict the outcome of clinical trials, it can also obviate the need for many clinical trials in populations where resistance is common. Here, we illustrate the construction of Hp-normo-graham and its use to describe the effects of resistance, duration of therapy, attempts to improve results, and the prevalence of resistance and to obviate the need for many clinical trials. PMID- 26612517 TI - Prediction of the next highly pathogenic avian influenza pandemic that can cause illness in humans. AB - BACKGROUND: In recent years, avian influenza viruses (AIVs) have seriously threatened human health. Questions such as: why do AIVs infect humans?, how quickly can an AIV become pandemic?, and which virus is the most dangerous? cannot be sufficiently answered using current bioinformatic studies. METHOD: Secondary structures and energies of representative 5'-untranslated region (UTR) of the HA gene were calculated. Then their secondary structures and energies were re-calculated after one or two nucleotide substitutions were introduced into the HA 5'-UTR. Phylogenetic trees on the basis of hemagglutinin (HA) and polymerase basic protein 2 (PB2) amino acid sequences and HA 5'-UTR nucleotide sequences were constructed. The connection between the energy and translation efficiency of 5'-UTR was confirmed by in vitro coupled transcription/translation assay. RESULTS: The simplicity of the secondary structure of the 5'-UTR of the HA gene determines the overall virus replication rate and transmission potential. Point mutation assays show that the 5'-UTR sequences of the HA gene in the influenza subtypes H2N2, H3N2, and H7N9 have greater variation potentials than other virus subtypes. CONCLUSION: Some high-virulent strains of avian influenza might emerge in the next two to three years. The H2N2 subtype, once disappeared in humans, may stage a comeback. The current outbreak of H7N9 may become pandemic and cause even more deaths, if one or two bases are substituted in the 5'-UTR sequence of the HA gene. PMID- 26612516 TI - G Protein-Gated K+ Channel Ablation in Forebrain Pyramidal Neurons Selectively Impairs Fear Learning. AB - BACKGROUND: Cognitive dysfunction occurs in many debilitating conditions including Alzheimer's disease, Down syndrome, schizophrenia, and mood disorders. The dorsal hippocampus is a critical locus of cognitive processes linked to spatial and contextual learning. G protein-gated inwardly rectifying potassium ion (GIRK/Kir3) channels, which mediate the postsynaptic inhibitory effect of many neurotransmitters, have been implicated in hippocampal-dependent cognition. Available evidence, however, derives primarily from constitutive gain-of-function models that lack cellular specificity. METHODS: We used constitutive and neuron specific gene ablation models targeting an integral subunit of neuronal GIRK channels (GIRK2) to probe the impact of GIRK channels on associative learning and memory. RESULTS: Constitutive Girk2-/- mice exhibited a striking deficit in hippocampal-dependent (contextual) and hippocampal-independent (cue) fear conditioning. Mice lacking GIRK2 in gamma-aminobutyric acid neurons (GAD Cre:Girk2flox/flox mice) exhibited a clear deficit in GIRK-dependent signaling in dorsal hippocampal gamma-aminobutyric acid neurons but no evident behavioral phenotype. Mice lacking GIRK2 in forebrain pyramidal neurons (CaMKII Cre(+):Girk2flox/flox mice) exhibited diminished GIRK-dependent signaling in dorsal, but not ventral, hippocampal pyramidal neurons. CaMKII Cre(+):Girk2flox/flox mice also displayed a selective impairment in contextual fear conditioning, as both cue fear and spatial learning were intact in these mice. Finally, loss of GIRK2 in forebrain pyramidal neurons correlated with enhanced long-term depression and blunted depotentiation of long-term potentiation at the Schaffer collateral/cornu ammonis 1 synapse in the dorsal hippocampus. CONCLUSIONS: Our data suggest that GIRK channels in dorsal hippocampal pyramidal neurons are necessary for normal learning involving aversive stimuli and support the contention that dysregulation of GIRK-dependent signaling may underlie cognitive dysfunction in some disorders. PMID- 26612518 TI - Darunavir/cobicistat for the treatment of HIV-1: a new era for compact drugs with high genetic barrier to resistance. AB - INTRODUCTION: Cobicistat-boosted darunavir is a boosted protease inhibitor in a fixed-dose combination to be approved for the treatment of human immunodeficiency virus type1 infection. It contains darunavir, a well-known protease inhibitor with a good efficacy and safety profile, and the new pharmacokinetic enhancer cobicistat. The convenience of this combination in a single pill makes this compound easier to take, thus improving adherence. AREAS COVERED: PubMed and www.clinicaltrials.gov were searched with the term "darunavir/cobicistat" for all clinical trials conducted up to date, as well as for those ongoing and to be opened in the near future as well as for pharmacology data. A review of abstracts from major infectious diseases (particularly those dedicated to human immunodeficiency disease) and pharmacology conferences from 2010 to 2015 was also conducted. EXPERT OPINION: improving adherence, particularly by minimizing pill burden with convenient formulations (i.e., fixed-dose combination), is one of the major objectives of modern antiretroviral treatment of patients with human immunodeficiency virus disease. Cobicistat is an alternative agent to ritonavir for boosting plasma drug levels for several antiretrovirals. Darunavir co administered with low-dose ritonavir, in combination with other antiretrovirals, is recommended in several guidelines for treatment of patients with human immunodeficiency disease. Darunavir/cobicistat fixed-dose combination allows for a once-daily treatment regimen with a reduced pill burden. This new co formulation makes this compound easier to take, thus improving adherence. PMID- 26612519 TI - 'Moral Perception' Reflects Neither Morality Nor Perception. PMID- 26612520 TI - Genetically determined differences in noradrenergic function: The spontaneously hypertensive rat model. AB - While genetic predisposition is a major factor, it is not known how development of attention-deficit/hyperactivity disorder (ADHD) is modulated by early life stress. The spontaneously hypertensive rat (SHR) displays the behavioral characteristics of ADHD (poorly sustained attention, impulsivity, hyperactivity) and is the most widely studied genetic model of ADHD. We have previously shown that SHR have disturbances in the noradrenergic system and that the early life stress of maternal separation failed to produce anxiety-like behavior in SHR, contrary to control Sprague-Dawley and Wistar-Kyoto (WKY) who showed typical anxiety-like behavior in later life. In the present study we investigated the effect of maternal separation on approach behavior (response to a novel object in a familiar environment) in preadolescent SHR and WKY. We also investigated whether maternal separation altered GABAA and NMDA receptor-mediated regulation of norepinephrine release in preadolescent SHR and WKY hippocampus. We found that female SHR, similar to male SHR, exhibited greater exploratory activity than WKY. Maternal separation significantly increased GABAA receptor-mediated inhibition of glutamate-stimulated release of norepinephrine in male and female SHR hippocampus but had no significant effect in WKY. Maternal separation had opposite effects on NMDA receptor-mediated inhibition of norepinephrine release in SHR and WKY hippocampus, as it increased inhibition of both glutamate-stimulated and depolarization-evoked release in SHR hippocampus but not in WKY. The results of the present study show that noradrenergic function is similarly altered by the early life stress of maternal separation in male and female SHR, while GABA- and glutamate-regulation of norepinephrine release remained unaffected by maternal separation in the control, WKY, rat strain. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID- 26612521 TI - Uncovering diversity in the development of central noradrenergic neurons and their efferents. AB - Uncovering the mechanisms that underlie central noradrenergic neuron heterogeneity is essential to understanding selective subtype vulnerability to disease and environmental insult. Using recombinase-based intersectional genetic fate mapping we have previously demonstrated that molecularly distinct progenitor populations give rise to mature noradrenergic neurons differing in their anatomical location, axon morphology and efferent projection pattern. Here we review the findings from our previous study and extend our analysis of the noradrenergic subpopulation defined by transient developmental expression of Hoxb1. Using a combination of intersectional genetic fate mapping and analysis of a targeted loss of function mutation in Hoxb1, we have now uncovered additional heterogeneity based on the requirement of some noradrenergic neurons for Hoxb1 expression. By comparing the distribution of noradrenergic neurons derived from the Hoxb1 expression domain in wild-type and mutant mice, we demonstrate that Hoxb1 expression is required by a subset of neurons in the pons. Additional fate mapping, using a Hoxb1 enhancer element that drives Cre recombinase expression exclusively in rhombomere 4 of the hindbrain, reveals the existence of a subpopulation of noradrenergic neurons in the pons with more restricted axonal targets than the full Hoxb1-derived subpopulation. The unique projection profile of this newly defined subpopulation suggests that it may be functionally distinct. These analyses shed new light on the molecular determinants of noradrenergic identity in the pons and the overall complexity of the central noradrenergic system. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID- 26612523 TI - Biomarkers in rheumatic diseases: how can they facilitate diagnosis and assessment of disease activity? AB - Serological and proteomic biomarkers can help clinicians diagnose rheumatic diseases earlier and assess disease activity more accurately. These markers have been incorporated into the recently revised classification criteria of several diseases to enable early diagnosis and timely initiation of treatment. Furthermore, they also facilitate more accurate subclassification and more focused monitoring for the detection of certain disease manifestations, such as lung and renal involvement. These biomarkers can also make the assessment of disease activity and treatment response more reliable. Simultaneously, several new serological and proteomic biomarkers have become available in the routine clinical setting--for example, a protein biomarker panel for rheumatoid arthritis and a myositis antibody panel for dermatomyositis and polymyositis. This review will focus on commercially available antibody and proteomic biomarkers in rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (scleroderma), dermatomyositis and polymyositis, and axial spondyloarthritis (including ankylosing spondylitis). It will discuss how these markers can facilitate early diagnosis as well as more accurate subclassification and assessment of disease activity in the clinical setting. The ultimate goal of current and future biomarkers in rheumatic diseases is to enable early detection of these diseases and their clinical manifestations, and to provide effective monitoring and treatment regimens that are tailored to each patient's needs and prognosis. PMID- 26612522 TI - 5-hydroxytryptamine1A (5-HT1A) receptor agonists: A decade of empirical evidence supports their use as an efficacious therapeutic strategy for brain trauma. AB - Traumatic brain injury (TBI) is a significant and enduring health care issue with limited treatment options. While several pre-clinical therapeutic approaches have led to enhanced motor and/or cognitive performance, the benefits of these treatments have not translated to the clinic. One plausible explanation is that the therapies may not have been rigorously evaluated, thus rendering the bench-to bedside leap premature and subsequently unsuccessful. An approach that has undergone considerable empirical research after TBI is pharmacological targeting of 5-HT1A receptors with agonists such as repinotan HCl, 8-hydroxy-2-(di-n propylamino) tetralin (8-OH-DPAT), and buspirone. The goal of this review is to integrate and interpret the findings from a series of studies that evaluated the efficacy of 5-HT1A receptor agonists on functional, histological, and molecular outcome after acquired brain injury. The overwhelming consensus of this exhaustive review is that a decade of empirical evidence supports their use as an efficacious therapeutic strategy for brain trauma. This article is part of a Special Issue entitled SI:Brain injury and recovery. PMID- 26612524 TI - Outcomes of parathyroidectomy in renal hyperparathyroidism in patients with No access to renal transplantation in Singapore. AB - BACKGROUND: Total parathyroidectomy with autotransplantation (TPTX + AT) and subtotal parathyroidectomy (SPTX) are considered standard surgical treatments for refractory renal hyperparathyroidism. However, there is little data available comparing their outcomes in an area with poor access to renal transplant and calcimimetics. METHODS: Patients with renal hyperparathyroidism who underwent TPTX + AT and SPTX in a tertiary institution from 2006 to 2013 were studied. Patient characteristics, pre- and post-operative biochemical marker levels, and outcomes including recurrence rates, post-operative morbidity and mortality were analysed. RESULTS: 87 patients underwent parathyroidectomy for renal hyperthyroidism. Transplant patients were excluded in this study. 81 patients were on long-term dialysis, with a median time of 7 years from initiation of haemodialysis to parathyroidectomy. 57 patients (70.4%) underwent TPTX + AT while 24 (29.6%) underwent SPTX. Post-operatively, there was significant decrease in parathyroid hormone (PTH), calcium and phosphate levels in both groups. PTH and phosphate levels were significantly lowered with TPTX compared to SPTX (p = 0.004, 0.003). Symptomatic hypocalcaemia was seen in both groups. In a median follow-up of 4 years, 11 patients developed biochemical recurrence, with a median time of 29 months to recurrence. Median PTH at recurrence was 67.1 pmol/L. Rate of recurrence was higher in patients who underwent SPTX (20.8% vs 10.5%), with a shorter median time to recurrence (median 62.1 vs 81.3 months). 2 patients required resection of the autograft. Cohort mortality was 11 patients (13.4%), with 3 deaths secondary to cardiovascular events. CONCLUSION: Total parathyroidectomy with autoimplantation is superior to subtotal parathyroidectomy in the short to intermediate term. PMID- 26612525 TI - Shock wave as biological therapeutic tool: From mechanical stimulation to recovery and healing, through mechanotransduction. AB - Extracorporeal Shock Wave Therapy (ESWT) is a form of "mechanotherapy", that, from its original applications as urological lithotripsy, gained the field of musculo-skeletal diseases as Orthotripsy (mainly tendinopaties and bone regenerative disorders) and Regenerative Medicine as well. The mechanisms of action of Shock Waves (SW), when applied in non-urological indications, are not related to the direct mechanical effect, but to the different pathways of biological reactions, that derive from that acoustic stimulations, through "mechano-transduction". So, the "mechanical model" of urological lithotripsy has been substituted by a "biological model", also supported by current knowledge in "mechanobiology", the emerging multidisciplinary field of science that investigates how physical forces and changes in cell/tissue mechanics can influence the tissue development, physiology and diseases. Although some details are still under study, it is known that SW are able to relief pain, as well to positively regulate inflammation (probably as immunomodulator), to induce neoangiogenesis and stem cells activities, thus improving tissue regeneration and healing. ESWT can be nowadays considered an effective, safe, versatile, repeatable, noninvasive therapy for the treatment of many musculo-skeletal diseases, and for some pathological conditions where regenerative effects are desirable, especially when some other noninvasive/conservative therapies have failed. Moreover, based on the current knowledge in SW mechanobiology, it seems possible to foresee new interesting and promising applications in the fields of Regenerative Medicine, tissue engineering and cell therapies. PMID- 26612526 TI - The value of ultrasonography in the diagnosis of appendicitis: A pediatric surgeon's perspective. PMID- 26612527 TI - Accurate triage of lower gastrointestinal bleed (LGIB) - A cohort study. AB - INTRODUCTION: Acute lower gastrointestinal bleeding (LGIB) is a common acute presenting complaint to hospital. Unlike upper gastrointestinal bleeding, the diagnostic and therapeutic approach is not well-standardised. Intensive monitoring and urgent interventions are essential for patients with severe LGIB. The aim of this study is to investigate factors that predict severe LGIB and develop a clinical predictor tool to accurately triage LGIB in the emergency department of a busy metropolitan teaching hospital. METHODS: We retrospectively identified all adult patients who presented to Middlemore Hospital Emergency Department with LGIB over a one year period. We recorded demographic variables, Charlson Co-morbidities Index, use of anticoagulation, examination findings, vital signs on arrival, laboratory test results, treatment plans and further investigations results. We then identified a subgroup of patients who suffered severe LGIB. RESULTS: A total of 668 patients presented with an initial triage diagnosis of LGIB. 83 of these patients (20%) developed severe LGIB. Binary logistic regression analysis identified four independent risk factors for severe LGIB: use of aspirin, history of collapse, haemoglobin on presentation of less than 100 mg/dl and albumin of less than 38 g/l. CONCLUSIONS: We have developed a clinical prediction tool for severe LGIB in our population with a negative predictive value (NPV) of 88% and a positive predictive value (PPV) of 44% respectively. We aim to validate the clinical prediction tool in a further cohort to ensure stability of the multivariate model. PMID- 26612528 TI - Copper-catalyzed, hypervalent iodine mediated C=C bond activation of enaminones for the synthesis of alpha-keto amides. AB - An unprecedented C=C bond cleavage of enaminones has been realized by means of copper catalysis in the presence of hypervalent iodine (PhI(OAc)2). The cascade transformation based on this bond cleavage leads to the synthesis of various alpha-keto amides. Isotope labeling experiments suggest that water has acted as a source of oxygen atoms during the generation of the new carbonyl group. PMID- 26612534 TI - Dynamic positioning accuracy of a novel multileaf collimator for volumetric modulated arc therapy. AB - We investigated the dynamic positioning accuracy of Agility (Elekta) for volumetric modulated arc therapy (VMAT). The accuracy of the multileaf collimator (MLC) leaf position during VMAT was evaluated using three different tests: (1) a dynamic multileaf collimator (DMLC) output test with various leaf speeds, and gantry angles; (2) a slit-fence test with and without gantry rotation; and (3) a complicated VMAT plans test with dose distributions compared with measurements using gamma analysis. The DMLC output was within 1.5 % under all test conditions. The agreement between the static and VMAT in the slit-fence test was within 0.5 mm. The pass rate of each complicated VMAT test plan was more than 93.9 % +/- 0.36 for gamma analysis. We confirmed the dynamic positioning accuracy of Agility, which during VMAT delivery is within VMAT tolerances. The fastest MLC was found to have the potential to offer clinical advantages, such as high quality rapid VMAT. PMID- 26612535 TI - Epithelial-mesenchymal transition: Untangling EMT's functions. PMID- 26612536 TI - Delivery of cell-penetrating peptide-peptide nucleic acid conjugates by assembly on an oligonucleotide scaffold. AB - Delivery to intracellular target sites is still one of the main obstacles in the development of peptide nucleic acids (PNAs) as antisense-antigene therapeutics. Here, we designed a self-assembled oligonucleotide scaffold that included a central complementary region for self-assembly and lateral regions complementing the PNAs. Assembly of cell-penetrating peptide (CPP)-PNAs on the scaffold significantly promoted endocytosis of PNAs by at least 10-fold in cell cultures, particularly for scaffolds in which the central complementary region was assembled by poly(guanine) and poly(cytosine). The antisense activity of CPP-PNAs increased by assembly on the scaffold and was further enhanced after co-assembly with endosomolytic peptide (EP)-PNA. This synergistic effect was also observed following the assembly of antigene CPP-PNAs?EP-PNAs on the scaffold. However, antigene activity was only observed by targeting episomal viral DNA or transfected plasmids, but not the chromosome in the cell cultures. In conclusion, assembly on oligonucleotide scaffolds significantly enhanced the antisense antigene activity of PNAs by promoting endocytosis and endosomal escape. This oligonucleotide scaffold provided a simple strategy for assembly of multiple functional peptide-PNA conjugates, expanding the applications of PNAs and demonstrating the potential of PNAs as antiviral therapeutics. PMID- 26612537 TI - An alternative covariance estimator to investigate genetic heterogeneity in populations. AB - BACKGROUND: For genomic prediction and genome-wide association studies (GWAS) using mixed models, covariance between individuals is estimated using molecular markers. Based on the properties of mixed models, using available molecular data for prediction is optimal if this covariance is known. Under this assumption, adding individuals to the analysis should never be detrimental. However, some empirical studies showed that increasing training population size decreased prediction accuracy. Recently, results from theoretical models indicated that even if marker density is high and the genetic architecture of traits is controlled by many loci with small additive effects, the covariance between individuals, which depends on relationships at causal loci, is not always well estimated by the whole-genome kinship. RESULTS: We propose an alternative covariance estimator named K-kernel, to account for potential genetic heterogeneity between populations that is characterized by a lack of genetic correlation, and to limit the information flow between a priori unknown populations in a trait-specific manner. This is similar to a multi-trait model and parameters are estimated by REML and, in extreme cases, it can allow for an independent genetic architecture between populations. As such, K-kernel is useful to study the problem of the design of training populations. K-kernel was compared to other covariance estimators or kernels to examine its fit to the data, cross validated accuracy and suitability for GWAS on several datasets. It provides a significantly better fit to the data than the genomic best linear unbiased prediction model and, in some cases it performs better than other kernels such as the Gaussian kernel, as shown by an empirical null distribution. In GWAS simulations, alternative kernels control type I errors as well as or better than the classical whole-genome kinship and increase statistical power. No or small gains were observed in cross-validated prediction accuracy. CONCLUSIONS: This alternative covariance estimator can be used to gain insight into trait-specific genetic heterogeneity by identifying relevant sub-populations that lack genetic correlation between them. Genetic correlation can be 0 between identified sub populations by performing automatic selection of relevant sets of individuals to be included in the training population. It may also increase statistical power in GWAS. PMID- 26612540 TI - COPD: Evidence-based medicine or the patient-centered medicine? PMID- 26612539 TI - Structural delineation of stem-loop RNA binding by human TAF15 protein. AB - Human TATA binding protein associated factor 2 N (TAF15) and Fused in sarcoma (FUS) are nucleic acid binding proteins belonging to the conserved FET family of proteins. They are involved in diverse processes such as pre-mRNA splicing, mRNA transport, and DNA binding. The absence of information regarding the structural mechanism employed by the FET family in recognizing and discriminating their cognate and non-cognate RNA targets has hampered the attainment of consensus on modes of protein-RNA binding for this family. Our study provides a molecular basis of this RNA recognition using a combination of solution-state NMR spectroscopy, calorimetry, docking and molecular dynamics simulation. Analysis of TAF15-RRM solution structure and its binding with stem-loop RNA has yielded conclusive evidence of a non-canonical mode of RNA recognition. Rather than classical stacking interactions that occur across nitrogen bases and aromatic amino acids on ribonucleoprotein sites, moderate-affinity hydrogen bonding network between the nitrogen bases in the stem-loop RNA and a concave face on the RRM surface primarily mediate TAF15-RRM RNA interaction. We have compared the binding affinities across a set of single-stranded RNA oligonucleotides to conclusively establish that RNA binding is dependent upon structural elements in the RNA rather than sequence. PMID- 26612541 TI - Emotion understanding, parent mental state language, and behavior problems in internationally adopted children. AB - Internationally adopted postinstitutionalized (PI) children are at risk for lower levels of emotion understanding. This study examined how postadoption parenting influences emotion understanding and whether lower levels of emotion understanding are associated with behavior problems. Emotion understanding and parent mental state language were assessed in 3-year-old internationally adopted PI children (N = 25), and comparison groups of children internationally adopted from foster care (N = 25) and nonadopted (NA) children (N = 36). At 5.5-year follow-up, PI children had lower levels of emotion understanding than NA children, a group difference not explained by language. In the total sample, parent mental state language at age 3 years predicted 5.5-year emotion understanding after controlling for child language ability. The association of parent mental state language and 5.5-year emotion understanding was moderated by adoption status, such that parent mental state language predicted 5.5-year emotion understanding for the internationally adopted children, but not for the NA children. While postadoption experience does not erase negative effects of early deprivation on emotion understanding, results suggest that parents can promote emotion understanding development through mental state talk. At 5.5 years, PI children had more internalizing and externalizing problems than NA children, and these behavioral problems related to lower levels of emotion understanding. PMID- 26612542 TI - Chronic Use of Theophylline and Mortality in Chronic Obstructive Pulmonary Disease: A Meta-analysis. AB - BACKGROUND: Theophylline has been shown to improve respiratory function and oxygenation in patients with chronic obstruction pulmonary disease (COPD). However, the impact of theophylline on mortality in COPD patients has not been not sufficiently evaluated. METHOD: Two investigators independently searched for eligible articles in 4 databases. The eligibility criterion for this meta analysis was an original research article that provided a hazard ratio for theophylline for all-cause mortality of COPD patients. Both randomized controlled trials and observational studies were accepted. After we confirmed no substantial heterogeneity (I(2)<50%), the fixed-model method with generic inverse variance was used for meta-analysis to estimate the pooled hazard ratio. RESULTS: We screened 364 potentially eligible articles. Of the 364 articles, 259 were excluded on the basis of title and abstract, and 99 were excluded after examination of the full text. Our final analysis included 6 observational studies and no randomized controlled trials. One study reported 2 cohorts. The number of patients in each cohort ranged from 47 to 46,403. Heterogeneity (I(2)=42%, P=.11) and publication bias (Begg's test r=0.21, P=.662) were not substantial. Fixed model meta-analysis yielded a pooled hazard ratio for theophylline for all-cause death of 1.07 (95% confidence interval: 1.02-1.13, P=.003). CONCLUSION: This meta analysis of 7 observational cohorts suggests that theophylline slightly increases all-cause death in COPD patients. PMID- 26612544 TI - Size dependent nanomechanics of coil spring shaped polymer nanowires. AB - Direct laser writing (DLW) via two-photon polymerization (TPP) has been established as a powerful technique for fabrication and integration of nanoscale components, as it enables the production of three dimensional (3D) micro/nano objects. This technique has indeed led to numerous applications, including micro- and nanoelectromechanical systems (MEMS/NEMS), metamaterials, mechanical metamaterials, and photonic crystals. However, as the feature sizes decrease, an urgent demand has emerged to uncover the mechanics of nanosized polymer materials. Here, we fabricate coil spring shaped polymer nanowires using DLW via two-photon polymerization. We find that even the nanocoil springs follow a linear response against applied forces, following Hooke's law, as revealed by compression tests using an atomic force microscope. Further, the elasticity of the polymer material is found to become significantly greater as the wire radius is decreased from 550 to 350 nm. Polarized Raman spectroscopy measurements show that polymer chains are aligned in nanowires along the axis, which may be responsible for the size dependence. Our findings provide insight into the nanomechanics of polymer materials fabricated by DLW, which leads to further applications based on nanosized polymer materials. PMID- 26612538 TI - Reactive p-block cations stabilized by weakly coordinating anions. AB - The chemistry of the p-block elements is a huge playground for fundamental and applied work. With their bonding from electron deficient to hypercoordinate and formally hypervalent, the p-block elements represent an area to find terra incognita. Often, the formation of cations that contain p-block elements as central ingredient is desired, for example to make a compound more Lewis acidic for an application or simply to prove an idea. This review has collected the reactive p-block cations (rPBC) with a comprehensive focus on those that have been published since the year 2000, but including the milestones and key citations of earlier work. We include an overview on the weakly coordinating anions (WCAs) used to stabilize the rPBC and give an overview to WCA selection, ionization strategies for rPBC-formation and finally list the rPBC ordered in their respective group from 13 to 18. However, typical, often more organic ion classes that constitute for example ionic liquids (imidazolium, ammonium, etc.) were omitted, as were those that do not fulfill the - naturally subjective "reactive"-criterion of the rPBC. As a rule, we only included rPBC with crystal structure and only rarely refer to important cations published without crystal structure. This collection is intended for those who are simply interested what has been done or what is possible, as well as those who seek advice on preparative issues, up to people having a certain application in mind, where the knowledge on the existence of a rPBC that might play a role as an intermediate or active center may be useful. PMID- 26612545 TI - Roflumilast for asthma: Safety findings from a pooled analysis of ten clinical studies. AB - BACKGROUND: The safety profile of roflumilast, a phosphodiesterase 4 inhibitor, has been extensively researched in patients with chronic obstructive pulmonary disease (COPD). Adverse events (AEs) including headache, diarrhoea and weight loss have been reported. Much less is known about the safety of roflumilast treatment in patients with bronchial asthma. AIM: To evaluate the safety and tolerability of roflumilast using safety data from one open-label and ten pooled placebo-controlled phase II and III clinical studies completed between 1997 and 2005. SUBJECTS AND METHODS: The studies were conducted at sites in Europe, North and South America, Africa, Australasia and Asia and study length varied from 4 to 40 weeks. Data for 5169 patients between 12 and 70 years of age, of whom 2851 received roflumilast at doses of 125, 250 and 500 MUg, were analyzed. At randomization patients had a forced expiratory flow of 45-100%. RESULTS: Headache was the most frequent AE with an incidence rate of 50 and 29.2 per 100 patient years in the 500 MUg roflumilast and placebo groups, respectively. Gastrointestinal AEs were common. Nausea and diarrhoea occurred in 28.7 and 28.3 per 100 patient-years in the 500 MUg roflumilast and placebo groups, respectively. The extent of weight loss in roflumilast-treated patients was small. AEs reported in 465 patients in the 4-week open-label follow-up study reflected those of the pooled studies. CONCLUSIONS: The severity and incidence of AEs reported from this pooled safety analysis confirm that roflumilast is generally well tolerated by patients with asthma. This reflects the general safety profile reported previously in patients with COPD. All studies were funded by Takeda. Trial registration numbers available on ClinicalTrials.gov: NCT00073177, NCT00076076, NCT00163527. PMID- 26612547 TI - Spedali Degli Innocenti, the Foundling Hospital in Florence, Italy. AB - The author reflects on a visit to the Ospedale Degli Innocenti, the former Renaissance foundling hospital in Florence, having escaped from an international clinical conference. He considers the symbolism of the architecture and artwork in relation to its function as a sanctuary for abandoned children. PMID- 26612546 TI - Radiofrequency ablation versus magnetic resonance guided focused ultrasound surgery for minimally invasive treatment of osteoid osteoma: a propensity score matching study. AB - OBJECTIVES: To compare outcomes in pain relief and motor functional recovery in patients with an osteoid osteoma treated by magnetic resonance guided focused ultrasound surgery (MRgFUS) or radiofrequency ablation (RFA) using a propensity score matching study design. METHODS: Thirty patients with osteoid osteomas were included in this institutional review board (IRB)-approved study. MRgFUS was performed in 15 subjects. These subjects were matched by propensity analysis with a group of 15 subjects treated by RFA. Pain relief in terms of complete response (CR) and motor functional recovery were measured. RESULTS: A similar proportion of subjects treated by MRgFUS (94 %) or RFA (100 %) experienced CR 12 weeks after treatment, with no significant difference. The improvement in pain control following MRgFUS or RFA paralleled with improved motor functional recovery. The treatment failure rate was 6.6 % in the MRgFUS group and 0 % in the RFA group. No major complications were observed following either ablative treatment. CONCLUSIONS: Although this study involved a limited number of patients, MRgFUS favourably improves perceived pain and motor functional recovery, with no major complications. No difference was found in the achievement of primary and secondary outcome measures with respect to RFA. KEY POINTS: * To demonstrate the effectiveness of a recent technique for treating osteoid osteoma * MRgFUS results compared with results of the gold standard treatment (RFA) * MRgFUS is effective both from a clinical and functional point of view * No significant side effects compared with RFA. PMID- 26612550 TI - In Memory of Professor Je Geun Chi, a Great Mentor and Pathologist. PMID- 26612551 TI - Erratum: WHO Grade IV Gliofibroma: A Grading Label Denoting Malignancy for an Otherwise Commonly Misinterpreted Neoplasm. AB - [This corrects the article on p. 325 in vol. 49, PMID: 26081826.]. PMID- 26612552 TI - The Effects of 4-Methylethcathinone on Conditioned Place Preference, Locomotor Sensitization, and Anxiety-Like Behavior: A Comparison with Methamphetamine. AB - BACKGROUND: 4-Methylethcathinone is a drug that belongs to the second generation of synthetic cathinones, and recently it has been ranked among the most popular "legal highs". Although it has similar in vitro neurochemical actions to other drugs such as cocaine, the behavioral effects of 4-methylethcathinone remain to be determined. METHODS: The addictive potential and locomotor potentiation by 4 methylethcathinone were investigated in rats using the conditioned place preference and sensitization paradigm. Methamphetamine was used as a positive control. Because synthetic cathinones can have psychological effects, we also examined anxiety-like behavior using the elevated plus maze. RESULTS: A conditioning dose of 10 mg/kg 4-methylethcathinone was able to induce conditioned place preference and reinstatement (following 2 weeks of withdrawal). Acute or repeated injections of 4-methylethcathinone at 3 or 10mg/kg failed to alter locomotor activity. At 30 mg/kg, however, acute 4-methylethcathinone increased locomotor activity compared with saline, while chronic 4-methylethcathinone induced a delayed and attenuated sensitization compared with methamphetamine. Additionally, repeated daily injections of 4-methylethcathinone (30 mg/kg) reduced, whereas methamphetamine increased time spent by rats in the open arm of an elevated plus maze compared with saline injections. Interestingly, a 2-week withdrawal period following chronic injections of 4-methylethcathinone or methamphetamine increased time spent in the open arm in all rats. CONCLUSIONS: The rewarding properties of 4-methylethcathinone were found to be dissociated from its effects on locomotor activity. Additionally, chronic 4 methylethcathinone use may trigger abnormal anxious behaviors. These behavioral effects caused by 4-methylethcathinone appear to last even after a withdrawal period. PMID- 26612553 TI - [A subacute dementia: Inflammatory cerebral amyloid angiopathy]. AB - We report a case of inflammatory cerebral amyloid angiopathy (CAA) that led to rapid cognitive decline, seizures, visual hallucinations, hyperproteinorrachia and right hemispheric leukopathy. Brain biopsy gave the diagnosis of CAA. Although no inflammatory infiltrate was found in the biopsy sample, corticosteroids led to a regression of the radiological lesions without significant clinical improvement. CAA is a rare disease, defined by lesions of classical cerebral amyloid angiopathy and perivascular infiltrates in contact with the affected vessels. In cases of rapidly progressive dementia associated with leukopathy, inflammatory amyloid angiopathy should be considered as cognitive disorders may improve after immunosuppressive therapy. PMID- 26612554 TI - Evaluation of nephrotoxic effects of aristolochic acid on zebrafish (Danio rerio) larvae. AB - To analyze the toxic effects of aristolochic acid (AA) on developed kidneys in zebrafish larvae, zebrafish at 3 days postfertilization were treated with various concentrations of AA for 24 h before the status of kidney injury was investigated from several points of view. It was found that 21% of the larvae treated with 10 umoL/L AA exhibited evident periocular edema. When the concentrations of AA were increased to 20 and 40 umoL/L, defect in the cardiovascular system characterized by slow heart beat and blood flow was seen coupled with periocular edema. Creatinine in the whole larval tissue determined by liquid chromatography-mass spectrometry/mass spectrometry exhibited dramatic increase in the treated groups in a dose-dependent manner within a certain range of doses. Several evident protein bands were detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in supernatant of the treated larvae, indicating leakage of glomerular filtration barrier. Results of quantitative polymerase chain reaction show that the messenger RNA expression of nephrin in the 20 and 40 umoL/L AA treated groups decreased to 0.58 +/- 0.062 and 0.37 +/- 0.075-folds of the control, respectively. Kidney damage was further confirmed by the histological changes in paraffin sections of treated larvae, for example, cystic glomeruli and disorganized epithelia cells of pronephric tubules. Our results revealed that AA exerted toxic effects on developed kidney of zebrafish larvae in a dose-dependent manner and podocyte dysfunction may be involved in the kidney injury and proteinuria. PMID- 26612555 TI - Secondhand smoke induces hepatic apoptosis and fibrosis in hamster fetus. AB - Secondhand smoke (SHS) is an important health issue worldwide. Inhaling SHS during pregnancy could cause abnormalities in the internal tissues of newborns, which may then impair fetal development and even cause severe intrauterine damage and perinatal death. However, the understanding of cytopathic mechanisms of SHS by maternal passive smoking on fetus liver during pregnancy is still limited. This study analyzed the effects of high-dose SHS (SHSH) on fetus liver using a maternal passive smoking animal model. Experiments showed that hepatic matrix metalloproteinase-9 activity and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling-positive cells were significantly increased in livers from fetuses of hamsters treated with SHSH. Similarly, expressions of both extrinsic and intrinsic apoptotic molecules were significantly higher in livers from fetuses of hamsters exposed to SHSH. Additionally, significantly increased inflammatory proteins, including transforming growth factor beta, inducible nitric oxide synthase, and interleukin 1beta, and fibrotic signaling molecules, including phosphorylated Smad2/3, SP1, and alpha-smooth muscle actin, were observed in the fetus livers from hamsters treated with SHSH. This study revealed that SHSH not only increased apoptosis through intrinsic and extrinsic pathways in the livers of fetuses from hamsters exposed to SHSH but also augmented hepatic fibrosis via Smad2/3 signaling. PMID- 26612556 TI - Thirteen years of oxcarbazepine exposures reported to US poison centers: 2000 to 2012. AB - OBJECTIVES: Oxcarbazepine (OXC) is a 10-keto analogue of carbamazepine used in patients with partial and secondary generalized seizures. We evaluated ingestions of OXC reported to US poison centers for adverse effects from supratherapeutic doses and/or overdose. METHOD: Retrospective analysis of data reported to National Poison Data System from single-substance OXC ingestions between January 2000 and December 2012. RESULTS: There were 18,867cases with a mean of 1451 exposures/year. The patients were predominantly adults with 5464 exposures in children <6 years (29%). The most commonly reported clinical effects were drowsiness (n = 4703, 25%), vomiting (n = 1559, 8%), tachycardia (n = 590, 3%), agitated (n = 342, 1.8%), hypotension (n = 178, 0.9%), electrolyte disturbance (n = 153, 0.8%), coma (n = 156, 0.8%), and seizures (n = 121, 0.6%). There were 176 patients with a major effect of which 31 involved were children and 1728 (9%) patients with moderate effects of which 300 involved were children. Five deaths were reported in adults. Intentional exposure (e.g. suicide) was the reason for exposure in 68% of patients with major effects and in all fatalities. Fifty-three percent of adults and 38% of children were managed in a health-care facility (HCF). HCF utilization levels remained consistent. DISCUSSION: Severe outcomes appear to be infrequent (<1%). Unlike other anticonvulsants OXC does not appear to be proconvulsant in overdose. CONCLUSION: Serious outcomes for OXC overdoses are unlikely in the pediatric patient. With only mild symptoms likely, observation at home may be appropriate for the majority of cases. In the adult population there appears to be few neurologic and cardiovascular complications even in the intentional exposure. PMID- 26612557 TI - Successful scaling-up of self-sustained pyrolysis of oil palm biomass under pool type reactor. AB - An appropriate technology for waste utilisation, especially for a large amount of abundant pressed-shredded oil palm empty fruit bunch (OFEFB), is important for the oil palm industry. Self-sustained pyrolysis, whereby oil palm biomass was combusted by itself to provide the heat for pyrolysis without an electrical heater, is more preferable owing to its simplicity, ease of operation and low energy requirement. In this study, biochar production under self-sustained pyrolysis of oil palm biomass in the form of oil palm empty fruit bunch was tested in a 3-t large-scale pool-type reactor. During the pyrolysis process, the biomass was loaded layer by layer when the smoke appeared on the top, to minimise the entrance of oxygen. This method had significantly increased the yield of biochar. In our previous report, we have tested on a 30-kg pilot-scale capacity under self-sustained pyrolysis and found that the higher heating value (HHV) obtained was 22.6-24.7 MJ kg(-1) with a 23.5%-25.0% yield. In this scaled-up study, a 3-t large-scale procedure produced HHV of 22.0-24.3 MJ kg(-1) with a 30% 34% yield based on a wet-weight basis. The maximum self-sustained pyrolysis temperature for the large-scale procedure can reach between 600 degrees C and 700 degrees C. We concluded that large-scale biochar production under self sustained pyrolysis was successfully conducted owing to the comparable biochar produced, compared with medium-scale and other studies with an electrical heating element, making it an appropriate technology for waste utilisation, particularly for the oil palm industry. PMID- 26612558 TI - [Correlation between retinal angiography and optical coherence tomography in diabetic macular edema: Report of 72 patients]. PMID- 26612559 TI - [Swept-source OCT imaging of an optic pit]. PMID- 26612560 TI - [Non-specific bilateral compressive orbital inflammation: Case report]. PMID- 26612561 TI - [Deep intracorneal foreign body: Anterior segment OCT]. PMID- 26612562 TI - [Intraoperative OCT of a Mittendorf dot with persistent hyaloid artery]. PMID- 26612563 TI - The physicochemical characteristics and anaerobic degradability of desiccated coconut industry waste water. AB - Desiccated coconut industries (DCI) create various intermediates from fresh coconut kernel for cosmetic, pharmaceutical and food industries. The mechanized and non-mechanized DCI process between 10,000 and 100,000 nuts/day to discharge 6 150 m(3) of malodorous waste water leading to a discharge of 264-6642 kg chemical oxygen demand (COD) daily. In these units, three main types of waste water streams are coconut kernel water, kernel wash water and virgin oil waste water. The effluent streams contain lipids (1-55 g/l), suspended solids (6-80 g/l) and volatile fatty acids (VFA) at concentrations that are inhibitory to anaerobic bacteria. Coconut water contributes to 20-50% of the total volume and 50-60% of the total organic loads and causes higher inhibition of anaerobic bacteria with an initial lag phase of 30 days. The lagooning method of treatment widely adopted failed to appreciably treat the waste water and often led to the accumulation of volatile fatty acids (propionic acid) along with long-chain unsaturated free fatty acids. Biogas generation during biological methane potential (BMP) assay required a 15-day adaptation time, and gas production occurred at low concentrations of coconut water while the other two streams did not appear to be inhibitory. The anaerobic bacteria can mineralize coconut lipids at concentrations of 175 mg/l; however; they are severely inhibited at a lipid level of >=350 mg/g bacterial inoculum. The modified Gompertz model showed a good fit with the BMP data with a simple sigmoid pattern. However, it failed to fit experimental BMP data either possessing a longer lag phase and/or diauxic biogas production suggesting inhibition of anaerobic bacteria. PMID- 26612564 TI - The influences of selected soil properties on Pb availability and its transfer to wheat (Triticum aestivum L.) in a polluted calcareous soil. AB - Accumulated anthropogenic heavy metals in the surface layer of agricultural soils may be transferred through the food chain via plant uptake processes. The objectives of this study were to assess the spatial distribution of lead (Pb) in the soils and wheat plants and to determine the soil properties which may affect the Pb transferring from soil to wheat plants in Zanjan Zinc Town area, northwestern Iran. A total of 110 topsoil samples (0-20 cm) were systematically collected from an agricultural area near a large metallurgical factory for the analyses of physico-chemical properties and total and bioavailable Pb concentrations. Furthermore, a total of 65 wheat samples collected at the same soil sampling locations were analyzed for Pb concentration in different plant parts. The results showed that elevated Pb concentrations were mostly found in soils located surrounding the industrial source of pollution. The bioavailable Pb concentration in the studied soils was up to 128.4 mg kg(-1), which was relatively high considering the observed soil alkalinity. 24.6% of the wheat grain samples exceeded the FAO/WHO maximum permitted concentration of Pb in wheat grain (0.2 mg kg(-1)). Correlation analyses revealed that soil organic matter, soil pH, and clay content showed insignificant correlation with Pb concentration in the soil and wheat grains, whereas calcium carbonate content showed significantly negative correlations with both total and bioavailable Pb in the soil, and Pb content in wheat grains, demonstrating the strong influences of calcium carbonate on Pb bioavailability in the polluted calcareous soils. PMID- 26612565 TI - Assessing groundwater quality in Greece based on spatial and temporal analysis. AB - The recent industrial growth together with the urban expansion and intensive agriculture in Greece has increased groundwater contamination in many regions of the country. In order to design successful remediation strategies and protect public health, it is very important to identify those areas that are most vulnerable to groundwater contamination. In this work, an extensive contamination database from monitoring wells that cover the entire Greek territory during the last decade (2000-2008) was used in order to study the temporal and spatial distribution of groundwater contamination for the most common and serious anionic and cationic trace element pollutants (heavy metals). Spatial and temporal patterns and trends in the occurrence of groundwater contamination were also identified highlighting the regions where the higher groundwater contamination rates have been detected across the country. As a next step, representative contaminated aquifers in Greece, which were identified by the above analysis, were selected in order to analyze the specific contamination problem in more detail. To this end, geostatistical techniques (various types of kriging, co kriging, and indicator kriging) were employed in order to map the contaminant values and the probability of exceeding critical thresholds (set as the parametric values of the contaminant of interest in each case). The resulting groundwater contamination maps could be used as a useful tool for water policy makers and water managers in order to assist the decision-making process. PMID- 26612566 TI - Pesticide residues in some herbs growing in agricultural areas in Poland. AB - The aim of this paper was to assess residue content of plant protection products in selected herbs: Achillea millefolium L., Cichorium intybus L., Equisetum arvense L., Polygonum persicaria L., Plantago lanceolata L., and Plantago major L. The study comprises herbs growing in their natural habitat, 1 and 10 m away from crop fields. The herbs, 30 plants of each species, were sampled during the flowering stage between 1 and 20 July 2014. Pesticide residue content was measured with the QuECHERS method in the dry matter of leaves, stalks, and inflorescence, all mixed together. Out of six herb species growing close to wheat and maize fields, pesticide residues were found in three species: A. millefolium L., E. arvense L., and P. lanceolata L. Most plants containing the residues grew 1 m away from the wheat field. Two active substances of fungicides were found: diphenylamine and tebuconazole, and one active substance of insecticides: chlorpyrifos-ethyl. Those substances are illegal to use on herbal plants. Samples of E. arvense L. and P. lanceolata L. contained two active substances each, which constituted 10% of all samples, while A. millefolium L. contained one substance, which is 6.6% of all samples. PMID- 26612567 TI - High field superconducting properties of Ba(Fe1-xCox)2As2 thin films. AB - In general, the critical current density, Jc, of type II superconductors and its anisotropy with respect to magnetic field orientation is determined by intrinsic and extrinsic properties. The Fe-based superconductors of the '122' family with their moderate electronic anisotropies and high yet accessible critical fields (Hc2 and Hirr) are a good model system to study this interplay. In this paper, we explore the vortex matter of optimally Co-doped BaFe2As2 thin films with extended planar and c-axis correlated defects. The temperature and angular dependence of the upper critical field is well explained by a two-band model in the clean limit. The dirty band scenario, however, cannot be ruled out completely. Above the irreversibility field, the flux motion is thermally activated, where the activation energy U0 is going to zero at the extrapolated zero-kelvin Hirr value. The anisotropy of the critical current density Jc is both influenced by the Hc2 anisotropy (and therefore by multi-band effects) as well as the extended planar and columnar defects present in the sample. PMID- 26612568 TI - Male competition fitness landscapes predict both forward and reverse speciation. AB - Speciation is facilitated when selection generates a rugged fitness landscape such that populations occupy different peaks separated by valleys. Competition for food resources is a strong ecological force that can generate such divergent selection. However, it is unclear whether intrasexual competition over resources that provide mating opportunities can generate rugged fitness landscapes that foster speciation. Here we use highly variable male F2 hybrids of benthic and limnetic threespine sticklebacks, Gasterosteus aculeatus Linnaeus, 1758, to quantify the male competition fitness landscape. We find that disruptive sexual selection generates two fitness peaks corresponding closely to the male phenotypes of the two parental species, favouring divergence. Most surprisingly, an additional region of high fitness favours novel hybrid phenotypes that correspond to those observed in a recent case of reverse speciation after anthropogenic disturbance. Our results reveal that sexual selection through male competition plays an integral role in both forward and reverse speciation. PMID- 26612569 TI - Molecular dynamics study on the nucleation of Al-Si melts on sheet substrates at the nanoscale. AB - Molecular dynamics (MD) simulations are performed to study the freezing process of Al-Si melts on heterogeneous Si substrates in detail. We highlight the inherent nanostructure of both the Si primary phase and the Al-Si binary phase. It is found for the first time that the primary Si phase displays a "pyramidal configuration" when the Al-Si melt congeals. Experimental measurements could also verify our simulation results. It can be found that the binary Al-Si phase turns into a "Si-Al-Si sandwich construction" during solidification, regardless of freezing on a single substrate or in the restricted space between substrates. This peculiar phenomenon results from the combined effects of the van der Waals potential well and the interatomic interaction between Al and Si. Furthermore, it is also able to control the thickness of the Si atomic shell of the "sandwich construction", resulting in the silicene-like unilaminar Si nanostructure. Our findings provide novel strategies to fabricate desired shaped nanostructures by means of nanocasting in Al-Si melts at the nanoscale. PMID- 26612570 TI - The long road to reproducibility. PMID- 26612572 TI - Rethinking glutamine addiction. AB - Tumours reprogram their metabolism to maximize macromolecule biosynthesis for growth. However, which of the common tumour-associated metabolic activities are critical for proliferation remains unclear. Glutamate-derived glutamine is now shown to satisfy the glutamine needs of glioblastoma, indicating that glutamine anaplerosis is dispensable for growth. PMID- 26612573 TI - A motor relay on ciliary tracks. AB - A powerful combination of two-colour imaging in vivo, Fourier-filtered kymography and simulations provides a high-resolution view of kinesin-2 transport dynamics in cilia. This study reveals heterotrimeric kinesin-II as an 'obstacle-course runner' and homodimeric OSM-3 (KIF17) as a 'long-distance runner', and elucidates the 'baton handoff' between these two kinesin-2 motors on the microtubule track. PMID- 26612574 TI - Metabolic exit from naive pluripotency. AB - Spatiotemporally distinct pluripotent states captured in vitro provide an accessible way of modelling early human development. An intricate interplay between the metabolome and histone modifications is now shown to drive the metabolic switch from human naive to primed pluripotency, one of the earliest steps of embryogenesis. PMID- 26612575 TI - Addendum: A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. PMID- 26612577 TI - Skin suicide note written in mehndi (henna). AB - Suicide messages on the skin are rare. Until now, in all reported cases, the writing tool used by the victims has been a pen. We report a suicide case by hanging in which the victim had written a note on her palm in mehndi, or henna, at a wedding ceremony three days before the fatal act. The note was discovered at autopsy. PMID- 26612576 TI - Complete twelve month bone remodeling with a bi-phasic injectable bone substitute in benign bone tumors: a prospective pilot study. AB - BACKGROUND: Benign primary bone tumors are commonly treated by surgery involving bone grafts or synthetic bone void fillers. Although synthetic bone grafts may provide early mechanical support while minimizing the risk of donor-site morbidity and disease transmission, difficult handling properties and less than optimal transformation to bone have limited their use. METHODS: In a prospective series, patients with benign bone tumors were treated by minimal invasive intervention with a bi-phasic and injectable ceramic bone substitute (CERAMENTTM BONE VOID FILLER, BoneSupport, Sweden) with the hypothesis that open surgery with bone grafting might be avoided. The defects were treated by either mini-invasive surgery (solid tumors) or percutaneous injection (cysts) and followed clinically and radiologically for 12 months. CT scan was performed after 12 months to confirm bone remodeling of the bone substitute. All patients were allowed full weight bearing immediately after surgery. RESULTS: Fourteen patients with a median age of 13 years (range 7-75) were consecutively recruited during 11 months. Eleven lesions were bone cysts (eight unicameral and three post traumatic) and three were solid benign tumors. The median size of the lesions was 40 mL (range 1-152). The most common location was humerus (n = 10). After 12 months the defects completely or partially filled with median 18 mL (range 5-28) of bone substitute demonstrated full resolution (Neer Classification grade I) in 11 patients, partial resolution (Neer II) in 2 patients and in 1 patient the cyst persisted (Neer III). No lesions required recurrent surgery during the observation period. No post-operative fracture or infection was recorded. CONCLUSIONS: Minimal invasive treatment with a bi-phasic and injectable ceramic bone substitute might offer an alternative to regular bone grafting due to convenient handling properties and rapid bone remodeling. TRIAL REGISTRATION: ClinicalTrials NCT02567084 Release Date 10/01/2015. PMID- 26612578 TI - Duty of care to a quasi patient. PMID- 26612580 TI - Casting light on coronary evaginations: different mechanisms in different coronary devices? PMID- 26612579 TI - Atrial fibrillation is associated with the fibrotic remodelling of adipose tissue in the subepicardium of human and sheep atria. AB - AIMS: Accumulation of atrial adipose tissue is associated with atrial fibrillation (AF). However, the underlying mechanisms remain poorly understood. We examined the relationship between the characteristics of fatty infiltrates of the atrial myocardium and the history of AF. METHODS AND RESULTS: Atrial samples, collected in 92 patients during cardiac surgery and in a sheep model of persistent AF, were subjected to a detailed histological analysis. In sections of human right atrial samples, subepicardial fatty infiltrations were commonly observed in the majority of patients. A clear difference in the appearance and fibrotic content of these fatty infiltrations was observed. Fibro-fatty infiltrates predominated in patients with permanent AF (no AF: 37 +/- 24% vs. paroxysmal AF: 50 +/- 21% vs. permanent AF: 64 +/- 23%, P < 0.001). An inverse correlation between fibrotic remodelling and the amount of subepicardial adipose tissue suggested the progressive fibrosis of fatty infiltrates with permanent AF. This hypothesis was tested in a sheep model of AF. In AF sheep, an increased accumulation of peri-atrial fat depot was observed on cardiac magnetic resonance imaging and dense fibro-fatty infiltrations predominated in the left atria of AF sheep. Cellular inflammation, mainly consisting of functional cytotoxic T lymphocytes, was observed together with adipocyte cell death in human atria. CONCLUSION: Atrial fibrillation is associated with the fibrosis of subepicardial fatty infiltrates, a process in which cytotoxic lymphocytes might be involved. This remodelling of the atrial subepicardium could contribute to structural remodelling forming a substrate for AF. PMID- 26612581 TI - Nocturnal hypoxaemia is associated with increased mortality in stable heart failure patients. AB - AIM: This study investigated the prognostic value of sleep-disordered breathing (SDB) in a large cohort of patients with heart failure with reduced left ventricular function (HF-REF), with focus on the role of nocturnal hypoxaemia. METHODS: This single-centre prospective cohort study enrolled patients with chronic stable HF-REF (NYHA >=II) receiving guideline-based treatment. Unattended in-hospital polygraphy was performed to determine the apnoea-hypopnoea index (AHI). Pulse oximetry was used to determine hypoxaemic burden [time with oxygen saturation <90% (T90)], and all-cause mortality was recorded. RESULTS: Complete data were available for 963 of 1249 patients. At baseline, 58% of patients had moderate-to-severe SDB. The median follow-up was 7.35 years; 480 of 963 (49.8%) patients died. Mortality rate (per 100 person-years) was 8.1 [95% confidence interval (CI) 7.0-9.4] in patients with no or mild SDB, but 12.2 (95% CI 10.9 13.7) in moderate-to-severe SDB. Apnoea-hypopnoea index was significantly associated with time to death from any cause in a simple Cox model [hazard ratio (HR) 1.011, P < 0.001], but was no longer significant after adjustment for confounding factors (HR 1.005, P = 0.085). T90 was significantly (P < 0.001) associated with time to death from any cause even after adjustment for confounding factors. The risk of death increased by 16.1% (95% CI 8.6-24.2) per hour of T90. Five-year survival probabilities for patients in T90 quartiles 1, 2, 3, and 4 were 70, 63, 60, and 50%, respectively. CONCLUSION: Hypoxaemic burden was a robust and independent predictor of all-cause mortality in chronic stable HF-REF patients. Whether or not targeting nocturnal hypoxaemia is associated with beneficial effects on mortality in HF-REF patients remains to be determined. PMID- 26612582 TI - Coronary pressure and flow relationships in humans: phasic analysis of normal and pathological vessels and the implications for stenosis assessment: a report from the Iberian-Dutch-English (IDEAL) collaborators. AB - BACKGROUND: Our understanding of human coronary physiological behaviour is derived from animal models. We sought to describe physiological behaviour across a large collection of invasive pressure and flow velocity measurements, to provide a better understanding of the relationships between these physiological parameters and to evaluate the rationale for resting stenosis assessment. METHODS AND RESULTS: Five hundred and sixty-seven simultaneous intracoronary pressure and flow velocity assessments from 301 patients were analysed for coronary flow velocity, trans-stenotic pressure gradient (TG), and microvascular resistance (MVR). Measurements were made during baseline and hyperaemic conditions. The whole cardiac cycle and the diastolic wave-free period were assessed. Stenoses were assessed according to fractional flow reserve (FFR) and quantitative coronary angiography DS%. With progressive worsening of stenoses, from unobstructed angiographic normal vessels to those with FFR <= 0.50, hyperaemic flow falls significantly from 45 to 19 cm/s, Ptrend < 0.001 in a curvilinear pattern. Resting flow was unaffected by stenosis severity and was consistent across all strata of stenosis (Ptrend > 0.05 for all). Trans-stenotic pressure gradient rose with stenosis severity for both rest and hyperaemic measures (Ptrend < 0.001 for both). Microvascular resistance declines with stenosis severity under resting conditions (Ptrend < 0.001), but was unchanged at hyperaemia (2.3 +/- 1.1 mmHg/cm/s; Ptrend = 0.19). CONCLUSIONS: With progressive stenosis severity, TG rises. However, while hyperaemic flow falls significantly, resting coronary flow is maintained by compensatory reduction of MVR, demonstrating coronary auto-regulation. These data support the translation of coronary physiological concepts derived from animals to patients with coronary artery disease and furthermore, suggest that resting pressure indices can be used to detect the haemodynamic significance of coronary artery stenoses. PMID- 26612584 TI - Bacillus cavernae sp. nov. isolated from cave soil. AB - A Gram-stain-positive, spore-forming, motile, strictly aerobic, rod-shaped bacterium, designated strain L5T, was isolated from soil of Tenglong cave, China. 16S rRNA gene sequence analysis showed that strain L5T was related most closely to Bacillus asahii MA001T (96.5 %) (the highest 16S rRNA gene sequence similarity), Bacillus kribbensis BT080T (96.4 %) and Bacillus deserti ZLD-8T (96.2 %). The DNA G+C content of strain L5T was 45.6 mol%. The major menaquinone was MK-7. The major fatty acids were iso-C14 : 0, anteiso-C15 : 0 and iso-C16 : 0, and the major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. The diagnostic diamino acid in the cell-wall peptidoglycan was meso-diaminopimelic acid. In addition, strain L5T had different characteristics compared with the other Bacillus strains such as pink colony colour, low growth temperature and low nutrient requirement. The results indicate that strain L5T represents a novel species of the genus Bacillus, for which the name Bacillus cavernae sp. nov. is proposed. The type strain is L5T ( = KCTC 33637T = CCTCC AB 2015055T). PMID- 26612585 TI - Biomarkers for diagnosis: looking for change. PMID- 26612583 TI - Genome-wide DNA methylation map of human neutrophils reveals widespread inter individual epigenetic variation. AB - The extent of variation in DNA methylation patterns in healthy individuals is not yet well documented. Identification of inter-individual epigenetic variation is important for understanding phenotypic variation and disease susceptibility. Using neutrophils from a cohort of healthy individuals, we generated base resolution DNA methylation maps to document inter-individual epigenetic variation. We identified 12851 autosomal inter-individual variably methylated fragments (iVMFs). Gene promoters were the least variable, whereas gene body and upstream regions showed higher variation in DNA methylation. The iVMFs were relatively enriched in repetitive elements compared to non-iVMFs, and were associated with genome regulation and chromatin function elements. Further, variably methylated genes were disproportionately associated with regulation of transcription, responsive function and signal transduction pathways. Transcriptome analysis indicates that iVMF methylation at differentially expressed exons has a positive correlation and local effect on the inclusion of that exon in the mRNA transcript. PMID- 26612586 TI - Fractal dimension and lacunarity of tumor microscopic images as prognostic indicators of clinical outcome in early breast cancer. AB - AIM: Research in the field of breast cancer outcome prognosis has been focused on molecular biomarkers, while neglecting the discovery of novel tumor histology structural clues. We thus aimed to improve breast cancer prognosis by fractal analysis of tumor histomorphology. PATIENTS & METHODS: This retrospective study included 92 breast cancer patients without systemic treatment. RESULTS: Fractal dimension and lacunarity of the breast tumor microscopic histology possess prognostic value comparable to the major clinicopathological prognostic parameters. CONCLUSION: Fractal analysis was performed for the first time on routinely produced archived pan-tissue stained primary breast tumor sections, indicating its potential for clinical use as a simple and cost-effective prognostic indicator of distant metastasis risk to complement the molecular approaches for cancer risk prognosis. PMID- 26612587 TI - Biological and methodological aspects of assessment of locus specific de novo methylation in blood. AB - AIM: Locus-specific methylation in blood differs between individuals. As those changes may represent de novo methylation, induced by environmental factors, we aimed to evaluate the biological and methodological limitations of detection of methylation in blood. MATERIALS & METHODS: We used Methylation-Sensitive High Resolution Melting to analyze methylation at 21 gene loci in peripheral blood DNA samples from 203 healthy women. RESULTS: Overall nine of the screened loci displayed marked inter-individual variation in methylation frequency with methylation levels predominantly around 1%. The methylation of specific loci showed different association with age and reproducibility of detection. CONCLUSIONS: Our results allowed benchmarking of both technological and biological limitations that need to be accounted for when evaluating locus specific methylation in blood as potential biomarker. PMID- 26612588 TI - Plasma IL-1 receptor antagonist levels correlate with the development of non alcoholic steatohepatitis. AB - AIM: Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by lipid accumulation and inflammation. Here, we aimed to evaluate plasma IL-1Ra as a marker for NASH and to determine whether diagnosis of NASH can be further improved by adding IL-1Ra measurements. MATERIALS & METHODS: Therefore, plasma concentrations of IL-1Ra were measured from 146 subjects of a biopsy-proven NASH cohort with matched controls. RESULTS: NASH patients had higher levels of plasma IL-1Ra compared with patients with steatosis or healthy controls. CONCLUSION: Our data confirm that IL-1Ra can be a useful tool in the diagnosis of hepatic inflammation and suggest that measuring plasma IL-1Ra levels in addition to ALT will improve the diagnosis for NASH at all stages of the disease. PMID- 26612589 TI - An overlooked parameter in coronary slow flow phenomenon: whole blood viscosity. AB - AIMS: We aimed to assess the relationship between coronary slow flow phenomenon (CSFP) and whole blood viscosity (WBV). MATERIALS & METHODS: Two hundred patients with CSFP and 200 subjects with normal coronary arteries as control group were enrolled. WBV was calculated from hematocrit and plasma protein concentration at low shear rate (LSR) (0.5 s(-1)) and high shear rate (HSR) (208 s(-1)) by a validated equation. RESULTS: CSFP patients had significantly higher WBV for LSR and HSR. The mean corrected TIMI frame count was highest in the highest tertile group for both shear rates. Corrected TIMI frame count revealed a significant relationship with WBV for LSR (r = 0.562) and HSR (r = 0.611). At multivariate analysis, WBV at LSR and HSR were independent predictors of CSFP. CONCLUSION: WBV seemed to have a significant and an independent predictor of CSFP. PMID- 26612590 TI - Clinical evaluation of the Heart Check system, a new quantitative measurement of fresh capillary BNP. AB - AIM: We have evaluated here the clinical and analytical performance of the AlereTM Heart Check (AHC) test, a rapid point-of-care immunoassay designed for the measurement of BNP from fresh capillary whole blood. PATIENTS & METHODS: One hundred-and-sixty-three patients with stable chronic heart failure followed at the cardiac rehabilitation were submitted to simultaneous capillary (AHC) and plasma (Abbott architect system) BNP measurements. RESULTS: Both methods showed a good correlation, although the values diverged when BNP was higher than 2000 pg/ml. Despite a relatively poor precision of AHC, however, both methods showed the same performances to assess patients' dyspnea and equivalent sensitivity, specificity, negative and positive predicting values. CONCLUSION: AHC BNP test is a good POC for the management of heart failure despite a relatively poor precision. PMID- 26612591 TI - Cancer stem cell markers: premises and prospects. AB - Over the last decade, compelling evidence has shown that cancer stem cells (CSCs) exist in a variety of malignancies. The conventional method for anticancer therapy involves targeting only the proliferating mitotic cells, sparing the slow cycling cells that eventually evade chemotherapy and become a source of post therapy relapses. With the increasing awareness of CSCs supported by sophisticated experimental evidence, therapeutic strategies today are aimed at selectively identifying and targeting CSCs using biomarkers. The ability to identify CSCs allows targeted elimination of these cancer-initiating cells. Herein, we discuss CSC markers in the context of different types of cancers, their significance in selectively identifying CSCs and the therapeutic implications of using these biomarkers to prevent invasion and metastasis of cancer. PMID- 26612592 TI - The Anatomical Society core regional anatomy syllabus for undergraduate medicine. AB - The Anatomical Society's core syllabus for anatomy (2003 and later refined in 2007) set out a series of learning outcomes that an individual medical student should achieve on graduation. The core syllabus, with 182 learning outcomes grouped in body regions, referenced in the General Medical Council's Teaching Tomorrow's Doctors, was open to criticism on the grounds that the learning outcomes were generated by a relatively small group of anatomists, albeit some of whom were clinically qualified. We have therefore used a modified Delphi technique to seek a wider consensus. A Delphi panel was constructed involving 'experts' (n = 39). The revised core syllabus of 156 learning outcomes presented here is applicable to all medical programmes and may be used by curriculum planners, teachers and students alike in addressing the perennial question: 'What do I need to know ?' PMID- 26612593 TI - Appendiceal mixed adenoneuroendocrine carcinomas, a rare entity that can present as a Krukenberg tumor: case report and review of the literature. AB - BACKGROUND: Mixed adenoneuroendocrine carcinoma is a rare tumor recently recognized as a new category in the last World Health Organization (WHO) classification of appendiceal tumors (2010). This term has been proposed to designate carcinomas of the appendix that arise by progression from a pre existing goblet cell carcinoid. Mixed adenoneuroendocrine carcinomas are more aggressive tumors than typical goblet cell carcinoids and usually present with peritoneal spreading and ovarian masses. Staging, some histological features, and completeness of surgery are factors that determine its evolution. CASE PRESENTATION: We report the case of a mixed adenoneuroendocrine carcinoma--signet ring cell subtype--that presented as a Krukenberg tumor of unknown primary. CONCLUSION: The review of literature is focused on the most recent WHO pathologic classification of appendiceal tumors containing goblet cell clusters, which seems to correlate with prognosis. A management proposal for mixed adenoneuroendocrine carcinomas reported in previous literature is also discussed. This ranges from right hemicolectomy to cytoreduction plus hyperthermic intraperitoneal chemotherapy, in both cases usually followed by intravenous chemotherapy. PMID- 26612594 TI - Interleukin-29 induces epithelial production of CXCR3A ligands and T-cell infiltration. AB - Psoriasis is considered as a model for chronic immune-mediated disorders. Th17 cells are pivotal players in those diseases. Recently, we demonstrated that Th17 cells produce interleukin (IL)-29 and that IL-29 is highly present in psoriatic lesions. Whether IL-29, with its action on epithelial cells and melanocytes, contributes to psoriasis pathogenesis, was unknown so far. Analysis of IL-29 treated human keratinocytes revealed induction of the chemokines CXCL10, CXCL11, and, to a much lesser extent, CXCL9. Unlike these CXCR3A ligands, known to attract Th1-, CD8(+), NK-, and Th1/Th17 transient cells, no influence was found on chemokines attracting other immune cell populations or on molecules modulating the CXCR3A/CXCR3A ligand interaction. CXCR3A ligand expression was also induced by IL-29 in melanocytes and in epidermis models and explanted skin. Regarding other psoriasis-relevant cytokines, interferon-gamma and, less potently, tumor necrosis factor-alpha and IL-1beta shared and strengthened IL-29's capacity. Murine IL-29 counterpart injected into mouse skin provoked local CXCL10 and CXCL11 expression, T-cell infiltration, and, in consequence, skin swelling. The elevated IL-29 expression in psoriatic lesions was associated with upregulation of CXCR3A ligands compared to non-lesional skin of these patients and to the skin of healthy donors and atopic dermatitis patients, which lack IL-29 production. Importantly, neutralization of IL-29 reduced CXCR3A ligand levels in explant cultures of psoriatic lesions. Finally, elevated blood CXCL11 levels were found in psoriasis that might be useful for monitoring lesional activity of the IL-29 axis. In summary, the Th17-cytokine IL-29 induces specific chemokines and, in consequence, provokes skin infiltration of potentially pathogenic T-cells. KEY MESSAGES: IL-29 selectively induces CXCR3A-binding chemokines (CXCL9, CXCL10, CXCL11) in skin cells. Murine IL-29 counterpart induces skin T-cell infiltration and inflammation in mice. CXCR3A ligands are IL-29-dependently increased in lesional skin of psoriasis patients. CXCR3A ligand levels in psoriatic skin correlate with epidermal T-cell numbers. Increased blood CXCL11 levels in psoriasis may be a biomarker for local IL-29 action. PMID- 26612595 TI - Prevalence of physical violence against children in Haiti: A national population based cross-sectional survey. AB - Although physical violence against children is common worldwide, there are no national estimates in Haiti. To establish baseline national estimates, a three stage clustered sampling design was utilized to administer a population-based household survey about victimization due to physical violence to 13-24 year old Haitians (n=2,916), including those residing in camps or settlements. Descriptive statistics and weighted analysis techniques were used to estimate national lifetime prevalence and characteristics of physical violence against children. About two-thirds of respondents reported having experienced physical violence during childhood (67.0%; 95% CI 63.4-70.4), the percentage being similar in males and females. More than one-third of 13-17 year old respondents were victimized in the 12 months prior to survey administration (37.8%; 95% CI 33.6-42.1). The majority of violence was committed by parents and teachers; and the perceived intent was often punishment or discipline. While virtually all (98.8%; 95% CI 98.0-99.3) victims of childhood physical violence were punched, kicked, whipped or beaten; 11.0% (95% CI 9.2-13.2) were subject to abuse by a knife or other weapon. Injuries sustained from violence varied by victim gender and perpetrator, with twice as many females (9.6%; 95% CI 7.1-12.7) than males (4.0%; 95% CI 2.6 6.1) sustaining permanent injury or disfigurement by a family member or caregiver (p-value<.001). Our findings suggest that physical violence against children in Haiti is common, and may lead to severe injury. Characterization of the frequency and nature of this violence provides baseline estimates to inform interventions. PMID- 26612597 TI - Acceptance of progestogen-only contraceptives by indigenous women from south Mexico. PMID- 26612596 TI - Analgesic Use and Daytime Sleepiness in Residents With and Without Dementia in Residential Aged Care Facilities. AB - BACKGROUND: Managing pain in residents of residential aged care facilities (RACFs) is challenging, especially for people with dementia. Clinicians must weigh the benefits of analgesic use against the potential for adverse events, particularly daytime sleepiness. OBJECTIVES: The aim was to investigate the association between analgesic use and daytime sleepiness in residents with and without dementia in RACFs. METHODS: This was a cross-sectional study of 383 permanent residents from six low-level and high-level RACFs in South Australia. Main measures included analgesic use in the previous 24 h, analgesic load and self-reported daytime sleepiness. Covariates included relevant comorbidities (insomnia, depression, painful conditions), Charlson's Comorbidity Index, sedative load, self-reported and clinician-observed pain and dementia severity. Logistic regression was used to compute odds ratios (ORs) and confidence intervals (CIs) for the association between analgesic use and daytime sleepiness. RESULTS: Analgesics were used by 288 residents (75.2%) in the previous 24 h. These included paracetamol (n = 264, 68.9%), opioids (n = 110, 28.7%) and oral NSAIDs (n = 14, 3.7%). Overall, 116 (30.3%) residents were categorized as having daytime sleepiness. Of those with dementia, 77 (45.6%) were categorized as having daytime sleepiness. Opioid use in the previous 24 h was not associated with daytime sleepiness in unadjusted or adjusted analyses. Paracetamol use was positively associated with daytime sleepiness (OR 2.31; 95% CI 1.20-4.42). CONCLUSION: Although daytime sleepiness occurred in a large number of residents, especially those with dementia, this sleepiness was not necessarily associated with use of opioids. The risk of opioid-induced sedation may have been managed by strategies including preferential prescribing of paracetamol to residents at risk of sleepiness, opioid discontinuation in residents who experienced sleepiness, and use of low doses of opioids. PMID- 26612598 TI - Renal Injury After Endovascular Aneurysm Repair: An Overlooked Entity. PMID- 26612599 TI - Modified Sandwich-graft Technique Employing Aorfix and Viabahn Stent-grafts to Preserve Hypogastric Flow in Cases of Complex Aortoiliac and Isolated Common Iliac Artery Aneurysms Including the Internal Iliac Artery Ostium. AB - OBJECTIVE: The aim was to assess the early and mid-term safety and clinical outcomes of a modified sandwich-graft technique (MSGT) that employed the Aorfix and Viabahn stent-grafts to preserve hypogastric flow in cases of complex aortoiliac and isolated common iliac artery (CIA) aneurysms including internal iliac artery (IIA) ostium who were not suitable for an iliac branch device (IBD). METHODS: A review of prospective collected data of all consecutive cases of treatment of complex aortoiliac or isolated CIA aneurysms including IIA ostium using the MSGT to preserve the hypogastric flow in three European centres between April 1, 2010, and December 31, 2013, was performed. All patients included were unfit for open repair and not suitable for an IBD. RESULTS: During the study period, 21 patients met the study criteria and had 25 MSGTs. The mean follow-up duration was 17.2 months. The technical success rate was 100%, with no perioperative mortality and stent-graft or MSGT-treated IIA occlusions. There were two cases with Type Ib endoleaks and one Type III endoleaks intraoperatively that were successfully managed. There was also no reported early and late pelvic ischaemia. The primary patency rate was 90.5%, and two cases of MGST treated IIA occlusions with no reported symptoms of pelvic ischaemia during follow-up. CONCLUSIONS: MSGT was a safe and feasible strategy to preserve hypogastric flow in cases of complex aortoiliac and isolated CIA aneurysms including IIA ostium and who were not suitable for IBD, with encouraging early and mid-term outcomes. PMID- 26612601 TI - Long noncoding RNAs in hematopoietic malignancies. AB - Recent years have witnessed the discovery of several classes of noncoding RNAs (ncRNAs), which are indispensable for the regulation of cellular processes. Many of these RNAs are regulatory in nature with functions in gene expression regulation such as piwi-interacting RNAs, small interfering RNAs and micro RNAs. Long noncoding RNAs (lncRNAs) comprise the most recently characterized class. LncRNAs are involved in transcriptional regulation, chromatin remodeling, imprinting, splicing, and translation, among other critical functions in the cell. Recent studies have elucidated the importance of lncRNAs in hematopoietic development. Dysregulation of lncRNA expression is a feature of various diseases and cancers, and is also seen in hematopoietic malignancies. This article focuses on lncRNAs that have been implicated in the pathogenesis of hematopoietic malignancies. PMID- 26612600 TI - Antibacterial effect of roselle extracts (Hibiscus sabadariffa), sodium hypochlorite and acetic acid against multidrug-resistant Salmonella strains isolated from tomatoes. AB - Antibiotic-resistant Salmonella strains were isolated from saladette and red round type tomatoes, and an analysis done of the antibacterial activity of roselle calyx extracts against any of the identified strains. One hundred saladette tomato samples and 100 red round tomato samples were collected from public markets. Each sample consisted of four whole tomatoes. Salmonella was isolated from the samples by conventional culture procedure. Susceptibility to 16 antibiotics was tested for the isolated Salmonella strains by standard test. The antibacterial effect of four roselle calyx extracts (water, methanol, acetone and ethyl acetate), sodium hypochlorite and acetic acid against antibiotic-resistant Salmonella isolates was evaluated on contaminated tomatoes. Twenty-four Salmonella strains were isolated from 12% of each tomato type. Identified Salmonella serotypes were Typhimurium and Typhi. All isolated strains exhibited resistance to at least three antibiotics and some to as many as 12. Over contaminated tomatoes, the roselle calyx extracts produced a greater reduction (2 2.6 log) in antibiotic-resistant Salmonella strain concentration than sodium hypochlorite and acetic acid. SIGNIFICANCE AND IMPACT OF THE STUDY: The presence of multidrug-resistant Salmonella in vegetables is a significant public health concern. Multidrug-resistant Salmonella strains were isolated from raw tomatoes purchased in public markets in Mexico and challenged with roselle Hibiscus sabdariffa calyx extracts, sodium hypochlorite and acetic acid. On tomatoes, the extracts caused a greater reduction in the concentration of antibiotic-resistant Salmonella strains than sodium hypochlorite and acetic acid. Roselle calyx extracts are a potentially useful addition to disinfection procedures of raw tomatoes in the field, processing plants, restaurants and homes. PMID- 26612603 TI - MicroRNAs in Bladder Outlet Obstruction: Relationship to Growth and Matrix Remodelling. AB - The discovery of microRNAs (miRNAs), which are ~22 nucleotide RNAs that inhibit protein synthesis in a sequence-specific manner and are present in a range of species, has born hope of new therapeutic strategies. miRNAs play important roles in development and disease, but they remain poorly studied in uropathologies beyond cancer. Here, we discuss biological functions of miRNAs in the lower urogenital tract. A special focus is on miRNAs that change in bladder outlet obstruction (BOO). This is a condition that affects nearly one third of all men over 60 years and that involves growth and fibrosis of the urinary bladder. Animal models of BOO, such as that in rat, have been developed, and they feature a massive 6-fold bladder growth over 6 weeks. Using microarrays, we have charted the miRNAs that change during the time course of this process and identified several with important modulatory roles. We discuss known and predicted functions of miR-1, miR-29, miR-30, miR-132/212, miR-204 and miR-221, all of which change in BOO. The majority of the miRNA-mediated influences in BOO are expected to favour growth. We also outline evidence that miR-29 represents a key effector molecule in a generic response to mechanical distension that is designed to counteract exaggerated organ deformation via effects on matrix deposition and stiffness. We conclude that miRNAs play important roles in bladder remodelling and growth and that they may be targeted pharmacologically to combat diseases of the lower urinary tract. PMID- 26612604 TI - The influence of (central) auditory processing disorder in speech sound disorders. AB - INTRODUCTION: Considering the importance of auditory information for the acquisition and organization of phonological rules, the assessment of (central) auditory processing contributes to both the diagnosis and targeting of speech therapy in children with speech sound disorders. OBJECTIVE: To study phonological measures and (central) auditory processing of children with speech sound disorder. METHODS: Clinical and experimental study, with 21 subjects with speech sound disorder aged between 7.0 and 9.11 years, divided into two groups according to their (central) auditory processing disorder. The assessment comprised tests of phonology, speech inconsistency, and metalinguistic abilities. RESULTS: The group with (central) auditory processing disorder demonstrated greater severity of speech sound disorder. The cutoff value obtained for the process density index was the one that best characterized the occurrence of phonological processes for children above 7 years of age. CONCLUSION: The comparison among the tests evaluated between the two groups showed differences in some phonological and metalinguistic abilities. Children with an index value above 0.54 demonstrated strong tendencies towards presenting a (central) auditory processing disorder, and this measure was effective to indicate the need for evaluation in children with speech sound disorder. PMID- 26612605 TI - The multivariate Wright-Fisher process with mutation: Moment-based analysis and inference using a hierarchical Beta model. AB - We consider the diffusion approximation of the multivariate Wright-Fisher process with mutation. Analytically tractable formulas for the first-and second-order moments of the allele frequency distribution are derived, and the moments are subsequently used to better understand key population genetics parameters and modeling frameworks. In particular we investigate the behavior of the expected homozygosity (the probability that two randomly sampled genes are identical) in the transient and stationary phases, and how appropriate the Dirichlet distribution is for modeling the allele frequency distribution at different evolutionary time scales. We find that the Dirichlet distribution is adequate for the pure drift model (no mutations allowed), but the distribution is not sufficiently flexible for more general mutation models. We suggest a new hierarchical Beta distribution for the allele frequencies in the Wright-Fisher process with a mutation model on the nucleotide level that distinguishes between transitions and transversions. PMID- 26612607 TI - Activation of Electron-Deficient Quinones through Hydrogen-Bond-Donor-Coupled Electron Transfer. AB - Quinones are important organic oxidants in a variety of synthetic and biological contexts, and they are susceptible to activation towards electron transfer through hydrogen bonding. Whereas this effect of hydrogen bond donors (HBDs) has been observed for Lewis basic, weakly oxidizing quinones, comparable activation is not readily achieved when more reactive and synthetically useful electron deficient quinones are used. We have successfully employed HBD-coupled electron transfer as a strategy to activate electron-deficient quinones. A systematic investigation of HBDs has led to the discovery that certain dicationic HBDs have an exceptionally large effect on the rate and thermodynamics of electron transfer. We further demonstrate that these HBDs can be used as catalysts in a quinone-mediated model synthetic transformation. PMID- 26612606 TI - Rrp6: Integrated roles in nuclear RNA metabolism and transcription termination. AB - The yeast RNA exosome is a eukaryotic ribonuclease complex essential for RNA processing, surveillance, and turnover. It is comprised of a barrel-shaped core and cap as well as a 3'-5' ribonuclease known as Dis3 that contains both endo- and exonuclease domains. A second exonuclease, Rrp6, is added in the nucleus. Dis3 and Rrp6 have both shared and distinct roles in RNA metabolism, and this review will focus primarily on Rrp6 and the roles of the RNA exosome in the nucleus. The functions of the nuclear exosome are modulated by cofactors and interacting partners specific to each type of substrate. Generally, the cofactor TRAMP (Trf4/5-Air2/1-Mtr4 polyadenylation) complex helps unwind unstable RNAs, RNAs requiring processing such as rRNAs, tRNAs, or snRNAs or improperly processed RNAs and direct it toward the exosome. In yeast, Rrp6 interacts with Nrd1, the cap-binding complex, and RNA polymerase II to aid in nascent RNA processing, termination, and polyA tail length regulation. Recent studies have shown that proper termination and processing of short, noncoding RNAs by Rrp6 is particularly important for transcription regulation across the genome and has important implications for regulation of diverse processes at the cellular level. Loss of proper Rrp6 and exosome activity may contribute to various pathologies such as autoimmune disease, neurological disorders, and cancer. WIREs RNA 2016, 7:91-104. doi: 10.1002/wrna.1317 For further resources related to this article, please visit the WIREs website. PMID- 26612608 TI - Rapid fat suppression for three-dimensional echo planar imaging with minimized specific absorption rate. AB - PURPOSE: To investigate a method for rapid water excitation with minimal radiofrequency power deposition for efficient functional MRI at ultrahigh fields. THEORY AND METHODS: The suitability of the spectral response of a single rectangular radiofrequency pulse (rect) as a replacement of conventional fat saturation in segmented three-dimensional (3D) echo planar imaging (EPI) is explored. A pulse duration formula for lipid signal nulling independent of the small-tip-angle approximation is derived and tested by means of simulations and experiments at 3 and 7 Tesla (T). RESULTS: Compared with conventional binomial-11 water excitation, the single rect method is more selective and less sensitive to shim imperfections. In functional MRI, a significant measurement speedup (25%) and specific absorption rate reduction (from 44% to 1% at 7T) compared with conventional fat saturation are achieved. Furthermore, magnetization transfer effects are reduced resulting in up to 25% higher brain tissue signal-to-noise ratio. CONCLUSION: The proposed method is well suited for whole-brain functional MRI, not only at ultra-high fields, as it maximizes the sensitivity per unit time and at the same time minimizes radiofrequency power deposition. It requires little implementation effort and may thus be used in other spatially nonselective imaging methods that require fat suppression at minimal specific absorption rate and time requirements. Magn Reson Med 76:1517-1523, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26612602 TI - Antibiotic use and good practice in 314 French hospitals: The 2010 SPA2 prevalence study. AB - OBJECTIVES: We aimed to assess antibiotic prescriptions to identify potential targets for improvement. METHODS: We conducted a point prevalence survey (November 2010) of antibiotic use in 314 voluntary hospitals recruited by the French Infectious Diseases Society (SPILF) and the National Observatory for Epidemiology of Bacterial Resistance to Antimicrobials (ONERBA). Data were entered online, immediately analyzed and exported. RESULTS: The prevalence of antibiotic use was 19.5% (9059/46,446patients). A higher prevalence was observed in the infectious disease (58.4%), hematology (58%), and intensive care (48.7%) units. The three most frequently used antibiotic classes were aminopenicillins (23.8%), fluoroquinolones (17.9%), and 3rd-generation cephalosporins (16.7%). A monotherapy was prescribed to 64% of patients. The reasons for the antibiotic prescription were written in the medical records of 74% of patients and 62% were consistent with the local guidelines. CONCLUSION: Our results are similar to that of other studies. Various local targets for improvement have been identified to help hospitals define a better antibiotic stewardship. PMID- 26612609 TI - Nephrotoxicity during tenofovir treatment: a three-year follow-up study in a Brazilian reference clinic. AB - In this study, 275 patients in use of tenofovir were retrospectively followed-up for three years to evaluate risk factors involved in impaired renal function. Analysis of variance (ANOVA) and Tukey's test were used to verify any differences in creatinine levels and estimated clearance at 0, 6, 12, 24 and 36 months, adjusting for the co-variables sex, skin color, age >50 years, arterial hypertension, diabetes and the use of the ritonavir-boosted protease inhibitors (PI/r) lopinavir/r or atazanavir/r. The software package STATISTICA 10((r)) was used for statistical analysis. The patients' mean age was 43.2+/-10.7 years. Systemic arterial hypertension (SAH) and diabetes were found in 20.4% and 8.7% of the patients, respectively. Overall, 96.7% were on tenofovir associated with lamivudine (TDF+3TC), 39.3% on lopinavir/r, 29.8% on efavirenz, and 17.6% on atazanavir/r. There was a statistically significant difference in estimated creatinine clearance at 24 months, when the co-variables male (F=3.95; p=0.048), SAH (F=6.964; p=0.009), and age over 50 years (F=45.81; p<0.001) were taken into consideration. Analysis of the co-variable use of atazanavir/r showed a tendency toward an increased risk over time (F=2.437; p=0.063); however, no significant time interaction was seen. At 36-month, a statistically significant difference was found for age over 50 years, (F=32.02; p<0.05) and there was a significant time-by-sex interaction (F=3.117; p=0.0149). TDF was discontinued in 12 patients, one because of a femoral neck fracture (0.7%) and 11 due to nephrotoxicity (4%). Of these latter cases, 9/11 patients were also using protease inhibitors. These data strongly alert that tenofovir use should be individualized with careful attention to renal function especially in male patients, over 50 years, with SAH, and probably those on ATV/r. PMID- 26612610 TI - The progene hypothesis: the nucleoprotein world and how life began. AB - In this article, I review the results of studies on the origin of life distinct from the popular RNA world hypothesis. The alternate scenario postulates the origin of the first bimolecular genetic system (a polynucleotide gene and a polypeptide processive polymerase) with simultaneous replication and translation and includes the following key features: 1. The bimolecular genetic system emerges not from mononucleotides and monoamino acids, but from progenes, namely, trinucleotides aminoacylated on 3'-end by a non-random amino acid (NpNpNp ~ pX ~ Aa, where N--deoxyribo- or ribonucleoside, p--phosphate, X--a bifunctional agent, for example ribose, Aa--amino acid, ~ macroerge bond). Progenes are used as substrates for simultaneous synthesis of a polynucleotide and a polypeptide. Growth of the system is controlled by the growing polypeptide, and the bimolecular genetic system emerges as an extremely rare event. The first living being (virus-like organism protoviroid, Protoviroidum primum) arises and reproduces in prebiotic liposome-like structures using progenes. A population of protoviroids possessing the genetic system evolves in accordance with the Darwinian principle. Early evolution from protoviroid world to protocell world is shortly described. 2. The progene forming mechanism (NpNp + Np ~ pX ~ Aa) makes it possible to explain the emergence of the prebiotic physicochemical group genetic code, as well as the selection of organic compounds for the future genetic system from the racemic environment. 3. The protoviroid is reproduced on a progene basis via replicative transcription-translation (RTT, the first molecular genetic process) that is similar to its modern counterparts. Nothing is required for the emergence and reproduction of the protoviroid except for progenes and conditions for their formation. 4. The general scheme of early evolution is as follows: prebiotic world -> protoviroid (nucleoprotein) world -> protocell (DNA-RNA-protein) world -> LUCA (Last Universal Common Ancestor) -> modern cell world. This scheme exclude the existence of an independent RNA world as predecessor of the cellular world. PMID- 26612611 TI - Attitudes towards the sharing of genetic information with at-risk relatives: results of a quantitative survey. AB - To investigate public attitudes towards receiving genetic information arising from a test on a relative, 955 University of Sheffield students and staff were surveyed using disease vignettes. Strength of attitude was measured on whether, in the event of relevant information being discovered, they, as an at-risk relative, would want to be informed, whether the at-risk relative's interest should override proband confidentiality, and, if they had been the proband, willingness to give up confidentiality to inform such relatives. Results indicated considerably more complexity to the decision-making than simple statistical risk. Desire for information only slightly increased with risk of disease manifestation [log odds 0.05 (0.04, 0.06) per percentage point increase in manifestation risk]. Condition preventability was the primary factor increasing desire [modifiable baseline, non-preventable log odds -1.74 (-2.04, 1.44); preventable 0.64 (0.34, 0.95)]. Disease seriousness also increased desire [serious baseline, non-serious log odds -0.89 (-1.19, -0.59); fatal 0.55 (0.25, 0.86)]. Individuals with lower education levels exhibited much greater desire to be informed [GCSE log odds 1.67 (0.64, 2.66)]. Age did not affect desire. Our findings suggest that attitudes were influenced more by disease characteristics than statistical risk. Respondents generally expressed strong attitudes demonstrating that this was not an issue which people felt ambivalent about. We provide estimates of the British population in favour/against disclosure for various disease scenarios. PMID- 26612612 TI - Successful management of ivermectin-induced blindness in an African lion (Panthera leo) by intravenous administration of a lipid emulsion. AB - BACKGROUND: Ivermectin is widely used in veterinary practice for the treatment of ecto- and endo-parasites. In wildlife, an extra-label use this parasiticide is sometimes associated with toxicity. Different treatment regimens have been used in ivermectin toxicosis. The present report describes a successful reversal of ivermectin toxicity by intravenous administration of a commercially available lipid emulsion in a captive African lion (Panthera leo). CASE PRESENTATION: A 2 year old captive African lion (Panthera leo) weighing ~130 kg was presented with acute neurological impairment and bilateral blindness that had developed 24 h after ivermectin exposure. The animal was treated with a commercially available lipid emulsion along with supportive therapy and experienced complete recovery. CONCLUSION: To our knowledge, this is the first case report of the use of lipid emulsion in the management of ivermectin induced blindness in an African lion and it appears that intravenous lipid emulsion may be an effective therapy in ivermectin toxicity in lions. Further testing in expanded clinical trials is clearly warranted. PMID- 26612614 TI - Low-dose prophylaxis for severe haemophilia: a little goes a long way. PMID- 26612613 TI - Cognitive screening tools in multiple sclerosis revisited: sensitivity and specificity of a short version of Rao's Brief Repeatable Battery. AB - BACKGROUND: Cognitive deficits are common in multiple sclerosis (MS) and require continuous monitoring. In routine examinations, screening instruments such as the Brief Repeatable Battery (BRB) may serve this purpose. It was suggested that even a shortened version of the BRB, comprising the Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT) and Selective Reminding Test (SRT), may be feasible. However, an evaluation of sensitivity and specificity of the short BRB in comparison to an independent battery of established tests has not yet occurred. Therefore in the current study, this short version of the BRB was matched against the gold standard of an extensive test battery comprehensively assessing neuropsychological functions. METHODS: 127 MS-patients were tested with a short version of the BRB and an extensive procedure. The latter served as the gold standard for defining sensitivity and specificity. RESULTS: For subtests of the short BRB, estimates of sensitivity (38-44 %) and specificity (81-94 %) were obtained. Combining subtests into a single indicator of cognitive deficits yielded increased sensitivity (78 %), while reducing specificity (65 %). CONCLUSION: The short BRB is reasonably sensitive and specific in detecting cognitive deficits. However, these qualities only emerge, if the short BRB is administered as a whole, whereas sensitivity is considerably lower than suggested by previous work, when relying on subtests separately (SDMT, PASAT, SRT). While the short BRB may not be regarded as conclusive as an extensive test battery, it represents a valid and economic screening instrument. PMID- 26612615 TI - Catalytic-independent inhibition of cIAP1-mediated RIP1 ubiquitination by EGLN3. AB - EGLN3 belongs to the EGLN family of prolyl hydroxylases that are able to catalyze the hydroxylation of proteins such as the alpha subunits of hypoxia-inducible factor. We and others have shown that EGLN3 negatively regulates the canonical NFkappaB pathway. Mechanistically, we demonstrated that EGLN3 inhibits ubiquitination of IKKgamma (the regulatory subunit of IkappaB kinase complex) which is vitally important for NFkappaB activation. Polyubiquitination of the RIP1 (receptor-interacting protein 1) kinase is important for NFkappaB activation triggered by tumor necrosis factor alpha. It remains to be determined whether EGLN3 is able to modulate RIP1 ubiquitination catalyzed by cIAP1 (cellular inhibitor of apoptosis protein 1). This study shows that EGLN3 interacts with cIAP1 and suppresses cIAP1-mediated RIP1 ubiquitination via the C-terminal region. The hydroxylase activity is not required for the ability of EGLN3 to restrain RIP1 ubiquitination. Furthermore, EGLN3 is a novel binding protein of RIP1. The C-terminal region of EGLN3 is responsible for its interaction with RIP1. EGLN3 hydroxylase activity is not essential for the EGLN3-RIP1 interaction. EGLN3 interferes with the association between RIP1 and cIAP1, and attenuates RIP1 induced NFkappaB activation. This study provides novel insight into the mechanism underlying EGLN3 inhibition of NFkappaB signaling and sheds light on the regulation of RIP1 ubiquitination. PMID- 26612616 TI - Effects of the nicotinic agonist varenicline on the performance of tasks of cognition in aged and middle-aged rhesus and pigtail monkeys. AB - RATIONALE: Due to the rising costs of drug development especially in the field of neuropsychiatry, there is increasing interest in efforts to identify new clinical uses for existing approved drugs (i.e., drug repurposing). OBJECTIVES: The purpose of this work was to evaluate in animals the smoking cessation agent, varenicline, a partial agonist at alpha4beta2 and full agonist at alpha7 nicotinic acetylcholine receptors, for its potential as a repurposed drug for disorders of cognition. METHODS: Oral doses of varenicline ranging from 0.01 to 0.3 mg/kg were evaluated in aged and middle-aged monkeys for effects on the following: working/short-term memory in a delayed match to sample (DMTS) task, distractibility in a distractor version of the DMTS (DMTS-D), and cognitive flexibility in a ketamine-impaired reversal learning task. RESULTS: In dose effect studies in the DMTS and DMTS-D tasks, varenicline was not associated with statistically significant effects on performance. However, individualized "optimal doses" were effective when repeated on a separate occasion (i.e., improving DMTS accuracy at long delays and DMTS-D accuracy at short delays by approximately 13.6 and 19.6 percentage points above baseline, respectively). In reversal learning studies, ketamine impaired accuracy and increased perseverative responding, effects that were attenuated by all three doses of varenicline that were evaluated. CONCLUSIONS: While the effects of varenicline across the different behavioral tasks were modest, these data suggest that varenicline may have potential as a repurposed drug for disorders of cognition associated with aging (e.g., Alzheimer's disease), as well as those not necessarily associated with advanced age (e.g., schizophrenia). PMID- 26612617 TI - Enhanced cocaine-induced locomotor sensitization and intrinsic excitability of NAc medium spiny neurons in adult but not in adolescent rats susceptible to diet induced obesity. AB - RATIONALE: Basal and diet-induced differences in mesolimbic function, particularly within the nucleus accumbens (NAc), may contribute to human obesity; these differences may be more pronounced in susceptible populations. OBJECTIVES: We examined differences in cocaine-induced behavioral plasticity in rats that are susceptible vs. resistant to diet-induced obesity and basal differences in striatal neuron function in adult and in adolescent obesity-prone and obesity resistant rats. METHODS: Susceptible and resistant outbred rats were identified based on "junk-food" diet-induced obesity. Then, the induction and expression of cocaine-induced locomotor sensitization, which is mediated by enhanced striatal function and is associated with increased motivation for rewards and reward paired cues, were evaluated. Basal differences in mesolimbic function were examined in selectively bred obesity-prone and obesity-resistant rats (P70-80 and P30-40) using both cocaine-induced locomotion and whole-cell patch clamping approaches in NAc core medium spiny neurons (MSNs). RESULTS: In rats that became obese after eating junk-food, the expression of locomotor sensitization was enhanced compared to non-obese rats, with similarly strong responses to 7.5 and 15 mg/kg cocaine. Without diet manipulation, obesity-prone rats were hyper responsive to the acute locomotor-activating effects of cocaine, and the intrinsic excitability of NAc core MSNs was enhanced by ~60 % at positive and negative potentials. These differences were present in adult, but not adolescent rats. Post-synaptic glutamatergic transmission was similar between groups. CONCLUSIONS: Mesolimbic systems, particularly NAc MSNs, are hyper-responsive in obesity-prone individuals, and interactions between predisposition and experience influence neurobehavioral plasticity in ways that may promote weight gain and hamper weight loss in susceptible rats. PMID- 26612618 TI - Exploring the therapeutic potential of Ayahuasca: acute intake increases mindfulness-related capacities. AB - BACKGROUND: Ayahuasca is a psychotropic plant tea used for ritual purposes by the indigenous populations of the Amazon. In the last two decades, its use has expanded worldwide. The tea contains the psychedelic 5-HT2A receptor agonist N,N dimethyltryptamine (DMT), plus beta-carboline alkaloids with monoamine-oxidase inhibiting properties. Acute administration induces an introspective dream-like experience characterized by visions and autobiographic and emotional memories. Studies of long-term users have suggested its therapeutic potential, reporting that its use has helped individuals abandon the consumption of addictive drugs. Furthermore, recent open-label studies in patients with treatment-resistant depression found that a single ayahuasca dose induced a rapid antidepressant effect that was maintained weeks after administration. Here, we conducted an exploratory study of the psychological mechanisms that could underlie the beneficial effects of ayahuasca. METHODS: We assessed a group of 25 individuals before and 24 h after an ayahuasca session using two instruments designed to measure mindfulness capacities: The Five Facets Mindfulness Questionnaire (FFMQ) and the Experiences Questionnaire (EQ). RESULTS: Ayahuasca intake led to significant increases in two facets of the FFMQ indicating a reduction in judgmental processing of experiences and in inner reactivity. It also led to a significant increase in decentering ability as measured by the EQ. These changes are classic goals of conventional mindfulness training, and the scores obtained are in the range of those observed after extensive mindfulness practice. CONCLUSIONS: The present findings support the claim that ayahuasca has therapeutic potential and suggest that this potential is due to an increase in mindfulness capacities. PMID- 26612619 TI - Prospective memory impairments in heavy social drinkers are partially overcome by future event simulation. AB - BACKGROUND: Recent research suggests that alcohol acutely impairs prospective memory (PM), and this impairment can be overcome using a strategy called 'future event simulation' (FES). Impairment in event-based PM found in detoxifying alcohol-dependent participants is reversed through FES. However, the impact of the most common problematic drinking patterns that do not involve alcohol dependence on PM remains unclear. AIMS: Here, we examine the impact of frequent heavy drinking on PM and the degree to which any impairments can be reversed through FES. METHODS: PM was assessed in 19 heavy drinkers (AUDIT scores >= 15) and 18 matched control participants (AUDIT scores <= 7) using the 'Virtual Week' task both at baseline and again following FES. RESULTS: Heavy drinkers performed significantly worse than controls on regular and irregular time-based PM tasks. FES improved the performance of controls but not of heavy drinkers on time-based tasks. In contrast, FES improved heavy drinkers' performance on event-based PM tasks. CONCLUSIONS: These findings suggest that heavy drinkers experience deficits in strategic monitoring processing associated with time-based PM tasks which do not abate after FES. That the same strategy improves their event-based PM suggests that FES may be helpful for individuals with problematic drinking patterns in improving their prospective memory. PMID- 26612620 TI - Negative allosteric modulation of GABAA receptors inhibits facilitation of brain stimulation reward by drugs of abuse in C57BL6/J mice. AB - RATIONALE: There is an emerging body of evidence that implicates a crucial role of gamma-aminobutyric acid subtype A (GABAA) receptors in modulating the rewarding effects of a number of abused drugs. Modulation of GABAA receptors may therefore represent a novel drug-class independent mechanism for the development of abuse treatment pharmacotherapeutics. OBJECTIVES: We tested the hypothesis that the GABAA receptor benzodiazepine-site (BDZ) negative modulator Ro15-4513 would reduce the reward-related effects of three pharmacologically dissimilar drugs; toluene vapor, d-methamphetamine, and diazepam using intracranial self stimulation (ICSS) in mice. We also examined whether Ro15-4513 attenuated dopamine release produced by d-methamphetamine in an in vivo microdialysis procedure. RESULTS: Ro15-4513 abolished ICSS reward facilitation produced by all three abused drugs at Ro15-4513 doses which had no effect on ICSS when administered alone. In contrast, the BDZ antagonist flumazenil only attenuated the ICSS-facilitating effects of diazepam. Administration of the same dose of Ro15-4513 which abolished drug-facilitated ICSS produced a 58 % decrease in d methamphetamine-stimulated dopamine in the nucleus accumbens of mice relative to d-methamphetamine alone. CONCLUSIONS: These results demonstrate that negative modulation of GABAA receptors can produce profound reductions in reward-related effects of a diverse group of drugs that activate the mesolimbic reward pathway through different mechanisms. These data suggest that pharmacological modulation of GABAA receptors may represent a viable pathway for the development of drug abuse pharmacotherapies. PMID- 26612621 TI - Time-Kill Kinetics and In Vitro Antifungal Susceptibility of Non-fumigatus Aspergillus Species Isolated from Patients with Ocular Mycoses. AB - Aspergillus species can cause ocular morbidity and blindness, and thus, appropriate antifungal therapy is needed. We investigated the in vitro activity of itraconazole, voriconazole, posaconazole, caspofungin, anidulafungin, and amphotericin B against 14 Aspergillus isolates obtained from patients with ocular mycoses, using the CLSI reference broth microdilution methodology. In addition, time-kill assays were performed, exposing each isolate separately to 1-, 4-, and 16-fold concentrations above the minimum inhibitory concentration (MIC) of each antifungal agent. A sigmoid maximum-effect (E max) model was used to fit the time kill curve data. The drug effect was further evaluated by measuring an increase/decrease in the killing rate of the tested isolates. The MICs of amphotericin B, itraconazole, voriconazole, and posaconazole were 0.5-1.0, 1.0, 0.5-1.0, and 0.25 ug/ml for A. brasiliensis, A. niger, and A. tubingensis isolates, respectively, and 2.0-4.0, 0.5, 1.0 for A. flavus, and 0.12-0.25 ug/ml for A. nomius isolates, respectively. A. calidoustus had the highest MIC range for the azoles (4.0-16.0 ug/ml) among all isolates tested. The minimum effective concentrations of caspofungin and anidulafungin were <=0.03-0.5 ug/ml and <=0.03 ug/ml for all isolates, respectively. Posaconazole demonstrated maximal killing rates (E(max) = 0.63 h(-1), r(2) = 0.71) against 14 ocular Aspergillus isolates, followed by amphotericin B (E(max) = 0.39 h(-1), r(2) = 0.87), voriconazole (E(max) = 0.35 h(-1), r(2) = 0.098), and itraconazole (E(max) = 0.01 h(-1), r(2) = 0.98). Overall, the antifungal susceptibility of the non-fumigatus Aspergillus isolates tested was species and antifungal agent dependent. Analysis of the kinetic growth assays, along with consideration of the killing rates, revealed that posaconazole was the most effective antifungal against all of the isolates. PMID- 26612622 TI - Exosomes from hypoxic endothelial cells have increased collagen crosslinking activity through up-regulation of lysyl oxidase-like 2. AB - Exosomes are important mediators of intercellular communication. Additionally, they contain a variety of components capable of interacting with the extracellular matrix (ECM), including integrins, matrix metalloproteinases and members of the immunoglobin superfamily. Despite these observations, research on exosome-ECM interactions is limited. Here, we investigate whether the exosome associated lysyl oxidase family member lysyl oxidase-like 2 (LOXL2) is involved in ECM remodelling. We found that LOXL2 is present on the exterior of endothelial cell (EC)-derived exosomes, placing it in direct vicinity of the ECM. It is up regulated twofold in EC-derived exosomes cultured under hypoxic conditions. Intact exosomes from hypoxic EC and LOXL2 overexpressing EC show increased activity in a fluorometric lysyl oxidase enzymatic activity assay as well as in a collagen gel contraction assay. Concordantly, knockdown of LOXL2 in exosome producing EC in both normal and hypoxic conditions reduces activity of exosomes in both assays. Our findings show for the first time that ECM crosslinking by EC derived exosomes is mediated by LOXL2 under the regulation of hypoxia, and implicate a role for exosomes in hypoxia-regulated focal ECM remodelling, a key process in both fibrosis and wound healing. PMID- 26612623 TI - Predictive factors on the efficacy and risk/intensity of tooth sensitivity of dental bleaching: A multi regression and logistic analysis. AB - OBJECTIVES: The aim of this study was to identify predictor factors associated with the whitening outcome and risk and intensity of bleaching-induced tooth sensitivity from pooled data of 11 clinical trials of dental bleaching performed by the same research group. METHODS: The individual patient data of several published and ongoing studies about dental bleaching was collected and retrospectively analyzed. At the patient-level, independent variables (bleaching techniques [at-home and in-office protocols], sex, age and baseline tooth color in shade guide unit [SGU]) as well as dependent variables (color change in shade guide units (DeltaSGU), color change in the CIEL*a*b* system (DeltaE), risk and intensity of TS in a visual analog scale) were collected. Multivariable linear regression and multivariable logistic regression models were carried out using backward elimination whenever the p-values were higher than 0.05. RESULTS: A significant relationship between baseline color and age on color change estimates was detected (p<0.001). Every increase of one SGU in the baseline color resulted in an increase of approximate 0.66 in the final DeltaSGU and 2.48 for the DeltaE. For every increase of one year in the participant's age we observed a decrease of the whitening degree of 0.07 for the final DeltaSGU and 0.69 for the DeltaE. The bleaching technique was shown to be a significant predictor of DeltaSGU (p<0.001) but not of DeltaE. In regard to TS, baseline color and bleaching technique are significant predictors (p<0.001). The risk of TS for at-home bleaching was 51% (95% CI 41.4-60.6) and for the in-office 62.9% (95% CI 56.9-67.3). CONCLUSIONS: Younger patients with darker teeth reach a higher degree of whitening. Patient with darker teeth and submitted to at-home bleaching presents lower risk and intensity of TS. CLINICAL SIGNIFICANCE: The baseline color of the teeth and the patient's age is directly related to the effectiveness of dental bleaching and TS. PMID- 26612625 TI - Identification of Central Nervous System Proteins in Human Blood Serum and Plasma. AB - Mass-spectrometric identification of proteins in human blood plasma and serum was performed by comparing mass-spectra of fragmented peptides using Swiss-Prot and UniProtKB databases of amino acid sequences. After choosing the appropriate identification conditions we found that combination of spectrum search parameters are optimal for identification of CNS proteins. In the studied plasma and serum samples, 9 proteins involved into pathological processes in the nervous tissue were identified; 7 of them were identified in both plasma and serum. PMID- 26612624 TI - Conditioned media from hypoxic-cultured human dental pulp cells promotes bone healing during distraction osteogenesis. AB - Distraction osteogenesis (DO) is a surgical procedure used to correct various skeletal disorders. Improving the technique by reducing the healing time would be of clinical relevance. The aim of this study was to determine the angiogenic and regenerative potential of conditioned media (CMs) collected from human dental pulp cells (hDPCs) grown under different culture conditions. CM collected from cells under hypoxia was used to improve bone healing and the DO procedure in vivo. The angiogenic potentials of CMs collected from hDPCs grown under normoxic (-Nor) and hypoxic (-Hyp) conditions were evaluated by quantitative PCR (VEGF-A, angiopoietin-1, angiopoietin-2, interleukin-6 (IL-6) and CXCL12), ELISA assays (VEGF-A, Ang-2), tube-formation and wound-healing assays, using human umbilical vein endothelial cells. The results demonstrated that hypoxic CM had significantly higher angiogenic potential than normoxic CM. Human fetal osteoblasts (hFOBs) were exposed to CM, followed by alizarin red staining, to assess the osteogenic potential. It was found that CM did not enhance the mineralization capacity of hFOBs. DO was performed in the tibiae of 30 mice, followed by a local injection of 20 ul CM (CM-Nor and CM-Hyp groups) or serum free DMEM (control group) into the distraction zone every second day. The mice were sacrificed at days 13 and 27. The CM-Hyp treatment revealed a higher X-ray density than the control group (p < 0.05). Our study suggests that the angiogenic effect promoted by hypoxic culture conditions is dependent on VEGF-A and Ang-2 released from hDPCs. Furthermore, CM-Hyp treatment may thus improve the DO procedure, accelerating bone healing. (c) 2015 The Authors. Journal of Tissue Engineering and Regenerative Medicine published by John Wiley & Sons, Ltd. PMID- 26612626 TI - Production and Analysis of Biological Properties of Recombinant Human Apolipoprotein A-I. AB - Production of recombinant human apolipoprotein A-I (apoA-I) in E. coli cells is described and its biological properties are compared with those of natural protein. Recombinant apoA-I was isolated as a chimeric polypeptide and then processed to a mature form apoA-I (rapo-I). We studied the ability of the resulting protein to penetrate into hepatocyte nuclei and regulate the rate of DNA biosynthesis in complex with estriol. Penetration of rapoA-I conjugated with FITC into hepatocyte nuclei was demonstrated. rapoA-I-estriol and apoA-I-estriol complexes induced similar increase in DNA biosynthesis rate in isolated hepatocytes, which confi rms functional similarity of the obtained recombinant mature protein (rapoA-I) and native human apoA-I. PMID- 26612627 TI - Probabilistic numerical discrimination in mice. AB - Previous studies showed that both human and non-human animals can discriminate between different quantities (i.e., time intervals, numerosities) with a limited level of precision due to their endogenous/representational uncertainty. In addition, other studies have shown that subjects can modulate their temporal categorization responses adaptively by incorporating information gathered regarding probabilistic contingencies into their time-based decisions. Despite the psychophysical similarities between the interval timing and nonverbal counting functions, the sensitivity of count-based decisions to probabilistic information remains an unanswered question. In the current study, we investigated whether exogenous probabilistic information can be integrated into numerosity based judgments by mice. In the task employed in this study, reward was presented either after few (i.e., 10) or many (i.e., 20) lever presses, the last of which had to be emitted on the lever associated with the corresponding trial type. In order to investigate the effect of probabilistic information on performance in this task, we manipulated the relative frequency of different trial types across different experimental conditions. We evaluated the behavioral performance of the animals under models that differed in terms of their assumptions regarding the cost of responding (e.g., logarithmically increasing vs. no response cost). Our results showed for the first time that mice could adaptively modulate their count based decisions based on the experienced probabilistic contingencies in directions predicted by optimality. PMID- 26612629 TI - Erratum to: Gecko proteins induce the apoptosis of bladder cancer 5637 cells by inhibiting Akt and activating the intrinsic caspase cascade. AB - The BMB Reports would like to correct in the reference of BMB Rep. 48(9), 531-536 titled "Gecko proteins induce the apoptosis of bladder cancer 5637 cells by inhibiting Akt and activating the intrinsic caspase cascade". The ACKNOWLEDGEMENTS should be corrected as follows, "This work was supported by the National Research Foundation of Korea (NRF-2010-0009086, NRF-2012R1A1A2039992, and 2012M3A9C7050184) and the Brain Busan 21 Project." and not "This work was partially supported by the National Research Foundation of Korea (NRF-2010 0009086, NRF-2003-003-C00110, and 2012M3A9C7050184) and the Brain Busan 21 Project." The online version reflects this change. PMID- 26612628 TI - Examining the effects of adjuvant chemotherapy on cognition and the impact of any cognitive impairment on quality of life in colorectal cancer patients: study protocol. AB - BACKGROUND: Research suggests that chemotherapy can cause deficits in both patients' objectively measured and self-reported cognitive abilities which can in turn affect their quality of life (QoL). The majority of research studies have used post-treatment retrospective designs or have not included a control group in prospective cohorts. This has limited the conclusions that can be drawn from the results. There have also been a disproportionate number of studies focussed on women with breast cancer, which has limited the generalisability of the results to other cancer populations. AIM: This study aims to identify the extent and impact of chemotherapy-induced cognitive decline in colorectal cancer patients. Possible associations with poorer QoL will also be explored. DESIGN: This will be a longitudinal controlled cohort study. Questionnaires measuring subjective cognitive functioning, QoL, fatigue and mood, and neuropsychological assessments of objective cognitive function will be collected pre-, mid- and post- chemotherapy treatment from a consecutive sample of 78 colorectal cancer patients from five London NHS Trusts. A further 78 colorectal cancer surgery only patients will be assessed at equivalent time points; this will allow the researchers to compare the results of patients undergoing surgery, but not chemotherapy against those receiving both treatments. Pre- and post-chemotherapy difference scores will be calculated to detect subtle changes in cognitive function as measured by the objective neuropsychological assessments and the self-reported questionnaires. A standardised z-score will be computed for every patient on each neuropsychological test, and for each test at each time point. The post chemotherapy score will then be subtracted from the pre-chemotherapy score to produce a relative difference score for each patient. ANCOVA will be used to compare mean difference z-scores between the chemotherapy and surgery-only groups while controlling for the effects of gender, age, depression, anxiety, fatigue and education. DISCUSSION: The result from this study will indicate whether a decline in cognitive functioning can be attributed to chemotherapy or to disease, surgical or some other confounding factor. Identification of risk factors for cognitive deficits may be used to inform targeted interventions, in order to improve QoL and help patients' cope. PMID- 26612630 TI - Mechanistic Insights into the Mode of Action of Bifunctional Pyrrolidine Squaramide-Derived Organocatalysts. AB - The catalytic modes of action of three squaramide-derived bifunctional organocatalysts have been investigated using DFT methods. The [5+2] cycloaddition between oxidopyrylium ylides and enals was used as the model reaction. Two primary modes were possible for the different catalysts studied. The preference for one mode over the other was due to the possibility of additional favorable pi pi interactions between the hydrogen-bond activated pyrylium ylide and an electron-deficient aromatic ring bonded to the squaramide NH group. The model can be extended to other reactions catalyzed by the same catalysts, such as formal [2+2] cycloadditions between nitroalkenes and alpha,beta-unsaturated aldehydes. The computational results were in excellent concurrence with the available experimental reports on the observed total enantioselectivity and differences in diastereoselectivity depending on the substrate and the reaction. PMID- 26612631 TI - Outpatient outcomes and satisfaction in pediatric population: data from the postoperative phone call. AB - BACKGROUND: Quality and patient/parent satisfaction are goals for pediatric perioperative services. As part of the implementation of our operating room electronic medical record (EMR), a postoperative phone call questionnaire was developed to assess patients discharged after outpatient surgery. The goal of this initiative was to determine the rate of common postoperative complications and understand reasons for patient/parent dissatisfaction. METHODS: Institutional Review Board approval was obtained for chart review. The postoperative phone call survey was attempted by our postanesthesia care unit nursing staff on all pediatric outpatients. The call was attempted for 3 days. From 2009 to 2013, more than 37 000 phone records existed in our EMR, Epic Optime (Epic Systems, Verona, WI). These data were extracted to a business intelligence (BI) program, QlikView (Qliktech, Radnor, PA, USA). A BI dashboard was constructed to obtain phone call results for any given time frame from monthly to spanning several years. Complications were logged as 4-point severity rating scales (none, mild, moderate, severe) with descriptions for each level. The BI dashboard calculated the overall and rates by severity for the following: (i) nausea, (ii) vomiting, (iii) pain, (iv) bleeding, (v) hoarseness, and (vi) difficulty eating. RESULTS: Of 42 688 outpatient cases, 37 620 postoperative phone calls were completed for an overall response rate of 88%. Pain, at 11.1%, was the highest reported postoperative complication. The rate of dissatisfaction was reported to be 0.31%. Most patients reporting dissatisfaction (62%) did not report any complications. Contingency coefficient showed that there was little relationship between satisfaction and presence of complications. CONCLUSION: A postoperative phone survey is cost-effective and appreciated by patients. We found that satisfaction with our perioperative services was not related to the rates of reported complications. Although reducing complications is of utmost importance, improvements in wait times and other operational issues would yield greater improvements in satisfaction. PMID- 26612633 TI - Clinical Outcomes of the Flexor Carpi Ulnaris Turnover Flap for Posterior Elbow Soft Tissue Defects. AB - PURPOSE: To report the clinical outcomes from 2 academic centers of the flexor carpi ulnaris (FCU) flap for coverage of posterior elbow soft tissue defects. METHODS: We retrospectively reviewed 17 patients who underwent an FCU flap for posterior elbow wound reconstruction over an 8-year period at 2 academic centers. Outcome measures included visual analog score for pain; Disabilities of the Arm, Shoulder, and Hand score; Mayo Elbow Performance score; range of motion; wound healing; grip strength; and isokinetic dynamometry for wrist flexion. Wilcoxon signed-rank test was used to make side-to-side comparisons between the operative and nonsurgical extremities, and nonparametric statistical methods were used to analyze results. RESULTS: All wounds healed successfully without need for revision surgery. Average visual analog, Disabilities of the Arm, Shoulder, and Hand, and Mayo Elbow Performance scores in the operative elbow were 1.8, 34, and 86, respectively. Average elbow arc of motion was 11 degrees to 140 degrees with 70 degrees forearm pronation and 73 degrees forearm supination. Compared with the nonsurgical side, grip strength on the operated side was 97% and wrist flexion peak torque was 89%. The operative limb had an average wrist flexion fatigue of 7%, compared with 22% for the nonsurgical arm. CONCLUSIONS: Patients receiving an FCU flap had reliable healing, minimal pain, good functional outcomes, and no meaningful deficits in grip strength or wrist flexion strength. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26612634 TI - Recurrent Compartment Syndrome Leading to the Diagnosis of McArdle Disease: Case Report. AB - Glycogen storage disorders are rare diseases of metabolism that are usually diagnosed when a patient presents with recurrent fatigue, muscle pains, and exercise intolerance. In this case report, we describe a patient who presented with the second episode of nontraumatic compartment syndrome over a 10-year span. Because of the obscure presentation, we performed a muscle biopsy, which on muscle phosphorylase staining revealed McArdle disease (glycogen storage disease type V). PMID- 26612635 TI - Total Wrist Arthroplasty: A Single-Center Study of 219 Cases With 5-Year Follow up. AB - PURPOSE: To assess implant survival and radiographic loosening after total wrist arthroplasty (TWA) operated at a single tertiary referral center in Sweden. METHODS: In a prospective cohort study, we evaluated 189 consecutive patients with a TWA (219 wrists). The wrists were implanted between 2002 and 2013. The primary end point was revision for any reason. The mean follow-up period was 7 years (range, 2-13 years). In addition, radiological examination was done for evidence of prosthetic loosening 5 years postoperatively. Implant survival was estimated using the Kaplan-Meier method. Secondary outcome measures included range of motion, visual analog scale pain scores, hand grip strength, and patient related outcome measures. RESULTS: Cumulative implant survival after 8 years was 81% for Biax, 94% for Remotion, and 95% for Maestro implants. Radiographic loosening was present in 26% of wrists with the Biax design, 18% of those with Remotion, and 2% of those with Maestro. Visual analog scale pain scores and patient-related outcome scores improved significantly for all TWAs. Improved hand grip strength was noted for all TWAs except for the Universal 2. Range of motion improved somewhat, especially for the Biax and Maestro TWAs. CONCLUSIONS: Good midterm to long-term results were achieved in patients undergoing TWA. Radiographic loosening did not necessarily correlate with implant survival rates, but rather to severe arthritic destruction of the wrist preoperatively. All TWA implants studied offered a high level of patient satisfaction. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 26612636 TI - Arthroscopic Partial Capitate Resection for Type Ia Avascular Necrosis: A Short Term Outcome Analysis. AB - PURPOSE: To examine short-term clinical results of arthroscopic partial resection for type Ia avascular necrosis of the capitate. METHODS: Patients who underwent arthroscopic treatment for type 1a avascular necrosis of the capitate with at least 1-year follow-up were identified through a retrospective chart review. The necrotic capitate head was arthroscopically resected with removal of the lunate facet and preservation of the scaphoid and hamate facets. Wrist range of motion, grip strength, and radiographic parameters--carpal height ratio, radioscaphoid angle, and radiolunate angle-were determined before surgery and at the latest follow-up. Patients completed a visual analog scale for pain; Disabilities of the Arm, Shoulder, and Hand measure; and the Patient-Rated Wrist Evaluation score before surgery and at the latest follow-up. RESULTS: Five patients (1 male, 4 females) with a mean age of 34 years (range, 16-49 years) and a mean follow-up duration of 20 months (range, 12-36 months) were identified during the chart review. All were type Ia (Milliez classification). Arthroscopy revealed fibrillation or softening with cartilage detachment at the lunate facet of the capitate head and an intact articular surface at the scaphoid and hamate facet. At the latest follow-up, the mean wrist flexion-extension was 123 degrees (vs 81 degrees before surgery) and grip strength was 74% (vs 37% before surgery). The visual analog scale score for pain; the Disabilities of the Arm, Shoulder, and Hand score; and the Patient-Rated Wrist Evaluation score before surgery showed a significant improvement following treatment. Radiographic parameters did not significantly change at the final follow-up, although the proximal carpal row trended toward flexion. CONCLUSIONS: Arthroscopic partial resection of the capitate head was an acceptable treatment for type Ia avascular necrosis of the capitate. It provided adequate pain relief and improved the range of wrist motion and grip strength during short-term follow-up. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26612637 TI - Perceptions of Emergency Medicine Residency and Hand Surgery Fellowship Program Directors in the Appropriate Disposition of Upper Extremity Emergencies. AB - PURPOSE: To survey emergency medicine (EM) residency and hand surgery fellowship program directors (PDs) to identify consensus in their perceptions of appropriate emergency care of upper extremity emergencies. METHODS: We created a framework to group common upper extremity emergency diagnoses and surveyed PDs to evaluate the training background--EM, general orthopedic or plastic surgery, or hand fellowship--most appropriate to provide acute, point-of-care management for each of these diagnostic groupings. Responses were pooled and consensus was established with greater than 75% agreement between groups. RESULTS: We received 79 responses from hand fellowship PDs (90% response rate) and 151 responses from EM PDs (49% response rate). We identified consensus for the training background that PDs in both specialties felt was appropriate to care for 17 of 21 diagnostic groupings in the framework. CONCLUSIONS: There was a high level of consensus between EM and hand surgery PDs regarding diagnoses that acutely require training in hand surgery versus those that can be managed by an EM physician. Our diagnostic framework may help reduce unnecessary hand surgery consultation and may help to identify patients who do not require more specialized acute care and thus decrease unnecessary transfers. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic and Decision Analyses IV. PMID- 26612638 TI - Forget What the Statisticians Told You: Size Matters. Commentary on "The Relationship Between Catastrophic Thinking and Hand Diagram Areas". PMID- 26612639 TI - Southern California Society for Surgery of the Hand (SCSSH) Award for JHS 2014 Article of the Year. PMID- 26612640 TI - Melanoma in an Amputated Fingertip. PMID- 26612641 TI - Letter Regarding "A 10- or 12-Strand Core Suture in a Flexor Tendon in Zones I, II, and III". PMID- 26612642 TI - In Reply. PMID- 26612643 TI - Overview of PAF-Degrading Enzymes. AB - Because the acetyl group of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF) is essential for its biological activity, the degradation of PAF is the most important mechanism that regulates the level of PAF. The enzyme that catalyzes the hydrolysis of acetyl group at the sn-2 position of PAF was termed PAF acetylhydrolase (PAF-AH). Subsequent research revealed that the PAF-AH family includes intracellular forms called PAF-AH I and PAF-AH II as well as an extracellular isoform, plasma PAF-AH. PAF-AH I forms a complex consisting of catalytic subunits alpha1, alpha2, and beta regulatory subunits. PAF-AH I was identified from the brain, and previous studies focused on the role of PAF-AH I in brain development. However, subsequent studies found that PAF-AH I is involved in diverse functions such as spermatogenesis, amyloid-beta generation, cancer pathogenesis, and protein trafficking. Another intracellular enzyme, PAF-AH II, has no homology with PAF-AH I, although this enzyme shares sequence similarity to plasma PAF-AH. Because PAF-AH preferentially hydrolyzes oxidatively modulated or truncated phospholipids, it is considered to play a protective role against oxidative stress. Homologs of this enzyme are widely distributed among evolutionarily diverse organisms. For example, studies of Caenorhabditis elegans PAF-AH II demonstrate its contribution to epidermal morphogenesis. Extracellular plasma PAF-AH associates strongly with plasma lipoproteins. Because PAF-AH is mainly associated with LDL particles, it is considered to play an anti inflammatory role by removing oxidized phospholipids generated in LDLs exposed to oxidative stress. In this overview, we describe the crucial roles of these three PAF-degrading enzymes in cell function and cell pathology. PMID- 26612644 TI - Intracellular PAF-Acetylhydrolase Type I. AB - Platelet-activating factor (PAF) is a phospholipid mediator whose synthesis and degradation depend on specific sets of enzymes. PAF-acetylhydrolase (PAF-AH) hydrolyzes the acetyl moiety of PAF at its sn-2 position and thereby inactivates it. PAF-AH Ib, originally identified in brain, exists in the cytoplasm of many (probably all) types of mammalian cells and tissues. PAF-AH Ib consists of three subunits (alpha1, alpha2, and beta), in which the alpha subunits provide the catalytic activity. The finding that the beta subunit is the product of the causative gene for Miller-Dieker lissencephaly led to extensive analyses of PAF AH Ib subunits in the field of cell biology and neurobiology. More than 20 molecules are known to bind to PAF-AH Ib subunits, and PAF-AH Ib has been implicated in neuronal development, neuronal functions, Alzheimer's disease, bipolar disorder, cancer, spermatogenesis, and tolerance to hypoxia. However, in almost all of these cases, how the catalytic activity is involved and the identity of the most important substrate of this enzyme are unclear. In this chapter, the structure and functions of PAF-AH Ib and its subunit proteins are summarized and their contributions to human diseases are discussed. PMID- 26612645 TI - Platelet-Activating Factor Acetylhydrolase and Brain Development. AB - The heterotrimeric brain platelet-activating factor acetylhydrolase (PAFAH1B1) contains two catalytic subunits and a regulatory subunit. This complex plays important, surprising roles in brain development and in spermatogenesis. The regulatory subunit, PAFAH1B1 (LIS1 protein), is critically regulated and when deficient leads to the devastating human neurological disorder Lissencephaly, or smooth brain. The role of the protein in brain development is not the catalysis of platelet-activating factor, rather the entire brain platelet-activating factor acetylhydrolase complex serves a signaling role, coordinating important pathways in brain development. The role of this complex in spermatogenesis was not foreseen, but appears to function to regulate a critical level of the PAFAH1B1 protein, such that too much of this protein or too little of this protein can lead to a disruption of spermatogenesis. Brain platelet-activating factor is thus a signaling complex, important for brain development and for spermatogenesis. PMID- 26612647 TI - Trafficking and Oligomeric Regulation of Platelet-Activating Factor Acetylhydrolase Type II. AB - Platelet-activating factor acetylhydrolase type II, PAFAH-II, is an intracellular phospholipase A2 enzyme present in various tissues and cells. PAFAH-II hydrolyzes a known phospholipid-derived mediator, platelet-activating factor, as well as oxidatively fragmented phospholipids in cellular membranes. Although the crystal structure of PAFAH-II remains unsolved, homology modeling has provided insight into the components of its structure that are necessary for membrane localization and binding. PAFAH-II contains an N-terminal myristoyl tail as well as two hydrophobic helices that help to control the oligomeric state and the association of the enzyme to membranes. This chapter presents an overview of the experimental methods and results that have developed our current understanding of the trafficking of PAFAH-II to the cellular membranes, as well as the enzyme's natural oligomeric states related to its function. PMID- 26612646 TI - Intracellular Platelet-Activating Factor Acetylhydrolase, Type II: A Unique Cellular Phospholipase A2 That Hydrolyzes Oxidatively Modified Phospholipids. AB - Intracellular platelet-activating factor acetylhydrolase, type II [PAF-AH (II)] is a monomeric 40kDa enzyme that was originally purified as an enzyme that hydrolyzes the acetyl group of PAF (1-O-alkyl-2-acetyl-sn-glycero-3 phosphocholine). It can also hydrolyze phospholipids with short length or oxidatively modified sn-2 acyl chains, whereas it can hardly hydrolyze phospholipids with two long fatty acyl chains. PAF-AH (II) is the only phospholipase A2 that is myristoylated at its N-terminus and is evolutionarily conserved from lower organisms to mammals. Studies using cultured cells and mice suggest that PAF-AH (II) functions as an antioxidant phospholipase. Here, we will review our current understanding of PAF-AH (II) and discuss its potential functions in physiological and pathological conditions. PMID- 26612648 TI - Plasma PAF-AH (PLA2G7): Biochemical Properties, Association with LDLs and HDLs, and Regulation of Expression. AB - This chapter is focused on the plasma form of PAF-acetylhydrolase (PAF-AH), a lipoprotein-bound, calcium-independent phospholipase A2 activity also referred to as lipoprotein-associated phospholipase A2 and PLA2G7. PAF-AH catalyzes the removal of the acyl group at the sn-2 position of PAF and truncated phospholipids generated in settings of inflammation and oxidant stress. Here, I discuss current knowledge related to the structural features of this enzyme, including the molecular basis for association with lipoproteins and susceptibility to oxidative inactivation. The circulating form of PAF-AH is constitutively active and its expression is upregulated by mediators of inflammation at the transcriptional level. Several new mechanisms of regulation have been identified in recent years, including effects mediated by PPARs, VEGFR, and the state of cellular differentiation. Moreover, I discuss recent studies describing significant variations in the structure and regulation of PAF-AH from diverse species, which is likely to have important implications for the function of this enzyme in vivo. PMID- 26612649 TI - Crystal Structure and Atomic Level Analysis of Plasma PAF-AH. AB - The structure of plasma PAF-AH was solved to a resolution of 1.5A using X-ray crystallography. The enzyme has a classic alpha/beta serine hydrolase fold containing a catalytic triad of Ser273, Asp296, and His351. A hydrophobic patch of the enzyme involving two alpha-helices (114-126 and 362-369) and neighboring residues have been shown to be essential for lipoprotein particle binding by mutagenesis and mass spectrometry hydrogen/deuterium exchange experiments. An interface-bound model of the enzyme positions the active site above the hydrophobic-hydrophilic interface and is consistent with the known substrate specificity of the enzyme. Several ligand-bound structures of plasma PAF-AH have been solved with organophosphorus compounds and modeled with competitive inhibitors of high affinity and selectivity. This chapter presents an overview of the structure of plasma PAF-AH, molecular details of its functional role, and the interaction of the enzyme with lipoprotein particles. PMID- 26612650 TI - Naturally Occurring Missense Mutation in Plasma PAF-AH Among the Japanese Population. AB - A single nucleotide polymorphism in the plasma PAF-AH enzyme, i.e., G994T, which causes the substitution of Val at amino acid 279 with Phe (V279F), has been found in the Japanese population. This enzyme preferentially degrades oxidatively modulated or truncated phospholipids; therefore, it has been suggested that this enzyme may prevent the accumulation of proinflammatory and proatherogenic oxidized phospholipids. This hypothesis is supported by the higher prevalence of the V279F mutation in patients with asthmatic and atherosclerotic diseases, as compared with healthy controls. This mutation is rare in the Caucasian population. The plasma PAF-AH mass and enzyme activity are distributed over a wide range in the plasma and they are positively correlated with low-density lipoprotein (LDL) cholesterol. However, several clinical studies in the Caucasian population have suggested that this enzyme has the opposite role. This enzyme plays an active role in the development and progression of atherosclerosis via proinflammatory and proatherogenic lysophosphatidylcholine and oxidized fatty acids produced through the oxidation of LDL by this enzyme. Thus, plasma PAF-AH is a unique enzyme with dual roles in human inflammatory diseases. In this chapter, on the basis of recent findings we describe the association between a naturally occurring missense mutation in plasma PAF-AH and human diseases especially including atherosclerosis and asthma. PMID- 26612651 TI - Plasma PAFAH/PLA2G7 Genetic Variability, Cardiovascular Disease, and Clinical Trials. AB - PAFAH is specific for short acyl groups esterified at the sn-2 position of glycerol in phospholipids, and apart from PAF, it hydrolyzes oxidized phospholipids produced during LDL oxidation. As the majority of the plasma PAFAH activity is bound in humans to LDL, it is also called the lipoprotein-associated phospholipase A2 (Lp-PLA2), and it was associated with the proinflammatory processes in atherosclerosis. The epidemiological studies in Caucasian populations demonstrated that high PAFAH levels might be a risk factor for cardiovascular disease through generation of proinflammatory lysoPC/lysoPAF and oxidized fatty free acids and led to the development of darapladib, a reversible PAFAH inhibitor. In the preclinical study in diabetic and hypercholesterolemic pigs, darapladib decreased both plasma and in situ lesion PAFAH/Lp-PLA2 activity, reduced lesion lysoPC content, and also reduced the complex coronary lesion development by reducing the necrotic core. In the recently published double-blind trial with darapladib (STABILITY study), it was shown that darapladib did not affect the time to cardiovascular death, myocardial infarction, or stroke. Similarly, in the SOLID-TIMI 52 study, darapladib did not reduce the risk of major coronary events; for those reasons, the clinical trials with darapladib will probably definitely stop in this pathology. Finally, in the absence of a tangible effect of V279F loss-of-function mutation on the cardiovascular risk in Asiatic populations and no effect of A379V polymorphism which modifies PAFAH activity in Caucasians, combined with no effect of the anti-PAFAH/Lp-PLA2 drug darapladib in clinical trials, let us conclude that it is unlikely that PAFAH could be implicated in atherosclerosis per se. We rather believe that PAFAH/Lp PLA2 is a biomarker of atherosclerosis. PMID- 26612653 TI - Preface. PMID- 26612652 TI - Diverse Functions of Plasma PAF-AH in Tumorigenesis. AB - This chapter is focused on the role of the plasma form of platelet-activating factor-acetylhydrolase (PAF-AH), heretofore referred to as PAF-AH, in tumorigenic responses. Biochemical and other properties of this enzyme were discussed in detail in chapter "Plasma PAF-AH (PLA2G7): Biochemical Properties, Association with LDLs and HDLs, and Regulation of Expression" by Stafforini and in other chapters. Although phospholipases tend not to be drivers of tumorigenesis themselves, these enzymes and the lipid mediators whose levels they regulate interact with a variety of oncogenes and tumor suppressors [1]. Like other phospholipases, the functions of PAF-AH in cancer likely are related to its ability to regulate the levels of lipid mediators that participate in cellular processes related to initial tumorigenic events (e.g., proliferation, growth, inflammation) and/or spreading of the disease (e.g., matrix metalloproteinase secretion, actin cytoskeleton reorganization, migration, and angiogenesis) [1]. The importance of substrates and products of PAF-AH on key cellular functions has been evaluated in cell-based analyses which revealed that these metabolites can have pro- and antitumorigenic functions. Studies in genetically engineered mice lacking PAF-AH expression and genetic manipulation of PAF-AH levels in cancer cells demonstrated diverse functions of the protein in models of melanoma, prostate cancer, colon cancer, and others. The following sections highlight lessons learned from studies in cell lines and in mouse models regarding the diversity of functions of PAF-AH in cancer, and the potential of PAFAH transcripts, protein, and/or activity levels to become cancer biomarkers and therapeutic targets. PMID- 26612654 TI - Anti-apoptotic and anti-inflammatory effects of naringin on cisplatin-induced renal injury in the rat. AB - Nephrotoxicity is a common complication of cisplatin chemotherapy and thus limits the use of cisplatin in clinic. Naringin, a natural flavonoid, plays important roles in inflammation and apoptosis in some inflammatory diseases; however, its roles in cisplatin-induced nephrotoxicity remain unclear. In this study, we first assessed the involvement of ROS overproduction and inflammation in cisplatin induced nephrotoxicity in aged rats, and then we investigated the changes of renal function, histological injury, inflammatory response, and apoptosis in renal tissues after treatment with naringin (20, 50 or 100 mg/kg body weight). Cisplatin resulted in an increase of renal markers, lipid peroxidation, protein and DNA oxidation, and ROS formation. Renal tumor necrosis factor-alpha (TNF alpha) and nitrite levels were also elevated. Expressions of nuclear factor-kappa B (NF-kappaB), inductible nitric oxide synthase (iNOS), caspase-3 and p53 were up regulated in renal tissues of Cis-treated rats compared with the normal control group. Histopathological changes were also observed in cisplatin group. Adminstration of naringin at different doses (25, 50 and 100 mg/kg) was able to protect against the deterioration in kidney function, abrogate the decline in antioxidant enzyme activities and suppressed the increase in TBARS, nitrite and TNF-alpha concentrations. Moreover, naringin inhibited NF-kappaB and iNOS pathways, caspase-3 and p53 activation and improved the histological changes induced by cisplatin. In conclusion, our studies suggest that oxidative stress and inflammation might play important roles in the development of cisplatin induced nephrotoxicity and naringin might become an effective therapeutic strategy for this disease. PMID- 26612655 TI - SZC015, a synthetic oleanolic acid derivative, induces both apoptosis and autophagy in MCF-7 breast cancer cells. AB - Breast cancer is one of the most common cancers among women with high mortality and morbidity. The present study was aimed to investigate the cytotoxic mechanism of SZC015, a synthetic oleanolic acid (OA) derivative, in MCF-7 human breast cancer cells. SZC015 reduced MCF-7 cell viability with an IC50 value of only 24.19 MUM at 24 h by activating both apoptosis and autophagy pathways. More specifically, we found that SZC015 was able to activate intrinsic apoptosis, which was proved by activations of caspase3, caspase9, release of cytochrome C, cleavage of PARP and increasing ratio of Bax/Bcl-2. SZC015 induced autophagy in MCF-7 cells evidenced by the increase of LC3II/LC3I and up-regulation of Atg5 and beclin1. Moreover, these two cell death pathways were modulated by inhibiting phosphatidylinositide 3-kinase/protein kinase B/mammalian target of rapamycin/nuclear factor-kappaB (PI3K/Akt/mTOR/NF-kappaB), mitogen-activated protein kinase (MAPK) signaling pathways. SZC015 also induced S phase cell cycle arrest in MCF-7 cells. Furthermore, analysis of topoisomerase I (Top I) and topoisomerase IIalpha (Top IIalpha) proteins suggested that SZC015 may interfere the DNA topological phenomenon. The computer-assisted molecular docking study also showed SZC015 had lower interaction energy with Top I and Top IIalpha than that of OA. In conclusion, the current study revealed SZC015 played an important role in the regulation of autophagy and apoptosis in breast cancer cells. PMID- 26612656 TI - Bardoxolone methyl prevents the development and progression of cardiac and renal pathophysiologies in mice fed a high-fat diet. AB - Obesity caused by the consumption of a high-fat (HF) diet is a major risk factor for the development of associated complications, such as heart and kidney failure. A semi-synthetic triterpenoid, bardoxolone methyl (BM) was administrated to mice fed a HF diet for 21 weeks to determine if it would prevent the development of obesity-associated cardiac and renal pathophysiologies. Twelve week old male C57BL/6J mice were fed a lab chow (LC), HF (40% fat), or a HF diet supplemented with 10 mg/kg/day BM in drinking water. After 21 weeks, the left ventricles of hearts and cortex of kidneys of mice were collected for analysis. Histological analysis revealed that BM prevented HF diet-induced development of structural changes in the heart and kidneys. BM prevented HF diet-induced decreases in myocyte number in cardiac tissue, although this treatment also elevated cardiac endothelin signalling molecules. In the kidneys, BM administration prevented HF diet-induced renal corpuscle hypertrophy and attenuated endothelin signalling. Furthermore, in both the hearts and kidneys of mice fed a HF diet, BM administration prevented HF diet-induced increases in fat accumulation, macrophage infiltration and tumour necrosis factor alpha (TNFalpha) gene expression. These findings suggest that BM prevents HF diet-induced developments of cardiac and renal pathophysiologies in mice fed a chronic HF diet by preventing inflammation. Moreover, these results suggest that BM has the potential as a therapeutic for preventing obesity-induced cardiac and renal pathophysiologies. PMID- 26612657 TI - Why there might not be an evolutionary explanation for psychological altruism. AB - The existence of psychological altruism is hotly debated in the psychological and philosophical literature. In this paper I argue that even if psychological altruism does exist in some (or all) human groups, there may be no purely evolutionary explanation for existence of psychological altruism. PMID- 26612658 TI - Unconscious bias harms patients and staff. PMID- 26612659 TI - Anti-Outer membrane protein C antibodies in colorectal neoplasia. AB - Sporadic colorectal cancer (CRC) represents an enormous problem worldwide. Large intestinal microbiota play an important role in the colorectal carcinogenesis. The aim of the study was to investigate anti-Outer membrane protein C (anti-OmpC) antibodies, aimed at porin C, which is embedded in the outer membrane of gram negative bacteria, in patients with colorectal adenoma (CRA), CRC and controls. The study included 22 patients with CRA (11 men, 11 women, aged 26-79, mean 65 +/ 12), 11 patients with CRC (9 men, 2 women, aged 50-83, mean 66 +/- 11) and 45 controls, blood donors (24 men, 21 women, aged 20-58, mean 38 +/- 10). Serum anti OmpC antibodies were investigated by means of ELISA. Values of 0-20 U/mL were considered to be negative; values >25 U/mL were assessed as positive. A total of 9/11 (82 %) patients with CRC had positive anti-OmpC antibodies. Anti-OmpC antibodies were negative or grey-zone in 37/45 (82 %) controls. Serum anti-OmpC were found to be significantly higher in patients with CRC (median 42.4, interquartile range (IQR) 22.2) compared to controls (median 18.3, IQR 12.4), p < 0.001. No statistically significant difference in anti-OmpC was found between controls (median 18.3, IQR 12.4) and CRA patients (median 17.7, IQR 16.5), p = 0.326. Anti-OmpC were significantly higher in patients with CRC (median 42.4, IQR 22.2) compared to patients with CRA (median 17.7, IQR 16.5), p = 0.011. Positivity of anti-OmpC antibodies was found in patients with CRC, which supports the contribution of gram-negative large intestinal microbiota to the pathogenesis of CRC. PMID- 26612661 TI - Tailoring luminescence color conversion via affinitive co-assembly of glutamates appended with pyrene and naphthalene dicarboximide units. AB - Structural matching of two organic building blocks bearing glutamate units and different luminophores assembled into unilamellar nanovesicles in aqueous media through a co-assembly process. Aggregation-induced energy transfer took place in the co-assembled system, leading to controllable generation of multiple luminescence colors including white light. PMID- 26612660 TI - Genome-wide scan for selection signatures in six cattle breeds in South Africa. AB - BACKGROUND: The detection of selection signatures in breeds of livestock species can contribute to the identification of regions of the genome that are, or have been, functionally important and, as a consequence, have been targeted by selection. METHODS: This study used two approaches to detect signatures of selection within and between six cattle breeds in South Africa, including Afrikaner (n = 44), Nguni (n = 54), Drakensberger (n = 47), Bonsmara (n = 44), Angus (n = 31) and Holstein (n = 29). The first approach was based on the detection of genomic regions in which haplotypes have been driven towards complete fixation within breeds. The second approach identified regions of the genome that had very different allele frequencies between populations (F ST). RESULTS AND DISCUSSION: Forty-seven candidate genomic regions were identified as harbouring putative signatures of selection using both methods. Twelve of these candidate selected regions were shared among the breeds and ten were validated by previous studies. Thirty-three of these regions were successfully annotated and candidate genes were identified. Among these genes the keratin genes (KRT222, KRT24, KRT25, KRT26, and KRT27) and one heat shock protein gene (HSPB9) on chromosome 19 between 42,896,570 and 42,897,840 bp were detected for the Nguni breed. These genes were previously associated with adaptation to tropical environments in Zebu cattle. In addition, a number of candidate genes associated with the nervous system (WNT5B, FMOD, PRELP, and ATP2B), immune response (CYM, CDC6, and CDK10), production (MTPN, IGFBP4, TGFB1, and AJAP1) and reproductive performance (ADIPOR2, OVOS2, and RBBP8) were also detected as being under selection. CONCLUSIONS: The results presented here provide a foundation for detecting mutations that underlie genetic variation of traits that have economic importance for cattle breeds in South Africa. PMID- 26612662 TI - Identification of regulated proteins in naked barley grains (Hordeum vulgare nudum) after Fusarium graminearum infection at different grain ripening stages. AB - We analyzed the effect of Fusarium graminearum infection on field-grown naked barley (Hordeum vulgare nudum). The ears were inoculated with F. graminearum spores during anthesis. In the course of ripening, grains in five phenological growth stages of naked barley from milk ripe to plant death were sampled. The albumin and globulin proteins of inoculated grains and untreated (control) grains were separated by two-dimensional gel electrophoresis. Forty-five spots composing of proteins that were changed in abundance due to F. graminearum infection were subsequently identified by mass spectrometry. Various proteins showing altered expression pattern after Fusarium infection were linked to stress response such as plant signal transduction pathways, fungal defense and oxidative burst. More proteins changed during early grain ripening stages than during later ripening stages. Protease inhibitors occurred at increased abundancy during milk ripe stage. A thaumatin-like protein accumulated at plant death stage. Proteins linked to nitrogen metabolism and protein biosynthesis were mainly reduced, whereas those linked to carbon metabolism were predominantly increased in infected grains. BIOLOGICAL SIGNIFICANCE: Fusarium graminearum infection can lead to significant contamination of grains with mycotoxins. With this 2D-based proteomics study we give an insight into plant-pathogen interactions between the non-model plant naked barley and the fungus F. graminearum during five stages of grain development. Over the multiple developmental stages we observed specific patterns of changes induced by the fungus: the primary plant metabolism and inhibition of fungal protease were predominantly affected during early grain development stages. During the entire grain development we found an induced accumulation of thaumatin-like proteins due to the fungal infection indicating their fundamental role for naked barley defense. PMID- 26612663 TI - Proteomic characterization of mucosal secretions in the eastern oyster, Crassostrea virginica. AB - The soft body surface of marine invertebrates is covered by a layer of mucus, a slippery gel secreted by mucocytes lining epithelia. The functions of this gel are diverse including locomotion, cleansing, food particles processing and defense against physicochemical injuries and infectious agents. In oysters, mucus covering pallial organs has been demonstrated to have a major importance in the processing of food particles and in the interactions with waterborne pathogens. Given the limited information available on mucus in bivalves and the apparent wide spectra of activity of bioactive molecules present in this matrix, the characterization of these mucosal secretions has become a research priority. In this study, mucus was separately collected from the mantle, gills and labial palps of the eastern oyster (Crassostrea virginica) and analyzed by liquid chromatography and tandem mass spectrometry. Results showed the presence of a wide variety of molecules involved in host-microbe interactions, including putative adhesion molecules (e.g. c-type lectins) confirming that transcripts previously identified in epithelial cells are translated into proteins secreted in mucus. Mucus composition was different among samples collected from different organs. These results generate a reference map for C. virginica pallial mucus to better characterize the various physiological functions of mucosal secretions. PMID- 26612665 TI - Moving from 'diagnose and treat' to 'predict and pre-empt' in neuropsychiatric disorders. AB - What could be the benefits of moving the treatment paradigm for serious neuropsychiatric disorders towards earlier intervention, and what is needed to achieve this? PMID- 26612667 TI - Glove-related hand urticaria: an increasing occupational problem among healthcare workers. PMID- 26612664 TI - Targeting vascular and leukocyte communication in angiogenesis, inflammation and fibrosis. AB - Regulation of vascular permeability, recruitment of leukocytes from blood to tissue and angiogenesis are all processes that occur at the level of the microvasculature during both physiological and pathological conditions. The interplay between microvascular cells and leukocytes during inflammation, together with the emerging roles of leukocytes in the modulation of the angiogenic process, make leukocyte-vascular interactions prime targets for therapeutics to potentially treat a wide range of diseases, including pathological and dysfunctional vessel growth, chronic inflammation and fibrosis. In this Review, we discuss how the different cell types that are present in and around microvessels interact, cooperate and instruct each other, and in this context we highlight drug targets as well as emerging druggable processes that can be exploited to restore tissue homeostasis. PMID- 26612668 TI - Magnetic resonance imaging evaluation of shoulder joint in patients with early stage of ankylosing spondylitis: A case-control study. AB - PURPOSE: The goal of this prospective study was to determine the prevalence of shoulder abnormalities on magnetic resonance imaging (MRI) in patients with ankylosing spondylitis (AS) who have normal shoulder X-ray examinations and no clinical shoulder abnormalities using a case-control study. MATERIALS AND METHODS: Fifty-three patients with AS according to the SpondyloArthritis international Society (ASAS) criteria were enrolled in the study. Fifty-three patients with no AS served as control subjects. Shoulder MRI examinations of patients in the two groups were analyzed and results were compared. RESULTS: In the patient group, 26/53 patients (49.1%) demonstrated one or two of the defined pathological shoulder MRI findings, whereas 5/53 patients (9.4%) had similar findings in the control group. In the patient group, 11/53 patients (20.8%) had enthesal bone marrow edema, 19/53 patients (35.8%) had increased synovial fluid, 8/53 patients (15.1%) had tendinitis, and 2/53 patients (3.8%) had bursitis. There was statistically significant difference between the patient and control groups in terms of prevalence of enthesal bone marrow edema, increase in synovial fluid, and tendinitis. CONCLUSION: Shoulder involvement is often overlooked in AS. Knowledge of the early-stage findings of the shoulder involvement due to AS is important to establish an early diagnosis and select treatment options. PMID- 26612669 TI - Radiation dose and diagnostic accuracy of high-pitch dual-source coronary angiography in the evaluation of coronary artery stenoses. AB - PURPOSE: "Flash Spiral" imaging is a new prospective ECG-triggered spiral scan mode that uses a very high-pitch for coronary computed tomography angiography (CTA). This enables complete image acquisition within one cardiac cycle with a very low radiation exposure. The aim of this study was to investigate the diagnostic accuracy, image quality, and effective radiation dose of prospectively ECG-triggered high-pitch spiral method (Flash spiral mode) of coronary CTA using dual-source technology for the evaluation of coronary artery stenoses. MATERIAL AND METHODS: The study included 186 consecutive patients (115men, 71women; mean age: 53.37 years) who underwent coronary CTA. Coronary CTA was performed with a 128*2-slice dual-source CT (Somatom Definition Flash, Siemens, Germany) using a prospectively ECG-triggered high-pitch spiral mode. Patients were divided into three groups according to heart rate (<=65bpm, 66-75bpm, >=76bpm) and body mass index (BMI) (20-24kg/m(2), 25-29kg/m(2), 30-34kg/m(2)) values. The correlation between heart rates, image quality and BMI values are investigated. A four-point scale (1=excellent, 4=poor/non-diagnostic) was used to rank the comparative image quality. Effective radiation doses were calculated. Also the correlation between radiation dose, sex and BMI values were investigated. In addition, diagnostic accuracy of CTA for detection of significant (>=50%) coronary artery stenoses was compared with invasive coronary angiography findings of 612vessel segments in 38patients. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy rate were calculated. RESULTS: A total of 2976coronary artery segments were present. Of all coronary artery segments, 2381 (80%) had an image quality score of 1, and 1.5% segments were rated as "poor/non-diagnostic". When the correlation between heart rate and image quality is investigated, there was a significant difference between <=65bpm and >=76bpm groups. However, there was no significant difference between <=65bpm and 66-75bpm groups. The mean effective dose was found as 1.3mSv (min: 0.5, max: 2.4mSv). The correlation between effective radiation dose and BMI was moderate. However, the correlation between gender and radiation dose was significant. Sensitivity, specificity, negative predictive value and accuracy of coronary CTA on a per vessel segment were 90.1%, 97.4%, 98.6%, and 96.5%, respectively. CONCLUSIONS: Prospectively ECG-triggered high-pitch spiral mode coronary CTA provides high image quality and diagnostic accuracy, with very low radiation dose for evaluation and exclusion of coronary artery stenoses. PMID- 26612666 TI - Optogenetics enlightens neuroscience drug discovery. AB - Optogenetics - the use of light and genetics to manipulate and monitor the activities of defined cell populations - has already had a transformative impact on basic neuroscience research. Now, the conceptual and methodological advances associated with optogenetic approaches are providing fresh momentum to neuroscience drug discovery, particularly in areas that are stalled on the concept of 'fixing the brain chemistry'. Optogenetics is beginning to translate and transit into drug discovery in several key domains, including target discovery, high-throughput screening and novel therapeutic approaches to disease states. Here, we discuss the exciting potential of optogenetic technologies to transform neuroscience drug discovery. PMID- 26612670 TI - The road to the synthesis of "difficult peptides". AB - The last decade has witnessed a renaissance of peptides as drugs. This progress, together with advances in the structural behavior of peptides, has attracted the interest of the pharmaceutical industry in these molecules as potential APIs. In the past, major peptide-based drugs were inspired by sequences extracted from natural structures of low molecular weight. In contrast, nowadays, the peptides being studied by academic and industrial groups comprise more sophisticated sequences. For instance, they consist of long amino acid chains and show a high tendency to form aggregates. Some researchers have claimed that preparing medium sized proteins is now feasible with chemical ligation techniques, in contrast to medium-sized peptide syntheses. The complexity associated with the synthesis of certain peptides is exemplified by the so-called "difficult peptides", a concept introduced in the 80's. This refers to sequences that show inter- or intra molecular beta-sheet interactions significant enough to form aggregates during peptide synthesis. These structural associations are stabilized and mediated by non-covalent hydrogen bonds that arise on the backbone of the peptide and depending on the sequence-are favored. The tendency of peptide chains to aggregate is translated into a list of common behavioral features attributed to "difficult peptides" which hinder their synthesis. In this regard, this manuscript summarizes the strategies used to overcome the inherent difficulties associated with the synthesis of known "difficult peptides". Here we evaluate several external factors, as well as methods to incorporate chemical modifications into sequences, in order to describe the strategies that are effective for the synthesis of "difficult peptides". These approaches have been classified and ordered to provide an extensive guide for achieving the synthesis of peptides with the aforementioned features. PMID- 26612671 TI - Development of Endothelial-Specific Single Inducible Lentiviral Vectors for Genetic Engineering of Endothelial Progenitor Cells. AB - Endothelial progenitor cells (EPC) are able to migrate to tumor vasculature. These cells, if genetically modified, can be used as vehicles to deliver toxic material to, or express anticancer proteins in tumor. To test this hypothesis, we developed several single, endothelial-specific, and doxycycline-inducible self inactivating (SIN) lentiviral vectors. Two distinct expression cassettes were inserted into a SIN-vector: one controlled by an endothelial lineage-specific, murine vascular endothelial cadherin (mVEcad) promoter for the expression of a transactivator, rtTA2S-M2; and the other driven by an inducible promoter, TREalb, for a firefly luciferase reporter gene. We compared the expression levels of luciferase in different vector constructs, containing either the same or opposite orientation with respect to the vector sequence. The results showed that the vector with these two expression cassettes placed in opposite directions was optimal, characterized by a robust induction of the transgene expression (17.7- to 73-fold) in the presence of doxycycline in several endothelial cell lines, but without leakiness when uninduced. In conclusion, an endothelial lineage-specific single inducible SIN lentiviral vector has been developed. Such a lentiviral vector can be used to endow endothelial progenitor cells with anti-tumor properties. PMID- 26612672 TI - PExFInS: An Integrative Post-GWAS Explorer for Functional Indels and SNPs. AB - Expression quantitative trait loci (eQTLs) mapping and linkage disequilibrium (LD) analysis have been widely employed to interpret findings of genome-wide association studies (GWAS). With the availability of deep sequencing data of 423 lymphoblastoid cell lines (LCLs) from six global populations and the microarray expression data, we performed eQTL analysis, identified more than 228 K SNP cis eQTLs and 21 K indel cis-eQTLs and generated a LCL cis-eQTL database. We demonstrate that the percentages of population-shared and population-specific cis eQTLs are comparable; while indel cis-eQTLs in the population-specific subsection make more contribution to gene expression variations than those in the population shared subsection. We found cis-eQTLs, especially the population-shared cis-eQTLs are significantly enriched toward transcription start site. Moreover, the National Human Genome Research Institute cataloged GWAS SNPs are enriched for LCL cis-eQTLs. Specifically, 32.8% GWAS SNPs are LCL cis-eQTLs, among which 12.5% can be tagged by indel cis-eQTLs, suggesting the fundamental contribution of indel cis-eQTLs to GWAS association signals. To search for functional indels and SNPs tagging GWAS SNPs, a pipeline Post-GWAS Explorer for Functional Indels and SNPs (PExFInS) has been developed, integrating LD analysis, functional annotation from public databases, cis-eQTL mapping with our LCL cis-eQTL database and other published cis-eQTL datasets. PMID- 26612673 TI - Factors Associated with Time to Arrival at a Regional Pediatric Trauma Center. AB - OBJECTIVE: The goal of this study was to test the hypothesis that the prehospital time between injury and arrival at a trauma center for critically injured children is associated with patient injury severity and mode of transport. METHODS: Secondary analysis of prospectively collected data on children 0-17 years of age admitted with traumatic injuries to a designated Level I pediatric trauma center from January 1, 2006 through September 30, 2007 was conducted. Multivariate regression methods were used to assess for factors independently associated with prehospital time. RESULTS: Of 1,175 admissions during the study period, only 355 (30%) had a prehospital time within 60 minutes of injury. Prehospital time within 60 minutes of injury was associated with higher frequency of coma, higher mean injury severity scores (ISS), and greater frequency of admission to the intensive care unit when compared with prehospital time beyond 60 minutes of injury. Children who arrived at the trauma center within 60 minutes versus beyond 60 minutes were 13-fold (odds ratio [OR]: 12.9; 95% Confidence Interval [CI], 7.6-22.0) more likely to be transported via air ambulance than a private vehicle, and had 4.8-fold greater odds (95% CI, 2.2-10.3) of transport via ground ambulance than private vehicle. For each kilometer of distance between the injury zip code and the trauma center, the odds of arrival within 60 minutes versus beyond 60 minutes decreased by 15% (OR: 0.85; 95% CI, 0.79-0.91). CONCLUSION: Field triage and decision making appeared to correlate with severity of patient injury with expeditious transport of the most severely injured children to definitive trauma care. This finding serves as important groundwork that might enable further study into factors that influence triage and overall prehospital care for critically injured children. PMID- 26612675 TI - Carriage of Neisseria meningitidis in the Hajj and Umrah mass gatherings. AB - Meningococcal disease is a serious public health threat, especially during mass gatherings such as Hajj and Umrah which provide optimal conditions for disease transmission. The disease is caused by Neisseria meningitidis and transmitted mainly via asymptomatic carriers. A review of the literature on asymptomatic N. meningitidis carriage among Hajj and Umrah pilgrims and their household contacts was performed. Carriage studies reported carriage rates to be higher in Hajj pilgrims compared to Umrah pilgrims and that these events promote acquisition of carriage among pilgrims. With some outliers, most studies found carriage rates among pilgrims to be comparable to those in populations under non-epidemic settings. However, these results should be interpreted with caution, taking into account the limitations within the studies identified. A wide variety of N. meningitidis serogroups appear to be circulating among Hajj and Umrah pilgrims, with serogroups W135 and B being most prominent. Current Hajj and Umrah meningococcal disease preventative measures do not necessarily prevent carriage and transmission, which may result in local and international outbreaks among susceptible populations. Monitoring carriage states of visitors and local inhabitants in the Kingdom of Saudi Arabia, as well as the implementation of preventive measures that impact carriage, are warranted to reduce the risk of Hajj and Umrah-related meningococcal disease outbreaks. PMID- 26612676 TI - Radiotherapy for isolated lymph node metastases in patients with locally advanced prostate cancer after primary therapy. AB - PURPOSE: To evaluate the outcome of radiotherapy for isolated lymph node metastases in patients with progression towards castration-resistant prostate cancer (CRPC) after definitive therapy. METHODS: Between 11/2009 and 06/2014, 18 patients with isolated lymph node metastases after definitive prostate cancer therapy received radiotherapy to the affected lymph nodes with a total dose of 50.4 or 54.0 Gray (Gy). All patients had continuously rising levels of PSA despite androgen deprivation therapy (ADT). Biochemical progression-free survival (BPFS), clinical failure-free survival (CFFS) and freedom from local failure were assessed, as was the toxicity profile. RESULTS: Of the 18 patients, 17 had high risk prostate cancer. Radiotherapy was performed at a median interval of 64.55 [interquartile range (IQR) 23.2-153.8] months after definitive therapy. ADT was administered for a median (IQR) time of 3.8 (3.2-24.7) months prior to irradiation. The median (IQR) follow-up was 15.59 (5.3-28.5) months with 94.1 % freedom from local failure. The median BPFS and CFFS were 5.85 (IQR 3.0-20.3) and 9.60 months (IQR 5.9-28.8), respectively. No grade III acute or grade II late toxicity was observed. Only two patients developed local relapse. No patients exhibited deterioration of urinary or faecal continence. CONCLUSION: Radiotherapy of isolated lymph node metastases in patients who develop CRPC provides effective local control, is not associated with clinically important acute or long-term side effects, improves PSA kinetics and may delay the necessity of chemotherapy. PMID- 26612677 TI - Incidental melanomas detected in veterans referred to dermatology. AB - BACKGROUND: Early detection of melanoma is integral to preventing morbidity and mortality. OBJECTIVE: We sought to characterize and compare incidental versus consult melanomas detected in veterans referred to the Minneapolis, MN, Department of Veterans Affairs Medical Center dermatology clinic. METHODS: We retrospectively reviewed charts of all dermatology consults between January 2004 and March 2012. RESULTS: Of the 28,405 consults sent during the study period, 17,174 met inclusion criteria. There were 231 melanomas identified in 221 patients. In all, 144 melanomas were identified on the consult and 87 melanomas were discovered incidentally. The incidental melanoma detection rate was 0.5% (84/17,174). Consult melanomas were more likely to be invasive than incidental melanomas (relative risk 1.51, 95% confidence interval 1.23-1.86, P < .0001) and less likely to have a Breslow depth of less than 1.00 mm (relative risk 0.73, 95% confidence interval 0.61-0.88, P = .0036). Incidental melanomas were smaller than consult melanomas (mean diameter 0.98 vs 1.3 cm, respectively) and thinner (mean Breslow depth 0.64 vs 1.74 mm). Consult melanomas were more likely to be detected on the head/neck (relative risk 1.25, 95% confidence interval 1.03-1.52, P = .0295). LIMITATIONS: Nondiverse patient population is a limitation. CONCLUSION: Melanomas detected during an in-person skin examination by a dermatologist were more likely to be detected at an earlier stage of disease. PMID- 26612678 TI - The mechanism for microsporidian parasite suppression of the hindgut bacteria of the migratory locust Locusta migratoria manilensis. AB - Locusts aggregate into bands of nymphs and swarms of adults that can pose a major threat to crop. Previous studies have shown that infection by the microsporidian parasite Paranosema locustae prevents locust aggregation behavior and we show that gut bacteria, which produce components of locust aggregation pheromones, are substantially reduced in locusts infected with P. locustae. We found that P. locustae could reduce the diversity, abundance and community composition of Locusta migratoria's gut bacteria. The parasite infection was also shown to interrupt the peroxidase activity of locust hindgut. Genome-wide expression analysis showed that the parasite infection suppressed peroxidase mRNA relative expression of locust hindgut, but had no effects on attacin expression and superoxide dismutase at 16 d post-inoculation with 20,000 P. locustae spores. Our findings reveal the mechanisms by which P. locustae impairs bacterial diversity and community structure of Locusta migratoria's gut bacteria. PMID- 26612679 TI - Identification of a Polyketide Synthase Gene in the Synthesis of Phleichrome of the Phytopathogenic Fungus Cladosporium phlei. AB - Phleichrome, a pigment produced by the phytopathogenic fungus Cladosporium phlei, is a fungal perylenequinone whose photodynamic activity has been studied intensively. To determine the biological function of phleichrome and to engineer a strain with enhanced production of phleichrome, we identified the gene responsible for the synthesis of phleichrome. Structural comparison of phleichrome with other fungal perylenequinones suggested that phleichrome is synthesized via polyketide pathway. We recently identified four different polyketide synthase (PKS) genes encompassing three major clades of fungal PKSs that differ with respect to reducing conditions for the polyketide product. Based on in silico analysis of cloned genes, we hypothesized that the non-reducing PKS gene, Cppks1, is involved in phleichrome biosynthesis. Increased accumulation of Cppks1 transcript was observed in response to supplementation with the application of synthetic inducer cyclo-(l-Pro-l-Phe). In addition, heterologous expression of the Cppks1 gene in Cryphonectria parasitica resulted in the production of phleichrome. These results provide convincing evidence that the Cppks1 gene is responsible for the biosynthesis of phleichrome. PMID- 26612680 TI - Crystal Structure and Comparative Sequence Analysis of GmhA from Colwellia psychrerythraea Strain 34H Provides Insight into Functional Similarity with DiaA. AB - The psychrophilic organism Colwellia psychrerythraea strain 34H produces extracellular polysaccharide substances to tolerate cold environments. Sedoheptulose 7-phosphate isomerase (GmhA) is essential for producing d-glycero-d mannoheptose 7-phosphate, a key mediator in the lipopolysaccharide biosynthetic pathway. We determined the crystal structure of GmhA from C. psychrerythraea strain 34H (CpsGmhA, UniProtKB code: Q47VU0) at a resolution of 2.8 A. The tetrameric structure is similar to that of homologous GmhA structures. Interestingly, one of the catalytic residues, glutamate, which has been reported to be critical for the activity of other homologous GmhA enzymes, is replaced by a glutamine residue in the CpsGmhA protein. We also found differences in the conformations of several other catalytic residues. Extensive structural and sequence analyses reveal that CpsGmhA shows high similarity to Escherichia coli DnaA initiator-associating protein A (DiaA). Therefore, the CpsGmhA structure reported here may provide insight into the structural and functional correlations between GmhA and DiaA among specific microorganisms. PMID- 26612681 TI - Neural correlates of and processes underlying generalized and differential return of fear. AB - Relapse represents a major limitation to long-term remission of psychopathology (anxiety, addiction). Relapse of anxiety can be modeled in the laboratory as return of fear (ROF) following un-signaled re-presentation of the aversive event (reinstatement, RI) after extinction. In humans, response enhancement to both the CS+ and CS- (generalized RI) or specifically to the CS+ (differential RI) has been described following RI. The (psychological) mechanisms and boundary conditions underlying these different RI qualities were investigated in 76 healthy participants using autonomic measures and functional magnetic resonance imaging. Our results suggest that both processes reflect distinct albeit intertwined (psychological) processes which are reflected in different neural activation patterns. Differential RI was linked to CS+ related hippocampal activation and CS- related disinhibition of the ventromedial prefrontal cortex (vmPFC). The latter likely contributes to robust generalized RI which was mirrored in thalamic and visual areas (as well as the bed nucleus of the striatum and inusula) possibly indicating generally facilitated salience processing. In addition, we also present data on experimental boundary conditions of RI (trial sequence effects, time stability). Taken together, this first comprehensive analysis of RI-induced ROF aids not only experimental research on ROF but also understanding of factors promoting clinical relapse and the role of the vmPFC. PMID- 26612682 TI - Covariance modulates the effect of joint temperature and food variance on ectotherm life-history traits. AB - Understanding animal performance in heterogeneous or variable environments is a central question in ecology. We combine modelling and experiments to test how temperature and food availability variance jointly affect life-history traits of ectotherms. The model predicts that as mean temperatures move away from the ectotherm's thermal optimum, the effect size of joint thermal and food variance should become increasingly sensitive to their covariance. Below the thermal optimum, performance should be positively correlated with food-temperature covariance and the opposite is predicted above it. At lower temperatures, covariance should determine whether food and temperature variance increases or decreases performance compared to constant conditions. Somewhat stronger than predicted, the covariance effect below the thermal optimum was confirmed experimentally on an aquatic ectotherm (Daphnia magna) exposed to diurnal food and temperature variance with different amounts of covariance. Our findings have important implications for understanding ectotherm responses to climate-driven alterations of thermal mean and variance. PMID- 26612683 TI - Metal induced self-assembly of designed V-shape protein into 2D wavy supramolecular nanostructure. AB - In order to understand and imitate the more complex bio-processes and fascinating functions in nature, protein self-assembly has been studied and has attracted more and more interest in recent years. Artificial self-assemblies of proteins have been constructed through many strategies. However, the design of complicated protein self-assemblies utilizing the special profile of building blocks remains a challenge. We herein report linear and 2D nanostructures constructed from a V shape SMAC protein and induced by metal coordination. Zigzag nanowires and wavy 2D nanostructures have been demonstrated by AFM and TEM. The zigzag nanowires can translate to a 2D nanostructure with an excess of metal ions, which reveals the step by step assembly process. Fluorescence and UV/Vis spectra have also been obtained to further study the mechanism and process of self-assembly. Upon the protein nanostructure, fluorescence resonance energy transfer (FRET) could also be detected using fluorescein modified proteins as building blocks. This article provides an approach for designing and controlling self-assembled protein nanostructures with a distinctive topological morphology. PMID- 26612685 TI - Early habituation of maize (Zea mays) suspension-cultured cells to 2,6 dichlorobenzonitrile is associated with the enhancement of antioxidant status. AB - The cellulose biosynthesis inhibitor 2,6-dichlorobenzonitrile (DCB) has been widely used to gain insights into cell wall composition and architecture. Studies of changes during early habituation to DCB can provide information on mechanisms that allow tolerance/habituation to DCB. In this context, maize-cultured cells with a reduced amount of cellulose (~20%) were obtained by stepwise habituation to low DCB concentrations. The results reported here attempt to elucidate the putative role of an antioxidant strategy during incipient habituation. The short term exposure to DCB of non-habituated maize-cultured cells induced a substantial increase in oxidative damage. Concomitantly, short-term treated cells presented an increase in class III peroxidase and glutathione S-transferase activities and total glutathione content. Maize cells habituated to 0.3-1 uM DCB (incipient habituation) were characterized by a reduction in the relative cell growth rate, an enhancement of ascorbate peroxidase and class III peroxidase activities, and a net increment in total glutathione content. Moreover, these cell lines showed increased levels of glutathione S-transferase activity. Changes in antioxidant/conjugation status enabled 0.3 and 0.5 uM DCB-habituated cells to control lipid peroxidation levels, but this was not the case of maize cells habituated to 1 MUM DCB, which despite showing an increased antioxidant capacity were not capable of reducing the oxidative damage to control levels. The results reported here confirm that exposure and incipient habituation of maize cells to DCB are associated with an enhancement in antioxidant/conjugation activities which could play a role in incipient DCB habituation of maize-cultured cells. PMID- 26612684 TI - Janus-faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains. AB - Sestrins are stress-inducible metabolic regulators with two seemingly unrelated but physiologically important functions: reduction of reactive oxygen species (ROS) and inhibition of the mechanistic target of rapamycin complex 1 (mTORC1). How Sestrins fulfil this dual role has remained elusive so far. Here we report the crystal structure of human Sestrin2 (hSesn2), and show that hSesn2 is twofold pseudo-symmetric with two globular subdomains, which are structurally similar but functionally distinct from each other. While the N-terminal domain (Sesn-A) reduces alkylhydroperoxide radicals through its helix-turn-helix oxidoreductase motif, the C-terminal domain (Sesn-C) modified this motif to accommodate physical interaction with GATOR2 and subsequent inhibition of mTORC1. These findings clarify the molecular mechanism of how Sestrins can attenuate degenerative processes such as aging and diabetes by acting as a simultaneous inhibitor of ROS accumulation and mTORC1 activation. PMID- 26612686 TI - A review of methods for interpretation of glycopeptide tandem mass spectral data. AB - Despite the publication of several software tools for analysis of glycopeptide tandem mass spectra, there remains a lack of consensus regarding the most effective and appropriate methods. In part, this reflects problems with applying standard methods for proteomics database searching and false discovery rate calculation. While the analysis of small post-translational modifications (PTMs) may be regarded as an extension of proteomics database searching, glycosylation requires specialized approaches. This is because glycans are large and heterogeneous by nature, causing glycopeptides to exist as multiple glycosylated variants. Thus, the mass of the peptide cannot be calculated directly from that of the intact glycopeptide. In addition, the chemical nature of the glycan strongly influences product ion patterns observed for glycopeptides. As a result, glycopeptidomics requires specialized bioinformatics methods. We summarize the recent progress towards a consensus for effective glycopeptide tandem mass spectrometric analysis. PMID- 26612687 TI - Resection rate of lung cancer in Teesside (UK) and Varese (Italy): a comparison after implementation of the National Cancer Plan. AB - BACKGROUND: In a lung cancer survey in 2000 we showed significantly less favourable stage distribution and lower resection rate in Teesside (UK) than in the comparable industrialised area of Varese (Italy). Lung cancer services in Teesside were subsequently reorganised according to National Cancer Plan recommendations. METHODS: For all new lung cancer cases diagnosed in Teesside (n=324) and Varese (n=260) during the 12 months October 2010 to September 2011 (hereafter 'the 2010 cohort'), demographic, clinico-pathological and disease management data were prospectively recorded using the same database and protocol as the 2000 survey. Findings were analysed focusing on resection rate. RESULTS: In the 2010 cohort compared with 2000, both in Teesside and Varese emergency referral decreased (p<0.001), performance status improved (p<0.001), but cancer stage shift was not seen; resection rate improved in Teesside, from 7% to 11% (p=0.054), and was unchanged in Varese (24%). Moreover, in Teesside compared with Varese the stage distribution remained less favourable, stage I-II non-small cell lung cancer (NSCLC) proportion being respectively 12% and 19% (p=0.040), and resection rate in all lung cancers remained lower (11% and 24%; p<0.001). On multivariate analysis, resection predictors in Teesside were as follows: stage I II NSCLC (OR 86.14; 95% CI 31.80 to 233.37), performance status 0-1 (OR 5.02; 95% CI 1.48 to 17.07), belonging to 2010 cohort (OR 2.85; 95% CI 1.06 to 7.64). CONCLUSIONS: In Teesside the main independent predictor of resection was disease stage; in 2010-2011 compared with 2000, lung cancer service improved but stage shift did not occur, and resection rate increased but remained significantly lower than in Varese. PMID- 26612688 TI - Alcohol-soluble Star-shaped Oligofluorenes as Interlayer for High Performance Polymer Solar Cells. AB - Two star-shaped oligofluorenes with hexakis(fluoren-2-yl)benzene as core are designed and sythesized for interfacial materials in polymer solar cell. Diethanolamino groups are attached to the side chain of fluorene units for T0-OH and T1-OH to enable the alcohol solubility, and additional hydrophobic n-hexyl chains are also grafted on the increased fluorene arms for T1-OH. In conventional device with PCDTBT/PC71BM as active layer, a 50% enhanced PCE is obtained by incorporating T0-OH and T1-OH as the interlayer compared with device without interlayer. By optimizing the active material with PTB7 and with the inverted device structure, a maximum PCE of 9.30% is achieved, which is among the highest efficiencies for PTB7 based polymer solar cells. The work function of modified electrode, the surface morphology and the suraface properties are systematically studied. By modifying the structures of the star-shaped molecules, a balance between the hydrophobic and hydrophilic property is finely tuned, and thus facilitate the interlayer for high performance of PSCs. PMID- 26612690 TI - Paenibacillus radicis sp. nov., an endophytic bacterium isolated from maize root. AB - A novel Gram-stain-positive, aerobic, endospore-forming, and rod-shaped strain designated 694T was isolated from surface-sterilized root tissue of a maize planted in the Fangshan District of Beijing, People's Republic of China. A polyphasic taxonomic study was performed on the new isolate. On the basis of 16S rRNA gene sequence similarity studies, this isolate belongs to the genus Paenibacillus. High levels of 16S rRNA gene sequence similarity were found between strain 694T and Paenibacillus xinjiangensis DSM 30034T (98.5 %) and Paenibacillus glycanilyticus (98.1 %), respectively. However, the DNA-DNA hybridization values between strain 694T and its close relatives P. xinjiangensis 16970T and Paenibacillus algorifonticola CGMCC 1.10223T were 30.0 % and 36.7 % respectively. The DNA G+C content of strain 694T was determined to be 46.9 mol%. The predominant respiratory quinone was identified as menaquinone-7 and the polar lipid profile was found to be composed of the major lipids diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. The major fatty acids were found to be anteiso-C15 : 0 (42.1 %), iso-C15 : 0 (18.4 %), iso-C16 : 0 (11.2 %) and C16 : 0 (12.1 %). The results of physiological and biochemical tests and minor differences in the fatty acid profiles allowed a clear phenotypic differentiation of strain 694T from the closely related species in the genus Paenibacillus. Strain 694T is concluded to represent a novel species within the genus Paenibacillus, for which the name Paenibacillus radicis sp. nov. is proposed, with the type strain 694T ( = CGMCC 1.15286T = DSM 100762T). PMID- 26612689 TI - Virus encoded circulatory miRNAs for early detection of prostate cancer. AB - BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed cancer and kills about 28,000 American men annually. Although progress has been made in understanding the molecular features of different forms of the disease, PCa is considered incurable when it becomes resistant to standard therapies. Prostate specific antigen (PSA) test has been a gold standard of diagnosis for PCa, however, it can result in lead to the unnecessary biopsies and treatment of indolent cancers due to the low specificity. Thus, the limitations of PSA screening for PCa have prompted much focus on strategies how to enhance the accuracy of PSA for distinction between aggressive and indolent cancers. DISCUSSION: Studies of miRNAs in PCa patients have suggested differentially expressed miRNAs between healthy controls and those with PCa, providing potential biomarker candidates using body fluids including urine and blood. Virus infection has been considered to associate with PCa incidence. Virus infected PCa cells may shed extracellular vesicles and communicate with neighboring cells, which were not infected yet, however, no mechanistic approaches were performed to understand the biology. The miRNAs composition in the shedding extracellular vesicles, and its role in PCa are completely undefined. In the near future, new insights to connect between the viral derived miRNAs and PCa progression might provide an opportunity to diagnose, risk prediction and therapeutic strategies. The goal of this debate article is to provide a short review on miRNAs, virus infection and viral encoded miRNAs in PCa, with a primary focus on circulating miRNAs as potential non-invasive biomarkers for PCa patients. PMID- 26612691 TI - Theory's role in shaping behavioral health research for population health. AB - The careful application of theory often is used in the behavioral health field to enhance our understanding of how the world currently works. But theory also can help us visualize what the world can become, particularly through its potential impacts on population-wide health. Applying a multi-level ecological perspective can help in expanding the field's focus upward toward the population at large. While ecological frameworks have become increasingly popular, arguably such perspectives have fallen short of their potential to actively bridge conceptual constructs and, by extension, intervention approaches, across different levels of population impact. Theoretical and conceptual perspectives that explicitly span levels of impact offer arguably the greatest potential for achieving scientific insights that may in turn produce the largest population health effects. Examples of such "bridging" approaches include theories and models that span behavioral + micro-environment, behavioral + social/cultural, and social + physical environment constructs. Several recommendations are presented related to opportunities for leveraging theories to attain the greatest impact in the population health science field. These include applying the evidence obtained from person-level theories to inform methods for positively impacting the behaviors of community gatekeepers and decision-makers for greater population change and reach; leveraging the potential of residents as "citizen scientists"- a resource for enacting behavioral health changes at the individual, environmental, and policy levels; using empirical observations and theory in equal parts to build more robust, relevant, and solution-oriented behavior change programs; exploring moderators and mediators of change at levels of impact that go beyond the individual; and considering the circumstances in which applying conceptual methods that embrace a "complexity" as opposed to "causality" perspective may lead to more flexible and agile scientific approaches that could accelerate both population-relevant discoveries and applications in the field. The commentary closes with suggestions concerning additional areas to be considered to facilitate continued advances in the health behavior field more generally to attain the greatest impacts on population health. PMID- 26612692 TI - The immune mechanisms of abscopal effect in radiation therapy. AB - Radiation therapy (RT) is a cornerstone in oncologic management and is employed in various curative and palliative scenarios for local-regional control. RT is thought to locally control tumor cells by direct physical DNA damage or indirect insults from reactive oxygen species. Therapeutic effects apart from those observed at the treatment target, that is, abscopal effect, have been observed for several decades, though the underlying mechanisms regulating this phenomenon have been unclear. Accumulating evidence now suggests that the immune system is a major determinant in regulating the abscopal effect. It is now evident that RT may also enhance immunologic responses to tumors by creating an in situ vaccine by eliciting antigen release from dying tumor cells. Harnessing the specificity and dynamic nature of the immune system to target tumors in conjunction with RT is an emerging field with much promise. To optimize this approach, it is important to systematically evaluate the intricacies of the host immune system, the new generation of immunotherapeutics and the RT approach. Here we will discuss the current biologic mechanisms thought to regulate the RT-induced abscopal effect and how these may be translated to the clinical setting. PMID- 26612693 TI - An Integrative Therapeutic Concept for Surgical Treatment of Severe Cases of Lymphedema of the Lower Extremity. AB - BACKGROUND: Lymphedema results from insufficient lymphatic drainage and typically affects the extremities. Recent studies revealed obesity as another cause of extremity lymphedema. Conservative treatment of patients with elephantiastic lymphedema of the lower extremity is limited and often inadequate. Resecting surgery plays an important role in these cases. Here, we investigated the effects of an integrated therapy concept on outcome and complication rates. METHODS: We retrospectively analyzed the clinical outcome of 26 patients with elephantiastic lymphedema of the lower limb who underwent a complex decongestive physical therapy (CDP) perioperatively and reduction surgery in our clinic between 1998 and 2011. We subsequently compared these patients (group A) with a control group of 30 patients (group B) who received medial thigh lift due to post-bariatric or aesthetic issues between 2011 and 2013. The incidence of complications, reoperations, blood transfusion, and duration of hospital stay was analyzed. All patients in group A received CDP perioperatively in a specialized lymphological clinic. RESULTS: Both groups are comparable in terms of age and sex. Patients significantly differ in terms of BMI (p < 0.001). Thirty-six reductive procedures were performed in group A and 30 in group B. We did not see any significant difference in the incidence of complications (p = 1.000) and the rate of postoperative blood transfusions (p = 0.116). CONCLUSIONS: We were able to show that an integrative concept including surgery is a good additional option for the treatment of severe cases of lymphedema in appropriate candidates. Furthermore, an adequate perioperative conservative setting helps to minimize possible complications. PMID- 26612694 TI - Is Sleeve Gastrectomy Always an Absolute Contraindication in Patients with Barrett's? AB - The incidence of esophageal adenocarcinoma is not rising at the same rate as severe obesity, and incidence-based mortality is marginally going down since 2000. Laparoscopic sleeve gastrectomy (LSG) is now the preferred operation for weight loss in several countries including the USA. Recent objective studies of reflux before and 2 years after LSG show improvement by GERD Symptom Assessment Scale score, DeMeester score, total acid exposure, as well as unchanged lower esophageal sphincter pressure measurements. Therefore, sleeve gastrectomy improves symptoms and reduces reflux in most morbidly obese patients with preoperative reflux. At the last LSG consensus conference, 94.5% of experts mentioned Barrett's esophagus to be a major contraindication for the performance of LSG, a change from 2011 (81%). But the actual incidence of Barrett's is only 1% in the severely obese. Therefore, 99% of patients should be able to get a LSG. Further, after 25 years of duodenal switch operations (which includes a sleeve gastrectomy, there are still no reports of esophageal adenocarcinoma. Hence, LSG is not a contraindication in GERD patients without Barrett's. PMID- 26612695 TI - Changes in Serum Fatty Acid Levels During the First Year After Bariatric Surgery. AB - BACKGROUND: We have assessed the effects of laparoscopic sleeve gastrectomy (LSG) and biliopancratic diversion with a duodenal switch (BPDDS) on fatty acid (FA) levels in serum. In particular, we examine the impact of surgery on the ratio of the FAs eicosapentaenoic acid (EPA) to arachidonic acid (AA) which impacts, e.g., cardiovascular health. Our hypothesis is that LSG and BPDDS influence the FA levels but that BPDDS may have a more persistent impact since BPDSS superimposes intestinal malabsorption on gastric restriction. METHODS: Serum samples after overnight fasting were collected 3 months and 1 day before surgery and 3 days, 3 months, and 12 months after surgery from 10 BPDDS patients and 23 LSG patients. The levels of 16 FAs were quantified by gas chromatography. Preoperative and postoperative concentrations of EPA and AA and the ratio of EPA to AA were compared by Wilcoxon signed-rank test corrected for multiple testing using false discovery rate. RESULTS: The ratio of EPA/AA at each of the three postoperative sampling points was lower than at the two preoperative sampling points for BPDDS with p < 0.05 after correcting significance levels for multiple testing. For LSG, the ratio was lower with p < 0.05 at 3 days and at 3 months after surgery, but not after 12 months. CONCLUSION: Both LSG and BPDDS lower the ratio of EPA/AA significantly and below recommended values, but LSG patients resurge toward normal values after approximately 12 months, while BPDDS patients do not. PMID- 26612696 TI - Family caregivers of patients with frontotemporal dementia: An integrative review. AB - OBJECTIVES: The purpose of this integrative review is to: (1) identify the characteristics of family caregivers of patients with frontotemporal dementia, (2) explore the impact of providing care on family caregivers' health and well being, and (3) identify coping strategies used by family caregivers. BACKGROUND: Frontotemporal dementia is thought to be the second most common form of dementia after Alzheimer's disease. Family caregivers of patients with frontotemporal dementia face unique challenges due to its early onset, behavioral symptoms, and slow progression of decline. However, there is a dearth of research evaluating the health and wellbeing of family caregivers of patients with frontotemporal dementia. DESIGN AND DATA SOURCES: An integrative review was conducted using the Whittemore and Knafl methodology. An electronic search of the literature was conducted using four electronic databases: PubMed, Embase, CINAHL, and Web of Science. The Crowe Critical Appraisal tool was used to evaluate the quality of the selected articles. RESULTS: Findings of 11 articles informed this integrative review. Family caregivers of patients with frontotemporal dementia identify behavioral disturbances as most troubling. Spouses and female caregivers experience greater caregiver burden, distress, increased rates of depression, as well as decreased sleep related to behavior disturbances. Though less explored, providing care to those with behavioral disturbances may also impact caregiver physical health. Additionally, female caregivers are most likely to employ coping strategies, most commonly, adaptation and reframing. Effective interventions to reduce family caregiver burden are poorly understood but family caregivers suggest education and internet-based support groups are most helpful. CONCLUSIONS: Family caregivers of patients with frontotemporal dementia experience significant distress, which impacts their health and wellbeing. It is important for healthcare providers who care for patients with frontotemporal dementia to recognize the unique needs of family caregivers. Future research should focus on examining interventions and strategies to reduce caregiver burden. PMID- 26612697 TI - The Evolution of Beer. PMID- 26612698 TI - Impact of prostate catheter displacement in inverse planning--simulated annealing and geometric optimization. AB - PURPOSE: The aim of this study was to compare inverse planning-simulated annealing (IPSA) with geometric optimization (GO) in high-dose-rate (HDR) prostate brachytherapy, to assess variations in dosimetric indices associated to catheter displacement. METHODS AND MATERIALS: We retrospectively studied the dosimetric effect of catheter displacement in 20 patients treated with HDR prostate brachytherapy with salvage intention. The catheter loadings, with optimized dwell positions, from the first fraction were transferred to the catheter positions in the second fraction. RESULTS: Median catheter displacement was 8.7 +/- 3.3 mm (range, 2.7 +/- 1.1 mm-14.7 +/- 1.7 mm). D90% median variations for IPSA and GO were -10% with a maximum of -59%, and -29% with a maximum of -63%, respectively. V100% median variation was -11% with a maximum of 37% for IPSA, and -20% with a maximum of -37% for GO. V150/V100 implant median variations were 15% and 9% for IPSA and GO with maximum values of 65% and 47%, respectively (p < 0.05). No significant differences were observed for V200/V100 indices, nor were any significant differences found for organs at risk. Correlation between mean catheter displacement and dosimetric indices was found only in the planning target volume D90% and V100%; linear regression slopes were 2.0% per mm and -2.6% per mm for IPSA vs. -2.4% per mm and -3.5% per mm for GO. CONCLUSIONS: IPSA does not present any additional risk compared with GO in HDR prostate brachytherapy when catheter uncertainties are taken into account. Moreover, IPSA optimization preserves planning target volume coverage better than GO, suggesting that it may be superior when catheter displacement is considered. PMID- 26612699 TI - Rectal contrast increases rectal dose during vaginal cuff brachytherapy. AB - PURPOSE: To evaluate the impact of rectal dose on rectal contrast use during vaginal cuff brachytherapy (VCB). METHODS AND MATERIALS: A retrospective review of gynecology patients who received some brachytherapy fractions with and without rectal contrast was carried out. Rectal contrast was instilled at the clinician's discretion to increase rectal visibility. Thirty-six pairs of CT scans in preparation for brachytherapy were analyzed. Pairs of CTs were segmented and planned using the same parameters. The rectum was always defined from 1 cm above the cylinder tip up to 1.5 cm below the last activated dwell source position. An individual plan was computed at every VCB fraction. A set of values (Dmax, D(0.1cc), D(1cc), and D(2cc)) derived from dose-volume histograms were extracted and compared according to the rectal status. RESULTS: Rectal volume was 26.7% larger in the fractions with rectal contrast. Such an increase in volume represented a significant increase from 7.7% to 10.4% in all parameters analyzed except Dmax dose-volume histogram. CONCLUSIONS: Avoiding rectal contrast is a simple way of decreasing the rectal dose parameters of VCB, which would mean a better therapeutic ratio. Results also suggest that action directed at maintaining the rectum empty might have the same effect. PMID- 26612700 TI - Simulation analysis of optimized brachytherapy for uterine cervical cancer: Can we select the best brachytherapy modality depending on tumor size? AB - PURPOSE: To choose the optimal brachytherapeutic modality for uterine cervical cancer, we performed simulation analysis. METHODS AND MATERIALS: For each high risk clinical target volume (HR CTV), we compared four modalities [classical conventional intracavitary brachytherapy (ConvICBT), Image-guided ICBT (IGICBT), intracavitary/interstitial brachytherapy (ICISBT), and interstitial brachytherapy (ISBT) with perineal approach] using dose-volume histograms using eight sizes of HR CTV (2 * 2 * 2 cm to 7 * 4 * 4 cm) and organs at risk model. RESULTS: In ConvICBT, the doses covered 90% of the HR CTV [D90(HR CTV)] decreased from 197% prescribed dose (PD) for the HR CTV size (2 * 2 * 2 cm) to 73% PD for 5 * 4 * 4 cm, whereas the other three modalities could achieve 100% PD for all HR CTV sizes. The minimum doses received by the maximally irradiated 2-cm(3) volumes for organs at risks of IGICBT demonstrated lower values than those of ConvICBT for the HR CTV size of 4 * 3 * 3 cm or smaller. ICISBT demonstrated lower values than those of IGICBT for 4 * 3 * 3 cm or larger. ISBT demonstrated lowest values for 5 * 4 * 4 cm or larger. CONCLUSIONS: HR CTV size of 4 * 3 * 3 cm seems to be a threshold volume in this simulation analysis, and IGICBT is a better choice for smaller HR CTV than the threshold volume. On larger HR CTV, ICISBT or ISBT is the better choice. PMID- 26612701 TI - Exposure to acid-suppressing drugs during pregnancy and the risk of asthma in childhood: an observational cohort study. AB - BACKGROUND: Some research has suggested a potential link between prenatal exposure to proton pump inhibitors (PPIs) or H2 -receptor antagonists (H2 RAs) and the development of childhood asthma. AIM: To quantify the relative risk of asthma in children who experienced pre-natal exposure to PPIs and/or H2 RAs, adjusting for potential confounders. METHODS: In this observational cohort study (NCT01787435), women aged 18-45 years with completed pregnancies between January 1996 and December 2010 were identified from The Health Improvement Network in the United Kingdom, and were linked to infants. Hazard ratios (HRs) were estimated using Cox proportional hazard models. RESULTS: Our analysis identified 2371 prenatally exposed and 7745 unexposed infants. The incidence of asthma (per 1000 person-years) was 19.52 in the unexposed cohort, 23.88 in the PPI cohort and 32.16 in the H2 RA cohort. After adjusting for maternal healthcare utilisation during the year before pregnancy, the HR for asthma in infants whose mothers received prescriptions at any time during pregnancy was 1.12 (95% confidence interval: 0.88-1.44) for PPIs and 1.43 (1.20-1.70) for H2 RAs, when compared with unexposed infants. With further adjustment for maternal comorbidities and other medications, the HR for asthma was 1.03 (0.76-1.40) for PPIs and 1.32 (1.05-1.64) for H2 RAs. CONCLUSIONS: Our analysis showed no association between prenatal exposure to PPIs and asthma in childhood after adjusting for confounders. The association found for H2 RAs may be explained largely by underlying environmental or genetic factors, as suggested by reductions in hazard ratio estimates following adjustment for maternal comorbidities. PMID- 26612702 TI - The end of early-goal directed therapy? AB - Emergency medicine practitioners around the world have been confronted with the increasing challenge of managing patients in severe sepsis and septic shock. Introduction of early goal-directed therapy (EGDT) revolutionized sepsis care and was adopted worldwide. Since then, multiple randomized controlled trials have been published questioning the superiority of EGDT. The purpose of this article is to review and provide clinical commentary on the ProCESS, ARISE, and ProMISE trials, which address whether invasive, expensive interventions are needed to achieve mortality reduction goals in septic patients. This article discusses that EGDT bundled care is not necessary to achieve mortality reduction goals. PMID- 26612703 TI - Randomized trial of the chest compressions effectiveness comparing 3 feedback CPR devices and standard basic life support by nurses. AB - BACKGROUND: Out-of-hospital cardiac arrest is a leading cause of mortality and serious neurological morbidity in Europe. We aim to investigate the effect of 3 cardiopulmonary resuscitation (CPR) feedback devices on effectiveness of chest compression during CPR. METHODS: This was prospective, randomized, crossover, controlled trial. Following a brief didactic session, 140 volunteer nurses inexperienced with feedback CPR devices attempted chest compression on a manikin using 3 CPR feedback devices (TrueCPR, CPR-Ezy, and iCPR) and standard basic life support (BLS) without feedback. RESULTS: Comparison of standard BLS, TrueCPR, CPR Ezy, and iCPR showed differences in the effectiveness of chest compression (compressions with correct pressure point, correct depth, and sufficient decompression), which are, respectively, 37.5%, 85.6%, 39.5%, and 33.4%; compression depth (44.6 vs 54.5 vs 45.6 vs 39.6 mm); and compression rate (129.4 vs 110.2 vs 101.5 vs 103.5 min(-1)). CONCLUSIONS: During the simulated resuscitation scenario, only TrueCPR significantly affected the increased effectiveness compression compared with standard BLS, CPR-Ezy, and iCPR. Further studies are required to confirm the results in clinical practice. PMID- 26612704 TI - Does the Venner A.P. Advance video laryngoscope improve success of first intubation attempt of trauma patient? PMID- 26612705 TI - Prehospital activated charcoal use in antipsychotic overdose. PMID- 26612706 TI - Modelling of the Sedative Effects of Propofol in Patients undergoing Spinal Anaesthesia: A Pharmacodynamic Analysis. AB - Sedation can increase patient comfort during spinal anaesthesia. Understanding the relationship between the propofol effect-site concentration (Ce) and patient sedation level could help clinicians achieve the desired sedation level with minimal side effects. We aimed to model the relationship between the propofol Ce and adequate and deep sedation and also incorporate covariates. Thirty patients scheduled for orthopaedic surgery received spinal anaesthesia with 0.5% bupivacaine. Propofol was administered via an effect-site target-controlled infusion device using the Schnider pharmacokinetic model. The pharmacodynamic models for both adequate sedation [Observer's Assessment of Alertness/Sedation (OAA/S) scores of 3-4] and deep sedation (OAA/S scores of 1-2) were developed using nonlinear mixed-effects modelling. Increments in the propofol Ce were associated with increased depths of sedation. In the basic model, the estimated population Ce50 values for adequate and deep sedation were 0.94 and 1.52 MUg/ml, respectively. The inclusion of the patient's age and sensory block level for adequate sedation and of age for deep sedation as covariates significantly improved the basic model by decreasing the objective function's minimum value from 10696.72 to 10677.92 (p = 0.0003). The simulated Ce50 values for adequate sedation in 20-year-old patients with a T12 sensory level and in 80-year-old patients with a T4 level were 1.63 and 0.53 MUg/ml, respectively. Both age and sensory block level should be considered for adequate sedation, and the propofol concentration should be reduced for elderly patients with a high spinal block to avoid unnecessarily deep levels of sedation. PMID- 26612707 TI - Improved bioavailability of targeted Curcumin delivery efficiently regressed cardiac hypertrophy by modulating apoptotic load within cardiac microenvironment. AB - Cardiomyocyte apoptosis acts as a prime modulator of cardiac hypertrophy leading to heart failure, a major cause of human mortality worldwide. Recent therapeutic interventions have focussed on translational applications of diverse pharmaceutical regimes among which, Curcumin (from Curcuma longa) is known to have an anti-hypertrophic potential but with limited pharmacological efficacies due to low aqueous solubility and poor bioavailability. In this study, Curcumin encapsulated by carboxymethyl chitosan (CMC) nanoparticle conjugated to a myocyte specific homing peptide was successfully delivered in bioactive form to pathological myocardium for effective regression of cardiac hypertrophy in a rat (Rattus norvegicus) model. Targeted nanotization showed higher cardiac bioavailability of Curcumin at a low dose of 5 mg/kg body weight compared to free Curcumin at 35 mg/kg body weight. Moreover, Curcumin/CMC-peptide treatment during hypertrophy significantly improved cardiac function by downregulating expression of hypertrophy marker genes (ANF, beta-MHC), apoptotic mediators (Bax, Cytochrome c) and activity of apoptotic markers (Caspase 3 and PARP); whereas free Curcumin in much higher dose showed minimal improvement during compromised cardiac function. Targeted Curcumin treatment significantly lowered p53 expression and activation in diseased myocardium via inhibited interaction of p53 with p300-HAT. Thus attenuated acetylation of p53 facilitated p53 ubiquitination and reduced the apoptotic load in hypertrophied cardiomyocytes; thereby limiting cardiomyocytes' need to enter the regeneration cycle during hypertrophy. This study elucidates for the first time an efficient targeted delivery regimen for Curcumin and also attributes towards probable mechanistic insight into its therapeutic potential as a cardio-protective agent for regression of cardiac hypertrophy. PMID- 26612708 TI - To edit or not to edit: regulation of ADAR editing specificity and efficiency. AB - Hundreds to millions of adenosine (A)-to-inosine (I) modifications are present in eukaryotic transcriptomes and play an essential role in the creation of proteomic and phenotypic diversity. As adenosine and inosine have different base-pairing properties, the functional consequences of these modifications or 'edits' include altering coding potential, splicing, and miRNA-mediated gene silencing of transcripts. However, rather than serving as a static control of gene expression, A-to-I editing provides a means to dynamically rewire the genetic code during development and in a cell-type specific manner. Interestingly, during normal development, in specific cells, and in both neuropathological diseases and cancers, the extent of RNA editing does not directly correlate with levels of the substrate mRNA or the adenosine deaminase that act on RNA (ADAR) editing enzymes, implying that cellular factors are required for spatiotemporal regulation of A-to I editing. The factors that affect the specificity and extent of ADAR activity have been thoroughly dissected in vitro. Yet, we still lack a complete understanding of how specific ADAR family members can selectively deaminate certain adenosines while others cannot. Additionally, in the cellular environment, ADAR specificity and editing efficiency is likely to be influenced by cellular factors, which is currently an area of intense investigation. Data from many groups have suggested two main mechanisms for controlling A-to-I editing in the cell: (1) regulating ADAR accessibility to target RNAs and (2) protein-protein interactions that directly alter ADAR enzymatic activity. Recent studies suggest cis- and trans-acting RNA elements, heterodimerization and RNA binding proteins play important roles in regulating RNA editing levels in vivo. WIREs RNA 2016, 7:113-127. doi: 10.1002/wrna.1319. PMID- 26612709 TI - Hydrogen Bond Fluctuations Control Photochromism in a Reversibly Photo-Switchable Fluorescent Protein. AB - Reversibly switchable fluorescent proteins (RSFPs) are essential for high resolution microscopy of biological samples, but the reason why these proteins are photochromic is still poorly understood. To address this problem, we performed molecular dynamics simulations of the fast switching Met159Thr mutant of the RSFP Dronpa. Our simulations revealed a ground state structural heterogeneity in the chromophore pocket that consists of three populations with one, two, or three hydrogen bonds to the phenolate moiety of the chromophore. By means of non-adiabatic quantum mechanics/molecular dynamics simulations, we demonstrated that the subpopulation with a single hydrogen bond is responsible for off-switching through photo-isomerization of the chromophore, whereas two or more hydrogen bonds inhibit the isomerization and promote fluorescence instead. While rational design of new RSFPs has so far focused on structure alone, our results suggest that structural heterogeneity must be considered as well. PMID- 26612710 TI - Bullous Pemphigoid Arising in Lower Leg Vein Graft Incision Site. AB - Bullous pemphigoid is a blistering disorder which can be idiopathic or arise secondary to drugs or trauma; however, blistering arising within surgical scars is rare. We present a patient with no prior skin history who developed blistering in his left calf vein harvesting scar soon after coronary artery bypass surgery. PMID- 26612711 TI - Characterization of Deletions of the HBA and HBB Loci by Array Comparative Genomic Hybridization. AB - Thalassemia is among the most common genetic diseases worldwide. alpha Thalassemia is usually caused by deletion of one or more of the duplicated HBA genes on chromosome 16. In contrast, most beta-thalassemia results from point mutations that decrease or eliminate expression of the HBB gene on chromosome 11. Deletions within the HBB locus result in thalassemia or hereditary persistence of fetal Hb. Although routine diagnostic testing cannot distinguish thalassemia deletions from point mutations, deletional hereditary persistence of fetal Hb is notable for having an elevated HbF level with a normal mean corpuscular volume. A small number of deletions accounts for most alpha-thalassemias; in contrast, there are no predominant HBB deletions causing beta-thalassemia. To facilitate the identification and characterization of deletions of the HBA and HBB globin loci, we performed array-based comparative genomic hybridization using a custom oligonucleotide microarray. We accurately mapped the breakpoints of known and previously uncharacterized HBB deletions defining previously uncharacterized deletion breakpoints by PCR amplification and sequencing. The array also successfully identified the common HBA deletions --(SEA) and --(FIL). In summary, comparative genomic hybridization can be used to characterize deletions of the HBA and HBB loci, allowing high-resolution characterization of novel deletions that are not readily detected by PCR-based methods. PMID- 26612712 TI - Hepatitis C Virus RNA Real-Time Quantitative RT-PCR Method Based on a New Primer Design Strategy. AB - Viral nucleic acids are unstable when improperly collected, handled, and stored, resulting in decreased sensitivity of currently available commercial quantitative nucleic acid testing kits. Using known unstable hepatitis C virus RNA, we developed a quantitative RT-PCR method based on a new primer design strategy to reduce the impact of nucleic acid instability on nucleic acid testing. The performance of the method was evaluated for linearity, limit of detection, precision, specificity, and agreement with commercial hepatitis C virus assays. Its clinical application was compared to that of two commercial kits--Cobas AmpliPrep/Cobas TaqMan (CAP/CTM) and Kehua. The quantitative RT-PCR method delivered a good performance, with a linearity of R(2) = 0.99, a total limit of detection (genotypes 1 to 6) of 42.6 IU/mL (95% CI, 32.84 to 67.76 IU/mL), a CV of 1.06% to 3.34%, a specificity of 100%, and a high concordance with the CAP/CTM assay (R(2) = 0.97), with a means +/- SD value of -0.06 +/- 1.96 log IU/mL (range, -0.38 to 0.25 log IU/mL). The method was superior to commercial assays in detecting unstable hepatitis C virus RNA (P < 0.05). This quantitative RT-PCR method can effectively eliminate the influence of RNA instability on nucleic acid testing. The principle of primer design strategy may be applied to the detection of other RNA or DNA viruses. PMID- 26612713 TI - Chemical manipulation of plant water use. AB - Agricultural productivity is dictated by water availability and consequently drought is the major source of crop losses worldwide. The phytohormone abscisic acid (ABA) is elevated in response to water deficit and modulates drought tolerance by reducing water consumption and inducing other drought-protective responses. The recent identification of ABA receptors, elucidation of their structures and understanding of the core ABA signaling network has created new opportunities for agrochemical development. An unusually large gene family encodes ABA receptors and, until recently, it was unclear if selective or pan agonists would be necessary for modulating water use. The recent identification of the selective agonist quinabactin has resolved this issue and defined Pyrabactin Resistance 1 (PYR1) and its close relatives as key targets for water use control. This review provides an overview of the structure and function of ABA receptors, progress in the development of synthetic agonists, and the use of orthogonal receptors to enable agrochemical control in transgenic plants. PMID- 26612714 TI - Mutation analysis of Swedish haemophilia B families - high frequency of unique mutations. AB - INTRODUCTION: Haemophilia B is caused by a heterogeneous spectrum of mutations. Mutation characterization is important in genetic counselling, prenatal diagnosis and to predict risk of inhibitor development. AIMS: To study the mutation spectrum, frequency of unique recurrent mutations, genotype-phenotype association and inhibitor development in a population-based study of the complete Swedish haemophilia B population. METHODS: The study included, facilitated by centralized DNA diagnostics, the complete registered Swedish haemophilia B population (113 families: 47 severe, 22 moderate and 44 mild), each represented by a single patient. Mutation characterization was performed by conventional sequencing of all exons and haplotyping by genotyping of single nucleotide variants and microsatellites. RESULTS: A mutation was found in every family: eight had large deletions, three had small deletions (<10 base pair) and 102 had single base pair substitutions (69 missense, 26 nonsense, four splice site and three promoter). Ten novel mutations were found and were predicted to be deleterious. Sixteen mutations (one total gene deletion, 14 substitutions and one acceptor splice site) were present in more than one family. Of the single nucleotide mutations (37/102), 36% arose at CpG sites. Haplotyping of families with identical mutations and present analyses showed that the frequency of unique mutations was at least 65%. Inhibitors developed in 9/47 (19%) patients with severe haemophilia B. CONCLUSION: The spectrum of haemophilia B mutations reveals at least 65% of the families carry a unique mutation, but with more inhibitor patients than reported internationally, probably as a result of many 'null' mutations. PMID- 26612715 TI - Open thoracoabdominal aortic aneurysm repair in the modern era: results from a 20 year single-centre experience. AB - OBJECTIVES: The efficacy and durability of actual treatments (open, endovascular and hybrid) for thoracoabdominal aortic aneurysm (TAAA) repair are not yet completely defined. Open surgical repair using a multi-adjunct (ADJ) approach has been the standard of care for many years and may still be an effective treatment option. This study aimed to assess the outcomes of open TAAA repair since the introduction of the available ADJ. METHODS: From 1994 to 2014, 542 consecutive patients underwent open TAAA repair in our institution, routinely receiving aortic distal perfusion and the other ADJ (either for visceral and spinal cord protection). The aetiology of TAAA was identified to be degenerative in 325 (60%) patients and chronic post-dissection in 160 (29.5%) patients. Other causes such as connective tissue disorders, vasculitis and infective aneurysms were less represented (10.5%). Extensive type I and II repair was required in 128 (23.6%) and 285 (52.6%) patients, respectively. All patients were followed up at 3 and 6 months after surgery and yearly thereafter using computed tomography angiogram. RESULTS: The overall 30-day mortality and paraplegia rates were 8.5 and 4.2%, respectively. Age [odds ratio (OR) 1.07 per year, 95% confidence interval (CI) 1.02-1.13], female gender (OR 2.52, 95% CI 1.27-4.99), urgency (OR 2.78, 95% CI 1.12-6.20) and emergency (OR 3.81, 95% CI 1.00-11.50) emerged as independent risk factors for 30-day mortality. Follow-up was 100% complete (mean 6.32 years). Overall 1-, 5- and 10-year survival was 85.9 +/- 1.5, 74.2 +/- 2.0 and 61.6 +/- 2.5%, respectively. The extent of surgical repair did not significantly influence late hospital death (P = 0.56). For patients surviving the first 30 days, a degenerative aneurysm aetiology negatively impaired long-term survival compared with the other diseases [hazard ratio = 1.66; 95% CI (1.13-2.44)]. Five- and 10 year freedom from reoperation was 86.3 +/- 1.8 and 80.7 +/- 2.3%, respectively, and 8.5% of patients required aortic reinterventions. CONCLUSIONS: In elective cases, open TAAA repair has to be considered an effective option associated with low necessity of reoperation at follow-up. The extent of aortic resection did not affect long-term mortality. Conversely, survival was mainly determined by patient age and preoperative condition. PMID- 26612716 TI - Mortality in patients with acute aortic dissection type A-analysis of pre- and intraoperative risk factors from the German Registry for Acute Aortic Dissection Type A: is this the real world? PMID- 26612718 TI - Identification of melanoma cells and lymphocyte subpopulations in lymph node metastases by FTIR imaging histopathology. AB - While early stages of melanoma are usually cured by surgery, metastatic melanomas are difficult to treat because the widely available options have low response rates. Careful and precise diagnosis and staging are essential to determine patient's risk and to select appropriate treatments. Fortunately, the recent progress in immunotherapy is very encouraging. In this context, it is important to characterize the intratumoral infiltration of immune cells in each patient, which is however not done routinely due to the lack of standardized methods. In this study, we used Fourier transform infrared (FTIR) imaging combined with multivariate statistical analyses to investigate non-metastatic and metastatic lymph nodes from melanoma patients. Our results show that the different cell types have different infrared spectral features allowing automated identification of these cell types. High recognition rates were obtained using a supervised partial least square discriminant analysis (PLS-DA) model. Melanoma cells were recognized with 87.1% sensitivity and 85.7% specificity, showing that FTIR spectroscopy has similar detection power as immunohistochemistry. Besides, FTIR imaging could also distinguish lymphocyte subpopulations (B and T cells). Finally, we investigated the changes in lymphocytes due to the presence of metastases. Interestingly, specific features of spectra of lymphocytes present in metastatic or tumor-free lymph nodes could be evidenced by PCA. A PLS-DA model was capable of predicting whether lymphocytes originated from invaded or non invaded lymph nodes. These data demonstrate that FTIR imaging is capable to distinguish known and also novel biological features in human tissues, with potential practical relevance for histopathological diagnosis and biomarker assessment. PMID- 26612717 TI - Single-port video-assisted thoracoscopic pulmonary segmentectomy: a report on 30 cases?. AB - OBJECTIVES: This study aimed to evaluate the feasibility of a single-port video assisted thoracoscopic surgery for pulmonary segmentectomy in patients with malignant or benign lung diseases. METHODS: Thirty patients (17 women; mean age, 61.7 +/- 10.9 years) who underwent a single-port thoracoscopic segmentectomy were consecutively included in this study. A 2- to 4-cm incision was made at the fifth intercostal space on the anterior or posterior axillary line, depending on the tumour location. We investigated the postoperative outcomes according to the size of the incision (2 vs 3-4 cm) or the location of segmentectomy. RESULTS: Fifteen primary lung cancers, 5 metastatic lung cancers, 1 pulmonary sarcoma, 7 cases of inflammatory lung disease and 2 benign lung tumours were diagnosed. A 3- to 4-cm incision was used in 16 patients (53.3%), and a 2-cm incision in 14 patients. The most frequent segment removed was the left upper division (9 patients, 30%). A single-port thoracoscopic segmentectomy was completed in all of the patients except one (96.7%). This 1 patient underwent lobectomy instead because the lesion was not found in the initial segment removed. The mean operation time was 159 +/- 56 min, and no significant difference in the size of incision was observed (P = 0.651). The right middle and superior segments tended to require shorter operation times (97.1 +/- 44.9 min) than the other segments (p < 0.001). One patient died (3.3%) because of septic shock. The chest tube drain was removed 4.6 +/- 1.6 days after the operation. CONCLUSIONS: This study results suggest that a single-port thoracoscopic surgery might be a feasible option for pulmonary segmentectomy with acceptable postoperative outcomes in the early stages of lung cancer or for benign lung disease. PMID- 26612719 TI - Diagnosis and treatment of vascular damage in dementia. AB - This paper provides an overview of cognitive impairment due to vascular brain damage, which is referred to as vascular cognitive impairment (VCI). Over the past decades, we have seen marked progress in detecting VCI, both through maturation of diagnostic concepts and through advances in brain imaging, especially MRI. Yet in daily practice, it is often challenging to establish the diagnosis, particularly in patients where there is no evident temporal relation between a cerebrovascular event and cognitive dysfunction. Because vascular damage is such a common cause of cognitive dysfunction, it provides an obvious target for treatment. In patients whose cognitive dysfunction follows directly after a stroke, the etiological classification of this stroke will direct treatment. In many patients however, VCI develops due to so-called "silent vascular damage," without evident cerebrovascular events. In these patients, small vessel diseases (SVDs) are the most common cause. Yet no SVD-specific treatments currently exist, which is due to incomplete understanding of the pathophysiology. This review addresses developments in this field. It offers a framework to translate diagnostic criteria to daily practice, addresses treatment, and highlights some future perspectives. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia, edited by M. Paul Murphy, Roderick A. Corriveau, and Donna M. Wilcock. PMID- 26612720 TI - Age differences in body image responses to idealized male figures in music television. AB - Little is known about how middle-aged and older men are affected by idealized depictions of male singers in music television. A total of 116 males completed pre- and post-test measures of body satisfaction, mood, and social comparison and viewed 5 minutes of clips containing scenery, muscular- or average-looking singers. Negative effects were restricted to young men who viewed the muscular clips. The younger men also reported more comparison while viewing the muscular and average-looking singers compared to the middle-aged and older men. These findings suggest that younger (but not middle-aged or older) men are particularly susceptible to idealized depictions of the male appearance. PMID- 26612721 TI - Children's body image and social comparisons with peers and the media. AB - Social comparisons are related to the development of body dissatisfaction among adolescents and adults, yet this relationship remains relatively unexamined among children. This study examines children's peer and media-related social comparisons, and how this impacts on their body image. Children aged 8-10 years completed interviews (17 girls and 19 boys in individual interviews, and 16 girls and 16 boys in focus groups). Analyses revealed that appearance-related comparisons were more common among girls, whereas sports/ability-related comparisons were more common for boys. In addition, boys viewed media comparisons as inspiring, whereas girls reported negative emotions. Implications for future research and prevention programmes are discussed. PMID- 26612722 TI - Validation of the Danish language Injustice Experience Questionnaire. AB - The Injustice Experience Questionnaire has shown promising ability to predict problematic rehabilitation in pain conditions, especially concerning work status. A Danish language version of the Injustice Experience Questionnaire was developed and completed by 358 patients with long-lasting pain/somatoform symptoms. These patients also completed questionnaires concerning sociodemographics, anxiety and depression, subjective well-being, and overall physical and mental functioning. Our results showed satisfactory interpretability and face validity, and high internal consistency (Cronbach's alpha = .90). The original one-factor structure was confirmed, but subscales should be interpreted cautiously. The Danish version of the Injustice Experience Questionnaire is found to be valid and reliable. PMID- 26612723 TI - Examining the psychometric properties of the Chinese Post-Traumatic Growth Inventory for patients suffering from chronic diseases. AB - This study examined the psychometric properties of the Chinese Post-Traumatic Growth Inventory among Hong Kong chronic disease patients. Using a cross sectional design and multistage stratification sampling, 265 chronic disease patients were recruited from a selection of non-governmental organizations and patient self-help groups across Hong Kong. The Chinese Post-Traumatic Growth Inventory total scale and subscales showed satisfactory internal consistency, reliability and concurrent validity. The factor structure of the Chinese Post Traumatic Growth Inventory fit well with a higher-order intrapersonal factor (self, spiritual and life orientation) and a first-order interpersonal factor. The Chinese Post-Traumatic Growth Inventory was predictive of hope and positive coping but negatively predictive of anxiety. The five Chinese Post-Traumatic Growth Inventory subscales can help practitioners identify meaningful health outcomes for Chinese chronic disease patients. PMID- 26612724 TI - Acute Chagas outbreaks: molecular and biological features of Trypanosoma cruzi isolates, and clinical aspects of acute cases in Santander, Colombia. AB - BACKGROUND: Outbreaks of acute Chagas disease associated with oral transmission are easily detected nowadays with trained health personnel in areas of low endemicity, or in which the vector transmission has been interrupted. Given the biological and genetic diversity of Trypanosoma cruzi, the high morbidity, mortality, and the observed therapeutic failure, new characteristics of these outbreaks need to be addressed at different levels, both in Trypanosoma cruzi as in patient response. The aim of this work was to evaluate the patient's features involved in six outbreaks of acute Chagas disease which occurred in Santander, Colombia, and the characteristics of Trypanosoma cruzi clones isolated from these patients, to establish the potential relationship between the etiologic agent features with host behavior. METHODS: The clinical, pathological and epidemiological aspects of outbreaks were analyzed. In addition, Trypanosoma cruzi clones were biologically characterized both in vitro and in vivo, and the susceptibility to the classical trypanocidal drugs nifurtimox and benznidazole was evaluated. Trypanosoma cruzi clones were genotyped by means of mini-exon intergenic spacer and cytochrome b genes sequencing. RESULTS: All clones were DTU I, and based on the mini-exon intergenic spacer, belong to two genotypes: G2 related with sub-urban, and G11 with rural outbreaks. Giron outbreak clones with higher susceptibility to drugs presented G2 genotype and C/T transition in Cyt b. The outbreaks affected mainly young population (+/-25.9 years), and the mortality rate was 10 %. The cardiac tissue showed intense inflammatory infiltrate, myocardial necrosis and abundant amastigote nests. However, although the gastrointestinal tissue was congestive, no inflammation or parasites were observed. CONCLUSIONS: Although all clones belong to DTU I, two intra-DTU genotypes were found with the sequencing of the mini-exon intergenic spacer, however there is no strict correlation between genetic groups, the cycles of the parasite or the clinical forms of the disease. Trypanosoma cruzi clones from Giron with higher sensitivity to nifurtimox presented a particular G2 genotype and C/T transition in Cyt b. When the diagnosis was early, the patients responded well to antichagasic treatment, which highlights the importance of diagnosis and treatment early to prevent fatal outcomes associated with these acute episodes. PMID- 26612726 TI - The influence of the surface properties of silicon-fluorine hydrogel on protein adsorption. AB - A range of fluorinated hydrogels were synthesized using the copolymerization of 1, 1, 1, 3, 3, 3-hexafluoroisopropyl methacrylate (HFMA) or 1H, 1H, 7H dodecafluoroheptyl methacrylate (DFMA) with hydrophilic monomers. Bovine serum albumin (BSA) and Lysozyme (LZM) were chosen as model proteins to investigate the performance of protein adsorption on the surface of these fluorinated hydrogels. It was found that the performance of the fluorinated hydrogels toward protein adsorption was different for different proteins; simultaneously, the amount of protein adsorption was related to but not linear with the fluorine content on the hydrogel surface. With increasing HFMA content, the mass of BSA adsorption increased in the first stage and then decreased, meanwhile the mass of LZM adsorption exhibited an upward trend in general. In addition, the amount of protein adsorption was also related to the type and length of the fluorinated groups. The hydrogels made from DFMA behaved better than HFMA hydrogels in terms of reducing protein adsorption. This study might provide further reference in choosing fluorine monomer to prepare protein-repelling hydrogels. PMID- 26612725 TI - Nrdp1S, short variant of Nrdp1, inhibits human glioma progression by increasing Nrdp1-mediated ErbB3 ubiquitination and degradation. AB - The ubiquitin ligase neuregulin receptor degradation protein 1 (Nrdp1) is involved in the induction of apoptosis and suppression of tumour formation. We previously showed that it was expressed at lower levels in human glioma tissues compared with normal brain tissues. However, the mechanism underlying this is unclear. Here, we reported that a novel short variant (Nrdp1S), lacking 71 amino acids at the N-terminal, was expressed in normal human brain tissue, but absent from glioma tissues. Similar to Nrdp1, Nrdp1S could be degraded by the proteasomal pathway, but exhibited an even longer half-life than Nrdp1. Nrdp1S was also shown to form a heterodimer with Nrdp1, which increased its stability, thereby augmenting the Nrdp1-mediated ubiquitination and degradation of ErbB3. EdU incorporation, MTT assay and in vitro colony formation demonstrated that Nrdp1S significantly inhibited the cell tumourigenicity. These results together suggest that Nrdp1S is a tumour suppressor that which potentiates the Nrdp1 mediated ubiquitination and degradation of ErbB3. An Nrdp1S deficiency may also be an important factor in the loss of Nrdp1. PMID- 26612727 TI - Characterization of the Interaction Between Pancreatic Trypsin and an Enteric Copolymer as a Tool for Several Biotechnological Applications. AB - Protein-polyelectrolyte complexes are very interesting systems since they can be applied in many long-established and emerging areas of biotechnology. From nanotechnology to industrial processing, these complexes are used for many purposes: to build multilayer particles for biosensors; to entrap and deliver proteins for pharmaceutical applications; to isolate and immobilize proteins. The enteric copolymer poly(methacrylic acid-co-methyl methacrylate) 1:2 (MMA) has been designed for drug delivery although its chemical properties allow to use it for other applications. Understanding the interaction between trypsin and this polymer is very important in order to optimize the mechanism of formation of this complex for different biotechnological applications.The formation of the trypsin MMA complex was studied by spectroscopy and isothermal titration calorimetry. Structural analysis of trypsin was carried out by catalytic activity assays, circular dichroism and differential scanning calorimetry. Isothermal titration calorimetry experiments showed that the insoluble complex contains 12 trypsin molecules per MMA molecule at pH 5 and they interact with high affinity to form insoluble complexes. Both electrostatic and hydrophobic forces are involved in the formation of the complex. The structure of trypsin is not affected by the presence of MMA, although it interacts with some domains of trypsin affecting its thermal denaturation as seen in the differential scanning calorimetry experiments. Its catalytic activity is not altered. Dynamic light scattering demonstrated the presence of a soluble trypsin-copolymer complex at pH 5 and 8. Turbidimetric assays show that the insoluble complex can be dissolved by low ionic strength and/or pH in order to obtain free native trypsin. PMID- 26612728 TI - Advantages of masting in European beech: timing of granivore satiation and benefits of seed caching support the predator dispersal hypothesis. AB - The predator satiation and predator dispersal hypotheses provide alternative explanations for masting. Both assume satiation of seed-eating vertebrates. They differ in whether satiation occurs before or after seed removal and caching by granivores (predator satiation and predator dispersal, respectively). This difference is largely unrecognized, but it is demographically important because cached seeds are dispersed and often have a microsite advantage over nondispersed seeds. We conducted rodent exclosure experiments in two mast and two nonmast years to test predictions of the predator dispersal hypothesis in our study system of yellow-necked mice (Apodemus flavicollis) and European beech (Fagus sylvatica). Specifically, we tested whether the fraction of seeds removed from the forest floor is similar during mast and nonmast years (i.e., lack of satiation before seed caching), whether masting decreases the removal of cached seeds (i.e., satiation after seed storage), and whether seed caching increases the probability of seedling emergence. We found that masting did not result in satiation at the seed removal stage. However, masting decreased the removal of cached seeds, and seed caching dramatically increased the probability of seedling emergence relative to noncached seeds. European beech thus benefits from masting through the satiation of scatterhoarders that occurs only after seeds are removed and cached. Although these findings do not exclude other evolutionary advantages of beech masting, they indicate that fitness benefits of masting extend beyond the most commonly considered advantages of predator satiation and increased pollination efficiency. PMID- 26612729 TI - Parasitic fauna of domestic cavies in the western highlands of Cameroon (Central Africa). AB - BACKGROUND: Domestic cavies (Cavia porcellus) are increasingly reared in rural areas of Cameroon for meat and income generation. Unfortunately, health constraints due to various pathogens including parasites stand as one of the major obstacles to the development of cavy industry in the country. The main objective of this study was to investigate the species of gastrointestinal parasites in cavy husbandry in the western highlands of Cameroon and to detect external parasites in those animals affected with dermatological disorders. METHODS: Pooled fecal samples were collected from 62 privately-own farms, as well as individual fecal samples from 21 animals at the Teaching and Research Farm of the University of Dschang, and examined for parasite eggs and oocysts/cysts. Ectoparasites were also collected from cavies and identified. RESULTS: The overall infection rate with both helminthes and arthropods was 40.3 %. Ectoparasites were found in 19 out of 62 farms (30.6 %) while 12.9 % of farms were infected with helminthes. Eggs of Graphidium strigosum (8.1 %), Trichostrongylus sp. (3.2 %) and Paraspidodera uncinata (3.2 %) were found at farm level. Oocysts of Eimeria caviae and eggs of Paraspidodera uncinata were found in 14.3 and 9.5 % of examined animals respectively. Concerning ectoparasites, Cordylobia anthropophaga and Pulex sp. were observed in 25.8 % and 6.6 % of farms respectively. CONCLUSION: The parasites are apparently composed of host-specific species in the original habitat (South America) and species acquired later from other mammals. These parasites are either deleterious to cavy health or zoonotic. Preventive measures should be put in practice to avoid their presence on farms due to their harmful effect on cavy rearing. PMID- 26612730 TI - Cytoplasmic peptidoglycan intermediate levels in Staphylococcus aureus. AB - Intracellular cytoplasmic peptidoglycan (PG) intermediate levels were determined in Staphylococcus aureus during log-phase growth in enriched media. Levels of UDP linked intermediates were quantitatively determined using ion pairing LC-MS/MS in negative mode, and amine intermediates were quantitatively determined stereospecifically as their Marfey's reagent derivatives in positive mode. Levels of UDP-linked intermediates in S. aureus varied from 1.4 MUM for UDP-GlcNAc Enolpyruvyate to 1200 MUM for UDP-MurNAc. Levels of amine intermediates (L-Ala, D Ala, D-Ala-D-Ala, L-Glu, D-Glu, and L-Lys) varied over a range of from 860 MUM for D-Ala-D-Ala to 30-260 mM for the others. Total PG was determined from the D Glu content of isolated PG, and used to estimate the rate of PG synthesis (in terms of cytoplasmic metabolite flux) as 690 MUM/min. The total UDP-linked intermediates pool (2490 MUM) is therefore sufficient to sustain growth for 3.6 min. Comparison of UDP-linked metabolite levels with published pathway enzyme characteristics demonstrates that enzymes on the UDP-branch range from >80% saturation for MurA, Z, and C, to <5% saturation for MurB. Metabolite levels were compared with literature values for Escherichia coli, with the major difference in UDP-intermediates being the level of UDP-MurNAc, which was high in S. aureus (1200 MUM) and low in E. coli (45 MUM). PMID- 26612731 TI - Octacalcium phosphate collagen composite facilitates bone regeneration of large mandibular bone defect in humans. AB - Recently it was reported that the implantation of octacalcium phosphate (OCP) and collagen composite (OCP-collagen) was effective at promoting bone healing in small bone defects after cystectomy in humans. In addition, OCP-collagen promoted bone regeneration in a critical-sized bone defect of a rodent or canine model. In this study, OCP-collagen was implanted into a human mandibular bone defect with a longer axis of approximately 40 mm, which was diagnosed as a residual cyst with apical periodontitis. The amount of OCP-collagen implanted was about five times greater than the amounts implanted in previous clinical cases. Postoperative wound healing was satisfactory and no infection or allergic reactions occurred. The OCP-collagen-treated lesion was gradually filled with radio-opaque figures, and the alveolar region occupied the whole of the bone defect 12 months after implantation. This study suggests that OCP-collagen could be a useful bone substitute material for repairing large bone defects in humans that might not heal spontaneously. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26612732 TI - A systematic review of randomised controlled trials on the effectiveness of exercise programs on Lumbo Pelvic Pain among postnatal women. AB - BACKGROUND: A substantial number of women tend to be affected by Lumbo Pelvic Pain (LPP) following child birth. Physical exercise is indicated as a beneficial method to relieve LPP, but individual studies appear to suggest mixed findings about its effectiveness. This systematic review aimed to synthesise evidence from randomised controlled trials on the effectiveness of exercise on LPP among postnatal women to inform policy, practice and future research. METHODS: A systematic review was conducted of all randomised controlled trials published between January 1990 and July 2014, identified through a comprehensive search of following databases: PubMed, PEDro, Embase, Cinahl, Medline, SPORTDiscus, Cochrane Pregnancy and Childbirth Group's Trials Register, and electronic libraries of authors'institutions. Randomised controlled trials were eligible for inclusion if the intervention comprised of postnatal exercise for women with LPP onset during pregnancy or within 3 months after delivery and the outcome measures included changes in LPP. Selected articles were assessed using the PEDro Scale for methodological quality and findings were synthesised narratively as meta analysis was found to be inappropriate due to heterogeneity among included studies. RESULTS: Four randomised controlled trials were included, involving 251 postnatal women. Three trials were rated as of 'good' methodological quality. All trials, except one, were at low risk of bias. The trials included physical exercise programs with varying components, differing modes of delivery, follow up times and outcome measures. Intervention in one trial, involving physical therapy with specific stabilising exercises, proved to be effective in reducing LPP intensity. An improvement in gluteal pain on the right side was reported in another trial and a significant difference in pain frequency in another. CONCLUSION: Our review indicates that only few randomised controlled trials have evaluated the effectiveness of exercise on LPP among postnatal women. There is also a great amount of variability across existing trials in the components of exercise programs, modes of delivery, follow up times and outcome measures. While there is some evidence to indicate the effectiveness of exercise for relieving LPP, further good quality trials are needed to ascertain the most effective elements of postnatal exercise programs suited for LPP treatment. PMID- 26612733 TI - Biased cyclical electrical field-flow fractionation for separation of submicron particles. AB - The potential of biased cyclical electrical field-flow fractionation (BCyElFFF), which applies the positive cycle voltage longer than the negative cycle voltage, for characterization of submicron particles, was investigated. Parameters affecting separation and retention such as voltage, frequency, and duty cycle were examined. The results suggest that the separation mechanism in BCyElFFF in many cases is more related to the size of particles, as is the case with normal ElFFF, in the studied conditions, than the electrophoretic mobility, which is what the theory predicts for CyElFFF. However, better resolution was obtained when separating using BCyElFFF mode than when using normal CyElFFF. BCyElFFF was able to demonstrate simultaneous baseline separations of a mixture of 0.04-, 0.1 , and 0.2-MUm particles and near separation of 0.5-MUm particles. This study has shown the applicability of BCyElFFF for separation and characterization of submicron particles greater than 0.1-MUm in size, which had not been demonstrated previously. The separation and retention results suggest that for particles of this size, retention is based more on particle size than on electrophoretic mobility, which is contrary to existing theory for CyElFFF. PMID- 26612734 TI - Usefulness of 11C-methionine positron emission tomography for treatment-decision making in cases of non-enhancing glioma-like brain lesions. AB - The present study evaluated usefulness of the positron emission tomography with (11)C-methionine for prediction of the clinical course and treatment decision making in adult patients with newly diagnosed non-enhancing brain lesions mimicking low-grade gliomas. Retrospective analysis was done in 163 cases. In overall, 131 tumors underwent surgical resection, which in 34 cases was done after initial period of observation. Among the latter 5 patients were operated on after significant clinical deterioration. In overall, 3 resected neoplasms corresponded to WHO histopathological grade I, 87 to grade II, 39 to grade III, and 2 to grade IV. In all 163 cases the tumor/normal brain uptake ratio (T/N ratio) of (11)C-methionine ranged from 0.68 to 8.02 (mean 2.21 +/- 1.16, median 1.81). Mean T/N ratios of non-operated lesions, low-grade and high-grade tumors were 1.60 +/- 0.85, 2.27 +/- 1.22, and 2.54 +/- 1.09, respectively (P < 0.0001), but overlap between 3 groups was prominent. In patients who had clinical deterioration during the period of observation T/N ratios of the lesion varied from 1.49 to 3.38 (mean 2.23 +/- 0.70, median 2.15). Comparison of the deterioration-free survival of patients with T/N ratios of the lesion above and below 1.90 revealed statistically significant difference (P < 0.0001). In conclusion, "wait-and-scan" strategy with delay of surgical treatment does not seem reasonable option if T/N ratio of (11)C-methionine in the non-enhancing glioma-like brain lesion constitutes >=1.90, since it may be associated with significant risk of tumor progression and clinical deterioration during follow up. PMID- 26612735 TI - Amplification of rabbit hepatocyte growth factor and detection of its expression in COS-7 cell line. AB - We used RT-PCR, nested PCR to acquire the partial 5'- race fragment of rabbit HGF cDNA and the partial 3'- race fragment of rabbit HGF cDNA. Then, we used recombination PCR to acquire rabbit HGF successfully. Homology analysis was conducted among the sequence of RABHGF and known human and rat HGF by DNAStar. It was proved that high level of homology existed among the sequences of those three HGF genes. We used the acquired gene of RABHGF to construct its recombinant eukaryotic expression vector pcDNA3.1(+)-RABHGF (pRABHGF). The identification of the eukaryotic expression vector pRABHGF by PCR, restriction enzyme and sequencing analysis showed that rabbit HGF gene was correctly inserted into the vector. pRABHGF and pcDNA3.1(+) as controls were transfected into COS-7 cells by lipofectamine. It takes 24h-36h after transfection to detect the expression of RABHGF protein by indirect immunofluorescence assay (IFA). The proliferation of cos-7 cells were evaluated by MTT assay. The result displayed positive effect of RABHGF protein on the proliferation of COS-7 cells. This study lays the foundation for a new gene therapy method for ischemic heart disease. PMID- 26612736 TI - New insights into the mechanisms of multidrug resistance in cancers. AB - Drug resistance is one of the major obstacles in the treatment of various cancers. Since chemotherapy serves as a most beneficial method for the repression of tumor progression and due to its desirable cell death potency in tumors which reducing metastasis, failure of such a pivotal treatment lead to tumor recurrence and consequent mortality. Multidrug resistance, the principal mechanism by which many cancers develop resistance to chemotherapy drugs, is a major factor in the failure of many forms of chemotherapy. MDR1 overexpression is one form of the multidrug resistance (MDR) phenotype, which can be acquired by patients initially responsive to chemotherapy. In this review, we briefly look inside the recent mechanisms of chemotherapeutic resistance, the MDR1 gene expression in tumors and some novel inhibition-based approaches. PMID- 26612737 TI - Ethanolic extract of Trigonella Foenum Graecum attenuates cisplatin-induced nephro- and hepatotoxicities in rats. AB - Nephro-and hepatotoxicities are important complications in cancer patients undergoing cisplatin (CP) therapy. We aimed to study the protective effect of fenugreek (FG) on CP induced renal and hepatic injuries in rats. Cisplatin intoxication resulted in structural and functional renal and hepatic impairments, which were revealed by massive histopathological changes and elevated kidney and liver function tests. However, it was associated with oxidative stress and lipid peroxidation as evident by increased reactive oxygen species (ROS) and malondialdehyde (MDA) with decreased levels of total antioxidant activity. Cisplatin administration triggered inflammatory responses and apoptosis in rat livers and kidneys as evident by increased expression of pro-inflammatory cytokine, tumor necrosis factor- alpha (TNF-alpha) and apoptotic marker p38 mitogen-activated protein kinase (p38 MAPK) as results of overproduction of ROS. FG significantly attenuated the cisplatin-induced biochemical and histopathological alterations, inflammation and apoptosis in rat livers and kidneys. Results suggested that fenugreek co-administration has a powerful antioxidant effect and may serves as a novel and promising preventive strategy against cisplatin-induced nephron- and hepatotoxicities. PMID- 26612738 TI - Polysaccharide-induced apoptosis in H22 cells through G2/M arrest and BCL2/BAX caspase-activated Fas pathway. AB - The aim of the present work was to investigate the effect and the mechanism of growth inhibition on mouse H22 hepatocarcinoma cell of ascitic tumor induced by cartilage polysaccharides (PS). Our results showed that PS prolonged the survival time of the mice and increased the life span. In addition, PS induced the apoptosis of the H22 cells with the typical apoptotic morphological and biochemical changes confirmed by HE staining and TUNEL assay. The subsequent analysis of cell cycle distribution and relevant proteins revealed that decrease of cells in G0/G1phase and a G2/M arrest might due to the down-regulation of Cyclin D1 and AFP and up-regulation of P21 proteins. Moreover, BCL2/BAX caspase activated Fas pathway was activated in PS-induced H22 apoptosis. PMID- 26612739 TI - Preparation and Isolation of a Chiral Methandiide and Its Application as Cooperative Ligand in Bond Activation. AB - The activation of element-hydrogen bonds by means of metal-ligand cooperation has received increasing attention as alternative to classical activation processes, which exclusively occur at the metal center. Carbene complexes derived from methandiide precursors have been applied in this chemistry enabling the activation of a series of E-H bonds by addition reactions across the M-C bond. However, no chiral carbene complexes have been applied to realize stereoselective transformations to date. Herein, we report the isolation and structure elucidation of an enantiomerically pure dilithiomethane, which could be prepared by direct double deprotonation. The obtained dilithium salt was used for the preparation of the first chiral methandiide-derived carbene complex, which was applied in stereoselective cooperative S-H bond activation. PMID- 26612740 TI - Outcomes of dexmedetomidine treatment in pediatric patients undergoing congenital heart disease surgery: a meta-analysis. AB - BACKGROUND: Dexmedetomidine decreases cardiac complications in adults undergoing cardiovascular surgery. This systematic review assessed whether perioperative dexmedetomidine improves congenital heart disease (CHD) surgery outcomes in children. METHODS: The PubMed, Embase, and Cochrane Library databases were searched for randomized controlled trials (RCTs) or observational studies that were published until 16 April 2015 and compared dexmedetomidine with placebo or an alternative anesthetic agent during pediatric CHD surgery. The assessed outcomes included hemodynamics, ventilation length, intensive care unit (ICU) and hospital stays, blood glucose and serum cortisol levels, postoperative analgesia requirements, and postoperative delirium. RESULTS: Five RCTs and nine observational studies involving 2229 patients were included. In pooled analyses, dexmedetomidine was associated with shorter length of mechanical ventilation (mean difference: -93.36, 95% CI: -137.45, -49.27), lower postoperative fentanyl (mean difference: -24.11, 95% CI: -36.98, -11.24) and morphine (mean difference: 0.07, 95% CI: -0.14, 0.00) requirements, reduced stress response (i.e., lower blood glucose and serum cortisol levels), and lower risk of delirium (OR: 0.39, 95% CI: 0.21, 0.74). The hemodynamics of dexmedetomidine-treated patients appeared more stable, but there were no significant differences in the ICU or hospital stay durations. Dexmedetomidine may increase the bradycardia and hypotension risk (OR: 3.14, 95% CI: 1.47, 6.69). CONCLUSIONS: Current evidence indicates that dexmedetomidine improves outcomes in children undergoing CHD surgery. However, this finding largely relies on data from observational studies; high-quality RCTs are warranted because of the potential for subject selection bias. PMID- 26612741 TI - Physiological implications of mammalian ferritin-binding proteins interacting with circulating ferritin and a new aspect of ferritin- and zinc-binding proteins. AB - Serum ferritin levels are relatively low (<1 ug/ml) and serum ferritin generally disappears rapidly from the circulation (t 1/2 < 10 min). There are various mammalian ferritin-binding proteins (FBPs) in the blood. Ferritin is cleared by direct uptake by ferritin receptors and by indirect receptor-mediated uptake of FBP complexed with ferritin. Mammalian ferritin binds both heme and iron, and binding occurs through two mechanisms: direct binding with ferritin to H kininogen and anti-ferritin autoantibody, and indirect heme-mediated binding of fibrinogen and apolipoprotein B to ferritin. Anti-ferritin autoantibody and fibrinogen are proposed to be common mammalian FBPs, as is alpha2-macroglobulin. FBP-ferritin binding may affect blood coagulation and influence iron metabolism, oxidative condition, angiogenesis, inflammatory condition and immune response. Aside from apolipoprotein B, FBPs bind zinc ion to form antioxidant and anti inflammatory agents. The possible simultaneous uptake of zinc ion with FBP ferritin complex is likely to attenuate iron- and/or heme-mediated oxidative damage and inflammatory response. PMID- 26612742 TI - Temperature responsive behavior of polymer brush/polyelectrolyte multilayer composites. AB - The complex interaction of polyelectrolyte multilayers (PEMs) physisorbed onto end-grafted polymer brushes with focus on the temperature-responsive behavior of the system is addressed in this work. The investigated brush/multilayer composite consists of a poly(styrene sulfonate)/poly(diallyldimethylammonium chloride) (PSS/PDADMAC) multilayer deposited onto the poly(N-isopropylacrylamide-b dimethylaminoethyl methacrylate) P(NIPAM-b-DMAEMA) brush. Ellipsometry and neutron reflectometry were used to monitor the brush collapse with the thickness decrease as a function of temperature and the change in the monomer distribution perpendicular to the substrate at temperatures below, across and above the phase transition, respectively. It was found that the adsorption of PEMs onto polymer brushes had a hydrophobization effect on PDMAEMA, inducing the shift of its phase transition to lower temperatures, but without suppressing its temperature responsiveness. Moreover, the diffusion of the free polyelectrolyte chains inside the charged brush was proved by comparing the neutron scattering length density profile of pure and the corresponding PEM-capped brushes, eased by the enhanced contrast between hydrogenated brushes and deuterated PSS chains. The results presented herein demonstrate the possibility of combining a temperature responsive brush with polyelectrolyte multilayers without quenching the responsive behavior, even though significant interpolyelectrolyte interactions are present. This is of importance for the design of multicompartment coatings, where the brush can be used as a reservoir for the controlled release of substances and the multilayer on the top as a membrane to control the diffusion in/out by applying different stimuli. PMID- 26612743 TI - Defining the Systemic Inflammatory Response Syndrome in Equine Neonates. AB - Defining and describing the systemic inflammatory response syndrome (SIRS) and sepsis facilitated recognition and investigation of the complex disease processes involving the host response to infection and trauma. Over the years a variety of definitions of SIRS have been examined and applied to numerous research studies to improve critical care in both human and veterinary clinical practice. This article summarizes the history of the development of the SIRS definition, outlines the pathophysiologic processes that are involved in SIRS, and provides a specific definition for use in foal medicine. PMID- 26612744 TI - Sepsis and Septic Shock in the Equine Neonate. AB - Sepsis and septic shock represent a major cause of morbidity and mortality in equine neonates and in all species. Early recognition of the condition is important, but definitive examination and laboratory variables to predict equine neonatal sepsis are lacking. Early and aggressive treatment should include broad spectrum antimicrobial coverage, source control, and hemodynamic support. Field practitioners and intensive care clinicians work together in the management of this condition because the recognition and initial treatment should begin as early as possible. PMID- 26612745 TI - Diagnostic Imaging of the Lower Respiratory Tract in Neonatal Foals: Radiography and Computed Tomography. AB - Diagnostic imaging plays an essential role in the diagnosis and monitoring of lower respiratory disease in neonatal foals. Radiography is most widely available to equine practitioners and is the primary modality that has been used for the characterization of respiratory disease in foals. Computed tomography imaging, although still limited in availability to the general practitioner, offers advantages over radiography and has been used diagnostically in neonatal foals with respiratory disease. Recognition of appropriate imaging protocols and patient-associated artifacts is critical for accurate image interpretation regardless of the modality used. PMID- 26612746 TI - Ultrasonographic Examination of the Equine Neonate: Thorax and Abdomen. AB - Diagnostic imaging can substantially augment physical examination findings in neonatal foals. Used in combination with radiography or as a stand-alone imaging modality, ultrasound evaluation of the thoracic and abdominal body cavities can be a high-yield diagnostic undertaking. Many of the conditions that afflict neonatal foals are highly amenable to sonographic interrogation, including pneumonia and other changes in the lungs associated with sepsis, systemic inflammatory response syndrome, multiple organ dysfunction, and prematurity; colic arising from medical and surgical causes; and urinary tract disorders. Sonographic imaging is not affected by intracavitary fluid accumulation and reveals abnormalities of soft tissue and bony origin. PMID- 26612747 TI - The Equine Neonatal Cardiovascular System in Health and Disease. AB - The neonatal foal is in a transitional state from prenatal to postnatal circulation. Healthy newborn foals often have cardiac murmurs and dysrhythmias, which are usually transient and of little clinical significance. The neonatal foal is prone to infection and cardiac trauma. Echocardiography is the main tool used for valuation of the cardiovascular system. With prompt identification and appropriate action, dysrhythmias and other sequel to cardiac trauma can be corrected. With infection, the management and prognosis are driven by concurrent sepsis. Congenital disease represents an interesting diagnostic challenge for the neonatologist, but surgical correction is not appropriate for most equids. PMID- 26612748 TI - Anesthesia of the Equine Neonate in Health and Disease. AB - Anesthetizing the neonatal foal presents significant challenges as a result of physiologic differences from the adult equine. This article gives the reader an overview of these differences and the impact they have on anesthetic drug selection, monitoring, and support of the equine neonate. Special emphasis is directed to the sick neonate and appropriate preparation and maintenance of anesthesia in the face of commonly presented disease conditions. PMID- 26612749 TI - The Equine Neonatal Central Nervous System: Development and Diseases. AB - Neonatal encephalopathy is the most common neurologic condition affecting newborn foals and shares similarities with perinatal asphyxia syndrome of human infants. In many cases of neonatal encephalopathy there is no obvious episode of acute or chronic hypoxia and other mechanisms likely play a role in the pathogenesis. Increased concentrations of neuroactive progestagens are found in affected foals; whether these molecules are protective, as has been suggested, or play a role in the pathogenesis is unknown. Neurologic diseases other than neonatal encephalopathy affect foals occasionally and should be considered when evaluating sick foals with clinical signs of neurologic dysfunction. PMID- 26612750 TI - The Normal and Abnormal Equine Neonatal Musculoskeletal System. AB - The first weeks of life are critical in many aspects, and the musculoskeletal system is no exception. Being able to stand and nurse within hours of life is necessary for survival. Laxity, flexural deformities, and skeletal immaturity can all make it difficult for neonates to ambulate. The increased vascularity to bones and cartilage mixed with the newly forming immune system also make neonates susceptible to infections that we rarely see in adult animals. This article concentrates on orthopedic conditions seen in the first 2 weeks of life. PMID- 26612751 TI - Prognostic Indicators for Survival and Athletic Outcome in Critically Ill Neonatal Foals. AB - Equine neonatal intensive care units have expanded knowledge and understanding of the normal and abnormal physiology of the equine neonate, resulting in successful treatment of critically ill equine neonates. The overall survival rate has increased tremendously since the early 1980s, from a little more than 50% to 80% or more for most facilities. The severely septic foal and the very premature foal still remain large treatment challenges, but less severely septic foals and foals challenged by adverse peripartum events such as dystocia and placentitis are surviving to hospital discharge and performing to the owners' expectation in larger numbers. PMID- 26612756 TI - Discount pharmacies in India will reduce financial burden on patients. PMID- 26612754 TI - Prion-like propagation of human brain-derived alpha-synuclein in transgenic mice expressing human wild-type alpha-synuclein. AB - INTRODUCTION: Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases that are characterized by the intracellular accumulation of alpha-synuclein containing aggregates. Recent increasing evidence suggests that Parkinson's disease and MSA pathology spread throughout the nervous system in a spatiotemporal fashion, possibly by prion-like propagation of alpha synuclein positive aggregates between synaptically connected areas. Concurrently, intracerebral injection of pathological alpha-synuclein into transgenic mice overexpressing human wild-type alpha-synuclein, or human alpha-synuclein with the familial A53T mutation, or into wild-type mice causes spreading of alpha synuclein pathology in the CNS. Considering that wild-type mice naturally also express a threonine at codon 53 of alpha-synuclein, it has remained unclear whether human wild-type alpha-synuclein alone, in the absence of endogenously expressed mouse alpha-synuclein, would support a similar propagation of alpha synuclein pathology in vivo. RESULTS: Here we show that brain extracts from two patients with MSA and two patients with probable incidental Lewy body disease (iLBD) but not phosphate-buffered saline induce prion-like spreading of pathological alpha-synuclein after intrastriatal injection into mice expressing human wild-type alpha-synuclein. Mice were sacrificed at 3, 6, and 9 months post injection and analyzed neuropathologically and biochemically. Mice injected with brain extracts from patients with MSA or probable iLBD both accumulated intraneuronal inclusion bodies, which stained positive for phosphorylated alpha synuclein and appeared predominantly within the injected brain hemisphere after 6 months. After 9 months these intraneuronal inclusion bodies had spread to the contralateral hemisphere and more rostral and caudal areas. Biochemical analysis showed that brains of mice injected with brain extracts from patients with MSA and probable iLBD contained hyperphosphorylated alpha-synuclein that also seeded aggregation of recombinant human wild-type alpha-synuclein in a Thioflavin T binding assay. CONCLUSIONS: Our results indicate that human wild-type alpha synuclein supports the prion-like spreading of alpha-synuclein pathology in the absence of endogenously expressed mouse alpha-synuclein in vivo. PMID- 26612755 TI - RRM1, ERCC1 and TS1 Immunofluorescence Expression in Leiomyosarcoma: A Tissue Microarray Study with Clinical Outcome Correlation Analysis. AB - ERCC1, RRM1 and TS1 are reportedly linked to chemotherapy resistance in lung and other cancers. However, there are currently no studies reporting the relationship between these genes and clinical parameters in leiomyosarcomas. METHOD: This study investigated the expression pattern of ERCC1, RRM1 and TS1 in forty-four leiomyosarcoma samples by the use of tissue microarray (TMA), immunofluorescence and AQUA methods. The results were then analyzed for expression level and correlations were made with clinical outcome to determine their potential prognostic value in leiomyosarcoma. RESULTS: In the forty-four samples studied, the expression level of these three proteins can be well quantified in the AQUA system and reflected by the AQUA score. RRM1 and ERCC1 expression levels did not show any relationship with overall survival. However, a correlation was found between TS1 expression in the cytoplasm and overall survival. The high expression group had a shorter overall survival time (log-rank p = 0.0498). This trend was confirmed by the Cox proportional hazards model. DISCUSSION: The poor overall survival of leiomyosarcoma is linked to TS1 cytoplasm expression which may be useful in predicting prognoses of this tumor, methods targeting expression of TS1 may lead to improved overall survival in leiomyosarcoma, though more detailed information regarding treatment information and a larger sample size is needed to confirm this phenomenon. PMID- 26612757 TI - [Acute monocular visual loss in a child with acute lymphoblastic leukemia]. PMID- 26612758 TI - [Refractory pseudofollicular conjunctivitis]. PMID- 26612759 TI - [Frosted branch angiitis : Clinical findings and Spectralis OCT follow-up]. AB - Frosted branch angiitis is a special form of retinal vasculitis, which has only rarely been reported in the literature. Although the majority of cases of frosted branch angiitis are idiopathic, a systematic clinical work-up should be done in order to exclude other causes, such as infectious and autoimmune diseases. The aim of this study was to correlate the clinical findings with the images obtained during follow-up by spectral domain optical coherence tomography (OCT). PMID- 26612760 TI - 'Tipping the Balance': Karl Friedrich Meyer, Latent Infections, and the Birth of Modern Ideas of Disease Ecology. AB - The Swiss-born medical researcher Karl Friedrich Meyer (1884-1974) is best known as a 'microbe hunter' who pioneered investigations into diseases at the intersection of animal and human health in California in the 1920s and 1930s. In particular, historians have singled out Meyer's 1931 Ludwig Hektoen Lecture in which he described the animal kingdom as a 'reservoir of disease' as a forerunner of 'one medicine' approaches to emerging zoonoses. In so doing, however, historians risk overlooking Meyer's other intellectual contributions. Developed in a series of papers from the mid-1930s onwards, these were ordered around the concept of latent infections and sought to link microbial behavior to broader bio ecological, environmental, and social factors that impact hostpathogen interactions. In this respect Meyer-like the comparative pathologist Theobald Smith and the immunologist Frank Macfarlane Burnet-can be seen as a pioneer of modern ideas of disease ecology. However, while Burnet's and Smith's contributions to this scientific field have been widely acknowledged, Meyer's have been largely ignored. Drawing on Meyer's published writings and private correspondence, this paper aims to correct that lacuna while contributing to a reorientation of the historiography of bacteriological epidemiology. In particular I trace Meyer's intellectual exchanges with Smith, Burnet and the animal ecologist Charles Elton, over brucellosis, psittacosis and plague exchanges that not only showed how environmental and ecological conditions could 'tip the balance' in favor of parasites but which transformed Meyer thinking about resistance to infection and disease. PMID- 26612761 TI - Clustering of immunological, metabolic and genetic features in latent autoimmune diabetes in adults: evidence from principal component analysis. AB - Latent autoimmune diabetes in adults (LADA) which accounts for more than 10 % of all cases of diabetes is characterized by onset after age 30, absence of ketoacidosis, insulin independence for at least 6 months, and presence of circulating islet-cell antibodies. Its marked heterogeneity in clinical features and immunological markers suggests the existence of multiple mechanisms underlying its pathogenesis. The principal component (PC) analysis is a statistical approach used for finding patterns in data of high dimension. In this study the PC analysis was applied to a set of variables from a cohort of Sardinian LADA patients to identify a smaller number of latent patterns. A list of 11 variables including clinical (gender, BMI, lipid profile, systolic and diastolic blood pressure and insulin-free time period), immunological (anti GAD65, anti-IA-2 and anti-TPO antibody titers) and genetic features (predisposing gene variants previously identified as risk factors for autoimmune diabetes) retrieved from clinical records of 238 LADA patients referred to the Internal Medicine Unit of University of Sassari, Italy, were analyzed by PC analysis. The predictive value of each PC on the further development of insulin dependence was evaluated using Kaplan-Meier curves. Overall 4 clusters were identified by PC analysis. In component PC-1, the dominant variables were: BMI, triglycerides, systolic and diastolic blood pressure and duration of insulin-free time period; in PC-2: genetic variables such as Class II HLA, CTLA-4 as well as anti-GAD65, anti-IA-2 and anti-TPO antibody titers, and the insulin-free time period predominated; in PC-3: gender and triglycerides; and in PC-4: total cholesterol. These components explained 18, 15, 12, and 12 %, respectively, of the total variance in the LADA cohort. The predictive power of insulin dependence of the four components was different. PC-2 (characterized mostly by high antibody titers and presence of predisposing genetic markers) showed a faster beta-cells failure and PC-3 (characterized mostly by gender and high triglycerides) and PC-4 (high cholesterol) showed a slower beta-cells failure. PC-1 (including dislipidemia and other metabolic dysfunctions), showed a mild beta-cells failure. In conclusion variable clustering might be consistent with different pathogenic pathways and/or distinct immune mechanisms in LADA and could potentially help physicians improve the clinical management of these patients. PMID- 26612763 TI - Conflicts of interest in tobacco control in India: an exploratory study. AB - INTRODUCTION: The government of India introduced a tobacco control legislation in 2003 and is a party to the WHO Framework Convention on Tobacco Control. However, anecdotal evidence points to the government's conflicting interests in tobacco control and trade. This research seeks to scope instances of conflicts of interests within the government and analyse how they operate in the Indian context. METHODS: We conducted an exploratory study analysing documents over a 2 year period. We scanned media reports related to tobacco, documents of the tobacco industry, information retrieved from governments using the Right to Information Act and relevant websites. The data were analysed through thematic coding. RESULTS: 100 instances of conflicts of interest were found and classified under six categories: public support for the tobacco industry by government institutions or individuals; stakeholding or ownership of tobacco companies by government functionaries; individuals holding positions both in tobacco companies and the government; formal partnerships between the tobacco industry and public agencies; conflicting policies; and incentives available for the tobacco industry. These instances occur at all three levels of government: the individual, institutional and policy levels. CONCLUSIONS: Conflicts of interest are rampant in India and operate in many different ways. These conflicts can lead to negative consequences for tobacco control with far-reaching effects. Varied strategies using legal, administrative and legislative tools need to be adopted to manage conflicts of interest. PMID- 26612762 TI - The classification of hospitalized patients with hyperglycemia and its implication on outcome: results from a prospective observational study in Internal Medicine. AB - The relevance of classifying hyperglycemic hospitalized subjects (HS) as known diabetes (D), newly discovered diabetes (ND), and stress hyperglycemia (SH) is unclear. The aim of this study was to determine the prevalence, in-hospital mortality, and length of stay (LOS) of three different phenotypes of HS. Fasting glucose >=126 mg/dL (7 mmol/L) or random blood glucose >=200 mg/dL (11.1 mmol/L) defined HS who were categorized into three groups: D; ND (no history of diabetes and HbA1c >=48 mmol/mol); SH (no history of diabetes and HbA1c <48 mmol/mol). The end points of the study were in-hospital mortality and LOS. Of 1447 consecutive enrolled subjects, the prevalence of HS was 28.6 % (415/1447), of these 71.6 % had D, 21.2 % SH, and 7.2 % ND, respectively. In-hospital death was 3.9 % in normoglycemic and 6.0 % in hyperglycemic subjects. Individuals with SH had an increased risk of in-hospital death (7.9 %) (HR 2.17, 95 % CI 1.18-4.9; p = 0.039), while this was not observed for D and ND patients. The mean LOS was greater in ND and SH subjects. Hyperglycemia is common, and is associated with an increased risk of in-hospital mortality and extension of hospital stay. HbA1c along with clinical history is a useful tool to identify subgroups of hyperglycemic hospitalized subjects. Individuals with SH have a longer LOS, and a double risk of in-hospital mortality. Additionally, identifying previously unknown diabetes represents a remarkable opportunity for prevention of diabetes related acute and chronic complications. PMID- 26612765 TI - Evaluation of CONSORT compliance in TRANSFUSION. PMID- 26612764 TI - Effect of proximal versus distal 50% enterectomy on nutritional parameters in rats preconditioned with a high-fat diet or regular chow. AB - Obesity may protect against the nutritional consequences of short bowel syndrome. We hypothesized that rats preconditioned with an obesogenic diet would have better outcomes after surgical induction of short bowel syndrome compared to rats on regular chow. Rats were fed a high-fat diet or regular rat chow for six months, and then underwent 50% proximal, 50% distal, or sham enterectomy. Food intake, weight, and body composition were monitored before and for 4 weeks after surgery. The high-fat diet consistently produced obesity (>25% body fat). All procedures induced weight loss, but there was no discernable difference between resection vs. sham resection. Rats on the high-fat diet had a greater post resection loss of body fat compared to rats on chow (36 vs. 26 g, respectively). There was a nonsignificant trend of less lean mass loss in the former compared to the latter rats (16 vs. 33 g, respectively). Enterectomy moderated serum ghrelin, GIP, PPY, insulin, and leptin. Intestinal adaptation was not different between obese vs. non-obese rats. Rats preconditioned with the high-fat diet may have had better retention of lean body mass after a surgical procedure compared to rats on chow. The effect of 50% enterectomy was less than expected. PMID- 26612766 TI - Exome sequencing revealed a novel biallelic deletion in the DCAF17 gene underlying Woodhouse Sakati syndrome. AB - Woodhouse Sakati syndrome (WSS, MIM 241080) is a rare autosomal recessive genetic condition characterized by alopecia, hypogonadism, hearing impairment, diabetes mellitus, learning disabilities and extrapydamidal manifestations. Sequence variants in the gene DCAF17, encoding nucleolar substrate receptor, were identified as the underlying cause of inherited WSS. Considerable phenotypic heterogeneity exists in WSS with regard to severity, organs involvement and age of onset, both in inter-familial and intra-familial cases. In this study, the genetic characterization of a consanguineous pedigree showing mild features of WSS was performed, followed by structural analysis of truncated protein. Exome sequencing identified a novel single base deletion variant (c.270delA; K90Nfs8*) in third exon of the gene DCAF17 (RefSeq; NM_025000), resulting in a truncated protein. Structural analysis of truncated DCAF17 revealed absence of amino acid residues crucial for interaction with DDB1. Taken together, the data confirmed the single base pair deletion as the underlying cause of this second report of WSS from Pakistan. This signifies the vital yet unexplored role of DCAF17 both in development and maintenance of adult tissues homeostasis. PMID- 26612767 TI - Switching first contact: photocontrol of E. coli adhesion to human cells. AB - We have shown previously that carbohydrate-specific bacterial adhesion to a non physiological surface can be photocontrolled by reversible E/Z isomerisation using azobenzene-functionalised sugars. Here, this approach is applied to the surface of human cells. We show not only that bacterial adhesion to the azobenzene glycoside-modified cell surface is higher in the E than in the Z state, but add data about the specific modulation of the effect. PMID- 26612768 TI - Weight Perception, Satisfaction, Control, and Low Energy Dietary Reporting in the U.S. Adult Population: Results from the National Health and Nutrition Examination Survey 2007-2012. AB - BACKGROUND: Prior research has indicated that several factors are associated with low energy dietary reporting; however, there is comparatively little information on the association between body image, weight control, and low energy reporting. OBJECTIVE: Our aim was to evaluate the association between low energy reporting and aspects of weight perception, satisfaction, and control in a nationally representative US adult sample. DESIGN: This was a cross-sectional study. PARTICIPANTS/SETTING: Data were analyzed from 13,581 adults aged 20 years and older who participated in the 2007-2012 National Health and Nutrition Examination Survey. Data on sociodemographic, clinical, and lifestyle characteristics, and weight perception, satisfaction, and control were collected. The ratio of reported energy intake to estimated basal metabolic rate (EI/BMR) was calculated and used for the assessment of low energy reporting. MAIN OUTCOME MEASURES: The relationship of low energy reporting with various aspects of weight perception, satisfaction, and control was evaluated. STATISTICAL ANALYSES PERFORMED: Multivariable logistic regression was used to assess the association between the variables. RESULTS: Low energy reporters were significantly more likely to consider themselves overweight (perception), want to weigh less (satisfaction), and to have tried to lose weight in the past 12 months (control). Compared with having no desire for weight change, wanting to weigh less was associated with 1.28 (95% CI 1.07 to 1.53) times higher odds for low energy reporting. Trying to lose weight was also associated with low energy reporting (odds ratio=1.56; 95% CI 1.38 to 1.76). Effect modification by obesity status was observed for the weight perception, satisfaction, and control variables where the odds ratios of these factors for low energy reporting were higher among those who were not obese. CONCLUSION: Weight perception, satisfaction, and control are related to low energy reporting, and should be taken into account in nutritional assessments. In addition, the effect of these factors can differ by obesity status. PMID- 26612769 TI - American Diet Quality: Where It Is, Where It Is Heading, and What It Could Be. AB - BACKGROUND: Diet quality is critically important to the prevention of many types of chronic disease. The federal government provides recommendations for optimal diet quality through the Dietary Guidelines for Americans, and sets benchmarks for progress toward these recommendations through the Healthy People objectives. OBJECTIVE: This analysis estimated recent trends in American diet quality and compared those trends to the quality of diets that would meet the Healthy People 2020 objectives and the 2010 Dietary Guidelines for Americans in order to measure progress toward our national nutrition goals. DESIGN: This analysis used 24-hour recall data from the cross-sectional National Health and Nutrition Examination Survey, between the years of 1999-2000 and 2011-2012, to determine mean intakes of various dietary components for the US population over time. Mean intakes were estimated using the population ratio method, and diet quality was assessed using the Healthy Eating Index 2010 (HEI-2010). RESULTS: The mean HEI-2010 total score for the US population has increased from 49 in 1999-2000 to 59 in 2011-2012; continuing on that trajectory, it would reach a score of 65 by 2019-2020. A diet that meets the Healthy People 2020 objectives would receive a score of 74 and, by definition, a diet that meets the 2010 Dietary Guidelines for Americans would receive a score of 100. Trends in HEI-2010 component scores vary; all HEI-2010 component scores except sodium have increased over time. CONCLUSIONS: Diet quality is improving over time, but not quickly enough to meet all of the Healthy People 2020 objectives. Whole fruit and empty calories are the only HEI-2010 components on track to meet their respective Healthy People 2020 targets. Furthermore, the country falls short of the 2010 Dietary Guidelines for Americans by a large margin in nearly every component of diet quality assessed by the HEI 2010. PMID- 26612770 TI - A simple approach to obtain hybrid Au-loaded polymeric nanoparticles with a tunable metal load. AB - A new strategy to nanoengineer multi-functional polymer-metal hybrid nanostructures is reported. By using this protocol the hurdles of most of the current developments concerning covalent and non-covalent attachment of polymers to preformed inorganic nanoparticles (NPs) are overcome. The strategy is based on the in situ reduction of metal precursors using the polymeric nanoparticle as a nanoreactor. Gold nanoparticles and poly(DL-lactic-co-glycolic acid), PLGA, are located in the core and shell, respectively. This novel technique enables the production of PLGA NPs smaller than 200 nm that bear either a single encapsulated Au NP or several smaller NPs with tunable sizes and a 100% loading efficiency. In situ reduction of Au ions inside the polymeric NPs was achieved on demand by using heat to activate the reductive effect of citrate ions. In addition, we show that the loading of the resulting Au NPs inside the PLGA NPs is highly dependent on the surfactant used. Electron microscopy, laser irradiation, UV-Vis and fluorescence spectroscopy characterization techniques confirm the location of Au nanoparticles. These promising results indicate that these hybrid nanomaterials could be used in theranostic applications or as contrast agents in dark-field imaging and computed tomography. PMID- 26612771 TI - MMP-2 serum concentrations predict mortality in hemodialysis patients: a 5-year cohort study. AB - BACKGROUND: We evaluated the ability of matrix metalloproteinase (MMP)-2, MMP-9, myeloperoxidase, osteopontin and stromal cell-derived factor 1 to predict mortality in hemodialysis (HD) patients. METHODS: One hundred forty HD patients were enrolled and followed from December 2007 until December 2012. At the end of this 5-year period, data were compared between the patients who were alive and those who had died. RESULTS: The patients who alive were younger (56 vs. 63y), with lower frequency of diabetes mellitus (34.34% vs. 58.53%), higher concentrations of albumin (4.13 vs. 3.91mg/dl) and lower concentrations of MMP-2 (430.76 vs. 521.59ng/ml). Multivariate analysis showed that age (HR=1.03, p=0.02), diabetes mellitus (HR=2.395, p=0.012), albumin (HR=0.475, p=0.047) and MMP-2 (HR=1.003, p=0.005) were independent factors predicting mortality in HD patients. Receiver operating characteristic curve analysis showed that albumin (AUC=0.628, p=0.027) and MMP-2 (AUC=0.643, p=0.004) had a similar ability (p=0.76) to predict survival of HD patients. CONCLUSIONS: Compared with albumin, serum MMP-2 is a non-inferior prognostic marker for predicting the survival of HD patients. PMID- 26612772 TI - Homozygous familial hypobetalipoproteinemia: A Turkish case carrying a missense mutation in apolipoprotein B. AB - The autosomal co-dominant disorder familial hypobetalipoproteinemia (FHBL) may be due to mutations in the APOB gene encoding apolipoprotein B (apoB), the main constituent peptide of chylomicrons, very low and low density lipoproteins. We describe an 11month-old child with failure to thrive, intestinal lipid malabsorption, hepatic steatosis and severe hypobetalipoproteinemia, suggesting the diagnosis of homozygous FHBL, abetalipoproteinemia (ABL) or chylomicron retention disease (CMRD). The analysis of candidate genes showed that patient was homozygous for a variant (c.1594 C>T) in the APOB gene causing arginine to tryptophan conversion at position 505 of mature apoB (Arg505Trp). No mutations were found in a panel of other potential candidate genes for hypobetalipoproteinemia. In vitro studies showed a reduced secretion of mutant apoB-48 with respect to the wild-type apoB-48 in transfected McA-RH7777 cells. The Arg505Trp substitution is located in the betaalpha1 domain of apoB involved in the lipidation of apoB mediated by microsomal triglyceride transfer protein (MTP), the first step in VLDL and chylomicron formation. The patient's condition improved in response to a low fat diet supplemented with fat-soluble vitamins. Homozygosity for a rare missense mutation in the betaalpha1 domain of apoB may be the cause of both severe hypobetalipoproteinemia and intestinal lipid malabsorption. PMID- 26612774 TI - Formative evaluation of a patient-specific clinical knowledge summarization tool. AB - OBJECTIVE: To iteratively design a prototype of a computerized clinical knowledge summarization (CKS) tool aimed at helping clinicians finding answers to their clinical questions; and to conduct a formative assessment of the usability, usefulness, efficiency, and impact of the CKS prototype on physicians' perceived decision quality compared with standard search of UpToDate and PubMed. MATERIALS AND METHODS: Mixed-methods observations of the interactions of 10 physicians with the CKS prototype vs. standard search in an effort to solve clinical problems posed as case vignettes. RESULTS: The CKS tool automatically summarizes patient specific and actionable clinical recommendations from PubMed (high quality randomized controlled trials and systematic reviews) and UpToDate. Two thirds of the study participants completed 15 out of 17 usability tasks. The median time to task completion was less than 10s for 12 of the 17 tasks. The difference in search time between the CKS and standard search was not significant (median=4.9 vs. 4.5m in). Physician's perceived decision quality was significantly higher with the CKS than with manual search (mean=16.6 vs. 14.4; p=0.036). CONCLUSIONS: The CKS prototype was well-accepted by physicians both in terms of usability and usefulness. Physicians perceived better decision quality with the CKS prototype compared to standard search of PubMed and UpToDate within a similar search time. Due to the formative nature of this study and a small sample size, conclusions regarding efficiency and efficacy are exploratory. PMID- 26612775 TI - Dual mode ratiometric recognition of zinc acetate: nanomolar detection with in vitro tracking of endophytic bacteria in rice root tissue. AB - Several naphthalene-based aldazine derivatives were developed as efficient colorimetric and fluorescence probes for selective ratiometric recognition of traces of zinc acetate. The derivative structures were characterized by single crystal X-ray diffraction. The probes were used for in vitro tracking of zinc acetate in endophytic bacteria within rice root tissue and to image zinc acetate in human breast cancer cells (MCF7) by normal and fluorescence microscopy. Density functional theoretical studies were in close agreement with the experimental findings. PMID- 26612773 TI - Recommendations Concerning the First-Line Treatment of Children with Tuberculosis. AB - This document describes the recommendations of a group of scientific societies concerning the first-line therapeutic approach to paediatric tuberculosis (TB). The treatment of pulmonary TB should be based on the existence of parenchymal involvement and the risk of antibiotic resistance. The treatment of extra pulmonary TB is based on the regimens used for severe pulmonary TB. The administration of corticosteroids is recommended only in cases of miliary TB, tuberculous meningitis and tuberculous pericarditis. Vitamin B6 may be indicated in the case of isoniazid-treated TB in breastfeeding infants, severely malnourished subjects, or patients with other diseases at high risk of vitamin deficiency. Once having started treatment, children with TB should be carefully followed up in order to evaluate compliance, the response to treatment, the need for treatment changes, and the presence of drug-related adverse events. Primary care paediatricians can support reference centres in providing family healthcare education and encouraging treatment compliance. PMID- 26612778 TI - Pathogenesis and treatments of TGFBI corneal dystrophies. AB - Transforming growth factor beta-induced (TGFBI) corneal dystrophies are a group of inherited progressive corneal diseases. Accumulation of transforming growth factor beta-induced protein (TGFBIp) is involved in the pathogenesis of TGFBI corneal dystrophies; however, the exact molecular mechanisms are not fully elucidated. In this review article, we summarize the current knowledge of TGFBI corneal dystrophies including clinical manifestations, epidemiology, most common and recently reported associated mutations for each disease, and treatment modalities. We review our current understanding of the molecular mechanisms of granular corneal dystrophy type 2 (GCD2) and studies of other TGFBI corneal dystrophies. In GCD2 corneal fibroblasts, alterations of morphological characteristics of corneal fibroblasts, increased susceptibility to intracellular oxidative stress, dysfunctional and fragmented mitochondria, defective autophagy, and alterations of cell cycle were observed. Other studies of mutated TGFBIp show changes in conformational structure, stability and proteolytic properties in lattice and granular corneal dystrophies. Future research should be directed toward elucidation of the biochemical mechanism of deposit formation, the relationship between the mutated TGFBIp and the other materials in the extracellular matrix, and the development of gene therapy and pharmaceutical agents. PMID- 26612779 TI - Changes in the dominant assembly mechanism drive species loss caused by declining resources. AB - The species-energy hypothesis predicts that more productive areas support higher species richness. Conversely, when resources are reduced, species richness is reduced. Empirical tests of whether extinctions are predominantly caused by environmental constraints or competitive exclusion are lacking. We experimentally reduced dead wood to c. 15% of the initial amount after a major windstorm and examined changes in assembly mechanisms by combining trait-based and evolutionary species dissimilarities of eight taxonomic groups, differing in their dependence on dead wood (saproxylic/non-saproxylic). Species richness and assembly mechanisms of non-saproxylic taxa remained largely unaffected by removal of dead wood. By contrast, extinctions of saproxylic species were caused by reversing the predominant assembly mechanisms (e.g. increasing importance of competitive exclusion for communities assembled through environmental filtering or vice versa). We found no evidence for an intensification of the predominant assembly mechanism (e.g. competitive exclusion becoming stronger in a competitively structured community). PMID- 26612780 TI - Incorporation of a Non-Natural Arginine Analogue into a Cyclic Peptide Leads to Formation of Positively Charged Nanofibers Capable of Gene Transfection. AB - Functionalization of the tetracationic cyclic peptide (Ka)4 with a single guanidiniocarbonyl pyrrole (GCP) moiety, a weakly basic but highly efficient arginine analogue, completely alters the self-assembly properties of the peptide. In contrast to the nonfunctionalized peptide 2, which does not self-assemble, GCP containing peptide 1 forms cationic nanofibers of micrometer length. These aggregates are efficient gene transfection vectors. DNA binds to their cationic surface and is efficiently delivered into cells. PMID- 26612781 TI - A monotopic aluminum telluride with an Al=Te double bond stabilized by N heterocyclic carbenes. AB - Aluminum chalcogenides are mostly encountered in the form of bulk aluminum oxides that are structurally diverse but typically consist of networks with high lattice energy in which the chalcogen atoms bridge the metal centres. This makes their molecular congeners difficult to synthesize because of a pronounced tendency for oligomerization. Here we describe the isolation of the monotopic aluminum chalcogenide (L(Dip)N)AlTe(L(Et))2 (L(Dip)=1,3-(2,6-diisopropylphenyl)-imidazolin 2-imine, L(Et)=1,3-diethyl-4,5-dimethyl-imidazolin-2-ylidene). Unique features of (L(Dip)N)AlTe(L(Et))2 are the terminal position of the tellurium atom, the shortest aluminum-tellurium distance hitherto reported for a molecular complex and the highest bond order reported for an interaction between these elements, to the best of our knowledge. At elevated temperature (L(Dip)N)AlTe(L(Et))2 equilibrates with dimeric {(L(Dip)N)AlTe(L(Et))}2 in which the chalcogen atoms assume their common role as bridges between the metal centres. These findings demonstrate that (L(Dip)N)AlTe(L(Et))2 comprises the elusive Al=Te double bond in the form of an N-heterocyclic carbene-stabilized species. PMID- 26612782 TI - Expression profiles of human epididymis epithelial cells reveal the functional diversity of caput, corpus and cauda regions. AB - STUDY HYPOTHESIS: Region-specific transcriptional profiling of tissues and cultured epithelial cells from the human epididymis will predict functional specialization along the duct. STUDY FINDING: We identified the molecular signature driving functions of the caput, corpus and cauda epithelium, and determined how these differ to establish the regional differentiation of the organ. WHAT IS KNOWN ALREADY: The epithelium lining the human male genital ducts has a critical role in fertility. In particular, it controls the luminal environment in the epididymis, which is required for normal sperm maturation and reproductive competence. Studies in many animal species have largely informed our understanding of the molecular basis of epididymis function. However, there are substantial differences between species. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Using RNA sequencing on biological replicates, we described gene expression profiles for tissue from each region of the epididymis and cultured epithelial cells derived from these regions. Bioinformatic tools were then utilized to identify differentially expressed genes (DEGs) between tissues and cells from the caput, corpus and cauda. MAIN RESULTS AND THE ROLE OF CHANCE: The data showed that the caput is functionally divergent from the corpus and cauda, which have very similar transcriptomes. Interrogation of DEGs using gene ontology process enrichment analyses showed that processes of ion transport, response to hormone stimulus and urogenital tract development are more evident in the caput, while defense response processes are more important in the corpus/cauda. Consistent with these regional differences in epididymis function, we observed differential expression of transcription factors in the caput and corpus/cauda. LIMITATIONS, REASONS FOR CAUTION: Cultured caput, corpus and cauda cells may not faithfully represent the same cells in the intact organ, due to loss of hormonal signals from the testis and communication from other cell types. WIDER IMPLICATIONS OF THE FINDINGS: Our data provide a molecular characterization that will facilitate advances in understanding human epididymis epithelium biology in health and disease. They may also reveal the mechanisms coordinating epididymis luminal environment and sperm maturation. LARGE SCALE DATA: Data deposited at http://www.ncbi.nlm.nih.gov/geo/GSE72986. STUDY FUNDING AND COMPETING INTERESTS: This work was supported by the National Institutes of Health: R01HD068901 (PI: A.H.). The authors declare no conflict of interest. PMID- 26612783 TI - Can dicoumarol be used as a gonad-safe anticancer agent: an in vitro and in vivo experimental study. AB - STUDY HYPOTHESIS: Dicoumarol (DC) has potential for use as a gonad-safe anticancer agent. STUDY FINDING: DC altered cell proliferation, decreased viability and increased apoptosis in Vero and MCF-7 cell lines but did not show any toxic effect on mouse ovarian tissues and developing oocytes in vitro and in vivo. WHAT IS KNOWN ALREADY: DC suppresses cell proliferation and increases apoptosis in various cancer cells such as breast, urogenital and melanoma. DC has also been reported to alter the anticancer effects of several chemotherapeutics, including cisplatin, gemcitabine and doxorubicin in prostate, liver and uroepithelial cancer cells, respectively. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Vero (African green monkey kidney epithelial cells) and MCF-7 (human cancerous breast epithelial cells) cell lines and mouse granulosa cells isolated from 21-day-old female BALB/c mice (n = 21) were used to assess the effects of DC (10, 50, 100 and 200 um) for 24 and 48 h on cell proliferation, viability and apoptotic cell death. In vivo experiments were performed with a single i.p. injection of 32 mg/kg DC in 21-day-old female BALB/c mice (n = 12). Following 48 h, animals were sacrificed by cervical dislocation and histological sections of isolated ovaries were evaluated for apoptosis. Viability assays were based on the trypan blue dye exclusion method and an automated cell counter device was used. Terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling (TUNEL) and Annexin-V immunofluorescence were assessed by 3D confocal microscopy to address apoptotic cell death. We also assessed whether DC inhibits cell proliferation and viability through NQO1 [NAD(P)H Quinone Oxidoreductase 1], an intracellular inhibitor of reactive oxygen species (ROS). The meiotic spindle and chromosomes were studied in mouse oocytes by alpha-beta-tubulin and 7-aminoactinomycine D (7 AAD) immunostaining in vitro and in vivo. MAIN RESULTS AND THE ROLE OF CHANCE: DC does not block oocyte maturation and no significant alteration was noted in meiotic spindle or chromosome morphology in metaphase-II (M-II) stage oocytes following DC treatment in vitro or in vivo. In contrast, exposure to DC for 24 h suppressed cell proliferation (P = 0.026 at 200 um), decreased viability (P = 0.002 at 200 um) and increased apoptosis (P = 0.048 at 100 um) in Vero and MCF-7 cell lines, compared with controls. These changes were not related to intracellular NQO1 levels. Mouse granulosa cells were unaffected by 50 or 100 um DC treatment for 24 and 48 h in vitro. DC treatment in vivo did not alter the number of primordial follicles or the ratio of apoptosis in primordial, primary and secondary follicles, as well as in antral follicles, compared with the controls. LIMITATIONS, REASONS FOR CAUTION: DC was tested for ovarian toxicity only in isolated mouse oocytes/ovaries and healthy BALB/c mice. No cancer formation was used as an in vivo test model. The possibility that DC may potentiate ovarian toxicity when combined with traditional chemotherapeutic agents, such as mitomycin-C, cisplatin, gemcitabine and doxorubicin, must be taken into account, as DC is known to alter their effects in some cancer cells. WIDER IMPLICATIONS OF THE FINDINGS: The present study evaluated, for the first time, the effect of DC on ovarian tissue. The results suggested that DC is not toxic to ovarian tissues and developing oocytes; therefore, DC should be assessed further as a potential anticancer agent when female fertility preservation is a concern. LARGE SCALE DATA: N/A. STUDY FUNDING AND COMPETING INTERESTS: This work includes data from dissertation thesis entitled 'Effects of dicoumarol on mitotic and meiotic cells as an anticancer agent' by DA, 2014 and was partly supported by The National Scientific and Technological Research Council of Turkey (SBAG 109S415) to AC, OC and SO. The authors confirm that this article content presents no conflicts of interest. PMID- 26612785 TI - The need for long-term remedies for Indonesia's forest fires. PMID- 26612784 TI - A Chinese Decoction, Kuan-Sin-Yin, Improves Autonomic Function and Cancer-Related Symptoms of Metastatic Colon Cancer. AB - BACKGROUND: Kuan-Sin-Yin (KSY) is a traditional Chinese medicine (TCM) decoction, which has been shown to have cytostatic effects on cancer cells and involved in the TCM theory of promoting yin-yang balance.Sonce many cancer patients suffer from autonomic dysfunction (AD), which correspond to yin-yang imbalance in TCM. The aim of this study is to evaluate the possible effect of KSY in metastatic colon cancer (mCRC) patients with AD. METHODS: We conducted a single-group experiment. Total 52 qualified patients were enrolled. Participants took the KSY daily for 2 weeks. The primary outcome was KSY efficacy as reflected in the heart rate variability (HRV) and electrical conductivity (uA) over 12 meridian points. Autonomic function was examined before and after the KSY intervention. The vagal and sympathetic tone were recorded by HRV; 12 meridian energies were measured using a meridian energy analysis device. Secondary outcomes were cancer-related symptoms and patient quality of life (QoL). RESULTS: The results showed that the KSY intervention improved AD via increasing the vagal tone (HF: P = .041), but not the sympathetic tone (LF: P = .154); total autonomic activity was significantly enhanced (HRV activity: P = .013). Intriguingly, energy increased more over the yin meridian (P = .010) than over the yang meridian (P = .015). Cancer-related symptoms and QoL were significantly improved (P < .05). CONCLUSION: The safety and effectiveness of KSY in improving AD in mCRC patients are through regulating the vagal-sympathetic dynamic balance, which correspond to the TCM yin-yang concept of energy. PMID- 26612788 TI - Meta-analysis in Stata using gllamm. AB - There are several user-written programs for performing meta-analysis in Stata (Stata Statistical Software: College Station, TX: Stata Corp LP). These include metan, metareg, mvmeta, and glst. However, there are several cases for which these programs do not suffice. For instance, there is no software for performing univariate meta-analysis with correlated estimates, for multilevel or hierarchical meta-analysis, or for meta-analysis of longitudinal data. In this work, we show with practical applications that many disparate models, including but not limited to the ones mentioned earlier, can be fitted using gllamm. The software is very versatile and can handle a wide variety of models with applications in a wide range of disciplines. The method presented here takes advantage of these modeling capabilities and makes use of appropriate transformations, based on the Cholesky decomposition of the inverse of the covariance matrix, known as generalized least squares, in order to handle correlated data. The models described earlier can be thought of as special instances of a general linear mixed-model formulation, but to the author's knowledge, a general exposition in order to incorporate all the available models for meta-analysis as special cases and the instructions to fit them in Stata has not been presented so far. Source code is available at http:www.compgen.org/tools/gllamm. PMID- 26612786 TI - Hypersexuality, Paraphilic Behaviors, and Gender Dysphoria in Individuals with Klinefelter's Syndrome. AB - INTRODUCTION: An increased risk of autistic traits in Klinefelter syndrome (KS) has been reported. In addition, some studies have shown an increased incidence of gender dysphoria (GD) and paraphilia in autism spectrum disorder. AIM: The aim of this study was to evaluate the presence of (i) paraphilic fantasies and behaviors; and (ii) GD symptomatology in KS. METHODS AND MAIN OUTCOMES MEASURES: A sample of 46 KS individuals and 43 healthy male controls (HC) were evaluated. Subjects were studied by means of several psychometric tests, such as Autism Spectrum Quotient (AQ) and Reading the Mind in the Eyes Revised (RME) to measure autistic traits, Gender Identity/GD questionnaire (GIDYQ-AA), and Sexual Addiction Screening Test (SAST). In addition, body uneasiness psychopathological symptoms were assessed using Symptom Checklist 90 Revised (SCL-90-R). The presence and frequency of any paraphilic fantasy and behavior was assessed by means of a clinical interview based on Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria. Finally, all individuals included were assessed by Wechsler Adult Intelligence Scale-Revised to evaluate intelligence quotient (IQ). Data from a subsample of a previous published series of male to female GD individuals, with the battery of psychological measures useful to provide a psychopathological explanation of GD in KS population available, was also considered. RESULTS: When compared with HC, KS reported significantly lower total, verbal and performance IQ scores and higher SCL-90 obsession-compulsive symptoms (all P < 0.001). In line with previously reported findings, KS showed higher autistic traits according with both RME and AQ tests (P < 0.001). With respect to sexuality, KS showed a significant higher frequency of voyeuristic fantasies during masturbation (52.2% vs. 25.6%) and higher SAST scores (P = 0.012). A mediation role of obsessive symptoms on the relationship between Klinefelter and SAST was confirmed (unstandardized estimate b = 2.75, standard error = 0.43 P < 0.001). Finally, KS individuals showed significantly higher gender dysphoric symptoms than HC (P = 0.004), which were mediated by the presence of autistic traits (Sobel's test; P < 0.05). CONCLUSIONS: KS is associated with hypersexuality, paraphilic behaviors, and GD, which were mediated by obsessive-compulsive and autistic traits. PMID- 26612787 TI - Exploring the relationship between the causal-inference and meta-analytic paradigms for the evaluation of surrogate endpoints. AB - Nowadays, two main frameworks for the evaluation of surrogate endpoints, based on causal-inference and meta-analysis, dominate the scene. Earlier work showed that the metrics of surrogacy introduced in both paradigms are related, although in a complex way that is difficult to study analytically. In the present work, this relationship is further examined using simulations and the analysis of a case study. The results indicate that the extent to which both paradigms lead to similar conclusions regarding the validity of the surrogate, depends on a complex interplay between multiple factors like the ratio of the between and within trial variability and the unidentifiable correlations between the potential outcomes. All the analyses were carried out using the newly developed R package Surrogate, which is freely available via CRAN. PMID- 26612789 TI - [Not Available]. PMID- 26612791 TI - Systemic therapy of metastatic melanoma. AB - For patients with metastatic melanoma, there are currently several effective therapeutic options. The BRAF inhibitors vemurafenib and dabrafenib are characterized by rapid tumor control and high response rates. In combination with one of the two MEK inhibitors trametinib and cobimetinib, they achieve response rates (CR + PR, complete plus partial remissions) of 70%, while delaying the development of treatment resistance, as well as a median overall survival of > 2 years with tolerable side effects. Showing long-term survival rates of approximately 20%, the anti-CTLA-4 antibody ipilimumab is the first substance that has led to a significant prolongation of overall survival in patients with metastatic melanoma. However, delayed treatment response and severe immune mediated side effects may pose limitations to its therapeutic benefit. Usually well tolerated, anti-PD-1 antibody monotherapy using nivolumab and pembrolizumab has yielded response rates (CR + PR) of up to 45% and one-year survival rates of > 70%. The combination of ipilimumab and nivolumab has shown response rates of up to 58% and a median progression-free survival of > 11 months. While this combination is expected to result in a rapid and long-lasting response, this potential benefit comes at the expense of a high level of toxicity. Strategies for treatment sequencing and treatment combinations are currently being investigated in clinical studies. Overall, the prognosis for patients with metastatic melanoma has significantly improved. With long-term survival a possibility, not only acute but also long-term therapeutic side effects must be taken into account. PMID- 26612792 TI - Daylight PDT with MAL - current data and practical recommendations of an expert panel. AB - Photodynamic Therapy (PDT) is one of the standard treatment modalities for actinic keratoses (AKs). Daylight PDT (DL-PDT) with MAL cream is a rather recent development, which, instead of an artificial light source, uses daylight for the activation of the photosensitizer. The present review summarizes available data based on a selective literature search, highlights practical aspects, and reflects the authors' expert knowledge in using DL-PDT. With respect to efficacy, study data shows that DL-PDT is noninferior to conventional PDT (cPDT). However, given that DL-PDT is markedly less painful, it is significantly better tolerated than cPDT. In Europe, DL-PDT can be performed from March to October, on sunny as well as on cloudy days. UV protection of untreated areas of the body should be observed. Outside temperature should not fall below 10 degrees C. On hot days, patients should be advised to stay in the shade if necessary. Representing a useful addition to current therapeutic options, DL-PDT with MAL cream is, among others, suitable for patients with field cancerization and/or those who have experienced severe pain associated with cPDT. PMID- 26612794 TI - Solar urticaria. AB - Solar urticaria is a rare IgE-mediated and chromophore-dependent photodermatosis. In some cases, these chromophores, designated as "serum factor", may be detected in serum or plasma. To date, the exact pathogenesis of solar urticaria has, however, not been elucidated. Typical clinical features include the onset of urticarial lesions within a few minutes after light exposure, which already raises diagnostic suspicion. The most common triggers are UVA and visible light. Determination of the action spectrum as well as the minimal urticarial dose (MDU) is diagnostically crucial. Other photodermatoses such as polymorphic light eruption or porphyrias (especially erythropoietic protoporphyria) have to be ruled out. Apart from sunlight avoidance, which is always required, further therapeutic options used include nonsedating antihistamines as well as light hardening. Newer treatment modalities such as plasmapheresis or the anti-IgE antibody omalizumab are reserved for severe, recalcitrant forms of solar urticaria. PMID- 26612796 TI - Pseudosyndactyly - an inflammatory and fibrotic wound healing disorder in recessive dystrophic epidermolysis bullosa. AB - BACKGROUND: A genetic blistering skin disease, recessive dystrophic epidermolysis bullosa (RDEB), is marked by severe wound healing defects and finger contractures. The purpose of this investigation was to elucidate the mechanisms of impaired wound healing and pseudosyndactyly occurring in RDEB patients by studying the role of known inflammation and fibrosis markers in RDEB pseudosyndactyly tissue. PATIENTS AND METHODS: We studied the expression of the fibrosis and/or inflammation markers tenascin-C, alpha-smooth muscle actin, transforming growth factor-beta1, interleukin-1beta, and interleukin-6 in scarring and nonscarring tissue from healthy donors and RDEB patients by semiquantitative real time-PCR and, where applicable, by immunoblots. Furthermore, the distribution pattern of alpha-smooth muscle actin and tenascin-C were assessed by immunofluorescence microscopy. RESULTS: Based on mRNA and protein analysis, we found upregulation of tenascin-C, interleukin-1beta, and interleukin-6 - but not of transforming growth factor-beta1 - in recessive dystrophic epidermolysis bullosa scar samples taken from pseudosyndactyly hands. Unexpectedly, alpha-smooth muscle actin was not upregulated. CONCLUSIONS: Our results confirm inflammation and fibrosis in recessive dystrophic epidermolysis bullosa, especially in scars, suggesting major roles for these processes in pseudosyndactyly. Our data therefore suggests the potential use of antiinflammatory and antifibrotic drugs in the prevention of pseudosyndactyly. PMID- 26612798 TI - Diagnostic relevance of direct immunofluorescence in ocular mucous membrane pemphigoid. AB - BACKGROUND AND OBJECTIVES: The objective was to determine the diagnostic value of direct immunofluorescence (DIF) in ocular mucous membrane pemphigoid (ocular MMP), taking into account immunofluorescence patterns and biopsy sites. PATIENTS AND METHODS: DIF results and medical records of 54 patients with a suspected diagnosis of ocular MMP were reviewed. RESULTS: There was an overall prevalence of ocular MMP in 70.4 % of cases. Linear deposition of IgA, IgG, or C3 showed a high positive predictive value (84-100 %). Sensitivity and negative predictive value of IgG, IgM, IgG, and C3 in DIF were higher in cutaneous samples than in conjunctival biopsies, thus yielding a higher diagnostic accuracy. The sensitivity of DIF in ocular MMP seems to be lower than in bullous pemphigoid. CONCLUSIONS: The diagnostic value of DIF in the workup of ocular MMP was confirmed. However, biopsies taken from non-conjunctival, cutaneous tissue appear to yield more accurate results. PMID- 26612802 TI - Don't miss the base - keratoacanthoma-type squamous cell carcinoma with perineural invasion during BRAF inhibitor therapy for melanoma. PMID- 26612804 TI - Fibrous hamartoma of infancy within a congenital nevus. PMID- 26612805 TI - Occupational skin cancer caused by natural UV light - essential causation by occupational versus nonoccupational exposure. PMID- 26612808 TI - Direct brow lift for the correction of unilateral brow ptosis due to frontal branch injury following cutaneous surgery in the frontotemporal region. PMID- 26612810 TI - German-Austrian guidelines on anal dysplasia and anal cancer in HIV-positive individuals: prevention, diagnosis, and treatment. PMID- 26612812 TI - [Not Available]. PMID- 26612814 TI - [Not Available]. PMID- 26612815 TI - [Not Available]. PMID- 26612816 TI - Vasculitic wheel - an algorithmic approach to cutaneous vasculitides. PMID- 26612819 TI - Extensive purpuric lesions on the face. PMID- 26612821 TI - [Abstracts]. PMID- 26612823 TI - Sequence-non-specific effects generated by various types of RNA interference triggers. AB - RNA interference triggers such as short interfering RNA (siRNA) or genetically encoded short hairpin RNA (shRNA) and artificial miRNA (sh-miR) are widely used to silence the expression of specific genes. In addition to silencing selected targets, RNAi reagents may induce various side effects, including immune responses. To determine the molecular markers of immune response activation when using RNAi reagents, we analyzed the results of experiments gathered in the RNAimmuno (v 2.0) and GEO Profiles databases. To better characterize and compare cellular responses to various RNAi reagents in one experimental system, we designed a reagent series in corresponding siRNA, D-siRNA, shRNA and sh-miR forms. To exclude sequence-specific effects the reagents targeted 3 different transcripts (Luc, ATXN3 and HTT). We demonstrate that RNAi reagents induce a broad variety of sequence-non-specific effects, including the deregulation of cellular miRNA levels. Typical siRNAs are weak stimulators of interferon response but may saturate the miRNA biogenesis pathway, leading to the downregulation of highly expressed miRNAs, whereas plasmid-based reagents induce known markers of immune response and may alter miRNA levels and their isomiR composition. PMID- 26612824 TI - Osteogenic protein 1 does not stimulate a regenerative effect in cultured human degenerated nucleus pulposus tissue. AB - Low back pain is a major cause of disability and is heavily associated with intervertebral disc degeneration. Osteogenic protein 1 (OP-1) is a growth factor that has shown potential to regenerate the intervertebral disc in human cells and animal models. However, high doses are required, presumably due to clearance from the tissue; controlled release may be a solution to this problem. In this study, we developed a preclinical, pathophysiological human tissue explant culture model of degenerated nucleus pulposus (NP). The NP explants were cultured for 28 days and injected with 100 ug OP-1 as a bolus, or with sustained-release biodegradable microspheres loaded with 16 or 1.6 ug OP-1. After culture, the tissue explants were analysed for biochemical content [water, sulphated glycosaminoglycans (GAGs), hydroxyproline and DNA], histology, cell viability and gene expression (disc matrix anabolic and catabolic markers). Untreated degenerated NP explants lost some of their GAG content when cultured for 4 weeks, but maintained other tissue constituents. Gene expression levels were close to native values. A bolus injection of OP-1 partially restored GAG content to the native level in half of the donors, while the sustained release of OP-1 did not affect the NP explants. No effect of treatment was observed on anabolic or catabolic gene expression at day 28. These results demonstrated that the regenerative potential of OP-1 is donor dependent, and only at very high doses. This questions the clinical use of OP-1 as a regenerative agent, as these high doses may increase the incidence of complications. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26612826 TI - Clinical overview of Fanhdi/Alphanate (plasma-derived, VWF-containing FVIII concentrate) in immune tolerance induction in haemophilia A patients with inhibitors. PMID- 26612825 TI - Distinct expression patterns for type II topoisomerases IIA and IIB in the early foetal human telencephalon. AB - TOP2A and TOP2B are type II topoisomerase enzymes that have important but distinct roles in DNA replication and RNA transcription. Recently, TOP2B has been implicated in the transcription of long genes in particular that play crucial roles in neural development and are susceptible to mutations contributing to neurodevelopmental conditions such as autism and schizophrenia. This study maps their expression in the early foetal human telencephalon between 9 and 12 post conceptional weeks. TOP2A immunoreactivity was restricted to cell nuclei of the proliferative layers of the cortex and ganglionic eminences (GE), including the ventricular zone and subventricular zone (SVZ) closely matching expression of the proliferation marker KI67. Comparison with sections immunolabelled for NKX2.1, a medial GE (MGE) marker, and PAX6, a cortical progenitor cell and lateral GE (LGE) marker, revealed that TOP2A-expressing cells were more abundant in MGE than the LGE. In the cortex, TOP2B is expressed in cell nuclei in both proliferative (SVZ) and post-mitotic compartments (intermediate zone and cortical plate) as revealed by comparison with immunostaining for PAX6 and the post-mitotic neuron marker TBR1. However, co-expression with KI67 was rare. In the GE, TOP2B was also expressed by proliferative and post-mitotic compartments. In situ hybridisation studies confirmed these patterns of expression, except that TOP2A mRNA is restricted to cells in the G2/M phase of division. Thus, during early development, TOP2A is likely to have a role in cell proliferation, whereas TOP2B is expressed in post-mitotic cells and may be important in controlling expression of long genes even at this early stage. PMID- 26612827 TI - Gatekeeper role of brain antigen-presenting CD11c+ cells in neuroinflammation. AB - Multiple sclerosis is the most frequent chronic inflammatory disease of the CNS. The entry and survival of pathogenic T cells in the CNS are crucial for the initiation and persistence of autoimmune neuroinflammation. In this respect, contradictory evidence exists on the role of the most potent type of antigen presenting cells, dendritic cells. Applying intravital two-photon microscopy, we demonstrate the gatekeeper function of CNS professional antigen-presenting CD11c(+) cells, which preferentially interact with Th17 cells. IL-17 expression correlates with expression of GM-CSF by T cells and with accumulation of CNS CD11c(+) cells. These CD11c(+) cells are organized in perivascular clusters, targeted by T cells, and strongly express the inflammatory chemokines Ccl5, Cxcl9, and Cxcl10. Our findings demonstrate a fundamental role of CNS CD11c(+) cells in the attraction of pathogenic T cells into and their survival within the CNS. Depletion of CD11c(+) cells markedly reduced disease severity due to impaired enrichment of pathogenic T cells within the CNS. PMID- 26612828 TI - Microarray Expression Analysis for the Paradoxical Roles of Acanthopanax senticosus Harms in Treating alpha-Synucleinopathies. AB - alpha-Synuclein is a key player in the pathogenesis of neurodegenerative disorders with Lewy bodies. Our previous studies have also showed that Acanthopanax senticosus harms (AS) could significantly suppress alpha-synuclein overexpression and toxicity. Identifying the RNAs related to alpha synucleinopathies may facilitate understanding the pathogenesis of the diseases and the safe application of AS in the clinic. Microarray expression profiling of long non-coding RNAs (lncRNAs) and mRNAs was undertaken in control non-transgenic and human alpha-synuclein transgenic mice. The effects of AS on central nervous system (CNS) in pathology and physiology were investigated based on the lncRNA/mRNA targets analysis. In total, 341 lncRNAs and 279 mRNAs were differentially expressed by alpha-synuclein stimulus, among which 29 lncRNAs and 25 mRNAs were involved in the anti-alpha-synucleinopathies mechanism of AS. However, the levels of 19/29 lncRNAs and 12/25 mRNAs in AS group were similar to those in alpha-synuclein group, which may cause potential neurotoxicity analogous to alpha-synuclein. This study demonstrated that some of lncRNAs/mRNAs were involved in alpha-synuclein related pathophysiology, and AS produced the bidirectional effects on CNS under pathological and physiological conditions. PMID- 26612829 TI - Development and evaluation of a support program for prostate cancer survivors in Alaska. AB - BACKGROUND: Prostate cancer survivors in Alaska and elsewhere have unmet support needs. The Men's Prostate Cancer Survivorship Retreat, or "men's retreat," was developed targeting Alaska Native and non-Native men who were survivors of prostate cancer. The program brought together survivors in a supportive environment to discuss and share their experiences. OBJECTIVE: Despite the proven effectiveness of support groups for improving quality of life for cancer patients, men typically do not participate in formal support groups. This descriptive study was conducted to explore the needs of Alaska Native and non Native prostate cancer survivors and assess satisfaction and acceptability of a men's cancer survivorship retreat in Alaska. METHODS: Prostate cancer survivors (N=80) who attended men's retreats during 2009-2013 were asked to complete a retreat application and post-retreat evaluation. Comments regarding social support, helpful and valuable aspects of the retreat including overall satisfaction were reported. RESULTS: A men's retreat with activities that engage men can be successful for prostate cancer survivors. Many men returned for successive retreats. After the retreat, 97% of the participants said they would continue with support activities. CONCLUSION: The men's retreat provides a valued opportunity for men to interact with other survivors and access information from health professionals. The results from this study highlight a successful model for social support and resources specific to male prostate cancer survivors. PMID- 26612830 TI - Seven days in medicine: 21-27 November. PMID- 26612831 TI - Ultrahigh power factor and thermoelectric performance in hole-doped single crystal SnSe. AB - Thermoelectric technology, harvesting electric power directly from heat, is a promising environmentally friendly means of energy savings and power generation. The thermoelectric efficiency is determined by the device dimensionless figure of merit ZT(dev), and optimizing this efficiency requires maximizing ZT values over a broad temperature range. Here, we report a record high ZT(dev) ~1.34, with ZT ranging from 0.7 to 2.0 at 300 to 773 kelvin, realized in hole-doped tin selenide (SnSe) crystals. The exceptional performance arises from the ultrahigh power factor, which comes from a high electrical conductivity and a strongly enhanced Seebeck coefficient enabled by the contribution of multiple electronic valence bands present in SnSe. SnSe is a robust thermoelectric candidate for energy conversion applications in the low and moderate temperature range. PMID- 26612832 TI - Electron-hole pair excitation determines the mechanism of hydrogen atom adsorption. AB - How much translational energy atoms and molecules lose in collisions at surfaces determines whether they adsorb or scatter. The fact that hydrogen (H) atoms stick to metal surfaces poses a basic question. Momentum and energy conservation demands that the light H atom cannot efficiently transfer its energy to the heavier atoms of the solid in a binary collision. How then do H atoms efficiently stick to metal surfaces? We show through experiments that H-atom collisions at an insulating surface (an adsorbed xenon layer on a gold single-crystal surface) are indeed nearly elastic, following the predictions of energy and momentum conservation. In contrast, H-atom collisions with the bare gold surface exhibit a large loss of translational energy that can be reproduced by an atomic-level simulation describing electron-hole pair excitation. PMID- 26612833 TI - A radio jet from the optical and x-ray bright stellar tidal disruption flare ASASSN-14li. AB - The tidal disruption of a star by a supermassive black hole leads to a short lived thermal flare. Despite extensive searches, radio follow-up observations of known thermal stellar tidal disruption flares (TDFs) have not yet produced a conclusive detection. We present a detection of variable radio emission from a thermal TDF, which we interpret as originating from a newly launched jet. The multiwavelength properties of the source present a natural analogy with accretion state changes of stellar mass black holes, which suggests that all TDFs could be accompanied by a jet. In the rest frame of the TDF, our radio observations are an order of magnitude more sensitive than nearly all previous upper limits, explaining how these jets, if common, could thus far have escaped detection. PMID- 26612834 TI - Millennial-scale plankton regime shifts in the subtropical North Pacific Ocean. AB - Climate change is predicted to alter marine phytoplankton communities and affect productivity, biogeochemistry, and the efficacy of the biological pump. We reconstructed high-resolution records of changing plankton community composition in the North Pacific Ocean over the past millennium. Amino acid-specific delta(13)C records preserved in long-lived deep-sea corals revealed three major plankton regimes corresponding to Northern Hemisphere climate periods. Non dinitrogen-fixing cyanobacteria dominated during the Medieval Climate Anomaly (950-1250 Common Era) before giving way to a new regime in which eukaryotic microalgae contributed nearly half of all export production during the Little Ice Age (~1400-1850 Common Era). The third regime, unprecedented in the past millennium, began in the industrial era and is characterized by increasing production by dinitrogen-fixing cyanobacteria. This picoplankton community shift may provide a negative feedback to rising atmospheric carbon dioxide concentrations. PMID- 26612835 TI - CLIMATE POLICY. Can Paris pledges avert severe climate change? PMID- 26612836 TI - Multidecadal increase in North Atlantic coccolithophores and the potential role of rising CO2. AB - As anthropogenic carbon dioxide (CO2) emissions acidify the oceans, calcifiers generally are expected to be negatively affected. However, using data from the Continuous Plankton Recorder, we show that coccolithophore occurrence in the North Atlantic increased from ~2 to more than 20% from 1965 through 2010. We used random forest models to examine more than 20 possible environmental drivers of this change, finding that CO2 and the Atlantic Multidecadal Oscillation were the best predictors, leading us to hypothesize that higher CO2 levels might be encouraging growth. A compilation of 41 independent laboratory studies supports our hypothesis. Our study shows a long-term basin-scale increase in coccolithophores and suggests that increasing CO2 and temperature have accelerated the growth of a phytoplankton group that is important for carbon cycling. PMID- 26612837 TI - Mechanical influence of tissue culture plates and extracellular matrix on mesenchymal stem cell behavior: A topical review. AB - Tissue engineering applications need a continuous development of new biomaterials able to generate an ideal cell-extracellular matrix interaction. The stem cell fate is regulated by several factors, such as growth factors or transcription factors. The most recent literature has reported several publications able to demonstrate that environmental factors also contribute to the regulation of stem cell behavior, leading to the opinion that the environment plays the major role in the cell differentiation.The interaction between mesenchymal stem cells (MSCs) and extracellular environment has been widely described, and it has a crucial role in regulating the cell phenotype. In our laboratory (Tecnologica Research Institute, Crotone, Italy), we have recently studied how several physical factors influence the distribution and the morphology of MSCs isolated from dental pulp, and how they are able to regulate stem cell differentiation. Mechanical and geometrical factors are only a small part of the environmental factors able to influence stem cell behavior, however, this influence should be properly known: in fact, this assumption must be clearly considered during those studies involving MSCs; furthermore, these interactions should be considered as an important bias that involves an high number of studies on the MSCs, since in worldwide laboratories the scientists mostly use tissue culture plates for their experiments. PMID- 26612838 TI - Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-alcoholic-Steatohepatitis. AB - Polychlorinated biphenyls (PCBs) are environmental pollutants associated with non alcoholic-steatohepatitis (NASH), diabetes, and obesity. We previously demonstrated that the PCB mixture, Aroclor 1260, induced steatohepatitis and activated nuclear receptors in a diet-induced obesity mouse model. This study aims to evaluate PCB interactions with the pregnane-xenobiotic receptor (Pxr: Nr1i2) and constitutive androstane receptor (Car: Nr1i3) in NASH. Wild type C57Bl/6 (WT), Pxr(-/-) and Car(-/-) mice were fed the high fat diet (42% milk fat) and exposed to a single dose of Aroclor 1260 (20 mg/kg) in this 12-week study. Metabolic phenotyping and analysis of serum, liver, and adipose was performed. Steatohepatitis was pathologically similar in all Aroclor-exposed groups, while Pxr(-/-) mice displayed higher basal pro-inflammatory cytokine levels. Pxr repressed Car expression as evident by increased basal Car/Cyp2b10 expression in Pxr(-/-) mice. Both Pxr(-/-) and Car(-/-) mice showed decreased basal respiratory exchange rate (RER) consistent with preferential lipid metabolism. Aroclor increased RER and carbohydrate metabolism, associated with increased light cycle activity in both knockouts, and decreased food consumption in the Car(-/-) mice. Aroclor exposure improved insulin sensitivity in WT mice but not glucose tolerance. The Aroclor-exposed, Pxr(-/-) mice displayed increased gluconeogenic gene expression. Lipid-oxidative gene expression was higher in WT and Pxr(-/-) mice although RER was not changed, suggesting PCB-mediated mitochondrial dysfunction. Therefore, Pxr and Car regulated inflammation, behavior, and energy metabolism in PCB-mediated NASH. Future studies should address the 'off-target' effects of PCBs in steatohepatitis. PMID- 26612839 TI - Aflatoxin B1 Induced Compositional Changes in Gut Microbial Communities of Male F344 Rats. AB - Aflatoxins are a group of potent foodborne toxicants naturally occurring in maize and groundnuts. Differential species-specific sensitivity to aflatoxins has been documented but cannot be fully explained by the differences in metabolism of these toxicants among animal species. Commensal microbial communities (microbiota) are critical to human and animal health, but few studies have assessed interactions between xenobiotic toxins and those microbiota, and its potential effects to humans and animals. Here, an exploratory dosing experiment was conducted to explore effects of Aflatoxin B1 (AFB1) on the gut microbiota in a commonly used rat model. Male F344 rats were randomly divided into groups and treated with different concentrations of AFB1. Microbial communities in fecal samples were assessed using 16S rRNA sequence analysis. We found that samples from the control group had a phylogenetically diverse community, and that increasing AFB1 doses decreased this diversity but increased evenness of community composition. In addition, the gut microbiota from different samples was clustered according to their dosing regimens. There is no community shift at the phylum level but some lactic acid bacteria were significantly depleted by AFB1. These findings suggested that AFB1 could modify the gut microbiota in a dose dependent manner. PMID- 26612841 TI - Stealing sleep: is sport or society to blame? PMID- 26612840 TI - Proinflammatory Effects of Pyrogenic and Precipitated Amorphous Silica Nanoparticles in Innate Immunity Cells. AB - Amorphous silica nanoparticles (ASNP) can be synthetized via several processes, 2 of which are the thermal route (to yield pyrogenic silica) and the wet route from a solution containing silicate salts (to obtain precipitated, colloidal, mesoporous silica, or silica gel). Both methods of synthesis lead to ASNP that are applied as food additive (E551). Current food regulation does not require that production methods of additives are indicated on the product label, and, thus, the ASNP are listed without mentioning the production method. Recent results indicate, however, that pyrogenic ASNP are more cytotoxic than ASNP synthesized through the wet route. The present study was aimed at clarifying if 2 representative preparations of ASNP, NM-203 (pyrogenic) and NM-200 (precipitated), of comparable size, specific surface area, surface charge, and hydrodynamic radius in complete growth medium, had different effects on 2 murine macrophage cell lines (MH-S and RAW264.7 cells). Our results show that, when incubated in protein-rich fluids, NM-203 adsorbed on their surface more proteins than NM-200 and, once incubated with macrophages, elicited a greater oxidative stress, assessed from Hmox1 induction and ROS production. Flow cytometry and helium ion microscopy indicated that pyrogenic NM-203 interacted with macrophages more strongly than the precipitated NM-200 and triggered a more evident inflammatory response, evaluated with Nos2 induction, NO production and the secretion of TNF-alpha, IL-6 and IL-1beta. Moreover, both ASNP synergized macrophage activation by bacterial lipopolysaccharide (LPS), with a higher effect observed for NM-203. In conclusion, the results presented here demonstrate that, compared to precipitated, pyrogenic ASNP exhibit enhanced interaction with serum proteins and cell membrane, and cause a larger oxidative stress and stronger proinflammatory effects in macrophages. Therefore, these 2 nanomaterials should not be considered biologically equivalent. PMID- 26612842 TI - Systematic review hacks for the sports and exercise clinician: five essential methodological elements. PMID- 26612843 TI - The prevalence and impact of heavy menstrual bleeding among athletes and mass start runners of the 2015 London Marathon. PMID- 26612844 TI - Sudden cardiac death associated with physical exertion in the US military, 2005 2010. AB - BACKGROUND: Sudden cardiac death associated with physical exertion (SCD/E) is a complicated pathophysiological event. This study aims to calculate the incidence rate of SCD/E in the US military population from 2005 to 2010, to characterise the demographic and cardiovascular risk profiles of decedents, and to evaluate aetiologies of and circumstances surrounding the deaths. METHODS: Perimortem and other relevant data were collected from the Armed Forces Medical Examiners Tracking System, Armed Forces Health Longitudinal Technology Application, and Defense Medical Epidemiology Database for decedents meeting SCD/E case definition. Incidence rates were calculated and compared using negative binomial regression. RESULTS: The incidence of SCD/E in the Active Component (ie, full time active duty) US military from 2005 to 2010 was 1.63 per 100 000 person-years (py): 0.98 and 3.84 per 100 000 py in those aged <35 and >=35 years, respectively. Atherosclerotic cardiovascular disease was the leading cause of death overall (55%) and in the >=35-year age group (78%), whereas the leading cause of death in the <35-year age group (31%) could not be precisely determined and was termed idiopathic SCD/E (iSCD/E). SCD/E was more common in males than females (incidence rate ratio (IRR) = 5.28, 95% CI 2.16 to 12.93) and more common in blacks than whites (IRR=2.60, 95% CI 1.81 to 3.72). All female cases were black. CONCLUSIONS: From 2005 to 2010, the incidence of SCD/E in US military members aged <35 years was similar to most reported corresponding civilian SCD rates. However, the leading cause of death was iSCD/E and not cardiomyopathy. Improved surveillance and age-based prevention strategies may reduce these rates. PMID- 26612845 TI - The impact of diagnosis: measuring the psychological response to being diagnosed with serious or potentially lethal cardiac disease in young competitive athletes. AB - AIM: To determine the psychological impact of athletes diagnosed with cardiac disease. METHODS AND DESIGN: Athletes diagnosed with cardiovascular disorders were recruited to complete the Impact of Event Scale (IES), a validated tool measuring responses to a traumatic event. IES scoring =0-88 (<12= normal, 12 32=recommend monitoring, >33=significant stress reaction). Subscales include: intrusion, avoidance and hyperarousal. RESULTS: 30 athletes (53% male, 83% Caucasian, median age 18.0, median age at diagnosis 15.7) participated. Diagnoses included: 6 hypertrophic cardiomyopathy, 9 Wolff Parkinson White, 4 Long QT syndrome, 3 atrial septal defect, 2 supraventricular tachycardia and 6 other. For the group, the mean IES-Revised (IES-R) score=16.6 (SD=12.1), subscales: intrusion 6.6 (SD=4.3), avoidance=7.4 (SD=6.5), hyperarousal=2.7 (SD=3.5). Higher risk individuals included: permanently disqualified athletes (p<0.01), athletes requiring daily medication (p<0.01), those with genetically inheritable conditions (p<0.01), and athletes undergoing medical management instead of definitive therapy (p<0.01). No differences were reported by gender (male=16.6, female=16.6). Higher IES-R scores were reported in more competitive athletes (college=17.8, high school=13.3; p=0.369) and African-American individuals (African-American=25.8, Caucasian=14.8 p=0.061), although not statistically significant. Athletes with cardiomyopathy (IES-R=24) and channelopathy (IES-R=28) reported the highest IES results. Athletes with high IES-R scores were most likely to psychologically respond through avoidance of feelings/situations/ideas. CONCLUSIONS: Athletes diagnosed with potentially lethal cardiac disorders are at risk for significant psychological distress. These athletes tend to avoid thoughts, feelings and conversations associated with their diagnosis and should be offered consistent emotional support to mitigate psychological morbidity. SIGNIFICANCE: Currently, there are no recommendations to guide physicians on how to support an athlete that is newly diagnosed with a potentially career altering heart condition. Proper planning and use of appropriate support mechanisms can be useful for emotionally vulnerable athletes. PMID- 26612846 TI - Effects of exercise and manual therapy on pain associated with hip osteoarthritis: a systematic review and meta-analysis. AB - AIM: To explore the effects of exercise (water-based or land-based) and/or manual therapies on pain in adults with clinically and/or radiographically diagnosed hip osteoarthritis (OA). METHODS: A systematic review and meta-analysis was performed, with patient reported pain assessed using a visual analogue scale (VAS) or the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale. Data were grouped by follow-up time (0-3 months=short term; 4-12 months=medium term and; >12 months=long term), and standardised mean differences (SMD) with 95% CIs were used to establish intervention effect sizes. Study quality was assessed using modified PEDro scores. RESULTS: 19 trials were included. Four studies showed short-term benefits favouring water-based exercise over minimal control using the WOMAC pain subscale (SMD -0.53, 95% CI -0.96 to 0.10). Six studies supported a short-term benefit of land-based exercise compared to minimal control on VAS assessed pain (SMD -0.49, 95% CI -0.70 to -0.29). There were no medium (SMD -0.23, 95% CI -0.48 to 0.03) or long (SMD -0.22, 95% CI -0.51 to 0.06) term benefits of exercise therapy, or benefit of combining exercise therapy with manual therapy (SMD -0.38, 95% CI -0.88 to 0.13) when compared to minimal control. CONCLUSIONS: Best available evidence indicates that exercise therapy (whether land-based or water-based) is more effective than minimal control in managing pain associated with hip OA in the short term. Larger high quality RCTs are needed to establish the effectiveness of exercise and manual therapies in the medium and long term. PMID- 26612847 TI - Gynecomastia With Atypical Ductal Hyperplasia and Ductal Carcinoma In Situ Associated With Invasive Breast Carcinoma in a Male Patient on Antiretroviral Therapy: A Case Report. AB - Breast carcinoma in males is rare although a 4-fold increased incidence is reported in HIV-infected men. Herein we report a case of invasive breast carcinoma in a HIV-positive man on antiretroviral therapy. The carcinoma was associated with features of florid gynecomastia, atypical ductal hyperplasia, ductal carcinoma in situ, and columnar cell change. This combination of morphological changes has not previously been reported in the context of male breast carcinoma and their etiopathological associations are discussed. PMID- 26612848 TI - FGF23-Associated Tumor-Induced Osteomalacia in a Patient With Small Cell Carcinoma: A Case Report and Regulatory Mechanism Study. AB - Tumor-induced osteomalacia (TIO) is typically caused by phosphaturic mesenchymal tumor (PMT) that secretes the phosphaturic hormone, fibroblast growth factor-23 (FGF23), resulting in decreased phosphate reabsorption in kidneys, hypophosphatemia, and finally osteomalacia. Rare cases of malignant tumor manifesting with TIO other than PMT had been reported, although in most of these reports, except one, circulating FGF23 levels were not evaluated and tissue expressing of FGF23 was not confirmed. In this article, we report a case of TIO in a patient with pulmonary small cell carcinoma with liver metastasis. The patient manifested with hypophosphatemia. His circulating level of FGF23 was markedly increased. The expression of FGF23 in tumor cells was confirmed. Furthermore, the regulatory mechanism of FGF23 in this patient was also investigated. PMID- 26612849 TI - How regulation of phloem transport could link potassium fertilization to increased growth. PMID- 26612850 TI - Drought avoidance and vulnerability in the Australian Araucariaceae. AB - The Araucariaceae is an iconic tree family. Once globally important, the Araucariaceae declined dramatically over the Cenozoic period. Increasing aridity is thought to be responsible for extinction and range contraction of Araucariaceae in Australia, yet little is known about how these trees respond to water stress. We examined the response to water stress of the recently discovered tree Wollemia nobilis Jones, W.G., Hill, K.D. & Allen, J.M. (Araucariaceae) and two closely related and widespread tree species, Araucaria bidwillii Hook. and Araucaria cunninghamii Mudie, and the island-endemic species, Araucaria heterophylla (Salisb.) Franco. Leaf water potential in all Araucaria spp. remained remarkably unchanged during both dehydration and rehydration, indicating strong isohydry. The xylem tensions at which shoot and stem hydraulic conductances were reduced to 50% (P50shoot and P50stem) were closely correlated in all species. Among the four species, W. nobilis exhibited greater resistance to xylem hydraulic dysfunction during water stress (as indicated by P50shoot and P50stem). Unexpectedly, W. nobilis also experienced the highest levels of crown mortality in response to dehydration, suggesting that this was the most drought sensitive species in this study. Our results highlight that single traits (e.g., P50) should not be used in isolation to predict drought survival. Further, we found no clear correlation between species' P50 and rainfall across their distributional range. Diversity in drought response among these closely related Araucariaceae species was surprisingly high, considering their reputation as a functionally conservative family. PMID- 26612851 TI - Perspective and investments in health system strengthening of Gavi, the Vaccine Alliance: a content analysis of health system strengthening-specific funding. AB - BACKGROUND: This paper aimed to compare the health systems strengthening (HSS) framework of Gavi and WHO and to analyze resource allocation in HSS by Gavi. METHODS: Among 76 countries which received HSS funding from Gavi from 2006 to 2013, summary reports of 44 countries and approved proposals of 10 countries were collected. After comparing the HSS framework of WHO and Gavi, each activity described in documents was categorized according to Gavi's framework and funding allocation was analyzed. RESULTS: Compared with WHO's HSS framework, Gavi's has a distinctive function within the building block 'Drugs, Equipment, Supplies, Facilities' and a distinctive function of 'providing incentive and bonuses' under the building block 'Human Resource/Performance Management'. Gavi has steadily invested 10% of their total budget on HSS, but 47% were allocated in these categories, whereas 78% were for activities arguably not covered by WHO's HSS framework. In Africa, 70% of Gavi's budget fell under 'Drugs, Equipment, Supplies, Facilities' and 92.8% were for activities arguably not deemed as HSS by WHO. CONCLUSIONS: Gavi's HSS support emphasized inputs with short-term measurable outcomes. Harmonization of the concept of HSS and collaboration between Gavi and multilateral international agencies, such as World Bank and WHO, are needed. PMID- 26612852 TI - Innovative financing for late-stage global health research and development: the Global Health Investment Fund. AB - Innovative financing strategies for global health are urgently needed to reinvigorate investment and new tools for impact. Bottleneck areas along the research and development (R&D) pipeline require particular attention, such as the transitions from preclinical discovery to clinical study, and product development to implementation and delivery. Successful organizations mobilizing and disbursing resources through innovating financing mechanisms include UNITAID, the Global Fund, and Gavi, the Vaccine Alliance. Although precise numbers are poorly documented, estimated investment in low-income settings falls seriously short of local need. This commentary discusses the newly established Global Health Investment Fund as a case study to support late-stage global health R&D. PMID- 26612853 TI - Taking local ownership: government and household contribution to indoor residual spraying in Zanzibar and mainland Tanzania. AB - BACKGROUND: While donor funding is instrumental in initiation and implementation of malaria control efforts, national government contributions are key to local ownership and sustainability. This study explored in-kind contributions of local government and households towards the cost of indoor residual spraying (IRS) interventions in Tanzania. METHODS: Data were collected through interviews with local government officials and technical teams in the IRS project. Household contribution was based on provision of water for IRS. Government contributions included government-provided warehouse and office space, vehicles, and staff labour. In-kind contributions were aggregated at the district, regional and national level. Calculations were based on proportion of total costs of IRS from 2010 to 2012. RESULTS: The mainland government provided larger amounts of in-kind contribution in absolute value (mean of US$454 200) compared to Zanzibar (US$89 163). On average, in-kind contribution was 5.5% of total costs in Zanzibar and 2.9% in mainland. The proportion of government in-kind contribution was higher in Zanzibar versus the mainland (86% vs 50%) while household contribution was higher in mainland compared to Zanzibar (50% vs 14%). CONCLUSION: Government involvement, particularly through budgetary allocations and increased in-kind contribution, needs to be encouraged for malaria control efforts to be locally owned, managed and sustained. PMID- 26612854 TI - Mitochondrial disease in adults: what's old and what's new? AB - Ten years ago, there was an emerging view that the molecular basis for adult mitochondrial disorders was largely known and that the clinical phenotypes had been well described. Nothing could have been further from the truth. The establishment of large cohorts of patients has revealed new aspects of the clinical presentation that were not previously appreciated. Over time, this approach is starting to provide an accurate understanding of the natural history of mitochondrial disease in adults. Advances in molecular diagnostics, underpinned by next generation sequencing technology, have identified novel molecular mechanisms. Recently described mitochondrial disease phenotypes have disparate causes, and yet share common mechanistic themes. In particular, disorders of mtDNA maintenance have emerged as a major cause of mitochondrial disease in adults. Progressive mtDNA depletion and the accumulation of mtDNA mutations explain some of the clinical features, but the genetic and cellular processes responsible for the mtDNA abnormalities are not entirely clear in each instance. Unfortunately, apart from a few specific examples, treatments for adult mitochondrial disease have not been forthcoming. However, the establishment of international consortia, and the first multinational randomised controlled trial, have paved the way for major progress in the near future, underpinned by growing interest from the pharmaceutical industry. Adult mitochondrial medicine is, therefore, in its infancy, and the challenge is to harness the new understanding of its molecular and cellular basis to develop treatments of real benefit to patients. PMID- 26612855 TI - Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes. AB - Fragile X syndrome (FXS) is mostly caused by a CGG triplet expansion in the fragile X mental retardation 1 gene (FMR1). Up to 60% of affected males fulfill criteria for autism spectrum disorder (ASD), making FXS the most frequent monogenetic cause of syndromic ASD. It is unknown, however, whether normal variants (independent of mutations) in the fragile X gene family (FMR1, FXR1, FXR2) and in FMR2 modulate autistic features. Here, we report an accumulation model of 8 SNPs in these genes, associated with autistic traits in a discovery sample of male patients with schizophrenia (N = 692) and three independent replicate samples: patients with schizophrenia (N = 626), patients with other psychiatric diagnoses (N = 111) and a general population sample (N = 2005). For first mechanistic insight, we contrasted microRNA expression in peripheral blood mononuclear cells of selected extreme group subjects with high- versus low-risk constellation regarding the accumulation model. Thereby, the brain-expressed miR 181 species emerged as potential "umbrella regulator", with several seed matches across the fragile X gene family and FMR2. To conclude, normal variation in these genes contributes to the continuum of autistic phenotypes. PMID- 26612857 TI - The test characteristics of physician clinical gestalt for determining the presence and severity of anaemia in patients seen at the emergency department of a tertiary referral hospital in Tanzania. AB - OBJECTIVES: To evaluate the test characteristics of clinical gestalt for detecting the presence and severity of anaemia in emergency department patients at a tertiary referral hospital in Tanzania. METHODS: This prospective study enrolled a convenience sample of emergency department patients who had a complete blood count ordered by the treating physician in the course of their clinical care. Physicians recorded their impression of the presence and severity of anaemia before viewing the laboratory results. To assess interobserver agreement, a second physician provided their blinded gestalt impression of the patient's haemoglobin level. RESULTS: We enrolled 216 patients and complete data were available for 210 patients (97%), 59% male, median age 30 years. The range of measured haemoglobin values was 1.5-15.4 g/dL. The physicians rated anaemia mild or absent in 74 (35%), moderate in 72 (34%) and severe in 64 patients (30%). These estimates were significantly concordant with the laboratory haemoglobin measurements (Kendall's tau b=0.63, 95% CI 0.57 to 0.69, p<0.0001). The test characteristics of physician gestalt estimates for severe anaemia were: sensitivity 64% (95% CI 53% to 74%), specificity 91% (95% CI 85% to 96%), positive likelihood ratio of 7.4 (95% CI 4.2 to 13.3) and negative likelihood ratio of 0.40 (0.3 to 0.5). The weighted Cohen's kappa for interobserver agreement between physicians on the gestalt estimate of the degree of anaemia was 0.87 (95% CI 0.76 to 0.98). CONCLUSION: Physicians' estimates of the severity of anaemia were significantly concordant with laboratory haemoglobin measurements. Sensitivity of the gestalt estimate for severe anaemia was moderate. Interobserver agreement was 'almost perfect'. PMID- 26612858 TI - Bovine rabies in Greece in 2013. PMID- 26612856 TI - KLF4 is a key determinant in the development and progression of cerebral cavernous malformations. AB - Cerebral cavernous malformations (CCMs) are vascular malformations located within the central nervous system often resulting in cerebral hemorrhage. Pharmacological treatment is needed, since current therapy is limited to neurosurgery. Familial CCM is caused by loss-of-function mutations in any of Ccm1, Ccm2, and Ccm3 genes. CCM cavernomas are lined by endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition (EndMT). This switch in phenotype is due to the activation of the transforming growth factor beta/bone morphogenetic protein (TGFbeta/BMP) signaling. However, the mechanism linking Ccm gene inactivation and TGFbeta/BMP-dependent EndMT remains undefined. Here, we report that Ccm1 ablation leads to the activation of a MEKK3-MEK5-ERK5-MEF2 signaling axis that induces a strong increase in Kruppel-like factor 4 (KLF4) in ECs in vivo. KLF4 transcriptional activity is responsible for the EndMT occurring in CCM1-null ECs. KLF4 promotes TGFbeta/BMP signaling through the production of BMP6. Importantly, in endothelial-specific Ccm1 and Klf4 double knockout mice, we observe a strong reduction in the development of CCM and mouse mortality. Our data unveil KLF4 as a therapeutic target for CCM. PMID- 26612859 TI - Development of a new welfare assessment protocol for practical application in long-term dog shelters. AB - In many European shelters, dogs may spend many years confined. A poor environment and inappropriate management may lead to a low quality of life. The absence of harmonised European regulatory frameworks defining the minimum requirements for shelter facilities makes the definition of welfare standards for kennelled dogs challenging. Here, a new protocol was developed and tested to help identify the main welfare issues for shelter dogs. Twenty-six indicators were identified including management, resource and animal based measures. Accuracy and interobserver reliability were checked between four assessors. The protocol was applied in 29 shelters (n=1308 dogs) in six European countries. Overall prevalence of poor health conditions was below 10%. Test-retest reliability and validity of the protocol were investigated with encouraging results. A logistic regression was carried out to assess the potential of the protocol as a tool to identify welfare hazards in shelter environments. Inappropriate space allowance, for example, was found to be a risk factor potentially affecting the animal's cleanliness, skin condition and body condition. The protocol was designed to be concise and easy to implement. Systematic data collection could help identify welfare problems that are likely to arise in certain shelter designs and thus determine improvement in animal care standards. PMID- 26612860 TI - FOXO factors and breast cancer: outfoxing endocrine resistance. AB - The majority of metastatic breast cancers cannot be cured and present a major public health problem worldwide. Approximately 70% of breast cancers express the estrogen receptor, and endocrine-based therapies have significantly improved patient outcomes. However, the development of endocrine resistance is extremely common. Understanding the molecular pathways that regulate the hormone sensitivity of breast cancer cells is important to improving the efficacy of endocrine therapy. It is becoming clearer that the PI3K-AKT-forkhead box O (FOXO) signaling axis is a key player in the hormone-independent growth of many breast cancers. Constitutive PI3K-AKT pathway activation, a driver of breast cancer growth, causes down-regulation of FOXO tumor suppressor functions. This review will summarize what is currently known about the role of FOXOs in endocrine resistance mechanisms. It will also suggest potential therapeutic strategies for the restoration of normal FOXO transcriptional activity. PMID- 26612862 TI - BIGNASim: a NoSQL database structure and analysis portal for nucleic acids simulation data. AB - Molecular dynamics simulation (MD) is, just behind genomics, the bioinformatics tool that generates the largest amounts of data, and that is using the largest amount of CPU time in supercomputing centres. MD trajectories are obtained after months of calculations, analysed in situ, and in practice forgotten. Several projects to generate stable trajectory databases have been developed for proteins, but no equivalence exists in the nucleic acids world. We present here a novel database system to store MD trajectories and analyses of nucleic acids. The initial data set available consists mainly of the benchmark of the new molecular dynamics force-field, parmBSC1. It contains 156 simulations, with over 120 MUs of total simulation time. A deposition protocol is available to accept the submission of new trajectory data. The database is based on the combination of two NoSQL engines, Cassandra for storing trajectories and MongoDB to store analysis results and simulation metadata. The analyses available include backbone geometries, helical analysis, NMR observables and a variety of mechanical analyses. Individual trajectories and combined meta-trajectories can be downloaded from the portal. The system is accessible through http://mmb.irbbarcelona.org/BIGNASim/. Supplementary Material is also available on-line at http://mmb.irbbarcelona.org/BIGNASim/SuppMaterial/. PMID- 26612861 TI - Substantial DNA methylation differences between two major neuronal subtypes in human brain. AB - The brain is built from a large number of cell types which have been historically classified using location, morphology and molecular markers. Recent research suggests an important role of epigenetics in shaping and maintaining cell identity in the brain. To elucidate the role of DNA methylation in neuronal differentiation, we developed a new protocol for separation of nuclei from the two major populations of human prefrontal cortex neurons--GABAergic interneurons and glutamatergic (GLU) projection neurons. Major differences between the neuronal subtypes were revealed in CpG, non-CpG and hydroxymethylation (hCpG). A dramatically greater number of undermethylated CpG sites in GLU versus GABA neurons were identified. These differences did not directly translate into differences in gene expression and did not stem from the differences in hCpG methylation, as more hCpG methylation was detected in GLU versus GABA neurons. Notably, a comparable number of undermethylated non-CpG sites were identified in GLU and GABA neurons, and non-CpG methylation was a better predictor of subtype specific gene expression compared to CpG methylation. Regions that are differentially methylated in GABA and GLU neurons were significantly enriched for schizophrenia risk loci. Collectively, our findings suggest that functional differences between neuronal subtypes are linked to their epigenetic specification. PMID- 26612863 TI - A general strategy to inhibiting viral -1 frameshifting based on upstream attenuation duplex formation. AB - Viral -1 programmed ribosomal frameshifting (PRF) as a potential antiviral target has attracted interest because many human viral pathogens, including human immunodeficiency virus (HIV) and coronaviruses, rely on -1 PRF for optimal propagation. Efficient eukaryotic -1 PRF requires an optimally placed stimulator structure downstream of the frameshifting site and different strategies targeting viral -1 PRF stimulators have been developed. However, accessing particular -1 PRF stimulator information represents a bottle-neck in combating the emerging epidemic viral pathogens such as Middle East respiratory syndrome coronavirus (MERS-CoV). Recently, an RNA hairpin upstream of frameshifting site was shown to act as a cis-element to attenuate -1 PRF with mechanism unknown. Here, we show that an upstream duplex formed in-trans, by annealing an antisense to its complementary mRNA sequence upstream of frameshifting site, can replace an upstream hairpin to attenuate -1 PRF efficiently. This finding indicates that the formation of a proximal upstream duplex is the main determining factor responsible for -1 PRF attenuation and provides mechanistic insight. Additionally, the antisense-mediated upstream duplex approach downregulates -1 PRF stimulated by distinct -1 PRF stimulators, including those of MERS-CoV, suggesting its general application potential as a robust means to evaluating viral -1 PRF inhibition as soon as the sequence information of an emerging human coronavirus is available. PMID- 26612864 TI - DIANA-LncBase v2: indexing microRNA targets on non-coding transcripts. AB - microRNAs (miRNAs) are short non-coding RNAs (ncRNAs) that act as post transcriptional regulators of coding gene expression. Long non-coding RNAs (lncRNAs) have been recently reported to interact with miRNAs. The sponge-like function of lncRNAs introduces an extra layer of complexity in the miRNA interactome. DIANA-LncBase v1 provided a database of experimentally supported and in silico predicted miRNA Recognition Elements (MREs) on lncRNAs. The second version of LncBase (www.microrna.gr/LncBase) presents an extensive collection of miRNA:lncRNA interactions. The significantly enhanced database includes more than 70 000 low and high-throughput, (in)direct miRNA:lncRNA experimentally supported interactions, derived from manually curated publications and the analysis of 153 AGO CLIP-Seq libraries. The new experimental module presents a 14-fold increase compared to the previous release. LncBase v2 hosts in silico predicted miRNA targets on lncRNAs, identified with the DIANA-microT algorithm. The relevant module provides millions of predicted miRNA binding sites, accompanied with detailed metadata and MRE conservation metrics. LncBase v2 caters information regarding cell type specific miRNA:lncRNA regulation and enables users to easily identify interactions in 66 different cell types, spanning 36 tissues for human and mouse. Database entries are also supported by accurate lncRNA expression information, derived from the analysis of more than 6 billion RNA-Seq reads. PMID- 26612866 TI - The autoinhibitory CARD2-Hel2i Interface of RIG-I governs RNA selection. AB - RIG-I (Retinoic Acid Inducible Gene-I) is a cytosolic innate immune receptor that detects atypical features in viral RNAs as foreign to initiate a Type I interferon signaling response. RIG-I is present in an autoinhibited state in the cytoplasm and activated by blunt-ended double-stranded (ds)RNAs carrying a 5' triphosphate (ppp) moiety. These features found in many pathogenic RNAs are absent in cellular RNAs due to post-transcriptional modifications of RNA ends. Although RIG-I is structurally well characterized, the mechanistic basis for RIG I's remarkable ability to discriminate between cellular and pathogenic RNAs is not completely understood. We show that RIG-I's selectivity for blunt-ended 5' ppp dsRNAs is ~3000 times higher than non-blunt ended dsRNAs commonly found in cellular RNAs. Discrimination occurs at multiple stages and signaling RNAs have high affinity and ATPase turnover rate and thus a high katpase/Kd. We show that RIG-I uses its autoinhibitory CARD2-Hel2i (second CARD-helicase insertion domain) interface as a barrier to select against non-blunt ended dsRNAs. Accordingly, deletion of CARDs or point mutations in the CARD2-Hel2i interface decreases the selectivity from ~3000 to 150 and 750, respectively. We propose that the CARD2 Hel2i interface is a 'gate' that prevents cellular RNAs from generating productive complexes that can signal. PMID- 26612867 TI - The Dfam database of repetitive DNA families. AB - Repetitive DNA, especially that due to transposable elements (TEs), makes up a large fraction of many genomes. Dfam is an open access database of families of repetitive DNA elements, in which each family is represented by a multiple sequence alignment and a profile hidden Markov model (HMM). The initial release of Dfam, featured in the 2013 NAR Database Issue, contained 1143 families of repetitive elements found in humans, and was used to produce more than 100 Mb of additional annotation of TE-derived regions in the human genome, with improved speed. Here, we describe recent advances, most notably expansion to 4150 total families including a comprehensive set of known repeat families from four new organisms (mouse, zebrafish, fly and nematode). We describe improvements to coverage, and to our methods for identifying and reducing false annotation. We also describe updates to the website interface. The Dfam website has moved to http://dfam.org. Seed alignments, profile HMMs, hit lists and other underlying data are available for download. PMID- 26612869 TI - Climate change on Twitter: Content, media ecology and information sharing behaviour. AB - This article presents a study of the content, use of sources and information sharing about climate change analysing over 60,000 tweets collected using a random week sample. We discuss the potential for studying Twitter as a communicative space that is rich in different types of information and presents both new challenges and opportunities. Our analysis combines automatic thematic analysis, semantic network analysis and text classification according to psychological process categories. We also consider the media ecology of tweets and the external web links that users shared. In terms of content, the network of topics uncovered presents a multidimensional discourse that accounts for complex causal links between climate change and its consequences. The media ecology analysis revealed a narrow set of sources with a major role played by traditional media and that emotionally arousing text was more likely to be shared. PMID- 26612865 TI - Regulation of mammalian transcription and splicing by Nuclear RNAi. AB - RNA interference (RNAi) is well known as a mechanism for controlling mammalian mRNA translation in the cytoplasm, but what would be the consequences if it also functions in cell nuclei? Although RNAi has also been found in nuclei of plants, yeast, and other organisms, there has been relatively little progress towards understanding the potential involvement of mammalian RNAi factors in nuclear processes including transcription and splicing. This review summarizes evidence for mammalian RNAi factors in cell nuclei and mechanisms that might contribute to the control of gene expression. When RNAi factors bind small RNAs, they form ribonucleoprotein complexes that can be selective for target sequences within different classes of nuclear RNA substrates. The versatility of nuclear RNAi may supply a previously underappreciated layer of regulation to transcription, splicing, and other nuclear processes. PMID- 26612871 TI - Assessment of a phenotypic algorithm to detect plasmid-mediated quinolone resistance in Enterobacteriaceae. PMID- 26612870 TI - Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease. AB - BACKGROUND: Antifungal prophylaxis with a new oral tablet formulation of posaconazole may be beneficial to patients at high risk for invasive fungal disease. A two-part (Phase 1B/3) study evaluated posaconazole tablet pharmacokinetics (PK) and safety. METHODS: Patients with neutropenia following chemotherapy for haematological malignancy or recipients of allogeneic HSCT receiving prophylaxis or treatment for graft-versus-host disease received 300 mg posaconazole (as tablets) once daily (twice daily on day 1) for up to 28 days without regard to food intake. Weekly trough PK sampling was performed during therapy, and a subset of patients had sampling on days 1 and 8. Cmin-evaluable subjects received >=6 days of dosing, and were compliant with specified sampling timepoints. Steady-state PK parameters, safety, clinical failure and survival to day 65 were assessed. ClinicalTrials.gov, NCT01777763; EU Clinical Trials Register, EUDRA-CT 2008-006684-36. RESULTS: Two hundred and ten patients received 300 mg posaconazole (as tablets) once daily. Among Cmin-evaluable subjects (n = 186), steady-state mean Cmin was 1720 ng/mL (range = 210-9140). Steady-state Cmin was >=700 ng/mL in 90% of subjects with 5% (10 of 186) <500 ng/mL and 5% (10 of 186) 500-700 ng/mL. Six (3%) patients had steady-state Cmin >=3750 ng/mL. One patient (<1%) had an invasive fungal infection. The most common treatment-related adverse events were nausea (11%) and diarrhoea (8%). There was no increase in adverse event frequency with higher posaconazole exposure. CONCLUSIONS: In patients at high risk for invasive fungal disease, 300 mg posaconazole (as tablets) once daily was well tolerated and demonstrated a safety profile similar to that reported for posaconazole oral suspension: most patients (99%) achieved steady-state pCavg exposures >500 ng/mL and only one patient (<1%) had a pCavg <500 ng/mL. PMID- 26612872 TI - Toxicity to sensory neurons and Schwann cells in experimental linezolid-induced peripheral neuropathy. AB - OBJECTIVES: Peripheral neuropathy is a common side effect of prolonged treatment with linezolid. This study aimed to explore injurious effects of linezolid on cells of the peripheral nervous system and to establish in vivo and in vitro models of linezolid-induced peripheral neuropathy. METHODS: C57BL/6 mice were treated with linezolid or vehicle over a total period of 4 weeks. Animals were monitored by weight, nerve conduction studies and behavioural tests. Neuropathic changes were assessed by morphometry on sciatic nerves and epidermal nerve fibre density in skin sections. Rodent sensory neuron and Schwann cell cultures were exposed to linezolid in vitro and assessed for mitochondrial dysfunction. RESULTS: Prolonged treatment with linezolid induced a mild, predominantly small sensory fibre neuropathy in vivo. Exposure of Schwann cells and sensory neurons to linezolid in vitro caused mitochondrial dysfunction primarily in neurons (and less prominently in Schwann cells). Sensory axonopathy could be partially prevented by co-administration of the Na(+)/Ca(2+) exchanger blocker KB-R7943. CONCLUSIONS: Clinical and pathological features of linezolid-induced peripheral neuropathy can be replicated in in vivo and in vitro models. Mitochondrial dysfunction may contribute to the axonal damage to sensory neurons that occurs after linezolid exposure. PMID- 26612873 TI - Pharmacokinetics and safety of intravesicular cidofovir in allogeneic HSCT recipients. AB - OBJECTIVES: The objective of this study was to evaluate the pharmacokinetics and safety of cidofovir administered via the intravesicular route to patients with haemorrhagic cystitis following allogeneic HSCT (allo-HSCT). METHODS: Patients with gross haematuria and confirmed BK or adenovirus viruria following allo-HSCT were prospectively enrolled in an open-label pharmacokinetic study (ClinicalTrials.gov registration: NCT01816646). Three hours after an oral probenecid dose (2 g), cidofovir (2.5-5 mg/kg in 50-100 mL of normal saline) was given via a transurethral catheter for up to 2 h of dwell time. Serial plasma samples were obtained over 24 h and assayed for cidofovir concentrations using LC MS/MS. A custom pharmacokinetic model with a time-limited absorption compartment was fitted to the concentration-time profile of each patient. Systemic drug exposure was expressed as AUC0-24, by integrating the best-fit profile with respect to time. RESULTS: Six subjects (mean +/- SD age = 38 +/- 21 years) with baseline serum creatinine <1.4 mg/dL were enrolled. Mean values for volume of distribution, clearance and elimination half-life were 19.5 L, 5.6 L/h and 2.8 h, respectively. Compared with the reported AUC0-24 for an equivalent intravenous dose, intravesicular instillation of cidofovir resulted in 1%-74% of the corresponding systemic exposure. Owing to primarily lower abdominal pain, only two patients were able to tolerate a 2 h dwell time. One patient developed a >50% increase in serum creatinine within 7 days of administration. CONCLUSIONS: Intravesicular administration of cidofovir resulted in highly variable systemic exposures. The safety and efficacy of intravesicular cidofovir should be further evaluated before routine use. PMID- 26612875 TI - The risk of chemical cocktail effects and how to deal with the issue. PMID- 26612874 TI - Evaluation of CTX-M steady-state mRNA, mRNA half-life and protein production in various STs of Escherichia coli. AB - OBJECTIVES: High levels of beta-lactamase production can impact treatment with a beta-lactam/beta-lactamase inhibitor combination. Goals of this study were to: (i) compare the mRNA and protein levels of CTX-M-15- and CTX-M-14-producing Escherichia coli from 18 different STs and 10 different phylotypes; (ii) evaluate the mRNA half-lives and establish a role for chromosomal- and/or plasmid-encoded factors; and (iii) evaluate the zones of inhibition for piperacillin/tazobactam and ceftolozane/tazobactam. METHODS: Disc diffusion was used to establish zone size. RNA analysis was accomplished using real-time RT-PCR and CTX-M protein levels were evaluated by immunoblotting. Clinical isolates, transformants and transconjugants were used to evaluate mRNA half-lives. RESULTS: mRNA levels of CTX-M-15 were up to 165-fold higher compared with CTX-M-14. CTX-M-15 protein levels were 2-48-fold less than their respective transcript levels, while CTX-M 14 protein production was comparable to the observed transcript levels. Nineteen of 25 E. coli (76%) had extended CTX-M-15 mRNA half-lives of 5-15 min and 16 (100%) CTX-M-14 isolates had mRNA half-lives of <2-3 min. Transformants had mRNA half-lives of <2 min for both CTX-M-type transcripts, while transconjugant mRNA half-lives corresponded to the half-life of the donor. Ceftolozane/tazobactam zone sizes were >=19 mm, while piperacillin/tazobactam zone sizes were >=17 mm. CONCLUSIONS: CTX-M-15 mRNA and protein production did not correlate. Neither E. coli ST nor phylotype influenced the variability observed for CTX-M-15 mRNA or protein produced. mRNA half-life is controlled by a plasmid-encoded factor and may influence mRNA transcript levels, but not protein levels. PMID- 26612877 TI - Prevalence of hypertension subtypes in 2011 and the trends from 1991 to 2011 among Chinese adults. AB - BACKGROUND: This study aims to estimate the current prevalence and trends of hypertension subtypes among Chinese adults from 1991 to 2011. METHODS: We analysed the measurements of systolic and diastolic blood pressure among adults aged >=18 years from the China Health and Nutrition Survey (CHNS) 1991-2011. The prevalence was age-adjusted to the 2010 census of Chinese adults. RESULTS: The adjusted prevalence in 2011 was 20.9% (95% CI 20.2% to 21.6%) of hypertension, 3.30% (95% CI 2.99% to 3.62%) of isolated systolic hypertension, 4.44% (95% CI 4.08% to 4.80%) of isolated diastolic hypertension, 4.11% (95% CI 3.76% to 4.46%) of systolic-diastolic hypertension and 9.01% (95% CI 8.51% to 9.51%) of current use of antihypertensive medication, respectively. From 1991 to 2011, the prevalence increased from 15.6% to 20.9% for hypertension (p<0.001) and from 3.04% to 3.30% for isolated systolic hypertension (p<0.001). However, the prevalence decreased from 4.77% to 4.44% for isolated diastolic hypertension (p=0.023) and from 5.27% to 4.11% for systolic-diastolic hypertension (p<0.001). Consistent with these findings, the percentage of current use of antihypertensive medication increased from 2.55% to 9.01%, which accounted for approximately 43.1% of the total number of cases in 2011. Importantly, only 36.9% (equivalent to 17.5% of the total number of hypertensive people) of cases of current use of antihypertensive medication were adequately controlled. CONCLUSIONS: Both the prevalence of hypertension and the percentage of current use of antihypertensive medication significantly increased from 1991 to 2011. Currently, about one-fifth of Chinese adults are hypertensive; however, only 17.5% of hypertension is controlled. PMID- 26612876 TI - Nickel exposure and prevalent albuminuria and beta2-microglobulinuria: evidence from a population-based study. AB - BACKGROUND: High exposure to nickel could induce renal dysfunction in rodents and occupational workers. However, little is known about the effects of non occupational exposure to nickel on renal health in the general population. We aimed to examine the associations of urinary nickel concentrations with albuminuria and beta2-microglobulinuria in Chinese adults. METHODS: 2115 non institutionalised Chinese men and women aged 55-76 years from Beijing and Shanghai were included. Urinary nickel concentrations were assessed by inductively coupled plasma mass spectroscopy. Plasma uric acid, urea nitrogen, C reactive protein and urinary albumin, beta2-microglobulin and creatinine were measured. Albuminuria was defined as urinary albumin >=30 mg/g creatinine, and beta2-microglobulinuria was defined as urinary beta2-microglobulin >=200 ug/g creatinine. RESULTS: Median concentration of urinary nickel was 3.95 MUg/g creatinine (IQR: 2.57-6.71 MUg/g creatinine), and prevalence of albuminuria, beta2-microglobulinuria and both albuminuria and beta2-microglobulinuria was 22.1%, 24.5% and 9.7%, respectively. Comparing the highest with the lowest quartile of urinary nickel, the ORs (95% CIs) were 1.99 (1.46 to 2.78) for albuminuria, 1.44 (1.07 to 1.95) for beta2-microglobulinuria, and 2.95 (1.74 to 4.97) for both albuminuria and beta2-microglobulinuria, after adjustment for demographic characteristics, lifestyle behaviours, body mass index, hypertension and diabetes. The association remained significant when further controlling for inflammatory markers or other heavy metals (all p trend <0.05). CONCLUSIONS: This study suggested that urinary nickel levels were positively associated with albuminuria and beta2-microglobulinuria in Chinese men and women, who had relatively low background nickel exposure. More prospective studies are needed to confirm our findings. PMID- 26612878 TI - Reduced long-term overall mortality in heart failure patients with prolonged QRS treated with CRT combined with ICD vs. heart failure patients with narrow QRS treated with ICD only. AB - AIMS: It is not known whether heart failure (HF) patients with prolonged QRS who undergo cardiac resynchronization therapy combined with a defibrillator (CRT-D) have a prognostic advantage over HF patients with narrow QRS (therefore without indication for CRT) treated with an implantable cardioverter defibrillator (ICD) only. The aim of this study was to compare the long-term mortality of a group of HF patients with prolonged QRS receiving CRT-D with that of a similar group of patients with narrow QRS receiving ICD only. METHODS AND RESULTS: A total of 312 patients (mean age 66 +/- 13 years; 84% male, mean left ventricular ejection fraction 25 +/- 4%, mean New York Heart Association class 2.6 +/- 0.5) were included in the analysis. Of these, 138 with a QRS complex duration >=120 ms received a CRT-D. During follow-up, the time and cause of death were assessed. During a median follow-up of 46 months, CRT-D patients showed significantly lower overall mortality (P = 0.038). Compared with patients receiving ICD only, CRT-D patients showed lower HF mortality (P = 0.003). Coronary mortality, non-cardiac mortality, and sudden mortality were similar in both groups (all P > 0.05). A positive response to CRT was an independent predictor of reduced mortality on multivariate analysis (hazard ratio: 0.27; P = 0.047). CONCLUSION: In HF patients treated with ICD, the subgroup of patients with prolonged QRS who receive CRT-D displays better long-term survival than narrow QRS ICD recipients, owing to their reduced HF mortality. PMID- 26612879 TI - Novel electrophysiological characteristics of atrioventricular nodal continuous conduction curves in atrioventricular nodal re-entrant tachycardia with concomitant cavotricuspid isthmus-dependent atrial flutter. AB - AIMS: The detailed electrophysiological characteristics of patients with both atrioventricular nodal re-entrant tachycardia (AVNRT) and atrial flutter (AFL) have not been clarified. This study investigated the related electrophysiological differences in a large series of patients undergoing radiofrequency catheter ablation of AVNRT. METHODS AND RESULTS: A total of 1063 clinically documented AVNRT patients underwent catheter ablation were enrolled. Before the slow pathway (SP) ablation, 61 patients (5.7%) had inducible sustained cavotricuspid isthmus (CTI)-dependent AFL (Group 1), and the others (94.3%) without inducible sustained CTI-dependent AFL were defined as Group 2. The electrophysiological characteristics of these two groups and effect of the SP ablation on the inducibility of AFL were assessed. In Group 1, 36 patients (59%) had inducible/sustained AFL after the ablation of AVNRT and required a CTI ablation. The Group 1 patients had more AVNRT with continuous atrioventricular (AV) node function curves (P < 0.001, odds ratio = 7.55 [3.70-16.7], multivariate regression), and a younger age (P = 0.02, odds ratio = 1.02 [1.003-1.03], multivariate regression) than Group 2. The other characteristics were comparable between the two groups. The long-term follow-up (64.9 +/- 34.9 months) revealed that the recurrence of AFL/atrial fibrillation was similar between the two groups (P > 0.05). CONCLUSION: Atrioventricular nodal re-entrant tachycardia patients with concomitant CTI-dependent AFL had more continuous AV node function curves. Forty-one per cent of these patients had non-inducible AFL after the SP ablation, indicating a slow conduction isthmus in the triangle of Koch area. PMID- 26612880 TI - Standardized algorithm for cardiac pacing in older patients affected by severe unpredictable reflex syncope: 3-year insights from the Syncope Unit Project 2 (SUP 2) study. AB - AIMS: The aim of this study was to determine the long-term effects and determinants of success of cardiac pacing in patients affected by reflex syncope enrolled in the Syncope Unit Project 2 (SUP 2) study. Initial results have validated the effectiveness of a standardized guideline-based algorithm which can be used in clinical practice in order to select suitable candidates for cardiac pacing. METHODS AND RESULTS: In this prospective, multicentre, observational study, patients aged >40 years, affected by severe unpredictable recurrent reflex syncope, underwent carotid sinus massage (CSM), followed by tilt testing (TT) if CSM was negative, followed by implantation of an implantable loop recorder (ILR) if TT was negative. Those who had an asystolic response to one of these tests received a dual-chamber pacemaker. Of 281 patients who met the inclusion criteria, 137 (49%) received a pacemaker and were followed up for a mean of 26 +/ 11 months: syncope recurred in 25 (18%) of them. At 3 years, the actuarial syncope recurrence rate was 20% [95% confidence interval (CI) 12-30] and was significantly lower than in 142 patients who did not receive a pacemaker and were observed by means of an ILR [43% (95% CI 29-57), P = 0.01]. The 3-year recurrence rate was not different among 78 CSM+, 38 TT+, and 21 ILR+ patients, whereas it was lower in 20 patients with negative TT [5% (95% CI 0-15)] than in 61 patients with positive TT [24% (95% CI 10-38)]. CONCLUSION: The benefit of cardiac pacing is maintained at 3 years, irrespective of the index diagnostic test, and is maximum in patients with negative TT. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01509534. PMID- 26612881 TI - Outcomes of catheter ablation of atrial fibrillation in patients with hypertrophic cardiomyopathy: a systematic review and meta-analysis. AB - AIMS: Over the past decade, catheter ablation (CA) has become an established therapy for symptomatic atrial fibrillation (AF). Atrial fibrillation is common in hypertrophic cardiomyopathy (HCM) patients, and restoring sinus rhythm is of great clinical benefit to them. Therefore, we conducted a systematic review and meta-analysis of the available data to evaluate the effectiveness and safety of CA for AF in patients with HCM. METHODS AND RESULTS: Six databases were searched to identify studies describing outcomes of CA of AF in HCM patients with a mean follow-up of >=12 months after the index procedure. The following data were extracted: (i) single-procedure success, (ii) multiple-procedure success, and (iii) drug-free success. Fifteen studies involving 531 patients were included. Single-procedure freedom from atrial arrhythmia at the latest follow-up was 45.5% [95% confidence interval (CI): 34.8-56.2%]. With multiple procedures, the final success rate was 66.1% (95% CI: 55.3-76.9%) overall, 71.8% (95% CI: 61.6-82.0%) in paroxysmal AF, and 47.5% (95% CI: 36.0-59.0%) in non-paroxysmal AF. Without anti-arrhythmic drugs (AADs), single-procedure success rate at latest follow-up was 32.9% (95% CI: 21.7-41.1%); after multiple procedures, this raised to 50.4% (95% CI: 39.2-61.6%). The incidence of serious periprocedural complications was acceptable [5.1% (95% CI: 2.8-9.6%)]. Substantial heterogeneity (I(2)> 50%) was noted in the above groups. CONCLUSIONS: Catheter ablation of AF in patients with HCM is feasible, although more repeat procedures and AAD are needed to prevent AF recurrence. PMID- 26612882 TI - Safety and efficiency of ventricular pacing prevention with an AAI-DDD changeover mode in patients with sinus node disease or atrioventricular block: impact on battery longevity-a sub-study of the ANSWER trial. AB - AIMS: This ANSWER (EvaluAtioN of the SafeR mode in patients With a dual chambER pacemaker indication) sub-study assesses safety and effectiveness of SafeRTM and the impact of ventricular pacing (VP) prevention on anticipated device longevity and replacement rate. METHODS AND RESULTS: Patients implanted for atrioventricular block (AVB, n = 310) or sinus node dysfunction (SND, n = 336) were randomly assigned to SafeR (n = 314) or DDD (n = 318) and followed for 36 months. Safety, median VP, estimated device longevity (mean difference, 95% confidence interval [CI]), and anticipated replacement rates were analysed by pacing mode and implant indication. No difference in mortality, syncope, or mode intolerance was observed between randomization groups regardless of the indication. Ventricular pacing on SafeR vs. DDD was 11.5 vs. 93.6% in the overall population (P < 0.001), 89.2 vs. 83.8% in permanent AVB (P = 0.944), 53.5 vs. 98.2% in intermittent AVB (P < 0.001), and 2.2 vs. 84.7% in SND (P < 0.001). Anticipated median device longevity increased on SafeR by 14 [Q1 10; Q3 17] months [10; 17] (P < 0.001) in the overall population, 9 months [-5; 22] (P = 0.193) in permanent AVB, 14 months [8; 19] (P < 0.001) in intermittent AVB, and 14 months [9; 19] (P < 0.001) in SND. In intermittent AVB and SND, prolonged estimated battery longevity translated into the prevention of one anticipated replacement in at least 23% of patients. CONCLUSION: SafeR was effective in reducing VP in intermittent AVB and in SND. No effect was observed in permanent AVB. No safety issue was observed. Ventricular pacing reduction by SafeR translated into relevant estimated prolongation of device longevity and anticipated reduction of required replacements. PMID- 26612883 TI - Factors determining the magnitude of the pre-ejection leftward septal motion in left bundle branch block. AB - AIMS: An abnormal large leftward septal motion prior to ejection is frequently observed in left bundle branch block (LBBB) patients. This motion has been proposed as a predictor of response to cardiac resynchronization therapy (CRT). Our goal was to investigate factors that influence its magnitude. METHODS AND RESULTS: Left (LVP) and right ventricular (RVP) pressures and left ventricular (LV) volume were measured in eight canines. After induction of LBBB, LVP and, hence, the transmural septal pressure (PLV-RV = LVP-RVP) increased more slowly (P < 0.01) during the phase when septum moved leftwards. A biventricular finite element LBBB simulation model confirmed that the magnitude of septal leftward motion depended on reduced rise of PLV-RV. The model showed that leftward septal motion was decreased with shorter activation delay, reduced global or right ventricular (RV) contractility, septal infarction, or when the septum was already displaced into the LV at end diastole by RV volume overload. Both experiments and simulations showed that pre-ejection septal hypercontraction occurs, in part, because the septum performs more of the work pushing blood towards the mitral valve leaflets to close them as the normal lateral wall contribution to this push is lost. CONCLUSIONS: Left bundle branch block lowers afterload against pre ejection septal contraction, expressed as slowed rise of PLV-RV, which is a main cause and determinant of the magnitude of leftward septal motion. The motion may be small or absent due to septal infarct, impaired global or RV contractility or RV volume overload, which should be kept in mind if this motion is to be used in evaluation of CRT response. PMID- 26612884 TI - Arab-Jewish gap in life expectancy in Israel. AB - BACKGROUND: Studies about the health status of ethnic minorities in the Middle East are rare. This article examines changes in the life expectancy gap during 1970-2010 between the Arab-Palestinian minority and the Jewish majority in Israel, a persistent gap that has widened over the last 20 years. It examines the gap in a period over which the minority group was undergoing an epidemiological transition and demonstrates consequences of the transition on changes in the main causes of death contributing to the life expectancy gap. METHODS: Decomposition methods estimate the contribution of specific age groups and causes of death to the total gap in life expectancy at any given year and changes in these contributions over the studied period. RESULTS: The contribution of mortality differentials at ages <45 years to the Arab-Jewish gap in life expectancy declined while that of differentials at ages >45 has been gradually growing reaching >70% of the total gap. For both males and females, trends in cancer and diabetes mortality differentials contributed to widening the gap among the elderly. Trends in heart mortality lead to increasing the gap among males but to decreasing it among females. CONCLUSIONS: While differences in infant and child mortality have declined, old-age (>45) mortality differentials have emerged and have been gradually widening. These findings calls for a special attention to the various factors responsible for the widening mortality gap including social inequality between Arabs and Jews and higher levels of smoking and obesity among the Arab population. PMID- 26612885 TI - An Auto-Ethnographic Study of the Disembodied Experience of a Novice Researcher Doing Qualitative Cancer Research. AB - Qualitative health researchers who explore individuals' experiences of illness are exposed to an emotionally demanding work environment. After doing 49 interviews with cancer patients living alone, I was confronted with serious emotional distress that kept me from my work for almost 6 months. Because there is a need for discussion within academia about the emotional risks encountered by researchers, I used auto-ethnography to explore what I call the "three disembodied experiences" I encountered during the research: disembodiment linked with suppression of emotions, disembodiment linked with distal traumatization, and disembodiment linked with overidentification with the participant. I illustrate these concepts with personal stories of doing research with cancer patients living alone. I conclude that writing down experiences of doing qualitative research in an embodied and reflexive way holds two advantages: It can protect the researcher and enhance the quality of research. PMID- 26612886 TI - "Live It to Understand It": The Experiences of Mothers of Children With Autism Spectrum Disorder. AB - Mothers of children with an autism spectrum disorder (ASD) variably experience challenges in their caregiving role. This ethnographic study examined the caregiving experiences of mothers of a young person with ASD (aged <=25 years). Semistructured interviews were conducted with 85 mothers across three Canadian regions. A follow-up subsample of 10 mothers took part in participant observation sessions in the home and/or other environments within the community. Analysis yielded themes that depicted the following: redefining child and family aspirations, forging a shifted identity, and the need to "live it" to understand mothering a young person with ASD. Supports and services were perceived to be required but often insufficient to meet the needs. Findings identify a range of challenges, lessons learned, and a reconfigured sense of mothering. An emerging model of mothering a child with ASD is presented. Implications for practice, policy, and research are offered. PMID- 26612888 TI - Finding Motivation: Online Information Seeking Following Newborn Screening for Cystic Fibrosis. AB - Cystic fibrosis (CF) is a genetic disease that has no manifestations for carriers but is terminal for those diagnosed with it. CF is identified through newborn screening (NBS) tests, and most families have no knowledge about CF before their contact with a NBS program. Acknowledging the Internet as a popular health information source, this study examined information exchange about CF in online community forums. This article, guided by self-determination theory, aimed at providing understanding of psychological needs and motivation for health information seeking and active communication about CF. Through online communication with other families who share similar experience, caregivers of newborns diagnosed with CF sought and received support for their competence, autonomy, and relatedness needs during the initial CF testing and diagnosis reconciliation process. Online communities play an important role in the information seeking related to CF diagnosis and could become active partners in strategic knowledge dissemination efforts. PMID- 26612887 TI - Family and Friend Influence on Urban-Dwelling American Indian Adolescent Girl's Sexual Risk Behavior. AB - Previous research with American Indian (AI) adolescent sexual risk behavior primarily focused on reservation-dwelling youth despite 70% of AIs living off Native lands. Using grounded theory methodology, I sampled 20 adolescent AI girls via talking circles and interviews to explore the perceptions of AI adolescent girls living in an urban, Midwest area about the influence of family and friends on their sexual behavior. Similar to research with other racial groups, participants cited their family and friends as a major influence. Five unique themes emerged related to family and friend influence. Urban-dwelling AI girls rely on their female family members and peers for information related to sex and receive varying messages from their networks of family and friends, which often overlap. AI youth have unique family groups yet have some similarities to other ethnic groups with regard to family and friend relationships that may allow for enhanced intervention development. PMID- 26612889 TI - Worth the Risk? Muddled Relationships in Community-Based Participatory Research. AB - Community-based participatory research (CBPR) is a collaborative research approach that has two purposes: (a) to generate knowledge about and (b) to take action to improve the lives of people facing health, social, economic, political, and environmental inequities. The foundation of all CBPR projects is its partnership--its cooperative relationship between community members, service providers, program planners, policy makers, and academics. It is with people--and through relationships--that partnerships are built and sustained. Although relationships between academics and community members are critical to creating knowledge and change, they are overlooked in the literature. We often hear about CBPR "gone wrong," when tensions and conflicts arise because relationship boundaries become blurred. Our purpose is to expose the muddled relationships that can be created between academics and community members in CBPR projects. Drawing upon our experiences presented in a series of vignettes, we consider the nature of these relationships. We explore whether we conduct, in CBPR, good research at the expense of muddling relationships. Despite the potential for muddled relationships, we believe that CBPR is the best approach for research aimed at achieving a more equitable and just society. PMID- 26612890 TI - The Future of Theory-Generating Meta-Synthesis Research. PMID- 26612891 TI - Reference Gene Selection and Evaluation for Gene Expression Studies Using qRT-PCR in the White-Backed Planthopper, Sogatella furcifera (Hemiptera: Delphacidae). AB - The white-backed planthopper, Sogatella furcifera (Hemiptera, Delphacidae), is one of the most devastating rice pests. For a better control strategy, various genetic studies have been conducted using reverse-transcription quantitative real time polymerase chain reaction (qRT-PCR). The appropriate application of qRT-PCR requires reliable endogenous controls; however, studies on this aspect of the white-backed planthopper are lacking. In the present study, nine commonly used reference genes, elongation factor 1-alpha (EF1-alpha), polyubiquitin (UB), ribosomal protein S18 (RPS18), actin 1 (ACT), alpha-1 tubulin (TUB), glyceraldehyde-3-phosphate (GAPDH), ribosomal protein L9 (RPL9), ribosomal protein L10 (RPL10), and 18S ribosomal RNA (18S), were evaluated by qRT-PCR for their expression stability under four different experimental conditions (different developmental stages, acquisition of Southern rice black-streaked dwarf virus (SRBSDV), different tissues, and different temperature stress). These results were analyzed using four software programs (geNorm, NormFinder, BestKeeper, and the delta Ct method) and a Web-based comprehensive tool RefFinder to compare and rank candidate reference genes. According to the results of RefFinder analysis, which integrates the abovementioned four software programs, TUB was ranked as the most suitable reference gene at different developmental stages and under different temperature stress, and GAPDH and RPL9 showed the highest stability for acquisition of SRBSDV and different tissues, respectively. These results will provide a solid foundation for future gene expression study on the white-backed planthopper, and also will give aids in establishing a standardized qRT-PCR procedure for other related insects. PMID- 26612892 TI - Effects of Induced High Carbon Dioxide and Desiccated Atmospheres on the Water Loss and Survival of Subterranean and Invading Drywood Termites. AB - Termites have evolved a variety of morphological, physiological, and behavioral adaptations that together increase the chances of survival in unfavorable environments. Morphological advantages (i.e., a relatively large body size, a large mass of reserves that are metabolized by reducing body water mass, a mass of cuticular lipids, and cuticular hydrocarbons) increase the cuticular resistance to water loss under desiccating conditions. However, termites are incapacitated when exposed to high levels of CO2 and can be eradicated at sufficiently high levels. Based on the results of this study, in an artificially induced high CO2 atmosphere, the loss of body water from drywood termites increased, which generally led to increased rates of mortality. Although the mechanism for the increased loss of body water under high CO2 conditions was not determined, for practical application, the time required for fumigation can be reduced because of the increase in the rate of body water loss from drywood termites in high CO2 conditions. PMID- 26612893 TI - Nutritional Physiology of the Khapra Beetle, Trogoderma granarium Everts (Coleoptera: Dermestidae) Fed on Various Barley Cultivars. AB - The Khapra beetle, Trogoderma granarium Everts (Coleoptera: Dermestidae), is known as one of the mostserious pests of grains in many parts of the world. In this study, the effect of nine barley cultivars ('Bahman','CB-84-10', 'Fajr 30', 'Makuyi', 'Nosrat', 'Yousof', '13A1', '18A1', and '19 A1') and a wheat cultivar ('MV17', as a control) was determined on the nutritional indices and digestive enzymatic activity of T. granarium at 33 6 1C,relative humidity of 6565%, and a photoperiod of 14:10 (L:D) h. The highest and lowest values of larval weight gain of sixth instar were detected on wheat (0.757+/-0.068 mg) and cultivar Bahman (0.342+/-0.071 mg). Also, T. granarium larvae fed on cultivar Bahman had the lowest value of efficiency of conversion of ingested food(10.90+/-2.09%) as compared with wheat and other barley cultivars. Also, the highest midgut amylolytic and proteolytic activities of sixth instar were on cultivar Bahman (0.364+/-0.024 mU/mg and 80.54+/-1.73 U/mg, respectively)and the lowest activities were on cultivar Nosrat (0.043+/-0.004 mU/mg and 7.15+/-0.01 U/mg, respectively).It is concluded that barley cultivar Bahman was the most unsuitable host for feeding of T. granarium. PMID- 26612894 TI - Dynamics and thermal sensitivity of ballistic and non-ballistic feeding in salamanders. AB - Low temperature reduces the performance of muscle-powered movements, but in movements powered by elastic recoil mechanisms, this effect can be mitigated and performance can be increased. To better understand the morphological basis of high performance and thermal robustness of elastically powered movements, we compared feeding dynamics at a range of temperatures (5-25 degrees C) in two species of terrestrial plethodontid salamanders, Plethodon metcalfi and Ensatina eschscholtzii, which differ in tongue muscle architecture and the mechanism of tongue projection. We found that Ensatina is capable of ballistic projection with a mean muscle mass-specific power of 2100 W kg(-1), revealing an elastic mechanism. Plethodon, in contrast, projected its tongue non-ballistically with a mean power of only 18 W kg(-1), indicating it is muscle powered. Ensatina projected its tongue significantly farther than Plethodon and with dynamics that had significantly lower thermal sensitivity at temperatures below 15 degrees C. These performance differences were correlated with morphological differences, namely elongated collagenous aponeuroses in the projector muscle of Ensatina as compared with Plethodon, which are likely the site of energy storage, and the absence in Ensatina of projector muscle fibers attaching to the tongue skeleton that allows projection to be truly ballistic. These findings demonstrate that, in these otherwise similar species, the presence in one species of elaborated connective tissue in series with myofibers confers not only 10-fold greater absolute performance but also greater thermal robustness of performance. We conclude that changes in muscle and connective tissue architecture are sufficient to alter significantly the mechanics, performance and thermal robustness of musculoskeletal systems. PMID- 26612895 TI - MYC in DLBCL: partners matter. AB - In this issue of Blood, Copie-Bergman et al demonstrate that MYC rearrangements (MYC-Rs) with IG genes, but not with other partner genes, have a negative prognostic impact in patients with diffuse large B-cell lymphomas (DLBCLs) treated with immunochemotherapy. PMID- 26612896 TI - DNA damage response impacts macrophage functions. AB - In this issue of Blood, Pereira-Lopes et al demonstrate that a defect in a DNA damage response (DDR) component alters homeostasis of macrophages and their inflammatory responses. PMID- 26612897 TI - Awareness of Animal Welfare Acts at 'an all time low'. PMID- 26612898 TI - Kennel Club launches an online reporting system for operations on dogs. PMID- 26612899 TI - Retailers 'getting to grips' with Campylobacter. PMID- 26612901 TI - Correction. PMID- 26612900 TI - Practice standards: 'a pathway to improvement for aspiring practices'. PMID- 26612902 TI - Vets and doctors pledge to cooperate on One Health. PMID- 26612903 TI - Shaping the right future for the veterinary profession. PMID- 26612905 TI - Hip, hip, hooray! PMID- 26612904 TI - Is professionalism dead? PMID- 26612906 TI - Looking to ExCel. PMID- 26612907 TI - BVNA celebrates its golden jubilee. PMID- 26612908 TI - BVNA awards 2015. PMID- 26612909 TI - Team training: the future of continuing professional development? PMID- 26612910 TI - Clinical research: developing an appropriate career structure. PMID- 26612911 TI - Trends in complaints. PMID- 26612912 TI - Use of antibiotics in animals and people. PMID- 26612913 TI - Shortage of experienced vets. PMID- 26612916 TI - Students, challenge yourselves on anaesthesia. PMID- 26612917 TI - Ten-minute chat. PMID- 26612918 TI - Calcium versus strontium handling by the heart muscle. AB - Calcium plays a crucial role in numerous processes in living systems, from both intracellular and intercellular signalling to blood clotting. Calcium can be replaced by strontium in various intracellular processes due to high level of their similarity and strontium thus may serve as a valuable tool for different experimental studies. On the other hand, strontium is also used in clinical medicine and is commonly taken to the human body with food and water. The negative cardiac side effects of strontium therapy of osteoporosis and bone metastases are well known, but still not fully explained. This fact explains enhanced interest in this element and its impact on human body. This article reviews effects of calcium and strontium on several biochemical and physiological processes, with special emphasis on cardiac muscle. PMID- 26612919 TI - Sulforaphene promotes Bax/Bcl2, MAPK-dependent human gastric cancer AGS cells apoptosis and inhibits migration via EGFR, p-ERK1/2 down-regulation. AB - Gastric cancer migration and invasion considered as main causes of this cancer related death around the world. Sulforaphene (4-isothiocyanato-4R (methylsulfinyl)-1-butene), a structural analog of sulforaphane, has been found to exhibit anticancer potential against different cancers. Our aim was to investigate whether dietary isothiocyanate sulforaphene (SFE) can promote human gastric cancer (AGS) cells apoptosis and inhibit migration. Cells were treated with various concentrations of SFE and cell viability, morphology, intracellular ROS, migration and different signaling protein expressions were investigated. The results indicate that SFE decreases AGS cell viability and induces apoptosis in a dose-dependent manner. Intracellular ROS generation, dose- and time-dependent Bax/Bcl2 alteration and signaling proteins like cytochrome c, Casp-3, Casp-8 and PARP-1 higher expression demonstrated the SFE-induced apoptotic pathway in AGS cells. Again, SFE induced apoptosis also accompanied by the phosphorylation of mitogen-activated protein kinases (MAPKs) like JNK and P-38. Moreover, dose dependent EGFR, p-ERK1/2 down-regulation and cell migration inhibition at non toxic concentration confirms SFE activity in AGS cell migration inhibition. Thus, this study demonstrated effective chemotherapeutic potential of SFE by inducing apoptisis as well as inhibiting migration and their preliminary mechanism for human gastric cancer management. PMID- 26612920 TI - Remote limb ischemic preconditioning (rIPC) activates antioxidant and antiapoptotic genes and inhibits proinflammatory cytokine genes in renal ischemia/reperfusion injury. AB - The mechanisms underlying the renoprotective effect for remote limb ischemic preconditioning (rIPC) against renal ischemia/reperfusion injury need further elucidation. In our work, one hundred and twenty male Sprague Dawley rats were randomized into 3 groups; sham, I/R group (left renal 45 min ischemia) and rIPC (as I/R group with 3 cycles of left femoral ischemic PC just before renal ischemia). Rats were sacrificed at 2 h, 24 h, 48 h and 7 days. Serum creatinine and urea were measured at the baseline and endpoints. Also, histopathological examination and assessment of the expression of inflammatory cytokines e.g. TNF alpha, IL-1beta and ICAM-1 and antioxidant genes: Nrf2, HO-1 and NQO-1 and anti apoptotic gene Bcl-2 in left kidney were done by the end of experiment. The results of this study demonstrated that, rIPC caused significant improvement in serum creatinine and BUN levels and in the expression of antioxidant genes and Bcl-2 antiapoptotic gene with significant attenuation of pro-inflammatory cytokines and histopathological damage score at all-time points compared to I/R group (p <= 0.05). In conclusion, inhibition of inflammatory cytokine (TNF-alpha, IL-1beta and ICAM-1) formation and activation of antioxidant genes: Nrf2, HO-1 and NQO-1 and anti-apoptotic gene Bcl-2 could be possible underlying mechanisms for the renoprotective effect of rIPC. PMID- 26612921 TI - Stress increased ghrelin secretion from pancreatic isolated islets in male rats. AB - It has been demonstrated that plasma ghrelin is likely affected by stress, but little attention has been paid to the effect of stress on ghrelin release from pancreatic islets. This study investigates the effect of stress on ghrelin secretion from pancreatic islets in rats. Male Wistar rats were divided into control and stressed groups. The stressed group was further divided into foot shock and psychological stress subgroups. Stress was induced by a communication box. After stress exposure, blood sampling was performed to determine the plasma levels of corticosterone, glucose, and ghrelin. Then the animals' pancreatic islets were isolated to assess their ghrelin output at 5.6, 8.3, and 16.7 mM glucose concentrations. Acute exposure to foot-shock and psychological stress both increased plasma corticosterone concentration. Moreover, plasma glucose concentration increased in the foot-shock stress group. Chronic exposure to foot shock decreased plasma ghrelin concentration, whereas acute exposure had no significant effect. Acute and chronic exposure to foot-shock and psychological stress increased ghrelin secretion from isolated islets in the presence of different glucose concentrations. The results of the present study suggest that ghrelin secretion from isolated islets is not glucose-dependent. However, ghrelin secretion appears to be intensely responsive to both acute and chronic stress. PMID- 26612923 TI - Turning the focus to solutions. PMID- 26612925 TI - FUSION ENERGY. More delays for ITER fusion project. PMID- 26612922 TI - Properties of anaerobic fungi isolated from several habitats: complexity of phenotypes. AB - Isolates of anaerobic fungi from rumen, animal faeces and compost displayed morphological similarity with known anaerobic fungi. According to their ITS sequences, species were related to Neocallimastix and Piromyces. Rumen fungi tolerated exposure to an aerobic atmosphere for at least four days. Under anaerobic conditions, they could grow on both, defined or complex substrates. Growth in liquid media was monitored by the continuous measurement of metabolic gases (O2, CO2, H2, CO, H2S, CH4). Monitored metabolism was complex, showed that both CO2 and H2 were produced and subsequently consumed by yet unknown metabolic pathway(s). CO and H2S were evolved similarly, but not identically with the generation of CO2 and H2 suggesting their connection with energetic metabolism. Anaerobic fungi from snail faeces and compost produced concentrations of H2S, H2, CO near the lower limit of detection. The rumen isolates produced cellulases and xylanases with similar pH and temperature optima. Proteolytic enzymes were secreted as well. Activities of some enzymes of the main catabolic pathways were found in cell-free homogenates of mycelia. The results indicate the presence of the pentose cycle, the glyoxylate cycle and an incomplete citrate cycle in these fungi. Differences between isolates indicate phenotypic variability between anaerobic fungi. PMID- 26612926 TI - INFECTIOUS DISEASES. An obscure mosquito-borne disease goes global. PMID- 26612927 TI - BIOMEDICAL RESEARCH. An end to U.S. chimp research. PMID- 26612928 TI - SCIENCE AND SOCIETY. Gene drive turns mosquitoes into malaria fighters. PMID- 26612930 TI - Climate crossroads. PMID- 26612929 TI - ACADEMIC MISCONDUCT. China pursues fraudsters in science publishing. PMID- 26612931 TI - After Paris: The rocky road ahead. PMID- 26612932 TI - Clean revolution. PMID- 26612933 TI - Can India keep its promises? PMID- 26612934 TI - HUMAN GENOME. The indispensable genome. PMID- 26612935 TI - SOLAR FUELS. A quick look at how photoelectrodes work. PMID- 26612936 TI - IMMUNOTHERAPY. Could microbial therapy boost cancer immunotherapy? PMID- 26612937 TI - APPLIED OPTICS. Optical meta-atoms: Going nonlinear. PMID- 26612938 TI - ENERGY AND ENVIRONMENT. Understanding China's non-fossil energy targets. PMID- 26612939 TI - ECOLOGY. Learning from Africa's herbivores. PMID- 26612940 TI - EVOLUTION. How Victoria's fishes were knocked from their perch. PMID- 26612941 TI - RETROSPECTIVE. Alan Hall (1952-2015). PMID- 26612942 TI - RETROSPECTIVE. Christopher Marshall (1949-2015). PMID- 26612943 TI - Brazilian aquatic biodiversity in peril. PMID- 26612944 TI - Waste not, want not: Recycled science art. PMID- 26612945 TI - Nurturing the microbiome field. PMID- 26612946 TI - A continent-wide assessment of the form and intensity of large mammal herbivory in Africa. AB - Megafaunal extinctions and a lack of suitable remote sensing technology impede our understanding of both the ecological legacy and current impacts of large mammal herbivores in the Earth system. To address this, we reconstructed the form and intensity of herbivory pressure across sub-Saharan Africa ~1000 years ago. Specifically, we modeled and mapped species-level biomass for 92 large mammal herbivores using census data, species distributions, and environmental covariates. Trait-based classifications of these species into herbivore functional types, and analyses of their biomass surfaces, reveal four ecologically distinct continental-scale herbivory regimes, characterized by internally similar forms and intensities of herbivory pressure. Associations between herbivory regimes, fire prevalence, soil nutrient status, and rainfall provide important insights into African ecology and pave the way for integrating herbivores into global-scale studies. PMID- 26612947 TI - Semiconductor interfacial carrier dynamics via photoinduced electric fields. AB - Solar photoconversion in semiconductors is driven by charge separation at the interface of the semiconductor and contacting layers. Here we demonstrate that time-resolved photoinduced reflectance from a semiconductor captures interfacial carrier dynamics. We applied this transient photoreflectance method to study charge transfer at p-type gallium-indium phosphide (p-GaInP2) interfaces critically important to solar-driven water splitting. We monitored the formation and decay of transient electric fields that form upon photoexcitation within bare p-GaInP2, p-GaInP2/platinum (Pt), and p-GaInP2/amorphous titania (TiO2) interfaces. The data show that a field at both the p-GaInP2/Pt and p-GaInP2/TiO2 interfaces drives charge separation. Additionally, the charge recombination rate at the p-GaInP2/TiO2 interface is greatly reduced owing to its p-n nature, compared with the Schottky nature of the p-GaInP2/Pt interface. PMID- 26612948 TI - Near-unity photoluminescence quantum yield in MoS2. AB - Two-dimensional (2D) transition metal dichalcogenides have emerged as a promising material system for optoelectronic applications, but their primary figure of merit, the room-temperature photoluminescence quantum yield (QY), is extremely low. The prototypical 2D material molybdenum disulfide (MoS2) is reported to have a maximum QY of 0.6%, which indicates a considerable defect density. Here we report on an air-stable, solution-based chemical treatment by an organic superacid, which uniformly enhances the photoluminescence and minority carrier lifetime of MoS2 monolayers by more than two orders of magnitude. The treatment eliminates defect-mediated nonradiative recombination, thus resulting in a final QY of more than 95%, with a longest-observed lifetime of 10.8 +/- 0.6 nanoseconds. Our ability to obtain optoelectronic monolayers with near-perfect properties opens the door for the development of highly efficient light-emitting diodes, lasers, and solar cells based on 2D materials. PMID- 26612949 TI - Deformation-assisted fluid percolation in rock salt. AB - Deep geological storage sites for nuclear waste are commonly located in rock salt to ensure hydrological isolation from groundwater. The low permeability of static rock salt is due to a percolation threshold. However, deformation may be able to overcome this threshold and allow fluid flow. We confirm the percolation threshold in static experiments on synthetic salt samples with x-ray microtomography. We then analyze wells penetrating salt deposits in the Gulf of Mexico. The observed hydrocarbon distributions in rock salt require that percolation occurred at porosities considerably below the static threshold due to deformation-assisted percolation. Therefore, the design of nuclear waste repositories in salt should guard against deformation-driven fluid percolation. In general, static percolation thresholds may not always limit fluid flow in deforming environments. PMID- 26612950 TI - Predicting poverty and wealth from mobile phone metadata. AB - Accurate and timely estimates of population characteristics are a critical input to social and economic research and policy. In industrialized economies, novel sources of data are enabling new approaches to demographic profiling, but in developing countries, fewer sources of big data exist. We show that an individual's past history of mobile phone use can be used to infer his or her socioeconomic status. Furthermore, we demonstrate that the predicted attributes of millions of individuals can, in turn, accurately reconstruct the distribution of wealth of an entire nation or to infer the asset distribution of microregions composed of just a few households. In resource-constrained environments where censuses and household surveys are rare, this approach creates an option for gathering localized and timely information at a fraction of the cost of traditional methods. PMID- 26612951 TI - A pharyngeal jaw evolutionary innovation facilitated extinction in Lake Victoria cichlids. AB - Evolutionary innovations, traits that give species access to previously unoccupied niches, may promote speciation and adaptive radiation. Here, we show that such innovations can also result in competitive inferiority and extinction. We present evidence that the modified pharyngeal jaws of cichlid fishes and several marine fish lineages, a classic example of evolutionary innovation, are not universally beneficial. A large-scale analysis of dietary evolution across marine fish lineages reveals that the innovation compromises access to energy rich predator niches. We show that this competitive inferiority shaped the adaptive radiation of cichlids in Lake Tanganyika and played a pivotal and previously unrecognized role in the mass extinction of cichlid fishes in Lake Victoria after Nile perch invasion. PMID- 26612952 TI - Malaria parasites target the hepatocyte receptor EphA2 for successful host infection. AB - The invasion of a suitable host hepatocyte by mosquito-transmitted Plasmodium sporozoites is an essential early step in successful malaria parasite infection. Yet precisely how sporozoites target their host cell and facilitate productive infection remains largely unknown. We found that the hepatocyte EphA2 receptor was critical for establishing a permissive intracellular replication compartment, the parasitophorous vacuole. Sporozoites productively infected hepatocytes with high EphA2 expression, and the deletion of EphA2 protected mice from liver infection. Lack of host EphA2 phenocopied the lack of the sporozoite proteins P52 and P36. Our data suggest that P36 engages EphA2, which is likely to be a key step in establishing the permissive replication compartment. PMID- 26612953 TI - Cotranslational protein folding on the ribosome monitored in real time. AB - Protein domains can fold into stable tertiary structures while they are synthesized on the ribosome. We used a high-performance, reconstituted in vitro translation system to investigate the folding of a small five-helix protein domain-the N-terminal domain of Escherichia coli N5-glutamine methyltransferase HemK-in real time. Our observations show that cotranslational folding of the protein, which folds autonomously and rapidly in solution, proceeds through a compact, non-native conformation that forms within the peptide tunnel of the ribosome. The compact state rearranges into a native-like structure immediately after the full domain sequence has emerged from the ribosome. Both folding transitions are rate-limited by translation, allowing for quasi-equilibrium sampling of the conformational space restricted by the ribosome. Cotranslational folding may be typical of small, intrinsically rapidly folding protein domains. PMID- 26612954 TI - The best decision I ever made. PMID- 26612955 TI - Vibrational spectroscopic imaging of living systems: An emerging platform for biology and medicine. AB - Vibrational spectroscopy has been extensively applied to the study of molecules in gas phase, in condensed phase, and at interfaces. The transition from spectroscopy to spectroscopic imaging of living systems, which allows the spectrum of biomolecules to act as natural contrast, is opening new opportunities to reveal cellular machinery and to enable molecule-based diagnosis. Such a transition, however, involves more than a simple combination of spectrometry and microscopy. We review recent efforts that have pushed the boundary of the vibrational spectroscopic imaging field in terms of spectral acquisition speed, detection sensitivity, spatial resolution, and imaging depth. We further highlight recent applications in functional analysis of single cells and in label free detection of diseases. PMID- 26612956 TI - Erratum for the Report "14-Step Synthesis of (+)-Ingenol from (+)-3-Carene" by L. Jorgensen, S. J. McKerrall, C. A. Kuttruff, F. Ungeheuer, J. Felding, P. S. Baran. PMID- 26612958 TI - Left isomerism syndrome with total anomalous systemic connection. AB - We present a case of left isomerism with total anomalous systemic venous connection where the inferior vena cava was absent and all other systemic veins connected abnormally to the left atrium. The right atrium was hypoplastic with an intact atrial septum. Blood flow to the lungs was through a large ventricular septal defect. The diagnosis was made with echocardiography, angiography, and computed tomography. Complete repair was performed successfully, and the 7-year old patient had an uneventful recovery. PMID- 26612957 TI - Principles of connectivity among morphologically defined cell types in adult neocortex. AB - Since the work of Ramon y Cajal in the late 19th and early 20th centuries, neuroscientists have speculated that a complete understanding of neuronal cell types and their connections is key to explaining complex brain functions. However, a complete census of the constituent cell types and their wiring diagram in mature neocortex remains elusive. By combining octuple whole-cell recordings with an optimized avidin-biotin-peroxidase staining technique, we carried out a morphological and electrophysiological census of neuronal types in layers 1, 2/3, and 5 of mature neocortex and mapped the connectivity between more than 11,000 pairs of identified neurons. We categorized 15 types of interneurons, and each exhibited a characteristic pattern of connectivity with other interneuron types and pyramidal cells. The essential connectivity structure of the neocortical microcircuit could be captured by only a few connectivity motifs. PMID- 26612959 TI - Primary pulmonary monophasic synovial sarcoma: Evading diagnosis. AB - Primary pulmonary synovial sarcoma is a very rare tumor, thus there is no consensus as to the most appropriate management. A 78-year-old man presented with nonspecific symptoms of weight loss and shortness of breath. Imaging confirmed a large right-sided mass and accompanying pleural effusion. Strong 18F fluorodeoxyglucose uptake was found on positron-emission tomography. The preoperative work-up and intraoperative frozen section were inconclusive. Immunohistochemistry and molecular analysis confirmed the diagnosis of primary pulmonary monophasic synovial sarcoma. PMID- 26612960 TI - Unilateral anhidrosis: A rare complication of thoracic epidural analgesia. AB - Management of pain following thoracotomy is an important issue for the control of early morbidity. We herein present the case of a patient who was referred to our hospital after a fall from a height. Right-sided multiple rib fractures, hemopneumothorax, and diaphragmatic rupture were detected. Thoracic epidural catheterization was performed for pain management just before thoracotomy. The patient developed unilateral anhidrosis postoperatively. We discuss this rare complication of thoracic epidural analgesia with a review of relevant literature. PMID- 26612961 TI - Repair of lung herniation with titanium prosthetic ribs and Prolene mesh. AB - We present a rare case of intercostal lung herniation due to blunt trauma. A 40 year-old man was admitted to our hospital with lung herniation due to falling off a donkey. Computed tomography demonstrated a fracture of the 8th left rib, a comminuted fracture of the 9th rib, and lung herniation into the 8th intercostal space. The herniation was repaired using a titanium prosthetic rib, a rib plate, and Prolene mesh via a thoracotomy. PMID- 26612962 TI - Sensitivity of fluvial sediment source apportionment to mixing model assumptions: A Bayesian model comparison. AB - : Mixing models have become increasingly common tools for apportioning fluvial sediment load to various sediment sources across catchments using a wide variety of Bayesian and frequentist modeling approaches. In this study, we demonstrate how different model setups can impact upon resulting source apportionment estimates in a Bayesian framework via a one-factor-at-a-time (OFAT) sensitivity analysis. We formulate 13 versions of a mixing model, each with different error assumptions and model structural choices, and apply them to sediment geochemistry data from the River Blackwater, Norfolk, UK, to apportion suspended particulate matter (SPM) contributions from three sources (arable topsoils, road verges, and subsurface material) under base flow conditions between August 2012 and August 2013. Whilst all 13 models estimate subsurface sources to be the largest contributor of SPM (median ~76%), comparison of apportionment estimates reveal varying degrees of sensitivity to changing priors, inclusion of covariance terms, incorporation of time-variant distributions, and methods of proportion characterization. We also demonstrate differences in apportionment results between a full and an empirical Bayesian setup, and between a Bayesian and a frequentist optimization approach. This OFAT sensitivity analysis reveals that mixing model structural choices and error assumptions can significantly impact upon sediment source apportionment results, with estimated median contributions in this study varying by up to 21% between model versions. Users of mixing models are therefore strongly advised to carefully consider and justify their choice of model structure prior to conducting sediment source apportionment investigations. KEY POINTS: An OFAT sensitivity analysis of sediment fingerprinting mixing models is conductedBayesian models display high sensitivity to error assumptions and structural choicesSource apportionment results differ between Bayesian and frequentist approaches. PMID- 26612963 TI - Parenting While Incarcerated: Tailoring the Strengthening Families Program for Use with Jailed Mothers. AB - Most incarcerated women are mothers. Parenting programs may benefit women, children and families, yet effectively intervening in correctional settings is a challenge. An evidence-based parenting intervention (the Strengthening Families Program) was tailored and implemented with women in a jail setting. Goals were to assess mothers' needs and interests regarding parenting while they were incarcerated, adapt the program to address those needs, and establish intervention delivery and evaluation methods in collaboration with a community based agency. Women reported wanting to know more about effective communication; how children manage stress; finances; drug and alcohol use; self-care; and stress reduction. They reported high program satisfaction and reported reduced endorsement of corporal punishment after the intervention. Barriers to implementation included unpredictable attendance from session to session due to changing release dates, transfer to other facilities, and jail policies (e.g., lock-down; commissary hours). Implications for sustainable implementation of parenting programs in jail settings are discussed. PMID- 26612964 TI - Early Postnatal Myelin Content Estimate of White Matter via T1w/T2w Ratio. AB - PURPOSE: To develop and evaluate a novel processing framework for the relative quantification of myelin content in cerebral white matter (WM) regions from brain MRI data via a computed ratio of T1 to T2 weighted intensity values. DATA: We employed high resolution (1mm3 isotropic) T1 and T2 weighted MRI from 46 (28 male, 18 female) neonate subjects (typically developing controls) scanned on a Siemens Tim Trio 3T at UC Irvine. METHODS: We developed a novel, yet relatively straightforward image processing framework for WM myelin content estimation based on earlier work by Glasser et al. We first co-register the structural MRI data to correct for motion. Then, background areas are masked out via a joint T1w and T2 foreground mask computed. Raw T1w/T2w-ratios images are computed next. For purpose of calibration across subjects, we first coarsely segment the fat-rich facial regions via an atlas co-registration. Linear intensity rescaling based on median T1w/T2w-ratio values in those facial regions yields calibrated T1w/T2w ratio images. Mean values in lobar regions are evaluated using standard statistical analysis to investigate their interaction with age at scan. RESULTS: Several lobes have strongly positive significant interactions of age at scan with the computed T1w/T2w-ratio. Most regions do not show sex effects. A few regions show no measurable effects of change in myelin content change within the first few weeks of postnatal development, such as cingulate and CC areas, which we attribute to sample size and measurement variability. CONCLUSIONS: We developed and evaluated a novel way to estimate white matter myelin content for use in studies of brain white matter development. PMID- 26612966 TI - On the history of Ludwig von Bertalanffy's "General Systemology", and on its relationship to cybernetics - part III: convergences and divergences. AB - Bertalanffy's so-called "general system theory" (GST) and cybernetics were and are often confused: this calls for clarification. In this article, Bertalanffy's conceptions and ideas are compared with those developed in cybernetics in order to investigate the differences and convergences. Bertalanffy was concerned with first order cybernetics. Nonetheless, his perspectivist epistemology is also relevant with regard to developments in second order cybernetics, and the latter is therefore also considered to some extent. W. Ross Ashby's important role as mediator between GST and cybernetics is analysed. The respective basic epistemological approaches, scientific approaches and inherent world views are discussed. We underline the complementarity of cybernetic and "organismic" trends in systems research within the unitary hermeneutical framework of "general systemology". PMID- 26612965 TI - Clinicopathological Significance of MicroRNA-20b Expression in Hepatocellular Carcinoma and Regulation of HIF-1alpha and VEGF Effect on Cell Biological Behaviour. AB - miRNA-20b has been shown to be aberrantly expressed in several tumor types. However, the clinical significance of miRNA-20b in the prognosis of patients with hepatocellular carcinoma (HCC) is poorly understood, and the exact role of miRNA 20b in HCC remains unclear. The aim of the present study was to investigate the association of the expression of miR-20b with clinicopathological characteristics and overall survival of HCC patients analyzed by Kaplan-Meier analysis and Cox proportional hazards regression models. Meanwhile, the HIF-1alpha and VEGF targets of miR-20b have been confirmed. We found not only miR-20b regulation of HIF-1alpha and VEGF in normal but also regulation of miR-20b in hypoxia. This mechanism would help the tumor cells adapt to the different environments thus promoting the tumor invasion and development. The whole study suggests that miR 20b, HIF-1alpha, and VEGF serve as a potential therapeutic agent for hepatocellular carcinoma. PMID- 26612967 TI - Application of Biased Metropolis Algorithms: From protons to proteins. AB - We show that sampling with a biased Metropolis scheme is essentially equivalent to using the heatbath algorithm. However, the biased Metropolis method can also be applied when an efficient heatbath algorithm does not exist. This is first illustrated with an example from high energy physics (lattice gauge theory simulations). We then illustrate the Rugged Metropolis method, which is based on a similar biased updating scheme, but aims at very different applications. The goal of such applications is to locate the most likely configurations in a rugged free energy landscape, which is most relevant for simulations of biomolecules. PMID- 26612968 TI - Psychotherapy for Bipolar II Disorder: The Role of Interpersonal and Social Rhythm Therapy. AB - Although bipolar II disorder is a highly prevalent, chronic illness that is associated with burdensome psychosocial impairment, relatively little is known about the best ways to treat the disorder. Moreover, psychosocial interventions for the management of bipolar II disorder have been largely unexplored, leaving psychologists with few evidence-based recommendations for best treatment practices. In this article, we provide information about interpersonal and social rhythm therapy (IPSRT), an empirically supported treatment for bipolar I disorder that has preliminary evidence supporting its efficacy in bipolar II disorder. After reviewing the phenomenology of bipolar II disorder and differentiating it from bipolar I disorder, we summarize the extant empirical support for using psychotherapy in the management of bipolar II disorder. We explore what is known about the role of psychotherapy in the management of bipolar II disorder as well as lacunae in the evidence base. Next, we introduce IPSRT and discuss how it has been adapted for use as a treatment for individuals suffering from bipolar II disorder. Specific strategies of the treatment are detailed, and preliminary evidence for the efficacy of IPSRT in bipolar II disorder is described. Finally, we present a case vignette demonstrating the use of IPSRT for an individual with bipolar II disorder. PMID- 26612969 TI - Family Formation Processes: Assessing the Need for a New Nationally Representative Household Panel Survey in the United States. AB - The American family has undergone rapid transformation. Careful measurement attention to family formation is important because families are at the heart of numerous decisions, roles, and responsibilities with implications for understanding the well-being of families, adults and children. This paper considers whether there is a need for a new household panel study that addresses family formation. This paper consists of a review of the recent body of population-based, American surveys and finds a considerable gap in the ability to study the implications of families for the health and well-being of Americans. Earlier panel surveys used to assess family life anchored questions around marital events, but changes in family patterns require attention to a more diverse set of family forms. The paper concludes with recommendations for a multi purpose panel study. The key challenge is to keep to pace with complexity and changes in American family life while at the same time maintaining a parsimonious set of survey questions. PMID- 26612970 TI - Inhibitory Effects of Antimicrobial Peptides on Lipopolysaccharide-Induced Inflammation. AB - Antimicrobial peptides (AMPs) are usually small molecule peptides, which display broad-spectrum antimicrobial activity, high efficiency, and stability. For the multiple-antibiotic-resistant strains, AMPs play a significant role in the development of novel antibiotics because of their broad-spectrum antimicrobial activities and specific antimicrobial mechanism. Besides broad-spectrum antibacterial activity, AMPs also have anti-inflammatory activity. The neutralization of lipopolysaccharides (LPS) plays a key role in anti-inflammatory action of AMPs. On the one hand, AMPs can readily penetrate the cell wall barrier by neutralizing LPS to remove Gram-negative bacteria that can lead to infection. On the contrary, AMPs can also inhibit the production of biological inflammatory cytokines to reduce the inflammatory response through neutralizing circulating LPS. In addition, AMPs also modulate the host immune system by chemotaxis of leukocytes, to promote immune cell proliferation, epithelialization, and angiogenesis and thus play a protective role. This review summarizes some recent researches about anti-inflammatory AMPs, with a focus on the interaction of AMPs and LPS on the past decade. PMID- 26612972 TI - Bayesian Reconstruction of Two-Sex Populations by Age: Estimating Sex Ratios at Birth and Sex Ratios of Mortality. AB - The original version of Bayesian reconstruction, a method for estimating age specific fertility, mortality, migration and population counts of the recent past with uncertainty, produced estimates for female-only populations. Here we show how two-sex populations can be similarly reconstructed and probabilistic estimates of various sex ratio quantities obtained. We demonstrate the method by reconstructing the populations of India from 1971 to 2001, Thailand from 1960 to 2000, and Laos from 1985 to 2005. We found evidence that in India, sex ratio at birth exceeded its conventional upper limit of 1.06, and, further, increased over the period of study, with posterior probability above 0.9. In addition, almost uniquely, we found evidence that life expectancy at birth (e0) was lower for females than for males in India (posterior probability for 1971-1976 equal to 0.79), although there was strong evidence for a narrowing of the gap through to 2001. In both Thailand and Laos, we found strong evidence for the more usual result that e0 was greater for females and, in Thailand, that the difference increased over the period of study. PMID- 26612973 TI - Aging Cohabiting Couples and Family Policy: Different-Sex and Same-Sex Couples. PMID- 26612971 TI - Novel Roles for Chloride Channels, Exchangers, and Regulators in Chronic Inflammatory Airway Diseases. AB - Chloride transport proteins play critical roles in inflammatory airway diseases, contributing to the detrimental aspects of mucus overproduction, mucus secretion, and airway constriction. However, they also play crucial roles in contributing to the innate immune properties of mucus and mucociliary clearance. In this review, we focus on the emerging novel roles for a chloride channel regulator (CLCA1), a calcium-activated chloride channel (TMEM16A), and two chloride exchangers (SLC26A4/pendrin and SLC26A9) in chronic inflammatory airway diseases. PMID- 26612974 TI - Molecular cloning and heterologous expression analysis of JrVTE1 gene from walnut (Juglans regia). AB - Tocopherol cyclase (VTE1) plays a key role in promoting the production of gamma tocopherol and improving total tocopherol content in photosynthetic organisms. Walnut is an important source of tocopherols in the human diet, and gamma tocopherol is the major tocopherol compound in walnut kernels. In this study, a full-length cDNA of the VTE1 gene was isolated from walnut using RT-PCR and RACE, and designated as JrVTE1. The full-length cDNA of the JrVTE1 gene contained a 1353-bp open-reading frame encoding a 451-amino-acid protein with a calculated molecular weight of 49.5 kDa. The deduced JrVTE1 protein had a considerable homology with other plant VTE1s and belonged to the tocopherol cyclase family. Functional characterization of JrVTE1 by heterologous expression was carried out in E. coli BL21 (DE3) and microshoot lines of the fruit trees jujube (Zizyphus jujuba var. spinosa) and pear (Pyrus communis) cultivar 'Old Home'. JrVTE1 in E. coli expressed as a 50 kDa protein, as expected. One or two copies of the transferred JrVTE1 gene were detected in the genomes of representative transgenic lines (from the initial transgenic plants) of jujube and pear by gel blots analysis. Over-expression of JrVTE1 in jujube and pear resulted in an accumulation of tocopherol and a shift in tocopherol composition in leaf, root and stem tissues. In the transgenic jujube, the total tocopherol content increased by 29.8 MUg/g in the stems of line J3, 43.7 and 22.5 MUg/g in the roots and leaves of line J1, respectively, whereas in the transgenic pear it increased by 47.3 MUg/g in the leaf of line P3, and 16.7 and 10.4 MUg/g in roots and stems of line P9, respectively. In the examined tissues of transgenic plants, the highest accumulation rate was the gamma-tocopherol. These results indicate that JrVTE1 is one of the rate-limiting enzymes for tocopherol production and could be used to improve the tocopherol content of tree crops through genetic engineering. PMID- 26612976 TI - A curved exponential family model for complex networks. AB - Networks are being increasingly used to represent relational data. As the patterns of relations tends to be complex, many probabilistic models have been proposed to capture the structural properties of the process that generated the networks. Two features of network phenomena not captured by the simplest models is the variation in the number of relations individual entities have and the clustering of their relations. In this paper we present a statistical model within the curved exponential family class that can represent both arbitrary degree distributions and an average clustering coefficient. We present two tunable parameterizations of the model and give their interpretation. We also present a Markov Chain Monte Carlo (MCMC) algorithm that can be used to generate networks from this model. PMID- 26612975 TI - Novel candidate genes AuxRP and Hsp90 influence the chip color of potato tubers. AB - Potato (Solanum tuberosum L.) tubers exhibit significant variation in reducing sugar content directly after harvest, cold storage and reconditioning. Here, we performed QTL analysis for chip color, which is strongly influenced by reducing sugar content, in a diploid potato mapping population. Two QTL on chromosomes I and VI were detected for chip color after harvest and reconditioning. Only one region on chromosome VI was linked with cold-induced sweetening. Using the RT-PCR technique, we showed differential expression of the auxin-regulated protein (AuxRP) gene. The AuxRP transcript was presented in light chip color parental clone DG 97-952 and the RNA progeny of the bulk sample consisting of light chip color phenotypes after cold storage. This amplicon was absent in dark chip parental clone DG 08-26/39 and the RNA bulk sample of dark chip progeny. Genetic variation of AuxRP explained up to 16.6 and 15.2 % of the phenotypic variance after harvest and 3 months of storage at 4 degrees C, respectively. Using an alternative approach, the RDA-cDNA method was used to recognize 25 gene sequences, of which 11 could be assigned to potato chromosome VI. One of these genes, Heat-shock protein 90 (Hsp90), demonstrated higher mRNA and protein expression in RT-qPCR and western blotting assays in the dark chip color progeny bulk sample compared with the light chip color progeny bulk sample. Our study, for the first time, suggests that the AuxRP and Hsp90 genes are novel candidate genes capable of influencing the chip color of potato tubers. PMID- 26612977 TI - Assignment Of Hexuronic Acid Stereochemistry In Synthetic Heparan Sulfate Tetrasaccharides With 2-O-Sulfo Uronic Acids Using Electron Detachment Dissociation. AB - The present work focuses on the assignment of uronic acid stereochemistry in heparan sulfate (HS) oligomers. The structural elucidation of HS glycosaminoglycans is the subject of considerable importance due to the biological and biomedical significance of this class of carbohydrates. They are highly heterogeneous due to their non-template biosynthesis. Advances in tandem mass spectrometry activation methods, particularly electron detachment dissociation (EDD), has led to the development of methods to assign sites of sulfo modification in glycosaminoglycan oligomers, but there are few reports of the assignment of uronic acid stereochemistry, necessary to distinguish glucuronic acid (GlcA) from iduronic acid (IdoA). Whereas preceding studies focused on uronic acid epimers with no sulfo modification, the current work extends the assignment of the hexuronic acid stereochemistry to 2-O-sulfo uronic acid epimeric tetrasaccharides. The presence of a 2-O-sulfo group on the central uronic acid was found to greatly influence the formation of B3, C2, Z2, and Y1 ions in glucuronic acid and Y2 and 1,5X2 for iduronic acid. The intensity of these peaks can be combined to yield a diagnostic ratios (DR), which can be used to confidently assign the uronic acid stereochemistry. PMID- 26612978 TI - Morphological and molecular characterization of the human breast epithelial cell line M13SV1 and its tumorigenic derivatives M13SV1-R2-2 and M13SV1-R2-N1. AB - BACKGROUND: The estrogen receptor-positive M13SV1 breast epithelial cell line was proposed to be a suitable in vitro model for breast cancer research since two derivatives with graduated tumorigenicity-M13SV1-R2-2 and M13SV1-R2-N1-are available for this cell line. In the present study, these three cell lines were comparatively examined for their morphological and their biochemical properties on the molecular level. METHODS: A transcriptomic approach (gene array analysis) was chosen to unravel differences in gene expression among the three cell lines. Network analysis was conducted to identify deregulated signaling pathways. Cellular viability was determined by impedance measurements as well as by neutral red uptake assay. Apoptosis was determined by using a caspase assay. For morphological characterization, cells were grown in three-dimensional cell culture, and cellular differentiation and spheroid formation was followed by immunofluorescence staining by using confocal laser scanning microscopy. RESULTS: The gene array results indicated that there were only marginal differences in gene expression among the three cell lines. Network analysis predicted the R2-N1 derivative (1) to display enhanced apoptosis and (2) to have a higher migration capability compared to its parent cell line M13SV1. Enhanced apoptosis was confirmed by elevated caspase activity, and increased migration was observed in 3D culture when cells migrated out of the globular spheroids. In 3D cell culture, all three cell lines similarly formed spheroids within three days, but there was no acini formation until day 21 which is indicated by a growth arrest around day 15, cellular polarization, and the formation of hollow lumen inside the spheroids. These characteristics, however, are crucial to study, e.g., the differentiation process of breast epithelial cells in vitro. CONCLUSION: Due to the molecular and morphological features, the M13SV1 cell line and its tumorigenic derivatives seem to be less suitable as in vitro models than other cell lines such as the MCF-10A cell line which displays proper acini formation in 3D culture. PMID- 26612979 TI - Safety and efficacy of switching from low molecular weight heparin to dabigatran in patients undergoing elective total hip or knee replacement surgery. AB - BACKGROUND: The aim of this study was to assess the safety and efficacy of switching therapy from low molecular weight heparin (LMWH; enoxaparin) to dabigatran for prevention of venous thromboembolic events (VTE) in patients undergoing elective total hip or knee replacement surgery (THR/TKR). METHODS: This was a prospective, multicenter, open-label, single-arm, observational, study in patients undergoing THR or TKR who were to receive enoxaparin 40 mg for thromboprophylaxis. Enoxaparin was initiated before or after surgery according to local practice, and was switched to dabigatran 220 mg once daily at a time point chosen by the investigator. The coprimary endpoints were major bleeding events, and the composite of symptomatic VTE and all-cause mortality, from last use of enoxaparin to 24 h after last intake of dabigatran. RESULTS: Altogether, 168 (81 THR, 87 TKR) patients were enrolled, of whom 161 received both enoxaparin and dabigatran, 2 received dabigatran only and 5 received enoxaparin only. The median time of the first dabigatran tablet was 24.0 h after the last LMWH dosage and the median number of days on dabigatran treatment was 36 days. No symptomatic VTE or death occurred during the study. One major bleeding event was seen at the surgical site and required treatment cessation. Three minor bleeding events were observed. CONCLUSIONS: In the normal clinical setting, switching from LMWH to dabigatran in patients who had undergone THR and TKR was safe and effective in preventing VTE. The reported adverse events and serious adverse events were consistent with the known safety profile for dabigatran. Switching from a subcutaneous to an oral anticoagulant may offer greater convenience in the outpatient setting after discharge. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01153698. PMID- 26612981 TI - Granular computing in mosaicing of images from capsule endoscopy. AB - This article introduces methods for modeling compound granules used in algorithms which could successfully construct a mosaic from the images coming from an endoscope capsule. In order to apply the algorithm, combined images must have a common area where the correspondence of points is determined. That allows to determine the transformation parameters to compensate movement of the capsule that occurs between moments when the mosaic images were acquired. The developed algorithm for images from the capsule endoscopy has proved to be faster and comparably accurate as commercial GDB-ICP algorithm. PMID- 26612980 TI - Acute effectiveness of a "fat-loss" product on substrate utilization, perception of hunger, mood state and rate of perceived exertion at rest and during exercise. AB - BACKGROUND: Achieving fat-loss outcomes by ingesting multi-ingredient mixtures may be further enhanced during exercise. This study tested the acute thermogenic effectiveness of a commercially available multi-ingredient product (Shred Matrix(r)), containing Green Tea Extract, Yerba Mate, Guarana Seed Extract, Anhydrous caffeine, Saw palmetto, Fo-Ti, Eleuthero root, Cayenne Pepper, and Yohimbine HCI, on fatty acid oxidation (FAO), perception of hunger, mood state and rate of perceived exertion (RPE) at rest and during 30 min of submaximal exercise. METHODS: Following institutional ethical approval, twelve healthy recreationally active participants, five females and seven males, were randomized to perform two separate experimental ergometry cycling trials, and to ingest 1.5 g (3 * capsules) of either a multi-ingredient supplement (SHRED) or placebo (PL). Participants rested for 3 h, before performing a 30-min cycling exercise corresponding to their individually-determined intensity based on their maximal fat oxidation (Fatmax). Fatty acid oxidation (FAO) was determined at rest, 3 h before exercise (Pre1), immediately before exercise (Pre2) and during exercise (Post), using expired gasses and indirect calorimetry. Rate of perceived exertion (RPE) was measured every 3 min during the 30-min exercise. Additionally both mood state and perception of hunger were assessed at Pre1, Pre2 and Post exercise. A repeated measures ANOVA design and Cohen's d effect sizes were used to analyze potential differences between times and treatment conditions. RESULTS: FAO increased in SHRED from Pre1 to Pre2 [0.56 +/- 0.26 to 0.96 +/- 0.37, (p = 0.003, d =1.34)] but not in PL [0.67 +/- 0.25 to 0.74 +/- 0.19, (p = 0.334) d = 0.49], with no differences were found between conditions (p = 0.12, d = 0.49). However, Cohen's d = 0.77 revealed moderate effect size in favor of SHRED from Pre to Post exercise. RPE values were lower in SHRED compared to Pl (p< 0.001). Mood state and perception of hunger were not different between conditions, with no interaction effects. However, a trend was shown towards improved satiety in SHRED compared with PL, [F(1,11) = 3.58, p = 0.085]. CONCLUSIONS: The multi-ingredient product's potential enhancement of FAO during exercise, satiety, and RPE reduction suggests an acute effectiveness of SHRED in improving the exercise related fat loss benefits. PMID- 26612982 TI - Knowledge representation of motor activity of patients with Parkinson's disease. AB - An approach to the knowledge representation extraction from biomedical signals analysis concerning motor activity of Parkinson disease patients is proposed in this paper. This is done utilizing accelerometers attached to their body as well as exploiting video image of their hand movements. Experiments are carried out employing artificial neural networks and support vector machine to the recognition of characteristic motor activity disorders in patients. Obtained results indicate that it is possible to interpret some selected patient's body movements with a sufficiently high effectiveness. PMID- 26612983 TI - China's Population Policy at the Crossroads: Social Impacts and Prospects. AB - China's total fertility rate fell below replacement level in the 1990s. From the 1970s the fertility rate declined dramatically, mainly as a consequence of the national population policy whose aim has been to limit birth numbers, control population growth and boost economic growth. Having achieved such a low fertility rate, how will China's population policy evolve in the future? This paper first reviews the history of China's population policy since 1970 in terms of three stages: 1970-1979; 1980-1999; and after 2000. We explore the impacts of China's population policy, including relief of pressure on China's environment and resources, fertility decline, the unexpectedly high male-biased sex ratio at birth (SRB), the coming shortage of labor force, and the rapid aging of the population. We also investigate ethical issues raised by the implementation of the policy and its results. Finally we introduce the controversy over potential adjustment of the policy, acknowledging the problems faced by western countries with low fertility and countermeasures they have taken. We offer some suggestions that might be appropriate in the Chinese context. PMID- 26612984 TI - Lipidomic and metabolomic characterization of a genetically modified mouse model of the early stages of human type 1 diabetes pathogenesis. AB - The early mechanisms regulating progression towards beta cell failure in type 1 diabetes (T1D) are poorly understood, but it is generally acknowledged that genetic and environmental components are involved. The metabolomic phenotype is sensitive to minor variations in both, and accordingly reflects changes that may lead to the development of T1D. We used two different extraction methods in combination with both liquid- and gas chromatographic techniques coupled to mass spectrometry to profile the metabolites in a transgenic non-diabetes prone C57BL/6 mouse expressing CD154 under the control of the rat insulin promoter (RIP) crossed into the immuno-deficient recombination-activating gene (RAG) knockout (-/-) C57BL/6 mouse, resembling the early stages of human T1D. We hypothesized that alterations in the metabolomic phenotype would characterize the early pathogenesis of T1D, thus metabolomic profiling could provide new insight to the development of T1D. Comparison of the metabolome of the RIP CD154 * RAG-/- mice to RAG-/- mice and C57BL/6 mice revealed alterations of >100 different lipids and metabolites in serum. Low lysophosphatidylcholine levels, accumulation of ceramides as well as methionine deficits were detected in the pre-type 1 diabetic mice. Additionally higher lysophosphatidylinositol levels and low phosphatidylglycerol levels where novel findings in the pre-type 1 diabetic mice. These observations suggest that metabolomic disturbances precede the onset of T1D. PMID- 26612986 TI - Development of a HPLC Method for the Quantitative Determination of Capsaicin in Collagen Sponge. AB - Controlling the concentration of drugs in pharmaceutical products is essential to patient's safety. In this study, a simple and sensitive HPLC method is developed to quantitatively analyze capsaicin in collagen sponge. The capsaicin from sponge was extracted for 30 min with ultrasonic wave extraction technique and methanol was used as solvent. The chromatographic method was performed by using isocratic system composed of acetonitrile-water (70 : 30) with a flow rate of 1 mL/min and the detection wavelength was at 280 nm. Capsaicin can be successfully separated with good linearity (the regression equation is A = 9.7182C + 0.8547; R (2) = 1.0) and perfect recovery (99.72%). The mean capsaicin concentration in collagen sponge was 49.32 mg/g (RSD = 1.30%; n = 3). In conclusion, the ultrasonic wave extraction method is simple and the extracting efficiency is high. The HPLC assay has excellent sensitivity and specificity and is a convenient method for capsaicin detection in collagen sponge. This paper firstly discusses the quantitative analysis of capsaicin in collagen sponge. PMID- 26612987 TI - Evaluation of the Nasal Surgical Questionnaire for Monitoring Results of Septoplasty. AB - Monitoring the results of surgery is important. The otorhinolaryngology department of our hospital currently uses preoperative and postoperative versions of the Nasal Surgical Questionnaire (NSQ) for continuous evaluation of nasal septoplasty. In this study, 55 patients undergoing septoplasty answered the preoperative version twice to assess the NSQ's test-retest precision, and 75 patients answered the preoperative questionnaire before and the postoperative one 6 months after surgery to evaluate the NSQ's ability to detect change in symptoms following surgery. Both the pre- and postoperative versions of the NSQ use separate visual analogue scales (VAS) to assess nasal obstruction during the day, at night, and during exercise. Other nasal symptoms are graded as secondary outcomes using 4-point Likert scales. The mean VAS scores for the two preoperative obstruction ratings were not significantly different. The scores were significantly higher than in a normal population. There were also significant differences between preoperative and postoperative ratings. The mean pre- and postoperative scores at night for those who reported complete improvement were 66.1 and 8.4, substantial improvement 74.5 and 24.2, and no improvement 83.3 and 76.4. The NSQ reliably assesses nasal symptoms in patients and may be useful for both short and long term prospective studies of septoplasty. PMID- 26612985 TI - Data standards can boost metabolomics research, and if there is a will, there is a way. AB - Thousands of articles using metabolomics approaches are published every year. With the increasing amounts of data being produced, mere description of investigations as text in manuscripts is not sufficient to enable re-use anymore: the underlying data needs to be published together with the findings in the literature to maximise the benefit from public and private expenditure and to take advantage of an enormous opportunity to improve scientific reproducibility in metabolomics and cognate disciplines. Reporting recommendations in metabolomics started to emerge about a decade ago and were mostly concerned with inventories of the information that had to be reported in the literature for consistency. In recent years, metabolomics data standards have developed extensively, to include the primary research data, derived results and the experimental description and importantly the metadata in a machine-readable way. This includes vendor independent data standards such as mzML for mass spectrometry and nmrML for NMR raw data that have both enabled the development of advanced data processing algorithms by the scientific community. Standards such as ISA-Tab cover essential metadata, including the experimental design, the applied protocols, association between samples, data files and the experimental factors for further statistical analysis. Altogether, they pave the way for both reproducible research and data reuse, including meta-analyses. Further incentives to prepare standards compliant data sets include new opportunities to publish data sets, but also require a little "arm twisting" in the author guidelines of scientific journals to submit the data sets to public repositories such as the NIH Metabolomics Workbench or MetaboLights at EMBL-EBI. In the present article, we look at standards for data sharing, investigate their impact in metabolomics and give suggestions to improve their adoption. PMID- 26612988 TI - Long-Lasting Fever and Lymphadenitis: Think about F. tularensis. AB - We report the case of glandular tularemia that developed in a man supposedly infected by a tick bite in Western Switzerland. Francisella tularensis (F. tularensis) was identified. In Europe tularemia most commonly manifests itself as ulcero-glandular or glandular disease; the diagnosis of tularemia may be delayed in glandular form where skin or mucous lesion is absent, particularly in areas which are assumed to have a low incidence of the disease. PMID- 26612989 TI - A Fatal Twist: Volvulus of the Small Intestine in a 46-Year-Old Woman. AB - A 46-year-old woman presented to two emergency departments within 12 hours because of acute abdominal pain. Physical exam demonstrated tenderness and epigastric guarding. An ultrasound was interpreted as negative; she was discharged home. Later that evening, she was found dead. Postmortem exam revealed acute hemorrhagic necrosis of a segment of jejunum secondary to volvulus. Clinical clues suggesting presentations of small bowel volvulus are usually nonspecific; the diagnosis is typically confirmed at surgery. Her unremitting abdominal pain, persistent vomiting, and absolute neutrophilia were consistent with an acute process. The etiology of this volvulus was caused by an elastic fibrous band at the root of the jejunal mesentery. While congenital fibrous bands are rare in adults, this interpretation is favored for two reasons. First, the band was located 20 cm superior to postsurgical adhesions in the lower abdomen and pelvis. Second, there was no history of trauma or previous surgery involving the site of volvulus. PMID- 26612990 TI - Association between Severe Dehydration in Rotavirus Diarrhea and Exclusive Breastfeeding among Infants at Dr. Hasan Sadikin General Hospital, Bandung, Indonesia. AB - Background. Rotavirus is the leading cause of severe acute diarrhea in children. Infants who are exclusively breastfed develop fewer infections and have less severe illnesses. This study aimed to determine association between severe dehydration in rotavirus diarrhea and exclusive breastfeeding. Methods. This is a cross-sectional study in infants <= 6 months old with acute diarrhea in Dr. Hasan Sadikin Hospital, Bandung, Indonesia. Results. From 134 infants <= 6 months old with acute diarrhea enrolled from April 2009 to December 2012, there were 88 (65.6%) boys and 46 (34.4%) girls in this study. Rotavirus was detected in 60 (44.8 %), 32 (53.3%) of whom were exclusively breastfed. From rotavirus positive subjects, severe dehydration occurred in 4 (12.6%) exclusively breastfed infants and 6 (21.5%) not exclusively breastfed infants. No significant association was found between severe dehydration and exclusive breastfeeding (p = 0.491) in rotavirus diarrhea. Conclusions. In rotavirus diarrhea, there was no significant association between exclusive breastfeeding and severe dehydration. PMID- 26612991 TI - Effects of ascorbic acid on alpha-l-arabinofuranosidase and alpha-l arabinopyranosidase activities from Bifidobacterium longum RD47 and its application to whole cell bioconversion of ginsenoside. AB - Bifidobacterium longum RD47 was cultured in 24 kinds of modified MRS broths containing various ingredients to select the most promising source that induces microbial enzymes. Among the various ingredients, ascorbic acid significantly enhanced alpha-l-arabinofuranosidase and alpha-l-arabinopyranosidase activities in Bifidobacterium longum RD47. Addition of 2 % ascorbic acid (w/v) to MRS showed the maximum enzyme activities. Both whole cell and disrupted cell homogenates showed efficient rho-nitrophenyl-beta-d-glucopyranoside and rho-nitrophenyl-beta d-glucofuranoside hydrolysis activities. The initially enhanced alpha-l arabinopyranosidase and alpha-l-arabinofuranosidase activities by ascorbic acid were maintained over the cell disruption process. The optimal pH of alpha-l arabinofuranosidase and alpha-l-arabinopyranosidase was 5.0 and 7.0, respectively. Both enzymes showed the maximum activities at 40.0 degrees C. Under the controlled condition using Bifidobacterium longum RD47, ginsenoside Rb2, and Rc were converted to ginsenoside Rd. PMID- 26612992 TI - The Reporting Quality of Acupuncture-Related Infections in Korean Literature: A Systematic Review of Case Studies. AB - Objective. Acupuncture is generally accepted as a safe intervention when it is administered in appropriate clinical setting by well-educated and experienced practitioners. In this study, we reviewed observational studies on adverse events (AEs) or complications relevant to acupuncture practice in Korean literature for assessing their reporting quality and suggested recommendations for future ones on acupuncture-related infections. Method. Electronic databases including Medline, Embase, Cochrane library, Korean studies Information Service System, DBpia, National Digital Science Library, and Korean National Assembly Library were searched until May 2015. Combination of keywords including "acupuncture" and "infection" were used for searching databases. Result. A total of 23 studies from 2,739 literature articles were identified from electronic database searching until May 2015. From this review, we found that most case studies did not report enough information for judging causality between acupuncture and the AEs (or complications) as well as appropriateness of the acupuncture practice. In addition, acupuncture experts rarely participated in the reporting of these AEs (or complications). Conclusion. Based on these limitations, we suggest a tentative recommendation for future case studies on acupuncture-related infection. We hope that this recommendation would contribute to the improvement of the reporting quality of acupuncture-related AEs (or complications) in the future. PMID- 26612993 TI - Acupuncture Attenuated Inflammation and Inhibited Th17 and Treg Activity in Experimental Asthma. AB - Acupuncture is an effective therapeutic method in asthma treatment in traditional Chinese medicine. Here, we evaluated the effect of acupuncture on airway hyperresponsiveness (AHR) and the associated inflammatory changes as well as Th17 and Treg activity in ovalbumin- (OVA-) induced experimental asthma. Our results revealed that acupuncture treatment significantly inhibited AHR, lung inflammation, and mucus secretion of experimental asthma mice. Furthermore, a decrease in lymphocytes and eosinophils as well as neutrophils was observed in bronchoalveolar lavage fluid (BALF) of mice treated with acupuncture. Acupuncture reduced the OVA specific IgE level as well as the Th17 cytokine levels including IL-17A, IL-17F, and IL-22 in the serum of the experimental asthma mice. Acupuncture treatment group also had reduced CD4+IL-17A+ cell numbers and increased CD4+Foxp3+ cell numbers in BALF. In addition, acupuncture could inhibit IL-17R, RORgammat, p65, and the inhibitor of NF-kappaB kinase-alpha (IKKalpha) protein expression. Our results indicated that acupuncture was effective in inhibiting AHR and inflammation in OVA-induced experimental asthma, which may be associated with the regulation of Th17 and Treg activity and NF-kappaB pathway. PMID- 26612994 TI - Gas Chromatography-Mass Spectrometry Analysis of Ulva fasciata (Green Seaweed) Extract and Evaluation of Its Cytoprotective and Antigenotoxic Effects. AB - The chemical composition and biological properties of Ulva fasciata aqueous ethanolic extract were examined. Five components were identified in one fraction prepared from the extract by gas chromatography-mass spectrometry, and palmitic acid and its ethyl ester accounted for 76% of the total identified components. Furthermore, we assessed the extract's antioxidant properties by using the DPPH, ABTS, and lipid peroxidation assays and found that the extract had a moderate scavenging effect. In an experiment involving preexposition and coexposition of the extract (1-500 ug/mL) and benzo[a]pyrene (BP), the extract was found to be nontoxic to C9 cells in culture and to inhibit the cytotoxicity induced by BP. As BP is biotransformed by CYP1A and CYP2B subfamilies, we explored the possible interaction of the extract with these enzymes. The extract (25-50 ug/mL) inhibited CYP1A1 activity in rat liver microsomes. Analysis of the inhibition kinetics revealed a mixed-type inhibitory effect on CYP1A1 supersome. The effects of the extract on BP-induced DNA damage and hepatic CYP activity in mice were also investigated. Micronuclei induction by BP and liver CYP1A1/2 activities significantly decreased in animals treated with the extract. The results suggest that Ulva fasciata aqueous-ethanolic extract inhibits BP bioactivation and it may be a potential chemopreventive agent. PMID- 26612995 TI - Antioxidant Formulae, Shengmai San, and LingGuiZhuGanTang, Prevent MPTP Induced Brain Dysfunction and Oxidative Damage in Mice. AB - The present study was designed to evaluate the preventive effect of antioxidative traditional oriental medicine formulae, Shengmai San (SMS) and LingGuiZhuGanTang (LGZGT), against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (i.p 30 mg.kg(-1) for 5 consecutive days) induced neurotoxicity. In in vitro antioxidant assays measured with Trolox and butyl hydroxyl toluene as reference antioxidant revealed that SMS has higher scavenging potential against hydroxyl radical than superoxide anion radical, but LGZGT was the reverse. The neuroprotective effect of SMS and LGZGT against MPTP was evaluated in mice by behavioral, biochemical, and immunohistochemical studies. In the behavioral study, both SMS and LGZGT significantly reversed the locomotive impairment induced by MPTP. Simultaneously, both formulae significantly prevented the MPTP induced dopaminergic neuron loss assessed by tyrosine hydroxylase in the midbrain. Both SMS and LGZGT significantly attenuated the elevated lipid peroxidation and protein carbonyls levels by MPTP. The DNA damage induced by MPTP was also prevented by both formulae. Although a little difference in the protective functions was observed between the two formulae, such as in DNA damage and behavioral studies, the results indicate that both SMS and LGZGT with antioxidant property act as a good candidate applicable for the antioxidant based complementary therapies of neurodegenerative diseases. PMID- 26612996 TI - The Adjuvant Activity of Epimedium Polysaccharide-Propolis Flavone Liposome on Enhancing Immune Responses to Inactivated Porcine Circovirus Vaccine in Mice. AB - Objectives. The adjuvant activity of Epimedium polysaccharide-propolis flavone liposome (EPL) was investigated in vitro and in vivo. Methods. In vitro, the effects of EPL at different concentrations on splenic lymphocytes proliferation and mRNA expression of IFN-gamma and IL-6 were determined. In vivo, the adjuvant activities of EPL, EP, and mineral oil were compared in BALB/c mice through vaccination with inactivated porcine circovirus type 2 (PCV2) vaccine. Results. In vitro, EPL promoted lymphocytes proliferation and increased the mRNA expression of IFN-gamma and IL-6, and the effect was significantly better than EP at all concentrations. In vivo, EPL significantly promoted the lymphocytes proliferation and the secretion of cytokines and improved the killing activity of NK cells, PCV2-specific antibody titers, and the proportion of T-cell subgroups. The effects of EPL were significantly better than EP and oil adjuvant at most time points. Conclusion. EPL could significantly improve both PCV2-specific cellular and humoral immune responses, and its medium dose had the best efficacy. Therefore, EPL would be exploited in an effective immune adjuvant for inactivated PCV2 vaccine. PMID- 26612999 TI - Silica-titania xerogel for solid phase spectrophotometric determination of salicylate and its derivatives in biological liquids and pharmaceuticals. AB - BACKGROUND: Salicylic acid and its derivatives are widely used drugs with potential toxicity. The main areas of salicylate derivatives determination are biological liquids and pharmaceuticals analysis. RESULTS: Silica-titania xerogel has been used for solid phase spectrophotometric determination of various salicylate derivatives (salicylate, salicylamide, methylsalicylate). The reaction conditions influence on the interaction of salicylate derivatives with silica titania xerogels has been investigated; the characteristics of titanium(IV) salicylate derivatives complexes in solid phase have been described. The simple solid phase spectrophotometric procedures are based on the formation of xerogel incorporated titanium(IV) colored complexes with salicylate derivatives. A linear response has been observed in the following concentration ranges 0.1-5, 0.5-10 and 0.05-4.7 mM for salicylate, salicylamide, and methylsalicylate, respectively. The proposed procedures have been applied to the analysis of human urine, synthetic serum, and pharmaceuticals. CONCLUSIONS: The simple solid phase spectrophotometric procedures of salicylate derivatives determination based on the new sensor materials have been proposed for biological liquids and pharmaceuticals analysis. Graphical abstractComplexation of titanium (IV), incorporated in silica-titania xerogels (Si-Ti), with salicylate derivatives (L) resulting in yellow-colored xerogels (Si-Ti/Ln) has been proposed for salicylate derivatives determination in biological liquids and pharmaceuticals. PMID- 26612998 TI - Higher visceral fat area increases the risk of vitamin D insufficiency and deficiency in Chinese adults. AB - BACKGROUND: Visceral fat area (VFA), a novel sex-specific index for visceral fat obesity (VFO) might play a major role in the development of vitamin D deficiency. However, the association between VFA and vitamin D insufficiency and deficiency in Chinese population is less clear. The aim of this study was to explore the population-level association between VFA and vitamin D insufficiency and deficiency among Chinese men and women. METHODS: This cross-sectional study involved 1105 adults aged 20-70 years living in Tianjin who were randomly selected and medically examined. All subjects underwent the bioelectrical impedance analysis (BIA) method to estimate the VFA. Serum 25-hydroxyvitamin D3 (25(OH) D3) level was assayed by the high-performance liquid chromatography (HPLC) method and defined insufficiency and deficiency following recommended cutoffs. The association between VFA and vitamin D insufficiency and deficiency was estimated using binary regression analysis. RESULTS: The total prevalence of vitamin D insufficiency (25(OH) D3: 20-29 MUg/L) and deficiency (25(OH) D3 < 20 MUg/L) were 26.60 % and 24.89 %, respectively. Significant negative association was observed for VFA with serum 25(OH) D3 levels in men and pre-menopausal women (P < 0.05), not in post-menopausal women (P > 0.05). Moreover, increased VFA was observed to be associated with higher vitamin D insufficiency or deficiency risk with a positive dose-response trend (P for trend < 0.001). As compared to individuals with the lowest VFA, those who had the highest VFA were at 4.9-fold risk of vitamin D insufficiency and deficiency [95 % confidence interval (95 % CI): 1.792-13.365] in men and 1.8-fold risk of vitamin D insufficiency and deficiency (95 % CI: 1.051-3.210) in pre-menopausal women, but not in post menopausal women [odds ratio (OR) (95 % CI): 2.326(0.903-5.991)]. CONCLUSIONS: These results suggest that higher VFA increases the risk of vitamin D insufficiency and deficiency in men and pre-menopausal women, but not in post menopausal women. VFA is a better and convenience surrogate marker for visceral adipose measurement and could be used in identifying the risk of vitamin D insufficiency and deficiency in routine health examination. PMID- 26613000 TI - Bioaugmentation of Lactobacillus delbrueckii ssp. bulgaricus TISTR 895 to enhance bio-hydrogen production of Rhodobacter sphaeroides KKU-PS5. AB - BACKGROUND: Bioaugmentation or an addition of the desired microorganisms or specialized microbial strains into the anaerobic digesters can enhance the performance of microbial community in the hydrogen production process. Most of the studies focused on a bioaugmentation of native microorganisms capable of producing hydrogen with the dark-fermentative hydrogen producers while information on bioaugmentation of purple non-sulfur photosynthetic bacteria (PNSB) with lactic acid-producing bacteria (LAB) is still limited. In our study, bioaugmentation of Rhodobacter sphaeroides KKU-PS5 with Lactobacillus delbrueckii ssp. bulgaricus TISTR 895 was conducted as a method to produce hydrogen. Unfortunately, even though well-characterized microorganisms were used in the fermentation system, a cultivation of two different organisms in the same bioreactor was still difficult because of the differences in their metabolic types, optimal conditions, and nutritional requirements. Therefore, evaluation of the physical and chemical factors affecting hydrogen production of PNSB augmented with LAB was conducted using a full factorial design followed by response surface methodology (RSM) with central composite design (CCD). RESULTS: A suitable LAB/PNSB ratio and initial cell concentration were found to be 1/12 (w/w) and 0.15 g/L, respectively. The optimal initial pH, light intensity, and Mo concentration obtained from RSM with CCD were 7.92, 8.37 klux and 0.44 mg/L, respectively. Under these optimal conditions, a cumulative hydrogen production of 3396 +/- 66 mL H2/L, a hydrogen production rate (HPR) of 9.1 +/- 0.2 mL H2/L h, and a hydrogen yield (HY) of 9.65 +/- 0.23 mol H2/mol glucose were obtained. KKU PS5 augmented with TISTR 895 produced hydrogen from glucose at a relatively high HY, 9.65 +/- 0.23 mol H2/mol glucose, i.e., 80 % of the theoretical yield. CONCLUSIONS: The ratio of the strains TISTR 895/KKU-PS5 and their initial cell concentrations affected the rate of lactic acid production and its consumption. A suitable LAB/PNSB ratio and initial cell concentration could balance the lactic acid production rate and its consumption in order to avoid lactic acid accumulation in the fermentation system. Through use of appropriate environmental conditions for bioaugmentation of PNSB with LAB, a hydrogen production could be enhanced. PMID- 26613001 TI - RNA-Seq transcriptomic analysis with Bag2D software identifies key pathways enhancing lipid yield in a high lipid-producing mutant of the non-model green alga Dunaliella tertiolecta. AB - BACKGROUND: For many years, increasing demands for fossil fuels have met with limited supply. As a potential substitute and renewable source of biofuel feedstock, microalgae have received significant attention. However, few of the current algal species produce high lipid yields to be commercially viable. To discover more high yielding strains, next-generation sequencing technology is used to elucidate lipid synthetic pathways and energy metabolism involved in lipid yield. When subjected to manipulation by genetic and metabolic engineering, enhancement of such pathways may further enhance lipid yield. RESULTS: In this study, transcriptome profiling of a random insertional mutant with enhanced lipid production generated from a non-model marine microalga Dunaliella tertiolecta is presented. D9 mutant has a lipid yield that is 2- to 4-fold higher than that of wild type. Using novel Bag2D-workflow scripts developed and reported here, the non-redundant transcripts from de novo assembly were annotated based on the best hits in five model microalgae, namely Chlamydomonas reinhardtii, Coccomyxa subellipsoidea C-169, Ostreococcus lucimarinus, Volvox carteri, Chlorella variabilis NC64A and a high plant species Arabidopsis thaliana. The assembled contigs (~181 Mb) includes 481,381 contigs, covering 10,185 genes. Pathway analysis showed that a pathway from inositol phosphate metabolism to fatty acid biosynthesis is the most significantly correlated with higher lipid yield in this mutant. CONCLUSIONS: Herein, we described a pipeline to analyze RNA-Seq data without pre-existing transcriptomic information. The draft transcriptome of D. tertiolecta was constructed and annotated, which offered useful information for characterizing high lipid-producing mutants. D. tertiolecta mutant was generated with an enhanced photosynthetic efficiency and lipid production. RNA-Seq data of the mutant and wild type were compared, providing biological insights into the expression patterns of contigs associated with energy metabolism and carbon flow pathways. Comparison of D. tertiolecta genes with homologs of five other green algae and a model high plant species can facilitate the annotation of D. tertiolecta and lead to a more complete annotation of its sequence database, thus laying the groundwork for optimization of lipid production pathways based on genetic manipulation. PMID- 26613002 TI - Enhanced short chain fatty acids production from waste activated sludge conditioning with typical agricultural residues: carbon source composition regulates community functions. AB - BACKGROUND: A wide range of value-added by-products can be potentially produced from waste activated sludge (WAS) through anaerobic fermentation, among which short-chain fatty acids (SCFAs) are versatile green chemicals, but the conversion yield of SCFAs is usually constrained by the low carbon-to-nitrogen ratio of the original WAS. Conditioning of the WAS with cellulose-containing agricultural residues (ARs) has been reported to be an efficient and economical solution for balancing its nutrient components. However, contributions of different ARs to SCFAs production are still not well understood. RESULTS: To optimize SCFAs production through carbon conditioning of WAS, we investigated the effects of two typical ARs [straws and spent mushroom substrates (SMSs)] on WAS hydrolysis and acidification in semi-continuous anaerobic fermentation. Straw-conditioning group showed a threefold increase in short-chain fatty acids yield over blank test (without conditioning), which was 1.2-fold higher than that yielded by SMS conditioning. The maximum SCFAs yield in straw-conditioning groups reached 486.6 mgCOD/gVSS (Sludge retention time of 8 d) and the highest volumetric SCFAs productivity was 1.83 kgCOD/([Formula: see text]) (Sludge retention time of 5 d). In batch WAS fermentation tests, higher initial SCFAs production rates were achieved in straw-conditioning groups [49.5 and 52.2 mgCOD/(L.h)] than SMS conditioning groups [41.5 and 35.2 mgCOD/(L.h)]. High-throughput sequencing analysis revealed that the microbial communities were significantly shifted in two conditioning systems. Carbohydrate-fermentation-related genera (such as Clostridium IV, Xylanibacter, and Parabacteroides) and protein-fermentation related genus Lysinibacillus were enriched by straw-conditioning, while totally different fermentation genera (Levilinea, Proteiniphilum, and Petrimonas) were enriched by SMS-conditioning. Canonical correlation analysis illustrated that the enrichment of characteristic genera in straw-conditioning group showed positive correlation with the content of cellulose and hemicellulose, but showed negative correlation with the content of lignin and humus. CONCLUSIONS: Compared with SMSs, straw-conditioning remarkably accelerated WAS hydrolysis and conversion, resulting in higher SCFAs yield. Distinct microbial communities were induced by different types of ARs. And the communities induced by straw-conditioning were verified with better acid production ability than SMS-conditioning. High cellulose accessibility of carbohydrate substrates played a crucial role in enriching bacteria with better hydrolysis and acidification abilities. PMID- 26613003 TI - Single-cell screening of photosynthetic growth and lactate production by cyanobacteria. AB - BACKGROUND: Photosynthetic cyanobacteria are attractive for a range of biotechnological applications including biofuel production. However, due to slow growth, screening of mutant libraries using microtiter plates is not feasible. RESULTS: We present a method for high-throughput, single-cell analysis and sorting of genetically engineered l-lactate-producing strains of Synechocystis sp. PCC6803. A microfluidic device is used to encapsulate single cells in picoliter droplets, assay the droplets for l-lactate production, and sort strains with high productivity. We demonstrate the separation of low- and high-producing reference strains, as well as enrichment of a more productive l-lactate synthesizing population after UV-induced mutagenesis. The droplet platform also revealed population heterogeneity in photosynthetic growth and lactate production, as well as the presence of metabolically stalled cells. CONCLUSIONS: The workflow will facilitate metabolic engineering and directed evolution studies and will be useful in studies of cyanobacteria biochemistry and physiology. PMID- 26612997 TI - Mitochondria: a new therapeutic target in chronic kidney disease. AB - Cellular metabolic changes during chronic kidney disease (CKD) may induce higher production of oxygen radicals that play a significant role in the progression of renal damage and in the onset of important comorbidities. This condition seems to be in part related to dysfunctional mitochondria that cause an increased electron "leakage" from the respiratory chain during oxidative phosphorylation with a consequent generation of reactive oxygen species (ROS). ROS are highly active molecules that may oxidize proteins, lipids and nucleic acids with a consequent damage of cells and tissues. To mitigate this mitochondria-related functional impairment, a variety of agents (including endogenous and food derived antioxidants, natural plants extracts, mitochondria-targeted molecules) combined with conventional therapies could be employed. However, although the anti-oxidant properties of these substances are well known, their use in clinical practice has been only partially investigated. Additionally, for their correct utilization is extremely important to understand their effects, to identify the correct target of intervention and to minimize adverse effects. Therefore, in this manuscript, we reviewed the characteristics of the available mitochondria-targeted anti oxidant compounds that could be employed routinely in our nephrology, internal medicine and renal transplant centers. Nevertheless, large clinical trials are needed to provide more definitive information about their use and to assess their overall efficacy or toxicity. PMID- 26613004 TI - Cranberry (Vaccinium macrocarpon) oligosaccharides decrease biofilm formation by uropathogenic Escherichia coli. AB - The preventive effects of the American cranberry (Vaccinium macrocarpon) against urinary tract infections are supported by extensive studies which have primarily focused on its phenolic constituents. Herein, a phenolic-free carbohydrate fraction (designated cranf1b-F2) was purified from cranberry fruit using ion exchange and size exclusion chromatography. MALDI-TOF-MS analysis revealed that the cranf1b-F2 constituents are predominantly oligosaccharides possessing various degrees of polymerisation and further structural analysis (by GC-MS and NMR) revealed mainly xyloglucan and arabinan residues. In antimicrobial assays, cranf1b-F2 (at 1.25 mg/mL concentration) reduced biofilm production by the uropathogenic Escherichia coli CFT073 strain by over 50% but did not inhibit bacterial growth. Cranf1b-F2 (ranging from 0.625 - 10 mg/mL) also inhibited biofilm formation of the non-pathogenic E. coli MG1655 strain up to 60% in a concentration-dependent manner. These results suggest that cranberry oligosaccharides, in addition to its phenolic constituents, may play a role in its preventive effects against urinary tract infections. PMID- 26613005 TI - Accuracy enhancement in the estimation of molecular hydration free energies by implementing the intramolecular hydrogen bond effects. AB - BACKGROUND: The formation of intramolecular hydrogen bonds (IHBs) may induce the remarkable changes in molecular physicochemical properties. Within the framework of the extended solvent-contact model, we investigate the effect of implementing the IHB interactions on the accuracy in estimating the molecular hydration free energies. RESULTS: The performances of hydration free energy functions including and excluding the IHB parameters are compared using the molecules distributed for SAMPL4 blind prediction challenge and those in Free Solvation Database (FSD). The calculated hydration free energies with IHB effects are found to be in considerably better agreement with the experimental data than those without them. For example, the root mean square error of the estimation decreases from 2.56 to 1.66 and from 1.73 to 1.54 kcal/mol for SAMPL4 and FSD molecules, respectively, due to the extension of atomic parameter space to cope with IHBs. CONCLUSIONS: These improvements are made possible by reducing the overestimation of attractive interactions between water and the solute molecules involving IHBs. The modified hydration free energy function is thus anticipated to be useful for estimating the desolvation cost for various organic molecules. PMID- 26613006 TI - The association of circulating levels of complement-C1q TNF-related protein 5 (CTRP5) with nonalcoholic fatty liver disease and type 2 diabetes: a case-control study. AB - BACKGROUND: It is well-established that nonalcoholic fatty liver disease (NAFLD) is associated with type 2 diabetes mellitus (T2DM). Complement-C1q TNF-related protein 5 (CTRP5) is a novel adipokine involved in the regulation of lipid and glucose metabolism. We aimed to assess plasma levels of CTRP5 in patients with NAFLD (n = 22), T2DM (n = 22) and NAFLD with T2DM (NAFLD + T2DM) (n = 22) in comparison with healthy subjects (n = 21) and also to study the association between CTRP5 levels and NAFLD and diabetes-related parameters. METHODS: All subjects underwent anthropometric assessment, biochemical evaluation and liver stiffness (LS) measurement. Insulin resistance (IR) was determined by the homeostasis model assessment (HOMA). Plasma CTRP5 levels were measured by enzyme linked immunosorbent assay. RESULTS: We found significantly lower plasma levels of CTRP5 in patients with NAFLD + T2DM, NAFLD and T2DM (122.52 +/- 1.92, 124.7 +/ 1.82 and 118.31 +/- 1.99 ng/ml, respectively) in comparison with controls (164.96 +/- 2.95 ng/ml). In the whole study population, there was a significant negative correlations between CTRP5 and body mass index (r = -0.337; p = 0.002), fasting blood glucose (FBG) (r = -0.488; p < 0.001), triglyceride (TG) (r = 0.245; p = 0.031), HOMA-IR (r = -0.492; p < 0.001), insulin(r = -0.338; p = 0.002), LS (r = -0.544; p < 0.001), alanine aminotransferase (ALT) (r = -0.251; p = 0.027), waist-to-hip ratio (WHR) (r = -0.352; p = 0.002) and waist circumference (WC) (r = -0.357; p = 0.001). After adjustment for BMI, decrease in circulating levels of CTRP5 remained as a significant risk factor for NAFLD, T2DM and NAFLD + T2DM. The receiver operating characteristic (ROC) curves of circulating CTRP5 in predicting NAFLD and T2DM demonstrated an area under the curve (AUC) of 0.763 in T2DM, and 0.659 in NAFLD + T2DM. CONCLUSIONS: It appears that the decreased levels of CTRP5 contribute to the increased risk of T2DM and NAFLD. PMID- 26613007 TI - Kilimanjaro Abruzzo expedition: effects of high-altitude trekking on anthropometric, cardiovascular and blood biochemical parameters. AB - The effect of the combination of trekking and balanced appropriated diet were studied in mountaineers who spent 6 days at an altitude ranging from 900 to 5895 m above sea level (a.s.l.), during the Kilimanjaro Abruzzo Expedition. This study explored whether anthropometric, cardiovascular and blood biochemical parameters were significantly changed by a regular trekking performed at high altitude, with reduced oxygen levels, together with a macronutrient-containing balanced diet (total daily caloric intake: 3000-3500 Kcals). In consideration of the short period of high-altitude exposure, high-altitude exercise appeared to provide beneficial and rapid effects on the lipid profile and to modulate cardiovascular functions. These effects rely on both high-altitude hypoxia and physical activity. The most interesting observation is that even just a few days of high altitude exercise, along with a balanced diet, was able to improve plasma lipid profiles. PMID- 26613008 TI - Towards the Ideal Synthesis of Homoallylic Ketones. PMID- 26613009 TI - Enzyme-Modified Particles for Selective Biocatalytic Hydrogenation by Hydrogen Driven NADH Recycling. AB - We describe a new approach to selective H2-driven hydrogenation that exploits a sequence of enzymes immobilised on carbon particles. We used a catalyst system that comprised alcohol dehydrogenase, hydrogenase and an NAD+ reductase on carbon black to demonstrate a greater than 98 % conversion of acetophenone to phenylethanol. Oxidation of H2 by the hydrogenase provides electrons through the carbon for NAD+ reduction to recycle the NADH cofactor required by the alcohol dehydrogenase. This biocatalytic system operates over the pH range 6-8 or in un buffered water, and can function at low concentrations of the cofactor (10 MUm NAD+) and at H2 partial pressures below 1 bar. Total turnover numbers >130 000 during acetophenone reduction indicate high enzyme stability, and the immobilised enzymes can be recovered by a simple centrifugation step and re-used several times. This offers a route to convenient, atom-efficient operation of NADH dependent oxidoreductases for selective hydrogenation catalysis. PMID- 26613010 TI - Surface Segregation of Fe in Pt-Fe Alloy Nanoparticles: Its Precedence and Effect on the Ordered-Phase Evolution during Thermal Annealing. AB - Coupling electron microscopy techniques with in situ heating ability allows us to study phase transformations on the single-nanoparticle level. We exploit this setup to study disorder-to-order transformation of Pt-Fe alloy nanoparticles, a material that is of great interest to fuel-cell electrocatalysis and ultrahigh density information storage. In contrast to earlier reports, we show that Fe (instead of Pt) segregates towards the particle surface during annealing and forms a Fe-rich FeO x outer shell over the alloy core. By combining both ex situ and in situ approaches to probe the interplay between ordering and surface segregation phenomena, we illustrate that the surface segregation of Fe precedes the ordering process and affects the ordered phase evolution dramatically. We show that the ordering initiates preferably at the pre-existent Fe-rich shell than the particle core. While the material-specific findings from this study open interesting perspectives towards a controlled phase evolution of Pt-Fe nanoalloys, the characterization methodologies described are general and should prove useful to probing a wide-range of nanomaterials. PMID- 26613011 TI - X-ray Fluorescence Tomography of Aged Fluid-Catalytic-Cracking Catalyst Particles Reveals Insight into Metal Deposition Processes. AB - Microprobe X-ray fluorescence tomography was used to investigate metal poison deposition in individual, intact and industrially deactivated fluid catalytic cracking (FCC) particles at two differing catalytic life-stages. 3 D multi element imaging, at submicron resolution was achieved by using a large-array Maia fluorescence detector. Our results show that Fe, Ni and Ca have significant concentration at the exterior of the FCC catalyst particle and are highly co localized. As concentrations increase as a function of catalytic life-stage, the deposition profiles of Fe, Ni, and Ca do not change significantly. V has been shown to penetrate deeper into the particle with increasing catalytic age. Although it has been previously suggested that V is responsible for damaging the zeolite components of FCC particles, no spatial correlation was found for V and La, which was used as a marker for the embedded zeolite domains. This suggests that although V is known to be detrimental to zeolites in FCC particles, a preferential interaction does not exist between the two. PMID- 26613012 TI - Usability Evaluation of the Spatial OLAP Visualization and Analysis Tool (SOVAT). AB - Increasingly sophisticated technologies, such as On-Line Analytical Processing (OLAP) and Geospatial Information Systems (GIS), are being leveraged for conducting community health assessments (CHA). Little is known about the usability of OLAP and GIS interfaces with respect to CHA. We conducted an iterative usability evaluation of the Spatial OLAP Visualization and Analysis Tool (SOVAT), a software application that combines OLAP and GIS. A total of nine graduate students and six community health researchers were asked to think-aloud while completing five CHA questions using SOVAT. The sessions were analyzed after every three participants and changes to the interface were made based on the findings. Measures included elapsed time, answers provided, erroneous actions, and satisfaction. Traditional OLAP interface features were poorly understood by participants and combined OLAP-GIS features needed to be better emphasized. The results suggest that the changes made to the SOVAT interface resulted in increases in both usability and user satisfaction. PMID- 26613013 TI - Erratum to: An updated genome annotation for the model marine bacterium Ruegeria pomeroyi DSS-3. AB - [This corrects the article DOI: 10.1186/1944-3277-9-11.]. PMID- 26613015 TI - The influence of water on visible-light initiated free-radical/cationic ring opening hybrid polymerization of methacrylate/epoxy: Polymerization kinetics, crosslinking structure and dynamic mechanical properties. AB - The objective of this study was to determine the influence of water on the polymerization kinetics, crosslinking structure and dynamic mechanical properties of methacrylate/epoxy polymers cured by visible-light initiated free radical/cationic ring-opening hybrid polymerization. Water-containing formulations were prepared by adding ~4-7 wt% D2O depending on the water miscibility of monomer resins. The water-containing adhesives were compared with the adhesives photo-cured in the absence of water. The results show an improved degree of conversion for both methacrylates and epoxy by adding water. The rate of the epoxy cationic ring-opening reaction is increased while the rate of free radical polymerization is decreased in the presence of water. The decreased crosslinking density noted in the presence of water suggests that the chain transfer reaction between water and epoxy competes with the hydroxyl-based chain transfer mechanism. There is potential application of this visible-light initiated hybrid polymerization in biomaterials, e.g. dental restorations and tissue engineering scaffolds. PMID- 26613016 TI - Multi-platform microRNA profiling of hepatoblastoma patients using formalin fixed paraffin embedded archival samples. AB - BACKGROUND: Formalin fixed paraffin embedded (FFPE) samples are a valuable resource in cancer research and have the potential to be extensively used. However, they are often underused because of degradation and chemical modifications occurring in the RNA that can present obstacles in downstream analysis. In routine medical care, FFPE material is examined and archived, therefore clinical collections of many types of cancers exist. It is beneficial to assess and record the quality of data that can be obtained from this type of material. The current study investigated three independent platforms and their ability to profile microRNAs (miRNAs) within FFPE samples from hepatoblastoma (HB) patients. FINDINGS: Here we present three types of datasets consisting of miRNA profiles for 13 HB patients with different tumour types and molecular variations. The three platforms that were used to generate these data are: next generation sequencing (Illumina MiSeq), microarray (Affymetrix((r)) GeneChip((r)) miRNA 3.0 array) and NanoString (nCounter, Human v2 miRNA Assay). The mature miRNAs identified are based on miRBase version 17 and 18. CONCLUSIONS: These datasets provide a global landscape of miRNA expression for a rare childhood cancer that has not previously been well characterised. These data could serve as a resource for future studies aiming to make comparisons of HB miRNA profiles and to document aberrant miRNA expression in this type of cancer. PMID- 26613017 TI - Exemplary multiplex bisulfite amplicon data used to demonstrate the utility of Methpat. AB - BACKGROUND: DNA methylation is a complex epigenetic marker that can be analyzed using a wide variety of methods. Interpretation and visualization of DNA methylation data can mask complexity in terms of methylation status at each CpG site, cellular heterogeneity of samples and allelic DNA methylation patterns within a given DNA strand. Bisulfite sequencing is considered the gold standard, but visualization of massively parallel sequencing results remains a significant challenge. FINDINGS: We created a program called Methpat that facilitates visualization and interpretation of bisulfite sequencing data generated by massively parallel sequencing. To demonstrate this, we performed multiplex PCR that targeted 48 regions of interest across 86 human samples. The regions selected included known gene promoters associated with cancer, repetitive elements, known imprinted regions and mitochondrial genomic sequences. We interrogated a range of samples including human cell lines, primary tumours and primary tissue samples. Methpat generates two forms of output: a tab-delimited text file for each sample that summarizes DNA methylation patterns and their read counts for each amplicon, and a HTML file that summarizes this data visually. Methpat can be used with publicly available whole genome bisulfite sequencing and reduced representation bisulfite sequencing datasets with sufficient read depths. CONCLUSIONS: Using Methpat, complex DNA methylation data derived from massively parallel sequencing can be summarized and visualized for biological interpretation. By accounting for allelic DNA methylation states and their abundance in a sample, Methpat can unmask the complexity of DNA methylation and yield further biological insight in existing datasets. PMID- 26613014 TI - Large-scale transcriptome sequencing reveals novel expression patterns for key sex-related genes in a sex-changing fish. AB - BACKGROUND: Teleost fishes exhibit remarkably diverse and plastic sexual developmental patterns. One of the most astonishing is the rapid socially controlled female-to-male (protogynous) sex change observed in bluehead wrasses (Thalassoma bifasciatum). Such functional sex change is widespread in marine fishes, including species of commercial importance, yet its underlying molecular basis remains poorly explored. METHODS: RNA sequencing was performed to characterize the transcriptomic profiles and identify genes exhibiting sex-biased expression in the brain (forebrain and midbrain) and gonads of bluehead wrasses. Functional annotation and enrichment analysis were carried out for the sex-biased genes in the gonad to detect global differences in gene products and genetic pathways between males and females. RESULTS: Here we report the first transcriptomic analysis for a protogynous fish. Expression comparison between males and females reveals a large set of genes with sex-biased expression in the gonad, but relatively few such sex-biased genes in the brain. Functional annotation and enrichment analysis suggested that ovaries are mainly enriched for metabolic processes and testes for signal transduction, particularly receptors of neurotransmitters and steroid hormones. When compared to other species, many genes previously implicated in male sex determination and differentiation pathways showed conservation in their gonadal expression patterns in bluehead wrasses. However, some critical female-pathway genes (e.g., rspo1 and wnt4b) exhibited unanticipated expression patterns. In the brain, gene expression patterns suggest that local neurosteroid production and signaling likely contribute to the sex differences observed. CONCLUSIONS: Expression patterns of key sex-related genes suggest that sex-changing fish predominantly use an evolutionarily conserved genetic toolkit, but that subtle variability in the standard sex-determination regulatory network likely contributes to sexual plasticity in these fish. This study not only provides the first molecular data on a system ideally suited to explore the molecular basis of sexual plasticity and tissue re-engineering, but also sheds some light on the evolution of diverse sex determination and differentiation systems. PMID- 26613018 TI - A cross-sectional observational study about media and infection control practices: are photographic portrayals of healthcare workers setting a bad example? AB - BACKGROUND: Attempts to increase compliance with infection control practices are complex and are - in part - based on attempts to change behaviour. In particular, the behaviour of significant peers (role models) has been shown to be a strong motivator. While role models within the working environment are obviously the most important, some experts suggest that media and public display cannot be ignored. The aim of this present study was to examine the display of technique recommended by current infection control guidelines including the "bare below the elbow" principle, which is considered a basic requirement for good infection control in many countries, in sets of professional stock photos. FINDINGS: From 20 random photo-stock websites we selected pictures with search terms "doctor and patient" and "nurse and patient". In all selected photos a doctor or nurse and a patient were presented, healthcare workers (HCWs) were wearing white coats or uniforms, and their arms were visible. Each photo was evaluated with regard to: closure of white coat, sleeve length, personal clothing covered, hairstyle and presence of a wristwatch, bracelet and/or ring. Overall, 1600 photos were evaluated. The most common mistakes were with regard to HCWs' white coats/uniforms. Eighty-nine percent of the photos containing doctor's images were considered incorrect while 28 % of nurse-containing photos were incorrect. CONCLUSIONS: The results seem to reflect the real world with only 40 % displaying correct behaviour with doctors being worse than nurses. It seems that the stereotypical image of a doctor does not agree with the current infection control guidelines. If we aim for higher compliance rates of HCWs, we need to change the social image of doctors and improve production, selection and display of stock photo images. PMID- 26613020 TI - Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis: clinical and molecular characteristics. AB - Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal-recessive renal tubular disorder characterized by excessive urinary losses of magnesium and calcium, bilateral nephrocalcinosis and progressive chronic renal failure. Presentation with FHHNC symptoms generally occurs early in childhood or before adolescence. At present, the only therapeutic option is supportive and consists of oral magnesium supplementation and thiazide diuretics. However, neither treatment seems to have a significant effect on the levels of serum magnesium or urine calcium or on the decline of renal function. In end stage renal disease patients, renal transplantation is the only effective approach. This rare disease is caused by mutations in the CLDN16 or CLDN19 genes. Patients with mutations in CLDN19 also present severe ocular abnormalities such as myopia, nystagmus and macular colobamata. CLDN16 and CLDN19 encode the tight junction proteins claudin-16 and claudin-19, respectively, which are expressed in the thick ascending limb of Henle's loop and form an essential complex for the paracellular reabsorption of magnesium and calcium. Claudin-19 is also expressed in retinal epithelium and peripheral neurons. Research studies using mouse and cell models have generated significant advances on the understanding of the pathophysiology of FHHNC. A recent finding has established that another member of the claudin family, claudin-14, plays a key regulatory role in paracellular cation reabsorption by inhibiting the claudin-16-claudin-19 complex. Furthermore, several studies on the molecular and cellular consequences of disease-causing CLDN16 and CLDN19 mutations have provided critical information for the development of potential therapeutic strategies. PMID- 26613021 TI - Proteomics and mass spectrometry in the diagnosis of renal amyloidosis. AB - The amyloidoses are a 'group' of disorders, all of which are associated with deposits that display similar staining and ultrastructural features and are toxic to tissues. Many proteins-currently 31 protein types and many more variants-have been shown to undergo such transformations. Among the various currently known amyloidoses, there are marked differences with regard to their pathogenesis and incidence, while the associated clinical picture is frequently overlapping. However, the therapies that are currently available are amyloid-type specific. The diagnosis of amyloidosis thus involves two steps: (i) a generic diagnosis, followed by (ii) an amyloid type-specific diagnosis or 'amyloid typing'. Immunofluorescence in frozen sections or immunohistochemistry (IHC) in paraffin sections has traditionally been used in the typing of amyloid. However, IHC of amyloid differs significantly from IHC in other areas of surgical pathology; both caution and experience are necessary for its interpretation. The rationale for the application of proteomic methods to amyloid typing lies in the relative abundance of amyloid proteins in tissue where, frequently, it is the 'dominant' protein. Proteomic techniques include the following steps: sample preparation, protein extraction and digestion into peptide fragments, followed by their subsequent separation and measurement by mass spectrometry (MS) and protein identification by informatics. The advantages as well as the limitations of both methods-immunohistochemistry and MS-based proteomics-are discussed. The current recommendations for the application of proteomics in renal amyloidosis are summarized. PMID- 26613019 TI - Translational research in nephrology: chronic kidney disease prevention and public health. AB - This narrative review evaluates translational research with respect to five important risk factors for chronic kidney disease (CKD): physical inactivity, high salt intake, smoking, diabetes and hypertension. We discuss the translational research around prevention of CKD and its complications both at the level of the general population, and at the level of those at high risk, i.e. people at increased risk for CKD or CKD complications. At the population level, all three lifestyle risk factors (physical inactivity, high salt intake and smoking) have been translated into implemented measures and clear population health improvements have been observed. At the 'high-risk' level, the lifestyle studies reviewed have tended to focus on the individual impact of specific interventions, and their wider implementation and impact on CKD practice are more difficult to establish. The treatment of both diabetes and hypertension appears to have improved, however the impact on CKD and CKD complications was not always clear. Future studies need to investigate the most effective translational interventions in low and middle income countries. PMID- 26613022 TI - Acute kidney injury risk assessment at the hospital front door: what is the best measure of risk? AB - BACKGROUND: We examined the prevalence of acute kidney injury (AKI) risk factors in the emergency medical unit, generated a modified risk assessment tool and tested its ability to predict AKI. METHODS: A total of 1196 patients admitted to medical admission units were assessed for patient-associated AKI risk factors. Subsequently, 898 patients were assessed for a limited number of fixed risk factors with the addition of hypotension and sepsis. This was correlated to AKI episodes. RESULTS: In the first cohort, the prevalence of AKI risk factors was 2.1 +/- 2.0 per patient, with a positive relationship between age and the number of risk factors and a higher number of risk factors in patients >=65 years. In the second cohort, 12.3% presented with or developed AKI. Patients with AKI were older and had a higher number of AKI risk factors. In the AKI cohort, 72% of the patients had two or more AKI risk factors compared with 43% of the cohort with no AKI. When age >=65 years was added as an independent risk factor, 84% of those with AKI had two or more AKI risk factors compared with 55% of those with no AKI. Receiver operating characteristic analysis suggests that the use of common patient-associated known AKI risk factors performs no better than age alone as a predictor of AKI. CONCLUSIONS: Detailed assessment of well-established patient associated AKI risk factors may not facilitate clinicians to apportion risk. This suggests that additional work is required to develop a more sensitive validated AKI-predictive tool that would be useful in this clinical setting. PMID- 26613024 TI - Thrombotic microangiopathy: expanding genetic, clinical and therapeutic spectra and the need for worldwide implementation of recent advances. AB - In this issue of CKJ, four reports address different aspects of a rare condition, thrombotic microangiopathy, including atypical haemolytic uraemic syndrome. For rare diseases, a single case report may provide hypothesis-generating information that may lead to concept-changing research with the potential to influence patient care. The present reports and small series illustrate the following aspects of thrombotic microangiopathy: (i) the role of whole-exome sequencing and of repeating the family history assessment over time in reducing the number of chronic kidney disease patients with non-specific diagnosis (e.g. focal segmental glomerulosclerosis without any further indication as to aetiology or hypertension attributed kidney disease) and the need for further studies on the potential for type IV collagen mutations to be associated with thrombotic microangiopathy, i.e. the potential for an expanding genetic spectrum; (ii) the expanding clinical spectrum from an acute catastrophic disease to a chronic, mild, stable condition with unknown long-term consequences and uncharted therapeutic approaches; (iii) the expanding therapeutic spectrum, with the successful use of eculizumab to treat thrombotic microangiopathy in the context of overlap autoimmune disease and (iv) the huge worldwide inequalities in the implementation of these and other advances. International collaboration is needed to address these issues and should encompass the wider use of already available registries for this rare disease and the worldwide implementation of current effective, yet expensive, therapies. PMID- 26613023 TI - Dengue-associated acute kidney injury. AB - Dengue is presently the most relevant viral infection transmitted by a mosquito bite that represents a major threat to public health worldwide. Acute kidney injury (AKI) is a serious and potentially lethal complication of this disease, and the actual incidence is unknown. In this review, we will assess the most relevant epidemiological and clinical data regarding dengue and the available evidence on the frequency, etiopathogenesis, outcomes and treatment of dengue associated AKI. PMID- 26613025 TI - A COL4A5 mutation with glomerular disease and signs of chronic thrombotic microangiopathy. AB - COL4A5 mutations are a known cause of Alport syndrome, which typically manifests with haematuria, hearing loss and ocular symptoms. Here we report on a 16-year old male patient with a negative family history who presented with proteinuria, progressive renal failure and haemolysis, but without overt haematuria or hearing loss. A renal biopsy revealed features of atypical IgA nephropathy, while a second biopsy a year later showed features of focal segmental glomerulosclerosis, but was finally diagnosed as chronic thrombotic microangiopathy. Targeted sequencing of candidate genes for steroid-resistant nephrotic syndrome and congenital thrombotic microangiopathy was negative. Despite all therapeutic efforts, including angiotensin-converting enzyme inhibition, immunosuppressive therapy, plasma exchanges and rituximab, the patient progressed to end-stage renal disease. When a male cousin presented with nephrotic syndrome years later, whole-exome sequencing identified a shared disruptive COL4A5 mutation (p.F222C) that showed X-linked segregation. Thus, mutations in COL4A5 give rise to a broader spectrum of clinical presentation than commonly suspected, highlighting the benefits of comprehensive rather than candidate genetic testing in young patients with otherwise unexplained glomerular disease. Our results are in line with an increasing number of atypical presentations of single-gene disorders identified through genome-wide sequencing. PMID- 26613026 TI - New combined CFH/MCP mutations and a rare clinical course in atypical haemolytic uraemic syndrome. AB - Atypical haemolytic uraemic syndrome (aHUS) is a rare, life-threatening, chronic, genetic disease due to uncontrolled alternative pathway complement activation. In this report, we discuss the case of a heterozygous carrier of a mutation on both factor H and membrane cofactor protein, who persistently presents haemolytic anaemia without need for blood transfusions, normal platelet count, normal renal function and no signs or symptoms of organ injury due to thrombotic microangiopathy 4 years after the diagnosis of aHUS. PMID- 26613027 TI - Eculizumab for rescue of thrombotic microangiopathy in PM-Scl antibody-positive autoimmune overlap syndrome. AB - A 46-year-old female with interstitial lung disease presented with proximal muscle weakness, worsening hypertension, microangiopathic hemolysis, thrombocytopenia and deteriorating renal function. She had no sclerodactyly, but had abnormal capillaroscopy. She tested positive for PM-Scl antibodies, and a renal biopsy showed an acute thrombotic microangiopathy consistent with scleroderma renal crisis (SRC). She failed to respond to corticosteroids, plasmapheresis and renin-angiotensin pathway inhibitors. She recovered quickly with the anti-C5 antibody, eculizumab. She had no genetic abnormalities associated with atypical hemolytic uremic syndrome except a DNA variant of unknown significance in C3. This case suggests that eculizumab may be effective for SRC. PMID- 26613028 TI - Plasma exchange for paediatric kidney disease-indications and outcomes: a single centre experience. AB - BACKGROUND: Outcome data in paediatrics regarding the use of plasmapheresis for immunological kidney disease are scarce. OBJECTIVES: We aimed to evaluate the role of plasmapheresis in children presenting with severe renal impairment secondary to immunological kidney diseases. METHODS: A retrospective chart review of children admitted between January 2009 and August 2013 to the Paediatric Nephrology Unit, Christian Medical College, Vellore, India, and requiring plasma exchange was undertaken. Demographic and clinical data were studied and descriptive statistics applied for analysis. RESULTS: Sixteen children underwent plasmapheresis with a male:female ratio of 10:6 and a mean age of 10.2 years (range 5-15 years). Twelve children had atypical haemolytic uraemic syndrome, two had anti-glomerular basement disease and one each had lupus nephritis with neurological manifestation and anti-nuclear cytoplasmic antibody-associated vasculitis. The mean serum creatinine at presentation was 6.52 [interquartile range (IQR) 4.96-7.85] mg/dL with a mean eGFR of 43 (IQR 27.54-56.7) mL/min/1.73 m(2). Other presenting features included nephrotic range proteinuria (69%), gross haematuria (27%), hypertension (94%) and seizures (37.5%). All children received 1.5 times plasma volume plasmapheresis (mean 11 sessions, range 5-26), dialysis and immunosuppressive therapy. The mean duration of follow-up was 4 months (range 2-24 months) with a majority of the children (15/16, 93.75%) surviving acute illness. One child died of overwhelming sepsis and another was lost to follow-up. Of the survivors, eight had eGFR >60 mL/min/1.73 m(2), while eGFR was 15-60 mL/min/1.73 m(2) in the remaining six children. Eight children were still requiring antihypertensive medications and two were continuing peritoneal dialysis at the last follow-up. Thus early introduction of plasmapheresis along with other supportive therapy in immunological kidney disease may improve outcome. PMID- 26613029 TI - A circulating permeability factor in focal segmental glomerulosclerosis: the hunt continues. AB - Primary focal segmental glomerulosclerosis (FSGS) is one of the major causes of steroid-resistant nephrotic syndrome, and renal prognosis in patients with steroid-resistant FSGS is poor. It has been long speculated that a circulating permeability factor should be implicated in the pathogenesis of the disease because a substantial portion of the patients with primary FSGS experience recurrence shortly after transplantation. Although molecules such as cardiotrophin-like cytokine 1 (CLC-1) and anti-CD40 antibody have been proposed to be potential circulating permeability factors, a definitive factor remains to be discovered. Soluble urokinase-type plasminogen activator receptor (suPAR) has attracted substantial attention and garnered scrutiny by renal researchers since Reiser's group suggested that it was linked to the pathogenesis of primary FSGS and that it might be useful as a diagnostic biomarker. A number of different cohort studies have shown that serum suPAR levels are negatively associated with renal function and can scarcely differentiate FSGS from the other glomerular/renal diseases. In contrast to initial studies, several in vivo studies investigating the effects of forced suPAR upregulation could not show the induction of proteinuria or podocyte injury. Currently it is suggested that a different form of suPAR, which cannot be measured by presently available enzyme linked immunosorbent assay, might be the culprit; however, it remains to be determined whether this is the case. Because a circulating permeability factor might be a useful biomarker for diagnosing FSGS as well as a potent therapeutic target for primary and recurrent FSGS, further dedicated work will be needed. PMID- 26613030 TI - Ambulatory blood pressure and tubulointerstitial injury in patients with IgA nephropathy. AB - BACKGROUND: Few studies have been conducted to assess the ambulatory blood pressure (ABP) in IgA nephropathy (IgAN) patients. This study aimed to determine the relationships between ABP and renal histopathological findings assessed using the Oxford classification (OC) and the Japanese classification (JC), which have recently established histopathological criteria for IgAN. METHODS: This cross sectional study included biopsy-diagnosed IgAN patients, in whom both a renal biopsy and ABP measurement were performed. The histopathological findings were assessed using the OC and the JC and were analyzed in relation to the ABP. RESULTS: A total of 111 IgAN patients were included. The score of interstitial fibrosis and tubular atrophy (T score) using the OC was a significantly associated factor with both the daytime and nighttime ABP values. In contrast, the other histopathological scores, including mesangial hypercellularity, endocapillary hypercellularity and segmental glomerulosclerosis, did not show significant associations with the ABP. The histological grade (H-grade) using the JC, which was based on the sum of injured glomeruli, was associated with the daytime ABP, but not with the nighttime ABP. The associations between the T score using the OC (%) and the daytime and nighttime ABP values were independent of age, gender, renal function, proteinuria and the use of antihypertensive medications, whereas the H-grade using the JC (%) did not show significant associations after adjusting for these clinical parameters. CONCLUSIONS: These results suggest that the T score using the OC is the most relevant renal histopathological parameter associated with abnormalities of circadian blood pressure in IgAN patients. PMID- 26613031 TI - Proliferative glomerulonephritis with monoclonal immunoglobulin in renal allografts. AB - Glomerulopathy due to dysproteinemia can have a wide spectrum of pathologic and clinical features based on specific characteristics of the abnormal protein and the response induced within the parenchymal tissue. Monoclonal immunoglobulin G (IgG) deposition can manifest as a different glomerular disease. Proliferative glomerulonephritis (GN) with monoclonal IgG deposits (PGNMID) is a unique entity mimicking immune complex GN that does not conform to any of those subtypes. IgG monoclonal granular deposition in the glomeruli with a pattern similar to immune complex disease suggested by C3 and C1q deposition should prompt consideration of PGNMID. Literature is scarce in terms of recurrence of disease in renal allografts. In this article we present the clinical-pathologic features of three cases of PGNMID in the renal allograft showing the variable course and manifestation of the disease. PMID- 26613032 TI - Where is the link between mineral bone markers and cardiovascular disease in CKD? PMID- 26613033 TI - Fibroblast growth factor 23 and parathyroid hormone predict extent of aortic valve calcifications in patients with mild to moderate chronic kidney disease. AB - BACKGROUND: Cardiac valve calcifications are present in dialysis patients and regarded as dependent on a deranged mineral metabolism. Few data are available for patients with chronic kidney disease (CKD) not on dialysis. This study evaluates the potential association between the extent of cardiac valve calcification and levels of intact parathyroid hormone (i-PTH), phosphorus, calcium, 25-OH vitamin D, fibroblast growth factor 23 (FGF-23), Klotho and C reactive protein (CRP) simultaneously measured in patients with mild to moderate CKD. METHODS: Consecutive non-hospitalized patients referring to five nephrology units were evaluated. Inclusion criteria were age >18 years, CKD Stages 3-4, and the presence of aortic and/or mitral valve calcification assessed by echocardiography as routinely clinical evaluation. Patients underwent clinical examination and routine biochemistry. Baseline i-PTH, phosphorus, calcium, 25-OH vitamin D, FGF-23, Klotho and CRP were simultaneously ascertained. RESULTS: Extent of aortic valve calcification (n = 100 patients) was moderate in 68 patients and mild in the remaining patients. Mitral valve calcification (n = 96 patients) score was 1, 2 and 3 in 61, 34 and 1 patients, respectively. In univariate analysis, no association was found between extent of mitral valve calcification and markers of mineral metabolism and CRP; aortic valve extent of calcification was positively associated with i-PTH (r(2) = 0.212; P = 0.03) and FGF-23 (r(2) = 0.272; P = 0.01), and negatively with Klotho (r(2) = -0.208; P = 0.04). In multivariable analysis, extent of aortic valve calcification was associated with FGF-23 (P = 0.01) and PTH (P = 0.01) levels. CONCLUSIONS: Extent of aortic valve calcification is associated to FGF-23 and PTH in naive CKD patients with mild to moderate CKD. Further studies should examine whether FGF-23 assay should be included in routine clinical evaluation of CKD as part of cardiovascular risk stratification. PMID- 26613034 TI - Independent association between serum sclerostin levels and carotid artery atherosclerosis in prevalent haemodialysis patients. AB - BACKGROUND: Sclerostin is a soluble inhibitor of the Wnt signalling pathway and has been shown to be associated with decreased bone turnover and vascular and/or valvular calcification in patients with chronic kidney disease. Common carotid artery intima-media thickness (CIMT) assessment and common carotid artery (CCA) plaque identification with ultrasound imaging are well-recognized tools for the identification and monitoring of atherosclerosis. The aim of the present study was to investigate whether the circulating levels of sclerostin might be associated with carotid artery atherosclerosis in prevalent haemodialysis patients. METHODS: In this cross-sectional study, serum sclerostin concentrations were measured using a commercially available enzyme-linked immunosorbent assay kit. CIMT was measured and carotid plaques were identified by B-mode and Doppler ultrasound imaging. RESULTS: One hundred and twenty-two prevalent haemodialysis patients were involved in the study. Serum sclerostin levels were higher in patients with plaques in CCA than patients free of plaques (227 +/- 166 versus 117 +/- 91 pmol/L, P = 0.016). A significant correlation was recorded between serum sclerostin levels and CIMT (r = 0.459, P < 0.0001). In the multiple regression analysis, sclerostin concentrations were one of the independent factors that remained significantly associated with CIMT. CONCLUSION: Sclerostin is independently associated with CIMT although further studies are needed. PMID- 26613035 TI - Contribution of dysregulated serum magnesium to mortality in hemodialysis patients with secondary hyperparathyroidism: a 3-year cohort study. AB - BACKGROUND: The extent of contribution of disturbed magnesium balance to mortality remains unclear among hemodialysis patients. METHODS: This was a cohort study involving 3276 patients on maintenance hemodialysis at 86 facilities in Japan from 2008 to 2010 who had secondary hyperparathyroidism (SHPT). Baseline serum magnesium (sMg) values were categorized into quintiles (<=2.3, >2.3-2.5, >2.5-2.7, >2.7-3.0 and >3.0 mg/dL), and the middle quintile was set as the reference. Outcome was all-cause death. Independent contribution to all-cause death was assessed via Cox regression to generate population-attributable fractions (PAFs). RESULTS: A total of 2165 patients from 68 facilities were analyzed. The lowest quintile of sMg was positively associated with lower serum potassium and albumin levels, higher C-reactive protein (CRP) levels and prevalence of atrial fibrillation and cerebrovascular disease than the other quintiles. The highest sMg quintile was positively associated with higher potassium levels, and negatively associated with lower serum albumin levels and higher intact parathyroid hormone and CRP levels and prevalence of cerebrovascular disease than the other quintiles. During a median follow-up of 3 years, the lowest and the second lowest quintiles of sMg were associated with all cause death [adjusted hazard ratio (HR) 1.737, 95% confidence interval (95% CI) 1.200-2.512 and HR 1.675, 95% CI 1.254-2.238, respectively). Point estimates of adjusted HRs of the highest and the second highest sMg quintiles were higher than those of the middle quintile for all-cause death. Adjusted PAFs of lower sMg and of higher and lower sMg for all-cause death were 24.0% (95% CI 13.0-35.0%) and 30.7% (95% CI 14.5-46.8%), respectively. CONCLUSION: In hemodialysis patients with SHPT, dysregulated sMg is an important contributor to all-cause death. Further studies are warranted to examine whether or not correction of sMg improves survival. PMID- 26613036 TI - Effects of exercise in the whole spectrum of chronic kidney disease: a systematic review. AB - Chronic kidney disease (CKD) is a public health problem. Although physical activity is essential for the prevention and treatment of most chronic diseases, exercise is rarely prescribed for CKD patients. The objective of the study was to search for and appraise evidence on the effectiveness of exercise interventions on health endpoints in CKD patients. A systematic review was performed of randomized clinical trials (RCTs) designed to compare exercise with usual care regarding effects on the health of CKD patients. MEDLINE, EMBASE, Cochrane Central, Clinical Trials registry, and proceedings of major nephrology conference databases were searched, using terms defined according to the PICO (Patient, Intervention, Comparison and Outcome) methodology. RCTs were independently evaluated by two reviewers. A total of 5489 studies were assessed for eligibility, of which 59 fulfilled inclusion criteria. Most of them included small samples, lasted from 8 to 24 weeks and applied aerobic exercises. Three studies included only kidney transplant patients, and nine included pre-dialysis patients. The remaining RCTs allocated hemodialysis patients. The outcome measures included quality of life, physical fitness, muscular strength, heart rate variability, inflammatory and nutritional markers and progression of CKD. Most of the trials had high risk of bias. The strongest evidence is for the effects of aerobic exercise on improving physical fitness, muscular strength and quality of life in dialysis patients. The benefits of exercise in dialysis patients are well established, supporting the prescription of physical activity in their regular treatment. RCTs including patients in earlier stages of CKD and after kidney transplantation are urgently required, as well as studies assessing long-term outcomes. The best exercise protocol for CKD patients also remains to be established. PMID- 26613037 TI - Barriers to effective communication between veterans with chronic kidney disease and their healthcare providers. AB - BACKGROUND: Many patients with chronic kidney disease (CKD) have insufficient knowledge about CKD, which is associated with poorer health outcomes. Effective patient-provider communication can improve CKD patients' knowledge, thereby augmenting their participation in self-care practices. However, barriers to addressing CKD patients' information needs have not been previously characterized. METHODS: Adults with an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m(2) or on chronic dialysis or with a kidney transplant were recruited from a Department of Veterans Affairs (VA) nephrology clinic. Semi structured telephone interviews were conducted to assess patients' CKD information needs and demographic characteristics. A qualitative approach was used to analyze interview transcripts and identify themes pertaining to communication dynamics. RESULTS: Thirty-two patients participated. The mean age of participants was 63 years; most were male (94%) and non-Hispanic white (53%). CKD severity groups represented included CKD-3 (eGFR 30-59 mL/min/1.73 m(2); 34%), CKD-4 (eGFR 15-29 mL/min/1.73 m(2); 25%), CKD-5 (eGFR <15 mL/min/1.73 m(2); 16%), end-stage kidney disease on dialysis (13%) and kidney transplant recipients (12%). Several key themes emerged about barriers to patient-provider communication based on patients' reported care at both VA and non-VA facilities, including patients perceived their role as a 'listener', reported limited CKD knowledge, did not understand physicians' explanations and were dissatisfied with the patient-provider relationship. CONCLUSIONS: Several barriers to patient provider communication prevent patients from meeting their information needs and perpetuate patient passivity. Future research should evaluate whether interventions that empower CKD patients to actively participate in their care increase knowledge and improve health outcomes. PMID- 26613038 TI - Nephrology care prior to end-stage renal disease and outcomes among new ESRD patients in the USA. AB - BACKGROUND: Longer nephrology care before end-stage renal disease (ESRD) has been linked with better outcomes. METHODS: We investigated whether longer pre-end stage renal disease (ESRD) nephrology care was associated with lower mortality at both the patient and state levels among 443 761 incident ESRD patients identified in the USA between 2006 and 2010. RESULTS: Overall, 33% of new ESRD patients had received no prior nephrology care, while 28% had received care for >12 months. At the patient level, predictors of >12 months of nephrology care included having health insurance, white race, younger age, diabetes, hypertension and US region. Longer pre-ESRD nephrology care was associated with lower first-year mortality (adjusted hazard ratio = 0.58 for >12 months versus no care; 95% confidence interval 0.57-0.59), higher albumin and hemoglobin, choice of peritoneal dialysis and native fistula and discussion of transplantation options. Living in a state with a 10% higher proportion of patients receiving >12 months of pre-ESRD care was associated with a 9.3% lower relative mortality rate, standardized for case mix (R (2) = 0.47; P < 0.001). CONCLUSIONS: This study represents the largest cohort of incident ESRD patients to date. Although we did not follow patients before ESRD onset, our findings, both at the individual patient and state levels, reflect the importance of early nephrology care among those with chronic kidney disease. PMID- 26613039 TI - Pseudomonas exit-site infection: treatment outcomes with topical gentamicin in addition to systemic antibiotics. AB - BACKGROUND: Although, Pseudomonas exit-site infection (ESI) is recognized as a major complication of peritoneal dialysis (PD) with high risk of catheter loss due to refractory/recurrent infection or peritonitis, there is remarkably little literature about treatment outcomes. International Society for Peritoneal Dialysis guidelines advise the use of one to two antibiotics; in addition, we change standard exit-site care by stopping prophylactic mupirocin and starting regular use of gentamicin 1% cream. METHODS: Retrospective review of outcomes of Pseudomonas ESI from January 2012 to March 2015. RESULTS: During the study period, a total of 135 patients were on PD with an overall incidence of any ESI of 0.36/patient-year. There were 14 patients with ESI episodes with Pseudomonas with a rate of 0.12/patient-year. In total, 13 of 14 patients with ESI episodes were treated with oral ciprofloxacin and/or intraperitoneal (IP) gentamicin or ceftazidime, plus topical gentamicin, with a success rate of 38% (5/13). One patient had gentamicin-resistant Pseudomonas species and was treated successfully with topical polymyxin/bacitracin cream. Median follow-up time in cured patients was 385 days (range 74-1107). Six patients had associated with Pseudomonas peritonitis, four during follow-up and two at initial presentation. Three patients had recurrent ESI with Pseudomonas, with one successfully re-treated with topical and IP gentamicin. In total, in only 50% of the patients was Pseudomonas ESI successfully treated. Five of the patients (36%) changed modality to permanent haemodialysis following catheter removal. CONCLUSION: Eradication of Pseudomonas ESI remains difficult even with the addition of topical gentamicin to the exit site. There should be a low threshold for catheter replacement. PMID- 26613040 TI - Opinion of French nephrologists on renal replacement therapy: survey on their personal choice. AB - BACKGROUND: In France, like in most developed countries, peritoneal dialysis (PD) is less used than haemodialysis (HD). This is not based on medical evidence supporting HD superiority. As the practitioner's opinion is important to patients and may influence their treatment choice, we conducted a survey among French nephrologists to determine which renal replacement therapy (RRT) they would choose if they had end-stage renal disease (ESRD). METHODS: We e-mailed a self administered questionnaire to all members of the French-speaking Nephrology Society between 19 October 2008 and 12 January 2009. We then selected from the French Renal Epidemiology and Information Network (REIN) registry a reference population of 20- to 64-year-old patients with ESRD who began RRT [HD, PD or pre emptive transplantation, (PT)] in 2008. RESULTS: The survey response rate was 17.8%. Results showed that 59.6% of respondents chose early inscription on the transplantation waiting list in view of PT, 20.2% selected HD and 20.2% selected PD. When dialysis was the only choice, 50.2% chose HD and 49.8% chose PD. Younger nephrologists (<=44 years old) selected PD more frequently than older nephrologists (>=45 years old) (58.9 versus 40.5%; P < 0.01). Similarly, PD was chosen more often by nephrologists from regions with 'more PD' than from regions with 'less PD' (79.0 versus 48.8%; P < 0.05). The nephrologists' choices were different from the RTT distribution among the reference population: 81.7% HD, 10.1% PD and 8.2% PT. CONCLUSION: Our survey on the theoretical choice of RTT suggests that the low PD rate in France cannot be explained by a negative opinion of PD among French nephrologists. PMID- 26613041 TI - A 4-month programme of in-centre nocturnal haemodialysis was associated with improvements in patient outcomes. AB - BACKGROUND: Extended periods of haemodialysis (HD) can improve patient outcomes. In-centre nocturnal haemodialysis (INHD) should be explored as a method of offering extended periods of HD to patients unsuitable for or unable to perform home therapy. METHODS: Ten self-selecting, prevalent HD patients started an INHD programme to assess feasibility and patient satisfaction. Quality-of-life (QOL) measures were evaluated at enrolment and after 4 months of INHD using the EQ-5D, the Hospital Anxiety and Depression Scale (HADS) and the SF-12 questionnaires. Demographic, biochemical and haematological data and data on dialysis adequacy were collected before starting INHD and after 4 months. RESULTS: Three of the 10 patients failed to complete the 2-week run-in period. Seven patients completed the 4-month programme, with mean dialysis time of 355 +/- 43.92 min throughout the period. The EQ-5D visual analogue score improved from 48 +/- 16.89 to 72 +/- 13.2 (P = 0.003) and the HADS anxiety score decreased from 9 +/- 5.83 to 3.57 +/- 3.04 (P = 0.029). The urea reduction ratio improved from 71.57 +/- 2.29% to 80.43 +/- 3.101% (P < 0.001), with improvements in phosphate control, reducing to within the target range from 1.73 +/- 0.6 to 1.2 +/- 0.2 (P = 0.08). Ultrafiltration (UF) volumes increased during the study from 2000 +/- 510 to 2606 +/- 343 mL (P = 0.015); there was a significant reduction in mean UF rate adjusted for body weight from 6.47 +/- 1.71 to 4.61 +/- 1.59 mL/kg/h (P = 0.032). Sensitivity analyses confirmed the significance of these results. CONCLUSIONS: This single-centre study showed a 4-month programme of extended hours INHD is safe and associated with improvements in QOL measures, decreased UF rates and measures of dialysis adequacy. These data have been used to expand our service and inform the design of future randomized controlled trials to examine medical endpoints. PMID- 26613042 TI - Treatment of amitriptyline intoxications by extended high cut-off dialysis. AB - Antidepressants, especially amitriptyline, are among the most frequent drug classes involved in intoxications. Despite its small molecular weight, amitriptyline is not considered to be eliminated by extracorporeal treatment methods due to its high protein binding and large volume of distribution. New high cut-off dialysers have so far not been used for removal of amitriptyline. We report two cases of amitriptyline poisoning in which we measured the amitriptyline elimination using extended high cut-off (HCO) dialysis. Despite dialyser clearances of 33 and 58 mL/min, resulting in the reduction of initial serum concentrations by ~30%, only 211 and 920 ug of amitryptilin, respectively, (<3% of the ingested amount) could be recovered in the total collected dialysate. Hence, due to the high volume of distribution of amitriptyline, even HCO dialysis does not contribute substantially to the extracorporeal removal of amitryptilin. PMID- 26613043 TI - Prospective evaluation of inappropriate unable-to-assess CAM-ICU documentations of critically ill adult patients. AB - BACKGROUND: Delirium occurs in the intensive care unit and identification is often performed using a validated assessment tool such as the Confusion Assessment Method for Intensive Care Unit (CAM-ICU) patients. The CAM-ICU has three ratings: positive, negative, and unable to assess (UTA). Patients may often be assigned UTA when it is inappropriate given the level of sedation or medical condition. The purpose of this study is to evaluate the rate of inappropriate UTA CAM-ICU documentations. METHODS: A single-center prospective observational analysis was performed evaluating CAM-ICU documentations from October 27, 2014, to December 26, 2014. Patients admitted to the medical and surgical ICU were included and excluded if admitted to the ICU for less than 24 h. CAM-ICU assessments were performed per institutional guidelines using CAM-ICU scoring as validated in literature. CAM-ICU patient documentations were recorded as positive, negative, UTA, or not assessed. Patients with an appropriate UTA documentation were deeply sedated, non-English speaking, or not medically able to participate in the assessment. The major endpoint assessed rates of inappropriate UTA CAM-ICU documentations. Minor endpoints evaluated adherence to CAM-ICU documentations and use of pharmacologic agents for symptoms of delirium. RESULTS: Sixty-one patients were identified with 45 (74 %) medical, 16 (26 %) surgical, of which 27 (44.3 %) were mechanically ventilated. There were 116 UTA documentations with 35 (30.2 %) identified as inappropriate. Of the 906 identified CAM-ICU documentation opportunities, adherence was 439 (48.5 %). Overall, 18 (29.5 %) of the 61 patients were administered pharmacologic agents for delirium management and 5 (27.7 %) had a positive CAM-ICU documented within 24 h. CONCLUSIONS: Rates of inappropriate UTA CAM-ICU documentations may be significantly higher than reported in literature. Additional research is needed to identify an acceptable rate of inappropriate UTA CAM-ICU assessments and its clinical impact on delirium management. PMID- 26613044 TI - Validity of treadmill- and track-based individual calibration methods for estimating free-living walking speed and VO2 using the Actigraph accelerometer. AB - BACKGROUND: For many patients clinical prescription of walking will be beneficial to health and accelerometers can be used to monitor their walking intensity, frequency and duration over many days. Walking intensity should include establishment of individual specific accelerometer count, walking speed and energy expenditure (VO2) relationships and this can be achieved using a walking protocol on a treadmill or overground. However, differences in gait mechanics during treadmill compared to overground walking may result in inaccurate estimations of free-living walking speed and VO2. The aims of this study were to compare the validity of track- and treadmill-based calibration methods for estimating free-living level walking speed and VO2 and to explain between-method differences in accuracy of estimation. METHODS: Fifty healthy adults [32 women and 18 men; mean (SD): 40 (13) years] walked at four pre-determined speeds on an outdoor track and a treadmill, and completed three 1-km self-paced level walks while wearing an Actigraph monitor and a mobile oxygen analyser. Speed- and VO2 to-Actigraph count individual calibration equations were computed for each calibration method. Between-method differences in calibration equation parameters, prediction errors, and relationships of walking speed with VO2 and Actigraph counts were assessed. RESULTS: The treadmill-calibration equation overestimated free-living walking speed (on average, by 0.7 km . h(-1)) and VO2 (by 4.99 ml . kg(-1) . min(-1)), while the track-calibration equation did not. This was because treadmill walking, from which the calibration equation was derived, produced lower Actigraph counts and higher VO2 for a given walking speed compared to walking on a track. The prediction error associated with the use of the treadmill-calibration method increased with free-living walking speed. This issue was not observed when using the track-calibration method. CONCLUSIONS: The proposed track-based individual accelerometer calibration method can provide accurate and unbiased estimates of free-living walking speed and VO2 from walking. The treadmill-based calibration produces calibration equations that tend to substantially overestimate both VO2 and speed. PMID- 26613045 TI - Can previously sedentary females use the feeling scale to regulate exercise intensity in a gym environment? an observational study. AB - BACKGROUND: Recent research suggests that the Feeling Scale (FS) can be used as a method of exercise intensity regulation to maintain a positive affective response during exercise. However, research to date has been carried out in laboratories and is not representative of natural exercise environments. The purpose of this study was to evaluate whether sedentary women can self-regulate their exercise intensity using the FS to experience positive affective responses in a gym environment using their own choice of exercise mode; cycling or treadmill. METHODS: Fourteen females (24.9 years +/- 5.2; height 166.7 +/- 5.7 cm; mass 66.3 +/- 13.4 kg; BMI 24.1 +/- 5.5)) completed a submaximal exercise test and each individual's ventilatory threshold ([Formula: see text]) was identified. Following this, three 20 min gym-based exercise trials, either on a bike or treadmill were performed at an intensity that was self-selected and perceived to correspond to the FS value of +3 (good). Oxygen uptake, heart rate (HR) and ratings of perceived exertion (RPE) were measured during exercise at the participants chosen intensity. RESULTS: Results indicated that on average participants worked close to their [Formula: see text] and increased their exercise intensity during the 20-min session. Participants worked physiologically harder during cycling exercise. Consistency of oxygen uptake, HR and RPE across the exercise trials was high. CONCLUSION: The data indicate that previously sedentary women can use the FS in an ecological setting to regulate their exercise intensity and that regulating intensity to feel 'good' should lead to individuals exercising at an intensity that would result in cardiovascular gains if maintained. PMID- 26613046 TI - On the origin of vertebrate somites. AB - INTRODUCTION: Somites, blocks of mesoderm tissue located on either side of the neural tube in the developing vertebrate embryo, are derived from mesenchymal cells in the presomitic mesoderm (PSM) and are a defining characteristic of vertebrates. In vertebrates, the somite segmental boundary is determined by Notch signalling and the antagonistic relationship of the downstream targets of Notch, Lfng, and Delta1 in the anterior PSM. The presence of somites in the basal chordate amphioxus (Branchiostoma floridae) indicates that the last common ancestor of chordates also had somites. However, it remains unclear how the genetic mechanisms underlying somitogenesis in vertebrates evolved from those in ancestral chordates. RESULTS: We demonstrate that during the gastrula stages of amphioxus embryos, BfFringe expression in the endoderm of the archenteron is detected ventrally to the ventral limit of BfDelta expression in the presumptive rostral somites along the dorsal/ventral (D/V) body axis. Suppression of Notch signalling by DAPT (a gamma-secretase inhibitor that indirectly inhibits Notch) treatment from the late blastula stage reduced late gastrula stage expression of BfFringe in the endodermal archenteron and somite markers BfDelta and BfHairy-b in the mesodermal archenteron. Later in development, somites in the DAPT-treated embryo did not separate completely from the dorsal roof of the archenteron. In addition, clear segmental boundaries between somites were not detected in DAPT treated amphioxus embryos at the larva stage. Similarly, in vertebrates, DAPT treatment from the late blastula stage in Xenopus (Xenopus laevis) embryos resulted in disruption of somite XlDelta-2 expression at the late gastrula stage. At the tail bud stage, the segmental expression of XlMyoD in myotomes was diminished. CONCLUSIONS: We propose that Notch signalling and the Fringe/Delta cassette for dorso-ventral boundary formation in the archenteron that separates somites from the gut in an amphioxus-like ancestral chordate were co-opted for anteroposterior segmental boundary formation in the vertebrate anterior PSM during evolution. PMID- 26613048 TI - The Role of the Endothelin System in the Vascular Dysregulation Involved in Retinitis Pigmentosa. AB - Retinitis pigmentosa is a clinical and genetic group of inherited retinal disorders characterized by alterations of photoreceptors and retinal pigment epithelium leading to a progressive concentric visual field restriction, which may bring about severe central vision impairment. Haemodynamic studies in patients with retinitis pigmentosa have demonstrated ocular blood flow abnormalities both in retina-choroidal and in retroocular vascular system. Moreover, several investigations have studied the augmentation of endothelin-1 plasma levels systemically in the body and locally in the eye. This might account for vasoconstriction and ischemia, typical in vascular dysregulation syndrome, which can be considered an important factor of reduction of the ocular blood flow in subjects affected by retinitis pigmentosa. PMID- 26613049 TI - Pentraxin 3 Plasma Levels and Disease Activity in Systemic Lupus Erythematosus. AB - SLE is an autoimmune disorder that involves polyclonal autoimmunity against multiple autoantigens. PTX3, a marker of the acute-phase inflammatory response, plays an important role in innate immunity and in modulation of the adaptive immune response. Our study tried to resolve some rather controversial aspects of the use of PTX3 as a biomarker of disease activity in SLE patients. We demonstrated that plasma PTX3 concentration of the SLE patients was significantly higher than the healthy control groups and reflected disease activity. ROC curve analysis was used to determine best cut-off point (2.8 ng/mL) with a good sensitivity and specificity. In patients with SLE, PTX3 concentrations were correlated with SLEDAI. Trend to remission (TTR) curve was created by plotting PTX3 levels and SLEDAI and we applied the curve as a model for the analysis of two patients with different follow-up. PTX3 plasma levels declined significantly and this decline occurred parallel to the clinical improvement with a complete remission of disease. In patients who experienced a clinical relapse, an increase in PTX3 levels followed the lupus flare. The proposal of PTX3 cut-off associated with TTR and monitoring of PTX3 plasma levels could be an innovative approach to follow-up of SLE patients. PMID- 26613050 TI - Mandibular Ramus Fracture: An Overview of Rare Anatomical Subsite. AB - Aim. The present study aims at exemplifying the incidence, and aetiology and analyses the outcomes of open reduction internal fixation (ORIF) over closed treatment of mandibular ramus fractures. Patients and Method. In the present retrospective analysis of mandibular fracture patients, variables analysed were age, sex, cause of injury, pretreatment occlusion, treatment given, period of maxillo-mandibular fixation (MMF), and posttreatment occlusion. Results. Out of 388 mandibular fractures treated, ramus fractures were 12 (3.09%). In the present study, predominant cause of mandibular ramus fracture was road traffic accident (RTA) n = 07 (58.33%) followed by fall n = 04 (33.33%) and assault n = 1 (8.33%). The average age was 35.9 years with a male predilection. Of these, 9 patients were treated with ORIF while remaining 3 with closed treatment. The average MMF after closed treatment was 21 days and 3 to 5 days after ORIF. There was improvement in occlusion in all 12 patients posttreatment with no major complication except for reduced mouth opening in cases treated with ORIF which recovered with physiotherapy and muscle relaxants. Conclusion. Mandibular ramus fractures accounted for 3.09% with RTA as a common aetiology. ORIF of ramus fractures facilitated adequate functional and anatomic reduction with early return of function. PMID- 26613047 TI - Coarse-Grained Models for Protein-Cell Membrane Interactions. AB - The physiological properties of biological soft matter are the product of collective interactions, which span many time and length scales. Recent computational modeling efforts have helped illuminate experiments that characterize the ways in which proteins modulate membrane physics. Linking these models across time and length scales in a multiscale model explains how atomistic information propagates to larger scales. This paper reviews continuum modeling and coarse-grained molecular dynamics methods, which connect atomistic simulations and single-molecule experiments with the observed microscopic or mesoscale properties of soft-matter systems essential to our understanding of cells, particularly those involved in sculpting and remodeling cell membranes. PMID- 26613051 TI - Sucupira as a Potential Plant for Arthritis Treatment and Other Diseases. AB - Trees of the genus Pterodon, commonly known as "sucupira-branca" or "faveira," are native to central Brazil. The Pterodon fruits are traditionally used in ethnomedicine as an infusion, in small doses, and at regular time intervals as an antirheumatic, anti-inflammatory, tonic, and depurative agent. The various compounds present in the Pterodon class are, generally, water-insoluble and derived from the fusion of high-molecular weight pentacarbonate units. Scientific research has shown that the major compounds isolated from Pterodon species are linear and/or tetracyclic diterpenes with vouacapane skeletons that partly underlie the pharmacological activities of the fruit-derived oil. Material from Pterodon species has several biological properties, such as analgesic, anti inflammatory, and anticancer effects. Therefore, recent studies have sought to microencapsulate these extracts to protect them from potential chemical degradation and improve their water solubility, ensuring greater stability and quality of the end products. This review presents a succinct overview of the available scientific evidence of the biological activity and toxicity of Pterodon species in addition to other important aspects, including phytochemical and technological features. PMID- 26613052 TI - Late Onset and Protracted Course of Steroid Refractory Chronic Graft-versus-Host Disease. AB - Chronic graft-versus-host disease (cGVHD) is one of the most important causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (aHSCT). Occurring in 30% to 70% of patients, cGVHD has a median time to onset of 4 to 6 months and most cases present within 2 years after aHSCT. Here, we present a patient transplanted at the age of 55 who developed refractory cutaneous cGVHD more than 5.5 years after aHSCT. PMID- 26613053 TI - Long-Term Therapeutic Plasma Exchange to Prevent End-Stage Kidney Disease in Adult Severe Resistant Henoch-Schonlein Purpura Nephritis. AB - A 27-year-old man presented with a palpable purpuric skin rash and joint and abdominal pain in April 2010. He had acute kidney injury and his creatinine quickly deteriorated to 687 MUmol/L, with associated nephrotic range proteinuria. Kidney biopsy showed crescentic Henoch-Schonlein nephritis. He was treated with intravenous cyclophosphamide and prednisolone despite which his renal function deteriorated; he required haemodialysis for a short duration and seven sessions of therapeutic plasma exchange (TPE). Renal function improved, but after discharge from hospital he suffered 2 further relapses, each with AKI, in 4 months. Cyclophosphamide was not effective and therefore Rituximab was introduced. He initially had a partial response but his renal function deteriorated despite continued therapy. TPE was the only treatment that prevented rapid renal functional deterioration. A novel long-term treatment strategy involving regular TPE every one to two weeks was initiated. This helped to slow his progression to end-stage kidney disease over a 3-year period and to prolong the need for renal replacement therapy over this time. PMID- 26613054 TI - Three Siblings with Prader-Willi Syndrome: Brief Review of Sleep and Prader-Willi Syndrome. AB - Prader-Willi syndrome (PWS) is a genetic disorder characterized by short stature, mental retardation, hypotonia, functionally deficient gonads, and uncontrolled appetite leading to extreme obesity at an early age. Patients with this condition require multidisciplinary medical care, which facilitates a significant improvement in quality of life. PWS is the first human disorder to be attributed to genomic imprinting. Prevalence varies in the literature, ranging from 1 in 8,000 in the Swedish population to 1 in 54,000 in the United Kingdom. Rarely, the genetic mechanism responsible for Prader-Willi syndrome can be inherited. We report a highly unique case of three siblings who share this condition. This report describes a case of two brothers and one half sister with PWS. All three siblings have sleep-related complaints. The sister died at the age of 24 years in her sleep, with the cause of death reported as obstructive sleep apnea. The outcome was positive in both of the brothers' cases as a result of professional medical care and specific tailored recommendations implemented by their mother. A review of the relevant literature vis-a-vis sleep and PWS is provided. PMID- 26613055 TI - Prostate Cancer-Associated Disseminated Intravascular Coagulation with Excessive Fibrinolysis Treated with Degarelix. AB - Disseminated intravascular coagulation (DIC) with excessive fibrinolysis (XFL) is a rare and acute life-threatening variant of DIC in patients with prostate cancer. Patients present with coagulopathy, hypofibrinogenemia, and systemic bleeding. We describe a case of DIC XFL caused by prostate cancer (PC) successfully treated with a single injection of degarelix, a gonadotropin releasing hormone (GnRH) receptor antagonist. This led to prompt control of the patient's coagulopathy within ten days of treatment. Our case highlights features of this rare and devastating hemorrhagic complication of PC along with a fast acting and effective therapeutic drug option. PMID- 26613056 TI - Left Vocal Cord Paralysis Detected by PET/CT in a Case of Lung Cancer. AB - We report a patient with lung cancer. The first PET/CT imaging revealed hypermetabolic mass in the left aortopulmonary region and hypermetabolic nodule in the anterior segment of the upper lobe of the left lung. After completing chemotherapy and radiotherapy against the primary mass in the left lung, the patient underwent a second PET/CT examination for evaluation of treatment response. This test demonstrated, compared with the first PET/CT, an increase in the size and metabolic activity of the primary mass in the left lung in addition to multiple, pathologic-sized, hypermetabolic metastatic lymph nodes as well as multiple metastatic sclerotic areas in bones. These findings were interpreted as progressive disease. In addition, an asymmetrical FDG uptake was noticed at the level of right vocal cord. During follow-up, a laryngoscopy was performed, which demonstrated left vocal cord paralysis with no apparent mass. Thus, we attributed the paralytic appearance of the left vocal cord to infiltration of the left recurrent laryngeal nerve by the primary mass located in the apical region of the left lung. In conclusion, the knowledge of this pitfall is important to avoid false-positive PET results. PMID- 26613057 TI - An Unusual Cause of Posterior Elbow Impingement: Detachment of a Hypertrophied Posterior Fat Pad. AB - We report a case of a 47-year-old woman who developed posterior impingement of the elbow due to detachment of a hypertrophied posterior fat pad. She reported acute left elbow pain after leaning back onto a hard object with her hand and subsequently experienced a "catching" sensation. Comparison with the magnetic resonance images of a normal elbow revealed a hypertrophied posterior fat pad interposed between the olecranon and olecranon fossa in both elbows, with the fat pad in the left elbow located more inferiorly than that in the right elbow. Elbow arthroscopy showed the olecranon fossa covered by the fat pad, a portion of which was detached from the rest of the pad. Debridement of the detached portion was performed until no impingement was evident. Postoperatively, full extension of the elbow did not elicit pain. Clinicians should include this pathology among the differential diagnoses for posterior elbow pain. PMID- 26613058 TI - Migration of the Anterior Spinal Rod to the Right Thigh, a Rare Complication of Anterior Spinal Instrumentations: A Case Report and a Literature Review. AB - Posterior and anterior fusion procedures with instrumentation are well-known surgical treatments for scoliosis. Rod migration has been described as unusual complication in anterior spinal instrumentations; migration beyond pelvis is a rare complication. A 32-year-old female presented to the consultant with right thigh pain, rod migration was diagnosed, rod extraction by minimal approach was performed, and spinal instrumentation after nonunion diagnosis was underwent. A rod migration case to the right thigh is presented; this uncommon complication of spinal instrumentation should be ruled out as unusual cause of sudden pain without any other suspicions, and long-term follow-up is important to prevent and diagnose this problem. PMID- 26613059 TI - Repair of Unstable Posterior Sternoclavicular Dislocation Using Nonabsorbable Tape Suture and Tension Band Technique: A Case Report with Good Results. AB - Posterior sternoclavicular joint dislocation (PSCJD) is quite a rare condition. Nearly half of the closed reduction attempts fail due to various reasons. In this paper, we present a 25-year-old male patient who was admitted to the emergency department in our hospital after having a motor-vehicle accident. It was decided to do PSCJD after physical and imaging studies. Following necessary preparations, closed reduction was attempted with abduction-traction maneuver under general anesthesia; however, adequate stabilization could not be achieved and redislocation was detected during control. Therefore, joint was stabilized with tension band technique using 6 mm polyamide nonabsorbable type suture during open reduction. Painless and complete range of motion in shoulder was achieved at the postoperative 10th week. PMID- 26613060 TI - Acute Lymphocytic Leukemia with Bilateral Renal Masses Masquerading as Nephroblastomatosis. AB - Acute lymphoblastic leukemia (ALL) is the most common malignancy in the pediatric patient population. However, renal involvement as the primary manifestation of ALL is rare. We report a case of a 4-year-old boy with bilateral renal lesions resembling nephroblastic rests as the first finding of early stage ALL preceding hematological changes and subsequent classic clinical findings by two weeks. These renal hypodensities completely resolved after one week of induction chemotherapy. This case demonstrates that renal involvement can be the only initial presenting finding of leukemia. Children with lesions resembling nephroblastic rests need appropriate surveillance due to the risk of malignant disease. PMID- 26613061 TI - Urinary Incontinence during Sleep Associated with Extended Release Form of Bupropion HCI. AB - Bupropion hydrochloride (HCI) is an antidepressant that acts as a norepinephrine and dopamine reuptake inhibitor and has three different dosage forms including immediate release (IR), sustained release (SR), and extended release (ER). Despite its relatively safe side effect profile bupropion may cause several side effects. Here, we aimed to report a case with major depression using extended release form of bupropion hydrochloride who was presented with urinary incontinence during sleep, an uncommon side effect of bupropion. PMID- 26613062 TI - Pulmonary Peripheral Carcinoids after Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia and Tumorlets: Report of 3 Cases. AB - Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and tumorlets are neuroendocrine cells proliferations smaller than 5 mm. The former confines to bronchial/bronchiolar wall, while the latter broke through epithelial basement membrane. The authors present 3 cases of DIPNECH and tumorlets associated with a typical peripheral carcinoid tumor without underlying lung disease. The patients presented with nonspecific pulmonary symptoms: 3 females, 60, 72, and 84 years old, whose CT-scans showed well-defined pulmonary nodules, 2.2, 1.6, and 1.4 cm, respectively; first patient was submitted to lobectomy and the others underwent surgical biopsy. Whitish/brownish lobulated tumors corresponded to typical carcinoids (less than 2 mitoses/2 mm(2) and without necrosis); polygonal/elongated cells under lobular pattern expressed CD56, chromogranin A, synaptophysin, and CK7; Ki-67 positivity was between 1 and 3%. Bronchial/bronchiolar wall neuroendocrine cell hyperplasia and several neuroendocrine nodules under 5 mm, with identical morphologic and immunoexpression, were observed, without lung disease. Typical carcinoid associated with DIPNECH and tumorlets without other pulmonary diseases is rare. Sporadic cases may recall embryonal neuroendocrine differentiation potentiality to develop peripheral hyperplasia, most commonly in underoxygenated parenchyma. The described cases are elucidative of peripheral spectrum of neuroendocrine cell tumour evolution, reinforcing higher female incidence as in central carcinoids, still without a clear preneoplastic lesion. PMID- 26613063 TI - Primary Desmoplastic Melanoma of the Penis. AB - Desmoplastic melanomas are rare amelanotic melanomas that usually occur on skin with sun exposure. In this report, we present a 72-year-old man who presented with a desmoplastic melanoma of the penis. To our knowledge this represents the first reported case of primary desmoplastic melanoma of the penis. We discuss the pathologic differential and histologic evaluation. PMID- 26613064 TI - Autophagy Inhibition to Increase Radiosensitization in Breast Cancer. AB - Currently, many breast cancer patients with localized breast cancer undergo breast-conserving therapy, consisting of local excision followed by radiation therapy. Following radiation therapy, breast cancer cells are noted to undergo induction of autophagy, development of radioresistance, and enrichment of breast cancer stem cell subpopulations. It is hypothesized that inhibition of the cytoprotective autophagy that arises following radiation therapy increases radiosensitivity and confers longer relapse-free survival by eliminating tumor initiating breast cancer stem cells. Therefore, we reviewed the controversial role of autophagy in breast cancer tumorigenesis and progression, autophagy induction by radiotherapy, and utilization of autophagy inhibitors to increase radiosensitivity of breast cancer and to target radioresistant breast cancer stem cells. PMID- 26613066 TI - Do entrepreneurial food systems innovations impact rural economies and health? Evidence and gaps. AB - A potential solution for weakened rural economies is the development of local food systems, which include affordable foods sources for consumers and economically feasible structures for producers. Local food systems are purported to promote sustainability, improve local economies, increase access to healthy foods, and improve the local diets. Four entrepreneurial food systems innovations that support local economies include farmers' markets, community supported agriculture, farm to institution programs and food hubs. We review current literature to determine whether innovations for aggregation, processing, distribution and marketing in local food systems: 1) enable producers to make a living; 2) improve local economies; 3) provide local residents with greater access to affordable, healthy food; and 4) contribute to greater consumption of healthy food among residents. While there is some evidence for each, more transdisciplinary research is needed to determine whether entrepreneurial food systems innovations provide economic and public health benefits. PMID- 26613067 TI - Successful Medical Weight Loss in a Community Setting. AB - BACKGROUND: Research has shown that meal replacement calorie reduction combined with lifestyle change can more than double the weight loss seen with other diets. However, its widespread acceptance by physicians has been limited, perhaps waiting on evidence that patients are successful in keeping lost weight off. METHODS: Obese patients (108.4 +/- 25.7 kg, BMI 38.1 +/- 7.9 kg/m2) used a diet of meal replacements combined with weekly classes. While learning about nutrition, exercise, and accountability, patients tracked calorie intake and physical activity. Weight loss and retention rates for rapid weight loss and maintenance phases were measured. Weights then obtained years after treatment ended showed that patients were keeping lost weight off without any ongoing clinic intervention. RESULTS: Records of 714 patients treated in a medical weight loss practice from 2004 through 2012 were reviewed. For all patients, weight loss was 13.6 +/- 8.3 kg, and 12.5% of initial weight. The 469 patients who completed 16 weeks of weight loss classes lost 16.7 +/- 7.2 kg and 15.1%. 433 patients then enrolled in maintenance classes, and after 12 months had regained only 0.1 +/- 9.1 kg and 0.4%. Follow up weights obtained from 173 patients more than 2 years after treatment ended showed persisting weight loss of 14.3 +/- 13.7 kg and 12.9%. Final BMI was 32.7 +/- 7.7 kg/m2. CONCLUSION: In a medical weight loss program that used meal replacements to reduce calorie intake combined with weekly behavior change classes, weight loss was 16.2 kg and 14.4% for the 61% of all enrollees who completed 16 months of treatment. More importantly, over 2 years later, weight loss of 14.3 kg and 12.9% of initial weight persisted, and patients were not regaining their lost weight. PMID- 26613065 TI - T Cell Dynamic Activation and Functional Analysis in Nanoliter Droplet Microarray. AB - OBJECTIVE: Characterization of the heterogeneity in immune reactions requires assessing dynamic single cell responses as well as interactions between the various immune cell subsets. Maturation and activation of effector cells is regulated by cell contact-dependent and soluble factor-mediated paracrine signalling. Currently there are few methods available that allow dynamic investigation of both processes simultaneously without physically constraining non-adherent cells and eliminating crosstalk from neighboring cell pairs. We describe here a microfluidic droplet microarray platform that permits rapid functional analysis of single cell responses and co-encapsulation of heterotypic cell pairs, thereby allowing us to evaluate the dynamic activation state of primary T cells. METHODS: The microfluidic droplet platform enables generation and docking of monodisperse nanoliter volume (0.523 nl) droplets, with the capacity of monitoring a thousand droplets per experiment. Single human T cells were encapsulated in droplets and stimulated on-chip with the calcium ionophore ionomycin. T cells were also co-encapsulated with dendritic cells activated by ovalbumin peptide, followed by dynamic calcium signal monitoring. RESULTS: Ionomycin-stimulated cells depicted fluctuation in calcium signalling compared to control. Both cell populations demonstrated marked heterogeneity in responses. Calcium signalling was observed in T cells immediately following contact with DCs, suggesting an early activation signal. T cells further showed non-contact mediated increase in calcium level, although this response was delayed compared to contact-mediated signals. CONCLUSIONS: Our results suggest that this nanoliter droplet array-based microfluidic platform is a promising technique for assessment of heterogeneity in various types of cellular responses, detection of early/delayed signalling events and live cell phenotyping of immune cells. PMID- 26613068 TI - Binary Classifier Calibration Using a Bayesian Non-Parametric Approach. AB - Learning probabilistic predictive models that are well calibrated is critical for many prediction and decision-making tasks in Data mining. This paper presents two new non-parametric methods for calibrating outputs of binary classification models: a method based on the Bayes optimal selection and a method based on the Bayesian model averaging. The advantage of these methods is that they are independent of the algorithm used to learn a predictive model, and they can be applied in a post-processing step, after the model is learned. This makes them applicable to a wide variety of machine learning models and methods. These calibration methods, as well as other methods, are tested on a variety of datasets in terms of both discrimination and calibration performance. The results show the methods either outperform or are comparable in performance to the state of-the-art calibration methods. PMID- 26613069 TI - A Generalized Mixture Framework for Multi-label Classification. AB - We develop a novel probabilistic ensemble framework for multi-label classification that is based on the mixtures-of-experts architecture. In this framework, we combine multi-label classification models in the classifier chains family that decompose the class posterior distribution P(Y1, ..., Yd |X) using a product of posterior distributions over components of the output space. Our approach captures different input-output and output-output relations that tend to change across data. As a result, we can recover a rich set of dependency relations among inputs and outputs that a single multi-label classification model cannot capture due to its modeling simplifications. We develop and present algorithms for learning the mixtures-of-experts models from data and for performing multi-label predictions on unseen data instances. Experiments on multiple benchmark datasets demonstrate that our approach achieves highly competitive results and outperforms the existing state-of-the-art multi-label classification methods. PMID- 26613070 TI - A spatial analysis of functional outcomes and quality of life outcomes after pediatric injury. AB - BACKGROUND: Changes in health-related quality of life (HRQoL) are more regularly being monitored during the first year after injury. Monitoring changes in HRQoL using spatial cluster analysis can potentially identify concentrations of geographic areas with injury survivors with similar outcomes, thereby improving how interventions are delivered or in how outcomes are evaluated. METHODS: We used a spatial scan statistic designed for oridinal data to test two different spatial cluster analysis of very low, low, high, and very high HRQoL scores. Our study was based on HRQoL scores returned by children treated for injury at British Columbia Children's Hospital and discharged to the Vancouver Metropolitan Area. Spatial clusters were assessed at 4 time periods - baseline (based on pre injury health as reported prior to discharge from hospital), and one, four, and twelve months after discharge. Outcome data were measured used the PedsQLTM outcome scale. Outcome values of very low, low, high, and very high HRQoL scores were defined by classifying PedsQLTM scores into quartiles. In the first test, all scores were assessed for clustering without specifying whether the response score was from a baseline or follow-up response. In the second analysis, we built a space-time model to identify whether HRQoL responses could be identified at specific time points. RESULTS: Among all participants, geographic clustering of response scores were observed globally and at specific time periods. In the purely spatial analysis, five significant clusters of 'very low' PedsQL physical and psychosocial health outcomes were identified within geographic zones ranging in size from 1 to 21 km. A space-time analysis of outcomes identified significant clusters of both 'very low' and 'low' outcomes between survey months within zones ranging in size from 3 to 5 km. CONCLUSION: Monitoring patient health outcomes following injury is important for planning and targeting interventions. A common theme in the literature is that future prevention efforts may benefit from identifying those most a risk of developing ongoing problems after injury in effort to target resources to those most in need. Spatial scan statistics are tools that could be applied for identifying concentrations of poor recovery outcomes. By classifying outcomes as a categorical variable, clusters of 'potentially low' outcomes can also be mapped, thereby identifying populations whose recovery status may decrease. PMID- 26613071 TI - Implementing injury surveillance systems alongside injury prevention programs: evaluation of an online surveillance system in a community setting. AB - BACKGROUND: Previous research aimed at improving injury surveillance standards has focused mainly on issues of data quality rather than upon the implementation of surveillance systems. There are numerous settings where injury surveillance is not mandatory and having a better understanding of the barriers to conducting injury surveillance would lead to improved implementation strategies. One such setting is community sport, where a lack of available epidemiological data has impaired efforts to reduce injury. This study aimed to i) evaluate use of an injury surveillance system following delivery of an implementation strategy; and ii) investigate factors influencing the implementation of the system in community sports clubs. METHODS: A total of 78 clubs were targeted for implementation of an online injury surveillance system (approximately 4000 athletes) in five community Australian football leagues concurrently enrolled in a pragmatic trial of an injury prevention program called FootyFirst. System implementation was evaluated quantitatively, using the RE-AIM framework, and qualitatively, via semi structured interviews with targeted-users. RESULTS: Across the 78 clubs, there was 69% reach, 44% adoption, 23% implementation and 9% maintenance. Reach and adoption were highest in those leagues receiving concurrent support for the delivery of FootyFirst. Targeted-users identified several barriers and facilitators to implementation including personal (e.g. belief in the importance of injury surveillance), socio-contextual (e.g. understaffing and athlete underreporting) and systems factors (e.g. the time taken to upload injury data into the online system). CONCLUSIONS: The injury surveillance system was implemented and maintained by a small proportion of clubs. Outcomes were best in those leagues receiving concurrent support for the delivery of FootyFirst, suggesting that engagement with personnel at all levels can enhance uptake of surveillance systems. Interview findings suggest that increased uptake could also be achieved by educating club personnel on the importance of recording injuries, developing clearer injury surveillance guidelines, increasing club staffing and better remunerating those who conduct surveillance, as well as offering flexible surveillance systems in a range of accessible formats. By increasing the usage of surveillance systems, data will better represent the target population and increase our understanding of the injury problem, and how to prevent it, in specific settings. PMID- 26613072 TI - Posttraumatic stress disorder, depression, and non-fatal intentional self-harm in Massachusetts Veterans. AB - BACKGROUND: The literature on the association between Posttraumatic Stress Disorder (PTSD) and fatal and non-fatal intentional self-harm (ISH) among Veterans who receive care within the Veterans Health Administration (VHA) is limited in scope and contradictory. The current study examines the association between PTSD and non-fatal ISH in a gender-stratified sample of patients who received care at a Massachusetts VHA treatment facility between 2000 and 2008. METHODS: VHA electronic medical record data were obtained for patients who received a PTSD diagnosis at a Massachusetts treatment facility (n = 16,004) and a gender/age matched comparison group (n = 52,502). Rate ratios for the association between PTSD and non-fatal ISH were computed adjusting for marital status, depression, alcohol or drug abuse or dependence, anxiety disorder diagnoses and prior ISH and clustering by hospital using Poisson regression. The interaction between PTSD and depression diagnoses in predicting non-fatal ISH was assessed as the departure from additive effects by calculating the interaction contrast (IC) while adjusting for identified confounders. RESULTS: Over the eight year study period 146 (0.91%) of those with PTSD experienced non-fatal ISH, while 71 (0.14%) of those without PTSD experienced non-fatal ISH. Strong adjusted associations between PTSD and non-fatal ISH were found for both male (RR = 3.3, 95% CI = 2.3, 4.6) and female (RR = 16, 95% CI = 4.7, 55) VHA patients. Evidence of an interaction between PTSD and depression diagnoses in predicting non-fatal ISH was found as a departure from additive effects for both sexes, but this association was more marked among women than among men. CONCLUSIONS: Our results indicate that non-fatal ISH among women may be more strongly related to PTSD than prior work focusing on suicide has suggested and highlight the importance of gender-stratified examinations of these associations. Further, our results suggest that suicide prevention approaches in the VHA should integrate treatment for PTSD and depression. PMID- 26613074 TI - Performance analysis of 3-D shape measurement algorithm with a short baseline projector-camera system. AB - A number of works for 3-D shape measurement based on structured light have been well-studied in the last decades. A common way to model the system is to use the binocular stereovision-like model. In this model, the projector is treated as a camera, thus making a projector-camera-based system unified with a well established traditional binocular stereovision system. After calibrating the projector and camera, a 3-D shape information is obtained by conventional triangulation. However, in such a stereovision-like system, the short baseline problem exists and limits the measurement accuracy. Hence, in this work, we present a new projecting-imaging model based on fringe projection profilometry (FPP). In this model, we first derive a rigorous mathematical relationship that exists between the height of an object's surface, the phase difference distribution map, and the parameters of the setup. Based on this model, we then study the problem of how the uncertainty of relevant parameters, particularly the baseline's length, affects the 3-D shape measurement accuracy using our proposed model. We provide an extensive uncertainty analysis on the proposed model through partial derivative analysis, relative error analysis, and sensitivity analysis. Moreover, the Monte Carlo simulation experiment is also conducted which shows that the measurement performance of the projector-camera system has a short baseline. PMID- 26613073 TI - In-hospital mortality among patients injured in motor vehicle crashes in a Saudi Arabian hospital relative to large U.S. trauma centers. AB - BACKGROUND: Traffic-related fatalities are a leading cause of premature death worldwide. According to the 2012 report the Global Burden of Disease 2010, traffic injuries ranked 8th as a cause of death in 2010, compared to 10th in 1990. Saudi Arabia is estimated to have an overall traffic fatality rate more than double that of the U.S., but it is unknown whether mortality differences also exist for injured patients seeking medical care. We aim to compare in hospital mortality between Saudi Arabia and the United States, adjusting for severity and demographic variables. METHODS: The analysis included 485,611 patients from the U.S. National Trauma Data Bank (NTDB) and 5,290 patients from a trauma registry at King Abdulaziz Medical City (KAMC) in Riyadh, Saudi Arabia. For comparability, we restricted our sample to NTDB data from level-I public trauma centers (>=400 beds) in the U.S. Multiple logistic regression analyses were performed to evaluate the effect of setting (KAMC vs. NTDB) on in-hospital mortality after adjusting for age, sex, Triage-Revised Scale (T-RTS), Injury Severity Score (ISS), mechanism of injury, hypotension, surgery and head injuries. Interactions between setting and ISS, and predictors were also evaluated. RESULTS: Injured patients in the Saudi registry were more likely to be males, and younger than those from the NTDB. Patients at the Saudi hospital were at higher risk of in-hospital death than their U.S. counterparts. In the highest severity group (ISSs, 25-75), the odds ratio of in-hospital death in KAMC versus NTDB was 5.0 (95% CI 4.3-5.8). There were no differences in mortality between KAMC and NTDB among patients from lower ISS groups (ISSs, 1-8, 9-15, and 16-24). CONCLUSIONS: Patients who are severely injured following traffic crash injuries in Saudi Arabia are significantly more likely to die in the hospital than comparable patients admitted to large U.S. trauma centers. Further research is needed to identify reasons for this disparity and strategies for improving the care of patients severely injured in traffic crashes in Saudi Arabia. PMID- 26613075 TI - Path following control of planar snake robots using virtual holonomic constraints: theory and experiments. AB - This paper considers path following control of planar snake robots using virtual holonomic constraints. In order to present a model-based path following control design for the snake robot, we first derive the Euler-Lagrange equations of motion of the system. Subsequently, we define geometric relations among the generalized coordinates of the system, using the method of virtual holonomic constraints. These appropriately defined constraints shape the geometry of a constraint manifold for the system, which is a submanifold of the configuration space of the robot. Furthermore, we show that the constraint manifold can be made invariant by a suitable choice of feedback. In particular, we analytically design a smooth feedback control law to exponentially stabilize the constraint manifold. We show that enforcing the appropriately defined virtual holonomic constraints for the configuration variables implies that the robot converges to and follows a desired geometric path. Numerical simulations and experimental results are presented to validate the theoretical approach. PMID- 26613077 TI - Into the eye of the storm: breast cancer's somatic mutation landscape points to DNA damage and repair. PMID- 26613078 TI - Change in the prevalence of metabolic syndrome in a population of medical students: 6-year follow-up. AB - Students of a university hospital were assessed in 2007 and later in 2013 to determine the prevalence of metabolic syndrome. Statistical analysis was done with SPSS version 17.0. A total of 213 students were evaluated in both 2007 and 2013 (48.3 % women and 51.7 % men). The diagnosis of overweight and obesity increased from 24.9 to 37.1 % (p < 0.05), central obesity from 17.8 to 28.6 % (p < 0.05), and prevalence of metabolic syndrome from 9.8 to 14.5 % (p >= 0.05); up to 20 % in male gender. It is important to implement programs for early diagnosis of metabolic syndrome. PMID- 26613076 TI - The Role of Organelle Stresses in Diabetes Mellitus and Obesity: Implication for Treatment. AB - The type 2 diabetes pandemic in recent decades is a huge global health threat. This pandemic is primarily attributed to the surplus of nutrients and the increased prevalence of obesity worldwide. In contrast, calorie restriction and weight reduction can drastically prevent type 2 diabetes, indicating a central role of nutrient excess in the development of diabetes. Recently, the molecular links between excessive nutrients, organelle stress, and development of metabolic disease have been extensively studied. Specifically, excessive nutrients trigger endoplasmic reticulum stress and increase the production of mitochondrial reactive oxygen species, leading to activation of stress signaling pathway, inflammatory response, lipogenesis, and pancreatic beta-cell death. Autophagy is required for clearance of hepatic lipid clearance, alleviation of pancreatic beta cell stress, and white adipocyte differentiation. ROS scavengers, chemical chaperones, and autophagy activators have demonstrated promising effects for the treatment of insulin resistance and diabetes in preclinical models. Further results from clinical trials are eagerly awaited. PMID- 26613079 TI - Thyroid Peroxidase Antibodies in Non-Interferon Treated Hepatitis C Patients in Pakistan. AB - OBJECTIVE: Interferon therapy of HCV infected patients is associated with development of thyroid dysfunctions. Patients with pretreatment presence of antithyroid peroxidase (TPO-Ab) are at greater risk. This study, probably the first in Pakistan, was planned to determine TPO-Ab in sera of treatment-naive local HCV patients. Setting. Centre for Nuclear Medicine (CENUM), Mayo Hospital, Lahore. PATIENTS AND METHODS: During July to December 2012, 190 patients (140 females, 50 males) newly diagnosed for HCV infection were selected for this study. Their age range was 15-55 years (mean: 35.3 +/- 9.1 years). 262 age matched healthy subjects (211 females and 50 males) were recruited as control. Serum-free thyroxin (FT4) and thyroid stimulating hormone (TSH) were detected by radioimmunoassay techniques. Serum TPO-Ab titer was determined by ELISA method using commercial kits. RESULTS: Serum FT4 and TSH levels in HCV patients and controls were within normal range. Between two groups there was no significant difference in mean value of FT4 (16.0 +/- 3.0 versus 16.2 +/- 3.9; P = 0.619) but mean TSH value was significantly lower in HCV patients (1.5 +/- 0.8 versus 1.8 +/ 0.9; P = 0.003). Among HCV patients 51 (26.8%) were TPO-Ab positive and among control subjects 18 (6.9%) were TPO-Ab positive. The difference was statistically significant (P < 0.001). Further analysis showed that among HCV patients 39 (27.8%) females and 12 (24.0%) males were TPO-Ab positive, respectively, and difference was not statistically significant (P = 0.873). Moreover, TPO-Ab positive patients were older and had significantly higher serum TSH as compared to TPO-Ab negative HCV patients. CONCLUSION: Independent of patient's gender and increasing with advancing age, about one-fourth of local untreated HCV patients are TPO-Ab positive and are at greater risk of developing thyroid disorders during and after interferon treatment. PMID- 26613080 TI - Sequence Variation in HSP40 Gene among 16 Toxoplasma gondii Isolates from Different Hosts and Geographical Locations. AB - Toxoplasma gondii with worldwide distribution has received substantial medical and scientific attentions as it causes serious clinical and veterinary problems especially for pregnant women and immunocompromised patients. Heat shock protein 40 (HSP40) plays a variety of essential roles in the pathogenesis of this protozoan parasite. In order to detail the genetic diversity of HSP40 gene, 16 T. gondii strains from different hosts and geographical locations were used in this study. Our results showed that HSP40 sequence of the examined strains was between 6621 bp and 6644 bp in length, and their A+T content was from 48.54% to 48.80%. Furthermore, sequence analysis presented 195 nucleotide mutation positions (0.12% 1.14%) including 29 positions in CDS (0.02%-0.12%) compared with T. gondii ME49 strain (ToxoDB: TGME49_265310). Phylogenetic assay revealed that T. gondii strains representing three classical genotypes (Types I, II, and III) were completely separated into different clusters by maximum parsimony (MP) method, but Type II and ToxoDB#9 strains were grouped into the same cluster. These results suggested that HSP40 gene is not a suitable marker for T. gondii population genetic research, though three classical genotypes of T. gondii could be differentiated by restriction enzymes MscI and EarI existing in amplicon C. PMID- 26613081 TI - Antileukemic Effect of Tualang Honey on Acute and Chronic Leukemia Cell Lines. AB - Complementary medicine using natural product as antitumor is on the rise. Much research has been performed on Tualang Honey and it was shown to have therapeutic potential in wound healing, and antimicrobial activity and be antiproliferative against several cancer models such as human osteosarcoma (HOS), human breast (MCF 7 and MDA-MB-231), and cervical (HeLa) cancer cell lines. To date, there was limited study on antileukemic properties of Tualang (Koompassia excelsa) Honey. The aim of this study was to evaluate the antileukemic effect of Tualang Honey on acute and chronic leukemia cell lines. Leukemia cell lines (K562 and MV4-11) and human mononuclear cell isolated from peripheral blood were grown in RPM1 1640 culture medium. The cells were incubated with increasing concentrations of Tualang Honey. After incubation, the evaluation of viability and apoptosis was performed. The morphological changes of leukemia cells were the presence of cytoplasmic blebs followed by apoptotic bodies and round shape of cells. IC50 against K562 and MV4-11 was determined. Tualang Honey gave 53.9% and 50.6% apoptosis activity on K562 and MV4-11, respectively, while on human mononuclear cell it was 37.4%. Tualang Honey has the apoptosis-inducing ability for acute and chronic myeloid leukemia (K562 and MV4-11) cell lines. PMID- 26613082 TI - Facets of Nanotechnology as Seen in Food Processing, Packaging, and Preservation Industry. AB - Nanotechnology has proven its competence in almost all possible fields we are aware of. However, today nanotechnology has evolved in true sense by contributing to a very large extent to the food industry. With the growing number of mouths to feed, production of food is not adequate. It has to be preserved in order to reach to the masses on a global scale. Nanotechnology made the idea a reality by increasing the shelf life of different kinds of food materials. It is not an entirely full-proof measure; however it has brought down the extent of wastage of food due to microbial infestation. Not only fresh food but also healthier food is being designed with the help of nano-delivery systems which act as a carrier for the food supplements. There are regulations to follow however as several of them pose serious threats to the wellbeing of the population. In coming days, newer modes of safeguarding food are going to be developed with the help of nanotechnology. In this paper, an overview has been given of the different methods of food processing, packaging, and preservation techniques and the role nanotechnology plays in the food processing, packaging, and preservation industry. PMID- 26613083 TI - Developing an International Combined Applied Surgical Science and Wet Lab Simulation Course as an Undergraduate Teaching Model. AB - BACKGROUND: Essential Skills in the Management of Surgical Cases (ESMSC) is an international, animal model-based course. It combines interactive lectures with basic ex vivo stations and more advanced wet lab modules, that is, in vivo dissections and Heart Transplant Surgery on a swine model. MATERIALS AND METHODS: Forty-nine medical students (male, N = 27, female N = 22, and mean age = 23.7 years) from King's College London (KCL) and Greek Medical Schools attended the course. Participants were assessed with Direct Observation of Procedural Skills (DOPS), as well as Multiple Choice Questions (MCQs). Paired t-test associations were used to evaluate whether there was statistically significant improvement in their performance. AIM: To evaluate the effectiveness of a combined applied surgical science and wet lab simulation course as a teaching model for surgical skills at the undergraduate level. RESULTS: The mean MCQ score was improved by 2.33/32 (P < 0.005). Surgical skills competences, as defined by DOPS scores, were improved in a statically significant manner (P < 0.005 for all paired t-test correlations). CONCLUSIONS: ESMSC seems to be an effective teaching model, which improves the understanding of the surgical approach and the basic surgical skills. In vivo models could be used potentially as a step further in the Undergraduate Surgical Education. PMID- 26613084 TI - Vitamin E Supplementation Delays Cellular Senescence In Vitro. AB - Vitamin E is an important antioxidant that protects cells from oxidative stress induced damage, which is an important contributor to the progression of ageing. Ageing can be studied in vitro using primary cells reaching a state of irreversible growth arrest called senescence after a limited number of cellular divisions. Generally, the most utilized biomarker of senescence is represented by the expression of the senescence associated beta-galactosidase (SA-beta-gal). We aimed here to study the possible effects of vitamin E supplementation in two different human primary cell types (HUVECs and fibroblasts) during the progression of cellular senescence. Utilizing an unbiased automated system, based on the detection of the SA-beta-gal, we quantified cellular senescence in vitro and showed that vitamin E supplementation reduced the numbers of senescent cells during progression of ageing. Acute vitamin E supplementation did not affect cellular proliferation, whereas it was decreased after chronic treatment. Mechanistically, we show that vitamin E supplementation acts through downregulation of the expression of the cycline dependent kinase inhibitor P21. The data obtained from this study support the antiageing properties of vitamin E and identify possible mechanisms of action that warrant further investigation. PMID- 26613086 TI - Polymorphisms Associated with Age at Onset in Patients with Moderate-to-Severe Plaque Psoriasis. AB - Psoriasis is a chronic skin disease in which genetics play a major role. Although many genome-wide association studies have been performed in psoriasis, knowledge of the age at onset remains limited. Therefore, we analyzed 173 single-nucleotide polymorphisms in genes associated with psoriasis and other autoimmune diseases in patients with moderate-to-severe plaque psoriasis type I (early-onset, <40 years) or type II (late-onset, >=40 years) and healthy controls. Moreover, we performed a comparison between patients with type I psoriasis and patients with type II psoriasis. Our comparison of a stratified population with type I psoriasis (n = 155) and healthy controls (N = 197) is the first to reveal a relationship between the CLMN, FBXL19, CCL4L, C17orf51, TYK2, IL13, SLC22A4, CDKAL1, and HLA-B/MICA genes. When we compared type I psoriasis with type II psoriasis (N = 36), we found a significant association between age at onset and the genes PSORS6, TNF alpha, FCGR2A, TNFR1, CD226, HLA-C, TNFAIP3, and CCHCR1. Moreover, we replicated the association between rs12191877 (HLA-C) and type I psoriasis and between type I and type II psoriasis. Our findings highlight the role of genetics in age of onset of psoriasis. PMID- 26613087 TI - CYP4F18-Deficient Neutrophils Exhibit Increased Chemotaxis to Complement Component C5a. AB - CYP4Fs were first identified as enzymes that catalyze hydroxylation of leukotriene B4 (LTB4). CYP4F18 has an unusual expression in neutrophils and was predicted to play a role in regulating LTB4-dependent inflammation. We compared chemotaxis of wild-type and Cyp4f18 knockout neutrophils using an in vitro assay. There was no significant difference in the chemotactic response to LTB4, but the response to complement component C5a increased 1.9-2.25-fold in knockout cells compared to wild-type (P < 0.01). This increase was still observed when neutrophils were treated with inhibitors of eicosanoid synthesis. There were no changes in expression of other CYP4 enzymes in knockout neutrophils that might compensate for loss of CYP4F18 or lead to differences in activity. A mouse model of dextran sodium sulfate colitis was used to investigate the consequences of increased C5a-dependent chemotaxis in vivo, but there was no significant difference in weight loss, disease activity, or colonic tissue myeloperoxidase between wild-type and Cyp4f18 knockout mice. This study demonstrates the limitations of inferring CYP4F function based on an ability to use LTB4 as a substrate, points to expanding roles for CYP4F enzymes in immune regulation, and underscores the in vivo challenges of CYP knockout studies. PMID- 26613085 TI - Mining for Candidate Genes Related to Pancreatic Cancer Using Protein-Protein Interactions and a Shortest Path Approach. AB - Pancreatic cancer (PC) is a highly malignant tumor derived from pancreas tissue and is one of the leading causes of death from cancer. Its molecular mechanism has been partially revealed by validating its oncogenes and tumor suppressor genes; however, the available data remain insufficient for medical workers to design effective treatments. Large-scale identification of PC-related genes can promote studies on PC. In this study, we propose a computational method for mining new candidate PC-related genes. A large network was constructed using protein-protein interaction information, and a shortest path approach was applied to mine new candidate genes based on validated PC-related genes. In addition, a permutation test was adopted to further select key candidate genes. Finally, for all discovered candidate genes, the likelihood that the genes are novel PC related genes is discussed based on their currently known functions. PMID- 26613089 TI - The European registry of quality outcomes for cataract and refractive surgery (EUREQUO): a database study of trends in volumes, surgical techniques and outcomes of refractive surgery. AB - BACKGROUND: A European web-based registry for refractive surgery was established in 2008; The European Registry of Quality Outcomes for Cataract and Refractive Surgery (EUREQUO). The aim of the registry was to improve treatment and standards of care for refractive surgery. Further aims were to offer a tool for benchmarking by establishing a reference database and for surgeons to enter and analyze their own outcomes. The purpose of this study was to characterize the registry and analyze the data collected during its first decade. METHODS: The characteristics of the web-based registry are described. Data collected from February 4(th) 2004 until June 30(th) 2014 are included in the analysis. The database is analyzed in terms of surgical technique, indications for surgery, complications, and refractive and visual outcomes. RESULTS: Data have been reported from 47 centers in 14 countries until mid-2014. About 4,000 procedures were reported annually. The most frequent procedure was laser-assisted in-situ keratomileusis (LASIK) with 11697 reported surgeries. Over time in the database, LASIK declined (p < 0.001) while photorefractive keratectomy (PRK) and refractive lens exchange (RLE) increased (p < 0.001 for both procedures). The indications for surgery, in terms of preoperative refraction and age, were stable over time, for all types of procedures. Surgical complications were reported infrequently and with a well-known relationship to the type of surgical procedure. The reported refractive outcomes were good. The visual outcomes indicate a significant increase of visual acuity after high myopia treatment by phakic intraocular lens in the anterior (phakic IOL AC) and the posterior (phakic IOL PC) chamber and a poorer visual outcome, after both myopia and hyperopia treatment, by epithelial LASIK (Epi-LASIK). CONCLUSIONS: We describe the establishment of a European registry for refractive surgery. The database increases at a rate of approximately 4000 refractive procedures per year. The most frequent procedure is LASIK, but both PRK and RLE are an increasing part of the reported procedures. The indications for surgery have been stable over time. Surgical complications and visual outcome vary, depending on the type of surgery. PMID- 26613088 TI - Fludarabine- (C2-methylhydroxyphosphoramide)- [anti-IGF-1R]: Synthesis and Selectively "Targeted"Anti-Neoplastic Cytotoxicity against Pulmonary Adenocarcinoma (A549). AB - INTRODUCTION: Many if not most conventional small molecular weight chemotherapeutics are highly potent against many forms of neoplastic disease. Unfortunately, majority of an administered dose unintentionally diffuses passively into normal tissues and healthy organ systems following intravenous administration. One strategy for both increasing potency and reducing dose limited sequela is the selective "targeted" delivery of conventional chemotherapeutic agents. MATERIALS AND METHODS: The fludarabine-(C2- methylhydroxyphosphoramide)-[anti-IGF-1R] was synthesized by initially reacting fludarabine with a carbodiimide to form a fludarabine carbodiimide phosphate ester intermediate that was subsequently reacted with imidazole to create an amine-reactive fludarabine- (C2-phosphorylimidazolide) intermediate. Monoclonal anti-IGF-1R immunoglobulin was combined with the amine-reactive fludarabine- (C2 phosphorylimidazolide) intermediate resulting in the synthesis of covalent fludarabine-(C2-methylhydroxyphosphoramide)- [anti-IGF-1R] immunochemotherapeutic. Residual fludarabine and un-reacted reagents were removed by serial microfiltration (MWCO 10,000) and monitored by analytical-scale HP-TLC. Retained IGF-1R binding-avidity of fludarabine-(C2- methylhydroxyphosphoramide) [anti-IGF-1R] was established by cell-ELISA using pulmonary adenocarcinoma cell (A549) which over-expresses IGF-1R and EGFR. Anti-neoplastic cytotoxic potency of fludarabine-(C2-methylhydroxyphosphoramide)-[anti- IGF-1R] was determined against pulmonary adenocarcinoma (A549) using an MTT-based vitality stain methodology. RESULTS: The fludarabine molar-incorporation-index for fludarabine- (C2 methylhydroxyphosphoramide)-[anti-IGF-R1] was 3.67:1 while non-covalently bound fludarabine was not detected by analytical scale HP-TLC following serial micro filtration. Size-separation fludarabine-(C2-methylhydroxyphosphoramide)-[anti- IGF-1R] by SDS-PAGE with chemo luminescent autoradiography detected only a single 150-kDa band. Cell-ELISA of fludarabine- (C2-methylhydroxyphosphoramide)-[anti IGF-1R] measuring total immunoglobulin bound to exterior surface membranes of pulmonary adenocarcinoma (A549) increased with elevations in immunoglobulin equivalent concentrations of the covalent fludarabine immunochemotherapeutic. Between the fludarabine-equivalent concentrations of 10-10 M and 10-5 M both fludarabine-(C2- methylhydroxyphosphoramide)-[anti-IGF-1R] and fludarabine had ex vivo anti-neoplastic cytotoxic potency levels that increased rapidly between the fludarabine-equivalent concentrations of 10-6 M and 10-5 M where cancer cell death percentages increased from 24.4% to a maximum of 94.7% respectively. CONCLUSION: The molecular design and organic chemistry reaction schemes were developed for synthesizing fludarabine-(C2- methylhydroxyphosphoramide)-[anti-IGF 1R] which possessed both properties of selective "targeted" delivery and anti neoplastic cytotoxic potency equivalent to fludarabine chemotherapeutic. PMID- 26613090 TI - Outer retinal tubulation in diabetic macular edema following anti-VEGF treatment. AB - BACKGROUND: To address the presence and features of outer retinal tubulation (ORT) found in diabetic macular edema (DME) treated with anti-vascular endothelial growth factor (anti-VEGF) and to differentiate between ORT and cystoid DME, which have different plans of management. METHODS: This was a retrospective review of a total of 514 patients investigated with spectral domain optical coherence tomography (OCT) in patients with diabetic macular edema treated with anti-VEGF. ORT was seen in 12 eyes of 11 patients. The morphologic characteristics of ORT and its progress over time were examined using OCT data. The retinal images were obtained by horizontal and vertical scans to analyze the possible presence of ORT and to explore their morphologic features and location in the retinal layers. RESULTS: ORT was seen in DME treated with anti-VEGF. ORT was shown as round or ovoid hyporeflective spaces with hyperreflective borders on the B-scans, measuring 30 to 120 MUm high and 30 to 1775 MUm wide. The tubules generally remained stable over time. In a retinal practice specializing in advanced diabetic retinopathy clinic, this ORT was seen in 12 eyes of 11 patients during a 12-month period. ORT presented either after receiving 0.05 mL open-label intravitreal injections of 0.5 mg ranibizumab or 1.25 mg bevacizumab. CONCLUSION: ORT is found in DME treated with anti-VEGF that may show damage to the outer retina secondary to the severity and chronicity of the DME. ORT may be a result of underlying chronic and severe diabetic macular edema that may occur later possibly secondary to retinal layers rearrangement after several anti-VEGF injections. It is important to differentiate between ORT and cystoids DME. The presence of the ORT entity alone without the presence of DME does not require further anti-VEGF re-injections. PMID- 26613091 TI - An experimental model of vitreous motion induced by eye rotations. AB - BACKGROUND: During eye rotations the vitreous humour moves with respect to the eye globe. This relative motion has been suggested to possibly have an important role in inducing degradation of the gel structure, which might lead to vitreous liquefaction and/or posterior vitreous detachment. Aim of the present work is to study the characteristics of vitreous motion induced by eye rotations. METHODS: We use an experimental setup, consisting of a Perspex model of the vitreous chamber that, for simplicity, is taken to have a spherical shape. The model is filled with an artificial vitreous humour, prepared as a solution of agar powder and hyaluronic acid sodium salt in deionised water, which has viscoelastic mechanical properties similar to those of the real vitreous. The model rotates about an axis passing through the centre of the sphere and velocity measurements are taken on the equatorial plane orthogonal to the axis of rotation, using an optical technique. RESULTS: The results show that fluid viscoelasticity has a strong influence on flow characteristics. In particular, at certain frequencies of oscillation of the eye model, fluid motion can be resonantly excited. This means that fluid velocity within the domain can be significantly larger than that of the wall. CONCLUSIONS: The frequencies for which resonant excitation occurs are within the range of possible eye rotations frequencies. Therefore, the present results suggest that resonant excitation of vitreous motion is likely to occur in practice. This, in turn, implies that eye rotations produce large stresses on the retina and within the vitreous that may contribute to the disruption of the vitreous gel structure. The present results also have implications for the choice of the ideal properties for vitreous substitute fluids. PMID- 26613092 TI - Aviremia 10 Years Postdiscontinuation of Antiretroviral Therapy Initiated During Primary Human Immunodeficiency Virus-1 Infection and Association With Gag Specific T-Cell Responses. AB - Combination antiretroviral therapy during primary human immunodeficiency virus-1 infection may enable long-term drug-free virological control in rare individuals. We describe a female who maintained aviremia and a normal CD4(+)/CD8(+) T cell ratio for 10 years after stopping therapy, despite a persistent viral reservoir. Cellular immune responses may have contributed to this outcome. PMID- 26613093 TI - FCGR2A and FCGR3A Genotypes in Human Immunodeficiency Virus Mother-to-Child Transmission. AB - Background. Fc-mediated effector functions have been suggested to influence human immunodeficiency virus (HIV) acquisition and disease progression. Analyzing the role of host Fc gamma receptor (FcgammaR) polymorphisms on HIV outcome in mother-to-child transmission (MTCT) will increase our understanding of how host genetics may alter immune responses in prevention, therapy, and disease. This study analyzed the impact of FCGR2A and FCGR3A genotypes on MTCT in a cohort in which Fc-mediated antibody functions are predictive of infant HIV outcome. Methods. Human immunodeficiency virus-positive mothers and their infants from a historical MTCT cohort were genotyped for FCGR2A and FCGR3A. We assessed the impact of these genotypes on transmission and acquisition of HIV and disease progression using chi(2) tests, survival analyses, and logistic regression. Results. Among 379 mother-infant pairs, infant FCGR2A and FCGR3A genotypes were not associated with infant HIV infection or disease progression. Maternal FCGR2A was not associated with transmission, but there was a trend between maternal FCGR3A genotype and transmission (P = .07). When dichotomizing mothers into FCGR3A homozygotes and heterozygotes, heterozygotes had a 64.5% higher risk of transmission compared with homozygotes (P = .02). This risk was most evident in the early breastfeeding window, but a trend was only observed when restricting analyses to breastfeeding mothers (hazards ratio, 1.64; P = .064). Conclusions. Infant FCGR2A and FCGR3A genotypes were not associated with HIV infection or disease progression, and, thus, host FcgammaR genotype may not significantly impact vaccination or therapeutic regimens that depend on Fc-mediated antibody functions. Maternal FCGR3A genotype may influence early breastfeeding transmission risk, but more studies should be conducted to clarify this association and its mechanism. PMID- 26613094 TI - Cytomegalovirus Genotype Distribution Among Congenitally and Postnatally Infected Patients: Association of Particular Glycoprotein (g)B and gN Types With Symptomatic Disease. AB - Background. Human cytomegalovirus is a leading cause of congenital infection, and there are limited data on prognosis markers in disease development. We aimed to study 3 virology targets (glycoprotein [g]B, gN, and UL144) to assess their correlation with congenital infection and various organ system involvement. Methods. Forty-eight congenital cases and 58 postnatally infected children were included (2003-2014). Genotyping for the 3 targets and distribution among the cohorts were investigated, and the relationship between the gB, gN, and UL144 types with clinical manifestations in congenital infection was also studied. Results. All of the genotypes were similarly represented among cohorts, and the most prevalent were the UL144B, gB1, and gN1 genotypes. The gB2 genotype was associated with abnormal image findings by ultrasound and/or magnetic resonance in congenital infection (odds ratio [OR], 6.2; 95% confidence interval [CI], 1.1 34.3; P = .036); the gN1 genotype was associated with an elevated risk of developing neurological disorders (OR, 7.0; 95% CI, 1.1-45.9; P = .043). Both gN1 and gB2 were independent factors for symptomatic infection. Statistical analyses showed no association between any UL144 genotype and disease severity. Conclusions. All of the genotypes can be involved in congenital infection, although the gB2 and gN1 genotypes might be associated with a more serious illness. PMID- 26613095 TI - Self-Collected Nasal Swabs for Respiratory Virus Surveillance. AB - We tested whether 135 patients reporting acute respiratory illness (ARI) could self-collect nasal swab specimens and ship them for laboratory testing. Most subjects (78.2%) collected and shipped their specimens without errors; 10.5% excluded >=1 packing components; 12.9% made >=1 packing errors. Self-swabbing at home is feasible for confirming ARI etiology. PMID- 26613096 TI - Optimizing Human Immunodeficiency Virus Testing Interventions for Men Who Have Sex With Men in the United States: A Modeling Study. AB - Background. In the United States, public health recommendations for men who have sex with men (MSM) include testing for human immunodeficiency virus (HIV) at least annually. We model the impact of different possible HIV testing policies on HIV incidence in a simulated population parameterized to represent US MSM. Methods. We used exponential random graph models to explore, among MSM, the short-term impact on baseline (under current HIV testing practices and care linkage) HIV incidence of the following: (1) increasing frequency of testing; (2) increasing the proportion who ever test; (3) increasing test sensitivity; (4) increasing the proportion of the diagnosed population achieving viral suppression; and combinations of 1-4. We simulated each scenario 20 times and calculated the median and interquartile range of 3-year cumulative incidence of HIV infection. Results. The only intervention that reduced HIV incidence on its own was increasing the proportion of the diagnosed population achieving viral suppression; increasing frequency of testing, the proportion that ever test or test sensitivity did not appreciably reduce estimated incidence. However, in an optimal scenario in which viral suppression improved to 100%, HIV incidence could be reduced by an additional 17% compared with baseline by increasing testing frequency to every 90 days and test sensitivity to 22 days postinfection. Conclusions. Increased frequency, coverage, or sensitivity of HIV testing among MSM is unlikely to result in reduced HIV incidence unless men diagnosed through enhanced testing programs are also engaged in effective HIV care resulting in viral suppression at higher rates than currently observed. PMID- 26613097 TI - Tuberculosis Incidence and Risk Factors Among Human Immunodeficiency Virus (HIV) Infected Adults Receiving Antiretroviral Therapy in a Large HIV Program in Nigeria. AB - Background. Despite the benefits of antiretroviral therapy (ART), tuberculosis (TB) is the leading cause of mortality among human immunodeficiency virus (HIV) infected persons in Africa. Nigeria bears the highest TB burden in Africa and second highest HIV burden globally. This long-term multicenter study aimed to determine the incidence rate and predictors of TB in adults in the Harvard/AIDS Prevention Initiative in Nigeria (APIN) and President's Emergency Plan for AIDS Relief (PEPFAR) Nigeria ART program. Methods. This retrospective evaluation used data collected from 2004 to 2012 through the Harvard/APIN PEPFAR program. Risk factors for incident TB were determined using multivariate Cox proportional hazards regression with time-dependent covariates. Results. Of 50 320 adults enrolled from 2005 to 2010, 11 092 (22%) had laboratory-confirmed active TB disease at ART initiation, and 2021 (4%) developed active TB after commencing ART. During 78 228 total person-years (PY) of follow-up, the TB incidence rate was 25.8 cases per 1000 PY (95% confidence interval [CI], 24.7-27.0) overall, and it decreased significantly both with duration on ART and calendar year. Risk factors at ART initiation for incident TB included the following: earlier ART enrollment year, tenofovir-containing initial ART regimen, and World Health Organization clinical stage above 1. Time-updated risk factors included the following: low body mass index, low CD4(+) cell count, unsuppressed viral load, anemia, and ART adherence below 80%. Conclusions. The rate of incident TB decreased with longer duration on ART and over the program years. The strongest TB risk factors were time-updated clinical markers, reinforcing the importance of consistent clinical and laboratory monitoring of ART patients in prompt diagnosis and treatment of TB and other coinfections. PMID- 26613098 TI - Spontaneous parkinsonisms and striatal impairment in neuroleptic free youth at ultrahigh risk for psychosis. AB - BACKGROUND: Spontaneous movement abnormalities, occurring independent of medication status, are thought to reflect basal ganglia pathology in patients at ultrahigh risk (UHR) for psychosis. To date, the research literature has primarily focused on movements associated with elevated striatal dopamine (i.e., hyperkinesia) while little is known about motor symptoms associated with low levels of subcortical dopamine (i.e., spontaneous parkinsonisms; SPs). As SPs (e.g., bradykinesia) may be governed by distinct neural mechanisms, this line of research can provide a clearer picture of the etiological processes in the prodrome. AIMS: To examine SPs and striatal structural correlates in youth at risk for psychosis. METHODS: A total of 81 (35 UHR, 46 healthy controls) adolescents were administered a structured clinical interview, structural MRI scan, and handwriting kinematic analysis capable of assessing SPs that are not detectable by traditional observer-based inventories. RESULTS: The UHR group exhibited significant decreased velocity scaling (indicative of SPs), t(79) = 2.65, P <= 0.01, as well as decreased ipsilateral t(68) = -3.16, P <= 0.001 and contralateral t(68) = -3.32, P <= 0.001 putamen volume compared with the healthy control group. Further, decreased velocity scaling was significantly associated with smaller ipsilateral putamen r(68) = 0.23, P <= 0.05, 95% confidence interval (CI) (-0.005, 0.44), left r(68) = 0.23, P <= 0.05, 95% CI (-0.005, 0.44) and right r(68) = 0.21, P <= 0.05, 95% CI (-0.03, 0.42) caudate volume, as well as increased positive r(79) = - 0.20, P = 0.05, 95% CI (-0.40, - 0.02) and negative r(79) = - 0.27, P <= 0.05, 95% CI (-0.46, -0.06) symptoms across the sample. CONCLUSIONS: These findings represent the first evidence for hypokinetic movement abnormalities in the UHR period, indicating that pathophysiological processes in UHR patients may also involve hypodopaminergia. The results implicate a dopamine induced imbalance contributing to frontal-subcortical circuit dysfunction in the psychosis prodrome. PMID- 26613100 TI - A Novel Multiobjective Control of DVR to Enhance Power Quality of Sensitive Load. AB - The Dynamic Voltage Restorer (DVR) is one of the fast, flexible, and cost effective solutions available in compensating the voltage-related power quality problems in power distribution systems. In this paper is discussed how power quality enhancement of sensitive load is achieved by applying three versions of Autonomous Group Particle Swarm Optimization like AGPSO1, AGPSO2, and AGPSO3 for tuning the Proportional-Integral DVR controller under balanced and nonlinear load conditions. A novel multiobjective function is formulated to express the control performance of the system, which is quantified using three power quality indices such as Total Harmonic Distortion (THD), voltage sag index, and RMS voltage variation. The obtained results are compared with the Proportional-Integral (PI) controller tuned by Ziegler-Nichols (ZN) method and also by Simple Particle Swarm Optimization based PI controlled DVR. The proposed methodology has improved the performance in terms of the considered power quality indices and the simulation has been carried out in MATLAB/Simulink environment. PMID- 26613099 TI - Dialogue on economic choice, learning theory, and neuronal representations. AB - In recent years, two distinct lines of work have focused on the substrates of associative learning and on the mechanisms of economic decisions. While experiments often focused the same brain regions - most notably the orbitofrontal cortex - the two literatures have remained largely distinct. Here we engage in a dialogue with the intent to clarify the relationship between the two frameworks. We identify a potential correspondence between the concept of outcome defined in learning theory and that of good defined in neuroeconomics, and we specifically discuss the concept of value defined in the two frameworks. While many differences remain unresolved, a common idea is that good/outcome values are subjective, devaluation-sensitive and computed on the fly, not "cached" or pre computed. PMID- 26613101 TI - Enhanced High Performance Power Compensation Methodology by IPFC Using PIGBT IDVR. AB - Currently, power systems are involuntarily controlled without high speed control and are frequently initiated, therefore resulting in a slow process when compared with static electronic devices. Among various power interruptions in power supply systems, voltage dips play a central role in causing disruption. The dynamic voltage restorer (DVR) is a process based on voltage control that compensates for line transients in the distributed system. To overcome these issues and to achieve a higher speed, a new methodology called the Parallel IGBT-Based Interline Dynamic Voltage Restorer (PIGBT-IDVR) method has been proposed, which mainly spotlights the dynamic processing of energy reloads in common dc-linked energy storage with less adaptive transition. The interline power flow controller (IPFC) scheme has been employed to manage the power transmission between the lines and the restorer method for controlling the reactive power in the individual lines. By employing the proposed methodology, the failure of a distributed system has been avoided and provides better performance than the existing methodologies. PMID- 26613102 TI - Modeling and Simulation of Control Actuation System with Fuzzy-PID Logic Controlled Brushless Motor Drives for Missiles Glider Applications. AB - A control actuation system has been used extensively in automotive, aerospace, and defense applications. The major challenges in modeling control actuation system are rise time, maximum peak to peak overshoot, and response to nonlinear system with percentage error. This paper addresses the challenges in modeling and real time implementation of control actuation system for missiles glider applications. As an alternative fuzzy-PID controller is proposed in BLDC motor drive followed by linkage mechanism to actuate fins in missiles and gliders. The proposed system will realize better rise time and less overshoot while operating in extreme nonlinear dynamic system conditions. A mathematical model of BLDC motor is derived in state space form. The complete control actuation system is modeled in MATLAB/Simulink environment and verified by performing simulation studies. A real time prototype of the control actuation is developed with dSPACE 1104 hardware controller and a detailed analysis is carried out to confirm the viability of the proposed system. PMID- 26613103 TI - The Effects of Interpregnancy Intervals and Previous Pregnancy Outcome on Fetal Loss in Rwanda (1996-2010). AB - In 2005, a WHO consultation meeting on pregnancy intervals recommended a minimum interval of 6 months after a pregnancy disruption and an interval of two years after a live birth before attempting another pregnancy. Since then, studies have found contradictory evidence on the effect of shorter intervals after a pregnancy disruption. A binary regression analysis on 21532 last pregnancy outcomes from the 2000, 2005, and 2010 Rwanda Demographic and Health Surveys was done to assess the combined effects of the preceding pregnancy outcome and the interpregnancy intervals (IPIs) on fetal mortality in Rwanda. Risks of pregnancy loss are higher for primigravida and for mothers who lost the previous pregnancy and conceived again within 24 months. After a live birth, interpregnancy intervals less than two years do not increase the risk of a pregnancy loss. This study also confirms higher risks of fetal death when IPIs are beyond 5 years. An IPI of longer than 12 months after a fetal death is recommended in Rwanda. Particular attention needs to be directed to postpregnancy abortion care and family planning programs geared to spacing pregnancies should also include spacing after a fetal death. PMID- 26613104 TI - Experiential Learning in Kinesiology: A Student Perspective. AB - OVERVIEW: Service learning is a form of experiential learning that pairs academic educational experiences and community organizations to promote training, civic engagement, and meaningful service by students to their community. Kinesiology programs have moved toward increasing experiential and service learning options in health promotion for their students, but few have evaluated the student perceptions of these programs. PURPOSE: The purpose of the current study was to conduct a qualitative evaluation of a service learning course for Kinesiology majors located in a low-income urban area. METHODS: Ten recent graduates of a department of Kinesiology were enrolled in focus groups, stratified by gender, facilitated by a graduate research assistant not affiliated with their school. Focus group discussions were audiotaped, transcribed and analyzed for themes. RESULTS: Nine themes were identified including: (1) Personal and professional experience, (2) decision to participate, (3) location decision, (4) self efficacy, (5) perceptions of program members, (6) social interaction, (7) personal and program communication, (8) physical facilities and (9) program outcomes. Students positively evaluated the learning experience as valuable to their personal and professional development; noted changes in their perceptions of low-income communities and increases to self-efficacy and skill acquisition from the beginning to the end of the course; and observed significant needs and improvements in physical, emotional and social outcomes of community members. CONCLUSIONS: This study demonstrated multiple and varied benefits of a service learning program for Kinesiology students. On-going evaluation of service learning programs in health promotion is needed to enhance student and community outcomes. PMID- 26613105 TI - SMiRK: an Automated Pipeline for miRNA Analysis. AB - BACKGROUND: Micro RNAs (miRNAs), important regulators of cell function, can be interrogated by high-throughput sequencing in a rapid and cost-effective manner. However, the tremendous amount of data generated by such methods is not easily analyzed. In order to extract meaningful information and draw biological conclusions from miRNA data, many challenges in quality control, alignment, normalization, and analysis must be overcome. Typically, these would only be possible with the dedicated efforts of a specialized computational biologist for a sustained period of time. RESULTS: Here, we present SMiRK, an automated pipeline that allows such tasks to be completed with minimal time and without dedicated bioinformatics personnel. SMiRK's flexibility also allows experienced users to exert more control, if they wish. We describe how SMiRK automatically normalizes the data, removes low-information miRNAs, and produces heatmaps of the processed data. We give details on SMiRK's implementation and use cases for novice and advanced users. As a demonstration of its capabilities, SMiRK was used to rapidly and automatically analyze a dataset taken from the literature. CONCLUSION: SMiRK is a useful and efficient tool that can be used by investigators at multiple skill levels. Those who lack bioinformatics training can use it to easily and automatically analyze their data, while those with experience will find it beneficial to not need to write tools from scratch. PMID- 26613106 TI - Icatibant Use in Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema. PMID- 26613107 TI - Alexander Whitehill Clowes, M.D. (1947-2015): The Strength of Innovative Thinking. PMID- 26613108 TI - Retraction Note to: Preference for immediate reinforcement over delayed reinforcement: relation between delay discounting and health behavior. AB - Retraction Note to: J Behav Med (2013) 36:34-43DOI 10.1007/s10865-012-9399-z. At the request of Kevin Larkin, this article has been retracted due to research misconduct of Shane Melanko. Mister Melanko was solely responsible for the actions that resulted in the retraction of this article, and Dr. Larkin was unaware of his actions until after the article was published. No other published work was implicated during the investigation of research misconduct, and any data collected by Mr. Melanko for other studies have been discarded and will not be analyzed or published. The online version of the original article can be found under doi:10.1007/s10865-012-9399-z. The first retraction note of the article can be found under doi:10.1007/s10865-014-9602-5. PMID- 26613109 TI - MicroRNA: A Newcomer to Biological Science. PMID- 26613110 TI - [54-year old woman with diffuse back pain]. PMID- 26613111 TI - [Dealing with adverse incidents]. PMID- 26613112 TI - [In the footsteps of fathers]. PMID- 26613113 TI - [In the army: Service at station and in the field hospital]. PMID- 26613114 TI - Clinical and neuroimaging characterization of two C9orf72-positive siblings with amyotrophic lateral sclerosis and schizophrenia. PMID- 26613116 TI - Understanding the pathology and treatment of traumatic brain injury and posttraumatic stress disorder: a therapeutic role for hyperbaric oxygen therapy. AB - Traumatic brain injury (TBI) is an intracranial injury caused by external trauma leading to different degrees of brain damage. TBI can cause a wide array of symptoms and range in severity from concussion to coma and death. The link between TBI and posttraumatic stress disorder (PTSD) has received increasing attention due to the high incidence of these conditions in soldiers returning from recent conflicts. TBI has been associated with an increased risk of PTSD. Additionally, TBI and PTSD often demonstrate overlapping symptoms. In this article, we discuss the different forms of TBI and their links to PTSD. We also discuss current therapies for TBI and PTSD, in particular detailing the therapeutic potential of hyperbaric oxygen therapy in the management of these conditions. PMID- 26613117 TI - Discovery of Small Molecules for Fluorescent Detection of Complement Activation Product C3d. AB - Complement activation plays a major role in many acute and chronic inflammatory conditions. C3d, a terminal product of complement activation, remains covalently attached to cells and is an excellent biomarker of complement-mediated inflammation. We employed a virtual high-throughput screening protocol to identify molecules with predicted binding to complement C3d and with intrinsic fluorescence properties to enable detection. Pharmacophore models were developed based on known C3d-ligand interactions and information from computational analysis of structural and molecular dynamics data. Iterative pharmacophore-based virtual screening was performed to identify druglike molecules with physicochemical similarity to the natural C3d ligand CR2. Hits from the pharmacophore screens were docked to C3d and ranked based on predicted binding free energies. Top-ranked molecules were selected for experimental validation of binding affinity to C3d, using microscale thermophoresis, and for their suitability to become molecular imaging agents, using fluorescence spectroscopy. This work serves as a foundation for identifying additional fluorescent molecules with high-affinity for C3d that will subsequently be explored as noninvasive in vivo diagnostics of complement-mediated inflammation, for spatiotemporal monitoring of disease progression, and for targeting therapeutics to sites of inflammation. PMID- 26613118 TI - Cost-effectiveness analysis of second-line tyrosine kinase inhibitor treatment for chronic myelogenous leukemia. AB - AIM: A cost-effectiveness analysis was performed for sequential treatments of chronic myelogenous leukemia (CML) with tyrosine kinase inhibitors (TKIs) after failure of 1st line imatinib, from a commercial payer perspective in the US. METHODS: A Markov model was developed to simulate lifetime treatment costs and health outcomes for TKI sequences for treatment of patients resistant or intolerant to 1st-line imatinib. Five health states were included, chronic phase 2nd-line TKI, chronic phase 3rd-line TKI, chronic phase post-TKI, advanced phases, and death. Efficacy (response achievement, loss of response, transformation, death) and safety (adverse events incidence, discontinuation) data are based on clinical trials. Resource utilization, costs, and utilities were based on product labels and publically available data. Uncertainty analyses were conducted for key inputs. RESULTS: In patients failing imatinib, dasatinib initiating treatment sequences provide the most survival (DeltaLYs = 0.2-2.0), QALYs (DeltaQALYs = 0.2-1.9), and accrue highest CML-related costs (DeltaCosts = $64,000-$222,000). The average ICER per QALY for dasatinib- vs imatinib initiating sequences is $100,000 for an imatinib-resistant population. The average ICER per QALY for dasatinib- vs nilotinib-initiating sequences is $170,000 for an imatinib-resistant population, and $160,000 for an imatinib intolerant population. CONCLUSIONS: This analysis suggests that dasatinib is associated with increased survival and quality of life compared to high dose imatinib and to a smaller extent with nilotinib, among patients resistant or intolerant to 1st-line imatinib, primarily based on higher cytogenetic response rates observed in clinical studies of dasatinib. Head-to-head studies of sequential use of dasatinib and nilotinib are needed to validate the model findings of improved survival (LYs) with better quality-of-life (QALYs) for patients initiating dasatinib in 2nd-line. However, the model findings (in light of higher cytogenetic response rates with dasatinib) are supported by other studies showing improved quality-of-life for responders, and improved survival for patients achieving cytogenetic response. PMID- 26613120 TI - Physical/Chemical Treatment of Organically Contaminated Soils and Sediments. PMID- 26613119 TI - Natural products, micronutrients, and nutraceuticals for the treatment of depression: A short review. AB - OBJECTIVES: Depression is one of the most common psychiatric disorders, and the fourth leading cause of long-term disability throughout the world. Despite the availability of different classes of antidepressant drugs, most of them are not completely effective and above all are associated with many serious adverse effects. Recently, accumulating evidence suggests that dietary supplements rich in important phytochemicals possess beneficial therapeutic roles in depression. METHODS: In this review, we will first consider what is known about the pathogenesis of depression and discuss the need for more safe and efficacious treatment. We will then review the potential clinical relevance of natural plant derived products based on data derived from pre-clinical animal studies, randomized controlled studies and placebo-controlled trials published on this topic within the last decade. RESULTS: Among the natural compounds that show antidepressive-like activity, green tea catechins have been shown to decrease depressive symptoms in experimental animals, possibly in part through the inhibition of monoamine oxidase (MAO). Anthocyanins and their aglycons, responsible for the typical color of berries, inhibit MAO isoforms A or B with IC50 values corresponding to the micromolar range. Other studies suggest that cocoa extracts, whose main components are procyanidins, attenuate depressive symptoms in rats. Resveratrol, one of the most important natural stilbenoid, inhibits noradrenaline and serotonin reuptake in rats, and significantly decreases anxiety/depressive behaviours while increasing hippocampal serotonin and noradrenaline levels. Trans-resveratrol possesses MAO-A inhibitory effects in different brain areas, particularly in the frontal cortex and hippocampus, as already reported for tea catechins. Although these effects have been documented in rodent models, further randomized controlled trials in this area are warranted. However, so far, there is only correlative evidence between certain nutrients, such as omega-3 polyunsaturated fatty acids and B vitamins, and depression in human population studies. DISCUSSION: Growing evidence suggests that consumption of these compounds may represent an alternative strategy to delay the onset and progression of depression, and depressive-like symptoms. However, further randomized and placebo-controlled trials are necessary to confirm the potential of these compounds as a possible remedy for this debilitating disorder. PMID- 26613121 TI - An Indicator of Solid Waste Generation Potential for Illinois Using Principal Components Analysis and Geographic Information Systems. AB - An indicator of solid waste generation potential (SWGP) is proposed as a versatile means to assist the development of integrated solid waste (SW) management plans. The proposed indicator is based on key sodoeconomic variables for the State of Illinois which were found to be highly correlated with variables describing the SW stream of the State. The proposed indicator was derived by applying the principal components analysis (PCA) technique. The technique is used to merge the rank transformed socioeconomic variables into a single variable, the SWGP indicator, while maintaining the regional information of the original variables. An innovative aspect of this indicator approach is the use of the ordinal scale for all these diverse variables. The validity of this approach was assessed and the proposed indicator was found to be directly proportional to a composite variable describing the SW stream for the State of Illinois. The use of Geographic Information Systems (GIS) to depict the spatial distribution of the SWGP will help planners visualize the expected overall refuse generation pattern and to identify critical regions. In addition, the proposed indicator could be used as an instrument to validate the solid waste generation (SWG) quantities reported by counties to state agencies. PMID- 26613122 TI - Thermal Immobilization of Lead Contaminants in Soils Treated in a Fixed- and Fluidized-Bed Incinerator at Moderate Temperatures. AB - Artificially lead-contaminated soils with different lead contents (200, 450, 600, and 900 ppm) were thermally immobilized in both fixed-bed and fluidized-bed modes at moderate treating temperatures (less than 500 degrees C) for various retention times. Cement powder and brick powder were added to the artificially contaminated soils to enhance lead immobilization. Results indicate that increasing treating temperature and time increases the extent of lead immobilization, as determined by the U.S. Environmental Protection Agency's (U.S. EPA) Toxicity Characteristics Leachability Procedure (TCLP). The percentage of lead leached from the soil/ cement mixtures was in the range of less than 0.251%, compared with the range between 13.6% and 40.7% for the corresponding soil/brick mixtures. As the amount of brick dust added to the Pb-doped soil was increased, the specific Pb immobilization effectiveness increased from 0.0675 to 0.149 mg Pb/g brick (for the 20- and 50-gram brick addition, respectively). An increase in air flow rate from 2 to 40 L/min caused a slight decrease in the Pb leaching percentage from 14.96% to 11.59%. Both the Freundlich and Langmuir isotherms give a satisfactory fit (r = 0.945 ~ 0.998) for the data derived from a TCLP test of the thermally-treated soil samples (105 degrees C and 500 degrees C) that contained lead contaminants. Sorption of lead contaminants in soil and sorbent matrices was the primary type of chemisorption. The kinetic results indicated that the Pb-doped soil system was too complicated to be described by a simple calculation. PMID- 26613123 TI - Identification of Candidate Clean Air Corridors for the Colorado Plateau. AB - The U.S. Clean Air Act, amended in 1990, mandated the establishment of the Grand Canyon Visibility Transport Commission (GCVTC). The commission is required to submit a report to the U.S. Environmental Protection Agency addressing visibility issues in the region, including "the establishment of clean air corridors, in which additional restrictions on increases in emissions may be appropriate to protect visibility in affected Class I areas." This paper presents a methodology to identify candidate geographic areas for consideration for Clean Air Corridor (CAC) status for Colorado Plateau Class I areas. The methodology uses thousands of model determined trajectories over a five year period (1988 to 1992) to indicate the paths taken by air that arrives during clean air conditions at Class I areas. These clean air back-trajectories identify upwind areas where pollution emissions could jeopardize currently pristine visibility. Using this methodology, six candidate areas are identified, ranging in size from 75,000 to 506,000 square miles, and permitting varying levels of visibility protection for clean air days at Grand Canyon, Canyonlands, and Petrified Forest National Parks. Assuming effective emissions management of the CAC, the larger the CAC, the greater the visibility protection during clean air conditions. PMID- 26613124 TI - Characterization of Airborne Dust from Two Nonferrous Foundries by Physico chemical Methods and Multivariate Statistical Analyses. AB - Airborne particulate matter was sampled at a copper smelter and at an aluminum casting plant. Size, shape, quantity, and microlocalization of chemical species in the particulates were measured using closed cassettes, cascade impactors, scanning electron microscopy, X-ray diffraction, infrared and atomic absorption spectrophotometries, secondary ion mass spectrometry, and photoelectron spectroscopy. Cluster and principal components analyses were used in interpreting results. Aerosol chemistry varies as a function of size, and composition becomes more complex as the aerosol size drops into the respirable fraction and lower. Surface chemical properties are evidenced where, generally, volatile species are enriched. A few site-specific elements and characteristics were identified. The formation of particulates may often be related to process and practices, yet the actual distribution of species in the air remains an intricate matter. PMID- 26613125 TI - Treatment of Halogenated Organic Vent Streams for the Reduction of Air Emissions. AB - This work presents a three-stage treatment system to process halogenated organic vent streams for compliance with the Hazardous Organic NESHAP (HON) Rule. The three stages are incineration, energy recovery, and wet scrubbing. In particular, this work concentrates on the design of the scrubber, which the HON Rule states must remove at least 99% of any halogens or hydrogen halides generated during the combustion step. Computerized process simulation was found to be ineffective in designing a scrubber for this application, so laboratory data on the partial pressure of the hydrogen halide species over aqueous solutions was employed. The number of overall gas transfer units required for 99% removal was found to be slightly less than 5, and the overall gas transfer unit height was found to be approximately 0.5 m. PMID- 26613126 TI - EPA SITE Emerging Technology Program: COGNIS TERRAMET(r) Lead Extraction Process. AB - Under a cooperative agreement with the U.S. Environmental Protection Agency's (USEPA) Superfund Innovative Technology Evaluation (SITE) Emerging Technology Program, COGNIS, Inc. conducted bench-scale studies on the COGNIS TERRAMET(r) Lead Extraction Process. The process leaches, or extracts, lead from contaminated soil and consists of a lead leaching stage followed by recovery of the dissolved lead from the leachant. Prior to treatment, the soil is characterized, the type and extent of lead contamination is identified, and the soil is pretreated by physical separation methods to facilitate the extraction process. The physical pretreatment, for example, may include particle size separation to allow separate leaching of the sand and fines fractions and removal of larger lead particles by density separation techniques. As part of the SITE Program, COGNIS investigated seven different lead-contaminated soil samples in small bench-scale batch studies and three soils in larger bench-scale continuous-treatment studies. This bench scale work led to the design, construction, and operation of a full-scale treatment plant by COGNIS at the Twin Cities Army Ammunition Plant (TCAAP), New Brighton, MN where lead and seven other heavy metals were extracted and recovered from over 20,000 tons of treated soil to meet cleanup criteria. PMID- 26613127 TI - [Not Available]. PMID- 26613128 TI - [Not Available]. PMID- 26613129 TI - The immune system in traumatic brain injury. AB - Traumatic brain injury (TBI) is the major cause of death in children and young adults and one of the major reasons for long-term disability worldwide, however, no specific clinical treatment option could be established so far. This is surprising since it is well known that following the initial mechanical damage to the brain a plethora of delayed processes are activated which ultimately result in additional brain damage. Among these secondary mechanisms, acute and chronic activation of the innate and adaptive immune system is increasingly believed to play an important role for the pathogenesis of TBI. Understanding these processes may results in new, clinically applicable therapeutic options for TBI patients. PMID- 26613130 TI - Portable device for the analysis of liver function: a boon to liver surgery and critical care. AB - Liver biology, liver disease and its management present a myriad of challenges to clinicians. Difficulties arise in determining liver functional capacity, which must be effectively measured in a quantitative reproducible manner. Measurement of indocyanine green (ICG) clearance, an exceptional tool that has been used for decades to assess liver function, has traditionally been cumbersome to perform. New technology now allows for rapid and noninvasive determination of ICG clearance making it clinically accessible. This adds ICG clearance measurement to the armamentarium of physiologic monitors that could be routinely used in the evaluation of patients undergoing liver surgery or in the intensive care setting. PMID- 26613131 TI - Sodium hyaluronate's effect on xerophthalmia: a meta-analysis of randomized controlled trials. AB - BACKGROUND AND AIMS: Several studies in the past have attempted to demonstrate the efficacy of sodium hyaluronate in the treatment of xerophthalmia. However, results have been conflicting and a definite conclusion has not yet been reached. In order to provide integrated evidence for the effectiveness of sodium hyaluronate and to judge the methodological value of relevant randomized controlled trials (RCTs) in nearly thirty years, we conducted this meta-analysis. METHODS: A range of electronic databases were searched: MEDLINE, the Cochrane Library Database, EMBASE, CINAHL, Web of Science and the Chinese Biomedical Database (CBM) without language restrictions. Two independent reviewers assessed trials for eligibility and quality, and meta-analysis was performed using the STATA 12.0 software. An integrated odds ratio (OR) with its corresponding 95% confidence interval (95% CI) was calculated. RESULTS: Six RCTs were included with a total of 839 xerophthalmia patients. The meta-analysis results revealed that patients with xerophthalmia who received the intervention of sodium hyaluronate eye drops didn't have significantly higher remission rate of dry eye symptoms than those in controlled groups (OR = 1.811, 95% CI = 0.741-4.429, p = 0.193). Sensitivity analysis suggested that the statistical results were robust. No publication bias was detected in this meta-analysis (p > 0.05). CONCLUSION: Although sodium hyaluronate can be used to help relieve the symptoms of dry eyes, present evidence cannot show in unequivocal terms that patients with xerophthalmia can benefit more from the clinical application of sodium hyaluronate than other eye drops or therapies. PMID- 26613132 TI - Ab Initio Investigation on Cu/Cr Codoped Amorphous Carbon Nanocomposite Films with Giant Residual Stress Reduction. AB - Amorphous carbon films (a-C) codoped by two metal elements exhibit the desirable combination of tribological and mechanical properties for widely potential applications, but are also prone to catastrophic failure due to the inevitable residual compressive stress. Thus far, the residual stress reduction mechanism remains unclear due to the insufficient understanding of the structure from the atomic and electronic scale. In this paper, using ab initio calculations, we first designed a novel Cu/Cr codoped a-C film and demonstrated that compared with pure and Cu/Cr monodoped cases, the residual stress in Cu/Cr codoped a-C films could be reduced by 93.6% remarkably. Atomic bond structure analysis revealed that the addition of Cu and Cr impurities in amorphous carbon structure resulted in the critical and significant relaxation of distorted C-C bond lengths. On the other hand, electronic structure calculation indicated a weak bonding interaction between the Cr and C atoms, while the antibonding interaction was observed for the Cu-C bonds, which would play a pivot site for the release of strain energy. Those interactions combined with the structural evolution could account for the drastic residual stress reduction caused by Cu/Cr codoping. Our results provide the theoretical guidance and desirable strategy to design and fabricate a new nanocomposite a-C films with combined properties for renewed applications. PMID- 26613133 TI - Statement of principles on the return of research results and incidental findings in paediatric research: a multi-site consultative process. AB - This paper proposes a set of recommendations for the return of research results and incidental findings in paediatrics. The Network of Applied Genetic Medicine of Quebec spearheaded the initiative to develop the Statement of Principles on the Return of Research Results and Incidental Findings, which was the result of a consultation process with clinical and research experts in the field. To formulate the Statement of Principles, the authors (i) reviewed empirical and grey literature on the return of research results and incidental findings in Europe and Canada, (ii) conducted a qualitative study of stakeholder groups, (iii) developed, and (iv) validated the recommendations through consultations with the stakeholder groups. The Statement of Principles provides a useful disclosure tool for deciding when, and under what circumstances to return research results and incidental findings. It addresses the issue of return of results in genetic research generally, and has also specific principles for various research contexts, including paediatric research. It delineates ethical issues unique to paediatric research, and provides a framework to guide research ethics committees as well as the research community in addressing these issues. PMID- 26613134 TI - Design and Synthesis of DiselenoBisBenzamides (DISeBAs) as Nucleocapsid Protein 7 (NCp7) Inhibitors with anti-HIV Activity. AB - The interest in the synthesis of Se-containing compounds is growing with the discovery of derivatives exhibiting various biological activities. In this manuscript, we have identified a series of 2,2'-diselenobisbenzamides (DISeBAs) as novel HIV retroviral nucleocapsid protein 7 (NCp7) inhibitors. Because of its pleiotropic functions in the whole viral life cycle and its mutation intolerant nature, NCp7 represents a target of great interest which is not reached by any anti-HIV agent in clinical use. Using the diselenobisbenzoic scaffold, amino acid, and benzenesulfonamide derivatives were prepared and biologically profiled against different models of HIV infection. The incorporation of amino acids such as glycine and glutamate into DISeBAs 7 and 8 resulted in selective anti-HIV activity against both acutely and chronically infected cells as well as an interesting virucidal effect. DISeBAs demonstrated broad antiretroviral activity, encompassing HIV-1 drug-resistant strains including clinical isolates, as well as simian immunodeficiency virus (SIV). Time of addition experiments, along with the observed dose dependent inhibition of the Gag precursor proper processing, confirmed that their mechanism of action is based on NCp7 inhibition. PMID- 26613135 TI - Decomposing valence intensity effects in disgusting and fearful stimuli: an event related potential study. AB - We are sensitive to valence intensity in negative emotional stimuli, but not in positive emotional stimuli, a phenomenon known as the valence intensity effect. However, whether this valence intensity effect is processed similarly within different negative stimuli, e.g., fear-inducing and disgust-inducing, remains unclear. In the present study, we investigated whether the valence intensity effects for fearful and disgusting stimuli were perceived in a unique way by using event-related potentials (ERPs). Electroencephalogram was recorded from 22 participants as they performed a standard/deviant categorization task using extremely disgusting pictures, moderately disgusting pictures, extremely fearful pictures, moderately fearful pictures, and neutral pictures. The ERP analysis revealed that the extremely fearful stimuli elicited a larger amplitude N2 than moderately fearful stimuli, whereas the extremely disgusting stimuli elicited a smaller amplitude late positive component than moderately disgusting stimuli. This study is the first to provide evidence that fear and disgust may have different valence intensity effects, which was revealed at early attention allocation stages for fearful stimuli and at late emotional evaluation stages for disgusting stimuli. PMID- 26613136 TI - Direct comparison of the psychometric properties of multiple interview and patient-rated assessments of suicidal ideation and behavior in an adult psychiatric inpatient sample. AB - OBJECTIVE: Compare the accuracy, agreement, internal consistency, and interrater reliability of 3 interviews to assess suicidal ideation and behavior in accordance with US Food and Drug Administration guidance about reporting categories. METHOD: Adults admitted to a psychiatric inpatient unit (N = 199) completed 3 assessments of past month and lifetime suicidal ideation and behavior the Columbia Suicide Severity Rating Scale (C-SSRS), the Suicide Tracking Scale (STS), and the Sheehan Suicidality Tracking Scale (S-STS)-in randomized, counterbalanced order. "Missing gold standard" latent class analyses defined categories for ideation and behavior. Analyses also evaluated the S-STS mapping to C-SSRS categories. Three trained judges re-rated 89 randomly selected interview videotapes. Cohen kappa, the primary outcome measure, quantified agreement above chance. Data were collected between November 2011 and June 2013. RESULTS: All 3 assessments showed excellent accuracy for suicidal ideation (kappa = 0.72 to 1.00) and attempts (kappa = 0.82 to 0.95) calibrated against latent classes. Interrater agreement ranged from kappa = 0.52 to 1.00. Interrater agreement about more granular C-SSRS categories varied more widely (kappa = 0.48 to 1.00), and the C-SSRS and S-STS assigned significantly different numbers of cases to many categories. Cronbach alpha was < 0.55 for the C-SSRS ideation and between 0.78 and 0.92 for the other scales. CONCLUSIONS: All 3 assessments showed good accuracy for broad categories of suicidal ideation and behavior. More granular, specific categories usually were rated reliably, but the C-SSRS and S STS differed significantly in regard to which patients were assigned to these subcategories. Using any of these interviews would improve reliability over unstructured assessment in evaluating suicidal ideation and behavior. Clinical predictive validity of these interviews, and particularly the more granular categories, remains to be shown. PMID- 26613138 TI - Theoretical Insights into Hydrogen Bonding and Its Influence on the Structural and Spectral Properties of Aquo Palladium(II) Complexes: cis [(dppp)Pd(H2O)2](2+), cis-[(dppp)Pd(H2O)(OSO2CF3)](+)(OSO2CF3)(-), and cis [(dppp)Pd(H2O)2](2+)(OSO2CF3)(-)2. AB - Density functional theory (DFT) and time-dependent density functional theory (TDDFT) methods have been performed to investigate the ground and excited states of aquo palladium(II) complexes cis-[(dppp)Pd(H2O)2](2+), cis [(dppp)Pd(H2O)(OSO2CF3)](+)(OSO2CF3)(-), and cis-[(dppp)Pd(H2O)2](2+)(OSO2CF3)( )2. Insights into the influence of hydrogen bonding on the structural and spectral properties of these three aquo Pd(II) complexes are presented. The structures and the HOMO-LUMO energy gap of the three aquo Pd(II) complexes can be markedly influenced by hydrogen bonding interactions. Hydrogen bonds can also significantly influence their absorption spectra. PMID- 26613137 TI - Common gynecological challenges in adolescents with sickle cell disease. AB - Sickle cell anemia is one of the most common genetic blood disorders worldwide. Individuals with sickle cell disease (SCD) experience clinical manifestations such as chronic anemia, developmental delay, vaso-occlusive pain, acute chest syndrome, and neurological complications. Adolescent girls with SCD face unique gynecological challenges including delayed puberty marked by a later onset in menarche, vaso-occlusive pain associated with their menstrual cycle, and underdiagnosed abnormal uterine bleeding. This review focuses on these challenges with particular emphasis on delayed menarche and vaso-occlusive pain episodes associated with menstruation, in addition to the evaluation and initial management of heavy menstrual bleeding for adolescents with SCD. We highlight research opportunities in this neglected area to help enhance the comprehensive care model for this population. PMID- 26613139 TI - Effects of Long-Range Electrostatics on Time-Dependent Stokes Shift Calculations. AB - Molecular dynamics simulations are essential to the correct interpretation of the response measured in time-dependent Stokes shift (TDSS) experiments of fluorescent probe molecules in biological environments. Within linear response theory, the TDSS response is the time correlation function of the fluctuations of DeltaE(t), the difference between the solute environment interaction energy with the probe, modeled in both its electronically excited and ground states. DeltaE(t) is dominated by electrostatic interactions between the environment and the ground- and excited-state charge distributions of the probe. The treatment of the long-ranged electrostatics in the calculation of the TDSS response in MD simulations is systematically investigated for three probes in aqueous solution: a model diatomic, coumarin 102, and Hoechst 33258. Nine different protocols for the treatment of the electrostatics were compared to particle mesh Ewald (PME), which was utilized as a reference standard. A computationally efficient pairwise alternative to PME, the damped shifted force method, was shown to reproduce the TDSS response calculated with PME for all three systems. In contrast, neglecting the role of the long-ranged electrostatics in the calculation of the TDSS response results in artifacts. PMID- 26613140 TI - Monte Carlo Sampling with Hierarchical Move Sets: POSH Monte Carlo. AB - We present a new Monte Carlo method for sampling rugged energy landscapes that allows for efficient transitions across sparsely distributed local basins. The trial move consists of two steps. The first step is a large initial trial move, and the second step is a Monte Carlo trajectory generated using smaller trial moves. To maintain detailed balance, a reverse transition probability is estimated along a path that differs from the forward path. Since the forward and reverse transitions are different, we name the algorithm POSH (port out, starboard home) Monte Carlo. The process obeys detailed balance to the extent that the transition probabilities are correctly estimated. There is an optimal range of performance for a given energy landscape, which depends on how sparsely the low energy states of the system are distributed. For simple model systems, adequate precision is obtained over a large range of inner steps settings. Side chain sampling of residues in the binding region of progesterone antibody 1dba are studied, and show that significant improvement over a comparable standard protocol can be obtained using POSH sampling. To compare with experimental data, the phosphopeptide Ace-Gly-Ser-pSer-Ser-Nma is also studied, and the resulting NMR observables compare well with experiment. For the biomolecular systems studied, we show that POSH sampling generates precise distributions using the number of inner steps set up to 20. PMID- 26613141 TI - Simple Expressions for Contact Values of Density Profiles in a Planar Double Layer. AB - Exact, or even accurate, results are very valuable for developing improved statistical mechanical theories of, for example, the double layer formed by the ions in an electrolyte near a charged electrode. In this paper we consider the primitive model of the double layer. For simplicity, we assume the electrolyte to be binary and symmetric. In our previous work, we proposed an exact local expression for the contact value of the total ion density, which is valid for all electrode charges, and local expressions for the individual ion density contact values for an electrode with a small charge. Previously, no local expression was known for the individual density contact values at high electrode charge. On the basis of our work and a recent paper by Lou and Lee [J. Chem. Theory Comput. 2009, 5, 1079-1083], we suggest local, empirical expressions for these contact values and test them by comparison with our extensive simulation results. The simulations are performed in the canonical ensemble with the 'charged sheets' method being utilized to treat long-range electrostatic interactions. The simulation results for the various contact quantities are seen to validate the empirical results for all electrode charges treated. The results are also likely to be (i) useful pointers for simulation of more complex, realistic models and (ii) relevant for expreriments in that most electrochemistry occurs near the electrode where the classical Gouy-Chapman-Stern theory may not be adequate. PMID- 26613142 TI - Frequency-Dependent Diffusion Constant of Quantum Fluids from Path Integral Monte Carlo and Tikhonov's Regularizing Functional. AB - We present a novel implementation of the analytic continuation of the velocity autocorrelation function method that has been developed to study the transport properties of quantum liquids at finite temperatures. To invert the ill-posed linear Fredholm integral equation of the first kind, we combine Tikhonov's first order regularizing functional with several methods used for automatic selection of the regularization parameter. Taking into account our results, we recommend two methods for automatic selection of the regularization parameter, namely: L curve and quasi-optimality criterion. We found that the frequency-dependent diffusion power spectrum of normal liquid (4)He at T = 4 K and rho = 0.01873 A( 3) (rho = 31.1 mmol cm(-3)) is characterized by a single asymmetric peak. The predicted self-diffusion coefficient of (4)He at this state point of 0.57-0.58 A(2)/ps is in excellent agreement with previous works. We demonstrate that, within proposed mathematical treatment of the quantum transport at finite temperatures, the entire real-time frequency-dependent diffusion power spectrum of liquid normal (4)He, can be successfully reconstructed from the limited number of Trotter slices and without the knowledge of covariance matrix. Moreover, the small values of regularization parameters (i.e., order of 10(-7)) indicate that the information about quantum dynamics of normal liquid (4)He can be easily withdrawn from the high quality imaginary-time correlation function collected in the standard path integral Monte Carlo simulation. PMID- 26613143 TI - Gauge-Origin Independent Formulation and Implementation of Magneto-Optical Activity within Atomic-Orbital-Density Based Hartree-Fock and Kohn-Sham Response Theories. AB - A Lagrangian approach has been used to derive gauge-origin independent expressions for two properties that rationalize magneto-optical activity, namely the Verdet constant V(omega) of the Faraday effect and the B term of magnetic circular dichroism. The approach is expressed in terms of an atomic-orbital density-matrix based formulation of response theory and use London atomic orbitals to parametrize the magnetic field dependence. It yields a computational procedure which is both gauge-origin independent and suitable for linear-scaling at the level of time-dependent Hartree-Fock and density functional theory. The formulation includes a modified preconditioned conjugated gradient algorithm, which projects out the excited state component from the solution to the linear response equation. This is required when solving one of the response equations for the determination of the B term and divergence is encountered if this component is not projected out. Illustrative results are reported for the Verdet constant of H2, HF, CO, N2O, and CH3CH2CH3 and for the B term of pyrimidine, phosphabenzene, and pyridine. The results are benchmarked against gauge-origin independent CCSD values. PMID- 26613144 TI - Theoretical Investigation of the Reaction of Imidogen with Fulminic Acid. AB - The mechanism of the reaction of imidogen (NH) with fulminic acid (HCNO) has been investigated theoretically using the multiconfigurational self-consistent-field theory (MCSCF), multireference Rayleigh-Schrodinger perturbation theory (RSPT2), and coupled cluster theory (CC) along with the complete basis set extrapolations (CBS). The calculations show that the NH + HCNO reaction takes place via an N -> C addition mechanism predominantly by surmounting a small barrier (ca. ~3 kcal/mol). The adduct is HC(NH)NO in the triplet state with an exothermicity of more than 60 kcal/mol. The subsequent C-N cleavage, which is nearly barrierless, leads to HCNH and NO as the final products. This represents the most energetically favorable product channel of the title reaction. The channels leading to HCN, HNC, HNO, or HON via O- or H-migration mechanisms involve higher barriers and thus are negligible. The singlet-triplet crossing has been investigated as well for the HCNH + NO product channel by locating the conical interactions. Using transition state theory, the rate constants were predicted as a function of temperatures. It is suggested that the NH + HCNO reaction might be an alternative source for the NO regeneration under the combustion conditions. This calculation is useful to simulate experimental investigations of the NH + HCNO reaction. PMID- 26613145 TI - Topology of the Effectively Paired and Unpaired Electron Densities for Complex Bonding Patterns: The Three-Center Two-Electron Bonding Case. AB - Our previously reported local formalism of the electron density decomposition into effectively paired and unpaired densities is applied to electron deficient molecular systems possessing complex bonding patterns. It is shown that the unpaired density is not only near the nuclear positions, like in classical bonds, but also spills out over the bonding regions, to compensate the electron deficiency. Topological information obtained from the effectively unpaired density, which may not be directly observed from the total density, allows us to establish a procedure to detect complex interactions. This study is complemented with results arising from nonlocal formalism of topological population analyses. The conclusions from both formalisms are in complete agreement and permit to interpret the well-known structural information from Lipscomb styx numbers going beyond it in cases where the electronic description becomes ambiguous, pointing out the subtle information contained in the unpaired density. Numerical results for three-center two-electron bondings in the boranes B2H6, B4H10, B5H9, and B5H11 are reported. PMID- 26613146 TI - Unexpected Trimerization of Pyrazine in the Coordination Sphere of Low-Valent Titanocene Fragments. AB - The titanium mediated trimerization of pyrazine leads to the formation of a tris chelate complex employing a 4a,4b,8a,8b,12a,12b-hexahydrodiyprazino[2,3-f:2',3' h]quinoxaline ligand (HATH6, 3). The driving force in the formation of the (Cp*2Ti)3(HATH6) complex 2 is attributed to the formation of six Ti-N bonds. We show that density functional theory (DFT) fails to predict quantitatively correct results. Therefore, post-Hartree-Fock methods, such as second-order Moller Plesset perturbation theory (MP2), in combination with coupled-cluster (CC) methods must be used. Both MP2 and CCSD(T) levels of theory provide endothermic trimerization energies, showing that the plain pyrazine trimer is not stable with respect to decomposition into its monomers. Complete basis set (CBS) results for the MP2 level of theory were computed using explicitly correlated wave functions. With these, we estimate the CCSD(T) CBS limit of the hypothetical trimerization energy to be +0.78 eV. Thus, the trimerization is facilitated by the formation of six Ti-N bonds with a calculated formation energy of -1.32 eV per bond. PMID- 26613147 TI - Reaction Path Optimization with Holonomic Constraints and Kinetic Energy Potentials. AB - Two methods are developed to enhance the stability, efficiency, and robustness of reaction path optimization using a chain of replicas. First, distances between replicas are kept equal during path optimization via holonomic constraints. Finding a reaction path is, thus, transformed into a constrained optimization problem. This approach avoids force projections for finding minimum energy paths (MEPs), and fast-converging schemes such as quasi-Newton methods can be readily applied. Second, we define a new objective function - the total Hamiltonian - for reaction path optimization, by combining the kinetic energy potential of each replica with its potential energy function. Minimizing the total Hamiltonian of a chain determines a minimum Hamiltonian path (MHP). If the distances between replicas are kept equal and a consistent force constant is used, then the kinetic energy potentials of all replicas have the same value. The MHP in this case is the most probable isokinetic path. Our results indicate that low-temperature kinetic energy potentials (<5 K) can be used to prevent the development of kinks during path optimization and can significantly reduce the required steps of minimization by 2-3 times without causing noticeable differences between a MHP and MEP. These methods are applied to three test cases, the C7eq-to-Cax isomerization of an alanine dipeptide, the (4)C1-to-(1)C4 transition of an alpha d-glucopyranose, and the helix-to-sheet transition of a GNNQQNY heptapeptide. By applying the methods developed in this work, convergence of reaction path optimization can be achieved for these complex transitions, involving full atomic details and a large number of replicas (>100). For the case of helix-to-sheet transition, we identify pathways whose energy barriers are consistent with experimental measurements. Further, we develop a method based on the work energy theorem to quantify the accuracy of reaction paths and to determine whether the atoms used to define a path are enough to provide quantitative estimation of energy barriers. PMID- 26613148 TI - Convergence and Heterogeneity in Peptide Folding with Replica Exchange Molecular Dynamics. AB - Replica exchange molecular dynamics (REMD) techniques have emerged as standard tools for simulating peptides and small proteins, in part, to evaluate the accuracy of modern classical force fields for polypeptides. However, it often remains a challenge to unambiguously discriminate force field flaws from simulations that do not reach equilibrium convergence. Here, we examine closely the convergence behavior of REMD runs for 14 test alpha and beta peptide systems, using an AMBER force field with a generalized Born/surface area implicit solvation model. Somewhat surprisingly, we find that convergence times can be quite large compared to the time scales reached in many earlier REMD efforts, with some short peptides requiring up to 60 ns of run time (per replica). Moreover, we detect a high degree of run-to-run heterogeneity, finding that REMD runs of the same peptide seeded with different initial velocities can exhibit a range of fast- and slow-folding behavior. By increasing the number of swap attempts per REMD cycle, we are able to reduce heterogeneity by diminishing the presence of slower-folding trajectories. Finally, we notice that convergence often can be signaled by a spike in the population of the most populated configurational cluster - a metric that is independent of the native structure. These results suggest that the systematic application of long runs, multiple trials, and convergence indicators may be important in future folding studies and in force field development efforts. PMID- 26613149 TI - Absorption Spectrum of the Green Fluorescent Protein Chromophore: A Difficult Case for ab Initio Methods? AB - We perform a thorough comparative investigation of the excitation energies of the anionic and neutral forms of the green fluorescent protein (GFP) chromophore in the gas phase using a variety of first-principle theoretical approaches commonly used to access excited state properties of photoactive molecules. These include time-dependent density functional theory (TDDFT), complete-active-space second order perturbation theory (CASPT2), equation-of-motion coupled cluster (EOM-CC), and quantum Monte Carlo (QMC) methods. We find that all approaches give roughly the same vertical excitation for the anionic form, while TDDFT predicts an excitation for the neutral chromophore significantly lower than the highly correlated methods. Our findings support the picture emerging from the extrapolation of the Kamlet-Taft fit of absorption experimental data in solution and indicate that the protein gives rise to a considerable bathochromic shift with respect to vacuum. These results also open some questions on the interpretation of photodestruction spectroscopy experiments in the gas phase as well as on the accuracy of previous theoretical calculations in the more complex protein environment. PMID- 26613150 TI - A Density Functional Theory Study of Ground and Low-Lying Excited Electronic States in Defective Graphenes. AB - Electronic states of graphenes, whose carbon atoms are terminated by hydrogen atoms (hydrogenated graphene, denoted H-graphene) and defective graphene (one carbon atom was removed from H-graphene, denoted D-graphene) have been investigated by density functional theory. The sizes of graphenes examined in the present study were n = 7, 14, 19, 29, 37, 44, and 52; where n is the number of benzene rings in the graphene. The excitation energies of H-graphenes were gradually decreased as a function of the number of rings. In D-graphene, new energy levels for the first and second excited states appeared as low-lying excited states. It was found that the formation of defect sites in graphene produces large decreases in the excitation energies for third and higher excited states. The highest occupied molecular orbital and lowest unoccupied molecular orbital (LUMO) in H-graphene were widely delocalized over the graphene surface. On the other hand, LUMO in D-graphene was localized only in the defect sites. The effects of vacancy defects on both the ground and excited electronic states of graphene were discussed on the basis of theoretical results. PMID- 26613151 TI - A Quantum Chemical Interpretation of Compressibility in Solids. AB - The ability of the electron localization function to perform a partition of the unit cell volume of crystalline solids into well-defined, disjoint, and space filling regions enables us to decompose the bulk compressibility into local contributions with a full chemical meaning. This partition has been applied to a set of prototype crystals of the chemical elements of the first three periods of the periodic table, and the equations of state for core, valence, bond, and lone electron pairs have been obtained. Solids are unequivocally classified into two groups according to their response to hydrostatic pressure. Those with sharing electrons (metals and covalent crystals) obey a simple relationship between the average valence electron density and the zero pressure bulk modulus. The stiffness of the closed-shell systems (molecular and ionic solids) is rationalized resorting to the Pauli principle. Overall, the results clearly correlate with chemical intuition: periodic trends are revealed, cores are almost incompressible and do not contribute appreciably to the macroscopic compressibility, and lone pair basins are rather easier to compress than bond basins. PMID- 26613152 TI - Effect of Force Field Parameters on Sodium and Potassium Ion Binding to Dipalmitoyl Phosphatidylcholine Bilayers. AB - The behavior of electrolytes in molecular dynamics simulations of zwitterionic phospholipid bilayers is very sensitive to the force field parameters used. Here, several 200 ns molecular dynamics of simulations of dipalmitoyl phosphotidylcholine (PC) bilayers in 0.2 M sodium or potassium chloride using various common force field parameters for the cations are presented. All employed parameter sets give a larger number of Na(+) ions than K(+) ions that bind to the lipid heads, but depending on the parameter choice quite different results are seen. A wide range of coordination numbers for the Na(+) and K(+) ions is also observed. These findings have been analyzed and compared to published experimental data. Some simulations produce aggregates of potassium chloride, indicating (in accordance with published simulations) that these force fields do not reproduce the delicate balance between salt and solvated ions. The differences between the force fields can be characterized by one single parameter, the electrostatic radius of the ion, which is correlated to sigmaMO (M represents Na(+)/K(+)), the Lennard-Jones radius. When this parameter exceeds a certain threshold, binding to the lipid heads is no longer observed. One would, however, need more accurate experimental data to judge or rank the different force fields precisely. Still, reasons for the poor performance of some of the parameter sets are clearly demonstrated, and a quality control procedure is provided. PMID- 26613153 TI - Determination of Free Energy Profiles for the Translocation of Polynucleotides through alpha-Hemolysin Nanopores using Non-Equilibrium Molecular Dynamics Simulations. AB - The translocation of polynucleotides through transmembrane protein pores is a fundamental biological process with important technological and medical relevance. The translocation process is complex, and it is influenced by a range of factors including the diameter and inner surface of the pore, the secondary structure of the polymer, and the interactions between the polymer and protein. In this paper, we perform nonequilibrium constant velocity-steered molecular dynamics simulations of nucleic acid molecule translocation through the protein nanopore alpha-hemolysin and use Jarzynski's identity to determine the associated free energy profiles. With this approach we are able to explain the observed differences in experimental translocation time through the nanopore between polyadenosine and polydeoxycytidine. The translocation of polynucleotides and single nucleotides through alpha-hemolysin is investigated. These simulations are computationally intensive as they employ models with atomistic level resolution; in addition to their size, these systems are challenging to study due to the time scales of translocation of large asymmetric molecules. Our simulations provide insight into the role of the interactions between the nucleic acid molecules and the protein pore. Mutated protein pores provide confirmation of residue-specific interactions between nucleotides and the protein pore. By harnessing such molecular dynamics simulations, we gain new physicochemical insight into the translocation process. PMID- 26613154 TI - Modeling DNA Dynamics under Steady Deforming Forces and Torques. AB - An algorithm is developed for modeling atom-level dynamics of DNA subjected to steady external torques. For completeness, simulations with steady stretching loads are also considered. The algorithms were tested in Brownian dynamics simulations of discrete wormlike chain models with calibrated elastic properties to confirm that the elastic responses induced are of desired type and magnitude and that no side effects appear. The same methods were next used in a series of 100-ns all-atom MD simulations of tetradecamer DNA fragments with explicit water and counterions. The results demonstrate the possibility of probing regular elastic responses in DNA under low, nearly physiological amplitudes of forces and torques. PMID- 26613155 TI - Ab Initio Raman Spectra of beta-Lactamase Inhibitor Intermediates Bound to E166A SHV beta-Lactamase. AB - The assignment and the analysis of the experimental vibrational Raman spectra of enzyme bound beta-lactamase inhibitors may be of help to understand the mechanisms responsible for bacterial drug resistance. We present a computational study of the structural and vibrational properties of clavulanic acid and tazobactam intermediates, two important beta-lactamase inhibitors, bound to the singly mutated E166A SHV beta-lactamase in aqueous solution by hybrid molecular mechanics/quantum mechanics (QM/MM) simulations at ambient conditions. We compare the Raman spectra obtained from the time autocorrelation function of polarizability tensor as obtained from a QM/MM protocol to those obtained from the instantaneous normal modes analysis performed on top of the QM/MM trajectory in order to establish the accuracy of these two computational methods and to review the previously made assignments. It is shown that the O?C-C?C-NH- trans enamine moiety symmetric and asymmetric stretchings are strongly coupled with the N-H in-plane rocking and originate the band structure between 1600 cm(-1) and 1640 cm(-1). Results indicate also that to properly describe Raman scattering properties of the trans-enamine intermediate, it is crucial to include both mechanical (beyond the second derivative of the potential energy at equilibrium) and electrical (beyond the first derivative of polarizability) anharmonicity. In addition, we show that the environment electrostatic field dynamically modulates the Raman activity, enhancing or inhibiting it. PMID- 26613156 TI - Developing Improved Charge Sets for the Modeling of the KcsA K(+) Channel Using QM/MM Electrostatic Potentials. AB - The performance of popular molecular mechanics (MM) force fields in treating problems that involve ion-channel interactions is explored. We have used quantum mechanical/molecular mechanical (QM/MM) calculations to compute the electrostatic potential inside the selectivity filter of the KcsA potassium channel. A comparison is made with the result of classical electrostatic calculations with nonpolarizable MM force fields (AMBER, CHARMM, and GROMOS). An effective procedure is proposed to improve force field charges by performing a fit on the electrostatic potential computed along QM/MM simulations, using a dynamical electrostatic potential derived charge set. The optimized charge set is able to reproduce the QM/MM electrostatic potentials along the channel axis within 1-2 kcal/mol, which represents an improvement relative to the corresponding electrostatic potentials obtained with popular MM force fields. By providing quantum mechanical benchmark charges and energies for the KcsA selectivity filter, we hope to facilitate developments toward the modeling of ion channels by providing an objective test as to whether a given implementation of a new, polarizable, model represents a real improvement over existing fixed point charge models. PMID- 26613157 TI - Effects of Hydration on the Conformational Energy Landscape of the Pentapeptide Met-Enkephalin. AB - We report here a study of the conformational energy landscape of the pentapeptide Met-enkephalin in the presence of explicit solvent (water) molecules. A sample of 1 500 low-energy structures of this molecule was generated using the mutually orthogonal Latin squares (MOLS) technique with the CHARMM22 force field. This technique, developed in our laboratory, allows us to sample the conformational space of a molecule in an unbiased and exhaustive manner. The study shows that inclusion of explicit solvation is important to correctly model the conformational behavior of the molecule. Structures modeled in the presence of water molecules are far more similar to the experimental structures than when the water molecules are excluded. The results also indicate that the pentapeptide Met enkephalin prefers extended structures in an aqueous environment, as against tightly folded structures in the absence of water. Thus, the biologically relevant structure, when the molecule is not bound to the receptor, is probably the extended structure, as seen in the crystallographic and NMR experiments, rather than the GEM structures calculated by various workers. PMID- 26613158 TI - Perspective on Diabatic Models of Chemical Reactivity as Illustrated by the Gas Phase SN2 Reaction of Acetate Ion with 1,2-Dichloroethane. PMID- 26613159 TI - Extracting Kinetic and Stationary Distribution Information from Short MD Trajectories via a Collection of Surrogate Diffusion Models. PMID- 26613160 TI - Facilitative effect of repetitive presentation of one stimulus on cortical responses to other stimuli in macaque monkeys--a possible neural mechanism for mismatch negativity. AB - The event-related potential 'mismatch negativity' (MMN) is an indicator of a perceiver's ability to detect deviations in sensory signal streams. MMN and its homologue in animals, mismatch activity (MMA), are differential neural responses to a repeatedly presented stimulus and a subsequent deviant stimulus (oddball). Because neural mechanisms underlying MMN and MMA remain unclear, there is a controversy as to whether MMN and MMA arise solely from stimulus-specific adaptation (SSA), in which the response to a stimulus cumulatively attenuates with its repetitive presentation. To address this issue, we used electrocorticography and the auditory roving-oddball paradigm in two awake macaque monkeys. We examined the effect of stimulus repetition number on MMA and on responses to repeated stimuli and oddballs across the cerebral cortex in the time-frequency domain. As the repetition number increased, MMA spread across the temporal, frontal and parietal cortices, and each electrode yielded a larger MMA. Surprisingly, this increment in MMA largely depended on response augmentation to the oddball rather than on SSA to the repeated stimulus. Following sufficient repetition, the oddball evoked a spectral power increment in some electrodes on the frontal cortex that had shown no power increase to the stimuli with less or no preceding repetition. We thereby revealed that repetitive presentation of one stimulus not only leads to SSA but also facilitates the cortical response to oddballs involving a wide range of cortical regions. This facilitative effect might underlie the generation of MMN-like scalp potentials in macaques that potentially shares similar neural mechanisms with MMN in humans. PMID- 26613161 TI - Effect of salt types and concentrations on the high-pressure inactivation of Listeria monocytogenes in ground chicken. AB - National and international health agencies have recommended a significant reduction in daily intake of sodium by reducing the amount of NaCl in foods, specifically processed meats. However, sodium reduction could increase the risk of survival and growth of spoilage and pathogenic microorganisms on these products. Therefore, alternate processing technologies to improve safety of sodium reduced foods are necessary. This study examined the effects of three different salt types and concentrations on high-pressure inactivation of Listeria monocytogenes in pre-blended ground chicken formulations. Ground chicken formulated with three salt types (NaCl, KCl, CaCl2), at three concentrations (0, 1.5, 2.5%) and inoculated with a four strain cocktail of L. monocytogenes (10(8) CFU g(-1)) were subjected to four pressure treatments (0, 100, 300, 600 MPa) and two durations (60, 180 s) in an experiment with factorial design. Surviving cells were enumerated by plating on Oxford agar and analysed by factorial ANOVA. Pressure treatments at 100 or 300 MPa did not significantly (P=0.19-050) reduce L. monocytogenes populations. Neither salt type nor concentration had a significant effect on L. monocytogenes populations at these pressure levels. At 600 MPa, salt types, concentrations and duration of pressure treatment all had a significant effect on L. monocytogenes populations. Formulations with increasing concentrations of NaCl or KCl showed significantly lower reduction in L. monocytogenes, while increase in CaCl2 concentration resulted in a significantly higher L. monocytogenes reduction. For instance, increase in NaCl concentration from 0 to 1.5 or 2.5% resulted in a log reduction of 6.16, 2.49 and 1.29, respectively, when exposed to 600 MPa for 60s. In the case of CaCl2, increase from 0 to 1.5 or 2.5% resulted in a log reduction of 6.16, 7.28 and 7.47, respectively. These results demonstrate that high-pressure processing is a viable process to improve microbial safety of sodium reduced poultry products. PMID- 26613163 TI - Electric-field control of magnetism via strain transfer across ferromagnetic/ferroelectric interfaces. AB - By taking advantage of the coupling between magnetism and ferroelectricity, ferromagnetic (FM)/ferroelectric (FE) multiferroic interfaces play a pivotal role in manipulating magnetism by electric fields. Integrating the multiferroic heterostructures into spintronic devices significantly reduces energy dissipation from Joule heating because only an electric field is required to switch the magnetic element. New concepts of storage and processing of information thus can be envisioned when the electric-field control of magnetism is a viable alternative to the traditional current based means of controlling magnetism. This article reviews some salient aspects of the electric-field effects on magnetism, providing a short overview of the mechanisms of magneto-electric (ME) coupling at the FM/FE interfaces. A particular emphasis is placed on the ME effect via interfacial magneto-elastic coupling arising from strain transfer from the FE to FM layer. Recent results that demonstrate the electric-field control of magnetic anisotropy, magnetic order, magnetic domain wall motion, and etc are described. Obstacles that need to be overcome are also discussed for making this a reality for future device applications. PMID- 26613162 TI - The effect of NaCl reduction in the microbiological quality of cracked green table olives of the Macanilha Algarvia cultivar. AB - The present work aimed at studying the effect of the partial replacement of NaCl with KCl and CaCl2 of the fermenting brines on the microbiological quality of natural cracked green Macanilha Algarvia table olives. Olives were fermented in different salt combinations (Brine 1-8% NaCl, Brine 2-4% NaCl 4% KCl, Brine 3-4% NaCl 4% CaCl2, Brine 4-4% KCl 4% CaCl2, and Brine 5-2.7% NaCl 2.7% KCl 2.7% CaCl2) and the abundance of yeasts and enterobacteria was determined. At the end of fermentation, the main microbial safety parameters were evaluated. Samples were analyzed according to standard methodologies and using Chromocult Agar (coliforms and Escherichia coli). The yeasts collected were grouped by restriction analysis of the ITS-5.8S rRNA gene and identified by partial sequencing of the 26S rRNA. Throughout the study, a decrease of the enterobacteria population was observed in all the fermentations, which was greater and faster in brines containing potassium and calcium. The main yeasts identified were Pichia membranaefaciens, Candida boidinii, Zygosaccharomyces mrakii, Priceomyces carsonii, Saccharomyces cerevisiae, Wickerhamomyces anomalus and the yeast-like fungus Galactomyces geotrichum. The highest yeast diversity was found in olives produced in Brines 1, 2 and 3 and the lowest in Brines 4 and 5, where only the species P. membranaefaciens, C. boidinii and G. geotrichum were identified. No Pseudomonas, E. coli, Salmonella, Staphylococcus aureus and Listeria monocytogenes were found in the table olives produced. PMID- 26613164 TI - The SPA arrangement of the branches of the upper trunk of the brachial plexus: a correction of a longstanding misconception and a new diagram of the brachial plexus. AB - OBJECT Brachial plexus (BP) diagrams in most textbooks and papers represent the branches and divisions of the upper trunk (UT) in the following sequence from cranial to caudal: suprascapular nerve, anterior division, and then posterior division. This concept contradicts what is seen in the operating room and is noticed by most peripheral nerve surgeons. This cadaveric study was conducted to look specifically at the exact pattern of branching of the upper trunk of the BP. METHODS Ten cadavers (20 BPs) were dissected. Both supra- and infraclavicular exposures were performed. The clavicle was retracted or resected to identify the divisions of the BP. A posterior approach was used in 2 cases. RESULTS In all dissections the origin of the posterior division was in a more cranial and dorsal plane in relation to the anterior division. In most dissections the supra scapular nerve branched off distally from the UT, giving it the appearance of a trifurcation, taking off just cranial and dorsal to the posterior division. The branching pattern of the UT consistently had the following sequential arrangement from cranial and posterior to caudal and anterior: suprascapular nerve (S), posterior division (P), and anterior division (A), hence the acronym SPA. CONCLUSIONS Supraclavicular exposure of the BP exposes only the trunks and divisions. Recognizing the "SPA" arrangement of the branches helps in identifying the correct targets for neurotization, especially given that these 3 branches are the most common targets for BP repair. Understanding the anatomy means better surgical planning and better patient outcomes. PMID- 26613165 TI - Decompressive hemicraniectomy: predictors of functional outcome in patients with ischemic stroke. AB - OBJECT Patients presenting with large-territory ischemic strokes may develop intractable cerebral edema that puts them at risk of death unless intervention is performed. The purpose of this study was to identify predictors of outcome for decompressive hemicraniectomy (DH) in ischemic stroke. METHODS The authors conducted a retrospective electronic medical record review of 1624 patients from 2006 to 2014. Subjects were screened for DH secondary to ischemic stroke involving the middle cerebral artery, internal carotid artery, or both. Ninety five individuals were identified. Univariate and multivariate analyses were performed for an array of clinical variables in relationship to functional outcome according to the modified Rankin Scale (mRS). Clinical outcome was assessed at 90 days and at the latest follow-up (mean duration 16.5 months). RESULTS The mean mRS score at 90 days and at the latest follow-up post-DH was 4. Good functional outcome was observed in 40% of patients at 90 days and in 48% of patient at the latest follow-up. The mortality rate at 90 days was 18% and at the last follow-up 20%. Univariate analysis identified a greater likelihood of poor functional outcome (mRS scores of 4-6) in patients with a history of stroke (OR 6.54 [95% CI1.39-30.66]; p = 0.017), peak midline shift (MLS) > 10 mm (OR 3.35 [95% CI 1.33-8.47]; p = 0.011), or a history of myocardial infarction (OR 8.95 [95% CI1.10-72.76]; p = 0.04). Multivariate analysis demonstrated elevated odds of poor functional outcome associated with a history of stroke (OR 9.14 [95% CI 1.78-47.05]; p = 0.008), MLS > 10 mm (OR 5.15 [95% CI 1.58-16.79; p = 0.007), a history of diabetes (OR 5.63 [95% CI 1.52-20.88]; p = 0.01), delayed time from onset of stroke to DH (OR 1.32 [95% CI 1.02-1.72]; p = 0.037), and evidence of pupillary dilation prior to DH (OR 4.19 [95% CI 1.06-16.51]; p = 0.04). Patients with infarction involving the dominant hemisphere had higher odds of unfavorable functional outcome at 90 days (OR 4.73 [95% CI 1.36-16.44]; p = 0.014), but at the latest follow-up, cerebral dominance was not significantly related to outcome (OR 1.63 [95% CI 0.61-4.34]; p = 0.328). CONCLUSIONS History of stroke, diabetes, myocardial infarction, peak MLS > 10 mm, increasing duration from onset of stroke to DH, and presence of pupillary dilation prior to intervention are associated with a worse functional outcome. PMID- 26613166 TI - Intracranial application of near-infrared light in a hemi-parkinsonian rat model: the impact on behavior and cell survival. AB - OBJECT The authors of this study used a newly developed intracranial optical fiber device to deliver near-infrared light (NIr) to the midbrain of 6 hydroxydopamine (6-OHDA)-lesioned rats, a model of Parkinson's disease. The authors explored whether NIr had any impact on apomorphine-induced turning behavior and whether it was neuroprotective. METHODS Two NIr powers (333 nW and 0.16 mW), modes of delivery (pulse and continuous), and total doses (634 mJ and 304 J) were tested, together with the feasibility of a midbrain implant site, one considered for later use in primates. Following a striatal 6-OHDA injection, the NIr optical fiber device was implanted surgically into the midline midbrain area of Wistar rats. Animals were tested for apomorphine-induced rotations, and then, 23 days later, their brains were aldehyde fixed for routine immunohistochemical analysis. RESULTS The results showed that there was no evidence of tissue toxicity by NIr in the midbrain. After 6-OHDA lesion, regardless of mode of delivery or total dose, NIr reduced apomorphine-induced rotations at the stronger, but not at the weaker, power. The authors found that neuroprotection, as assessed by tyrosine hydroxylase expression in midbrain dopaminergic cells, could account for some, but not all, of the observed behavioral improvements; the groups that were associated with fewer rotations did not all necessarily have a greater number of surviving cells. There may have been other "symptomatic" elements contributing to behavioral improvements in these rats. CONCLUSIONS In summary, when delivered at the appropriate power, delivery mode, and dosage, NIr treatment provided both improved behavior and neuroprotection in 6-OHDA-lesioned rats. PMID- 26613167 TI - Cerebellar liponeurocytoma: a rare intracranial tumor with possible familial predisposition. Case report. AB - The biological origin of cerebellar liponeurocytomas is unknown, and hereditary forms of this disease have not been described. Here, the authors present clinical and histopathological findings of a young patient with a cerebellar liponeurocytoma who had multiple immediate family members who harbored similar intracranial tumors. A 37-year-old otherwise healthy woman presented with a history of progressive headaches. Lipomatous medulloblastoma had been diagnosed previously in her mother and maternal grandfather, and her maternal uncle had a supratentorial liponeurocytoma. MRI revealed a large, poorly enhancing, lipomatous mass emanating from the superior vermis that produced marked compression of posterior fossa structures. An uncomplicated supracerebellar infratentorial approach was used to resect the lesion. Genetic and histopathological analyses of the lesion revealed neuronal, glial, and lipomatous differentiation and confirmed the diagnosis of cerebellar liponeurocytoma. A comparison of the tumors resected from the patient and, 22 years previously, her mother revealed similar features. Cerebellar liponeurocytoma is a poorly understood entity. This report provides novel evidence of an inheritable predisposition for tumor development. Accurate diagnosis and reporting of clinical outcomes and associated genetic and histopathological changes are necessary for guiding prognosis and developing recommendations for patient care. PMID- 26613168 TI - Neuron-derived orphan receptor 1 transduces survival signals in neuronal cells in response to hypoxia-induced apoptotic insults. AB - OBJECT Hypoxia can induce cell death or trigger adaptive mechanisms to guarantee cell survival. Neuron-derived orphan receptor 1 (NOR-1) works as an early response protein in response to a variety of environmental stresses. In this study, the authors evaluated the roles of NOR-1 in hypoxia-induced neuronal insults. METHODS Neuro-2a cells were exposed to oxygen/glucose deprivation (OGD). Cell viability, cell morphology, cas-pase-3 activity, DNA fragmentation, and cell apoptosis were assayed to determine the mechanisms of OGD-induced neuronal insults. RNA and protein analyses were carried out to evaluate the effects of OGD on expressions of NOR-1, cAMP response element-binding (CREB), and cellular inhibitor of apoptosis protein 2 (cIAP2) genes. Translations of these gene expressions were knocked down using RNA interference. Mice subjected to traumatic brain injury (TBI) and NOR-1 was immunodetected. RESULTS Exposure of neuro-2a cells to OGD decreased cell viability in a time-dependent manner. Additionally, OGD led to cell shrinkage, DNA fragmentation, and cell apoptosis. In parallel, treatment of neuro-2a cells with OGD time dependently increased cellular NOR-1 mRNA and protein expressions. Interestingly, administration of TBI also augmented NOR-1 levels in the impacted regions of mice. As to the mechanism, exposure to OGD increased nuclear levels of the transcription factor CREB protein. Downregulating CREB expression using RNA interference simultaneously inhibited OGD-induced NOR-1 mRNA expression. Also, levels of cIAP2 mRNA and protein in neuro-2a cells were augmented by OGD. After reducing cIAP2 translation, OGD induced cell death was reduced. Sequentially, application of NOR-1 small interfering RNA to neuro-2a cells significantly inhibited OGD-induced cIAP2 mRNA expression and concurrently alleviated hypoxia-induced alterations in cell viability, caspase-3 activation, DNA damage, and cell apoptosis. CONCLUSIONS This study shows that NOR-1 can transduce survival signals in neuronal cells responsible for hypoxiainduced apoptotic insults through activation of a CREB/cIAP2-dependent mechanism. PMID- 26613169 TI - Evidence of increased brain amyloid in severe TBI survivors at 1, 12, and 24 months after injury: report of 2 cases. AB - Traumatic brain injury (TBI) is a major risk factor for Alzheimer's disease. With respect to amyloid deposition, there are no published serial data regarding the deposition rate of amyloid throughout the brain after TBI. The authors conducted serial (18)F-AV-45 (florbetapir F18) positron emission tomography (PET) imaging in 2 patients with severe TBI at 1, 12, and 24 months after injury. A total of 12 brain regions were surveyed for changes in amyloid levels. Case 1 involved a 50 year-old man who experienced a severe TBI. Compared with the 1-month time point, of the 12 brain regions that were surveyed, a decrease in amyloid (as indicated by standard uptake value ratios) was only observed in the hippocampus (-16%, left; -12%, right) and caudate nucleus (-18%, left; -18%, right), suggesting that initial amyloid accumulation in the brain was cleared between time points 1 and 12 months after injury. Compared to the scan at 1 year, a greater increase in amyloid (+15%) was observed in the right hippocampus at the 24-month time point. The patient in Case 2 was a 37-year-old man who suffered severe trauma to the head and a subsequent stroke; he had poor cognitive/functional outcomes and underwent 1.5 years of rehabilitation. Due to a large infarct area on the injured side of the brain (right side), the authors focused primarily on brain regions affected within the left hemisphere. Compared with the 1-month scan, they only found an increase in brain amyloid within the left anterior putamen (+11%) at 12 months after injury. In contrast, decreased amyloid burden was detected in the left caudate nucleus (-48%), occipital cortex (-21%), and precuneus (-19%) brain regions at the 12-month time point, which is indicative of early accumulation and subsequent clearance. In comparison with 12-month values, more clearance was observed, since a reduction in amyloid was found at 24 months after trauma within the left anterior putamen (-12%) and occipital cortex (-15%). Also, by 24 months, most of the amyloid had been cleared and the patient demonstrated improved results on the Rivermead symptom questionnaire, Glasgow Outcome Scale-Extended, and Disability Rating Scale. With respect to APOE status, the patient in Case 1 had two epsilon3 alleles and the patient in Case 2 had one epsilon2 and one epsilon3 allele. In comparison to the findings of the initial scan at 1 month after TBI, by 12 and 24 months after injury amyloid was cleared in some brain regions and increased in others. Serial imaging conducted here suggests that florbetapir F18 PET imaging may be useful in monitoring amyloid dynamics within specific brain regions following severe TBI and may be predictive of cognitive deficits. PMID- 26613170 TI - Early craniometric tools as a predecessor to neurosurgical stereotaxis. AB - In this paper the authors trace the history of early craniometry, referring to the technique of obtaining cranial measurements for the accurate correlation of external skull landmarks to specific brain regions. Largely drawing on methods from the newly emerging fields of physical anthropology and phrenology in the late 19th and early 20th centuries, basic mathematical concepts were combined with simplistic (yet at the time, innovative) mechanical tools, leading to the first known attempts at craniocerebral topography. It is important to acknowledge the pioneers of this pre-imaging epoch, who applied creativity and ingenuity to tackle the challenge of reproducibly and reliably accessing a specific target in the brain. In particular, with the emergence of Broca's theory of cortical localization, in vivo craniometric tools, and the introduction of 3D coordinate systems, several innovative devices were conceived that subsequently paved the way for modern-day stereotactic techniques. In this context, the authors present a comprehensive and systematic review of the most popular craniometric tools developed during this time period (prior to the stereotactic era) for the purposes of craniocerebral measurement and target localization. PMID- 26613171 TI - Late malignant transformation of vestibular schwannoma in the absence of irradiation: case report. AB - Late malignant transformation of vestibular schwannoma (VS) following irradiation has previously been reported 29 times in the literature. Here, the authors report the first late malignant transformation of VS unrelated to neurofibromatosis or radiation exposure. After undergoing a near-total excision of a histologically benign VS, the patient developed malignant regrowth of the tumor remnant 42 months after the primary excision. This case challenges the dogmatic belief of absolute causality between radiation exposure and late malignant transformation of VS, and has important implications regarding future counseling and consent for the treatment of patients with VS. PMID- 26613172 TI - A multicenter prospective cohort study of volume management after subarachnoid hemorrhage: circulatory characteristics of pulmonary edema after subarachnoid hemorrhage. AB - OBJECT Subarachnoid hemorrhage (SAH) is often accompanied by pulmonary complications, which may lead to poor outcomes and death. This study investigated the incidence and cause of pulmonary edema in patients with SAH by using hemodynamic monitoring with PiCCO-plus pulse contour analysis. METHODS A total of 204 patients with SAH were included in a multicenter prospective cohort study to investigate hemodynamic changes after surgical clipping or coil embolization of ruptured cerebral aneurysms by using a PiCCO-plus device. Changes in various hemodynamic parameters after SAH were analyzed statistically. RESULTS Fifty-two patients (25.5%) developed pulmonary edema. Patients with pulmonary edema (PE group) were significantly older than those without pulmonary edema (non-PE group) (p = 0.017). The mean extravascular lung water index was significantly higher in the PE group than in the non-PE group throughout the study period. The pulmonary vascular permeability index (PVPI) was significantly higher in the PE group than in the non-PE group on Day 6 (p = 0.029) and Day 10 (p = 0.011). The cardiac index of the PE group was significantly decreased biphasically on Days 2 and 10 compared with that of the non-PE group. In the early phase (Days 1-5 after SAH), the daily water balance of the PE group was slightly positive. In the delayed phase (Days 6-14 after SAH), the serum C-reactive protein level and the global end-diastolic volume index were significantly higher in the PE group than in the non-PE group, whereas the PVPI tended to be higher in the PE group. CONCLUSIONS Pulmonary edema that occurs in the early and delayed phases after SAH is caused by cardiac failure and inflammatory (i.e., noncardiogenic) conditions, respectively. Measurement of the extravascular lung water index, cardiac index, and PVPI by PiCCO-plus monitoring is useful for identifying pulmonary edema in patients with SAH. PMID- 26613173 TI - Rescue N-butyl-2 cyanoacrylate embolectomy using a Solitaire FR device after venous glue migration during arteriovenous malformation embolization: technical note. AB - One of the procedural risks in arteriovenous malformation (AVM) embolization is possible migration of the embolic agent into the venous drainage with an incomplete nidus occlusion, which may lead to severe hemorrhagic complications. This report presents the case of a 29-year-old man who presented with a deep intraparenchymal hematoma on the left side secondary to the spontaneous rupture of a claustral AVM. Upon resorption of the hematoma, the patient underwent an initial therapeutic session of N-butyl-2 cyanoacrylate endovascular embolization, with the purpose of reducing the AVM volume and flow before performing Gamma Knife radiosurgery. After glue injection into one of the arterial feeders, the control angiography showed a partial migration of the glue cast into the straight sinus, with most of the nidus still visible. Because of the bleeding risk due to possible venous hypertension, it was decided to try to retrieve the glue from the vein by using a stent retriever via jugular access. This maneuver allowed a nearly complete removal of the glue cast, thereby restoring normal venous flow drainage. The patient showed no clinical worsening after the procedure. To the authors' knowledge, this is the first report of the use of the Solitaire FR device as a rescue glue retriever. This method should be considered by physicians in cases of unintended glue migration into the venous circulation during AVM embolization. PMID- 26613175 TI - Surgical anatomy and utility of pedicled vascularized tissue flaps for multilayered repair of skull base defects. AB - OBJECT The objective of this study was to describe the surgical anatomy and technical nuances of various vascularized tissue flaps. METHODS The surgical anatomy of various tissue flaps and their vascular pedicles was studied in 5 colored silicone-injected anatomical specimens. Medical records were reviewed of 11 consecutive patients who underwent repair of extensive skull base defects with a combination of various vascularized flaps. RESULTS The supraorbital, supratrochlear, superficial temporal, greater auricular, and occipital arteries contribute to the vascular supply of the pericranium. The pericranial flap can be designed based on an axial blood supply. Laterally, various flaps are supplied by the deep or superficial temporal arteries. The nasoseptal flap is a vascular pedicled flap based on the nasoseptal artery. Patients with extensive skull base defects can undergo effective repair with dual flaps or triple flaps using these pedicled vascularized flaps. CONCLUSIONS Multiple pedicled flaps are available for reconstitution of the skull base. Knowledge of the surgical anatomy of these flaps is crucial for the skull base surgeon. These vascularized tissue flaps can be used effectively as single or combination flaps. Multilayered closure of cranial base defects with vascularized tissue can be used safely and may lead to excellent repair outcomes. PMID- 26613174 TI - The cognitive and behavioral effects of meningioma lesions involving the ventromedial prefrontal cortex. AB - OBJECT Anterior skull base meningiomas are frequently associated with changes in personality and behavior. Although such meningiomas often damage the ventromedial prefrontal cortex (vmPFC), which is important for higher cognition, the cognitive and behavioral effects of these meningiomas remain poorly understood. Using detailed neuropsychological assessments in a large series of patients, this study examined the cognitive and behavioral effects of meningioma lesions involving the vmPFC. METHODS The authors reviewed neuropsychology and lesion mapping records of 70 patients who underwent resection of meningiomas. The patients were drawn from the Neurological Patient Registry at the University of Iowa. Patients were sorted into 2 groups: those with lesions involving the vmPFC and those with lesions that did not involve the vmPFC. Neuropsychological data pertaining to a comprehensive array of cognitive and behavioral domains were available preoperatively in 20 patients and postoperatively in all 70 patients. RESULTS No change occurred in basic cognitive functions (e.g., attention, perception, memory, construction and motor performance, language, or executive functions) from the preoperative to postoperative epochs for the vmPFC and non-vmPFC groups. There was a significant decline in the behavioral domain, specifically adaptive function, for both the vmPFC and non-vmPFC groups, and this decline was more pronounced for the vmPFC group. Additionally, postoperative data indicated that the vmPFC group had a specific deficit in value-based decision making, as evidenced by poor performance on the Iowa Gambling Task, compared with the non-vmPFC group. The vmPFC and non vmPFC groups did not differ postoperatively on other cognitive measures, including intellect, memory, language, and perception. CONCLUSIONS Lesions of the vmPFC resulting from meningiomas are associated with specific deficits in adaptive function and value-based decision making. Meningioma patients showed a decline in adaptive function postoperatively, and this decline was especially notable in patients with vmPFC region meningiomas. Early detection and resection of meningiomas of the anterior skull base (involving the gyrus rectus) may prevent these deficits. PMID- 26613176 TI - Periventricular anastomosis in moyamoya disease: detecting fragile collateral vessels with MR angiography. AB - OBJECT The authors' aim in this paper was to determine whether periventricular anastomosis, a novel term for the abnormal collateral vessels typical of moyamoya disease, is reliably measured with MR angiography and is associated with intracranial hemorrhage. METHODS This cross-sectional study sampled consecutive patients with moyamoya disease or moyamoya syndrome at a single institution. Periventricular anastomoses were detected using MR angiography images reformatted as sliding-thin-slab maximum-intensity-projection coronal images and were scored according to 3 subtypes: lenticulostriate, thalamic, and choroidal types. The association between periventricular anastomosis and hemorrhagic presentation at onset was evaluated using multivariate analyses. RESULTS Of 136 eligible patients, 122 were analyzed. Eighteen (14.8%) patients presented with intracranial hemorrhage with neurological symptoms at onset. Intra- and interrater agreement for rating of the periventricular anastomosis score was good (kappaw = 0.65 and 0.70, respectively). The prevalence of hemorrhagic presentation increased with the periventricular anastomosis score: 2.8% for Score 0, 8.8% for Score 1, 18.9% for Score 2, and 46.7% for Score 3 (p < 0.01 for trend). Univariate analysis revealed that age (p = 0.02) and periventricular anastomosis score (p < 0.01) were factors tentatively associated with hemorrhagic presentation. The score remained statistically significant after adjustment for age (OR 3.38 [95% CI 1.84-7.00]). CONCLUSIONS The results suggest that periventricular anastomosis detected with MR angiography can be scored with good intra- and interrater reliability and is associated with hemorrhagic presentation at onset in moyamoya disease. The clinical utility of periventricular anastomosis as a predictor for hemorrhage should be validated in further prospective studies. PMID- 26613177 TI - "Asleep" deep brain stimulation for essential tremor. AB - OBJECT Deep brain stimulation (DBS) performed under general anesthesia ("asleep" DBS) has not been previously reported for essential tremor. This is in part due to the inability to visualize the target (the ventral intermediate nucleus [VIM]) on MRI. The authors evaluate the efficacy of this asleep technique in treating essential tremor by indirect VIM targeting. METHODS The authors retrospectively reviewed consecutive cases of initial DBS for essential tremor performed by a single surgeon. DBS was performed with patients awake (n = 40, intraoperative test stimulation without microelectrode recording) or asleep (n = 17, under general anesthesia). Targeting proceeded with standardized anatomical coordinates on preoperative MRI. Intraoperative CT was used for stereotactic registration and lead position confirmation. Functional outcomes were evaluated with pre- and postoperative Bain and Findley Tremor Activities of Daily Living scores. RESULTS A total of 29 leads were placed in asleep patients, and 60 were placed in awake patients. Bain and Findley Tremor Activities of Daily Living Questionnaire scores were not significantly different preoperatively for awake versus asleep cohorts (p = 0.2). The percentage of postoperative improvement was not significantly different between asleep (48.6%) and awake (45.5%) cohorts (p = 0.35). Euclidean error (mm) was higher for awake versus asleep patients (1.7 +/- 0.8 vs 1.2 +/- 0.4, p = 0.01), and radial error (mm) trended higherfor awake versus asleep patients (1.3 +/- 0.8 vs 0.9 +/- 0.5, p = 0.06). There were no perioperative complications. CONCLUSIONS In the authors' initial experience, asleep VIM DBS for essential tremor without intraoperative test stimulation can be performed safely and effectively. PMID- 26613178 TI - Antidepressant nonadherence in routine clinical settings determined from discarded blood samples. AB - OBJECTIVE: Antidepressant nonadherence is common and represents a potentially modifiable risk factor for treatment nonresponse. We used a novel approach based on discarded blood samples from routine clinical blood draws to assess treatment nonadherence in a general clinical population. METHOD: Individuals diagnosed with or without major depressive disorder (using ICD-9) and prescribed sertraline, citalopram, bupropion, or venlafaxine in January 2014 were identified by querying the electronic health record of 2 academic medical centers. Discarded blood samples from routine blood draws for 109 individuals within 14-90 days of treatment initiation were anonymized and then assessed for detectable serum antidepressant levels. RESULTS: Overall, 17% of samples lacked detectable levels of the index antidepressant. Individuals with public versus private insurance were more likely to have undetectable antidepressant levels (chi(2)1 = 5.07, P = .02) as were those receiving shorter-term (< 90 days) prescriptions (chi(2)1 = 4.03, P = .05). CONCLUSIONS: In general, electronic prescribing data provided a reasonable proxy for actual antidepressant use. Additionally, up to 1 in 5 individuals prescribed an antidepressant may not be adherent, suggesting the need for further efforts to reduce treatment nonadherence. PMID- 26613179 TI - Arsenate uptake by Al nanoclusters and other Al-based sorbents during water treatment. AB - In many parts of the world, arsenic from geogenic and anthropogenic sources deteriorates the quality of drinking water resources. Effective methods of arsenic removal include adsorption and coagulation with iron- and aluminum-based materials, of which polyaluminum chloride is widely employed as coagulant in water treatment due to its low cost and high efficiency. We compared the arsenic uptake capacity and the arsenic bonding sites of different Al-based sorbents, including Al nanoclusters, polyaluminum chloride, polyaluminum granulate, and gibbsite. Extended X-ray absorption fine structure (EXAFS) spectroscopy revealed that As(V) forms bidentate-binuclear complexes in interaction with all Al-based removal agents. The octahedral configuration of nanoclusters and the distribution of sorption sites remain the same in all types of removal agents consisting of nano-scale Al oxyhydroxide particles. The obtained distances for As(V)-O and As(V)-Al agreed with previously published data and were found to be 1.69 +/- 0.02 A and 3.17-3.21 A, respectively. Our study suggests that As(V) binds to Al nanoclusters as strongly as to Al oxide surfaces. The As sorption capacity of Al nanoclusters was found to be very similar to that of Al clusters in a polyaluminum chloride. The most efficient Al-based sorbents for arsenic removal were Al nanoclusters, followed by polyaluminum granulate. PMID- 26613180 TI - Characterization and adsorption properties of a lanthanum-loaded magnetic cationic hydrogel composite for fluoride removal. AB - In this study, a novel lanthanum-loaded magnetic cationic hydrogel (MCH-La) was synthesized for fluoride adsorption from drinking water. The adsorption kinetics, isotherms, and effects of pH and co-existing anions on fluoride uptake by MCH-La were evaluated. FTIR, Raman and XPS were used to analyze the fluoride adsorption mechanism of MCH-La. Results showed that MCH-La had positive zeta potential values of 23.6-8.0 mV at pH 3.0-11.0, with the magnitude of saturation magnetization up to 10.3 emu/g. The fluoride adsorption kinetics by MCH-La fitted well with the fractal-like-pseudo-second-order model, and the adsorption capacity reached 93% of the ultimate adsorption capacity within the first 10 min. The maximum fluoride adsorption capacity for MCH-La was 136.78 mg F(-)/g at an equilibrium fluoride concentration of 29.3 mg/L and pH 7.0. Equilibrium adsorption data showed that the Sips model was more suitable than the Langmuir and Freundlich models. MCH-La still had more than 100 mg of F(-)/g adsorption capacity at a strongly alkaline solution (pH > 10). The adsorption process was highly pH-dependent, and the optimal adsorption was attained at pH 2.8-4.0, corresponding to ligand exchange, electrostatic interactions, and Lewis acid-base interactions. With the exception of both anions of HCO3(-) and SiO4(4-), Cl(-), NO3(-), and SO4(2-) did not evidently prevent fluoride removal by MCH-La at their real concentrations in natural groundwater. The fluoride adsorption capacity of the regenerated MCH-La approached 70% of the fresh MCH-La from the second to fifth recycles. FTIR and Raman spectra revealed that C-O and CO functional groups on MCH contributed to the fluoride adsorption, this finding was also confirmed by the XPS F 1s spectra. Deconvolution of C 1s spectra before and after fluoride adsorption indicated that the carboxyl, anhydride, and phenol groups of MCH were involved in the fluoride removal. PMID- 26613181 TI - New hydrolysis products of the beta-lactam antibiotic amoxicillin, their pH dependent formation and search in municipal wastewater. AB - Amoxicillin (AMX) is a widespread beta-lactam-antibiotic and, together with some of its transformation products (TPs) originating from hydrolysis, a known environmental contaminant. To shed light on the abiotic degradation of AMX and the stability of its known TPs, laboratory hydrolysis experiments of AMX were carried out at pH 3, 7 and 11. Not only the rate of hydrolysis but also the pattern of TPs was strongly pH-dependent. The time courses of the obtained transformation products were analyzed by UPLC-HR-QToF-MS. AMX penicilloic acid (TP 1), AMX 2',5'-diketopiperazine (TP 2), AMX penilloic acid (TP 3) and 3-(4 hydroxyphenyl)pyrazinol (TP 4) were found at neutral pH. Surprisingly, the first three were not stable but transformed into 23 yet unknown TPs within three to four weeks. Seven TPs were tentatively identified, based on their product ion spectra and, where possible, confirmed with reference standards, e.g. penicillamine disulfide, 2-[amino(carboxy)methyl]-5,5-dimethyl-1,3-thiazolidine-4 carboxylic acid and dehydrocarboxylated amoxicillin penilloic acid. Analysis of samples from municipal wastewater treatment plants confirmed these findings with TP 1 being the dominant TP in the influent and a shift towards TP 2, TP 3 and TP 4 in the effluents. The lab experiments predicted up to 13 consecutive TPs from TP 1, TP 2 and TP 3 under neutral conditions. Their detection from surface waters will be difficult, because their large number and slow formation kinetics will lead to comparatively low environmental concentrations. Nevertheless the abiotic degradation of TP 1, TP 2 and TP 3 to further TPs needs to be considered in future studies of the environmental fate of amoxicillin. PMID- 26613182 TI - Towards a selective adsorbent for arsenate and selenite in the presence of phosphate: Assessment of adsorption efficiency, mechanism, and binary separation factors of the chitosan-copper complex. AB - The potential for a chitosan-copper polymer complex to select for the target contaminants in the presence of their respective competitive ions was evaluated by synthesizing chitosan-copper beads (CCB) for the treatment of (arsenate:phosphate), (selenite:phosphate), and (selenate:sulfate). Based on work by Rhazi et al., copper (II) binds to the amine moiety on the chitosan backbone as a monodentate complex (Type I) and as a bidentate complex crosslinking two polymer chains (Type II), depending on pH and copper loading. In general, the Type I complex exists alone; however, beyond threshold conditions of pH 5.5 during synthesis and a copper loading of 0.25 mol Cu(II)/mol chitosan monomer, the Type I and Type II complexes coexist. Subsequent chelation of this chitosan copper ligand to oxyanions results in enhanced and selective adsorption of the target contaminants in complex matrices with high background ion concentrations. With differing affinities for arsenate, selenite, and phosphate, the Type I complex favors phosphate chelation while the Type II complex favors arsenate chelation due to electrostatic considerations and selenite chelation due to steric effects. No trend was exhibited for the selenate:sulfate system possibly due to the high Ksp of the corresponding copper salts. Binary separation factors, alpha12, were calculated for the arsenate-phosphate and selenite-phosphate systems, supporting the mechanistic hypothesis. While, further research is needed to develop a synthesis method for the independent formation of the Type II complexes to select for target contaminants in complex matrices, this work can provide initial steps in the development of a selective adsorbent. PMID- 26613183 TI - Effect of nanoscale zero-valent iron and magnetite (Fe3O4) on the fate of metals during anaerobic digestion of sludge. AB - Anaerobic digestion (AD) is one of the most widely used processes to stabilize waste sewage sludge and produce biogas renewable energy. In this study, two different iron nanoparticles [nanoscale zero-valent iron (nZVI) and magnetite (Fe3O4)] were used in the mesophilic AD processes (37 +/- 1 degrees C) to improve biogas production. In addition, changes of heavy metal (Cd, Co, Cu, Zn, Ni and Cr) speciation during AD of sludge with and without iron nanoparticles have been investigated. Concentrations of metals in the initial sludge were as follows: 63.1, 73.4, 1102.2, 2060.3, 483.9 and 604.1 mg kg(-1) (dry sludge basis) for Cd, Co, Cu, Zn, Ni and Cr, respectively. Sequential fractionation showed that metals were predominantly bonded to organic matter and carbonates in the initial sludge. Compared with AD without iron nanoparticles, the application of iron nanoparticles (at dose of 0.5% in this study) showed positive impact not only on biogas production, but also on improvement of metals stabilization in the digestate. Metals were found concentrated in Fe-Mn bound and residual fractions and little was accumulated in the liquid digestate and most mobile fractions of solid digestate (water soluble, exchangeable and carbonates bound). Therefore, iron nanoparticles when properly used, could improve not only biogas yield, but also regulate and control the mobilization of metals during AD process. However, our study also observed that iron nanoparticles could promote the immobilization of phosphorus within the sludge during AD, and more research is needed to fully address the mechanism behind this phenomenon and the impact on future phosphorus reuse. PMID- 26613184 TI - Laser Activated Electron Tunneling Based Mass Spectrometric Imaging of Molecular Architectures of Mouse Brain Revealing Regional Specific Lipids. AB - A comprehensive description of overall brain architecture at the molecular level is essential for understanding behavioral and cognitive processes in health and diseases. Although fluorescent labeling of target proteins has been successfully established to visualize a brain connectome, the molecular basis for diverse neurophysiological phenomena remains largely unknown. Here we report a brain wide, molecular-level, and microscale imaging of endogenous metabolites, in particular, lipids of mouse brain by using laser activated electron tunneling (LAET) and mass spectrometry. In this approach, atomic electron emission along with finely tuned laser beam size provides high resolution that can be down to the sub-micrometer level to display spatial distribution of lipids in mouse brain slices. Electron-directed soft ionization has been achieved through exothermal capture of tunneling photoelectrons as well as unpaired electron-initiated chemical bond cleavages. Regionally specific lipids including saturated, mono unsaturated, and poly-unsaturated fatty acids as well as other lipids, which may be implicated in neurological signaling pathways, have been discovered by using this laser activated electron tunneling based mass spectrometric imaging (LAET MSI) technique. PMID- 26613185 TI - Relationship between income generating activities of rural women and their reproductive health behavior in Bangladesh. AB - INTRODUCTION: The objective of the study was to find out the effects of income generating activities of rural women and their reproductive health behavior (contraceptive use) in Bangladesh. METHODS: A cross-sectional study using a multi stage sampling technique was carried out among 200 married rural women in Cox's Bazar, Bangladesh. Data were collected using a structured questionnaire on socioeconomic factors, income generating activities, women's empowerment in mobility, decision making and reproductive health behavior in terms of contraceptive use, number of children and desire for more children. Logistic regression analysis was used to determine the relationship between income generating activities and contraceptive use. RESULTS: Almost half (45.5%) of the participants were involved in income generating activities. A great majority (63.9%) worked year-round, two-thirds (75.0%) earned cash for their family and 21.3% were engaged in poultry farms. Women aged 26-35 years, members of any non governmental organization and from a poor family were more likely to be engaged in income generating activities (<=0.001). Highly educated women worked more than their less educated counterparts and the opposite was true for their husbands (<=0.001). Almost half of the women (45.0%) did not use any contraceptive. Contraceptive use was significantly higher among working women (73.4%) than with non-working women (33.0%). Women engaged in income generating activities were more likely to use contraceptives compared to non-working women (odds ratio 5.6, 95% confidence interval 3.1-7.0, <=0.001). RESULTS: Income generating activities seem to empower women, increase their likelihood of using contraception and are one of the key issues for changing the life of rural women in Bangladesh. PMID- 26613186 TI - Extending RAD tag analysis to microbial ecology: a comparison between MultiLocus Sequence Typing and 2b-RAD to investigate Listeria monocytogenes genetic structure. AB - The advent of next-generation sequencing (NGS) has dramatically changed bacterial typing technologies, increasing our ability to differentiate bacterial isolates. Despite it is now possible to sequence a bacterial genome in a few days and at reasonable costs, most genetic analyses do not require whole-genome sequencing, which also remains impractical for large population samples due to the cost of individual library preparation and bioinformatics. More traditional sequencing approaches, however, such as MultiLocus Sequence Typing (mlst) are quite laborious and time-consuming, especially for large-scale analyses. In this study, a genotyping approach based on restriction site-associated (RAD) tag sequencing, 2b-RAD, was applied to characterize Listeria monocytogenes strains. To verify the feasibility of the method, an in silico analysis was performed on 30 available complete genomes. For the same set of strains, in silico mlst analysis was conducted as well. Subsequently, 2b-RAD and mlst analyses were experimentally carried out on 58 isolates collected from food samples or food-processing sites. The obtained results demonstrate that 2b-RAD predicts mlst types and often provides more detailed information on population structure than mlst. Moreover, the majority of variants differentiating identical sequence type isolates mapped against accessory fragments, thus providing additional information to characterize strains. Although mlst still represents a reliable typing method, large-scale studies on molecular epidemiology and public health, as well as bacterial phylogenetics, population genetics and biosafety could benefit of a low cost and fast turnaround time approach such as the 2b-RAD analysis proposed here. PMID- 26613187 TI - A simultaneous population pharmacokinetic analysis of rifampicin in Malawian adults and children. AB - AIMS: Low rifampicin plasma concentrations can lead to treatment failure and increased risk of developing drug resistant tuberculosis. The objectives of this study were to characterize the population pharmacokinetics (popPK) of rifampicin in Malawian children and adults with tuberculosis, simulate exposures under revised WHO dosing guidelines that aim to reduce the risk of low exposures of rifampicin and examine predicted exposures using weight- and age-based dosing bands under new dosing recommendations. METHODS: Patients were recruited at least two weeks after initiation of the intensive phase of treatment and received RIF in FDC of anti-TB drugs. A total of 5-6 rich and 1-2 sparse samples were collected. nonmem (v7.2) was used to build a population-PK model. RESULTS: A 165 TB patients, 115 adults and 50 children, aged 7 months to 65 years and weighing 4.8 to 87 kg, were included in the one compartment model with first order absorption best described the data. The mean population estimate for CL/F was 23.9 (l h(-1) 70 kg(-1) ) with inter-individual variability of 46.6%. Exposure was unaffected by HIV status. Relative bioavailability in children was estimated at 49% lower compared to adults (100% relative bioavailability). Simulations showed significantly lower rifampicin exposure in children vs. adults. In children average AUC was 13.5 mg l(-1) h, which was nearly half that was observed in adults (26.3 mg l(-1) h). Using age as a surrogate for weight in dosing bands gave similar results compared with the weight bands. Increasing dose to approximately 15 mg kg(-1) , increased AUC in children to an average of 22 mgl( 1) h. bringing expected exposures in children closer to those predicted for adults. CONCLUSION: The popPK model developed can be used to optimize rifampicin exposures through dosing simulations. WHO dosing recommendations may not be achieved using currently licensed fixed dose combination formulations of TB therapy. PMID- 26613188 TI - Do sarcomere length, collagen content, pH, intramuscular fat and desmin degradation explain variation in the tenderness of three ovine muscles? AB - The longissimus (n=118) (LL), semimembranosus (n=104) (SM) and biceps femoris (n=134) (BF) muscles were collected from lamb and sheep carcases and aged for 5days (LL and SM) and 14days (BF) to study the impact of muscle characteristics on tenderness as assessed by shear force (SF) and sensory evaluation. The impact of gender, animal age, collagen content, sarcomere length (SL), desmin degradation, ultimate pH and intramuscular fat (IMF) on tenderness was examined. The main factors which influenced SF of the LL were IMF, SL and desmin degradation, but for sensory tenderness, IMF, ultimate pH and gender were the main factors. The SF and sensory tenderness of the SM was best predicted by the degree of desmin degradation. For the BF soluble collagen and animal age both influenced SF. Different factors affect tenderness across muscles and not one prediction model applied across all muscles equally well. PMID- 26613189 TI - A rapid method for the nonselective enumeration of Yersinia enterocolitica, a foodborne pathogen associated with pork. AB - An impedance method was developed as a rapid, convenient method to enumerate pure culture of Yersinia enterocolitica. Cultures were incubated in trypticase soy broth (TSB) at 30 degrees C. The BacTracTM 4000 microorganism growth analyser was used to detect impedance change of TSB representing bacteria cell numbers in the samples. Good correlations with standard plate counts were obtained (r(2)>0.95). This method is also reliable to enumerate Y. enterocolitica growing in biofilms attached to stainless steel. Compared with a standard plate count which involves dislodging biofilms from surfaces, this method is more convenient saving both time and effort. Therefore, it will be useful to study the conditions required for the biofilm growth and control of Y. enterocolitica that could be applied to the pork industry. PMID- 26613190 TI - Electric field control of magnetic properties and electron transport in BaTiO3 based multiferroic heterostructures. AB - In this paper, we report on a purely electric mechanism for achieving the electric control of the interfacial spin polarization and magnetoresistance in multiferroic tunneling junctions. We investigate micrometric devices based on the Co/Fe/BaTiO3/La0.7Sr0.3MnO3 heterostructure, where Co/Fe and La0.7Sr0.3MnO3 are the magnetic electrodes and BaTiO3 acts both as a ferroelectric element and tunneling barrier. We show that, at 20 K, devices with a 2 nm thick BaTiO3 barrier present both tunneling electroresistance (TER = 12 +/- 0.1%) and tunneling magnetoresistance (TMR). The latter depends on the direction of the BaTiO3 polarization, displaying a sizable change of the TMR from -0.32 +/- 0.05% for the polarization pointing towards Fe, to -0.12 +/- 0.05% for the opposite direction. This is consistent with the on-off switching of the Fe magnetization at the Fe/BaTiO3 interface, driven by the BaTiO3 polarization, we have previously demonstrated in x-ray magnetic circular dichroism experiments. PMID- 26613191 TI - Expression analysis of Cdx2 and Pou5f1 in a marsupial, the stripe-faced dunnart, during early development. AB - The first lineage allocation during mouse development forms the trophectoderm and inner cell mass, in which Cdx2 and Pou5f1 display reciprocal expression. Yet Cdx2 is not required for trophectoderm specification in other mammals, such as the human, cow, pig, or in two marsupials, the tammar and opossum. The role of Cdx2 and Pou5f1 in the first lineage allocation of Sminthopsis macroura, the stripe faced dunnart, is unknown. In this study, expression of Cdx2 and Pou5f1 during oogenesis, development from cleavage to blastocyst stages, and in the allocation of the first three lineages was analyzed for this dunnart. Cdx2 mRNA was present in late antral-stage oocytes, but not present again until Day 5.5. Pou5f1 mRNA was present from primary follicles to zygotes, and then expression resumed starting at the early unilaminar blastocyst stage. All cleavage stages and the pluriblast and trophoblast cells co-expressed CDX2 and POU5F1 proteins, which persisted until early stages of hypoblast formation. Hypoblast cells also show co localisation of POU5F1 and CDX2 once they were allocated, and this persisted during their division and migration. Our studies suggest that CDX2, and possibly POU5F1, are maternal proteins, and that the first lineage to differentiate is the trophoblast, which differentiates to trophectoderm after shell loss one day before implantation. In the stripe-faced dunnart, cleavage cells, as well as trophoblast and pluriblast cells, are polarized, suggesting the continued presence of CDX2 in both lineages until late blastocyst stages may play a role in the formation and maintenance of polarity. PMID- 26613192 TI - Prospective study of signalling pathways in myeloma bone disease with regard to activity of the disease, extent of skeletal involvement and correlation to bone turnover markers. AB - AIMS: The aim of our study was to address the utility of serum levels of selected parameters of myeloma bone disease (MBD) signalling with regard to the pathogenesis of multiple myeloma (MM), activity, markers of bone turnover and extent of skeletal changes. PATIENTS AND METHODS: We assessed prospectively 77 individuals with monoclonal gammopathies - 46 patients with active MM (AMM), 12 patients with smouldering MM (SMM) and 19 individuals with monoclonal gammopathy of undetermined significance (MGUS) to determine the role of HGF, MIP-1alpha, Syndecan-1, osteoprotegerin, Activin A, DKK1, Annexin A2 and NF-kappaB. RESULTS: We found significant differences of most of the parameters between MGUS and AMM, and with respect to the activity of MM assessed by International Staging System. Most of the parameters of MBD signalling correlated with traditional markers of bone turnover. CONCLUSIONS: All the signalling pathways were activated in MM with more pronounced osteoclastogenesis in comparison with bone formation but not in MGUS regardless of its risk category, suggesting that MBD is not activated in MGUS until the process of transformation into MM. The parameters of MBD signalling might precede the increase of conventional parameters of bone turnover suggesting their possible role in early indication of anti-resorption therapy. PMID- 26613193 TI - Individuals with current suicidal ideation demonstrate implicit "fearlessness of death". AB - BACKGROUND AND OBJECTIVES: Suicidal behaviour has proved to be difficult to predict, due in part to the particular limitations of introspection within suicidality. In an effort to overcome this, recent research has demonstrated the utility of indirect measures of "implicit" attitudes within the study of suicidality. However, research to date has focused predominantly on implicit self evaluations and self-death associations. No work has examined implicit evaluations of death, despite the theoretical importance of such evaluations; "fearlessness of death" is central to both the Interpersonal Theory of Suicide and the Integrated Motivational-Volitional model of suicide.. METHODS: Twenty three psychiatric patients with current suicidal ideation and twenty-five normative university students completed two versions of the Implicit Relational Assessment Procedure (IRAP) that targeted evaluations of death. One task specified personal death (i.e., was self-focused) and the other targeted death in the abstract. RESULTS: Self-focused evaluations of death reliably distinguished between the two groups, correctly classifying 74% of cases, but evaluations of death in the abstract did not. The suicidal group produced specific biases indicating a rejection of the negativity of death. Results are consistent with the definition of suicidality as involving a self-focused wish to die.. LIMITATIONS: For ethical reason, suicidal behaviours were not assessed in the normative group. Groups were therefore not mutually exclusive. This may have decreased the specificity of the IRAP. CONCLUSIONS: Suicidal ideation is associated with an implicit "fearlessness of death". The utility of implicit death-evaluations should therefore be considered alongside self-evaluations and self-death associations in the future.. PMID- 26613194 TI - An electrochemically aminated glassy carbon electrode for simultaneous determination of hydroquinone and catechol. AB - In this contribution, a very simple and reliable strategy based on the easy modification of a glassy carbon electrode (GCE) by pre-electrolyzing GCE in ammonium carbamate aqueous solution was employed for the simultaneous determination of hydroquinone (HQ) and catechol (CC). Compared with bare GCE, the incorporation of nitrogen into the GCE surface structure improved the electrocatalytic properties of GCE towards the electro-oxidation of HQ and CC. The nitrogen-introduced GCE (N-GCE) was evaluated for the simultaneous detection of HQ and CC and the linear ranges for HQ and CC were both from 5 to 260 MUM. Their detection limits were both evaluated to be 0.2 MUM (S/N = 3). The present method was applied for the determination of HQ and CC in real river water samples with recoveries of 95.0-102.1%. In addition, a possible detection mechanism of HQ and CC was discussed. PMID- 26613196 TI - Biomarkers of waterborne copper exposure in the Neotropical fish Prochilodus lineatus. AB - The main goal of the present study was to investigate the effects of acute exposure to copper (Cu) using a Neotropical freshwater fish as sentinel species through multi biomarkers analysis at different biological levels. Juveniles of Prochilodus lineatus were kept under control condition (no Cu addition in the water) or exposed to environmentally relevant concentrations of waterborne Cu (5, 9 and 20MUgL(-1)) for 96h. These concentrations were selected to bracket the current Brazilian water quality criteria for Cu in fresh water (9 and 13MUgL(-1) dissolved copper). Endpoints analyzed included ethoxyresorufin-O-deethylase (EROD), glutathione-S-transferase (GST), catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity, reduced glutathione (GSH) and metallothionein-like protein (MT) concentration, lipid peroxidation (LPO) level, tissue damage index, and incidence of free melano-macrophages (FMM) and melano macrophage centers (MMC) in the liver. They also included DNA damage (frequency of nucleoids per comet class, number of damaged nucleoids per fish and DNA damage score) in erythrocytes, as well as muscle and brain acetylcholinesterase (AChE) activity and behavioral parameters (swimming distance and velocity, time spent swimming and swimming activity in the upper and lower layers of the water column). Fish exposed to any of the Cu concentrations tested showed increased liver MT concentration and LPO level, higher number of damaged nucleoids in erythrocytes per fish, and inhibited muscle AChE activity. Also, increased liver SOD activity was observed in fish exposed to 9 and 20MUgL(-1) Cu. Fish exposed to 5 and 9MUgL(-1) Cu spent lower amount of time swimming. Fish exposed to 9MUgL(-1) Cu showed increased swimming distance and velocity while those exposed to 20MUgL( 1) Cu had lower swimming distance and velocity, as well as, spent less time swimming in the lower layer of the water column when compared to those kept under control condition. These findings indicate that Cu exposure at environmentally relevant concentrations (below or close to the current Brazilian water quality criteria) induced significant biological (histological, biochemical and genetic) and ecological (swimming and exploratory abilities) damages in the Neotropical fish P. lineatus. They also suggest that MT concentration, DNA damage (comet assay), LPO (TBARS method), SOD and AChE activity, together with swimming behavior analyses are potential biomarkers to assess and monitor areas impacted by Cu in fresh water. PMID- 26613198 TI - Quantifying plant phenotypes with isotopic labeling & metabolic flux analysis. AB - Analyses of metabolic flux using stable isotopes in plants have traditionally been restricted to tissues with presumed homogeneous cell populations and long metabolic steady states such as developing seeds, cell suspensions, or cultured roots and root tips. It is now possible to describe these and other metabolically more dynamic tissues such as leaves in greater detail using novel methods in mass spectrometry, isotope labeling strategies, and transient labeling-based flux analyses. Such studies are necessary for a systems level description of plant function that more closely represents biological reality, and provides insights into the genes that will need to be modified as natural resources become ever more limited and environments change. PMID- 26613197 TI - Skin conductance at baseline and postheel lance reflects sympathetic activation in neonatal opiate withdrawal. AB - AIM: Skin conductance (SC) provides an objective measure of autonomic system regulation through sympathetic-mediated filling of sweat glands. This study aimed to test the utility of SC to detect sympathetic activation in neonatal abstinence syndrome (NAS). METHODS: Fourteen term (mean, SE: 38.8 +/- 0.35 weeks gestational age) neonates with chronic prenatal opiate exposure were enrolled. SC (peaks/seconds and mean of peaks) was measured at baseline, during heel lance/squeeze (HLS) and recovery from HLS at 24-48 (mean 38) hours of life prior to treatment for NAS. Blinded coders with established reliability assessed neonates using the Modified Finnegan Neonatal Scoring System (MFNSS). Nonparametric tests were used to determine group differences, phase differences from baseline to HLS and HLS to recovery, and associations between MFNSS and SC measures. RESULTS: Neonates that would later require morphine treatment for NAS (n = 6) had higher baseline SC mean of peaks than those that did not require treatment (n = 8) (p < 0.05). Moreover, there were unique phase differences between groups and SC positively correlated with MFNSS (p < 0.05). CONCLUSION: SC provides early identification of NAS severity. However, a larger sample is needed to determine sensitivity and specificity of SC for early identification of NAS and treatment effectiveness. PMID- 26613199 TI - Matrix assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) for direct visualization of plant metabolites in situ. AB - Direct visualization of plant tissues by matrix assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) has revealed key insights into the localization of metabolites in situ. Recent efforts have determined the spatial distribution of primary and secondary metabolites in plant tissues and cells. Strategies have been applied in many areas of metabolism including isotope flux analyses, plant interactions, and transcriptional regulation of metabolite accumulation. Technological advances have pushed achievable spatial resolution to subcellular levels and increased instrument sensitivity by several orders of magnitude. It is anticipated that MALDI-MSI and other MSI approaches will bring a new level of understanding to metabolomics as scientists will be encouraged to consider spatial heterogeneity of metabolites in descriptions of metabolic pathway regulation. PMID- 26613195 TI - Measurement and comparison of individual external doses of high-school students living in Japan, France, Poland and Belarus-the 'D-shuttle' project. AB - Twelve high schools in Japan (of which six are in Fukushima Prefecture), four in France, eight in Poland and two in Belarus cooperated in the measurement and comparison of individual external doses in 2014. In total 216 high-school students and teachers participated in the study. Each participant wore an electronic personal dosimeter 'D-shuttle' for two weeks, and kept a journal of his/her whereabouts and activities. The distributions of annual external doses estimated for each region overlap with each other, demonstrating that the personal external individual doses in locations where residence is currently allowed in Fukushima Prefecture and in Belarus are well within the range of estimated annual doses due to the terrestrial background radiation level of other regions/countries. PMID- 26613200 TI - Examining Associations of Sexual Attraction and Attitudes on Women's Disordered Eating Behavior. AB - OBJECTIVE: We aimed to expand the scant research on disordered eating in women identifying same-sex sexual attractions. METHOD: We used multiple linear regressions to explore potential mechanisms driving disordered eating--both explicit and implicit weight bias and heterosexism--in a cross-sectional, online recruited community sample of women (N = 437). Participants endorsed a range of sexual attractions from exclusively opposite-sex (21.1%) to exclusively same-sex (19.5%) attraction. RESULTS: Findings revealed no associations between sexual attraction and disordered eating. Awareness of sociocultural norms valuing thinness accounted for disordered eating for all women, regardless of sexual attraction, and was influenced by attitudes regarding weight. Among women endorsing same-sex attractions, self-reported internalized heterosexism influenced disordered eating. DISCUSSION: Findings contradict long-held beliefs that same-sex attracted women are protected from disordered eating. They emphasize a universal risk, for all women, of sociocultural norms valuing thinness, as well as the risk of internalized heterosexism among same-sex attracted women. PMID- 26613201 TI - Improvement of renal dysfunction in a patient with hepatitis C virus-related liver cirrhosis by daclatasvir and asunaprevir combination therapy: A case report. AB - Recently, treatments for chronic hepatitis C virus (HCV) infection have been drastically improved by the development of direct-acting antiviral agents. In September 2014, dual oral therapy using daclatasvir (DCV) and asunaprevir (ASV) was approved for the treatment of chronic HCV infection in Japan. We treated a patient with HCV-related liver cirrhosis with severe leg edema due to chronic renal dysfunction using this dual oral therapy. Although serum alanine aminotransferase increased rapidly during the first week of treatment, the antiviral therapy was able to continue, and liver function recovered spontaneously. After 1 month of treatment, serum HCV RNA became continuously undetectable, and serum albumin level gradually increased. Throughout the therapy, serum creatinine level nearly normalized, and leg edema gradually improved. These improvements continued after the combination therapy was completed. HCV RNA remained undetectable following the end of therapy, and sustained virological response at 12 weeks was achieved. It has been reported that chronic HCV infection is associated with renal dysfunction and that HCV eradication can improve it. DCV and ASV combination therapy is safe for patients who have renal dysfunction and may be a suitable therapy for chronic hepatitis C patients with renal dysfunction. PMID- 26613202 TI - Stability of diagnostic assessment for autism spectrum disorder between 18 and 36 months in a high-risk cohort. AB - Children with autism spectrum disorder (ASD) are diagnosed, on average, around the age of 4 years. However, previous research has shown that the diagnosis can be made as early as 2 years, and that if the child is seen a year or more later, it is highly likely that the diagnosis will be confirmed. In this study, to examine whether diagnoses made as early as 18 months of age are also "stable," we followed a group of younger siblings of children with ASD (who are known to be at higher risk). We also examined whether the age of ASD diagnosis within this high risk group was related to the severity of children's ASD symptoms or developmental delays. Participants (n = 381) were seen at three ages: 18 months, 24 months, and 3 years. ASD symptoms, general development, and adaptive functioning were assessed at each time point. Twenty-three children were diagnosed with ASD at 18 months and a total of 61 at 24 months. Of these diagnoses, 19/23 (82.6%) and 56/61 (91.8%), respectively, were confirmed independently at 3 years. However, 45 children were diagnosed with ASD at 3 years who had not been identified at earlier visits. Children diagnosed at 18 months, in comparison to those diagnosed at 24 months, had less advanced language and adaptive skills at 18 months. Children not diagnosed with ASD until 3 years, compared with those diagnosed earlier, had more advanced language and adaptive skills, and milder ASD symptoms. Autism Res 2016, 9: 790-800. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26613203 TI - A Randomized Clinical Trial of Primary Care Brief Mindfulness Training for Veterans with PTSD. AB - OBJECTIVES: Primary care (PC) patients typically do not receive adequate posttraumatic stress disorder (PTSD) treatment. This study tested if a brief mindfulness training (BMT) offered in PC can decrease PTSD severity. METHOD: VA PC patients with PTSD (N = 62) were recruited for a randomized clinical trial comparing PCBMT with PC treatment as usual. PCBMT is a 4-session program adapted from mindfulness-based stress reduction. RESULTS: PTSD severity decreased in both conditions, although PCBMT completers reported significantly larger decreases in PTSD and depression from pre- to posttreatment and maintained gains at the 8-week follow-up compared with the control group. Exploratory analyses revealed that the describing, nonjudging, and acting with awareness facets of mindfulness may account for decreases in PTSD. CONCLUSION: Our data support preliminary efficacy of BMT for Veterans with PTSD. Whether PCBMT facilitates engagement into, or improves outcomes of, full-length empirically supported treatment for PTSD remains to be evaluated. PMID- 26613204 TI - Stepwise evolution of Elk-1 in early deuterostomes. AB - Metazoans have multiple ETS paralogues with overlapping or indiscriminate biological functions. Elk-1, one of three mammalian ternary complex factors (TCFs), is a well-conserved, ETS domain-containing transcriptional regulator of mitogen-responsive genes that operates in concert with serum response factor (SRF). Nonetheless, its genetic role remains unresolved because the elk-1 gene could be deleted from the mouse genome seemingly without adverse effect. Here we have explored the evolution of Elk-1 to gain insight into its conserved biological role. We identified antecedent Elk-1 proteins in extant early metazoans and used amino acid sequence alignments to chart the appearance of domains characteristic of human Elk-1. We then performed biochemical studies to determine whether putative domains apparent in the Elk-1 protein of a primitive hemichordate were functionally orthologous to those of human Elk-1. Our findings imply the existence of primordial Elk-1 proteins in primitive deuterostomes that could operate as mitogen-responsive ETS transcription factors but not as TCFs. The role of TCF was acquired later, but presumably prior to the whole genome duplications in the basal vertebrate lineage. Thus its evolutionary origins link Elk-1 to the appearance of mesoderm. PMID- 26613205 TI - Role of c-Jun N-terminal kinase in late nerve regeneration monitored by in vivo imaging of thy1-yellow fluorescent protein transgenic mice. AB - The restoration of function to injured peripheral nerves separated by a gap requires regeneration across it and reinnervation to target organs. To elucidate these processes, we have established an in vivo monitoring system of nerve regeneration in thy1-yellow fluorescent protein transgenic mice expressing a fluorescent protein in their nervous system. Here we demonstrated that motor and sensory nerves were regenerated in a coordinated fashion across the gap and that the functional recovery of the response to mechanical stimuli correlated well with sensory innervation to the foot. Among the mitogen-activated protein kinase inhibitors examined, only the c-Jun N-terminal kinase (JNK) inhibitors delayed functional recovery. Although it did not affect the reinnervation of the muscle, the JNK inhibitor delayed sensory nerve innervation to the skin for over 8 weeks and increased the expression of activatng transcription factor 3 (ATF3), a neuronal injury marker, in the dorsal root ganglion over the same time period. Antibodies against nerve growth factor, glia-derived neurotrophic factor, and brain-derived neurotrophic factor applied to the transection site delayed the functional recovery in this order of potency. These neurotrophic factors enhanced neurite outgrowth from cultured dorsal root ganglion neurons, and the JNK inhibitor reversed their stimulatory effects. These results suggest that JNK played roles in nerve regeneration at both early and late phases. Taken together, the present study demonstrated that neurotrophic factors released from the distal nerve may accelerate motor and sensory nerve regeneration across the gap in a coordinated fashion and reinnervation of the target organs independently. The model characterized here has the advantage of in vivo monitoring of the evaluation of morphological and functional recovery in the same mice for a long period of time. PMID- 26613206 TI - Multi-objective optimization of media nutrients for enhanced production of algae biomass and fatty acid biosynthesis from Chlorella pyrenoidosa NCIM 2738. AB - This study aimed to optimize significant medium nutrient parameters for maximization of algal lipid and biomass production by using multi objective optimization strategy. Nutrients (nitrate, phosphate and carbohydrate) were investigated to improve the lipid accumulation, biomass production and carbohydrate consumption individually and cumulative manner using a central composite design for the Chlorella pyrenoidosa NCIM 2738 cultivation. Maximum lipid, algal biomass and carbohydrate utilization for individual response optimization were found 34.8% (w/w), 1464.3mgL(-1) and 93.4%, respectively at different optimum level of selected parameters. Whereas, maximum lipid accumulation, biomass production and glucose consumption values in multi-response optimization were observed 28.9%, 1271.2mgL(-1) and 89.2%, respectively at optimum level of 16.8mM NaNO3, 300.9MUM K2HPO4 and 2.6% (w/v) glucose. The overall enhancements in lipid productivities by single and multi-response optimization in comparison with control medium conditions were found 2.35 and 2.90-fold with productivity level of 24.8 and 30.6mgL(-1)day(-1), respectively. PMID- 26613207 TI - Preparation, characterization and in vitro response of bioactive coatings on polyether ether ketone. AB - Polyether ether ketone (PEEK) is a highly heat-resistant thermoplastic with excellent strength and elastic modulus similar to human bone, making it an attractive material for orthopedic implants. However, the hydrophobic surface of PEEK implants induces fibrous encapsulation which is unfavorable for stable implant anchorage. In this study, PEEK was coated via ion-beam-assisted deposition (IBAD) using a two-layer design of yttria-stabilized zirconia (YSZ) as a heat-protection layer, and hydroxyapatite (HA) as a top layer to improve osseointegration. Microstructural analysis of the coatings showed a dense, uniform columnar grain structure in the YSZ layer and no delamination from the substrate. The HA layer was found to be amorphous and free of porosities in its as-deposited state. Subsequent heat treatment via microwave energy followed by autoclaving crystallized the HA layer, confirmed by SEM and XRD analysis. An in vitro study using MC3T3 preosteoblast cells showed improved bioactivity in heat treated sample groups. Cell proliferation, differentiation, and mineralization were analyzed by MTT assay and DNA content, osteocalcin expression, and Alizarin Red S (AR-S) content, respectively. Initial cell growth was increased, and osteogenic maturation and mineralization were accelerated most on coatings that underwent a combined microwave and autoclave heat treatment process as compared to uncoated PEEK and amorphous HA surfaces. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 560-567, 2017. PMID- 26613208 TI - Deoxycytidine kinase is downregulated under hypoxic conditions and confers resistance against cytarabine in acute myeloid leukaemia. AB - OBJECTIVES: Leukaemia initiating cells reside within specialised niches in the bone marrow where they undergo complex interactions with different stromal cell types. The bone marrow niche is characterised by a low oxygen content resulting in high expression of hypoxia-inducible factor 1 alpha in leukaemic cells conferring a negative prognosis to patients with acute myeloid leukaemia (AML). METHODS AND RESULTS: In the current study, we investigated the impact of hypoxic vs. normoxic conditions on the sensitivity of AML cell lines and primary AML blasts to cytarabine. AML cells cultured under 6% oxygen were significantly more resistant against cytarabine compared to cells cultured under normoxic conditions in proliferation and colony-formation assays. Interestingly upon cultivation under hypoxia, the expression of the cytarabine-activating enzyme deoxycytidine kinase was downregulated in all analysed AML cell lines and primary AML samples representing a possible mechanism for resistance to chemotherapy. Furthermore, the downregulation of deoxycytidine kinase could be associated with hypoxia inducible factor 1 alpha as treatment with its inhibitor BAY87-2243 hampered the downregulation of deoxycytidine kinase expression under hypoxic conditions. CONCLUSIONS: In conclusion, our data reveal that hypoxia-induced downregulation of deoxycytidine kinase represents one stroma-cell-independent mechanism of drug resistance to cytarabine in acute myeloid leukaemia. PMID- 26613209 TI - Underweight and obesity increase the risk of mortality after lung transplantation: a systematic review and meta-analysis. AB - Many studies have found an association between abnormal body mass index (BMI) and poor outcomes among lung transplant recipients. We performed a systematic review and meta-analysis to identify outcomes associated with an abnormal pretransplant BMI after lung transplantation (LTx). The MEDLINE and EMBASE databases were searched from inception to May 2015 with focus on original observational studies with post-transplant survival data in candidates with abnormal BMI (underweight, overweight, or obese). We performed meta-analyses examining survival and primary graft dysfunction after LTx. We identified 866 citations; 13 observational cohort studies involving 40 742 participants met our inclusion criteria for systematic review. Seven of the 13 were included in the meta-analysis. There was a significant risk of mortality after LTx in candidates with underweight and obesity (underweight versus normal, relative risk [RR] 1.36, 95% confidence interval [CI] 1.11-1.66, I(2) = 0%; obesity vs. normal, RR 1.90, 95% CI 1.45 2.56, I(2) = 0%; overweight vs. normal, RR 1.36, 95% CI 1.11-1.66, I(2) = 0). There was also a significant risk of primary graft dysfunction in obese (RR 1.92, 95% CI 1.39-2.65, I(2) = 0%) and overweight (RR 1.72, 95% CI, 1.32-2.24, I(2) = 0%) candidates. Lung transplant candidates who are underweight or obese have a higher risk of post-transplant mortality than recipients with a normal BMI. PMID- 26613211 TI - Incorporating Nurse-Midwifery Students into Graduate Medical Education: Lessons Learned in Interprofessional Education. AB - There is a current emphasis on interprofessional education in health care with the aim to improve teamwork and ultimately the quality and safety of care. As part of a Health Resources and Services Administration Advanced Nursing Education project, an interprofessional faculty and student team planned and implemented the first didactic coursework for nurse-midwifery and medical students at the University of California, San Francisco and responded to formative feedback in order to create a more meaningful educational experience for future combined cohorts. This article describes the process of including advanced nurse-midwifery students into 2 classes previously offered solely to medical students: 1) an elective in which students are matched with a pregnant woman to observe care that she receives before, during, and after giving birth; and 2) a required course on basic clinical care across the human lifespan. The development of these interprofessional courses, obstacles to success, feedback from students, and responses to course evaluations are reviewed. Themes identified in student course evaluations included uncertainty about interprofessional roles, disparity in clinical knowledge among learners, scheduling difficulties, and desire for more interprofessional education opportunities and additional time for facilitated interprofessional discussion. As a result of this feedback, more class time was designated for interprofessional exchange; less experienced rather than advanced midwifery students were included in both classes; and more interdisciplinary panel presentations were provided, along with clearer communication about student and clinician roles. Early project activities indicated nurse-midwifery students can be effectively included in existing medical student courses with revised curriculum and highlighted challenges that should be considered in the planning phase of similar projects in the future. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health. PMID- 26613212 TI - Fear of dental pain in Italian children: child personality traits and parental dental fear. AB - OBJECTIVES: Dental anxiety could impede dental treatment in children. Evidence shows that parents' fear of dentists contributes to children's anxiety towards dentists. The aim of the present study was to determine whether and to what extent: a) parents' anxiety and depression personality traits, b) parent's dental fear, and c) child personality traits can predict children's dental anxiety in an Italian population. METHODS: One hundred and four children (5-14 years old) and one of their parents participated in the study. Well-known and validated questionnaires were administered to children (MCDASf, CFSS-DS, TAD) and parents (FDPQ, STAI Y1, Y2, and BDI-II). RESULT: Dental anxiety is significantly associated with the anxiety personality trait and depression of the child and with parental fear of dental pain. A hierarchical regression analysis showed that, regardless of age and gender, the best predictor of child dental anxiety is parent's fear of dental pain, rather than relatively stable temperaments of the child. CONCLUSIONS: In line with the literature concerning adults, these findings highlight the children dental anxiety as a complex phenomena consisting of different components, including the child's personality traits (anxiety trait and depression) and parents' dental fear. Clinical implications of this evidence are discussed. PMID- 26613210 TI - New perspectives on the involvement of mTOR in depression as well as in the action of antidepressant drugs. AB - Despite the revolution in recent decades regarding monoamine involvement in the management of major depressive disorder (MDD), the biological mechanisms underlying this psychiatric disorder are still poorly understood. Currently available treatments require long time courses to establish antidepressant response and a significant percentage of people are refractory to single drug or combination drug treatment. These issues, and recent findings demonstrating the involvement of synaptic plasticity in the pathophysiological mechanisms of MDD, are encouraging researchers to explore the molecular mechanisms underlying psychiatric disease in more depth. The discovery of the rapid antidepressant effect exerted by glutamatergic and cholinergic agents highlights the mammalian target of rapamycin (mTOR) pathway as a critical pathway that contributes to the efficacy of these pharmacological agents in clinical and pre-clinical research. The mTOR pathway is a downstream intracellular signal that transmits information after the direct activation of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionate (AMPA) and neurotrophic factor receptors. Activation of these receptors is hypothesized to be one of the major axes involved in the synthesis of synaptogenic proteins underlying synaptic plasticity and critical to both the rapid and delayed effects exerted by classic antidepressants. This review focuses on the involvement of mTOR in the pathophysiology of depression and on molecular mechanisms involved in the activity of emerging and classic antidepressant agents. PMID- 26613213 TI - Hematologic and serum biochemical reference intervals for wild Tasmanian devils (Sarcophilus harrisii). AB - BACKGROUND: The Tasmanian devil (Sarcophilus harrisii) is a carnivorous marsupial threatened with extinction by a fatally infectious cancer known as devil facial tumor disease (DFTD). Conservation efforts including captive breeding and island translocations are underway to address this threat. OBJECTIVES: The objectives of this study were to determine hematologic and serum biochemical reference intervals (RI) to aid in health assessment of Tasmanian devils, and to examine seasonal, sex, reproductive status and age variations. METHODS: We collected jugular blood samples from individual wild Tasmanian devils at 2 different locations over a 2-year period to determine hematologic and serum biochemical RI by nonparametric methods using the central 0.95 fraction. RESULTS: A total of 307 blood samples were collected from 187 devils. Significant age differences were found for ALP, CK, cholesterol, calcium, phosphate, albumin, globulins, albumin: globulin ratio, and glucose. Significant differences between sexes were observed for AST, creatinine, and potassium. Significant seasonal or reproductive status variation in adult males or breeding females were observed for PCV, HGB, RBC, MCHC, MCH, MCV, neutrophils and lymphocytes, fibrinogen, total plasma protein, AST, ALP, ALT, GLDH, bilirubin, urea, calcium, chloride, total protein, albumin, A:G, and glucose. CONCLUSIONS: Many of the differences observed between subgroups can be explained by growth requirements, reproductive demands, and seasonal effects on activity. This study has determined comprehensive RI for the Tasmanian devil, which will be used to assess animals targeted for captive breeding and translocations, or affected by DFTD. PMID- 26613214 TI - Early or later prophylactic INSURE in preterm infants of less than 30 weeks' gestation. AB - We aimed to determine whether an early prophylactic INSURE strategy combined with early nasal continuous positive airway pressure (nCPAP) treatment could decrease the subsequent need for mechanical ventilation (MV) compared to the administration of surfactant prophylaxis later, at the 15th minute after birth, combined with early nCPAP. Infants born at <30 weeks' gestation were randomized to receive surfactant prophylaxis immediately or at the 15th minute after birth. All infants received 100 mg/kg poractant alpha, were ventilated with a T-piece resuscitator and were extubated to nCPAP if they had sufficient respiratory drive. Forty infants were analyzed in each group. Ten (25%) infants in the early prophylactic INSURE group, and 13 (32.5%) infants in the later prophylactic INSURE group could not be extubated after surfactant administration in the delivery room. Among the infants who were initially extubated to nCPAP after surfactant administration, 6 in the early prophylactic INSURE group and 4 in the later prophylactic INSURE group needed intubation for MV within the first 3 days of life (20% vs. 16.7%; P=0.73). The duration of total respiratory support (CPAP plus MV) of infants who were intubated within the first 3 days of life was shorter in the early prophylactic INSURE group than in the later prophylactic INSURE group (median: 96 h vs. 309 h; P=0.038). The incidence of all neonatal morbidities and mortality and the duration of hospitalization were similar between the groups. Our study did not demonstrate superiority of early surfactant prophylaxis combined with early nCPAP to the later administration of prophylactic surfactant with early nCPAP; however, it did detect an absolute difference in the primary outcome: need for MV within the first 3 days of life. PMID- 26613215 TI - Circulating fibroblast growth factor 23 in children on peritoneal dialysis is associated with effective dialysis. AB - Our purpose was to assess the relationship between serum fibroblast growth factor 23 (FGF23) and left ventricular function, carotid intima-media thickness (CIMT) and laboratory features in children on peritoneal dialysis (PD). The study population consisted of 17 patients (11 female; median age 7.83 years, range 0.66 17.75) undergoing PD for 22 months (range 2-98). Serum FGF23, serum phosphorus, calcium, intact parathyroid hormone (iPTH), 25(OH) vitamin D, 1,25(OH)2 vitamin D and Kt/V urea, left ventricular mass (LVM) and LVM index (LVMI) were assessed. Median FGF23 level was 29.92 pg/ml (22.7-74.76), phosphorus was 5.2 mg/dl (3.1 9.9), iPTH was 438 pg/ml (16-1446), 25(OH) vitamin D was 11 ng/ml (5-35), 1,25(OH)2 vitamin D was 11 pg/ml (2-106), Kt/V urea was 2.33 (1.01-3.84). FGF23 level was independently associated with Kt/V urea (p<0.001). We found that effective dialysis may be the leading determinant of FGF level, independent from the calcium-phosphorus-PTH axis, in pediatric PD patients. PMID- 26613216 TI - Decreased bone ultrasound velocity in premature infants conceived with assisted reproduction. AB - Quantitative ultrasound (QUS) measurement of tibial speed of sound (SOS) can be used to determine bone strength. Children conceived with assisted reproduction treatments (ART) are taller than naturally conceived (NC) children, so we hypothesized that these infants would have higher SOS levels than NC infants. Thirty-seven ART (ART group) and 51 NC neonates (NC group) were included in the study. Tibial initial SOS (iSOS) was measured within 96 hours of birth using QUS. Measurements were performed weekly until the infant was discharged from the hospital. The iSOS levels of the ART group (2823.41+/-110.8 m/sec) were lower than those of the NC group (2917.14+/-145.6 m/sec) (p=0.001). A decrease in SOS levels was observed in 39 of 53 infants who had serial scans. The difference in SOS levels between the first and last scan was significant (p<0.02). In vitro manipulation during the periconceptual period can result in metabolic alterations in bone mineral content. Contrary to our null hypothesis, bone SOS of infants in the ART group was found to be lower than in the NC group. Moreover, bone SOS decreases in early postnatal life. This result emphasizes the fact that even with advances in nutritional care, the ex utero environment remains a poor substitute for in utero development. PMID- 26613217 TI - Mannose-binding lectin may affect pregnancy outcome. AB - Mannose-binding lectin (MBL) is a component of the innate immune system and acts as a complement activator through the lectin pathway. Genetic variations of MBL and low MBL levels cause several infection problems, which may also be related to pregnancy problems. We aimed to investigate the role of MBL gene codon 54 polymorphism and serum MBL levels in pregnancy problems and premature delivery. In this prospective study, MBL gene codon 54 polymorphism and serum MBL levels were studied in 45 mothers who delivered earlier than 35 gestational weeks. The frequency of MBL gene codon 54 variant allele B was much higher (homozygous 4.4% and heterozygous 33.3%) in the study group mothers than the previously reported frequency in the healthy Turkish population (homozygous 2-6%, heterozygous 12 20%). MBL variant allele B frequency was closely related to low MBL levels (<0.1 MUg/ml), vaginitis and increased IL-6 levels. The median MBL levels were lower than the critical level of 0.1 MUg/ ml in study mothers who had recurrent miscarriage, infertility, preeclampsia, gestational diabetes mellitus, preterm premature rupture of membranes with duration of longer than 72 hours, tocolysis, histological chorioamnionitis, urinary tract infection and vaginitis. MBL gene codon 54 variant allele B is related to low serum MBL levels, increased IL-6 levels, genitourinary infections and may cause pregnancy-related problems such as infertility, recurrent miscarriage and preterm delivery. PMID- 26613218 TI - Parental perceptions concerning the effect of center-based childcare on quality of life for healthy 2- to 4-year-old children. AB - In this study, we investigated the effects of center-based childcare on the quality of life in healthy 2- to 4-year-old children. The study was conducted in the Baskent University School of Medicine Department of Pediatrics, and comprised 168 healthy 2- to 4-year-old children followed in the well-child outpatient clinic. After giving informed consent, the accompanying parent was asked to complete the parent proxy report of the Pediatric Quality of Life Inventory TM 4.0 and a sociodemographic information form. Among the children in the study group, 42.26% (n=71) were girls and 31.36 % (n=51) were attending childcare; 69% of the respondent parents were mothers (n=116). The mean total scale score of the study sample was 82.71 +/-11.77. Total scale scores as well as psychosocial health, physical health, social functioning and emotional functioning subscale scores were significantly higher in children attending childcare. In particular, mothers whose children were attending center-based childcare perceived their children's quality of life as higher, regardless of their educational and employment status. Improving access to center-based childcare may help to improve the quality of life for young children in Turkey. PMID- 26613219 TI - Brainstem auditory evoked potentials in late preterm infants at term-equivalent age. AB - To detect differences between late preterm and term infants in the brainstem auditory evoked response (BAER) variables that predispose to neurodevelopmental abnormalities, 36 late preterm infants and 87 term infants were recruited. Data collected with the click level at 70 dB nHL were used for analysis. The latencies of waves I (2.74+/-0.20 msec vs. 2.74+/-0.42 msec), III (5.55+/-0.33 msec vs. 5.53+/-0.45 msec) and V (7.55+/-0.34 msec vs. 7.59+/-0.44 msec), and the interpeak intervals for late preterm infants were similar to those for term infants. There were no significant differences between late preterm and term infants in amplitudes I (0.26+/-0.11 MUV vs. 0.24+/-0.10 MUV) and V (0.25+/-0.06 MUV vs. 0.28+/-0.11 MUV), and in the V/I amplitude ratio (1.10+/-0.47 vs. 1.23+/ 0.46). There were no significant differences in the BAER variables between late preterm infants and term infants. Late preterm birth does not appear to have marked effects on neonatal BAER or development of the brainstem. PMID- 26613220 TI - Neonates with inborn errors of metabolism: spectrum and short-term outcomes at a tertiary care hospital. AB - We aimed to evaluate the neonates diagnosed as IEM in our neonatal intensive care unit and their outcomes. Among 2994 neonates hospitalized, 51 were diagnosed as IEM (1.7%). Admission complaints were poor feeding, decreased activity, jaundice, seizures, abnormal screening and respiratory problems. Phenylketonuria (11), organic acidemias (8), maple syrup urine disease (5), citrullinemia (5), galactosemia (4), nonketotic hyperglycinemia (4) and tyrosinemia (2) were the most commonly diagnosed IEMs. The follow-up period was 2.5-43 months. Among the 33 neonates followed, 19 had normal development, 9 had developmental delays and 5 had cerebral palsy according to the Guide for Monitoring Child Development. Postnatal age on admission, Apgar score at 5 minutes, being transferred, peritoneal dialysis, cranial ultrasonographic findings, consanguinity and sibling history had significant effects on outcome. Early diagnosis through expanded neonatal screening in countries with high rates of consanguinity, enabling the initiation of early treatment, is essential for achieving low mortality rates and good prognoses. PMID- 26613221 TI - Association between teething and independent walking in healthy children. AB - Developing teeth provide a reliable indication of maturation and biological age. The objective of this study was to establish whether there is any association between the time of emergence of the first primary tooth and the time when independent walking occurs. A cross-sectional study was conducted with a sample of 206 healthy children (95 girls and 111 boys) aged 12 to 60 (mean: 29.79+/ 0.66) months who were able to walk independently. The study was conducted using a questionnaire that was filled out by the parents. The first primary tooth emerged at 6.86+/-0.14 (min: 3-max: 13) months; the mean independent walking time was 12.58+/-2.15 (min: 8.50-max: 24.00) months. There was no correlation between the first teething and independent walking times (r=0.045, p=0.523). Factors such as breastfeeding status, intake of vitamins, walker usage and body mass index were found not to affect the time of either emergence of the first deciduous tooth or independent walking. To the best of our knowledge, this is the first paper in literature to have researched the relationship between the time of emergence of the first deciduous tooth and that of independent walking. It should be explained to parents that there is no relationship between the two in order to resolve anxiety when their child acquires a tooth but does not walk, or vice versa. PMID- 26613222 TI - The effect of gynecomastia on body image perception and gender roles in adolescents. AB - The aim of our study was to evaluate the effect of gynecomastia on body image perception and gender roles in adolescents. Forty-seven adolescents with gynecomastia and 63 healthy adolescents were enrolled in the study. The Body Image Perception Scale (BIPS) and the Bem Gender Role Inventory (BGRI) were administered to the study group after the first evaluation and also one month later. The percentage of adolescents with a BIPS score lower than the median was higher in the study group than in the control group, although there was no significant difference. Additionally, considering the single item "my breasts," it was observed that body image perception disturbance existed mostly, if not entirely, in relation to this body part. After detailed information regarding gynecomastia was given during the first clinical session, the BIPS score improved at the one-month follow-up, emphasizing the importance of informing and educating patients regarding this condition. BGRI results showed that gender roles of patients with gynecomastia are not influenced in the feminine direction. PMID- 26613223 TI - Eight different viral agents in childhood acute gastroenteritis. AB - Viral gastroenteritis is the most frequent cause of acute gastroenteritis (AGE) of childhood. The aim of this study was to determine the prevalence of viral agents including astrovirus, rotavirus, adenovirus, enterovirus, norovirus, parechovirus, Aichivirus and sapovirus in children with AGE in a pediatric Turkish population. Fecal specimens of 240 children with AGE were investigated by polymerase chain reaction, and viral agents were identified in 131 (54.6%) samples. The distribution of viral agents was as follows: 56 (42.8%) norovirus, 44 (33.6%) rotavirus, 29 (22.1%) enterovirus, 21 (16.0%) adenovirus, 21 (16.0%) parechovirus, 5 (3.8%) sapovirus and 1 (0.8%) Aichivirus. Single and multiple viral agents were detected in 38.8% and 15.8% of patients, respectively. The duration of hospitalization was longer in children with multiple viral agents than in those infected with a single viral agent (p<0.001). While the highest rate of rotavirus infection was detected in winter, the highest rate of norovirus was found in the summer. In conclusion, norovirus and rotavirus are the most frequent causes of childhood AGE in our country. PMID- 26613224 TI - Human herpesvirus 6 infection mimicking measles: two pediatric cases. AB - Measles is a highly contagious viral infection associated with clinical symptoms such as fever, cough, conjunctivitis, coryza, eruption and increased serum immunoglobulin M (IgM) antibodies. A clinical diagnosis is easily established when the chain of infection can be followed. However, Japan is currently experiencing sporadic measles outbreaks, which complicate the establishment of diagnosis. Furthermore, other exanthematous infections such as rubella, human parvovirus B19, human herpesvirus 6 (HHV-6) and HHV-7 present with clinical symptoms and IgM antibody levels similar to those in measles. Therefore, real time polymerase chain reaction virogene testing has been part of Japan's standard diagnostic protocol for measles since 2010. This report presents two pediatric cases clinically resembling measles that were diagnosed as HHV-6 based on a virogene detection test. This underscores the importance of performing pathogen testing to confirm a diagnosis when measles is suspected. PMID- 26613225 TI - Primary laryngeal lymphoma in a child. AB - Malignant tumors of the larynx are very rare in children. They are often diagnosed late, since the initial symptoms are attributed to the process of larynx development or to other, more common pediatric diseases. Early visualization of the larynx with the aid of flexible or rigid fiberoptic laryngoscopy is essential in children having symptoms suggestive of laryngeal disease. Laryngeal lymphoma in children is exceptionally unusual. The certainty of the diagnosis, which is often very difficult to achieve, is generally confirmed by a tissue biopsy. In the present work, we describe the case of a non Hodgkin lymphoblastic T-cell lymphoma of the larynx in an eight-year-old boy. PMID- 26613226 TI - Datura stramonium poisoning in a child. AB - Hallucinogenic plant poisoning in children is a significant problem for the emergency physician. We describe the case of a boy who had slurred speech, fever, hallucinations, tachycardia, dilated pupils, confusion and disorientation. He had no history of drug use or toxin intake. All signs and symptoms were improved by supportive therapy within 48 hours. It turned out that the patient had ingested seeds of Datura stramonium in a neighbor's garden two days previously. The medical history should be taken repeatedly in cases of unknown etiology, and physicians should keep in mind the possibility that unexplained anticholinergic toxidromes could be the result of exposure to toxic plants, in particular those containing atropine and atropine derivates. PMID- 26613227 TI - Tuberculous liver abscess in an immunocompetent child with pulmonary tuberculosis as a cause of fever of unknown origin. AB - Infectious diseases are the leading cause of FUO. A case of prolonged fever with hepatic and pulmonary tuberculosis as a final diagnosis is herein presented. A 4 year-old, otherwise healthy boy presented with an axillary temperature of up to 39.5oC for the previous 3 weeks. His medical history revealed an occasional increase in body temperature up to 38.5oC for the last 6 months. Physical examination revealed coarse breath sounds on the basal lung area. Chest X-ray showed mediastinal lymphadenomegaly and computed tomography revealed paratracheal conglomerated lymph nodes and a groundglass appearance on the right lung. There were multiple contrast-enhanced, hypoechoic nodules with central necrosis in the liver parenchyma on abdominal magnetic resonance imaging. Open liver biopsy yielded chronic granulomatous inflammation compatible with pathological findings of tuberculosis infection. The culture specimen was positive for Mycobacterium tuberculosis. The patient improved rapidly after antituberculous therapy was initiated. Tuberculosis, especially in its disseminated form, poses a distinct diagnostic challenge in cases of prolonged fever with unproven etiology, and thus persistence should be exercised in disclosing the cause of such fevers. PMID- 26613228 TI - Idiopathic central diabetes insipidus presenting in a very low birth weight infant successfully managed with lyophilized sublingual desmopressin. AB - Neonatal central diabetes insipidus (DI) is an extremely rare disorder that can cause severe morbidity and mortality. We have reported a very low birth weight infant with idiopathic central DI presenting in the first month of life who was successfully treated with sublingual desmopressin therapy. In this report, we emphasize that central DI should be kept in mind in an infant with unexplained hypernatremia and polyuria. Timely diagnosis and treatment with lyophilized desmopressin may prevent severe morbidity and mortality. PMID- 26613229 TI - Two cases of hereditary benign telangiectasia in Turkey: sporadic occurrence with punctate telangiectasias surrounded by anemic halos. AB - Hereditary benign telangiectasia (HBT) is a very uncommon, genetically inherited, benign skin disorder, identified by widespread cutaneous telangiectasias. Herein, we present two sporadic cases of HBT that were admitted to the dermatology clinic for multiple punctate telangiectasias surrounded by anemic halos, favoring sun exposed areas. These cases had no mucosal or visceral involvement and exhibited no family history of the disorder. The phenotypes of HBT are clinically and genetically heterogeneous. More clinical experience and genetic analyses are needed to understand the basis for the genetic heterogeneity and to determine genotype-phenotype correlations. We aimed to emphasize the hereditary and clinical heterogeneity of HBT by presenting two cases of HBT with punctate telangiectasias surrounded by anemic halos, with a sporadic occurrence. PMID- 26613230 TI - Chronic lip swelling as the sole presentation of Crohn's disease: three case reports. AB - Chronic lip swelling may be a clinical sign of a systemic disease, such as Crohn's. We report two cases of children in Greece where the chronic lip swelling was not only the initial, but the sole clinical symptom of Crohn's, and another case with only granulomatous cheilitis up to now. All lip biopsies revealed granulomatous cheilitis. The ileocolonoscopy revealed granulomatous ileitis, and the video capsule endoscopy aphthous lesions in the jejunum in the first two cases. The diagnosis of Crohn's was then established, and treatment was started. In the third case only granulomatous cheilitis was revealed. He was started on minocycline and corticosteroids and remains under frequent monitoring in case he should develop Crohn's. Clinicians should bear in mind that inflammatory bowel disease may present with atypical symptoms. This could thus be the case for any child with persistent lip swelling, and therefore further examinations should be performed to establish the diagnosis. PMID- 26613231 TI - Angiomatoid fibrous histiocytoma: case report and review of the literature. AB - Angiomatoid fibrous histiocytoma is a rare soft tissue tumor of uncertain differentiation and low metastatic potential, which occurs predominantly in children and young adults. It occurs mostly within the extremities, trunk, head and neck. It can be associated with systemic manifestations such as anemia, pyrexia and malaise. Its morphology is distinct, with an outer shell of lymphoid tissue, sheets of dendritic-like tumor cells with bland nuclei and blood-filled cystic cavities. Herein, we present a case of angiomatoid fibrous histiocytoma with systemic symptoms before any mass was clinically detectable, arising in the scalp of a 10-year-old girl. PMID- 26613232 TI - Acute lobar nephronia: value of unique magnetic resonance imaging findings in diagnosis and management. AB - Acute lobar nephronia (ALN) as a focal form of acute renal bacterial infection is a fairly rare entity. Although the treatment approaches differ considerably, ALN is clinically indistinguishable from renal abscess. Therefore, urinary imaging studies play a crucial role in accurate diagnosis and follow-up. Renal ultrasonography and computed tomography imaging findings have previously been reported; herein for the first time in the English-language literature, we report a case of a 5-year-old girl with ALN whose diagnosis was based upon magnetic resonance imaging findings. PMID- 26613233 TI - Spasmodic torticollis associated with sertraline in a child and an adolescent. AB - Movement disorders or extrapyramidal symptoms (EPS) associated with selective serotonin reuptake inhibitors (SSRIs) have been reported. Although akathisia was found to be the most common EPS, and fluoxetine was implicated in the majority of the adverse reactions, there were also cases with EPS due to sertraline treatment. We present a child and an adolescent who developed torticollis (cervical dystonia) after using sertraline. To our knowledge, the child case is the first such report of sertraline-induced torticollis, and the adolescent case is the third in the literature. PMID- 26613234 TI - Resolution of food-induced anaphylaxis in DOCK8-deficient patients following bone marrow transplantation. PMID- 26613236 TI - Narcissistic Vulnerability and Grandiosity as Mediators Between Insecure Attachment and Future Eating Disordered Behaviors: A Prospective Analysis of Over 2,000 Freshmen. AB - OBJECTIVE: This study aimed to build on existing literature by examining the potential mediating role of two variants of narcissism (grandiosity and vulnerability) in explaining part of the underlying mechanism by which insecure (avoidant and anxiety) attachment affects behavioral elements of eating pathology (dieting and bulimic behaviors). METHOD: Longitudinal data collected from 2,055 freshman college students (52.2% women; mean age 18.34 years) were analysed using a latent variable structural equation modelling approach, controlling for initial levels of the endogenous (i.e., dependent) latent variables and holding body mass index, anxiety, stress, depression, and self-esteem levels as time-varying covariates. RESULTS: The effect of attachment anxiety on future bulimic behaviors was fully mediated through vulnerable narcissism (i.e., no significant direct link between attachment anxiety and bulimic behaviors), whereas grandiose narcissism fully mediated the association between attachment avoidance and future dieting behaviors. Dieting also predicted future bulimic behaviors and served as an additional (full) mediator between grandiose narcissism and bulimic behaviors. Differences in the strength of these associations across gender were not observed, and all indirect effects were statistically significant. CONCLUSION: Overall, the findings (a) seem to support the theoretical postulations linking different insecure attachment experiences to different narcissistic tendencies, (b) imply that specific insecure attachment patterns may pass through different mediating pathways (narcissistic grandiosity and vulnerability) to specific behavioral elements of eating pathology (dieting and bulimic behaviors) regardless of gender, and (c) suggest that individuals with high grandiose narcissistic levels may not be protected from bulimic behaviors as previously indicated. PMID- 26613237 TI - Simultaneous quantification of catechin, epicatechin, liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, piperine and glycyrrhetinic acid in rat plasma by HPLC-MS/MS: application to a pharmacokinetic study of Longhu Rendan pills. AB - A sensitive, specific, accurate HPLC-MS/MS method was developed and validated for the simultaneous quantification of catechin, epicatechin, liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, piperine and glycyrrhetinic acid from Longhu Rendan pills in rat plasma. Chromatographic separation was performed with a Hypersil Gold C18 column using a gradient of methanol and 0.01% acetic acid containing 0.2 mm ammonium acetate as mobile phase. The analytes were quantified on a triple quadrupole mass spectrometer, operating in selected reaction monitoring mode and switching the electrospray ion source polarity between positive and negative modes in a single run. The calibration curves of catechin, epicatechin, liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, piperine and glycyrrhetinic acid were linear over the concentration ranges of 5-2000, 5-2000, 0.5-200, 0.5-200, 0.25-100, 0.25-100, 0.025-10 and 0.50-200 ng mL(-1) , respectively. The intra- and inter-assay precisions and accuracies were <11.6 and 91.9-108.2%, respectively, for all analytes. Matrix effects for all analytes were between 88.2 and 114.2%. Stability testing showed that all analytes were stable in plasma at 24 degrees C for 3 h, at 4 degrees C for 24 h, after three freeze-thaw cycles, and at -80 degrees C for 15 days. The method was successfully applied to an in vivo study evaluating the pharmacokinetics of multiple nonvolatile compounds following intragastric administration of Longhu Rendan pills to rats. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26613235 TI - The Effects of Exogenous Administration of Human Coagulation Factors Following Pig-to-Baboon Liver Xenotransplantation. AB - We sought to determine the effects of exogenous administration of human coagulation factors following pig-to-baboon liver xenotransplantation (LXT) using GalT-KO swine donors. After LXT, baboons received no coagulation factors (historical control, n = 1), bolus administration of a human prothrombin concentrate complex (hPCC; 2.5 mL/kg, n = 2), continuous infusion of hPCC (1.0 mL/h, n = 1) or continuous infusion of human recombinant factor VIIa (1 ug/kg per hour, n = 3). The historical control recipient demonstrated persistent thrombocytopenia despite platelet administration after transplant, along with widespread thrombotic microangiopathy (TMA). In contrast, platelet levels were maintained in bolus hPCC recipients; however, these animals quickly developed large-vessel thrombosis and TMA, leading to graft failure with shortened survival. Recipients of continuous coagulation factor administration experienced either stabilization or an increase in their circulating platelets with escalating doses. Furthermore, transfusion requirements were decreased, and hepatic TMA was noticeably absent in recipients of continuous coagulation factor infusions compared with the historical control and bolus hPCC recipients. This effect was most profound with a continuous, escalating dose of factor VIIa. Further studies are warranted because this regimen may allow for prolonged survival following LXT. PMID- 26613238 TI - Synthesis of New Congeners of 1-methyl-3-aminoisoquinolines, Evaluation of Their Cytotoxic Activity, In Silico and In Vitro Study of Their Molecular Targets as PDE4B. AB - To examine the cytotoxic activity of congeners of 3-amino-isoquinoline, we performed the phenotypic screening using panel of 60 cell lines and found that (N (6,7-dimethoxy-1-methyl-isoquinolin-3-yl)-4-{[(1-ethyl-4-methyl-1H-pyrazol-3 yl)methyl]amino}benzamide (4d)) exhibited the significant effect against different tumor cell lines while showing the high activity toward human colorectal cancer HCT-116 cells (IC50 = 18 MUm) and human breast cancer T-47D cells (GI50 = 1.9 MUm). Virtual screening indicated that these compounds target protein kinases and phosphodiesterases (PDE). However, wet screening among panel of protein kinases did not show any significant activity. By contrast, 50 MUm of 4c and 4d inhibited the growth of HKe3-mtKRAS spheroids in the 3D floating (3DF) culture suggesting that 4c and 4d target PDE4B which is selectively upregulated by mtKRAS in 3DF culture. PMID- 26613239 TI - Blood-brain barrier permeability following traumatic brain injury. AB - BACKGROUND: Brain edema and intracranial hypertension is deleterious after traumatic brain injury (TBI), but the underlying pathophysiology is complex and poorly understood. One major subject of controversy is the time course and extent of blood-brain barrier (BBB) dysfunction following trauma, and previous studies in humans have only provided semi-quantitative data. The objective of the present study was therefore to quantify changes in BBB-permeability in the early course of TBI, when brain edema is still evolving. METHODS: Sixteen non-consecutive brain trauma patients and two controls were included. Following i.v. injection of iohexol and CT perfusion scans, patients were scanned eight times from 4 to 25 minutes. Blood to brain transfer constant (Ki) for iohexol (molecular weight 821 D), reflecting permeability and available area for diffusion, was calculated offline by Patlak plot analysis of the enhancement curves of intracerebral large venous vessels and pericontusional brain parenchyma. RESULTS: In non-ischemic tissue surrounding contusions and hematomas Ki was increased 2- to 10-fold compared to normal tissue, reaching maximal values of 0.5 mL/min/100 g. In non injured areas and in controls Ki was about 0.06 mL/min/100 g. The increase was more pronounced in the most severely injured patients, and was detectable within 24 hours after trauma and up to five days after. CONCLUSIONS: Our results suggest that traumatic brain injury is associated with early focal increases in small molecular BBB-permeability. The results indicate that in the injured brain, capillary hydrostatic and oncotic pressures may influence edema formation. PMID- 26613240 TI - The association between the ultrasound-guided Serratus Plane Block and PECS I Block can represent a valid alternative to conventional anesthesia in breast surgery in a seriously ill patient. PMID- 26613245 TI - Incidence and characteristics of early childhood wheezing, Dhaka, Bangladesh, 2004-2010. AB - BACKGROUND: Early childhood wheezing substantially impacts quality of life in high-income countries, but data are sparse on early childhood wheezing in low income countries. We estimate wheezing incidence, describe wheezing phenotypes, and explore the contribution of respiratory viral illnesses among children aged <5 years in urban Bangladesh. METHODS: During 2004-2010, respiratory illness surveillance was conducted through weekly home visits. Children with fever or respiratory illness were referred for examination by study physicians including lung auscultation. During 2005-2007, every fifth referred child had nasal washes tested for human metapneumovirus, respiratory syncytial viruses, and influenza and parainfluenza viruses. RESULTS: During April 2004-July 2010, 23,609 children were enrolled in surveillance. Of these, 11,912 (50%) were male, median age at enrollment was 20 months (IQR 5-38), and 4,711 (20%) had >=1 wheezing episode accounting for 8,901 episodes (733 [8%] associated with hospitalization); 25% wheezed at <1 year of age. Among children aged <5 years, incidences of wheezing and wheezing hospitalizations were 2,335/10,000 and 192/10,000 child-years. Twenty-eight percent had recurrent wheezing. Recurrent versus non-recurrent wheezing episodes were more likely to be associated with oxygen saturation <93% (OR 6.9, 95%CI 2.8-17.3), increased work of breathing (OR 1.6, 95%CI 1.4-1.8), and hospitalization (OR 2.0, 95%CI 1.6-2.4). Respiratory viruses were detected in 66% (578/873) of episodes with testing. CONCLUSION: In urban Bangladesh, early childhood wheezing is common and largely associated with respiratory virus infections. Recurrent wheezing is associated with more severe illness and may predict children who would benefit most from closer follow-up and targeted interventions. Pediatr Pulmonol. 2016;51:588-595. (c) 2015 Wiley Periodicals, Inc. PMID- 26613246 TI - Functional and Morphological Parameters with Tissue Characterization of Cardiovascular Magnetic Imaging in Clinically Verified "Infarct-like Myocarditis". AB - PURPOSE: Cardiac magnetic resonance (CMR) has increasingly proved to be a valuable diagnostic tool for evaluating patients with suspected myocarditis. The objective of this study was to evaluate the diagnostic value of functional and morphological parameters including tissue characterization in patients with "infarct-like myocarditis". MATERIALS AND METHODS: 43 patients with clinically verified cases of "infarct-like myocarditis" (median time to MRI scanning after admission for acute symptoms 3 days) and 35 control patients matched by age and sex were included in this retrospective case control study. In this study we used a 1.5 T MRI scanner conducting steady-state-free-precession sequences, T2 weighted imaging, T1-weighted imaging before and after contrast administration and late gadolinium enhancement sequences. According to the recommendations for CMR diagnosis of myocarditis (Lake Louise consensus criteria), a scan was positive for acute myocarditis if 2 of 3 CMR criteria were present. RESULTS: 30 % of the patients with "infarct-like myocarditis" had a reduced left ventricular ejection fraction, 11 % had an increased LV end-diastolic volume index and 35 % had an increased LV mass index. The sensitivity of wall motion abnormalities was 63 % with a regional distribution in 49 %. In 47 % of cases regional wall motion abnormalities were present in the lateral left ventricular segments. Pericardial effusions were discovered in 65 % of cases with a circular appearance in 21 % and focal manifestation in 44 %. The diagnostic sensitivity, specificity, and accuracy of CMR in patients with "infarct-like myocarditis" were 67 %, 100 % and 82 %, respectively. The LGE alone was the most sensitive test parameter with 86 %, providing a specificity of 100 % and accuracy of 92 %. CONCLUSION: Our study results can be applied to the subgroup of patients with "infarct-like myocarditis", where we found that LGE alone was the most sensitive test parameter. In addition to tissue characterization, the functional and morphological analysis of patients with acute myocarditis provides a useful further diagnostic tool. KEY POINTS: *Infarct-like myocarditis can be diagnosed by CMR with high validity and reliability. *LGE allone performed best with a sensitivity of 86 %. *Functional and morphological CMR parameters in addition to tissue characterization are useful tool in the diagnosis of acute myocarditis. PMID- 26613247 TI - Structural determinants of ligand binding in the ternary complex of human ileal bile acid binding protein with glycocholate and glycochenodeoxycholate obtained from solution NMR. AB - Besides aiding digestion, bile salts are important signal molecules exhibiting a regulatory role in metabolic processes. Human ileal bile acid binding protein (I BABP) is an intracellular carrier of bile salts in the epithelial cells of the distal small intestine and has a key role in the enterohepatic circulation of bile salts. Positive binding cooperativity combined with site selectivity of glycocholate and glycochenodeoxycholate, the two most abundant bile salts in the human body, make human I-BABP a unique member of the family of intracellular lipid binding proteins. Solution NMR structure of the ternary complex of human I BABP with glycocholate and glycochenodeoxycholate reveals an extensive network of hydrogen bonds and hydrophobic interactions stabilizing the bound bile salts. Conformational changes accompanying bile salt binding affects four major regions in the protein including the C/D, E/F and G/H loops as well as the helical segment. Most of these protein regions coincide with a previously described network of millisecond time scale fluctuations in the apo protein, a motion absent in the bound state. Comparison of the heterotypic doubly ligated complex with the unligated form provides further evidence of a conformation selection mechanism of ligand entry. Structural and dynamic aspects of human I-BABP-bile salt interaction are discussed and compared with characteristics of ligand binding in other members of the intracellular lipid binding protein family. PROTEIN DATA BANK ACCESSION NUMBERS: The coordinates of the 10 lowest energy structures of the human I-BABP : GCDA : GCA complex as well as the distance restraints used to calculate the final ensemble have been deposited in the Brookhaven Protein Data Bank with accession number 2MM3. PMID- 26613248 TI - Use of Palliative Endocrine Therapy in Patients with Hormone Receptor-Positive Distant Metastatic Breast Cancer: How Often, How Effective, How Long? AB - BACKGROUND: This study provides real-world clinical evidence regarding palliative endocrine therapy (ET) in breast cancer (BC). The main questions to be answered were: how often and how long did patients receive ET? A particular aspect was the analysis of compliance and persistence with ET. METHODS: An analysis of a nonselected/consecutive cohort of women with distant metastatic hormone receptor positive BC (n = 205) was conducted. RESULTS: In all, 165 patients (80.5%) received ET during the palliative disease course. The noncompliance rate was 1.5%. Sixty-seven patients (40.6%) had ET as the only antineoplastic therapy. The median number of therapy lines was 2, and the median duration was 18 months. The median metastatic disease survival (MDS) was 34 months. In patients who had an MDS of >=9 months (n = 145; 87.9%), during 70.6% of the MDS time only ET had been administered. Patients who were naive to ET more often had a good response to and a longer duration of palliative ET than those who were not. The nonpersistence rate was 4.3%. CONCLUSIONS: Excluding the few patients who had a rapidly progressive course, the disease was controlled for about 70% of the entire palliative disease course with ET alone. Only very few patients were nonpersistent with ET and consciously stopped a still effective, ongoing ET. PMID- 26613249 TI - Evaluating the Ability of the Bedside Index for Severity of Acute Pancreatitis Score to Predict Severe Acute Pancreatitis: A Meta-Analysis. AB - OBJECTIVE: To evaluate the diagnostic performance of the bedside index for severity in acute pancreatitis (BISAP) score in predicting severe acute pancreatitis (SAP). MATERIALS AND METHODS: A systematic search was conducted using PubMed, Cochrane library and EMBASE databases up to May 2014, and 9 related studies, including 1,972 subjects, were reviewed. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnosis of odds ratio (DOR) and hierarchic summary receiver-operating characteristic (HSROC) curves, as well as the area under the HSROC curve (AUC), were assessed using the HSROC and bivariate mixed effects models. Moreover, a subgroup analysis stratified by cutoff value was performed to measure the effect of the diagnostic threshold on the performance of the BISAP score. Finally, publication bias was assessed using Deeks' funnel plot asymmetry test. Statistical analyses were performed using the STATA 12.0 software. RESULTS: The pooled sensitivity, specificity, PLR, NLR and DOR of the BISAP for predicting SAP were 64.82% (95% CI: 54.47-73.74%), 83.62% (95% CI: 70.03-91.77%), 3.96 (95% CI: 2.27-6.89), 0.42 (95% CI: 0.34-0.52) and 9.41 (95% CI: 5.38-16.45), respectively. The AUC was 0.77 (95% CI: 0.73-0.80). Moreover, the subgroup analysis results demonstrated that the BISAP cutoff point at 3 had a higher specificity and greater accuracy than at 2 to predict SAP. No significant publication bias was detected across the studies (p = 0.359). CONCLUSION: The BISAP score showed low sensitivity but high specificity for assessing the severity of acute pancreatitis. PMID- 26613250 TI - Effects of FGFR Signaling on Cell Proliferation and Differentiation of Apert Dental Cells. AB - The Apert syndrome is a rare congenital disorder most often arising from S252W or P253R mutations in fibroblast growth factor receptor (FGFR2). Numerous studies have focused on the regulatory role of Apert FGFR2 signaling in bone formation, whereas its functional role in tooth development is largely unknown. To investigate the role of FGFR signaling in cell proliferation and odontogenic differentiation of human dental cells in vitro, we isolated dental pulp and enamel organ epithelia (EOE) tissues from an Apert patient carrying the S252W FGFR2 mutation. Apert primary pulp and EOE cells were established and shown to exhibit normal morphology and express alkaline phosphatase under differentiation conditions. Similar to control cells, Apert dental pulp and EOE cells expressed all FGFRs, with highest levels of FGFR1 followed by FGFR2 and low levels of FGFR3 and FGFR4. However, Apert cells had increased cell growth compared with control cells. Distinct from previous findings in osteoblast cells, gain-of-function S252W FGFR2 mutation did not upregulate the expression of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFRalpha), but elevated extracellular signal-regulated kinase (ERK) signaling in cells after EGF stimulation. Unexpectedly, there was little effect of the S252W mutation on odontogenic gene expression in dental pulp and EOE cells. However, after inhibition of total FGFR signaling or ERK signaling, the expression of odontogenic genes was upregulated in both dental cell types, indicating the negative effect of whole FGFR signaling on odontogenic differentiation. This study provides novel insights on FGFR signaling and a common Apert FGFR2 mutation in the regulation of odontogenic differentiation of dental mesenchymal and epithelial cells. PMID- 26613251 TI - Resveratrol Regulates Activated Hepatic Stellate Cells by Modulating NF-kappaB and the PI3K/Akt Signaling Pathway. AB - In the present study, we investigated whether resveratrol could suppress the hepatic fibrogenesis in activated hepatic stellate cells. The immortalized rat hepatic stellate cells, t-HSC/Cl-6, were treated with resveratrol 1 h prior to lipopolysaccharide (LPS, 1 MUg/mL). Resveratrol decreased t-HSC/Cl-6 cell viability at much lower concentrations within 24 h. Resveratrol pretreatment also decreased the LPS-induced protein expression of alpha-SMA and collagen I. In addition, resveratrol significantly reduced the protein expression of Toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88), and the expression of phosphorylated phosphatidylinositol 3-kinase (PI3K) and phosphorylated serine/threonine kinase B (Akt). Moreover, resveratrol markedly blocked the translocation of nuclear factor (NF)-kappaB in LPS-activated HSCs. Furthermore, resveratrol inhibited HSCs activation through stimulating LXRbeta, but did not influence LXRalpha. Overall, we conclude that the antifibrotic effect of resveratrol is the result of blocking NF-kappaB activation and PI3K/Akt phosphorylation, which inhibits HSC activation to obstruct liver fibrosis. Thus, resveratrol may be a natural agent for preventing hepatic fibrosis. PMID- 26613252 TI - Iron in Frontotemporal Lobar Degeneration: A New Subcortical Pathological Pathway? AB - INTRODUCTION: Brain iron homeostasis dysregulation has been widely related to neurodegeneration. In particular, human haemochromatosis protein (HFE) is involved in iron metabolism, and HFE H63D polymorphism has been related to the risk of amyotrophic lateral sclerosis and Alzheimer's disease. Recently, iron accumulation in the basal ganglia of frontotemporal lobar degeneration (FTLD) patients has been described. OBJECTIVE: To explore the relationship between HFE genetic variation and demographic, clinical and imaging characteristics in a large cohort of FTLD patients. METHODS: A total of 110 FTLD patients underwent neuropsychological and imaging evaluation and blood sampling for HFE polymorphism determination. HFE H63D polymorphism was considered in the present study. Two imaging approaches were applied to evaluate the effect of HFE genetic variation on brain atrophy, namely voxel-based morphometry and region of interest-based probabilistic approach (SPM8; Wellcome Trust Centre for Neuroimaging). RESULTS: FTLD patients carrying the D* genotype (H/D or D/D) showed greater atrophy in the basal ganglia, bilaterally, compared to H/H carriers (x, y, z: -22, -4, 0; T = 3.45; cluster size: 33 voxels, x, y, z: 24, 4, -2; T = 3.38; cluster size: 36 voxels). The former group had even more pronounced behavioural symptoms, as defined by the Frontal Behavioural Inventory total scores. CONCLUSIONS: Our data suggest that H63D polymorphism could represent a disease-modifying gene in FTLD, fostering iron deposition in the basal ganglia. This suggests a new possible mechanism of FTLD-associated neurodegeneration. PMID- 26613253 TI - Autologous Peripheral Blood Mononuclear Cells as Treatment in Refractory Acute Respiratory Distress Syndrome. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) is a devastating disorder. Despite enormous efforts in clinical research, effective treatment options are lacking, and mortality rates remain unacceptably high. OBJECTIVES: A male patient with severe ARDS showed no clinical improvement with conventional therapies. Hence, an emergent experimental intervention was performed. METHODS: We performed intratracheal administration of autologous peripheral blood-derived mononuclear cells (PBMCs) and erythropoietin (EPO). RESULTS: We found that after 2 days of initial PBMC/EPO application, lung function improved and extracorporeal membrane oxygenation (ECMO) support was reduced. Bronchoscopy and serum inflammatory markers revealed reduced inflammation. Additionally, serum concentration of miR 449a, b, c and miR-34a, a transient upregulation of E-cadherin and associated chromatin marks in PBMCs indicated airway epithelial differentiation. Extracellular vesicles from PBMCs demonstrated anti-inflammatory capacity in a TNF-alpha-mediated nuclear factor-x03BA;B in vitro assay. Despite improving respiratory function, the patient died of multisystem organ failure on day 38 of ECMO treatment. CONCLUSIONS: This case report provides initial encouraging evidence to use locally instilled PBMC/EPO for treatment of severe refractory ARDS. The observed clinical improvement may partially be due to the anti inflammatory effects of PBMC/EPO to promote tissue regeneration. Further studies are needed for more in-depth understanding of the underlying mechanisms of in vivo regeneration. PMID- 26613254 TI - Grapevine Downy Mildew Plasmopara viticola Infection Elicits the Expression of Allergenic Pathogenesis-Related Proteins. AB - BACKGROUND: Downy mildews are a group of microorganisms belonging to the Chromista kingdom that can infect specific plants. When growing on plant tissues these microbes can elicit the expression of pathogenesis-related proteins (PRs), a group of stress-induced proteins frequently described as allergens in many plant species. Our aim was to verify by a proteomic approach whether the allergic reactions experienced by a farmer working in a vineyard infected by Plasmopara viticola (Pv), the etiological agent of downy mildew, are elicited by PRs expressed by the grapevine upon infection or by allergens present in Pv. METHODS: A skin prick test and prick-to-prick test with infected field grapevine leaves and control leaves were carried out. Field leaves and ad hoc Pv-inoculated leaves were compared by SDS-PAGE and IgE-immunoblotting with extracts from control leaves and Pv sporangia. IgE-binding proteins were further separated by two dimensional electrophoresis and the positive spots analyzed by nanoHPLC-Chip and tandem mass spectrometry (MS/MS) for identification. RESULTS: Only infected leaves showed IgE-binding protein bands at 42 and 36 kDa. This agreed with the positive skin prick test experienced by the patient only with the infected leaves extract. Two-dimensional electrophoresis followed by MS/MS analysis led to the identification of PR-2 (beta-1,3-glucanase) and harpin-binding protein 1 as putative allergens, the latter having never been reported before. CONCLUSION: The results indicate that Pv infection might represent a new source of plant allergens. PMID- 26613255 TI - Efficient Identification of Null-Allele Single Nucleotide Polymorphism Markers. AB - OBJECTIVES: At the beginning of a genome-wide association study, many markers are discarded because they fail to meet standard quality control criteria. Some of these markers are out of Hardy-Weinberg equilibrium (HWE) because they have 'null alleles' (which may be deletions or third alleles that do not hybridize to standard probes). It may be useful to identify null-allele markers so that they can be analyzed under different models or in order to explore regions of copy number variation. METHODS: We present a model for the chip-based genotype data that are produced when a null-allele single nucleotide polymorphism (SNP) is genotyped under standard (2-allele) assumptions. We show that this model can be combined with the standard HWE model to develop classification procedures based on the supervised learning algorithms Support Vector Machines (SVM), Classification and Regression Trees (CART) or Random Forests for identifying null allele SNPs. RESULTS: We report a list of null-allele SNPs we identified on the Illumina 660W-Quad chip and provide suggestions for applying our CART model to other SNP sets. CONCLUSIONS: Properly identified null-allele SNPs can be used to test for genotype-phenotype associations or to identify regions which may contain copy number variants. PMID- 26613256 TI - Prostatic Urethral Lift: A New Minimally Invasive Treatment for Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia. AB - INTRODUCTION: Prostatic urethral lift (PUL) is a minimally invasive procedure for the treatment of lower urinary tract symptoms (LUTSs) secondary to benign prostatic hyperplasia (BPH). The PUL procedure involves the placement of implants that retract the obstructing prostate lobes. This procedure achieves quantifiable improvements in functional outcomes and quality of life (QoL), while preserving erectile and ejaculatory functions. METHODS: Seventeen patients diagnosed with BPH who had undergone the UroLift(r) procedure between March 2011 and June 2015 were retrospectively evaluated. The parameters evaluated in the pre-operative, intra-operative and 1-year post-operative period were demographic data, and pre operative, intra-operative and 1-year post-operative results were obtained from the International Prostate Symptom Score (IPSS), Uroflowmetry QoL index, International Index of Erectile Function (IIEF) and Male Sexual Health Questionnaire (MSHQ) for ejaculatory function (MSHQ-EjD). RESULTS: The average improvements from baseline to 12 months after intervention were significant for the total IPSS 9.6. There was a 4.2-point increase in Qmax, a 0.9-point improvement in QoL and a 32% decrease in PVR. No statistically significant difference was found in the IIEF and MSHQ-EjD scores when the pre-operative and post-operative 3rd and 12th month scores were evaluated (p > 0.05). CONCLUSIONS: PUL offers rapid improvement in voiding and storage symptoms, QoL and flow rate that is durable to 12 months after intervention. PUL is a minimally invasive procedure that has the moderate effect in treating troublesome LUTS secondary to benign prostatic obstruction and preserving total sexual function. PMID- 26613257 TI - Is it Time to Update How Suspected Angina Is Evaluated prior to the Use of Specialized Tests Implications Based on a Systematic Review. AB - OBJECTIVES: Appropriate use of specialized tests to assess chest pain is based classically on minimal information such as age, gender and the patient's description of pain. This approach has not been reevaluated in decades. We examined the relationship between history, examination and routine laboratory tests to identify factors warranting prospective validation as predictors of underlying coronary artery disease (CAD). METHODS: Studies linking obstructive CAD (>=50% diameter stenosis of at least one vessel by invasive angiography or cardiac computed tomographic angiography) and elements of history, examination and laboratory tests were identified. RESULTS: Forty-one prospectively identified papers were analyzed. Advanced age, gender and chest pain descriptors were extremely important, although the last was less so in women, in whom the presence of risk factors may be more important. Physical examination and chest X-ray were largely noncontributory. Laboratory tests were of variable utility other than to identify risk factors not already known from the history. However, biomarkers such as troponin, brain natriuretic factor and inflammatory markers were promising. The electrocardiogram was mainly important for the identification of ST-T abnormalities. CONCLUSIONS: This review identifies the most promising factors warranting prospective validation for improving the pretest probability estimation of CAD, so appropriate use criteria for the utilization of specialized diagnostic tests can be updated and improved. PMID- 26613258 TI - Classification of Dopamine Receptor Genes in Vertebrates: Nine Subtypes in Osteichthyes. AB - Dopamine neurotransmission regulates various brain functions, and its regulatory roles are mediated by two families of G protein-coupled receptors: the D1 and D2 receptor families. In mammals, the D1 family comprises two receptor subtypes (D1 and D5), while the D2 family comprises three receptor subtypes (D2, D3 and D4). Phylogenetic analyses of dopamine receptor genes strongly suggest that the common ancestor of Osteichthyes (bony jawed vertebrates) possessed four subtypes in the D1 family and five subtypes in the D2 family. Mammals have secondarily lost almost half of the ancestral dopamine receptor genes, whereas nonmammalian species kept many of them. Although the mammalian situation is an exception among Osteichthyes, the current classification and characterization of dopamine receptors are based on mammalian features, which have led to confusion in the identification of dopamine receptor subtypes in nonmammalian species. Here we begin by reviewing the history of the discovery of dopamine receptors in vertebrates. The recent genome sequencing of coelacanth, gar and elephant shark led to the proposal of a refined scenario of evolution of dopamine receptor genes. We also discuss a current problem of nomenclature of dopamine receptors. Following the official nomenclature of mammalian dopamine receptors from D1 to D5, we propose to name newly identified receptor subtypes from D6 to D9 in order to facilitate the use of an identical name for orthologous genes among different species. To promote a nomenclature change which allows distinguishing the two dopamine receptor families, a nomenclature consortium is needed. This comparative perspective is crucial to correctly interpret data obtained in animal studies on dopamine-related brain disorders, and more fundamentally, to understand the characteristics of dopamine neurotransmission in vertebrates. PMID- 26613259 TI - T-Cell Responses to Tyrosinase-Derived Self-Peptides in Patients with Leukoderma Induced by Rhododendrol: Implications for Immunotherapy Targeting Melanoma. AB - BACKGROUND: Rhododendrol, a phenolic compound contained in lightening/whitening cosmetics, can bind and inhibit tyrosinase and was reported to induce leukoderma in Japan. Only 2% of the cosmetics users are affected, and tacrolimus is effective in treatment of the condition. OBJECTIVE: To test the hypothesis that the disease is an autoimmune disorder. METHODS: Short-term T-cell lines were established using peripheral blood mononuclear cells from 8 patients with human melanoma-associated and tyrosinase-derived synthetic peptides. The effects of rhododendrol on melanoma immunization were also examined. RESULTS: Seven out of 8 patients were positive for HLA-DR4. Both class I- and class II-restricted and tyrosinase peptide-specific T-cell responses were observed. Immunization of mice with rhododendrol-treated and irradiated B16 melanoma cells successfully delayed the growth of melanoma cells in vivo. CONCLUSION: Rhododendrol-induced leukoderma is an autoimmune disorder, with rhododendrol as an environmental factor and HLA DR4 as a genetic factor. Rhododendrol might be effective in treating melanomas. PMID- 26613260 TI - Aesthetic crown lengthening: periodontal and patient-centred outcomes. AB - AIM: The objective of this prospective study was to assess clinical and patient centred outcomes of aesthetic crown lengthening surgery for the treatment of altered passive eruption. MATERIALS AND METHODS: Twenty-two patients were treated and followed up for 6 months. The evaluated clinical parameters included, among others, probing depth, clinical attachment level, clinical crown length (CLc ), cemento-enamel junction to alveolar bone crest distance, gingival width (GW) and gingival display (GD). Subjects completed surveys to evaluate satisfaction with smile, gingiva and tooth features and experience with the procedure. RESULTS: Average CLc was 8.5 +/- 0.5 mm at baseline and significantly increased (9.9 +/- 0.5 mm; p < 0.0001) at 6 months. Concomitantly, GW significantly decreased from baseline (5.8 +/- 1.2 mm) to 6 months (4.9 +/- 1.1 mm; p < 0.008), as did GD (from 2.6 +/- 2.0 mm to 1.1 +/- 1.9 mm; p < 0.0001). In contrast to their pre operative satisfaction level, the majority (>=73%) of patients were very satisfied post-operatively with gingival and tooth display, when smiling or talking, and with maxillary anterior tooth size and shape. All patients would undergo the procedure again and would recommend it to someone with a similar problem. CONCLUSION: Aesthetic crown lengthening surgery results in high levels of patient satisfaction and predictable and stable outcomes in the short term. PMID- 26613261 TI - Severe malformations of eelpout (Zoarces viviparus) fry are induced by maternal estrogenic exposure during early embryogenesis. AB - Pregnant eelpout were exposed via the water to known endocrine disrupting compounds (EDCs) to clarify if EDCs could be causing the increased eelpout fry malformation frequencies observed in coastal areas receiving high anthropogenic input. The presence of a teratogenic window for estrogen-induced malformations was also investigated by starting the exposure at different times during eelpout pregnancy. Both 17alpha-ethinylestradiol (EE2) (17.8 ng/L) and pyrene (0.5 MUg/L) significantly increased fry malformation frequency whereas 4-t-octylphenol (4-t OP) up to 14.3 MUg/L did not. Vitellogenin was significantly induced by EE2 (5.7 and 17.8 ng/L) but not by 4-t-OP and pyrene. A critical period for estrogen induced fry malformations was identified and closed between 14 and 22 days post fertilization (dpf). Exposure to 17beta-estradiol (E2) between 0 and 14 dpf caused severe malformations and severity increased the closer exposure start was to fertilization, whereas malformations were absent by exposure starting later than 14 dpf. Data on ovarian fluid volume and larval length supported the suggested teratogenic window. Larval mortality also increased when exposure started right after fertilization. PMID- 26613262 TI - In Reply. PMID- 26613263 TI - Exposure and response prevention helps adults with obsessive-compulsive disorder who do not respond to pharmacological augmentation strategies. AB - OBJECTIVE: Serotonin reuptake inhibitors (SRIs) are a first-line treatment for obsessive-compulsive disorder (OCD). Yet, most patients with OCD who are taking SRIs do not show excellent response. Recent studies show that augmenting SRIs with risperidone benefits a minority of patients. We evaluated the effectiveness of exposure and response prevention (EX/RP) among nonresponders to SRI augmentation with 8 weeks of risperidone or placebo. METHOD: The study was conducted from January 2007 to August 2012. Nonresponders to SRI augmentation with risperidone or pill placebo (N = 32) in a randomized controlled trial for adults meeting DSM-IV-TR criteria for OCD were offered up to 17 twice-weekly EX/RP sessions. Independent evaluators, blind to treatment, evaluated patients at crossover baseline (week 8), midway through crossover treatment (week 12), post EX/RP treatment (week 16), and follow-up (weeks 20, 24, 28, and 32). The primary outcome was OCD severity, measured with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Secondary outcomes were depression, quality of life, insight, and social functioning. RESULTS: Between crossover baseline and follow-up, nonresponders to SRI augmentation with risperidone or placebo who received EX/RP showed significant reductions in OCD symptoms and depression, as well as significant increases in insight, quality of life, and social functioning (all P < .001). CONCLUSIONS: Exposure and response prevention is an effective treatment for patients who have failed to respond to SRI augmentation with risperidone or placebo. This study adds to the body of evidence supporting the use of EX/RP with patients who continue to report clinically significant OCD symptoms after multiple pharmacologic trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00389493. PMID- 26613264 TI - Clinical monitoring and management of complications related to chelation therapy in patients with beta-thalassemia. AB - Iron chelating agents - deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX) - are used to treat chronic iron overload in patients with beta-thalassemia in an attempt to reduce morbidity and mortality related to siderosis. Each of the approved iron chelating agents has its own advantages over the others and also has its own risks, whether related to over-chelation or not. In this review, we briefly discuss the methods to monitor the efficacy of iron chelation therapy (ICT) and the evidence behind the use of each iron chelating agent. We also portray the risks and complications associated with each iron chelating agent and recommend strategies to manage adverse events. PMID- 26613265 TI - Temperature stability of Poly-[hemoglobin-superoxide dismutase-catalase-carbonic anhydrase] in the form of a solution or in the lyophilized form during storage at -80 degrees C, 4 degrees C, 25 degrees C and 37 degrees C or pasteurization at 70 degrees C. AB - Polyhemoglobin-superoxide dismutase-catalase-carbonic anhydrase (Poly-[Hb-SOD-CAT CA]) contains all three major functions of red blood cells (RBCs) at an enhanced level. It transports oxygen, removes oxygen radicals and transports carbon dioxide. Our previous studies in a 90-min 30 mm Hg Mean Arterial Pressure (MAP) sustained hemorrhagic shock rat model shows that it is more effective than blood in the lowering of elevated intracellular pCO2, recovery of ST-elevation and histology of the heart and intestine. This paper is to analyze the storage and temperature stability. Allowable storage time for RBC is about 1 d at room temperature and 42 d at 4 degrees C. Also, RBC cannot be pasteurized to remove infective agents like HIV and Ebola. PolyHb can be heat sterilized and can be stored for 1 year even at room temperature. However, Poly-[Hb-SOD-CAT-CA] contains both Hb and enzymes and enzymes are particularly sensitive to storage and heat. We thus carried out studies to analyze its storage stability at different temperatures and heat pasteurization stability. Results of storage stability show that lyophilization extends the storage time to 1 year at 4 degrees C and 40 d at room temperature (compared to respectively, 42 d and 1 d for RBC). After the freeze-dry process, the enzyme activities of Poly-[SFHb-SOD CAT-CA] was 100 +/- 2% for CA, 100 +/- 2% for SOD and 93 +/- 3.5% for CAT. After heat pasteurization at 70 degrees C for 2 h, lyophilized Poly-[Hb-SOD-CAT-CA] retained good enzyme activities of CA 97 +/- 4%, SOD 100 +/- 2.5% and CAT 63.8 +/ 4%. More CAT can be added during the crosslinking process to maintain the same enzyme ratio after heat pasteurization. Heat pasteurization is possible only for the lyophilized form of Poly-[Hb-SOD-CAT-CA] and not for the solution. It can be easily reconstituted by dissolving in suitable solutions that continues to have good storage stability though less than that for the lyophilized form. According to the P50 value, Poly-[SFHb-SOD-CAT-CA] retains its oxygen carrying ability before and after long-term storage. PMID- 26613267 TI - The potential of the novel leukocyte removal filter in cardiopulmonary bypass. AB - Cardiopulmonary bypass (CPB) is indispensable for cardiac surgery but leads to systemic inflammatory responses and leukocyte activation, possibly due to blood contact with the surface of the CPB unit, surgical, ischemic reperfusion injury, etc. Systemic inflammatory responses during CPB result in increased morbidity and mortality. Activation of leukocytes is an important part of this process and directly contributes to coagulopathy and hemorrhage. This inflammatory response may contribute to the development of postoperative complications, including myocardial dysfunction, respiratory failure, renal and neurologic dysfunction, altered liver function and ultimately, multiple organ failure. Various pharmacologic and mechanical strategies have been developed to minimize the systemic inflammatory response during CPB. For example, leukocyte removal filters were developed in the 1990s for incorporation into the CPB circuit. However, studies of this approach have yielded conflicting findings. The purpose of this was to review the studies of a novel leukocyte removal filter in patients undergoing CPB. PMID- 26613268 TI - The impact of economic factors on treatment results for tumor inpatients in the under-developed Western region of China. AB - OBJECTIVE: To discuss the influences of economic factors on the treatment outcomes of cancer patients and the relaxation effects of medical insurance policies on the influences of economic factors. METHOD: The concentration index (CI) and horizontal inequality (HI) of treatment outcomes of cancer patients were calculated and the role of the economy, disease, and other factors to HI was analyzed by describing the influence of treatment expense on the treatment outcomes of different cancer patients. RESULTS: The study showed that the equity of the death rate and the effective rate of six types of cancer patients was good. The HI of the cure rate was 0.225, indicating a strong, pro-rich inequity of the cancer inpatient cure rate, while the contribution of the economic factors to HI was 0.158. The uncured rate in the low-cost group represented the rate of patients who discontinued the treatment; the HI was -0.324, indicating a strong, pro-poor inequity. The relaxation effect on the HI of the cured rate by medical insurance was 14.9%, while the effect on the HI of the uncured rate was 18.7%. CONCLUSION: At present, medical insurance has demonstrated relaxation effects on the fairness of treatment outcomes to some extent. The main reason for this inequity comes from the payment of the items at present. To relieve such inequity to a greater extent, the payment system should be changed and diagnosis-related groups should be implemented. PMID- 26613269 TI - Computer-mediated communication preferences predict biobehavioral measures of social-emotional functioning. AB - The use of computer-mediated communication (CMC) as a form of social interaction has become increasingly prevalent, yet few studies examine individual differences that may shed light on implications of CMC for adjustment. The current study examined neurocognitive individual differences associated with preferences to use technology in relation to social-emotional outcomes. In Study 1 (N = 91), a self report measure, the Social Media Communication Questionnaire (SMCQ), was evaluated as an assessment of preferences for communicating positive and negative emotions on a scale ranging from purely via CMC to purely face-to-face. In Study 2, SMCQ preferences were examined in relation to event-related potentials (ERPs) associated with early emotional attention capture and reactivity (the frontal N1) and later sustained emotional processing and regulation (the late positive potential (LPP)). Electroencephalography (EEG) was recorded while 22 participants passively viewed emotional and neutral pictures and completed an emotion regulation task with instructions to increase, decrease, or maintain their emotional responses. A greater preference for CMC was associated with reduced size of and satisfaction with social support, greater early (N1) attention capture by emotional stimuli, and reduced LPP amplitudes to unpleasant stimuli in the increase emotion regulatory task. These findings are discussed in the context of possible emotion- and social-regulatory functions of CMC. PMID- 26613270 TI - Ventriculo-bipleural shunt as last resort in a 4-year-old child in whom a VP and VA shunt failed. AB - The authors present the unusual case of a 4-year-old boy who had a complex history of posthemorrhagic hydrocephalus and who underwent more than 40 surgeries related to this condition. In the course of trying to treat his condition, ventriculoperitoneal, ventriculoatrial, and ventriculopleural shunts were inserted and failed. The child presented with a dysfunction of his shunt system. A ventriculopleural shunt was inserted, but within days the patient developed dyspnea as a clinical symptom of pleural effusion that required repeated thoracentesis. A bipleural drainage system was inserted, and no relevant pleural effusions developed during the follow-up period. Although the authors' experience is based on a single case, they do suggest bipleural drainage in patients with clinically relevant pleural effusions when the more common alternatives are not a good choice. Bipleural drainage might particularly be an option in children, who are prone to pleural effusion because of the smaller absorbing pleural surface. The authors reviewed the English-language literature on PubMed dating back to 1952. To their knowledge, this is the only published case in which a patient was treated with a ventriculo-bipleural shunt. PMID- 26613271 TI - Etiology of postoperative hyponatremia following pediatric intracranial tumor surgery. AB - OBJECT Cerebral salt wasting (CSW) and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) cause postoperative hyponatremia in neurosurgery patients, can be difficult to distinguish clinically, and are associated with increased morbidity. The authors aimed to determine risk factors associated with CSW and SIADH among children undergoing surgery for intracranial tumors. METHODS This retrospective cohort study included children 0-19 years of age who underwent a first intracranial tumor surgery with postoperative hyponatremia (sodium <= 130 mEq/L). CSW was differentiated from SIADH by urine output and fluid balance, exclusive of other causes of hyponatremia. The CSW and SIADH groups were compared with basic bivariate analysis and recursive partitioning. RESULTS Of 39 hyponatremic patients, 17 (44%) had CSW and 10 (26%) had SIADH. Patients with CSW had significantly greater natriuresis compared with those with SIADH (median urine sodium 211 vs 28 mEq/L, p = 0.01). Age <= 7 years and female sex were significant risk factors for CSW (p = 0.03 and 0.04, respectively). Both patient groups had hyponatremia onset within the first postoperative week. Children with CSW had trends toward increased sodium variability and symptomatic hyponatremia compared with those with SIADH. Most received treatment, but inappropriate treatment was noted to worsen hyponatremia. CONCLUSIONS The authors found that CSW was more common following intracranial tumor surgery and was associated with younger age and female sex. Careful assessment of fluid balance and urine output can separate patients with CSW from those who have SIADH, and high urine sodium concentrations (> 100 mEq/L) support a CSW diagnosis. Patients with CSW and SIADH had similar clinical courses, but responded to different interventions, making appropriate diagnosis and treatment imperative to prevent morbidity. PMID- 26613272 TI - Mild traumatic brain injury in children is associated with a low risk for posttraumatic seizures. AB - OBJECT Of the 1.7 million traumatic brain injuries (TBIs) in the US, a third occur in patients under 14 years of age. The rate of posttraumatic epilepsy (PTE) may be as high as 19% after severe pediatric TBI, but the risk for seizures after mild TBI is unknown. Although the rate of seizures after mild TBI may be low, current practice is often driven by high clinical concern for posttraumatic seizures. In this study, the authors evaluated electroencephalography (EEG) results and antiepileptic drug (AED) use in a large cohort of children with mild TBI to estimate the incidence of posttraumatic seizures in this population. METHODS Patients presenting to Children's Hospital of Atlanta for mild TBI from 2010 to 2013 were evaluated. Five thousand one hundred forty-eight patients with mild TBI were studied and divided into 3 groups: 4168 who were discharged from the emergency department, 868 who were admitted without neurosurgical intervention, and 112 who underwent neurosurgical procedures (craniotomy for hematoma evacuation or elevation of depressed skull fractures) but were discharged without an extended stay. Demographic information, CT characteristics, EEG reports, and prescriptions for AEDs were analyzed. Long-term follow-up was sought for all patients who underwent EEG. Correlation between EEG result and AED use was also evaluated. RESULTS All patients underwent head CT, and admitted patients were more likely to have an abnormal study (p < 0.0001). EEG evaluations were performed for less than 1.0% of patients in all 3 categories, without significant differences between groups (p = 0.97). Clinicians prescribed AEDs in less than 2.0% of patients for all groups, without significant differences between groups (p = 0.094). Even fewer children continue to see a neurologist for long-term seizure management. The EEG result had good negative predictive value, but only an abnormal EEG reading that was diagnostic of seizures correlated significantly with AED prescription (p = 0.04). CONCLUSIONS EEG utilization and AED prescription was low in all 3 groups, indicating that seizures following mild TBI are likely rare events. EEG has good negative predictive value for patients who did not receive AEDs, but has poorer positive predictive value for AED use. PMID- 26613273 TI - Clinical significance of changes in pB-C2 distance in patients with Chiari Type I malformations following posterior fossa decompression: a single-institution experience. AB - OBJECT The coexistence of Chiari malformation Type I (CM-I) and ventral brainstem compression (VBSC) has been well documented, but the change in VBSC after posterior fossa decompression (PFD) has undergone little investigation. In this study the authors evaluated VBSC in patients with CM-I and determined the change in VBSC after PFD, correlating changes in VBSC with clinical status and the need for further intervention. METHODS Patients who underwent PFD for CM-I by the senior author from November 2005 to January 2013 with complete radiological records were included in the analysis. The following data were obtained: objective measure of VBSC (pB-C2 distance); relationship of odontoid to Chamberlain's, McGregor's, McRae's, and Wackenheim's lines; clival length; foramen magnum diameter; and basal angle. Statistical analyses were performed using paired t-tests and a mixed-effects ANOVA model. RESULTS Thirty-one patients were included in the analysis. The mean age of the cohort was 10.0 years. There was a small but statistically significant increase in pB-C2 postoperatively (0.5 mm, p < 0.0001, mixed-effects ANOVA). Eleven patients had postoperative pB-C2 values greater than 9 mm. The mean distance from the odontoid tip to Wackenheim's line did not change after PFD, signifying postoperative occipitocervical stability. No patients underwent transoral odontoidectomy or occipitocervical fusion. No patients experienced clinical deterioration after PFD. CONCLUSIONS The increase in pB-C2 in patients undergoing PFD may occur as a result of releasing the posterior vector on the ventral dura, allowing it to relax posteriorly. This increase appears to be well-tolerated, and a postoperative pB-C2 measurement of more than 9 mm in light of stable craniocervical metrics and a nonworsened clinical examination does not warrant further intervention. PMID- 26613275 TI - Raised intracranial pressure in Crouzon syndrome: incidence, causes, and management. AB - OBJECT Patients with Crouzon syndrome (CS) are at risk for developing raised intracranial pressure (ICP), which has the potential to impair both vision and neurocognitive development. For this reason, some experts recommend early prophylactic cranial vault expansion on the basis that if ICP is not currently raised, it is likely to become so. The aim of this study was to examine the justification for such a policy. This was done by analyzing the incidence, causes, and subsequent risk of recurrence in a series of patients with CS, in whom raised ICP was treated only after it had been diagnosed. METHODS This study was a retrospective review of the medical records and imaging data of patients with a clinical diagnosis of CS. RESULTS There were 49 patients in the study, of whom 30 (61.2%) developed at least 1 episode of raised ICP. First episodes occurred at an average age of 1.42 years and were attributable to craniocerebral disproportion/venous hypertension (19 patients), hydrocephalus (8 patients), and airway obstruction (3 patients). They were managed, respectively, by vault expansion, ventriculoperitoneal shunt insertion, and airway improvement. Fourteen of the 30 patients developed a second episode of raised ICP an average of 1.42 years after treatment for their initial episode, and 3 patients developed a third episode an average of 3.15 years after that. Causes of subsequent episodes of raised ICP often differed from previous episodes and required different management. Patients who were < 1 year old when the first episode was diagnosed were at increased risk of recurrence. CONCLUSIONS Although the incidence of raised ICP in CS is high, it did not occur in nearly 40% of children during the course of this study. The several possible causes of CS require different management and may vary from episode to episode. The authors recommend an expectant policy toward these children with careful clinical, ophthalmological, respiratory, and radiological monitoring for raised ICP, reserving intervention for when it has been detected and the appropriate treatment can be initiated. PMID- 26613274 TI - De novo arteriovenous malformation in a patient with hereditary hemorrhagic telangiectasia. AB - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant systemic disorder characterized by the enlargement of capillaries, recurrent nosebleeds, and multiple arteriovenous malformations (AVMs). Although cerebral AVMs are traditionally considered to be congenital lesions, some reports have described de novo AVMs, which suggests that the authors believed them to be dynamic conditions. In this article, the authors describe the case of a 5-year-old boy with HHT in whom a de novo cerebral AVM was detected after a negative MRI result at 5 months. To the authors' knowledge, this is the first report of a de novo AVM in a patient with HHT. In patients with a family history of HHT, de novo AVMs are possible, even when no lesions are detected at the first screening. Therefore, regular screenings need to be performed, and the family should be informed that AVMs could still develop despite normal MRI results. PMID- 26613276 TI - Posterior cervical spinal fusion in a 3-week-old infant with a severe subaxial distraction injury. AB - Unstable spinal injuries in the neonate pose particular challenges in the clinical and radiographic assessment as well as the surgical stabilization of the spine. In this report, the authors present the unfortunate case of a 3-week-old infant who suffered a severe subaxial cervical fracture dislocation with spinal cord injury that occurred as a result of nonaccidental trauma. Imaging demonstrated severe distraction at C5-6 and near-complete spinal cord transection resulting in quadri-paresis. Open surgical reduction was performed with noninstrumented posterior fusion augmented with split rib autograft and recombinant human bone morphogenetic protein-2. Postoperative imaging demonstrated progressive bony fusion at 2 months, and clinical examination findings progressed to a motor examination classification of ASIA C. At 2 years, the fusion mass is stable and cervical alignment is maintained. The patient remains flaccid in the bilateral lower extremities, but has movement with some dexterity in both hands. Follow-up MRI shows severe spinal cord injury with evidence of bilateral C-5 nerve root avulsions. This case represents the first report of spinal fusion in an infant of less than 1 month of age. Given the extreme young age of the patient, the diagnostic challenges as well as the mechanical and technical considerations of surgical fusion are discussed. PMID- 26613277 TI - Predicting the limits of the endoscopic endonasal approach in children: a radiological anatomical study. AB - OBJECT The endoscopic endonasal approach (EEA) has been established as an alternative approach to craniovertebral junction (CVJ) pathology in adults. The authors have previously described the nasoaxial line (NAxL) as an accurate predictor of the lower limit of the EEA to the CVJ in adults. The surgical anatomy limiting the EEA to the pediatric CVJ has not been well studied. Furthermore, predicting the lower limit of the EEA in various pediatric age groups is important in surgical planning. To better understand the anatomy affecting the EEA to the CVJ, the authors examined the skull base anatomy relevant to the EEA in children of different age groups and used the NAxL to predict the EEA lower limit in children. METHODS Axial brain CT scans of 39 children with normal skull base anatomy were reconstructed sagittally. Children were divided into 4 groups according to age: 3-6, 7-10, 11-14, and 15-18 years old. The intersection of the NAxL with the odontoid process of C-2 was described for each group. Analyses of variance were used to estimate the effect of age, sex, interaction between age and sex on different anatomical parameters relevant to the endonasal corridor (including the length of the hard palate [HPLe]), dimensions of choana and piriform aperture, and the length of the NAxL to C-2. The effect of the HPLe on the working distance of NAxL to the odontoid was also estimated using analysis of covariance, controlling for age, sex, and their interaction. RESULTS The NAxL extended to the odontoid process in 38 of the 39 children. Among the 39 children, the NAxL intersected the upper third of the odontoid process in 25 while intersecting the middle third in the remaining 13 children. The measurements of the inferior limits did not differ with age, varying between 9 and 11 mm below the hard palate line at the ventral surface of C-2. Significant increases in the size of the piriform aperture and choana and the HPLe were observed after age 10. The HPLe predicted the length of the NAxL (p < 0.0001). CONCLUSIONS The caudal limit of the EEA extends as far as the middle third of the odontoid process in children, as predicted by the NAxL. The most prominent increase in the size of the choana and piriform aperture occurs after age 10. The HPLe is a significant predictor of the working distance to C-2. Utilizing the NAxL preoperatively may help in planning the EEA to the CVJ in children. PMID- 26613278 TI - Dydrogesterone treatment for menstrual-cycle regularization in routine clinical practice: a multicenter observational study. AB - Dydrogesterone is an oral retroprogesterone widely used to treat progesterone deficiencies, including irregular menstrual cycles (MCs). This prospective, non interventional, single-arm, post-marketing, observational study evaluated the effects of dydrogesterone on MC regularization. Women aged 18-40 years who had been prescribed dydrogesterone to treat irregular MCs due to progesterone deficiency were enrolled across 64 centers in Russia, Ukraine, Kazakhstan and Uzbekistan. Study objectives included: patients reporting >=1 regular MC during treatment; the number of regular MCs after the end of treatment over a 6-month follow-up (FU) period. In total, 996 women were enrolled. Of those who completed treatment, 946/955 patients (99.1%) achieved >=1 regular MC. During FU, 680/860 patients (79.1%) maintained >=6 regular MCs. Patient grading of menstrual pain and anxiety decreased significantly during treatment (p <= 0.0001 versus baseline); this persisted during FU. Dydrogesterone was associated with high or very high patient satisfaction (856/955; 89.6%); the clinical response was considered good or excellent in 819/955 patients (85.8%). In total, 16/986 patients (1.6%) reported an adverse event (AE); two had serious AEs (SAEs) (unrelated to treatment) and three discontinued treatment due to non-SAEs. Dydrogesterone therapy was effective in achieving MC regularization and reducing menstrual pain and anxiety, during both treatment and 6-month FU. PMID- 26613279 TI - Magnetic resonance imaging artifact following anterior cervical discectomy and fusion with a trabecular metal cage. AB - OBJECT: This study was undertaken to evaluate the impact of postoperative MRI artifact on the assessment of ongoing spinal cord or nerve root compression after anterior cervical discectomy and fusion (ACDF) using a trabecular tantalum cage or bone autograft or allograft. METHODS: The authors conducted a retrospective review of postoperative MRI studies of patients treated surgically for cervical disc degenerative disease or cervical instability secondary to trauma. Standard ACDF with either a trabecular tantalum cage or interbody bone graft had been performed. Postoperative MR images were shown twice in random order to each of 3 assessors (2 spine surgeons, 1 neuroradiologist) to determine whether the presence of a tantalum interbody cage and/or anterior cervical fixation plate or screws imparted MRI artifact significant enough to prevent reliable postoperative assessment of ongoing spinal cord or nerve root compression. RESULTS: A total of 63 patients were identified. One group of 29 patients received a tantalum interbody cage, with 13 patients (45%) undergoing anterior plate fixation. A second group of 34 patients received bone auto- or allograft, with 23 (68%) undergoing anterior plate fixation. The paramagnetic implant construct artifact had minimal impact on visualization of postoperative surgical level spinal cord compression. In the cage group, 98% (171/174) of the cases were rated as assessable versus 99% in the bone graft group (201/204), with high intraobserver reliability. In contrast, for the assessment of ongoing surgical level nerve root compression, the presence of a tantalum cage significantly decreased visualization of nerve roots to 70% (121/174) in comparison with 85% (173/204) in the bone graft group (p < 0.001). When sequences using turbo spin echo (TSE), a T2-weighted axial sequence, were acquired, nerve roots were rated as assessable in 88% (69/78) of cases; when only axial T2-weighted sequences were available, the nerve roots were rated as assessable in 54% (52/96) of cases (p < 0.01). The presence of anterior plate fixation had minimal impact on visualization of the spinal cord (99% [213/216] for plated cases vs 98% [159/162] for nonplated cases; p = 1.0) or nerve roots (79% [170/216] for plated cases vs 77% [124/162] for nonplated cases; p = 0.62). CONCLUSIONS: Interbody fusion with tantalum cage following anterior cervical discectomy imparts significant paramagnetic artifact, which significantly decreases visualization and assessment of ongoing surgical level nerve root, but not spinal cord, compression. Anterior plate constructs do not affect visualization of these structures. TSE T2-weighted sequences significantly improve nerve root visualization and should be performed as part of a standard postoperative protocol when imaging the cervical spine following interbody implantation of materials with potential for paramagnetic artifact. PMID- 26613280 TI - Correlation of quality of life and functional outcome measures for cervical spondylotic myelopathy. AB - OBJECT: Studies comparing surgical treatments for cervical spondylotic myelopathy (CSM) are heterogeneous, using a variety of different quality of life (QOL) outcomes and myelopathy-specific measures. This study sought to evaluate the relationship of these measures to each other, and to better understand their use in evaluating patients with CSM. METHODS: A retrospective study was performed in all patients with CSM who underwent either ventral or dorsal cervical spine surgery at a single tertiary-care institution between January 2008 and July 2013. Severity of myelopathy was assessed pre- and postoperatively using both the Nurick scale and the modified Japanese Orthopaedic Association (mJOA) classification of disability. Prospectively collected QOL outcomes data included Pain Disability Questionnaire (PDQ), Patient Health Questionnaire-9 (PHQ-9), and EQ-5D. Spearman rank correlations were calculated to assess the construct convergent validity for each pair of health status measures (HSMs). To assess each HSM's ability to discriminate favorable EQ-5D index, we performed receiver operating characteristic (ROC) curve analysis and assessed the area under the curve (AUC). RESULTS: A total of 119 patients were included. The PDQ total score had the highest correlation with EQ-5D index (Spearman's rho = -0.82). Neither of the myelopathy scales (mJOA or Nurick) had strong correlations between themselves (0.41) or with the other QOL measures (absolute value range 0.13-0.49). In contrast, the QOL measures correlated relatively well with each other (absolute value range 0.68-0.97). For predicting favorable EQ-5D outcomes, PDQ total score had an AUC of 0.909. The AUCs were significantly greater for the QOL measures in comparison with the myelopathy measures (AUCs were 0.677 and 0.607 for mJOA and Nurick scale scores, respectively). CONCLUSIONS: The authors found that all included measures of QOL and CSM-specific (mJOA or Nurick scale) measures were valid and responsive. The PDQ was the most predictive of positive QOL after surgery (as measured by the EQ-5D index) for patients with CSM. The substantially lower correlation between myelopathy and QOL outcomes, compared with the various QOL measures themselves, suggests that these questionnaires are measuring different aspects of the patient experience. Solely assessing the myelopathy or disease-specific signs and symptoms is likely insufficient to fully understand and appreciate clinical outcome in its totality. These questionnaire types should be used together to best evaluate patients pre- and postoperatively. PMID- 26613281 TI - Multiple recurrent postoperative spinal infections due to an unrecognized presacral abscess following placement of bicortical sacral screws: case report. AB - Postoperative wound infections in spinal surgery remain an important complication to diagnose and treat successfully. In most cases of deep infection, even with instrumentation, aggressive soft-tissue debridement followed by intravenous antibiotics is sufficient. This report presents a patient who underwent L3-S1 laminectomy and pedicle screw placement including bicortical sacral screws. This patient went on to develop multiple (7) recurrent infections at the operative site over a 5-year period. Continued investigation eventually revealed a large presacral abscess, which remained the source of recurrent bacterial seeding via the remaining bone tracts of the bicortical sacral screws placed during the original lumbar surgery. Two years after drainage of this presacral collection via a retroperitoneal approach, the patient remains symptom free. PMID- 26613282 TI - Outcomes in cases of lumbar degenerative spondylolisthesis more than 5 years after treatment with minimally invasive decompression: examination of pre- and postoperative slippage, intervertebral disc changes, and clinical results. AB - OBJECT: There are reports that fusion is the standard treatment of choice for cases of lumbar degenerative spondylolisthesis (LDS) associated with lumbar spinal canal stenosis with a large degree of slippage. The reasons why, however, have not been clarified. On the other hand, it is known that the progress of slippage decreases and restabilization occurs over the natural course of LDS. Therefore, if minimally invasive decompression could be performed, there would be little possibility of it influencing the natural course of LDS, so it would not be necessary to include preoperative percentage slip in the criteria for the selection of fusion. This study examined the course of LDS cases more than 5 years after treatment with minimally invasive decompression to determine whether pre- and postoperative slippage and disc changes influence the clinical results. METHODS: A total of 51 intervertebral segments in 51 cases with the chief complaint of radicular or cauda equina symptoms due to lumbar spinal canal stenosis were examined after prospective treatment with minimally invasive decompression for LDS. The mean age of the patients at the time of surgery was 66.7 years and the mean follow-up period was 7 years 4 months. Minimally invasive decompression was performed regardless of the degree of low-back pain or percentage slip. The outcome variables were clinical results and changes in imaging findings. RESULTS: Over the follow-up period, postoperative percentage slip increased and disc height decreased, but the Japanese Orthopaedic Association score improved. Regardless of the preoperative percentage slip, disc height, or degree of intervertebral disc degeneration or segmental instability, the clinical results were favorable. In the high preoperative percentage slip group, low disc height group, and progressive disc degeneration group, there was little postoperative progress of slippage. In the group with a postoperative slippage increase of more than 5%, slippage increased significantly at postoperative year 2, but no significant difference was observed at the final follow-up. CONCLUSIONS: When minimally invasive decompression was performed to treat LDS, the postoperative change in slippage was no different from that during the natural course. Furthermore, regardless of the degree of preoperative slippage or intervertebral disc degeneration, the clinical results were favorable. Also, the higher the preoperative percentage slip and the more that disc degeneration progressed, the more the progress of postoperative slippage decreased. Because the postoperative progress of slippage decreased, it is believed that even after minimally invasive decompression, restabilization occurs as it would during the natural course. If minimally invasive decompression can be performed to treat LDS, it is believed that preoperative percentage slip and intervertebral disc degeneration do not have to be included in the appropriateness criteria for fusion. PMID- 26613283 TI - Exploratory meta-analysis on dose-related efficacy and morbidity of bone morphogenetic protein in spinal arthrodesis surgery. AB - OBJECT: Bone morphogenetic protein (BMP) is frequently used for spinal arthrodesis procedures in an "off-label" fashion. Whereas complications related to BMP usage are well recognized, the role of dosage is less clear. The objective of this meta-analysis was to assess dose-dependent effectiveness (i.e., bone fusion) and morbidity of BMP used in common spinal arthrodesis procedures. A quantitative exploratory meta-analysis was conducted on studies reporting fusion and complication rates following anterior cervical discectomy and fusion (ACDF), posterior cervical fusion (PCF), anterior lumbar interbody fusion (ALIF), transforaminal lumbar interbody fusion (TLIF), posterior lumbar interbody fusion (PLIF), and posterolateral lumbar fusion (PLF) supplemented with BMP. METHODS: A literature search was performed to identify studies on BMP in spinal fusion procedures reporting fusion and/or complication rates. From the included studies, a database for each spinal fusion procedure, including patient demographic information, dose of BMP per level, and data regarding fusion rate and complication rates, was created. The incidence of fusion and complication rates was calculated and analyzed as a function of BMP dose. The methodological quality of all included studies was assessed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Data were analyzed using a random-effects model. Event rates are shown as percentages, with a 95% CI. RESULTS: Forty-eight articles met the inclusion criteria: ACDF (n = 7), PCF (n = 6), ALIF (n = 9), TLIF/PLIF (n = 17), and PLF (n = 9), resulting in a total of 5890 patients. In ACDF, the lowest BMP concentration analyzed (0.2-0.6 mg/level) resulted in a fusion rate similar to the highest dose (1.1-2.1 mg/level), while permitting complication rates comparable to ACDF performed without BMP. The addition of BMP to multilevel constructs significantly (p < 0.001) increased the fusion rate (98.4% [CI 95.4%-99.4%]) versus the control group fusion rate (85.8% [CI 77.4%-91.4%]). Studies on PCF were of poor quality and suggest that BMP doses of <= 2.1 mg/level resulted in similar fusion rates as higher doses. Use of BMP in ALIF increased fusion rates from 79.1% (CI 57.6% 91.3%) in the control cohort to 96.9% (CI 92.3%-98.8%) in the BMP-treated group (p < 0.01). The rate of complications showed a positive correlation with the BMP dose used. Use of BMP in TLIF had only a minimal impact on fusion rates (95.0% [CI 92.8%-96.5%] vs 93.0% [CI 78.1%-98.0%] in control patients). In PLF, use of >= 8.5 mg BMP per level led to a significant increase of fusion rate (95.2%; CI 90.1%-97.8%) compared with the control group (75.3%; CI 64.1%-84.0%, p < 0.001). BMP did not alter the rate of complications when used in PLF. CONCLUSIONS: The BMP doses used for various spinal arthrodesis procedures differed greatly between studies. This study provides BMP dosing recommendations for the most common spine procedures. PMID- 26613285 TI - Letter to the Editor: Modified Bohlman technique. PMID- 26613287 TI - Multifunctional magnetoelectric materials for device applications. AB - Over the past decade magnetoelectric (ME) mutiferroic (MF) materials and their devices are one of the highest priority research topics that has been investigated by the scientific ferroics community to develop the next generation of novel multifunctional materials. These systems show the simultaneous existence of two or more ferroic orders, and cross-coupling between them, such as magnetic spin, polarisation, ferroelastic ordering, and ferrotoroidicity. Based on the type of ordering and coupling, they have drawn increasing interest for a variety of device applications, such as magnetic field sensors, nonvolatile memory elements, ferroelectric photovoltaics, nano-electronics etc. Since single-phase materials exist rarely in nature with strong cross-coupling properties, intensive research activity is being pursued towards the discovery of new single-phase multiferroic materials and the design of new engineered materials with strong magneto-electric (ME) coupling. This review article summarises the development of different kinds of multiferroic material: single-phase and composite ceramic, laminated composite and nanostructured thin films. Thin-film nanostructures have higher magnitude direct ME coupling values and clear evidence of indirect ME coupling compared with bulk materials. Promising ME coupling coefficients have been reported in laminated composite materials in which the signal to noise ratio is good for device fabrication. We describe the possible applications of these materials. PMID- 26613286 TI - Q-TWiST analysis of panitumumab plus FOLFOX4 versus FOLFOX4 alone in patients with previously untreated wild-type RAS metastatic colorectal cancer. AB - INTRODUCTION: Panitumumab plus infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) significantly improved overall survival versus FOLFOX4 alone in patients with previously untreated wild-type RAS metastatic colorectal cancer (mCRC). We applied a quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis to provide an integrated measure of clinical benefit, with the objective of comparing quality-adjusted survival between the two arms. We acknowledge that there are limitations associated with Q-TWIST methodology for crossover trials. METHODS: For each treatment arm, the truncated mean times spent in the toxicity (TOX: grade 3 or 4 adverse events), time without symptoms of disease or toxicity (TWiST), and relapse (REL: after disease progression) states were estimated by the product-limit method, and adjusted using utility weights derived from patient-reported EuroQol 5-dimension measures. Sensitivity analyses were performed in which utility weights (varying from 0 to 1) were applied to time in the TOX and REL health states. RESULTS: Quality-adjusted overall survival time was statistically significantly longer with panitumumab plus FOLFOX4 (20.5 months) than with FOLFOX4 alone (18.2 months) (P = 0.025). CONCLUSION: In patients with previously untreated wild-type RAS mCRC, panitumumab plus FOLFOX4 significantly improved quality-adjusted survival compared with FOLFOX4 alone. PMID- 26613284 TI - Screening via CT angiogram after traumatic cervical spine fractures: narrowing imaging to improve cost effectiveness. Experience of a Level I trauma center. AB - OBJECT: Screening for vertebral artery injury (VAI) following cervical spine fractures is routinely performed across trauma centers in North America. From 2002 to 2007, the total number of neck CT angiography (CTA) studies performed in the Medicare population after trauma increased from 9796 to 115,021. In the era of cost-effective medical care, the authors aimed to evaluate the utility of CTA screening in detecting VAI and reduce chances of posterior circulation strokes after traumatic cervical spine fractures. METHODS: A retrospective review of all patients presenting with cervical spine fractures to Northeast Ohio's Level I trauma institution from 2002 to 2012 was performed. RESULTS: There was a total of 1717 cervical spine fractures in patients presenting to Northeast Ohio's Level I trauma institution between 2002 and 2012. CTA screening was performed in 732 patients, and 51 patients (0.7%) were found to have a VAI. Fracture patterns with increased odds of VAI were C-1 and C-2 combined fractures, transverse foramen fractures, and subluxation of adjacent vertebral levels. Ten posterior circulation strokes were identified in this patient population (0.6%) and found in only 4 of 51 cases of VAI (7.8%). High-risk fractures defined by Denver Criteria, VAI, and antiplatelet treatment of VAI were not independent predictors of stroke. CONCLUSIONS: Cost-effective screening must be reevaluated in the setting of blunt cervical spine fractures on a case-by-case basis. Further prospective studies must be performed to elucidate the utility of screening for VAI and posterior circulation stroke prevention, if identified. PMID- 26613288 TI - A Randomized Controlled Clinical Trial of the Strength at Home Men's Program for Partner Violence in Military Veterans. AB - OBJECTIVE: We evaluated the efficacy of the Strength at Home Men's Program (SAH M), a trauma-informed group intervention based on a social information processing model to end intimate partner violence (IPV) use in a sample of veterans/service members and their partners. To date, no randomized controlled trial has supported the efficacy of an IPV intervention in this population. METHOD: Participants included 135 male veterans/service members and 111 female partners. Recruitment was conducted from February 2010 through August 2013, and participation occurred within 2 Department of Veterans Affairs hospitals. Male participants completed an initial assessment that included diagnostic interviews and measures of physical and psychological IPV using the Revised Conflict Tactics Scales and were randomly assigned to an enhanced treatment as usual (ETAU) condition or SAH-M. Those randomized to SAH-M were enrolled in this 12-week group immediately after baseline. Those randomized to ETAU received clinical referrals and resources for mental health treatment and IPV services. All male participants were reassessed 3 and 6 months after baseline. Female partners completed phone assessments at the same intervals that were focused both on IPV and on the provision of safety information and clinical referrals. RESULTS: Primary analyses using hierarchical linear modeling indicated significant time-by-condition effects such that SAH-M participants compared with ETAU participants evidenced greater reductions in physical and psychological IPV use (beta = -0.135 [SE = 0.061], P = .029; beta = 0.304 [SE = 0.135], P = .026; respectively). Additional analyses of a measure that disaggregated forms of psychological IPV showed that SAH-M, relative to ETAU, reduced controlling behaviors involving isolation and monitoring of the partner (beta = -0.072 [SE = 0.027], P = .010). CONCLUSIONS: Results provide support for the efficacy of SAH-M in reducing and ending IPV in male veterans and service members. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01435512. PMID- 26613289 TI - Exploring example models of cross-sector, sessional employment of pharmacists to improve medication management and pharmacy support in rural hospitals. AB - INTRODUCTION: Many rural hospitals in Australia are not large enough to sustain employment of a full-time pharmacist, or are unable to recruit or retain a full time pharmacist. The absence of a pharmacist may result in hospital nurses undertaking medication-related roles outside their scope of practice. A potential solution to address rural hospitals' medication management needs is contracted part-time ('sessional') employment of a local pharmacist external to the hospital ('cross-sector'). The aim of this study was to explore the roles and experiences of pharmacists in their provision of sessional services to rural hospitals with no on-site pharmacist and explore how these roles could potentially address shortfalls in medication management in rural hospitals. METHODS: A qualitative study was conducted to explore models with pharmacists who had provided sessional services to a rural hospital. A semi-structured interview guide was informed by a literature review, preliminary research and stakeholder consultation. Participants were recruited via advertisement and personal contacts. Consenting pharmacists were interviewed between August 2012 and January 2013 via telephone or Skype for 40-55 minutes. RESULTS: Thirteen pharmacists with previous or ongoing hospital sessional contracts in rural communities across Australia and New Zealand participated. Most commonly, the pharmacists provided weekly services to rural hospitals. All believed the sessional model was a practical solution to increase hospital access to pharmacist-mediated support and to address medication management gaps. Roles perceived to promote quality use of medicines were inpatient consultation services, medicines information/education to hospital staff, assistance with accreditation matters and system reviews, and input into pharmaceutical distribution activities. CONCLUSIONS: This study is the first to explore the concept of sessional rural hospital employment undertaken by pharmacists in Australia and New Zealand. Insights from participants revealed that their sessional employment model increased access to pharmacist-mediated medication management support in rural hospitals. The contracting arrangements and scope of services may be evaluated and adapted in other rural hospitals. PMID- 26613290 TI - Fluorescence Up-Conversion Studies of [2,2'-Bipyridyl]-3,3'-diol in Octyl-beta-d glucoside and Other Micellar Aggregates. AB - In this present work, excited state double proton transfer dynamics (ESIDPT) of 2,2'-bipyridyl-3,3'-diol (BP(OH)2) molecules has been probed in a nontoxic, biocompatible sugar surfactant assembly, namely, octyl-beta-d-glucoside (OBG) micelle with the help of steady state and fluorescence up-conversion techniques. Moreover, the ultrafast double proton transfer dynamics in conventional micelles (SDS, CTAB) and bile salts aggregates have been probed and compared. Interestingly, in all these supramolecular aggregates, the ESIDPT dynamics is found to follow sequential pathway; however, the time-scale of proton transfer dynamics varies from 11 to 30 ps. This difference in proton transfer time scale in different supramolecular aggregates has been explained in terms of accessibility of water molecules in the vicinity of probe. PMID- 26613291 TI - Structure-Based Discovery of Novel Cyclophilin A Inhibitors for the Treatment of Hepatitis C Virus Infections. AB - Hepatitis C virus (HCV) is a major cause of end-stage liver disease. Direct acting antivirals (DAAs), including inhibitors of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment, but these are associated with increased drug resistance and toxicity. Thus, the development of host-targeted antiviral agents, such as cyclophilin A inhibitors, is an alternative approach for more effective, selective, and safer treatment. Starting with the discovery of a bis-amide derivative 5 through virtual screening, the lead compound 25 was developed using molecular modeling based design and systematic exploration of the structure-activity relationship. The lead 25 lacked cytotoxicity, had potent anti-HCV activity, and showed selective and high binding affinity for CypA. Unlike cyclosporin A, 25 lacked immunosuppressive effects, successfully inhibited the HCV replication, restored host immune responses without acute toxicity in vitro and in vivo, and exhibited a high synergistic effect in combination with other drugs. These findings suggest that the bis-amides have significant potential to extend the arsenal of HCV therapeutics. PMID- 26613292 TI - Multiple Src Homology 3 Binding to the Ubiquitin Ligase Itch Conserved Proline Rich Region. AB - Itch is a member of the C2-WW-HECT (CWH) family of ubiquitin ligases involved in the control of inflammatory signaling pathways, several transcription factors, and sorting of surface receptors to the degradative pathway. In addition to these common domains, Itch also contains a conserved proline-rich region (PRR) allowing its interaction with Src homology 3 (SH3) domain-containing proteins. This region is composed of 20 amino acids and contains one consensus class I and three class II SH3-binding motifs. Several SH3 domain-containing partners have been shown to recognize the Itch PRR, but their binding properties have been poorly defined. Here we compare a subset of endocytic SH3 domain-containing proteins using bioluminescence resonance energy transfer, isothermal titration calorimetry, and pull-down assays. Results indicate that Endophilin is a high-affinity binding partner of Itch both in vivo and in vitro, with a calculated KD placing this complex among the highest-affinity SH3 domain-mediated interactions reported to date. All of the SH3 domains tested here bind to Itch with a 1:1 stoichiometry, except for beta-PIX that binds with a 2:1 stoichiometry. Together, these results indicate that Itch PRR is a versatile binding module that can accommodate several different SH3 domain-containing proteins but has a preference for Endophilin. Interestingly, the catalytic activity of Itch toward different SH3 domain containing proteins was similar, except for beta-PIX that was not readily ubiquitylated even though it could interact with an affinity comparable to those of other substrates tested. PMID- 26613293 TI - Dynamic in situ visualization of voltage-driven magnetic domain evolution in multiferroic heterostructures. AB - Voltage control of magnetism in multiferroic heterostructures provides a promising solution to the excessive heating in spintronic devices. Direct observation of voltage-modulated magnetic domain evolution dynamics is desirable for studying the mechanism of the voltage control of magnetism at mesoscale, but has remained challenging. Here we explored a characterization method for the dynamic in situ evolution of pure voltage modulated magnetic domains in the heterostructures by employing the scanning Kerr microscopy function in the magneto optic Kerr effect system. The local magnetization reorientation of a Ni/PMN-PT heterostructure were characterized under sweeping applied voltage on the PMN-PT single crystal, and the results show that the magnetization rotation angle in the local regions is much greater than that obtained from macroscopic magnetization hysteresis loops. PMID- 26613294 TI - Efficient Diffuse Basis Sets for Density Functional Theory. AB - Eliminating all but the s and p diffuse functions on the non-hydrogenic atoms and all diffuse functions on the hydrogen atoms from the aug-cc-pV(x+d)Z basis sets of Dunning and co-workers, where x = D, T, Q, ..., yields the previously proposed "minimally augmented" basis sets, called maug-cc-pV(x+d)Z. Here, we present extensive and systematic tests of these basis sets for density functional calculations of chemical reaction barrier heights, hydrogen bond energies, electron affinities, ionization potentials, and atomization energies. The tests show that the maug-cc-pV(x+d)Z basis sets are as accurate as the aug-cc-pV(x+d)Z ones for density functional calculations, but the computational cost savings are a factor of about two to seven. PMID- 26613295 TI - Single Electron Transfer and SN2 Reactions: The Importance of Ionization Potential of Nucleophiles. PMID- 26613296 TI - Entropy from Correlations in TIP4P Water. AB - We use molecular dynamics to compute the pair distribution function of liquid TIP4P water as a function of the intermolecular distance and of the five angles that are needed to specify the relative position and orientation of two water molecules. We also calculate the translational and orientational contributions to the two-body term in the multiparticle correlation expansion of the configurational entropy at three selected thermodynamic states, where we also test various approximations for the angular dependence of the pair distribution function. We finally compare the results obtained for the pair entropy of TIP4P water with the experimental values of the excess entropy of ordinary water. PMID- 26613297 TI - The Exchange-Energy Density Functional Based on the Modified Becke-Roussel Model. PMID- 26613298 TI - Study of the Ground State Dissociation of Diatomic Molecular Systems Using State Specific Multireference Perturbation Theory: A Brillouin-Wigner Scheme. AB - The size-extensive second-order state-specific (or single root) multireference (MR) perturbation theory (SS-MRPT) in the Brillouin-Wigner (BW) form using Mphiller-Plesset perturbative evaluations of orders up to 2 [termed as SS MRMPPT(BW)] presents a viable, as well as promising, approach to include both nondynamic and dynamic correlations in the study of the bond-stretching (in multireference/quasidegenerate situations) of molecular species with a manageable cost/accuracy ratio. It combines numerical stability in the presence of an intruder state problem with strict size consistency (when localized orbitals are used). In this paper, the SS-MRMPPT(BW) method has been shown to properly break the bonds (in the ground state) of several diatomic molecules (such as F2, Cl2 and Br2, and BH) that have posed a severe challenge to any many-body theoretical approach due to the presence of quasidegeneracy of varying degrees in the ground state. A comparison of the resulting potentials with the various theoretical results reveals that the method represents a valuable tool that is capable of properly accounting even for very strong quasidegeneracies, while also performing well in nondegenerate situations. In this work, we have also calculated spectroscopic constants (such as equilibrium bond lengths, vibrational frequencies, and dissociation energies) of the ground state of these molecular systems. The SS-MRMPPT spectroscopic constants are compared with the most accurate available ab initio calculations and other theoretical estimates of previous works to calibrate the efficacy of the method. For the sake of completeness, we also compare the computed spectroscopic constants with the experimental observations. The accuracy of computed spectroscopic parameters appears to be rather consistent over a multitude of systems for various basis sets. The SS-MRMPPT enables quantitatively accurate and computationally affordable analysis of potential energy surfaces and spectroscopic constants of various multireference systems in the ground state. It is particularly visible for spectroscopic parameters and nonparallelism error (NPE) calculations. The calculations further reveal that the SS-MRMPPT(BW) method compared to its Rayleigh-Schrodinger counterpart [SS-MRMPPT(RS)] provides a more accurate and consistent solution for the whole dissociation path and spectroscopic constants. PMID- 26613299 TI - A First Principles Development of a General Anisotropic Potential for Polycyclic Aromatic Hydrocarbons. AB - Standard empirical atom-atom potentials are shown to be unable to describe the binding of polycyclic aromatic hydrocarbon (PAH) molecules in the variety of configurations seen in clusters. The main reason for this inadequacy is the lack of anisotropy in these potentials. We have constructed an anisotropic atom-atom intermolecular potential for the benzene molecule from first principles using a symmetry-adapted perturbation theory based on density functional theory (SAPT(DFT)), interaction energy calculations and the Williams-Stone-Misquitta method for obtaining molecular properties in distributed form. Using this potential as a starting point, we have constructed a transferable anisotropic potential to model intermolecular interactions between PAHs. This new potential has been shown to accurately model interaction energies for a variety of dimer configurations for four different PAH molecules, including certain configurations which are poorly modeled with current isotropic potentials. It is intended that this potential will form the basis for further work on the aggregation of PAHs. PMID- 26613300 TI - Uncontracted Rys Quadrature Implementation of up to G Functions on Graphical Processing Units. AB - An implementation is presented of an uncontracted Rys quadrature algorithm for electron repulsion integrals, including up to g functions on graphical processing units (GPUs). The general GPU programming model, the challenges associated with implementing the Rys quadrature on these highly parallel emerging architectures, and a new approach to implementing the quadrature are outlined. The performance of the implementation is evaluated for single and double precision on two different types of GPU devices. The performance obtained is on par with the matrix-vector routine from the CUDA basic linear algebra subroutines (CUBLAS) library. PMID- 26613301 TI - Ionization-Induced Structural Changes in Uracil Dimers and Their Spectroscopic Signatures. AB - The electronic structure of the three representative isomers of the ionized uracil dimers is characterized by high-level electronic structure calculations. Noncovalent interactions between the fragments lower the vertical ionization energies by 0.13-0.35 eV, the largest drop being observed for the stacked and the T-shaped isomers. The initial hole is delocalized in the stacked and the H-bonded isomers and is localized in the T-shaped one. The ionization induces significant structural relaxation and increases the binding energies. The stacked dimer cation relaxes to the symmetric structure bound by 22.7 kcal/mol. The T-shaped dimer cation has a binding energy of 25.1 kcal/mol. Thus, the relative order of the stacked and T-shaped isomers is reversed upon ionization. Finally, the H bonded isomer, which relaxes to the proton-transferred structure, is bound by 37.0 kcal/mol. The electronic spectra of all three isomers characterized at the vertical and the relaxed geometries show different patterns, which may be exploited in spectroscopic probing of ionization-induced dynamics in these species. PMID- 26613302 TI - Blending Determinism with Evolutionary Computing: Applications to the Calculation of the Molecular Electronic Structure of Polythiophene. AB - A density matrix based soft-computing solution to the quantum mechanical problem of computing the molecular electronic structure of fairly long polythiophene (PT) chains is proposed. The soft-computing solution is based on a "random mutation hill climbing" scheme which is modified by blending it with a deterministic method based on a trial single-particle density matrix [P((0))(R)] for the guessed structural parameters (R), which is allowed to evolve under a unitary transformation generated by the Hamiltonian H(R). The Hamiltonian itself changes as the geometrical parameters (R) defining the polythiophene chain undergo mutation. The scale (lambda) of the transformation is optimized by making the energy [E(lambda)] stationary with respect to lambda. The robustness and the performance levels of variants of the algorithm are analyzed and compared with those of other derivative free methods. The method is further tested successfully with optimization of the geometry of bipolaron-doped long PT chains. PMID- 26613303 TI - An Assessment of Density Functional Methods for Potential Energy Curves of Nonbonded Interactions: The XYG3 and B97-D Approximations. AB - A recently proposed double-hybrid functional called XYG3 and a semilocal GGA functional (B97-D) with a semiempirical correction for van der Waals interactions have been applied to study the potential energy curves along the dissociation coordinates of weakly bound pairs of molecules governed by London dispersion and induced dipole forces. Molecules treated in this work were the parallel sandwich, T-shaped, and parallel-displaced benzene dimer, (C6H6)2; hydrogen sulfide and benzene, H2S.C6H6; methane and benzene, CH4.C6H6; the methane dimer, (CH4)2; and the pyridine dimer, (C5H5N)2. We compared the potential energy curves of these functionals with previously published benchmarks at the coupled cluster singles, doubles, and perturbative triplets [CCSD(T)] complete-basis-set limit. Both functionals, XYG3 and B97-D, exhibited very good performance, reproducing accurate energies for equilibrium distances and a smooth behavior along the dissociation coordinate. Overall, we found an agreement within a few tenths of one kcal mol(-1) with the CCSD(T) results across the potential energy curves. PMID- 26613304 TI - Metal-Metal Quintuple and Sextuple Bonding in Bent Dimetallocenes of the Third Row Transition Metals. AB - Theoretical studies on the dimetallocenes Cp2M2 (M = Os, Re, W, Ta) predict bent structures with short metal-metal distances suggesting high-order metal-metal multiple bonds. Analysis of the frontier bonding molecular orbitals indicates a formal Os-Os quintuple bond (sigma + 2pi + 2delta) in singlet Cp2Os2 and a formal Re-Re sextuple bond (2sigma + 2pi + 2delta) in singlet Cp2Re2, thereby giving the metals in both molecules the favored 18-electron metal configurations. Predicted low-energy triplet structures for Cp2M2 (M = Os, Re) have formal quintuple bonds but with only two delta one-electron "half" bonds (M = Os) or a single delta two electron bond (M = Re) and a second sigma component derived from overlap of the d(z(2)) orbitals. A quintuple bond similar to that found in triplet Cp2Re2 is found in singlet Cp2W2, giving both tungsten atoms a 16-electron configuration. The formal Ta-Ta quadruple bond in the lowest energy singlet Cp2Ta2 structure is different from that in the original Re2Cl8(2-) in that it is a 2sigma + 2pi bond with no delta components but only sigma and pi components. PMID- 26613305 TI - Calibration of Cholesky Auxiliary Basis Sets for Multiconfigurational Perturbation Theory Calculations of Excitation Energies. AB - The accuracy of auxiliary basis sets derived from Cholesky decomposition of two electron integrals is assessed for excitation energies calculated at the state average complete active space self-consistent field (CASSCF) and multiconfigurational second order perturbation theory (CASPT2) levels of theory using segmented as well as generally contracted atomic orbital basis sets. Based on 196 valence excitations in 26 organic molecules and 72 Rydberg excitations in 3 organic molecules, the results show that Cholesky auxiliary basis sets can be used without compromising the accuracy of the multiconfigurational methods. Specifically, with a decomposition threshold of 10(-4) au, the mean error due to the Cholesky auxiliary basis set is 0.001 eV, or smaller, decreasing with increasing atomic orbital basis set quality. PMID- 26613306 TI - Protein Backbone Dynamics Simulations Using Coarse-Grained Bonded Potentials and Simplified Hydrogen Bonds. AB - A new set of bonded potentials is introduced to model the flexibility of coarse grained polypeptide chains. Based on a statistical analysis of known structures, the bonded potentials are sequence-dependent, and the secondary-structure propensity of each amino acid is partially reflected in the Si-Bi-Bi+1-Bi+2 pseudotorsion angle, where Si and Bi denote the side-chain and backbone beads, respectively. To stabilize the secondary structures during simulations, the bonded force field must be balanced by a simplified model of the protein hydrogen bonds, based on dipole-dipole interactions. Tested on eight polypeptides with sequence lengths ranging from 17 to 98, using 200-ns molecular dynamics simulations, the coarse-grained model yields trajectories with RMSDs ranging from 3 to 8 A from the experimental conformations. The less-structured regions of the simulated proteins exhibit the largest-amplitude movements. PMID- 26613307 TI - Development of a Polarizable Force Field Using Multiple Fluctuating Charges per Atom. AB - A polarizable force field (PFF) using multiple fluctuating charges per atom, ABEEMsigmapi PFF, is presented in this work. The fluctuating partial charges are obtained from the electronegativity equalization principle applied to the decomposition scheme of atom-bond regions into multiple charge sites: atomic, lone-pair electron, and sigma and pi bond regions. These multiple partial charges per atom should better account for the polarization effect than single atomic charge in other PFFs. To evaluate the PFF, structural and energetic properties for some organic and biochemical systems, including rotational barriers; binding energies of base pairs; a base-base interaction in a B-DNA decamer; and interaction energies of ten stationary conformers of a water dimer, peptides, and bases with water molecules, have been calculated and compared with the experimental data or ab initio MP2 results. Molecular dynamics simulations using the PFF have been performed for crambin and BPTI protein systems. Better performances in modeling root-mean-square deviations of backbone bond lengths, bond angles, key dihedral angles, the coordinate root-mean-square shift of atoms, and the distribution of hydrogen bonds have been observed in comparison with other PFFs. These results indicate that the fluctuating charge force field, ABEEMsigmapi/MM, is accurate and reliable and can be applied to wide ranges of organic and biomolecular systems. PMID- 26613308 TI - Electric-Field-Assisted Electron Transfer in a Porphine-Quinone Complex: A Theoretical Study. AB - The effects of a static external electric field on the ground state electronic structure of a porphine-quinone (PQ) complex have been studied by using density functional theory (DFT). The energies of the excited states have been calculated with time-dependent density functional theory (TDDFT) and with the approximate coupled cluster singles and doubles (CC2) method. The geometries of porphine and quinone have been optimized with B3LYP. The influence of the external electric field on the PQ complex has been studied at six different intermolecular distances between 2.5 and 5.0 A with the BH&HLYP functional. An external electric field clearly affects the orbitals localized mostly on quinone but not the orbitals localized on porphine. Additionally, the effect of the external field increases with the increasing intermolecular distance. The optical absorption spectrum of porphine obtained by using the BH&HLYP functional is consistent with the Gouterman model and with the spectrum previously calculated with CAM-B3LYP. The potential energy curves of the Q and B states and the lowest charge transfer (CT) states of the PQ complex calculated by using the BH&HLYP with TDDFT functional have also been compared with those obtained with the CC2 method. Both methods show that the lowest CT state is clearly above the Q states when no external field is applied. Therefore, when the Q states of a porphine-quinone system are excited, the conical intersection is not possible and cannot thus provide a path for electron transfer (ET). The calculations show that the Q and B states are affected by the field much less than the lowest CT state. Consequently, the calculations show that the CT state crosses the Q and B states at certain field strengths. Thus, it is possible that the external electric field triggers ET in porphine-quinone systems via conical intersection. PMID- 26613309 TI - Theoretical Study of Vibrationally Averaged Dipole Moments for the Ground and Excited C?O Stretching States of trans-Formic Acid. AB - Recent experimental studies of trans-formic acid (FA) in solid para-hydrogen (pH2) highlighted the importance of vibrationally averaged dipole moments for the interpretation of the high-resolution infrared (IR) spectra, in particular for the C?O stretch (nu3) mode. In this report, dipole moments for the nu3 ground (v = 0) and excited (v = 1, 2, 3, and 4) anharmonic vibrational states in trans-FA are investigated using two different approaches: a single mode approximation, where the vibrational states are obtained from the solution of the one dimensional Schrodinger equation for the harmonic normal coordinate, and a limited vibrational configuration interaction (VCI) approximation. Density functional theory (B3LYP, BPW91) and correlated ab initio (MP2 and CCSD(T)) electronic methods were employed with a number of double- and triple-zeta and correlation consistent basis sets. Both single mode and VCI approaches show comparable agreement with experimental data, which is more dependent on the level of theory used. In particular, the BPW91/cc-pVDZ level appears to perform remarkably well. Effects of solvation of FA in solid state Ar and pH2 matrices were simulated at the BPW91/cc-pVDZ level using a conductor-like polarized continuum model (CPCM). The Ar and pH2 solid-state matrices cause quite a substantial increase in the FA dipole moments. Compared to gas-phase calculations, the CPCM model for pH2 better reproduces the experimental FA spectral shifts caused by interaction with traces of ortho-hydrogen (oH2) species in solid pH2. The validity of the single mode approach is tested against the multidimensional VCI results, suggesting that the isolated (noninteracting) mode approximation is valid up to the third vibrationally excited state (v = 3). Finally, the contribution of the ground anharmonic vibrational states of the remaining modes to the resulting nu3 single mode dipole moments is examined and discussed. PMID- 26613310 TI - Accurate Harmonic/Anharmonic Vibrational Frequencies for Open-Shell Systems: Performances of the B3LYP/N07D Model for Semirigid Free Radicals Benchmarked by CCSD(T) Computations. AB - Impressive growth of computer facilities and effective implementation of very accurate quantum mechanical methods allow, nowadays, the determination of structures and vibrational characteristics for small- to medium-sized molecules to a very high accuracy. Since the situation is much less clear for open-shell species, we decided to build a suitable database of harmonic and anharmonic frequencies for small-sized free radicals containing atoms of the first two rows of the periodic table. The level of theory employed is the CCSD(T) model in conjunction with triple- and quadruple-zeta basis sets, whose accuracy has been checked with respect to the available experimental data and/or converged quantum mechanical computations. Next, in view of studies of larger open-shell systems, we have validated the B3LYP/N07D model with reference to the above database: our results confirm previous suggestions about the remarkable reliability and reduced computational cost of this computational method. A number of test computations show that basis set extension has negligible effects and other density functionals (including last generation ones) deliver significantly worse results. Increased accuracy can be obtained, instead, by using CCSD(T) harmonic frequencies and B3LYP/N07D anharmonic corrections. PMID- 26613311 TI - Approximate Inclusion of Triple Excitations in Combined Coupled Cluster/Molecular Mechanics: Calculations of Electronic Excitation Energies in Solution for Acrolein, Water, Formamide, and N-Methylacetamide. AB - Electronic excitation energies are often significantly affected by perturbing surroundings such as, for example, solvent molecules. Correspondingly, for an accurate comparison between theory and experiment, the inclusion of solvent effects in high-level theoretical predictions is important. Here, we introduce the CCSDR(3)/MM model designed for an effective, flexible, and accurate prediction of electronic excitation energies in solution. The method is based on a hybrid coupled cluster/molecular mechanics (CC/MM) strategy including interactions between a solute described by CC methods and a solvent described by polarizable MM methods. The CCSDR(3)/MM includes triples effects in a computational tractable noniterative fashion. The resulting approach allows for both high-accuracy inclusion of triples effects and inclusion of solute-solvent interactions with polarization effects, as well as being applicable for averaging over many solvent configurations derived from, for example, molecular simulations. We test the proposed model using as a benchmark the two lowest-lying valence singlet excitations (n -> pi* and pi -> pi*) of acrolein, formamide, and N-methylacetamide in aqueous solution as well as liquid water, demonstrating how a systematic inclusion of many different effects leads to good agreement with experimental values. In doing so we also illustrate the theoretical challenges involved when investigating UV properties of solvated molecules. PMID- 26613312 TI - A Coarse-Grained Model Based on Morse Potential for Water and n-Alkanes. AB - In order to extend the time and distance scales of molecular dynamics simulations, it is essential to create accurate coarse-grained force fields, in which each particle contains several atoms. Coarse-grained force fields that utilize the Lennard-Jones potential form for pairwise nonbonded interactions have been shown to suffer from serious inaccuracy, notably with respect to describing the behavior of water. In this paper, we describe a coarse-grained force field for water, in which each particle contains four water molecules, based on the Morse potential form. By molecular dynamics simulations, we show that our force field closely replicates important water properties. We also describe a Morse potential force field for alkanes and a simulation method for alkanes in which individual particles may have variable size, providing flexibility in constructing complex molecules comprised partly or solely of alkane groups. We find that, in addition to being more accurate, the Morse potential also provides the ability to take larger time steps than the Lennard-Jones, because the short distance repulsion potential profile is less steep. We suggest that the Morse potential form should be considered as an alternative for the Lennard-Jones form for coarse-grained molecular dynamics simulations. PMID- 26613313 TI - Applications of Screened Hybrid Density Functionals with Empirical Dispersion Corrections to Rare Gas Dimers and Solids. AB - An empirical dispersion correction is added to the range-separated hybrid density functionals HSE and HISS via parametrization versus a standard test bed of weakly bound complexes. The performance of the resulting HSE-D and HISS-D functionals is evaluated by calculating the equilibrium bond length, harmonic frequency, and dissociation energy for a number of rare gas dimers, and the lattice constants, band gaps, and sublimation energies of the rare gas solids. Both HSE-D and HISS-D are shown to provide accurate results for both molecules and extended systems, suggesting that the combination of a screened hybrid functional with an empirical dispersion correction provides an accurate, widely applicable method for use in solid-state and gas-phase electronic structure theory. PMID- 26613314 TI - Formation of Interconnected Aggregates in Aqueous Dicationic Ionic Liquid Solutions. AB - The structure and organization in an aqueous solution of a gemini surfactant, the dicationic ionic liquid 1,3-bis(3-decylimidazolium-1-yl) propane bromide, and its vapor-liquid interface have been studied using molecular dynamics simulations at room temperature. Starting from a uniform distribution of cations, the system is found to spontaneously evolve forming cross-linked cationic micellar aggregates. Alkyl tails are typically found buried inside the aggregates to minimize their unfavorable interactions with water, whereas the polar head groups are present at the micellar surfaces, exposed to water. Anions are found throughout the solution and are not strongly bound to the cations. Cationic micellar aggregates exhibit an interesting behavior: interconnection mediated by head groups, a phenomenon which is not observed in monocationic ionic liquid solutions. The structure of the vapor-liquid interface of the solution, the structure of the micellar aggregates, and the distribution of counterions are also discussed. PMID- 26613315 TI - Acidity of the Aqueous Rutile TiO2(110) Surface from Density Functional Theory Based Molecular Dynamics. AB - The thermodynamics of protonation and deprotonation of the rutile TiO2(110) water interface is studied using a combination of density functional theory based molecular dynamics (DFTMD) and free energy perturbation methods. Acidity constants are computed from the free energy for chaperone assisted insertion/removal of protons in fully atomistic periodic model systems treating the solid and solvent at the same level of theory. The pKa values we find for the two active surface hydroxyl groups on TiO2(110), the bridge OH (Ti2OH(+)), and terminal H2O adsorbed on a 5-fold Ti site (TiOH2) are -1 and 9, leading to a point of zero proton charge of 4, well within the computational error margin (2 pKa units) from the experimental value (4.5-5.5). The computed intrinsic surface acidities have also been used to estimate the dissociation free energy of adsorbed water giving 0.6 eV, suggesting that water dissociation is unlikely on a perfect aqueous TiO2(110) surface. For further analysis, we compare to the predictions of the MUltiSIte Complexation (MUSIC) and Solvation, Bond strength, and Electrostatic (SBE) models. The conclusion regarding the MUSIC model is that, while there is good agreement for the acidity of an adsorbed water molecule, the proton affinity of the bridging oxygen obtained in the DFTMD calculation is significantly lower (more than 5 pKa units) than the MUSIC model value. Structural analysis shows that there are significant differences in hydrogen bonding, in particular to a bridging oxygen which is assumed to be stronger in the MUSIC model compared to what we find using DFTMD. Using DFTMD coordination numbers as input for the MUSIC model, however, led to a pKa prediction which is inconsistent with the estimates obtained from the DFTMD free energy calculation. PMID- 26613316 TI - An RNA Molecular Switch: Intrinsic Flexibility of 23S rRNA Helices 40 and 68 5' UAA/5'-GAN Internal Loops Studied by Molecular Dynamics Methods. AB - Functional RNA molecules such as ribosomal RNAs (rRNAs) frequently contain highly conserved internal loops with a 5'-UAA/5'-GAN (UAA/GAN) consensus sequence. The UAA/GAN internal loops adopt a distinctive structure inconsistent with secondary structure predictions. The structure has a narrow major groove and forms a trans Hoogsteen/Sugar edge (tHS) A/G base pair followed by an unpaired stacked adenine, a trans Watson-Crick/Hoogsteen (tWH) U/A base pair, and finally a bulged nucleotide (N). The structure is further stabilized by a three-adenine stack and base-phosphate interaction. In the ribosome, the UAA/GAN internal loops are involved in extensive tertiary contacts, mainly as donors of A-minor interactions. Further, this sequence can adopt an alternative 2D/3D pattern stabilized by a four-adenine stack involved in a smaller number of tertiary interactions. The solution structure of an isolated UAA/GAA internal loop shows substantially rearranged base pairing with three consecutive non-Watson-Crick base pairs. Its A/U base pair adopts an incomplete cis Watson-Crick/Sugar edge (cWS) A/U conformation instead of the expected Watson-Crick arrangement. We performed 3.1 MUs of explicit solvent molecular dynamics (MD) simulations of the X-ray and NMR UAA/GAN structures, supplemented by molecular mechanics, Poisson Boltzmann, and surface area free energy calculations; locally enhanced sampling (LES) runs; targeted MD (TMD); and nudged elastic band (NEB) analysis. We compared parm99 and parmbsc0 force fields and net-neutralizing Na(+) versus excess salt KCl ion environments. Both force fields provide a similar description of the simulated structures, with the parmbsc0 leading to modest narrowing of the major groove. The excess salt simulations also cause a similar effect. While the NMR structure is entirely stable in simulations, the simulated X-ray structure shows considerable widening of the major groove, a loss of base-phosphate interaction, and other instabilities. The alternative X-ray geometry even undergoes a conformational transition toward the solution 2D structure. Free energy calculations confirm that the X-ray arrangement is less stable than the solution structure. LES, TMD, and NEB provide a rather consistent pathway for interconversion between the X-ray and NMR structures. In simulations, the incomplete cWS A/U base pair of the NMR structure is water-mediated and alternates with the canonical A-U base pair, which is not indicated by the NMR data. Completion of the full cWS A/U base pair is prevented by the overall internal loop arrangement. In summary, the simulations confirm that the UAA/GAN internal loop is a molecular switch RNA module that adopts its functional geometry upon specific tertiary contexts. PMID- 26613317 TI - Hydration of the Lowest Triplet States of the DNA/RNA Pyrimidines. AB - The effects of hydration on the lowest triplet states of the DNA/RNA pyrimidines have been studied by including one and two water molecules explicitly. Three configurations for the singly hydrated cytosine moiety were located, and six for the doubly hydrated system. For thymine and uracil, four singly and eight doubly hydrated structures were found. The singlet-triplet energy gaps of all three pyrimidines (cytosine, thymine, and uracil) fall in the low-energy range of ultraviolet radiation (UVA). Energetic excited states can be a step leading to lesions in DNA, such as a mismatched base pairs. Although the adiabatic and vertical electronic excitation energies for all three pyrimidines slightly increase upon inclusion of additional water molecules, this effect upon the excitation energies is much smaller than hydration effects upon the electron affinities and ionization energies of the three nucleobases. Because both the ground state and the triplet state are neutral, the hydration energy difference between the two states is not significant (compared to those between the neutral and charged species), making the excitation energy less sensitive to hydration. PMID- 26613318 TI - Multiple Low-Lying States for Compound I of P450cam and Chloroperoxidase Revealed from Multireference Ab Initio QM/MM Calculations. AB - The hybrid CASPT2/MM approach is employed to systematically study the ground and low-lying excited states of the ultimate active species of the enzymes P450cam and chloroperoxidase (CPO): the oxoiron(IV)-porphyrin cation-radical Por(*+)Fe(IV)?O(Cys) species, the so-called Compound I (Cpd I). The results underscore the fact that the B3LYP/MM method is quite accurate on the most part. However, the CASPT2/MM energies for the ferryl-pentaradicaloid quartet state and the perferryl Fe(V)O doublet and quartet states are significantly lower than the B3LYP/MM results. Thus, while the present CASPT2/MM may still overestimate the stability of these states, nevertheless, taken at its face value, the result raises the question whether these states actually contribute to the reactivity of Cpd I. Our paper tries to grapple with this question in view of (a) the recent speculations that the perferryl Fe(V)O states may be involved in unusual reactivities of Cpd I species (Pan, Z. Z.; Wang, Q.; Sheng, X.; Horner, J. H.; Newcomb, M. J. Am. Chem. Soc. 2009, 131, 2621-2628) and (b) the DFT/MM results which show that the pentaradicaloid states have intrinsically low barriers for H abstraction (Altun, A.; Shaik, S.; Thiel, W. J. Am. Chem. Soc. 2007, 129, 8978 8987). The application of CASPT2/MM to high valent transition metal states like the perferryl are far from being trivial, and the experience and insight gained in this study are expected to be helpful for future successful application of this type of method to resolve key issues in P450 reactivity. PMID- 26613319 TI - Efficient, Regularized, and Scalable Algorithms for Multiscale Coarse-Graining. AB - The multiscale coarse-graining (MS-CG) method obtains CG interactions from atomistic configurations, as demonstrated previously for a variety of soft matter and biological systems. In this article, recent advances in MS-CG algorithms are described, and a recently developed computer program MSCGFM for MS-CG calculations is introduced. The algorithms enhance the efficiency and stability of MS-CG computations, and these algorithms are incorporated into the MSCGFM program. As a result of these efforts, MS-CG calculations on large scale systems such as peptide and proteins can become tractable, and the numerical stability of solutions for ill-posed MS-CG problems can be regularized efficiently. Various parallelization strategies are also discussed. PMID- 26613321 TI - Rigorous Extraction of the Anisotropic Multispin Hamiltonian in Bimetallic Complexes from the Exact Electronic Hamiltonian. PMID- 26613320 TI - Membrane/Toxin Interaction Energetics via Serial Multiscale Molecular Dynamics Simulations. AB - Computing free energies of complex biomolecular systems via atomistic (AT) molecular dynamics (MD) simulations remains a challenge due to the need for adequate sampling and convergence. Recent coarse-grained (CG) methodology allows simulations of significantly larger systems (~10(6) to 10(8) atoms) over longer (MUs/ms) time scales. Such CG models appear to be capable of making semiquantitative predictions. However, their ability to reproduce accurate thermodynamic quantities remains uncertain. We have recently used CG MD simulations to compute the potential of mean force (PMF) or free energy profile of a small peptide toxin interacting with a lipid bilayer along a 1D reaction coordinate. The toxin studied was VSTx1 (Voltage Sensor Toxin 1) from spider venom which inhibits the archeabacterial voltage-gated potassium (Kv) channel KvAP by binding to the voltage-sensor (VS) domains. Here, we re-estimate this PMF profile using (i) AT MD simulations with explicit membrane and solvent and (ii) an implicit membrane and solvent (generalized Born; GBIM) model where only the peptide was explicit. We used the CG MD free energy simulations to guide the setup of the corresponding AT MD simulations. The aim was to avoid local minima in the AT simulations which would be difficult over shorter AT time scales. A cross-comparison of the PMF profiles revealed a conserved topology, although there were differences in the magnitude of the free energies. The CG and AT simulations predicted a membrane/water interface free energy well of -27 and -23 kcal/mol, respectively (with respect to water). The GBIM model, however, gave a reduced interfacial free energy well (-12 kcal/mol). In addition, the CG and GBIM models predicted a free energy barrier of +61 and +96 kcal/mol, respectively, for positioning the toxin at the center of the bilayer, which was considerably smaller in the AT simulations (+26 kcal/mol). Thus, we present a framework for serially combining CG and AT simulations to estimate the free energy of peptide/membrane interactions. Such approaches for combining simulations at different levels of granularity will become increasingly important in future studies of complex membrane/protein systems. PMID- 26613324 TI - Idiopathic environmental intolerance. PMID- 26613322 TI - Silole-Containing Polymer Nanodot: An Aqueous Low-Potential Electrochemiluminescence Emitter for Biosensing. AB - A novel D-A conjugated polymer backbone containing silole and 9-octyl-9H carbazole units was synthesized via Sonogashira reaction. This silole-containing polymer (SCP) was further used to prepare SCP dots with a nanoprecipitation method, which showed an electrochemiluminescence (ECL) emission at relatively low potential in aqueous solution. The strong anodic ECL emission could be observed at +0.4 V (vs Ag/AgCl) with a peak value at +0.78 V in the presence of tri-n propylamine (TPrA) as a co-reactant, which came from the band gap emission of the excited SCP dots. The ECL emission could be quenched via resonance energy transfer from the excited SCP dots to an acceptor. Thus, a low-potential anodic ECL sensing strategy was proposed for ECL detection of the acceptor-related analytes. Using dopamine as the analyte, whose electro-oxidation product could act as the energy acceptor to quench the ECL emission of SCP dots, the ECL detection method showed a detection limit of 50 nM and high anti-interference ability. This work demonstrates an example of polymer dots as an ECL emitter and its potential application in ECL detection methodology. PMID- 26613325 TI - Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: an evidence-based approach to diagnosis and management by clinicians. AB - This review was written from the viewpoint of the treating clinician to educate health care professionals and the public about Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). It includes: the clinical definition of ME/CFS with emphasis on how to diagnose ME/CFS; the etiology, pathophysiology, management approach, long-term prognosis and economic cost of ME/CFS. After reading this review, you will be better able to diagnose and treat your patients with ME/CFS using the tools and information provided. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic medical condition characterized by symptom clusters that include: pathological fatigue and malaise that is worse after exertion, cognitive dysfunction, immune dysfunction, unrefreshing sleep, pain, autonomic dysfunction, neuroendocrine and immune symptoms. ME/CFS is common, often severely disabling and costly. The Institute of Medicine (IOM) reviewed the ME/CFS literature and estimates that between 836,000 and 2.5 million Americans have ME/CFS at a cost of between 17 and 24 billion dollars annually in the US. The IOM suggested a new name for ME/CFS and called it Systemic Exertion Intolerance Disease (SEID). SEID's diagnostic criteria are less specific and do not exclude psychiatric disorders in the criteria. The 2010 Canadian Community Health Survey discovered that 29% of patients with ME/CFS had unmet health care needs and 20% had food insecurity--lack of access to sufficient healthy foods. ME/CFS can be severely disabling and cause patients to be bedridden. Yet most patients (80%) struggle to get a diagnosis because doctors have not been taught how to diagnose or treat ME/CFS in medical schools or in their post-graduate educational training. Consequently, the patients with ME/CFS suffer. They are not diagnosed with ME/CFS and are not treated accordingly. Instead of compassionate care from their doctors, they are often ridiculed by the very people from whom they seek help. The precise etiology of ME/CFS remains unknown, but recent advances and research discoveries are beginning to shed light on the enigma of this disease including the following contributors: infectious, genetic, immune, cognitive including sleep, metabolic and biochemical abnormalities. Management of patients with ME/CFS is supportive symptomatic treatment with a patient centered care approach that begins with the symptoms that are most troublesome for the patient. Pacing of activities with strategic rest periods is, in our opinion, the most important coping strategy patients can learn to better manage their illness and stop their post-exertional fatigue and malaise. Pacing allows patients to regain the ability to plan activities and begin to make slow incremental improvements in functionality. PMID- 26613326 TI - Reliable disease biomarkers characterizing and identifying electrohypersensitivity and multiple chemical sensitivity as two etiopathogenic aspects of a unique pathological disorder. AB - Much of the controversy over the causes of electro-hypersensitivity (EHS) and multiple chemical sensitivity (MCS) lies in the absence of both recognized clinical criteria and objective biomarkers for widely accepted diagnosis. Since 2009, we have prospectively investigated, clinically and biologically, 1216 consecutive EHS and/or MCS-self reporting cases, in an attempt to answer both questions. We report here our preliminary data, based on 727 evaluable of 839 enrolled cases: 521 (71.6%) were diagnosed with EHS, 52 (7.2%) with MCS, and 154 (21.2%) with both EHS and MCS. Two out of three patients with EHS and/or MCS were female; mean age (years) was 47. As inflammation appears to be a key process resulting from electromagnetic field (EMF) and/or chemical effects on tissues, and histamine release is potentially a major mediator of inflammation, we systematically measured histamine in the blood of patients. Near 40% had a increase in histaminemia (especially when both conditions were present), indicating a chronic inflammatory response can be detected in these patients. Oxidative stress is part of inflammation and is a key contributor to damage and response. Nitrotyrosin, a marker of both peroxynitrite (ONOO degrees -) production and opening of the blood-brain barrier (BBB), was increased in 28% the cases. Protein S100B, another marker of BBB opening was increased in 15%. Circulating autoantibodies against O-myelin were detected in 23%, indicating EHS and MCS may be associated with autoimmune response. Confirming animal experiments showing the increase of Hsp27 and/or Hsp70 chaperone proteins under the influence of EMF, we found increased Hsp27 and/or Hsp70 in 33% of the patients. As most patients reported chronic insomnia and fatigue, we determined the 24 h urine 6 hydroxymelatonin sulfate (6-OHMS)/creatinin ratio and found it was decreased (<0.8) in all investigated cases. Finally, considering the self-reported symptoms of EHS and MCS, we serially measured the brain blood flow (BBF) in the temporal lobes of each case with pulsed cerebral ultrasound computed tomosphygmography. Both disorders were associated with hypoperfusion in the capsulothalamic area, suggesting that the inflammatory process involve the limbic system and the thalamus. Our data strongly suggest that EHS and MCS can be objectively characterized and routinely diagnosed by commercially available simple tests. Both disorders appear to involve inflammation-related hyper-histaminemia, oxidative stress, autoimmune response, capsulothalamic hypoperfusion and BBB opening, and a deficit in melatonin metabolic availability; suggesting a risk of chronic neurodegenerative disease. Finally the common co-occurrence of EHS and MCS strongly suggests a common pathological mechanism. PMID- 26613327 TI - Electrohypersensitivity: a functional impairment due to an inaccessible environment. AB - In Sweden, electrohypersensitivity is recognized as a functional impairment which implies only the environment as the culprit. The Swedish view provides persons with this impairment a maximal legal protection, it gives them the right to get accessibility measures for free, as well as governmental subsidies and municipality economic support, and to provide them with special Ombudsmen (at the municipality, the EU, and the UN level, respectively), the right and economic means to form disability organizations and allow these to be part of national and international counterparts, all with the simple and single aim to allow persons with the functional impairment electrohypersensitivity to live an equal life in a society based on equality. They are not seen as patients, the do not have an overriding medical diagnosis, but the 'patient' is only the inferior and potentially toxic environment. This does not mean that a subjective symptom of a functionally impaired can not be treated by a physician, as well as get sick leave from their workplace as well as economic compensation, and already in the year 2000 such symptoms were identified in the Internal Code of Diagnoses, version 10 (ICD-10; R68.8/now W90), and have been since. But the underlying cause still remains only the environment. PMID- 26613328 TI - Radiofrequency exposure in young and old: different sensitivities in light of age relevant natural differences. AB - Our environment is now permeated by anthropogenic radiofrequency electromagnetic radiation, and individuals of all ages are exposed for most of each 24 h period from transmitting devices. Despite claims that children are more likely to be vulnerable than healthy adults to unwanted effects of this exposure, there has been no recent examination of this, nor of comparative risk to the elderly or ill. We sought to clarify whether research supports the claim of increased risk in specific age-groups. First, we identified the literature which has explored age-specific pathophysiological impacts of RF-EMR. Natural life-span changes relevant to these different impacts provides context for our review of the selected literature, followed by discussion of health and well-being implications. We conclude that age-dependent RF-EMR study results, when considered in the context of developmental stage, indicate increased specific vulnerabilities in the young (fetus to adolescent), the elderly, and those with cancer. There appears to be at least one mechanism other than the known thermal mechanism causing different responses to RF-EMR depending upon the exposure parameters, the cell/physiological process involved, and according to age and health status. As well as personal health and quality-of-life impacts, an ageing population means there are economic implications for public health and policy. PMID- 26613329 TI - EUROPAEM EMF Guideline 2015 for the prevention, diagnosis and treatment of EMF related health problems and illnesses. AB - Chronic diseases and illnesses associated with unspecific symptoms are on the rise. In addition to chronic stress in social and work environments, physical and chemical exposures at home, at work, and during leisure activities are causal or contributing environmental stressors that deserve attention by the general practitioner as well as by all other members of the health care community. It seems certainly necessary now to take "new exposures" like electromagnetic field (EMF) into account. Physicians are increasingly confronted with health problems from unidentified causes. Studies, empirical observations, and patient reports clearly indicate interactions between EMF exposure and health problems. Individual susceptibility and environmental factors are frequently neglected. New wireless technologies and applications have been introduced without any certainty about their health effects, raising new challenges for medicine and society. For instance, the issue of so-called non-thermal effects and potential long-term effects of low-dose exposure were scarcely investigated prior to the introduction of these technologies. Common EMF sources include Wi-Fi access points, routers and clients, cordless and mobile phones including their base stations, Bluetooth devices, ELF magnetic fields from net currents, ELF electric fields from electric lamps and wiring close to the bed and office desk. On the one hand, there is strong evidence that long-term-exposure to certain EMF exposures is a risk factor for diseases such as certain cancers, Alzheimer's disease and male infertility. On the other hand, the emerging electromagnetic hypersensitivity (EHS) is more and more recognized by health authorities, disability administrators and case workers, politicians, as well as courts of law. We recommend treating EHS clinically as part of the group of chronic multisystem illnesses (CMI) leading to a functional impairment (EHS), but still recognizing that the underlying cause remains the environment. In the beginning, EHS symptoms often occur only occasionally, but over time they may increase in frequency and severity. Common EHS symptoms include headaches, concentration difficulties, sleeping problems, depression, lack of energy, fatigue and flu-like symptoms. A comprehensive medical history, which should include all symptoms and their occurrences in spatial and temporal terms and in the context of EMF exposures, is the key to the diagnosis. The EMF exposure can be assessed by asking for typical sources like Wi Fi access points, routers and clients, cordless and mobile phones and measurements at home and at work. It is very important to take the individual susceptibility into account. The primary method of treatment should mainly focus on the prevention or reduction of EMF exposure, that is, reducing or eliminating all sources of EMF at home and in the workplace. The reduction of EMF exposure should also be extended to public spaces such as schools, hospitals, public transport, and libraries to enable persons with EHS an unhindered use (accessibility measure). If a detrimental EMF exposure is reduced sufficiently, the body has a chance to recover and EHS symptoms will be reduced or even disappear. Many examples have shown that such measures can prove effective. Also the survival rate of children with leukemia depends on ELF magnetic field exposure at home. To increase the effectiveness of the treatment, the broad range of other environmental factors that contribute to the total body burden should also be addressed. Anything that supports a balanced homeostasis will increase a person's resilience against disease and thus against the adverse effects of EMF exposure. There is increasing evidence that EMF exposure has a major impact on the oxidative and nitrosative regulation capacity in affected individuals. This concept also may explain why the level of susceptibility to EMF can change and why the number of symptoms reported in the context of EMF exposures is so large. Based on our current understanding, a treatment approach that minimizes the adverse effects of peroxynitrite - as has been increasingly used in the treatment of multisystem disorders - works best. This EMF Guideline gives an overview of the current knowledge regarding EMF-related health risks and provides concepts for the diagnosis and treatment and accessibility measures of EHS to improve and restore individual health outcomes as well as for the development of strategies for prevention. PMID- 26613330 TI - Preface to special issue on Peripheral and Central Control of Human Reproduction: Endocrine Aspects--Part 1. PMID- 26613331 TI - Endocrine and metabolic adaptations to pregnancy; impact of obesity. AB - Adaptations of maternal endocrine and metabolic homeostasis are central to successful pregnancy. They insure that an adequate and continuous supply of metabolic fuels is available for the growing fetus. Healthy pregnancy is classically described as a mild diabetogenic state with significant adjustments in both insulin production and sensitivity. The placenta contributes to the endocrine adaptations to pregnancy through the synthesis of various hormones which may impact insulin action. Obesity has the highest prevalence among metabolic disease in pregnancy. This article summarizes the literature addressing the endocrine and metabolic adaptations implemented during normal pregnancy. Mechanisms of regulation are further examined in the context of maternal obesity. PMID- 26613332 TI - Insulin sensitivity affects corticolimbic brain responses to visual food cues in polycystic ovary syndrome patients. AB - BACKGROUND: This study examined the effect of insulin sensitivity on the responsiveness of appetite regulatory brain regions to visual food cues. MATERIALS AND METHODS: Nineteen participants diagnosed with polycystic ovary syndrome (PCOS) were divided into insulin-sensitive (n=8) and insulin-resistant (n=11) groups based on the homeostatic model assessment of insulin resistance (HOMA2-IR). Subjects underwent functional magnetic resonance imaging (fMRI) while viewing food pictures following water or dextrose consumption. The corticolimbic blood oxygen level dependent (BOLD) responses to high-calorie (HC) or low-calorie (LC) food pictures were compared within and between groups. RESULTS: BOLD responses to food pictures were reduced during a glucose challenge in numerous corticolimbic brain regions in insulin-sensitive but not insulin-resistant subjects. Furthermore, the degree of insulin resistance positively correlated with the corticolimbic BOLD response in the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), anterior cingulate and ventral tegmental area (VTA) in response to HC pictures, and in the dorsolateral prefrontal cortex (DLPFC), mPFC, anterior cingulate, and insula in response to LC pictures following a glucose challenge. BOLD signal in the OFC, midbrain, hippocampus, and amygdala following a glucose challenge correlated with HOMA2-IR in response to HC-LC pictures. CONCLUSION: We conclude that the normal inhibition of corticolimbic brain responses to food pictures during a glucose challenge is compromised in insulin-resistant subjects. The increase in brain responsiveness to food pictures during postprandial hyperinsulinemia may lead to greater non-homeostatic eating and perpetuate obesity in insulin-resistant subjects. PMID- 26613333 TI - The crosstalk between alpha-irradiated Beas-2B cells and its bystander U937 cells through MAPK and NF-kappaB signaling pathways. AB - Although accumulated evidence suggests that alpha-particle irradiation induced bystander effect may relevant to lung injury and cancer risk assessment, the exact mechanisms are not yet elucidated. In the present study, a cell co-culture system was used to investigate the interaction between alpha-particle irradiated human bronchial epithelial cells (Beas-2B) and its bystander macrophage U937 cells. It was found that the cell co-culture amplified the detrimental effects of alpha-irradiation including cell viability decrease and apoptosis promotion on both irradiated cells and bystander cells in a feedback loop which was closely relevant to the activation of MAPK and NF-kappaB pathways in the bystander U937 cells. When these two pathways in U937 cells were disturbed by special pharmacological inhibitors before cell co-culture, it was found that a NF-kappaB inhibitor of BAY 11-7082 further enhanced the proliferation inhibition and apoptosis induction in bystander U937 cells, but MAPK inhibitors of SP600125 and SB203580 protected cells from viability loss and apoptosis and U0126 presented more beneficial effect on cell protection. For alpha-irradiated epithelial cells, the activation of NF-kappaB and MAPK pathways in U937 cells participated in detrimental cellular responses since the above inhibitors could largely attenuate cell viability loss and apoptosis of irradiated cells. Our results demonstrated that there are bilateral bystander responses between irradiated lung epithelial cells and macrophages through MAPK and NF-kappaB signaling pathways, which accounts for the enhancement of alpha-irradiation induced damage. PMID- 26613334 TI - Enhanced interlayer trapping of a tetracycline antibiotic within montmorillonite layers in the presence of Ca and Mg. AB - The formation of a ternary antibiotic-metal-clay complex is hypothesized as the primary adsorption mechanism responsible for the increased adsorption of tetracycline antibiotics on smectites in the presence of divalent metal cations under circumneutral and higher pH conditions. To evaluate this hypothesis, we conducted a spectroscopic investigation of oxytetracycline (OTC) interacting with Na-montmorillonite in the presence and absence of Ca or Mg salts at pH 6 and pH 8. Despite a two-fold increase in OTC adsorbed in the presence of Ca or Mg, both solid-state nuclear magnetic resonance and infrared signatures of the OTC functional groups involved in metal complexation implied that the formation of an inner-sphere ternary complexation was not significant in stabilizing the adsorbate structures. The spectroscopic data further indicated that the positively-charged amino group mediated the OTC adsorption both in the absence and presence of the divalent metal cations. Focusing on the experiments with Mg, X-ray diffraction analysis revealed that the metal-promoted adsorption was coupled with an increased intercalation of OTC within the montmorillonite layers. The resulting interstratified clay layers were characterized by simulating X-ray diffraction of theoretical stacking compositions using molecular dynamics optimized montmorillonite layers with and without OTC. The simulations uncovered the evolution of segregated interstratification patterns that demonstrated how increased access to smectite interlayers in the presence of the divalent metal cations enhanced adsorption of OTC. Our findings suggest that specific aqueous structures of the clay crystallites in response to the co-presence of Mg and OTC in solution served as precursors to the interlayer trapping of the antibiotic species. Elucidation of these structures is needed for further insights on how aqueous chemistry influences the role of smectite clay minerals in trapping organic molecules in natural and engineered soil particles. PMID- 26613335 TI - Amino acid induced fractal aggregation of gold nanoparticles: Why and how. AB - Gold colloids are the object of many studies as they are reported to have potential biological sensing, imaging and drug delivery applications. In the presence of certain amino acids the aggregation of the gold nanoparticles into linear structures is observed, as highlighted by the appearance of a second plasmon band in the UV-Vis spectra of the colloid. The mechanism behind this phenomenon is still under debate. In order to help elucidate this issue, the interaction between gold colloids and different amino acids, modified amino acids and molecules mimicking their side-chain was monitored by UV-Vis absorption, DLS and TEM. The results show that phenomenon can be rationalized in terms of the Diffusion Limited Colloid Aggregation (DLCA) model which gives rise to the fractal aggregation colloids. The global charge of the compound, which influences the ionic strength of the solution, and the ease with which the compound can interact with the GNPs and affect their surface potential, are, the two parameters which control the DLCA regime. Calculations based on the Derjaguin, Landau, Verwey and Overbeek (DLVO) theory confirm all the experimental observations. PMID- 26613336 TI - Optical properties of Er(3+)-doped oxyfluoride glasses. AB - Er(3+)-singly doped and Er(3+)/Yb(3+)-codoped 50SiO2-(50-x)BaF2-xZnF2(SBZx) oxyfluoride glasses are prepared and the optical properties of Er(3+)-singly doped glasses are investigated by using the Judd-Ofelt theory. Bright green and red upconversion luminescence of Er(3+)/Yb(3+)-codoped glasses is obtained under 980nm excitation. Furthermore, factors affecting this phenomenon such as glass composition, doping concentration of Er(3+) and Yb(3+) ions, and pump power are discussed in details. PMID- 26613337 TI - Decision aids for people considering taking part in clinical trials. AB - BACKGROUND: Several interventions have been developed to promote informed consent for participants in clinical trials. However, many of these interventions focus on the content and structure of information (e.g. enhanced information or changes to the presentation format) rather than the process of decision making. Patient decision aids support a decision making process about medical options. Decision aids support the decision process by providing information about available options and their associated outcomes, alongside information that enables patients to consider what value they place on particular outcomes, and provide structured guidance on steps of decision making. They have been shown to be effective for treatment and screening decisions but evidence on their effectiveness in the context of informed consent for clinical trials has not been synthesised. OBJECTIVES: To assess the effectiveness of decision aids for clinical trial informed consent compared to no intervention, standard information (i.e. usual practice) or an alternative intervention on the decision making process. SEARCH METHODS: We searched the following databases and to March 2015: Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library; MEDLINE (OvidSP) (from 1950); EMBASE (OvidSP) (from 1980); PsycINFO (OvidSP) (from 1806); ASSIA (ProQuest) (from 1987); WHO International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/); ClinicalTrials.gov; ISRCTN Register (http://www.controlled-trials.com/isrctn/). We also searched reference lists of included studies and relevant reviews. We contacted study authors and other experts. There were no language restrictions. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials comparing decision aids in the informed consent process for clinical trials alone, or in conjunction with standard information (such as written or verbal) or alongside alternative interventions (e.g. paper-based versus web-based decision aids). Included trials involved potential trial participants, or their guardians, being asked to consider participating in a real or hypothetical clinical trial. DATA COLLECTION AND ANALYSIS: At least two authors independently assessed studies for inclusion, extracted reported data and assessed risk of bias. Findings were pooled where appropriate. We used GRADE to assess the quality of the evidence for each outcome. MAIN RESULTS: We identified one study (290 randomised participants) that investigated the effectiveness of decision aids compared to standard information in the informed consent process for clinical trials. This study reported two separate decision aid randomised controlled trials (RCTs). The decision aid trials were nested within two different parent trials focusing on breast cancer in postmenopausal women. One trial focused on informed consent for treatment in women who had previously had surgery for ductal carcinoma in situ (DCIS), the other on informed consent for prevention in women at high risk for breast cancer. Two different decision aids were used in these RCTs, and were compared with standard information.The pooled findings highlight the uncertainty surrounding most reported outcomes, including knowledge, decisional conflict, anxiety, trial participation and attrition. There was very low quality evidence that decision aids lower levels of decisional regret to a small degree (MD -5.53, 95% CI -10.29 to -0.76). No data were identified on several prespecified primary outcomes, including accurate risk perception, values-based decision, or whether potential participants recognised that a decision needed to be made, were able to identify features of options that matter most to individuals, or were involved in the decision. AUTHORS' CONCLUSIONS: There was insufficient evidence to determine whether decision aids to support the informed consent process for clinical trials are more effective than standard information. Additional well designed, adequately powered clinical trials in more diverse clinical and social populations are needed to strengthen the results of this review. More generally, future research on which outcomes are most relevant for assessment in this context would be helpful. PMID- 26613338 TI - Bacterial predation in a marine host-associated microbiome. AB - In many ecological communities, predation has a key role in regulating community structure or function. Although predation has been extensively explored in animals and microbial eukaryotes, predation by bacteria is less well understood. Here we show that predatory bacteria of the genus Halobacteriovorax are prevalent and active predators on the surface of several genera of reef-building corals. Across a library of 198 16S rRNA samples spanning three coral genera, 79% were positive for carriage of Halobacteriovorax. Cultured Halobacteriovorax from Porites asteroides corals tested positive for predation on the putative coral pathogens Vibrio corallyticus and Vibrio harveyii. Co-occurrence network analysis showed that Halobacteriovorax's interactions with other bacteria are influenced by temperature and inorganic nutrient concentration, and further suggested that this bacterial predator's abundance may be driven by prey availability. Thus, animal microbiomes can harbor active bacterial predators, which may regulate microbiome structure and protect the host by consuming potential pathogens. PMID- 26613339 TI - Reverse transcriptase genes are highly abundant and transcriptionally active in marine plankton assemblages. AB - Genes encoding reverse transcriptases (RTs) are found in most eukaryotes, often as a component of retrotransposons, as well as in retroviruses and in prokaryotic retroelements. We investigated the abundance, classification and transcriptional status of RTs based on Tara Oceans marine metagenomes and metatranscriptomes encompassing a wide organism size range. Our analyses revealed that RTs predominate large-size fraction metagenomes (>5 MUm), where they reached a maximum of 13.5% of the total gene abundance. Metagenomic RTs were widely distributed across the phylogeny of known RTs, but many belonged to previously uncharacterized clades. Metatranscriptomic RTs showed distinct abundance patterns across samples compared with metagenomic RTs. The relative abundances of viral and bacterial RTs among identified RT sequences were higher in metatranscriptomes than in metagenomes and these sequences were detected in all metatranscriptome size fractions. Overall, these observations suggest an active proliferation of various RT-assisted elements, which could be involved in genome evolution or adaptive processes of plankton assemblage. PMID- 26613340 TI - Functional analysis of liverworts in dual symbiosis with Glomeromycota and Mucoromycotina fungi under a simulated Palaeozoic CO2 decline. AB - Most land plants form mutualistic associations with arbuscular mycorrhizal fungi of the Glomeromycota, but recent studies have found that ancient plant lineages form mutualisms with Mucoromycotina fungi. Simultaneous associations with both fungal lineages have now been found in some plants, necessitating studies to understand the functional and evolutionary significance of these tripartite associations for the first time. We investigate the physiology and cytology of dual fungal symbioses in the early-diverging liverworts Allisonia and Neohodgsonia at modern and Palaeozoic-like elevated atmospheric CO2 concentrations under which they are thought to have evolved. We found enhanced carbon cost to liverworts with simultaneous Mucoromycotina and Glomeromycota associations, greater nutrient gain compared with those symbiotic with only one fungal group in previous experiments and contrasting responses to atmospheric CO2 among liverwort-fungal symbioses. In liverwort-Mucoromycotina symbioses, there is increased P-for-C and N-for-C exchange efficiency at 440 p.p.m. compared with 1500 p.p.m. CO2. In liverwort-Glomeromycota symbioses, P-for-C exchange is lower at ambient CO2 compared with elevated CO2. No characteristic cytologies of dual symbiosis were identified. We provide evidence of a distinct physiological niche for plant symbioses with Mucoromycotina fungi, giving novel insight into why dual symbioses with Mucoromycotina and Glomeromycota fungi persist to the present day. PMID- 26613341 TI - High levels of heterogeneity in diazotroph diversity and activity within a putative hotspot for marine nitrogen fixation. AB - Australia's tropical waters represent predicted 'hotspots' for nitrogen (N2) fixation based on empirical and modelled data. However, the identity, activity and ecology of diazotrophs within this region are virtually unknown. By coupling DNA and cDNA sequencing of nitrogenase genes (nifH) with size-fractionated N2 fixation rate measurements, we elucidated diazotroph dynamics across the shelf region of the Arafura and Timor Seas (ATS) and oceanic Coral Sea during Austral spring and winter. During spring, Trichodesmium dominated ATS assemblages, comprising 60% of nifH DNA sequences, while Candidatus Atelocyanobacterium thalassa (UCYN-A) comprised 42% in the Coral Sea. In contrast, during winter the relative abundance of heterotrophic unicellular diazotrophs (delta-proteobacteria and gamma-24774A11) increased in both regions, concomitant with a marked decline in UCYN-A sequences, whereby this clade effectively disappeared in the Coral Sea. Conservative estimates of N2 fixation rates ranged from <1 to 91 nmol l(-1) day( 1), and size fractionation indicated that unicellular organisms dominated N2 fixation during both spring and winter, but average unicellular rates were up to 10-fold higher in winter than in spring. Relative abundances of UCYN-A1 and gamma 24774A11 nifH transcripts negatively correlated to silicate and phosphate, suggesting an affinity for oligotrophy. Our results indicate that Australia's tropical waters are indeed hotspots for N2 fixation and that regional physicochemical characteristics drive differential contributions of cyanobacterial and heterotrophic phylotypes to N2 fixation. PMID- 26613342 TI - Synbiotic approach restores intestinal homeostasis and prolongs survival in leukaemic mice with cachexia. AB - Cancer cachexia is a multifactorial syndrome that includes muscle wasting and inflammation. As gut microbes influence host immunity and metabolism, we investigated the role of the gut microbiota in the therapeutic management of cancer and associated cachexia. A community-wide analysis of the caecal microbiome in two mouse models of cancer cachexia (acute leukaemia or subcutaneous transplantation of colon cancer cells) identified common microbial signatures, including decreased Lactobacillus spp. and increased Enterobacteriaceae and Parabacteroides goldsteinii/ASF 519. Building on this information, we administered a synbiotic containing inulin-type fructans and live Lactobacillus reuteri 100-23 to leukaemic mice. This treatment restored the Lactobacillus population and reduced the Enterobacteriaceae levels. It also reduced hepatic cancer cell proliferation, muscle wasting and morbidity, and prolonged survival. Administration of the synbiotic was associated with restoration of the expression of antimicrobial proteins controlling intestinal barrier function and gut immunity markers, but did not impact the portal metabolomics imprinting of energy demand. In summary, this study provided evidence that the development of cancer outside the gut can impact intestinal homeostasis and the gut microbial ecosystem and that a synbiotic intervention, by targeting some alterations of the gut microbiota, confers benefits to the host, prolonging survival and reducing cancer proliferation and cachexia. PMID- 26613343 TI - Resource limitation drives spatial organization in microbial groups. AB - Dense microbial groups such as bacterial biofilms commonly contain a diversity of cell types that define their functioning. However, we have a limited understanding of what maintains, or purges, this diversity. Theory suggests that resource levels are key to understanding diversity and the spatial arrangement of genotypes in microbial groups, but we need empirical tests. Here we use theory and experiments to study the effects of nutrient level on spatio-genetic structuring and diversity in bacterial colonies. Well-fed colonies maintain larger well-mixed areas, but they also expand more rapidly compared with poorly fed ones. Given enough space to expand, therefore, well-fed colonies lose diversity and separate in space over a similar timescale to poorly fed ones. In sum, as long as there is some degree of nutrient limitation, we observe the emergence of structured communities. We conclude that resource-driven structuring is central to understanding both pattern and process in diverse microbial communities. PMID- 26613344 TI - Incidence of nephrolithiasis in relation to environmental exposure to lead and cadmium in a population study. AB - Whether environmental exposure to nephrotoxic agents that potentially interfere with calcium homeostasis, such as lead and cadmium, contribute to the incidence of nephrolithiasis needs further clarification. We investigated the relation between nephrolithiasis incidence and environmental lead and cadmium exposure in a general population. In 1302 participants randomly recruited from a Flemish population (50.9% women; mean age, 47.9 years), we obtained baseline measurements (1985-2005) of blood lead (BPb), blood cadmium (BCd), 24-h urinary cadmium (UCd) and covariables. We monitored the incidence of kidney stones until October 6, 2014. We used Cox regression to calculate multivariable-adjusted hazard ratios for nephrolithiasis. At baseline, geometric mean BPb, BCd and UCd was 0.29umol/L, 9.0nmol/L, and 8.5nmol per 24h, respectively. Over 11.5 years (median), nephrolithiasis occurred in 40 people. Contrasting the low and top tertiles of the distributions, the sex- and age-standardized rates of nephrolithiasis expressed as events per 1000 person-years were 0.68 vs. 3.36 (p=0.0016) for BPb, 1.80 vs. 3.28 (p=0.11) for BCd, and 1.65 vs. 2.95 (p=0.28) for UCd. In continuous analysis, with adjustments applied for sex, age, serum magnesium, and 24-h urinary volume and calcium, the hazard ratios expressing the risk associated with a doubling of the exposure biomarkers were 1.35 (p=0.015) for BPb, 1.13 (p=0.22) for BCd, and 1.23 (p=0.070) for UCd. In conclusion, our results suggest that environmental lead exposure is a risk factor for nephrolithiasis in the general population. PMID- 26613346 TI - Framing the impact of physical pain on suicide attempts. A reply to Stubbs. PMID- 26613345 TI - Association between satellite-based estimates of long-term PM2.5 exposure and coronary artery disease. AB - BACKGROUND: Epidemiological studies have identified associations between long term PM2.5 exposure and cardiovascular events, though most have relied on concentrations from central-site air quality monitors. METHODS: We utilized a cohort of 5679 patients who had undergone cardiac catheterization at Duke University between 2002-2009 and resided in North Carolina. We used estimates of daily PM2.5 concentrations for North Carolina during the study period based on satellite derived Aerosol Optical Depth (AOD) measurements and PM2.5 concentrations from ground monitors, which were spatially resolved with a 10*10km resolution, matched to each patient's residential address and averaged for the year prior to catheterization. The Coronary Artery Disease (CAD) index was used to measure severity of CAD; scores >23 represent a hemodynamically significant coronary artery lesion in at least one major coronary vessel. Logistic regression modeled odds of having CAD or an MI with each 1MUg/m(3) increase in annual average PM2.5, adjusting for sex, race, smoking status and socioeconomic status. RESULTS: In adjusted models, a 1MUg/m(3) increase in annual average PM2.5 was associated with an 11.1% relative increase in the odds of significant CAD (95% CI: 4.0-18.6%) and a 14.2% increase in the odds of having a myocardial infarction (MI) within a year prior (95% CI: 3.7-25.8%). CONCLUSIONS: Satellite-based estimates of long-term PM2.5 exposure were associated with both coronary artery disease (CAD) and incidence of myocardial infarction (MI) in a cohort of cardiac catheterization patients. PMID- 26613347 TI - Earliest events in alpha-synuclein fibrillation probed with the fluorescence of intrinsic tyrosines. AB - The fluorescence of the four tyrosines of alpha-synuclein (Syn) was used for probing the earliest events preceding the fibrillation of Syn, during the onset of the so-called lag-time of fibrillation. Steady-state fluorescence experiments revealed an increase in the fluorescence intensity (FI) for Syn solutions at pH values 3 and 2, in comparison with pH7, and fluorescence decays indicated that the FI increase did not result from suppression of excited-state proton transfer from the tyrosines to aspartates and glutamates, exposure of tyrosines to more hydrophobic environments, or reduction of homo-energy transfer. Instead, the FI increase was due to changes in the population of the tyrosine rotamers at low pH values. Stopped-flow experiments (pH-jumps) showed that the FI enhancement involves two processes: a fast (sub-7 ms) intramolecular (concentration independent) process, which we assign to the protein collapse at low pH, and a slower intermolecular (concentration-dependent) process of protein dimerization/oligomerization, starting at 4-10s after acidification. To the best of our knowledge, this is the first work on the experimental detection of these earliest processes in the fibrillation of Syn. PMID- 26613349 TI - An empirical assessment of which inland floods can be managed. AB - Riverine flooding is a significant global issue. Although it is well documented that the influence of landscape structure on floods decreases as flood size increases, studies that define a threshold flood-return period, above which landscape features such as topography, land cover and impoundments can curtail floods, are lacking. Further, the relative influences of natural versus built features on floods is poorly understood. Assumptions about the types of floods that can be managed have considerable implications for the cost-effectiveness of decisions to invest in transforming land cover (e.g., reforestation) and in constructing structures (e.g., storm-water ponds) to control floods. This study defines parameters of floods for which changes in landscape structure can have an impact. We compare nine flood-return periods across 31 watersheds with widely varying topography and land cover in the southeastern United States, using long term hydrologic records (>=20 years). We also assess the effects of built flow regulating features (best management practices and artificial water bodies) on selected flood metrics across urban watersheds. We show that landscape features affect magnitude and duration of only those floods with return periods <=10 years, which suggests that larger floods cannot be managed effectively by manipulating landscape structure. Overall, urban watersheds exhibited larger (270 m(3)/s) but quicker (0.41 days) floods than non-urban watersheds (50 m(3)/s and 1.5 days). However, urban watersheds with more flow-regulating features had lower flood magnitudes (154 m(3)/s), but similar flood durations (0.55 days), compared to urban watersheds with fewer flow-regulating features (360 m(3)/s and 0.23 days). Our analysis provides insight into the magnitude, duration and count of floods that can be curtailed by landscape structure and its management. Our findings are relevant to other areas with similar climate, topography, and land use, and can help ensure that investments in flood management are made wisely after considering the limitations of landscape features to regulate floods. PMID- 26613350 TI - Evaluating a microbial water quality prediction model for beach management under the revised EU Bathing Water Directive. AB - The revised Bathing Water Directive (2006/7/EC) requires EU member states to minimise the risk to public health from faecal pollution at bathing waters through improved monitoring and management approaches. While increasingly sophisticated measurement methods (such as microbial source tracking) assist in the management of bathing water resources, the use of deterministic predictive models for this purpose, while having the potential to provide decision making support, remains less common. This study explores an integrated, deterministic catchment-coastal hydro-environmental model as a decision-making tool for beach management which, based on advance predictions of bathing water quality, can inform beach managers on appropriate management actions (to prohibit bathing or advise the public not to bathe) in the event of a poor water quality forecast. The model provides a 'moving window' five-day forecast of Escherichia coli levels at a bathing water compliance point off the Irish coast and the accuracy of bathing water management decisions were investigated for model predictions under two scenarios over the period from the 11th August to the 5th September, 2012. Decisions for Scenario 1 were based on model predictions where rainfall forecasts from a meteorological source (www.yr.no) were used to drive the rainfall-runoff processes in the catchment component of the model, and for Scenario 2, were based on predictions that were improved by incorporating real-time rainfall data from a sensor network within the catchment into the forecasted meteorological input data. The accuracy of the model in the decision-making process was assessed using the contingency table and its metrics. The predictive model gave reasonable outputs to support appropriate decision making for public health protection. Scenario 1 provided real-time predictions that, on 77% of instances during the study period where both predicted and E. coli concentrations were available, would correctly inform a beach manager to either take action to mitigate for poor bathing water quality or take no action. However, Scenario 1 also provided data to support a decision to take action (when none was necessary - a type I error) in 4% of instances and to take no action (when action was required - a type II error) in 19% of the instances analysed. Type II errors are critical in terms of public health protection given that for this error, bathers can be exposed to risks from poor bathing water quality. Scenario 2, on the other hand, provided predictions that would support correct management actions for 79% of the instances but would result in type I and type II errors for 4% and 17% of the instances respectively. Comparison of Scenarios 1 and 2 for this study indicate that Scenario 2 gave a marginally better overall performance in terms of supporting correct management decisions, as it provided data that could result in a lower occurrence of the more critical type II errors. Given that the 28 member states of the European Union are required to engage with the public health provisions of the revised Bathing Water Directive, issues of compliance, pertaining particularly to the management of bathing water resources, remain topical. Decision supports for managing bathing waters in the context of the Directive are likely to become the focus of much attention and although, the current study has been validated in bathing waters off the east coast of Ireland, the approach of using a deterministic and integrated catchment-coastal model for such purposes is easily transferable to other bathing water jurisdictions. PMID- 26613351 TI - Full cost accounting in the analysis of separated waste collection efficiency: A methodological proposal. AB - Recycling implies additional costs for separated municipal solid waste (MSW) collection. The aim of the present study is to propose and implement a management tool - the full cost accounting (FCA) method - to calculate the full collection costs of different types of waste. Our analysis aims for a better understanding of the difficulties of putting FCA into practice in the MSW sector. We propose a FCA methodology that uses standard cost and actual quantities to calculate the collection costs of separate and undifferentiated waste. Our methodology allows cost efficiency analysis and benchmarking, overcoming problems related to firm specific accounting choices, earnings management policies and purchase policies. Our methodology allows benchmarking and variance analysis that can be used to identify the causes of off-standards performance and guide managers to deploy resources more efficiently. Our methodology can be implemented by companies lacking a sophisticated management accounting system. PMID- 26613348 TI - Rapid generation of sub-type, region-specific neurons and neural networks from human pluripotent stem cell-derived neurospheres. AB - Stem cell-based neuronal differentiation has provided a unique opportunity for disease modeling and regenerative medicine. Neurospheres are the most commonly used neuroprogenitors for neuronal differentiation, but they often clump in culture, which has always represented a challenge for neurodifferentiation. In this study, we report a novel method and defined culture conditions for generating sub-type or region-specific neurons from human embryonic and induced pluripotent stem cells derived neurosphere without any genetic manipulation. Round and bright-edged neurospheres were generated in a supplemented knockout serum replacement medium (SKSRM) with 10% CO2, which doubled the expression of the NESTIN, PAX6 and FOXG1 genes compared with those cultured with 5% CO2. Furthermore, an additional step (AdSTEP) was introduced to fragment the neurospheres and facilitate the formation of a neuroepithelial-type monolayer that we termed the "neurosphederm". The large neural tube-type rosette (NTTR) structure formed from the neurosphederm, and the NTTR expressed higher levels of the PAX6, SOX2 and NESTIN genes compared with the neuroectoderm-derived neuroprogenitors. Different layers of cortical, pyramidal, GABAergic, glutamatergic, cholinergic neurons appeared within 27 days using the neurosphederm, which is a shorter period than in traditional neurodifferentiation protocols (42-60 days). With additional supplements and timeline dopaminergic and Purkinje neurons were also generated in culture too. Furthermore, our in vivo results indicated that the fragmented neurospheres facilitated significantly better neurogenesis in severe combined immunodeficiency (SCID) mouse brains compared with the non-fragmented neurospheres. Therefore, this neurosphere-based neurodifferentiation protocol is a valuable tool for studies of neurodifferentiation, neuronal transplantation and high throughput screening assays. PMID- 26613352 TI - Estimating biokinetic coefficients in the PACTTM system. AB - When powdered activated carbon (PAC) is continuously added to the aeration tank of an activated sludge reactor, the modification is called a PACTTM process (for powdered activated carbon treatment). The PAC provides many benefits, but complicates the determination of biological phenomena. Determination of bio oxidation kinetics in a PACT system is a key to fully understanding enhanced biological mechanisms resulting from PAC addition. A model is developed to account for the main mechanisms involved in the PACT system -- adsorption, air stripping and bio-oxidation. The model enables the investigation of biokinetic information, including possible synergistic effects. Six parallel reactors were used to treat a synthetic waste; three activated sludge and three PACT. The PACT reactors provided significantly reduced effluent TOC (total organic carbon). Biokinetic coefficients were obtained from steady-state data using averaged reactor data and by using all data (22 points for each reactor). As expected, the PACT reactors resulted in a substantial reduction in the effluent concentration of non-biodegradable total organic carbon. The Monod equation's half-saturation coefficient (Ks) was reduced significantly in the PACT reactors, resulting in higher growth rates at lower concentrations. The maximum specific substrate utilization (qm) rate was also reduced about 25% using the averaged data and remained unchanged using all the data. The substrate utilization values are affected by errors in biomass determination and more research is needed to accurately determine biomass. PMID- 26613353 TI - A novel modelling framework to prioritize estimation of non-point source pollution parameters for quantifying pollutant origin and discharge in urban catchments. AB - Stormwater runoff in urban catchments contains heavy metals (zinc, copper, lead) and suspended solids (TSS) which can substantially degrade urban waterways. To identify these pollutant sources and quantify their loads the MEDUSA (Modelled Estimates of Discharges for Urban Stormwater Assessments) modelling framework was developed. The model quantifies pollutant build-up and wash-off from individual impervious roof, road and car park surfaces for individual rain events, incorporating differences in pollutant dynamics between surface types and rainfall characteristics. This requires delineating all impervious surfaces and their material types, the drainage network, rainfall characteristics and coefficients for the pollutant dynamics equations. An example application of the model to a small urban catchment demonstrates how the model can be used to identify the magnitude of pollutant loads, their spatial origin and the response of the catchment to changes in specific rainfall characteristics. A sensitivity analysis then identifies the key parameters influencing each pollutant load within the stormwater given the catchment characteristics, which allows development of a targeted calibration process that will enhance the certainty of the model outputs, while minimizing the data collection required for effective calibration. A detailed explanation of the modelling framework and pre calibration sensitivity analysis is presented. PMID- 26613354 TI - Dredging for dilution: A simulation based case study in a Tidal River. AB - A 2-D hydrodynamic finite element model with a Lagrangian particle module is used to investigate the effects of dredging on the hydrodynamics and the horizontal dilution of pollutant particles originating from a wastewater treatment facility (WWTF) in tidal Oyster River in New Hampshire, USA. The model is driven by the semi-diurnal (M2) tidal component and includes the effect of flooding and drying of riverine mud flats. The particle tracking method consists of tidal advection plus a horizontal random walk model of sub-grid scale turbulent processes. Our approach is to perform continuous pollutant particle releases from the outfall, simulating three different scenarios: a base-case representing the present conditions and two different dredged channel/outfall location configurations. Hydrodynamics are investigated in an Eulerian framework and Lagrangian particle dilution improvement ratios are calculated for all cases. Results show that the simulated hydrodynamics are consistent with observed conditions. Eulerian and Lagrangian residuals predict an outward path suggesting flushing of pollutants on longer (>M2) time scales. Simulated dilution maps show that, in addition to dredging, the relocation of the WWTF outfall into the dredged main channel is required for increased dilution performance. The methodology presented here can be applied to similar managerial problems in all similar systems worldwide with relatively little effort, with the combination of Lagrangian and Eulerian methods working together towards a better solution. The statistical significance brought into methodology, by using a large number of particles (16000 in this case), is to be emphasized, especially with the growing number of networked parallel computer clusters worldwide. This paper improves on the study presented in Bilgili et al., 2006b, by adding an Eulerian analysis. PMID- 26613355 TI - The developmental trajectory of contrast sensitivity in autism spectrum disorder. AB - Autism Spectrum Disorder (ASD) is characterized by a detail-driven visual processing strategy, evidence for which has been based largely on cross-sectional studies in small participant groups of limited age ranges. It is therefore unknown when sensitivity to detailed information emerges and develops in ASD. Contrast sensitivity to sinusoidal gratings of different spatial frequencies (0.5, 1, 2, 4, and 8 cycles per degree (cpd)) was measured for 34 participants with ASD and 55 typically developing participants (aged 6-16 years). Cross sectional, developmental trajectories were constructed to examine within and between group differences across the range of spatial frequencies tested. Developmental trajectories indicated that sensitivity across low (i.e., 0.5 and 1 cpd) and mid (2 and 4 cpd) spatial frequencies varied by chronological age within each group, with mid frequencies developing at a more significant rate than low frequencies. There was no overall difference between groups in terms of the relationship of sensitivity and age across spatial frequencies, yet the ASD group had an overall lower level of sensitivity. Closer examination revealed that the youngest participants with ASD had a reduced sensitivity for mid frequencies. Moreover, the ASD group showed a statistically significant developmental relationship at 8 cpd, which suggests that a trend for increased sensitivity to early detailed information may manifest beyond the ages tested. These findings demonstrate a differential development of contrast sensitivity for spatial frequencies in ASD and underscore the need to better identify what drives such differences in the "building blocks" of visual perception. Autism Res 2016, 9: 866-878. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26613357 TI - Novel flame retardants: Estimating the physical-chemical properties and environmental fate of 94 halogenated and organophosphate PBDE replacements. AB - In the wake of the listing by the Stockholm Convention of PBDEs, an increasing number of "novel" flame retardants (NFRs) are being used in products. The properties that make for desirable flame retardants can also lead to negative health effects, long environmental residence times and an affinity for organic matrices. While NFRs are currently in use, little information is available regarding their physical-chemical properties and environmental fate. In this study, 94 halogenated and organophosphate NFRs were evaluated for their persistence and long-range transport potential. Physical-chemical properties (namely liquid sub-cooled vapor pressure P(l) and solubility S(l), air-water (K(AW)), octanol-water (K(OW)), and octanol-air (K(OA)) partition coefficients) of the NFRs were predicted using three chemical property estimation tools: EPI Suite, SPARC and Absolv. Physical-chemical properties predicted using these tools were generally within 10(2)-10(3) for compounds with molecular weight < 800 g/mol. Estimated physical-chemical properties of compounds with >800 g/mol, and/or the presence of a heteroatom and/or a polar functional group could deviate by up to 10(12). According to the OECD P(OV) and LRTP Screening Tool, up to 40% of the NFRs have a persistence and/or long range transport potential of medium to high level of concern and up to 60% have persistence and or long range transport potential similar to the PBDEs they are replacing. Long range transport potential could be underestimated by the OECD model since the model under-predicts long range transport potential of some organophosphate compounds. PMID- 26613356 TI - Experience-dependent escalation of glucose drinking and the development of glucose preference over fructose - association with glucose entry into the brain. AB - Glucose, a primary metabolic substrate for cellular activity, must be delivered to the brain for normal neural functions. Glucose is also a unique reinforcer; in addition to its rewarding sensory properties and metabolic effects, which all natural sugars have, glucose crosses the blood-brain barrier and acts on glucoreceptors expressed on multiple brain cells. To clarify the role of this direct glucose action in the brain, we compared the neural and behavioural effects of glucose with those induced by fructose, a sweeter yet metabolically equivalent sugar. First, by using enzyme-based biosensors in freely moving rats, we confirmed that glucose rapidly increased in the nucleus accumbens in a dose dependent manner after its intravenous delivery. In contrast, fructose induced a minimal response only after a large-dose injection. Second, we showed that naive rats during unrestricted access consumed larger volumes of glucose than fructose solution; the difference appeared with a definite latency during the initial exposure and strongly increased during subsequent tests. When rats with equal sugar experience were presented with either glucose or fructose in alternating order, the consumption of both substances was initially equal, but only the consumption of glucose increased during subsequent sessions. Finally, rats with equal glucose-fructose experience developed a strong preference for glucose over fructose during a two-bottle choice procedure; the effect appeared with a definite latency during the initial test and greatly amplified during subsequent tests. Our results suggest that direct entry of glucose in the brain and its subsequent effects on brain cells could be critical for the experience-dependent escalation of glucose consumption and the development of glucose preference over fructose. PMID- 26613358 TI - Anthropogenic and naturally produced brominated substances in Baltic herring (Clupea harengus membras) from two sites in the Baltic Sea. AB - In the eutrophicated Baltic Sea, several naturally produced hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have been found in marine biota. OH PBDEs are toxic to adult and developing zebrafish and shown to be potent disruptors of oxidative phosphorylation (OXPHOS). Disturbed OXPHOS can result in altered energy metabolism and weight loss. In herring, the concentration of OH PBDEs (i.e. 2'-OH-BDE68 and 6-OH-BDE47) has increased during the period 1980-2010 in the Baltic Proper. Over the same time period, the condition and fat content in Baltic herring have decreased. Given the toxicity and increasing trends of OH PBDEs in Baltic herring it is important to further assess the exposure to OH PBDEs in Baltic herring. In this study, the concentrations of OH-PBDEs and related brominated substances i.e. polybrominated phenols (PBPs), polybrominated anisoles (PBAs), methoxylated polybrominated diphenyl ethers (MeO-PBDEs) and polybrominated diphenyl ethers (PBDEs) were measured in herring sampled in the northern Baltic Proper (Asko, n = 12) and the southern Bothnian Sea (Angskarsklubb, n = 12). The geometric mean (GM) concentrations (ng/g l.w.) at Asko and Angskarsklubb were; Sigma2PBPs: 4.3 and 9.6, Sigma(2)PBAs: 34 and 20, Sigma(6)OH-PBDEs: 9.4 and 10, Sigma(7)MeO-PBDEs: 42 and 150, Sigma(6)PBDEs: 54 and 27, respectively. 6-OH-BDE47 dominated the OH-PBDE profile and comprised 87% (Asko) and 91% (Angskarsklubb) of the SigmaOH-PBDEs. At Angskarsklubb the mean concentration of SigmaMeO-PBDEs (150 ng/g l.w.) was 15 times higher than SigmaOH PBDEs. As other fish species are known to metabolically transform MeO-PBDEs to OH PBDEs, high levels of MeO-PBDEs can be of concern as a precursor for more toxic OH-PBDEs in herring and their roe. PMID- 26613359 TI - Enhanced AOX accumulation and aquatic toxicity during 2,4,6-trichlorophenol degradation in a Co(II)/peroxymonosulfate/Cl- system. AB - Chloride ion is known to affect on degradation kinetics in different ways during HO. and SO4(.-)-based advanced oxidation processes (AOPs). However, its effect on absorbable organic halogen (AOX) evolution and acute toxicity of treated water remains unknown, despite the importance of the two parameters in evaluating the applicability of AOPs. In the present study, Co/peroxymonosulfate (Co/PMS) and UV/hydrogen peroxide (UV/H2O2) treatment of 2,4,6-trichlorophenol was compared in terms of AOX formation, chlorinated byproducts and acute toxicity. Both Co/PMS and UV/H2O2 systems were more reactive under acidic conditions, resulting in elevated AOX levels when compared with those at neutral pH. The presence of high levels of chloride led to an accumulation and increase of AOX in the Co/PMS system. The toxicity of chlorinated byproducts was evaluated using Photobacterium phosphoreum, and the results revealed a sharp increase in acute toxicity of Co/PMS reaction solutions on addition of chloride ion. However, addition of Cl(-) had no apparent impact on AOX and toxicity of UV/H2O2 reaction solutions. These findings may have significant technical implications for selecting feasible technologies to treat high salinity wastewater. PMID- 26613361 TI - Prebiotic Low Sugar Chocolate Dairy Desserts: Physical and Optical Characteristics and Performance of PARAFAC and PCA Preference Map. AB - The addition of prebiotic and sweeteners in chocolate dairy desserts opens up new opportunities to develop dairy desserts that besides having a lower calorie intake still has functional properties. In this study, prebiotic low sugar dairy desserts were evaluated by 120 consumers using a 9-point hedonic scale, in relation to the attributes of appearance, aroma, flavor, texture, and overall liking. Internal preference map using parallel factor analysis (PARAFAC) and principal component analysis (PCA) was performed using the consumer data. In addition, physical (texture profile) and optical (instrumental color) analyses were also performed. Prebiotic dairy desserts containing sucrose and sucralose were equally liked by the consumers. These samples were characterized by firmness and gumminess, which can be considered drivers of liking by the consumers. Optimization of the prebiotic low sugar dessert formulation should take in account the choice of ingredients that contribute in a positive manner for these parameters. PARAFAC allowed the extraction of more relevant information in relation to PCA, demonstrating that consumer acceptance analysis can be evaluated by simultaneously considering several attributes. Multiple factor analysis reported Rv value of 0.964, suggesting excellent concordance for both methods. PMID- 26613360 TI - The risk of major cardiac malformations associated with paroxetine use during the first trimester of pregnancy: a systematic review and meta-analysis. AB - AIMS: The aim of this study was to perform an up-to-date meta-analysis on the risk of cardiac malformations associated with gestational exposure to paroxetine, taking into account indication, study design and reference category. METHOD: A systematic review of studies published between 1966 and November 2015 was conducted using embase and MEDLINE. Studies reporting major malformations with first trimester exposure to paroxetine were included. Potentially relevant articles were assessed and relevant data extracted to calculate risk estimates. Outcomes included any major malformations and major cardiac malformations. Pooled odds ratios and 95% confidence intervals were calculated using random-effects models. RESULTS: Twenty-three studies were included. Compared with non-exposure to paroxetine, first trimester use of paroxetine was associated with an increased risk of any major congenital malformations combined (pooled OR 1.23, 95% CI 1.10, 1.38; n = 15 studies), major cardiac malformations (pooled OR 1.28, 95% CI 1.11, 1.47; n = 18 studies), specifically bulbus cordis anomalies and anomalies of cardiac septal closure (pooled OR 1.42, 95% CI 1.07, 1.89; n = 8 studies), atrial septal defects (pooled OR 2.38, 95% CI 1.14, 4.97; n = 4 studies) and right ventricular outflow track defect (pooled OR 2.29, 95% CI 1.06, 4.93; n = 4 studies). Although the estimates varied depending on the comparator group, study design and malformation detection period, a trend towards increased risk was observed. CONCLUSIONS: Paroxetine use during the first trimester of pregnancy is associated with an increased risk of any major congenital malformations and cardiac malformations. The increase in risk is not dependent on the study method or population. PMID- 26613362 TI - Efficacy and safety of a 5-day regimen of azacitidine for patients with high-risk myelodysplastic syndromes. AB - Although a 7-day (d) regimen of azacitidine (AZA) is the standard treatment of high-risk myelodysplastic syndromes (MDS), AZA is difficult to administer during weekends in an outpatient setting. We retrospectively investigated the outcome of a 5-d regimen of AZA in patients with high-risk MDS. High-risk MDS was defined as MDS with intermediate-2- or high-risk MDS according to the International Prognostic Scoring System. Every months AZA was given at 75 mg/m(2) per day for 5 7 d in hospital for first cycle and 5 d in outpatient for second cycle and later. Between April 2011 and December 2013, AZA treatment was initiated in 25 patients (men, 22; women, 3; median age, 75 yr; age range, 59-86 yr). The median number of AZA cycles was 10 (range, 1-24). Twenty patients received more than three cycles of AZA and 13 (52%) achieved any hematological improvement (HI). The median time to first response was two cycles (1-3). The most common non-hematological adverse events were neutropenia in 21 patients and thrombocytopenia in 17 patients. Nineteen patients died. The main cause of death was disease progression (five patients) and infectious complications (11 patients). The median overall survival was 13.2 months. The 5-d AZA regimen showed a good continuation rate of more than three cycles and an equivalent HI with the 7-d regimen. PMID- 26613364 TI - Successful treatment of cytomegalovirus enteritis after unrelated allogeneic stem cell transplantation by the infusion of ex vivo-expanded CD4+ lymphocytes derived from the recipient's peripheral blood donor cells. AB - Adoptive immunotherapies have been developed for antiviral agent-refractory cytomegalovirus (CMV) disease after stem cell transplantation (SCT). However, the application of such strategies is limited, particularly in terms of need for donor cooperation regarding blood sampling and inaccessibility in the setting of cord blood transplantation. Herein, we describe the first successful treatment of antiviral agent-refractory CMV enteritis after allogeneic SCT by the infusion of ex vivo-expanded donor-derived CD4(+) lymphocytes obtained from the recipient's peripheral blood. PMID- 26613363 TI - County-level pesticide use and risk of shortened gestation and preterm birth. AB - AIM: This study assesses the association between pesticide exposure in pregnancy, preterm birth (PTB) and shortened gestation. METHODS: Pregnancy information was abstracted from the Centers for Disease Control (CDC) Non-Public Use Natality Datasets 1990-2005. Pesticide use in maternal county of residence was calculated using California Pesticide Use Reporting (PUR) data 1990-2005. Counties were ranked by pesticide use, and birth months were sorted by peak (May-June) or nonpeak (other months) pesticide use. Multivariate logistical regression models were used. RESULTS: Counties with higher pesticide use were associated with higher PTB (low 8.59 +/- 0.11%, moderate 9.25 +/- 0.07%, high 10.0 +/- 0.06%, p's < 0.001) and shorter gestations (low 39.197 +/- 0.014 weeks, moderate 39.126 +/- 0.011 weeks, high 39.049 +/- 0.011 weeks, p's < 0.001). Peak pesticide months were associated with higher PTB (10.01 +/- 0.05% vs. 9.36 +/- 0.05%, p < 0.001) and shorter gestations (39.069 +/- 0.007 weeks vs. 39.122 +/- 0.007 weeks, p < 0.001). The pesticide effect on shortened gestation and higher PTB was found in all racial groups. Pesticide use was highest for fungicides > insecticides > fumigants > herbicides > others. Each pesticide type was found to be associated with higher PTB and shorter gestation. CONCLUSION: PTB and shortened gestation were significantly associated with pesticide use in maternal county of residence regardless of race, gestation at birth, and in most risk categories. PMID- 26613365 TI - Graduated compression stockings for the prevention of deep-vein thrombosis in postoperative surgical patients: a systematic review and economic model with a value of information analysis. AB - BACKGROUND: Deep-vein thrombosis (DVT) can occur in surgical patients. Routine prophylaxis can be pharmacological and/or mechanical [e.g. graduated compression stockings (GCSs)]. GCSs are available in knee length or thigh length. OBJECTIVE: To establish the expected value of undertaking additional research addressing the relative effectiveness of thigh-length GCSs versus knee-length GCSs, in addition to pharmacoprophylaxis, for prevention of DVT in surgical patients. DESIGN: Systematic review and economic model, including value of information (VOI) analysis. REVIEW METHODS: Randomised controlled trials (RCTs) assessing thigh- or knee-length GCSs in surgical patients were eligible for inclusion. The primary outcome was incidence of DVT. DVT complications and GCSs adverse events were assessed. Random-effects meta-analysis was performed. To draw on a wider evidence base, a random-effects network meta-analysis (NMA) was undertaken for the outcome DVT. A review of trials and observational studies of patient adherence was also conducted. A decision-analytic model was developed to assess the cost effectiveness of thigh- and knee-length GCSs and the VOI. RESULTS: Twenty-three RCTs were included in the review of effectiveness. There was substantial variation between trials in terms of the patient characteristics, interventions and methods of outcome assessment. Five trials comparing knee-length with thigh length GCSs with or without pharmacoprophylaxis were pooled; the summary estimate of effect indicated a non-significant trend favouring thigh-length GCSs [odds ratio (OR) 1.48, 95% confidence interval (CI) 0.80 to 2.73]. Thirteen trials were included in the NMA. In the base-case analysis, thigh-length GCSs with pharmacoprophylaxis were more effective than knee-length GCSs with pharmacoprophylaxis (knee vs. thigh OR 1.76, 95% credible interval 0.82 to 3.53). Overall, thigh-length stockings with pharmacoprophylaxis was the most effective treatment, with a 0.73 probability of being the most effective treatment in a new trial of all the treatments. Patient adherence was generally higher with knee length GCSs, and patients preferred knee-length GCSs. Thigh-length GCSs were found to be cost-effective in all but the subgroup with the lowest baseline risk, although the absolute differences in costs and effects were relatively small. The expected value of perfect information ranged from L0.2M to L178.0M depending on the scenario and subgroup. The relative effect parameters had the highest expected value of partial perfect information and ranged from L2.0M to L39.4M. The value of further research was most evident in the high-risk subgroups. LIMITATIONS: There was substantial variation across the included trials in terms of patient and intervention characteristics. Many of the included trials were old and poorly reported, which reduces the reliability of the results of the review. CONCLUSIONS: Given that the results from both the standard meta-analysis and the NMA lacked precision (CIs were wide) owing to the heterogeneous evidence base, a new definitive trial in high-risk patients may be warranted. However, the efficiency of any further research (i.e. whether this represents value for money) is dependent on several factors, including the acquisition price of GCSs, expected compliance with thigh-length GCSs wear, and whether or not uncertainty can be resolved around possible effect modifiers, as well as the feasibility and actual cost of undertaking the proposed research. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014007202. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 26613366 TI - Expression of salivary biomarkers in patients with oral mucositis: evaluation by SELDI-TOF/MS. AB - OBJECTIVE: This study aims to evaluate changes in proteomic salivary profile of patients with oral mucositis after adjuvant cancer treatments. MATERIALS AND METHODS: Samples were collected from patients after adjuvant cancer therapies, and were analyzed by means of SELDI/TOF. Patients were separated in two groups: patients affected by mucositis (MUCOSITIS) and patient without mucositis (NO MUCOSITIS). All patients were divided in function of the anticancer treatment: patients who had radiotherapy (MUCOSITIS RADIO), had not radiotherapy (MUCOSITIS NO RADIO), had chemotherapy (MUCOSITIS CHEMO), and those who had not chemotherapy (MUCOSITIS NO CHEMO). Statistical evaluation PCA (Principal Component Analysis) was conducted with the software BIO-RAD Data Manager(TM) (Version 3.5). RESULTS: We found the increased peaks of 3443, 3487, and 4135 m/z in MUCOSITIS group, while 6237 m/z was reduced. These same peaks would the same modifications in MUCOSITIS RADIO, while in MUCOSITIS CHEMIO are increased 3443 and 6237 m/z but 3487, 4135 m/z are reduced. These data were confirmed by the PCA. CONCLUSION: Anticancer therapy influenced the level expression of many salivary biomarkers in mucositis with a good significance. Therefore, 3443, 3487, 4135, and 6237 m/z are good biomarker candidates of oral mucositis. PMID- 26613367 TI - Subdivision of Broca's region based on individual-level functional connectivity. AB - Broca's region is composed of two adjacent cytoarchitectonic areas, 44 and 45, which have distinct connectivity to superior temporal and inferior parietal regions in both macaque monkeys and humans. The current study aimed to make use of prior knowledge of sulcal anatomy and resting-state functional connectivity, together with a novel visualization technique, to manually parcellate areas 44 and 45 in individual brains in vivo. One hundred and one resting-state functional magnetic resonance imaging datasets from the Human Connectome Project were used. Left-hemisphere surface-based correlation matrices were computed and visualized in brainGL. By observation of differences in the connectivity patterns of neighbouring nodes, areas 44 and 45 were manually parcellated in individual brains, and then compared at the group-level. Additionally, the manual labelling approach was compared with parcellation results based on several data-driven clustering techniques. Areas 44 and 45 could be clearly distinguished from each other in all individuals, and the manual segmentation method showed high test retest reliability. Group-level probability maps of areas 44 and 45 showed spatial consistency across individuals, and corresponded well to cytoarchitectonic probability maps. Group-level connectivity maps were consistent with previous studies showing distinct connectivity patterns of areas 44 and 45. Data-driven parcellation techniques produced clusters with varying degrees of spatial overlap with the manual labels, indicating the need for further investigation and validation of machine learning cortical segmentation approaches. The current study provides a reliable method for individual-level cortical parcellation that could be applied to regions distinguishable by even the most subtle differences in patterns of functional connectivity. PMID- 26613368 TI - Dynamics of the mammalian cell cycle in physiological and pathological conditions. AB - A network of cyclin-dependent kinases (Cdks) controls progression along the successive phases G1, S, G2, and M of the mammalian cell cycle. Deregulations in the expression of molecular components in this network often lead to abusive cell proliferation and cancer. Given the complex nature of the Cdk network, it is fruitful to resort to computational models to grasp its dynamical properties. Investigated by means of bifurcation diagrams, a detailed computational model for the Cdk network shows how the balance between quiescence and proliferation is affected by activators (oncogenes) and inhibitors (tumor suppressors) of cell cycle progression, as well as by growth factors and other external factors such as the extracellular matrix (ECM) and cell contact inhibition. Suprathreshold changes in all these factors can trigger a switch in the dynamical behavior of the network corresponding to a bifurcation between a stable steady state, associated with cell cycle arrest, and sustained oscillations of the various cyclin/Cdk complexes, corresponding to cell proliferation. The model for the Cdk network accounts for the dependence or independence of cell proliferation on serum and/or cell anchorage to the ECM. Such computational approach provides an integrated view of the control of cell proliferation in physiological or pathological conditions. Whether the balance is tilted toward cell cycle arrest or cell proliferation depends on the direction in which the threshold associated with the bifurcation is passed once the cell integrates the multiple signals, internal or external to the Cdk network, that promote or impede progression in the cell cycle. PMID- 26613369 TI - Dispensability of the [4Fe-4S] cluster in novel homologues of adenine glycosylase MutY. AB - 7,8-Dihydro-8-deoxyguanine (8oG) is one of the most common oxidative lesions in DNA. DNA polymerases misincorporate an adenine across from this lesion. Thus, 8oG is a highly mutagenic lesion responsible for G:C->T:A transversions. MutY is an adenine glycosylase, part of the base excision repair pathway that removes adenines, when mispaired with 8oG or guanine. Its catalytic domain includes a [4Fe-4S] cluster motif coordinated by cysteinyl ligands. When this cluster is absent, MutY activity is depleted and several studies concluded that the [4Fe-4S] cluster motif is an indispensable component for DNA binding, substrate recognition and enzymatic activity. In the present study, we identified 46 MutY homologues that lack the canonical cysteinyl ligands, suggesting an absence of the [4Fe-4S] cluster. A phylogenetic analysis groups these novel MutYs into two different clades. One clade is exclusive of the order Lactobacillales and another clade has a mixed composition of anaerobic and microaerophilic bacteria and species from the protozoan genus Entamoeba. Structural modeling and sequence analysis suggests that the loss of the [4Fe-4S] cluster is compensated by a convergent solution in which bulky amino acids substitute the [4Fe-4S] cluster. We functionally characterized MutYs from Lactobacillus brevis and Entamoeba histolytica as representative members from each clade and found that both enzymes are active adenine glycosylases. Furthermore, chimeric glycosylases, in which the [4Fe-4S] cluster of Escherichia coli MutY is replaced by the corresponding amino acids of LbY and EhY, are also active. Our data indicates that the [4Fe-4S] cluster plays a structural role in MutYs and evidences the existence of alternative functional solutions in nature. PMID- 26613370 TI - Impact of Intra-Abdominal Adhesion on Living Donor Right Hepatectomy. AB - The impact of intra-abdominal adhesion (IAA) on living donor right hepatectomy (LDRH) remains to be clarified. The purpose of this study was to compare both the donor and recipient outcomes of right lobe living donor liver transplantation according to IAA detected intraoperatively. LDRH donors were identified through a prospectively maintained database at the authors' institution between March 2008 and February 2014. IAA was graded according to Beck et al (Dis Colon Rectum 2000; 43: 1749-1753). LDRH donors with IAA (group A) were matched 1:3 to those without IAA (group B) based on age, gender, and BMI. Perioperative data, complications by the Clavien classification, and the outcomes with at least 12 months follow-up were compared. Thirty-two (7.6%) of a total of 420 LDRH donors had IAA around the liver. Nineteen donors had previous abdominal surgery. LDRH was successfully completed under upper midline laparotomy in all donors. Compared with group B, group A had a longer operative time (270 vs. 172 min; p < 0.001), a higher wound complication rate (28.1% vs. 4.2%; p = 0.009), and a longer postoperative stay (10 vs. 7 days; p = 0.009). All donors recovered completely to their previous activities. The 1-year graft and recipient survivals of recipients were comparable between two groups. These findings support the feasibility and safety of LDRH in patients with IAA. PMID- 26613371 TI - Methods to characterize selective sweeps using time serial samples: an ancient DNA perspective. AB - With hundreds of ancient genomes becoming available this year, ancient DNA research has now entered the genomics era. Utilizing the temporal aspect of these new data, we can now address fundamental evolutionary questions such as the characterization of selection processes shaping the genomes. The temporal dimension in the data has spurred the development in the last 10 years of new methods allowing the detection of loci evolving non-neutrally but also the inference of selection coefficients across genomes capitalizing on these time serial data. To guide empirically oriented researchers towards the statistical approach most appropriate for their data, this article reviews several of those methods, discussing their underlying assumptions and the parameter ranges for which they have been developed. While I discuss some methods developed for experimental evolution, the main focus is ancient DNA. PMID- 26613372 TI - A Double-Edged Sword: A Review of Benefits and Risks of Online Nonsuicidal Self Injury Activities. AB - OBJECTIVE: This review aimed to synthesize current evidence on the perceived benefits and risks of online activity pertinent to nonsuicidal self-injury (NSSI). METHOD: A systematic literature search was conducted to identify peer reviewed articles, which yielded a total of 27 articles published between 2005 and 2015. Following this, a thematic analysis was employed to identify perceived benefits and risks of online NSSI activity. RESULTS: Our thematic analysis identified 4 potential benefits (mitigation of social isolation, recovery encouragement, emotional self-disclosure, curbing NSSI urges) and 3 potential risks (NSSI reinforcement, triggering NSSI urges, stigmatization of NSSI) associated with online NSSI activities. CONCLUSION: Given the double-edged effect of online NSSI activities, clinicians may benefit from incorporating clients' online NSSI activity in the context of NSSI assessment and treatment. Future research ought to directly examine the link between online NSSI activity and NSSI behavior to better understand the nature of these benefits and risks. PMID- 26613373 TI - Formula with long-chain polyunsaturated fatty acids reduces incidence of allergy in early childhood. AB - BACKGROUND: Allergy has sharply increased in affluent Western countries in the last 30 years. N-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) may protect the immune system against development of allergy. METHODS: We prospectively categorized illnesses by body system in a subset of 91 children from the Kansas City cohort of the DIAMOND (DHA Intake and Measurement of Neural Development) study who had yearly medical records through 4 years of age. As infants, they were fed either a control formula without LCPUFA (n = 19) or one of three formulas with LCPUFA from docosahexaenoic acid (DHA) and arachidonic acid (ARA) (n = 72). RESULTS: Allergic illnesses in the first year were lower in the combined LCPUFA group compared to the control. LCPUFAs significantly delayed time to first allergic illness (p = 0.04) and skin allergic illness (p = 0.03) and resulted in a trend to reduced wheeze/asthma (p = 0.1). If the mother had no allergies, LCPUFAs reduced the risk of any allergic diseases (HR = 0.24, 95% CI = 0.1, 0.56, p = 0.0.001) and skin allergic diseases (HR = 0.35, 95% CI = 0.13, 0.93, p = 0.04). In contrast, if the mother had allergies, LCPUFAs reduced wheezing/asthma (HR = 0.26, 95% CI = 0.07, 0.9, p = 0.02). CONCLUSIONS: LCPUFA supplementation during infancy reduced the risk of skin and respiratory allergic diseases in childhood with effects influenced by maternal allergies. PMID- 26613375 TI - Proton pump inhibitor associated hypomagnasaemia - a cause for concern? AB - AIMS: In recent years, there have been a number of case reports of severe hypomagnesaemia associated with proton pump inhibitor (PPI) use, such that both the FDA and MHRA have issued drug safety warnings. They have recommended periodic serum magnesium testing in patients prescribed PPIs but provide no guidance on timing of these measurements. METHODS: To our knowledge, we are the first to perform a prospective study to explore specifically proton pump inhibitor associated hypomagnesaemia (PPIAH). We followed 56 patients new to PPIs prospectively as well as a further 100 patients on long term PPIs cross sectionally to identify what factors may be influencing the development of significant hypomagnesaemia. RESULTS: For the prospective arm of the study, we measured serum magnesium levels prior to starting a PPI and again at regular intervals for the next 8 months. For the cross-sectional arm of the study we measured serum magnesium levels on patients on PPI therapy ranging from less than 1 year to over 5 years. CONCLUSION: We found that, although there was a significant downward trend in serum magnesium levels in patients new to PPI therapy with time, clinically relevant hypomagnesaemia was not readily identifiable on regular blood testing. We did however identify patients on concurrent diuretic therapy as being at higher risk and so would recommend regular serum magnesium testing alongside their regular renal function monitoring on a more frequent basis such as annually. PMID- 26613374 TI - Individual variation in incentive salience attribution and accumbens dopamine transporter expression and function. AB - Cues (conditioned stimuli; CSs) associated with rewards can come to motivate behavior, but there is considerable individual variation in their ability to do so. For example, a lever-CS that predicts food reward becomes attractive and wanted, and elicits reward-seeking behavior, to a greater extent in some rats ('sign-trackers'; STs) than others ('goal-trackers'; GTs). Variation in dopamine (DA) neurotransmission in the nucleus accumbens (NAc) core is thought to contribute to such individual variation. Given that the DA transporter (DAT) exerts powerful regulation over DA signaling, we characterized the expression and function of the DAT in the accumbens of STs and GTs. STs showed greater DAT surface expression in ventral striatal synaptosomes than GTs, and ex vivo fast scan cyclic voltammetry recordings of electrically evoked DA release confirmed enhanced DAT function in STs, as indicated by faster DA uptake, specifically in the NAc core. Consistent with this, systemic amphetamine (AMPH) produced greater inhibition of DA uptake in STs than in GTs. Furthermore, injection of AMPH directly into the NAc core enhanced lever-directed approach in STs, presumably by amplifying the incentive value of the CS, but had no effect on goal-tracking behavior. On the other hand, there were no differences between STs and GTs in electrically-evoked DA release in slices, or in total ventral striatal DA content. We conclude that greater DAT surface expression may facilitate the attribution of incentive salience to discrete reward cues. Investigating this variability in animal sub-populations may help explain why some people abuse drugs while others do not. PMID- 26613376 TI - Qualitative Analysis of the American College of Nurse-Midwives Student Reports, 2005 to 2014. AB - INTRODUCTION: The Patient Protection and Affordable Care Act (ACA) is changing the health care landscape in the United States. It is now more important than ever to understand the needs of students who are preparing for roles as health care providers. The purpose of this study was to describe and analyze the American College of Nurse-Midwives (ACNM) Student Reports from 2005 through 2014 to acquire a better understanding of student needs in light of the historic change in health care reform. METHODS: A document analysis was conducted to review and evaluate 10 student reports using qualitative content analysis. Data were coded, categories were formed, and themes were discovered. The interpretation of the student reports elicited meaning, gained understanding, and developed empirical knowledge. RESULTS: Eight themes emerged from the data contained in the 10 student reports. These were: 1) public awareness and marketing; 2) midwifery education; 3) funding for midwifery education; 4) preceptor issues; 5) communication and professional issues; 6) diversity and inclusion; 7) transition to practice; and 8) the ACNM Annual Meeting. DISCUSSION: Students bring a unique perspective to the profession of midwifery and ACNM. This study revealed 8 themes emanating from the student reports spanning 10 years. Each theme showcased in this study is presented through a student lens and was deemed important enough to be mentioned in the majority of the student reports. These themes identify key areas affecting students such as education program content and clinical experiences, diversity and inclusion, preceptor availability and relationships, funding for graduate school and for attending the ACNM Annual Meeting, and a myriad of other significant topics. These students will begin their new careers with the changing structure of the health care industry under the ACA. At this complex and vulnerable time, it is imperative that student voices be heard and that their professional organization remains receptive to their concerns. A continuing dialogue between students and midwifery leadership, faculty, and preceptors will be beneficial to move our profession in the direction of achieving access to high-quality health care for all. PMID- 26613377 TI - An HPLC-ECD method for monoamines and metabolites quantification in cuttlefish (cephalopod) brain tissue. AB - The cuttlefish belongs to the mollusk class Cephalopoda, considered as the most advanced marine invertebrates and thus widely used as models to study the biology of complex behaviors and cognition, as well as their related neurochemical mechanisms. Surprisingly, methods to quantify the biogenic monoamines and their metabolites in cuttlefish brain remain sparse and measure a limited number of analytes. This work aims to validate an HPLC-ECD method for the simultaneous quantification of dopamine, serotonin, norepinephrine and their main metabolites in cuttlefish brain. In comparison and in order to develop a method suitable to answer both ecological and biomedical questions, the validation was also carried out on a phylogenetically remote species: mouse (mammals). The method was shown to be accurate, precise, selective, repeatable and sensitive over a wide range of concentrations for 5-hydroxyindole-3-acetic acid, serotonin, dopamine, 3,4 dihydroxyphenylacetic acid and norepinephrine in the both extracts of cuttlefish and mouse brain, though with low precision and recovery for 4-hydroxy-3 methoxyphenylethylene glycol. Homovanillic acid, accurately studied in rodents, was not detectable in the brain of cuttlefish. Overall, we described here the first fully validated HPLC method for the routine measurement of both monoamines and metabolites in cuttlefish brain. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26613378 TI - Interventions for Posttraumatic Stress With Children Exposed to Violence: Factors Associated With Treatment Success. AB - BACKGROUND: In the past 15 years, there have been a substantial number of rigorous studies examining the effectiveness of various treatments for child trauma and posttraumatic stress disorder (PTSD). Although a number of review articles exist, many have focused on randomized controlled trials or specific treatment methodologies, both of which limit the ability to draw conclusions across studies and the statistical power to test the effect of particular treatment characteristics on treatment outcomes. The current study is a review and meta-analysis of 74 studies examining treatments for children exposed to violence. METHODS: After reviewing the literature, we examined the relationship of a variety of treatment characteristics (e.g., group or individual treatments) and sample characteristics (e.g., average age) on treatment effect sizes. RESULTS: Results indicated that individual therapies and those with exposure paradigms within a cognitive-behavioral therapy or skills-building framework show the most promise, but treatment is somewhat less effective for those with more severe symptomology and for younger children. CONCLUSIONS: Future treatments should consider the developmental and social contexts that may impede treatment progress for young children and consider how best to develop the effectiveness of group interventions that can be readily delivered in settings of mass trauma. PMID- 26613379 TI - Hematology of dugongs (Dugong dugon) in southern Queensland. AB - BACKGROUND: Little is known of the hematology of the dugong (Dugong dugon), a secretive and endangered coastal marine mammal. OBJECTIVES: This paper reports hematologic reference intervals (RI) for dugongs and characterizes morphologic, cytochemical, and ultrastructural features of dugong leukocytes. METHODS: Blood was collected from live, apparently healthy dugongs and analyzed using Cell-Dyn 3700 or Sysmex XT-2000iV hematology analyzers. Blood films were subjected to a series of cytochemical stains, and leukocyte structure was examined using transmission electron microscopy. RESULTS: Reference intervals were established for 14 hematologic variables, total solids, and fibrinogen for 92 dugongs. Significant differences in some variables were found for animal size class, sex, and pregnancy status, and between analyzers. Subadults had higher leukocyte and lymphocyte counts than adults. Males had higher total solids and fibrinogen than females. Pregnant females had higher HCT, MCV, and circulating nucleated RBC, and lower platelet counts than nonpregnant females. Lymphocytes were usually the predominant circulating leukocyte. Heterophil cytoplasmic granules were abundant, fine, round to ovoid, and intensely eosinophilic, and round to ovoid or rod shaped, and variably electron dense in electron microscopy. Eosinophils contained larger round eosinophilic to orange cytoplasmic granules, which ultrastructurally were bicompartmental with a round eccentric electron-dense core. Cytochemical staining of dugong heterophils suggests biochemical similarity to those of manatees and elephants, and for eosinophils, similarity to those of elephants, ruminants, and equids. CONCLUSIONS: Generation of hematologic RI and characterization of leukocyte morphology improves evaluation of dugong health across this population and serves as a reference for other populations outside southern Queensland. PMID- 26613380 TI - Chaperone patterns in vernal keratoconjunctivitis are distinctive of cell and Hsp type and are modified by inflammatory stimuli. AB - BACKGROUND: Vernal keratoconjunctivitis (VKC) is a severe ocular allergy with pathogenic mechanism poorly understood and no efficacious treatment. The aims of the study were to determine quantities and distribution of Hsp chaperones in the conjunctiva of VKC patients and assess their levels in conjunctival epithelial and fibroblast cultures exposed to inflammatory stimuli. METHODS: Hsp10, Hsp27, Hsp40, Hsp60, Hsp70, Hsp90, Hsp105, and Hsp110 were determined in conjunctiva biopsies from nine patients and nine healthy age-matched normal subjects, using immunomorphology and qPCR. Conjunctival epithelial cells and fibroblasts were cultured and stimulated with IL-1beta, histamine, IL-4, TNF-alpha, or UV-B irradiation, and changes in Hsp levels were determined by Western blotting. RESULTS: Hsp27, Hsp40, Hsp70, and Hsp90 levels increased in the patients' conjunctiva, whereas Hsp10, Hsp60, Hsp100, and Hsp105 did not. Double immunofluorescence demonstrated colocalization of Hsp27, Hsp40, Hsp70, and Hsp90 with CD68 and tryptase. Testing of cultured conjunctival cells revealed an increase in the levels of Hsp27 in fibroblasts stimulated with IL-4; Hsp40 in epithelial cells stimulated with IL-4 and TNF-alpha and in fibroblasts stimulated with IL-4, TNF-alpha, and IL-1beta; Hsp70 in epithelial cells stimulated with histamine and IL-4; and Hsp90 in fibroblasts stimulated with IL-1beta, TNF-alpha, and IL-4. UV-B did not induce changes. CONCLUSIONS: VKC conjunctiva displays distinctive quantitative patterns of Hsps as compared with healthy controls. Cultured conjunctival cells respond to cytokines and inflammatory stimuli with changes in the Hsps quantitative patterns. The data suggest that interaction between the chaperoning and the immune systems drives disease progression. PMID- 26613381 TI - Renal Contrast-Enhanced Sonography Findings in a Model of Acute Cellular Allograft Rejection. AB - Noninvasive methods to diagnose and differentiate acute cellular rejection from acute tubular necrosis or acute calcineurin inhibitor toxicity are still missing. Because T lymphocytes play a decisive role in early states of rejection, we investigated the suitability and feasibility of antibody-mediated contrast enhanced ultrasound by using microbubbles targeted to CD3(+) , CD4(+) , or CD8(+) T cells in different models of renal disease. In an established rat renal transplantation model, CD3-mediated ultrasound allows the detection of acute rejection as early as on postoperative day 2. Ultrasound signal intensities increased with the severity of inflammation. Further, an early response to therapy could be monitored by using contrast-enhanced sonography. Notably, acute tubular necrosis occurring after ischemia-reperfusion injury as well as acute calcineurin inhibitor toxicity could easily be differentiated. Finally, the quantified ultrasound signal correlated significantly with the number of infiltrating T cells obtained by histology and with CD3 mRNA levels, as well as with chemokine CXCL9, CXCL11, and CCL19 mRNA but not with KIM-1 mRNA expression, thereby representing the severity of graft inflammation but not the degree of kidney injury. In summary, we demonstrate that antibody-mediated contrast enhanced ultrasound targeting T lymphocytes could be a promising tool for an easy and reproducible assessment of acute rejection after renal transplantation. PMID- 26613382 TI - A Note on Derivatives of Isoniazid, Rifampicin, and Pyrazinamide Showing Activity Against Resistant Mycobacterium tuberculosis. AB - Drug-resistant tuberculosis (DR-TB) is a serious problem that impedes the success of the TB control program. Of note, multidrug-resistant (MDR)-TB and extensively drug-resistant (XDR)-TB have certainly complicated the scenario. One of the possible strategies to overcome drug resistance in an economic and simple manner would involve modification of existing anti-TB drugs to obtain derivatives that can work on resistant TB bacilli. These may have improved half-life and increased bioavailability, be more efficacious, and serve as cost-effective alternatives, as compared to new drugs identified through conventional methods of drug discovery and development. Although extensive literature is available on the activity of various derivatives of first-line drugs (isoniazid, rifampicin and pyrazinamide) on drug-susceptible Mycobacterium tuberculosis (MTB), reports on the activity of derivatives on resistant MTB are very limited, to our knowledge. In light of this, the present review aims to provide a concise report on the derivatives of first-line drugs that have the potential to overcome the resistance to the parental drug and could thus serve as effective alternatives. PMID- 26613383 TI - Sensorimotor Decoupling Contributes to Triadic Attention: A Longitudinal Investigation of Mother-Infant-Object Interactions. AB - Previous developmental accounts of joint object activity identify a qualitative "shift" around 9-12 months. In a longitudinal study of 26 dyads, videos of joint object interactions at 4, 6, 9, and 12 months were coded for all targets of gaze and manual activity (at 10 Hz). At 12 months, infants distribute their sensorimotor modalities between objects handled by the parent and others controlled by the infant. Analyses reveal novel trajectories in distributed joint object activity across the 1st year. At 4 months, infants predominantly look at and manipulate a single object, typically held by their mothers. Between 6 and 9 months, infants increasingly decouple their visual and haptic modalities and distribute their attention between objects held by their mothers and by themselves. These previously unreported developments in the distribution of multimodal object activity might "bridge the gap" to coordinated joint activity between 6 and 12 months. PMID- 26613384 TI - Novel Quinazoline Derivatives Bearing Various 4-Aniline Moieties as Potent EGFR Inhibitors with Enhanced Activity Against NSCLC Cell Lines. AB - A class of novel quinazoline derivatives bearing various C-4 aniline moieties was synthesized and biologically evaluated as potent epidermal growth factor receptor (EGFR) inhibitors for intervention of non-small-cell lung cancer (NSCLC). Most of these inhibitors are comparable to gefitinib in inhibiting these cancer cell lines, and several of them even displayed superior inhibitory activity. In particular, analogue 5b with an IC50 of 0.10 MUm against the EGFR wild-type A431 cells and 5c with an IC50 of 0.001 MUm against the gefitinib-sensitive HCC827 cells (EGFR del E746-A750) was identified as highly active EGFR inhibitors. It was also significant that the discovered analogue 2f, not only has high potency against the gefitinib-sensitive cells (IC50 = 0.031 MUm), but also possesses remarkably improved activity against the gefitinib-resistant cells. In addition, the enzymatic assays and the Western blot analysis for evaluating the effects of the typical inhibitors indicated that these molecules strongly interfere with the EGFR target. PMID- 26613385 TI - Serum vitamin B12 is inversely associated with periodontal progression and risk of tooth loss: a prospective cohort study. AB - AIM: The aim of this study was to investigate the association of serum vitamin B12 with the progression of periodontitis and risk of tooth loss in a prospective cohort study. MATERIALS AND METHODS: In the Study of Health in Pomerania, 1648 participants were followed from 2002-2006 to 2008-2012 (mean duration 5.9 years). Serum vitamin B12 was measured by chemiluminescent enzyme immunoassay. Probing pocket depth (PD) and clinical attachment loss (CAL) were measured to reflect periodontal status on a half-mouth basis at each survey cycle. Tooth numbers are based upon a full-mouth tooth count. RESULTS AND CONCLUSIONS: In multivariate regression models, baseline vitamin B12 was inversely associated with changes in mean PD (Ptrend = 0.06) and mean CAL (Ptrend = 0.01), and risk ratios of tooth loss (TL; Ptrend = 0.006) over time. Compared to participants in the highest vitamin B12 quartile, those in the lowest quartile had 0.10 mm (95%CI: 0.03, 0.17; Pdifference = 0.007) greater increase in mean PD, 0.23 mm (95%CI: 0.09, 0.36; Pdifference = 0.001) greater increase in mean CAL and a relative risk of 1.57 (95%CI: 1.22, 2.03; Pdifference < 0.001) for TL. Stratified analyses showed stronger associations between vitamin B12 and changes in mean CAL among never smokers (Pinteraction = 0.058). Further studies are needed to understand the potential mechanisms of these findings. PMID- 26613386 TI - Magnifying visual target information and the role of eye movements in motor sequence learning. AB - An experiment investigated the influence of eye movements on learning a simple motor sequence task when the visual display was magnified. The task was to reproduce a 1300 ms spatial-temporal pattern of elbow flexions and extensions. The spatial-temporal pattern was displayed in front of the participants. Participants were randomly assigned to four groups differing on eye movements (free to use their eyes/instructed to fixate) and the visual display (small/magnified). All participants had to perform a pre-test, an acquisition phase, a delayed retention test, and a transfer test. The results indicated that participants in each practice condition increased their performance during acquisition. The participants who were permitted to use their eyes in the magnified visual display outperformed those who were instructed to fixate on the magnified visual display. When a small visual display was used, the instruction to fixate induced no performance decrements compared to participants who were permitted to use their eyes during acquisition. The findings demonstrated that a spatial-temporal pattern can be learned without eye movements, but being permitting to use eye movements facilitates the response production when the visual angle is increased. PMID- 26613387 TI - "The face of ostracism": The impact of the social categorization on the thermal facial responses of the target and the observer. AB - Ostracism has been shown to elicit pain in both the target and the observers. Two experiments investigated the autonomic thermal signature associated with an ostracism experience and assessed whether and how social categorization impacts the autonomic arousal of both the target and the observer. Autonomic response was assessed using thermal infrared imaging, recording facial temperature variation during an online game of ball toss (i.e., Cyberball). Social categorization was manipulated using a minimal group paradigm. The results show a more intense autonomic response during ostracism (vs. inclusion), marked by an increase in facial temperature in the nose and the perioral area. This autonomic response is stronger when individuals are ostracized by ingroup (vs. outgroup) members. Similar pattern of temperature variations emerge when individuals observe an ostracism episode involving ingroup members. Our findings advance the understanding of psycho-physiological mechanisms underlying the ostracism experience and emphasize the impact of social categorization in such mechanisms. PMID- 26613388 TI - Inhibition of return and attentional facilitation: Numbers can be counted in, letters tell a different story. AB - Prior research has provided strong evidence for spatial-numerical associations. Single digits can for instance act as attentional cues, orienting visuo-spatial attention to the left or right hemifield depending on the digit's magnitude, thus facilitating target detection in the cued hemifield (left/right hemifield after small/large digits, respectively). Studies using other types of behaviourally or biologically relevant central cues known to elicit automated symbolic attention orienting effects such as arrows or gaze have shown that the initial facilitation of cued target detection can turn into inhibition at longer stimulus onset asynchronies (SOAs). However, no studies so far investigated whether inhibition of return (IOR) is also observed using digits as uninformative central cues. To address this issue we designed an attentional cueing paradigm using SOAs ranging from 500 ms to 1650 ms. As expected, the results showed a facilitation effect at the relatively short 650 ms SOA, replicating previous findings. At the long 1650 ms SOA, however, participants were faster to detect targets in the uncued hemifield compared to the cued hemifield, showing an IOR effect. A control experiment with letters showed no such congruency effects at any SOA. These findings provide the first evidence that digits not only produce facilitation effects at shorter intervals, but also induce inhibitory effects at longer intervals, confirming that Arabic digits engage automated symbolic orienting of attention. PMID- 26613389 TI - Association of obesity and inflammatory marker levels on treatment outcome: results from a double-blind, randomized study of adjunctive L-methylfolate calcium in patients with MDD who are inadequate responders to SSRIs. AB - OBJECTIVE: Adjunctive treatment with L-methylfolate calcium significantly improved treatment outcomes in patients with major depressive disorder (MDD) and an inadequate response to antidepressants. This post hoc exploratory analysis evaluated baseline concentrations of cytokines (interleukin [IL]-1alpha, IL 1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, and IL-17; tumor necrosis factor alpha [TNF-alpha]; and interferon gamma [IFN-gamma]), high sensitivity C-reactive protein (hsCRP), insulin, adiponectin and leptin and body mass index (BMI [kg/m2]) on L-methylfolate calcium treatment response. METHOD: Adults with DSM-IV MDD and an inadequate response to a selective serotonin reuptake inhibitor (SSRI) were eligible. Patients were randomized 3:3:2 according to the sequential parallel comparison design to placebo versus placebo, placebo versus L-methylfolate calcium (15 mg/d), or L-methylfolate calcium versus L methylfolate calcium (15 mg/d) during two 30-day phases. The primary outcome was change on the 17-item Hamilton Depression Rating Scale (HDRS-17). Treatment effect with 95% CIs was estimated from baseline concentrations of individual biomarkers and combinations. Cytokines were measured by immunoassay; adiponectin, insulin, and leptin by radioimmunoassay; and hsCRP by a standard turbidimetric assay. The effects of baseline biomarker levels (above and below the median) on outcome were analyzed. The first participant was enrolled July 14, 2009, and the last participant completed April 28, 2011. RESULTS: Mean change on HDRS-17 from baseline was significantly improved with L-methylfolate calcium versus placebo (pooled treatment effect, -2.74; 95% CI, -4.99 to -0.48; P = .017) overall and for those with baseline BMI >= 30 (pooled treatment effect, -4.66; 95% CI, -7.22 to -1.98; P = .001) but not BMI < 30. Pooled mean changes in depression across treatment for baseline levels of individual markers above median were significant (L-methylfolate calcium vs placebo) for TNF-alpha, IL-8, hsCRP, and leptin (pooled treatment effects, -4.33 to -3.94 [P <= .02]) and for combinations of BMI >= 30 with elevated levels of TNF-alpha, IL-6, IL-8, hsCRP, and leptin (pooled treatment effects, -6.31 to -3.98 [P <= .05]). CONCLUSIONS: In this exploratory analysis, inflammatory and obesity-related factors were associated with greater symptom improvement with L-methylfolate calcium. Combinations of BMI >= 30 with elevated IL-6, IL-8, hsCRP, TNF-alpha, and leptin predicted improved response to L-methylfolate calcium in MDD patients with an inadequate antidepressant response. Further studies are necessary to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00955955. PMID- 26613391 TI - Pitting new treatments for chronic lymphocytic leukemia against old ones: how do they fare? AB - Significant progress has been made in the treatment of chronic lymphocytic leukemia (CLL) patients during the last two decades. In this review we present a personal case study for discussion on contemporary management in CLL. Presently immunochemotherapy using fludarabine, cyclophosphamide, and rituximab (FCR) is the standard upfront regimen for physically fit patients requiring treatment. Patients older than 65 years can be treated with modified doses of FCR, bendamustine, or chlorambucil combined with anti-CD20 antibody. This treatment can be repeated at relapse when the duration of response is over 2 years. Patients at high risk (with 17p deletion or early relapse) need alternative treatment with novel agents, e.g. ibrutinib or idelalisib. However, the optimal use of the novel agents in terms of duration, combinations, and long-term adverse effects is unknown. In selected eligible patients at high risk, allogeneic transplantation should be considered. Clinical trials in all stages of treatment are encouraged. PMID- 26613390 TI - Calcium-Alginate-Inulin Microbeads as Carriers for Aqueous Carqueja Extract. AB - Carqueja (Pterospartum tridentatum) is an endemic species and various bioactive compounds have been identified in its aqueous extract. The aim of this study was to protect the natural antioxidants from the aqueous extract of carqueja by encapsulation in Ca-alginate microbeads and Ca-alginate microbeads containing 10% and 20% (w/v) of inulin. The microbeads produced by electrostatic extrusion technique had an average diameter from 625 MUm to 830 MUm depending on the portion of inulin. The sphericity factor of the hydrogel microbeads had values between 0.014 and 0.026, while freeze dried microbeads had irregular shape, especially those with no excipient. The reduction in microbeads size after freeze drying process (expressed as shrinkage factor) ranged from 0.338 (alginate microbeads with 20% (w/v) of inulin) to 0.523 (plain alginate microbeads). The expressed radical scavenging activity against ABTS and DPPH radicals was found to be between 30% and 40% for encapsulated extract, while the fresh extract showed around 47% and 57% of radical scavenging activity for ABTS and DPPH radicals, respectively. The correlation between antioxidant activity and the total phenolic content were found to be positive (in both assay methods, DPPH and ABTS), which indicate that the addition of inulin didn't have influence on antioxidant activity. The presence of inulin reduced stiffness of the hydrogel, and protected bead structure from collapse upon freeze-drying. Alginate-inulin beads are envisaged to be used for delivery of aqueous P. tridentatum extract in functional food products. PMID- 26613392 TI - The Effect of Gum Chewing, Early Oral Hydration, and Early Mobilization on Intestinal Motility After Cesarean Birth. AB - AIM: The aim of the study was to investigate the effect of gum chewing, early oral hydration, and early mobilization after cesarean birth on intestinal sounds, passing gas, and intestinal evacuation. DESIGN: Randomized controlled study. SETTING: This study was conducted at the Obstetrics Service of the one Obstetrics and Child Diseases Hospital. PARTICIPANTS: A total of 240 females divided into 8 groups of 30 subjects each were included within the scope of the sample. METHODS: The women who underwent cesarean birth were divided into eight groups by using 2(3) factorial test levels, depending on the use of three different methods of gum chewing, early oral hydration, and early mobilization. No intervention was applied to the women in the control group. For the other seven groups, the intestinal sounds were checked every 30 minutes with a stethoscope over the abdomen and the first time of passing gas and the first evacuation time were recorded by asking the mother. The data were evaluated with numbers, mean, and percentage calculations, Student's t test, one-way variance analysis, correlation, and Tukey HSD test. RESULTS: The intestinal sounds were heard earlier, gas was passed earlier, and bowel movements were earlier in the first group that received all interventions compared to the other groups (p < .05). The patient could not be discharged before 48 hours had passed after the cesarean birth according to the hospital protocol and the time of discharge was therefore not affected by interventions. LINKING EVIDENCE TO ACTION: All of the three different interventions, such as gum chewing, early oral hydration, and early mobilization after cesarean birth, increase intestinal motility. The interventions are recommended during postoperative routine care to shorten hospital stay and prevent postoperative ileus. PMID- 26613394 TI - Index for Volume 35. PMID- 26613393 TI - Antisense oligonucleotide delivery to cancer cell lines for the treatment of different cancer types. AB - Amphiphilic poly(3-hydroxylalkanoate) (PHA) copolymers find interesting applications in drug delivery. The aim of this study was to prepare nucleic acid adsorbed on (PHB-b-PEG-NH2) nanoparticle platform for gene delivery. For this purpose, PHB-b-PEG-NH2 block copolymers were synthesized via transesterification reactions. The copolymers obtained were characterized by Proton Nuclear Magnetic Resonance (1H-NMR), Fourier Transform Infrared Spectrometer (FTIR), Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) techniques. The cytotoxic, apoptotic and necrotic effects of these nanoparticles in the MDA 231 human breast cancer cell, the A549 human lung cancer cell and the L929 fibroblast cell lines were also investigated. PMID- 26613395 TI - The role of the SenseWear device and ghrelin for metabolism in amyotrophic lateral sclerosis. PMID- 26613398 TI - How does peer teaching compare to faculty teaching? A systematic review and meta analysis (.). AB - PURPOSE: In undergraduate medical education, peer-teaching has become an established and common method to enhance student learning. Evidence suggests that peer-teaching provides learning benefits for both learners and tutors. We aimed to describe the outcomes for medical students taught by peers through systematic review and meta-analysis of existing literature. METHODS: Seven databases were searched through 21 terms and their Boolean combinations. Studies reporting knowledge or skills outcomes of students taught by peers compared to those taught by faculty or qualified clinicians were included. Extracted data on students' knowledge and skills outcomes were synthesised through a random effects model meta-analysis. RESULTS: The search yielded 2292 studies. Five hundred and fifty three duplicates and 1611 irrelevant articles were removed during title screening. The abstracts of 128 papers were screened against the inclusion and exclusion criteria. Ten studies have been included in the review. Meta-analyses showed no significant difference in peer-teaching compared to faculty teaching for knowledge or skills outcomes, standardised mean differences were 0.07 (95% CI: -0.07, 0.21) and 0.11 (95% CI: -0.07, 1.29), respectively. CONCLUSION: Students taught by peers do not have significantly different outcomes to those taught by faculty. As the process of teaching helps to develop both tutor knowledge and teaching skills, peer-teaching should be supported. PMID- 26613396 TI - Family accommodation in obsessive-compulsive and anxiety disorders: a five-year update. AB - Family accommodation describes changes that individuals make to their behavior, to help their relative who is dealing with a psychiatric and/or psychological disorder(s), avoid or alleviate distress related to the disorder. Research on family accommodation has advanced rapidly. In this update we aim to provide a synthesis of findings from the past five years. A search of available, peer reviewed, English language papers was conducted through PubMed and PsycINFO, cross referencing psychiatric disorders with accommodation and other family related terms. The resulting 121 papers were individually reviewed and evaluated and the main findings were discussed. Family accommodation is common in obsessive compulsive disorder (OCD) and in anxiety disorders, and manifests similarly across these disorders. Family accommodation is associated with more severe psychopathology and poorer clinical outcomes. Treatments have begun to focus on the reduction of family accommodation as a primary therapeutic goal and finally, neurobiological underpinnings of family accommodation are beginning to be investigated. PMID- 26613399 TI - Technical performance and match-to-match variation in elite football teams. AB - Recent research suggests that match-to-match variation adds important information to performance descriptors in team sports, as it helps measure how players fine tune their tactical behaviours and technical actions to the extreme dynamical environments. The current study aims to identify the differences in technical performance of players from strong and weak teams and to explore match-to-match variation of players' technical match performance. Performance data of all the 380 matches of season 2012-2013 in the Spanish First Division Professional Football League were analysed. Twenty-one performance-related match actions and events were chosen as variables in the analyses. Players' technical performance profiles were established by unifying count values of each action or event of each player per match into the same scale. Means of these count values of players from Top3 and Bottom3 teams were compared and plotted into radar charts. Coefficient of variation of each match action or event within a player was calculated to represent his match-to-match variation of technical performance. Differences in the variation of technical performances of players across different match contexts (team and opposition strength, match outcome and match location) were compared. All the comparisons were achieved by the magnitude-based inferences. Results showed that technical performances differed between players of strong and weak teams from different perspectives across different field positions. Furthermore, the variation of the players' technical performance is affected by the match context, with effects from team and opposition strength greater than effects from match location and match outcome. PMID- 26613400 TI - Good vibrations: Global processing can increase the pleasantness of touch. AB - Visual-tactile carry-over effects of global/local processing (attention to the whole, versus the details) have been reported under active touch conditions. We investigated whether carry-over effects of global/local processing also occur for passive touch and whether global/local processing has differential effects on affective and discriminative aspects of touch. Participants completed two tactile tasks involving pleasantness rating and discrimination of a set of tactile vibrations before and after completing a version of the Navon task that encouraged a focus on the global (n = 30), local (n = 30), or both (n = 30) features of a series of visual stimuli. In line with previous research suggesting a link between global processing and positive emotion, global processing increased pleasantness ratings of high-frequency (but not low-frequency) tactile vibrations. Local processing did not improve the ability to discriminate between vibrations of different frequencies, however. There was some evidence of a tactile-visual carry-over effect; prior local processing of tactile vibrations reduced global precedence during the Navon task in the control group. We have shown carry-over effects of global versus local processing on passive touch perception. These findings provide further evidence suggesting that a common perceptual mechanism determines processing level across modalities and show for the first time that prior global processing affects the pleasantness of touch. PMID- 26613401 TI - Impromptu everyday disclosure dances: how women with fibromyalgia respond to disclosure risks at work. AB - PURPOSE: Findings from a study examining how women with fibromyalgia remain employed are used to explicate a conceptualization that adds to literature on workplace disclosure of stigmatized illnesses and impairments: disclosure dances that employees improvise in response to workplace-relationships needs and disclosure risks. METHODS: Critical-discourse-analysis (CDA) methodology framed the study. Data were collected through 26 semi-structured, individual interviews with participant triads or dyads comprising women with fibromyalgia, family members and supervisors or co-workers. Interviews with managers who supervised disabled employees other than the women supplemented these data. Following coding, data were compared within and across triads/dyads through code-dimension summaries, narrative summaries and relational diagrams. RESULTS: Women with fibromyalgia and other stigmatized illnesses improvised everyday disclosures when they needed to explain fluctuating work ability, when others needed reminding about invisible impairments, and when workplace relationships changed. These impromptu disclosures comprised three dimensions: exposing oneself to scrutiny by disclosing both illness and impairments, divulging stigmatized illness, and revealing invisible impairments selectively. CONCLUSION: Through impromptu disclosure dances, women tailored disclosure to changing immediate circumstances. While assumptions from psychological theories of risk underlie current conceptualizations of disclosure as planned in advance, this article examines disclosure through a different lens: social theories of everyday risk. Implications for rehabilitation For women with fibromyalgia, disclosing illness and impairments at work may entail risks to their jobs and workplace relationships. Rehabilitation professionals need to consider these risks when advising women with fibromyalgia about disclosing their illness and impairments at work. Professionals may first want to learn from clients about their workplace cultures and relationships, and their perceptions of disclosure risk. Professionals can then suggest a range of disclosure responses, depending on the relationship and risk. PMID- 26613402 TI - Anti-skeletal muscle atrophy effect of Oenothera odorata root extract via reactive oxygen species-dependent signaling pathways in cellular and mouse model. AB - Skeletal muscle atrophy can be defined as a decrease of muscle volume caused by injury or lack of use. This condition is associated with reactive oxygen species (ROS), resulting in various muscular disorders. We acquired 2D and 3D images using micro-computed tomography in gastrocnemius and soleus muscles of sciatic denervated mice. We confirmed that sciatic denervation-small animal model reduced muscle volume. However, the intraperitoneal injection of Oenothera odorata root extract (EVP) delayed muscle atrophy compared to a control group. We also investigated the mechanism of muscle atrophy's relationship with ROS. EVP suppressed expression of SOD1, and increased expression of HSP70, in both H2O2 treated C2C12 myoblasts and sciatic-denervated mice. Moreover, EVP regulated apoptotic signals, including caspase-3, Bax, Bcl-2, and ceramide. These results indicate that EVP has a positive effect on reducing the effect of ROS on muscle atrophy. PMID- 26613403 TI - Purification and characterization of enantioselective N-acetyl-beta-Phe acylases from Burkholderia sp. AJ110349. AB - For the production of enantiopure beta-amino acids, enantioselective resolution of N-acyl beta-amino acids using acylases, especially those recognizing N-acetyl beta-amino acids, is one of the most attractive methods. Burkholderia sp. AJ110349 had been reported to exhibit either (R)- or (S)-enantiomer selective N acetyl-beta-Phe amidohydrolyzing activity, and in this study, both (R)- and (S) enantioselective N-acetyl-beta-Phe acylases were purified to be electrophoretically pure and determined the sequences, respectively. They were quite different in terms of enantioselectivities and in their amino acids sequences and molecular weights. Although both the purified acylases were confirmed to catalyze N-acetyl hydrolyzing activities, neither of them show sequence similarities to the N-acetyl-alpha-amino acid acylases reported thus far. Both (R)- and (S)-enantioselective N-acetyl-beta-Phe acylase were expressed in Escherichia coli. Using these recombinant strains, enantiomerically pure (R) beta-Phe (>99% ee) and (S)-beta-Phe (>99% ee) were obtained from the racemic substrate. PMID- 26613404 TI - Preferential binding of E. coli with type 1 fimbria to D-mannobiose with the Manalpha1 -> 2Man structure. AB - Manalpha1 -> 2Man, Manalpha1 -> 3Man, Manalpha1 -> 4Man, and Manalpha1 -> 6Man were converted to the glycosylamine derivatives. Then, they were mixed with monobenzyl succinic acid to obtain their amide derivatives. After removing the benzyl group by hydrogenation, the succinylamide derivatives were coupled with the hydrazino groups on BlotGlycoTM beads in the presence of water-soluble carbodiimide. d-Mannobiose-linked beads were incubated with fluorescence-labeled Escherichia coli with type 1 fimbria, and the number of the fluorescent dots associated with the beads was counted in order to determine the binding preference among d-mannobiose isomers. The results showed that the bacteria bind strongly to Manalpha1 -> 2Man1 -> beads, Manalpha1 -> 3Man1 -> beads, Manalpha1 > 4Man1 -> beads, and Manalpha1 -> 6Man1 -> beads, in order. In the presence of 0.1 M methyl alpha-d-mannopyranoside, most of the bacteria failed to bind to these beads. These results indicate that E. coli with type 1 fimbria binds to all types of d-mannobiose isomers but preferentially to Manalpha1 -> 2Man disaccharide. PMID- 26613405 TI - The plausibility of maternal toxicant exposure and nutritional status as contributing factors to the risk of autism spectrum disorders. AB - : Recent research suggests the maternal environment may be especially important for the risk of developing autism spectrum disorders (ASD). In particular maternal infections, micronutrient deficiencies, obesity, and toxicant exposures are likely to interact with genetic risk factors to disrupt fetal brain development. OBJECTIVES: The goal of this paper is to investigate the plausibility of maternal toxicant exposure and nutritional status as causal factors in the development of ASD. METHODS: This paper reviews current research investigating the hypothesis that maternal toxicant exposure and prenatal micronutrient intake are important modifiable risk factors for ASD. RESULTS: Zinc, copper, iron, and vitamin B9 are identified as specific micronutrients with relevance to the etiology of ASD. Specific toxicants induce a maternal inflammatory response leading to fetal micronutrient deficiencies that disrupt early brain development. Importantly, maternal micronutrient supplementation is associated with reduced risk of ASD. Furthermore, animal studies show that micronutrient supplementation can prevent the teratogenicity and developmental neurotoxicity of specific toxicants. DISCUSSION: These findings lead to the hypothesis that maternal infection, obesity, and toxicant exposures (e.g. valproic acid, endocrine disrupting plasticizers, ethanol, and heavy metals) are all environmental risk factors for ASD that lead to fetal micronutrient deficiencies resulting from a maternal inflammatory response. It could be possible to use markers of inflammation and micronutrient status to identify women that would benefit from micronutrient supplementation or dietary interventions to reduce the risk of ASD. However, more research is needed to demonstrate a causal role of fetal micronutrient deficiencies and clarify the underlying mechanisms that contribute to ASD. PMID- 26613406 TI - Imaging magnetic and ferroelectric domains and interfacial spins in magnetoelectric La0.7Sr0.3MnO3/PbZr0.2Ti0.8O3 heterostructures. AB - Strong magnetoelectric coupling can occur at the interface between ferromagnetic and ferroelectric films. Similar to work on interfacial exchange bias, photoemission electron microscopy was utilized to image both magnetic and ferroelectric domains and the resulting interfacial Ti spin in the same locations of La0.7Sr0.3MnO3/PbZr0.2Ti0.8O3 heterostructures. Multiple image analysis techniques, which could be applicable for a variety of fields needing quantitative data on image switching, confirm both improved magnetic switching and an increased population of interfacial spins with increased thickness of the ultrathin La0.7Sr0.3MnO3 layer. The perpendicular orientation of the interfacial spins is also discussed. This work suggests a magnetoelectric dead layer, with reduced interfacial magnetoelectricity when thin magnetic films are present. PMID- 26613407 TI - Greatwall promotes cell transformation by hyperactivating AKT in human malignancies. AB - The PP2A phosphatase is often inactivated in cancer and is considered as a tumour suppressor. A new pathway controlling PP2A activity in mitosis has been recently described. This pathway includes the Greatwall (GWL) kinase and its substrates endosulfines. At mitotic entry, GWL is activated and phosphorylates endosulfines that then bind and inhibit PP2A. We analysed whether GWL overexpression could participate in cancer development. We show that GWL overexpression promotes cell transformation and increases invasive capacities of cells through hyperphosphorylation of the oncogenic kinase AKT. Interestingly, AKT hyperphosphorylation induced by GWL is independent of endosulfines. Rather, GWL induces GSK3 kinase dephosphorylation in its inhibitory sites and subsequent SCF dependent degradation of the PHLPP phosphatase responsible for AKT dephosphorylation. In line with its oncogenic activity, we find that GWL is often overexpressed in human colorectal tumoral tissues. Thus, GWL is a human oncoprotein that promotes the hyperactivation of AKT via the degradation of its phosphatase, PHLPP, in human malignancies. PMID- 26613408 TI - Distinct functional determinants of influenza hemagglutinin-mediated membrane fusion. AB - Membrane fusion is the critical step for infectious cell penetration by enveloped viruses. We have previously used single-virion measurements of fusion kinetics to study the molecular mechanism of influenza-virus envelope fusion. Published data on fusion inhibition by antibodies to the 'stem' of influenza virus hemagglutinin (HA) now allow us to incorporate into simulations the provision that some HAs are inactive. We find that more than half of the HAs are unproductive even for virions with no bound antibodies, but that the overall mechanism is extremely robust. Determining the fraction of competent HAs allows us to determine their rates of target-membrane engagement. Comparison of simulations with data from H3N2 and H1N1 viruses reveals three independent functional variables of HA mediated membrane fusion closely linked to neutralization susceptibility. Evidence for compensatory changes in the evolved mechanism sets the stage for studies aiming to define the molecular constraints on HA evolvability. PMID- 26613409 TI - Sequential selection of economic good and action in medial frontal cortex of macaques during value-based decisions. AB - Value-based decisions could rely either on the selection of desired economic goods or on the selection of the actions that will obtain the goods. We investigated this question by recording from the supplementary eye field (SEF) of monkeys during a gambling task that allowed us to distinguish chosen good from chosen action signals. Analysis of the individual neuron activity, as well as of the population state-space dynamic, showed that SEF encodes first the chosen gamble option (the desired economic good) and only ~100 ms later the saccade that will obtain it (the chosen action). The action selection is likely driven by inhibitory interactions between different SEF neurons. Our results suggest that during value-based decisions, the selection of economic goods precedes and guides the selection of actions. The two selection steps serve different functions and can therefore not compensate for each other, even when information guiding both processes is given simultaneously. PMID- 26613410 TI - Intracellular sphingosine releases calcium from lysosomes. AB - To elucidate new functions of sphingosine (Sph), we demonstrate that the spontaneous elevation of intracellular Sph levels via caged Sph leads to a significant and transient calcium release from acidic stores that is independent of sphingosine 1-phosphate, extracellular and ER calcium levels. This photo induced Sph-driven calcium release requires the two-pore channel 1 (TPC1) residing on endosomes and lysosomes. Further, uncaging of Sph leads to the translocation of the autophagy-relevant transcription factor EB (TFEB) to the nucleus specifically after lysosomal calcium release. We confirm that Sph accumulates in late endosomes and lysosomes of cells derived from Niemann-Pick disease type C (NPC) patients and demonstrate a greatly reduced calcium release upon Sph uncaging. We conclude that sphingosine is a positive regulator of calcium release from acidic stores and that understanding the interplay between Sph homeostasis, calcium signaling and autophagy will be crucial in developing new therapies for lipid storage disorders such as NPC. PMID- 26613411 TI - Using an achiasmic human visual system to quantify the relationship between the fMRI BOLD signal and neural response. AB - Achiasma in humans causes gross mis-wiring of the retinal-fugal projection, resulting in overlapped cortical representations of left and right visual hemifields. We show that in areas V1-V3 this overlap is due to two co-located but non-interacting populations of neurons, each with a receptive field serving only one hemifield. Importantly, the two populations share the same local vascular control, resulting in a unique organization useful for quantifying the relationship between neural and fMRI BOLD responses without direct measurement of neural activity. Specifically, we can non-invasively double local neural responses by stimulating both neuronal populations with identical stimuli presented symmetrically across the vertical meridian to both visual hemifields, versus one population by stimulating in one hemifield. Measurements from a series of such doubling experiments show that the amplitude of BOLD response is proportional to approximately 0.5 power of the underlying neural response. Reanalyzing published data shows that this inferred relationship is general. PMID- 26613412 TI - The CUL4-DDB1 ubiquitin ligase complex controls adult and embryonic stem cell differentiation and homeostasis. AB - Little is known on post-transcriptional regulation of adult and embryonic stem cell maintenance and differentiation. Here we characterize the role of Ddb1, a component of the CUL4-DDB1 ubiquitin ligase complex. Ddb1 is highly expressed in multipotent hematopoietic progenitors and its deletion leads to abrogation of both adult and fetal hematopoiesis, targeting specifically transiently amplifying progenitor subsets. However, Ddb1 deletion in non-dividing lymphocytes has no discernible phenotypes. Ddb1 silencing activates Trp53 pathway and leads to significant effects on cell cycle progression and rapid apoptosis. The abrogation of hematopoietic progenitor cells can be partially rescued by simultaneous deletion of Trp53. Conversely, depletion of DDB1 in embryonic stem cell (ESC) leads to differentiation albeit negative effects on cell cycle and apoptosis. Mass spectrometry reveals differing protein interactions between DDB1 and distinct DCAFs, the substrate recognizing components of the E3 complex, between cell types. Our studies identify CUL4-DDB1 complex as a novel post-translational regulator of stem and progenitor maintenance and differentiation. PMID- 26613413 TI - Maturation of metabolic connectivity of the adolescent rat brain. AB - Neuroimaging has been used to examine developmental changes of the brain. While PET studies revealed maturation-related changes, maturation of metabolic connectivity of the brain is not yet understood. Here, we show that rat brain metabolism is reconfigured to achieve long-distance connections with higher energy efficiency during maturation. Metabolism increased in anterior cerebrum and decreased in thalamus and cerebellum during maturation. When functional covariance patterns of PET images were examined, metabolic networks including default mode network (DMN) were extracted. Connectivity increased between the anterior and posterior parts of DMN and sensory-motor cortices during maturation. Energy efficiency, a ratio of connectivity strength to metabolism of a region, increased in medial prefrontal and retrosplenial cortices. Our data revealed that metabolic networks mature to increase metabolic connections and establish its efficiency between large-scale spatial components from childhood to early adulthood. Neurodevelopmental diseases might be understood by abnormal reconfiguration of metabolic connectivity and efficiency. PMID- 26613414 TI - Successful retrieval of competing spatial environments in humans involves hippocampal pattern separation mechanisms. AB - The rodent hippocampus represents different spatial environments distinctly via changes in the pattern of "place cell" firing. It remains unclear, though, how spatial remapping in rodents relates more generally to human memory. Here participants retrieved four virtual reality environments with repeating or novel landmarks and configurations during high-resolution functional magnetic resonance imaging (fMRI). Both neural decoding performance and neural pattern similarity measures revealed environment-specific hippocampal neural codes. Conversely, an interfering spatial environment did not elicit neural codes specific to that environment, with neural activity patterns instead resembling those of competing environments, an effect linked to lower retrieval performance. We find that orthogonalized neural patterns accompany successful disambiguation of spatial environments while erroneous reinstatement of competing patterns characterized interference errors. These results provide the first evidence for environment specific neural codes in the human hippocampus, suggesting that pattern separation/completion mechanisms play an important role in how we successfully retrieve memories. PMID- 26613415 TI - The evolution of adhesiveness as a social adaptation. AB - Cellular adhesion is a key ingredient to sustain collective functions of microbial aggregates. Here, we investigate the evolutionary origins of adhesion and the emergence of groups of genealogically unrelated cells with a game theoretical model. The considered adhesiveness trait is costly, continuous and affects both group formation and group-derived benefits. The formalism of adaptive dynamics reveals two evolutionary stable strategies, at each extreme on the axis of adhesiveness. We show that cohesive groups can evolve by small mutational steps, provided the population is already endowed with a minimum adhesiveness level. Assortment between more adhesive types, and in particular differential propensities to leave a fraction of individuals ungrouped at the end of the aggregation process, can compensate for the cost of increased adhesiveness. We also discuss the change in the social nature of more adhesive mutations along evolutionary trajectories, and find that altruism arises before directly beneficial behavior, despite being the most challenging form of cooperation. PMID- 26613417 TI - Gratitude and coping among familial caregivers of persons with dementia. AB - OBJECTIVES: Gratitude is widely perceived as a key factor to psychological well being by different cultures and religions. The relationship between gratitude and coping in the context of familial dementia caregiving has yet to be investigated. DESIGN: This study is the first to examine the associations among gratitude, coping strategies, psychological resources and psychological distress using a structural equation modelling approach. RESULTS: Findings with 101 Chinese familial caregivers of persons with dementia (mean age = 57.6, range = 40-76; 82% women) showed that gratitude was related to the greater use of emotion-focused coping (positive reframing, acceptance, humour, emotional social support seeking, religious coping) and psychological resources (caregiving competence and social support). Psychological resources and emotion-focused coping in turn explained the association between gratitude and lower levels of psychological distress (caregiving burden and depressive symptoms). CONCLUSION: The present results indicate the beneficial role of gratitude on coping with caregiving distress and provide empirical foundation for incorporating gratitude in future psychological interventions for caregivers. PMID- 26613418 TI - High pressure behaviour and elastic properties of a dense inorganic-organic framework. AB - The high pressure behaviour of a cubic dense inorganic-organic framework [DABCOH2(2+)][K(ClO4)3] (DABCOH2(2+) = diazabicyclo[2.2.2]octane-1,4-diium) has been systematically studied via synchrotron X-ray powder diffraction, over the range of 0-3.12 GPa. The framework [DABCOH2(2+)][K(ClO4)3] shows a more rigid response, with a bulk modulus of 30(1) GPa and an axial compressibility of 7.6(4) * 10(-3) GPa(-1), compared with ZIF-8 and the dense hybrid solar cell perovskite CH3NH3PbI3. Density functional theory calculations reveal that the structural change in [DABCOH2(2+)][K(ClO4)3] is attributed to the contraction of the KO12 polyhedra, which consequently results in the rotation of the perchlorate linkers and synergistic movement of the DABCOH2(2+) guest. Further extensive theoretical calculations of full elastic tensors give full mapping of the Young's moduli, shear moduli and Poisson's ratios of [DABCOH2(2+)][K(ClO4)3], which are in the range of 31.6-36.6, 12.3-14.6 GPa and 0.2-0.32, respectively. The Young's and shear moduli of [DABCOH2(2+)][K(ClO4)3] are larger than those of cubic MOF-5, ZIF 8 and CH3NH3PbI3. In addition, the narrow range of Poisson's ratios in [DABCOH2(2+)][K(ClO4)3] indicates its very isotropic nature in response to biaxial stress. PMID- 26613416 TI - Stable G protein-effector complexes in striatal neurons: mechanism of assembly and role in neurotransmitter signaling. AB - In the striatum, signaling via G protein-coupled neurotransmitter receptors is essential for motor control. Critical to this process is the effector enzyme adenylyl cyclase type 5 (AC5) that produces second messenger cAMP upon receptor mediated activation by G protein Golf. However, the molecular organization of the Golf-AC5 signaling axis is not well understood. In this study, we report that in the striatum AC5 exists in a stable pre-coupled complex with subunits of Golf heterotrimer. We use genetic mouse models with disruption in individual components of the complex to reveal hierarchical order of interactions required for AC5-Golf stability. We further identify that the assembly of AC5-Golf complex is mediated by PhLP1 chaperone that plays central role in neurotransmitter receptor coupling to cAMP production motor learning. These findings provide evidence for the existence of stable G protein-effector signaling complexes and identify a new component essential for their assembly. PMID- 26613421 TI - Tensor Network Renormalization Yields the Multiscale Entanglement Renormalization Ansatz. AB - We show how to build a multiscale entanglement renormalization ansatz (MERA) representation of the ground state of a many-body Hamiltonian H by applying the recently proposed tensor network renormalization [G. Evenbly and G. Vidal, Phys. Rev. Lett. 115, 180405 (2015)] to the Euclidean time evolution operator e(-betaH) for infinite beta. This approach bypasses the costly energy minimization of previous MERA algorithms and, when applied to finite inverse temperature beta, produces a MERA representation of a thermal Gibbs state. Our construction endows tensor network renormalization with a renormalization group flow in the space of wave functions and Hamiltonians (and not merely in the more abstract space of tensors) and extends the MERA formalism to classical statistical systems. PMID- 26613420 TI - Synthesis, Biological Activities, and X-ray Crystal Structural Analysis of 25 Hydroxy-25(or 26)-adamantyl-17-[20(22),23-diynyl]-21-norvitamin D Compounds. AB - Novel 19-norvitamin D analogues (ADYW1-4, 5a-d) in which an adamantyl diyne side chain is attached directly to the 17-position of the D ring are designed and stereoselectively synthesized. The adamantane ring of these analogues was expected to interfere with helix 12 (H12, activation function 2) of the vitamin D receptor (VDR) to modulate its activities. The analogue 5b binds to the VDR (7% of the natural hormone) and shows significant partial agonistic activity in transactivation assay. Compound 5b showed considerable selectivity in VDR target genes expressions in vitro, it was taken up by target cells 2-3 times more readily, and its lifetime was three times longer than the natural hormone. The X ray crystal structure of 5b in complex with VDR reveals that the ligand binds similarly to the natural hormone, but the diyne moiety is slightly bent (angles around the diyne 5 degrees to 8 degrees ) with respect to the original diyne vitamin D compound 6 in VDR (<1 degrees ) due to steric hindrance with helix 12. PMID- 26613419 TI - Computation of Hydration Free Energies Using the Multiple Environment Single System Quantum Mechanical/Molecular Mechanical Method. AB - A recently developed MESS-E-QM/MM method (multiple-environment single-system quantum mechanical molecular/mechanical calculations with a Roothaan-step extrapolation) is applied to the computation of hydration free energies for the blind SAMPL4 test set and for 12 small molecules. First, free energy simulations are performed with a classical molecular mechanics force field using fixed geometry solute molecules and explicit TIP3P solvent, and then the non-Boltzmann Bennett method is employed to compute the QM/MM correction (QM/MM-NBB) to the molecular mechanical hydration free energies. For the SAMPL4 set, MESS-E-QM/MM NBB corrections to the hydration free energy can be obtained 2 or 3 orders of magnitude faster than fully converged QM/MM-NBB corrections, and, on average, the hydration free energies predicted with MESS-E-QM/MM-NBB fall within 0.10-0.20 kcal/mol of full-converged QM/MM-NBB results. Out of five density functionals (BLYP, B3LYP, PBE0, M06-2X, and omegaB97X-D), the BLYP functional is found to be most compatible with the TIP3P solvent model and yields the most accurate hydration free energies against experimental values for solute molecules included in this study. PMID- 26613422 TI - Topologically Protected Defect States in Open Photonic Systems with Non-Hermitian Charge-Conjugation and Parity-Time Symmetry. AB - We show that topologically protected defect states can exist in open (leaky or lossy) systems even when these systems are topologically trivial in the closed limit. The states appear from within the continuum, thus in the absence of a band gap, and are generated via exceptional points (a spectral transition that occurs in open wave and quantum systems with a generalized time-reversal symmetry), or via a degeneracy induced by charge-conjugation symmetry (which is related to the pole transition of Majorana zero modes). We demonstrate these findings for a leaking passive coupled-resonator optical waveguide with asymmmetric internal scattering, where the required symmetries (non-Hermitian versions of time reversal symmetry, chirality, and charge conjugation) emerge dynamically. PMID- 26613423 TI - Quantum Nondemolition Measurement Enables Macroscopic Leggett-Garg Tests. AB - We show how a test of macroscopic realism based on Leggett-Garg inequalities (LGIs) can be performed in a macroscopic system. Using a continuous-variable approach, we consider quantum nondemolition (QND) measurements applied to atomic ensembles undergoing magnetically driven coherent oscillation. We identify measurement schemes requiring only Gaussian states as inputs and giving a significant LGI violation with realistic experimental parameters and imperfections. The predicted violation is shown to be due to true quantum effects rather than to a classical invasivity of the measurement. Using QND measurements to tighten the "clumsiness loophole" forces the stubborn macrorealist to recreate quantum backaction in his or her account of measurement. PMID- 26613424 TI - Quantum Error-Correction-Enhanced Magnetometer Overcoming the Limit Imposed by Relaxation. AB - When incorporated in quantum sensing protocols, quantum error correction can be used to correct for high frequency noise, as the correction procedure does not depend on the actual shape of the noise spectrum. As such, it provides a powerful way to complement usual refocusing techniques. Relaxation imposes a fundamental limit on the sensitivity of state of the art quantum sensors which cannot be overcome by dynamical decoupling. The only way to overcome this is to utilize quantum error correcting codes. We present a superconducting magnetometry design that incorporates approximate quantum error correction, in which the signal is generated by a two qubit Hamiltonian term. This two-qubit term is provided by the dynamics of a tunable coupler between two transmon qubits. For fast enough correction, it is possible to lengthen the coherence time of the device beyond the relaxation limit. PMID- 26613425 TI - Dissipative Quantum Control of a Spin Chain. AB - A protocol is discussed for preparing a spin chain in a generic many-body state in the asymptotic limit of tailored nonunitary dynamics. The dynamics require the spectral resolution of the target state, optimized coherent pulses, engineered dissipation, and feedback. As an example, we discuss the preparation of an entangled antiferromagnetic state, and argue that the procedure can be applied to chains of trapped ions or Rydberg atoms. PMID- 26613426 TI - Critical Exponents Can Be Different on the Two Sides of a Transition: A Generic Mechanism. AB - We present models where gamma(+) and gamma(-), the exponents of the susceptibility in the high- and low-temperature phases, are generically different. In these models, continuous symmetries are explicitly broken down by discrete anisotropies that are irrelevant in the renormalization-group sense. The Z(q)-invariant models are the simplest examples for two-component order parameters (N=2) and the model with icosahedral symmetry for N=3. We accurately compute gamma(+)-gamma(-) as well as the ratio nu/nu' of the exponents of the two correlation lengths present for T=2) and the pseudogap (k<2) regimes. Both k and the effective gap scale with the hopping integral and the e-e interaction in a wide doping range. The motion of doped holes is confined by the closest defect potential and the overall spin orbital structure. Such a generic behavior leads to complex nonhydrogenlike defect states that tend to preserve the underlying C-type spin and G-type orbital order and can be detected and analyzed via scanning tunneling microscopy. PMID- 26613459 TI - Spin-Resolved Fermi Surface of the Localized Ferromagnetic Heusler Compound Cu2MnAl Measured with Spin-Polarized Positron Annihilation. AB - We determined the bulk electronic structure of the prototypical Heusler compound Cu(2)MnAl by measuring the angular correlation of annihilation radiation using spin-polarized positrons. To this end, a new algorithm for reconstructing 3D densities from projections is introduced that allows us to corroborate the excellent agreement between our electronic structure calculations and the experimental data. The contribution of each individual Fermi surface sheet to the magnetization was identified, and summed to a total spin magnetic moment of 3.6+/ 0.5 MU(B)/f.u.. PMID- 26613460 TI - Microwave-Induced Magneto-Oscillations and Signatures of Zero-Resistance States in Phonon-Drag Voltage in Two-Dimensional Electron Systems. AB - We observe the phonon-drag voltage oscillations correlating with the resistance oscillations under microwave irradiation in a two-dimensional electron gas in perpendicular magnetic field. This phenomenon is explained by the influence of dissipative resistivity modified by microwaves on the phonon-drag voltage perpendicular to the phonon flux. When the lowest-order resistance minima evolve into zero-resistance states, the phonon-drag voltage demonstrates sharp features suggesting that current domains associated with these states can exist in the absence of external dc driving. PMID- 26613461 TI - Mechanical Signatures of the Current Blockade Instability in Suspended Carbon Nanotubes. AB - Transport measurements allow sensitive detection of nanomechanical motion of suspended carbon nanotubes. It has been predicted that when the electromechanical coupling is sufficiently large a bistability with a current blockade appears. Unambiguous observation of this transition by current measurements may be difficult. Instead, we investigate the mechanical response of the system, namely, the displacement spectral function, the linear response to a driving, and the ring-down behavior. We find that by increasing the electromechanical coupling the peak in the spectral function broadens and shifts at low frequencies while the oscillator dephasing time shortens. These effects are maximum at the transition where nonlinearities dominate the dynamics. These strong signatures open the way to detect the blockade transition in devices currently studied by several groups. PMID- 26613462 TI - Exploring the Single Atom Spin State by Electron Spectroscopy. AB - To control the spin state of an individual atom is an ultimate goal for spintronics. A single atom magnet, which may lead to a supercapacity memory device if realized, requires the high-spin state of an isolated individual atom. Here, we demonstrate the realization of well isolated transition metal (TM) atoms fixed at atomic defects sparsely dispersed in graphene. Core-level electron spectroscopy clearly reveals the high-spin state of the individual TM atoms at the divacancy or edge of the graphene layer. We also show for the first time that the spin state of single TM atoms systematically varies with the coordination of neighboring nitrogen or oxygen atoms. These structures can be thus regarded as the smallest components of spintronic devices with controlled magnetic behavior. PMID- 26613463 TI - Campbell Response in Type-II Superconductors under Strong Pinning Conditions. AB - Measuring the ac magnetic response of a type II superconductor provides valuable information on the pinning landscape (pinscape) of the material. We use strong pinning theory to derive a microscopic expression for the Campbell length lambda(C), the penetration depth of the ac signal. We show that lambda(C) is determined by the jump in the pinning force, in contrast to the critical current j(c), which involves the jump in pinning energy. We demonstrate that the Campbell lengths generically differ for zero-field-cooled and field-cooled samples and predict that hysteretic behavior can appear in the latter situation. We compare our findings with new experimental data and show the potential of this technique in providing information on the material's pinscape. PMID- 26613464 TI - Odd-Parity Superconductivity in the Vicinity of Inversion Symmetry Breaking in Spin-Orbit-Coupled Systems. AB - We study superconductivity in spin-orbit-coupled systems in the vicinity of inversion symmetry breaking. We find that, because of the presence of spin-orbit coupling, fluctuations of the incipient parity-breaking order generate an attractive pairing interaction in an odd-parity pairing channel, which competes with the s-wave pairing. We show that Coulomb repulsion or an external Zeeman field suppresses the s-wave pairing and promotes the odd-parity superconducting state. Our work provides a new mechanism for odd-parity pairing and opens a route to novel topological superconductivity. PMID- 26613465 TI - Strong Coupling Superconductivity in the Vicinity of the Structural Quantum Critical Point in (Ca(x)Sr(1-x))3Rh4Sn13. AB - The family of the superconducting quasiskutterudites (Ca(x)Sr(1-x))(3)Rh(4)Sn(13) features a structural quantum critical point at x(c)=0.9, around which a dome shaped variation of the superconducting transition temperature T(c) is found. Using specific heat, we probe the normal and the superconducting states of the entire series straddling the quantum critical point. Our analysis indicates a significant lowering of the effective Debye temperature on approaching x(c), which we interpret as a result of phonon softening accompanying the structural instability. Furthermore, a remarkably large enhancement of 2Delta/k(B)T(c) and DeltaC/gammaT(c) beyond the Bardeen-Cooper-Schrieffer values is found in the vicinity of the structural quantum critical point. The phase diagram of (Ca(x)Sr(1-x))(3)Rh(4)Sn(13) thus provides a model system to study the interplay between structural quantum criticality and strong electron-phonon coupling superconductivity. PMID- 26613466 TI - Complex Magnetism of Lanthanide Intermetallics and the Role of their Valence Electrons: Ab Initio Theory and Experiment. AB - We explain a profound complexity of magnetic interactions of some technologically relevant gadolinium intermetallics using an ab initio electronic structure theory which includes disordered local moments and strong f-electron correlations. The theory correctly finds GdZn and GdCd to be simple ferromagnets and predicts a remarkably large increase of Curie temperature with a pressure of +1.5 K kbar(-1) for GdCd confirmed by our experimental measurements of +1.6 K kbar(-1). Moreover, we find the origin of a ferromagnetic-antiferromagnetic competition in GdMg manifested by noncollinear, canted magnetic order at low temperatures. Replacing 35% of the Mg atoms with Zn removes this transition, in excellent agreement with long-standing experimental data. PMID- 26613467 TI - Roton Minimum as a Fingerprint of Magnon-Higgs Scattering in Ordered Quantum Antiferromagnets. AB - A quantitative description of magnons in long-range ordered quantum antiferromagnets is presented which is consistent from low to high energies. It is illustrated for the generic S=1/2 Heisenberg model on the square lattice. The approach is based on a continuous similarity transformation in momentum space using the scaling dimension as the truncation criterion. Evidence is found for significant magnon-magnon attraction inducing a Higgs resonance. The high-energy roton minimum in the magnon dispersion appears to be induced by strong magnon Higgs scattering. PMID- 26613468 TI - Giant Spin-Driven Ferroelectric Polarization in BiFeO3 at Room Temperature. AB - The spin-driven polarizations of type-I multiferroics are veiled by the preexisting ferroelectric (FE) polarization. Using first-principles calculations combined with a spin model, we uncover two hidden but huge spin-driven polarizations in the room-temperature multiferroic BiFeO(3). One is associated with the global inversion symmetry broken by a FE distortion, and the other is associated with the local inversion symmetry broken by an antiferrodistortive octahedral rotation. Comparison with recent neutron scatterings reveals tha first polarization reaches ~3.0 MUC/cm(2), which is larger than in any other multiferroic material. Our exhaustive study paves a way to uncover the various magnetoelectric couplings that generate hidden spin-driven polarizations in other type-I multiferroics. PMID- 26613469 TI - Influence of the Nuclear Electric Quadrupolar Interaction on the Coherence Time of Hole and Electron Spins Confined in Semiconductor Quantum Dots. AB - The real-time spin dynamics and the spin noise spectra are calculated for p and n charged quantum dots within an anisotropic central spin model extended by additional nuclear electric quadrupolar interactions and augmented by experimental data. Using realistic estimates for the distribution of coupling constants including an anisotropy parameter, we show that the characteristic long time scale is of the same order for electron and hole spins strongly determined by the quadrupolar interactions even though the analytical form of the spin decay differs significantly consistent with our measurements. The low frequency part of the electron spin noise spectrum is approximately 1/3 smaller than those for hole spins as a consequence of the spectral sum rule and the different spectral shapes. This is confirmed by our experimental spectra measured on both types of quantum dot ensembles in the low power limit of the probe laser. PMID- 26613470 TI - Ultrafast Optical Control of the Electronic Properties of ZrTe5. AB - We report on the temperature dependence of the ZrTe(5) electronic properties, studied at equilibrium and out of equilibrium, by means of time and angle resolved photoelectron spectroscopy. Our results unveil the dependence of the electronic band structure across the Fermi energy on the sample temperature. This finding is regarded as the dominant mechanism responsible for the anomalous resistivity observed at T*~160 K along with the change of the charge carrier character from holelike to electronlike. Having addressed these long-lasting questions, we prove the possibility to control, at the ultrashort time scale, both the binding energy and the quasiparticle lifetime of the valence band. These experimental evidences pave the way for optically controlling the thermoelectric and magnetoelectric transport properties of ZrTe(5). PMID- 26613471 TI - Gradient Nonlinear Pancharatnam-Berry Metasurfaces. AB - We apply the Pancharatnam-Berry phase approach to plasmonic metasurfaces loaded by highly nonlinear multiquantum-well substrates, establishing a platform to control the nonlinear wave front at will based on giant localized nonlinear effects. We apply this approach to design flat nonlinear metasurfaces for efficient second-harmonic radiation, including beam steering, focusing, and polarization manipulation. Our findings open a new direction for nonlinear optics, in which phase matching issues are relaxed, and an unprecedented level of local wave front control is achieved over thin devices with giant nonlinear responses. PMID- 26613472 TI - Separating Exchange Splitting from Spin Mixing in Gadolinium by Femtosecond Laser Excitation. AB - Employing spin-, time-, and energy-resolved photoemission spectroscopy, we present the first study on the spin polarization of a single electronic state after ultrafast optical excitation. Our investigation concentrates on the majority-spin component of the d-band-derived Gd(0001) surface state d(z(2))(?). While its binding energy shows a rapid Stoner-like shift by 90 meV with an exponential time constant of tau(E)=0.6+/-0.1 ps, the d(z(2))(?) spin polarization remains nearly constant within the first picoseconds and decays with tau(S)=15+/-8 ps. This behavior is in clear contrast to the equilibrium phase transition, where the spin polarization vanishes at the Curie temperature. PMID- 26613473 TI - Polar Dynamics at the Jahn-Teller Transition in Ferroelectric GaV4S8. AB - We present a dielectric spectroscopy study of the polar dynamics linked to the orbitally driven ferroelectric transition in the Skyrmion host GaV(4)S(8). By combining THz and MHz-GHz spectroscopy techniques, we succeed in detecting the relaxational dynamics arising from coupled orbital and polar fluctuations in this material and trace its temperature dependence in the paraelectric as well as in the ferroelectric phase. The relaxation time significantly increases when approaching the critical temperature from both sides of the transition. It is natural to assume that these polar fluctuations map the orbital dynamics at the Jahn-Teller transition. Because of the first-order character of the orbital ordering transition, the relaxation time shows an enormous jump of about 5 orders of magnitude at the polar and structural phase transition. PMID- 26613474 TI - Genetic Toggle Switch in the Absence of Cooperative Binding: Exact Results. AB - We present an analytical treatment of a genetic switch model consisting of two mutually inhibiting genes operating without cooperative binding of the corresponding transcription factors. Previous studies have numerically shown that these systems can exhibit bimodal dynamics without possessing two stable fixed points at the deterministic level. We analytically show that bimodality is induced by the noise and find the critical repression strength that controls a transition between the bimodal and nonbimodal regimes. We also identify characteristic polynomial scaling laws of the mean switching time between bimodal states. These results, independent of the model under study, reveal essential differences between these systems and systems with cooperative binding, where there is no critical threshold for bimodality and the mean switching time scales exponentially with the system size. PMID- 26613475 TI - Pulled Polymer Loops as a Model for the Alignment of Meiotic Chromosomes. AB - During recombination, the DNA of parents exchange their genetic information to give rise to a genetically unique offspring. For recombination to occur, homologous chromosomes need to find each other and align with high precision. Fission yeast solves this problem by folding chromosomes in loops and pulling them through the viscous nucleoplasm. We propose a theory of pulled polymer loops to quantify the effect of drag forces on the alignment of chromosomes. We introduce an external force field to the concept of a Brownian bridge and thus solve for the statistics of loop configurations in space. PMID- 26613476 TI - Entropy, Ergodicity, and Stem Cell Multipotency. AB - Populations of mammalian stem cells commonly exhibit considerable cell-cell variability. However, the functional role of this diversity is unclear. Here, we analyze expression fluctuations of the stem cell surface marker Sca1 in mouse hematopoietic progenitor cells using a simple stochastic model and find that the observed dynamics naturally lie close to a critical state, thereby producing a diverse population that is able to respond rapidly to environmental changes. We propose an information-theoretic interpretation of these results that views cellular multipotency as an instance of maximum entropy statistical inference. PMID- 26613477 TI - Evolution Arrests Invasions of Cooperative Populations. AB - Population expansions trigger many biomedical and ecological transitions, from tumor growth to invasions of non-native species. Although population spreading often selects for more invasive phenotypes, we show that this outcome is far from inevitable. In cooperative populations, mutations reducing dispersal have a competitive advantage. Such mutations then steadily accumulate at the expansion front, bringing invasion to a halt. Our findings are a rare example of evolution driving the population into an unfavorable state, and they could lead to new strategies to combat unwelcome invaders. PMID- 26613478 TI - Contact Kinetics in Fractal Macromolecules. AB - We consider the kinetics of first contact between two monomers of the same macromolecule. Relying on a fractal description of the macromolecule, we develop an analytical method to compute the mean first contact time for various molecular sizes. In our theoretical description, the non-Markovian feature of monomer motion, arising from the interactions with the other monomers, is captured by accounting for the nonequilibrium conformations of the macromolecule at the very instant of first contact. This analysis reveals a simple scaling relation for the mean first contact time between two monomers, which involves only their equilibrium distance and the spectral dimension of the macromolecule, independently of its microscopic details. Our theoretical predictions are in excellent agreement with numerical stochastic simulations. PMID- 26613479 TI - Inducing Propulsion of Colloidal Dimers by Breaking the Symmetry in Electrohydrodynamic Flow. AB - We show that dielectric colloidal dimers with broken symmetry in geometry, composition, or interfacial charges can all propel in directions that are perpendicular to the applied ac electric field. The asymmetry in particle properties ultimately results in an unbalanced electrohydrodynamic flow on two sides of the particles. Consistent with scaling laws, the propulsion direction, speed, and orientation of dimers can be conveniently tuned by frequency. The new propulsion mechanism revealed here is important for building colloidal motors and studying collective behavior of active matter. PMID- 26613480 TI - Comment on "Penrose Tilings as Jammed Solids". PMID- 26613481 TI - Stenull and Lubensky Reply. PMID- 26613482 TI - Erratum: Quantum Stress Focusing in Descriptive Chemistry [Phys. Rev. Lett. 100, 206405 (2008)]. PMID- 26613484 TI - Practically Efficient QM/MM Alchemical Free Energy Simulations: The Orthogonal Space Random Walk Strategy. AB - The difference between free energy changes occurring at two chemical states can be rigorously estimated via alchemical free energy (AFE) simulations. Traditionally, most AFE simulations are carried out under the classical energy potential treatment; then, accuracy and applicability of AFE simulations are limited. In the present work, we integrate a recent second-order generalized ensemble strategy, the orthogonal space random walk (OSRW) method, into the combined quantum mechanical/molecular mechanical (QM/MM) potential based AFE simulation scheme. Thereby, within a commonly affordable simulation length, accurate QM/MM alchemical free energy simulations can be achieved. As revealed by the model study on the equilibrium of a tautomerization process of hydrated 3 hydroxypyrazole and by the model calculations of the redox potentials of two flavin derivatives, lumichrome (LC) and riboflavin (RF) in aqueous solution, the present OSRW-based scheme could be a viable path toward the realization of practically efficient QM/MM AFE simulations. PMID- 26613485 TI - Solute Partitioning into Lipid Bilayers: An Implicit Model for Nonuniform and Ordered Environment. AB - We have developed a theoretical and computational methodology to evaluate the coupled orientational-positional distribution of solutes in lipid bilayers. Four different contributions to the solute free energy are considered, which can be traced back to (i) electrostatic and (ii) dispersion interactions between the solute and environment, (iii) work for the formation of a solute-shaped cavity, and (iv) anisotropic interactions with the ordered acyl chains. An atomistic representation of the solute is adopted, which includes the conformational degrees of freedom, whereas an implicit model is used for the water/bilayer environment. The highly nonuniform and anisotropic nature of this is introduced through the profiles of density, dielectric permittivity, lateral pressure, and acyl chain order parameters, which can be derived from experiments or simulations. Effects of chemical composition and physical state of the bilayer can be accounted for by a proper form of these profiles. The methodology which we propose is suitable for the integrated calculation of spectroscopic observables for probes in membranes, for the estimate of partition and permeability coefficients of solutes, and for the implicit modeling of the membrane environment in molecular dynamics and Monte Carlo simulations. Here, the method is presented, and the underlying assumptions are discussed. Cholesterol in the liquid crystalline DPPC bilayer is taken as a case study, to illustrate the capabilities of the proposed approach. Free energy maps, distribution profiles, and orientational properties are shown; they compare well with those obtained from all-atom molecular dynamics simulations, as well as with available experimental data, suggesting that the model used is able to capture the subtle effects of the interplay between intermolecular interaction and nanoscale architecture of the lipid bilayer. The detailed picture provided by our calculations appears suitable to investigate the determinants of the behavior of solutes in lipid membranes, highlighting even nonstraightforward issues, which may have biophysical implications. PMID- 26613483 TI - Publisher's Note: (37)(97)Rb(60): The Cornerstone of the Region of Deformation around A~100 [Phys. Rev. Lett. 115, 172501 (2015)]. PMID- 26613486 TI - Benchmarking of DFT Functionals for the Hydrolysis of Phosphodiester Bonds. AB - Phosphodiester bonds are an important chemical component of biological systems, and their hydrolysis and formation reactions are involved in major steps throughout metabolic pathways of all organisms. In this work, we applied dimethylphosphate as a model for this kind of bonds and calculated the potential energy surface for its hydrolysis at the approximated CCSD(T)/CBS//B3LYP/6 311++G(2d,2p) level. By varying the nucleophile (water or hydroxide) and the medium (vacuum or aqueous implicit solvent) we obtained and described four reaction paths. These structures were then used in a DFT functional benchmarking in which we tested a total of 52 functionals. Furthermore, the performances of HF, MP2, MP3, MP4, and CCSD were also evaluated. This benchmarking showed that MPWB1K, MPW1B95, and PBE1PBE are the more accurate functionals to calculate the energies of dimethylphosphate hydrolysis as far as activation and reaction energies are concerned. If considering only the activation energies, MPWB1K, MPW1B95, and B1B95 give the lowest errors when comparing to CCSD(T). A basis set benchmarking on the same system shows that 6-311+G(2d,2p) is the best basis set concerning the relationship between computational time and accuracy. We believe that our results will be of great help to further studies on related phosphodiester systems. This includes not only pure chemical problems but also biochemical studies in which DNA, RNA, and phospholipids are required to be depicted at a quantum level. PMID- 26613487 TI - Quantum Chemistry Calculations Provide Support to the Mechanism of the Light Induced Structural Changes in the Flavin-Binding Photoreceptor Proteins. AB - The proposed mechanisms of photoinduced reactions in the blue light using flavin chromophore photoreceptor proteins are primarily based on the results of X-ray crystallography and spectroscopy studies. Of particular value are the observed band shifts in optical and vibrational spectra upon formation of the signaling (light-induced) state. However, the same set of experimental data has given rise to contradictory interpretations suggesting different structures of the dark and signaling states. To verify the specific mechanism of light-induced changes involving the rotation/tautomerization transformations with the conserved Gln residue near the flavin chromophore, we performed accurate quantum chemical calculations of the equilibrium structures, vibrational and absorption bands of the model systems mimicking the BLUF domain of flavoprotein AppA. Geometry optimization and calculations of vibrational frequencies were carried out with the QM(B3LYP/cc-pVDZ)/MM(AMBER) approach starting from the representative molecular dynamics (MD) snapshots. The MD simulations were initiated from the available crystal structures of the AppA protein. Calculations of the vertical excitation energies were performed with the scaled opposite spin configuration interaction with single substitutions SOS-CIS(D) method that enables efficient treatment of excited states in large molecular systems. The computed molecular structures as well as the spectral shifts (the red shift by 12/16 nm in absorption and the downshift by 25 cm(-1) for the C4?O flavin vibrational mode) are in excellent agreement with the experimental results, lending a strong support to the mechanism proposed by Domratcheva et al. (Biophys. J. 2008, 94, 3872). PMID- 26613488 TI - Dependence of Excited State Potential Energy Surfaces on the Spatial Overlap of the Kohn-Sham Orbitals and the Amount of Nonlocal Hartree-Fock Exchange in Time Dependent Density Functional Theory. AB - Time-dependent density functional theory (TDDFT) with standard GGA or hybrid exchange-correlation functionals is not capable of describing the potential energy surface of the S1 state of Pigment Yellow 101 correctly; an additional local minimum is observed at a twisted geometry with substantial charge transfer (CT) character. To investigate the influence of nonlocal exact orbital (Hartree Fock) exchange on the shape of the potential energy surface of the S1 state in detail, it has been computed along the twisting coordinate employing the standard BP86, B3LYP, and BHLYP xc-functionals as well as the long-range separated (LRS) exchange-correlation (xc)-functionals LC-BOP, omegaB97X, omegaPBE, and CAM-B3LYP and compared to RI-CC2 benchmark results. Additionally, a recently suggested Lambda-parameter has been employed that measures the amount of CT in an excited state by calculating the spatial overlap of the occupied and virtual molecular orbitals involved in the transition. Here, the error in the calculated S1 potential energy curves at BP86, B3LYP, and BHLYP can be clearly related to the Lambda-parameter, i.e., to the extent of charge transfer. Additionally, it is demonstrated that the CT problem is largely alleviated when the BHLYP xc functional is employed, although it still exhibits a weak tendency to underestimate the energy of CT states. The situation improves drastically when LRS-functionals are employed within TDDFT excited state calculations. All tested LRS-functionals give qualitatively the correct potential energy curves of the energetically lowest excited states of P. Y. 101 along the twisting coordinate. While LC-BOP and omegaB97X overcorrect the CT problem and now tend to give too large excitation energies compared to other non-CT states, omegaPBE and CAM-B3LYP are in excellent agreement with the RI-CC2 results, with respect to both the correct shape of the potential energy curve as well as the absolute values of the calculated excitation energies. PMID- 26613489 TI - Efficient Structure Optimization with Second-Order Many-Body Perturbation Theory: The RIJCOSX-MP2 Method. AB - Efficient energy calculations and structure optimizations employing second-order Moller-Plesset perturbation theory (MP2) are presented. The application of the RIJCOSX approximation, which involves different approximations for the formation of the Coulomb- and exchange-type matrices, to MP2 theory is demonstrated. The RIJCOSX approximation incorporates the 'resolution of the identity' approximation in terms of a Split-RI-J variant for the evaluation of the Coulomb matrices and a seminumeric exchange treatment via the 'chain-of-spheres' algorithm for the formation of the exchange-type matrices. Beside the derivation of the working equations, the RIJCOSX-MP2 method is benchmarked against the original MP2 and the already highly efficient RI-MP2 method. Energies as well as gradients are computed employing various basis sets and are compared to the conventional MP2 results concerning accuracy and total wall clock times. Speedups of typically a factor of 5-7 in comparison to MP2 can be obeserved for the largest basis set employed in our study. Total energies are reproduced with an average error of <=0.8 kcal/mol and minimum energy geometries differ by ~0.1 pm in bond lengths and typically ~0.2 degrees in bond angles. The RIJCOSX-MP2 gradient parallelizes with a speedup of 8.2 on 10 processors. The algorithms are implemented into the ORCA electronic structure package. PMID- 26613490 TI - Parallel Calculation of CCSDT and Mk-MRCCSDT Energies. AB - A scheme for the parallel calculation of energies at the coupled-cluster singles, doubles, and triples (CCSDT) level of theory, several approximate iterative CCSDT schemes (CCSDT-1a, CCSDT-1b, CCSDT-2, CCSDT-3, and CC3), and for the state specific multireference coupled-cluster ansatz suggested by Mukherjee with a full treatment of triple excitations (Mk-MRCCSDT) is presented. The proposed scheme is based on the adaptation of a highly efficient serial coupled-cluster code leading to a communication-minimized implementation by parallelizing the time-determining steps. The parallel algorithm is tailored for affordable cluster architectures connected by standard communication networks such as Gigabit Ethernet. In this way, CCSDT and Mk-MRCCSDT computations become feasible even for larger molecular systems and basis sets. An analysis of the time-determining steps for CCSDT and Mk-MRCCSDT, namely the computation of the triple-excitation amplitudes and their individual contributions, is carried out. Benchmark calculations are presented for the N2O, ozone, and benzene molecules, proving that the parallelization of these steps is sufficient to obtain an efficient parallel scheme. A first application to the case of 2,6-pyridyne using a triple-zeta quality basis (222 basis functions) is presented demonstrating the efficiency of the current implementation. PMID- 26613491 TI - Auxiliary Density Matrix Methods for Hartree-Fock Exchange Calculations. AB - The calculation of Hartree-Fock exchange (HFX) is computationally demanding for large systems described with high-quality basis sets. In this work, we show that excellent performance and good accuracy can nevertheless be obtained if an auxiliary density matrix is employed for the HFX calculation. Several schemes to derive an auxiliary density matrix from a high-quality density matrix are discussed. Key to the accuracy of the auxiliary density matrix methods (ADMM) is the use of a correction based on standard generalized gradient approximations for HFX. ADMM integrates seamlessly in existing HFX codes and, in particular, can be employed in linear scaling implementations. Demonstrating the performance of the method, the effect of HFX on the structure of liquid water is investigated in detail using Born-Oppenheimer molecular dynamics simulations (300 ps) of a system of 64 molecules. Representative for large systems are calculations on a solvated protein (Rubredoxin), for which ADMM outperforms the corresponding standard HFX implementation by approximately a factor 20. PMID- 26613492 TI - Comparative Study of Selected Wave Function and Density Functional Methods for Noncovalent Interaction Energy Calculations Using the Extended S22 Data Set. AB - In this paper, an extension of the S22 data set of Jurecka et al. ( Jurecka , P. ; Sponer , J. ; Cerny , J. ; Hobza , P. Phys. Chem. Chem. Phys. 2006 , 8 , 1985. ), the data set of benchmark CCSD(T)/CBS interaction energies of twenty-two noncovalent complexes in equilibrium geometries, is presented. The S22 data set has been extended by including the stretched (one shortened and three elongated) complex geometries of the S22 data set along the main noncovalent interaction coordinate. The goal of this work is to assess the accuracy of the popular wave function methods (MP2-, MP3- and, CCSD-based) and density functional methods (with and without empirical correction for the dispersion energy) for noncovalent complexes based on a statistical evaluation not only in equilibrium, but also in nonequilibrium geometries. The results obtained in this work provide information on whether an accurate and balanced description of the different interaction types and complex geometry distortions can be expected from the tested methods. This information has an important implication in the calculation of large molecular complexes, where the number of distant interacting molecular fragments, often in far from equilibrium geometries, increases rapidly with the system size. The best performing WFT methods were found to be the SCS-CCSD (spin-component scaled CCSD, according to Takatani , T. ; Hohenstein , E. G. ; Sherrill , C. D. J. Chem. Phys. 2008 , 128 , 124111 ), MP2C (dispersion-corrected MP2, according to Hesselmann , A. J. Chem. Phys. 2008 , 128 , 144112 ), and MP2.5 (scaled MP3, according to Pitonak , M. ; Neogrady , P. ; Cerny , J. ; Grimme , S. ; Hobza , P. ChemPhysChem 2009 , 10 , 282. ). Since none of the DFT methods fulfilled the required statistical criteria proposed in this work, they cannot be generally recommended for large-scale calculations. The DFT methods still have the potential to deliver accurate results for large molecules, but most likely on the basis of an error cancellation. PMID- 26613493 TI - Potential Energy Landscape of the Electronic States of the GFP Chromophore in Different Protonation Forms: Electronic Transition Energies and Conical Intersections. AB - We present the results of quantum chemical calculations of the transition energies and conical intersection points for the two lowest singlet electronic states of the green fluorescent protein chromophore, 4'-hydroxybenzylidene-2,3 dimethylimidazolinone, in the vicinity of its cis conformation in the gas phase. Four protonation states of the chromophore, i.e., anionic, neutral, cationic, and zwitterionic, were considered. Energy differences were computed by the perturbatively corrected complete active space self-consistent field (CASSCF) based approaches at the corresponding potential energy minima optimized by density functional theory and CASSCF (for the ground and excited states, respectively). We also report the EOM-CCSD and SOS-CIS(D) results for the excitation energies. The minimum energy S0/S1 conical intersection points were located using analytic state-specific CASSCF gradients. The results reproduce essential features of previous ab initio calculations of the anionic form of the chromophore and provide an extension for the neutral, cationic, and zwitterionic forms, which are important in the protein environment. The S1 PES of the anion is fairly flat, and the barrier separating the planar bright conformation from the dark twisted one as well as the conical intersection point with the S0 surface is very small (less than 2 kcal/mol). On the cationic surface, the barrier is considerably higher (~13 kcal/mol). The PES of the S1 state of the zwitterionic form does not have a planar minimum in the Franck-Condon region. The S1 surface of the neutral form possesses a bright planar minimum; the energy barrier of about 9 kcal/mol separates it from the dark twisted conformation as well as from the conical intersection point leading to the cis-trans chromophore isomerization. PMID- 26613494 TI - Discrete Variable Representation Implementation of the One-Electron Polarization Model. PMID- 26613495 TI - Generalized X-Pol Theory and Charge Delocalization States. AB - The mixed molecular orbital and valence bond (MOVB) method has been used to generalize the explicit polarization (X-Pol) potential to incorporate charge delocalization resonance effects in the framework of valence bond theory. In the original X-Pol method, a macromolecular system is partitioned into individual fragments or blocks, and the molecular orbitals of the system are strictly localized within each block. Consequently, these block-localized molecular orbitals (BLMOs) are nonorthogonal across different blocks. In the generalized X Pol (GX-Pol) theory, we construct charge delocalization VB states by expanding the localization space from monomer blocks into pairwise delocalized blocks. Thus, the expansion of the basis space leads to charge delocalization between monomer pairs, and a series of pairwise delocalization states can be constructed. In general, L-body delocalized states can be analogously defined by grouping L monomer blocks into one. The Hartree product wave function for each state can be fully antisymmetrized, which introduces explicitly exchange repulsion among all blocks. The GX-Pol wave function is a linear combination of all L-body charge transfer (valence bond) states, which incorporates charge delocalization and their resonance as well as static correlation effects. The GX-Pol method provides a general and rigorous theory to incorporate charge delocalization explicitly into these fragment-based electronic structural methods for macromolecular systems. PMID- 26613496 TI - Atomistic details of the Catalytic Mechanism of Fe(III)-Zn(II) Purple Acid Phosphatase. AB - In the present work, we performed a theoretical investigation of the reaction mechanism of the Fe(III)-Zn(II) purple acid phosphatase from red kidney beans (rkbPAP), using the hybrid density functional theory and employing different exchange-correlation potentials. Characterization of the transition states and intermediates involved and the potential energy profiles for the reaction in different environments (gas phase, protein environment, and water) are reported. Our results show that the Fe(III)-Zn(II)PAP catalyzes the hydrolysis of methylphosphate via direct attack by a bridging metals-coordinated hydroxide leading to the cleavage of the ester bond. From our study emerges that the rate limiting step of the reaction is the nucleophilic attack followed by the less energetically demanding release of the leaving group. Furthermore, we provide insights into some important points of contention concerning the precatalytic complex and the substrate coordination mode into the active site prior to hydrolysis. In particular: (i) Two models of enzyme-substrate with different orientations of the substrate into the active site were tested to evaluate the possible roles played by the conserved histidine residues (His 202 and His 296); (ii) Different protonation states of the substrate were taken into account in order to reproduce different pH values and to verify its influence on the catalytic efficiency and on the substrate binding mode; (iii) The metals role in each step of the catalytic mechanism was elucidated. We were also able to ascertain that the activation of the leaving group by the protonated His 296 is decisive to reach an optimal catalytic efficiency, while the bond scission without activation requires higher energy to occur. PMID- 26613497 TI - Transferability of Nonbonded Interaction Potentials for Coarse-Grained Simulations: Benzene in Water. AB - Methods to parametrize coarse-grained simulation models for molecular fluids frequently either attempt to match the fluid structure (e.g., pair correlation functions) previously obtained with detailed atomistic models or aim at reproducing macroscopically observable thermodynamic properties. In either case, the coarse-grained models are state-point-dependent, and it is unclear to what extent the models obtained at a given state point are transferable, for example, to different compositions in the case of solution mixtures. Usually, it remains unclear as well whether structure-based potentials reproduce macroscopic thermodynamic properties and, vice versa, if thermodynamics-based potentials reproduce microscopic structural properties. In this paper, we use the Kirkwood Buff theory of solutions in order to link local structural information and thermodynamic properties sampled with structure-based potentials. We investigate benzene/water mixtures at varying concentrations as a model hydrophobic/hydrophilic system and study the transferability of a coarse-grained model that describes the water and benzene molecules as single interaction sites. The coarse-grained model, parametrized at a high aqueous dilution of benzene, reproduces the Kirkwood-Buff integrals of mixtures obtained with the detailed atomistic model, and it reproduces the change in the benzene chemical potential with composition up to the concentration of thermodynamic instability. The observed transferability of the potential supports the idea that hydrophobic interactions between small molecules are pairwise additive. PMID- 26613498 TI - Theoretical Study of the Dual Fluorescence of 4-(N,N-Dimethylamino)benzonitrile in Solution. AB - We have performed high-level quantum calculations of absorption and emission properties of 4-(N,N-dimethylamino)benzonitrile (DMABN) in gas phase and in polar solvents, including the solvent effects with an explicit mean field model. Two excited states of DMABN have been found and optimized, corresponding to the two excited states assumed by the generally accepted hypotheses for the dual fluorescence of this molecule: a locally excited (LE) state and a charge transfer (CT) state. The results show that, in the gas phase, the charge transfer state is severely distorted and higher in energy than the locally excited state, while in polar solvents, it becomes almost an ideal twisted intramolecular charge transfer state (TICT) and is stabilized with respect to the locally excited state and the Franck-Condon point. The relative free energies calculated for the two excited states in solution suggest that both states are accessible from initial Franck Condon excitation, the charge transfer state being highly favored in aqueous solution and less so in tetrahydrofuran. The results support the validity of the TICT model in this system. PMID- 26613499 TI - Chemically Meaningful Atomic Charges That Reproduce the Electrostatic Potential in Periodic and Nonperiodic Materials. AB - Net atomic charges (NACs) can be used both to understand the chemical states of atoms in a material as well as to represent the electrostatic potential, V, of the material outside its electron distribution. However, many existing definitions of NACs have limitations that prevent them from adequately fulfilling this dual purpose. Some charge methods are not applicable to periodic materials or are inaccurate for systems containing buried atoms, while others work for both periodic and nonperiodic materials containing buried atoms but give NACS that do not accurately reproduce V. We present a new approach, density derived electrostatic and chemical (DDEC) charges, that overcomes these limitations by simultaneously optimizing the NACs to be chemically meaningful and to reproduce V outside the electron distribution. This atoms-in-molecule method partitions the total electron density among atoms and uses a distributed multipole expansion to formally reproduce V exactly outside the electron distribution. We compare different methods for computing NACs for a broad range of materials that are periodic in zero, one, two, and three dimensions. The DDEC method consistently performs well for systems with and without buried atoms, including molecules, nonporous solids, solid surfaces, and porous solids like metal organic frameworks. PMID- 26613500 TI - Protein Folding Simulations Combining Self-Guided Langevin Dynamics and Temperature-Based Replica Exchange. AB - Computer simulations are increasingly being used to predict thermodynamic observables for folding small proteins. Key to continued progress in this area is the development of algorithms that accelerate conformational sampling. Temperature-based replica exchange (ReX) is a commonly used protocol whereby simulations at several temperatures are simultaneously performed and temperatures are exchanged between simulations via a Metropolis criterion. Another method, self-guided Langevin dynamics (SGLD), expedites conformational sampling by accelerating low-frequency, large-scale motions through the addition of an ad hoc momentum memory term. In this work, we combined these two complementary techniques and compared the results against conventional ReX formulations of molecular dynamics (MD) and Langevin dynamics (LD) simulations for the prediction of thermodynamic folding observables of the Trp-cage mini-protein. All simulations were performed with CHARMM using the PARAM22+CMAP force field and the generalized Born molecular volume implicit solvent model. While SGLD-ReX does not fold up the protein significantly faster than the two conventional ReX approaches, there is some evidence that the method improves sampling convergence by reducing topological folding barriers between energetically similar near native states. Unlike MD-ReX and LD-ReX, SGLD-ReX predicts melting temperatures, heat capacity curves, and folding free energies that are closer in agreement to the experimental observations. However, this favorable result may be due to distortions of the relative free energies of the folded and unfolded conformational basins caused by the ad hoc force term in the SGLD model. PMID- 26613501 TI - Simulating the Transition between Gel and Liquid-Crystal Phases of Lipid Bilayers: Dependence of the Transition Temperature on the Hydration Level. AB - Explicit-solvent molecular dynamics (MD) simulations of the monoglyceride glycerol-1-monopalmitin (GMP; bilayer patch of 2 * 6 * 6 lipids) at different hydration levels (full, half, or quarter hydration) and at different temperatures (318 to 338 K) are reported. The 40 ns simulations (some extended to 200 ns) are initiated from structures appropriate for the gel (GL) or liquid-crystal (LC) phases, with the goal of investigating whether atomistic MD simulations on this time scale can be used to monitor GL <-> LC transitions in lipid bilayers, and to evaluate the corresponding transition temperatures Tm (as well as the influence of hydration on Tm) in a reliable fashion. The main conclusions are as follows: (i) The GL -> LC transition of GMP can be observed on the 40 ns time scale. (ii) The LC -> GL transition is comparatively slower, requiring simulations on the 200 ns time scale. (iii) A set of simulations initiated from a structure appropriate for the GL phase and carried out at slightly different temperatures permits the determination of a reliable value for Tm. (iv) The calculated Tm values reproduce the experimentally observed increase in this transition temperature upon decreasing the bilayer hydration. (v) The Tm values calculated at the three hydration levels considered are in essentially quantitative agreement with the experimental phase diagram of GMP. To our knowledge, this study represents the first accurate determination of the Tm of a lipid via atomistic simulations of the (reversible) GL <-> LC phase transition, as well as the first direct simulation evidence for the increase in the transition temperature upon dehydration. The possible direct determination of Tm and the characterization of environmental effects on this quantity by simulation opens up promising perspectives in the contexts of force field refinement and the investigation of dehydration-induced damages in living cells (and bioprotection by cosolutes). PMID- 26613502 TI - Human Inducible Hsp70: Structures, Dynamics, and Interdomain Communication from All-Atom Molecular Dynamics Simulations. AB - The 70 kDa human heat shock protein is a major molecular chaperone involved in de novo folding of proteins in vivo and refolding of proteins under stress conditions. Hsp70 is related to several "misfolding diseases" and other major pathologies, such as cancer, and is a target for new therapies. Hsp70 is comprised of two main domains: an N-terminal nucleotide binding domain (NBD) and a C-terminal substrate protein binding domain (SBD). The chaperone function of Hsp70 is based on an allosteric mechanism. Binding of ATP in NBD decreases the affinity of the substrate for SBD, and hydrolysis of ATP is promoted by binding of polypeptide segments in the SBD. No complete structure of human Hsp70 is known. Here, we report two models of human Hsp70, constructed by homology with Saccharomyces cerevisiae cochaperone protein Hsp110 (open model) and with Escherichia coli 70 kDa DnaK (closed model) and relaxed for several tens to hundreds of nanoseconds by using all-atom molecular dynamics simulations in explicit solvent. We obtain two stable states, Hsp70 with SBD open and SBD closed, which agree with experimental and structural information for ATP-Hsp70 and ADP-Hsp70, respectively. The dynamics of the transition from the open to closed states is investigated with a coarse-grained model and normal-mode analysis. The results show that the conformational change between the two states can be represented by a relatively small number of collective modes which involved major conformational changes in the two domains. These modes provide a mechanistic representation of the communication between NBD and SBD and allow us to identify subdomains and residues that appear to have a critical role in the conformational change mechanism that guides the chaperoning cycle of Hsp70. PMID- 26613503 TI - A Note on the Standard State's Binding Free Energy. AB - The relation between the equilibrium constant of a given chemical reaction and the associated free energy is an issue well studied in chemistry books, but when the reaction involves changes in the number of components in the system, as is the case in binding, things become a little more obscure since one needs to define the so-called standard state. This is reflected in the literature, especially in computational studies of binding, where contradicting approaches are followed when treating this problem. In this work, we present a detailed and unifying explanation of the concepts involved and derive the necessary relations to convert a binding free energy from an arbitrary state to some given standard state. This is done in three independent ways, from the point of view of (1) the dimensions of the quantities involved, (2) the energy and entropy of the molecules, and (3) their chemical potentials. PMID- 26613504 TI - Ab Initio Studies of Structural and Vibrational Properties of Protonated Water Cluster H7O3(+) and Its Deuterium Isotopologues: An Application of Driven Molecular Dynamics. AB - In this work, we present infrared (IR) spectra of H7O3(+) and its deuterium isotopomers calculated by direct molecular dynamics (MD) simulations at the B3LYP/6-31+G** computational level. The calculated spectra obtained at 100, 300, and 500 K were compared to available experimental observations, and spectral features were assigned using normal-mode analysis (NMA) and driven molecular dynamics (DMD). Spectral peaks at 2410 and 2540 cm(-1) were assigned to asymmetric and symmetric stretches of the bridging hydrogen (BH) using NMA. The weak spectral features at 2166 and 2275 cm(-1) were assigned to a combination band of BH asymmetric stretch, H2O in phase wagging, OO stretch, and H3O(+) rocking vibrations by DMD simulations. Our observation of BH stretch vibrations as low as 2166 cm(-1) is in good agreement with the assignment of the low resolution spectrum obtained by Schwarz at 2200-2300 cm(-1) [Schwarz, H. A. J. Chem. Phys. 1977, 67, 5525-5534] and vibrational predissociation spectrum by Lee et al. ~2300 cm(-1) [Okumura, M.; Yeh, L. I.; Myers, J. D.; Lee, Y. T. J. Chem. Phys. 1990, 94, 3416-3427]. PMID- 26613505 TI - Geometry Optimization of Large and Flexible van der Waals Dimers: A Fragmentation Reconstruction Approach. AB - A novel approach for exploring the energy minima of the potential energy surface of large and flexible van der Waals dimers is proposed and tested. The total dimer energy is divided into intra- and intermolecular contributions, which can be computed at different levels of theory. The intermolecular energy, which is the time-consuming part of the calculation, is computed by means of the fragmentation reconstruction method (FRM), making possible the calculation of the interaction energy of large molecules. The method is validated by performing geometry optimizations through a quasi-Newton technique on two benchmark medium sized systems, where the comparison with a direct ab initio calculation is still computationally feasible. In both cases, good agreement is achieved between geometries and energies of the resulting energy minima. PMID- 26613506 TI - Ensemble Docking from Homology Models. AB - We present here a systematic exploration of the quality of protein structures derived from homology modeling when used as templates for high-throughput docking. It is found that structures derived from homology modeling are often similar in quality for docking purposes than real crystal structures, even in cases where the template used to create the structural model shows only a moderate sequence identity with the protein of interest. We designed an "ensemble docking" approach based on the use of multiple homology models. The method provides results which are usually of better quality than those expected from single experimental X-ray structures. The use of this approach allows us to increase around five times the universe of use of high-throughput docking approaches for human proteins, by covering over 75% of known human therapeutic targets. PMID- 26613507 TI - Molecular probe dynamics and free volume in organic glass-formers and their relationships to structural relaxation: 1-propanol. AB - A joint study of the rotational dynamics and free volume in amorphous 1-propanol (1-PrOH) as a prototypical monohydroxy alcohol by electron spin resonance (ESR) or positron annihilation lifetime spectroscopy (PALS), respectively, is reported. The dynamic parameters of the molecular spin probe 2,2,6,6-tetramethyl-1 piperidinyloxy (TEMPO) and the annihilation ones of the atomic ortho-positronium (o-Ps) probe as a function of temperature are compared. A number of coincidences between various effects in the ESR and PALS responses at the corresponding characteristic ESR and PALS temperatures were found suggesting a common origin of the underlying dynamic processes that were identified using viscosity (VISC) in terms of the two-order parameter (TOP) model and broadband dielectric spectroscopy (BDS) data. PMID- 26613508 TI - Collision-Induced Dissociation Ion Mobility Mass Spectrometry for the Elucidation of Unknown Structures in Strained Polycyclic Aromatic Hydrocarbon Macrocycles. AB - Structure determination of unexpected products obtained during synthesis of large carbon nanotube sidewall segments with more than 200 carbon atoms represents a challenging task for traditional analytical methods. Herein, we investigate a homologous series of four products having the same number of carbon atoms but slightly different hydrogen numbers ranging from 168 to 162. We demonstrate that the combination of mass spectrometry, ion mobility separation, and collision induced dissociation (CID) can be used to finally elucidate the complete structures with high certainty. The postulated 1,2-phenyl shift as origin for the side reaction could be proven by changes in the minimum fragment sizes. A combination of CID and ion mobility spectrometry was applied for the first time to prove the cyclic nature of all molecules by the significant size increase upon ring opening. Thereby, also, more compact molecules were discovered in the gas phase with thus far unknown structures. Finally, the potential presence of numerous isomers could be ruled out by drift time measurements and molecular modeling together with theoretical collision cross-section (CCS) calculations. Surprisingly, only one defined structure could be assigned to each macrocycle in the homologous series, most likely as a result of natural selection rules driven by ring strain and steric hindrance. With a decreasing hydrogen content, the macrocycles undergo a stepwise transition from a cylindrical to conical shape. Overall, ion mobility mass spectrometry together with molecular modeling shows great potential to analyze unknown structures, especially in cases where structure determination by X-ray single-crystal analysis is not applicable. PMID- 26613509 TI - Myeloid human cell lines lack functional regulation of aryl hydrocarbon receptor dependent phase I genes. AB - Primary dendritic cells and myeloid cell lines are used to assess the skin sensitization hazard in in vitro approaches. The aryl hydrocarbon receptor (AhR) modulates expression of CYP enzymes which play a significant role in the bioactivation of various xenobiotics. These studies revealed a strong constitutive expression of the AhR in primary human monocytes, monocyte-derived immature dendritic cells (iDC) and cord blood-derived Langerhans cells (LC). In contrast, mRNA and protein expression of AhR was hardly detectable in the cell lines THP-1 and MUTZ-3. U937 cells and MUTZ-3-derived dendritic (MUTZ-DC) or Langerhans cells (MUTZ-LC) showed about half the expression of AhR compared to iDC. Incubation of cells with the specific AhR-inducer benzo[a]anthracene resulted in an upregulation of CYP and IL-1beta mRNA expression in primary monocytes and iDC. CYP1A1 but not CYP1B1 and IL-1beta expression was increased by benzo[a]anthracene in these cell lines except for U937 cells. AhR-independent CYP genes were not regulated by benzo[a]anthracene. Constitutive mRNA expression of other non AhR-dependent CYP enzymes was higher in some of the cell lines compared to the corresponding primary cells. This study demonstrates significant differences in expression and regulation of phase I genes in cell lines currently used for in vitro skin sensitization hazard assessment compared to primary cells. Additional studies are required regarding the combination of cutaneous xenobiotic metabolizing enzymes and APC-sensitization for the development of valid in vitro models for skin sensitization assessment. PMID- 26613510 TI - Selective amyloid beta oligomer assay based on abasic site-containing molecular beacon and enzyme-free amplification. AB - Amyloid-beta (Abeta) oligomers are highly toxic species in the process of Abeta aggregation and are regarded as potent therapeutic targets and diagnostic markers for Alzheimer's disease (AD). Herein, a label-free molecular beacon (MB) system integrated with enzyme-free amplification strategy was developed for simple and highly selective assay of Abeta oligomers. The MB system was constructed with abasic site (AP site)-containing stem-loop DNA and a fluorescent ligand 2-amino 5,6,7-trimethyl-1,8-naphyridine (ATMND), of which the fluorescence was quenched upon binding to the AP site in DNA stem. Enzyme-free amplification was realized by target-triggered continuous opening of two delicately designed MBs (MB1 and MB2). Target DNA hybridization with MB1 and then MB2 resulted in the release of two ATMND molecules in one binding event. Subsequent target recycling could greatly amplify the detection sensitivity due to the greatly enhanced turn-on emission of ATMND fluorescence. Combining with Abeta oligomers aptamers, the strategy was applied to analyze Abeta oligomers and the results showed that it could quantify Abeta oligomers with high selectivity and monitor the Abeta aggregation process. This novel method may be conducive to improve the diagnosis and pathogenic study of Alzheimer's disease. PMID- 26613511 TI - Detecting trypsin at liquid crystal/aqueous interface by using surface immobilized bovine serum albumin. AB - We report a new mechanism for liquid crystal (LC)-based sensor system for trypsin detection. In this system, bovine serum albumin (BSA) was immobilized on gold grids as the enzymatic substrate. When the BSA-modified grid was filled with LC and immersed in the solution containing trypsin, the peptide bonds of BSA were hydrolyzed and peptide fragments were desorbed from the surface of gold grid, which disrupted the orientation of LC at the vicinity and resulted in a dark-to bright transition of optical image of LCs. By using this mechanism, the limit of detection (LOD) of trypsin is 10 ng/mL, and it does not respond to thrombin and pepsin. Besides, the cleavage behavior on gold surfaces was directly visualized by the scanning photoelectron microscopy (SPEM), in particular for the chemical composition identification and element-resolved image. The loss of BSA fragments and the enhancement of Au photoelectron signal after trypsin cleavage were corresponding to the proposed mechanism of the LC-based sensor system. Because the signals reported by LC can be simply interpreted through the human naked-eye, it provides a simple method for fast-screening trypsin activity in aqueous solution. PMID- 26613512 TI - Effects of mTOR and calcineurin inhibitors combined therapy in Epstein-Barr virus positive and negative Burkitt lymphoma cells. AB - Post-transplant lymphoproliferative disorder is a severe complication in solid organ transplant recipients, which is highly associated with Epstein-Barr virus infection in pediatric patients and occasionally presents as Burkitt- or Burkitt like lymphoma. The mammalian target of rapamycin (mTOR) pathway has been described as a possible antitumor target whose inhibition may influence lymphoma development and proliferation after pediatric transplantation. We treated Epstein Barr virus positive (Raji and Daudi) and negative (Ramos) human Burkitt lymphoma derived cells with mTOR inhibitor everolimus alone and in combination with clinically relevant immunosuppressive calcineurin inhibitors (tacrolimus or cyclosporin A). Cell proliferation, toxicity, and mitochondrial metabolic activity were analyzed. The effect on mTOR Complex 1 downstream targets p70 S6 kinase, eukaryotic initiation factor 4G, and S6 ribosomal protein activation was also investigated. We observed that treatment with everolimus alone significantly decreased Burkitt lymphoma cell proliferation and mitochondrial metabolic activity. Everolimus in combination with cyclosporin A had a stronger suppressive effect in Epstein-Barr virus negative but not in Epstein-Barr virus positive cells. In contrast, tacrolimus completely abolished the everolimus-mediated suppressive effects. Moreover, we showed a significant decrease in activation of mTOR Complex 1 downstream targets after treatment with everolimus that was attenuated when combined with tacrolimus, but not with cyclosporin A. For the first time we showed the competitive effect between everolimus and tacrolimus when used as combination therapy on Burkitt lymphoma derived cells. Thus, according to our in vitro data, the combination of calcineurin inhibitor cyclosporin A with everolimus is preferred to the combination of tacrolimus and everolimus. PMID- 26613513 TI - Seasonal occurrence, removal, mass loading and environmental risk assessment of 55 pharmaceuticals and personal care products in a municipal wastewater treatment plant in Central Greece. AB - A comprehensive study, which contains the seasonal occurrence, removal, mass loading and environmental risk assessment of 55 multi-class pharmaceuticals and personal care products (PPCPs), took place in the wastewater treatment plant (WWTP) of Volos, Greece. A one year monitoring study was performed and the samples were collected from the influent and the effluent of the WWTP. Solid phase extraction was used for the pre-concentration of the samples followed by an LC-DAD-ESI/MS analysis. Positive samples were further confirmed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The maximum concentrations of the PPCPs varied between 21 ng/L and 15,320 ng/L in the influents and between 18 ng/L and 9965 ng/L in the effluents. The most commonly detected PPCPs were the diuretic furosemide, the beta-blockers atenolol and metoprolol, the analgesics paracetamol, nimesulide, salicylic acid and diclofenac and the psychomotor stimulant caffeine. The removal efficiencies ranged between negative and high removal rates, demonstrating that the WWTP is not able to efficiently remove the complex mixture of PPCPs. The estimated mass loads ranged between 5.1 and 3513 mg/day/1000 inhabitants for WWTP influent and between 4.1 to 2141 mg/day/1000 inhabitants for WWTP effluent. Finally, environmental risk assessment has been regarded a necessary part of the general research. According to the results produced from the calculation of the risk quotient on three trophic levels, the anti-inflammatory drug diclofenac and the antibiotics, trimethoprim and ciprofloxacin, identified to be of high potential environmental risk for acute toxicity, while diclofenac also for chronic toxicity. PMID- 26613514 TI - Surface modeling of soil antibiotics. AB - Large numbers of livestock and poultry feces are continuously applied into soils in intensive vegetable cultivation areas, and then some veterinary antibiotics are persistent existed in soils and cause health risk. For the spatial heterogeneity of antibiotic residues, developing a suitable technique to interpolate soil antibiotic residues is still a challenge. In this study, we developed an effective interpolator, high accuracy surface modeling (HASM) combined vegetable types, to predict the spatial patterns of soil antibiotics, using 100 surface soil samples collected from an intensive vegetable cultivation area located in east of China, and the fluoroquinolones (FQs), including ciprofloxacin (CFX), enrofloxacin (EFX) and norfloxacin (NFX), were analyzed as the target antibiotics. The results show that vegetable type is an effective factor to be combined to improve the interpolator performance. HASM achieves less mean absolute errors (MAEs) and root mean square errors (RMSEs) for total FQs (NFX+CFX+EFX), NFX, CFX and EFX than kriging with external drift (KED), stratified kriging (StK), ordinary kriging (OK) and inverse distance weighting (IDW). The MAE of HASM for FQs is 55.1 MUg/kg, and the MAEs of KED, StK, OK and IDW are 99.0 MUg/kg, 102.8 MUg/kg, 106.3 MUg/kg and 108.7 MUg/kg, respectively. Further, RMSE simulated by HASM for FQs (CFX, EFX and NFX) are 106.2 MUg/kg (88.6 MUg/kg, 20.4 MUg/kg and 39.2 MUg/kg), and less 30% (27%, 22% and 36%), 33% (27%, 27% and 43%), 38% (34%, 23% and 41%) and 42% (32%, 35% and 51%) than the ones by KED, StK, OK and IDW, respectively. HASM also provides better maps with more details and more consistent maximum and minimum values of soil antibiotics compared with the measured data. The better performance can be concluded that HASM takes the vegetable type information as global approximate information, and takes local sampling data as its optimum control constraints. PMID- 26613515 TI - Polychlorinated biphenyl (PCBs) in rice grains and straw; risk surveillance, congener specific analysis, distribution and source apportionment from selected districts of Punjab Province, Pakistan. AB - The current study presents health risk surveillance by investigating the levels of polychlorinated biphenyls (PCBs) in rice (Oryza sativa L.) grains and rice straw. Samples were collected from four districts (Okara, Sahiwal, Lahore and Sheikhpura) of Punjab Province, Pakistan for congener specific analysis of PCBs, and to observe the spatial distribution pattern and point sources. Level of Sigma30 PCB (ng g(-1)) in rice grains and rice straw ranged from 4.31 to 29.68 and 6.11-25.35, respectively. Tetra-CBs were found predominant in rice straw (49%) and grains (38%) over other PCB homologs. No significant variation (P>0.005) was observed for most of the screened PCBs congeners except, PCB-66, 77, -60, -101, -74, -138, -153 and -105 in rice grains and PCB-66 in rice straw. Reported toxicity equivalency (TEQ) values for dioxin like PCBs in rice grains were found lower than the previously published reports from Asian countries, however higher TEQ values are reported for rice straw in this study. Health was found at risk of cancer among one in million by consumption of the study area food stuffs, though no considerable carcinogenic risks to human health was found. PMID- 26613516 TI - Associated factors for higher lead and cadmium blood levels, and reference values derived from general population of Sao Paulo, Brazil. AB - Human activities are associated with emissions of various metals into the environment, among which the heavy metals lead and cadmium stand out, as they pose a risk to human life even at low concentrations. Thus, accurate knowledge of the levels of these metals exhibited by the overall population, including children, is important. The aim of this study was to estimate the concentrations of lead and cadmium in the blood of adults, adolescents and children residing in the city of Sao Paulo, assess factors associated with higher lead and cadmium blood levels, and to establish reference values for this population. The study sample consisted of 669 adults over 20 years old, 264 adolescents aged 12 to 19 years old and 391 children under 11 years old from both genders. The samples were collected at the end of 2007 and during 2008 in different city zones. Higher blood lead concentration was significantly associated with gender, smoking, offal intake, area of residence and age. The blood cadmium concentration was significantly associated with gender, smoking, consumption of distilled beverages and age. The reference values of lead and cadmium established for adults above 20 years old were 33 MUg/L and 0.6 MUg/L, respectively, for adolescents (12 to 19 years old) were 31 MUg/L and 0.6 MUg/L, respectively and for children under 11 years old were 29 MUg/L and 0.2 MUg/L, respectively. The results of this study indicate that the exposure levels of the investigated population to lead and cadmium are low. PMID- 26613517 TI - Non-target effects of repeated chlorothalonil application on soil nitrogen cycling: The key functional gene study. AB - The widespread and increasing application of chlorothalonil (CTN) raises concerns about its non-target impacts, but little information is available on the effect of CTN on the key functional genes related to soil nitrogen (N) cycling, especially in the case of repeated applications. In the present study, a microcosm incubation was conducted to determine CTN residues and the impacts on the abundances of key functional genes related to N cycling after repeated CTN applications. The results demonstrated that repeated CTN applications at the recommended application rate and five times the recommended rate led to the accumulation of CTN residue in soil at concentrations of 5.59 and 78.79 mg kg( 1), respectively, by the end of incubation. Real time PCR (RT-PCR) revealed that repeated CTN applications had negative effects on the chiA and aprA gene abundances. There were significantly negative correlations between CTN residues and abundances of AOA and AOB genes. In addition, the abundances of key functional genes involved in soil denitrification were declined by repeated CTN applications with the sole exception of the nosZ gene. This study suggests that repeated CTN applications could lead to the accumulation of CTN residue and generate somewhat inconsistent and erratic effects on the abundances of key functional genes related to soil N cycling. PMID- 26613518 TI - The effects of weathering and chemical dispersion on Deepwater Horizon crude oil toxicity to mahi-mahi (Coryphaena hippurus) early life stages. AB - To better understand the impact of the Deepwater Horizon (DWH) incident on commercially and ecologically important pelagic fish species, a mahi-mahi spawning program was developed to assess the effect of embryonic exposure to DWH crude oil with particular emphasis on the effects of weathering and dispersant on the magnitude of toxicity. Acute lethality (96 h LC50) ranged from 45.8 (28.4 63.1) MUg l(-1) SigmaPAH for wellhead (source) oil to 8.8 (7.4-10.3) MUg l(-1) SigmaPAH for samples collected from the surface slick, reinforcing previous work that weathered oil is more toxic on a SigmaPAH basis. Differences in toxicity appear related to the amount of dissolved 3 ringed PAHs. The dispersant Corexit 9500 did not influence acute lethality of oil preparations. Embryonic oil exposure resulted in cardiotoxicity after 48 h, as evident from pericardial edema and reduced atrial contractility. Whereas pericardial edema appeared to correlate well with acute lethality at 96 h, atrial contractility did not. However, sub lethal cardiotoxicity may impact long-term performance and survival. Dispersant did not affect the occurrence of pericardial edema; however, there was an apparent reduction in atrial contractility at 48 h of exposure. Pericardial edema at 48 h and lethality at 96 h were equally sensitive endpoints in mahi-mahi. PMID- 26613519 TI - Exposure of wood in floodplains affects its chemical quality and its subsequent breakdown in streams. AB - In stream ecosystems, coarse organic matter from the riparian vegetation, a key food resource, is often retained in the floodplains before reaching the channel. During floodplain exposure, organic matter can be affected by abiotic and biotic processes ("preconditioning"), which alter its quality and affect its subsequent decomposition in streams. We analyzed the effect of floodplain preconditioning on wood quality (lignin, C, N, P, K, among others), and its subsequent aquatic breakdown, paying special attention to microbial activity. We simulated preconditioned standard wooden sticks on one arid stream floodplain for 3 and 4 months, and then monitored their breakdown in three different streams, together with control (non-preconditioned) sticks. Preconditioning reduced lignin mass and C:N and lignin:N ratios, caused the leaching of soluble nutrients such as P and K, as well as N immobilization by microbes. These changes enhanced the breakdown of wood in the first week of immersion, but had no effect on breakdown rates after 4 months of incubation in the streams, although N immobilization was diminished. Our results suggest that terrestrial preconditioning could alter the role of wood as a long-lasting nutrients and energy source for freshwater ecosystem. PMID- 26613520 TI - Magnetoelectronics--electric field control of magnetism in the solid state. PMID- 26613521 TI - A Comparison of the Hot Spot and the Average Cancer Cell Counting Methods and the Optimal Cutoff Point of the Ki-67 Index for Luminal Type Breast Cancer. AB - OBJECTIVE: In this case-control study, we investigated the most suitable cell counting area and the optimal cutoff point of the Ki-67 index. METHODS: Thirty recurrent cases were selected among hormone receptor (HR)-positive/HER2-negative breast cancer patients. As controls, 90 nonrecurrent cases were randomly selected by allotting 3 controls to each recurrent case based on the following criteria: age, nodal status, tumor size, and adjuvant endocrine therapy alone. Both the hot spot and the average area of the tumor were evaluated on a Ki-67 immunostaining slide. RESULTS: The median Ki-67 index value at the hot spot and average area were 25.0 and 14.5%, respectively. Irrespective of the area counted, the Ki-67 index value was significantly higher in all of the recurrent cases (p < 0.0001). The multivariate analysis revealed that the Ki-67 index value of 20% at the hot spot was the most suitable cutoff point for predicting recurrence. Moreover, higher x0394;Ki-67 index value (the difference between the hot spot and the average area, >=10%) and lower progesterone receptor expression (<20%) were significantly correlated with recurrence. CONCLUSION: A higher Ki-67 index value at the hot spot strongly correlated with recurrence, and the optimal cutoff point was found to be 20%. PMID- 26613522 TI - No Change in Executive Performance in ALS Patients: A Longitudinal Neuropsychological Study. AB - BACKGROUND/AIMS: A substantial proportion of amyotrophic lateral sclerosis (ALS) patients develop cognitive impairments. Longitudinal investigations of cognition in ALS have shown mixed results. While some authors report that cognitive performance remains stable as the disease progresses, others have found evidence for deterioration in various domains. Our objective was to investigate cognitive performance in ALS longitudinally, using the example of executive functions. METHODS: 93 ALS patients and 73 age-, sex- and education-matched healthy controls underwent up to four neuropsychological evaluations, separated by 3- to 6-month intervals. We examined whether performance declined longitudinally on seven tests assessing various sub-components of executive functioning. Furthermore, we assigned an executive-performance-based 'cognitive status' to each participant for every evaluation, examining whether cognitive deterioration (if present) was modulated by their baseline cognitive status and whether cognitive status changed over time. RESULTS: Regardless of their cognitive status at baseline, ALS patients showed no significant decline in the sub-components of executive functioning. CONCLUSION: Our findings imply that the executive deficits which develop in some ALS patients emerge before motor symptoms and remain stable after an initial decline. The discrepancy between this trajectory and the progressive decline in motor functions may result from a differential vulnerability of motor and non-motor prefrontal neurons to the pathomechanism of ALS. PMID- 26613524 TI - Biodegradable Airway Stents - Bench to Bedside: A Comprehensive Review. AB - Airway stents are indicated to treat symptomatic narrowing or to close fistulas of the central airways. They are generally divided into two types: the silicone stents and the metallic stents. Unlike in malignancies, removability is a major objective of temporary stenting in benign conditions, which poses the challenge of a new rigid bronchoscopic procedure under general anesthesia and stent removal with all its attendant risks and costs. The concept of a biodegradable (BD) stent that could maintain the patency of an airway for a predetermined duration of time is very appealing. These BD stents would gradually degrade and eventually vanish from the airway once they are no longer needed. Such stents are currently an area of intense research. Another very promising concept of drug delivery with such stents is also a very exciting area of current research. The aim of this comprehensive review is to discuss all pertinent available literature on the use of BD materials in various clinical applications and to extensively review all animal and humans trials involving BD airway stents. PMID- 26613523 TI - Echocardiographic Evaluation of Biventricular Function in Patients with Euthyroid Hashimoto's Thyroiditis. AB - OBJECTIVE: The aim of this study was to evaluate the left (LV) and right (RV) ventricular function in euthyroid Hashimoto's thyroiditis (eHT) patients. SUBJECTS AND METHODS: Forty-five patients diagnosed with eHT and 45 age- and gender-matched control subjects were enrolled in this study. Echocardiographic parameters reflecting RV and LV functions such as chamber dimensions, ejection fraction, fractional shortening, conventional and tissue Doppler-derived early and late filling velocities (E, A, E', A'), isovolumic relaxation (IVRT) and contraction (IVCT) times, ejection time (ET), deceleration time (DT), Tei index, pulmonary acceleration time (PAcT) and tricuspid annular plane systolic excursion (TAPSE) of patients with eHT were compared to those of control subjects using the paired-samples t test or Wilcoxon signed-rank test. RESULTS: Regarding the LV function, compared to the controls patients with eHT had a higher LV-Tei index (0.6 +/- 0.2 vs. 0.4 +/- 0.1, p < 0.001), higher DT (p < 0.001) and IVRT (p < 0.001) values, and higher E/E' ratios (p = 0.04). In contrast, the peak E wave velocity (p = 0.02), E/A ratio (p = 0.01) and ET (p = 0.02) were significantly lower in the eHT group than amongst the controls. The RV, Tei index (0.40 +/- 0.11 vs. 0.28 +/- 0.07, p < 0.001), TAPSE (2.0 +/- 0.3 vs. 2.2 +/- 0.2 mm, p < 0.001), PAcT (124.3 +/- 22.6 vs. 149.4 +/- 18.3 ms, p < 0.001), A' (p = 0.007) and IVCT (p = 0.001) were significantly higher in patients with eHT than the controls. However, the tricuspid E/A ratio (p = 0.01), E' (p = 0.03) and E'/A' ratio (p = 0.001) were significantly lower in the eHT patients than the control group. CONCLUSIONS: This study demonstrated that both RV and LV functions were impaired in patients with eHT. PMID- 26613525 TI - Parkinson's Disease in the Gulf Countries: An Updated Review. AB - BACKGROUND: The Arabian Gulf region is a rapidly developing part of the world. With the increase in average life-expectancy, idiopathic Parkinson's disease (PD), is also expected to increase in prevalence. Furthermore, the high rate of consanguinity among Arabs probably makes familial cases of PD more likely to be encountered than other areas in the world. This review provides an update on the published literature on sporadic and familial PD in Gulf Arabs. SUMMARY: Although the Arab population of this region shares religious beliefs and demographic characteristics with other Arabs, their environmental exposures and genetic makeup may be different. This could account for the relatively low prevalence of PD reported in the Al-Thugba study (27 per 100,000) compared with prevalence rates by most other studies on Arab (mainly North African) populations (31.4 557.4 per 100,000). KEY MESSAGES: Gulf countries are considered rich countries, which makes conducting nation-wide or even international studies logistically easier than it is in many other countries. Such multinational research can be organized by the existing Gulf Cooperation Council, or through a collaboration of the Ministries of Health. This would, hopefully, culminate in the introduction of more research centers, as well as the implementation of better health care policies and practices for the ageing community. PMID- 26613526 TI - Sound Classification and Call Discrimination Are Decoded in Order as Revealed by Event-Related Potential Components in Frogs. AB - Species that use communication sounds to coordinate social and reproductive behavior must be able to distinguish vocalizations from nonvocal sounds as well as to identify individual vocalization types. In this study we sought to identify the neural localization of the processes involved and the temporal order in which they occur in an anuran species, the music frog Babina daunchina. To do this we measured telencephalic and mesencephalic event-related potentials (ERPs) elicited by synthesized white noise (WN), highly sexually attractive (HSA) calls produced by males from inside nests and male calls of low sexual attractiveness (LSA) produced outside of nests. Each stimulus possessed similar temporal structures. The results showed the following: (1) the amplitudes of the first negative ERP component (N1) at ~ 100 ms differed significantly between WN and conspecific calls but not between HSA and LSA calls, indicating that discrimination between conspecific calls and nonvocal sounds occurs in ~ 100 ms, (2) the amplitudes of the second positive ERP component (P2) at ~ 200 ms in the difference waves between HSA calls and WN were significantly higher than between LSA calls and WN in the right telencephalon, implying that call characteristic identification occurs in ~ 200 ms and (3) WN evoked a larger third positive ERP component (P3) at ~ 300 ms than conspecific calls, suggesting the frogs had classified the conspecific calls into one category and perceived WN as novel. Thus, both the detection of sounds and the identification of call characteristics are accomplished quickly in a specific temporal order, as reflected by ERP components. In addition, the most dynamic ERP patterns appeared in the left mesencephalon and the right telencephalon, indicating the two brain regions might play key roles in anuran vocal communication. PMID- 26613527 TI - An examination of the cross-cultural validity of the Identity Capital Model: American and Japanese students compared. AB - The Identity Capital Model proposes that forms of personal agency are associated with identity development as part of the transition to adulthood. This model was examined in two cultural contexts, taking into account age and gender, among college and university students aged 18 to 24 (N = 995). Confirmatory Factor Analyses verified cultural, age, and gender invariance of the two key operationalizations of the model. A Structural Equation Model path analysis confirmed that the model applies in both cultures with minor variations-types of personal agency are associated with the formation of adult- and societal identities as part of the resolution of the identity stage. It was concluded that forms of personal agency providing the most effective ways of dealing with "individualization" (e.g., internal locus of control) are more important in the transition to adulthood among American students, whereas types of personal agency most effective in dealing with "individualistic collectivism" (e.g., ego strength) are more important among Japanese students. PMID- 26613528 TI - Early Glucose Derangement Detected by Continuous Glucose Monitoring and Progression of Liver Fibrosis in Nonalcoholic Fatty Liver Disease: An Independent Predictive Factor? AB - BACKGROUND: Glucose derangement has been reported to increase oxidative stress, one of the most important factors underlying the progression of hepatic fibrosis in adults with nonalcoholic fatty liver disease (NAFLD). To date, careful evaluation of the glucose profile in pediatric NAFLD has not been performed. METHODS: A total of 30 severely obese children (15 males; mean age 12.87 +/- 2.19 years) with biopsy-proven NAFLD were enrolled in this study from September to December 2013. All patients underwent anthropometric and laboratory evaluation, including the oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM). RESULTS: Our study reveals some differences between OGTT and CGM in detecting NAFLD children with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). OGTT showed 2 (6.67%) patients with IFG and 1 (3.34%) with IGT, while CGM showed 5 (16.67%) patients with IFG and 6 (20%) with IGT. The daily blood glucose profile positively correlated with the baseline blood glucose (r = 0.39, p = 0.04) and the homeostatic model assessment (r = 0.56, p = 0.05). A positive correlation between hyperglycemia and liver fibrosis was found (r = 0.65, p < 0.05). Mean glucose values (F3-F4 group: 163.2 +/- 35.92 mg/dl vs. F1 group: 136.58 +/- 46.83 mg/dl and F2 group: 154.12 +/- 22.51 mg/dl) and the difference between the minimum and maximum blood glucose levels (F3-F4 group: 110.21 +/- 25.26 mg/dl vs. F1 group: 91.67 +/- 15.97 mg/dl and F2 group: 92 +/- 15.48 mg/dl) were significantly (p < 0.05) higher in the F3-F4 group compared to the F1 and F2 groups. CONCLUSION: Glucose profile derangement as detected by CGM is associated with the severity of hepatic fibrosis in children with NAFLD. PMID- 26613530 TI - Neuron Types in the Presumptive Primary Somatosensory Cortex of the Florida Manatee (Trichechus manatus latirostris). AB - Within afrotherians, sirenians are unusual due to their aquatic lifestyle, large body size and relatively large lissencephalic brain. However, little is known about the neuron type distributions of the cerebral cortex in sirenians within the context of other afrotherians and aquatic mammals. The present study investigated two cortical regions, dorsolateral cortex area 1 (DL1) and cluster cortex area 2 (CL2), in the presumptive primary somatosensory cortex (S1) in Florida manatees (Trichechus manatus latirostris) to characterize cyto- and chemoarchitecture. The mean neuron density for both cortical regions was 35,617 neurons/mm(3) and fell within the 95% prediction intervals relative to brain mass based on a reference group of afrotherians and xenarthrans. Densities of inhibitory interneuron subtypes labeled against calcium-binding proteins and neuropeptide Y were relatively low compared to afrotherians and xenarthrans and also formed a small percentage of the overall population of inhibitory interneurons as revealed by GAD67 immunoreactivity. Nonphosphorylated neurofilament protein-immunoreactive (NPNFP-ir) neurons comprised a mean of 60% of neurons in layer V across DL1 and CL2. DL1 contained a higher percentage of NPNFP-ir neurons than CL2, although CL2 had a higher variety of morphological types. The mean percentage of NPNFP-ir neurons in the two regions of the presumptive S1 were low compared to other afrotherians and xenarthrans but were within the 95% prediction intervals relative to brain mass, and their morphologies were comparable to those found in other afrotherians and xenarthrans. Although this specific pattern of neuron types and densities sets the manatee apart from other afrotherians and xenarthrans, the manatee isocortex does not appear to be explicitly adapted for an aquatic habitat. Many of the features that are shared between manatees and cetaceans are also shared with a diverse array of terrestrial mammals and likely represent highly conserved neural features. A comparative study across manatees and dugongs is necessary to determine whether these traits are specific to one or more of the manatee species, or can be generalized to all sirenians. PMID- 26613531 TI - Enhanced recovery pathways in abdominal gynecologic surgery: a systematic review and meta-analysis. AB - INTRODUCTION: Enhanced recovery pathways have been widely accepted and implemented for different types of surgery. Their overall effect in abdominal gynecologic surgery is still underdetermined. A systematic review and meta analysis were performed to provide an overview of current evidence and to examine their effect on postoperative outcomes in women undergoing open gynecologic surgery. MATERIAL AND METHODS: Searches were conducted using Embase, Medline, CINAHL, and the Cochrane Library up to 27 June 2014. Reference lists were screened to identify additional studies. Studies were included if at least four individual items of an enhanced recovery pathway were described. Outcomes included length of hospital stay, complication rates, readmissions, and mortality. Quantitative analysis was limited to comparative studies. Effect sizes were presented as relative risks or as mean differences (MD) with 95% confidence intervals (CI). RESULTS: Thirty-one records, involving 16 observational studies, were included. Diversity in reported elements within studies was observed. Preoperative education, early oral intake, and early mobilization were included in all pathways. Five studies, with a high risk of bias, were eligible for quantitative analysis. Enhanced recovery pathways reduced primary (MD -1.57 days, 95% CI CI -2.94 to -0.20) and total (MD -3.05 days, 95% CI -4.87 to -1.23) length of hospital stay compared with traditional perioperative care, without an increase in complications, mortality or readmission rates. CONCLUSION: The available evidence based on a broad range of non-randomized studies at high risk of bias suggests that enhanced recovery pathways may reduce length of postoperative hospital stay in abdominal gynecologic surgery. PMID- 26613532 TI - NOD-2 and TLR-4 Signaling Reinforces the Efficacy of Dendritic Cells and Reduces the Dose of TB Drugs against Mycobacterium tuberculosis. AB - Tuberculosis (TB) is one of the leading killer infectious diseases. TB patients are inflicted with devastating side effects and the toxicity of a lengthy drug regime, accentuating an urgent need to explore newer and safer treatment methods. Recently, an improved understanding of host-pathogen interaction has opened new avenues for TB treatment, including immunotherapy. This has emboldened us to devise a novel strategy to restrict Mycobacterium tuberculosis(Mtb) growth by activating dendritic cells (DCs) through the NOD-2 and TLR-4 molecules of innate immunity. Triggered DCs show a robust release of cytokines and nitric oxide, autophagy and improved migration towards the lymph nodes, and consequently impede the intracellular survival of Mtb. Of note, this approach enhanced the efficacy of TB drugs by reducing their dose to a 5-fold lesser concentration than recommended. In vivo administration of ligands of NOD-2 (NOD-2L) and TLR-4 (TLR 4L) substantially increased the pool of effector memory CD4 and CD8 T cells. Additionally, NOD-2L and TLR-4L, in conjunction with the reduced dose of isoniazid, substantially declined the Mtb burden in the lungs. In the future, adjunct therapy involving NOD-2L, TLR-4L and TB drugs may have enough potential to reduce the dose and duration of treatment of TB patients. PMID- 26613533 TI - Combining the Rowland Universal Dementia Assessment Scale and the Informant Questionnaire on Cognitive Decline in the Elderly to Improve Detection of Dementia in an Arabic-Speaking Population. AB - BACKGROUND/AIMS: The aim of this study was to assess whether combining the Rowland Universal Dementia Assessment Scale (RUDAS) and Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) could improve diagnostic accuracy when screening for dementia in an Arabic-speaking population with low levels of literacy. METHODS: Based on data from 225 elderly participant and informant dyads, the screening performances of the two instruments were compared and three methods for combining them--'or', 'and' and 'weighted sum' rules--were assessed. RESULTS: The 'weighted sum' method had a significantly better area under the curve value compared to the RUDAS used alone. The 'weighted sum' method and the 'and' rule had the highest specificity, while the 'or' rule had the best sensitivity. CONCLUSION: Harnessing the RUDAS and IQCODE increased diagnostic accuracy when screening for dementia in this study population. PMID- 26613534 TI - How clinical rationing works in practice: A case study of morbid obesity surgery. AB - Difficulties in setting healthcare priorities are encountered throughout the world. There is no agreement on the most appropriate principles or methods for healthcare rationing although there is some consensus that it should be undertaken as systematically and accountably as possible. Although some steps towards achieving accountability have been made at the macro and meso level, at the consultation level rationing remains implicit and poorly understood. Using morbid obesity surgery as a case study, we observed a series of UK National Health Service consultations where rationing was ongoing and conducted in-depth interviews with doctors and patients (2011-2014). A longitudinal approach was taken to research and in total 22 consultations were observed and 78 interviews were undertaken. Sampling was undertaken purposively and theoretically and analyses were undertaken thematically. Clinicians needed to prioritise 55 patients from 450 eligible referrals, but disagreed over the extent to which clinical and financial factors were the driving force behind decision-making. The most prominent rationing technique observed in consultations was rationing by selection, but examples of rationing by delay, by deterrence, and by deflection were also commonplace. Although all clinicians sought to avoid rationing by denial, only six of the 22 patients recruited to the research were known to have been treated at the end of the three-year period. Most clinicians sought to manage rationing implicitly, and only one explained the link between decision making criteria and financial constraints on care availability. Although existing frameworks for categorising NHS rationing techniques were useful in identifying implicit strategies, in practice these techniques over-lapped substantially and we have proposed a simpler framework for analysing NHS rationing decisions at the consultation level, which includes just three categories - rationing by exclusion, rationing by deterrence, and rationing by delay. PMID- 26613535 TI - Long-term impact of the 2011 Great East Japan Earthquake and tsunami on functional disability among older people: A 3-year longitudinal comparison of disability prevalence among Japanese municipalities. AB - It has been unclear whether the prevalence of disability is higher in an area affected by natural disaster than in other areas even if more than one year has passed since the disaster. The aim of this ecological study was to examine whether the rate of increase in disability prevalence among the older population was higher in disaster-stricken areas during the 3 years after the Great East Japan Earthquake (GEJE) and tsunami. This analysis used public Long-term Care Insurance (LTCI) data covering 1570 municipalities. "Disaster areas" were considered to be the three prefectures most affected by the earthquake and tsunami: Iwate, Miyagi, and Fukushima. The outcome measure was the number of aged people (>=65 years) with LTCI disability certification. Rates of change in disability prevalence from January 2011 to January 2014 were used as the primary outcome variable, and compared by analysis of covariance between "coastal disaster areas", "inland disaster areas" and "non-disaster areas". The mean rate of increase in disability prevalence in coastal (14.7%) and inland (10.0%) disaster areas was higher than in non-disaster areas (6.2%) (P < 0.001). During the 3 years after the earthquake, the increase of disability prevalence from before the GEJE continued to be higher in the disaster-stricken areas. PMID- 26613536 TI - Suppression of abdominal aortic aneurysm formation by AR-R17779, an agonist for the alpha7 nicotinic acetylcholine receptor. AB - OBJECTIVE: Activation of vagal nerve suppresses inflammatory responses through activation of alpha7 nicotinic acetylcholine receptor (nAchR). We sought to determine whether AR-R17779, a selective agonist of alpha7nAchR, affects the development of abdominal aortic aneurysm (AAA). METHODS AND RESULTS: AAA was induced by topical application of calcium chloride (CaCl2) to abdominal aorta (AAA group). NaCl (0.9%) was substituted for CaCl2 as a sham operation (SHAM group). AR-R17779 was administered in drinking water (AAA/AR-R group). One and 6 weeks after the operation, aortic tissue was excised for histological and molecular analyses. Aortic diameter and macrophage infiltration into the aortic adventitia were increased in AAA group compared with SHAM group at 6 weeks. Treatment with AR-R17779 reduced the diameter of the aorta and macrophage infiltration compared with AAA group. Wavy morphology of the elastic lamellae was lost in AAA group while it was preserved in AAA/AR-R group. Expression of inflammatory cytokines and matrix metalloproteinase (MMP) activities were enhanced in AAA group, which was suppressed in AAA/AR-R group. AR-R17779 treatment suppressed CaCl2-induced expression of cytokines, activities of MMPs and NF-kappaB activation at 1 week when aortic dilatation had not developed. CONCLUSION: Treatment with AR-R17779 prevented the enlargement of abdominal aorta induced by CaCl2 in association with reduced inflammation and extracellular matrix disruption. These findings suggest therapeutic potential of alpha7nAchR activation for prevention of AAA development. PMID- 26613537 TI - A new simultaneous derivatization and microextration method for the determination of memantine hydrochloride in human plasma. AB - A simple and sensitive method for simultaneous derivatization and hollow fiber liquid phase microextraction (HF-LPME) followed by high performance liquid chromatography-fluorescence detection (HPLC-FL) to determine memantine hydrochloride (MT) in human plasma was developed. The derivatization and microextraction was combined to a single step to ensure the precision. What is more, the derivatization reaction accelerated the mass transfer during the process of microextraction. The hollow fiber was filled with cyclohexane and dansyl chloride (derivatization agent) as acceptor phase and submersed in the alkalinized plasma sample. The system was submitted to stirring at 800rpm for 50min at 40 degrees C. Different experimental parameters were systematically evaluated by response surface methodology. Under the optimized conditions, the calibration curve was linear in the range of 1-100ng/mL (r=0.9991) with a limit of detection of 0.1ng/mL (S/N=3). The precision estimated as the relative standard deviation (RSD) was less than 4.5% and the accuracy was 94.3-100.7%. The present method was successfully applied to determine MT in human plasma samples. PMID- 26613538 TI - Simultaneous determination of three triterpenes in rat plasma by LC-MS/MS and its application to a pharmacokinetic study of Rhizoma Alismatis extract. AB - We have developed a sensitive and specific LC-MS/MS method for the simultaneous determination of alisol A (A), alisol A 23-acetate (A23) and alisol A 24-acetate (A24), the major active components in Rhizoma Alismatis extract (RAE), in rat plasma. In brief, plasma samples were extracted by methyl tert-butyl ether and chromatographically separated by using a C18 column. A tandem mass spectrometric detection with an electrospray ionization (ESI) interface was conducted via multiple reaction monitoring (MRM) under positive ionization mode. This method was validated for specificity, linearity, accuracy (within +/-15.4%), intra- and inter-day precision (CV<11.4%) over the concentration range of 25-5000ng/mL for A, and 5-1000ng/mL for both A23 and A24. The significantly lower detection limit was determined as 25ng/mL for A, 5ng/mL for A23 and A24. This validated method of ours was then used to study the pharmacokinetics of RAE in rat. The elimination half-lives (t1/2) of A, A23 and A24 was determined as 0.75, 0.83 and 0.82h respectively after intravenous injection, and the oral absolute bioavailability of A, A23 and A24 was 43.1+/-18.1%, 6.3+/-1.5% and 7.9+/-1.2%. This new determination method of us for alisols is proven to very useful to study the pharmacological activities of RAE in future. PMID- 26613539 TI - Purification and characterization of oligonucleotide binding (OB)-fold protein from medicinal plant Tinospora cordifolia. AB - The oligonucleotide binding fold (OB-fold) is a small structural motif present in many proteins. It is originally named for its oligonucleotide or oligosaccharide binding properties. These proteins have been identified as essential for replication, recombination and repair of DNA. We have successfully purified a protein contains OB-fold from the stem of Tinospora cordifolia, a medicinal plants of north India. Stems were crushed and centrifuged, and fraction obtained at 60% ammonium sulphate was extensively dialyzed and applied to the weak anion exchange chromatography on Hi-Trap DEAE-FF in 50mM Tris-HCl buffer at pH 8.0. Eluted fractions were concentrated and applied to gel filtration column to get pure protein. We observed a single band of 20-kDa on SDS-PAGE. Finally, the protein was identified as OB-fold by MALDI-TOF. The purified OB-fold protein was characterized for its secondary structural elements using circular dichroism (CD) in the far-UV region. Generally the OB-fold has a characteristic feature as five stranded beta-sheet coiled to form a closed beta- barrel. To estimate its chemical stability, guanidinium chloride-induced denaturation curve was followed by observing changes in the far-UV CD as a function of the denaturant concentration. Analysis of this denaturation curve gave values of 8.90+/ 0.25kcalmol(-1) and 3.78+/-0.18M for DeltaGD degrees (Gibbs free energy change at 25 degrees C) and Cm (midpoint of denaturation), respectively. To determine heat stability parameters of OB-fold protein, differential scanning calorimetry was performed. Calorimetric values of DeltaGD degrees , Tm (midpoint of denaturation), DeltaHm (enthalpy change at Tm), and DeltaCp (constant-pressure heat capacity change) are 9.05+/-0.27kcalmol(-1), 85.2+/-0,3 degrees C, 105+/ 4kcalmol(-1) and 1.6+/-0.08kcalmol(-1)K(-1). This is the first report on the isolation, purification and characterization of OB-fold protein from a medicinal plant T. cordifolia. PMID- 26613541 TI - Semantic mapping reveals distinct patterns in descriptions of social relations in adults with autism spectrum disorder. AB - Adults with autism spectrum disorder (ASD) may describe other individuals differently compared with typical adults. In this study, we first asked participants to describe closely related individuals such as parents and close friends with 10 positive and 10 negative characteristics. We then used standard natural language processing methods to digitize and visualize these descriptions. The complex patterns of these descriptive sentences exhibited a difference in semantic space between individuals with ASD and control participants. Machine learning algorithms were able to automatically detect and discriminate between these two groups. Furthermore, we showed that these descriptive sentences from adults with ASD exhibited fewer connections as defined by word-word co occurrences in descriptions, and these connections in words formed a less "small world" like network. Autism Res 2016, 9: 846-853. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26613540 TI - Perinatal and childhood factors and risk of breast cancer subtypes in adulthood. AB - BACKGROUND: Accumulated exposure to hormones and growth factors during early life may influence the future risk of breast cancer (BC). This study examines the influence of childhood-related, socio-demographic and anthropometric variables on BC risk, overall and by specific pathologic subtypes. METHODS: This is a case control study where 1539 histologically-confirmed BC cases (23-85 years) and 1621 population controls, frequency matched by age, were recruited in 10 Spanish provinces. Perinatal and childhood-related characteristics were directly surveyed by trained staff. The association with BC risk, globally and according to menopausal status and pathologic subtypes, was evaluated using logistic and multinomial regression models, adjusting for tumor specific risk factors. RESULTS: Birth characteristics were not related with BC risk. However, women with high socioeconomic level at birth presented a decreased BC risk (OR=0.45; 95% CI=0.29-0.70), while those whose mothers were aged over 39 years at their birth showed an almost significant excess risk of hormone receptor positive tumors (HR+) (OR=1.35; 95% CI=0.99-1.84). Women who were taller than their girl mates before puberty showed increased postmenopausal BC risk (OR=1.26; 95% CI=1.03 1.54) and increased HR+ BC risk (OR=1.26; 95% CI=1.04-1.52). Regarding prepubertal weight, while those women who were thinner than average showed higher postmenopausal BC risk (OR=1.46; 95% CI=1.20-1.78), associated with HR+ tumors (OR=1.34; 95% CI=1.12-1.61) and with triple negative tumors (OR=1.56; 95% CI=1.03 2.35), those who were heavier than average presented lower premenopausal BC risk (OR=0.64; 95% CI=0.46-0.90) and lower risk of epidermal growth factor receptor positive tumors (OR=0.61; 95% CI=0.40-0.93). CONCLUSION: These data reflect the importance of hormones and growth factors in the early stages of life, when the mammary gland is in development and therefore more vulnerable to proliferative stimuli. PMID- 26613542 TI - Functional dissociation between regularity encoding and deviance detection along the auditory hierarchy. AB - Auditory deviance detection based on regularity encoding appears as one of the basic functional properties of the auditory system. It has traditionally been assessed with the mismatch negativity (MMN) long-latency component of the auditory evoked potential (AEP). Recent studies have found earlier correlates of deviance detection based on regularity encoding. They occur in humans in the first 50 ms after sound onset, at the level of the middle-latency response of the AEP, and parallel findings of stimulus-specific adaptation observed in animal studies. However, the functional relationship between these different levels of regularity encoding and deviance detection along the auditory hierarchy has not yet been clarified. Here we addressed this issue by examining deviant-related responses at different levels of the auditory hierarchy to stimulus changes varying in their degree of deviation regarding the spatial location of a repeated standard stimulus. Auditory stimuli were presented randomly from five loudspeakers at azimuthal angles of 0 degrees , 12 degrees , 24 degrees , 36 degrees and 48 degrees during oddball and reversed-oddball conditions. Middle latency responses and MMN were measured. Our results revealed that middle-latency responses were sensitive to deviance but not the degree of deviation, whereas the MMN amplitude increased as a function of deviance magnitude. These findings indicated that acoustic regularity can be encoded at the level of the middle latency response but that it takes a higher step in the auditory hierarchy for deviance magnitude to be encoded, thus providing a functional dissociation between regularity encoding and deviance detection along the auditory hierarchy. PMID- 26613543 TI - Spatially localized recruitment of anti-inflammatory monocytes by SDF-1alpha releasing hydrogels enhances microvascular network remodeling. AB - Tissue repair processes are characterized by the biphasic recruitment of distinct subpopulations of blood monocytes, including classical ("inflammatory") monocytes (IMs, Ly6C(hi)Gr1(+)CX3CR1(lo)) and non-classical anti-inflammatory monocytes (AMs, Ly6C(lo)Gr1(-)CX3CR1(hi)). Drug-eluting biomaterial implants can be used to tune the endogenous repair process by the preferential recruitment of pro regenerative cells. To enhance recruitment of AMs during inflammatory injury, a novel N-desulfated heparin-containing poly(ethylene glycol) diacrylate (PEG-DA) hydrogel was engineered to deliver exogenous stromal derived factor-1alpha (SDF 1alpha), utilizing the natural capacity of heparin to sequester and release growth factors. SDF-1alpha released from the hydrogels maintained its bioactivity and stimulated chemotaxis of bone marrow cells in vitro. Intravital microscopy and flow cytometry demonstrated that SDF-1alpha hydrogels implanted in a murine dorsal skinfold window chamber promoted spatially-localized recruitment of AMs relative to unloaded internal control hydrogels. SDF-1alpha delivery stimulated arteriolar remodeling that was correlated with AM enrichment in the injury niche. SDF-1alpha, but not unloaded control hydrogels, supported sustained arteriogenesis and microvascular network growth through 7 days. The recruitment of AMs correlated with parameters of vascular remodeling suggesting that tuning the innate immune response by biomaterial SDF-1alpha release is a promising strategy for promoting vascular remodeling in a spatially controlled manner. PMID- 26613544 TI - Population pharmacokinetics of tanezumab in phase 3 clinical trials for osteoarthritis pain. AB - AIMS: The aims were to 1) develop the pharmacokinetics model to describe and predict observed tanezumab concentrations over time, 2) test possible covariate parameter relationships that could influence clearance and distribution and 3) assess the impact of fixed dosing vs. a dosing regimen adjusted by body weight. METHODS: Individual concentration-time data were determined from 1608 patients in four phase 3 studies conducted to assess efficacy and safety of intravenous tanezumab. Patients received two or three intravenous doses (2.5, 5 or 10 mg) every 8 weeks. Blood samples for assessment of tanezumab PK were collected at baseline, 1 h post-dose and at weeks 4, 8, 16 and 24 (or early termination) in all studies. Blood samples were collected at week 32 in two studies. Plasma samples were analyzed using a sensitive, specific, validated enzyme-linked immunosorbent assay. RESULTS: A two compartment model with parallel linear and non-linear elimination processes adequately described the data. Population estimates for clearance (CL), central volume (V1 ), peripheral volume (V2 ), inter-compartmental clearance, maximum elimination capacity (VM) and concentration at half-maximum elimination capacity were 0.135 l day(-1) , 2.71 l, 1.98 l, 0.371 l day(-1) , 8.03 MUg day(-1) and 27.7 ng ml(-1) , respectively. Inter-individual variability (IIV) was included on CL, V1 , V2 and VM. A mixture model accounted for the distribution of residual error. While gender, dose and creatinine clearance were significant covariates, only body weight as a covariate of CL, V1 and V2 significantly reduced IIV. CONCLUSIONS: The small increase in variability associated with fixed dosing is consistent with other monoclonal antibodies and does not change risk : benefit. PMID- 26613545 TI - Temperature and Time of Steeping Affect the Antioxidant Properties of White, Green, and Black Tea Infusions. AB - Tea (Camellia sinensis) is the most highly consumed beverage in the world next to water. The common way of preparation is steeping in hot water which is varying for different type of tea. We investigated the antioxidant properties of 6 type of tea leaves under different time and temperatures of extraction method used. In general, all samples tested in this study demonstrated high levels of antioxidant capacity and antioxidant activity. The results indicate that the antioxidants activity is significantly affected by time and temperature of steeping and the highest was depending on the variety. White state values, green and black teas showed different levels of antioxidants under different extraction conditions. Overall, the highest activity for white tea was in prolonged hot and in some assays prolonged hot and cold extracts, whereas for green tea the highest activity observed in prolonged cold steeping while, for black tea was in short hot water infusion. The results of this study showed the antioxidant capacity of white and green tea was greater than black tea. PMID- 26613546 TI - Enteric-coated mycophenolate sodium containing GvHD prophylaxis reduces GvHD rate after allogeneic HSCT. AB - OBJECTIVES: The aim of this study was to evaluate whether cyclosporine A (CsA) based Graft vs. Host Disease (GvHD) prophylaxis with enteric-coated mycophenolate sodium (EC-MPS) instead of mycophenolate mofetil (MMF) or methotrexate (MTX) reduces the GvHD incidence and lowers gastrointestinal (GI-) toxicities. METHODS: In a retrospective analysis of 102 allogeneic hematopoietic stem cell transplant (HSCT) patients, incidences of overall and severe aGvHD (>II degrees ), cGvHD as well as overall and severe (CTC >II degrees ) GI-toxicities were compared between GvHD prophylaxis containing EC-MPS vs. MMF or MTX (control group). RESULTS: The overall aGvHD rate was significantly lower in the EC-MPS group compared to the control (47% vs. 72%, P = 0.022) with lower rates of severe aGvHD (10% vs. 25%, P = 0.088) and cGvHD (20% vs. 39%, P = 0.065). Prophylaxis with EC-MPS remained significantly associated with a lower aGvHD rate in a multiple logistic regression model. GI-toxicities did not differ between both groups except for severe abdominal pain for which the incidence was increased in the EC-MPS group (17% vs. 3%, P = 0.022). CONCLUSIONS: This data support the hypothesis that replacement of MMF or MTX by EC-MPS reduces GvHD rates after HSCT. This appears not to be due to a reduced GI-toxicity of EC-MPS. PMID- 26613547 TI - Using contact networks to explore mechanisms of parasite transmission in wildlife. AB - A hallmark assumption of traditional approaches to disease modelling is that individuals within a given population mix uniformly and at random. However, this assumption does not always hold true; contact heterogeneity or preferential associations can have a substantial impact on the duration, size, and dynamics of epidemics. Contact heterogeneity has been readily adopted in epidemiological studies of humans, but has been less studied in wildlife. While contact network studies are becoming more common for wildlife, their methodologies, fundamental assumptions, host species, and parasites vary widely. The goal of this article is to review how contact networks have been used to study macro- and microparasite transmission in wildlife. The review will: (i) explain why contact heterogeneity is relevant for wildlife populations; (ii) explore theoretical and applied questions that contact networks have been used to answer; (iii) give an overview of unresolved methodological issues; and (iv) suggest improvements and future directions for contact network studies in wildlife. PMID- 26613548 TI - A pilot study: the role of the autonomic nervous system in cardiorespiratory regulation in infant feeding. AB - AIM: The purpose of this pilot study was to examine the interplay between the parasympathetic (PNS) and sympathetic nervous systems' (SNS) contributions to prefeeding, feeding and satiation in young, healthy infants. METHOD: This prospective study was completed on eleven full-term infants, less than 6 months old. Respiratory rate, heart rate, heart rate variability (HRV), electrodermal activity and low-frequency/high-frequency heart rate variability ratio were sampled from the infant during prefeeding, feeding and satiation periods. RESULTS: A repeated-measures ANOVA revealed a significant difference in respiratory patterning during the three feeding phases (p = .049); however, none of the other physiological measures reached significance. An emerging trend across physiological measures suggests that the feeding phase was influenced by the SNS with increasing respiratory rate, heart rate, low-frequency HRV, electrodermal activity and decreasing high-frequency HRV compared to the prefeeding and satiation phases, which were influenced predominantly by the PNS. CONCLUSION: Respiration rate increased significantly during the feeding phase compared to prefeeding and postfeeding phases. Emerging trends indicate a pattern of alternating relative tone in PNS versus SNS across feeding phases - with SNS predominating the feeding phase. More clinical research examining the SNS and PNS contributions to feeding should be completed across patient populations. PMID- 26613549 TI - Atypical developmental of dorsal and ventral attention networks in autism. AB - Individuals with autism spectrum disorders (ASD) exhibit early and lifelong impairments in attention across multiple domains. While the disorder is known to affect attention processes, very little is currently known about the brain networks underlying attention in ASD, and even less is known about whether these atypicalities persist across the lifespan. We used functional connectivity analysis applied to resting state functional magnetic resonance imaging (fMRI) data to explore the dorsal (DAN) and ventral (VAN) attention networks in two separate age cohorts of children and adults with and without ASD. We find significant developmental differences in functional connectivity of brain regions that are critical for attention in children and adults with ASD. Specifically, children with ASD show hyper-connectivity of regions-of-interest (ROIs) in both attention networks compared with both typically developing (TD) children and adults with ASD. In contrast, adults with ASD show hypo-connectivity of these networks compared with neurotypical adults. These findings are consistent with the notion that consideration of developmental stage is critical in studies of functional connectivity in ASD. This study further illustrates diverging developmental patterns for top-down and bottom-up attention systems in autism. PMID- 26613550 TI - Surface plasmon resonance biosensors for simultaneous monitoring of amyloid-beta oligomers and fibrils and screening of select modulators. AB - Oligomeric amyloid-beta (Abeta) peptides are considered as the most toxic species in Alzheimer's disease (AD). Monitoring of the Abeta aggregation profiles is critical for elucidating the oligomer toxicity and may serve as a therapeutic target for AD. By immobilizing the capture antibodies of A11 and OC that are specific to the oligomers and fibrils, respectively, in separate fluidic channels, a novel surface plasmon resonance (SPR) biosensor was designed for monitoring the oligomeric and fibrillar species of Abeta(1-42) simultaneously. The influence of curcumin, Cu(2+) and methylene blue on the amount of toxic oligomers and fibrils was evaluated. The half maximal inhibitory concentration (IC50) of curcumin and methylene blue was determined. The formation of Abeta fibrils was also validated by the thioflavin T (ThT) fluorescence assay. The results demonstrate the utility of SPR as an analytical tool for rapid and comprehensive monitoring of Abeta aggregation and screening of Abeta modulators. PMID- 26613551 TI - Antipsychotic reexposure and recurrent pneumonia in schizophrenia: a nested case control study. AB - OBJECTIVE: Few studies have used systematic datasets to assess the safety of antipsychotic rechallenge after an adverse event. This nested case-control study estimated the risk for recurrent pneumonia after reexposure to antipsychotic treatment. METHOD: In a nationwide schizophrenia (ICD-9-CM code 295) cohort (derived from the National Health Insurance Research Database in Taiwan) who were hospitalized for pneumonia (ICD-9-CM codes 480-486, 507) between 2000 and 2008 (N = 2,201), we identified 494 subjects that developed recurrent pneumonia after a baseline pneumonia episode. Based on risk-set sampling in a 1:3 ratio, 1,438 matched controls were selected from the cohort. Exposures to antipsychotics were categorized by type, duration, and defined daily dose. Using propensity score adjusted analysis, we assessed individual antipsychotics for the risk of recurrent pneumonia; we furthermore assessed the effect of reexposure to these antipsychotics on the risk of recurrent pneumonia. RESULTS: Of the antipsychotics studied, current use of clozapine was the only one associated with a clear dose dependent increase in the risk for recurrent pneumonia (adjusted risk ratio = 1.40, P = .024). Intriguingly, patients reexposed to clozapine had a higher risk for recurrent pneumonia (adjusted risk ratio = 1.99, P = .023) than those receiving clozapine only prior to the baseline pneumonia, and this risk was associated with gender. Women reexposed to clozapine were more susceptible to recurrent pneumonia (adjusted risk ratio = 4.93, P = .050). CONCLUSIONS: In patients experiencing pneumonia while undergoing clozapine treatment, physicians should carefully consider the increased risk of pneumonia recurrence when clozapine is reintroduced. Future studies should try to quantify the risk of other medical conditions associated with clozapine reexposure. PMID- 26613553 TI - Four-locus gene interaction between IL13, IL4, FCER1B, and ADRB2 for asthma in Chinese Han children. AB - RATIONALE: IL13, IL4, IL4RA, FCER1B, and ADRB2 are important inflammatory genes associated with immunoglobulin E levels. This study attempts to determine whether there are gene-gene interactions in the five genes among asthmatic children of Chinese Han nationality. METHODS: Nine single-nucleotide polymorphisms (SNPs) in the five genes were genotyped in 1,000 asthmatic children and 1,000 healthy controls using TaqMan real-time quantitative polymerase chain reaction. Multifactor-dimensionality reduction method was applied for the analysis. RESULTS: A four-way gene-gene interaction model consisting of IL13 rs20541, IL4 rs2243250, ADRB2 rs1042713, and FCER1B rs569108 was chosen as the optimal one for determining asthma susceptibility (testing balanced accuracy = 0.6089, cross validation consistency = 10/10, P = 6.98E-05). Each of the four SNPs was identified to have an independent association with childhood asthma (G allele of rs20541, odds ratio (OR) = 1.24, P = 1.23E-03; T allele of rs2243250, OR = 1.25, P = 3.81E-03; A allele of rs1042713, OR = 1.29, P = 6.75E-05; G allele of rs569108, OR = 1.27, P = 3.86E-03). Individuals homozygous for the risk alleles at all the four loci (rs20541 GG, rs2243250 TT, rs1042713 AA, and rs569108 GG) had a significantly higher risk of asthma compared with those without any risk homozygotes (OR = 13.55, P = 4.28E-03), and also greater than those with less than four risk homozygotes (OR = 10.09, P = 6.51E-03). CONCLUSIONS: Our results suggest that IL13 rs20541, IL4 rs2243250, ADRB2 rs1042713, and FCER1B rs569108, four SNPs with significant sole effect on asthma, interact to confer a higher risk for the disease in Chinese Han children. PMID- 26613554 TI - Interaction of Chlamydiae with human macrophages. AB - The phylum Chlamydiae contains several members that are well-known human pathogens, like Chlamydia trachomatis and C. pneumoniae. Establishing a chronic bacterial infection requires the active evasion of the host immune response. A major arm of the innate immune defence is constituted by macrophages, which fight infections by removing bacteria and triggering an adaptive immune response. However, some pathogenic Chlamydia infect and survive in macrophages at least for a certain period of time. Therefore, macrophages can serve as vehicles for the dissemination of bacterial infections from the primary infection site via the urogenital or respiratory tract to distant sites in the body. The capacity to infect macrophages seems to depend on the chlamydial strain and the source of macrophages. In vitro infections of macrophages with C. trachomatis, C. psittaci and C. pneumoniae reveal low efficiency of infection and progeny formation, as well as failure to develop mature inclusions. In contrast, the emerging pathogen, Simkania negevensis, actively replicates in macrophages. Here we summarize the current knowledge of the intracellular and molecular key mechanisms of C. trachomatis, C. pneumoniae and S. negevensis infections in human macrophages. PMID- 26613552 TI - Sex-Dependent Effects of Prenatal Stress on Social Memory in Rats: A Role for Differential Expression of Central Vasopressin-1a Receptors. AB - Prenatal stress (PNS) affects a number of traits in the offspring, including stress axis regulation, emotionality and cognition; however, much less is known about the effects of PNS on social memory and the underlying central mechanisms. In the present study, we investigated social preference, social memory under basal and stress conditions and olfactory memory for social and nonsocial odours in the adult offspring of dams exposed to social stress during late pregnancy. Given the key roles that the central oxytocin and vasopressin systems play in facilitating social memory, we further investigated the effects of PNS on the central expression of mRNA for oxytocin (Oxtr) and vasopressin-1a (Avpr1a) receptors. PNS did not affect social preference in either sex; however, social memory was impaired under basal conditions in PNS females but not PNS males. Accordingly, Avpr1a mRNA expression in the lateral septum and bed nucleus of stria terminalis (BNST) was unaltered in males but was significantly lower in PNS females compared to controls. No differences in Oxtr mRNA expression were detected between control and PNS offspring in either sex in any of the brain regions examined. Social memory deficits in PNS females persisted when social odours were used; however, this does not appear to be a result of impaired olfaction because memory for nonsocial odours was similar in control and PNS females. Under acute stress conditions, deficits in social memory were observed in both male and female control offspring; however, PNS males were unaffected. Moreover, acute stress facilitated social memory in PNS females and this was associated with an up-regulation of Avpr1a mRNA in the lateral septum and BNST. Our data support a role for altered signalling via central Avpr1a in PNS-induced sex-dependent changes in social memory and may have implications for understanding the aetiology of neurodevelopmental disorders characterised by social behaviour deficits in humans. PMID- 26613555 TI - Cancer Incidence in Heart Transplant Recipients With Previous Neoplasia History. AB - Neoplasm history increases morbidity and mortality after solid organ transplantation and has disqualified patients from transplantation. Studies are needed to identify factors to be considered when deciding on the suitability of a patient with previous tumor for heart transplantation. A retrospective epidemiological study was conducted in heart transplant (HT) recipients (Spanish Post-Heart Transplant Tumor Registry) comparing the epidemiological data, immu nosuppressive treatments and incidence of post-HT tumors between patients with previous malignant noncardiac tumor and with no previous tumor (NPT). The impact of previous tumor (PT) on overall survival (OS) was also assessed. A total of 4561 patients, 77 PT and 4484 NPT, were evaluated. The NPT group had a higher proportion of men than the PT group (p < 0.001). The incidence of post-HT tumors was 1.8 times greater in the PT group (95% confidence interval [CI] 1.2-2.6; p < 0.001), mainly due to the increased risk in patients with a previous hematologic tumor (rate ratio 2.3, 95% CI 1.3-4.0, p < 0.004). OS during the 10-year posttransplant period was significantly lower in the PT than the NPT group (p = 0.048) but similar when the analysis was conducted after a first post-HT tumor was diagnosed. In conclusion, a history of PT increases the incidence of post-HT tumors and should be taken into account when considering a patient for HT. PMID- 26613557 TI - Violence Risk Assessment and Management in Outpatient Clinical Practice. AB - OBJECTIVE: The aims of this review were to highlight fundamental distinctions between risk assessment in forensic versus therapeutic settings, review the best available evidence regarding key risk and protective factors for violence of particular relevance to clinicians in outpatient therapeutic settings, and describe an approach to evaluating and managing violence risk in outpatient treatment. METHOD: An integrative literature review was undertaken to examine violence risk and protective factors most relevant to outpatient clinicians in therapeutic settings. RESULTS: Based on the available research, the Integrative Outpatient Violence Risk Assessment and Management (IVRAM) model, a 5-step strategy for evaluating and managing violence risk in therapeutic contexts, is introduced. The IVRAM emphasizes the integration of nomothetic and idiographic data through a focus on empirically derived dynamic risk and protective factors in the context of an individualized anamnestic analysis. CONCLUSION: Clinicians working in forensic and therapeutic settings will increasingly benefit from the contributions of the other as the distinctions between risk assessment and risk management continue to decrease. PMID- 26613556 TI - Targeting Notch Signaling and Autophagy Increases Cytotoxicity in Glioblastoma Neurospheres. AB - Glioblastomas are highly aggressive tumors that contain treatment resistant stem like cells. Therapies targeting developmental pathways such as Notch eliminate many neoplastic glioma cells, including those with stem cell features, but their efficacy can be limited by various mechanisms. One potential avenue for chemotherapeutic resistance is the induction of autophagy, but little is known how it might modulate the response to Notch inhibitors. We used the gamma secretase inhibitor MRK003 to block Notch pathway activity in glioblastoma neurospheres and assessed its effects on autophagy. A dramatic, several fold increase of LC3B-II/LC3B-I autophagy marker was noted on western blots, along with the emergence of punctate LC3B immunostaining in cultured cells. By combining the late stage autophagy inhibitor chloroquine (CQ) with MRK003, a significant induction in apoptosis and reduction in growth was noted as compared to Notch inhibition alone. A similar beneficial effect on inhibition of cloogenicity in soft agar was seen using the combination treatment. These results demonstrated that pharmacological Notch blockade can induce protective autophagy in glioma neurospheres, resulting in chemoresistance, which can be abrogated by combination treatment with autophagy inhibitors. PMID- 26613558 TI - Sports activities enhance the prevalence of rhinitis symptoms in schoolchildren. AB - BACKGROUND: To evaluate the association between sports activities and allergic symptoms, especially rhinitis, among schoolchildren. METHODS: This longitudinal survey of schoolchildren collected data from questionnaires regarding allergic symptoms based on the International Study of Asthma and Allergies in Childhood (ISAAC) program and sports participation that were distributed to the parents of children at all 12 public primary schools in Ohmi-Hachiman City, Shiga Prefecture, Japan. Data were collected annually from 2011 until 2014, when the children reached 10 years of age. Blood samples were obtained in 2014, and the levels of immunoglobulin (Ig)E specific to four inhalant allergens were measured. RESULTS: Data from 558 children were analyzed. At 10 years of age, prevalence of asthma and eczema did not differ significantly, while rhinitis was significantly higher (p = 0.009) among children who participated in sports. Prevalence of rhinitis increased as the frequency or duration of sports participation increased (p < 0.01). The prevalence of new-onset rhinitis increased significantly among 10 year-olds with increasing duration of participation in sports (p = 0.03). Among those who participated in continuous sports activities, the prevalence of rhinitis was significantly higher with prolonged eczema (p = 0.006). Sports activities did not increase sensitization to inhalant allergens. CONCLUSION: Sports activities enhance the prevalence of rhinitis in schoolchildren. Prolonged eczema, together with sports participation, further promotes the symptoms. The mechanisms of these novel findings warrant further investigation. PMID- 26613559 TI - Motion-induced disturbance of auditory-motor synchronization and its modulation by transcranial direct current stimulation. AB - The timing of personal movement with respect to external events has previously been investigated using a synchronized finger-tapping task with a sequence of auditory or visual stimuli. While visuomotor synchronization is more accurate with moving stimuli than with stationary stimuli, it remains unclear whether the same principle holds true in the auditory domain. Although the right inferior superior parietal lobe (IPL/SPL), a center of auditory motion processing, is expected to be involved in auditory-motor synchronization with moving sounds, its functional relevance has not yet been investigated. The aim of the present study was thus to clarify whether horizontal auditory motion affects the accuracy of finger-tapping synchronized with sounds, as well as whether the application of transcranial direct current stimulation (tDCS) to the right IPL/SPL affects this. Nineteen healthy right-handed participants performed a task in which tapping was synchronized with both stationary sounds and sounds that created apparent horizontal motion. This task was performed before and during anodal, cathodal and sham tDCS application to the right IPL/SPL in separate sessions. The time difference between the onset of the sounds and tapping was larger with apparently moving sounds than with stationary sounds. Cathodal tDCS decreased this difference, anodal tDCS increased the variance of the difference and sham stimulation had no effect. These results supported the hypothesis that auditory motion disturbs efficient auditory-motor synchronization and that the right IPL/SPL plays an important role in tapping in synchrony with moving sounds via auditory motion processing. PMID- 26613560 TI - Effects of a geriatric intervention aiming to improve quality care in nursing homes on benzodiazepine use and discontinuation. AB - BACKGROUND: Benzodiazepines and "Z drugs" are often prescribed in residents of nursing homes (NH) despite their well-known deleterious effects. We aimed to investigate if a general intervention on quality of care led to discontinuation of benzodiazepine, and to examine which NH-related factors were associated in change of benzodiazepines use. METHODS: IQUARE is a quasi-experimental study, investigating the impact of an intervention based on a geriatric education with NH staff on several quality indicators of care (including appropriate prescriptions). All participating NH received an initial and 18-month audit regarding drug prescriptions and other quality of care variables. The analysis included 3973 residents, 2151 subjects (mean age: 84.6 +/- 8.5 years; 74.3% women) in the control group and 1822 (mean age: 85.5 +/- 8.1 years; 77.4% women) in the intervention group. Outcomes at 18 months were benzodiazepines use, long acting benzodiazepines use, new-use of benzodiazepines, and discontinuation. The effect of the intervention was investigated using mixed-effect logistic regression models, including NH variables and residents' health status as confounders. RESULTS: Higher reductions in benzodiazepine use (-2.8% vs. -1.5%) and long-acting benzodiazepine (-3.7% vs. -3.5%) were observed in intervention group, but not statistically significant. None of the structural and organisational NH-related variables predicted either discontinuation or new-use of benzodiazepines; hospitalisations and initial use of meprobamate increased the likelihood of becoming a new-user of benzodiazepines. Multivariate analysis suggested that living in a particular NH could affect benzodiazepines discontinuation. CONCLUSIONS: A general intervention designed to improve overall NH quality indicators did not succeed in reducing benzodiazepines use. External factors interfered with the intervention. Further studies are needed to examine which NH-related aspects could impact benzodiazepines discontinuation. PMID- 26613561 TI - Waterbirth: An Integrative Analysis of Peer-Reviewed Literature. PMID- 26613562 TI - What did Hadropithecus eat, and why should paleoanthropologists care? AB - Over 40 years ago, Clifford Jolly noted different ways in which Hadropithecus stenognathus converged in its craniodental anatomy with basal hominins and with geladas. The Malagasy subfossil lemur Hadropithecus departs from its sister taxon, Archaeolemur, in that it displays comparatively large molars, reduced incisors and canines, a shortened rostrum, and thickened mandibular corpus. Its molars, however, look nothing like those of basal hominins; rather, they much more closely resemble molars of grazers such as Theropithecus. A number of tools have been used to interpret these traits, including dental microwear and texture analysis, molar internal and external morphology, and finite element analysis of crania. These tools, however, have failed to provide support for a simple dietary interpretation; whereas there is some consistency in the inferences they support, dietary inferences (e.g., that it was graminivorous, or that it specialized on hard objects) have been downright contradictory. Cranial shape may correlate poorly with diet. But a fundamental question remains unresolved: why do the various cranial and dental convergences exemplified by Hadropithecus, basal hominins, and Theropithecus exist? In this paper we review prior hypotheses regarding the diet of Hadropithecus. We then use stable carbon and nitrogen isotope data to elucidate this species' diet, summarizing earlier stable isotope analyses and presenting new data for lemurs from the central highlands of Madagascar, where Hadropithecus exhibits an isotopic signature strikingly different from that seen in other parts of the island. We offer a dietary explanation for these differences. Hadropithecus likely specialized neither on grasses nor hard objects; its staples were probably the succulent leaves of CAM plants. Nevertheless, aspects of prior hypotheses regarding the ecological significance of its morphology can be supported. Am. J. Primatol. 78:1098-1112, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26613563 TI - Platelet indices in dogs with Babesia rossi infection. AB - BACKGROUND: Thrombocytopenia without clinical bleeding is a consistent finding in virulent canine babesiosis. OBJECTIVES: The purpose of the study was to investigate the platelet index phenotype in Babesia rossi-infected dogs and the association with disease outcome. We hypothesized that an increased proportion of large, activated platelets would be present. METHODS: Ninety-six infected and 15 control dogs were included. Babesia-infected dogs were further divided into survivors and nonsurvivors. Platelet count, mean platelet volume (MPV), platelet volume distribution width (PDW), plateletcrit (PCT), mean platelet mass (MPM), mean platelet component concentration (MPC), and platelet component distribution width (PCDW) were measured at presentation, and at 24 and 48 hours in admitted survivors. RESULTS: Mortality rate was 13% (12/96). At presentation, compared to controls, PLT and PCT were significantly decreased in survivors and nonsurvivors (P < .001 for both). Mean platelet volume was significantly increased in survivors and nonsurvivors compared to the controls (P < .001 for both); however, MPM was only significantly increased in the survivors (P < .001). There were no differences between the survivors and nonsurvivors for any of the indices at presentation. Platelet count and PCT were significantly increased at 24 and 48 hours, and MPC significantly increased at 24 hours for admitted survivors compared to the values at presentation. CONCLUSION: Large, activated platelets were significantly increased and may play a role in the lack of a bleeding phenotype, despite severe thrombocytopenia, in canine babesiosis. PMID- 26613564 TI - Simultaneous evaluation of one-electron reducing systems and radical reactions in cells by nitroxyl biradical as probe. AB - In the present study, a novel probe for the simultaneous evaluation of one electron reducing systems (electron transport chain) and one-electron oxidizing systems (free radical reactions) in cells by electron chemical detection was developed. Six-membered cyclic nitroxyl radicals (2,2,6,6-tetramethylpiperidine-1 oxyl; TEMPO series) are sensitive to one-electron redox systems, generating the hydroxylamine form [TEMPO(H)] via one-electron reduction, and the secondary amine form [TEMPO(N)] via one-electron oxidation in the presence of thiols. In contrast, the sensitivities of five-membered cyclic nitroxyl radicals (2,2,5,5 tetramethylpyrrolidine-1-oxyl; PROXYL series) to the one-electron redox systems are comparatively low. The electron chemical detector can detect 2,2,6,6 tetramethylpiperidine-1-oxyl (TEMPO), TEMPO(H) and PROXYL but not TEMPO(N). Therefore, nitroxyl biradical, TEMPO-PROXYL, as a probe for the evaluation of one electron redox systems was employed. TEMPO-PROXYL was synthesized by the conjunction of 4-amino-TEMPO with 3-carboxyl-PROXYL via the conventional dicyclohexyl carbodiimide reaction. TEMPO-PROXYL, TEMPO(H)-PROXYL and TEMPO(N) PROXYL were simultaneously quantified by HPLC with Coularray detection. Calibration curves for the quantification of TEMPO-PROXYL, TEMPO(H)-PROXYL and TEMPO(N)-PROXYL were linear in the range from 80 nm to 80 MUm, and the lowest quantification limit of each molecule was estimated to be <80 nm. The relative standard deviations at 0.8 and 80 MUm were within 10% (n = 5). Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26613565 TI - Improved Clinical Functioning for Patients Receiving Fee Discounts That Reward Treatment Engagement. AB - OBJECTIVE: Financial incentives may have utility in promoting psychotherapy attendance and adherence, leading to improved clinical functioning. This study presents results from a novel application of financial incentives-a progressively lowered pay scale that rewards therapy attendance and adherence. METHOD: Overall, 110 outpatients participated; 56 patients (51%) were enrolled in the financial incentives condition and received a 5% fee discount-applied iteratively across sessions-if they followed defined criteria (e.g., completed homework). RESULTS: There were no statistically significant differences between groups in terms of the number of sessions attended, therapy duration, and number of no-shows and cancellations. However, adjusting for Global Assessment of Functioning (GAF) at intake, patients receiving the financial incentives had significantly higher GAF rating at termination compared with those who did not receive the intervention. CONCLUSIONS: Financial incentives that reward therapy attendance and adherence with discounted fees is associated with improved clinical functioning. PMID- 26613566 TI - Stoichiometry and deletion analyses of subunits in the heterotrimeric F-ATP synthase c ring from the acetogenic bacterium Acetobacterium woodii. AB - The ion-translocating c ring of the Na(+) F1 Fo ATP synthase of the anaerobic bacterium Acetobacterium woodii is the first heteromeric c ring found in nature that contains one V- (c1 ) and two F-type-like c subunits (c2 /c3 ), the latter of identical amino acid sequence. To address whether they are of equal or different importance for function, they were deleted in combination or individually. Deletion of c1 was compensated by incorporation of two c2 /c3 subunits but the enzyme was unstable and largely impaired in Na(+) transport. Deletion of c2 was compensated by incorporation of c3 but also led to a reduction of Na(+) transport. Deletion of c3 had no effect. In contrast, deletion of both c2 and c3 led to a complete loss of ATPase activity at the cytoplasmic membrane. Mass spectrometric analysis of c2 +1 Ala and c2 +2 Ala variants revealed a copy number of 8 : 1 for c2 /c3 which is consistent with the biochemical characteristics of the variants. These data indicate a role of c1 in assembly and a function of c2 as the predominant c ring constituent. PMID- 26613567 TI - Review: Parkinson's disease: from synaptic loss to connectome dysfunction. AB - Parkinson's disease (PD) is a common neurodegenerative disorder with prominent loss of nigro-striatal dopaminergic neurons. The resultant dopamine (DA) deficiency underlies the onset of typical motor symptoms (MS). Nonetheless, individuals affected by PD usually show a plethora of nonmotor symptoms (NMS), part of which may precede the onset of motor signs. Besides DA neuron degeneration, a key neuropathological alteration in the PD brain is Lewy pathology. This is characterized by abnormal intraneuronal (Lewy bodies) and intraneuritic (Lewy neurites) deposits of fibrillary aggregates mainly composed of alpha-synuclein. Lewy pathology has been hypothesized to progress in a stereotypical pattern over the course of PD and alpha-synuclein mutations and multiplications have been found to cause monogenic forms of the disease, thus raising the question as to whether this protein is pathogenic in this disorder. Findings showing that the majority of alpha-synuclein aggregates in PD are located at presynapses and this underlies the onset of synaptic and axonal degeneration, coupled to the fact that functional connectivity changes correlate with disease progression, strengthen this idea. Indeed, by altering the proper action of key molecules involved in the control of neurotransmitter release and re-cycling as well as synaptic and structural plasticity, alpha-synuclein deposition may crucially impair axonal trafficking, resulting in a series of noxious events, whose pressure may inevitably degenerate into neuronal damage and death. Here, we provide a timely overview of the molecular features of synaptic loss in PD and disclose their possible translation into clinical symptoms through functional disconnection. PMID- 26613568 TI - Binding Free Energy Calculations of Nine FDA-approved Protease Inhibitors Against HIV-1 Subtype C I36T?T Containing 100 Amino Acids Per Monomer. AB - In this work, have investigated the binding affinities of nine FDA-approved protease inhibitor drugs against a new HIV-1 subtype C mutated protease, I36T?T. Without an X-ray crystal structure, homology modelling was used to generate a three-dimensional model of the protease. This and the inhibitor models were employed to generate the inhibitor/I36T?T complexes, with the relative positions of the inhibitors being superimposed and aligned using the X-ray crystal structures of the inhibitors/HIV-1 subtype B complexes as a reference. Molecular dynamics simulations were carried out on the complexes to calculate the average binding free energies for each inhibitor using the molecular mechanics generalized Born surface area (MM-GBSA) method. When compared to the binding free energies of the HIV-1 subtype B and subtype C proteases (calculated previously by our group using the same method), it was clear that the I36T?T proteases mutations and insertion had a significant negative effect on the binding energies of the non-pepditic inhibitors nelfinavir, darunavir and tipranavir. On the other hand, ritonavir, amprenavir and indinavir show improved calculated binding energies in comparison with the corresponding data for wild-type C-SA protease. The computational model used in this study can be used to investigate new mutations of the HIV protease and help in establishing effective HIV drug regimes and may also aid in future protease drug design. PMID- 26613569 TI - Chemical RNA Editing for Genetic Restoration: The Relationship between the Structure and Deamination Efficiency of Carboxyvinyldeoxyuridine Oligodeoxynucleotides. AB - Oligodeoxynucleotides containing 5-carboxyvinyl-2'-deoxyuridine ((CV) U containing ODNs) for successful site-specific transition of cytosine to uridine by photo-cross-linking have three parts: the complementary sequence, hairpin loop and the 5'-terminal photoresponsive nucleobase (CV) U. Photo-cross-linking with (CV) U-containing ODNs was performed using UV (366 nm) irradiation, followed by heat treatment for deamination. The cross-linked nucleotide was cleaved by photosplitting (UV, 312 nm). The products were analyzed using restriction fragment length polymorphism and fluorescence measurements. In previous studies, we have successfully performed site-directed photochemical base substitution toward a synthetic single-stranded 100-mer ODN target (ss100-nt) and in vitro synthesized full-length blue fluorescent protein mRNA as targets. Although the efficiency of C-to-U site-specific transition strongly depends on the sequence and structure of (CV) U-containing ODNs, the relationship between (CV) U containing ODNs and the deamination efficiency of targeted editing remains unclear. Therefore, in this study, we attempted to identify the optimal sequence and primary structure of (CV) U-containing ODNs for site-directed specific transition. To evaluate the structure-deamination efficiency relationship, a series of eight (CV) U-containing ODNs were designed and studied. We showed that the optimal deamination efficiency was achieved with ODNs having a complementary sequence length slightly more than 14 nt and a hairpin length of 9 nt. PMID- 26613570 TI - Using Fish Sauce as a Substitute for Sodium Chloride in Culinary Sauces and Effects on Sensory Properties. AB - Historically, fish sauce has been a standard condiment and ingredient in various Southeast Asian cuisines. Moreover, fish sauce imparts umami taste, which may enhance perceived saltiness in food. This quality suggests that fish sauce may be used as a partial substitute for sodium chloride (NaCl) in food preparation, which may present a valuable option for health-conscious and salt-restricted consumers. However, the degree to which NaCl can be decreased in food products without compromising taste and consumer acceptance has not been determined. We hypothesized that NaCl content in food may be reduced by partial replacement with fish sauce without diminishing palatability and consumer acceptance. Preparations of 3 types of food were assessed to test this hypothesis: chicken broth (n = 72); tomato sauce (n = 73); and coconut curry (n = 70). In the first session, the percentage of NaCl that could be replaced with fish sauce without a significant change in overall taste intensity was determined for each type of food using the 2-Alternative Forced Choice method. In the second session, subjects rated 5 samples for each food with varying NaCl and/or fish sauce content on 3 sensory attributes: deliciousness; taste intensity; and saltiness. Our results demonstrate that NaCl reduction was possible in chicken broth, tomato sauce, and coconut curry at 25%, 16%, and 10%, respectively, without a significant loss (P < 0.05) in deliciousness and overall taste intensity. These results suggest that it is possible to replace NaCl in foods with fish sauce without reducing overall taste intensity and consumer acceptance. PMID- 26613571 TI - Preactivated silicone oil as potential long-term vitreous replacement with nonemulsifying properties. AB - AIM: Assessment of preactivated and thiolated silicone oils as potential long term vitreous replacement. METHODS: Thioglycolic acid (TGA) and 3 mercaptopropionic acid (MPA) were covalently coupled to amino-modified silicone oil and subsequently preactivated with 2-mercaptonicotinic acid (2-MNA). Each silicone thiomer was evaluated in view of oxidation, reductive reliquefaction, emulsification, and cytotoxicity. RESULTS: Both thiol ligands were coupled in almost quantitative yield to the silicone oils' backbone with a total amount of thiol groups of 223 +/- 25 and 219 +/- 11 umol/g for silicone-TGA and silicone MPA, respectively. A following preactivation with 2-MNA of around 50% of all thiol groups could be achieved. Preactivated silicones showed a protection against oxidation as the viscosity of silicone-TGA and silicone-MPA after iodine treatment were two- and fourfold higher than the preactivated counterparts, respectively. The percentage of emulsification was below 8% for both preactivated silicones in comparison to control with 100% emulsification. Silicone-TGA-MNA and silicone-MPA-MNA could be aspired via a 20 G needle within 35 s and showed a reversible sol-gel transition. CONCLUSION: Preactivated silicone oils tackle the shortcomings of currently available silicone oils as they unite suitable handling qualities with a resistance against emulsification, which renders them promising for long-term vitreous replacement. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2015. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 551-559, 2017. PMID- 26613572 TI - Cost effectiveness of a systematic guidelines-based approach to the prevention and management of vascular disease in a primary care setting. AB - BACKGROUND: In Ontario, Canada, the Comprehensive Vascular Disease Prevention and Management Initiative (CVDPMI) was undertaken to improve the vascular health in communities. The CVDPMI significantly improved cardiovascular (CV) risk factor profiles from baseline to follow-up visits including the 10 year Framingham Risk Score (FRS). Although the CVDPMI improved CV risk, the economic value of this program had not been evaluated. METHODS: We examined the cost effectiveness of the CVDPMI program compared to no CVDPMI program in adult patients identified at risk for an initial or subsequent vascular event in a primary care setting. A one year and a ten year cost effectiveness analyses were conducted. To determine the uncertainty around the cost per life year gained ratio, a non-parametric bootstrap analysis was conducted. RESULTS: The overall population base case analysis at one year resulted in a cost per CV event avoided of $70,423. FRS subgroup analyses showed the high risk cohort (FRS >20%) had an incremental cost effectiveness ratio (ICER) that was dominant. In the moderate risk subgroup (FRS 10%-20%) the ICER was $47,439 per CV event avoided and the low risk subgroup (FRS <10%) showed a highly cost ineffective result of greater than $5 million per CV event avoided. The ten year analysis resulted in a dominant ICER. CONCLUSIONS: At one year, the CVDPMI program is economically acceptable for patients at moderate to high risk for CV events. The CVDPMI results in increased life expectancy at an incremental cost saving to the healthcare system over a ten year period. PMID- 26613573 TI - Bioinspired multi-block molecules. AB - Multiblock motifs occur in proteins such as silk, elastin and ion channels. These motifs are advantageous to develop the characteristic mechanical properties through the formation of segregated intermolecular assemblies, and utilized to construct cylindrical channels in a membrane by folding and assembly with intra- or intermolecular interactions. As nature shows such elegant examples of multiblock molecules exerting sophisticated functions, synthetic multiblock molecules and copolymers have gained increasing attention as emerging structural motifs for realizing unique properties and functions. Recent notable examples of synthetic multiblock molecules and copolymers are highlighted, where linear molecules not only undergo folding elaborately but also form controlled and compartmentalized self-assemblies to realize characteristic functions in solution, the crystalline state, and membranous media. PMID- 26613575 TI - False Alarms, Pseudoepidemics, and Reality: A Case Study with American College of Obstetricians and Gynecologists Practice Bulletins (Podcast). PMID- 26613574 TI - Purple carrot anthocyanins suppress lipopolysaccharide-induced inflammation in the co-culture of intestinal Caco-2 and macrophage RAW264.7 cells. AB - This study was designed to evaluate the anti-inflammatory effects of purple carrot anthocyanins (PCA) with respect to gut inflammation, simulated in a co culture system consisting of intestinal epithelial Caco-2 cells and RAW264.7 macrophages. The obtained results indicated that PCA extract down-regulates the mRNA expression of proinflammatory interleukins Il-1beta (?91%) and Il-6 (?69%) as well as inflammatory mediators, such as cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (iNos), in lipopolysaccharide-activated RAW264.7 cells. The decrease in the generation of prostaglandin E2 (?48%) and nitric oxide (?26%) was observed as a result of the inhibition of Cox-2 (?25%) and iNos (?12%) mRNA expressions, respectively. Moreover, the PCA reduced mRNA expression (?40%) and production (?17%) of IL-8 in intestinal cells. The anti-inflammatory effect of PCA was contributed to the protection of the intestinal barrier, which was disrupted upon the stimulation of macrophages. These findings may provide preliminary justification for the use of PCA in further studies focused on the prevention and therapy supporting the conventional treatment of inflammatory bowel diseases. PMID- 26613576 TI - Prevention and Treatment of Life-Threatening Bleeding After Thyroid Surgery. AB - BACKGROUND Few reports have discussed life- threatening bleeding that occurs postoperatively in patients who have undergone thyroid surgery. In this article, we discuss the causes, treatment measures, and possible ways of preventing this severe complication. MATERIAL AND METHODS From Jan 2002 to Dec 2014 we retrospectively analyzed 7 patients who developed life-threatening bleeding after undergoing thyroid surgery at our center. RESULTS Among the group of 7 patients, there was 1 case of superior thyroid artery hemorrhage (STAH), 5 cases of carotid blowout syndrome (CBS), and 1 case of tracheo-innominate fistula (TIF). The STAH was caused by unreliable ligation. All the cases of CBS and TIF were caused by surgical wound infection. Six patients were transferred to the operating room immediately; open surgical treatment was performed on these 6 patients. Out of these 6 patients, 1 patient did not survive the operation, and hemorrhage was successfully controlled in 3 patients. The remaining 2 patients again experienced bleeding even after undergoing open surgery. Only 1 patient developed long-term neurological complications. CONCLUSIONS Infection is the most common cause of life-threatening bleeding that occurs postoperatively in some patients who have undergone thyroid surgery. Early surgical intervention can save the lives of these patients without causing any severe neurological complications. PMID- 26613577 TI - Silencing Matrix Metalloproteinases 9 and 2 Inhibits Human Retinal Microvascular Endothelial Cell Invasion and Migration. AB - PURPOSE: Proliferative retinal angiogenesis may severely impair the retina. Previous studies have indicated that matrix metalloproteinase (MMP)-2 and MMP-9 play important roles in the process of retinal angiogenesis. In this study, we suppressed MMP-2 and MMP-9 expression with RNA interference (RNAi) and then observed the inhibitory effects on the invasion and migration of human retinal microvascular endothelial cells (HRMECs). METHODS: Small interfering RNAs against MMP-2 mRNA and MMP-9 mRNA were synthesized. After transfection, the MMP-2 and MMP 9 expression in HRMECs was examined by real-time polymerase chain reaction and Western blot analysis. Cell migration and invasion were measured with a migration assay and a scratch wound assay, respectively. RESULTS: RNAi against MMP-2 and MMP-9 successfully inhibited the mRNA and protein expression of MMP-2 and MMP-9 in HRMECs. MMP-2 and MMP-9 knockdown could inhibit the invasion and migration of HRMECs. CONCLUSIONS: These findings suggest that the RNAi approach towards MMP-2 and MMP-9 may be a potentially effective therapeutic method for the treatment of proliferative retinal angiogenesis. PMID- 26613578 TI - TGFbeta-Induced Actin Cytoskeleton Rearrangement in Podocytes Is Associated with Compensatory Adaptation of Mitochondrial Energy Metabolism. AB - BACKGROUND/AIMS: In podocytes, the overexpression of TGFbeta ligands and receptors during glomerulosclerosis could be a causal factor for injury induction and perpetuation in glomerular tufts. Mitochondrial dysfunction and oxidative stress are emerging as potential therapeutic targets in glomerular injury, and TGFbeta has been shown to modulate mitochondrial metabolism in different cell types. This study aims at investigating the role of TGFbeta in podocyte energy metabolism and cytoskeleton dynamics. METHODS: Mitochondrial function and cytoskeleton dynamics were analyzed in TGFbeta-treated WT and Smad2/3 double KO podocytes. RESULTS: TGFbeta treatment in podocytes induced a significant Smad dependent increase of mitochondrial oxygen consumption rate (OCR). ATP content was unchanged and increased respiration was not associated with increased mitochondrial mass. Increased cellular reactive oxygen species induced by Smad mediated TGFbeta signaling were reverted by NADPH oxidase inhibitor apocynin. TGFbeta treatment did not induce mitochondrial oxidative stress, and Smad2/3 dependent TGFbeta signaling and increased mitochondrial OCR were found to be associated with actin cytoskeleton dynamics. The role of motor proteins myosin II and dynamin in TGFbeta-induced actin polymerization was demonstrated by specific inhibition, resulting in actin stabilization and normalization of mitochondrial OCR. CONCLUSION: TGFbeta-induced rearrangements of actin cytoskeleton are controlled by Smad2/3 signaling pathways and coupled with the activation of mitochondrial ATP synthesis as bioenergetic adaptation to ATP consumption by ATP- and GTP-dependent motor proteins, myosin II and dynamin. PMID- 26613579 TI - The Reliability and Concurrent Validity of a Modified Version of the International Physical Activity Questionnaire for Adolescents (IPAQ-A) in Tunisian Overweight and Obese Youths. AB - OBJECTIVE: The aim of the present study was to assess the reliability and validity of an Arabic version of the International Physical Activity Questionnaire for Adolescents (IPAQ-A) modified for use in Tunisia among overweight and obese adolescents. SUBJECTS AND METHODS: Fifty-one voluntary healthy, overweight or obese adolescents (15-18 years old) participated in the study. Physical activity (PA) indicators derived from the modified self administered IPAQ-A were compared with pedometer-recorded data of step counts. The test-retest reliability of the IPAQ-A was evaluated using intraclass correlation coefficients (ICC) and Kappa tests between the response of participants in the two interviews. Validity was assessed using Spearman's rank correlation coefficient between the scores of the IPAQ-A and the step count pedometer. RESULTS: ICC revealed that the reliability of IPAQ-A values was high and ranged from 0.73 to 0.95. IPAQ-A scores were also significantly related to pedometer step counts (r = 0.66, p < 0.001). Strong relationships were observed between pedometer step count data and the IPAQ-A data for vigorous PA (r = 0.57, p < 0.001) and walking (r = 0.61, p < 0.001). However, a weaker relationship for moderate PA was observed (r = 0.24, p < 0.05). CONCLUSIONS: The modified version of the IPAQ-A questionnaire demonstrated an acceptable reliability and validity when used to assess the levels and patterns of PA in overweight or obese Tunisian adolescents. PMID- 26613580 TI - Severity of Fetal Brain Abnormalities in Congenital Heart Disease in Relation to the Main Expected Pattern of in utero Brain Blood Supply. AB - OBJECTIVES: We evaluated the hypothesis that in fetuses with congenital heart disease (CHD) there is a correlation between the expected pattern of in utero brain blood supply and the severity of neurodevelopmental impairment. METHODS: A total of 58 fetuses with CHD and 58 controls underwent a Doppler ultrasound and fetal MRI at 36-38 weeks. Fetuses with CHD were divided into two functional classes: class A with an expected severe reduction in oxygenated brain blood supply (left outflow tract obstruction and transposition of great vessels) and class B with theoretically near-normal or mildly impaired oxygenated brain blood supply (other CHD). Head biometry and cerebroplacental Doppler were assessed by ultrasound, and brain volumetry, cortical development and metabolism by MRI. RESULTS: Both class A and B CHD fetuses had significant differences in head biometry, brain perfusion, cortical development and brain metabolism compared with controls. However, there was a significant linear tendency for head biometry, cerebral Doppler, volumes, cortical sulcation and metabolic ratios across the three clinical groups, with signs of more severe brain alterations in type A CHD fetuses. CONCLUSIONS: All fetuses with CHD showed significant brain developmental changes, but differences were more pronounced in CHD associated with an expected severe reduction in oxygenated blood supply to the brain. PMID- 26613582 TI - 11th International Congress on Coronary Artery Disease (ICCAD), Florence, Italy November 29 - December 2, 2015: Abstracts. PMID- 26613583 TI - Effect of Canavalia gladiata Extract Fermented with Aspergillus oryzae on the Development of Atopic Dermatitis in NC/Nga Mice. AB - Canavalia gladiata has been used as a Chinese traditional folk medicine for its anti-inflammatory properties. However, the use of C. gladiata is limited because it contains antinutritional and allergy-causing proteins. We fermented C. gladiata with Aspergillus oryzae and investigated the effects of fermented C. gladiata (FCG) on the development of atopic dermatitis (AD) in mice. The mice were divided into five groups: untreated Balb/c mice; AD control (NC/Nga mice); FCGH (NC/Nga mice fed a dietary supplement of 300 mg/kg fermented C. gladiata water extract); FCG30 (NC/Nga mice fed a dietary supplement of 300 mg/kg of fermented C. gladiata 30% ethanol extract), and FCG80 (NC/Nga mice fed a dietary supplement of 300 mg/kg of fermented C. gladiata 80% ethanol extract). We found increases in the nonessential amino acids and essential amino acid in the FCG compared with the non-FCG. FCG attenuated macroscopic and histopathological changes in dorsal skin of mice when compared with the AD control group. The FCG30 and FCG80 groups, in particular, showed significant decreases in scratching episodes when compared with the AD control group. FCG improved immune responses, including increases in IgE and histamine for AD, through attenuation of Th1/Th2 cytokine imbalance and the production of proinflammatory cytokines and chemokines. We suggest that FCG may have benefits for improvement of AD function by improving the balance of Th1/Th2 cytokines and by producing anti-inflammatory effects. PMID- 26613584 TI - Left Subclavian Artery Revascularization in Preparation for Coronary Artery Bypass Grafting. AB - Coronary subclavian steal syndrome is a rare but important condition that occurs after a left internal mammary artery (LIMA) to coronary artery bypass in the setting of a stenotic left subclavian artery. The lack of blood flow through the subclavian artery causes the reversal of flow in the LIMA so that it essentially steals blood from the myocardium. In order to avoid this complication, many surgeons now opt to either revascularize the stenotic subclavian artery prior to coronary artery bypass grafting or to use an alternate vessel as the bypass graft. Here, we present the case of an asymptomatic patient with poor exercise tolerance who was recently diagnosed with both triple-vessel coronary disease and peripheral arterial disease, which was most notably characterized by occlusion of the left subclavian artery. This case demonstrates the surgical management of this complex clinical entity. PMID- 26613581 TI - The Genetic and Environmental Factors Underlying Hypospadias. AB - Hypospadias results from a failure of urethral closure in the male phallus and affects 1 in 200-300 boys. It is thought to be due to a combination of genetic and environmental factors. The development of the penis progresses in 2 stages: an initial hormone-independent phase and a secondary hormone-dependent phase. Here, we review the molecular pathways that contribute to each of these stages, drawing on studies from both human and mouse models. Hypospadias can occur when normal development of the phallus is disrupted, and we provide evidence that mutations in genes underlying this developmental process are causative. Finally, we discuss the environmental factors that may contribute to hypospadias and their potential immediate and transgenerational epigenetic impacts. PMID- 26613586 TI - Analysis of Pediatric Pancreatitis (APPLE Trial): Pre-Study Protocol of a Multinational Prospective Clinical Trial. AB - BACKGROUND: Single-centered studies show increased number of acute pancreatitis (AP) in children. Here, the Pediatric Section of the Hungarian Pancreatic Study Group introduces an international observational clinical trial (APPLE) to collect a critical mass of clinical data and biomedical research samples in a uniform prospective manner. SUMMARY: The APPLE-R is for patients under 18 years of age with a history of pancreatitis. The study primarily provides information on possible genetic variants behind the disease and their impact on the prognosis. The APPLE-P is for patients under 18 years of age with a diagnosis of AP. Children with AP diagnosed based on the fulfillment of '2 out of 3' of the Atlanta criteria will be selected. This subtrial requests detailed information from the medical history, etiology, complains and symptoms, physical examinations, laboratory parameters, imaging, immediate therapy at admission and complications of the disease. The APPLE trial has been registered at the ISRCTN registry and has received the relevant ethical approval. The study is open for all pediatric centers throughout the world. KEY MESSAGE: This is the first worldwide study tracking earlier (APPLE-R) and ongoing episodes (APPLE-P) of pancreatitis. PMID- 26613585 TI - Gingipains: Critical Factors in the Development of Aspiration Pneumonia Caused by Porphyromonas gingivalis. AB - Aspiration pneumonia is a life-threatening infectious disease often caused by oral anaerobic and periodontal pathogens such as Porphyromonas gingivalis. This organism produces proteolytic enzymes, known as gingipains, which manipulate innate immune responses and promote chronic inflammation. Here, we challenged mice with P. gingivalis W83 and examined the role of gingipains in bronchopneumonia, lung abscess formation, and inflammatory responses. Although gingipains were not required for P. gingivalis colonization and survival in the lungs, they were essential for manifestation of clinical symptoms and infection related mortality. Pathologies caused by wild-type (WT) P. gingivalis W83, including hemorrhage, necrosis, and neutrophil infiltration, were absent from lungs infected with gingipain-null isogenic strains or WT bacteria preincubated with gingipain-specific inhibitors. Damage to lung tissue correlated with systemic inflammatory responses, as manifested by elevated levels of TNF, IL-6, IL-17, and C-reactive protein. These effects were unequivocally dependent on gingipain activity. Gingipain activity was also implicated in the observed increase in IL-17 in lung tissues. Furthermore, gingipains increased platelet counts in the blood and activated platelets in the lungs. Arginine-specific gingipains made a greater contribution to P. gingivalis-related morbidity and mortality than lysine-specific gingipains. Thus, inhibition of gingipain may be a useful adjunct treatment for P. gingivalis-mediated aspiration pneumonia. PMID- 26613587 TI - The Conditions Favoring Between-Community Raiding in Chimpanzees, Bonobos, and Human Foragers. AB - Chimpanzees, bonobos, and human foragers share a fission-fusion social system and a mating system of joint male resource defense polygyny. Within-community skew in male strength varies among and within species. In this study, we extend a mathematical model of within-group male coalition formation among primates to derive the conditions for between-community conflicts in the form of raids. We show that the main factor affecting the presence of successful raiding is the likelihood of major discrepancies in party strength, which are set by party size distributions (and thus community size) and the skew in strength. This study confirms the functional similarities between the raiding of chimpanzees and human foragers, and it supports the "imbalance of power" hypothesis for raiding. However, it also proposes two amendments to this model. First, the absence of raiding in bonobos may be attributable more to potential female involvement in defense against raids, which increases the size of defensive coalitions. Second, the model attributes some of the raiding in humans to major contrasts in instantaneous fighting ability created by surprise raids on unarmed victims; it also draws attention to the distinction between minor raids and major raids that involve multiple bands of the same community. PMID- 26613588 TI - Caloric Intake on the Sabbath: A Pilot Study of Contributing Factors to Obesity in the Orthodox Jewish Community. AB - The American Orthodox Jewish community has specific cultural factors that may contribute to overweight and obesity. This study aimed to look at caloric intake on the Sabbath and its contribution to overweight and obesity. Twelve married or previously married women who identify themselves as Orthodox Jews were recruited to do 24-h food recalls over the phone. The participants were divided into three weight groups (normal, overweight, and obese) based on their BMI. The overweight and obese participants' data were combined into one group for the purposes of statistical testing. Paired t tests looking at the data for all participants showed significantly great caloric intake during an average Sabbath day than an average weekday [t(4) = 7.58, p < 0.001]. A repeated-measures ANOVA showed significantly greater energy intake on the Sabbath for the overweight-obese women compared to the normal weight women [F(1) = 7.83, p = 0.02]. No statistical difference was seen between the weekday energy intake of the normal weight women as compared to the combined group of overweight-obese women [F(1) = 0.501, p = 0.499]. These results support the hypotheses that all groups eat significantly more on the Sabbath than on weekdays, and overweight and obese individuals eat significantly more on the Sabbath than normal weight individuals. This supports the theory that caloric intake on the Sabbath is a contributing factor to overweight and obesity within the American Orthodox Jewish community. PMID- 26613589 TI - Predictors of Physician Recommendation for Ethically Controversial Medical Procedures: Findings from an Exploratory National Survey of American Muslim Physicians. AB - Physician religiosity can influence their ethical attitude toward medical procedures and can thereby impact healthcare delivery. Using a national survey of American Muslim physicians, we explored the association between physician recommendation of three controversial medical procedures--tubal ligation, abortion, and porcine-based vaccine--and their (1) religiosity, (2) utilization of bioethics resources, and (3) perception of whether the procedure was a medical necessity and if the scenario represented a life threat. Generally, multivariate models found that physicians who read the Qur'an more often as well as those who perceived medical necessity and/or life threat had a higher odds recommending the procedures, whereas those who sought Islamic bioethical guidance from Islamic jurists (or juridical councils) more often had a lower odds. These associations suggest that the bioethical framework of Muslim physicians is influenced by their reading of scripture, and the opinions of Islamic jurists and that these influences may, paradoxically, be interpreted to be in opposition over some medical procedures. PMID- 26613590 TI - Mortality of populations potentially exposed to ionising radiation, 1953-2010, in the closed city of Ozyorsk, Southern Urals: a descriptive study. AB - BACKGROUND: The city of Ozyorsk (Southern Urals) was created as a secret city in 1945 and is a closed city until today. It housed workers of the earliest and one of the country's largest nuclear facilities. Workers of the nuclear reactors, radiochemical or reprocessing plants were exposed to high levels of ionising radiation in the early years of operation and possibly further exposed from inhalation of plutonium aerosols. METHODS: The cause-of-death registry of Ozyorsk received paper copies of original death certificates of all deaths of residents of the city. Data were analysed for recent mortality rates (1998-2010) and time trends in age-standardised mortality rates between 1953 and 2010 of main groups of causes of deaths, in particular cancer. RESULTS: Comparing workers of the three main plant types with the remainder of the Ozyorsk residents, and with national figures, all-cause mortality rates were lowest among workers, with ratios compared to national figures of 0.65 (men) and 0.56 (women), and compared to the other residents of 0.77 (men) and of 0.74 (women). For cancer overall, the differences were smaller in men (ratio between workers and national figures of 0.86) and there were no differences in women (ratio of 1.00), but ratios differed by cancer type. Most cancer deaths were however least common in the workers, including leukaemia. Over the last 60 years, all-cause mortality has gradually increased among men in all three groups but was stable among women, whereas cancer death rates have slightly declined in both sexes. CONCLUSIONS: Healthy worker effect, relatively better living conditions in Ozyorsk and healthier lifestyles may explain the lower mortality rates in Ozyorsk. Overall mortality time trends in Ozyorsk were similar to the entire country. No apparent radiation related effects were seen in this population-level analysis, but the radiation related risks can be better addressed in individual-level studies. PMID- 26613591 TI - Coronary microvascular function, insulin sensitivity and body composition in predicting exercise capacity in overweight patients with coronary artery disease. AB - BACKGROUND: Coronary artery disease (CAD) has a negative impact on exercise capacity. The aim of this study was to determine how coronary microvascular function, glucose metabolism and body composition contribute to exercise capacity in overweight patients with CAD and without diabetes. METHODS: Sixty-five non diabetic, overweight patients with stable CAD, BMI 28-40 kg/m(2) and left ventricular ejection fraction (LVEF) above 35 % were recruited. A 3-hour oral glucose tolerance test was used to evaluate glucose metabolism. Peak aerobic exercise capacity (VO2peak) was assessed by a cardiopulmonary exercise test. Body composition was determined by whole body dual-energy X-ray absorptiometry scan and magnetic resonance imaging. Coronary flow reserve (CFR) assessed by transthoracic Doppler echocardiography was used as a measure of microvascular function. RESULTS: Median BMI was 31.3 and 72 % had impaired glucose tolerance or impaired fasting glucose. VO2peak adjusted for fat free mass was correlated with CFR (r = 0.41, p = 0.0007), LVEF (r = 0.33, p = 0.008) and left ventricular end diastolic volume (EDV) (r = 0.32, p = 0.01) while it was only weakly linked to measures of glucose metabolism and body composition. CFR, EDV and LVEF remained independent predictors of VO2peak in multivariable regression analysis. CONCLUSION: The study established CFR, EDV and LVEF as independent predictors of VO2peak in overweight CAD patients with no or only mild functional symptoms and a LVEF > 35 %. Glucose metabolism and body composition had minor impact on VO2peak. The findings suggest that central hemodynamic factors are important in limiting exercise capacity in overweight non-diabetic CAD patients. PMID- 26613592 TI - Patterns of nicotine dependence in four Eastern European countries. AB - BACKGROUND: Evidence of patterns of nicotine dependence, although crucial for developing and implementing effective tobacco control strategies, is limited in the Eastern European countries. The purpose of this study was to evaluate the correlates of high nicotine dependence among adults in Poland, Romania, the Russian Federation and Ukraine. METHODS: The data used in the current analysis is available from the Global Adult Tobacco Survey (2009-2011). Nicotine dependence was assessed using the Heaviness of Smoking Index (HSI), which covers two measures: reported cigarettes smoked per day and time to the first cigarette upon waking. Based on a six-point scale of HSI, nicotine dependence was categorized into low to moderate (score 0-3), and high dependence (score 4-6). Out of 31,936 completed interviews, we used data from 8229 daily smokers. RESULTS: The study results indicate that more than 25 % of daily smokers were highly dependent on nicotine. Higher odds of high nicotine dependence were identified for males (OR = 1.5 in Poland and Romania, OR = 2.7 in Russia; p <= 0.001), people between 50-59 years of age (the highest odds in Romania; OR = 4.8; p <= 0.001) and those who had started smoking at a young age (the highest odds in Romania, OR = 5.0; p <= 0.001). Having fewer restrictions on smoking at home was significantly associated with a high level of nicotine dependence (the highest odds in Romania, OR = 3.0; p <= 0.001). A high proportion of the participants had no interest in quitting smoking, with a statistically significantly higher percentage observed among smokers highly dependent on nicotine compared to the less addicted (p <= 0.01). CONCLUSIONS: Smokers highly dependent on nicotine constitute a quarter of the Romanian group of daily smokers and even more in the remaining three analyzed countries. Similar patterns of nicotine dependence were observed in all of the investigated countries showing that male gender, younger age at the smoking onset, and fewer restrictions on smoking at home were significantly associated with higher nicotine dependence. The study highlighted the fact that a high proportion of the participants had no interest in quitting smoking. These results underscore importance of policy measures as well as prevention and cessation interventions for smokers who are highly dependent on nicotine, which need to take into account the social gradient in smoking patterns. PMID- 26613593 TI - How chimpanzees (Pan troglodytes) perform in a modified emotional Stroop task. AB - The emotional Stroop task is an experimental paradigm developed to study the relationship between emotion and cognition. Human participants required to identify the color of words typically respond more slowly to negative than to neutral words (emotional Stroop effect). Here we investigated whether chimpanzees (Pan troglodytes) would show a comparable effect. Using a touch screen, eight chimpanzees were trained to choose between two simultaneously presented stimuli based on color (two identical images with differently colored frames). In Experiment 1, the images within the color frames were shapes that were either of the same color as the surrounding frame or of the alternative color. Subjects made fewer errors and responded faster when shapes were of the same color as the frame surrounding them than when they were not, evidencing that embedded images affected target selection. Experiment 2, a modified version of the emotional Stroop task, presented subjects with four different categories of novel images: three categories of pictures of humans (veterinarian, caretaker, and stranger), and control stimuli showing a white square. Because visits by the veterinarian that include anaesthetization can be stressful for subjects, we expected impaired performance in trials presenting images of the veterinarian. For the first session, we found correct responses to be indeed slower in trials of this category. This effect was more pronounced for subjects whose last anaesthetization experience was more recent, indicating that emotional valence caused the slowdown. We propose our modified emotional Stroop task as a simple method to explore which emotional stimuli affect cognitive performance in nonhuman primates. PMID- 26613594 TI - [How many patient transfer rooms are necessary for my OR suite? : Effect of the number of OR transfer rooms on waiting times and patient throughput in the OR - analysis by simulation]. AB - INTRODUCTION: In most hospitals the operating rooms (OR) are separated from the rest of the hospital by transfer rooms where patients have to pass through for reasons of hygiene. In the OR transfer room patients are placed on the OR table before surgery and returned to the hospital bed after surgery. It could happen that the number of patients who need to pass through a transfer room at a certain point in time exceed the number of available transfer rooms. As a result the transfer rooms become a bottleneck where patients have to wait and which, in turn, may lead to delays in the OR suite. In this study the ability of a discrete event simulation to analyze the effect of the duration of surgery and the number of ORs on the number of OR transfer rooms needed was investigated. METHODS: This study was based on a discrete event simulation model developed with the simulation software AnyLogic(r). The model studied the effects of the number of OR transfer rooms on the processes in an OR suite of a community hospital by varying the number of ORs from one to eight and using different surgical portfolios. Probability distributions for the process duration of induction, surgery and recovery and transfer room processes were calculated on the basis of real data from the community hospital studied. Furthermore, using a generic simulation model the effect of the average duration of surgery on the number of OR transfer rooms needed was examined. RESULTS: The discrete event simulation model enabled the analysis of both quantitative as well as qualitative changes in the OR process and setting. Key performance indicators of the simulation model were patient throughput per day, the probability of waiting and duration of waiting time in front of OR transfer rooms. In the case of a community hospital with 1 transfer room the average proportion of patients waiting before entering the OR was 17.9 % +/- 9.7 % with 3 ORs, 37.6 % +/- 9.7 % with 5 ORs and 62.9 % +/ 9.1 % with 8 ORs. The average waiting time of patients in the setting with 3 ORs was 3.1 +/- 2.7 min, with 5 ORs 5.0 +/- 5.8 min and with 8 ORs 11.5 +/- 12.5 min. Based on this study the community hospital needs a second transfer room starting from 4 ORs so that there is no bottleneck for the subsequent OR processes. The average patient throughput in a setting with 4 ORs increased significantly by 0.3 patients per day when a second transfer room is available. The generic model showed a strong effect of the average duration of surgery on the number of transfer rooms needed. CONCLUSION: There was no linear correlation between the number of transfer rooms and the number of ORs. The shorter the average duration of surgery, the earlier an additional transfer room is required. Thus, hospitals with shorter duration of surgery and fewer ORs may need the same or more transfer rooms than a hospital with longer duration of surgery and more ORs. However, with respect to an economic analysis, the costs and benefits of installing additional OR transfer rooms need to be calculated using the profit margins of the specific hospital. PMID- 26613595 TI - An HLA-C amino-acid variant in addition to HLA-B*27 confers risk for ankylosing spondylitis in the Korean population. AB - INTRODUCTION: The presence of the HLA-B*27 allele is a major risk factor for the development of ankylosing spondylitis (AS), which causes chronic inflammation of the spine and other sites. We investigated residual effects outside HLA-B within the major histocompatibility complex (MHC) region in the Korean population. METHODS: Using the Korean HLA reference panel, we inferred the classic HLA alleles and amino-acid residues of the six HLA genes (HLA-A, -B, -C, -DPB1, DQB1, and -DRB1) and MHC single-nucleotide polymorphisms in 3820 Korean subjects, including 654 Korean cases of AS and 3166 controls, who were genotyped by using Immunochip. Logistic regression and log-likelihood ratio tests were used in AS association tests for imputed markers. RESULTS: The most significant associations were identified at amino-acid positions in the epitope-binding site of HLA-B (P = 1.71 * 10(-481) at position 70, P = 7.20 * 10(-479) at position 97, and P = 2.54 * 10(-484) at positions 114), highlighting the risk effect of the HLA-B*27 allele and the protective effects of other classic alleles. A secondary effect was located at the leucine at amino-acid position 116 in the epitope-binding site of HLA-C (P = 1.69 * 10(-14)), completely tagging the HLA-C*15:02 allele. This residue had a large effect in HLA-B*27-negative patients (odds ratio = 6.6, 95 % confidence interval = 3.8 to 11.4). CONCLUSIONS: The four amino-acid positions of HLA-B and -C account for most of the associations between AS and MHC in the Korean population. This finding updates the list of AS susceptibility loci and provides new insight into AS pathogenesis mediated by MHC class I molecules. PMID- 26613596 TI - The Debate on the Moral Responsibilities of Online Service Providers. AB - Online service providers (OSPs)-such as AOL, Facebook, Google, Microsoft, and Twitter-significantly shape the informational environment (infosphere) and influence users' experiences and interactions within it. There is a general agreement on the centrality of OSPs in information societies, but little consensus about what principles should shape their moral responsibilities and practices. In this article, we analyse the main contributions to the debate on the moral responsibilities of OSPs. By endorsing the method of the levels of abstract (LoAs), we first analyse the moral responsibilities of OSPs in the web (LoAIN). These concern the management of online information, which includes information filtering, Internet censorship, the circulation of harmful content, and the implementation and fostering of human rights (including privacy). We then consider the moral responsibilities ascribed to OSPs on the web (LoAON) and focus on the existing legal regulation of access to users' data. The overall analysis provides an overview of the current state of the debate and highlights two main results. First, topics related to OSPs' public role-especially their gatekeeping function, their corporate social responsibilities, and their role in implementing and fostering human rights-have acquired increasing relevance in the specialised literature. Second, there is a lack of an ethical framework that can (a) define OSPs' responsibilities, and (b) provide the fundamental sharable principles necessary to guide OSPs' conduct within the multicultural and international context in which they operate. This article contributes to the ethical framework necessary to deal with (a) and (b) by endorsing a LoA enabling the definition of the responsibilities of OSPs with respect to the well-being of the infosphere and of the entities inhabiting it (LoAFor). PMID- 26613597 TI - Basing Science Ethics on Respect for Human Dignity. AB - A "no ethics" principle has long been prevalent in science and has demotivated deliberation on scientific ethics. This paper argues the following: (1) An understanding of a scientific "ethos" based on actual "value preferences" and "value repugnances" prevalent in the scientific community permits and demands critical accounts of the "no ethics" principle in science. (2) The roots of this principle may be traced to a repugnance of human dignity, which was instilled at a historical breaking point in the interrelation between science and ethics. This breaking point involved granting science the exclusive mandate to pass judgment on the life worth living. (3) By contrast, respect for human dignity, in its Kantian definition as "the absolute inner worth of being human," should be adopted as the basis to ground science ethics. (4) The pathway from this foundation to the articulation of an ethical duty specific to scientific practice, i.e., respect for objective truth, is charted by Karl Popper's discussion of the ethical principles that form the basis of science. This also permits an integrated account of the "external" and "internal" ethical problems in science. (5) Principles of the respect for human dignity and the respect for objective truth are also safeguards of epistemic integrity. Plain defiance of human dignity by genetic determinism has compromised integrity of claims to knowledge in behavioral genetics and other behavioral sciences. Disregard of the ethical principles that form the basis of science threatens epistemic integrity. PMID- 26613598 TI - [Age(ing) and ambivalence]. PMID- 26613599 TI - Understanding intentionality in children with attention-deficit/hyperactivity disorder. AB - One of the main aspects of theory of mind is intentionality which refers to recognizing other people's intentions in their behaviors. The aim of this study was to investigate intentionality in children with attention deficit/hyperactivity disorder (ADHD). Thirty children with ADHD were compared to thirty age- and IQ-matched normal children. All participants were assessed using the moving shapes paradigm task which contains one large red and one small blue triangle moving around a black screen. They were asked to describe what the movements mean and how the triangles interact with each other. The answers were rated based on the accuracy, type of descriptions applied, mental states, and length of phrases. With regard to intentionality score, children with ADHD performed significantly worse than normal children (P < .05). Based on appropriateness score, the accuracy of patients' answers was lower in comparison with the control group. Children with ADHD used longer phrases as compared to controls. Children with ADHD can have problems with comprehending others' intentionality. This leads to impairment in social relationship. PMID- 26613600 TI - Towards the development of an oral vaccine against porcine cysticercosis: expression of the protective HP6/TSOL18 antigen in transgenic carrots cells. AB - MAIN CONCLUSION: The Taenia solium HP6/TSOL18 antigen was produced in carrot cells, yielding an immunogenic protein that induced significant protection in an experimental murine model against T. crassiceps cysticercosis when orally administered. This result supports the potential of HP6/TSOL18-carrot as a low cost anti-cysticercosis vaccine candidate. Cysticercosis is a zoonosis caused by Taenia solium that can be prevented by interrupting the parasite life cycle through pig vaccination. Several injectable vaccine candidates have been reported, but the logistic difficulties and costs for its application limited its use in nationwide control programs. Oral plant-based vaccines can deal with this limitation, because of their easy administration and low cost. A stable expression of the HP6/TSOL18 anti-T. solium cysticercosis protective antigen in carrot calli transformed with an optimized transgene is herein reported. An antigen accumulation up to 14 ug g(-1) of dry-weight biomass was achieved in the generated carrot lines. Mouse immunization with one of the transformed calli induced both specific IgG and IgA anti-HP6/TSOL18 antibodies. A statistically significant reduction in the expected number of T. crassiceps cysticerci was observed in mice orally immunized with carrot-made HP6/TSOL18, in a similar extent to that obtained by subcutaneous immunization with recombinant HP6/TSOL18 protein. In this study, a new oral plant-made version of the HP6/TSOL18 anti cysticercosis vaccine is reported. The vaccine candidate should be further tested against porcine cysticercosis. PMID- 26613601 TI - Possible involvement of inflammatory/reparative processes in the development of uterine fibroids. AB - Uterine leiomyomas are benign tumors in the smooth muscle layer of the uterus. The most common histological type is the "usual leiomyoma", characterized by overexpression of ECM proteins, whereas the "cellular type" has higher cellular content. Our objective is to investigate the involvement of inflammatory and reparative processes in leiomyoma pathobiology. Using a morphological approach, we investigate the presence of inflammatory cells. Next, we determine the localization of the ECM, the presence/absence of fibrotic cells via alpha-sma and desmin and the immunohistochemical profile of the mesenchymal cells with respect to CD34. Finally, we explore the effect of inflammatory mediators (TNF-alpha, IL 1beta, IL-6, IL-15, GM-CSF and IFN-gamma) on pro-fibrotic factor activin A mRNA expression in vitro. Higher numbers of macrophages were found inside and close to leiomyomas as compared to the more distant myometrium. Cellular leiomyomas showed more macrophages and mast cells than the "usual type". Inside the fibroid tissue, we found cells positive for alpha-sma, but negative for desmin and a large amount of collagen surrounding the nodule, suggestive of myofibroblasts producing ECM. In the myometrium and leiomyomas of the "usual type", we identified numerous CD34+ fibroblasts, which are known to give rise to myofibroblasts upon loss of CD34 expression. In leiomyomas of the "cellular type", stromal fibroblasts were CD34-negative. Finally, we found that TNF-alpha increased activin A mRNA in myometrial and leiomyoma cells. In conclusion, this study demonstrates the presence of inflammatory cells in uterine leiomyomas, which may contribute to excessive ECM production, tissue remodeling and leiomyoma growth. PMID- 26613602 TI - bFGF signaling-mediated reprogramming of porcine primordial germ cells. AB - Primordial germ cells (PGCs) have the ability to be reprogrammed into embryonic germ cells (EGCs) in vitro and are an alternative source of embryonic stem cells. Other than for the mouse, the systematic characterization of mammalian PGCs is still lacking, especially the process by which PGCs convert to pluripotency. This hampers the understanding of germ cell development and the derivation of authenticated EGCs from other species. We observed the morphological development of the genital ridge from Bama miniature pigs and found primary sexual differentiation in the E28 porcine embryo, coinciding with Blimp1 nuclear exclusion in PGCs. To explore molecular events involved in porcine PGC reprogramming, transcriptome data of porcine EGCs and fetal fibroblasts (FFs) were assembled and 1169 differentially expressed genes were used for Gene Ontology analysis. These genes were significantly enriched in cell-surface receptor-linked signal transduction, in agreement with the activation of LIF/Stat3 signaling and FGF signaling during the derivation of porcine EG-like cells. Using a growth-factor-defined culture system, we explored the effects of bFGF on the process and found that bFGF not only functioned at the very beginning of PGC dedifferentiation by impeding Blimp1 nuclear expression via a PI3K/AKT dependent pathway but also maintained the viability of cultured PGCs thereafter. These results provide further insights into the development of germ cells from livestock and the mechanism of porcine PGC reprogramming. PMID- 26613603 TI - Expression studies of neuronatin in prenatal and postnatal rat pituitary. AB - The pituitary gland, an indispensable endocrine organ that synthesizes and secretes pituitary hormones, develops with the support of many factors. Among them, neuronatin (NNAT), which was discovered in the neonatal mouse brain as a factor involved in neural development, has subsequently been revealed to be coded by an abundantly expressing gene in the pituitary gland but its role remains elusive. We analyze the expression profile of Nnat and the localization of its product during rat pituitary development. The level of Nnat expression was high during the embryonic period but remarkably decreased after birth. Immunohistochemistry demonstrated that NNAT appeared in the SOX2-positive stem/progenitor cells in the developing pituitary primordium on rat embryonic day 11.5 (E11.5) and later in the majority of SOX2/PROP1 double-positive cells on E13.5. Thereafter, during pituitary embryonic development, Nnat expression was observed in some stem/progenitor cells, proliferating cells and terminally differentiating cells. In postnatal pituitaries, NNAT-positive cells decreased in number, with most coexpressing Sox2 or Pit1, suggesting a similar role for NNAT to that during the embryonic period. NNAT was widely localized in mitochondria, peroxisomes and lysosomes, in addition to the endoplasmic reticulum but not in the Golgi. The present study thus demonstrated the variability in expression of NNAT-positive cells in rat embryonic and postnatal pituitaries and the intracellular localization of NNAT. Further investigations to obtain functional evidence for NNAT are a prerequisite. PMID- 26613604 TI - Mensenchymal stem cells can delay radiation-induced crypt death: impact on intestinal CD44(+) fragments. AB - Intestinal stem cells are primitive cells found within the intestinal epithelium that play a central role in maintaining epithelial homeostasis through self renewal and commitment into functional epithelial cells. Several markers are available to identify intestinal stem cells, such as Lgr5, CD24 and EphB2, which can be used to sort intestinal stem cells from mammalian gut. Here, we identify and isolate intestinal stem cells from C57BL/6 mice by using a cell surface antigen, CD44. In vitro, some CD44(+) crypt cells are capable of forming "villus crypt"-like structures (organoids). A subset strongly positive for CD44 expresses high levels of intestinal stem-cell-related genes, including Lgr5, Bmi1, Hopx, Lrig1, Ascl2, Smoc2 and Rnf43. Cells from this subset are more capable of developing into organoids in vitro, compared with the subset weakly positive for CD44. However, the organoids are sensitive to ionizing irradiation. We investigate the specific roles of mesenchymal stem cells in protecting organoids against radiation-induced crypt death. When co-cultured with mesenchymal stem cells, the crypt domains of irradiated organoids possess more proliferative cells and fewer apoptotic cells than those not co-cultured with mesenchymal stem cells. Cd44v6 continues to be expressed in the crypt domains of irradiated organoids co cultured with mesenchymal stem cells. Our results indicate specific roles of mesenchymal stem cells in delaying radiation-induced crypt death in vitro. PMID- 26613606 TI - Netupitant/Palonosetron: A Review in the Prevention of Chemotherapy-Induced Nausea and Vomiting. AB - An oral fixed combination of netupitant/palonosetron (NEPA; Akynzeo((r))) is available for use in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Netupitant is a highly selective neurokinin-1 receptor antagonist and palonosetron is a serotonin 5-HT3 receptor antagonist with a distinct pharmacological profile. Complete response rates during the delayed, acute and overall phases were significantly higher with single-dose netupitant 300 mg plus palonosetron 0.5 mg than with single-dose palonosetron 0.5 mg in cycle 1 of cisplatin-based highly emetogenic chemotherapy (HEC) in a phase II trial and with single-dose netupitant/palonosetron 300/0.5 mg than with single dose palonosetron 0.5 mg in cycle 1 of anthracycline-cyclophosphamide (AC) moderately emetogenic chemotherapy (MEC) in a phase III trial; the greater efficacy of netupitant/palonosetron was maintained over repeated cycles of AC MEC in the phase III trial. In another phase III trial, netupitant/palonosetron 300/0.5 mg was effective over repeated cycles of non-AC MEC or HEC. Netupitant/palonosetron was well tolerated, with no cardiac safety concerns. The convenience of administering netupitant/palonosetron as a single dose in a fixed combination has the potential to improve adherence to CINV prevention guidelines. In conclusion, netupitant/palonosetron is an important option to consider in the prevention of acute and delayed CINV in patients receiving MEC or HEC. PMID- 26613605 TI - Associating a negatively charged GdDOTA-derivative to the Pittsburgh compound B for targeting Abeta amyloid aggregates. AB - We have conjugated the tetraazacyclododecane-tetraacetate (DOTA) chelator to Pittsburgh compound B (PiB) forming negatively charged lanthanide complexes, Ln(L4), with targeting capabilities towards aggregated amyloid peptides. The amphiphilic Gd(L4) chelate undergoes micellar aggregation in aqueous solution, with a critical micellar concentration of 0.68 mM, lower than those for the neutral complexes of similar structure. A variable temperature (17)O NMR and NMRD study allowed the assessment of the water exchange rate, k ex (298) = 9.7 * 10(6) s(-1), about the double of GdDOTA, and for the description of the rotational dynamics for both the monomeric and the micellar forms of Gd(L4). With respect to the analogous neutral complexes, the negative charge induces a significant rigidity of the micelles formed, which is reflected by slower and more restricted local motion of the Gd(3+) centers as evidenced by higher relaxivities at 20-60 MHz. Surface Plasmon Resonance results indicate that the charge does not affect significantly the binding strength to Abeta1-40 [K d = 194 +/- 11 MUM for La(L4)], but it does enhance the affinity constant to human serum albumin [K a = 6530 +/- 68 M(-1) for Gd(L4)], as compared to neutral counterparts. Protein-based NMR points to interaction of Gd(L4) with Abeta1-40 in the monomer state as well, in contrast to neutral complexes interacting only with the aggregated form. Circular dichroism spectroscopy monitored time- and temperature-dependent changes of the Abeta1-40 secondary structure, indicating that Gd(L4) stabilizes the random coil relative to the alpha-helix and beta-sheet. TEM images confirm that the Gd(L4) complex reduces the formation of aggregated fibrils. PMID- 26613607 TI - Locus ceruleus neurons in people with autism contain no histochemically detectable mercury. AB - Exposure to environmental mercury has been proposed to play a part in autism. Mercury is selectively taken up by the human locus ceruleus, a region of the brain that has been implicated in autism. We therefore looked for the presence of mercury in the locus ceruleus of people who had autism, using the histochemical technique of autometallography which can detect nanogram amounts of mercury in tissues. In addition, we sought evidence of damage to locus ceruleus neurons in autism by immunostaining for hyperphosphorylated tau. No mercury was found in any neurons of the locus ceruleus of 6 individuals with autism (5 male, 1 female, age range 16-48 years). Mercury was present in locus ceruleus neurons in 7 of 11 (64%) age-matched control individuals who did not have autism, which is significantly more than in individuals with autism. No increase in numbers of locus ceruleus neurons containing hyperphosphorylated tau was detected in people with autism. In conclusion, most people with autism have not been exposed early in life to quantities of mercury large enough to be found later in adult locus ceruleus neurons. Human locus ceruleus neurons are sensitive indicators of mercury exposure, and mercury appears to remain in these neurons indefinitely, so these findings do not support the hypothesis that mercury neurotoxicity plays a role in autism. PMID- 26613609 TI - Former health secretary takes on another advisory role in private health sector. PMID- 26613608 TI - Potential determinants of deductible uptake in health insurance: How to increase uptake in The Netherlands? AB - In health insurance, voluntary deductibles are offered to the insured in return for a premium rebate. Previous research has shown that 11 % of the Dutch insured opted for a voluntary deductible (VD) in health insurance in 2014, while the highest VD level was financially profitable for almost 50 % of the population in retrospect. To explain this discrepancy, this paper identifies and discusses six potential determinants of the decision to opt for a VD from the behavioral economic literature: loss aversion, risk attitude, ambiguity aversion, debt aversion, omission bias, and liquidity constraints. Based on these determinants, five potential strategies are proposed to increase the number of insured opting for a VD. Presenting the VD as the default option and providing transparent information regarding the VD are the two most promising strategies. If, as a result of these strategies, more insured would opt for a VD, moral hazard would be reduced. PMID- 26613610 TI - Dominance from the perspective of gene-gene and gene-chemical interactions. AB - In this study, we used genetic interaction (GI) and gene-chemical interaction (GCI) data to compare mutations with different dominance phenotypes. Our analysis focused primarily on Saccharomyces cerevisiae, where haploinsufficient genes (HI; genes with dominant loss-of-function mutations) were found to be participating in gene expression processes, namely, the translation and regulation of gene transcription. Non-ribosomal HI genes (mainly regulators of gene transcription) were found to have more GIs and GCIs than haplosufficient (HS) genes. Several properties seem to lead to the enrichment of interactions, most notably, the following: importance, pleiotropy, gene expression level and gene expression variation. Importantly, after these properties were appropriately considered in the analysis, the correlation between dominance and GI/GCI degrees was still observed. Strikingly, for the GCIs of heterozygous strains, haploinsufficiency was the only property significantly correlated with the number of GCIs. We found ribosomal HI genes to be depleted in GIs/GCIs. This finding can be explained by their high variation in gene expression under different genetic backgrounds and environmental conditions. We observed the same distributions of GIs among non ribosomal HI, ribosomal HI and HS genes in three other species: Schizosaccharomyces pombe, Drosophila melanogaster and Homo sapiens. One potentially interesting exception was the lack of significant differences in the degree of GIs between non-ribosomal HI and HS genes in Schizosaccharomyces pombe. PMID- 26613612 TI - Skunk-like cannabis may damage white matter in the brain, study shows. PMID- 26613611 TI - Occupational Exposure to Multi-Walled Carbon Nanotubes During Commercial Production Synthesis and Handling. AB - The world-wide production of carbon nanotubes (CNTs) has increased substantially in the last decade, leading to occupational exposures. There is a paucity of exposure data of workers involved in the commercial production of CNTs. The goals of this study were to assess personal exposure to multi-walled carbon nanotubes (MWCNTs) during the synthesis and handling of MWCNTs in a commercial production facility and to link these exposure levels to specific activities. Personal full shift filter-based samples were collected, during commercial production and handling of MWCNTs, R&D activities, and office work. The concentrations of MWCNT were evaluated on the basis of EC concentrations. Associations were studied between observed MWCNT exposure levels and location and activities. SEM analyses showed MWCNTs, present as agglomerates ranging between 200 nm and 100 um. Exposure levels of MWCNTs observed in the production area during the full scale synthesis of MWCNTs (N = 23) were comparable to levels observed during further handling of MWCNTs (N = 19): (GM (95% lower confidence limit-95% upper confidence limit)) 41 MUg m(-3) (20-88) versus 43 MUg m(-3) (22-86), respectively. In the R&D area (N = 11) and the office (N = 5), exposure levels of MWCNTs were significantly (P < 0.05) lower: 5 MUg m(-3) (2-11) and 7 MUg m(-3) (2-28), respectively. Bagging, maintenance of the reactor, and powder conditioning were associated with higher exposure levels in the production area, whereas increased exposure levels in the R&D area were related to handling of MWCNTs powder. PMID- 26613613 TI - Substrate elasticity regulates the behavior of human monocyte-derived macrophages. AB - Macrophages play a key role in atherosclerosis, cancer, and in the response to implanted medical devices. In each of these situations, the mechanical environment of a macrophage can vary from soft to stiff. However, how stiffness affects macrophage behavior remains uncertain. Using substrates of varying stiffness, we show macrophage phenotype and function depends on substrate stiffness. Notably, the cell area increases slightly from a sphere after 18 h on substrates mimicking healthy arterial stiffness (1-5 kPa), whereas macrophages on stiffer substrates (280 kPa-70 GPa) increased in area by nearly eight-fold. Macrophage migration is random regardless of substrate stiffness. The total average track speed was 7.8 +/- 0.5 MUm/h, with macrophages traveling fastest on the 280-kPa substrate (12.0 +/- 0.5 MUm/h) and slowest on the 3-kPa substrate (5.0 +/- 0.4 MUm/h). In addition F-actin organization in macrophages depends on substrate stiffness. On soft substrates, F-actin is spread uniformly throughout the cytoplasm, whereas on stiff substrates F-actin is functionalized into stress fibers. The proliferation rate of macrophages was faster on stiff substrates. Cells plated on the 280-kPa gel had a significantly shorter doubling time than those plated on the softer substrate. However, the ability of macrophages to phagocytose 1-MUm particles did not depend on substrate stiffness. In conclusion, the results herein show macrophages are mechanosensitive; they respond to changes in stiffness by modifying their area, migration speed, actin organization, and proliferation rate. These results are important to understanding how macrophages respond in complex mechanical environments such as an atherosclerotic plaque. PMID- 26613614 TI - Why do older people with multi-morbidity experience unplanned hospital admissions from the community: a root cause analysis. AB - BACKGROUND: Increasing demand for hospital services by older people is a major concern for Australian health care providers. To date there has been little in depth research that encompasses contextual and systems factors contributing to hospital admissions. The objective of this study was to determine the reasons why older patients experienced unplanned hospital admissions to a major public hospital. METHODS: A retrospective qualitative study using a Root Cause Analysis (RCA) methodology was conducted in a major public hospital in Adelaide, South Australia and surrounding community. Community dwelling older people admitted to the hospital who were well enough to give informed consent and be interviewed were invited to take part in the study. With patients consent, family members, general practitioners (GPs) and specialists were also interviewed and patient hospital records reviewed. Using a purposive sampling technique to obtain maximum variability, thirty-six older people (aged 70 years and older) participated in the study. GPs (n = 17), family members (n = 14), and other healthcare providers (n = 12) involved in their care were also interviewed. Cases were then analysed according to a standardized protocol to determine the root cause of admission. Root causes were then assigned to broader categories using thematic analysis. RESULTS: The root causes of unplanned admissions were identified and categorised into six causal groups: a consequence of minimal care, progression of disease, home care accessibility, high complexity, clinical error, and delayed care seeking by the patient. CONCLUSIONS: RCA can be effectively applied to determine the causes of unplanned hospital admissions although the process is time consuming. Four categories of admission (minimal care, clinical error, home care access, delayed care-seeking) were deemed potentially preventable. This methodology and classification approach may assist in designing interventions to prevent future hospitalisations in this high-risk population. PMID- 26613615 TI - Comparative Analysis of Microbial Diversity in Termite Gut and Termite Nest Using Ion Sequencing. AB - Termite gut and termite nest possess complex microbial communities. However, only limited information is available on the comparative investigation of termite gut- and nest-associated microbial communities. In the present study, we examined and compared the bacterial diversity of termite gut and their respective nest by high throughput sequencing of V3 hypervariable region of 16S rDNA. A total of 14 barcoded libraries were generated from seven termite gut samples and their respective nest samples, and sequenced using Ion Torrent platform. The sequences of each group were pooled, which yielded 170,644 and 132,000 reads from termite gut and termite nest samples, respectively. Phylogenetic analysis revealed significant differences in the bacterial diversity and community structure between termite gut and termite nest samples. Phyla Verrucomicrobia and Acidobacteria were observed only in termite gut, whereas Synergistetes and Chlorobi were observed only in termite nest samples. These variations in microbial structure and composition could be attributed with the differences in physiological conditions prevailing in the termite gut (anoxic and alkaline) and termite nest (oxic, slightly acidic and rich in organic matter) environment. Overall, this study unmasked the complexity of bacterial population in the respective niche. Interestingly, majority of the sequence reads could be classified only up to the domain level indicating the presence of a huge number of uncultivable or unidentified novel bacterial species in both termite gut and nest samples. Whole metagenome sequencing and assessing the metabolic potential of these samples will be useful for biotechnological applications. PMID- 26613616 TI - Binariimonas pacifica gen. nov., sp. nov., a Novel Marine Bacterium of Family Sphingomonadaceae Isolated from East Pacific Ocean Surface Seawater. AB - A novel rod-shaped binary fission, and yellow-pigmented bacterial strain, JLT 2480(T), was isolated from surface seawater in the East Pacific Ocean. The strain is Gram negative and oxidase negative. Phylogenetic analyses based on 16S rRNA gene sequence indicate that strain JLT 2480(T) falls in the family Sphingomonadaceae, sharing highest similarity (95.6 %) with the species Blastomonas ursincola. The DNA G+C content of JLT 2480(T) is 65.5 mol%, and the sole respiratory quinone is coenzyme Q10. The predominant polar lipids are sphingoglycolipids (SGL1 and SGL2), phosphatidylglycerols, phosphatidylethanolamines, phospholipids, glycolipids, and phosphatidylcholines. The predominant cellular fatty acids are C16:0, C18:0, C18:1omega7c, C12:0, and C16:1omega7c. Strain JLT 2480(T) is distinct from the B. ursincola type strain DSM 9006(T) as reflected by major chemotaxonomic distinctions between the two. Furthermore, two notable characteristics of the genus Blastomonas, that is, the presence of bacteriochlorophyll a and the puf genes, are not detected in JLT 2480(T). On the basis of present evidence, we consider JLT 2480(T) to be a novel species in a new genus of the family Sphingomonadaceae, and propose the name Binariimonas pacifica gen. nov., sp. nov., with strain JLT 2480(T) (=CGMCC 1.12850(T) = DSM 28646(T)) to be the type strain for genus Binariimonas. PMID- 26613617 TI - Influence of Flaxseed Oil on Fecal Microbiota, Egg Quality and Fatty Acid Composition of Egg Yolks in Laying Hens. AB - Although there have been many attempts to produce omega-3 fatty acid-rich eggs using alpha-linolenic acid (ALA) that is a popular fatty acid in the poultry feed industry, only limited knowledge about the effects of ALA-enriched diets on chicken fecal microbiota is currently available. Herein we examined the changes in the fecal microbiota composition, egg quality traits and fatty acid composition of the egg yolks of laying hens fed ALA-rich flaxseed oil for 8 weeks. The animals fed the experimental diets that contained 0 % (group C), 0.5 % (group T1), and 1.0 % (group T2) of flaxseed oil, respectively, and eggs and feces were obtained for the analyses. omega-3 fatty acids, including ALA, were increased in T1 and T2 compared with C. Furthermore, the freshness of eggs was improved with no side effects on the eggs. The diet also changed the fecal microbiota; Firmicutes was increased in T1 and T2 (48.6 to 83 and 79.6 %) and Bacteroidetes was decreased (40.2 to 8.8 and 4.2 %). Principal coordinate analysis revealed that Lactobacillus, among the 56 examined genera, was the most influenced bacterial group in terms of the fecal microbial community shifts. These results indicate that ALA-rich diets influenced both the egg and fecal microbiota in beneficial manners in laying hens although the association between the fatty acid composition of the egg yolk and the fecal microbiota was not clear. This study is a first step to understand the effect of flaxseed oil as well as intestinal microbiota of laying hens. PMID- 26613618 TI - Astrocytes, Metabolism, Signaling and Brain Drains: Introduction to the Special Issue in Honor of Gerald Dienel. PMID- 26613619 TI - Validation of a brief mental health screener for Karen refugees in primary care. AB - BACKGROUND: Karen refugees from Burma are one of the largest refugee groups currently resettling in the USA. Karen people have endured decades of civil war and human rights violations, leaving them more likely to develop serious mental health disorders. There is a noted lack of brief, culturally validated tools present in primary care settings for detecting posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) in Karen refugees. OBJECTIVE: To create the Karen Mental Health Screener, a five-question screening tool used to identify depression and PTSD and to validate it against a clinical reference standard. METHODS: This validation study was conducted during a primary care visit. Participants completed a 20-item questionnaire using a 4-point visual aid and the PTSD and MDD portions of the Structured Clinical Interview for DSM Disorders (SCID-CV for DSM-IV) as the reference standard. Both the questionnaire and the relevant sections of the SCID-IV were rigorously translated and administered by trained researchers along with a trained Karen interpreter. RESULTS: Logistic regression models and receiver operating characteristic curve analyses were used to determine a subset of items that could be used to construct a screener to identify Karen patients who were most likely to have PTSD and/or MDD. A final five-question screener was created with very strong performance characteristics. With a clinical cut score of 4, these items displayed very strong performance characteristics with sensitivity = 0.96, specificity = 0.97, positive predicted value = 0.83 and negative predicted value = 0.99. CONCLUSION: The Karen Mental Health Screener is a valid measure for detecting PTSD and major depression in Karen people from refugee backgrounds presenting in a primary care setting. PMID- 26613620 TI - More Than A Meal? A Randomized Control Trial Comparing the Effects of Home Delivered Meals Programs on Participants' Feelings of Loneliness. AB - OBJECTIVE: Nutrition service providers are seeking alternative delivery models to control costs and meet the growing need for home-delivered meals. The objective of this study was to evaluate the extent to which the home-delivered meals program, and the type of delivery model, reduces homebound older adults' feelings of loneliness. METHODS: This project utilizes data from a three-arm, fixed randomized control study conducted with 626 seniors on waiting lists at eight Meals on Wheels programs across the United States. Seniors were randomly assigned to either (i) receive daily meal delivery; (ii) receive once-weekly meal delivery; or (iii) remain on the waiting list. Participants were surveyed at baseline and again at 15 weeks. Analysis of covariance was used to test for differences in loneliness between groups, over time and logistic regression was used to assess differences in self-rated improvement in loneliness. RESULTS: Participants receiving meals had lower adjusted loneliness scores at follow-up compared with the control group. Individuals who received daily-delivered meals were more likely to self-report that home-delivered meals improved their loneliness than the group receiving once-weekly delivered meals. DISCUSSION: This article includes important implications for organizations that provide home delivered meals in terms of cost, delivery modality, and potential recipient benefits. PMID- 26613621 TI - Total plasma proANP increases with atrial dilatation in horses. AB - Equine atrial natriuretic peptide (ANP) plasma concentrations are correlated with left atrial size. However, species-specific assays are lacking and the results from human assays are poorly reproducible. A new methodology called processing independent analysis (PIA) that measures the total proANP product in plasma has proven to be successful in human medicine, but has never been used in horses. The aims were to establish an equine proANP reference interval by measurement of the total proANP product using PIA and to examine the proANP concentrations in horses with atrial dilatation. Sample stability was studied by comparison of storage at 80 degrees C and -20 degrees C. Plasma samples were obtained from 23 healthy horses, 12 horses with moderate or severe valvular regurgitation without atrial dilatation and 42 horses with valvular regurgitation and atrial dilatation. The proANP concentration was significantly (P<0.001) higher in horses with atrial dilatation (761.4 (442.1-1859.1) pmol/l) than in healthy horses (491.6 (429.5 765.9) pmol/l; P<0.001) or horses with cardiac disease but without atrial dilatation (544.4 (457.0-677.6) pmol/l). A cut-off value (573.8 pmol/l) for detection of atrial dilatation was calculated. Sample storage at -80 degrees C did not differ from sample storage at -20 degrees C. The measurement of total proANP in plasma detects atrial dilatation in horses and may be useful for clinical evaluation in equine medicine. PMID- 26613622 TI - [Rupture of hepatocarcinoma and early tumour dissemination]. PMID- 26613623 TI - Multifunctional nanobiodevices in medical sciences. PMID- 26613624 TI - [Primary care in Sweden]. AB - Sweden was one of the first European Union countries that saw the opportunity in the free movement of professionals. First offers for jobs were managed in 2000. Since then, a large number of professionals have taken the opportunity of a decent job and have moved from Spain to Sweden. The Swedish health care model belongs to the group of national health systems. The right to health care is linked to legal citizenship. Health is financed through regional taxes, but there is a compulsory co-payment regardless of the financial situation of the patient. The provision of health care is decentralised at a regional level, and there is a mixture of private and public medical centres. Primary care is similar to that in Spain. Health professionals work as a team with a division of tasks. Like in Spain, waiting lists and coordination between primary and specialised care are a great problem. Patients may register with any public or private primary care centre and hospital provider within their region. Access to diagnostic tests and specialists are restricted to those selected by specialists. Doctors are salaried and their job and salary depend on their experience, professional abilities and regional needs. Medicine is curative. General practitioners are the gateway to the system, but they do not act as gatekeeper. Hospitals offer a number of training post, and the access is through an interview. Continuing medical education is encouraged and financed by the health centre in order to increase its revenues. PMID- 26613625 TI - Context Effects in Western Herbal Medicine: Fundamental to Effectiveness? AB - Western herbal medicine (WHM) is a complex healthcare system that uses traditional plant-based medicines in patient care. Typical preparations are individualized polyherbal formulae that, unlike herbal pills, retain the odor and taste of whole herbs. Qualitative studies in WHM show patient-practitioner relationships to be collaborative. Health narratives are co-constructed, leading to assessments, and treatments with personal significance for participants. It is hypothesized that the distinct characteristics of traditional herbal preparations and patient-herbalist interactions, in conjunction with the WHM physical healthcare environment, evoke context (placebo) effects that are fundamental to the overall effectiveness of herbal treatment. These context effects may need to be minimized to demonstrate pharmacological efficacy of herbal formulae in randomized, placebo-controlled trials, optimized to demonstrate effectiveness of WHM in pragmatic trials, and consciously harnessed to enhance outcomes in clinical practice. PMID- 26613626 TI - Epidemiology and outcomes of pediatric burns over 35 years at Parkland Hospital. AB - BACKGROUND: Since opening its doors in 1962, the Parkland Burn Center has played an important role in improving the care of burned children through basic and clinical research while also sponsoring community prevention programs. The aim of our study was to retrospectively analyze the characteristics and outcomes of pediatric burns at a single institution over 35 years. STUDY DESIGN: The institutional burn database, which contains data from January 1974 until August 2010, was retrospectively reviewed. Patients older than 18 years of age were excluded. Patient age, cause of burn, total body surface area (TBSA), depth of burn, and patient outcomes were collected. Demographics were compared with regional census data. RESULTS: Over 35 years, 5748 pediatric patients were admitted with a thermal injury. Males comprised roughly two-thirds (66.2%) of admissions. Although the annual admission rate has risen, the incidence of pediatric burn admissions, particularly among Hispanic and African American children has declined. The most common causes of admission were scald (42%), flame (29%), and contact burns (10%). Both the median length of hospitalization and burn size have decreased over time (r(2)=0.75 and 0.62, respectively). Mortality was significantly correlated with inhalation injury, size of burn, and history of abuse. It was negatively correlated with year of admission. CONCLUSIONS: Over 35 years in North Texas, the median burn size and incidence of pediatric burn admissions has decreased. Concomitantly, length of stay and mortality have also decreased. PMID- 26613627 TI - Thermographic analysis of facially burned patients. PMID- 26613628 TI - [Prepubertal Hidradenitis suppurativa: Report of 2 clinical cases]. AB - Hidradenitis suppurativa (HS) is an inflammatory follicular skin disease. It usually presents as recurrent, deep nodules in flexural apocrine gland bearing areas. It appears mainly in women, in the second and third decade of life. OBJECTIVE: To present 2 cases of patients with prepuberal HS. CASE 1: A 10-year old female, Tanner stage I-II and obesity. History of 4 months of evolution with bilateral recurrent groin lesions that occasionally drain pus; HS Hurley stage i was diagnosed, and topical antibiotics and nutritional management were prescribed, with a good response. CASE 2: A 10 years old female, Tanner stage I II and obesity. Since the age of 6 years, recurrent episodes of lesions in the inner side of the left thigh were observed, and multiple antibiotics with poor response were prescribed. HS Hurley stage i was diagnosed, and photodynamic therapy and nutritional management were used, with good response. CONCLUSIONS: The etiology of HS is unclear. Usually the presentation at early age is associated with a family history and more extensive compromise in the future. Treatment is difficult and depends on each case and severity. PMID- 26613629 TI - [Retroperitoneal lipoblastoma in an infant. A case report]. AB - INTRODUCTION: Lipoblastoma is a benign neoplasia of the adipose tissue. It is a rare conditionand almost exclusively presents in children under 3 years old. It usually occurs in extremities as a painless volume increase of progressive growth, with the definitive diagnosis being established by pathological and cytogenetic analysis. The treatment of choice is complete resection, and follow up period of up to five years is recommended due to a recurrence of up to 25%. OBJECTIVE: To present an unusual location of this uncommon condition in an infant, and review the related literature. CASE REPORT: A sixteen-month child with an increase in abdominal growth of six-months progression, associated with a decreased food intake, and with no other symptoms. The imaging study revealed a lipoid-like image compromising almost the entire abdominal cavity, very suggestive of lipoblastoma. A resection was performed on an 18cm diameter retroperitoneal tumour that rejected the adjacent organs. Histological analysis was enough to confirm diagnosis without the need for cytogenetic analysis. The follow-up showed no recurrence of the disease. CONCLUSION: Given the rarity of this disease and its unusual presentation, we communicate this clinical case, in order to be considered in the differential diagnosis of abdominal mass in chilhood. PMID- 26613630 TI - [Mucopolysaccharidosis: clinical features, diagnosis and management]. AB - The mucopolysaccharidoses (MPS) are a group of rare (orphan) diseases, characterised by a deficiency of enzymes involved in the metabolism of glycosaminoglycans (GAGs) at lysosomal level. When there is a deficiency of a particular enzyme there is an accumulation of GAGs in the cells resulting in progressive cellular damage, which can affect multiple organ systems and lead to organ failure. Diagnosis is based on knowledge of the clinical manifestations, performing biochemical analyses to identify the type of GAG that is accumulating, and confirm the type of disorder with the corresponding enzymatic determination. Their identification is essential to initiate early treatment, taking into account that multidisciplinary management and enzyme replacement therapy is available for MPS I (Hurler syndrome), MPS II (Hunter syndrome), MPS IV (Morquio syndrome), and MPS VI (Maroteaux-Lamy syndrome. In this review, an analysis is made of each of these syndromes, as well as their diagnosis and treatment. PMID- 26613631 TI - Complications in leg lengthening using an Ilizarov external fixator and intramedullary alignment in children: comparative study during a fourteen-year period. AB - BACKGROUND: The purpose of this retrospective study was to evaluate the complications associated with leg lengthening in children treated with the Ilizarov external fixator (IEF) and compare them between two groups of patients: one group was treated using an IEF alone and the other group was treated using an IEF in association with intramedullary alignment (IA). PATIENTS AND METHODS: The study was performed at the University Children's Hospital in Belgrade, Serbia during a fourteen-year period (from 2000 to 2014). Complications occurred in 73 paediatric patients who underwent the leg lengthening procedure. Complications were classified according to the Caton classification and compared between two groups. Group I comprised 39 patients who underwent the limb lengthening procedure using IEF alone. Group II consisted of 34 patients who were treated with the combination of IEF and IA using two Kirschner wires (K-wires) or Titanium Elastic Nails (TEN). The duration of hospital treatment was also compared between the two groups and the impact of the type of IA on the occurrence of complications was assessed. RESULTS: There was a high rate of complications in patients treated using an IEF compared with those treated using the combination of IEF and IA, but there was no statistically significant difference between the two groups. There was a statistically significant difference in the duration of initial hospitalisation between the two groups, particularly when comparing TEN usage in IA. A comparison of the group of patients treated using an IEF in association with K-wires and patients treated using IEF and TEN showed there was no statistically significant difference in complication rate and duration of initial hospitalisation. CONCLUSION: IA has multiple advantages as a method of treatment of leg length inequality. The major effect of applying IA in association with a circular IEF is significantly reduced complication rate and duration of initial hospitalisation, particularly when using TEN as a method of IA. This method of treatment also decreases hospital costs. PMID- 26613632 TI - Lectin histochemistry shows the comparative biosynthesis and cellular biodistribution of alpha L-fucose residues in some tissues of tetrapoda representatives. AB - Fucose is a monosaccharide that plays several immunological roles. This study investigated the comparative biosynthesis and cellular biodistribution of fucose residues in some tissues of tetrapoda representatives using lectin histochemistry. In this study, the mouse was used as a representative for mammalian, pigeon for avian, lizard for reptilian, and toad for amphibians. The localization of the fucose residues was seen in several cell types of mice ileum, such as villi microfold (M) cells, goblet cells, some of intestinal crypts cells, and lamina propria cells. In other tetrapoda representatives, fucose was only seen in M cells of lizard ileum and some cells of villi lamina propria of pigeon, lizard, and toad. It was also observed in the pancreatic acinar cells of the mouse and some cell aggregations of pancreatic parenchyma of the lizard. Contrarily, it was not seen either in pigeon or in toad pancreases parenchyma. Spleen of all animals showed the fucose residues in some splenic cells in the red pulp only, barring the white pulp. The liver parenchyma of all tetrapoda representatives hadn't fucose residues. The fucose cellular biodistribution in some cells of tetrapoda representatives differed based on the cell type. In the mouse, it was highly seen in the apical cytoplasm of the villi M cells as well as in the cup-like part of goblet cells. In addition, it was seen as "rings" in the granule membranes of the Ulex europeaus agglutinin I (UEAI(+)) cells in the intestinal crypts cells. Furthermore, the UEAI(+) cells in the lamina propria showed fucose granules in their cytoplasm. There is no clear evidence about the relation between the cellular biosynthesis of fucose residues and mucosal immune cells. The role of fucose residues in the pancreatic acinar cells are not well understood and need further investigations. In this study, fucose residues were synthesized in several types of cells in the mouse ileum, spleen and pancreas as compared with other tetrapoda. The data obtained from this study can help us to get more information about the cellular biodistribution and synthesis of fucose residues in several animal species rather than mammalians. PMID- 26613633 TI - Emotion Regulation in Alcohol Dependence. AB - BACKGROUND: The main aim of this study was to investigate, in alcohol-dependent (AD) patients, the use of the 5 emotion regulation strategies specified in Gross's (1998, Rev Gen Psychol, 2, 271) process model of emotion regulation with the use of a semi-structured interview allowing a detailed and high-quality assessment of emotion regulation strategies. A secondary aim was to examine the possible influence of protracted abstinence and detoxification on emotion dysregulation. Finally, the association between the level of craving and the types of regulation strategies was investigated. METHODS: Forty-four treatment seeking AD patients with varying time spent in rehabilitation, and 26 healthy controls were interviewed using a version of the Emotion Regulation Interview (Werner et al., 2011, J Psychopathol Behav Assess, 33, 346) adapted to alcohol dependence. RESULTS: Compared to controls, AD patients reported significantly greater use of response modulation and attentional deployment, but lesser use of cognitive change. Among patients, (1) rehabilitation duration was positively correlated with the use of cognitive change and (2) the use of response modulation was positively associated with the level of craving. CONCLUSIONS: These findings clarify the specific pattern of emotion dysregulation associated with alcohol dependence. They also suggest that (1) abstinence is associated with a shift toward more adaptive emotion regulation patterns and that (2) inefficient regulation strategies may lead to craving and the maintenance of alcohol use. If these findings are confirmed through longitudinal and mediation designs, they will have important clinical implications. PMID- 26613634 TI - Modification of a dihydropyrrolopyrimidine phosphoinositide 3-kinase (PI3K) inhibitor to improve oral bioavailability. AB - Phosphoinositide 3-kinase (PI3K) is activated in various human cancer cells and well known as a cancer therapy target. We previously reported a dihydropyrrolopyrimidine derivative as a highly potent PI3K inhibitor that has strong tumor growth inhibition in a xenograft model. In this report, we describe further optimization to improve its bioavailability. PMID- 26613635 TI - Design, synthesis and evaluation of antiestrogen and histone deacetylase inhibitor molecular hybrids. AB - The combination of antiestrogens and histone deacetylase inhibitors (HDACi) has been found to be antiproliferative in breast cancer models. We designed and synthesized hybrid structures which combined structural features of the pure antiestrogen ICI-164,384 and HDACi's SAHA and entinostat in a single bifunctional molecule. The hybrids retained antiestrogenic and HDACi activity and, in the case of benzamide hybrids, were selective for Class I HDAC3 over Class II HDAC6. The hybrids possessed low micromolar to high nanomolar activity against both ER+ MCF 7 and ER- MDA-MB-231 breast cancer cell models. PMID- 26613636 TI - Malmo Treatment Referral and Intervention Study (MATRIS)-effective referral from syringe exchange to treatment for heroin dependence: a pilot randomized controlled trial. AB - AIMS: Syringe exchange has been suggested as a potential conduit to treatment for drug dependence, but this has never been documented in Europe. The primary aim was to compare the effectiveness of strength-based case management intervention (CMI) against referral only to facilitate treatment attendance in a syringe exchange programme. We also assessed the effectiveness of a syringe exchange programme for referral of heroin-dependent patients to evidence-based treatment with methadone or buprenorphine (buprenorphine-naloxone). DESIGN: Single-site, two-group randomized controlled trial. SETTING: The syringe exchange programme in Malmo, Sweden and an out-patient clinic (research treatment facility) for maintenance treatment, situated outside the hospital area and run by Malmo Addiction Centre. PARTICIPANTS: Heroin-dependent patients willing to participate (n = 75) were referred to maintenance treatment and randomized to either a strength-based case management intervention aiming to facilitate referral (n = 36) or to referral-only (n = 39). INTERVENTION: The intervention group received an appointment for maintenance treatment and a CMI adjusted to individual patient needs. The CMI was semi-structured, assessing the patients' strengths and needs and identifying what practical help they might need to get to the appointment for maintenance treatment. The control group received an appointment for maintenance treatment. MEASURES: The primary outcome was treatment entry. FINDINGS: Among patients who turned up for recruitment interview and randomization, the percentage of patients who started treatment was 95% in the intervention group and 94% in the control group. Treatment entry was unrelated to intervention status [unadjusted odds ratio (OR) = 0.92 (0.12-6.89), P = 1.00 and adjusted OR = 0.96 (0.12-7.83)]. CONCLUSIONS: A randomized controlled trial in a syringe exchange programme showed no evidence that a strength-based case management intervention improved attendance for treatment over referral alone. Attendance rates were high in both groups. PMID- 26613637 TI - Management of drug eluting stent in-stent restenosis: A systematic review and meta-analysis. AB - BACKGROUND: The optimal management for coronary drug eluting stent in-stent restenosis (DES ISR) is unclear. We performed a meta-analysis of observational and randomized studies to compare the outcomes of management of DES ISR using DES, drug eluting balloon (DEB), or balloon angioplasty (BA). METHODS: Eligible studies (25 single arm and 13 comparative, including 4 randomized studies with a total of 7,474 patients with DES ISR) were identified using MEDLINE search and proceedings of international meetings. Outcomes studied include major adverse cardiac events (MACE), target lesion revascularization (TLR), target vessel revascularization (TVR), myocardial infarction (MI), stent thrombosis (ST), and mortality. Follow-up ranged from 0.5 to 3.5 years (mean 1.4 years). RESULTS: The rate of TLR was significantly lower in the DES (odds ratio [OR] 0.50, 95% confidence interval [CI] 0.36-0.69) and DEB (OR 0.31, 95% CI 0.18-0.55) groups compared to BA. Similarly, TVR rate was significantly lower in the DES (OR 0.55, 95% CI 0.39-0.77) and DEB (OR 0.32, 95% CI 0.18-0.58) groups compared to BA. All other outcomes were similar between the DES/BA and DEB/BA comparisons. TLR was significantly lower in the DES group compared to BA for vessels < or > 2.75 mm. CONCLUSION: Treatment of coronary DES ISR with DES or DEB is associated with a reduction in the risk of TLR and TVR compared to BA alone. The relative risk reduction for TLR with DES is similar to DEB. DEBs have a potential role in the treatment of DES ISR by avoiding placement of another layer of stent. (c) 2015 Wiley Periodicals, Inc. PMID- 26613638 TI - An observational study of clozapine induced sedation and its pharmacological management. AB - Clozapine induced sedation is common but its management is unclear. We analyzed the factors associated with clozapine-induced sedation and the efficacy of common pharmacological strategies. We conducted a naturalistic observational study using two years electronic records of a cohort patients and three analyses: a cross sectional analysis of factors associated with total number of hours slept (as an objective proxy of sedation), and two prospective analyses of which factors were associated with changes in hours slept and the efficacy of two pharmacological strategies. 133 patients were included, of which 64.7% slept at least 9h daily. Among monotherapy patients (n=30), only norclozapine levels (r=.367, p=.03) correlated with hours slept. Using the prospective cohort (n=107), 42 patients decreased the number of hours slept, due to decreasing clozapine (40%) or augmenting with aripiprazole (36%). These two strategies were recommended to 22 (20.6%) and 23 (21.5%) subjects respectively but the majority (81.8% and 73.9%) did not reduce number of hours slept. Thus, pharmacological and non pharmacological factors are involved in sedation. Norclozapine plasma levels correlated with total sleeping hours. Reducing clozapine and aripiprazole augmentation were associated to amelioration of sedation, although both strategies were effective only in a limited numbers of subjects. PMID- 26613639 TI - Gut microbiota regulates key modulators of social behavior. AB - Social behavior plays a pivotal role in the mental well-being of an individual. Continuous efforts in the past have led to advancements in the area of how the brain regulates emotion and cognition, while the understanding of human social behavior still remains eluded. A major breakthrough in understanding the etiology of neurological disorders is the recent insight on the role of the gut microbiota (GM). Human GM also referred to as the "forgotten organ" is home to 10(13-14) microorganisms, which is 10 times the number of cells present in the human body. In addition, the gut microbiome (total genome of GM) is 150 times greater as compared to the human genome. An emerging concept gaining worldwide focus and acceptance is that, this much big genome can potentially control human behavior and other biological functions. Herein we hypothesize on the basis of GM's ability to modify brain and behavior and that it can directly or indirectly control social behavior. This review focuses on the association of GM with various domains of social behavior like stress, cognition and anxiety. PMID- 26613640 TI - Depression and Frailty in Patients With End-Stage Liver Disease Referred for Transplant Evaluation. AB - End-stage liver disease (ESLD) patients are believed to have a high prevalence of depression, although mental health in ESLD has not been studied comprehensively. Further, the relationship between depression and severity of liver disease is unclear. Using baseline data from a large prospective cohort study (N = 500) of frailty in ESLD patients, we studied the association of frailty with depression. Frailty was assessed with the five-component Fried Frailty Index. Patients were assigned a composite score of 0 to 5, with scores >=3 considered frail. Depression was assessed using the 15-question Geriatric Depression Scale, with a threshold of >=6 indicating depression; 43.2% of patients were frail and 39.4% of patients were depressed (median score 4, range 0-15). In multivariate analysis, frailty was significantly associated with depression (odds ratio 2.78, 95% confidence interval 1.87-4.15, p < 0.001), whereas model for ESLD score was not associated with depression. After covariate adjustment, depression prevalence was 3.6 times higher in the most-frail patients than the least-frail patients. In conclusion, depression is common in ESLD patients and is strongly associated with frailty but not with severity of liver disease. Transplant centers should address mental health issues and frailty; targeted interventions may lower the burden of mental illness in this population. PMID- 26613641 TI - Different Heparin Contents in Prothrombin Complex Concentrates May Impair Blood Clotting in Outpatients With Ventricular Assist Devices Receiving Phenprocoumon. AB - OBJECTIVES: Prothrombin complex concentrates (PCCs) are used to rapidly reverse anticoagulation by oral vitamin K antagonists. They differ in the content of clotting factors, endogenous anticoagulants, and heparin. The authors hypothesized that PCCs' specific heparin content may compromise the hemostatic effect. DESIGN: Prospective ex-vivo investigation. SETTING: University hospital. PARTICIPANTS: Venous blood samples were obtained from 8 patients with implanted ventricular assist devices who also were receiving phenprocoumon. INTERVENTIONS: Four different 4-factor PCCs were added to patient blood to attain a calculated increase in prothrombin time by 20%, 40%, and 60% greater than baseline in paired experiments. MEASUREMENTS AND MAIN RESULTS: Clotting was measured using thromboelastometry and endogenous thrombin potential. Two heparin-containing PCCs prolonged the clotting times in a concentration-dependent manner compared with baseline (p<0.01) and compared with PCCs containing significantly less or no heparin (p<0.01). The PCCs containing low or no heparin enhanced the area under the curve of thrombin generation and peak thrombin several fold relative to the heparin-containing PCCs (p<0.01). One of the PCCs containing heparin even decreased peak thrombin generation by ~90% compared with baseline (p<0.01). PCC with low or no heparin shortened the lag phase (p<0.01), whereas 1 heparin containing PCC prolonged the lag phase by 66% (p<0.01). CONCLUSIONS: Physicians should be aware of the differences in heparin contents. Extrapolation of results from one agent to other PCC preparations may be difficult. Patients with an implanted left ventricular assist device and anticoagulated with vitamin-K antagonists could benefit from the use of PCC with low heparin content when surgery or bleeding requires emergency reversal. Further clinical studies are warranted. PMID- 26613642 TI - Adult Congenital Heart Defects: How Many Is Too Many? PMID- 26613643 TI - Con: Antifibrinolytics Should Not Be Used Routinely in Low-Risk Cardiac Surgery. PMID- 26613644 TI - Impact of oncogenic BRAF mutations and p16 expression on the growth rate of early melanomas and naevi in vivo. AB - BACKGROUND: It is important to know what drives and arrests melanocytic growth in vivo but observations linking oncogenic mutations to growth rates of melanocytic neoplasms in vivo are sparse. OBJECTIVES: To clarify the relationship between BRAF(V) (600E) mutations and p16 expression and the growth rate of melanocytic neoplasms in vivo. METHODS: We measured the growth rate of 54 melanocytic lesions (26 melanomas, 28 naevi) in vivo with digital dermatoscopy and correlated it with BRAF(V) (600E) and p16 expression, and with dermatoscopic and histological patterns. RESULTS: Melanomas grew faster than naevi (mean 2.7 vs. 0.8 mm(2) /year; P < 0.001) and the growth rate was faster in lesions with more nests (> 25% nests: 2.0 mm(2) /year vs. < 25% nests: 1.0 mm(2) /year; P = 0.036). Melanomas with the BRAF(V) (600E) mutation grew significantly faster than melanomas without the mutation (mean 3.36 vs. 1.60 mm(2) /year, P = 0.018). This effect of the BRAF(V) (600E) mutation on the growth rate was not observed in melanocytic naevi (mean 1.01 vs. 0.47 mm(2) /year, P = 0.274). Histopathologically, extensive nesting, larger nests and larger cell sizes were more common in melanocytic neoplasms with the BRAF(V) (600E) mutation than in those without the mutation. Melanomas expressing p16 had a slower growth rate than melanomas without p16 expression (2.27 vs. 4.34 mm(2) /year, P = 0.047). This effect was not observed in naevi (0.81 vs. 0.68 mm(2) /year, P = 0.836). CONCLUSIONS: The expression of BRAF(V) (600E) and the loss of p16 accelerate the growth rate of early melanomas in vivo but not in melanocytic naevi. In comparison to melanocytic proliferations that lack the mutation, the epidermal melanocytes in lesions that harbour BRAF(V) (600E) mutations are larger and more frequently arranged in large nests. PMID- 26613646 TI - Our Students: Our Future. PMID- 26613647 TI - Food Waste Reduction Efforts at the USDA. PMID- 26613645 TI - Dynorphin inhibits basal forebrain cholinergic neurons by pre- and postsynaptic mechanisms. AB - KEY POINTS: The basal forebrain is an important component of the ascending arousal system and may be a key site through which the orexin neurons promote arousal. It has long been known that orexin-A and -B excite basal forebrain cholinergic neurons, but orexin-producing neurons also make the inhibitory peptide dynorphin. Using whole-cell recordings in brain slices, we found that dynorphin-A directly inhibits basal forebrain cholinergic neurons via kappa opioid receptors, and decreases afferent excitatory synaptic input to these neurons. While the effects of dynorphin-A and orexin-A desensitize over multiple applications, co-application of dynorphin-A and orexin-A produces a sustained response that reverses depending on the membrane potential of basal forebrain cholinergic neurons. At -40 mV the net effect of the co-application is inhibition by dynorphin-A, whereas at -70 mV the excitatory response to orexin-A prevails. ABSTRACT: The basal forebrain (BF) is an essential component of the ascending arousal systems and may be a key site through which the orexin (also known as hypocretin) neurons drive arousal and promote the maintenance of normal wakefulness. All orexin neurons also make dynorphin, and nearly all brain regions innervated by the orexin neurons express kappa opiate receptors, the main receptor for dynorphin. This is remarkable because orexin excites target neurons including BF neurons, but dynorphin has inhibitory effects. We identified the sources of dynorphin input to the magnocellular preoptic nucleus and substantia innominata (MCPO/SI) in mice and determined the effects of dynorphin-A on MCPO/SI cholinergic neurons using patch-clamp recordings in brain slices. We found that the orexin neurons are the main source of dynorphin input to the MCPO/SI region, and dynorphin-A inhibits MCPO/SI cholinergic neurons through kappa-opioid receptors by (1) activation of a G protein-coupled inwardly rectifying potassium current, (2) inhibition of a voltage-gated Ca(2+) current and (3) presynaptic depression of the glutamatergic input to these neurons. The responses both to dynorphin-A and to orexin-A desensitize, but co-application of dynorphin-A and orexin-A produces a sustained response. In addition, the polarity of the response to the co-application depends on the membrane potential of BF neurons; at -40 mV the net effect of the co-application is inhibition by dynorphin-A, whereas at -70 mV the excitatory response to orexin-A prevails. This suggests that depending on their state of activation, BF cholinergic neurons can be excited or inhibited by signals from the orexin neurons. PMID- 26613648 TI - Ethics in Action: Conducting Ethical Research Involving Human Subjects: A Primer. PMID- 26613649 TI - Where Can I Find Resources to Assist Clients with At-Home Meal Planning for Therapeutic Diets? PMID- 26613650 TI - Thoracic ultrasound: Potential new tool for physiotherapists in respiratory management. A narrative review. AB - The use of diagnostic ultrasound by physiotherapists is not a new concept; it is frequently performed in musculoskeletal physiotherapy. Physiotherapists currently lack accurate, reliable, sensitive, and valid measurements for the assessment of the indications and effectiveness of chest physiotherapy. Thoracic ultrasound may be a promising tool for the physiotherapist and could be routinely performed at patients' bedsides to provide real-time and accurate information on the status of pleura, lungs, and diaphragm; this would allow for assessment of lung aeration from interstitial syndrome to lung consolidation with much better accuracy than chest x-rays or auscultation. Diaphragm excursion and contractility may also be assessed by ultrasound. This narrative review refers to lung and diaphragm ultrasound semiology and describes how physiotherapists could use this tool in their clinical decision-making processes in various cases of respiratory disorders. The use of thoracic ultrasound semiology alongside typical examinations may allow for the guiding, monitoring, and evaluating of chest physiotherapy treatments. Thoracic ultrasound is a potential new tool for physiotherapists. PMID- 26613651 TI - An ERP source imaging study of the oddball task in children with Attention Deficit/Hyperactivity Disorder. AB - OBJECTIVE: Children with ADHD have difficulties attending to task-relevant events, which has been consistently associated with reductions in the amplitude of the P3b event-related potential (ERP) component. However, the underlying neural networks involved in this P3b reduction remain elusive. Therefore, this study explored source localization of P3b alterations in children with ADHD, aiming at a more detailed account of attentional difficulties. METHODS: Dense array ERPs were obtained for 36 children with ADHD and 49 typically developing children (TD) using an auditory oddball task. The P3b component (310-410 ms) was individually localized with the LAURA distributed linear inverse solution method and compared between groups. RESULTS: The ADHD group showed reduced P3b amplitudes in response to targets compared to the TD group. Differences were located primarily in frontopolar (cinguloopercular network, BA10) and temporoparietal regions (ventral attention network, BA39 and 19) in the left hemisphere. Reductions in P3b amplitudes were related to more inattention and hyperactivity/impulsivity problems in the ADHD group. CONCLUSIONS: The results show alterations in both top-down and bottom-up attention-related brain areas, which may underlie P3b amplitude reductions in children with ADHD. SIGNIFICANCE: This study provides novel data on both temporal and spatial aspects of dysfunctional attention processes in ADHD. PMID- 26613652 TI - Spatial-temporal patterns of electrocorticographic spectral changes during midazolam sedation. AB - OBJECTIVE: To better understand 'when' and 'where' wideband electrophysiological signals are altered by sedation. METHODS: We generated animation movies showing electrocorticography (ECoG) amplitudes at eight spectral frequency bands across 1.0-116 Hz, every 0.1s, on three-dimensional surface images of 10 children who underwent epilepsy surgery. We measured the onset, intensity, and variance of each band amplitude change at given nonepileptic regions separately from those at affected regions. We also determined the presence of differential ECoG changes depending on the brain anatomy. RESULTS: Within 20s following injection of midazolam, beta (16-31.5 Hz) and sigma (12-15.5 Hz) activities began to be multifocally augmented with increased variance in amplitude at each site. Beta sigma augmentation was most prominent within the association neocortex. Augmentation of low-delta activity (1.0-1.5 Hz) was relatively modest and confined to the somatosensory-motor region. Conversely, injection of midazolam induced attenuation of theta (4.0-7.5 Hz) and high-gamma (64-116 Hz) activities. CONCLUSIONS: Our observations support the notion that augmentation beta-sigma and delta activities reflects cortical deactivation or inactivation, whereas theta and high-gamma activities contribute to maintenance of consciousness. The effects of midazolam on the dynamics of cortical oscillations differed across regions. SIGNIFICANCE: Sedation, at least partially, reflects a multi-local phenomenon at the cortical level rather than global brain alteration homogeneously driven by the common central control structure. PMID- 26613653 TI - Mapping of bowel occult microscopic endometriosis implants surrounding deep endometriosis nodules infiltrating the bowel. AB - OBJECTIVE: To provide a mapping of bowel occult microscopic endometriosis implants from colorectal specimens removed from patients who had undergone colorectal resection for deep endometriosis infiltrating the rectum. DESIGN: A series of consecutive patients with deep endometriosis infiltrating the rectum or/and sigmoid colon, between January 2013 and December 2013. SETTING: University tertiary referral center. PATIENT(S): Twenty-six patients with deep endometriosis infiltrating the rectum or/and sigmoid colon. INTERVENTION(S): Surgical management by colorectal resection. MAIN OUTCOME MEASURE(S): Twenty-six patients with prospective recording of data (age, clinical history, symptoms, preoperative assessment, and intraoperative findings) underwent colorectal resection for bowel endometriosis. Mapping of occult microscopic endometriosis implants from specimens was established by histologic examination of 1,051 microsection slides taken from transversal macrosections of 3-mm thickness (40 microsections per patient on average). RESULT(S): The mean (SD) length of colorectal specimens was 110 (42) mm. Microimplants were found at varying distances up to 54 mm from macronodule limits. Multiple macroscopic nodules were identified in five patients (19.2%). In 18 specimens (69%) diffusion of endometriosis microimplants was longitudinal, whereas in 8 specimens (31%) diffusion was concentrated around the macroscopic nodule. Respectively, 31%, 19%, 8%, and 4% of patients presented with endometriosis microimplants at 2, 3, 4, and 5 cm from macroscopic nodules. CONCLUSION(S): The present data suggest that in patients presenting with deep colorectal endometriosis, microscopically complete excision of rectal endometriosis may be unachievable because of bowel occult microscopic endometriosis implants located far from macroscopic nodules. PMID- 26613654 TI - New approaches for multifactor preimplantation genetic diagnosis of monogenic diseases and aneuploidies from a single biopsy. PMID- 26613655 TI - [Harmonisation of databases for the study of frailty in older people: INTAFRADE study]. AB - OBJECTIVES: The main objective of the present work is to evaluate the feasibility of harmonising the available information from different independent databases, in order to build an integrated database to study frailty. MATERIAL AND METHODS: This work is based on the European project, Integral Approach to the Transition between Frailty and Dependence on older adults: Patterns of occurrence, identification tools and model of care (INTAFRADE), developed by 4 groups, 3 in Spain and one in France. Each partner provided their databases related to the study of frailty. As a previous step to the creation of an integrated database the characteristics and variables included in each study were mapped, specifying whether their harmonisation was possible or not. RESULTS: A total of 30 different variables that corresponded to 8 dimensions were identified: Sociodemographic and social characteristics, health status, lifestyle habits, anthropometric measures, other physical measurements, use of health services, and adverse health results. Of them all, 28 (93%) variables were harmonisable, although only 20% were present in all databases, with 47% in 3 of them. In relation to the frailty instruments, all of them were lacking at least 50% of the items. The harmonisation process will allow us to jointly analyse information available on 2,361 people. CONCLUSIONS: The European INTAFRADE study will allow a deeper understanding of the frailty process in older people by harmonising information from heterogeneous databases. PMID- 26613656 TI - [Effectiveness of occupational therapy and other non-pharmacological therapies in cognitive impairment and Alzheimer's disease]. AB - A review is presented on the existing knowledge about the usefulness of the occupational therapy in the non-pharmacological treatment of Alzheimer's disease. After conducting a literature search of the period 2010-2015, 25 articles that met the inclusion criteria were selected. The evidence obtained showed the efficiency and effectiveness of OT in delaying the progression of various disorders, especially when structured home OT programs are used. These programs should include aerobic and strengthening, sensory stimulation, and cognitive and memory training exercises based on learning without mistakes. These have shown benefits in the performance of activities of daily living, cognitive and emotional functioning. The importance is stressed of the combined and individual household level intervention and caregiver education. Finally, the need for more studies on the effectiveness of long-term sensory stimulation is highlighted. PMID- 26613658 TI - The effects on cow performance and calf birth and weaning weight of replacing grass silage with brewers grains in a barley straw diet offered to pregnant beef cows of two different breeds. AB - The effects on cow and calf performance of replacing grass silage with brewers grains in diets based on barley straw and fed to pregnant beef cows are reported. Using a 2 * 2 factorial arrangement of breed and diet, cows pregnant by artificial insemination (n = 34) of two breeds (cross-bred Limousin, n = 19 and pure-bred Luing, n = 15) were fed diets ad libitum which consisted of either (g/kg dry matter) barley straw (664) and grass silage (325; GS) or barley straw (783) and brewers grains (206, BG) and offered as total mixed rations. From gestation day (GD) 168 until 266, individual daily feed intakes were recorded and cow body weight (BW) and body condition score (BCS) measured weekly. Calving date, calf sex, birth and weaning BW, and calf age at weaning were also recorded. Between GD 168 and 266, cross-bred Limousin cows gained more weight than Luing cows (p < 0.05) and cows offered BG gained more weight than cows offered GS (p < 0.001). Luing cows lost more BCS than cross-bred Limousin cows (p < 0.05), but diet did not affect BCS. There were no differences in dry matter intake as a result of breed or diet. Calf birth BW, however, was greater for cows fed BG than GS (44 vs. 38 kg, SEM 1.0, p < 0.001) with no difference between breeds. At weaning, calves born to BG-fed cows were heavier than those born to GS-fed cows (330 vs. 286 kg, SEM 9.3, p < 0.01). In conclusion, replacement of grass silage with brewers grains improved the performance of beef cows and increased calf birth and weaning BW. Further analysis indicated that the superior performance of cows offered the BG diet was most likely due to increases in protein supply which may have improved both energy and protein supply to the foetus. PMID- 26613657 TI - The Alzheimer's disease peptide beta-amyloid promotes thrombin generation through activation of coagulation factor XII. AB - Essentials How the Alzheimer's disease (AD) peptide beta-amyloid (Abeta) disrupts neuronal function in the disease is unclear. Factor (F) XII initiates blood clotting via FXI, and thrombosis has been implicated in AD. Abeta triggers FXII dependent FXI and thrombin activation, evidence of which is seen in AD plasma. Abeta-triggered clotting could contribute to neuronal dysfunction in AD and be a novel therapeutic target. SUMMARY: Background beta-Amyloid (Abeta) is a key pathologic element in Alzheimer's disease (AD), but the mechanisms by which it disrupts neuronal function in vivo are not completely understood. AD is characterized by a prothrombotic state, which could contribute to neuronal dysfunction by affecting cerebral blood flow and inducing inflammation. The plasma protein factor XII triggers clot formation via the intrinsic coagulation cascade, and has been implicated in thrombosis. Objectives To investigate the potential for Abeta to contribute to a prothrombotic state. Methods and results We show that Abeta activates FXII, resulting in FXI activation and thrombin generation in human plasma, thereby establishing Abeta as a possible driver of prothrombotic states. We provide evidence for this process in AD by demonstrating decreased levels of FXI and its inhibitor C1 esterase inhibitor in AD patient plasma, suggesting chronic activation, inhibition and clearance of FXI in AD. Activation of the intrinsic coagulation pathway in AD is further supported by elevated fibrin levels in AD patient plasma. Conclusions The ability of Abeta to promote coagulation via the FXII-driven contact system identifies new mechanisms by which it could contribute to neuronal dysfunction and suggests potential new therapeutic targets in AD. PMID- 26613659 TI - Tyrosine kinase inhibitors in renal cell cancer: Losing an empire and yet to find a role. PMID- 26613660 TI - How should we use anti-CTLA-4 antibodies? PMID- 26613661 TI - Influence of social factors on patient-reported late symptoms: Report from a controlled trial among long-term head and neck cancer survivors in Denmark. AB - BACKGROUND: The incidence of head and neck cancer and morbidity and mortality after treatment are associated with social factors. Whether social factors also play a role in the prevalence of late-onset symptoms after treatment for head and neck cancer is not clear. METHODS: Three hundred sixty-nine survivors completed questionnaires on late symptoms and functioning. RESULTS: Survivors with short education were more likely to report severe problems than those with medium or long education. In the fully adjusted model, the risk for problems with opening the mouth remained significantly increased (odds ratio [OR] = 3.20; 95% confidence interval [CI] = 1.18-8.63). For survivors who lived alone, the adjusted ORs were significantly increased for physical functioning (2.17; 95% CI = 1.01-4.68) and trouble with social eating (OR = 2.26; 95% CI = 1.14-4.47). CONCLUSION: Self-reported severe late symptoms were more prevalent in survivors with short education and in those living alone, suggesting differences in perception of late symptoms between social groups. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1713-E1721, 2016. PMID- 26613662 TI - Population genetic structure of Theileria parva field isolates from indigenous cattle populations of Uganda. AB - Theileria parva causes East Coast Fever (ECF) a protozoan infection which manifests as a non-symptomatic syndrome among endemically stable indigenous cattle populations. Knowledge of the current genetic diversity and population structure of T. parva is critical for predicting pathogen evolutionary trends to inform development of effective control strategies. In this study the population genetic structure of 78 field isolates of T. parva from indigenous cattle (Ankole, n=41 and East African shorthorn Zebu (EASZ), n=37) sampled from the different agro ecological zones (AEZs) of Uganda was investigated. A total of eight mini- and micro-satellite markers encompassing the four chromosomes of T. parva were used to genotype the study field isolates. The genetic diversity of the surveyed T. parva populations was observed to range from 0.643+/-0.55 to 0.663+/-0.41 among the Central and Western AEZs respectively. The overall Wright's F index showed significant genetic variation between the surveyed T. parva populations based on the different AEZs and indigenous cattle breeds (FST=0.133, p<0.01) and (FST=0.101, p<0.01) respectively. Significant pairwise population genetic differentiations (p<0.05) were observed with FST values ranging from 0.048 to 0.173 between the eastern and northern, eastern and western populations respectively. The principal component analysis (PCA) showed a high level of genetic and geographic sub-structuring among populations. Linkage disequilibrium was observed when populations from all the study AEZs were treated as a single population and when analysed separately. On the overall, the significant genetic diversity and geographic sub-structuring exhibited among the study T. parva isolates has critical implications for ECF control. PMID- 26613663 TI - Transplacental transmission of bovine tick-borne pathogens: Frequency, co infections and fatal neonatal anaplasmosis in a region of enzootic stability in the northeast of Brazil. AB - Bovine tick-borne disease (TBD) constitutes a worldwide group of diseases that result in great losses for dairy and beef cattle. With regard to the epidemiological profile of the diseases, the importance of transplacental transmission is still not very well understood. The aim of this study was to determine the transplacental transmission of TBD agents (Anaplasma marginale, Babesia bovis and B. bigemina) in a herd of dairy cattle that had been naturally infected in an area of enzootic stability in northeastern Brazil. Blood for serology of the three agents was collected from cows within 120 days of gestation and serology, haemogram and nPCR assays were performed after birth. Blood was collected from the calves within 3h of birth, and haemogram and nPCR assays were performed in all animals. Pre-colostrum serology was achieved in 34 animals. The Student's t-test was used to compare the haemogram results between animals that were positive and negative for the haemoparasites. The cows were seropositive for all agents in at least one of the examinations. We detected 15 cases of vertical transmission of A. marginale, 4 of B. bovis and 2 of B. bigemina in the 60 cows. In infected animals, co-infection was detected for A. marginale and B. bovis in 1 of 60 calves, and a triple infection was detected in one other calf. Fatal neonatal anaplasmosis was observed in 1 of 15 calves, in which death occurred within 24h of birth. From the results, we concluded that transplacental transmission of TBD agents occurs, including in cases of co- and triple infection. Such transplacental transmission can cause neonatal death, increasing the importance of this form of epidemiological transmission and suggesting its role as a cause of undiagnosed neonatal death. PMID- 26613665 TI - Glycophorins, Blood Groups, and Protection from Severe Malaria. AB - In Malawi, Malungo alibe odi is a saying that translates as: 'Malaria does not ask permission before coming in'. The recent finding of a new severe malaria resistance locus next to a cluster of glycophorin genes involved in Plasmodium falciparum erythrocyte invasion seems to suggest otherwise: that evolutionary pressure is enabling erythrocytes to lock the door to keep malaria out. PMID- 26613664 TI - Coinfection by Ixodes Tick-Borne Pathogens: Ecological, Epidemiological, and Clinical Consequences. AB - Ixodes ticks maintain a large and diverse array of human pathogens in the enzootic cycle, including Borrelia burgdorferi and Babesia microti. Despite the poor ecological fitness of B. microti, babesiosis has recently emerged in areas endemic for Lyme disease. Studies in ticks, reservoir hosts, and humans indicate that coinfection with B. burgdorferi and B. microti is common, promotes transmission and emergence of B. microti in the enzootic cycle, and causes greater disease severity and duration in humans. These interdisciplinary studies may serve as a paradigm for the study of other vector-borne coinfections. Identifying ecological drivers of pathogen emergence and host factors that fuel disease severity in coinfected individuals will help guide the design of effective preventative and therapeutic strategies. PMID- 26613666 TI - The necessity-concerns framework predicts adherence to medication in multiple illness conditions: A meta-analysis. AB - OBJECTIVE: This meta-analysis investigated whether beliefs in the necessity and concerns of medicine and the necessity-concerns differential are correlated with medication adherence on a population level and in different conditions. METHODS: An electronic search of Web of Science, EMBASE, PubMed and CINAHL was conducted for manuscripts utilising the Beliefs about Medicines Questionnaire and comparing it to any measure of medication adherence. Studies were pooled using the random effects model to produce a mean overall effect size correlation. Studies were stratified for condition, adherence measure, power and study design. RESULTS: Ninety-four papers were included in the meta-analysis. The overall effect size(r) for necessity, concerns, and necessity-concerns differential was 0.17, -0.18 and 0.24 respectively and these were all significant (p<0.0001). Effect size for necessity was stronger in asthma and weaker in the cardiovascular group compared to the overall effect size. CONCLUSION: Necessity and concerns beliefs and the necessity-concerns differential were correlated with medication adherence on a population level and across the majority of included conditions. The effect sizes were mostly small with a magnitude comparable to other predictors of adherence. PRACTICE IMPLICATIONS: This meta-analysis suggests that necessity and concern beliefs about medicines are one important factor to consider when understanding reasons for non-adherence. PMID- 26613667 TI - Nursing staff and euthanasia in the Netherlands. A nation-wide survey on attitudes and involvement in decision making and the performance of euthanasia. AB - OBJECTIVES: To give insight into Dutch nursing staff's attitudes and involvement regarding euthanasia. METHODS: The sample was recruited from a nation-wide existent research panel of registered nurses and certified nursing assistants. Descriptive analyses and multivariate logistic regression analyses were performed. RESULTS: 587 respondents (response of 65%) completed the questionnaire. The majority (83%) state that physicians have to discuss the decision about euthanasia with the nurses involved. Besides, 69% state that a physician should discuss a euthanasia request with nurses who have regular contact with a patient. Nursing staff who have religious or other beliefs that they consider important for their attitude towards end-of-life decisions, and staff working in a hospital or home care, are most likely to have this opinion. Being present during the euthanasia is quite unusual: only a small group (7%) report that this has ever been the case in their entire working life. Seven% (incorrectly) think they are allowed to administer the lethal drugs. CONCLUSION: The majority want to be involved in decision-making processes about euthanasia. Not all are aware that they are not legally allowed to administer the lethal drugs. PRACTICE IMPLICATIONS: Nursing staff should be informed of relevant existing legislation and professional guidelines. PMID- 26613668 TI - Exploring principles of hibernation for organ preservation. AB - Interest in mimicking hibernating states has led investigators to explore the biological mechanisms that permit hibernating mammals to survive for months at extremely low ambient temperatures, with no food or water, and awaken from their hibernation without apparent organ injury. Hibernators have evolved mechanisms to adapt to dramatic reductions in core body temperature and metabolic rate, accompanied by prolonged periods without nutritional intake and at the same time tolerate the metabolic demands of arousal. This review discusses the inherent resilience of hibernators to kidney injury and provides a potential framework for new therapies targeting ex vivo preservation of kidneys for transplantation. PMID- 26613669 TI - Enhanced left ventricular training in corrected transposition of the great arteries by increasing the preload. AB - OBJECTIVES: Patients with congenitally corrected transposition of the great arteries (ccTGA) without ventricular septal defect or left ventricular outflow tract obstruction need training of the morphological left ventricle (mLV) to undergo a double switch operation (DS) (atrial plus arterial switch). Establishing a sufficient gradient by pulmonary artery banding (PAB) is difficult and multiple re-pulmonary artery bandings (re-PABs) may be necessary to achieve the required physiology. We evaluate a new approach, consisting of a loose PAB in combination with an artificial atrial septal defect (aASD) to not only increase afterload but to dynamically enhance preload as well, in terms of the effectiveness of training of the mLV and the subsequent functional outcome after a DS. METHODS: Six consecutive patients under 6 years of age with ccTGA, who were eligible for anatomical correction, underwent enhanced left ventricular training (eLVT). Four of these patients had failed to reach sufficient mLV pressure by PAB only. RESULTS: Required systemic pressures in the mLV were achieved after a mean of 1.2 years of eLVT with no further re-PAB necessary in any patient. All patients underwent a successful DS with an uneventful postoperative period. At a mean follow-up period of 1.9 (range 0.4-3.8) years, stable LV cardiac function was observed in all patients. CONCLUSIONS: The eLVT provides additional training of the mLV to bring patients to a DS. Even in situations when isolated conventional PAB is not effective enough, the novel combination of pressure and volume loading may help with LV retraining and reduce the need for sequential pulmonary band tightening. PMID- 26613670 TI - Durability of down-sized homografts for the reconstruction of the right ventricular outflow tract. AB - OBJECTIVES: Small-sized homografts are rare but may be required for the reconstruction of the right ventricular outflow tract (RVOT). Down-sizing adult sized homografts can be an option to overcome the shortage of availability. METHODS: Since 1994, we have been down-sizing adult-sized homografts by excising one cusp. The aim of the study was to analyse the durability of down-sized homografts and compare it with small-sized homografts in a paediatric population. All patients below a body weight of 14 kg were included in the study. The end point of the study was homograft failure. RESULTS: A total of 152 patients met the inclusion criteria of the study, of which 82 patients (54%) received a down sized homograft. The median age was 17.1 (0.3-64.8) months and the mean weight 8.4 +/- 3.4 kg. Fifty-eight patients (38%) were under 1 year and 10 (6.5%) under 1 month of age at the time of homograft implantation. The mean homograft size of the whole study population was 14.7 +/- 2.5 mm and the mean z-score was 1.6 +/- 0.9. The median follow-up time was 10 (0.03-19.7) years. Early mortality after homograft implantation was 5% (n = 8), 4 of these patients had received a down sized homograft. The study population comprised early survivors, that is, 144 patients. During follow-up, a total of 46 homografts failed, 23 in each group, after a mean time of 5.7 +/- 4.2 years. Freedom from homograft failure was 94.6 +/- 2.6, 87.2 +/- 4 and 68.6 +/- 6.6% for down-sized homografts and 95.2 +/- 2.7, 78.7 +/- 5.5 and 61 +/- 7% for small-sized homografts at 1, 5 and 10 years, respectively (P = 0.3). Risk factors for homograft failure in the multivariable analysis were a homograft z-score of <1 and age below 1 year at the time of implantation (P = 0.02). CONCLUSION: Down-sized homografts demonstrated a durability similar to that of small-sized homografts. Therefore, down-sizing adult-sized homografts by creating a bicuspid valve to fit into the corresponding RVOT in children with congenital heart defects is an excellent method to overcome the shortage of small-sized homografts. PMID- 26613671 TI - CD4+ CD28-Negative Cells: Armed and Dangerous. PMID- 26613672 TI - Size matters--The phototoxicity of TiO2 nanomaterials. AB - Under solar radiation several titanium dioxide nanoparticles (nano-TiO2) are known to be phototoxic for daphnids. We investigated the influence of primary particle size (10, 25, and 220 nm) and ionic strength (IS) of the test medium on the acute phototoxicity of anatase TiO2 particles to Daphnia magna. The intermediate sized particles (25 nm) showed the highest phototoxicity followed by the 10 nm and 220 nm sized particles (median effective concentrations (EC50): 0.53, 1.28, 3.88 mg/L). Photoactivity was specified by differentiating free OH radicals (therephthalic acid method) and on the other hand surface adsorbed, as well as free OH, electron holes, and O2(-) (electron paramagnetic resonance spectroscopy, EPR). We show that the formation of free OH radicals increased with a decrease in primary particle size (terephthalic acid method), whereas the total measured ROS content was highest at an intermediate particle size of 25 nm, which consequently revealed the highest photoxicity. The photoactivities of the 10 and 220 nm particles as measured by EPR were comparable. We suggest that phototoxicity depends additionally on the particle-daphnia interaction area, which explains the higher photoxicity of the 10 nm particles compared to the 220 nm particles. Thus, phototoxicity is a function of the generation of different ROS and the particle-daphnia interaction area, both depending on particle size. Phototoxicity of the 10 nm and 25 nm sized nanoparticles decreased as IS of the test medium increased (EC50: 2.9 and 1.1 mg/L). In conformity with the Derjaguin Landau-Verwey-Overbeek (DLVO) theory we suggest that the precipitation of nano TiO2 was more pronounced in high than in low IS medium, causing a lower phototoxicity. In summary, primary particle size and IS of the medium were identified as factors influencing phototoxicity of anatase nano-TiO2 to D. magna. PMID- 26613673 TI - Tracking the fingerprints and combined TOC-black carbon mediated soil-air partitioning of polychlorinated naphthalenes (PCNs) in the Indus River Basin of Pakistan. AB - This study reports the first investigation of polychlorinated naphthalenes (PCNs) in air and soil samples from ecologically important sites of the Indus River Basin, Pakistan. The concentrations of ?39-PCNs in air and soil were found in a range between 1-1588 pg m(-3) and 0.02-23 ng g(-1) while the mean TEQ values were calculated to be 5.4E(-04) pg TEQ m(-3) and 1.6E(+01) pg TEQ g(-1), respectively. Spatially, air and soil PCN concentrations were found to be high at Rahim Yar Khan (agricultural region). Lower-medium chlorinated PCNs (sum of tri-, tetra- and penta-CNs) predominated in both air and soil, altogether constituting 87 and 86% of total PCNs in the two environmental matrices, respectively. According to the data, soil-air partitioning of PCNs was interpreted to be similarly controlled by the combined effect of black carbon and organic matter in the Indus River Basin, with no preferential implication of the recalcitrant organic form. PMID- 26613674 TI - Child-Adult Relationship Enhancement (CARE): An evidence-informed program for children with a history of trauma and other behavioral challenges. AB - Child maltreatment impacts approximately two million children each year, with physical abuse and neglect the most common form of maltreatment. These children are at risk for mental and physical health concerns and the ability to form positive social relationships is also adversely affected. Child Adult Relationship Enhancement (CARE) is a set of skills designed to improve interactions of any adult and child or adolescent. Based on parent training programs, including the strong evidence-based treatment, Parent-Child Interaction Therapy (PCIT), CARE was initially developed to fill an important gap in mental health services for children of any age who are considered at-risk for maltreatment or other problems. CARE subsequently has been extended for use by adults who interact with children and youth outside of existing mental health therapeutic services as well as to compliment other services the child or adolescent may be receiving. Developed through discussions with Parent-Child Interaction Therapy (PCIT) therapists and requests for a training similar to PCIT for the non-mental health professional, CARE is not therapy, but is comprised of a set of skills that can support other services provided to families. Since 2006, over 2000 caregivers, mental health, child welfare, educators, and other professionals have received CARE training with a focus on children who are exposed to trauma and maltreatment. This article presents implementation successes and challenges of a trauma-informed training designed to help adults connect and enhance their relationships with children considered at-risk. PMID- 26613675 TI - Enhanced resolution of Mentha piperita volatile fraction using a novel medium polarity ionic liquid gas chromatography stationary phase. AB - The evaluation of a novel medium-polarity ionic-liquid-based gas chromatography column, SLB-IL60, towards the analysis of a complex essential oil, namely, a peppermint essential oil sample, is reported. The SLB-IL60 30 m column was subjected to bleeding measurements, by means of conventional gas chromatography with mass spectrometry. The SLB-IL60 column was then evaluated in the analysis of pure standard compounds, chosen as typical constituents of peppermint essential oil. Resolution and peak symmetry (expressed as tailing factors at 10% of peak height) were measured and the results were compared to those obtained on the most widely used columns in such an application, namely a medium-polarity [100% poly(ethyleneglycol)] stationary phase, and an apolar 5% diphenyl/95% dimethyl siloxane. The final part of the evaluation was dedicated to the gas chromatography with mass spectrometry analysis of a peppermint essential oil sample and again the data were compared to those obtained on the 100% poly(ethyleneglycol) and the 5% diphenyl/95% dimethyl siloxane phase. Linear retention indices were determined for all the identified components on the ionic liquid capillary. PMID- 26613676 TI - Elucidating the Molecular Function of Human BOLA2 in GRX3-Dependent Anamorsin Maturation Pathway. AB - In eukaryotes, the interaction between members of the monothiol glutaredoxin family and members of the BolA-like protein family has been involved in iron metabolism. To investigate the still unknown functional role of the interaction between human glutaredoxin-3 (GRX3) and its protein partner BOLA2, we characterized at the atomic level the interaction of apo BOLA2 with the apo and holo states of GRX3 and studied the role of BOLA2 in the GRX3-dependent anamorsin maturation pathway. From these studies, it emerged that apo GRX3 and apo BOLA2 form a heterotrimeric complex, composed by two BOLA2 molecules and one GRX3 molecule. This complex is able to bind two [2Fe-2S](2+) clusters, each being bridged between a BOLA2 molecule and a monothiol glutaredoxin domain of GRX3, and to transfer both [2Fe-2S](2+) clusters to apo anamorsin producing its mature holo state. Collectively, the data suggest that the heterotrimeric complex can work as a [2Fe-2S](2+) cluster transfer component in cytosolic Fe/S protein maturation pathways. PMID- 26613677 TI - Fifty years of the International Agency for Research on Cancer (1965 to 2015). PMID- 26613678 TI - The perioperative surgical home: An innovative, patient-centred and cost effective perioperative care model. AB - Contrary to the intraoperative period, the current perioperative environment is known to be fragmented and expensive. One of the potential solutions to this problem is the newly proposed perioperative surgical home (PSH) model of care. The PSH is a patient-centred micro healthcare system, which begins at the time the decision for surgery is made, is continuous through the perioperative period and concludes 30 days after discharge from the hospital. The model is based on multidisciplinary involvement: coordination of care, consistent application of best evidence/best practice protocols, full transparency with continuous monitoring and reporting of safety, quality, and cost data to optimize and decrease variation in care practices. To reduce said variation in care, the entire continuum of the perioperative process must evolve into a unique care environment handled by one perioperative team and coordinated by a leader. Anaesthesiologists are ideally positioned to lead this new model and thus significantly contribute to the highest standards in transitional medicine. The unique characteristics that place Anaesthesiologists in this framework include their systematic role in hospitals (as coordinators between patients/medical staff and institutions), the culture of safety and health care metrics innate to the specialty, and a significant role in the preoperative evaluation and counselling process, making them ideal leaders in perioperative medicine. PMID- 26613680 TI - Identification of a Japanese Lynch syndrome patient with large deletion in the 3' region of the EPCAM gene. AB - Germline deletion of the 3' portion of the Epithelial Cell Adhesion Molecule (EPCAM) gene located 5' upstream of MutS Homolog 2 (MSH2) is a novel mechanism for its inactivation in Lynch syndrome. However, its contribution in Japanese Lynch syndrome patients is poorly understood. Moreover, somatic events inactivating the remaining allele of MSH2 in cancer tissue have not been elucidated in Lynch syndrome patients with such EPCAM deletions. We identified a Japanese Lynch syndrome patient with colon cancer who evidenced germline deletion of a 4130 bp fragment of EPCAM encompassing exons 8 and 9 (c.859-672_*2170del). In normal colonic mucosa, two known fusion-transcripts of EPCAM/MSH2 generated from the rearranged gene were observed and heterozygous methylation of the MSH2 gene promoter was detected. In cancer tissue, dense methylation of MSH2 was observed and MLPA analysis demonstrated somatic deletion of the remaining EPCAM allele including exon 9, indicating that somatic deletion of EPCAM is responsible for complete inactivation of MSH2. PMID- 26613681 TI - Sociodemographic correlates of continuing tobacco use - a descriptive report from the Nigerian Survey of Mental Health and Wellbeing. AB - OBJECTIVE: To investigate whether sociodemographic factors were associated with continuing tobacco use in a nationwide Nigerian sample. METHOD: The World Mental Health Survey Schedule was used to interview 6752 Community dwelling participants 18 years and over, selected in a complex multistage sampling from the six geopolitical zones of Nigeria. Ever and current smokers were identified with their sociodemographic characteristics. RESULTS: About 17% (1137/6752) of the participants were ever smokers, 24.8% of whom were current smokers. Participants who completed primary school, had some College education, were never married, or students were more likely to continue using smoke once they commenced its use. Being in the older age group or having had graduate college education was associated with much less likelihood of continuing to use tobacco among ever smokers. CONCLUSION: In general, tobacco smoking rate in Nigeria is lower compared to most developed countries. Younger participants, having some education, those who were never married were more likely to continue tobacco smoking. Determinants of factors associated with continuing tobacco use should be adequately investigated to permit appropriate interventions. PMID- 26613679 TI - Transformation to small-cell lung cancer as a mechanism of acquired resistance to crizotinib and alectinib. AB - A 56-year-old woman, a never-smoker, had postoperative recurrence of anaplastic lymphoma kinase rearranged lung cancer. She achieved a partial response to treatment with an anaplastic lymphoma kinase tyrosine kinase inhibitor, crizotinib. After the tumor regrowth, crizotinib was switched to alectinib; once again a partial response was observed. At the second recurrence, transbronchial needle aspiration of the right paratracheal node was performed, which revealed cytological findings of small-cell carcinoma. While treatment with cisplatin irinotecan chemotherapy made reduction of some tumor shadows, including the biopsied mediastinal lymph nodes, new, small, nodular shadows, highly suggestive of pulmonary metastases, were detected in both lung fields. This case may show proof of the transformation to small-cell lung cancer as a mechanism of resistance to anaplastic lymphoma kinase tyrosine kinase inhibitors in anaplastic lymphoma kinase rearranged tumor. However, this transformation may also be only one part of the resistance mechanism of the heterogeneous tumor. PMID- 26613682 TI - Psychometric evaluation of the Swallowing Outcomes After Laryngectomy (SOAL) patient-reported outcome measure. AB - BACKGROUND: The purpose of this study was to evaluate the psychometric properties of the Swallowing Outcomes After Laryngectomy (SOAL) in a large group of people who underwent a laryngectomy. METHODS: We conducted a cross-sectional psychometric study of laryngectomy patients (minimum 3 months posttreatment) attending routine hospital follow-up for the psychometric evaluation of SOAL. RESULTS: One hundred ten people participated in this study. Thirteen percent of the patients had a laryngectomy, 63% had laryngectomy with radiotherapy, and 24% had laryngectomy with chemoradiation therapy. The SOAL showed good quality of data (minimal missing data and floor effects); good internal consistency (alpha = 0.91); and adequate test-retest reliability (intra-class correlation coefficient = 0.73). In terms of validity, it differentiated people by treatment group (F(2,85) = 8.02; p = .001) and diet texture group (t(102) = -7.33; p < .001). CONCLUSION: The SOAL demonstrates good validity and has potential for use in research. Further study is required to determine its clinical application. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1639-E1645, 2016. PMID- 26613683 TI - Clinical and Pathological Features of Pheochromocytoma in the Horse: A Multi Center Retrospective Study of 37 Cases (2007-2014). AB - BACKGROUND: Pheochromocytoma is the most common adrenal medullary neoplasm of domestic animals, but it is rare in horses. Antemortem diagnosis in horses is difficult, with clinical signs often being vague or non-specific. OBJECTIVE: The objective of this study was to describe the clinical, laboratory, and pathologic findings of pheochromocytoma in horses. ANIMALS: Thirty-seven horses diagnosed with pheochromocytoma based on postmortem examination from 2007 to 2014. METHODS: Retrospective case series. RESULTS: Pheochromocytoma was identified in 37/4094 horses during postmortem examination. Clinical signs consistent with pheochromocytoma had been observed antemortem in only 7 cases, with the remainder being incidental findings. Colic was the most common presenting complaint (13 of 37 cases) and tachycardia was noted in 95% of cases (median heart rate of 86 bpm in clinical cases). Hyperlactatemia (median, 4.9 mmol/L) and hyperglycemia (median, 184 mg/dL) were the most common clinicopathologic abnormalities. Hemoperitoneum caused by rupture of pheochromocytoma was noted in 4/7 clinical cases. Concurrent endocrine abnormalities (eg, thyroid adenoma, adrenal hyperplasia, pituitary pars intermedia hyperplasia or adenoma, parathyroid C-cell carcinoma) were found in 27/37 horses, with 8/37 horses having lesions consistent with multiple endocrine neoplasia syndrome as described in humans. CONCLUSIONS: Pheochromocytoma was diagnosed in 0.95% of horses presented for necropsy. The majority of these were incidental findings, but pheochromocytoma was thought to contribute to clinical findings in 19% of cases, and multiple endocrine neoplasms were commonly seen. Usually an incidental finding at necropsy, pheochromocytoma may cause acute death from intraperitoneal exsanguination and should be considered in horses presenting with colic, tachycardia, and hemoperitoneum. PMID- 26613684 TI - Prevalence of type 2 diabetes in Nepal: a systematic review and meta-analysis from 2000 to 2014. AB - BACKGROUND: Understanding the prevalence of type 2 diabetes in Nepal can help in planning for health services and recognising risk factors. This review aims to systematically identify and collate studies describing the prevalence of type 2 diabetes, to summarise the findings, and to explore selected factors that may influence prevalence estimates. DESIGN: This systematic review was conducted in adherence to the MOOSE Guidelines for Meta-Analysis and Systematic Reviews of Observational Studies. Medical Literature Analysis and Retrieval System (MEDLINE) database from 1 January 2000 to 31 December 2014 was searched for the prevalence of type 2 diabetes among Nepalese populations with a combination of search terms. We exploded the search terms to include all possible synonyms and spellings obtained in the search strategy. Additionally, we performed a manual search for other articles and references of published articles. RESULTS: We found 65 articles; 10 studies fulfilled the inclusion criteria and were included in the analyses. These 10 studies comprised a total of 30,218 subjects. The sample size ranged from 489 to 14,009. All the studies used participants older than age 15, of whom 41.5% were male and 58.5% female. All the studies were cross-sectional and two were hospital-based. Prevalence of type 2 diabetes ranged from a minimum of 1.4% to a maximum of 19.0% and pooled prevalence of type 2 diabetes was 8.4% (95% CI: 6.2-10.5%). Prevalence of type 2 diabetes in urban and rural populations was 8.1% (95% CI: 7.3-8.9%) and 1.0% (95% CI: 0.7-1.3%), respectively. CONCLUSIONS: This is, to our knowledge, the first study to systematically evaluate the literature of prevalence of type 2 diabetes in Nepal. Results showed that type 2 diabetes is currently a high-burden disease in Nepal, suggesting a possible area to deliberately expand preventive interventions as well as efforts to control the disease. PMID- 26613686 TI - Global Maternal, Newborn, and Child Health: Successes, Challenges, and Opportunities. AB - Considerable progress has been made towards reducing under-5 childhood mortality in the Millennium Development Goals era. Reduction in newborn mortality has lagged behind maternal and child mortality. Effective implementation of innovative, evidence-based, and cost-effective interventions can reduce maternal and newborn mortality. Interventions aimed at the most vulnerable group results in maximal impact on mortality. Intervention coverage and scale-up remains low, inequitable and uneven in low-income countries due to numerous health-systems bottle-necks. Innovative service delivery strategies, increased integration and linkages across the maternal, newborn, child health continuum of care are vital to accelerate progress towards ending preventable maternal and newborn deaths. PMID- 26613687 TI - Global Threats to Child Safety. AB - Children have rights, as enumerated in the Declaration of the Rights of the Child, and need protection from violence, exploitation, and abuse. Global threats to child safety exist. These threats include lack of basic needs (food, clean water, sanitation), maltreatment, abandonment, child labor, child marriage, female genital mutilation, child trafficking, disasters, and armed conflicts/wars. Recent disasters and armed conflicts have led to a record number of displaced people especially children and their families. Strategies and specific programs can be developed and implemented for eliminating threats to the safety of children. PMID- 26613685 TI - Genetic associations with reflexive visual attention in infancy and childhood. AB - This study elucidates genetic influences on reflexive (as opposed to sustained) attention in children (aged 9-16 years; N = 332) who previously participated as infants in visual attention studies using orienting to a moving bar (Dannemiller, 2004). We investigated genetic associations with reflexive attention measures in infancy and childhood in the same group of children. The genetic markers (single nucleotide polymorphisms and variable number tandem repeats on the genes APOE, BDNF, CHRNA4, COMT, DRD4, HTR4, IGF2, MAOA, SLC5A7, SLC6A3, and SNAP25) are related to brain development and/or to the availability of neurotransmitters such as acetylcholine, dopamine, or serotonin. This study shows that typically developing children have differences in reflexive attention associated with their genes, as we found in adults (Lundwall, Guo & Dannemiller, 2012). This effort to extend our previous findings to outcomes in infancy and childhood was necessary because genetic influence may differ over the course of development. Although two of the genes that were tested in our adult study (Lundwall et al., 2012) were significant in either our infant study (SLC6A3) or child study (DRD4), the specific markers tested differed. Performance on the infant task was associated with SLC6A3. In addition, several genetic associations with an analogous child task occurred with markers on CHRNA4, COMT, and DRD4. Interestingly, the child version of the task involved an interaction such that which genotype group performed poorer on the child task depended on whether we were examining the higher or lower infant scoring group. These findings are discussed in terms of genetic influences on reflexive attention in infancy and childhood. PMID- 26613688 TI - Infectious Diseases of Poverty in Children: A Tale of Two Worlds. AB - "Infectious diseases of poverty" (IDoP) describes infectious diseases that are more prevalent among poor and vulnerable populations, namely human immunodeficiency virus (HIV) infection, tuberculosis (TB), malaria, and neglected tropical diseases (NTDs). In 2013, 190,000 children died of HIV-related causes and there were 550,000 cases and 80,000 TB deaths in children. Children under age 5 account for 78% of malaria deaths annually. NTDs remain a public health challenge in low- and middle-income countries. This article provides an overview of the major IDoP that affect children. Clinicians must be familiar with the epidemiology and clinical manifestations to ensure prompt diagnosis and treatment. PMID- 26613690 TI - Global Delivery of Human Papillomavirus Vaccines. AB - Worldwide, cervical cancer is the fourth most common cancer among women. Human papillomavirus (HPV) vaccination, if broadly implemented, has the potential to significantly reduce global rates of morbidity and mortality associated with cervical and other HPV-related cancers. More than 100 countries around the world have licensed HPV vaccines. As of February, 2015, there were an estimated 80 national HPV immunization programs and 37 pilot programs. This article discusses global implementation of HPV vaccination programs and issues such as vaccine financing and different approaches to HPV vaccine delivery. PMID- 26613689 TI - Prevention and Control of Childhood Pneumonia and Diarrhea. AB - Pneumonia and diarrhea are the 2 leading infectious causes of death in children younger than 5 years worldwide, most of which occur in low- and middle-income countries (LMICs) in sub-Saharan Africa and Southern Asia. The past decade has seen large reductions in global childhood mortality, partly due to expansion of nonspecific public health interventions and vaccines against Streptococcus pneumoniae, Haemophilus influenzae, and rotavirus in LMICs. Further progress in this field depends on the international community's commitment to fund and implement programs using currently available vaccines and development of new vaccines against pathogens common to children in LMICs. PMID- 26613692 TI - Caring for Children in Immigrant Families: Vulnerabilities, Resilience, and Opportunities. AB - Demographics indicate that pediatricians increasingly care for children in immigrant families in routine practice. Although these children may be at risk for health disparities relating to socioeconomic disadvantage and cultural or linguistic challenges, immigrant families have unique strengths and potential for resilience. Adaptive and acculturation processes concerning health and well-being can be mediated by cultural media. Pediatricians have a professional responsibility to address the medical, mental health, and social needs of immigrant families. Advocacy and research at the practice level and beyond can further explore the unique needs of this population and evidence-based strategies for health promotion. PMID- 26613691 TI - Integrating Children's Mental Health into Primary Care. AB - Children's mental health problems are among global health advocates' highest priorities. Nearly three-quarters of adult disorders have their onset or origins during childhood, becoming progressively harder to treat over time. Integrating mental health with primary care and other more widely available health services has the potential to increase treatment access during childhood, but requires re design of currently-available evidence-based practices to fit the context of primary care and place a greater emphasis on promoting positive mental health. While some of this re-design has yet to be accomplished, several components are currently well-defined and show promise of effectiveness and practicality. PMID- 26613693 TI - Orphans and Vulnerable Children Affected by Human Immunodeficiency Virus in Sub Saharan Africa. AB - In Sub-Saharan Africa, 15.1 million children have been orphaned because of human immunodeficiency virus (HIV). They face significant vulnerabilities, including stigma and discrimination, trauma and stress, illness, food insecurity, poverty, and difficulty accessing education. Millions of additional children who have living parents are vulnerable because their parents or other relatives are infected. This article reviews the current situation of orphans and vulnerable children, explores the underlying determinants of vulnerability and resilience, describes the response by the global community, and highlights the challenges as the HIV pandemic progresses through its fourth decade. PMID- 26613694 TI - Children's Environmental Health: Beyond National Boundaries. AB - Children are especially vulnerable to environmental pollution, a major cause of disease, death, and disability in countries at every level of development. This article reviews threats to children, including air and water pollution, toxic industrial chemicals, pesticides, heavy metals, and hazardous wastes. Global climate change is expected to exacerbate many of these issues. Examples of innovative nongovernmental organizations and governmental programs that address the impacts of environmental hazards on children are included. International travel, adoption, migration, and movement of goods and pollutants worldwide make these conditions concerns for all pediatricians. PMID- 26613695 TI - Our Shrinking Globe: Implications for Child Unintentional Injuries. AB - Unintentional injuries are a leading cause of deaths for children of all ages. Globally, they accounted for 15.4% of 2.6 million deaths recorded among children aged 1 to 14 years in 2013. The 12 highest burden countries in the world by absolute death count and mortality are low- and middle-income countries (LMIC) except for Russia and Equatorial Guinea. These countries accounted for 58% of the 406,442 unintentional injury deaths among 1 to 14 year olds in 2013. Globalization drives inequalities in the distribution of economic gains, risks, and opportunities for preventing child unintentional injuries between high-income countries and LMIC. PMID- 26613696 TI - Adolescent Health Implications of New Age Technology. AB - This article examines the health implications of new age technology use among adolescents. As Internet prevalence has increased, researchers have found evidence of potential negative health consequences on adolescents. Internet addiction has become a serious issue. Pornography is now easily accessible to youth and studies have related pornography with several negative health effects. Cyberbullying has become a large problem as new age technologies have created a new and easy outlet for adolescents to bully one another. These technologies are related to increased morbidity and mortality, such as suicides due to cyberbullying and motor vehicle deaths due to texting while driving. PMID- 26613697 TI - Ethical Issues in Pediatric Global Health. AB - Children are vulnerable to the priorities and decision-making of adults. Usually, parents/caregivers make the difficult healthcare decisions for their children based on the recommendations from the child's healthcare providers. In global health work, healthcare team members from different countries and cultures may guide healthcare decisions by parents and children, and as a result ethical assumptions may not be shared. As a result, ethical issues in pediatric global health are numerous and complex. Here we discuss critical ethical issues in global health at an individual and organizational level in hopes this supports optimized decision-making on behalf of children worldwide. PMID- 26613698 TI - Our Shrinking Globe: Implications for Child Safety. PMID- 26613699 TI - Keeping Children Healthy and Safe Worldwide in the Era of Sustainable Development. PMID- 26613700 TI - Monte Carlo Analysis of Payer and Provider Risks in Shared Savings Arrangements. AB - This article provides a thorough empirical analysis of random variation in shared savings arrangements. It uses claims data from seven provider coalitions that applied for certification to become Medicaid accountable care organizations (ACOs) in New Jersey to conduct Monte Carlo simulations under varying assumptions about true ACO savings. Among all the ACOs examined, the observed savings rate can be several percentage points higher or lower than the assumed true savings rate, leading to large probabilities of Type I and Type II error in determining the existence of savings. Although the effects of random variation are smaller for larger ACOs, the ACO-level coefficient of variation in health care spending also stands out as a highly relevant parameter. The risks of overpayment and underpayment can be minimized through modified specification of the savings measurement methodology. These findings have implications for the terms of shared savings arrangements negotiated between payers and providers. PMID- 26613701 TI - Continued Gains in Health Insurance but Few Signs of Increased Utilization: An Update on the ACA's Dependent Coverage Mandate. AB - OBJECTIVES: To evaluate the Affordable Care Act's dependent coverage mandate impact on insurance take-up and health services use through the second full year of implementation. DATA: Medical Expenditure Panel Survey from 2006 to 2012. STUDY DESIGN: Difference-in-difference regressions comparing pre-/postpolicy outcome changes between 19- to 25-year-olds and 27- to 34-year-olds. PRINCIPAL FINDINGS: Following significant increases in 2011, insurance take-up among 19- to 25-year-olds leveled off overall in 2012. However, increases in coverage for Black young adults were higher in 2012 compared to 2011. Despite increased coverage, there is little evidence of an overall effect on health services use postmandate. Evidence points to increased doctor visits and emergency department visits among Hispanics in the first year postmandate. CONCLUSIONS: The Affordable Care Act young adult mandate led to significant gains in insurance take-up, though evidence suggests that the bulk of the gains occurred in the first year after the mandate. Gains for Black young adults appear to have picked up in 2012. PMID- 26613702 TI - Effects of Hospital Type and Distance on Lymph Node Assessment for Colon Cancer Among Metropolitan and Nonmetropolitan Patients in Appalachia. AB - We studied differences in access to large or accredited cancer programs as a possible explanation for geographic disparities in adherence to the national guideline on lymph node assessment for Stages I to III colon cancer. State cancer registries were linked with Medicare claims of patients diagnosed from 2006 to 2008 from Appalachian counties of four states. Metropolitan and nonmetropolitan patients differed on adherence, proximity to high-volume or accredited hospitals, and hospital type. We modeled effects of hospital type on adherence with ordinary least squares and instrumental variables (instrumenting for hospital type with relative distance). The evidence was strongest for improved adherence in high volume hospitals for nonmetropolitan patients. We estimate that roughly 100 deaths might be prevented over 5 years among each year's incident cases if the nonmetropolitan disparity in hospital volume were eliminated nationally. We conclude that regionalization or targeting smaller hospitals would improve adherence in nonmetropolitan areas, but also argue for improving adherence generally. PMID- 26613703 TI - Routine identification and mixed species detection in 6,192 clinical yeast isolates. AB - The clinical laboratory methods used to diagnose yeast infections should be rapid, reliable, and capable of detecting mixed infections with species exhibiting a distinct antifungal susceptibility profile. In this study, we report the performance of a procedure combining the detection of mixed yeast cultures with a chromogenic medium and MALDI-TOF identification of the colonies. We then evaluated the impact that (i) the isolation medium and (ii) lowering the identification log score (LS) threshold value have on yeast identification performance in the routine laboratory.Among 15,661 clinical samples analyzed, 5,671 tested positive and 6,192 yeasts of 42 distinct species were identified. Overall, 6,117 isolates (98.79%) were identified on the first or second MALDI-TOF Mass Spectrometry (MS) attempt, yielding an average yeast species identification turnaround time of 0.346 days (95% CI [0.326 to 0.364]). The 75 remaining isolates were identified via nucleotide sequencing. Mixed infections accounted for 498 (8.78%) of the positive samples. The MALDI-TOF MS identification procedure performed well, regardless of the culture media tested. Lowering the recommended 2.0 LS threshold value to 1.8 would reduce the number of required (i) second MALDI-TOF MS identification attempts (178 vs. 490) and (ii) ITS2 and D1-D2 sequence-based identifications (17 vs. 75), while achieving an adequate identification rate (6,183/6,192, 99.85%).In conclusion, we propose applying a 1.8 LS threshold combined with chromogenic medium subculture to optimize the yeast identification workflow and detect mixed infection in the clinical laboratory. PMID- 26613704 TI - Schizophyllum commune: an emergent or misdiagnosed fungal pathogen in rhinology? AB - Schizophyllum commune is a common basidiomycete fungus that is rarely involved in human disease. The medical records of patients operated on for fungal rhinosinusitis (FRS) in two University Hospitals between 2012 and 2014 were reviewed. Within the two-year survey, six female, and notably no male, patients were diagnosed with S. commune rhinosinusitis. Mean age was 44.6 years at diagnosis (30 to 68 years). Mean time between onset of symptoms and diagnosis was 8.5 months (2 to 12 months). All six patients were immunocompetent and had no particular host factor for FRS. S. commune was identified using MALDI-TOF mass spectrometry and identifications were confirmed via DNA sequence analysis. Chronic invasive fungal rhinosinusitis was diagnosed in three of our six patients. Based on histological findings, antifungal treatment was delivered in association with surgery. The basidiomycete fungus S. commune is an emerging cause of rhinosinusitis probably as a direct consequence of the recent technological progress in fungal identification methods (DNA sequencing and MALDI TOF mass spectrometry). PMID- 26613705 TI - Uphill both ways: Fatigue and quality of life in valley fever. AB - Primary pulmonary coccidioidomycosis is characterized by prolonged respiratory and systemic symptoms and fatigue. We prospectively administered the fatigue severity scale (FSS) and Short Form-36 Health Status Questionnaire (SF-36) to patients with proven or probable primary pulmonary coccidioidomycosis to quantify disease effect on quality of life (QOL). The 24-week observational study did not specify whether antifungal treatment would be provided; the treating physician made treatment decisions. FSS and SF-36 were completed at 4-week intervals. Thirty-six patients participated, of whom 20 received antifungal treatment. At onset of coccidioidal illness, mean FSS score was higher (ie, more fatigue) in the treatment group. However, in early illness, both groups had higher fatigue levels than reference populations with other diseases (eg, multiple sclerosis). FSS scores gradually improved, and scores in each group were below the severe fatigue level at week 12 and week 16 in the nontreatment and treatment groups, respectively. By week 24, mean FSS score of the nontreatment group equaled the general population. SF-36 component and profile scores were lower (with more symptoms) in the treatment group at each time point than the nontreatment group; both groups showed similar improvement. Mental and emotional health SF-36 scores were not as severely affected as physical scores. Most patients reached a physical functioning level similar to the general population at week 12. Pulmonary coccidioidomycosis causes severe fatigue and substantially affects physical abilities. Fatigue was found to be prolonged, with gradual improvement in QOL, regardless of antifungal administration. PMID- 26613706 TI - 'Locus of control', health-related quality of life, emotional distress and disability in Parkinson's disease. AB - This cross-sectional study evaluated locus of control and its subscales in Parkinson's disease. A total of 50 consecutive Parkinson's disease participants and 50 healthy volunteers (control group) were enrolled. External locus of control was significantly higher in Parkinson's disease participants, whereas internal locus of control had no significant differences. External locus of control and internal locus of control were correlated in control group, but not in Parkinson's disease. In Parkinson's disease participants, external locus of control was negatively associated with health-related quality of life as well as positively associated with emotional distress and disease severity (but not with disability). After adjusting to confound variables, the associations remained. On the other hand, internal locus of control was negatively associated with depression. PMID- 26613707 TI - Predicting negative emotional states following first onset acute coronary syndrome. AB - This study identified predictors of anxiety and depression in patients with acute coronary syndrome. Predictors included illness beliefs, fear/threat at the time of the cardiac event, threat reappraisal over time and social support. A total of 97 participants completed questionnaires in hospital and 1- and 6-month follow up. Perceived threat and fear at the time of the cardiac event predicted affective response at both time points, partly mediated by threat reappraisal. Contemporaneous measures of illness beliefs contributed additional variance, although not always in the predicted direction: high concern and control over the illness were associated with emotional distress. Assessment of patients for risk of negative emotional outcomes of acute coronary syndrome needs to consider their beliefs about their illness and the degree of threat and fear experienced at the time of the event. Interventions need to help people cope with negative emotional states as well as challenging inappropriate illness beliefs. PMID- 26613708 TI - Religious beliefs, coping, and psychological well-being among Greek cancer patients. AB - Using a prospective design, the aim of this study was to examine the relationship between coping and psychological well-being (distress and positive affect) in a sample of Greek cancer patients ( N = 86), giving a special emphasis on the role of religiosity (religious beliefs and coping). Results showed that religious coping during chemotherapy was the only predictor of positive affect 7 months later, when engagement and disengagement strategies were included in the model. The present findings suggest that religious coping may play a positive role in the well-being of patients facing a life-threatening disease, such as cancer. PMID- 26613709 TI - Predicting prostate cancer treatment choices: The role of numeracy, time discounting, and risk attitudes. AB - Prostate cancer is the most common cancer among males in the United States, and there is lack of consensus as to whether active surveillance or radical prostatectomy is the best course of treatment. In this study, we examined the role of numeracy, time discounting, and risk taking on decision-making about prostate cancer treatment-in 279 men over age 50 without a prior prostate cancer diagnosis. Results showed that active surveillance was the most chosen option and its preference was predicted by numeracy and time discounting. However, radical prostatectomy was significantly predicted by participants' propensity to take risks. PMID- 26613710 TI - Commentary: Macroeconomic conditions and social outcomes through a 90-year lens. PMID- 26613711 TI - Commentary: William Ogburn, Dorothy Thomas and the influence of recessions and expansions on mortality. PMID- 26613712 TI - The influence of the business cycle on certain social conditions. PMID- 26613713 TI - Data Resource Profile: the Dutch National Intensive Care Evaluation (NICE) Registry of Admissions to Adult Intensive Care Units. PMID- 26613714 TI - A case report of image-based dosimetry of bone metastases with Alpharadin ((223)Ra-dichloride) therapy: inter-fraction variability of absorbed dose and follow-up. AB - A 70-year-old man affected by bone metastases from castration resistant prostate cancer underwent Alpharadin ((223)Ra-dichloride) therapy (6 administrations of 50 kBq per kg i.v., once every 4 weeks). The inter-fraction variability of the absorbed dose to lesions was evaluated for four injections. Dosimetric assessments were performed following the MIRD approach and a recently published methodology. The mean absorbed dose and standard deviation for 4 lesions [mean (sigma %)] were: 434 mGy (15%) and 516 mGy (21%) for the right and left humeral head, 1205 mGy (14%) and 781 mGy (8%) for the right and left glenoid. The estimated total absorbed dose after the whole treatment, considering also the relative-biological effectiveness of alpha particles (RBE = 5), yielded a D RBE range of 13-36 Gy. A good correlation between (99m)Tc and (223)Ra uptake was obtained (R (2) = 0.7613). The tumour-non-tumour (TNT) ratio of 8 lesions (those above, plus 4 additional), monitored by six (99m)Tc-MDP bone scans over a period of about 10 months, evidenced a TNT reduction in two lesions (-42 and -48 %), but in most lesions the TNT remained fairly constant, evidencing that (223)Ra dichloride therapy tends to prevent further progression of osseous disease, leading to chronicity of the metastatic status. PMID- 26613715 TI - FDG PET/CT for assessing the resectability of NSCLC patients with N2 disease after neoadjuvant therapy. AB - OBJECTIVE: Neoadjuvant chemoradiotherapy (CMRT) is the most effective treatment of stage III non-small-cell lung cancer (NSCLC). The present study aimed at assessing FDG PET/CT for defining the response of N2 disease to neoadjuvant CMRT, as surgical resection after such therapy significantly improves 5-year survival in responding N2 disease. METHODS: Forty-five patients with locally advanced NSCLC underwent both pre-neoadjuvant therapy FDG PET/CT and post-neoadjuvant therapy FDG PET/CT followed by anatomical resection of lung and ipsilateral mediastinal lymph nodes (LN). Seventeen of these patients who had PET/CT studies in our institution and were operated after CMRT were retrospectively included in the study group (12 males, ages 43-78 years; stage IIIA: 14 patients, stage IIIB: 3 patients). PET/CT response in N2 was visually scored per-lymph node station and per patient. Quantitative N2 response was evaluated by SUVmax and total lesion glycolysis (TLG) measurements after therapy alone and in comparison with pre therapy values. PET/CT N2 response was confirmed at surgery. RESULTS: Seventeen NSCLC patients with 29 metastatic N2 lymph nodes (LN) were assessed. Histopathology confirmed 14 responders and 3 non-responders, and was available in 20/29 metastatic LN, showing complete response in 17 and residual disease in 3 LN. LN-based visual analysis of N2 response on PET/CT defined 3 TP, 16 TN and 1 FP, for sensitivity, specificity, accuracy, negative and positive predictive values (NPV and PPV) of 100, 94, 95, 100 and 75%, respectively. Patient-based visual analysis defined 3 TP, 13 TN and 1 FP study, for sensitivity, specificity, accuracy, NPV and PPV of 100, 93, 94, 100 and 75%, respectively. Nodal-based quantitative analysis of FDG uptake in N2 nodes revealed a significant difference between responding and non-responding LN only of SUVmax post-therapy (2.5 +/- 1.21 vs. 3.5 +/- 2.36, P = 0.04). CONCLUSION: FDG PET/CT after neoadjuvant therapy accurately defined response in metastatic N2 nodes of NSCLC patients, presenting very high sensitivity and NPV for detecting responding nodes. PET/CT may enable selection of candidates for curative resection of stage III NSCLC. Mediastinoscopy may not be mandatory in patients with a negative PET/CT after neoadjuvant therapy. PMID- 26613716 TI - Predictors of skilled assistance seeking behavior to pregnancy complications among women at southwest Ethiopia: a cross-sectional community based study. AB - BACKGROUND: In Ethiopia, about 20,000 women die each year from complications of pregnancy and child birth with many more maternal morbidities occurring for each maternal deaths. This makes Ethiopia one of the highest countries for maternal deaths in the developing world. This study attempted to assess women's skilled assistance seeking behaviour for pregnancy complications among those who gave birth. METHOD: A cross-sectional community based study was conducted among women who gave birth within one year regardless of their delivery place. The study was carried out in fifteen randomly selected villages at Arba Minch Zuria district, south west Ethiopia. Data was collected house-to-house using a pretested Amharic questionnaire. During the survey, 798 women were interviewed. Logistic regression model was applied to control confounders. RESULTS: Out of the total sample, 344 (43.1 %) respondents reported at least any one of the pregnancy complications faced in the recent pregnancy. The most common complications reported were malaria (57 %), nausea/vomiting (47.1 %) and severe head ache (29.1 %). of those women who faced complications, around 254 (73.8 %) sought assistance from a skilled provider. Ninety (26.2 %) of the respondents sought assistance either from unskilled provider or home based self-care. Unable to understand the seriousness of the complications, thought as unnecessary, and family disapproval were the major reasons for not seeking care from skilled providers. Belonging to monthly household income $US25- 100 (AOR = 3.4, 95 % CI; 1.04, 11.4), getting antenatal care from a skilled provider (AOR = 10.6, 95 % CI; 3.3, 34.5), Women in the age 20-34 years old (AOR = 3.8; 95 % CI, 1.2, 12.3), Availability of transport access (AOR = 72.2; 95 % CI; 17.2, 303.5) were significantly associated with seeking assistance from a skilled provider. CONCLUSIONS: Nearly half (43.1 %) of the women had faced pregnancy complications to the recent birth of last one year. Majority (2/3(rd)) of the women who reported complications sought skilled assistance. Family, income, transport issue and antenatal care use were independent predictors for skilled assistance from skilled provider. PMID- 26613717 TI - Barriers to Effective Deliberation in Clinical Research Oversight. AB - Ethical oversight of clinical research is one of the primary means of ensuring that human subjects are protected from the natural bias of researchers and research institutions in favor of experimentation. At a minimum, effective oversight should ensure that risks are minimized and reasonable in relation to anticipated benefits, protect vulnerable subjects from potential coercion or undue influence, ensure full and informed consent, and promote the equitable distribution of the risks and benefits of research. Because these assessments often involve value judgments for which there are no agreed-upon objective standards, we rely on deliberative procedures thought to have the greatest likelihood of producing the right or best outcomes. Concerns about the potential for improperly functioning IRBs to waste scarce human and institutional resources and impede biomedical progress have motivated a surge in empirical research assessing their procedures and outcomes. Yet within this literature, there has been minimal attention paid to the social scientific evidence regarding how individuals and deliberating groups make decisions, nor how those data might inform IRB practice. This essay seeks to fill that gap, locating recent empirical data on IRB composition and process within the context of data regarding what I call "deliberative pathologies," or instances when deliberation fails to live up to one or more aspect of the deliberative ideal because of systematic biases in the ways participants interact. The paper goes on to make evidence-based recommendations to reduce the vulnerability of IRB deliberations to the kinds of pathologies discussed and indicate directions for future research. PMID- 26613718 TI - Molar incisor hypomineralisation: experience and perceived challenges among dentists specialising in paediatric dentistry and a group of general dental practitioners in the UK. AB - AIM: To assess the views and experience of the UK dentists specialising in paediatric dentistry (trainees) about molar incisor hypomineralisation (MIH) and compare the findings with the responses from a group of UK general dental practitioners. METHOD: A web-based questionnaire was sent to dentists undergoing specialist training in paediatric dentistry. The same questionnaire was completed by a group of general dentists who stated an interest in treating children, with various levels of experience. The questionnaire sought information on clinical experience and the views of the dentists on the impact of MIH on children and families. RESULTS: Specialty trainees (37) from different paediatric dental departments in the UK completed the online survey, giving a total response rate of 71%. The questionnaire was also completed by 31 general dental practitioners. There was difficulty in distinguishing MIH from other conditions for both groups. Increased sensitivity of affected teeth was the most frequently encountered problem with 51% of the trainees and 76% of the dentists saying this was often or always a challenge. The trainees were particularly concerned about the pain children experienced and about the appearance of the condition. Both groups felt that parental anxiety occurred in almost all cases. CONCLUSIONS: Both groups felt that MIH presents several clinical challenges and has a negative effect on the quality of life of the affected children and their families. There were significant differences in the views and perceptions between the two groups. PMID- 26613719 TI - Monoallelic BAFFR P21R/H159Y Mutations and Familiar Primary Antibody Deficiencies. PMID- 26613720 TI - ACC and IPL networks in the perception of the faces of parents during selective tasks. AB - The perception of the faces of parents is different from that of other faces. Mother's face perception is associated with childbearing and parenting and has specific cognitive processing properties. Yet, the underlying mechanism remains unknown. We investigated the neural network that is involved in the perception of parent's face based upon parental face selective tasks that were completed by 23 normal adults. Resting state functional magnetic resonance imaging (fMRI) and a task block design with fixation cross sign control fMRI were used. The faces activated the right inferior frontal gyrus, the left and right middle frontal gyri, and the left and right inferior parietal lobule. In addition, the parental faces task resulted in more activation than the control tasks in the left and right anterior cingulate, left middle (superior) temporal gyrus, right and left inferior frontal gyrus. The anterior cingulate cortex (ACC) and the inferior parietal lobe (IPL) are central nodes of the brain network, while the parental face perception network includes the anterior cingulate cortex and superior temporal gyrus (ACC-STG)/parahippocampal network as well as the inferior frontal and inferior parietal lobule (IFG-IPL) network. The network of father's face perception involves the left inferior parietal lobule and left middle frontal gyrus/right middle frontal gyrus/right inferior frontal gyrus, while mother's face perception involves the right inferior parietal lobe and frontal network (MFG.L/IFG.R). The experiments showed that the ACC-STG/parahippocampal network and IFG-IPL network are neural networks used in parental face perception, and the ACC and IPL are central nodes in the network. The neural pathway of parental face perception is similar to the perception of a stranger's face, as both include the STG, but is different in that the perception of the stranger's face involves a connected STG and IPL as a specific neural pathway. PMID- 26613721 TI - Clinical characteristics of supine hypertension in de novo Parkinson disease. AB - PURPOSE: Supine hypertension is frequently associated with autonomic failure. However, its clinical characteristics in patients with Parkinson disease (PD) remain unclear. The present study aimed to clarify the characteristics of supine hypertension in patients with de novo PD. METHODS: The subjects were 72 patients with de novo PD. We studied blood pressure and plasma norepinephrine levels after the patients rested for 20 min in the supine position. Changes in blood pressure were also examined on head-up tilt-table testing. RESULTS: The disease duration was 1.7 +/- 1.6 years (average +/- SD). Thirty-three (45.8 %) patients had supine hypertension (defined as a blood pressure of >=140/90 mmHg). Supine blood pressure positively correlated with the degree of orthostatic hypotension. Age and the proportion of patients with akinetic-rigid motor subtype or preexisting hypertension were higher among patients with supine hypertension than among those without supine hypertension. The Mini-Mental State Examination score was lower in patients with supine hypertension than in those without supine hypertension. Sex, disease duration, disease severity, and peripheral sympathetic nervous activity as evaluated by the cardiac uptake of (123)I-metaiodobenzylguanidine and the plasma norepinephrine level did not differ between patients with and those without supine hypertension. CONCLUSION: Older age, akinetic-rigid motor subtype, and preexisting hypertension are independent risk factors for supine hypertension. Supine hypertension alone may be associated with milder peripheral sympathetic nervous denervation than orthostatic hypotension alone. As for global cognitive decline, supine hypertension is a far riskier comorbidity of early stage PD than is orthostatic hypotension. PMID- 26613722 TI - Guillain-Barre syndrome following dengue fever and literature review. AB - BACKGROUND: Dengue is an arboviral infection that classically presents with fever, joint pain, headaches, skin flush and morbilliform rashes. The incidence of neurological symptoms and complications in dengue varies from 1 to 25% that include encephalopathy, Guillain-Barre syndrome (GBS), acute motor weakness, seizures, neuritis, hypokalaemic paralysis, pyramidal tract signs, and a few more. Dengue fever as an antecedent infection in GBS is uncommon. CASE PRESENTATION: A 34-years-old Sri Lankan Sinhalese male presented with fever, headache and myalgia of 3 days and developed leucopenia and thrombocytopenia without evidence of haemoconcentration. The diagnosis of dengue fever was confirmed as he had positive dengue NS1 antigen test on the third day of fever. He made full recovery and was discharged after 4 days of hospital stay. Six days later, he presented with history of acute flaccid weakness of both lower limbs and upper limbs which was of progressive ascending nature. The electromyography had evidence of demyelinating neuropathy and cerebrospinal fluid showed albuminocytological dissociation. Subsequently, IgM for dengue virus was positive. CONCLUSION: Dengue is endemic in Sri Lanka. Post dengue Guillain-Barre syndrome is a potential neurological complications of this infection. PMID- 26613723 TI - Diagnostic tools for assessment of urinary dysfunction in MS patients without urinary disturbances. AB - Many guidelines are available for the management of lower urinary tract symptoms (LUTSs) in multiple sclerosis (MS) patients, but no agreement exists on the best approach for subjects without LUTSs. The objective of this study was to evaluate whether LUTSs can be detected in MS patients asymptomatic for urinary dysfunction, comparing three different tools [measure of post-void residual volume (PRV), bladder diary (BD), a focused questionnaire (IPSS)], and whether disability, disease duration and signs of pyramidal involvement are linked to their subclinical presence. 178 MS patients (118 women) have been included (mean age 41.2 years, mean disease duration 11.3 years, mean EDSS 2.2), and tested with the above-mentioned tools. PRV was abnormal in 14 subjects (7.8%), associated to abnormal findings at IPSS in 3 cases, at BD in 2 cases, at both in 1. BD was abnormal in 37 subjects (20.8%), with concomitant abnormal PRV in 2, abnormal IPSS in 10 cases, abnormal IPSS and BD in 1. IPSS was >= 9 in 43 subjects (24.1%). At least one test was abnormal in 76 patients (42.7%): 1 in 57 patients (32.0%), 2 in 17 (9.5%), and 3 tests in 2 (1.1%). Patients with at least one abnormal urinary variable, compared to patients without urinary abnormalities, had a more frequent pyramidal involvement (69.5 vs. 16.8%, chi(2) = 48.6, p < 0.00001), a more frequent occurrence of EDSS >=2 (83.1 vs. 23.5%, chi(2) = 56.9, p < 0.00001), and a longer disease duration (15.7 +/- 7.3 vs. 9.1 +/- 7.1, t = 5.7, p < 0.00001). Asymptomatic LUTS were frequent but none of the tests used permitted to better identify asymptomatic patients. PMID- 26613724 TI - A Novel Approach Based on Data Redundancy for Feature Extraction of EEG Signals. AB - Feature extraction and classification for electroencephalogram (EEG) in medical applications is a challenging task. The EEG signals produce a huge amount of redundant data or repeating information. This redundancy causes potential hurdles in EEG analysis. Hence, we propose to use this redundant information of EEG as a feature to discriminate and classify different EEG datasets. In this study, we have proposed a JPEG2000 based approach for computing data redundancy from multi channels EEG signals and have used the redundancy as a feature for classification of EEG signals by applying support vector machine, multi-layer perceptron and k nearest neighbors classifiers. The approach is validated on three EEG datasets and achieved high accuracy rate (95-99 %) in the classification. Dataset-1 includes the EEG signals recorded during fluid intelligence test, dataset-2 consists of EEG signals recorded during memory recall test, and dataset-3 has epileptic seizure and non-seizure EEG. The findings demonstrate that the approach has the ability to extract robust feature and classify the EEG signals in various applications including clinical as well as normal EEG patterns. PMID- 26613726 TI - Age-Related Neural Oscillation Patterns During the Processing of Temporally Manipulated Speech. AB - This EEG-study aims to investigate age-related differences in the neural oscillation patterns during the processing of temporally modulated speech. Viewing from a lifespan perspective, we recorded the electroencephalogram (EEG) data of three age samples: young adults, middle-aged adults and older adults. Stimuli consisted of temporally degraded sentences in Swedish-a language unfamiliar to all participants. We found age-related differences in phonetic pattern matching when participants were presented with envelope-degraded sentences, whereas no such age-effect was observed in the processing of fine structure-degraded sentences. Irrespective of age, during speech processing the EEG data revealed a relationship between envelope information and the theta band (4-8 Hz) activity. Additionally, an association between fine-structure information and the gamma band (30-48 Hz) activity was found. No interaction, however, was found between acoustic manipulation of stimuli and age. Importantly, our main finding was paralleled by an overall enhanced power in older adults in high frequencies (gamma: 30-48 Hz). This occurred irrespective of condition. For the most part, this result is in line with the Asymmetric Sampling in Time framework (Poeppel in Speech Commun 41:245-255, 2003), which assumes an isomorphic correspondence between frequency modulations in neurophysiological patterns and acoustic oscillations in spoken language. We conclude that speech specific neural networks show strong stability over adulthood, despite initial processes of cortical degeneration indicated by enhanced gamma power. The results of our study therefore confirm the concept that sensory and cognitive processes undergo multidirectional trajectories within the context of healthy aging. PMID- 26613725 TI - Neurological Gait Abnormalities Moderate the Functional Brain Signature of the Posture First Hypothesis. AB - The posture first hypothesis suggests that under dual-task walking conditions older adults prioritize gait over cognitive task performance. Functional neural confirmation of this hypothesis, however, is lacking. Herein, we determined the functional neural correlates of the posture first hypothesis and hypothesized that the presence of neurological gait abnormalities (NGA) would moderate associations between brain activations, gait and cognitive performance. Using functional near-infrared spectroscopy we assessed changes in oxygenated hemoglobin levels in the pre-frontal cortex (PFC) during normal walk and walk while talk (WWT) conditions in a large cohort of non-demented older adults (n = 236; age = 75.5 +/- 6.49 years; female = 51.7 %). NGA were defined as central (due to brain diseases) or peripheral (neuropathic gait) following a standardized neurological examination protocol. Double dissociations between brain activations and behavior emerged as a function of NGA. Higher oxygenation levels during WWT were related to better cognitive performance (estimate = 0.145; p < 0.001) but slower gait velocity (estimate = -6.336, p < 0.05) among normals. In contrast, higher oxygenation levels during WWT among individuals with peripheral NGA were associated with worse cognitive performance (estimate = -0.355; p < 0.001) but faster gait velocity (estimate = 14.855; p < 0.05). Increased activation in the PFC during locomotion may have a compensatory function that is designed to support gait among individuals with peripheral NGA. PMID- 26613727 TI - Regulation of mitochondrial inner membrane fusion: divergent evolution with similar solutions? AB - Continuous mitochondrial fusion and fission define the dynamic shape of mitochondria. One essential player of mitochondrial fusion is the conserved inner membrane dynamin-like GTPase Mgm1/OPA1. Limited proteolysis of this protein has been proposed as a mechanism to separate and subsequently eliminate dysfunctional parts from the mitochondrial network. Here, I briefly summarize our current knowledge about the underlying proteolytic processing steps in mammals, baker's yeast, Schizosaccharomyces pombe, Drosophila melanogaster and Aspergillus fumigatus. The apparent great diversity in Mgm1/OPA1 processing among the analyzed species indicates a surprising mechanistic heterogeneity in the regulation of mitochondrial inner membrane fusion. PMID- 26613728 TI - Post-transcriptional regulation in budding yeast meiosis. AB - The precise regulation of gene expression is essential for developmental processes in eukaryotic organisms. As an important post-transcriptional regulatory point, translational control is complementary to transcriptional regulation. Sporulation in the budding yeast Saccharomyces cerevisiae is a developmental process controlled by a well-studied transcriptional cascade that drives the cell through the events of DNA replication, meiotic chromosome segregation, and spore assembly. Recent studies have revealed that as cells begin the meiotic divisions, translational regulation of gene expression fine tunes this transcriptional cascade. The significance and mechanisms of this translational regulation are beginning to emerge. These studies may also provide insights into translational regulation in germ cell development of multicellular organisms. PMID- 26613729 TI - Evolutionary concept analysis of health seeking behavior in nursing: a systematic review. AB - BACKGROUND: Although the research in health seeking behavior has been evolving, its concept remains ambiguous. Concept clarification, as a central basis of developing knowledge, plays an undeniable role in the formation of nursing sciences. As the initial step toward the development of theories and theoretical models, concept analysis is broadly used through which the goals can be used and tested. The aim of this study was to report an analysis of the concept of "health seeking behavior". METHOD: Employing a rigorous evolutionary concept analysis approach, the concept of health seeking behavior was examined for its implications, use, and significance in the discipline of nursing between 2000 and 2012. After applying inclusion and exclusion criteria, a total of 40 articles and 3 books were selected for the final analysis. RESULTS: The definition of attributes, antecedents, and consequences of health seeking behavior was performed through concept analysis. Core attributes (interactional, processing, intellectual, active, decision making based and measurable) were studied. The antecedents of concept were categorized as social, cultural, economic, disease pattern and issues related to health services. Health-seeking behavior resulted in health promotion and disease risk reduction. In addition, it led to predicting the future probable burden of the diseases, facilitation of the health status, early diagnosis, complete and effective treatment, and complication control. CONCLUSION: Health-seeking behavior, as a multi-dimensional concept, relies on time and context. An awareness of health-seeking behavior attributes antecedents and consequences results in promoting the status, importance and application of this concept in the nursing profession. PMID- 26613730 TI - Characterization of UGPase from Aureobasidium pullulans NRRL Y-12974 and Application in Enhanced Pullulan Production. AB - UDPG pyrophosphatase (UGPase) plays an important role in carbohydrate metabolism, catalyzing a reversible production of uridine diphosphate glucose (UDPG) and pyrophosphate (PPi) from Glc-1-P and UTP. UGPase gene from Aureobasidium pullulans NRRL Y-12974 was cloned, overexpressed in Escherichia coli. The recombinant UGPase possess molecular mass of 55 KDa and specific activity of 7.33 U/mg protein. The K m values of rUGPase were 5.045 MUM against UTP and 3.333 MUM against Glc-1-P. The V max values of rUGPase were 3.467 MUM min(-1)against UTP and 2.817 MUM min(-1) against Glc-1-P. And, it does not catalyze Glc-1-P and ATP, nor galactose-1-P and UTP. Homolgous expression of UGPase in native organism can improve the intracellular UDPG concentration by 4.7-fold time. The yield of pullulan in engineering strain A4 was improved to 18.2 g g(-1) cell dry weight which is 1.3-fold time of parent strain. No obvious change of growth was found between engineering strain and parent strain. To the best of our knowledge, this is the first report of improving pullulan yield in A. pullulans using metabolic engineering technique. PMID- 26613731 TI - Tumour budding in colorectal cancer: what do we know and what can we do? AB - Budding is a process during which individual or small clusters of up to five tumour cells detach from the main tumour mass and invade into the surrounding stroma. In colorectal cancer, this feature is observed in 20-40% of cases and is associated with lymphovascular invasion, lymph node and distant metastases, and poor prognosis. A variety of scoring systems for budding have been proposed but so far a gold standard is lacking, hampering implementation of a budding score in guidelines for pathological examination of colorectal cancer. Furthermore, little is known about the mechanisms which cause tumour cells to detach from the main tumour mass and obtain increased invasive potential. In this review, we present an overview of tumour budding including its definition, scoring systems, prognostic relevance and biological mechanisms involved. PMID- 26613732 TI - Radiation dose and intra-articular access: comparison of the lateral mortise and anterior midline approaches to fluoroscopically guided tibiotalar joint injections. AB - PURPOSE: To compare the lateral mortise and anterior midline approaches to fluoroscopically guided tibiotalar joint injections with respect to successful intra-articular needle placement, fluoroscopy time, radiation dose, and dose area product (DAP). MATERIALS AND METHODS: This retrospective study was IRB-approved and HIPAA-compliant. 498 fluoroscopically guided tibiotalar joint injections were performed or supervised by one of nine staff radiologists from 11/1/2010 12/31/2013. The injection approach was determined by operator preference. Images were reviewed on a PACS workstation to determine the injection approach (lateral mortise versus anterior midline) and to confirm intra-articular needle placement. Fluoroscopy time (minutes), radiation dose (mGy), and DAP (MUGy-m(2)) were recorded and compared using the student's t-test (fluoroscopy time) or the Wilcoxon rank sum test (radiation dose and DAP). RESULTS: There were 246 lateral mortise injections and 252 anterior midline injections. Two lateral mortise injections were excluded from further analysis because no contrast was administered. Intra-articular location of the needle tip was documented in 242/244 lateral mortise injections and 252/252 anterior midline injections. Mean fluoroscopy time was shorter for the lateral mortise group than the anterior midline group (0.7 +/- 0.5 min versus 1.2 +/- 0.8 min, P < 0.0001). Mean radiation dose and DAP were less for the lateral mortise group than the anterior midline group (2.1 +/- 3.7 mGy versus 2.5 +/- 3.5 mGy, P = 0.04; 11.5 +/- 15.3 MUGy-m(2) versus 13.5 +/- 17.3 MUGy-m(2), P = 0.006). CONCLUSION: Both injection approaches resulted in nearly 100% rates of intra-articular needle placement, but the lateral mortise approach used approximately 40% less fluoroscopy time and delivered 15% lower radiation dose and DAP to the patient. PMID- 26613733 TI - Progression of inflammation during immunodeficient mouse skeletal muscle regeneration. AB - The skeletal muscle injury triggers the inflammatory response which is crucial for damaged muscle fiber degradation and satellite cell activation. Immunodeficient mice are often used as a model to study the myogenic potential of transplanted human stem cells. Therefore, it is crucial to elucidate whether such model truly reflects processes occurring under physiological conditions. To answer this question we compared skeletal muscle regeneration of BALB/c, i.e. animals producing all types of inflammatory cells, and SCID mice. Results of our study documented that initial stages of muscles regeneration in both strains of mice were comparable. However, lower number of mononucleated cells was noticed in regenerating SCID mouse muscles. Significant differences in the number of CD14 /CD45+ and CD14+/CD45+ cells between BALB/c and SCID muscles were also observed. In addition, we found important differences in M1 and M2 macrophage levels of BALB/c and SCID mouse muscles identified by CD68 and CD163 markers. Thus, our data show that differences in inflammatory response during muscle regeneration, were not translated into significant modifications in muscle regeneration. PMID- 26613734 TI - Interactions between imidazoline I2 receptor ligands and acetaminophen in adult male rats: antinociception and schedule-controlled responding. AB - RATIONALE: Recent evidence suggests that imidazoline I2 receptor ligands are suitable for combination therapy with opioids. Quantitative analysis of I2 receptor ligands combined with non-opioid drugs is necessary for the justification of alternative pain therapies. OBJECTIVE: This study systematically examined the antihyperalgesic and response rate-suppressing effects of selective I2 receptor ligands (2-BFI and phenyzoline) alone and in combination with acetaminophen. METHODS: Von Frey and Hargreaves tests were used to examine the antihyperalgesic effects of drugs in complete Freund's adjuvant (CFA)-induced inflammatory pain in rats. Food-reinforced schedule-controlled responding was used to assess the rate-suppressing effects of study drugs. Dose-addition and isobolographic analyses were used to assess drug-drug interactions for all assays. RESULTS: 2-BFI (3.2-17.8 mg/kg, i.p.), phenyzoline (17.8-100 mg/kg, i.p.), and acetaminophen (56-178 mg/kg, i.p.) all dose-dependently produced significant antinociceptive effects. When studied as combinations, 2-BFI and acetaminophen produced infra-additive to additive interactions while phenyzoline and acetaminophen produced additive to supra-additive interactions. The same drug combinations suppressed response rate in a supra-additive manner. CONCLUSIONS: Quantitative analysis of the antihyperalgesic and response rate-suppressing effects suggests that I2 receptor ligands are not well suited to combination therapy with acetaminophen. PMID- 26613735 TI - Brain Angiotensin II AT1 receptors are involved in the acute and long-term amphetamine-induced neurocognitive alterations. AB - RATIONALE: Angiotensin II, by activation of its brain AT1-receptors, plays an active role as neuromodulator in dopaminergic transmission. These receptors participate in the development of amphetamine-induced behavioral and dopamine release sensitization. Dopamine is involved in cognitive processes and provides connectivity between brain areas related to these processes. Amphetamine by its mimetic activity over dopamine neurotransmission elicits differential responses after acute administration or after re-exposure following long-term withdrawal periods in different cognitive processes. OBJECTIVE: The purpose of this study is to evaluate the AT1-receptor involvement in the acute and long-term amphetamine induced alterations in long-term memory and in cellular-related events. METHODS: Male Wistar rats (250-300 g) were used in this study. Acute effects: Amphetamine (0.5/2.5 mg/kg i.p.) was administered after post-training in the inhibitory avoidance (IA) response. The AT1-receptor blocker Losartan was administered i.c.v. before a single dose of amphetamine (0.5 mg/kg i.p.). Long-term effects: The AT1-receptors blocker Candesartan (3 mg/kg p.o.) was administered for 5 days followed by 5 consecutive days of amphetamine (2.5 mg/kg/day, i.p.). The neuroadaptive changes were evidenced after 1 week of withdrawal by an amphetamine challenge (0.5 mg/kg i.p.). The IA response, the neuronal activation pattern, and the hippocampal synaptic transmission were evaluated. RESULTS: The impairing effect in the IA response of post-training acute amphetamine was partially prevented by Losartan. The long-term changes induced by repeated amphetamine (resistance to acute amphetamine interference in the IA response, neurochemical altered response, and increased hippocampal synaptic transmission) were prevented by AT1-receptors blockade. CONCLUSIONS: AT1-receptors are involved in the acute alterations and in the neuroadaptations induced by repeated amphetamine associated with neurocognitive processes. PMID- 26613736 TI - Systematic review of patient safety interventions in dentistry. AB - BACKGROUND: The concept of patient safety in dentistry is in its infancy, with little knowledge about the effectiveness of tools or interventions developed to improve patient safety or to minimise the occurrence of adverse events. METHODS: The aim of this qualitative systematic review was to search the academic and grey literature to identify and assess tools or interventions used in dental care settings to maintain or improve patient safety. All study designs were included from all dental care settings. Outcome measures were: patient safety, harm prevention, risk minimization, patient satisfaction and patient acceptability, professional acceptability, efficacy, cost-effectiveness and efficiency. Quality assessments were performed on the included studies based on CASP tools. Further analysis was undertaken to discover whether any of the tools had been trialled or verified by the authors, or by subsequent authors. RESULTS: Following abstract screening, and initial qualitative synthesis, nine studies were found to meet the inclusion criteria with 31 being excluded following initial analysis. Tools identified included: checklists (4 studies), reporting systems (3), the use of electronic notes (1) and trigger tools (1). Grey literature searching did not identify any further appropriate studies. In terms of study design, there were observational studies including audit cycles (5 studies), epidemiological studies (3) and prospective cluster randomised clinical trials (1). The quality of the studies varied and none of their outcomes were verified by other researchers. The tools identified have the potential to be used for measuring and improving patient safety in dentistry, with two surgical safety checklists demonstrating a reduction in erroneous dental extractions to nil following their introduction. Reporting systems provide epidemiological data, however, it is not known whether they lead to any improvement in patient safety. The one study on trigger tools demonstrates a 50 % positive predictive value for safety incidents. It is not clear as to what impact the introduction of electronic guidelines has on patient safety outcomes. CONCLUSIONS: This systematic review finds that the only interventions in dentistry that reduce or minimise adverse events are surgical safety checklists. We believe this to be the first systematic review in this field; it demonstrates the need for further research into patient safety in dentistry across several domains: epidemiological, conceptual understanding and patient and practitioner involvement. PMID- 26613737 TI - Colloidal silica-induced hypersensitivity: myth or reality. AB - BACKGROUND: Many excipients have been reported to induce drug hypersensitivity (e.g. colouring additives, preservatives). Colloidal silica has never been reported to induce drug hypersensitivity reactions. CASE REPORT: We report herein a 40-year-old patient who developed a skin eruption 2 days after Voltarene((r)) (diclofenac) intake, confirmed by a positive patch test. Investigation of cross reactivity, assessed by patch testing to other non steroidal anti-inflammatory drugs, have showed a positive reaction only to piroxicam (Piroxen((r))), ketoprofen (Oki((r))) and indometacin (Indocid((r))). A hypersensivity to colloidal silica, a common excipient, was suspected. A patch test to this compound was performed showing a positive reaction. CONCLUSION: Colloidal silica, a compound widely used in drug manufacturing, could be another culprit excipient in inducing skin hypersensitivity reactions. PMID- 26613738 TI - Pharmacist independent prescribing in secondary care: opportunities and challenges. AB - In recent years a number of countries have extended prescribing rights to pharmacists in a variety of formats. The latter includes independent prescribing, which is a developing area of practice for pharmacists in secondary care. Potential opportunities presented by wide scale implementation of pharmacist prescribing in secondary care include improved prescribing safety, more efficient pharmacist medication reviews, increased scope of practice with greater pharmacist integration into acute patient care pathways and enhanced professional or job satisfaction. However, notable challenges remain and these need to be acknowledged and addressed if a pharmacist prescribing is to develop sufficiently within developing healthcare systems. These barriers can be broadly categorised as lack of support (financial and time resources), medical staff acceptance and the pharmacy profession itself (adoption, implementation strategy, research resources, second pharmacist clinical check). Larger multicentre studies that investigate the contribution of hospital-based pharmacist prescribers to medicines optimisation and patient-related outcomes are still needed. Furthermore, a strategic approach from the pharmacy profession and leadership is required to ensure that pharmacist prescribers are fully integrated into future healthcare service and workforce strategies. PMID- 26613739 TI - Narrative interviewing. AB - Introduction Narrative interviews place the people being interviewed at the heart of a research study. They are a means of collecting people's own stories about their experiences of health and illness. Narrative interviews can help researchers to better understand people's experiences and behaviours. Narratives may come closer to representing the context and integrity of people's lives than more quantitative means of research. Methodology Researchers using narrative interview techniques do not set out with a fixed agenda, rather they tend to let the interviewee control the direction, content and pace of the interview. The paper describes the interview process and the suggested approach to analysis of narrative interviews, We draw on the example from a study that used series of narrative interviews about people's experiences of taking antidepressants. Limitations Some people may find it particularly challenging to tell their story to a researcher in this way rather than be asked a series of questions like in a television or radio interview. Narrative research like all qualitative research does not set out to be generalisable and may only involve a small set of interviews. PMID- 26613740 TI - Interdental papilla loss: treatment by hyaluronic acid gel injection: a case series. AB - OBJECTIVES: The purpose of this prospective clinical trial was to examine the clinical and patient outcomes following esthetic reconstruction of interdental papilla loss in anterior teeth, using an injectable, non-animal-based, hyaluronic acid gel. MATERIALS AND METHODS: Ten systemically healthy adults, with at least one anterior site with class I or II interdental papilla loss, were recruited. Following local anesthesia, ~0.2 ml of hyaluronic acid gel was injected directly into the base of the papilla. The injection was repeated twice 21 days later. Patients were seen monthly for follow-up. Lost papilla surface area was calculated from digital clinical photographs taken at baseline and at 4 and 6 months postoperatively. Differences in lost papilla surface area between baseline and postoperative time points were statistically analyzed. Participants completed questionnaires (satisfaction surveys). RESULTS: Seventeen sites (13 maxillary, 4 mandibular) were treated in 9 females who completed the study. The lost inderdental papilla area at baseline and at the 4- and 6-month postoperative visits was 1.2 +/- 1.8 mm(2) (mean +/- SD), 0.6 +/- 0.9 mm(2), and 0.7 +/- 0.7 mm(2), respectively. Differences between baseline and postoperative visits were statistically significant (p < 0.0001). Two thirds of the patients would choose to undergo the procedure again. CONCLUSIONS: Use of hyaluronic acid gel to treat interdental papilla loss resulted in significant improvement at 6 months. Patients expressed satisfaction with the obtained improvement and dissatisfaction with the associated procedure discomfort. CLINICAL RELEVANCE: Treatment of interdental papilla loss (black triangle) by hyaluronic acid gel injection appears a promising modality to address this esthetic patient concern. PMID- 26613741 TI - [Social inequalities in the occurrence of chronic diseases]. AB - The risks of the occurrence of most chronic diseases are unequally distributed. The highest risks occur in men and women with the lowest incomes, the lowest educational qualifications, and in occupations with the lowest decision latitude. Education, occupational position, and income as indicators of socio-economic position differ with regard to their latent content and can thus not be considered to be interchangeable. The relative magnitudes of their effects differ according to the diseases considered, but all three are not available in all studies. After an explanation of the latent content of the most frequently used indicators of social differentiation, health inequalities are considered by using four groups of chronic illnesses: oral, type 2 diabetes, cardiovascular diseases, and cancers. The description is not designed to be an exhaustive assessment of the available empirical findings, but rather a representative presentation of the results and the explanatory value of education, occupation and income. PMID- 26613742 TI - Evaluation of right atrial function using right atrial speckle tracking analysis in patients with pulmonary artery hypertension. AB - BACKGROUND: In patients with pulmonary artery hypertension (PAH), right ventricular pressure overload eventually causes right heart failure (RHF), leading to a poor prognosis. Right atrial (RA) overload and RA dysfunction occur in patients with PAH-complicated RHF. OBJECTIVES: We evaluated RA function using right atrial longitudinal strain (RALS) by two-dimensional speckle tracking echocardiography (2D-STE) and investigated the association between RALS and the severity of RHF in patients with pulmonary artery hypertension (PAH) noninvasively. METHODS: We performed 2D-STE in 56 PAH patients and 20 normal control subjects. The peak global RALS and peak global RA longitudinal strain rate (RALSR) were analyzed by 2D-STE. Simultaneous right heart catheterization was performed to determine the right atrial pressure (RAP) and cardiac index (CI). RESULTS: Peak global RALS (34.6 +/- 14.1 vs. 58.3 +/- 9.9%, p < 0.0001) and peak global RALSR (2.5 +/- 1.3 vs. 3.1 +/- 1.2 s(-1), p < 0.0001) were significantly lower in PAH patients compared with normal controls. There was a significant negative correlation between peak global RALS and RAP (r = -0.8037, p < 0.0001). There was a significant positive correlation between peak global RALS and CI (r = 0.8179, p < 0.0001). Peak global RALSR was also correlated with RAP (r = -0.7308, p < 0.0001) and CI (r = 0.7596, p < 0.0001). CONCLUSIONS: RALS and RALSR by 2D-STE were useful for noninvasive evaluation of RA dysfunction and the severity of RHF in patients with PAH. PMID- 26613743 TI - Rare but Lethal Hepatopathy-Sickle Cell Intrahepatic Cholestasis and Management Strategies. AB - BACKGROUND: Sickle cell disease can affect the liver by way of the disease process, including sickling in hepatic sinusoids, as well as its treatment, including repeated blood transfusions leading to hemosiderosis and hepatitis. Sickle cell intrahepatic cholestasis (SCIC) is an extreme variant of sickle cell hepatopathy, and is associated with high fatality. CASE REPORT: We present the case of a 31-year-old man with past medical history of sickle cell disease and cholecystectomy who was admitted with uncomplicated vaso occlusive crisis and during the hospital stay developed fever, upper abdominal pain, and jaundice. There was an accelerated rise in total bilirubin to 50 mg/dL, direct bilirubin 38 mg/dL, and Cr 3.0 mg/dL. Hb was 6.4 g/dL, reticulocyte count 16%, ALT 40 IU/L, AST 155 IU/L, ALP 320 IU/L, and LDH 475 IU/L. Hepatitis panel was negative and MRCP showed normal caliber of the common bile duct, with no obstruction. Exchange transfusion of 9 units of packed red blood cells led to great improvement in his condition. CONCLUSIONS: SCIC, unlike the other sickle cell hepatopathies, requires urgent and vigorous exchange transfusion. Renal impairment in SCIC has not been well studied but usually is reversible with the hepatic impairment, as in this case. Unresolved renal impairment requires dialysis and is associated with poor outcome. There is limited data on use of hydroxyurea to prevent SCIC, and liver transplant is associated with high mortality. A timely diagnosis of SCIC and appropriate management is life-saving. PMID- 26613744 TI - Western blood pressure guidelines may not be appropriate for Asian populations, experts say. PMID- 26613745 TI - Filial Obligation and Marital Satisfaction in Middle-aged Couples. AB - Purpose of the Study: Although prior research suggests that high filial obligation has an adverse impact on psychological well-being, little is known about the implications of these beliefs for marital quality during midlife. Therefore, the purpose of this study was to examine dyadic associations between middle-aged husbands' and wives' filial obligation beliefs and their marital satisfaction. Design and Methods: Using a sample of 132 middle-aged husbands (M = 51.45 years) and wives (M = 49.75 years) drawn from Wave 1 of the Family Exchanges Study, we tested actor-partner interdependence models to determine associations between husbands' and wives' filial obligation beliefs and marital satisfaction in both spouses. We also examined associations between spousal dissimilarity in filial obligation and marital satisfaction. Results: Wives' greater filial obligation was associated with their own lower marital satisfaction. Conversely, husbands' greater filial obligation was associated with their own higher marital satisfaction. Greater spousal dissimilarity in filial obligation was associated with lower levels of marital satisfaction for husbands but not for wives. Implications: Given that support provided to aging parents most often occurs within the context of marriage, findings highlight the importance of examining dyadic associations between filial obligation beliefs and marital quality among middle-aged couples. PMID- 26613746 TI - New cases of HIV in Europe reach highest level since 1980s. PMID- 26613747 TI - Value of mechanical dyssynchrony as assessed by radionuclide ventriculography to predict the cardiac resynchronization therapy response. AB - AIMS: To assess the value of mechanical dyssynchrony measured by equilibrium radionuclide angiography (ERNA) in predicting long-term outcome in cardiac resynchronization therapy (CRT) patients. METHODS AND RESULTS: We reviewed 146 ERNA studies performed in heart failure patients between 2001 and 2011 at our institution. Long-term follow-up focused on death from any cause or heart transplantation. Phase images were computed using the first harmonic Fourier transform. Intra-ventricular dyssynchrony was calculated as the delay between the earliest and most delayed 20% of the left ventricular (LV) (IntraV-20/80) and inter-ventricular dyssynchrony as the difference between LV- and right ventricular (RV)-mode phase angles (InterV). Eighty-three patients (57%) were implanted with a CRT device after ERNA. Median follow-up was 35 [21-50] months. Twenty-four events were observed during the first 41 months. Median baseline ERNA dyssynchrony values were 28 [3 to 46] degrees for intraV-20/80 and 9 [-6 to 24] degrees for interV. Comparing survival between CRT and non-CRT patients according to dyssynchrony status, log-rank tests showed no difference in survival in patients with no ERNA dyssynchrony (P = 0.34) while a significant difference was observed in ERNA patients with high level of mechanical dyssynchrony (P = 0.004). CONCLUSION: ERNA mechanical dyssynchrony could be of value in CRT patient selection. PMID- 26613748 TI - Phylogenetic and genomic analysis of Methanomassiliicoccales in wetlands and animal intestinal tracts reveals clade-specific habitat preferences. AB - Methanogenic Thermoplasmata of the novel order Methanomassiliicoccales were recently discovered in human and animal gastro-intestinal tracts (GITs). However, their distribution in other methanogenic environments has not been addressed systematically. Here, we surveyed Methanomassiliicoccales presence in wetland soils, a globally important source of methane emissions to the atmosphere, and in the GITs of different animals by PCR targeting their 16S rRNA and methyl:coenzyme M reductase (alpha-subunit) genes. We detected Methanomassiliicoccales in all 16 peat soils investigated, indicating their wide distribution in these habitats. Additionally, we detected their genes in various animal faeces. Methanomassiliicoccales were subdivided in two broad phylogenetic clades designated 'environmental' and 'GIT' clades based on differential, although non exclusive, habitat preferences of their members. A well-supported cluster within the environmental clade comprised more than 80% of all wetland 16S rRNA gene sequences. Metagenome assembly from bovine rumen fluid enrichments resulted in two almost complete genomes of both Methanomassiliicoccales clades. Comparative genomics revealed that members of the environmental clade contain larger genomes and a higher number of genes encoding anti-oxidative enzymes than animal GIT clade representatives. This study highlights the wide distribution of Methanomassiliicoccales in wetlands, which suggests that they contribute to methane emissions from these climate-relevant ecosystems. PMID- 26613749 TI - Purine catabolic pathway revealed by transcriptomics in the model marine bacterium Ruegeria pomeroyi DSS-3. AB - Purines are nitrogen-rich compounds that are widely distributed in the marine environment and are an important component of the dissolved organic nitrogen (DON) pool. Even though purines have been shown to be degraded by bacterioplankton, the identities of marine bacteria capable of purine degradation and their underlying catabolic mechanisms are currently unknown. This study shows that Ruegeria pomeroyi, a model marine bacterium and Marine Roseobacter Clade (MRC) representative, utilizes xanthine as a source of carbon and nitrogen. The R. pomeroyi genome contains putative genes that encode xanthine dehydrogenase (XDH), which is expressed during growth with xanthine. RNAseq-based analysis of the R. pomeroyi transcriptome revealed that the transcription of an XDH-initiated catabolic pathway is up-regulated during growth with xanthine, with transcription greatest when xanthine was the only available carbon source. The RNAseq-deduced pathway indicates that glyoxylate and ammonia are the key intermediates from xanthine degradation. Utilising a laboratory model, this study has identified the potential genes and catabolic pathway active during xanthine degradation. The ability of R. pomeroyi to utilize xanthine provides novel insights into the capabilities of the MRC that may contribute to their success in marine ecosystems and the potential biogeochemical importance of the group in processing DON. PMID- 26613750 TI - Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases. AB - BACKGROUND: In 30-50% of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, or POLE or POLD1, causing polymerase proofreading-associated polyposis can be identified, although a hereditary aetiology is likely. This study aimed to explore the impact of APC mutational mosaicism in unexplained polyposis. METHODS: To comprehensively screen for somatic low-level APC mosaicism, high-coverage next-generation sequencing of the APC gene was performed using DNA from leucocytes and a total of 53 colorectal tumours from 20 unrelated patients with unexplained sporadic adenomatous polyposis. APC mosaicism was assumed if the same loss-of-function APC mutation was present in >= 2 anatomically separated colorectal adenomas/carcinomas per patient. All mutations were validated using diverse methods. RESULTS: In 25% (5/20) of patients, somatic mosaicism of a pathogenic APC mutation was identified as underlying cause of the disease. In 2/5 cases, the mosaic level in leucocyte DNA was slightly below the sensitivity threshold of Sanger sequencing; while in 3/5 cases, the allelic fraction was either very low (0.1-1%) or no mutations were detectable. The majority of mosaic mutations were located outside the somatic mutation cluster region of the gene. CONCLUSIONS: The present data indicate a high prevalence of pathogenic mosaic APC mutations below the detection thresholds of routine diagnostics in adenomatous polyposis, even if high-coverage sequencing of leucocyte DNA alone is taken into account. This has important implications for both routine work-up and strategies to identify new causative genes in this patient group. PMID- 26613751 TI - Vesicles from different Trypanosoma cruzi strains trigger differential innate and chronic immune responses. AB - Trypomastigote forms of Trypanosoma cruzi, the causative agent of Chagas Disease, shed extracellular vesicles (EVs) enriched with glycoproteins of the gp85/trans sialidase (TS) superfamily and other alpha-galactosyl (alpha-Gal)-containing glycoconjugates, such as mucins. Here, purified vesicles from T. cruzi strains (Y, Colombiana, CL-14 and YuYu) were quantified according to size, intensity and concentration. Qualitative analysis revealed differences in their protein and alpha-galactosyl contents. Later, those polymorphisms were evaluated in the modulation of immune responses (innate and in the chronic phase) in C57BL/6 mice. EVs isolated from YuYu and CL-14 strains induced in macrophages higher levels of proinflammatory cytokines (TNF-alpha and IL-6) and nitric oxide via TLR2. In general, no differences were observed in MAPKs activation (p38, JNK and ERK 1/2) after EVs stimulation. In splenic cells derived from chronically infected mice, a different modulation pattern was observed, where Colombiana (followed by Y strain) EVs were more proinflammatory. This modulation was independent of the T. cruzi strain used in the mice infection. To test the functional importance of this modulation, the expression of intracellular cytokines after in vitro exposure was evaluated using EVs from YuYu and Colombiana strains. Both EVs induced cytokine production with the appearance of IL-10 in the chronically infected mice. A high frequency of IL-10 in CD4+ and CD8+ T lymphocytes was observed. A mixed profile of cytokine induction was observed in B cells with the production of TNF-alpha and IL-10. Finally, dendritic cells produced TNF-alpha after stimulation with EVs. Polymorphisms in the vesicles surface may be determinant in the immunopathologic events not only in the early steps of infection but also in the chronic phase. PMID- 26613752 TI - Attempted suicide and violent criminality among Danish second-generation immigrants according to parental place of origin. AB - BACKGROUND: Immigrant populations in Western European countries have grown in their size and diversity, but little is known about risks of self-directed and externalised violence among second-generation immigrants. AIMS: To compare risks for attempted suicides and violent offending among second-generation immigrants to Denmark according to parental region of origin versus the native Danish population. METHODS: Data from interlinked national Danish registers were used (N = 1,973,614). Parental origin outside Denmark was categorised thus: Asia, Africa, Middle East, Greenland, other Scandinavian countries, elsewhere in Europe and all other regions. We estimated gender-specific cumulative incidence and incidence rate ratios (IRRs) versus native Danes. RESULTS: In virtually all subgroups of second-generation immigrants, risk was elevated for the two adverse outcomes in both genders. Females generally had greater elevations in attempted suicide risk, and males had greater elevations in violent offending risk. For attempted suicide, especially large IRRs were observed for males and females whose parents emigrated from Greenland; for violent offending, risks were particularly raised for males and females of Middle Eastern, Greenlandic and African origin. Adjustment for socioeconomic status partially explained these associations. CONCLUSION: Western European nations should develop preventive programmes tailored towards specific second-generation immigrant populations, with integrated approaches jointly tackling suicidality and violence. PMID- 26613753 TI - Evaluation of the effects of subject thickness on the exposure index in digital radiography. AB - The exposure index (EI) was proposed as a new X-ray dose index by the International Electrotechnical Commission (IEC) and has since been implemented as an international standard. The EI is calculated by use of an approximation equation under IEC-specified calibration conditions. However, several factors encountered in clinical practice, including the patient's body thickness and the tube voltage, differ with regard to these calibration conditions. We, therefore, require a solid water phantom-based function that can incorporate the IEC specified conditions and different subject thicknesses to evaluate the effects of subject thickness on the EI. Here, we assumed average thicknesses of 10 cm for a child, 15 cm for slender patients, and 21 cm for an average adult abdomen and we evaluated errors, that are included in the EI, which were calculated by use of the function. Our results suggested that the EI depends on the subject thickness. At the 21-cm thickness (average adult abdomen), the display EI exhibited a small error level. In contrast, EI values calculated from the calibration conditions exhibited maximum errors that were as high as 34 % at the lower subject thicknesses (10 and 15 cm), suggesting a significant influence of the subject thickness on the EI. In conclusion, the EI should be used cautiously during the examination of children and thin patients, with a complete understanding of the discrepancy revealed by our study results. PMID- 26613754 TI - Erratum to: The visual amplification of goal-oriented movements counteracts acquired non-use in hemiparetic stroke patients. AB - Unfortunately, in the original version of this article [1] the sentence "This project was supported through ERC project cDAC (FP7-IDEAS-ERC 341196), EC H2020 project socSMCs (H2020-EU.1.2.2. 641321) and MINECO project SANAR (Gobierno de Espana)" was missing from the acknowledgements.The acknowledgements have been correctly included in full in this erratum. PMID- 26613755 TI - Plasma levels of thrombomodulin, plasminogen activator inhibitor-1 and fibrinogen in elderly, diabetic patients with depressive symptoms. AB - BACKGROUND: Diabetes, depression and aging have been associated with pro inflammatory and prothrombotic state. AIM: The aim of the study was to determine the plasma levels of thrombomodulin, plasminogen activator inhibitor-1 (PAI-1) and fibrinogen in elderly diabetic patients with and without depressive symptoms and to examine factors (including thrombomodulin, PAI-1, fibrinogen levels) associated with depressive symptoms in elderly patients with type 2 diabetes (T2DM). METHODS: A total of 276 T2DM elders were evaluated: 82 subjects with depressive symptoms and 194 controls. Data were collected concerning biochemical parameters and biomarkers. RESULTS: Plasma thrombomodulin, PAI-1 and fibrinogen were elevated in patients with depressive symptoms compared to controls. Thrombomodulin level was correlated with fibrinogen and PAI-1 levels. All parameters were correlated with the Geriatric Depression Scale-30 score. The univariate logistic regression models revealed that variables which increased the likelihood of diagnosis of depressive symptoms in elderly patients with T2DM were: female sex, smoking habit, longer duration of T2DM, hyperlipidemia, neuropathy, increased number of co-morbidities, higher BMI, and higher levels of total and LDL cholesterol, thrombomodulin, PAI-1 and fibrinogen. In addition, the multivariable analysis indicated that female sex, smoking habit, increased number of co-morbidities, higher BMI, and higher levels of LDL cholesterol and thrombomodulin are the predisposing factors for depressive symptoms. CONCLUSIONS: Elderly diabetic patients with depressive symptoms have higher levels of thrombomodulin, PAI-1 and fibrinogen. Further prospective larger studies are needed to provide potential directions for the research, treatment and prevention of co-morbid depression and diabetes. PMID- 26613756 TI - Accelerometer-Measured Versus Self-Reported Physical Activity Levels and Sedentary Behavior in Women Before and 9 Months After Roux-en-Y Gastric Bypass. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) patients report significant pre- to post-surgery increases in physical activity (PA). Conversely, objectively assessed PA does not increase after RYGB. The aim of the study was to compare self-reported and accelerometer-measured changes in moderate-to-vigorous PA (MVPA) and exercise from pre- to post-surgery, in women undergoing RYGB. METHODS: Forty-three women with an average pre-surgery body mass index of 39.2 kg/m2 (SD 3.1) were recruited at Swedish hospitals. PA was measured by the Actigraph GT3X+ and by a previously validated short PA questionnaire, at home visits 3 months before and 9 months after surgery, thus limiting seasonal effects. RESULTS: Self reported time spent in exercise increased with 75 % and time spent in MVPA increased with 51 %, whereas accelerometer-assessed time spent in exercise increased with 0.9 % and time spent in MVPA increased with 2.1 %, from before to after surgery. Correlations comparing accelerometers with the questionnaire were 0.35 (P = 0.02) for MVPA and 0.13 (P = 0.4) for exercise before RYGB and 0.52 (P <= 0.001) for MVPA and 0.12 (P = 0.4) for exercise after RYGB. CONCLUSIONS: Pre- to post-RYGB surgery increases in self-reported PA were not confirmed by accelerometer-measured PA. Thus, health care workers should use objective measures of PA in patients undergoing RYGB, in order to assess whether patients achieve sufficient levels of PA. PMID- 26613757 TI - Gastrin Secretion After Bariatric Surgery-Response to a Protein-Rich Mixed Meal Following Roux-En-Y Gastric Bypass and Sleeve Gastrectomy: a Pilot Study in Normoglycemic Women. AB - BACKGROUND: Recent investigations have linked elevated gastrin levels to the improvement of type 2 diabetes mellitus (T2DM). Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are effective treatments for T2DM, but it is not known if this is related to postoperative alterations of gastrin secretion. METHODS: Twenty women previously operated with RYGB or SG and 13 female controls were enrolled and evaluated for body mass index, lipids, C-peptide, HbA1c, and anti-H. pylori IgG. Glucose, gastrin, insulin, and glucagon-like peptide 1 (GLP 1) concentrations were measured before and 30, 60, 90, and 120 min after ingestion of a protein-rich mixed meal. RESULTS: Six participants primarily selected were excluded due to usage of proton pump inhibitors, positive H.pylori IgG, or history of T2DM, yielding the following groups: RYGB (n = 9), SG (n = 8), and controls (n = 10). There were no differences in age, body mass index, HbA1c, or C-peptide levels between groups. RYGB had significantly lower area under the curve (AUC) for glucose during the test compared to controls (p = 0.013). RYGB showed lower serum gastrin levels compared to SG and controls (p < 0.05 for all). There was a non-significant increased gastrin release in SG compared to controls (p = 0.091). For SG and controls, there was a negative correlation between glucose and gastrin response (p = 0.0043). CONCLUSION: Gastrin secretion is diminished after RYGB. Hypergastrinemia was not present after SG, but a tendency of enhanced gastrin secretion was observed. These findings require further investigation in prospective studies. PMID- 26613758 TI - Nellore cattle (Bos indicus) and ticks within the Brazilian Pantanal: ecological relationships. AB - Pantanal is a huge floodplain mostly in Brazil, and its main economic activity is extensive cattle raising, in farms characterized by an extremely wildlife-rich environment. We herein describe tick infestations of cattle and of the natural environment in Pantanal of Nhecolandia in Brazil, at areas with and without cattle during both dry and wet seasons. Environmental sampling resulted in three tick species: Amblyomma sculptum (423 nymphs and 518 adults), Amblyomma parvum (7 nymphs and 129 adults), Amblyomma ovale (3 adults) as well as three clusters and two individuals of Amblyomma sp. larvae. A significantly higher number of adult A. sculptum ticks was found in areas with cattle in the wet season. From 106 examinations of bovines 1710 ticks from three species were collected: Rhipicephalus microplus (55.7% of the total), A. sculptum (38%) and A. parvum (4.1%), as well as 32 Amblyomma sp. larvae. A significant similarity was found between Amblyomma tick fauna from environment and on cattle during both seasons. All A. sculptum females on bovines were flat whereas many of A. parvum females and A. sculptum nymphs were engorging. Although R. microplus was the most abundant tick species on cattle, overall highest tick prevalence on bovines in the dry season was of A. sculptum nymphs. Lack of R. microplus in environmental sampling, relationship between cattle and increase in adult A. sculptum numbers in the environment as well as suitability of bovine for the various tick species are discussed. PMID- 26613759 TI - Prevalence and diversity of human pathogenic rickettsiae in urban versus rural habitats, Hungary. AB - Tick-borne rickettsioses belong to the important emerging infectious diseases worldwide. We investigated the potential human exposure to rickettsiae by determining their presence in questing ticks collected in an urban park of Budapest and a popular hunting and recreational forest area in southern Hungary. Differences were found in the infectious risk between the two habitats. Rickettsia monacensis and Rickettsia helvetica were identified with sequencing in questing Ixodes ricinus, the only ticks species collected in the city park. Female I. ricinus had a particularly high prevalence of R. helvetica (45%). Tick community was more diverse in the rural habitat with Dermacentor reticulatus ticks having especially high percentage (58%) of Rickettsia raoultii infection. We conclude that despite the distinct eco-epidemiological traits, the risk (hazard and exposure) of acquiring human pathogenic rickettsial infections in both the urban and the rural study sites exists. PMID- 26613760 TI - Serum Cystatin C as an Inflammatory Marker in Exacerbated and Convalescent COPD Patients. AB - Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease with high morbidity and mortality rates. Cystatin C (Cys C) is a sensitive indicator for various chronic inflammatory diseases. In this study, we aimed to evaluate the role of Cys C in COPD patients comparing with the other well-known inflammatory markers. Ninety patients with acute exacerbated COPD were studied and were reassessed when convalescent. Ninety controls were matched for age, gender, body mass index, smoking index, and comorbidity. Serum Cys C was significantly increased in convalescent COPD patients compared with healthy controls and further increased in COPD patients with an acute exacerbation. Serum Cys C was positively correlated with hsCRP both in the exacerbation and convalescence periods of COPD and negatively correlated with FEV1% predicted and FEV1/FVC in the convalescent COPD patients. In conclusion, serum Cys C is a positive acute-phase reactant in COPD patients and might indicate systemic inflammation during the progression of COPD. PMID- 26613761 TI - Whole genome sequencing provides possible explanations for the difference in phage susceptibility among two Salmonella Typhimurium phage types (DT8 and DT30) associated with a single foodborne outbreak. AB - BACKGROUND: Phage typing has been used for decades as a rapid, low cost approach for the epidemiological surveillance of Salmonella enterica subsp. enterica serovar Typhimurium. Although molecular methods are replacing phage typing the system is still in use and provides a valuable model for study of phage-host interaction. Phage typing depends on the pattern of bacterial resistance or sensitivity to a panel of specific bacteriophages. In the phage typing scheme, S. Typhimurium definitive phage types (DT) 8 and 30 differ greatly in their susceptibility to the 30 typing phages of S. Typhimurium; DT8 is susceptible to 11 phages whereas DT30 is resistant to all typing phages except one phage although both DT8 and DT30 were reported to be associated with a single foodborne salmonellosis outbreak in Ireland between 2009 and 2011. We wished to study the genomic correlates of the DT8 and DT30 difference in phage susceptibility using the whole genome sequence (WGS) of S. Typhimurium DT8 and DT30 representatives. RESULTS: Comparative genome analysis revealed that both S. Typhimurium DT8 and DT30 are lysogenic for three prophages including two S. Typhimurium associated prophages (Gifsy-2 and ST64B) and one S. Enteritidis associated prophage (Enteritidis lysogenic phage S) which has not been detected previously in S. Typhimurium. Furthermore, DT8 and DT30 contain identical clustered regularly interspaced short palindromic repeats (CRISPRs). Interestingly, S. Typhimurium DT8 harbours an accessory genome represented by a virulence plasmid that is highly related to the pSLT plasmid of S. Typhimurium strain LT2 (phage typed as DT4) and codes a unique methyltransferase (MTase); M.EcoGIX related MTase. This plasmid is not detected in DT30. On the other hand, DT30 carries a unique genomic island similar to the integrative and conjugative element (ICE) of Enterotoxigenic Escherichia coli (ETEC) and encodes type IV secretion pathway system (T4SS) and several hypothetical proteins. This genomic island is not detected in DT8. CONCLUSIONS: We suggest that differences in phage susceptibility between DT8 and DT30 may be related to acquisition of ICE in DT30 and loss of pSLT like plasmid that might be associated with DT30 resistance to almost all phages used in the typing scheme. Additional studies are required to determine the significance of the differences among DT8 and DT30 in relation to the difference in phage susceptibility. This study represents an initial step toward understanding the molecular basis of this host-phage relationship. PMID- 26613763 TI - Triple pigtail technique: a novel way to determine the optimal angle of implantation during transcatheter aortic valve replacement while minimizing contrast load. PMID- 26613762 TI - Complementary Proteomic and Biochemical Analysis of Peptidases in Lobster Gastric Juice Uncovers the Functional Role of Individual Enzymes in Food Digestion. AB - Crustaceans are a diverse group, distributed in widely variable environmental conditions for which they show an equally extensive range of biochemical adaptations. Some digestive enzymes have been studied by purification/characterization approaches. However, global analysis is crucial to understand how digestive enzymes interplay. Here, we present the first proteomic analysis of the digestive fluid from a crustacean (Homarus americanus) and identify glycosidases and peptidases as the most abundant classes of hydrolytic enzymes. The digestion pathway of complex carbohydrates was predicted by comparing the lobster enzymes to similar enzymes from other crustaceans. A novel and unbiased substrate profiling approach was used to uncover the global proteolytic specificity of gastric juice and determine the contribution of cysteine and aspartic acid peptidases. These enzymes were separated by gel electrophoresis and their individual substrate specificities uncovered from the resulting gel bands. This new technique is called zymoMSP. Each cysteine peptidase cleaves a set of unique peptide bonds and the S2 pocket determines their substrate specificity. Finally, affinity chromatography was used to enrich for a digestive cathepsin D1 to compare its substrate specificity and cold adapted enzymatic properties to mammalian enzymes. We conclude that the H. americanus digestive peptidases may have useful therapeutic applications, due to their cold-adaptation properties and ability to hydrolyze collagen. PMID- 26613764 TI - The advantages of live/real time three-dimensional transesophageal echocardiography during assessments of pulmonary stenosis. AB - This report sought to compare live/real-time three-dimensional transesophageal echocardiography (3D-TEE) with two-dimensional transesophageal echocardiography (2D-TEE) and to determine whether there are advantages to using 3D-TEE on patients with pulmonary stenosis (PS). Sixteen consecutive adult patients (50 % male and 50 % female; mean age 33 +/- 13.4 years) with PS and indications of TEE were prospectively enrolled in this study. Following this, initial 2D-TEE and 3D TEE examinations were performed, and 3D-TEE images were analyzed using an off line Q-lab software system. Finally, the 2D-TEE and 3D-TEE findings were compared. In the present study, 3D-TEE allowed us to obtain the en face views of pulmonary valves (PVs) in all but one patient. While this patient was without a PV due to a previous tetralogy of Fallot operation, we could detect the type of PV in the other 15 (93.7 %) patients by using 3D-TEE. Due to poor image quality, the most stenotic area was not measurable in only one (6.2 %) of the patients. In eight (50 %) of the patients, severity and localization of stenosis were more precisely determined with 3DTEE than with 2D-TEE. The PVs' maximal annulus dimensions were found to be significantly larger when they were measured using 3D modalities. This study provides evidence of the incremental value of using 3D-TEE rather than 2D-TEE during assessments of PS, specifically in cases where special conditions (pregnancy, pulmonary regurgitation, and concomitant atrial septal defects) cause recordings of the transvalvular peak gradient to be inaccurate. Therefore, 3D-TEE should be used as a complementary imaging tool to 2D-TEE during routine echocardiographic examinations. PMID- 26613765 TI - The Emotional and Functional Impact of the Type of Tinnitus Sensation. AB - One to three percent of individuals with tinnitus experience significant reduction in quality of life. Factors that contribute to distress include personality variables, intolerance to loud noises, external locus of control, and pre-existing anxiety. Characteristics of tinnitus itself, such as perceived loudness, can also cause functional impairment. It is unknown whether different tinnitus sensations have various effects on either emotional or functional impairment, which can reduce quality of life. While audiological tests can determine pitch and loudness of tinnitus, questionnaires also can be easily used to assess subjective characteristics of tinnitus. In this study, 370 participants, recruited via email from a national tinnitus organization, completed online surveys that assessed tinnitus-related distress and provided qualitative descriptions of their tinnitus sensation. Self-reports of tinnitus sensation were rated by five independent coders, with excellent agreement. Individuals who reported a combination of tinnitus sensations were found to experience significantly more functional impairment and avoidant behavior. Future research should utilize more sophisticated approaches to categorize individuals' tinnitus sensation and to examine associated emotional and functional differences. Providers should appropriately refer patients for tinnitus management and empirically-supported therapies aimed at reducing tinnitus related distress and functional impairment. PMID- 26613767 TI - Prevalence of ultrasound synovial inflammatory findings in healthy subjects. AB - OBJECTIVE: To evaluate the prevalence of joint inflammatory abnormalities and erosions detected by grey-scale and Doppler ultrasound (US) in the small joints of hands and feet in healthy subjects. METHODS: US of the dorsal surface of 32 joints (10 metacarpophalangeal, 10 proximal interphalangeal, 10 metatarsophalangeal (MTP) and 2 wrists) was performed in 207 healthy subjects without joint symptom. Synovial effusion (SE), synovial hypertrophy (SH) and power Doppler (PD) signal were scored using a semiquantitative grading scale (0 3) and erosion binary. RESULTS: One-hundred and eighty-two subjects had at least one US abnormality: 52% of the subjects had SE alone, 13% SH alone (5% with and 8% without PD) and 35% both SH and SE. US findings were detected in 9% of the total joints examined, mostly in the feet, and in particular in the MTP1 (33% of the positive joints). SE was the most frequently detected finding (68% of the positive joints), followed by SH (31%). Severity was mild (grade 1 in average) whatever the finding recorded (SH, SE or PD). Four erosions were detected (MTP1). CONCLUSIONS: This study describes for the first time, in a large cohort of healthy subjects, the prevalence and location of US signs of joint inflammation and of structural damage in small joints of hands and feet. US abnormalities were quite common, and mostly located in the feet. Further studies are needed to define which US components may allow to discriminate between pathological and physiological findings in the joints commonly affected by inflammatory arthritis conditions. PMID- 26613766 TI - Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism. AB - OBJECTIVE: An interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation. METHODS: Antibodies purified from human patients with RA, healthy donors and murinised monoclonal ACPA were injected into mice. Pain-like behaviour was monitored for up to 28 days, and tissues were analysed for signs of pathology. Mouse osteoclasts were cultured and stimulated with antibodies, and supernatants analysed for release of factors. Mice were treated with CXCR1/2 (interleukin (IL) 8 receptor) antagonist reparixin. RESULTS: Mice injected with either human or murinised ACPA developed long-lasting pronounced pain-like behaviour in the absence of inflammation, while non-ACPA IgG from patients with RA or control monoclonal IgG were without pronociceptive effect. This effect was coupled to ACPA-mediated activation of osteoclasts and release of the nociceptive chemokine CXCL1 (analogue to human IL-8). ACPA-induced pain-like behaviour was reversed with reparixin. CONCLUSIONS: The data suggest that CXCL1/IL-8, released from osteoclasts in an autoantibody-dependent manner, produces pain by activating sensory neurons. The identification of this new pain pathway may open new avenues for pain treatment in RA and also in other painful diseases associated with autoantibody production and/or osteoclast activation. PMID- 26613769 TI - Clinical factors, anticitrullinated peptide antibodies and MRI-detected subclinical inflammation in relation to progression from clinically suspect arthralgia to arthritis. AB - INTRODUCTION: Patients with clinically suspect arthralgia (CSA) have, according to their rheumatologists, an increased risk of rheumatoid arthritis (RA), but their actual outcome is unexplored. This longitudinal study investigated (1) progression from CSA to clinically detectable arthritis and (2) associations of clinical factors, serological factors (among which are anticitrullinated peptide antibodies (ACPAs)) and MRI-detected subclinical inflammation with arthritis development. METHODS: 150 patients with CSA were followed for >=6 months. At baseline, clinical and serological data were collected and unilateral 1.5 T-MRI of metacarpophalangeal (MCP), wrist and metatarsophalangeal (MTP) joints was made. MRI scoring was done according to the RA MRI scoring system. Subclinical MRI inflammation was defined based on MRI results of 193 symptom-free persons. RESULTS: During follow-up (median=75 weeks, IQR=41-106 weeks), 30 patients developed clinical arthritis; 87% did so <20 weeks after inclusion. In multivariable analyses, age, localisation of initial symptoms in small and large joints (compared with small joints only), C-reactive protein level, ACPA positivity and subclinical MRI inflammation significantly associated with arthritis development; ACPA and MRI inflammation were most strongly associated (HR (95% CI) respectively, 6.43 (2.57 to 16.05) and 5.07 (1.77 to 14.50)). After 1-year follow-up, 31% of the patients with MRI inflammation and 71% of the ACPA positive patients with MRI inflammation had progressed to arthritis. Forty-three per cent of the patients that developed arthritis within 1 year were ACPA negative; 78% of them had subclinical MRI inflammation at baseline. When MRI inflammation was absent arthritis development was infrequent (6% in all patients with CSA and 3% in ACPA-negative patients with CSA). CONCLUSIONS: Subclinical MRI inflammation precedes clinical arthritis with a few months. Subclinical MRI inflammation is, independent of other factors such as ACPA, associated with arthritis development. PMID- 26613770 TI - Use of the Beck Anxiety and Depression Inventories for Primary Care with Medical Outpatients. AB - The effectiveness of the Beck Anxiety (BAI-PC) and Depression (BDI-PC) Inventories for Primary Care for discriminating 56 primary care patients with and without revised, third edition Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) diagnosed anxiety and mood disorders was studied. The Anxiety and Mood modules from the Primary Care Evaluation of Mental Disorders (PRIME-MD) were used to establish diagnoses. The coefficient alphas for the BAI PC and BDI-PC were, respectively, .90 and .88. A BAI-PC cutoff score of 5 and above yielded the highest clinical efficiency (82%) with 85% sensitivity and 81% specificity for identifying patients with and without panic, generalized anxiety, or both disorders, whereas a BDI-PC cutoff score of 6 and above afforded the highest clinical efficiency (92%) with 83% sensitivity and 95% specificity for detecting patients with and without major depressive disorders. The use of these instruments to screen primary care patients before conducting extensive diagnostic evaluations with them was discussed. PMID- 26613768 TI - Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis. AB - OBJECTIVE: Compare changes in lipids and lipid-associated cardiovascular (CV) risk markers in patients with rheumatoid arthritis (RA) treated with tocilizumab or adalimumab. METHODS: Post-hoc analysis was performed in patients with RA who received tocilizumab intravenously every 4 weeks or adalimumab subcutaneously every 2 weeks for 24 weeks in the ADACTA trial. Lipid and lipid-associated CV risk biomarkers, including high-density lipoprotein-associated serum amyloid-A (HDL-SAA), secretory phospholipase A2 IIA (sPLA2 IIA) and lipoprotein(a) (Lp(a)), were measured at baseline and at week 8. RESULTS: The study included 162 patients treated with tocilizumab and 162 patients treated with adalimumab; HDL-SAA and sPLA2 IIA were measured in a subpopulation of 87 and 97 patients, respectively. Greater increases in mean low-density lipoprotein cholesterol (LDL-C) (0.46 mmol/L (95% CI 0.30 to 0.62)), high-density lipoprotein cholesterol (HDL-C) (0.07 mmol/L (0.001 to 0.14)), total cholesterol (TC) (0.67 mmol/L (0.47 to 0.86)), triglycerides (0.24 mmol/L (0.10 to 0.38)) and TC:HDL ratio (0.27 (0.12 to 0.42)) occurred with tocilizumab from baseline to 8 weeks. HDL-SAA, sPLA2 IIA and Lp(a) decreased more with tocilizumab than adalimumab. Median changes from baseline to week 8 were -3.2 and -1.1 mg/L (p=0.0077) for HDL-SAA and -4.1 and -1.3 ng/mL (p<0.0001) for sPLA2 IIA; difference in adjusted means was -7.12 mg/dL (p<0.0001) for Lp(a). Similar results were observed in efficacy responders and non responders per American College of Rheumatology and European League against Rheumatism criteria. CONCLUSION: LDL-C and HDL-C increased more with tocilizumab than adalimumab. HDL-SAA, sPLA2 IIA and Lp(a) decreased more with tocilizumab. Lipid change effects of interleukin-6 and tumour necrosis factor (TNF) inhibition, manifest by their net impact on lipids and lipoproteins, are not synonymous; the clinical significance is unclear and requires further study. TRIAL REGISTRATION NUMBER: NCT01119859.; post-results. PMID- 26613771 TI - Estimating Full Scale IQ While Minimizing the Effects of Practice. AB - The present study attempted to ascertain the best estimate of true Wechsler Adult Intelligence Scale-Revised (WAIS-R) Full Scale IQ (FSIQ) when confronted with an individual who recently had been administered the WAIS-R. Sixty-five college undergraduate participants were administered the WAIS-R twice within 14 days. WAIS-R summary scores, factor scores, and short-form estimates obtained from the second assessment were compared to FSIQ at the first evaluation. The results indicated that Verbal IQ, the Verbal Comprehension factor score, and subtracting 6 points from the current FSIQ are the least affected by repeat assessment and the most accurate estimates of FSIQ at the first evaluation. Use of these estimates of FSIQ are encouraged when evaluating an individual who has been administered the WAIS-R in the recent past. PMID- 26613772 TI - MMPI and Rorschach Characteristics of Individuals Approved for Gender Reassignment Surgery. AB - Results of past empirical studies utilizing the Minnesota Multiphasic Personality Inventory (MMPI) and the Rorschach Inkblot Test (Rorschach) have tended to be equivocal regarding the level and nature of psychopathology associated with samples of individuals requesting gender reassignment surgery. The present study compared the MMPI-2 basic scale T scores from a gender reassignment applicant sample (56 male-to-female transsexuals and 56 female-to-male transsexuals) to T scores obtained from a general psychiatric adult inpatient sample (n = 112) and T scores obtained from a normal adult sample (n = 112). The comparison groups were matched to the gender reassignment sample on the variables of biological gender and age. Rorschach data obtained from the gender reassignment sample were also compared to frequency data reported by Exner for normal, character disorder, and schizophrenic adults. Apart from a clinical range elevation on Scale 5, the gender reassignment candidates produced a normal range mean MMPI-2 profile. In contrast, the Rorschach findings suggested that reassignment candidates produce a high frequency of invalid protocols and manifest various psychological problems that are characteristic of individuals with personality disorders. These findings are discussed in terms of salient methodological and theoretical issues as well as promising directions for future research. PMID- 26613773 TI - The Construct Validity of the Hooper Visual Organization Test. AB - Although the Hooper Visual Organization Test (VOT) is commonly described as a measure of "visual-spatial integration," face validity suggests it measures global visual-spatial intelligence similar to the revised edition of the Wechsler Adult Intelligence Scale (WAIS-R) performance IQ (PIQ) subtests. The present study investigated the construct validity of the VOT by comparing it to conceptually similar and dissimilar cognitive abilities in a principal components factor analysis of 240 participants with cognitive impairment. Results indicated that the VOT falls within a global visual-spatial factor and shares the following variance with the other tests that loaded on this factor: WAIS-R PIQ subtests, 12% to 23%; Category Test, 11%; the revised edition of the Wechsler Memory Scale Visual Reproduction I subtest, 10%; and the Rey-Osterrieth Complex Figure, 9%. Previous studies, current results, and face validity suggest the VOT is best considered a measure of global visual-spatial intelligence. Clinical implications are discussed. PMID- 26613774 TI - Towers of Hanoi and London: Reliability and Validity of Two Executive Function Tasks. AB - The Towers of Hanoi and London are presumed to measure executive functions such as planning and working memory. Both have been used as a putative assessment of frontal lobe function. In this study, both tasks were administered to 61 normal adult participants to test the assumption that the two tasks are measuring the same cognitive processes. The results revealed a significant, but relatively low (.37) correlation between performances on the two tasks. Follow-up analyses indicated that the likely source of the lack of convergence was the unreliability of the Tower of London. Thus, the common assumption that the two tasks are isomorphic must be questioned. PMID- 26613775 TI - Development of a Brief, Multidimensional, Self-Report Instrument for Treatment Outcomes Assessment in Psychiatric Settings: Preliminary Findings. AB - Preliminary reliability and validity data are reported on a new, brief measure of psychiatric symptomatology. The Symptom Assessment-45 Questionnaire (SA-45) is a 45-item, patient self-report symptom inventory derived from the original Symptom Checklist-90-R (SCL-90), using cluster analytic methods. The SA-45 consists of nine 5-item scales assessing each of the same symptom domains as its parent instrument with no item overlap across domains. The vast majority of the internal consistency reliabilities for the SA-45's nine scales were in the .70s and .80s across different age and patient status samples. As expected, both adolescent and adult patient samples generally differed significantly from nonpatient control samples, and patients at treatment follow-up differed significantly from patients at intake. Moreover, depressed patients with and without psychotic features differed significantly on three scales. A cluster analysis generally supported the nine-scale structure of the inventory, but it failed to consistently support the distinction between the Paranoid Ideation and Interpersonal Sensitivity scales. Limitations to the study are noted, but overall, the initial findings support the use of the SA-45 in clinical settings. Suggestions for needed future research are presented. PMID- 26613776 TI - Comparison of the Halstead-Reitan and Infrared Light Beam Finger Tappers. AB - Computer mediated motor tests can provide highly reliable means for evaluating gross and subtle aspects of psychomotor speed and rhythmicity. A computer mediated test of finger and foot tapping, making use of infrared light beam technology, was recently developed, but little is known regarding its psychometric properties. The purpose of this study was to compare performance of healthy right-handed respondents on the new Light Beam Finger & Foot Tapping Device to a traditional finger tapping test used in the Halstead-Reitan Neuropsychological Battery. Performance on the Halstead-Reitan Finger Tapping Test and on the Light Beam Finger Tapping Test was compared in 16 men and 17 women. The light beam test showed similar psychometric properties to those of the Halstead-Reitan Finger Tapping Test, and scores were moderately correlated between the two tests. Respondents had faster scores on the light beam test; on both tests men were faster than women, and all respondents tapped faster with their dominant hand. Tapping was faster on the Light Beam Finger Tapping Test, possibly because it does not require application of pressure to a mechanical key and a smaller movement registers a tap. In addition to measures of right- and left-hand tapping speed, the light beam test assesses synchronous and alternating tapping and foot tapping. Scores between these subtests showed moderate to high correlations. PMID- 26613777 TI - Self- and Observer Ratings on the NEO-FFI in Couples: Initial Evidence of the Psychometric Properties of an Observer Form. AB - The present study investigated the psychometric properties of the NEO Five-Factor Inventory (NEO-FFI) Observer form of the five-factor model of personality by examining agreement between self- and observer ratings. Both partners of 49 young, adult couples rated themselves and their partners on the NEO-FFI. The results provide preliminary evidence of the measurement utility of the NEO-FFI Observer form. Specifically, (a) each personality scale possessed acceptable levels of internal reliability, (b) five factors consistent with the five-factor model of personality emerged in both ratings forms, and (c) there was significant self-observer agreement for all five personality scales. Self-observer agreement was assessed by correlations as well as analyses that test a more stringent definition of agreement. Overall, there is consensus across analyses that points to a substantial amount of concordance between partners' self- and observer ratings. PMID- 26613778 TI - Construct Validity of the Wisc-III Verbal and Performance Factors for Black Special Education Students. AB - The underlying factor structure of the revised edition of the Wechsler Intelligence Scale for Children (WISC-R) was consistently found to be comparable between regular and special education students as well as across Anglo, Black, and Hispanic populations. A commensurate research base across exceptionality and ethnic group has not been established for the recently published third edition of the Wechsler Intelligence Scale for Children (WISC-III), making it vital that information regarding the psychometric properties of the WISC-III among diverse groups of children be collected. This study examines the factor structure of the 10 WISC-III core subtests among a sample of Black students receiving special education services. Results provided evidence of a large, first principal factor as well as the expected Verbal and Performance factors. Implications for psychologists are presented, and recommendations for future research are provided. PMID- 26613779 TI - The Detection of Faking Good on the Personality Diagnostic Questionnaire-4. AB - The aim of this study was to examine the ability of the fake good indicators on the Personality Diagnostic Questionnaire-4 (PDQ-4) for DSMIV Axis II disorders to assess fake good responding. A sample of 99 university students completed the PDQ 4 under respond honestly and fake good instructions. Participants were able to significantly alter their clinical profiles. However, although the two validity scales on the PDQ-4 differed significantly under the instructional set, the overall classification rates of these scales were too low to warrant use in a clinical setting. PMID- 26613780 TI - Targeted imputation of sequence variants and gene expression profiling identifies twelve candidate genes associated with lactation volume, composition and calving interval in dairy cattle. AB - Dairy cattle are an interesting model for gaining insights into the genes responsible for the large variation between and within mammalian species in the protein and fat content of their milk and their milk volume. Large numbers of phenotypes for these traits are available, as well as full genome sequence of key founders of modern dairy cattle populations. In twenty target QTL regions affecting milk production traits, we imputed full genome sequence variant genotypes into a population of 16,721 Holstein and Jersey cattle with excellent phenotypes. Association testing was used to identify variants within each target region, and gene expression data were used to identify possible gene candidates. There was statistical support for imputed sequence variants in or close to BTRC, MGST1, SLC37A1, STAT5A, STAT5B, PAEP, VDR, CSF2RB, MUC1, NCF4, and GHDC associated with milk production, and EPGN for calving interval. Of these candidates, analysis of RNA-Seq data demonstrated that PAEP, VDR, SLC37A1, GHDC, MUC1, CSF2RB, and STAT5A were highly differentially expressed in mammary gland compared to 15 other tissues. For nine of the other target regions, the most significant variants were in non-coding DNA. Genomic predictions in a third dairy breed (Australian Reds) using sequence variants in only these candidate genes were for some traits more accurate than genomic predictions from 632,003 common SNP on the Bovine HD array. The genes identified in this study are interesting candidates for improving milk production in cattle and could be investigated for novel biological mechanisms driving lactation traits in other mammals. PMID- 26613781 TI - Substrate Selectivity of Lysophospholipid Transporter LplT Involved in Membrane Phospholipid Remodeling in Escherichia coli. AB - Lysophospholipid transporter (LplT) was previously found to be primarily involved in 2-acyl lysophosphatidylethanolamine (lyso-PE) recycling in Gram-negative bacteria. This work identifies the potent role of LplT in maintaining membrane stability and integrity in the Escherichia coli envelope. Here we demonstrate the involvement of LplT in the recycling of three major bacterial phospholipids using a combination of an in vitro lysophospholipid binding assay using purified protein and transport assays with E. coli spheroplasts. Our results show that lyso-PE and lysophosphatidylglycerol, but not lysophosphatidylcholine, are taken up by LplT for reacylation by acyltransferase/acyl-acyl carrier protein synthetase on the inner leaflet of the membrane. We also found a novel cardiolipin hydrolysis reaction by phospholipase A2 to form diacylated cardiolipin progressing to the completely deacylated headgroup. These two distinct cardiolipin derivatives were both translocated with comparable efficiency to generate triacylated cardiolipin by acyltransferase/acyl-acyl carrier protein synthetase, demonstrating the first evidence of cardiolipin remodeling in bacteria. These findings support that a fatty acid chain is not required for LplT transport. We found that LplT cannot transport lysophosphatidic acid, and its substrate binding was not inhibited by either orthophosphate or glycerol 3-phosphate, indicating that either a glycerol or ethanolamine headgroup is the chemical determinant for substrate recognition. Diacyl forms of PE, phosphatidylglycerol, or the tetra-acylated form of cardiolipin could not serve as a competitive inhibitor in vitro. Based on an evolutionary structural model, we propose a "sideways sliding" mechanism to explain how a conserved membrane embedded alpha-helical interface excludes diacylphospholipids from the LplT binding site to facilitate efficient flipping of lysophospholipid across the cell membrane. PMID- 26613782 TI - Survey of patient perceptions towards short-term mobile medical aid for those living in a medically underserved area of Swaziland. AB - BACKGROUND: An increasing number of short-term medical missions (STMMs) are being dispatched to provide humanitarian healthcare; however, extensive investigations on how recipient patients perceive STMMs are lacking. The current study evaluated the perceptions of patients toward medical services provided by a Taiwanese STMM in a resource-poor area of Swaziland. METHODS: A structured questionnaire survey was completed by patients who had received medical services from the medical mission of Taipei Medical University in Swaziland in July 2014. RESULTS: In total, 349 questionnaires were valid for the analysis. More respondents were female than male (69.6% vs 30.4%). The most common chief complaint was musculoskeletal problems (45.8%), followed by respiratory symptoms (35.0%). Most of the patients stated that their overall experience with the medical services was excellent (91.4%). Universal patients would like to see the service provided in the future (99.7%). Nearly 90% of the patients were aware of how to take care of the medical problem they were diagnosed with. A majority of the patients comprehended what their medical providers said. Only a few patients did not understand what physicians said (5.2%). CONCLUSION: Medical services provided by the STMM were helpful in resolving patients' problems. The data have crucial implications for evaluating overseas mobile medical aid from the viewpoint of patients. PMID- 26613783 TI - It's the End of the World and I Feel Fine: Soul Belief and Perceptions of End-of the-World Scenarios. AB - Five studies tested the effects that soul beliefs have on reactions to end-of-the world scenarios. In Studies 1 and 2, participants who firmly believe in an immortal soul showed less resistance to an article predicting the end of humanity than those without such belief. However, in Studies 3 to 5, thoughts of symbolic immortality made soul believers more resistant to scientific evidence predicting the end of humanity. These results suggest that belief in an immortal soul provides psychological protection against the threat of humanity's demise that does not hold for symbolic immortality beliefs. PMID- 26613784 TI - The Whitewashing Effect: Using Racial Contact to Signal Trustworthiness and Competence. AB - The present research examines whether people use racial contact to signal positive and negative social attributes. In two experiments, participants were instructed to fake good (trustworthy/competent) or fake bad (untrustworthy/incompetent) when reporting their amount of contact with a range of different racial groups. In Experiment 1 (N = 364), participants faking good reported significantly more contact with White Americans than with non-White Americans, whereas participants faking bad did not. In Experiment 2 (N = 1,056), this pattern was replicated and was found to be particularly pronounced among those with stronger pro-White bias. These findings suggest that individuals may use racial contact as a social signal, effectively "whitewashing" their apparent contact and friendships when trying to present positively. PMID- 26613785 TI - Reductions in Goal-Directed Cognition as a Consequence of Being the Target of Empathy. AB - Although empathy is widely promoted as a beneficial practice across both intergroup and interpersonal contexts, the implications of being the target of empathy for the target's own psychological state are unclear. Three experiments examined how being the target of empathy affects goal-directed cognition outcomes related to a psychological sense of power, namely, the ability to maintain goal focus and readiness to ask for more in negotiations. We reasoned that because individuals typically empathize with others they perceive as disadvantaged and needing support, trying to empathize would raise individuals up in terms of such outcomes at the same time as it pushed the targets of their empathy down in a complementary fashion. Results were consistent with these predictions across intergroup and intragroup interaction. The findings thus suggest that individuals' efforts to empathize can undermine the targets of their empathy in a subtle manner by hindering their ability to pursue their goals. PMID- 26613786 TI - Emergence of Antimicrobial-Resistant Escherichia coli of Animal Origin Spreading in Humans. AB - In the context of the great concern about the impact of human activities on the environment, we studied 403 commensal Escherichia coli/Escherichia clade strains isolated from several animal and human populations that have variable contacts to one another. Multilocus sequence typing (MLST) showed a decrease of diversity 1) in strains isolated from animals that had an increasing contact with humans and 2) in all strains that had increased antimicrobial resistance. A specific B1 phylogroup clonal complex (CC87, Institut Pasteur schema nomenclature) of animal origin was identified and characterized as being responsible for the increased antimicrobial resistance prevalence observed in strains from the environments with a high human-mediated antimicrobial pressure. CC87 strains have a high capacity of acquiring and disseminating resistance genes with specific metabolic and genetic determinants as demonstrated by high-throughput sequencing and phenotyping. They are good mouse gut colonizers but are not virulent. Our data confirm the predominant role of human activities in the emergence of antimicrobial resistance in the environmental bacterial strains and unveil a particular E. coli clonal complex of animal origin capable of spreading antimicrobial resistance to other members of microbial communities. PMID- 26613788 TI - Bone remodelling after femoral short stem implantation in total hip arthroplasty: 1-year results from a randomized DEXA study. AB - INTRODUCTION: Short stem prostheses have been developed to preserve proximal femoral bone stock. This prospective, randomized study compared periprosthetic bone remodelling following short and straight stem implantation 1 year after surgery. MATERIALS AND METHODS: One hundred and forty-four consecutive patients undergoing total hip arthroplasty were randomized to either a Fitmore short or a cementless straight stem (both Zimmer, Winterthur, Switzerland). Periprosthetic bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry performed the day before surgery and at 7 days, 3 months and 1 year postoperatively. Furthermore, the HHS and the WOMAC were obtained. RESULTS: One hundred and thirty-eight patients completed 1-year follow-up. Periprosthetic BMD changes at 1 year were most pronounced in the proximal medial region of interest (ROI) 7 with -17.2% after short stem and -16.7% after straight implantation (p = 0.67). However, there was significantly less BMD reduction in ROI 6 following short (-4.7%) versus straight stem (-10.8%) implantation (p = 0.01). There were no significant differences between the two groups in terms of the HHS and the WOMAC either before or after surgery. CONCLUSION: One year after surgery, both stems showed an implant-specific periprosthetic bone remodelling. Nevertheless, proximal load transfer was more pronounced after short stem implantation than with a straight stem. PMID- 26613787 TI - Population Structure Shapes Copy Number Variation in Malaria Parasites. AB - If copy number variants (CNVs) are predominantly deleterious, we would expect them to be more efficiently purged from populations with a large effective population size (Ne) than from populations with a small Ne. Malaria parasites (Plasmodium falciparum) provide an excellent organism to examine this prediction, because this protozoan shows a broad spectrum of population structures within a single species, with large, stable, outbred populations in Africa, small unstable inbred populations in South America and with intermediate population characteristics in South East Asia. We characterized 122 single-clone parasites, without prior laboratory culture, from malaria-infected patients in seven countries in Africa, South East Asia and South America using a high-density single-nucleotide polymorphism/CNV microarray. We scored 134 high-confidence CNVs across the parasite exome, including 33 deletions and 102 amplifications, which ranged in size from <500 bp to 59 kb, as well as 10,107 flanking, biallelic single-nucleotide polymorphisms. Overall, CNVs were rare, small, and skewed toward low frequency variants, consistent with the deleterious model. Relative to African and South East Asian populations, CNVs were significantly more common in South America, showed significantly less skew in allele frequencies, and were significantly larger. On this background of low frequency CNV, we also identified several high-frequency CNVs under putative positive selection using an FST outlier analysis. These included known adaptive CNVs containing rh2b and pfmdr1, and several other CNVs (e.g., DNA helicase and three conserved proteins) that require further investigation. Our data are consistent with a significant impact of genetic structure on CNV burden in an important human pathogen. PMID- 26613789 TI - Changes in Liver Antioxidant Status of Offspring Mice Induced by Maternal Fluoride Exposure During Gestation and Lactation. AB - Excessive fluoride intake for a long time has been demonstrated to provoke hepatic oxidative stress in adults. However, the response to fluoride toxicity of liver in newborns exposed to fluoride during embryonic and suckling stages remains unclear. In this study, female Kunming mice were administrated with 25, 50, and 100 mg/L sodium fluoride (NaF) from prenatal day 0 to day 21 after delivery, and the antioxidative status in the liver of their pups at postnatal day 21 was evaluated. The results showed that compared with the control group, NaF significantly increased malondialdehyde (MDA) level and reduced catalase (CAT) activity, while no statistical difference was observed in activities and mRNA expressions of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR). Notably, with comparison to the controls, the protein level of CAT was significantly reduced in medium- and high-fluoride groups, while its relative mRNA abundance was enhanced which could result from the encouragement of the lowered CAT protein expression. These findings suggested that CAT was more susceptible to low-fluoride exposure in early life. PMID- 26613790 TI - The Effects of Chromium Supplementation on Endocrine Profiles, Biomarkers of Inflammation, and Oxidative Stress in Women with Polycystic Ovary Syndrome: a Randomized, Double-Blind, Placebo-Controlled Trial. AB - Limited data are available indicating the effects of chromium administration on endocrine profiles, biomarkers of inflammation, and oxidative stress among women with polycystic ovary syndrome (PCOS). This study was done to assess the effects of chromium administration on endocrine profiles, biomarkers of inflammation, and oxidative stress in women with PCOS. Participants of this randomized, double blind, placebo-controlled trial consisted of 60 patients with PCOS who received either 200 MUg chromium supplements (n = 30) or placebo daily (n = 30) for 8 weeks. Endocrine profiles, inflammatory factors, and biomarkers of oxidative stress were assessed at study baseline and at the end of intervention. After 8 weeks of intervention, pregnancy rate in chromium group was higher than that in the placebo group: 16.7 % (5/30) vs. 3.3 % (1/30), P = 0.08. In addition, prevalence of acne (20.0 vs. 3.3 %, P = 0.04) decreased following the administration of chromium supplements compared with the placebo. Taking chromium led to a significant reduction in hirsutism (-1.8 +/- 2.5 vs. -0.2 +/- 0.8, P = 0.002), serum high-sensitivity C-reactive protein (hs-CRP) (-717.0 +/- 1496.1 vs. +227.1 +/- 1669.6 ng/mL, P = 0.02), plasma malondialdehyde (MDA) (-0.1 +/- 0.7 vs. +1.1 +/- 1.5 MUmol/L, P < 0.001), and a significant increase in plasma total antioxidant capacity (TAC) concentrations (+250.7 +/- 265.2 vs. +13.0 +/- 201.6 mmol/L, P < 0.001). We failed to find any significant effect of chromium administration on endocrine profiles and nitric oxide (NO) and glutathione (GSH) levels. Overall, taking chromium for 8 weeks among women with PCOS had beneficial effects on acne, hirsutism, hs-CRP, TAC, and MDA levels, but it did not affect endocrine profiles, NO, and GSH. CLINICAL TRIAL REGISTRATION NUMBER: IRCT201506105623N44 ( www.irct.ir ). PMID- 26613791 TI - Factors associated with leisure-time physical activity among patients undergoing hemodialysis. AB - BACKGROUND: End-stage renal disease patients are characterized by low levels of physical activity, especially during leisure time. However, the recognition of variables associated with patterns of physical activity in this population has been little explored. Thus, the objective was to assess factors associated with levels of physical activity during leisure time among patients on haemodialysis. METHODS: Ninety-eight patients (51.6 +/- 15.7 years, 57 M/41 F) from two dialysis centres in Sao Paulo, Brazil participated in this cross-sectional study. Participants were divided into those who never exercised during leisure-time (inactive) and those who exercised at least once a week (active). The independent factors assessed were: socio-demographic data, comorbidities, personal barriers to exercise and physical activity records from childhood to adulthood (tracking of physical activity). RESULTS: Only 27 % of patients were engaged in PA during their leisure time at least once a week. Patients who engaged in regular physical activity during adulthood before the initiation of the hemodialysis treatment (adjusted OR: 7.24 95 % IC: 1.99; 26.50), those who developed the renal disease through diseases other than diabetes or hypertension (adjusted OR: 4.82; 95 % IC: 1.48; 15.68), and those who had no cardiovascular diseases (adjusted OR: 11.33; 95 % IC: 1.23; 103.8) where more likely to be active during their leisure-time. CONCLUSION: Comorbidities such as cardiovascular disease, hypertension and diabetes mellitus as well as the level of physical activity prior to end-stage renal disease could predict leisure-time physical activity among patients receiving hemodialysis therapy. PMID- 26613793 TI - Amyloid-independent functional neural correlates of episodic memory in amnestic mild cognitive impairment. AB - PURPOSE: Although amnestic mild cognitive impairment (aMCI) could have various biological characteristics, little attention has been given to the nature of episodic memory decline in aMCI with pathophysiologies other than Alzheimer's disease (AD), i.e., aMCI with low beta-amyloid (Abeta) burden. This study aimed to identify the functional neural basis of episodic memory impairment in aMCI with Abeta burden negative (aMCI-Abeta-) and to compare these results with aMCI with Abeta burden positive (aMCI-Abeta+). METHODS: Individuals with aMCI (n = 498) were selected from the Alzheimer's Disease Neuroimaging Initiative database. Based on the mean florbetapir standard uptake value ratio, participants were classified as aMCI-Abeta- or aMCI-Abeta+. Correlations between memory scores and regional cerebral glucose metabolism (rCMglc) were analyzed separately for the two subgroups using a multiple regression model. RESULTS: For aMCI-Abeta-, significant positive correlations between memory and rCMglc were found in the bilateral claustrum, right thalamus, left anterior cingulate cortex, left insula, and right posterior cingulate. For aMCI-Abeta+, significant positive correlations between memory and rCMglc were found in the temporoparietal areas. These correlation patterns remained unchanged when clinical severity was added as a covariate CONCLUSION: Our findings indicate that memory impairment in aMCI-Abeta- is related to multimodal integrative processing and the attentional control system, whereas memory impairment in aMCI-Abeta+ is related to the typical brain memory systems and AD signature. These results suggest that although the two subgroups are clinically in the same category as aMCI, the memory impairment process depends on completely different functional brain regions according to their Abeta burden level. PMID- 26613792 TI - Diagnostic accuracy of (18)F amyloid PET tracers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. AB - Imaging or tissue biomarker evidence has been introduced into the core diagnostic pathway for Alzheimer's disease (AD). PET using (18)F-labelled beta-amyloid PET tracers has shown promise for the early diagnosis of AD. However, most studies included only small numbers of participants and no consensus has been reached as to which radiotracer has the highest diagnostic accuracy. First, we performed a systematic review of the literature published between 1990 and 2014 for studies exploring the diagnostic accuracy of florbetaben, florbetapir and flutemetamol in AD. The included studies were analysed using the QUADAS assessment of methodological quality. A meta-analysis of the sensitivity and specificity reported within each study was performed. Pooled values were calculated for each radiotracer and for visual or quantitative analysis by population included. The systematic review identified nine studies eligible for inclusion. There were limited variations in the methods between studies reporting the same radiotracer. The meta-analysis results showed that pooled sensitivity and specificity values were in general high for all tracers. This was confirmed by calculating likelihood ratios. A patient with a positive ratio is much more likely to have AD than a patient with a negative ratio, and vice versa. However, specificity was higher when only patients with AD were compared with healthy controls. This systematic review and meta-analysis found no marked differences in the diagnostic accuracy of the three beta-amyloid radiotracers. All tracers perform better when used to discriminate between patients with AD and healthy controls. The sensitivity and specificity for quantitative and visual analysis are comparable to those of other imaging or biomarker techniques used to diagnose AD. Further research is required to identify the combination of tests that provides the highest sensitivity and specificity, and to identify the most suitable position for the tracer in the clinical pathway. PMID- 26613794 TI - Fluorescent monomers: "bricks" that make a molecularly imprinted polymer "bright". AB - Molecularly imprinted polymers (MIPs) are potent and established recognition phases in separation and enrichment applications. Because of their robustness, versatility and format adaptability, they also constitute very promising sensing phases, especially when the active sensing element is directly integrated into the MIP. Fluorescent MIPs incorporating fluorescent monomers are perhaps the best developed and most successful approach here. This article reviews the state of the art in this field, discussing the pros and cons of the use of fluorescent dye and probe derivatives as such monomers, the different molecular interaction forces for template complexation, signalling modes and a variety of related approaches that have been realized over the years, including Forster resonance energy transfer processes, covalent imprinting, postmodification attachment of fluorescent units and conjugated polymers as MIPs; other measurement schemes and sensing chemistries that use MIPs and fluorescence interrogation to solve analytical problems (fluorescent competitive assays, fluorescent analytes, etc.) are not covered here. Throughout the article, photophysical processes are discussed to facilitate understanding of the effects that can occur when one is planning for a fluorescence response to happen in a constrained polymer matrix. The article concludes with a concise assessment of the suitability of the different formats for sensor realization. PMID- 26613795 TI - Characterization of Lactococcus lactis response to ampicillin and ciprofloxacin using surface-enhanced Raman spectroscopy. AB - Decades of antibiotic use or misuse has resulted in antibiotic resistance in lactic acid bacteria, a group of common culture starters and probiotic microorganisms. This has urged researchers to study how lactic acid bacteria respond to antibiotics, so as to have a better strategy to identify and predict the antibiotic-resistant bacteria. This study aimed to characterize the biochemical profiles of Lactococcus lactis responding to antibiotics using surface-enhanced Raman spectroscopy (SERS). Lactococcus lactis exposed to antibiotics was mixed with 50-nm gold nanoparticles for subsequent SERS measurements. The SERS spectra analyzed by principal component analysis showed no significant change after 30 min of antibiotic treatment, whereas distinct changes were clearly observed after 60 and 90 min of antibiotic treatment. Different antibiotics induced different spectral changes, and these changes revealed the detailed biochemical information of cellular responses. This study demonstrates that the SERS method developed not only senses the changes in the bacterial cell wall, but also reveals details of the biochemical profiles, which help us to understand how lactic acid bacteria respond to antibiotics, as well as to set a base for the detection of antibiotic susceptibility of bacteria by SERS. PMID- 26613796 TI - A cleavable biotin tagging reagent that enables the enrichment and identification of carbonylation sites in proteins. AB - The utility of a new, cleavable tag for identifying and enriching protein carbonyls is examined. Using a model system, human serum albumin modified with acrolein, the EZ-Link alkoxyamine-PEG4-SS-PEG4-biotin affinity tag, was tested for its ability to label protein carbonyls in proteomic analyses of protein carbonylation. The efficiency of the labeling was assayed and compared to standard biotin hydrazide reagents. The label was also tested in liquid chromatography-tandem mass spectrometry (LC/MS/MS) experiments. The quality of the fragmentation spectra was assessed and the relative detection efficiency of various modification sites was compared to standard biotin hydrazide reagents. Finally, the viability of using the label with streptavidin bead enrichment protocols in a standard proteomics workflow was probed. PMID- 26613797 TI - Hypoxia promotes Mycobacterium tuberculosis-specific up-regulation of granulysin in human T cells. AB - Oxygen tension affects local immune responses in inflammation and infection. In tuberculosis mycobacteria avoid hypoxic areas and preferentially persist and reactivate in the oxygen-rich apex of the lung. Oxygen restriction activates antimicrobial effector mechanisms in macrophages and restricts growth of intracellular Mycobacterium tuberculosis (M.Tb). The effect of oxygen restriction on T cell-mediated antimicrobial effector mechanisms is unknown. Therefore we determined the influence of hypoxia on the expression of granulysin, an antimicrobial peptide of lymphocytes. Hypoxia increased the antigen-specific up regulation of granulysin mRNA and protein in human CD4(+) and CD8(+) T lymphocytes. This observation was functionally relevant, because oxygen restriction supported the growth-limiting effect of antigen-specific T cells against virulent M.Tb residing in primary human macrophages. Our results provide evidence that oxygen restriction promotes the expression of granulysin and suggest that this effect-in conjunction with additional T cell-mediated immune responses-supports protection against mycobacteria. The therapeutic modulation of oxygen availability may offer a new strategy for the host-directed therapy of infectious diseases with intracellular pathogens. PMID- 26613798 TI - Changes in views on digital intraoral scanners among dental hygienists after training in digital impression taking. AB - BACKGROUNDS: Despite the rapid development of digital dentistry, the use of digital intraoral scanners remains limited. The aim of this study was to evaluate the changes in views on intraoral scanners among dental hygienists after training. METHODS: Thirty-four dental hygienists with >3 years of clinical experience participated and were divided into 2 groups : iTero and Trios groups. Participants of each group practiced the usage of both intraoral scanners, for total 12 times over 4 sessions, Questionnaires were given to participants at two different times; prior to and after the completion of the training sessions. The parameters of questionnaires included on difficulty of use, patient discomfort, awareness, preference, and clinical usefulness of intraoral scanners and comparison of two types of scanners. RESULTS: Upon the completion of the training, both iTero and Trios groups gave positive feedback on anticipated accuracy, efficiency, and clinical usefulness. More participants of the iTero group responded that the level of difficulty of use and patient discomfort was greater than Trios. Both groups preferred Trios for its clinical usefulness. CONCLUSIONS: The perceptions of dental hygienists on usage of intraoral scanner and digital impression improved positively with the training. The participants favored Trios over iTero in terms of difficulty of use , patient comfort, and clinical usefulness. This study showed that appropriate training could change the views on the efficiency of intraoral scanners positively among dental hygienists. PMID- 26613799 TI - Polypatex: an R package for paternity exclusion in autopolyploids. AB - Microsatellite markers have demonstrated their value for performing paternity exclusion and hence exploring mating patterns in plants and animals. Methodology is well established for diploid species, and several software packages exist for elucidating paternity in diploids; however, these issues are not so readily addressed in polyploids due to the increased complexity of the exclusion problem and a lack of available software. We introduce polypatex, an r package for paternity exclusion analysis using microsatellite data in autopolyploid, monoecious or dioecious/bisexual species with a ploidy of 4n, 6n or 8n. Given marker data for a set of offspring, their mothers and a set of candidate fathers, polypatex uses allele matching to exclude candidates whose marker alleles are incompatible with the alleles in each offspring-mother pair. polypatex can analyse marker data sets in which allele copy numbers are known (genotype data) or unknown (allelic phenotype data) - for data sets in which allele copy numbers are unknown, comparisons are made taking into account all possible genotypes that could arise from the compared allele sets. polypatex is a software tool that provides population geneticists with the ability to investigate the mating patterns of autopolyploids using paternity exclusion analysis on data from codominant markers having multiple alleles per locus. PMID- 26613800 TI - Efficacy of suit therapy on functioning in children and adolescents with cerebral palsy: a systematic review and meta-analysis. AB - AIM: This systematic review and meta-analysis presents an overview of the efficacy of suit therapy on functioning in children and adolescents with cerebral palsy (CP). METHOD: A systematic review with meta-analysis was conducted. A comprehensive search of peer-reviewed articles was performed on electronic databases, from their inception to May 2014. Studies included were rated for methodological quality using the Physiotherapy Evidence Database scale. Effects of suit therapy on functioning were assessed using meta-analytic techniques. RESULTS: From the 46 identified studies, four met the inclusion criteria and were included in the meta-analysis. Small, pooled effect sizes were found for gross motor function at post-treatment (g=0.46, 95% confidence interval [CI] 0.10-0.82) and follow-up (g=0.47, 95% CI 0.03-0.90). INTERPRETATION: The small number of studies, the variability between them, and the low sample sizes are limitations of this review. Findings suggest that to weigh and balance benefits against harms, clinicians, patients, and families need better evidence to examine and prove the effects of short intensive treatment such as suit therapy on gross motor function in children and adolescents with CP. Therefore, more research based on high-quality studies focusing on functioning in all dimensions of the International Classification of Functioning, Disability and Health perspective is necessary to clarify the impact of suit therapy. PMID- 26613801 TI - Oral creatine supplementation on performance of Quarter Horses used in barrel racing. AB - The aim of this study was to evaluate the effects of oral creatine supplementation on the athletic performance of equines used for barrel racing. Ten healthy Quarter Horses, or Quarter Horse crossbred, weighing 429.7 +/- 25.3 kg and with mean age of 3.8 +/- 1.2 years, were used. Animals were evaluated in four different moments (M1, M2, M3, M4), and between M3 and M4, they were supplemented with 28 g of creatine/100 kg of body weight, orally, for 45 days. Although significant alterations for LDH activity, plasma glucose and packed cell volume were observed, it was possible to conclude that there was no improvement in the athletic performance for the animals used on the experiment, as there were no changes in time scores, heart rate and plasma lactate, variables considered as performance indicators, before and after supplementation. PMID- 26613802 TI - Treatment of squamous cell carcinoma of the posterior pharyngeal wall: Radiotherapy versus surgery. AB - BACKGROUND: Treatment strategy in squamous cell carcinoma (SCC) of the posterior pharyngeal wall is still being debated. METHODS: We performed a retrospective analysis according to delivered treatment. RESULTS: One hundred eighty patients were treated between 1997 and 2011. Eighty-nine patients (49.4%) received surgery +/- radiotherapy (RT), whereas 91 (50.6%) received definitive RT +/- chemoradiotherapy (RT/CRT). Five-year overall survival (OS) was 33.4%. There was a significant 5-year OS benefit in surgical treatment versus RT/CRT (43% vs 24.1%; p = .002). Multivariate analysis showed that current smokers, T3 to T4 classification, well-differentiated SCC, and nonsurgical treatment were associated with reduced OS. Subgroup analysis showed significant survival benefit of surgical treatment compared with RT/CRT in patients with T1 to T2 but not in T3 to T4 disease. CONCLUSION: Surgical management translated into a survival benefit, even in early T classification. These results should be interpreted with caution for selection bias. Surgery remains the standard of care in localized posterior pharyngeal wall SCC. Primary CRT should be considered for nonoperable disease. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1722-E1729. PMID- 26613803 TI - The effect of long-term under- and overfeeding on the expression of six major milk proteins' genes in the mammary tissue of goats. AB - Milk protein synthesis in the mammary gland involves expression of six major milk proteins' genes whose nutritional regulation remains poorly defined. In this study, the effect of long-term under- and overfeeding on the expression of as1 casein: CSN1S1, as2-casein: CSN1S2, beta-casein: CSN2, kappa-casein: CSN3, alpha lactalbumin: LALBA and beta-lactoglobulin: BLG gene in goat mammary tissue (MT) was examined. Twenty-four lactating dairy goat, at 90-98 days in milk, were divided into three homogenous subgroups and fed the same ration, for 60 days, in quantities which met 70% (underfeeding), 100% (control) and 130% (overfeeding) of their energy and crude protein requirements. The results showed a significant decrease in mRNA of CSN1S2, CSN2, CSN3 and LALBA genes in the MT of underfed goats compared with the overfed and on the CSN1S1 and BLG gene expressions in the MT of underfed goats compared with the respective control and overfed. CSN2 was the most abundant transcript in goat MT relative to the other milk proteins' genes. Significantly positive correlations were observed between the mRNA levels of caseins' and BLG genes with the milk yield. Moreover, a significant correlation was found between the mRNA levels of CSN1S2 with the milk protein, lactose content and lactose yield and also between the LALBA gene expression with the lactose content and lactose yield respectively. In conclusion, the feeding level and consequently the nutrients availability affected the milk lactose content, protein and lactose yield as well as the milk volume by altering the CSN1S1, CSN1S2, CSN2, CSN3, LALBA and BLG gene expression involved in their metabolic pathways. PMID- 26613804 TI - Mechanism for transport of ivermectin to the stratum corneum in rats. AB - Ivermectin (IVM) is used as an oral medication for scabies, a skin infection caused by a mite, sarcoptes scabiei, which parasitizes in the stratum corneum. After oral administration IVM is absorbed from the intestine, and finally distributed to the stratum corneum to eliminate the mites. However its transport mechanism remains unclear. A pharmacokinetic study was performed using hairless Wistar Yagi (HWY) rats, which have no or atrophied sebaceous glands, and Wistar rats as a reference. After oral administration of IVM to both groups, the area under the concentration-time curve of IVM in the dermis and epidermis (dermis epidermis) of HWY rats were about 60% lower than that of Wistar rats, even though the plasma concentration profiles were comparable in both groups. In addition at 12 h after the administration, IVM concentration in the outer stratum corneum, the shallower layer of the dermis-epidermis, was higher compared to that in the deeper layer. In the dermis-epidermis of the skin from various locations, the concentrations of IVM and squalene, the latter of which is secreted to the skin surface via the sebaceous gland, were positively well correlated. Those results suggest that IVM is transported to the stratum corneum via the sebaceous glands. PMID- 26613805 TI - Application of metabolomics to toxicology of drugs of abuse: A mini review of metabolomics approach to acute and chronic toxicity studies. AB - Metabolomics has been widely applied to toxicological fields, especially to elucidate the mechanism of action of toxicity. In this review, metabolomics application with focus on the studies of chronic and acute toxicities of drugs of abuse like stimulants, opioids and the recently-distributed designer drugs will be presented in addition to an outline of basic analytical techniques used in metabolomics. Limitation of metabolomics studies and future perspectives will be also provided. PMID- 26613806 TI - Recent advances in optical diagnosis of oral cancers: Review and future perspectives. AB - Optical diagnosis techniques offer several advantages over traditional approaches, including objectivity, speed, and cost, and these label-free, noninvasive methods have the potential to change the future workflow of cancer management. The oral cavity is particularly accessible and, thus, such methods may serve as alternate/adjunct tools to traditional methods. Recently, in vivo human clinical studies have been initiated with a view to clinical translation of such technologies. A comprehensive review of optical methods in oral cancer diagnosis is presented. After an introduction to the epidemiology and etiological factors associated with oral cancers currently used, diagnostic methods and their limitations are presented. A thorough review of fluorescence, infrared absorption, and Raman spectroscopic methods in oral cancer diagnosis is presented. The applicability of minimally invasive methods based on serum/saliva is also discussed. The review concludes with a discussion on future demands and scope of developments from a clinical point of view. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E2403-E2411, 2016. PMID- 26613807 TI - The Renal Connexome and Possible Roles of Connexins in Kidney Diseases. AB - Connexins are membrane-spanning proteins that allow for the formation of cell-to cell channels and cell-to-extracellular space hemichannels. Many connexin subtypes are expressed in kidney cells. Some mutations in connexin genes have been linked to various human pathologies, including cardiovascular, neurodegenerative, lung, and skin diseases, but the exact role of connexins in kidney disease remains unclear. Some hypotheses about a connection between genetic mutations, endoplasmic reticulum (ER) stress, and the unfolded protein response (UPR) in kidney pathology have been explored. The potential relationship of kidney disease to abnormal production of connexin proteins, mutations in their genes together with ER stress, or the UPR is still a matter of debate. In this scenario, it is tantalizing to speculate about a possible role of connexins in the setting of kidney pathologies that are thought to be caused by a deregulated podocyte protein expression, the so-called podocytopathies. In this article, we give examples of the roles of connexins in kidney (patho)physiology and propose avenues for further research concerning connexins, ER stress, and UPR in podocytopathies that may ultimately help refine drug treatment. PMID- 26613808 TI - Direct effect of chronic hypoxia in suppressing large conductance Ca(2+) activated K(+) channel activity in ovine uterine arteries via increasing oxidative stress. AB - KEY POINTS: Chronic hypoxia has a direct effect in down-regulating the BKCa channel beta1 subunit and inhibiting the BKCa channel activity in uterine arteries of pregnant sheep. Oxidative stress plays a causal role in hypoxia mediated suppression of BKCa channel function. The steroid hormone-induced effect on BKCa channels is a target of hypoxia-mediated oxidative stress. Inhibition of oxidative stress ameliorates the adverse effect of hypoxia both ex vivo and in vivo in pregnant sheep exposed to long-term high-altitude hypoxia. Our findings provide novel evidence of a causative role of oxidative stress in hypoxia mediated inhibition of the BKCa channel activity in uterine arteries and new insights in understanding and alleviating pregnancy complications associated with gestational hypoxia such as pre-eclampsia and fetal growth restriction. ABSTRACT: Uterine arteries of pregnant sheep acclimatized to long-term high-altitude hypoxia were associated with a decrease in large-conductance Ca(2+)-activated K(+) (BKCa) channel activity. The present study tested the hypothesis that prolonged hypoxia has a direct effect in suppressing BKCa channel activity by increasing oxidative stress. Uterine arteries were isolated from non-pregnant and near-term (~142 days) pregnant sheep, and were treated ex vivo with 21.0 or 10.5% O2 for 48 h. The hypoxia treatment significantly increased the production of reactive oxygen species in uterine arteries, which was blocked by N acetylcysteine. In uterine arteries of pregnant sheep, hypoxia significantly inhibited BKCa channel current density, decreased NS1619-induced relaxations and increased pressure-dependent tone, which were annulled by N-acetylcysteine. In accordance, hypoxia resulted in down-regulation of BKCa channel beta1 subunit, which was restored in the presence of N-acetylcysteine. In addition, the N acetylcysteine treatment significantly increased BKCa channel beta1 subunit abundance and BKCa channel current density in uterine arteries from pregnant sheep exposed to high-altitude hypoxia (3801 m, PaO2: 60 mmHg) for 110 days. In uterine arteries of non-pregnant animals, hypoxia inhibited steroid hormone induced up-regulation of BKCa channel current density and NS1619-mediated relaxations, which were reversed by N-acetylcysteine. Furthermore, the synthetic superoxide dismutase and catalase mimetic EUK-134 also ablated the effects of hypoxia on BKCa channel currents in uterine arteries. The results demonstrate a direct effect of hypoxia in inhibiting the BKCa channel activity in uterine arteries via increased oxidative stress. PMID- 26613809 TI - Thrombotic microangiopathy without renal involvement: two novel mutations in complement-regulator genes. AB - ESSENTIALS: The differential diagnosis among thrombotic microangiopathies (TMAs) is challenging. We studied a case of TMA with neurologic symptoms, no renal impairment and normal ADAMTS-13 levels. Two novel mutations in complement factor I and thrombomodulin genes were identified. Complement-regulator genes can be involved in TMAs with normal ADAMTS-13 regardless of renal damage. BACKGROUND: Thrombotic microangiopathies (TMAs) often represent a challenge for clinicians, because clinical, laboratory, and even genetic features are not always sufficient to distinguish among different TMAs. OBJECTIVES: The aim of this study was to investigate the pathogenetic mechanisms underlying an acute case of TMA with features of both thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS). PATIENTS/METHODS: We report the case of a 49-year-old woman who developed an acute TMA with neurologic involvement and no renal impairment. ADAMTS-13, von Willebrand factor, and complement-system biochemical characterization was performed on acute phase samples. Exome sequencing and direct Sanger sequencing of previously aHUS-associated genes were performed. The functional consequences of the thrombomodulin (THBD) mutation were investigated by in vitro expression studies. RESULTS: Despite a clinical diagnosis of TTP, the patient had normal ADAMTS-13 levels and increased VWF antigen levels with ultra large von Willebrand factor multimers. C3, C4, and complement factors H and I (CFI) were normal. Molecular analysis confirmed two novel heterozygous mutations in CFI (c.805G>A, p.G269S) and THBD (c.1103C>T, p.P368L), and in vitro expression studies showed a reduction in the generation of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) caused by mutated THBD. This proinflammatory condition, associated with the p.G269S mutation in CFI, probably leads to a complement-mediated endothelial activation, with a relevant prothrombotic potential in case of transient environmental triggers. CONCLUSIONS: This study identified the first case of acute TMA without renal involvement but with neurological damage carrying two novel mutations in complement-regulator genes, highlighting the possible role of the complement system as a common pathogenetic mechanism in TMAs. PMID- 26613810 TI - Biological effect on drug distribution and vascular healing via paclitaxel-coated balloon technology in drug eluting stent restenosis swine model. AB - OBJECTIVES: To evaluate the biological effect of a paclitaxel-coated balloon (PCB) technology on vascular drug distribution and healing in drug eluting stent restenosis (DES-ISR) swine model. BACKGROUND: The mechanism of action and healing response via PCB technology in DES-ISR is not completely understood. METHODS: A total of 27 bare metal stents were implanted in coronary arteries and 30 days later the in-stent restenosis was treated with PCB. Treated segments were harvested at 1 hr, 14 days and 30 days post treatment for the pharmacokinetic analysis. In addition, 24 DES were implanted in coronary arteries for 30 days, then all DES-ISRs were treated with either PCB (n = 12) or uncoated balloon (n = 12). At day 60, vessels were harvested for histology following angiography and optical coherence tomography (OCT). RESULTS: The paclitaxel level in neointimal tissue was about 18 times higher (P = 0.0004) at 1 hr Cmax , and retained about five times higher (P = 0.008) at day 60 than that in vessel wall. A homogenous distribution of paclitaxel in ISR was demonstrated by using fluorescently labeled paclitaxel. Notably, in DES-ISR, both termination OCT and quantitative coronary angioplasty showed a significant neointimal reduction and less late lumen loss (P = 0.05 and P = 0.03, respectively) post PCB versus post uncoated balloon. The PES ISR + PCB group displayed higher levels of peri-strut inflammation and fibrin scores compared to the -limus DES-ISR + PCB group. CONCLUSIONS: In ISR, paclitaxel is primarily deposited in neointimal tissue and effectively retained over time following PCB use. Despite the presence of metallic struts, a uniform distribution was characterized. PCB demonstrated an equivalent biological effect in DES-ISR without significantly increasing inflammation. (c) 2015 Wiley Periodicals, Inc. PMID- 26613811 TI - Optoelectric patterning: Effect of electrode material and thickness on laser induced AC electrothermal flow. AB - Rapid electrokinetic patterning (REP) is an emerging optoelectric technique that takes advantage of laser-induced AC electrothermal flow and particle-electrode interactions to trap and translate particles. The electrothermal flow in REP is driven by the temperature rise induced by the laser absorption in the thin electrode layer. In previous REP applications 350-700 nm indium tin oxide (ITO) layers have been used as electrodes. In this study, we show that ITO is an inefficient electrode choice as more than 92% of the irradiated laser on the ITO electrodes is transmitted without absorption. Using theoretical, computational, and experimental approaches, we demonstrate that for a given laser power the temperature rise is controlled by both the electrode material and its thickness. A 25-nm thick Ti electrode creates an electrothermal flow of the same speed as a 700-nm thick ITO electrode while requiring only 14% of the laser power used by ITO. These results represent an important step in the design of low-cost portable REP systems by lowering the material cost and power consumption of the system. PMID- 26613812 TI - [Informed consent as evidence]. PMID- 26613813 TI - Robert John (Robin) Ferrier: 1932-2013. PMID- 26613814 TI - Synthetic Approaches to L-Iduronic Acid and L-Idose: Key Building Blocks for the Preparation of Glycosaminoglycan Oligosaccharides. AB - L-Iduronic acid (IdoA) is an important monosaccharide component of glycosaminoglycans (GAGs) such as heparin, heparan sulfate and dermatan sulfate. GAGs are complex, highly sulfated polysaccharides that mediate a multitude of physiological and pathological processes via their interactions with a range of diverse proteins. The main challenge in the synthesis of GAG oligosaccharides is the efficient gram-scale preparation of IdoA building blocks since neither IdoA nor L-idose is commercially available or readily accessible from natural sources. In this review, the different synthetic approaches for the preparation of IdoA and its derivatives, including L-idose, are presented and discussed. Derivatives of the latter are often used in GAG synthesis and are elaborated to IdoA via selective oxidation at C-6 after incorporation into a GAG chain. Particular focus will be given to the preparation of IdoA synthons most commonly used for GAG oligosaccharide synthesis, and on the progress made since the last systematic review in this area. PMID- 26613815 TI - Glycosylation of Cellulases: Engineering Better Enzymes for Biofuels. AB - Cellulose in plant cell walls is the largest reservoir of renewable carbon on Earth. The saccharification of cellulose from plant biomass into soluble sugars can be achieved using fungal and bacterial cellulolytic enzymes, cellulases, and further converted into fuels and chemicals. Most fungal cellulases are both N- and O-glycosylated in their native form, yet the consequences of glycosylation on activity and structure are not fully understood. Studying protein glycosylation is challenging as glycans are extremely heterogeneous, stereochemically complex, and glycosylation is not under direct genetic control. Despite these limitations, many studies have begun to unveil the role of cellulase glycosylation, especially in the industrially relevant cellobiohydrolase from Trichoderma reesei, Cel7A. Glycosylation confers many beneficial properties to cellulases including enhanced activity, thermal and proteolytic stability, and structural stabilization. However, glycosylation must be controlled carefully as such positive effects can be dampened or reversed. Encouragingly, methods for the manipulation of glycan structures have been recently reported that employ genetic tuning of glycan active enzymes expressed from homogeneous and heterologous fungal hosts. Taken together, these studies have enabled new strategies for the exploitation of protein glycosylation for the production of enhanced cellulases for biofuel production. PMID- 26613816 TI - Human Milk Oligosaccharides (HMOS): Structure, Function, and Enzyme-Catalyzed Synthesis. AB - The important roles played by human milk oligosaccharides (HMOS), the third major component of human milk, in the health of breast-fed infants have been increasingly recognized, as the structures of more than 100 different HMOS have now been elucidated. Despite the recognition of the various functions of HMOS as prebiotics, antiadhesive antimicrobials, and immunomodulators, the roles and the applications of individual HMOS species are less clear. This is mainly due to the limited accessibility to large amounts of individual HMOS in their pure forms. Current advances in the development of enzymatic, chemoenzymatic, whole-cell, and living-cell systems allow for the production of a growing number of HMOS in increasing amounts. This effort will greatly facilitate the elucidation of the important roles of HMOS and allow exploration into the applications of HMOS both as individual compounds and as mixtures of defined structures with desired functions. The structures, functions, and enzyme-catalyzed synthesis of HMOS are briefly surveyed to provide a general picture about the current progress on these aspects. Future efforts should be devoted to elucidating the structures of more complex HMOS, synthesizing more complex HMOS including those with branched structures, and developing HMOS-based or HMOS-inspired prebiotics, additives, and therapeutics. PMID- 26613817 TI - Preface. PMID- 26613818 TI - "Do the Right Thing. It Will Gratify Some People and Astonish the Rest."--M. Twain. PMID- 26613819 TI - A randomized trial of sublingual misoprostol to augment routine third-stage management among women at risk of postpartum hemorrhage. AB - OBJECTIVE: To assess whether a combination of misoprostol and oxytocin is more beneficial than oxytocin alone in reducing blood loss after vaginal delivery among women with known risk factors for postpartum hemorrhage (PPH). METHODS: A randomized, double-blind trial was conducted in a medical college in eastern India among women aged at least 18 years who had known high-risk factors for PPH. Using a computer-generated random number sequence (block size 6-8), participants were randomly assigned to receive 400 MUg misoprostol or matched placebo tablets sublingually, in addition to 10 units of oxytocin, after vaginal delivery. The primary outcomes were postpartum blood loss at 1 hour and frequency of PPH. Analyses were by intention to treat. RESULTS: Both groups contained 144 participants. Postpartum blood loss at 1 hour after delivery was significantly lower among women who received misoprostol than among those who received placebo (225.8+/-156.7 mL vs 302.4+/-230.3 mL; P<0.001). The frequency of moderate PPH (500-999 mL) was significantly lower in the group receiving misoprostol than in the placebo group (5 [3.5%] vs 15 [10.4%] participants; P=0.03). CONCLUSION: As compared with oxytocin alone, misoprostol with oxytocin more effectively reduced blood loss after vaginal delivery among women at risk of PPH. Clinical Trial Registry India:CTRI/2014/03/004491. PMID- 26613820 TI - A randomized controlled trial of clomifene citrate, metformin, and pioglitazone versus letrozole, metformin, and pioglitazone for clomifene-citrate-resistant polycystic ovary syndrome. AB - OBJECTIVE: To examine the efficacy of clomifene citrate, metformin, and pioglitazone versus letrozole, metformin, and pioglitazone among women with polycystic ovary syndrome (PCOS) resistant to clomifene citrate. METHODS: A prospective double-blind randomized controlled trial of women younger than 40 years who had primary/secondary infertility associated with PCOS and had not ovulated in response to clomifene citrate regimens previously was conducted at a center in Cairo, Egypt, between August 1, 2013, and December 31, 2014. Computer generated random number tables and opaque envelopes were used to assign participants to group A or group B. Participants allocated to group A received 100mg clomifene citrate daily for 5 days from the third day of the menstrual cycle, whereas those in group B received 5mg letrozole daily in the same regimen. All patients received 850 mg metformin and 15 mg pioglitazone for 10 days from the first day of the menstrual cycle. The primary outcome was cumulative ovulation rate. Analyses were by intention to treat. RESULTS: Fifty women were assigned to each group. Ovulation occurred in 108 (92.3%) of 117 cycles in group A and 93 (86.9%) of 107 cycles in Group B (P=0.184). CONCLUSION: Combined treatment with letrozole, metformin, and pioglitazone was efficacious among women with PCOS resistant to clomifene citrate. ClinicalTrials.gov: NCT01909141. PMID- 26613821 TI - Application of the PRECEDE model to improve sexual function among women with hysterectomy. AB - OBJECTIVE: To determine the effect of an educational program based on the PRECEDE model to improve sexual function among women with hysterectomy. METHODS: The present randomized trial, conducted in Iran during 2014, included 48 women with hysterectomy who were selected through convenience sampling and randomly divided into two equal groups. Women in the experimental group received an educational program based on constructs of the PRECEDE model. The control group received only routine interventions. Before the interventions, the women completed two questionnaires: one that measured the PRECEDE model constructs and the Rosen Female Sexual Function Index. The questionnaires were repeated 4 weeks after the intervention and the results were compared within and between groups. RESULTS: In each group, a significant improvement in sexual function was demonstrated after the intervention (P<0.001). The mean sexual function score increased to a greater extent in the experimental group (difference 16.95+/-6.33) than in the control group (difference 4.35+/-1.94; P<0.001). CONCLUSION: The findings confirm the effectiveness of an educational program based on the PRECEDE model in terms of improving sexual function among women with hysterectomy. Iranian Registry of Clinical Trials: IRCT2014122220401N1. PMID- 26613822 TI - Empowering adolescent girls in Sub-Saharan Africa to prevent unintended pregnancy and HIV: A critical research gap. AB - The need to prevent early pregnancy and HIV among adolescent girls in Sub-Saharan Africa has been recognized increasingly over recent years. Although extensive work has been done to determine appropriate interventions for girls in high income countries, very little evidence is available to guide programmatic interventions in Sub-Saharan Africa. The available evidence has been equivocal regarding improved outcomes. While knowledge and self-reported behaviors frequently change with interventions, including those performed at the community level, educational programs, and direct contraceptive provision, downstream outcomes rarely reflect a significant effect of the interventions; however, provision of financial or other interventions to incentivize continued school enrollment are a promising development. We suggest directions for future research to fill this critical gap in the literature. PMID- 26613823 TI - Comparison of two contraceptive pills containing drospirenone and 20 MUg or 30 MUg ethinyl estradiol for polycystic ovary syndrome. AB - OBJECTIVE: To compare the effects of 30 MUg and 20 MUg ethinyl estradiol (EE) among women with polycystic ovary syndrome (PCOS). METHODS: In a randomized study, patients with PCOS, a history of six or fewer menstrual cycles in the previous 12 months, and abnormal body hair growth were enrolled at a center in Kolkata, India, between May 1, 2012, and January 31, 2014. Participants were randomly assigned (1:1) using a computer-generated randomization table to receive an oral contraceptive pill containing 3mg drospirenone and either 30 MUg EE or 20 MUg EE. Patients were followed up after 6 and 12 months. The primary outcome was the absolute change in the free androgen index. Participants were masked to group assignment but investigators were not. Analyses were by intention to treat. RESULTS: Overall, 112 patients were enrolled. At 6 months, the free androgen index had decreased by 4.96+/-6.01 among patients receiving 30 MUg (n=55) and by 4.81+/-6.03 among those receiving 20 MUg (n=57; P=0.89). At 12 months, the decrease from baseline was 5.23+/-5.79 with 30 MUg and 4.99+/-5.86 with 20 MUg (P=0.82). CONCLUSION: Among patients with PCOS, an oral contraceptive pill containing 20 MUg EE has similar effects on androgen levels to those of a pill containing 30 MUg. CLINICAL TRIAL REGISTRATION NUMBER: CTRI/2012/04/002571. PMID- 26613824 TI - Medium-term outcomes after combined trachelectomy and uterosacral ligament suspension among young women with severe uterine prolapse. AB - OBJECTIVE: To evaluate anatomic and sexual outcomes among young women with severe pelvic organ prolapse undergoing combined trachelectomy and laparoscopic high uterosacral ligament suspension (LHUS). METHODS: In a prospective study in Beijing, China, patients (aged <=50 years) with pelvic organ prolapse of stage III or higher according to the Pelvic Organ Prolapse Quantification (POP-Q) were enrolled between November 2007 and August 2011. After combined trachelectomy and LHUS, patients were followed up at 6 weeks, 6 months, 12 months, and yearly thereafter. Anatomic success was defined as POP-Q lower than stage II. Sexual outcomes were assessed at 6 months via the validated Short-Form Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12), and compared with a control group of 39 healthy age-matched women. RESULTS: Among 49 patients, surgical success and patient satisfaction rates were 100% after a median follow-up of 54 months. Among 48 patients who were sexually active at follow-up, 39 (81%) completed the PISQ-12 questionnaire. The 6-month PISQ-12 score was higher than the preoperative score overall (38.1 vs 26.4, P<0.001) and for all three subscale domains (P<=0.001). The PISQ-12 score of postoperative patients was similar to that of control women (36.8, P=0.52). CONCLUSION: Trachelectomy combined with LHUS produced satisfactory medium-term anatomic and functional outcomes for young women with severe uterine prolapse. PMID- 26613825 TI - Introduction of cardiotocograph monitoring improves birth outcomes in women with preeclampsia in Ghana. PMID- 26613826 TI - Sex, Nativity, and Disability in Older Mexican Americans. AB - OBJECTIVES: To examine the effect of nativity and sex on activities of daily living (ADLs) and mobility limitations in older Mexican Americans. DESIGN: Cross sectional. SETTING: Hispanic Established Population for the Epidemiological Study of the Elderly (Hispanic EPESE) (2004-05). PARTICIPANTS: Noninstitutionalized Mexican Americans aged 75 and older (N = 2,069; 56.3% U.S. born, 43.7% Mexican born). MEASUREMENTS: Sociodemographic characteristics, self-reported medical conditions (arthritis, cancer, diabetes mellitus, stroke, heart attack, hip fracture), ADLs, and gross mobility function. RESULTS: The prevalence of ADL limitation was 32.9% in U.S.-born participants and 33.9% in Mexican-born participants of mobility limitation was 56.6% in U.S.-born participants and 55.6% in Mexican-born participants. Mexican-born participants tended to report less ADL limitation (odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.59-1.05)) after controlling for sociodemographic variables and medical conditions. They were also less likely to report mobility limitation (OR = 0.64, 95% CI = 0.48 0.86) after controlling for all covariates. There was a significant effect of the interaction between nativity and sex (OR = 0.42, 95% CI = 0.24-0.74) on ADL limitation, suggesting that Mexican-born men were less disabled than U.S.-born men, whereas the opposite was true for women. No significant interaction between nativity and sex was found for mobility limitation. CONCLUSION: Mexican-born men were less disabled than their U.S.-born counterparts, and Mexican-born women were more likely to report disability than Mexican-born men. PMID- 26613827 TI - Auditory and proprioceptive spatial impairments in blind children and adults. AB - It is not clear what role visual information plays in the development of space perception. It has previously been shown that in absence of vision, both the ability to judge orientation in the haptic modality and bisect intervals in the auditory modality are severely compromised (Gori, Sandini, Martinoli & Burr, 2010; Gori, Sandini, Martinoli & Burr, 2014). Here we report for the first time also a strong deficit in proprioceptive reproduction and audio distance evaluation in early blind children and adults. Interestingly, the deficit is not present in a small group of adults with acquired visual disability. Our results support the idea that in absence of vision the audio and proprioceptive spatial representations may be delayed or drastically weakened due to the lack of visual calibration over the auditory and haptic modalities during the critical period of development. PMID- 26613829 TI - Application of continuous normal-lognormal bivariate density functions in a sensitivity analysis of municipal solid waste landfill. AB - The variability of untreated municipal solid waste (MSW) shear strength parameters, namely cohesion and shear friction angle, with respect to waste stability problems, is of primary concern due to the strong heterogeneity of MSW. A large number of municipal solid waste (MSW) shear strength parameters (friction angle and cohesion) were collected from published literature and analyzed. The basic statistical analysis has shown that the central tendency of both shear strength parameters fits reasonably well within the ranges of recommended values proposed by different authors. In addition, it was established that the correlation between shear friction angle and cohesion is not strong but it still remained significant. Through use of a distribution fitting method it was found that the shear friction angle could be adjusted to a normal probability density function while cohesion follows the log-normal density function. The continuous normal-lognormal bivariate density function was therefore selected as an adequate model to ascertain rational boundary values ("confidence interval") for MSW shear strength parameters. It was concluded that a curve with a 70% confidence level generates a "confidence interval" within the reasonable limits. With respect to the decomposition stage of the waste material, three different ranges of appropriate shear strength parameters were indicated. Defined parameters were then used as input parameters for an Alternative Point Estimated Method (APEM) stability analysis on a real case scenario of the Jakusevec landfill. The Jakusevec landfill is the disposal site of the capital of Croatia - Zagreb. The analysis shows that in the case of a dry landfill the most significant factor influencing the safety factor was the shear friction angle of old, decomposed waste material, while in the case of a landfill with significant leachate level the most significant factor influencing the safety factor was the cohesion of old, decomposed waste material. The analysis also showed that a satisfactory level of performance with a small probability of failure was produced for the standard practice design of waste landfills as well as an analysis scenario immediately after the landfill closure. PMID- 26613828 TI - Attitudes Toward Restricting the Sexual and Reproductive Rights of Women Living With HIV Infection in Yemen. AB - A considerable amount of research has demonstrated the pervasive and destructive power of discrimination against people living with HIV, which limits their full and equal participation in society. This study surveyed 613 young adults from Yemen about their attitudes toward the sexual and reproductive rights of women living with HIV (WLWH). Among survey respondents, 80% believed that WLWH should be sterilized and not allowed to get married. Furthermore, 62% thought that WLWH should be forced to have abortions if they became pregnant. Men were more likely than women to impose restrictions on the sexual and reproductive rights of WLWH. HIV stigma predicted respondent attitudes toward WLWH, but religiosity and knowledge about HIV did not. The results of the study have implications for developing programs to protect and promote the rights of WLWH in Yemen. PMID- 26613830 TI - Kinetic modelling of RDF pyrolysis: Model-fitting and model-free approaches. AB - In this study, refuse derived fuel (RDF) was selected as solid fuel and it was pyrolyzed in a thermal analyzer from room temperature to 900 degrees C at heating rates of 5, 10, 20, and 50 degrees C/min in N2 atmosphere. The obtained thermal data was used to calculate the kinetic parameters using Coats-Redfern, Friedman, Flylnn-Wall-Ozawa (FWO) and Kissinger-Akahira-Sunose (KAS) methods. As a result of Coats-Redfern model, decomposition process was assumed to be four independent reactions with different reaction orders. On the other hand, model free methods demonstrated that activation energy trend had similarities for the reaction progresses of 0.1, 0.2-0.7 and 0.8-0.9. The average activation energies were found between 73-161kJ/mol and it is possible to say that FWO and KAS models produced closer results to the average activation energies compared to Friedman model. Experimental studies showed that RDF may be a sustainable and promising feedstock for alternative processes in terms of waste management strategies. PMID- 26613831 TI - [Big data in health in Spain: now is the time for a national strategy]. PMID- 26613832 TI - [Controversies over vaccines in Spain, a chance for social vaccinology]. PMID- 26613833 TI - Multiple Discordant Histology After Nephrectomy: Descriptive Analysis and Outcomes. AB - BACKGROUND: While RCC is the most common primary renal neoplasm, few cases of ipsilateral renal lesions of different RCC histologic subtypes have been described. The objective of this study was to evaluate our experience with synchronous, histologically unique, primary renal neoplasms within the same kidney. PATIENTS AND METHODS: We retrospectively analyzed 2 institutional nephrectomy databases from 2000 to 2013. The study cohort comprised 15 patients with multiple, discordant renal histology after partial or radical nephrectomy. Demographic data, immunohistochemical analysis, and clinical course were assessed and analyzed. RESULTS: Eight patients (53%) were black, 10 (60%) were male, and 5 (36%) were tobacco users. Median follow-up time was 13 months (range, 1-62 months), and 9 patients (56%) underwent radical nephrectomy. Among 36 tumors, the median tumor size was 2.3 cm (range, 0.4-9 cm). The most common combination of discordant tumor histology among patients with >= 2 tumors was clear-cell (cc) renal-cell carcinoma (RCC) with chromophobe RCC (3 cases, 19%). In 3 patients (19%), a single tumor was noted to have 2 distinct patterns; all patients had ccRCC with papillary RCC. Three (20%) of 15 patients developed metastatic disease. The median cancer-free survival time for patients with metastasis was 2 months. CONCLUSION: Multiple, discordant renal pathology represents a rarely reported entity in patients receiving nephrectomy. We introduce the largest cohort of synchronous renal tumors, of which ccRCC/chromophobe RCC was the most common pairing. PMID- 26613835 TI - Inviting family to be present during cardiopulmonary resuscitation: Impact of education. AB - Encouraging and permitting family members to stay together during cardiopulmonary resuscitation benefits the patient, family and staff. Health care professionals (HCP) attitudes and experiences are documented as barriers to initiating family presence during cardiopulmonary resuscitation (FPDR). The aim of this pilot study was to explore the influence of education on changing HCPs attitudes and intent to provide families with the option to be present at the next cardiac arrest. A purposive sample of 29 HCP from an acute care hospital participated in this quasi experimental study. 18 of the original 29 HCP completed both the education package and the post-test questionnaire. RESULTS: The majority of participants in this study had previous experience with FPDR (62%) and supported FPDR (69%). While participants had slightly more positive attitudes towards FPDR post education, this change was not significant (p = 0.79). Similarly, participation in education did not change participants concerns about safety issues or increase participant's intention to invite a family member to be present at the next cardiac arrest. The majority of participants strongly supported the development of a dedicated family support person. Education has limited impact on change participant's attitudes or intentions to invite family to be present at the next cardiac arrest. PMID- 26613834 TI - New insights on the role of luteinizing hormone releasing hormone agonists in premenopausal early breast cancer patients. AB - Luteinising hormone releasing hormone agonists (LH-RHa) are effective in the treatment of advanced endocrine-sensitive breast cancer in premenopausal patients, but their role in the adjuvant setting has remained controversial for a long time. Tamoxifen for 5 years has been traditionally considered the standard endocrine therapy for premenopausal patients and this is still valid for many patients. However, the recently reported SOFT trial has suggested that adding ovarian function suppression (OFS) to tamoxifen could improve DFS in women at sufficient risk to warrant adjuvant chemotherapy and who remained premenopausal after this therapy. The administration of an aromatase inhibitor plus OFS represents an additional therapeutic option for hormone-receptor positive premenopausal breast cancer patients, according to the combined analysis of the SOFT and TEXT trials. Temporary ovarian suppression induced by LH-RHa has been recognized as an effective strategy to preserve ovarian function from the toxic effects of chemotherapy and is now recommended in young breast cancer patients with endocrine-insensitive tumors. In this review, we discuss recent data on the role of LH-RHa in combination with tamoxifen or with an aromatase inhibitor, and we comment on its role as a strategy to preserve ovarian function in young patients candidates for adjuvant or neo-adjuvant chemotherapy. PMID- 26613836 TI - Long-term outcomes of biliary atresia with splenic malformation. AB - BACKGROUND: We assessed the long-term outcomes of patients with biliary atresia with splenic malformation (BASM). METHODS: We retrospectively assessed outcomes of 255 patients who underwent the Kasai procedure (KP) at our hospital between 1972 and 2014. Clinical outcomes of 11 patients with BASM (group A: nine with polysplenia, two with asplenia) and 244 patients with isolated BA (group B) were compared. RESULTS: The incidence of early cholangitis and hepatopulmonary syndrome (HPS) was significantly higher in group A than in group B. Of the 11 group A patients, three died of severe cardiac defects during early infancy. Seven became jaundice free following KP, with three patients subsequently requiring liver transplantation (LTx). Four survived with their native livers for 2, 5, 22, and 23years, respectively. Overall 20-year survival rates were 63.6% and 66.5% and 20-year native liver survival rates were 29.0% and 47.3% in groups A and B, respectively. No significant difference in cumulative survival rates was observed between both groups. CONCLUSIONS: Long-term outcomes in BASM patients without lethal cardiac defects were comparable to patients with isolated BA. Careful follow-up may be required in patients with BASM because of a potentially higher risk of secondary complications such as HPS. PMID- 26613838 TI - The long-term effects of school dropout and GED attainment on substance use disorders. AB - BACKGROUND: Epidemiologic research suggests that 14% of the population do not complete high school, and dropout has been linked to mental health conditions, substance use, chronic health problems, and criminal behavior. Few studies have assessed whether attainment of the general education development (GED) credential is protective from substance use. PURPOSE: To assess the long-term outcomes of school dropout and GED attainment on past year substance use disorders, age of onset, and current smoking status. METHODS: Longitudinal data were included for lifetime substance users who participated in the National Epidemiological Survey on Alcohol and Related Conditions (Waves I and II). Eligible participants (N=30,608) were classified as having completed high school, dropped out of high school and did not complete a GED, or completed GED at Wave I. Survey logistic regression analyses were used to determine whether high school graduation status was associated with substance use disorders and smoking at Wave II. RESULTS: Multivariate results suggest that participants who dropped out of high school (OR=1.53; p<.01) or attained a GED were more likely to have a past year marijuana use disorder (OR=1.62 p<.01) compared to high school graduates. High school dropouts were also more likely to be current smokers (OR=1.88; p<.05) than graduates. CONCLUSIONS: High school dropouts have higher long-term rates of marijuana use disorder and smoking in adulthood than graduates. Attainment of a GED does not appear to be protective from marijuana use disorders in adulthood. PMID- 26613837 TI - Hematologic outcomes after total splenectomy and partial splenectomy for congenital hemolytic anemia. AB - PURPOSE: The purpose of this study was to define the hematologic response to total splenectomy (TS) or partial splenectomy (PS) in children with hereditary spherocytosis (HS) or sickle cell disease (SCD). METHODS: The Splenectomy in Congenital Hemolytic Anemia (SICHA) consortium registry collected hematologic outcomes of children with CHA undergoing TS or PS to 1 year after surgery. Using random effects mixed modeling, we evaluated the association of operative type with change in hemoglobin, reticulocyte counts, and bilirubin. We also compared laparoscopic to open splenectomy. RESULTS: The analysis included 130 children, with 62.3% (n=81) undergoing TS. For children with HS, all hematologic measures improved after TS, including a 4.1g/dl increase in hemoglobin. Hematologic parameters also improved after PS, although the response was less robust (hemoglobin increase 2.4 g/dl, p<0.001). For children with SCD, there was no change in hemoglobin. Laparoscopy was not associated with differences in hematologic outcomes compared to open. TS and laparoscopy were associated with shorter length of stay. CONCLUSION: Children with HS have an excellent hematologic response after TS or PS, although the hematologic response is more robust following TS. Children with SCD have smaller changes in their hematologic parameters. These data offer guidance to families and clinicians considering TS or PS. PMID- 26613839 TI - Reproducibility and differential item functioning of the alcohol dependence syndrome construct across four alcohol treatment studies: An integrative data analysis. AB - BACKGROUND: The validity of the alcohol dependence syndrome has been supported. The question of whether different measures of the construct are comparable across studies and patient subgroups has not been examined. This study examined the alcohol dependence construct across four diverse large-scale treatment samples using integrative data analysis (IDA). METHOD: We utilized existing data (n=4393) from the COMBINE Study, Project MATCH, the Relapse Replication and Extension Project (RREP), and the United Kingdom Alcohol Treatment Trial (UKATT). We focused on four measures of alcohol dependence: the Alcohol Dependence Scale (COMBINE and RREP), Alcohol Use Inventory (MATCH), the Leeds Dependence Questionnaire (UKATT), and the Diagnostic and Statistical Manual of Mental Disorders (COMBINE and MATCH). Moderated nonlinear factor analysis was used to create a measure of alcohol dependence severity that was moderated by study membership, gender, age, and marital status. RESULTS: A commensurate measure of alcohol dependence severity was successfully created using 20 items available in four studies. We identified differential item functioning by study membership, age, gender, and/or marital status for 12 of the 20 items, indicating specific patient subgroups who responded differently to items based on their underlying dependence severity. CONCLUSIONS: Alcohol dependence severity is a single unidimensional construct that is comparable across studies. The use of IDA provided a strong test of the validity of the alcohol dependence syndrome and clues as to how some items used to measure dependence severity may be more or less central to the construct for some patients. PMID- 26613841 TI - General Hospital Psychiatry: a time of transition. PMID- 26613840 TI - Impact of Everolimus and Low-Dose Cyclosporin on Cytomegalovirus Replication and Disease in Pediatric Renal Transplantation. AB - In order to investigate the hypothesis that the mammalian target of rapamycin inhibitor everolimus (EVR) shows anticytomegalovirus (CMV) activity in pediatric patients, we analyzed the impact of EVR-based immunosuppressive therapy on CMV replication and disease in a large cohort (n = 301) of pediatric kidney allograft recipients. The EVR cohort (n = 59), who also received low-dose cyclosporin, was compared with a control cohort (n = 242), who was administered standard-dose cyclosporin or tacrolimus and an antimetabolite, mostly mycophenolate mofetil (91.7%). Multivariate analysis revealed an 83% lower risk of CMV replication in the EVR cohort than in the control cohort (p = 0.005). In CMV high-risk (donor+/recipient-) patients (n = 88), the EVR-based regimen was associated with a significantly lower rate of CMV disease (0% vs. 14.3%, p = 0.046) than the standard regimen. In patients who had received chemoprophylaxis with (val )ganciclovir (n = 63), the CMV-free survival rates at 1 year and 3 years posttransplant (100%) were significantly (p = 0.015) higher in the EVR cohort (n = 15) than in the control cohort (n = 48; 1 year, 75.0%; 3 years, 63.3%). Our data suggest that in pediatric patients at high risk of CMV, an EVR-based immunosuppressive regimen is associated with a lower risk of CMV disease than a standard-dose calcineurin inhibitor-based regimen. PMID- 26613842 TI - Prevention of lithium-associated renal failure: recent evidence. PMID- 26613843 TI - Parity begins at home. PMID- 26613844 TI - Mental health and wellbeing in the Sustainable Development Goals. PMID- 26613845 TI - Using GRADE to update WHO recommendations for MNS. PMID- 26613846 TI - The Lancet Psychiatry Editorial Board Development Programme. PMID- 26613847 TI - The paroxetine controversy: lessons for ketamine trials. PMID- 26613848 TI - Canadian ADHD black-box warnings. PMID- 26613850 TI - Michael Krausz: psychiatry for the most vulnerable. PMID- 26613851 TI - Neurodevelopment and ages of onset in depressive disorders. AB - How and why do clinical depressive disorders emerge in adolescence? In this Personal View, we present a neurodevelopmental theory to address causes for adolescent onsets of clinical depressive disorders. We argue that theories should account for three perplexing aspects of depressive disorders in adolescence: the episodic nature of depression; differences between sexes in rates of depression across development; and age-differentiated onsets. We consider how theories such as psychosocial acceleration, heterochronic brain development, dual-process models, glucocorticoid vulnerability hypothesis linked to early life stress, and epigenetic and genetic susceptibility might explain some aspects of adolescent depressive disorders. We argue that some synthesis between existing theories might be needed to establish a sufficient neurodevelopmental theoretical framework to explain onsets of depressive disorders in adolescence. PMID- 26613852 TI - Non-consent bias in OCTET. PMID- 26613853 TI - Non-consent bias in OCTET--Authors' reply. PMID- 26613854 TI - A retrospective study of canine prostatic diseases from 2002 to 2009 at the Alfort Veterinary College in France. AB - A retrospective study was used to investigate the incidence of prostatic diseases in a large population of dogs at Alfort Veterinary Hospital and to clarify epidemiologic features, which might be of a great help to veterinarians in managing and discriminating prostatic disorders. During the investigation period, a total of 72,300 male dogs (coming mainly from the Ile-de-France region) were registered in the Alfort Veterinary College database, and 481 of them (0.7%) were found to have prostatic disorder. The diagnosis was carried out on the basis of clinical signs and ultrasound findings. Among dogs experiencing a prostatic disorder, most frequently recorded diseases were benign prostatic hyperplasia (45.9%) and prostatitis (38.5%), followed by abscesses (7.7%), cysts (5.0%), neoplasia (2.6%), and squamous metaplasia (0.2%). Our study revealed an incidence of 0.3% of prostatic disorders observed in intact male dogs, except in the case of prostatic neoplasia. The mean age of the dogs experiencing prostatic disorders was 8.6 +/- 3.2 years. This was significantly different (P < 0.001). Large dogs were significantly more affected by prostatic disorders (P < 0.05), except for prostatic neoplasia. A breed predisposition was suspected in German Shepherd (odds ratio [OR] = 2.1; 95% confidence interval [CI]: 1.5-2.9), Rottweiler (OR = 1.8; 95% CI: 1.2-2.7), American Staffordshire Terrier (OR = 3.8; 95% CI: 2.5 5.8), Berger de Beauce (OR = 3.7; 95% CI: 2.2-6.1), and Bernese Mountain Dog (OR = 2.5; 95% CI: 1.3-4.7). PMID- 26613855 TI - Estrous cycle staging before mating led to increased efficiency in the production of pseudopregnant recipients without negatively affecting embryo transfer in mice. AB - The goal was to increase pseudopregnant mice production by estrous cycle staging by visual examination before pairing and to determine the effect of such pseudopregnant recipients on embryo transfer. To compare methods of estrous cycle staging over 14 days, groups consisted of 10 females in proestrus-estrus and 10 vasectomized males; group 1: only daily visual observation; group 2: daily visual observation and cytological examination on day 1; group 3: daily visual observation and daily cytological examination. The average time to first vaginal plug was 1.8 days in group 1, 2.7 days in group 2, and 3.2 days in group 3, whereas the average time between consecutive vaginal plugs was 9.2 days (group 1), 10 days (group 2), and 9.25 days (group 3). The average time between consecutive estrous cycles was 9.7 days (group 1), 11.8 days (group 2), and 9.4 days (group 3). The congruence between visual and cytological examination in determining proestrus-estrus in group 2 was 100% and that for the four stages in group 3 was 79% with a range of 44% to 100%. From 162 plug-positive females originally selected in proestrus-estrus, 49%, 30%, 19%, and 2% were plug-positive on Day 1, Day 2, Day 3, and Day 4, respectively, showing that pseudopregnant mice production was significantly increased on the first 2 days. From 192 plug positive females originally selected randomly, these values were 31%, 21%, 35%, 10%, and 3% on d1, d2, d3, d4, and d5, respectively. No significant differences were observed between groups with respect to embryo transfers with fresh or cryopreserved embryos although the number of pups born per litter was higher in group A with fresh (7.57 vs. 6.39) and cryopreserved-thawed embryos (5.0 vs. 4.38). Furthermore, the sex ratio and the genotype of the pups were not significantly affected. PMID- 26613856 TI - External magnetic fields affect the biological impacts of superparamagnetic iron nanoparticles. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) are recognized as one of the promising nanomaterials for applications in various field of nanomedicine such as targeted imaging/drug delivery, tissue engineering, hyperthermia, and gene therapy. Besides their suitable biocompatibility, SPIONs' unique magnetic properties make them an outstanding candidate for theranostic nanomedicine. Very recent progress in the field revealed that the presence of external magnetic fields may cause considerable amount of SPIONs' agglomeration in their colloidal suspension. As variation of physicochemical properties of colloidal nanoparticles has strong effect on their biological outcomes, one can expect that the SPIONs' agglomeration in the presence of external magnetic fields could change their well recognized biological impacts. In this case, here, we probed the cellular uptake and toxicity of the SPIONs before and after exposure to external magnetic fields. We found that the external magnetic fields can affect the biological outcome of magnetic nanoparticles. PMID- 26613857 TI - Supramolecular design of coordination bonding architecture on zein nanoparticles for pH-responsive anticancer drug delivery. AB - A pH-responsive system by constructing a designable coordination bonding-based metal-tannic acid (TA) architecture on zein nanoparticles (NPs) has been investigated. Film formation was initiated by the adsorption of the polyphenol and directed by pH-dependent, multivalent coordination bonding. The prepared metal-TA coated zein NPs (zein-TA/metal NPs) demonstrated good stability to maintain particle size in cell culture medium at 37 degrees C. The microstructure of the NPs was revealed by transmission electron microscopy (TEM). To confirm the surface chemical information of the NPs, XPS analysis was performed. Furthermore, in vitro viability studies revealed that the zein TA/metal NPs showed no significant cytotoxicity against HepG2 cells for 24h. Because of the pH-responsive coordination bonding between TA and metal ions, the functional property of the metal-TA films was tailored for drug delivery. Biocompatible AuNPs were produced using zein-TA/metal NPs as reducing and stabilizing agents which were promising in the photothermal therapy of cancers and other diseases. PMID- 26613858 TI - REDV/Rapamycin-loaded polymer combinations as a coordinated strategy to enhance endothelial cells selectivity for a stent system. AB - A major challenge in the development of drug eluting stent platform is the sustained inhibition of smooth muscle cell (SMC) proliferation while endothelial cell (EC) coverage is promoted. We demonstrated in this study that the combination of rapamycin-loaded polymer base layer and Arg-Glu-Asp-Val (REDV) peptide tethered top layer is a coordinated strategy to enhance EC-specific selectivity. A 2-methacryloyloxyethyl phosphorylcholine(MPC)-co-n-stearyl methacrylate (SMA) [PMS] film was prepared as a base coating to load rapamycin. MPC-co-SMA-co-p-nitrophenyloxycarbonyl polyethyleneglycol methacrylate (MEONP) [PMSN] was synthesized to form the top layer, which conjugated the EC-specific ligand REDV peptide that promotes EC attachment. The top layer functioned as a diffusion barrier, and the polymer film can sustain the rapamycin release of for over 120 days. The In vitro cell behavior of EC and SMC indicated that the rapamycin loaded polymer film inhibited cell growth in the first few days of drug release. After 8 days of drug release, the composite coating consistently resisted the nonspecific adsorption of SMC, whereas REDV enhanced EC attachment specifically. A rabbit iliac injury model was used to evaluate the in vivo of the application of this kind of surface-modified stainless steel stent. The composite polymer coating approach could significantly promote re-endothelialization without causing neointimal hyperplasia. The combination of an EC-specific ligand with rapamycin-loaded polymeric coating may potentially be an effective therapeutic alternative to improve currently available drug-eluting stents. PMID- 26613859 TI - PEG-induced molecular crowding leads to a relaxed conformation, higher thermal stability and lower catalytic efficiency of Escherichia coli beta-galactosidase. AB - Enzymatic activities were historically assayed in dilute solutions where molecular crowding, molecular confinement and their consequences were not taken into account. Here we report how macromolecular crowding tunes catalytic parameters for the tetrameric beta-Galactosidase from Escherichia coli, beta-Gal. We detected increases in KM (weaker substrate binding) and a nonlinear variation in Vmax, with a minimum at 25% W/P of the crowding agent (polyethyleneglycol molecular mass 6000, PEG(6000)) resulting in a linear decrease in the catalytic efficiency (kcat/KM) within the whole [PEG(6000)] range tested). Presence of crowding agent affected beta-Gal structural content and increased its thermal resistance. Steady state fluorescence and Fourier transformed infrared spectroscopic observations are compatible with crowding-induced disordering and restricted internal dynamics as a result of excluded volume and solvent structuring effects. This leads to a non-optimal substrate-binding site and a less conformationally strained protein. PMID- 26613860 TI - Nucleobase-modified dendrimers as nonviral vectors for efficient and low cytotoxic gene delivery. AB - Cationic dendrimers are associated with relatively low transfection efficacy and high toxicity in gene delivery. Surface modification of these dendrimers with functional ligands may resolve these issues. Here, we proposed a novel strategy to prepare surface-engineered dendrimers with high transfection efficacy and low toxicity on transfected cells. Several nucleobase analogues were modified on cationic dendrimers by a facile method. These nucleobase-modified dendrimers show improved transfection efficacy and reduced cytotoxicity compared to unmodified dendrimers on HEK293 and HeLa cells. Efficacy of the most efficient polymer is comparable to that of commercial transfection reagents such as SuperFect, PolyFect, and Lipofectamine 2000. The improved transfection efficacy of dendrimers after nucleobase modification is probably attributed to easier intracellular DNA unpacking and lower cytotoxicity. The results provide a valuable insight to guide the design of efficient and low cytotoxic gene vectors. PMID- 26613861 TI - Safety and efficacy evaluation of gelatin-based nanoparticles associated with UV filters. AB - The safety and efficacy assessment of nanomaterials is a major concern of industry and academia. These materials, due to their nanoscale size, can have chemical, physical, and biological properties that differ from those of their larger counterparts. The encapsulation of natural ingredients can provide marked improvements in sun protection efficacy. This strategy promotes solubility enhancement of flavonoids and yields an improved active ingredient with innovative physical, physicochemical and functional characteristics. Rutin, a flavonoid, has chemical and functional stability in topical vehicles exerting a synergistic effect in association with ultraviolet (UV) filters. However, the solubility of rutin is a limiting factor. Additionally, this bioactive compound does not have tendency to permeate across the stratum corneum. As an alternative to common synthetic based sunscreens, rutin-entrapped gelatin nanoparticles were designed. The present study investigated the pre-clinical safety of gelatin nanoparticles (GNPs) using an in vitro method and also assessed the clinical safety and efficacy of the association of GNPs with three commonly used chemical UV filters (ethylhexyl dimethyl PABA, ethylhexyl methoxycinnamate and methoxydibenzoylmethane). The non-irritant and adequate safety profile under sun exposed skin conditions of the nanomaterials and the emulsions qualified the products for clinical efficacy assays. The in vivo results indicated that the GNPs increased the antioxidant protection of the emulsions developed. However, the presence of rutin in the nanosized material did not enhance performance on the SPF test. In conclusion, these findings characterized the nanomaterials as an innovative platform for multifunctional bioactive sunscreens. PMID- 26613862 TI - Electrokinetic characteristics of HSA dimer and its monolayers at mica. AB - Human serum albumin (HSA) dimer was synthesized in a reaction of the monomer with 1,6-bis(maleimido)hexane (BMH) cross-linker. Thorough physicochemical characteristics of the dimer were performed. They comprised the diffusion coefficient, hydrodynamic diameter, electrophoretic mobility as a function of pH, isoelectric point and electrokinetic charge. The adsorption of the dimer molecules at mica was studied using the atomic force microscopy (AFM) and in situ streaming potential measurements. The kinetics of adsorption was determined by a direct AFM imaging of single molecules over various substrate areas and interpreted in terms of the random sequential adsorption model. These results were consistent with streaming potential measurements carried out for the parallel-plate channel flow. It was also shown by these measurements that the desorption of the monomer under flow conditions was negligible. In this way, the amount of irreversibly bound dimer was quantitatively evaluated to be 0.5 mgm(-2) for ionic strength of 0.01 and pH 3.5 that is similar that to previous result obtained for the albumin monomer. This indicates that the dimer adsorption occurs mostly in the side-on orientation. Finally, the electrokinetic characteristics of the dimer monolayers on mica were performed by the streaming potential method. It was observed that for lower pHs the zeta potential of monolayers is much lower than the bulk zeta potential of the dimer molecules. This was attributed to a heterogeneous charge distribution. It was concluded that the well-characterized HSA dimer monolayers can be used for quantitatively determining ligand and drug binding that has an essential practical significance. PMID- 26613863 TI - Characteristics of the influence of auxins on physicochemical properties of membrane phospholipids in monolayers at the air/aqueous solution interface. AB - Interactions between representatives of plant hormones and selected membrane lipids have been studied in monolayers at the air/aqueous solutions interface with pi-A isotherm analysis, microscopic visualization and grazing incidence X ray diffraction technique (GIXD). Four phytohormones: indole-3-acetic acid (IAA), indole-3-butyric acid (IBA), 2-naphthoxyacetic acid (BNOA) and 2,4 dichlorophenoxyacetic acid (2,4-D), belonging to the class of auxins differ as regards the chemical structure of the aromatic molecular fragment. The studied phospholipids have been chosen since they are omnipresent in the biological membranes of plant and animal kingdom. Our results revealed that both natural (IAA and IBA) and synthetic (2,4-D and BNOA) phytohormones modify the physicochemical characteristics of the investigated lipid monolayers. Auxins caused strong diminishing of the monolayer condensation, especially for DPPC and SOPE, which may be attributed to the phase transition in these monolayers. In the performed experiments the key step of auxins action occurs when the molecules interact with monolayers in the expanded state-when the space in the lipid head group region is large enough to accommodate the molecules of water soluble auxins. The application of GIXD technique confirmed that auxin molecules are also present at the interface at higher surface pressure (30 mN/m). The obtained results showed that among the investigated auxins, the largest influence on the lipid monolayers occurred in the case of BNOA, which molecule possesses the largest aromatic fragment. In contrast, 2,4-D, having the smallest aryl group affects the studied lipid systems to the smallest extent. PMID- 26613864 TI - Co-grafting of antiadhesive and antimicrobial agents onto UV-micropatterned copper surfaces. AB - Adhesion of proteins and bacteria was reduced by a factor close to one order of magnitude, and adhered bacteria were dramatically damaged on copper surfaces by grafting a PEG-modified PMMA-based (polymethyl methacrylate) copolymer together with an antimicrobial peptide. To obtain PEG and a peptide grafted together on the surface, a UV sensitive copolymer (containing PMMA, PEG and a UV sensitive reagent) was primary synthesized and deposited. After selective UV irradiation of this copolymer layer, an antimicrobial peptide, Magainin I, was grafted onto freed-polymer coated-copper surface via a spacer molecule (a mercapto carboxylic acid). The functionalization was characterized at each step by Polarization Modulation Reflection Absorption Infrared Spectroscopy (PM-RAIRS). The antiadhesive properties of the copolymer layer and antibacterial activity of the anchored Magainin I, were individually tested toward adsorption of bovine serum albumin (BSA) proteins, and against Gram positive bacteria, Listeria ivanovii, respectively. The results revealed that adhesion of both proteins and bacteria has been considerably reduced; moreover, the peptide still displays some antimicrobial activity after grafting. This work gives new ideas and perspectives to elaborate complex surface coatings where several agents are needed like for anti-biofilm or sensing applications. PMID- 26613865 TI - Effect of particle size in a colloidal hydrogel scaffold for 3D cell culture. AB - The in situ-forming colloidal hydrogels from the thermal gelation of poly(N isopropylacrylamide) (PNIPAM) microgel dispersions have been exploited for 3D cell culture. The properties of the hydrogel scaffold need to be tuned to further improve its performance. In addition, cellular uptake of the microgel particles need to be reduced to avoid their potential undesired influence. For these purposes we systematically examined the effect of microgel particle size on the hydrogel scaffold. It was found that gel properties could be tuned via changing particle size. Increasing particle size reduces the gel strength and its syneresis degree, both of which are favorable for cell growth. Meanwhile increasing particle size could also reduce significantly the cellular uptake of the microgel particles. Microgel with a size of ~162 nm shows the highest cellular uptake, beyond which cellular uptake decreases with increasing particle size. Hydrogel scaffold from 300 nm microgel, with suitable physical properties and reduced cellular uptake, were successfully used for multicellular spheroid generation. PMID- 26613866 TI - Synthesis and characterization of new microgel from tris(2-aminoethyl)amine and glycerol diglycidyl ether as poly(TAEA-co-GDE). AB - Here, we report a new microgel preparation from tris(2-aminoethyl)amine (TAEA) and glycerol diglycidyl ether (GDE) as p(TAEA-co-GDE) via simple microemulsion polymerization/crosslinking by using L-alpha lecithin as surfactant and gasoline as organic phase. The p(TAEA-co-GDE) microgels were visualized using optical microscopy and scanning electron microscopy (SEM) with size ranges <10 MUm. The prepared particles were found to be positively charged, 23.61 +/- 1.2 mV at pH~4.5, according to zeta-potential measurements, and the charge of particles decreased with increase in pH of the medium and become negatively charged after pH 10. The microgel particles were protonated (quaternized) or deprotanated by HCl and NaOH treatments, changing their zeta potential to 33 +/- 1.3 mV and 14.53 +/- 1.8 mV, respectively. Thermal properties of the prepared particles were observed by TG analysis before and after quaternization, and also after Co(II), Cu(II) and Cd(II) metal ion absorption. Here, we also demonstrated in situ CdS quantum dot (Q-dots) preparation within p(TAEA-co-GDE) microgels. The peak energy of 2.5 eV was observed in the fluorescence spectrum of p(TAEA-co-GDE)-CdS microgel by applying an excitation wavelength of 300 nm. Furthermore, the prepared p(TAEA-co-GDE) particles showed antibacterial characteristics against common bacteria such as Escherichia coli ATCC 8739, Staphylococcus aureus ATCC 6538, Bacillus subtilis ATCC 6633 and Pseudomonas aeruginosa ATCC 10145 and have great potential for biomedical use. Additionally, p(TAEA-co-GDE) particles are found to be biocompatible against L929 Fibroblast cells. PMID- 26613867 TI - Elevated Plasma P-Selectin Autoantibodies in Primary Sjogren Syndrome Patients with Thrombocytopenia. AB - BACKGROUND Primary Sjogren's syndrome (pSS) is one of the most common chronic systemic autoimmune diseases, and thrombocytopenia is one of the hematological manifestations of pSS. When platelet and endothelial cells are activated, P selectin is expressed on the cell surface. This study aimed to investigate the role of P-selectin autoantibodies in the pathogenesis of thrombocytopenia in pSS. MATERIAL AND METHODS P-selectin autoantibodies were measured by enzyme-linked immunosorbent assay (ELISA) in 38 pSS patients without thrombocytopenia and 32 pSS patients with thrombocytopenia, 32 idiopathic thrombocytopenic purpura (ITP) patients, and 35 healthy controls. RESULTS The plasma P-selectin autoantibodies (A490) in ITP patients and pSS patients with/without thrombocytopenia were significantly higher than those in healthy controls, but there were no significant differences between ITP patients and pSS patients with thrombocytopenia. The positive rate of P-selectin autoantibodies in pSS patients with thrombocytopenia was significantly higher than that in ITP patients. The platelet count was lower in P-selectin autoantibodies-positive patients, while among pSS patients with thrombocytopenia, the platelet count was lower in P selectin autoantibodies-positive patients than in P-selectin autoantibodies negative patients. In ITP patients and pSS patients with thrombocytopenia, the platelet count was lower in P-selectin autoantibodies-positive patients. CONCLUSIONS Elevated plasma P-selectin autoantibodies may play a role in the pathogenesis of thrombocytopenia in pSS patients. PMID- 26613869 TI - Long-term Cardiovascular Risk After Acute Coronary Syndrome, An Ongoing Challenge. PMID- 26613868 TI - Defining risk and identifying predictors of mortality for open conversion after endovascular aortic aneurysm repair. AB - OBJECTIVE: Risk of open conversion after endovascular aortic aneurysm repair (EVAR-c) is poorly defined. The purpose of this analysis was to determine outcomes of elective EVAR-c compared with elective primary open abdominal aortic aneurysm repair (PAR) in the Vascular Quality Initiative. METHODS: Vascular Quality Initiative patients who underwent elective EVAR-c and PAR (2002-2014) were reviewed. Candidate predictors of major adverse cardiac event (MACE) and/or 30-day mortality were entered into a multivariable model, and stepwise elimination was used to reduce the number of covariates to a best subset of predictors. To estimate the additive risk of EVAR-c for MACE or 30-day mortality over PAR, this variable was added along with the best subset of predictors into generalized estimating equations logistic regression models. RESULTS: We identified 159 EVAR-c and 3741 PAR patients. EVAR-c patients were older (73.5 +/- 8.1 vs 69.5 +/- 8.4 years; P < .0001), more likely to have diabetes (21% vs 15%; P = .03), and history of lower extremity bypass (9% vs 4%; P = .0006). EVAR-c was associated with a higher incidence of retroperitoneal aortic exposure (41%; n = 64 vs PAR, 26%, n = 976; P < .0001), use of a bifurcated graft (65%; n = 101 vs PAR, 52%; n = 1923; P = .001), greater blood loss (median [interquartile range], 2000 mL [1010-3500] vs PAR, 1200 mL [750-2000]; P < .0001) and longer procedure times (EVAR-c, 275 +/- 122 minutes vs PAR, 232 +/- 9 minutes; P < .0001). However, PAR more frequently was completed with a suprarenal and/or mesenteric cross-clamp (74%, n = 2749 vs EVAR-c, 53%, n = 83; P < .0001) and had a higher incidence of concomitant procedures (26%; n = 972 vs EVAR-c, 18%; n = 28; P = .03). Nonadjusted 30-day mortality was greater after EVAR-c: EVAR-c, 8% (n = 10) vs PAR, 3% (n = 105); P = .009. There was no difference in complication rates: EVAR-c, 33% (n = 52) vs PAR, 28% (n = 1056); P =.3. Preoperative 30-day mortality predictors included age (odds ratio [OR], 1.06/y, 95% confidence interval [CI], 1.04-1.1; P < .0001), chronic obstructive pulmonary disease (OR, 2.4; 95% CI, 1.6 3.5; P < .0001), history of leg bypass (OR, 2.3, 1.2-4.4;P =.01), suprarenal cross-clamp (OR 2.2, 1.2-4.1;P =.01), prior carotid revascularization (OR 2.2; 95% CI, 1.3-3.8; P = .0004), congestive heart failure (OR, 1.8; 95% CI, 0.9-3.5; P = .08), and female sex (OR, 1.6; 95% CI, 1.1-2.3; P = .02; area under the curve, 0.75). When controlling for covariates, EVAR-c was not significantly associated with MACE (OR, 1.2; 95% CI, 0.7-2.0; P = .4) or 30-day mortality (OR, 2.0; 0.9-4.2; P = .08). CONCLUSIONS: EVAR-c patients are typically older, have more comorbidities, and experience greater blood loss and longer procedure times compared with PAR patients. However, postoperative morbidity and mortality are primarily driven by patient covariates and intraoperative factors, rather than the need for endograft explantation. Several preoperative variables were identified as predictors of 30-day mortality after elective EVAR-c and should be considered during the decision-making process for remedial treatment of failed endovascular PAR. PMID- 26613870 TI - Ventricular Support With Extracorporeal Membrane Oxygenation: A Double-edged Sword. PMID- 26613871 TI - Continuous intraoperative neuromonitoring in thyroid surgery: Safety analysis of 400 consecutive electrode probe placements with standardized procedures. AB - BACKGROUND: Continuous intraoperative neuromonitoring (C-IONM) is a new technology and it is appropriate to analyze its safety. METHODS: C-IONM was performed according to a standardized technique to control any adverse events and electrode positioning issues. RESULTS: Four hundred vagal nerve dissections were analyzed considering vagal nerve diameter, mean time effort for C-IONM probe positioning, and electrode dislocation rate. A significant superior dislocation rate in case of: (a) when a 3 mm automatic periodic stimulating (APS) electrode size was used in a vagal nerve diameter <2 mm; (b) anterior access; and (c) vagal nerve A subtype in relation (p < .05). No related additional local or systemic morbidity was registered in this series. There was a statistically significant positive relationship between increased diameter of vagal nerve and increased electromyography (EMG) amplitude (p = .03). There was also a significant increase of amplitude between initial and final vagal nerve stimulation in uneventful cases (p = .02). CONCLUSION: We analyzed the technical issues to achieve improved vagal nerve critical view of safety dissection, stimulation, and C-IONM probe placement. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1568-E1574, 2016. PMID- 26613872 TI - Functional MR Imaging Techniques in Oncology in the Era of Personalized Medicine. AB - DW and DCE MR imaging contribute significantly to diagnosis, treatment planning, response assessment, and prognosis in personalized cancer medicine. Nevertheless, the need for further standardization of these techniques needs to be addressed. Whole-body DW MR imaging is an exciting field; however, future studies need to investigate in more depth the biologic significance of the findings depicted, their prognostic relevance, and cost-effectiveness in comparison with MDCT and PET/CT. New MR imaging probes, such as targeted or activatable contrast agents and dynamic nuclear hyperpolarization, show great promise to further improve the care of patients with cancer in the near future. PMID- 26613874 TI - Body Diffusion-weighted MR Imaging in Oncology: Imaging at 3 T. AB - Advances in hardware and software enable high-quality body diffusion-weighted images to be acquired for oncologic assessment. 3.0 T affords improved signal/noise for higher spatial resolution and smaller field-of-view diffusion weighted imaging (DWI). DWI at 3.0 T can be applied as at 1.5 T to improve tumor detection, disease characterization, and the assessment of treatment response. DWI at 3.0 T can be acquired on a hybrid PET-MR imaging system, to allow functional MR information to be combined with molecular imaging. PMID- 26613875 TI - Assessment of Tumor Angiogenesis: Dynamic Contrast-enhanced MR Imaging and Beyond. AB - Dynamic contrast-enhanced (DCE) MR imaging is used increasingly often to evaluate tumor angiogenesis and the efficacy of antiangiogenic drugs. In clinical practice DCE-MR imaging applications are largely centered on lesion detection, characterization, and localization. In research, DCE-MR imaging helps inform decision making in early-phase clinical trials by showing efficacy and by selecting dose and schedule. However, the role of these techniques in patient selection is uncertain. Future research is required to optimize existing DCE-MR imaging methods and to fully validate these biomarkers for wider use in patient care and in drug development. PMID- 26613873 TI - MR Imaging Biomarkers in Oncology Clinical Trials. AB - The authors discuss eight areas of quantitative MR imaging that are currently used (RECIST, DCE-MR imaging, DSC-MR imaging, diffusion MR imaging) in clinical trials or emerging (CEST, elastography, hyperpolarized MR imaging, multiparameter MR imaging) as promising techniques in diagnosing cancer and assessing or predicting response of cancer to therapy. Illustrative applications of the techniques in the clinical setting are summarized before describing the current limitations of the methods. PMID- 26613876 TI - Clinical Imaging of Tumor Metabolism with 1H Magnetic Resonance Spectroscopy. AB - Magnetic resonance spectroscopy (MRS) is a noninvasive functional technique to evaluate the biochemical behavior of human tissues. This property has been widely used in assessment and therapy monitoring of brain tumors. MRS studies can be implemented outside the brain, with successful and promising results in the evaluation of prostate and breast cancer, although still with limited reproducibility. As a result of technical improvements, malignancies of the musculoskeletal system and abdominopelvic organs can benefit from the molecular information that MRS provides. The technical challenges and main applications in oncology of (1)H MRS in a clinical setting are the focus of this review. PMID- 26613877 TI - Multiparametric MR Imaging in the Assessment of Brain Tumors. AB - Functional MR imaging methods make possible the quantification of dynamic physiologic processes that occur in the brain. Moreover, the use of these advanced imaging techniques in the setting of oncologic treatment of the brain is widely accepted and has found worldwide routine clinical use. PMID- 26613878 TI - Evaluation of Head and Neck Tumors with Functional MR Imaging. AB - Head and neck cancer is one of the most common cancers worldwide. MR imaging based diffusion and perfusion techniques enable the noninvasive assessment of tumor biology and physiology, which supplement information obtained from standard structural scans. Diffusion and perfusion MR imaging techniques provide novel biomarkers that can aid monitoring in pretreatment, during treatment, and posttreatment stages to improve patient selection for therapeutic strategies; provide evidence for change of therapy regime; and evaluate treatment response. This review discusses pertinent aspects of the role of diffusion and perfusion MR imaging and computational analysis methods in studying head and neck cancer. PMID- 26613879 TI - Functional MR Imaging in Chest Malignancies. AB - With recent advances in MR imaging, its application in the thorax has been feasible. The performance of both morphologic and functional techniques in the evaluation of thoracic malignances has improved not only differentiation from benign etiologies but also treatment monitoring based on a multiparametric approach. Several MR imaging-derived parameters have been described as potential biomarkers linked with prognosis and survival. Therefore, an integral approach with a nonradiating and noninvasive technique could be an optimal alternative for evaluating those patients. PMID- 26613880 TI - Multiparametric MR Imaging in Abdominal Malignancies. AB - Modern MR imaging protocols can yield both anatomic and functional information for the assessment of hepatobiliary and pancreatic malignancies. Diffusion weighted imaging is fully integrated into state-of-the-art protocols for tumor detection, characterization, and therapy monitoring. Hepatobiliary contrast agents have gained ground in the evaluation of focal liver lesions during the last years. Perfusion MR imaging is expected to have a central role for monitoring therapy in body tumors treated with antivascular drugs. Approaches such as Magnetic resonance (MR) elastography and (1)H-MR spectroscopy are still confined to research centers, but with the potential to grow in a short time frame. PMID- 26613882 TI - Functional MR Imaging in Gynecologic Cancer. AB - Dynamic-contrast enhanced (DCE) and diffusion-weighted (DW) MR imaging are invaluable in the detection, staging, and characterization of uterine and ovarian malignancies, for monitoring treatment response, and for identifying disease recurrence. When used as adjuncts to morphologic T2-weighted (T2-W) MR imaging, these techniques improve accuracy of disease detection and staging. DW-MR imaging is preferred because of its ease of implementation and lack of need for an extrinsic contrast agent. MR spectroscopy is difficult to implement in the clinical workflow and lacks both sensitivity and specificity. If used quantitatively in multicenter clinical trials, standardization of DCE- and DW-MR imaging techniques and rigorous quality assurance is mandatory. PMID- 26613881 TI - Role of Multiparametric MR Imaging in Malignancies of the Urogenital Tract. AB - Multiparametric MR imaging (mpMRI) combine different sequences that, properly tailored, can provide qualitative and quantitative information about the tumor microenvironment beyond traditional tumor size measures and/or morphologic assessments. This article focuses on mpMRI in the evaluation of urogenital tract malignancies by first reviewing technical aspects and then discussing its potential clinical role. This includes insight into histologic subtyping and grading of renal cell carcinoma and assessment of tumor response to targeted therapies. The clinical utility of mpMRI in the staging and grading of ureteral and bladder tumors is presented. Finally, the evolving role of mpMRI in prostate cancer is discussed. PMID- 26613884 TI - Assessment of Musculoskeletal Malignancies with Functional MR Imaging. AB - Functional MR imaging is the technique of choice to evaluate and manage malignant musculoskeletal masses. Advanced MR imaging sequences include chemical shift MR imaging, diffusion-weighted imaging with apparent diffusion coefficient mapping, MR spectroscopy imaging, and dynamic contrast-enhanced perfusion imaging. Functional MR imaging adds value to morphologic sequences in the detection, characterization, staging, and posttherapy assessment of malignant musculoskeletal malignancies. This article reviews the technical role of each functional sequence and their clinical applications to allow more confident decisions to be made. Multiparametric analysis of functional and anatomic MR sequences allows musculoskeletal tumors analysis to be improved. PMID- 26613885 TI - Therapy Monitoring with Functional and Molecular MR Imaging. AB - Cancer therapy is mainly based on different combinations of surgery, radiotherapy, and chemotherapy. Additionally, targeted therapies (designed to disrupt specific tumor hallmarks, such as angiogenesis, metabolism, proliferation, invasiveness, and immune evasion), hormonotherapy, immunotherapy, and interventional techniques have emerged as alternative oncologic treatments. Conventional imaging techniques and current response criteria do not always provide the necessary information regarding therapy success particularly to targeted therapies. In this setting, MR imaging offers an attractive combination of anatomic, physiologic, and molecular information, which may surpass these limitations, and is being increasingly used for therapy response assessment. PMID- 26613883 TI - Multiparametric MR Imaging of Breast Cancer. AB - Breast MR imaging has increased in popularity over the past 2 decades due to evidence of its high sensitivity for cancer detection. Current clinical MR imaging approaches rely on the use of a dynamic contrast-enhanced acquisition that facilitates morphologic and semiquantitative kinetic assessments of breast lesions. The use of more functional and quantitative parameters holds promise to broaden the utility of MR imaging and improve its specificity. Because of wide variations in approaches for measuring these parameters and the considerable technical challenges, robust multicenter data supporting their routine use are not yet available, limiting current applications of many of these tools to research purposes. PMID- 26613886 TI - Functional MR Imaging in Oncology. PMID- 26613887 TI - MR Imaging Pushes Radiologists to Move Forward in Oncologic Imaging. PMID- 26613888 TI - Reply. PMID- 26613889 TI - CA-125, but not galectin-3, complements CA 19-9 for discriminating ductal adenocarcinoma versus non-malignant pancreatic diseases. AB - BACKGROUND/OBJECTIVES: CA 19-9 is the gold standard biomarker of pancreatic adenocarcinoma despite several weaknesses in particular a high rate of false positives or negatives. CA-125 corresponding to MUC16 and galectin-3, a lectin able to interact with mucin-associated carbohydrates, are tumor-associated proteins. We investigated whether combined measurement of CA 19-9, galectin-3 and CA-125 may help to better discriminate pancreatic adenocarcinoma versus non malignant pancreatic diseases. METHODS: We evaluated by immunohistochemistry the expression of MUC4, MUC16 (CA-125) and galectin-3 in 31 pancreatic adenocarcinomas. We measured CA 19-9, CA-125 and Gal-3 in the serum from patients with pancreatic benign diseases (n = 58) or adenocarcinoma (n = 44). Clinical performance of the 3 biomarkers for cancer diagnosis and prognosis was analyzed. RESULTS: By immunohistochemistry, MUC16 and Gal-3 were expressed in 74% and 84% of adenocarcinomas versus 0% and 3.2% in peri-tumoral regions, respectively. At the serum level, CA 19-9 and CA125 were significantly higher in patients with pancreatic adenocarcinoma whereas Gal-3 levels did not differ. The performance of CA 19-9 for cancer detection was higher than those of CA-125 or Gal-3 by ROC analysis. However, CA-125 offers the highest specificity for malignancy (81%) because of an absence of false positives among type 2 diabetic patients. Cancer deaths assessed 6 or 12 months after diagnosis varied according to the initial CA 125 level (p < 0.006). CONCLUSION: Gal-3 is not an interesting biomarker for pancreatic adenocarcinoma detection. CA 19-9 alone exhibits the best performance but measuring CA-125 provides complementary information in terms of diagnosis and prognosis. PMID- 26613890 TI - The Interleaved Genome. AB - Eukaryotic genomes are pervasively transcribed but until recently this noncoding transcription was considered to be simply noise. Noncoding transcription units overlap with genes and genes overlap other genes, meaning genomes are extensively interleaved. Experimental interventions reveal high degrees of interdependency between these transcription units, which have been co-opted as gene regulatory mechanisms. The precise outcome depends on the relative orientation of the transcription units and whether two overlapping transcription events are contemporaneous or not, but generally involves chromatin-based changes. Thus transcription itself regulates transcription initiation or repression at many regions of the genome. PMID- 26613891 TI - Persistence of cirrhosis is maintained by intrahepatic regulatory T cells that inhibit fibrosis resolution by regulating the balance of tissue inhibitors of metalloproteinases and matrix metalloproteinases. AB - Fibrosis is the result of the abnormal accumulation of the extracellular matrix and ineffective clearance of fibroplasia. CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are immunosuppressive lymphocytes that are highly expressed in the fibrotic tissues and peripheral blood of patients with cirrhosis or hepatocellular carcinoma. The role of Tregs in the progression of liver fibrosis is not well understood. Our experiments reveal that abundant of Tregs was scattered around sites of fibroplasia. Conversely, the depletion of Tregs promoted the resolution of liver fibrosis. As a consequence of Tregs depletion, the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) was altered; mmp9 and timp1 were reduced, whereas mmp2 and mmp14 were enhanced. The mmp9/timp1, mmp13/timp1, and mmp14/timp2 ratios were significantly increased in association with fibrosis resolution. Kupffer cells (KCs) are the main source of MMP. We observed that when KCs were cocultured with Tregs, the Tregs were able to inhibit MMP expression of KCs even at a low ratio; and anti-transforming growth factor-beta (TGF-beta) significantly reversed the inhibition of Tregs on MMP. Meanwhile, we also found that after Tregs depletion, TGF-beta levels decreased in the mice liver, unlike in fibrosis. Furthermore, double depletion of both KCs and Tregs did not cause fiber resolution in mice. Thus, our results demonstrate that the persistence of liver cirrhosis is maintained by increased Tregs in the sites of fibroplasia and the subsequent regulation of the MMP/TIMP balance and that the suppression of KC-mediated MMP expression contributed to the regulatory process. PMID- 26613892 TI - Elevated serum CA 19-9 levels in patients with pulmonary nontuberculous mycobacterial disease. AB - Increased serum CA 19-9 levels in patients with nonmalignant diseases have been investigated in previous reports. This study evaluates the clinical significance of serum CA 19-9 elevation in pulmonary nontuberculous mycobacterial disease and pulmonary tuberculosis. The median CA 19-9 level was higher in patients with pulmonary nontuberculous mycobacterial disease than in patients with pulmonary tuberculosis (pulmonary nontuberculous mycobacterial disease: 13.80, tuberculosis: 5.85, p<0.001). A multivariate logistic regression analysis performed in this study showed that Mycobacterium abscessus (OR 9.97, 95% CI: 1.58, 62.80; p=0.014) and active phase of pulmonary nontuberculous mycobacterial disease (OR 12.18, 95% CI: 1.07, 138.36, p=0.044) were found to be risk factors for serum CA 19-9 elevation in pulmonary nontuberculous mycobacterial disease. The serum CA 19-9 levels showed a tendency to decrease during successful treatment of pulmonary nontuberculous mycobacterial disease but not in pulmonary tuberculosis. These findings suggest that CA 19-9 may be a useful marker for monitoring therapeutic responses in pulmonary nontuberculous mycobacterial disease, although it is not pulmonary nontuberculous mycobacterial disease specific marker. PMID- 26613893 TI - Mutations in the S gene and in the overlapping reverse transcriptase region in chronic hepatitis B Chinese patients with coexistence of HBsAg and anti-HBs. AB - BACKGROUND: The mechanism underlying the coexistence of hepatitis B surface antigen and antibodies to HBsAg in chronic hepatitis B patients remains unknown. AIMS: This research aimed to determine the clinical and virological features of the rare pattern. METHODS: A total of 32 chronic hepatitis B patients infected by HBV genotype C were included: 15 carrying both HBsAg and anti-HBs (group I) and 17 solely positive for HBsAg (group II). S gene and reverse transcriptase region sequences were amplified, sequenced and compared with the reference sequences. RESULTS: The amino acid variability within major hydrophilic region, especially the "a" determinant region, and within reverse transcriptase for regions overlapping the major hydrophilic region in group I is significantly higher than those in group II. Mutation sI126S/T within the "a" determinant was the most frequent change, and only patients from group I had the sQ129R, sG130N, sF134I, sG145R amino acid changes, which are known to alter immunogenicity. CONCLUSIONS: In chronic patients, the concurrent HBsAg/anti-HBs serological profile is associated with an increased aa variability in several key areas of HBV genome. Additional research on these genetic mutants are needed to clarify their biological significance for viral persistence. PMID- 26613894 TI - Single-molecular diodes based on opioid derivatives. AB - We propose an efficient single-molecule rectifier based on a derivative of opioid. Electron transport properties are investigated within the non-equilibrium Green's function formalism combined with density functional theory. The analysis of the current-voltage characteristics indicates obvious diode-like behavior. While heroin presents rectification coefficient R>1, indicating preferential electronic current from electron-donating to electron-withdrawing, 3 and 6 acetylmorphine and morphine exhibit contrary behavior, R<1. Our calculations indicate that the simple inclusion of acetyl groups modulate a range of devices, which varies from simple rectifying to resonant-tunneling diodes. In particular, the rectification rations for heroin diodes show microampere electron current with a maximum of rectification (R=9.1) at very low bias voltage of ~0.6 V and (R=14.3)~1.8 V with resistance varying between 0.4 and 1.5 M Omega. Once most of the current single-molecule diodes usually rectifies in nanoampere, are not stable over 1.0 V and present electrical resistance around 10 M. Molecular devices based on opioid derivatives are promising in molecular electronics. PMID- 26613896 TI - Longitudinal three-dimensional visualisation of autoimmune diabetes by functional optical coherence imaging. AB - AIMS/HYPOTHESIS: It is generally accepted that structural and functional quantitative imaging of individual islets would be beneficial to elucidate the pathogenesis of type 1 diabetes. We here introduce functional optical coherence imaging (FOCI) for fast, label-free monitoring of beta cell destruction and associated alterations of islet vascularisation. METHODS: NOD mouse and human islets transplanted into the anterior chamber of the eye (ACE) were imaged with FOCI, in which the optical contrast of FOCI is based on intrinsic variations of the index of refraction resulting in a faster tomographic acquisition. In addition, the phase sensitivity allows simultaneous label-free acquisition of vascularisation. RESULTS: We demonstrate that FOCI allows longitudinal quantification of progressive autoimmune insulitis, including the three dimensional quantification of beta cell volume, inflammation and vascularisation. The substantially increased backscattering of islets is dominated by the insulin zinc nanocrystals in the beta cell granules. This translates into a high specificity for the functional beta cell volume of islets. Applying FOCI to a spontaneous mouse model of type 1 diabetes, we quantify the modifications of the pancreatic microvasculature accompanying the progression of diabetes and reveal a strong correlation between increasing insulitis and density of the vascular network of the islet. CONCLUSIONS/INTERPRETATION: FOCI provides a novel imaging technique for investigating functional and structural diabetes-induced alterations of the islets. The label-free detection of beta cell volume and infiltration together with vascularisation offers a unique extension to study ACE transplanted human islets. These results are contributing to a deeper understanding of human islet transplant rejection and label-free in vivo monitoring of drug efficacy. PMID- 26613895 TI - Duality of Antidepressants and Neuroprotectants. AB - The co-morbidity of neuropsychiatric disorders, particularly major depressive disorder (MDD) with neurodegenerative diseases, in particular Parkinson's disease (PD) is now well recognized. Indeed, it is suggested that depressive disorders, especially in late life, may be an indication of latent neurodegeneration. Thus, it is not unreasonable to expect that deterrents of MDD may also deter the onset and/or progression of the neurodegenerative diseases including PD. In this review, examples of neuroprotective efficacy of established as well as prospective antidepressants are provided. Conversely, mood-regulating effects of some neuroprotective drugs are also presented. Thus, in addition to currently used antidepressants, ketamine, nicotine, curcumin, and resveratrol are discussed for their dual efficacy. In addition, potential neurobiological substrates for their actions are presented. It is concluded that pharmacological developments of mood-regulating or neuroprotective drugs can have cross benefit in co-morbid conditions of neuropsychiatric and neurodegenerative disorders and that inflammatory and neurotrophic factors play important roles in both conditions. PMID- 26613897 TI - Establishment and Characterization of Orthotopic Mouse Models for Human Uveal Melanoma Hepatic Colonization. AB - Uveal melanoma (UM) is a rare type of melanoma, although it is the most common primary ocular malignant tumor in adults. Nearly one-half the patients with primary UM subsequently develop systemic metastasis, preferentially to the liver. Currently, no treatment is effective for UM hepatic metastasis, and the prognosis is universally poor. The main challenge in designing a treatment strategy for UM hepatic metastasis is the lack of suitable animal models. We developed two orthotopic mouse models for human UM hepatic metastases: direct hepatic implantation model (intrahepatic dissemination model) and splenic-implantation model (hematogenous dissemination model) and investigated the tumorgenesis in the liver. A human UM cell line, established from a hepatic metastasis and nonobese diabetic severe combined immunodeficient gamma mice, were used for development of in vivo tumor models. In the direct hepatic implantation model, a localized tumor developed in the liver in all cases and intrahepatic dissemination was subsequently seen in about one-half of cases. However, in the splenic implantation model, multiple hepatic metastases were observed after splenic implantation. Hepatic tumors subsequently seeded intra-abdominal metastasis; however, lung metastases were not seen. These findings are consistent with those observed in human UM hepatic metastases. These orthotopic mouse models offer useful tools to investigate the biological behavior of human UM cells in the liver. PMID- 26613899 TI - Erratum to: Iron metabolism and iron supplementation in cancer patients. PMID- 26613898 TI - Quantitative phosphoproteomic analysis of early seed development in rice (Oryza sativa L.). AB - Rice (Oryza sativa L.) seed serves as a major food source for over half of the global population. Though it has been long recognized that phosphorylation plays an essential role in rice seed development, the phosphorylation events and dynamics in this process remain largely unknown so far. Here, we report the first large scale identification of rice seed phosphoproteins and phosphosites by using a quantitative phosphoproteomic approach. Thorough proteomic studies in pistils and seeds at 3, 7 days after pollination resulted in the successful identification of 3885, 4313 and 4135 phosphopeptides respectively. A total of 2487 proteins were differentially phosphorylated among the three stages, including Kip related protein 1, Rice basic leucine zipper factor 1, Rice prolamin box binding factor and numerous other master regulators of rice seed development. Moreover, differentially phosphorylated proteins may be extensively involved in the biosynthesis and signaling pathways of phytohormones such as auxin, gibberellin, abscisic acid and brassinosteroid. Our results strongly indicated that protein phosphorylation is a key mechanism regulating cell proliferation and enlargement, phytohormone biosynthesis and signaling, grain filling and grain quality during rice seed development. Overall, the current study enhanced our understanding of the rice phosphoproteome and shed novel insight into the regulatory mechanism of rice seed development. PMID- 26613901 TI - Low antimullerian hormone levels may be associated with cardiovascular risk markers in women with diminished ovarian reserve. AB - There is growing evidence that diminished ovarian reserve (DOR) may be associated with cardiovascular disease (CVD). The aim of the study was to investigate whether there was any relationship between antimullerian hormone (AMH) and CVD risk markers in the study. Ninety women with DOR and 90 women with normal ovarian reserve (NOR) attending the infertility unit at XXXX, were enrolled in the study. CVD risk markers such as insulin resistance [defined by the homeostasis model assessment ratio (HOMA-IR)], C-reactive protein (CRP), low density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), and triglyceride (TG) were assessed. HOMA-IR, CRP, TG, LDL levels were higher and HDL and AMH were lower among patients with DOR compared with controls (p < 0.05, for all). There were positive associations between low AMH and HOMA-IR, CRP, TG, LDL levels and a negative correlation with HDL (p < 0.05, for all). However, multivariate logistic regression analysis showed that HOMA-IR, CRP, TG and HDL were independent variables that were associated with low AMH. There was a close relationship between low AMH and CVD risk markers in the study. Further studies with larger groups are needed to investigate the nature of this link in these patients. PMID- 26613902 TI - The lung study promising a breath of fresh air in research world. PMID- 26613900 TI - Adjusting HIV prevalence estimates for non-participation: an application to demographic surveillance. AB - INTRODUCTION: HIV testing is a cornerstone of efforts to combat the HIV epidemic, and testing conducted as part of surveillance provides invaluable data on the spread of infection and the effectiveness of campaigns to reduce the transmission of HIV. However, participation in HIV testing can be low, and if respondents systematically select not to be tested because they know or suspect they are HIV positive (and fear disclosure), standard approaches to deal with missing data will fail to remove selection bias. We implemented Heckman-type selection models, which can be used to adjust for missing data that are not missing at random, and established the extent of selection bias in a population-based HIV survey in an HIV hyperendemic community in rural South Africa. METHODS: We used data from a population-based HIV survey carried out in 2009 in rural KwaZulu-Natal, South Africa. In this survey, 5565 women (35%) and 2567 men (27%) provided blood for an HIV test. We accounted for missing data using interviewer identity as a selection variable which predicted consent to HIV testing but was unlikely to be independently associated with HIV status. Our approach involved using this selection variable to examine the HIV status of residents who would ordinarily refuse to test, except that they were allocated a persuasive interviewer. Our copula model allows for flexibility when modelling the dependence structure between HIV survey participation and HIV status. RESULTS: For women, our selection model generated an HIV prevalence estimate of 33% (95% CI 27-40) for all people eligible to consent to HIV testing in the survey. This estimate is higher than the estimate of 24% generated when only information from respondents who participated in testing is used in the analysis, and the estimate of 27% when imputation analysis is used to predict missing data on HIV status. For men, we found an HIV prevalence of 25% (95% CI 15-35) using the selection model, compared to 16% among those who participated in testing, and 18% estimated with imputation. We provide new confidence intervals that correct for the fact that the relationship between testing and HIV status is unknown and requires estimation. CONCLUSIONS: We confirm the feasibility and value of adopting selection models to account for missing data in population-based HIV surveys and surveillance systems. Elements of survey design, such as interviewer identity, present the opportunity to adopt this approach in routine applications. Where non participation is high, true confidence intervals are much wider than those generated by standard approaches to dealing with missing data suggest. PMID- 26613903 TI - UK's health and social care spending plans: more of the same? PMID- 26613904 TI - Physics of Fresh Produce Safety: Role of Diffusion and Tissue Reaction in Sanitization of Leafy Green Vegetables with Liquid and Gaseous Ozone-Based Sanitizers. AB - Produce safety has received much recent attention, with the emphasis being largely on discovery of how microbes invade produce. However, the sanitization operation deserves more attention than it has received. The ability of a sanitizer to reach the site of pathogens is a fundamental prerequisite for efficacy. This work addresses the transport processes of ozone (gaseous and liquid) sanitizer for decontamination of leafy greens. The liquid sanitizer was ineffective against Escherichia coli K-12 in situations where air bubbles may be trapped within cavities. A model was developed for diffusion of sanitizer into the interior of produce. The reaction rate of ozone with the surface of a lettuce leaf was determined experimentally and was used in a numerical simulation to evaluate ozone concentrations within the produce and to determine the time required to reach different locations. For aqueous ozone, the penetration depth was limited to several millimeters by ozone self-decomposition due to the significant time required for diffusion. In contrast, gaseous sanitizer was able to reach a depth of 100 mm in several minutes without depletion in the absence of reaction with surfaces. However, when the ozone gas reacted with the produce surface, gas concentration was significantly affected. Simulation data were validated experimentally by measuring ozone concentrations at the bottom of a cylinder made of lettuce leaf. The microbiological test confirmed the relationship between ozone transport, its self-decomposition, reaction with surrounding materials, and the degree of inactivation of E. coli K-12. Our study shows that decontamination of fresh produce, through direct contact with the sanitizer, is more feasible with gaseous than with aqueous sanitizers. Therefore, sanitization during a high-speed washing process is effective only for decontaminating the wash water. PMID- 26613905 TI - Effects of Domestic Storage and Thawing Practices on Salmonella in Poultry-Based Meat Preparations. AB - Among consumer food handling practices, time-temperature abuse has been reported as one of the most common contributory factors in salmonellosis outbreaks where the evidence is strong. The present study performed storage tests of burgers, sausages, and kebabs and investigated (i) the effect of refrigerator temperatures (4 degrees C versus 8 or 12 degrees C, which were the temperatures recorded in 33 and 3%, respectively, of domestic refrigerators in Italy), with or without prior temperature abuse (25 degrees C for 2 h, simulating transport of meats from shop to home), and (ii) the impact of the thawing method (overnight in the refrigerator at 8 degrees C versus on the kitchen countertop at 23 degrees C) on the presence and numbers of Salmonella bacteria. Storage tests were carried out on naturally or artificially (Salmonella enterica serovar Typhimurium at ca. 10 CFU/g) contaminated products, while freezing-thawing tests were conducted only on artificially contaminated products (Salmonella Typhimurium at ca. 10, 100, and 1,000 CFU/g). The results from the artificially contaminated products showed significant (P < 0.05) growth of Salmonella Typhimurium at 12 degrees C (i.e., from ca. 8 most probable number [MPN]/g to > 710 MPN/g) in kebabs after 7 and 10 days but more moderate growth in sausages (i.e., from ca. 14 MPN/g to a maximum of 96 MPN/g after 9 days of storage). Storage of naturally contaminated burgers or sausages (contamination at or below 1 MPN/g) at 4, 8, or 12 degrees C and a short time of temperature abuse (2 h at 25 degrees C) did not facilitate an increase in the presence and numbers of Salmonella bacteria. Thawing overnight in the refrigerator led to either a moderate reduction or no change of Salmonella Typhimurium numbers in burgers, sausages, and kebabs. Overall, this study showed that domestic storage and thawing practices can affect food safety and that time temperature abuse can cause a substantial increase of Salmonella numbers in some types of poultry-based meat preparations, highlighting that efforts for the dissemination of consumer guidelines on the correct storage and handling of meats need to be continued. PMID- 26613906 TI - Microbiological Safety of Commercial Prime Rib Preparation Methods: Thermal Inactivation of Salmonella in Mechanically Tenderized Rib Eye. AB - Boneless beef rib eye roasts were surface inoculated on the fat side with ca. 5.7 log CFU/g of a five-strain cocktail of Salmonella for subsequent searing, cooking, and warm holding using preparation methods practiced by restaurants surveyed in a medium-size Midwestern city. A portion of the inoculated roasts was then passed once through a mechanical blade tenderizer. For both intact and nonintact roasts, searing for 15 min at 260 degrees C resulted in reductions in Salmonella populations of ca. 0.3 to 1.3 log CFU/g. For intact (nontenderized) rib eye roasts, cooking to internal temperatures of 37.8 or 48.9 degrees C resulted in additional reductions of ca. 3.4 log CFU/g. For tenderized (nonintact) rib eye roasts, cooking to internal temperatures of 37.8 or 48.9 degrees C resulted in additional reductions of ca. 3.1 or 3.4 log CFU/g, respectively. Pathogen populations remained relatively unchanged for intact roasts cooked to 37.8 or 48.9 degrees C and for nonintact roasts cooked to 48.9 degrees C when held at 60.0 degrees C for up to 8 h. In contrast, pathogen populations increased ca. 2.0 log CFU/g in nonintact rib eye cooked to 37.8 degrees C when held at 60.0 degrees C for 8 h. Thus, cooking at low temperatures and extended holding at relatively low temperatures as evaluated herein may pose a food safety risk to consumers in terms of inadequate lethality and/or subsequent outgrowth of Salmonella, especially if nonintact rib eye is used in the preparation of prime rib, if on occasion appreciable populations of Salmonella are present in or on the meat, and/or if the meat is not cooked adequately throughout. PMID- 26613907 TI - Antimicrobial Efficacy of a Lactic Acid and Citric Acid Blend against Shiga Toxin Producing Escherichia coli, Salmonella, and Nonpathogenic Escherichia coli Biotype I on Inoculated Prerigor Beef Carcass Surface Tissue. AB - Studies were conducted to (i) determine whether inoculants of nonpathogenic Escherichia coli biotype I effectively served as surrogates for E. coli O157:H7, non-O157 Shiga toxin-producing E. coli, and Salmonella when prerigor beef carcass tissue was treated with a commercially available blend of lactic acid and citric acid (LCA) at a range of industry conditions of concentration, temperature, and pressure; (ii) determine the antimicrobial efficacy of LCA; and (iii) investigate the use of surrogates to validate a hot water and LCA sequential treatment as a carcass spray intervention in a commercial beef harvest plant. In an initial laboratory study, beef brisket tissue samples were left uninoculated or were inoculated (~6 log CFU/cm(2)) on the adipose side with E. coli O157:H7 (5-strain mixture), non-O157 Shiga toxin-producing E. coli (12-strain mixture), Salmonella (6-strain mixture), or nonpathogenic E. coli (5-strain mixture). Samples were left untreated (control) or were treated with LCA, in a spray cabinet, at one of eight combinations of solution concentration (1.9 and 2.5%), solution temperature (43 and 60 degrees C), and application pressure (15 and 30 lb/in(2)). In a second study, the E. coli surrogates were inoculated (~6 log CFU/cm(2)) on beef carcasses in a commercial facility to validate the use of a hot water treatment (92.2 to 92.8 degrees C, 13 to 15 lb/in(2)) followed by an LCA treatment (1.9%, 50 to 51.7 degrees C, 13 to 15 lb/in(2), 10 s). In the in vitro study, surrogate and pathogen bacteria did not differ in their response to the tested LCA treatments. Treatment with LCA reduced (P < 0.05) inoculated populations by 0.9 to 1.5 log CFU/cm(2), irrespective of inoculum type. The hot water and LCA sequential treatments evaluated in the commercial facility reduced (P < 0.05) the inoculated nonpathogenic E. coli surrogates on carcasses by 3.7 log CFU/cm(2). This study therefore provides the meat industry with data for this sequential multiple hurdle system for the operation parameters described. PMID- 26613908 TI - Physiological and Molecular Characterization of Salmonella Bacteriophages Previously Used in Phage Therapy. AB - The use of bacteriophages as biocontrol agents to control Salmonella in food production has gained popularity over the last two decades. Previously, our laboratory demonstrated that bacteriophages can be direct fed to limit Salmonella colonization and transmission in pigs. Here, we characterized the bacteriophages in our treatment cocktail in terms of lytic spectrum, growth kinetics, survivability under various conditions, and genomic sequencing. PCR-based fingerprinting indicated that 9 of the 10 phages, while related, were distinct isolates. Single-step growth kinetics analysis determined that the eclipse periods, latent periods, and burst sizes averaged 21.5 min, 31.5 min, and 43.3 particles, respectively. The viability of the phages was measured after exposure to various pH ranges, temperatures, digestive enzymes, UV light, and chlorinated water. Temperatures greater than 87.5 degrees C, pH of <2.0, UV light (302 and 365 nm), and chlorinated water (500 ppm) inactivated the tested phages. Only select bacteriophages, however, were affected by incubation at temperatures of <=75.0 degrees C or pH of 4.0 to 10.0. Genomic sequencing of the phage with the broadest spectrum in the collection (effectively lysed all four Salmonella serovars tested), vB_SalM_SJ2, revealed it to belong to the Viunalikevirus genus of the Myoviridae family. Of the 197 predicted open reading frames, no toxin associated, lysogenic, Salmonella virulence, or antimicrobial resistance genes were identified. Taken together, these data indicate that phages, as biologicals, may require some manner of protection (e.g., microencapsulation) to remain viable under various physiological and manufacturing conditions. In addition, based on its ability to effectively lyse diverse Salmonella serovars, phage vB_SalM-SJ2 could be further developed as an important biocontrol agent in various aspects of food production when the exact serovar or strain of contaminating Salmonella is not yet known. PMID- 26613909 TI - Shoot Injury Increases the Level of Persistence of Salmonella enterica Serovar Sofia and Listeria innocua on Cos Lettuce and of Salmonella enterica Serovar Sofia on Chive. AB - Minor shoot injury significantly (P < 0.05) increased the level at which Salmonella enterica serovar Sofia persisted on cos lettuce in the greenhouse. Initial mean counts of the Salmonella on the injured and uninjured cos lettuce were on the order of 6 log CFU/g. After 3 days, the mean count decreased to 4.8 log CFU/g on the injured plants compared with the significantly (P < 0.05) smaller count of 3.4 log CFU/g on the uninjured plants. By the end of the 3-week experiment, the count from the injured plants was 2.9 log CFU/g compared with a count of below the level of detection from the uninjured plants. A similar pattern of bacterial persistence was observed on injured versus uninjured plants by using Listeria innocua on cos lettuce and S. enterica serovar Sofia on chive. The findings reaffirm earlier results with Escherichia coli and increase the impetus to avoid shoot injury during the production of cos lettuce and chive, if bacteria of food safety concern are present. PMID- 26613910 TI - Development of Models To Relate Microbiological and Headspace Volatile Parameters in Stored Atlantic Salmon to Acceptance and Willingness To Prepare the Product by Senior Consumers. AB - Microbial spoilage of salmon occurs during extended refrigerated storage and is often accompanied by unpleasant aromas. When spoilage is detected, it is assumed that consumers will reject the product for consumption. Because sensory panels of trained individuals or consumers are expensive and labor intensive, identification of microbiological or chemical indicators to characterize the extent to which fish has spoiled is needed when experimental process and storage treatments are being evaluated. A consumer panel of 53 senior citizens (60 to 85 years of age) evaluated in duplicate raw salmon subjected to 10 storage conditions, and the fish quality was targeted to range from fresh to very spoiled. This population group was chosen because they would be expected to have a greater prevalence of olfactory impairments and higher odor thresholds than the general population; in turn, a shorter safety margin or time period between product rejection due to spoilage and the generation of Clostridium botulinum toxins would be likely. Low hedonic scores for aroma and overall acceptance (2 or 3 of 9), corresponding to "dislike very much" to "dislike moderately," did not equate with unwillingness to prepare the sample for consumption by up to seven panelists (13%) when the product was presumed to have already been purchased. Despite these outliers, significant models (P = 0.0000) were developed for the willingness of consumers to prepare the sample for consumption and the sample's aerobic and anaerobic microbiological populations and two volatile peaks with Kovats indices of 640 and 753. However, these models revealed that the levels of microbiological and chemical markers must be very high before some consumers would reject the sample; hence, spoilage detection by smell would likely not be an adequate safeguard against consuming salmon in which C. botulinum toxin had been generated. PMID- 26613911 TI - Detection and Genotyping of Leuconostoc spp. in a Sausage Processing Plant. AB - Some Leuconostoc spp. have the ability to produce slime and undesirable compounds in cooked sausage. The objectives of this research were to identify Leuconostoc sources in a Vienna-type sausage processing plant and to evaluate the genetic diversity of the isolated strains. Three hundred and two samples of sausage batter, sausages during processing, spoiled sausage, equipment surfaces, chilling brine, workers' gloves and aprons, and used casings were collected (March to November 2008 and February to April 2010) from a sausage processing plant. Lactic acid bacteria (LAB) were quantified, and Leuconostoc were detected using PCR. Strains were isolated and identified in Leuconostoc-positive samples. Leuconostoc strains were genotyped using randomly amplified polymorphic DNA and pulsed-field gel electrophoresis. LAB content of nonspoiled and spoiled sausage ranged from <0.8 to 4.4 log CFU/g and from 4.9 to 8.3 log CFU/g, respectively. LAB levels on equipment surfaces ranged from <1.3 to 4.8 log CFU/100 cm(2). Leuconostoc was detected in 35% of the samples, and 88 Leuconostoc spp. strains were isolated and genotyped. The main Leuconostoc spp. isolated were L. mesenteroides (37 genotypes), L. fallax (29 genotypes), and L. lactis (6 genotypes). Some strains of Leuconostoc isolated from equipment surfaces and sausages showed the same genotype. One L. lactis genotype included strains isolated from spoiled sausages analyzed in April 2008 and March to April 2010. Equipment and conveyor belts constitute Leuconostoc contamination sources. Leuconostoc persistence in the sausage processing environment and in the final product suggests the existence of microbial reservoirs, possibly on equipment surfaces. PMID- 26613912 TI - Use of Health Belief Model Variables To Examine Self-Reported Food Handling Behaviors in a Sample of U.S. Adults Attending a Tailgate Event. AB - Unsafe food handling behaviors are common among consumers, and, given the venue, individuals attending a tailgating event may be at risk for foodborne illness. The objective of this study was to measure the association between Health Belief Model variables and self-reported usual food handling behaviors in a convenience sample of men and women at a tailgate event. Participants (n = 128) completed validated subscales for self-reported food handling behaviors (i.e., cross contamination, sanitation), perceived threat of foodborne illness (i.e., perceived severity, perceived susceptibility), and safe food handling cues to action (i.e., media cues, educational cues). Perceived severity of foodborne illness was associated with safer behaviors related to sanitation (r = 0.40; P < 0.001) and cross-contamination (r = 0.33; P = 0.001). Perceived severity of foodborne illness was also associated with exposure to safe food handling media cues (r = 0.20; P = 0.027) but not with safe food handling educational cues. A large proportion of participants reported that they never or seldom (i) read newspaper or magazine articles about foodborne illness (65.6%); (ii) read brochures about safe ways to handle food (61.7%); (iii) see store displays that explain ways to handle food (51.6%); or (iv) read the "safe handling instructions" on packages of raw meat and poultry (46.9%). Perceived severity of foodborne illness was positively related to both dimensions of safe food handling as well as with safe food handling media cues. Except for the weak correlation between media cues and perceived severity, the relationships between safe food handling cues and perceived threat, as well as between safe food handling cues and behaviors, were nonsignificant. This finding may be due, in part, to the participants' overall low exposure to safe food handling cues. The overall results of this study reinforce the postulate that perceived severity of foodborne illness may influence food handling behaviors. PMID- 26613913 TI - Examination of Listeria monocytogenes in Seafood Processing Facilities and Smoked Salmon in the Republic of Ireland. AB - Listeria monocytogenes is a foodborne pathogen that causes listeriosis, a relatively rare but life-threatening disease primarily affecting immunocompromised individuals. The aim of this study was to determine the prevalence of L. monocytogenes in the seafood processing industry in the Republic of Ireland. The occurrence of L. monocytogenes was determined by regular sampling of both food samples and processing environment swabs at eight seafood processing facilities over two calendar years. All samples were analyzed by the International Organization for Standardization 11290-1 standard method, and the isolates were characterized by PCR, pulsed-field gel electrophoresis, serotyping, and the occurrence of some genes related to survival under stress (SSI-1, Tn6188, and bcrABC). A prevalence of 2.5% in 508 samples (433 environmental swabs and 75 food samples) was found. From the isolates obtained, eight different pulsed-field gel electrophoresis profiles were identified, two occurring in more than one facility and one occurring in food and the environment. Five of the eight pulsotypes identified contained at least one of the three stress survival-related genes tested. The tolerance of the isolates to benzalkonium chloride, a representative quaternary ammonium compound, was also examined and ranged from 5.5 +/- 0.5 to 8.5 +/- 0.5 ppm of benzalkonium chloride. To evaluate the ability of smoked salmon to support the growth of L. monocytogenes, including the T4 widespread pulsotype that was isolated, a challenge test was performed on cold smoked salmon obtained from two separate producers. The results showed clearly that both types of smoked salmon supported the growth of L. monocytogenes. Although occurrence of L. monocytogenes on seafood was low, this study showed that the smoked salmon used in this study can support the growth of L. monocytogenes; therefore, vigilance is required in the processing facilities to reduce the associated risk. PMID- 26613914 TI - Low Temperature and Modified Atmosphere: Hurdles for Antibiotic Resistance Transfer? AB - Food is an important dissemination route for antibiotic-resistant bacteria. Factors used during food production and preservation may contribute to the transfer of antibiotic resistance genes, but research on this subject is scarce. In this study, the effect of temperature (7 to 37 degrees C) and modified atmosphere packaging (air, 50% CO2-50% N2, and 100% N2) on antibiotic resistance transfer from Lactobacillus sakei subsp. sakei to Listeria monocytogenes was evaluated. Filter mating was performed on nonselective agar plates with high density inocula. A more realistic setup was created by performing modified atmosphere experiments on cooked ham using high-density and low-density inocula. Plasmid transfer was observed between 10 and 37 degrees C, with plasmid transfer also observed at 7 degrees C during a prolonged incubation period. When high density inocula were used, transconjugants were detected, both on agar plates and cooked ham, under the three atmospheres (air, 50% CO2-50% N2, and 100% N2) at 7 degrees C. This yielded a median transfer ratio (number of transconjugants/number of recipients) with an order of magnitude of 10(-4) to 10(-6). With low-density inocula, transfer was only detected under the 100% N2 atmosphere after 10-day incubation at 7 degrees C, yielding a transfer ratio of 10(-5). Under this condition, the highest bacterial density was obtained. The results indicate that low temperature and modified atmosphere packaging, two important hurdles in the food industry, do not necessarily prevent plasmid transfer from Lactobacillus sakei subsp. sakei to Listeria monocytogenes. PMID- 26613915 TI - Synergistic Antibacterial Effect of the Combination of epsilon-Polylysine and Nisin against Enterococcus faecalis. AB - This study evaluated the antibacterial effect of the combination of epsilon polylysine (epsilon-PL) and nisin against Enterococcus faecalis strains. The combination of epsilon-PL and nisin showed synergistic antibacterial activity against three Enterococcus strains. Scanning electron microscopy and a membrane permeability assay revealed that the combined treatment with epsilon-PL and nisin synergistically damaged the cell morphology of E. faecalis strain R612Z1 cells. Both epsilon-PL and nisin can dissipate the transmembrane electric potential of E. faecalis R612Z1 cells, but these peptides did not affect the transmembrane pH gradient. The combination of epsilon-PL and nisin can produce a high reactive oxygen species level in E. faecalis R612Z1 cells. The results indicated that the uptake of epsilon-PL into cells was promoted through nisin and that the combination of epsilon-PL and nisin could produce a high reactive oxygen species level in E. faecalis R612Z1 cells, leading to cell growth inhibition. PMID- 26613916 TI - Qualitative Assessment for Toxoplasma gondii Exposure Risk Associated with Meat Products in the United States. AB - Toxoplasma gondii is a global protozoan parasite capable of infecting most warm blooded animals. Although healthy adult humans generally have no symptoms, severe illness does occur in certain groups, including congenitally infected fetuses and newborns, immunocompromised individuals including transplant patients. Epidemiological studies have demonstrated that consumption of raw or undercooked meat products is one of the major sources of infection with T. gondii. The goal of this study was to develop a framework to qualitatively estimate the exposure risk to T. gondii from various meat products consumed in the United States. Risk estimates of various meats were analyzed by a farm-to-retail qualitative assessment that included evaluation of farm, abattoir, storage and transportation, meat processing, packaging, and retail modules. It was found that exposure risks associated with meats from free-range chickens, nonconfinement raised pigs, goats, and lamb are higher than those from confinement-raised pigs, cattle, and caged chickens. For fresh meat products, risk at the retail level was similar to that at the farm level unless meats had been frozen or moisture enhanced. Our results showed that meat processing, such as salting, freezing, commercial hot air drying, long fermentation times, hot smoking, and cooking, are able to reduce T. gondii levels in meat products. whereas nitrite and/or nitrate, spice, low pH, and cold storage have no effect on the viability of T. gondii tissue cysts. Raw-fermented sausage, cured raw meat, meat that is not hot-air dried, and fresh processed meat were associated with higher exposure risks compared with cooked meat and frozen meat. This study provides a reference for meat management control programs to determine critical control points and serves as the foundation for future quantitative risk assessments. PMID- 26613917 TI - Inactivation of Escherichia coli O157 Bacteriophages by Using a Mixture of Ferrous Sulfate and Tea Extract. AB - Bacteriophages (phages) have been used for biocontrol of Escherichia coli O157 and other pathogenic bacteria in many different matrices and foods, but few studies have included inactivation of residual phages in culture medium before plating and enumeration of surviving host bacteria for the assessment of phage efficacy. This oversight may lead to overestimation of phage efficacy. The ability of virucidal solution containing a mixture of ferrous sulfate [iron(II) sulfate, FeSO4] and tea extract [Fe(II)T] to inactivate residual T5-like, T1 like, T4-like, and rV5-like phages was assessed using E. coli O157 as the host. At concentrations of >=10 mM FeSO4, all phages were not detected after 20 min in a broth culture model. Compared with the virucidal solution-free samples (1 to 96% recovery), Fe(II)T (10 mM FeSO4 plus 15% tea extract) recovered a greater (P < 0.01) number of E. coli O157 from phage-treated broth culture (97 to 100% recovery) and beef samples (52 to 100% recovery). Moreover, with the addition of Fe(II)T, the number of bacteria surviving after exposure to T5-like or T4-like phages was greater (P < 0.01) than that after exposure to T1-like or rV5-like phages. Consequently, use of a virucide for phage inactivation is recommended to improve the accuracy of evaluations of phage efficacy for biocontrol of E. coli O157. PMID- 26613918 TI - Microbiological Examination of Bulk Tank Goat's Milk in the Castilla y Leon Region in Northern Spain. AB - The purpose of the study was to evaluate the microbiological status (mesophilic aerobic microorganism counts) of 68 samples of bulk tank goat's milk and determine the risk associated with the foodborne pathogens Staphylococcus aureus, enteropathogenic and Shiga toxin-producing Escherichia coli, and Cronobacter sakazakii. Most samples (83.8%) complied with the limits of mesophilic aerobe counts set in the European Union for milk of species other than cows. A total of 144 isolates of coagulase-positive staphylococci were characterized, and 11 (7.6%) of them carried staphylococcal enterotoxin (SE) genes of the classical types (encoding SEA to SEE), distributed as follows: 4 carried the SEA gene, 1 the SEB gene, and 6 the SED gene. C. sakazakii was not detected in any sample. Regarding detection of E. coli virulence-related genes in enriched milk samples, 12 milk samples were positive only for the presence of stx genes, 4 were positive for both stx and eae genes, and 20 were negative for stx amplification and positive for eae amplification. Seven enteropathogenic E. coli and 9 Shiga toxin producing E. coli isolates (one of them of serogroup O157) were recovered. In conclusion, goat's milk produced on farms in Castilla y Leon is generally in accordance with European Union standards, but the presence of pathogenic E. coli isolates indicates that the consumption of raw goat's milk may pose a risk to public health. PMID- 26613919 TI - Changes in the Microbial Composition of Microbrewed Beer during the Process in the Actual Manufacturing Line. AB - This study investigated changes in the microbial composition of microbrewed beer during the manufacturing processes and identified potential microbial hazards, effective critical quality control points, and potential contamination routes. Comprehensive quantitative (aerobic plate count, lactic acid bacteria, fungi, acetic acid bacteria, coliforms, and Bacillus cereus) and qualitative (Escherichia coli and eight foodborne pathogens) microbiological analyses were performed using samples of raw materials (malt and manufacturing water), semiprocessed products (saccharified wort, boiled wort, and samples taken during the fermentation and maturation process), and the final product obtained from three plants. The initial aerobic plate count and lactic acid bacteria counts in malt were 5.2 and 4.3 log CFU/g, respectively. These counts were reduced to undetectable levels by boiling but were present at 2.9 and 0.9 log CFU/ml in the final product. Fungi were initially present at 3.6 log CFU/g, although again, the microbes were eliminated by boiling; however, the level in the final product was 4.6 log CFU/ml. No E. coli or foodborne pathogens (except B. cereus) were detected. B. cereus was detected at all stages, although it was not present in the water or boiled wort (total detection rate 1/4 16.4%). Results suggest that boiling of the wort is an effective microbial control measure, but careful management of raw materials and implementation of effective control measures after boiling are needed to prevent contamination of the product after the boiling step. The results of this study may constitute useful and comprehensive information regarding the microbiological quality of microbrewed beer. PMID- 26613920 TI - Real-Time PCR Assay Targeting the veA Gene for Quantification of Aspergillus carbonarius in Grapes. AB - In this work, a SYBR Green I real-time PCR method has been developed for the detection and quantification of Aspergillus carbonarius in grapes by targeting the veA gene with a primer pair (veAF4/veAR4) that specifically amplifies a 91-bp PCR product. The quantification of the fungal DNA was performed by generation of standard curves for two A. carbonarius strains, using spectrophotometrically measured DNA quantities (Log) with a linearity range from 50 to 5 * 10(-4) ng of DNA. A high positive correlation (R(2) > 0.99) between exponential increases of DNA and real-time PCR threshold cycles showed a high amplification efficiency for the assay (E values 100.06 and 101.51%, respectively). Quantification of the fungal genomic DNA in grape samples artificially inoculated with A. carbonarius conidia was successfully performed with a minimum threshold of 10(4) conidia per g of grape berry. The assay developed would allow reliable, specific, and efficient detection and quantification of A. carbonarius in grapes. PMID- 26613921 TI - Pilot-Scale Pulsed UV Light Irradiation of Experimentally Infected Raspberries Suppresses Cryptosporidium parvum Infectivity in Immunocompetent Suckling Mice. AB - Cryptosporidium spp., a significant cause of foodborne infection, have been shown to be resistant to most chemical food disinfectant agents and infective for weeks in irrigation waters and stored fresh vegetal produce. Pulsed UV light (PL) has the potential to inactivate Cryptosporidium spp. on surfaces of raw or minimally processed foods or both. The present study aimed to evaluate the efficacy of PL on viability and in vivo infectivity of Cryptosporidium parvum oocysts present on raspberries, a known source of transmission to humans of oocyst-forming apicomplexan pathogens. The skin of each of 20 raspberries was experimentally inoculated with five 10-MUl spots of an oocyst suspension containing 6 * 10(7) oocysts per ml (Nouzilly isolate). Raspberries were irradiated by PL flashes (4 J/cm(2) of total fluence). This dose did not affect colorimetric or organoleptic characteristics of fruits. After immunomagnetic separation from raspberries, oocysts were bleached and administered orally to neonatal suckling mice. Seven days after infection, mice were euthanized, and the number of oocysts in the entire small intestine was individually assessed by immunofluorescence flow cytometry. Three of 12 and 12 of 12 inoculated mice that received 10 and 100 oocysts isolated from nonirradiated raspberries, respectively, were found infected. Four of 12 and 2 of 12 inoculated mice that received 10(3) and 10(4) oocysts from irradiated raspberries, respectively, were found infected. Oocyst counts were lower in animals inoculated with 10(3) and 10(4) oocysts from irradiated raspberries (92 +/- 144 and 38 +/- 82, respectively) than in animals infected with 100 oocysts from nonirradiated raspberries (35,785 +/- 66,221, P = 0.008). PL irradiation achieved oocyst reductions of 2 and 3 log for an inoculum of 10(3) and 10(4) oocysts, respectively. The present pilot-scale evaluation suggests that PL is an effective mode of decontamination for raspberries and prompts further applicability studies in industrial contexts. PMID- 26613922 TI - Levels of Cadmium in White and Brown Meat of Warty Crab (Eriphia verrucosa). AB - European Union regulations that establish the maximum cadmium (Cd) levels for crab take into account only concentrations found in crab muscle (white meat), mainly from appendages; therefore, other organs and tissues (brown meat) are excluded. The objective of the present study was to evaluate Cd levels in both white and brown crab meat, in order to achieve a more complete assessment of health risk related to human consumption of warty crab. Microwave digestion and atomic absorption spectrometry were used to determine Cd concentrations in warty crab (Eriphia verrucosa) samples collected from the southern Tyrrhenian Sea in Italy. Cd concentrations in all samples of white crab meat were found to be very low (below the limit of quantification), although brown crab meat showed significantly higher Cd concentrations (up to 5.629 mg/kg wet weight; mean value, 1.465 mg/kg). Thus, the consumption of brown meat, common among certain populations of the Mediterranean region, where whole crustaceans are traditionally eaten, substantially increased Cd intake, resulting in alarmingly high estimated weekly intake values. PMID- 26613923 TI - Metals in Mullus surmuletus and Pseudupeneus prayensis from the Canary Islands (Atlantic Ocean). AB - A total of 20 metals (Na, K, Ca, Mg, B, Ba, Co, Cr, Cu, Sr, Fe, Li, Mn, Mo, Ni, V, Zn, Al, Cd, and Pb) were analyzed by inductively coupled plasma optical emission spectrometry in muscle and liver tissue from a total of 28 examples of the fishes Mullus surmuletus and Pseudupeneus prayensis marketed in Tenerife, Canary Islands (Spain). Significant differences (P < 0.05) in B, K, Mg, Mn, and Na concentrations were found between muscle and liver. The mean concentrations of K (1,388.04 mg/kg wet weight [wet wt]) and Mg (153.33 mg/kg wet wt) were higher in muscle than in liver (697.49 and 114.21 mg/kg wet wt, respectively). The mean concentrations of B in liver (0.18 mg/kg wet wt), Mn (0.70 mg/kg wet wt), and Na (892.09 mg/kg wet wt) were higher than those in muscle (0.15, 0.11, and 375.55 mg/kg wet wt, respectively). The mean concentrations of Al, Cd, and Pb in muscle tissue were 2.72 mg/kg wet wt and 4.28 and 10.29 MUg/kg wet wt, and those in liver tissue were 31.31 mg/kg wet wt and 612.91 and 232.08 MUg/kg wet wt, respectively. When comparing the two fish species, the muscle tissue of M. surmuletus has significantly higher concentrations (P < 0.05) of Al, B, Ba, Ca, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, Sr, and Zn than did P. prayensis muscle, whereas the concentrations of Cd and V were significantly higher (P < 0.05) in P. prayensis muscle. Toxicological assessment of Cd and Pb concentrations was performed using the maximum limits set by the European Commission Regulations 1881/2006 and 629/2008 for muscle tissue (50 and 300 MUg/kg wet wt, respectively). The concentrations of Cd and Pb in muscle detected in the present study for all the analyzed examples of M. surmuletus and P. prayensis were lower than the maximums established for muscle tissue by European legislation. Therefore, consumption of the muscle of these fish is considered safe in terms of Al, Cd, and Pb concentrations. However, the consumption of liver tissue should be avoided because of its high levels of metals. Constant monitoring of the concentrations of metals of toxicological concern in fish products available in the market is an essential part of food safety. PMID- 26613925 TI - Erratum to: Up-Regulation of miR-21 Expression Predicate Advanced Clinicopathological Features and Poor Prognosis in Patients with Non-Small Cell Lung Cancer. PMID- 26613924 TI - Application of a Rapid Knowledge Synthesis and Transfer Approach To Assess the Microbial Safety of Low-Moisture Foods. AB - Low-moisture foods (LMF) are increasingly implicated in outbreaks of foodborne illness, resulting in a significant public health burden. To inform the development of a new Codex Alimentarius code of hygienic practice for LMF, we applied a rapid knowledge synthesis and transfer approach to review global research on the burden of illness, prevalence, and interventions to control nine selected microbial hazards in eight categories of LMF. Knowledge synthesis methods included an integrated scoping review (search strategy, relevance screening and confirmation, and evidence mapping), systematic review (detailed data extraction), and meta-analysis of prevalence data. Knowledge transfer of the results was achieved through multiple reporting formats, including evidence summary cards. We identified 214 unique outbreaks and 204 prevalence and 126 intervention studies. Cereals and grains (n = 142) and Salmonella (n = 278) were the most commonly investigated LMF and microbial hazard categories, respectively. Salmonella was implicated in the most outbreaks (n = 96, 45%), several of which were large and widespread, resulting in the most hospitalizations (n = 895, 89%) and deaths (n = 14, 74%). Salmonella had a consistently low prevalence across all LMF categories (0 to 3%), but the prevalence of other hazards (e.g., Bacillus cereus) was highly variable. A variety of interventions were investigated in small challenge trials. Key knowledge gaps included underreporting of LMF outbreaks, limited reporting of microbial levels in prevalence studies, and a lack of intervention efficacy research under commercial conditions. Summary cards were a useful knowledge transfer format to inform complementary risk ranking activities. This review builds upon previous work in this area by synthesizing a broad range of evidence using a structured, transparent, and integrated approach to provide timely evidence informed inputs into international guidelines. PMID- 26613926 TI - The Association Between Transportation and Life-Space Mobility in Community Dwelling Older People With or Without Walking Difficulties. AB - OBJECTIVE: The aim of this study is to examine whether a persons' most frequently used mode of transportation is associated with life-space mobility and whether the association differs between persons with or without walking difficulties. METHOD: Life-space mobility was measured with the Life-Space Assessment in 848 community-dwelling men and women aged 75 to 90 years. Six separate mobility groups were formed according to the most frequently used mode of transportation (car driver, car passenger, public transportation) combined with the presence or absence of difficulties walking 2 km. RESULTS: Car drivers without walking difficulties had the highest life-space mobility scores, and car passengers with walking difficulties had the lowest scores. Mode of transportation influenced the odds for restricted life space differently depending on whether or not the person had walking difficulties. DISCUSSION: To support community mobility among older persons, it would be important to improve different transportation options to meet older persons' individual wishes, needs, and resources. PMID- 26613927 TI - Microcystins do not necessarily lower the sensitivity of Microcystis aeruginosa to tannic acid. AB - Different phytoplankton strains have been shown to possess varying sensitivities towards macrophyte allelochemicals, yet the reasons for this are largely unknown. To test whether microcystin (MC) is responsible for strain-specific sensitivities of Microcystis aeruginosa to macrophyte allelochemicals, we compared the sensitivity of 12 MC- and non-MC-producing M. aeruginosa strains, including an MC deficient mutant and its wild type, to the polyphenolic allelochemical tannic acid (TA). Non-MC-producing strains showed a significantly higher sensitivity to TA than MC-producing strains, both in Chlorophyll a concentrations and quantum yields of photosystem II. In contrast, an MC-deficient mutant displayed a higher fitness against TA compared to its wild type. These results suggest that the resistance of M. aeruginosa to polyphenolic allelochemicals is not primarily related to MCs per se, but to other yet unknown protective mechanisms related to MCs. PMID- 26613928 TI - Magnetic resonance imaging and magnetic resonance spectroscopy in a young male patient with anti-N-methyl-D-aspartate receptor encephalitis and uncommon cerebellar involvement: A case report with review of the literature. AB - We report a case of a 17-year-old man presenting with new onset psychiatric symptoms. Magnetic resonance imaging (MRI) and proton magnetic resonance (MR) spectroscopy revealed some lesions in the right cerebellar hemisphere and ipsilateral cerebellar tonsil suggestive of encephalitis. An extensive workup was negative for both infectious and neoplastic diseases and he was afterward diagnosed with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. This disorder is an autoimmune encephalitis, highly lethal but curable, predominantly found in young female with ovarian teratoma. He received methylprednisolone. His clinical findings gradually improve and he made a complete recovery. Accordingly, repeated brain MRI and proton MR spectroscopy showed a gradual reduction of the lesions; MRI taken six months after starting therapy showed complete resolution of the lesions. Our case shows that, although rare, anti-NMDAR encephalitis should be considered also in young men for whom a rapid onset of psychiatric neurological disorders cannot be explained by more frequent causes. Our report underlines also the usefulness of MRI and proton MR spectroscopic findings in the diagnosis and follow-up of this disease. PMID- 26613929 TI - Long-term outcomes of pericardiectomy for constrictive pericarditis. AB - BACKGROUND: Constrictive pericarditis is a rare and disabling disease that can result in chronic fibrous thickening of the pericardium. The purpose of this study was to evaluate the long-term outcomes following treatment of constrictive pericarditis by pericardiectomy. METHODS: Between September 1992 and May 2014, 47 patients who underwent pericardiectomy for constrictive pericarditis were retrospectively examined. Demographic, pre-, intra- and postoperative data and long-term outcomes were analyzed. RESULTS: Thirty of the patients were male, the mean age was 45.8 +/- 16.7. Aetiology of constrictive pericarditis was tuberculosis in 22 (46.8 %) patients, idiopathic in 15 (31.9 %), malignancy in 3 (6.4 %), prior cardiac surgery in 2 (4.3 %), non-tuberculosis bacterial infections in 2 (4.3 %), radiotherapy in 1 (2.1 %), uraemia in 1 (2.1 %) and post traumatic in 1 (2.1 %). The surgical approach was achieved via a median sternotomy in all patients except only 1 patient. The mean operative time was 156.4 +/- 45.7 min. Improvement in functional status in 80 % of patients' at least one New York Heart Association (NYHA) functional class was observed. In hospital mortality rate was 2.1 % (1 of 47 patients). The cause of death was pneumonia leading to progressive respiratory failure. The late mortality rate was 23.4 % (11 of 47 patients). The mean follow-up time was 61.2 +/- 66 months. The actuarial survival rates were 91 %, 85 % and 81 % at 1, 5 and 10 years, respectively. Recurrence requiring a repeat pericardiectomy was developed in no patient during follow-up. CONCLUSION: Pericardiectomy is associated with high morbidity and mortality rates. Cases with neoplastic diseases, diminished cardiac output, cases in need of reoperation are expected to have high mortality rates and less chance of functional recovery. PMID- 26613930 TI - An overview of targeted cancer therapy. AB - Cancer is a multifactorial disease and is one of the leading causes of death worldwide. The contributing factors include specific genetic background, chronic exposure to various environmental stresses and improper diet. All these risk factors lead to the accumulation of molecular changes or mutations in some important proteins in cells which contributes to the initiation of carcinogenesis. Chemotherapy is an effective treatment against cancer but undesirable chemotherapy reactions and the development of resistance to drugs which results in multi-drug resistance (MDR) are the major obstacles in cancer chemotherapy. Strategies which are in practice with limited success include alternative formulations e.g., liposomes, resistance modulation e.g., PSC833, antidotes/toxicity modifiers e.g., ICRF-187 and gene therapy. Targeted therapy is gaining importance due to its specificity towards cancer cells while sparing toxicity to off-target cells. The scope of this review involves the various strategies involved in targeted therapy like-monoclonal antibodies, prodrug, small molecule inhibitors and nano-particulate antibody conjugates. PMID- 26613931 TI - SIMMED SIMulation in MEDicine, Italian Society for simulation in medicine position paper: executive summary. PMID- 26613932 TI - Effect of yellow filter on visual acuity and contrast sensitivity under glare condition among different age groups. AB - The aim of this study is to investigate the effect of yellow filter on visual acuity and contrast sensitivity under glare condition for various ages. A total of 60 subjects, aged 5-60 years, with no ocular pathology and no previous surgery were assessed in this cross-sectional study. We divided subjects into six subgroups according to their ages, and the number of subjects in each group was 10: group 1, aged 5-10 years; group 2, aged 11-20 years; group 3, aged 21-30 years; group 4, aged 31-40 years; group 5, aged 41-50 years; and group 6, aged 51 60 years. Snellen visual acuity and Pelli Robson contrast sensitivity with and without glare and with the use of yellow filter under glare condition were determined. Data analysis was carried out using SPSS, version 20. Our results showed a significant reduction in contrast sensitivity under glare condition in all age groups (p = 0.000), which improved significantly with the use of yellow filter (p = 0.000). Although when data in different age groups were analyzed separately, this improvement was only significant in older subjects, aged 51-60 years (p = 0.007). No significant difference was found between Snellen visual acuity with and without glare (p = 0.083), and also we found no yellow filter effect on visual acuity under glare condition. We conclude that yellow filter, which absorbs short wavelength, may provide significant contrast sensitivity benefits for individuals and influences older subjects more than younger ones. PMID- 26613933 TI - Multiple primary synchronous malignant tumors. AB - BACKGROUND: Patients with primary multiple malignancies are progressively increasing due to prolonged survival of cancer patients and to the advances in diagnostic techniques and therapeutic options. CASE PRESENTATION: Here we present a 66 year-old caucasian patient with four synchronous primary malignant tumors affecting the lung, oropharynx, large bowel and prostate gland, respectively, treated with multidisciplinary approach. CONCLUSIONS: The increased incidence of multiple malignant tumors is a real challenge to the clinician and clinical attention should be made to avoid a misdiagnosis. In addition an early diagnosis is essential to achieve a radical treatment. We believe that the treatment modality should be carefully made and tailored on the individual patient suffering from this disease. PMID- 26613934 TI - Case-control study on association of peroxisome proliferator-activated receptor delta and SNP-SNP interactions with essential hypertension in Chinese Han population. AB - The aim of this study was to investigate the association of peroxisome proliferator-activated receptor-delta (PPAR-delta) and additional SNP-SNP interaction with essential hypertension (EH) in Chinese Han population. A total of 1248 subjects (625 males, 623 females), including 620 EH patients and 628 normotension subjects, were included in the study. The mean age was 51.2 +/- 15.1 years old. Logistic regression model was used to examine the association between four SNP and EH; odds ratio (OR) and 95% confident interval (95%CI) were calculated. Generalized multifactor dimensionality reduction (GMDR) was employed to analyze SNP-SNP interaction. EH risk was significantly lower in carriers of C allele of the rs2016520 polymorphism than those with TT (TC + CC versus TT, adjusted OR (95%CI) = 0.61 (0.49-0.78)). In addition, we also found a significant association between rs9794 and EH; EH risk was also significantly lower in carriers of G allele of the rs9794 polymorphism than those with CC (CG + GG versus CC, adjusted OR (95%CI) = 0.65 (0.53-0.83)). We also found a potential SNP SNP interaction between rs2016520 and rs9794; subjects with TC or CC of rs2016520 and CG or GG of rs9794 genotype have the lowest EH risk, compared to subjects with TT of rs2016520 and CC of rs9794 genotype; OR (95%CI) was 0.32 (0.23-0.62) after covariate adjustment. Our results support an important association between rs2016520 and rs9794 minor allele of PPAR-delta and decreased risk of EH and additional interaction between rs2016520 and rs9794. PMID- 26613935 TI - Parents' Verbal Communication and Childhood Anxiety: A Systematic Review. AB - Parents' verbal communication to their child, particularly the expression of fear relevant information (e.g., attributions of threat to the environment), is considered to play a key role in children's fears and anxiety. This review considers the extent to which parental verbal communication is associated with child anxiety by examining research that has employed objective observational methods. Using a systematic search strategy, we identified 15 studies that addressed this question. These studies provided some evidence that particular fear-relevant features of parental verbal communication are associated with child anxiety under certain conditions. However, the scope for drawing reliable, general conclusions was limited by extensive methodological variation between studies, particularly in terms of the features of parental verbal communication examined and the context in which communication took place, how child anxiety was measured, and inconsistent consideration of factors that may moderate the verbal communication-child anxiety relationship. We discuss ways in which future research can contribute to this developing evidence base and reduce further methodological inconsistency so as to inform interventions for children with anxiety problems. PMID- 26613936 TI - Social Media Use and Perceived Emotional Support Among US Young Adults. AB - Low emotional support is associated with poor health outcomes. Engagement with face-to-face social networks is one way of increasing emotional support. However, it is not yet known whether engagement with proliferating electronic social networks is similarly associated with increased emotional support. Thus, the purpose of this study was to assess associations between social media use and perceived emotional support in a large, nationally-representative sample. In October 2014, we collected data from 1796 U.S. adults ages 19-32. We assessed social media use using both total time spent and frequency of visits to each of the 11 most popular social media platforms. Our dependent variable was perceived emotional support as measured by the brief Patient-Reported Outcomes Measurement Information System (PROMIS) emotional support scale. A multivariable model including all sociodemographic covariates and accounting for survey weights demonstrated that, compared with the lowest quartile of time on social media, being in the highest quartile (spending two or more hours per day) was significantly associated with decreased odds of having higher perceived emotional support (AOR 0.62, 95 % CI 0.40, 0.94). However, compared with those in the lowest quartile, being in the highest quartile regarding frequency of social media use was not significantly associated with perceived emotional support (AOR 0.70, 95 % CI 0.45, 1.09). In conclusion, while the cross-sectional nature of these data hinder inference regarding directionality, it seems that heavy users of social media may actually feel less and not more emotional support. PMID- 26613938 TI - Narrowing of racial disparities in breast cancer incidence: insights from menopausal hormone therapy study findings. PMID- 26613937 TI - Postmenopausal Female Hormone Use and Estrogen Receptor-Positive and -Negative Breast Cancer in African American Women. AB - BACKGROUND: Use of estrogen with progestin (combination therapy) is associated with increased incidence of estrogen receptor-positive (ER+) breast cancer in observational studies and randomized trials among postmenopausal white women. Whether this is also the case among African American women is not established. METHODS: Using data from the AMBER consortium collected from 1993 to 2013, we assessed use of estrogen alone and of combination therapy in relation to ER+ and ER-negative (ER-) breast cancer risk in postmenopausal African American women, based on 1132 ER+ case patients, 512 ER- case patients, and 6693 control patients. Odds ratios (ORs) and confidence intervals (CIs) were estimated using multinomial logistic regression with control for breast cancer risk factors. RESULTS: Forty-seven percent of control patients had used estrogen alone, combination therapy, or both. The odds ratio for ER+ breast cancer associated with combination use, relative to never use of either estrogen alone or combination therapy, was 1.50 (95% CI = 1.25 to 1.79). The increase was greater for recent (OR = 1.55, 95% CI = 1.21 to 1.99) and long-term use (OR = 1.75, 95% CI = 1.13 to 2.73) and among nonobese women (OR = 1.91, 95% CI = 1.29 to 2.83). Breast cancer risk was increased regardless of the interval between onset of menopause and initiation of combination use (OR = 1.43, 95% CI = 1.11 to 1.85, for <5 year interval; OR = 1.78, 95% CI = 1.34 to 2.37, for >=5 year interval). Combination use was not associated with risk of ER- breast cancer, and use of estrogen alone was not associated with risk of either ER+ or ER- breast cancer. CONCLUSION: Use of estrogen with progestin increases risk of ER+ breast cancer in African American women. A decrease in use would be expected to reduce the number of ER+ cancers. PMID- 26613939 TI - When endothelial cells go rogue. PMID- 26613941 TI - [Complications of corneal lamellar refractive surgery]. AB - Techniques available for corneal lamellar refractive surgery are laser-assisted in situ keratomileusis (LASIK) using a microkeratome or femtosecond laser incision followed by excimer laser corneal ablation, and femtosecond laser assisted refractive lenticule extraction (ReLEx). These treatments are nowadays considered to be safe and effective standard procedures for surgical correction of mild to moderate ametropia. Possible complications include too small or decentered optical zones, intraoperative flap cutting errors and postoperative inflammation (e.g. diffuse lamellar keratitis, DLK), epithelial or flap folds, epithelial ingrowths or iatrogenic ectasia. The occurrence of complications may be significantly reduced by compliance to corresponding standards of indication and treatment that are based on current scientific knowledge. PMID- 26613942 TI - State-to-State Mode Specificity: Energy Sequestration and Flow Gated by Transition State. AB - Energy flow and sequestration at the state-to-state level are investigated for a prototypical four-atom reaction, H2 + OH -> H + H2O, using a transition-state wave packet (TSWP) method. The product state distribution is found to depend strongly on the reactant vibrational excitation, indicating mode specificity at the state-to-state level. From a local-mode perspective, it is shown that the vibrational excitation of the H2O product derives from two different sources, one attributable to the energy flow along the reaction coordinate into the newly formed OH bond and the other due to the sequestration of the vibrational energy in the OH spectator moiety during the reaction. The analysis provided a unified interpretation of some seemingly contradicting experimental observations. It is further shown that the transfer of vibrational energy from the OH reactant to H2O product is gated by the transition state, accomplished coherently by multiple TSWPs with the corresponding OH vibrational excitation. PMID- 26613940 TI - Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy. AB - Synaptic inhibition is essential for shaping the dynamics of neuronal networks, and aberrant inhibition plays an important role in neurological disorders. Gephyrin is a central player at inhibitory postsynapses, directly binds and organizes GABAA and glycine receptors (GABAARs and GlyRs), and is thereby indispensable for normal inhibitory neurotransmission. Additionally, gephyrin catalyzes the synthesis of the molybdenum cofactor (MoCo) in peripheral tissue. We identified a de novo missense mutation (G375D) in the gephyrin gene (GPHN) in a patient with epileptic encephalopathy resembling Dravet syndrome. Although stably expressed and correctly folded, gephyrin-G375D was non-synaptically localized in neurons and acted dominant-negatively on the clustering of wild-type gephyrin leading to a marked decrease in GABAAR surface expression and GABAergic signaling. We identified a decreased binding affinity between gephyrin-G375D and the receptors, suggesting that Gly375 is essential for gephyrin-receptor complex formation. Surprisingly, gephyrin-G375D was also unable to synthesize MoCo and activate MoCo-dependent enzymes. Thus, we describe a missense mutation that affects both functions of gephyrin and suggest that the identified defect at GABAergic synapses is the mechanism underlying the patient's severe phenotype. PMID- 26613943 TI - Parvovirus B19 myocarditis in children: an observational study. AB - BACKGROUND: The advent of PCR testing for the presence of viral genomes has led to the identification of parvovirus B19 (PVB19) as a causative agent of myocarditis. METHODS: The clinical presentation, course and outcome of children with PVB19 myocarditis was ascertained through a retrospective review. The PVB19 viral genome was detected by PCR from whole blood or endomyocardial biopsy specimens in patients presenting with new onset heart failure. RESULTS: Seventeen patients presented at a median age of 1.3 years (range: 0.4-15.4 years) in cardiac failure with a mean fractional shortening of 15+/-3%. Eleven patients required mechanical ventilation and intravenous inotropes and seven required extra-corporeal mechanical oxygenation. Four of the five deaths occurred in patients who had a short prodromal illness of less than 48 hours. All patients with ST segment elevation died (n=4). All non-fulminant cases survived. Event free survival occurred in 11/17 (65%) patients. Five (29%) patients died and one patient underwent heart transplantation. Complete recovery of cardiac function occurred within a median of 12 months (range: 1-48) in five patients. There was incomplete recovery in five patients and one patient had persistent dilated cardiomyopathy. CONCLUSIONS: PVB19 can cause a devastating myocarditis in children. Children with fulminant myocarditis, ST segment changes or a short prodrome have the worst outcome. Transplantation may be considered, but is rarely required in the acute period if mechanical circulatory support is utilised. If the initial presentation is survived, recovery of the myocardium can occur even in those who had fulminant myocarditis. PMID- 26613944 TI - Sick-listed persons' experiences with taking part in an in-patient occupational rehabilitation program based on Acceptance and Commitment Therapy: a qualitative focus group interview study. AB - BACKGROUND: Occupational medicine has shifted emphasis from disease treatment to disability rehabilitation and management. Hence, newly developed occupational rehabilitation programs are often generic and multicomponent, aiming to influence the sick-listed persons' perception on return to work, and thereby support the return to work process. The aim of this study was to explore sick-listed persons' experiences with taking part in an in-patient occupational rehabilitation program based on Acceptance and Commitment Therapy. METHODS: Twenty-nine adults on sickness benefit or work assessment allowance due to musculoskeletal and/or common mental health disorders participated in this study. They were interviewed in focus groups at the beginning and at the end of a 3.5 week inpatient group based occupational rehabilitation program in Central Norway. Key elements in the program were Acceptance and Commitment Therapy (ACT), physical exercise and creating a work-participation plan. The program was mainly group-based including participants with different diagnoses. Data was analyzed according to a phenomenological approach. RESULTS: At the start of the program most participants expressed frustration regarding being sick-listed, external anticipations as well as hindrances towards returning to work, and described hope that the program would provide them with the skills and techniques necessary to cope with health problems and being able to return to work. At the end of the program the participants described that they had embarked upon a long process of increased awareness. This process encompassed four areas; an increased awareness of what was important in life, realizing the strain from external expectations and demands, a need to balance different aspects of life, and return to work as part of a long and complex process. CONCLUSIONS: The occupational rehabilitation program induced a perceived meaningful reorientation encompassing several aspects of life. However, the return to work process was described as diffuse and uncertain for most participants. The providers of occupational rehabilitation program should balance this reorientation with specific steps towards return to work. Effect studies and long-term qualitative studies evaluating how this affects long-term work- and health outcomes are underway. PMID- 26613946 TI - Interdependence of ATP signalling and pannexin channels; the servant was really the master all along? AB - Pannexin channels are recognized as important conduits for the release of ATP, which contributes to purinergic signalling. Pathologically, ATP release via these channels acts as a find-me signal for apoptotic cell clearance. Accordingly, there is considerable and growing interest in understanding the function and regulation of pannexin channels. In a recent issue of the Biochemical Journal, Boyce et al. provide evidence that the surface expression of pannexin channels is regulated by extracellular ATP. They propose a model in which ATP triggers pannexin channel internalization through a pathway involving clathrin- and caveolin-independent entry into early endosomes. Intriguingly, their evidence suggests that internalization is initiated through the association of ATP with pannexin channels themselves as well as ionotropic purinergic receptor 7 (P2X7) receptors. PMID- 26613945 TI - High-density lipoprotein mimetics: promises and challenges. AB - The concept of lipoprotein mimetics was developed and extensively tested in the last three decades. Most lipoprotein mimetics were designed to recreate one or several functions of high-density lipoprotein (HDL) in the context of cardiovascular disease; however, the application of this approach is much broader. Lipoprotein mimetics should not just be seen as a set of compounds aimed at replenishing a deficiency or dysfunctionality of individual elements of lipoprotein metabolism but rather as a designer concept with remarkable flexibility and numerous applications in medicine and biology. In the present review, we discuss the fundamental design principles used to create lipoprotein mimetics, mechanisms of their action, medical indications and efficacy in animal models and human studies. PMID- 26613947 TI - Reply to comments on the relationship between green tea consumption and the risk of endometrial cancer. PMID- 26613948 TI - SAGA DUB-Ubp8 Deubiquitylates Centromeric Histone Variant Cse4. AB - Aneuploidy, the unbalanced segregation of chromosomes during cell division, is recurrent in many tumors and the cause of birth defects and genetic diseases. Centromeric chromatin represents the chromosome attachment site to the mitotic spindle, marked by specialized nucleosomes containing a specific histone variant, CEN-H3/Cse4, in yeast. Mislocalization of Cse4 outside the centromere is deleterious and may cause aberrant chromosome behavior and mitotic loss. For this reason, ubiquitylation by the E3-ubiquitin ligase Psh1 and subsequent proteolysis tightly regulates its restricted localization. Among multiproteic machineries, the SAGA complex is not merely engaged in acetylation but also directly involved in deubiquitylation. In this study, we investigated the role of SAGA-DUB's Ubp8 driven deubiquitylation of the centromeric histone variant Cse4 in budding yeast. We found that Ubp8 works in concert with the E3-ubiquitin ligase Psh1, and that its loss causes defective deubiquitylation and the accumulation of a short ubiquitin oligomer on Cse4. We also show that lack of Ubp8 and defective deubiquitylation increase mitotic instability, cause faster Cse4 proteolysis and induce mislocalization of the centromeric histone outside the centromere. Our data provide evidence for a fundamental role of DUB-Ubp8 in deubiquitylation and the stability of the centromeric histone in budding yeast. PMID- 26613951 TI - Cardiomyopathy from 1,1-Difluoroethane Inhalation. AB - Consumer aerosol products can be inhaled for their psychoactive effects, but with attendant adverse health effects including "sudden sniffing death." Cardiomyopathy has rarely been described in association with 1,1-difluoroethane (DFE), a common aerosol propellant. We report a 33-year-old male who developed acute myocardial injury and global hypokinesis along with rhabdomyolysis, acute kidney injury, and fulminant hepatitis after 2 days' nearly continuous huffing. Workup for other causes, including underlying coronary artery disease, was negative. His cardiac function improved over time. The exact mechanism of DFE's effects is uncertain but may include catecholamine-induced cardiomyopathy, coronary vasospasm, or direct cellular toxicity. PMID- 26613952 TI - Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 suppresses tumor growth in breast cancer-bearing mice by negatively regulating myeloid-derived suppressor cell functions. AB - Myeloid-derived suppressor cells (MDSCs) are one of the most important cell types that contribute to negative regulation of immune responses in the tumor microenvironment. Recently, aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1), a novel pleiotropic cytokine, was identified as an antitumor protein that inhibits angiogenesis and induces antitumor responses. However, the effect of AIMP1 on MDSCs in the tumor environment remains unclear. In the present study, we demonstrated that AIMP1 significantly inhibited tumor growth in 4T1 breast cancer-bearing mice and reduced MDSCs population of tumor sites and spleens of tumor-bearing mice. AIMP1 reduced expansion of MDSCs from bone marrow derived cells in the tumor-conditioned media. AIMP1 also negatively regulated suppressive activities of MDSCs by inhibiting IL-6 and NO production, and Arg-1 expression. Furthermore, treatment of breast cancer-bearing mice with AIMP1 decreased the capacity of MDSCs to suppress T cell proliferation and Treg cell induction. Western blot and inhibition experiments showed that downregulation of MDSCs functions by AIMP1 may result from attenuated activation of STATs, Akt, and ERK. These findings indicate that AIMP1 plays an essential role in negative regulation of suppressive functions of MDSCs. Therefore, it has a significant potential as a therapeutic agent for cancer treatment. PMID- 26613949 TI - The wavy Mutation Maps to the Inositol 1,4,5-Trisphosphate 3-Kinase 2 (IP3K2) Gene of Drosophila and Interacts with IP3R to Affect Wing Development. AB - Inositol 1,4,5-trisphosphate (IP3) regulates a host of biological processes from egg activation to cell death. When IP3-specific receptors (IP3Rs) bind to IP3, they release calcium from the ER into the cytoplasm, triggering a variety of cell type- and developmental stage-specific responses. Alternatively, inositol polyphosphate kinases can phosphorylate IP3; this limits IP3R activation by reducing IP3 levels, and also generates new signaling molecules altogether. These divergent pathways draw from the same IP3 pool yet cause very different cellular responses. Therefore, controlling the relative rates of IP3R activation vs. phosphorylation of IP3 is essential for proper cell functioning. Establishing a model system that sensitively reports the net output of IP3 signaling is crucial for identifying the controlling genes. Here we report that mutant alleles of wavy (wy), a classic locus of the fruit fly Drosophila melanogaster, map to IP3 3 kinase 2 (IP3K2), a member of the inositol polyphosphate kinase gene family. Mutations in wy disrupt wing structure in a highly specific pattern. RNAi experiments using GAL4 and GAL80(ts) indicated that IP3K2 function is required in the wing discs of early pupae for normal wing development. Gradations in the severity of the wy phenotype provide high-resolution readouts of IP3K2 function and of overall IP3 signaling, giving this system strong potential as a model for further study of the IP3 signaling network. In proof of concept, a dominant modifier screen revealed that mutations in IP3R strongly suppress the wy phenotype, suggesting that the wy phenotype results from reduced IP4 levels, and/or excessive IP3R signaling. PMID- 26613950 TI - Comparative Phylogenomics of Pathogenic and Nonpathogenic Species. AB - The Ascomycete Onygenales order embraces a diverse group of mammalian pathogens, including the yeast-forming dimorphic fungal pathogens Histoplasma capsulatum, Paracoccidioides spp. and Blastomyces dermatitidis, the dermatophytes Microsporum spp. and Trichopyton spp., the spherule-forming dimorphic fungal pathogens in the genus Coccidioides, and many nonpathogens. Although genomes for all of the aforementioned pathogenic species are available, only one nonpathogen had been sequenced. Here, we enhance comparative phylogenomics in Onygenales by adding genomes for Amauroascus mutatus, Amauroascus niger, Byssoonygena ceratinophila, and Chrysosporium queenslandicum--four nonpathogenic Onygenales species, all of which are more closely related to Coccidioides spp. than any other known Onygenales species. Phylogenomic detection of gene family expansion and contraction can provide clues to fungal function but is sensitive to taxon sampling. By adding additional nonpathogens, we show that LysM domain-containing proteins, previously thought to be expanding in some Onygenales, are contracting in the Coccidioides-Uncinocarpus clade, as are the self-nonself recognition Het loci. The denser genome sampling presented here highlights nearly 800 genes unique to Coccidiodes, which have significantly fewer known protein domains and show increased expression in the endosporulating spherule, the parasitic phase unique to Coccidioides spp. These genomes provide insight to gene family expansion/contraction and patterns of individual gene gain/loss in this diverse order--both major drivers of evolutionary change. Our results suggest that gene family expansion/contraction can lead to adaptive radiations that create taxonomic orders, while individual gene gain/loss likely plays a more significant role in branch-specific phenotypic changes that lead to adaptation for species or genera. PMID- 26613953 TI - Biomarkers of nutrition and stress in pregnant women with a history of eating disorders in relation to head circumference and neurocognitive function of the offspring. AB - BACKGROUND: Eating disorders during pregnancy can affect fetal growth and the child's early development, but the underlying mechanisms have not been elucidated. The aim of the present study was to investigate serum biomarkers of nutrition and stress in pregnant women with previous eating disorders compared to controls and in relation to head circumference and early neurocognitive development of the offspring. METHODS: In a longitudinal cohort study, pregnant nulliparous non-smoking women with a history of anorexia nervosa (n = 20), bulimia nervosa (n = 17) and controls (n = 59) were followed during pregnancy and their children's growth and neurocognitive development were followed up to five years of age. We investigated maternal serum biomarkers of nutrition and stress (ferritin, cortisol, thyroid-stimulating hormone, free thyroxine, insulin, insulin-like growth factor I (IGF-I) and IGF binding protein 1) in blood samples collected during early pregnancy and compared between groups (ANOVA, LSD post-hoc test). The results were related to previous data on head circumference at birth and neurocognitive development at five years of age of the offspring (Spearman rank correlation or Pearson correlation test). RESULTS: Serum levels of ferritin in the women with previous anorexia nervosa, but not in those with a history of bulimia nervosa, were significantly lower than in the controls (p < 0.01), and correlated strongly to impaired memory function in their children (rs = -0.70, p < 0.001). Maternal serum levels of free thyroxine were similar between groups but correlated positively to reduced head circumference at birth of the children in the bulimia nervosa group (r = 0.48, p < 0.05), and with the same tendency in the anorexia nervosa group (r = 0.42, p = 0.07), but not in the controls (r = 0.006). There were no significant differences in cortisol or the other biomarkers between groups. CONCLUSIONS: Low maternal serum ferritin in women with previous anorexia nervosa may be of importance for impaired memory capacity in the offspring at five years of age. Our results also indicate that thyroxin levels in pregnant women with previous eating disorders are positively associated with fetal head growth. PMID- 26613954 TI - Comparison of treatment persistence with different oral anticoagulants in patients with atrial fibrillation. AB - PURPOSE: Oral anticoagugulants (OACs) effectively reduce the risk for ischemic stroke in patients with atrial fibrillation (AF), but undertreatment and poor persistence with treatment are important problems. NOACs now provide alternatives to warfarin. This study compares the persistence with presently available antithrombotic treatments in AF patients with a CHA2DS2VASc score >=2. METHODS: All first claims of either warfarin (n = 9969), dabigatran (n = 2701), rivaroxaban (n = 2074), apixaban (n = 1352), or aspirin (n = 4540) from April 2011 until December 2014, in individuals with non-valvular AF and CHA2DS2VASc scores of 2-9, were identified in the administrative health data register (VAL) of the Stockholm region (2.1 million inhabitants). Prescription claims were analyzed with and without multivariate analysis in relation to age, sex, prescriber category, prior OAC treatment, number of drugs, and death. RESULTS: The overall persistence with any OAC was 88.2% (CI 87.5-88.9) at 1 year and 82.9% (CI 81.8-83.9) at 2 years. After 1 year, the crude persistence was 85.0% (CI 84.2 85.9) with warfarin, 85.9% (CI 81.8-90.1) with apixaban, 74.4% (CI 72.3-76.5) with dabigatran, and 77.4% (CI 74.6-80.2) with rivaroxaban. Multivariate analysis confirmed significantly higher persistence with warfarin and apixaban than with dabigatran or rivaroxaban. The adherence (proportion of days covered >80%) was above 90% for all NOACs; significantly higher with rivaroxaban compared to dabigatran (p < 0.001), but not compared to apixaban (p = 0.14). CONCLUSIONS: After 2 years, the persistence with any anticoagulant treatment was high in patients with non-valvular AF. Our results indicate better persistence with warfarin and apixaban than with dabigatran or rivaroxaban in regular care. PMID- 26613955 TI - Effect of commercial Rhodiola rosea on CYP enzyme activity in humans. AB - PURPOSE: The aim of the present study was to evaluate the effect of the herbal drug Rhodiola rosea on the activity of the cytochrome P-450 (CYP) enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in humans. METHODS: In a randomized cross over study, 13 healthy volunteers were given a cocktail with single doses of the CYP substrates caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4) with and without 14 days of pretreatment with a commercially available R. rosea product (Arctic Root, produced by the Swedish Herbal Institute). Four hours after intake of the drug cocktail, a blood sample was obtained, the serum concentrations of the drugs and their metabolites were analyzed, and the metabolic ratios were calculated as a measure of CYP enzyme activity. RESULTS: A statistically significant 21% decrease in the EXP-3174/losartan ratio was found after pretreatment with R. rosea (p = 0.023), indicating a reduced CYP2C9 metabolic activity. The effect was more pronounced in CYP2C9 extensive metabolizers than in CYP2C9 intermediate and poor metabolizers. For the other CYP enzymes tested, no significant effects were observed. CONCLUSIONS: This study indicates that R. rosea inhibits the metabolic capacity of CYP2C9 in humans. Although the effect is modest, it might be clinically relevant during treatment with CYP2C9 substrates with a narrow therapeutic index, such as phenytoin and warfarin. PMID- 26613957 TI - IRF5 and IRF8 modulate the CAL-1 human plasmacytoid dendritic cell line response following TLR9 ligation. AB - Synthetic oligonucleotides (ODNs) containing CpG motifs stimulate human plasmacytoid dendritic cells (pDCs) to produce type-1 interferons (IFNs) and proinflammatory cytokines. Previous studies demonstrated that interferon regulatory factors (IRFs) play a central role in mediating CpG-induced pDC activation. This work explores the inverse effects of IRF5 and IRF8 (also known as IFN consensus sequence-binding protein) on CpG-dependent gene expression in the human CAL-1 pDC cell line. This cell line shares many of the phenotypic and functional properties of freshly isolated human pDCs. Results from RNA interference and microarray studies indicate that IRF5 upregulates TLR9-driven gene expression whereas IRF8 downregulates the same genes. Several findings support the conclusion that IRF8 inhibits TLR9-dependent gene expression by directly blocking the activity of IRF5. First, the inhibitory activity of IRF8 is only observed when IRF5 is present. Second, proximity ligation analysis shows that IRF8 and IRF5 colocalize within the cytoplasm of resting human pDCs and cotranslocate to the nucleus after CpG stimulation. Taken together, these findings suggest that IRF5 and IRF8, two transcription factors with opposing functions, control TLR9 signaling in human pDCs. PMID- 26613956 TI - Therapeutic drug monitoring of second-generation antipsychotics in pediatric patients: an observational study in real-life settings. AB - PURPOSE: Available guidelines on therapeutic drug monitoring of second-generation antipsychotics were designed for adults; therefore, they cannot be transferred as such in pediatric patients, who may have different drug absorption, distribution, metabolism, and elimination. Moreover, available tools that guide dosing in neuropsychiatric pediatric patients are scant, leading to the possibility of reduced efficacy and/or increased risks of toxicity. Here we describe the results of observational therapeutic drug monitoring conducted in three pediatric neuropsychiatry units across Italy in 2012-2014, with the following aims: (1) to describe the distribution of plasma concentrations of second-generation antipsychotics in our pediatric patients and (2) to identify clinical covariates associated with plasma drug levels. METHODS: Five hundred fifty-six plasma trough concentrations of the second-generation antipsychotics risperidone (plus 9 hydroxy-risperidone), aripiprazole, olanzapine, and quetiapine were measured from 172 pediatric outpatients overall. The distribution of drug concentrations was described and correlated with drug doses and clinical variables. RESULTS: Risperidone plasma levels were lower than in adults (median 13.6 ng/ml), with a high inter-patient (78.9%) but lower intra-patient (34.2%) variability. In multiple regression analyses, risperidone plasma levels depended only on drug dose (p < 0.001). Aripiprazole plasma levels were similar to those described in adults (median 165.8 ng/ml) and were widely distributed, with an inter-patient variability of 81.1%, while the intra-patient variability was much lower (29.3%). Multiple regression analyses indicated that aripiprazole plasma levels were influenced by the daily doses (p < 0.001) and by the number of concomitant drugs (p < 0.01). CONCLUSION: Our study described the distribution of plasma levels of SGAs in a real-life setting involving pediatric patients, significantly increasing the amount of available data for this fragile population. If confirmed in larger dataset, these data may contribute to the definition of optimal therapeutic window for risperidone and aripiprazole plasma levels in pediatric patients. PMID- 26613958 TI - Novel mutation in an Egyptian patient with infantile Canavan disease. AB - Canavan disease (CD) is a rare fatal childhood neurological autosomal recessive genetic disease caused by mutations in the ASPA gene, which lead to catalytic deficiency of the ASPA enzyme that catalyzes the deacetylation of NAA. It is a severe progressive leukodystrophy characterized by spongiform degeneration of the white matter of the brain. CD occurs frequently among Ashkenazi Jewish population, however it has been reported in many other ethnic groups with significantly lower frequency. Here, we report on a 2 year-old Egyptian child with severe CD who harbors a novel homozygous missense variant (c.91G > T, p.V31F) in the ASPA gene. The clinical, radiological, and molecular genetic profiles are reviewed in details. PMID- 26613960 TI - Effect of dietary inclusion of spray-dried porcine plasma on performance, some physiological and immunological response of broiler chickens challenged with Salmonella sofia. AB - This study was conducted to investigate the effect of spray-dried porcine plasma (SDPP) in broiler chickens under Salmonella sofia disease challenge. The experiment comprised five starter diets: positive control (no supplement), diet supplemented with in-feed antibiotics (IFA; salinomycin 0.05% + zinc bacitracin 0.033%) and diets supplemented with SDPP at 10 or 20 g/kg diet. All four of these groups were challenged with S. sofia, while a fifth group was unchallenged and used as the negative control. The experimental diets were fed to 14 days; then, the birds were switched to commercial-type grower and finisher diets. Oral inoculation of the challenged groups with S. sofia occurred on day 8, 10 and 12. Body weight was significantly higher in the birds fed diets containing IFA and SDPP than in the challenged control group, but it was only significant in starter and grower phases. In general, there was an improvement in the weights of the immune-related organs, but it was only significant for the weight of the bursa of SDPP-fed birds at 13 days. At day 13, blood potassium content was lower and the concentrations of IgG and IgM tended to be lower in the birds fed on low-SDPP starter diets than those of the other groups. There were significant differences in the concentration of lactic acid in the ileum and acetic acid, formic acid, butyric acid and propionic acid in the caeca. Inclusion of SDPP to the starter diets of broiler chicks had positive effects on broiler performance, immunity and gut health during exposure to highly pathogenic conditions. PMID- 26613959 TI - Phytochemical constituents and biological activities of different extracts of Strobilanthes crispus (L.) Bremek leaves grown in different locations of Malaysia. AB - BACKGROUND: Strobilanthes crispus is a well-known herb in Malaysia with various pharmaceutical properties. S. crispus is known to contain several biologically active chemical constituents which are responsible for its pharmaceutical quality. METHODS: Strobilanthes crispus leaves grown in three different locations in Malaysia [Kelantan (North-east), Selangor (Central), and Penang (North)], were investigated for differences in the content of secondary metabolites [total phenolics content (TPC), total flavonoids content (TFC), and total saponins content (TSC)] as well as for their antioxidant and anticancer properties. Phenolic acids and flavonoids were identified using ultra-high performance liquid chromatography (UHPLC). Ferric reducing antioxidant potential (FRAP) and 1,1 diphenyl-2-picrylhydrazyl (DPPH) assays were used to evaluate the antioxidant activities. The anticancer activity of extracts against HeLa cancer cell line was evaluated using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. RESULTS: Samples from the three different locations when extracted with two solvents (aqueous and ethanol extracts) yielded significantly different results for TPC, TFC, and TSC as well as for antioxidant activity. Aqueous extract of S. crispus leaves collected from Kelantan exhibited the highest values: TPC [12.62 mg gallic acid equivalents (GAE)/g dry matter (DM)], TFC (7.44 mg quercetin equivalents (QE)/g DM), TSC (44.7 mg diosgenin equivalents (DE)/g DM), DPPH (73.8 %), and FRAP (267.5 MUM of Fe (II)/g) activity with a half maximal inhibitory concentration (IC50) of 44.1 MUg/mL compared to the extracts of leaves collected from the other two locations. The most important secondary metabolites identified in this study, based on concentration, were phenolics classified as followed: caffeic acid>ferulic acid>gallic acid>chlorogenic acid>trans-cinnamic acid; flavonoids: quercetin>rutin>catechin>apigenin>naringenin>kaempferol. Extracts of leaves collected from Kelantan exhibited better anticancer activity against HeLa cancer cell line with an IC50 of 182.5 MUg/mL compared to the extracts of leaves from Selangor (IC50 = 266.4 MUg/mL) and Penang (IC50 = 331.5 MUg/mL) and to tamoxifen (IC50 = 63.4 MUg/mL). S. crispus leaves with the highest content of secondary metabolites exhibited the most potent antioxidant and anticancer activity. CONCLUSIONS: Therefore, based on the potent antioxidant and anticancer activity of leaves extracts, it appears that S. crispus grown in the North-east of Malaysia (Kelantan) is a potential source of anticarcinogenic therapeutic compounds. PMID- 26613962 TI - Signaling output: it's all about timing and feedbacks. AB - The central questions in understanding signaling pathway specificity are how these pathways encode which stimulus is present and how this stimulus is decoded to yield the correct cell fate decision. In their recent work, Ryu et al (2015) show by stimulation experiments with different ligands how the differential engagement of feedback and feed-forward regulation leads to different dynamics of pathway activity, which in turn alters cell fate.Moreover, they show that by considering the timescales of the feedback regulations,the different cellular responses can be triggered with pulsed stimulations by a single ligand. PMID- 26613961 TI - Frequency modulation of ERK activation dynamics rewires cell fate. AB - Transient versus sustained ERK MAP kinase (MAPK) activation dynamics induce proliferation versus differentiation in response to epidermal (EGF) or nerve (NGF) growth factors in PC-12 cells. Duration of ERK activation has therefore been proposed to specify cell fate decisions. Using a biosensor to measure ERK activation dynamics in single living cells reveals that sustained EGF/NGF application leads to a heterogeneous mix of transient and sustained ERK activation dynamics in distinct cells of the population, different than the population average. EGF biases toward transient, while NGF biases toward sustained ERK activation responses. In contrast, pulsed growth factor application can repeatedly and homogeneously trigger ERK activity transients across the cell population. These datasets enable mathematical modeling to reveal salient features inherent to the MAPK network. Ultimately, this predicts pulsed growth factor stimulation regimes that can bypass the typical feedback activation to rewire the system toward cell differentiation irrespective of growth factor identity. PMID- 26613963 TI - Synchrotron nanoscopy imaging study of scalp hair in breast cancer patients and healthy individuals: Difference in medulla loss and cortical membrane enhancements. AB - Nanoscopic synchrotron X-ray imaging was performed on scalp hair samples of patients with breast cancer and healthy individuals to investigate any structural differences as diagnostic tool. Hair strands were divided into 2-3 segments along the strands from root to tip, followed by imaging either in projection or in CT scanning with a monochromatic 6.78-keV X-ray using zone-plate optics with a resolving power of 60 nm. All the examined cancer hairs exhibited medulla loss with cancer stage-dependent pattern; complete loss, discontinuous or trace along the strands. In contrast, medullas were well retained without complete loss in the healthy hair. In the CT-scanned axial images, the cortical spindle compartments had no contrast in the healthy hair, but appeared hypointense in contrast to the surrounding hyperintense cortical membrane complex in the cancer hair. In conclusion, observation of medulla loss and cortical membrane enhancements in the hair strands of breast cancer patients demonstrated structural variations in the cancer hair, providing a new platform for further synchrotron X-ray imaging study of screening breast cancer patients. PMID- 26613964 TI - Effect of monensin and essential oils on performance and energy metabolism of transition dairy cows. AB - This work examined preventive effects of a dietary and a medical intervention measure on postpartum (p.p.) ketogenesis in dairy cows overconditioned in late pregnancy. Sixty German Holstein cows were allocated 6 weeks antepartum (a.p.) to three high body condition score (BCS) groups (BCS 3.95 +/- 0.08) and one low BCS group (LC, BCS 2.77 +/- 0.14). Concentrate proportion in diet a.p. was higher (60% vs. 20%) and increase in proportion p.p. from 30% up to 50% decelerated (3 vs. 2 weeks) in high BCS groups. High BCS cows received a monensin controlled release capsule (CRC) (HC/MO), a blend of essential oils (HC/EO) or formed a control group (HC). Performance parameters and energy status were evaluated in three periods [day (d) -42 until calving, one until 14 days in milk (DIM), 15 until 56 DIM]. Feed efficiency was 65% and 53% higher in HC/MO than in LC (p < 0.001) and HC groups (p = 0.002) in the second period. Milk fat content was higher in HC/EO (5.60 vs. 4.82%; p = 0.012) and milk urea higher in HC/MO (135 mg/kg) than in LC cows (107 mg/kg; p < 0.001). Increased p.p. levels of non esterified fatty acids in serum were found in HC (p = 0.003), HC/MO (p = 0.068) and HC/EO (p = 0.002) in comparison with LC cows. Prevalence of subclinical and clinical ketosis was 54% and 46%, respectively, in HC group. Monensin decreased the prevalence to 50% and 7% respectively. Ruminal fermentation pattern showed higher proportions of propionate (23.43 mol % and 17.75 mol %, respectively; p < 0.008) and lower acetate:propionate ratio (2.66 vs. 3.76; p < 0.001) in HC/MO than HC group. Results suggest that a monensin CRC improved energy status and feed efficiency of transition dairy cows while essential oils failed to elicit any effect. PMID- 26613965 TI - Adjuvant radiotherapy for early head and neck squamous cell carcinoma with perineural invasion: A systematic review. AB - Perineural invasion (PNI) is widely regarded as a negative prognostic factor in head and neck squamous cell carcinoma (HNSCC). Treatment guidelines recommend adjuvant radiotherapy (RT) for patients with adverse pathologic features, including PNI. The purpose of this study was to systematically review the literature to determine if patients with PNI as their only indication for adjuvant therapy benefit from adjuvant RT. In total, 339 abstracts were reviewed for relevance leaving 85 articles, which were evaluated in detail. Thirteen retrospective studies addressed the role of adjuvant RT for patients with PNI. Evidence is lacking to recommend adjuvant RT for all patients with HNSCC with PNI. However, the literature suggests that large nerve or multifocal PNI may predict worse outcome and may be a more appropriate indication for adjuvant therapy. We advocate that patients decide whether to undergo adjuvant therapy after a discussion of the limitations of current evidence. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E2350-E2357, 2016. PMID- 26613966 TI - A patient with 41 CAG repeats in SCA17 presenting with parkinsonism and chorea. PMID- 26613968 TI - Severe connective tissue laxity including aortic dilatation in Sotos syndrome. PMID- 26613967 TI - Attenuated hypothalamic responses to alpha-melanocyte stimulating hormone during pregnancy in the rat. AB - KEY POINTS: Increased appetite and weight gain occurs during pregnancy, associated with development of leptin resistance, and satiety responses to the anorectic peptide alpha-melanocyte stimulating hormone (alpha-MSH) are suppressed. This study investigated hypothalamic responses to alpha-MSH during pregnancy, using c-fos expression in specific hypothalamic nuclei as a marker of neuronal signalling, and in vivo electrophysiology in supraoptic nucleus (SON) oxytocin neurons, as a representative alpha-MSH-responsive neuronal population that shows a well-characterised alpha-MSH-induced inhibition of firing. While icv injection of alpha-MSH significantly increased the number of c-fos-positive cells in the paraventricular, supraoptic, arcuate and ventromedial hypothalamic nuclei in non-pregnant rats, this response was suppressed in pregnant rats. Similarly, SON oxytocin neurons in pregnant rats did not demonstrate characteristic alpha MSH-induced inhibition of firing that was observed in non-pregnant animals. Given the known functions of alpha-MSH in the hypothalamus, the attenuated responses are likely to facilitate adaptive changes in appetite regulation and oxytocin secretion during pregnancy. ABSTRACT: During pregnancy, a state of positive energy balance develops to support the growing fetus and to deposit fat in preparation for the subsequent metabolic demands of lactation. As part of this maternal adaptation, the satiety response to the anorectic peptide alpha melanocyte stimulating hormone (alpha-MSH) is suppressed. To investigate whether pregnancy is associated with changes in the response of hypothalamic alpha-MSH target neurons, non-pregnant and pregnant rats were treated with alpha-MSH or vehicle and c-fos expression in hypothalamic nuclei was then examined. Furthermore, the firing rate of supraoptic nucleus (SON) oxytocin neurons, a known alpha-MSH responsive neuronal population, was examined in non-pregnant and pregnant rats following alpha-MSH treatment. Intracerebroventricular injection of alpha-MSH significantly increased the number of c-fos-positive cells in the paraventricular, arcuate and ventromedial hypothalamic nuclei in non-pregnant rats, but no significant increase was observed in any of these regions in pregnant rats. In the SON, alpha-MSH did induce expression of c-fos during pregnancy, but this was significantly reduced compared to that observed in the non-pregnant group. Furthermore, during pregnancy, SON oxytocin neurons did not demonstrate the characteristic alpha-MSH-induced inhibition of firing rate that was observed in non-pregnant animals. Melanocortin receptor mRNA levels during pregnancy were similar to non-pregnant animals, suggesting that receptor down regulation is unlikely to be a mechanism underlying the attenuated responses to alpha-MSH during pregnancy. Given the known functions of alpha-MSH in the hypothalamus, the attenuated responses will facilitate adaptive changes in appetite regulation and oxytocin secretion during pregnancy. PMID- 26613969 TI - Anthropological Perspectives on Participation in CBPR: Insights From the Water Project, Maras, Peru. AB - In this article, we anthropologically explore one part of the process of Community-Based Participatory Research (CBPR): participation. Participation in CBPR is usually conceptualized as whether, and the degree to which, community members are involved in the research process. Our focus regarding participation is less on quantity and more on quality of the interaction between community members and researchers; within this context, we elaborate the concept of "bridging" as it is understood in CBPR. Using data from our ongoing "Water Project" in the Peruvian Andes, we explore how interaction, as a participative act of the research interview, creates the space for participating and imagining. Out of this interaction come data that are elaborated, contextualized, and, ultimately, from a CBPR perspective, made useful for meaningful engagement and community action. PMID- 26613970 TI - Sample Size in Qualitative Interview Studies: Guided by Information Power. AB - Sample sizes must be ascertained in qualitative studies like in quantitative studies but not by the same means. The prevailing concept for sample size in qualitative studies is "saturation." Saturation is closely tied to a specific methodology, and the term is inconsistently applied. We propose the concept "information power" to guide adequate sample size for qualitative studies. Information power indicates that the more information the sample holds, relevant for the actual study, the lower amount of participants is needed. We suggest that the size of a sample with sufficient information power depends on (a) the aim of the study, (b) sample specificity, (c) use of established theory, (d) quality of dialogue, and (e) analysis strategy. We present a model where these elements of information and their relevant dimensions are related to information power. Application of this model in the planning and during data collection of a qualitative study is discussed. PMID- 26613971 TI - Little White Lies: Interrogating the (Un)acceptability of Deception in the Context of Dementia. AB - This metasynthesis surveyed extant literature on deception in the context of dementia and, based on specific inclusion criteria, included 14 articles from 12 research studies. By doing so, the authors accomplished three goals: (a) provided a systematic examination of the literature-to-date on deception in the context of dementia, (b) elucidated the assumptions that have guided this line of inquiry and articulated the way those shape the research findings, and (c) determined directions for future research. In particular, synthesizing across studies allowed the authors to develop a dynamic model comprised of three temporally linear elements-(a) motives, (b) modes, and (c) outcomes that describe how deception emerges communicatively through interaction in the context of dementia. PMID- 26613973 TI - Simultaneous transcatheter pulmonary and tricuspid valve-in-valve implantation for the treatment of failing pulmonary and tricuspid bioprostheses. AB - We report a case of a patient with a history of bioprosthetic pulmonary and tricuspid valve replacement who developed significant stenosis and regurgitation of the bioprosthetic valves. Due to multiple comorbidities, he was deemed high risk for redo-valve replacement surgery. He subsequently underwent percutaneous transcatheter pulmonary and tricuspid valve-in-valve procedure at the same setting. This is the first of such that is reported in the literature. (c) 2015 Wiley Periodicals, Inc. PMID- 26613972 TI - The effect of perceptual expectation on repetition suppression to faces is not modulated by variation in autistic traits. AB - There is substantial variation in the magnitude of the repetition suppression (RS) effects across individuals; however the causes of this variation remain unclear. In a recent study, we found that RS in occipitotemporal cortex was negatively related to individual variation in autistic traits in a neurotypical population. Recent proposals have considered autistic behaviours within a Bayesian framework, suggesting that individuals with autism may have 'attenuated priors' (i.e., their perception is less influenced by prior information). Predictive coding represents a neural instantiation of Bayesian inference, and characterises RS as reduction in prediction error between 'top-down' (prior beliefs) and 'bottom-up' (stimulus related) inputs. In accordance with this, evidence shows that RS is greater when repetition of a stimulus is expected relative to when it is unexpected. Here, using an established paradigm which manipulates the probability of stimulus repetition, we investigated the effect of perceptual expectation on RS in a group of neurotypical individuals varying on a measure of autistic traits. We predicted that the magnitude of the perceptual expectation effect would be negatively related to individual differences in autistic traits. We found a significant effect of perceptual expectation on RS in face-selective regions (i.e., greater RS when repetitions were expected relative to unexpected). However, there was no evidence of a relationship between autistic traits and the magnitude of this effect in any face-selective region of interest (ROI). These findings provide a challenge for the proposal that autism spectrum conditions (ASC) may be associated with the attenuated influence of prior information. PMID- 26613974 TI - Stratum corneum reservoir as a predictive method for in vitro percutaneous absorption. AB - Interaction between drug and proteins and lipids in stratum corneum (SC) is an important pharmacokinetic parameter in early steps of absorption. Previous in vivo studies showed that the total amount of compound, regardless of properties, penetrating over a 96 h period could be predicted by the amount present in SC 30 min after application by a linear relationship. Validating this linear relationship through in vitro study would facilitate testing of transdermal drug delivery platforms. We aimed to determine in vitro penetration behavior across SC of humans by determining the relationship between quantity present in SC reservoir 30 min after application with 24 h skin absorption and penetration. In this study, use of the SC reservoir effect to predict absorption and penetration of topical compounds is reaffirmed with in vitro models involving human skin. These results indicate the amount in short-term (30 min) SC reservoir predict long-term (24 h) skin absorption and penetration, as characterized by statistically significant linear relationships determined via regression. This may be explained by the fact that SC is a rate-limiting barrier to percutaneous drug transport. After molecules diffuse through SC barrier, passage into deeper dermal layers and systemic uptake occur relatively quickly. These results enable one to measure quantity in SC reservoir shortly after topical application as a proxy for absorption and penetration over longer periods. With respect to drug development and risk assessment of toxic substances, this may simplify assays attempting to quantitate penetration capacity. Further investigation with a larger range of compounds is needed to clarify the observations recorded here. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26613975 TI - Preface. PMID- 26613976 TI - Kidney Injury Due to Warm Ischemia During Transplantation Can Be Reduced. PMID- 26613977 TI - Postdural puncture headache as presentation of horsetail syndrome secondary to tuberculosis meningitis. PMID- 26613978 TI - Selective expression of a constitutively active erythropoietin receptor in GABAergic neurons alters hippocampal network properties without affecting cognition. AB - We have previously shown that treatment with erythropoietin (EPO) improves cognition in patients with neuropsychiatric disorders as well as in healthy mice, and that transgenic expression of a constitutively active form of the EPO receptor (cEPOR) in glutamatergic neurons boosts higher cognitive functions in mice. In the present work, we examined whether selective activation of EPOR signaling in GABAergic neurons would also modulate cognitive performance. We generated transgenic mice that express cEPOR under the control of the vesicular inhibitory amino acid transporter (Viaat) promoter and subjected them to comprehensive behavioral, cognitive, and electrophysiological analyses. We demonstrate that transgenic expression of cEPOR in GABAergic neurons alters hippocampal gamma-oscillations and enhances long-term potentiation but neither impairs nor improves cognition. To conclude, constitutively active EPOR in GABAergic neurons changes hippocampal network properties without affecting cognition, which suggests that the effect of EPO on cognition is dominated by its effect on the glutamatergic system. Treatment with EPO improves cognitive performance. We previously demonstrated that this effect is replicated by constitutive autoactivation of cEPOR in glutamatergic neurons. By contrast, cEPOR in GABAergic neurons changes hippocampal network properties but neither impairs nor enhances cognition. Thus, EPO modulates neuronal plasticity, and the cognitive benefits may be mainly attributable to its effect on the glutamatergic system. PMID- 26613979 TI - Microbial dynamics in mixed culture biofilms of bacteria surviving sanitation of conveyor belts in salmon-processing plants. AB - AIMS: The microbiota surviving sanitation of salmon-processing conveyor belts was identified and its growth dynamics further investigated in a model mimicking processing surfaces in such plants. METHODS AND RESULTS: A diverse microbiota dominated by Gram-negative bacteria was isolated after regular sanitation in three salmon processing plants. A cocktail of 14 bacterial isolates representing all genera isolated from conveyor belts (Listeria, Pseudomonas, Stenotrophomonas, Brochothrix, Serratia, Acinetobacter, Rhodococcus and Chryseobacterium) formed stable biofilms on steel coupons (12 degrees C, salmon broth) of about 10(9) CFU cm(-2) after 2 days. High-throughput sequencing showed that Listeria monocytogenes represented 0.1-0.01% of the biofilm population and that Pseudomonas spp dominated. Interestingly, both Brochothrix sp. and a Pseudomonas sp. dominated in the surrounding suspension. CONCLUSIONS: The microbiota surviving sanitation is dominated by Pseudomonas spp. The background microbiota in biofilms inhibit, but do not eliminate L. monocytogenes. SIGNIFICANCE AND IMPACT OF THE STUDY: The results highlights that sanitation procedures have to been improved in the salmon-processing industry, as high numbers of a diverse microbiota survived practical sanitation. High-throughput sequencing enables strain level studies of population dynamics in biofilm. PMID- 26613981 TI - Survival After Suspected Urinary Tract Infection in Individuals with Advanced Dementia. AB - OBJECTIVES: To determine whether antimicrobial treatment for suspected urinary tract infections (UTIs) improves survival in nursing home residents with advanced dementia. DESIGN: Prospective cohort study. SETTING: Thirty-five nursing homes in Boston, Massachusetts. PARTICIPANTS: Nursing home residents who experienced at least one suspected UTI over a 12-month period (N = 110); mean participant age 86.4 +/- 6.2, 84% female. MEASUREMENTS: Analyses were at the level of the UTI episode. Antimicrobial treatment for each suspected UTI was categorized as none, oral, intramuscular, or intravenous or hospitalization. Survival was calculated from the date of suspected UTI episode until death or last known follow-up date. Covariates included resident and episode characteristics. Cox proportional hazards regression was used to examine the association between treatment group and risk of death after adjusting for covariates. RESULTS: Residents experienced 196 suspected UTIs over the follow-up period; 33% (n = 36) died during follow-up. There was no antimicrobial use for 25.0% of the 196 suspected UTIs, oral antimicrobial use in 59.7%; intramuscular antimicrobial use in 9.2%, and intravenous antimicrobial use or hospital transfer in 6.1%. After multivariable adjustment, antimicrobial treatment was not significantly associated with mortality (oral, adjusted hazard ratio for death (AHR) = 1.09, 95% confidence interval (CI) = 0.43-2.75; intramuscular, AHR = 0.66, 95% CI = 0.08-5.66; intravenous or hospitalization, AHR = 1.83, 95% CI = 0.44-7.60). CONCLUSION: Although the majority of suspected UTIs that nursing home residents with advanced dementia experienced were treated with antimicrobials, treatment was not associated with survival. PMID- 26613980 TI - 2-Amino-4-(3,4-(methylenedioxy)benzylamino)-6-(3-methoxyphenyl)pyrimidine is an anti-inflammatory TLR-2, -4 and -5 response mediator in human monocytes. AB - OBJECTIVE AND DESIGN: To elucidate the influence of 2-amino-4-(3,4 (methylenedioxy)benzylamino)-6-(3-methoxyphenyl)pyrimidine (AMBMP), a canonical Wnt/beta-catenin pathway activator, on the inflammatory response of TLR-engaged innate cells in vitro. MATERIAL OR SUBJECT: Primary human monocytes. TREATMENT: AMPMB (0-10 MUM), LPS (0-1.0 MUg/ml), Pam3CSK4, FSL-1, or S. typhimurium flagellin (0-0.25 MUg/ml). METHODS: TLR-induced cytokine release (TNF, IL-6, IL 12 p40) was monitored by ELISA while Wnt-related signals (GSK3beta, p65, IkappaB, beta-catenin) were assessed by Western blot, pharmaceutical inhibition and gene silencing. RESULTS: AMBMP induced the rapid phosphorylation of NFkappaB p65 at Ser(536) and abrogated total IkappaB, accompanied by a subsequent increase in pro inflammatory cytokine production (TNF, IL-6, IL-12 p40) in otherwise naive monocytes. However, in TLR2, -4 and -5-engaged monocytes, AMBMP-suppressed cytokine production. In the context of LPS stimulation, this occurred concomitant with the phosphorylative inactivation of GSK3beta at Ser(9), beta-catenin accumulation and abrogation of NFkappaB p65 phosphorylation. AMBMP-mediated suppression of the TLR4 -induced inflammatory response was reversed by two pharmaceutical Wnt/beta-catenin pathway inhibitors, IWP-2 and PNU-74654 and by Wnt3a silencing. CONCLUSIONS: Herein, we show that AMBMP induces canonical Wnt signaling events and acts as a suppressor of inflammation in surface TLR-engaged primary human monocytes. PMID- 26613982 TI - Interferon response of the cystic fibrosis bronchial epithelium to major and minor group rhinovirus infection. AB - Rhinoviruses (RVs) are associated with exacerbations of cystic fibrosis (CF), asthma and COPD. There is growing evidence suggesting the involvement of the interferon (IFN) pathway in RV-associated morbidity in asthma and COPD. The mechanisms of RV-triggered exacerbations in CF are poorly understood. In a pilot study, we assessed the antiviral response of CF and healthy bronchial epithelial cells (BECs) to RV infection, we measured the levels of IFNs, pattern recognition receptors (PRRs) and IFN-stimulated genes (ISGs) upon infection with major and minor group RVs and poly(IC) stimulation. Major group RV infection of CF BECs resulted in a trend towards a diminished IFN response at the level of IFNs, PRRs and ISGs in comparison to healthy BECs. Contrary to major group RV, the IFN pathway induction upon minor group RV infection was significantly increased at the level of IFNs and PRRs in CF BECs compared to healthy BECs. PMID- 26613983 TI - Editorial overview: Carbohydrate-protein interactions and glycosylation: Glycan synthesis and recognition: finding the perfect partner in a sugar-coated life. AB - Oligosaccharides expressed on the surface of cells and in biological fluids as glycoproteins, glycolipids, proteoglycans and polysaccharides can be recognized by partner proteins, and these interactions have been shown to mediate fundamental biological events such as occur in the immune system, signal transduction, development and cancer metastasis. The specificities of these partner proteins (lectins) for their glycan ligands are determined by factors such as glycan composition, shape and density of expression and the involvement of the aglycone moiety as part of the recognition motif. There is increasing knowledge on the mechanisms of these interactions as new secondary binding sites continue to be elucidated adding to the functional awareness of sugar-binding proteins. This issue focuses on recent advances in understanding how C-type lectins in the immune system work, how novel motifs involving asymmetric glycan branch recognition and protein-protein interactions influence critical biological functions including signal transduction and bactericidal pore formation, recent studies on novel glycan-binding proteins produced by bacteriophage, analysis of the interactions between heparin/heparan sulphate and their binding proteins, and recent findings on the molecular interactions between chondroitin-dermatan sulphate and various bioactive protein components. We conclude with a review on a recent fascinating class of processive enzymes responsible for synthesis of high molecular weight extracellular polysaccharides such as hyaluronic acid, chitin and alginate. PMID- 26613984 TI - Arthroscopic Bankart repair and subscapularis augmentation: an alternative technique treating anterior shoulder instability with bone loss. AB - BACKGROUND: This study presents the preliminary results of a new arthroscopic technique consisting of the association of 2 procedures, capsulolabral repair and subscapularis augmentation tenodesis, in the treatment of traumatic anterior shoulder instability with both glenoid bone loss and a Hill-Sachs lesion. METHODS: Eighty-nine patients engaged in sports were enrolled in this retrospective case-series study with 2 to 5 years' follow-up. All patients underwent a computed tomography scan to assess the percentage of glenoid bone loss by the Pico method. A prior stabilization procedure had failed in 20 patients, who were then segregated into a different group. Visual analog scale (VAS), Rowe, and American Shoulder and Elbow Surgeons (ASES) scores were used to assess the results. RESULTS: Only 3 of 89 patients had a post-traumatic redislocation. The mean length of follow-up was 31.5 months (range, 25-60 months). The VAS, Rowe, and ASES scores showed significant improvements: The VAS score decreased from a mean of 3.1 to 0.5 (P = .0157), the Rowe score increased from 58.9 to 94.1 (P = .0215), and the ASES score increased from 68.5 to 95.5 (P = .0197). The mean deficit of external rotation was 6 degrees with the arm at the side of the trunk, and the mean deficit was 3 degrees with the arm in 90 degrees of abduction. CONCLUSIONS: The described procedure is a reproducible and effective technique used to restore joint stability in patients engaged in sports who have incurred anterior recurrent shoulder dislocation associated with glenoid bone loss (<25%) and a Hill-Sachs lesion. PMID- 26613986 TI - Caenorhabditis elegans, a Biological Model for Research in Toxicology. AB - Caenorhabditis elegans is a nematode of microscopic size which, due to its biological characteristics, has been used since the 1970s as a model for research in molecular biology, medicine, pharmacology, and toxicology. It was the first animal whose genome was completely sequenced and has played a key role in the understanding of apoptosis and RNA interference. The transparency of its body, short lifespan, ability to self-fertilize and ease of culture are advantages that make it ideal as a model in toxicology. Due to the fact that some of its biochemical pathways are similar to those of humans, it has been employed in research in several fields. C. elegans' use as a biological model in environmental toxicological assessments allows the determination of multiple endpoints. Some of these utilize the effects on the biological functions of the nematode and others use molecular markers. Endpoints such as lethality, growth, reproduction, and locomotion are the most studied, and usually employ the wild type Bristol N2 strain. Other endpoints use reporter genes, such as green fluorescence protein, driven by regulatory sequences from other genes related to different mechanisms of toxicity, such as heat shock, oxidative stress, CYP system, and metallothioneins among others, allowing the study of gene expression in a manner both rapid and easy. These transgenic strains of C. elegans represent a powerful tool to assess toxicity pathways for mixtures and environmental samples, and their numbers are growing in diversity and selectivity. However, other molecular biology techniques, including DNA microarrays and MicroRNAs have been explored to assess the effects of different toxicants and samples. C. elegans has allowed the assessment of neurotoxic effects for heavy metals and pesticides, among those more frequently studied, as the nematode has a very well defined nervous system. More recently, nanoparticles are emergent pollutants whose toxicity can be explored using this nematode. Overall, almost every type of known toxicant has been tested with this animal model. In the near future, the available knowledge on the life cycle of C. elegans should allow more studies on reproduction and transgenerational toxicity for newly developed chemicals and materials, facilitating their introduction in the market. The great diversity of endpoints and possibilities of this animal makes it an easy first-choice for rapid toxicity screening or to detail signaling pathways involved in mechanisms of toxicity. PMID- 26613987 TI - Pore Water Collection, Analysis and Evolution: The Need for Standardization. AB - Investigating the ecological impacts of contaminants released into the environment requires integration of multiple lines of evidence. Collection and analysis of interstitial water is an often-used line of evidence for developing benthic exposure estimates in aquatic ecosystems. It is a well-established principle that chemical and toxicity data on interstitial water samples should represent in-situ conditions; i.e., sample integrity must be maintained throughout the sample collection process to avoid alteration of the in-situ geochemical conditions. Unfortunately, collection and processing of pore water is not standardized to address possible geochemical transformations introduced by atmospheric exposure. Furthermore, there are no suitable benchmarks (ecological or human health) against which to evaluate adverse effects from chemicals in pore water; i.e., empirical data is lacking on the toxicity of inorganic contaminants in sediment interstitial water. It is clear that pore water data is best evaluated by considering the bioavailability of trace elements and the partitioning of contaminants between the aqueous and solid phases. It is also evident that there is a need for sediment researchers and regulatory agencies to collaborate in developing a standardized approach for sediment/pore water collection and data evaluation. Without such guidelines, the number of different pore water collection and extraction techniques will continue to expand, and investigators will continue to evaluate potentially questionable data by comparison to inappropriate criteria. PMID- 26613988 TI - Environmental Fate and Toxicology of Dimethoate. AB - The insecticide dimethoate, an organophosphate, was first introduced in 1962 for broad spectrum control of a wide range of insects including mites, flies, aphids, and plant hoppers. It inhibits AChE activity, resulting in nerve damage, which may lead to death. It is considered highly toxic to insects although dimethoate resistance has been observed. Dimethoate has both a low vapor pressure (0.247 mPa) and Henry's law constant (l.42x10(-6) Pa m3/mol), thus volatilization is not a major route of dissipation from either water or moist soils. Photolysis is considered a minor dissipation pathway. However, studies have shown that in the presence of a catalyst, the rate of photolysis does increase. The insecticide has high water solubility (39,800 mg/L) and under alkaline conditions, hydrolysis predominates representing a major degradation pathway. It has a low soil sorption capacity (Koc=20) which varies by soil type and organic matter content. Dimethoate is degraded by microbes under anaerobic conditions and bacterial species have been identified that are capable of using dimethoate as a carbon source. Although many intermediate by-products have been identified by abiotic and biotic processes, the major degradation product is omethoate. Dimethoate has been found to adversely impact many organisms. In plants, photosynthesis and growth are highly impacted, whereas birds exhibit inhibition in brain enzyme activity, thus sublethal effects are apparent. Furthermore, aquatic organisms are expected to be highly impacted via direct exposure, often displaying changes in swimming behavior. Toxicity results include inhibition in growth and more importantly, inhibition of acetylcholinesterase activity. PMID- 26613985 TI - Outcome at 2 Years after Dextrose Gel Treatment for Neonatal Hypoglycemia: Follow Up of a Randomized Trial. AB - OBJECTIVE: To determine neurodevelopmental outcome at 2 years' corrected age in children randomized to treatment with dextrose gel or placebo for hypoglycemia soon after birth (The Sugar Babies Study). STUDY DESIGN: This was a follow-up study of 184 children with hypoglycemia (<2.6 mM [47 mg/dL]) in the first 48 hours and randomized to either dextrose (90/118, 76%) or placebo gel (94/119, 79%). Assessments were performed at Kahikatea House, Hamilton, New Zealand, and included neurologic function and general health (pediatrician assessed), cognitive, language, behavior, and motor skills (Bayley Scales of Infant and Toddler Development, Third Edition), executive function (clinical assessment and Behaviour Rating Inventory of Executive Function-Preschool Edition), and vision (clinical examination and global motion perception). Coprimary outcomes were neurosensory impairment (cognitive, language or motor score below -1 SD or cerebral palsy or blind or deaf) and processing difficulty (executive function or global motion perception worse than 1.5 SD from the mean). Statistical tests were two sided with 5% significance level. RESULTS: Mean (+/- SD) birth weight was 3093 +/- 803 g and mean gestation was 37.7 +/- 1.6 weeks. Sixty-six children (36%) had neurosensory impairment (1 severe, 6 moderate, 59 mild) with similar rates in both groups (dextrose 38% vs placebo 34%, relative risk 1.11, 95% CI 0.75-1.63). Processing difficulty also was similar between groups (dextrose 10% vs placebo 18%, relative risk 0.52, 95% CI 0.23-1.15). CONCLUSIONS: Dextrose gel is safe for the treatment of neonatal hypoglycemia, but neurosensory impairment is common among these children. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN 12608000623392. PMID- 26613989 TI - Exposure to Crystal Violet, Its Toxic, Genotoxic and Carcinogenic Effects on Environment and Its Degradation and Detoxification for Environmental Safety. AB - Crystal Violet (CV), a triphenylmethane dye, has been extensively used in human and veterinary medicine as a biological stain, as a textile dye in textile processing industries and also used to provide a deep violet color to paints and printing ink. CV is also used as a mutagenic and bacteriostatic agent in medical solutions and antimicrobial agent to prevent the fungal growth in poultry feed. Inspite of its many uses, CV has been reported as a recalcitrant dye molecule that persists in environment for a long period and pose toxic effects in environment. It acts as a mitotic poison, potent carcinogen and a potent clastogene promoting tumor growth in some species of fish. Thus, CV is regarded as a biohazard substance. Although, there are several physico-chemical methods such as adsorption, coagulation and ion-pair extraction reported for the removal of CV, but these methods are insufficient for the complete removal of CV from industrial wastewaters and also produce large quantity of sludge containing secondary pollutants. However, biological methods are regarded as cost-effective and eco-friendly for the treatment of industrial wastewaters, but these methods also have certain limitations. Therefore, there is an urgent need to develop such eco-friendly and cost-effective biological treatment methods, which can effectively remove the dye from industrial wastewaters for the safety of environment, as well as human and animal health. PMID- 26613990 TI - Metabolic Pathways for Degradation of Aromatic Hydrocarbons by Bacteria. AB - The aim of this review was to build an updated collection of information focused on the mechanisms and elements involved in metabolic pathways of aromatic hydrocarbons by bacteria. Enzymes as an expression of the genetic load and the type of electron acceptor available, as an environmental factor, were highlighted. In general, the review showed that both aerobic routes and anaerobic routes for the degradation of aromatic hydrocarbons are divided into two pathways. The first, named the upper pathways, entails the route from the original compound to central intermediate compounds still containing the aromatic ring but with the benzene nucleus chemically destabilized. The second, named the lower pathway, begins with ring de-aromatization and subsequent cleavage, resulting in metabolites that can be used by bacteria in the production of biomass. Under anaerobic conditions the five mechanisms of activation of the benzene ring described show the diversity of chemical reactions that can take place. Obtaining carbon and energy from an aromatic hydrocarbon molecule is a process that exhibits the high complexity level of the metabolic apparatus of anaerobic microorganisms. The ability of these bacteria to express enzymes that catalyze reactions, known only in non-biological conditions, using final electron acceptors with a low redox potential, is a most interesting topic. The discovery of phylogenetic and functional characteristics of cultivable and noncultivable hydrocarbon degrading bacteria has been made possible by improvements in molecular research techniques such as SIP (stable isotope probing) tracing the incorporation of (13)C, (15)N and (18)O into nucleic acids and proteins. Since many metabolic pathways in which enzyme and metabolite participants are still unknown, much new research is required. Therefore, it will surely allow enhancing the known and future applications in practice. PMID- 26613991 TI - A Review and Assessment of Spent Lead Ammunition and Its Exposure and Effects to Scavenging Birds in the United States. PMID- 26613992 TI - Assessment of Mental Status. AB - Assessing the mental status of patients with a neurobehavioral disorder is a critical element in the diagnosis and treatment of these patients. This assessment should always be performed after the patient's history it taken and a general physical as well as a neurologic examination is completed. The mental status examination commences with observing the patient's appearance and level of consciousness. The examiner should also pay attention to patient's social behavior, emotional state and mood. There are 3 major means of assessing a patient's mental status. One type attempts to determine if the patient is demented and the severity of the dementia as it pertains to their ability to perform activities of daily living as well as instrumental activities. A second type of assessment utilizes what may be termed as "screening tests" or "omnibus tests". These brief tests are performed independent of the patient's history and examination. The two most frequently used screening tests are the Mini-Mental Status Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). The third means of assessing a patient's mental status is by using specific neuropsychological tests that focus on specific domains of cognition, such as frontal executive functions, attention, episodic verbal and visuospatial memory, declarative knowledge such as language (speech, reading and writing) and arithmetical, as well as visuospatial and perceptual abilities. These neurobehavioral, neuropsychiatric and neuropsychological assessments of patients with a cognitive decline and behavioral abnormalities should often be accompanied by laboratory tests, and neuroimaging that can help determine the underlying pathologic process so that effective therapeutic and management approaches can be provided. PMID- 26613993 TI - Behavioral Neurology of Multiple Sclerosis and Autoimmune Encephalopathies. AB - Multiple sclerosis (MS) is the most common nontraumatic cause of physical disability in young adults. Cognitive and neuropsychiatric problems are common in this disease independent of motor disability. Such problems especially in mild cases are ignored by physicians, although they may have a major impact on quality of life. Neurobehavioral changes may affect the adherence to treatment and worsen the ultimate prognosis. Although many studies have been performed in this regard, it seems that combining cognitive evaluations with other outcome measures in MS will enhance the understanding of neurobehavioral changes in MS. PMID- 26613995 TI - Traumatic Brain Injury and Behavior: A Practical Approach. AB - Traumatic brain injury (TBI) is a complex neurologic and neuropathologic process that may affect the patient's behavior permanently. Clinically, TBI is associated with a wide gamut of neurologic and psychiatric disorders, such as amnesia, cognitive decline, seizures, attention and concentration deficits, depression, manic behavior, psychosis, hostile and violent behavior, and personality alterations. Therapy and rehabilitative efforts should be designed based on the type of injury and the patient's specific needs. Gaining familiarity with the behavioral disorders outlined in this article and understanding how to identify and treat them plays a significant role in the management of patients with TBI. PMID- 26613996 TI - Alzheimer's Disease: Prototype of Cognitive Deterioration, Valuable Lessons to Understand Human Cognition. AB - It is important for neurologists to become more familiar with neuropsychological evaluation for Alzheimer disease. The growth of this method in research, as an available, inexpensive, and noninvasive diagnostic approach, which can be administered even by non-specialist-trained examiners, makes this knowledge more necessary than ever. Such knowledge has a basic role in planning national programs in primary health care systems for prevention and early detection of Alzheimer disease. This is more crucial in developing countries, which have higher rates of dementia prevalence along with cardiovascular risk factors, lack of public knowledge about dementia, and limited social support. In addition compared to the neurological hard signs which are tangible and measurable, the concept of cognition seems to be more difficult for the neurologists to evaluate and for the students to understand. Dementia in general and Alzheimer's disease as the prototype of cognitive disorders specifically, play an important role to explore all domains of human cognition through its symptomatology and neuropsychological deficits. PMID- 26613994 TI - Neurobehavioral Manifestations of Human Immunodeficiency Virus/AIDS: Diagnosis and Treatment. AB - Behavioral disorders are common in persons infected with human immunodeficiency virus (HIV). The differential includes preexisting psychiatric diseases, substance abuse, direct effects of HIV infection, opportunistic infection, and the adverse effects of medical therapies. Many patients have more than one contributing or comorbid problem to explain these behavioral changes. The differential should always include consideration of psychosocial, genetic, and medical causes of disease. Treatment strategies must take into account the coadministration of antiretroviral therapy and the specific neurologic problems common in patients infected with HIV. PMID- 26613997 TI - Medicinal-Induced Behavior Disorders. AB - Commonly used medications can have neuropsychiatric and behavioral effects that may be idiosyncratic or metabolic in nature, or a function of interactions with other drugs, toxicity, or withdrawal. This article explores an approach to the patient with central nervous system toxicity, depending on presentation of sedation versus agitation and accompanying physical signs and symptoms. The effects of antihypertensives, opioids, antibiotics, antiepileptic agents, steroids, Parkinson's disease medications, antipsychotics, medications for human immunodeficiency virus infection, cancer chemotherapeutics, and immunotherapies are discussed. A look at the prevalence of adverse reactions to medications and the errors underlying such occurrences is included. PMID- 26613998 TI - Frontotemporal Dementia. AB - Frontotemporal dementia (FTD) is a not-uncommon explanation for progressive cognitive deficit in patients who often have a genetic susceptibility for such a neurodegenerative process. However, FTD does not seem to identify one particular pathogenetic mechanism but rather a spectrum of pathologies with particular predilection for the frontal and temporal lobes of the brain. There have been various subcategorizations of this form of dementia that have a tendency to be of earlier onset than typical Alzheimer disease and heralded by behavioral or communication manifestations. There is a behavioral variant and a language variant, referred to as primary progressive aphasia. PMID- 26613999 TI - Treatment of Cognitive Deficits in Epilepsy. AB - Cognitive deficits, including attention, language, memory, and executive dysfunction, are common in the setting of epilepsy and can greatly impair quality of life. The etiology is often multifactorial and may be due to the underlying seizure disorder, treatment adverse effects, and psychiatric comorbidities, among other factors. Management of cognitive deficits aims to address these underlying etiologies as well as provide rehabilitative strategies. Several investigational therapies are also currently under study. This article examines current and future treatments for cognitive dysfunction in epilepsy. PMID- 26614000 TI - Stroke and Behavior. AB - Most patients who have endured a stroke sustain behavioral changes, although in many instances these effects can be subtle. Although behavioral changes after a stroke tend to improve, they may persist and have serious effects on daily living activities. This article reviews the more familiar behavioral changes that follow stroke, as well as exotic, less often encountered manifestations. This article acquaints the clinician with the diversity of the behavioral effects of stroke, along with methods for their assessment and management. PMID- 26614001 TI - Cognitive and Psychiatric Disturbances in Parkinsonian Syndromes. AB - Parkinsonian syndromes share clinical signs including akinesia/bradykinesia and rigidity, which are consequences of pathology involving dopaminergic substantia nigra neurons. Yet cognitive and psychiatric disturbances are common, even early in the course of disease. Executive dysfunction is often measurable in newly diagnosed Parkinson's disease. Treatment with dopaminergic medications, particularly dopamine agonists, has been associated with hallucinations and impulse control disorder. Older age, presence of APOE-4 gene, and/or other factors result in amyloid plaque deposition that, in turn, accelerates cortical Lewy body plus tau pathology, linking Dementia with Lewy Bodies and Parkinson's disease with early dementia with Alzheimer's disease. Treatments available for cognitive deficits, depression, and psychotic symptoms are discussed. PMID- 26614002 TI - Neuropsychiatric Features in Primary Mitochondrial Disease. AB - Mitochondrial diseases are a clinically heterogeneous group of disorders that ultimately result from dysfunction of the mitochondrial respiratory chain. There is some evidence to suggest that mitochondrial dysfunction plays a role in neuropsychiatric illness; however, the data are inconclusive. This article summarizes the available literature published in the area of neuropsychiatric manifestations in both children and adults with primary mitochondrial disease, with a focus on autism spectrum disorder in children and mood disorders and schizophrenia in adults. PMID- 26614003 TI - Neurobehavioral Manifestations of Neurological Diseases: Diagnosis and Treatment. PMID- 26614004 TI - Zinc supplementation induces regulatory T cells by inhibition of Sirt-1 deacetylase in mixed lymphocyte cultures. AB - SCOPE: Zinc is an essential trace element, regulating immune function. Its deficiency results in immune dysfunction and transplant rejection. In here, a benefit of zinc supplementation for the induction of tolerance was investigated, focusing on the TH 1-dominated allogeneic immune reaction. METHODS AND RESULTS: Allogeneic immune reaction was modeled by mixed lymphocyte culture (MLC). The effect of zinc supplementation was monitored via expression of cytokines and surface lineage markers using ELISA and flow cytometry. Epigenetic analyses were performed to investigate mechanisms underlying zinc-induced changes in regulatory T cell (Treg) activation. Results reveal that Tregs are induced when MLCs are treated with 50 MUM zinc causing a decrease in IFNgamma production. IL-2 and IL 10 expression were not affected. The teleology of this effect includes the inhibition of histone deacetylase Sirt-1-mediated Foxp3 deacetylation, resulting in its decreased degradation. CONCLUSION: In conclusion, zinc should be considered to prevent graft-versus-host disease (GVHD) as it is capable of stabilizing iTregs, resulting in increased numbers of this cell type while not suppressing the immune system. PMID- 26614005 TI - Extraintestinal manifestations in inflammatory bowel disease: Prevalence and predictors in Indian patients. AB - BACKGROUND: There is a paucity of reports on extraintestinal manifestations (EIMs) in patients with inflammatory bowel diseases (IBD) from Asia and India. METHODS: From May 2011 to October 2012, consecutive IBD patients underwent a detailed history and physical examination, also by trained rheumatologist, dermatologist, and ophthalmologist, about whether they experienced any EIM at the time of inclusion or in the past. The disease phenotype/severity and location was classified according to the Montreal classification. All underwent magnetic resonance imaging (MRI) of sacroiliac joints, liver function test (LFT), transabdominal ultrasound, and dual energy X-ray absorptiometry (DEXA) scanning at neck femur (bilateral) and L4-L5 spine. RESULTS: One hundred twenty patients were analyzed, 62 had Crohn's disease (CD) and 58 had ulcerative colitis (UC). Thirty-eight percent had at least one while 20% suffered from multiple EIMs. Except for uveitis and episcleritis, the frequency of individual EIMs did not differ between CD and UC patients. Twenty-three percent had peripheral arthritis, 18% had ankylosing spondylitis, and 13% had ophthalmological manifestations. Mucocutaneous manifestations, aphthous stomatitis and pyoderma gangrenosum (PG), were seen in 9%. None had erythema nodosum (EN) or primary sclerosing cholangitis (PSC). Fifty percent of patients had either osteopenia or osteoporosis on DEXA. Multivariable analysis revealed female gender, Hindu religion, severe disease, and steroid usage were significantly associated with the presence of EIMs. CONCLUSION: The prevalence of EIM is similar to that reported from Europe and USA, albeit higher than that previously reported in Asian patients. Female sex, religion, severe disease, and steroid use were associated with EIM. PMID- 26614006 TI - Religion involvement and quality of life in patients with schizophrenia in Latin America. AB - OBJECTIVE: The aim of the study was to explore the relationship between religion involvement (RI) and quality of life (QoL) in patients with schizophrenia from three countries in Latin America, while considering key confounding factors such as socio-demographic and clinical characteristics. METHODS: This cross-sectional study was conducted in the public mental health services in La Paz, Bolivia; Arica, Chile; and Tacna, Peru. The data collected included RI, socio-demographic information, clinical characteristics, type of treatment and QoL using the S-QoL 18 questionnaire. A multivariate analysis using multiple linear regressions was performed to determine variables associated with QoL levels. RESULTS: Two hundred and fifty-three patients with schizophrenia were enrolled in our study. Significant positive associations were found between RI and QoL (the S-QoL 18 index: beta = 0.13; p = 0.048; autonomy dimension: beta = 0.15; p = 0.027). Other socio-cultural and economic factors were also associated with low QoL level: being a woman, older patient, low education level and being Aymara. Severity of the psychotic symptoms was associated to a lower QoL for all the dimension (beta from 0.15 to 0.31), except for the resilience. CONCLUSION: Our study found that socio-cultural and economic factors including RI were associated with QoL in patients with schizophrenia in Latin America, suggesting that these factors may influence positively health outcome. However, these relationships were moderate in strength, especially in comparison to symptoms severity which remained the most important features associated with QoL. PMID- 26614007 TI - A potent therapeutics for gallbladder cancer by combinatorial inhibition of the MAPK and mTOR signaling networks. AB - BACKGROUND: Gallbladder cancer (GBC) is the most common type of cancer with the worst prognosis among the bile duct cancers. There still remains a clear need for effective mechanism-based novel therapeutic approaches. A crosstalk between mitogen-activated protein kinase (MAPK) and the mammalian target of Rapamycin (mTOR) signaling pathways has been reported in several cancers. We hypothesized that targeting both pathways in combination will be a potent therapeutic for GBC. METHODS: Expression of phospho-ERK and phospho-S6rp protein were evaluated by immunostaining in surgically resected GBC specimens (n = 30). GBC cell lines and a xenograft model were treated with CI-1040, an inhibitor of MEK (mitogen activated protein kinase kinase) and RAD001, an inhibitor of mTOR, alone or in combination, and then, we examined the cell proliferation and tumor growth, cell cycle status, and apoptosis. RESULTS: Analysis of human GBC tissues demonstrated that MAPK and mTOR signaling pathways were frequently coordinately dysregulated in one third of them. The combination therapy inhibited both signaling pathways and subsequently inhibited human GBC cell proliferation in vitro and xenograft tumor growth in vivo. Compared to the single treatment, the combination therapy significantly induced cell cycle arrest and apoptosis with decreased cyclin D1 expression. CONCLUSIONS: The double blockade of MAPK and mTOR signaling pathways inhibits the signal crosstalk and shows anti-tumor activity, which can be a potent therapeutic for GBC, especially for the patients with hyperactivated signaling of both pathways. PMID- 26614008 TI - [Aerobic capacity, weight status and self-concept in schoolchildren]. AB - OBJETIVES: To analyze the relationship between self-concept, aerobic capacity and weight status in schoolchildren. MATERIAL AND METHOD: Relational descriptive design in which was assessed the weight status and aerobic capacity of 256 schoolchildren among 8-11 years. Aerobic capacity (low vs high) and the body mass index (normal-weight vs overweight-obesity) were categorized using standard criteria. The self-concept was assessed through the Piers Harris self-concept scale for children. RESULTS: Schoolchildren with normal-weight and high fitness level showed better levels of conductual self-concept (P=.030), physical (P<.001), lack of anxiety (P=.048), and global self-concept (P=.002). The schoolchildren with normal-weight show higher levels of conductual self-concpt (P=.016), intellectual (P=.050), physical (P<.001), life satisfaction (P=.036), and global self-concept (P=.001). The schoolchildren with a higher fitness level showed better conductual self-concept (P=.024), physical (P=.004), lack of anxiety (P=.011), social (P=.024), and global (P=.003). CONCLUSIONS: The results of the study strengthen the importance to transmit to the educative community the knowledge of the relationship between the variables analyzed aiming to improve the schoolchildren self-concept. PMID- 26614009 TI - Interpretation of Renal Quality of Life Profile scores in routine clinical practice: an aid to treatment decision-making. AB - PURPOSE: High Renal Quality of Life Profile (RQLP) scores are associated with impaired health-related quality of life; however, the clinical meaning of the scores is difficult for clinicians and healthcare planners to interpret. The aim of this study was to determine clinical significance of RQLP scores which could be used to aid clinical decision-making. METHODS: The anchor-based technique (a method for categorizing numeric scores to ease interpretation) was used to develop a categorization system for the RQLP scores using a global question (GQ). The GQ scores (i.e. no effect to extremely large effect) were mapped against the RQLP scores, and intraclass correlation coefficient (ICC) was used to test their agreement. The RQLP and the GQ were administered to 260 adult patients (males = 165 and females = 95) with chronic renal failure (CRF). RESULTS: The mean RQLP score was 67.2, median = 61, SD = 41.5, and range 0-172. The mean GQ score was 1.74, median = 2, SD = 1.27, and range 0-4. The mean, mode, and median of the GQ scores for each RQLP score were used to devise several sets of categories of RQLP score, and the ICC test of agreement was calculated. The proposed set of RQLP score banding for adoption includes: 0-20 = no effect on patient's life (GQ = 0, n = 35); 21-51 = small effect on patient's life (GQ = 1, n = 66); 52-93 = moderate effect on patient's life (GQ = 2, n = 87); 94-134 = very large effect on patient's life (GQ = 3, n = 54); and 135-172 = extremely large effect on patient's life (GQ = 4, n = 18). The ICC coefficient for the proposed banding system was 0.80. CONCLUSION: The proposed categorization of the RQLP will aid the clinical interpretation of change in RQLP score informing treatment decision making in routine practice. PMID- 26614010 TI - Degree of nephrotoxicity after intermediate- or high-dose cisplatin-based chemoradiotherapy in patients with locally advanced head and neck cancer. AB - BACKGROUND: The purpose of this study was to compare the occurrence of cisplatin induced nephrotoxicity between concomitant chemoradiotherapy with high versus intermediate-dose cisplatin. METHODS: One hundred forty-four patients with locally advanced head and neck or nasopharyngeal cancer (NPC) were included; 40 patients received cisplatin 100 mg/m(2) (high dose) on days 1, 22, and 43, and 104 patients received cisplatin 40 mg/m(2) weekly (intermediate dose) during 6 weeks in combination with radiotherapy. RESULTS: During treatment with intermediate-dose cisplatin, 6.7% developed an increase of >=50% serum creatinine versus 60.0% treated with high-dose cisplatin (p < .05). Nephrotoxicity (all grades) scored by Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0 or CTCAE version 4.03 was 53% and 100% in the high-dose group and 4.8% and 68% in the intermediate-dose group, respectively. CONCLUSION: Significantly less nephrotoxicity occurs during chemoradiotherapy with intermediate-dose cisplatin compared with high-dose cisplatin. The CTCAE version 4.03 seems to be more appropriate in scoring nephrotoxicity than the CTCAE version 3.0. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1575-E1581, 2016. PMID- 26614011 TI - Childhood predictors of persistent ADHD in early adulthood: Results from the first follow-up study in China. AB - It is known that childhood attention-deficit/hyperactivity disorder (ADHD) persists into adulthood. Previous studies have demonstrated that gender, ADHD symptoms, functional impairment severity, medication treatment, IQ, comorbid with oppositional defiant disorder, conduct disorder and follow-up periods were associated with ADHD persistence in longitudinal samples of western population. In this study, we attempted to widely investigate the predictors particularly in a Chinese Han ADHD cohort. 399 children who met DSM-IV ADHD criteria were followed up into early adulthood. Ordinal logistic regression combined with survival analysis were conducted to examine the association of retrospectively reported childhood factors with adult ADHD persistence based on both categorical indicators and quantitative traits. 46.37% of the participants still met ADHD criteria in adulthood. Logistic models and survival analyses indicated that ADHD combined type appeared as a significant risk factor for ADHD persistence while superior IQ played a protective role even after controlling for the other potential confounders. When quantitative traits were applied, a number of hyperactivity/impulsivity symptoms and IQ still made significant contributions. In conclusion, our results indicated the syndromic continuity of ADHD. Further, a number of hyperactivity/impulsivity symptoms were a risk factor while higher IQ was protective for ADHD persistence. PMID- 26614012 TI - Prevalence and associated factors of hypnotics dependence among Japanese outpatients with psychiatric disorders. AB - This study aimed to investigate the prevalence of the dependence for benzodiazepine or their agonist (BZDs) hypnotics, as well as factors associated with this dependence among Japanese psychiatric outpatients. One thousand and forty-three patients in the psychiatric outpatient clinic of Tokyo Medical University Hospital receiving treatment with BZDs hypnotics were analyzed. The subjects answered questionnaires including demographic variables, subjective sleep difficulty assessed by the Pittsburg Sleep Quality Index (PSQI), duration of hypnotics medication, dose of diazepam equivalent BZDs hypnotics, the presence or absence of subjective side effects due to BZDs hypnotics (dizziness, fatigue, daytime sleepiness, amnesia, and headache), and dependency assessed by the Dependency 2-A (D 2-A) score. Subjects with a D 2-A score >=10 were considered as having BZDs hypnotics dependence, and the variables associated with the presence of dependence were examined using logistic regression analyses. Eighty-two out of the 1043 subjects (7.9%) were determined to have BZDs hypnotics dependence. Compared with the non-dependence group, the dependence group had a significantly higher proportion of positive respondents for all the side effects. Multiple logistic regression analyses showed that the dependence was significantly associated with younger age, higher total PSQI score, and higher daily dose of BZDs hypnotics. Younger age, higher total PSQI score, and higher dose may be associated with BZDs hypnotics dependence. The finding that patients with BZDs hypnotics dependence frequently suffered from subjective side effects and had greater sleep difficulty encourages the establishment of alternative treatments for patients with insomnia symptoms refractory to BZDs hypnotics treatment. PMID- 26614013 TI - Role of G-protein coupled receptor kinase 5 gene in cognitive impairment in Parkinson's disease. AB - The objective of our study was to investigate the association of two single nucleotide polymorphisms (SNPs) with genetic risk of dementia. In 212 patients with Parkinson's disease (PD), we investigated two polymorphisms within the G protein coupled receptor kinase 5 (GRK5) gene (rs2420616, rs4752293) to determine a possible risk factor for dementia. We identified two alleles most significantly present in PD patients with dementia: G and T alleles. We also identified risk haplotypes: GC, and AT. We demonstrated that the SNPs and the related haplotypes could play a central role in predisposing PD patients to cognitive impairment. PMID- 26614014 TI - Effects of caffeine intake and smoking on neurocognition in schizophrenia. AB - Although most studies support the beneficial effects of caffeine on neurocognition, its effects have never been assessed in psychiatric patients. In addition, results from studies in smokers are contradictory. Moreover, there are no data available about the neurocognitive effects of caffeine and tobacco together. We explored the concomitant effects of regular caffeine and tobacco intake on neurocognition in 52 schizophrenic patients and 61 healthy controls. Verbal fluency, processing speed, and working, visual and verbal memory were assessed. For each measurement, two tasks with two levels of complexity were administered. Our results showed that caffeine intake had beneficial effects on male schizophrenic patients only in complex tasks requiring deeper cognitive processing (semantic fluency, cognitive speed, working memory, and visual memory). Female patients and controls were unaffected. In contrast, smoking had a negative effect on male, but not on female, schizophrenic patients in semantic fluency. The effects of smoking in controls were inconsistent. In conclusion, our data showed, for the first time, beneficial effects of caffeine intake on neurocognition in male schizophrenic patients. These data suggest that further research of therapeutics based on caffeine is needed, as this could be beneficial for schizophrenic patients. In contrast, smoking appears to be detrimental. PMID- 26614015 TI - Immunoprotective potential of in silico predicted Acinetobacter baumannii outer membrane nuclease, NucAb. AB - Acinetobacter baumannii is an emerging multi-drug resistant pathogen causing significant mortality in hospitalized ICU patients which demands developing new methods for prevention and treatment. A. baumannii 19606 proteome was analysed in silico through the online tool Vaxign for finding potential vaccine candidates. The selected nuclease (NucAb) was predicted to possess all the attributes of a promising vaccine candidate like outer membrane localization, high adhesin probability (0.53), one transmembrane helix only, non-homology to human proteins and presence of B-cell and T-cell epitopes binding with high affinity (percentile rank<=1) to HLA alleles prevalent at high frequency in North Indian populations. nucAb gene was highly prevalent (100%) among the clinical isolates (40/40) and conserved (>98%) among NCBI sequenced Acinetobacter strains. It was cloned in pET28a, purified and its immunoprotective potential was validated in murine pneumonia model. Immunization of BALB/c mice with recombinant NucAb (25MUg) elicited high antibody titre (1-5*10(5)) which reduced bacterial load by 5 log cycles in lungs of mice challenged with optimized lethal dose (10(8)CFU). Lung histopathology revealed marked suppression of inflammation. Pro-inflammatory cytokines (TNF-alpha and IL-6) levels were reduced significantly and anti inflammatory (IL-10) cytokine increased in lungs and serum leading to decreased severity and slow progression of disease. Though active immunization showed low survival rate (20%), passive immunization improved the survival (40%). This is the first study reporting an outer membrane nuclease as a vaccine candidate in Gram negative bacterium, A. baumannii through reverse vaccinology approach. PMID- 26614016 TI - The Influence of Cervical Preflaring on the Amount of Apically Extruded Debris after Root Canal Preparation Using Different Instrumentation Systems. AB - INTRODUCTION: The objective of this study was to evaluate the influence of cervical preflaring on the amount of apically extruded debris after root canal preparation using different instrumentation systems. METHODS: One hundred eighty human maxillary central incisors were selected and randomly divided into 12 groups (n = 15). Root canals were instrumented according to manufacturers' instructions using 2 reciprocating single-file systems (Reciproc [VDW, Munich, Germany] and WaveOne [Dentsply Maillefer, Ballaigues, Switzerland]), 3 full sequence rotary systems (ProTaper Universal [Dentsply Maillefer], ProTaper Next [Dentsply Tulsa Dental, Tulsa, OK], and ProFile [Dentsply Maillefer]), and K files (Dentsply Maillefer) driven by an oscillatory system with and without cervical preflaring. Bidistilled water was used as irrigant. Apically extruded debris was collected in preweighed glass vials using the Myers and Montgomery method. After drying, the mean weight of debris was determined using a microbalance. Kolmogorov-Smirnov and Levene tests followed by the Tukey post hoc test were used for statistical analysis. RESULTS: K-files produced significantly more debris than all of the other systems (P < .05). For all systems, cervical preflaring reduced the amount of apically extruded debris when compared with no cervical preflaring (P < .05). CONCLUSIONS: All of the systems extruded debris, irrespective of the preparation technique used (with or without cervical preflaring). Cervical preflaring was associated with the extrusion of smaller quantities of apical debris. PMID- 26614017 TI - Comparison of the Incidence of Postoperative Pain after Using 2 Reciprocating Systems and a Continuous Rotary System: A Prospective Randomized Clinical Trial. AB - INTRODUCTION: The objective of the present study was to clinically compare the incidence of postoperative pain and the intake of analgesic medication (frequency and quantity) after endodontic treatment of posterior teeth using 2 reciprocating systems and a continuous rotary system. METHODS: In a prospective randomized clinical study, 210 patients with vital teeth indicated for conventional endodontic treatment were treated by 5 specialists according to a pre-established protocol. The teeth were randomly assigned to 1 of 3 groups (n = 70) according to the instrumentation system used: ProTaper Next (Dentsply Tulsa Dental Specialties, Johnson City, TN), WaveOne (Dentsply Tulsa Dental Specialties), or Reciproc (VDW, Munich, Germany). Treatments were performed in a single visit. After the visit, the patients were given a prescription for ibuprofen 400 mg to be taken every 6 hours if they experienced pain. Participants were asked to rate the intensity of the postoperative pain on a visual analog scale according to 4 classes (no pain, mild pain, moderate pain, and severe pain) after 24 hours, 48 hours, 72 hours, and 7 days. Patients were also asked to record the number of prescribed analgesic medication tablets taken at these time points. RESULTS: No statistically significant difference was found among the 3 groups in relation to postoperative pain or analgesic medication intake at the 4 time points assessed (P > .05, Kruskal-Wallis test). CONCLUSIONS: The reciprocating systems and the continuous rotary system were found to be equivalent in regard to the incidence of postoperative pain and intake of analgesic medication at the time points assessed. PMID- 26614018 TI - From sodium intake restriction to nitrate supplementation: Different measures with converging mechanistic pathways? AB - Endothelial nitric oxide synthase is at the centre of endothelial physiology producing nitric oxide which dilates blood vessels, inhibits platelet aggregation and smooth muscle cell proliferation and reduces adhesion molecule production. The laminar shear stress is a common test used usually as the flow mediated dilatation test (FMD) which is sensitive to saturated fat, sodium and potassium although with the latter ion it is possible potassium has direct effects on ion channels in the smooth muscle cell as well as the endothelial cell. High blood pressure and blood cholesterol both reduce nitric oxide production, the latter probably by increasing caveolin-1 which binds nitric oxide synthase. Saturated fat reduces nitric oxide by elevating LDL cholesterol and caveolin-1 while insulin stimulates nitric oxide synthase activity by serine phosphorylation. Polyphenols from tea, coffee and cocoa and virgin olive oil enhance FMD and eNOS activity is essential for this activity. Wine polyphenols produce mixed results and it is not clear at present that they are beneficial. Blackberries and other polyphenol-rich fruit also enhance FMD. Dietary nitrate from beetroot and green leafy vegetables is converted to nitrite by salivary microbes and then to nitric oxide and this acts directly on the smooth muscle to lower blood pressure particularly in a low oxygen environment. Dietary nitrate also improves work efficiency and improves flow mediated dilatation. PMID- 26614019 TI - Detecting left ventricular impaired relaxation in cardiac MRI using moving mesh correspondences. AB - Anatomical cine cardiovascular magnetic resonance (CMR) imaging is widely used to assess the systolic cardiac function because of its high soft tissue contrast. Assessment of diastolic LV function has not regularly been performed due the complex and time consuming procedures. This study presents a semi-automated assessment of the left ventricular (LV) diastolic function using anatomical short axis cine CMR images. The proposed method is based on three main steps: (1) non rigid registration, which yields a sequence of endocardial boundary points over the cardiac cycle based on a user-provided contour on the first frame; (2) LV volume and filling rate computations over the cardiac cycle; and (3) automated detection of the peak values of early (E) and late ventricular (A) filling waves. In 47 patients cine CMR imaging and Doppler-echocardiographic imaging were performed. CMR measurements of peak values of the E and A waves as well as the deceleration time were compared with the corresponding values obtained in Doppler Echocardiography. For the E/A ratio the proposed algorithm for CMR yielded a Cohen's kappa measure of 0.70 and a Gwet's AC1 coefficient of 0.70. CONCLUSION: Semi-automated assessment of the left ventricular (LV) diastolic function using anatomical short-axis cine CMR images provides mitral inflow measurements comparable to Doppler-Echocardiography. PMID- 26614020 TI - Evaluating topic model interpretability from a primary care physician perspective. AB - BACKGROUND AND OBJECTIVE: Probabilistic topic models provide an unsupervised method for analyzing unstructured text. These models discover semantically coherent combinations of words (topics) that could be integrated in a clinical automatic summarization system for primary care physicians performing chart review. However, the human interpretability of topics discovered from clinical reports is unknown. Our objective is to assess the coherence of topics and their ability to represent the contents of clinical reports from a primary care physician's point of view. METHODS: Three latent Dirichlet allocation models (50 topics, 100 topics, and 150 topics) were fit to a large collection of clinical reports. Topics were manually evaluated by primary care physicians and graduate students. Wilcoxon Signed-Rank Tests for Paired Samples were used to evaluate differences between different topic models, while differences in performance between students and primary care physicians (PCPs) were tested using Mann Whitney U tests for each of the tasks. RESULTS: While the 150-topic model produced the best log likelihood, participants were most accurate at identifying words that did not belong in topics learned by the 100-topic model, suggesting that 100 topics provides better relative granularity of discovered semantic themes for the data set used in this study. Models were comparable in their ability to represent the contents of documents. Primary care physicians significantly outperformed students in both tasks. CONCLUSION: This work establishes a baseline of interpretability for topic models trained with clinical reports, and provides insights on the appropriateness of using topic models for informatics applications. Our results indicate that PCPs find discovered topics more coherent and representative of clinical reports relative to students, warranting further research into their use for automatic summarization. PMID- 26614021 TI - Factors influencing accuracy of referral and the likelihood of false positive referral by optometrists in Bradford, United Kingdom. AB - AIMS: Levels of false positive referral to ophthalmology departments can be high. This study aimed to evaluate commonality between false positive referrals in order to find the factors which may influence referral accuracy. METHODS: In 2007/08, a sample of 431 new Ophthalmology referrals from the catchment area of Bradford Royal Infirmary were retrospectively analysed. RESULTS: The proportion of false positive referrals generated by optometrists decreases with experience at a rate of 6.2% per year since registration (p<0.0001). Community services which involved further investigation done by the optometrist before directly referring to the hospital were 2.7 times less likely to refer false positively than other referral formats (p=0.007). Male optometrists were about half as likely to generate a false positive referral than females (OR=0.51, p=0.008) and as multiple/corporate practices in the Bradford area employ less experienced and more female staff, independent practices generate about half the number of false positive referrals (OR=0.52, p=0.005). CONCLUSIONS: Clinician experience has the greatest effect on referral accuracy although there is also a significant effect of gender with women tending to refer more false positives. This may be due to a different approach to patient care and possibly a greater sensitivity to litigation. The improved accuracy of community services (which often refer directly after further investigation) supports further growth of these schemes. PMID- 26614022 TI - Vismodegib, itraconazole and sonidegib as hedgehog pathway inhibitors and their relative competencies in the treatment of basal cell carcinomas. AB - The advent of more sophisticated studies published has clarified the understating of the root cause of various skin cancers or basal cell carcinomas (BCCs). The remarkable role is played by the comprehensive work done on unraveling the mechanism controlling the function of hedgehog (Hh) pathway. The defective Hh pathway has been found as the major cause for BCCs as activated Hh signaling within primary cilia plays a key role in the pathogenesis of BCCs. The BCC accounts for up to 40% of all cancers in the US, with growing incidences in other countries as well. Thus, it is considered to be utmost important by the researchers all over the world developing drugs for the treatment of skin cancers targeting Hh pathway. Fewer drugs like vismodegib, itraconazole and sonidegib have shown promising results inhibiting the awry function of Hh pathway resulting in treatment of different forms of skin cancers. These drugs have shown positive results but failed to prove their potential as expected. Vismodegib and sonidegib are better but fail in case of resistant tumors. This review article describes the mechanism of actions of these Hh pathway inhibitors and provides the rationale for their effectiveness/non-effectiveness for the treatment of metastatic or locally advanced BCC. PMID- 26614023 TI - Optimal assessment of lymph node status in gallbladder cancer. AB - BACKGROUND: Lymph node (LN) metastasis is an important prognostic factor in gallbladder cancer (GBCA). LN status has been adopted as a critical element of staging systems. However, the influence of total lymph node count (TLNC) remains unclear. We determined the optimal minimum TLNC and compared the prognostic significance of LN status indices in GBCA. METHODS: We retrospectively reviewed medical records of 128 patients with T2 or greater GBCA who underwent LN dissection. We analyzed overall survival (OS) and relevance of the number of metastatic LNs, ratio of metastatic LNs to retrieved LNs (LNR), and TLNC in predicting OS. RESULTS: The median OS durations were 120, 35, and 18 months in T2, T3, and T4 GBCA. Five-year OS rates were 73%, 43%, and 0% in T2, T3, and T4 GBCA. LN status did not significantly impact OS in T2 or T4 GBCA. However, all LN indices were significantly correlated with OS in T3 GBCA. Furthermore, multivariate analysis revealed that a metastatic LN count of more than four and a TLNC of more than eight were independent prognostic factors of OS in T3 GBCA. CONCLUSIONS: TLNC and the number of positive LNs may be more important prognostic factors than LNR in T3 GBCA. Additionally, accurate staging may not be achieved in cases of T3 GBCA if the total number of retrieved LNs is less than eight. Thus, to ensure proper staging, we recommend that surgeons harvest more than eight LNs in patients with T3 GBCA. PMID- 26614024 TI - The Prostate Health Index: Its Utility in Prostate Cancer Detection. AB - The Prostate Health Index is a Food and Drug Administration-approved blood test combining total, free, and [-2]pro prostate-specific antigen with greater specificity than free and total prostate-specific antigen for clinically significant prostate cancer. This article reviews the evidence on the performance of the Prostate Health Index to predict prostate biopsy outcome, its incorporation into multivariable risk-assessment tools, and its ability to predict prognosis after conservative management or prostate cancer treatment. PMID- 26614025 TI - New Genetic Markers for Prostate Cancer. AB - Prostate cancer risk stratification based on conventional clinical and pathologic characteristics alone may misclassify a proportion of men at various stages of the disease process. Many gene-based assays have emerged in recent years that seek to improve the predictive accuracy in the prediagnostic and postdiagnostic settings. Following primary treatment failure, gene expression tests may offer improved stratification of individuals at risk for disease progression and inform refinements in the necessity of additional treatment. Unifying limitations among all novel gene-based tests are include clinical validation derived from historical cohorts and a dearth of empirical clinical effectiveness data. PMID- 26614026 TI - Urinary Biomarkers for Prostate Cancer. AB - In light of the overdiagnosis and overtreatment associated with widespread prostate-specific antigen-based screening, controversy persists surrounding the detection and diagnosis of prostate cancer (PCa). Given its anatomic proximity to the prostate, urine has been proposed as a noninvasive substrate for prostatic biomarkers. With greater understanding of the molecular pathways of carcinogenesis and significant technological advances, the breadth of potential biomarkers is substantial. In this review, the authors aim to provide an evidence based assessment of current and emerging urinary biomarkers used in the detection and prognostication of PCa and high-grade PCa, with particular attention on clinically relevant findings. PMID- 26614027 TI - 4-Kallikrein Test and Kallikrein Markers in Prostate Cancer Screening. AB - A preponderance of clinical evidence supports a significant public health benefit for prostate-specific antigen (PSA)-based screening and early detection of prostate cancer in appropriately counseled and selected men. Population-based screening with PSA decreases prostate cancer mortality; however, because of relatively poor specificity, PSA-based screening may also increase the detection of clinically insignificant cancers that would otherwise never require treatment. Use of newer biomarkers that increase the specificity for prostate cancer detection may aid in risk stratification and the appropriate identification of men for prostate biopsy. The authors review the 4-kallikrein panel and 4K probability score. PMID- 26614028 TI - Current Status of Urinary Biomarkers for Detection and Surveillance of Bladder Cancer. AB - The standard of care for detection and surveillance of bladder cancer consists of cytology and cystoscopy, but both examinations suffer from many limitations, including issues related to accuracy, invasiveness, and cost. Several noninvasive methods for detection and surveillance of bladder cancer have been developed and urine-based biomarkers seem the most promising. This nonsystematic review critically analyzes the commercially available biomarkers and highlights some upcoming investigational biomarkers. To date, none of these biomarkers has sufficient validation to serve as a reliable alternative to cystoscopy. PMID- 26614029 TI - Emerging Bladder Cancer Biomarkers and Targets of Therapy. AB - Bladder cancer is a heterogeneous disease characterized by complex networks of molecular alterations and gene expression. This review summarizes some of the recent genomic studies that have further advanced the understanding of the pathways driving bladder cancer, highlighting several important biomarkers and potential targeted therapeutic strategies that are now in clinical trials. In addition, noninvasive techniques to evaluate biomarkers in patients' urine and serum for early detection and surveillance are discussed. PMID- 26614031 TI - Diagnostic Biomarkers in Eosinophilic Renal Neoplasms. AB - Incidental small renal masses identified on imaging are increasingly investigated via needle core or fine needle aspiration biopsies with limited material provided for rendering a diagnosis. Lesions with a prominent eosinophilic or oncocytic cell presence showing morphologic overlap between well-known eosinophilic neoplasms are challenging to diagnose. We review the range of known benign and malignant eosinophilic renal neoplasms and their immunoprofiles to elucidate a useful panel of stains that may assist the pathologist in making an accurate diagnosis. PMID- 26614030 TI - Pharmacogenomics: Biomarker-Directed Therapy for Bladder Cancer. AB - The clinical management of bladder cancer has seen little change over the last three decades and there is pressing need to identify more effective treatments for advanced disease. Low clinical use of neoadjuvant therapies stems from historical limitations in the ability to predict patients most likely to respond to combination chemotherapies. This article focuses on recent molecular and genetic studies, highlighting promising clinical trials and retrospective studies, and discusses emerging trials that use predictive biomarkers to match patients with therapies to which they are most likely to respond. The implementation of predictive genomic and molecular biomarkers will revolutionize urologic oncology and the clinical management of bladder cancer. PMID- 26614032 TI - Prognostic Biomarkers for Response to Vascular Endothelial Growth Factor-Targeted Therapy for Renal Cell Carcinoma. AB - Improved understanding of renal carcinoma disease biology has led to the discovery and approval of five novel therapies targeting specific molecules in the vascular endothelial growth factor (VEGF) biochemical pathway. Biomarker studies attempting to predict response to VEGF-targeted therapies have largely focused on circulating proteins, tissue-based molecules, and germline polymorphisms. Thus far studies have yielded conflicting results that require prospective validation; therefore no definitive biomarker has yet been integrated into the clinician's armamentarium. However, early analyses featuring genomic biomarkers have generated promising findings. This article provides an overview of available biomarkers evaluated with respect to VEGF-targeted therapies in patients with advanced renal cell carcinoma. PMID- 26614033 TI - Prognostic Role of Cell Cycle and Proliferative Markers in Clear Cell Renal Cell Carcinoma. AB - The cell cycle is one of the most important regulatory mechanisms of cellular growth and proliferation. Dysregulation of this pathway is thought to be the first step in carcinogenesis of renal cell carcinoma (RCC), important for tumor invasion and metastases. Multiple different parts and regulators of the cell cycle are detectable via assays like immunohistochemistry and have been studied extensively. This review aims to provide an overview of current data regarding individual cell cycle and proliferative markers and their association with clinicopathologic parameters and their impact on prognosis for patients with RCC. Furthermore, the value of marker combinations is discussed. PMID- 26614034 TI - Current Clinical Applications of Testicular Cancer Biomarkers. AB - Current use of testicular biomarkers for screening, diagnosis, and follow-up is reviewed in the context of potential clinical utility of these tests. This information will be of value to clinicians to determine patient suitability for certain treatments and will also assist in reviewing current literature regarding potential biomarkers that may be used for testicular cancer. PMID- 26614035 TI - MicroRNAs in Testicular Cancer Diagnosis and Prognosis. AB - Testicular cancer processes a unique and clear miRNA expression signature. This differentiates testicular cancer from most other cancer types, which are usually more ambiguous when assigning miRNA patterns. As such, testicular cancer may represent a unique cancer type in which miRNAs find their use as biomarkers for cancer diagnosis and prognosis, with a potential to surpass the current available markers usually with low sensitivity. In this review, we present literature findings on miRNAs associated with testicular cancer, and discuss their potential diagnostic and prognostic values, as well as their potential as indicators of drug response in patients with testicular cancer. PMID- 26614036 TI - The Emerging Role and Promise of Biomarkers in Penile Cancer. AB - Penile cancer is a rare malignancy, which can be a source of devastating psychosexual distress because of its implication on sexual function and self image. Current penile staging relies on invasive techniques and is often inaccurate. The authors review the promising biomarkers currently under investigation and their application to the staging and prognosis of penile cancer. Further development of such biomarkers provides the potential of improved clinical management of this disease. PMID- 26614037 TI - Biomarkers in Urologic Cancer. PMID- 26614038 TI - Biomarkers in Urologic Cancer. PMID- 26614039 TI - Two-level septocolumellar suture technique for correction of septal caudal dislocation. AB - INTRODUCTION: Caudal septal dislocation is a respiratory and cosmetic problem. The correction of caudal septal dislocation is a challenging issue. Although different modalities have been described for the treatment, it is still controversial. OBJECTIVES: This study aims to describe a two-level suture technique which can be used to correct and stabilize the septum in the columellar pocket. METHODS: The caudal septum was fixed to the nasal spine with suturing, and an anterior columellar pocket was formed. Two septocolumellar sutures including superior and inferior were performed to correct the dislocated caudal septum and to increase the stability of caudal septum in the columellar pocket. RESULTS: Anterior rhinoscopy showed no recurrent deviation or dislocation in our patients. CONCLUSION: Our suture technique is an effective and easy-to-use method to correct the caudal septal dislocation. It can also be used to increase the stability of corrected septum by other techniques. A two-level suture technique increases the success of correction and reduces the risk of postoperative septal caudal luxation, stabilizing the superior portion of the caudal septum, in particular. Therefore, it would reduce the rate of redo surgeries. PMID- 26614040 TI - The effect of Foreign Body Aspiration training on the knowledge level of pupils. AB - INTRODUCTION: Educators dealing with 0-6 years old children must be individuals who are willing to take all kind of measures in order to ensure the safety of children in educational institutions and playgrounds, providing protection from diseases, and who are able to apply first aid measures in case of an accident. OBJECTIVE: In this study, we aimed to determine the level of knowledge of all students continuing their education in the department for child development, regarding Foreign Body Aspiration (FBA) and the effect of FBA training on their knowledge level. METHODS: This semi-experimental study was carried out on high school students (n=123) continuing their education in the department for child development in Corum, Turkey. The data was evaluated with appropriate statistical methods, and p<0.05 was determined as statistically significant. RESULTS: Before the training, 80% of the high-school children knew the importance of age factor in cases of FBA, improving to 92% after training. The increase in the number of students who were aware of the importance of age factor was statistically significant (p<0.05). CONCLUSION: As a result of the training, the visual presentation and training on models related to FBA have led to an increase in the knowledge level of the students. PMID- 26614041 TI - Experimental study on the effects of bismuth subgallate on the inflammatory process and angiogenesis of the oral mucosa. AB - INTRODUCTION: Bismuth subgallate is a salt derived from heavy metal. The aim of this study was to evaluate the effect of this salt on some phases of healing. OBJECTIVES: To assess the effect of subgallate on mucosa and to evaluate the association between the use of bismuth subgallate and neogenesis of vessels in oral mucosal wounds. METHODS: This was a prospective and experimental study. This study used sixty rats, which were divided into control and experimental groups. The animals were submitted to a surgical procedure, which caused oral mucosal injury. A saline solution was applied on the wound of the control group, and in the experimental group, a solution of bismuth subgallate was administrated. RESULTS: The experimental group showed greater inflammatory reaction with increasing monomorphic proliferation. There was increased vessel proliferation in the control group. CONCLUSION: Bismuth subgallate had a negative influence on the healing process, delaying the rate of new vessel formation and optimal wound healing. PMID- 26614042 TI - Vestibular migraine: clinical and epidemiological aspects. AB - INTRODUCTION: Vestibular migraine (VM) is one of the most often common diagnoses in neurotology, but only recently has been recognized as a disease. OBJECTIVE: To analyze the clinical and epidemiological profile of patients with VM. METHODS: This was a retrospective, observational, and descriptive study, with analysis of patients' records from an outpatient VM clinic. RESULTS: 94.1% of patients were females and 5.9% were males. The mean age was 46.1 years; 65.6% of patients had had headache for a longer period than dizziness. A correlation was detected between VM symptoms and the menstrual period. 61.53% of patients had auditory symptoms, with tinnitus the most common, although tonal audiometry was normal in 68.51%. Vectoelectronystagmography was normal in 67.34%, 10.20% had hyporeflexia, and 22.44% had vestibular hyperreflexia. Electrophysiological assessment showed no abnormalities in most patients. Fasting plasma glucose and glycemic curve were normal in most patients, while the insulin curve was abnormal in 75%. 82% of individuals with MV showed abnormalities on the metabolism of carbohydrates. CONCLUSION: VM affects predominantly middle-aged women, with migraine headache representing the first symptom, several years before vertigo. Physical, auditory, and vestibular evaluations are usually normal. The most frequent vestibular abnormality was hyperreflexia. Most individuals showed abnormality related to carbohydrate metabolism. PMID- 26614043 TI - Cases requiring increased number of repositioning maneuvers in benign paroxysmal positional vertigo. AB - INTRODUCTION: Benign paroxysmal positional vertigo (BPPV) is a clinical syndrome that is proposed to be caused by dislocated utricular debris into semicircular canals. Although the majority of patients are treated by one or two repositioning maneuvers, some of the patients need repeated maneuvers for relief. OBJECTIVE: The goal of this study was to investigate the factors associated with patients with benign paroxysmal positional vertigo who required multiple repositioning procedures for treatment. METHODS: Data were obtained from the clinical records of 153 patients diagnosed with benign paroxysmal positional vertigo. Patients were treated by repositioning maneuvers. Demographic data and the factors including age, sex, canal type, duration of symptoms, comorbidities and number of repositioning maneuvers for relief were documented for statistical analysis. RESULTS: Age, sex, canal type and the duration of symptoms had no impact on the number of maneuvers. The most common comorbidity was spine problems. Hypertension was the only comorbidity that significantly associated with increased number of maneuvers. CONCLUSION: The presence of hypertension is a risk factor for repeated maneuvers in benign paroxysmal positional vertigo treatment. Physicians should be aware of the increased probability of repeated repositioning maneuvers in these group of patients. The role of comorbidities and vascular factors need to be further clarified in the course of benign paroxysmal positional vertigo. PMID- 26614044 TI - Facial trauma among victims of terrestrial transport accidents. AB - INTRODUCTION: In developing countries, terrestrial transport accidents - TTA, especially those involving automobiles and motorcycles - are a major cause of facial trauma, surpassing urban violence. OBJECTIVE: This cross-sectional census study attempted to determine facial trauma occurrence with terrestrial transport accidents etiology, involving cars, motorcycles, or accidents with pedestrians in the northeastern region of Brazil, and examine victims' socio-demographic characteristics. METHODS: Morbidity data from forensic service reports of victims who sought care from January to December 2012 were analyzed. RESULTS: Altogether, 2379 reports were evaluated, of which 673 were related to terrestrial transport accidents and 103 involved facial trauma. Three previously trained and calibrated researchers collected data using a specific form. Facial trauma occurrence rate was 15.3% (n=103). The most affected age group was 20-29 years (48.3%), and more men than women were affected (2.81:1). Motorcycles were involved in the majority of accidents resulting in facial trauma (66.3%). CONCLUSION: The occurrence of facial trauma in terrestrial transport accident victims tends to affect a greater proportion of young and male subjects, and the most prevalent accidents involve motorcycles. PMID- 26614045 TI - Transeptal suturing - a cost-efficient alternative for nasal packing in septal surgery. AB - INTRODUCTION: Nasal packing is routinely used in septal surgery to prevent postoperative bleeding. OBJECTIVE: To demonstrate the possibility of transeptal suture as a safe and effective way to avoid nasal packing and to improve efficiency. METHODS: This is a prospective, descriptive, inferential cost study comprising 92 patients. Two randomized groups of patients were analyzed, one with nasal packing and the other with transeptal suture. RESULTS: In the group of transeptal suture no patient experienced postoperative bleeding, and a statistically significant reduction of pain and headache was demonstrated. At the same time, we improved efficiency by saving on material costs. CONCLUSIONS: Transeptal suture is an effective and safe alternative to classic nasal packing in septal surgery. Moreover, it improves the efficiency of the intervention by saving costs. PMID- 26614046 TI - Lymphangiogenesis and angiogenesis in oral cavity and lower lip squamous cell carcinoma. AB - INTRODUCTION: Tumors of the lip and oral cavity differ in various aspects; therefore a clarification of the distinctions among these sites may help to better understand the biologic behavior of neoplasms occurring in these locations. OBJECTIVE: Considering that angiogenesis and lymphangiogenesis are two major elements that can influence various aspects of tumor biology, we aimed to compare these factors between squamous cell carcinoma of the lower lip and oral cavity. METHODS: A total of 84 primary squamous cell carcinomas including 45 oral and 39 lower lip tumors were selected and immunohistochemically stained with monoclonal antibody against D2-40 and CD105. Mean microvessel density was assessed in tumoral tissue, while lymphatic vessel density was calculated in both neoplastic tissue and invasion front. Data were statistically analyzed using t test and p-values of <0.05 were considered significant. RESULTS: We found a mean microvessel density+/-standard deviation of 31.94+/-18.9 in oral cavity and 27.54+/-20.8 in lower lip squamous cell carcinomas, with no significant difference (p=0.32). Mean lymphatic vessel density+/-standard deviation was 13.05+/-8.2 and 16.57+/-10.79 in of oral cavity and lower lip neoplastic tissue, respectively. The corresponding values were 9.94+/-5.59 and 12.50+/-7.8 in the invasive front. Significant differences were not observed in either of the lymphatic vessel density variables between the two sites. CONCLUSION: According to our results, it seems that the search for additional factors other than those related to the vasculature should continue, to help clarify the differences in biologic behavior between lower lip and oral cavity squamous cell carcinomas. PMID- 26614047 TI - Partial laryngectomy in glottic cancer: complications and oncological results. AB - INTRODUCTION: Most patients with laryngeal carcinoma present tumors in the glottis that can be treated by different treatment modalities. Some authors consider open partial laryngectomy as obsolete, while others still deem this as a viable and cost-efficient option. OBJECTIVES: To compare the oncological and functional results of a series of patients undergoing partial laryngectomy vs. external radiotherapy for the treatment of glottic cancer. METHODS: Historical cohort study with a series of glottic carcinoma patients undergoing partial laryngectomy or external radiotherapy during a period of ten years. RESULTS: Sixty-two patients with glottic carcinoma were included. Group A comprised those submitted to partial laryngectomy (n=30), and Group B, those who underwent radiotherapy (n=32). They were homogeneous in the comparison of mean age, 56.4 vs. 60.4 years (p=0.12) and distribution in pathological stage (p=0.91). With regard to oncological outcome, there were no differences in distant metastasis rates, or second primary tumor between groups (p=1.0), as well as in disease-free time, laryngeal rescue-free time, and overall five-year survival. Severe complication rates were also similar between groups. CONCLUSION: Open partial laryngectomy had complication rates and oncological results similar to those of radiotherapy for patients with glottic carcinomas and should still be considered among the main available therapeutic options. PMID- 26614048 TI - Speech recognition in individuals with sensorineural hearing loss. AB - INTRODUCTION: Hearing loss can negatively influence the communication performance of individuals, who should be evaluated with suitable material and in situations of listening close to those found in everyday life. OBJECTIVE: To analyze and compare the performance of patients with mild-to-moderate sensorineural hearing loss in speech recognition tests carried out in silence and with noise, according to the variables ear (right and left) and type of stimulus presentation. METHODS: The study included 19 right-handed individuals with mild-to-moderate symmetrical bilateral sensorineural hearing loss, submitted to the speech recognition test with words in different modalities and speech test with white noise and pictures. RESULTS: There was no significant difference between right and left ears in any of the tests. The mean number of correct responses in the speech recognition test with pictures, live voice, and recorded monosyllables was 97.1%, 85.9%, and 76.1%, respectively, whereas after the introduction of noise, the performance decreased to 72.6% accuracy. CONCLUSIONS: The best performances in the Speech Recognition Percentage Index were obtained using monosyllabic stimuli, represented by pictures presented in silence, with no significant differences between the right and left ears. After the introduction of competitive noise, there was a decrease in individuals' performance. PMID- 26614049 TI - Otoacariasis: demographic and clinical outcomes of patients with ticks in the ear canal. AB - INTRODUCTION: Otoacariasis, the attachment of ticks and mites within the ear canal is a common phenomenon especially in rural areas. OBJECTIVE: To determine the clinical and demographic features of cases with detected ticks in the ear canal, which is a common health problem, and identify tick species. METHODS: Data of patients who had otoacariasis were collected. We also investigated all ticks at the Veterinary Department of Kafkas University. RESULTS: We present the data of patients with otoacariasis. All ticks were identified as otobius. Otobius ticks were found not related with any complications. CONCLUSION: It is very important to detect ticks in the ear canal as they act as vector of some diseases. Identifying species of ticks may help clinicians to prevent further complications associated with vector-borne diseases. PMID- 26614050 TI - A Big-Data-based platform of workers' behavior: Observations from the field. AB - Behavior-Based Safety (BBS) has been used in construction to observe, analyze and modify workers' behavior. However, studies have identified that BBS has several limitations, which have hindered its effective implementation. To mitigate the negative impact of BBS, this paper uses a case study approach to develop a Big Data-based platform to classify, collect and store data about workers' unsafe behavior that is derived from a metro construction project. In developing the platform, three processes were undertaken: (1) a behavioral risk knowledge base was established; (2) images reflecting workers' unsafe behavior were collected from intelligent video surveillance and mobile application; and (3) images with semantic information were stored via a Hadoop Distributed File System (HDFS). The platform was implemented during the construction of the metro-system and it is demonstrated that it can effectively analyze semantic information contained in images, automatically extract workers' unsafe behavior and quickly retrieve on HDFS as well. The research presented in this paper can enable construction organizations with the ability to visualize unsafe acts in real-time and further identify patterns of behavior that can jeopardize safety outcomes. PMID- 26614051 TI - Multiplexed High Resolution Melting Assay for Versatile Sample Tracking in a Diagnostic and Research Setting. AB - Modern experimental procedures in molecular genetics, such as next-generation sequencing experiments, require that samples are taken along a whole series of wet- and dry-laboratory steps. It generally is accepted that by increasing the complexity and number of steps in the experimental pipeline, the risk of sample swaps increases. It therefore is recommended to confirm the identity of each individual sample at the end of any pipeline. Here, we present a versatile assay to determine the identity of samples rapidly and efficiently by genotyping 21 single-nucleotide polymorphisms (SNPs) using multiplex high resolution melting. The selected SNPs also are present in whole-exome sequencing data, and comparison of the differentially obtained genotypes allows reliable identification of individual samples. In this assay, we combined primers interrogating two to three SNPs per high resolution melting reaction, enabling the generation of the SNP genotype profile in only eight reactions per sample, limiting the hands-on time and minimizing the amount of reagents. This SNP profiling approach also can be used to track samples in custom next-generation sequencing enrichment panels by including these 21 SNPs in the target region, allowing for the often-required independent validation of sample identity in both clinical and research settings. PMID- 26614052 TI - Molecularly imprinted polymer doped with Hectorite for selective recognition of sinomenine hydrochloride. AB - In this work, a new and facile method was introduced to prepare molecularly imprinted polymers (MIPs) based on nano clay hectorite (Hec) for sinomenine hydrochloride (SM) analysis. Hec was firstly dissolved in distilled water in order to swell adequately, followed by a common precipitation polymerization with SM as the template, methacrylic acid as monomer, ethylene glycol dimethacrylate as a crosslinker and 2,2-azobisisobutyronitrile as an initiator. Hec@SM-MIPs were characterized by Fourier transform infrared spectrometer, transmission electron microscopy, scanning electron microscopy, energy dispersive X-ray spectroscopy and X-ray diffraction. The maximum binding capacity of Hec@SM-MIPs, SM-MIPs and non-imprinted polymers (NIPs) (Hec@NIPs) was 57.4, 16.8 and 11.6 mg/g, respectively. The reason for this result may be that Hec@SM-MIPs have more binding sites and imprinted cavities for template molecule. Equilibrium data were described by the Langmuir and Freundlich isotherm models. The results showed that the Hec@SM-MIPs adsorption data correlated better with the Langmuir equation than the Freundlich equation under the studied concentration range. In vitro drug release experiment, Hec@SM-MIPs have a better ability to control SM release than SM-MIPs. Therefore, Hec@SM-MIPs were successfully applied to extraction of SM and used as the materials for drug delivery system. PMID- 26614053 TI - Metabolomics of meat exudate: Its potential to evaluate beef meat conservation and aging. AB - In this study we analyzed the exudate of beef to evaluate its potential as non invasive sampling for nuclear magnetic resonance (NMR) based metabolomic analysis of meat samples. Exudate, as the natural juice from raw meat, is an easy to obtain matrix that it is usually collected in small amounts in commercial meat packages. Although meat exudate could provide complete and homogeneous metabolic information about the whole meat piece, this sample has been poorly studied. Exudates from 48 beef samples of different breeds, cattle and storage times have been studied by (1)H NMR spectroscopy. The liquid exudate spectra were compared with those obtained by High Resolution Magic Angle Spinning (HRMAS) of the original meat pieces. The close correlation found between both spectra (>95% of coincident peaks in both registers; Spearman correlation coefficient = 0.945) lead us to propose the exudate as an excellent alternative analytical matrix with a view to apply meat metabolomics. 60 metabolites could be identified through the analysis of mono and bidimensional exudate spectra, 23 of them for the first time in NMR meat studies. The application of chemometric tools to analyze exudate dataset has revealed significant metabolite variations associated with meat aging. Hence, NMR based metabolomics have made it possible both to classify meat samples according to their storage time through Principal Component Analysis (PCA), and to predict that storage time through Partial Least Squares (PLS) regression. PMID- 26614054 TI - Analytical methods for determination of mycotoxins: An update (2009-2014). AB - Mycotoxins are a problematic and toxic group of small organic molecules that are produced as secondary metabolites by several fungal species that colonise crops. They lead to contamination at both the field and postharvest stages of food production with a considerable range of foodstuffs affected, from coffee and cereals, to dried fruit and spices. With wide ranging structural diversity of mycotoxins, severe toxic effects caused by these molecules and their high chemical stability the requirement for robust and effective detection methods is clear. This paper builds on our previous review and summarises the most recent advances in this field, in the years 2009-2014 inclusive. This review summarises traditional methods such as chromatographic and immunochemical techniques, as well as newer approaches such as biosensors, and optical techniques which are becoming more prevalent. A section on sampling and sample treatment has been prepared to highlight the importance of this step in the analytical methods. We close with a look at emerging technologies that will bring effective and rapid analysis out of the laboratory and into the field. PMID- 26614055 TI - Multivariate optimization of photochemical vapor generation for direct determination of arsenic in seawater by inductively coupled plasma mass spectrometry. AB - Photochemical vapor generation (PVG) sample introduction coupled to inductively coupled plasma mass spectrometry (ICPMS) is described for the determination of As in seawater. A Plackett-Burman design (PBD) and central composite design (CCD) were employed to evaluate the significance of experimental variables relevant to the optimization of PVG-ICPMS detection. The impact of the saline matrix on the suppression of analyte signal was eliminated by use of a mixture of 20% (v/v) formic and 20% acetic acid (v/v) as the photochemical reductants. Optimized conditions yielded equivalent PVG generation efficiencies for As(III), As(V), monomethylarsonic acids (MMAs) and dimethylarsinic acids (DMAs), permitting direct and rapid determination of total arsenic in seawater without any other sample pre-treatment. Quantitation was accomplished using one point gravimetric standard addition along with a spike of (82)Se internal standard to compensate for signal drift and fluctuation during analysis. The resulting method detection limit of 3 pg g(-1) (3sigma) provided a 15-fold improvement over that obtained using direct solution nebulization, and is comparable to that for conventional chemical hydride generation (HG)-ICPMS. Accuracy was demonstrated by analysis of two Certified Reference Materials (NASS-6 and CASS-5 seawater) with satisfying results characterized by precisions of 3.5% and 3.2% RSD for CASS-5 and NASS-6, respectively. PMID- 26614056 TI - Sensitive and selective determination of gallic acid in green tea samples based on an electrochemical platform of poly(melamine) film. AB - In this work, an electrochemical sensor coupled with an effective flow-injection amperometry (FIA) system is developed, targeting the determination of gallic acid (GA) in a mild neutral condition, in contrast to the existing electrochemical methods. The sensor is based on a thin electroactive poly(melamine) film immobilized on a pre-anodized screen-printed carbon electrode (SPCE*/PME). The characteristics of the sensing surface are well-characterized by field emission scanning electron microscopy (FE-SEM), X-ray photoelectron spectroscopy (XPS) and surface water contact angle experiments. The proposed assay exhibits a wide linear response to GA in both pH 3 and pH 7.0 phosphate buffer solutions (PBS) under the optimized flow-injection amperometry. The detection limit (S/N = 3) is 0.076 MUM and 0.21 MUM in the pH 3 and pH 7 solutions, respectively. A relative standard deviation (RSD) of 3.9% is obtained for 57 successive measurements of 50 MUM GA in pH 7 solutions. Interference studies indicate that some inorganic salts, catechol, caffeine and ascorbic acid do not interfere with the GA assay. The interference effects from some orthodiphenolic compounds are also investigated. The proposed method and a conventional Folin-Ciocalteu method are applied to detect GA in green tea samples using the standard addition method, and satisfactory spiked recoveries are obtained. PMID- 26614057 TI - pH-controlled quaternary ammonium herbicides capture/release by carboxymethyl beta-cyclodextrin functionalized magnetic adsorbents: Mechanisms and application. AB - In our work, the pH-controlled magnetic solid phase extraction for the determination of paraquat and diquat was introduced firstly. Furthermore, to clarify the mechanism of carboxymethyl-beta-cyclodextrin functionalized magnetic adsorbents, we studied the pH-responsive supramolecular interaction between carboxymethyl-beta-cyclodextrin (CM-beta-CD) and paraquat/diquat by ultraviolet visible (UV-vis) spectroscopy and nuclear magnetic resonance (NMR) experiment, and the energy-minimized structures were also obtained. Then, the functional group CM-beta-CD was modified on the surface of magnetic materials to synthesize the adsorbent. The Fourier transform infrared spectrum (FT-IR) results proved the successful modification of CM-beta-CD. Thus, this absorbent was applied for the determination of paraquat and diquat in water. Under the optimal condition, limits of detection (LODs) of paraquat and diquat were 0.8 MUg L(-1) and 0.9 MUg L(-1), relative standard deviations (RSD) and recoveries varied 0.7-4.6% and 86.5 106.6%, respectively. Good recoveries (70.2-100.0%) and low RSD (1.7-9.6%) were achieved in analyzing spiked water samples. Furthermore, with the capillary electrophoresis (CE) as the analyser, the whole analytical process did not need the attendance of organic solvents. PMID- 26614058 TI - A disposable laser print-cut-laminate polyester microchip for multiplexed PCR via infra-red-mediated thermal control. AB - Infrared (IR)-mediated thermal cycling system, a method proven to be a effective for sub-MUL scale polymerase chain reaction (PCR) on microchips, has been integrated with DNA extraction and separation on a glass microchip in a fully integrated micro Total Analysis System by Easley et al., in 2006. IR-PCR has been demonstrated on both glass and PMMA microdevices where the fabrication (bonding) is not trivial. Polyester-toner (PeT) microfluidic devices have significant potential as cost-effective, disposable microdevices as a result of the ease of fabrication (~$0.25 USD and <10 min per device) and availability of commercial substrates. For the first time, we demonstrate here the thermal cycling in PeT microchips on the IR-PCR system. Undesirable IR absorption by the black-toner bonding layer was eliminated with a spatial filter in the form of an aluminum foil mask. The solution heating rate for a black PeT microchip using a tungsten lamp was 10.1 +/- 0.7 degrees C s(-1) with a cooling rate of roughly -12 +/- 0.9 degrees C s(-1) assisted by forced air cooling. Dynamic surface passivation strategies allowed the successful amplification of a 520 bp fragment of the lambda-phage genome (in 11 min) and a 1500 bp region of Azospirillum brasilense. Using a centrosymmetric chamber configuration in a multichamber PeT microchip, homogenous temperature distribution over all chambers was achieved with inter chamber temperature differences at annealing, extension and denaturing steps of less than +/-2 degrees C. The effectiveness of the multichamber system was demonstrated with the simultaneous amplification of a 390 bp amplicon of human beta-globin gene in five PeT PCR microchambers. The relative PCR amplification efficiency with a human beta-globin DNA fragment ranged from 70% to 90%, in comparison to conventional thermal cyclers, with an inter-chamber standard deviation of ~10%. Development of PeT microchips for IR-PCR has the potential to provide rapid, low-volume amplification while also integrating PCR with extraction upstream and separation/detection downstream. PMID- 26614059 TI - Determination of histamine in canned tuna by molecularly imprinted polymers surface enhanced Raman spectroscopy. AB - We introduce a rapid, cost effective and reliable approach to determine histamine level in canned tuna. Molecularly imprinted polymers (MIPs) were synthesized as artificial antibodies towards histamine by utilizing the interaction between histamine and a functional monomer (methacrylic acid) to impress specific binding sites on polymer particles after polymerization. Polyvinyl chloride (PVC) was used to immobilize the MIPs, yielding a MIPs-PVC film that functioned as a recognition element to specifically separate histamine from tuna extract. A gold colloid solution served both as an eluting solvent to extract histamine from MIPs PVC film and furnish a substrate for surface enhanced Raman spectroscopy (SERS) detection of histamine signals. Principal component analysis together with a partial least square regression (PLSR) model (R(2) = 0.947, RMSECV = 3.526) verified the reliability of MIPs-PVC-SERS approach for the detection and spectral analysis of histamine. Linear regression models were also constructed to relate the intensity of different histamine SERS bands with the corresponding spiking levels. One such model (using a band at 1576 cm(-1)) performed slightly better in predicting histamine content in tuna than the PLSR model. We conclude that our new MIPs-PVC-SERS approach can rapidly and reliably determine histamine at levels from 3 to 90 ppm in canned tuna meat. PMID- 26614060 TI - Old, white, rich patients find it easier to get GP appointments than young, poor, black patients. PMID- 26614061 TI - Poor working conditions in England pose threat to health, says expert. PMID- 26614062 TI - Ultrasonographic and clinicopathological features of pyloroduodenal adenomatous polyps in cats. AB - Objectives The aim of the study was to report the ultrasonographic and clinicopathological findings in cats with confirmed pyloroduodenal adenomatous polyps. Methods Clinicopathological data, ultrasonographic and histopathological findings were collected retrospectively from medical records. Results Pyloroduodenal polyps appeared as small moderately echogenic and homogeneous nodules filling most of the proximal duodenal or pyloroduodenal lumen. The most common presenting signs in this study included acute vomiting and anorexia in 4/6 cats and lethargy in 3/6 cats. Two cats presented with severe anemia, suggestive of active bleeding. One cat presented with increased bilirubin without anemia, suggestive of impaired bile flow. Five cats survived surgical removal of the polyp and were free of clinical signs 817 days after the procedure. Conclusions and relevance Pyloroduodenal polyps have subtle ultrasonographic changes that can easily be mistaken for ingesta. They are characterized by a discrete small (up to 1.5 cm in diameter) homogeneous echogenic nodule filling the pyloroduodenal lumen. Pyloroduodenal polyps are benign lesions but can cause severe clinical signs including gastrointestinal bleeding or biliary obstruction. The prognosis is excellent with surgical removal. PMID- 26614064 TI - Overview of Microarray Technology. AB - Microarray technology, with its high-throughput advantage, has been applied to analyze various biomaterials, such as nucleic acids, proteins, glycans, peptides, and cells. PMID- 26614065 TI - Surface Functionalization for Immobilization of Probes on Microarrays. AB - The microarray technology has been a tremendous advance in molecular-based testing methods for biochemical and biomedical applications. As a result, the immobilization techniques and grafting chemistries of biochemical molecules have experienced great progress. The particularities of the grafting techniques adapted to the microarray development will be presented here. PMID- 26614063 TI - Identification of low abundance microbiome in clinical samples using whole genome sequencing. AB - Identifying the microbiome composition from primary tissues directly affords an opportunity to study the causative relationships between the host microbiome and disease. However, this is challenging due the low abundance of microbial DNA relative to the host. We present a systematic evaluation of microbiome profiling directly from endoscopic biopsies by whole genome sequencing. We compared our methods with other approaches on datasets with previously identified microbial composition. We applied this approach to identify the microbiome from 27 stomach biopsies, and validated the presence of Helicobacter pylori by quantitative PCR. Finally, we profiled the microbial composition in The Cancer Genome Atlas gastric adenocarcinoma cohort. PMID- 26614066 TI - The "Clickable" Method for Oligonucleotide Immobilization Onto Azide Functionalized Microarrays. AB - The DNA microarray technique was supposed to help identifying and analyzing the expression level of tens of thousands of genes in the whole genome. But there is a serious problem concerning fabrication of the microarrays by chemical synthesis, such as specific and efficient linking of probes to a solid support. Therefore, we reckon that applying "click" chemistry to covalently anchor oligonucleotides on chemically modified supports may help construct microarrays in applications such as gene identification. Silanization of the glass support with organofunctional silane makes it possible to link azide groups on glass surface and the nucleic acid probe that is equipped with a pentynyl group. This is followed by direct spotting of the nucleic acid on the azide-modified glass support in the presence of copper ions, and this is a frequently applied method of "click" chemistry. PMID- 26614067 TI - Microarray Developed on Plastic Substrates. AB - There is a huge potential interest to use synthetic polymers as versatile solid supports for analytical microarraying. Chemical modification of polycarbonate (PC) for covalent immobilization of probes, micro-printing of protein or nucleic acid probes, development of indirect immunoassay, and development of hybridization protocols are described and discussed. PMID- 26614068 TI - Detection and Quantification of MicroRNAs by Ligase-Assisted Sandwich Hybridization on a Microarray. AB - Extracellular microRNAs (miRNAs) in body fluids have been identified as promising biomarkers for different human diseases. The high-throughput, multiplexed detection and quantification of these miRNAs are highly beneficial for the rapid and accurate diagnosis of diseases. Here, we developed a simple and convenient microarray-based technique, named ligase-assisted sandwich hybridization (LASH), for the detection and quantification of miRNAs. The LASH assay involves the hybridization of capture and detection probe pairs with the target miRNA to form a double-stranded structure which is then nick-sealed by T4 DNA ligase. Using this assay, we successfully demonstrated the multiplexed detection and quantification of different miRNAs in total RNA samples derived from blood obtained within 3 h. Here, we provide a detailed protocol for the LASH assay to detect a specific miRNA, as a model for the detection and quantification of extracellular miRNAs. PMID- 26614069 TI - Probe Design Strategies for Oligonucleotide Microarrays. AB - Oligonucleotide microarrays have been widely used for gene detection and/or quantification of gene expression in various samples ranging from a single organism to a complex microbial assemblage. The success of a microarray experiment, however, strongly relies on the quality of designed probes. Consequently, probe design is of critical importance and therefore multiple parameters should be considered for each probe in order to ensure high specificity, sensitivity, and uniformity as well as potentially quantitative power. Moreover, to assess the complete gene repertoire of complex biological samples such as those studied in the field of microbial ecology, exploratory probe design strategies must be also implemented to target not-yet-described sequences. To design such probes, two algorithms, KASpOD and HiSpOD, have been developed and they are available via two user-friendly web services. Here, we describe the use of this software necessary for the design of highly effective probes especially in the context of microbial oligonucleotide microarrays by taking into account all the crucial parameters. PMID- 26614070 TI - Analyzing Illumina Gene Expression Microarray Data Obtained From Human Whole Blood Cell and Blood Monocyte Samples. AB - Microarray profiling of gene expression is widely applied to studies in molecular biology and functional genomics. Experimental and technical variations make not only the statistical analysis of single studies but also meta-analyses of different studies very challenging. Here, we describe the analytical steps required to substantially reduce the variations of gene expression data without affecting true effect sizes. A software pipeline has been established using gene expression data from a total of 3358 whole blood cell and blood monocyte samples, all from three German population-based cohorts, measured on the Illumina HumanHT 12 v3 BeadChip array. In summary, adjustment for a few selected technical factors greatly improved reliability of gene expression analyses. Such adjustments are particularly required for meta-analyses of different studies. PMID- 26614071 TI - Microarray Technology and Its Applications for Detecting Plasma microRNA Biomarkers in Digestive Tract Cancers. AB - Many cancers are known to be regulated by microRNAs (miRNAs), and the relationships between tissue miRNA expression levels and the amounts of miRNA circulating in the plasma (or plasma miRNA) have been examined in many types of cancers, including digestive tract cancers. The role of plasma miRNAs has yet to be elucidated in detail; therefore a comprehensive analysis of plasma miRNAs using microarrays should assist in establishing the utility of liquid biopsy or companion diagnosis. We here described the 3D-Gene((r)) miRNA microarray (TORAY) currently used in our laboratory and introduced a trial application in digestive tract cancer diagnosis. PMID- 26614072 TI - Application of DNA Microarray to Clinical Diagnostics. AB - Microarray-based technology to conduct array comparative genomic hybridization (aCGH) has made a significant impact on the diagnosis of human genetic diseases. Such diagnoses, previously undetectable by traditional G-banding chromosome analysis, are now achieved by identifying genomic copy number variants (CNVs) using the microarray. Not only can hundreds of well-characterized genetic syndromes be detected in a single assay, but new genomic disorders and disease causing genes can also be discovered through the utilization of aCGH technology. Although other platforms such as single nucleotide polymorphism (SNP) arrays can be used for detecting CNVs, in this chapter we focus on describing the methods for performing aCGH using Agilent oligonucleotide arrays for both prenatal (e.g., amniotic fluid and chorionic villus sample) and postnatal samples (e.g., blood). PMID- 26614073 TI - High-Throughput DNA Array for SNP Detection of KRAS Gene Using a Centrifugal Microfluidic Device. AB - Here, we describe detection of single nucleotide polymorphism (SNP) in genomic DNA samples using a NanoBioArray (NBA) chip. Fast DNA hybridization is achieved in the chip when target DNAs are introduced to the surface-arrayed probes using centrifugal force. Gold nanoparticles (AuNPs) are used to assist SNP detection at room temperature. The parallel setting of sample introduction in the spiral channels of the NBA chip enables multiple analyses on many samples, resulting in a technique appropriate for high-throughput SNP detection. The experimental procedure, including chip fabrication, probe array printing, DNA amplification, hybridization, signal detection, and data analysis, is described in detail. PMID- 26614074 TI - Single Nucleotide Polymorphisms as Genomic Markers for High-Throughput Pharmacogenomic Studies. AB - Genetic variations in patients have strong impact on their drug therapies and responses because the variations may contribute to the efficacy and/or produce undesirable side effects for any given drug. The Drug Metabolizing Enzymes and Transporters (DMET) assay is a high-throughput technology by Affymetrix that is able to simultaneously genotype variants in multiple genes involved in absorption, distribution, metabolism, and excretion of drugs for subsequent clinical applications, i.e., the assay allows for a precise genetic map that can guide therapeutic interventions and avoid side effects. PMID- 26614075 TI - DNA Microarray-Based Diagnostics. AB - The DNA microarray technology is currently a useful biomedical tool which has been developed for a variety of diagnostic applications. However, the development pathway has not been smooth and the technology has faced some challenges. The reliability of the microarray data and also the clinical utility of the results in the early days were criticized. These criticisms added to the severe competition from other techniques, such as next-generation sequencing (NGS), impacting the growth of microarray-based tests in the molecular diagnostic market.Thanks to the advances in the underlying technologies as well as the tremendous effort offered by the research community and commercial vendors, these challenges have mostly been addressed. Nowadays, the microarray platform has achieved sufficient standardization and method validation as well as efficient probe printing, liquid handling and signal visualization. Integration of various steps of the microarray assay into a harmonized and miniaturized handheld lab-on a-chip (LOC) device has been a goal for the microarray community. In this respect, notable progress has been achieved in coupling the DNA microarray with the liquid manipulation microsystem as well as the supporting subsystem that will generate the stand-alone LOC device.In this chapter, we discuss the major challenges that microarray technology has faced in its almost two decades of development and also describe the solutions to overcome the challenges. In addition, we review the advancements of the technology, especially the progress toward developing the LOC devices for DNA diagnostic applications. PMID- 26614076 TI - High-Throughput Screening of Substrate Specificity for Protein Tyrosine Phosphatases (PTPs) on Phosphopeptide Microarrays. AB - Phosphatases are a family of enzymes responsible for the dephosphorylation of biomolecules. Phosphatases play essential roles in cell cycle regulation, signal transduction, and cellular communication. In recent years, one type of phosphatases, protein tyrosine phosphatases (PTPs), emerges as important therapeutic targets for complex and devastating diseases. Nevertheless, the physiological roles, substrate specificity, and downstream targets for PTPs remain largely unknown. To demonstrate how microarrays can be applied to characterizing PTPs, we describe here a phosphopeptide microarray strategy for activity-based high-throughput screening of PTPs substrate specificity. This is followed by a kinetic microarray assay and microplate assay to determine the rate constants of dephosphorylation by PTPs. This microarray strategy has been successfully applied to identifying several potent and selective substrates against different PTPs. These substrates could be used to design potent and selective PTPs inhibitors in the future. PMID- 26614077 TI - Nanotechnology in the Fabrication of Protein Microarrays. AB - Protein biochips are the heart of many medical and bioanalytical applications. Increasing interest of protein biochip fabrication has been focused on surface activation and subsequent functionalization strategies for the immobilization of these molecules. PMID- 26614078 TI - Epitope Mapping Using Peptide Microarray in Autoantibody Profiling. AB - The use of peptide microarrays for epitope mapping of autoantibodies greatly facilitates the early diagnosis of allergic, cytotoxin-associated diseases and especially inflammatory diseases. A common approach to create the microarrays utilizes nitrocellulose-coated glass slides for peptide probe binding, which is based on surface adsorption. Advantages of this method include excellent peptide binding capacity and long-term stability. To ensure equal accessibility to all antibodies on the peptide microarray during epitope mapping, all probes are immobilized in a random manner, thus avoiding concentration-dependent effects on signal intensity.In this chapter, we provide a step-by-step protocol on how to construct the peptide microarrays and perform epitope mapping of autoantibodies using them. Finally we present a comparative approach for the evaluation of the data. PMID- 26614079 TI - Preparation of Glycan Arrays Using Pyridylaminated Glycans. AB - We describe the method to prepare neoglycoproteins from the conjugation of bovine serum albumin and pyridylaminated glycans. Large quantities of glycans (>1 mg) can be pyridylaminated and then converted to their 1-amino-1-deoxy derivatives by reaction with hydrogen followed by hydrazine. These pyridylaminated glycans can then be conjugated to bovine serum albumin via esterification with N-( m maleimidobenzoyloxy)succinimide to form a neoglycoprotein, e.g., glycosylated bovine serum albumin. As a demonstration, we prepared High-mannose bovine serum albumin, which was immobilized on an activated glass slide. Then, we showed that the neoglycoprotein bind to Cy3-labeled Lens culinaris agglutinin, a mannose specific plant lectin, as detected using an evanescent-field-activated fluorescence scanner system. PMID- 26614081 TI - Parallel Syntheses of Peptides on Teflon-Patterned Paper Arrays (SyntArrays). AB - Screening of peptides to find the ligands that bind to specific targets is an important step in drug discovery. These high-throughput screens require large number of structural variants of peptides to be synthesized and tested. This chapter describes the generation of arrays of peptides on Teflon-patterned sheets of paper. First, the protocol describes the patterning of paper with a Teflon solution to produce arrays with solvophobic barriers that are able to confine organic solvents. Next, we describe the parallel syntheses of 96 peptides on Teflon-patterned arrays using the SPOT synthesis method. PMID- 26614080 TI - Competitive Immunoassays Using Antigen Microarrays. AB - In this work, a non-fouling antigen competitive immunoassay microarray based on the polymer brush is reported to detect multiple mycotoxins. The detection is achieved by utilizing highly specific monoclonal antibodies produced in our laboratory. The polymer brush, poly[oligo(ethylene glycol) methacrylate-co glycidyl methacrylate] (POEGMA-co-GMA), is synthesized via surface-initiated atom transfer radical polymerization (SI-ATRP) on standard glass slides. In the polymer brush, the epoxy groups of glycidyl methacrylate (GMA) residues provide covalent binding sites for spotted antigens. Moreover, the abundant poly(ethylene glycol) (PEG) side chains in the brush are able to ultimately suppress the nonspecific protein adsorption in solution (non-fouling). The polymer brush shows a high and uniform protein loading, along with a high resistance to nonspecific protein absorption that are both important to achieve a highly sensitive immunoassay. As a demonstration of a multiplex assay, aflatoxin B1 (AFB1), ochratoxin A (OTA), and zearalenone (ZEN) are selected as antigen targets for simultaneous detections using the microarray. PMID- 26614082 TI - Cell Microarrays for Biomedical Applications. AB - In this chapter the state of the art of live cell microarrays for high-throughput biological assays are reviewed. The fabrication of novel microarrays with respect to material science and cell patterning methods is included. A main focus of the chapter is on various aspects of the application of cell microarrays by providing selected examples in research fields such as biomaterials, stem cell biology and neuroscience. Additionally, the importance of microfluidic technologies for high throughput on-chip live-cell microarrays is highlighted for single-cell and multi cell assays as well as for 3D tissue constructs. PMID- 26614083 TI - Inter- and intra-observer agreement of the AO classification for operatively treated distal radius fractures. AB - The reproducibility of the AO classification for distal radius fractures remains a topic of debate. Previous studies showed variable reproducibility results. Important treatment decisions depend on correct classification, especially in comminuted, intra-articular fractures. Therefore, reliable reproducibility results need to be undisputedly determined. Hence, the study objective was to assess inter- and intra-observer agreement of the AO classification for operatively treated distal radius fractures. A database of 54 radiographs of all AO types (A, B and C) and groups (A2-3, B1-3, and C1-3) of distal radius fractures was assessed in twofold. Likewise, a subset of 152 radiographs of solely C-type groups (C1-3) was assessed. All fractures were classified by six observers with different experience levels: three consultant trauma surgeons, one sixth-year trauma surgery resident, a consultant trauma radiologist, and an intern with limited experienced. The inter-observer agreement of both main types and groups was moderate (kappa = 0.49 resp. kappa = 0.48) in combination with a good intra-observer agreement (kappa = 0.68 resp. kappa = 0.70). The inter observer agreement of the subset C-type fractures group was fair (kappa = 0.27) with moderate intra-observer agreement (kappa = 0.43). According to these results, the reproducibility of the AO classification of main types and groups of distal radius fractures based on conventional radiographs is insufficient (kappa < 0.50), especially at group level of C-type fractures. PMID- 26614084 TI - Bimodal Virtual Reality Stroop for Assessing Distractor Inhibition in Autism Spectrum Disorders. AB - Executive functioning deficits found in college students with ASD may have debilitating effects on their everyday activities. Although laboratory studies tend to report unimpaired inhibition in autism, studies of resistance to distractor inhibition reveal difficulties. In two studies, we compared a Virtual Classroom task with paper-and-pencil and computerized Stroop modalities in typically developing individuals and individuals with ASD. While significant differences were not observed between ASD and neurotypical groups on the paper and-pencil and computerized task, individuals with ASD performed significantly worse on the virtual task with distractors. Findings suggest the potential of the Virtual Classroom Bimodal Stroop task to distinguish between prepotent response inhibition (non-distraction condition) and resistance to distractor inhibition (distraction condition) in adults with high functioning autism. PMID- 26614085 TI - A Meta-analysis of the Wisconsin Card Sort Task in Autism. AB - We conducted a meta-analysis of 31 studies, spanning 30 years, utilizing the WCST in participants with autism. We calculated Cohen's d effect sizes for four measures of performance: sets completed, perseveration, failure-to-maintain-set, and non-perseverative errors. The average weighted effect size ranged from 0.30 to 0.74 for each measure, all statistically greater than 0. No evidence was found for reduced impairment when WCST is administered by computer. Age and PIQ predicted perseverative error rates, while VIQ predicted non-perseverative error rates, and both perseverative and non-perseverative error rates in turn predicted number of sets completed. No correlates of failure-to-maintain set errors were found; further research is warranted on this aspect of WCST performance in autism. PMID- 26614087 TI - Giant inguinoscrotal hernia containing intestinal segments and urinary bladder successfully repaired by simple hernioplasty technique: a case report. AB - INTRODUCTION: Giant inguinoscrotal hernias are extremely rare nowadays, but they may still be encountered after years or even decades of neglect. Such hernias containing both bowel loops and urinary bladder have not been reported in the medical literature to date, to the best of our knowledge. CASE PRESENTATION: We report a case of a 65-year-old Moroccan man who presented with giant right-sided and long-standing inguinoscrotal hernia with compromised quality of life due to walking difficulties and sexual discomfort. Computed tomography revealed a voluminous hernia sac containing small and large bowel loops, greater omentum, and urinary bladder. Surgical repair was done through the classical inguinal incision using the Lichtenstein tension-free hernioplasty technique. No debulking or abdominal enlargement procedure had to be performed, apart from a partial omentectomy. CONCLUSIONS: Giant inguinoscrotal hernia containing intestinal segments and urinary bladder is a challenging surgical disease. A Lichtenstein tension-free technique seems to be the best surgical procedure for both the patient and the operating surgeon. It should be used whenever possible in such cases. PMID- 26614086 TI - Stratification of yeast cells during chronological aging by size points to the role of trehalose in cell vitality. AB - Cells of the budding yeast Saccharomyces cerevisiae undergo a process akin to differentiation during prolonged culture without medium replenishment. Various methods have been used to separate and determine the potential role and fate of the different cell species. We have stratified chronologically-aged yeast cultures into cells of different sizes, using centrifugal elutriation, and characterized these subpopulations physiologically. We distinguish two extreme cell types, very small (XS) and very large (L) cells. L cells display higher viability based on two separate criteria. They respire much more actively, but produce lower levels of reactive oxygen species (ROS). L cells are capable of dividing, albeit slowly, giving rise to XS cells which do not divide. L cells are more resistant to osmotic stress and they have higher trehalose content, a storage carbohydrate often connected to stress resistance. Depletion of trehalose by deletion of TPS2 does not affect the vital characteristics of L cells, but it improves some of these characteristics in XS cells. Therefore, we propose that the response of L and XS cells to the trehalose produced in the former differs in a way that lowers the vitality of the latter. We compare our XS- and L-fraction cell characteristics with those of cells isolated from stationary cultures by others based on density. This comparison suggests that the cells have some similarities but also differences that may prove useful in addressing whether it is the segregation or the response to trehalose that may play the predominant role in cell division from stationary culture. PMID- 26614088 TI - Incidence and severity of adverse events associated with re-irradiation for spine or pelvic bone metastases. AB - BACKGROUND: Adverse events associated with re-irradiation for painful bone metastases have not been adequately evaluated. The purpose of this study was to clarify the incidence and severity of adverse events associated with re irradiation for spine or pelvic bone metastases. METHODS: Data for 61 consecutive patients who required re-irradiation for spine or pelvic bone metastases between April 2009 and March 2013 were retrospectively evaluated in this study. The adverse events, biologically effective dose (BED), and the responses to pain and/or symptoms caused by cord compression were evaluated. RESULTS: Of the 61 patients, 52 were included in the study and their data were analyzed. The site of re-irradiation was the spine in 35 patients (67 %), and the pelvic bone in the remaining 17 patients (33 %). The median follow-up period was 170 days (range 5 1,644 days) for all eligible patients. The median interval from initial radiation therapy to re-irradiation was 161 days (range 26-2,909 days). The median cumulative BED from the initial radiation and re-irradiation was 115 Gy (range 80 155 Gy2). The acute adverse events were all below grade 2 in severity, except for two patients who showed grade 3 pain flare within a few days after the start of re-irradiation. No late adverse events were observed in this study that were grade 3 or of worse severity. CONCLUSIONS: The incidence and severity of adverse events after re-irradiation for spine or pelvic bone metastases were within acceptable limits in this study. PMID- 26614089 TI - Human papillomavirus type-specific persistence and reappearance after successful conization in patients with cervical intraepithelial neoplasia. AB - OBJECTIVE: To assess the relationship between pre- and postoperative high-risk human papillomavirus (hrHPV) genotypes and hrHPV type-specific persistence and reappearance of abnormal cytology after successful conization. METHODS: A retrospective analysis was performed of 211 patients who were undergoing conization after hrHPV genotype testing at Tottori University Hospital between July 2009 and June 2013. Of the 211 women, 129 underwent pre- and postoperative hrHPV genotype testing and were diagnosed with cervical intraepithelial neoplasia (CIN) grades 1-3 with negative margins. RESULTS: The postoperative pathological diagnosis was CIN 1 in 8 patients, CIN 2 in 12, CIN 3 in 108 and adenocarcinoma in situ in 1 patient. Before conization, the most frequent hrHPV genotypes were HPV16 (n = 52; 40.3 %), followed by HPV52 (n = 32; 24.8 %) and HPV58 (n = 28; 21.7 %), while HPV18 was detected in 6 cases (4.7 %). Of the 23 postoperative hrHPV-positive cases, the same genotypes were detected in 10 cases while a different genotype was detected in 11 cases; type did not affect the frequency of persistent postoperative infection. The 3-year cumulative risk for the reappearance of abnormal cytology was significantly higher in postoperative hrHPV positive patients than in postoperative hrHPV-negative patients (31.6 vs 9.7 %, P = 0.0014). A high-grade squamous intraepithelial lesion (HSIL) was observed during the follow-up period in one patient with persistent HPV16 infection. CONCLUSIONS: Postoperative hrHPV infection was a significant positive predictor for the reappearance of abnormal cytology and HPV16 infection-induced HSIL after treatment. Therefore, our study suggests that hrHPV genotype testing may be useful to follow-up CIN patients. PMID- 26614092 TI - Benchmark Applications of Variations of Multireference Equation of Motion Coupled Cluster Theory. AB - In this work, several variations of the multireference equation of motion (MR EOM) methodology are investigated for the calculation of excitation spectra. These variants of MR-EOM are characterized by the following aspects: (1) the operators included in the sequence of similarity transformations of the molecular electronic Hamiltonian, (2) whether permutational symmetries (i.e., hermitization, vertex symmetry) are imposed on the final elements of the similarity-transformed Hamiltonian, (3) the size of the manifold over which the similarity-transformed Hamiltonian is diagonalized, (4) whether the two-body cumulant is included in the expressions defining the amplitudes and the elements of the transformed Hamiltonian. The MR-EOM methods are benchmarked for the calculation of the excitation energies of a test set of organic molecules. With the availability of reliable benchmark data for this test set, it is possible to gauge the relative accuracy of these approaches. We also further examine a subset of the MR-EOM methods for the calculation of the excitation energies of some transition-metal complexes. These systems prove to be particularly difficult for single-reference coupled-cluster methods. PMID- 26614091 TI - Latino Mother/Daughter Dyadic Attachment as a Mediator for Substance Use Disorder and Emotional Abuse. AB - To date, no studies have investigated emotional abuse of adult Latina women by their mothers despite evidence that emotional maternal abuse may significantly contribute to the emotional abuse experienced by Latina women in their lifetime. Cross-sectional data including 316 women was analyzed using mediation and logistic regression. Overall, 7.1 % of mothers and 24.1 % of daughters abused drugs; and, 19.5 % of daughters were emotionally abused by their mothers. Mother's attachment to her daughter mediated the association between mother's drug abuse and emotionally abusing her adult daughter (indirect effect: 0.863). Latina women can serve as perpetrators of emotional abuse of their adult children. Since drug-abusing daughters are more likely to be victims of emotional abuse by their mothers and drug-abusing mothers are more likely to abuse their daughters, drug-rehabilitation practitioners should incorporate a family abuse component into rehabilitation programs. PMID- 26614093 TI - Species specificity of temporal processing in the auditory midbrain of gray treefrogs: long-interval neurons. AB - In recently diverged gray treefrogs (Hyla chrysoscelis and H. versicolor), advertisement calls that differ primarily in pulse shape and pulse rate act as an important premating isolation mechanism. Temporally selective neurons in the anuran inferior colliculus may contribute to selective behavioral responses to these calls. Here we present in vivo extracellular and whole-cell recordings from long-interval-selective neurons (LINs) made during presentation of pulses that varied in shape and rate. Whole-cell recordings revealed that interplay between excitation and inhibition shapes long-interval selectivity. LINs in H. versicolor showed greater selectivity for slow-rise pulses, consistent with the slow-rise pulse characteristics of their calls. The steepness of pulse-rate tuning functions, but not the distributions of best pulse rates, differed between the species in a manner that depended on whether pulses had slow or fast-rise shape. When tested with stimuli representing the temporal structure of the advertisement calls of H. chrysoscelis or H. versicolor, approximately 27 % of LINs in H. versicolor responded exclusively to the latter stimulus type. The LINs of H. chrysoscelis were less selective. Encounter calls, which are produced at similar pulse rates in both species (~5 pulses/s), are likely to be effective stimuli for the LINs of both species. PMID- 26614090 TI - Centrosomes in the DNA damage response--the hub outside the centre. AB - Here, we review how DNA damage affects the centrosome and how centrosomes communicate with the DNA damage response (DDR) apparatus. We discuss how several proteins of the DDR are found at centrosomes, including the ATM, ATR, CHK1 and CHK2 kinases, the BRCA1 ubiquitin ligase complex and several members of the poly(ADP-ribose) polymerase family. Stereotypical centrosome organisation, in which two centriole barrels are orthogonally arranged in a roughly toroidal pericentriolar material (PCM), is strongly affected by exposure to DNA-damaging agents. We describe the genetic dependencies and mechanisms for how the centrioles lose their close association, and the PCM both expands and distorts after DNA damage. Another consequence of genotoxic stress is that centrosomes undergo duplication outside the normal cell cycle stage, meaning that centrosome amplification is commonly seen after DNA damage. We discuss several potential mechanisms for how centrosome numbers become dysregulated after DNA damage and explore the links between the DDR and the PLK1- and separase-dependent mechanisms that drive centriole separation and reduplication. We also describe how centrosome components, such as centrin2, are directly involved in responding to DNA damage. This review outlines current questions on the involvement of centrosomes in the DDR. PMID- 26614094 TI - Bumblebee flight performance in environments of different proximity. AB - Flying animals are capable of navigating through environments of different complexity with high precision. To control their flight when negotiating narrow tunnels, bees and birds use the magnitude of apparent image motion (known as optic flow) generated by the walls. In their natural habitat, however, these animals would encounter both cluttered and open environments. Here, we investigate how large changes in the proximity of nearby surfaces affect optic flow-based flight control strategies. We trained bumblebees to fly along a flight and recorded how the distance between the walls--from 60 cm to 240 cm--affected their flight control. Our results reveal that, as tunnel width increases, both lateral position and ground speed become increasingly variable. We also find that optic flow information from the ground has an increasing influence on flight control, suggesting that bumblebees measure optic flow flexibly over a large lateral and ventral field of view, depending on where the highest magnitude of optic flow occurs. A consequence of this strategy is that, when flying in narrow spaces, bumblebees use optic flow information from the nearby obstacles to control flight, while in more open spaces they rely primarily on optic flow cues from the ground. PMID- 26614095 TI - Performing Survival Analyses in the Presence of Competing Risks: A Clinical Example in Older Breast Cancer Patients. AB - An important consideration in studies that use cause-specific endpoints such as cancer-specific survival or disease recurrence is that risk of dying from another cause before experiencing the event of interest is generally much higher in older patients. Such competing events are of major importance in the design and analysis of studies with older patients, as a patient who dies from another cause before the event of interest cannot reach the endpoint. In this Commentary, we present several clinical examples of research questions in a population-based cohort of older breast cancer patients with a high frequency of competing events and discuss implications of choosing models that deal with competing risks in different ways. We show that in populations with high frequency of competing events, it is important to consider which method is most appropriate to estimate cause-specific endpoints. We demonstrate that when calculating absolute cause specific risks the Kaplan-Meier method overestimates risk of the event of interest and that the cumulative incidence competing risks (CICR) method, which takes competing risks into account, should be used instead. Two approaches are commonly used to model the association between prognostic factors and cause specific survival: the Cox proportional hazards model and the Fine and Gray model. We discuss both models and show that in etiologic research the Cox Proportional Hazards model is recommended, while in predictive research the Fine and Gray model is often more appropriate. In conclusion, in studies with cause specific endpoints in populations with a high frequency of competing events, researchers should carefully choose the most appropriate statistical method to prevent incorrect interpretation of results. PMID- 26614096 TI - Teammate familiarity and risk of injury in emergency medical services. AB - OBJECTIVE: We investigated the association between teammate familiarity and workplace injury in the emergency medical services (EMS) setting. METHODS: From January 2011 to November 2013, we abstracted a mean of 29 months of shift records and Occupational Safety Health Administration injury logs from 14 EMS organisations with 37 total bases located in four US Census regions. Total teammate familiarity was calculated for each dyad as the total number of times a clinician dyad worked together over the study period. We used negative binomial regression to examine differences in injury incidence rate ratios (IRRs) by familiarity. RESULTS: We analysed 715 826 shift records, representing 4197 EMS clinicians and 60 701 unique dyads. We determined the mean shifts per dyad was (5.9, SD 19.7), and quartiles of familiarity were 1 shift worked together over the study period, 2-3 shifts, 4-9 shifts and >=10 shifts worked together. More than half of all dyads worked one shift together (53.9%, n=32 739), 24.8% of dyads 2-3 shifts, 11.8% worked 4-9 shifts and 9.6% worked >=10 shifts. The overall incidence rate of injury across all organisations was 17.5 per 100 full time equivalent (FTE), range 4.7-85.6 per 100 FTE. The raw injury rate was 33.5 per 100 FTEs for dyads with one shift of total familiarity, 14.2 for 2-3 shifts, 8.3 for 4-9 shifts and 0.3 for >=10 shifts. Negative binomial regression confirmed that dyads with >=10 shifts had the lowest incidence of injury (IRR 0.03; 95% CI 0.02 to 0.04). CONCLUSIONS: Familiarity between teammates varies in the EMS setting, and less familiarity is associated with greater incidence of workplace injury. PMID- 26614097 TI - Experimental evolution of recombination and crossover interference in Drosophila caused by directional selection for stress-related traits. AB - BACKGROUND: Population genetics predicts that tight linkage between new and/or pre-existing beneficial and deleterious alleles should decrease the efficiency of natural selection in finite populations. By decoupling beneficial and deleterious alleles and facilitating the combination of beneficial alleles, recombination accelerates the formation of high-fitness genotypes. This may impose indirect selection for increased recombination. Despite the progress in theoretical understanding, interplay between recombination and selection remains a controversial issue in evolutionary biology. Even less satisfactory is the situation with crossover interference, which is a deviation of double-crossover frequency in a pair of adjacent intervals from the product of recombination rates in the two intervals expected on the assumption of crossover independence. Here, we report substantial changes in recombination and interference in three long term directional selection experiments with Drosophila melanogaster: for desiccation (~50 generations), hypoxia, and hyperoxia tolerance (>200 generations each). RESULTS: For all three experiments, we found a high interval-specific increase of recombination frequencies in selection lines (up to 40-50% per interval) compared to the control lines. We also discovered a profound effect of selection on interference as expressed by an increased frequency of double crossovers in selection lines. Our results show that changes in interference are not necessarily coupled with increased recombination. CONCLUSIONS: Our results support the theoretical predictions that adaptation to a new environment can promote evolution toward higher recombination. Moreover, this is the first evidence of selection for different recombination-unrelated traits potentially leading, not only to evolution toward increased crossover rates, but also to changes in crossover interference, one of the fundamental features of recombination. PMID- 26614099 TI - Binocular Perception of 2D Lateral Motion and Guidance of Coordinated Motor Behavior. AB - Zannoli, Cass, Alais, and Mamassian (2012) found greater audiovisual lag between a tone and disparity-defined stimuli moving laterally (90-170 ms) than for disparity-defined stimuli moving in depth or luminance-defined stimuli moving laterally or in depth (50-60 ms). We tested if this increased lag presents an impediment to visually guided coordination with laterally moving objects. Participants used a joystick to move a virtual object in several constant relative phases with a laterally oscillating stimulus. Both the participant controlled object and the target object were presented using a disparity-defined display that yielded information through changes in disparity over time (CDOT) or using a luminance-defined display that additionally provided information through monocular motion and interocular velocity differences (IOVD). Performance was comparable for both disparity-defined and luminance-defined displays in all relative phases. This suggests that, despite lag, perception of lateral motion through CDOT is generally sufficient to guide coordinated motor behavior. PMID- 26614098 TI - Relationship between hippocampal subfield volumes and memory deficits in patients with thalamus infarction. AB - Clinical studies have shown that thalamus infarction (TI) affects memory function. The thalamic nucleus is directly or indirectly connected to the hippocampal system in animal models. However, this connection has not been investigated using structural magnetic resonance imaging (MRI) in humans. From the pathological perspective, TI patients may serve as valid models for revealing the interaction between the thalamus and hippocampus in memory function. In this study, we aim to assess different hippocampal subfield volumes in TI patients and control subjects using MRI and test their associations with memory function. A total of 37 TI patients (TI group), 38 matched healthy control subjects (HC group), and 22 control patients with other stroke location (SC group) underwent 3.0-T MRI scans and clinical memory examinations. Hippocampal subfield volumes were measured and compared by using FreeSurfer software. We examined the correlation between hippocampal subfield volumes and memory scores. Smaller ipsilesional presubiculum and subiculum volumes were observed, and former was related to graphics recall in both left and right TI patients. The left subiculum volume was correlated with short-delayed recall in left TI patients. The right presubiculum volume was correlated with short- and long-delayed recall in right TI patients. TI was found to result in hippocampal abnormality and memory deficits, and its neural mechanisms might be related with and interaction between the thalamus and hippocampus. PMID- 26614100 TI - Comparison of Tactile Temporal Numerosity Judgments Between Unimanual and Bimanual Presentations. AB - In recent years a growing interest has emerged in numerosity perception in touch. Most of the studies on tactile numerosity perception have investigated its spatial aspect by testing the ability to count the number of items presented simultaneously. On the other hand, only a small number of studies have examined its temporal aspect, and the underlying mechanisms of tactile temporal numerosity judgments (TTNJs) remain elusive. In this study, we presented a rapid sequence of vibrations, each of which was presented to one of two bodily locations, and then compared the performance of the TTNJ between two stimulus-location conditions. In one condition, each of the vibration trains was presented to one of two fingers of the left hand (unimanual condition). In the other condition, each of the vibration trains was presented to the index finger of either the right or left hand (bimanual condition). With these conditions, we aimed to examine how the differences in stimulus locations and in types of tasks affect TTNJ performance. Our results showed that when the participants were asked to count the total number of vibrations presented at two locations, the performance (proportion of correct answers) was not so much different between the two conditions. In contrast, when the participants had to report the two numbers of vibrations presented at each location or to focus on the number of vibrations at a single location, the TTNJ performance in the bimanual condition was drastically better than in the unimanual condition. These results suggest that the underlying mechanism for tactile temporal numerosity perception can segregate the interhemispheric information (bimanual condition) more precisely than the within hemispheric information (unimanual condition), when spatiotemporal tasks are performed. PMID- 26614101 TI - Counting On Your Senses. PMID- 26614102 TI - Prevalence and Characterization of Salmonella Isolated from Feral Pigs Throughout Texas. AB - Feral pigs are one of the most abundant free-roaming ungulates in the United States, yet their role in the ecology and transmission of foodborne pathogens is poorly understood. Our objectives were to estimate the prevalence of Salmonella shedding among feral pigs throughout Texas, to identify risk factors for infection, and to characterize the isolates. Faecal samples were collected from feral pigs in Texas from June 2013 through May 2015. Standard bacteriologic culture methods were used to isolate Salmonella from samples, and isolates were characterized via serotyping and anti-microbial susceptibility testing. The prevalence of faecal Salmonella shedding among sampled pigs was 43.9% (194/442), with positive pigs originating from 50 counties. Pigs sampled during fall and summer were significantly more likely to be shedding Salmonella than pigs sampled during winter. High serovar diversity was evident among the isolates, and many of the detected serovars are leading causes of human salmonellosis. The most common serovars were Montevideo (10.0%), Newport (9.1%), and Give (8.2%). Resistance to anti-microbial agents was rare. The burgeoning feral pig population in the United States may represent an emerging threat to food safety. PMID- 26614103 TI - T follicular helper (Tfh) cells in lupus: Activation and involvement in SLE pathogenesis. AB - Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory autoimmune disease characterized by a breakdown of tolerance to self. The autoantibodies generated in SLE are directed against nuclear components, with which they form immune complexes (ICs). ICs play key roles in organ and tissue damage, as well as in the activation of the innate and adaptive immune system during the disease course. Therefore, it is of prime importance to understand the mechanisms responsible for the development of B cells producing these pathogenic autoantibodies. There is compelling evidence that T follicular helper (Tfh) cells play a fundamental role in this process. In this review, we will summarize the current knowledge regarding the involvement of Tfh cells in SLE pathogenesis, and discuss potential strategies to target Tfh cells and/or molecules as a therapeutic modality of SLE. PMID- 26614104 TI - Long-term results of the European achalasia trial: a multicentre randomised controlled trial comparing pneumatic dilation versus laparoscopic Heller myotomy. AB - OBJECTIVE: Achalasia is a chronic motility disorder of the oesophagus for which laparoscopic Heller myotomy (LHM) and endoscopic pneumodilation (PD) are the most commonly used treatments. However, prospective data comparing their long-term efficacy is lacking. DESIGN: 201 newly diagnosed patients with achalasia were randomly assigned to PD (n=96) or LHM (n=105). Before randomisation, symptoms were assessed using the Eckardt score, functional test were performed and quality of life was assessed. The primary outcome was therapeutic success (presence of Eckardt score <=3) at the yearly follow-up assessment. The secondary outcomes included the need for re-treatment, lower oesophageal sphincter pressure, oesophageal emptying and the rate of complications. RESULTS: In the full analysis set, there was no significant difference in success rate between the two treatments with 84% and 82% success after 5 years for LHM and PD, respectively (p=0.92, log-rank test). Similar results were obtained in the per-protocol analysis (5-year success rates: 82% for LHM vs. 91% for PD, p=0.08, log-rank test). After 5 years, no differences in secondary outcome parameter were observed. Redilation was performed in 24 (25%) of PD patients. Five oesophageal perforations occurred during PD (5%) while 12 mucosal tears (11%) occurred during LHM. CONCLUSIONS: After at least 5 years of follow-up, PD and LHM have a comparable success rate with no differences in oesophageal function and emptying. However, 25% of PD patients require redilation during follow-up. Based on these data, we conclude that either treatment can be proposed as initial treatment for achalasia. TRIAL REGISTRATION NUMBERS: Netherlands trial register (NTR37) and Current Controlled Trials registry (ISRCTN56304564). PMID- 26614105 TI - Compliance with national recommendations for exercise during early pregnancy in a Danish cohort. AB - BACKGROUND: Exercise during pregnancy is associated with health benefits for both the mother and the fetus, and is therefore recommended in several national guidelines. Only few studies investigate whether these guideline recommendations are met. The aims of this study were 1. To assess the prevalence of pregnant women meeting the Danish recommendations for exercise during early pregnancy, 2. To identify pre-pregnancy factors associated with a lower probability for meeting the recommendations, and 3. To describe which types of exercise pregnant women prefer before and during pregnancy. METHODS: We conducted a cross-sectional study based on a questionnaire during the first trimester among 7,915 women participating in the prospective Copenhagen Pregnancy Cohort. Associations were estimated by multivariate regression analyses. RESULTS: In early pregnancy, 38 % of the study population met the recommendation for exercise from the Danish Health and Medicines Authority (>=3.5 hours a week). Multiparity, previous miscarriage use of assisted reproductive technology, no engagement in exercise before pregnancy, smoking, pregnancy following assisted reproductive technology, overweight, not understanding Danish language and a low educational level were all factors associated a lower probability for meeting the recommendations. The preferred types of exercise before and during pregnancy were bicycling, brisk walking, running and strength training. The proportion of women engaged in any type of exercise decreased in early pregnancy with the exception of swimming and aquatic exercise. CONCLUSIONS: In this cohort, more than one-third met the Danish recommendation for exercise during early pregnancy. Exercise in pregnancy is still an issue to address because the most vulnerable groups of pregnant women do not exercise. This is a cause of concern because it may reflect social inequalities in health and highlights the need for a structural and systematic approach to preconception care and early antenatal counselling. PMID- 26614106 TI - Retrospective analysis of the radiographic indicators for peri-acetabular osteotomy of developmental dysplasia in children. AB - PURPOSE: Open surgery, nonsurgical positioning device and casting are mainstay treatments of developmental dysplasia of the hip (DDH). The optimal indicators for surgical interventions remain unclear. In this study, we aim to establish empirical, sensitive radiographic indicators for peri-acetabular osteotomy intervention in developmental dysplasia in Chinese children. METHODS: One hundred and three DDH patients treated in The Soochow University Children's Hospital between 2006 and 2012 were assessed; patients with known causes of neuron muscular and abnormal hip joint origin were excluded. Fifty-four suitable patients, demonstrating 71 dysplasia hips with complete clinical record and adequate X-ray films, were enrolled in this study. Patients were divided into group A (conservative interventions failed, followed by salvage peri-acetabular osteotomy) and group B (conservative treatment only); a total of 16 quantitative parameters were measured on each pelvic X-ray film. RESULTS: Among 71 hip joints measured, 29 hips of group A underwent salvage peri-acetabular osteotomy (40.8 %,) showed higher X2, Y, h, and Smith c/b (Vh) (p < 0.05). The age, c, HT, b, A2 in the group A salvage operation were statistically significantly different compared to group B patients (without salvage operations) (p < 0.05). CONCLUSIONS: Pre-operative pelvic X-ray film assessment of acetabulum lateralization markers (X2, c, HT, c/b ratio) and the superior migration measurements (Y, h, h/b ratio) are potentially valuable radiographic indicators for determining which DDH patients will require peri-acetabular osteotomy. PMID- 26614107 TI - Quality orthopaedic care in sudden-onset disasters: suggestions from Medecins Sans Frontieres-France. AB - A huge change is needed in the conception and implementation of surgical care during sudden-onset disasters (SOD). The inadequate surgical response mounted by the majority of foreign medical teams (FMT) after Haiti's earthquake is a striking example of the need for a structured professional approach. Logistical capacity already exists to provide safe, timely, effective, efficient, equitable and ethical patient-centred care with minimum standards. However, knowledge, skills and training in the fields of general, orthopaedic and plastic surgery need further clarification. Surgical activity data and clinical examples from several Medecins Sans Frontieres-France (MSF) projects are used here to describe the skill set and experience essential for surgeons working in SOD contexts. PMID- 26614108 TI - Endovascular embolisation is a successful and safe treatment for post-operative arterial complications after total hip arthroplasty and revision surgery. AB - PURPOSE: Arterial complications are rare but clinically critical during or following total hip arthroplasty (THA) surgery. They usually require secondary interventions, either through open or endovascular approaches. In a retrospective study, we analysed indications for, as well as success and safety of, endovascular embolisation for arterial complications after THA. METHODS: We reviewed all arterial complications that had occurred through THA surgery and been treated by endovascular embolisation. We analysed angiographic findings, endovascular treatment, location in relation to the surgical approach and success of the interventions. RESULTS: Between 1997 and 2013 we performed 3,891 THAs at our hospital. We identified 14 patients with acute arterial complications treated by minimally invasive endovascular embolisation. Clinical findings included swelling of the ipsilateral leg, pain, prolonged wound bleeding, decreased haemoglobin and/or haemodynamic instability. Angiography revealed pseudoaneurysm in 11 patients, arteriovenous fistulas in two and extravasation of contrast media in one. Two patients showed no signs of acute bleeding. Twelve patients were treated, each with a single session of endovascular embolisation; in two additional patients, the haematoma was evacuated. No complications from the endovascular treatment were observed in this series. CONCLUSION: Endovascular embolisation is a safe and successful minimally-invasive method to treat arterial injuries occurring through THA. Therefore, it should be considered as a first line option of treatment for those injuries. PMID- 26614109 TI - Lowering urinary oxalate excretion to decrease calcium oxalate stone disease. AB - Dietary modifications should be considered as a first line approach in the treatment of idiopathic calcium oxalate nephrolithiasis. The amounts of oxalate and calcium consumed in the diet are significant factors in the development of the disease due to their impact on urinary oxalate excretion. There are a number of strategies that can be employed to reduce oxalate excretion. The consumption of oxalate-rich foods should be avoided and calcium intake adjusted to 1000-1200 mg/day. To encourage compliance it should be emphasized to patients that they be vigilant with this diet as a deviation in any meal or snack could potentially result in significant stone growth. The evidence underlying these two modifications is outlined and other strategies to reduce urinary oxalate excretion are reviewed. PMID- 26614110 TI - Metabolic risk-evaluation and prevention of recurrence in stone disease: does it make sense? AB - In this review, aspects on the importance of information on urine composition and selection of the most appropriate regimen for prevention of recurrence are discussed. For patients with urolithiasis the treatment is facilitated by urine analysis with estimates of supersaturation levels. Despite lack of strong scientific evidence for the benefit of selective versus non-selective prevention of recurrence in patients with calcium stone disease, there is currently both convincing and logical information in support of tailored/selective treatment regimens aiming at correction of abnormal target variables. Such an approach is also recommended in the EAU and AUA guidelines. It is important, however, that every preventive regimen is balanced between the effects on urine composition and patients' tolerance to the treatment in order to achieve satisfactory compliance. It is possible that future improved understanding of the causes of calcium stone formation might provide a different therapeutic approach. PMID- 26614111 TI - Simplified methods for the evaluation of the risk of forming renal stones and the follow-up of stone-forming propensity during the preventive treatment of stone formation. AB - Renal lithiasis is a complex multifactorial disease in which recurrence is common. Thus, simple and reliable procedures are needed to evaluate patients with previous kidney stones to determine the risk of recurrence. In this paper we review simple biochemical procedures that can be used to determine the risk for renal stone formation when the stone is available or unavailable for analysis. Our present knowledge of renal lithiasis indicates that renal stones form due to several well-defined factors. Analysis of the renal stone itself can provide important information about clinical factors that require further investigation. When the stone is unavailable, it is necessary to perform a general evaluation of main urinary risk factors associated to renal stone formation, but this study should be complemented considering information related to direct familial antecedents, recidivant degree, radiological images, medical history, and life style habits. Finally, tools for patient follow-up of stone-forming propensity during the preventive treatment are discussed . PMID- 26614113 TI - Can the manipulation of urinary pH by beverages assist with the prevention of stone recurrence? AB - The formation of various types of stones in the urinary tract is strongly influenced by urinary pH. An acidic urinary pH promotes the crystallization of uric acid and cystine, respectively. Moreover, changes in systemic acid-base homeostasis alter urinary excretion of citrate, an important inhibitor of calcium oxalate stone formation. The effect of beverages on urinary pH and citrate excretion is mainly determined by the presence of bicarbonate and citrate. The bicarbonate content of mineral water can replace alkalization therapy with potassium citrate and contribute to urine inhibitory power by increasing urinary pH and citrate excretion. Citrus juices are rich sources of citrate. Oral citrate is absorbed in the intestine and nearly completely metabolized to bicarbonate, providing an alkali load, which in turn increases urinary pH and citrate excretion. However, data from observational and interventional studies on the effect of different types of citrus juices on the risk of urinary stone formation are conflicting. In conclusion, favourable changes in urinary pH and citrate excretion can be attained by various beverages. However, the long-term efficacy of certain beverages for the recurrence prevention of different types of stones has yet to be determined. PMID- 26614112 TI - How should patients with cystine stone disease be evaluated and treated in the twenty-first century? AB - Cystinuria continues to be one of the most challenging stone diseases. During the latest decades our knowledge of the molecular basis of cystinuria has expanded. Today 160 different mutations in the SLC3A1 gene and 116 in the SLC7A9 gene are listed. The full implications of type A, B or AB status are not yet fully understood but may have implications for prognosis, management and treatment. Despite better understanding of the molecular basis of cystinuria the principles of recurrence prevention have remained essentially the same through decades. No curative treatment of cystinuria exists, and patients will have a life long risk of stone formation, repeated surgery, impaired renal function and quality of life. Therapy to reduce stone formation is directed towards lowering urine cystine concentration and increasing cystine solubility. Different molecules that could play a role in promoting nucleation and have a modulating effect on cystine solubility may represent new targets for cystinuria research. Investigation of newer thiol-containing drugs with fewer adverse effects is also warranted. Determining cystine capacity may be an effective tool to monitor the individual patient's response. Compliance in cystinuric patients concerning both dietary and pharmacological intervention is poor. Frequent clinical follow-up visits in dedicated centres seem to improve compliance. Cystinuric patients should be managed in dedicated centres offering the complete range of minimal invasive treatment modalities, enabling a personalized treatment approach in order to reduce risk and morbidity of multiple procedures. PMID- 26614114 TI - The effects of dietary dried fruit pomaces on growth performance and gastrointestinal biochemistry of turkey poults. AB - One-day-old female turkeys were randomly assigned to five dietary treatments and were fed for 15 weeks diets containing 5% of cellulose (control, C) or 5% of dried fruit pomaces (apple, black currant, strawberry, seedless strawberry; AP, BCP, SP, SSP respectively). In weeks 11-15 of feeding, all diets were supplemented with 2.5% of linseed oil. The crude fibre content of fruit pomaces ranged from 56.5% in AP to 62.9% in SP. In comparison with AP, berry fruit pomaces (BCP, SP and SSP) were characterised by a higher content of neutral detergent fibre - NDF (41.2% vs. 52.7-59.3%) and lignin (13.24% vs. 21.80 25.56%). A monomer analysis revealed that cellulose was the main non-starch polysaccharide (NSP) in fruit pomaces, whereas their pectin content was low. Polyphenol content was determined at below 6 g/kg in AP, at approximately 12 g/kg in BCP and SP, and at 32.8 g/kg in SSP. There were no significant differences (p > 0.05) in final body weight of birds. After 15 weeks of feeding fruit pomaces to turkeys, the relative weight of the small intestine with digesta was higher in group AP, and lower in group SSP, as compared to controls. Dietary fruit pomaces decreased the dry matter (DM) concentration and lowered the pH of the small intestinal digesta, except the AP and SSP treatments respectively. In the caeca, significantly reduced concentrations of ammonia or putrefactive short-chain fatty acids (SCFA) upon dietary fruit pomaces were observed. Fruit pomaces did not influence the concentrations or the total pool of short-chain fatty acids, but led to a significant increase in butyric proportion in the SCFA profile at the expense propionate. PMID- 26614115 TI - Atypical presentation of multicentric Castleman disease in a pediatric patient: pleural and pericardial effusion. AB - Castleman disease (CD) is a rare poorly understood lymphoproliferative disorder. Pediatric onset CD has been reported before. However, most of them have benign unicentric pattern. Multicentric CD (MCD) is quite rare in children. Herein, we report a 13-year-old adolescent boy with MCD of the hyaline vascular variant presenting with pleural and pericardial effusion, which is an uncommon presentation. CONCLUSION: MCD should be considered in the differential diagnosis of pleural and/or pericardial effusion with unexplained lymph nodes in children. What is Known *Pediatric Castleman disease (CD) most commonly occurs in the unicentric form, which typically is asymptomatic and cured by lymph node excision. *The diagnosis of MCD can be difficult owing to the heterogeneity of presentation and potential for nonspecific multisystem involvement. What is New *A 13-year-old adolescent boy was diagnosed with MCD of the hyaline vascular variant presenting with pleural and pericardial effusion, which is an uncommon presentation. *In a pediatric patient with fever, pleural-pericardial effusion and multiple lymph nodes, MCD should be considered in differantial diagnosis. PMID- 26614116 TI - Fragments of illness: The Death of a Beekeeper as a literary case study of cancer. AB - The first decisive steps of medicine towards becoming a science in its present shape happen to coincide with "the rise of the novel" in the eighteenth century. Before this well known and in our days still growing scientific specialization of medicine, the connections between literature and medicine were both many and close. By reading and analyzing a contemporary novel, The Death of a Beekeeper by the Swedish author Lars Gustafsson (1978), this article is an attempt to explore to which extent a fictional narrative about a unique case of cancer may illuminate challenges associated with the experience of serious illness. Our claim is that medicine might draw wisdom from literature, its ability to create connections through narrative, to illuminate the complexity of ethical dilemmas, and to intertwine symptoms, life stories, and contexts. We argue that by being in the company of literary narratives and philosophical questions, physicians as well as other health care professionals may acquire clinically relevant skills which help them reach the ethically defined goals of their profession. PMID- 26614118 TI - Effect of l-glutamic acid supplementation on performance and nitrogen balance of broilers fed low protein diets. AB - The aim of this study was to evaluate the effect of protein reduction and supplementation of l-glutamic acid in male broiler diets. A total of 648 chicks of the Cobb 500 strain were distributed in a completely randomized design with six treatments and six replications with eighteen birds per experimental unit. The study comprised pre-starter (1-7 days), starter (8-21 days), growth (22-35 days) and final (36-45 days) phases. The first treatment consisted of a control diet formulated according to the requirements of essential amino acids for each rearing phase. The second and third treatments had crude protein (CP) reduced by 1.8 and 3.6 percentage points (pp) in relation to the control diet respectively. In the fourth treatment, l-glutamic acid was added to provide the same glutamate level as the control diet, and in the last two treatments, the broilers were supplemented with 1 and 2 pp of glutamate above that of the control diet respectively. The reduction in CP decreased the performance of broilers and the supplementation of l-glutamic acid did not influence performance when supplied in the diets with excess of glutamate. The lowest excreted nitrogen values were observed in the control diet, and treatments 2 and 3, respectively, in comparison with treatments with the use of l-glutamic acid (5 and 6). Retention efficiency of nitrogen was better in the control diet and in the treatment with a reduction of 1.8 pp of CP. It was verified that the serum uric acid level decreased with the CP reduction. A reduction in CP levels of up to 21.3%, 18.8%, 18.32% and 17.57% is recommended in phases from 1 to 7, 8 to 21, 22 to 35 and at 36 to 42 days, respectively, with a level of glutamate at 5.32%, 4.73%, 4.57%, 4.38%, also in these phases. PMID- 26614119 TI - Impact of elective neck dissection on the outcome of oral squamous cell carcinomas arising in the maxillary alveolus and hard palate. AB - BACKGROUND: Whether elective lymph neck dissection (ELND) is associated with improved survival in oral squamous cell carcinomas (SCC) of the maxillary alveolus/hard palate is not known. METHODS: One hundred ninety-nine patients presenting de novo and receiving treatment for clinically node negative SCC of the maxillary alveolus/hard palate at 2 cancer centers between 1985 and 2011 were analyzed. RESULTS: Forty-two patients (21%) received ELND. Occult nodal metastases were present in 29% of the dissected necks. The ELND group had more T3 to T4 status tumors (62% vs 34%; p < .001) and positive-margin resections (59% vs 38%; p = .019). Patients undergoing ELND experienced lower rates of neck recurrence (6% vs 21%; p = .031), superior 5-year recurrence-free survival (68% vs 45%; p = .026), and overall survival (86% vs 62%; p = .043). ELND was associated with a 2-fold decrease in risk of recurrence in multivariable analysis. CONCLUSION: ELND was associated with lower rates of recurrence and improved survival in SCC of the maxillary alveolus/hard palate. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1688-E1694, 2016. PMID- 26614121 TI - Undergraduate palliative care teaching in Swiss medical faculties: a nationwide survey and improved learning objectives. AB - BACKGROUND: In 2007, a first survey on undergraduate palliative care teaching in Switzerland has revealed major heterogeneity of palliative care content, allocation of hours and distribution throughout the 6 year curriculum in Swiss medical faculties. This second survey in 2012/13 has been initiated as part of the current Swiss national strategy in palliative care (2010 - 2015) to serve as a longitudinal monitoring instrument and as a basis for redefinition of palliative care learning objectives and curriculum planning in our country. METHODS: As in 2007, a questionnaire was sent to the deans of all five medical faculties in Switzerland in 2012. It consisted of eight sections: basic background information, current content and hours in dedicated palliative care blocks, current palliative care content in other courses, topics related to palliative care presented in other courses, recent attempts at improving palliative care content, palliative care content in examinations, challenges, and overall summary. Content analysis was performed and the results matched with recommendations from the EAPC for undergraduate training in palliative medicine as well as with recommendations from overseas countries. RESULTS: There is a considerable increase in palliative care content, academic teaching staff and hours in all medical faculties compared to 2007. No Swiss medical faculty reaches the range of 40 h dedicated specifically to palliative care as recommended by the EAPC. Topics, teaching methods, distribution throughout different years and compulsory attendance still differ widely. Based on these results, the official Swiss Catalogue of Learning Objectives (SCLO) was complemented with 12 new learning objectives for palliative and end of life care (2013), and a national basic script for palliative care was published (2015). CONCLUSION: Performing periodic surveys of palliative care teaching at national medical faculties has proven to be a useful tool to adapt the national teaching framework and to improve the recognition of palliative medicine as an integral part of medical training. PMID- 26614120 TI - Regulation of autophagy in human skeletal muscle: effects of exercise, exercise training and insulin stimulation. AB - KEY POINTS: Regulation of autophagy in human muscle in many aspects differs from the majority of previous reports based on studies in cell systems and rodent muscle. An acute bout of exercise and insulin stimulation reduce human muscle autophagosome content. An acute bout of exercise regulates autophagy by a local contraction-induced mechanism. Exercise training increases the capacity for formation of autophagosomes in human muscle. AMPK activation during exercise seems insufficient to regulate autophagosome content in muscle, while mTORC1 signalling via ULK1 probably mediates the autophagy-inhibiting effect of insulin. Studies in rodent muscle suggest that autophagy is regulated by acute exercise, exercise training and insulin stimulation. However, little is known about the regulation of autophagy in human skeletal muscle. Here we investigate the autophagic response to acute one-legged exercise, one-legged exercise training and subsequent insulin stimulation in exercised and non-exercised human muscle. Acute one-legged exercise decreased (P<0.01) lipidation of microtubule-associated protein 1A/1B-light chain 3 (LC3) (~ 50%) and the LC3-II/LC3-I ratio (~ 60%) indicating that content of autophagosomes decreases with exercise in human muscle. The decrease in LC3-II/LC3-I ratio did not correlate with activation of 5'AMP activated protein kinase (AMPK) trimer complexes in human muscle. Consistently, pharmacological AMPK activation with 5-aminoimidazole-4-carboxamide riboside (AICAR) in mouse muscle did not affect the LC3-II/LC3-I ratio. Four hours after exercise, insulin further reduced (P<0.01) the LC3-II/LC3-I ratio (~ 80%) in muscle of the exercised and non-exercised leg in humans. This coincided with increased Ser-757 phosphorylation of Unc51 like kinase 1 (ULK1), which is suggested as a mammalian target of rapamycin complex 1 (mTORC1) target. Accordingly, inhibition of mTOR signalling in mouse muscle prevented the ability of insulin to reduce the LC3-II/LC3-I ratio. In response to 3 weeks of one-legged exercise training, the LC3-II/LC3-I ratio decreased (P<0.05) in both trained and untrained muscle and this change was largely driven by an increase in LC3-I content. Taken together, acute exercise and insulin stimulation reduce muscle autophagosome content, while exercise training may increase the capacity for formation of autophagosomes in muscle. Moreover, AMPK activation during exercise may not be sufficient to regulate autophagy in muscle, while mTORC1 signalling via ULK1 probably mediates the autophagy-inhibiting effect of insulin. PMID- 26614122 TI - Massive hemoptysis in Loeys-Dietz syndrome. AB - We describe four unrelated individuals with Loeys-Dietz syndrome (LDS) who presented with massive hemoptysis of unknown etiology. LDS is an autosomal dominant connective-tissue disorder characterized by altered cardiovascular, craniofacial, and skeletal development that is attributed to mutations in the TGFBR1, TGFBR2, SMAD3, or TGFB2 genes. Massive hemoptysis (MH) is a rare and often fatal pulmonary medical emergency. This is the first report of MH in individuals with LDS and establishes it as part of the LDS spectrum. It compels providers to educate their LDS patients on MH, although much investigation needs to be done to determine etiology and appropriate treatment for this newly described LDS feature. PMID- 26614117 TI - Macrophages: An Inflammatory Link Between Angiogenesis and Lymphangiogenesis. AB - Angiogenesis and lymphangiogenesis often occur in response to tissue injury or in the presence of pathology (e.g., cancer), and it is these types of environments in which macrophages are activated and increased in number. Moreover, the blood vascular microcirculation and the lymphatic circulation serve as the conduits for entry and exit for monocyte-derived macrophages in nearly every tissue and organ. Macrophages both affect and are affected by the vessels through which they travel. Therefore, it is not surprising that examination of macrophage behaviors in both angiogenesis and lymphangiogenesis has yielded interesting observations that suggest macrophages may be key regulators of these complex growth and remodeling processes. In this review, we will take a closer look at macrophages through the lens of angiogenesis and lymphangiogenesis, examining how their dynamic behaviors may regulate vessel sprouting and function. We present macrophages as a cellular link that spatially and temporally connects angiogenesis with lymphangiogenesis, in both physiological growth and in pathological adaptations, such as tumorigenesis. As such, attempts to therapeutically target macrophages in order to affect these processes may be particularly effective, and studying macrophages in both settings will accelerate the field's understanding of this important cell type in health and disease. PMID- 26614123 TI - Upstream clopidogrel, prasugrel, or ticagrelor for patients treated with primary angioplasty: Results of an angiographic randomized pilot study. AB - OBJETIVES: The main objective of the present randomized pilot study was to explore the effects of upstream prasugrel or ticagrelor or clopidogrel for patients with ST-segment-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). BACKGROUND: Administration of clopidogrel "as soon as possible" has been advocated for STEMI. Pretreatment with prasugrel and ticagrelor may improve reperfusion. Currently, the angiographic effects of upstream administration of these agents are poorly understood. METHODS: A total of 132 patients with STEMI within the first 12 hr of chest pain referred to primary angioplasty were randomized to upstream clopidogrel (600 mg), prasugrel (60 mg), or ticagrelor (180 mg) while still in the emergency room. All patients underwent protocol-mandated thrombus aspiration. RESULTS: Macroscopic thrombus material was retrieved in 79.5% of the clopidogrel group, 65.9% of the prasugrel group, and 54.3% of the ticagrelor group (P = 0.041). At baseline angiography, large thrombus burden was 97.7% vs. 87.8% vs. 80.4% in the clopidogrel, prasugrel, and ticagrelor groups, respectively (P = 0.036). Also, at baseline, 97.7% presented with an occluded target vessel in the clopidogrel group, 87.8% in the prasugrel group and 78.3% in the ticagrelor group (P = 0.019). At the end of the procedure, the percentages of patients with combined TIMI grade III flow and myocardial blush grade III were 52.3% for clopidogrel, 80.5% for prasugrel, and 67.4% for ticagrelor (P = 0.022). CONCLUSIONS: In patients with STEMI undergoing primary PCI within 12 hr, upstream clopidogrel, prasugrel or ticagrelor have varying angiographic findings, with a trend toward better results for the latter two agents. (c) 2015 Wiley Periodicals, Inc. PMID- 26614124 TI - The minipig as a new model for the evaluation of doxorubicin-induced chronic toxicity. AB - Doxorubicin can cause life-threatening toxic effects in several organs, with cardiotoxicity being the major concern. Although a large number of animal models have been utilized to study doxorubicin toxicity, several restrictions limit their use. Since the Gottingen minipig is an accepted species for non-clinical safety assessment and translation to man, we aimed at exploring its use as a non rodent animal model for safety assessment and regulatory toxicity studies using doxorubicin. Three groups of three males and three females adult Gottingen minipigs received 1.5 mg kg(-1) , 3/2.3 mg kg(-1) or vehicle at intervals of 3 weeks for 7 cycles. Doxorubicin treatment resulted in a dose-related decrease in the erythrocytes, hemoglobin and hematocrit count, accompanied by leukopenia and thrombocytopenia. Bone marrow smears revealed dose-related hypocellularity. Urea and creatinine levels were elevated in treated animals, associated with proteinuria and hematuria. Histopathological evaluation detected nephropathy and atrophy of hematopoietic tissues/organs, mucosa of the intestinal tract and male genital tract. Cardiac lesions including chronic inflammation, endocardial hyperplasia, hemorrhage and myxomatous changes were evident in hematoxylin and eosin stains, and evaluation of semi-thin sections showed the presence of dose related vacuolation in the atrial and ventricular cardiomyocytes. Cardiac troponin levels were increased in the high-dose group, but there was no direct correlation to the severity of the histopathological lesions. This study confirms that the Gottingen minipig has a comparable toxicity profile to humans and considering its anatomical, physiological, genetic and biochemical resemblance to humans, it should be considered as the non-rodent species of choice for studies on doxorubicin toxicity. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26614125 TI - SVD-phy: improved prediction of protein functional associations through singular value decomposition of phylogenetic profiles. AB - A successful approach for predicting functional associations between non homologous genes is to compare their phylogenetic distributions. We have devised a phylogenetic profiling algorithm, SVD-Phy, which uses truncated singular value decomposition to address the problem of uninformative profiles giving rise to false positive predictions. Benchmarking the algorithm against the KEGG pathway database, we found that it has substantially improved performance over existing phylogenetic profiling methods. AVAILABILITY AND IMPLEMENTATION: The software is available under the open-source BSD license at https://bitbucket.org/andrea/svd phy CONTACT: lars.juhl.jensen@cpr.ku.dk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26614126 TI - Identification of drug-target interaction from interactome network with 'guilt-by association' principle and topology features. AB - MOTIVATION: Identifying drug-target protein interaction is a crucial step in the process of drug research and development. Wet-lab experiment are laborious, time consuming and expensive. Hence, there is a strong demand for the development of a novel theoretical method to identify potential interaction between drug and target protein. RESULTS: We use all known proteins and drugs to construct a nodes and edges-weighted biological relevant interactome network. On the basis of the 'guilt-by-association' principle, novel network topology features are proposed to characterize interaction pairs and random forest algorithm is employed to identify potential drug-protein interaction. Accuracy of 92.53% derived from the 10-fold cross-validation is about 10% higher than that of the existing method. We identify 2272 potential drug-target interactions, some of which are associated with diseases, such as Torg-Winchester syndrome and rhabdomyosarcoma. The proposed method can not only accurately predict the interaction between drug molecule and target protein, but also help disease treatment and drug discovery. CONTACTS: zhanchao8052@gmail.com or ceszxy@mail.sysu.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26614127 TI - MetaQUAST: evaluation of metagenome assemblies. AB - During the past years we have witnessed the rapid development of new metagenome assembly methods. Although there are many benchmark utilities designed for single genome assemblies, there is no well-recognized evaluation and comparison tool for metagenomic-specific analogues. In this article, we present MetaQUAST, a modification of QUAST, the state-of-the-art tool for genome assembly evaluation based on alignment of contigs to a reference. MetaQUAST addresses such metagenome datasets features as (i) unknown species content by detecting and downloading reference sequences, (ii) huge diversity by giving comprehensive reports for multiple genomes and (iii) presence of highly relative species by detecting chimeric contigs. We demonstrate MetaQUAST performance by comparing several leading assemblers on one simulated and two real datasets. AVAILABILITY AND IMPLEMENTATION: http://bioinf.spbau.ru/metaquast CONTACT: aleksey.gurevich@spbu.ru SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26614128 TI - Letter From the Editor: Fetal Magnetic Resonance Imaging. PMID- 26614129 TI - Prenatal Imaging of Craniosynostosis Syndromes. AB - This article reviews the prenatal diagnosis of those syndromes in which craniosynostosis is a key feature. Although not an exhaustive list, the authors highlight conditions that may be encountered with some regularity, especially in a higher volume fetal imaging center. Rare conditions are also discussed. Normal sutural anatomy and development are first reviewed, followed by a discussion of specific syndromes, the salient imaging findings, and pathologic as well as postnatal correlations when possible. PMID- 26614130 TI - Fetal Cerebral Magnetic Resonance Imaging Beyond Morphology. AB - The recent technological advancement of fast magnetic resonance imaging (MRI) sequences allowed the inclusion of diffusion tensor imaging, functional MRI, and proton MR spectroscopy in prenatal imaging protocols. These methods provide information beyond morphology and hold the key to improving several fields of human neuroscience and clinical diagnostics. Our review introduces the fundamental works that enabled these imaging techniques, and also highlights the most recent contributions to this emerging field of prenatal diagnostics, such as the structural and functional connectomic approach. We introduce the advanced image processing approaches that are extensively used to tackle fetal or maternal movement-related image artifacts, and which are necessary for the optimal interpretation of such imaging data. PMID- 26614131 TI - Fetal Brain Magnetic Resonance Imaging Findings In Congenital Cytomegalovirus Infection With Postnatal Imaging Correlation. AB - Fetal brain magnetic resonance imaging (MRI) is a powerful tool in the diagnosis of symptomatic congenital cytomegalovirus infection, requiring a detailed search for specific features. A combination of anterior temporal lobe abnormalities, white matter lesions, and polymicrogyria is especially predictive. Fetal MRI may provide a unique opportunity to detect anterior temporal cysts and occipital horn septations, as dilation of these areas may decrease later in development. Cortical migration abnormalities, white matter abnormalities, cerebellar dysplasia, and periventricular calcifications are often better depicted on postnatal imaging but can also be detected on fetal MRI. We present the prenatal brain MRI findings seen in congenital cytomegalovirus infection and provide postnatal imaging correlation, highlighting the evolution of findings at different times in prenatal and postnatal developments. PMID- 26614132 TI - Magnetic Resonance Imaging Evaluation of Fetal Neural Tube Defects. AB - Spinal dysraphism occurs early in gestation because of an abnormality in the closure of the neural tube. Defects can be classified as open or closed lesions based on clinical and imaging features. Biochemical evaluation and ultrasound studies are used as screening tools for neural tube defects. Ultrasound alone can accurately diagnose most neural tube lesions. Magnetic resonance imaging has increasingly been used as an adjuvant study and is useful in the assessment of the degree of hindbrain herniation and evaluation of the fetal brain and spinal cord anatomy when ultrasound is limited. This additional information can be useful in counseling, helping to determine if fetal surgery is an option as well as helping to plan delivery and postnatal management. PMID- 26614133 TI - Perinatal Thoracic Mass Lesions: Pre- and Postnatal Imaging. AB - Chest masses present a common problem in the perinatal period. Advances in prenatal ultrasound, supplemented by fetal magnetic resonance imaging, now allow early detection and detailed characterization of many thoracic lesions in utero. As such, in asymptomatic infants, assessment with postnatal computed tomography or magnetic resonance imaging can often be delayed for several months until the time at which surgery is being contemplated. Bronchopulmonary malformations comprise most of the thoracic masses encountered in clinical practice. However, a variety of other pathologies can mimic their appearances or produce similar effects such as hypoplasia of a lung or both lungs. Understanding of the key differentiating clinical and imaging features can assist in optimizing prognostication and timely management. PMID- 26614134 TI - When Closure Fails: What the Radiologist Needs to Know About the Embryology, Anatomy, and Prenatal Imaging of Ventral Body Wall Defects. AB - Ventral body wall defects (VBWDs) are one of the main categories of human congenital malformations, representing a wide and heterogeneous group of defects sharing a common feature, that is, herniation of one or more viscera through a defect in the anterior body wall. Gastroschisis and omphalocele are the 2 most common congenital VBWDs. Other uncommon anomalies include ectopia cordis and pentalogy of Cantrell, limb-body wall complex, and bladder and cloacal exstrophy. Although VBWDs are associated with multiple abnormalities with distinct embryological origins and that may affect virtually any system organs, at least in relation to anterior body wall defects, they are thought (except for omphalocele) to share a common embryologic mechanism, that is, a failure involving the lateral body wall folds responsible for closing the thoracic, abdominal, and pelvic portions of the ventral body wall during the fourth week of development. Additionally, many of the principles of diagnosis and management are similar for these conditions. Fetal ultrasound (US) in prenatal care allows the diagnosis of most of such defects with subsequent opportunities for parental counseling and optimal perinatal management. Fetal magnetic resonance imaging may be an adjunct to US, providing global and detailed anatomical information, assessing the extent of defects, and also helping to confirm the diagnosis in equivocal cases. Prenatal imaging features of VBWDs may be complex and challenging, often requiring from the radiologist a high level of suspicion and familiarity with the imaging patterns. Because an appropriate management is dependent on an accurate diagnosis and assessment of defects, radiologists should be able to recognize and distinguish between the different VBWDs and their associated anomalies. In this article, we review the relevant embryology of VBWDs to facilitate understanding of the pathologic anatomy and diagnostic imaging approach. Features will be illustrated with prenatal US and magnetic resonance imaging and correlated with postnatal and clinical imaging. PMID- 26614135 TI - Imaging Evaluation of Fetal Megacystis: How Can Magnetic Resonance Imaging Help? AB - Evaluation of the kidneys, bladder, and amniotic fluid volume forms part of any standard obstetrical ultrasound. When a fetal genitourinary anomaly is suspected, a more detailed evaluation is necessary. This detailed imaging can be challenging in the setting of decreased or absent amniotic fluid or large maternal body habitus, and in complex malformations. In these situations, magnetic resonance imaging can help to better define the fetal anatomy and provide a more confident and specific prenatal diagnosis. PMID- 26614136 TI - Extrafetal Findings on Fetal Magnetic Resonance Imaging: A Pictorial Essay. AB - Although US is the mainstay of fetal imaging, magnetic resonance imaging (MRI) has become an invaluable adjunct in recent years. MRI offers superb soft tissue contrast that allows for detailed evaluation of fetal organs, particularly the brain, which enhances understanding of disease severity. MRI can yield results that are similar to or even better than those of US, particularly in cases of marked oligohydramnios, maternal obesity, or adverse fetal positioning. Incidentally detected extrafetal MRI findings are not uncommon and may affect clinical care. Physicians interpreting fetal MRI studies should be aware of findings occurring outside the fetus, including those structures important for the pregnancy. A systematic approach is necessary in the reading of such studies. This helps to ensure that important findings are not missed, appropriate clinical management is implemented, and unnecessary follow-up examinations are avoided. In this pictorial essay, the most common extrafetal abnormalities are described and illustrated. PMID- 26614137 TI - Brazilian consensus on anesthetic depth monitoring. PMID- 26614138 TI - Use of remifentanil to reduce propofol injection pain and the required propofol dose in upper digestive tract endoscopy diagnostic tests. AB - BACKGROUND AND OBJECTIVES: The introduction of propofol (2,6-diisopropylphenol) as a sedative agent has transformed the area of sedation for endoscopic procedures. However, a major drawback of sedation with the use of propofol is its high incidence of injection pain. The most widely used technique in reducing propofol injection pain is through the association of other drugs. The aim of this study was to evaluate the effect of remifentanil-propofol combination on the incidence of propofol injection pain and its influence on the total dose of propofol required for sedation in upper digestive tract endoscopy (UDE) diagnostic tests. METHOD: One hundred and five patients undergoing upper digestive tract endoscopy were evaluated and randomly divided into 3 groups of 35 patients each. The Control Group received propofol alone; Study-group 1 received remifentanil at a fixed dose of 0.2mg/kg combined with propofol; Study-group 2 received remifentanil at a fixed dose of 0.3mg/kg combined with propofol. The incidence of propofol injection pain and the total dose of propofol required for the test were evaluated. The sample was very similar regarding age, weight, height, sex, and physical status. Statistical analysis was performed according to the nature of the evaluated data. Student's t-test was used to compare the mean of age, weight, height (cm), and dose (mg/kg) variables between groups. The chi(2) test was used to compare sex, physical status, and propofol injection pain between groups. The significance level was alpha<0.05. RESULTS: There was significant statistical difference between the study groups and the control group regarding the parameters of propofol injection pain and total dose of propofol (mg/kg) used. However, there were no statistical differences between the two study groups for these parameters. CONCLUSION: We conclude that the use of remifentanil at doses of 0.2mg/kg and 0.3mg/kg was effective for reducing both the propofol injection pain and the total dose of propofol used. PMID- 26614139 TI - Assessment of the perioperative period in civilians injured in the Syrian Civil War. AB - BACKGROUND: wars and its challenges have historically afflicted humanity. In Syria, severe injuries occurred due to firearms and explosives used in the war between government forces and civilians for a period of over 2 years. MATERIALS AND METHODS: the study included 364 cases, who were admitted to Mustafa Kemal University Hospital, Medicine School (Hatay, Turkey), and underwent surgery. Survivors and non-survivors were compared regarding injury site, injury type and number of transfusions given. The mortality rate found in this study was also compared to those reported in other civil wars. RESULTS: the mean age was 29 (3 68) years. Major sites of injury included extremities (56.0%), head (20.1%), abdomen (16.2%), vascular structures (4.4%) and thorax (3.3%). Injury types included firearm injury (64.4%), blast injury (34.4%) and miscellaneous injuries (1.2%). Survival rate was 89.6% while mortality rate was 10.4%. A significant difference was observed between mortality rates in this study and those reported for the Bosnia and Lebanon civil wars; and the difference became extremely prominent when compared to mortality rates reported for Vietnam and Afghanistan civil wars. CONCLUSION: among injuries related to war, the highest rate of mortality was observed in head-neck, abdomen and vascular injuries. We believe that the higher mortality rate in the Syrian Civil War, compared to the Bosnia, Vietnam, Lebanon and Afghanistan wars, is due to seeing civilians as a direct target during war. PMID- 26614140 TI - Reducing sore throat following laryngeal mask airway insertion: comparing lidocaine gel, saline, and washing mouth with the control group. AB - BACKGROUND: Laryngeal mask airway is still accompanied by complications such as sore throat. In this study, effects of three methods of reducing postoperative sore throat were compared with the control group. METHODS: 240 patients with ASA I, II candidates for cataract surgery were randomly divided into four same groups. No supplementary method was used in the control group. In the second, third and fourth groups, lidocaine gel, washing cuff before insertion, and washing mouth before removing laryngeal mask airway were applied, respectively. Anesthesia induction was done with fentanyl, atracurium, and propofol and maintained with propofol infusion. The incidence of sore throat was evaluated during the recovery, 3-4h later and after 24h using verbal analog scale. The data were analyzed by t-test, analysis of variance and chi-square using SPSS V11.5. RESULTS: Age, gender, duration of surgery and cuff pressure were the same in all the four groups. Incidence of sore throat at recovery room was highest in the control group (43.3%) and lowest in the washing mouth group (25%). However, no significant statistical difference was observed between these four groups (recovery, p=0.30; discharge, p=0.31; examination, p=0.52). In this study, increased duration of operation had a significant relationship with the incidence of sore throat (p=0.041). CONCLUSION: Sore throat is a common postoperative problem, but no special method has been found completely efficient yet. In this study, cuff washing, lidocaine gel, and mouth washing before removing laryngeal mask airway were not helpful for sore throat. PMID- 26614141 TI - Impact of the practising anesthesiologist team member on the laryngeal mask cuff pressures and adverse event rate. AB - OBJECTIVE: We have planned to evaluate the laryngeal mask cuff pressures (LMcp) inflated by anesthesia workers of several seniority, without using manometer. METHODS: 180 patients scheduled to have short duration surgery with laryngeal mask were included in the study. Five anesthesia specialists (Group S), 10 residents (Group R) and 6 technicians (Group T) inflated the LMc; thereafter LMcp were measured with pressure manometer. Participants have repeated this practice in at least five different cases. LMcp higher than 60 cm H2O at the initial placement or intraoperative period were adjusted to normal range. Sore throat was questioned postoperatively. Groups were compared in terms of mean LMcp and occupational experience. RESULTS: At the settlement of LM, LMcp pressures within the normal range were determined in 26 (14.4%) cases. Mean LMcp after LM placement in Group S, R and T were 101.2 +/- 14.0, 104.3 +/- 20.5 cm H2O and 105.2 +/- 18.4 cm H2O respectively (p > 0.05). Mean LMcp values in all measurement time periods within the groups were above the normal limit (60 cm H2O). When groups were compared in terms of LMcp, no difference has been found among pressure values. Occupational experience was 14.2 +/- 3.9; 3.3 +/- 1.1 and 6.6 +/- 3.8 years for specialists, residents and technicians respectively and measured pressure values were not different in regard of occupational experience. Seven (3.9%) patients had sore throat at the 24th hour interview. CONCLUSION: Considering lower possibility of normal adjustment of LMcp and ineffectiveness of occupational experience to obtain normal pressure values, it is suitable that all anesthesia practitioners should adjust LMcp with manometer. PMID- 26614142 TI - Low-dose levobupivacaine plus fentanyl combination for spinal anesthesia in anorectal surgery. AB - BACKGROUND: the aim of this study was to investigate the effects of spinal anesthesia using two different doses of fentanyl combined with low-dose levobupivacaine in anorectal surgery. METHODS: in this prospective, double-blind study, 52 American Society of Anaesthesiologists I-II patients scheduled for elective anorectal surgery were randomized into two groups. The patients in group I received intrathecal 2.5mg hyperbaric levobupivacaine plus 12.5 MUg fentanyl and in group II received intrathecal 2.5mg hyperbaric levobupivacaine plus 25 MUg fentanyl. All the patients remained in the seated position for 5 min after completion of the spinal anesthesia. Sensory block was evaluated with pin-prick test and motor block was evaluated with a modified Bromage scale. RESULTS: motor block was not observed in both of the groups. The sensory block was limited to the S2 level in group I, and S1 level in group II. None of the patients required additional analgesics during the operation. Time to two-segment regression was shorter in group I compared with group II (p<0.01). One patient in group I and 5 patients in group II had pruritus. Hemodynamic parameters were stable during the operation in both of the groups. CONCLUSION: spinal saddle block using hyperbaric levobupivacaine with both 12.5 MUg and 25 MUg fentanyl provided good quality of anesthesia without motor block for anorectal surgery in the prone position. PMID- 26614143 TI - To study the effect of injection dexmedetomidine for prevention of pain due to propofol injection and to compare it with injection lignocaine. AB - BACKGROUND: Pain due to injection propofol is a common problem. Different methods are used to decrease the pain but with limited success. The objective of this study was to assess the effect of injection dexmedetomidine 0.2 mcg/kg for prevention of pain due to propofol injection and compare it with injection lignocaine 0.2mg/kg. METHOD: After taking permission of the Institutional Ethical Committee, written informed consent was obtained from all patients, in a randomized prospective study. 60 American Society of Anesthesiology I and II patients of age range 20-60 years of either sex posted for elective surgeries under general anaesthesia were randomly allocated into two groups. Group I (dexmedetomidine group): Inj. dexmedetomidine 0.2 mcg/kg diluted in 5 mL normal saline and Group II (lignocaine group): Inj. lignocaine 0.2mg/kg diluted in 5 mL normal saline. IV line was secured with 20 G cannula and venous occlusion was applied to forearm using a pneumatic tourniquet and inflated to 70 mm Hg for 1 min. Study drug was injected, tourniquet released and then 25% of the calculated dose of propofol was given intravenously over 10s. After 10s of injection, severity of pain was evaluated using McCrirrick and Hunter scale and then remaining propofol and neuromuscular blocking agent was given. Endotracheal intubation was done and anaesthesia was maintained on O2, N2O and isoflurane on intermittent positive pressure ventilation with Bain's circuit and inj. vecuronium was used as muscle relaxant. RESULTS: Demographic data showed that there was no statistically significant difference between the 2 groups. There was no statistically significant difference between 2 groups in respect to inj. propofol pain. No adverse effects like oedema, pain, wheal response at the site of injection were observed in the two groups. PMID- 26614144 TI - Comparison of propofol and midazolam on patients undergoing spinal surgery with intraoperative wake-up test: randomized clinical trial. AB - BACKGROUND AND OBJECTIVES: Instrumentation in correction operations for spinal deformities carries a 0.5-5% risk of injuring the spinal cord. The wake-up test is used for early detection of these injuries. In this study we compared the effects of propofol and midazolam during wake-up test in scoliosis surgery. METHODS: Thirty patients were randomly assigned as group P and group M. Anesthesia was induced with propofol 2.5 mg kg(-1) for group P or midazolam 0.5 mg kg(-1) for group M with remifentanil 0.5 MUg kg(-1) and cisatracurium 0.15 mg kg(-1) for both groups. At the maintenance of anesthesia O2/air and infusions of remifentanil and cisatracurium were used. In group P, propofol 6-10 mg kg(-1)h( 1) and in group M, midazolam 0.5 mg mg kg(-1) were preferred. Approximately 15 min before the wake-up test, all drugs were discontinued. At the wake-up test, anesthesiologist asked the patients to open their eyes and squeeze his/her hand at every 30s until the patients responded. Then patients were told to wiggle their toes. Hemodynamic parameters, time of eye-opening, appropriate movement upon verbal command were evaluated. BIS frequency throughout the operation was recorded. RESULTS: The eye opening time was 9 +/- 2.15 min in group P and 7 +/- 3.15 min in group M. Motor movement time was 12 +/- 2.55 min in group P and 21.25 +/- 3.93 min in group M. CONCLUSION: Propofol provided better wake-up conditions and conducted a better neurologic assessment within the same BIS values than midazolam. PMID- 26614145 TI - Administration of paracetamol versus dipyrone by intravenous patient-controlled analgesia for postoperative pain relief in children after tonsillectomy. AB - BACKGROUND AND OBJECTIVE: We compared the efficacy of intravenous (IV) paracetamol versus dipyrone via patient-controlled analgesia (PCA) for postoperative pain relief in children. METHODS: The study was composed of 120 children who had undergone elective tonsillectomy after receiving general anesthesia. Patients were divided into 3 groups according to the dosage of postoperative intravenous-patient-controlled analgesia: paracetamol, dipyrone, or placebo. Pain was evaluated using a 0- to 100-mm visual analog scale and 1- to 4 pain relief score at 30 min, 1, 2, 4, 6, 12, and 24h postoperatively. Pethidine (0.25 mg kg(-1)) was administered intravenously to patients requiring rescue analgesia. Pethidine requirements were recorded during the first 24h postoperatively, and treatment related adverse effects were noted. RESULTS: Postoperative visual analog scale scores were significantly lower with paracetamol group compared with placebo group at 6h (p<0.05), dipyrone group compared with placebo group at 30 min and 6h (p<0.05). No significant differences regarding visual analog scale values at 1, 2, 4, 12, and 24h were found. No significant differences were found between groups with respect to pain relief score (p>0.05). Postoperative pethidine requirements were significantly lower with paracetamol and dipyrone groups compared with placebo group (62.5%, 68.4% vs 90%, p<0.05). No significant differences were found between groups with respect to nausea, vomiting and the any other adverse effects of the drugs (p>0.05). CONCLUSIONS: Paracetamol and dipyrone have well tolerability profile and effective analgesic properties when administered IV-PCA for postoperative analgesia in children after tonsillectomy. PMID- 26614146 TI - Pretreatment with remifentanil protects against the reduced-intestinal contractility related to the ischemia and reperfusion injury in rat. AB - BACKGROUND AND OBJECTIVES: Serious functional and structural alterations of gastrointestinal tract are observed in failure of blood supply, leading to gastrointestinal dismotility. Activation of opioid receptors provides cardioprotective effect against ischemia-reperfusion (I/R) injury. The aim of the present study was to determine whether or not remifentanil could reduce I/R injury of small intestine. METHODS: Male Wistar Albino rats were subjected to mesenteric ischemia (30 min) followed by reperfusion (3h). Four groups were designed: sham control; remifentanil alone; I/R control; and remifentanil+I/R. Animals in remifentanil+I/R group were subjected to infusion of remifentanil (2 ug kg(-1)min(-1)) for 60 min, half of which started before inducing ischemia. Collecting the ileum tissues, evaluation of damage was based on contractile responses to carbachol, levels of lipid peroxidation and neutrophil infiltration, and observation of histopathological features in intestinal tissue. RESULTS: Following reperfusion, a significant decrease in carbachol-induced contractile response, a remarkable increase in both lipid peroxidation and neutrophil infiltration, and a significant injury in mucosa were observed. An average contractile response of remifentanil+I/R group was significantly different from that of the I/R group. Lipid peroxidation and neutrophil infiltration were also significantly suppressed by the treatment. The tissue samples of the I/R group were grade 4 in histopathological evaluation. In remifentanil+I/R group, on the other hand, the mucosal damage was moderate, staging as grade 1. CONCLUSIONS: The pretreatment with remifentanil can attenuate the intestinal I/R injury at a remarkable degree possibly by lowering lipid peroxidation and leukocyte infiltration. PMID- 26614147 TI - In vitro comparison of epidural bacteria filters permeability and screening scanning electron microscopy. AB - BACKGROUND AND OBJECTIVES: Epidural catheter bacteria filters are barriers in the patient-controlled analgesia/anaesthesia for preventing contamination at the epidural insertion site. The efficiency of these filters varies according to pore sizes and materials. METHOD: The bacterial adhesion capability of the two filters was measured in vitro experiment. Adhesion capacities for standard Staphylococcus aureus (ATCC 25923) and Pseudomonas aeruginosa (ATCC 27853) strains of the two different filters (Portex and Rusch) which have the same pore size were examined. Bacterial suspension of 0.5 Mc Farland was placed in the patient-controlled analgesia pump, was filtered at a speed of 5 mL/h. in continuous infusion for 48 h and accumulated in bottle. The two filters were compared with colony counts of bacteria in the filters and bottles. At the same time, the filters and adhered bacteria were monitored by scanning electron microscope. RESULTS: Electron microscopic examination of filters showed that the Portex filter had a granular and the Rusch filter fibrillary structure. Colony counting from the catheter and bottle showed that both of the filters have significant bacterial adhesion capability (p<0.001). After the bacteria suspension infusion, colony countings showed that the Portex filter was more efficient (p<0.001). There was not any difference between S. aureus and P. aeruginosa bacteria adhesion. In the SEM monitoring after the infusion, it was physically shown that the bacteria were adhered efficiently by both of the filters. CONCLUSION: The granular structured filter was found statistically and significantly more successful than the fibrial. Although the pore sizes of the filters were same - of which structural differences shown by SEM were the same - it would not be right to attribute the changes in the efficiencies to only structural differences. Using microbiological and physical proofs with regard to efficiency at the same time has been another important aspect of this experiment. PMID- 26614148 TI - Anesthesiologist: the patient's perception. AB - BACKGROUND AND OBJECTIVES: Anesthesia is still a major concern for patients, although the anesthetic complications have decreased significantly. Additionally, the role assigned to the anesthesiologist remains inaccurate. The aim of this study was to evaluate the concerns with anesthesia and assess the patient's knowledge about the anesthesiologist's duties. METHODS: Prospective study conducted over three months with patients in the preoperative anesthetic visit in a university hospital. Demographic information about the level of education and prior anesthesia was obtained. The knowledge of patients regarding the anesthesiologists' education was evaluated. Patients' concerns and anesthesiologist and surgeon responsibilities were classified with a 5-point scale. The analysis was performed with SPSS 21, and p<0.05 was considered statistically significant. RESULTS: We included 204 patients, and 135 (66.2%) recognized the anesthesiologist as a specialist physician. Not waking up after surgery and postoperative infection were the main concerns compared to all others (p<0.05). Women expressed more concern than men about not waking up after surgery, nausea and postoperative vomiting, medical problems, and waking up during surgery (p<0.05). Ensure that patients do not wake up during surgery was the anesthesiologist task most recognized, compared to all other (p<0.05). The surgeon was more recognized (p<0.05) than the anesthesiologist in post-operative, antibiotics administration, and blood transfusions pain management. CONCLUSIONS: Patients need to be informed about the current safety of anesthesia and the anesthesiologist's functions. The patient involvement will demystify some fears and reassure the confidence in the health system. PMID- 26614149 TI - Work-related mental and behaviour disorders in anesthesiologists. AB - BACKGROUND: Anaesthesiology is a specialty whose specificity of the working process results in high levels of stress as an inevitable condition - a particularly worrying situation in the daily life of these professionals. OBJECTIVES: This study, based on data from national and international literature, aims to discuss the basis of the occurrence of mental and behavioural disorders or of psychopathological injuries (psychological distress) related to working activity in anesthesiologists. METHOD: A literature review was conducted, with papers selected from Medline and Lilacs databases, published between 2000 and 2012 in Portuguese, English and Spanish, and addressing the possible association between occupational hazards of the anaesthesiologist profession and mental health problems and psychic distress. Twenty-six publications were listed. RESULTS: Several aspects of the anesthesiologist's work are important points to better understand the relationship between mental health at work and working organization. Poor temporal structuring of work, conflictuous interpersonal relationships and poor control over the activity itself may be mentioned as illness enhancers. CONCLUSION: The working organization, when not appropriate, is an important occupational risk factor for the life and mental health of workers, mainly of professionals focused on the care of people. This paper focuses on anesthesiologists, who are constantly exposed to stressful and anxiogenic factors. PMID- 26614150 TI - Tooth injury in anaesthesiology. AB - BACKGROUND AND OBJECTIVES: Dental injury is the most common complication of general anaesthesia and has significant physical, economic and forensic consequences. The aim of this study is to review on the characteristics of dental injury associated with anaesthesiology and existing methods of prevention. CONTENTS: In this review, the time of anaesthesia in which the dental injury occurs, the affected teeth, the most frequent type of injury, established risk factors, prevention strategies, protection devices and medico-legal implications inherent to its occurrence are approached. CONCLUSIONS: Before initiating any medical procedure that requires the use of classic laryngoscopy, a thorough and detailed pre-aesthetic evaluation of the dental status of the patient is imperative, in order to identify teeth at risk, analyze the presence of factors associated with difficult intubation and outline a prevention strategy that is tailored to the risk of dental injury of each patient. PMID- 26614151 TI - Management of abdominal compartment syndrome after transurethral resection of the prostate. AB - Acute abdominal compartment syndrome is most commonly associated with blunt abdominal trauma, although it has been seen after ruptured abdominal aortic aneurysm, liver transplantation, pancreatitis, and massive volume resuscitation. Acute abdominal compartment syndrome develops once the intra-abdominal pressure increases to 20-25 mmHg and is characterized by an increase in airway pressures, inadequate ventilation and oxygenation, altered renal function, and hemodynamic instability. This case report details the development of acute abdominal compartment syndrome during transurethral resection of the prostate with extra- and intraperitoneal bladder rupture under general anesthesia. The first signs of acute abdominal compartment syndrome in this patient were high peak airway pressures and difficulty delivering tidal volumes. Management of the compartment syndrome included re-intubation, emergent exploratory laparotomy, and drainage of irrigation fluid. Difficulty with ventilation should alert the anesthesiologist to consider abdominal compartment syndrome high in the list of differential diagnoses during any endoscopic bladder or bowel case. PMID- 26614152 TI - Anesthetic management of a pediatric patient with hypohidrotic ectodermal dysplasia undergoing emergency surgery. AB - Ectodermal dysplasias are rare conditions with a triad of hypotrichosis, anodontia and anhidrosis. In literature review there have been only a few reports of anesthetic management of patients with ectodermal dysplasias. Hyperthermia is a very serious risk which may occur due to the defect of sweat glands. The present case involves a 10-year-old child with ectodermal dysplasia who presented with an acute abdomen and was considered for an emergency surgery. Our aim was to demonstrate the successful management of this case using a combination of general and epidural anesthesia. It is important for anesthesiologist to have information about this syndrome in case of emergency operations, since it can prevent serious complications and even save lives. PMID- 26614153 TI - Anesthesia for ex utero intrapartum treatment: renewed insight on a rare procedure. AB - The ex utero intrapartum treatment is a rare surgical procedure performed in cases of expected postpartum fetal airway obstruction. The technique lies on a safe establishment of a patent airway during labor in anticipation of a critical respiratory event, without interrupting maternal-fetal circulation. Anesthetic management is substantially different from that regarding standard cesarean delivery and its main goals include uterine relaxation, fetal anesthesia and preservation of placental blood flow. We present the case of an ex utero intrapartum treatment procedure performed on a fetus with a large cervical lymphangioma and prenatal evidence of airway compromise. Modifications to the classic ex utero intrapartum treatment management strategies were successfully adopted and will be discussed in the following report. PMID- 26614154 TI - Anesthesia for EXIT procedure (ex utero intrapartum treatment) in congenital cervical malformation--a challenge to the anesthesiologist. AB - The ex utero intrapartum treatment (EXIT) procedure consists of partial externalization of the fetus from the uterine cavity during delivery, allowing the maintenance of placental circulation. It is indicated in the presence of congenital malformation when difficulty in fetal airway access is anticipated, allowing it to be ensured by direct laryngoscopy, bronchoscopy, tracheostomy, or surgical intervention. Anesthesia for EXIT procedure has several special features, such as the appropriate uterine relaxation, maintenance of maternal blood pressure, fetal airway establishment, and maintenance of postpartum uterine contraction. The anesthesiologist should be prepared for the anesthetic particularities of this procedure in order to contribute to a favorable outcome for the mother and particularly the fetus. PMID- 26614155 TI - Endotracheal intubation using the Airtraq optical laryngoscope when the glottis is off-center of the viewfinder: are the options of optimization exhausted? PMID- 26614156 TI - Comparison of effects and complications of unilateral versus standard spinal anesthesia in orthopedic surgery of lower limbs. PMID- 26614157 TI - Liver Transplantation in Type III von Willebrand Disease. PMID- 26614158 TI - Traditionally reported adverse events related to EUS-guided FNA biopsy and endobronchial US-guided transbronchial needle aspiration biopsy: Just the tip of the iceberg? PMID- 26614159 TI - Nonsurgical management of cholecystitis: a tailored approach. PMID- 26614160 TI - Fully covered self-expandable metal stents: The "be all and end all" for pancreatic fluid collections? PMID- 26614161 TI - Traditional serrated adenoma: An enigmatic and aggressive polyp? PMID- 26614162 TI - The natural history of steroid-naive eosinophilic esophagitis: the other end of the spectrum. PMID- 26614163 TI - Single-operator cholangioscopy in the diagnosis of indeterminate biliary strictures. PMID- 26614164 TI - Response. PMID- 26614165 TI - ASGE Technology Committee reviews on real-time endoscopic assessment of the histology of diminutive colorectal polyps, and high-definition and high magnification endoscopes. PMID- 26614166 TI - Response. PMID- 26614168 TI - Rotary ultrasonic machining of CFRP: A comparison with grinding. AB - Carbon fiber reinforced plastic (CFRP) composites have been intensively used in various industries due to their superior properties. In aircraft and aerospace industry, a large number of holes are required to be drilled into CFRP components at final stage for aircraft assembling. There are two major types of methods for hole making of CFRP composites in industry, twist drilling and its derived multi points machining methods, and grinding and its related methods. The first type of methods are commonly used in hole making of CFRP composites. However, in recent years, rotary ultrasonic machining (RUM), a hybrid machining process combining ultrasonic machining and grinding, has also been successfully used in drilling of CFRP composites. It has been shown that RUM is superior to twist drilling in many aspects. However, there are no reported investigations on comparisons between RUM and grinding in drilling of CFRP. In this paper, these two drilling methods are compared in five aspects, including cutting force, torque, surface roughness, hole diameter, and material removal rate. PMID- 26614167 TI - Integrin-linked kinase regulates oligodendrocyte cytoskeleton, growth cone, and adhesion dynamics. AB - Integrin-linked kinase (ILK), a focal adhesion protein, brokers the link between cytoskeleton, cell membrane, and extracellular environment. Here, we demonstrate a role for ILK in laminin-2-mediated adhesion in primary murine oligodendrocytes (OLs) - with ILK loss leading to severe defects in process branching and outgrowth. These defects were partially recovered when the ILK-depleted OLs were instead grown on the non-integrin-activating substrate poly-l-lysine. Intriguingly, ILK loss on the neutral poly-l-lysine substrate led to swelling at the tips of OL processes, which we identified as enlarged growth cones. Employing the bloated ILK-depleted growth cones as template, we demonstrate the appearance of distinct cytoskeletal domains within OL growth cones bearing classic neuronal growth cone architecture. Further, microtubule organization was severely perturbed following ILK loss, with centripetal microtubule looping and failure to bundle occurring in a laminin-2-independent manner. Together, our work highlights differences in specific aspects of OL biology as driven by laminin-2-dependent or independent ILK governed mechanisms. We also reinforce the idea of OLs as growth cone bearing cells and describe the neuronal-like cytoskeleton therein. Finally, we demonstrate a role for ILK in OL growth cone maturation through microtubule regulation, the loss of which translates to decreased process length and myelin production capacity. We describe herein how different substrates fundamentally alter the oligodendrocyte's response to loss of integrin-linked kinase (ILK). On laminin-2 (Ln-2), ILK-depleted oligodendrocytes appear stunted and malformed, while on the non-integrin-activating substrate PLL branching and membrane formation are restored. We also reinforce the idea of oligodendrocytes as growth cone-bearing cells, detailing the growth cone's cytoskeletal architecture. Strikingly, loss of ILK on poly-l-lysine leads to growth cone swelling, the structure's size and motility rendered less dynamic. Together, our work helps reconcile the phenotypic discrepancy between ILK loss in vitro and in vivo, informs on the oligodendrocyte's growth cone, and ascribes a role for ILK in growth cone dynamics. PMID- 26614169 TI - Emulsification liquid-liquid microextraction based on deep eutectic solvent: An extraction method for the determination of benzene, toluene, ethylbenzene and seven polycyclic aromatic hydrocarbons from water samples. AB - In this study, for the first time, a simple, inexpensive and sensitive method named emulsification liquid-liquid microextraction based on deep eutectic solvent (ELLME-DES) was used for the extraction of benzene, toluene, ethylbenzene (BTE) and seven polycyclic aromatic hydrocarbons (PAHs) from water samples. In a typical experiment, 100MUL of DES (as water-miscible extraction solvent) was added to 1.5mL of sample solution containing target analytes. A homogeneous solution was formed immediately. Injection of 100MUL of THF (as emulsifier agent) into homogeneous solution provided a turbid state. After extraction, phase separation (aqueous phase/DES rich phase) was performed by centrifugation. DES rich phase was withdrawn by a micro-syringe and submitted to isocratic reverse phase HPLC with UV detection. Under optimum conditions obtained by response surface methodology (RSM) and desirability function (DF), the calibration graphs were linear in the concentration range from 10 to 200MUg/L for benzene, 10 400MUg/L for toluene, 1-400MUg/L for ethylbenzene, biphenyl, chrysene and fluorene, and 0.1-400MUg/L for anthracene, benzo[a]pyrene, phenanthrene and pyrene. The coefficients of determination (r(2)) and limits of detection were 0.9924-0.9997 and 0.02-6.8MUg/L, respectively. This procedure was successfully applied to the determination of target analytes in spiked water samples. The relative mean recoveries ranged from 93.1 to 103.3%. PMID- 26614170 TI - Determination of ultratrace levels of tributyltin in waters by isotope dilution and gas chromatography coupled to tandem mass spectrometry. AB - The current EU legislation lays down the Environmental Quality Standards (EQS) of 45 priority substances in surface water bodies. In particular, the concentration of tributyltin (TBT) must not exceed 0.2ngL(-1) and analytical methodologies with a Limit of Quantification (LOQ) equal or below 0.06ngL(-1) are urged to be developed. This work presents a procedure for the determination of ultratrace levels of TBT in water samples by Isotope Dilution and GC-MS/MS operating in Selected Reaction Monitoring (SRM) mode which meets current EU requirements. The method requires the monitorization of five consecutive transitions (287>175 to 291>179) for the sensitive and selective detection of TBT. The measured isotopic distribution of TBT fragment ions was in agreement with the theoretical values computed by a polynomial expansion algorithm. The combined use of Tandem Mass Spectrometry, a sample volume of 250mL, the preconcentration of 1mL of organic phase to 30MUL and an injection volume of 25MUL by Programmed Temperature Vaporization provided a LOQ of 0.0426ngL(-1) for TBT (calculated as ten times the standard deviation of nine independent blanks). The recovery for TBT calculated in Milli-Q water at the EQS level was 106.3+/-4%. A similar procedure was also developed for the quantification of dibutyltin (DBT) and monobutyltin (MBT) in water samples showing satisfactory results. The method was finally implemented in a routine testing laboratory to demonstrate its applicability to real samples obtaining quantitative recoveries for TBT at the EQS level in mineral water, river water and seawater. PMID- 26614171 TI - In-line micro-matrix solid-phase dispersion extraction for simultaneous separation and extraction of Sudan dyes in different spices. AB - A novel, simple, fast, and miniaturized method, termed in-line micro-matrix solid phase dispersion (in-line MMSPD), coupled with high performance liquid chromatography (HPLC) was developed for the simultaneous extraction and determination of Sudan dyes (i.e. Sudan I-IV, Sudan orange G, Sudan black B, and Sudan red G) with the aid of an experimental design strategy. In this method, a matrix solid-phase dispersion (MSPD) column including a suitable mixture of polar sorbents was inserted in the mobile phase pathway, and while the interfering compounds were retained, the analytes were eluted and entered into the analytical column. In this way, the extraction, elution, and separation of the analytes were performed sequentially. Under the optimal experimental conditions (including the amount of sample, 0.0426g; amount of dispersant phase, 0.0216g of florisil, 0.0227g of silica, 0.0141g of alumina; and blending time, 112s), the limits of detection (LODs), limits of quantification, linear dynamic ranges, and recoveries were obtained to be 0.3-15.3MUgkg(-1), 1-50MUgkg(-1), 50-28,000MUgkg(-1), and 94.5-99.1%, respectively. The results obtained showed that determination of the selected Sudan dyes in food samples using an enough sensitive and a simple analytically validated method like in-line MMSPD may offer a suitable screening method, which could be useful for food analysis and adulteration. PMID- 26614172 TI - Application of acetone acetals as water scavengers and derivatization agents prior to the gas chromatographic analysis of polar residual solvents in aqueous samples. AB - The sensitivity of gas chromatography (GC) combined with the full evaporation technique (FET) for the analysis of aqueous samples is limited due to the maximum tolerable sample volume in a headspace vial. Using an acetone acetal as water scavenger prior to FET-GC analysis proved to be a useful and versatile tool for the analysis of high boiling analytes in aqueous samples. 2,2-Dimethoxypropane (DMP) was used in this case resulting in methanol and acetone as reaction products with water. These solvents are relatively volatile and were easily removed by evaporation enabling sample enrichment leading to 10-fold improvement in sensitivity compared to the standard 10MUL FET sample volumes for a selection of typical high boiling polar residual solvents in water. This could be improved even further if more sample is used. The method was applied for the determination of residual NMP in an aqueous solution of a cefotaxime analogue and proved to be considerably better than conventional static headspace (sHS) and the standard FET approach. The methodology was also applied to determine trace amounts of ethylene glycol (EG) in aqueous samples like contact lens fluids, where scavenging of the water would avoid laborious extraction prior to derivatization. During this experiment it was revealed that DMP reacts quantitatively with EG to form 2,2 dimethyl-1,3-dioxolane (2,2-DD) under the proposed reaction conditions. The relatively high volatility (bp 93 degrees C) of 2,2-DD makes it possible to perform analysis of EG using the sHS methodology making additional derivatization reactions superfluous. PMID- 26614173 TI - Development of solid-phase microextraction fibers based on multi-walled carbon nanotubes for pre-concentration and analysis of alkanes in human breath. AB - In this work, a laboratory preparation method based on sol-gel technology was proposed to develop a new kind of SPME (solid phase microextraction) fibers. Multi-walled carbon nanotubes (MWCNT) were selected as sol-gel active organic component. Stainless steel wires were used as the substrate of the fibers. Instead of traditional modification methods, microwave induced plasma was used to modify the stainless steel wire surface, resulting in a significant improvement in chemical adhesion of the fiber substrate and coating. The MWCNT coating exhibited several good properties. Acceptable fiber-to-fiber reproducibility (RSD<=13%) and repeatability (RSD<7%) were obtained. End-tidal breath of 10 normal humans were collected by Bio-VOC((r)) sampler and assayed by the optimized SPME-GC-MS method. The calibration curves were all linear (R(2)>=0.994) in the range from 0.03 to 403.3ppbv for five alkanes. Detection limits (down to 0.001ppbv) were about one order of magnitude better than those of commercial PDMS fibers. The recovery of the spiked alkanes in real breath sample at 1ppbv ranged from 89.71 to 101.08% and the relative standard deviations were less than 8%. These results demonstrated the feasibility and practicality of the proposed preparation procedure. Applications of the in-house fabricated fibers for human breath analysis were successfully verified. PMID- 26614174 TI - Combined urea-thin layer chromatography and silver nitrate-thin layer chromatography for micro separation and determination of hard-to-detect branched chain fatty acids in natural lipids. AB - A simple, fast and efficient procedure was developed for micro separation and enrichment of branched chain fatty acids (BCFA) from natural products using successive thin layer chromatography (TLC) technique coupling novel urea-TLC with AgNO3-TLC, which rely on the formation of urea adduction and AgNO3 bonding in methanol. These natural lipids contain a significant amount of straight chain fatty acids (FA). Fresh and fast urea-TLC and AgNO3-TLC plate making techniques were developed with more even coating and less coating material contamination before being utilized for separation. Goat milk fat was used as a model. Various experimental parameters that affect urea-TLC and AgNO3-TLC separation of BCFA were investigated and optimized, including coating of urea, concentration of original oil sample, mobile phase and sample application format. High efficiency of removal of straight chain FA was achieved with a low amount of sample in an easy and fast way. A total BCFA mix with much higher purity than previous studies was successfully achieved. The developed method has also been applied for the concentration and analysis of BCFA in cow milk fat and Anchovy oil. PMID- 26614175 TI - Absence of experimental evidence of a delta-shock in the system phenetole and 4 tert-butylphenol on Zorbax 300SB-C18. AB - We investigate the system consisting of phenetole (PNT) and 4-tert-butylphenol (TBP) in methanol-water (63:37 v:v) on a Zorbax 300SB-C18 column by characterising single component isotherms, by performing a large number of binary experiments of different types and by describing the experiments through simulations carried out using a novel, rather powerful competitive adsorption isotherm, that we call the generalized bi-Langmuir isotherm. This system is of great interest because it was previously reported to yield a new type of transition in nonlinear chromatography, the so-called delta-shock. Such transition had been discovered earlier through a theoretical analysis and confirmed by detailed simulations. The initial aim of this work was to reach a satisfactory agreement between delta-shock experiments and corresponding numerical simulations. In the course of this work however, a number of inconsistencies in the interpretation of the previous experimental results were highlighted and explained. This led to a new experimental campaign, which is reported here and has allowed to reach two important conclusions: (1) The binary system PNT-TBP mentioned above does not exhibit a delta-shock; the spike in the UV profile, which has previously been interpreted as an experimental evidence of the delta-shock, results from liquid-liquid phase separation within the chromatographic column. (2) The same system exhibits a rather peculiar behavior in breakthrough and displacement experiments, which could be well described using the generalized bi-Langmuir isotherm. PMID- 26614176 TI - Comparison of prophylactic use of intravenous immunoglobulin versus Pentaglobin(r) in pediatric patients after hematopoietic stem cell transplantation. AB - There are few studies evaluating the use of IgM-enriched IVIG (Pentaglobin((r)) ) in HSCT recipients. This study aimed to compare the efficacy of prophylactic use of IVIG versus prophylactic use of Pentaglobin((r)) within the first 100 days after allogeneic HSCT. We performed a prospective, randomized study of the use of prophylactic IVIG versus prophylactic use of Pentaglobin((r)) in patients after allogeneic HSCT. The first dose of IVIG or Pentaglobin((r)) was given before conditioning regimen and after transplant was given on day +1, +8, +15, and +22. And then, it was given if IgG level was below 400 mg/dL. Twenty-seven patients in IVIG group and 32 patients in Pentaglobin((r)) group were included in the study. There were no significant differences in the duration of neutropenia, hospitalization, fever, and in the number of pyrexial episode, septicemia, bacteremia, local infection, CMV infection, acute GVHD, VOD, and adverse events between the IVIG group and Pentaglobin((r)) group. Randomized placebo-controlled trials are needed to conclude that utilization of IVIG or Pentaglobin((r)) has no beneficial effect in HSCT. PMID- 26614177 TI - Chest X-rays for screening of paediatric PTB: child selection and standardised radiological criteria are key. PMID- 26614178 TI - How can we sensibly rule out previous episodes of pulmonary tuberculosis disease? PMID- 26614179 TI - The cost of 'free' tuberculosis care. PMID- 26614180 TI - Expanding human immunodeficiency virus testing and counseling to reach tuberculosis clients' partners and families. AB - Recent years have shown important increases in human immunodeficiency virus (HIV) testing and counseling (HTC), diagnosis, and coverage of antiretroviral therapy (ART) among HIV-infected tuberculosis (TB) patients. Expansion of HTC for partners and families are critical next steps to increase earlier HIV diagnoses and access to ART, and to achieve international goals for reduced TB and HIV related morbidity, mortality, transmission and costs. TB and HIV programs should develop and evaluate feasible and effective strategies to increase access to HTC among the partners and families of TB patients, and ensure that newly diagnosed people living with HIV and HIV-infected TB patients who complete anti tuberculosis treatment are successfully linked to ongoing HIV clinical care. PMID- 26614181 TI - Clinical research in the treatment of tuberculosis: current status and future prospects. AB - To supplement previous state-of-art reviews on anti-tuberculosis treatment and to pave the way forward with reference to the current status, we systematically reviewed published literature on clinical research on tuberculosis (TB) over the past decade in the treatment of drug-susceptible and multidrug-resistant TB (MDR TB), with a focus on drugs, dosing factors and regimens. Our review was restricted to Phase II/III clinical trials, cohort and case-control studies, and systematic reviews of clinical studies. TB programmatic and patient behavioural factors, non-TB drugs, adjunctive surgery, new vaccines, immunotherapy, antiretroviral therapy and management of latent tuberculous infection are outside the scope of this review. An algorithm was used to systematically search PubMed for relevant articles published in English from 1 January 2005 to 31 December 2014. Articles without evaluated factors (drugs, dosing factors and regimens) or comparative analysis of specified anti-tuberculosis treatment outcomes were excluded. Of the 399 articles initially identified, 294 were excluded. The main findings of the remaining 105 articles are described under two categories: presumed drug-susceptible TB and MDR-TB. Fifty-nine articles included under drug susceptible TB were divided into 12 subcategories: isoniazid, rifampicin, pyrazinamide, fluoroquinolones, fixed-dose combination drugs, dosing frequency, treatment phases, treatment duration, experimental regimens for pulmonary (surrogate markers vs. clinical outcomes) and extra-pulmonary TB. Forty-nine articles included under MDR-TB were divided into seven subcategories: fluoroquinolones, pyrazinamide, second-line injectable drugs, World Health Organization Group 4 and Group 5 drugs, MDR-TB regimens and novel drugs. Clinical research in the last decade and ongoing trials might furnish new paradigms for improving the treatment of this recalcitrant ancient disease. PMID- 26614182 TI - An evaluation of chest X-ray in the context of community-based screening of child tuberculosis contacts. AB - BACKGROUND: There are no published data on the critical review of chest X-ray (CXR) findings of children in the context of community-based contact screening. OBJECTIVES: To describe the quality, findings and inter-observer agreement of CXRs in child TB contacts in Indonesia. METHODS: We performed antero-posterior (AP) and lateral CXR in children who had had close contact with a pulmonary TB case. The CXRs were interpreted independently by four reviewers. RESULTS: A total of 530 CXRs of 265 children were reviewed. Most (63%) of the children were asymptomatic at the time of CXR. Only 60% of the CXRs were reported as moderate to good quality by all reviewers, and inter-observer agreement on quality was slight to moderate (weighted kappa = 0.16-0.35) for AP view. The majority of the CXRs were reported as normal (range 65-77%), with fair to moderate inter-observer agreement (kappa = 0.25-0.46). Hilar lymphadenopathy (6-16%) was the most common CXR abnormality reported with poor inter-observer agreement (kappa = -0.03 to 0.25). CONCLUSION: The CXRs of child TB contacts investigated in the community were characterised by low quality, low agreement and low yield. Our findings support guidelines that CXR is not routinely indicated in asymptomatic child TB contacts in this setting. PMID- 26614183 TI - Assessment of previous tuberculosis status using questionnaires, chest X-rays and computed tomography scans. AB - SETTING: Accurate diagnosis of previous pulmonary tuberculosis disease (PPTB) status is important clinically and in research. Reliable records of bacteriologically confirmed tuberculosis (TB) are frequently unavailable. OBJECTIVES: To evaluate the use of questionnaires and chest imaging to determine PPTB status in a high TB prevalence population. DESIGN: PPTB status was assessed using two questionnaires, chest X-ray (CXR) and high-resolution chest computed tomography (CT) scans reported by experienced readers. The study population comprised adults aged >40 years diagnosed with obstructive lung disease in a community-based prevalence survey. RESULTS: The Burden of Obstructive Lung Disease (BOLD) questionnaire and a second comprehensive questionnaire (PTbQ) provided a history of PPTB in respectively 38% (n = 41) and 36.4% (n = 39) of 107 participants. On CXR, 43.3% (45/104) had evidence of PPTB, with good inter-reader agreement (kappa = 0.73). Changes compatible with PPTB were identified on chest CT in 68.3% (71/104) of the subjects. Questionnaire and CXR had negative predictive values for PPTB of 48% and 47%, respectively, compared to a composite definition. CONCLUSION: Both questionnaire and CXR markedly underestimate the prevalence of previous TB in patients with chronic obstructive pulmonary disease. The combination of a structured questionnaire and CT scan is more useful when a diagnosis of PPTB needs to be ruled out. PMID- 26614184 TI - Computerised tomography and intravenous pyelography in urinary tuberculosis: a retrospective descriptive study. AB - OBJECTIVE: To assess the radiological findings of urinary tuberculosis (TB) in patients from multiple centres to improve understanding of this disease among urologists and radiologists. MATERIALS AND METHODS: A total of 192 consecutive patients (98 males and 94 females) with urinary TB underwent computed tomography; 28 of the 192 also underwent contrast agent-enhanced intravenous pyelography of the kidney, ureter and bladder (KUB/IVP). RESULTS: The most common finding was hydronephrosis, observed in 79.1% of the patients, with 81.4% of the destructive renal lesions identified in the medulla. The numbers of lesions in the dorsal medulla and the lower pole of the renal medulla were greater than those in the ventral, middle and upper poles (P = 0.0361). CONCLUSION: Hydronephrosis is a frequently observed radiological finding among patients with urinary TB. Most TB lesions were observed in the renal medulla, especially the dorsal and lower poles of the medulla. PMID- 26614185 TI - Magnetic resonance angiography manifestations and prognostic significance in HIV negative tuberculosis meningitis. AB - OBJECTIVE: To evaluate the patterns, related factors and prognostic value of abnormal magnetic resonance angiography (MRA) in human immunodeficiency virus negative tuberculous meningitis. MATERIALS AND METHODS: We performed a prospective study in patients aged >14 years. Abnormality on MRA was correlated with clinical, laboratory and magnetic resonance imaging findings. Modified Barthel index was used to assess outcome at 6 months after inclusion. RESULTS: Of 101 patients included, MRA was abnormal in 45 (44.6%). The distribution of MRA abnormality was classified as disseminated irregular calibres of intracranial arteries with or without reduction in distant branches (29.7%, pattern 1) and localised stenosis at the base of the brain (26.7%, pattern 2). In logistic regression analysis, pattern 2 was related to stage of the disease (P = 0.002), basal exudates (P = 0.03) and infarction (P = 0.000), while pattern 1 was related to duration of disease (P = 0.050), hydrocephalus (P = 0.032) and age (P = 0.002). Pattern 1 was also correlated with infarction (P = 0.000), particularly infarction in the tubercular zone (P = 0.035) in univariate analysis. MRA abnormality was associated with paradoxical worsening (P = 0.022) and poor prognosis in univariate analysis (P = 0.035). CONCLUSION: MRA abnormality is associated with stroke and poor outcomes. Although it indicates mild vascular injury, pattern 1 MRA abnormality is nevertheless associated with infarction and needs proper intervention. PMID- 26614187 TI - Interferon gamma inducible protein-10 in the diagnosis of paediatric tuberculosis infection in a low TB incidence country. AB - OBJECTIVE: To assess interferon-gamma inducible protein 10 (IP-10) as a diagnostic marker for tuberculous infection in children, particularly in relation to its differential diagnostic performance in young children. DESIGN AND RESULTS: A case-control study was conducted among 161 children and adolescents (mean age 6.3 years +/- standard deviation 1.7; males n = 79, 49%). Fifty-four (33.5%) had active TB, 53 (33%) had latent tuberculous infection (LTBI), and 54 (33.5%) were non-LTBI controls. Unstimulated IP-10 levels did not differ between groups (P > 0.05 for all comparisons). TB-specific antigen stimulated IP-10 levels were more profoundly increased in infected groups than in controls (P < 0.001 for all comparisons). None of the IP-10-based diagnostic indexes demonstrated the ability to discriminate active disease from LTBI. A value of IP-10 ? 1222 pg/ml had 83.3% sensitivity, 79.6% specificity, 80.4% positive predictive value and 82.7% negative predictive value for the diagnosis of LTBI. IP-10 based indexes demonstrated a trend towards better performance in the population group aged <5 years. CONCLUSION: The IP-10 assay could be useful in improving the diagnosis of LTBI in patients aged <5 years in combination with existing interferon-gamma release assays. PMID- 26614186 TI - Pott's disease in Moroccan children: clinical features and investigation of the interleukin-12/interferon-gamma pathway. AB - SETTING: Tuberculosis spondylodiscitis (TS), or Pott's disease, an extra pulmonary form of tuberculosis (TB), is rare and difficult to diagnose in children. Some cases of severe TB in children were recently explained by inborn errors of immunity affecting the interleukin-12/interferon-gamma (IL-12/IFN gamma) axis. OBJECTIVE: To analyse clinical data on Moroccan children with TS, and to perform immunological and genetic explorations of the IL-12/IFN-gamma axis. DESIGN: We studied nine children with TS diagnosed between 2012 and 2014. We investigated the IL-12/IFN-gamma circuit by both whole-blood assays and sequencing of the coding regions of 14 core genes of this pathway. RESULTS: A diagnosis of TS was based on a combination of clinical, biological, histological and radiological data. QuantiFERON((r))-TB Gold In-Tube results were positive in 75% of patients. Whole-blood assays showed normal IL-12 and IFN-gamma production in all but one patient, who displayed impaired decreased response to IL-12. No candidate disease-causing mutations were detected in the exonic regions of the 14 genes. CONCLUSIONS: TS diagnosis in children remains challenging, and is based largely on imaging. Further investigations of TS in children are required to determine the role of genetic defects in pathways that may or may not be related to the IL-12/IFN-gamma axis. PMID- 26614188 TI - Evaluation of variants of carbol fuchsin solution to stain acid-fast bacilli in situ by the pot method. AB - BACKGROUND: Ziehl-Neelsen (ZN) staining requires heating, and pre-stained smears contain viable bacilli. OBJECTIVE: To evaluate four variants of carbol fuchsin solution by the pot method and compare the results with ZN staining, taking culture as gold standard. METHOD: Five hundred sputum samples from presumptive tuberculosis cases were homogenised and divided into two parts. One part was subjected to routine ZN staining and culture on solid medium, the other was equally distributed into four pots. Equal quantities of the basic fuchsin (BF) variant were added to each pot. Variant I contained 2% BF with 10% phenol and 4% ammonium sulphate (PhAS), while Variant II had 0.6% BF with PhAS; Variants III and IV contained respectively 2% and 0.6% BF with 10% phenol only. After 1 h, smears were made from each pot and culture was performed on Lowenstein-Jensen medium. Smear results were compared with the ZN results and evaluated against culture. RESULTS AND CONCLUSION: Variant III gave excellent results compared to ZN (kappa = 0.97), with sensitivity, specificity, and positive and negative predictive values similar to those of ZN, taking culture as gold standard. Pot contents were negative for Mycobacterium tuberculosis culture. PMID- 26614189 TI - Serum CXCR3 ligands as biomarkers for the diagnosis and treatment monitoring of tuberculosis. AB - SETTING: Tertiary care academic medical centre. OBJECTIVE: To evaluate the clinical utility of CXC chemokine receptor 3 (CXCR3) ligands in the diagnosis and monitoring of tuberculosis (TB). DESIGN: Presumptive TB patients (active TB, 256; non-TB disease, 52) and 201 healthy controls were enrolled. The serum levels of interferon-gamma (IFN-gamma) and CXCR3 ligands (CXCL9, a monokine induced by IFN gamma [MIG] and CXCL11, an IFN-inducible T-cell alpha chemoattractant [I-TAC]) were measured using enzyme-linked immunosorbent assay. An IFN-gamma release assay (IGRA) was also performed. Serial samplings were performed in 19 TB patients at baseline and at 1, 2, 3, 6 and 12 months after treatment initiation. RESULTS: All marker levels were higher in TB patients than in controls and non-TB patients. The area under the curve (AUC) for differentiating between all TB patients and controls was 0.96 (95%CI 0.94-0.98) for CXCL9, 0.84 (95%CI 0.80-0.87) for CXCL11 and 0.61 (95%CI 0.57-0.66) for IFN-gamma. CXCL9 levels afforded particularly high discriminatory power between TB patients and IGRA-positive controls (AUC = 0.95, 95%CI 0.92-0.97). The levels of CXCR3 ligands decreased significantly during follow-up, and these changes were correlated with treatment response. CONCLUSION: CXCR3 ligands CXCL9 and CXCL11 may be useful surrogate markers for the diagnosis and follow-up of TB. PMID- 26614191 TI - Risk of active tuberculosis in chronic kidney disease: a systematic review and meta-analysis. AB - BACKGROUND: Although the global prevalence of chronic kidney disease (CKD) is increasing, the relationship between CKD and active TB is not well described. OBJECTIVE: To conduct a systematic review to evaluate active TB risk in CKD populations. METHODS: We searched Ovid Medline, EMBASE and Cochrane databases and relevant journals to identify multicentre or regional studies reporting quantitative effect estimates of an association between CKD and active TB. Risk ratios and rate ratios were used as common measures of association. Pooled estimates were generated using a random-effects model. RESULTS: Of 3406 papers screened, 12 eligible studies were identified with 71,374 end-stage renal disease (ESRD) patients and 560 TB cases. Meta-analysis of adjusted rate ratio data in dialysis populations showed an increased rate of 3.62 (95%CI 1.79-7.33, P < 0.001) compared to the general population, while unadjusted risk ratio data in transplant populations showed an increased risk of 11.35 (95%CI 2.97-43.41) compared to the general population. CONCLUSION: We found consistent evidence of an increased risk of active TB in ESRD compared to the general population. This relationship persisted despite variability in study population, design and renal replacement therapy (RRT) modality. Further research into the role of comorbidities, RRT modality and CKD stage is required to better understand the association between CKD and active TB. PMID- 26614192 TI - Increased risk of pulmonary and extra-pulmonary tuberculosis in patients with rheumatic diseases. AB - SETTING: Impaired immunity in patients with rheumatic diseases can increase the risk of pulmonary tuberculosis (PTB). However, it is less clear whether rheumatic diseases affect the risk of extra-pulmonary tuberculosis (EPTB). OBJECTIVE: To investigate the risk of PTB and EPTB in patients with rheumatic diseases using a population-based database. DESIGN: From Taiwan's National Health Insurance Research Database, 8536 patients with tuberculosis (TB) were frequency-matched with 42,680 controls for sex, 10-year age group and index year. Subjects were retrospectively traced back for their first diagnosis of rheumatic diseases. The association between TB and rheumatic diseases was assessed using multivariate logistic regression analyses. RESULTS: The risk of developing PTB was significantly higher in patients with systemic lupus erythematosus (adjusted odds ratio [aOR] 4.90, P < 0.001), rheumatoid arthritis (RA) (aOR 2.00, P < 0.001) and Sjogren's syndrome (aOR 6.11, P < 0.001). In addition, the risks of developing EPTB were significantly higher in RA patients (aOR 4.67, P < 0.001), those with Sjogren's syndrome (aOR 5.94, P < 0.001), and the group comprising progressive systemic sclerosis, polymyositis or dermatomyositis (aOR 8.31, P = 0.021). CONCLUSION: Elevated risks of PTB and EPTB were associated with various rheumatic diseases. Rheumatologists should be vigilant to the possibility of TB, and particularly EPTB, in their patients. PMID- 26614190 TI - Risk factors for transmission of tuberculosis among United States-born African Americans and Whites. AB - SETTING: Tuberculosis (TB) patients and their contacts enrolled in nine states and the District of Columbia from 16 December 2009 to 31 March 2011. OBJECTIVE: To evaluate characteristics of TB patients that are predictive of tuberculous infection in their close contacts. DESIGN: The study population was enrolled from a list of eligible African-American and White TB patients from the TB registry at each site. Information about close contacts was abstracted from the standard reports of each site. RESULTS: Close contacts of African-American TB patients had twice the risk of infection of contacts of White patients (adjusted risk ratio [aRR] 2.1, 95%CI 1.3-3.4). Close contacts of patients whose sputum was positive for acid-fast bacilli on sputum smear microscopy had 1.6 times the risk of tuberculous infection compared to contacts of smear-negative patients (95%CI 1.1 2.3). TB patients with longer (>3 months) estimated times to diagnosis did not have higher proportions of infected contacts (aRR 1.2, 95%CI 0.9-1.6). CONCLUSION: African-American race and sputum smear positivity were predictive of tuberculous infection in close contacts. This study did not support previous findings that longer estimated time to diagnosis predicted tuberculous infection in contacts. PMID- 26614193 TI - Factors associated with diabetes mellitus among adults with tuberculosis in a large European city, 2000-2013. AB - BACKGROUND: Diabetes mellitus (DM) can contribute to the development of tuberculosis (TB). OBJECTIVE: To analyse the prevalence of DM and its associated factors among adults with TB in a large city in an industrialised country. METHODS: This is a population-based study in adults diagnosed with TB between 2000 and 2013 in Barcelona. We studied potentially associated sociodemographic and clinical/epidemiological factors. Logistic regression was used to calculate odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS: Of 5849 TB patients, 349 (5.9%) had DM. The annual prevalence of DM ranged from 4.0% to 7.2%. Factors associated with DM were being Spanish-born (OR 1.46, 95%CI 1.11 1.96), age ?40 years (OR 6.08, 95%CI 4.36-8.66), cavitary patterns on chest X-ray (OR 1.42, 95%CI 1.08-1.86), experiencing more side effects due to anti tuberculosis treatment (OR 1.86, 95%CI 1.28-2.64) and hospitalisation at the time of diagnosis (OR 1.8, 95%CI 1.40-2.31). Human immunodeficiency virus infection was associated with a lower probability of DM in both subjects with a history of injection drug use (OR 0.27, 95%CI 0.10-0.57) and those without (OR 0.04, 95%CI 0.002-0.19). CONCLUSIONS: DM prevalence among adults with TB in Barcelona is low and remained stable over the 14-year study period. However, TB patients with DM were potentially more infectious and their clinical management was more complicated. PMID- 26614194 TI - Patients' costs associated with seeking and accessing treatment for drug resistant tuberculosis in South Africa. AB - SETTING: South Africa is one of the world's 22 high tuberculosis (TB) burden countries, with the second highest number of notified rifampicin-resistant TB (R(R)-TB) and multidrug-resistant TB (MDR-TB) cases. OBJECTIVE: To estimate patient costs associated with the diagnosis and treatment of R(R)-TB/MDR-TB in South Africa. DESIGN: Patients diagnosed with R(R)-TB/MDR-TB and accessing care at government health care facilities were surveyed using a structured questionnaire. Direct and indirect costs associated with accessing R(R)-TB/MDR-TB care were estimated at different treatment durations for each patient. RESULTS: A total of 134 patients were surveyed: 84 in the intensive phase and 50 in the continuation phase of treatment, 82 in-patients and 52 out-patients. The mean monthly patient costs associated with the diagnosis and treatment of R(R)-TB/MDR TB were higher during the intensive phase than the continuation phase (US$235 vs. US$188) and among in-patients than among out-patients (US$269 vs. US$122). Patients in the continuation phase and those accessing care as out-patients reported higher out-of-pocket costs than other patients. Most patients did not access social protection for costs associated with R(R)-TB/MDR-TB illness. CONCLUSION: Despite free health care, patients bear high costs when accessing diagnosis and treatment services for R(R)-TB/MDR-TB; appropriate social protection mechanisms should be provided to assist them in coping with these costs. PMID- 26614195 TI - Nosocomial transmission of multidrug-resistant tuberculosis. AB - Nosocomial transmission of multidrug-resistant tuberculosis (MDR-TB) was ascertained by 24-locus mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) and spoligotyping at four hospitals in the Republic of Moldova, a high MDR-TB burden country. Overall, 5.1% of patients with pan-susceptible TB at baseline were identified with MDR-TB during in-patient treatment. In 75% of cases, the MDR-TB strain was genetically distinct from the non-MDR-TB strain at baseline, suggesting a high rate of nosocomial transmission of MDR-TB. The highest proportion (40.3%) of follow-up MDR-TB isolates was associated with the M. tuberculosis URAL 163-15 strain. PMID- 26614197 TI - Systematic screening for drug-resistant tuberculosis with Xpert((r)) MTB/RIF in a referral hospital in Cambodia. AB - SETTING: Limited access to drug susceptibility testing (DST) in referral hospitals contributes to delayed detection of multidrug-resistant tuberculosis (MDR-TB). OBJECTIVE: To document the impact of identifying rifampicin (RMP) resistance using Xpert((r)) MTB/RIF on time to diagnosis and time to treatment, and evaluate its performance under programmatic conditions. METHODS: Using a prospective observational study, we screened presumptive MDR-TB cases with Xpert and solid culture/conventional DST. RMP resistance was confirmed using a line probe assay (LPA). We recorded diagnostic and treatment delays. We performed rpoB gene sequencing post hoc to resolve discordant RMP susceptibilities. RESULTS: We screened 299 of 345 presumptive MDR-TB individuals, and identified 44 Xpert RMP resistant cases: 16/165 (10%) were new and 28/136 (20%) retreated. The median time to diagnosis was 2 days (Xpert) vs. an additional 6 with LPA; the median time to treatment was 14 days. Confirmatory LPA on 39/44 revealed 27 concordant, 6 discordant and 6 invalid results. Xpert RMP resistance was confirmed in respectively 24/30 (80%) and 21/23 (91%) by phenotypic DST and rpoB sequencing. CONCLUSION: Screening presumptive MDR-TB patients with Xpert enabled rapid diagnosis and treatment of MDR-TB. Xpert performed well, provided appropriate risk assessment was done. Rapid confirmatory testing added little to clinical decision making. Our findings support the latest World Health Organization guidelines to abandon confirmatory LPA in favour of repeat Xpert when in clinical doubt, pending phenotypic DST. PMID- 26614198 TI - Rapid detection of rifampicin resistance in Mycobacterium tuberculosis by high resolution melting curve analysis. AB - SETTING: High-resolution melting curve analysis (HRMA) can be used to screen for mutations in genes without the need for specific probes, with low turnaround time and high cost-effectiveness. OBJECTIVE: To detect the sensitivity and specificity of a line-probe assay (LPA) and HRMA in comparison with BACTECTM MGITTM 960 for the detection of rifampicin (RMP) resistance. DESIGN: A total of 219 Mycobacterium tuberculosis isolates tested by MGIT 960 for RMP susceptibility were tested with HRMA and LPA. Discordant samples were processed for sequencing of the RMP resistance-determining region (RRDR) of the rpoB gene. RESULTS: HRMA identified 93 of 103 (90.3%) isolates that were resistant and 113/116 (97.4%) that were susceptible on MGIT 960, with a sensitivity and specificity of respectively 90.3% and 97.4%. HRMA identified 117/119 (98.3%) LPA-susceptible and 94/100 (94%) resistant isolates, with 98.3% specificity and 94% sensitivity. Two isolates that were susceptible on LPA but resistant on HRMA showed silent mutations at 539 and 541 codons on sequencing, while 6 isolates that were susceptible on HRMA but resistant on LPA showed D516V (n = 4) and H526C/D (n = 2) mutations. Four isolates (3.9%) that were resistant on MGIT were susceptible on all three genotypic methods, which could be due to mutations outside the RRDR or efflux pumps. CONCLUSION: HRMA shows good potential as a rapid screening tool for the detection of drug resistance. PMID- 26614199 TI - New AnyplexTM II MTB/MDR/XDR kit for detection of resistance mutations in M. tuberculosis cultures. AB - SETTINGS: The new AnyplexTM II MTB/MDR/XDR PCR assay enables the joint analysis of mutations conferring resistance to first- and second-line anti-tuberculosis drugs and the detection of Mycobacterium tuberculosis. OBJECTIVES: To evaluate the performance of the new Anyplex assay in detecting mutations that confer resistance to first- and second-line drugs in M. tuberculosis cultures. DESIGN: Results obtained using the new technique were compared with those obtained by phenotypic drug susceptibility testing (DST) and with two GenoType tests for the detection of mutations: GenoType((r)) MTBDRplus and GenoType((r)) MTBDRsl. RESULTS: For rifampicin resistance mutations, Anyplex displayed 97% sensitivity and 100% specificity compared with 100% and 100% for MTBDRplus. For isoniazid (INH) resistance, Anyplex displayed 61% sensitivity and 98% specificity compared with 62% and 98% for MTBDRplus. For second-line drugs, Anyplex recorded 95% sensitivity and 99% specificity in the detection of resistance to quinolones compared with 100% and 98% for the MTBDRsl. While both techniques displayed 100% specificity for aminoglycoside resistance mutations, sensitivity was 100% for Anyplex and 88% for MTBDRsl. CONCLUSIONS: Results obtained using Anyplex agreed strongly with those obtained using the two GenoType molecular techniques and with phenotypic DST, except in the case of INH, due to the large number of genes involved in resistance to this drug. PMID- 26614196 TI - Beyond multidrug-resistant tuberculosis in Europe: a TBNET study. AB - The emergence of drug-resistant tuberculosis (TB) is a challenge to TB control in Europe. We evaluated second-line drug susceptibility testing in Mycobacterium tuberculosis isolates from patients with multidrug-resistant, pre-extensively drug-resistant (pre-XDR-TB) and XDR-TB at 23 TBNET sites in 16 European countries. Over 30% of bacilli from patients with pre-XDR-TB showed resistance to any fluoroquinolone and almost 70% to any second-line injectable drug. Respectively >90% and >80% of the XDR-TB strains tested showed phenotypic resistance to pyrazinamide and ethambutol. Resistance to prothionamide/ethionamide was high in bacilli from pre-XDR-TB patients (43%) and XDR-TB patients (49%). PMID- 26614200 TI - The thin-layer agar method for direct phenotypic detection of multi- and extensively drug-resistant tuberculosis. AB - BACKGROUND: Molecular techniques rapidly detect resistance to rifampicin (RMP) and isoniazid (INH), but do not eliminate the need for culture-based drug susceptibility testing (DST) against other drugs. The thin-layer agar (TLA) test, a non-commercial direct DST method, has demonstrated good performance for INH and RMP; however, evidence is still limited, and its applicability for DST of ofloxacin (OFX) and kanamycin (KM) is unknown. DESIGN: We compared 279 TLA DST results with those of MGIT for INH and RMP, and 280 results for OFX and KM with those of the 7H11 agar proportion method, obtained from 320 smear-positive samples from 165 Georgian TB patients. Discrepancies were solved by comparison with a composite reference standard. The prevalence of multidrug-resistant tuberculosis (TB) was 30 of 164 patients (18.3%), 2 (6.7%) of whom had extensively drug-resistant TB. RESULTS: TLA showed 94.7%, 98.2%, 100% and 78.9% sensitivity, respectively, for INH, RMP, OFX and KM, with 100% specificity. Average time to results was 7 days in TLA, 23 in MGIT and 49 for 7H11 agar. CONCLUSIONS: In low-resource settings, TLA can be applied for the rapid detection of resistance to INH, RMP and fluoroquinolones. Further studies are necessary to improve sensitivity to KM and further assess its performance for OFX and other drugs and its applicability in field conditions. PMID- 26614201 TI - In reply. PMID- 26614202 TI - Tiotropium add-on therapy in patients with uncontrolled asthma. PMID- 26614203 TI - HIV screening in tuberculosis patients in the northern region of Portugal. PMID- 26614204 TI - Xpert((r)) MTB/RIF assay sensitivity with different methods of CSF processing for the diagnosis of TB meningitis. PMID- 26614205 TI - Can resuscitation-promoting factors be used to improve culture rates of extra pulmonary tuberculosis? PMID- 26614206 TI - Rapid diagnosis of TB in HIV-positive in-patients with M. tuberculosis bacteraemia in sub-Saharan Africa. PMID- 26614207 TI - In reply. PMID- 26614208 TI - Clinical Application of Fiber Visualization with LIC Maps Using Multidirectional Anisotropic Glyph Samples (A-Glyph LIC). AB - Recently, a fiber visualization method for high-angular resolution diffusion weighted magnetic resonance imaging (MRI) data was proposed using a multiple kernel line integral convolution (LIC) algorithm and an anisotropic spot pattern. This processing routine leads to high contrast color-coded LIC maps that are capable of visualizing local anisotropy information and regional fiber architecture. In this paper, we evaluate and validate this method by applying it to simulated datasets and to in vivo diffusion MRI data of children and adults with different disease conditions and healthy volunteers. Compared to routine clinical fiber visualization (color-coded fractional anisotropy, FA maps, and fiber tractography), it has the advantage of visualizing complex local fiber architecture in a fully automated way. The results indicate that this method is capable of reliably delineating normal fiber architecture and fibers infiltrated, displaced, or disrupted by lesions and is therefore a promising tool in the clinical context. PMID- 26614209 TI - The Annual Conference It Makes Sense. PMID- 26614210 TI - Voting and the Future of IAAO. PMID- 26614211 TI - Sound Off. PMID- 26614212 TI - Regional News. PMID- 26614213 TI - Who Cares? PMID- 26614214 TI - Finaincia Statements. PMID- 26614215 TI - Global Solutions for Success. PMID- 26614216 TI - Some Lessons from the History of the Property Tax. PMID- 26614218 TI - Assessor's Library. PMID- 26614217 TI - Property Taxation of Telecommunications Companies in California. PMID- 26614219 TI - Market Value: Private or Public? Value of Environmentally Sensitive Land. PMID- 26614220 TI - Cyberservice:,Providing Superior Public Service on the World Wide Web. PMID- 26614221 TI - Assessment and Valuation Legal Reporter. PMID- 26614222 TI - Disposable microcolumns with welded metal frits. AB - This study reports the preparation of disposable microcolumns with welded metal frits for the first time. First, the bottom of glass-lined stainless-steel tubing of 30 cm length, 1.6 mm od, and 0.5 mm id was welded with a stainless-steel screen frit of 1.6 mm diameter. A micro-welding machine was used for this. Next, the column was connected to a slurry packer and packed with porous silica particles. Then, the inlet of the column was carefully welded with another frit. The column was tested for separation of a test mix composed of phenol, 2 nitrophenol, acetophenone, aceanilide, and benzamide. Another column of the same physical dimension was also prepared with frits that were not welded to the column. The chromatographic performances of the two groups of columns (welded frits versus non-welded frits) were examined. The columns of welded frits showed ca. 18% better separation efficiency (number of theoretical plates) than those of non-welded frits. PMID- 26614224 TI - Management of subglottic hemangiomas with carbon dioxide laser: Our 25-year experience and comparison with the literature. AB - INTRODUCTION: Subglottic hemangiomas (SGH) are rare tumors of infancy arising between the perichondrium and the mucosa of the subglottic space. It is a potential life-threatening condition. Many therapeutic options exist for this disease, including lasers. OBJECTIVE: To report our 25-year experience of laser treatment of SGH. MATERIAL AND METHODS: Retrospective review of charts. SETTING: Claros' Otolaryngology and Head and Neck Surgery Clinic in Barcelona, Spain. RESULTS: We recruited a total of 97 patients of whom 89 were treated with CO2 laser. Mean age at first contact was 2.1 months (range: 1.5-6.5). Sex ratio was 10 girls for 1 boy. Eighty percent of patients presented with stridor and 30.3% with recurrent acute laryngitis. Forty percent had associated cutaneous hemangiomas. They received an average of 1.85 laser session (range: 1-4) and 78.5% were healed after a maximum of 2. We had a 100% success rate and 1.1% complication rate (subglottic stenosis). CONCLUSION: CO2 laser is a very effective and recommendable tool against subglottic hemangiomas. To achieve good results traditional laser safety measures should be respected besides some useful surgical tips. PMID- 26614223 TI - Pretreatment serum xanthophyll concentrations as predictors of head and neck cancer recurrence and survival. AB - BACKGROUND: The purpose of this study was to examine associations of pretreatment serum carotenoids, tocopherols, and quercetin with prognosis in 154 patients newly diagnosed with head and neck cancer. METHODS: Pretreatment blood and health surveys were collected. Serum micronutrients were measured by high performance liquid chromatography. Data on recurrence and death were collected annually. Cox proportional hazards models measured associations of serum nutrient concentrations with recurrence and overall survival. RESULTS: During a median follow-up time of 37 months, there were 32 recurrences and 27 deaths. After controlling for covariates, subjects with high versus low serum xanthophyll and total carotenoid concentrations had significantly longer recurrence-free time (p = .002 and p = .02, respectively). Overall survival time was significantly longer in patients with high versus low serum xanthophyll concentrations (p = .02). CONCLUSION: Future research should evaluate the possible benefits of interventions to increase intakes of rich food sources of xanthophylls in this patient population. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1591-E1597, 2016. PMID- 26614225 TI - A critical review of analytical methods in pretreatment of lignocelluloses: Composition, imaging, and crystallinity. AB - Lignocelluloses are widely investigated as renewable substrates to produce biofuels, e.g., ethanol, methane, hydrogen, and butanol, as well as chemicals such as citric acid, lactic acid, and xanthan gum. However, lignocelluloses have a recalcitrance structure to resist microbial and enzymatic attacks; therefore, many physical, thermal, chemical, and biological pretreatment methods have been developed to open up their structure. The efficiency of these pretreatments was studied using a variety of analytical methods that address their image, composition, crystallinity, degree of polymerization, enzyme adsorption/desorption, and accessibility. This paper presents a critical review of the first three categories of these methods as well as their constraints in various applications. The advantages, drawbacks, approaches, practical details, and some points that should be considered in the experimental methods to reach reliable and promising conclusions are also discussed. PMID- 26614226 TI - Lipid extraction from microalgae cell using persulfate-based oxidation. AB - In this study, persulfate, a solid-type oxidant, was adopted as a substitute for hydrogen peroxide in extracting lipid from microalgae biomass. Microalgae cells were concentrated at pH 3 and with 200mg/L of ferric chloride, conditions which can activate oxidants such as hydrogen peroxide and persulfate. At a persulfate concentration of 2mM and a reaction temperature of 90 degrees C, exceedingly high extraction efficiency over 95% was obtained, which was higher than with 0.5% hydrogen peroxide at the same temperature. This result showed that persulfate is sufficiently powerful and incomparably cheap enough to replace the potent yet expensive oxidant. It appears that combining iron-based coagulation and persulfate-based lipid extraction is indeed a competitive approach that can possibly lighten the process burden for the microalgae-derived biodiesel production. PMID- 26614227 TI - Six-Month-Old Boy with "Milky" Serum. PMID- 26614228 TI - Commentary. PMID- 26614229 TI - Commentary. PMID- 26614230 TI - Just Another Hemolysed Sample? PMID- 26614232 TI - Against Medical Silos. PMID- 26614233 TI - Rectal dose constraints for salvage iodine-125 prostate brachytherapy. AB - PURPOSE: Organ-confined prostate cancer recurrences after primary radiotherapy can be treated with salvage iodine-125 brachytherapy. Options include total salvage (TS) or focal salvage (FS). TS often leads to severe late gastrointestinal (GI) toxicity. Differences in rectal dosimetry between TS and FS are presented and dose constraints proposed to reduce late severe GI toxicity (>90 days). METHODS AND MATERIALS: Intraoperative dosimetry and 30-day CT dosimetry of 20 FS and 28 TS patients were evaluated. GI toxicity was evaluated using the common terminology criteria for adverse events-4. With receiver operating characteristic analysis, dosimetry cutoff values to prevent severe late GI toxicity were assessed. RESULTS: FS reduces rectal dose significantly. Median D(0.1cc), D(1cc), D(2cc), and V100 reductions were 38 Gy (p = 0.002), 46 Gy (p < 0.0001), 46 Gy (p < 0.0001), and 0.41 cc (p = 0.0001), respectively, compared with TS. FS patients had no late severe GI toxicity. TS patients with severe GI toxicity (41%, n = 11) showed significantly higher rectal doses than TS patients without GI toxicity (59%, n = 16). Median D(0.1cc), D(1cc), D(2cc), and V100 differences were 29 Gy (p < 0.001), 17 Gy (p = 0.001), 28 Gy (p < 0.001), and 0.45 cc (p = 0.001). With receiver operating characteristic analysis, restrictions for the D(0.1cc), D(1cc), D(2cc), and V100 are <160 Gy (area under the curve [AUC], 0.88; 95% confidence interval [CI] 0.76-1.00), <119 Gy (AUC, 0.87; 95% CI, 0.74-1.00), <102 Gy (AUC, 0.89; 95% CI, 0.77-1.00), and <0.38 cc (AUC, 0.88; 95% CI, 0.75-1.00), respectively. Thirty-day CT dosimetry showed minor overestimation of intraoperative D(2cc) (median, 10 Gy [p = 0.02]). CONCLUSIONS: FS reduces rectal dose compared with TS. D(0.1cc), D(1cc), D(2cc), and V100 restrictions were 160 Gy, 120 Gy, 100 Gy, and 0.35 cc. Taking correlation into account, the D2cc <100 Gy might be sufficient for clinical practice. Larger series and multivariable models are necessary to further assess the found restrictions. PMID- 26614234 TI - Simulation study of high-dose-rate brachytherapy for early glottic cancer. AB - PURPOSE: External beam radiation therapy (EBRT) is effective for early glottic cancers, with cure rates of ~90% for T1 tumors. EBRT has strengths but also disadvantages including radiation to healthy tissues and duration of 5-7 weeks. With advances in laryngeal framework surgery, new devices can provide reliable, minimally invasive access to the larynx. Such devices could be modified to insert brachytherapy catheters. Brachytherapy could provide focused radiation while limiting dose to normal structures in the larynx and neck. As a preliminary step, we performed simulations comparing EBRT to high-dose-rate brachytherapy to assess if this approach could provide dosimetric advantage. METHODS AND MATERIALS: One- and 2-catheter brachytherapy simulations were performed for 3 patients with T1 glottic carcinoma. Percentage of dose delivered to the target and adjacent structures was compared with conventional EBRT using 3D and intensity-modulated radiation therapy approaches. RESULTS: Percentage of structures exposed to 50% of the dose was lower for brachytherapy compared with 3D EBRT and intensity modulated radiation therapy, particularly for the cricoid and contralateral arytenoid. Dose was also lower for the carotid-internal jugular vein complexes compared with 3D EBRT. Dose profiles did not differ significantly between 1- and 2-catheter simulations. CONCLUSION: Brachytherapy can decrease radiation to normal tissues including laryngeal cartilages and carotid-internal jugular vein complexes. Recent advancements allowing catheter placement may afford the potential to decrease radiation to healthy tissues with decreased treatment time. However, careful, stepwise evaluation of feasibility and outcomes in model systems is required before recommending this approach for such high cure rate cancers in humans. PMID- 26614235 TI - Reproducibility and interoperator reliability of obtaining images and measurements of the cervix and uterus with brachytherapy treatment applicators in situ using transabdominal ultrasound. AB - PURPOSE: To validate interoperator reliability of brachytherapy radiation therapists (RTs) in obtaining an ultrasound image and measuring the cervix and uterine dimensions using transabdominal ultrasound. METHODS AND MATERIALS: Patients who underwent MRI with applicators in situ after the first insertion were included in the study. Imaging was performed by three RTs (RT1, RT2, and RT3) with varying degrees of ultrasound experience. All RTs were required to obtain a longitudinal planning image depicting the applicator in the uterine canal and measure the cervix and uterus. The MRI scan, taken 1 hour after the ultrasound, was used as the reference standard against which all measurements were compared. Measurements were analyzed with intraclass correlation coefficient and Bland-Altman plots. RESULTS: All RTs were able to obtain a suitable longitudinal image for each patient in the study. Mean differences (SD) between MRI and ultrasound measurements obtained by RTs ranged from 3.5 (3.6) to 4.4 (4.23) mm and 0 (3.0) to 0.9 (2.5) mm on the anterior and posterior surface of the cervix, respectively. Intraclass correlation coefficient for absolute agreement between MRI and RTs was >0.9 for all posterior measurement points in the cervix and ranged from 0.41 to 0.92 on the anterior surface. Measurements were not statistically different between RTs at any measurement point. CONCLUSIONS: RTs with variable training attained high levels of interoperator reliability when using transabdominal ultrasound to obtain images and measurements of the uterus and cervix with brachytherapy applicators in situ. Access to training and use of a well-defined protocol assist in achieving these high levels of reliability. PMID- 26614236 TI - Quantification of image distortions on the Utrecht interstitial CT/MR brachytherapy applicator at 3T MRI. AB - PURPOSE: To quantify distortions on MR images of the Utrecht interstitial CT/MR applicator at a field strength of 3T using an MRI-only method. MATERIALS AND METHODS: An MR-compatible phantom suspending the applicator in water was built and imaged on a Philips Ingenia 3T MRI scanner. A map of the magnetic field (B0) was calculated from multiecho images and used to quantify the field inhomogeneity. The expected displacements of the applicator could be quantified using the measured field inhomogeneity and sequence bandwidth. Additionally, two scans were acquired using opposing readout gradients. These scans were rigidly matched and their displacement was compared with the expected displacements from the B0 map. These same methods were applied in 4 patients. By rigid matching of the scans acquired with opposing readout direction the applicator displacement due to image distortion from B0 inhomogeneity as well as patient movement and organ deformation was determined. RESULTS: According to the B0 map, the displacement on the intrauterine device of the plastic brachytherapy applicator was <0.4 mm for both the phantom and patients. Displacements obtained by the opposing readout method were <=0.8 mm for each patient with a mean +/- SD over the patients of 0.3 +/- 0.1 mm. CONCLUSION: The results of our study indicate that the B0 method agrees with the opposing readout method. Displacements caused by magnetic field inhomogeneity on 3T MRI were small compared with displacements due to patient movement and organ deformation. PMID- 26614237 TI - Computed tomography-planned interstitial brachytherapy for locally advanced gynecologic cancer: Outcomes and dosimetric predictors of urinary toxicity. AB - PURPOSE: To identify dosimetric predictors of outcome and toxicity in patients receiving CT-planned interstitial brachytherapy (ISBT) for gynecologic cancers. METHODS AND MATERIALS: Patients who received ISBT between 2009 and 2014 were reviewed. Demographic, disease specific, treatment, and toxicity data were collected. Logistic regression was used to model toxicity. A least absolute shrinkage and selection operator penalty was used to identify relevant predictors. Receiver operating characteristic curves were used to analyze the relation between dosimetric factors and urinary toxicity. RESULTS: Seventy-three patients received ISBT (21 at time of cancer recurrence and 52 at the first presentation). Thirty-six patients had cervical cancer, 16 had vaginal cancer, 13 had uterine cancer, and 8 had vulvar cancer. ISBT was performed using both high dose-rate and low-dose-rate 192Ir sources (27 low dose rate and 46 high dose rate). With a median followup of 12 months, Grade 3 vaginal, urinary, and rectal toxicity occurred in 17.8%, 15.1%, and 6.8% of patients, respectively. No patients experienced Grade 4 or 5 toxicity. Dose to 0.1cc of urethra predicted for development of Grade 3 urinary toxicity (area under the curve of 0.81; 95% confidence interval: 0.66, 0.96). A 10% probability of a Grade 3 urinary toxicity associated with a dose of 23.1 equivalent dose in 2 Gy fractions (95% confidence interval: 9.51, 36.27 equivalent dose in 2 Gy fractions). CONCLUSIONS: ISBT is a safe treatment for gynecologic malignancies. The dose to 0.1cc significantly predicts for severe urinary toxicity. Our data suggests that dose to a small urethral volume may be the most significant predictor of urinary toxicity in patients receiving ISBT for gynecologic cancer. PMID- 26614238 TI - Early Treatment of Severe Acute Respiratory Distress Syndrome. AB - Acute respiratory distress syndrome (ARDS) is defined by acute diffuse inflammatory lung injury invoked by a variety of systemic or pulmonary insults. Despite medical progress in management, mortality remains 27% to 45%. Patients with ARDS should be managed with low tidal volume ventilation. Permissive hypercapnea is well tolerated. Conservative fluid strategy can reduce ventilator and hospital days in patients without shock. Prone positioning and neuromuscular blockers reduce mortality in some patients. Early management of ARDS is relevant to emergency medicine. Identifying ARDS patients who should be transferred to an extracorporeal membrane oxygenation center is an important task for emergency providers. PMID- 26614239 TI - Management of Acute Exacerbation of Asthma and Chronic Obstructive Pulmonary Disease in the Emergency Department. AB - Acute asthma and chronic obstructive pulmonary disease (COPD) exacerbations are the most common respiratory diseases requiring emergent medical evaluation and treatment. Asthma and COPD are chronic, debilitating disease processes that have been differentiated traditionally by the presence or absence of reversible airflow obstruction. Asthma and COPD exacerbations impose an enormous economic burden on the US health care budget. In daily clinical practice, it is difficult to differentiate these 2 obstructive processes based on their symptoms, and on their nearly identical acute treatment strategies; major differences are important when discussing anatomic sites involved, long-term prognosis, and the nature of inflammatory markers. PMID- 26614240 TI - Respiratory Emergencies in Geriatric Patients. AB - Acute dyspnea in older patients is a common presentation to the emergency department. Acute dyspnea in older adults is often the consequence of multiple overlapping disorders, such as pneumonia precipitating acute heart failure. Emergency physicians must be comfortable managing patients with acute dyspnea of uncertain cause and varying goals of care. In addition to the important role noninvasive ventilation (NIV) plays in full resuscitation, NIV can be useful as a method of providing supportive or nearly fully supportive care while more information is gathered from the patients and their loved ones. PMID- 26614241 TI - Noninvasive Ventilation for the Emergency Physician. AB - Noninvasive ventilation (NIV) improves oxygenation and ventilation, prevents endotracheal intubation, and decreases the mortality rate in select patients with acute respiratory failure. Although NIV is used commonly for acute exacerbations of chronic obstructive pulmonary disease and acute cardiogenic pulmonary edema, there are emerging indications for its use in the emergency department. Emergency physicians must be knowledgeable regarding the indications and contraindications for NIV in emergency department patients with acute respiratory failure as well as the means of initiating it and monitoring patients who are receiving it. PMID- 26614242 TI - Emergency Department Treatment of the Mechanically Ventilated Patient. AB - Mechanical ventilation has a long and storied history, but until recently the process required little from the emergency physician. In the modern emergency department, critically ill patients spend a longer period under the care of the emergency physician, requiring a greater understanding of ventilator management. This article serves as an introduction to mechanical ventilation and a user friendly bedside guide. PMID- 26614243 TI - Pediatric Respiratory Emergencies. AB - Respiratory emergencies are 1 of the most common reasons parents seek evaluation for the their children in the emergency department (ED) each year, and respiratory failure is the most common cause of cardiopulmonary arrest in pediatric patients. Whereas many respiratory illnesses are mild and self limiting, others are life threatening and require prompt diagnosis and management. Therefore, it is imperative that emergency clinicians be able to promptly recognize and manage these illnesses. This article reviews ED diagnosis and management of foreign body aspiration, asthma exacerbation, epiglottitis, bronchiolitis, community-acquired pneumonia, and pertussis. PMID- 26614244 TI - Airway Management of Respiratory Failure. AB - Patients in respiratory distress often require airway management, including endotracheal intubation. It takes a methodical approach to transition from an unstable patient in distress with an unsecured airway, to a stable, sedated patient with a definitive airway. Through a deliberate course of advanced preparation, the emergency physician can tailor the approach to the individual clinical situation and optimize the chance of first-pass success. Sedation of the intubated patient confers physiologic benefits and should be included in the plan for airway control. PMID- 26614245 TI - Approach to Adult Patients with Acute Dyspnea. AB - Undifferentiated patients in respiratory distress require immediate attention in the emergency department. Using a thorough history and clinical examination, clinicians can determine the most likely causes of dyspnea. Understanding the pathophysiology of the most common diseases contributing to dyspnea guides rational testing and informed, expedited treatment decisions. PMID- 26614246 TI - Advances in Point-of-Care Thoracic Ultrasound. AB - Pulmonary ultrasound continues to develop and is ideally suited for the evaluation and treatment of respiratory emergencies. It is portable, can be performed rapidly, has no ionizing radiation, and is highly sensitive and specific for the diagnosis of pneumothorax, pneumonia, pulmonary edema, and free fluid in the chest. PMID- 26614247 TI - Pulmonary Emergencies. PMID- 26614248 TI - Respiratory Emergencies. PMID- 26614249 TI - Antibiotics for Acute Uncomplicated Diverticulitis: Time for a Paradigm Change? PMID- 26614250 TI - Association of Carbon Monoxide exposure with blood pressure among pregnant women in rural Ghana: Evidence from GRAPHS. AB - BACKGROUND AND OBJECTIVE: The Ghana Randomized Air Pollution and Health Study (GRAPHS) is a community-level randomized-controlled trial of cookstove interventions for pregnant women and their newborns in rural Ghana. Given that household air pollution from biomass burning may be implicated in adverse cardiovascular outcomes, we sought to determine whether exposure to carbon monoxide (CO) from woodsmoke was associated with blood pressure (BP) among 817 adult women. METHODS: Multivariate linear regression models were used to evaluate the association between CO exposure, determined with 72 hour personal monitoring at study enrollment, and BP, also measured at study enrollment. At the time of these assessments, women were in the first or second trimester of pregnancy. RESULTS: A significant positive association was found between CO exposure and diastolic blood pressure (DBP): on average, each 1 ppm increase in exposure to CO was associated with 0.43 mmHg higher DBP [0.01, 0.86]. A non-significant positive trend was also observed for systolic blood pressure (SBP). CONCLUSION: This study is one of very few to have examined the relationship between household air pollution and blood pressure among pregnant women, who are at particular risk for hypertensive complications. The results of this cross-sectional study suggest that household air pollution from wood-burning fires is associated with higher blood pressure, particularly DBP, in pregnant women at early to mid-gestation. The clinical implications of the observed association toward the eventual development of chronic hypertension and/or hypertensive complications of pregnancy remain uncertain, as few of the women were overtly hypertensive at this point in their pregnancies. PMID- 26614251 TI - Levels of persistent contaminants in relation to fish consumption among older male anglers in Wisconsin. AB - Fish are an important source of nutrients which may reduce risk of adverse health outcomes such as cardiovascular disease; however, fish may also contain significant amounts of environmental pollutants such as mercury, polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and perfluorinated compounds (PFCs, also called perfluoroalkyl compounds), which confer increased risk for adverse health effects. The Wisconsin Departments of Health Services and Natural Resources developed a survey instrument, along with a strategy to collect human biological samples to assess the risks and benefits associated with long term fish consumption among older male anglers in Wisconsin. The target population was men aged 50 years and older, who fish Wisconsin waters and live in the state of Wisconsin. Participants provided blood and hair samples and completed a detailed (paper) questionnaire, which included questions on basic demographics, health status, location of catch and species of fish caught/eaten, consumption of locally caught and commercially purchased fish, and awareness and source of information for local and statewide consumption guidelines. Biological samples were used to assess levels of PCBs, PBDEs, PFCs (blood), and mercury (hair and blood). Quantile regression analysis was used to investigate the associations between biomarker levels and self-reported consumption of fish from the Great Lakes and other areas of concern, other locally caught fish, and commercially purchased fish (meals per year). Respondents had a median age of 60.5 (interquartile range: 56, 67) years. The median fish consumption was 54.5 meals per year, with most fish meals coming from locally-caught fish. Participants had somewhat higher mercury levels compared with the US general population, while levels of other contaminants were similar or lower. Multivariate regression models showed that consumption of fish from the Great Lakes and areas of concern was associated with higher levels of each of the contaminants with the exception of PBDEs, as was consumption of locally caught fish from other water bodies. All commercial fish consumption was also associated with both hair and blood mercury. When looking at specific PCB, PBDE and PFC analytes, consumption of fish from the Great Lakes and areas of concern was associated with higher levels of each of the individual PCB congeners examined, as well as higher levels of all of the PFCs examined, with the exception of PFHxS. Among the PFCs, locally caught fish from other water bodies was also associated with higher levels of each of the congeners examined except PFHxS. Finally, all commercial fish was associated with higher levels of PFHxS. PMID- 26614252 TI - A case of cerebral astroblastoma with rhabdoid features: a cytological, histological, and immunohistochemical study. AB - Astroblastoma is a rare neuroepithelial neoplasm of unknown origin, usually occurring in children and young adults. Here we report a case of astroblastoma with uncommon features in an 18-year-old female. The tumor was a well circumscribed cystic and solid mass with marked gadolinium enhancement in the right frontal lobe. Cytological examination showed polarized monopolar cells with diminished cohesiveness. Tumor cells possessed eccentric round to oval nuclei with abundant eosinophilic cytoplasm, sometimes having cytoplasmic processes. Histopathologically, the tumor showed perivascular pseudorosettes with prominent vascular sclerosis. Foam cells were frequently infiltrated around blood vessels and among tumor cells. In some areas, a solid growth pattern of plump tumor cells with abundant inclusion-like eosinophilic cytoplasm showing rhabdoid appearance was observed. The immunohistochemical study revealed strong and diffuse positivity for vimentin and epithelial membrane antigen. Tumor cells were focally positive for glial fibrillary acidic protein and cytokeratin AE1/AE3. Nuclear immunoreactivity for INI1 protein was evident. The Ki-67 labeling index was 10.8%. This tumor was finally diagnosed as low-grade astroblastoma and the patient had no evidence of recurrence without postoperative radiotherapy or chemotherapy during the last 6 months of follow-up. This report describes novel cytological, histopathological, and immunohistochemical features of the rare tumor. PMID- 26614253 TI - [Probiotics in broilers' rearing: A strategy for intensive production models]. AB - The broiler industry has become an important economic activity in Argentina. Global production of broiler meat has been growing in Argentina faster than for any other meats, possibly due to declining poultry prices and increasing incomes. Modern rearing systems can produce broilers ready to slaughter in 50 days, with the required 2.7kg of weight and a feed conversion of about 1.6kg feed/kg of meat. Nevertheless, broilers raised under these intensive conditions are exposed to various stressors every day. For many years, feed supplementation with antibiotics was widely used to stabilize the gut flora, improve general parameters and prevent avian diseases. However, the utility of antibiotics has been questioned because of the emergence and spread of antibiotic-resistant bacteria in meat. Therefore, there is a renewed interest in finding viable alternatives to antibiotics. One potential method is the supplementation of broiler diets with probiotics. This review provides an updated summary of the use of probiotics to improve sanitary conditions and enhance performance in broilers, demonstrating the role of probiotics as a reliable option to replace antimicrobial growth promoters. PMID- 26614254 TI - Relation between plasma antioxidant vitamin levels, adiposity and cardio metabolic profile in adolescents: Effects of a multidisciplinary obesity programme. AB - BACKGROUND & AIMS: In vivo and in vitro evidence suggests that antioxidant vitamins and carotenoids may be key factors in the treatment and prevention of obesity and obesity-associated disorders. Hence, the objective of the present study was to determine the relationship between plasma lipid-soluble antioxidant vitamin and carotenoid levels and adiposity and cardio-metabolic risk markers in overweight and obese adolescents participating in a multidisciplinary weight loss programme. METHODS: A therapeutic programme was conducted with 103 adolescents aged 12-17 years old and diagnosed with overweight or obesity. Plasma concentrations of alpha-tocopherol, retinol, beta-carotene and lycopene, anthropometric indicators of general and central adiposity, blood pressure and biochemical parameters were analysed at baseline and at 2 and 6 months of treatment. RESULTS: Lipid-corrected retinol (P < 0.05), beta-carotene (P = 0.001) and alpha-tocopherol (P < 0.001) plasma levels increased significantly, whereas lipid-corrected lycopene levels remained unaltered during the treatment. Anthropometric indicators of adiposity (P < 0.001), blood pressure (P < 0.01) and biochemical parameters (P < 0.05) decreased significantly, whereas fat free mass increased significantly (P < 0.001). These clinical and biochemical improvements were related to changes in plasma lipid-corrected antioxidant vitamin and carotenoid levels. The adolescents who experienced the greatest weight loss also showed the largest decrease in anthropometric indicators of adiposity and biochemical parameters and the highest increase in fat free mass. Weight loss in these adolescents was related to an increase in plasma levels of lipid-corrected alpha-tocopherol (P = 0.001), beta-carotene (P = 0.034) and lycopene (P = 0.019). CONCLUSIONS: Plasma lipid-soluble antioxidant vitamin and carotenoid levels are associated with reduced adiposity, greater weight loss and an improved cardio metabolic profile in overweight and obese adolescents. PMID- 26614255 TI - [Operative therapy of fractures of the distal femur. Predictive factors for a complicated course]. AB - BACKGROUND: Fractures of the distal femur are rare injuries that are mainly treated operatively. Complication rates remain high. OBJECTIVES: This study aimed to analyse complications following the operative treatment of these fractures and to identify predictive factors that have the potential to identify patients who are at risk for a complicated course of treatment. MATERIALS AND METHODS: We retrospectively analysed all fractures of the distal femur that were treated operatively at our institution between 2005 and 2015. Besides patient and fracture-specific data, surgical details and the types of complications that occurred were recorded and analysed. RESULTS: Open soft tissue damage, the polytraumatised patient and the timing of surgery (i.e. emergency surgery) are significant risk factors for the development of a nonunion. A risk factor that predicts a postoperative infection is open soft tissue damage. Type C fractures, stabilisation as emergency surgery and an accompanying polytrauma are risk factors for a postoperative pneumonia. CONCLUSIONS: The complication rate is significantly determined by surgical factors. To reduce the rate of nonunion, infection and pneumonia, the optimisation of the patient's general condition before surgery and optimal surgical care is more important than an immediate emergency surgery. PMID- 26614256 TI - Analysis of Quality of Life Subjective Perception by Patients Treated for Prostate Cancer with the EORTC QLQ-C30 Questionnaire and QLQ-PR25 Module. AB - Prostate cancer in men is the second most occurring cancer in Poland and represents approximately 13.2 % of all cancers. At the same time, it is the third largest cause of death in men, being responsible for approximately 8 % of deaths. The study was conducted among patients of Oncological Hospital in Wieliszew. The study included 83 men diagnosed with prostate cancer at the age of 51-84 years. The patients gave their written consent to participate in the study, to which the overall standardized questionnaires EORTC QLQ-C30 and QLQ-PR25 for patients with prostate cancer was applied. Significant deterioration of the state of health due to cancer was indicated by a total of 10.84 % of patients. At the same time, it was found that although there are differences between quality of life in various age groups of respondents, they are statistically insignificant (Chi2 = 59.96; p = 0.00734; R = 0.09; p > 0.05). Subjective QoL did not depend on the stage of cancer treatment, type of therapy, or significant deterioration in the patient's state of health in the last stage of disease. Both disease and therapy have impact on quality of life in all its dimensions, in particular as regards the patient's physical functioning and his frequent fatigue. There is a strong relationship between a patient's subjective assessment of quality of life and pain that significantly hampers everyday activities. This demonstrates the need for continuous monitoring and relieving pain directly associated with cancer and methods of its treatment. PMID- 26614257 TI - EMAS position statement: Testosterone replacement therapy in the aging male?. AB - INTRODUCTION: Late-onset hypogonadism (LOH) represents a common clinical entity in aging males, characterized by the presence of symptoms (most usually of a sexual nature, such as decreased libido, decreased spontaneous erections and erectile dysfunction) and signs, in combination with low serum testosterone concentrations. Whether testosterone replacement therapy (TRT) should be offered to those individuals is still under extensive debate. AIMS: The aim of this position statement is to provide and critically appraise evidence on TRT in the aging male, focusing on pathophysiology and characteristics of LOH, indications for TRT, available therapeutic agents, monitoring and treatment-associated risks. MATERIALS AND METHODS: Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS: Diagnosis and treatment of LOH is justified, if a combination of symptoms of testosterone deficiency and low testosterone is present. Patients receiving TRT could profit with regard to obesity, metabolic syndrome, type 2 diabetes mellitus, sexual function and osteoporosis and should undergo scheduled testing for adverse events regularly. Potential adverse effects of TRT on cardiovascular disease, prostate cancer and sleep apnea are as yet unclear and remain to be investigated in large-scale prospective studies. Management of aging men with LOH should include individual evaluation of co-morbidities and careful risk versus benefit assessment. PMID- 26614258 TI - [Duration of breastfeeding in preterm infants followed at a secondary referral service]. AB - OBJECTIVE: Identify and analyze variables associated with shorter duration of breastfeeding in preterm infants. METHODS: Retrospective cohort of premature infants followed up at secondary referral service in the period of 2010-2015. INCLUSION: first appointment in the first month of corrected age and have undergone three or more consultations. Exclusion: diseases that impaired oral feeding. OUTCOME: duration of breastfeeding. A total of 103 preterm infants were evaluated, accounting for 28.8% of the preterm infants born in the municipality in that period, with a power of study of 80%. Descriptive analysis, t-test, chi square test, Kaplan-Meier curves and Cox regression were used. p-values<0.05 were considered significant. RESULTS: The median duration of breastfeeding among preterm infants was 5.0 months. The risk of breastfeeding discontinuation among preterm infants with gestational age <32 weeks was 2.6-fold higher than for those born at 32 weeks or more and the risk of breastfeeding interruption in preterm infants who were receiving breastfeeding supplementation in the first outpatient visit was 3-fold higher when compared to those who were exclusively breastfed in the first consultation. CONCLUSIONS: The median duration of breastfeeding in preterm infants was below the recommended one and discontinuation was associated with gestational <32 weeks and the fact that the infant was no longer receiving exclusive breastfeeding in the first outpatient visit. When these two variables were associated, their negative effect on the median duration of breastfeeding was potentiated. PMID- 26614259 TI - Generation and evaluation of a chimeric classical swine fever virus expressing a visible marker gene. AB - Classical swine fever virus (CSFV) is a noncytopathogenic virus, and the incorporation of an enhanced green fluorescent protein (EGFP) tag into the viral genome provides a means of direct monitoring of viral infection without immunostaining. It is well established that the 3' untranslated region (3'-UTR) of the CSFV plays an important role in viral RNA replication. Although CSFV carrying a reporter gene and chimeric CSFV have been generated and evaluated, a chimeric CSFV with a visible marker has not yet been reported. Here, we generated and evaluated a chimeric virus containing the EGFP tag and the 3'-UTR from vaccine strain HCLV (C-strain) in the genetic background of the highly virulent CSFV Shimen strain. The chimeric marker CSFV was fluorescent and had an approximately 100-fold lower viral titer, lower replication level of viral genome, and weaker fluorescence intensity than the recombinant CSFV with only the EGFP tag or the parental virus. Furthermore, the marker chimera was avirulent and displayed no viremia in inoculated pigs, which were completely protected from lethal CSFV challenge as early as 15 days post-inoculation. The chimeric marker virus was visible in vitro and attenuated in vitro and in vivo, which suggests that CSFV can be engineered to produce attenuated variants with a visible marker to facilitate in vitro studies of CSFV infection and replication and to develop of novel vaccines against CSF. PMID- 26614260 TI - RETRACTED ARTICLE: Anticoagulant agents for the prevention of hemodialysis catheter-related complications: systematic review and meta-analysis of prospective randomized controlled trials. PMID- 26614261 TI - The effects of ozone therapy on caspase pathways, TNF-alpha, and HIF-1alpha in diabetic nephropathy. AB - BACKGROUND: Accelerated apoptosis plays a vital role in the development of diabetic vascular complications. Ozone may attenuate diabetic nephropathy by means of decreased apoptosis-related genes. The aim of our study was to investigate the effect of ozone therapy on streptozotocin-induced diabetic nephropathy in rats. Also the histopathological changes in diabetic kidney tissue with ozone treatment were evaluated. METHODS: The rats were randomly divided into six groups (n = 7): control (C), ozone (O), diabetic (D), ozone-treated diabetic (DO), insulin-treated diabetic (DI), and ozone- and insulin-treated diabetic (DOI). D, DI, and DOI groups were induced by a single intraperitoneal injection of streptozotocin. Ozone was given to the O, DO, and DOI groups. Group DI and DOI received subcutaneous (SC) insulin (3 IU). All animals received daily treatment for 6 weeks. RESULTS: Expressions of caspase-1-3-9, HIF-1alpha, and TNF-alpha genes were significantly higher in D group compared to C group (p < 0.05 for all). Ozone treatment resulted in significant decrease in the expressions of these genes in diabetic kidney tissue compared to both C and D group (p < 0.05 for all). Caspase-1-3-9, HIF-1alpha, and TNF-alpha gene expressions were found to be lower in DOI group compared to C group (p < 0.05 for all). Also adding ozone treatment to insulin therapy resulted in more significantly decrease in the expressions of these genes in diabetic tissue compared to only insulin-treated diabetic group (p < 0.05 for all). Regarding histological changes, ozone treatment resulted in decrease in the renal corpuscular inflammation and normal kidney morphology was observed. Both insulin and ozone therapies apparently improved kidney histological findings with less degenerated tubules and less inflammation of renal corpuscle compared to D, DO, and DI groups. CONCLUSION: Ozone therapy decreases the expressions of apoptotic genes in diabetic kidney tissue and improves the histopathological changes. PMID- 26614262 TI - [Retinal arterial macroaneurysms with intraretinal exudates]. PMID- 26614263 TI - Exposure to "Exergames" Increases Older Adults' Perception of the Usefulness of Technology for Improving Health and Physical Activity: A Pilot Study. AB - BACKGROUND: High rates of sedentary behaviors in older adults can lead to poor health outcomes. However, new technologies, namely exercise-based videogames ("exergames"), may provide ways of stimulating uptake and ongoing participation in physical activities. Older adults' perceptions of the use of technology to improve health are not known. OBJECTIVE: The study aimed to determine use and perceptions of technology before and after using a 5-week exergame. METHODS: Focus groups determined habitual use of technology and the participant's perceptions of technology to assist with health and physical activity. Surveys were developed to quantitatively measure these perceptions and were administered before and after a 5-week intervention. The intervention was an exergame that focused on postural balance ("Your Shape Fitness Evolved 2012"). Games scores, rates of game participation, and enjoyment were also recorded. RESULTS: A total of 24 healthy participants aged between 55 and 82 years (mean 70, SD 6 years) indicated that after the intervention there was an increased awareness that technology (in the form of exergames) can assist with maintaining physical activity (P<.001). High levels of enjoyment (Physical Activity Enjoyment Scale [PACES-8] score mean 53.0, SE 0.7) and participation rates over the whole study (83%-100%) were recorded. CONCLUSIONS: Older adults' have low perception of the use of technology for improving health outcomes until after exposure to exergames. Technology, in the form of enjoyable exergames, may be useful for improving participation in physical activity that is relevant for older adults. PMID- 26614265 TI - Hyperandrogenism Decreases GRP78 Protein Level and Glucose Uptake in Human Endometrial Stromal Cells. AB - BACKGROUND: Women with polycystic ovary syndrome (PCOS) exhibit a low fertility by chronic hyperandrogenemia. Different evidence have shown that androgens could regulate the endoplasmic reticulum (ER) homeostasis and glucose metabolism. However, it is unclear whether androgens can exert these effects on human endometrial stromal cells. Our goal was to study the protein content of GRP78 (an ER homeostasis marker) in endometria from women with PCOS and healthy women and to assess the GRP78 protein levels and its relationship with glucose uptake on a human endometrial stromal cell line stimulated with testosterone. METHODS: Immunohistochemistry assays for GRP78 were performed on endometrial samples obtained from women with PCOS (n = 8) and control women subjected to hysterectomy (n = 8). Western blot analysis for GRP78 and glucose uptake was assessed in a telomerase-immortalized human endometrial stromal cell line (T-HESC) exposed to testosterone for 24 or 48 hours and challenged to an insulin short-term stimulation. Tukey test was performed for human samples comparison. Student t test or ANOVA-Bonferroni test was carried out according to the in vitro experiment. P < .05 was considered as significant. RESULTS: GRP78 stromal immunostaining was reduced in PCOS endometria compared to controls (P < .05). The T-HESC shows a testosterone-dependent downregulation of GRP78 protein content (P < .05), concomitant with half-reduction in glucose uptake compared to controls (P < .05). Moreover, enhanced small interfering RNA against GRP78 messenger RNA leads to a decrease in glucose uptake (P < .05). Such effects were reverted by hydroxyflutamide, an inhibitor of androgen receptor. CONCLUSION: These results suggest that hyperandrogenemic PCOS environment could compromise the endometrial homeostasis confirmed by the decrease in glucose uptake induced by testosterone and exhibited by stromal cells. PMID- 26614264 TI - Peri-Implantation Hormonal Milieu: Elucidating Mechanisms of Adverse Neurodevelopmental Outcomes. AB - While live births resulting from assisted reproductive technology (ART) exceed 1% of total births annually, the effect of ART on fetal development is not well understood. Data have demonstrated that IVF leads to alterations in DNA methylation and gene expression in the placenta that may have long-term effects on health and disease. Studies have linked adverse neurodevelopmental outcomes to ART, although human studies are inconclusive. In order to isolate the peri implantation environment and its effects on brain development, we utilized a mouse model with and without superovulation and examined the effect of adult behavior as well as adult cortical neuronal density. Adult offspring of superovulated dams showed increased anxiety-like behavior compared to offspring of naturally mated dams (P < .05). There was no difference in memory and learning tests between the 2 groups. The adult brains from offspring of superovulated recipients had fewer neurons per field compared to naturally mated control offspring (P < .05). In order to examine potential pathways leading to these changes, we measured messenger RNA and microRNA (miRNA) expression in fetal brains at E18.5. Microarray analysis found that miRNAs miR-122, miR-144, and miR 211, involved in regulation of neuronal migration and differentiation, were downregulated in brains of offspring exposed to a superovulated environment(P < .05). There was also altered expression of genes involved in neuronal development. These results suggest that the peri-implantation environment can affect neurodevelopment and can lead to behavioral changes in adulthood. Human studies with long-term follow-up of children from ART are necessary to further investigate the influence of ART on the offspring. PMID- 26614266 TI - Altered Maternal Plasma Glycogen Phosphorylase Isoenzyme BB as a Biomarker for Preeclampsia and Small for Gestational Age. AB - OBJECTIVES: To investigate whether maternal plasma glycogen phosphorylase BB (GPBB) levels were altered in early pregnancy and/or at the time of diagnosis of disease in preeclampsia (term and preterm <37 weeks' gestation) or small for gestational age (SGA). METHODS: We conducted 6 nested case-control studies within the Screening of Pregnancy Endpoint (SCOPE) Ireland cohort. Blood samples from women with preeclampsia or SGA were analyzed both from the time of disease presentation and at 15 and 20 weeks' gestation. These were compared with control samples obtained from SCOPE women with healthy uncomplicated pregnancies matched for age, ethnicity, parity, body mass index, and gestational age. Glycogen phosphorylase BB levels were measured using the Diacordon GPBB enzyme-linked immunosorbent assay (Diagenics, Germany). RESULTS: Glycogen phosphorylase BB levels were higher in women with preeclampsia compared with controls at the time of disease (term preeclampsia median [interquartile range (IQR)]: 22.2 [15.1 39.8] ng/mL vs 16.9 [10.4-19.1] ng/mL; P = .04; N = 14 and preterm preeclampsia median [IQR]: 23.1 [11.2-30.9] ng/mL vs 17.2 [9.8-19.1] ng/mL; P = .04; N = 11) and at 20 weeks' gestation (median [IQR]: 23.0 [15.6-31.4] ng/mL vs 17.0 [13.4 23.6] ng/mL; N = 39; P = .04). Glycogen phosphorylase BB levels were also significantly higher in women with SGA compared with normal controls at the time of disease detection (median [IQR]: 22.7 [12.6-25.5] ng/mL vs 17.0 [9.8-18.0] ng/mL; N = 23; P = .03) but significantly less than controls at 15 weeks' gestation prior to disease detection (median [IQR]: 16.0 [12.1-23.2] ng/mL vs 22.2 [17.0-28.9] ng/mL; N = 25; P = .02). CONCLUSION: Glycogen phosphorylase BB alone has modest predictive abilities for the development of preeclampsia or SGA. Further research may examine its use in combination with other markers. PMID- 26614267 TI - Usefulness of the Ultrasensitive Anti-Mullerian Hormone Assay for Predicting True Ovarian Reserve. AB - Serum concentration of anti-Mullerian hormone (AMH) is a useful marker for ovarian reserve. Measurement of AMH in clinical practice has gained widespread use to predict parameters such as the ovarian response, menopause, and recovery after chemotherapy. However, undetectable AMH levels assayed by conventional enzyme-linked immunosorbent assay (ELISA) kits fail to predict depletion of follicles because of low sensitivity of the kits. We investigated whether a recently developed ultrasensitive ELISA kit, picoAMH, would be more effective at detecting very low AMH levels in association with menstrual status. We analyzed 68 women with undetectable serum AMH levels using an ELISA kit, AMH Gen II. The AMH concentration of the same samples was detected in 36 samples using picoAMH; 32 samples were within the standard range, and 4 samples were out of the standard range but still detectable. Thirty-two women whose AMH levels were undetectable using the picoAMH all showed amenorrhea. We also found a significant correlation between the classes of serum AMH levels (undetectable, detectable under the limit of quantification, and measurable within the assay range) and menstrual status. Five of the 6 amenorrheic women with detectable AMH eventually achieved follicle growth. The present study demonstrated that very low AMH levels detectable using picoAMH correspond well to current and future ovulation status. This suggests that serum AMH levels can be useful for the assessment of ovarian reserve and follow-up of women with a declined ovarian reserve. PMID- 26614269 TI - Role of miR-422a and kallikrein-related peptidase 4 implicated in the development of lupus nephritis. Do we work in this direction? PMID- 26614268 TI - Renal hemodynamic effects of the HMG-CoA reductase inhibitors in autosomal dominant polycystic kidney disease. AB - BACKGROUND: To determine the effect of statins on renal hemodynamics in normal volunteers and those with autosomal dominant polycystic kidney disease either with mild or moderate renal dysfunction. METHODS: Thirty-two study subjects were enrolled in this study: 11 normal volunteers, 11 study subjects with autosomal dominant polycystic kidney disease (ADPKD) and mild kidney disease and 10 study subjects with ADPKD and moderate kidney disease. Subjects in each group received simvastatin 40 mg once daily for a period of 4 weeks. Renal blood flow was measured based on para-amino-hippurate (PAH) clearance and with the use of a magnetic resonance (MR) scanner at the beginning and following 4 weeks of therapy with statins. RESULTS: At the end of the study, except for the lipid profile, which was significantly lower in all groups, other laboratory results showed no change. Four weeks of therapy with simvastatin resulted in no change in serum creatinine, 24-h urinary protein, sodium, iothalamate clearance, PAH clearance or renal blood flow as measured by MRI or based on PAH clearance. CONCLUSIONS: Four weeks of therapy with simvastatin did not change renal blood flow in the study subjects with ADPKD with mild-to-moderate renal dysfunction or in healthy volunteers. CLINICAL TRIAL REGISTRATION NUMBER: NCT02511418. PMID- 26614270 TI - Pregnancy in dialysis patients in the new millennium: a systematic review and meta-regression analysis correlating dialysis schedules and pregnancy outcomes. AB - BACKGROUND: Advances have been made in the management of pregnancies in women receiving dialysis; however, single-centre studies and small numbers of cases have so far precluded a clear definition of the relationship between dialysis schedules and pregnancy outcomes. The aim of the present systematic review was to analyse the relationship between dialysis schedule and pregnancy outcomes in pregnancies in chronic dialysis in the new millennium. METHODS: Medline-PubMed, Embase and the Cochrane library were searched (1 January 2000-31 December 2014: MESH, Emtree, free terms on pregnancy and dialysis). A separate analysis was performed for case series (more than five cases) and case reports. Meta regression was performed in case series dealing with the larger subset of haemodialysis (HD) patients; case reports were analysed separately [according to peritoneal dialysis (PD) versus HD; conception before or during dialysis]. RESULTS: We obtained 190 full texts and 25 congress abstracts from 2048 references. We selected 101 full papers and 25 abstracts (36 series; 90 case reports), for a total of 681 pregnancies in 647 patients. In the case series (574 pregnancies in 543 patients), preterm delivery was extremely frequent (83%). Meta regression analysis showed a relationship between hours of dialysis per week in HD and preterm delivery, and was significant for preterm deliveries (<37 gestational weeks: P = 0.044; r2 = 0.22) and for small for gestational age (SGA) (P = 0.017; r2 = 0.54). SGA was closely associated with the number of dialysis sessions per week (P = 0.003; r2 = 0.84). Case report analysis suggests a lower incidence of SGA on HD versus PD (31 versus 66.7%; P = 0.015). No evidence of an increased risk of congenital abnormality was found in the retrieved papers. CONCLUSIONS: Data on pregnancy on dialysis are heterogeneous but rapidly accumulating; the main determinant of outcomes on HD is the dialysis schedule. The differences between PD and HD should be further analysed. PMID- 26614271 TI - Fibroblast growth factor 23 and heart failure: the plot thickens. PMID- 26614272 TI - Pre-transplant donor-specific anti-human leukocyte antigen antibodies are associated with high risk of delayed graft function after renal transplantation. AB - BACKGROUND: Sensitive screening methods have revealed that many patients have donor-specific human leucocyte antigen antibodies (DSAs) prior to transplantation, regardless of negative crossmatch results. The clinical significance of pre-transplant (pre-Tx) DSAs for early graft function has remained unclear. Our aim was to examine the association of DSAs with delayed graft function (DGF). METHODS: Pre-Tx sera of 771 patients who received kidney transplants in our single-centre study were retrospectively screened. All transplantations were performed after negative complement-dependent cytotoxicity (CDC) crossmatch. RESULTS: DSAs were detected in 13% of the patients. The overall DGF rate in our study was 29%. Patients with DSAs had a higher incidence of DGF when compared with non-sensitized patients (48 and 26%, respectively; P < 0.0001). Third-party antibodies had no effect for DGF incidence (28%; P = 0.6098). The relative risk (RR) of DGF for patients with DSAs in the multivariate analysis was 2.039 (95% CI 1.246-3.335; P = 0.0046). Analyses of the cumulative mean fluorescent intensity (MFI) value of the DSAs revealed a rate of DGF more than two times higher in patients with a cumulative value of 3000-5000 MFI compared with a cumulative value of 1000-3000 (65 versus 31%; P = 0.0351). DSAs against any loci showed an elevated DGF incidence of 44-69% when compared with patients without DSA (27%). CONCLUSIONS: The risk of DGF is twice as high in patients having pre-formed DSAs. Pre-Tx DSAs is a modifiable risk factor that can be obviated with careful organ allocation relying on careful pre-Tx analysis of non-accepted mismatches determined with sensitive solid phase methods. PMID- 26614273 TI - Can the laryngeal mask play a role in electroconvulsive treatment? A pilot study. AB - INTRODUCTION: Optimising ventilation control in the anaesthetic process of electroconvulsive therapy (ECT) can be a method for improving the effectiveness and safety of some treatments. There are several approaches for inducing adequate therapeutic seizures in patients with medical co-morbidity or in those with high seizure thresholds, although all of them present limitations. A new approach is hyperventilation with laryngeal mask, a method that improves oxygenation, achieves hypocapnia, and lowers seizure threshold. Thus, hyperventilation with laryngeal mask could, hypothetically, be useful to decrease the energy needed to obtain adequate therapeutic seizures. MATERIAL AND METHODS: A randomized crossover study was conducted on 14 patients on maintenance ECT, using a laryngeal mask versus a facemask. When laryngeal masks were applied, the energy was reduced by 45% compared with the energy required when ventilated with facemasks (performed with standard dose). RESULTS: The results of the study revealed that, despite a 45% energy reduction with laryngeal mask, there were no significant differences in seizure length in either group. CONCLUSIONS: These results prompt us to propose ventilation with laryngeal mask as an alternative to decrease energy applied without lowering seizure times. This is a preliminary study with a small sample, which opens new lines of research. Larger samples and other measurements of seizure adequacy are needed in future studies, in order to study possible improvements in ventilation and minimising adverse effects of ECT, especially in patients with medical co-morbidities. PMID- 26614274 TI - Characterization of Childhood Obesity and Behavioral Factors. AB - INTRODUCTION: Childhood obesity is a major public health threat in the United States. Recent data indicate that 34.2% of children ages 6 to 11 years are overweight or obese. The purpose of this study is to describe childhood obesity levels and identify risk behaviors in two school-based health centers in Michigan, one urban and one rural. METHODS: This study is a secondary data analysis from a multicenter comparative effectiveness trial. Multiple logistic regression was used to examine behavioral factors associated with overweight/obesity in children. RESULTS: In this sample (n = 105), 41.9% were obese and 16.2% were overweight. The duration of sleep per night (p = .04) and the frequency of eating breakfast (p = .04) were significant predictors of being overweight/obese. DISCUSSION: Health care providers in school-based health centers must be comfortable assessing, preventing, and treating childhood obesity in this high-risk group of patients. Interventions should encourage children to eat breakfast daily and to get adequate sleep. PMID- 26614275 TI - Use of a Pediatric Bleeding Questionnaire in the Screening of Von Willebrand Disease in Young Females at Menarche in the Primary Care Setting. AB - Von Willebrand disease (VWD), the most common inherited bleeding disorder, is caused by deficiency or dysfunction in von Willebrand factor. Assessment of hemorrhagic symptoms is essential for early diagnosis, although bleeding histories are taken in a nonstandardized manner. Validated bleeding assessment tools provide objectivity in evaluating bleeding patterns of females at menarche and may improve provider confidence in screening for VWD. Utilizing a pretest/posttest design, in this project we implemented and evaluated the use of a pediatric bleeding questionnaire in eight pediatric primary care clinics for 3 months. Results indicate improved provider knowledge, confidence, and skills after implementation. The importance and quality of the tool were rated highly by the providers, while the ease of use was rated low. Providers were satisfied with the practice change and believed that it improved their clinical abilities. The use of this tool can improve VWD screening in this practice setting. PMID- 26614276 TI - National and State-Specific Td and Tdap Vaccination of Adult Populations. AB - INTRODUCTION: The Advisory Committee on Immunization Practices recommends a single dose of tetanus, diphtheria, and acellular pertussis vaccine (Tdap) for adults followed by tetanus and diphtheria toxoids (Td) booster doses every 10 years thereafter. This study assessed recent Td and Tdap vaccination among adult populations. METHODS: The 2013 Behavioral Risk Factor Surveillance System data were analyzed in 2015 to assess Td and Tdap vaccination coverage among adults at national and state levels. Multivariable logistic regression and predictive marginal models were performed to identify factors independently associated with vaccination. RESULTS: Overall, national vaccination coverage among adults aged >=18 years for Td was 57.5% and for Tdap was 28.9%. Among states, Td vaccination coverage ranged from 47.8% in Nevada to 73.1% in Minnesota, and Tdap coverage ranged from 17.7% in Mississippi to 47.6% in Minnesota. Characteristics independently associated with an increased likelihood of Tdap vaccination among adults aged >=18 years were younger age; being female; American Indian/Alaska Native race; being never married; higher education; not being in the workforce; reporting a household income >=$75,000; living in the West or Midwest U.S.; reporting excellent, very good, good, or fair health; having health insurance; having a healthcare provider; having a routine checkup in the previous year; receipt of influenza vaccination in the previous year; and having ever received pneumococcal vaccination. CONCLUSIONS: By 2013, Td and Tdap vaccination coverage were 57.5% and 28.9%, respectively. Coverage varied by state. Implementation of evidence-based programs is needed to improve Td and Tdap vaccination levels among adult populations. PMID- 26614278 TI - Chloroplast-Based Expression of Recombinant Proteins by Gateway(r) Cloning Technology. AB - Plastid transformation for the expression of recombinant proteins and entire enzymatic pathways has become a promising tool for plant biotechnology in the past decade. Several improvements of the technology have turned plant plastids into robust and dependable expression platforms for multiple high value compounds. In this chapter, we describe our current methodology based on Gateway((r)) recombinant cloning, which we have adapted for plastid transformation. We describe the steps required for cloning, biolistic transformation, identification, and regeneration of transplastomic plant lines and Western blot analysis. PMID- 26614277 TI - Cognitive behaviour therapy for older adults experiencing insomnia and depression in a community mental health setting: Study protocol for a randomised controlled trial. AB - BACKGROUND: Cognitive behaviour therapy for insomnia (CBT-I) is a well established treatment; however, the evidence is largely limited to homogenous samples. Although emerging research has indicated that CBT-I is also effective for comorbid insomnia, CBT-I has not been tested among a complex sample of older adults with comorbid insomnia and depression. Furthermore, no study has explored whether modifying CBT-I to target associated depressive symptoms could potentially enhance sleep and mood outcomes. Therefore, this study aims to report a protocol designed to test whether an advanced form of CBT for insomnia and depression (CBT-I-D) is more effective at reducing insomnia and depressive symptoms compared to a standard CBT-I and psychoeducation control group (PCG) for older adults in a community mental health setting. METHODS/DESIGN: We aim to recruit 150 older adults with comorbid insomnia who have presented to community mental health services for depression. Eligible participants will be randomly allocated via block/cluster randomisation to one of three group therapy conditions: CBT-I, CBT-I-D, or PCG. Participants who receive CBT-I will only practice strategies designed to improve their sleep, whereas participants who receive CBT-I-D will practice additional strategies designed to also improve their mood. This trial will implement a mixed-methods design involving quantitative outcome measures and qualitative focus groups. The primary outcome measures are insomnia and depression severity, and secondary outcomes are anxiety, hopelessness, beliefs about sleep, comorbid sleep conditions, and health. Outcomes will be assessed at pre-intervention (week 0), post-intervention (week 8), and 3-month follow-up (week 20). DISCUSSION: This CBT study protocol has been designed to address comorbid insomnia and depression for older adults receiving community mental health services. The proposed trial will determine whether CBT-I is more effective for older adults with comorbid insomnia and depression compared to a PCG. It will also establish whether an advanced form of CBT-I-D generates greater reductions in insomnia and depression severity compared to standard CBT-I. The results from the proposed trial are anticipated to have important clinical implications for older adults, researchers, therapists, and community mental health services. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN: 12615000067572 , Date Registered 12 December 2014. PMID- 26614279 TI - Multigene Engineering in Rice Using High-Capacity Agrobacterium tumefaciens BIBAC Vectors. AB - The high-capacity binary bacterial artificial chromosome (BIBAC) vector system permits the insertion of large fragments of DNA, up to 150 kb, into plants via Agrobacterium-mediated transformation. Here, we describe an optimized protocol for transformation of japonica rice (Oryza sativa L.) using this system. Calli derived from mature embryos are transformed using Agrobacterium strain LBA4404 that carries the BIBAC vector and the super-virulent helper plasmid pCH32. Transformed calli are then regenerated using optimized media and tested for transgene integration by PCR, GUS assay, and Southern blot analyses. PMID- 26614280 TI - Virus-Derived Vectors for the Expression of Multiple Proteins in Plants. AB - This chapter constitutes a practical guide to using the "pEAQ" vector series for transient or stable expression of one or more protein(s) in Nicotiana benthamiana plants. The pEAQ vectors are a series of small binary vectors designed for controlled expression of multiple proteins in plants. To achieve high levels of expression, an expression system based on translational enhancement by the untranslated regions of RNA-2 from cowpea mosaic virus (CPMV), named CPMV-HT, is used. The expression vector pEAQ-HT combines the user-friendly pEAQ plasmid with CPMV-HT to provide a system for high-level expression of proteins in plants. PMID- 26614281 TI - Transient Protein Expression by Agroinfiltration in Lettuce. AB - Current systems of recombinant protein production include bacterial, insect, and mammalian cell culture. However, these platforms are expensive to build and operate at commercial scales and/or have limited abilities to produce complex proteins. In recent years, plant-based expression systems have become top candidates for the production of recombinant proteins as they are highly scalable, robust, safe, and can produce complex proteins due to having a eukaryotic endomembrane system. Newly developed "deconstructed" viral vectors delivered via Agrobacterium tumefaciens (agroinfiltration) have enabled robust plant-based production of proteins with a wide range of applications. The leafy Lactuca sativa (lettuce) plant with its strong foundation in agriculture is an excellent host for pharmaceutical protein production. Here, we describe a method for agroinfiltration of lettuce that can rapidly produce high levels of recombinant proteins in a matter of days and has the potential to be scaled up to an agricultural level. PMID- 26614282 TI - Production of Recombinant Proteins in the Chloroplast of the Green Alga Chlamydomonas reinhardtii. AB - Chloroplast transformation in the green algae Chlamydomonas reinhardtii can be used for the production of valuable recombinant proteins. Here, we describe chloroplast transformation of C. reinhardtii followed by protein detection. Genes of interest integrate stably by homologous recombination into the chloroplast genome following introduction by particle bombardment. Genes are inherited and expressed in lines recovered after selection in the presence of an antibiotic. Recombinant proteins can be detected by conventional techniques like immunoblotting and purified from liquid cultures. PMID- 26614283 TI - Efficient, Antibiotic Marker-Free Transformation of a Dicot and a Monocot Crop with Glutamate 1-Semialdehyde Aminotransferase Selectable Marker Genes. AB - Antibiotic-free, efficient in vitro selection in plant genetic engineering can improve risk perception and speed up pre-market scrutiny of genetically modified crops. We provide a protocol for genetic transformation of two important crops, durum wheat and alfalfa, using a bacterial and a plant-derived selectable marker gene encoding mutated, gabaculine-insensitive glutamate 1-semialdehyde aminotransferase (GSA) enzymes. These methods can potentially be applied, with minor adaptations, to many other monocot and dicot crop plants. PMID- 26614284 TI - Transient Expression of Mammalian Genes in N. benthamiana to Modulate N Glycosylation. AB - Nicotiana benthamiana has shown great success as a platform for the production of recombinant proteins. Here, we describe methods to transiently express high levels of recombinant proteins and simultaneously modulate their glycosylation pattern toward human-like structures. The method aims to generate recombinant proteins with a targeted largely homogeneous glycosylation profile for structure function studies. PMID- 26614285 TI - Companion Protease Inhibitors for the In Situ Protection of Recombinant Proteins in Plants. AB - We previously described a procedure for the use of plant protease inhibitors as "companion" accessory proteins to prevent unwanted proteolysis of clinically useful recombinant proteins in leaf crude protein extracts (Benchabane et al. Methods Mol Biol 483:265-273, 2009). Here we describe the use of these inhibitors for the protection of recombinant proteins in planta, before their extraction from leaf tissues. A procedure is first described involving inhibitors co expressed along-and co-migrating-with the protein of interest in host plant cells. An alternative, single transgene scheme is then described involving translational fusions of the recombinant protein and companion inhibitor. These approaches may allow for a significant improvement of protein steady-state levels in leaves, comparable to yield improvements observed with protease-deficient strains of less complex protein expression hosts such as E. coli or yeasts. PMID- 26614286 TI - Production of Recombinant Cholera Toxin B Subunit in Nicotiana benthamiana Using GENEWARE(r) Tobacco Mosaic Virus Vector. AB - Here, we describe a method to produce a recombinant cholera toxin B subunit in Nicotiana benthamiana plants (CTBp) using the GENEWARE((r)) tobacco mosaic virus vector system. Infectious transcripts of the vector RNA are generated in vitro and inoculated on N. benthamiana seedlings. After 11 days, CTBp is extracted in a simple tris buffer at room temperature. No protease inhibitor is required. The leaf homogenate is treated with mild heat and a pH shift to selectively precipitate host-derived proteins. CTBp is purified to >95 % homogeneity by two step chromatography using immobilized metal affinity and ceramic hydroxyapatite resins. This procedure yields on average 400 mg of low-endotoxin CTBp from 1 kg of fresh leaf material. PMID- 26614287 TI - Total Soluble Protein Extraction for Improved Proteomic Analysis of Transgenic Rice Plant Roots. AB - With the advent of high-throughput platforms, proteomics has become a powerful tool to search for plant gene products of agronomic relevance. Protein extractions using multistep protocols have been shown to be effective to achieve better proteome profiles than simple, single-step extractions. These protocols are generally efficient for above ground tissues such as leaves. However, each step leads to loss of some amount of proteins. Additionally, compounds such as proteases in the plant tissues lead to protein degradation. While protease inhibitor cocktails are available, these alone do not seem to suffice when roots are included in the plant sample. This is obvious given the lack of high molecular weight (HMW) proteins obtained from samples that include root tissue. For protein/proteome analysis of transgenic plant roots or of seedlings, which include root tissue, such pronounced protein degradation is especially undesirable. A facile protein extraction protocol is presented, which ensures that despite the inclusion of root tissues there is minimal loss in total protein components. PMID- 26614288 TI - Temporary Immersion Bioreactors for the Contained Production of Recombinant Proteins in Transplastomic Plants. AB - Despite the largely maternal inheritance of plastid genomes, the risk of transgene dissemination from transplastomic plants can limit the scope for field cultivation. There is a need for a cost-effective, scalable process to grow large quantities of transplastomic plant biomass for biosynthesis of biopharmaceuticals and other high-value heterologous proteins. Temporary immersion culture is a means of achieving this under fully contained conditions. This method describes the organogenesis of transplastomic Nicotiana tabacum callus in RITA((r)) temporary immersion bioreactors to produce rootless leafy biomass, and subsequent total soluble protein extraction, SDS-PAGE, and Western immunoblot analysis of heterologous protein expression. This method can be used for propagation of plastid or nuclear transformants, though is especially suitable for transplastomic biomass, as organogenesis leads to greater expression and accumulation of transplastomic proteins due to increases in chloroplast number and size. PMID- 26614289 TI - Plant Cell-Based Recombinant Antibody Manufacturing with a 200 L Orbitally Shaken Disposable Bioreactor. AB - Tobacco BY-2 cells are an attractive platform for the manufacture of a variety of biopharmaceutical proteins, including antibodies. Here, we describe the scaled-up cultivation of human IgG-secreting BY-2 cells in a 200 L orbitally shaken disposable bioreactor, resulting in cell growth and recombinant protein yields that are proportionately comparable with those obtained from cultivations in 500 mL shake flasks. Furthermore, we present an efficient downstream process for antibody recovery from the viscous spent culture medium using expanded bed adsorption (EBA) chromatography. PMID- 26614290 TI - Liquid-Liquid Phase Separation of Oil Bodies from Seeds. AB - Fundamentally, oil bodies are discrete storage organelles found in oilseeds, comprising a hydrophobic triacylglycerol core surrounded by a half-unit phospholipid membrane and an outer shell of specialized proteins known as oleosins. Oil bodies possess a number of attributes that were exploited by SemBioSys Genetics to isolate highly enriched fractions of oil bodies through liquid-liquid phase separation for a number of commercial applications. The current chapter provides a general guide for the isolation of oil bodies from Arabidopsis and/or safflower seed, from which protocols can be refined for different oilseed sources. For SemBioSys Genetic's recombinant technology, therapeutic proteins were covalently attached to oleosins or fused in-frame with ligands which bound oil bodies, facilitating their recovery to high levels of purity during "upstream processing" of transformed seed. Core to this technology was oil body isolation consisting of simple manipulation including homogenization of seeds to free the oil bodies, followed by the removal of insoluble fractions, and phase separation to recover the oil bodies. During oil body enrichment (an increase in oil body content concomitant with removal of impurities), a number of options and tips are provided to aid researchers in the manipulation and monitoring of these robust organelles. PMID- 26614291 TI - Continuous Flow Separation of Hydrophobin Fusion Proteins from Plant Cell Culture Extract. AB - Fusion to fungal hydrophobins has proven to be a useful tool to enhance accumulation and recovery of recombinant proteins in plants. Aqueous two-phase separation (ATPS) is an attractive system to capture hydrophobin fusion proteins from plant extracts. The process can simultaneously purify and concentrate target protein with minimal background. ATPS avoids the use of chromatographic column steps, can be carried out in a short time frame, and is amenable to industrial scale protein purification. A drawback of performing ATPS in large volumes is the lengthy time required for phase separation; however, this can be avoided by incorporating continuous systems, which are often preferred by the processing industry. This method chapter illustrates the capture of GFP-HFBI hydrophobin fusion protein from BY-2 plant cell suspension extract using a semi-continuous ATPS method. PMID- 26614292 TI - Molecular Analyses of Transgenic Plants. AB - One of the major challenges in plant molecular biology is to generate transgenic plants that express transgenes stably over generations. Here, we describe some routine methods to study transgene locus structure and to analyze transgene expression in plants: Southern hybridization using DIG chemiluminescent technology for characterization of transgenic locus, SYBR Green-based real-time RT-PCR to measure transgene transcript level, and protein immunoblot analysis to evaluate accumulation and stability of transgenic protein product in the target tissue. PMID- 26614293 TI - Analysis of Recombinant Proteins in Transgenic Rice Seeds: Identity, Localization, Tolerance to Digestion, and Plant Stress Response. AB - Rice seeds are an ideal production platform for high-value recombinant proteins in terms of economy, scalability, safety, and stability. Strategies for the expression of large amounts of recombinant proteins in rice seeds have been established in the past decade and transgenic rice seeds that accumulate recombinant products such as bioactive peptides and proteins, which promote the health and quality of life of humans, have been generated in many laboratories worldwide. One of the most important advantages is the potential for direct oral delivery of transgenic rice seeds without the need for recombinant protein purification (downstream processing), which has been attributed to the high expression levels of recombinant products. Transgenic rice will be beneficial as a delivery system for pharmaceuticals and nutraceuticals in the future. This chapter introduces the strategy for producing recombinant protein in the edible part (endosperm) of the rice grain and describes methods for the analysis of transgenic rice seeds in detail. PMID- 26614294 TI - Real-Time PCR-Based Quantitation Method for the Genetically Modified Soybean Line GTS 40-3-2. AB - This chapter describes a real-time PCR-based method for quantitation of the relative amount of genetically modified (GM) soybean line GTS 40-3-2 [Roundup Ready((r)) soybean (RRS)] contained in a batch. The method targets a taxon specific soybean gene (lectin gene, Le1) and the specific DNA construct junction region between the Petunia hybrida chloroplast transit peptide sequence and the Agrobacterium 5-enolpyruvylshikimate-3-phosphate synthase gene (epsps) sequence present in GTS 40-3-2. The method employs plasmid pMulSL2 as a reference material in order to quantify the relative amount of GTS 40-3-2 in soybean samples using a conversion factor (Cf) equal to the ratio of the RRS-specific DNA to the taxon specific DNA in representative genuine GTS 40-3-2 seeds. PMID- 26614295 TI - A Standardized Lepidopteran Bioassay to Investigate the Bioactivity of Insecticidal Proteins Produced in Transgenic Crops. AB - Insecticidal bioassays are the only reliable method to investigate the biological activity of an insecticidal protein and therefore provide an essential toolkit for the characterization and potency determination of these proteins. Here we present a standardized method for a lepidopteran larval bioassay, which is optimized to specifically estimate activity of insecticidal proteins produced in transgenic plants. The treatment can be either applied to the surface of the artificial diet, or blended into the diet. PMID- 26614296 TI - Antibody-Mediated Pathogen Resistance in Plants. AB - The methods described in this chapter were developed in order to produce transgenic plants expressing pathogen-specific single-chain variable fragment (scFv) antibodies fused to antifungal peptides (AFPs), conferring resistance against fungal pathogens. We describe the selection from a phage display library of avian scFv antibodies that recognize cell surface proteins on fungi from the genus Fusarium, and the construction of scFv-AFP fusion protein constructs followed by their transient expression in tobacco (Nicotiana spp.) plants and stable expression in Arabidopsis thaliana plants. Using these techniques, the antibody fusion with the most promising in vitro activity can be used to generate transgenic plants that are resistant to pathogens such as Fusarium oxysporum f. sp. matthiolae. PMID- 26614297 TI - "It's the duty of every doctor to get involved with research". PMID- 26614298 TI - Glycated apolipoprotein B-A surrogate marker of subclinical atherosclerosis. AB - AIMS: Sustained hyperglycemia is a causative factor for glycation of proteins. Glycated low-density lipoprotein (LDL) is strongly associated with an increased risk of CAD (Coronary Artery Disease) in diabetics. Hence, we planned to evaluate the association of glycated apo B with subclinical atherosclerosis. METHOD: Forty five non obese and 45 obese diabetics were recruited. Glycated hemoglobin (HbA1c) levels were estimated by HPLC (High Pressure Liquid Chromatography) and small dense low-density lipoprotein (sdLDL) was calculated using standard formula. Plasma Insulin was done by RIA. Insulin resistance was calculated using homeostatic model assessment insulin resistance (HOMA-IR) model. Glycated apo B in serum was estimated using ELISA. Carotid intimal media thickness (CIMT) was estimated using B mode USG of carotid arteries. RESULTS: Glycated apo B levels were correlated significantly with fasting blood glucose (FBG) (p=0.001), post prandial glucose (PPG) (p=0.001), HbA1c (p=0.013). The percent glycated apo B levels correlated significantly with FBG (p=0.032), PPG (p=0.004) in obese diabetic group. Multivariate regression analysis of glycated apo B and percent glycated apo B, showed that glycated apo B (p=0.009) and percent glycated apo B (p=0.006) were significantly correlated to FPG in diabetic population. The percent glycated apo B was also significantly correlated to PPG (p=0.003) and sdLDL (p=0.009). CIMT levels were higher in obese diabetics with 2 plaques positive when compared to obese non diabetic controls; however levels were not statistically significant. CONCLUSION: Persistent hyperglycemia and sdLDL are independently associated with glycation of apo B. Presence of plaques and increased thickness of intima indicates that glycated apo B predisposes diabetics to atherosclerosis. PMID- 26614299 TI - His electrogram alternans (Zhang's phenomenon) and a new model of dual pathway atrioventricular node conduction. AB - BACKGROUND: In contrast to the current textbook model and the current clinical index of dual pathway atrioventricular (AV) nodal conduction, here we summarize the discovery and validation of Zhang's phenomenon (originally His electrogram alternans) as a new index of dual pathway conduction. We also describe the new findings of transverse-versus-longitudinal electrical propagation within the AV node as the electrophysiological basis underlining this new index. Thus, a new index and a new model of dual pathway AV conduction are being developed. METHODS: We have reviewed current literature and provided evidence supporting a new index and a new model of dual pathway AV conduction. RESULTS: Recent data revealed that during fast pathway conduction, electrical excitation in the AV node propagates in a superior to inferior direction across AV conduction axis and fiber orientation to reach first the superior His bundle fibers. However, this transverse conduction can fail easily within the superior nodal domain at fast rates. The failing of transverse propagation permits electrical excitation formed at the posterior/inferior nodal region to propagate longitudinally along fiber orientation in a posterior to anterior direction through the inferior nodal domain to reach the inferior His bundle (slow pathway conduction). This transverse-versus-longitudinal electrical propagation within the AV node results in a functional dissociation in the distal node and formation of dual inputs into the His bundle, providing the electrophysiological basis for the formation of Zhang's phenomenon (His electrogram alternans). CONCLUSIONS: Based on strong experimental data, a new index and a new model of dual pathway AV nodal conduction are emerging, although they are still awaiting clinical validation. PMID- 26614300 TI - Metabolic engineering of Saccharomyces cerevisiae for linalool production. AB - OBJECTIVES: To engineer the yeast Saccharomyces cerevisiae for the heterologous production of linalool. RESULTS: Expression of linalool synthase gene from Lavandula angustifolia enabled heterologous production of linalool in S. cerevisiae. Downregulation of ERG9 gene, that encodes squalene synthase, by replacing its native promoter with the repressible MET3 promoter in the presence of methionine resulted in accumulation of 78 ug linalool l(-1) in the culture medium. This was more than twice that produced by the control strain. The highest linalool titer was obtained by combined repression of ERG9 and overexpression of tHMG1. The yeast strain harboring both modifications produced 95 MUg linalool l( 1). CONCLUSIONS: Although overexpression of tHMG1 and downregulation of ERG9 enhanced linalool titers threefold in the engineered yeast strain, alleviating linalool toxicity is necessary for further improvement of linalool biosynthesis in yeast. PMID- 26614301 TI - Laryngeal metastasis from bile duct adenocarcinoma. PMID- 26614302 TI - Orbital emphysema after blowing the nose. PMID- 26614303 TI - Dual endolaparoscopic technique (DUET) for TAMIS proctectomy and concomitant parastomal hernia repair. PMID- 26614304 TI - Systematic review of pre-operative exercise in colorectal cancer patients. AB - The aim of this systematic review was to evaluate the evidence for exercise interventions prior to surgery for colorectal cancer resection. The evidence for use of exercise to improve physical fitness and surgical outcomes is as yet unknown. A systematic search was performed of MEDLINE, EMBASE, CINAHL, AMED and BNI databases for studies involving pre-operative exercise in colorectal cancer patients. Eight studies were included in the review. There is evidence that pre operative exercise improves functional fitness, and to a lesser extent objectively measurable cardio-respiratory fitness prior to colorectal cancer resection. There is no clear evidence at present that this improvement in fitness translates into reduced peri-operative risk or improved post-operative outcomes. Current studies are limited by risk of bias. This review highlights the common difficulty in transferring promising results in a research setting, into significant improvements in the clinical arena. Future research should focus on which type of exercise is most likely to maximise patient adherence and improvements in cardio-respiratory fitness. Ultimately, adequately powered, randomised controlled trials are needed to investigate whether pre-operative exercise improves post-operative morbidity and mortality. PMID- 26614305 TI - Intraoperative herniation of an L5-S1 disc during microdiscectomy and transforaminal lumbar interbody fusion: a case report. AB - INTRODUCTION: We report the progression of an intraoperative L5-S1 lumbar disc herniation that occurred during a routine microdiscectomy and transforaminal lumbar interbody fusion, which, to the best of our knowledge, has never been previously reported in the literature. The objective of this report is to bring to light the possibility of a lumbar disc herniating intraoperatively, and to demonstrate that accompanying neurologic involvement can be detected and subsequently addressed with the aid of neurophysiologic monitoring. CASE PRESENTATION: A 36-year-old African American woman, who had previously undergone minimally invasive microdiscectomy for a right L5-S1 herniated nucleus pulposus with full recovery, presented with a large reherniation of the L5-S1 disc on the right side. During her operation, while a tap was followed into the L5 left pedicle, there was a sudden profound spasm of our patient's legs and back that lasted for the duration of 15 seconds, culminating in the loss of all somatosensory evoked potentials in our patient's lower extremities. Exploration of this previous microlaminotomy site revealed a massive disc extrusion protruding through the microlaminotomy. Immediate removal of this extruded disc material restored all somatosensory evoked potentials and our patient awoke with no neurologic deficits. CONCLUSIONS: An intraoperative disc herniation in the lumbar spine, though very rare, can occur and can result in neurologic compromise as evidenced by the loss of somatosensory evoked potentials. By identifying the event, it can be remedied by evaluating the disc visually, removing extruded fragments and decompressing nerve roots with recovery of somatosensory evoked potentials and normal neurologic function postoperatively. If neurophysiological monitoring shows there is a sudden loss of response, then consideration should be given to the possibility of an acute intraoperative herniation. PMID- 26614306 TI - Land use change detection and impact assessment in Anzali international coastal wetland using multi-temporal satellite images. AB - Anzali is one of the 18 Iranian wetlands of international importance listed in Ramsar Convention. This unique ecosystem in the world with high ecological diversity is highly threatened by various factors such as pollutants, sedimentation, unauthorized development of urban infrastructure, over-harvesting of wetland resources, land use changes, and invasive species. Among which, one of the most challenging destructive factors, land use change, was scrutinized in this study. For this, remotely sensed data and Geographical Information System (GIS) were used to detect land changes and corresponding impacts on the study area over a 38-year period from 1975 to 2013.. Changes in the study area were traced in five dominant land-use classes at four time intervals of 1975, 1989, 2007, and 2013. Accordingly, changes in different categories were quantified using satellite images. The methodology adopted in this study includes an integrated approach of supervised classification, zonal and object-oriented image analyses. According to the Kappa coefficient of 0.84 for the land use map of 2013, the overall accuracy of the method was estimated at 89%, which indicated that this method can be useful for monitoring and behavior analysis of other Iranian wetlands. The obtained results revealed extensive land use changes over the study period. As the results suggest, between the years 1975 to 2013, approximately 6500 ha (~69%) rangeland area degraded. Further, urban and agricultural areas have been extended by 2982 ha (~74%) and 2228 ha (~6%), respectively. This could leave a negative impact on water quality of the wetland. PMID- 26614307 TI - Rasch Analysis of the General Self-Efficacy Scale in Workers with Traumatic Limb Injuries. AB - Purpose The purpose of this study was to apply Rasch analysis to examine the unidimensionality and reliability of the General Self-Efficacy Scale (GSE) in workers with traumatic limb injuries. Furthermore, if the items of the GSE fitted the Rasch model's assumptions, we transformed the raw sum ordinal scores of the GSE into Rasch interval scores. Methods A total of 1076 participants completed the GSE at 1 month post injury. Rasch analysis was used to examine the unidimensionality and person reliability of the GSE. The unidimensionality of the GSE was verified by determining whether the items fit the Rasch model's assumptions: (1) item fit indices: infit and outfit mean square (MNSQ) ranged from 0.6 to 1.4; and (2) the eigenvalue of the first factor extracted from principal component analysis (PCA) for residuals was <2. Person reliability was calculated. Results The unidimensionality of the 10-item GSE was supported in terms of good item fit statistics (infit and outfit MNSQ ranging from 0.92 to 1.32) and acceptable eigenvalues (1.6) of the first factor of the PCA, with person reliability = 0.89. Consequently, the raw sum scores of the GSE were transformed into Rasch scores. Conclusions The results indicated that the items of GSE are unidimensional and have acceptable person reliability in workers with traumatic limb injuries. Additionally, the raw sum scores of the GSE can be transformed into Rasch interval scores for prospective users to quantify workers' levels of self-efficacy and to conduct further statistical analyses. PMID- 26614308 TI - What makes Cryptococcus gattii a pathogen? AB - Cryptococcosis is an invasive fungal infection of humans and other animals, typically caused by the species Cryptococcus neoformans in patients with impaired immunity. However, there is growing recognition of the importance of the related species C. gattii in causing infections in apparently immunocompetent individuals. In particular, an ongoing outbreak of cryptococcal disease in the Pacific Northwest region, which started in 1999, has driven an intense research effort into this previously neglected pathogen. Here, we discuss some of the recent discoveries in this organism from the Pacific Northwest region and highlight areas for future investigation. PMID- 26614309 TI - Serum neutrophil gelatinase-associated lipocalin concentration reflects severity of coronary artery disease in patients without heart failure and chronic kidney disease. AB - Serum neutrophil gelatinase-associated lipocalin (NGAL) is recognized as a useful biomarker for acute kidney injury. Recently, elevated NGAL levels were reported in patients with heart failure and cardiac events, but the association between serum NGAL and severity of coronary artery disease (CAD) has not been investigated adequately. This study aimed to evaluate the association between serum NGAL concentration and CAD severity in patients without heart failure and chronic kidney disease. Two-hundred thirteen patients [mean age: 66.2 +/- 9.2 (SD)] without heart failure and chronic kidney disease (estimated glomerular filtration rate >60 mL/min/1.73 m(2)) who underwent coronary angiography were retrospectively analyzed using the SYNTAX score. The mean concentration of serum NGAL was 134.3 +/- 111.3 ng/mL. A statistically significant correlation was observed between serum NGAL levels and the SYNTAX score (R = 0.18, P = 0.0091). Multivariable analysis also showed elevated serum NGAL as an independent risk factor for a high SYNTAX score (P < 0.01). Moreover, we evaluated the association of serum NGAL and brain natriuretic peptide (BNP) with the SYNTAX score. Patients with high levels of serum NGAL (>100 ng/mL) and high levels of BNP (>25 pg/mL) had a higher SYNTAX score (low-low vs. high-high: 13.8 +/- 13.4 vs. 20.8 +/- 18.9, P < 0.05). Serum NGAL levels were positively and significantly associated with CAD severity, and the evaluation of both serum NGAL and BNP was useful for predicting CAD in patients without renal dysfunction and heart failure. Serum NGAL might be a biomarker for CAD severity. PMID- 26614310 TI - Mixtures with relatives and linked markers. AB - Mixture DNA profiles commonly appear in forensic genetics, and a large number of statistical methods and software are available for such cases. However, most of the literature concerns mixtures where the contributors are assumed unrelated and the genetic markers are unlinked. In this paper, we consider mixtures of linked markers and related contributors. If no relationships are involved, linkage can be ignored. While unlinked markers can be treated independently, linkage introduces dependencies. The use of linked markers presents statistical and computational challenges, but may also lead to a considerable increase in power since the number of markers available is much larger if we do not require the markers to be unlinked. In addition, some cases that cannot be solved with an unlimited number of unlinked autosomal markers can be solved with linked markers. We focus on two special cases of linked markers: pairs of linked autosomal markers and X-chromosomal markers. A framework is presented for calculation of likelihood ratios for mixtures with general relationships and with linkage between any number of markers. Finally, we explore the effect of linkage disequilibrium, also called allelic association, on the likelihood ratio. PMID- 26614311 TI - Q&A: How do plants respond to cytokinins and what is their importance? AB - Cytokinins comprise a family of signaling molecules essential for regulating the growth and development of plants, acting both locally and at a distance. Although much is known about their biosynthesis and transport, important open questions remain. PMID- 26614312 TI - Looking, seeing and believing in autism: Eye movements reveal how subtle cognitive processing differences impact in the social domain. AB - Adults with High Functioning Autism Spectrum Disorders (ASD) viewed scenes with people in them, while having their eye movements recorded. The task was to indicate, using a button press, whether the pictures were normal, or in some way weird or odd. Oddities in the pictures were categorized as violations of either perceptual or social norms. Compared to a Typically Developed (TD) control group, the ASD participants were equally able to categorize the scenes as odd or normal, but they took longer to respond. The eye movement patterns showed that the ASD group made more fixations and revisits to the target areas in the odd scenes compared with the TD group. Additionally, when the ASD group first fixated the target areas in the scenes, they failed to initially detect the social oddities. These two findings have clear implications for processing difficulties in ASD for the social domain, where it is important to detect social cues on-line, and where there is little opportunity to go back and recheck possible cues in fast dynamic interactions. Autism Res 2016, 9: 879-887. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26614313 TI - Open-Shell Formulation of the Fragment Molecular Orbital Method. AB - Performing accurate calculations on large molecular systems is desirable for closed- and open-shell systems. In this work, the fragment molecular orbital method is extended to open-shell systems and implemented in the GAMESS (General Atomic and Molecular Electronic Structure System) program package. The accuracy of the method is tested, and the ability to reproduce reaction enthalpies is demonstrated. These tests also demonstrate its utility in providing an efficient means to model large open-shell systems. PMID- 26614314 TI - Least-Action Tunneling Transmission Coefficient for Polyatomic Reactions. AB - We present a new least-action variational approximation for tunneling in polyatomic reactions based on the procedure developed by Garrett and Truhlar for atom-diatom reactions. (63) The method calculates the semiclassical ground-state tunneling probability at every tunneling energy by minimizing the value of imaginary action integral along a family of paths ranging from the minimum energy path to the straight path. The method is illustrated by applications to two hydrogen-atom abstraction reactions from methane using analytical potential energy surfaces. PMID- 26614315 TI - Properties of a Method for Performing Adaptive, Multilevel QM Simulations of Complex Chemical Reactions in the Gas-Phase. AB - The properties of a new method of performing molecular dynamic simulations of complex chemical processes are presented. The method is formulated to give a time dependent, multilevel representation of the total potential that is derived from spatially resolved quantum mechanical regions. An illustrative simulation is performed on a 110 atom system to demonstrate the continuity and energy conserving properties of the method. The effect of a discontinuous total potential upon the kinetic energy of the system is examined. The discontinuities in the magnitude of atomic force vectors due to changing the electronic structure during the simulation are examined as well as the effect that these discontinuities have upon the atomic kinetic energies. The method, while not conserving total energy, does yield canonical (NVT) simulations. The time reversibility property of the simulation with an extremely discontinuous total potential is discussed. The computational scaling associated with the formation of the spatially resolved, time-dependent groups is also investigated. PMID- 26614316 TI - Permutationally Invariant Polynomial Basis for Molecular Energy Surface Fitting via Monomial Symmetrization. AB - We describe a procedure to develop a fitting basis for molecular potential energy surfaces (PESs) that is invariant with respect to permutation of like atoms. The method is based on a straightforward symmetrization of a primitive monomial basis and illustrated for several classes of molecules. A numerically efficient method to evaluate the resulting expression for the PES is also described. The fitting basis is used to obtain a new PES for H3O(+) based on roughly 62 000 ab initio energies. PMID- 26614317 TI - Exploring Multidimensional Free Energy Landscapes Using Time-Dependent Biases on Collective Variables. AB - A new implementation of the adaptive biasing force (ABF) method is described. This implementation supports a wide range of collective variables and can be applied to the computation of multidimensional energy profiles. It is provided to the community as part of a code that implements several analogous methods, including metadynamics. ABF and metadynamics have not previously been tested side by side on identical systems. Here, numerical tests are carried out on processes including conformational changes in model peptides and translocation of a halide ion across a lipid membrane through a peptide nanotube. On the basis of these examples, we discuss similarities and differences between the ABF and metadynamics schemes. Both approaches provide enhanced sampling and free energy profiles in quantitative agreement with each other in different applications. The method of choice depends on the dimension of the reaction coordinate space, the height of the barriers, and the relaxation times of degrees of freedom in the orthogonal space, which are not explicitly described by the chosen collective variables. PMID- 26614318 TI - Symmetry Conservation in Fukui Functions. AB - The problem of symmetry breaking in the evaluation of Fukui functions is addressed. It is also demonstrated that a reliable solution of the problem can be achieved using analytic methods. An automatic method that avoids occurrence of symmetry breaks has been implemented in a computer code and is described here. Negative regions of the Fukui function are shown to play a key role for the interpretation of reactivity. Example plots are presented for diatomic molecules, inorganic molecules, conjugated systems, and molecular cages. The potentiality of the Fukui functions as molecular scalar fields for prediction and analysis of regioselectivity is enhanced. Its advantages with respect to the use of condensed Fukui functions are discussed. PMID- 26614319 TI - Rigorous Extraction of the Anisotropic Multispin Hamiltonian in Bimetallic Complexes from the Exact Electronic Hamiltonian. AB - The magnetic anisotropy of the [Ni2(en)4Cl2](2+) (en = ethylenediamine) complex has been studied using wave function based computational schemes. The spin-orbit state interaction methodology provides accurate ab initio energies and wave functions that are used to interpret the anisotropy in bimetallic complexes. The extraction of the anisotropic spin Hamiltonian is performed using the effective Hamiltonian theory. This procedure which has successfully been applied to mononuclear complexes enables one to solve the weak exchange limit. It is shown that the standard coupled spin Hamiltonian only describes a part of the anisotropy of the molecule. Important higher order terms such as the biquadratic anisotropic exchange should be included in the model for an appropriate description of the anisotropy. PMID- 26614320 TI - On the Structure and Geometry of Biomolecular Binding Motifs (Hydrogen-Bonding, Stacking, X-H...pi): WFT and DFT Calculations. AB - The strengths of noncovalent interactions are generally very sensitive to a number of geometric parameters. Among the most important of these parameters is the separation between the interacting moieties (in the case of an intermolecular interaction, this would be the intermolecular separation). Most works seeking to characterize the properties of intermolecular interactions are mainly concerned with binding energies obtained at the potential energy minimum (as determined at some particular level of theory). In this work, in order to extend our understanding of these types of noncovalent interactions, we investigate the distance dependence of several types of intermolecular interactions, these are hydrogen bonds, stacking interactions, dispersion interactions, and X-H...pi interactions. There are several methods that have traditionally been used to treat noncovalent interactions as well as many new methods that have emerged within the past three or four years. Here we obtain reference data using estimated CCSD(T) values at the complete basis set limit (using the CBS(T) method); potential energy curves are also produced using several other methods thought to be accurate for intermolecular interactions, these are MP2/cc-pVTZ, MP2/aug-cc-pVDZ, MP2/6-31G*(0.25), SCS(MI)-MP2/cc-pVTZ, estimated MP2.5/CBS, DFT SAPT/aug-cc-pVTZ, DFT/M06-2X/6-311+G(2df,2p), and DFT-D/TPSS/6-311++G(3df,3pd). The basis set superposition error is systematically considered throughout the study. It is found that the MP2.5 and DFT-SAPT methods, which are both quite computationally intensive, produce potential energy curves that are in very good agreement to those of the reference method. Among the MP2 techniques, which can be said to be of medium computational expense, the best results are obtained with MP2/cc-pVTZ and SCS(MI)-MP2/cc-pVTZ. DFT-D/TPSS/6-311++G(3df,3pd) is the DFT based method that can be said to give the most well-balanced description of intermolecular interactions. PMID- 26614321 TI - Describing Both Dispersion Interactions and Electronic Structure Using Density Functional Theory: The Case of Metal-Phthalocyanine Dimers. AB - Noncovalent interactions, of which London dispersion is an important special case, are essential to many fields of chemistry. However, treatment of London dispersion is inherently outside the reach of (semi)local approximations to the exchange-correlation functional as well as of conventional hybrid density functionals based on semilocal correlation. Here, we offer an approach that provides a treatment of both dispersive interactions and the electronic structure within a computationally tractable scheme. The approach is based on adding the leading interatomic London dispersion term via pairwise ion-ion interactions to a suitably chosen nonempirical hybrid functional, with the dispersion coefficients and van der Waals radii determined from first-principles using the recently proposed "TS-vdW" scheme (Tkatchenko, A.; Scheffler, M. Phys. Rev. Lett. 2009, 102, 073005). This is demonstrated via the important special case of weakly bound metal-phthalocyanine dimers. The performance of our approach is additionally compared to that of the semiempirical M06 functional. We find that both the PBE hybrid+vdW functional and the M06 functional predict the electronic structure and the equilibrium geometry well, but with significant differences in the binding energy and in their asymptotic behavior. PMID- 26614322 TI - Multilevel Fragment-Based Approach (MFBA): A Novel Hybrid Computational Method for the Study of Large Molecules. AB - We present a novel method for the calculation of large molecules and systems, the multilevel fragment-based approach. It is based on dividing the system into small fragments followed by separate calculations of these fragments and the interactions between them. Unlike previous fragmentation-based methods, we use multiple computational methods for the individual calculations. Using an accurate method only to calculate local interactions and more approximate methods for interactions over larger distances, it is possible to achieve results very close to a more demanding fragmented calculation using the higher level method only. The number of calculations performed at the higher level scales linearly with the size of the system, which significantly improves the efficiency and allows this scheme to be used for very large systems. In this work, we have combined density functional theory with the more approximate density functional tight binding method and applied this method to the calculation of model peptides. Formulation of first derivatives of the total energy within this fragmentation scheme is also presented and tested. PMID- 26614323 TI - An Atomic Counterpoise Method for Estimating Inter- and Intramolecular Basis Set Superposition Errors. AB - An atomic counterpoise method is proposed to calculate estimates of inter- and intramolecular basis set superposition errors. The method estimates the basis set superposition error as a sum of atomic contributions and can be applied for both independent particle and electron correlation models. It is shown that the atomic counterpoise method provides results very similar to the molecular counterpoise method for intermolecular basis set superposition errors at both the HF and MP2 levels of theory with a sequence of increasingly larger basis sets. The advantage of the atomic counterpoise method is that it can be applied with equal ease to estimate intramolecular basis set superposition errors, for which few other methods exist. The atomic counterpoise method is computationally quite efficient, requiring typically double the amount of computer time as required for calculating the uncorrected energy. PMID- 26614324 TI - A General Database for Main Group Thermochemistry, Kinetics, and Noncovalent Interactions - Assessment of Common and Reparameterized (meta-)GGA Density Functionals. AB - We present a quantum chemistry benchmark database for general main group thermochemistry, kinetics, and noncovalent interactions (GMTKN24). It is an unprecedented compilation of 24 different, chemically relevant subsets that either are taken from already existing databases or are presented here for the first time. The complete set involves a total of 1.049 atomic and molecular single point calculations and comprises 731 data points (relative chemical energies) based on accurate theoretical or experimental reference values. The usefulness of the GMTKN24 database is shown by applying common density functionals on the (meta-)generalized gradient approximation (GGA), hybrid-GGA, and double-hybrid-GGA levels to it, including an empirical London dispersion correction. Furthermore, we refitted the functional parameters of four (meta-)GGA functionals based on a fit set containing 143 systems, comprising seven chemically different problems. Validation against the GMTKN24 and the molecular structure (bond lengths) databases shows that the reparameterization does not change bond lengths much, whereas the description of energetic properties is more prone to the parameters' values. The empirical dispersion correction also often improves for conventional thermodynamic problems and makes a functional's performance more uniform over the entire database. The refitted functionals typically have a lower mean absolute deviation for the majority of subsets in the proposed GMTKN24 set. This, however, is also often accompanied at the expense of poor performance for a few other important subsets. Thus, creating a broadly applicable (and overall better) functional by just reparameterizing existing ones seems to be difficult. Nevertheless, this benchmark study reveals that a reoptimized (i.e., empirical) version of the TPSS-D functional (oTPSS-D) performs well for a variety of problems and may meet the standards of an improved functional. We propose validation against this new compilation of benchmark sets as a definitive way to evaluate a new quantum chemical method's true performance. PMID- 26614325 TI - The RPA Atomization Energy Puzzle. AB - There is current interest in the random phase approximation (RPA), a "fifth-rung" density functional for the exchange-correlation energy. RPA has full exact exchange and constructs the correlation with the help of the unoccupied Kohn-Sham orbitals. In many cases (uniform electron gas, jellium surface, and free atom), the correction to RPA is a short-ranged effect that is captured by a local spin density approximation (LSDA) or a generalized gradient approximation (GGA). Nonempirical density functionals for the correction to RPA were constructed earlier at the LSDA and GGA levels (RPA+), but they are constructed here at the fully nonlocal level (RPA++), using the van der Waals density functional (vdW-DF) of Langreth, Lundqvist, and collaborators. While they make important and helpful corrections to RPA total and ionization energies of free atoms, they correct the RPA atomization energies of molecules by only about 1 kcal/mol. Thus, it is puzzling that RPA atomization energies are, on average, about 10 kcal/mol lower than those of accurate values from experiment. We find here that a hybrid of 50% Perdew-Burke-Ernzerhof GGA with 50% RPA+ yields atomization energies much more accurate than either one does alone. This suggests a solution to the puzzle: While the proper correction to RPA is short-ranged in some systems, its contribution to the correlation hole can spread out in a molecule with multiple atomic centers, canceling part of the spread of the exact exchange hole (more so than in RPA or RPA+), making the true exchange-correlation hole more localized than in RPA or RPA+. This effect is not captured even by the vdW-DF nonlocality, but it requires the different kind of full nonlocality present in a hybrid functional. PMID- 26614326 TI - Accelerating Correlated Quantum Chemistry Calculations Using Graphical Processing Units and a Mixed Precision Matrix Multiplication Library. AB - Two new tools for the acceleration of computational chemistry codes using graphical processing units (GPUs) are presented. First, we propose a general black-box approach for the efficient GPU acceleration of matrix-matrix multiplications where the matrix size is too large for the whole computation to be held in the GPU's onboard memory. Second, we show how to improve the accuracy of matrix multiplications when using only single-precision GPU devices by proposing a heterogeneous computing model, whereby single- and double-precision operations are evaluated in a mixed fashion on the GPU and central processing unit, respectively. The utility of the library is illustrated for quantum chemistry with application to the acceleration of resolution-of-the-identity second-order Moller-Plesset perturbation theory calculations for molecules, which we were previously unable to treat. In particular, for the 168-atom valinomycin molecule in a cc-pVDZ basis set, we observed speedups of 13.8, 7.8, and 10.1 times for single-, double- and mixed-precision general matrix multiply (SGEMM, DGEMM, and MGEMM), respectively. The corresponding errors in the correlation energy were reduced from -10.0 to -1.2 kcal mol(-1) for SGEMM and MGEMM, respectively, while higher accuracy can be easily achieved with a different choice of cutoff parameter. PMID- 26614327 TI - Fisher Information Study in Position and Momentum Spaces for Elementary Chemical Reactions. AB - The utility of the Fisher information measure is analyzed to detect the transition state, the stationary points of a chemical reaction, and the bond breaking/forming regions of elementary reactions such as the simplest hydrogen abstraction and the identity SN2 exchange ones. This is performed by following the intrinsic reaction path calculated at the MP2 and QCISD(T) levels of theory with a 6-311++G(3df, 2p) basis set. Selected descriptors of both position and momentum space densities are utilized to support the observations, such as the molecular electrostatic potential (MEP), the hardness, the dipole moment, along with geometrical parameters. Our results support the concept of a continuum of transient of Zewail and Polanyi for the transition state rather than a single state, which is also in agreement with reaction force analyses. PMID- 26614328 TI - Spatially Homogeneous QM/MM for Systems of Interacting Molecules with on-the-Fly ab Initio Force-Field Parametrization. AB - Quantum and classical mechanics are combined in a hybrid many-body interaction model to enable the computationally affordable study of systems containing many interacting molecules. This model treats intramolecular and pairwise intermolecular interactions quantum mechanically, while many-body electrostatic induction effects are approximated using a polarizable force field. In this paper, we demonstrate that parametrizing the force field with distributed multipoles and atom-centered polarizabilities obtained on-the-fly from ab initio quantum mechanical monomer calculations makes the model very accurate and eliminates nearly all empiricism. Test calculations on water, formamide, hydrogen fluoride, and glycine-water clusters, all of which exhibit strong many-body interactions, are presented. The performance of the hybrid model is competitive with related point-charge embedding models. PMID- 26614329 TI - Accurate Intermolecular Interaction Energies from a Combination of MP2 and TDDFT Response Theory. AB - A new method is presented that improves the supermolecular second-order Moller Plesset (MP2) method for dimer systems with strong dispersion interactions while preserving the generally good performance of MP2 for other types of intermolecular interactions, e.g., hydrogen-bonded systems. This is achieved by adding a correction term to the supermolecular MP2 energy that is determined using time-dependent density functional (TDDFT) response theory and that accounts for the error of the dispersion energy contained in the supermolecular MP2 method. It is shown for the S22 database set of noncovalent complexes and some potential energy curves of noncovalent bound aromatic dimers that the approach gives strong improvements over MP2 if compared to coupled-cluster singles, doubles, and perturbative triples (CCSD(T)) reference energies. An efficient computer implementation of the method is presented that is shown to scale only with the fourth power of the system size and thus leads only to a slightly higher computational cost than that of the supermolecular MP2 itself. PMID- 26614330 TI - Ab Initio Study of the Diels-Alder Reaction of Cyclopentadiene with Acrolein in a Ionic Liquid by KS-DFT/3D-RISM-KH Theory. AB - We study the Diels-Alder reaction between cyclopentadiene and acrolein in a model room-temperature ionic liquid ([mmim][PF6]) as a solvent. The calculations have been performed with the KS-DFT/3D-RISM-SCF theory, where the reactants and transition state (TS) have been represented at a QM level, while the solvent is represented by a 3D distribution of classical (charge + LJ) sites obtained by solving the 3D-RISM integral equation. We show that this method, being computationally efficient, is able to reproduce the main experimental features displayed by the experiments, concerning the reaction rate enhancement and augmentation of the endo/exo ratio in ionic liquids (ILs). We find that the IL distorts noticeably the transition state geometry, inverting the order of the frontier orbitals and leading to an enhancement of the asynchronicity of the reaction. Finally, we find, in agreement with recent work, that formation of the hydrogen bond between the unique C2 hydrogen of the imidazolium ring is not essential to explain the peculiar features of these reactions in ILs. PMID- 26614331 TI - Free Energy Barriers for the N-Terminal Asparagine to Succinimide Conversion: Quantum Molecular Dynamics Simulations for the Fully Solvated Model. AB - Deamidation of asparagine residues represents one of the main routes for the post translational modification of protein sequences. We computed the estimates of the free energy barriers for three stages of the deamidation process, deprotonation, cyclization, and deamination, of the conversion of asparagine to the succinimide intermediate within the fully solvated model with explicit water molecules. The Born-Oppenheimer molecular dynamics in the Gaussian and Plane Wave (GPW) approximation as implemented in the CP2K quantum chemistry package was utilized to sample the configurational space. By applying the metadynamics technique, the estimates of the free energy barriers were obtained for three separated stages of the reaction. In agreement with the experimental kinetic measurements, the estimated activation barriers do not exceed 21 kcal/mol. We demonstrate that the use of fully solvated models is the critical issue in theoretical studies of these reactions. We also conclude that more extensive sampling is necessary to obtain full free energy profiles and accurate barriers for the reaction stages. PMID- 26614332 TI - Conformational Analysis of Arabinofuranosides: Prediction of (3)JH,H Using MD Simulations with DFT-Derived Spin-Spin Coupling Profiles. AB - A molecular dynamics (MD) investigation on a series of oligo-alpha arabinofuranosides (1-8) using the AMBER force field and the GLYCAM carbohydrate parameter set is reported. The validation of the method was carried out by direct comparison of experimental vicinal proton-proton coupling constants ((3)JH,H) with those obtained by using an empirically determined Karplus equation and density functional theory (DFT)-derived relationships specifically tailored for alpha-arabinofuranosyl systems. A simple code was developed to implement the determination of (3)JH,H by applying these relationships to the probability distributions of rotamers and ring conformations displayed by the simulations. The empirical Karplus relationship and the DFT-derived equations yielded, in most cases, the same trend as experiment for intra-ring (3)JH,H values. This direct comparison circumvents additional sources of errors that may arise from the assumptions introduced by the deconvolution procedures often used to calculate population of rotamers and ring conformations from experimental (3)JH,H. PMID- 26614333 TI - Relativistic Zeroth-Order Regular Approximation Combined with Nonhybrid and Hybrid Density Functional Theory: Performance for NMR Indirect Nuclear Spin-Spin Coupling in Heavy Metal Compounds. AB - A benchmark study for relativistic density functional calculations of NMR spin spin coupling constants has been performed. The test set contained 47 complexes with heavy metal atoms (W, Pt, Hg, Tl, Pb) with a total of 88 coupling constants involving one or two heavy metal atoms. One-, two-, three-, and four-bond spin spin couplings have been computed at different levels of theory (nonhybrid vs hybrid DFT, scalar vs two-component relativistic). The computational model was based on geometries fully optimized at the BP/TZP scalar relativistic zeroth order regular approximation (ZORA) and the conductor-like screening model (COSMO) to include solvent effects. The NMR computations also employed the continuum solvent model. Computations in the gas phase were performed in order to assess the importance of the solvation model. The relative median deviations between various computational models and experiment were found to range between 13% and 21%, with the highest-level computational model (hybrid density functional computations including scalar plus spin-orbit relativistic effects, the COSMO solvent model, and a Gaussian finite-nucleus model) performing best. PMID- 26614334 TI - New Formulation and Implementation of Vibrational Self-Consistent Field Theory. AB - A new implementation of the vibrational self-consistent field (VSCF) method is presented on the basis of a second quantization formulation. A so-called active terms algorithm is shown to be a significant improvement over a standard implementation reducing the computational effort by one order in the number of degrees of freedom. Various types of screening provide even further reductions in computational scaling and absolute CPU time. VSCF calculations on large polyaromatic hydrocarbon model systems are presented. Further, it is demonstrated that in cases where distant modes are not directly coupled in the Hamiltonian, down to linear scaling of the required CPU time with respect to the number of vibrational modes can be obtained. This is illustrated with calculations on simple model systems with up to 1 million degrees of freedom. PMID- 26614335 TI - Solvatochromic Shifts in Uracil: A Combined MD-QM/MM Study. AB - Uracil is a commonly occurring pyrimidine derivative found in RNA where it base pairs with adenine. Rationalizing the electronic properties of uracil in both gas phase and aqueous solution is of fundamental importance because of the significant biological role played by this molecule. This paper presents accurate predictions of the solvatochromic shifts of the lowest pi -> pi* and n -> pi* vertical electronic excitation energies in uracil due to an aqueous solution. The calculations are conducted using a recently developed combined quantum mechanics/molecular mechanics (QM/MM) method, and nuclear dynamical effects are accounted for through molecular dynamics simulations. The electronic structure is described using either density functional theory employing the CAM-B3LYP exchange correlation functional or the coupled cluster singles and approximate doubles (CC2) method. The predicted solvatochromic shifts using CAM-B3LYP/MM and CC2/MM are -0.12 +/- 0.01 eV and -0.20 +/- 0.01 eV, respectively, for the pi -> pi* transition and 0.42 +/- 0.03 eV and 0.43 +/- 0.03 eV, respectively, for the n -> pi* transition. Our best estimate of the solvatochromic shifts are derived using a self-consistent polarizable model in both the MD and QM/MM simulations and are 0.29 +/- 0.01 eV and 0.45 +/- 0.03 eV for the pi -> pi* and n -> pi* transitions, respectively. The estimate is based on CC2 with electrostatic corrections defined from CAM-B3LYP and dispersion corrections derived from CC2 model system calculations. These solvatochromic shifts are in excellent agreement with experimental data, indicating the importance of explicit inclusion of polarization effects in MD-based QM/MM methods. PMID- 26614336 TI - Modeling the Excited States of Biological Chromophores within Many-Body Green's Function Theory. AB - First-principle many-body Green's function theory (MBGFT) has been successfully used to describe electronic excitations in many materials, from bulk crystals to nanoparticles. Here we assess its performance for the calculations of the excited states of biological chromophores. MBGFT is based on a set of Green's function equations, whose key ingredients are the electron's self-energy Sigma, which is obtained by Hedin's GW approach, and the electron-hole interaction, which is described by the Bethe-Salpeter equation (BSE). The GW approach and the BSE predict orbital energies and excitation energies with high accuracy, respectively. We have calculated the low-lying excited states of a series of model biological chromophores, related to the photoactive yellow protein (PYP), rhodopsin, and the green fluorescent protein (GFP), obtaining a very good agreement with the available experimental and accurate theoretical data; the order of the excited states is also correctly predicted. MBGFT bridges the gap between time-dependent density functional theory and high-level quantum chemistry methods, combining the efficiency of the former with the accuracy of the latter: this makes MBGFT a promising method for studying excitations in complex biological systems. PMID- 26614337 TI - An Improved Self-Consistent-Charge Density-Functional Tight-Binding (SCC-DFTB) Set of Parameters for Simulation of Bulk and Molecular Systems Involving Titanium. AB - A new self-consistent-charge density-functional tight-binding (SCC-DFTB) set of parameters for Ti-X pairs of elements (X = Ti, H, C, N, O, S) has been developed. The performance of this set has been tested with respect to TiO2 bulk phases and small molecular systems. It has been found that the band structures, geometric parameters, and cohesive energies of rutile and anatase polymorphs are in good agreement with the reference DFT data and with experiment. Low-index rutile and anatase surfaces were also tested. For molecular systems, binding and atomization energies close to their DFT analogues have been achieved. Large errors, however, have been found for systems in high-spin states and/or having multireference character of their wave functions. The correct performance of SCC-DFTB for surface reactions has been demonstrated via the water splitting on anatase (001) surface. The current SCC-DFTB set is a suitable tool for future in-depth investigation of chemical processes occurring on the surfaces of TiO2 polymorphs as well as for other processes of physicochemical interest. PMID- 26614338 TI - Local Bonding Effects in the Oxidation of CO on Oxygen-Covered Au(111) from Ab Initio Molecular Dynamics Simulations. AB - A fully dynamical approach using ab initio molecular dynamics (AIMD) simulations is applied to the investigation of CO oxidation on O-covered Au(111). We investigate how the activity of gold depends upon temperature, oxygen coverage, and surface structure. On clean Au(111) at 500 K, CO binds transiently on top of Au atoms, spending a small fraction (~7%) of the total simulation time adsorbed on the surface. The presence of O on the surface increases the residence time for CO by more than 4 times on a surface containing 0.22 ML of O. On the other hand, the probability for CO adsorption decreases with oxygen coverage from 31% at 0.22 ML of oxygen to 15% at 0.55 ML of oxygen. Our simulations show that the activity for CO reaction with O to yield CO2 decreases with increasing oxygen coverage. We attribute this decrease of activity to (1) the decrease in the CO adsorption probability as the oxygen coverage increases and (2) the decreasing amount of reactive chemisorbed oxygen (oxygen bound in a 3-fold site) with increasing total oxygen coverage. We show that oxygen bound in sites of local 3-fold coordination (chemisorbed oxygen) is nearly 2 times more reactive than other oxygen species observed on the surface, namely, surface and subsurface oxide. Our work demonstrates the value and feasibility of using AIMD to study surface reactions. PMID- 26614339 TI - Computational Analysis of Solvent Effects in NMR Spectroscopy. AB - Solvent modeling became a standard part of first principles computations of molecular properties. However, a universal solvent approach is particularly difficult for the nuclear magnetic resonance (NMR) shielding and spin-spin coupling constants that in part result from collective delocalized properties of the solute and the environment. In this work, bulk and specific solvent effects are discussed on experimental and theoretical model systems comprising solvated alanine zwitterion and chloroform molecules. Density functional theory computations performed on larger clusters indicate that standard dielectric continuum solvent models may not be sufficiently accurate. In some cases, more reasonable NMR parameters were obtained by approximation of the solvent with partial atomic charges. Combined cluster/continuum models yielded the most reasonable values of the spectroscopic parameters, provided that they are dynamically averaged. The roles of solvent polarizability, solvent shell structure, and bulk permeability were investigated. NMR shielding values caused by the macroscopic solvent magnetizability exhibited the slowest convergence with respect to the cluster size. For practical computations, however, inclusion of the first solvation sphere provided satisfactory corrections of the vacuum values. The simulations of chloroform chemical shifts and CH J-coupling constants were found to be very sensitive to the molecular dynamics model used to generate the cluster geometries. The results show that computationally efficient solvent modeling is possible and can reveal fine details of molecular structure, solvation, and dynamics. PMID- 26614340 TI - A Nonradial Coarse-Grained Potential for Proteins Produces Naturally Stable Secondary Structure Elements. AB - We introduce a nonradial potential term for coarse-grained (CG) molecular simulations of proteins. This term mimics the backbone dipole-dipole interactions and accounts for the needed directionality to form stable folded secondary structure elements. We show that alpha-helical and beta-sheet peptide chains are correctly described in dynamics without the need of introducing any a priori bias potentials or ad hoc parametrizations, which limit broader applicability of CG simulations for proteins. Moreover, our model is able to catch the formation of supersecondary structural motifs, like transitions from long single alpha-helices to helix-coil-helix or beta-hairpin assemblies. This novel scheme requires the structural information of Calpha beads only; it does not introduce any additional degrees of freedom to the system and has a general formulation, which allows it to be used in synergy with various CG protocols, leading to an improved description of the structural and dynamic properties of protein assemblies and networks. PMID- 26614341 TI - On the Validation of Molecular Dynamics Simulations of Saturated and cis Monounsaturated Phosphatidylcholine Lipid Bilayers: A Comparison with Experiment. AB - Molecular dynamics simulations of fully hydrated pure bilayers of four widely studied phospholipids, 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), 1,2 dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3 phosphocholine (DOPC), and 2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine (POPC) using a recent revision of the GROMOS96 force field are reported. It is shown that the force field reproduces the structure and the hydration of bilayers formed by each of the four lipids with high accuracy. Specifically, the solvation and the orientation of the dipole of the phosphocholine headgroup and of the ester carbonyls show that the structure of the primary hydration shell in the simulations closely matches experimental findings. This work highlights the need to reproduce a broad range of properties beyond the area per lipid, which is poorly defined experimentally, and to consider the effect of system size and sampling times well beyond those commonly used. PMID- 26614342 TI - A Transferable H-Bonding Correction for Semiempirical Quantum-Chemical Methods. AB - Semiempirical methods could offer a feasible compromise between ab initio and empirical approaches for the calculation of large molecules with biological relevance. A key problem for attempts in this direction is the rather bad performance of current semiempirical methods for noncovalent interactions, especially hydrogen-bonding. On the basis of the recently introduced PM6-DH method, which includes empirical corrections for dispersion (D) and hydrogen-bond (H) interactions, we have developed an improved and transferable H-bonding correction for semiempirical quantum chemical methods. The performance of the improved correction is evaluated for PM6, AM1, OM3, and SCC-DFTB (enhanced by standard empirical dispersion corrections) with several test sets for noncovalent interactions and is shown to reach the quality of current DFT-D approaches for these types of problems. PMID- 26614343 TI - Aging affects B-cell antigen receptor repertoire diversity in primary and secondary lymphoid tissues. AB - The elderly immune system is characterized by reduced responses to infections and vaccines, and an increase in the incidence of autoimmune diseases and cancer. Age related deficits in the immune system may be caused by peripheral homeostatic pressures that limit bone marrow B-cell production or migration to the peripheral lymphoid tissues. Studies of peripheral blood B-cell receptor spectratypes have shown that those of the elderly are characterized by reduced diversity, which is correlated with poor health status. In the present study, we performed for the first time high-throughput sequencing of immunoglobulin genes from archived biopsy samples of primary and secondary lymphoid tissues in old (74 +/- 7 years old, range 61-89) versus young (24 +/- 5 years old, range 18-45) individuals, analyzed repertoire diversities and compared these to results in peripheral blood. We found reduced repertoire diversity in peripheral blood and lymph node repertoires from old people, while in the old spleen samples the diversity was larger than in the young. There were no differences in somatic hypermutation characteristics between age groups. These results support the hypothesis that age related immune frailty stems from altered B-cell homeostasis leading to narrower memory B-cell repertoires, rather than changes in somatic hypermutation mechanisms. PMID- 26614344 TI - Feed-drug interaction of orally applied butyrate and phenobarbital on hepatic cytochrome P450 activity in chickens. AB - The expression of hepatic drug-metabolizing cytochrome P450 (CYP) enzymes may be affected by several nutrition-derived compounds, such as by the commonly applied feed additive butyrate, possibly leading to feed-drug interactions. The aim of this study was to provide some evidence if butyrate can alter the activity of hepatic CYPs in chickens exposed to CYP-inducing xenobiotics, monitoring for the first time the possibility of such interaction. Ross 308 chickens in the grower phase were treated with daily intracoelomal phenobarbital (PB) injection (80 mg/kg BW), applied as a non-specific CYP-inducer, simultaneously with two different doses of intra-ingluvial sodium butyrate boluses (0.25 and 1.25 g/kg BW) for 5 days. Activity of CYP2H and CYP3A subfamilies was assessed by specific enzyme assays from isolated liver microsomes. According to our results, the lower dose of orally administered butyrate significantly attenuated the PB-triggered elevation of both hepatic CYP2H and CYP3A activities, which might be in association with the partly common signalling pathways of butyrate and CYP inducing drugs, such as that of PB. Based on these data, butyrate may take part in pharmacoepigenetic interactions with simultaneously applied drugs or other CYP inducing xenobiotics, with possible consequences for food safety and pharmacotherapy. Butyrate was found to be capable to maintain physiological CYP activity by attenuating CYP induction, underlining the safety of butyrate application in poultry nutrition. PMID- 26614345 TI - C6 Glioma-Secreted NGF and FGF2 Regulate Neuronal APP Processing Through Up Regulation of ADAM10 and Down-Regulation of BACE1, Respectively. AB - Excessive accumulation of amyloid-beta (Abeta) caused by cleavage of amyloid precursor protein (APP) is thought to be the primary cause of Alzheimer's disease (AD). Two key enzymes ADAM10 and BACE1 are involved in the initial cleavage of APP, resulting in the onset of two pathways, the amyloidogenic pathway and the non-amyloidogenic pathway, respectively. Altering APP metabolism towards the non amyloidogenic pathway is thought to reduce Abeta production. It has been reported that, in vivo, exogenous neurotrophic factors make APP apt to entering the non amyloidogenic pathway. Since astrocytes secrete a battery of neurotrophic factors, we investigated the role of astrocyte-derived factors in the dynamics of Abeta generation in neural cells. Results show that C6 glioma cell-conditioned medium (GCM), obtained from cultured astrocyte-derived C6 glioma cells, inhibit Abeta1-42 production and shift APP processing towards the non-amyloidogenic pathway in APPswe-HEK293 cells. Such effect is attributed to two key APP cleavage enzymes, ADAM10 and BACE1. Two neurotrophic factors in the GCM, nerve growth factor and fibroblast growth factor 2, are responsible for the up-regulation of ADAM10 and down-regulation of BACE1, respectively. Our findings enhance our understanding of the relationship between astrocytes and Abeta generation, indicating that stimulation of astrocytic neurotrophic factors could slow AD progression. PMID- 26614346 TI - BDNF/TrkB Signaling as a Potential Novel Target in Pediatric Brain Tumors: Anticancer Activity of Selective TrkB Inhibition in Medulloblastoma Cells. AB - Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Deregulation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling has been associated with increased proliferative capabilities, invasiveness, and chemoresistance in several types of cancer. However, the relevance of this pathway in MB remains unknown. Here, we show that the selective TrkB inhibitor N-[2-[[(hexahydro-2-oxo-1H-azepin-3 yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide (ANA-12) markedly reduced the viability and survival of human cell lines representative of different MB molecular subgroups. These findings provide the first evidence supporting further investigation of TrkB inhibition as a potential novel strategy for MB treatment. PMID- 26614347 TI - In Vitro and In Vivo Modeling of Spinal and Bulbar Muscular Atrophy. AB - Spinal and bulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease characterized by late-onset, progressive degeneration of lower motor neurons and skeletal muscle atrophy. SBMA is caused by expansions of a CAG trinucleotide repeat in the gene encoding the androgen receptor (AR). One striking feature of SBMA is sex specificity: SBMA fully manifests only in males, whereas females show subclinical or mild disease manifestations even when homozygous for the mutation. Since the identification of the mutation responsible for SBMA in 1991, several cell and animal models have been developed to recapitulate the main features of disease in vitro and in vivo. In this review, we describe the most widely used cellular and animal models of SBMA, highlighting advantages and disadvantages in the use of these models to gain mechanistic and therapeutic insights into SBMA. PMID- 26614348 TI - Psychometric properties of the Chinese version of the fatigue scale-adolescent. AB - BACKGROUND: The availability of a valid and reliable instrument that accurately assesses the level of fatigue among adolescent cancer survivors is crucial before any appropriate interventions to reduce their fatigue can be appropriately planned and evaluated. The study aimed to test the psychometric properties of the Chinese version of the Fatigue Scale for Adolescents. In particular, confirmatory factor analysis was conducted to examine its factorial structure. METHODS: A cross-sectional study was employed. Adolescents (13- to 18-year-olds) who had survived cancer and attended medical follow-up at the outpatient clinic in Hong Kong were invited to participate. The internal consistency, content validity and construct validity and test-retest reliability of the Chinese version of the Fatigue Scale for Adolescents were assessed. RESULTS: The content validity index was 0.92. There was a strong positive correlation between adolescents' levels of fatigue and depressive symptoms (r = 0.53) and a strong negative correlation between adolescents' levels of fatigue and quality of life (r = -0.58). The mean levels of fatigue of the survivors group was significantly lower than that of those still receiving treatment in hospital, but significantly higher than that of their healthy counterparts. Confirmatory factor analysis indicated that there were 4 factors underlying the Chinese version of the Cancer Module. CONCLUSIONS: The findings of the study add further evidence that the Chinese version of the Fatigue Scale for Adolescents (12-item) can be used as a reliable and valid tool in assessing cancer-related fatigue among Hong Kong Chinese adolescents who have survived cancer. PMID- 26614349 TI - Quantifying Urban Watershed Stressor Gradients and Evaluating How Different Land Cover Datasets Affect Stream Management. AB - Watershed management and policies affecting downstream ecosystems benefit from identifying relationships between land cover and water quality. However, different data sources can create dissimilarities in land cover estimates and models that characterize ecosystem responses. We used a spatially balanced stream study (1) to effectively sample development and urban stressor gradients while representing the extent of a large coastal watershed (>4400 km(2)), (2) to document differences between estimates of watershed land cover using 30-m resolution national land cover database (NLCD) and <1-m resolution land cover data, and (3) to determine if predictive models and relationships between water quality and land cover differed when using these two land cover datasets. Increased concentrations of nutrients, anions, and cations had similarly significant correlations with increased watershed percent impervious cover (IC), regardless of data resolution. The NLCD underestimated percent forest for 71/76 sites by a mean of 11 % and overestimated percent wetlands for 71/76 sites by a mean of 8 %. The NLCD almost always underestimated IC at low development intensities and overestimated IC at high development intensities. As a result of underestimated IC, regression models using NLCD data predicted mean background concentrations of NO3 (-) and Cl(-) that were 475 and 177 %, respectively, of those predicted when using finer resolution land cover data. Our sampling design could help states and other agencies seeking to create monitoring programs and indicators responsive to anthropogenic impacts. Differences between land cover datasets could affect resource protection due to misguided management targets, watershed development and conservation practices, or water quality criteria. PMID- 26614350 TI - Recreational Diver Behavior and Contacts with Benthic Organisms in the Abrolhos National Marine Park, Brazil. AB - In the last two decades, coral reefs have become popular among recreational divers, especially inside marine protected areas. However, the impact caused by divers on benthic organisms may be contributing to the degradation of coral reefs. We analyzed the behavior of 142 scuba divers in the Abrolhos National Marine Park, Brazil. We tested the effect of diver profile, reef type, use of additional equipment, timing, and group size on diver behavior and their contacts with benthic organisms. Eighty-eight percent of divers contacted benthic organism at least once, with an average of eight touches and one damage per dive. No significant differences in contacts were verified among gender, group size, or experience level. Artificial reef received a higher rate of contact than pinnacle and fringe reefs. Specialist photographers and sidemount users had the highest rates, while non-users of additional equipment and mini camera users had the lowest contact rates. The majority of contacts were incidental and the highest rates occurred in the beginning of a dive. Our findings highlight the need of management actions, such as the provision of pre-dive briefing including ecological aspects of corals and beginning dives over sand bottoms or places with low coral abundance. Gathering data on diver behavior provides managers with information that can be used for tourism management. PMID- 26614351 TI - Incorporating Resource Protection Constraints in an Analysis of Landscape Fuel Treatment Effectiveness in the Northern Sierra Nevada, CA, USA. AB - Finding novel ways to plan and implement landscape-level forest treatments that protect sensitive wildlife and other key ecosystem components, while also reducing the risk of large-scale, high-severity fires, can prove to be difficult. We examined alternative approaches to landscape-scale fuel-treatment design for the same landscape. These approaches included two different treatment scenarios generated from an optimization algorithm that reduces modeled fire spread across the landscape, one with resource-protection constrains and one without the same. We also included a treatment scenario that was the actual fuel-treatment network implemented, as well as a no-treatment scenario. For all the four scenarios, we modeled hazardous fire potential based on conditional burn probabilities, and projected fire emissions. Results demonstrate that in all the three active treatment scenarios, hazardous fire potential, fire area, and emissions were reduced by approximately 50 % relative to the untreated condition. Results depict that incorporation of constraints is more effective at reducing modeled fire outputs, possibly due to the greater aggregation of treatments, creating greater continuity of fuel-treatment blocks across the landscape. The implementation of fuel-treatment networks using different planning techniques that incorporate real world constraints can reduce the risk of large problematic fires, allow for landscape-level heterogeneity that can provide necessary ecosystem services, create mixed forest stand structures on a landscape, and promote resilience in the uncertain future of climate change. PMID- 26614352 TI - MU-Opioid agonists for preventing emergence agitation under sevoflurane anesthesia in children: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Emergence agitation (EA) is an adverse effect after sevoflurane anesthesia in pediatric patients. The effectiveness of prophylactic MU-opioid agonists fentanyl, remifentanil, sufentanil, and alfentanil in preventing EA is debatable. METHODS: A literature search was conducted to identify clinical trials that observed the effect of MU-opioid agonists fentanyl, remifentanil, sufentanil, and alfentanil on preventing EA in pediatric patients under sevoflurane anesthesia. The statistical software RevMan 5.3 was used for meta analysis. Data from each study were combined using the relative ratio (RR), weighted mean differences, and their associated 95% confidence intervals. I(2) was used to evaluate heterogeneity. Subgroup analysis was conducted to investigate the possible influences of patient age, adenotonsillectomy, premedication, N2 O, propofol, and regional block/local anesthetics on preventing EA with prophylactic administration of MU-opioid agonists. Publication bias was checked using funnel plots and Begg's test. RESULTS: This meta-analysis showed the inclusion of 19 randomized controlled trials with 1528 patients (857 patients received MU-opioid agonists therapy and 671 patients had placebo). The pooled data indicated that prophylactic MU-opioid agonists fentanyl, remifentanil, sufentanil, and alfentanil significantly decreased the incidence of EA [RR = 0.49 (0.38, 0.64), I(2) = 42%, P = 0.04; RR = 0.57 (0.33, 0.99), I(2) = 37%, P = 0.19; RR = 0.18 (0.08, 0.39), I(2) = 0%, P = 0.98; and RR = 0.56 (0.40, 0.78), I(2) = 6%, P = 0.34, respectively]. All subgroup analyses strengthened the proof for lower incidence of EA under sevoflurane anesthesia after fentanyl administration. A possibility of publication bias was detected in the fentanyl group. CONCLUSIONS: This meta-analysis suggested that prophylactic MU-opioid agonists fentanyl, remifentanil, sufentanil, and alfentanil could significantly decrease the incidence of EA under sevoflurane anesthesia in children compared to placebo. Considering the limitations of the included studies, more clinical studies are required. PMID- 26614353 TI - High levels of whole raw soya beans in dairy cow diets: digestibility and animal performance. AB - The aim of this study was to evaluate the effects of high levels of whole raw soya beans in the diets of lactating cows. Twelve Holstein dairy cows were used, randomized in three 4 * 4 balanced and contemporary Latin squares and fed the following diets: (i) control (C), without including whole raw soya beans; (ii) 80 g/kg in DM of whole raw soya beans (G80); (iii) 160 g/kg in DM of whole raw soya beans (G160); and (iv) 240 g/kg in DM of whole raw soya beans (G240). There was significant reduction (p < 0.05) in dry matter intake (kg/day) in cows supplemented with G240 compared with C (23.8 vs. 25.3 respectively). G240 diets presented lower crude protein digestibility (g/kg) (p < 0.05) in comparison with C diet (683 vs. 757 respectively). There was significant effect of experimental rations in nitrogen balance (p < 0.05), G240 diet presenting significant reduction in comparison with the other diets, and faecal excretion of nitrogen was higher for G240 diet. The concentration of ruminal ammoniacal nitrogen was significantly higher (p < 0.05) for cows receiving control diet, compared to other diets. G240 diet resulted in significantly lower milk and protein yield (p < 0.05) in comparison with C diet. Significant C18:2 cis fatty acids were observed in milk concentrations (p < 0.05) for G240 diet. The use of high level of whole raw soya beans in dairy cow diets improves the unsaturated fatty acid profile in milk, and the diets (G80 and G160) led to minor alterations in the digestive processes and animal metabolism. PMID- 26614354 TI - Evaluation of confocal laser endomicroscopy as an aid to differentiate primary flat lesions of the larynx: A prospective clinical study. AB - BACKGROUND: In this trial, the ability of confocal laser endomicroscopy (CLE), a new imaging modality with a cellular resolution, to further differentiate primary flat lesions of the larynx was evaluated. METHODS: First, an optical coherence tomography was used to filter out normal tissue and carcinoma. All other lesions (30 lesions in 19 patients) were investigated with CLE. The suspected diagnosis was compared to histopathology. RESULTS: Optical coherence tomography identified all noninvasive lesions. CLE provided further information with cellular resolution. In 2 of 30 cases, low image quality prevented classification. In laryngeal lesions (27 of 30), moderate to high-grade dysplasia was correctly suspected in 10 of 10 cases (100%). Hyperplasia was overrated as dysplasia in 7 of 15 cases (46.7%). Sensitivity was 100% and specificity was 40%. CONCLUSION: When used in conjunction with optical coherence tomography, CLE seems helpful for discrimination of noninvasive lesions, although it tends to overrate the severity of the changes. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1695-E1704, 2016. PMID- 26614355 TI - Determination of Lead in Water Samples Using a New Vortex-Assisted, Surfactant Enhanced Emulsification Liquid-Liquid Microextraction Combined with Graphite Furnace Atomic Absorption Spectrometry. AB - A low toxic solvent-based vortex-assisted surfactant-enhanced emulsification liquid-liquid microextraction (LT-VSLLME) combined with graphite furnace atomic absorption spectrometry was developed for the extraction and determination of lead (Pb) in water samples. In the LT-VSLLME method, the extraction solvent was dispersed into the aqueous samples by the assistance of vortex agitator. Meanwhile, the addition of a surfactant, which acted as an emulsifier, could enhance the speed of the mass-transfer from aqueous samples to the extraction solvent. The influences of analytical parameters, including extraction solvent type and its volume, surfactant type and its volume, pH, concentration of chelating agent, salt effect and extraction time were investigated. Under the optimized conditions, a good relative standard deviation of 3.69% at 10 ng L(-1) was obtained. The calibration graph showed a linear pattern in the ranges of 5-30 ngL(-1), with a limit of detection of 0.76 ng L(-1). The linearity was obtained by five points in the concentration range of 5-30 ngL(-1). The enrichment factor was 320. The procedure was applied to wastewater and river water, and the accuracy was assessed through the analysis of the recovery experiments. PMID- 26614356 TI - First record of Aedes koreicus (Diptera: Culicidae) in Germany. AB - Within the framework of a national mosquito monitoring programme, a mosquito specimen collected in mid-2015 in southern Germany was identified as Aedes koreicus, a non-endemic species originating from East Asia. After the Asian bush mosquito Aedes japonicus, which is already established in Germany and widely distributed, and the Asian tiger mosquito Aedes albopictus, which is increasingly often introduced from southern Europe, A. koreicus is the third demonstrated invasive mosquito species in Germany supposed to have significant vector potential for disease agents. PMID- 26614357 TI - A molecular phylogeny of Asian species of the genus Metagonimus (Digenea)--small intestinal flukes--based on representative Japanese populations. AB - Metagonimus Katsurada, 1912 is a genus of small intestinal parasites. The genus comprises eight species, primarily from far-eastern Asia, with two exceptions reported from Europe. Metagonimus yokogawai, the most widespread species, is the main agent responsible for the intestinal disease, metagonimiasis, in Japan and some other East Asian countries. On the basis of the ratio of the size of the ventral and oral suckers, Metagonimus has traditionally been morphologically divided into two groups; however, the genus has not been extensively studied using molecular data. To reveal phylogenetic relationships within Metagonimus based on molecular data, we analyzed six of the seven species present in Asia using samples collected in central Japan. Maximum likelihood and Bayesian analyses of a combined 28S ribosomal DNA (rDNA), internal transcribed spacer 2 (ITS2), and mitochondrial cox1 gene sequence dataset separated the six species into two well-supported clades. One clade comprised M. yokogawai, M. takahashii, M. miyatai, and M. hakubaensis, whereas the other consisted of M. otsurui and M. katsuradai. Genetic distances calculated from 28S rDNA and ITS2 nucleotide sequences and a comparison of the predicted amino acid sequences of cox1 gene suggested that M. otsurui and M. katsuradai may have diverged recently. None of the four main morphological characters used to delimit species of Metagonimus (i.e., sucker ratio, positions of the uterus and testes, and distribution of vitelline follicles) was consistent with the distribution of species in the molecular tree. PMID- 26614359 TI - Surface ultrastructural characteristics of Dictyocotyle coeliaca Nybelin, 1941 (Monopisthocotylea: Monocotylidae), an endoparasitic monogenean of rays. AB - Scanning and transmission electron microscopical observations were made of the surface topography of Dictyocotyle coeliaca (Nybelin, 1941) (Monopisthocotylea: Monocotylidae), a unique endoparasitic monogenean from the body cavity of the ray Amblyraja radiata (Elasmobranchii: Rajidae). Scanning investigation show the presence on the ventral side of the anterior body of smooth areas with pit-like depressions and shallow ridges, whereas the tegument of the middle and posterior regions of the body is extensively folded, and on the dorsal surface the tegument is smooth but interrupted by deep depressions. Transmission observation revealed the presence of invaginations of varying irregularity and depth, which form the various depressions of the tegumental surface. Non-ciliated, dome-shaped papillae occur singly or in groups and are common around the mouth and both the genital and vaginal pores, but exhibit no particular orientation. The haptor is much reduced, compared with that of ectoparasitic monocotylids, and is covered ventrally with an irregular array of 40-70 shallow loculi. Internal differences occur in the thickness of the syncytial tegumentary layer of the haptoral loculi and septa and also in the number of cytoplasmic inclusions. The locular surface has distinct ultrastructural characteristics, the most obvious of which are a honeycomb arrangement of small pockets measuring 0.6 * 0.75 to 1.0 * 1.7 MUm in diameter, a terminal web beneath the surface plasma membrane and large outgrowths on the surface of the loculi filled with lysosome-like bodies. The surface specializations of the body and haptoral tegument of D. coeliaca are discussed in relation to their being adaptations to an endoparasitic environment. PMID- 26614358 TI - Carbon and silver nanoparticles in the fight against the filariasis vector Culex quinquefasciatus: genotoxicity and impact on behavioral traits of non-target aquatic organisms. AB - Mosquito-borne diseases represent a deadly threat for millions of people worldwide. The Culex genus, with special reference to Culex quinquefasciatus, comprises the most common vectors of filariasis across urban and semi-urban areas of Asia. In recent years, important efforts have been conducted to propose green synthesized nanoparticles as a valuable alternative to synthetic insecticides. However, the mosquitocidal potential of carbon nanoparticles has been scarcely investigated. In this study, the larvicidal and pupicidal activity of carbon nanoparticle (CNP) and silver nanoparticle (AgNP) was tested against Cx. quinquefasciatus. UV-Vis spectrophotometry, Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD) analysis, scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray (EDX) spectroscopy, and Raman analysis confirmed the rapid and cheap synthesis of carbon and silver nanoparticles. In laboratory assays, LC50 (lethal concentration that kills 50 % of the exposed organisms) values ranged from 8.752 ppm (first instar larvae) to 18.676 ppm (pupae) for silver nanoparticles and from 6.373 ppm (first-instar larvae) to 14.849 ppm (pupae) for carbon nanoparticles. The predation efficiency of the water bug Lethocerus indicus after a single treatment with low doses of silver and carbon nanoparticles was not reduced. Moderate evidence of genotoxic effects induced by exposure to carbon nanoparticles was found on non-target goldfish, Carassius auratus. Lastly, the plant extract used for silver nanosynthesis was tested for 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging activity. Overall, our results pointed out that AgNP and CNP can be a candidate for effective tools to reduce larval and pupal populations of filariasis vectors, with reduced genotoxicity and impact on behavioral traits of other aquatic organisms sharing the same ecological niche of Cx. quinquefasciatus. PMID- 26614360 TI - Target selected treatment with levamisole to control the development of anthelmintic resistance in a sheep flock. AB - Levamisole phosphate, chosen based on its 100 % efficacy demonstrated by a previous fecal egg count reduction test (FECRT), was used as the exclusive anthelmintic treatment in the Embrapa Southeast Livestock sheep flock from 2009 to 2014 in a target selected treatment scheme. In the present study, the effectiveness of this nematode control scheme was evaluated after 5 years by FECRT, larval development test (LDT), and a molecular test to assess the development of levamisole resistance in Haemonchus contortus. Animals were submitted to treatments with albendazole, levamisole, closantel, ivermectin, moxidectin, and monepantel. Eggs per gram of feces (EPG) counts and fecal cultures were performed, and anthelmintic efficacy was calculated by the RESO 4.0 program. The helminths of the flock (GIN Embrapa2014) were compared to susceptible (McMaster) and resistant (Embrapa2010) H. contortus isolates in the LDT to estimate the LC50 and LC90 of levamisole and in a molecular test to evaluate the 63-bp indel in the acr8 gene associated with levamisole resistance. In the FECRT, parasites were susceptible to monepantel (99.6 %) and closantel (98.3 %), but resistant to moxidectin (93.8 %), levamisole (70.4 %), ivermectin (48.1 %), and albendazole (0 %). In the coproculture on D14, and the control group presented 80 % H. contortus and 20 % Trichostrongylus sp., while in the monepantel group L1 were observed as well as Oesophagostomum sp. L3. LDT and resistance factors provided good separation between susceptible and resistant parasites. The genotypic frequencies of the 63-bp insertion in the acr8 gene in H. contortus were 11.9, 6.7, and 0 % in GIN Embrapa2014, Embrapa2010, and McMaster isolates, respectively. After 5 years of exclusive use, the nematodes developed resistance to levamisole, detected by FECRT and by increase in LC50 and LC90 for levamisole in the LDT. The 63-bp indel was not confirmed as a molecular marker of levamisole resistance in our isolates. The target selected treatment scheme was effective to control helminths in the sheep flock for 5 years, when levamisole's inefficacy was perceived because of no change in the clinical situation of treated animals. Through this scheme, it was possible to promote reversion towards susceptibility or increase of efficacy for other chemical classes. Thus, this is a valid recommendation to control worms and to delay the development of resistance, preserving other anthelmintic classes for future use. PMID- 26614363 TI - OX40 signaling in head and neck squamous cell carcinoma: Overcoming immunosuppression in the tumor microenvironment. AB - OX40 is a member of the tumor necrosis factor (TNF) receptor family and a potent co-stimulatory pathway that when triggered can enhance T-cell memory, proliferation and anti-tumor activity in patients with metastatic cancer. Ongoing investigations at our institution have demonstrated that OX40 expressing T cells are found in abundance in the tumors of patients with advanced stage head and neck squamous cell carcinoma (HNSCC). This has led to the initiation of human clinical trials investigating OX40-directed therapy for patients with HNSCC in both the metastatic and curative setting. The purpose of this review is to explore what is known about OX40 signaling and discuss how this pathway potentially can be modulated to improve outcome for patients with HNSCC. PMID- 26614361 TI - Dinotefuran-induced morphophysiological changes in the ovaries and midgut of semi engorged females Rhipicephalus sanguineus Latreille, 1806 (Acari: Ixodidae) ticks. AB - The present study demonstrated the effects of dinotefuran (active compound of the Protetor Pet(r) acaricide) in germ cells and the digestive processes of semi engorged females of R. sanguineus exposed to different concentrations of the chemical. For this purpose, 120 semi-engorged females were divided into four treatment groups with 30 individuals each: group I or control (distilled water), group II (5000 ppm), group III (6250 ppm), and group IV (8334 ppm of dinotefuran). All ticks were immersed in different concentrations of dinotefuran or in distilled water for 5 min and then were dried and stored in biological oxygen demand (BOD) incubator for 7 days. The results show the action of this compound, exhibiting morphohistologic and histochemical changes in the oocytes and the midgut cells of individuals of different groups, which were compared with those of group I (control). The alterations occurred mainly in relation to the size of the germ cells and yolk granules; presence, quantity, size, and location of vacuoles found in the cytoplasm of these germ cells; the damage occurred in the generative cells of the midgut; the size of the digestive cells; the quantity of blood elements captured, accumulated digestive wastes and digestive vacuoles found in the cytoplasm of the digestive cells of the midgut, as well as the amount and distribution of proteins, polysaccharides, lipids of all cells in both organs. So, it has demonstrated the effectiveness of dinotefuran in the reduction of fertility and digestive processes of semi-engorged females of R. sanguineus, data that points the possibility of employing this chemical to control these ectoparasites. PMID- 26614364 TI - Chains of (dis)trust: exploring the underpinnings of knowledge-sharing and quality care across mental health services. AB - Quality and safety in healthcare settings are underpinned by organisational cultures, which facilitate or impede the refinement, sharing and application of knowledge. Avoiding the use of the term culture as a residual category, we focus specifically on describing chains of (dis)trust, analysing their development across relatively low-trust service contexts and their impact upon knowledge sharing and caregiving. Drawing upon data from in-depth interviews with service users, healthcare professionals, service managers and other stakeholders across three mental healthcare (psychosis) teams in southern England, we identify micro mechanisms that explain how (dis)trust within one intra-organisational relationship impacts upon other relationships. Experiences and inferences of vulnerability, knowledge, uncertainty, interests and time, among actors who are both trustees and trusters across different relationships, are pertinent to such analyses. This more micro-level understanding facilitates detailed conceptualisations of trust chains as meso-level tendencies that contribute to wider vicious or virtuous cycles of organisational (dis)trust. We explore how knowledge-sharing and caregiving are vitally interwoven within these chains of trust or distrust, enhancing and/or inhibiting the instrumental and communicative aspects of quality healthcare as a result. PMID- 26614362 TI - Possible Role of Trichophytin Antigen in Inducing Impaired Immunological Clearance of Fungus in Onychomycosis. AB - The immunology of onychomycosis is poorly understood. Th1 and Th17 are the principal effector cells responsible for protective immunity against fungi, while it is assumed that Th2 responses are associated with deleterious effects. The study was conducted to appraise the role of interleukin-6 (IL-6), transforming growth factor beta (TGF-beta) and immunoglobulin E (IgE) in onychomycosis patients and to study skin reactivity to trichophytin antigen in them. Serum samples of 60 cases of chronic onychomycosis and 30 healthy controls were assayed for serum IgE, IL-6 and TGF-beta levels using specific immunoassay kits; 0.01 ml of trichophytin antigen, Candida antigen and phosphate-buffered saline using separate syringes were injected intradermal at three independent sites of the forearm in cases and controls. Serum IL-6 levels were significantly lower in cases as compared to controls, while serum TGF-beta levels in both cases and controls were comparable. Serum IgE levels in cases were significantly higher when compared with controls. Thirty-eight patients showed immediate hypersensitivity response to trichophytin antigen, while none showed delayed hypersensitivity reaction to trichophytin antigen. Constant fungal antigenic stimuli induce a state of anergy as indicated by low serum IL-6 levels and the absence of delayed hypersensitivity reaction to trichophytin antigen in cases, leading to chronicity of infection. High total IgE may indicate a high probability of prior fungal sensitization. PMID- 26614365 TI - Exploring the value of qualitative research films in clinical education. AB - BACKGROUND: Many healthcare professionals use both quantitative and qualitative research to inform their practice. The usual way to access research findings is through peer-reviewed publications. This study aimed to understand the impact on healthcare professionals of watching and discussing a short research based film. The film, 'Struggling to be me' portrays findings from a qualitative synthesis exploring people's experiences of chronic pain, and was delivered as part of an inter-professional postgraduate e-learning module. The innovation of our study is to be the first to explore the impact of qualitative research portrayed through the medium of film in clinical education. METHODS: All nineteen healthcare professionals enrolled on the course in December 2013 took part in on-line interviews or focus groups. We recorded and transcribed the interviews verbatim and used the methods of Grounded Theory to analyse the interview transcripts. RESULTS: Watching and discussing the film became a stimulus for learning : (a) A glimpse beneath the surface explored a pro-active way of seeing the person behind the pain (b) Pitfalls of the Medical Model recognised the challenge, for both patient and clinician, of 'sitting with' rather than 'fixing' an ill person; (c) Feeling bombarded by despair acknowledged the intense emotions that the clinicians brings to the clinical encounter; (d) Reconstructing the clinical encounter as a shared journey reconstructed the time-constrained clinical encounter as a single step on a shared journey towards healing, rather than fixing. CONCLUSIONS: Films portraying qualitative research findings can stimulate a pro-active and dialectic form of knowing. Research-based qualitative films can make qualitative findings accessible and can be a useful resource in clinical training. Our research presents, for the first time, specific learning themes for clinical education. PMID- 26614366 TI - Pathologic Classification of Neuroendocrine Neoplasms. AB - The pathologic classification of neuroendocrine neoplasms has evolved over the past decades, as new understanding of the biological behavior, histologic characteristics, and genetic features have emerged. Nonetheless, many aspects of the classification systems remain confusing or controversial. Despite these difficulties, much progress has been made in determining the features predicting behavior. Genetic findings have helped establish relationships among different types of neuroendocrine neoplasms and revealed potential therapeutic targets. This review summarizes the current approach to the diagnosis, classification, grading, and therapeutic stratification of neuroendocrine neoplasms, with a focus on those arising in the lung and thymus, pancreas, and intestines. PMID- 26614367 TI - Clinical Presentation and Diagnosis of Neuroendocrine Tumors. AB - Neuroendocrine tumors (NETs) are slow-growing neoplasms capable of storing and secreting different peptides and neuroamines. Some of these substances cause specific symptom complexes, whereas others are silent. They usually have episodic expression, and the diagnosis is often made at a late stage. Although considered rare, the incidence of NETs is increasing. For these reasons, a high index of suspicion is needed. In this article, the different clinical syndromes and the pathophysiology of each tumor as well as the new and emerging biochemical markers and imaging techniques that should be used to facilitate an early diagnosis, follow-up, and prognosis are reviewed. PMID- 26614368 TI - Surgical Treatment of Small Bowel Neuroendocrine Tumors. AB - Neuroendocrine tumors of the small bowel are rare, slow-growing malignancies that commonly metastasize to nodes at the root of the mesentery and the liver. Liver metastases are associated with carcinoid syndrome. Mesenteric nodal masses can cause bowel obstruction, intestinal angina, or variceal hemorrhage. Patients die of liver failure or bowel obstruction. Primary resection is associated with improved survival rates. Selected patients may benefit from liver debulking operations. Liver resection has excellent survival rates even in the event of an incomplete resection, as well as improvement in hormonal symptoms. Radiofrequency ablation can help to preserve hepatic parenchyma during resection. PMID- 26614369 TI - Systemic Therapies for Advanced Gastrointestinal Carcinoid Tumors. AB - Well-differentiated gastrointestinal neuroendocrine tumors (GINETs) tend to be slow growing, but treatment of advanced disease remains a challenge. Somatostatin analogues (SSAs) are considered standard therapy for carcinoid syndrome. SSAs delay tumor progression in advanced well-differentiated gastroenteropancreatic NETs. Cytotoxic chemotherapy and interferon play a limited role in the treatment of nonpancreatic GINETs. There is no standard approach to treatment of patients with disease progression. Identification of systemic agents with antitumor activity in advanced disease remains an unmet medical need. Enrollment to clinical trials is encouraged; potential therapeutic targets include the vascular endothelial growth factor and mammalian target of rapamycin signaling pathways. PMID- 26614370 TI - Bronchial and Thymic Carcinoid Tumors. AB - Bronchial and thymic carcinoids are rare. We present epidemiologic data and potential risk factors. The approach to bronchial and thymic carcinoid patients is discussed, from the initial diagnosis and evaluations to treatment. These malignancies follow staging systems of their site of origin. Because bronchial and thymic carcinoids are rare, we use many treatment strategies that have been demonstrated in gastrointestinal and pancreatic neuroendocrine tumors. The lack of information regarding efficacy in bronchial and thymic carcinoids, as well as the scarcity of therapeutic options available, demands the importance of clinical trials that include these patients. PMID- 26614371 TI - Surgical Management of Pancreatic Neuroendocrine Tumors. AB - Pancreatic neuroendocrine tumors (PNETs) are uncommon tumors with a range of clinical behavior. Some PNETs are associated with symptoms of hormone secretion, with increased systemic levels of insulin, gastrin, glucagon, or other hormones. More commonly, PNETs are nonfunctional, without hormone secretion. Surgical resection is the mainstay of therapy, particularly for localized disease. Surgical therapy must be tailored to tumor and clinical characteristics. Resection may be particularly indicated in the setting of hormone hypersecretion. Small, incidental PNETs are increasingly managed nonoperatively. Surgery may also be indicated in some instances of metastatic disease, if all metastatic foci may be removed. PMID- 26614373 TI - Pheochromocytoma and Paraganglioma: Genetics, Diagnosis, and Treatment. AB - Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare but unique neuroendocrine tumors. The hypersecretion of catecholamines from the tumors can be associated with high morbidity and mortality, even when tumors are benign. Up to 40% of PCCs/PGLs are associated with germline mutations in susceptibility genes. About one-quarter are malignant, defined by the presence of distant metastases. Treatment options for unresectable metastatic disease, including chemotherapy, (131)I-MIBG, and radiation, can offer limited tumor and hormone control, although none are curative. This article reviews the inherited genetics, diagnosis, and treatment of PCCs and PGLs. PMID- 26614372 TI - Systemic Therapies for Advanced Pancreatic Neuroendocrine Tumors. AB - Pancreatic neuroendocrine tumors are an uncommon tumor type and compose 1% to 2% of all pancreatic neoplasms. They are rarely localized at presentation and are typically diagnosed in the presence of metastatic disease. The management poses a significant challenge because of the heterogeneous clinical presentations and varying degrees of aggressiveness. A variety of systemic therapies have been developed for the management of pancreatic neuroendocrine tumors, including somatostatin analogues, a select group of cytotoxic chemotherapy agents, and targeted or biological agents. This article reviews the available systemic therapy options for advanced pancreatic neuroendocrine tumors. PMID- 26614374 TI - Poorly Differentiated Neuroendocrine Tumors. AB - Poorly differentiated neuroendocrine carcinomas of the gastrointestinal tract are rare and limited data are available to guide treatment. These tumors have been treated akin to small cell lung cancer given the histologic similarities. Their pathology is complex. Over the last decade, these tumors are shown as likely a distinct disease entity that is more heterogeneous than accounted for by the current classification system. This article discusses the epidemiology, prognosis, clinical presentation and pathologic nuances and provides a review of the existing clinical data in poorly differentiated neuroendocrine carcinomas and small cell lung cancers. PMID- 26614375 TI - Role of Somatostatin Analogues in the Treatment of Neuroendocrine Tumors. AB - Neuroendocrine tumors (NETs) are rare epithelial neoplasms with neuroendocrine differentiation originating most commonly in the lungs and gastroenteropancreatic. Treatment includes surgery and other local therapies; treatment of inoperable disease centers around symptom management and control of tumor growth. Somatostatin analogues (SSAs) have been a mainstay of managing hormone-related symptoms. Emerging evidence suggests that they are effective therapies for tumor control also. Peptide receptor radionuclide therapy with radiolabeled SSAs is a new, promising treatment for inoperable or metastatic NETs. This article reviews the role of SSAs in the treatment of NETs. PMID- 26614376 TI - Peptide Receptor Radionuclide Therapy in the Treatment of Neuroendocrine Tumors. AB - Peptide receptor radionuclide therapy (PRRT) is a promising new treatment modality for inoperable or metastasized gastroenteropancreatic neuroendocrine tumors patients. Most studies report objective response rates in 15% to 35% of patients. Progression-free (PFS) and overall survival (OS) compare favorably with that for somatostatin analogues, chemotherapy, or newer, "targeted" therapies. Prospective, randomized data regarding the potential PFS and OS benefit of PRRT compared with standard therapies is anticipated. PMID- 26614377 TI - Hepatic-directed Therapies in Patients with Neuroendocrine Tumors. AB - Neuroendocrine tumors (NETs) of the gastrointestinal (GI) tract have a propensity for producing hepatic metastases. Most GI NETs arise from the foregut or midgut, are malignant, and can cause severe debilitating symptoms adversely affecting quality of life. Aggressive treatments to reduce symptoms have an important role in therapy. Patients with GI NETs usually present with inoperable metastatic disease and severe symptoms from a variety of hormones and biogenic amines. This article describes intra-arterial hepatic-directed therapies for metastases from NETs, a group of treatments in which the therapeutic and/or embolic agents are released intra-arterially in specific hepatic vessels to target tumors. PMID- 26614378 TI - Clinical Trial Design in Neuroendocrine Tumors. AB - Neuroendocrine tumors (NETs) present tremendous opportunities for productive clinical investigation, but substantial challenges as well. Investigators must be aware of common pitfalls in study design, informed by an understanding of the history of trials in the field, to make the best use of available data and our patient volunteers. We believe the salient issues in clinical trial design and interpretation in the NET field are patient homogeneity, standardized response assessment, and rigorous design and execution. Whether designing or interpreting a study in patients with NET, these principles should drive assessment. PMID- 26614379 TI - Neuroendocrine Tumors--Current and Future Clinical Advances. PMID- 26614380 TI - A need for precision medicine to enable tailored special education. PMID- 26614381 TI - Tubular Secretion in CKD. AB - Renal function generally is assessed by measurement of GFR and urinary albumin excretion. Other intrinsic kidney functions, such as proximal tubular secretion, typically are not quantified. Tubular secretion of solutes is more efficient than glomerular filtration and a major mechanism for renal drug elimination, suggesting important clinical consequences of secretion dysfunction. Measuring tubular secretion as an independent marker of kidney function may provide insight into kidney disease etiology and improve prediction of adverse outcomes. We estimated secretion function by measuring secreted solute (hippurate, cinnamoylglycine, p-cresol sulfate, and indoxyl sulfate) clearance using liquid chromatography-tandem mass spectrometric assays of serum and timed urine samples in a prospective cohort study of 298 patients with kidney disease. We estimated GFR by mean clearance of creatinine and urea from the same samples and evaluated associations of renal secretion with participant characteristics, mortality, and CKD progression to dialysis. Tubular secretion rate modestly correlated with eGFR and associated with some participant characteristics, notably fractional excretion of electrolytes. Low clearance of hippurate or p-cresol sulfate associated with greater risk of death independent of eGFR (hazard ratio, 2.3; 95% confidence interval, 1.1 to 4.7; hazard ratio, 2.5; 95% confidence interval, 1.0 to 6.1, respectively). Hazards models also suggested an association between low cinnamoylglycine clearance and risk of dialysis, but statistical analyses did not exclude the null hypothesis. Therefore, estimates of proximal tubular secretion function correlate with glomerular filtration, but substantial variability in net secretion remains. The observed associations of net secretion with mortality and progression of CKD require confirmation. PMID- 26614382 TI - Impaired Lysosomal Function Underlies Monoclonal Light Chain-Associated Renal Fanconi Syndrome. AB - Monoclonal gammopathies are frequently complicated by kidney lesions that increase the disease morbidity and mortality. In particular, abnormal Ig free light chains (LCs) may accumulate within epithelial cells, causing proximal tubule (PT) dysfunction and renal Fanconi syndrome (RFS). To investigate the mechanisms linking LC accumulation and PT dysfunction, we used transgenic mice overexpressing human control or RFS-associated kappaLCs (RFS-kappaLCs) and primary cultures of mouse PT cells exposed to low doses of corresponding human kappaLCs (25 MUg/ml). Before the onset of renal failure, mice overexpressing RFS kappaLCs showed PT dysfunction related to loss of apical transporters and receptors and increased PT cell proliferation rates associated with lysosomal accumulation of kappaLCs. Exposure of PT cells to RFS-kappaLCs resulted in kappaLC accumulation within enlarged and dysfunctional lysosomes, alteration of cellular dynamics, defective proteolysis and hydrolase maturation, and impaired lysosomal acidification. These changes were specific to the RFS-kappaLC variable (V) sequence, because they did not occur with control LCs or the same RFS-kappaLC carrying a single substitution (Ala30->Ser) in the V domain. The lysosomal alterations induced by RFS-kappaLCs were reflected in increased cell proliferation, decreased apical expression of endocytic receptors, and defective endocytosis. These results reveal that specific kappaLCs accumulate within lysosomes, altering lysosome dynamics and proteolytic function through defective acidification, thereby causing dedifferentiation and loss of reabsorptive capacity of PT cells. The characterization of these early events, which are similar to those encountered in congenital lysosomal disorders, provides a basis for the reported differential LC toxicity and new perspectives on LC-induced RFS. PMID- 26614383 TI - Tubuloreticular Inclusions in Renal Allografts Associate with Viral Infections and Donor-Specific Antibodies. AB - The presence of tubuloreticular inclusions (TRIs) in native glomerular endothelial cells associates with viral infections and lupus nephritis. However, the associations of TRIs in renal transplant biopsy specimens are not known. We analyzed data from 316 patients who had a transplant biopsy with electron microscopy examination; 41 of 316 (13.0%) patients had TRIs. Patients with TRIs had significantly lower allograft survival rates (50.9%) than patients without TRIs (74.3%; P=0.03). Transplant glomerulopathy-free survival was also inferior in the TRI-positive group (57.5%) compared with the TRI-negative group (87.3%; P=0.002). Serologically, hepatitis C associated with the presence of TRIs (P=0.04) along with donor-specific antibodies (P=0.01). Furthermore, patients who were TRI positive were more likely than patients who were TRI negative to have had a previous rejection episode (P=0.02). On multivariate analysis, TRIs associated with prior rejection, viral infections, and class 1 HLA donor-specific antibodies. These results show that the presence of TRIs in renal allograft biopsy specimens associates with poor allograft outcomes and serologic evidence of viral infections and alloimmunity. The association with alloimmunity is a novel finding that warrants additional investigation. PMID- 26614384 TI - Sparse regression and marginal testing using cluster prototypes. AB - We propose a new approach for sparse regression and marginal testing, for data with correlated features. Our procedure first clusters the features, and then chooses as the cluster prototype the most informative feature in that cluster. Then we apply either sparse regression (lasso) or marginal significance testing to these prototypes. While this kind of strategy is not entirely new, a key feature of our proposal is its use of the post-selection inference theory of Taylor and others (2014, Exact post-selection inference for forward stepwise and least angle regression, Preprint, arXiv:1401.3889) and Lee and others (2014, Exact post-selection inference with the lasso, Preprint, arXiv:1311.6238v5) to compute exact [Formula: see text]-values and confidence intervals that properly account for the selection of prototypes. We also apply the recent "knockoff" idea of Barber and Candes (2014, Controlling the false discovery rate via knockoffs, Preprint, arXiv:1404.5609) to provide exact finite sample control of the FDR of our regression procedure. We illustrate our proposals on both real and simulated data. PMID- 26614385 TI - Thyroid Imaging Reporting and Data System and Ultrasound Elastography: Diagnostic Accuracy as a Tool in Recommending Repeat Fine-Needle Aspiration for Solid Thyroid Nodules with Non-Diagnostic Fine-Needle Aspiration Cytology. AB - The Thyroid Imaging Reporting and Data System (TIRADS) has been found to be accurate in the stratification of malignancy risk, and elastography has been found to have a high negative predictive value in non-diagnostic thyroid nodules. Through assessment of 104 solid non-diagnostic thyroid nodules, this study investigated the role of both in recommending repeat ultrasonography-guided fine needle aspiration for solid thyroid nodules with non-diagnostic cytology. All nodules were classified by TIRADS (categories 4a, 4b, 4c and 5), and elastography scores were assigned according to the Rago and Asteria criteria. The malignancy risks for TIRADS categories 4a, 4b, 4c and 5 were 12.5%, 25.0%, 25.8% and 16.7%, respectively. Elastography revealed the highest diagnostic performance for TIRADS category 4a, with a sensitivity, specificity, negative predictive value, positive predictive value and accuracy of 100%, 85.7%, 100%, 50% and 87.5% for the Asteria criteria. Observation may be considered for non-diagnostic solid nodules that have no other suspicious ultrasonographic features and are also benign on real time strain elastography using the Asteria criteria. PMID- 26614386 TI - Validity of Carotid Duplex Sonography in Screening for Intracranial Dural Arteriovenous Fistula among Patients with Pulsatile Tinnitus. AB - Pulsatile tinnitus may result from intracranial dural arteriovenous fistula (DAVF), which requires early diagnosis and management. This study validated the role of carotid duplex sonography in screening for DAVF in patients with pulsatile tinnitus. The criteria used for DAVF screening were low resistance index of the external carotid artery or occipital artery (OA). Patients then underwent head magnetic resonance imaging to confirm the diagnosis. Of the 155 patients with pulsatile tinnitus who were prospectively screened, 25 (16.1%) had a low resistance index in either the external carotid artery or occipital artery. All were proven to have DAVF. The diagnostic sensitivity, specificity, positive predictive value and negative predictive value were 96%, 100%, 100% and 98%, respectively. Thus, carotid duplex sonography focusing on low resistance indexes of the external carotid and occipital arteries may be a valuable tool in screening for DAVF in patients with pulsatile tinnitus. PMID- 26614387 TI - Co-registration of angiography and intravascular ultrasound images through image based device tracking. AB - OBJECTIVES: To determine the feasibility of automated co-registration of angiography and intravascular ultrasound (IVUS) to facilitate integration of these two imaging modalities in a synchronous manner. BACKGROUND: IVUS provides cross-sectional imaging of coronary arteries but lacks overview of the vascular territory provided by angiography. Co-registration of angiography and IVUS would increase utility of IVUS in the clinical setting. METHODS: Forty-nine consecutive patients undergoing surveillance for cardiac allograft vasculopathy with angiography and IVUS of the left anterior descending artery (LAD) were enrolled. A pre-IVUS angiogram of the LAD was performed followed by an ECG-triggered fluoroscopy (ECGTF) during IVUS pullback at 0.5 mm/s using an automatic pullback device. ECGTF was used to track the IVUS catheter during pullback and establish a spatial relationship to the pre-IVUS angiogram. Angio-IVUS co-registration was performed with a research prototype (Siemens Healthcare, Germany) and accuracy was evaluated by distance mismatch between angiography and IVUS images at vessel bifurcations. RESULTS: Median age was 54 (44.5, 67) years. The population was 82.6% male with minimal risk factors. The median (IQR) co-registration distance mismatch measured at 108 bifurcations in 42 (85%) patients was 0.35 (0.00-1.16) mm. Seven patients were excluded due to inappropriate data acquisition (n = 3) and failure of tracking (n = 4), e.g., due to overlapping sternal wires. Estimated effective radiation dose for ECGTF was 0.09 mSv. CONCLUSION: This study demonstrates the feasibility of angio-IVUS co-registration which may be used as a clinical tool for localizing IVUS cross-sections along an angiographic roadmap. (c) 2015 Wiley Periodicals, Inc. PMID- 26614388 TI - Fine mapping of meiotic NAHR-associated crossovers causing large NF1 deletions. AB - Large deletions encompassing the NF1 gene and its flanking regions belong to the group of genomic disorders caused by copy number changes that are mediated by the local genomic architecture. Although nonallelic homologous recombination (NAHR) is known to be a major mutational mechanism underlying such genomic copy number changes, the sequence determinants of NAHR location and frequency are still poorly understood since few high-resolution mapping studies of NAHR hotspots have been performed to date. Here, we have characterized two NAHR hotspots, PRS1 and PRS2, separated by 20 kb and located within the low-copy repeats NF1-REPa and NF1 REPc, which flank the human NF1 gene region. High-resolution mapping of the crossover sites identified in 78 type 1 NF1 deletions mediated by NAHR indicated that PRS2 is a much stronger NAHR hotspot than PRS1 since 80% of these deletions exhibited crossovers within PRS2, whereas 20% had crossovers within PRS1. The identification of the most common strand exchange regions of these 78 deletions served to demarcate the cores of the PRS1 and PRS2 hotspots encompassing 1026 and 1976 bp, respectively. Several sequence features were identified that may influence hotspot intensity and direct the positional preference of NAHR to the hotspot cores. These features include regions of perfect sequence identity encompassing 700 bp at the hotspot core, the presence of PRDM9 binding sites perfectly matching the consensus motif for the most common PRDM9 variant, specific pre-existing patterns of histone modification and open chromatin conformations that are likely to facilitate PRDM9 binding. PMID- 26614389 TI - TDP-43 functions within a network of hnRNP proteins to inhibit the production of a truncated human SORT1 receptor. AB - The aggregation and mislocalization of RNA-binding proteins leads to the aberrant regulation of RNA metabolism and is a key feature of many neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia. However, the pathological consequences of abnormal deposition of TDP-43 and other RNA-binding proteins remain unclear, as the specific molecular events that drive neurodegeneration have been difficult to identify and continue to be elusive. Here, we provide novel insight into the complexity of the RNA-binding protein network by demonstrating that the inclusion of exon 17b in the SORT1 mRNA, a pathologically relevant splicing event known to be regulated by TDP-43, is also considerably affected by additional RNA-binding proteins, such as hnRNP L, PTB/nPTB and hnRNP A1/A2. Most importantly, the expression of hnRNP A1/A2 and PTB/nPTB is significantly altered in patients with frontotemporal dementia with TDP-43-positive inclusions (FTLD-TDP), indicating that perturbations in RNA metabolism and processing in FTLD-TDP are not exclusively driven by a loss of TDP 43 function. These results also suggest that a comprehensive assessment of the RNA-binding protein network will dramatically advance our current understanding of the role of TDP-43 in disease pathogenesis, as well as enhance both diagnostic and therapeutic capabilities. PMID- 26614391 TI - Water-dilutable microemulsions for transepithelial ocular delivery of riboflavin phosphate. AB - Riboflavin phosphate (RFP) is an essential compound in the treatment of keratoconus - a degenerative, non-inflammatory disease of the cornea. Currently, the quantitative and efficient transport of riboflavin to the cornea is possible after mechanical removal of the epithelium. To avoid surgical intervention, it is therefore important to develop a method for quantitatively transporting riboflavin across the intact epithelium. In the present study, an RFP-loaded microemulsion was prepared, which could potentially function as an ocular drug delivery system crossing the eye epithelium. The specially designed water dilutable microemulsion was based on a mixture of nonionic surfactants. Propylene glycol and glycerol acted as cosurfactant and cosolvent assisting in the solubilization of the RFP. The glycerol-rich water-free concentrate consisted of direct micelles for which glycerol served as the hydrophilic phase. In formulations with up to 40wt% water, the hydrophilic surfactant headgroups and glycerol strongly bind water molecules (DSC and SD-NMR). Above 60wt% water, globular, O/W nanodroplets, ~14nm in diameter, are formed (SAXS, cryo-TEM, and SD NMR). The structure of microemulsions loaded with 0.14-4.25wt% RFP (0.29-8.89mmol per 100g formulation) is not significantly influenced by the presence of the RFP. However, in the microemulsions containing 10-80wt% water, the mobility of RFP in the microemulsion is constrained by strong interactions with the surfactants and cosurfactant, and therefore free transport of the molecule can be achieved only upon higher (>80wt%) water dilutions. PMID- 26614390 TI - Adeno-associated viral vectors for the treatment of hemophilia. AB - Gene transfer studies for the treatment of hemophilia began more than two decades ago. A large body of pre-clinical work evaluated a variety of vectors and target tissues, but by the start of the new millennium it became evident that adeno associated viral (AAV)-mediated gene transfer to the liver held great promise as a therapeutic tool. The transition to the clinical arena uncovered a number of unforeseen challenges, mainly in the form of a human-specific immune response against the vector that poses a significant limitation in the application of this technology. While the full nature of this response has not been elucidated, long term expression of therapeutic levels of factor IX is already a reality for a small number of patients. Extending this success to a greater number of hemophilia B patients remains a major goal of the field, as well as translating this strategy to clinical therapy for hemophilia A. This review summarizes the progress of AAV-mediated gene therapy for the hemophilias, along with its upcoming prospects and challenges. PMID- 26614392 TI - End-point disease investigation for virus strains of intermediate virulence as illustrated by flavivirus infections. AB - Viruses of intermediate virulence are defined as isolates causing an intermediate morbidity/mortality rate in a specific animal model system, involving specific host and inoculation parameters (e.g. dose and route). Therefore, variable disease phenotype may exist between animals that develop severe disease or die and those that are asymptomatic or survive after infection with these isolates. There may also be variability amongst animals within each of these subsets. Such potential variability may confound the use of time-point sacrifice experiments to investigate pathogenesis of this subset of virus strains, as uniformity in disease outcome is a fundamental assumption for time-course sacrifice experiments. In the current study, we examined the disease phenotype, neuropathology, neural infection and glial cell activity in moribund/dead and surviving Swiss white (CD-1) mice after intraperitoneal infection with various Australian flaviviruses, including West Nile virus (WNV) strains of intermediate virulence (WNVNSW2011 and WNVNSW2012), and highly virulent Murray Valley encephalitis virus (MVEV) isolates. We identified notable intragroup variation in the end-point disease in mice infected with either WNVNSW strain, but to a lesser extent in mice infected with MVEV strains. The variable outcomes associated with WNVNSW infection suggest that pathogenesis investigations using time-point sacrifice of WNVNSW-infected mice may not be the best approach, as the assumption of uniformity in outcomes is violated. Our study has therefore highlighted a previously unacknowledged challenge to investigating pathogenesis of virus isolates of intermediate virulence. We have also set a precedent for routine examination of the disease phenotype in moribund/dead and surviving mice during survival challenge experiments. PMID- 26614393 TI - Scanned ion beam therapy for prostate carcinoma: Comparison of single plan treatment and daily plan-adapted treatment. AB - BACKGROUND AND PURPOSE: Intensity-modulated particle therapy (IMPT) for tumors showing interfraction motion is a topic of current research. The purpose of this work is to compare three treatment strategies for IMPT to determine potential advantages and disadvantages of ion prostate cancer therapy. MATERIALS AND METHODS: Simulations for three treatment strategies, conventional one-plan radiotherapy (ConvRT), image-guided radiotherapy (IGRT), and online adaptive radiotherapy (ART) were performed employing a dataset of 10 prostate cancer patients with six CT scans taken at one week intervals. The simulation results, using a geometric margin concept (7-2 mm) as well as patient-specific internal target volume definitions for IMPT were analyzed by target coverage and exposure of critical structures on single fraction dose distributions. RESULTS: All strategies led to clinically acceptable target coverage in patients exhibiting small prostate motion (mean displacement <4 mm), but IGRT and especially ART led to significant sparing of the rectum. In 20% of the patients, prostate motion exceeded 4 mm causing insufficient target coverage for ConvRT (V95mean = 0.86, range 0.63-0.99) and IGRT (V95mean = 0.91, range 0.68-1.00), while ART maintained acceptable target coverage. CONCLUSION: IMPT of prostate cancer demands consideration of rectal sparing and adaptive treatment replanning for patients exhibiting large prostate motion. PMID- 26614394 TI - Sustained efficacy of the novel topical repellent TT-4302 against mosquitoes and ticks. AB - Mosquitoes and ticks are blood-feeding pests of humans and animals that can vector many important aetiological agents of disease. Previous research demonstrated that TT-4302 (Guardian((r)) Wilderness) containing 5% geraniol applied to human subjects gave 5-6 h of repellency against mosquitoes (depending on species) and was repellent to ticks in vitro. This study was conducted to obtain an independent third-party evaluation of TT-4302 against Stegomyia aegypti (= Aedes aegypti) (Diptera: Culicidae) mosquitoes and to test the efficacy of the product in the field against ticks. TT-4302 provided an average of 6.5 h of repellency of >= 95% [Weibull mean protection time: 7.4 h, 95% confidence interval (CI) 5.8-11.3 h] for St. aegypti, whereas a 15% DEET formulation provided 4.7 h of repellency (Weibull mean protection time: 5.2 h, 95% CI 3.7-6.9 h). In tick field trials, the efficacy of TT-4302 did not differ significantly from that of a 25% DEET formulation against Amblyomma americanum (Ixodida: Ixodidae). TT-4302 was 81.3% repellent at 2.5 h after application, whereas DEET was 77.2% repellent at the same time-point. Results at 3.5 h after application were 71.4% for TT-4302 and 72.9% for DEET. PMID- 26614396 TI - Inflammatory Cytokines, Endothelial Function, and Chronic Allograft Vasculopathy in Children: An Investigation of the Donor and Recipient Vasculature After Heart Transplantation. AB - Chronic allograft vasculopathy (CAV) limits the lifespan of pediatric heart transplant recipients. We investigated blood markers of inflammation, endothelial dysfunction, and damage to both the native and transplanted vasculature in children after heart transplantation. Serum samples were taken from pediatric heart transplant recipients for markers of inflammation and endothelial activation. The systemic vasculature was investigated using brachial artery flow mediated dilatation and carotid artery intima-medial hyperplasia. CAV was investigated using intravascular ultrasound. Mean intima-media thickness (mIMT) > 0.5 mm was used to define significant CAV. Forty-eight children (25 male) aged 8 18 years were enrolled in the study. Patients were a median (interquartile range) 4.1 (2.2-8.7) years after transplant. Patients had increased levels of circulating IL6 (3.86 [2.84-4.95] vs. 1.66 [1.22-2.63] p < 0.0001), vascular cell adhesion molecule 1 (539 [451-621] vs. 402 [342-487] p < 0.001), intracellular adhesion molecule 1 305 (247-346) vs. 256 (224-294) p = 0.002 and thrombomodulin (7.1 [5.5-8.1] vs. 3.57 [3.03-4.71] p < 0.0001) and decreased levels of tumor necrosis factor-alpha, E selectin, and P selectin, compared with controls. The systemic vasculature was unaffected. Patients with severe CAV had raised serum von Willebrand factor and decreased serum thrombomodulin. Posttransplant thrombomodulin levels are elevated after transplant but significantly lower in those with mIMT > 0.5 mm. This suggests that subclinical inflammation is present and that natural anticoagulant/thrombomodulin activity is important after transplant. PMID- 26614395 TI - Symmorphosis and skeletal muscle VO2 max : in vivo and in vitro measures reveal differing constraints in the exercise-trained and untrained human. AB - The concept of symmorphosis postulates a matching of structural capacity to functional demand within a defined physiological system, regardless of endurance exercise training status. Whether this concept applies to oxygen (O2 ) supply and demand during maximal skeletal muscle O2 consumption (VO2 max ) in humans is unclear. Therefore, in vitro skeletal muscle mitochondrial VO2 max (Mito VO2 max , mitochondrial respiration of fibres biopsied from vastus lateralis) was compared with in vivo skeletal muscle VO2 max during single leg knee extensor exercise (KE VO2 max , direct Fick by femoral arterial and venous blood samples and Doppler ultrasound blood flow measurements) and whole-body VO2 max during cycling (Body VO2 max , indirect calorimetry) in 10 endurance exercise-trained and 10 untrained young males. In untrained subjects, during KE exercise, maximal O2 supply (KE QO2max ) exceeded (462 +/- 37 ml kg(-1) min(-1) , P < 0.05) and KE VO2 max matched (340 +/- 22 ml kg(-1) min(-1) , P > 0.05) Mito VO2 max (364 +/- 16 ml kg(-1) min(-1) ). Conversely, in trained subjects, both KE QO2max (557 +/- 35 ml kg(-1) min(-1) ) and KE VO2 max (458 +/- 24 ml kg(-1) min(-1) ) fell far short of Mito VO2 max (743 +/- 35 ml kg(-1) min(-1) , P < 0.05). Although Mito VO2 max was related to KE VO2 max (r = 0.69, P < 0.05) and Body VO2 max (r = 0.91, P < 0.05) in untrained subjects, these variables were entirely unrelated in trained subjects. Therefore, in untrained subjects, VO2 max is limited by mitochondrial O2 demand, with evidence of adequate O2 supply, whereas, in trained subjects, an exercise training-induced mitochondrial reserve results in skeletal muscle VO2 max being markedly limited by O2 supply. Taken together, these in vivo and in vitro measures reveal clearly differing limitations and excesses at VO2 max in untrained and trained humans and challenge the concept of symmorphosis as it applies to O2 supply and demand in humans. PMID- 26614397 TI - Remote infarct of the temporal lobe with coexistent hippocampal sclerosis in mesial temporal lobe epilepsy. AB - In patients undergoing surgery for temporal lobe epilepsy, hippocampal sclerosis remains the most commonly observed pathology. In addition to hippocampal sclerosis, 5% to 30% of these resections on magnetic resonance imaging contain a second independently epileptogenic lesion, commonly referred to as dual pathology. A second etiology of seizure activity, as seen in dual pathology, may serve as an important cause of treatment failure in striving for post-operative seizure control. Dual pathology, consisting of hippocampal sclerosis and a remote infarct of the adjacent cortex, has been rarely reported. Cases of pathologically confirmed hippocampal sclerosis diagnosed between January 2000 and December 2012 (n = 349) were reviewed, and 7 cases of coexistent infarct (2%) formed the study group. Seven individuals (mean age, 29years; range, 5-47 years) with a mean epilepsy duration of 12.5years (3.3-25 years) and a mean pre-surgery frequency of 15 seizures per week (range, 0.5-56 seizures/week) were followed up postoperatively for a mean duration of 64months (range, 3-137 months). Pathologically, the most common form of hippocampal sclerosis observed was International League against Epilepsy type Ib or severe variant (n = 4). Four of the six individuals with post-surgery follow-up were seizure free at last encounter. The reported incidence of dual pathology, including hippocampal sclerosis and remote infarct, is low (2% in the present study) but may indicate a slightly increased risk of developing hippocampal sclerosis in the setting of a remote infarct. Surgical intervention for such cases anecdotally appears effective in achieving seizure control. PMID- 26614398 TI - Concordance study between one-step nucleic acid amplification and morphologic techniques to detect lymph node metastasis in papillary carcinoma of the thyroid. AB - Tumor resection in papillary thyroid carcinoma (PTC) is often accompanied by lymph node (LN) removal of the central and lateral cervical compartments. One step nucleic acid amplification (OSNA) is a polymerase chain reaction-based technique that quantifies cytokeratin 19 (CK19) messenger RNA copies. Our aim is to assess the value of OSNA in detection of LN metastases in PTC, in comparison with imprints and microscopic analysis of formalin-fixed, paraffin-embedded (FFPE) tissue. A total of 387 LNs from 37 patients were studied. From each half LN, 2 imprints were taken and analyzed with hematoxylin and eosin (H&E) and CK19 immunostaining. One half of the LN was submitted to OSNA and one half to FFPE processing and H&E and CK19 staining. For concordance analysis, every single LN was considered as a case. A group of 11 cases with discordant results between OSNA and H&E/CK19 FFPE sections were subjected to additional FFPE serial sectioning and H&E and CK19 staining. We found a high degree of concordance between the assays used, with sensitivities ranging from 0.81 to 0.95, and specificities ranging from 0.87 and 0.98. OSNA allowed upstaging of patients from pN0 to pN1, in comparison with standard pathologic analysis. Identification of a metastatic LN with more than 15000 CK19 messenger RNA copies predicted the presence of a second LN with macrometastasis (<5000 copies). In summary, the study shows that OSNA application in sentinel or suspicious LN may be helpful in assessing nodal status in PTC patients. PMID- 26614399 TI - Acute oxalate nephropathy due to pancreatic atrophy in newly diagnosed pancreatic carcinoma. AB - Acute oxalate nephropathy can occur due to primary hyperoxaluria and secondary hyperoxaluria. The primary hyperoxalurias are a group of autosomal recessive disorders of endogenous oxalate overproduction. Secondary hyperoxaluria may occur as a result of excess dietary intake, poisoning with oxalate precursors (ethylene glycol), or enteric hyperoxaluria. The differential diagnosis of enteric hyperoxaluria includes inflammatory bowel disease, short bowel syndrome, bariatric surgery (with jejunoileal bypass or Roux-en-Y gastric bypass), celiac disease, partial colectomy, and chronic pancreatitis. The common etiology in all these processes is fat malabsorption, steatorrhea, saponification of calcium, and absorption of free oxalate. Hyperoxaluria causes increased urinary oxalate excretion, urolithiasis (promoted by hypovolemia, decreased urinary pH caused by metabolic acidosis, and decreased citrate and magnesium concentrations in urine), tubulointerstitial oxalate deposits, and tubulointerstitial nephritis. We report a rare case of acute oxalate nephropathy due to pancreatic atrophy and exocrine insufficiency caused by newly diagnosed pancreatic cancer. PMID- 26614400 TI - Aquaporin 5 expression is frequent in prostate cancer and shows a dichotomous correlation with tumor phenotype and PSA recurrence. AB - Aquaporin 5 (AQP5) is an androgen-regulated member of a family of small hydrophobic integral transmembrane water channel proteins regulating cellular water homeostasis and growth signaling. To evaluate its clinical impact and relationship with key genomic alterations in prostate cancer, AQP5 expression was analyzed by immunohistochemistry on a tissue microarray containing 12427 prostate cancers. The analysis revealed weak to moderate immunostaining in normal prostate epithelium. In prostate cancers AQP5 staining levels were more variable and also included completely negative and highly overexpressing cases. Negative, weak, moderate, and strong AQP5 staining was found in 25.0%, 32.5%, 32.5%, and 10.0% of 10239 interpretable tumors. Comparison of AQP5 expression levels with tumor characteristics showed a dichotomous pattern with both high and low staining levels being linked to unfavorable tumor phenotype. AQP5 was negative in 28%, 23%, 24%, and 35% of tumors with Gleason score <=3 + 3, 3 + 4, 4 + 3 and >=4 + 4, while the rate of strongly positive cases continuously increased from 7.0% over 10.0% and 12.0% to 13.0% in cancers with Gleason score <=3 + 3, 3 + 4, 4 + 3 and >=4 + 4. AQP5 expression was also related to ERG positivity and phosphatase and tensin homolog (PTEN) deletion (P < .0001 each). Strong AQP5 positivity was seen in 15.5% of ERG-positive and 5.8% of ERG-negative cancers (P < .0001) as well as in 14.7% of cancers with PTEN deletion and 9.4% of cancers without PTEN deletion. Remarkably, both negativity and strong positivity of AQP5 were linked to unfavorable disease outcome. This was however only seen in subgroups defined by TMPRSS2-ERG fusion and/or PTEN deletion. In summary, AQP5 can be both overexpressed and lost in subgroups of prostate cancers. Both alterations are linked to unfavorable outcome in molecularly defined cancer subgroups. It is hypothesized that this dichotomous role of AQP5 is due to two highly different mechanisms as to how the protein can influence cancer cells, that is, hydraulic motility regulation and Ras/MAPK pathway activation. PMID- 26614401 TI - Assessing early implementation of state autism insurance mandates. AB - In the United States, health insurance coverage for autism spectrum disorder treatments has been historically limited. In response, as of 2015, 40 states and Washington, DC, have passed state autism insurance mandates requiring many health plans in the private insurance market to cover autism diagnostic and treatment services. This study examined five states' experiences implementing autism insurance mandates. Semi-structured, key-informant interviews were conducted with 17 participants representing consumer advocacy organizations, provider organizations, and health insurance companies. Overall, participants thought that the mandates substantially affected the delivery of autism services. While access to autism treatment services has increased as a result of implementation of state mandates, states have struggled to keep up with the demand for services. Participants provided specific information about barriers and facilitators to meeting this demand. Understanding of key informants' perceptions about states' experiences implementing autism insurance mandates is useful for other states considering adopting or expanding mandates or other policies to expand access to autism treatment services. PMID- 26614402 TI - Comparison of toxicity following different conditioning regimens (busulfan/melphalan and carboplatin/etoposide/melphalan) for advanced stage neuroblastoma: Experience of two transplant centers. AB - The outcome for advanced neuroblastoma has improved with combined modality therapy: induction chemotherapy, surgery, and consolidation with high-dose chemotherapy/autologous HSCT, followed by local radiation, cisretinoic acid, and recently antibody therapy. In the United States, the most common conditioning regimen is CEM, while in Europe/Middle East, Bu/Mel has been widely used; it remains unclear which regimen has the best outcome. Assess renal, hepatic, and infectious toxicity through Day+100 in 2 different regimens. Retrospective comparison between CEM-DFCHCC Boston and Bu/Mel- CCHE-57357. Thirty-five patients, median age 4, in Boston (2007-2011) and 38 patients, median age 3, in Cairo (2009-2011). Renal toxicity; creatinine was significantly higher in CEM than Bu/Mel: 57% (median day+90) vs. 29% (median>day+100), p = 0.004. One CEM patient died from renal dialysis at day+19. Hepatic toxicity was significantly higher in CEM than Bu/Mel: 80% (median day+26) vs. 58% (median day+60), p = 0.04. In infectious complications with CEM 14%, bacteremia (n = 4) and fungemia (n = 1), 3 had culture-negative sepsis requiring vasopressors. With Bu/Mel 18%, bacteremia (n = 7), none required pressors, p = 0.4. Bu/Mel was associated with less acute hepatic and renal toxicity and thus may be preferable for preserving organ functions. PMID- 26614403 TI - Quantitative analysis of arachidonic acid, endocannabinoids, N-acylethanolamines and steroids in biological samples by LCMS/MS: Fit to purpose. PMID- 26614404 TI - Detection of related substances in polyene phosphatidyl choline extracted from soybean and in its commercial capsule by comprehensive supercritical fluid chromatography with mass spectrometry compared with HPLC with evaporative light scattering detection. AB - Supercritical fluid chromatography with tandem mass spectrometry was used to comprehensively profile polyene phosphatidyl choline (PPC) extracted from soybean. We achieved an efficient chromatographic analysis using a BEH-2EP column (3 * 100 mm(2) , 1.7 MUm) with a mobile phase consisting of CO2 and a cosolvent in gradient combination at a flow rate of 1.0 mL/min. The cosolvent consisted of methanol, acetonitrile, and water (containing 10 mM ammonium acetate and 0.2% formic acid). The total single-run time was 7 min. We used this method to accurately detect ten different phospholipids (PLs) during extraction. The limits of quantification for phosphatidyl choline, lyso-phosphatidylcholine (LPC), phosphatidic acid (PA), sphingomyelin, phosphatidyl glycerol, phosphatidyl inositol (PI), cholesterol, cardiolipin, phosphatidyl serine, and phosphatidyl ethanolamine (PE) were 20.6, 19.52, 1.21, 2.38, 0.50, 2.28, 54.3, 0.60, 0.65, and 4.85 ng/mL, respectively. However, adopting the high-performance liquid chromatography with evaporative light scattering detection method issued by the China Food and Drug Administration, only PA, LPC, PE, PI, and PPC could be analyzed accurately, and the limits of quantification were 33.89, 60.5, 30.3, 10.9, and 61.79 MUg/mL, respectively. The total single-run time was at the least 20 min. Consequently, the supercritical fluid chromatography with tandem mass spectrometry method was more suitable for the analysis of related PLs. PMID- 26614405 TI - Management of the cervico-petrous internal carotid artery in class C tympanojugular paragangliomas. AB - BACKGROUND: Management of the cervical and petrous internal carotid artery (ICA) is frequently required in Fisch class C tympanojugular paragangliomas (TJPs). The purpose of this study was to discuss the perioperative intervention of the ICA in patients who underwent surgical resection of a TJP. METHODS: A retrospective study of 237 patients surgically treated for Fisch class C TJPs was done to identify cases that required ICA management. RESULTS: Management of the ICA was required in 176 patients (74.2%). Forty-two patients required just an ICA decompression, 88 underwent a subperiosteal dissection, 19 underwent subadventitial dissection without intraluminal stenting, 17 underwent subadventitial dissection with intraluminal stenting, and 12 underwent arterial resection after permanent balloon occlusion. There were no complications associated with the endovascular procedures. Gross total tumor resection was achieved in 91.5% of the cases. CONCLUSION: Preoperative endovascular intervention, in selected cases, facilitates gross total tumor removal and significantly reduces the risk of an intraoperative ICA injury. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: 899-905, 2016. PMID- 26614406 TI - Lessons Learned from EVOLVE for Planning of Future Randomized Trials in Patients on Dialysis. AB - The effect of the calcimimetic cinacalcet on cardiovascular disease in patients undergoing hemodialysis with secondary hyperparathyroidism was assessed in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events trial. This was the largest (in size) and longest (in duration) randomized controlled clinical trial undertaken in this population. During planning, execution, analysis, and reporting of the trial, many lessons were learned, including those related to the use of a composite cardiovascular primary endpoint, definition of endpoints (particularly heart failure and severe unremitting hyperparathyroidism), importance of age for optimal stratification at randomization, use of unadjusted and adjusted intention-to-treat analysis for the primary outcome, how to respond to a lower-than-predicted event rate during the trial, development of a prespecified analytic plan that accounted for nonadherence and for cointerventions that diminished the power of the trial to observe a treatment effect, determination of the credibility of a subgroup effect, use of adverse effects database to investigate rare diseases, collection of blood for biomarker measurement not designated before trial initiation, and interpretation of the benefits-to-harms ratio for individual patients. It is likely that many of these issues will arise in the planning of future trials in CKD. PMID- 26614407 TI - Tumour necrosis factor-alpha plays a significant role in the Aldara-induced skin inflammation in mice. AB - BACKGROUND: Recently, the Aldara-induced psoriasis-like skin inflammation model in mice has attracted increased attention, due to its dependence on the same immunological pathways and cell types as in human psoriasis. OBJECTIVES: To study the impact of constitutive deficiency of tumour necrosis factor (TNF)-alpha and its upstream regulator mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK-2, herein MK2) in the Aldara-induced psoriasis-like skin inflammation model. METHODS: TNF-alpha knockout (KO), MK2 KO and wild-type (WT) mice divided into separate groups received either 45-mg Aldara cream or control cream for 5 consecutive days. The skin inflammation was evaluated clinically, histologically, and by quantitative reverse transcription-polymerase chain reaction. RESULTS: We found that TNF-alpha KO mice developed significantly less skin inflammation compared with WT mice, as evaluated clinically and histologically. At the molecular level, we demonstrated that the Aldara-induced mRNA expression of the psoriasis-related inflammatory markers interleukin (IL)-17C, IL-23p19, IL-12p40, IL-17A, IL-22 and S100A8 was significantly decreased in TNF-alpha KO mice compared with WT mice. No significant difference in the mRNA expression of these inflammatory markers between MK2 KO mice and WT mice was found, although Aldara treated MK2 KO mice showed a tendency towards a lower mRNA expression of IL-17A and IL-22 compared with WT mice. CONCLUSIONS: We were able to demonstrate significantly lower levels of inflammation in TNF-alpha KO mice compared with WT mice, supporting the use of this model in future studies characterizing the role of TNF-alpha in psoriasis. PMID- 26614408 TI - Identification of azabenzimidazoles as potent JAK1 selective inhibitors. AB - We have identified a class of azabenzimidazoles as potent and selective JAK1 inhibitors. Investigations into the SAR are presented along with the structural features required to achieve selectivity for JAK1 versus other JAK family members. An example from the series demonstrated highly selective inhibition of JAK1 versus JAK2 and JAK3, along with inhibition of pSTAT3 in vivo, enabling it to serve as a JAK1 selective tool compound to further probe the biology of JAK1 selective inhibitors. PMID- 26614409 TI - Rational design, synthesis and in vitro evaluation of allylidene hydrazinecarboximidamide derivatives as BACE-1 inhibitors. AB - BACE-1 (beta-secretase) is considered to be one of the promising targets for treatment of Alzheimer's disease as it catalyzes the rate limiting step of Abeta 42 production. Herein, we report a novel class of allylidene hydrazinecarboximidamide derivatives as moderately potent BACE-1 inhibitors, having aminoguanidine substitution on allyl linker with two aromatic groups on either side. A library of derivatives was designed based on the docking studies, synthesized and evaluated for BACE-1 inhibition in vitro. The designed ligands displayed interactions with the catalytic aspartate dyad through guanidinium functionality. Further, the aromatic rings placed on either side of the linker occupied S1 and S3 active site regions contributing to the activity. These ligands were also predicted to follow Lipinski rule and cross blood brain barrier. Compound 2.21, having high docking score, was found to be most active with IC50 of 6.423MUM indicating good correlation with docking prediction. PMID- 26614410 TI - Implementing an Electronic Health Record Medical Device Module-A Critical Patient Safety Enhancement. PMID- 26614411 TI - The Haptic Radiologist: Being There, Always. PMID- 26614412 TI - Prosthesis-patient mismatch in high-risk patients with severe aortic stenosis: A randomized trial of a self-expanding prosthesis. AB - OBJECTIVES: We compared the incidence of prosthesis-patient mismatch (PPM) between transcatheter aortic valve replacement (TAVR) using a self-expanding bioprosthesis and surgical aortic valve replacement (SAVR) in the CoreValve US High Risk Pivotal Trial. We sought to determine the influence of PPM on clinical outcomes. METHODS: Patients with severe aortic stenosis and at increased risk for surgery were randomized 1:1 to TAVR or SAVR. Postoperative PPM was defined by the effective orifice area index (EOAi) as severe PPM (EOAi <= 0.65 cm(2)/m(2)) and no severe PPM (EOAi > 0.65 cm(2)/m(2)); clinical outcomes were analyzed in the TAVR arm (n = 389) and SAVR arm (n = 353). Left ventricular mass index and regression were analyzed at baseline and 1 year. RESULTS: The incidence of severe PPM in the SAVR group at 1 year was 25.7% versus 6.2% in the TAVR group (P < .0001). Left ventricular mass index regression at 1 year was 6.8% for TAVR and 15.1% for SAVR in patients with severe PPM. At 1 year the rate of all-cause mortality and acute kidney injury were significantly greater in all patients (TAVR + SAVR) with severe PPM compared with no severe PPM (20.6% vs 12.0% [P = .0145] for death and 19.2% vs 8.5% [P = .0008] for acute kidney injury). CONCLUSIONS: In patients with high surgical risk and severe aortic stenosis, severe PPM is more common in patients treated with SAVR than those treated with TAVR. Patients with severe PPM are a greater risk for death and acute kidney injury than patients without severe PPM. PMID- 26614413 TI - Accelerated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma. AB - OBJECTIVE: To evaluate a new protocol of accelerated hemithoracic intensity modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP) for patients with resectable malignant pleural mesothelioma (MPM). METHODS: A total of 25 Gy of radiation was delivered in 5 daily fractions over 1 week to the entire ipsilateral hemithorax with concomitant boost of 5 Gy to volumes at high risk based on computed tomography and positron emission tomography scan findings. EPP was performed at 6 +/- 2 days after the end of radiation therapy. Adjuvant chemotherapy was offered to patients with ypN2 disease. RESULTS: A total of 62 patients were included between November 2008 and October 2014. One patient died in the hospital 2 months after EPP, for an operative mortality of 1.6%, and 2 died after discharged from the hospital for an overall treatment-related mortality (grade 5 toxicity) of 4.8%. Twenty-four patients (39%) developed grade 3 to 5 (grade 3+) complications. On final pathology, 94% of the patients were stage III or IV, and 52% had ypN2 disease. The median survival for all patients as an intention-to-treat analysis was 36 months. The median overall survival and disease-free survival was 51 and 47 months, respectively, in epithelial subtypes, compared with 10 and 8 months in biphasic subtypes (P = .001). Ipsilateral chest recurrence occurred in 8 patients. CONCLUSIONS: Accelerated hemithoracic IMRT followed by EPP has become our preferred approach for resectable MPM. The results have been encouraging in patients with epithelial subtype. PMID- 26614414 TI - Discussion. PMID- 26614415 TI - Discussion. PMID- 26614416 TI - Rare but relevant. PMID- 26614417 TI - Pulmonary venous blood sampling significantly increases the yield of circulating tumor cells in early-stage lung cancer. AB - OBJECTIVE: To identify circulating tumor cells (CTCs) in the blood of patients with early-stage lung cancer and to show that sampling pulmonary vein (PV) blood using microfluidic chip technology will yield significantly more CTCs. Improving early detection of lung cancer is critical to improving lung cancer survival. Reproducible detection of CTCs is limited currently in early stage tumors. METHODS: Patients undergoing pulmonary resection had PV blood drawn before resection. Peripheral blood was sampled at preoperative, intraoperative, and postoperative times. Samples were analyzed on microfluidic chips using antibody based capture. RESULTS: A total of 32 patients with primary lung cancer were evaluated. Twenty patients had 1 or more CTCs detected in at least 1 sample (62.5%). The mean number of CTCs from peripheral vein sources at the preoperative, intraoperative, and postoperative time points was 1.3, 1.9, and 0.6 respectively. The average number of CTCs in the PV was 340.0 (range, 0.0-5422.50; P > .01). When PV CTCs were present, the number of CTCs was correlated with pathological tumor size (P = .0236). The number of PV CTCs was not correlated with any other clinical feature (eg, smoking status, preoperative or postoperative stage). Furthermore, the number of PV CTCs was significantly higher when preoperative bronchoscopic biopsy was performed, compared with computed tomography-guided biopsy (P = .0311). Seven patients had evidence of CTC clusters, or microemboli. CONCLUSIONS: With a single vein draining the entire tumor basin, lung cancers are unique, allowing the high-yield isolation of CTCs from the PV. This method may facilitate future studies to improve the detection and analysis of early-stage lung CTCs. PMID- 26614418 TI - Discussion. PMID- 26614419 TI - Discussion. PMID- 26614421 TI - Does load influence shoulder muscle recruitment patterns during scapular plane abduction? AB - OBJECTIVES: Load is used to increasingly challenge muscle function and has been shown to increase muscle activity levels with no change in activation patterns during shoulder flexion, extension, adduction and rotation. However, the effect of load during shoulder abduction, a movement commonly used in assessment of shoulder dysfunction and to improve shoulder function, has not been comprehensively examined. Therefore, the purpose of this study was to determine if load influences shoulder muscle activation patterns and levels during scapular plane abduction in normal subjects. DESIGN: Experimental study. METHODS: Fourteen volunteers performed shoulder abduction in the scapular plane at 25%, 50% and 75% of maximum load. Eight shoulder muscles were investigated using a combination of indwelling and surface electromyographic recordings: middle deltoid, infraspinatus, subscapularis, supraspinatus, serratus anterior, upper and lower trapezius and rhomboid major. RESULTS: All muscles tested showed increasing average muscle activation levels with increasing load and strong correlations in the activation patterns between loads. CONCLUSIONS: Increasing shoulder abduction load not only increases activity in middle deltoid but also in the rotator cuff (infraspinatus, subscapularis, supraspinatus) and axioscapular (serratus anterior, upper and lower trapezius, rhomboid major) muscles. The functional stabilising role of both the rotator cuff and axioscapular muscles is considered an important contribution to the increased activation levels in these muscle groups as they function to counterbalance potential translation forces produced by other muscles during shoulder abduction. The activation patterns of all shoulder muscle groups during abduction can be trained at low load and progressively challenged with increasing load. PMID- 26614420 TI - Postinduction positron emission tomography assessment of N2 nodes is not associated with ypN2 disease or overall survival in stage IIIA non-small cell lung cancer. AB - OBJECTIVE: Induction therapy is often recommended for patients with clinical stage IIIA-N2 (cIIIA/pN2) lung cancer. We examined whether postinduction positron emission tomography (PET) scans were associated with ypN2 disease and survival of patients with cIIIA/pN2 disease. METHODS: We performed a retrospective review of a prospectively maintained database to identify patients with cIIIA/pN2 non-small cell lung cancer treated with induction chemotherapy followed by surgery between January 2007 and December 2012. The primary aim was the association between postinduction PET avidity and ypN2 status; the secondary aims were overall survival, disease-free survival, and recurrence. RESULTS: Persistent pathologic N2 disease was present in 61% of patients (61 out of 100). PET N2-negative disease increased from 7% (6 out of 92) before induction therapy to 47% (36 out of 77) afterward. The sensitivity, specificity, and accuracy of postinduction PET for identification of ypN2 disease were 59%, 55%, and 57%, respectively. Logistic regression analysis indicated that postinduction PET N2 status was not associated with ypN2 disease. Of the 39 patients with both pre- and postinduction PET N2 avidity, 25 (64%) had ypN2 disease. The 5-year overall survival was 40% for ypN2 disease versus 38% for N2-persistent disease (P = .936); the 5-year overall survival was 43% for postinduction PET N2-negative disease versus 39% for N2-avid disease (P = .251). The 5-year disease-free survival was 34% for ypN2-negative disease versus 9% for N2-persistent disease (P = .079). CONCLUSIONS: Postinduction PET avidity for N2 nodes is not associated with ypN2 disease, overall survival, or disease-free survival in patients undergoing induction chemotherapy for stage IIIA/pN2 disease. PMID- 26614422 TI - The effects of cold water immersion with different dosages (duration and temperature variations) on heart rate variability post-exercise recovery: A randomized controlled trial. AB - OBJECTIVES: The aim of the present study was to investigate the effects of cold water immersion during post-exercise recovery, with different durations and temperatures, on heart rate variability indices. DESIGN: Hundred participants performed a protocol of jumps and a Wingate test, and immediately afterwards were immersed in cold water, according to the characteristics of each group (CG: control; G1: 5' at 9+/-1 degrees C; G2: 5' at 14+/-1 degrees C; G3: 15' at 9+/-1 degrees C; G4: 15' at 14+/-1 degrees C). METHODS: Analyses were performed at baseline, during the CWI recuperative technique (TRec) and 20, 30, 40, 50 and 60min post-exercise. The average HRV indices of all RR-intervals in each analysis period (MeanRR), standard deviation of normal RR-intervals (SDNN), square root of the mean of the sum of the squares of differences between adjacent RR-intervals (RMSSD), spectral components of very low frequency (VLF), low frequency (LF) and high frequency (HF), scatter of points perpendicular to the line of identity of the Poincare Plot (SD1) and scatter points along the line of identity (SD2) were assessed. RESULTS: Mean RR, VLF and LF presented an anticipated return to baseline values at all the intervention groups, but the same was observed for SDNN and SD2 only in the immersion for 15min at 14 degrees C group (G4). In addition, G4 presented higher values when compared to CG. CONCLUSIONS: These findings demonstrate that if the purpose of the recovery process is restoration of cardiac autonomic modulation, the technique is recommended, specifically for 15min at 14 degrees C. PMID- 26614424 TI - Theoretical Benefits of Dynamic Collimation in Pencil Beam Scanning Proton Therapy for Brain Tumors: Dosimetric and Radiobiological Metrics. AB - PURPOSE: To quantify the dosimetric benefit of using a dynamic collimation system (DCS) for penumbra reduction during the treatment of brain tumors by pencil beam scanning proton therapy (PBS PT). METHODS AND MATERIALS: Collimated and uncollimated brain treatment plans were created for 5 patients previously treated with PBS PT and retrospectively enrolled in an institutional review board approved study. The in-house treatment planning system, RDX, was used to generate the plans because it is capable of modeling both collimated and uncollimated beamlets. The clinically delivered plans were reproduced with uncollimated plans in terms of target coverage and organ at risk (OAR) sparing to ensure a clinically relevant starting point, and collimated plans were generated to improve the OAR sparing while maintaining target coverage. Physical and biological comparison metrics, such as dose distribution conformity, mean and maximum doses, normal tissue complication probability, and risk of secondary brain cancer, were used to evaluate the plans. RESULTS: The DCS systematically improved the dose distribution conformity while preserving the target coverage. The average reduction of the mean dose to the 10-mm ring surrounding the target and the healthy brain were 13.7% (95% confidence interval [CI] 11.6%-15.7%; P<.0001) and 25.1% (95% CI 16.8%-33.4%; P<.001), respectively. This yielded an average reduction of 24.8% (95% CI 0.8%-48.8%; P<.05) for the brain necrosis normal tissue complication probability using the Flickinger model, and 25.1% (95% CI 16.8%-33.4%; P<.001) for the risk of secondary brain cancer. A general improvement of the OAR sparing was also observed. CONCLUSION: The lateral penumbra reduction afforded by the DCS increases the normal tissue sparing capabilities of PBS PT for brain cancer treatment while preserving target coverage. PMID- 26614425 TI - A systematic review and meta-analysis of the diagnostic accuracy of MRI for suspected ACL and meniscal tears of the knee. AB - PURPOSE: To determine the diagnostic accuracy of magnetic resonance imaging (MRI) and ultrasound (US) in the diagnosis of anterior cruciate ligament (ACL), medial meniscus and lateral meniscus tears in people with suspected ACL and/or meniscal tears. METHODS: MEDLINE, Web of Science and the Cochrane library were searched from inception to March 2014. All prospective studies of the diagnostic accuracy of MRI or US against arthroscopy as the reference standard were included in the systematic review. Studies with a retrospective design and those with evidence of verification bias were excluded. Methodological quality of included studies was assessed using the QUADAS-2 tool. A meta-analysis of studies evaluating MRI to calculate the pooled sensitivity and specificity for each target condition was performed using a bivariate model with random effects. Sub-group and sensitivity analysis were used to examine the effect of methodological and other study variables. RESULTS: There were 14 studies included in the meta-analysis of the accuracy of MRI for ACL tears, 19 studies included for medial meniscal tears and 19 studies for lateral meniscal tears. The summary estimates of sensitivity and specificity of MRI were 87 % (95 % CI 77-94 %) and 93 % (95 % CI 91-96 %), respectively, for ACL tears; 89 % (95 % CI 83-94 %) and 88 % (95 % CI 82-93 %), respectively, for medial meniscal tears; and 78 % (95 % CI 66-87 %) and 95 % (95 % CI 91-97 %), respectively, for lateral meniscal tears. Magnetic field strength had no significant effect on accuracy. Most studies had a high or unclear risk of bias. There were an insufficient number of studies that evaluated US to perform a meta-analysis. CONCLUSION: This study provides a systematic review and meta analysis of diagnostic accuracy studies of MRI and applies strict exclusion criteria in relation to the risk of verification bias. The risk of bias in most studies is high or unclear in relation to the reference standard. Concerns regarding the applicability of patient selection are also present in most studies. LEVEL OF EVIDENCE: III. PMID- 26614426 TI - Femoral tunnel enlargement after anterior cruciate ligament reconstruction using RigidFix compared with extracortical fixation. AB - PURPOSE: The aim of this study was to compare femoral tunnel enlargement after anterior cruciate ligament (ACL) reconstruction surgery using hamstring autograft tendons fixed by bioabsorbable femoral trans-tunnel pins with that in patients in which the graft was fixed with extracortical fixation. METHODS: Forty-three patients were randomly selected from our database and included in the study. Femoral tunnel diameter was measured by computed tomography in 20 patients who underwent ACL reconstruction via anteromedial portal technique using autologous quadruple hamstrings, fixed with two bioabsorbable trans-tunnel pins, RigidFix, on the femoral side and compared with 23 patients in whom extracortical fixation, EndoButton CL, was used. The diameter of the femoral tunnel was measured at a distance of 5 mm from the tunnel entrance and at the largest diameter along the tunnel axis. Data were compared with the diameter of the drill used during surgery. Clinical evaluation was performed using the Lysholm score, IKDC subjective score and anterior knee laxity measurements. RESULTS: Femoral tunnel enlargement 5 mm from the entrance and at the largest diameter was greater in the RigidFix group than the EndoButton group. There were no significant differences between the two groups regarding age, gender, post-operative Lysholm score, IKDC subjective score or knee laxity measurements. CONCLUSION: The present study showed greater enlargement of the femoral bone tunnel when a bioabsorbable trans tunnel pin system was used with the medial portal technique when compared to extracortical fixation. These findings confirm that femoral tunnel widening should be considered when RigidFix was used in ACL reconstruction by anteromedial portal technique. LEVEL OF EVIDENCE: III. PMID- 26614427 TI - Non-destructive evaluation of an internal adaptation of resin composite restoration with swept-source optical coherence tomography and micro-CT. AB - Swept-source optical coherence tomography (SS-OCT) and micro-CT can be useful non destructive methods for evaluating internal adaptation. There is no comparative study evaluating the two methods in the assessment of internal adaptation in composite restoration. The purpose of this study was to compare internal adaptation measurements of SS-OCT and micro-CT. Two cylindrical cavities were created on the labial surface of twelve bovine incisors. The 24 cavities were randomly assigned to four groups of dentin adhesives: (1) three-step etch-and rinse adhesive, (2) two-step etch-and-rinse adhesive, (3) two-step self-etch adhesive, and (4) one-step self-etch adhesive. After application, the cavities were filled with resin composite. All restorations underwent a thermocycling challenge, and then, eight SS-OCT images were taken using a Santec OCT-2000TM (Santec Co., Komaki, Japan). The internal adaptation was also evaluated using micro-CT (Skyscan, Aartselaar, Belgium). The image analysis was used to calculate the percentage of defective spot (%DS) and compare the results. The groups were compared using one-way ANOVA with Duncan analysis at the 95% significance level. The SS-OCT and micro-CT measurements were compared with a paired t-test, and the relationship was analyzed using a Pearson correlation test at the 95% significance level. The %DS results showed that Group 3<=Group 4 Cr > Ni > Fe > Cd (56.35, 14.90, 5.3, 4.6, and 0.62 MUg/g(1) dry weight). Bernam River sediments have moderate to severe enrichment for Sn, moderate for Cd, and no enrichment for Cr, Ni, and Fe. The contamination factor (CF) results demonstrated that Cd and Sn are responsible for the high contamination. The pollution load index (PLI), for all the sampling sites, suggests that the sampling stations were generally unpolluted with the exception of the Bagan Tepi Sungai, Sabak Bernam, and Tanjom Malim stations. Multivariate techniques including Pearson's correlation and hierarchical cluster analysis were used to apportion the various sources of the metals. The results suggested that the sediment samples collected from the upper course of the river had lower metal concentrations, while sediments in the middle and lower courses of the river had higher metal concentrations. Therefore, our results can be useful as a baseline data for government bodies to adopt corrective measure on the issues related to heavy metal pollution in the Bernam River in the future. PMID- 26614453 TI - PCDD/F and PCB water column partitioning examination using natural organic matter and black carbon partition coefficient models. AB - A 9-year water dataset from the Houston Ship Channel (HSC) was analyzed to understand partitioning in polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans (PCDD/Fs). Total PCBs had more mass as dissolved (74%) whereas total PCDD/Fs did not (11%). Generally, the limited number of PCDD/Fs (only 2378 substituted) explained these differences though differences in chemical behavior beyond log K ow also likely influence partitioning. The particular fractionation seen in the HSC also seemed related to a wide variation in particulate organic carbon (POC)/dissolved organic carbon (DOC) ratio (0.42-180%). Published and unaltered linear free energy and linear solvation energy relationships for DOC, POC, and particulate black carbon (BC) resulted in predictions that were at best 27% (PCB) and 25% root-mean-square error (RMSE) (PCDD/F) partition fraction compared to observed (using estimated BC/POC fractions of 10 and 25%, respectively). These results show, at least in light of the uncertainties in this data (e.g., precise fraction of BC), that a 25% accuracy in model prediction of operationally dissolved or suspended fraction for any one PCB or PCDD/F congener is the best prediction that may be expected. It is therefore recommended that site-specific data be used to calibrate most any water column-partitioning model if it is to be expected to describe what actually occurs in field conditions. PMID- 26614455 TI - Ethanolic extract of dandelion (Taraxacum mongolicum) induces estrogenic activity in MCF-7 cells and immature rats. AB - Plants of the genus Taraxacum, commonly known as dandelions, are used to treat breast cancer in traditional folk medicine. However, their use has mainly been based on empirical findings without sufficient scientific evidence. Therefore, we hypothesized that dandelions would behave as a Selective estrogen receptor modulator (SERM) and be effective as hormone replacement therapy (HRT) in the postmenopausal women. In the present study, in vitro assay systems, including cell proliferation assay, reporter gene assay, and RT-PCR to evaluate the mRNA expression of estrogen-related genes (pS2 and progesterone receptor, PR), were performed in human breast cancer cells. Dandelion ethanol extract (DEE) significantly increased cell proliferation and estrogen response element (ERE) driven luciferase activity. DEE significantly induced the expression of estrogen related genes such as pS2 and PR, which was inhibited by tamoxifen at 1 MUmol.L( 1). These results indicated that DEE could induce estrogenic activities mediated by a classical estrogen receptor pathway. In addition, immature rat uterotrophic assay was carried out to identify estrogenic activity of DEE in vivo. The lowest concentration of DEE slightly increased the uterine wet weight, but there was no significant effect with the highest concentration of DEE. The results demonstrate the potential estrogenic activities of DEE, providing scientific evidence supporting their use in traditional medicine. PMID- 26614454 TI - Cancer therapy using natural ligands that target estrogen receptor beta. AB - Estrogen receptor beta (ERbeta) is one of the two key receptors (ERalpha, ERbeta) that facilitate biological actions of 17beta-estradiol (E2). ERbeta is widely expressed in many tissues, and its expression is reduced or lost during progression of many tumors. ERbeta facilitates estrogen signaling by both genomic (classical and non-classical) and extra-nuclear signaling. Emerging evidence suggests that ERbeta functions as a tissue-specific tumor suppressor with anti proliferative actions. Recent studies have identified a number of naturally available selective ERbeta agonists. Targeting ERbeta using its naturally available ligands is an attractive approach for treating and preventing cancers. This review presents the beneficial actions of ERbeta signaling and clinical utility of several natural ERbeta ligands as potential cancer therapy. PMID- 26614456 TI - Pharmacodynamics and potential synergistic effects of Mai-Luo-Ning injection on cardiovascular protection, based on molecular docking. AB - As a computer-assisted approach, molecular docking has been universally applied in drug research and development and plays an important role in the investigation and evaluation of herbal medicines. Herein, the method was used to estimate the pharmacodynamics of Mai-Luo-Ning injection, a traditional Chinese compound herbal prescription. Through investigating the interactions between several important proteins in cardiovascular system and characteristic components of the formula, its effect on cardiovascular protection was evaluated. Results showed the differences in the interactions between each component and the selected target proteins and revealed the possible mechanisms for synergistic effects of various characteristic components on cardiovascular protection. The study provided scientific evidence supporting the mechanistic study of the interactions among multi-components and targets, offering a general approach to investigating the pharmacodynamics of complicated materials in compound herbal prescriptions. PMID- 26614457 TI - Tongqiao Huoxue Decoction ameliorates learning and memory defects in rats with vascular dementia by up-regulating the Ca(2+)-CaMKII-CREB pathway. AB - The present study was aimed at determining the effects of Tongqiao Huoxue Decoction (TQHXD) on the Ca(2+)-CaMKII-CREB pathway and the memory and learning capacities of rats with vascular dementia (VD). The rat VD model was established by using an improved bilateral carotid artery ligation method. The Morris water maze experiment was used to evaluate the ethology of the VD rats following treatments with TQHXD at 3.01, 6.02, and 12.04 g.kg(-1) per day for 31 days. At the end of experiment, the hippocampus were harvested and analyzed. Western blotting and RT-PCR were used to measure the expression levels of calmodulin binding protein kinase II(CaMKII), protein kinase A(PKA), cAMP-response element binding protein(CREB), and three N-methyl-D-aspartic acid receptor subunits (NR1, NR2A, and NR2B). Our results revealed that TQHXD could alleviate the loss of learning abilities and increase the memory capacity (P < 0.05 and P < 0.01 vs the model group, respectively). The treatment with 6.02 and 12.04 g.kg(-1) of TQHXD significantly up-regulated the Ca(2+)-CaMKII-CREB pathway in the hippocampus. In conclusion, TQHXD showed therapeutic effects on a bilateral carotid artery ligation-induced vascular dementia model, through the up-regulation of calcium signalling pathways. PMID- 26614458 TI - Tetrandrine inhibits migration and invasion of rheumatoid arthritis fibroblast like synoviocytes through down-regulating the expressions of Rac1, Cdc42, and RhoA GTPases and activation of the PI3K/Akt and JNK signaling pathways. AB - Tetrandrine (Tet), the main active constituent of Stephania tetrandra root, has been demonstrated to alleviate adjuvant-induced arthritis in rats. The present study was designed to investigate the effects of Tet on the migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and explore the underlying mechanisms. By using cultures of primary FLS isolated from synoviums of RA patients and cell line MH7A, Tet (0.3, 1 MUmol.L(-1)) was proven to significantly impede migration and invasion of RA-FLS, but not cell proliferation. Tet also greatly reduced the activation and expressions of matrix degrading enzymes MMP-2/9, the expression of F-actin and the activation of FAK, which controlled the morphologic changes in migration process of FLS. To identify the key signaling pathways by which Tet exerts anti-migration effect, the specific inhibitors of multiple signaling pathways LY294002, Triciribine, SP600125, U0126, SB203580, and PDTC (against PI3K, Akt, JNK, ERK, p38 MAPK and NF kappaB-p65, respectively) were used. Among them, LY294002, Triciribine, and SP600125 were shown to obviously inhibit the migration of MH7A cells. Consistently, Tet was able to down-regulate the activation of Akt and JNK as demonstrated by Western blotting assay. Moreover, Tet could reduce the expressions of migration-related proteins Rho GTPases Rac1, Cdc42, and RhoA in MH7A cells. In conclusion, Tet can impede the migration and invasion of RA-FLS, which provides a plausible explanation for its protective effect on RA. The underlying mechanisms involve the reduction of the expressions of Rac1, Cdc42, and RhoA, inhibition of the activation of Akt and JNK, and subsequent down regulation of activation and/or expressions of MMP-2/9, F-actin, and FAK. PMID- 26614459 TI - Anti-inflammatory and anti-arthritic effects of Guge Fengtong Formula: in vitro and in vivo studies. AB - Rheumatoid arthritis (RA) is the most common inflammatory arthritis and a major cause of disability. Presently, the clinical therapeutic medicines for inflammatory and arthritic diseases are unsatisfactory due to severe adverse effects or ineffectiveness. The Guge Fengtong formula (GGFT), containing the standardized extracts of Dioscoreae Nipponicae Rhizoma, Spatholobi Caulis, and Zingiberis Rhizoma, has long been used for RA treatment by Chinese doctorsin China. However, the detailed anti-inflammatory and anti-arthritic activity of GGFT has not been reported so far. In the present work, we aimed to evaluate the anti-inflammatory and anti-arthritic effects of GGFT using three in vivo animal models, and tried to uncover its preliminarythe underlying mechanism of action mechanism in RAW 264.7 macrophages. The obtained results indicated that GGFT significantly attenuated ear edema, decreased carrageenan-induced paw edema, reduced the arthritis score, and reversed the weight loss of the complete Freund's adjuvant (CFA)CFA-injected rats. Additionally, marked decrease of in synovial inflammatory infiltration and synovial lining hyperplasia in the joints and decline of inflammatory factors (TNF-alpha and IL-1beta) in the serum were observed in the GGFT-treated rats. In lipopolysaccharide-activated RAW264.7 macrophages, GGFT reduced the production of NO, PGE2, and IL-6, and inhibited the expression of iNOS, COX-2, and NF-kappaB expression. Our results demonstrated that GGFT possessed considerable anti-inflammatory activity and have had potential therapeutic effects on adjuvant induced arthritis in rats, which provided providing experimental evidences for its traditional application in the treatment of RA and other inflammatory diseases. PMID- 26614460 TI - The importance of start codon of nosM in nosiheptide production. AB - The present study was designed to investigate the effects of start codon of nosM on the biosynthesis of nosiheptide. Target genes were amplified by overlap PCR. After homologous recombination to construct engineered strains, nosiheptide production was analyzed by HPLC. Three mutants with different start codon of nosM were constructed, and nosiheptide production of each mutant was analyzed and compared. Replacement of the start codon of nosM significantly decreased the production of nosiheptide. In conclusion, start codon usage could greatly affect the biosynthetic efficiency in the biosynthetic gene cluster of nosiheptide. PMID- 26614461 TI - Preparation and physicochemical characterization of a solid dispersion of (3, 5, 6-trimethylpyrazin-2-yl) methyl 3-methoxy-4-[(3, 5, 6-trimethylpyrazin-2-yl) methoxy] benzoate (VA-T) and polyvinylpyrrolidone. AB - Ischemic brain injury is a major disease which threatens human health and safety. (3, 5, 6-trimethylpyrazin-2-yl) methyl 3-methoxy-4-[(3, 5, 6-trimethylpyrazin-2 yl) methoxy] benzoate (VA-T), a newly discovered lead compound, is effective for the treatment of ischemic brain injury and its sequelae. But the poor solubility of VA-T leads to poor dissolution and limited clinical application. In order to improve the dissolution of VA-T, the pharmaceutical technology of solid dispersions was used in the present study. VA-T/polyvinylpyrrolidone (PVP) solid dispersion was prepared by the solvent method. The dissolution studies were carried out and solid state characterization was evaluated by differential scanning calorimetry (DSC), infrared spectroscopy (IR), x-ray diffraction (XRD) and scanning electron microscopy (SEM). The dissolution rate of VA-T was significantly improved by solid dispersion compared to that of the pure drug and physical mixture. The results of DSC and XRD indicated that the VA-T solid dispersion was amorphous. The IR spectra showed the possible interaction between VA-T and PVP was the formulation of hydrogen bonding. The SEM analysis demonstrated that there was no VA-T crystal observed in the solid dispersions. The ideal drug-to-PVP ratio was 1:5. In conclusion, the solid dispersion technique can be successfully used for the improvement of the dissolution profile of VA-T. PMID- 26614462 TI - Elucidation of the fragmentation pathways of a complex 3,7-O-glycosyl flavonol by CID, HCD, and PQD on an LTQ-Orbitrap Velos Pro hybrid mass spectrometer. AB - The present study was designed to systematically investigate the ESI-MS(n) behavior of a complex 3, 7-O-glycosyl flavonol, kaempferol 3-O-alpha-L-[2,3-di-O beta-D-(6-E-p-coumaroyl)glucopyranosyl]-rhamnopyranosyl-7-O-alpha-L rhamnopyranoside (KO) isolated from Epimedium wushanense, and to address the elimination priority among different glycosylation sites and different sugars/substituents. The direct-infusion ESI-MS(n) experiment of KO was performed on a hybrid LTQ-Orbitrap Velos Pro mass spectrometer in both negative and positive ion modes by three different fragmentation mechanisms (CID, HCD, and PQD). The CID, HCD, and PQD analyses of KO exhibited remarkable discrimination in respect of the scan range, richness, and distribution of product ions through the entire spectra. KO experienced different fragmentation pathways between two ionization modes: the negative mode CID of KO eliminated the glycosyl portions (priority: 7-sugar > 3-substituent and terminal substituents > inner sugar) and produced aglycone product ions at m/z 284.03/285.04; however, abundant sodium adduct B(3)2 together with subsequent (i,j)X(3)0 cleavages were found characteristic for the positive mode CID-MS(n). The fragmentation pathways by CID for KO were proposed by analyzing the high accuracy ESI-MS(n) data. Complementary structural information of KO regarding the aglycone and glycosyl portions was obtained by analyzing the ESI-MS(n) data in both ionization modes. In conclusion, the LTQ-Orbitrap method facilitates highly reliable qualitative analysis of bioactive flavonoids with three alternative fragmentation modes. PMID- 26614463 TI - Simultaneous quantification of ten constituents of Xanthoceras sorbifolia Bunge using UHPLC-MS methods and evaluation of their radical scavenging, DNA scission protective, and alpha-glucosidase inhibitory activities. AB - The present study was designed to investigate the bioactive constituents of Xanthoceras sorbifolia in terms of amounts and their antioxidant, DNA scission protection, and alpha-glucosidase inhibitory activities. Simultaneous quantification of 10 X. sorbifolia constituents was carried out by a newly established ultra-high performance liquid chromatography-quadrupole mass spectrometry method (UHPLC-MS). The antioxidant activities were evaluated by measuring DPPH radical scavenging and DNA scission protective activities. The alpha-glucosidase inhibitory activities were investigated by using an assay with alpha-glucosidase from Bacillus Stearothermophilus and disaccharidases from mouse intestine. We found that the wood of X. sorbifolia was rich in phenolic compounds with the contents of catechin, epicatechin, myricetin, and dihydromyricetin being 0.12-0.19, 1.94-2.16, 0.77-0.91, and 6.76-7.89 mg.g(-1), respectively. The four constituents strongly scavenged DPPH radicals (with EC50 being 4.2, 3.8 and 5.7 MUg.mL(-1), respectively) and remarkably protected peroxyl radical-induced DNA strand scission (92.10%, 94.66%, 75.44% and 89.95% of protection, respectively, at a concentration of 10 MUmol.L(-1)). A dimeric flavan 3-ol, epigallocatechin (4beta->8, 2beta->O-7)-epicatechin potently inhibited alpha-glucosidase with an IC50 value being as low as 1.2 MUg.mL(-1). The established UHPLC-MS method could serve as a quality control tool for X. sorbifolia. In conclusion, the high contents of antioxidant and alpha-glucosidase inhibitory constituents in X. sorbifolia support its use as complementation of other therapeutic agents for metabolic disorders, such as diabetes and hypertension. PMID- 26614464 TI - The Impact of Interpersonal Style on Ruptures and Repairs in the Therapeutic Alliance Between Offenders and Therapists in Sex Offender Treatment. AB - The therapeutic relationship is a critical component of psychological treatment. Strain can occur in the relationship, particularly when working with offenders, and more specifically, those offenders with interpersonal difficulties; strain can lead to a rupture, which may affect treatment participation and performance. This study examined ruptures in the therapeutic relationship in sexual offenders participating in offense-focused group treatment. Fifty-four sex offenders rated the therapeutic alliance at the commencement and completion of treatment; at the completion of treatment, they also reported on the occurrence of ruptures and whether they believed these ruptures were repaired. Ruptures were separated by type, according to severity-Each relationship was therefore characterized as experiencing no rupture, a minor rupture, or a major rupture. Offender characteristics including interpersonal style (IPS) and psychopathy were assessed at the commencement of treatment; their relationship with ruptures was examined. Results revealed that more than half of the offenders (approximately 55%) experienced a rupture in the therapeutic alliance, with one in four of these ruptures remaining unresolved. Offenders who did not report a rupture rated the therapeutic alliance significantly higher at the end of treatment compared with those offenders who reported a rupture that was not repaired. Offenders who reported a major rupture in the therapeutic relationship were higher in interpersonal hostility and hostile-dominance. No interpersonal or offense specific factors affected the likelihood of a rupture repair. PMID- 26614465 TI - Clinically Relevant Anatomy and Biomechanics of the Proximal Biceps. AB - The biceps-labral complex represents the shared anatomic and clinical features of the biceps and labrum. It has 3 clinically relevant zones: inside, the superior labrum and the biceps anchor; junction, the intra-articular portion of the long head of the biceps tendon and its stabilizing pulley; and bicipital tunnel, the extra-articular long head of the biceps tendon from the articular margin through the subpectoral region and its fibro-osseous confinement. By embracing this more comprehensive understanding of the anatomy, pathoanatomy, and functional implications, clinicians can proceed with greater confidence and can more accurately select patient-specific surgical techniques. PMID- 26614466 TI - Injuries to the Biceps Pulley. AB - The biceps reflection pulley is a soft tissue sling that stabilizes the long head of the biceps tendon (LHB) before it enters the bicipital groove. Injuries to the biceps pulley and related instability of the LHB are common diagnoses in patients with anterior shoulder pain. This article summarizes the current concepts for treatment of injuries to the biceps pulley. Clinical and radiological presentation, arthroscopic assessment, and current treatment options are outlined. PMID- 26614467 TI - Examination of the Biceps Tendon. AB - The examination of the shoulder for conditions involving the biceps tendon continues to be challenging. Numerous examination tests for biceps and superior labrum anterior and posterior (SLAP) lesions have been scientifically evaluated. This section reports on how to perform these tests and summarizes the clinical utility of the tests. Many of the tests for the examination of the biceps and for SLAP lesions do not have high sensitivity and specificity, which limits their usefulness. Although the dynamic shear test has promise for making the diagnosis of SLAP lesions, the studies reporting its clinical utility are disparate. PMID- 26614468 TI - How Accurate Are We in Detecting Biceps Tendinopathy? AB - Biceps tendon pain is frequently called biceps "tendinitis," or inflammation of the biceps tendon. Histologic analysis of biceps tendon biopsies demonstrates changes in tenocyte size, ground substance, collagen organization, and vascularity observed with many different tendinopathies. There are distinct symptoms of biceps tendinopathy and a few provocative maneuvers can help make the diagnosis. Imaging studies (eg, MRI) can show changes in signal sequence or tears. However, MRI has a low sensitivity and frequently results in missed or misdiagnosed biceps pathology. Clinical decision making is best guided by a strong clinical suspicion based on patient history, physical examination, and MRI. PMID- 26614469 TI - Nonoperative Management (Including Ultrasound-Guided Injections) of Proximal Biceps Disorders. AB - Nonoperative management of conditions of the long head of biceps tendon (LHBT) involves a multifaceted approach, addressing the entire shoulder complex in addition to conditions that involve the LHBT. LHBT pathologic conditions are divided into 3 categories: inflammation, instability and rupture. This article provides an overview of a nonoperative treatment algorithm that addresses these specific categories and includes a review of ultrasound-guided injection techniques used in the diagnosis and management of LHBT disorders. PMID- 26614470 TI - The Painful Long Head of the Biceps Brachii: Nonoperative Treatment Approaches. AB - The long head of the biceps has garnered increased attention and interest due to the high prevalence of pain that can be a primary condition or occur secondary to shoulder dysfunction. The successful treatment of biceps tendinopathy is dependent on an accurate diagnosis and recognizing all causative factors. The treatment program will be individualized with a rehabilitation program designed to restore strength and flexibility and restore normal tendon mechanics. PMID- 26614471 TI - Biceps Tenotomy Versus Tenodesis. AB - Long head biceps tendon is a common cause of anterior shoulder pain. Failure of conservative treatment may warrant surgical intervention. Surgical treatment involves long head biceps tenotomy or tenodesis. Several different techniques have been described for biceps tenodesis, including arthroscopic versus open and suprapectoral versus subpectoral. Most studies comparing tenodesis to tenotomy are limited by the level of evidence and confounding factors, such as concomitant rotator cuff tear. Many studies demonstrate similar outcomes for both procedures. Surgeon preference is likely more influential in choosing between tenotomy and tenodesis. Higher-powered studies are necessary to elucidate any differences in outcomes if present. PMID- 26614472 TI - Arthroscopic Surgical Techniques for the Management of Proximal Biceps Injuries. AB - Current arthroscopic surgical techniques for the management of proximal biceps tendon disorders encompass 3 commonly advocated procedures: proximal biceps anchor reattachment (superior labrum anterior to posterior or SLAP repair), biceps tenotomy, and arthroscopic biceps tenodesis. The indications for each procedure vary based on injury pattern, symptomatic presentation, concomitant pathologic abnormality, and most notably, patient factors, such as age, functional demand, and specific sport or activity participation. Outcomes after SLAP repair are generally favorable, although recent studies have found biceps tenodesis to be the preferred treatment for certain patient populations. PMID- 26614473 TI - Open Subpectoral Tenodesis of the Proximal Biceps. AB - This article summarizes both the various techniques for an open subpectoral biceps tenodesis as well as the biomechanics associated with these procedures. It provides information regarding the indications and contraindications to support the surgeon's decision. Furthermore, a postoperative protocol as well as an outcome overview is presented to address postoperative care. A short summary of the recent literature regarding potential complications is included to provide further insight on this technique. The open subpectoral tenodesis of the long head of the biceps is a safe and reproducible technique with a low complication rate for patients with pathologies of the proximal biceps. PMID- 26614474 TI - Proximal Biceps Tendon and Rotator Cuff Tears. AB - The long head of biceps tendon (LHBT) is frequently involved in rotator cuff tears and can cause anterior shoulder pain. Tendon hypertrophy, hourglass contracture, delamination, tears, and tendon instability in the bicipital groove are common macroscopic pathologic findings affecting the LHBT in the presence of rotator cuff tears. Failure to address LHBT disorders in the setting of rotator cuff tear can result in persistent shoulder pain and poor satisfaction after rotator cuff repair. Tenotomy or tenodesis of the LHBT are effective options for relieving pain arising from the LHBT in the setting of reparable and selected irreparable rotator cuff tears. PMID- 26614475 TI - Proximal Biceps in Overhead Athletes. AB - The proximal long head of the biceps tendon and its attachment at the superior glenoid tubercle and labrum are subject to a spectrum of disorders in overhead athletes. Biceps disorders are commonly characterized by intermittent anterior or deep-seated shoulder pain exacerbated by activity. Diagnosis is reached via various physical examination maneuvers; MRI can be uncertain. Nonsteroidal anti inflammatory medications, targeted ultrasound-guided corticosteroid injections, and supervised physical therapy are the mainstays of nonoperative treatment. Operative treatment, which remains controversial, provides reliable pain relief, restoration of function for activities of daily living, and low complication rates, but return to play can be unpredictable. PMID- 26614476 TI - Complications of Proximal Biceps Tenotomy and Tenodesis. AB - The long head of biceps tendon (LHBT) is a well-recognized cause of anterior shoulder pain. Tenotomy or tenodesis of the LHBT is an effective surgical solution for relieving pain arising from the LHBT. Cosmetic deformity of the arm, cramping or soreness in the biceps muscle, and strength deficits in elbow flexion and supination are the three most common adverse events associated with tenotomy of the LHBT. Complications associated with tenodesis of the LHBT include loss of fixation resulting in cosmetic deformity, residual groove pain, pain or soreness in the biceps muscle, infection, stiffness, hematoma, neurologic injury, vascular injury, proximal humerus fracture, and reflex sympathetic dystrophy. PMID- 26614478 TI - The Proximal Biceps Tendon. PMID- 26614479 TI - What is left of adaptive servo-ventilation after the results of the SERVE-HF study? PMID- 26614480 TI - Torsion of the gallbladder, localized in right subphrenic space in a patient with liver cirrhosis. AB - We report a case of torsion of the gallbladder displaced under the right subphrenic space in a patient with liver cirrhosis. An 82-year-old Japanese woman was admitted to our hospital for acute pain in the right upper quadrant. Clinical features suggested gallbladder torsion. She was under treatment for hepatitis C virus-related cirrhosis at our hospital. Abdominal CT showed the swollen fundus and body of the gallbladder under the right subphrenic space. Emergency laparoscopic cholecystectomy was performed. Intraoperative findings included a grossly necrotic gallbladder in the right subphrenic space with 360 degrees clockwise torsion, together with liver cirrhosis and localized peritonitis. The clinical features and imaging findings in this rare case of misplaced gallbladder in right subphrenic space resembled those described in typical strangulated gallbladder. The displacement was probably related to right liver lobe atrophy associated with liver cirrhosis. Appropriate diagnosis and prompt surgical treatment are essential for a positive outcome. PMID- 26614481 TI - Impact of certolizumab pegol on patient-reported outcomes in rheumatoid arthritis and correlation with clinical measures of disease activity. AB - INTRODUCTION: The effect of certolizumab pegol (CZP) on patient-reported outcomes (PROs) was investigated in 1063 patients with rheumatoid arthritis (RA) from the REALISTIC trial (double-blind, placebo-controlled to week 12, open-label to week 28; randomized 4:1 [CZP:placebo]). Correlations between PROs and RA signs and symptoms, and the relative efficacy of these measures, were examined. METHODS: Adults with RA and an inadequate response to at least one disease-modifying antirheumatic drug were enrolled. PROs assessed included physical function (using the Health Assessment Questionnaire-Disability Index), pain, fatigue, sleep disturbance, Patient Global Assessment of Disease Activity (PtGA), Routine Assessment of Patient Index Data 3 (RAPID3), and Rheumatoid Arthritis Disease Activity Index (RADAI). RESULTS: Early significant and clinically meaningful improvements in all PROs were observed to week 12 with CZP vs. placebo and were maintained to the end of the trial (week 28). At week 12, up to one-third more CZP patients showed improvements compared with placebo that were greater than or equal to the minimal clinically important difference (MCID) in fatigue, sleep problems, pain, PtGA, RADAI, and RAPID3. The changes in PROs were correlated with clinical measures of disease activity, including the Disease Activity Score in 28 joints using C-reactive protein as well as tender and swollen joint counts. CONCLUSIONS: Rapid improvements in PROs were seen in patients with RA treated with CZP. The magnitude of improvement exceeded the MCID in multiple domains and demonstrated that CZP improves aspects of health-related quality of life that are meaningful to patients and superior to placebo. PROs provide information complementary to clinical outcomes in assessment of treatment benefits. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00717236 . Registered on 15 July 2008. PMID- 26614482 TI - The effect of bisphosphonate treatment on the biochemical and cellular events during bone remodelling in response to microinjury stimulation. AB - Osteoporosis is one of the most prevalent bone diseases worldwide and is characterised by high levels of bone turnover, a marked loss in bone mass and accumulation of microdamage, which leads to an increased fracture incidence that places a huge burden on global health care systems. Bisphosphonates have been used to treat osteoporosis and have shown great success in conserving bone mass and reducing fracture incidence. In spite of the existing knowledge of the in vivo responses of bone to bisphosphonates, the cellular responses to these drugs have yet to be fully elucidated. In vitro model systems that allow the decoupling of complex highly integrated events, such as bone remodelling, provide a tool whereby these biological processes may be studied in a more simplified context. This study firstly utilised an in vitro model system of bone remodelling and comprising all three major cell types of the bone (osteocytes, osteoclasts and osteoblasts), which was representative of the bone's capacity to sense microdamage and subsequently initiate a basic multicellular unit response. Secondly, this system was used to study the effect of two commonly utilised aminobisphosphonate treatments for osteoporosis, alendronate and zoledronate. We demonstrated that microinjury to osteocyte networks being treated with bisphosphonates modulates receptor activator of nuclear factor kappa-B ligand and osteoprotegerin activity, and subsequently osteoclastogenesis. Furthermore, bisphosphonates increased the osteogenic potential following microinjury. Thus, we have shown for the first time that bisphosphonates act at all three stages of bone remodelling, from microinjury to osteoclastogenesis and ultimately osteogenesis. PMID- 26614483 TI - In situ vascular regeneration using substance P-immobilised poly(L-lactide-co epsilon-caprolactone) scaffolds: stem cell recruitment, angiogenesis, and tissue regeneration. AB - In situ tissue regeneration holds great promise for regenerative medicine and tissue engineering applications. However, to achieve control over long-term and localised presence of biomolecules, certain barriers must be overcome. The aim of this study was to develop electrospun scaffolds for the fabrication of artificial vascular grafts that can be remodelled within a host by endogenous cell recruitment. We fabricated scaffolds by mixing appropriate proportions of linear poly (l-lactide-co-epsilon-caprolactone) (PLCL) and substance P (SP)-immobilised PLCL, using electrospinning to develop vascular grafts. Substance P was released in a sustained fashion from electrospun membranes for up to 30 d, as revealed by enzyme-linked immunosorbent assay. Immobilised SP remained bioactive and recruited human bone marrow-derived mesenchymal stem cells (hMSCs) in an in vitro Trans-well migration assay. The biocompatibility and biological performance of the scaffolds were evaluated by in vivo experiments involving subcutaneous scaffold implantations in Sprague-Dawley rats for up to 28 d followed by histological and immunohistochemical studies. Histological analysis revealed a greater extent of accumulative host cell infiltration and collagen deposition in scaffolds containing higher contents of SP than observed in the control group at both time points. We also observed the presence of a large number of laminin positive blood vessels and Von Willebrand factor (vWF+) cells in the explants containing SP. Additionally, scaffolds containing SP showed the existence of CD90+ and CD105+ MSCs. Collectively, these findings suggest that the methodology presented here may have broad applications in regenerative medicine, and the novel scaffolding materials can be used for in situ tissue regeneration of soft tissues. PMID- 26614484 TI - Metaflammatory responses during obesity: Pathomechanism and treatment. AB - Obesity induced inflammation acts as a reflex produced due to altered metabolic homeostasis in accordance to the nutrient overload on the metabolic cells. It involves up-regulation of the genes encoding for cytokines, chemokines and other inflammatory mediators through activated transcription factors - nuclear factor kB, activator protein-1, nuclear factor of activated T cells and signal transducer and activator of transcription 3. These execute macromolecular innate immune cell sensor - inflammasome to activate caspase-1 pathway resulting in proteolytic maturation. Secretion of pro-inflammatory cytokines including TNF alpha, IL-6, CRP, IL-1beta, etc. from the M1 macrophages of white adipose tissue is increased, whereas there occurs a steep decline in the production of anti inflammatory cytokines like IL-10, IL-Ra, adiponectin. Not only the adipose tissue, but also the immune cells, liver, brain, muscles and pancreas suffers from the inflammatory insult during obese condition and are exaggeratedly affected. The inflammatory kinases like JNK and IKK apart from inhibiting insulin action and glucose uptake, down-regulate transcriptional process resulting in increased expression of pro-inflammatory cytokines. Macrophage-like Kupffer cells initiate the inflammatory process in the liver preceding the inflammatory signals produced by the white adipose tissue which may further lead to hepatic-necro inflammation. The muscle-fibre is affected by the cytokines and therefore results in decreased glycogen synthesis. The triggered hypothalamic-pituitary-adrenal axis further affects the expression of inflammatory cytokines thus altering insulin homeostasis and initiating glucose intolerance. Anti-inflammatory treatment so as to curb the severity of inflammatory responses includes administration of synthetic drugs to target the actual inflammatory molecules and various therapeutic interventions. PMID- 26614485 TI - Stony-Hard Subcutaneous Mass on the Arm of a Young Woman. PMID- 26614486 TI - Methotrexate in Moderate to Severe Psoriasis: Review of the Literature and Expert Recommendations. AB - Methotrexate (MTX) is the most frequently used conventional systemic drug in the treatment of psoriasis. Despite over 50years of experience in this setting, certain aspects of the use of this drug in clinical practice are still little standardized and poorly understood. For this reason, a group of 15 experts took part in a consensus development conference to achieve consensus on a series of recommendations on the use of MTX in psoriasis. The guidelines, which were developed on the basis of a systematic review of the literature, were validated by 2 rounds of voting and categorized by level of evidence and grade of recommendation. Before MTX can be used to treat moderate to severe psoriasis, the patient must be evaluated to assess the suitability of the treatment, including consideration of vaccination status and screening for tuberculosis and pregnancy. The recommended starting dose for a patient with no risk factors is 10 to 20mg/wk, the therapeutic dose for most patients is 15mg/wk, and the maximum dose is 20mg/wk. Most patients who respond to treatment will show improvement within 8weeks. Parenteral administration of MTX is desirable when there is a risk of erroroneous dosing, nonadherence, gastrointestinal intolerance, or inadequate response to the therapeutic dose taken orally. Noninvasive methods are preferred for monitoring hepatotoxicity. MTX is a good treatment option for patients with a history of cancer, but is not recommended in patients with chronic hepatitisB infection or individuals who are seropositive for human immunodeficiency virus. PMID- 26614487 TI - Distal Digital Keratoacanthoma in Patients With Incontinentia Pigmenti. PMID- 26614489 TI - German doctor is criticised for saying he would refuse to treat refugees. PMID- 26614488 TI - Nuclear overhauser spectroscopy of chiral CHD methylene groups. AB - Nuclear magnetic resonance spectroscopy (NMR) can provide a great deal of information about structure and dynamics of biomolecules. The quality of an NMR structure strongly depends on the number of experimental observables and on their accurate conversion into geometric restraints. When distance restraints are derived from nuclear Overhauser effect spectroscopy (NOESY), stereo-specific assignments of prochiral atoms can contribute significantly to the accuracy of NMR structures of proteins and nucleic acids. Here we introduce a series of NOESY based pulse sequences that can assist in the assignment of chiral CHD methylene protons in random fractionally deuterated proteins. Partial deuteration suppresses spin-diffusion between the two protons of CH2 groups that normally impedes the distinction of cross-relaxation networks for these two protons in NOESY spectra. Three and four-dimensional spectra allow one to distinguish cross relaxation pathways involving either of the two methylene protons so that one can obtain stereospecific assignments. In addition, the analysis provides a large number of stereospecific distance restraints. Non-uniform sampling was used to ensure optimal signal resolution in 4D spectra and reduce ambiguities of the assignments. Automatic assignment procedures were modified for efficient and accurate stereospecific assignments during automated structure calculations based on 3D spectra. The protocol was applied to calcium-loaded calbindin D9k. A large number of stereospecific assignments lead to a significant improvement of the accuracy of the structure. PMID- 26614490 TI - Increasing concentrations of phenol progressively affect anaerobic digestion of cellulose and associated microbial communities. AB - Performance stability is a key issue when managing anaerobic digesters. However it can be affected by external disturbances caused by micropollutants. In this study the influence of phenol on the methanization of cellulose was evaluated through batch toxicity assays. Special attention was given to the dynamics of microbial communities by means of automated ribosomal intergenic spacer analysis. We observed that, as phenol concentrations increased, the different steps of anaerobic cellulose digestion were unevenly and progressively affected, methanogenesis being the most sensitive: specific methanogenic activity was half inhibited at 1.40 g/L of phenol, whereas hydrolysis of cellulose and its fermentation to VFA were observed at up to 2.00 g/L. Depending on the level of phenol, microbial communities resisted either through physiological or structural adaptation. Thus, performances at 0.50 g/L were maintained in spite of the microbial community's shift. However, the communities' ability to adapt was limited and performances decreased drastically beyond 2.00 g/L of phenol. PMID- 26614491 TI - Standard and Guidelines: Intracranial Dural Arteriovenous Shunts. PMID- 26614492 TI - Safety and efficacy of a new prophylactic tirofiban protocol without oral intraoperative antiplatelet therapy for endovascular treatment of ruptured intracranial aneurysms. AB - BACKGROUND: Coil embolization of intracranial aneurysms is being increasingly used; however, thromboembolic events have become a major periprocedural complication. OBJECTIVE: To determine the safety and efficacy of prophylactic tirofiban in patients with ruptured intracranial aneurysms. METHODS: Tirofiban was administered as an intravenous bolus (8.0 MUg/kg over 3 min) followed by a maintenance infusion (0.10 MUg/kg/min) before stent deployment or after completion of single coiling. Dual oral antiplatelet therapy (loading doses) was overlapped with half the tirofiban dose 2 h before cessation of the tirofiban infusion. Cases of intracranial hemorrhage or thromboembolism were recorded. RESULTS: Tirofiban was prophylactically used in 221 patients, including 175 (79.19%) who underwent stent-assisted coiling and 46 (20.81%) who underwent single coiling, all in the setting of aneurysmal subarachnoid hemorrhage. Six (2.71%) cases of intracranial hemorrhage occurred, including four (1.81%) tirofiban-related cases and two (0.90%) antiplatelet therapy-related cases. There were two (0.90%) cases of fatal hemorrhage, one related to tirofiban and the other related to dual antiplatelet therapy. Thromboembolic events occurred in seven (3.17%) patients (6 stent-assisted embolization, 1 single coiling), of which one (0.45%) event occurred during stenting and six (2.72%) occurred during intravenous tirofiban maintenance. No thromboembolic events related to dual antiplatelet therapy were found. CONCLUSIONS: Tirofiban bolus over 3 min followed by maintenance infusion appears to be a safe and efficient prophylactic protocol for the endovascular treatment of ruptured intracranial aneurysms and may be an alternative to intraoperative oral antiplatelet therapy, especially in the case of stent-assisted embolization. PMID- 26614493 TI - Anesthetic variation and potential impact of anesthetics used during endovascular management of acute ischemic stroke. AB - BACKGROUND: Many authors have reported that general anesthesia (GA), as a generic and uncharacterized therapy, is contraindicated for patients undergoing endovascular management of acute ischemic stroke (EMAIS). The recent American Heart Association update cautiously suggests that it might be reasonable to favor conscious sedation over GA during EMAIS. We are concerned that such recommendations will result in patients undergoing endovascular treatment without consideration of the effects of specific anesthetic agents and anesthetic dose, and without appropriate critical consideration of the individual patient's issues. We hypothesized that significant variation in anesthetic practice comprises GA, and that outcome differences among types of GA would arise. METHODS: With IRB approval, we examined the records of patients who underwent anterior circulation EMAIS at the University of Pennsylvania from 2010 to 2015. Patients were managed by different anesthesiologists with no specific protocol. We analyzed American Society of Anesthesiologists status, NIH Stroke Scale, type of stroke, procedure, different types of anesthetic, blood pressure control, and outcome metrics. Modified Rankin Scale (mRS) scores were determined from medical records. RESULTS: GA was used in 91% of patients. Several types of GA were employed: intravenous, volatile, and intravenous/volatile combined. mRS scores <=2 at discharge were observed in 42.8% of patients receiving volatile anesthesia and were better in patients receiving only volatile agents after induction of anesthesia (p<0.05). CONCLUSIONS: Our data support the notion that anesthetic techniques and associated physiology used in EMAIS are not homogeneous, making any statements about the effects of generic GA in stroke ambiguous. Moreover, our data suggest that the type of GA may affect the outcome after EMAIS. PMID- 26614494 TI - Cardiac syndrome X in Ireland: incidence and phenotype. AB - BACKGROUND: Cardiac syndrome X (CSX) is typical angina pectoris with objective signs of myocardial ischaemia despite a normal coronary angiogram and may be due to microvascular dysfunction. The incidence of CSX has not been greatly investigated worldwide and its incidence in Ireland is unknown. AIMS: We aimed to determine the incidence of CSX in Cork University Hospital (CUH) and to establish the phenotype of the typical Irish CSX patient. METHODS: All patients undergoing coronary angiography in CUH during regular working hours over a 3-month period were investigated. CSX was diagnosed using standard criteria. An extended recruitment period of 14 months allowed enrolment of a sufficient number of CSX patients to enable phenotyping. RESULTS: Only 5 of 372 (1.3 %) patients undergoing angiography to investigate chest pain met the diagnostic criteria for CSX. None were given a discharge diagnosis of CSX or received cardiology follow up. Irish CSX patients were predominantly female (88 %) with a mean age of 59.2 +/- 6.6 years. Although they were significantly less functionally limited than patients with obstructive CAD, they had an equally substantial impairment in quality of life. CONCLUSIONS: CSX is relatively uncommon in Ireland and is most frequently seen in middle-aged women with hyperlipidaemia. It has significant impacts on patients' quality of life. None of the CSX patients were diagnosed as such, highlighting the lack of awareness or acceptance of this condition in Ireland. These patients require diagnosis and active cardiology follow-up to effectively manage their symptoms. PMID- 26614495 TI - Segregation in a model system for tapped wet disks in two dimensions. AB - The problem of segregation of mixtures in a column of wet disks subjected to tapping is studied through a simple model that simulates, through a pseudo dynamics algorithm, the formation of the packing and the successive tapping of it. The particles consist in a binary mixture of disks with two different sizes and the capillary forces are simulated stochastically by a sticking probability between the particles. We have recently shown that arch formation is one of the chief mechanisms determining size segregation in a non-convecting ensemble of dry disks (R.O. Unac et al., Eur. Phys. J. E 37, 117 (2014)). In the present paper, we focus on the special role that capillary bridges can have on this type of segregation process, besides the proven effect of the presence of arches. We find that humidity between grains can enhance the segregation process in a binary mixture. In particular, for the case of the segregation of an intruder, humidity can promote the rise of the big particle even in cases where the number or the size of the arches would not normally favor the climb. PMID- 26614496 TI - Non-local rheology in dense granular flows: Revisiting the concept of fluidity. AB - The aim of this article is to discuss the concepts of non-local rheology and fluidity, recently introduced to describe dense granular flows. We review and compare various approaches based on different constitutive relations and choices for the fluidity parameter, focusing on the kinetic elasto-plastic model introduced by Bocquet et al. (Phys. Rev. Lett 103, 036001 (2009)) for soft matter, and adapted for granular matter by Kamrin et al. (Phys. Rev. Lett. 108, 178301 (2012)), and the gradient expansion of the local rheology MU(I) that we have proposed (Phys. Rev. Lett. 111, 238301 (2013)). We emphasise that, to discriminate between these approaches, one has to go beyond the predictions derived from linearisation around a uniform stress profile, such as that obtained in a simple shear cell. We argue that future tests can be based on the nature of the chosen fluidity parameter, and the related boundary conditions, as well as the hypothesis made to derive the models and the dynamical mechanisms underlying their dynamics. PMID- 26614497 TI - Sliding droplets of Xanthan solutions: A joint experimental and numerical study. AB - We have investigated the sliding of droplets made of solutions of Xanthan, a stiff rodlike polysaccharide exhibiting a non-Newtonian behavior, notably characterized by a shear thinning viscosity accompanied by the emergence of normal stress difference as the polymer concentration is increased. These experimental results are quantitatively compared with those of Newtonian fluids (water). The impact of the non-Newtonian behavior on the sliding process was shown through the relation between the average dimensionless velocity (i.e. the capillary number) and the dimensionless volume forces (i.e. the Bond number). To this aim, it is needed to define operative strategies to compute the capillary number for the shear thinning fluids and compare with the corresponding Newtonian case. The resulting capillary number for the Xanthan solutions scales linearly with the Bond number at small inclinations, as well known for Newtonian fluids, while it shows a plateau as the Bond number is increased. Experimental data were complemented with lattice Boltzmann numerical simulations of sliding droplets, aimed to disentangle the specific contribution of shear thinning and elastic effects on the sliding behavior. In particular the deviation from the linear (Newtonian) trend is more likely attributed to the emergence of normal stresses inside the non-Newtonian droplet. PMID- 26614498 TI - The importance of chemical potential in the determination of water slip in nanochannels. AB - We investigate the slip properties of water confined in graphite-like nanochannels by non-equilibrium molecular dynamics simulations, with the aim of identifying and analyze separately the influence of different physical quantities on the slip length. In a system under confinement but connected to a reservoir of fluid, the chemical potential is the natural control parameter: we show that two nanochannels characterized by the same macroscopic contact angle--but a different microscopic surface potential--do not exhibit the same slip length unless the chemical potential of water in the two channels is matched. Some methodological issues related to the preparation of samples for the comparative analysis in confined geometries are also discussed. PMID- 26614499 TI - Single-dose pharmacokinetics of 2 or 3 tablets of biphasic immediate release/extended-release hydrocodone bitartrate/acetaminophen (MNK-155) under fed and fasted conditions: two randomized open-label trials. AB - BACKGROUND: Biphasic immediate-release (IR)/extended-release (ER) hydrocodone bitartrate (HB)/acetaminophen (APAP) 7.5/325-mg tablets are formulated with gastroretentive ER drug delivery technology that has been associated with clinically meaningful food effects in other approved products. Two phase 1 studies evaluated potential effects of food on single-dose pharmacokinetics of IR/ER HB/APAP tablets. METHODS: These were single-center, open-label, randomized, single-dose, 3-period crossover studies in healthy volunteers (aged 18-55 years). IR/ER HB/APAP was administered as a single 2-tablet dose (study 1) or 3-tablet dose (study 2) under fed (high- and low-fat) and fasted conditions. Area under the plasma concentration-time curve from 0 h to time t (AUC0-t) and from time 0 extrapolated to infinity (AUC0-inf) and maximum observed plasma concentration (Cmax) of hydrocodone and APAP under fed versus fasted conditions were compared using analysis of variance. A 90% confidence interval of the geometric least squares mean ratio fully contained within 80 to 125 % indicated no treatment difference. Safety and tolerability were assessed. RESULTS: Forty of 48 participants in study 1 and 21 of 30 in study 2 completed all treatments. In both studies, under fed (high- or low-fat meal) versus fasted conditions, 90% CIs for AUC0-t and AUC0-inf for both hydrocodone and APAP were entirely contained within the bioequivalent range (80-125%), indicating that high- and low-fat meals did not affect the extent of exposure. In both studies, a high-fat meal did not affect the Cmax for hydrocodone. Hydrocodone Cmax was not affected by a low-fat meal in study 1 but increased by approximately 19% in study 2. A high-fat meal decreased APAP Cmax by approximately 20 % (study 1) and 13 % (study 2); a low-fat meal decreased APAP Cmax by 22% (study 1) and 21% (study 2). Approximately 50% of participants in both studies reported >=1 treatment-emergent adverse event (TEAE), with no notable difference based on food intake. There were no serious or severe AEs. The most common TEAEs were nausea, vomiting, and dizziness. CONCLUSIONS: Pharmacokinetic and safety findings were similar regardless of food intake. TEAEs were consistent with those reported with low-dose combination opioids. IR/ER HB/APAP can be administered without regard to food. TRIAL REGISTRATION: ClinicalTrials.gov NCT02561650 and NCT02561741 . PMID- 26614500 TI - Effects of heat stress on respiratory burst, oxidative damage and SERPINH1 (HSP47) mRNA expression in rainbow trout Oncorhynchus mykiss. AB - For rainbow trout Oncorhynchus mykiss, high temperature is a major abiotic stress that limits its growth and productivity. In this study, spleen macrophage respiratory burst (RB), serum superoxide dismutase (SOD), serum malondialdehyde (MDA) and mRNA expression of the SERPINH1 (HSP47) gene in different tissues (liver, spleen, head kidney and heart) were measured in unstressed (18 degrees C) and heat-stressed (25 degrees C) fish. Spleen macrophage RB activity, serum SOD activity and MDA content all increased significantly (P < 0.05) during heat shock, and peaked at 8, 12 and 4 h, respectively. SERPINH1 mRNA expression responded in a time- and tissue-specific manner to heat stress, which was mainly reflected in the significant up-regulation in all tissues (P < 0.05) and greater expression in the liver than the other tissues (P < 0.05). During the heat-shock recovery period, the MDA content returned to the unstressed level. These results indicate that heat shock causes cell injury, induces oxidative damage and promotes SERPINH1 mRNA expression, which plays an important protective function during heat stress in O. mykiss. In practice, close attention should be given to temperature changes in O. mykiss production to reduce the effects of high temperature. PMID- 26614501 TI - Adaptive alterations on gill Na+, K+-ATPase activity and mitochondrion-rich cells of juvenile Acipenser sinensis acclimated to brackish water. AB - Understanding the physiological changes and osmoregulatory strategy is critical for anadromous species to adapt to large changes between freshwater and marine environments. In this study, juvenile Chinese sturgeon (Acipenser sinensis) were acclimated for 2 months to freshwater (FW, c. 00/00) and brackish water (BW, 150/00). Blood was assessed for changes in osmolality and ions. Gill tissue was assayed for Na(+), K(+)-ATPase (NKA) activity and immunohistochemical analysis on mitochondria-rich cells (MRCs). Serum osmolality and ions concentrations (Na(+), Cl(-) and K(+)) examined, except K(+), increased significantly in those specimens adapted to BW. However, the variations were within the range of effective hyperosmotic adaptation. The specific activity of gill NKA of juveniles adapted to BW was significantly higher (c. 1.6 times) than that of fish adapted to FW. MRCs were mainly presented in the interlamellar region of the filament and at the base of the lamella in either FW- or BW-acclimated individuals. In BW, the number and size of MRCs on filaments greatly increased. However, there was no significant difference in the number and size of the MRCs at the lamella region. Results show that juvenile Chinese sturgeon keep osmotic homeostasis in hyperosmotic environments by increasing gill NKA activity and MRCs' size and number, which is similar to other sturgeons and euryhaline teleosts. PMID- 26614502 TI - Inhibition of BMP signaling reduces MMP-2 and MMP-9 expression and obstructs wound healing in regenerating fin of teleost fish Poecilia latipinna. AB - The tail fin of teleost fish responds to amputation by expressing few putative factors that promote scar-free wound healing, which paves the way for restoration of the lost part. Among the factors playing a role in this initial response, bone morphogenetic proteins (BMPs) are crucial. In the current study, we have analyzed the effect of BMP inhibition on wound healing in sailfin molly Poecilia latipinna. The study involved histological assessment of wound epithelium formation, an expression profile of proteins, and gelatinase activity as well as expression in response to BMP signal inhibition. LDN193189, a pharmacological inhibitor of BMP receptor, was administered to experimental fish. Our observations include incomplete wound healing and a significant reduction in the expression of a number of proteins as a result of LDN treatment at 24 h post amputation. A pronounced effect was also seen on the gelatinases MMP-9 and MMP-2, which showed significantly reduced activities on a zymogram. Reduced expression of these MMPs after inhibitor treatment was also confirmed by western blot and real-time PCR analyses. In view of these results, we confirm that BMP signaling has a definitive role in the early stages of fin regeneration in P. latipinna. The effect of BMP inhibition is especially seen on the expression of MMP-9 and MMP-2, which are very important effectors of tissue remodeling immediately following amputation. PMID- 26614503 TI - Purification of Glutathione S-Transferase pi from Erythrocytes and Evaluation of the Inhibitory Effect of Hypericin. AB - Hypericin is a photosensitizer compound used in the photodynamic therapy (PDT). PDT is an alternative cancer treatment strategy whose function is dependent on the photosensitizers accumulating selectively in tumor cells and following visible or infra-red light induced activation lead to the apoptosis/necrosis of the tumor cells via the formation of reactive oxygen species. Thus, the cellular redox balance is essential for the efficacy of PDT. Among the protective enzyme systems glutathione S-transferases (GST, E.C.2.5.1.18) function in detoxification, protection against oxidative stress and intracellular transport of molecules. It is known that isoenzymes of GST and especially GST-pi is increased in cancer cells and it plays very important functions in the development of resistance to anticancer drugs. Since photosensitizers are used intravenously, it is important to elucidate the effects of photosensitizers on the erythrocyte enzymes. The aim of the present study was to investigate the impact of hypericin on human erythrocyte GST-pi (heGST-pi). Purification yield of 71% and purification fold of 2550 were achieved by using conventional chromatographic methods. The specific activity of the enzyme is found as 51 U/mg protein. Hypericin inhibited heGST-pi in a dose dependent manner and inhibition was biphasic. Noncompetitive type of inhibition was observed with both substrates, GSH and CDNB. The inhibitory constant (K i ) values obtained from Lineweaver-Burk, Dixon, secondary plots; slope and y-intercept versus 1/S (substrate) and from non-linear regression analysis were in good correlation: K i (GSH) was calculated as 0.19 +/- 0.01 MUM and K i (CDNB) as 0.26 +/- 0.03 MUM. PMID- 26614504 TI - Purification and Characterization of beta-Glucosidase from Agaricus bisporus (White Button Mushroom). AB - beta-Glucosidase (beta-D-glucoside glucohydrolase, EC 3.2.1.21) is a catalytic enzyme present in both prokaryotes and eukaryotes that selectively catalyzes either the linkage between two glycone residues or between glycone and aryl or alkyl aglycone residue. Growing edible mushrooms in the soil with increased cellulose content can lead to the production of glucose, which is a process dependent on beta-glucosidase. In this study, beta-glucosidase was isolated from Agaricus bisporus (white button mushroom) using ammonium sulfate precipitation and hydrophobic interaction chromatography, giving 10.12-fold purification. Biochemical properties of the enzyme were investigated and complete characterization was performed. The enzyme is a dimer with two subunits of approximately 46 and 62 kDa. Optimum pH for the enzyme is 4.0, while the optimum temperature is 55 degrees C. The enzyme was found to be exceptionally thermostable. The most suitable commercial substrate for this enzyme is p-NPGlu with Km and Vmax values of 1.751 mM and 833 U/mg, respectively. Enzyme was inhibited in a competitive manner by both glucose and delta-gluconolactone with IC50 values of 19.185 and 0.39 mM, respectively and Ki values of 9.402 mM and 7.2 uM, respectively. Heavy metal ions that were found to inhibit beta-glucosidase activity are I(-), Zn(2+), Fe(3+), Ag(+), and Cu(2+). This is the first study giving complete biochemical characterization of A. bisporus beta-glucosidase. PMID- 26614505 TI - Meta-analysis of local gentamicin for prophylaxis of surgical site infections in colorectal surgery. AB - PURPOSE: Surgical site infections (SSIs) following colorectal surgery is common, and local application of gentamicin for SSIs in the surgery remains controversial. OBJECTIVE: To identify whether local application of gentamicin reduces incidence of SSIs in colorectal surgery. METHODS: PubMed, Embase, the Cochrane Library, and Science Citation Index were searched for relevant randomized controlled trials (RCTs) and reference list up to November 2014. Two independent reviewers screened the records from the electronic databases, selected relevant studies, assessed the methodological quality, and extracted the data from included articles. Stata 12.0 was used to conduct a pooled analysis for main outcomes. RESULTS: Eight relevant randomized controlled trials with a total of 1685 patients were included in the meta-analysis. All included studies were of moderate to high quality by the Cochrane Collaboration's tool for assessing risk of bias. There was no significant difference being found in the total pooled results for wound infection (relative risk (RR) 0.73, 95% confidence interval (CI) 0.47 to 1.12) and organ space infection (RR 0.90, 95% CI 0.51 to 1.59). However, subgroup analysis showed that the significant decrease of wound infection was associated with the population in the Western Europe (RR 0.60, 95% CI 0.42 to 0.87) and follow-up periods of 30 days (RR 0.63, 95% CI 0.42 to 0.94). CONCLUSIONS: Local application of gentamicin significantly reduced incidence of wound infection following colorectal surgery in Western Europe, and it was also associated with lower risk of wound infection during follow-up period of 30 days. However, its effectiveness on prophylaxis of perineal wound infection and organ space infection still lacked evidence. PMID- 26614506 TI - Influence of beetroot juice supplementation on intermittent exercise performance. AB - PURPOSE: This study tested the hypothesis that nitrate (NO3-) supplementation would improve performance during high-intensity intermittent exercise featuring different work and recovery intervals. METHOD: Ten male team-sport players completed high-intensity intermittent cycling tests during separate 5-day supplementation periods with NO3 (-)-rich beetroot juice (BR; 8.2 mmol NO3- day( 1)) and NO3 (-)-depleted beetroot juice (PL; 0.08 mmol NO3- day(-1)). Subjects completed: twenty-four 6-s all-out sprints interspersed with 24 s of recovery (24 * 6-s); seven 30-s all-out sprints interspersed with 240 s of recovery (7 * 30 s); and six 60-s self-paced maximal efforts interspersed with 60 s of recovery (6 * 60-s); on days 3, 4, and 5 of supplementation, respectively. RESULT: Plasma [NO2-] was 237% greater in the BR trials. Mean power output was significantly greater with BR relative to PL in the 24 * 6-s protocol (568 +/- 136 vs. 539 +/- 136 W; P < 0.05), but not during the 7 * 30-s (558 +/- 95 vs. 562 +/- 94 W) or 6 * 60-s (374 +/- 57 vs. 375 +/- 59 W) protocols (P > 0.05). The increase in blood [lactate] across the 24 * 6-s and 7 * 30-s protocols was greater with BR (P < 0.05), but was not different in the 6 * 60-s protocol (P > 0.05). CONCLUSION: BR might be ergogenic during repeated bouts of short-duration maximal-intensity exercise interspersed with short recovery periods, but not necessarily during longer duration intervals or when a longer recovery duration is applied. These findings suggest that BR might have implications for performance enhancement during some types of intermittent exercise. PMID- 26614507 TI - Pulmonary capillary reserve and exercise capacity at high altitude in healthy humans. AB - PURPOSE: We determined whether well-acclimatized humans have a reserve to recruit pulmonary capillaries in response to exercise at high altitude. METHODS: At sea level, lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (DmCO), and pulmonary capillary blood volume (V c) were measured at rest before maximal oxygen consumption ([Formula: see text]) was determined in seven adults. Then, DLCO, DmCO and V c were measured pre- and post exhaustive incremental exercise at 5150 m after ~40 days of acclimatization. RESULTS: Immediately after exercise at high altitude, there was an increase in group mean DmCO (14 +/- 10%, P = 0.040) with no pre- to post-exercise change in group mean DLCO (46.9 +/- 5.8 vs. 50.6 +/- 9.6 ml/min/mmHg, P = 0.213) or V c (151 +/- 28 vs. 158 +/- 37 ml, P = 0.693). There was, however, a ~20% increase in DLCO from pre- to post-exercise at high altitude (51.2 +/- 0.2 vs. 61.1 +/- 0.2 ml/min/mmHg) with a concomitant increase in DmCO (123 +/- 2 vs. 156 +/- 4 ml/min/mmHg) and V c (157 +/- 3 vs. 180 +/- 8 ml) in 2 of the 7 participants. There was a significant positive relationship between the decrease in [Formula: see text] from sea level to high altitude and the change in DLCO and lung diffusing capacity for nitric oxide (DLNO) from rest to end-exercise at high altitude. CONCLUSION: These data suggest that recruitment of the pulmonary capillaries in response to exercise at high altitude is limited in most well acclimatized humans but that any such a reserve may be associated with better exercise capacity. PMID- 26614508 TI - The druggability of intracellular nucleotide-degrading enzymes. AB - Nucleotide metabolism is the target of a large number of anticancer drugs including antimetabolites and specific enzyme inhibitors. We review scientific findings that over the last 10-15 years have allowed the identification of several intracellular nucleotide-degrading enzymes as cancer drug targets, and discuss further potential therapeutic applications for Rcl, SAMHD1, MTH1 and cN II. We believe that enzymes involved in nucleotide metabolism represent potent alternatives to conventional cancer chemotherapy targets. PMID- 26614509 TI - High CYP2C19 phenotypic variability in gastrointestinal cancer patients. AB - PURPOSE: CYP2C19 contributes to the metabolism of several chemotherapeutic agents. The CYP2C19 homozygous null function genotype strongly predicts activity phenotype in healthy populations. An additional acquired loss of function has been reported in up to one-third of cancer patients. It is not known whether this phenomenon also occurs in patients with earlier stage or in resected disease. METHODS: This study investigated whether acquired loss of CYP2C19 function was detectable in patients with stage III-IV or resected gastrointestinal cancer. CYP2C19 genotype was determined in 49 patients, and subjects were probed for CYP2C19 activity on three test occasions. RESULTS: An acquired loss of CYP2C19 activity was observed in 20% of stage III-IV and 17% of resected patients at the first test. Significant (p < 0.01) genotype-phenotype discordance was observed in both groups. There were no direct associations between this discordance and inflammatory markers, tumour burden or chemotherapeutic history. Notably, hepatic CYP2C19 function was not stable over time and phenotype conversion occurred in 23 patients over the period of testing. CONCLUSION: Reliance on germ-line genotype to infer a poor metaboliser status could substantially underestimate the number of patients with deficient CYP2C19 function. This could compromise the interpretation of genotype-based clinical association studies. PMID- 26614510 TI - Phospholipase C Beta 1: a Candidate Signature Gene for Proneural Subtype High Grade Glioma. AB - Phospholipase C beta 1 (PLCbeta1) expresses in gliomas and cultured glial cells, but its expression is barely detectable in normal glial cells. We analyzed data from Gene Expression Omnibus (GEO-GDSxxx), The Cancer Genome Atlas (TCGA), and the Repository for Molecular Brain Neoplasia Data (REMBRANDT) to explore the potential role of PLCbeta1 as a biomarker in high-grade glioma (HGG). PLCbeta1 expression is significantly higher in grade III gliomas than that in grade IV gliomas from GDS1815 (n = 24 vs. 76), GDS1962 (n = 19 vs. 81), and GDS1975 (n = 26 vs. 59). In GDS1815, PLCbeta1 expression correlates with several known proneural (PN) signature genes; its expression from PN subtype (n = 15) is significantly higher than that from mesenchymal (Mes) subtype (n = 33) HGG. In GDS1962, PLCbeta1 expression is the highest in nontumor brain tissue (n = 23) and is significantly higher than its expression in grade II gliomas [astrocytomas (n = 7) and oligodendrogliomas (n = 37)]. A Kaplan-Meier survival curve from a REMBRANDT cohort demonstrates that glioma patients with intermediate PLCbeta1 expression (n = 103) survived significantly longer than PLCbeta1 downregulated (2X) groups (n = 226). From TCGA data, PLCbeta1 RNA-Seq signal inversely correlates with the pathological grades, and PLCbeta1 expression in PN (n = 8) is of significantly higher levels than that in Mes (n = 8) subtypes of glioblastoma. The top 50 % of PLCbeta1 expression subgroup (n = 294) of gliomas (grades II to IV merged) survived significantly longer than the low 50 percentile of the PLCbeta1 expression subgroup (n = 293). p values are less than 0.05 for all these analyses. We conclude that PLCbeta1 is a candidate signature gene for PN subtype HGG, and its expression inversely correlates with glioma pathological grade and is a potential prognostic factor. PMID- 26614513 TI - CT cystography for evaluation of augmented bladder perforation: be safe and know the limitations. PMID- 26614511 TI - Tetramethylpyrazine Promotes Migration of Neural Precursor Cells via Activating the Phosphatidylinositol 3-Kinase Pathway. AB - Stem cell therapy may provide a novel therapeutic method for the replacement and regeneration of damaged neural cells in the central nervous system. However, insufficient stem cell migrating into the injured regions limits its applications. Although tetramethylpyrazine (TMP) originally isolated from Ligusticum walliichi (Chuanxiong) has been widely used to treat ischemic stroke in the clinic for many years because of its role in neuroprotection, how TMP impacts the migration of neural progenitor/precursor cells (NPCs) and what is the underlying cellular and molecular mechanism remain largely unknown. Here, we found that TMP promoted NPC migration through increasing the expression and secretion of stromal cell-derived factor 1 (SDF-1), a chemokine that has been well demonstrated to direct NPC cell trafficking, in a dose-dependent fashion as analyzed by using different methods. The role of TMP in NPC migration could be inhibited by AMD 3100, a chemokine (C-X-C motif) receptor 4 (CXCR4) antagonist. Further investigation of the molecular mechanisms revealed that TMP treatment rapidly activated phosphatidylinositol 3-kinase (PI3K)/Akt, protein kinase C (PKC), and extracellular signal-regulated kinase (ERK), but not Pyk2, in NPCs. NPC migration could be blocked by using pharmacological inhibitors for these signaling pathways such as LY294002 (a PI3K inhibitor), Myr-psiPKC (a PKC inhibitor), and an ERK1/2 inhibitor. Furthermore, TMP enhanced NPC migration toward the ischemic region in the MCAO rat model. Our findings provide mechanistic insights into the role of TMP in treating the neuropathological diseases, which suggest that TMP may be used as a potent drug for improving NPC migration in stem cell-based therapy. PMID- 26614512 TI - IL-1beta Is Involved with the Generation of Pain in Experimental Autoimmune Encephalomyelitis. AB - Pain is one of the main symptoms of multiple sclerosis, a demyelinating disease of the central nervous system that affects millions of people worldwide. The experimental autoimmune encephalomyelitis (EAE) is considered an experimental model of multiple sclerosis, and besides motor weakness, hypernociception is one of the clinical signs of animals with EAE. In this study, we investigated the influence of some cytokines in the generation of the hypernociceptive response in a mouse model of EAE using MOG35-55. We measured some cytokines in the dorsal root ganglia (DRG), an important anatomical structure involved in pain. We found increased levels of the cytokines TNF-alpha, IL-1beta, and Kc in DRGs of animals with EAE. We used the antibody IL-1ra to antagonize the effects of IL-1beta, and animals presented a decrease in the hypernociceptive response. Thus, our results suggest that hypernociception in this experimental model of EAE may be a consequence of the increase in some cytokines in DRGs, especially IL-1beta. PMID- 26614514 TI - De novo assembly and characterization of the leaf, bud, and fruit transcriptome from the vulnerable tree Juglans mandshurica for the development of 20 new microsatellite markers using Illumina sequencing. AB - Manchurian walnut (Juglans mandshurica Maxim.) is a vulnerable, temperate deciduous tree valued for its wood and nut, but transcriptomic and genomic data for the species are very limited. Next generation sequencing (NGS) has made it possible to develop molecular markers for this species rapidly and efficiently. Our goal is to use transcriptome information from RNA-Seq to understand development in J. mandshurica and develop polymorphic simple sequence repeats (SSRs, microsatellites) to understand the species' population genetics. In this study, more than 47.7 million clean reads were generated using Illumina sequencing technology. De novo assembly yielded 99,869 unigenes with an average length of 747 bp. Based on sequence similarity search with known proteins, a total of 39,708 (42.32 %) genes were identified. Searching against the Kyoto Encyclopedia of Genes and Genomes Pathway database (KEGG) identified 15,903 (16.9 %) unigenes. Further, we identified and characterized 63 new transcriptome derived microsatellite markers. By testing the markers on 4 to 14 individuals from four populations, we found that 20 were polymorphic and easily amplified. The number of alleles per locus ranged from 2 to 8. The observed and expected heterozygosity per locus ranged from 0.209 to 0.813 and 0.335 to 0.842, respectively. These twenty microsatellite markers will be useful for studies of population genetics, diversity, and genetic structure, and they will undoubtedly benefit future breeding studies of this walnut species. Moreover, the information uncovered in this research will also serve as a useful genetic resource for understanding the transcriptome and development of J. mandshurica and other Juglans species. PMID- 26614515 TI - Temozolomide for recurrent meningiomas: a case-report with unexpected clinical and radiological response. PMID- 26614516 TI - Increased diffusion in the normal appearing white matter of brain tumor patients: is this just tumor infiltration? AB - Altered diffusion in the normal appearing white matter (NAWM) of glioma patients has been explained by tumor infiltration. The goal of the present study was to test this explanation indirectly by examining whether these alterations were also present in the contralateral NAWM of non-infiltrative tumors like meningiomas; and to search for other possible reasons for this abnormality. Twenty-seven patients with histologically verified glioma (grade II-IV), 22 meningioma patients and two groups of age- and sex-matched healthy controls underwent diffusion weighted imaging (DWI) on a 3T MR. All patients were examined before treatment. Apparent diffusion coefficient (ADC) values were calculated in the entire NAWM of the hemisphere contralateral to the tumor. ADC values of the NAWM were compared between groups with Mann-Whitney U-test and multiple linear regression. The relations of ADC in NAWM to glioma grade and to tumor volume were also investigated. ADC values of the contralateral NAWM were significantly higher in both glioma and meningioma patients compared to controls (P = 0.0006 and 0.0099, respectively). ADC value was higher in the NAWM of high grade gliomas than in low grade gliomas (P = 0.0181) and in healthy control subjects (P = 0.0003). ADC did not depend on tumor volume in any of the patient groups. Elevated ADC in the NAWM of both glioma and meningioma patients might indicate that the effect of infiltrating tumor cells is not the only reason for the alteration as it has been previously suggested. Although the role of mass effect was not proved, other mechanisms might also contribute to ADC elevation. PMID- 26614517 TI - Temozolomide therapy in patients with aggressive pituitary adenomas or carcinomas. AB - Temozolomide is effective in some patients with progressive pituitary adenoma or carcinoma. We report a survey study of Italian patients treated with Temozolomide because of aggressive pituitary adenoma or carcinoma resistant to standard therapies. Italian endocrinologists were surveyed and asked to participate into the study. A questionnaire was sent to all those who agreed and had used Temozolomide in at least one patient with pituitary tumor. Database was closed in December 2013. A literature review was also performed. Thirty-one patients were included into the analysis. Mean age at start of Temozolomide treatment was 58.3 +/- 1.9 years (+/- standard error). Six of the 31 (19.4%) Italian patients had a pituitary carcinoma. Twenty-five patients (80.6%) had disease control during Temozolomide treatment, while 6 patients (19.4%) had disease progression. Median follow-up after beginning Temozolomide was 43 months. Thirteen patients had tumor growth after stopping Temozolomide. The 2-year progression-free survival was 47.7% (95% CI 29.5-65.9%), while the 2-year disease control duration was 59.1% (95% CI 39.1-79.1%). Eleven patients died of progressive disease and other two patients of unrelated causes. The 2-year and 4-year overall survival rates were 83.9% (95% CI 70.7-97.1%) and 59.6% (95% CI 40.0-79.2%), respectively. Temozolomide is an additional effective therapeutic option for the treatment of aggressive pituitary tumors. The drug is well tolerated and causes few severe adverse effects. Recurrence of the tumor can occur after an initial positive response and usually portends a grim outcome. PMID- 26614518 TI - Progression-free and overall survival in patients with recurrent Glioblastoma multiforme treated with last-line bevacizumab versus bevacizumab/lomustine. AB - Bevacizumab (BEV) is widely used for treatment of patients with recurrent glioblastoma multiforme (GBM). 1-(2-Chlorethyl)-cyclohexyl-nitrosourea (CCNU, lomustine) monotherapy is an approved chemotherapeutical option for recurrent GBM. Recent evidence demonstrated a survival benefit of combined treatment with BEV and CCNU in patients with a first recurrence of GBM. We examined the outcome of recurrent GBM patients with BEV monotherapy versus BEV/CCNU therapy when used as last-line therapy. 35 patients with recurrent GBM treated between 2010 and 2014 were included in this retrospective study. Progression-free and overall survival was determined with reference to the beginning of BEV or BEV/CCNU therapy and initial diagnosis. 17 patients received BEV monotherapy, 18 patients received combined BEV and CCNU therapy. The impact of parameters such as IDH mutation, MGMT promoter methylation, tumor localization, histology and the number of surgeries were included in a multivariate ANOVA analysis. Furthermore, Karnofsky performance score (KPS), neurological function and toxicity were assessed. BEV/CCNU treatment led to an extension of PFS (6.11 months; 95% CL 3.41 12.98 months; log-rank p = 0.00241) and OS (6.59 months; 95% CL 5.51-16.3 months; log-rank p = 0.0238) of 2 months compared to BEV monotherapy. This survival advantage was independent of histology, IDH mutation status or the number of previous surgeries. Neurological function, KPS and toxicity were not significantly different between both treatment groups. Last-line therapy with BEV/CCNU results in a longer PFS and OS compared to BEV monotherapy and is well tolerated. These findings confirm the role of these agents in the treatment of recurrent GBM and are in line with other studies. PMID- 26614519 TI - Using concept mapping to evaluate knowledge structure in problem-based learning. AB - BACKGROUND: Many educational programs incorporate problem-based learning (PBL) to promote students' learning; however, the knowledge structure developed in PBL remains unclear. The aim of this study was to use concept mapping to generate an understanding of the use of PBL in the development of knowledge structures. METHODS: Using a quasi-experimental study design, we employed concept mapping to illustrate the effects of PBL by examining the patterns of concepts and differences in the knowledge structures of students taught with and without a PBL approach. Fifty-two occupational therapy undergraduates were involved in the study and were randomly divided into PBL and control groups. The PBL group was given two case scenarios for small group discussion, while the control group continued with ordinary teaching and learning. Students were asked to make concept maps after being taught about knowledge structure. A descriptive analysis of the morphology of concept maps was conducted in order to compare the integration of the students' knowledge structures, and statistical analyses were done to understand the differences between groups. RESULTS: Three categories of concept maps were identified as follows: isolated, departmental, and integrated. The students in the control group constructed more isolated maps, while the students in the PBL group tended toward integrated mapping. Concept Relationships, Hierarchy Levels, and Cross Linkages in the concept maps were significantly greater in the PBL group; however, examples of concept maps did not differ significantly between the two groups. CONCLUSIONS: The data indicated that PBL had a strong effect on the acquisition and integration of knowledge. The important properties of PBL, including situational learning, problem spaces, and small group interactions, can help students to acquire more concepts, achieve an integrated knowledge structure, and enhance clinical reasoning. PMID- 26614520 TI - Role of insertable cardiac monitors in anticoagulation therapy in patients with atrial fibrillation at high risk of bleeding. AB - AIMS: We aimed to ascertain whether an insertable cardiac monitor (ICM)-guided rhythm-control strategy and assessment of atrial fibrillation (AF) burden may allow safe withdrawal and obviate long-term use of oral anticoagulants (OACs) in AF patients at high bleeding risk. METHODS AND RESULTS: We implanted ICMs in 70 patients with AF with high risk of stroke (CHADS2 >=2, CHA2DS2-VASc score >=2) and bleeding (HAS-BLED score >=3) after restoration of normal sinus rhythm (NSR) for continuous rhythm monitoring and optimization of antiarrhythmic drugs (AADs) when necessary. Patients were categorized into: (i) Group A (NSR/low AF burden, <1%), (ii) Group B (moderate/variable AF burden), and (iii) Group C (high AF burden, always AF). At patients' insistence, OACs were discontinued after proper counselling only if they maintained NSR/low AF burden for >=3 consecutive months. All patients (age 73.3 +/- 11.7 years; 53% male) were followed clinically and with ICM monitoring for 23.5 +/- 10.5 months for outcomes including stroke, bleeding, death, device malfunction or infection, and AADs' adverse effects. Patients in Group A (n = 43), Group B (n = 20), and Group C (n = 7) had similar CHADS2 (2.09 +/- 0.65, 2.05 +/- 0.51, and 2.14 +/- 0.38, respectively), CHA2DS2 VASc (3.05 +/- 1.05, 2.85 +/- 0.99, and 2.42 +/- 0.53, respectively), and HAS BLED (3.02 +/- 1.01, 3.40 +/- 0.68, and 3.00 +/- 0.58, respectively) scores (P > 0.05). In 53 (76%) patients (Group A = 41 and Group B = 12) who maintained NSR/low AF burden, OACs were discontinued without adverse events. Severe bleeding occurred in 4 of 17 (24%) patients who remained on OACs. CONCLUSION: In AF patients with high bleeding risk, ICM-guided rhythm control with AADs and assessment of AF burden may allow safe discontinuation of OACs. PMID- 26614521 TI - Fluoroscopic position of the second-generation cryoballoon during ablation in the right superior pulmonary vein as a predictor of phrenic nerve injury. AB - AIMS: Phrenic nerve injury (PNI) is the most frequently observed complication during pulmonary vein isolation procedure using the second-generation cryoballoon (CB). Our objective was to analyse the correlation between the fluoroscopic position of the 28 mm CB during ablation in the right superior pulmonary vein (RSPV) and the occurrence of PNI. METHODS AND RESULTS: A total of 165 patients having undergone the large 28 mm CB ablation were retrospectively reviewed. Positioning of the CB relative to the cardiac silhouette was classified under fluoroscopic guidance in antero-posterior projection during RSPV ablation. Regarding the lower half of the balloon, CB positioning was defined as follows: (A) completely inside the cardiac shadow; (B1) <1/3 outside the cardiac shadow; and (B2) >=1/3 outside the cardiac shadow. Phrenic nerve injury occurred in 9.7% (16/165) during ablation in the RSPV. The occurrence of PNI was 0.9, 10.6, and 90.1% in positions A, B1, and B2, respectively (A vs. B1, P = 0.01; B1 vs. B2, P < 0.0001). Among other pre-procedural and procedural variables, the B2 position was the strongest independent determinant for predicting PNI at RSPV (P = 0.001, odds ratio: 119.9; 95% confidence interval: 11.6-1234.7) after multivariable analysis. CONCLUSION: The incidence of PNI at the RSPV significantly increased in case of more distal positioning of the CB relative to the cardiac shadow. This simple and straightforward intra-procedural indicator might prone the operators to attempt occluding the RPSV more proximally in order to avoid PNI. PMID- 26614522 TI - Evaluating a handwashing with soap program in Australian remote Aboriginal communities: a pre and post intervention study design. AB - BACKGROUND: The No Germs on Me (NGoM) Social Marketing Campaign to promote handwashing with soap to reduce high rates of infection among children living in remote Australian Aboriginal communities has been ongoing since 2007. Recently three new television commercials were developed as an extension of the NGoM program. This paper reports on the mass media component of this program, trialling an evaluation design informed by the Theory of Planned Behaviour (TPB). METHODS: A survey questionnaire taking an ecological approach and based on the principals and constructs of the TPB was developed. Surveys were completed in six discrete Aboriginal communities immediately before and on completion of four weeks intensive televising of the three new commercials. RESULTS: Across the six communities access in the home to a television that worked ranged from 49 to 83 % (n = 415). Seventy-seven per cent (n = 319) of participants reported having seen one or more of the new commercials. Levels of acceptability and comprehension of the content of the commercials was high (97 % n = 308). Seventy-five per cent (n = 651) of participants reported they would buy more soap, toilet paper and facial tissues if these were not so expensive in their communities. For TPB constructs demonstrated to have good internal reliability the findings were mixed and these need to be interpreted with caution due to limitations in the study design. CONCLUSIONS: Cultural, social-economic and physical barriers in remote communities make it challenging to promote adults and children wash their hands with soap and maintain clean faces such that these behaviours become habit. Low levels of access to a television in the home illustrate the extreme level of disadvantage experienced in these communities. Highlighting that social marketing programs have the potential to increase disadvantage if expensive items such as television sets are needed to gain access to information. This trial of a theory informed evaluation design allowed for new and rich information to be obtained about community members' beliefs, attitudes and intentions towards teaching and assisting children so safe hygiene behaviours become habit. Findings will support an evidence-based approach is taken to plan future NGoM program activities. PMID- 26614523 TI - Leptospira interrogans Lsa23 protein recruits plasminogen, factor H and C4BP from normal human serum and mediates C3b and C4b degradation. AB - It has been reported that pathogenic Leptospira are resistant to normal human serum (NHS) due to their ability to evade the complement immune system by interacting with factor H (FH) and C4b-binding protein (C4BP) regulators. Moreover, plasmin generation on the leptospiral surface diminishes C3b and IgG deposition, decreasing opsonophagocytosis by immune competent cells. We have previously reported that Lsa23 (LIC11360) is a multipurpose protein capable of binding purified extracellular matrix molecules, FH, C4BP and plasminogen (PLG)/plasmin in the presence of PLG activators. In this work, we provide further evidence that Lsa23 is located at the bacterial surface by using immunofluorescence microscopy. We show that Lsa23 has the ability to acquire FH, C4BP and PLG from NHS, and use these interactions to evade innate immunity. The binding with the complement regulators FH and C4BP preserves factor I (FI) activity, leading to C3b and C4b degradation products, respectively. C3b and C4b alpha-chain cleavage was also observed when Lsa23 bound to PLG generating plasmin, an effect blocked by the protease inhibitor aprotinin. Lsa23 also inhibited lytic activity by NHS mediated by both classical and alternative complement pathways. Thus, Lsa23 has the ability to block both pathways of the complement system, and may help pathogenic Leptospira to escape complement mediated clearance in human hosts. Indeed, NHS treated with Lsa23 confers a partial serum resistance phenotype to Leptospira biflexa, whereas blocking this protein with anti-Lsa23 renders pathogenic L. interrogans more susceptible to complement-mediated killing. Thus, Lsa23 is a multifunctional protein involved in many pathways, featuring C4b cleavage by plasmin, knowledge that may help in the development of preventive approaches to intervene with human complement escape by this versatile pathogen. PMID- 26614524 TI - Extensive Admixture and Selective Pressure Across the Sahel Belt. AB - Genome-wide studies of African populations have the potential to reveal powerful insights into the evolution of our species, as these diverse populations have been exposed to intense selective pressures imposed by infectious diseases, diet, and environmental factors. Within Africa, the Sahel Belt extensively overlaps the geographical center of several endemic infections such as malaria, trypanosomiasis, meningitis, and hemorrhagic fevers. We screened 2.5 million single nucleotide polymorphisms in 161 individuals from 13 Sahelian populations, which together with published data cover Western, Central, and Eastern Sahel, and include both nomadic and sedentary groups. We confirmed the role of this Belt as a main corridor for human migrations across the continent. Strong admixture was observed in both Central and Eastern Sahelian populations, with North Africans and Near Eastern/Arabians, respectively, but it was inexistent in Western Sahelian populations. Genome-wide local ancestry inference in admixed Sahelian populations revealed several candidate regions that were significantly enriched for non-autochthonous haplotypes, and many showed to be under positive selection. The DARC gene region in Arabs and Nubians was enriched for African ancestry, whereas the RAB3GAP1/LCT/MCM6 region in Oromo, the TAS2R gene family in Fulani, and the ALMS1/NAT8 in Turkana and Samburu were enriched for non-African ancestry. Signals of positive selection varied in terms of geographic amplitude. Some genomic regions were selected across the Belt, the most striking example being the malaria-related DARC gene. Others were Western-specific (oxytocin, calcium, and heart pathways), Eastern-specific (lipid pathways), or even population restricted (TAS2R genes in Fulani, which may reflect sexual selection). PMID- 26614525 TI - Low Temperature Adaptation Is Not the Opposite Process of High Temperature Adaptation in Terms of Changes in Amino Acid Composition. AB - Previous studies focused on psychrophilic adaptation generally have demonstrated that multiple mechanisms work together to increase protein flexibility and activity, as well as to decrease the thermostability of proteins. However, the relationship between high and low temperature adaptations remains unclear. To investigate this issue, we collected the available predicted whole proteome sequences of species with different optimal growth temperatures, and analyzed amino acid variations and substitutional asymmetry in pairs of homologous proteins from related species. We found that changes in amino acid composition associated with low temperature adaptation did not exhibit a coherent opposite trend when compared with changes in amino acid composition associated with high temperature adaptation. This result indicates that during their evolutionary histories the proteome-scale evolutionary patterns associated with prokaryotes exposed to low temperature environments were distinct from the proteome-scale evolutionary patterns associated with prokaryotes exposed to high temperature environments in terms of changes in amino acid composition of the proteins. PMID- 26614526 TI - Sutureless aortic valve replacement with Perceval bioprosthesis: are there predicting factors for postoperative pacemaker implantation? AB - OBJECTIVES: Aortic valve replacement (AVR) with sutureless bioprostheses has become an alternative to conventional AVR for patients with intermediate to high operative risk. However, this technique is associated with an increased risk of postoperative conduction disorders. METHODS: We analysed 258 patients who underwent AVR with the Perceval prosthesis from July 2010 to September 2014 at our centre. Electrocardiography were obtained at baseline to record preoperatively the presence of conduction disorders. Preoperative risk factors, intraoperative procedures and complications (61 variables) were compared between patients with permanent pacemaker (PPM group) and without (no-PPM group) need for postoperative PPM implantation. RESULTS: One hundred and sixty-nine patients underwent isolated AVR with the Perceval bioprosthesis, 89 patients had associated surgery and 23 patients underwent redo operations. The mean age was 77.7 +/- 5 years, 139 patients were female (46%) and the mean logistic EuroSCORE was 13.2 +/- 11%. At baseline, 8 patients had already an implanted pacemaker. Postoperatively, 27 patients (10.5%) required new PPM implantation due to complete atrioventricular block. On univariate analysis, age (PPM vs no-PPM group: 80 +/- 5 vs 77 +/- 5 years, P = 0.009) and preoperative presence of right bundle branch block (RBBB) [overall n = 20 (7.8%); PPM vs no-PPM group: 9 vs 11 (33 vs 4.8%); P < 0.001] were identified as independent predictors of postoperative conduction disorders, but only pre-existing RBBB persisted on multivariate analysis (odds ratio 11.3-C-statistic 0.74, error estimate 0.064, confidence interval 0.672-0.801; P = 0.0002). Among patients undergoing sutureless AVR, the rate of PPM implantation was high. CONCLUSIONS: The analysis of the data collected made it possible to identify preoperatively a subset of patients undergoing sutureless AVR at higher risk of postoperative atrioventricular block. Additional surgical precautions should be implemented to prevent the occurrence of conduction disorders after sutureless AVR. PMID- 26614527 TI - Residual disease at the bronchial stump is positively associated with the risk of bronchoplerual fistula in patients undergoing lung cancer surgery: a meta analysis. AB - OBJECTIVES: Residual disease at the bronchial stump (RDBS) is regarded as an important factor possibly resulting in bronchopleural fistula (BPF) after lung cancer surgery, but this has not been confirmed. We conducted this meta-analysis to evaluate the effects of RDBS on BPF formation in patients undergoing lung cancer surgery. METHODS: PubMed and EMBASE databases were searched for full-text articles that met our eligibility criteria. Odds ratios (ORs) with 95% confidence interval (95% CI) served as the summarized outcomes. Q-test and I(2) statistic were used to evaluate the level of heterogeneity, determining the fixed-effect model or random-effect model for quantitative synthesis. Sensitivity analysis was conducted to identify the possible origins of heterogeneity. The publication bias was assessed by Begg's test. RESULTS: A total of eight retrospective observational studies were included in our meta-analysis. In overall analysis, the pooled outcomes indicated that RDBS was significantly associated with BPF formation after lung cancer surgery (OR: 3.12; 95% CI: 1.72-5.64; P < 0.001). In subgroup analysis, the pooled outcomes revealed a significantly increased risk of post-pneumonectomy BPF in patients with RDBS (OR: 2.78; 95% CI: 1.06-7.28; P = 0.037). The subgroup analysis assessing the effects of RDBS on post-lobectomy BPF was given up due to the scarcity of available data. No heterogeneity was revealed within this meta-analysis. No evidence for publication bias was detected by Begg's test. CONCLUSIONS: Our meta-analysis indicates that RDBS is positively associated with the increased risk of BPF in patients undergoing lung cancer surgery. The further analysis also reveals an increased risk of post pneumonectomy BPF in patients with RDBS. More accurate and comprehensive evidence should be collected and summarized in updated meta-analyses. PMID- 26614529 TI - Efficacy of glutathione mesotherapy in burns: an experimental study. AB - BACKGROUND: Thermal burns are the leading cause of trauma worldwide. Currently, no consensus on optimal treatment of deep partial-thickness (second-degree) burns has emerged, as reflected by the wide variability in available wound-care materials. The relative efficacies of products used for treatment of partial thickness thermal burns remain unclear. Mesotherapy features intradermal administration of various agents, depending on burn location. In the present experimental study, we explored the efficacy of mesotherapy used to treat partial thickness thermal burns in 50 male Wistar rats divided into five groups of equal number. No procedure was performed after infliction of thermal burns in control group (Group 1). Mesotherapy was applied with physiological saline in sham group (Group 2), glutathione, taurine, and L-carnitine were separately applied in Group 3, Group 4, and Group 5, respectively. MATERIALS AND METHODS: Mesotherapeutic agents were injected intradermally into the reticular layer of the dermis using the point technique. The first course of mesotherapy was given within the first 2 h after infliction of thermal burns, and therapy was continued to day 10. On day 22, unhealed thermal burn areas were measured prior to sacrifice, and biopsies covering the total areas of burns were performed to allow of pathological evaluation. RESULTS: Group 3 (the glutathione group) showed the best extent of healing, followed by Group 4 (the taurine group) and Group 5 (the L-carnitine group). The healed thermal burn areas in these groups were significantly greater than those in the control and sham groups (P = 0.001). All of healing, acute and chronic inflammation, the amount of granulation tissue, the level of fibroblast maturation, the amount of collagen, the extent of re-epithelization and neovascularization, and ulcer depth were scored upon pathological examination of tissue cross-sections. The best outcomes were evident in the glutathione group, with statistical significance. Although wound healing in the L-carnitine and taurine groups was better than in the control and sham groups, the differences were not statistically significant. CONCLUSION: Thus, glutathione mesotherapy was effective when used to treat partial-thickness thermal burns and may be a useful treatment option for various human burns. PMID- 26614530 TI - Experimental Validation of ARFI Surveillance of Subcutaneous Hemorrhage (ASSH) Using Calibrated Infusions in a Tissue-Mimicking Model and Dogs. AB - Acoustic radiation force impulse (ARFI) Surveillance of Subcutaneous Hemorrhage (ASSH) has been previously demonstrated to differentiate bleeding phenotype and responses to therapy in dogs and humans, but to date, the method has lacked experimental validation. This work explores experimental validation of ASSH in a poroelastic tissue-mimic and in vivo in dogs. The experimental design exploits calibrated flow rates and infusion durations of evaporated milk in tofu or heparinized autologous blood in dogs. The validation approach enables controlled comparisons of ASSH-derived bleeding rate (BR) and time to hemostasis (TTH) metrics. In tissue-mimicking experiments, halving the calibrated flow rate yielded ASSH-derived BRs that decreased by 44% to 48%. Furthermore, for calibrated flow durations of 5.0 minutes and 7.0 minutes, average ASSH-derived TTH was 5.2 minutes and 7.0 minutes, respectively, with ASSH predicting the correct TTH in 78% of trials. In dogs undergoing calibrated autologous blood infusion, ASSH measured a 3-minute increase in TTH, corresponding to the same increase in the calibrated flow duration. For a measured 5% decrease in autologous infusion flow rate, ASSH detected a 7% decrease in BR. These tissue mimicking and in vivo preclinical experimental validation studies suggest the ASSH BR and TTH measures reflect bleeding dynamics. PMID- 26614532 TI - What are the benefits of phenotype analyses to special education? PMID- 26614531 TI - Plasma level of metastasis-associated lung adenocarcinoma transcript 1 is associated with liver damage and predicts development of hepatocellular carcinoma. AB - Recent studies have shown that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was overexpressed in many human solid cancers, however, its roles in plasma of hepatocellular carcinoma (HCC) patients were unclear. The aim of this study was to investigate the significance of plasma MALAT1 levels in HCC patients. Plasma samples were collected from pre-operative HCC, hepatic disease patients, and healthy controls, and tissue samples from HCC patients and colorectal cancer patients with liver metastasis. Plasma and tissue MALAT1 levels were measured. Plasma MALAT1 levels were progressively and significantly higher in HCC patients than hepatic disease patients, and higher in hepatic disease patients than healthy controls. The expression of MALAT1 in HCC tissue was slightly higher than that in paired non-cancerous liver tissue, but not significant. The expression of MALAT1 in the non-cancerous liver tissue of 20 HCC patients was significantly higher than that in normal liver tissue of 13 colorectal cancer patients. In contrast, plasma MALAT1 levels were significantly low in HCC patients with hepatitis B infection, and significantly high in patients with liver damage B or liver cirrhosis. In a receiver-operator curve analysis of HCC and hepatic disease patients, the cut-off value of plasma MALAT1 was 1.60 and the area under the curve was 0.66. Plasma MALAT1 levels were not correlated with alpha-fetoprotein or protein induced by vitamin K absence II, whereas sensitivity and specificity for the detection of HCC with the combination of MALAT1, alpha-fetoprotein, and protein induced by vitamin K absence II were 88.6% and 75%, respectively. In conclusion, the plasma MALAT1 level is associated with liver damage, and has clinical utility for predicting development of HCC. PMID- 26614534 TI - Social rhythm disrupting events increase the risk of recurrence among individuals with bipolar disorder. AB - OBJECTIVES: As outlined in the social zeitgeber hypothesis, social rhythm disrupting (SRD) life events begin a cascade of social and biological rhythm disruption that may lead to the onset of affective episodes in those vulnerable to bipolar disorder. Thus, the study of SRD events is particularly important in individuals with this chronic condition. The purpose of the current study was to evaluate (i) the extent to which SRD life events increased the risk of recurrence of a bipolar mood episode, and (ii) whether the social rhythm disruption associated with the event conferred an increased risk of recurrence, after accounting for the level of threat associated with the life event. METHODS: We examined the effect of SRD events on recurrence during preventative treatment in a sample of 118 patients with bipolar disorder who achieved remission from an acute episode after receiving psychotherapy and pharmacotherapy. Life events were measured with the Bedford College Life Events and Difficulty Schedule and were rated for degree of SRD and threat. RESULTS: Time-dependent Cox proportional hazards models showed that having a higher SRD rating was significantly associated with an increased risk of recurrence, even when accounting for the threat effect of a life event and psychosocial treatment (hazard ratio = 1.33, 95% confidence interval: 1.04-1.70, p = 0.023). However, this finding fell below conventional levels of statistical significance when accounting for other covariates. CONCLUSIONS: Our findings lend partial support to the social zeitgeber hypothesis. PMID- 26614535 TI - Increased carotid intima-media thickness in rheumatoid arthritis: an update meta analysis. AB - This study aims to derive a more precise estimation on carotid intima-media thickness (CIMT) level in patients with rheumatoid arthritis (RA) and related factors. Studies published from January 1, 1982 to December 31, 2014 in English, which comparing CIMT between RA group and control group were searched in PubMed, Embase, and Cochrane Library databases. Heterogeneity test was performed, and publication bias was evaluated. Stata software 12.0 was used to perform the meta analysis. Two-thousand one hundred sixty-three articles were obtained after searching databases, and 47 studies were finally included in the meta-analysis. The result of the analysis in random effect model showed that RA group had significantly higher CIMT than control group, with the standardized mean difference (SMD) of 1.04 and 95% CI (0.81,1.27). To evaluate the stability of our results, sensitivity analyses were performed, and the results showed no significant change when any one study was excluded. Subgroup analyses showed that region, race, age, BMI, and disease duration were associated with CIMT in RA patients. In summary, CIMT in RA patients is thicker than healthy controls, and it is influenced by region, race, age, BMI, and disease duration. PMID- 26614536 TI - Individuals with incident accelerated knee osteoarthritis have greater pain than those with common knee osteoarthritis progression: data from the Osteoarthritis Initiative. AB - We evaluated whether accelerated knee osteoarthritis (AKOA) was associated with greater pain and other outcomes and if outcomes varied over time differently among those with incident AKOA or common knee osteoarthritis (KOA), which we defined as a gradual onset of disease. We conducted longitudinal analyses among participants in the Osteoarthritis Initiative who had no radiographic KOA at baseline (Kellgren-Lawrence [KL] <2). Participants were considered AKOA if >=1 knees progressed to KL grade >=3 and common KOA if >=1 knees increased in radiographic scoring within 48 months. We defined the index visit as the study visit when they met the AKOA or common KOA criteria. Our observation period included up to 3 years before and after the index visit. Our primary outcome was WOMAC pain converted to an ordinal scale: none (pain score = 0/1 out of 20), mild (pain score = 2/3), and moderate-severe pain (pain score >3). We explored 11 other secondary outcome measures. We performed an ordinal logistic regression or linear models with generalized estimating equations. The predictors were group (AKOA or common KOA), time (seven visits), and a group-by-time interaction. Overall, individuals with AKOA (n = 54) had greater pain, functional disability, and global rating scale as well as slower chair-stand and walking pace compared with those with common KOA (n = 187). There was no significant interaction between group and time for knee pain; however, there was for chair-stand pace and global rating scale. In conclusion, AKOA may be a painful and disabling phenotype that warrants more attention by clinicians and researchers. PMID- 26614537 TI - What is the impact of multidisciplinary team simulation training on team performance and efficiency of patient care? An integrative review. AB - BACKGROUND: In hospital emergencies require a structured team approach to facilitate simultaneous input into immediate resuscitation, stabilisation and prioritisation of care. Efforts to improve teamwork in the health care context include multidisciplinary simulation-based resuscitation team training, yet there is limited evidence demonstrating the value of these programmes.(1) We aimed to determine the current state of knowledge about the key components and impacts of multidisciplinary simulation-based resuscitation team training by conducting an integrative review of the literature. METHODS: A systematic search using electronic (three databases) and hand searching methods for primary research published between 1980 and 2014 was undertaken; followed by a rigorous screening and quality appraisal process. The included articles were assessed for similarities and differences; the content was grouped and synthesised to form three main categories of findings. RESULTS: Eleven primary research articles representing a variety of simulation-based resuscitation team training were included. Five studies involved trauma teams; two described resuscitation teams in the context of intensive care and operating theatres and one focused on the anaesthetic team. Simulation is an effective method to train resuscitation teams in the management of crisis scenarios and has the potential to improve team performance in the areas of communication, teamwork and leadership. CONCLUSION: Team training improves the performance of the resuscitation team in simulated emergency scenarios. However, the transferability of educational outcomes to the clinical setting needs to be more clearly demonstrated. PMID- 26614539 TI - [Big Data- challenges and risks]. AB - The term "Big Data" is commonly used to describe the growing mass of information being created recently. New conclusions can be drawn and new services can be developed by the connection, processing and analysis of these information. This affects all aspects of life, including health and medicine. The authors review the application areas of Big Data, and present examples from health and other areas. However, there are several preconditions of the effective use of the opportunities: proper infrastructure, well defined regulatory environment with particular emphasis on data protection and privacy. These issues and the current actions for solution are also presented. PMID- 26614538 TI - Involvement of Inhibitory Receptors in Modulating Dopamine Signaling and Synaptic Activity Following Acute Ethanol Exposure in Striatal Subregions. AB - BACKGROUND: Alcohol acts on both inhibitory and excitatory receptor systems resulting in a net increase in dopamine output in the ventral striatum (nucleus accumbens [nAc]), which is implicated in drug reward. However, the dorsal striatum may also be involved in reward-related behaviors. The objectives of this study were to investigate the role of inhibitory receptors in modulating the acute effects of ethanol (EtOH) on dopamine release and synaptic activity in the shell region of the nAc (nAcS) and dorsolateral striatum (DLS). METHODS: EtOH (300 mM) was administered via reversed microdialysis in the nAcS or DLS of Wistar rats following pretreatment with glycine or GABAA receptor antagonist strychnine and bicuculline, respectively. Dopamine content in dialysate samples was quantified using high-performance liquid chromatography. In addition, local field potential recordings were performed in the nAcS and DLS in slices from Wistar rats. Population spike (PS) amplitude was measured following treatment with EtOH (50 mM) in slices pretreated with strychnine or bicuculline. RESULTS: Local EtOH increased dopamine levels in both regions, an effect that strychnine pretreatment inhibited in the nAcS. EtOH-induced increases in accumbal dopamine were not blocked by a low (5 MUM) concentration of bicuculline, but were inhibited by pretreatment with higher bicuculline concentrations. None of the antagonists administered in the DLS prevented the EtOH-induced dopamine increase. Field potential recordings in the nAcS showed that acute EtOH produced an increase in PS amplitude which was blocked by both strychnine and bicuculline. In the DLS, EtOH induced a decrease in PS amplitude which was not influenced by strychnine or bicuculline. CONCLUSIONS: The current results show that changes in striatal dopamine output and synaptic activity induced by acute EtOH administration are modulated by inhibitory receptors in a subregion-specific manner. PMID- 26614540 TI - [Risk of maternal and fetal disease among women older than 40 years]. AB - A rising trend in advanced maternal age has been observed over the last few decades. Several studies have assessed the association between advanced maternal age and adverse pregnancy outcome, including miscarriage, stillbirth, pre eclampsia, gestational hypertension, gestational diabetes mellitus, preterm birth, delivery of a small- or large-for-gestational-age neonates and elective or emergency Cesarean section. These studies reported contradictory findings. The aim of the present paper is to summarize the evidence-based information regarding advanced maternal age and pregnancy outcomes. PMID- 26614541 TI - [Report of the Hungarian Vascular Registry's data of infrarenal aortic aneurysms (2010-2014)]. AB - INTRODUCTION: The Hungarian Society for Vascular Surgery decided to analyse and publish regularly the data of the Hungarian Vascular Registry. AIM: The aim of the authors was to present the outcome of infrarenal aortic aneurysm surgeries performed during the past five years. METHOD: Prospectively collected multicentric data obtained from the Hungarian Vascular Registry between January 1, 2010 and December 31, 2014 were analysed retrospectively. Statistical analysis was performed using Fisher's exact test and odds ratio calculation. RESULTS: It was found that 16.72% of the 1435 operations were performed for ruptured aneurysms. Five institutes having the highest capacity performed 78.4% of the operations. In the ruptured aortic aneurysm group the age of patients was 71.77+/ 9.82 years (mean+/-SD), and perioperative mortality was 33.75%. In the intact aortic aneurysm group the age of patients was 69.50+/-8.46 years and the perioperative mortality was 3.51%. In both groups perioperative mortality (ruptured: p<0,05, OR = 0.11; intact: p<0.05, OR = 0.26) and the length of hospital stay (ruptured: p<0.05, OR = 4.55; intact: p<0.001, OR = 4.27) were significantly lower in patients who had endovascular repair compared to those with open repair. In both groups perioperative mortality (ruptured: p<0.0001, OR = 0.32; intact: p<0.0001, OR = 0.23) and length of hospital stay (ruptured: p<0.05, OR = 3.16; intact: p<0.001, OR = 3.84) were significantly lower in the five institutes having the highest capacity than in the remaining institutes. CONCLUSIONS: In patients having endovascular repair and in institutes with high capacity the perioperative mortality and length of hospital stay were significantly lower. PMID- 26614542 TI - [Sleep quality of nurses working in shifts - Hungarian adaptation of the Bergen Shift Work Sleep Questionnaire]. AB - INTRODUCTION: Sleep disorders among shift workers are common problems due to the disturbed circadian rhythm. The Bergen Shift Work Sleep Questionnaire assesses discrete sleep problems related to work shifts (day, evening and night shifts) and rest days. AIM: The aim of the study was to develop the Hungarian version of this questionnaire and to compare the sleep quality of nurses in different work schedules. METHOD: 326 nurses working in shifts filled in the questionnaire. The authors made convergent and discriminant validation of the questionnaire with the Athens Insomnia Scale and the Perceived Stress Questionnaire. RESULTS: The questionnaire based on psychometric characteristics was suitable to assess sleep disorders associated with shift work in a Hungarian sample. The frequency of discrete symptoms significantly (p<0.001) differed with the shifts. Nurses experienced the worst sleep quality and daytime fatigue after the night shift. Nurses working in irregular shift system had worse sleep quality than nurses working in regular and flexible shift system (p<0.001). CONCLUSIONS: The sleep disorder of nurses working in shifts should be assessed with the Hungarian version of the Bergen Shift Work Sleep Questionnaire on a nationally representative sample, and the least burdensome shift system could be established. PMID- 26614543 TI - [De novo SCN1A gene deletion in therapy-resistant Dravet syndrome]. AB - Severe myoclonic epilepsy in infancy (Dravet's syndrome) is a very rare form of epilepsy. Mutations of SCN1A gene encoding voltage-gated sodium channel alpha-1 subunit are major causes of the autosomal dominant disorder. Most cases are associated with a de novo point mutation, but some patients have copy number variations. The protein encoded by the SCN1A gene plays a role in the generation and propagation of action potentials. Loss of function caused by the majority of gene mutations leads to hyperexcitability of the neuronal network that finally results in the formation of the epileptic seizures. Molecular genetic test for copy number variations of SCN1A gene is available in the department of the authors since 2013 besides sequencing analysis of the whole gene. This article presents the case of a 7-year-old patient with two years of recorded patient history outside of the author's department. Molecular genetic test, which detected a de novo SCN1A gene deletion in heterozygous form, revealed SCN1A gene associated monogenic epileptic syndrome being in the genetic background of therapy-resistant seizures. PMID- 26614546 TI - Proceedings from The 8th Annual International Society for Musculoskeletal Imaging in Rheumatology (ISEMIR) Conference. AB - The International Society for Musculoskeletal Imaging in Rheumatology (ISEMIR) was founded in 2005 with the goal of discussing matters related to imaging in rheumatology, particularly, validation, education, and use in both clinical practice and research. The field of musculoskeletal (MSK) imaging is continuously evolving; therefore, education for healthcare providers in this field is of paramount importance. ISEMIR's international faculty and world-renowned experts presented the newest information as it relates to the use of magnetic resonance imaging (MRI) and ultrasound (US) at the 8th annual ISEMIR meeting that took place on April 17-18 in Santa Monica, California. Presentations from the meeting can be viewed at www.isemir.org. PMID- 26614545 TI - Quality assessment in head and neck oncologic surgery in a Brazilian cancer center compared with MD Anderson Cancer Center benchmarks. AB - BACKGROUND: Quality assessment is a major tool for evaluation of health care delivery. In head and neck surgery, the University of Texas MD Anderson Cancer Center (MD Anderson) has defined quality standards by publishing benchmarks. METHODS: We conducted an analysis of 360 head and neck surgeries performed at the AC Camargo Cancer Center (AC Camargo). The procedures were stratified into low acuity procedures (LAPs) or high-acuity procedures (HAPs) and outcome indicators where compared to MD Anderson benchmarks. RESULTS: In the 360 cases, there were 332 LAPs (92.2%) and 28 HAPs (7.8%). Patients with any comorbid condition had a higher incidence of negative outcome indicators (p = .005). In the LAPs, we achieved the MD Anderson benchmarks in all outcome indicators. In HAPs, the rate of surgical site infection and length of hospital stay were higher than what is established by the benchmarks. CONCLUSION: Quality assessment of head and neck surgery is possible and should be disseminated, improving effectiveness in health care delivery. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: 1002-1007, 2016. PMID- 26614547 TI - Eliminating "ductal carcinoma in situ" and "lobular carcinoma in situ" (DCIS and LCIS) terminology in clinical breast practice: The cognitive psychology point of view. AB - There is evidence from the literature that the terms "ductal carcinoma in situ" and "lobular carcinoma in situ" (DCIS and LCIS) should be eliminated in clinical breast cancer practice and replaced with the new "ductal intraepithelial neoplasia" (DIN) and "lobular intraepithelial neoplasia" (LIN) terminology. The main purpose of the present article is to expand on this argument from a cognitive psychology perspective and offer suggestions for further research, emphasizing how the elimination of the term "carcinoma" in "in situ" breast cancer diagnoses has the potential to reduce both patient and health care professional confusion and misperceptions that are often associated with the DCIS and LCIS diagnoses, as well as limit the adverse psychological effects of women receiving a DCIS or LCIS diagnosis. We comment on the recent peer-reviewed literature on the clinical implications and psychological consequences for breast cancer patients receiving a DCIS or LCIS diagnosis and we use a cognitive perspective to offer new insight into the benefits of embracing the new DIN and LIN terminology. Using cognitive psychology and cognitive science in general, as a foundation, further research is advocated in order to yield data in support of changing the terminology and therefore, offer a chance to significantly improve the lives and psychological sequelae of women facing such a diagnosis. Typology: Controversies/Short Commentary. PMID- 26614548 TI - Vitamin D (25-0H D3) status and pathological response to neoadjuvant chemotherapy in stage II/III breast cancer: Data from the NEOZOTAC trial (BOOG 10-01). AB - BACKGROUND: Serum levels of 25-OH vitamin D3 (vitamin D) have been shown to be prognostic for disease-free survival in patients with breast cancer. We investigated the predictive value of these levels for pathological response after neoadjuvant chemotherapy in patients with breast cancer taking part in the NEOZOTAC phase-III trial. Additionally, the effect of chemotherapy on vitamin D levels was studied. MATERIALS AND METHODS: Serum vitamin D was measured at baseline and before the last cycle of chemotherapy. The relationship between these measurements and clinical outcome, as defined by pathological complete response in breast and lymph nodes (pCR) was examined. RESULTS: Baseline and end of treatment vitamin D data were available in 169 and 91 patients, respectively. Median baseline vitamin D values were 58.0 nmol/L. In patients treated with chemotherapy only, serum vitamin D levels decreased during neoadjuvant chemotherapy (median decrease of 16 nmol/L, P = 0.003). The prevalence of vitamin D levels < 50 nmol/L increased from 38.3% at baseline to 55.9% after chemotherapy. In the total population, baseline and end of therapy vitamin D levels were not related to pathological response. No associations were found between pCR and vitamin D level changes. CONCLUSION: The significant decrease in vitamin D post-neoadjuvant chemotherapy suggests that vitamin D levels should be monitored and in case of decrease of vitamin D levels, correction may be beneficial for skeletal health and possibly breast cancer outcome. PMID- 26614549 TI - Re: Christian Turk, Ales Petrik, Kemal Sarica, et al. EAU Guidelines on Diagnosis and Conservative Management of Urolithiasis. Eur Urol 2016;69:468-74: Magnetic Resonance Urography Can be Used to Detect Urinary Stones. PMID- 26614550 TI - Are congenital urinary tract and genital organ anomalies related to folic acid? PMID- 26614551 TI - Use of complementary and alternative medicine (CAM) by parents in their children and adolescents with epilepsy - Prevelance, predictors and parents' assessment. AB - BACKGROUND: The use of complementary and alternative medicine (CAM) is popular. Parents of children suffering from epilepsy may also consider administering CAM to their children. Systematic data about frequency of and motivations for CAM use, however, are scarce. METHODS: In a university hospital's neuropaediatric department parents of patients aged 0-18 years suffering from epilepsy were consecutively invited to take part in a structured interview during 4 months in 2014. RESULTS: Of the invited parents, 164/165 (99%) agreed to participate. From those, 21/164 (13%) stated that they used CAM in their child. The highest independent predictive value of CAM use was the occurrence of adverse drug events (ADE) of anticonvulsants as judged by parents. Patients affected by ADE had a 5.6 higher chance of receiving CAM compared to patients without ADE. Most commonly used were homeopathy (14/21, 67%) and osteopathy (12/21, 57%). The internet was the most frequently used source of information (14/21, 67%). Of the parents, 10/21 (48%) described positive effects of CAM on seizure frequency, 12/21 (57%) on general condition of their child, and 20/21 (95%) wished to continue CAM for epilepsy therapy. From the non-users of CAM, 91/143 (66%) expressed the desire to learn more about CAM for epilepsy therapy. LIMITATIONS: Our study was performed in a university hospital in a large urban city in Eastern Germany. CAM user rates can differ in other parts of Germany and Europe, in other institutions and for chronic diseases other than epilepsy. CONCLUSION: The main reason for CAM use was the occurrence of ADE of anticonvulsants. More than half of the parents saw a benefit of CAM for their children. Almost all parents wished to continue CAM use, even those who did not see concrete positive effects. PMID- 26614552 TI - Two types of psychological hedonism. AB - I develop a distinction between two types of psychological hedonism. Inferential hedonism (or "I-hedonism") holds that each person only has ultimate desires regarding his or her own hedonic states (pleasure and pain). Reinforcement hedonism (or "R-hedonism") holds that each person's ultimate desires, whatever their contents are, are differentially reinforced in that person's cognitive system only by virtue of their association with hedonic states. I'll argue that accepting R-hedonism and rejecting I-hedonism provides a conciliatory position on the traditional altruism debate, and that it coheres well with the neuroscientist Anthony Dickinson's theory about the evolutionary function of hedonic states, the "hedonic interface theory." Finally, I'll defend R-hedonism from potential objections. PMID- 26614553 TI - A life full of life-science polymer research. PMID- 26614554 TI - Drug delivery's quest for polymers: Where are the frontiers? AB - Since the legendary 1964 article of Folkman and Long entitled "The use of silicone rubber as a carrier for prolonged drug therapy" the role of polymers in controlled drug delivery has come a long way. Today it is evident that polymers play a crucial if not the prime role in this field. The latest boost owes to the interest in drug delivery for the purpose of tissue engineering in regenerative medicine. The focus of this commentary is on a selection of general and personal observations that are characteristic for the current state of polymer therapeutics and carriers. It briefly highlights selected examples for the long march of synthetic polymer-drug conjugates from bench to bedside, comments on the ambivalence of selected polymers as inert excipients versus biological response modifiers, and on the yet unsolved dilemma of cationic polymers for the delivery of nucleic acid therapeutics. Further subjects are the complex design of multifunctional polymeric carriers including recent concepts towards functional supramolecular polymers, as well as observations on stimuli-sensitive polymers and the currently ongoing trend towards natural and naturally-derived biopolymers. The final topic is the discovery and early development of a novel type of biodegradable polyesters for parenteral use. Altogether, it is not the basic and applied research in polymer therapeutics and carriers, but the translational process that is the key hurdle to proceed towards an authoritative approval of new polymer therapeutics and carriers. PMID- 26614555 TI - Novel biodegradable polymers for local growth factor delivery. AB - Growth factors represent an important therapeutic protein drug class, and would benefit significantly from formulations that provide sustained, local release to realize their full clinical potential. Biodegradable polymer-based delivery platforms have been examined to achieve this end; however, formulations based on conventional polymers have yet to yield a clinical product. This review examines new polymer biomaterials that have been developed for growth factor delivery. The dosage forms are discussed in terms of their mechanism of release, the stability of the released growth factor, their method of preparation, and their potential for clinical translation. PMID- 26614556 TI - Thermoresponsive hydrogels in biomedical applications: A seven-year update. AB - Thermally responsive hydrogels modulate their gelation behavior upon temperature change. Aqueous solutions solidify into hydrogels when a critical temperature is reached. In biomedical applications, the change from ambient temperature to physiological temperature can be employed. Their potential as in situ forming biomaterials has rendered these hydrogels very attractive. Advances in drug delivery, tissue engineering and cell sheet engineering have been made in recent years with the use of thermoresponsive hydrogels. The scope of this article is to review the literature on thermosensitive hydrogels published over the past seven years. The article concentrates on natural polymers as well as synthetic polymers, including systems based on N-isopropylacrylamide (NIPAAm), poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO-PPO PEO), poly(ethylene glycol) (PEG)-biodegradable polyester copolymers, poly(organophosphazenes) and 2-(dimethylamino) ethyl methacrylate (DMAEMA). PMID- 26614557 TI - Aliphatic polyesters for medical imaging and theranostic applications. AB - Medical imaging is a cornerstone of modern medicine. In that context the development of innovative imaging systems combining biomaterials and contrast agents (CAs)/imaging probes (IPs) for improved diagnostic and theranostic applications focuses intense research efforts. In particular, the classical aliphatic (co)polyesters poly(lactide) (PLA), poly(lactide-co-glycolide) (PLGA) and poly(E-caprolactone) (PCL), attract much attention due to their long track record in the medical field. This review aims therefore at providing a state-of the-art of polyester-based imaging systems. In a first section a rapid description of the various imaging modalities, including magnetic resonance imaging (MRI), optical imaging, computed tomography (CT), ultrasound (US) and radionuclide imaging (SPECT, PET) will be given. Then, the two main strategies used to combine the CAs/IPs and the polyesters will be discussed. In more detail we will first present the strategies relying on CAs/IPs encapsulation in nanoparticles, micelles, dendrimers or capsules. We will then present chemical modifications of polyesters backbones and/or polyester surfaces to yield macromolecular imaging agents. Finally, opportunities offered by these innovative systems will be illustrated with some recent examples in the fields of cell labeling, diagnostic or theranostic applications and medical devices. PMID- 26614558 TI - Polydioxanone-based bio-materials for tissue engineering and drug/gene delivery applications. AB - Since the commercialization of polydioxanone (PDX) as a biodegradable monofilament suture by Ethicon in 1981, the polymer has received only limited interest until recently. The limitations of polylactide-co-glycolide (PLGA) coupled with the growing need for materials with enhanced features and the advent of new fabrication techniques such as electrospinning have revived interest for PDX in medical devices, tissue engineering and drug delivery applications. Electrospun PDX mats show comparable mechanical properties as the major structural components of native vascular extracellular matrix (ECM) i.e. collagen and elastin. In addition, PDX's unique shape memory property provides rebound and kink resistance when fabricated into vascular conduits. The synthesis of methyl dioxanone (MeDX) monomer and copolymers of dioxanone (DX) and MeDX have opened up new perspectives for poly(ester-ether)s, enabling the design of the next generation of tissue engineering scaffolds for application in regenerating such tissues as arteries, peripheral nerve and bone. Tailoring of polymer properties and their formulation as nanoparticles, nanomicelles or nanofibers have brought along important developments in the area of controlled drug or gene delivery. This paper reviews the synthesis of PDX and its copolymers and provides for the first time an exhaustive account of its applications in the (bio)medical field with focus on tissue engineering and drug/gene delivery. PMID- 26614559 TI - Hyaluronic acid and its derivatives in drug delivery and imaging: Recent advances and challenges. AB - Hyaluronic acid (HA) is a biodegradable, biocompatible, nontoxic, and non immunogenic glycosaminoglycan used for various biomedical applications. The interaction of HA with the CD44 receptor, whose expression is elevated on the surface of many types of tumor cells, makes this polymer a promising candidate for intracellular delivery of imaging and anticancer agents exploiting a receptor mediated active targeting strategy. Therefore, HA and its derivatives have been most investigated for the development of several carrier systems intended for cancer diagnosis and therapy. Nonetheless, different and important delivery applications of the polysaccharide have also been described, including gene and peptide/protein drugs delivery. The aim of this review was to provide an overview of the existing recent literature on the use of HA and its derivatives for drug delivery and imaging. Notable attention is given to nanotheranostic systems obtained after conjugation of HA to nanocarriers as quantum dots, carbon nanotubes and graphene. Meanwhile, attention is also paid to some challenging aspects that need to be addressed in order to allow translation of preclinical models based on HA and its derivatives for drug delivery and imaging purposes to clinical testing and further their development. PMID- 26614560 TI - Chitosan as a starting material for wound healing applications. AB - Chitosan and its derivatives have attracted great attention due to their properties beneficial for application to wound healing. The main focus of the present review is to summarize studies involving chitosan and its derivatives, especially N,N,N-trimethyl-chitosan (TMC), N,O-carboxymethyl-chitosan (CMC) and O carboxymethyl-N,N,N-trimethyl-chitosan (CMTMC), used to accelerate wound healing. Moreover, formulation strategies for chitosan and its derivatives, as well as their in vitro, in vivo and clinical applications in wound healing are described. PMID- 26614562 TI - The Diels-Alder reaction: A powerful tool for the design of drug delivery systems and biomaterials. AB - Click reactions have the potential to greatly facilitate the development of drug delivery systems and biomaterials. These reactions proceed under mild conditions, give high yields, and form only inoffensive by-products. The Diels-Alder cycloaddition is one of the click reactions that do not require any metal catalyst; it is one of the most useful reactions in synthetic organic chemistry and material design. Herein, we highlight possible applications of the Diels Alder reaction in pharmaceutics and biomedical engineering. Particular focus is placed on the synthesis of polymers and dendrimers for drug delivery, the preparation of functionalized surfaces, bioconjugation techniques, and applications of the Diels-Alder reaction in nanotechnology. Moreover, applications of the reaction for the preparation of hydrogels for drug delivery and tissue engineering are reviewed. A general introduction to the Diels-Alder reaction is presented, along with a discussion of potential pitfalls and challenges. At the end of the article, we provide a set of tools that may facilitate the application of the Diels-Alder reaction to solve important pharmaceutical or biomedical problems. PMID- 26614561 TI - Improving oral drug bioavailability with polycations? AB - The administration of drugs via the oral route is challenging due to the (bio)chemical aggressivity of the digestive system and to the presence of barriers that hinder cell uptake and access to the bloodstream. Indeed, the gastrointestinal tract is characterized by large variations of pH, the presence of enzymes and surfactants, and by absorption barriers such as mucus and the epithelium. Thus, many compounds such as proteins and nucleic acids do not reach the systemic circulation due to their premature degradation and/or large size. Among the different strategies that have been investigated to address these challenges, polycations have been explored to improve the oral absorption of many types of drugs. Because of their multiple positive charges and repetitive structure, polycations can protect sensitive drugs against rapid degradation and interact with the gastrointestinal mucosa. Moreover, cationic polymers promote drug transfer across intestinal barriers through various mechanisms, including the opening of the tight junctions, and change in uptake pathway. This contribution provides an overview of the most common polycations currently investigated as absorption enhancers for the oral route, and discusses the manner in which they are employed (co-administration, micro- and nanoparticles, conjugation) to improve the oral drug delivery of different classes of therapeutics. PMID- 26614563 TI - Efficacy Interactions of PEG-DOX-N-acetyl Glucosamine Prodrug Conjugate for Anticancer Therapy. AB - Present investigation is exploring structure-biocompatibility interaction of tumour targeted polyethylene glycol (PEG) based drug conjugate of doxorubicin using N-acetyl glucosamine as targeting ligand. The synthesized polymer drug conjugate was evaluated for particle size, zeta potential, molecular weight, haemolysis activity, cytotoxicity, protein binding and in vitro receptor (lectin) binding study. The particle size of synthesized conjugate was observed to be around 30 nm with polydispersability index of 0.213 indicating mono-disperse particles. Fluorescence quenching assay addressed relatively lower binding interactions of polymer drug conjugate to bovine serum albumin in comparison with free doxorubicin which may be governed to the hydrophilicity of polyethylene glycol and N-acetyl glucosamine. The cell compatibility and haemolysis study showed that PEG drug conjugate was nontoxic and biocompatible, which recommends the suitability of polymer drug conjugates for delivering biological active agents systemically. In vitro ligand-lectin receptor binding assays of synthesized targeted polymer conjugate suggest the possibility of promising interaction of N-acetyl glucosamine in vivo. Thus, the study indicated the suitability of N-acetyl glucosamine anchored targeted polymer drug conjugate in delivering bio-therapeutics for specifically targeting to tumour tissues. PMID- 26614564 TI - Utility of fine needle aspiration cytology in detecting metastatic deposits in an uncommon case of malignant transformation in a giant cell tumour of bone. PMID- 26614565 TI - Adaptive evolution in locomotor performance: How selective pressures and functional relationships produce diversity. AB - Despite the complexity of nature, most comparative studies of phenotypic evolution consider selective pressures in isolation. When competing pressures operate on the same system, it is commonly expected that trade-offs will occur that will limit the evolution of phenotypic diversity, however, it is possible that interactions among selective pressures may promote diversity instead. We explored the evolution of locomotor performance in lizards in relation to possible selective pressures using the Ornstein-Uhlenbeck process. Here, we show that a combination of selection based on foraging mode and predator escape is required to explain variation in performance phenotypes. Surprisingly, habitat use contributed little explanatory power. We find that it is possible to evolve very different abilities in performance which were previously thought to be tightly correlated, supporting a growing literature that explores the many-to-one mapping of morphological design. Although we generally find the expected trade off between maximal exertion and speed, this relationship surprisingly disappears when species experience selection for both performance types. We conclude that functional integration need not limit adaptive potential, and that an integrative approach considering multiple major influences on a phenotype allows a more complete understanding of adaptation and the evolution of diversity. PMID- 26614566 TI - Phonological Concept Learning. AB - Linguistic and non-linguistic pattern learning have been studied separately, but we argue for a comparative approach. Analogous inductive problems arise in phonological and visual pattern learning. Evidence from three experiments shows that human learners can solve them in analogous ways, and that human performance in both cases can be captured by the same models. We test GMECCS (Gradual Maximum Entropy with a Conjunctive Constraint Schema), an implementation of the Configural Cue Model (Gluck & Bower, ) in a Maximum Entropy phonotactic-learning framework (Goldwater & Johnson, ; Hayes & Wilson, ) with a single free parameter, against the alternative hypothesis that learners seek featurally simple algebraic rules ("rule-seeking"). We study the full typology of patterns introduced by Shepard, Hovland, and Jenkins () ("SHJ"), instantiated as both phonotactic patterns and visual analogs, using unsupervised training. Unlike SHJ, Experiments 1 and 2 found that both phonotactic and visual patterns that depended on fewer features could be more difficult than those that depended on more features, as predicted by GMECCS but not by rule-seeking. GMECCS also correctly predicted performance differences between stimulus subclasses within each pattern. A third experiment tried supervised training (which can facilitate rule-seeking in visual learning) to elicit simple rule-seeking phonotactic learning, but cue-based behavior persisted. We conclude that similar cue-based cognitive processes are available for phonological and visual concept learning, and hence that studying either kind of learning can lead to significant insights about the other. PMID- 26614567 TI - The need for carefully reading. Time matters! PMID- 26614568 TI - Impact of supplementing diets with propolis on productive performance, egg quality traits and some haematological variables of laying hens. AB - One hundred and twenty eight, 28-weeks-old Lohmann LSL hybrid layers were used in this experiment, which lasted 12 weeks to investigate the effect of propolis supplementation on the productive performance, egg quality traits and haematological variables of laying hens. All hens were randomly classified into four equal experimental groups, eight replicates (4 birds/each). Hens in group 1 were fed on a commercial diet and considered as control group, while those in groups 2, 3 and 4 were fed on the same commercial diet and supplemented with 250, 500 and 1000 mg propolis/kg diet. The obtained results revealed that daily feed consumption/hen increased insignificantly with increasing propolis level than that of the control group. Regarding the means of egg mass and egg production rate, it was observed that the laying hens fed diets containing 250 and 1000 mg propolis/kg significantly (p < 0.05) produced more and heaver egg in comparison with control group. External egg quality traits have not affected with increasing the level of propolis, while eggshell weight was significantly (p < 0.05) increased. The internal egg quality traits except albumen and yolk percentages increased significantly (p < 0.05) with increasing propolis level for treated hens as compared to those in the control. Concerning the haematological parameters, the results showed that the levels of total protein and globulin increased significantly with increasing propolis level, while cholesterol and liver enzymes were significantly decreased (p < 0.05). Heterophils count of hens in the treated groups significantly decreased, whereas the lymphocyte count significantly increased, resulting in a decreased H/L ratio than that of the control group. Thus, it could be concluded that the supplementation of 250 mg propolis/kg diet is highly recommended to improving egg production, blood constituent and haematological parameters of the commercial laying hens. PMID- 26614569 TI - Caffeine enhances the antidepressant-like activity of common antidepressant drugs in the forced swim test in mice. AB - Caffeine is the most widely used behaviorally active drug in the world which exerts its activity on central nervous system through adenosine receptors. Worrying data indicate that excessive caffeine intake applies to patients suffering from mental disorders, including depression. The main goal of the present study was to evaluate the influence of caffeine on animals' behavior in forced swim test (FST) as well as the effect of caffeine (5 mg/kg) on the activity of six typical antidepressants, such as imipramine (15 mg/kg), desipramine (10 mg/kg), fluoxetine (5 mg/kg), paroxetine (0.5 mg/kg), escitalopram (2 mg/kg), and reboxetine (2.5 mg/kg). Locomotor activity was estimated to verify and exclude false-positive/negative results. In order to assess the influence of caffeine on the levels of antidepressant drugs studied, their concentrations were determined in murine serum and brains using high performance liquid chromatography. The results showed that caffeine at a dose of 10, 20, and 50 mg/kg exhibited antidepressant activity in the FST, and it was not related to changes in locomotor activity in the animals. Caffeine at a dose of 5 mg/kg potentiated the activity of all antidepressants, and the observed effects were not due to the increase in locomotor activity in the animals. The interactions between caffeine and desipramine, fluoxetine, escitalopram, and reboxetine were exclusively of pharmacodynamic character, because caffeine did not cause any changes in the concentrations of these drugs neither in blood serum nor in brain tissue. As a result of joint administration of caffeine and paroxetine, an increase in the antidepressant drug concentrations in serum was observed. No such change was noticed in the brain tissue. A decrease in the antidepressant drug concentrations in brain was observed in the case of imipramine administered together with caffeine. Therefore, it can be assumed that the interactions caffeine-paroxetine and caffeine-imipramine occur at least in part in the pharmacokinetic phase. PMID- 26614570 TI - Sodium nitrite attenuates MMP-9 production by endothelial cells and may explain similar effects of atorvastatin. AB - Imbalanced matrix metalloproteinase (MMP) activity promotes cardiovascular alterations that are attenuated by statins. These drugs exert pleiotropic effects independent of cholesterol concentrations, including upregulation of nitric oxide (NO) formation and MMP downregulation. However, statins also increase tissue concentrations of nitrites, which activate new signaling pathways independent of NO. We examined whether atorvastatin attenuates MMP-9 production by human umbilical vein endothelial cells (HUVEC) stimulated with phorbol 12-myristate 13 acetate (PMA) by mechanisms possibly involving increased nitrite, and whether this effect results of NO formation. We also examined whether such an effect is improved by sildenafil, an inhibitor of phosphodiesterase-5 which potentiates NO induced increases in cyclic GMP. MMP activity and nitrite concentrations were measured by gelatin zymography and ozone-based reductive chemiluminescence, respectively, in the conditioned medium of HUVECs incubated for 24 h with these drugs. Phospho-NFkappaB p65 concentrations were measured in cell lysate to assess NFkappaB activation. Atorvastatin attenuated PMA-induced MMP-9 gelatinolytic activity by mechanisms not involving NO, although it increased nitrite concentrations, whereas sildenafil had no effects. Combining both drugs showed no improved responses compared to atorvastatin alone. While sodium nitrite attenuated MMP-9 production by HUVECs, adding hemoglobin (NO scavenger) did not affect the responses to nitrite. Neither atorvastatin nor nitrite inhibited PMA induced increases in phospho-NFkappaB p65 concentrations. These findings show that sodium nitrite attenuates MMP-9 production by endothelial cells and may explain similar effects exerted by atorvastatin. With both drugs, the inhibitory effects on MMP-9 production are not dependent on NO formation or on inhibition of NFkappaB activation. Our findings may help to elucidate important new nitrite mediated mechanisms by which statins affect imbalanced MMP activity in a variety of cardiovascular disease. PMID- 26614571 TI - Microwave-assisted extraction and high-throughput monolithic-polymer-based micro solid-phase extraction of organophosphorus, triazole, and organochlorine residues in apple. AB - A high-throughput micro-solid-phase extraction device based on a 96-well plate was constructed and applied to the determination of pesticide residues in various apple samples. Butyl methacrylate and ethylene glycol dimethacrylate were copolymerized as a monolithic polymer and placed in the cylindrically shaped stainless-steel meshes of 96-micro-solid-phase extraction device and used as an extracting unit. Before the micro-solid-phase extraction, microwave-assisted extraction was employed to facilitate the transfer of the pesticide residues from the apple matrix to liquid media. Then, 1 mL of the aquatic samples was transferred into the 96-well plate and the 96-micro-solid-phase extraction device was applied for the extraction of the selected pesticides. Influential parameters, such as sorbent-to-sorbent reproducibility, microwave-assisted extraction time, ionic strength and micro-solid-phase extraction time, were optimized. The limits of quantitation were below 120 MUg/kg, which are lower than the maximum residue limits. The developed method was successfully implemented for the extraction and determination of the selected pesticides from 20 different apple samples gathered from local markets. Phosalone was identified and quantified at the concentration level of 147 (+/-16.4) MUg/kg in one of the samples. PMID- 26614573 TI - Parents' difficulties as co-therapists in CBT among non-responding youths with anxiety disorders: Parent and therapist experiences. AB - No increased effect has been associated with parent involvement in cognitive behavioral therapy (CBT) for youths with anxiety disorders. The purpose of this study was to explore parent and therapist experiences of CBT among non-responding youths with anxiety disorders, with a primary focus on parent involvement in therapy. Interpretative phenomenological analysis was applied to 24 sets of semi structured interviews with families and therapists of anxiety-disordered youths who had not profited from CBT with parental inclusion. From the superordinate theme parents' difficulties acting as co-therapists, which emerged from the analyses, two master themes represented the perspectives of parents (difficulty working together with the youth and feeling unqualified, with limited resources), and two represented the perspectives of therapists (family dynamics stood in the way of progress and difficulty transferring control to parents). Parent and therapist experiences complemented each other, offering two different perspectives on parent difficulties as co-therapists. However, the two groups' views on their respective roles in therapy were in conflict. Parents wished to remain being "just the parents" and for the experts to take over, while therapists wished to act as facilitators transferring the control to parents. Clinical implications are drawn for parental involvement and enhancement of treatment outcomes for likely non-responders. PMID- 26614572 TI - System struggles and substitutes: A qualitative study of general practitioner and psychiatrist experiences of prescribing antipsychotics to children and adolescents. AB - There are significant controversies regarding rising antipsychotic prescription trends in children and adolescents. Many pharmacoepidemiology trend studies have been published, and interpretations of these data are helpful in explaining what is happening in prescribing practices, but not why these patterns exist. There is a lack of qualitative data in this area, and the experience of prescribing antipsychotics to children and adolescents has not been adequately researched. We conducted a qualitative study using an interpretive phenomenological analysis of physicians' experiences of antipsychotic prescribing to children and adolescents. Prescribers participated in individual interviews and a focus group. We used a staged approach for data analysis of transcriptions. In all, 11 physicians including psychiatrists and general practitioners participated in our study. We identified themes related to context, role and identity, and decision-making and filtering Struggles with health system gaps were significant leading to the use of antipsychotics as substitutes for other treatments. Physicians prescribed antipsychotics to youth for a range of indications and had significant concerns regarding adverse effects. Our results provide knowledge regarding the prescribers' experience of antipsychotics for children and adolescents. Important gaps exist within the health system that are creating opportunities for the initiation and continued use of these agents. PMID- 26614574 TI - Lower Resting State Heart Rate Variability Relates to High Pain Catastrophizing in Patients with Chronic Whiplash-Associated Disorders and Healthy Controls. AB - Vagally mediated heart rate variability (vmHRV) is widely respected as a psychophysiological measure of emotion regulation capacity and serves as a readily available index of executive brain areas that exert an inhibitory influence on subcortical structures. Pain catastrophizing (PC) is conceptualized as the tendency to misinterpret and exaggerate pain-related situations that may be threatening. Chronic pain patients show lower vmHRV and higher PC. Previously, no study has investigated the association of PC and vmHRV. We examined the association of PC and vmHRV in a sample of patients with chronic whiplash associated disorders (WAD, n = 30) and healthy controls (n = 31). Patients with WAD showed lower vmHRV, indexed by high-frequency HRV (effect size, Cohen's d = 0.442), and greater PC (d = 0.815). Zero-order and partial correlations controlling for age and sex revealed that vmHRV and PC are inversely related. The results provide evidence for a psychophysiological mechanism underlying PC, in particular in chronic pain patients. PMID- 26614575 TI - Is age a barrier to pancreaticoduodenectomy? An Italian dual-institution study. AB - The aim of this study is to evaluate the role of age after pancreaticoduodenectomy. This is a retrospective study of 223 patients who underwent pancreaticoduodenectomy for periampullary diseases. Three age groups of patients were compared: <=70 years of age (group A); between 71 and 79 years of age (group B) and 80 years of age or older (group C). The primary endpoint was the postoperative mortality rate. Secondary endpoints were the overall postoperative morbidity, postoperative pancreatic fistula, postoperative pancreatic haemorrhage, bile leakage, delayed gastric emptying rates, the length of hospital stay, intensive care unit stay, the type of discharge from hospital, reoperation rate and overall survival. Uni-multivariate analyses and Kaplan-Meier curve were carried out. At univariate analysis, only the type of discharge from hospital showed that group B and C patients required a period of rehabilitation more frequently than group A (P = 0.047 and P < 0.001, respectively). Multivariate analysis confirmed that age was not related to postoperative mortality (P = 0.258), morbidity (P = 0.912) and overall survival (P = 0.658), but it was related to type of discharge (P < 0.001). The present study seems to suggest that a pancreaticoduodenectomy is a feasible and safe procedure, even in elderly and very elderly patients even if the latter require a longer period of rehabilitation. PMID- 26614576 TI - Human papillomavirus and induction chemotherapy versus concurrent chemoradiotherapy in locally advanced oropharyngeal cancer: The Dana Farber Experience. AB - BACKGROUND: Human papillomavirus (HPV) infection indicates favorable prognosis in oropharyngeal squamous cell carcinoma (SCC). The purpose of this study was for us to assess the impact of HPV in patients treated with sequential therapy versus concomitant chemoradiotherapy (CRT). METHODS: Patients with stage III and IVA and B oropharyngeal SCC were reviewed spanning 10 years. RESULTS: Among 500 cases, 291 (58%) received CRT versus 209 (42%) sequential therapy. HPV status was known in 279 of patients (56%) and positive in 77% (determined by polymerase chain reaction [PCR; 91%], p16 immunohistochemical [IHC], or both). Median follow-up was 2.8 years. Overall survival (OS) did not differ for sequential therapy versus CRT overall (hazard ratio [HR] = 0.90; p = .66; 3-year OS = 86% and 87%) or within HPV-positive patients (HR = 0.89; p = .81; 3-year OS = 91% and 91%) or within HPV-negative patients (HR = 0.55; p = .32; 3-year OS = 85% and 75%). CONCLUSION: Survival for all patients was high and notable for HPV-negative patients treated with sequential therapy. Further studies in this patient population are warranted. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1618 E1624, 2016. PMID- 26614577 TI - Effect of head pitch and roll orientations on magnetically induced vertigo. AB - KEY POINTS: Lying supine in a strong magnetic field, such as in magnetic resonance imaging scanners, can induce a perception of whole-body rotation. The leading hypothesis to explain this invokes a Lorentz force mechanism acting on vestibular endolymph that acts to stimulate semicircular canals. The hypothesis predicts that the perception of whole-body rotation will depend on head orientation in the field. Results showed that the direction and magnitude of apparent whole-body rotation while stationary in a 7 T magnetic field is influenced by head orientation. The data are compatible with the Lorentz force hypothesis of magnetic vestibular stimulation and furthermore demonstrate the operation of a spatial transformation process from head-referenced vestibular signals to Earth-referenced body motion. ABSTRACT: High strength static magnetic fields are known to induce vertigo, believed to be via stimulation of the vestibular system. The leading hypothesis (Lorentz forces) predicts that the induced vertigo should depend on the orientation of the magnetic field relative to the head. In this study we examined the effect of static head pitch (-80 to +40 deg; 12 participants) and roll (-40 to +40 deg; 11 participants) on qualitative and quantitative aspects of vertigo experienced in the dark by healthy humans when exposed to the static uniform magnetic field inside a 7 T MRI scanner. Three participants were additionally examined at 180 deg pitch and roll orientations. The effect of roll orientation on horizontal and vertical nystagmus was also measured and was found to affect only the vertical component. Vertigo was most discomforting when head pitch was around 60 deg extension and was mildest when it was around 20 deg flexion. Quantitative analysis of vertigo focused on the induced perception of horizontal-plane rotation reported online with the aid of hand-held switches. Head orientation had effects on both the magnitude and the direction of this perceived rotation. The data suggest sinusoidal relationships between head orientation and perception with spatial periods of 180 deg for pitch and 360 deg for roll, which we explain is consistent with the Lorentz force hypothesis. The effects of head pitch on vertigo and previously reported nystagmus are consistent with both effects being driven by a common vestibular signal. To explain all the observed effects, this common signal requires contributions from multiple semicircular canals. PMID- 26614578 TI - Electrocardiographic abnormalities in patients with pericardial disease- Association of PR segment depression with arrhythmias and clinical signs: Experience of cardiac surgery center. AB - OBJECTIVE: We aimed to describe clinical, morphological, intraoperative, echocardiographic and electrocardiographic (ECG) associations of PR segment depression (PRsd), as well as its relationship with arrhythmias and outcomes in pericardial diseases (PD). METHODS: Overall, 79 patients among 197 patients with PD, referred to cardiac surgery center for treatment, were eligible for inclusion in the study. ECGs were analyzed for presence of PRsd, abnormal P-wave, low voltage QRS, QRS alternans, STj deviation and arrhythmias. We analyzed patients' clinical, echocardiographic and intraoperative data, as well as arrhythmias and outcomes (death, rehospitalization, heart failure). RESULTS: Overall 45.5% of patients with PD had signs of PRsd. PRsd was associated with elevated markers of inflammation, purulent content of pericardial fluid, extent of effusion and pericardial calcification, signs of constriction and tamponade. We also observed significant association of PRsd with ECG abnormalities--STj changes, notched P wave, low voltage QRS and QRS alternans, as well as arrhythmias. Overall, 30.6% of patients with PRsd had unfavorable composite outcome as compared to 7% in patients without PRsd (p=0.006). Logistic regression analysis results demonstrated compression (tamponade or constriction) (OR 14.93, 95% CI 2.71-82.0, p=0.002), inflammation (OR -11.42, 95% CI 2.16-60.35, p=0.004) and notched P-wave (OR -5.27, 95% CI 1.32-20.99, p=0.018) as independent predictors of PRsd. The model allowed predicting presence of PRsd in 80% of cases. CONCLUSIONS: PRsd in patients with PD is associated with signs of inflammation, diffuse effusion and calcification, and compression (tamponade and constriction), arrhythmias and unfavorable outcomes. The independent predictors of PR segment depression are signs of compression, inflammation and notched P-wave. PMID- 26614579 TI - The electrocardiographic characteristics of an acute embolism in the pulmonary trunk and the main pulmonary arteries. AB - OBJECTIVE: Pulmonary embolism (PE) is a common cardiovascular disease that can be easily missed or misdiagnosed. Electrocardiogram (ECG) is valuable in making early diagnoses and performing risk stratification with regard to acute PE. METHODS: A total of 147 hospitalized patients diagnosed with acute PE were enrolled in this study and divided into the following 2 groups: main pulmonary artery trunk or main pulmonary artery (MPA) embolism and lobar artery or remote branch embolism. Electrocardiographic abnormalities associated with acute PE were subsequently identified. RESULTS: Electrocardiographic abnormalities were significantly different between the pulmonary trunk/MPA embolism group and the lobar artery/remote branch embolism group. The incidence of pulmonary trunk/MPA emboli was significantly related to the number of ECG abnormalities (t = -7.086, P = 5.556e-11). Furthermore, the number of ECG abnormalities noted among patients with pulmonary trunk/MPA emboli was 5.276 times greater than the number observed among the lobar artery/remote branch embolism group (P < .001, 95% confidence interval = -6.57 to 3.97). The risk of either moderate or severe right ventricular hypertrophy was increased by 16.18% among patients with either pulmonary trunk or MPA emboli compared with patients with either lobar artery or remote branch emboli (P < .001, 95% confidence interval = -2.76 to 0.876). The correct classification rate was as high as 92.3% when ECG was used to classify the prognosis of PE patients. CONCLUSIONS: The number of ECG abnormalities and the degree of right ventricular hypertrophy as determined via ECG can be used to assess the probability of developing a PE in the pulmonary trunk and MPA. Furthermore, ECGs can assist clinicians with risk stratification. PMID- 26614580 TI - Comparison of ultrasonography and surface landmarks in detecting the localization for cricothyroidotomy. AB - OBJECTIVE: The aim of the study was to compare ultrasonography (US) and surface landmark techniques for detecting the cricothyroid membrane (CTM) to perform a cricothyroidotomy on healthy volunteers. METHODS: In this prospective observational study, 5 operators and 24 models were included. The borders of the CTM were marked with an invisible pen. The operators were asked to point the CTM either with the palpation method or the US-guided fashion. RESULTS: The CTM was detected accurately in 80 (66.7%) attempts with palpation and 83 (69.2%) attempts with US. There was no statistically significant difference in the accuracy of detection of the CTM with palpation and US. The mean time for detecting the CTM with palpation was 8.25 +/- 4.8 seconds (95% confidence interval, 7.3-9.1). The mean time for detecting CTM with US was 17 +/- 9.2 seconds (95% confidence interval, 15.3-18.7). The duration for detecting the localization of the CTM was longer with US. CONCLUSION: According to the results of this study, the accuracy of US and palpation was similar in detecting the localization of the CTM. However, the duration for detecting the CTM was longer with US when compared with the palpation technique. PMID- 26614581 TI - Respiratory depression in the intoxicated trauma patient: are opioids to blame? AB - Providing effective pain management to acutely intoxicated trauma patients represents a challenge of balancing appropriate pain management with the risk of potential respiratory depression from opioid administration. The objective of this study was to quantify the incidence of respiratory depression in trauma patients acutely intoxicated with ethanol who received opioids as compared with those who did not and identify potential risk factors for respiratory depression in this population. Retrospective medical record review was conducted for subjects identified via the trauma registry who were admitted as a trauma activation and had a detectable serum ethanol level upon admission. Risk factors and characteristics compared included demographics, Injury Severity Score, Glasgow Coma Score, serum ethanol level upon arrival, urine drug screen results, incidence of respiratory depression, and opioid and other sedative medication use. A total of 233 patients were included (78.5% male). Patients who received opioids were more likely to have a higher Injury Severity Score and initial pain score on admission as compared with those who did not receive opioids. Blood ethanol content was higher in patients who did not receive opioids (0.205 vs 0.237 mg/dL, P = .015). Patients who did not receive opioids were more likely to be intubated within 4 hours of admission (1.7% vs 12.1%, P = .02). Opioid administration was not associated with increased risk of respiratory depression (19.7% vs 22.4%, P = .606). Increased cumulative fentanyl dose was associated with increased risk of respiratory depression. Increased cumulative fentanyl dose, but not opioid administration alone, was found to be a risk factor for respiratory depression. PMID- 26614582 TI - Novel technique to diagnose parotid duct injuries at the bedside using fluorescein. PMID- 26614583 TI - Computed tomography angiography in acute stroke (revisiting the 4Ps of imaging). AB - Imaging in acute stroke has traditionally focussed on the 4Ps-parenchyma, pipes, perfusion, and penumbra-and has increasingly relied upon advanced techniques including magnetic resonance imaging to evaluate such patients. However, as per European Magnetic Resonance Forum estimates, the availability of magnetic resonance imaging scanners for the general population in India (0.5 per million inhabitants) is quite low as compared to Europe (11 per million) and United States (35 per million), with most of them only present in urban cities. On the other hand, computed tomography (CT) is more widely available and has reduced scanning duration. Computed tomography angiography of cervical and intracranial vessels is relatively simpler to perform with extended coverage and can provide all pertinent information required in such patients. This imaging review will discuss relevant imaging findings on CT angiography in patients with acute ischemic stroke through illustrated cases. PMID- 26614584 TI - Clinical application of rapid B-line score with lung ultrasonography in differentiating between pulmonary infection and pulmonary infection with acute left ventricular heart failure. AB - BACKGROUND: We have found that there are usually 2 causes of acute dyspnea in our emergency department: (1) pulmonary infection only and (2) pulmonary infection in the setting of acute left ventricular heart failure (LVHF). These conditions are sometimes difficult to differentiate. Lung ultrasonography (LUS) is easily performed at the bedside and provides accurate information for diagnosis. In this study, we propose a simple B-line score to allow rapid differential diagnosis between these 2 lung conditions. METHODS: A prospective, single-blind trial was conducted on 98 patients with acute dyspnea in the emergency department. Lung ultrasonography and transthoracic echocardiography were performed within 30 minutes after enrollment. The final clinical diagnosis was recorded for all patients. Using the Bedside Lung Ultrasound in Emergency protocol, we recorded the number of B lines at 4 standardized points. Based on the theory of Lichtenstein, scores of 1, 2, 3, and 4 were categorized by the number of B lines on a static screen (0 to <3, 3 to <6, 6 to <8, and >=8, respectively). The B-line score of 4 Bedside Lung Ultrasound in Emergency protocol points was recorded, and the total B-line score was calculated. Receiver operating characteristic (ROC) curves were used to evaluate the accuracy of the rapid ultrasound measurements for the final clinical diagnosis. RESULTS: In our study, 27 patients were diagnosed with pulmonary infection and acute LVHF. The total number of B lines and the B-line score in patients with pulmonary infection in the setting of acute LVHF were 24.2+/-2.5 and 11.5+/-1.5, respectively, which were significantly higher than those in patients with pulmonary infection (12.5+/-6.4 and 7.2+/-1.9) (P=.000). In patients with pulmonary infection and acute LVHF, the effective diagnostic value of left ventricular ejection fraction and the total B-line score were similar (area under the ROC curve: 0.986 vs 0.962, P=.2607). The cutoff value of the total B-line score was 8, with a sensitivity of 80.7% and a specificity of 100%. A combination of LUS and echocardiography might improve the diagnostic accuracy (area under the ROC curve: 0.994; 95% confidence interval, 0.981-1.000; P=.000). CONCLUSIONS: This simple B-line score with LUS can help make a rapid differential diagnosis between pulmonary infection and pulmonary infection with acute LVHF. The diagnostic accuracy may be enhanced when used in conjunction with echocardiography. PMID- 26614585 TI - Herpes zoster in patients with bullous pemphigoid: a population-based case control and cohort study. PMID- 26614586 TI - The Glasgow splint: modification of occlusal splint for cleft osteotomies. PMID- 26614587 TI - HLA Class II Antibody Activation of Endothelial Cells Promotes Th17 and Disrupts Regulatory T Lymphocyte Expansion. AB - Kidney transplantation is the most successful treatment option for patients with end-stage renal disease, and chronic antibody-mediated rejection is the principal cause of allograft loss. Predictive factors for chronic rejection include high levels of HLA alloantibodies (particularly HLA class II) and activation of graft endothelial cells (ECs). The mechanistic basis for this association is unresolved. We used an experimental model of HLA-DR antibody stimulation of microvascular ECs to examine the mechanisms underlying the association between HLA class II antibodies, EC activation and allograft damage. Activation of ECs with the F(Ab')2 fragment of HLA-DR antibody led to phosphorylation of Akt, ERK and MEK and increased IL-6 production by ECs cocultured with allogeneic peripheral blood mononuclear cells (PBMCs) in an Akt-dependent manner. We previously showed that HLA-DR-expressing ECs induce polarization of Th17 and FoxP3(bright) regulatory T cell (Treg) subsets. Preactivation of ECs with anti HLA-DR antibody redirected EC allogenicity toward a proinflammatory response by decreasing amplification of functional Treg and by further increasing IL-6 dependent Th17 expansion. Alloimmunized patient serum containing relevant HLA-DR alloantibodies selectively bound and increased EC secretion of IL-6 in cocultures with PBMCs. These data contribute to understanding of potential mechanisms of antibody-mediated endothelial damage independent of complement activation and FcR expressing effector cells. PMID- 26614588 TI - Estimation of parameters related to vaccine efficacy and dengue transmission from two large phase III studies. AB - BACKGROUND: A tetravalent dengue vaccine was shown to be efficacious against symptomatic dengue in two phase III efficacy studies performed in five Asian and five Latin American countries. The objective here was to estimate key parameters of a dengue transmission model using the data collected during these studies. METHODS: Parameter estimation was based on a Sequential Monte Carlo approach and used a cohort version of the transmission model. Serotype-specific basic reproduction numbers were derived for each country. Parameters related to serotype interactions included duration of cross-protection and level of cross enhancement characterized by differences in symptomaticity for primary, secondary and post-secondary infections. We tested several vaccine efficacy profiles and simulated the evolution of vaccine efficacy over time for the scenarios providing the best fit to the data. RESULTS: Two reference scenarios were identified. The first included temporary cross-protection and the second combined cross protection and cross-enhancement upon wild-type infection and following vaccination. Both scenarios were associated with differences in efficacy by serotype, higher efficacy for pre-exposed subjects and against severe dengue, increase in efficacy with doses for naive subjects and by a more important waning of vaccine protection for subjects when naive than when pre-exposed. Over 20 years, the median reduction of dengue risk induced by the direct protection conferred by the vaccine ranged from 24% to 47% according to country for the first scenario and from 34% to 54% for the second. CONCLUSION: Our study is an important first step in deriving a general framework that combines disease dynamics and mechanisms of vaccine protection that could be used to assess the impact of vaccination at a population level. PMID- 26614589 TI - Annual influenza vaccination reduces total hospitalization in patients with chronic hepatitis B virus infection: A population-based analysis. AB - BACKGROUND: This study evaluated hospitalization and mortality in patients with chronic hepatitis B virus infection (HBV (+)) and matched comparison patients after stratifying the patients according to annual influenza vaccination (Vaccine (+)). METHODS: Data from Taiwan's National Health Insurance program from 2000 to 2009 were used to identify HBV(+)/vaccine(+) (n=4434), HBV(+)/Vaccine(-) (n=3646), HBV(-)/Vaccine(+) (n=8868), and HBV(-)/Vaccine(-) (n=8868) cohorts. The risk of pneumonia/influenza, respiratory failure, intensive care, hospitalization, and mortality in the four cohorts was evaluated. RESULTS: The total hospitalization rate was significantly lower in patients with chronic HBV infection who received an annual influenza vaccination than in chronic HBV infected patients who did not receive an influenza vaccination (16.29 vs. 24.02 per 100 person-years), contributing to an adjusted hazard ratio (HR) of 0.56 (95% confidence interval (CI)=0.50-0.62). The HBV(+)/Vaccine(+) cohort also had lower risks than the HBV(+)/Vaccine(-) cohort for pneumonia and influenza (adjusted HR=0.79, 95% CI=0.67-0.92), intensive care unit admission (adjusted HR=0.33, 95% CI=0.25-0.43), and mortality (adjusted HR=0.19, 95% CI=0.15-0.24). CONCLUSIONS: Our results suggest that annual influenza vaccination can reduce the risk of hospitalization and mortality in patients with chronic HBV infection. PMID- 26614590 TI - Toxicity assessment of Clostridium difficile toxins in rodent models and protection of vaccination. AB - Clostridium difficile is the leading cause of hospital-acquired diarrhea, also known as C. difficile associated diarrhea. The two major toxins, toxin A and toxin B are produced by most C. difficile bacteria, but some strains, such as BI/NAP1/027 isolates, produce a third toxin called binary toxin. The precise biological role of binary toxin is not clear but it has been shown to be a cytotoxin for Vero cells. We evaluated the toxicity of these toxins in mice and hamsters and found that binary toxin causes death in both animals similar to toxins A and B. Furthermore, immunization of mice with mutant toxoids of all three toxins provided protection upon challenge with native toxins. These results support the concept that binary toxin contributes to the pathogenicity of C. difficile and provide a method for monitoring the toxicity of binary toxin components in vaccines. PMID- 26614591 TI - Effects of non-sporting and sporting qigong on frailty and quality of life among breast cancer patients receiving chemotherapy. AB - PURPOSE: To explore the effects of non-sporting qigong (NSQG) and sporting qigong (SQG) on frailty and quality of life (QOL) of breast cancer patients during chemotherapy. METHODS: A time series (three-group, pre-test-post-test) quasi experimental design was applied in the study. Ninety-five participants were assigned to three groups: controls (n = 31), NSQG (n = 33), or SQG (n = 31). All patients performed the qigong interventions three times per week for at least 30 min per session. Data were collected in face-to-face interviews before chemotherapy and at 1 and 3 months after chemotherapy. Frailty was assessed using the Edmonton Frail Scale. The Medical Outcomes Survey Short-Form 36-Taiwanese version was used to evaluate the physical and mental component scores of QOL. RESULTS: In the 1st and 3rd months after practicing qigong, patients in the SQG group had lower frailty scores than those in the control group. In the 3rd month after the intervention, patients in the NSQG group also had lower frailty scores and higher mental component scores for QOL than those in the control group. Patients with higher frailty scores had worse physical and mental component scores for QOL than those with lower frailty scores. The Sobel test showed that the frailty score mediated SQG and physical component scores for QOL. CONCLUSIONS: SQG and NSQG appeared to be beneficial for improving frailty and QOL among the breast cancer patients receiving chemotherapy in the study. The results are preliminary and larger, well-constructed clinical studies are needed to verify the findings. PMID- 26614593 TI - Collateral Ligament Reconstruction of the Proximal Interphalangeal Joint. AB - Proximal interphalangeal joint collateral ligament injuries are common; however, chronic instability of this joint is rare. In such cases, however, there is no consensus on optimal management. Various repairs and reconstructions have been devised, although the literature on outcomes remains scant. We present a method of reconstruction of the proximal interphalangeal joint collateral ligament using a distally based slip of the flexor digitorum superficialis tendon. PMID- 26614592 TI - The Effect of Treatment on Stereognosis in Children With Hemiplegic Cerebral Palsy. AB - PURPOSE: To determine if rehabilitation alone or combined with surgery or botulinum toxin injection improved stereognosis in children with hemiplegic cerebral palsy. METHODS: Inclusion criteria were children with spastic hemiplegic cerebral palsy who had stereognosis testing 2 separate times with documentation of intervening treatment. Sixty-three children were included, 30 girls and 33 boys at an average age of 9.1 years (range, 4.4-16.0 years). Twelve standardized objects were used for manual identification. Baseline and postintervention stereognosis results were recorded for the hemiplegic and the dominant limb of each patient. The patients were separated into 3 groups based on intervening treatment: surgery with rehabilitation (27 patients), botulinum toxin injection with rehabilitation (19 subjects), and rehabilitation alone (7 subjects). Results were also analyzed by patient age group. RESULTS: Baseline testing of the hemiplegic limb revealed that 27 patients (43%) exhibited severe stereognosis impairment (0-4 objects identified correctly), 18 (28%) were moderately impaired (5-8 objects), 13 (21%) were mildly impaired (9-11 objects), and 5 (8%) had intact stereognosis (12 objects). There was no statistically significant difference in change in stereognosis scores postintervention among the 3 different treatment groups or between patients who had surgery and those who did not have surgery. There was no statistically significant difference in stereognosis function or postintervention change based on patient age at time of testing. CONCLUSIONS: In this study, 92% of children with spastic hemiplegic cerebral palsy had stereognosis impairment with a wide spectrum of severity. After operative or nonoperative treatment interventions, stereognosis as a secondary outcome measure was not changed. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 26614594 TI - Achieving asthma control with ICS/LABA: A review of strategies for asthma management and prevention. AB - Maintenance treatment with an inhaled corticosteroid (ICS) and a long-acting beta2-agonist (LABA) is recommended for patients whose asthma is not controlled with a low-to-moderate dose of ICS alone; a separate reliever medication is used on an as-needed basis. The Gaining Optimal Asthma ControL (GOAL) study demonstrated that salmeterol/fluticasone maintenance treatment can improve asthma control and reduce future risk compared with fluticasone alone, although the dose escalation design of this study meant that most patients treated with salmeterol/fluticasone were receiving the highest dose of ICS at the end of the study. Similarly, budesonide/formoterol maintenance therapy improved asthma control and reduced future risk compared with budesonide alone in the Formoterol and Corticosteroids Establishing Therapy (FACET) study. An alternative approach to asthma management is to use an ICS/LABA for both maintenance and reliever therapy. A large body of clinical evidence has shown that the use of budesonide/formoterol in this way improves both current control and reduces future risk compared with ICS/LABA plus as-needed short-acting beta2-agonist (SABA), even when patients receive lower maintenance doses of ICS as part of the maintenance and reliever therapy regimen. In addition, one study has shown that beclometasone/formoterol maintenance and reliever therapy reduces exacerbations more effectively than beclometasone/formoterol plus as-needed SABA. The use of ICS/LABA as both maintenance and reliever therapy ensures that an increase in reliever use in response to worsening symptoms is automatically matched by an increase in ICS. PMID- 26614595 TI - Respiratory symptoms/diseases prevalence is still increasing: a 25-yr population study. AB - BACKGROUND: Few epidemiological surveys on general population samples estimated changes in prevalence of respiratory symptoms/diseases over a long time interval; our study aims to quantify the temporal changes in the prevalence rates of asthma, allergic rhinitis and Chronic Obstructive Pulmonary Disease (COPD) after 25 years from baseline. METHODS: A general population sample participated in 3 cross-sectional surveys carried out in Central Italy (Pisa) in 1985-88 (n = 3865), 1991-93 (n = 2841), 2009-11 (n = 1620). 2276 (47%) subjects participated in at least 1 survey, 1723 (35.5%) in at least 2 surveys and 849 (17.5%) in all the 3 surveys. All subjects filled in a standardized questionnaire about health status and risk factors; a sub-sample performed spirometry. Chi-square test was used to compare adjusted prevalence rates of respiratory symptoms/diseases and descriptive characteristics among the surveys. Generalised estimating equations (GEE) were used to analyze the association between respiratory symptoms/diseases and risk factors. RESULTS: There was an increasing trend in prevalence rates of all respiratory symptoms/diseases throughout the surveys: current asthma attacks (1st-3rd survey prevalence: 3.4-7.2%), allergic rhinitis (16.2-37.4%), usual phlegm (8.7-19.5%) and COPD (2.1-6.8%) more than doubled. The GEE model confirmed these increasing trends, indicating higher risk of having respiratory symptoms/diseases in the second and third surveys. CONCLUSIONS: While asthma and allergic rhinitis increasing trends were confirmed, with respect to other international studies, also a COPD increasing prevalence rates was shown. PMID- 26614596 TI - Quality Improvement Guidelines for Transjugular Intrahepatic Portosystemic Shunts. PMID- 26614598 TI - Best Practices for Growing and Managing Online Communities. PMID- 26614597 TI - Effect of monthly intravenous ibandronate injections on vertebral or non vertebral fracture risk in Japanese patients with high-risk osteoporosis in the MOVER study. AB - We examined the efficacy of intravenous (IV) ibandronate 1 mg/month in patient subgroups in the phase III MOVER study. Here we present results of analyses on the incidence of fractures in patients with prevalent vertebral fractures (1 or >=2, and >=3) at screening and femoral neck (FN) bone mineral density (BMD) T scores >=-2.5 or <-2.5, and <-3.0 at baseline. The per-protocol set comprised 1134 patients (ibandronate 0.5 mg/month n = 376; ibandronate 1 mg/month n = 382; risedronate oral 2.5 mg/day n = 376). The incidence of vertebral fractures in patients with 1 or >=2 prevalent vertebral fractures was 11.2 and 20.4 %, respectively, with ibandronate 1 mg/month, and 12.6 and 22.1 %, respectively, with risedronate. In patients with FN BMD T scores >=-2.5 or <-2.5, the vertebral fracture incidence was 13.7 and 16.4 %, respectively, with ibandronate 1 mg/month, and 17.3 and 19.1 %, respectively, with risedronate. The incidence of non-vertebral fractures in patients with >=2 prevalent vertebral fractures or FN BMD T score <-2.5 was 7.6 and 7.6 %, respectively, with ibandronate 1 mg/month, and 9.5 and 9.4 %, respectively, with risedronate. Fracture incidence was consistently lower, but not significant, with ibandronate 1 mg/month than with risedronate in patients with >=2 prevalent vertebral fractures and FN BMD T score <-2.5. The efficacy of the fracture reduction of monthly IV ibandronate appears consistent and seemingly independent of the number of prevalent vertebral fractures or baseline BMD values. PMID- 26614600 TI - Sexual and reproductive health and rights: A matter of life and death. PMID- 26614599 TI - Association of Coffee Consumption With Overall and Cause-Specific Mortality in a Large US Prospective Cohort Study. AB - Concerns about high caffeine intake and coffee as a vehicle for added fat and sugar have raised questions about the net impact of coffee on health. Although inverse associations have been observed for overall mortality, data for cause specific mortality are sparse. Additionally, few studies have considered exclusively decaffeinated coffee intake or use of coffee additives. Coffee intake was assessed at baseline by self-report in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Hazard ratios were estimated using Cox proportional hazards models. Among 90,317 US adults without cancer at study baseline (1998-2001) or history of cardiovascular disease at study enrollment (1993-2001), 8,718 deaths occurred during 805,644 person-years of follow-up from 1998 through 2009. Following adjustment for smoking and other potential confounders, coffee drinkers, as compared with nondrinkers, had lower hazard ratios for overall mortality (<1 cup/day: hazard ratio (HR) = 0.99 (95% confidence interval (CI): 0.92, 1.07); 1 cup/day: HR = 0.94 (95% CI: 0.87, 1.02); 2-3 cups/day: HR = 0.82 (95% CI: 0.77, 0.88); 4-5 cups/day: HR = 0.79 (95% CI: 0.72, 0.86); >=6 cups/day: HR = 0.84 (95% CI: 0.75, 0.95)). Similar findings were observed for decaffeinated coffee and coffee additives. Inverse associations were observed for deaths from heart disease, chronic respiratory diseases, diabetes, pneumonia and influenza, and intentional self-harm, but not cancer. Coffee may reduce mortality risk by favorably affecting inflammation, lung function, insulin sensitivity, and depression. PMID- 26614601 TI - Physical exercise and pelvic girdle pain in pregnancy: A nested case-control study within the Danish National Birth Cohort. AB - OBJECTIVE: Pelvic girdle pain is a frequent cause of sick leave among pregnant women in Denmark. Studies regarding prevention of pelvic girdle pain are sparse. The aim of this study was to examine the association between physical exercise and pelvic girdle pain in pregnancy. STUDY DESIGN: A nested case-control study within the Danish National Birth Cohort (n = 5304). METHODS: This study used self reported data on pelvic girdle pain obtained from an interview six months after childbirth. Information on physical exercise was obtained from the pregnancy interview around gestational week 16. The association was estimated using logistic regression analysis. RESULTS: Physical exercise in pregnancy was associated with decreased risk of overall pelvic girdle pain (OR = 0.87; 95% CI: 0.77-0.99, p = 0.028). Tests for trend indicated decreasing odds for pelvic girdle pain with increasing number of hours per week spent on exercise (p < 0.001). Compared to no exercise, swimming was associated with a decreased risk of pelvic girdle pain (OR = 0.73; 95% CI: 0.58-0.91, p = 0.005). CONCLUSIONS: The findings suggest a possible protective effect of physical exercise on pelvic girdle pain during pregnancy. PMID- 26614602 TI - Identifying women who are afraid of giving birth: A comparison of the fear of birth scale with the WDEQ-A in a large Australian cohort. AB - BACKGROUND: The WDEQ-A is the most widely used measure of childbirth fear in pregnant women; however there is increasing discussion in the literature that simpler, more culturally transferrable tools may offer a better solution to identifying fearful women in clinical practice. AIM: To compare the two item Fear of Birth Scale (FOBS) with the 33 item WDEQ-A in a large cohort of Australian pregnant women. METHOD: Self-report questionnaires during second trimester including Wijma Delivery Expectancy Questionnaire (WDEQ-A) and Fear of Birth Scale (FOBS). Correlation of FOBS and WDEQ-A was tested using Spearman's correlation coefficients. Receiver operating characteristic (ROC) curve assessed the sensitivity and specificity of possible cut-points on the FOBS against WDEQ-A cut-point of >=85. Sensitivity, specificity, positive and negative predictive values were determined. Fearful and non-fearful women as classified by both instruments were compared for differences in demographic, psycho-social and obstetric characteristics. RESULTS: 1410 women participated. The correlation between the instruments was strong (Spearman's Rho = 0.66, p < 0.001). The area under the ROC was 0.89 indicating high sensitivity with a FOBS cut-point of 54. Sensitivity was 89%, specificity 79% and Youden index 0.68. Positive predictive value was 85% and negative predictive value 79%. Both instruments identified high fear as significantly associated with first time mothers, previous emergency caesarean and women with self-reported anxiety and/or depression. Additionally FOBS identified a significant association between fearful women and preference for caesarean. CONCLUSION: This study supports the use of the FOBS in clinical practice to identify childbirth fear in pregnant women. PMID- 26614603 TI - Pregnant women's expectations about pain intensity during childbirth and their attitudes towards pain management: Findings from an Icelandic national study. AB - BACKGROUND: Pregnant women expect childbirth to be painful. However, little is known about their expectations of the intensity of pain in childbirth (EIPC) and their attitudes to pain management. METHOD: The design was a cross-sectional survey, with self-reported questionnaires used to collect data from low-risk pregnant women (N = 1111) early in pregnancy at 26 of the largest primary health care centres in Iceland. This consecutive national sample was stratified by residency. RESULTS: The mean score for the EIPC was 5.58 (SD = 1.38) measured on a 7 point scale. The strongest predictors of a high EIPC score were: negative attitude to the impending childbirth (OR = 2.39), low manifestation of a sense of security (OR = 1.80), and a positive attitude to pain management with medication (OR = 1.63). Women living outside the capital area were less likely to have a high EIPC (OR = 0.68). Most women (77%) had a positive attitude towards pain management without medication and 35% had a positive attitude to pain management with medication. CONCLUSIONS: The study detected multiple predictors of women's EIPC and attitude to pain management. Early and throughout pregnancy, midwives and health care professionals need to address these predictors in order to assist women to prepare themselves for the pain of labour. PMID- 26614604 TI - Women's experiences of cervical ripening as inpatients on an antenatal ward. AB - OBJECTIVE: To gain an insight into women's lived experiences of inpatient cervical ripening, in the context of usual care, whilst they were admitted as inpatients on an antenatal ward. METHODS: A qualitative design was used guided by an interpretative phenomenological approach. Seven women who had experienced inpatient cervical ripening on an antenatal ward in Wales (UK) agreed to participate in the study. Data were gathered from semi-structured interviews and analysed thematically. RESULTS: Four overarching themes were identified relating to participants' support from significant others, their understanding of the procedure, perception of their own physiological sensations, and their sense of freedom within the ward environment. CONCLUSIONS: Strict adherence to ward rules and procedures appeared to undermine women's experiences of cervical ripening as inpatients on an antenatal ward. Facilitating the continued presence of family members, improving the provision of information, listening to women and enhancing their perception of freedom within the ward environment are strategies that may have a positive influence on women's experiences of inpatient cervical ripening. This study has provided an insight into women's experiences of usual care, during the cervical ripening procedure, as inpatients on an antenatal ward. PMID- 26614605 TI - Women's experience of unplanned out-of-hospital birth in Sweden - a phenomenological description. AB - BACKGROUND: Between 0.5 and 2 percent of women planning to give birth in a hospital environment in Sweden will have an unplanned out-of-hospital birth. Few studies have described mothers' experiences of out-of-hospital births and none on a Swedish population. In an attempt to fill this gap, we have made this pilot study designed to capture mothers' experiences of unplanned out-of-hospital births in Sweden. METHOD: Qualitative interviews with eight Swedish women, one to three years after they experienced an unplanned out-of-hospital birth. Data were analysed using the method of phenomenological description. RESULTS: The meaning of giving unplanned birth outside a hospital environment was "The lived experience of a pendular movement between the good fortune and pride in managing the situation and the fear of what could have happened when giving unplanned birth outside a hospital environment." In the analysis two clusters emerged that supported the essence: Balancing Emotions and Handling Unfamiliar Actions. CONCLUSIONS: This study contributes to an understanding of the natural processes when giving birth. The findings can be useful when communicating the experience of unplanned out-of-hospital birth to parents in antenatal classes. The women could be encouraged to listen and trust their own body signs as a preparation for giving birth in any type of setting. Guidelines for taking care of women with out of-hospital birth experiences are suggested. PMID- 26614606 TI - Midwives' experiences of labour care in midwifery units. A qualitative interview study in a Norwegian setting. AB - OBJECTIVE: In some economically developed countries, women's choice of birth care and birth place is encouraged. The aim of this study was to explore and describe the experiences of midwives who started working in alongside/free-standing midwifery units (AMU/FMU) and their experiences with labour care in this setting. METHODS: A qualitative explorative design using a phenomenographic approach was used. Semi-structured interviews were conducted with ten strategically sampled midwives working in midwifery units. RESULTS: The analysis revealed the following five categories of experiences noted by the midwives: mixed emotions and de learning obstetric unit habits, revitalising midwifery philosophy, alertness and preparedness, presence and patience, and coping with time. CONCLUSIONS: Starting to work in an AMU/FMU can be a distressing period for a midwife. First, it may require de-learning the medical approach to birth, and, second, it may entail a revitalisation (and re-learning) of birth care that promotes physiological birth. Midwifery, particularly in FMUs, requires an especially careful assessment of the labouring process, the ability to be foresighted, and capability in emergencies. The autonomy of midwives may be constrained also in AMUs/FMUs. However, working in these settings is also viewed as experiencing "the art of midwifery" and enables revitalisation of the midwifery philosophy. PMID- 26614607 TI - Challenges and benefits of conducting parental classes in Sweden: Midwives' perspectives. AB - OBJECTIVE: There is lack of knowledge regarding antenatal care midwives' perspectives concerning parental classes provided during pregnancy, and this study aimed to explore midwives' experiences and thoughts about these parental class activities. METHODS: Twenty-six semi-structured, individual, telephone interviews were carried out with midwives at antenatal clinics across Sweden, and the data were analysed using systematic text condensation (STC). RESULTS: The midwives noted that parental classes were a demanding task, and they appeared to lack the confidence and skills required to manage the classes. They expressed a "need for collaborators to achieve the objectives" (theme 1). The midwives felt that "creating new networks is most valuable for parents" (theme 2), and they were also "striving to give the 'whole picture' to both parents" (theme 3), i.e. looking beyond just the delivery. Although they had the ambition, midwives realised it was "not possible to reach all" (theme 4). CONCLUSIONS: Organisational resources as well as developing skills to lead groups are imperative for midwives to fulfil the goals of the parental classes. The midwives are aware that they cannot reach all parents with the group format; thus, it is important to acknowledge the needs of minority populations and develop multidisciplinary collaborations to be able to better address their needs. PMID- 26614608 TI - Prevalence and predictors of female genital mutilation among infants in a semi urban community in northern Nigeria. AB - OBJECTIVES: To determine the prevalence, predictors, of female genital mutilation (FGM) among infants and ascertain if their mothers knew what was done to them in Birnin Kudu northern Nigeria. METHODS: Cross sectional study which utilised a pretested interviewer administered semi-structured questionnaire to assess occurrence of FGM with physical examination of the infants. Logistic regression analysis was used to assess the relative effect of determinants, after adjusting for other predictor variables. RESULTS: Of the 450 infants, 215(47.8%) (95% Confidence Interval [CI]: 43.1%-52.5%) had experienced one form of FGM. The ages at genital mutilation ranged from 1 to 50 days with a median of 4 days and interquartile range of 7 days. Maternal occupation, education and religion and type of facility accessed were significantly associated with occurrence of FGM in infants (p <= 0.05). After controlling for confounders, having a mother without formal education [AOR = 6.39 and 95% CI = 3.99-10.23] (p = 0.001) and one who was employed [Adjusted odds ratio (AOR) = 2.89 and 95% CI = 1.66-5.03] (p = 0.001) increased the likelihood of infant FGM remarkably while utilising tertiary institution for health care reduced the risk by about half [AOR = 0.49 and 95% CI = 0.26-0.92] (p = 0.03). Of the 215 infants that had undergone FGM, there was correlation between the reported and the observed forms of FGM in 16 (7.4%) of the cases. CONCLUSION: The prevalence of FGM is high with mothers' educational status, type of health facility utilised and occupational status being predictors of FGM among infants in Birnin Kudu. Majority of the mothers are not aware of what was done. Strategies aimed at discouraging this dangerous practice in the community should include female education, involvement of the men as husbands, fathers, traditional and religious leaders. PMID- 26614609 TI - Menstrual hygiene practices and its association with reproductive tract infections and abnormal vaginal discharge among women in India. AB - OBJECTIVE: The objective was to explore the determinants of menstrual hygienic practices and its effect on Reproductive Tract Infections (RTI) among ever married women in India. METHODS: District Level Household and Facility Survey-3 (DLHS) India data have been used in the study. The respondents constituted ever married women (N = 577,758) in the age group of 15-49. Bivariate and multivariate techniques were employed using IBM SPSS statistics 20. Individual effects of socio economic, demographic and gynecological factors on menstrual hygienic practices, RTIs and abnormal vaginal discharged respectively were calculated using binary logistic regression. RESULTS: A meager 15% of women used sanitary pad/locally prepared napkins during menstruation in India. Both RTI and Vaginal discharge were positively related with non-use of hygienic methods. The women who used unhygienic method during menstruation were more likely to have any symptom of RTI (OR = 1.046, p < 0.001, CI = 1.021-1.071) and vaginal discharge (OR = 1.303, p < 0.001, CI = 1.266-1.341). CONCLUSION: The reason for the symptoms of RTI may be diverse and not only limited to the unhygienic menstrual practices although this may be one of the reasons causing reproductive morbidity. Awareness, affordability and privacy are some of the major concerns that need immediate attention to promote the use of sanitary pad during the time of menstruation. Establishing relation between menstrual practices and RTI is in its initial stage of investigation and hence needs further research. PMID- 26614610 TI - Clinical experience and perception of abortion: A cross-sectional survey of gynecologists in Japan. AB - This study describes aspects of early induced abortion from the experience and perspectives of a sample of gynecologists in Japan. The survey questionnaire data were collected from 343 gynecologists from September to October 2010. Approximately 83% of participants preferred using only dilation and curettage (D&C), and 10.4% used electric vacuum aspiration (EVA). The cost of surgical abortion was not covered by insurance. Most gynecologists used intravenous pain management during abortion. Approximately 50% of the gynecologists were opposed to introducing medical abortion in Japan. PMID- 26614611 TI - The clinical phenotypes of autoimmune hepatitis: A comprehensive review. AB - Autoimmune hepatitis (AIH) fulfills the generally accepted contemporary criteria of an autoimmune liver disease: the presence of autoantibodies and autoreactive T cells, a female gender bias, association with other autoimmune diseases, response to immunosuppressive therapy and strong associations with the major histocompatibility complex HLA loci. It occurs worldwide in both children and adults and is marked by both etiopathogenic and clinical heterogeneity, differing from the other putative autoimmune liver diseases, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), albeit occasionally presenting with overlapping features of PBC or PSC. Although diagnostic criteria have been established and validated, there are still major issues to be clarified due to its variability, such as autoantibody-negative AIH, drug-induced AIH, AIH sharing features with PBC or PSC, and post-transplant de novo AIH. In view of the diverse presentations and courses, including classical chronic onset, acute and acute severe onset, cirrhosis and decompensated cirrhosis, individualized management of patients is indicated. Each patient should receive a personalized analysis of the benefits and side effect risks of drugs. Herein we describe a comprehensive review of the clinical phenotypes of AIH underscoring its clinical heterogeneity. PMID- 26614612 TI - Effects of an Educational Workshop on Pediatric Nurses' Attitudes and Beliefs About Family-Centered Bedside Rounds. AB - This pilot study evaluated the effects of an educational workshop on nurses' (N=36) attitudes and beliefs toward family-centered bedside rounds (FBR) using a single group, pretest/posttest design on two pediatric inpatient units at an academic tertiary-care center in Western Canada. The theory of planned behavior was used to develop the Nurses Attitudes and Behaviors about Rounds (NABAR) questionnaire. There were statistically significant increases between pretest and posttest scores on nurses' intentions, subjective norms and perceived behavioral control related to FBR, and on providing education to families about FBR. A brief, educational workshop can positively affect nurses' attitudes and beliefs about FBR. Future research should include additional psychometric evaluation of the NABAR. PMID- 26614613 TI - Semi-Prone Position Can Influence Variability in Respiratory Rate of Premature Infants Using Nasal CPAP. AB - To determine the effect of positions (supine, lateral, semiprone) on the physiological parameters (HR, RR, SpO2) of premature infants receiving NCPAP who were non-oxygen-dependent and non-BPD, and to identify significant clinical changes associated with these variables. METHODS: A crossover study design with three different positions in the assigned sequence (supine-supine, supine-lateral and supine-semiprone) was used, and each position was maintained for 1h. The subjects' vital signs were recorded 30 min after initiation of each position and measured for 30 min. RESULTS: Forty-seven infants with a median GA of 28.6 weeks (range 26-35) were studied, and their median BW was 1210g (range 776-2920). Overall, position-related effects showed significant difference in the variability in RR (OR=0.68; CI 0.51-0.89), with the variability in RR being significantly lower in the semiprone position. The lateral position was associated with increased RR (B=2.9; p=0.02). Previous use of ventilator (PUV) was associated with increased HR, whereas BW and GA were negatively associated with higher HR. Cesarean birth, use of surfactant and PUV were associated with lower SpO2, whereas BW and GA were correlated with higher SpO2. GA was identified as a protective factor, while PUV was a risk factor for the variability in both HR and SpO2. CONCLUSIONS: Premature infants receiving NCPAP sleeping in the semiprone position may have more stable RR, while the lateral position did not improve RR. Thus, the semiprone and supine positions may be considered preferable when positioning the monitored premature infants with NCPAP. PMID- 26614614 TI - Multi-tissue transcriptome profiles for coho salmon (Oncorhynchus kisutch), a species undergoing rediploidization following whole-genome duplication. AB - Salmonids are an important family of fish both from economic and basic research perspectives, and have been subjected to extensive research at whole-animal and molecular levels. Most research to date has been conducted on Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss), but more recently other salmonids have become a focus of study due to their interesting life histories and because of their potential for use in commercial aquaculture. However, molecular biology and genetic analyses for these emerging species are currently hampered due to the lack of extensive genomic resources. To overcome some of these limitations, we have constructed a 43,228 sequence transcriptome from 13 tissues from coho salmon, Oncorhynchus kisutch using de novo transcriptome assembly methods. The transcriptome profiling analysis has provided data distinguishing allelic variation from paralogues that arose during the recent whole-genome duplication event in this family, thus allowing simplified analysis of gene-specific expression. Additionally, 1599 novel coho sequences have been identified through comparison with transcriptomes from two other salmonids species (Atlantic salmon and rainbow trout), and with northern pike. The transcriptome presented here will be useful for genomic analysis of coho salmon and other closely related salmonid species. PMID- 26614615 TI - Evaluating the feasibility and effectiveness of a critical care discharge information pack for patients and their families: a pilot cluster randomised controlled trial. AB - OBJECTIVES: To evaluate the feasibility and effectiveness of an information pack, based on self-regulation theory, designed to support patients and their families immediately before, during and after discharge from an intensive care unit (ICU). DESIGN AND SETTING: Prospective assessor-blinded pilot cluster randomised controlled trial (RCT; in conjunction with a questionnaire survey of trial participants' experience) in 2 ICUs in England. PARTICIPANTS: Patients (+/- a family member) who had spent at least 72 h in an ICU, declared medically fit for discharge to a general ward. RANDOMISATION: Cluster randomisation (by day of discharge decision) was used to allocate participants to 1 of 3 study groups. INTERVENTION: A user-centred critical care discharge information pack (UCCDIP) containing 2 booklets; 1 for the patient (which included a personalised discharge summary) and 1 for the family, given prior to discharge to the ward. PRIMARY OUTCOME: Psychological well-being measured using Hospital Anxiety and Depression Scores (HADS), assessed at 5+/-1 days postunit discharge and 28 days/hospital discharge. Statistical significance (p<=0.05) was determined using chi(2) and Kruskal-Wallis (H). RESULTS: 158 patients were allocated to: intervention (UCCDIP; n=51), control 1: ad hoc verbal information (n=59), control 2: booklet published by ICUsteps (n=48). There were no statistically significant differences in the primary outcome. The a priori enrolment goal was not reached and attrition was high. Using HADS as a primary outcome measure, an estimated sample size of 286 is required to power a definitive trial. CONCLUSIONS: Findings from this pilot RCT provide important preliminary data regarding the circumstances under which an intervention based on the principles of UCCDIP could be effective, and the sample size required to demonstrate this. TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN47262088; results. PMID- 26614616 TI - Use of surrogate outcomes in US FDA drug approvals, 2003-2012: a survey. AB - OBJECTIVE: To evaluate, across a spectrum of diseases, how often surrogate outcomes are used as a basis for drug approvals by the US Food and Drug Administration (FDA), and whether and how the rationale for using treatment effects on surrogates as predictors of treatment effects on patient-centred outcomes is discussed. STUDY DESIGN AND SETTING: We used the Drugs@FDA website to identify drug approvals produced from 2003 to 2012 by the FDA. We focused on four diseases (chronic obstructive pulmonary disease (COPD), type 1 or 2 diabetes, glaucoma and osteoporosis) for which surrogates are commonly used in trials. We reviewed the drug labels and medical reviews to provide empirical evidence on how surrogate outcomes are handled by the FDA. RESULTS: Of 1043 approvals screened, 58 (6%) were for the four diseases of interest. Most drugs for COPD (7/9, 78%), diabetes (26/26, 100%) and glaucoma (9/9, 100%) were approved based on surrogates while for osteoporosis, most drugs (10/14, 71%) were also approved for patient centred outcomes (fractures). The rationale for using surrogates was discussed in 11 of the 43 (26%) drug approvals based on surrogates. In these drug approvals, we found drug approvals for diabetes are more likely than the other examined conditions to contain a discussion of trial evidence demonstrating that treatment effects on surrogate outcomes predict treatment effects on patient-centred outcomes. CONCLUSIONS: Our results suggest that the FDA did not use a consistent approach to address surrogates in assessing the benefits and harms of drugs for COPD, type 1 or 2 diabetes, glaucoma and osteoporosis. For evaluating new drugs, patient-centred outcomes should be chosen whenever possible. If the use of surrogate outcomes is necessary, then a consistent approach is important to review the evidence for surrogacy and consider surrogate's usage in the treatment and population under study. PMID- 26614617 TI - Determinants of access to chronic illness care: a mixed-methods evaluation of a national multifaceted chronic disease package for Indigenous Australians. AB - OBJECTIVES: Indigenous Australians have a disproportionately high burden of chronic illness, and relatively poor access to healthcare. This paper examines how a national multicomponent programme aimed at improving prevention and management of chronic disease among Australian Indigenous people addressed various dimensions of access. DESIGN: Data from a place-based, mixed-methods formative evaluation were analysed against a framework that defines supply and demand-side dimensions to access. The evaluation included 24 geographically bounded 'sentinel sites' that included a range of primary care service organisations. It drew on administrative data on service utilisation, focus group and interview data on community members' and service providers' perceptions of chronic illness care between 2010 and 2013. SETTING: Urban, regional and remote areas of Australia that have relatively large Indigenous populations. PARTICIPANTS: 670 community members participated in focus groups; 374 practitioners and representatives of regional primary care support organisations participated in in-depth interviews. RESULTS: The programme largely addressed supply-side dimensions of access with less focus or impact on demand-side dimensions. Application of the access framework highlighted the complex inter relationships between dimensions of access. Key ongoing challenges are achieving population coverage through a national programme, reaching high-need groups and ensuring provision of ongoing care. CONCLUSIONS: Strategies to improve access to chronic illness care for this population need to be tailored to local circumstances and address the range of dimensions of access on both the demand and supply sides. These findings highlight the importance of flexibility in national programme guidelines to support locally determined strategies. PMID- 26614618 TI - The burden of stroke in the Netherlands: estimating quality of life and costs for 1 year poststroke. AB - OBJECTIVES: To assess and explore over 1 year poststroke (1) the societal costs, (2) changes in costs and quality of life (QoL) and (3) the relation between costs and QoL. DESIGN: The current study is a burden of disease study focusing on the cost-of-illness (in Euros) and QoL (in utilities) after stroke. SETTING: Adult patients with stroke were recruited from stroke units in hospitals and followed for 1 year. PARTICIPANTS: Data were collected from 395 patients with stroke. MAIN OUTCOME MEASURES: Costs and QoL expressed in utilities. METHODS: Cost categories were identified through a bottom-up method. The Dutch 3-level 5-dimensional EuroQol (EQ-5D-3L) was used to calculate utilities. Non-parametric bootstrapping was applied to test for statistical differences in costs. Subgroup analyses were performed to identify predictors for costs and QoL. Robustness of results was tested via sensitivity analyses. RESULTS: The total societal costs for 1 year poststroke were ?29 484 (n=352) of which 74% were in the first 6 months. QoL remained stable over time. The discharge location was a significant predictor for cost and QoL; men had a significantly higher QoL than women and younger patients (<65) had significantly more costs than older patients (>65). Ceiling effects appear on all dimension of the EQ-5D-3L. Costs and QoL show a weak correlation (r=-0.29). Sensitivity analyses showed robustness of results. CONCLUSIONS: We found lower patient costs and higher QoL than expected. This may be explained by the good state of health of our study population and by change in the Dutch healthcare system, which has led to considerable shorter hospitalisation poststroke. Future research must question the use of the EQ-5D-3L in a similar population due to ceiling effects. TRIAL REGISTRATION NUMBER: NTR3051. PMID- 26614619 TI - Trends from the surveillance of suicidal behaviour by the Belgian Network of Sentinel General Practices over two decades: a retrospective observational study. AB - OBJECTIVES: First, we describe trends in characteristics of suicidal events using new (2011-2012) and previous (1993-1995, 2000-2001 and 2007-2008) data reported by the Belgian Network of Sentinel General Practices (SGP); second, we examine patient age-related trends in on-site attendance of sentinel general practitioners (GPs) as first professional caregivers following suicidal behaviour; third, we investigate the accuracy of suicide incidence estimates derived from the SGP data. DESIGN: Retrospective observational study. SETTING: General practices from the nationwide representative Belgian Network of SGP. OUTCOME MEASURES: Patient gender and age, suicide methods, whether the patient was new, whether the GP was the first caregiver on-site, and the outcome of the suicidal behaviour (fatal or not) were recorded on standard registration forms. The accuracy of suicide incidence estimates was tested against suicide mortality data. RESULTS: Over the four time periods, 1671 suicidal events were reported: 275 suicides, 1287 suicide attempts and 109 events of suicidal behaviour of unknown outcome. In 2011-2012, sentinel GPs' on-site attendance following the suicidal behaviour of patients <65 years had continued to decrease (from 71% in 1993-1995 to 58% in 2000-2001, 39% in 2007-2008 and 25% in 2011-2012). In 2011 2012, it had also decreased steeply in the population >=65 years (from 70% in 1993-1995, 76% in 2000-2001 and 79% in 2007-2008 to 35% in 2011-2012). No significant differences were found between the SGP-based suicide incidence estimates for 2011-2012 and the available suicide mortality rates for people <65 and >=65 years. CONCLUSIONS: GPs' on-site attendance as first professional caregivers following suicidal behaviour continues to decline since 2011-2012 also in the population >=65 years. Unawareness of patients' suicidal behaviour endangers both care for surviving patients and the completeness of SGP surveillance data. Yet, the incidence of suicide for 2011-2012 was estimated accurately by the SGP. PMID- 26614620 TI - Contact with the baby following stillbirth and parental mental health and well being: a systematic review. AB - OBJECTIVE: To collate and critically appraise extant evidence for the impact of contact with the stillborn infant on parental mental health, well-being and satisfaction. DESIGN: Systematic review. DATA SOURCES: A structured systematic search was conducted in 13 databases, complemented by hand-searching. STUDY ELIGIBILITY CRITERIA: English language studies providing quantitative comparison of outcomes for parents who held their baby or engaged in other memory-making activities, such as having photos and handprints, compared to those who did not, were eligible for inclusion. OUTCOME MEASURES: Primary outcomes included clinically diagnosed mental health issues, standardised assessment of mental health issues or self-reported psychological distress. Secondary outcomes included poor health, relationship difficulties and satisfaction with the decision to have contact with the baby. RESULTS: Two authors independently screened abstracts, selected potentially eligible studies, extracted data and evaluated the quality of included papers. 11 eligible studies, reported in 18 papers, were included. Studies were heterogeneous, precluding quantitative synthesis, thus a narrative synthesis is presented. Studies presented high risks of bias, particularly in regard to sample representativeness, and confounder identification and adjustment. Results were mixed concerning the impact of holding the stillborn baby on mental health and well-being. One study found no significant effects, and two studies reported no impact on depression. Conflicting effects were found for anxiety and post-traumatic stress. Other memory-making activities were not found to have a significant association with mental health or well-being outcomes. Across studies, mothers were satisfied with their decision to hold their baby or engage in other memory making. CONCLUSIONS: Evidence for the impact of holding the stillborn baby on mental health and well being is sparse, and of poor quality. High-quality research guided by a priori hypotheses, with attention to potential confounders and moderating effects, is needed to provide more rigorous evidence to guide practitioners' and parents' decision-making for care following stillbirth. REVIEW PROTOCOL NUMBER: PROSPERO CRD42014013890. PMID- 26614621 TI - System hazards in managing laboratory test requests and results in primary care: medical protection database analysis and conceptual model. AB - OBJECTIVES: To analyse a medical protection organisation's database to identify hazards related to general practice systems for ordering laboratory tests, managing test results and communicating test result outcomes to patients. To integrate these data with other published evidence sources to inform design of a systems-based conceptual model of related hazards. DESIGN: A retrospective database analysis. SETTING: General practices in the UK and Ireland. PARTICIPANTS: 778 UK and Ireland general practices participating in a medical protection organisation's clinical risk self-assessment (CRSA) programme from January 2008 to December 2014. MAIN OUTCOME MEASURES: Proportion of practices with system risks; categorisation of identified hazards; most frequently occurring hazards; development of a conceptual model of hazards; and potential impacts on health, well-being and organisational performance. RESULTS: CRSA visits were undertaken to 778 UK and Ireland general practices of which a range of systems hazards were recorded across the laboratory test ordering and results management systems in 647 practices (83.2%). A total of 45 discrete hazard categories were identified with a mean of 3.6 per practice (SD=1.94). The most frequently occurring hazard was the inadequate process for matching test requests and results received (n=350, 54.1%). Of the 1604 instances where hazards were recorded, the most frequent was at the 'postanalytical test stage' (n=702, 43.8%), followed closely by 'communication outcomes issues' (n=628, 39.1%). CONCLUSIONS: Based on arguably the largest data set currently available on the subject matter, our study findings shed new light on the scale and nature of hazards related to test results handling systems, which can inform future efforts to research and improve the design and reliability of these systems. PMID- 26614622 TI - Preschool children's vision screening in New Zealand: a retrospective evaluation of referral accuracy. AB - OBJECTIVES: To assess the accuracy of preschool vision screening in a large, ethnically diverse, urban population in South Auckland, New Zealand. DESIGN: Retrospective longitudinal study. METHODS: B4 School Check vision screening records (n=5572) were compared with hospital eye department data for children referred from screening due to impaired acuity in one or both eyes who attended a referral appointment (n=556). False positive screens were identified by comparing screening data from the eyes that failed screening with hospital data. Estimation of false negative screening rates relied on data from eyes that passed screening. Data were analysed using logistic regression modelling accounting for the high correlation between results for the two eyes of each child. PRIMARY OUTCOME MEASURE: Positive predictive value of the preschool vision screening programme. RESULTS: Screening produced high numbers of false positive referrals, resulting in poor positive predictive value (PPV=31%, 95% CI 26% to 38%). High estimated negative predictive value (NPV=92%, 95% CI 88% to 95%) suggested most children with a vision disorder were identified at screening. Relaxing the referral criteria for acuity from worse than 6/9 to worse than 6/12 improved PPV without adversely affecting NPV. CONCLUSIONS: The B4 School Check generated numerous false positive referrals and consequently had a low PPV. There is scope for reducing costs by altering the visual acuity criterion for referral. PMID- 26614623 TI - Patient and healthcare perspectives on the importance and efficacy of addressing spiritual issues within an interdisciplinary bone marrow transplant clinic: a qualitative study. AB - OBJECTIVES: The purpose of this study was to use a qualitative approach to better understand the importance and efficacy of addressing spiritual issues within an interdisciplinary bone marrow transplant clinic from the perspectives of patients and healthcare providers. SETTING: Participants were recruited from the bone marrow transplant clinic of a large urban outpatient cancer care centre in western Canada. PARTICIPANTS: Focus groups were conducted with patients (n=7) and healthcare providers (n=9) to explore the importance of addressing spiritual issues across the treatment trajectory and to identify factors associated with effectively addressing these needs. RESULTS: Data were analysed using the qualitative approach of latent content analysis. Addressing spiritual issues was understood by patients and healthcare providers, as a core, yet under addressed, component of comprehensive care. Both sets of participants felt that addressing basic spiritual issues was the responsibility of all members of the interdisciplinary team, while recognising the need for specialised and embedded support from a spiritual care professional. While healthcare providers felt that the impact of the illness and treatment had a negative effect on patients' spiritual well-being, patients felt the opposite. Skills, challenges, key time points and clinical indicators associated with addressing spiritual issues were identified. CONCLUSIONS: Despite a number of conceptual and clinical challenges associated with addressing spiritual issues patients and their healthcare providers emphasised the importance of an integrated approach whereby basic spiritual issues are addressed by members of the interdisciplinary team and by an embedded spiritual care professional, who in addition also provides specialised support. The identification of clinical issues associated with addressing spiritual needs provides healthcare providers with clinical guidance on how to better integrate this aspect of care into their clinical practice, while also identifying acute incidences when a more targeted and specialised approach may be of benefit. PMID- 26614624 TI - Potential for advice from doctors to reduce the number of patients referred to emergency departments by NHS 111 call handlers: observational study. AB - OBJECTIVE: To determine the effect of using experienced general practitioners (GPs) to review the advice given by call handlers in NHS 111, a national service giving telephone advice to people seeking medical care. DESIGN: Observational study following the introduction of GPs to review call handlers' decisions which had been made using decision support software. SETTING: NHS 111 call centre covering Cambridgeshire and Peterborough. INTERVENTION: When a call handler using standard NHS 111 decision support software would have advised the caller to attend the hospital accident and emergency (A&E) department, the decision was reviewed by an experienced GP. MAIN OUTCOME MEASURES: Percentage of calls where an outcome other than A&E attendance was recommended by the GP. RESULTS: Of 1474 cases reviewed, the GP recommended A&E attendance in 400 cases (27.1%). In the remainder of cases, the GP recommended attendance at a primary care out-of-hours centre or minor injury unit in 665 cases (45.2%) and self-management or some alternative strategy in 409 (27.8%). CONCLUSIONS: Fewer callers to NHS 111 would be sent to emergency departments if the decision was reviewed by an experienced GP. Telephone triage services need to consider whether using relatively unskilled call handlers supported by computer software is the most cost-effective way to handle requests for medical care. PMID- 26614625 TI - Multiple myeloma and physical activity: a scoping review. AB - OBJECTIVES: Multiple myeloma is the second most common haematological cancer. A growing body of literature is emerging that investigates the role physical activity plays in all stages of multiple myeloma (prevention and survivorship) and to date no attempt has been made to collate and understand this literature. Therefore, this scoping review aims to (1) outline what is already known about physical activity in all stages of multiple myeloma (2) map the literature on physical activity and multiple myeloma and (3) identify future directions for research. DESIGN: Scoping Review. DATA SOURCES: Searches were carried out in May 2015. Searchers were conducted in PubMed, Web of Science, SPORTdiscus and MEDLINE. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: To be included studies had to report original data, investigate physical activity per se or physical activity correlates and multiple myeloma or smouldering multiple myeloma. RESULTS: A total of 19 papers received full screening, 5 of these papers were excluded. This review identified three journal articles relating to the role of physical activity in the prevention of multiple myeloma, nine papers were identified in the treatment of multiple myeloma and two on smouldering multiple myeloma. CONCLUSIONS: The search identified that the literature surrounding multiple myeloma and physical activity is very limited. We encourage those designing new cohort studies to allow for future assessment of associations between physical activity and onset of multiple myeloma and smouldering multiple myeloma, as well as the potential role that physical activity plays in the progression from smouldering multiple myeloma to multiple myeloma. Second, we encourage the design and investigation of gender and treatment-specific physical activity interventions in patients with multiple myeloma. Finally, we highlight the need for more randomised controlled trials to evaluate the impact of different types, frequencies and intensities of physical activity on various health parameters in multiple myeloma survivors. PMID- 26614626 TI - Delayed/back up antibiotic prescriptions: what do the public think? AB - OBJECTIVE: To describe the general public's understanding, acceptance and use of delayed antibiotics. DESIGN: Face to face computer-assisted survey using an Ipsos MORI Capibus survey. SETTING: Randomly selected households in England using multistage sampling. RESPONDENTS: A representative sample of 1625 adults aged over 15 years and recruited from household visits in England, using age and gender quotas for each area. DATA COLLECTION AND ANALYSIS: The survey was undertaken in January 2014. Weights based on gender, age, ethnicity, working status, social grade, housing tenure and Government Office Region corrected for selection biases, so that results are broadly representative of the population. MAIN OUTCOMES MEASURES: Proportion of respondents; understanding the meaning of the term delayed antibiotic prescription and how the strategy is used in general practice; in favour of, or opposed to clinicians offering them a delayed antibiotic; reporting receipt, use and acceptability of delayed antibiotic prescriptions in the past year. RESULTS: 17% reported fully understanding the meaning of delayed antibiotic prescription and strategy use in general practice;72% were unaware of the term or strategy; 36-39% were in favour of, and 28-30% opposed to clinicians offering them a delayed antibiotic for throat, urine, ear or chest infections. Half of those who were fully aware of the term and practice were in favour of delayed antibiotics. Women, and older respondents, were more strongly opposed to delayed prescribing. Only 4% of all respondents, and 15% of those prescribed an antibiotic, reported being offered a delayed antibiotic in the last year. CONCLUSIONS: Wider understanding and acceptance of delayed prescribing may facilitate increased uptake. Further research is needed to determine why groups are so strongly in favour or opposed to delayed prescribing. PMID- 26614628 TI - Seven days in medicine: 21-27 November. PMID- 26614629 TI - Assessing interventions to increase compliance to patching treatment in children with amblyopia: a systematic review and meta-analysis. AB - BACKGROUND/AIMS: Amblyopia is the most common condition affecting visual acuity in childhood. Left untreated it will not resolve itself, leading to increased risk of blindness. Occluding the good eye with a patch is a highly effective treatment if carried out before age 7 years but compliance is a major problem. This systematic review addresses the question: How effective are existing interventions at increasing compliance to patching treatment in children with amblyopia? METHODS: Electronic searches were carried out in June 2014 and updated in April 2015 to identify studies reporting primary data on interventions to increase patching compliance. Data screening, extraction and quality ratings were performed independently by two researchers. RESULTS: Nine papers were included. Interventions including an educational element (5 studies) significantly increased patching compliance and had higher quality ratings than interventions that changed aspects of the patching regime (3 studies) or involved supervised occlusion (1 study). Meta-analysis was conducted on four studies and indicated that overall interventions involving an educational element have a significant small effect r=0.249, p<0.001. CONCLUSIONS: Interventions to increase patching compliance should include educational elements. High quality research is needed to further assess the effectiveness of specific elements of educational interventions and additional behaviour change techniques. PMID- 26614627 TI - Randomised, single-masked non-inferiority trial of femtosecond laser-assisted versus manual phacoemulsification cataract surgery for adults with visually significant cataract: the FACT trial protocol. AB - INTRODUCTION: Cataract is one of the leading causes of low vision in the westernised world, and cataract surgery is one of the most commonly performed operations. Laser platforms for cataract surgery are now available, the anticipated advantages of which are broad and may include better visual outcomes through greater precision and reproducibility, and improved safety. FACT is a randomised single masked non-inferiority trial to establish whether laser assisted cataract surgery is as good as or better than standard manual phacoemulsification. METHODS AND ANALYSIS: 808 patients aged 18 years and over with visually significant cataract will be randomised to manual phacoemulsification cataract surgery (standard care) or laser-assisted cataract surgery (intervention arm). Outcomes will be measured at 3 and 12 months after surgery. The primary clinical outcome is uncorrected distance visual acuity (UDVA, logMAR) at 3 months in the study eye recorded by an observer masked to the trial group. Secondary outcomes include UDVA at 12 months, corrected distance visual acuity at 3 and 12 months, complications, endothelial cell loss, patient reported outcome measures and a health economic analysis conforming to National Institute for Health and Care Excellence standards. ETHICS AND DISSEMINATION: Research Ethics Committee Approval was obtained on 6 February 2015, ref: 14/LO/1937. Current protocol: v2.0 (08/04/2015). Study findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN: 77602616. PMID- 26614630 TI - Evaluation of a new rebound tonometer for self-measurement of intraocular pressure. AB - BACKGROUND/AIMS: To compare the accuracy of self-obtained, partner-obtained and trainer-obtained measurements using the handheld Icare Home rebound tonometer with Goldmann applanation tonometry (GAT), and to evaluate the acceptability to subjects of Icare Home measurement. METHODS: 76 subjects were trained to use Icare Home for self-measurement using a standardised protocol. A prespecified checklist was used to assess the ability of a subject to perform self-tonometry. Accuracy of Icare Home self-measurement was compared with GAT using one eye per subject, randomly selected. Bland-Altman difference analysis was used to compare Icare Home and GAT intraocular pressure (IOP) estimates. Acceptability of self tonometry was evaluated using a questionnaire. RESULTS: 56 subjects (74%, 95% CI 64 to 84) were able to correctly perform self-tonometry. Mean bias (95% limits of agreement) was 0.3 mm Hg (-4.6 to 5.2), 1.1 mm Hg (-3.2 to 5.3) and 1.2 mm Hg ( 3.9 to 6.3) for self-assessment, partner-assessment and trainer-assessment, respectively, suggesting underestimation of IOP by Icare Home tonometry. Differences between GAT and Icare Home IOP were greater for central corneal thickness below 500 um and above 600 um than data points within this range. Acceptability questionnaire responses showed high agreement that the self pressure device was easy to use (84%), the reading was quick to obtain (88%) and the measurement was comfortable (95%). CONCLUSIONS: Icare Home tonometry can be used for self-measurement by a majority of trained subjects. IOP measurements obtained using Icare Home tonometry by self-assessment and third party-assessment showed slight underestimation compared with GAT. PMID- 26614631 TI - Macular nerve fibre and ganglion cell layer changes in acute Leber's hereditary optic neuropathy. AB - AIMS: To evaluate longitudinal retinal ganglion cell inner plexiform layer (GC IPL) and macular retinal nerve fibre layer (mRNFL) thickness changes in acute Leber's hereditary optic neuropathy (LHON). METHODS: Six eyes of four patients with LHON underwent SD-OCT (optical coherence tomography) at month 1, 3, 6 and 12 after visual loss. In two eyes, the examination was carried out in the presymptomatic stage. The relationship and curves for area under the receiver operator characteristic (AUROC) were generated to assess the ability of each parameter to detect ganglion cell loss. RESULTS: Significant longitudinal thinning of GC-IPL and mRNFL was detected in LHON. GC-IPL thinning was detectable in the deviation map during the presymptomatic stage in the inner ring of the nasal sector and then it progressively extended following a centrifugal and spiral pattern. Similarly, mRNFL thinning began in the inferonasal sector and it progressively extended. No further statistically significant changes were detected after month 3. The highest level of AUROC values at 1 month were detected in the nasal sectors and inferonasal mRNFL thickness reached AUROC value=1. All the parameters were equally able to detect ganglion cell loss from month 2 to 12. CONCLUSIONS: The natural history of GC-IPL thinning follows a specific pattern of reduction, reflecting the anatomical course of papillomacular fibres. Month 6 represents the end of GC-IPL loss. GC-IPL and mRNFL thinning is detectable before onset of visual loss. These observations can help future therapeutic approaches for both LHON carriers at high risk of conversion and patients with acute early LHON. PMID- 26614632 TI - Extramacular drusen are highly associated with age-related macular degeneration, but not with CFH and ARMS2 genotypes. AB - BACKGROUND: To evaluate the association of extramacular drusen (EMD) with age related macular degeneration (AMD) and with complement factor H (CFH rs1061170) and age-related maculopathy susceptibility 2 (ARMS2 rs10490924) polymorphisms in individuals with and without AMD. METHODS: In this case-control study, AMD staging was performed in 622 individuals. EMD were defined as >=10 drusen (including >=1 intermediate drusen) outside the Early Treatment of Diabetic Retinopathy Study Grid within field 2. Genotype associations for CFH and ARMS2 variants were assessed using logistic regression analysis. RESULTS: EMD (n=213) showed a strong association with AMD (OR=3.85; p=1.66*10(-13)). AMD (n=316) was strongly associated with CFH (p=1.78*10(-7)) and ARMS2 genotypes (p=1.67*10(-8)). After adjustment for AMD, age and gender, EMD were neither associated with CFH (p=0.11) nor with ARMS2 (p=0.45) genotypes. In individuals without AMD, the groups with and without EMD showed no differences regarding both genetic variants. CONCLUSIONS: The strong association between drusen within and outside of the macula suggests a common pathogenesis. However, EMD were not AMD independently associated with CFH or ARMS2 genotypes. Our results indicate that patients without AMD but with EMD can serve as controls in studies evaluating AMD risk factors. Further studies are required to elucidate the aetiology and clinical relevance of EMD. PMID- 26614633 TI - Good work ability despite multisite musculoskeletal pain? A study among occupationally active Finns. AB - AIM: Although multisite pain (MSP) often threatens work ability (WA), some of those with MSP retain good WA. Our aim was to identify factors associated with good WA among subjects with MSP. METHODS: A nationally representative sample (the Health 2000-Study, response rate 87%) comprising 3884 occupationally active Finns aged 30-64 years. Data on WA, musculoskeletal pain, physical and psychosocial working conditions, chronic diseases, lifestyle and domestic situation were gathered by questionnaire, interview and clinical examination. Good current WA compared with the lifetime best was defined as ?9 on a 0-10 scale. Musculoskeletal pain in 18 body locations was combined into four sites, and thereafter pain in two or more sites was defined as MSP (N=1351). Poisson regression analysis was used to obtain prevalence rate ratios (PRR). RESULTS: Good WA was reported by 48% of the women and 37% of the men with MSP. In a multivariable model good WA was associated with younger age, female gender, physically non-strenuous work (PRR 1.3, 95% CI 1.1-1.5), low job strain (1.2, 1.0 1.4), high supervisor support (1.2, 1.0-1.4), and not having musculoskeletal diseases (1.3, 1.1-1.5), mental disorders (1.4, 1.1-1.9), daytime tiredness (1.4, 1.2-1.7) or economic troubles (1.5, 1.1-1.9). Age-stratified analyses revealed also associations with high coworker support (1.2, 1.0-1.4) and strenuous leisure time physical exercise (1.2, 1.0-1.4) in those aged 30-44 and low alcohol consumption (1.8, 1.2-2.6) in the age-group 45-64. CONCLUSIONS: Several potentially modifiable factors related to health, work, and lifestyle were associated with good WA among occupationally active subjects with MSP. PMID- 26614634 TI - Sickness allowance histories among disability retirees due to mental disorders: A retrospective case-control study. AB - OBJECTIVES: The aim was to describe sickness allowance histories before disability retirement due to mental disorders and to examine whether receiving sickness allowance due to mental disorders and somatic conditions predicts future disability retirement. METHOD: Pre-retirement sickness allowance histories were traced backwards for 7 years among Finnish residents aged 25-64 years who had retired due to mental disorders in 2011 (n=5.544). For each retiree, five sex- and age-matched controls were drawn from the non-retired population. Conditional logistic regression was used to calculate the risk for disability retirement by sickness allowance history and to control for the effects of educational level, social class, marital status and the urbanisation level of the municipality. RESULTS: The proportion of sickness allowance recipients increased steadily during the years preceding disability retirement, and was highest among those who retired due to bipolar disorders or depression. Those who had received sickness allowance due to mental disorders 6-7 years earlier had 6.5 times higher risk and those with sickness allowance 1-2 years earlier 11.7 times higher risk for disability retirement. Sickness allowance due to somatic conditions increased the risk for disability retirement 1.6-1.9 times. Sickness allowance most strongly predicted retirement due to bipolar disorders and depression. Adjustment for covariates had little effect. CONCLUSION: Those who retired due to mental disorders more often had sickness allowance due to both mental disorders and somatic conditions, but in particular sickness allowance due to mental disorders predicted disability retirement due to mental disorders. PMID- 26614635 TI - Socio-economic status and major trauma in a Scandinavian urban city: A population based case-control study. AB - AIMS: Epidemiological studies of patients with major trauma, including both hospitalized and immediately deceased whom are undergoing medico-legal autopsy, are very rare. We studied the incidence and mortality of major trauma in all 10 districts in the Scandinavian city of Malmo, Sweden, and the association between socio-economic status and major trauma. METHODS: Major trauma was defined as a New Injury Severity Score > 15, or a lethal outcome due to trauma. Cases with a registration address in Malmo between 1 January 2011 and 31 December 2013 were identified from the red trauma alarm list in the hospital and the autopsy register in the Forensic Department. Statistics Sweden matched each case with four randomly selected age-, gender- and district-matched controls. Social assistance within the household, level of education, income and capital income were compared. RESULTS: We identified 117 cases (80 men and 37 women) with a median age of 48.0 years (IQR 28.5-65.0). The incidence of major trauma in Malmo was 12.7 (95% CI 10.4-15.0) per 100,000 person-years; and 69 died due to major trauma, with 8.4 (95% CI 6.4-10.4) per 1000 deaths. Lower income (p = 0.024), no income (OR 1.6; 95% CI 1.0-2.4; p = 0.037) and social assistance (OR 2.3; 95% CI 1.3-4.1; p = 0.003) were associated with major trauma. The level of education was not found to be related to major trauma (p = 0.47). CONCLUSIONS: Low income and social assistance within the household were associated with major trauma in the city of Malmo, but not the level of education; in this age-, gender- and district matched case-control study of major trauma. PMID- 26614636 TI - How have trends in lifespan variation changed since 1950? A comparative study of 17 Western European countries. AB - Lifespan variation adds to life expectancy by measuring the inequality surrounding age of death that a population faces. Countries that tackle premature mortality generally have decreasing lifespan variation but this is the first study to compare and statistically assess when and to what extent trends in lifespan variation have changed across Western Europe. Lifespan variation was measured using e? and joinpoint regression analysed the timing and rate of change. Trends have been mostly downward with the recent exception of men in Scotland, Northern Ireland, Ireland and Finland where trends have flattened or show slight increases. Future research aimed at identifying the ages and causes of death, driving trends in these countries, is key to preventing increasing inequalities. PMID- 26614637 TI - ABO-Incompatible Kidney Transplants: Twice as Expensive, Half as Good. PMID- 26614638 TI - Testing enhances subsequent learning in older but not in younger elementary school children. AB - In adults, testing can enhance subsequent learning by reducing interference from the tested information. Here, we examined this forward effect of testing in children. Younger and older elementary school children and adult controls studied four lists of items in anticipation of a final cumulative recall test. Following presentation of each of the first three lists, participants were immediately tested on the respective list, or the list was re-presented for additional study. Results revealed that, compared to additional study, immediate testing of Lists 1 3 enhanced memory for the subsequently studied List 4 in adults and older elementary school children, but not in younger elementary school children. The findings indicate that the forward effect of testing is a relatively late maturing phenomenon that develops over middle childhood and is still inefficient in the early elementary school years. Together with the results of other recent studies, these findings point to a more general problem in young children in combating interference. PMID- 26614639 TI - Nuclear selenoproteins and genome maintenance. AB - Selenium is an essential metalloid required for the expression of selenoproteins. While cells are constantly challenged by clastogens of endogenous and exogenous origins, genome integrity is maintained by direct repair of DNA damage, redox balance, and epigenetic regulation. To date, only five selenoproteins are experimentally demonstrated to reside in nucleus, exclusively or partially, including selenoprotein H, methionine-R-sulfoxide reductase 1, glutathione peroxidase-4, thioredoxin reductase-1, and thioredoxin glutathione reductase. All these five selenoproteins have demonstrated or potential roles in redox regulation and genome maintenance. Selenoprotein H is known to transactivate the expression of a couple of genes against oxidative stress. The thioredoxin reductase-1b isoform delivers estrogen receptor-alpha and -beta to the nucleus. Nuclear glutathione peroxidase-4 epigenetically and globally inhibits gene expression through the maintenance of chromatin compactness in testes. Continued studies on how these and additional nuclear selenoproteins regulate genome stability will have profound impact on advancing our understanding in selenium regulation of optimal health. (c) 2015 IUBMB Life, 68(1):5-12, 2016. PMID- 26614640 TI - CXCR6 regulates the recruitment of pro-inflammatory IL-17A-producing T cells into atherosclerotic aortas. AB - The adaptive immune response is involved in the development and progression of atherosclerosis and IL-17A(+) cells play a role in this disease. Although elevated number of CD4(+) IL-17A(+) (Th17) and IL-17A(+)TCRgammadelta(+) T cells are found within murine atherosclerotic aortas and human plaques, the mechanisms governing IL-17A(+) T-cell migration to atherosclerotic lesions are unclear. The chemokine receptor CXCR6 is expressed on several T-cell subsets and plays a pro atherogenic role in atherosclerosis. Here, we used CXCR6-deficient (Cxcr6 (GFP/GFP) ) apolipoprotein E-deficient (Apoe (-/-) ) mice to investigate the involvement of CXCR6 in the recruitment IL-17A(+) T cells to atherosclerotic aortas. Flow cytometric analyses revealed reductions in Th17 and IL 17A(+)TCRgammadelta(+) T cells within aged Cxcr6 (GFP/GFP) Apoe (-/-) aortas, in comparison with age-matched Cxcr6 (GFP/+) Apoe (-/-) aortas. Although CXCR6 sufficient IL-17A(+) T cells efficiently migrated toward CXCL16, the migration of CXCR6-deficient IL-17A(+) T cells was abolished in transwell assays. Importantly, the recruitment of Cxcr6 (GFP/GFP) Apoe (-/-) IL-17A(+) T cells into the aortas of Apoe (-/-) recipients was markedly reduced in short-term adoptive transfer experiments. Altogether these results demonstrate an important role of CXCR6 in the regulation of pathological Th17 and IL-17A(+)TCRgammadelta(+) T-cell recruitment into atherosclerotic lesions. PMID- 26614641 TI - Treatment of type 2 diabetes mellitus by viral eradication in chronic hepatitis C: Myth or reality? AB - Chronic hepatitis C is a systemic disease inducing metabolic alterations leading to extrahepatic consequences. In particular, hepatitis C virus (HCV) infection seems to increase the risk of incident type 2 diabetes mellitus in predisposed individuals, independently of liver disease stage. The mechanisms through which hepatitis C induces T2DM involve direct viral effects, insulin resistance, pro inflammatory cytokines and other immune-mediated processes. Many studies have reported the clinical consequences of type 2 diabetes mellitus on hepatitis C outcome, but very few studies have addressed the issue of microangiopathic complications among patients with hepatitis C only, who develop type 2 diabetes mellitus. Moreover, clinical trials in HCV-positive patients have reported improvement in glucose metabolism after antiviral treatment; recent studies have suggested that this metabolic amelioration might have a clinical impact on type 2 diabetes mellitus-related complications. These observations raise the question as to whether the HCV eradication may also have an impact on the future morbidity and mortality due to type 2 diabetes mellitus. The scope of this review is to summarise the current evidence linking successful antiviral treatment and the prevention of type 2 diabetes mellitus and its complications in hepatitis C infected patients. PMID- 26614642 TI - Squamous cell carcinoma antigen-IgM is associated with hepatocellular carcinoma in patients with cirrhosis: A prospective study. AB - BACKGROUND: Squamous cell carcinoma antigen (SCCA)-IgM complex has been described as a promising tool to identify patients with progressive liver disease at higher risk of hepatocellular carcinoma (HCC) development in retrospective studies. AIM: To assess the clinical value of this biomarker in patients with cirrhosis in a prospective study. METHODS: Patients with overt cirrhosis were prospectively evaluated at 6-month intervals for HCC development and decompensation with clinical examination, liver ultrasound, alpha-fetoprotein measurement. SCCA-IgM was measured in serum by immunoenzymatic assay. Median follow-up duration was 52 months (range 12-68 months). RESULTS: 70 patients (26% male; mean age 56+/-10 years) were enrolled. The main aetiological factors were alcohol (44%) and hepatitis C (34%). Baseline values of SCCA-IgM were significantly higher in patients who developed HCC. Positivity of the biomarker at baseline was associated with a significantly shorter HCC-free survival, while alpha fetoprotein (cut off >20 ng/ml) was not significant. SCCA-IgM positivity and hepatitis C were significant prognostic factors for HCC development. The biomarker was not associated with the development of clinical complications of cirrhosis. CONCLUSION: This prospective study demonstrates that in patients with cirrhosis SCCA-IgM is associated with HCC development and may be useful for clinical management of cirrhotic patients at higher risk of HCC development. PMID- 26614643 TI - Long-term infliximab therapy is needed for sustained steroid-free remission in patients with ulcerative colitis. PMID- 26614644 TI - Clinical relevance and inter-test reliability of anti-infliximab antibodies and infliximab trough levels in patients with inflammatory bowel disease. AB - BACKGROUND: Treatment with infliximab is a common option for inflammatory bowel disease (IBD) patients. Therapeutic drug monitoring could improve treatment management. AIMS: To test inter-test reliability of two commercially available diagnostic kits for infliximab trough levels and infliximab antibodies, and their association with treatment outcomes. METHODS: 86 IBD outpatients on infliximab maintenance treatment were enrolled in a prospective cross-sectional study, 115 samples were available for inter-test reliability. RESULTS: Inter-test agreement was good both for trough levels (concordance correlation coefficient 0.78, weighted kappa 0.60, Sperman's rho 0.937) and for infliximab antibodies (weighted kappa 0.79) measurement, when comparing Promonitor and ImmunDiagnostik kits. According to manufacturers' cut-off values, trough levels were classified as undetectable (17%), low (21%) or in range (63%). The only significant associations were: mucosal healing (p=0.026; OR 6.50), infliximab antibody status (p=0.0015; OR 0.031) and adverse events (p=0.009; OR 0.115). Higher trough levels were observed among patients on concomitant steroid/immunosuppressive therapy and among patients with dose-intensification. Infliximab antibodies were significantly associated to treatment-related adverse events (p=0.0003, OR 30.42), and to lower trough levels, but not to other clinical variables. CONCLUSION: The two tests performed equally well. Infliximab antibodies were associated to adverse events, while trough levels were not associated to treatment outcomes. PMID- 26614645 TI - The economic crisis in Greece affects HCVRNA RTPCR determination. PMID- 26614646 TI - Intestinal metaplasia in Barrett's oesophagus: An essential factor to predict the risk of dysplasia and cancer development. AB - BACKGROUND: To date, there is still uncertainty on the role of specialized intestinal metaplasia in the carcinogenic process of Barrett's oesophagus (BE); this fact seems of importance for planning adequate surveillance programs. AIMS: To predict the risk of progression towards dysplasia/cancer based on typical morphological features by evaluating the importance of intestinal metaplasia in BE patients. METHODS: 647 cases with a histological diagnosis of BE, referred to the Endoscopy Unit of a tertiary centre between 2000 and 2012 were retrospectively identified, and divided into two groups according to the presence/absence of intestinal metaplasia. For each patient, all histological reports performed during a follow-up of 4-8 years were analyzed. RESULTS: Overall, 537 cases (83%) with intestinal metaplasia and 110 cases (17%) without intestinal metaplasia were included. During the follow-up period, none of the patients without intestinal metaplasia developed dysplasia/cancer nor progressed to metaplasia, whereas 72 patients with intestinal metaplasia (13.4%) showed histological progression of the disease. CONCLUSION: The histological identification of intestinal metaplasia seems to be an essential factor for the progression towards dysplasia and cancer in BE patients. PMID- 26614647 TI - Immediate and Complex Cardiovascular Adaptation to an Acute Alcohol Dose. AB - BACKGROUND: The detrimental effects of chronic heavy alcohol use on the cardiovascular system are well established and broadly appreciated. Integrated cardiovascular response to an acute dose of alcohol has been less studied. This study examined the early effects of an acute dose of alcohol on the cardiovascular system, with particular emphasis on system variability and sensitivity. The goal was to begin to understand how acute alcohol disrupts dynamic cardiovascular regulatory processes prior to the development of cardiovascular disease. METHODS: Healthy participants (N = 72, age 21 to 29) were randomly assigned to an alcohol, placebo, or no-alcohol control beverage condition. Beat-to-beat heart rate (HR) and blood pressure (BP) were assessed during a low-demand cognitive task prior to and following beverage consumption. Between-group differences in neurocardiac response to an alcohol challenge (blood alcohol concentration ~ 0.06 mg/dl) were tested. RESULTS: The alcohol beverage group showed higher average HR, lower average stroke volume, lower HR variability and BP variability, and increased vascular tone baroreflex sensitivity after alcohol consumption. No changes were observed in the placebo group, but the control group showed slightly elevated average HR and BP after beverage consumption, possibly due to juice content. At the level of the individual, an active alcohol dose appeared to disrupt the typically tight coupling between cardiovascular processes. CONCLUSIONS: A dose of alcohol quickly invoked multiple cardiovascular responses, possibly as an adaptive reaction to the acute pharmacological challenge. Future studies should assess how exposure to alcohol acutely disrupts or dissociates typically integrated neurocardiac functions. PMID- 26614648 TI - Influence of thyroid gland status on the thyroglobulin cutoff level in washout fluid from cervical lymph nodes of patients with recurrent/metastatic papillary thyroid cancer. AB - BACKGROUND: The influence of serum thyroglobulin (Tg) and thyroidectomy status on Tg in fine-needle aspiration cytology (FNAC) washout fluid is unclear. METHODS: A total of 282 lymph nodes were prospectively subjected to FNAC, fine-needle aspiration (FNA)-Tg measurement, and frozen and permanent biopsies. We evaluated the diagnostic performance of several predetermined FNA-Tg cutoff values for recurrence/metastasis in lymph nodes according to thyroidectomy status. RESULTS: The diagnostic performance of FNA-Tg varied according to thyroidectomy status. The optimized cutoff value of FNA-Tg was 2.2 ng/mL. However, among FNAC-negative lymph nodes, the FNA-Tg cutoff value of 0.9 ng/mL showed better diagnostic performance in patients with a thyroid gland. An FNA-Tg/serum-Tg cutoff ratio of 1 showed the best diagnostic performance in patients without a thyroid gland. CONCLUSION: Applying the optimal cutoff values of FNA-Tg according to thyroid gland status and serum Tg level facilitates the diagnostic evaluation of neck lymph node recurrences/metastases in patients with papillary thyroid carcinoma (PTC). (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1705-E1712, 2016. PMID- 26614649 TI - Dynamics of NAD-metabolism: everything but constant. AB - NAD, as well as its phosphorylated form, NADP, are best known as electron carriers and co-substrates of various redox reactions. As such they participate in approximately one quarter of all reactions listed in the reaction database KEGG. In metabolic pathway analysis, the total amount of NAD is usually assumed to be constant. That means that changes in the redox state might be considered, but concentration changes of the NAD moiety are usually neglected. However, a growing number of NAD-consuming reactions have been identified, showing that this assumption does not hold true in general. NAD-consuming reactions are common characteristics of NAD(+)-dependent signalling pathways and include mono- and poly-ADP-ribosylation of proteins, NAD(+)-dependent deacetylation by sirtuins and the formation of messenger molecules such as cyclic ADP-ribose (cADPR) and nicotinic acid (NA)-ADP (NAADP). NAD-consuming reactions are thus involved in major signalling and gene regulation pathways such as DNA-repair or regulation of enzymes central in metabolism. All known NAD(+)-dependent signalling processes include the release of nicotinamide (Nam). Thus cellular NAD pools need to be constantly replenished, mostly by recycling Nam to NAD(+). This process is, among others, regulated by the circadian clock, causing complex dynamic changes in NAD concentration. As disturbances in NAD homoeostasis are associated with a large number of diseases ranging from cancer to diabetes, it is important to better understand the dynamics of NAD metabolism to develop efficient pharmacological invention strategies to target this pathway. PMID- 26614650 TI - A reductionist approach to model photosynthetic self-regulation in eukaryotes in response to light. AB - Along with the development of several large-scale methods such as mass spectrometry or micro arrays, genome wide models became not only a possibility but an obvious tool for theoretical biologists to integrate and analyse complex biological data. Nevertheless, incorporating the dynamics of photosynthesis remains one of the major challenges while reconstructing metabolic networks of plants and other photosynthetic organisms. In this review, we aim to provide arguments that small-scale models are still a suitable choice when it comes to discovering organisational principles governing the design of biological systems. We give a brief overview of recent modelling efforts in understanding the interplay between rapid, photoprotective mechanisms and the redox balance within the thylakoid membrane, discussing the applicability of a reductionist approach in modelling self-regulation in plants and outline possible directions for further research. PMID- 26614651 TI - Manipulation of the ATP pool as a tool for metabolic engineering. AB - Cofactor engineering has been long identified as a valuable tool for metabolic engineering. Besides interventions targeting the pools of redox cofactors, many studies addressed the adenosine pools of microorganisms. In this mini-review, we discuss interventions that manipulate the availability of ATP with a special focus on ATP wasting strategies. We discuss the importance to fine-tune the ATP yield along a production pathway to balance process performance parameters like product yield and volumetric productivity. PMID- 26614652 TI - Hierarchical decomposition of metabolic networks using k-modules. AB - The optimal solutions obtained by flux balance analysis (FBA) are typically not unique. Flux modules have recently been shown to be a very useful tool to simplify and decompose the space of FBA-optimal solutions. Since yield maximization is sometimes not the primary objective encountered in vivo, we are also interested in understanding the space of sub-optimal solutions. Unfortunately, the flux modules are too restrictive and not suited for this task. We present a generalization, called k-module, which compensates the limited applicability of flux modules to the space of sub-optimal solutions. Intuitively, a k-module is a sub-network with low connectivity to the rest of the network. Recursive application of k-modules yields a hierarchical decomposition of the metabolic network, which is also known as branch decomposition in matroid theory. In particular, decompositions computed by existing methods, like the null-space based approach, introduced by Poolman et al. [(2007) J. Theor. Biol. 249: , 691 705] can be interpreted as branch decompositions. With k-modules we can now compare alternative decompositions of metabolic networks to the classical sub systems of glycolysis, tricarboxylic acid (TCA) cycle, etc. They can be used to speed up algorithmic problems [theoretically shown for elementary flux modes (EFM) enumeration] and have the potential to present computational solutions in a more intuitive way independently from the classical sub-systems. PMID- 26614653 TI - A multi-scale, multi-disciplinary approach for assessing the technological, economic and environmental performance of bio-based chemicals. AB - In recent years, bio-based chemicals have gained interest as a renewable alternative to petrochemicals. However, there is a significant need to assess the technological, biological, economic and environmental feasibility of bio-based chemicals, particularly during the early research phase. Recently, the Multi scale framework for Sustainable Industrial Chemicals (MuSIC) was introduced to address this issue by integrating modelling approaches at different scales ranging from cellular to ecological scales. This framework can be further extended by incorporating modelling of the petrochemical value chain and the de novo prediction of metabolic pathways connecting existing host metabolism to desirable chemical products. This multi-scale, multi-disciplinary framework for quantitative assessment of bio-based chemicals will play a vital role in supporting engineering, strategy and policy decisions as we progress towards a sustainable chemical industry. PMID- 26614654 TI - Quantitative analysis of drug effects at the whole-body level: a case study for glucose metabolism in malaria patients. AB - We propose a hierarchical modelling approach to construct models for disease states at the whole-body level. Such models can simulate effects of drug-induced inhibition of reaction steps on the whole-body physiology. We illustrate the approach for glucose metabolism in malaria patients, by merging two detailed kinetic models for glucose metabolism in the parasite Plasmodium falciparum and the human red blood cell with a coarse-grained model for whole-body glucose metabolism. In addition we use a genome-scale metabolic model for the parasite to predict amino acid production profiles by the malaria parasite that can be used as a complex biomarker. PMID- 26614656 TI - Modelling metabolic evolution on phenotypic fitness landscapes: a case study on C4 photosynthesis. AB - How did the complex metabolic systems we observe today evolve through adaptive evolution? The fitness landscape is the theoretical framework to answer this question. Since experimental data on natural fitness landscapes is scarce, computational models are a valuable tool to predict landscape topologies and evolutionary trajectories. Careful assumptions about the genetic and phenotypic features of the system under study can simplify the design of such models significantly. The analysis of C4 photosynthesis evolution provides an example for accurate predictions based on the phenotypic fitness landscape of a complex metabolic trait. The C4 pathway evolved multiple times from the ancestral C3 pathway and models predict a smooth 'Mount Fuji' landscape accordingly. The modelled phenotypic landscape implies evolutionary trajectories that agree with data on modern intermediate species, indicating that evolution can be predicted based on the phenotypic fitness landscape. Future directions will have to include structural changes of metabolic fitness landscape structure with changing environments. This will not only answer important evolutionary questions about reversibility of metabolic traits, but also suggest strategies to increase crop yields by engineering the C4 pathway into C3 plants. PMID- 26614655 TI - Genome-scale modelling of microbial metabolism with temporal and spatial resolution. AB - Most natural microbial systems have evolved to function in environments with temporal and spatial variations. A major limitation to understanding such complex systems is the lack of mathematical modelling frameworks that connect the genomes of individual species and temporal and spatial variations in the environment to system behaviour. The goal of this review is to introduce the emerging field of spatiotemporal metabolic modelling based on genome-scale reconstructions of microbial metabolism. The extension of flux balance analysis (FBA) to account for both temporal and spatial variations in the environment is termed spatiotemporal FBA (SFBA). Following a brief overview of FBA and its established dynamic extension, the SFBA problem is introduced and recent progress is described. Three case studies are reviewed to illustrate the current state-of-the-art and possible future research directions are outlined. The author posits that SFBA is the next frontier for microbial metabolic modelling and a rapid increase in methods development and system applications is anticipated. PMID- 26614657 TI - Metabolic flux prediction in cancer cells with altered substrate uptake. AB - Proliferating cells, such as cancer cells, are known to have an unusual metabolism, characterized by an increased rate of glycolysis and amino acid metabolism. Our understanding of this phenomenon is limited but could potentially be used in order to develop new therapies. Computational modelling techniques, such as flux balance analysis (FBA), have been used to predict fluxes in various cell types, but remain of limited use to explain the unusual metabolic shifts and altered substrate uptake in human cancer cells. We implemented a new flux prediction method based on elementary modes (EMs) and structural flux (StruF) analysis and tested them against experimentally measured flux data obtained from (13)C-labelling in a cancer cell line. We assessed the quality of predictions using different objective functions along with different techniques in normalizing a metabolic network with more than one substrate input. Results show a good correlation between predicted and experimental values and indicate that the choice of cellular objective critically affects the quality of predictions. In particular, lactate gives an excellent correlation and correctly predicts the high flux through glycolysis, matching the observed characteristics of cancer cells. In contrast with FBA, which requires a priori definition of all uptake rates, often hard to measure, atomic StruFs (aStruFs) are able to predict uptake rates of multiple substrates. PMID- 26614658 TI - Modelling metabolism of the diatom Phaeodactylum tricornutum. AB - Marine diatoms have potential as a biotechnological production platform, especially for lipid-derived products, including biofuels. Here we introduce some features of diatom metabolism, particularly with respect to photosynthesis, photorespiration and lipid synthesis and their differences relative to other photosynthetic eukaryotes. Since structural metabolic modelling of other photosynthetic organisms has been shown to be capable of representing their metabolic capabilities realistically, we briefly review the main approaches to this type of modelling. We then propose that genome-scale modelling of the diatom Phaeodactylum tricornutum, in response to varying light intensity, could uncover the novel aspects of the metabolic potential of this organism. PMID- 26614659 TI - Mathematical models for explaining the Warburg effect: a review focussed on ATP and biomass production. AB - For producing ATP, tumour cells rely on glycolysis leading to lactate to about the same extent as on respiration. Thus, the ATP synthesis flux from glycolysis is considerably higher than in the corresponding healthy cells. This is known as the Warburg effect (named after German biochemist Otto H. Warburg) and also applies to striated muscle cells, activated lymphocytes, microglia, endothelial cells and several other cell types. For similar phenomena in several yeasts and many bacteria, the terms Crabtree effect and overflow metabolism respectively, are used. The Warburg effect is paradoxical at first sight because the molar ATP yield of glycolysis is much lower than that of respiration. Although a straightforward explanation is that glycolysis allows a higher ATP production rate, the question arises why cells do not re-allocate protein to the high-yield pathway of respiration. Mathematical modelling can help explain this phenomenon. Here, we review several models at various scales proposed in the literature for explaining the Warburg effect. These models support the hypothesis that glycolysis allows for a higher proliferation rate due to increased ATP production and precursor supply rates. PMID- 26614660 TI - Resource allocation in metabolic networks: kinetic optimization and approximations by FBA. AB - Based on recent theoretical results on optimal flux distributions in kinetic metabolic networks, we explore the congruences and differences between solutions of kinetic optimization problems and results obtained by constraint-based methods. We demonstrate that, for a certain resource allocation problem, kinetic optimization and standard flux balance analysis (FBA) give rise to qualitatively different results. Furthermore, we introduce a variant of FBA, called satFBA, whose predictions are in qualitative agreement with kinetic optimization. PMID- 26614661 TI - T-cells require post-transcriptional regulation for accurate immune responses. AB - Cytotoxic T-cells are crucial to protect us from intracellular pathogens and malignant cells. When T-cells become activated, they rapidly secrete cytokines, chemokines and cytotoxic granules that are critical to clear infected cells. However, when not properly regulated, these toxic effector molecules become one of the key mediators of autoimmune diseases. Therefore, a tight and multi-layered regulation of gene expression and protein production is required to ensure a protective yet balanced immune response. In this review, we describe how post transcriptional events modulate the production of effector molecules in T-cells. In particular, we will focus on the role of cis-regulatory elements within the 3' UTR of specific mRNAs and on RNA-binding proteins (RBPs) and non-coding RNAs that control the initiation and resolution of T-cell responses. PMID- 26614662 TI - Mechanisms of regulation of mature miRNAs. AB - miRNAs are short RNA molecules of ~22-nt in length that play important roles in post-transcriptional control of gene expression. miRNAs normally function as negative regulators of mRNA expression by binding complementary sequences in the 3'-UTR of target mRNAs and causing translational repression and/or target degradation. Much research has been undertaken to enhance understanding of the biogenesis, function and targeting of miRNAs. However, until recently, the mechanisms underlying the regulation of the levels of mature miRNAs themselves have been largely overlooked. Although it has generally been assumed that miRNAs are stable molecules, recent evidence indicates that the stability of specific mature miRNAs can be regulated during key cellular and developmental processes in certain cell types. Here we discuss the current knowledge of the mechanisms by which mature miRNAs are regulated in the cell and the factors that contribute to the control of their stability. PMID- 26614663 TI - Quantifying the 'escapers' among RNA species. AB - tRNAs are fundamental components of translation and emerging evidence places them more centrally in various other cellular processes. However, rather than being uniformly conserved, tRNA abundance is instead highly variable and adaptable. The amount of tRNA genes greatly differs among species. Moreover, even within the same genome, tRNA abundance shapes the proteome in a tissue- and cell-specific manner and is dynamically regulated in response to stress. Here, we review approaches for identification and quantification of tRNAs and their functional integrity. We discuss the resolution of each method and highlight new approaches with cell-wide resolution based on deep-sequencing technologies. PMID- 26614664 TI - Co-translational assembly of protein complexes. AB - The interaction of biological macromolecules is a fundamental attribute of cellular life. Proteins, in particular, often form stable complexes with one another. Although the importance of protein complexes is widely recognized, we still have only a very limited understanding of the mechanisms underlying their assembly within cells. In this article, we review the available evidence for one such mechanism, namely the coupling of protein complex assembly to translation at the polysome. We discuss research showing that co-translational assembly can occur in both prokaryotic and eukaryotic organisms and can have important implications for the correct functioning of the complexes that result. Co translational assembly can occur for both homomeric and heteromeric protein complexes and for both proteins that are translated directly into the cytoplasm and those that are translated into or across membranes. Finally, we discuss the properties of proteins that are most likely to be associated with co translational assembly. PMID- 26614665 TI - Translational dysregulation in cancer: eIF4A isoforms and sequence determinants of eIF4A dependence. AB - The malignant phenotype is largely the consequence of dysregulated gene expression. Transformed cells depend upon not just a global increase in protein synthesis but an altered translational landscape in which pro-oncogenic mRNAs are translationally up-regulated. Such mRNAs have been shown to possess longer and more structured 5'-UTRs requiring high levels of eukaryotic initiation factor 4A (eIF4A) helicase activity for efficient translation. As such there is a developing focus on targeting eIF4A as a cancer therapy. In order for such treatments to be successful, we must develop a detailed understanding of the mechanisms which make specific mRNAs more dependent on eIF4A activity than others. It is also crucial to fully characterize the potentially distinct roles of eIF4A1 and eIF4A2, which until recently were thought to be functionally interchangeable. This review will highlight the recent advances made in this field that address these issues. PMID- 26614666 TI - eIF2B: recent structural and functional insights into a key regulator of translation. AB - The eukaryotic translation initiation factor (eIF) eIF2B is a key regulator of mRNA translation, being the guanine nt exchange factor (GEF) responsible for the recycling of the heterotrimeric G-protein, eIF2, which is required to allow translation initiation to occur. Unusually for a GEF, eIF2B is a multi-subunit protein, comprising five different subunits termed alpha through epsilon in order of increasing size. eIF2B is subject to tight regulation in the cell and may also serve additional functions. Here we review recent insights into the subunit organization of the mammalian eIF2B complex, gained both from structural studies of the complex and from studies of mutations of eIF2B that result in the neurological disorder leukoencephalopathy with vanishing white matter (VWM). We will also discuss recent data from yeast demonstrating a novel function of the eIF2B complex key for translational regulation. PMID- 26614667 TI - Regulation of the expression and activity of Unr in mammalian cells. AB - Unr (upstream of N-ras) is a post-transcriptional regulator of gene expression, essential for mammalian development and mutated in many human cancers. The expression of unr is itself regulated at many levels; transcription of unr, which also affects expression of the downstream N-ras gene, is tissue and developmental stage-dependent and is repressed by c-Myc and Max (Myc associated factor X). Alternative splicing gives rise to six transcript variants, which include three different 5'-UTRs. The transcripts are further diversified by the use of three alternative polyadenylation signals, which governs whether AU-rich instability elements are present in the 3'-UTR or not. Translation of at least some unr transcripts can occur by internal initiation and is regulated in a cell-cycle dependent manner; binding of PTB (polypyrimidine tract-binding protein) and Unr to the 5'-UTR inhibits translation, but these are displaced by heterogeneous nuclear ribonucleoproteins C1/C2 (hnRNPC1/C2) during mitosis to stimulate translation. Finally, Unr is post-translationally modified by phosphorylation and lysine acetylation, although it is not yet known how these modifications affect Unr activity. PMID- 26614668 TI - Tuning innate immunity by translation. AB - In multicellular organisms, the epithelia is a contact surface with the surrounding environment and is exposed to a variety of adverse biotic (pathogenic) and abiotic (chemical) factors. Multi-layered pathways that operate on different time scales have evolved to preserve cellular integrity and elicit stress-specific response. Several stress-response programs are activated until a complete elimination of the stress is achieved. The innate immune response, which is triggered by pathogenic invasion, is rather harmful when active over a prolonged time, thus the response follows characteristic oscillatory trajectories. Here, we review different translation programs that function to precisely fine-tune the time at which various components of the innate immune response dwell between active and inactive. We discuss how different pro inflammatory pathways are co-ordinated to temporally offset single reactions and to achieve an optimal balance between fighting pathogens and being less harmful for healthy cells. PMID- 26614669 TI - Ccr4-Not is at the core of the eukaryotic gene expression circuitry. AB - In this mini-review, we summarize our current knowledge about the cross-talk between the different levels of gene expression. We introduce the Ccr4 (carbon catabolite repressed 4)-Not (negative on TATA-less) complex as a candidate to be a master regulator that orchestrates between the different levels of gene expression. An integrated view of the findings about the Ccr4-Not complex suggests that it is involved in gene expression co-ordination. Since the discovery of the Not proteins in a selection for transcription regulators in yeast [Collart and Struhl (1994) Genes Dev. 8: , 525-537], the Ccr4-Not complex has been connected to every step of the mRNA lifecycle. Moreover, it has been found to be relevant for appropriate protein folding and quaternary protein structure by being involved in co-translational protein complex assembly. PMID- 26614670 TI - Mutation of genes controlling mRNA metabolism and protein synthesis predisposes to neurodevelopmental disorders. AB - Brain development is a tightly controlled process that depends upon differentiation and function of neurons to allow for the formation of functional neural networks. Mutation of genes encoding structural proteins is well recognized as causal for neurodevelopmental disorders (NDDs). Recent studies have shown that aberrant gene expression can also lead to disorders of neural development. Here we summarize recent evidence implicating in the aetiology of NDDs mutation of factors acting at the level of mRNA splicing, mRNA nuclear export, translation and mRNA degradation. This highlights the importance of these fundamental processes for human health and affords new strategies and targets for therapeutic intervention. PMID- 26614671 TI - Rate control in yeast protein synthesis at the population and single-cell levels. AB - Yeast commits approximately 76% of its energy budget to protein synthesis and the efficiency and control of this process are accordingly critical to organism growth and fitness. We now have detailed genetic, biochemical and biophysical knowledge of the components of the eukaryotic translation machinery. However, these kinds of information do not, in themselves, give us a satisfactory picture of how the overall system is controlled. This is where quantitative system analysis can enable a step-change in our understanding of biological resource management and how this relates to cell physiology and evolution. An important aspect of this more system-oriented approach to translational control is the inherent heterogeneity of cell populations that is generated by gene expression noise. In this short review, we address the fact that, although the vast majority of our knowledge of the translation machinery is based on experimental analysis of samples that each contain hundreds of millions of cells, in reality every cell is unique in terms of its composition and control properties. We have entered a new era in which research into the heterogeneity of cell systems promises to provide answers to many (previously unanswerable) questions about cell physiology and evolution. PMID- 26614672 TI - Ribosomal profiling adds new coding sequences to the proteome. AB - Next generation sequencing (NGS) has enabled an in-depth look into genes, transcripts and their translation at the genomic scale. The application of NGS sequencing of ribosome footprints (Ribo-Seq) reveals translation with single nucleotide (nt) resolution, through the deep sequencing of ribosome-bound fragments (RBFs). Some results of Ribo-Seq challenge our understanding of the protein-coding potential of the genome. Earlier bioinformatic approaches had shown the presence of hundreds of thousands of putative small ORFs (smORFs) in eukaryotic genomes, but they had been largely ignored due to their large numbers and difficulty in determining their translation and function. Ribo-Seq has revealed that hundreds of putative smORFs within previously assumed long non coding RNAs (lncRNAs) and UTRs of canonical mRNAs are associated with ribosomes, appearing to be translated. Here we review some of the approaches used to define translation within Ribo-Seq experiments and the challenges in defining translation of these novel smORFs in lncRNAs and UTRs. We also look at some of the bioinformatic and biochemical approaches used to independently corroborate these exciting new findings and elucidate real translation events. PMID- 26614673 TI - Poly(A)-binding proteins and mRNA localization: who rules the roost? AB - RNA-binding proteins are often multifunctional, interact with a variety of protein partners and display complex localizations within cells. Mammalian cytoplasmic poly(A)-binding proteins (PABPs) are multifunctional RNA-binding proteins that regulate multiple aspects of mRNA translation and stability. Although predominantly diffusely cytoplasmic at steady state, they shuttle through the nucleus and can be localized to a variety of cytoplasmic foci, including those associated with mRNA storage and localized translation. Intriguingly, PABP sub-cellular distribution can alter dramatically in response to cellular stress or viral infection, becoming predominantly nuclear and/or being enriched in induced cytoplasmic foci. However, relatively little is known about the mechanisms that govern this distribution/relocalization and in many cases PABP functions within specific sites remain unclear. Here we discuss the emerging evidence with respect to these questions in mammals. PMID- 26614674 TI - Modulation of the cytoplasmic functions of mammalian post-transcriptional regulatory proteins by methylation and acetylation: a key layer of regulation waiting to be uncovered? AB - Post-transcriptional control of gene expression is critical for normal cellular function and viability and many of the proteins that mediate post-transcriptional control are themselves subject to regulation by post-translational modification (PTM), e.g. phosphorylation. However, proteome-wide studies are revealing new complexities in the PTM status of mammalian proteins, in particular large numbers of novel methylated and acetylated residues are being identified. Here we review studied examples of methylation/acetylation-dependent regulation of post transcriptional regulatory protein (PTRP) function and present collated PTM data that points to the huge potential for regulation of mRNA fate by these PTMs. PMID- 26614675 TI - Correction: Molecular action of sulphonylureas on KATP channels: a real partnership between drugs and nucleotides. PMID- 26614676 TI - Efficacy, safety and pharmacokinetic profiles of a plasma-derived VWF/FVIII concentrate (VONCENTO(r)) in subjects with haemophilia A (SWIFT-HA study). AB - INTRODUCTION: VONCENTO(r) (CSL Behring) is a plasma-derived, high-concentration, low-volume, high-purity concentrate,which contains a high level of von Willebrand factor (VWF) high-molecular-weight multimers and aVWF/factor VIII (FVIII) ratio of ~2.4:1, similar to Haemate(r) P (CSL Behring). METHODS: The pharmacokinetic, efficacy and safety profiles of VONCENTO(r) were investigated in this multicentre,double-blind, randomised study. Subjects aged >= 12 years with haemophilia A who required treatment of nonsurgical bleeds, treatment during surgical events or who were receiving prophylaxis were included. Pharmacokinetics were investigated with a single dose of 50 IU FVIII/kg body weight of either VONCENTO(r) or BIOSTATE(r) reference product (Biostate-RP) (Day 1; Day 8 [n= 16], repeated on Day 180 [VONCENTO(r) only; n=15]). Efficacy and safety analyses were performed either during on-demand treatment (n=52) or prophylaxis (n=29)for >= 6 months and >= 50 exposure days, respectively. RESULTS: Besides the confirmation of bioequivalence between VONCENTO(r) and Biostate-RP, which displayed comparable PK profiles, haemostatic efficacy was rated by the investigators as either 'excellent' or 'good' in 96.4% of all bleeding events (96.5% spontaneous, 96.6% traumatic, 96.9% joint bleeds) as well as in 80% of major and 100% of minor surgical procedures at discharge. The median number of annualised bleeding events per subject [range] was significantly lower in the prophylaxis group (2.0 [0.0 34.6]) than in the on-demand group (14.0 [0.0-87.8], p = 0.0013).VONCENTO(r) was well tolerated and no inhibitory antibodies were identified during the study period. CONCLUSIONS: This study demonstrated the bioequivalence of VONCENTO(r) to Biostate-RP, and its excellent efficacy and safety profile in haemophilia A subjects. PMID- 26614677 TI - The DNA-Uptake Process of Naturally Competent Vibrio cholerae. AB - The sophisticated DNA-uptake machinery used during natural transformation is still poorly characterized, especially in Gram-negative bacteria where the transforming DNA has to cross two membranes as well as the peptidoglycan layer before entering the cytoplasm. The DNA-uptake machinery was hypothesized to take the form of a pseudopilus, which, upon repeated cycles of extension and retraction, would pull external DNA towards the cell surface or into the periplasmic space, followed by translocation across the cytoplasmic membrane. In this review, we summarize recent advances on the DNA-uptake machinery of V. cholerae, highlighting the presence of an extended competence-induced pilus and the contribution of a conserved DNA-binding protein that acts as a ratchet and reels DNA into the periplasm. PMID- 26614678 TI - Sliding mode controllers for a tempered glass furnace. AB - This paper investigates the design of two sliding mode controllers (SMCs) applied to a tempered glass furnace system. The main objective of the proposed controllers is to regulate the glass plate temperature, the upper-wall temperature and the lower-wall temperature in the furnace to a common desired temperature. The first controller is a conventional sliding mode controller. The key step in the design of this controller is the introduction of a nonlinear transformation that maps the dynamic model of the tempered glass furnace into the generalized controller canonical form; this step facilitates the design of the sliding mode controller. The second controller is based on a state-dependent coefficient (SDC) factorization of the tempered glass furnace dynamic model. Using an SDC factorization, a simplified sliding mode controller is designed. The simulation results indicate that the two proposed control schemes work very well. Moreover, the robustness of the control schemes to changes in the system's parameters as well as to disturbances is investigated. In addition, a comparison of the proposed control schemes with a fuzzy PID controller is performed; the results show that the proposed SDC-based sliding mode controller gave better results. PMID- 26614680 TI - The analysis of meat traits of Sussex cockerels and capons (S11) at different ages. AB - The aim of the study was to compare Sussex cockerels and capons as well as to estimate the influence of age on slaughter yield and meat quality. The tests were performed on cockerels and capons from strain S11 (Sussex). At 16, 18, and 20 wk of age, a dissection of the entire carcass was conducted. The breast and leg muscles were tested for physio-chemical traits, as well as chemical parameters. It was noted that, due to significant differences in BW of the eviscerated carcasses between wk 18 and 20 of slaughter, the best time to cease rearing S11 cockerels could be wk 20. However, for S11 capons, the optimal time for slaughter appeared to be wk 18 (no significant differences in BW and carcass weight or musculature between wk 18 and 20). The trait which did not differ between cockerels and capons slaughtered at different ages was slaughter yield. Fatness of the cockerels increased with age whilst the weight of capons' skin with subcutaneous fat was the same at wk 18 and 20 of evaluation. With increasing age, pH indicators of cockerels and capons' breast muscles were increasing; the water holding capacity of capons' breast muscles were also increasing. Both cockerels and capons showed darker color of breast muscle at wk 20 compared to wk 16 of evaluation. Redness of the breast muscle in the following periods of evaluation did not show significant differences, although with age, the yellowness of the cockerels and capons' breast muscle increased significantly. Among cockerels and capons, the water content in the breast and leg muscles were decreasing with age whilst the protein content was increasing. A significant growing tendency of the percentage of fat share in the breast and leg muscles with age was noted in the capon group. Conclusions for breeding practice are as follows: due to meat and quality traits, Sussex cockerels and capons can be used until wk 18 or 20 of life. PMID- 26614679 TI - Early experiences matter: a review of the effects of prenatal environment on offspring characteristics in poultry. AB - Early life experiences can be important in determining offspring phenotypes and may influence interaction with the environment and hence health, welfare, and productivity. The prenatal environment of poultry can be divided into the pre-lay environment and the egg storage/incubation environment, both of which can affect offspring outcomes. The ability to separate maternal and egg/incubation effects makes birds well suited to this type of research. There are many factors, including feeding and nutrition, environmental conditions, husbandry practices, housing system, social environment, infectious environment, and maternal health status, that can influence both the health and performance and behavior and cognition of the offspring. There are some aspects of the environments that can be changed to produce beneficial effects in the offspring, like addition of certain additives to feed or short changes in incubation temperatures, while other aspects should be avoided to reduce negative effects, such as unpredictable feeding and lighting regimens. Measures of offspring characteristics may prove to be a useful method of assessing parent stock welfare if known stressors result in predictable offspring outcomes. This has the advantage of assessing the parent environment without interfering with the animals and possibly affecting their responses and could lead to improved welfare for the animals. PMID- 26614681 TI - Genome-wide association study of 8 carcass traits in Jinghai Yellow chickens using specific-locus amplified fragment sequencing technology. AB - Carcass traits are important to the commercial chicken industry, and understanding the genetics of these traits will be useful in the development of commercially viable varieties of chickens. We conducted a genome-wide association study based on 8 carcass trait phenotypes in a population of 400 43-week-old Jinghai Yellow chickens. Specific-locus amplified fragment sequencing technology was used to identify 90,961 single nucleotide polymorphisms (SNP) distributed among 29 chromosomes and the mitochondrial genome. SNP that were significantly associated with phenotypic traits were identified by a simple general linear model. Fifteen SNP attained genome-wide significance (P < 1.87E-6) and were associated with 5 of the 8 carcass traits; only one SNP was significantly associated with 2 traits (foot weight and wing weight). Twelve genes were associated with these 15 SNP. A region of chromosome 4 between 75.5 and 76.1 Mb was associated with carcass weight, foot weight, and wing weight. An 84-kb region on chromosome 3 (51.2 Mb) was associated with eviscerated weight and semi eviscerated weight. PMID- 26614682 TI - Lysine mediation of neuroendocrine food regulation in guinea fowl. AB - In poultry, obesity is partly influenced by food intake, and is increasingly becoming a nationwide problem. Hypothalamic food intake mechanisms are involved metabolically and neurologically via two peptide hormones, leptin and ghrelin, and the amino acid glutamate, which is enzymatically derived from lysine metabolism. We hypothesize that lysine homeostasis mediates regulation of feed intake and performance characteristics via the brain-liver axis through glutamate sensing. The objective was to examine the effects of lysine homeostasis in avian food regulation and performance through neuroendocrine signaling. One-day-old male French Guinea fowl (GF) keets (n = 270) were weighed and randomly assigned to 5 dietary treatments (0.80%, 0.86%, 0.92%, 1.10% control, and 1.22% lysine) in 3 replicates. At 4 and 8 wk of age 20% of experimental birds were randomly selected, weighed and euthanatized. The liver, pancreas, and hypothalamus were excised, snap frozen in liquid nitrogen and stored at -80 degrees C until use. Tissue mRNA was extracted and cDNA synthesized for qPCR assays. Lysine at 0.80 and 0.86% hindered growth, development of digestive organs, expression of brain and liver glutamate and leptin receptors, and caused high mortality in GF. The fold change for metabotropic glutamate receptor I was lower (P < 0.05) in liver and higher in brain at 0.86 and 0.92% than the control (1.10%) and 1.22% lysine. The 1.22% lysine exhibited highest expression of ionotropic glutamate receptor, while brain ghrelin receptor expression was highest at 0.86 and 0.92% lysine. Therefore, dietary lysine concentration may influence signaling pathways regulating food intake in brain-liver axis via glutamate synthesis. PMID- 26614683 TI - Spontaneous resolution of traumatic acute subdural haematomas: A systematic review. AB - INTRODUCTION: Traumatic subdural haematomas often require emergency surgical evacuation. Spontaneous resolution of traumatic acute subdural haematomas (TASDH) is under-reported. Two patients are described with spontaneous resolution of TASDH correlating with previous reports. A discussion is presented on the clinical, pathological and radiological features of TASDH. METHODS: A review of the literature was performed using PubMed (Medline), Embase, and Cochrane Library for similar cases. RESULTS: A total 21 articles were included, involving 27 cases well detailed of TASDH with spontaneous resolution or neurological and radiological improvement in less than 24 h. CONCLUSIONS: There are two main mechanisms for the spontaneous resolution of acute subdural haematomas: dilution in subarachnoid space and redistribution of the haematoma in the subdural space. The primary radiological characteristic of these lesions is a hypodense rim on the outer surface of the clot. Spontaneous resolution of TASDH is unusual. Clinical and radiological surveillance is essential for appropriate management of these patients. PMID- 26614684 TI - Population trends in smoking, alcohol use and primary prevention variables among adolescents in Iceland, 1997-2014. AB - AIMS: To estimate linear time-trends in substance use and primary prevention variables in adolescents in Iceland from 1997 to 2014. DESIGN: Repeated, cross sectional population-based school surveys with seven waves of pooled data. SETTING: Iceland. PARTICIPANTS: All accessible students enrolled in the 9th and 10th grades in the national Icelandic school system during the spring of 1997, 2000, 2003, 2006, 2009, 2012 and 2014 (n = 50 412, boys = 50%). Response rates ranged between 81 and 90% of the population. MEASUREMENTS: Measures on substance use included smoking and alcohol use. Primary prevention measures included parental monitoring, parental social involvement, participation in organized sports and reduced participation in a party life-style. FINDINGS: Substance use decreased consistently during the study period. For example, 30-day drunkenness declined from 29.6 in 1997 to 3.6% in 2014 (linear trend: chi(2) (1) = 2846.8, P < 0.001), and daily smoking during the last 30 days declined from 17.0 to 1.6% during the same period (linear trend: chi(2) (1) = 1614.3, P < 0.001). Primary prevention factors strengthened over time. For example, the mean score for parents knowing where their children are in the evenings rose from 2.44 in 1997 to 3.08 in 2014 (Ftrend(1, 42635) , 2538.3, P < 0.001), and mean scores for participation in party life-style declined from 2.23 in 1997 to 1.71 in 2014 (Ftrend(1, 38773) , 2033.1, P < .001). CONCLUSIONS: Substance use among adolescents in Iceland has declined steadily from 1997 to 2014, while primary prevention factors for substance use have increased in strength during the same time-period. PMID- 26614686 TI - A review of the clinical performance of the Aptima HPV assay. AB - This comprehensive review compiles published data from 62 original articles comparing different HPV tests and one meta-analysis on the clinical performance of the Aptima HR HPV (AHPV) assay in either screening or referral populations as well as for the purpose of test of cure. A number of publications with technical issues were also considered. Besides a brief introduction in the development of E6/E7 mRNA testing, the review summarizes data on analytical sensitivies and specificities, as well as on clinical sensitivity, specificity, NPV and PPV with histological endpoints CIN2+ and CIN3+, where available. Although most studies were of cross-sectional design, five studies with a longitudinal prospective design or component were identified. In addition to the study design, sample size, age and CIN2/3+ prevalence of the respective cohort are listed. This allows direct comparison of the published data in the respective groups. One major outcome of this review is the remarkably stable similar sensitivities of AHPV and HC2 independent from study design for detection of CIN2/3+ combined with a higher specificity of the AHPV. The second outcome was the longitudinal predictive value derived from registry linkage and other prospective studies that would support the applicability of the AHPV test in primary screening with at least a three year screening interval. PMID- 26614687 TI - Effects of dietary Lactobacillus acidophilus and Bacillus subtilis on laying performance, egg quality, blood biochemistry and immune response of organic laying hens. AB - The objective of this study was to evaluate the effects of two different probiotic micro-organisms on the performance, egg quality and blood parameters of organically reared hens. A total of 900 16-week-old Hy-Line layer hybrids were randomly assigned to three groups of 300 birds each. The control (CTR) group was fed a corn-soya bean cake-based diet; the L group was fed the same diet supplemented with 0.1% Lactobacillus acidophilus, while the B group was fed the same diet supplemented with 0.05% Bacillus subtilis. Data were recorded at the beginning (weeks 5 and 6: T1) and at the end (weeks 19 and 20: T2) of the experiment, and no differences in hen performance were recorded between dietary groups or sampling times. All of the investigated clinical chemistry parameters, except GGT, were affected by diet (p < 0.05), with the best results recorded for the probiotic-treated groups. The immune-response values showed higher blood bactericidal activity in the B and L groups at T2 (p < 0.05) and a lower lysozime concentration in the B group at T1. Higher antibody production against Newcastle disease virus was observed in the L group compared to the CTR (p = 0.013). No differences in oxidative status were recorded, and no effects of diet on egg quality were observed. Among the physical egg characteristics, only the Roche scale colour was affected by diet (p < 0.05): the egg yolk was paler in the L group. The age of the hen was the most relevant factor affecting physical egg characteristics. The chemical parameters of the egg were almost unaffected by supplementation with probiotics except for the lipid content, which decreased with the L diet (p < 0.05). Both probiotic inclusions had beneficial effects on hen metabolism and welfare, and L. acidophilus induced the best immune response. PMID- 26614685 TI - The First European Evidence-based Consensus on Extra-intestinal Manifestations in Inflammatory Bowel Disease. PMID- 26614688 TI - Revisional single-anastomosis gastric bypass for a failed restrictive procedure: 5-year results. AB - BACKGROUND: Long-term outcomes of revisional laparoscopic single anastomosis gastric bypass for a failed restrictive procedure (rSAGB) have not been analyzed. OBJECTIVES: To assess 5-year outcomes of rSAGB compared with 5-year outcomes of primary SAGB (pSAGB). SETTING: University public hospital, France. METHODS: One hundred twenty-six patients who underwent SAGB between October 2006 and October 2008 were included in this retrospective study. rSAGB was defined as SAGB performed after failure of a first restrictive procedure. Five-year outcomes of each procedure regarding mortality, morbidity (i.e., Clavien-Dindo score), weight loss (change in body mass index [BMI] and percentage of excess BMI loss [%EBMIL]), co-morbidities remission, and Gastrointestinal Quality of Life Index (GIQLI) score, were assessed. RESULTS: Thirty patients (24%) who had prior restrictive bariatric surgery (including 22 laparoscopic adjustable gastric bandings, 4 vertical banded gastroplasties, and 4 sleeve gastrectomies) underwent conversion to rSAGB. Ninety-six patients (76%) underwent primary SAGB (pSAGB group). Both groups were comparable in age, gender, BMI, and preoperative co morbidities. Preoperative mean BMI of the rSAGB group was 45.5+/-7 kg/m(2). There were no deaths and the major complications rate was 10%. No increase in morbidity was found between the 2 groups. Two patients required conversion to RYGB after rSAGB because of intractable biliary reflux. At 5 years, mean BMI was 32 kg/m(2) and mean %EBMIL was 66% after rSAGB; no significant differences were found compared with pSAGB (BMI = 31 kg/m(2), %EBMIL = 73%). Co-morbidities and remission rates were statically similar. Overall, GIQLI score was significantly lower in the rSAGB group (104.1+/-17.6 versus 112.5+/-16.8, P = .025). Significant differences were found in "upper gastrointestinal symptoms" and "psychological" scores. CONCLUSION: At 5 years, rSAGB for a failed restrictive procedure was safe and effective, but quality of life and upper gastrointestinal function were lower compared with pSAGB. PMID- 26614689 TI - Genome-wide SNPs reveal fine-scale differentiation among wingless alpine stonefly populations and introgression between winged and wingless forms. AB - Insect flight loss is a repeated phenomenon in alpine habitats, where wing reduction is thought to enhance local recruitment and increase fecundity. One predicted consequence of flight loss is reduced dispersal ability, which should lead to population genetic differentiation and perhaps ultimately to speciation. Using a dataset of 15,123 SNP loci, we present comparative analyses of fine-scale population structure in codistributed Zelandoperla stonefly species, across three parallel altitudinal transects in New Zealand's Rock and Pillar mountain range. We find that winged populations (altitude 200-500 m; Zelandoperla decorata) show no genetic structuring within or among streams, suggesting substantial dispersal mediated by flight. By contrast, wingless populations (Zelandoperla fenestrata; altitude 200-1100 m) exhibit distinct genetic clusters associated with each stream, and additional evidence of isolation by distance within streams. Our data support the hypothesis that wing-loss can initiate diversification in alpine insect populations over small spatial scales. The often deep phylogenetic placement of lowland Z. fenestrata within their stream-specific clades suggests the possibility of independent alpine colonization events for each stream. Additionally, the detection of winged, interspecific hybrid individuals raises the intriguing possibility that a previously flightless lineage could reacquire flight via introgression. PMID- 26614690 TI - Improvement of mineral oil saturated and aromatic hydrocarbons determination in edible oil by liquid-liquid-gas chromatography with dual detection. AB - Mineral oils, which are mainly composed of saturated hydrocarbons and aromatic hydrocarbons, are widespread food contaminants. Liquid chromatography coupled to gas chromatography with flame ionization detection represents the method of choice to determine these two families. However, despite the high selectivity of this technique, the presence of olefins (particularly squalene and its isomers) in some samples as in olive oils, does not allow the correct quantification of the mineral oil aromatic hydrocarbons fraction, requiring additional off-line tools to eliminate them. In the present research, a novel on-line liquid chromatography coupled to gas chromatography method is described for the determination of hydrocarbon contamination in edible oils. Two different liquid chromatography columns, namely a silica one (to retain the bulk of the matrix) and a silver-ion one (which better retains the olefins), were coupled in series to obtain the mineral oil aromatic hydrocarbons hump free of interfering peaks. Furthermore, the use of a simultaneous dual detection, flame ionization detector and triple quadrupole mass spectrometer allowed us not only to quantify the mineral oil contamination, but also to evaluate the presence of specific markers (i.e. hopanes) to confirm the petrogenic origin of the contamination. PMID- 26614691 TI - Employer-sponsored health insurance and the gender wage gap. AB - During prime working years, women have higher expected healthcare expenses than men. However, employees' insurance rates are not gender-rated in the employer sponsored health insurance (ESI) market. Thus, women may experience lower wages in equilibrium from employers who offer health insurance to their employees. We show that female employees suffer a larger wage gap relative to men when they hold ESI: our results suggest this accounts for roughly 10% of the overall gender wage gap. For a full-time worker, this pay gap due to ESI is on the order of the expected difference in healthcare expenses between women and men. PMID- 26614692 TI - Genetic markers as instrumental variables. AB - The use of genetic markers as instrumental variables (IV) is receiving increasing attention from economists, statisticians, epidemiologists and social scientists. Although IV is commonly used in economics, the appropriate conditions for the use of genetic variants as instruments have not been well defined. The increasing availability of biomedical data, however, makes understanding of these conditions crucial to the successful use of genotypes as instruments. We combine the econometric IV literature with that from genetic epidemiology, and discuss the biological conditions and IV assumptions within the statistical potential outcomes framework. We review this in the context of two illustrative applications. PMID- 26614693 TI - 2D Pulses using spatially dependent frequency sweeping. AB - PURPOSE: To introduce a method of designing two-dimensional (2D) frequency modulated pulses that produce phase coherence in a spatiotemporal manner. Uniquely, this class of pulses provides the ability to compensate for field inhomogeneity using a spatiotemporally dependent trajectory of maximum coherence in a single-shot. THEORY AND METHODS: A pulse design method based on a k-space description is developed. Bloch simulations and phantom experiments are used to demonstrate sequential spatiotemporal phase coherence and compensation for B1+ and B0 inhomogeneity. RESULTS: In the presence of modulated gradients, the 2D frequency-modulated pulses were shown to excite a cylinder in a selective manner. With a surface coil transmitter, compensation of the effect of B1+ inhomogeneity was experimentally verified, in agreement with simulation results. In addition, simulations were used to demonstrate partial compensation for B0 inhomogeneity. CONCLUSION: The 2D frequency-modulated pulses are a new class of pulses that generate phase coherence sequentially along a spatial trajectory determined by gradient- and frequency-modulated functions. By exploiting their spatiotemporal nature, 2D frequency-modulated pulses can compensate for spatial variation of the radiofrequency field in a single-shot excitation. Preliminary results shown suggest extensions might also be used to compensate for static field inhomogeneity. Magn Reson Med 76:1364-1374, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26614694 TI - Clinical features of Japanese polycythemia vera and essential thrombocythemia patients harboring CALR, JAK2V617F, JAK2Ex12del, and MPLW515L/K mutations. AB - The risk of complication of polycythemia vera (PV) and essential thrombocythemia (ET) by thrombosis in Japanese patients is clearly lower than in western populations, suggesting that genetic background such as race may influence the clinical features. This study aimed to clarify the relationship between genetic mutations and haplotypes and clinical features in Japanese patients with PV and ET. Clinical features were assessed prospectively among 74 PV and 303 ET patients. There were no clinical differences, including JAK2V617F allele burden, between PV patients harboring the various genetic mutations. However, CALR mutation-positive ET patients had a significantly lower WBC count, Hb value, Ht value, and neutrophil alkaline phosphatase score (NAP), and significantly more platelets, relative to JAK2V617F-positive ET patients and ET patients with no mutations. Compared to normal controls, the frequency of the JAK246/1 haplotype was significantly higher among patients with JAK2V617F, JAK2Ex12del, or MPL mutations, whereas no significant difference was found among CALR mutation positive patients. CALR mutation-positive patients had a lower incidence of thrombosis relative to JAK2V617F-positive patients. Our findings suggest that JAK2V617F-positive ET patients and CALR mutation-positive patients have different mechanisms of occurrence and clinical features of ET, suggesting the potential need for therapy stratification in the future. PMID- 26614695 TI - Species-specific accumulation of methyl and total mercury in sharks from offshore and coastal waters of Korea. AB - Limited information is available on mercury (Hg) levels in various shark species consumed in Korea. The methyl-Hg (Me-Hg) and total Hg concentrations in all shark species ranged from 0.08 to 4.5 (mean: 1.2) mg/kg wet weight and from 0.1 to 7.0 (mean: 1.4) mg/kg wet weight, respectively. Inter-species differences in Hg accumulation were found among the species; however, Hg accumulation was homogenous between dorsal and pectoral fins within species. The highest Hg levels were found in aggressive carnivore shark species. Trophic position was important in determining Hg accumulation for aggressive carnivore sharks. Approximately 80% of shark species exceeded the safety limits for Me-Hg established by domestic and international authorities. The mean estimated daily intake of Me-Hg (1.3 MUg/kg body weight/day) for Korean populations consuming various sharks was higher than the guidelines proposed by international regulatory authorities, suggesting that excessive shark fin consumption may pose potential health risks for Koreans. PMID- 26614696 TI - Pediatric Benign Soft Tissue Oral and Maxillofacial Pathology. AB - Despite the many types of oral pathologic lesions found in infants and children, the most commonly encountered are benign soft tissue lesions. The clinical features, diagnostic criteria, and treatment algorithms of pathologies in the age group from birth to 18 years of age are summarized based on their prevalence in each given age distribution. Treatment modalities include both medical and surgical management. PMID- 26614697 TI - Pediatric Head and Neck Malignancies. AB - Head and neck malignancies are rare in pediatric patients, and represent 12% of all pediatric malignancies. The incidence for these head and neck tumors is 1.49 cases per 1,000,000 person-years. Among the most common pediatric head and neck malignancies are lymphomas (27%), neural tumors including primitive neurectodermal tumors (23%), thyroid malignancies (21%), soft tissue sarcomas including rhabdomyosarcoma (12%), nasopharyngeal carcinoma, skeletal and odontogenic malignancies including osteosarcoma, Ewing sarcoma, and ameloblastic carcinoma. This article presents an overview of pediatric head and neck malignancies with emphasis on diagnosis and management. PMID- 26614698 TI - Pediatric Odontogenic Cysts of the Jaws. AB - Odontogenic cysts represent a common form of pathology of the jaws, and the natural history, clinicopathologic findings, and appropriate management strategies are important to the oral and maxillofacial surgeon. Odontogenic cysts in the pediatric populations are important pathologic entities given their potential impact on the growth and development of the maxillofacial complex. Inappropriate management strategies can severely affect the form and function of the growing child. Categorizing pediatric odontogenic cysts into inflammatory or developmental causes provides a convenient way of conceptualizing these various entities and helps facilitate the appropriate diagnosis and the subsequent management. PMID- 26614699 TI - Nonodontogenic Cysts of the Jaws and Treatment in the Pediatric Population. AB - Nonodontogenic cysts within the jaws are not a common presentation in the pediatric population. Cysts within the pediatric population tend to be developmental and odontogenic in nature. Although nonodontogenic cysts of the jaws are relatively uncommon, it is imperative the clinician understand their clinical behavior and management because failure to do so can result in increased patient morbidity. The nonodontogenic cysts of the jaws that are most often encountered are the central giant cell granuloma, traumatic bone cavity, aneurysmal bone cyst, nasopalatine duct cyst, and nasolabial cyst. This article reviews common clinical findings, radiographic features, histopathologic features, and current treatments of nonodontogenic cysts. PMID- 26614700 TI - Pediatric Odontogenic Tumors. AB - Pediatric odontogenic tumors are rare, and are often associated with impacted teeth. Although they can develop anywhere in the jaws, odontogenic tumors mainly occur in the posterior mandible. This article discusses the diagnosis and treatment of the most common pediatric odontogenic tumors, such as ameloblastoma, keratocystic odontogenic tumor, odontoma, and cementoblastoma. PMID- 26614701 TI - Nonodontogenic Tumors of the Jaws. AB - Nonodontogenic tumors of the jaws are common in the pediatric population, accounting for approximately 70% of pediatric jaw tumors. This article focuses on the clinical characteristics and management of the benign nonodontogenic tumors (nonaggressive and aggressive) of the jaws most commonly encountered in children. PMID- 26614702 TI - Benign Pediatric Salivary Gland Lesions. AB - Salivary gland lesions are rare in pediatric patients. In addition, the types of salivary gland tumors are different in their distribution in specific sites in the major and minor salivary glands in children compared with adults. This article reviews benign neoplastic and nonneoplastic salivary gland disorders in pediatric patients to help clinicians to develop an orderly differential diagnosis that will lead to expedient treatment of pediatric patients with salivary gland lesions. PMID- 26614703 TI - Pediatric Salivary Gland Malignancies. AB - Pediatric malignant salivary gland tumors are extremely rare. The percentage of malignant tumors is higher than that seen in adults, although the outcomes in terms of survival are better in pediatric patients. The mainstay of treatment is surgical excision with negative margins. This article reviews current concepts in demographics, etiology, management, and outcomes of malignant salivary tumors in children. PMID- 26614704 TI - Strategies to Overcome Late Complications from Radiotherapy for Childhood Head and Neck Cancers. AB - Most pediatric head and neck cancers are treated with radiotherapy, but the morbidity associated with radiotherapy has become a prominent issue. This article discusses the common long-term complications associated with head and neck radiotherapy for childhood cancers. It reviews approaches to minimize toxicity and details the toxicities that head and neck radiation inflicts on relevant functional measures. In addition, it discusses the risk of radiation-induced secondary cancers in childhood cancer survivors, as well as strategies to reduce them. Thus, this article addresses approaches to minimize long-term radiation toxicities in order to improve the quality of life for childhood cancer survivors. PMID- 26614705 TI - Chemotherapy in Children with Head and Neck Cancers: Perspectives and Review of Current Therapies. AB - Cancers of the head and neck in children represent a heterogeneous group of malignancies requiring a variety of treatment modalities. In many instances of childhood head and neck cancers, chemotherapy will be required for treatment, often in conjunction with surgery and/or radiation therapy. Chemotherapy in children with head and neck cancers poses unique challenges in terms of immediate as well as long-term toxicities. This article focuses on the common chemotherapeutic agents, with a particular focus on early and late effects, used in the treatment of children with head and neck cancers. PMID- 26614706 TI - Current Therapy in Pediatric Oral and Maxillofacial Pathology. PMID- 26614707 TI - The lectin complement pathway serine proteases (MASPs) represent a possible crossroad between the coagulation and complement systems in thromboinflammation. AB - ESSENTIALS: The lectin pathway's MASP-1/2 activates coagulation factors but the trigger of the activation is unknown. MASP-1/2 activation was assessed by quantifying complexes between MASPs and antithrombin/C1-inhibitor. Activated platelets and fibrin were demonstrated to activate MASP-1 and MASP-2 both in vitro and in vivo. These findings may represent a crossroad between the complement and the coagulation systems. SUMMARY: BACKGROUND: The activated forms of the complement lectin pathway (LP) proteases MASP-1 and MASP-2 are able to cleave the coagulation factors prothrombin, fibrinogen, factor XIII and thrombin activatable fibrinolysis inhibitor in vitro. In vivo studies also show that MASP 1 is involved in thrombogenesis. OBJECTIVES: To clarify the not yet identified mechanisms involved in triggering activation of the LP during thrombotic reactions. METHODS: Novel sandwich-ELISAs for detection of complexes between MASP 1 or MASP-2 and the serpins C1 inhibitor (C1-INH) or antithrombin (AT), were used to specifically detect and quantify the activated forms of MASP-1 and MASP-2. RESULTS: Activated platelets were shown by flow cytometry to bind Ficolin-1, -2 and -3 but not MBL, which was associated with activation of MASP-1 and MASP-2. We also demonstrated that fibrin and the plasmin-generated fibrin fragment DD in plasma, bind and activate MASP-1 and MASP-2. As demonstrated by the ELISA and SDS PAGE/Western blotting, the fibrin-associated activation was reflected in a specific inactivation by AT during clotting without the assistance of heparin. In all other cases the MASPs were, as previously reported, inactivated by C1-INH. In systemic lupus erythematosus patients with thrombotic disease and in polytrauma patients, the levels of activated MASP-1 and MASP-2 in complex with both AT and C1-INH were associated with markers of thrombotic disease and contact/coagulation system activation. CONCLUSIONS: MASP-1 and MASP-2 are activated during blood clotting. This activation is triggered by activated platelets and by the generation of fibrin during thrombotic reactions in vitro and in vivo, and may represent a novel activation/amplification mechanism in thromboinflammation. PMID- 26614708 TI - Molecular profiling of head and neck squamous cell carcinoma. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) exhibits high rates of recurrence, and with few approved targeted agents, novel treatments are needed. We analyzed a molecular profiling database for the distribution of biomarkers predictive of chemotherapies and targeted agents. METHODS: Seven hundred thirty five patients with advanced HNSCC (88 with known human papillomavirus [HPV] status), were profiled using multiple platforms (gene sequencing, gene copy number, and protein expression). RESULTS: Among the entire patient population studied, epidermal growth factor receptor (EGFR) was the protein most often overexpressed (90%), TP53 gene most often mutated (41%), and phosphatidylinositol 3-kinase (PIK3CA) most often amplified (40%; n = 5). With the exception of TP53 mutation, other biomarker frequencies were not significantly different among HPV positive or HPV-negative patients. PIK3CA mutations and phosphatase and tensin homolog (PTEN) loss are frequent events, independent of HPV status. The immune response-modulating programmed cell death 1 (PD1) and programmed cell death ligand 1 (PDL1) axis was active across sites, stages, and HPV status. CONCLUSION: Molecular profiling utilizing multiple platforms provides a range of therapy options beyond standard of care. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1625-E1638, 2016. PMID- 26614710 TI - Cost-Utility of a Prognostic Test Guiding Adjuvant Chemotherapy Decisions in Early-Stage Non-Small Cell Lung Cancer. AB - BACKGROUND: A prognostic test was developed to guide adjuvant chemotherapy (ACT) decisions in early-stage non-small cell lung cancer (NSCLC) adenocarcinomas. The objective of this study was to compare the cost-utility of the prognostic test to the current standard of care (SoC) in patients with early-stage NSCLC. MATERIALS AND METHODS: Lifetime costs (2014 U.S. dollars) and effectiveness (quality adjusted life-years [QALYs]) of ACT treatment decisions were examined using a Markov microsimulation model from a U.S. third-party payer perspective. Cancer stage distribution and probability of receiving ACT with the SoC were based on data from an academic cancer center. The probability of receiving ACT with the prognostic test was estimated from a physician survey. Risk classification was based on the 5-year predicted NSCLC-related mortality. Treatment benefit with ACT was based on the prognostic score. Discounting at a 3% annual rate was applied to costs and QALYs. Deterministic one-way and probabilistic sensitivity analyses examined parameter uncertainty. RESULTS: Lifetime costs and effectiveness were $137,403 and 5.45 QALYs with the prognostic test and $127,359 and 5.17 QALYs with the SoC. The resulting incremental cost-effectiveness ratio for the prognostic test versus the SoC was $35,867/QALY gained. One-way sensitivity analyses indicated the model was most sensitive to the utility of patients without recurrence after ACT and the ACT treatment benefit. Probabilistic sensitivity analysis indicated the prognostic test was cost-effective in 65.5% of simulations at a willingness to pay of $50,000/QALY. CONCLUSION: The study suggests using a prognostic test to guide ACT decisions in early-stage NSCLC is potentially cost effective compared with using the SoC based on globally accepted willingness-to pay thresholds. IMPLICATIONS FOR PRACTICE: Providing prognostic information to decision makers may help some patients with high-risk early stage non-small cell lung cancer receive appropriate adjuvant chemotherapy while avoiding the associated toxicities and costs in patients with low-risk disease. This study used an economic model to assess the effectiveness and costs associated with using a prognostic test to guide adjuvant chemotherapy decisions compared with the current standard of care in patients with non-small cell lung cancer. When compared with current standard care, the prognostic test was potentially cost effective at commonly accepted thresholds in the U.S. This study can be used to help inform decision makers who are considering using prognostic tests. PMID- 26614709 TI - Circulating Tumor Cells, DNA, and mRNA: Potential for Clinical Utility in Patients With Melanoma. AB - : Circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and messenger RNA (mRNA), collectively termed circulating tumor products (CTPs), represent areas of immense interest from scientists' and clinicians' perspectives. In melanoma, CTP analysis may have clinical utility in many areas, from screening and diagnosis to clinical decision-making aids, as surveillance biomarkers or sources of real-time genetic or molecular characterization. In addition, CTP analysis can be useful in the discovery of new biomarkers, patterns of treatment resistance, and mechanisms of metastasis development. Here, we compare and contrast CTCs, ctDNA, and mRNA, review the extent of translational evidence to date, and discuss how future studies involving both scientists and clinicians can help to further develop this tool for the benefit of melanoma patients. IMPLICATIONS FOR PRACTICE: Scientific advancement has enabled the rapid development of tools to analyze circulating tumor cells, tumor DNA, and messenger RNA, collectively termed circulating tumor products (CTPs). A variety of techniques have emerged to detect and characterize melanoma CTPs; however, only a fraction has been applied to human subjects. This review summarizes the available human data that investigate clinical utility of CTP in cancer screening, melanoma diagnosis, prognosis, prediction, and genetic or molecular characterization. It provides a rationale for how CTPs may be useful for future research and discusses how clinicians can be involved in developing this exciting new technology. PMID- 26614711 TI - Use of Palliative Care Services in a Tertiary Cancer Center. AB - BACKGROUND: Despite increasing prevalence of palliative care (PC) services in cancer centers, most referrals to the service occur exceedingly late in the illness trajectory. Over the years, we have made several attempts to promote earlier patient access to our PC program, such as changing the name of our service from PC to supportive care (SC). This study was conducted to determine the use of PC/SC service over the past 8 years. METHODS: We reviewed billing data for all PC/SC encounters. We examined five metrics for use: inpatient consultations as a percentage of hospital admissions, ratio of inpatient consultations to average number of operational beds, time from hospital registration to outpatient consultation, time from advanced cancer diagnosis to consultation, and time from first outpatient consultation to death/last follow up. RESULTS: Over the years, we found a consistent increase in patient referrals to the PC/SC program. In the inpatient setting, we found approximate doubling of the inpatient consultations as a percentage of hospital admissions and the ratio of inpatient consultations to hospital beds (from 10% to 19% and from 2.4 to 4.9, respectively; p < .001). In the outpatient setting, we observed variations in referral pattern between oncology services, but, overall, the time from consultation to death/last follow-up increased from 4.8 months to 7.9 months (p = .001), which was accompanied by a significant decrease in the interval to consultation from hospital registration and advanced cancer diagnosis (p < .001). CONCLUSION: We have observed a consistent annual increase in new patient referrals as well as earlier access for outpatient referrals to our SC service, supporting increased use of palliative care at our cancer center. IMPLICATIONS FOR PRACTICE: In response to accumulating evidence on the benefits of palliative care (PC) referral to oncology patients, efforts are being made to increase PC use. This study, conducted at MD Anderson Cancer Center, demonstrates consistent annual growth in PC referrals, which was accompanied by a significant increase in the outpatient referral of patients with nonadvanced cancer and earlier referral of those with advanced cancer. However, significant variations in the referral patterns between oncology services were observed. These results have implications for other cancer centers looking to enhance use of PC services by having a business model that allows for appropriate space and staff expansion. PMID- 26614712 TI - Functionally heterogeneous synaptic vesicle pools support diverse synaptic signalling. AB - Synaptic communication between neurons is a highly dynamic process involving specialized structures. At the level of the presynaptic terminal, neurotransmission is ensured by fusion of vesicles to the membrane, which releases neurotransmitter in the synaptic cleft. Depending on the level of activity experienced by the terminal, the spatiotemporal properties of calcium invasion will dictate the timing and the number of vesicles that need to be released. Diverse presynaptic firing patterns are translated to neurotransmitter release with a distinct temporal feature. Complex patterns of neurotransmitter release can be achieved when different vesicles respond to distinct calcium dynamics in the presynaptic terminal. Specific vesicles from different pools are recruited during various modes of release as the particular molecular composition of their membrane proteins define their functional properties. Such diversity endows the presynaptic terminal with the ability to respond to distinct physiological signals via the mobilization of specific subpopulation of vesicles. There are several mechanisms by which a diverse vesicle population could be generated in single presynaptic terminals, including distinct recycling pathways that utilize various adaptor proteins. Several additional factors could potentially contribute to the development of a heterogeneous vesicle pool such as specialized release sites, spatial segregation within the terminal and specialized delivery pathways. Among these factors molecular heterogeneity plays a central role in defining the functional properties of different subpopulations of vesicles. PMID- 26614713 TI - Target-specific Oral Anticoagulants in the Emergency Department. AB - BACKGROUND: Emergency physicians make treatment decisions in patients who present to the emergency department (ED) with acute venous thromboembolism (VTE). They also encounter patients on target-specific oral anticoagulants (TSOACs) who require urgent intervention. New approvals and increasing prescriptions for TSOACs (e.g., apixaban, dabigatran, edoxaban, and rivaroxaban) for the management of several thromboembolic disorders warrant an evaluation of the impact of these agents in the ED setting. OBJECTIVE OF THE REVIEW: This review discusses the use of TSOACs in the ED for the treatment of acute VTE, and highlights strategies for the management of patients on TSOACs who present to the ED with other complications, such as bleeding complications or requiring emergency surgery. DISCUSSION: Apixaban, dabigatran, edoxaban, and rivaroxaban have been approved for the treatment of acute VTE. We discuss the impact of this on ED management of TSOAC-naive patients and highlight results with TSOACs in high-risk subgroups including the elderly and those with prior VTE or active cancer. This review also discusses management strategies for patients on TSOACs. For emergency physicians, strategies for the management of bleeding, approaches to patient care when emergency surgery is needed, laboratory assays for measuring plasma concentrations of TSOACs, and drug-drug interactions are of special importance. CONCLUSIONS: Familiarity with TSOACs will better position emergency physicians to provide state-of-the art care to their patients with VTE and help them manage potentially complicated circumstances related to the chronic use of these drugs. PMID- 26614714 TI - The influence of patient age and bone mineral density on osteotomy fixation stability after hallux valgus surgery: A biomechanical study. AB - BACKGROUND: Oblique osteotomies of the first metatarsal are common surgical treatments for moderate to severe hallux valgus deformity. Osteotomy fixation integrity is important to minimize interfragment motion and maintain correction during healing, and our clinical observations suggest that patient age and bone quality affect fixation stability and ultimately the clinical outcome. Accordingly, this study correlated these patient factors with key mechanical measures of osteotomy angulation resistance in a cadaver hallux valgus correction model. METHODS: Standard Ludloff osteotomies were created in 31 fresh-frozen first metatarsals and fixed with two cannulated, dual-pitch headless screws. Each specimen underwent 1000 plantar-to-dorsal bending loads while monitoring bending stiffness and distal fragment dorsal angulation. Donor age and bone mineral density were then correlated with each mechanical measure at selected cycling increments. FINDINGS: We found significant positive correlation between bone mineral density and osteotomy fixation stiffness for all evaluated load cycles. Moderate negative correlation between bone density and angulation was identified, significant for load cycle 500. There was a weak, nonsignificant negative correlation between donor age and osteotomy bending stiffness, with r ranging from -0.134 to -0.243 between the first and 1000th loads. Little correlation was demonstrable between age and angulation. INTERPRETATION: Because low bone density correlates with decreased osteotomy site stiffness and increased angulation under load, patient compliance and protected weight bearing in the early postoperative phase are particularly important if bone mineral density is exceptionally low. Correspondingly, patients with especially high bone mineral density may be considered candidates for earlier weight bearing and active physical therapy. PMID- 26614715 TI - Chronic Pain Management: An Overview of Taxonomy, Conditions Commonly Encountered, and Assessment. AB - Chronic pain has multiple mechanisms that result in pain amplification and maintenance, including central and peripheral sensitization and altered modulation of pain perception. Assessment of pain requires comprehensive assessment of symptoms and signs, suspected pain mechanisms, and the patient's biopsychosocial context. Multiple validated measures exist for the assessment of pain symptoms, pain-related disability, psychological impact of pain, and candidacy for opioid management. PMID- 26614716 TI - The Acute to Chronic Pain Transition: Can Chronic Pain Be Prevented? AB - Chronic postsurgical pain (CPSP) is a distressing disease process that can lead to long-term disability, reduced quality of life, and increased health care spending. Although the exact mechanism of development of CPSP is unknown, nerve injury and inflammation may lead to peripheral and central sensitization. Given the complexity of the disease process, no novel treatment has been identified. The preoperative use of multimodal analgesia has been shown to decrease acute postoperative pain, but it has no proven efficacy in preventing development of CPSP. PMID- 26614717 TI - What Do We Know About the Pathophysiology of Chronic Pain? Implications for Treatment Considerations. AB - We discuss the complex features of the pathophysiology of chronic pain and the implications for treatment and provide an overview of nociceptive processes, neuropathic pain, cold hyperalgesia, peripheral nerve injury, wind-up pain, central sensitization, and common clinical presentation and diagnostic criteria. Advanced medicine has proven that chronic pain need not involve any structural pathology as pain is a complex biopsychosocial experience. Treatment of the specific mechanisms responsible for pain should be aimed at preventing and or reducing dysfunctional neuro-plasticity resulting from poorly controlled chronic pain. Further study is needed to reduce the probability and of persistent changes that cause chronic pain. PMID- 26614718 TI - Biopsychosocial Approach to Assessing and Managing Patients with Chronic Pain. AB - Chronic pain affects nearly one-third of the American population. Chronic pain can lead to a variety of problems for a pain sufferer, including developing secondary medical problems, depression, functional and vocational disability, opioid abuse and suicide. Current pain care models are deficient in providing a necessary comprehensive approach. Most patients with chronic pain are managed by primary care clinicians who are typically ill prepared to effectively and efficiently manage these cases. A biopsychosocial approach to evaluate and treat chronic pain is clinically and economically efficacious, but unique delivery systems are required to meet the challenge of access to specialty care. PMID- 26614719 TI - Multimodal Treatment of Chronic Pain. AB - Most patients with chronic pain receive multimodal treatment. There is scant literature to guide us, but when approaching combination pharmacotherapy, the practitioner and patient must weigh the benefits with the side effects; many medications have modest effect yet carry significant side effects that can be additive. Chronic pain often leads to depression, anxiety, and deconditioning, which are targets for treatment. Structured interdisciplinary programs are beneficial but costly. Interventions have their place in the treatment of chronic pain and should be a part of a multidisciplinary treatment plan. Further research is needed to validate many common combination treatments. PMID- 26614720 TI - An Overview of Pharmacologic Management of Chronic Pain. AB - Patients with chronic pain can be challenging to manage and historically providers have relied on opiates to treat pain. Recent studies have brought into question the safety and efficacy of chronic opiate therapy in the noncancer population. There is a vast amount of literature to support the use of nonsteroidal anti-inflammatory medications, antidepressants, anticonvulsants, topical agents, cannabinoids, and botulinum toxin either in conjunction with or in lieu of opioids. Intrathecal drug delivery systems can deliver some of these medications directly to their primary site of action while minimizing the side effects seen with systemic administration. PMID- 26614721 TI - Exploring the Use of Chronic Opioid Therapy for Chronic Pain: When, How, and for Whom? AB - This article provides a broad overview regarding intent to initiate and consider ongoing chronic opioid therapy (COT) for treatment of chronic noncancer pain (CNCP). COT should be an individualized decision based on a comprehensive evaluation, assessment, and monitoring. It is imperative that providers discuss various risks and benefits of COT initially and at follow-up visits, and continue appropriate monitoring and follow-up at regular intervals. The decision to initiate or continue opioid therapy is based on clinical judgment; however, it is understood that opioid and other medication therapy represent one piece of the complete treatment plan for patients with CNCP. PMID- 26614722 TI - The Role of Invasive Pain Management Modalities in the Treatment of Chronic Pain. AB - Invasive analgesic therapies provide an alternative to medical management of chronic pain. With the increasing incidence of chronic pain not only in the United States but worldwide, more therapies have evolved to address the growing need for pain relief options. These therapies include spinal injections, nerve blocks, radiofrequency ablation, neurostimulation, and intrathecal drug delivery. PMID- 26614723 TI - Managing Chronic Headache Disorders. AB - Headaches are a very common disorder, more common than asthma and diabetes combined. Migraine is the most common headache disorder, but it remains underdiagnosed and therefore undertreated. The treatment of migraines is divided into acute and prophylaxis. Patients who are experiencing 8 or more headaches a month or those who experience disability with their headaches as determined by the Migraine Disability Assistance Score or MIDAS should be placed on prophylaxis. PMID- 26614724 TI - Managing Osteoarthritis and Other Chronic Musculoskeletal Pain Disorders. AB - Osteoarthritis (OA) is a common problem in society and can lead to significant disability and impairment of a patient's capacity to perform activities of daily living. The focus of this article is various treatment options for the management of OA, with emphasis on conservative management. The emphasis is on the role of exercise, pharmacology, intra-articular joint injections, and bracing options in the management of OA. PMID- 26614725 TI - Managing Neuropathic Pain. AB - Neuropathic pain (NP) arises from injuries or diseases affecting the somatosensory component of the nervous system at any level of the peripheral or central nervous system. NP is diagnosed based on common neurologic signs and symptoms. NP is best treated with a combination of multiple therapeutic approaches, and treatments include conservative, complementary, medical, interventional, and surgical treatment modalities. Goals of treatment are the same as in pain management and include improvement in pain control and in coping skills as well as restoration of functional status. Most patients with NP benefit most from an individualized, multimodal approach that emphasizes both pain and function. PMID- 26614726 TI - Acute and Chronic Low Back Pain. AB - Low back pain is an extremely common presenting complaint that occurs in upward of 80% of persons. Treatment of an acute episode of back pain includes relative rest, activity modification, nonsteroidal anti-inflammatories, and physical therapy. Patient education is also imperative, as these patients are at risk for further future episodes of back pain. Chronic back pain (>6 months' duration) develops in a small percentage of patients. Clinicians' ability to diagnose the exact pathologic source of these symptoms is severely limited, making a cure unlikely. Treatment of these patients should be supportive, the goal being to improve pain and function. PMID- 26614728 TI - Is Platelet-Rich Plasma a Future Therapy in Pain Management? AB - Platelet-rich plasma (PRP) has the potential to regenerate tissues and decrease pain through the effects of bioactive molecules and growth factors present in alpha granules. Several PRP preparation systems are available with varying end products, doses of growth factors, and bioactive molecules. This article presents the biology of PRP, the preparation of PRP, and the effects PRP-related growth factors have on tissue healing and repair. Based on available evidence-based literature, the success of PRP therapy depends on the method of preparation and composition of PRP, the patient's medical condition, anatomic location of the injection, and the type of tissue injected. PMID- 26614729 TI - Yes, You Can Manage Chronic Pain. PMID- 26614727 TI - Managing Chronic Pain in Special Populations with Emphasis on Pediatric, Geriatric, and Drug Abuser Populations. AB - In the adult population chronic pain can lead to loss of productivity and earning potential, and decreased quality of life. There are distinct groups with increased vulnerability for the emergence of chronic pain. These groups may be defined by developmental status and/or life circumstances. Within the pediatric, geriatric, and drug abuser populations, chronic pain represents a significant health issue. This article focuses on known anatomic, physiologic, and genetic mechanisms underlying chronic pain in these populations, and highlights the need for a multimodal approach from multiple health care professionals for management of chronic pain in those with the most risk. PMID- 26614730 TI - The Management of Chronic Pain: What Do We Know, What Do We Do, and How Should We Redesign Our Comprehensive Assessment and Treatment in order to Provide for More Patient-Centered Care? PMID- 26614731 TI - Where are you from? Preschoolers infer background from accent. AB - For adults, accent is an obvious indicator of a speaker's geographical background. The current study investigated whether preschoolers are sensitive to the relationship between background and accent. Experiment 1 shows that 3- to 5 year-olds believe that two speakers who share the same accent live in the same place but do not share the same personal preferences. Experiment 2 demonstrates that 4- and 5-year-olds believe that two speakers with the same accent share cultural norms associated with a particular place, but that two speakers with different accents have different cultural norms. As in Experiment 1, children did not think that personal preferences were related to accent. These findings show early awareness of the relationship between accent and geographical background. PMID- 26614732 TI - Pigmented epithelioid melanocytoma: clinical, dermoscopic and histopathological features. PMID- 26614733 TI - Predictive variables of sustained virological response after early discontinuation of triple therapy with telaprevir for genotype-1 HCV infection. AB - BACKGROUND: Pivotal phase studies of telaprevir (TLV) and boceprevir (BOV) showed 10-56% rates of early treatment interruption. However, there have been no reports on the sustained virological response (SVR) rates of these patients. AIM: To assess the SVR rate in a large cohort of patients who discontinued triple therapy with TLV or BOV for reasons other than stopping rules and to identify variables predicting SVR. MATERIAL AND METHOD: A survey was sent to 15 hospitals in Catalonia asking them to report all TLV/BOV treatments finished by 31 May 2014. Demographic, clinical, laboratory, liver fibrosis and therapeutic data were recorded for treatments with early discontinuation. Logistic regression analysis, ROC curves and prognostic assessment of the variables identified were calculated. RESULTS: Twelve hospitals responded to the survey, representing 467 treatments and 121 (21.2%) early discontinuations, 76 (62.8%) due to stopping rules and 45 (37.2%) for other reasons. Early discontinuation was more frequent with BOV [38.2% (50/131) versus 21.1% (71/336) p<0.005], mainly due to stopping rules [78% (39/50) versus 52.1% (37/71); p=0.004]. SVR was achieved in 21/121 patients (17.4%), 19/71 (26.8%) treated with TLV and 2/50 (4.0%) treated with BOV. In patients discontinuing treatment for reasons other than stopping rules, SVR was achieved in 19/37 (55.9%) treated with TLV and in 2/11 (18.2%) treated with BOV. The SVR rate in patients treated with TLV who discontinued due to a severe adverse event was 61.5% (16/26). A logistic regression analysis was performed only with triple therapy with TLV and early discontinuation. The predictive variables of SVR were undetectable HCV-RNA at treatment week 4 and treatment length longer than 11 weeks. Treatment duration longer than 11 weeks showed the best accuracy (0.794), with a positive predictive value of 0.928. CONCLUSIONS: Early discontinuation of TLV-based triple therapy due to reasons other than stopping rules still have a significant SVR rate (55.9%). Undetectable HVC-RNA at week 4 of treatment and treatment duration longer than 11 weeks are predictive of SVR in this subset of patients. PMID- 26614734 TI - The Role of Lymphoid Neogenesis in Allografts. AB - De novo induction of organized lymphoid aggregates at nonlymphoid sites has been observed in many chronic inflammatory conditions where foreign antigens such as infectious agents, autoantigens or alloantigens, persist. The prevailing opinion in the field of transplantation is that lymphoid neogenesis within allografts is detrimental to the establishment of immune tolerance. These structures, commonly referred to as tertiary lymphoid organs (TLOs), are thought to contribute to graft rejection by generating and propagating local alloimmune responses. However, recent studies have shown that TLOs rich in regulatory Foxp3(+) cells are present in long-term accepting allografts. The notion that TLOs can contribute to the local downregulation of immune responses has been corroborated in other chronic inflammation models. These findings suggest that contrary to previous suggestions that the induction of TLOs in allografts is necessarily harmful, the induction of "tolerogenic" TLOs may prove advantageous. In this review, we discuss our current understanding of how TLOs are induced and how they regulate immune responses with a particular focus on alloimmunity. PMID- 26614735 TI - Molecular Insights into the Pathogenesis of IgA Nephropathy. AB - Immunoglobulin IgA nephropathy (IgAN) is the leading form of primary glomerulonephritis associated with end-stage renal failure, requiring either dialysis or renal transplantation. Microscopic hematuria and proteinuria are the most common presentations, and mesangial cell proliferation with IgA deposition are found in renal biopsies. There is growing evidence that IgAN is an immune complex (IC)-mediated disease. To date, three key molecules have been implicated in IC formation, correlating with disease progression/recurrence after transplantation: galactose-deficient IgA1 (Gd-IgA1), IgG anti-Gd-IgA1 antibodies, and soluble CD89 (an Fc receptor for IgA). This review examines recent data on the role of these molecular players in IgAN. Understanding these factors is essential because such knowledge could lead to improved strategies for the future management of patients with IgAN. PMID- 26614736 TI - Results of a diabetic retinopathy screening. Risk markers analysis. AB - OBJECTIVE: To identify risk markers for retinopathy in patients from our geographic area, and to compare them with those published in other studies. To design a screening interval strategy, taking into account these results, and compare it with intervals suggested in published studies. MATERIAL AND METHODS: Cross-sectional observational study on 383 diabetic patients with no previous retinopathy diagnosis, who were screened for diabetic retinopathy. An analysis was made on the possible association between patient factors and presence of retinopathy. RESULTS: A greater probability for finding retinopathy in diabetic patients was associated to insulin treatment in our study, with a statistical significance level of 95%. In patients with less than 10year onset of their diabetes, only mild retinopathy without macular oedema was found. CONCLUSIONS: Insulin treatment and time of onset of diabetes should be taken into account when designing efficient screening strategies for diabetic retinopathy. PMID- 26614737 TI - A qualitative study of methamphetamine initiation in Cape Town, South Africa. AB - BACKGROUND: Despite a significant rise in methamphetamine use in low- and middle income countries, there has been little empirical examination of the factors that contribute to individuals' initiation of methamphetamine use in these settings. The goal of this study was to qualitatively examine factors associated with methamphetamine initiation in South Africa. METHODS: In-depth interviews were conducted with 30 active methamphetamine users (13 women and 17 men) in Cape Town, South Africa. Interviews included narrative descriptions of the circumstances surrounding methamphetamine initiation. Interviews were audio recorded, transcribed, and translated. Transcripts were analyzed with document memos, data display matrices, and a constant comparison technique to identify themes. RESULTS: On average, participants began regularly using methamphetamine around age 21 and had used for seven years. Four major themes emerged related to the initiation of methamphetamine use. The prevalence of methamphetamine users and distributors made the drug convenient and highly accessible to first time users. Methamphetamine has increased in popularity and is considered "trendy", which contributes to social pressure from friends, and less often, family members to initiate use. Initiation is further fueled by a lack of opportunities for recreation and employment, which leads to boredom and curiosity about the rumored positive effects of the drug. Young people also turn to methamphetamine use and distribution through gang membership as an attempt to generate income in impoverished communities with limited economic opportunities. Finally, participants described initiating methamphetamine as a means of coping with the cumulative stress and psychological burden provoked by the high rates of violence and crime in areas of Cape Town. CONCLUSION: The findings highlight the complex nature of methamphetamine initiation in low- and middle-income countries like South Africa. There is a need for community-level interventions to address the availability and perceived normality of methamphetamine use, and to provide young people opportunities for recreation. On an individual level, addressing mental health and misconceptions about the dangers and benefits of methamphetamine could ameliorate willingness for initiation. Potential points of intervention include mass media campaigns and school-based interventions to raise awareness of the physical and social impacts of methamphetamine, and structural interventions to create safer neighborhoods, provide opportunities for employment and recreation, and expand mental health services to improve emotional health and coping skills. PMID- 26614738 TI - Patient-Reported Factors Associated With Poor Phosphorus Control in a Maintenance Hemodialysis Population. AB - OBJECTIVE: The purpose of this study was to determine the influence of patient reported medication adherence and phosphorus-related knowledge on phosphorus control and pharmacy-reported adherence to phosphorus binding medication among patients on maintenance hemodialysis. DESIGN: Retrospective, cross-sectional cohort study. SUBJECTS: Seventy-nine hemodialysis patients (mean age 64.2 years, SD = 14 years; 46.8% female) in a stand-alone hemodialysis unit within an integrated learning healthcare system. Ten percent (10%) of subjects were Caucasian, 42% Latino, 19% African American, and 29% Asian. Forty-eight percent had diabetes; 72% had BMI >= 30. Inclusion criteria included the provision of survey data and having medication refill data available in the pharmacy system. 77.2% had mean phosphorus levels <= 5.5 mg/dL; 22.8% had mean phosphorus levels > 5.5 mg/dL. INTERVENTION: Subjects were administered the 8-item Morisky Medication Adherence Scale (MMAS-8) and also reported on their phosphorus-related knowledge. MAIN OUTCOME MEASURE: Phosphorus levels within an adequate range. RESULTS: The mean serum phosphorus level was 4.96 mg/dL (SD = 1.21). In the well-controlled group, mean phosphorus was 4.44 mg/dL (SD = 0.76). In the poorly controlled group, mean phosphorus was 6.69 mg/dL (SD = 0.74). A total of 61% of patients reported at least some unintentional medication nonadherence, and 48% reported intentional medication nonadherence. Phosphorus-specific knowledge was low, with just under half of patients reporting that they could not name two high phosphorus foods or identify a phosphorus-related health risk. Phosphorus binder related nonadherence was substantially higher in the uncontrolled than the controlled group. Adjusting for age, individuals with poorer self-reported binder adherence were less likely to have controlled phosphorus levels (odds ratio = 0.71, P = .06). CONCLUSION: Phosphorus-related non-adherence, but not low phosphorus-specific knowledge, was associated with poorer phosphorus control. Such findings provide important information for the development of evidence-based strategies for improving phosphorus control among patients on dialysis. PMID- 26614739 TI - Wnt Signaling in Sexual Dimorphism. AB - The embryonic gonad of Drosophila melanogaster begins to display sexually dimorphic traits soon after its formation. Here we demonstrate the involvement of a wnt family ligand, wnt-2, in the induction of these sex-specific differences. We show that wnt-2 contributes to the survival of a male-specific population of somatic gonadal precursor cells (SGPs), the male-specific SGPs that are located at the posterior of the male gonad. We also show that the Wnt-2 ligand synergizes with the JAK-STAT ligand Upd, which is produced by SGPs at the anterior of the gonad to activate the STAT pathway in male germ cells. We suggest that the use of two spatially separated signaling systems to initiate the JAK-STAT stem cell maintenance pathway in germ cells provides a mechanism for increasing the pool of potential progenitors of the germline stem cells in the adult testes. Finally, we present evidence indicating that, like the JAK-STAT pathway, wnt-2 stimulates germ cells in male embryos to re-enter the cell cycle. PMID- 26614740 TI - Genetic Architectures of Quantitative Variation in RNA Editing Pathways. AB - RNA editing refers to post-transcriptional processes that alter the base sequence of RNA. Recently, hundreds of new RNA editing targets have been reported. However, the mechanisms that determine the specificity and degree of editing are not well understood. We examined quantitative variation of site-specific editing in a genetically diverse multiparent population, Diversity Outbred mice, and mapped polymorphic loci that alter editing ratios globally for C-to-U editing and at specific sites for A-to-I editing. An allelic series in the C-to-U editing enzyme Apobec1 influences the editing efficiency of Apob and 58 additional C-to-U editing targets. We identified 49 A-to-I editing sites with polymorphisms in the edited transcript that alter editing efficiency. In contrast to the shared genetic control of C-to-U editing, most of the variable A-to-I editing sites were determined by local nucleotide polymorphisms in proximity to the editing site in the RNA secondary structure. Our results indicate that RNA editing is a quantitative trait subject to genetic variation and that evolutionary constraints have given rise to distinct genetic architectures in the two canonical types of RNA editing. PMID- 26614741 TI - Primary Sex Determination in Drosophila melanogaster Does Not Rely on the Male Specific Lethal Complex. AB - It has been proposed that the Male Specific Lethal (MSL) complex is active in Drosophila melanogaster embryos of both sexes prior to the maternal-to-zygotic transition. Elevated gene expression from the two X chromosomes of female embryos is proposed to facilitate the stable establishment of Sex-lethal (Sxl) expression, which determines sex and represses further activity of the MSL complex, leaving it active only in males. Important supporting data included female-lethal genetic interactions between the seven msl genes and either Sxl or scute and sisterlessA, two of the X-signal elements (XSE) that regulate early Sxl expression. Here I report contrary findings that there are no female-lethal genetic interactions between the msl genes and Sxl or its XSE regulators. Fly stocks containing the msl3(1) allele were found to exhibit a maternal-effect interaction with Sxl, scute, and sisterlessA mutations, but genetic complementation experiments showed that msl3 is neither necessary nor sufficient for the female-lethal interactions, which appear to be due to an unidentified maternal regulator of Sxl. Published data cited as evidence for an early function of the MSL complex in females, including a maternal effect of msl2, have been reevaluated and found not to support a maternal, or other effect, of the MSL complex in sex determination. These findings suggest that the MSL complex is not involved in primary sex determination or in X chromosome dosage compensation prior to the maternal-to-zygotic transition. PMID- 26614742 TI - Centromere Locations in Brassica A and C Genomes Revealed Through Half-Tetrad Analysis. AB - Locating centromeres on genome sequences can be challenging. The high density of repetitive elements in these regions makes sequence assembly problematic, especially when using short-read sequencing technologies. It can also be difficult to distinguish between active and recently extinct centromeres through sequence analysis. An effective solution is to identify genetically active centromeres (functional in meiosis) by half-tetrad analysis. This genetic approach involves detecting heterozygosity along chromosomes in segregating populations derived from gametes (half-tetrads). Unreduced gametes produced by first division restitution mechanisms comprise complete sets of nonsister chromatids. Along these chromatids, heterozygosity is maximal at the centromeres, and homologous recombination events result in homozygosity toward the telomeres. We genotyped populations of half-tetrad-derived individuals (from Brassica interspecific hybrids) using a high-density array of physically anchored SNP markers (Illumina Brassica 60K Infinium array). Mapping the distribution of heterozygosity in these half-tetrad individuals allowed the genetic mapping of all 19 centromeres of the Brassica A and C genomes to the reference Brassica napus genome. Gene and transposable element density across the B. napus genome were also assessed and corresponded well to previously reported genetic map positions. Known centromere-specific sequences were located in the reference genome, but mostly matched unanchored sequences, suggesting that the core centromeric regions may not yet be assembled into the pseudochromosomes of the reference genome. The increasing availability of genetic markers physically anchored to reference genomes greatly simplifies the genetic and physical mapping of centromeres using half-tetrad analysis. We discuss possible applications of this approach, including in species where half-tetrads are currently difficult to isolate. PMID- 26614744 TI - PET/CT imaging with 18F-FDG in Castleman disease. PMID- 26614743 TI - Differential Masking of Natural Genetic Variation by miR-9a in Drosophila. AB - Genetic variation is prevalent among individuals of the same species and yet the potential effects of genetic variation on developmental outcomes are frequently suppressed. Understanding the mechanisms that are responsible for this suppression is an important goal. Previously, we found that the microRNA miR-9a mitigates the impact of natural genetic variants that promote the development of scutellar bristles in adult Drosophila. Here we find that miR-9a does not affect the impact of genetic variants that inhibit the development of scutellar bristles. We show this using both directional and stabilizing selection in the laboratory. This specificity of action suggests that miR-9a does not interact with all functional classes of developmental genetic variants affecting sensory organ development. We also investigate the impact of miR-9a on a fitness trait, which is adult viability. At elevated physiological temperatures, miR-9a contributes to viability through masking genetic variants that hinder adult viability. We conclude that miR-9a activity in different developmental networks contributes to suppression of natural variants from perturbing development. PMID- 26614745 TI - IL-10-producing regulatory B cells are decreased in patients with psoriasis. AB - BACKGROUNDS: Interleukin (IL)-10-producing regulatory B cells (B10 cells) have been shown to ameliorate psoriasis in mice. Human B10 progenitor cells are characterized as CD19(+)CD24(hi)CD38(hi) B cells that exert their regulatory functions via the production of IL-10. However, the role of B10 cells in the pathogenesis of psoriasis remains unclear. OBJECTIVES: We examined B10 cells in patients with psoriasis and healthy controls. METHODS: Peripheral blood mononuclear cells were isolated from psoriasis patients without a history of receiving any immunosuppressants during the 6-month period before enrollment in the study. Using flow cytometry, we determined the frequencies of blood B cell subsets, B10 progenitor cells, and B10 cells for 31 patients with psoriasis and 26 healthy controls. RESULTS: Both psoriasis patients and healthy controls showed similar frequencies of total B cells, IgD(+)CD27(-) naive B cells, and IgD( )CD27(+) memory B cells. However, the frequency of CD19(+)CD24(hi)CD38(hi) B10 progenitor cells was significantly higher in patients with psoriasis than in the healthy controls. In contrast, the frequency of B10 cells in patients with psoriasis was significantly lower than that in healthy controls. Furthermore, treatment with immunosuppressants resulted in a decrease in B10 progenitor cells and an increase in B10 cells. CONCLUSION: B10 progenitor cells were increased, while IL-10-producing regulatory B10 cells were decreased in patients with psoriasis, suggesting that B10 cells may be functionally impaired in patients with psoriasis. PMID- 26614746 TI - Meta-Analysis of Outcomes of a Single-Radius Versus Multi-Radius Femoral Design in Total Knee Arthroplasty. AB - BACKGROUND: Although the single-radius (SR) femoral design is known to have theoretical advantages in many aspects, studies of clinical outcomes that compare the SR with the multiple-radius (MR) femoral design are controversial. We performed a meta-analysis to address the hypothesis that a SR femoral design in primary total knee arthroplasty improves patient outcomes. METHODS: The meta analysis identified 15 articles reporting the clinical outcomes of 2212 knee replacements using the SR (n = 948) compared with the multiradius (MR; n = 1361) femoral design. Comparing SR with MR, we examined the Knee Society Score for the knee (KSS-knee), KSS-function, knee flexion, range of motion, complications, isometric peak torque of knee, and survival rate. RESULTS: The range of motion of SR knees was lower than that of MR knees. No differences were found in the analyses of KSS-knee, KSS-function, knee flexion, complications, isometric peak torque of the knee, and survival rate. CONCLUSION: Our meta-analysis does not provide clinical support for the previously reported theoretical advantages of the SR implant design. PMID- 26614747 TI - Independent Evaluation of a Mechanical Hip Socket Navigation System in Total Hip Arthroplasty. AB - BACKGROUND: Acetabular cup malpositioning during total hip arthroplasty may lead to impingement, instability, wear-induced osteolysis, and increased rates of revision surgery. The purpose of this study was to independently evaluate the accuracy of acetabular cup orientation using a novel mechanical navigation device. METHODS: An adjustable, reusable mechanical navigation device was used in a consecutive series of patients. Angles (inclination and anteversion) were measured by 2 independent reviewers with a validated 2-dimensional/3-dimensional matching application using a preoperative computed tomographic scan and a postoperative plain film. RESULTS: There were no outliers for inclination or anteversion for errors within 10 degrees of the preoperative plan. There were 6 (12.8%) outliers for inclination and 11 (23.4%) for anteversion for errors within 5 degrees of the preoperative plan. All patients simultaneously met both targets when an outlier was considered 10 degrees , whereas 30 (63.8%) simultaneously met both targets when the criteria was tightened to 5 degrees . The absolute errors for both inclination and anteversion were significantly less than both 5 degrees and 10 degrees (P<.001). CONCLUSION: This device reliably navigates acetabular cup inclination and anteversion individualized for each patient to within 10 degrees of a preoperative plan. Outliers increased when this criteria is tightened to 5 degrees but still appears to be more accurate than conventional acetabular cup component placement. Further research is warranted to assess the clinical impact of reducing outliers using this device. PMID- 26614748 TI - The Assessment of Limb Length Discrepancy Before Total Hip Arthroplasty. AB - INTRODUCTION: The clinical relevance of limb length discrepancy (LLD) after total hip arthroplasty gains attention as the number of total hip arthroplasties increases. Although several techniques are commonly used to assess LLD using a pelvic radiograph, their accuracy is not well established. This study measures LLD using different techniques viewing the pelvis and compares the measurements with the true LLD. METHOD: Pelvic landmarks used included the femoral head, lesser trochanter, acetabular teardrop, ischial tuberosity, and tibial plafond. The true LLD was determined by finding the difference in distance between the lowest point of the ischial tuberosity and the tibial plafond as well as the top of the femoral head to the center of the tibial plafond for each lower limb. RESULTS: Using pelvic landmarks to assess LLD is significantly different (P < .001) from the true LLD. The difference in distance from the center of the tibial plafond to the ischial tuberosity was not significantly different from the measurement from the top of the femoral head to the center of the tibial plafond (P = .08). Also, using the acetabular teardrop as a landmark has less reliability when compared to the ischial tuberosity. DISCUSSION: Owing to the extensive variety of pathologies that are associated with LLD, preoperative planning should include an assessment of any preexisting LLD. Although it may be reasonable to compare pelvic measurements preoperatively and postoperatively to assess for changes, the data from this study do not support the estimation of the true LLD using a pelvic radiograph. PMID- 26614749 TI - Calibration Marker Position in Digital Templating of Total Hip Arthroplasty. AB - BACKGROUND: We report a mathematical method to assess the vertical and horizontal positions of spherical radiopaque objects of known size in conventional radiographs. METHODS: The reliability and validity of the method were tested in an experimental setting and applied to 100 anteroposterior pelvic radiographs with external calibration markers and unilateral total hip arthroplasty (THA). RESULTS: We found excellent reliabilities; intraclass correlation coefficients for interobserver and intraobserver reliabilities were 0.999-1.000 (P = .000). The mean normal height of THA was 198 mm (range: 142-243 mm, standard deviation: 18 mm) above the detector. Vertical and horizontal external marker positions differed significantly from the true hip center (THA; P < .001 and P = .017). CONCLUSION: This method could enhance patient safety by enabling automated detection of malpositioned calibration markers by templating software. PMID- 26614750 TI - Single Versus Multiple-Radii Cruciate-Retaining Total Knee Arthroplasty: An In Vivo Mobile Fluoroscopy Study. AB - BACKGROUND: Previous fluoroscopic studies, using static C-arm systems, have shown nonnormal kinematic patterns in cruciate-retaining (CR) total knee arthroplasty (TKA). This study compares in vivo the kinematic differences in subjects implanted with single sagittal radius (SR) vs multiradii (MR) CR TKA for various activities using a novel mobile fluoroscopic system. METHODS: Using mobile fluoroscopy and 3D to 2D registration, tibiofemoral kinematics were analyzed for 25 subjects with an SR, symmetrical condylar CR TKA and 25 subjects with an MR, asymmetric condylar CR TKA for three dynamic weight-bearing activities: (1) deep knee bend (DKB), (2) walking up a ramp, and (3) walking down a ramp. RESULTS: During DKB, from full extension to maximum knee flexion, the SR (-0.43 +/- 3.43 mm) and MR (-1.00 +/- 3.23 mm) groups experienced statistically similar anterior/posterior (AP) motion in the lateral condyle. The SR (3.51 +/- 2.68 mm) group had significant anterior movement compared to the MR (-0.42 +/- 2.20 mm) group in the medial condyle. This resulted in a significantly larger amount of normal axial rotation experienced by the SR (5.20 +/- 3.93 degrees ) group compared to the MR (0.75 +/- 5.12 degrees ) group. During ramp activities, the SR TKA consistently exhibited a significantly more posterior position of both condyles compared to the MR TKA. CONCLUSION: Although the SR TKA exhibited larger amounts of axial rotation compared to the MR TKA in DKB, neither design exhibited weight-bearing kinematics as previously reported for the normal knee. Additional research on the normal knee for ramp activities is required to understand the importance of condylar position during these activities. PMID- 26614751 TI - Apoplasmic loading in the rice phloem supported by the presence of sucrose synthase and plasma membrane-localized proton pyrophosphatase. AB - BACKGROUND AND AIMS: Although Oryza sativa (rice) is one of the most important cereal crops, the mechanism by which sucrose, the major photosynthate, is loaded into its phloem is still a matter of debate. Current opinion holds that the phloem loading pathway in rice could involve either a symplasmic or an apoplasmic route. It was hypothesized, on the basis of a complementary body of evidence from arabidopsis, which is an apoplasmic loader, that the membrane specificity of proton pyrophosphatases (H(+)-PPases; OVPs) in the sieve element-companion cell (SE-CC) complexes of rice source leaves would support the existence of either of the aforementioned phloem loading mechanisms. Additionally, it was contended that the presence of sucrose synthase in the SE-CC complexes would be consistent with an apoplasmic sucrose loading route in rice. METHODS: Conventional chemical fixation methods were used for immunohistochemical localization of H(+)-PPases and sucrose synthase in rice and arabidopsis at the light microscopy level, while ultrastructural immunogold labelling of H(+)-PPases and sucrose synthase was performed on high-pressure frozen source leaves of rice. KEY RESULTS: Using immunogold labelling, it was found that OVPs predominantly localize at the plasma membrane (PM) of the SE-CC complexes in rice source leaf minor veins, while in the root meristematic cells, OVPs preferentially localize at the vacuoles. The PM specificity of OPVs in the SE-CC complexes was deemed to support apoplasmic loading in the rice phloem. Further backing for this interpretation came from the sucrose synthase-specific immunogold labelling at the SE-CC complexes of rice source leaves. CONCLUSION: These findings are consistent with the idea that, in the same way as in arabidopsis and a majority of grasses, sucrose is actively loaded into the SE-CC complexes of rice leaves using an apoplasmic step. PMID- 26614752 TI - Antibacterial activity of Baccharis dracunculifolia in planktonic cultures and biofilms of Streptococcus mutans. AB - Streptococcus mutans is an important cariogenic microorganism, and alternative methods for its elimination are required. Different concentrations of Baccharis dracunculifolia essential oil (EO) were tested to determine its minimal inhibitory concentration (MIC) in planktonic cultures, and this concentration was used in S. mutans biofilms. Additionally, we assessed the effect of a 0.12% chlorhexidine (CHX) and saline solution in S. mutans biofilms. The biofilms were grown in discs of composite resin for 48h and exposed to B. dracunculifolia, CHX or saline solution for 5min. The viability of the biofilms was determined by counting the colony-forming units per milliliter (CFU/ml) in agar, which was statistically significant (P<0.05). The MIC of the B. dracunculifolia EO to planktonic growth of S. mutans was 6%. In biofilms of S. mutans clinical isolates, B. dracunculifolia EO (6%) and CHX resulted in reductions of 53.3-91.1% and 79.1-96.6%, respectively. For the biofilm formed by the S. mutans reference strain, the reductions achieved with B. dracunculifolia EO and CHX were, respectively, 39.3% and 88.1%. It was concluded that B. dracunculifolia EO showed antibacterial activity and was able to control this oral microorganism, which otherwise causes dental caries. PMID- 26614755 TI - Standardized likelihood ratio test for comparing several log-normal means and confidence interval for the common mean. AB - Standardized likelihood ratio test (SLRT) for testing the equality of means of several log-normal distributions is proposed. The properties of the SLRT and an available modified likelihood ratio test (MLRT) and a generalized variable (GV) test are evaluated by Monte Carlo simulation and compared. Evaluation studies indicate that the SLRT is accurate even for small samples, whereas the MLRT could be quite liberal for some parameter values, and the GV test is in general conservative and less powerful than the SLRT. Furthermore, a closed-form approximate confidence interval for the common mean of several log-normal distributions is developed using the method of variance estimate recovery, and compared with the generalized confidence interval with respect to coverage probabilities and precision. Simulation studies indicate that the proposed confidence interval is accurate and better than the generalized confidence interval in terms of coverage probabilities. The methods are illustrated using two examples. PMID- 26614756 TI - Optimal two-stage enrichment design correcting for biomarker misclassification. AB - The enrichment design is an important clinical trial design to detect the treatment effect of the molecularly targeted agent (MTA) in personalized medicine. Under this design, patients are stratified into marker-positive and marker-negative subgroups based on their biomarker statuses and only the marker positive patients are enrolled into the trial and randomized to receive either the MTA or a standard treatment. As the biomarker plays a key role in determining the enrollment of the trial, a misclassification of the biomarker can induce substantial bias, undermine the integrity of the trial, and seriously affect the treatment evaluation. In this paper, we propose a two-stage optimal enrichment design that utilizes the surrogate marker to correct for the biomarker misclassification. The proposed design is optimal in the sense that it maximizes the probability of correctly classifying each patient's biomarker status based on the surrogate marker information. In addition, after analytically deriving the bias caused by the biomarker misclassification, we develop a likelihood ratio test based on the EM algorithm to correct for such bias. We conduct comprehensive simulation studies to investigate the operating characteristics of the optimal design and the results confirm the desirable performance of the proposed design. PMID- 26614757 TI - Promoting healthy nutrition: a long and winding road. PMID- 26614753 TI - Is amyloid-beta harmful to the brain? Insights from human imaging studies. AB - Although the amyloid-beta protein associated with the Alzheimer's disease plaque has been detectable in living people for over a decade, its importance in the pathogenesis of Alzheimer's disease is still debated. The frequent presence of amyloid-beta in the brains of cognitively healthy older people has been interpreted as evidence against a causative role. If amyloid-beta is crucial to the development of Alzheimer's disease, it should be associated with other Alzheimer's disease-like neurological changes. This review examines whether amyloid-beta is associated with other biomarkers indicative of early Alzheimer's disease in normal older people. The preponderance of evidence links amyloid-beta to functional change, progressive brain atrophy, and cognitive decline. Individuals at greatest risk of decline seem to be those with evidence of both amyloid-beta and findings suggestive of neurodegeneration. The crucial question is thus how amyloid-beta is related to brain degeneration and how these two processes interact to cause cognitive decline and dementia. PMID- 26614760 TI - The 'common knowledge' of Quebecers: quantifying the evidence of historians testifying for defendant tobacco companies. AB - The 'common knowledge' defence is a legal strategy which has been successfully used by defendant tobacco companies to avoid legal responsibility for the harms caused by smoking. Tobacco companies have hired professional historians to try to persuade courts about a longstanding high level of public awareness regarding the risks of tobacco use. To support this argument, they have used archival news clippings and media reports. Two historians were hired by tobacco companies to offer this defence during a recent class action trial in Canada, following which they were required to submit to the court the collection of media materials which had been gathered by history students to assist their testimony. Included in this collection were tobacco advertisements and other news items about tobacco products which the students had inadvertently also collected. Quantifying this collection reveals that even by the tobacco industry's own construct, the information environment surrounding Quebec smokers in the middle 20th century included more prosmoking messages than information about the risks of smoking. PMID- 26614754 TI - Delayed intramuscular human neurotrophin-3 improves recovery in adult and elderly rats after stroke. AB - There is an urgent need for a therapy that reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. We show here that intramuscular delivery of neurotrophin-3 (NT3, encoded by NTF3) can induce sensorimotor recovery when treatment is initiated 24 h after stroke. Specifically, in two randomized, blinded preclinical trials, we show improved sensory and locomotor function in adult (6 months) and elderly (18 months) rats treated 24 h following cortical ischaemic stroke with human NT3 delivered using a clinically approved serotype of adeno-associated viral vector (AAV1). Importantly, AAV1-hNT3 was given in a clinically-feasible timeframe using a straightforward, targeted route (injections into disabled forelimb muscles). Magnetic resonance imaging and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, treatment caused corticospinal axons from the less affected hemisphere to sprout in the spinal cord. This treatment is the first gene therapy that reverses disability after stroke when administered intramuscularly in an elderly body. Importantly, phase I and II clinical trials by others show that repeated, peripherally administered high doses of recombinant NT3 are safe and well tolerated in humans with other conditions. This paves the way for NT3 as a therapy for stroke. PMID- 26614763 TI - Understanding depression and suicide in college athletes: emerging concepts and future directions. PMID- 26614761 TI - Consensus statement on the methodology of injury and illness surveillance in FINA (aquatic sports). AB - BACKGROUND: Injury and illness surveillance in the aquatic disciplines has been conducted during the FINA World Championships and Olympic Games. The development of an aquatic-specific injury and illness surveillance system will improve the quality of the data collected and the development of preventive measures. Our ultimate objective is to enhance aquatic athlete health and performance. OBJECTIVE: The objective was to refine the injury and illness surveillance protocols to develop aquatic-specific definitions of injury and illness; define aquatic-specific injury location and causation; better describe overuse injuries; regard pre-existing and recurrent injuries; more accurately define aquatic athlete exposures and develop a protocol to capture out-of-competition aquatic athlete health parameters. METHODS: FINA compiled an Injury and Illness Surveillance Expert Working Group comprised of international experts to review the scientific literature in the field. A consensus meeting was convened to provide an opportunity for debate, following which recommendations were collated. RESULTS: Aquatic-specific injury and illness surveillance protocols covering both the in-competition and out-of-competition time periods were developed. Definitions for all relevant variables were outlined, and documentation forms for athletes and for clinicians were proposed. Recommendations for the implementation of an injury and illness surveillance system for FINA are presented. CONCLUSION: The FINA consensus authors recommend ongoing in-competition and out-of competition surveillance to determine injury and illness trends over time. The implementation of the definitions and methodology outlined in this paper will improve the accuracy and value of injury and illness surveillance, and provide important information for injury prevention. PMID- 26614764 TI - Depression is under-recognised in the sport setting: time for primary care sports medicine to be proactive and screen widely for depression symptoms. PMID- 26614765 TI - Stoichiometry of the eIF2B complex is maintained by mutual stabilization of subunits. AB - The eukaryotic translation initiation factor eIF2B is a multi-subunit complex with a crucial role in the regulation of global protein synthesis in the cell. The complex comprises five subunits, termed alpha through epsilon in order of increasing size, arranged as a heterodecamer with two copies of each subunit. Regulation of the co-stoichiometric expression of the eIF2B subunits is crucial for the proper function and regulation of the eIF2B complex in cells. We have investigated the control of stoichiometric eIF2B complexes through mutual stabilization of eIF2B subunits. Our data show that the stable expression of the catalytic eIF2Bepsilon subunit in human cells requires co-expression of eIF2Bgamma. Similarly, stable expression of eIF2Bdelta requires both eIF2Bbeta and eIF2Bgamma+epsilon. The expression of these subunits decreases despite there being no change in either the levels or the translation of their mRNAs. Instead, these subunits are targeted for degradation by the ubiquitin-proteasome system. The data allow us to propose a model for the formation of stoichiometric eIF2B complexes which can ensure their stoichiometric incorporation into the holocomplex. PMID- 26614767 TI - The cancer-promoting gene fatty acid-binding protein 5 (FABP5) is epigenetically regulated during human prostate carcinogenesis. AB - FABPs (fatty-acid-binding proteins) are a family of low-molecular-mass intracellular lipid-binding proteins consisting of ten isoforms. FABPs are involved in binding and storing hydrophobic ligands such as long-chain fatty acids, as well as transporting these ligands to the appropriate compartments in the cell. FABP5 is overexpressed in multiple types of tumours. Furthermore, up regulation of FABP5 is strongly associated with poor survival in triple-negative breast cancer. However, the mechanisms underlying the specific up-regulation of the FABP5 gene in these cancers remain poorly characterized. In the present study, we determined that FABP5 has a typical CpG island around its promoter region. The DNA methylation status of the CpG island in the FABP5 promoter of benign prostate cells (PNT2), prostate cancer cells (PC-3, DU-145, 22Rv1 and LNCaP) and human normal or tumour tissue was assessed by bisulfite sequencing analysis, and then confirmed by COBRA (combined bisulfite restriction analysis) and qAMP (quantitative analysis of DNA methylation using real-time PCR). These results demonstrated that overexpression of FABP5 in prostate cancer cells can be attributed to hypomethylation of the CpG island in its promoter region, along with up-regulation of the direct trans-acting factors Sp1 (specificity protein 1) and c-Myc. Together, these mechanisms result in the transcriptional activation of FABP5 expression during human prostate carcinogenesis. Importantly, silencing of Sp1, c-Myc or FABP5 expression led to a significant decrease in cell proliferation, indicating that up-regulation of FABP5 expression by Sp1 and c-Myc is critical for the proliferation of prostate cancer cells. PMID- 26614766 TI - Kinetic analysis of structural influences on the susceptibility of peroxiredoxins 2 and 3 to hyperoxidation. AB - Mammalian 2-cysteine peroxiredoxins (Prxs) are susceptible to hyperoxidation by excess H2O2. The cytoplasmic family member Prx2 hyperoxidizes more readily than mitochondrial Prx3 due to slower dimerization of the sulfenic acid (SpOH) intermediate. Four variant amino acids near the C-terminus have been shown to contribute to this difference. We have performed kinetic analysis of the relationship between hyperoxidation and disulfide formation, using whole-protein MS and comparing wild-type (WT) Prx2 and Prx3 with tail-swap mutants in which the four amino acids were reversed. These changes make Prx3 more sensitive and Prx2 less sensitive to hyperoxidation and accounted for ~70% of the difference between the two proteins. The tail swap mutant of Prx3 was also more susceptible when expressed in the mitochondria of HeLa cells. The hyperoxidized product at lower excesses of H2O2 was a semi-hyperoxidized dimer with one active site disulfide and the other a sulfinic acid. For Prx2, increasing the H2O2 concentration resulted in complete hyperoxidation. In contrast, only approximately half the Prx3 active sites underwent hyperoxidation and, even with high H2O2, the predominant product was the hyperoxidized dimer. Size exclusion chromatography (SEC) showed that the oligomeric forms of all redox states of Prx3 dissociated more readily into dimeric units than their Prx2 counterparts. Notably the species with one disulfide and one hyperoxidized active site was decameric for Prx2 and dimeric for Prx3. Reduction and re-oxidation of the hyperoxidized dimer of Prx3 produced hyperoxidized monomers, implying dissociation and rearrangement of the subunits of the functional homodimer. PMID- 26614768 TI - Arthroscopic Treatment and Prognostic Classification of Anterior Soft Tissue Impingement of the Ankle. AB - BACKGROUND: Anterior soft tissue impingement of the ankle has been described based on the etiology and location, but no classification has been reported. Arthroscopic treatment is usually considered effective, even if the behavior of the different forms of impingement is not clear. The purpose of this study was to analyze the factors affecting long-term results. METHODS: Forty-two patients with a mean age of 32.6 years were arthroscopically treated between 2004 and 2008. Impingement lesions were identified according to clinical examination and confirmed by MRI. Soft tissue impingement was detected and classified according to location (anteromedial, anterolateral, syndesmotic or diffuse). Patient data, foot morphology, and previous trauma or surgery were recorded. Patients were evaluated after a mean of 90.1 months' follow-up with the American Orthopaedic Foot & Ankle Society (AOFAS) scoring system. RESULTS: The mean AOFAS score improved from 40.6 preoperatively to 82.6, 78.4, and 74.8, respectively, at the 2 , 4-, and 6-year follow-ups (P < .05). The anterolateral form showed higher scores compared to the diffuse or anteromedial forms. Age, foot morphology, and previous trauma or surgery did not affect the results. Body mass index of more than 26 and male gender were associated with worse outcomes. CONCLUSION: Arthroscopic debridement proved effective in the treatment of soft tissue impingement. Furthermore, we were able to classify the location of the anterior soft tissue impingement of the ankle, which may have prognostic importance. LEVEL OF EVIDENCE: Level IV, case series. PMID- 26614769 TI - The Efficacy of Platelet-Rich Plasma for Incision Healing After Total Ankle Replacement Using the Agility Total Ankle Replacement System. AB - BACKGROUND: The use of platelet-rich plasma (PRP) to aid in healing of operative incisions has been well documented in the literature. Most studies have been conducted retrospectively with small sample sizes and are conflicting in their outcomes. As such, no consensus exists regarding the utility of PRP for augmenting incisional healing. The Agility total ankle replacement (TAR) poses a significant challenge with respect to incisional healing in the immediate postoperative time frame and was used as a standardized implant in this study. We hypothesized that treating the anterior incision with PRP after Agility TAR would reduce the incidence of incision healing complications. METHODS: A retrospective review of 133 consecutive Agility TAR performed by a single surgeon at a single institution was conducted. Platelet-rich plasma was used to augment incisional closure in 78 patients undergoing TAR. Fifty-five patients had incisional closure without PRP application. Incision healing complications were stratified into patients healing without any complications (none), patients requiring prolonged local wound care (minor), and patients requiring a return to the operation theater to address an incisional complication (major). RESULTS: No statistically significant difference existed between patients treated with PRP incisional augmentation and those without PRP augmentation. Eight patients (10.3%) receiving PRP underwent operative treatment of an incisional complication, whereas 3 patients (5.5%) who had a nonaugmented closure required operative treatment (P = .52). The incidence of minor complications was not statistically significant, with 25 (32.1%) patients receiving PRP and 15 (27.3) patients who had a nonaugmented closure requiring prolonged local treatment (P = .85). CONCLUSIONS: Limited data exist regarding the use of PRP in the augmentation of the closure of operative incisions. We were unable to find a statistically significant reduction in incision-related complications in patients who had their incisions augmented with PRP. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 26614770 TI - An Update on the Management of Pulmonary Arterial Hypertension and the Pharmacist's Role. AB - Pulmonary arterial hypertension (PAH) is a rare medical condition that significantly shortens life expectancy. The lack of understanding and complexity of treatments frequently lead to delays in diagnosis and treatment of patients. This is worsened by the gap in medical education related to the rarity of disease and the subspecialty nature of management. Advancements in diagnostics and treatment in recent years makes a review of this nature important and timely. Understanding the specialty nature of drug therapy, the complexities of managing prostacyclin analogs, and treatment algorithms are essential for pharmacists caring for these patients in both acute and ambulatory settings. This review article will provide an overview of published guidelines as well as discuss new therapies, clinical controversies, and the pharmacist's role in the management of these patients. PMID- 26614771 TI - Misinterpretation of meaning and intended use of potentially preventable readmissions. PMID- 26614772 TI - The Zen of quality improvement: the waves and the tide form a unity. PMID- 26614773 TI - Closing the loop: a process evaluation of inpatient care team communication. PMID- 26614774 TI - Paperless handover: are we ready? PMID- 26614775 TI - Response to: 'Misinterpretation of meaning and intended use of potentially preventable readmissions' by Goldfield et al. PMID- 26614776 TI - Beyond miR-122: Identification of MicroRNA Alterations in Blood During a Time Course of Hepatobiliary Injury and Biliary Hyperplasia in Rats. AB - Identification of circulating microRNAs for the diagnosis of liver injury and as an indicator of underlying pathology has been the subject of recent investigations. While several studies have been conducted, with particular emphasis on miR-122, the timing of miRNA release into the circulation and anchoring to tissue pathology has not been systematically evaluated. In this study, miRNA profiling was conducted over a time course of hepatobiliary injury and repair using alpha-naphthylisothiocyanate (ANIT) and a proprietary compound, FP004BA. ANIT administration (50 mg/kg) to rats caused significant biliary epithelial cell and hepatocellular necrosis between 24 and 72 h, followed by resolution and progression to biliary hyperplasia by 120 h which was associated with miRNA release into the blood. FP004BA (100 mg/kg) was used to confirm associations of miRNA along a time course with similar hepatic pathology to ANIT. Treatment with ANIT or FP004BA resulted in significant alterations of overlapping miRNAs during the early and peak injury phases. In addition to well-characterized liver injury markers miR-122-5p and miR-192-5p, multiple members of the 200 family and the 101 family along with miR-802-5p and miR-30d-5p were consistently elevated during hepatobiliary injury caused by both toxicants, suggesting that these species may be potential biomarker candidates for hepatobiliary injury. After 14 days of dosing with 4BA, miR-182-5p remained elevated-while miR-122-5p and miR-192-5p had returned to baseline-suggesting that miR-182-5p may have added utility to monitor for hepatobiliary injury in the repair phases when there remains histological evidence of ongoing cellular injury. PMID- 26614777 TI - Deficiency of IL-12p35 improves cardiac repair after myocardial infarction by promoting angiogenesis. AB - AIMS: IL-12p35 is a pro-inflammatory cytokine that participates in a variety of inflammatory diseases. This study aimed to determine whether IL-12 regulates cardiac injury and repair following acute myocardial infarction (AMI) and investigate the underlying mechanisms. METHODS AND RESULTS: Mice with AMI showed a marked increase in IL-12p35 expression of ischaemic cardiac tissues. IL-12 was mainly produced by CD11b(+) monocytes. Cardiac functions were significantly improved in IL-12p35 knockout (p35-KO) mice compared with wild-type (WT) littermates in response to AMI. IL-12p35 deficiency attenuated the infarct scar and hypertrophy compared with WT mice. RNA transcriptome sequencing and quantitative RT-PCR analysis of CD11b(+) monocytes isolated from WT and p35-KO ischaemic hearts revealed a distinct transcriptional profile in p35-KO CD11b(+) monocytes, displaying pro-angiogenesis and anti-inflammation properties. Angiogenesis was enhanced in p35-KO mice with AMI and hindlimb ischaemia. Moreover, tube formation assay and Matrigel plug analysis demonstrated that IL-12 inhibition of angiogenesis was dependent on monocytes. IL-12p35 deficiency inhibited inflammation by reducing chemokine production and monocyte infiltration into the heart. Finally, administration of an IL-12p35-neutralizing antibody limited AMI-induced inflammatory cell infiltration into the heart and improved angiogenesis and cardiac function. CONCLUSIONS: Deficiency of IL-12p35 limited AMI-induced cardiac injury by promoting pro-angiogenesis and anti-inflammatory functions of monocytes. PMID- 26614778 TI - A TRPC3 signalling complex promotes cerebral artery remodelling during hypertension. PMID- 26614779 TI - GSTM1 Gene Polymorphism is Implicated in Increased Susceptibility to Prostate Cancer in Caucasians and Asians. AB - Published reports on the relationship between GSTM1 gene polymorphisms and prostate cancer risk are heterogeneous in their conclusions, and the significance of these polymorphisms is still debated. This meta-analysis was performed to attempt to combine comparable studies, thereby increasing sample size and statistical significance in order to obtain a better evaluation of the association between GSTM1 polymorphisms and prostate cancer risk. The association investigations were identified from PubMed, Cochrane Library, and China Biological Medicine Database on March 1, 2014. Forty-three reports were recruited into this meta-analysis that contained data from 6741 patients and 9053 controls. There was a marked association between the GSTM1 null genotype and prostate cancer risk in the overall population (odds ratio = 1.39, 95% confidence interval: 1.21-1.60, P <00001), caucasians (odds ratio = 1.48, 95% confidence interval: 1.23-1.79, P <0001) and Asians (odds ratio = 1.62, 95% confidence interval: 1.16-2.27, P = .005). However, the GSTM1 null genotype was not associated with prostate cancer risk in Africans (odds ratio = 0.77, 95% confidence interval: 0.53-1.13, P = 0.19) and African Americans (odds ratio = 1.00, 95% confidence interval: 0.69-1.45, P = 0.99). In conclusion, GSTM1 null genotype was a risk factor to predict the prostate cancer risk in the overall population, Caucasians, and Asians. Although compelling, limitations inherent to meta-analysis, study design of the individual studies, and most importantly, possible gene-gene and gene-environment interactions, as well as the potential involvement of glutathione S-transferases in multiple cellular processes make drawing definite conclusions difficult. PMID- 26614780 TI - Metal Artifact Reduction in Cone-Beam Computed Tomography for Head and Neck Radiotherapy. AB - PURPOSE: To evaluate a method for reducing metal artifacts, arising from dental fillings, on cone-beam computed tomography images. MATERIALS AND METHODS: A projection interpolation algorithm is applied to cone-beam computed tomography images containing metal artifacts from dental fillings. This technique involves identifying metal regions in individual cone-beam computed tomography projections and interpolating the surrounding values to remove the metal from the projection data. Axial cone-beam computed tomography images are then reconstructed, resulting in a reduction in the streak artifacts produced by the metal. Both phantom and patient imaging data are used to evaluate this technique. RESULTS: The interpolation substitution technique successfully reduced metal artifacts in all cases. Corrected images had fewer or no streak artifacts compared to their noncorrected counterparts. Quantitatively, regions of interest containing the artifacts showed reduced variance in the corrected images versus the uncorrected images. Average pixel values in regions of interest around the metal object were also closer in value to nonmetal regions after artifact reduction. Artifact correction tended to perform better on patient images with less complex metal objects versus those with multiple large dental fillings. CONCLUSION: The interpolation substitution is potentially an efficient and effective technique for reducing metal artifacts caused by dental fillings on cone-beam computed tomography image. This technique may be effective in reducing such artifacts in patients with head and neck cancer receiving daily image-guided radiotherapy. PMID- 26614781 TI - Transforming growth factor-beta (TGF-beta) activates cytosolic phospholipase A2alpha (cPLA2alpha)-mediated prostaglandin E2 (PGE)2/EP1 and peroxisome proliferator-activated-gamma (PPAR-gamma)/Smad signaling pathways in human liver cancer cells. A novel mechanism for subversion of tgf-beta-induced mitoinhibition. PMID- 26614782 TI - Binding of anti-GRP78 autoantibodies to cell surface GRP78 increases tissue factor procoagulant activity via the release of calcium from endoplasmic reticulum stores. PMID- 26614783 TI - Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy. PMID- 26614784 TI - Estimation of fine-root production using rates of diameter-dependent root mortality, decomposition and thickening in forests. AB - Current studies indicate that fine roots of different diameter classes show different rates of decomposition. This study developed a new method to estimate fine-root production by considering the difference in the production of fine roots of two size classes, fine roots thinner than 1 mm and those between 1 and 2 mm, and their corresponding rates of decomposition. A litter bag experiment was used to estimate the decomposition rates, while the sequential soil core technique was used to identify mass values of live roots and dead roots at a given period of observation. The continuous inflow method was applied to estimate the amount of root decomposition, mortality and production with a framework of two diameter classes of fine roots and for quantification of the amount of mass transfer from the thicker fine-root class to the coarser root category (>2 mm). The results indicated that the estimate of fine-root production was greater when two size classes of fine roots were distinguished. Using a framework of two size classes developed in this study resulted in 21.3% higher fine-root production than a method that did not recognize fine-root size classes or mass transfer to the category of coarse roots. In addition, using shorter collection intervals led to higher production estimates than longer intervals. The production estimate with a 1-month interval was 21.4% higher than that with a 6-month interval. We consider that the use of the sequential soil core technique with continuous inflow estimate method by differentiating size classes of fine roots is likely to minimize the underestimation of the parameters of fine-root dynamics by accounting for decomposition and mortality of fine roots more appropriately. PMID- 26614785 TI - Leaf gas exchange performance and the lethal water potential of five European species during drought. AB - Establishing physiological thresholds to drought-induced mortality in a range of plant species is crucial in understanding how plants respond to severe drought. Here, five common European tree species were selected (Acer campestre L., Acer pseudoplatanus L., Carpinus betulus L., Corylus avellana L. and Fraxinus excelsior L.) to study their hydraulic thresholds to mortality. Photosynthetic parameters during desiccation and the recovery of leaf gas exchange after rewatering were measured. Stem vulnerability curves and leaf pressure-volume curves were investigated to understand the hydraulic coordination of stem and leaf tissue traits. Stem and root samples from well-watered and severely drought stressed plants of two species were observed using transmission electron microscopy to visualize mortality of cambial cells. The lethal water potential (psilethal) correlated with stem P99 (i.e., the xylem water potential at 99% loss of hydraulic conductivity, PLC). However, several plants that were stressed beyond the water potential at 100% PLC showed complete recovery during the next spring, which suggests that the psilethal values were underestimated. Moreover, we observed a 1 : 1 relationship between the xylem water potential at the onset of embolism and stomatal closure, confirming hydraulic coordination between leaf and stem tissues. Finally, ultrastructural changes in the cytoplasm of cambium tissue and mortality of cambial cells are proposed to provide an alternative approach to investigate the point of no return associated with plant death. PMID- 26614786 TI - Effect of Name Change of Schizophrenia on Mass Media Between 1985 and 2013 in Japan: A Text Data Mining Analysis. AB - BACKGROUND: Mass media such as newspapers and TV news affect mental health related stigma. In Japan, the name of schizophrenia was changed in 2002 for the purposes of stigma reduction; however, little has been known about the effect of name change of schizophrenia on mass media. METHOD: Articles including old and new names of schizophrenia, depressive disorder, and diabetes mellitus (DM) in headlines and/or text were extracted from 23169092 articles in 4 major Japanese newspapers and 1 TV news program (1985-2013). The trajectory of the number of articles including each term was determined across years. Then, all text in news headlines was segmented as per part-of-speech level using text data mining. Segmented words were classified into 6 categories and in each category of extracted words by target term and period were also tested. RESULTS: Total 51789 and 1106 articles including target terms in newspaper articles and TV news segments were obtained, respectively. The number of articles including the target terms increased across years. Relative increase was observed in the articles published on schizophrenia since 2003 compared with those on DM and between 2000 and 2005 compared with those on depressive disorder. Word tendency used in headlines was equivalent before and after 2002 for the articles including each target term. Articles for schizophrenia contained more negative words than depressive disorder and DM (31.5%, 16.0%, and 8.2%, respectively). CONCLUSIONS: Name change of schizophrenia had a limited effect on the articles published and little effect on its contents. PMID- 26614787 TI - Double staining of bacilli and antigen Ag85B improves the accuracy of the pathological diagnosis of pulmonary tuberculosis. AB - BACKGROUND: A pathological examination plays an important role in the confirmation of a diagnosis of tuberculosis, especially for smear- and culture negative cases. However, conventional Ziehl-Neelsen staining and histological tests lack sensitivity and specificity. OBJECTIVE: To evaluate the diagnostic value of immunohistochemical staining to detect Mycobacterium tuberculosis protein Ag85B and a newly developed double staining (ZC staining) method that can simultaneously detect acid-fast bacilli and M. tuberculosis antigen in the same histological section. METHODS: A total of 282 formalin-fixed paraffin-embedded lung tissues were identified following histological examination, including 212 cases of pulmonary tuberculosis and 70 other pulmonary diseases. Ziehl-Neelsen staining, Ag85B-immunohistochemistry and the newly developed ZC staining were performed on serial sections of all the specimens. RESULTS: Expression patterns of Ag85B were consistent with the distribution patterns of acid-fast bacilli. The signal produced by Ag85B-immunohistochemistry was much stronger than that produced by Ziehl-Neelsen staining. The sensitivity of Ag85B-immunohistochemistry was significantly higher than that of Ziehl-Neelsen staining, 53.8% (95% CI 47.0% to 60.5%) vs 34.4% (95% CI 28.0% to 40.9%). The newly developed ZC staining, integrating advantages of both Ziehl-Neelsen staining and immunohistochemistry, further improved the rate of sensitivity up to 65.6% (95% CI 59.1% to 72.0%). CONCLUSIONS: This new method, detecting both acid-fast bacilli and M. tuberculosis antigen, is a simple and sensitive method for the pathological diagnosis of tuberculosis and can be easily incorporated into routine tests of pathological laboratories. PMID- 26614788 TI - Prognostic significance of PAK4 expression in gastric cancer. AB - AIMS: p-21 activated kinase (PAK) 4, part of the six PAK families, plays an important role in growth factor signalling, cytoskeletal remodelling, gene transcription, cell proliferation and oncogenic transformation. However, the clinical significance of PAK4 in gastric cancer has yet to be fully elucidated. PAK4 expression was evaluated, and the correlations of PAK4 expression with clinicopathological features and outcomes in gastric cancer were examined. METHODS: Gastric adenocarcinomas obtained from 217 patients who underwent gastrectomy were analysed. PAK4 expression was evaluated using immunohistochemical staining. RESULTS: PAK4 overexpression was found in 95 (43.8%) of 217 tumours . High PAK4 expression was significantly correlated with clinicopathological variables related to tumour progression, including depth of invasion, metastatic lymph nodes, pathological stage, distant metastasis or recurrent disease. High PAK4 expression was significantly associated with poorer disease-specific survival (DSS) (p<0.001) and relapse-free survival (RFS) (p<0.001). On multivariable analysis, PAK4 was an independent prognostic factor for DSS (HR 2.5 (95% CI 1.4 to 4.7), p=0.003) and RFS (HR 2.8 (95% CI 1.4 to 5.6), p=0.004). Even in stage II and III disease, PAK4 was an independent prognostic factor for RFS (HR 2.2 (95% CI 1.1 to 4.5), p=0.029). CONCLUSIONS: PAK4 may become a new prognostic factor in patients with gastric cancer. PMID- 26614789 TI - Validation of the Ability of SYNTAX and Clinical SYNTAX Scores to Predict Adverse Cardiovascular Events After Stent Implantation: A Systematic Review and Meta Analysis. AB - To compare the predicative ability of SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) and clinical SYNTAX scores for major adverse cardiac events (MACEs) after stent implantation in patients with coronary artery disease (CAD). Studies were identified by electronic and manual searches. Twenty-six studies were included in the meta-analysis. The pooled C-statistics of SYNTAX score for 1 and 5-year all-cause mortality (ACM) were 0.65 (95% confidence interval [CI]: 0.61-0.68) and 0.62 (95% CI: 0.59-0.65), respectively, with weak heterogeneity. The 1- and 5-year ACM pooled C-statistics for clinical SYNTAX scores were significantly higher at 0.77 and 0.71, respectively (Ps < .05). Both scoring systems predicted 1- and 5-year MACE equally well. The pooled risk ratio of the SYNTAX score for predicting 1-year ACM per unit was 1.04 (95% CI: 1.03-1.05). Calibration analysis indicated SYNTAX scores overestimated the risk of major adverse cardiac and cerebrovascular events in each risk stratum. The SYNTAX score demonstrated minimal discrimination in predicting 1- or 5-year adverse cardiovascular events after percutaneous coronary intervention in patients with CAD. The clinical SYNTAX score could further improve the predictive capability for ACM but not MACE. PMID- 26614790 TI - Endocan Levels and Subclinical Atherosclerosis in Patients With Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology. A major cause of morbidity and mortality in SLE is accelerated atherosclerosis. Endothelial-specific molecule 1 (endocan) is a potential predictor of vascular events and is expressed in response to inflammatory cytokines in endothelial cells. We investigated the relationship between endocan and carotid intima-media thickness (cIMT) as a marker of early atherosclerosis. We included 44 women with SLE and 44 healthy women as controls. Disease severity of SLE was evaluated using the SLE Disease Activity Index. Endocan, C-reactive protein, erythrocyte sedimentation rate (ESR), and lipid panel were measured. The cIMT was 0.70 (range: 0.45-1.20) mm in patients with SLE and 0.40 (0.25-0.60) mm in controls (P < .001). Endocan value was 1.6 +/- 0.9 ng/mL in controls and 2.2 +/- 1.0 ng/mL in patients with SLE (P = .014). Endocan levels were positively correlated with cIMT (r = .469, P < .001), body mass index (r = .373, P = .013), and ESR (r = .393, P = .008). Endocan level may be associated with subclinical atherosclerosis in SLE. Consequently, endocan levels may be a promising clinical tool for patients with SLE as a guide for preventive strategy. PMID- 26614791 TI - Right Atrial Evaluation in Patients With Pulmonary Hypertension: A Real-time 3 Dimensional Transthoracic Echocardiographic Study. AB - OBJECTIVES: The purpose of this study was to investigate the changes in the morphologic characteristics and performance of the right atrium (RA) that occur secondary to structural remodeling of the right ventricle (RV) in patients with pulmonary hypertension by real-time 3-dimensional echocardiography (3DE). METHODS: Comprehensive 2-dimensional echocardiography and real-time 3DE were performed in 112 patients and 30 healthy control participants. Patients with pulmonary hypertension were divided into 3 subgroups: 1, normal RV dimension (n = 34); 2, RV enlargement and preserved systolic function (n = 36); and 3, RV enlargement and systolic dysfunction (n = 42). RESULTS: Patients had larger RA volume parameters and lower RA passive emptying fractions than controls (P< .01). The RA active emptying fraction was higher in patient groups 1 (mean +/- SD, 45.5% +/- 10.7%) and 2 (40.1% +/- 4.0%) and lower in group 3 (19.3% +/- 4.3%) compared to controls (35.4% +/- 3.5%). The RA total emptying fraction was similar between groups 1 and 2 (59.3% +/- 9.7% and 52.6% +/- 3.4%, respectively) but was significantly lower in group 3 compared to controls (26.8% +/- 5.1% versus 55.2% +/- 5.1%). Right atrial volume and phasic function were substantially affected by RV structure and function. CONCLUSIONS: Real-time 3DE is a feasible, repeatable, and noninvasive method for accessing cyclic RA volume and function changes, such as those that occur with varying RV status in patients with pulmonary hypertension. PMID- 26614792 TI - Effect of Anticoagulation Medication on the Thyroid Fine-Needle Aspiration Pathologic Diagnostic Sufficiency Rate. AB - OBJECTIVES: This study examined whether ultrasound-guided thyroid fine-needle aspiration (FNA) biopsy performed on patients taking anticoagulation medication results in a greater number of nondiagnostic pathologic samples due to a higher propensity to bleed, and thus fill the needle with blood rather than cellular material, compared to patients not taking anticoagulation medication. METHODS: In this retrospective review, data were collected on 1100 patients who underwent ultrasound-guided thyroid FNA over a 4-year period. Of these patients, 438 were included. Each thyroid FNA was performed by a board-certified radiologist using a 6-pass capillary fill technique. Data including patient age, sex, nodule size, nodule consistency, and whether the patient was or was not taking anticoagulation medication (and, if they were, which medication) were recorded from the electronic medical record, and the nodule characteristics were confirmed on imaging by a senior radiology resident (postgraduate year 5). RESULTS: Of the 438 patients included, 12 (2.7%) had an FNA aspirate that was deemed insufficient for diagnostic evaluation. Nondiagnostic pathologic yields were seen in 7 of the 309 patients (2.3%) who were not taking anticoagulation medication and 5 of 129 patients (3.9%) who were taking aspirin, warfarin, or clopidogrel, resulting in no statistically significant difference in the rates of nondiagnostic pathologic yields between the two groups (P = .35). CONCLUSIONS: Based on these data, cessation of anticoagulation medication before thyroid FNA is not necessary to obtain sufficient cellular material for diagnosis, thus eliminating the need for procedural delays, patient inconvenience, and risks associated with anticoagulation medication cessation. PMID- 26614793 TI - Application of Contrast-Enhanced Sonography for Diagnosis of Space-Occupying Lesions in the Extrahepatic Bile Duct: Comparison With Conventional Sonography and Contrast-Enhanced Computed Tomography. AB - OBJECTIVES: To investigate the application of contrast-enhanced sonography compared with conventional sonography and contrast-enhanced computed tomography (CT) for diagnosis of space-occupying lesions in the extrahepatic bile duct. METHODS: Seventy-two patients with pathologic diagnoses of space-occupying lesions in the extrahepatic bile duct were retrospectively recruited. All patients underwent conventional sonography, contrast-enhanced sonography, and contrast-enhanced CT. The sensitivity, specificity, and diagnostic accuracy were compared. RESULTS: Among the 72 patients, 11 cases were benign, and 61 were malignant. The diagnostic accuracy rates for conventional sonography, contrast enhanced sonography, and contrast-enhanced CT were 66.67% (48 of 72), 90.28% (65 of 72), and 88.89% (64 of 72), respectively. The Youden index showed that contrast-enhanced sonography (0.811) was comparable with contrast-enhanced CT (0.720) and better than conventional sonography (0.159). There were significant differences in accuracy between conventional and contrast-enhanced sonography (P= .001) and conventional sonography and contrast-enhanced CT (P = .001); however, there was no significant difference between contrast-enhanced sonography and contrast-enhanced CT (P = .785). There were significant differences in sensitivity between conventional and contrast-enhanced sonography (P= .006) and conventional sonography and contrast-enhanced CT (P = .006) but no significant difference between contrast-enhanced sonography and contrast-enhanced CT (P > .99). There were no significant differences in specificity among the techniques (P > .05). There was a significant difference in the number of lesions with clear boundaries displayed: 16 on conventional sonography and 56 on contrast-enhanced sonography (P = .006). CONCLUSIONS: Contrast-enhanced sonography can show the dynamic blood supply in space-occupying pathologic regions of the extrahepatic bile duct. The diagnostic accuracy of contrast-enhanced sonography in the extrahepatic bile duct was higher than that of conventional sonography and comparable with that of contrast-enhanced CT. Therefore, contrast-enhanced sonography may be a promising imaging technique for diagnosis of space-occupying lesions in the extrahepatic bile duct. PMID- 26614794 TI - Comparative Effectiveness of Two Ultrasound-Guided Regional Block Techniques for Surgical Anesthesia in Open Unilateral Inguinal Hernia Repair. AB - Transversus abdominis plane (TAP) and ilioinguinal/iliohypogastric (II/IH) nerve blocks have been described as analgesic adjuncts for inguinal hernia repair, but the efficacy of these techniques in providing intraoperative anesthesia, either individually or together, is not known. We designed this retrospective cohort study to test the hypothesis that combining TAP and II/IH nerve blocks ("double TAP" technique) results in greater accordance between the preoperative anesthetic plan and actual anesthetic technique provided when compared to TAP alone. Based on this study, double TAP may be preferred for patients undergoing open inguinal hernia repair who wish to avoid general anesthesia. PMID- 26614795 TI - A Comparison of Attractants for Sampling Stomoxys calcitrans (Diptera: Muscidae) on Dairy Farms in Saraburi Province, Thailand. AB - The efficacy of different stable fly attractants was evaluated at four dairy cattle farms in Muak Lek district, Saraburi province, Thailand. Dry ice, octenol, a mixture of cow dung and urine, a combination of dry ice plus octenol, and no attractants (control) were tested with Vavoua traps. In total, 7,000 individuals of Stomoxys species were collected between July 2013 to September 2014, of which 1,058, 867, 1,274, and 3,801 were trapped on farms 1-4, respectively. Four species of Stomoxys were identified: Stomoxys bengalensis Picard, 1908, Stomoxys calcitrans (L., 1758), Stomoxys indicus Picard, 1908, and Stomoxys sitiens Rondani, 1873. S. calcitrans was the predominant species, comprising 99% of all the samples collected. The number of male and female S. calcitrans collected differed significantly by attractant type. Significantly more S. calcitrans were attracted to dry ice or a combination of dry ice plus octenol-baited traps than to unbaited or octenol-baited traps. The Vavoua traps baited with dry ice alone or a combination of dry ice plus octenol were effective attractants for S. calcitrans. PMID- 26614796 TI - Hydrogels in Biomedical Use. PMID- 26614797 TI - Swelling and mechanical properties of physically crosslinked poly(vinyl alcohol) hydrogels. AB - Physically crosslinked poly(vinyl alcohol) gels are versatile biomaterials due to their excellent biocompatibility. In the past decades, physically crosslinked poly(vinyl alcohol) and poly(vinyl alcohol)-based hydrogels have been extensively studied for biomedical applications. However, these materials have not yet been implemented due to their mechanical strength. Physically crosslinked poly(vinyl alcohol) gels consist of a swollen amorphous network of poly(vinyl alcohol) physically crosslinked by microcrystallites. Although the mechanical properties can be improved to some extent by controlling the distribution of microcrystallites on the nano- and micro-scales, enhancing the mechanical properties while maintaining high water content remains very difficult. It may be technologically impossible to significantly improve the mechanical properties while keeping the gel's high water absorbance ability using conventional fabrication methods. Physical and chemical understandings of the swelling and mechanical properties of physically crosslinked poly(vinyl alcohol) gels are considered here; some promising strategies for their practical applications are presented. This review focuses more on the recent studies on swelling and mechanical properties of poly(vinyl alcohol) hydrogels, prepared using only poly(vinyl alcohol) and pure water with no other chemicals, as potential biomedical materials. PMID- 26614798 TI - Quantifying the lubricity of mechanically tough polyvinyl alcohol hydrogels for cartilage repair. AB - Polyvinyl alcohol hydrogels are biocompatible and can be used as synthetic articular cartilage. Their mechanical characteristics can be tailored by various techniques such as annealing or blending with other hydrophilic polymers. In this study, we quantified the coefficient of friction of various candidate polyvinyl alcohol hydrogels against cobalt-chrome alloy or swine cartilage using a new rheometer-based method. We investigated the coefficient of friction of polyvinyl alcohol-only hydrogels and blends with polyethylene glycol, polyacrylic acid, and polyacrylamide against swine cartilage and polished cobalt-chrome surfaces. The addition of the functional groups to polyvinyl alcohol, such as acrylamide (semi interpenetrating network) and acrylic acid (blend), significantly reduced the coefficient of friction. The coefficient of friction of the polyvinyl alcohol only hydrogel was measured as 0.4 +/- 0.03 against cobalt-chrome alloy, and 0.09 +/- 0.004 against cartilage, while those measurements for the polyvinyl alcohol polyacrylic acid blends and polyvinyl alcohol-polyacrylamide semi interpenetrating network were 0.07 +/- 0.01 and 0.1 +/- 0.003 against cobalt chrome alloy, and 0.03 +/- 0.001 and 0.02 +/- 0.001 against cartilage, respectively. There was no significant or minimal difference in the coefficient of friction between samples from different regions of the knee, or animals, or when the cartilage samples were frozen for 1 day or 2 days before testing. However, changing lubricant from deionized water to ionic media, for example, saline or simulated body fluid, increased the coefficient of friction significantly. PMID- 26614799 TI - Double-network hydrogel and its potential biomedical application: A review. AB - Double-network hydrogels are one of the most promising candidates as artificial soft supporting tissues owing to their excellent mechanical performance, water storage capability, and biocompatibility. A double-network hydrogel consists of two contrasting polymer networks: rigid and brittle first network and soft and ductile second network. To satisfy this double-network requirement, polyelectrolyte and neutral polymer are suitable as the first and the second networks, respectively. Combination of these two networks gives rise to extraordinarily tough double-network hydrogel as a result of substantial internal fracture of the brittle first network at large deformation, which contributes to the energy dissipation. Therefore, the first network serves as the sacrificial bonds to toughen the material. The double-network principle is universal and many kinds of double-network hydrogels composed of various chemical species have been developed. Moreover, a molecular stent technology has been developed to synthesize the double-network hydrogels using neutral polymer network as the brittle first network. The sulfonic double-network hydrogel was found to induce spontaneous hyaline cartilage regeneration in vivo. PMID- 26614800 TI - Biphasic and boundary lubrication mechanisms in artificial hydrogel cartilage: A review. AB - Various studies on the application of artificial hydrogel cartilage to cartilage substitutes and artificial joints have been conducted. It is expected in clinical application of artificial hydrogel cartilage that not only soft elastohydrodynamic lubrication but biphasic, hydration, gel-film and boundary lubrication mechanisms will be effective to sustain extremely low friction and minimal wear in daily activities similar to healthy natural synovial joints with adaptive multimode lubrication. In this review article, the effectiveness of biphasic lubrication and boundary lubrication in hydrogels in thin film condition is focused in relation to the structures and properties of hydrogels. As examples, the tribological behaviors in three kinds of poly(vinyl alcohol) hydrogels with high water content are compared, and the importance of lubrication mechanism in biomimetic artificial hydrogel cartilage is discussed to extend the durability of cartilage substitute. PMID- 26614801 TI - Review of the biomechanics and biotribology of osteochondral grafts used for surgical interventions in the knee. AB - A review of research undertaken to evaluate the biomechanical stability and biotribological behaviour of osteochondral grafts in the knee joint and a brief discussion of areas requiring further improvement in future studies are presented. The review takes into consideration osteochondral autografts, allografts, tissue engineered constructs and synthetic and biological scaffolds. PMID- 26614802 TI - Kinetics of aqueous lubrication in the hydrophilic hydrogel Gemini interface. AB - The exquisite sliding interfaces in the human body share the common feature of hydrated dilute polymer mesh networks. These networks, especially when they constitute a sliding interface such as the pre-corneal tear film on the ocular interface, are described by the molecular weight of the polymer chains and a characteristic size of a minimum structural unit, the mesh size, xi. In a Gemini interface where hydrophilic hydrogels are slid against each other, the aqueous lubrication behavior has been shown to be a function of sliding velocity, introducing a sliding timescale competing against the time scales of polymer fluctuation and relaxation at the surface. In this work, we examine two recent studies and postulate that when the Gemini interface slips faster than the single chain relaxation time, chains must relax, suppressing the amplitude of the polymer chain thermal fluctuations. PMID- 26614803 TI - Effect of calcium/sodium ion exchange on the osmotic properties and structure of polyelectrolyte gels. AB - We discuss the main findings of a long-term research program exploring the consequences of sodium/calcium ion exchange on the macroscopic osmotic and elastic properties, and the microscopic structure of representative synthetic polyelectrolyte (sodium polyacrylate, (polyacrylic acid)) and biopolymer gels (DNA). A common feature of these gels is that above a threshold calcium ion concentration, they exhibit a reversible volume phase transition. At the macroscopic level, the concentration dependence of the osmotic pressure shows that calcium ions influence primarily the third-order interaction term in the Flory-Huggins model of polymer solutions. Mechanical tests reveal that the elastic modulus is practically unaffected by the presence of calcium ions, indicating that ion bridging does not create permanent cross-links. At the microscopic level, small-angle neutron scattering shows that polyacrylic acid and DNA gels exhibit qualitatively similar structural features in spite of important differences (e.g. chain flexibility and chemical composition) between the two polymers. The main effect of calcium ions is that the neutron scattering intensity increases due to the decrease in the osmotic modulus. At the level of the counterion cloud around dissolved macroions, anomalous small-angle X-ray scattering measurements made on DNA indicate that divalent ions form a cylindrical sheath enveloping the chain, but they are not localized. Small-angle neutron scattering and small-angle X-ray scattering provide complementary information on the structure and interactions in polymer solutions and gels. PMID- 26614804 TI - Hydrogels for central nervous system therapeutic strategies. AB - The central nervous system shows a limited regenerative capacity, and injuries or diseases, such as those in the spinal, brain and retina, are a great problem since current therapies seem to be unable to achieve good results in terms of significant functional recovery. Different promising therapies have been suggested, the aim being to restore at least some of the lost functions. The current review deals with the use of hydrogels in developing advanced devices for central nervous system therapeutic strategies. Several approaches, involving cell based therapy, delivery of bioactive molecules and nanoparticle-based drug delivery, will be first reviewed. Finally, some examples of injectable hydrogels for the delivery of bioactive molecules in central nervous system will be reported, and the key features as well as the basic principles in designing multifunctional devices will be described. PMID- 26614805 TI - Simulation in paediatric training. PMID- 26614806 TI - The position and problems of toxicology. PMID- 26614807 TI - Identification of gene expression signature for cigarette smoke exposure response -from man to mouse. AB - Gene expression profiling data can be used in toxicology to assess both the level and impact of toxicant exposure, aligned with a vision of 21st century toxicology. Here, we present a whole blood-derived gene signature that can distinguish current smokers from either nonsmokers or former smokers with high specificity and sensitivity. Such a signature that can be measured in a surrogate tissue (whole blood) may help in monitoring smoking exposure as well as discontinuation of exposure when the primarily impacted tissue (e.g., lung) is not readily accessible. The signature consisted of LRRN3, SASH1, PALLD, RGL1, TNFRSF17, CDKN1C, IGJ, RRM2, ID3, SERPING1, and FUCA1. Several members of this signature have been previously described in the context of smoking. The signature translated well across species and could distinguish mice that were exposed to cigarette smoke from ones exposed to air only or had been withdrawn from cigarette smoke exposure. Finally, the small signature of only 11 genes could be converted into a polymerase chain reaction-based assay that could serve as a marker to monitor compliance with a smoking abstinence protocol. PMID- 26614808 TI - Hazards identified and the need for health risk assessment in the South African mining industry. AB - Although mining plays a prominent role in the economy of South Africa, it is associated with many chemical hazards. Exposure to dust from mining can lead to many pathological effects depending on mineralogical composition, size, shape and levels and duration of exposure. Mining and processing of minerals also result in occupational exposure to toxic substances such as platinum, chromium, vanadium, manganese, mercury, cyanide and diesel particulate. South Africa has set occupational exposure limits (OELs) for some hazards, but mine workers are still at a risk. Since the hazard posed by a mineral depends on its physiochemical properties, it is recommended that South Africa should not simply adopt OELs from other countries but rather set her own standards based on local toxicity studies. The limits should take into account the issue of mixtures to which workers could be exposed as well as the health status of the workers. The mining industry is also a source of contamination of the environment, due inter alia to the large areas of tailings dams and dumps left behind. Therefore, there is need to develop guidelines for safe land-uses of contaminated lands after mine closure. PMID- 26614809 TI - Skin sensitization: Implications for integration of clinical data into hazard identification and risk assessment. AB - Skin sensitization associated with allergic contact dermatitis is a common health problem and is an important consideration for toxicologists in safety assessment. Historically, in vivo predictive tests have been used with good success to identify substances that have the potential to induce skin sensitization, and these tests formed the basis of safety evaluation. These original tests are now being replaced gradually either by in vitro assays or by further refinements of in vivo methods such as the local lymph node assay. Human data have also been available to inform classification decisions for some substances and have been used by risk managers to introduce measures for exposure reduction. However, humans encounter hazards in the context of exposure rather than in the form of intrinsic hazards per se, and so in this article, we have examined critically the extent to which human data have been used to refine classification decisions and safety evaluations. We have also evaluated information on the burden of human allergic skin disease and used this to address the question of whether, and to what extent, the identification and evaluation of skin sensitization hazards has led to an improvement of public and/or occupational health. PMID- 26614810 TI - Toxicology research for precautionary decision-making and the role of Human & Experimental Toxicology. AB - A key aim of toxicology is the prevention of adverse effects due to toxic hazards. Therefore, the dissemination of toxicology research findings must confront two important challenges: one being the lack of information on the vast majority of potentially toxic industrial chemicals and the other being the strict criteria for scientific proof usually required for decision-making in regard to prevention. The present study ascertains the coverage of environmental chemicals in four volumes of Human & Experimental Toxicology and the presentation and interpretation of research findings in published articles. Links in SciFinder showed that the 530 articles published in four selected volumes between 1984 and 2014 primarily dealt with metals (126 links) and other toxicants that have received substantial attention in the past. Thirteen compounds identified by US authorities in 2006 as high-priority substances, for which toxicology documentation is badly needed, were not covered in the journal issues at all. When reviewing published articles, reliance on p values was standard, and non significant findings were often called 'negative.' This tradition may contribute to the perceived need to extend existing research on toxic hazards that have already been well characterized. Several sources of bias towards the null hypothesis can affect toxicology research, but are generally not considered, thus adding to the current inclination to avoid false positive findings. In this regard, toxicology is particularly prone to bias because of the known paucity of false positives and, in particular, the existence of a vast number of toxic hazards which by default are considered innocuous due to lack of documentation. The Precautionary Principle could inspire decision-making on the basis of incomplete documentation and should stimulate a change in toxicology traditions and in toxicology research publication. PMID- 26614811 TI - Insuring the unknown. AB - Uncertainty is the central element in insurance. This article examines how insurers evaluate and price risks that can present very high levels of uncertainty, and which many underwriters regard as especially hazardous in insurance terms. These are the risks associated with new medical devices, new pharmaceutical products and others substances for human consumption, such as food additives. Insurance is likely to be needed for these products both during their research and development phases, including insurance for clinical trials, and also once the device, drug or other substance gains approval and is in regular use.The article examines the types of insurance that are available to cover these risks, the organizations that provide insurance and how the insurance is organised. It discusses the basic principles that insurers use to price insurance before considering the difficulties presented by novel and complex risks generally. The article concludes with a description of the techniques that insurers employ to analyse and price the particular risks that are our subject and a discussion of how underwriters seek to overcome the special problems associated with them. PMID- 26614812 TI - Evidence-based causation in toxicology: A 10-year retrospective. AB - We introduced Evidence-based Toxicology (EBT) in 2005 to address the disparities that exist between the various Weight-of-Evidence (WOE) methods typically applied in the regulatory hazard decision-making arena and urged toxicologists to adopt the evidence-based guidelines long-utilized in medicine (i.e., Evidence-Based Medicine or EBM). This review of the activities leading to the adoption of evidence-based methods and EBT during the last decade demonstrates how fundamental concepts that form EBT, such as the use of systematic reviews to capture and consider all available information, are improving toxicological evaluations performed by various groups and agencies. We reiterate how the EBT framework, a process that provides a method for performing human chemical causation analyses in an objective, transparent and reproducible manner, differs significantly from past and current regulatory WOE approaches. We also discuss why the uncertainties associated with regulatory WOE schemes lead to a definition of the term "risk" that contains unquantifiable uncertainties not present in this term as it is used in epidemiology and medicine. We believe this distinctly different meaning of "risk" should be clearly conveyed to those not familiar with this difference (e.g., the lay public), when theoretical/nomologic risks associated with chemical-induced toxicities are presented outside of regulatory and related scientific parlance. PMID- 26614813 TI - Air pollution: The last 35 years. AB - Perceptions of the effects on health of air pollutants have changed dramatically over the past thirty five years. It is now clear that current, historically low, concentrations of air pollutants have significant effects on health and that these effects bear most heavily on deaths and illness caused by cardiovascular diseases. Epidemiological studies have provided the evidence for these conclusions; toxicological studies have provided explanations, not yet complete, for these effects. Most emphasis has been placed on the effects of airborne particles and the evidence for their effects is convincing. Less attention has been paid to the effects of gaseous air pollutants: it may be that their effects have been, and are, under-estimated. Recent work has allowed the effects on health of air pollutants to be quantified at both a national and global scale. This work has led to the realization that the effects are large and that air pollutants continue to pose an important threat to health. PMID- 26614814 TI - Regulatory risk assessments: Is there a need to reduce uncertainty and enhance robustness? AB - A critical evaluation of several recent regulatory risk assessments has been undertaken. These relate to propyl paraben (as a food additive, cosmetic ingredient or pharmaceutical excipient), cobalt (in terms of a safety-based limit for pharmaceuticals) and the cancer Threshold of Toxicological Concern as applied to food contaminants and pharmaceutical impurities. In all cases, a number of concerns can be raised regarding the reliability of the current assessments, some examples being absence of data audits, use of single-dose and/or non-good laboratory practice studies to determine safety metrics, use of a biased data set and questionable methodology and lack of consistency with precedents and regulatory guidance. Drawing on these findings, a set of recommendations is provided to reduce uncertainty and improve the quality and robustness of future regulatory risk assessments. PMID- 26614815 TI - On the roots of, and solutions to, the persistent battle between "chemonoia" and rationalist denialism of the subjective nature of human cognition. AB - Despite remarkable advances over the past 35 years in the field of toxicology generally, and the development of a vast body of knowledge detailing the nature and degree of many human and environmental toxicological risks, the excessive fear of anything connected with chemicals that some refer to as "chemonoia" persists. So too, unfortunately, does the rationalist belief that once the facts are all in, everyone will agree on what those facts say. This article examines the roots of what is essentially a cultural conflict, explains what various bodies of social science research reveal about the psychological roots of that conflict, and offers suggestions on how to move forward. PMID- 26614816 TI - A snapshot of biologic drug development: Challenges and opportunities. AB - Since the approval of insulin as the first recombinant therapeutic protein, the prominence of biologic therapies in drug development has grown significantly. Many modalities beyond traditional biologics are now being developed or explored for various indications with significant unmet medical needs. From early traditional replacement proteins to more recent, highly engineered antibodies, oligonucleotides, fusion proteins, and gene constructs, biologic agents have delivered life-changing therapies, despite often having scientifically and technically challenging development programs. This brief review outlines some of the major biotherapeutic classes and identifies the advantages and challenges with the development of these products. PMID- 26614817 TI - Current issues and perspectives in food safety and risk assessment. AB - In this review, current issues and opportunities in food safety assessment are discussed. Food safety is considered an essential element inherent in global food security. Hazard characterization is pivotal within the continuum of risk assessment, but it may be conceived only within a very limited frame as a true alternative to risk assessment. Elucidation of the mode of action underlying a given hazard is vital to create a plausible basis for human toxicology evaluation. Risk assessment, to convey meaningful risk communication, must be based on appropriate and reliable consideration of both exposure and mode of action. New perspectives, provided by monitoring human exogenous and endogenous exposure biomarkers, are considered of great promise to support classical risk extrapolation from animal toxicology. PMID- 26614818 TI - Toxicology in Asia--Past, present, and future. AB - The Asian Society of Toxicology (ASIATOX), which consists of the seven national toxicology member societies of Japan, Korea, China, Taiwan, Thailand, Singapore, and Iran, now boasts of more than 3,000 members from a variety of industries, academia, and regulatory organizations. ASIATOX congresses are spaced three years apart and rotated among the member societies. In 1995, ASIATOX joined the International Union of Toxicology (IUTOX) as a regional society, and now serves as the scientific voice of toxicology in Asia under the IUTOX umbrella. Since its inauguration, the society has worked diligently to handle matters deemed essential to promoting the vision set fourth by its founders. Future perspectives of ASIATOX include the establishment of education and training programs, and the certification and accreditation of toxicologists. As the leading voice of toxicology in Asia, the society seeks to extend knowledge of toxicological issues to developing nations in Asia based on the following missions and goals: (1) to provide leadership as a worldwide scientific organization that objectively addresses global issues involving the toxicological sciences, (2) to broaden the geographical base of toxicology as a discipline and profession to all countries of the world, and (3) to pursue capacity building in toxicology, particularly in developing countries, while utilizing its global perspective and network to contribute to the enhancement of toxicology education and the career development of young toxicologists. PMID- 26614819 TI - Animals and the 3Rs in toxicology research and testing: The way forward. AB - Despite efforts to eliminate the use of animals in testing and the availability of many accepted alternative methods, animals are still widely used for toxicological research and testing. While research using in vitro and computational models has dramatically increased in recent years, such efforts have not yet measurably impacted animal use for regulatory testing and are not likely to do so for many years or even decades. Until regulatory authorities have accepted test methods that can totally replace animals and these are fully implemented, large numbers of animals will continue to be used and many will continue to experience significant pain and distress. In order to positively impact the welfare of these animals, accepted alternatives must be implemented, and efforts must be directed at eliminating pain and distress and reducing animal numbers. Animal pain and distress can be reduced by earlier predictive humane endpoints, pain-relieving medications, and supportive clinical care, while sequential testing and routine use of integrated testing and decision strategies can reduce animal numbers. Applying advances in science and technology to the development of scientifically sound alternative testing models and strategies can improve animal welfare and further reduce and replace animal use. PMID- 26614820 TI - Computational toxicology: Its essential role in reducing drug attrition. AB - Predictive toxicology plays a critical role in reducing the failure rate of new drugs in pharmaceutical research and development. Despite recent gains in our understanding of drug-induced toxicity, however, it is urgent that the utility and limitations of our current predictive tools be determined in order to identify gaps in our understanding of mechanistic and chemical toxicology. Using recently published computational regression analyses of in vitro and in vivo toxicology data, it will be demonstrated that significant gaps remain in early safety screening paradigms. More strategic analyses of these data sets will allow for a better understanding of their domain of applicability and help identify those compounds that cause significant in vivo toxicity but which are currently mis-predicted by in silico and in vitro models. These 'outliers' and falsely predicted compounds are metaphorical lighthouses that shine light on existing toxicological knowledge gaps, and it is essential that these compounds are investigated if attrition is to be reduced significantly in the future. As such, the modern computational toxicologist is more productively engaged in understanding these gaps and driving investigative toxicology towards addressing them. PMID- 26614821 TI - The chemical, genetic and immunological basis of idiosyncratic drug-induced liver injury. AB - Idiosyncratic drug reactions can be extremely severe and are not accounted for by the regular pharmacology of a drug. Thus, the mechanism of idiosyncratic drug induced liver injury (iDILI), a phenomenon that occurs with many drugs including beta-lactams, anti-tuberculosis drugs and non-steroidal anti-inflammatories, has been difficult to determine and remains a pressing issue for patients and drug companies. Evidence has shown that iDILI is multifactorial and multifaceted, which suggests that multiple cellular mechanisms may be involved. However, a common initiating event has been proposed to be the formation of reactive drug metabolites and covalently bound adducts. Although the fate of these metabolites are unclear, recent evidence has shown a possible link between iDILI and the adaptive immune system. This review highlights the role of reactive metabolites, the recent genetic innovations which have provided molecular targets for iDILI, and the current literature which suggests an immunological basis for iDILI. PMID- 26614822 TI - Nanotechnology: History and future. PMID- 26614825 TI - Building a Successful Endoscopic Skull Base and Pituitary Surgery Practice. AB - Building an endoscopic cranial base practice can be challenging and is predicated on the right team. Successful outcomes stem from an efficient and talented team that improves its skills experientially in a supportive environment. As with most new endeavors that are beyond the traditional approach, there is a great deal of up-front effort and investment required. This article explores some of the key building blocks necessary for a successful endoscopic cranial base and pituitary program and highlights some of the lessons learned during the authors' journey at the Cleveland Clinic. PMID- 26614823 TI - A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve. AB - AIMS: The mechanistic basis of the symptoms and signs of myocardial ischaemia in patients without obstructive coronary artery disease (CAD) and evidence of coronary microvascular dysfunction (CMD) is unclear. The aim of this study was to mechanistically test short-term late sodium current inhibition (ranolazine) in such subjects on angina, myocardial perfusion reserve index, and diastolic filling. MATERIALS AND RESULTS: Randomized, double-blind, placebo-controlled, crossover, mechanistic trial in subjects with evidence of CMD [invasive coronary reactivity testing or non-invasive cardiac magnetic resonance imaging myocardial perfusion reserve index (MPRI)]. Short-term oral ranolazine 500-1000 mg twice daily for 2 weeks vs. placebo. Angina measured by Seattle Angina Questionnaire (SAQ) and SAQ-7 (co-primaries), diary angina (secondary), stress MPRI, diastolic filling, quality of life (QoL). Of 128 (96% women) subjects, no treatment differences in the outcomes were observed. Peak heart rate was lower during pharmacological stress during ranolazine (-3.55 b.p.m., P < 0.001). The change in SAQ-7 directly correlated with the change in MPRI (correlation 0.25, P = 0.005). The change in MPRI predicted the change in SAQ QoL, adjusted for body mass index (BMI), prior myocardial infarction, and site (P = 0.0032). Low coronary flow reserve (CFR <2.5) subjects improved MPRI (P < 0.0137), SAQ angina frequency (P = 0.027), and SAQ-7 (P = 0.041). CONCLUSIONS: In this mechanistic trial among symptomatic subjects, no obstructive CAD, short-term late sodium current inhibition was not generally effective for SAQ angina. Angina and myocardial perfusion reserve changes were related, supporting the notion that strategies to improve ischaemia should be tested in these subjects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01342029. PMID- 26614824 TI - One-year outcomes and predictors of mortality after MitraClip therapy in contemporary clinical practice: results from the German transcatheter mitral valve interventions registry. AB - AIMS: The transcatheter mitral valve interventions (TRAMI) registry was established in order to assess safety and efficacy of catheter-based mitral valve interventional techniques in Germany, and prospectively enrolled 828 MitraClip patients (median age 76 years, median log. EuroSCORE I 20.0%) between August 2010 and July 2013. We present the 1-year outcome in this MitraClip cohort-which is the largest published to date. METHODS AND RESULTS: Seven forty-nine patients (90.5%) were available for 1-year follow-up and included in the following analyses. Mortality, major adverse cardiovascular event rates, and New York Heart Association (NYHA) classes were recorded. Predictors of 1-year mortality were identified by multivariate analysis using a Cox regression model with stepwise forward selection. The 1-year mortality was 20.3%. At 1 year, 63.3% of TRAMI patients pertained to NYHA functional classes I or II (compared with 11.0% at baseline), and self-rated health status (on EuroQuol visual analogue scale) also improved significantly by 10 points. Importantly, a significant proportion of patients regained the complete independence in self-care after MitraClip implantation (independence in 74.0 vs. 58.6% at baseline, P = 0.005). Predictors of 1-year mortality were NYHA class IV (hazard ratio, HR 1.62, P = 0.02), anaemia (HR 2.44, P = 0.02), previous aortic valve intervention (HR 2.12, P = 0.002), serum creatinine >=1.5 mg/dL (HR 1.77, P = 0.002), peripheral artery disease (HR 2.12, P = 0.0003), left ventricular ejection fraction <30% (HR 1.58, P = 0.01), severe tricuspid regurgitation (HR 1.84, P = 0.003), and procedural failure (defined as operator-reported failure, conversion to surgery, failure of clip placement, or residual post-procedural severe mitral regurgitation) (HR 4.36, P < 0.0001). CONCLUSIONS: Treatment of significant MR with MitraClip resulted in significant clinical improvements in a high proportion of TRAMI patients after 12 months. In the TRAMI cohort, the failure of procedural success exhibited the highest hazard ratio concerning the prediction of 1-year mortality. PMID- 26614826 TI - Skull Base Anatomy. AB - The anatomy of the skull base is complex with multiple neurovascular structures in a small space. Understanding all of the intricate relationships begins with understanding the anatomy of the sphenoid bone. The cavernous sinus contains the carotid artery and some of its branches; cranial nerves III, IV, VI, and V1; and transmits venous blood from multiple sources. The anterior skull base extends to the frontal sinus and is important to understand for sinus surgery and sinonasal malignancies. The clivus protects the brainstem and posterior cranial fossa. A thorough appreciation of the anatomy of these various areas allows for endoscopic endonasal approaches to the skull base. PMID- 26614827 TI - Anatomy, Physiology, and Laboratory Evaluation of the Pituitary Gland. AB - The pituitary gland functions prominently in the control of most endocrine systems in the body. Diverse processes such as metabolism, growth, reproduction, and water balance are tightly regulated by the pituitary in conjunction with the hypothalamus and various downstream endocrine organs. Benign tumors of the pituitary gland are the primary cause of pituitary pathology and can result in inappropriate secretion of pituitary hormones or loss of pituitary function. First-line management of clinically significant tumors often involves surgical resection. Understanding of normal pituitary physiology and basic testing strategies to assess for pituitary dysfunction should be familiar to any skull base surgeon. PMID- 26614828 TI - Imaging in Endoscopic Cranial Skull Base and Pituitary Surgery. AB - Endoscopic endonasal approaches have widely accepted techniques for managing benign and malignant processes along the entire ventral skull base with similar or better results compared with open procedures, but with lower rates of complication. Managing pathology affecting the skull base can be challenging because of complex anatomy and the proximity of critical neurovascular structures. Postoperative imaging can be challenging, because of surgical alterations of normal anatomy and the now common use of complex reconstruction techniques. Understanding the normal imaging appearance of skull base reconstruction is important for accurate postoperative interpretation and delineation between normal reconstructive tissue and recurrent neoplasm. PMID- 26614829 TI - Sellar Lesions/Pathology. AB - The sellar region is a tiny anatomic compartment in which many lesions and developmental diseases can be found. If pituitary adenomas represent most of the sellar mass, it is important to recognize other pathologic conditions before any surgical procedure, because the optimal treatment may differ considerably from one lesion to another. A careful clinical evaluation followed by neuroimaging studies and an endocrinologic and ophtalmologic workup will lead, in most cases, to a diagnosis with near certainty. This article provides an overview of sellar diseases with emphasis on their most useful characteristics for clinical practice. PMID- 26614830 TI - Principles of Pituitary Surgery. AB - Since the description of a transnasal approach for treatment of pituitary tumors, transsphenoidal surgery has undergone continuous development. Hirsch developed a lateral endonasal approach before simplifying it to a transseptal approach. Cushing approached pituitary tumors using a transsphenoidal approach but transitioned to the transcranial route. Transsphenoidal surgery was not "rediscovered" until Hardy introduced the surgical microscope. An endoscopic transsphenoidal approach for pituitary tumors has been reported and further advanced. We describe the principles of pituitary surgery including the key elements of surgical decision making and discuss the technical nuances distinguishing the endoscopic from the microscopic approach. PMID- 26614831 TI - Reconstruction of Skull Base Defects. AB - "Endoscopic endonasal skull base surgery has dramatically changed and expanded over recent years due to significant advancements in instrumentation, techniques, and anatomic understanding. With these advances, the need for more robust skull base reconstructive techniques was vital. In this article, reconstructive options ranging from acellular grafts to vascular flaps are described, including the strengths, weaknesses, and common uses." PMID- 26614832 TI - Cerebrospinal Fluid Diversion in Endoscopic Skull Base Reconstruction: An Evidence-Based Approach to the Use of Lumbar Drains. AB - Before the vascularized pedicled nasoseptal flap was popularized, lumbar drains (LDs) were routinely used for cerebral spinal fluid (CSF) diversion in endoscopic skull base reconstruction. LDs are not necessary in most CSF leaks encountered during skull base surgery. In this article, the use is considered of an LD in select high-risk settings in which a high-flow leak is anticipated and the patient has significant risk factors that make closure of the leak more challenging. Evidence for the use of LDs in preventing postoperative after endoscopic skull base reconstruction is reviewed and a rational framework for their use is proposed. PMID- 26614833 TI - Strategies for Improving Visualization During Endoscopic Skull Base Surgery. AB - The nasal cavity has a robust vascular supply, and bleeding is a primary obstacle to the minimally invasive skull base technique. Venous bleeding, including the cavernous sinus, can be managed with various techniques using hemostatic materials and pressure. A thorough understanding of the skull base vascular anatomy is vital for avoiding injury to major arteries and having confidence to control venous bleeding to optimize the endoscopic view and tumor resection. PMID- 26614834 TI - An Overview of Anterior Skull Base Meningiomas and the Endoscopic Endonasal Approach. AB - Meningiomas represent 30% of all primary brain tumors. Anterior skull base meningiomas represent 8.8% of all meningiomas. Surgical resection is a main treatment option for tumors that are symptomatic and/or growing. Recurrence is directly related to the extent of resection of the tumor, the dural attachment, and pathologic bone. Endoscopic endonasal approaches represent an important addition to the treatment armamentarium for skull base meningiomas. This article provides an overview of meningiomas, with a focus on those of the anterior skull base and their management. PMID- 26614835 TI - Endoscopic Management of Esthesioneuroblastoma. AB - Esthesioneuroblastoma is a rare malignant tumor of sinonasal origin. These tumors typically present with unilateral nasal obstruction and epistaxis, and diagnosis is confirmed on biopsy. Over the past 15 years, significant advances have been made in endoscopic technology and techniques that have made this tumor amenable to expanded endonasal resection. There is growing evidence supporting the feasibility of safe and effective resection of esthesioneuroblastoma via an expanded endonasal approach. This article outlines a technique for endoscopic resection of esthesioneuroblastoma and reviews the current literature on esthesioneuroblastoma with emphasis on outcomes after endoscopic resection of these malignant tumors. PMID- 26614836 TI - Endoscopic Endonasal Management of Skull Base Chordomas: Surgical Technique, Nuances, and Pitfalls. AB - Chordoma is a rare primary bone tumor derived from transformed notochord remnants. It has a local aggressive behavior and high recurrence rates. Treatment of skull base chordomas is complex and challenging. Control of the disease relies mainly on surgical excision of the tumor, sometimes followed by high-dose radiation therapy. The main surgical goal is to achieve maximal tumor removal with minimal morbidity. Development of the expanded endoscopic endonasal approach has improved surgical and prognostic results of skull base chordomas. This article highlights important aspects of approach selection, technique, and nuances of surgical management of this tumor. PMID- 26614837 TI - Sinonasal Malignancies of Anterior Skull Base: Histology-driven Treatment Strategies. AB - The advances in endoscopy have revolutionized the management of sinonasal and skull base lesions. Many complex cancers that traditionally required open approaches are now amenable to purely endoscopic endonasal resection, providing less invasive surgery with lower morbidity but with comparable oncologic outcomes in terms of survival rates. This article discusses the current evidence for the multimodal management of sinonasal and anterior skull base cancers focusing on the different treatment protocols driven by histologic subtypes. PMID- 26614838 TI - Endoscopic Endonasal Management of Craniopharyngioma. AB - Craniopharyngioma is a rare clinical entity that poses a significant management challenge given their location and propensity to recur. As part of a minimally disruptive treatment paradigm, the expanded endonasal approach has the potential to improve rates of resection, improve postoperative visual recovery, and minimize surgical morbidity. This article updates the otolaryngologic community on the basic principles and techniques regarding the incorporation of the endoscopic, endonasal approach in the management paradigm of craniopharyngioma. PMID- 26614839 TI - Endoscopic Approaches to the Craniovertebral Junction. AB - The endoscopic endonasal approach provides a direct surgical trajectory to anteriorly located lesions at the craniovertebral junction. The inferior limit of surgical exposure is predicted by the nasopalatine line, and the lateral limit is demarcated by the lower cranial nerves. Endoscopic endonasal odontoidectomy allows preservation of the soft palate, and patients can restart an oral diet on the first postoperative day. Treating the condition at the craniovertebral junction using this approach requires careful preoperative planning and endoscopic endonasal surgical experience with a 2-surgeon 4-handed approach combining expertise in otolaryngology and neurosurgery. PMID- 26614840 TI - Complication Avoidance in Endoscopic Skull Base Surgery. AB - Endoscopic endonasal approaches to the skull base pathology have developed and evolved dramatically over the past 2 decades, particularly with collaboration between neurosurgery and otolaryngology physicians. These advances have increased significantly the use of such approaches beyond just resection of pituitary adenomas, including a variety of skull base pathologies. As the field has evolved, so has our understanding of the complications accompanying endoscopic skull base surgery, as well as techniques to both avoid and manage these complications. These are discussed here. PMID- 26614841 TI - Injury of the Internal Carotid Artery During Endoscopic Skull Base Surgery: Prevention and Management Protocol. AB - Injury of the internal carotid artery during endoscopic endonasal skull base surgery is a feared and perilous scenario. This article discusses perioperative strategies to prevent or manage an internal carotid artery injury to optimize outcomes. Meticulous preoperative planning is crucial in preventing its occurrence and minimizing its consequences. An effective plan of action relies on a well-prepared protocol, availability of proper instruments and devices, and an experienced multidisciplinary team. Intraoperative control of hemorrhage and stabilization of the patient's cardiovascular status is followed by an angiography and endovascular treatment whenever possible. Close clinical and radiologic monitoring of the patient prevents early and late complications. PMID- 26614842 TI - Comprehensive Postoperative Management After Endoscopic Skull Base Surgery. AB - To maximize outcomes from endoscopic skull base surgery, careful early postoperative management is critically important. Standardized postoperative regimens are lacking. The type of reconstruction and presence and type of cerebrospinal fluid leak dictate management. If a leak is encountered intraoperatively, patients should avoid maneuvers that increase intracranial pressures for at least 1 month. Early postoperative care focuses on minimizing and managing nasal crusting. This article reviews the evidence in the literature on postoperative management, complications, and quality of life after surgery, and outlines our experience in the management of patients after endoscopic skull base surgery. PMID- 26614843 TI - Endoscopic Cranial Base and Pituitary Surgery. PMID- 26614844 TI - Tumor suppressor maspin as a modulator of host immune response to cancer. AB - Despite the promising clinical outcome, the primary challenge of the curative cancer immunotherapy is to overcome the dichotomy of the immune response: tumor evoked immunostimulatory versus tumor-induced immunosuppressive. The goal needs to be two-fold, to re-establish sustainable antitumor-cancer immunity and to eliminate immunosuppression. The successful elimination of cancer cells by immunosurveillance requires the antigenic presentation of the tumor cells or tumor-associated antigens and the expression of immunostimulatory cytokines and chemokines by cancer and immune cells. Tumors are heterogeneous and as such, some of the tumor cells are thought to have stem cell characteristics that enable them to suppress or desensitize the host immunity due to acquired epigenetic changes. A central mechanism underlying tumor epigenetic instability is the increased histone deacetylase (HDAC)-mediated repression of HDAC-target genes regulating homeostasis and differentiation. It was noted that pharmacological HDAC inhibitors are not effective in eliminating tumor cells partly because they may induce immunosuppression. We have shown that epithelial-specific tumor suppressor maspin, an ovalbumin-like non-inhibitory serine protease inhibitor, reprograms tumor cells toward better differentiated phenotypes by inhibiting HDAC1. Recently, we uncovered a novel function of maspin in directing host immunity towards tumor elimination. In this review, we discuss the maspin and maspin/HDAC1 interplay in tumor biology and immunology. We propose that maspin based therapies may eradicate cancer. PMID- 26614845 TI - Prognostic significance of survivin, beta-catenin and p53 expression in urothelial carcinoma. AB - Survivin, beta-catenin, and p53 are well-known cell-cycle and apoptosis regulators of tumorigenesis. Urothelial carcinomas (UCs) are the most common of the human cancers. Compared to superficial tumors (Ta, CIS, or T1), invasive UCs are important with regard to recurrence, progression, and mortality. Therefore, we examined whether survivin, beta-catenin, and p53 could be used as the biomarkers for the early prediction of the invasiveness of UCs and the overall survival of the patients. We investigated the prognostic expressions of those biomarkers in UC (n=147) and in non-muscle invasive UC (NMI-UC) (n=113), using tissue microarray and immunohistochemistry. Spearman's correlation analysis and multivariate Cox regression analyses were used for statistical interpretation. High expressions of beta-catenin, survivin, and p53 were associated with a high T stage, recurrence, progression, mortality, low recurrence-free survival, low progression-free survival and low overall survival (p <0.01). Similar findings were achieved for recurrence and progression in the NMI-UC group, except for mortality. Moreover, a positive correlation was shown between p53 and beta catenin and between p53 and survivin (r=0.221, p <0.01; r=0.236, p <0.01, respectively). Survivin, p53, and beta-catenin overexpression, as prognostic markers, might suggest that the UCs are biologically aggressive with the poor prognosis. Thus, dysregulation of those these cell-cycle and apoptosis regulators in bladder carcinoma could be used as a molecular marker to determine the best treatment strategy and could contribute to the development of targeted therapies. PMID- 26614846 TI - Correlation between advanced glycation end-products and the expression of fatty inflammatory factors in type II diabetic cardiomyopathy. AB - Diabetic cardiomyopathy (DCM) is one of the most severe complications of diabetes without a clear pathogenesis. Th is study investigated the adiponectin (APN) and leptin levels in type II DCM, as well as their correlation with advanced glycation end-products (AGEs). From 2011-2013, 78 type II diabetes mellitus (T2DM) cases (40-65 years old) in the Taian region were randomly selected. Based on the results of colour Doppler ultrasonography and coronary angiography, the cases were divided into a simple T2DM group (40 cases) and a DCM group (38 cases). Forty healthy subjects were used as normal control (NC). An enzyme-linked immunosorbent assay was performed to determine the levels of fa tty inflammatory factors such as APN, leptin and AGEs, and a correlation analysis was conducted. In the T2DM group, the APN levels were decreased but the leptin and AGE levels were significantly increased compared to the NC group. In the DCM group, the APN levels were decreased but the leptin and AGE levels were significantly increased (P<0.01) compared to the T2DM group. Th e AGE levels were positively correlated with disease progression and with fasting plasma glucose levels, glycated haemoglobin, insulin resistance and leptin, but were negatively correlated with APN levels. Additionally, the APN and leptin levels were independently related to the AGE levels. Fatty inflammatory factors play a significant role in the progression of both simple T2DM and DCM. Th e results of this study revealed the pathogenesis of DCM and indicated the potential significance of AGEs in DCM prevention and treatment. PMID- 26614847 TI - Role of S180L polymorphism in etiology of malaria caused by Plasmodium falciparum in a small group of Pakistani population. AB - The aim of our study was to investigate the role of S180L polymorphism in modulation of acquisition of malaria caused by Plasmodium falciparum in a small group of Pakistani population. A total of 133 individuals including 60 controls and 73 patients of malaria, caused by Plasmodium falciparum, were genotyped using allele-specific PCR. Ninety-two samples successfully demonstrated the PCR amplification results, while forty-one samples could not be genotyped due to failure in PCR amplification. The allele frequency for S180L polymorphism was deviant from Hardy-Weinberg equilibrium (HWE) of the population under observation. Association was found between the observed polymorphism and the occurrence of malaria caused by Plasmodium falciparum (p = 0.01). Chances of malaria caused by Plasmodium falciparum were low in CC genotype carriers in comparison to other genotypes (Odds ratio: 0.3016; 95% CI: 0.124-0.729). The present findings suggest that S180L polymorphism is important in modulating the probability of acquisition of malaria caused by Plasmodium falciparum in Pakistani population. The CC genotype plays a protective role in local population against this type of malaria. PMID- 26614848 TI - A prospective evaluation of synergistic effect of sulbactam and tazobactam combination with meropenem or colistin against multidrug resistant Acinetobacter baumannii. AB - The present study evaluates the synergistic effect of sulbactam/tazobactam in combination with meropenem or colistin against multidrug resistant (MDR) Acinetobacter baumannii isolated from hospitalized patients from a tertiary care hospital in Saudi Arabia. During the study period, 54 multidrug and carbapenem resistant isolates of A. baumannii isolates were collected from blood and respiratory samples of patients with ventilator-associated pneumonia or bacteremia. Microbroth checkerboard assay (CBA) and E-test were performed to look for synergistic interface of sulbactam and tazobactam with meropenem or colistin. All 54 MDR isolates of A. baumannii were resistant to carbapenem. Minimum inhibitory concentration [50/90] value against sulbactam, tazobactam, meropenem, colistin was found to be 64/128, 64/128, 64/256, and 0.5/1.0 respectively. Synergy was detected in more isolates with CBA compared to E-test. All four combinations showed significant synergistic bactericidal activity. However, the combination with colistin showed greater synergistic effect than combination with meropenem. Antagonism was not detected with any of the combinations and any method, but indifference was seen in tazobactam and colistin combination alone. A significant bactericidal effect was seen with sulbactam combination with meropenem or colistin in both methods. A combination therapy can be a choice of treatment. As colistin is known to exhibit nephrotoxicity, the combination of sulbactam and meropenem might be considered as an alternative antibiotic treatment for such multi- and extremely resistant bacteria. Yet, sample size is small in our study, so further well-designed in vitro and clinical studies on large scale should confirm our findings. PMID- 26614849 TI - The frequency of pulmonary hypertension in patients with juvenile scleroderma. AB - Juvenile scleroderma (JS) represents a rarely seen group of connective tissue diseases with multiple organ involvement. Cardiac involvement in JSS is well known and, although rare in children, it may be an important cause of mortality and morbidity. Therefore, an early determination of cardio-vascular and pulmonary involvement is of the most relevance to reduce the mortality in patients with juvenile scleroderma. The aim of the study was to explore the non-invasive methods (Doppler echocardiography, pulmonary function tests), Forced vital capacity (FVC) and Carbon monoxide diffusion capacity (DLCO) in the assessment of the cardiopulmonary involvement in patients with JS. The assessment of pulmonary arterial pressure (PAP) and risk factors for pulmonary arterial hypertension (PAH) were made by the measurement of maximum tricuspid insufficiency (TI), end diastolic pulmonary insufficiency (PI), ratio of acceleration time (AT) to ejection time (ET) (AT/ET), right atrial pressure (RAP) and contraction of vena cava inferior during inspiration. Thirty-five patients with confirmed JS were included in the study. The mean age of onset of the disease was 9.57 years (median 10 years, range 2-18 years). The mean disease duration and follow-up time was 2 years (median 1 year, range 0.5-8 years) and 3.57 years (median 2 years, range 0.5-14.5 years), respectively.The values of all the analyzed parameters including TI, PI, AT/ET, PAP, FVC and DLCO were found to be within normal ranges in all the patients tested, confirming an uncommonness of cardiopulmonary involvement in patients with juvenile scleroderma. PMID- 26614850 TI - Different dose-dependent effects of ebselen in sciatic nerve ischemia-reperfusion injury in rats. AB - Ebselen is an organoselenium compound which has strong antioxidant and anti inflammatory effects. We investigated the neuroprotective role of ebselen pretreatment in rats with experimental sciatic nerve ischemia-reperfusion (I/R) injury. Adult male Sprague Dawley rats were divided into four groups (N = 7 in each group). Before sciatic nerve I/R was induced, ebselen was injected intraperitoneally at doses of 15 and 30 mg/kg. After a 2 h ischemia and a 3 h reperfusion period, sciatic nerve tissues were excised. Tissue levels of malondialdehyde (MDA) and nitric oxide (NO), and activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were measured. Sciatic nerve tissues were also examined histopathologically. The 15 mg/kg dose of ebselen reduced sciatic nerve damage and apoptosis (p<0.01), levels of MDA, NO, and inducible nitric oxide synthase (iNOS) positive cells (p<0.01, p<0.05, respectively), and increased SOD, GPx, and CAT activities (p<0.001, p<0.01, p<0.05, respectively) compared with the I/R group that did not receive ebselen. Conversely, the 30 mg/kg dose of ebselen increased sciatic nerve damage, apoptosis, iNOS positive cells (p<0.01, p<0.05, p<0.001) and MDA and NO levels (p<0.05, p<0.01) and decreased SOD, GPx, and CAT activities (p<0.05) compared with the sham group. The results of this study suggest that ebselen may cause different effects depending on the dose employed. Ebselen may be protective against sciatic nerve I/R injury via antioxidant and antiapoptotic activities at a 15 mg/kg dose, conversely higher doses may cause detrimental effects. PMID- 26614851 TI - The importance of speckle tracking echocardiography in the early detection of left ventricular dysfunction in patients with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is characterized by hormonal and metabolic abnormalities and is thought to increase a risk for cardiovascular diseases. In this study we use speckle tracking echocardiography (STE) to evaluate left ventricular (LV) dysfunction in the early period of the disease. We enrolled 31 patients with PCOS and 32 healthy volunteers as a control group. The participants' ages ranged between 18 and 40 years. PCOS was diagnosed according to the Rotterdam criteria. LV strain (LS) and strain rate (SR) were evaluated using apical two-chamber (2C), three-chamber (3C), and four-chamber (4C) imaging. Global LS and SR were calculated as average of three apical views. The waist-to hip ratio, homeostasis model assessment-insulin resistance (HOMA-IR), and fasting insulin and triglyceride levels were higher in the PCOS group than in the controls (p=0.001, p=0.001, p=0.001, and p=0.005, respectively). In the PCOS group, the mitral A wave, deceleration time (DT), and isovolumetric relaxation time (IVRT) were significantly higher than in the controls (all p<0.05). The LV global longitudinal strain (GLS) and global longitudinal SR systolic (GLSRS) were significantly lower in the PCOS patient group (both p= 0.001). There were strong negative correlations between GLS and both fasting insulin (r=-0.64) and DT (r= 0.62) (both p<0.05). The study demonstrated that PCOS patients had decreased LV function using STE. Therefore, STE imaging appears to be useful for the early detection of subclinical LV dysfunction in patients with PCOS. PMID- 26614852 TI - The impact of bismuth addition to sequential treatment on Helicobacter pylori eradication: A pilot study. AB - The success of the current anti-Helicobacter pylori (H. pylori) treatment protocols is reported to decrease by years, and research is needed to strengthen the H. pylori eradication treatment. Sequential treatment (ST), one of the treatment modalities for H. pylori eradication, includes amoxicillin 1 gr b.i.d and proton pump inhibitor b.i.d for first 5 days and then includes clarithromycin 500 mg b.i.d, metronidazole 500 mg b.i.d and a proton pump inhibitor b.i.d for remaining 5 days. In this study, we investigated efficacy and tolerability of bismuth addition in to ST. We included patients that underwent upper gastrointestinal endoscopy in which H. pylori infection was diagnosed by histological examination of antral and corporal gastric mucosa biopsy. Participants were randomly administered ST or bismuth containing ST (BST) protocols for the first-line H. pylori eradication therapy. Participants have been tested by urea breath test for eradication success 6 weeks after the completion of treatment. One hundred and fifty patients (93 female, 57 male) were enrolled. There were no significant differences in eradication rates for both intention to treat population (70.2%, 95% confidence interval [CI]: 66.3-74.1% vs. 71.8%, 95% CI: 61.8-81.7%, for ST and BST, respectively, p>0.05) and per protocol population (74.6%, 95% CI: 63.2-85.8% vs. 73.7%, 95% CI: 63.9-83.5% for ST and BST, respectively, p>0.05). Despite the undeniable effect of bismuth, there may be several possible reasons of unsatisfactory eradication success. Drug administration time, coadministration of other drugs, possible H. pylori resistance to bismuth may affect the eradication success. The addition of bismuth subcitrate to ST regimen does not provide significant increase in eradication rates. PMID- 26614854 TI - Optimization of induction of mild therapeutic hypothermia with cold saline infusion: A laboratory experiment. AB - Cold fluid infusions can be used to induce mild therapeutic hypothermia after cardiac arrest. Fluid temperature higher than 4 degrees C can increase the volume of fluid needed, prolong the induction phase of hypothermia and thus contribute to complications. We performed a laboratory experiment with two objectives. The first objective was to analyze the effect of wrapping fluid bags in ice packs on the increase of fluid temperature with time in bags exposed to ambient conditions. The second objective was to quantify the effect of insulating venous tubing and adjusting flow rate on fluid temperature increase from bag to the level of an intravenous cannula during a simulated infusion. The temperature of fluid in bags wrapped in ice packs was significantly lower compared to controls at all time points during the 120 minutes observation. The temperature increase from the bag to the level of intravenous cannula was significantly lower for insulated tubing at all infusion rates (median temperature differences between bag and intravenous cannula were: 8.9, 4.8, 4.0, and 3.1 degrees C, for non insulated and 5.9, 3.05, 1.1, and 0.3 degrees C, for insulated tubing, at infusion rates 10, 30, 60, and 100 mL/minute, respectively). The results from this study could potentially be used to decrease the volume of fluid infused when inducing mild hypothermia with an infusion of cold fluids. PMID- 26614853 TI - Genetic predictors of the response to the treatment of hepatitis C virus infection. AB - The genome-wide association studies have identified a strong association between interleukin 28B (IL28B) gene polymorphisms and the response to treatment in patients with hepatitis C virus (HCV) infection. The aim of the study was to evaluate the association between three most widely studied IL28B gene polymorphisms and the response to antiviral treatment of chronic hepatitis C. We performed the genotyping of the three IL28B gene polymorphisms: rs12979860, rs8099917, and rs12980275 in 72 Caucasian patients with chronic hepatitis C, previously treated with the combination therapy of pegylated interferon alpha (PEGIFN alpha) and ribavirin (RBV). The patients included in the study had finished the treatment regimen at least 6 months before enrolling in the study. We used the sustained viral response (SVR) for the evaluation of the effectiveness of the antiviral treatment, and it was tested with an assay with a sensitivity of 20 IU/mL. An SVR was achieved in 59.7% (43/72) of the treated patients. The three IL28B gene polymorphisms (CC genotype of rs12979860, TT genotype of rs8099917, and AA genotype of rs12980275) were associated with the SVR (p=0.029, p=0.016, and p=0.028, respectively) in the study patients with chronic hepatitis C treated with the combination therapy of PEGIFN alpha and RBV. The association of IL28B gene polymorphisms with the treatment response points to the possibility of personalized medicine for the treatment of HCV infection. PMID- 26614855 TI - Breast MRI, digital mammography and breast tomosynthesis: comparison of three methods for early detection of breast cancer. AB - Breast cancer is the most common malignancy in women and early detection is important for its successful treatment. The aim of this study was to investigate the sensitivity and specificity of three methods for early detection of breast cancer: breast magnetic resonance imaging (MRI), digital mammography, and breast tomosynthesis in comparison to histopathology, as well as to investigate the intraindividual variability between these modalities. We included 57 breast lesions, each detected by three diagnostic modalities: digital mammography, breast MRI, and breast tomosynthesis, and subsequently confirmed by histopathology. Breast Imaging-Reporting and Data System (BI-RADS) was used for characterizing the lesions. One experienced radiologist interpreted all three diagnostic modalities. Twenty-nine of the breast lesions were malignant while 28 were benign. The sensitivity for digital mammography, breast MRI, and breast tomosynthesis, was 72.4%, 93.1%, and 100%, respectively; while the specificity was 46.4%, 60.7%, and 75%, respectively. Receiver operating characteristics (ROC) curve analysis showed an overall diagnostic advantage of breast tomosynthesis over both breast MRI and digital mammography. The difference in performance between breast tomosynthesis and digital mammography was significant (p <0.001), while the difference between breast tomosynthesis and breast MRI was not significant (p=0.20). PMID- 26614857 TI - Cancer and Aging: General Principles, Biology, and Geriatric Assessment. AB - Cancer is a disease of aging as older adults are much more likely to develop cancer compared with their younger counterparts. Understanding the biology of cancer and aging remains complex, and numerous theories regarding the relationship between the two have been proposed. Cancer treatment decisions in older patients are particularly challenging, because the evidence is scarce and the risk of toxicity increases with age. Determination of biologic age is essential due to heterogeneity of functional status, comorbidity, and physiologic reserves between patients of the same chronologic age. PMID- 26614856 TI - Serum leptin, bone mineral density and the healing of long bone fractures in men with spinal cord injury. AB - Previously reported fracture rates in patients with spinal cord injury range from 1% to 20%. However, the exact role of spinal cord injury in bone metabolism has not yet been clarified. In order to investigate the effects of serum leptin and bone mineral density on the healing of long bone fractures in men with spinal cord injury, 15 male SCI patients and 15 matched controls were involved in our study. The outcome indicated that at 4 and 8 weeks after bone fracture, callus production in patients with spinal cord injury was lower than that in controls. Besides, bone mineral density was significantly reduced at 2, 4 and 8 weeks. In addition, it was found that at each time point, patients with spinal cord injury had significantly higher serum leptin levels than controls and no association was found between serum leptin level and bone mineral density of lumbar vertebrae. Moreover, bone mineral density was positively correlated with bone formation in both of the groups. These findings suggest that in early phases i.e. week 4 and 8, fracture healing was impaired in patients with spinal cord injury and that various factors participated in the complicated healing process, such as hormonal and mechanical factors. PMID- 26614858 TI - Cancer Screening in Older Adults. AB - Cancer screening is an important tool for reducing morbidity and mortality in the elderly. In this article, performance characteristics of commonly used screening tests for colorectal, lung, prostate, breast, and cervical cancers are discussed. Guidelines are emphasized and key issues to consider in screening older adults are highlighted. PMID- 26614859 TI - Socioeconomic Considerations and Shared-Care Models of Cancer Care for Older Adults. AB - Older adults with cancer require a geriatrics approach to treatment. Such an approach targets appropriate treatments based on physiologic, not chronologic, age. Patients older than 65 years of age constitute the largest group of patients with cancer, making them the most expensive group of patients with cancer, especially with the advent of expensive new treatments with minimal impact on overall survival. Geriatric assessment, combined with targeted inventions, can optimize the value propositions in caring for older patients with cancer. Over the past 20 years, geriatric oncology care models have emerged applying these care principles in clinical practice. PMID- 26614860 TI - Palliative Care and Symptom Management in Older Patients with Cancer. AB - Older patients with cancer are best served by a multidisciplinary approach with palliative care (PC) playing an integral role. PC focuses on symptom control irrespective of its cause and should not be associated only with terminal care. It provides an additional layer of support in the care of patients with cancer with an emphasis on quality of life. This article discusses the evaluation and management of pain and other common nonpain symptoms that occur in elderly patients with cancer, as well as end-of-life care. PMID- 26614863 TI - Management of Colorectal Cancer in Older Adults. AB - Treatment for colorectal cancer should not be based on age alone. Pooled analyses from clinical trials show that fit older adults are able to tolerate treatment well with similar efficacy as younger adults. When an older adult is considered for treatment, the clinical encounter must evaluate for deficits in physical and cognitive function, and assess comorbidities, medications, and the degree of social support, all which have may affect tolerance of treatment. Based on the degree of fitness of the patient, multiple alternatives to aggressive treatment regimens and strategies exist to minimize toxicity and preserve quality of life during treatment. PMID- 26614862 TI - Management of Lung Cancer in the Elderly. AB - Lung cancer disproportionately affects the elderly. Aging is typically associated with higher risk of comorbidity, declines in physical, organ, and cognitive function, and diminished social support. Hence the management of a disease as complex and potentially lethal as lung cancer in this population is challenging. Despite most patients with lung cancer being elderly, most high-level evidence has been derived from studies that included younger patients and only a minority of the fit elderly. This article reviews the literature on the care of older adults with lung cancer. The evolving role of geriatric assessment in lung cancer is discussed. PMID- 26614864 TI - Management of Prostate Cancer in the Elderly. AB - The impact of localized prostate cancer in the elderly depends on disease aggressiveness and life expectancy. In men with localized prostate cancer, those with low-risk disease or a shorter life expectancy should be managed expectantly, whereas those with long life expectancy or more aggressive disease may benefit from curative treatment. Comorbidity and quality-of-life concerns are key considerations during the selection of therapeutic modalities in the elderly in localized and metastatic settings. A variety of new agents have changed the therapeutic landscape in castrate-resistant prostate cancer, but their benefits need to be considered alongside their side effects and cost. PMID- 26614861 TI - Long-term Toxicity of Cancer Treatment in Older Patients. AB - With earlier cancer diagnosis among older patients with cancer, the possibility of curing cancer increases. However, cancer treatment may have a long-lasting impact on older cancer survivors. It is vital to screen, diagnose, and properly manage the long-term toxicities of cancer treatment in order to maintain the quality of life of older cancer survivors. PMID- 26614865 TI - Approach and Management of Breast Cancer in the Elderly. AB - Breast cancer is the mostly commonly diagnosed cancer in women both in the United States and worldwide. Although advanced age at diagnosis is associated with more favorable tumor biology, mortality rates are comparatively higher in older adults, possibly attributed to advanced stage at presentation. There are minimal specific treatment-based guidelines in elderly patients with cancer, mostly attributable to their limited inclusion on clinical trials. In addition to the existing evidence from clinical trials and retrospective studies, practitioners need to take into consideration functional status, social support, patient preference, presence of comorbidities, and life expectancy when selecting optimal treatment. PMID- 26614867 TI - Chronic Lymphocytic Leukemia and Other Lymphoproliferative Disorders. AB - Chronic lymphocytic leukemia affects less than 1% of US adults but is the most common leukemia and primarily affects older patients. Non-Hodgkin lymphomas are the seventh most common cancers in the United States and also primarily affect older patients. In general, older patients should be treated differently than their younger, fitter counterparts. Fitness level and comorbidities should be taken into account when planning treatment. First-line treatment of most of these B-cell lymphoproliferative disorders consists of chemoimmunotherapy. In relapsed and refractory disease, there is a growing role for therapies targeting the B cell receptor signaling pathway. PMID- 26614866 TI - Myelodysplastic Syndromes and Acute Myeloid Leukemia in the Elderly. AB - Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic diseases that frequently affect older adults. Treatment is challenging. Management of older adults with MDS and AML needs to be individualized, accounting for both the heterogeneity of disease biology and patient characteristics, which can influence life expectancy and treatment tolerance. Clinical trials accounting for the heterogeneity of tumor biology and physiologic changes of aging are needed to define optimal standards of care. This article highlights key evidence related to the management of older adults with MDS and AML and highlights future directions for research. PMID- 26614868 TI - Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma in Older Adults. AB - Multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are plasma cell disorders of aging. The landscape of the diagnosis and management of MM and MGUS are rapidly changing. This article provides an updated understanding of the clinical presentation, evaluation, diagnosis, and management of older adults with MM and MGUS. Because most oncology providers are not formally trained in geriatric medicine, geriatricians play a key role in providing oncologists with a broader understanding of patient health status in the hope of improving outcomes for older adults with MM. PMID- 26614869 TI - Preface. PMID- 26614870 TI - New Insight into the Mechanism and Function of Autophagy in Plant Cells. AB - Autophagy is a degradation pathway that is conserved throughout eukaryotic organisms and plays important roles in the tolerance of abiotic and biotic stresses. It functions as a housekeeping process to remove unwanted cell components under normal conditions, and is induced during stress and senescence to break down damaged cellular contents and to recycle materials. The target components are engulfed into specialized transport structures termed autophagosomes and are subsequently delivered to the vacuole for degradation. Here, we review milestones in the study of autophagy in plants, discuss recent advances in our understanding of the mechanism and physiological roles of plant autophagy, and highlight potential future directions of research. PMID- 26614871 TI - Ribosomal Protein S6 Phosphorylation: Four Decades of Research. AB - The phosphorylation of ribosomal protein S6 (rpS6) has been described for the first time about four decades ago. Since then, numerous studies have shown that this modification occurs in response to a wide variety of stimuli on five evolutionarily conserved serine residues. However, despite a large body of information on the respective kinases and the signal transduction pathways, the physiological role of rpS6 phosphorylation remained obscure until genetic manipulations were applied in both yeast and mammals in an attempt to block this modification. Thus, studies based on both mice and cultured cells subjected to disruption of the genes encoding rpS6 and the respective kinases, as well as the substitution of the phosphorylatable serine residues in rpS6, have laid the ground for the elucidation of the multiple roles of this protein and its posttranslational modification. This review focuses primarily on newly identified kinases that phosphorylate rpS6, pathways that transduce various signals into rpS6 phosphorylation, and the recently established physiological functions of this modification. It should be noted, however, that despite the significant progress made in the last decade, the molecular mechanism(s) underlying the diverse effects of rpS6 phosphorylation on cellular and organismal physiology are still poorly understood. PMID- 26614872 TI - Different Pathways to the Lysosome: Sorting out Alternatives. AB - Considerable research supports a model in which hydrolytic enzymes of mammalian lysosomes are sorted to their destinations in a receptor-dependent mechanism. The ligand for the mammalian sorting receptors is mannose 6-phosphate (M6P). Two M6P receptors have been defined in mammals. Here, we review the foundational evidence supporting this mechanism and highlight the remaining gaps in our understanding of the mammalian mechanism, including evidence for M6P-independent sorting, and its relevance to lysosomal enzyme sorting in metazoa. PMID- 26614873 TI - Intracellular Dynamics of Synucleins: "Here, There and Everywhere". AB - Synucleins are small, soluble proteins expressed primarily in neural tissue and in certain tumors. The synuclein family consists of three members: alpha-, beta-, and gamma-synucleins present only in vertebrates. Members of the synuclein family have high sequence identity, especially in the N-terminal regions. The synuclein gene family came into the spotlight, when one of its members, alpha-synuclein, was found to be associated with Parkinson's disease and other neurodegenerative disorders, whereas gamma-synuclein was linked to several forms of cancer. There are a lot of controversy and exciting debates concerning members of the synuclein family, including their normal functions, toxicity, role in pathology, transmission between cells and intracellular localization. Important findings which remain undisputable for many years are synuclein localization in synapses and their role in the regulation of synaptic vesicle trafficking, whereas their presence and function in mitochondria and nucleus is a debated topic. In this review, we present the data on the localization of synucleins in two intracellular organelles: the nucleus and mitochondria. PMID- 26614874 TI - Nuclear Pore Complexes and Nucleocytoplasmic Transport: From Structure to Function to Disease. AB - Nucleocytoplasmic transport is an essential cellular activity and occurs via nuclear pore complexes (NPCs) that reside in the double membrane of the nuclear envelope. Significant progress has been made during the past few years in unravelling the ultrastructural organization of NPCs and their constituents, the nucleoporins, by cryo-electron tomography and X-ray crystallography. Mass spectrometry and genomic approaches have provided deeper insight into the specific regulation and fine tuning of individual nuclear transport pathways. Recent research has also focused on the roles nucleoporins play in health and disease, some of which go beyond nucleocytoplasmic transport. Here we review emerging results aimed at understanding NPC architecture and nucleocytoplasmic transport at the atomic level, elucidating the specific function individual nucleoporins play in nuclear trafficking, and finally lighting up the contribution of nucleoporins and nuclear transport receptors in human diseases, such as cancer and certain genetic disorders. PMID- 26614875 TI - Cavin Family: New Players in the Biology of Caveolae. AB - Caveolae are specialized small plasma-membrane invaginations that play crucial cellular functions. Two essential protein families are required for caveola formation: membrane caveolin proteins and cytoplasmic cavin proteins. Each family includes members with specific tissue distribution, and their expression is altered under physiological and pathological conditions, implying highly specialized functions. Cavins not only stabilize caveolae, but modulate their morphology and functions as well. Before association with the plasma membrane, cavins form homo- and hetero-oligomers with strikingly strict stoichiometry in the cytosol. At the plasma membrane, they provide an outer peripheral cytosolic layer, necessary for caveola stability. Interestingly, upon stimulation, cavins can be released from caveolae into the cytoplasm in distinct subcomplexes, providing a rapid dynamic link between caveolae and cellular organelles including the nucleus. In this review, we detail the biology of cavins, their structural and functional roles, and their implication in pathophysiology. PMID- 26614876 TI - Right-Colon Ischemia, Acute Mesenteric Ischemia, and Vascular Imaging. PMID- 26614877 TI - Failure to Account for Immortal Person Time Likely Accounts for the Apparent Reduction in Surgery Among Natalizumab Users. PMID- 26614878 TI - Nonradiologists' Perspectives on Health Services Research and Policy in Radiology. PMID- 26614879 TI - The Impact of Hospital Characteristics on the Availability of Radiology Services at Critical Access Hospitals. AB - PURPOSE: Although all critical access hospitals (CAHs) provide basic medical and radiographic imaging services, it remains unclear how CAHs provide additional imaging services given relatively low patient volumes and high resource costs. The aim of this study was to examine whether CAHs with more resources or access to resources through affiliation with larger systems are more likely to offer other imaging services in their communities. METHODS: Linking data from the American Hospital Association's annual hospital surveys and the American Hospital Directory's annual surveys from 2009 to 2011, multivariate logistic regressions were performed to estimate the likelihood of individual CAHs with greater financial resources or network affiliations providing specific imaging services (MRI, CT, ultrasound, mammography, and PET/CT), while adjusting for the number of beds, personnel, inpatient revenue share, case mix, rural status, year, and geographic location. RESULTS: Hospital total expenditures were positively associated with the provision of MRI (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.07-1.19), mammography (OR, 1.11; 95% CI, 1.01-1.16), and PET/CT (OR, 1.04; 95% CI, 1.01-1.06). Network affiliation was positively associated with the availability of MRI (OR, 1.75; 95% CI, 1.27-2.39), CT (OR, 2.17; 95% CI, 1.15 4.09), ultrasound (OR, 2.03; 95% CI, 1.17-3.52), and mammography (OR, 2.00; 95% CI, 1.47-2.71). Rural location was negatively associated with the availability of PET/CT (OR, 0.65; 95% CI, 0.49-0.88). CONCLUSIONS: Total hospital expenditures and network participation are important determinants of whether CAHs provide certain imaging services. Encouraging CAHs' participation in larger systems or networks may facilitate access to highly specialized services in rural and underserved areas. PMID- 26614880 TI - Diagnostic Imaging Services in Magnet and Non-Magnet Hospitals: Trends in Utilization and Costs. AB - PURPOSE: The purpose of this study was to better understand trends in utilization and costs of diagnostic imaging services at Magnet hospitals (MHs) and non-Magnet hospitals (NMHs). METHODS: A data set was created by merging hospital-level data from the American Hospital Association's annual survey and Medicare cost reports, individual-level inpatient data from the Healthcare Cost and Utilization Project, and Magnet recognition status data from the American Nurses Credentialing Center. A descriptive analysis was conducted to evaluate the trends in utilization and costs of CT, MRI, and ultrasound procedures among MHs and NMHs in urban locations between 2000 and 2006 from the following ten states: Arizona, California, Colorado, Florida, Iowa, Maryland, North Carolina, New Jersey, New York, and Washington. RESULTS: When matched by bed size, severity of illness (case mix index), and clinical technological sophistication (Saidin index) quantiles, MHs in higher quantiles indicated higher rates of utilization of imaging services for MRI, CT, and ultrasound in comparison with NMHs in the same quantiles. However, average costs of MRI, CT, and ultrasounds were lower at MHs in comparison with NMHs in the same quantiles. CONCLUSIONS: Overall, MHs that are larger in size (number of beds), serve more severely ill patients (case mix index), and are more technologically sophisticated (Saidin index) show higher utilization of diagnostic imaging services, although costs per procedure at MHs are lower in comparison with similar NMHs, indicating possible cost efficiency at MHs. Further research is necessary to understand the relationship between the utilization of diagnostic imaging services among MHs and its impact on patient outcomes. PMID- 26614881 TI - Use of Health Information Exchange and Repeat Imaging Costs. AB - PURPOSE: The aim of this study was to quantify the association between health information exchange (HIE) use and cost savings attributable to repeat imaging. METHODS: Imaging procedures associated with HIE were compared with concurrent controls on the basis of propensity score matching over the period from 2009 to 2010 in a longitudinal cohort study. The study sample (n = 12,620) included patients ages 18 years and older enrolled in the two largest commercial health plans in a 13-county region of western New York State served by the Rochester Regional Health Information Organization. The primary outcome was a continuous measure of costs associated with repeat imaging. The determinant of interest, HIE use, was defined as system access after the initial imaging procedure and before repeat imaging. RESULTS: HIE use was associated with an overall estimated annual savings of $32,460 in avoided repeat imaging, or $2.57 per patient. Basic imaging (radiography, ultrasound, and mammography) accounted for 85% of the estimated avoided cases of repeat imaging. Advanced imaging (CT and MRI) accounted for 13% of avoided procedures but constituted half of the estimated savings (50%). CONCLUSIONS: HIE systems may reduce costs associated with repeat imaging. Although inexpensive imaging procedures constituted the largest proportion of avoided repeat imaging in our study, most of the estimated cost savings were due to small reductions in repeated advanced imaging procedures. HIE systems will need to be leveraged in ways that facilitate greater reductions in advanced imaging to achieve appreciable cost savings. PMID- 26614883 TI - Advanced Imaging Utilization Trends in Privately Insured Patients From 2007 to 2013. AB - OBJECTIVE: The aim of the study was to investigate whether the increase in utilization of advanced diagnostic imaging for privately insured patients in 2011 was the beginning of a new trend in imaging utilization growth, or an isolated deviation from the declining trend that began in 2008. METHODS: We extracted outpatient and inpatient CT, diagnostic ultrasound, MRI, and PET procedures from databases, for the years 2007 to 2013. This study extended previous work, covering 2012 to 2013, using the same methodology. For every year of the study period, we calculated the following: number of procedures per person-year covered by private health insurance; proportion of office and emergency visits that resulted in an imaging session; average payments per procedure; and total payments per person-year covered by private health insurance. RESULTS: Outpatient utilization of CT and PET decreased in both 2012 and 2013; outpatient utilization of MRI mildly increased in 2012, but then decreased in 2013. Outpatient utilization of diagnostic ultrasound showed a very different pattern, increasing throughout the study period. Inpatient utilization of all imaging modalities except PET decreased in both 2012 and 2013. Adjusted payments for all imaging modalities increased in 2012, and then dropped substantially in 2013, except the adjusted payments for diagnostic ultrasound that increased in 2013 again. CONCLUSIONS: The trend of increasing utilization of advanced diagnostic imaging seems to be over for some, but not all, imaging modalities. A combination of policy (eg, breast density notification laws), technologic advancement, and wider access seems to be responsible for at least part of an increasing utilization of diagnostic ultrasound. PMID- 26614882 TI - Image Sharing Technologies and Reduction of Imaging Utilization: A Systematic Review and Meta-analysis. AB - INTRODUCTION: Image sharing technologies may reduce unneeded imaging by improving provider access to imaging information. A systematic review and meta-analysis were conducted to summarize the impact of image sharing technologies on patient imaging utilization. METHODS: Quantitative evaluations of the effects of PACS, regional image exchange networks, interoperable electronic heath records, tools for importing physical media, and health information exchange systems on utilization were identified through a systematic review of the published and gray English-language literature (2004-2014). Outcomes, standard effect sizes (ESs), settings, technology, populations, and risk of bias were abstracted from each study. The impact of image sharing technologies was summarized with random effects meta-analysis and meta-regression models. RESULTS: A total of 17 articles were included in the review, with a total of 42 different studies. Image sharing technology was associated with a significant decrease in repeat imaging (pooled effect size [ES] = -0.17; 95% confidence interval [CI] = [-0.25, -0.09]; P < .001). However, image sharing technology was associated with a significant increase in any imaging utilization (pooled ES = 0.20; 95% CI = [0.07, 0.32]; P = .002). For all outcomes combined, image sharing technology was not associated with utilization. Most studies were at risk for bias. CONCLUSIONS: Image sharing technology was associated with reductions in repeat and unnecessary imaging, in both the overall literature and the most-rigorous studies. Stronger evidence is needed to further explore the role of specific technologies and their potential impact on various modalities, patient populations, and settings. PMID- 26614884 TI - Identifying Patients With Undiagnosed Chronic Conditions: An Examination of Patient Costs Before Chronic Disease Diagnosis. AB - PURPOSE: Identifying chronic conditions at earlier stages could produce dramatic savings to the health care system. This study sought to determine whether patients with chronic conditions experienced higher medical costs and imaging costs than patients with nonchronic conditions before the onset of chronic disease. METHODS: This retrospective study linked 2004-2012 Medicare Chronic Conditions Warehouse data to Medicare fee-for-service claims data, to examine whether elderly patients that have chronic conditions experienced higher overall medical costs, imaging costs, and imaging share of costs before their diagnosis, compared with patients who have nonchronic conditions, during the same period. Student's t tests were conducted comparing the mean annual costs and imaging share for patients with chronic conditions and patients with nonchronic conditions, for the six years before their diagnosis and two years afterward. RESULTS: Imaging costs for patients with chronic conditions were 9 times higher (P < .001) for 6 years before they were diagnosed with a chronic condition; overall medical costs were 18 times (P < .001) higher than those for patients with nonchronic conditions. A significant (P < .001) but small difference was found between the mean imaging share for patients with, versus without, a chronic condition, up until two years before diagnosis, at which point overall medical costs, imaging costs, and imaging share dramatically increased. CONCLUSIONS: Overall medical costs and imaging costs for patients with chronic conditions are significantly and substantially higher than those for patients with nonchronic conditions for many years before they are diagnosed with chronic conditions. Tracking health care expenditures may identify patients with chronic conditions sooner, potentially producing large savings within the health care system. PMID- 26614885 TI - Lung Cancer Screening With Low-Dose CT in the United States. AB - The findings of the landmark National Lung Screening Trial (NLST)-showing a 20% reduction in lung cancer mortality when screening with low-dose CT (LDCT), compared with chest radiography-marked a turning point in the field of lung cancer screening, influencing organizational recommendations and leading to increasing acceptance of LDCT for screening of individuals at high risk for lung cancer. However, many practices and institutions have experienced barriers in their attempts to implement successful screening programs; these include challenges in maintaining the same high caliber of screening programs as those in the NLST, confusion regarding insurance reimbursement protocols, and a lack of resources to help physicians discuss the specifics of LDCT screening with their patients. To address these challenges, standards are being established to ensure consistent quality of screening programs, including certification standards and protocols maintained by the ACR. In addition, the US Preventive Services Task Force's "B" rating, given to LDCT screening in late 2013, resulted in mandated private insurance coverage beginning in 2015 and the 2015 CMS coverage determination has spurred previously reluctant organizations to prepare for population-based screening. Despite these successes, protocols for billing and claims processing are still evolving and organizations are considering how best to implement the shared decision-making process required by CMS. Despite some procedural setbacks that have yet to be resolved, LDCT screening for individuals at high risk of lung cancer has grown substantially since its effectiveness was shown by the NLST in 2011. PMID- 26614886 TI - Malpractice Liability Risk and Use of Diagnostic Imaging Services: A Systematic Review of the Literature. AB - PURPOSE: A widespread concern among physicians is that fear of medical malpractice liability may affect their decisions for diagnostic imaging orders. The purpose of this article is to synthesize evidence regarding the defensive use of imaging services. METHODS: A literature search was conducted using a number of databases. The review included peer-reviewed publications that studied the link between physician orders of imaging tests and malpractice liability pressure. RESULTS: We identified 13 peer-reviewed studies conducted in the United States. Five of the studies reported physician assessments of the role of defensive medicine in imaging-order decisions; five assessed the association between physicians' liability risk and imaging ordering, and three assessed the impact of liability risk on imaging ordering at the state level. Although the belief that medical liability risk could influence decisions is highly prevalent among physicians, findings are mixed regarding the impact of liability risk on imaging orders at both the state and physician level. CONCLUSIONS: Inconclusive evidence suggests that physician ordering of imaging tests is affected by malpractice liability risk. Further research is needed to disentangle defensive medicine from other reasons for inefficient use of imaging. PMID- 26614887 TI - Imaging Practice Patterns: Referral Network Analysis of a Single State of Origination. AB - PURPOSE: The aim of this study was to examine the referral pattern of imaging studies requested in a single state compared with the potential location of interpretation. METHODS: Analysis of Medicare patients in a DocGraph data set was performed to identify sequential different physician services claims for the same patient for which the second claim was for services provided by a radiologist. RESULTS: In the 2011 Medicare population, radiology referrals from physicians practicing in Georgia resulted in 76.5% of radiology interpretations by radiologists inside the state of Georgia. The states bordering Georgia accounted for 11.6% of interpretations in the Georgia market. The remaining interpretations were distributed throughout the remainder of the country. CONCLUSIONS: A significant proportion of routine imaging interpretation occurs outside the state in which an examination is performed. Additional studies are needed to identify complex drivers of imaging referral patterns, such as patient geographic location and demographics, radiologist workforce distribution, contractual obligations, and social relationships. PMID- 26614888 TI - Characterizing the Mammography Technologist Workforce in North Carolina. AB - PURPOSE: Mammography technologists' level of training, years of experience, and feedback on technique may play an important role in the breast-cancer screening process. However, information on the mammography technologist workforce is scant. METHODS: In 2013, we conducted a survey mailed to 912 mammography technologists working in 224 facilities certified by the Mammography Quality Standards Act in North Carolina. Using standard survey methodology, we developed and implemented a questionnaire on the education and training, work experiences, and workplace interactions of mammography technologists. We aggregated responses using survey weights to account for nonresponse. We describe and compare lead (administrative responsibilities) and nonlead (supervised by another technologist) mammography technologist characteristics, testing for differences, using t-tests and chi(2) analysis. RESULTS: A total of 433 mammography technologists responded (survey response rate = 47.5%; 95% confidence interval [CI]: 44.2%-50.7%), including 128 lead and 305 nonlead technologists. Most mammography technologists were non Hispanic, white women; their average age was 48 years. Approximately 93% of lead and nonlead technologists had mammography-specific training, but <4% had sonography certification, and 3% had MRI certification. Lead technologists reported more years of experience performing screening mammography (P = .02) and film mammography (P = .03), more administrative hours (P < .0001), and more workplace autonomy (P = .002) than nonlead technologists. Nonlead technologists were more likely to report performing diagnostic mammograms (P = .0004) or other breast imaging (P = .001), discuss image quality with a peer (P = .013), and have frequent face-to-face interaction with radiologists (P = .03). CONCLUSIONS: Our findings offer insights into mammography technologists' training and work experiences, highlighting variability in characteristics of lead versus nonlead technologists. PMID- 26614889 TI - Minimally Invasive Prostate Convective Water Vapor Energy Ablation: A Multicenter, Randomized, Controlled Study for the Treatment of Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia. AB - PURPOSE: This report reveals the results of a multicenter, randomized, controlled study using transurethral prostate convective water vapor thermal energy to treat lower urinary tract symptoms associated with benign prostatic hyperplasia. MATERIALS AND METHODS: Men 50 years old or older with an International Prostate Symptom Score of 13 or greater, maximum flow rate of 15 ml per second or less and prostate size 30 to 80 cc were randomized 2:1 between thermal therapy with the Rezum(r) System and control. Thermal water vapor was injected into the transition zone and median lobe as needed. The control procedure was rigid cystoscopy with simulated active treatment sounds. The primary end point compared International Prostate Symptom Score reduction at 3 months. Treatment subjects were followed for 12 months. RESULTS: There were 197 men randomized (active 136, control 61). Thermal therapy and control International Prostate Symptom Score was reduced by 11.2 +/- 7.6 and 4.3 +/- 6.9 respectively (p <0.0001). Treatment subject baseline International Prostate Symptom Score of 22 decreased at 2 weeks (18.6, p=0.0006) and by 50% or greater at 3, 6 and 12 months, p <0.0001. The peak flow rate increased by 6.2 ml per second at 3 months and was sustained throughout 12 months (p <0.0001). No de novo erectile dysfunction was reported. Adverse events were mild to moderate and resolved quickly. CONCLUSIONS: Convective water vapor thermal therapy provides rapid and durable improvements in benign prostatic hyperplasia symptoms and preserves erectile and ejaculatory function. Treatment can be delivered in an office or hospital setting using oral pain medication and is applicable to all prostate zones including the median lobe. PMID- 26614890 TI - Erectile Dysfunction is Predictive of Endothelial Dysfunction in a Well Visit Population. AB - PURPOSE: The relationship between erectile dysfunction and endothelial dysfunction has been described and is associated with adverse cardiac events. Endothelial dysfunction is believed to precede erectile dysfunction. Our objective was to characterize the prevalence of subjective erectile dysfunction, endothelial dysfunction and commonly related comorbidities in a population of men undergoing wellness screening. MATERIALS AND METHODS: A total of 205 men presented for wellness screening. They underwent testing for endothelial dysfunction via peripheral arterial tonometry and completed a health screening questionnaire. Reactive hyperemia index scores were generated by peripheral arterial tonometry testing. A reactive hyperemia index score of 1.67 or less defined endothelial dysfunction. The Student t-test and Fisher exact test were performed for continuous and categorical variables, respectively. The association of endothelial dysfunction, erectile dysfunction and various comorbidities was calculated using univariate and multivariable analyses. RESULTS: Of 205 men 47 reported subjective erectile dysfunction. Median age was 44 years old. The mean reactive hyperemia index in patients with erectile dysfunction was significantly lower than in patients without erectile dysfunction (1.63 vs 1.87, p = 0.001). Endothelial dysfunction was more common in men with than without erectile dysfunction (55% vs 36%, p = 0.027). Multivariable analysis revealed that men with erectile dysfunction and obesity were twofold more likely to have concomitant endothelial dysfunction (OR 2.45, 95% CI 1.13-4.24, p = 0.02 and OR 2.08, 95% CI 1.16-3.75, p = 0.01, respectively). CONCLUSIONS: Among middle-aged men presenting for wellness screening erectile dysfunction and obesity independently predicted endothelial dysfunction, a known risk factor for long term adverse cardiac events. PMID- 26614891 TI - Effect of different carbon materials as electron shuttles in the anaerobic biotransformation of nitroanilines. AB - Aromatic amines resulted from azo dyes biotransformation under anaerobic conditions are generally recalcitrant to further anaerobic degradation. The catalytic effect of carbon materials (CM) on the reduction of azo dyes is known and has been confirmed in this work by increasing threefold the biological reduction rate of Mordant Yellow 1 (MY1). The resulting m-nitroaniline (m-NoA) was further degraded to m-phenylenediamine (m-Phe) only in the presence of CM. The use of CM to degraded anaerobically aromatic amines resulted from azo dye reduction was never reported before. In the sequence, we studied the effect of different CM on the bioreduction of o-, m-, and p-NoA. Three microporous activated carbons with different surface chemistry, original (AC0 ), chemical oxidized with HNO3 (ACHNO3 ), and thermal treated (ACH2 ), and three mesoporous carbons, xerogels (CXA and CXB) and nanotubes (CNT) were assessed. In the absence of CM, NoA were only partially reduced to the corresponding Phe, whereas in the presence of CM, more than 90% was converted to the corresponding Phe. ACH2 and AC0 were the best electron shuttles, increasing the rates up to eightfold. In 24 h, the biological treatment of NoA and MY1 with AC0 , decreased up to 88% the toxicity towards a methanogenic consortium, as compared to the non-treated solutions. Biotechnol. Bioeng. 2016;113: 1194-1202. (c) 2015 Wiley Periodicals, Inc. PMID- 26614892 TI - Expression of recombinant human bifunctional peptidylglycine alpha-amidating monooxygenase in CHO cells and its use for insulin analogue modification. AB - The availability of catalytically active peptidylglycine alpha-amidating monooxygenase (PAM) should provide the means to examine its potential use for the chemienzymatic synthesis of bioactive peptides for the purpose of pharmacological studies. Hypoglycemic activity is one of the most important features of insulin derivatives. Insulin glargine amide was found to show a time/effect profile which is distinctly more flat and thus more advantageous than insulin glargine itself. The aim of the study was to obtain recombinant PAM and use it for insulin analogue amidation. We stably expressed a recombinant PAM in CHO dhfr-cells in culture. Recombinant PAM was partially purified by fractional ammonium sulphate precipitation and ion-exchange chromatography. The enzyme was used to modify glycine-extended A22(G)-B31(K)-B32(R) human insulin analogue (GKR). Alpha amidated insulin was analyzed by HPLC and mass spectrometry. Hypoglycemic activity of amidated and non-amidated insulin was compared. The pharmacodynamic effect was based on glucose concentration measurement in Wistar rats with hyperglycemia induced by streptozotocin. The overall glycemic profile up to 36 h was evaluated after subcutaneous single dosing at a range of 2.5-7.5 U/kg b.w. The experiment on rats confirmed with a statistical significance (P < 0.05) hypoglycemic activity of GKR-NH2 in comparison to a control group receiving 0.9% NaCl. Characteristics for GKR-NH2 profile was a rather fast beginning of action (0.5-2.0 h) and quite prolonged return to initial values. GKR-NH2 is a candidate for a hypoglycemic drug product in diabetes care. In addition, this work also provides a valuable alternative method for preparing any other recombinant bioactive peptides with C-terminal amidation. PMID- 26614893 TI - Hairy cell leukemia. PMID- 26614894 TI - Historical overview of hairy cell leukemia. AB - Since its discovery in 1923 and further characterization in 1958, hairy cell leukemia (HCL) has undergone enormous advances in the understanding of the biology and treatment of the disease. Initially a uniformly fatal disease, new therapies in rapid succession transformed HCL into a chronic disease with a normal life expectancy in many cases. More recently, the identification of BRAFV600E mutations in the majority of patients with classic HCL have enabled targeted therapies as a therapeutic option. Additional discoveries into the biology of the disease have identified new subtypes of HCL. Modern approaches to the evaluation and treatment of HCL include detailed molecular analysis which informs therapeutic options, which may consist of traditional therapies such as purine nucleoside analogs, or targeted therapies with antibodies, BTK inhibitors, or BRAF inhibitors, or combination therapy. Because HCL is a rare disease, continued progress depends on patients being enrolled on clinical trials whenever possible. PMID- 26614895 TI - Epidemiology and environmental risk in hairy cell leukemia. AB - Hairy cell leukaemia (HCL) is an orphan subtype of leukaemia which constitutes less than 2% of all leukaemia's, with an incidence of less than 1 per 100,000 persons per annum. Median age at presentation is 55 years and it is 3-4 times more frequent in males. It is also more frequently encountered in whites and less in Asians, Africans and Arabs. The epidemiologic data are multi-factorial and influenced by ethnicity and geographical factors. Other reported associations relate to some environmental exposures and possible occupational factors. Smoking appears to have an inverse correlation with the development of hairy cell leukaemia, while farming and exposure to pesticides, petroleum products, diesel and ionizing radiation have also been reported to be associated with an increased risk. National and international collaborative efforts are needed in order to undertake more extensive studies involving larger patient cohorts, aiming to determine the role of occupational and environmental risk factors in the development of this rare form of chronic leukaemia. PMID- 26614896 TI - Clinical features and diagnosis of hairy cell leukemia. AB - Significant advances in the diagnosis and treatment of hairy cell leukemia (HCL) have recently been made. Improved distinction of HCL from its mimics though clinical presentations, morphologic and immunophenotypic features, and more recently molecular biology, has highlighted marked differences in treatment response and overall prognosis between these disorders. As our understanding of the unique pathobiology of HCL has grown, exciting new avenues of treatment as well as insight into immune function have been obtained. This review provides an overview of the clinical features and diagnostic attributes of HCL, with contrast to other mature B cell lymphoproliferative disorders with overlapping features. PMID- 26614897 TI - Hairy cell leukemia: Uncommon clinical features, unusual sites of involvement and some rare associations. AB - Unusual clinical manifestations and associations with auto-immunity or other systemic disorders are uncommon clinical features of hairy cell leukemia (HCL). The exact prevalence of these rare associations is difficult to determine as they are mostly published as anecdotal case reports and generally not included in larger published series. This chapter deals with uncommon clinical manifestations and rare sites of involvement in HCL. It also summarizes the association with systemic hemato-oncological disorders as well as second malignancies, based on review of the relevant literature and from personal experience. PMID- 26614898 TI - Bone marrow and splenic histology in hairy cell leukaemia. AB - Hairy cell leukaemia is a rare chronic neoplastic B-cell lymphoproliferation that characteristically involves blood, bone marrow and spleen with liver, lymph node and skin less commonly involved. Histologically, the cells have a characteristic appearance with pale/clear cytoplasm and round or reniform nuclei. In the spleen, the infiltrate involves the red pulp and is frequently associated with areas of haemorrhage (blood lakes). The cells stain for B-cell related antigens as well as with antibodies against tartrate-resistant acid phosphatase, DBA44 (CD72), CD11c, CD25, CD103, CD123, cyclin D1 and annexin A1. Mutation of BRAF -V600E is present and antibody to the mutant protein can be used as a specific marker. Bone marrow biopsy is essential in the initial assessment of disease as the bone marrow may be inaspirable or unrepresentative of degree of marrow infiltration as a result of the tumour associated fibrosis preventing aspiration of the tumour cell component. Bone marrow biopsy is important in the assessment of therapy response but in this context staining for CD11c and Annexin A1 is not helpful as they are also markers of myeloid lineage and identification of low level infiltration may be obscured. In this context staining for CD20 may be used in conjunction with morphological assessment and staining of serial sections for cyclin D1 and DBA44 to identify subtle residual infiltration. Staining for CD79a and CD19 is not recommended as these antibodies will identify plasma cells and can lead to over estimation of disease. Staining for CD20 should not be used in patients following with anti-CD20 based treatments. Down regulation of cyclin D1 and CD25 has been reported in patients following BRAF inhibitor therapy and assessment of these antigens should not be used in this context. Histologically, hairy cell leukaemia needs to be distinguished from other B-cell lymphoproliferations associated with splenomegaly including splenic marginal zone lymphoma, splenic diffuse red pulp small B-cell lymphoma and hairy cell leukaemia variant. This can be done by assessment of the spleen but as this is now rarely performed in this disorder distinction is almost always possible by a combination of morphological and immunophenotypic studies on bone marrow trephine biopsy, which can be supplemented by assessment of BRAF-V600E mutation assessment in borderline cases. PMID- 26614899 TI - The importance of the tissue microenvironment in hairy cell leukemia. AB - Hairy cell leukemia (HCL) cells engage in complex cellular and molecular interactions with accessory cells, matrix proteins, and various cytokines in the bone marrow and spleen, collectively referred to as the tissue microenvironment. Chemokine receptors and adhesion molecules are critical players for homing and retention within these microenvironments. Engagement of B cell antigen receptors and CD40 on HCL cells promote survival and proliferation. In this chapter, we summarize the current knowledge about the cellular and molecular interactions between HCL cells and their supportive tissue microenvironment, and provide insight into new therapeutic approaches targeting B cell receptor signaling in HCL. PMID- 26614900 TI - Long-term follow-up after purine analogue therapy in hairy cell leukaemia. AB - Since 2006 when we last reviewed the literature concerning the use of purine analogues in hairy cell leukaemia (HCL), results from several new and updated series have been published. Here we examine these reports and consider their implications for patient management. The two purine analogues pentostatin and cladribine remain the first-line treatments of choice for all patients with HCL. Although they have not been compared in randomised trials, they appear to be equally effective. A complete response is important for the long-term outcome and we look at how best this can be achieved. Evidence is emerging which supports the use of either purine analogue plus an anti-CD20 monoclonal antibody after relapse, though questions remain concerning the scheduling of the monoclonal antibody. Patients refractory to the purine analogues may require alternative agents. PMID- 26614901 TI - Chemoimmunotherapy for hairy cell leukemia. AB - Success in the treatment of patients with hairy cell leukemia (HCL) over the last several decades is largely due to the high efficacy of the nucleoside analogs, cladribine and pentostatin. However, the relapse-free survival curves have not shown a plateau and many patients treated with these agents will eventually relapse. Although better understanding of the pathogenic mechanisms in HCL have led to effective and novel options for the treatment of relapse, long term durability of the responses obtained with these agents still remains unclear. Combination of nucleoside analogs with monoclonal antibodies such as rituximab has been shown to be safe and effective and has the potential to supersede the nucleoside analogs as the frontline strategy. Such chemo-immunotherapy approaches are under further investigation and will have to be assessed with socioeconomic considerations in mind. Other novel monoclonal antibodies, approved for the treatment of other lymphoid neoplasms, may also be considered for future studies of chemo-immunotherapy. PMID- 26614903 TI - BRAF inhibitor therapy in HCL. AB - Targeted treatment approaches are transforming the therapeutic landscape of cancer care. The discovery of the BRAF V600E mutation in most cases of classical hairy cell leukemia opens up unique opportunities for tumor specific treatment of HCL targeting the MEK/ERK signaling pathway. The discovery and biological implications of BRAF V600E in HCL are summarized to form a basis for our current understanding of the potential for clinical exploitation. There is overwhelming clinical evidence for activity of inhibitors of BRAF in the disease. The review will review current trial activity as well as discuss novel trial concepts exploiting targeted treatment focusing on BRAF inhibition in HCL. PMID- 26614902 TI - Immunoconjugates in the management of hairy cell leukemia. AB - Hairy cell leukemia (HCL) is an indolent B-cell malignancy effectively treated but not often cured by purine analog therapy; after multiple courses of purine analogs, patients can become purine analog resistant and in need of alternative therapies. Complete remission to single-agent purine analog is often accompanied by minimal residual disease (MRD), residual HCL cells detectable by immunologic methods, considered a risk factor for eventual relapse. Several different non chemotherapy approaches are being used to target relapsed and refractory HCL, including inhibitors of BRAF, but so far only monoclonal antibody (MAb)-based approaches have been reported to eliminate MRD in a high percentage of patients. One of the MAb-based options for HCL currently under clinical investigation involves recombinant immunotoxins, containing a fragment of a MAb and a bacterial toxin. The bacterial toxin, a highly potent fragment from Pseudomonas exotoxin, catalytically ADP-ribosylates elongation factor 2 (EF2), resulting in protein synthesis inhibition and apoptotic cell death. Recombinant immunotoxins tested in HCL patients include LMB-2, targeting CD25, and BL22, targeting CD22. An affinity matured version of BL22, termed moxetumomab pasudotox (formerly HA22 or CAT-8015) achieved high CR rates in phase I, and is currently undergoing multicenter Phase 3 testing. Phase I testing was without dose-limiting toxicity, although 2 patients had grade 2 hemolytic uremic syndrome (HUS) with transient grade 1 abnormalities in platelets and creatinine. Preclinical work is underway to identify residues on moxetumomab pasudotox leading to immunogenicity. Moxetumomab pasudotox is undergoing pivotal testing for relapsed and refractory HCL. PMID- 26614904 TI - Hairy cell leukaemia-variant: Disease features and treatment. AB - Hairy cell leukaemia-variant (HCL-V) is a rare B-cell malignancy that affects elderly males and manifests with splenomegaly, lymphocytosis and cytopenias without monocytopenia. The neoplastic cells have morphological features of prolymphocytes and hairy cells. The immunophenotype is that of a clonal B-cell CD11c and CD103 positive but, unlike classical HCL, CD25, CD123 and CD200 negative. The spleen histology is similar to classical HCL and the pattern of bone marrow infiltration is interstitial and/or intrasinusoidal. Mutations of the immunoglobulin heavy chain (IGVH) are seen in two thirds of cases with a preferential VH4-34 family usage. There is no distinct chromosomal abnormality but del17p13 and mutations of the TP53 gene are frequent. Mutations in the MAP2K1 gene have been documented in half of the cases. The course is chronic with median survivals of 7-9 years. Patients are refractory to purine analogues and the most effective therapy is the combination of 2-chlorodeoxyadenosine and Rituximab. PMID- 26614905 TI - What your hairy cell leukemia patients want you to know. AB - Hairy cell leukemia is different from most other hematologic malignancies because it is so rare. Patient concerns include finding a knowledgeable physician, confirming the diagnosis at the initial presentation, coping with treatment side effects and monitoring for potential relapse of this chronic disease. PMID- 26614906 TI - Hairy cell leukemia: Past, present and future. AB - This brief review highlights the sequence of therapeutic milestones and advances in our understanding of the biology of hairy cell leukemia (HCL) with a focus on recent molecular findings and how these may be applied to improve disease outcomes in the future. Targeted therapy is discussed in the context of the recently identified BRAF mutation and other genetic findings. PMID- 26614908 TI - G-protein inhibition profile of the reported Gq/11 inhibitor UBO-QIC. AB - UBO-QIC (FR900359) is the only currently available Gq/11 protein inhibitor. However, its characterization has not been published, and we thus set out to do this. Gi, Gs and Gq protein-mediated responses were assessed utilizing endogenous or heterologously expressed receptors in Chinese hamster ovary cells. UBO-QIC, at 1 MUM, was an effective inhibitor of the Gq-mediated responses, but was inactive at Gi- and Gs-mediated responses. Gq/11 and G16 responses were additionally compared in HEL92.1.7 cells, showing inhibition of Gq/11 responses. However, UBO QIC also appeared to inhibit G16. Further studies are required to establish its profile with respect to the different Gq-family proteins. PMID- 26614907 TI - Identification and functional characterization of a novel bipartite nuclear localization sequence in ARID1A. AB - AT-rich interactive domain-containing protein 1A (ARID1A) is a recently identified nuclear tumor suppressor frequently altered in solid tumor malignancies. We have identified a bipartite-like nuclear localization sequence (NLS) that contributes to nuclear import of ARID1A not previously described. We functionally confirm activity using GFP constructs fused with wild-type or mutant NLS sequences. We further show that cyto-nuclear localized, bipartite NLS mutant ARID1A exhibits greater stability than nuclear-localized, wild-type ARID1A. Identification of this undescribed functional NLS within ARID1A contributes vital insights to rationalize the impact of ARID1A missense mutations observed in patient tumors. PMID- 26614909 TI - Two zebrafish G2A homologs activate multiple intracellular signaling pathways in acidic environment. AB - Human G2A is activated by various stimuli such as lysophosphatidylcholine (LPC), 9-hydroxyoctadecadienoic acid (9-HODE), and protons. The receptor is coupled to multiple intracellular signaling pathways, including the Gs-protein/cAMP/CRE, G12/13-protein/Rho/SRE, and Gq-protein/phospholipase C/NFAT pathways. In the present study, we examined whether zebrafish G2A homologs (zG2A-a and zG2A-b) could respond to these stimuli and activate multiple intracellular signaling pathways. We also examined whether histidine residue and basic amino acid residue in the N-terminus of the homologs also play roles similar to those played by human G2A residues if the homologs sense protons. We found that the zG2A-a showed the high CRE, SRE, and NFAT activities, however, zG2A-b showed only the high SRE activity under a pH of 8.0. Extracellular acidification from pH 7.4 to 6.3 ameliorated these activities in zG2A-a-expressing cells. On the other hand, acidification ameliorated the SRE activity but not the CRE and NFAT activities in zG2A-b-expressing cells. LPC or 9-HODE did not modify any activity of either homolog. The substitution of histidine residue at the 174(th) position from the N terminus of zG2A-a to asparagine residue attenuated proton-induced CRE and NFAT activities but not SRE activity. The substitution of arginine residue at the 32nd position from the N-terminus of zG2A-a to the alanine residue also attenuated its high and the proton-induced CRE and NFAT activities. On the contrary, the substitution did not attenuate SRE activity. The substitution of the arginine residue at the 10th position from the N-terminus of zG2A-b to the alanine residue also did not attenuate its high or the proton-induced SRE activity. These results indicate that zebrafish G2A homologs were activated by protons but not by LPC and 9-HODE, and the activation mechanisms of the homologs were similar to those of human G2A. PMID- 26614911 TI - Current and Future Treatments for Alzheimer Disease. PMID- 26614910 TI - Integrative properties of retinal ganglion cell electrical responsiveness depend on neurotrophic support and genotype in the mouse. AB - Early stages of glaucoma and optic neuropathies are thought to show inner retina remodeling and functional changes of retinal ganglion cells (RGCs) before they die. To assess RGC functional plasticity, we investigated the contrast-gain control properties of the pattern electroretinogram (PERG), a sensitive measure of RGC function, as an index of spatio-temporal integration occurring in the inner retina circuitry subserving PERG generators. We studied the integrative properties of the PERG in mice exposed to different conditions of neurotrophic support. We also investigated the effect of genotypic differences among mouse strains with different susceptibility to glaucoma (C57BL/6J, DBA/2J, DBA/2.Gpnmb(+)). Results show that the integrative properties of the PERG recorded in the standard C57BL/6J inbred mouse strain are impaired after deficit of neurotrophic support and partially restored after exogenous neurotrophic administration. Changes in PERG amplitude, latency, and contrast-dependent responses differ between mouse strains with different susceptibility to glaucoma. Results represent a proof of concept that the PERG could be used as a tool for in vivo monitoring of RGC functional plasticity before RGC death, the effect of neuroactive treatments, as well as for high-throughput tool for phenotypic screening of different mouse genotypes. PMID- 26614912 TI - The histone deacetylase inhibitor Entinostat enhances polymer-mediated transgene expression in cancer cell lines. AB - Eukaryotic cells maintain an immense amount of genetic information by tightly wrapping their DNA around positively charged histones. While this strategy allows human cells to maintain more than 25,000 genes, histone binding can also block gene expression. Consequently, cells express histone acetyl transferases (HATs) to acetylate histone lysines and release DNA for transcription. Conversely, histone deacetylases (HDACs) are employed for restoring the positive charge on the histones, thereby silencing gene expression by increasing histone-DNA binding. It has previously been shown that histones bind and silence viral DNA, while hyperacetylation of histones via HDAC inhibition restores viral gene expression. In this study, we demonstrate that treatment with Entinostat, an HDAC inhibitor, enhances transgene (luciferase) expression by up to 25-fold in human prostate and murine bladder cancer cell lines when used with cationic polymers for plasmid DNA delivery. Entinostat treatment altered cell cycle progression, resulting in a significant increase in the fraction of cells present in the G0/G1 phase at low micromolar concentrations. While this moderate G0/G1 arrest disappeared at higher concentrations, a modest increase in the fraction of apoptotic cells and a decrease in cell proliferation were observed, consistent with the known anticancer effects of the drug. DNase accessibility studies revealed no significant change in plasmid transcriptional availability with Entinostat treatment. However, quantitative PCR studies indicated that Entinostat treatment, at the optimal dose for enhancing transgene expression, led to an increase in the amount of plasmid present in the nucleus in two cancer cell lines. Taken together, our results show that Entinostat enhances polymer- mediated transgene expression and can be useful in applications related to transient protein expression in mammalian cells. Biotechnol. Bioeng. 2016;113: 1345-1356. (c) 2015 Wiley Periodicals, Inc. PMID- 26614913 TI - Two parametric cell cycle analyses of plant cell suspension cultures with fragile, isolated nuclei to investigate heterogeneity in growth of batch cultivations. AB - Plant cell suspensions are frequently considered to be heterogeneous with respect to growth in terms of progression of the cells through the cell cycle and biomass accumulation. Thus, segregated data of fractions in different cycle phases during cultivation is needed to develop robust production processes. Bromodeoxyuridine (BrdU) incorporation and BrdU-antibodies or 5-ethynyl-2'-deoxyuridine (EdU) click it chemistry are frequently used to acquire such information. However, their use requires centrifugation steps that cannot be readily applied to sensitive cells, particularly if nuclei have to be extracted from the protective cellular milieu and envelopes for DNA analysis. Therefore, we have established a BrdU-Hoechst stain quenching protocol for analyzing nuclei directly isolated from delicate plant cell suspension cultures. After adding BrdU to test Harpagophytum procumbens cell suspension cultures the cell cycle distribution could be adequately resolved using its incorporation for the following 72 h (after which BrdU slowed biomass accumulation). Despite this limitation, the protocol allows resolution of the cell cycle distribution of cultures that cannot be analyzed using commonly applied methods due to the cells' fragility. The presented protocol enabled analysis of cycling heterogeneities in H. procumbens batch cultivations, and thus should facilitate process control of secondary metabolite production from fragile plant in vitro cultures. Biotechnol. Bioeng. 2016;113: 1244-1250. (c) 2015 Wiley Periodicals, Inc. PMID- 26614914 TI - Environmental switching during biofilm development in a cold seep system and functional determinants of species sorting. AB - The functional basis for species sorting theory remains elusive, especially for microbial community assembly in deep-sea environments. Using artificial surface based biofilm models, our recent work revealed taxonomic succession during biofilm development in a newly defined cold seep system, the Thuwal cold seeps II, which comprises a brine pool and the adjacent normal bottom water (NBW) to form a metacommunity via the potential immigration of organisms from one patch to another. Here, we designed an experiment to investigate the effects of environmental switching between the brine pool and the NBW on biofilm assembly, which could reflect environmental filtering effects during bacterial immigration to new environments. Analyses of 16S rRNA genes of 71 biofilm samples suggested that the microbial composition of biofilms established in new environments was determined by both the source community and the incubation conditions. Moreover, a comparison of 18 metagenomes provided evidence for biofilm community assembly that was based primarily on functional features rather than taxonomic identities; metal ion resistance and amino acid metabolism were the major species sorting determinants for the succession of biofilm communities. Genome binning and pathway reconstruction of two bacterial species (Marinobacter sp. and Oleispira sp.) further demonstrated metal ion resistance and amino acid metabolism as functional traits conferring the survival of habitat generalists in both the brine pool and NBW. The results of this study shed new light on microbial community assembly in special habitats and bridge a gap in species sorting theory. PMID- 26614915 TI - Diagnosis of Periprosthetic Infection: Novel Developments. AB - The diagnosis of periprosthetic joint infection (PJI) has been performed by obtaining a history and physical examination, blood tests, and analysis of the synovial fluid and tissue samples. The measurement of serum biomarkers are routinely used to diagnose PJI. These markers may be elevated in other inflammatory conditions, necessitating the need for more specific biomarkers to diagnose PJI. Serum biomarkers may be more specific to PJI. Synovial CRP, alpha defensin, human beta-defensin-2 and -3, leukocyte esterase, and cathelicidin LL 37 biomarkers hold promise for the diagnosis of PJI. PMID- 26614916 TI - One-Stage Revision for Infected Total Hip Arthroplasty. AB - Prosthetic joint infection (PJI) is a challenging complication following total hip arthroplasty (THA). Two-stage exchange arthroplasty is preferred for treating chronic PJI of THA, although specialized centers have reported comparable outcomes with protocol-based, 1-stage exchange arthroplasty. A main requirement is presurgical determination of the infecting organism's sensitivity. The therapeutic goal is control of the infection and maintenance of joint function. It offers advantages, including a single operative procedure, fewer antibiotics, and reduced hospitalization time and relative overall costs. PMID- 26614917 TI - The Impact of Lumbar Spine Disease and Deformity on Total Hip Arthroplasty Outcomes. AB - Concurrent spine and hip disease is common. Spinal deformities can restrict lumbar range of motion and lumbar lordosis, leading to pelvic obliquity and increased pelvic tilt. A comprehensive preoperative workup and component templating ensure appropriate compensation for altered pelvic parameters for implantation of components according to functional positioning. Pelvic obliquity from scoliosis must be measured to calculate appropriate leg length. Cup positioning should be templated on standing radiograph to limit impingement from cup malposition. In spinal deformity, the optimal position of the cup that accommodates pelvic parameters and limits impingement may lie outside the classic parameters of the safe zone. PMID- 26614918 TI - Robotically Assisted Unicompartmental Knee Arthroplasty with a Handheld Image Free Sculpting Tool. AB - Although unicompartmental knee arthroplasty may pose a lower risk of perioperative complications and achieve better functional outcomes than total knee arthroplasty, a high degree of accuracy of implant positioning and soft tissue balance are required to optimize durability and implant survivorship. First-generation robotic technology improved implant position compared with conventional methods. This article reviews the next-generation robotic technology, an image-free handheld robotic sculpting tool, which offers an alternative method for optimizing implant positioning and soft tissue balance without the need for preoperative computed tomography scans and with price points that make it suitable for use in outpatient surgery centers. PMID- 26614919 TI - Does Malrotation of the Tibial and Femoral Components Compromise Function in Kinematically Aligned Total Knee Arthroplasty? AB - Internal and external malrotation of the femoral and tibial components is associated with poor function after total knee arthroplasty (TKA). We determined the degree of malrotation for both components in kinematically aligned TKA and whether this malrotation compromised function. Seventy-one patients (mean age 68 years) were followed after TKA. Malrotation was measured. Simple regression determined the association between malrotation and function. Even though the range of malrotation of the tibial component can be greater than that of the femoral component, the malrotation of the femoral and tibial components bounded by the ranges reported in this study is compatible with a well-functioning TKA. PMID- 26614920 TI - The Utility of Increased Constraint in Primary Total Knee Arthroplasty for Obese Patients. AB - Total knee arthroplasty (TKA) for obese patient entails more preoperative comorbidities and complications, and shorter longevity. This article is a retrospective review comparing longevity of the constrained implant with a standard prosthesis. Patient-specific data, Knee Society Scores, complications, and revisions were recorded and compared. No statistical differences were found. The constrained condylar knee for obese patients improves the intramedullary alignment of the prosthesis and supports the surrounding soft tissues. The clinical results are similar to a standard implant in the nonobese with similar longevity at midterm follow-up. PMID- 26614921 TI - Interlocked Intramedullary Nail Without Fluoroscopy. AB - Surgical Implant Generation Network (SIGN) was founded 15 years ago to create equality of fracture care throughout the world. This is done by education and supply of the appropriate implants and instruments to implement the education. SIGN implants have been used in 150,000 long bone fractures in developing countries. The same implants and instruments are used to provide intramedullary nail interlocking screw fixation in the tibia, femur, and humerus. The design of SIGN implants and the surgical technique are described. PMID- 26614922 TI - Management of Aseptic Tibial and Femoral Diaphyseal Nonunions Without Bony Defects. AB - An evidence-based description of aseptic tibial and femoral diaphyseal nonunions without segmental defects is based on a systematic search of MEDLINE. Aseptic nonunion of the femoral or tibial diaphysis without segmental defects and with an in situ nail, treated with reamed exchange nailing or augmentative plating and bone grafting, has consistently high union rates. Aseptic nonunion without segmental defects and with in situ plate and screw fixation is best managed with revision plate and screw fixation and autogenous bone graft. Various techniques and methods of biological stimulation have relatively high union rates. PMID- 26614923 TI - Surgical Management of Patellar Fractures. AB - The patella plays a crucial role in the extensor mechanism to increase the mechanical advantage of the quadriceps. Fractures can be classified based on displacement, comminution, and fracture pattern, which often guide treatment. Modern treatment options include internal fixation using tension bands with Kirschner wires or cannulated screws, lag screw fixation, partial patellectomy, and rarely total patellectomy. Nondisplaced, closed patellar fractures or fractures with less than 2-mm articular steps can be successfully treated conservatively. Open fractures, articular step of 2 mm or greater, and loss of knee extension are indications for surgical intervention. PMID- 26614924 TI - Management of Distal Femur Fractures in Adults: An Overview of Options. AB - Surgical treatment of periarticular and intra-articular fractures of the distal femur pose a significant challenge to the orthopedic surgeon. The primary goal of surgical treatment remains: restoration of the articular surface to the femoral shaft, while maintaining enough stability and alignment to enable early range of motion and rehabilitation. With appropriate surgical planning, these injuries can be managed with a variety of methods and techniques, while taking into account patients' functional goals, fracture characteristics, health comorbidities, bone quality, and risk of malunion and nonunion. PMID- 26614925 TI - Management of Adult Elbow Fracture Dislocations. AB - Elbow fracture dislocations are complicated injuries that are difficult to manage and fraught with complications. A complete series of radiographs is typically complemented with CT scan to evaluate the elbow and assist preoperative planning. Typically, operative intervention is necessary and a systematic approach to the elbow injuries should be chosen. This article addresses the coronoid and proceeds to the radial head, lateral soft tissues, and finally the medial ligaments if elbow instability persists. With a focused, systematic surgical approach, improved outcomes have been demonstrated and patients may recover full function and range of motion in the affected elbow. PMID- 26614926 TI - Management of the Morel-Lavallee Lesion. AB - Morel-Lavallee lesions are closed degloving injuries sustained during violent soft tissue shear that separate the subdermal fat from its strong underlying fascia. Lesions most often occur in the peritrochanteric region, and patients may have concomitant polytrauma. As a result, a hematoma develops that has a high rate of acute bacterial colonization and chronic recurrence. Conservative treatment outcomes are best for those managed acutely. However, diagnosis is often delayed or missed. Furthermore, there is no universally accepted treatment algorithm. Diagnosis and treatment depend on a surgeon's thorough understanding of the cause, pathophysiology, imaging characteristics, and treatment options of Morel-Lavallee lesions. PMID- 26614927 TI - Management of Major Traumatic Upper Extremity Amputations. AB - Traumatic upper extremity amputation is a life-altering event, and recovery of function depends on proper surgical management and postoperative rehabilitation. Many injuries require revision amputation and postoperative prosthesis fitting. Care should be taken to preserve maximal length of the limb and motion of the remaining joints. Skin grafting or free tissue transfer may be necessary for coverage to allow preservation of length. Early prosthetic fitting within 30 days of surgery should be performed so the amputee can start rehabilitation while the wound is healing and the stump is maturing. Multidisciplinary care is essential for the overall care of the patient following a traumatic amputation of the upper limb. PMID- 26614928 TI - Application of Tranexamic Acid in Trauma and Orthopedic Surgery. AB - Tranexamic acid has gained recent interest in orthopedics and trauma surgery because of its demonstrated benefit in several clinical trials. It is inexpensive and effective at reducing blood loss and blood transfusion requirements without a significant increase in morbidity or mortality. The optimal timing, dosing, and route of administration in orthopedics are yet to be elucidated. Significant investigation of tranexamic acid use in joint replacement and spine surgery has promoted its incorporation into the everyday practice of many of these surgeons. The paucity of studies regarding its use in orthopedic trauma has limited its integration into a field that may stand to benefit most from the drug. PMID- 26614929 TI - Classification of Lateral Patellar Instability in Children and Adolescents. AB - There is significant heterogeneity in the literature related to the causes and treatment of patellar instability. To address the multifactorial issue of patellar instability, the first task is to classify the instability pattern. Once a classification system is developed, future studies can differentiate between treatment recommendations and outcomes for each instability pattern. Existing classification systems do not include the entire spectrum of patellar instability patterns. The aim of this article is to review the nomenclature and existing patellar instability classification systems and analyze the different patterns into a comprehensive system. PMID- 26614930 TI - Congenital Anomalies of the Hand--Principles of Management. AB - Physicians who specialize in pediatric orthopedics and hand surgery frequently encounter congenital hand abnormalities, despite their relative rarity. The treating physician should be aware of the associated syndromes and malformations that may, in some cases, be fatal if not recognized and treated appropriately. Although these congenital disorders have a wide variability, their treatment principles are similar in that the physician should promote functional use and cosmesis for the hand. This article discusses syndactyly, preaxial polydactyly and post-axial polydactyly, and the hypoplastic thumb. PMID- 26614931 TI - Immobilization After Rotator Cuff Repair: What Evidence Do We Have Now? AB - Recurrent tears after rotator cuff repair are common. Postoperative rehabilitation after rotator cuff repair is a modifiable factor controlled by the surgeon that can affect re-tear rates. Some surgeons prefer early mobilization after rotator cuff repair, whereas others prefer a period of immobilization to protect the repair site. The tendon-healing process incorporates biochemical and biomechanical responses to mechanical loading. Healing can be optimized with controlled loading. Complete load removal and chronic overload can be deleterious to the process. Several randomized clinical studies have also characterized the role of postoperative mobilization after rotator cuff repair. PMID- 26614932 TI - Posterior Shoulder Instability in Overhead Athletes. AB - Posterior shoulder instability in overhead athletes presents a unique and difficult challenge. Often, this group has an inherent capsular laxity and/or humeral retroversion to accommodate the range of motion necessary to throw. This adaptation makes the diagnosis of posterior capsulolabral pathology challenging, as the examiner must differentiate between adaptive capsular laxity and pathologic instability. Further complicating matters, the intraoperative surgeon must find the delicate balance of achieving stability while still allowing the necessary range of motion. PMID- 26614933 TI - Surgical Treatment of Distal Biceps Ruptures. AB - Distal biceps ruptures occur from eccentric loading of a flexed elbow. Patients treated nonoperatively have substantial loss of strength in elbow flexion and forearm supination. Surgical approaches include 1-incision and 2-incision techniques. Advances in surgical technology have facilitated the popularity of single-incision techniques through a small anterior incision. Recently, there is increased focus on the detailed anatomy of the distal biceps insertion and the importance of anatomic repair in restoring forearm supination strength. Excellent outcomes are expected with early repair of the distal biceps, with restoration of strength and endurance to near-normal levels with minimal to no loss of motion. PMID- 26614934 TI - Prosthetic Design in Total Wrist Arthroplasty. AB - Total wrist arthroplasty (TWA) provides a motion-preserving alternative to total wrist arthrodesis for low-demand patients with debilitating pancarpal arthritis. The earlier generation total wrist implants had high complication and failure rates. Advances in prosthetic design have contributed to improved clinical outcomes and implant survivorship. The current fourth-generation implants allow for expansion of indications for TWA. Careful patient selection remains critical; patients with high-demand lifestyles and poor bone stock may not be candidates. Long-term studies on implant survival and patient outcomes are critical for the current generation total wrist implants in assessing their long-term value compared with total wrist arthrodesis. PMID- 26614935 TI - Flexor Tendon Repair: Healing, Biomechanics, and Suture Configurations. AB - Successful outcome after flexor tendon repair requires a delicate balance between tendon healing and limiting scar tissue formation. Recent studies have highlighted the importance of the number of core sutures crossing the repair and the benefits of specific suture configurations in determining the strength of tendon repair. Researchers have attempted to augment the biological environment to improve the speed and strength of tendon repair. PMID- 26614937 TI - Optimal Positioning for Volar Plate Fixation of a Distal Radius Fracture: Determining the Distal Dorsal Cortical Distance. AB - Distal radius fractures are currently among the most common fractures of the musculoskeletal system. With a population that is living longer, being more active, and the increasing incidence of osteoporosis, these injuries will continue to become increasingly prevalent. When operative fixation is indicated, the volar locking plate has recently become the treatment of choice. However, despite its success, suboptimal position of the volar locking plate can still result in radiographic loss of reduction. The distal dorsal cortical distance is being introduced as an intraoperative radiographic tool to help optimize plate position and minimize late loss of fracture reduction. PMID- 26614936 TI - Scapholunate Advanced Collapse: Motion-Sparing Reconstructive Options. AB - Scapholunate advanced collapse (SLAC) is a predictable pattern of degenerative wrist arthritis that develops as a result of scapholunate dissociation. The purpose of this article is to review outcomes for the various motion-sparing surgical treatments for SLAC wrist. PMID- 26614938 TI - Open Fractures of the Hand: Review of Pathogenesis and Introduction of a New Classification System. AB - Open fractures of the hand are a common and varied group of injuries. Although at increased risk for infection, open fractures of the hand are more resistant to infection than other open fractures. Numerous unique factors in the hand may play a role in the altered risk of postinjury infection. Current systems for the classification of open fractures fail to address the unique qualities of the hand. This article proposes a novel classification system for open fractures of the hand, taking into account the factors unique to the hand that affect its risk for developing infection after an open fracture. PMID- 26614939 TI - Innovations in Intraoperative Tumor Visualization. AB - In the surgical management of solid tumors, adequacy of tumor resection has implications for local recurrence and survival. The standard method of intraoperative identification of tumor margin is frozen section pathologic analysis, which is time-consuming with potential for sampling error. Intraoperative tumor visualization has the potential to significantly improve surgical cancer care across disciplines, by guiding accuracy of biopsies, increasing adequacy of resections, directing adjuvant therapy, and even providing diagnostic information. We provide an outline of various methods of intraoperative tumor visualization developed to aid in the real-time assessment of tumor extent and adequacy of resection. PMID- 26614940 TI - Reconstruction After Tumor Resection in the Growing Child. AB - Limb preservation surgery has gained acceptance as a viable alternative to amputation for the treatment of extremity bone tumors in the growing child. There are several options for reconstructing the potential loss of a physis and the defect created by tumor excision. Metallic endoprosthesis, massive allograft, and allograft-prosthesis composites have been described in the skeletally immature population. With the development of expandable prostheses, even those far from skeletal maturity may be candidates for limb salvage. However, improvements in the literature are needed, including reporting surgical and functional outcomes in a rigorous manner, specific to age, anatomic location, and reconstruction. PMID- 26614941 TI - Update on Survival in Osteosarcoma. AB - Osteosarcoma is the most common primary bone malignancy in children. Treatment has evolved to include systemic chemotherapy and local control surgery. Although survival improved initially in a drastic fashion with this approach, recent decades have seen little to no further gains in this area. Limb salvage surgery evolved with effective chemotherapy and advances in imaging, and continues to improve in the recent era. This article serves as a review of survival in high grade osteosarcoma: prognostic factors, advances in chemotherapy and surgery, late effects of chemotherapy and surgery in survivors, and future directions. PMID- 26614942 TI - Preface. PMID- 26614944 TI - Going Out with a Bang. PMID- 26614945 TI - Patellar Instability. PMID- 26614946 TI - Preface. PMID- 26614947 TI - Preface. PMID- 26614948 TI - Oral and Maxillofacial Imaging. AB - This article provides the reader with the knowledge and skills of identification and diagnostic interpretative skills using planar images, tomographic images, CBCT, MDCT, pertinent MR images, as well as bone scans and PET images. The goal is to provide sufficient in-depth knowledge of the technique, anatomy, and radiographic identifiers for the diagnosis of local and systemic pathoses. The information will train the reader to be an advocate of selection criteria as well as a follower of the "Image Gently" campaign and philosophy supported by the organized dentistry in the United States, especially in Diagnostic Radiology. PMID- 26614949 TI - Developmental Disorders Affecting Jaws. AB - Teeth are housed in mandible and maxilla and are known to undergo variations in clinical presentation depending on the degree of abnormality during growth and development. It is essential to identify these variations in normal anatomy so that appropriate treatment can be initiated to address the anomaly. Some normal anatomic variations are harmless and best left alone, whereas others require intervention. Radiology plays a vital role in identification of such anomalies. This article focuses on the diagnostic radiographic interpretation and strategies to include pertinent differential diagnosis. Also discussed is the importance of advanced imaging and its appropriateness in the diagnosis and interpretation. PMID- 26614950 TI - Radiologic Assessment of the Periodontal Patient. AB - Periodontal examination involves evaluation of soft and hard tissue parameters to gauge gingival inflammatory changes and quantify attachment loss. Conventional radiographs are vital components of this process and can be used to assess the presence of calculus and other local factors to establish a diagnosis, prognosis, and periodontal treatment plan. The 2-dimensional nature of these images limits their utility. The advent of high-resolution cone beam computed tomography (CBCT) offers 3-dimensional images that might overcome these limitations. We discuss the use of conventional radiographic techniques as well as CBCT for evaluating, diagnosing, and treatment planning patients presenting for periodontal and/or implant therapy. PMID- 26614951 TI - Temporomandibular Joint Disorders and Orofacial Pain. AB - Temporomandibular disorders (TMD) affect 5% to 12% of the United States population. This article discusses common conditions related to temporomandibular joints, including disc displacements, inflammatory disturbances, loose joint bodies, traumatic disturbances, and developmental conditions. Also addressed are the appropriate imaging modalities and diagnostic criteria for TMD. PMID- 26614952 TI - Benign Jaw Lesions. AB - There are both odontogenic and nonodontogenic benign lesions in the maxilla and mandible. These lesions may have similar imaging features, and the key radiographic features are presented to help the clinician narrow the differential diagnosis and plan patient treatment. Both intraoral and panoramic radiographs and advanced imaging features are useful in assessing the benign lesions of the jaws. The location, margins, internal contents, and effects of the lesions on adjacent structures are important features in diagnosing the lesions. PMID- 26614953 TI - Diagnostic Imaging of Malignant Tumors in the Orofacial Region. AB - Though rare, malignancies of the orofacial region often have serious consequences. Malignancies of the orofacial region are typically discovered during a clinical examination or from a patient complaint. Initial discovery from a radiograph is rare. Three-dimensional imaging using advanced imaging techniques often provides adequate information about the aggressive nature of a lesion. Radiographically based imaging demonstrates mainly hard-tissue destruction and, rarely, bone deposition. MRI provides excellent visualization of soft-tissue densities without using ionizing radiation. Functional imaging is used to visualize increased metabolic activity associated with malignancies, and is excellent for determining the metastatic spread of a lesion. PMID- 26614954 TI - Benign Fibro-Osseous Lesions of the Jaws. AB - Fibro-osseous lesions are grouped together because histologically they show similar cellular and mineralization patterns. Despite the histologic ubiquity, their behaviors vary significantly. Because of the histologic similarity and the broad range of morbidity among them, it is important to be able to differentiate between them in the preliminary diagnostic process. The radiographic presentations along with the location of the bony changes are often extremely critical diagnostic features to help render a differential or working diagnosis in lieu of an automatic biopsy procedure. Therefore the unique and specific radiographic presentations may be one of the main criteria for preliminary diagnosis. PMID- 26614955 TI - Granulomatous Diseases Affecting Jaws. AB - The common aspect of all granulomatous diseases is the typical form of chronic inflammatory response with distinct microscopic granulomas that are formed secondary to either definitive etiologic agents, like bacteria, fungal, or parasitic, or due to an unknown etiologic agent, such as trauma, autoimmune, or even neoplastic process. Although they can be histologically distinct, granulomatous diseases demonstrate a variety of clinical features that may not seem to be inflammatory. Two types of granulomas are typically encountered: foreign body granulomas and immune granulomas. The differences between the two types of granulomas lie in the pathogenesis. PMID- 26614956 TI - Systemic Diseases and Conditions Affecting Jaws. AB - This article discusses the radiographic manifestation of jaw lesions whose etiology may be traced to underlying systemic disease. Some changes may be related to hematologic or metabolic disorders. A group of bone changes may be associated with disorders of the endocrine system. It is imperative for the clinician to compare the constantly changing and dynamic maxillofacial skeleton to the observed radiographic pathology as revealed on intraoral and extraoral imagery. PMID- 26614958 TI - Diagnostic Imaging in Dentistry. PMID- 26614957 TI - Chemical and Radiation-Associated Jaw Lesions. AB - Osteonecrosis of the jaw is a major public health concern throughout the world. Use of radiotherapy for head and neck cancer and bone antiresorptives and antiangiogenic agents have increased its incidence. Medication-related osteonecrosis of the jaw is more common relative to other types of osteonecrosis. Osteoradionecrosis occurs despite better treatment planning and shielding to minimize collateral damage to bone. Other related necrotic lesions are secondary to usage of recreational drugs and steroids. This article provides comprehensive information about these different types of bone necrosis; provides the readers with radiographic diagnostic criteria and updates on current theories on pathophysiology of osteonecrosis. PMID- 26614959 TI - Celebrity, the media, and HIV--not always easy bedfellows. PMID- 26614960 TI - Uptake and effectiveness of PrEP for transgender women. PMID- 26614961 TI - Tackling latency as a barrier to an HIV cure: what next? PMID- 26614962 TI - HIV and tuberculosis in children: biology meets epidemiology. PMID- 26614963 TI - Mortality in migrants with HIV in western Europe. PMID- 26614964 TI - Should HIV testing week be blood-borne-virus testing week? PMID- 26614967 TI - Prevalence, incidence, and associated risk factors of tuberculosis in children with HIV living in the UK and Ireland (CHIPS): a cohort study. AB - BACKGROUND: Tuberculosis is the most common serious co-infection in people living with HIV worldwide, but little is known about its incidence in HIV-infected children living in high-resource settings with low tuberculosis prevalence. We aimed to assess the incidence and prevalence of tuberculosis in children with HIV living in the UK and Ireland to understand rates, risk factors, and outcomes of the disease in this group. METHODS: We did an analysis of children enrolled in CHIPS, an observational multicentre cohort of children receiving HIV care in the UK and Ireland. We assessed characteristics and prevalence of tuberculosis at baseline, measured incidence of disease through the follow-up period using the CHIPS database, and calculated associated risk factors in these children with multivariable logistic and Cox regression models. FINDINGS: Between Jan 1, 1996, to Sept 18, 2014, data for 1848 children with 14 761 years of follow-up were reported to CHIPS. 57 (3%) children were diagnosed with tuberculosis: 29 children had tuberculosis at presentation (prevalent tuberculosis) and 29 had the disease diagnosed during follow-up (incident tuberculosis), including one child with recurrent tuberculosis events. Median age at diagnosis was 9 years (IQR 5-12). 25 (43%) children had pulmonary tuberculosis, 24 (41%) had extrapulmonary tuberculosis with or without pulmonary involvement, and the remainder (n=9; 16%) had unspecified-site tuberculosis. The overall incidence rate for the follow-up period was 196 cases per 100 000 person-years (95% CI 137-283). In our multivariable model, tuberculosis at presentation was associated with more severe WHO immunological stage at baseline (odds ratio 0.25, 95% CI 0.08-0.74; p=0.0331; for none vs severe) and being born abroad (odds ratio 0.28, 0.10-0.73; p=0.0036; for UK and Ireland vs abroad). Incident tuberculosis was associated with time updated more severe WHO immunological stage (hazard ratio 0.15, 95% CI 0.06-0.41; p=0.0056; for none vs severe) and older age at baseline (1.11, 0.47-2.63; p=0.0027; for age >10 years vs 5-9 years). INTERPRETATION: Tuberculosis rates in HIV-infected children in the UK and Ireland were higher than those reported in the general paediatric population. Further study is warranted of tuberculosis screening and preventive treatment for children at high-risk of this disease to avoid morbidity and mortality in this population. FUNDING: NHS England, PENTA Foundation. PMID- 26614965 TI - HIV pre-exposure prophylaxis in transgender women: a subgroup analysis of the iPrEx trial. AB - BACKGROUND: Pre-exposure prophylaxis (PrEP) with oral emtricitabine and tenofovir disoproxil fumarate is used to prevent the sexual acquisition of HIV in groups at high risk such as transgender women. We used data from the iPrEx study to assess PrEP efficacy, effectiveness, and adherence in transgender women. METHODS: The iPrEx trial was a randomised controlled trial of PrEP with oral emtricitabine plus tenofovir disoproxil fumarate compared with placebo in men who have sex with men (MSM) and transgender women, followed by an open-label extension. Drug concentrations were measured in blood by liquid chromatography and tandem mass spectroscopy. We did unplanned exploratory analyses to investigate differences in PrEP outcomes among transgender women and between transgender women and MSM. FINDINGS: Of the 2499 participants enrolled in the randomised controlled trial, 29 (1%) identified as women, 296 (12%) identified as trans, 14 (1%) identified as men but reported use of feminising hormones, such that 339 (14%) reported one or more characteristics and are classified as transgender women for the purpose of this study. Compared with MSM, transgender women more frequently reported transactional sex, receptive anal intercourse without a condom, or more than five partners in the past 3 months. Among transgender women, there were 11 HIV infections in the PrEP group and ten in the placebo group (hazard ratio 1.1, 95% CI 0.5-2.7). In the PrEP group, drug was detected in none of the transgender women at the seroconversion visit, six (18%) of 33 seronegative transgender women (p=0.31), and 58 (52%) of 111 seronegative MSM (p<0.0001). PrEP use was not linked to behavioural indicators of HIV risk among transgender women, whereas MSM at highest risk were more adherent. INTERPRETATION: PrEP seems to be effective in preventing HIV acquisition in transgender women when taken, but there seem to be barriers to adherence, particularly among those at the most risk. Studies of PrEP use in transgender women populations should be designed and tailored specifically for this population, rather than adapted from or subsumed into studies of MSM. FUNDING: US National Institutes of Health and the Bill & Melinda Gates Foundation. PMID- 26614966 TI - Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study. AB - BACKGROUND: In vitro, disulfiram activated HIV transcription in a primary T-cell model of HIV latency and in a pilot clinical study increased plasma HIV RNA in individuals with adequate drug exposure. We assessed the effect of disulfiram on HIV transcription in a dose-escalation study. METHODS: In this prospective dose escalation study, to optimise disulfiram exposure we included adults with HIV on suppressive antiretroviral therapy, with plasma HIV RNA of less than 50 copies per mL and a CD4 cell count greater than 350 cells per MUL. Participants were allocated sequentially to one of three dosing groups (500 mg, 1000 mg, and 2000 mg) and received disulfiram daily for 3 days. Only the staff who did laboratory assays were masked to group assignment. The primary endpoint was change in cell associated unspliced HIV RNA in CD4 cells. The primary analysis method was a negative binomial regression, with the number of copies as the outcome variable and the input total RNA or plasma volume as an exposure variable, which is equivalent to modelling copies or input. We used these models to estimate changes from before disulfiram to timepoints during and after disulfiram administration. This study is registered with ClinicalTrials.gov, number NCT01944371. FINDINGS: Of 34 participants screened for eligibility at The Alfred Hospital (Melbourne, VIC, Australia), and San Francisco General Hospital (San Francisco, CA, USA), 30 people were enrolled between Sept 24, 2013, and March 31, 2014. The estimated fold increases in cell-associated unspliced HIV RNA from baseline were 1.7 (95% CI 1.3-2.2; p<0.0001) to the timepoint during disulfiram treatment and 2.1 (1.5 2.9; p<0.0001) to the timepoint after disulfiram in the 500 mg group; 1.9 (1.6 2.4; p<0.0001) and 2.5 (1.9-3.3; p<0.0001) in the 1000 mg group; and 1.6 (1.2 2.1; p=0.0026) and 2.1 (1.5-3.1; p=0.0001) in the 2000 mg group. No deaths occurred, and no serious adverse events were noted. Disulfiram was well tolerated at all doses. INTERPRETATION: Short-term administration of disulfiram resulted in increases in cell-associated unspliced HIV RNA at all doses, consistent with activating HIV latency. Disulfiram may be suited for future studies of combination and prolonged therapy to activate latent HIV. FUNDING: The Foundation for AIDS Research (amfAR); National Institute of Allergy and Infectious Diseases, National Institutes of Health; Australian National Health and Medical Research Council. PMID- 26614969 TI - Is nitrification the only cause of microbiologically induced chloramine decay? AB - Ammonia degradation was investigated in three batch reactors with differing initial concentrations of bacteria present in the same filtered water source based on pre-treatment filtration techniques. The potential for the bacterial community to degrade the ammonia present was determined in the absence of monochloramine, simulating a distribution system where a loss of disinfectant residual has occurred. Nitrification was observed in only one of the three batch reactors, whereas rapid microbiologically induced chloramine decay was present in two reactors. Results suggest that the microbial decay factor is not a valid tool for indication of nitrification, but may be used as an indicator of the occurrence of rapid monochloramine decay. Intact bacterial cell numbers did not to correlate with changes in ammonia, nitrite or nitrate concentrations and hence did not correlate with the nitrification observed. Neither use of the microbial decay factor or monitoring of ammonia oxidising prokaryotes provided an early indication for the occurrence of nitrification. Hence, monitoring of ammonia and nitrite would still be the most suitable tool for indicating nitrification. PMID- 26614968 TI - Mortality in migrants living with HIV in western Europe (1997-2013): a collaborative cohort study. AB - BACKGROUND: Many migrants face adverse socioeconomic conditions and barriers to health services that can impair timely HIV diagnosis and access to life-saving treatments. We aimed to assess the differences in overall mortality by geographical origin in HIV-positive men and women using data from COHERE, a large European collaboration of HIV cohorts from 1997 to 2013. METHODS: In this observational cohort study, we included HIV-positive, antiretroviral-naive people accessing care in western Europe from COHERE. Individuals were eligible if enrolled in a cohort that collected information on geographical origin or ethnic origin from Jan 1, 1997, to March 19, 2013, aged 18-75 years, they had available information about sex, they were not infected perinatally or after the receipt of clotting factor concentrates, and were naive to combination antiretroviral therapy at cohort entry. Migrants' origins were grouped into seven regions: western Europe and similar countries (Australia, Canada, New Zealand, and the USA); eastern Europe; North Africa and the Middle East; sub-Saharan Africa; Latin America; the Caribbean; and Asia and the rest of Oceania (excluding Australia and New Zealand). Crude and adjusted mortality rate ratios were calculated by use of Poisson regression stratified by sex, comparing each group with the native population. Multiple imputation with chained equations was used to account for missing values. FINDINGS: Between Oct 25, 1979, and March 19, 2013, we recruited 279 659 individuals to the COHERE collaboration in EuroCoord. Of these 123 344 men and 45 877 women met the inclusion criteria. Our data suggested effect modification by transmission route (pinteraction=0.12 for men; pinteraction=0.002 for women). No significant difference in mortality was identified by geographical origin in men who have sex with men. In heterosexual populations, most migrant men had mortality lower than or equal to that of native men, whereas no group of migrant women had mortality lower than that in native women. High mortality was identified in heterosexual men from Latin America (rate ratio [RR] 1.46, 95% CI 1.00-2.12, p=0.049) and heterosexual women from the Caribbean (1.48, 1.29-1.70, p<0.0001). Compared with that in the native population, mortality in injecting drug users was similar or low for all migrant groups. INTERPRETATION: Characteristics of and risks faced by migrant populations with HIV differ for men and women and for populations infected heterosexually, by sex between men, or by injecting drug use. Further research is needed to understand how inequalities are generated and maintained for the groups with higher mortality identified in this study. FUNDING: EuroCoord. PMID- 26614971 TI - Reply to Commentary by Strandvik: 'The development of infants born to obese mothers might be related to omega-3 fatty acid status'. PMID- 26614972 TI - A Psychophysiological Case Study of Orchestra Conductors. AB - The psychological and physiological effects of performance were investigated in two professional orchestral conductors, with data collected prior to, during, and after a rehearsal and a public performance. The participants were given a battery of psychological self-report tests (anxiety, dissociation, health inventory, fantasy proneness, shame, and flow). Ambulatory physiological monitoring (Vivometric LifeShirt(r) system) was conducted during both a rehearsal and public performance to gather information about the autonomic nervous system and heart rate variability (HRV). One conductor had a history of asthma and anxiety, and the second conductor had coronary artery disease. The results revealed within subject and between-subject differences in autonomic nervous system responses and HRV during several conditions (pre-performance rest, stair-climbing, rehearsal, and performance). Based on heart rate, the physiological demands of professional conducting are reflective of work intensities considered "hard." Both conductors experienced high flow states. Anxiety and coronary artery disease may have attenuated HRV resilience in this study. It is recommended that noninvasive methods be implemented to assess cardiac autonomic activity in professional conductors, particularly during engagement in their professional activities. The findings suggest a need to further study anxiety, respiratory conditions, and cardiovascular risks for conductors. PMID- 26614970 TI - Hydrogen Sulfide Is a Novel Regulator of Bone Formation Implicated in the Bone Loss Induced by Estrogen Deficiency. AB - Hydrogen sulfide (H2 S) is a gasotransmitter known to regulate bone formation and bone mass in unperturbed mice. However, it is presently unknown whether H2 S plays a role in pathologic bone loss. Here we show that ovariectomy (ovx), a model of postmenopausal bone loss, decreases serum H2 S levels and the bone marrow (BM) levels of two key H2 S-generating enzymes, cystathione beta-synthase (CBS) and cystathione gamma-lyase (CSE). Treatment with the H2 S-donor GYY4137 (GYY) normalizes serum H2 S in ovx mice, increases bone formation, and completely prevents the loss of trabecular bone induced by ovx. Mechanistic studies revealed that GYY increases murine osteoblastogenesis by activating Wnt signaling through increased production of the Wnt ligands Wnt16, Wnt2b, Wnt6, and Wnt10b in the BM. Moreover, in vitro treatment with 17beta-estradiol upregulates the expression of CBS and CSE in human BM stromal cells (hSCs), whereas an H2 S-releasing drug induces osteogenic differentiation of hSCs. In summary, regulation of H2 S levels is a novel mechanism by which estrogen stimulates osteoblastogenesis and bone formation in mice and human cells. Blunted production of H2 S contributes to ovx induced bone loss in mice by limiting the compensatory increase in bone formation elicited by ovx. Restoration of H2 S levels is a potential novel therapeutic approach for postmenopausal osteoporosis. (c) 2015 American Society for Bone and Mineral Research. PMID- 26614973 TI - Job-Related Stressors of Classical Instrumental Musicians: A Systematic Qualitative Review. AB - Epidemiological studies among performing artists have found elevated stress levels and health effects, but scarcely the full range of stressors has been reported. We review here the existing literature on job-related stressors of classical instrumental musicians (orchestra musicians). PubMed, Google Scholar and JSTOR databases were screened for relevant papers indexed up to August 2012. A total of 122 papers was initially identified which, after exclusion of duplicates and those not meeting eligibility criteria, yielded 67 articles for final analysis. We identified seven categories of stressors affecting musicians in their everyday working lives: public exposure, personal hazards, repertoire, competition, job context, injury/illness, and criticism, but with interrelated assigned factors. The proposed categories provide a framework for future comprehensive research on the impact and management of musician stressors. PMID- 26614974 TI - Anxiety's Effect on Muscle Activation and Fatigue in Trumpet Players: A Pilot Study. AB - Due to the high percentage of musicians who suffer from musculoskeletal disorders, there is a need for more research in the field of music and medicine. The purpose of this study was to analyze the possible relationship between anxiety, muscle activation, and muscle fatigue in undergraduate trumpet players. Assessment tools included surface electromyography (sEMG) data, State Trait Anxiety Inventory (STAI), and Visual Analogue Scales (VAS) of perceived anxiety. Data were collected from 27 undergraduate music students across five universities (22 males, 5 females) aged 18 to 24 years. The three muscles targeted by the sEMG were the upper trapezius, sternocleidomastoid, and masseter muscles. Participants were randomly divided into two single-blinded groups: (1) anxiety-induction and (2) control. The anxiety-induction group was instructed to play as accurately as possible and informed that mistakes were being counted and evaluated, while the control group was instructed to play without any concern for possible mistakes. The anxiety-induction group was shown to have more masseter muscle activation than the control; the anxiety-induction group also displayed a higher fatigue rate in all three muscles versus the controls. Subjects with high perceived anxiety (as measured by VAS) displayed higher masseter activation and higher fatigue rates in the upper trapezius and sternocleidomastoid than non-anxious participants. Despite these notable trends, there was no statistical significance for any of the muscle groups for muscle activation or fatigue. PMID- 26614975 TI - Mortality in American Hip-Hop and Rap Recording Artists, 1987-2014. AB - BACKGROUND: The deaths of American hip-hop and rap recording artists often receive considerable media attention. However, these artists' deaths have not been examined as a distinct group like the deaths of rock, classical, jazz, and pop music artists. This is a seminal epidemiological analysis on the deaths of an understudied group, American hip-hop and rap music recording artists. METHODS: Media reports were analyzed of the deaths of American hip-hop and rap music recording artists that occurred from January 1, 1987 to December 31, 2014. The decedents' age, sex, race, cause of death, stage names, and city and state of death were recorded for analysis. RESULTS: The most commonly reported cause of death was homicide. The 280 deaths were categorized as homicide (55%), unintentional injury (13%), cardiovascular (7%), undetermined/undisclosed (7%), cancer (6%), other (5%), suicide (4%), and infectious disease (3%). The mean reported age at death was 30 yrs (range 15-75) and the median was 29 yrs; 97% were male and 92% were black. All but one of the homicides were committed with firearms. CONCLUSIONS: Homicide was the most commonly reported cause of death. Public health focus and guidance for hip-hop and rap recording artists should mirror that for African-American men and adolescent males ages 15-54 yrs, for whom the leading causes of death are homicide, unintentional injury, and heart disease. Given the preponderance of homicide deaths in this analysis, premature mortality reduction efforts should focus on violence prevention and conflict mitigation. PMID- 26614976 TI - Use of a Textured Insole to Improve the Association Between Postural Balance and Ankle Discrimination in Young Male and Female Dancers. AB - Ballet dancers require a high level of postural balance (PB) and proprioception ability during performance. As textured insoles inserted into ballet shoes were found to improve proprioception ability, and better proprioceptive acuity was associated with better PB, the aim of the present study was to investigate whether the association between ankle inversion movement discrimination (AIMD) and PB changed following wearing textured insoles in young male and female dancers. METHODS: Forty-four dancers from the Australian Ballet School, ages 14 19 yrs, were tested for static and dynamic PB and AIMD under two conditions: in ballet shoes, and in ballet shoes with textured insoles inserted. RESULTS: Female dancers demonstrated a significant inverse relationship between AIMD and static PB in the medio-lateral direction when wearing ballet shoes, but not when wearing textured insoles. Male dancers showed a non-monotonic relationship when tested with ballet shoes only, but a significant inverse relationship between AIMD and dynamic PB in the vertical direction and with the waist/head cross-correlation acceleration in the three movement directions when they were tested with textured insoles. CONCLUSIONS: Male dancers demonstrated an improved association between dynamic PB and proprioception ability when using textured insoles, suggesting that the increased afferent information from the plantar surface had a beneficial effect on proprioception feedback about their PB. Conversely, for female dancers, that association was present when wearing ballet shoes, but not when using textured insoles, suggesting that the increased afferent information for female dancers who already had high proprioception ability was "overloaded" by wearing the textured insoles. PMID- 26614977 TI - Self-Reported Injury and Management in a Liberal Arts College Dance Department. AB - Dancers often view injuries as a necessary sacrifice for participating in their art form. The purpose of this research was to determine the frequency and patterns of injury in a non-conservatory, liberal arts dance environment. These data may enable dance departments to provide more effective health resources. METHODS: Dancers registered in technique courses in a liberal arts dance department (including ballet, modern, tap, and jazz) completed an injury questionnaire immediately following the occurrence of any dance-related injury over the course of one semester. RESULTS: Out of 168 students registered in the department, 46 injuries were reported throughout the semester. The greatest rate of injury was in September and December with 0.95 and 0.65 injuries reported per day, respectively. 89.1% of participants indicated that they would use a direct access, on-campus physical therapist or athletic trainer if available, though 45.7% of injured participants indicated that they would seek treatment off campus. CONCLUSIONS: Dancers in a liberal arts collegiate program may train at a higher intensity during the semester than summer break, which likely accounts for the high incidence of injury in September. Of those injured, most planned on self treating, but none planned on missing class. Pre-semester screening and post semester cross-training education should be implemented in liberal arts dance programs to help decrease the rate of injury seen when returning to dance following prolonged time off from dancing. Additionally, direct access to physical therapy or athletic training treatment would likely be utilized by these students if available. PMID- 26614979 TI - Conditioning Methodologies for DanceSport: Lessons from Gymnastics, Figure Skating, and Concert Dance Research. AB - OBJECTIVES: Dancesport, the competitive branch of ballroom dancing, places high physiological and psychological demands on its practitioners, but pedagogical resources in these areas for this dance form are limited. Dancesport competitors could benefit from strategies used in other aesthetic sports. In this review, we identify conditioning methodologies from gymnastics, figure skating, and contemporary, modern, and ballet dance forms that could have relevance and suitability for dancesport training, and propose several strategies for inclusion in the current dancesport curriculum. METHODS: We reviewed articles derived from Google Scholar, PubMed, ScienceDirect, Taylor & Francis Online, and Web of Science search engines and databases, with publication dates from 1979 to 2013. The keywords included MeSH terms: dancing, gymnastics, physiology, energy metabolism, physical endurance, and range of motion. Out of 47 papers examined, 41 papers met the inclusion criteria (validity of scientific methods, topic relevance, transferability to dancesport, publication date). Quality and validity of the data were assessed by examining the methodologies in each study and comparing studies on similar populations as well as across time using the PRISMA 2009 checklist and flowchart. RESULTS: The relevant research suggests that macro cycle periodization planning, aerobic and anaerobic conditioning, range of motion and muscular endurance training, and performance psychology methods have potential for adaptation for dancesport training. CONCLUSIONS: Dancesport coaches may help their students fulfill their ambitions as competitive athletes and dance artists by adapting the relevant performance enhancement strategies from gymnastics, figure skating, and concert dance forms presented in this paper. PMID- 26614978 TI - The Musician as (In)Active Athlete?: Exploring the Association Between Physical Activity and Musculoskeletal Complaints in Music Students. AB - OBJECTIVE: Musicians are often compared to athletes because of the physical exertion required to play music. The aim of this study was to explore the physical activity level of music students and to study its relationship with musculoskeletal complaints. A second goal was to assess associations between physical activity and pain, quality of life, and disability. METHODS: This cross sectional study among third- and fourth-year music students used an electronic survey including measures for physical activity (SQUASH-Short Questionnaire to Assess Health-enhancing physical activity), musculoskeletal complaints (DMQ-Dutch Musculoskeletal Questionnaire), disability (DASH-Disability Arm, Shoulder, Hand questionnaire) and quality of life (Short Form-12). Students were classified as compliers or non-compliers with moderate- and vigorous-intensity physical activity recommendations. Statistical analysis was done using (non)parametric tests (t-test, Pearson chi-square test, Mann-Whitney U-test) and correlational testing. RESULTS: Participants were 132 students, 63.6% female, with a median age of 23 yrs (range 21.3-25.0). 67% reported musculoskeletal complaints in the past 7 days. Their median physical activity level was 6,390 MET-min/wk, and 62% and 10% of the students accomplished recommendations for moderate-intensity and vigorous-intensity physical activity levels, respectively. No significant differences were found in prevalence of musculoskeletal complaints between students who met moderate- or vigorous-intensity physical activity recommendations and students who did not. Physical activity level was not associated with musculoskeletal complaints (r=0.12, p=0.26). Higher pain intensity was associated with a lower quality of life (r=-0.53 p<0.01) and higher disability (r=0.43, p<0.01). CONCLUSIONS: Music students are mainly involved in light- to moderate-intensity physical activities and rarely in vigorous-intensity activities. No correlation was found between physical activity level in the past months and musculoskeletal complaints in music students. PMID- 26614980 TI - Application of Infrared Thermal Imaging in a Violinist with Temporomandibular Disorder. AB - Temporomandibular disorders (TMD) consist of a group of pathologies that affect the masticatory muscles, temporomandibular joints (TMJ), and/or related structures. String instrumentalists, like many orchestra musicians, can spend hours with head postures that may influence the biomechanical behavior of the TMJ and the muscles of the craniocervicomandibular complex (CCMC). The adoption of abnormal postures acquired during performance by musicians can lead to muscular hyperactivity of the head and cervical muscles, with the possible appearance of TMD. Medical infrared thermography is a non-invasive procedure that can monitor the changes in the superficial tissue related to blood circulation and may serve as a complement to the clinical examination. The objective of this study was to use infrared thermography to evaluate, in one subject, the cutaneous thermal changes adjacent to the CCMC that occur before, during, and after playing a string instrument. PMID- 26614981 TI - The Bioethics of Music, the Music of Bioethics. AB - Bioethics is rarely referenced in the scholarship of performing arts medicine (PAM). This essay argues that bioethical concerns loom far larger in the care of PAM patients than might typically be understood. This essay presents Beauchamp and Childress's four principles of bioethics, with examples pertinent to PAM, drawn from the author's research and personal experience. PMID- 26614982 TI - Three Wishes for Performing Arts Healthcare. AB - As I think back over my 30-plus years as a physician and researcher in performing arts healthcare and try to imagine what might happen in the next 30 years, I sometimes fantasize about having three wishes that some supernatural force would grant. While waiting for something like that to happen is not likely to be an effective strategy for improving the health of performing artists around the world, the thought exercise might help to flesh out some ideas that could lead to further progress. While others will come up with different wishes (that I'm sure would be at least as valid), here are mine. PMID- 26614983 TI - The role of defensive ecological interactions in the evolution of conotoxins. AB - Venoms comprise of complex mixtures of peptides evolved for predation and defensive purposes. Remarkably, some carnivorous cone snails can inject two distinct venoms in response to predatory or defensive stimuli, providing a unique opportunity to study separately how different ecological pressures contribute to toxin diversification. Here, we report the extraordinary defensive strategy of the Rhizoconus subgenus of cone snails. The defensive venom from this worm hunting subgenus is unusually simple, almost exclusively composed of alphaD conotoxins instead of the ubiquitous alphaA-conotoxins found in the more complex defensive venom of mollusc- and fish-hunting cone snails. A similarly compartmentalized venom gland as those observed in the other dietary groups facilitates the deployment of this defensive venom. Transcriptomic analysis of a Conus vexillum venom gland revealed the alphaD-conotoxins as the major transcripts, with lower amounts of 15 known and four new conotoxin superfamilies also detected with likely roles in prey capture. Our phylogenetic and molecular evolution analysis of the alphaD-conotoxins from five subgenera of cone snails suggests they evolved episodically as part of a defensive strategy in the Rhizoconus subgenus. Thus, our results demonstrate an important role for defence in the evolution of conotoxins. PMID- 26614984 TI - Pediatric and Adolescent Gynecology in Europe: Clinical Services, Standards of Care, and Training. AB - STUDY OBJECTIVE: To identify current clinical services and training available across Europe within pediatric and adolescent gynecology (PAG) and establish the extent to which PAG services meet current European Board and College of Obstetrics and Gynecology (EBCOG) standards. DESIGN: Quantitative and qualitative questionnaire. SETTING: European countries that are members of the EBCOG and the European Association of Pediatric and Adolescent Gynecology. PARTICIPANTS: Thirty six countries that were approached beginning in September 2013; data were obtained from 27 countries. INTERVENTIONS: Questionnaires with 28 stems were sent to clinical leaders in 36 European countries. MAIN OUTCOME MEASURES: National society, national standards, legislation for female genital mutilation, protocols for transition to adult services, human papilloma virus vaccination programs, sex and contraception education, safeguarding, clinical leads for PAG, delivery of PAG services, and training available for PAG. RESULTS: Of 36 countries, 27 responded. Seventy-seven percent had a national PAG society but only 44% had national standards in PAG. There was agreement that PAG cases should be multidisciplinary but not all have clinical networks in place to facilitate this. Human papilloma virus programs are available in some European countries and not all have legislation against female genital mutilation. A significant proportion of cases continue to be seen in adult gynecology clinics as opposed to designated PAG clinics with only 41% with processes to transfer patients into adult care. CONCLUSION: In this article we provide a framework to explore areas for improvement within PAG services and training across Europe. The EBCOG standards of care are not being adhered to in many countries because processes and clinical networks are not in place to facilitate them. PMID- 26614986 TI - Demographic, socioeconomic and environmental changes affecting circulation of neglected tropical diseases in Egypt. AB - Egypt has been plagued by many neglected tropical diseases since Pharaonic time. These diseases are Schistosomiasis, soil-transmitted helminthiasis, lymphatic filariasis, leishmaniasis and fascioliasis beside the epidermal parasitic skin diseases. Indeed, theses diseases still persist as public health problem in the country by the influence of demographic, socioeconomic and environmental obstacles. This study seeks for understanding the contribution of each factor in each obstacle in neglected tropical diseases perpetuation which in turn could help the governorate in planning integrated control strategies. It was found that poverty, unregulated urbanization and inadequate sanitation are important socioeconomic factors that have great effect on the transmission dynamics of the diseases. The environmental factors which affect the epidemiology of these diseases in the country are scarcity of water, construction of dams, land reclamation for agriculture beside the climate factors. Unfortunately, the panic increase in the population growth rate minimizes the efforts done by the governorate to elevate the public health services. These conditions also affect the transmission of epidermal parasitic skin diseases including scabies, head lice and hookworm-related cutaneous larva migrans. The control programs and the recommendations to combat the diseases were discussed. The present study showed that the ecological factors affecting each neglected tropical disease in Egypt are somewhat similar which makes it worthy to develop an integrated control approaches aiming at improving the leading factors of neglected tropical diseases circulation in the country. PMID- 26614985 TI - Cardiovascular, muscular and perceptual contributions to physical fatigue in prevalent kidney transplant recipients. AB - Physical fatigue is debilitating and common among kidney transplant recipients (KTRs). This study investigated the mechanistic aetiology of physical fatigue in this setting through examinations of muscle mass, muscular and cardiovascular function, and perceived exertion. The incidence of physical fatigue, its association with quality of life (QoL), and the predictors of perceived exertion, were evaluated. This single-centre observational cross-sectional study enrolled 55 KTRs. Muscle mass was quantified using dual-energy x-ray absorptiometry. Muscular function was assessed by jumping mechanography. Cardiovascular function (maximal oxygen consumption and oxygen pulse) was estimated during submaximal exercise testing, with perceived exertion determined using age-adjusted Borg scale-ratings. Physical fatigue was measured using Multi-Dimensional Fatigue Inventory-20. QoL was assessed using Medical Outcomes Study Short Form-36. Demographic, clinical, nutritional, psychosocial and behavioural predictors of perceived exertion were assessed. Of clinical importance, increased perceived exertion was the only independent predictor of physical fatigue (P = 0.001), with no association found between physical fatigue and muscular or cardiovascular parameters. Physical fatigue occurred in 22% of KTRs, and negatively impacted on QoL (P < 0.001). Predictors of heightened perception included anxiety (P < 0.05) and mental fatigue (P < 0.05). Perception is a key determinant of physical fatigue in KTRs, paving the way for future interventions. PMID- 26614987 TI - Phenolic profile and biological potential of Endopleura uchi extracts. AB - OBJECTIVE: To improve the knowledge on the metabolite composition of Endopleura uchi bark, concerning phenolic compounds, and to evaluate some of its biological capacities for further possible exploitation in food and pharmaceutical industries associated to their health-promoting qualities. METHODS: Two different extracts (infusion and hydroethanolic) were studied concerning phenolic composition and biological potential. RESULTS: Five compounds were determined by HPLC-DAD, being bergenin the major one. In general way, infusion presents a greater richness in these metabolites. The antioxidant, acetylcholinesterase, butyrylcholinesterase, alpha-glucosidase and antibacterial activity were checked by in vitro assays. A dose-dependent response was noticed against DPPH, superoxide and nitric oxide radicals, acetylcholinesterase, butyrylcholinesterase and against alpha-glucosidase inhibitory assay. Antibacterial capacity of both extracts was investigated against Gram-positive and Gram-negative bacteria, being more effective against the first one. The concentrations of infusion extract tested here revealed that is non-toxic for intestinal (Caco-2) cells line. CONCLUSIONS: The results suggest that the extracts of Endopleura uchi may be interesting for incorporating in pharmaceutical preparations for human health, since it can suppress hyperglycaemia and inhibit cholinesteases, and or as food additive due to its antiradical and antibacterial activities. PMID- 26614989 TI - Anti-TB drug resistance in Tanga, Tanzania: A cross sectional facility-base prevalence among pulmonary TB patients. AB - OBJECTIVE: To determine the prevalence and risk factors associated with drug resistance tuberculosis (TB) at facility-base level in Tanga, Tanzania. METHODS: A total of 79 Mycobacterium tuberculosis (MTB) isolates included in the study were collected from among 372 (312 new and 60 previously treated) TB suspects self-referred to four TB clinics during a prospective study conducted from November 2012 to January 2013. Culture and drug susceptibility test of the isolates was performed at the institute of medical microbiology and epidemiology of infectious diseases, University hospital, Leipzig, Germany. Data on the patient's characteristics were obtained from structured questionnaire administered to the patients who gave informed verbal consent. Unadjusted bivariate logistic regression analysis was performed to assess the risk factors for drug resistant-TB. The significance level was determined at P < 0.05. RESULTS: The overall proportions of any drug resistance and MDR-TB were 12.7% and 6.3% respectively. The prevalence of any drug resistance and MDR-TB among new cases were 11.4% and 4.3% respectively, whereas among previously treated cases was 22.2% respectively. Previously treated patients were more likely to develop anti-TB drug resistance. There was no association between anti-TB drug resistances (including MDR-TB) with the risk factors analysed. CONCLUSIONS: High proportions of anti-TB drug resistance among new and previously treated cases observed in this study suggest that, additional efforts still need to be done in identifying individual cases at facility-base level for improved TB control programmes and drug resistance survey should continuously be monitored in the country. PMID- 26614988 TI - Roots extracts of Adenophora triphylla var. japonica improve obesity in 3T3-L1 adipocytes and high-fat diet-induced obese mice. AB - OBJECTIVE: To investigate the anti-obesity activity and the action mechanism of the roots of Adenophora triphylla var. japonica extract (ATE) in high-fat diet (HFD)-induced obese mice and 3T3-L1 adipocytes. METHODS: The roots of Adenophora triphylla were extracted with 70% ethanol. To demonstrate the compounds, linoleic acid was analyzed by using gas chromatography; and the anti-obesity effects and possible mechanisms of ATE were examined in 3T3-L1 adipocytes and HFD-induced obese mice. RESULTS: Treatment with ATE inhibited the lipid accumulation without cytotoxicity in 3T3-L1 adipocytes. Furthermore, 200 and 400 mg/kg ATE treatment significantly decreased the body weight gain, white adipose tissues (WATs) weight and plasma triglyceride level, while 100 and 200 mg/kg ATE treatment increased the plasma high-density lipoprotein cholesterol level in the HFD-induced obese mice, as compared with the HFD group. Treatment with 200 and 400 mg/kg ATE also lowered the size of adipocytes in adipose tissue and reduced the lipid accumulation in liver. ATE treatment showed significantly lower expression level of adipogenesis-related proteins, such as peroxisome proliferator-activated receptor gamma, fatty acid binding protein (aP2), fatty acid synthase in 3T3-L1 adipocytes; and furthermore, decreased peroxisome proliferator-activated receptor gamma, aP2, fatty acid synthase, sterol regulatory element binding protein-1c, and lipoprotein lipase mRNA expression levels in WAT of the HFD-induced obese mice. CONCLUSIONS: These results suggested that the ATE has an anti-obesity effect, which may be elicited by regulating the expression of adipogenesis and lipogenesis-related genes and proteins in adipocytes and WAT of the HFD-induced obese mice. PMID- 26614990 TI - In vitro inhibitory effects of plumbagin, the promising antimalarial candidate, on human cytochrome P450 enzymes. AB - OBJECTIVE: To investigate the propensity of plumbagin to inhibit the three isoforms of human cytochrome P450 (CYP), i.e., CYP1A2, CYP2C19, and CYP3A4 using human liver microsomes in vitro. METHODS: Inhibitory effects of plumbagin on the three human CYP isoforms were investigated using pooled human liver microsomes. Phenacetin O-deethylation, omeprazole hydroxylation and nifedipine oxidation were used as selective substrates for CYP1A2, CYP2C19 and CYP3A4 activities, respectively. Concentrations of paracetamol, 5-hydroxyomeprazole, and oxidized nifedipine were determined in microsomal incubation mixture using high performance liquid chromatography. RESULTS: Plumbagin showed significant inhibitory effects on all CYP isoforms, but with the most potent activity on CYP2C19-mediated omeprazole hydroxylation. The IC50 (concentration that inhibits enzyme activity by 50%) values of plumbagin and nootkatone (selective inhibitor) for CYP2C19 were (0.78 +/- 0.01) and (27.31 +/- 0.66) MUM, respectively. The inhibitory activities on CYP1A2-mediated phenacetin O-deethylation and CYP3A4 mediated nifedipine oxidation were moderate. The IC50 values of plumbagin and alpha-naphthoflavone (selective inhibitor) for CYP1A2 were (1.39 +/- 0.01) and (0.02 +/- 0.36) MUM, respectively. The corresponding IC50 values of plumbagin and ketoconazole (selective inhibitor) for CYP3A4 were (2.37 +/- 0.10) and (0.18 +/- 0.06) MUM, respectively. CONCLUSIONS: Clinical relevance of the interference of human drug metabolizing enzymes should be aware of for further development scheme of plumbagin as antimalarial drug when used in combination with other antimalarial drugs which are metabolized by these CYP isoforms. PMID- 26614991 TI - Vibrio spp. from Macrobrachium amazonicum prawn farming are inhibited by Moringa oleifera extracts. AB - OBJECTIVE: To investigate the in vitro antimicrobial potential of extracts of stem, leaves, flowers, pods and seeds of Moringa oleifera (M. oleifera) against Vibrio spp. from hatchery water and the prawn Macrobrachium amazonicum. METHODS: The ethanol extracts of stem, leaves, pods and seeds and chloroform extract of flowers of M. oleifera were tested against Vibrio cholerae (V. cholerae) serogroups non-O1/non-O139 (n = 4), Vibrio vulnificus (n = 1) and Vibrio mimicus (n = 1). Escherichia coli (E. coli) (ATCC((r)) 25922) was used as quality control. Vibrio species were obtained from Macrobrachium amazonicum prawns and from hatchery water from prawn farming. The Minimum Inhibitory Concentration (MIC) was determined by broth microdilution method. RESULTS: The best result was obtained with the ethanol extract of pods, which inhibited three strains of the V. cholerae, Vibrio vulnificus, Vibrio mimicus and E. coli (MIC range 0.312-5.000 mg/mL). The chloroform extract of flowers was effective against all V. cholerae strains and E. coli (MIC range 0.625-1.250 mg/mL). However, the ethanol extracts of stem and seeds showed low effectiveness in inhibiting the bacterial growth. CONCLUSIONS: The extracts of pods, flowers and leaves of M. oleifera have potential for the control of Vibrio spp. Further studies are necessary to isolate the bioactive compounds responsible for this antimicrobial activity. PMID- 26614992 TI - Inhibition effect of miR-577 on hepatocellular carcinoma cell growth via targeting beta-catenin. AB - OBJECTIVE: To investigate the expression and the regulation effect of cell growth of microRNA-577 in hepatocellular carcinoma (HCC). METHODS: qRT-PCR was applied to detect the relative expression of miR-577 in 70 paired HCC and matched tumor adjacent tissues collecting from resection between March 2011 and March 2014. Pearson chi-square test was used to analyze the relationship between the miR-577 expression and clinical features. The miR-577 mimics were transfected into HepG2 cells; cell cycles were detected by flow cytometry, cell proliferation was measured by MTT assay and BrdU incorporation assay, and cell apoptosis was determined by flow cytometry and caspase3/7 activity analysis. The expressions of beta-catenin were measured by immunohistochemistry. Spearman correlation analysis was used to analyze the relationship between miR-577 and beta-catenin. qRT-PCR and western-blot were used to detect the expression of beta-catenin in transfected HepG2 cells. RESULTS: The relative expressions of miR-577 was significantly lower in HCC tissues compared to the matched normal tumor-adjacent tissues (P < 0.05). Low expression of miR-577 was significantly associated with large tumor size (>=5 cm, P < 0.05) and advanced tumor node metastasis stage (III+IV, P < 0.05). Transfection of miR-577 mimics could inhibit repress cell proliferation, enhance cell apoptosis and block the cell cycles in G0/G1 phase (P < 0.05). miR-577 in HCC group had a significant negative correlation relationship with the expression of downstream target of beta-catenin (P < 0.05). Both the mRNA and protein expression in HepG2 cells were down-regulated after transfection (P < 0.05). CONCLUSIONS: Low expression of miR-577 is related to the malignant clinicopathological features in HCC tissues, and miR-577 may suppress HCC growth through down-regulating beta-catenin. PMID- 26614993 TI - Expression of Wnt and NCX1 and its correlation with cardiomyocyte apoptosis in mouse with myocardial hypertrophy. AB - OBJECTIVE: To study the correlation between expression of Wnt and NCX1 and cardiomyocyte apoptosis in mouse with myocardial hypertrophy. METHODS: C57B/16 male mice were given the subcutaneous injection of 1 mg/kg isoprenaline to build the myocardial hypertrophy model. After 14 d of model building, mice were executed by cervical vertebra luxation. The ratio of heart weight/body weight (HW/BW) and heart weight/tibia length (HW/TL) was observed and proved using HE staining that detected the size of cardiomyocytes. 40 male C57B/16 mice were randomly divided into the sham group (normal saline) and model group (isoprenaline), with 20 mice in each group. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling was applied to detect the cardiomyocyte apoptosis; while Western blot and immunohistochemistry were employed to detect the expression of Wnt and NCX1. Meanwhile, the correlation between these two proteins and cardiomyocyte apoptosis was explored. RESULTS: Compared with the sham group, the ratio of HW/BW and HW/TL was increased in the model group, as well as the bigger and hypertrophied cardiomyocytes, decreased number and increased apoptosis of cardiomyocytes, and increased positive expression of Wnt3a, Wnt5a and NCX1 in the cardiac muscle tissue. Besides, there was positive correlation between the expression of Wnt and NCX1 and the cardiomyocyte apoptosis. CONCLUSION: The expression of Wnt3a, Wnt5a and NCX1 in mouse with myocardial hypertrophy is increased and positively correlated with the cardiomyocyte apoptosis. PMID- 26614994 TI - Expression of MAPK1 in cervical cancer and effect of MAPK1 gene silencing on epithelial-mesenchymal transition, invasion and metastasis. AB - OBJECTIVE: To discuss the expression of mitogen-activated protein kinase 1 (MAPK1) in the cervical cancer and effect of MAPK1 gene silencing on epithelial mesenchymal transition and invasion and metastasis. METHODS: Immunohistochemistry, western blot and RT-PCR method were employed to detect the expression of MAPK1 protein and mRNA in cervical cancer tissue and adjacent normal tissue. The constructed siRNA-MAPK1 was transferred into human cervical cancer HeLa cells using LipofectamineTM2000. MTT method was used to detect the cell vitality, transwell method to detect the cell invasion, and western blot to detect the expression of matrix metalloproteinases (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, zinc finger transcription factor (Snail), epithelial-mesenchymal transition related protein (EMT) E-cadherin and vimentin in cells. RESULTS: The expression of MAPK1 protein and mRNA in the cervical cancer tissue was significantly higher than the one in the adjacent normal tissue (P < 0.01); after transfecting the siRNA-MAPK1 into the human cervical cancer HeLa cells through liposome, compared with the control group, its cell vitality was significantly decreased (P < 0.01), cell invasion was significantly decreased (P < 0.01); expressed of MMP-2, MMP-9, Snail and vimentin was significantly decreased (P < 0.01), and expression of TIMP-1, TIMP-2 and E cadherin was significantly increased (P < 0.01). CONCLUSIONS: Because of the high expression of MAPK1 in the cervical cancer tissue, the interference in the expression of MAPK1 can significantly inhibit the invasion and metastasis of cervical cancer HeLa cells, which is related to the interference in the expression of MMPs/TIMP and Snail-mediated generation of EMT. PMID- 26614995 TI - Effect of maxillary expansion on orthodontics. AB - OBJECTIVE: To explore the effect of maxillary expansion on orthodontics. METHODS: Eight beagle dogs were randomly divided into two groups, with 4 dogs in each group. Dogs in group 1 were executed immediately and received the direct physical measurement. The magnetic expansion appliance was used in group 2 for the maxillary expansion. After the expansion, the model was taken again and they were executed after cone beam CT (CBCT) scanning. The model measurement method was adopted in group 1 to measure the dental measurement indicators and width of base bone arch. The CBCT measurement method was employed to measure the above dental indicators and bone indicators. The difference in the indicators measured by different methods was compared and analyzed. RESULTS: Before the expansion, there was no significant difference in the bone measurement indicators between the CBCT measurement method and direct physical measurement method. After the expansion, there was no significant difference in indicators between the CBCT measurement method and direct physical measurement. But there was significant difference among the model measurement method, CBCT measurement method and direct physical measurement method. There was the significant difference in the dental indicators between the CBCT measurement method and model measurement, as well as the bone indicators of posterior marginal spacing of greater palatine foramen, posterior marginal spacing of incisive foramen, width of base bone arch and spacing of implant anchorage. CONCLUSIONS: There is no significant difference between the effect of CBCT measurement method and direct physical measurement method, but CBCT is significantly better than the model measurement. PMID- 26614996 TI - Annexin A2 silencing enhances apoptosis of human umbilical vein endothelial cells in vitro. AB - OBJECTIVE: To study the effects of inhibited Annexin A2 (ANXA2) on human umbilical vein endothelial cells (HUVECs) in vitro. METHODS: Short hairpin RNA (shRNA) targeting ANXA2 was designed and cloned into double marked lentivirial vector GV248 for RNAi to generate the recombinant expression plasmids, which were stably transfected into HUVECs. The protein and mRNA expression levels of ANXA2 were analyzed by western blotting and real-time polymerase chain reaction, respectively. Cell proliferation (cell counting kit-8 assay), apoptosis (flow cytometry analysis), the expression (western blotting) and the activity of caspases (enzyme-linked immunosorbent assay) were used to assess the effects of silencing ANXA2 on HUVECs in vitro. RESULTS: The plasmids to express ANXA2 specific shRNA were constructed and were infected into HUVEC resulting in the stably transfected experimental (ANXA2-shRNA), control (control-shRNA) and mock (no plasmid) cell lines, which were verified with western blot and real-time PCR. HUVEC/ANXA2-shRNA showed an inhibition rate 91.89% of ANXA2 expression compared to the mock HUVEC. ANXA2 silencing cell strain obviously presented a lower cell proliferation activity compared to the control and mock HUVECs, with an inhibition rate 82.35% on day 7 in vitro. FACS analysis indicated that the HUVEC/ANXA2-shRNA cells undergoing apoptosis increased by 102.61% compared to the mock HUVECs (P < 0.01). Moreover, the activity levels of caspase-3, caspase-8 and caspase-9 in HUVEC/ANXA2-shRNA cells were increased and the activated cleaved caspase-3, cleaved caspase-8 and cleaved caspase-9 were upregulated evidently compared with that of the control and mock HUVECs by 56.29%, 89.59% and 144.58% (P < 0.01). CONCLUSIONS: shRNA-mediated silencing of ANXA2 could not only be able to suppress HUVECs proliferation but to upregulate the enzyme activity of caspases, which bring to an increase of cell apoptosis. This work suggested that ANXA2 may represent a useful target of future molecular therapies. PMID- 26614997 TI - Abnormal expression of WIF1 in hepatocellular carcinoma cells and its regulating effect on invasion and metastasis factors of TIMP-3 and caveolin-1 of hepatocellular carcinoma. AB - OBJECTIVE: To discuss the abnormal expression of Wnt inhibitory factor (WIF1) in hepatocellular carcinoma cells and its regulating effect on the hepatocellular carcinoma invasion and metastasis factors of tissue inhibitor of matrix metalloproteinases-3 (TIMP-3) and caveolin-1. METHODS: RT-PCR and Western blot were employed to detect the expression of WIF1 in six hepatocellular carcinoma cell lines of HepG2, Hep3B, Huh7, PLC/PRF/5, SMMC-7721 and MHCC97 and the immortalized human liver cell line THLE-3. Besides, Lipofectamine 2000 was employed to transfect the eukaryotic expression vector pcDNA3.1-WIF1 and blank plasmid pcDNA3.1 into hepatocellular carcinoma cell lines. Transwell assay was used to detect the effect of WIF1 on the invasion ability of hepatocellular carcinoma cells; Western blot was used to detect the effect of WIF1 on the expression of TIMP-3 and caveolin-1 in hepatocellular carcinoma cells, it also discussed the effect on the expression of beta-catenin. RESULTS: The expression of WIF1 in hepatocellular carcinoma cell lines was lower than that in the normal liver cell lines (P < 0.01); while there was basically no expression of WIF1 in the human highly metastatic cell line MHCC-97 and moderate expression in HepG2 and SMMC-7721. Therefore, HepG2 and SMMC-7721 were chosen as the further experimental cell lines. After transfecting the eukaryotic expression vector pcDNA3.1-WIF1 and blank plasmid pcDNA3.1 into hepatocellular carcinoma cell lines, compared with the blank plasmid group, the cell viability and invasion ability in the WIF1 group were all reduced (P < 0.01), the expression of TIMP-3, caveolin-1 and mRNA were all down-regulated (P < 0.01), and the expression of beta-catenin was decreased (P < 0.01). CONCLUSIONS: Because of down-regulation or missing of expression of WIF1 in hepatocellular carcinoma cell lines, the up regulation of WIF1 expression can significantly inhibit the invasion and metastasis of HepG2 and SMMC-7721 of hepatocellular carcinoma cell lines, which are related to the up-regulated expression of TIMP-3 and down-regulated expression of caveolin-1 and may be realized through the Wnt/beta-catenin signaling pathway. PMID- 26614998 TI - Effect of propofol on generation of inflammatory mediator of monocytes. AB - OBJECTIVE: To evaluate the effect of propofol with different concentrations on the expression of inflammatory mediators of interleukin and tumor-necrosis factor alpha (TNF-alpha) by stimulating the mouse primary monocytes and human monocytic cell line with lipopolysaccharide (LPS) and also discuss the effect of propofol on the secretion of inflammatory mediator and its possible molecular mechanism. METHODS: The mononuclear cells of mouse spleen were separated and then purified to obtain the primary monocytes. The dose-effect relationship of production of pro-inflammatory cytokines by monocytes which were stimulated by LPS, namely the monocytes were stimulated by the dose of 0-500 ng/mL for 24 h. ELISA was employed to detect the concentration of IL-6, IL-8 and TNF-alpha. The effect of propofol on the secretion of above pro-inflammatory cytokines by the monocytes was observed. Cells were divided into the control group, the 0.1% DMSO group, the LPS group and the treatment group with LPS + different dose of propofol (propofol 1 100 MUg/mL). ELISA was employed to detect the concentration of IL-6, IL-8 and TNF alpha. The change in the expression of important signaling molecules in Toll-like receptor and NF-kappaB signaling pathway was detected after THP-1 cells were treated with propofol. RESULTS: The concentration of TNF-alpha was (3863 +/- 153) pg/mL after 12 h of stimulation by LPS and then its concentration was decreased gradually. But the concentration of IL-6 and IL-8 was relatively high after 24 h of stimulation by LPS, (5627 +/- 330) pg/mL and (1626 +/- 200) pg/mL, respectively. The propofol could inhibit the expression of IL-6, IL-8 and TNF alpha caused by LPS. After the intervention treatment of 50 MUg/mL propofol, the concentration of IL-6, IL-8 and TNF-alpha was significantly decreased (P < 0.01). CONCLUSIONS: The propofol can inhibit the expression of TLR-4 and NF-kappaB to inhibit the activation of p38 and the expression of pro-inflammatory cytokines. PMID- 26614999 TI - Mechanism of PEDF promoting the proliferation of lens epithelial cells in human eyes. AB - OBJECTIVE: To investigate the regulation effect of pigment epithelium-derived factor (PEDF) on the growth of human lens endothelial cells (LECs) and related mechanisms in vivo and in vitro. METHODS: In the part of in vivo study, 82 eyes of 82 patients with age-related cataract were included to collect the central lens anterior capsule (diameter at 5.0-5.5 mm) with the informed consent of surgery for patients. The selected specimens were divided into the LECs low density group and high density group with 20 specimens for each group based on hematoxylin and eosin staining results. The relative expression level of PEDF mRNA in LECs was detected by reverse transcription PCR. In the part of in vitro study, LEC line (HLE-B3) was cultured and 50 ng/mL PEDF was added in media for 72 h in PEDF culture group, while normally cultured cells were used as the control group. The percentage of LECs at G0 and S phases and apoptotic rate of cells were assayed by using flow cytometry with annexin V-FITC/7-AAD double staining method. Intracellular expression of vascular endothelial growth factor (VEGF) mRNA was detected by real-time fluorescence quantitative PCR. RESULTS: The central anterior subcapsular LECs density and relative expression level of PEDF mRNA were lower than those of high density group. There were no significant differences between two groups (P = 0.168). The apoptotic rate in the PEDF culture group was significantly reduced in comparison with the control group (P < 0.001). In addition, the expression level of VEGF mRNA was lower in the PEDF culture group compared with the control group (P < 0.001). CONCLUSIONS: In human eyes, PEDF may function as cytotropic factor to promote survival of LECs through anti-apoptosis and reducing-expression of VEGF. Decrease of PEDF content in LECs probably modulates the pathophysiological process of lens cells and further cataractogenesis. PMID- 26615000 TI - RETRACTED: Effect of thioredoxin-interacting protein on Wnt/beta-catenin signaling pathway and diabetic myocardial infarction. AB - OBJECTIVE: To explore the regulatory role of thioredoxin-interacting protein (TXNIP) in Wnt/beta-catenin signaling pathway and therefore to elucidate its function in diabetic myocardial infarction. METHODS: Diabetic myocardial infarction models were generated in mice. The expression levels of TXNIP and beta catenin and level of reactive oxygen species (ROS) were determined and compared with those in control group. Human umbilical vein endothelial cells were treated with high-concentration glucose and/or silencing TXNIP and/or H2O2. After 24 h, expression levels of TXNIP, beta-catenin and its downstream protein Cyclin D1, and C-myc gene were determined by real-time PCR, Western blot and immunofluorescence method. The cell proliferation and ROS production capability in different groups were determined by methyl thiazolyl tetrazolium assay. RESULTS: Compared with control group, hyperglycemia significantly up-regulated TXNIP expression and ROS level in the myocardium and endothelial cells of myocardial infarction area, whereas the beta-catenin expression was down regulated, and the difference was statistically significant (P < 0.05). In comparison with Human umbilical vein endothelial cells in the control group, high glucose level increased the levels of TXNIP expression and ROS level in cells, but reduced cell proliferation as well as migration capability and expression levels of beta-catenin, Cyclin D1 and C-myc; the difference was statistically significant (P < 0.05). However, this trend can be partially reversed by silencing TXNIP. CONCLUSIONS: Diabetic myocardial ischemia could up-regulate levels of TXNIP expression and ROS production in endothelial cells of myocardial infarction area. The regulation effect of TXNIP on beta-catenin was partially achieved by changing ROS levels. PMID- 26615001 TI - Therapeutic effect and apoptosis mechanism of lung-tonifying and expectorant decoction on lung cancer rats with Qi deficiency and blood stasis. AB - OBJECTIVE: To explore the effect and specific mechanism of lung-tonifying and expectorant decoction on lung cancer rats with Qi deficiency and blood stasis, and aim to provide a new idea on treating the disease with traditional Chinese medicine based on syndrome differentiation. METHODS: A total of 60 C57BL/6J male rats were included in the study. The model of Qi deficiency and blood stasis was established in 60 rats by using multiple-factor stimulation. About 10 rats were randomly taken to verify whether the model establishment was successful and the rest of 50 rats were divided into 5 groups with 10 rats each: blank control group, cisplatin group, low dose group, medium dose group and high dose group. The blank control group was treated with normal saline, and cisplatin group was treated with cisplatin while the other three groups were treated with lung tonifying and expectorant decoction at different doses. The volume change in transplanted tumor, tumor inhibition rate, apoptosis rate, and expression of Bcl 2, Bax, cleaved caspase-3 and cleaved caspase-9 in 5 groups were compared. RESULTS: The rapidest growth rate of transplanted tumor volume was observed in blank control group and the slowest in cisplatin group. The growth rate was gradually decreased with the increasing dose of lung-tonifying and expectorant decoction, and the difference in growth of tumor volume among groups was statistically significant (P < 0.05). The cisplatin group showed the highest tumor inhibition rate, with dose-dependent increase (P < 0.05). The apoptosis rate in low dose group was higher than blank control group but lower than high dose group (P < 0.05). The apoptosis rate in medium dose group was significantly higher than blank control group (P < 0.05). The apoptosis rate in high dose group was significantly higher than control group (P < 0.05). The positive expression rates of Bcl-2 and Bax in all groups showed statistically significant difference (P < 0.05), while expression of cleaved caspase-3 and cleaved caspase-9 in 5 groups was significantly different, with dose-dependent increase (P < 0.05). CONCLUSIONS: The lung-tonifying and expectorant decoction inhibits the proliferation of tumor cells by inducing and activating the cell apoptosis in treatment of lung cancer with Qi deficiency and blood stasis, probably with good clinical therapeutic effect. PMID- 26615002 TI - Trabecular bone score in patients with liver transplants after 1 year of risedronate treatment. AB - The aim of this study was to analyse the effect of risedronate on Trabecular Bone Score in liver transplant patients with low bone mass, during 1-year follow-up. In this retrospective cohort study, trabecular bone score (TBS) was calculated from dual X-ray absorptiometry images of the lumbar spine (LS), collected from a prospective randomized open-label 1-year trial performed in liver recipient patients. A total of 89 patients with osteopenia or osteoporosis were randomized to receive RIS plus calcium and vitamin D3 or calcium and vitamin D3. TBS was low in both groups at baseline, 6 and 12 months. Baseline TBS at the LS showed degraded microarchitecture in 22.8% of patients, partially degraded in 40.3%, and normal values in 36.8% of the patients. After 1 year of treatment, no difference in TBS was observed between both groups. No correlations were found between bone mineral density (BMD) and TBS values at any follow-up time point. No relationship was found between BMD, TBS or immunosuppressive drugs with incidental fracture. No significant effect in TBS was observed in liver transplant patients treated with RIS or calcium and vitamin D3 after 1 year of follow-up. In these patients, the clinical usefulness of this new tool should be established. PMID- 26615003 TI - Revised criteria for classification of the etiologies of acute liver failure and late-onset hepatic failure in Japan: A report by the Intractable Hepato-biliary Diseases Study Group of Japan in 2015. AB - In 2011, the Intractable Liver Diseases Study Group of Japan, established novel diagnostic criteria for "acute liver failure ", and published the classification criteria for the etiologies of acute liver failure and late-onset hepatic failure (LOHF) in 2013. According to this classification, HBV carriers showing acute hepatitis exacerbation were divided into 3 subgroups; asymptomatic or inactive HBV carriers without drug exposure, asymptomatic or inactive HBV carriers developing HBV reactivation during and after immunosuppressive therapies and/or antineoplastic chemotherapies and those with previously resolved HBV infection showing iatrogenic HBV reactivation. In an annual nationwide survey in 2013, however, a patient with previously resolved HBV infection was enrolled, in whom LOHF developed as a result of HBV reactivation despite in the absence of immunosuppressive therapies and/or antineoplastic chemotherapies. Thus, the study group revised the classification criteria in 2015; HBV carriers developing acute hepatitis exacerbation were classified into asymptomatic or inactive HBV carriers and patients with previously resolved HBV infection, and both groups were further sub-classified into those receiving immunosuppressive therapies and/or antineoplastic chemotherapies and those without such drugs exposure. PMID- 26615005 TI - Data Notes Series. PMID- 26615006 TI - Sociodemographic correlates of continuing tobacco use in lifetime smokers-a descriptive report. PMID- 26615004 TI - Antileishmanial and immunomodulatory effects of the essential oil from Tetradenia riparia (Hochstetter) Codd. AB - Cutaneous leishmaniasis usually presents therapeutic resistance to antimonials, and the existing therapies for leishmaniasis have many adverse effects and toxicity. Natural products may be regarded as possible candidates for alternative leishmaniasis treatment. The plant Tetradenia riparia has shown promise for the treatment of infectious diseases in folk medicine. We evaluated the antileishmanial activity of an essential oil from T. riparia (TrEO) and the modulatory effects of TrEO on cytokine modulation by peritoneal fluid cells that were infected with L. (L.) amazonensis. Peritoneal fluid cells were infected with Leishmania and incubated with TrEO (30 ng/mL) for 3, 6, and 24 h. Cytokines were screened using semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) and flow cytometry. Antileishmanial activity was evaluated at 24 h by microscopic counting and quantitative PCR (qPCR). TrEO treatment induced the death of 50% of Leishmania amastigotes (indicated by microscopic counting) and 91% of the parasite load (indicated by qPCR). TrEO inhibited some of the most critical cytokines for parasite growth and the establishment of infection, including granulocyte-macrophage colony-stimulating factor, interleukin-4 (IL-4), IL-10, and tumour necrosis factor. The parasite inhibited interferon-gamma and IL 12, and TrEO blocked this inhibition, indicating that these cytokines are critical for activating mechanisms associated with the death and elimination of the parasite. These results suggest that TrEO may be an alternative leishmaniasis therapy when considering its antileishmanial and immunomodulatory activity. PMID- 26615007 TI - Recognition of purified beta 1,3/1,6 glucan and molecular signalling in the intestine of Atlantic salmon. AB - Atlantic salmon was orally intubated with a highly purified beta-glucan product (MacroGard((r))) to study the recognition of the molecule by the receptor genes, the regulation of the downstream signalling genes and global proteins, and the micromorphological changes in the intestine. The beta-glucan receptor genes of Atlantic salmon, sclra, sclrb, sclrc and cr3, seem to recognize the molecule, and initiate the downstream ITAM-motif signalling, as evident from the significantly high mRNA levels of ksyk, mapkin2, il1b and mip2a levels. Among the altered proteins, the Apoa4 (involved in carbohydrate and lipid metabolism); Tagln, Actb (uptake of beta-glucan); Psma2 (associated with substrate recognition); and Ckt (energy metabolism-related) were the overexpressed ones. The underexpressed proteins included the Uk114, Rpl9, Ctsb and Lgal that are connected to proliferation, LPS-stimulation, Il1b and lactose recognition, respectively. Furthermore, the mRNA levels of igt and the number of immune cells in the distal intestine were found to increase upon beta-glucan uptake by the fish. This study provides some clues on the mechanisms by which the beta-glucan evokes response in Atlantic salmon, particularly at the intestinal level. PMID- 26615008 TI - A galectin related protein from Oplegnathus fasciatus: Genomic, molecular, transcriptional features and biological responses against microbial pathogens. AB - Galectins, a family of beta-galactoside-binding lectins, are pattern recognition receptors that recognize pathogen-associated molecular patterns and are subsequently involved in the opsonization, phagocytosis, complement activation, and killing of microbes. Here, we report a novel galectin related protein (GRP) identified from rock bream (Oplegnathus fasciatus), designated OfGal like B. The cDNA of OfGal like B is 517 bp with an open reading frame (ORF) of 438 bp, encoding 145 amino acids, with a single carbohydrate recognition domain (CRD). However, only two of the seven critical residues responsible for carbohydrate recognition were identified in the CRD. There was no signal peptide identified in the OfGal like B protein. The genomic structure of OfGal like B, determined using a bacterial artificial chromosome (BAC) genomic library, consists of four exons and three introns. Homology assessment, multiple sequence alignment, and phylogenetic analysis indicated that OfGal like B is an evolutionarily conserved lectin that is closely related to the proto-type galectins. OfGal like B mRNA was constitutively expressed in a wide range of tissues in healthy rock breams. When challenged with bacterial or viral stimulants, OfGal like B was up-regulated in the gills and spleen of rock breams, indicating that it likely plays an important role during bacterial and viral infections. Furthermore, recombinant OfGal like B (rOfGal like B) lacked carbohydrate-binding activity but was able to recognize and agglutinate bacteria, including Streptococcus iniae, Listeria monocytogenes, Vibrio tapetis, Escherichia coli, and Edwardsiella tarda, and a ciliate parasite, Miamiensis avidus. These results collectively suggest that OfGal like B is involved in pathogen recognition and plays a significant role(s) in the innate defense mechanism of rock bream. PMID- 26615009 TI - Editorial. PMID- 26615010 TI - Gene expression patterns underlying parasite-induced alterations in host behaviour and life history. AB - Many parasites manipulate their hosts' phenotype. In particular, parasites with complex life cycles take control of their intermediate hosts' behaviour and life history to increase transmission to their definitive host. The proximate mechanisms underlying these parasite-induced alterations are poorly understood. The cestode Anomotaenia brevis affects the behaviour, life history and morphology of parasitized Temnothorax nylanderi ants and indirectly of their unparasitized nestmates. To gain insights on how parasites alter host phenotypes, we contrast brain gene expression patterns of T. nylanderi workers parasitized with the cestode, their unparasitized nestmates and unparasitized workers from unparasitized colonies. Over 400 differentially expressed genes between the three groups were identified, with most uniquely expressed genes detected in parasitized workers. Among these are genes that can be linked to the increased lifespan of parasitized workers. Furthermore, many muscle (functionality) genes are downregulated in these workers, potentially causing the observed muscular deformations and their inactive behaviour. Alterations in lifespan and activity could be adaptive for the parasite by increasing the likelihood that infected workers residing in acorns are eaten by their definitive host, a woodpecker. Our transcriptome analysis reveals numerous gene expression changes in parasitized workers and their uninfected nestmates and indicates possible routes of parasite manipulation. Although causality still needs to be established, parasite-induced alterations in lifespan and host behaviour appear to be partly explained by morphological muscle atrophy instead of central nervous system interference, which is often the core of behavioural regulation. Results of this study will shed light upon the molecular basis of antagonistic species interactions. PMID- 26615011 TI - High serum Aspartate transaminase levels on day 3 postliver transplantation correlates with graft and patient survival and would be a valid surrogate for outcome in liver transplantation clinical trials. AB - Aspartate transaminase, a liver specific enzyme released into serum following acute liver injury, is used in experimental organ preservation studies as a measure of liver IR injury. Whether post-operative serum transaminases are a good indicator of IR injury and subsequent graft and patient survival in human liver transplantation remains controversial. A single centre prospectively collected liver transplant database was analysed for the period 1988-2012. All patients were followed up for 5 years or until graft failure. Transaminase levels on the 1st, 3rd and 7th post-operative days were correlated with the patient demographics, operative outcomes, post-operative complications and both graft and patient survival via a binary logistic regression analysis. Graft and patient survival at 3 months was 80.3% and 87.5%. AST levels on the 3rd (P = 0.005) and 7th (P = 0.001) post-operative days correlated with early graft loss. Patients were grouped by their AST level (day 3): <107iU, 107-1213iU, 1213-2744iU and >2744iU. The incidence of graft loss at 3 months was 10%, 12%. 27% and 59% and 1 year patient mortality was 12%, 14%, 27% and 62%. Day 3 AST levels correlate with patient and graft outcome post-liver transplantation and would be a suitable surrogate endpoint for clinical trials in liver transplantation. PMID- 26615012 TI - [Assessment of selected anthropometric parameters in children exposed to gestational diabetes in utero - preliminary results]. AB - INTRODUCTION: Current studies show uncreased risk of obesity cardiovascular diseases and diabetes mellitus in children exposed to gestational diabetes in utero. AIM: The aim of this study was to assess the selected anthropometric parameters in children exposed to gestational diabetes in utero. MATERIAL AND METHODS: 43 children, 7-15 years of age, exposed to gestational diabetes in utero were included in the study. Data including mother's pregestational anthropometric parameters, the course of pregnancy and anthropometric parameters of a newborn were obtained from the interview and medical records. Pediatric physical examination with Tanner assessment of pubertal development was conducted. In children and mothers the height and body mass were measured, and body mass index (BMI) was calculated. In participants of the study waist and hip circumferences were measured. RESULTS: Higher birth weight (p=0.02), head and chest circumferences (p=0,02 and p=0.03) were observed in newborns of mothers with pregestational overweight and obesity. The analysis of newborns growth parameters and type of gestational diabetes did not show a significant difference. Obesity (BMI z 95th percentile) was diagnosed in 9 children (20.9 %) and overweight (BMI between 85th and 94th percentile) in 6 participants (13.9%). Higher body mass (p=0.02), BMI (p=0.02) and waist circumference (p-0.03) were observed in children who reached III-V Tanner stage, comparing to participants in Tanner Ml. Higher body mass, BMI, waist and hip circumferences were observed in the offspring of mothers with pregestational overweight and obesity. Mothers of children with BMI > 90th percentile currently show higher body mass and BMI in comparison to mothers of slimmer participants. CONCLUSIONS: Excessive body weight before pregnancy in mothers with gestational diabetes can influence not only the anthropometric parameters of newborns and lead to fetal macrosomy, but also can be a predisposing factor for overweight and obesity in later childhood. PMID- 26615013 TI - [Risk factors for cardiovascular disease in children with type 1 diabetes in 2000 2010 in Podlasie Province]. AB - INTRODUCTION: There has been an increase over the last decade in the number of young patients with type 1 diabetes treated with a continuous subcutaneous insulin infusion (CSII). The accelerated development of atherosclerosis is closely linked to metabolic control and traditional risk factors. AIM: Analysis of changes in the treatment and clinical picture of type 1 diabetes in children over the years 2000-2010, with emphasis on risk factors for cardiovascular disease. MATERIALS AND METHODS: The study included 567 children diagnosed with type 1 diabetes. 251 children who were treated in 2000 were compared with 316 children treated in 2010. The study analyzed anthropometric parameters, laboratory tests and data obtained using questionnaires. RESULTS: In 2010, there was an increase in the percentage of children treated with CSU (up to 60.1%) and a decrease in the percentage of children using traditional insulin In favour of insulin analogues. An increase in HbA1c was observed from 7.4% to 8% (p < 0.001) and an increase in the percentage of patients with HbA1c>7.5%. There was an increase in the percentage of children with obesity from 5.2% to 13.7% (p =0.004) and an increase in BMI SDS. The number of children with hypertension was comparable in both groups (17.9% vs 15.8%), as was the percentage of children with dyslipidemia (48.6% ys 513%). Antihypertensive drugs were used in 97.8% vs. 70% of children with hypertension, metformin in 15.4% vs. 14% of children with obesity, and lipid-lowering drugs only in 3.3% vs; 2.5% of patients with dyslipidemia. It has been shown that nowadays children live in families burdened with risk factors for atherosclerosis. CONCLUSIONS: Contemporary patients frequently have excessive body weight and live in families burdened with risk factors for atherosclerosis. Despite the use of modern technology, metabolic control is not satisfactory. PMID- 26615014 TI - [The use of metabolomics in medicine - some examples of oncological and metabolic diseases]. AB - Metabolomics is a new field of medicine focused on examining and analyzing metabolites produced in biological cells. Biological fluids primarily used in this method include: plasma, cerebrospinal fluid, saliva and urine. The most common methods of evaluating the composition involve nuclear magnetic resonance (NMR) and magnetic resonance (MR) with addition of gas chromatography (GC-MS) or liquid chromatography (LC-MS). Metabolomics is used in a wide variety of medicine disciplines. The variability of biochemical processes in tumor cells in comparison to normal cells is the starting point of such studies. The metabolomic changes are observed not only in solid tumors, like the mammary tumor, ovarian cancer, prostate cancer but also in tumors of the hematopoietic and lymphoid tissues. Nowadays, the aim of studies is to find biomarkers which would help to diagnose a disease quickly, assess its progression, and implement effective treatment. Metabolomics is also widely applied in metabolic diseases, mainly the diabetes. The list of examined metabolites gives promising chances for a successful prognosis, diagnosis and comprehensive monitoring of the progression of this civilization disease. The development of metabolomics will also contribute to the individualization of treatment, proper drugs adjustment, which will make a therapy more successful, cause less side effects and improve the quality of patient's life. PMID- 26615015 TI - [The clinical utility of C-peptide measurement in diabetology]. AB - C-peptide is produced in equal amounts to insulin and is the best measure of endogenous insulin secretion in patients with diabetes. Measurement of insulin secretion using C-peptide can be helpful in clinical practice: differences in insulin secretion are fundamental to different requirements in the treatment of diabetes. An important clinical role of C-peptide is differentiating between type 1 and type 2 diabetes. Low basal C-peptide can be considered as criterion for transferring the patients, initially diagnosed as type 2 diabetes, in the type 1 diabetes group. C-peptide level may be a good predictor of the clinical partial remission during the first year of type 1 diabetes. Latent autoimmune diabetes in adults (LADA) is a special form of diabetes that is clinically similar to type 2 diabetes but with positivity for pancreatic autoantibodies and lower C-peptide levels. The measurement of C-peptide level and of immunological markers may represent important additional tools for establishing the correct diagnosis. The natural course of these patients shows that C-peptide will decrease with time in parallel with the curve for C-peptide in classical type 1 diabetic patients. Persistence of C-peptide is an important clinical feature of MODY. It is particularly important to identify these patients as they are commonly misdiagnosed as type 1 diabetes and treated with insulin, C-peptide can be used to assist in patient selection for islet cell transplantation and post-transplant monitoring. High uncorrected fasting C-peptid in the presence of hyperglycemia may suggest insulin resistance. PMID- 26615016 TI - [Cardiometabolic risk factors in Turner syndrome]. AB - Congenital cardiovascular structural abnormalities, hypertension, low birth weight, increased prevalence of obesity, frequent glucose intolerance and dyslipidemia are risk factors of premature mortality for cardiovascular events in Turner syndrome (TS). The life expectancy in TS is reduced by at least 10 years and the risk of premature death is increased 3-fold compared to general female population. Hormonal therapy in TS, both estrogens in different algorithms and growth hormone in supraphysiological dose, may additionally modify these factors. In this review we summarize cardiometabolic markers potentially present in girls and women with TS. PMID- 26615017 TI - Growth hormone therapy in a girl with Turner syndrome and diabetes type 1 - case report. AB - INTRODUCTION: The studies indicate the complex etiology of abnormal glucose metabolism in the Turner syndrome (TS). In the light of these carbohydrate disorders a therapy with recombinant growth hormone (rGH) in TS may be associated with complications, as growth hormone has a diabetogenic potential. PATIENT REPORT: Perinatal history is unknown since the patient was adopted at the age of 4 years. At 11 years old, due to typical phenotype, TS was diagnosed. The karyotype was 45,X[43]/46,X,i(X)(q10)[7]. At the same age, basing on laboratory results, insulin dependent diabetes was diagnosed and the conventional insulin therapy was initiated. During the hospitalization, at the age of 12 years, the patient was 123.5cm (-4.4SD). At the same age rGH tre-atment was initiated, with the dose 0.045 mg/kg/d. After 3 months of therapy the height velocity rose to 8.2 cm/ year. At the age of 13 years, substitution with 17beta-estradiol was started. After 3 years and 4 months the growth hormone treatment was stopped because of poor height velocity. The final height of the patient was 140 cm (-4,OSD). Two years after the end of rGH treatment the height was 141.2 cm. After termination of rGH treatment the need for daily insulin dose decreased from 50-60U/d to 38 44U/d. CONCLUSIONS: The decision of rGH therapy in TS with diabetes is certainly difficult. While starting the growth hormone treatment the clinician must keep in mind the risk of metabolic complications, but also the awareness that gives the patient a chance to improve the final height. In terms of the proper psycho emotional development the reduction of growth deficit is very important. PMID- 26615018 TI - Axial contraction and short-range compaction of chromatin synergistically promote mitotic chromosome condensation. AB - The segregation of eukaryotic chromosomes during mitosis requires their extensive folding into units of manageable size for the mitotic spindle. Here, we report on how phosphorylation at serine 10 of histone H3 (H3 S10) contributes to this process. Using a fluorescence-based assay to study local compaction of the chromatin fiber in living yeast cells, we show that chromosome condensation entails two temporally and mechanistically distinct processes. Initially, nucleosome-nucleosome interaction triggered by H3 S10 phosphorylation and deacetylation of histone H4 promote short-range compaction of chromatin during early anaphase. Independently, condensin mediates the axial contraction of chromosome arms, a process peaking later in anaphase. Whereas defects in chromatin compaction have no observable effect on axial contraction and condensin inactivation does not affect short-range chromatin compaction, inactivation of both pathways causes synergistic defects in chromosome segregation and cell viability. Furthermore, both pathways rely at least partially on the deacetylase Hst2, suggesting that this protein helps coordinating chromatin compaction and axial contraction to properly shape mitotic chromosomes. PMID- 26615019 TI - Interplay between kinesin-1 and cortical dynein during axonal outgrowth and microtubule organization in Drosophila neurons. AB - In this study, we investigated how microtubule motors organize microtubules in Drosophila neurons. We showed that, during the initial stages of axon outgrowth, microtubules display mixed polarity and minus-end-out microtubules push the tip of the axon, consistent with kinesin-1 driving outgrowth by sliding antiparallel microtubules. At later stages, the microtubule orientation in the axon switches from mixed to uniform polarity with plus-end-out. Dynein knockdown prevents this rearrangement and results in microtubules of mixed orientation in axons and accumulation of microtubule minus-ends at axon tips. Microtubule reorganization requires recruitment of dynein to the actin cortex, as actin depolymerization phenocopies dynein depletion, and direct recruitment of dynein to the membrane bypasses the actin requirement. Our results show that cortical dynein slides 'minus-end-out' microtubules from the axon, generating uniform microtubule arrays. We speculate that differences in microtubule orientation between axons and dendrites could be dictated by differential activity of cortical dynein. PMID- 26615020 TI - Delineation of MGMT Hypermethylation as a Biomarker for Veliparib-Mediated Temozolomide-Sensitizing Therapy of Glioblastoma. AB - BACKGROUND: Sensitizing effects of poly-ADP-ribose polymerase inhibitors have been studied in several preclinical models, but a clear understanding of predictive biomarkers is lacking. In this study, in vivo efficacy of veliparib combined with temozolomide (TMZ) was evaluated in a large panel of glioblastoma multiforme (GBM) patient-derived xenografts (PDX) and potential biomarkers were analyzed. METHODS: The efficacy of TMZ alone vs TMZ/veliparib was compared in a panel of 28 GBM PDX lines grown as orthotopic xenografts (8-10 mice per group); all tests of statistical significance were two-sided. DNA damage was analyzed by gammaH2AX immunostaining and promoter methylation of DNA repair gene O6 methylguanine-DNA-methyltransferase (MGMT) by Clinical Laboratory Improvement Amendments-approved methylation-specific polymerase chain reaction. RESULTS: The combination of TMZ/veliparib statistically significantly extended survival of GBM models (P < .05 by log-rank) compared with TMZ alone in five of 20 MGMT hypermethylated lines (average extension in median survival = 87 days, range = 20 150 days), while the combination was ineffective in six MGMT-unmethylated lines. In the MGMT promoter-hypermethylated GBM12 line (median survival with TMZ+veliparib = 189 days, 95% confidence interval [CI] = 59 to 289 days, vs TMZ alone = 98 days, 95% CI = 49 to 210 days, P = .04), the profound TMZ-sensitizing effect of veliparib was lost when MGMT was overexpressed (median survival with TMZ+veliparib = 36 days, 95% CI = 28 to 38 days, vs TMZ alone = 35 days, 95% CI = 32 to 37 days, P = .87), and a similar association was observed in two nearly isogenic GBM28 sublines with an intact vs deleted MGMT locus. In comparing DNA damage signaling after dosing with veliparib/TMZ or TMZ alone, increased phosphorylation of damage-responsive proteins (KAP1, Chk1, Chk2, and H2AX) was observed only in MGMT promoter-hypermethylated lines. CONCLUSION: Veliparib statistically significantly enhances (P < .001) the efficacy of TMZ in tumors with MGMT promoter hypermethylation. Based on these data, MGMT promoter hypermethylation is being used as an eligibility criterion for A071102 (NCT02152982), the phase II/III clinical trial evaluating TMZ/veliparib combination in patients with GBM. PMID- 26615021 TI - Longitudinal Cognitive Trajectories of Women Veterans from the Women's Health Initiative Memory Study. AB - PURPOSE OF THE STUDY: A comparison of longitudinal global cognitive functioning in women Veteran and non-Veteran participants in the Women's Health Initiative (WHI). DESIGN AND METHODS: We studied 7,330 women aged 65-79 at baseline who participated in the WHI Hormone Therapy Trial and its ancillary Memory Study (WHIMS). Global cognitive functioning (Modified Mini-Mental State Examination [3MSE]) in Veterans (n = 279) and non-Veterans (n = 7,051) was compared at baseline and annually for 8 years using generalized linear modeling methods. RESULTS: Compared with non-Veterans, Veteran women were older, more likely to be Caucasian, unmarried, and had higher rates of educational and occupational attainment. Results of unadjusted baseline analyses suggest 3MSE scores were similar between groups. Longitudinal analyses, adjusted for age, education, ethnicity, and WHI trial assignment revealed differences in the rate of cognitive decline between groups over time, such that scores decreased more in Veterans relative to non-Veterans. This relative difference was more pronounced among Veterans who were older, had higher educational/occupational attainment and greater baseline prevalence of cardiovascular risk factors (e.g., smoking) and cardiovascular disease (e.g., angina, stroke). IMPLICATIONS: Veteran status was associated with higher prevalence of protective factors that may have helped initially preserve cognitive functioning. However, findings ultimately revealed more pronounced cognitive decline among Veteran relative to non-Veteran participants, likely suggesting the presence of risks that may impact neuropathology and the effects of which were initially masked by Veterans' greater cognitive reserve. PMID- 26615024 TI - Multiple sequence alignment modeling: methods and applications. AB - This review provides an overview on the development of Multiple sequence alignment (MSA) methods and their main applications. It is focused on progress made over the past decade. The three first sections review recent algorithmic developments for protein, RNA/DNA and genomic alignments. The fourth section deals with benchmarks and explores the relationship between empirical and simulated data, along with the impact on method developments. The last part of the review gives an overview on available MSA local reliability estimators and their dependence on various algorithmic properties of available methods. PMID- 26615023 TI - Botulinum and Tetanus Neurotoxin-Induced Blockade of Synaptic Transmission in Networked Cultures of Human and Rodent Neurons. AB - Clinical manifestations of tetanus and botulism result from an intricate series of interactions between clostridial neurotoxins (CNTs) and nerve terminal proteins that ultimately cause proteolytic cleavage of SNARE (soluble N ethylmaleimide-sensitive factor attachment protein receptor) proteins and functional blockade of neurotransmitter release. Although detection of cleaved SNARE proteins is routinely used as a molecular readout of CNT intoxication in cultured cells, impaired synaptic function is the pathophysiological basis of clinical disease. Work in our laboratory has suggested that the blockade of synaptic neurotransmission in networked neuron cultures offers a phenotypic readout of CNT intoxication that more closely replicates the functional endpoint of clinical disease. Here, we explore the value of measuring spontaneous neurotransmission frequencies as novel and functionally relevant readouts of CNT intoxication. The generalizability of this approach was confirmed in primary neuron cultures as well as human and mouse stem cell-derived neurons exposed to botulinum neurotoxin serotypes A-G and tetanus neurotoxin. The sensitivity and specificity of synaptic activity as a reporter of intoxication was evaluated in assays representing the principal clinical and research purposes of in vivo studies. Our findings confirm that synaptic activity offers a novel and functionally relevant readout for the in vitro characterizations of CNTs. They further suggest that the analysis of synaptic activity in neuronal cell cultures can serve as a surrogate for neuromuscular paralysis in the mouse lethal assay, and therefore is expected to significantly reduce the need for terminal animal use in toxin studies and facilitate identification of candidate therapeutics in cell-based screening assays. PMID- 26615022 TI - A Prospective Investigation of PTEN Loss and ERG Expression in Lethal Prostate Cancer. AB - BACKGROUND: PTEN is a tumor suppressor frequently deleted in prostate cancer that may be a useful prognostic biomarker. However, the association of PTEN loss with lethal disease has not been tested in a large, predominantly surgically treated cohort. METHODS: In the Health Professionals Follow-up Study and Physicians' Health Study, we followed 1044 incident prostate cancer cases diagnosed between 1986 and 2009 for cancer-specific and all-cause mortality. A genetically validated PTEN immunohistochemistry (IHC) assay was performed on tissue microarrays (TMAs). TMPRSS2:ERG status was previously assessed in a subset of cases by a genetically validated IHC assay for ERG. Cox proportional hazards models adjusting for age and body mass index at diagnosis, Gleason grade, and clinical or pathologic TNM stage were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association with lethal disease. All statistical tests were two-sided. RESULTS: On average, men were followed 11.7 years, during which there were 81 lethal events. Sixteen percent of cases had complete PTEN loss in all TMA cores and 9% had heterogeneous PTEN loss across cores. After adjustment for clinical-pathologic variables, complete PTEN loss was associated with lethal progression (HR = 1.8, 95% CI = 1.2 to 2.9). The association of PTEN loss (complete or heterogeneous) with lethal progression was only among men with ERG-negative (HR = 3.1, 95% CI = 1.7 to 5.7) but not ERG positive (HR = 1.2, 95% CI = 0.7 to 2.2) tumors. CONCLUSIONS: PTEN loss is independently associated with increased risk of lethal progression, particularly in the ERG fusion-negative subgroup. These validated and inexpensive IHC assays may be useful for risk stratification in prostate cancer. PMID- 26615026 TI - Functions of innate immune cells and commensal bacteria in gut homeostasis. AB - The intestinal immune system remains unresponsive to beneficial microbes and dietary antigens while activating pro-inflammatory responses against pathogens for host defence. In intestinal mucosa, abnormal activation of innate immunity, which directs adaptive immune responses, causes the onset and/or progression of inflammatory bowel diseases. Thus, innate immunity is finely regulated in the gut. Multiple innate immune cell subsets have been identified in both murine and human intestinal lamina propria. Some innate immune cells play a key role in the maintenance of gut homeostasis by preventing inappropriate adaptive immune responses while others are associated with the pathogenesis of intestinal inflammation through development of Th1 and Th17 cells. In addition, intestinal microbiota and their metabolites contribute to the regulation of innate/adaptive immune responses. Accordingly, perturbation of microbiota composition can trigger intestinal inflammation by driving inappropriate immune responses. PMID- 26615028 TI - Active approach to hand osteoarthritis. PMID- 26615025 TI - Towards improved genome-scale metabolic network reconstructions: unification, transcript specificity and beyond. AB - Genome-scale metabolic network reconstructions provide a basis for the investigation of the metabolic properties of an organism. There are reconstructions available for multiple organisms, from prokaryotes to higher organisms and methods for the analysis of a reconstruction. One example is the use of flux balance analysis to improve the yields of a target chemical, which has been applied successfully. However, comparison of results between existing reconstructions and models presents a challenge because of the heterogeneity of the available reconstructions, for example, of standards for presenting gene protein-reaction associations, nomenclature of metabolites and reactions or selection of protonation states. The lack of comparability for gene identifiers or model-specific reactions without annotated evidence often leads to the creation of a new model from scratch, as data cannot be properly matched otherwise. In this contribution, we propose to improve the predictive power of metabolic models by switching from gene-protein-reaction associations to transcript-isoform-reaction associations, thus taking advantage of the improvement of precision in gene expression measurements. To achieve this precision, we discuss available databases that can be used to retrieve this type of information and point at issues that can arise from their neglect. Further, we stress issues that arise from non-standardized building pipelines, like inconsistencies in protonation states. In addition, problems arising from the use of non-specific cofactors, e.g. artificial futile cycles, are discussed, and finally efforts of the metabolic modelling community to unify model reconstructions are highlighted. PMID- 26615027 TI - Reticulate Speciation and Barriers to Introgression in the Anopheles gambiae Species Complex. AB - Speciation as a process remains a central focus of evolutionary biology, but our understanding of the genomic architecture and prevalence of speciation in the face of gene flow remains incomplete. The Anopheles gambiae species complex of malaria mosquitoes is a radiation of ecologically diverse taxa. This complex is well-suited for testing for evidence of a speciation continuum and genomic barriers to introgression because its members exhibit partially overlapping geographic distributions as well as varying levels of divergence and reproductive isolation. We sequenced 20 genomes from wild A. gambiae s.s., Anopheles coluzzii, Anopheles arabiensis, and compared these with 12 genomes from the "GOUNDRY" subgroup of A. gambiae s.l. Amidst a backdrop of strong reproductive isolation, we find strong evidence for a speciation continuum with introgression of autosomal chromosomal regions among species and subgroups. The X chromosome, however, is strongly differentiated among all taxa, pointing to a disproportionately large effect of X chromosome genes in driving speciation among anophelines. Strikingly, we find that autosomal introgression has occurred from contemporary hybridization between A. gambiae and A. arabiensis despite strong divergence (~5* higher than autosomal divergence) and isolation on the X chromosome. In addition to the X, we find strong evidence that lowly recombining autosomal regions, especially pericentromeric regions, serve as barriers to introgression secondarily to the X. We show that speciation with gene flow results in genomic mosaicism of divergence and introgression. Such a reticulate gene pool connecting vector taxa across the speciation continuum has important implications for malaria control efforts. PMID- 26615029 TI - Anti-carbamylated protein antibodies in patients with ageing associated inflammatory chronic disorders. PMID- 26615030 TI - Impact of pre-existing co-morbidities on mortality in granulomatosis with polyangiitis: a cohort study. AB - OBJECTIVE: To assess the impact of pre-existing co-morbidities on mortality among patients affected by granulomatosis with polyangiitis (GPA). METHODS: By means of the Danish National Hospital Register, we identified a cohort of patients hospitalized for GPA during 1994-2010 (n = 308). The burden of pre-existing co morbidities among the patients was quantified according to the Charlson Comorbidity Index (CCI). Each patient was matched with five age- and gender matched population controls with no pre-existing co-morbidities captured by the CCI (CCI score = 0). The study subjects were followed throughout 2010. Cox regression analyses were used to calculate mortality rate ratios (MRRs). RESULTS: The median duration of follow-up in the GPA cohort was 5.8 years (interquartile range 2.3-10.0). Compared with their matched population controls, the MRR for patients presenting with a CCI score of 0 (n = 246) was 3.9 (95% CI 2.0, 7.5) during years 0-2 and 1.4 (95% CI 0.9, 2.0) from the second year of follow-up onwards. The corresponding MRRs were 13.3 (95% CI 5.8, 31) and 1.9 (95% CI 1.1, 3.6) for patients with a CCI score ?1 (n = 62). In a direct comparison, GPA patients with a CCI score ?1 were found to have significantly higher mortality than GPA patients with a CCI score of 0 during years 0-2 [adjusted MRR 3.4 (95% CI 1.6, 7.0)] but not after >2 years of follow-up [adjusted MRR 1.3 (95% CI 0.7, 2.6)]. CONCLUSION: During early follow-up periods, the mortality among GPA patients with pre-existing co-morbidities is markedly higher than that among GPA patients with no pre-existing illnesses. Our analyses identify an increased CCI score for pre-existing co-morbidities as an important risk factor for a fatal outcome in GPA. PMID- 26615031 TI - Intestinal pseudo-obstruction in patients with systemic sclerosis: an analysis of the Nationwide Inpatient Sample. AB - OBJECTIVE: Intestinal pseudo-obstruction is a rare gastrointestinal complication in patients with SSc without large studies examining its prevalence or outcomes. We aimed to compare outcomes in SSc patients with intestinal pseudo-obstruction to patients with intestinal pseudo-obstruction secondary to other causes, and SSc patients without intestinal pseudo-obstruction. METHODS: This is a case-control study using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample for the period 2002-2011. We included patients with the previously validated International Classification of Diseases-Clinical Modification-9 code 710.1 for SSc in combination with codes for intestinal pseudo-obstruction, and determined length of hospitalization and the risks for surgical procedures, use of total parenteral nutrition (TPN) and in-hospital mortality. RESULTS: A total of 193 610 SSc hospitalizations occurred in the USA between 2002 and 2011, of which 5.4% (n = 10 386) were associated with a concurrent intestinal pseudo obstruction diagnosis (cases). In-hospital mortality was 7.3%. In multivariate analyses, cases were more likely to die during the inpatient stay and to receive TPN than patients with idiopathic intestinal pseudo-obstruction (control group 1), patients with intestinal pseudo-obstruction and diabetes (control group 2), and SSc patients without intestinal pseudo-obstruction (control group 3). Cases had longer in-hospital stay than control groups 2 and 3, and were less likely to undergo surgical procedures than control groups 1 and 2. CONCLUSION: Intestinal pseudo-obstruction is a rare cause of hospitalization in patients with SSc, but is associated with high in-hospital mortality in comparison with other SSc patients and those with intestinal pseudo-obstruction secondary to other causes. PMID- 26615032 TI - Differential Expression of Genes of the Calvin-Benson Cycle and its Related Genes During Leaf Development in Rice. AB - To understand how the machinery for photosynthetic carbon assimilation is formed and maintained during leaf development, changes in the mRNA levels of the Calvin Benson cycle enzymes, ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) activase and two key enzymes for sucrose synthesis were determined in rice (Oryza sativa L.). According to the patterns of changes in the mRNA levels, these genes were categorized into three groups. Group 1 included most of the genes involved in the carboxylation and reduction phases of the Calvin-Benson cycle, as well as three genes in the regeneration phase. The mRNA levels increased and reached maxima during leaf expansion and then rapidly declined, although there were some variations in the residual mRNA levels in senescent leaves. Group 2 included a number of genes involved in the regeneration phase, one gene in the reduction phase of the Calvin-Benson cycle and one gene in sucrose synthesis. The mRNA levels increased and almost reached maxima before full expansion and then gradually declined. Group 3 included Rubisco activase, one gene involved in the regeneration phase and one gene in sucrose synthesis. The overall pattern was similar to that in group 2 genes except that the mRNA levels reached maxima after the stage of full expansion. Thus, genes of the Calvin-Benson cycle and its related genes were differentially expressed during leaf development in rice, suggesting that such differential gene expression is necessary for formation and maintenance of the machinery of photosynthetic carbon assimilation. PMID- 26615033 TI - OsSIZ1, a SUMO E3 Ligase Gene, is Involved in the Regulation of the Responses to Phosphate and Nitrogen in Rice. AB - SIZ1-mediated SUMOylation regulates hormone signaling as well as abiotic and biotic stress responses in plants. Here, we investigated the expression profile of OsSIZ1 in rice using quantitative reverse transcription-PCR (qRT-PCR) and pOsSIZ1-GUS transgenic plants, and the function of OsSIZ1 in the responses to phosphate and nitrogen using a reverse genetics approach. OsSIZ1 is constitutively expressed throughout the vegetative and reproductive growth of rice, with stronger promoter activities in vascular bundles of culms. ossiz1 mutants had shorter primary roots and adventitious roots than wild-type plants, suggesting that OsSIZ1 is associated with the regulation of root system architecture. Total phosphorus (P) and phosphate (Pi) concentrations in both roots and shoots of ossiz1 mutants were significantly increased irrespective of Pi supply conditions compared with the wild type. Pi concentration in the xylem sap of ossiz1 mutants was significantly higher than that of the wild type under a Pi-sufficient growth regime. Total nitrogen (N) concentrations in the most detected tissues of ossiz1 mutants were significantly increased compared with the wild type. Analysis of mineral contents in ossiz1 mutants indicated that OsSIZ1 functions specifically in Pi and N responses, not those of other nutrients examined, in rice. Further, qRT-PCR analyses revealed that the expression of multiple genes involved in Pi starvation signaling and N transport and assimilation were altered in ossiz1 mutants. Together, these results suggested that OsSIZ1 may act as a regulator of the Pi (N)-dependent responses in rice. PMID- 26615034 TI - Antihistamines for the common cold. AB - BACKGROUND: The common cold is an upper respiratory tract infection, most commonly caused by a rhinovirus. It affects people of all age groups and although in most cases it is self limiting, the common cold still causes significant morbidity. Antihistamines are commonly offered over the counter to relieve symptoms for patients affected by the common cold, however there is not much evidence of their efficacy. OBJECTIVES: To assess the effects of antihistamines on the common cold. SEARCH METHODS: We searched CENTRAL (2015, Issue 6), MEDLINE (1948 to July week 4, 2015), EMBASE (2010 to August 2015), CINAHL (1981 to August 2015), LILACS (1982 to August 2015) and Biosis Previews (1985 to August 2015). SELECTION CRITERIA: We selected randomised controlled trials (RCTs) using antihistamines as monotherapy for the common cold. We excluded any studies with combination therapy or using antihistamines in patients with an allergic component in their illness. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We collected adverse effects information from the included trials. MAIN RESULTS: We included 18 RCTs, which were reported in 17 publications (one publication reports on two trials) with 4342 participants (of which 212 were children) suffering from the common cold, both naturally occurring and experimentally induced. The interventions consisted of an antihistamine as monotherapy compared with placebo. In adults there was a short-term beneficial effect of antihistamines on severity of overall symptoms: on day one or two of treatment 45% had a beneficial effect with antihistamines versus 38% with placebo (odds ratio (OR) 0.74, 95% confidence interval (CI) 0.60 to 0.92). However, there was no difference between antihistamines and placebo in the mid term (three to four days) to long term (six to 10 days). When evaluating individual symptoms such as nasal congestion, rhinorrhoea and sneezing, there was some beneficial effect of the sedating antihistamines compared to placebo (e.g. rhinorrhoea on day three: mean difference (MD) -0.23, 95% CI -0.39 to -0.06 on a four- or five-point severity scale; sneezing on day three: MD -0.35, 95% CI -0.49 to -0.20 on a four-point severity scale), but this effect is clinically non-significant. Adverse events such as sedation were more commonly reported with sedating antihistamines although the differences were not statistically significant. Only two trials included children and the results were conflicting. The majority of the trials had a low risk of bias although some lacked sufficient trial quality information. AUTHORS' CONCLUSIONS: Antihistamines have a limited short-term (days one and two of treatment) beneficial effect on severity of overall symptoms but not in the mid to long term. There is no clinically significant effect on nasal obstruction, rhinorrhoea or sneezing. Although side effects are more common with sedating antihistamines, the difference is not statistically significant. There is no evidence of effectiveness of antihistamines in children. PMID- 26615035 TI - Effects of a Stroke Primary Prevention Program on Risk Factors for At-Home Elderly. AB - BACKGROUND To prevent stroke from occurring, stroke risk factors in at-risk subjects should be controlled and the diseases causing stroke should be managed. This study evaluated a nursing intervention to prevent stroke in at-risk elderly living at home. The program consisted of stroke and nutrition education as well as exercise guidance. MATERIAL AND METHODS This study targeted 93 elderly people living at home residing in E province with 1 or more stroke risk factors, including high blood pressure, diabetes, hyperlipidemia, obesity, smoking, or drinking alcohol. The 12-week program included a stroke education class once a week, a nutrition management class once a week, and exercise guidance 3 times a week. Each session lasted 50-70 min. Each disease education and nutrition management session lasted for 20 min and each exercise session lasted for 30-50 min. RESULTS The experimental group's body mass index (BMI) (t=8.27, p<.001), systolic blood pressure (t=2.39, p=.021), fasting blood sugar (t=0.39, p=.700), total cholesterol (t=4.18, p<.001), triglyceride levels (t=2.50, p=.016), and depression scores (t=5.48, p<.001) were significantly reduced and high-density phospholipid protein levels increased significantly by the end of the program (t= 2.94, p=.005). CONCLUSIONS Based on the results of this study, participating in a stroke prevention program enabled at-risk elderly participants who lived at home in rural areas to perform health-promoting behaviors. This program may reduce the incidence of stroke by reducing risk factors and managing stroke precursor diseases. PMID- 26615036 TI - Disposition of Charges, Out-of-Home Mental Health Treatment, and Juvenile Justice Recidivism. AB - This study examined whether the disposition of juvenile justice encounters among youth with severe emotional disturbance was associated with the likelihood of recidivism. Court dispositions, such as probation and diversion, as well as Medicaid-funded out-of-home mental health treatment, were compared. Data sources included the Florida Department of Juvenile Justice and Medicaid claims data. Youth receiving probation had the highest recidivism rates. Among youth in out-of home treatment, those receiving treatment in foster care services had the lowest recidivism rates. Youth placed into a diversion program were less likely to be re arrested for a felony, whereas youth receiving inpatient psychiatric services were less likely to be re-arrested for a misdemeanor. Mental health treatment may reduce the likelihood of youth continuing on increasing criminal trajectories. PMID- 26615037 TI - New Horizons: The Obstacles to Space Exploration and Disentangling Criminal Profiling. PMID- 26615038 TI - A Systematic Review on the Functions of Rap Among Gangs. AB - Although the field of gangs is well studied, information regarding the way gangs may use or misuse music for different needs is sparse. The aim of this systematic review is to gather descriptive and empirical information to ascertain the important roles rap music possesses within gang life. This review suggests five main functions of rap used within gangs with an emphasis on the subgenre of gangsta rap. First, rap facilitates antisocial behavior by reinforcing such messages in its lyrics. Second, its deviant lyrics serve as a reflection of the violent reality experienced in many urban ghetto communities. Third, it operates as a means for constructing individual and collective identity, as well as resistance identity. Fourth, it functions as an educating force by teaching its members how to act and respond in the urban ghetto. Finally, rap glorifies gang norms among newcomers and successfully spreads its values to the general population. PMID- 26615039 TI - The Effects of Life Domains, Constraints, and Motivations on Academic Dishonesty: A Partial Test and Extension of Agnew's General Theory. AB - Recently, Robert Agnew introduced a new general theory of crime and delinquency in which he attempted to corral the vast array of theoretical "causes" of criminal conduct into a more parsimonious statement organized into one of five life domains: self, family, peers, school, and work as well as constraints against crime and motivation for it. These domains are depicted as the source of constraints and motivations and whose effects are, in part, mediated by these constraints and motivations. Based on self-report data on academic dishonesty from a sample of college students, the present study attempts to test this general theory. While several of the life domain variables had significant effects of cheating in the baseline model, all of these effects were fully mediated by constraints and motivations. In the final model, academic dishonesty was observed to be most significantly affected by the perceived severity of formal sanction threats, the number of credit hours enrolled, the frequency of skipping classes, and pressure from friends. PMID- 26615041 TI - Sex Offenses Against Minors in China: An Empirical Comparison. AB - In recent years, due to a number of notorious sex offense cases against minors, a new punitive public attitude emerged in China and pressed for harsher crackdown and punishment against sex offenders. In particular, an "engagement in prostitution with a minor" law (Article 360 of the Criminal Law) was targeted as "unjust" based on the belief that offenders of such crimes often received "lenient" punishment, and many called for its abolition. In this study, based on 440 adjudicated sex offense cases, we examine potential differences across three sex offenses (including rape, child molestation, and engagement in prostitution with a minor) in the demographics of defendants and victims, offending characteristics, and trials and sentences of convicted offenders. Our empirical inquiry pointed to the unique nature of engagement in prostitution with a minor. Offenders of such crimes seemingly carried a different profile, compared with offenders of the other two sex crimes. Moreover, our data casted some doubt on the "lenient" punishment received by offenders of engagement in prostitution with a minor. Policy implications were also drawn based on our findings. PMID- 26615042 TI - Domestic Violence Against Partners According to Wife-Beaters: Construction of Lifestyle and Life Meaning. AB - This qualitative study examines the life stories of men who committed violent crimes against their intimate partners, for which they have served prison sentences. For the study, nine men in a rehabilitation hostel in Israel were interviewed. The study aim was to understand the psychological process that had brought the participants to behave violently towards their partners. Narrative analysis of the life stories resulted in two main themes. The first, childhood, was related to how the interviewee during his childhood perceived his personal identity and his parents. The second theme represented the adult interviewee's worldview of violence in general and of intimate partner violence in particular. The findings revealed a subjective feeling of inferiority and lack of worth and volition during childhood, a feeling of chaos, and the absence of existential meaning. To avoid these feelings in adulthood, the participants chose a lifestyle that included the use of force and violence, which provided them with a sense of control and meaning. Discussion of the findings is based on the individual psychology theory of Adler and his followers, as well as on the existentialist orientation. According to these approaches, the study participants, who lacked a sense of positive "existential being," developed a negative lifestyle that enabled them to feel a sense of security, value, and meaning. PMID- 26615043 TI - Comparative performance evaluation of conventional and two-phase hydrophobic stirred tank reactors for methane abatement: Mass transfer and biological considerations. AB - This study demonstrated for the first time the capability of methanotrophs to grow inside silicone oil (SO200) and identified the optimum cultivation conditions for enrichment of hydrophobic methanotrophs (high dilution rates (D) and low CH4 transfer rates). The potential of the hydrophobic methanotrophs enriched was assessed in a single-phase stirred tank reactor (1P-STR) and in a two-phase stirred tank reactor (2P-STR). Different operational conditions were systematically evaluated in both reactors (SO200 fractions of 30 and 60 %, stirring rates of 250 and 500 rpm, and D of 0.1-0.35 day(-1) with and without biomass retention). The results showed that the TPPB only supported a superior CH4 abatement performance compared to the 1P-STR (40% enhancement at 250 rpm and 25% enhancement at 500 rpm) at a D of 0.3 day(-1) due to the retention of the biocatalytic activity inside the SO200, while the 1P-STR achieved higher elimination capacities (EC up to ~3 times) than the TPPB under the rest of conditions tested (ECmax = 91.1 g m(-3) h(-1) ). Furthermore, the microscopic examination and DGGE-sequencing of the communities showed that the presence of SO200 influenced the microbial population structure, impacting on bacterial biodiversity and favoring the growth of methanotrophs such as Methylosarcina. Biotechnol. Bioeng. 2016;113: 1203-1212. (c) 2015 Wiley Periodicals, Inc. PMID- 26615044 TI - The Pro12Ala PPARg2 gene polymorphism involves residual C-peptide secretionand BMI in type 1 diabetes. AB - INTRODUCTION AND AIM: Since insulin resistance is genetically determined and observed in type 1 diabetes, the study was designed to elucidate an involvement of Ala 12 Pro PPARg2 gene polymorphism in residual C-peptide secretion and BMI variation in children with type 1 diabetes. MATERIAL AND METHODS: In 103 patients with type 1 diabetes genetic analysis of PPARg2 polymorphism, C-peptide measurements and evaluation of BMI and clinical parameters were performed. Control group consisted of 109 healthy subjects. RESULTS: In diabetic patients, only three individuals exhibited Ala 12 Ala genotype (2.9%) and 29 patients were heterozygous Ala 12 Pro (28.2%). Interestingly, Ala12+ variants were associated with higher C-peptide levels in 6 th , 12 th and 24 th months after the onset than Pro 12 Pro genotype (0.39+/-0.24 pmol/mL vs. 0.22+/-0.14 pmol/mL, P=0.007 and 0.19+/-0.09 vs. 0.11+/-0.07, P=0.01 and 0.13+/-0.09 vs. 0.07+/-0.05, P=0.021, respectively). Similarly, C-peptide was also significantly increased in patients with history of type 2 diabetes in the first-degree relatives. The observation was even more evident when Ala12+ variants were taken together with family history of type 2 diabetes. Besides, in 24 th and 36 th months after the onset, Ala12+ variants revealed to be associated with higher BMI normalized by age and sex as compared to Pro 12 Pro (0.557+/-0.84 vs. -0.119+/-0.73, P=0.001 and 0.589+/-0.919 vs. 0.066+/-0.630, P=0.016, respectively). CONCLUSIONS: Thus, it is likely that PPARg2 gene polymorphism and/or the genetically determined insulin resistance may be associated with residual C-peptide secretion and involve excessive BMI in type 1 diabetes. PMID- 26615045 TI - The impact of having siblings - analysis of "hygiene theory" of chronic diseases in patients with type 1 diabetes in population of the Lodz region Hygiene theory and type 1 diabetes. AB - INTRODUCTION: In the recent years there has been a significant increase in the incidence of the type 1 diabetes mellitus. Therefore, numerous studies are underway to evaluate the possible factors underlying this trend. Some studies suggest that better sanitary conditions and lack of contact with microorganisms might be important, thus increasing the risk of disease in firstborns. Moreover, siblings could play an important role in the transmission of pathogens, which, by stimulating the immune system, may prevent the development of atopic and autoimmune diseases including such as type 1 diabetes. Current data, however, are still inconclusive. PURPOSE: The aim of the study was to evaluate the effect of having siblings on the incidence of type 1 diabetes among children and adults. MATERIALS AND METHODS: A group of 469 patients with type 1 diabetes was selected. The study population was composed of 245 adults and 224 youth patients. Information from Outpatient Diabetologic Departments database was gathered. Data such as age at the diagnosis of diabetes, sex of siblings, number and birth order were analyzed. RESULTS: In the studied population, 4.5% were only children, and 30.3% patients came from large families. In the group of type 1 diabetic patients 39.7% were firstborns and this proportion was comparable to the group of healthy subject. The highest proportion of firstborns was noted in the group that was diagnosed after 18 years of age (45,1%) compared to the group that was diagnosed between 10 and 14 (29,1%) (p<0.05). Type 1 diabetic patients that were not firstborns much more often had older siblings of the opposite sex than the same sex. CONCLUSIONS: he firstborns in the population of type 1 diabetes from the Lodz region did not outnumber the healthy subjects. Significantly higher proportion of firstborns in the group that was diagnosed after 18 years of age compared to the group that was diagnosed between 10 an 14 years was noted. PMID- 26615046 TI - Silver-Russell Syndrome - Part I: Clinical Characteristics and Genetic Background. AB - Silver-Russell syndrome (SRS) is a rare, clinically and genetically heterogeneous entity, caused by (epi)genetic alternations. It is characterized by prenatal and postnatal growth retardation, relative macrocephaly, the triangular face and body asymmetry. About 40-60% of cases are caused by hypomethylation of 11p.15.5 Imprinting Centre Region 1 (ICR1) on the paternal chromosome, and maternal uniparental disomy for chromosome 7 (UPD(7)mat) is found in 5-10% of cases. There are suggested correlations between genotype and the phenotype. Psychomotor development may be delayed, usually mildly, with school difficulties and speech delay more common in patients with UPD(7)mat. Children with 11p15 hypomethylation are shorter and lighter at birth in comparison to children with UPD(7)mat, however further deceleration tends to be more apparent in the latter group. The onset of puberty tends to occur early, with acceleration of bone age, resulting in less apparent growth spurt. Failure to thrive and feeding problems are characteristic for the infant period, and further development of a child may be conditioned by additional congenital defects. PMID- 26615047 TI - [Insulin resistance in children]. AB - Insulin resistance is the state of reduced tissue sensitivity to insulin. The frequency of this occurrence is increasing dramatically in developed countries. Both, environmental and genetic factors are involved in the pathogenesis of insulin resistance. Sedentary lifestyle and the excessive calorie intake cause the substantial increase of the fat issue, leading to overweight and obesity. Insulin resistance occurs physiologically during puberty, but it is also a pathological condition predisposing children to develop abnormal glucose tolerance, diabetes, hypertension and polycystic ovary syndrome among girls. More frequent occurrence of metabolic syndrome can be observed among children born small for gestational age (SGA). The article presents the current views on risk factors, etiology, diagnosis and consequences insulin resistance and disorders of glucose tolerance. PMID- 26615048 TI - [Transition of young adults with type 1 diabetes mellitus from a pediatric to adult diabetes clinic - problems, challenges and recommendations]. AB - ABSTRACT: Type 1 diabetes is a chronic disease associated with the risk of acute and chronic complications. The patients with type 1 diabetes require constant monitoring in a diabetes outpatient clinic, regardless of their age, and the cessation of diabetes care may result in deterioration of metabolic control and earlier development of chronic complications. When the children grow up and reach 18 years of age, they must transfer from the custody of the pediatric outpatient clinic to the care of adult diabetes center. This is a very important time in the life of a young patient. When the transition is well planned, it can help young adults to live with diabetes independently. The paper presents the differences between pediatric and adult diabetes care and factors influencing diabetes control during transition process. In the article we discuss programs implemented in other countries to help young people with diabetes during transition process. Moreover the paper also demonstrates the recommendations of some scientific societies for the optimal organization of the transition to prevent a deterioration of metabolic control of diabetes. ABBREVIATIONS: DMT1- type 1 diabetes mellitus, HbA1c - glycosylated hemoglobin, PTD - Polish Diabetes Association, ADA - America Diabetes Association, SEARCH - SEARCH for Diabetes in Youth study, NICE - National Institute for Excellence. PMID- 26615049 TI - [Suspicion of anorexia nervosa as a cause of delayed diagnosis of brain tumor. A case report]. AB - Tumors of the central nervous system (CNS) are the most common solid tumors diagnosed in children. The most frequent symptoms of brain tumors in this age group are headaches and vomiting, regardless of the location of the lesions. These symptoms are non-specific, and in each case require differential diagnosis, especially if there is no gradual improvement in the patient's condition or progression. The most common signs of anorexia nervosa are chronic vomiting, weakness of the body, pain and in extreme cases cachexia. These symptoms are similar to the clinical image of CNS tumor. Teenager, described in our case report presented the following signs for several weeks prior to the diagnosis of a brain tumor: vomiting (especially after meals), non-specific headache and epigastric pain. No significant progression in the patient's condition oriented the diagnostic process towards anorexia nervosa. Although anorexia in this age group is much more common disease, compared to a brain tumor, it is vital to ruled out/ exclude organic disorders prior to diagnosis of psychogenic disorder. At the same time the waiting for the specialist consultations (ophthalmologist, neurologist) and test results (head CT, head NMR) should not prolong the patients referral to a specialist center. PMID- 26615051 TI - Compartment-specific expression of natural killer cell markers in renal transplantation: immune profile in acute rejection. AB - Natural killer (NK) cells have been implicated in graft dysfunction. Here, we formulated hypothesis that distinct patterns of expression NK cells markers correlated with acute rejection in kidney transplantation. Therefore, we studied the pattern of NK cell markers CD56, CD57, and CD16 in different compartments of biopsies obtained from recipients diagnosed with acute graft rejection, with or without donor-specific antibodies (DSA). DSA-negative biopsies-from patients with acute T-cell mediated rejection (aTCMR) had an increased expression of CD56+ and CD57+ cells (P = 0.004 and P = 0.001) in the interstitial compartment in comparison with DSA-positive biopsies from patients acute antibody-mediated rejection (aABMR) with (aABMR C4d+) and without C4d deposition (aABMR C4d-). CD16+ cells was increased (P = 0.03) in the glomerular compartment in DSA positive biopsies. We assume that CD16+ expression and antibody-dependent cellular cytotoxicity (ADCC) in microvascular injury can be associated with aABMR. IFN-gamma release from cytoplasmic granules of NK cell could be associated with aTCMR. Our findings suggest that NK cells need to be carefully evaluated because variations in NK cell marker expression might imply the involvement of different immune system pathways in graft rejection. PMID- 26615052 TI - Genetic differentiation and reduced genetic diversity at the northern range edge of two species with different dispersal modes. AB - Theory predicts that genetic variation should be reduced at range margins, but empirical support is equivocal. Here, we used genotyping-by-sequencing technology to investigate genetic variation in central and marginal populations of two species in the marine gastropod genus Crepidula. These two species have different development and dispersal types and might therefore show different spatial patterns of genetic variation. Both allelic richness and the proportion of private alleles were highest in the most central populations of both species, and lower at the margin. The species with low dispersal, Crepidula convexa, showed high degrees of structure throughout the range that conform to the pattern found in previous studies using other molecular markers. The northernmost populations of the high-dispersing species, Crepidula fornicata, are distinct from more central populations, although this species has been previously observed to have little genetic structure over much of its range. Although genetic diversity was significantly lower at the range margin, the absolute reduction in diversity observed with these genomewide markers was slight, and it is not yet known whether there are functional consequences for the marginal populations. PMID- 26615053 TI - Lower tract respiratory infection in children younger than 5 years of age and adverse pregnancy outcomes related to household air pollution in Bariloche (Argentina) and Temuco (Chile). AB - The main objective of this study was to evaluate the association between household air pollution with lower tract respiratory infection (LRTI) in children younger than 5 years old and adverse pregnancy outcomes. This retrospective cohort study took place in two cities in Patagonia. Using systemic random sampling, we selected households in which at least one child <5 years had lived and/or a child had been born alive or stillborn. Trained interviewers administered the questionnaire. We included 926 households with 695 pregnancies and 1074 children. Household cooking was conducted indoors in ventilated rooms and the use of wood as the principal fuel for cooking was lower in Temuco (13% vs. 17%). In exposed to biomass fuel use, the adjusted OR for LRTI was 1.87 (95% CI 0.98-3.55; P = 0.056) in Temuco and 1.12 (95% CI 0.61-2.05; P = 0.716) in Bariloche. For perinatal morbidity, the OR was 3.11 (95% CI 0.86-11.32; P = 0.084) and 1.41 (95% CI 0.50-3.97; P = 0.518), respectively. However, none of the effects were statistically significant (P > 0.05). The use of biomass fuel to cook in traditional cookstoves in ventilated dwellings may increase the risk of perinatal morbidity and LRTI. PMID- 26615054 TI - Effect of renal function on serum concentration of 1,5-anhydroglucitol in type 2 diabetic patients in chronic kidney disease stages I-III: A comparative study with HbA1c and glycated albumin. AB - BACKGROUND: 1,5-Anhydroglucitol (1,5-AG) is a new blood glucose control marker reflecting temporary glucose elevations. However, 1,5-AG is of limited value in patients with advanced renal insufficiency. The aim of the present study was to assess the correlation between 1,5-AG levels and renal function in patients with earlier stages of nephropathy compared with another two markers of diabetes control, namely HbA1c and glycated albumin (GA). METHODS: The following parameters were measured in 377 patients with type 2 diabetes: HbA1c, serum concentrations of 1,5-AG, GA and creatinine, hemoglobin, urinary albumin/creatinine ratio, and urinary excretion of alpha1 -microglobulin (A1M). Estimated glomerular filtration rate (eGFR) was calculated according to the Cockgroft-Gault formula. RESULTS: There was a negative correlation between 1,5-AG and renal function (r = -0.18; P < 0.001). Concentrations of 1,5-AG were, on average, 27.2% lower in patients with glomerular hyperfiltration (eGFR >120 mL/min) compared with patients with moderate renal impairment (eGFR 30-59 mL/min; P = 0.016). In contrast, HbA1c, GA levels and urinary A1M excretion did not differ between the two patient groups. The mean age of patients with eGFR 30-59 mL/min was substantially higher than that of patients with glomerular hyperfiltration (P < 0.001). Thus, an age-related change in the renal glucose threshold could be the reason for the observed correlation between 1,5-AG and renal function. CONCLUSIONS: In clinical practice, age and renal function must be taken into consideration when interpreting 1,5-AG levels, even in the absence of advanced renal impairment. PMID- 26615050 TI - Progress and challenges in macroencapsulation approaches for type 1 diabetes (T1D) treatment: Cells, biomaterials, and devices. AB - Macroencapsulation technology has been an attractive topic in the field of treatment for Type 1 diabetes due to mechanical stability, versatility, and retrievability of the macro-capsule design. Macro-capsules can be categorized into extravascular and intravascular devices, in which solute transport relies either on diffusion or convection, respectively. Failure of macroencapsulation strategies can be due to limited regenerative capacity of the encased insulin producing cells, sub-optimal performance of encapsulation biomaterials, insufficient immunoisolation, excessive blood thrombosis for vascular perfusion devices, and inadequate modes of mass transfer to support cell viability and function. However, significant technical advancements have been achieved in macroencapsulation technology, namely reducing diffusion distance for oxygen and nutrients, using pro-angiogenic factors to increase vascularization for islet engraftment, and optimizing membrane permeability and selectivity to prevent immune attacks from host's body. This review presents an overview of existing macroencapsulation devices and discusses the advances based on tissue-engineering approaches that will stimulate future research and development of macroencapsulation technology. Biotechnol. Bioeng. 2016;113: 1381-1402. (c) 2015 Wiley Periodicals, Inc. PMID- 26615055 TI - Stuck in the catch 22: attitudes towards smoking cessation among populations vulnerable to social disadvantage. AB - AIM: To explore how smoking and smoking cessation is perceived within the context of disadvantage, across a broad cross-section of defined populations vulnerable to social disadvantage. DESIGN: Qualitative focus groups with participants recruited through community service organizations (CSO). SETTING: Metropolitan and regional settings in Queensland, Australia. Focus groups were held at the respective CSO facilities. PARTICIPANTS: Fifty-six participants across nine focus groups, including people living with mental illness, people experiencing or at risk of homelessness (adult and youth populations), people living with HIV, people living in a low-income area and Indigenous Australians. MEASUREMENTS: Thematic, in-depth analysis of focus group discussions. Participant demographic information and smoking history was recorded. FINDINGS: Smoking behaviour, smoking identity and feelings about smoking were reflective of individual circumstances and social and environmental context. Participants felt 'trapped' in smoking because they felt unable to control the stressful life circumstances that triggered and sustained their smoking. Smoking cessation was viewed as an individual's responsibility, which was at odds with participants' statements about the broader factors outside of their own control that were responsible for their smoking. CONCLUSION: Highly disadvantaged smokers' views on smoking involve contradictions between feeling that smoking cessation involves personal responsibility, while at the same time feeling trapped by stressful life circumstances. Tobacco control programmes aiming to reduce smoking among disadvantaged groups are unlikely to be successful unless the complex interplay of social factors is carefully considered. PMID- 26615056 TI - Bioengineered glaucomatous 3D human trabecular meshwork as an in vitro disease model. AB - Intraocular pressure (IOP) is mostly regulated by aqueous humor outflow through the human trabecular meshwork (HTM) and represents the only modifiable risk factor of glaucoma. The lack of IOP-modulating therapeutics that targets HTM underscores the need of engineering HTM for understanding the outflow physiology and glaucoma pathology in vitro. Using a 3D HTM model that allows for regulation of outflow in response to a pharmacologic steroid, a fibrotic state has been induced resembling that of glaucomatous HTM. This disease model exhibits HTM marker expression, ECM overproduction, impaired HTM cell phagocytic activity and outflow resistance, which represent characteristics found in steroid-induced glaucoma. In particular, steroid-induced ECM alterations in the glaucomatous model can be modified by a ROCK inhibitor. Altogether, this work presents a novel in vitro disease model that allows for physiological and pathological studies pertaining to regulating outflow, leading to improved understanding of steroid induced glaucoma and accelerated discovery of new therapeutic targets. Biotechnol. Bioeng. 2016;113: 1357-1368. (c) 2015 Wiley Periodicals, Inc. PMID- 26615057 TI - An orbital shear platform for real-time, in vitro endothelium characterization. AB - Electrical impedance techniques have been used to characterize endothelium morphology, permeability, and motility in vitro. However, these impedance platforms have been limited to either static endothelium studies and/or induced laminar fluid flow at a constant, single shear stress value. In this work, we present a microfabricated impedance sensor for real-time, in vitro characterization of human umbilical vein endothelial cells (HUVECs) undergoing oscillatory hydrodynamic shear. Oscillatory shear was applied with an orbital shaker and the electrical impedance was measured by a microfabricated impedance chip with discrete electrodes positioned at radial locations of 0, 2.5, 5.0, 7.5, 10.0, and 12.5 mm from the center of the chip. Depending on their radial position within the circular orbital platform, HUVECs were exposed to shear values ranging between 0.6 and 6.71 dyne/cm(2) (according to numerical simulations) for 22 h. Impedance spectra were fit to an equivalent circuit model and the trans endothelial resistance and monolayer's capacitance were extracted. Results demonstrated that, compared to measurements acquired before the onset of shear, cells at the center of the platform that experienced low steady shear stress (~2.2 dyne/cm(2) ) had an average change in trans-endothelial resistance of 6.99 +/- 4.06% and 1.78 +/- 2.40% change in cell capacitance after 22 hours of shear exposure; cells near the periphery of the well (r = 12.5 mm) experienced transient shears (2.5-6.7 dyne/cm(2) ) and exhibited a greater change in trans endothelial resistance (24.2 +/- 10.8%) and cell capacitance (4.57 +/- 5.39%). This study, demonstrates that the orbital shear platform provides a simple system that can capture and quantify the real-time cellular morphology as a result of induced shear stress. The orbital shear platform presented in this work, compared to traditional laminar platforms, subjects cells to more physiologically relevant oscillatory shear as well as exposes the sample to several shear values simultaneously. Biotechnol. Bioeng. 2016;113: 1336-1344. (c) 2015 Wiley Periodicals, Inc. PMID- 26615058 TI - Natural epigenetic variation contributes to heritable flowering divergence in a widespread asexual dandelion lineage. AB - Epigenetic variation has been proposed to contribute to the success of asexual plants, either as a contributor to phenotypic plasticity or by enabling transient adaptation via selection on transgenerationally stable, but reversible, epialleles. While recent studies in experimental plant populations have shown the potential for epigenetic mechanisms to contribute to adaptive phenotypes, it remains unknown whether heritable variation in ecologically relevant traits is at least partially epigenetically determined in natural populations. Here, we tested the hypothesis that DNA methylation variation contributes to heritable differences in flowering time within a single widespread apomictic clonal lineage of the common dandelion (Taraxacum officinale s. lat.). Apomictic clone members of the same apomictic lineage collected from different field sites showed heritable differences in flowering time, which was correlated with inherited differences in methylation-sensitive AFLP marker profiles. Differences in flowering between apomictic clone members were significantly reduced after in vivo demethylation using the DNA methyltransferase inhibitor zebularine. This synchronization of flowering times suggests that flowering time divergence within an apomictic lineage was mediated by differences in DNA methylation. While the underlying basis of the methylation polymorphism at functional flowering time affecting loci remains to be demonstrated, our study shows that epigenetic variation contributes to heritable phenotypic divergence in ecologically relevant traits in natural plant populations. This result also suggests that epigenetic mechanisms can facilitate adaptive divergence within genetically uniform asexual lineages. PMID- 26615059 TI - Successful pregnancy after ABO-incompatible kidney transplantation. PMID- 26615060 TI - The legacy of a vanished sea: a high level of diversification within a European freshwater amphipod species complex driven by 15 My of Paratethys regression. AB - The formation of continental Europe in the Neogene was due to the regression of the Tethys Ocean and of the Paratethys Sea. The dynamic geology of the area and repetitious transitions between marine and freshwater conditions presented opportunities for the colonization of newly emerging hydrological networks and diversification of aquatic biota. Implementing mitochondrial and nuclear markers in conjunction with a large-scale sampling strategy, we investigated the impact of this spatiotemporal framework on the evolutionary history of a freshwater crustacean morphospecies. The Gammarus balcanicus species complex is widely distributed in the area previously occupied by the Paratethys Sea. Our results revealed its high diversification and polyphyly in relation to a number of other morphospecies. The distribution of the studied amphipod is generally characterized by very high local endemism and divergence. The Bayesian time calibrated reconstruction of phylogeny and geographical distribution of ancestral nodes indicates that this species complex started to diversify in the Early Miocene in the central Balkans, partially in the shallow epicontinental sea. It is possible that there were several episodes of inland water colonization by local brackish water lineages. Subsequent diversification within clades and spread to new areas could have been induced by Alpine orogeny in the Miocene/Pliocene and, finally, by Pleistocene glaciations. The present distribution of clades, in many cases, still reflects Miocene palaeogeography of the area. Our results point out that investigations of the historical aspect of cryptic diversity in other taxa may help in a general understanding of the origins of freshwater invertebrate fauna of Europe. PMID- 26615062 TI - A Note from the Guest Editor. PMID- 26615061 TI - Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia. AB - AIMS: Hydroxyurea has emerged as the primary disease-modifying therapy for patients with sickle cell anaemia (SCA). The laboratory and clinical benefits of hydroxyurea are optimal at maximum tolerated dose (MTD), but the current empirical dose escalation process often takes up to 12 months. The purpose of this study was to develop a pharmacokinetic-guided dosing strategy to reduce the time required to reach hydroxyurea MTD in children with SCA. METHODS: Pharmacokinetic (PK) data from the HUSTLE trial (NCT00305175) were used to develop a population PK model using non-linear mixed effects modelling (nonmem 7.2). A D-optimal sampling strategy was developed to estimate individual PK and hydroxyurea exposure (area under the concentration-time curve (AUC)). The initial AUC target was derived from HUSTLE clinical data and defined as the mean AUC at MTD. RESULTS: PK profiles were best described by a one compartment with Michaelis Menten elimination and a transit absorption model. Body weight and cystatin C were identified as significant predictors of hydroxyurea clearance. The following clinically feasible sampling times are included in a new prospective protocol: pre-dose (baseline), 15-20 min, 50-60 min and 3 h after an initial 20 mg kg(-1) oral dose. The mean target AUC(0,infinity) for initial dose titration was 115 mg l(-1) h. CONCLUSION: We developed a PK model-based individualized dosing strategy for the prospective Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). This approach has the potential to optimize the dose titration of hydroxyurea therapy for children with SCA, such that the clinical benefits at MTD are achieved more quickly. PMID- 26615064 TI - A Climate and Health Groundswell. PMID- 26615065 TI - Climate Change, Human Rights, and Social Justice. AB - The environmental and health consequences of climate change, which disproportionately affect low-income countries and poor people in high-income countries, profoundly affect human rights and social justice. Environmental consequences include increased temperature, excess precipitation in some areas and droughts in others, extreme weather events, and increased sea level. These consequences adversely affect agricultural production, access to safe water, and worker productivity, and, by inundating land or making land uninhabitable and uncultivatable, will force many people to become environmental refugees. Adverse health effects caused by climate change include heat-related disorders, vector borne diseases, foodborne and waterborne diseases, respiratory and allergic disorders, malnutrition, collective violence, and mental health problems. These environmental and health consequences threaten civil and political rights and economic, social, and cultural rights, including rights to life, access to safe food and water, health, security, shelter, and culture. On a national or local level, those people who are most vulnerable to the adverse environmental and health consequences of climate change include poor people, members of minority groups, women, children, older people, people with chronic diseases and disabilities, those residing in areas with a high prevalence of climate-related diseases, and workers exposed to extreme heat or increased weather variability. On a global level, there is much inequity, with low-income countries, which produce the least greenhouse gases (GHGs), being more adversely affected by climate change than high-income countries, which produce substantially higher amounts of GHGs yet are less immediately affected. In addition, low-income countries have far less capability to adapt to climate change than high-income countries. Adaptation and mitigation measures to address climate change needed to protect human society must also be planned to protect human rights, promote social justice, and avoid creating new problems or exacerbating existing problems for vulnerable populations. PMID- 26615066 TI - Adolescent Girls, Human Rights and the Expanding Climate Emergency. PMID- 26615067 TI - Statement and Action Agenda from the Girls in Emergencies Collaborative. PMID- 26615068 TI - Temperature and Humidity Effects on Hospital Morbidity in Darwin, Australia. AB - BACKGROUND: Many studies have explored the relationship between temperature and health in the context of a changing climate, but few have considered the effects of humidity, particularly in tropical locations, on human health and well-being. To investigate this potential relationship, this study assessed the main and interacting effects of daily temperature and humidity on hospital admission rates for selected heat-relevant diagnoses in Darwin, Australia. METHODS: Univariate and bivariate Poisson generalized linear models were used to find statistically significant predictors and the admission rates within bins of predictors were compared to explore nonlinear effects. FINDINGS: The analysis indicated that nighttime humidity was the most statistically significant predictor (P < 0.001), followed by daytime temperature and average daily humidity (P < 0.05). There was no evidence of a significant interaction between them or other predictors. The nighttime humidity effect appeared to be strongly nonlinear: Hot days appeared to have higher admission rates when they were preceded by high nighttime humidity. CONCLUSIONS: From this analysis, we suggest that heat-health policies in tropical regions similar to Darwin need to accommodate the effects of temperature and humidity at different times of day. PMID- 26615069 TI - Climate Change and Water Scarcity: The Case of Saudi Arabia. AB - BACKGROUND: Climate change is expected to bring increases in average global temperatures (1.4 degrees C-5.8 degrees C [34.52 degrees F-42.44 degrees F] by 2100) and precipitation levels to varying degrees around the globe. The availability and quality of water will be severely affected, and public health threats from the lack of this valuable resource will be great unless water-scarce nations are able to adapt. Saudi Arabia provides a good example of how the climate and unsustainable human activity go hand in hand in creating stress on and depleting water resources, and an example for adaptation and mitigation. METHOD: A search of the English literature addressing climate change, water scarcity, human health, and related topics was conducted using online resources and databases accessed through the University at Albany, State University of New York library web page. RESULTS: Water scarcity, which encompasses both water availability and water quality, is an important indicator of health. Beyond drinking, water supply is intimately linked to food security, sanitation, and hygiene, which are primary contributors to the global burden of disease. Poor and disadvantaged populations are the ones who will suffer most from the negative effects of climate change on water supply and associated human health issues. Examples of adaptation and mitigation measures that can help reduce the strain on conventional water resources (surface waters and fossil aquifers or groundwater) include desalination, wastewater recycling and reuse, and outsourcing food items or "virtual water trade." These are strategies being used by Saudi Arabia, a country that is water poor primarily due to decades of irresponsible irrigation practices. The human and environmental health risks associated with these adaptation measures are examined. Finally, strategies to protect human health through international collaboration and the importance of these efforts are discussed. CONCLUSION: International, multidisciplinary cooperation and collaboration will be needed to promote global water security and to protect human health, particularly in low-income countries that do not have the resources necessary to adapt on their own. PMID- 26615070 TI - Chile Confronts its Environmental Health Future After 25 Years of Accelerated Growth. AB - BACKGROUND: Chile has recently been reclassified by the World Bank from an upper middle-income country to a high-income country. There has been great progress in the last 20 to 30 years in relation to air and water pollution in Chile. Yet after 25 years of unrestrained growth, there remain clear challenges posed by air and water pollution, as well as climate change. OBJECTIVE: The aim of this study was to review environmental health in Chile. METHODS: In late 2013, a 3-day workshop on environmental health was held in Santiago, Chile, bringing together researchers and government policymakers. As a follow-up to that workshop, here we review the progress made in environmental health in the past 20 to 30 years and discuss the challenges of the future. We focus on air and water pollution and climate change, which we believe are among the most important areas of environmental health in Chile. RESULTS: Air pollution in some cities remains among the highest in the continent. Potable water is generally available, but weak state supervision has led to serious outbreaks of infectious disease and ongoing issues with arsenic exposure in some regions. Climate change modeling in Chile is quite sophisticated, and a number of the impacts of climate change can be reasonably predicted in terms of which areas of the country are most likely to be affected by increased temperature and decreased availability of water, as well as expansion of vector territory. Some health effects, including changes in vector-borne diseases and excess heat mortality, can be predicted. However, there has yet to be an integration of such research with government planning. CONCLUSIONS: Although great progress has been made, currently there are a number of problems. We suspect that the Chilean experience in environmental health may be of some use for other Latin American countries with rapid economic development. PMID- 26615071 TI - A Systematic Review of Innate Immunomodulatory Effects of Household Air Pollution Secondary to the Burning of Biomass Fuels. AB - BACKGROUND: Household air pollution (HAP)-associated acute lower respiratory infections cause 455,000 deaths and a loss of 39.1 million disability-adjusted life years annually. The immunomodulatory mechanisms of HAP are poorly understood. OBJECTIVES: The aim of this study was to conduct a systematic review of all studies examining the mechanisms underlying the relationship between HAP secondary to solid fuel exposure and acute lower respiratory tract infection to evaluate current available evidence, identify gaps in knowledge, and propose future research priorities. METHODS: We conducted and report on studies in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. In all, 133 articles were fully reviewed and main characteristics were detailed, namely study design and outcome, including in vivo versus in vitro and pollutants analyzed. Thirty-six studies were included in a nonexhaustive review of the innate immune system effects of ambient air pollution, traffic-related air pollution, or wood smoke exposure of developed country origin. Seventeen studies investigated the effects of HAP-associated solid fuel (biomass or coal smoke) exposure on airway inflammation and innate immune system function. RESULTS: Particulate matter may modulate the innate immune system and increase susceptibility to infection through a) alveolar macrophage-driven inflammation, recruitment of neutrophils, and disruption of barrier defenses; b) alterations in alveolar macrophage phagocytosis and intracellular killing; and c) increased susceptibility to infection via upregulation of receptors involved in pathogen invasion. CONCLUSIONS: HAP secondary to the burning of biomass fuels alters innate immunity, predisposing children to acute lower respiratory tract infections. Data from biomass exposure in developing countries are scarce. Further study is needed to define the inflammatory response, alterations in phagocytic function, and upregulation of receptors important in bacterial and viral binding. These studies have important public health implications and may lead to the design of interventions to improve the health of billions of people daily. PMID- 26615072 TI - Household Air Pollution Exposures of Pregnant Women Receiving Advanced Combustion Cookstoves in India: Implications for Intervention. AB - BACKGROUND: Household air pollution (HAP) resulting from the use of solid cooking fuels is a leading contributor to the burden of disease in India. Advanced combustion cookstoves that reduce emissions from biomass fuels have been considered potential interventions to reduce this burden. Relatively little effort has been directed, however, to assessing the concentration and exposure changes associated with the introduction of such devices in households. OBJECTIVES: The aim of this study was to describe HAP exposure patterns in pregnant women receiving a forced-draft advanced combustion cookstove (Philips model HD 4012) in the SOMAARTH Demographic Development & Environmental Surveillance Site (DDESS) Palwal District, Haryana, India. The monitoring was performed as part of a feasibility study to inform a potential large-scale HAP intervention (Newborn Stove trial) directed at pregnant women and newborns. METHODS: This was a paired comparison exercise study with measurements of 24-hour personal exposures and kitchen area concentrations of carbon monoxide (CO) and particulate matter less than 2.5 MUm in aerodynamic diameter (PM2.5), before and after the cookstove intervention. Women (N = 65) were recruited from 4 villages of SOMAARTH DDESS. Measurements were performed between December 2011 and March 2013. Ambient measurements of PM2.5 were also performed throughout the study period. FINDINGS: Measurements showed modest improvements in 24-hour average concentrations and exposures for PM2.5 and CO (ranging from 16% to 57%) with the use of the new stoves. Only those for CO showed statistically significant reductions. CONCLUSION: Results from the present study did not support the widespread use of this type of stove in this population as a means to reliably provide health-relevant reductions in HAP exposures for pregnant women compared with open biomass cookstoves. The feasibility assessment identified multiple factors related to user requirements and scale of adoption within communities that affect the field efficacy of advanced combustion cookstoves as well as their potential performance in HAP intervention studies. PMID- 26615073 TI - Defining Polio: Closing the Gap in Global Surveillance. AB - BACKGROUND: By late 2012 the Global Polio Eradication Initiative (GPEI) had nearly eradicated this ancient infectious disease. Successful surveillance programs for acute flaccid paralysis however rely on broad governmental support for implementation. With the onset of conflict, public health breakdown has contributed to the resurgence of polio in a number of regions. The current laboratory based case definition may be a contributory factor in these regions. OBJECTIVE: We sought to compare case definition rates using strict laboratory based criteria to rates obtained using the clinical criteria in modern day Syria. We also sought to examine this distribution of cases by sub-region. METHODS: We examined the World Health Organization (WHO) reported figures for Syria from 2013 2014 using laboratory based criteria. We compared these with cases obtained when clinical criteria were applied. In addition we sought data from the opposition controlled Assistance Coordination Unit which operates in non-Government controlled areas where WHO data maybe incomplete. Cases were carefully examined for potential overlap to avoid double reporting. FINDINGS: Whilst the WHO data clearly confirmed the polio outbreak in Syria, it did so with considerable delay and with under reporting of cases, particularly from non-government controlled areas. In addition, laboratory based case definition led to a substantial underestimate of polio (36 cases) compared with those found with the clinically compatible definition (an additional 46 cases). Rates of adequate diagnostic specimens from suspected cases are well below target, no doubt reflecting the effect of conflict in these areas. CONCLUSIONS: We have identified a gap in the surveillance of polio, a global threat. The current laboratory based definition, in the setting of conflict and insecurity, leads to under diagnosis of polio with potential delays and inadequacies in coordinating effective responses to contain outbreaks and eradicate polio. Breakdown in public health measures as a contributing factor is likely to result in a resurgence of previously controlled infectious diseases. The clinical definition should be reinstituted to supplement the lab-based definition. PMID- 26615074 TI - Do Americans Understand That Global Warming Is Harmful to Human Health? Evidence From a National Survey. AB - BACKGROUND: Global warming has significant negative consequences for human health, with some groups at greater risk than others. The extent to which the public is aware of these risks is unclear; the limited extant research has yielded discrepant findings. OBJECTIVES: This paper describes Americans' awareness of the health effects of global warming, levels of support for government funding and action on the issue, and trust in information sources. We also investigate the discrepancy in previous research findings between assessments based on open- versus closed-ended questions. METHODS: A nationally representative survey of US adults (N = 1275) was conducted online in October 2014. Measures included general attitudes and beliefs about global warming, affective assessment of health effects, vulnerable populations and specific health conditions (open- and closed-ended), perceived risk, trust in sources, and support for government response. FINDINGS: Most respondents (61%) reported that, before taking the survey, they had given little or no thought to how global warming might affect people's health. In response to a closed-ended question, many respondents (64%) indicated global warming is harmful to health, yet in response to an open-ended question, few (27%) accurately named one or more specific type of harm. In response to a closed-ended question, 33% indicated some groups are more affected than others, yet on an open-ended question only 25% were able to identify any disproportionately affected populations. Perhaps not surprising given these findings, respondents demonstrated only limited support for a government response: less than 50% of respondents said government should be doing more to protect against health harms from global warming, and about 33% supported increased funding to public health agencies for this purpose. Respondents said their primary care physician is their most trusted source of information on this topic, followed by the Centers for Disease Control and Prevention, the World Health Organization, and their local public health department. CONCLUSIONS: Most Americans report a general sense that global warming can be harmful to health, but relatively few understand the types of harm it causes or who is most likely to be affected. Perhaps as a result, there is only moderate support for an expanded public health response. Primary care physicians and public health officials appear well positioned to educate the public about the health relevance of climate change. PMID- 26615075 TI - Inspire Hope, Not Fear: Communicating Effectively About Climate Change and Health. PMID- 26615076 TI - "Independence" Day. PMID- 26615077 TI - Health in National Climate Change Adaptation Planning. PMID- 26615078 TI - Climate Change and Health Adaptation: Consequences for Indigenous Physical and Mental Health. PMID- 26615079 TI - Climate Change and Health Inequities: A Framework for Action. PMID- 26615080 TI - Climate Change and Health: Transcending Silos to Find Solutions. AB - BACKGROUND: Climate change has myriad implications for the health of humans, our ecosystems, and the ecological processes that sustain them. Projections of rising greenhouse gas emissions suggest increasing direct and indirect burden of infectious and noninfectious disease, effects on food and water security, and other societal disruptions. As the effects of climate change cannot be isolated from social and ecological determinants of disease that will mitigate or exacerbate forecasted health outcomes, multidisciplinary collaboration is critically needed. OBJECTIVES: The aim of this article was to review the links between climate change and its upstream drivers (ie, processes leading to greenhouse gas emissions) and health outcomes, and identify existing opportunities to leverage more integrated global health and climate actions to prevent, prepare for, and respond to anthropogenic pressures. METHODS: We conducted a literature review of current and projected health outcomes associated with climate change, drawing on findings and our collective expertise to review opportunities for adaptation and mitigation across disciplines. FINDINGS: Health outcomes related to climate change affect a wide range of stakeholders, providing ready collaborative opportunities for interventions, which can be differentiated by addressing the upstream drivers leading to climate change or the downstream effects of climate change itself. CONCLUSIONS: Although health professionals are challenged with risks from climate change and its drivers, the adverse health outcomes cannot be resolved by the public health community alone. A phase change in global health is needed to move from a passive responder in partnership with other societal sectors to drive innovative alternatives. It is essential for global health to step outside of its traditional boundaries to engage with other stakeholders to develop policy and practical solutions to mitigate disease burden of climate change and its drivers; this will also yield compound benefits that help address other health, environmental, and societal challenges. PMID- 26615081 TI - How to Deliver the Most Important Public Health Treaty of the Century. PMID- 26615082 TI - The Post-2015 Sustainable Development Agenda-Are We Doing Mental Health Justice? PMID- 26615083 TI - The expanding spectrum of thyroid hormone resistance concerns the entire medical field. PMID- 26615084 TI - [Suicide headache]. PMID- 26615086 TI - Histomorphometry and Bone Matrix Mineralization Before and After Bisphosphonate Treatment in Boys With Duchenne Muscular Dystrophy: A Paired Transiliac Biopsy Study. AB - Duchenne muscular dystrophy (DMD) is a genetic disorder causing progressive muscle weakness. To prolong independent ambulation, DMD patients are treated with glucocorticoids, which, in turn, can increase bone fragility. In a cohort with vertebral fractures, intravenous bisphosphonate (iv BP) therapy stabilized vertebrae and reduced back pain. To characterize the effects of glucocorticoid therapy and bisphosphonate treatment on bone tissue and material properties, paired transiliac biopsy samples (before and after on average 2.4 years of iv BP) from 9 boys with DMD were studied for histomorphometry and bone mineralization density distribution (BMDD) and compared to reference values. Before iv BP, the boys had low cancellous bone volume (BV/TV) and cortical thickness (Ct.Wi) (both on average 56% of the healthy average, p < 0.001 versus reference), and mineralizing surface (MS/BS) in the lower normal range (on average 74% of the healthy average). The average degree of mineralization of cancellous (Cn.CaMean) and cortical compartments (Ct.CaMean) was 21.48 (20.70, 21.90) wt% and 20.42 (19.32, 21.64) wt%, respectively (median [25th, 75th percentiles]), which was not different from reference. After iv BP, BV/TV and Ct.Wi were, on average, unchanged. However, at the individual patient level, BV/TV Z-scores increased in 2, remained unchanged in 4, and declined in 3 patients. Additionally, on average, MS/BS decreased (-85%, p < 0.001), Cn.CaMean (+2.7%) increased, whereas the heterogeneity of cancellous (Cn.CaWidth -19%) and cortical bone mineralization (Ct.CaWidth -8%, all p < 0.05) decreased versus baseline. The changes in bone mineralization are consistent with the antiresorptive action of iv BP. At the same time, our observations point to the need for novel therapies with less or absent bone turnover suppression, including the fact that bone turnover was low even before bisphosphonate therapy, that bone turnover declined further (as expected) with treatment, and that declines in trabecular bone volume were observed in some boys despite bisphosphonate therapy. (c) 2015 American Society for Bone and Mineral Research. PMID- 26615085 TI - Preadult life history variation determines adult transcriptome expression. AB - Preadult determinants of adult fitness and behaviour have been documented in a variety of organisms with complex life cycles, but little is known about expression patterns of genes underlying these adult traits. We explored the effects of differences in egg-to-adult development time on adult transcriptome and cuticular hydrocarbon variation in order to understand the nature of the genetic correlation between preadult development time and premating isolation between populations of Drosophila mojavensis reared in different host cactus environments. Transcriptome variation was analysed separately in flies reared on each host and revealed that hundreds of genes in adults were differentially expressed (FDR P < 0.05) due to development time differences. For flies reared on pitaya agria cactus, longer preadult development times caused increased expression of genes in adults enriched for ribosome production, protein metabolism, chromatin remodelling and regulation of alternate splicing and transcription. Baja California flies reared on organ pipe cactus showed fewer differentially expressed genes in adults due to longer preadult development time, but these were enriched for ATP synthesis and the TCA cycle. Mainland flies reared on organ pipe cactus with shorter development times showed increased transcription of genes enriched for mitochondria and energy production, protein synthesis and glucose metabolism: adults with longer development times had increased expression of genes enriched for adult life span, cuticle proteins and ion binding, although most differentially expressed genes were unannotated. Differences due to population, sex, mating status and their interactions were also assessed. Adult cuticular hydrocarbon profiles also showed shifts due to egg to-adult development time and were influenced by population and mating status. These results help to explain why preadult life history variation determines subsequent expression of the adult transcriptome along with traits involved with reproductive isolation and revealed previously undocumented connections between genetic and environmental influences over the entire life cycle in this desert insect. PMID- 26615088 TI - Retrospective survey to evaluate the safety and efficacy of Japanese botulinum antitoxin therapy in Japan. AB - Japanese botulinum antitoxins have been used for more than 50 years; however, their safety and therapeutic efficacy are not clear. In order to analyze the available data on botulinum antitoxin therapy in Japan, we surveyed published reports about botulism cases in which botulinum antitoxins were used, and retrospectively analyzed the safety and efficacy of the therapy. A total of 134 patients administered botulinum antitoxins were identified from published reports. Two cases of side effects (1.5%) were detected after antitoxin administration, both not fatal. The fatality rate was 9.4%, and more than 70% of the patients showed improvement in their symptoms and better clinical conditions than those not treated with antitoxins. These data suggest that the therapy with Japanese antitoxins is safe and highly effective. PMID- 26615087 TI - Parental Restriction of Mature-rated Media and Its Association With Substance Use Among Argentinean Adolescents. AB - OBJECTIVE: To assess the independent relation between parental restrictions on mature-rated media (M-RM) and substance use among South American adolescents. METHODS: Cross-sectional school-based youth survey of 3,172 students (mean age, 12.8 years; 57.6% boys) in 3 large Argentinean cities. The anonymous survey queried tobacco, alcohol, and drug use using items adapted from global youth surveys. Adolescents reported M-RM restriction for internet and video game use, television programming, and movies rated for adults. Multivariate logistic regression models were used to assess the association between parental M-RM restriction and substance use after adjustment for hourly media use, measures of authoritative parenting style, sociodemographic characteristics, and sensation seeking. RESULTS: Substance use rates were 10% for current smoking, 32% for current drinking alcohol, 17% for past 30-day binge drinking, and 8% for illicit drug use (marijuana or cocaine). Half of the respondents reported parental M-RM restriction (internet 52%, TV 43%, adult movies 34%, video game 25%). Parental M RM restriction was only modestly correlated with authoritative parenting measures. In multivariate analyses M-RM restriction on all 4 venues was strongly protective for all substance use outcomes. Compared with no restriction, odds ratios for substance use for full restrictions were 0.32 (0.18-0.59), 0.53 (0.38 0.07), 0.36 (0.22-0.59), and 0.49 (0.26-0.92) for current smoking, drinking, binge drinking, and illicit drug use, respectively. The most important single M RM venue was movies. CONCLUSIONS: Results of this study confirmed the protective association between parental M-RM restriction during adolescence and multiple substance use outcomes, including illicit drugs. M-RM restriction is independent of traditional parenting measures. The preponderance of the evidence supports intervention development. PMID- 26615090 TI - Transcriptional and Epigenetic Control of Regulatory T Cell Development. AB - The control of immune responses against self and nonharmful environmental antigens is of critical importance to the immune homeostasis. Regulatory T (Treg) cells are the key players of such immune regulation and their deficiency and dysfunction are associated with various immune disorders, such as autoimmunity and allergy. It is therefore essential to understand the molecular mechanisms that make up Treg cell characteristics; that is, how their unique gene expression profile is regulated at transcriptional and epigenetic levels. In this chapter, we focus on the components of molecular features of Treg cells and discuss how they are introduced during their development. PMID- 26615089 TI - Alternagin-C (ALT-C), a disintegrin-like protein from Rhinocerophis alternatus snake venom promotes positive inotropism and chronotropism in fish heart. AB - Alternagin-C (ALT-C) is a disintegrin-like protein purified from the venom of the snake, Rhinocerophis alternatus. Recent studies showed that ALT-C is able to induce vascular endothelial growth factor (VEGF) expression, endothelial cell proliferation and migration, angiogenesis and to increase myoblast viability. This peptide, therefore, can play a crucial role in tissue regeneration mechanisms. The aim of this study was to evaluate the effects of a single dose of alternagin-C (0.5 mg kg(-1), via intra-arterial) on in vitro cardiac function of the freshwater fish traira, Hoplias malabaricus, after 7 days. ALT-C treatment increased the cardiac performance promoting: 1) significant increases in the contraction force and in the rates of contraction and relaxation with concomitant decreases in the values of time to the peak tension and time to half- and 90% relaxation; 2) improvement in the cardiac pumping capacity and maximal electrical stimulation frequency, shifting the optimum frequency curve upward and to the right; 3) increases in myocardial VEGF levels and expression of key Ca(2+) cycling proteins such as SERCA (sarcoplasmic reticulum Ca(2+)-ATPase), PLB (phospholamban), and NCX (Na(+)/Ca(2+) exchanger); 4) abolishment of the typical negative force-frequency relationship of fish myocardium. In conclusion, this study indicates that ALT-C improves cardiac function, by increasing Ca(2+) handling efficiency leading to a positive inotropism and chronotropism. The results suggest that ALT-C may lead to better cardiac output regulation indicating its potential application in therapies for cardiac contractile dysfunction. PMID- 26615091 TI - Microenvironment Matters: Unique Conditions Within Gut-Draining Lymph Nodes Favor Efficient De Novo Induction of Regulatory T Cells. AB - The gastrointestinal tract constitutes the largest surface of the body and thus has developed multitude mechanisms to either prevent pathogen entry or to efficiently eliminate invading pathogens. At the same time, the gastrointestinal system has to avoid unwanted immune responses against self and harmless nonself antigens, such as nutrients and commensal microbiota. Therefore, it is somewhat not unexpected that the gastrointestinal mucosa serves as the largest repository of immune cells throughout the body, harboring both potent pro- as well as anti inflammatory properties. One additional key element of this regulatory machinery is created by trillions of symbiotic commensal bacteria in the gut. The microbiota not only simply contribute to the breakdown of nutrients, but are essential in limiting the expansion of pathogens, directing the development of the intestinal immune system, and establishing mucosal tolerance by fostering the induction of regulatory T cells (Tregs). In this review, we will discuss our current understanding about the microenvironmental factors fostering the de novo generation of Tregs within the gastrointestinal immune system, focusing on unique properties of antigen-presenting cells, tolerogenic cytokines, commensal-derived metabolites and the contribution of lymph node stromal cells. PMID- 26615092 TI - Understanding the Roles of the NF-kappaB Pathway in Regulatory T Cell Development, Differentiation and Function. AB - The nuclear factor of kappaB (NF-kappaB) pathway has emerged as an important regulator of gene expression in CD4(+) regulatory T cells. Here, we review various aspects of the roles NF-kappaB signaling plays in the development and function of Tregs. PMID- 26615093 TI - The Molecular Control of Regulatory T Cell Induction. AB - Regulatory T cells (Tregs) are characterized by the expression of the master transcription factor forkhead box P3 (Foxp3). Although Foxp3 expression is widely used as a marker of the Treg lineage, recent data show that the Treg fate is determined by a multifactorial signaling pathway, involving cytokines, nuclear factors, and epigenetic modifications. Foxp3 expression and the Treg phenotype can be acquired by T cells in the periphery, illustrating that the Treg fate is not necessarily conferred during thymic development. The two main Treg populations in vivo, thymic Tregs and peripheral Tregs, differ in the pathways followed for their maturation. This chapter discusses the molecular control of Treg induction, in the thymus as well as the periphery. PMID- 26615094 TI - The Special Relationship in the Development and Function of T Helper 17 and Regulatory T Cells. AB - T helper 17 (Th17) cells play an essential role in the clearance of extracellular pathogenic bacteria and fungi. However, this subset is critically involved in the pathology of many autoimmune diseases, e.g., psoriasis, multiple sclerosis, allergy, rheumatoid arthritis, and inflammatory bowel diseases in humans. Therefore, Th17 responses need to be tightly regulated in vivo to mediate effective host defenses against pathogens without causing excessive host tissue damage. Foxp3(+) regulatory T (Treg) cells play an important role in maintaining peripheral tolerance to self-antigens and in counteracting the inflammatory activity of effector T helper cell subsets. Although Th17 and Treg cells represent two CD4(+) T cell subsets with opposing principal functions, these cell types are functionally connected. In this review, we will first give an overview on the biology of Th17 cells and describe their development and in vivo function, followed by an account on the special developmental relationship between Th17 and Treg cells. We will describe the identification of Treg/Th17 intermediates and consider their lineage stability and function in vivo. Finally, we will discuss how Treg cells may regulate the Th17 cell response in the context of infection and inflammation, and elude on findings demonstrating that Treg cells can also have a prominent function in promoting the differentiation of Th17 cells. PMID- 26615095 TI - Mechanisms of Surveillance of Dendritic Cells by Regulatory T Lymphocytes. AB - Regulatory T cells (Tregs) are critical to maintain the homeostasis of the organism, i.e., to prevent (excessive) inflammatory reactions against self and nonself. Data in the literature suggest that a variety of suppressive mechanisms exist that may act selectively depending on the tissue environment. An interesting question is whether dendritic cells (DCs), which are involved in immunity and tolerance, are targets of Tregs. We review herein some experimental evidence indicating that some suppressive mechanisms involve DCs, altering their function and inducing an immune control at the very first step of the immune response. PMID- 26615096 TI - Development and Function of Effector Regulatory T Cells. AB - Distinguishing self from nonself is a unique feature of the immune system. Although most self-reactive T cells are eliminated in the thymus, a few rogue cells escape the negative selection process and have the potential to mediate autoimmune disease. Over the last decade, there has been a vast improvement in our understanding of the cellular mechanisms that evolved to dampen the deleterious effects of these self-reactive T cells. In particular, T cells expressing the transcription factor FoxP3, known as regulatory T (Treg) cells, play a central role in maintaining immune homeostasis and suppressing autoimmune responses. In addition, Treg cells are endowed with the ability to suppress diverse inflammatory responses both in lymphoid and in nonlymphoid tissues. This requires Treg cells to undergo a peripheral differentiation and specialization program that results in the emergence of effector Treg (eTreg) cells that are characterized by their ability to produce high amounts of immunosuppressive molecules, including IL-10. This chapter discusses the recent advances in our understanding of the mechanisms governing the differentiation, migration, and maintenance of eTreg cells, in particular in nonlymphoid tissues, in health and disease. PMID- 26615097 TI - Treg Cell Differentiation: From Thymus to Peripheral Tissue. AB - Regulatory T cells (Tregs) are crucial mediators of self-tolerance in the periphery. They differentiate in the thymus, where interactions with thymus resident antigen-presenting cells, an instructive cytokine milieu, and stimulation of the T cell receptor lead to the selection into the Treg lineage and the induction of Foxp3 gene expression. Once mature, Treg cells leave the thymus and migrate into either the secondary lymphoid tissues, e.g., lymph nodes and spleen, or peripheral nonlymphoid tissues. There is growing evidence that Treg cells go beyond the classical modulation of immune responses and also play important functional roles in nonlymphoid peripheral tissues. In this review, we summarize recent findings about the thymic Treg lineage differentiation as well as the further specialization of Treg cells in the secondary lymphoid and in the peripheral nonlymphoid organs. PMID- 26615098 TI - Regulatory T cells in Arthritis. AB - Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and is characterized by inflammation and subsequent bone destruction in multiple joints. In mice, depletion of regulatory T (Treg) cells results in the onset of a variety of autoimmune diseases including arthritis, while replenishment of Treg cells alleviates arthritic symptoms. The importance of Treg cells in RA is supported by the effectiveness of CTLA4-Ig therapy, an increased Treg cell/effector T cell ratio after anti-IL-6R or anti-TNF-alpha treatment and the identification of CTLA 4 as an RA-associated gene. Thus, Treg cells constitute a useful target in the treatment of RA. Foxp3(+) T cells consist of heterogeneous populations in terms of their surface markers, suppressive function, and plasticity. Plastic Foxp3(+) T cells are able to convert into pathogenic Th17 cells, which have been shown to exacerbate arthritis in mice. Therefore, it is important to identify a stable suppressive Foxp3(+) Treg cell subpopulation along with suppressive molecules and surface markers. In addition, considering the recent studies on the identification of arthritic antigens, the generation of antigen-specific Treg cells from naive CD4(+) T cells or effector T cells is now feasible, along with the induction of Foxp3 and stabilization of the suppressive function by epigenetic modification of Treg cell signature genes. These approaches will lead to the establishment of new therapeutic strategies against arthritis that work by increasing the Treg cell/effector T cell ratio in favor of Treg cells. Here, we summarize our understanding of the role of Treg cells in arthritis based on recent human and murine studies. PMID- 26615101 TI - Preface. PMID- 26615100 TI - Regulatory T Cells in Autoimmune Diabetes: Mechanisms of Action and Translational Potential. AB - Since the discovery of specialized T cells with regulatory function, harnessing the power of these cells to ameliorate autoimmunity has been a major goal. Here we collate the evidence that regulatory T cells (Treg) can inhibit Type 1 diabetes in animal models and humans. We discuss the anatomical sites and molecular mechanisms of Treg suppressive function in the Type 1 diabetes setting, citing evidence that Treg can function in both the pancreatic lymph nodes and within the pancreatic lesion. Involvement of the CTLA-4 pathway, as well as TGF beta and IL-2 deprivation will be considered. Finally, we summarize current efforts to manipulate Treg therapeutically in individuals with Type 1 diabetes. The translation of this research area from bench to bedside is still in its infancy, but the remarkable therapeutic potential of successfully manipulating Treg populations is clear to see. PMID- 26615102 TI - Dietary alpha-linolenic acid/linoleic acid ratios modulate intestinal immunity, tight junctions, anti-oxidant status and mRNA levels of NF-kappaB p65, MLCK and Nrf2 in juvenile grass carp (Ctenopharyngodon idella). AB - This study was conducted to investigate the effects of dietary alpha-linolenic acid/linoleic acid (ALA/LNA) ratios on the immune response, tight junctions, antioxidant status and immune-related signaling molecules mRNA levels in the intestine of juvenile grass carp (Ctenopharyngodon idella). A total of 1260 juvenile grass carp with an average initial weight of 8.78 +/- 0.03 g were fed diets with different ALA/LNA ratios (0.01, 0.34, 0.68, 1.03, 1.41, 1.76 and 2.15) for 60 days. Results indicated that ALA/LNA ratio of 1.03 significantly increased acid phosphatase, lysozyme activities and complement C3 contents, promoted interleukin 10, transforming growth factor beta1 and kappaB inhibitor alpha mRNA abundance, whereas suppressed pro-inflammatory cytokines (interleukin 1beta, interleukin 8, tumor necrosis factor alpha and interferon gamma2) and signal molecules (IkappaB kinase beta, IkappaB kinase gamma and nuclear factor kappaB p65) mRNA levels in the intestine (P < 0.05), suggesting that optimal dietary ALA/LNA ratio improved intestinal immune response of juvenile fish. Additionally, ALA/LNA ratio of 1.03 significantly promoted Claudin-3, Claudin-b, Claudin-c, Occludin and ZO-1 gene transcription, whereas reduced Claudin-15a and myosin light-chain kinase mRNA levels in the intestine, suggesting that appropriate dietary ALA/LNA ratio strengthened tight junctions in the intestine of juvenile fish. Meanwhile, ALA/LNA ratio of 1.03 noticeably elevated glutathione contents, copper/zinc superoxide dismutase, glutathione peroxidase, glutathione S transferase and glutathione reductase activities and mRNA levels, as well as signaling molecule nuclear factor erythoid 2-related factor 2 gene transcriptional abundance in the intestine, suggesting that proper ratio of dietary ALA/LNA ameliorate the intestinal antioxidant status of juvenile fish. Based on the quadratic regression analysis of the complement C3 content in the distal intestine and malondialdehyde content in the whole intestine, optimal ALA/LNA ratio for maximum growth of juvenile grass carp (8.78-72.00 g) were estimated to be 1.13 and 1.12, respectively. PMID- 26615103 TI - Selective Amygdalohippocampectomy. AB - Mesial temporal lobe epilepsy is a common condition that is frequently drug resistant. Anterior temporal lobectomy has been shown to be effective in controlling seizures but entails resecting anterior and lateral temporal lobe regions that are not necessarily included in the epileptogenic zone. Selective amygdalohippocampectomy spares uninvolved structures while providing the same benefit as anterior temporal lobectomy. This article describes the 3 most common surgical approaches for performing selective amygdalohippocampectomy and discusses their relative merits and risks. PMID- 26615104 TI - Hippocampal Transections for Epilepsy. AB - Multiple hippocampal transection (MHT) is a novel surgical procedure that serves to disrupt seizure propagation fibers within the hippocampus without impairing verbal memory or the loss of stem cells. Given the paucity of literature regarding the utility and long-term outcome of MHT, a review is presented of the current literature to support the utility of this procedure in the treatment of intractable temporal lobe epilepsy. Long-term outcome analysis of this technique has been reported by 2 independent groups. Both groups used intraoperative electrocorticography. All patients underwent multiple subpial transection on the neocortex and MHT on the hippocampus. PMID- 26615099 TI - The Immune Fulcrum: Regulatory T Cells Tip the Balance Between Pro- and Anti inflammatory Outcomes upon Infection. AB - Regulatory T cells (Tregs) are indispensable for immune homeostasis and the prevention of autoimmunity. In the context of infectious diseases, Tregs are multidimensional. Here, we describe how they may potentiate effector responses by assisting in recruitment of T cells into the infection site to resolve infection, facilitate accelerated antigen-specific memory responses, limit pathology, and contribute to disease resolution and healing, to the great benefit of the host. We also explore the villainous functions of Tregs during infection by reviewing several diseases in which the depletion or reduction in Treg frequency allows for better generation of effector memory, and results in acute resolution of infection, as opposed to chronicity or severe long-term outcomes. We describe findings generated using mouse models of infection as well as experiments performed using human cells and tissues. We propose that Tregs represent an immunologic fulcrum, promoting both pathogen clearance and damage control by preventing excessive destruction of infected tissues though unchecked immune responses. PMID- 26615105 TI - History and Technical Approaches and Considerations for Ablative Surgery for Epilepsy. AB - The history of epilepsy surgery is generally noted to have begun in 1886 with Victor Horsley's first report of craniotomies for posttraumatic epilepsy. With increased understanding of brain function and development of electroencephalographic methods, nonlesional epilepsy began to be treated with resection in the 1950s. Methodological improvements and increased understanding of pathophysiology followed, and the advent of stereotaxy and ablative technology in the 1960s and 1970s heralded a new era of minimally invasive, targeted procedures for lesional and nonlesional epilepsy. Current techniques combine stereotactic methods, improved ablative technologies, and electroencephalographic methods for a multidisciplinary approach to the neurosurgical treatment of epilepsy. PMID- 26615107 TI - Minimally Invasive Neurosurgery for Epilepsy Using Stereotactic MRI Guidance. AB - Medically refractory epilepsy is associated with significant morbidity and mortality. Surgery is a safe and effective option for some patients, however the opportunity exists to develop less invasive and more effective surgical options. To this end, multiple minimally invasive, image-guided techniques have been applied to the treatment of epilepsy. These techniques can be divided into thermoablative and disconnective techniques. Each has been described in the treatment of epilepsy only in small case series. Larger series and longer follow up periods will determine each option's place in the surgical armamentarium for the treatment of refractory epilepsy but early results are promising. PMID- 26615106 TI - The Role of Stereotactic Laser Amygdalohippocampotomy in Mesial Temporal Lobe Epilepsy. AB - Stereotactic laser amygdalohippocampotomy (SLAH) uses laser interstitial thermal therapy guided by magnetic resonance thermography. This novel intervention can achieve seizure freedom while minimizing collateral damage compared to traditional open surgery, in patients with mesial temporal lobe epilepsy. An algorithm is presented to guide treatment decisions for initial and repeat procedures in patients with and without mesial temporal sclerosis. SLAH may improve access by medication-refractory patients to effective surgical treatments and thereby decrease medical complications, increase productivity, and minimize socioeconomic consequences in patients with chronic epilepsy. PMID- 26615108 TI - Stereotactic Laser Ablation for Hypothalamic Hamartoma. AB - Stereotactic laser ablation (SLA) is a minimally invasive approach to the treatment of medication-resistant epilepsy that accomplishes ablation of the seizure focus with real-time magnetic resonance thermal mapping. Rates of seizure freedom in early series suggest that SLA approaches and perhaps surpasses the effectiveness of open resection. SLA minimizes the neurocognitive and endocrine adverse effects of open surgery. Secondary benefits of SLA include decreased length of stay, elimination of intensive care unit stay, reduced procedure related discomfort, and improved access to surgical treatment for patients less likely to consider an open resective procedure. PMID- 26615109 TI - Laser Ablation in Pediatric Epilepsy. AB - Laser ablation is an emerging, minimally invasive treatment for selected children with intractable focal epilepsy with improved procedural morbidity. Data for children lag similar studies in adults, but the hope is for near-equivalent seizure-control rates and improved neuropsychological outcome when compared with standard open surgical resection. The approach seems particularly beneficial when dealing with deep, focal lesions, such as hypothalamic hamartomas or hippocampal sclerosis. PMID- 26615110 TI - Radiosurgery for Medial Temporal Lobe Epilepsy Resulting from Mesial Temporal Sclerosis. AB - Medial temporal lobe epilepsy associated with mesial temporal sclerosis (MTS) is perhaps the most well-defined epilepsy syndrome that is responsive to structural interventions such as surgery. Several minimally invasive techniques have arisen that provide additional options for the treatment of MTS while potentially avoiding many of open surgery's associated risks. By evading these risks, they also open up treatment options to patients who otherwise are poor surgical candidates. Radiosurgery is one of the most intensively studied of these alternatives and has found a growing role in the treatment of medial temporal lobe epilepsy. PMID- 26615111 TI - The Stereo-Electroencephalography Methodology. AB - The stereo-electroencephalography (SEEG) methodology and technique was developed almost 60 years ago in Europe. The efficacy and safety of SEEG has been proven. The main advantage is the possibility to study the epileptogenic neuronal network in its dynamic and 3-dimensional aspect, with optimal time and space correlation, with the clinical semiology of the patient's seizures. The main clinical challenge for the near future remains in the further refinement of specific selection criteria for the different methods of invasive monitoring, with the ultimate goal of comparing and validating the results (long-term seizure-free outcome) obtained from different methods of invasive monitoring. PMID- 26615112 TI - Stereo-Encephalography Versus Subdural Electrodes for Seizure Localization. AB - In today's practice, epileptologists and neurosurgeons have several options for seizure localization with intracranial electrodes during phase II evaluations. Traditionally, centers in North America have used subdural electrode grids (SDE or SDG) for intracranial seizure localization. However, improvements in technology led to the popularization of stereo-encephalography (SEEG) using depth electrodes. Epilepsy surgery centers highest in volume now offer both SDE and SEEG for seizure localization. This article provides a general guide for considering SEEG versus SDE for intracranial seizure localization based on our experience with both. Several paradigmatic cases are used illustrate the advantages and disadvantages of the different approaches. PMID- 26615113 TI - Responsive Direct Brain Stimulation for Epilepsy. AB - Closed-loop, responsive focal brain stimulation provides a new treatment option for patients with refractory partial onset seizures who are not good candidates for potentially curative epilepsy surgery. The first responsive brain neurostimulator (RNS(r) System, NeuroPace), provides stimulation directly to the seizure focus when abnormal electrocorticographic is detected. Seizure reductions of 44% at one year increase to 60 to 66% at years 3 to 6 of treatment. There is no negative impact on cognition and mood. Risks are similar to other implanted medical devices and therapeutic stimulation is not perceived. PMID- 26615114 TI - Neuromodulation for Epilepsy. AB - Several palliative neuromodulation treatment modalities are currently available for adjunctive use in the treatment of medically intractable epilepsy. Over the past decades, a variety of different central and peripheral nervous system sites have been identified, clinically and experimentally, as potential targets for chronic, nonresponsive therapeutic neurostimulation. Currently, the main modalities in clinical use, from most invasive to least invasive, are anterior thalamus deep brain stimulation, vagus nerve stimulation, and trigeminal nerve stimulation. Significant reductions in seizure frequency have been demonstrated in clinical trials using each of these neuromodulation therapies. PMID- 26615115 TI - Minimally Invasive Epilepsy Surgery. PMID- 26615117 TI - AGA Institute Guideline on the Management of Microscopic Colitis: Clinical Decision Support Tool. PMID- 26615116 TI - Early Detection of Alcoholic Liver Disease: Are We a Step Closer? PMID- 26615118 TI - The Morbidity and Mortality Conference in Gastroenterology and Hepatology: An Important Cornerstone of Patient Safety and Optimal Care. PMID- 26615119 TI - The Covalently Closed Circular Form of Hepatitis B Virus Genome: Is There Now an End in "Site"? PMID- 26615120 TI - Combination of Pegylated Interferon and Tenofovir for Hepatitis B Treatment: Screening and Counseling of Patients are Warranted. PMID- 26615121 TI - Antihepatotoxic efficacy of Mangifera indica L. polysaccharides against cyclophosphamide in rats. AB - The present study aims to evaluate the possible protective role of polysaccharides extracted from the Egyptian mango Mangifera indica L. (MPS) and/or silymarine against cyclophosphamide (CP) toxicity in male albino rats. The MPS and/or silymarin significantly decreased the activities of serum ASAT and ALAT. However, MPS (1000 mg/kg) normalized their activities towards the normal levels recording 28.75 and 78.75 U/ml respectively. The recorded data also showed the antioxidant effect of MPS by decreasing the level of malondialdehyde (MDA) and increasing the level of reduced glutathione (GSH) as well as normalized the activities of the antioxidant enzyme GST and SOD. Histopathological examinations also confirmed the protective efficacy of MPS against liver toxicity of CP. In conclusion, the recorded results of the present study support the protective role of MPS and/or silymarin against CP-induced hepatic damage. PMID- 26615122 TI - Letter to the Editor. PMID- 26615123 TI - Ratchetaxis: Long-Range Directed Cell Migration by Local Cues. AB - Directed cell migration is usually thought to depend on the presence of long range gradients of either chemoattractants or physical properties such as stiffness or adhesion. However, in vivo, chemical or mechanical gradients have not systematically been observed. Here we review recent in vitro experiments, which show that other types of spatial guidance cues can bias cell motility. Introducing local geometrical or mechanical anisotropy in the cell environment, such as adhesive/topographical microratchets or tilted micropillars, show that local and periodic external cues can direct cell motion. Together with modeling, these experiments suggest that cell motility can be viewed as a stochastic phenomenon, which can be biased by various types of local cues, leading to directional migration. PMID- 26615124 TI - Targeted Inhibitors: Novel Strategies for Response Optimization. PMID- 26615125 TI - The Personalization of Therapy: Molecular Profiling Technologies and Their Application. AB - Advances in tumor biology and human genetics that have identified driver events and critical dependencies, together with the development of drugs for specific targets, hold promise for an era of personalized oncology treatment. The efficacy of targeted therapies in patient populations selected for treatment on the basis of the molecular features of their tumors is shifting the current practice, and molecular profiling of patients to support clinical decision-making is becoming part of the everyday clinical practice in oncology. Actionable biomarkers are those that allow matching patients to specific therapies. Currently, there is a strong need to have accurate and reliable means of identifying these biomarkers. With the evolution of biotechnology and the advent of next-generation sequencing, platforms for molecular analysis have quickly evolved, allowing a high degree of multiplexing that aims to transform the use of targeted therapies in oncology. This article aims to summarize the different biomarker applications and discuss the current challenges along with the major technologies presently used in clinical practice. PMID- 26615126 TI - Targeting Cyclin-Dependent Kinases and Cell Cycle Progression in Human Cancers. AB - Uncontrolled cell division is a defining characteristic of cancer cells. Cyclin dependent kinases (Cdks) are critical regulators of cell cycle progression. Deregulated Cdk activities as a result of gene amplification, translocation, or point mutations of Cdks or cyclins, have been reported in a majority of human cancers. These kinases, therefore, represent potential therapeutic targets for the treatment of cancer. In this review, we offer an overview of Cdk functions in driving cell cycle progression and transcriptional regulation, a highlight of the DNA damage checkpoints, and an outline of the most relevant Cdk inhibitors currently in clinical trials with an emphasis on the Cdk inhibitors used for treatment of multiple myeloma. PMID- 26615127 TI - Fibroblast Growth Factor (FGF) Receptor/FGF Inhibitors: Novel Targets and Strategies for Optimization of Response of Solid Tumors. AB - The fibroblast growth factor receptor (FGFR) pathway plays a major role in several biological processes, from organogenesis to metabolism homeostasis and angiogenesis. Several aberrations, including gene amplifications, point mutations, and chromosomal translocations have been described across solid tumors. Most of these molecular alterations promote multiple steps of carcinogenesis in FGFR oncogene-addicted cells, increasing cell proliferation, angiogenesis, and drug resistance. Data suggest that upregulation of FGFR signaling is a common event in many cancer types. The FGFR pathway thus arises as a potential promising target for cancer treatment. Several FGFR inhibitors are currently under development. Initial preclinical results have translated into limited successful clinical responses when first-generation, nonspecific FGFR inhibitors were evaluated in patients. The future development of selective and unselective FGFR inhibitors will rely on a better understanding of the tissue specific role of FGFR signaling and identification of biomarkers to select those patients who will benefit the most from these drugs. Further studies are warranted to establish the predictive significance of the different FGFR aberrations and to incorporate them into clinical algorithms, now that second generation, selective FGFR inhibitors exist. PMID- 26615128 TI - Functional Crosstalk Between WNT Signaling and Tyrosine Kinase Signaling in Cancer. AB - Extensive molecular characterization of tumors has revealed that the activity of multiple signaling pathways is often simultaneously dampened or enhanced in cancer cells. Aberrant WNT signaling and tyrosine kinase signaling are two pathways that are frequently up- or downregulated in cancer. Although signaling pathways regulated by WNTs, tyrosine kinases, and other factors are often conceptualized as independent entities, the biological reality is likely much more complex. Understanding the mechanisms of crosstalk between multiple signal transduction networks is a key challenge for cancer researchers. The overall goals of this review are to describe mechanisms of crosstalk between WNT and tyrosine kinase pathways in cancer and to discuss how understanding intersections between WNT and tyrosine kinase signaling networks might be exploited to improve current therapies. PMID- 26615129 TI - Aurora Kinase Inhibitors in Oncology Clinical Trials: Current State of the Progress. AB - The Aurora kinase family of kinases (Aurora A, B, and C) are involved in multiple mitotic events, and aberrant expression of these kinases is associated with tumorigenesis. Aurora A and Aurora B are validated anticancer targets, and the development of Aurora kinase inhibitors has progressed from preclinical to clinical studies. A variety of Aurora A, B and pan-Aurora kinase inhibitors have entered the clinic. The main side effects include febrile neutropenia, stomatitis, gastrointestinal toxicity, hypertension, and fatigue. Responses including complete remissions have been described in diverse, advanced malignancies, most notably ovarian cancer and acute myelogenous leukemia. This review highlights the biologic rationale for Aurora kinase as a target, and clinical trials involving Aurora kinase inhibitors, with particular emphasis on published early phase studies, and the observed anti-tumor activity of these agents. PMID- 26615131 TI - Understanding Toxicities of Targeted Agents: Implications for Anti-tumor Activity and Management. AB - Targeted treatments have distinctive side effects: dermatologic problems (rash, hand-food skin reaction, skin/hair whitening), endocrine dysfunction (hyperglycemia, hypothyroidism, dyslipidemia), as well as hypertension, diarrhea, liver problems, ocular toxicity and proteinuria. Toxicities can be classified as: (1) on-target, mechanism-driven toxicities that are either related or unrelated to response; and (2) off-target side effects. Off-target toxicities may be specific to the class of agent, eg, small molecule tyrosine kinase inhibitor versus antibody versus cytotoxic; alternatively, they may also be mediated by metabolites or immune reactions. Both on- and off-target toxicities can be amplified or attenuated by drug concentrations or end-organ sensitivity, which in turn can be attributable to genetic polymorphisms regulating metabolism or tissue responsiveness. On-target side effects are important to identify as some are associated with response and, therefore, controlling these side effects is preferable to dose reduction or treatment discontinuation. Side effects caused by relevant target impact may be recognized when different types of agents, eg, small molecule inhibitors and antibodies, with the same target have the same side effect. These on-target effects may also correlate with better outcomes. We discuss toxicity of targeted agents in the context of understanding target impact, drug-drug interactions, and implications for optimized management. PMID- 26615130 TI - MEK1/2 Inhibitors: Molecular Activity and Resistance Mechanisms. AB - Aberrant activation of the three-layered protein kinase cascade, Raf/MEK/ERK, is often detected in human cancer, which is mainly attributed to the oncogenic alterations of RAF, or its upstream activators RAS or cell surface receptor tyrosine kinases. Deregulated activity of the Raf/MEK/ERK pathway drives uncontrolled tumor cell proliferation and survival, thus providing a rational therapeutic target for the treatment of many cancers. While Raf, MEK1/2, and ERK1/2 are equally important targets for the design of therapeutic small molecular weight inhibitors, the effort to develop MEK1/2-specific inhibitors has been greatly successful. Particularly, MEK1/2 have been relatively advantageous for the design of highly selective adenosine triphosphate (ATP)-noncompetitive inhibitors. Indeed, a plethora of highly selective and potent MEK1/2 inhibitors are now available and many of those inhibitors have been evaluated for their therapeutic potential. Herein, we review different MEK1/2 inhibitors that have been studied for their inhibitory mechanisms and therapeutic potential in cancer. Some of the key structural features of MEK1/2 that are important for the efficacy of these inhibitors are also discussed. In addition, we discuss current challenges and future prospective in using these advanced MEK1/2 inhibitors for cancer therapy. PMID- 26615133 TI - Better Together: Targeted Combination Therapies in Breast Cancer. AB - Recent discoveries both in cell proliferation and survival mechanisms and new antineoplastic agents have led to deep change in the breast cancer treatment paradigm. Nonetheless, all of the progress in knowledge and strategy has not been enough to overcome mechanisms of escape and resistance put in place by the tumor cells. New targeted agents mean new possibilities for combinations, a viable option to try to stop compensatory pathways of tumor growth activated in response to therapeutics. The main challenges in designing a combined therapy come from the variety of subtypes of breast cancer (luminal A, luminal B, HER2-enriched, and basal-like) and from the multitude of pathways each subtype can exploit. Recent research has focused on dual blockade of HER2 (trastuzumab-lapatinib; trastuzumab-pertuzumab) and concomitant blockade of the endocrine driver and other pathways such as the PI3K/AKT/mTOR pathway (everolimus-exemestane), HER2 (trastuzumab/lapatinib-endocrine therapy) and the cell cycle through cyclin dependent kinase inhibition (letrozole-palbociclib). This combined and personalized approach to treatment needs a profound knowledge of the mechanisms leading to proliferation in each tumor subtype. Deepening our understanding of tumor growth is mandatory to keep improving the efficacy of combination therapy. PMID- 26615132 TI - Tyrosine Kinase Inhibitors Early in the Disease Course: Lessons From Chronic Myelogenous Leukemia. AB - The landscape of chronic myeloid leukemia (CML) management has changed with the advent of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 oncoprotein. Imatinib mesylate, followed by nilotinib and dasatinib, has been approved for newly diagnosed patients. Since none of these TKIs show survival superiority, the drug choice is a challenge. Even so, the rate of deeper and earlier responses is higher with second-generation TKIs than it is with imatinib, and, in general, better response is associated with a survival advantage, regardless of TKI type being used. Patients should be monitored carefully for response, and treatment failure should prompt a timely switch to another TKI. Side effect profile and drug cost are other important considerations in therapy choice. In several clinical studies, achieving undetectable and durable disease status allowed some patients to discontinue the TKI and enjoy long-term treatment-free remission. Cure for CML may be possible with TKIs alone or TKIs in combination with other investigational therapies. However, due to lack of long-term outcome data and absence of consensus for the definition of optimal response and time to stop TKIs, discontinuation is discouraged outside of a clinical trial. PMID- 26615134 TI - Overcoming Resistance to Targeted Therapies in Cancer. AB - The recent discovery of oncogenic drivers and subsequent development of novel targeted strategies has significantly added to the therapeutic armamentarium of anti-cancer therapies. Targeting BCR-ABL in chronic myeloid leukemia (CML) or HER2 in breast cancer has led to practice-changing clinical benefits, while promising therapeutic responses have been achieved by precision medicine approaches in EGFR mutant lung cancer, colorectal cancer and BRAF mutant melanoma. However, although initial therapeutic responses to targeted therapies can be substantial, many patients will develop disease progression within 6-12 months. An increasing application of powerful omics-based approaches and improving preclinical models have enabled the rapid identification of secondary resistance mechanisms. Herein, we discuss how this knowledge has translated into rational, novel treatment strategies for relapsed patients in genomically selected cancer populations. PMID- 26615135 TI - Parathyroid Hormone-Related Peptide-Linked Hypercalcemia in a Melanoma Patient Treated With Ipilimumab: Hormone Source and Clinical and Metabolic Correlates. AB - A patient diagnosed with metastatic melanoma developed the paraneoplastic syndrome of humoral hypercalcemia of malignancy and cachexia after receiving ipilumumab. The cause of the hypercalcemia was thought to be secondary to parathyroid hormone-related peptide (PTHrP) as plasma levels were found to be elevated. The patient underwent two tumor biopsies: at diagnosis (when calcium levels were normal) and upon development of hypercalcemia and cachexia. PTHrP expression was higher in melanoma cells when hypercalcemia had occurred than prior to its onset. Metabolic characterization of melanoma cells revealed that, with development of hypercalcemia, there was high expression of monocarboxylate transporter 1 (MCT1), which is the main importer of lactate and ketone bodies into cells. MCT1 is associated with high mitochondrial metabolism. Beta galactosidase (beta-GAL), a marker of senescence, had reduced expression in melanoma cells upon development of hypercalcemia compared to pre-hypercalcemia. In conclusion, PTHrP expression in melanoma is associated with cachexia, increased cancer cell lactate and ketone body import, high mitochondrial metabolism, and reduced senescence. Further studies are required to determine if PTHrP regulates cachexia, lactate and ketone body import, mitochondrial metabolism, and senescence in cancer cells. PMID- 26615137 TI - The Last Chapter. PMID- 26615138 TI - A Young Female With Metastatic Nongestational Choriocarcinoma. PMID- 26615136 TI - Mitochondrial Metabolism as a Treatment Target in Anaplastic Thyroid Cancer. AB - Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancers. Key signal transduction pathways that regulate mitochondrial metabolism are frequently altered in ATC. Our goal was to determine the mitochondrial metabolic phenotype of ATC by studying markers of mitochondrial metabolism, specifically monocarboxylate transporter 1 (MCT1) and translocase of the outer mitochondrial membrane member 20 (TOMM20). Staining patterns of MCT1 and TOMM20 in 35 human thyroid samples (15 ATC, 12 papillary thyroid cancer [PTC], and eight non cancerous thyroid) and nine ATC mouse orthotopic xenografts were assessed by visual and Aperio digital scoring. Staining patterns of areas involved with cancer versus areas with no evidence of cancer were evaluated independently where available. MCT1 is highly expressed in human anaplastic thyroid cancer when compared to both non-cancerous thyroid tissues and papillary thyroid cancers (P<.001 for both). TOMM20 is also highly expressed in both ATC and PTC compared to non-cancerous thyroid tissue (P<.01 for both). High MCT1 and TOMM20 expression is also found in ATC mouse xenograft tumors compared to non-cancerous thyroid tissue (P<.001). These xenograft tumors have high (13)C- pyruvate uptake. ATC has metabolic features that distinguish it from PTC and non-cancerous thyroid tissue, including high expression of MCT1 and TOMM20. PTC has low expression of MCT1 and non-cancerous thyroid tissue has low expression of both MCT1 and TOMM20. This work suggests that MCT1 blockade may specifically target ATC cells presenting an opportunity for a new drug target. PMID- 26615139 TI - 55-Year-Old Woman With Estrogen Receptor-Positive Scalp Lesion. PMID- 26615140 TI - Four Difficult Thyroid Cancer Cases: Incorporating Medical Therapies. PMID- 26615141 TI - Adjuvant Chemotherapy for Stage II Rectal Cancer. PMID- 26615142 TI - Titania-functionalized graphene oxide for an efficient adsorptive removal of phosphate ions. AB - Titania-functionalized graphene oxide (T-F GO), synthesized by a sol-gel process, was used as a highly efficient material to remove phosphate ions from the simulated wastewater. X-ray diffraction spectra, Fourier transform infrared spectra and scanning electron micrographs of T-F GO confirmed that titania particles were successfully grown on graphene oxide (GO) surface. The phosphate ion adsorption capacities of GO, titania and T-F GO as a function of the contact time and the pH were investigated by a UV-visible spectrophotometer. Results showed that T-F GO could absorb phosphate ions better than titania and GO could. This indicated the synergistic effect between titania and GO in the phosphate ion adsorption. The pH increment lowered the absorption capacities due to increasing the repulsion between phosphate anions and the charges on the T-F GO surface, whereas the addition of sodium ions increased the adsorption capacities. Also, phosphate ions were absorbed by specific sites of T-F GO and formed a monolayer on its surface. Finally, the maximum adsorption capacity of T-F GO was 33.11 mg/g at pH 6, much higher than those of GO and titania. Therefore, T-F GO could be a promising material to remove phosphate ions from wastewater in the future. PMID- 26615143 TI - International Retrospective Comparison of Inpatient Rehabilitation for Patients With Spinal Cord Dysfunction: Differences According to Etiology. AB - OBJECTIVES: To describe and compare epidemiologic characteristics and clinical outcomes of patients with nontraumatic spinal cord dysfunction according to etiology. DESIGN: Retrospective, multicenter open-cohort case series. SETTING: Spinal rehabilitation units (SRUs) in 9 countries. PARTICIPANTS: Patients (N=956; men, 60.8%; median age, 59.0y [interquartile range, 46-70.0y]; paraplegia, n=691 [72.3%]) with initial onset of spinal cord dysfunction consecutively admitted between January 1, 2008, and December 31, 2010. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Etiology of spinal cord dysfunction, demographic characteristics, length of stay (LOS) in rehabilitation, pattern of spinal cord dysfunction onset, discharge destination, level of spinal cord damage, and the American Spinal Injury Association Impairment Scale (AIS) grade on admission and discharge. RESULTS: The most common etiologies were degenerative (30.8%), malignant tumors (16.2%), infections (12.8%), ischemia (10.9%), benign tumors (8.7%), other vascular (8.5%), and other conditions (12.1%). There were major differences in epidemiologic characteristics and clinical outcomes of patients with different etiologies of spinal cord dysfunction. Paraplegia was more common in patients with a malignant tumor and vascular etiologies, while tetraplegia was more common in those with a degenerative etiology, a benign tumor, and infections. Patients with a malignant tumor tended to have the shortest LOS in the SRU, while those with a vascular etiology tended to have the longest. Except for patients with a malignant tumor, all patient groups had a significant change in their AIS grade between admission and discharge. CONCLUSIONS: This international study of spinal cord dysfunction showed substantial variation between the different etiologies regarding demographic and clinical characteristics, including changes in AIS between admission and discharge. PMID- 26615144 TI - Frequency detection of imidacloprid resistance allele in Aphis gossypii field populations by real-time PCR amplification of specific-allele (rtPASA). AB - The Aphis gossypii Glover (Hemiptera: Aphididae) is one of the most serious pests worldwide, and imidacloprid has been widely used to control this insect pest. Just like other classes of insecticides, the resistance to imidacloprid has been found in A. gossypii. An amino acid mutation (R81T) in the nicotinic acetylcholine receptor (nAChR) beta1 subunit was detected in the imidacloprid resistant A. gossypii collected from Langfang (LF) and Dezhou (DZ) cities. To estimate the R81T mutation frequency of A. gossypii field populations, a simple, rapid and accurate rtPASA (real-time PCR amplification of specific allele) protocol was developed. The performance of the rtPASA protocol was evaluated by comparing with the data generated by a cPASA (competitive PCR amplification of specific allele) method from 50 individual genotypes. The R81T allele frequencies of the LF population (34.7%+/-1.3%) and DZ population (45.2%+/-5.2%) estimated by the rtPASA protocol matched the frequencies (LF 38.1%, DZ 48.2%) deduced by the cPASA method in specimens. The results indicated that the rtPASA format was applicable for the detection of mutation associated with imidacloprid resistance and will allow rapid and efficient monitoring of A. gossypii resistance in field populations in a high throughput format. PMID- 26615145 TI - An integrated genomic and proteomic approach to identify signatures of endosulfan exposure in hepatocellular carcinoma cells. AB - Present study reports the identification of genomic and proteomic signatures of endosulfan exposure in hepatocellular carcinoma cells (HepG2). HepG2 cells were exposed to sublethal concentration (15MUM) of endosulfan for 24h. DNA microarray and MALDI-TOF-MS analyses revealed that endosulfan induced significant alterations in the expression level of genes and proteins involved in multiple cellular pathways (apoptosis, transcription, immune/inflammatory response, carbohydrate metabolism, etc.). Furthermore, downregulation of PHLDA gene, upregulation of ACIN1 protein and caspase-3 activation in exposed cells indicated that endosulfan can trigger apoptotic cascade in hepatocellular carcinoma cells. In total 135 transcripts and 19 proteins were differentially expressed. This study presents an integrated approach to identify the alteration of biological/cellular pathways in HepG2 cells upon endosulfan exposure. PMID- 26615146 TI - A bifunctional alpha-amylase/trypsin inhibitor from pigeonpea seeds: Purification, biochemical characterization and its bio-efficacy against Helicoverpa armigera. AB - This paper evaluates alpha-amylase inhibitor (alpha-AI) mediated defense of pigeonpea against Helicoverpa armigera. A bifunctional alpha-amylase/trypsin inhibitor was purified from the seeds of pigeonpea by native liquid phase isoelectric focusing (N-LP-IEF), affinity chromatography and preparative electrophoresis. Its in-vivo and in-vitro interaction with midgut amylases of H. armigera was studied along with growth inhibitory activity. One and two dimensional (2D) zymographic analyses revealed that the purified inhibitor is dimeric glycoprotein (60.2kDa and 56kDa) exist in a multi-isomeric form with five pI variants (pI 5.5 to 6.3). It was found to be heat labile with complete inactivation up to 80 degrees C and stable over a wide range of pH (4-11). The slow binding and competitive type of alpha-amylase inhibition was observed with 0.08MUM of dissociation constant (Ki) for the enzyme-inhibitor complex (EI). The internal protein sequence of two subunits obtained by mass spectrometry matched with cereal-type alpha-AI, a conserved domain from AAI_LTSS superfamily and sialyltransferase-like protein respectively. In-vivo studies indicated up regulation of total midgut alpha-amylase activity with negative effect on growth rate of H. armigera suggesting its suitability for pest control. PMID- 26615147 TI - Validating the importance of two acetylcholinesterases in insecticide sensitivities by RNAi in Pardosa pseudoannulata, an important predatory enemy against several insect pests. AB - The pond wolf spider (Pardosa pseudoannulata) is an important predatory enemy against several insect pests and showed relative different sensitivities to organophosphate and carbamate insecticides compared to insect pests. In our previous studies, two acetylcholinesterases were identified in P. pseudoannulata and played important roles in insecticide sensitivities. In order to understand the contributions of the two acetylcholinesterases to insecticide sensitivities, we firstly employed the RNAi technology in the spider. For a suitable microinjection RNAi method, the injection site, injection volume and interference time were optimized, which then demonstrated that the injection RNAi method was applicable in this spider. With the new RNAi method, it was revealed that both Pp AChE1 and Pp-AChE2, encoded by genes Ppace1 and Ppace2, were the targets of organophosphate insecticides, but Pp-AChE1 would be more important. In contrast, the carbamate acted selectively on Pp-AChE1. The results showed that Pp-AChE1 was the major catalytic enzyme in P. pseudoannulata and the major target of organophosphate and carbamate insecticides. In a word, an RNAi method was established in the pond wolf spider, which further validated the importance of two acetylcholinesterases in insecticide sensitivities in this spider. PMID- 26615148 TI - Locomotory and physiological responses induced by clove and cinnamon essential oils in the maize weevil Sitophilus zeamais. AB - Plant essential oils have been suggested as a suitable alternative for controlling stored pests worldwide. However, very little is known about the physiological or behavioral responses induced by these compounds in insect populations that are resistant to traditional insecticides. Thus, this investigation evaluated the toxicity (including the impacts on population growth) as well as the locomotory and respiratory responses induced by clove, Syzygium aromaticum L., and cinnamon, Cinnamomum zeylanicum L., essential oils in Brazilian populations of the maize weevil Sitophilus zeamais. We used populations that are resistant to phosphine and pyrethroids (PyPhR), only resistant to pyrethroids (PyR1 and PyR2) or susceptible to both insecticide types (SUS). The PyPhR population was more tolerant to cinnamon essential oil, and its population growth rate was less affected by both oil types. Insects from this population reduced their respiratory rates (i.e., CO2 production) after being exposed to both oil types and avoided (in free choice-experiments) or reduced their mobility on essential oil-treated surfaces. The PyR1 and PyR2 populations reduced their respiratory rates, avoided (without changing their locomotory behavior in no choice experiments) essential oil-treated surfaces and their population growth rates were severely affected by both oil types. Individuals from SUS population increased their mobility on surfaces that were treated with both oil types and showed the highest levels of susceptibility to these oils. Our findings indicate that S. zeamais populations that are resistant to traditional insecticides might have distinct but possibly overlapping mechanisms to mitigate the actions of essential oils and traditional insecticides. PMID- 26615149 TI - Enantioselective phytotoxicity and bioacitivity of the enantiomers of the herbicide napropamide. AB - Enantioselectivity of chiral pesticide enantiomers should be taken into consideration in pesticide application and environmental risk assessment. The phytotoxicity of the enantiomers of napropamide to cucumber, soybean, and the bioactivity to the target weeds Poa annua and Festuca arundinacea have been studied in this work. To the nontarget crops, the influences of napropamide on the root, shoot, fresh weight, chlorophyll, superoxide dismutase (SOD) and catalase (CAT) activities and membrane lipid peroxides have been studied. (-) Napropamide was more toxic than the racemate and (+)-napropamide to soybean and cucumber in terms of root, shoot and fresh weight. The content of chlorophyll was not affected by napropamide. The impacts on the activities of SOD, CAT and membrane lipid peroxides showed that napropamide could induce the oxidative stress and rac-napropamide caused a stronger oxidative damage to cucumber and soybean than (-)-napropamide and (+)-napropamide. For the target weeds, the influences of napropamide on root, shoot and fresh weight have been studied. (-) Napropamid was more active to P. annua, while rac-napropamide was more active to F. arundinacea. To reduce environmental pollution and improve the effectiveness of chiral pesticide, single enantiomer should be developed and produced. This work may provide evidence for developing optical pure product. PMID- 26615150 TI - Leaf proteome analysis provides insights into the molecular mechanisms of bentazon detoxification in rice. AB - Bentazon is a widely used herbicide that selectively removes broad-leaf weeds by competing with plastoquinone for the binding site in the D1 protein and interrupting the PET (photosynthetic electron transfer) chain. However, monocotyledonous plants, such as rice, show strong resistance to bentazon due to CYP81A6 induction, which results in herbicide detoxification. Here, we confirmed that rice was sensitive to bentazon treatment during the initial exposure period, in which bentazon rapidly inhibited photosynthesis efficiency and electron transfer, based on results of chlorophyll fluorescence analysis. In order to gain a comprehensive, pathway-oriented, mechanistic understanding of the effects directly induced by bentazon, we employed 2D-DIGE (two-dimensional difference gel electrophoresis) to analyze the leaf proteome after 8h of bentazon treatment coupled with individual protein identification by MALDI-TOF (Matrix assisted laser desorption/ionization-time of flight) MS/MS. Proteomic analyses revealed that bentazon induced the relative upregulation or downregulation of 30 and 71 proteins (by 1.5-fold or more, p<0.05), respectively. The pathways involved include photosynthesis processes, carbohydrate metabolism, antioxidant systems, and DNA stabilization and protein folding. Protein analysis data revealed that bentazon primarily suppressed photosynthesis processes, and showed inhibitory effects on carbohydrate metabolism and ATP synthesis, whereas several stress response proteins were induced in response to bentazon. Importantly, we identified a 519kD protein containing two histidine kinase-like ATPase domains and a C3HC4 RING type zinc finger domain which may function as a transcript factor to drive expression of detoxification genes such as CYP81A6, leading to bentazon tolerance. This study identifies, for the first time, a candidate transcription factor that could up-regulate CYP81A6 expression, and provides a foundation for further research to advance our knowledge of mechanisms of bentazon resistance in rice. PMID- 26615151 TI - Synergism of herbicide toxicity by 5-aminolevulinic acid is related to physiological and ultra-structural disorders in crickweed (Malachium aquaticum L.). AB - Selection of effective herbicides to control weeds has been one of the major objectives of scientists. This study determines the differential tolerance or susceptibility of crickweed (Malachium aquaticum L.) to various concentration combinations of 5-aminolevulinic acid (ALA) (1, 10 and 100mg/L) and propyl 4-(2 (4,6-dimethoxypyrimidin-2-yloxy)benzylamino)benzoate (ZJ0273) (100, 200, and 500mg/L). ALA was applied as pre- and post-treatment alone or in combination with ZJ0273. Results showed that ZJ0273 stress alone imposed negative effects on M. aquaticum seedling's growth, net photosynthetic rates and SPAD values, and the rate of decline was consistently increased with the increase in ZJ0273 concentration. The ZJ0273 treatment showed a gradual decrease in the activities of antioxidant enzymes peroxidase (POD), superoxide dismutase (SOD), and ascorbate peroxidase (APX), and increase in the accumulation of malondialdehyde (MDA). Changes in chloroplast swelling, increased number of plastoglobuli, disruption of thylakoid, disintegrated mitochondria and turbid nucleoplasm were noticed. Moreover, SDS-PAGE analysis of total proteins revealed that herbicide stress in the leaves was associated with the decrease or disappearance of some protein bands. Further, two-dimensional gel electrophoresis (2-DE) results showed that proteins in different spots were classified into three types for M. aquaticum. These results indicate that the combined treatment of ALA and ZJ0273 synergizes the herbicide toxicity which is different from its independent effects on M. aquaticum and thus, could improve weed control efficacy. PMID- 26615152 TI - Mutation at residue 376 of ALS confers tribenuron-methyl resistance in flixweed (Descurainia sophia) populations from Hebei Province, China. AB - The acetolactate synthase (ALS) inhibitor tribenuron has been used continuously for approximately twenty years as an herbicide in winter wheat fields in China. Flixweed (Descurainia sophia) has evolved resistance to tribenuron, due to multiple amino acid mutations at the 197th residue of ALS. In this study, the molecular basis of tribenuron resistance was investigated using two resistant populations, Xingtai (XT) and Shijiazhuang (SJ), and two susceptible populations, Cangzhou (CZ) and Handan (HD). Whole-plant tests and ALS activity assays showed that the two resistant populations were highly resistant to tribenuron. Targeted amplification of ALS genes from the four populations showed that there were two ALS genes in each population, and both of them were expressed in flixweed; the full coding lengths of the two ALS genes were 1998bp and 2004bp. Mutations related to tribenuron resistance in flixweed were located in only the 1998bp paralog. An ALS activity assay showed that the resistant population SJ displayed slight cross-resistance to florasulam, with a resistance factor of 4.81, but the resistant population XT did not have cross-resistance to florasulam. The resistant population XT was found to carry the previously reported mutation Pro197Ser, but the resistant population SJ carried a different mutation, Asp376Glu, known from other weeds but novel in flixweed. Our results demonstrated that multiple versions of ALS genes exist in flixweed and that mutations at multiple sites may result in ALS-inhibitor resistance in this weed. PMID- 26615153 TI - Immune and metabolic responses of Chilo suppressalis Walker (Lepidoptera: Crambidae) larvae to an insect growth regulator, hexaflumuron. AB - Efficient control of Chilo suppressalis Walker is always controversial due to highly economic damage, resistance to insecticides and environmental pollutions. So, combination of safe pest controls e.g. biocontrol agents and insect growth regulators seems to be promising via integrated pest management program. Bioassay of hexaflumuron on 4th larval instars revealed concentrations of 44.34, 179.74 and 474.94ug/ml as LC10-50 values. Numbers of total hemocytes, plasmatocytes and granulocytes as well as phenoloxidase activity increased in the different time intervals following treatment by hexaflumuron. Combined effects of hexaflumuron and Beauveria bassiana Vuillemin also increased hemocyte numbers and phenoloxidase activity at different time intervals using all concentrations. Activities of general esterases assayed by alpha- and beta-naphtyl acetate and glutathione S-transferase using CDNB and DCNB increased 1-12h post-treatment. Activities of aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase and aldolase increased in the larvae treated by hexaflumuron. However enhanced activity of lactate dehydrogenase was only obtained by treating 180 and 470ug/ml concentrations of hexaflumuron. Activities of ACP and ALP were found to be higher than control for all time intervals even 1 12h post-treatment. The amounts of HDL and LDL increased in the highest concentrations of hexaflumuron after 12-24h of post-treatment. Amount of triglyceride was higher than that of control after 1 and 3h but it was lower in other time intervals. Amounts of glycogen and protein were lower than those of control for all time intervals except for 6 and 12h of post-treatment in case of protein. Results of the current study revealed negative effects of hexaflumuron on intermediary metabolism of Chilo suppressalis but it increased the number of hemocytes and activity of phenoloxidase which are responsible for spore removal from hemolymph. It can be concluded that hexaflumuron is able to decrease survival and biological performance of C. suppressalis via intervening in intermediary metabolism but the given results showed incompatibility of the IGR with possible microbial control. PMID- 26615154 TI - Triazolyl phenyl disulfides: 8-Amino-7-oxononanoate synthase inhibitors as potential herbicides. AB - The chemical validation of a potential herbicide target was investigated with 8 amino-7-oxononanoate synthase (AONS, also known as 7-keto-8-aminopelargonate synthase, KAPAS) and triazolyl phenyl disulfide derivatives in vitro and in vivo. AONS activity was completely inhibited by these synthesized compounds, with an IC50 of 48 to 592MUM in vitro. Forty five-day old Arabidopsis thaliana plants were completely killed by representative compound KHG23844 {N-(2-fluorophenyl)-3 (phenyldisulphanyl)-1H-1,2,4-triazole-1-carboxamide} at the application rate of 250gha(-1) of foliar treatment in greenhouse conditions. Foliar application of 1000gha(-1) KHG23844 induced 2.3-fold higher l-alanine accumulation in the treated A. thaliana plants. Foliar supplement of 1mM biotin at 1 and 2days before KHG23844 application effectively recovered the growth inhibition of A. thaliana plant treated with KHG23844. The results strongly suggested that representative compound KHG23844 and its derivatives are potential AONS inhibitors. PMID- 26615155 TI - Helpful Tool or Oversimplification? Concept of the Monosomal Karyotype from the Clinical and Cytogenetic Point of View. PMID- 26615156 TI - Hematopoietic niches, erythropoiesis and anemia of chronic infection. AB - Anemia is a significant co-morbidity of chronic infections, as well as other inflammatory diseases. Anemia of chronic infection results from defective bone marrow erythropoiesis. Although the limitation of iron availability has been considered a key factor, the exact mechanisms underlying blockade in erythroid generation during infection are not fully understood. Erythropoiesis is a tightly regulated process that is very sensitive to environmental changes. During the last decade, the importance of the bone marrow hematopoietic niche has been progressively acknowledged. Several bone marrow cell types (such as macrophages, mesenchymal stem cells, and progenitor cells) and molecular mediators (such as CXCL12) have been identified as fundamental for both the maintenance of hematopoietic stem cell pluripotency and their most adequate differentiation into each hematopoietic cell lineage. Importantly, both niche-supporting cells and hematopoietic progenitors were found to be able to sense local and systemic cues to adapt the hematopoietic output to needs of the organism. Here, we review how hematopoietic progenitors and niche-supporting cells sense and respond to stress cues and suggest a potential role for the hematopoietic niche in the development of anemia of chronic infection. PMID- 26615157 TI - Introduction. PMID- 26615158 TI - Noninvasive Imaging of the Biliary Tree for the Interventional Radiologist. AB - Patients with suspected biliary tract disease often pose a diagnostic challenge to the clinician and radiologist. Although advances across all imaging modalities, including ultrasound, computed tomography, and magnetic resonance, have improved our diagnostic accuracy for biliary disease, many of the imaging findings remain nonspecific. Recognition of key imaging findings combined with knowledge and understanding of the clinical context is essential to piecing together a diagnosis and guiding management for patients with biliary disease. Although there is a wide range of biliary pathology, interventional radiologists most commonly play a role in the management of biliary obstruction and leak. PMID- 26615159 TI - Clinical Approach to Patients With Obstructive Jaundice. AB - Obstructive jaundice is a clinical symptom that results from cholestasis. Cholestasis can be extrahepatic or intrahepatic and is typically associated with biochemical abnormalities in the liver function tests. Once these abnormalities are identified, more extensive imaging tests can be performed to determine the nature, etiology, and level of obstruction. This information is essential for clinicians as they decide on management and treatment strategies. PMID- 26615160 TI - Percutaneous Transhepatic Cholangioscopy. AB - The role of the interventional radiologist continues to expand in the treatment of biliary disease. Percutaneous transhepatic cholangioscopy (PTCS) provides direct visualization of the biliary system for diagnostic and therapeutic interventions, especially in cases where anatomical considerations prohibit a peroral approach. Visual inspection and endoscopically guided biopsy allow differentiation between benign and malignant lesions, as well as accurate assessment of the tumor extent for surgical planning. Studies have demonstrated greater than 95% accuracy with PTCS in diagnosing biliary malignancies. Cholangioscopy is also used to treat obstructive stones in the biliary system, which may require laser lithotripsy. PTCS-guided removal of biliary stones is highly successful, with complete stone removal from the bile ducts occurring in approximately 90% of cases. Overall, PTCS is a safe and effective procedure, with severe complications occurring in less than 8% of patients. The purpose of this review is to familiarize its reader with common indications for PTCS, techniques for procedural success, expected outcomes, and management of potential complications. PMID- 26615161 TI - Benign Biliary Strictures: Diagnostic Evaluation and Approaches to Percutaneous Treatment. AB - Interventional radiologists are often consulted to help identify and treat biliary strictures that can result from a variety of benign etiologies. Mainstays of noninvasive imaging for benign biliary strictures include ultrasound, contrast enhanced computed tomography and magnetic resonance imaging, magnetic resonance cholangiopancreatography, and computed tomography cholangiography. Endoscopic retrograde cholangiography is the invasive diagnostic procedure of choice, allowing both localization of a stricture and treatment. Percutaneous biliary interventions are reserved for patients who are not candidates for endoscopic retrograde cholangiography (eg, history of distal gastrectomy and biliary-enteric anastomosis to a jejunal roux limb). This review discusses the roles of percutaneous transhepatic cholangiography and biliary drainage in the diagnosis of benign biliary strictures. The methodology for crossing benign biliary strictures, approaches to balloon dilation, management of recalcitrant strictures (ie, large-bore biliary catheters and retrievable covered stents), and the expected outcomes and complications of percutaneous treatment of benign biliary strictures are also addressed. PMID- 26615162 TI - Percutaneous Management of Malignant Biliary Obstruction. AB - Malignancy resulting in impaired biliary drainage includes a number of diagnoses familiar to the interventional radiologist. Adequate drainage of such a system can significantly improve patient quality of life, and can facilitate the further treatment options and care of such patients. In the setting of prior instrumentation, cholangitis can present as an urgent indication for drainage. Current initial interventional management of malignant biliary duct obstruction frequently includes endoscopic or percutaneous intervention, with local practices and preprocedural imaging guiding interventional approaches and subsequent management. This article addresses the indications for percutaneous drainage, technical considerations in performing such drainage, and specific techniques useful in attempting to achieve clinical end points in patients with malignant biliary duct obstruction. PMID- 26615163 TI - Intrahepatic Cholangiocarcinoma. AB - Cholangiocarcinoma is a rare malignancy that arises from epithelial cells of the biliary system. Its desmoplastic histology and the heterogeneity of its presentation have contributed to its poor prognosis, with limited therapeutic options previously available. However, recent advances using locoregional therapy may expand the treatment arsenal used to manage this resistant malignancy. Although surgical resection has previously been reserved for relatively few patients because of inadequate hepatic reserve, portal vein embolization can induce contralateral hepatic lobe hypertrophy to increase the number of patients eligible for resection. For unresectable cases, both transarterial chemoembolization and yttrium-90 radioembolization have shown effectiveness in controlling tumor growth and prolonging survival. PMID- 26615164 TI - Etiology, Diagnosis, and Management of Bilomas: A Current Update. AB - A biloma is a well-demarcated collection of bile outside the biliary tree. Traumatic and iatrogenic injuries, most commonly secondary to cholecystectomy, are the usual causes. Although bilomas are relatively uncommon, this pathologic entity may lead to significant morbidity and mortality if not promptly diagnosed and properly managed. As clinical signs and symptoms of bilomas are often nonspecific and laboratory values may be unremarkable, imaging modalities including ultrasound, computed tomography, magnetic resonance imaging, and hepatobiliary cholescintigraphy play a crucial role in the diagnosis of this condition. It is paramount that interventional radiologists not only be well versed in the management of bilomas but also be knowledgeable in the diagnosis as well as key imaging findings that dictate the interventional management. The purpose of this article is to review the etiology, pathophysiology, and clinical presentation of bilomas to primarily focus on the relevant multimodal imaging findings and the minimally invasive management options. PMID- 26615165 TI - Choledocholithiasis: Diagnosis and Management. AB - Common bile duct stones constitute the main etiology of nonmalignant biliary obstruction. Endoscopic retrieval of common bile duct stones has been adopted as the primary treatment modality for extrahepatic biliary stones. However, endoscopic therapy may fail in patients who have had previous gastrointestinal tract surgeries, including partial gastrectomy with Billroth II reconstruction or bilioenteric anastomosis, or in patients with anatomical anomalies such as a duodenal periampullary diverticulum, which makes the biliary duct difficult to access via an endoscopic approach. Endoscopic therapy may also not be suitable for hepatolithiasis with large and impacted stones. In such situations, a percutaneous approach is generally the best option. A variety of percutaneous techniques are available for removal of intrahepatic and extrahepatic bile duct stones via transhepatic approach and T-tube tract. These techniques include extraction, fragmentation, and expulsion of stones into the duodenum. In this article, clinical presentations, imaging modalities, and different management options, particularly percutaneous techniques for the management of choledocholithiasis or hepatolithiasis, are reviewed. PMID- 26615166 TI - Clinical Presentation, Imaging, and Management of Acute Cholecystitis. AB - Acute cholecystitis (AC) is a life-threatening emergency that commonly occurs as a complication of gallstones. Severe right upper quadrant pain, abdominal guarding, fever, and a positive Murphy's sign with an elevated white blood cell count are the classical clinical manifestations of AC. Although ultrasonography is typically the initial diagnostic examination in patients with suspected AC, computed tomography and magnetic resonance imaging are commonly performed to identify complications; cholescintigraphy is recommended in patients with equivocal findings on the other imaging modalities, as this technique has the highest diagnostic accuracy in the diagnosis of AC. Imaging studies are also helpful in the timely detection of complications associated with AC. Although laparoscopic cholecystectomy is considered the gold-standard treatment for AC, percutaneous gallbladder drainage with or without cholecystostomy tube placement is a safe, effective management technique for surgically high-risk patients with multiple medical conditions. This treatment can be used as either a bridging therapy, with elective cholecystectomy performed at a later time after improvement of the patient's condition, or as definitive treatment in surgically unfit patients. Radiologists play a pivotal role in the initial diagnosis and management of patients with AC. PMID- 26615167 TI - The Role of Interventional Radiology in the Multidisciplinary Management of Biliary Complications After Liver Transplantation. AB - Interventional radiology is a key component of the multidisciplinary team that is required for a successful liver transplant program, as it provides safe, effective, and minimally invasive management of transplant-related complications. Biliary complications remain highly prevalent among transplant recipients, and radiologic techniques can improve graft and patient survival in this population. Such techniques can serve as definitive, first-line therapies in some cases and as adjuncts to multidisciplinary approaches in others. This article reviews vascular and nonvascular radiologic techniques for managing transplant-related biliary complications. PMID- 26615168 TI - Pediatric Biliary Interventions. AB - An interventional radiologist is frequently called to evaluate and treat biliary diseases in children; a tailored approach specific to this population is required. Imaging with an emphasis on minimizing ionizing radiation is used not only in the initial workup but also to guide interventions. The most common form of intervention generally consists of transhepatic biliary drainage to treat either biliary obstruction or bile leakage, a scenario frequently encountered after pediatric liver transplantation. Other pathologies referred for evaluation and management include biliary atresia and, rarely, symptomatic choledochal cysts. Biliary complications caused by an underlying malignancy are not a frequently encountered problem in the pediatric population. The initial evaluation, role of preprocedural imaging, and interventional management with an emphasis on technique are discussed regarding these common biliary pathologies in children. PMID- 26615169 TI - Interventions to Improve Adolescent Vaccination: What May Work and What Still Needs to Be Tested. AB - Since the development of the "adolescent platform" of vaccination in 1997, hundreds of studies have been conducted, identifying barriers to and facilitators of adolescent vaccination. More recent research has focused on developing and evaluating interventions to increase uptake of adolescent vaccines. This review describes a selection of recent intervention studies for increasing adolescent vaccination, divided into three categories: those with promising results that may warrant more widespread implementation, those with mixed results requiring more research, and those with proven effectiveness in other domains that have not yet been tested with regard to adolescent vaccination. PMID- 26615170 TI - Meeting the Challenges of Immunizing Adults. AB - The overall burden of illness from diseases for which vaccines are available disproportionately falls on adults. Adults are recommended to receive vaccinations based on their age, underlying medical conditions, lifestyle, prior vaccinations, and other considerations. Updated vaccine recommendations from CDC are published annually in the U.S. Adult Immunization Schedule. Vaccine use among U.S. adults is low. Although receipt of a provider (physician or other vaccinating healthcare provider) recommendation is a key predictor of vaccination, more often consumers report not receiving vaccine recommendations at healthcare provider visits. Although providers support the benefits of vaccination, they also report several barriers to vaccinating adults, including the cost of providing vaccination services, inadequate or inconsistent payment for vaccines and vaccine administration, and acute medical care taking precedence over preventive services. Despite these challenges, a number of strategies have been demonstrated to substantially improve adult vaccine coverage, including patient and provider reminders and standing orders for vaccination. Providers are encouraged to incorporate routine assessment of their adult patients' vaccination needs during all clinical encounters to ensure patients receive recommendations for needed vaccines and are either offered needed vaccines or referred for vaccination. PMID- 26615171 TI - Vaccine hesitancy: Causes, consequences, and a call to action. AB - Vaccine hesitancy reflects concerns about the decision to vaccinate oneself or one's children. There is a broad range of factors contributing to vaccine hesitancy, including the compulsory nature of vaccines, their coincidental temporal relationships to adverse health outcomes, unfamiliarity with vaccine preventable diseases, and lack of trust in corporations and public health agencies. Although vaccination is a norm in the U.S. and the majority of parents vaccinate their children, many do so amid concerns. The proportion of parents claiming non-medical exemptions to school immunization requirements has been increasing over the past decade. Vaccine refusal has been associated with outbreaks of invasive Haemophilus influenzae type b disease, varicella, pneumococcal disease, measles, and pertussis, resulting in the unnecessary suffering of young children and waste of limited public health resources. Vaccine hesitancy is an extremely important issue that needs to be addressed because effective control of vaccine-preventable diseases generally requires indefinite maintenance of extremely high rates of timely vaccination. The multifactorial and complex causes of vaccine hesitancy require a broad range of approaches on the individual, provider, health system, and national levels. These include standardized measurement tools to quantify and locate clustering of vaccine hesitancy and better understand issues of trust; rapid, independent, and transparent review of an enhanced and appropriately funded vaccine safety system; adequate reimbursement for vaccine risk communication in doctors' offices; and individually tailored messages for parents who have vaccine concerns, especially first-time pregnant women. The potential of vaccines to prevent illness and save lives has never been greater. Yet, that potential is directly dependent on parental acceptance of vaccines, which requires confidence in vaccines, healthcare providers who recommend and administer vaccines, and the systems to make sure vaccines are safe. PMID- 26615172 TI - Immunization equity. AB - Health inequities are the unjust differences in health among different social groups. Unfortunately, inequities are the norm, both in terms of health status and access to, and use of, health services. Childhood immunizations reduce the incidence of vaccine-preventable diseases and represent a cost-effective way to foster health equity. This paper reflects a 2015 review of data from surveys conducted in developing countries from 2005 to 2011 that show significant inequities in immunization coverage and discusses several initiatives currently underway (including Gavi, the Vaccine Alliance) that are directed at increasing childhood immunizations or reducing or abolishing overall health inequities. These initiatives have already had a significant impact on disease burden and childhood mortality and give rise to optimism that health disparities may further be reduced and health equity achieved as a result of investments made in immunization. PMID- 26615173 TI - Lessons learned from making and implementing vaccine recommendations in the U.S. AB - After publication of certain vaccine recommendations made by the Advisory Committee on Immunization Practices, several unexpected events have occurred during implementation of these recommendations. These have included changes in recommendations following adverse events involved with a particular vaccine and the conferral of community protection as an offshoot of vaccination of a specific population. Vaccine shortages and hesitancy have also been proven impediments to full implementation, and vaccine recommendations have not gone unaffected by either public perception of a vaccine or by cost considerations. PMID- 26615174 TI - Racial and ethnic disparities in vaccination coverage among adult populations in the U.S. AB - INTRODUCTION: Reducing racial/ethnic disparities in immunization rates is a compelling public health goal. Disparities in childhood vaccination rates have not been observed in recent years for most vaccines. The objective of this study is to assess adult vaccination by race/ethnicity in the U.S. METHODS: The 2012 National Health Interview Survey was analyzed in 2014 to assess adult vaccination by race/ethnicity for five vaccines routinely recommended for adults: influenza, tetanus, pneumococcal (two vaccines), human papilloma virus, and zoster vaccines. Multivariable logistic regression analysis was performed to identify factors independently associated with all adult vaccinations. RESULTS: Vaccination coverage was significantly lower among non-Hispanic blacks, Hispanics, and non Hispanic Asians compared with non-Hispanic whites, with only a few exceptions. Age, sex, education, health insurance, usual place of care, number of physician visits in the past 12 months, and health insurance were independently associated with receipt of most of the examined vaccines. Racial/ethnic differences narrowed, but gaps remained after taking these factors into account. CONCLUSIONS: Racial and ethnic differences in vaccination levels narrow when adjusting for socioeconomic factors analyzed in this survey, but are not eliminated, suggesting that other factors that are associated with vaccination disparities are not measured by the National Health Interview Survey and could also contribute to the differences in coverage. Additional efforts, including systems changes to ensure routine assessment and recommendations for needed vaccinations among adults for all racial/ethnic groups, are essential for improving vaccine coverage. PMID- 26615175 TI - Childhood immunizations: First-time expectant mothers' knowledge, beliefs, intentions, and behaviors. AB - INTRODUCTION: This study focused on how first-time mothers decide or intend to decide with respect to the recommended childhood immunization schedule. METHODS: This was the baseline survey of a larger longitudinal survey. Data were collected between June and September 2014 from 200 first-time mothers in their second trimester of pregnancy to examine vaccine-related knowledge, perceptions, intentions, and information-seeking behavior. RESULTS: Data were analyzed between January and June 2015. Seventy-five percent planned to have their child receive all the vaccinations consistent with the recommended childhood immunization schedule. Although participants expressed interest in childhood vaccine information, most had not received information directly from a primary care provider. One third reported receiving such information from their obstetrician/gynecologist but only about half of those were "very satisfied" with the information they received. About 70% indicated they were not familiar with the recommended vaccination schedule and number of routinely recommended vaccines. Familiarity with common vaccine education messages varied widely. Women who indicated they were planning to delay one or more recommended vaccinations were most likely to rely on Internet searches for childhood vaccine information. CONCLUSIONS: Overall, respondents had relatively positive beliefs and perceptions regarding childhood vaccines, which were associated with intentions to get their newborn vaccinated as recommended. However, most who were planning to delay recommended vaccinations or were undecided relied primarily on socially available sources of vaccine information, rather than information provided by a healthcare professional. Improved access to vaccine information from healthcare professionals could foster better vaccine-related knowledge and favorably impact vaccination decisions. PMID- 26615176 TI - Predictors of vaccination in India for children aged 12-36 months. AB - INTRODUCTION: India has one of the lowest immunization rates worldwide despite a longstanding Universal Immunization Program (UIP) that provides free childhood vaccines. This study characterizes the predictors for under- and non-vaccination among Indian children aged 12-36 months. METHODS: This study utilized District Level Household and Facility Survey Data, 2008 (DLHS3), from India. DLHS3 is a nationally representative sample collected from December 2007 through December 2008; this analysis was conducted during 2014. Children's vaccination status was categorized as fully, under-, and non-vaccinated based on whether children received all, some, or none of the UIP-recommended vaccines (one dose each of bacillus Calmette-Guerin and measles, and three doses of diphtheria-pertussis tetanus). A multinomial logistic regression model estimated the odds of undervaccination compared with full vaccination, and odds of non-vaccination compared with full vaccination. Analytic predictors included socioeconomic, cultural, household, maternal, and childhood characteristics. RESULTS: The analysis included 108,057 children; the estimated proportions of fully, under-, and non-vaccinated children were 57%, 31%, and 12%, respectively. After adjusting for state of residence, age, gender, household wealth, and maternal education, additional significant predictors of children's vaccination status were religion, caste, place of delivery, number of antenatal care visits, and maternal tetanus vaccination, all of which demonstrated large effect sizes. CONCLUSIONS: India's immunization coverage remained low in 2008, with just slightly more than half of all children aged 12-36 months fully vaccinated with UIP-recommended vaccines. A better understanding of the predictors for vaccination can help shape interventions to reduce disparities in full vaccination among children of differing demographic/cultural groups. PMID- 26615177 TI - Maximum Likelihood Phylogenetic Inference is Consistent on Multiple Sequence Alignments, with or without Gaps. AB - We prove that maximum likelihood phylogenetic inference is consistent on gapped multiple sequence alignments (MSAs) as long as substitution rates across each edge are greater than zero, under mild assumptions on the structure of the alignment. Under these assumptions, maximum likelihood will asymptotically recover the tree with edge lengths corresponding to the mean number of substitutions per site on each edge. This refutes Warnow's recent suggestion (Warnow 2012) that maximum likelihood phylogenetic inference might be statistically inconsistent when gaps are treated as missing data, even if the MSA is correct. We also derive a simple new proof of maximum likelihood consistency of ungapped alignments. PMID- 26615178 TI - Responses of Dendritic Cells to TLR-4 Stimulation Are Maintained in the Elderly and Resist the Effects of CMV Infection Seen in the Young. AB - Toll-like receptor 4 (TLR-4) plays a crucial role in the pathophysiology of several age-related diseases. Although poorer function of circulating myeloid dendritic cells (mDCs) has been reported in the elderly, data on TLR-4 function in these cells in older people are lacking. Here, we investigated TLR-4 functionality in the elderly by ex vivo analysis of cytokine production of mDCs in response to LPS in 39 younger (23-34 years) and 61 older (62-77 years) healthy people using flow cytometry. We matched these subjects for Cytomegalovirus (CMV) serostatus because a latent infection with this ubiquitous herpesvirus is known to affect numerous immune parameters. We found that TLR-4-dependent production of IL-6 and TNF was strongly stimulated in circulating mDCs from the elderly. However, mDCs of more than half of the young donors failed to respond in the same way. This was related to their already highly activated ex vivo state, predominantly observed in CMV-seropositive young donors and associated with lower CMV-specific IgG titres. This may reflect an increasingly important requirement for control of CMV infection throughout life. These data suggest that TLR-4 agonists may be the adjuvants of choice for elderly people, most of whom are CMV positive, and whose responses to immunization are frequently impaired. PMID- 26615179 TI - Symptoms and QOL as Predictors of Chemoprevention Adherence in NRG Oncology/NSABP Trial P-1. AB - BACKGROUND: Tamoxifen provides a 50% reduction in the incidence of breast cancer (BC) among high-risk women, yet many do not adhere to the five-year course of therapy. Using the prospective double-blind National Surgical Adjuvant Breast and Bowel Project P-1 study, we evaluated whether participant-reported outcomes were associated with drug adherence and whether baseline behavioral risk factors modified those associations. METHODS: P-1 participants were randomly assigned to placebo vs tamoxifen (20mg/day). Mixed effects logistic regression was used to evaluate whether baseline or three-month SF-36 quality of life (QOL) mental and physical component summaries (MCS, PCS), and participant-reported symptoms (gynecologic, vasomotor, sexual, and other) predicted 12-month drug adherence (76 100% of assigned medication). The evaluation accounted for age, treatment, estimated breast cancer risk, education, baseline smoking, alcohol consumption, and obesity. All statistical tests were two-sided. RESULTS: Participants enrolled at least three years before trial unblinding and without medically indicated discontinuation before 12 months were eligible for the present analyses (n = 10 576). At 12 months, 84.3% were adherent. Statistically significant predictors of adherence were: three-month MCS (odds ratio [OR] = 1.15 per 10 points, 95% confidence interval [CI] = 1.06 to 1.25); three-month gynecologic symptoms among moderate alcohol drinkers (OR = .79, 95% CI = 0.72 to 0.88); baseline vasomotor symptoms among participants assigned tamoxifen (OR = .88, 95% CI = 0.80 to 0.97); and three-month sexual symptoms among younger participants (OR = .89 at age 41 years, 95% CI = 0.80 to 0.99). The strongest association was with three-month other symptoms (OR = .77, 95% CI = 0.63 to 0.93). PCS was not associated with adherence. Symptom and QOL associations were not modified by smoking or obesity. CONCLUSIONS: Promoting QOL and managing symptoms early in therapy may be important strategies to improve adherence. PMID- 26615180 TI - Germ line genome editing in clinics: the approaches, objectives and global society. AB - Genome editing allows for the versatile genetic modification of somatic cells, germ cells and embryos. In particular, CRISPR/Cas9 is worldwide used in biomedical research. Although the first report on Cas9-mediated gene modification in human embryos focused on the prevention of a genetic disease in offspring, it raised profound ethical and social concerns over the safety of subsequent generations and the potential misuse of genome editing for human enhancement. The present article considers germ line genome editing approaches from various clinical and ethical viewpoints and explores its objectives. The risks and benefits of the following three likely objectives are assessed: the prevention of monogenic diseases, personalized assisted reproductive technology (ART) and genetic enhancement. Although genetic enhancement should be avoided, the international regulatory landscape suggests the inevitability of this misuse at ART centers. Under these circumstances, possible regulatory responses and the potential roles of public dialogue are discussed. PMID- 26615181 TI - Effect of Sucrose Analgesia, for Repeated Painful Procedures, on Short-term Neurobehavioral Outcome of Preterm Neonates: A Randomized Controlled Trial. AB - BACKGROUND: Safety of oral sucrose, commonly used procedural analgesic in neonates, is questioned. AIM: To evaluate the effect of sucrose analgesia, for repeated painful procedures, on short-term neurobehavioral outcome of preterm neonates. METHODS: Stable preterm neonates were randomized to receive either sucrose or distilled water orally, for every potentially painful procedure during the first 7 days after enrollment. Neurodevelopmental status at 40 weeks postconceptional age (PCA) measured using the domains of Neurobehavioral Assessment of Preterm Infants scale. RESULTS: A total of 93 newborns were analyzed. The baseline characteristics of the groups were comparable. No statistically significant difference was observed in the assessment at 40 weeks PCA, among the groups. Use of sucrose analgesia, for repeated painful procedures on newborns, does not lead to any significant difference in the short-term neurobehavioral outcome. PMID- 26615182 TI - The impact of real-time alerting on appropriate prescribing in kidney disease: a cluster randomized controlled trial. AB - BACKGROUND: Patients with kidney disease are at risk for adverse events due to improper medication prescribing. Few randomized controlled trials of clinical decision support (CDS) utilizing dynamic assessment of patients' kidney function to improve prescribing for patients with kidney disease have been published. METHODS: We developed a CDS tool for 20 medications within a commercial electronic health record. Our system detected scenarios in which drug discontinuation or dosage adjustment was recommended for adult patients with impaired renal function in the ambulatory and acute settings - both at the time of the initial prescription ("prospective" alerts) and by monitoring changes in renal function for patients already receiving one of the study medications ("look back" alerts). We performed a prospective, cluster randomized controlled trial of physicians receiving clinical decision support for renal dosage adjustments versus those performing their usual workflow. The primary endpoint was the proportion of study prescriptions that were appropriately adjusted for patients' kidney function at the time that patients' conditions warranted a change according to the alert logic. We employed multivariable logistic regression modeling to adjust for glomerular filtration rate, gender, age, hospitalized status, length of stay, type of alert, time from start of study, and clustering within the prescribing physician on the primary endpoint. RESULTS: A total of 4068 triggering conditions occurred in 1278 unique patients; 1579 of these triggering conditions generated alerts seen by physicians in the intervention arm and 2489 of these triggering conditions were captured but suppressed, so as not to generate alerts for physicians in the control arm. Prescribing orders were appropriate adjusted in 17% of the time vs 5.7% of the time in the intervention and control arms, respectively (odds ratio: 1.89, 95% confidence interval, 1.45 2.47, P < .0001). Prospective alerts had a greater impact than look-back alerts (55.6% vs 10.3%, in the intervention arm). CONCLUSIONS: The rate of appropriate drug prescribing in kidney impairment is low and remains a patient safety concern. Our results suggest that CDS improves drug prescribing, particularly when providing guidance on new prescriptions. PMID- 26615183 TI - The utility of web mining for epidemiological research: studying the association between parity and cancer risk. AB - BACKGROUND: The World Wide Web has emerged as a powerful data source for epidemiological studies related to infectious disease surveillance. However, its potential for cancer-related epidemiological discoveries is largely unexplored. METHODS: Using advanced web crawling and tailored information extraction procedures, the authors automatically collected and analyzed the text content of 79 394 online obituary articles published between 1998 and 2014. The collected data included 51 911 cancer (27 330 breast; 9470 lung; 6496 pancreatic; 6342 ovarian; 2273 colon) and 27 483 non-cancer cases. With the derived information, the authors replicated a case-control study design to investigate the association between parity (i.e., childbearing) and cancer risk. Age-adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for each cancer type and compared to those reported in large-scale epidemiological studies. RESULTS: Parity was found to be associated with a significantly reduced risk of breast cancer (OR = 0.78, 95% CI, 0.75-0.82), pancreatic cancer (OR = 0.78, 95% CI, 0.72 0.83), colon cancer (OR = 0.67, 95% CI, 0.60-0.74), and ovarian cancer (OR = 0.58, 95% CI, 0.54-0.62). Marginal association was found for lung cancer risk (OR = 0.87, 95% CI, 0.81-0.92). The linear trend between increased parity and reduced cancer risk was dramatically more pronounced for breast and ovarian cancer than the other cancers included in the analysis. CONCLUSION: This large web-mining study on parity and cancer risk produced findings very similar to those reported with traditional observational studies. It may be used as a promising strategy to generate study hypotheses for guiding and prioritizing future epidemiological studies. PMID- 26615184 TI - Phylogeography, Genetic Diversity, and Management Units of Hawksbill Turtles in the Indo-Pacific. AB - Hawksbill turtle (Eretmochelys imbricata) populations have experienced global decline because of a history of intense commercial exploitation for shell and stuffed taxidermied whole animals, and harvest for eggs and meat. Improved understanding of genetic diversity and phylogeography is needed to aid conservation. In this study, we analyzed the most geographically comprehensive sample of hawksbill turtles from the Indo-Pacific Ocean, sequencing 766 bp of the mitochondrial control region from 13 locations (plus Aldabra, n = 4) spanning over 13500 km. Our analysis of 492 samples revealed 52 haplotypes distributed in 5 divergent clades. Diversification times differed between the Indo-Pacific and Atlantic lineages and appear to be related to the sea-level changes that occurred during the Last Glacial Maximum. We found signals of demographic expansion only for turtles from the Persian Gulf region, which can be tied to a more recent colonization event. Our analyses revealed evidence of transoceanic migration, including connections between feeding grounds from the Atlantic Ocean and Indo Pacific rookeries. Hawksbill turtles appear to have a complex pattern of phylogeography, showing a weak isolation by distance and evidence of multiple colonization events. Our novel dataset will allow mixed-stock analyses of hawksbill turtle feeding grounds in the Indo-Pacific by providing baseline data needed for conservation efforts in the region. Eight management units are proposed in our study for the Indo-Pacific region that can be incorporated in conservation plans of this critically endangered species. PMID- 26615185 TI - Comparative Transcriptome Analysis between the Fungal Plant Pathogens Sclerotinia sclerotiorum and S. trifoliorum Using RNA Sequencing. AB - The fungal plant pathogens Sclerotinia sclerotiorum and S. trifoliorum are morphologically similar, but differ considerably in host range. In an effort to elucidate mechanisms of the host range difference, transcriptomes of the 2 species at vegetative growth stage were compared to gain further insight into commonality and uniqueness in gene expression and pathogenic mechanisms of the 2 closely related pathogens. A total of 23133 and 21043 unique transcripts were obtained from S. sclerotiorum and S. trifoliorum, respectively. Approximately 43% of the transcripts were genes with known functions for both species. Among 1411 orthologous contigs, about 10% (147) were more highly (>3-fold) expressed in S. trifoliorum than in S. sclerotiorum, and about 12% (173) of the orthologs were more highly (>3-fold) expressed in S. sclerotiorum than in S. trifoliorum. The expression levels of genes on the supercontig 30 have the highest correlation coefficient value between the 2 species. Twenty-seven contigs were found to be new and unique for S. trifoliorum. Additionally, differences in expressed genes involved in pathogenesis like oxalate biosynthesis and endopolygalacturonases were detected between the 2 species. The analyses of the transcriptomes not only discovered similarities and uniqueness in gene expression between the 2 closely related species, providing additional information for annotation the S. sclerotiorum genome, but also provided foundation for comparing the transcriptomes with host-infecting transcriptomes. PMID- 26615186 TI - New Standards for Negative Symptom Assessment. PMID- 26615187 TI - Birth by Caesarean Section and the Risk of Adult Psychosis: A Population-Based Cohort Study. AB - Despite the biological plausibility of an association between obstetric mode of delivery and psychosis in later life, studies to date have been inconclusive. We assessed the association between mode of delivery and later onset of psychosis in the offspring. A population-based cohort including data from the Swedish National Registers was used. All singleton live births between 1982 and 1995 were identified (n= 1,345,210) and followed-up to diagnosis at age 16 or later. Mode of delivery was categorized as: unassisted vaginal delivery (VD), assisted VD, elective Caesarean section (CS) (before onset of labor), and emergency CS (after onset of labor). Outcomes included any psychosis; nonaffective psychoses (including schizophrenia only) and affective psychoses (including bipolar disorder only and depression with psychosis only). Cox regression analysis was used reporting partially and fully adjusted hazard ratios (HR) with 95% confidence intervals (CI). Sibling-matched Cox regression was performed to adjust for familial confounding factors. In the fully adjusted analyses, elective CS was significantly associated with any psychosis (HR 1.13, 95% CI 1.03, 1.24). Similar findings were found for nonaffective psychoses (HR 1.13, 95% CI 0.99, 1.29) and affective psychoses (HR 1.17, 95% CI 1.05, 1.31) (chi(2)for heterogeneityP= .69). In the sibling-matched Cox regression, this association disappeared (HR 1.03, 95% CI 0.78, 1.37). No association was found between assisted VD or emergency CS and psychosis. This study found that elective CS is associated with an increase in offspring psychosis. However, the association did not persist in the sibling matched analysis, implying the association is likely due to familial confounding by unmeasured factors such as genetics or environment. PMID- 26615190 TI - Biocuration of functional annotation at the European nucleotide archive. AB - The European Nucleotide Archive (ENA; http://www.ebi.ac.uk/ena) is a repository for the submission, maintenance and presentation of nucleotide sequence data and related sample and experimental information. In this article we report on ENA in 2015 regarding general activity, notable published data sets and major achievements. This is followed by a focus on sustainable biocuration of functional annotation, an area which has particularly felt the pressure of sequencing growth. The importance of functional annotation, how it can be submitted and the shifting role of the biocurator in the context of increasing volumes of data are all discussed. PMID- 26615189 TI - Tetramerization and interdomain flexibility of the replication initiation controller YabA enables simultaneous binding to multiple partners. AB - YabA negatively regulates initiation of DNA replication in low-GC Gram-positive bacteria. The protein exerts its control through interactions with the initiator protein DnaA and the sliding clamp DnaN. Here, we combined X-ray crystallography, X-ray scattering (SAXS), modeling and biophysical approaches, with in vivo experimental data to gain insight into YabA function. The crystal structure of the N-terminal domain (NTD) of YabA solved at 2.7 A resolution reveals an extended alpha-helix that contributes to an intermolecular four-helix bundle. Homology modeling and biochemical analysis indicates that the C-terminal domain (CTD) of YabA is a small Zn-binding domain. Multi-angle light scattering and SAXS demonstrate that YabA is a tetramer in which the CTDs are independent and connected to the N-terminal four-helix bundle via flexible linkers. While YabA can simultaneously interact with both DnaA and DnaN, we found that an isolated CTD can bind to either DnaA or DnaN, individually. Site-directed mutagenesis and yeast-two hybrid assays identified DnaA and DnaN binding sites on the YabA CTD that partially overlap and point to a mutually exclusive mode of interaction. Our study defines YabA as a novel structural hub and explains how the protein tetramer uses independent CTDs to bind multiple partners to orchestrate replication initiation in the bacterial cell. PMID- 26615192 TI - Folding dynamics and conformational heterogeneity of human telomeric G-quadruplex structures in Na+ solutions by single molecule FRET microscopy. AB - G-quadruplex structures can occur throughout the genome, including at telomeres. They are involved in cellular regulation and are potential drug targets. Human telomeric G-quadruplex structures can fold into a number of different conformations and show large conformational diversity. To elucidate the different G-quadruplex conformations and their dynamics, we investigated telomeric G quadruplex folding using single molecule FRET microscopy in conditions where it was previously believed to yield low structural heterogeneity. We observed four FRET states in Na(+) buffers: an unfolded state and three G-quadruplex related states that can interconvert between each other. Several of these states were almost equally populated at low to medium salt concentrations. These observations appear surprising as previous studies reported primarily one G-quadruplex conformation in Na(+) buffers. Our results permit, through the analysis of the dynamics of the different observed states, the identification of a more stable G quadruplex conformation and two transient G-quadruplex states. Importantly these results offer a unique view into G-quadruplex topological heterogeneity and conformational dynamics. PMID- 26615191 TI - Database resources of the National Center for Biotechnology Information. AB - The National Center for Biotechnology Information (NCBI) provides a large suite of online resources for biological information and data, including the GenBank((r)) nucleic acid sequence database and the PubMed database of citations and abstracts for published life science journals. Additional NCBI resources focus on literature (PubMed Central (PMC), Bookshelf and PubReader), health (ClinVar, dbGaP, dbMHC, the Genetic Testing Registry, HIV-1/Human Protein Interaction Database and MedGen), genomes (BioProject, Assembly, Genome, BioSample, dbSNP, dbVar, Epigenomics, the Map Viewer, Nucleotide, Probe, RefSeq, Sequence Read Archive, the Taxonomy Browser and the Trace Archive), genes (Gene, Gene Expression Omnibus (GEO), HomoloGene, PopSet and UniGene), proteins (Protein, the Conserved Domain Database (CDD), COBALT, Conserved Domain Architecture Retrieval Tool (CDART), the Molecular Modeling Database (MMDB) and Protein Clusters) and chemicals (Biosystems and the PubChem suite of small molecule databases). The Entrez system provides search and retrieval operations for most of these databases. Augmenting many of the web applications are custom implementations of the BLAST program optimized to search specialized datasets. All of these resources can be accessed through the NCBI home page at www.ncbi.nlm.nih.gov. PMID- 26615193 TI - PDBFlex: exploring flexibility in protein structures. AB - The PDBFlex database, available freely and with no login requirements at http://pdbflex.org, provides information on flexibility of protein structures as revealed by the analysis of variations between depositions of different structural models of the same protein in the Protein Data Bank (PDB). PDBFlex collects information on all instances of such depositions, identifying them by a 95% sequence identity threshold, performs analysis of their structural differences and clusters them according to their structural similarities for easy analysis. The PDBFlex contains tools and viewers enabling in-depth examination of structural variability including: 2D-scaling visualization of RMSD distances between structures of the same protein, graphs of average local RMSD in the aligned structures of protein chains, graphical presentation of differences in secondary structure and observed structural disorder (unresolved residues), difference distance maps between all sets of coordinates and 3D views of individual structures and simulated transitions between different conformations, the latter displayed using JSMol visualization software. PMID- 26615194 TI - GWASdb v2: an update database for human genetic variants identified by genome wide association studies. AB - Genome-wide association studies (GWASs), now as a routine approach to study single-nucleotide polymorphism (SNP)-trait association, have uncovered over ten thousand significant trait/disease associated SNPs (TASs). Here, we updated GWASdb (GWASdb v2, http://jjwanglab.org/gwasdb) which provides comprehensive data curation and knowledge integration for GWAS TASs. These updates include: (i) Up to August 2015, we collected 2479 unique publications from PubMed and other resources; (ii) We further curated moderate SNP-trait associations (P-value < 1.0 * 10(-3)) from each original publication, and generated a total of 252,530 unique TASs in all GWASdb v2 collected studies; (iii) We manually mapped 1610 GWAS traits to 501 Human Phenotype Ontology (HPO) terms, 435 Disease Ontology (DO) terms and 228 Disease Ontology Lite (DOLite) terms. For each ontology term, we also predicted the putative causal genes; (iv) We curated the detailed sub populations and related sample size for each study; (v) Importantly, we performed extensive function annotation for each TAS by incorporating gene-based information, ENCODE ChIP-seq assays, eQTL, population haplotype, functional prediction across multiple biological domains, evolutionary signals and disease related annotation; (vi) Additionally, we compiled a SNP-drug response association dataset for 650 pharmacogenetic studies involving 257 drugs in this update; (vii) Last, we improved the user interface of website. PMID- 26615195 TI - Where does transcription start? 5'-RACE adapted to next-generation sequencing. AB - The variability and complexity of the transcription initiation process was examined by adapting RNA ligase-mediated rapid amplification of 5' cDNA ends (5' RACE) to Next-Generation Sequencing (NGS). We oligo-labelled 5'-m(7)G-capped mRNA from two genes, the simple mono-exonic Beta-2-Adrenoceptor (ADRB2R)and the complex multi-exonic Glucocorticoid Receptor (GR, NR3C1), and detected a variability in TSS location that has received little attention up to now. Transcription was not initiated at a fixed TSS, but from loci of 4 to 10 adjacent nucleotides. Individual TSSs had frequencies from <0.001% to 38.5% of the total gene-specific 5' m(7)G-capped transcripts. ADRB2R used a single locus consisting of 4 adjacent TSSs. Unstimulated, the GR used a total of 358 TSSs distributed throughout 38 loci, that were principally in the 5' UTRs and were spliced using established donor and acceptor sites. Complete demethylation of the epigenetically sensitive GR promoter with 5-azacytidine induced one new locus and 127 TSSs, 12 of which were unique. We induced GR transcription with dexamethasone and Interferon-gamma, adding one new locus and 185 additional TSSs distributed throughout the promoter region. In-vitro the TSS microvariability regulated mRNA translation efficiency and the relative abundance of the different GRN-terminal protein isoform levels. PMID- 26615196 TI - Nucleolar responses to DNA double-strand breaks. AB - Maintenance of cellular homeostasis is key to prevent transformation and disease. The cellular response to DNA double-strand breaks, primarily orchestrated by the ATM/ATR kinases is one of many mechanisms that serve to uphold genome stability and homeostasis. Upon detection of double-strand breaks (DSBs), several signaling cascades are activated to halt cell cycle progression and initiate repair. Furthermore, the DNA damage response (DDR) controls cellular processes such as transcription, splicing and metabolism. Recent studies have uncovered aspects of how the DDR operates within nucleoli. It appears that the DDR controls transcription in the nucleoli, not only when DNA breaks occur in the rDNA repeats, but also when a nuclear DDR is activated. In addition, we have gained first insights into how repair of DSBs is organized in the nucleolus. Collectively, these recent studies provide a more comprehensive picture of how the DDR regulates basic cellular functions to maintain cellular homeostasis. In this review we will summarize recent findings and discuss their implications for our understanding of how the DDR regulates transcription and repair in the nucleolus. PMID- 26615197 TI - StreptomeDB 2.0--an extended resource of natural products produced by streptomycetes. AB - Over the last decades, the genus Streptomyces has stirred huge interest in the scientific community as a source of bioactive compounds. The majority of all known antibiotics is isolated from these bacterial strains, as well as a variety of other drugs such as antitumor agents, immunosuppressants and antifungals. To the best of our knowledge, StreptomeDB was the first database focusing on compounds produced by streptomycetes. The new version presented herein represents a major step forward: its content has been increased to over 4000 compounds and more than 2500 host organisms. In addition, we have extended the background information and included hundreds of new manually curated references to literature. The latest update features a unique scaffold-based navigation system, which enables the exploration of the chemical diversity of StreptomeDB on a structural basis. We have included a phylogenetic tree, based on 16S rRNA sequences, which comprises more than two-thirds of the included host organisms. It enables visualizing the frequency, appearance, and persistence of compounds and scaffolds in an evolutionary context. Additionally, we have included predicted MS- and NMR-spectra of thousands of compounds for assignment of experimental data. The database is freely accessible via http://www.pharmaceutical-bioinformatics.org/streptomedb. PMID- 26615198 TI - Analysis of long-range interactions in primary human cells identifies cooperative CFTR regulatory elements. AB - A mechanism by which control DNA elements regulate transcription over large linear genomic distances is by achieving close physical proximity with genes, and looping of the intervening chromatin paths. Alterations of such regulatory 'chromatin looping' systems are likely to play a critical role in human genetic disease at large. Here, we studied the spatial organization of a ~790 kb locus encompassing the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Dysregulation of CFTR is responsible for cystic fibrosis, which is the most common lethal genetic disorder in Caucasian populations. CFTR is a relatively large gene of 189 kb with a rather complex tissue-specific and temporal expression profile. We used chromatin conformation at the CFTR locus to identify new DNA sequences that regulate its transcription. By comparing 5C chromatin interaction maps of the CFTR locus in expressing and non-expressing human primary cells, we identified several new contact points between the CFTR promoter and its surroundings, in addition to regions featuring previously described regulatory elements. We demonstrate that two of these novel interacting regions cooperatively increase CFTR expression, and suggest that the new enhancer elements located on either side of the gene are brought together through chromatin looping via CTCF. PMID- 26615199 TI - ELM 2016--data update and new functionality of the eukaryotic linear motif resource. AB - The Eukaryotic Linear Motif (ELM) resource (http://elm.eu.org) is a manually curated database of short linear motifs (SLiMs). In this update, we present the latest additions to this resource, along with more improvements to the web interface. ELM 2016 contains more than 240 different motif classes with over 2700 experimentally validated instances, manually curated from more than 2400 scientific publications. In addition, more data have been made available as individually searchable pages and are downloadable in various formats. PMID- 26615188 TI - The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases. AB - The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article. PMID- 26615200 TI - EK3D: an E. coli K antigen 3-dimensional structure database. AB - A very high rate of multidrug resistance (MDR) seen among Gram-negative bacteria such as Escherichia, Klebsiella, Salmonella, Shigella, etc. is a major threat to public health and safety. One of the major virulent determinants of Gram-negative bacteria is capsular polysaccharide or K antigen located on the bacterial outer membrane surface, which is a potential drug & vaccine target. It plays a key role in host-pathogen interactions as well as host immune evasion and thus, mandates detailed structural information. Nonetheless, acquiring structural information of K antigens is not straightforward due to their innate enormous conformational flexibility. Here, we have developed a manually curated database of K antigens corresponding to various E. coli serotypes, which differ from each other in their monosaccharide composition, linkage between the monosaccharides and their stereoisomeric forms. Subsequently, we have modeled their 3D structures and developed an organized repository, namely EK3D that can be accessed through www.iith.ac.in/EK3D/. Such a database would facilitate the development of antibacterial drugs to combat E. coli infections as it has evolved resistance against 2 major drugs namely, third-generation cephalosporins and fluoroquinolones. EK3D also enables the generation of polymeric K antigens of varying lengths and thus, provides comprehensive information about E. coli K antigens. PMID- 26615201 TI - The long noncoding RNA Gm15055 represses Hoxa gene expression by recruiting PRC2 to the gene cluster. AB - The Hox genes encode transcription factors that determine embryonic pattern formation. In embryonic stem cells, the Hox genes are silenced by PRC2. Recent studies have reported a role for long noncoding RNAs in PRC2 recruitment in vertebrates. However, little is known about how PRC2 is recruited to the Hox genes in ESCs. Here, we used stable knockdown and knockout strategies to characterize the function of the long noncoding RNAGm15055 in the regulation of Hoxa genes in mouse ESCs. We found that Gm15055 is highly expressed in mESCs and its expression is maintained by OCT4.Gm15055 represses Hoxa gene expression by recruiting PRC2 to the cluster and maintaining the H3K27me3 modification on Hoxa promoters. A chromosome conformation capture assay revealed the close physical association of the Gm15055 locus to multiple sites at the Hoxa gene cluster in mESCs, which may facilitate the in cis targeting of Gm15055RNA to the Hoxa genes. Furthermore, an OCT4-responsive positive cis-regulatory element is found in the Gm15055 gene locus, which potentially regulates both Gm15055 itself and the Hoxa gene activation. This study suggests how PRC2 is recruited to the Hoxa locus in mESCs, and implies an elaborate mechanism for Hoxa gene regulation in mESCs. PMID- 26615203 TI - Direct Estimate of the Spontaneous Mutation Rate Uncovers the Effects of Drift and Recombination in the Chlamydomonas reinhardtii Plastid Genome. AB - Plastids perform crucial cellular functions, including photosynthesis, across a wide variety of eukaryotes. Since endosymbiosis, plastids have maintained independent genomes that now display a wide diversity of gene content, genome structure, gene regulation mechanisms, and transmission modes. The evolution of plastid genomes depends on an input of de novo mutation, but our knowledge of mutation in the plastid is limited to indirect inference from patterns of DNA divergence between species. Here, we use a mutation accumulation experiment, where selection acting on mutations is rendered ineffective, combined with whole plastid genome sequencing to directly characterize de novo mutation in Chlamydomonas reinhardtii. We show that the mutation rates of the plastid and nuclear genomes are similar, but that the base spectra of mutations differ significantly. We integrate our measure of the mutation rate with a population genomic data set of 20 individuals, and show that the plastid genome is subject to substantially stronger genetic drift than the nuclear genome. We also show that high levels of linkage disequilibrium in the plastid genome are not due to restricted recombination, but are instead a consequence of increased genetic drift. One likely explanation for increased drift in the plastid genome is that there are stronger effects of genetic hitchhiking. The presence of recombination in the plastid is consistent with laboratory studies in C. reinhardtii and demonstrates that although the plastid genome is thought to be uniparentally inherited, it recombines in nature at a rate similar to the nuclear genome. PMID- 26615202 TI - Characteristics and Patterns of Black & Mild Use Among African American Smokers. AB - INTRODUCTION: Increased consumption of little cigars and cigarillos (LCCs) among late adolescent and young adult African American smokers is an emerging public health concern. Despite a growing body of epidemiological evidence, there is scant research on systematic variations in LCC use among young adult African Americans. This study aimed to disaggregate African American Black & Mild (B&M) smokers and to identify subgroups of cigarillo smokers' behaviors and associated characteristics. METHODS: Using telephone screening data for a NIH-funded clinical laboratory study of toxicant exposure associated with B&M use, latent class analysis (LCA) was used to classify 331 African American B&M smokers' based on daily use, average daily consumption, preference for flavors, preference for product design tips, and product modification behaviors. RESULTS: Results showed five classes, three of which (Daily-Hypers, Daily-Flavored, and Heavy-Daily Hypers) reflected daily use and average daily consumption rate ranging between 2.7 and 8.9 B&M cigarillos per day. Non-Daily-Hypers and Non-Daily-Flavored classes represented non-daily use patterns and averaged less than 1.0 B&M cigarillo per day. Both sets of classes defined by daily users and non-daily users included smokers who preferred flavored tobacco and who practiced product modification techniques involving hyping and blunting. CONCLUSIONS: Latent class analysis is a useful method to detect subtle differences in B&M product preferences and smoking behaviors among African Americans. Study findings highlight the importance of developing tailored interventions that consider within group differences in order to reduce the prevalence of cigarillo smoking among those with the greatest burden. IMPLICATIONS: The current study is the first to identify unique subgroups of African American B&M smokers based on cigarillo use behaviors and associated characteristics. Latent class analyses may prove useful for understanding other subgroups of tobacco users. Current findings concerning patterns of LCC use illustrate how future tobacco cessation and prevention interventions may be tailored for African American smokers. PMID- 26615212 TI - Admix'em: a flexible framework for forward-time simulations of hybrid populations with selection and mate choice. AB - We introduce a new forward-time simulator, Admix'em, that allows for rapid and realistic simulations of admixed populations with selection. Complex selection can be achieved through user-defined fitness and mating-preference probability functions. Users can specify realistic genomic landscapes and model neutral SNPs in addition to sites under selection. Admix'em is designed to simulate selection in admixed populations but can also be used as a general population simulator. Usage and examples are in the supplement. AVAILABILITY AND IMPLEMENTATION: C ++ and OpenMP, supports 64-bit Linux/Unix-like platforms. https://github.com/melop/admixem CONTACT: rcui@age.mpg.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26615204 TI - Comparative Genomics of Candidate Phylum TM6 Suggests That Parasitism Is Widespread and Ancestral in This Lineage. AB - Candidate phylum TM6 is a major bacterial lineage recognized through culture independent rRNA surveys to be low abundance members in a wide range of habitats; however, they are poorly characterized due to a lack of pure culture representatives. Two recent genomic studies of TM6 bacteria revealed small genomes and limited gene repertoire, consistent with known or inferred dependence on eukaryotic hosts for their metabolic needs. Here, we obtained additional near complete genomes of TM6 populations from agricultural soil and upflow anaerobic sludge blanket reactor metagenomes which, together with the two publicly available TM6 genomes, represent seven distinct family level lineages in the TM6 phylum. Genome-based phylogenetic analysis confirms that TM6 is an independent phylum level lineage in the bacterial domain, possibly affiliated with the Patescibacteria superphylum. All seven genomes are small (1.0-1.5 Mb) and lack complete biosynthetic pathways for various essential cellular building blocks including amino acids, lipids, and nucleotides. These and other features identified in the TM6 genomes such as a degenerated cell envelope, ATP/ADP translocases for parasitizing host ATP pools, and protein motifs to facilitate eukaryotic host interactions indicate that parasitism is widespread in this phylum. Phylogenetic analysis of ATP/ADP translocase genes suggests that the ancestral TM6 lineage was also parasitic. We propose the name Dependentiae (phyl. nov.) to reflect dependence of TM6 bacteria on host organisms. PMID- 26615213 TI - Comment on: 'ERGC: an efficient referential genome compression algorithm'. AB - MOTIVATION: Data compression is crucial in effective handling of genomic data. Among several recently published algorithms, ERGC seems to be surprisingly good, easily beating all of the competitors. RESULTS: We evaluated ERGC and the previously proposed algorithms GDC and iDoComp, which are the ones used in the original paper for comparison, on a wide data set including 12 assemblies of human genome (instead of only four of them in the original paper). ERGC wins only when one of the genomes (referential or target) contains mixed-cased letters (which is the case for only the two Korean genomes). In all other cases ERGC is on average an order of magnitude worse than GDC and iDoComp. CONTACT: sebastian.deorowicz@polsl.pl, iochoa@stanford.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26615214 TI - Accurate continuous geographic assignment from low- to high-density SNP data. AB - MOTIVATION: Large-scale genotype datasets can help track the dispersal patterns of epidemiological outbreaks and predict the geographic origins of individuals. Such genetically-based geographic assignments also show a range of possible applications in forensics for profiling both victims and criminals, and in wildlife management, where poaching hotspot areas can be located. They, however, require fast and accurate statistical methods to handle the growing amount of genetic information made available from genotype arrays and next-generation sequencing technologies. RESULTS: We introduce a novel statistical method for geopositioning individuals of unknown origin from genotypes. Our method is based on a geostatistical model trained with a dataset of georeferenced genotypes. Statistical inference under this model can be implemented within the theoretical framework of Integrated Nested Laplace Approximation, which represents one of the major recent breakthroughs in statistics, as it does not require Monte Carlo simulations. We compare the performance of our method and an alternative method for geospatial inference, SPA in a simulation framework. We highlight the accuracy and limits of continuous spatial assignment methods at various scales by analyzing genotype datasets from a diversity of species, including Florida Scrub jay birds Aphelocoma coerulescens, Arabidopsis thaliana and humans, representing 41-197,146 SNPs. Our method appears to be best suited for the analysis of medium sized datasets (a few tens of thousands of loci), such as reduced-representation sequencing data that become increasingly available in ecology. AVAILABILITY AND IMPLEMENTATION: http://www2.imm.dtu.dk/~gigu/Spasiba/ CONTACT: gilles.b.guillot@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26615216 TI - Genome-Wide Analysis of Evolutionary Markers of Human Influenza A(H1N1)pdm09 and A(H3N2) Viruses May Guide Selection of Vaccine Strain Candidates. AB - Here we analyzed whole-genome sequences of 3,969 influenza A(H1N1)pdm09 and 4,774 A(H3N2) strains that circulated during 2009-2015 in the world. The analysis revealed changes at 481 and 533 amino acid sites in proteins of influenza A(H1N1)pdm09 and A(H3N2) strains, respectively. Many of these changes were introduced as a result of random drift. However, there were 61 and 68 changes that were present in relatively large number of A(H1N1)pdm09 and A(H3N2) strains, respectively, that circulated during relatively long time. We named these amino acid substitutions evolutionary markers, as they seemed to contain valuable information regarding the viral evolution. Interestingly, influenza A(H1N1)pdm09 and A(H3N2) viruses acquired non-overlapping sets of evolutionary markers. We next analyzed these characteristic markers in vaccine strains recommended by the World Health Organization for the past five years. Our analysis revealed that vaccine strains carried only few evolutionary markers at antigenic sites of viral hemagglutinin (HA) and neuraminidase (NA). The absence of these markers at antigenic sites could affect the recognition of HA and NA by human antibodies generated in response to vaccinations. This could, in part, explain moderate efficacy of influenza vaccines during 2009-2014. Finally, we identified influenza A(H1N1)pdm09 and A(H3N2) strains, which contain all the evolutionary markers of influenza A strains circulated in 2015, and which could be used as vaccine candidates for the 2015/2016 season. Thus, genome-wide analysis of evolutionary markers of influenza A(H1N1)pdm09 and A(H3N2) viruses may guide selection of vaccine strain candidates. PMID- 26615215 TI - The Physarum polycephalum Genome Reveals Extensive Use of Prokaryotic Two Component and Metazoan-Type Tyrosine Kinase Signaling. AB - Physarum polycephalum is a well-studied microbial eukaryote with unique experimental attributes relative to other experimental model organisms. It has a sophisticated life cycle with several distinct stages including amoebal, flagellated, and plasmodial cells. It is unusual in switching between open and closed mitosis according to specific life-cycle stages. Here we present the analysis of the genome of this enigmatic and important model organism and compare it with closely related species. The genome is littered with simple and complex repeats and the coding regions are frequently interrupted by introns with a mean size of 100 bases. Complemented with extensive transcriptome data, we define approximately 31,000 gene loci, providing unexpected insights into early eukaryote evolution. We describe extensive use of histidine kinase-based two component systems and tyrosine kinase signaling, the presence of bacterial and plant type photoreceptors (phytochromes, cryptochrome, and phototropin) and of plant-type pentatricopeptide repeat proteins, as well as metabolic pathways, and a cell cycle control system typically found in more complex eukaryotes. Our analysis characterizes P. polycephalum as a prototypical eukaryote with features attributed to the last common ancestor of Amorphea, that is, the Amoebozoa and Opisthokonts. Specifically, the presence of tyrosine kinases in Acanthamoeba and Physarum as representatives of two distantly related subdivisions of Amoebozoa argues against the later emergence of tyrosine kinase signaling in the opisthokont lineage and also against the acquisition by horizontal gene transfer. PMID- 26615217 TI - Bulk Segregant Analysis Reveals the Genetic Basis of a Natural Trait Variation in Fission Yeast. AB - Although the fission yeast Schizosaccharomyces pombe is a well-established model organism, studies of natural trait variations in this species remain limited. To assess the feasibility of segregant-pool-based mapping of phenotype-causing genes in natural strains of fission yeast, we investigated the cause of a maltose utilization defect (Mal(-)) of the S. pombe strain CBS5557 (originally known as Schizosaccharomyces malidevorans). Analyzing the genome sequence of CBS5557 revealed 955 nonconservative missense substitutions, and 61 potential loss-of function variants including 47 frameshift indels, 13 early stop codons, and 1 splice site mutation. As a side benefit, our analysis confirmed 146 sequence errors in the reference genome and improved annotations of 27 genes. We applied bulk segregant analysis to map the causal locus of the Mal(-) phenotype. Through sequencing the segregant pools derived from a cross between CBS5557 and the laboratory strain, we located the locus to within a 2.23-Mb chromosome I inversion found in most S. pombe isolates including CBS5557. To map genes within the inversion region that occupies 18% of the genome, we created a laboratory strain containing the same inversion. Analyzing segregants from a cross between CBS5557 and the inversion-containing laboratory strain narrowed down the locus to a 200-kb interval and led us to identify agl1, which suffers a 5-bp deletion in CBS5557, as the causal gene. Interestingly, loss of agl1 through a 34-kb deletion underlies the Mal(-) phenotype of another S. pombe strain CGMCC2.1628. This work adapts and validates the bulk segregant analysis method for uncovering trait-gene relationship in natural fission yeast strains. PMID- 26615218 TI - Assessing the Unseen Bacterial Diversity in Microbial Communities. AB - For both historical and technical reasons, 16S ribosomal RNA has been the most common molecular marker used to analyze the contents of microbial communities. However, its slow rate of evolution hinders the resolution of closely related bacteria--individual 16S-phylotypes, particularly when clustered at 97% sequence identity, conceal vast amounts of species- and strain-level variation. Protein coding genes, which evolve more quickly, are useful for differentiating among more recently diverged lineages, but their application is complicated by difficulties in designing low-redundancy primers that amplify homologous regions from distantly related taxa. Given the now-common practice of multiplexing hundreds of samples, adopting new genes usually entails the synthesis of large sets of barcoded primers. To circumvent problems associated with use of protein coding genes to survey microbial communities, we develop an approach--termed phyloTAGs--that offers an automatic solution for primer design and can be easily adapted to target different taxonomic groups and/or different protein-coding regions. We applied this method to analyze diversity within the gorilla gut microbiome and recovered hundreds of strains that went undetected after deep sequencing of 16S rDNA amplicons. PhyloTAGs provides a powerful way to recover the fine-level diversity within microbial communities and to study stability and dynamics of bacterial populations. PMID- 26615221 TI - The MarR family transcription factor Rv1404 coordinates adaptation of Mycobacterium tuberculosis to acid stress via controlled expression of Rv1405c, a virulence-associated methyltransferase. AB - Coordinated regulation of gene expression is essential for pathogen adaptation in vivo. Understanding the control of these virulence circuits in the TB pathogen Mycobacterium tuberculosis is a key challenge if we are to increase our basic understanding of how this organism establishes infection. In this study we focused on the transcriptional regulator Rv1404 that shows similarity to the MarR family of transcriptional repressors. Rv1404 derepresses a set of genes in vivo that have been implicated in virulence and may therefore allow adaptation of M. tuberculosis to the intracellular environment. We used a combination of ChIP-qPCR and Electromobility Band Shift Assays (EMSA) to show that Rv1404 coordinates gene expression in response to stresses such as low pH in M. tuberculosis. Two genes regulated by Rv1404, rv1403c and rv1405c, encode putative SAM-dependent methyltransferases. To elucidate gene function, M. tuberculosis rv1403c and rv1405c mutants were constructed. The mutants showed attenuated growth in response to in vitro stress conditions that mimic the intracellular milieu. Our data sheds new light on the function of a novel regulon controlled by Rv1404 that coordinates adaptation of M. tuberculosis to the in vivo environment and reveals the Rv1405c and Rv1403c methyltransferases as playing a role in this adaptive process. PMID- 26615219 TI - Genome Analysis of Structure-Function Relationships in Respiratory Complex I, an Ancient Bioenergetic Enzyme. AB - Respiratory complex I (NADH:ubiquinone oxidoreductase) is a ubiquitous bioenergetic enzyme formed by over 40 subunits in eukaryotes and a minimum of 11 subunits in bacteria. Recently, crystal structures have greatly advanced our knowledge of complex I but have not clarified the details of its reaction with ubiquinone (Q). This reaction is essential for bioenergy production and takes place in a large cavity embedded within a conserved module that is homologous to the catalytic core of Ni-Fe hydrogenases. However, how a hydrogenase core has evolved into the protonmotive Q reductase module of complex I has remained unclear. This work has exploited the abundant genomic information that is currently available to deduce structure-function relationships in complex I that indicate the evolutionary steps of Q reactivity and its adaptation to natural Q substrates. The results provide answers to fundamental questions regarding various aspects of complex I reaction with Q and help re-defining the old concept that this reaction may involve two Q or inhibitor sites. The re-definition leads to a simplified classification of the plethora of complex I inhibitors while throwing a new light on the evolution of the enzyme function. PMID- 26615222 TI - Nursing staff work patterns in a residential aged care home: a time-motion study. AB - Objective Residential aged care services are challenged by an increasing number of residents and a shortage of nursing staff. Developing strategies to overcome this challenge requires an understanding of nursing staff work patterns. The aim of the present study was to investigate the work processes followed by nursing staff and how nursing time is allocated in a residential aged care home. Methods An observational time-motion study was conducted at two aged care units for 12 morning shifts. Seven nurses were observed, one per shift. Results In all, there were 91h of observation. The results showed that there was a common work process followed by all nurse participants. Medication administration, documentation and verbal communication were the most time-consuming activities and were conducted most frequently. No significant difference between the two units was found in any category of activities. The average duration of most activities was less than 1min. There was no difference in time utilisation between the endorsed enrolled nurses and the personal carers in providing nursing care. Conclusion Medication administration, documentation and verbal communication were the major tasks in morning shifts in a residential aged care home. Future research can investigate how verbal communication supports nursing care. What is known about the topic? The aging population will substantially increase the demand for residential aged care services. There is a lack of research on nurses' work patterns in residential aged care homes. What does this paper add? The present study provides a comprehensive understanding of nurses' work patterns in a residential aged care home. There is a common work process followed by nurses in providing nursing care. Medication administration, verbal communication and documentation are the most time-consuming activities and they are frequently conducted in the same period of time. Wound care, physical review and documentation on desktop computers are arranged flexibly by the nurses. What are the implications for practitioners? When developing a task reallocation strategy to improve work efficiency, effort can be put into tasks that can be arranged more flexibly. PMID- 26615220 TI - The Pangenome of the Anticarsia gemmatalis Multiple Nucleopolyhedrovirus (AgMNPV). AB - The alphabaculovirus Anticarsia gemmatalis multiple nucleopolyhedrovirus (AgMNPV) is the world's most successful viral bioinsecticide. Through the 1980s and 1990s, this virus was extensively used for biological control of populations of Anticarsia gemmatalis (Velvetbean caterpillar) in soybean crops. During this period, genetic studies identified several variable loci in the AgMNPV; however, most of them were not characterized at the sequence level. In this study we report a full genome comparison among 17 wild-type isolates of AgMNPV. We found the pangenome of this virus to contain at least 167 hypothetical genes, 151 of which are shared by all genomes. The gene bro-a that might be involved in host specificity and carrying transporter is absent in some genomes, and new hypothetical genes were observed. Among these genes there is a unique rnf12-like gene, probably implicated in ubiquitination. Events of gene fission and fusion are common, as four genes have been observed as single or split open reading frames. Gains and losses of genomic fragments (from 20 to 900 bp) are observed within tandem repeats, such as in eight direct repeats and four homologous regions. Most AgMNPV genes present low nucleotide diversity, and variable genes are mainly located in a locus known to evolve through homologous recombination. The evolution of AgMNPV is mainly driven by small indels, substitutions, gain and loss of nucleotide stretches or entire coding sequences. These variations may cause relevant phenotypic alterations, which probably affect the infectivity of AgMNPV. This work provides novel information on genomic evolution of the AgMNPV in particular and of baculoviruses in general. PMID- 26615223 TI - Clinical value of soluble urokinase-type plasminogen activator receptor in the diagnosis, prognosis, and therapeutic guidance of sepsis. AB - OBJECTIVES: The level of soluble urokinase-type plasminogen activator receptor (suPAR) is significantly increased in sepsis. We investigated whether suPAR could be a valuable biomarker in sepsis. METHODS: We measured suPAR and procalcitonin (PCT) levels, recorded the Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment scores of engaged subjects, and drew Receiver Operating Characteristics curves. RESULTS: The plasma suPAR and serum PCT levels of the sepsis group were higher than those of the systemic inflammatory response syndrome and control groups. Using suPAR to distinguish systemic inflammatory response syndrome from sepsis on day 1, the area under the curve (AUC) curve was 0.817, and when suPAR and PCT were used in combination to diagnose sepsis, the AUC was 0.927. At a cutoff point of 9.52 ng/mL, the sensitivity and specificity for diagnosis of sepsis using suPAR were 71.93% and 95.46%, respectively. At a cutoff point of 12.01 ng/mL, the sensitivity and specificity for distinguishing survival and mortality by suPAR were 87.1% and 72.5%, respectively. When suPAR and the APACHE II score were combined to distinguish survival from mortality, the AUC was 0.857. The plasma suPAR level was positively correlated with the serum PCT level (r = 0.326, P < .001), APACHE II score (r = 0.492, P < .001), and Sequential Organ Failure Assessment score (r = 0.386, P < .001). CONCLUSIONS: Use of both plasma suPAR and PCT levels enhanced the efficiency of sepsis diagnosis, and the combination of plasma suPAR and APACHE II score improved mortality prediction. PMID- 26615225 TI - Composite nanofibers for highly efficient photocatalytic degradation of organic dyes from contaminated water. AB - In this study highly efficient photocatalyst based on composite nanofibers containing polyacrylonitrile (PAN), carbon nanotubes (CNT), and surface functionalized TiO2 nanoparticles was developed. The composite nanofibers were fabricated using electrospinning technique followed by chemical crosslinking. The surface modification and morphology changes of the fabricated composite nanofibers were examined through SEM, TEM, and FTIR analysis. The photocatalytic performance of the composite nanofibers for the degradation of model molecules, methylene blue and indigo carmine, under UV irradiation in aqueous solutions was investigated. The results demonstrated that high photodegradation efficiency was obtained in a short time and at low power intensity compared to other reported studies. The effective factors on the degradation of the dyes, such as the amount of catalyst, solution pH and irradiation time were investigated. The experimental kinetic data were fitted using pseudo-first order model. The effect of the composite nanofibers as individual components on the degradation efficiency of MB and IC was evaluated in order to understand the overall photodegradation mechanism. The results obtained showed that all the components possess significant effect on the photodegradation activity of the composite nanofibers. The stability studies demonstrated that the photodegradation efficiency can remain constant at the level of 99% after five consecutive cycles. PMID- 26615224 TI - No evidence of association between subclinical thyroid disorders and common carotid intima medial thickness or atherosclerotic plaque. AB - BACKGROUND AND AIMS: Increased carotid artery intima-media thickness (IMT) and the presence of plaques have been shown to be predictors of cardiovascular disease. The cardiovascular risk in patients with overt thyroid diseases is related to increased risk of atherosclerosis, but there has been no clear evidence about subclinical disorders. We have assessed whether subclinical thyroid dysfunction is associated with arterial thickening and plaque. METHODS AND RESULTS: The SardiNIA study is a population-based survey on the Italian island of Sardinia. We reviewed data from 5815 subjects (aged 14-102 years), none of whom had overt hyperthyroidism or hypothyroidism or was taking thyroid medication. Serum thyrotropin (TSH), free thyroxine, together with carotid ultrasound IMT and the presence of common carotid plaques were analysed in all subjects. Possible association of IMT and carotid plaques with thyroid parameters was evaluated by univariate and multivariate analyses. IMT was significantly associated with age, sex, smoking, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol, pulse pressure (PP), history of arterial hypertension, diabetes, and previous cardiovascular events (p = 0.001 or lower, R(2) = 0.47). Carotid plaques were predicted by age, sex, LDL, PP, history of diabetes, previous cardiovascular events, and the use of statins (p = 0.029 or lower). Thyroid hormone was not predictive of carotid atherosclerosis when adjusted for confounders. CONCLUSION: Thyroid hormone is not associated with increased IMT or with the presence of carotid artery plaque. Our data do not support the idea that treating subclinical disorders might help to prevent arterial remodelling or carotid atherosclerosis. PMID- 26615226 TI - Greenhouse gas emissions and stocks of soil carbon and nitrogen from a 20-year fertilised wheat-maize intercropping system: A model approach. AB - Accurate modelling of agricultural management impacts on greenhouse gas emissions and the cycling of carbon and nitrogen is complicated due to interactions between various processes and the disturbance caused by field management. In this study, a process-based model, the Soil-Plant-Atmosphere Continuum System (SPACSYS), was used to simulate the effects of different fertilisation regimes on crop yields, the dynamics of soil organic carbon (SOC) and total nitrogen (SN) stocks from 1990 to 2010, and soil CO2 (2007-2010) and N2O (2007-2008) emissions based on a long-term fertilisation experiment with a winter-wheat (Triticum Aestivum L.) and summer-maize (Zea mays L.) intercropping system in Eutric Cambisol (FAO) soil in southern China. Three fertilisation treatments were 1) unfertilised (Control), 2) chemical nitrogen, phosphorus and potassium (NPK), and 3) NPK plus pig manure (NPKM). Statistical analyses indicated that the SPACSYS model can reasonably simulate the yields of wheat and maize, the evolution of SOC and SN stocks and soil CO2 and N2O emissions. The simulations showed that the NPKM treatment had the highest values of crop yields, SOC and SN stocks, and soil CO2 and N2O emissions were the lowest from the Control treatment. Furthermore, the simulated results showed that manure amendment along with chemical fertiliser applications led to both C (1017 +/- 470 kg C ha(-1) yr(-1)) and N gains (91.7 +/- 15.1 kg N ha(-1) yr(-1)) in the plant-soil system, while the Control treatment caused a slight loss in C and N. In conclusion, the SPACSYS model can accurately simulate the processes of C and N as affected by various fertilisation treatments in the red soil. Furthermore, application of chemical fertilisers plus manure could be a suitable management for ensuring crop yield and sustaining soil fertility in the red soil region, but the ratio of chemical fertilisers to manure should be optimized to reduce C and N losses to the environment. PMID- 26615228 TI - Hydration and health. PMID- 26615229 TI - The importance of hydration and education: challenges and opportunities. PMID- 26615227 TI - Use of ancient copper slags in Portland cement and alkali activated cement matrices. AB - Some Chilean copper slag dumps from the nineteenth century still remain, without a proposed use that encourages recycling and reduces environmental impact. In this paper, the copper slag abandoned in landfills is proposed as a new building material. The slags studied were taken from Playa Negra and Puquios dumps, both located in the region of Atacama in northern Chile. Pozzolanic activity in lime and Portland cement systems, as well as the alkali activation in pastes with copper slag cured at different temperatures, was studied. The reactivity of the slag was measured using thermogravimetric analysis (TGA), scanning electron microscopy (SEM), X-ray diffraction (XRD), electrical conductivity and pH in aqueous suspension and Fourier Transform Infrared Spectroscopy (FTIR). Furthermore, copper slag-Portland cement mortars with the substitution of 25% (by weight) of cement by copper slag and alkali-activated slag mortars cured at 20 and 65 degrees C were made, to determine the compressive strength. The results indicate that the ancient copper slags studied have interesting binding properties for the construction sector. PMID- 26615230 TI - Opening Remarks: The burden of disease attributable to hydration in Europe. PMID- 26615231 TI - Hydration and the human brain circulation and metabolism. PMID- 26615232 TI - Mild hypohydration increases the frequency of driver errors during a prolonged, monotonous driving task. PMID- 26615233 TI - Berevage intake methods and hydration status: validation aspects and limitations. PMID- 26615234 TI - Development of a hydration index: a randomized trial to assess the potential of different beverages to affect hydration status. PMID- 26615235 TI - Water intake and hydration indices in healthy adults; the European Hydration Research Study (EHRS). PMID- 26615236 TI - Adverse functional outcomes associated with body water deficits. PMID- 26615237 TI - Hydration and skeletal muscle. PMID- 26615238 TI - "Hydration. Fundamentals at different stages of life" handbook. PMID- 26615239 TI - Hydration guidelines for fractionation of liquid intake in hot environments: report of Latin America. PMID- 26615240 TI - Evidence behind daily water and beverage intake distribution recommendations. PMID- 26615241 TI - Basic concepts of Mediterranean lifestyle and their impacts in the genomic aspects. PMID- 26615242 TI - Water is life: an evolutionary perspective of hydration-related gene-environment interactions. PMID- 26615243 TI - Water intake and urine osmolarity in Spanish school children aged 7-11 years. PMID- 26615245 TI - Dehydration in the hospitalized elderly. PMID- 26615244 TI - Impact of physical activity and sedentary lifestyle on hydration status and liquid intake in Spanish older adults. PMID- 26615246 TI - Water consumption and hydration status affects fine motor skills in schoolchildren. PMID- 26615247 TI - Consumption of different types of fluids in Hungarian adults. PMID- 26615248 TI - Hydration needs during breast-feeding. PMID- 26615249 TI - Hydration for prevention of premature births. PMID- 26615250 TI - Conditions of fluid intake in the elderly. PMID- 26615251 TI - Dehydration, cognitive and skill performance in sport. Systematic review. PMID- 26615252 TI - Relation of liquid-intake habits and nutritional status, dependency and quality of life in malnourished patients. PMID- 26615253 TI - Influence of adequate hydration in the management of patients with Metabolic Syndrome. PMID- 26615254 TI - Is hydration enough in a healthy group of the elderly in a Valladolid neighbourhood? PMID- 26615255 TI - Development solution for water stress situations in military activities. PMID- 26615256 TI - Total water intake in 7-11 year-old Spanish children according to their physical activity level. PMID- 26615257 TI - Health education: an analysis of wine and carbonated beverage consumption in college students in Extremadura. PMID- 26615258 TI - Hydration and cognitive performance in elderly people. PMID- 26615259 TI - Liquid intake habits during competition in paddle players. PMID- 26615260 TI - Evolution of drinks availability in households from Spain in the last 50 years. PMID- 26615261 TI - Consumption trends of enriched/fortified beverages in Spain by the food consumption survey. PMID- 26615262 TI - Educative actions to promote hydration and rational use of herbal teas in pregnancy and lactation. PMID- 26615263 TI - Dose response effects of water on cognition in children and adults. PMID- 26615264 TI - Survey among elderly people related to their fluid intake. PMID- 26615265 TI - The importance of smoothies in hydration. PMID- 26615266 TI - Dehydration in the elderly treated in the emergency room of the regional hospital. PMID- 26615267 TI - Water and beverage consumption among a Mediterranean sample. PMID- 26615268 TI - Prevention of constipation during pregnancy with the hydration. PMID- 26615269 TI - Hydration campaigns: five years of experience. PMID- 26615270 TI - Liquid intake in elderly people. PMID- 26615271 TI - Hydration status using free water reserve in Portuguese adolescents. PMID- 26615272 TI - Beverages intake and hydration status in adolescents. PMID- 26615273 TI - Hydration status and water sources in free-living physically active elderly. PMID- 26615274 TI - Fluid needs of aging cerebral palsy patients. PMID- 26615275 TI - Isotonic sports drinks vs water in the hydration recovery after an immediate postpartum period. PMID- 26615276 TI - Spanish "Bilbilis" Foundation for research and innovation in medical hydrology and hydrotherapy. PMID- 26615277 TI - Beneficial effects of hydrotherapy on immunity and longevity in a mouse model of social isolation. PMID- 26615278 TI - Parents body mass index as modulator of fluid intake habits among their children. PMID- 26615279 TI - Fluid intake habits among school children in Madrid depend on the educational level of their parents. PMID- 26615280 TI - Questionnaire design to evaluate water balance. PMID- 26615281 TI - Relationship between hydration status and psychological tests in Spanish schoolchildren aged 7-11 years. PMID- 26615282 TI - Design of a beverage visual guide to facilitate data collection in research studies. PMID- 26615283 TI - Does seasonality affect fluid intake? PMID- 26615284 TI - Questionnaire design to facilitate water and beverage intake data collection in research studies. PMID- 26615285 TI - Evaluation of the Corporal Composition of Professional Acrobatic Parachutists with Bioelectrical Impedance and Anthropometry. PMID- 26615286 TI - Importance of dairy consumption on the total water intake in young Mexicans. PMID- 26615287 TI - Promoting the right nutrition and hydration in schools by community nursing. PMID- 26615288 TI - Water consumption, body composition and cardiometabolic parameters in children. PMID- 26615289 TI - Influence of oral intake of water in improving memory and visual acuity. PMID- 26615291 TI - Study on risk creatine and dehydration in athletes training in a gym. PMID- 26615290 TI - Hydration habits in Spanish elite athletes. PMID- 26615292 TI - Efficiency of the hydration and nutrition institutionalized elderly with pressure ulcers. PMID- 26615293 TI - Water compartmentalization and hydration state of patients attending to a cardiac rehabilitation program. PMID- 26615294 TI - Hydration status and associated dietary factors in children. PMID- 26615295 TI - Beverage consumption habits amongst the Spanish population: association with total water and energy intake. Findings of the ANIBES study. PMID- 26615296 TI - Drinking habits in a sample of university students. Relationship between the adherence to the Mediterranean Diet and BMI. PMID- 26615297 TI - Hydration patterns among a Latin American sample. PMID- 26615298 TI - Whole body water after 16 weeks of high intensity interval training in Metabolic Syndrome patients. PMID- 26615299 TI - Assessment of the body water content in the Spanish Women's National Waterpolo Team. PMID- 26615300 TI - Hydration included in graphical representations of food based dietary guidelines worldwide: an overview. PMID- 26615301 TI - Relationship between the hydric and nutritional knowledge of water and health in students of a Spanish penal institution. PMID- 26615302 TI - Body water percentage and its relationship with fat percentage, BMI, physical activity and fitness level. PMID- 26615303 TI - Water intake and body water percentage, role of physical activity in university women students. PMID- 26615304 TI - Influence of alcohol consumption on hydration status in healthy adults. PMID- 26615305 TI - Beverages consumption and energy contribution from the ANIBES study. PMID- 26615306 TI - Weights, measures and portion sizes for foods and beverages: findings from the ANIBES-study in Spain. PMID- 26615307 TI - Hydration status and water sources in 9-10 year soccer players. PMID- 26615309 TI - Importance of water consumption in a group of young women with overweight and obesity. PMID- 26615308 TI - Hydration level and mood status in adolescents. The Up & Down Study. PMID- 26615310 TI - Hydration habits of a group of university students. PMID- 26615312 TI - Short-term oral liquid ingestion decreases human milk osmolality. PMID- 26615311 TI - Calorie reduction in soft drinks during the last 5 years on the Spanish market. PMID- 26615313 TI - Taste workshops for children: importance of being hydrated. PMID- 26615314 TI - Correlation but no association of sugar sweetened beverage consumption with systolic and diastolic blood pressure among Mexican adolescents. PMID- 26615315 TI - Water intake in Mexican adolescents. Differences regarding the presence of cardiovascular risk factors. PMID- 26615316 TI - Fruits and vegetables as important contributors to an adequate hydration status. PMID- 26615317 TI - How can a 0.7% loss of body mass influence cognitive functioning? A mechanistic investigation. PMID- 26615318 TI - Lifestyles associated with the adhesion of the Mediterranean Diet in the elderly. PMID- 26615319 TI - Drunkorexia habits of University students. PMID- 26615320 TI - Gaining awareness of the hydration role in health. PMID- 26615321 TI - Dietary Guidelines in the world. PMID- 26615322 TI - Hydration status in patients diagnosed of chronic idiopathic constipation by rome III criteria. PMID- 26615323 TI - Hydration status of cancer patients with palliative care: hydrated or dehydrated? PMID- 26615324 TI - Intracellular water is related to half-marathon race time. PMID- 26615325 TI - Lawrence Gostin: legal activist in the cause of global health. PMID- 26615326 TI - Will Ebola change the game? Ten essential reforms before the next pandemic. The report of the Harvard-LSHTM Independent Panel on the Global Response to Ebola. PMID- 26615327 TI - The International Health Regulations 10 years on: the governing framework for global health security. PMID- 26615329 TI - Does temperament influence language development? Evidence from preterm and full term children. AB - The aims of this study are: (1) to describe language and temperament characteristics of one group of low risk preterm (PR) children and a group of full-term (FT) children and (2) to identify those factors which can predict language outcomes at 30 months of age, with special attention on temperament. There is evidence of differences between very or extremely PR and FT children in relation to characteristics of temperament and language development. However, not many studies have been carried out with healthy PR children. The participants were 142 low risk PR children (mean gestational age (GA): 32.60 weeks) and 49 FT children (mean GA 39.84 weeks). The temperament of the children was assessed at 10 months of age through the Infant Behavior Questionnaire-Revised (IBQ-R). At 22 months of age the cognitive development of the children was assessed through the Spanish adaptation of the Batelle Developmental Inventory (BDI). In order to assess the children's language development the Galician adaptation of the MacArthur-Bates CDI was applied at 30 months of age. In addition, socio demographic information about the children and their families was gathered at birth. The results indicate that there were no significant differences in the language measures of interest (word production, MLU3, and sentence complexity) between groups. The only differences found between the PR and the FT children in the IBQ-R were restricted to the smiling and laughter and the fear subscales. Hierarchical regression analyses performed indicate that GA did not have any predictive effect on language measures taken at 30 months. Cognitive scores were an important predictor of language measures, although certain temperament subscales contributed in a significant way to the variance of language measures, particularly low intensity pleasure, approach, high intensity pleasure, sadness, and vocal reactivity. Therefore, extroverted (positive affectivity) temperament seems to be beneficial for language development. PMID- 26615330 TI - Factor mixture modeling of the Penn State Worry Questionnaire: Evidence for distinct classes of worry. AB - Worry, the anticipation of future threat, is a common feature of anxiety and mood psychopathology. Considerable research has examined the latent structure of worry to determine whether this construct reflects a dimensional or taxonic structure. Recent taxometric investigations have provided support for a unidimensional structure of worry; however, the results of these studies are limited in that taxometric approaches are unable to assess for the presence of more than two classes of a given construct. Given the complex nature of worry, it is possible that worry may actually reflect a latent structure comprised of multiple classes that cannot be assessed through taxometric approaches. Thus, it is important to utilize newer statistical techniques, such as factor-mixture modeling (FMM), which allow for a more nuanced assessment of the latent structure of a given psychological construct. The aim of the current study was to examine the latent structure of worry using FMM. It was predicted that worry would reflect a three class structure comprised of (1) a class of low, normative levels of worry, (2) a class of moderate, subclinical worry, and (3) a class of high, pervasive worry. The latent class structure of worry was assessed using FMM in a sample of 1337 participants recruited from the community through a research clinic. Results revealed a three-class structure of the PSWQ comprising low, moderate-high, and high classes of worry. We also provided convergent and discriminant validity of the worry classes by demonstrating that the high worry class was most associated with GAD and that the low worry class was the least associated with GAD. The clinical utility of the worry classes, including the creation of empirically based cut-scores, and the implications for future research are discussed. PMID- 26615328 TI - Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. AB - BACKGROUND: Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population. METHODS: We did a global, phase 3, randomised, open-label trial at 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1:1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m(2) every 3 weeks, equivalent to 100 mg/m(2) of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m(2), equivalent to 70 mg/m(2) of irinotecan base) with fluorouracil and folinic acid every 2 weeks was added later (1:1:1), in a protocol amendment. Randomisation was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects. The primary endpoint was overall survival, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received study drug. This trial is registered at ClinicalTrials.gov, number NCT01494506. FINDINGS: Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus fluorouracil and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or fluorouracil and folinic acid (n=149). After 313 events, median overall survival in patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid was 6.1 months (95% CI 4.8-8.9) vs 4.2 months (3.3-5.3) with fluorouracil and folinic acid (hazard ratio 0.67, 95% CI 0.49-0.92; p=0.012). Median overall survival did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated fluorouracil and folinic acid (4.9 months [4.2-5.6] vs 4.2 months [3.6-4.9]; 0.99, 0.77-1.28; p=0.94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]). INTERPRETATION: Nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine based therapy. This agent represents a new treatment option for this population. FUNDING: Merrimack Pharmaceuticals. PMID- 26615331 TI - Conceptual and procedural distinctions between fractions and decimals: A cross national comparison. AB - Previous work has shown that adults in the United States process fractions and decimals in distinctly different ways, both in tasks requiring magnitude judgments and in tasks requiring mathematical reasoning. In particular, fractions and decimals are preferentially used to model discrete and continuous entities, respectively. The current study tested whether similar alignments between the format of rational numbers and quantitative ontology hold for Korean college students, who differ from American students in educational background, overall mathematical proficiency, language, and measurement conventions. A textbook analysis and the results of five experiments revealed that the alignments found in the United States were replicated in South Korea. The present study provides strong evidence for the existence of a natural alignment between entity type and the format of rational numbers. This alignment, and other processing differences between fractions and decimals, cannot be attributed to the specifics of education, language, and measurement units, which differ greatly between the United States and South Korea. PMID- 26615332 TI - Regulation of competence-mediated horizontal gene transfer in the natural habitat of Vibrio cholerae. AB - The human pathogen Vibrio cholerae is an autochthonous inhabitant of aquatic environments where it often interacts with zooplankton and their chitinous molts. Chitin induces natural competence for transformation in V. cholerae, a key mode of horizontal gene transfer (HGT). Recent comparative genomic analyses were indicative of extensive HGT in this species. However, we can still expand our understanding of the complex regulatory network that drives competence in V. cholerae. Here, we present recent advances, including the elucidation of bipartite competence regulation mediated by QstR, the inclusion of the type VI secretion system in the competence regulon of pandemic O1 El Tor strains, and the identification of TfoS as a transcriptional regulator that links chitin to competence induction in V. cholerae. PMID- 26615333 TI - Vibration and impulsivity analysis of hand held olive beaters. AB - To provide more effective evaluations of hand arm vibration syndromes caused by hand held olive beaters, this study focused on two aspects: the acceleration measured at the tool pole and the analysis of the impulsivity, using the crest factor. The signals were frequency weighted using the weighting curve Wh as described in the ISO 5349-1 standard. The same source signals were also filtered by the Wh-bl filter (ISO/TS 15694), because the weighting filter Wh (unlike the Wh-bl filter) could underestimate the effect of high frequency vibration on vibration-induced finger disorders. Ten (experienced) male operators used three beater models (battery powered) in the real olive harvesting condition. High vibration total values were obtained with values never lower than 20 m(-2). Concerning the crest factor, the values ranged from 5 to more than 22. This work demonstrated that the hand held olive beaters produced high impulsive loads comparable to the industry hand held tools. PMID- 26615334 TI - Construction of Nef-positive doxycycline-dependent HIV-1 variants using bicistronic expression elements. AB - Conditionally replicating HIV-1 variants that can be switched on and off at will are attractive tools for HIV research. We previously developed a genetically modified HIV-1 variant that replicates exclusively when doxycycline (dox) is administered. The nef gene in this HIV-rtTA variant was replaced with the gene encoding the dox-dependent rtTA transcriptional activator. Because loss of Nef expression compromises virus replication in primary cells and precludes studies on Nef function, we tested different approaches to restore Nef production in HIV rtTA. Strategies that involved translation via an EMCV or synthetic internal ribosome entry site (IRES) failed because these elements were incompatible with efficient virus replication. Fusion protein approaches with the FMDV 2A peptide and human ubiquitin were successful and resulted in genetically-stable Nef expressing HIV-rtTA strains that replicate more efficiently in primary T-cells and human immune system (HIS) mice than Nef-deficient variants, thus confirming the positive effect of Nef on in vivo virus replication. PMID- 26615335 TI - A comparison of product yields and inorganic content in process streams following thermal hydrolysis and hydrothermal processing of microalgae, manure and digestate. AB - Thermal hydrolysis and hydrothermal processing show promise for converting biomass into higher energy density fuels. Both approaches facilitate the extraction of inorganics into the aqueous product. This study compares the behaviour of microalgae, digestate, swine and chicken manure by thermal hydrolysis and hydrothermal processing at increasing process severity. Thermal hydrolysis was performed at 170 degrees C, hydrothermal carbonisation (HTC) was performed at 250 degrees C, hydrothermal liquefaction (HTL) was performed at 350 degrees C and supercritical water gasification (SCWG) was performed at 500 degrees C. The level of nitrogen, phosphorus and potassium in the product streams was measured for each feedstock. Nitrogen is present in the aqueous phase as organic-N and NH3-N. The proportion of organic-N is higher at lower temperatures. Extraction of phosphorus is linked to the presence of inorganics such as Ca, Mg and Fe in the feedstock. Microalgae and chicken manure release phosphorus more easily than other feedstocks. PMID- 26615337 TI - Arise, Awake and Act, till the Sustainable Development Goals are met! PMID- 26615336 TI - An individual-based rurality measure and its health application: A case study of Latino immigrants in North Florida, USA. AB - Rurality has been frequently noted by researchers as pathways to understand human health in rural and remote areas. Current measures of rurality are mostly oriented to places, not individuals, and have not accounted for individual mobility, thus inappropriate for studying health and well-being at an individual level. This research proposed a new concept of individual-based rurality by integrating personal activity spaces. A feasible method was developed to quantify individuals' rural experience using household travel surveys and geographic information systems (GIS). For illustration, the proposed method was applied to understand the well-being and social isolation among rural Latino immigrants, who had participated in a community-based participatory research (CBPR) study in North Florida, USA. The resulting individuals' rurality indices were paired with their scores of well-being and social isolation to identify potential associations. The correlation analysis showed that the proposed rurality can be related to the social isolation, mental and physical well-being of individuals in different gender groups, and hence could be a suitable tool to investigate rural health issues. PMID- 26615338 TI - Strengthening Health Systems for Evidence-informed Policy Making. PMID- 26615339 TI - Study of Common Illnesses Before and After Vaccination: A Risk interval Approach. AB - OBJECTIVE: To compare the proportion of children who developed a specified illness in the 7 day post-vaccination window, with the background rate of the same event in the 7 day pre-vaccination window. STUDY DESIGN: Risk interval approach (Self-controlled case-series). SETTING: Well Baby Clinic of Christian Medical College, Vellore. PARTICIPANTS: 1602 healthy infants and under-six children presenting for routine vaccination. OUTCOME MEASURES: Episode of any illness. METHODS: The interviewer enquired about any adverse event or illness experienced by the child for each day of the week preceding the administration of age-appropriate vaccines. A second interview (telephonic) was conducted by the same interviewer one week following vaccine administration to enquire about adverse event(s) experienced by the child for each day of the subsequent week using a similar protocol. RESULTS: With multiple vaccines delivered at appropriate ages, common childhood illnesses that could be reported as adverse events following immunization, except fever (RR=5.7, 95% CI=4.50-7.35), occurred at higher rates pre-vaccination. Risk Ratios of fever following whole cell (RR=9.3, 95% CI=6.43-13.52) and acellular (RR=8.5, 95% CI=3.82-18.91) vaccines were similar, with both showing a decreasing trend with increasing age. The gastrointestinal adverse event profile [diarrhea (RR=0.6, 95% CI=0.14-2.51) and vomiting (RR=1.0, 95% CI=0.14-7.10)] for rotavirus vaccine was similar pre- and post-immunization. CONCLUSIONS: Since most adverse events to vaccines are also common childhood illnesses, estimating the background rates of common illnesses is important to accurately ascertain a causal relationship. PMID- 26615340 TI - Oscillometric Blood Pressure in Indian School Children: Simplified Percentile Tables and Charts. AB - BACKGROUND: Data on blood pressure recorded by oscillometric method is limited. OBJECTIVE: To develop simplified tables and charts of blood pressure recorded by oscillometric method in children. DESIGN: Cross-sectional. SETTING: Ballabhgarh, Haryana. PARTICIPANTS: Healthy school-children. MAIN OUTCOME MEASURES: Blood pressure measured by oscillometric method. RESULTS: The study group included 7,761 children (58.4% males) with mean (SD) age of 10.5 (2.8) years. Age and gender were used to create simplified percentile tables and charts, as height was seen to explain very little variability of either systolic or diastolic blood pressure. Formulae for SBP and DBP thresholds for hypertension were derived as [110 + 1.6 x age] and [79 + 0.7 x age], respectively, with 1 mm Hg to be added for females. 95th percentile values suggest simple levels indicating hypertension to be 120/80, 125/85 and 135/90 at ages of 5, 10 and 15 years, respectively. CONCLUSIONS: Simplified reference tables and charts, formulae for SBP and DBP, and simple convenient thresholds may be useful for rapid screening of hypertension using oscillometric method. PMID- 26615341 TI - Genotypic Detection of Epstein Barr Virus in Pediatric Transplant Recipients From India. AB - OBJECTIVE: To determine the rate of occurrence and genotypes of Epstein-Barr Virus (EBV) among pediatric renal and liver transplants recipients. DESIGN: Observational study. SETTING: Vision Research Foundation referral center and Institute of Liver Disease and Transplantation, Chennai, India. PARTICIPANTS: 70 pediatric solid organ transplant recipients and 60 voluntary healthy donors. METHODS: Polymerase chain reaction (PCR) for detection and genotyping of EBV were carried out using genes targeting Viral capsid antigen, Nuclear antigen 1, 2 and 3, followed by real time PCR for viral load determination and further confirmed by phylogenetic analysis. RESULTS: EBV was detected in 35 (51.4%) samples (32 liver and 4 renal transplants) with high viral load. Type A was detected in 33 samples, Type B in 2 liver transplant patients, and co-infection in one liver transplant patient who developed Post-transplant Lymphoproliferative Disorder (PTLD). Real time PCR results correlated with conventional PCR. The mean viral load for patients who did not develop PTLD was 50,424 copies/mL. Overall EBV load in patient with PTLD ranged from 1,40,392 copies/mL prior to PTLD diagnosis to 62,124 copies /mL post treatment. CONCLUSION: EBV infection is the high risk factor for PTLD after liver transplantation. PCR targeting of EBV can be applied to diagnose EBV infections and monitor treatment for EBV in pediatric solid organ transplant recipients. PMID- 26615342 TI - Zinc Supplementation in Preterm Neonates and Neurological Development, A Randomized Controlled Trial. AB - OBJECTIVE: To assess the effect of zinc supplementation on neuro-development and growth of preterm neonates. SETTING: Referral neonatal unit of a teaching hospital. DESIGN: Open-labeled Randomized controlled trial. PARTICIPANTS: 100 preterm neonates. INTERVENTION: Participants randomized to receive oral zinc (study group) or not (controls). MAIN OUTCOME MEASURES: Primary: Neuro development status at 40 weeks post conceptional age and at 3 month corrected age using Amiel-Tison neurologic assessment. Secondary: anthropometry and serum alkaline phosphatase at 3 months corrected age. RESULTS: At 40 weeks post conceptional age, greater number of zinc supplemented infants demonstrated alertness and attention pattern normal for their age (P=0.02). Higher number of controls showed signs of hyper-excitability at 40 week post-conceptional age (P=0.001) and 3 months corrected age (P=0.003). At 3 month corrected age, mean serum alkaline phosphatase level was significantly higher in the study group compared to controls. CONCLUSION: Zinc supplementation till 3 month corrected age in preterm breastfed infants improves alertness and attention pattern; and decreases signs of hyperexcitability, and proportion with abnormal reflexes. PMID- 26615343 TI - Neurodevelopmental Status of Children Aged 6-30 Months With Congenital Heart Disease. AB - BACKGROUND: Children with congenital heart diseases (CHD) are considered to be at high-risk for neurodevelopmental delay, but scant Indian data are available. OBJECTIVE: To evaluate the neurodevelopmental status of children with CHD. METHODS: We enrolled consecutive children aged 6-30 months with echocardiographically-confirmed CHD between June 2013 and January 2014. Children with clinically recognizable genetic syndromes or disorders; visual and/or hearing deficits, and microcephaly; and post-cardiac surgery children were excluded. Development was assessed by Developmental Assessment Scale for Indian Infants (DASII) and Developmental delay defined as Development Quotient (DQ) <70 in either the mental or motor scale. RESULTS: 75 children (53 males) with CHD were enrolled. Acyanotic CHD was seen in 51 children (VSD in 47%), and Tetralogy of Fallot was the commonest cyanotic CHD (25%). Developmental delay was seen in 25% of these children, more in the motor domain (48%) than in mental (12%). Mean motor and mental DQ in acyanotic CHD was 77 and 84, respectively; and 65 and 85, respectively in cyanotic CHD. Mean motor DQ was significantly less than mental DQ in both acyanotic and cyanotic CHD children (P=0.048). CONCLUSION: Children with CHD are at an increased risk for developmental delay. Periodic surveillance, screening and evaluation should be instituted in them for early identification and appropriate interventions to enhance later academic, behavioral, psycho social and adaptive function. PMID- 26615344 TI - Comparison of Sucking Pattern in Premature Infants With Different Feeding Methods. AB - OBJECTIVE: To compare the sucking pattern of preterm infants on different feeding methods. METHODS: The sucking behavior on a gloved finger was evaluated for infants receiving breastfeeding, spoon-feeding and tube-feeding. RESULTS: The mean (SD) numbers of sucks in spoon-fed infants [49 (20) vs. 35 (23); P=0.04] were significantly higher, and the grade of suck was significantly better compared to the tube-fed group. The mean (SD) number of sucks was significantly higher [83 (30) vs. 49 (20), P<0.001] in breastfed infants compared to spoon-fed infants; all infants on breast feeds had grade 2 suction. CONCLUSION: The sucking behavior varies between tube-fed, spoon-fed, and breastfed preterm infant. PMID- 26615345 TI - Mortality and Other Outcomes in Relation to First Hour Fluid Resuscitation Rate: A Systematic Review. AB - OBJECTIVE: To determine the effect of different regimen of first hour fluid administration rates on mortality and severe consequences of impaired circulation in 2 to 60 months old children with impaired circulation. DESIGN: Systematic review of randomized controlled trials. DATA SOURCES: Various databases including PubMed, Cochrane Library and EMBASE were searched. RESULTS: We found only two relevant trials; one was excluded as there was no comparator arm. Only one study (The FEAST Trial) compared boluses with maintenance fluid alone in children with severe febrile illness and one or more signs of impaired perfusion. The 48 hour mortality was more in the bolus group (RR 1.45, 95% CI 1.13,1.86). The quality of evidence is rated as moderate. For the children who met the WHO criteria for shock (severely impaired circulation) (n=65 children), those receiving boluses had higher mortality (RR 2.40, 95% CI 0.84, 6.88); the quality of evidence was rated as very low. CONCLUSION: A single large randomized controlled trial conducted in low-resource settings indicates that administration of fluid bolus is associated with higher mortality in comparison to the maintenance fluids alone in children with severe febrile illness and one or more signs of impaired perfusion. The findings are not generalizable to contexts with different severity of and different causes of shock and in centers with better facilities. There is urgent need for research in different settings to determine the optimal rate of fluid resuscitation in the first hour in children presenting with impaired circulation, particularly with severely impaired circulation. PMID- 26615346 TI - Leukemoid Reaction--A Tale of 50 Years. PMID- 26615347 TI - Age of Introduction of Complementary Feeding and Iron Deficiency Anemia in Breastfed Infants: Evidence-based Medicine Viewpoint. PMID- 26615348 TI - Age of Introduction of Complementary Feeding and Iron Deficiency Anemia in Breastfed Infants: Pediatricians Viewpoint. PMID- 26615349 TI - Age of Introduction of Complementary Feeding and Iron Deficiency Anemia in Breastfed Infants,Child Health Viewpoint. PMID- 26615350 TI - Mucoepidermoid Carcinoma of Parotid as a Second Malignancy in Acute Lymphoblastic Leukemia. AB - BACKGROUND: Improved survival seen in Acute Lymphoblastic Leukemia (ALL) cases has led to increased reports of second malignant neoplasms. CASE CHARACTERISTICS: A 12-year-old female treated for ALL using UK ALL XI protocol nine years back presented with progressively increasing pre-auricular swelling. OBSERVATION: Investigations revealed it to be a Mucoepidermoid carcinoma. MESSAGE: Mucoepidermoid carcinoma should be a differential in any parotid swelling of treated case of pediatric ALL. PMID- 26615351 TI - Hypoglycemia due to 3beta-Hydroxysteroid Dehydrogenase type II Deficiency in a Newborn. AB - BACKGROUND: 3beta-hydroxysteroid dehydrogenase type II deficiency results in decreased production of all three groups of adrenal steroids. Recurrent hypoglycemia as a presenting feature of this disorder has not been reported earlier. CASE CHARACTERISTICS: A genotypically and phenotypically normal female newborn delivered by in-vitro fertilization presenting with recurrent hypoglycemia. Primary adrenal insufficiency with insignificant mineralocorticoid deficiency and slightly elevated levels of 17-hydro-xyprogesterone, dehydroepian drosterone sulphate and testosterone. OUTCOME: Successfully managed only with corticosteroid replacement. MESSAGE: Congenital adrenal hyperplasia can rarely cause recurrent hypoglycemia in newborns. PMID- 26615352 TI - Alveolar Capillary Dysplasia as a Cause of Persistent Pulmonary Hypertension. AB - BACKGROUND: Persistent pulmonary hypertension (PPHN) in a term or late preterm has varied etiology. CASE CHARACTERISTICS: A late preterm neonate operated for esophageal atresia with tracheo-esophageal fistula was complicated by severe pulmonary hypertension and unable to be weaned off from respiratory support. OUTCOME: The neonate expired by 15 weeks of life; diagnosis was made on postmortem lung biopsy. MESSAGE: Alveolarcapillary dysplasia should be considered in a neonate with idiopathic refractory PPHN, if associated with anomalies. PMID- 26615353 TI - Klippel-Trenaunay-Weber Syndrome with Kasabach-Merritt Coagulopathy and Hydronephrosis. AB - BACKGROUND: Klippel-Trenaunay-Weber Syndrome is a rare syndrome, consisting of vascular malformation of blood and lymph vessels. CASE CHARACTERISTICS: A newborn female with respiratory distress from birth, and having vascular malformation involving left thigh. OBSERVATION: The neonate also had hydronephrosis and developed complication of Kasabach Merritt syndrome. MESSAGE: Urogenital abnormalities can be present in Klippel-Trenaunay-Weber syndrome but hydronephrosis is rare. Mortality is high with development of Kasabach Merritt syndrome. PMID- 26615354 TI - Sedation Practice Outside the Operating Room for Pediatric Gastrointestinal Endoscopy. AB - Medical records of the 575 children who underwent gastrointestinal endoscopy outside the operating room were investigated retrospectively. The most frequently used combinations were propofol-midazolam-fentanyl in 83.2% of the procedures and propofol-midazolam in 13.8% of the procedures. 24 (3.4%) of 703 procedures had complications due to sedation anesthesia; 11 had hypoxia and 8 had pain in the injection area. Sedation anesthesia practice provided by an anesthesiologist outside the operating room enables gastrointestional endoscopic procedures to be carried out more safely. PMID- 26615355 TI - Intracerebral Hematoma in an Infant with Herpes Simplex Encephalitis. PMID- 26615356 TI - Primary Tubercular Abscess of Thigh in Infancy. PMID- 26615357 TI - Oculo-facio-cardio Dental Syndrome. PMID- 26615358 TI - Foreign Body Aspiration in Young Children: Keeping Things Simple. PMID- 26615359 TI - Enuresis and Sleep Disorders in Children. PMID- 26615360 TI - Enuresis and Sleep Disorders in Children: Authors Reply. PMID- 26615361 TI - Acquired Lung Cyst in a Newborn Baby with Cytomegalovirus Infection. PMID- 26615362 TI - Intermittent Ataxia with Early Onset Absence Epilepsy in Glucose Transporter Type 1 Deficiency Syndrome. PMID- 26615363 TI - Categories in the pigeon brain: A reverse engineering approach. AB - Pigeons are well known for their visual capabilities as well as their ability to categorize visual stimuli at both the basic and superordinate level. We adopt a reverse engineering approach to study categorization learning: Instead of training pigeons on predefined categories, we simply present stimuli and analyze neural output in search of categorical clustering on a solely neural level. We presented artificial stimuli, pictorial and grating stimuli, to pigeons without the need of any differential behavioral responding while recording from the nidopallium frontolaterale (NFL), a higher visual area in the avian brain. The pictorial stimuli differed in color and shape; the gratings differed in spatial frequency and amplitude. We computed representational dissimilarity matrices to reveal categorical clustering based on both neural data and pecking behavior. Based on neural output of the NFL, pictorial and grating stimuli were differentially represented in the brain. Pecking behavior showed a similar pattern, but to a lesser extent. A further subclustering within pictorial stimuli according to color and shape, and within gratings according to frequency and amplitude, was not present. Our study gives proof-of-concept that this reverse engineering approach-namely reading out categorical information from neural data- can be quite helpful in understanding the neural underpinnings of categorization learning. PMID- 26615364 TI - Predicting the transition from anxiety to depressive symptoms in early adolescence: Negative anxiety response style as a moderator of sequential comorbidity. AB - BACKGROUND: Anxiety often precedes depression. The anxiety response styles theory of comorbidity suggests anxious individuals with a tendency to ruminate or make hopeless attributions about anxiety symptoms (negative anxiety response styles [NARS]) are more vulnerable to subsequent depressive symptoms. However, this theory has never been tested in adolescence, when the anxiety-depression transition may frequently occur, or using an extended (one-year) follow-up period. METHOD: 128 early adolescent girls (M=12.39 years) participated with caregivers in a one-year longitudinal study. At baseline and follow-up, participants completed diagnostic interviews and self-report measures assessing child NARS and brooding rumination. RESULTS: T1 NARS predicted longitudinal elevations in depressive symptoms and increased associations between T1 anxiety and T2 depressive symptoms. LIMITATIONS: This study examines anxiety and depression comorbidity using a community sample. The sample is relatively low on sociodemographic diversity. CONCLUSIONS: Results support the anxiety response styles theory, with potential implications for early identification of anxious youth at risk for later development of comorbid depression. PMID- 26615365 TI - Affective instability, childhood trauma and major affective disorders. AB - BACKGROUND: Affective instability (AI), childhood trauma, and mental illness are linked, but evidence in affective disorders is limited, despite both AI and childhood trauma being associated with poorer outcomes. Aims were to compare AI levels in bipolar disorder I (BPI) and II (BPII), and major depressive disorder recurrent (MDDR), and to examine the association of AI and childhood trauma within each diagnostic group. METHODS: AI, measured using the Affective Lability Scale (ALS), was compared between people with DSM-IV BPI (n=923), BPII (n=363) and MDDR (n=207) accounting for confounders and current mood. Regression modelling was used to examine the association between AI and childhood traumas in each diagnostic group. RESULTS: ALS scores in descending order were BPII, BPI, MDDR, and differences between groups were significant (p<0.05). Within the BPI group any childhood abuse (p=0.021), childhood physical abuse (p=0.003) and the death of a close friend in childhood (p=0.002) were significantly associated with higher ALS score but no association was found between childhood trauma and AI in BPII and MDDR. LIMITATIONS: The ALS is a self-report scale and is subject to retrospective recall bias. CONCLUSIONS: AI is an important dimension in bipolar disorder independent of current mood state. There is a strong link between childhood traumatic events and AI levels in BPI and this may be one way in which exposure and disorder are linked. Clinical interventions targeting AI in people who have suffered significant childhood trauma could potentially change the clinical course of bipolar disorder. PMID- 26615366 TI - Metal contamination as a possible etiology of fibropapillomatosis in juvenile female green sea turtles Chelonia mydas from the southern Atlantic Ocean. AB - Environmental contaminants have been suggested as a possible cause of fibropapillomatosis (FP) in green sea turtles. In turn, a reduced concentration of serum cholesterol has been indicated as a reliable biomarker of malignancy in vertebrates, including marine turtles. In the present study, metal (Ag, Cd, Cu, Fe, Ni, Pb and Zn) concentrations, oxidative stress parameters [antioxidant capacity against peroxyl radicals (ACAP), protein carbonyls (PC), lipid peroxidation (LPO), frequency of micronucleated cells (FMC)], water content, cholesterol concentration and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) activity were analyzed in the blood/serum of juvenile (29.3-59.5cm) female green sea turtles (Chelonia mydas) with FP (n=14) and without FP (n=13) sampled at Ubatuba coast (Sao Paulo State, southeastern Brazil). Green sea turtles were grouped and analyzed according to the severity of tumors. Individuals heavily afflicted with FP showed significantly higher blood Cu, Pb and Fe concentrations, blood LPO levels, as well as significantly lower serum cholesterol concentrations and HMGR activity than turtles without FP. Significant and positive correlations were observed between HMGR activity and cholesterol concentrations, as well as LPO levels and Fe and Pb concentrations. In turn, Cu and Pb concentrations were significantly and negatively correlated with HMGR activity and cholesterol concentration. Furthermore, Cu, Fe and Pb were positively correlated with each other. Therefore, the reduced concentration of serum cholesterol observed in green sea turtles heavily afflicted with FP is related to a Cu- and Pb-induced inhibition of HMGR activity paralleled by a higher LPO rate induced by increased Fe and Pb concentrations. As oxidative stress is implicated in the pathogenesis of viral infections, our findings support the idea that metal contamination, especially by Cu, Fe and Pb, may be implicated in the etiology of FP in green sea turtles through oxidative stress generation. PMID- 26615368 TI - The need for longitudinal research on chronic pain and sleep disturbance. PMID- 26615370 TI - Poppy: The Elegant Flower or a Lethal Weapon of Addiction. PMID- 26615367 TI - DNA-gadolinium-gold nanoparticles for in vivo T1 MR imaging of transplanted human neural stem cells. AB - The unambiguous imaging of transplanted cells remains a major challenge to understand their biological function and therapeutic efficacy. In vivo imaging of implanted cells is reliant on tagging these to differentiate them from host tissue, such as the brain. We here characterize a gold nanoparticle conjugate that is functionalized with modified deoxythymidine oligonucleotides bearing Gd(III) chelates and a red fluorescent Cy3 moiety to visualize in vivo transplanted human neural stem cells. This DNA-Gd@Au nanoparticle (DNA-Gd@AuNP) exhibits an improved T1 relaxivity and excellent cell uptake. No significant effects of cell uptake have been found on essential cell functions. Although T1 relaxivity is attenuated within cells, it is sufficiently preserved to afford the in vivo detection of transplanted cells using an optimized voxel size. In vivo MR images were corroborated by a post-mortem histological verification of DNA Gd@AuNPs in transplanted cells. With 70% of cells being correctly identified using the DNA-Gd-AuNPs indicates an overall reliable detection. Less than 1% of cells were false positive for DNA-Gd@AuNPs, but a significant number of 30% false negatives reveals a dramatic underestimation of transplanted cells using this approach. DNA-Gd@AuNPs therefore offer new opportunities to visualize transplanted cells unequivocally using T1 contrast and use cellular MRI as a tool to derive biologically relevant information that allows us to understand how the survival and location of implanted cells determines therapeutic efficacy. PMID- 26615369 TI - Systemic expression of inflammatory mediators in patients with chronic rhinosinusitis and nasal polyps with and without Aspirin Exacerbated Respiratory Disease. AB - BACKGROUND: Systemic reactions are related to the pathogenesis of Aspirin Exacerbated Respiratory Disease (AERD). With this work we wanted to study the changes in the systemic levels of inflammatory mediators in both baseline and after oral aspirin challenge in patients with and without AERD. METHODS: Patients with nasal polyposis and asthma with AERD (n=20) and without (n=18) were orally challenged with aspirin in a single-blind placebo controlled study. Serum samples and urine were collected before and 6h after placebo and aspirin oral challenges. Serum levels of inflammatory mediators were assayed by using the Luminex technology and ELISA. The concentrations of 9-alpha, 11-beta prostaglandin F2, and leukotriene E4 (uLTE4) were measured in urine samples by ELISA. The expression of T-cell surface markers was analyzed in peripheral blood mononuclear cells isolated before and after the challenges. RESULTS: AERD patients showed significantly higher baseline levels of s-IL-5R-alpha, uLTE4 and percentage of CD4(+)CD25(+)CD127(pos) and CD4(+)CD45RA(-)CD45RO(+) but decreased levels of TGF beta1 and number of CD4(+)CD25(+)CD127(neg) cells. Aspirin challenge induced the release of uLTE4, IL-6 and increased the number of CD4(+)CD45RA(-)CD45RO(+) memory T-cells only in AERD patients but failed to reduce the levels of sCD40L as observed in non-AERD subjects. Further, IL-8 and sIL-5R-alpha levels directly correlated with the PD20ASA and the effects of aspirin on IL-6 and number of memory T-cells was more pronounced in subjects showing more strong reaction (bronchial and nasal). CONCLUSIONS: AERD patients have a differential baseline inflammatory pattern that supports the role inflammation as underlying mechanism of the disease. Systemic response to oral aspirin challenge was related to an increase in serum IL-6 and the number of circulating memory T-cells in AERD patients. PMID- 26615371 TI - Investigation of the Prevalence of Obesity in Iran: a Systematic Review and Meta Analysis Study. AB - Obesity is one of the main public health problems which underlie many chronic illnesses and socioeconomic difficulties. According to the literature review, there are limited data on the prevalence of obesity in different parts of Iran as well as its trend and prevalence among different age and gender groups. The aim of this study was to estimate the obesity prevalence in Iran using meta-analysis. All the corresponding articles published in the external and internal journals, final reports of research projects, articles of related congresses and the reference index of the correlated papers published between 1995 and 2010 were collected via the electronic research engines (PubMed, Scopus, SID, Magiran, IranMedex). Data were analyzed using meta-analysis (random effects model) and meta-regression). A total of 144 articles with the sample size of 377858 people (134588 males and 164858 females) were enrolled in the study. The prevalence of obesity in populations above the age of 18 was estimated as 21.7% (CI 95%: 18.5% 25%) and in populations below 18 as 6.1% (CI 95%: 6.8%-5.4%). Meta-regression analysis showed an ascending trend in the prevalence of obesity in Iran. The prevalence rates of obesity according to the BMI index, NCHC and percentile above 95 were 17.4%, 7.6% and 7.4%, respectively. The BMI mean was 19.3 in populations below the age of 18 (CI 95%: 17-21.6) and 25.2 in those above the age of 18 (CI 95%: 27.1-23.3). Considering the increasing rate of obesity in Iran and its effects on the public health, corresponding health authorities should revise the obesity preventive programs and, using public health interventions, reduce the rate of obesity in the country. PMID- 26615372 TI - The Effects of Sub-Chronic Treatment with Pioglitazone on the Septic Mice Mortality in the Model of Cecal Ligation and Puncture: Involvement of Nitric Oxide Pathway. AB - Sepsis is a systemic inflammatory response syndrome caused by an infection and remains as a major challenge in health care. Many studies have reported that pioglitazone may display anti-inflammatory effects. This study was designed to evaluate the effect of subchronic treatment with pioglitazone on high-grade septic mice survival and nitrergic system involvement. Diffused sepsis was induced by cecal ligation and puncture (CLP) surgery in male NMRI mice (20-30 g). Pioglitazone (5,10 and 20 mg/kg) was administered by gavage daily for 5 days prior to surgery. Nitric oxide involvement was assessed by sub-chronic administration of a non-selective nitric oxide synthase inhibitor, L-NAME and a selective inducible nitric oxide synthase inhibitor, aminoguanidine. TNF-alpha and IL-1beta plasma levels were measured by ELISA. Pioglitazone (10 and 20 mg/kg) significantly improved survival rate in septic mice. The chronic intraperitoneally co-administration of L-NAME (0.5 mg/kg, daily) or aminoguanidine (1 mg/kg, daily) with a daily dose of pioglitazone, 5 mg/kg, significantly increased the survival rate. This survival improving effect was accompanied by a significant reduction in pro-inflammatory cytokines TNF-alpha and IL-1beta plasma levels. In conclusion, sub-chronic pioglitazone treatment can improve survival in mouse sepsis model by CLP. Inhibition of nitric oxide release, probably through inducible nitric oxide synthase at least in part is responsible for this effect. Suppression of TNF-alpha and IL-1beta could be another mechanism in pioglitazone-induced survival improving effect in septic mice. PMID- 26615373 TI - The Optimal Surgical Approach for Treatment of Chronic Subdural Hematoma: Questionnaire Assessment of Practice in Iran and Review of Literature. AB - Chronic subdural hematoma (CSDH) is a curable entity frequently encountered by neurosurgeons. The present study was conducted to explore expert opinion and common practice in Iran. Besides, a Review of randomized clinical trials in literature was performed. A questionnaire including six questions discussing major aspects of practice on CSDH, with multiple choices was designed. A pilot study was performed for reliability analysis of the questionnaire. A total of 100 neurosurgeons were selected randomly from the members of Iranian Association of Neurological Surgeons. Frequency of answers to each item, differences in response rates and correlation of various categories were analyzed using Chi-square statistics. The mean duration of experience was 15.4 +/- 5 years, with a range of 10 to 37 years. The most common initial procedure of choice was burr-hole drainage (64%). At recurrent cases, surgical approach was changed to craniotomy at one-third of those treated initially with burr-hole drainage. The participants believed that surgical technique was predictive of outcome and recurrence. Burr hole without drainage was used by less expert neurosurgeons (mean 12.5 +/- 6), however, burr-hole drainage was the dominant technique at more than 15 years of experience and craniectomy was used only by participants with more than 30 years of experience (10%). Irrigation was used by most of the neurosurgeons (87.5%) in combination with drainage and burr-hole. The majority of participants used flat position at the postoperative period. At the current study, the pattern of management for CSDH was similar to other reports at literature suggesting the burr-hole drainage and irrigation as optimal treatment. Individualized decision making could be made at challenging cases. PMID- 26615374 TI - Association of Obstructive Sleep Apnea Syndrome and Buerger's Disease: a Pilot Study. AB - In this study we evaluated the incidence and severity of obstructive sleep apnea and Obstructive sleep apnea syndrome in patients with thromboangiitis obliterans for reduction of crisis. In 40 patients with Buerger's disease daily sleepiness and risk of Obstructive sleep apnea were evaluated using the Epworth sleeping scale (ESS) and the Stop-Bang score. An Apnea-link device was used for evaluation of chest motion, peripheral oxygenation, and nasal airflow during night-time sleep. The apnea/hypopnea index (AHI) and respiratory disurbance index were used for Obstructive sleep apnea syndrome diagnosis. All subjects were cigarette smokers and 80% were opium addicted. The prevalence of Obstructive sleep apnea (AHI>5) was 80%, but incidence of Obstructive sleep apnea syndrome (AHI>5 + ESS>=10) was 5% (2/40). There was no association between duration or frequency of hospitalization and Obstructive sleep apnea syndrome (P=0.74 and 0.86, respectively). In addition, no correlation between ESS and Stop-Bang scores and AHI was observed (P=0.58 and 0.41, respectively). There was an inverse correlation between smoking rate and AHI (P=0.032, r = -0.48). We did not find an association between Buerger's disease and Obstructive sleep apnea syndrome. Although the AHI was high (80%) and daily sleepiness was low. The negative correlation of smoking with AHI and on the other hand daily napping in addiction may be caused by the absence of a clear relationship between Obstructive sleep apnea syndrome and Buerger's disease. PMID- 26615375 TI - Morbidity and Mortality Following Short Course Preoperative Radiotherapy in Rectal Carcinoma. AB - The aim of this study was to evaluate the morbidity and mortality in patients with operable stage II and III rectal cancers within one or two months after surgery, who has been treated pre-operatively with short course radiotherapy. Twenty-eight patients with rectal adenocarcinoma, consecutively referred to the Cancer Institute of Imam Khomeini Hospital from March 2009 to March 2010, were selected for the study after staging by endorectal ultrasound and CT of abdomen, pelvis, and chest; and if they had inclusion criteria for short course schedule, they were treated with radiotherapy alone at 2500 cGy for 5 sessions, and then they were referred to the surgical service for operation one week later. They were visited there by a surgeon unaware of the research who completed a questionnaire about pre-operative, operative, and post-operative complications. Of 28 patients, 25 patients underwent either APR or LAR surgery with TME. One patient developed transient anal pain grade I and one patient had dysuria grade I; they were improved in subsequent follow-up. Short course schedule can be performed carefully in patients with staged rectal cancer without concerning about serious complications. This shorter treatment schedule is cost-effective and would be more convenient for patients due to fewer trips to the hospital and the main treatment, i.e. operating the patient, will be done with the shortest time the following diagnosis. PMID- 26615376 TI - Intravenous Valproate versus Subcutaneous Sumatriptan in Acute Migraine Attack. AB - Migraine is a common and incapacitating neurologic disorder manifesting with episodic moderate to a severe headache and other symptoms such as photophobia, phonophobia, nausea, and vomiting. Triptans and ergot compounds have been used as treatment options for an acute migraine headache for many years. Triptans are considered the first line of treatment in patients with moderate to a severe migraine. Although the triptans are commonly used at any time during a migraine attack; they are more efficacious when used in the early stages of a migraine. Intravenous valproic acid has been shown to be well tolerated, safe, and with rapid onset of action in patients with acute moderate to severe and even refractory migraine. Sodium valproate is a Food and Drug Administration (FDA) approved drug for prophylaxis of a migraine with and without aura. In this study, the main goal was to compare the effectiveness of sumatriptan versus valproate in an acute migraine. A randomized clinical trial including 37 patients with an acute migraine was considered to compare the effectiveness of sumatriptan versus valproate. The patients were divided into two groups. In first group, 6 mg subcutaneous of sumatriptan and in the second group 15 mg/Kg of valproate was administered. The outcomes including pain and drug adverse effects were compared across the groups. A total of 37 patients (7 male and 30 female) were evaluated in two groups. The difference between two groups regarding sex and age was not significant (P>0.05). The mean pain scores reduced from 8.3 to 4.7 and from 8.3 to 2.2 after one hour of treatment in sumatriptan and valproate groups, respectively. Response to treatment in valproate group was faster and more effective than sumatriptan group (P<0.05).The results indicated that valproate was more effective and with the faster response in patients with an acute migraine in comparison with sumatriptan without any recurrence and remarkable side effects. PMID- 26615377 TI - Comparison of the Effect of Thiopental Sodium with Midazolam-ketamine on Post tonsillectomy Agitation in Children. AB - The aim of this study was to determine the effect of thiopental sodium with that of midazolam-ketamine on relieving agitation after tonsillectomy in children. In a clinical trial, 50 children aged 5-10 years, candidates for tonsillectomy, were randomly divided into two 25-member groups. In the first group, thiopental sodium 5mg/kg/IV, and in the second group combination of midazolam 0.01 mg/kg/IV and ketamine 1 mg/kg/IV were used to induce anesthesia. The level of sedation was assessed after surgery with the Ramsay scale. There were no significant differences between the two groups in terms of heart rate, arterial oxygen pressure (PO2), and duration of anesthesia. The Ramsay sedation score was significantly higher in the thiopental sodium group than in the midazolam ketamine group (P=0.01). Thiopental sodium can be more effective than the combination of midazolam-ketamine for controlling agitation after tonsillectomy in children. PMID- 26615378 TI - Comparison of aPTT and CT Parameter of the ROTEM Test to Monitor Heparin Anti Coagulation Effect in ICU Patients: an Observational Study. AB - Heparin is frequently used in different clinical settings to reduce the coagulating ability of the blood. Because of probable adverse effects owing to heparin therapy and regarding variability of patients' responses to heparin, which make it very unreliable, it seems prudent to monitor meticulously its effects on the human body. There are a lot of laboratory tests to watch its effects on the body for example; aPTT and ROTEM are the most widely used tests that are performed today. We aimed to compare the aPTT test results against changes of CT parameter of the ROTEM test due to heparin administration. This study was conducted on 45 critically ill patients who needed to receive heparin according to their clinical status. All patients received 550 to 1500 unit heparin per hour (on average 17.5 unit heparin per kilogram weight). While the patients were under infusion of heparin, two blood samples (5 ml) were taken from a newly established cubital vein, just five hours after commencement of heparin therapy. One sample was used for aPTT and the other one for ROTEM. The correlation between aPTT and the changes of CT parameter of the ROTEM with heparin dosage and infusion was the primary outcome. The correlation between heparin therapy and the changes of other parameters like MCF, CFT, and a number of platelets were the secondary outcome of the study. The only significant correlation was between changes of CT and aPTT (P=0.000). The other variables were not correlated. Changes of CT parameter of ROTEM test can be used for monitoring of reduced coagulability during heparin infusion instead of aPTT test. PMID- 26615379 TI - Prevalence of Tuberculosis among Veterans, Military Personnel and their Families in East Azerbaijan Province Violators of the last 15 Years. AB - Nowadays in the world, tuberculosis is the second largest killer of adults after HIV. Due to the location of presidios that is mostly located in hazardous zones soldiers and army personnel are considered high risk, therefore we decided to determine the prevalence of tuberculosis status in this group of people. This was a cross-sectional descriptive research that studied the prevalence of pulmonary tuberculosis in soldiers and military personnel in the last 15 years in tuberculosis and lung disease research center at Tabriz University of Medical Sciences. The statistical population consisted of all the soldiers and military personnel. The detection method in this study was based on microscopic examination following Ziehl-Neelsen Stain and in Leuven Stein Johnson culturing. Descriptive statistics was used for statistical analysis and statistical values less than 0.05 were considered significant. By review information in this center since the 1988-2013 with 72 military personnel suffering from tuberculosis, it was revealed that among them 30 women, 42 men, 14 soldiers, 29 family members, and 29 military personnel are pointed. A significant correlation was found between TB rates among military personnel and their families. Although in recent years, the national statistics indicate a decline of tuberculosis, but the results of our study showed that TB is still a serious disease that must comply with the first symptoms of tuberculosis in military personnel and their families that should be diagnosed as soon as possible. PMID- 26615380 TI - Characteristics of Traumatic Brain Injury among Accident and Falling Down Cases. AB - Motor vehicle and falling down are responsible for the most number of traumatic injuries. This study aimed to compare the characteristics of traumatic brain injury among accident and falling down cases. In this analytical cross-sectional study, data were collected from the records of cadavers who died due to accident or falling down and referred to Kahrizak dissection hall, Tehran forensic medicine organization during 2013. A total of 237 subjects (183 (77.2%) accident and 54 (22.8%) falling down) with a mean age of 35.62 (SD=15.75) were evaluated. A number of 213 (89.9%) were male. From accident group, scalp injury was seen in 146 (79.8%), scalp abrasion in 122 (66.7%), scalp laceration in 104 (56.8%), sub skull bruising in 176 (96.3%), skull fracture in 119 (65%), hemorrhage in 166 (90.7%), Subdural hemorrhage (SDH) in 155 (84.7%), Subarachnoid hemorrhage (SAH) in 161 (88%), Epidural hemorrhage (EDH) in 41 (22.4%), contusion in 140 (76.5%), and skull base fracture in 140 (76.5%) of cases. In falling down group scalp injury was seen in 42 (77.8%) cadavers, scalp abrasion in 38 (70.4%), scalp laceration in 30 (55.6%), sub skull bruising in 49 (90.7%), skull fracture in 39 (72.2%), Hemorrhage in 49 (90.7%), SDH in 43 (79.6%), SAH in 47 (87%), EDH in 10 (18.5%), contusion in 33 (61.1%), and skull base fracture in 39 (72.2%) of cases. There was no significant difference between these two groups (P Value> 0.05). Accident and falling down had no difference in terms of any injury or hemorrhage. PMID- 26615381 TI - Early Onset Hepatocellular Disease in an Infant with Zellweger Syndrome. AB - Zellweger syndrome (ZS) is a peroxisomal disorder with a multiple congenital anomalies, characterized by stereotypical facies, profound hypotonia, organ involvement including cerebral, retinal, hepatic, and renal. Herein, a 3-month old female with ZS is presented who was referred because of increased liver enzymes (subclinical hepatitis), which was detected in work-up of her neck cyst, severe hypotonia, and abnormal facies. An increased concentration of very long chain fatty acid in lipid profile was detected. ZS should be considered in the list of differential diagnosis in infants with stereotypical phenotype, neurodevelopmental delay, and severe hypotonia in association with liver and other organs involvement. PMID- 26615382 TI - Diagnosing Mitochondrial Disorder without Sophisticated Means. AB - Mitochondrial disorders (MIDs) require biochemical or genetic investigations for being diagnosed. In some cases, however, the diagnosis can be suspected upon the syndromic phenotype or upon clinical presentation and family history, as in the following case. The patient was a 74-year-old male admitted for worsening of pre existing left-sided ptosis and ophthalmoparesis after a birthday party. The history was positive for arterial hypertension, hypertrophic cardiomyopathy with systolic dysfunction, diabetes-type 2, mild renal insufficiency, thyroiditis, and polyneuropathy. Instrumental investigations additionally revealed hepatopathy, hyperlipidemia, hyperuricemia, bifascicular block, white matter lesions, and subacute stroke. Systolic dysfunction resolved upon adequate cardiac treatment. On hospital day 11 the patient suddenly developed asystole. He was successfully resuscitated but died a few hours later from acute myocardial infarction. Surprisingly, a more extensive family history was positive for myopathy (patient, brother, daughter), neuropathy (patient), hypoacusis (patient), Parkinson syndrome (mother), spasticity (son), diabetes (patient, son), renal failure (patient), and generalized atherosclerosis (patient). The individual and family history was strongly suggestive of an MID. In conclusion, individual and family history may strongly suggest MID. Phenotypic variability may be high between family members affected by an MID. MID may be associated with an increasing atherosclerotic risk lastly resulting in coronary heart disease and death. PMID- 26615383 TI - Therapeutic and Ethical Dilemma of Puberty and Menstruation Problems in an Intellectually Disabled (Autistic) Female: a Case Report. AB - Intellectual disability is a term used when a person has certain limitations in mental functioning and skills. Autism is a group of developmental brain disorders, collectively called autism spectrum disorder (ASD). Teenagers with learning and physical disabilities are more likely to have menstrual problems compared to the general populations. The parents of a 12-year-old girl with autism spectrum disorder and intellectual disability referred to the coroner due to her numerous problems of puberty (menstruation) including: poor hygiene and polluting herself and the environment, not allowing to put or change the pads and changes in mood and physical health prior period, requested for the surgery (hysterectomy). In legal medicine organization after reviewing the medical records, physical exams and medical consultations with a gynecologist and psychiatric, surgery was not accepted. Hysterectomy (surgery) due to the age of the child, either physically or morally is not recommended. The use of hormone replacement therapy has side effects such as osteoporosis. In these cases, it seems noninvasive methods (behavioral therapy and learning care skills) under the welfare experts is also more effective and morally. PMID- 26615384 TI - Biomechanical properties of synthetic surgical meshes for pelvic prolapse repair. AB - Synthetic meshes are widely used for surgical repair of different kind of prolapses. In the light of the experience of abdominal wall repair, similar prostheses are currently used in the pelvic region, to restore physiological anatomy after organ prolapse into the vaginal wall, that represent a recurrent dysfunction. For this purpose, synthetic meshes are surgically positioned in contact with the anterior and/or posterior vaginal wall, to inferiorly support prolapsed organs. Nonetheless, while mesh implantation restores physiological anatomy, it is often associated with different complications in the vaginal region. These potentially dangerous effects induce the surgical community to reconsider the safety and efficacy of mesh transvaginal placement. For this purpose, the evaluation of state-of-the-art research may provide the basis for a comprehensive analysis of mesh compatibility and functionality. The aim of this work is to review synthetic surgical meshes for pelvic organs prolapse repair, taking into account the mechanics of mesh material and structure, and to relate them with pelvic and vaginal tissue biomechanics. Synthetic meshes are currently available in different chemical composition, fiber and textile conformations. Material and structural properties are key factors in determining mesh biochemical and mechanical compatibility in vivo. The most significant results on vaginal tissue and surgical meshes mechanical characterization are here reported and discussed. Moreover, computational models of the pelvic region, which could support the surgeon in the evaluation of mesh performances in physiological conditions, are recalled. PMID- 26615385 TI - CFD-aided modelling of activated sludge systems - A critical review. AB - Nowadays, one of the major challenges in the wastewater sector is the successful design and reliable operation of treatment processes, which guarantee high treatment efficiencies to comply with effluent quality criteria, while keeping the investment and operating cost as low as possible. Although conceptual design and process control of activated sludge plants are key to ensuring these goals, they are still based on general empirical guidelines and operators' experience, dominated often by rule of thumb. This review paper discusses the rationale behind the use of Computational Fluid Dynamics (CFD) to model aeration, facilitating enhancement of treatment efficiency and reduction of energy input. Several single- and multiphase approaches commonly used in CFD studies of aeration tank operation, are comprehensively described, whilst the shortcomings of the modelling assumptions imposed to evaluate mixing and mass transfer in AS tanks are identified and discussed. Examples and methods of coupling of CFD data with biokinetics, accounting for the actual flow field and its impact on the oxygen mass transfer and yield of the biological processes occurring in the aeration tanks, are also critically discussed. Finally, modelling issues, which remain unaddressed, (e.g. coupling of the AS tank with secondary clarifier and the use of population balance models to simulate bubbly flow or flocculation of the activated sludge), are also identified and discussed. PMID- 26615386 TI - A modeling approach to estimate the solar disinfection of viral indicator organisms in waste stabilization ponds and surface waters. AB - Sunlight is known to be a pertinent factor governing the infectivity of waterborne viruses in the environment. Sunlight inactivates viruses via endogenous inactivation (promoted by absorption of solar light in the UVB range by the virus) and exogenous processes (promoted by adsorption of sunlight by external chromophores, which subsequently generate inactivating reactive species). The extent of inactivation is still difficult to predict, as it depends on multiple parameters including virus characteristics, solution composition, season and geographical location. In this work, we adapted a model typically used to estimate the photodegradation of organic pollutants, APEX, to explore the fate of two commonly used surrogates of human viruses (coliphages MS2 and phiX174) in waste stabilization pond and natural surface water. Based on experimental data obtained in previous work, we modeled virus inactivation as a function of water depth and composition, as well as season and latitude, and we apportioned the contributions of the different inactivation processes to total inactivation. Model results showed that phiX174 is inactivated more readily than MS2, except at latitudes >60 degrees . phiX174 inactivation varies greatly with both season (20 fold) and latitude (10-fold between 0 and 60 degrees ), and is dominated by endogenous inactivation under all solution conditions considered. In contrast, exogenous processes contribute significantly to MS2 inactivation. Because exogenous inactivation can be promoted by longer wavelengths, which are less affected by changes in season and latitude, MS2 exhibits smaller fluctuations in inactivation throughout the year (10-fold) and across the globe (3-fold between 0 and 60 degrees ) compared to phiX174. While a full model validation is currently not possible due to the lack of sufficient field data, our estimated inactivation rates corresponded well to those reported in field studies. Overall, this study constitutes a step toward estimating microbial water quality as a function of spatio-temporal information and easy-to-determine solution parameters. PMID- 26615387 TI - Efficacy of Ligustrazine Injection as Adjunctive Therapy for Angina Pectoris: A Systematic Review and Meta-Analysis. AB - BACKGROUND In the past decades, a large number of randomized controlled trials (RCTs) on the efficacy of ligustrazine injection combined with conventional antianginal drugs for angina pectoris have been reported. However, these RCTs have not been evaluated in accordance with PRISMA systematic review standards. The aim of this study was to evaluate the efficacy of ligustrazine injection as adjunctive therapy for angina pectoris. MATERIAL AND METHODS The databases PubMed, Medline, Cochrane Library, Embase, Sino-Med, Wanfang Databases, Chinese Scientific Journal Database, Google Scholar, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, and the Chinese Science Citation Database were searched for published RCTs. Meta-analysis was performed on the primary outcome measures, including the improvements of electrocardiography (ECG) and the reductions in angina symptoms. Sensitivity and subgroup analysis based on the M score (the refined Jadad scores) were also used to evaluate the effect of quality, sample size, and publication year of the included RCTs on the overall effect of ligustrazine injection. RESULTS Eleven RCTs involving 870 patients with angina pectoris were selected in this study. Compared with conventional antianginal drugs alone, ligustrazine injection combined with antianginal drugs significantly increased the efficacy in symptom improvement (odds ratio [OR], 3.59; 95% confidence interval [CI]: 2.39 to 5.40) and in ECG improvement (OR, 3.42; 95% CI: 2.33 to 5.01). Sensitivity and subgroup analysis also confirmed that ligustrazine injection had better effect in the treatment of angina pectoris as adjunctive therapy. CONCLUSIONS The 11 eligible RCTs indicated that ligustrazine injection as adjunctive therapy was more effective than antianginal drugs alone. However, due to the low quality of included RCTs, more rigorously designed RCTs were still needed to verify the effects of ligustrazine injection as adjunctive therapy for angina pectoris. PMID- 26615388 TI - First detection of autochthonous Zika virus transmission in a HIV-infected patient in Rio de Janeiro, Brazil. AB - Since May 2015, Brazil's Ministry of Health has reported autochthonous transmission of Zika virus (ZIKV) in some states of the country. Simultaneous circulation of Dengue, Chikungunya and ZIKV in the country hinder both the diagnosis and the therapeutic approach of patients seeking care with acute febrile illnesses especially in patients with comorbidities. The association between HIV infection and endemic diseases has been described especially in tropical regions with varying levels of complications, although there has been no report of ZIKV in HIV-infected patients. We report the first autochthonous case of laboratory confirmed ZIKV infection in a HIV-infected patient in Rio de Janeiro, Brazil. He evolved with only mild symptoms and recovered well without major laboratory abnormalities. Phylogenetic analysis of the ZIKV detected in the patient sera clustered within the Asian clade. To the best of our knowledge, this is the first time that Zika virus co-infection is reported in a HIV-infected patient. PMID- 26615389 TI - Herpes simplex virus seroprevalence and seroconversion among active duty US air force members with HIV infection. AB - BACKGROUND: Herpes simplex virus (HSV) infection is associated with an increased risk of both HIV transmission and acquisition. We evaluated longitudinal HSV serology and sexually transmitted infections (STIs) among active duty US Air Force (USAF) members with HIV infection. METHODS: USAF members diagnosed with HIV between 1996 and 2012 were included and divided into 2 groups: 1996-2004 (n=131) and 2005-2012 (n=266). HSV-1 and -2 serology was evaluated at HIV diagnosis. Longitudinal HSV-1 and -2 serology and ICD-9 codes for HSV and non-HSV STIs were also examined for those with >= 1 year of follow-up. RESULTS: Patients were most commonly Caucasian (44.2%) or African American (43.4%) men with a median age of 28 years at HIV diagnosis. HSV-2 seroprevalence at HIV diagnosis decreased from the period of 1996-2004 (48.8%) to 2005-2012 (30.1%; P<0.01). Odds of HSV-2 seropositivity was significantly greater for non-Caucasians (OR 2.19, 95% CI 1.33 3.60) and for HIV diagnosis between 1996 and 2004 (OR 2.06, 95% CI 1.29-3.27), with a trend observed for those age >30 years at HIV diagnosis (OR 1.73, 95% CI 0.94-3.18). A total of 81 (20.4%) patients developed STIs by ICD-9 codes, including 24 (6.1%) new genital herpes diagnoses, during a median follow-up of 4.6 years. HSV-2 seroconversion occurred in 33 of 253 (13.0%) with an incidence rate of 5.07 per 100 person-years (95% CI 4.76-5.37). CONCLUSION: Although HSV-2 seroprevalence at HIV diagnosis decreased over time, high-risk sexual behaviors were ongoing as evidenced by the high proportion of new STI diagnoses and HSV-2 seroconversions. Continued education to reduce risk behaviors is warranted to prevent acquisition and transmission of STIs in HIV-infected persons. PMID- 26615390 TI - The experimental and numerical study of indirect effect of a rifle bullet on the bone. AB - We study the transient indirect effect of a rifle bullet on bone in the gelatin bone composite target experimentally and computationally. The process of a 56 type 7.62-mm rifle bullet penetrating the composite target has been simulated using numerical method. The experiment provided the criteria for verifying the correctness of the numerical model. We have obtained tomographic data of bone by CT scans, and also defined the bone as different layers by the gray scale to simulate its heterogeneity. The computed results are in good agreement with the experimental data. Effects of the impact velocity and bone location on damage caused to the composite target have also been studied. The numerical results imply the follows: When the velocity of bullet increases, the stress on bone also increases with the earlier pressure peak; When the bone is located in a certain distance from the trajectory, it will not be fractured, although it is affected by the stress wave. PMID- 26615391 TI - Living with AIDS in Uganda: a qualitative study of patients' and families' experiences following referral to hospice. AB - BACKGROUND: Globally, the majority of people with HIV/AIDS live in sub-Saharan Africa. While the increasing availability of antiretroviral therapy is improving the outlook for many, its effects are yet to reach all of those in need and patients still present with advanced disease. This paper reports findings from qualitative interviews with patients living with AIDS and their caregivers who were receiving palliative care from Hospice Africa Uganda (HAU). We aimed to understand what motivated patients and their families to seek formal healthcare, whether there were any barriers to help- seeking and how the help and support provided to them by HAU was perceived. METHODS: We invited patients with AIDS and their relatives who were newly referred to HAU to participate in qualitative interviews. Patients and carers were interviewed in their homes approximately four weeks after the patient's enrolment at HAU. Interviews were translated, transcribed and analysed using narrative and thematic approaches. RESULTS: Interviews were completed with 22 patients (10 women and 12 men) and 20 family caregivers, nominated by patients. Interviews revealed the extent of suffering patients endured and the strain that family caregivers experienced before help was sought or accessed. Patients reported a wide range of severe physical symptoms. Patients and their relatives reported worries about the disclosure of the AIDS diagnosis and fear of stigma. Profound poverty framed all accounts. Poverty and stigma were, depending on the patient and family situation, both motivators and barriers to help seeking behaviour. Hospice services were perceived to provide essential relief of pain and symptoms, as well as providing rehabilitative support and a sense of caring. The hospice was perceived relieve utter destitution, although it was unable to meet all the expectations that patients had. CONCLUSION: Hospice care was highly valued and perceived to effectively manage problems such as pain and other symptoms and to provide rehabilitation. Participants noted a strong sense of being "cared for". However, poverty and a sense of stigma were widespread. Further research is needed to understand how poverty and stigma can be effectively managed in hospice care for patients for advanced AIDS and their families. PMID- 26615392 TI - Effects of Community Mental Health Service in Subjects with Early Psychosis: One Year Prospective Follow Up. AB - The use of a multidisciplinary team approach is essential for increasing the likelihood of recovery among individuals with early psychosis. The aim of the present study was to investigate the effects of community-based mental health services on the symptoms and socio-occupational functioning of subjects with early psychosis. The study included participants who were referred to our Mental Health Promotion Center and who agreed to participate in diverse individual and group programs. During the 1-year follow-up, the medication adherence rate remained high, the recovery rate substantially increased, and the scores on the Positive and Negative Syndrome Scale, Psychotic Symptom Rating Scale-Delusion and Auditory Hallucinations subscales, Global Assessment of Functioning, Interpersonal Sensitivity Measure, and Social Functioning Questionnaire significantly improved over time. The findings suggest that the 1-year outcome of subjects with early psychosis can be improved by diverse community-based psychosocial interventions. PMID- 26615393 TI - Small-area spatio-temporal analyses of participation rates in the mammography screening program in the city of Dortmund (NW Germany). AB - BACKGROUND: The population-based mammography screening program (MSP) was implemented by the end of 2005 in Germany, and all women between 50 and 69 years are actively invited to a free biennial screening examination. However, despite the expected benefits, the overall participation rates range only between 50 and 55%. There is also increasing evidence that belonging to a vulnerable population, such as ethnic minorities or low income groups, is associated with a decreased likelihood of participating in screening programs. This study aimed to analyze in more detail the intra-urban variation of MSP uptake at the neighborhood level (i.e. statistical districts) for the city of Dortmund in northwest Germany and to identify demographic and socioeconomic risk factors that contribute to non response to screening invitations. METHODS: The numbers of participants by statistical district were aggregated over the three periods 2007/2008, 2009/2010, and 2011/2012. Participation rates were calculated as numbers of participants per female resident population averaged over each 2-year period. Bayesian hierarchical spatial models extended with a temporal and spatio-temporal interaction effect were used to analyze the participation rates applying integrated nested Laplace approximations (INLA). The model included explanatory covariates taken from the atlas of social structure of Dortmund. RESULTS: Generally, participation rates rose for all districts over the time periods. However, participation was persistently lowest in the inner city of Dortmund. Multivariable regression analysis showed that migrant status and long-term unemployment were associated with significant increases of non-attendance in the MSP. CONCLUSION: Low income groups and immigrant populations are clustered in the inner city of Dortmund and the observed spatial pattern of persistently low participation in the city center is likely linked to the underlying socioeconomic gradient. This corresponds with the findings of the ecological regression analysis manifesting socioeconomically deprived neighborhoods as risk factors for low attendance in the MSP. Spatio-temporal surveillance of participation in cancer screening programs may be used to identify spatial inequalities in screening uptake and plan spatially focused interventions. PMID- 26615394 TI - Unexpected Tumor: Primary Asymptomatic Schwannoma in Thyroid Gland. AB - The discovery of a tumor as a primary schwannoma in the thyroid gland is rare (Andrion et al. in Virchows Arch 413:367-372, 1988). It represents less than 1 % of mesenchymal neoplasms of this gland. Therefore, few cases of this type are described in medical literature (Aron et al. in Cytopathology 16:206-209, 2005; Cashman et al. in Medscape J Med 10(8):201, 2008; Coleman et al. in AJR Am J Roentgenol 140:383-7, 1983). In this article, we introduce the clinical case of a 27-year-old female patient, who presented a nodular mass located in the neck region. This mass was not associated with other symptoms and during the imagistic investigation it appeared to be a thyroglossal duct cyst. A fine needle aspiration biopsy was performed which revealed benign mesenchymal cells. After a pathology study of the piece resected through a thyroidectomy, it was confirmed that the tumor had neural characteristics, the final diagnosis being a primary schwannoma. The importance of a cytology study is emphasized, since in this case, it made it possible to accurately diagnose a mesenchymal tumor, despite their low frequency. It constitutes a highly useful tool for diagnosing non-epithelial neoplasia of the thyroid gland. PMID- 26615395 TI - Molecular characterization and heterologous expression of a Xanthophyllomyces dendrorhous alpha-glucosidase with potential for prebiotics production. AB - Basidiomycetous yeast Xanthophyllomyces dendrorhous expresses an alpha glucosidase with strong transglycosylation activity producing prebiotic sugars such as panose and an unusual tetrasaccharides mixture including alpha-(1-6) bonds as major products, which makes it of biotechnological interest. Initial analysis pointed to a homodimeric protein of 60 kDa subunit as responsible for this activity. In this study, the gene Xd-AlphaGlu was characterized. The 4131-bp long gene is interrupted by 13 short introns and encodes a protein of 990 amino acids (Xd-AlphaGlu). The N-terminal sequence of the previously detected 60 kDa protein resides in this larger protein at residues 583-602. Functionality of the gene was proved in Saccharomyces cerevisiae, which produced a protein of about 130 kDa containing Xd-AlphaGlu sequences. All properties of the heterologously expressed protein, including thermal and pH profiles, activity on different substrates, and ability to produce prebiotic sugars were similar to that of the alpha-glucosidase produced in X. dendrorhous. No activity was detected in S. cerevisiae containing exclusively the 1256-bp from gene Xd-AlphaGlu that would encode synthesis of the 60 kDa protein previously detected. Data were compatible with an active monomeric alpha-glucosidase of 990 amino acids and an inactive hydrolysis product of 60 kDa. Protein Xd-AlphaGlu contained most of the elements characteristic of alpha-glucosidases included in the glycoside hydrolases family GH31 and its structural model based on the homologous human maltase-glucoamylase was obtained. Remarkably, the Xd-AlphaGlu C-terminal domain presents an unusually long 115-residue insertion that could be involved in this enzyme's activity against long-size substrates such as maltoheptaose and soluble starch. PMID- 26615396 TI - Different mechanisms of resistance modulate sulfite tolerance in wine yeasts. AB - From a technological point of view, yeast resistance to sulfite is of great interest and represents an important technological character for winemaking. Several mechanisms are involved, and strain-dependent strategies to obtain SO2 resistance can deeply influence wine quality, although this choice is less relevant in determining the technological performance of the strain during fermentation. In this study, to better understand the strain-specific mechanisms of resistance, 11 Saccharomyces cerevisiae strains, whose genomes have been previously sequenced, were selected. Their attitude towards sulfites, in terms of resistance and production, was evaluated, and RNA-sequencing of four selected strains was performed during fermentation process in synthetic grape must in the presence of SO2. Results demonstrated that at molecular level, the physical effect of SO2 triggered multiple stress responses in the cell and high tolerance to general enological stressing condition increased SO2 resistance. Adaptation mechanism due to high basal gene expression level rather than specific gene induction in the presence of sulfite seemed to be responsible in modulating strain resistance. This mechanism involved higher basal gene expression level of specific cell wall proteins, enzymes for lipid biosynthesis, and enzymes directly involved in SO2 assimilation pathway and efflux. PMID- 26615397 TI - Application of genetically engineered microbial whole-cell biosensors for combined chemosensing. AB - The progress of genetically engineered microbial whole-cell biosensors for chemosensing and monitoring has been developed in the last 20 years. Those biosensors respond to target chemicals and produce output signals, which offer a simple and alternative way of assessment approaches. As actual pollution caused by human activities usually contains a combination of different chemical substances, how to employ those biosensors to accurately detect real contaminant samples and evaluate biological effects of the combined chemicals has become a realistic object of environmental researches. In this review, we outlined different types of the recent method of genetically engineered microbial whole cell biosensors for combined chemical evaluation, epitomized their detection performance, threshold, specificity, and application progress that have been achieved up to now. We also discussed the applicability and limitations of this biosensor technology and analyzed the optimum conditions for their environmental assessment in a combined way. PMID- 26615398 TI - The anti-bacterial poly(caprolactone)-poly(quaternary ammonium salt) as drug delivery carriers. AB - Anti-bacterial materials play significant role in biomedical field. Researches and applications of new anti-bacterial materials are necessary. Novel linear and star-shaped copolymers of poly(caprolactone)-poly(quaternary ammonium salt) (PCL PJDMA) were synthesized by a combination of ring-opening polymerization and atom transfer radical polymerization. The structures of the copolymers were confirmed by nuclear magnetic resonance ((1)H-NMR) and Fourier transform infrared spectroscopy. The copolymers self-assembled into ball-shaped micelles with low critical micelle concentration (10(-4) ~ 10(-3) mg/ml). An anti-bacterial drug, triclosan, was chosen as a model drug to investigate the potential application of the copolymers in drug-controlled release. The anti-bacterial experiments against Escherichia coli indicated that all the copolymer micelles had anti-bacterial ability and drug-loaded star-shaped PCL-PJDMA micelles were the best. The slow release of the drug from the drug-loaded micelles prolonged anti-bacterial effect. Therefore, PCL-PJDMA themselves have not only anti-bacterial ability but also the copolymer micelles can be used as carriers for anti-bacterial drugs. PMID- 26615399 TI - Novel 4-methyl-2-oxopentanoate reductase involved in synthesis of the Japanese sake flavor, ethyl leucate. AB - Ethyl-2-hydroxy-4-methylpentanoate (ethyl leucate) contributes to a fruity flavor in Japanese sake. The mold Aspergillus oryzae synthesizes leucate from leucine and then the yeast Saccharomyces cerevisiae produces ethyl leucate from leucate during sake fermentation. Here, we investigated the enzyme involved in leucate synthesis by A. oryzae. The A. oryzae gene/cDNA encoding the enzyme involved in leucate synthesis was identified and expressed in E. coli and A. oryzae host cells. The purified recombinant enzyme belonged to a D-isomer-specific 2 hydroxyacid dehydrogenase family and it NADPH- or NADH-dependently reduced 4 methyl-2-oxopentanate (MOA), a possible intermediate in leucine synthesis, to D leucate with a preference for NADPH. Thus, we designated this novel enzyme as MOA reductase A (MorA). Furthermore, an A. oryzae strain overexpressing morA produced 125-fold more leucate than the wild-type strain KBN8243. The strain overexpressing MorA produced 6.3-fold more ethyl leucate in the sake than the wild-type strain. These findings suggest that the strain overexpressing morA would help to ferment high-quality sake with an excellent flavor. This is the first study to identify the MOA reductase responsible for producing D-leucate in fungi. PMID- 26615400 TI - A molecular approach for the rapid, selective and sensitive detection of Exophiala jeanselmei in environmental samples: development and performance assessment of a real-time PCR assay. AB - Exophiala jeanselmei is an opportunistic pathogenic black yeast growing in humid environments such as water reservoirs of air-conditioning systems. Because this fungal contaminant could be vaporized into the air and subsequently cause health problems, its monitoring is recommended. Currently, this monitoring is based on culture and microscopic identification which are complex, sometimes ambiguous and time-demanding, i.e., up to 21 days. Therefore, molecular, culture-independent methods could be more advantageous for the monitoring of E. jeanselmei. In this study, we developed a SYBR(r)green real-time PCR assay based on the internal transcribed spacer 2 from the 18S ribosomal DNA complex for the specific detection of E. jeanselmei. The selectivity (100 %), PCR efficiency (95.5 %), dynamic range and repeatability of this qPCR assay were subsequently evaluated. The limit of detection for this qPCR assay was determined to be 1 copy of genomic DNA of E. jeanselmei. Finally, water samples collected from cooling reservoirs were analyzed using this qPCR assay to deliver a proof of concept for the molecular detection of E. jeanselmei in environmental samples. The results obtained by molecular analysis were compared with those of classical methods (i.e., culture and microscopic identification) used in routine analysis and were 100 % matching. This comparison demonstrated that this SYBR(r)green qPCR assay can be used as a molecular alternative for monitoring and routine investigation of samples contaminated by E. jeanselmei, while eliminating the need for culturing and thereby considerably decreasing the required analysis time to 2 days. PMID- 26615401 TI - NMR techniques for determination of lipid content in microalgal biomass and their use in monitoring the cultivation with biodiesel potential. AB - In the present investigation, the application of NMR spectroscopic techniques was extensively used with an objective to explore the biodiesel potential of biomass cultivated on a lab scale using strains of Chlorella vulgaris and Scenedesmus ecornis. The effect of variation in the composition of culturing medium on the neutral and polar lipids productivity, and fatty acid profile of solvent extracts of microalgae biomass was studied. Determination of unsaturated fatty acid composition (C18:N = 1-3, omega3 C20:5, omega3 C22:6), polyunsaturated fatty esters (PUFEs), saturated fatty acids (SFAs), unsaturated fatty acids (UFAs), free fatty acids (FFAs), and iodine value were achieved from a single (1)H NMR spectral analysis. The results were validated by (13)C NMR and GC-MS analyses. It was demonstrated that newly developed methods based on (1)H and (13)C NMR techniques are direct, rapid, and convenient for monitoring the microalgae cultivation process for enhancement of lipid productivity and their quality aspects in the solvent extracts of microalgal biomasses without any sample treatment and prior separation compared to other methods. The fatty acid composition of algae extracts was found to be similar to vegetable and fish oils, mostly rich in C16:0, C18:N (N = 0 to 3), and n-3 omega polyunsaturated fatty acids (PUFAs). The lipid content, particularly neutral lipids, as well as most of the quality parameters were found to be medium specific by both the strains. The newly developed methods based on NMR and ultrasonic procedure developed for efficient extraction of neutral lipids are cost economic and can be an effective aid for rapid screening of algae strains for modulation of lipid productivity with desired biodiesel quality and value-added products including fatty acid profile. PMID- 26615403 TI - Surgical management of a giant sternal chondromyxoid fibroma: a case report. AB - BACKGROUND: A primary chondromyxoid fibroma (CMF) arising from sternum is quite uncommon tumor in thoracic surgery. Removal of giant sternal tumors requires extensive resection of the anterior chest wall, and results in deformity and paradoxical movement. CASE PRESENTATION: A 40-year-old female presented a progressively enlarging mass of her anterior chest wall. Computed tomography revealed an osteolytic lesion with discrete calcification in the bone marrow of the sternum. The tumor extended across the destroyed cortex to the parietal and visceral soft aspects, involving some of the costal cartilage and most of the sternal body. Partial sternal resection was performed successfully and an individual-specific stainless steel plate was used to reconstruct the anterior chest wall. The early result was good, however, nine months after the first surgery, fractures of plate were found at bilateral plate-clavicular junction. The plate had to be removed, and a titanium mesh was used to reconstruction of the chest wall. The patient has been of disease free for more than 18 month after the second surgery. CONCLUSIONS: Our experience indicated that the individual specific plate may not be suitable for reconstructing both the anterior chest wall as well as the sternoclavicular joint after subtotal sternum resection. PMID- 26615402 TI - A high-fat, high-saturated fat diet decreases insulin sensitivity without changing intra-abdominal fat in weight-stable overweight and obese adults. AB - PURPOSE: We sought to determine the effects of dietary fat on insulin sensitivity and whether changes in insulin sensitivity were explained by changes in abdominal fat distribution or very low-density lipoprotein (VLDL) fatty acid composition. METHODS: Overweight/obese adults with normal glucose tolerance consumed a control diet (35 % fat/12 % saturated fat/47 % carbohydrate) for 10 days, followed by a 4 week low-fat diet (LFD, n = 10: 20 % fat/8 % saturated fat/62 % carbohydrate) or high-fat diet (HFD, n = 10: 55 % fat/25 % saturated fat/27 % carbohydrate). All foods and their eucaloric energy content were provided. Insulin sensitivity was measured by labeled hyperinsulinemic-euglycemic clamps, abdominal fat distribution by MRI, and fasting VLDL fatty acids by gas chromatography. RESULTS: The rate of glucose disposal (Rd) during low- and high-dose insulin decreased on the HFD but remained unchanged on the LFD (Rd-low: LFD: 0.12 +/- 0.11 vs. HFD: 0.37 +/- 0.15 mmol/min, mean +/- SE, p < 0.01; Rd-high: LFD: 0.11 +/- 0.37 vs. HFD: -0.71 +/- 0.26 mmol/min, p = 0.08). Hepatic insulin sensitivity did not change. Changes in subcutaneous fat were positively associated with changes in insulin sensitivity on the LFD (r = 0.78, p < 0.01) with a trend on the HFD (r = 0.60, p = 0.07), whereas there was no association with intra-abdominal fat. The LFD led to an increase in VLDL palmitic (16:0), stearic (18:0), and palmitoleic (16:1n7c) acids, while no changes were observed on the HFD. Changes in VLDL n-6 docosapentaenoic acid (22:5n6) were strongly associated with changes in insulin sensitivity on both diets (LFD: r = -0.77; p < 0.01; HFD: r = -0.71; p = 0.02). CONCLUSIONS: A diet very high in fat and saturated fat adversely affects insulin sensitivity and thereby might contribute to the development of type 2 diabetes. CLINICALTRIALS. GOV IDENTIFIER: NCT00930371. PMID- 26615404 TI - Ochrobactrum endophyticum sp. nov., isolated from roots of Glycyrrhiza uralensis. AB - A novel Gram-staining negative, motile, rod-shaped and aerobic bacterial strain, designated EGI 60010(T), was isolated from healthy roots of Glycyrrhiza uralensis F. collected from Yili County, Xinjiang Province, North-West China. The 16S rRNA gene sequence of strain EGI 60010(T) showed 97.2 % sequence similarities with Ochrobactrum anthropi ATCC 49188(T) and Ochrobactrum cytisi ESC1(T), and 97.1 % with Ochrobactrum lupini LUP21(T). The phylogenetic analysis based on 16S rRNA gene sequences showed that the new isolate clustered with members of the genera Ochrobactrum, and formed a distinct clade in the neighbour-joining tree. Q-10 was identified as the respiratory quinone for strain EGI 60010(T). The major fatty acids were summed feature 8 (C18:1 omega6c and/or C18:1 omega7c), C19:0 cyclo omega8c, summed feature 4 (C17:1 iso I/anteiso B) and C16:0. The polar lipids detected were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylglycerol and phosphatidylcholine. The DNA G+C content of strain EGI 60010(T) was determined to be 60.4 mol%. The genomic DNA relatedness values determined between strain EGI 60010(T) and the closely related strains O. anthropi JCM 21032(T), O. cytisi CCTCC AB2014258(T) and O. lupini NBRC 102587(T) were 50.3, 50.0 and 41.6 %, respectively. Based on the results of the molecular studies supported by its differentiating phenotypic characteristics, strain EGI 60010(T) was considered to represent a novel species within the genus Ochrobactrum, for which the name Ochrobactrum endophyticum sp. nov., is proposed. The type strain is EGI 60010(T) (=CGMCC 1.15082(T) = KCTC 42485(T) = DSM 29930(T)). PMID- 26615405 TI - The public debate on psychotropic medication and changes in attitudes 1990-2011. AB - Over the last 25 years, the appraisal of psychotropic drugs within the scientific community and their representation in the media has changed considerably. The initial optimism in the wake of the introduction of second-generation drugs has increasingly made room for a more critical evaluation of alleged advantages of these drugs. The question arises as to what extent this is reflected in similar changes in the public's attitudes towards psychiatric medication. Three representative population surveys on attitudes towards psychotropic medication were carried out in Germany in 1990 (N = 3075), 2001 (N = 2610) and 2011 (N = 1223), using the same sampling procedure, interview mode and instrument for assessing attitudes. In order to disentangle time-related effects, an age-period cohort analysis was performed. Over the time period of 21 years, the German public's evaluation of psychotropic medication has become markedly more favourable. This change was mostly due to a period effect, i.e. concurrent influences of the social environment people are exposed to. Changes were much more pronounced in the 1990s, while over the following decade only a small, although statistically significant, increase in the favourable appraisal of medication was found. Age and birth cohort had only a minor effect on public attitudes. Our findings suggest that changes in the evaluation of the effects of psychotropic drugs within the psychiatric community and their representation in the media also affect public opinion. Given the ongoing debate about side effects and efficacy of psychiatric medication, future changes of public opinion can be expected. PMID- 26615406 TI - Pharmacotherapy in Conjunction with a Diet and Exercise Program for the Treatment of Weight Recidivism or Weight Loss Plateau Post-bariatric Surgery: a Retrospective Review. AB - BACKGROUND: Bariatric surgery is an effective therapeutic option for management of obesity. However, weight recidivism (WR) and weight loss plateau (WLP) are common problems. We present our experience with the use of two pharmacotherapies in conjunction with our standard diet and exercise program in those patients who experienced WR or WLP. METHODS: From June 2010 to April 2014, bariatric surgery patients who experienced WR or WLP after undergoing Roux-en-Y gastric bypass (RYGB) or laparoscopic adjustable gastric banding (LAGB), and who were treated with phentermine (Ph) or phentermine-topiramate (PhT), were reviewed retrospectively. Generalized estimating equations were used to compare patient weights through 90 days between initial surgery type and medication type. Patient weights, medication side effect, and co-morbidities were collected during the first 90 days of therapy. RESULTS: Fifty-two patients received Ph while 13 patients received PhT. Overall, patients in both groups lost weight. Among those whose weights were recorded at 90 days, patients on Ph lost 6.35 kg (12.8% excess weight loss (EWL); 95% confidence interval (CI) 4.25, 8.44) and those prescribed PhT lost 3.81 kg (12.9% EWL; CI 1.08, 6.54). Adjusting for baseline weight, time since surgery, and visit through 90 days, patients treated with Ph weighed significantly less than those on PhT throughout the course of this study (1.35 kg lighter; 95% CI 0.17, 2.53; p = 0.025). There were no serious side effects reported. CONCLUSIONS: Phentermine and phentermine-topirimate in addition to diet and exercise appear to be viable options for weight loss in post-RYGB and LAGB patients who experience WR or WLP. PMID- 26615408 TI - Estimating human papillomavirus vaccination coverage among young women in Victoria and reasons for non-vaccination. AB - Background Adult Australian women aged 18 to 26 years were offered human papillomavirus (HPV) vaccine in a mass catch up campaign between 2007 and 2009. Not all doses administered were notified to Australia's HPV vaccine register and not all young women commenced or completed the vaccine course. METHODS: We surveyed vaccine age-eligible women as part of the Victorian Population Health Survey 2011-2012, a population based telephone survey, to ascertain self-reported vaccine uptake and reasons for non-vaccination or non-completion of vaccination among young women resident in the state of Victoria, Australia. RESULTS: Among 956 women surveyed, 62.3 per cent (57.8-66.6%) had been vaccinated against HPV and coverage with three doses was estimated at 53.7 per cent (49.1-58.2%). These estimates are higher than register-based estimates for the same cohort, which were 57.8 per cent and 37.2 per cent respectively. A lack of awareness about needing three doses and simply forgetting, rather than fear or experience of side effects, were the most common reasons for failure to complete all three doses. Among women who were not vaccinated, the most frequent reasons were not knowing the vaccine was available, perceiving they were too old to benefit, or not being resident in Australia at the time. CONCLUSIONS: It is likely that at least half of Victoria's young women were vaccinated during the catch-up program. This high level of coverage is likely to explain the marked reductions in HPV infection, genital warts and cervical disease already observed in young women in Victoria. PMID- 26615407 TI - Duodenojejunal Bypass Leads to Altered Gut Microbiota and Strengthened Epithelial Barriers in Rats. AB - BACKGROUND: Gastrointestinal bypass changes the gut microbiota and decreases systemic endotoxemia in obese subjects. Epithelial barrier integrity is crucial for confining enteric bacteria in the lumen and preventing gut-derived endotoxemia. The effect of bypass surgery on intestinal barrier functions remains poorly understood. This study aimed to evaluate the changes in intestinal permeability and gut barrier between rats receiving Roux-en-Y duodenojejunal bypass (DJB) or sham operation (SO). METHODS: Eighteen Sprague-Dawley rats were assigned to DJB or SO groups. Tissues of the alimentary, biliopancreatic, and common limbs in the small intestine, and the colon, were collected 2 weeks after operation. Mucosa-associated bacteria were quantified by colony forming units. Intestinal permeability was determined by mucosal-to-serosal dextran flux measured in Ussing chambers. Expression of occludin and proliferating cell nuclear antigen (PCNA) in the intestinal mucosa was examined by western blots. RESULTS: Enteric bacterial numbers were increased in the alimentary and common limbs after DJB. Reduced dextran permeability was found in the alimentary limb, common limb, and colon after DJB. Moreover, increased villus height and crypt depth were found to be associated with higher mucosal levels of occludin and PCNA levels in the alimentary and common limbs after DJB. CONCLUSIONS: DJB in rats altered gut microbiota and reduced intestinal permeability due to increased epithelial proliferation and tight junctional protein expression. Our results show that bypass surgery led to fortification of the intestinal barrier functions, which may provide an explanation for the decreased risk of systemic endotoxemia in postoperative patients. PMID- 26615409 TI - The importance of post hoc approaches for overcoming non-response and attrition bias in population-sampled studies. AB - Population-based health studies are critical resources for monitoring population health and related factors such as substance use, but reliable inference can be compromised in various ways. Non-response and attrition are major methodological problems which reduce power and can hamper the generalizability of findings if individuals who participate and who remain in a study differ systematically from those who do not. In this issue of SPPE, McCabe et al. studied participants of the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions, comparing attrition in Wave 2 across participants with different patterns of substance use at Wave 1. The implications of differential follow-up and further possibilities for addressing selective participation are discussed. PMID- 26615410 TI - Investigation of the association between Rho/Rho-kinase gene polymorphisms and systemic sclerosis. AB - Systemic sclerosis (SSc) is a disease characterized by inflammation, vascular abnormalities and fibrosis. The role of Rho/Rho-kinase pathway was demonstrated in the pathogenesis of fibrosis, inflammation and vascular abnormalities. This study was aimed to investigate the relation between SSc and Rho/Rho-kinase gene polymorphisms. The study included 339 patients with SSc and 302 healthy subjects who were apparently healthy and at similar age and gender. Genotype distributions and allele frequencies were detected by using Chi-square test or Fisher's exact Chi-square test between groups, and the haplotype analysis was applied using online program (SHEsis). Significant association was found in a polymorphism in the ROCK1 gene (rs35996865), a polymorphism in ROCK2 gene (rs10178332), a polymorphism in RhoA gene (rs2177268) and two polymorphisms in RhoC gene (rs11102522 and rs11538960) with SSc disease (p < 0.0022). In this study, association between SSc disease and Rho/Rho-kinase gene polymorphisms was investigated for the first time; significant associations between ROCK1, ROCK2, RhoA and RhoC gene polymorphisms and SSc disease were demonstrated. The results strongly suggest that this SNP may be an important risk factor for development of SSc. However, further validation of these findings in an independent cohort is necessary. PMID- 26615411 TI - Obstetric brachial plexus palsy: reviewing the literature comparing the results of primary versus secondary surgery. AB - Obstetric brachial plexus injuries (OBPP) are a relatively common stretch injury of the brachial plexus that occurs during delivery. Roughly 30 % of patients will not recover completely and will need a surgical repair. Two main treatment strategies have been used: primary surgery, consisting in exploring and reconstructing the affected portions of the brachial plexus within the first few months of the patient's life, and secondary procedures that include tendon or muscle transfers, osteotomies, and other orthopedic techniques. Secondary procedures can be done as the only surgical treatment of OBPP or after primary surgery, in order to minimize any residual deficits. Two things are crucial to achieving a good outcome: (1) the appropriate selection of patients, to separate those who will spontaneously recover from those who will recover only partially or not at all; and (2) a good surgical technique. The objective of the present review is to assess the published literature concerning certain controversial issues in OBPP, especially in terms of the true current state of primary and secondary procedures, their results, and the respective roles each plays in modern-day treatment of this complex pathology. Considerable published evidence compiled over decades of surgical experience favors primary nerve surgery as the initial therapeutic step in patients who do not recover spontaneously, followed by secondary surgeries for further functional improvement. As described in this review, the results of such treatment can greatly ameliorate function in affected limbs. For best results, multi-disciplinary teams should treat these patients. PMID- 26615412 TI - Correspondence in Stakeholder Assessment of Health, Work Capacity and Sick Leave in Workers with Comorbid Subjective Health Complaints? A Video Vignette Study. AB - Purpose The purpose of this study is to test if there is correspondence in stakeholders' assessments of health, work capacity and sickness certification in four workers with comorbid subjective health complaints based on video vignettes. Methods A cross sectional survey among stakeholders (N = 514) in Norway in 2009/2010. Logistic regression and multinomial logistic regression was used to obtain the estimated probability of stakeholders choosing 100 % sick leave, partial sick leave or work and the estimation of odds ratio of stakeholder assessment compared to the other stakeholders for the individual worker. Results The supervisors were less likely to assess poor health and reduced work capacity, and more likely to suggest partial sick leave and full time work compared to the GPs for worker 1. The public was less likely to assess comorbidity and reduced work capacity, and 6 and 12 times more likely to suggest partial sick leave and full time work compared to the GPs for worker 1. Stakeholders generally agreed in their assessments of workers 2 and 3. The public was more likely to assess poor health, comorbidity and reduced work capacity, and the supervisors more likely to assess comorbidity and reduced work capacity, compared to the GPs for worker 4. Compared to the GPs, all other stakeholders were less likely to suggest full time work for this worker. Conclusions Our results seem to suggest that stakeholders have divergent assessments of complaints, health, work capacity, and sickness certification in workers with comorbid subjective health complaints. PMID- 26615413 TI - Extracellular Iron is a Modulator of the Differentiation of Osteoclast Lineage Cells. AB - Osteoclasts originate from the hematopoietic stem cell and share a differentiation pathway with the cells of the monocyte/macrophage lineages. Development and activation of osteoclasts, and as a consequence regulation of bone resorption, depend on two growth factors: macrophage colony-stimulating factor and receptor activator of NF-kappaB ligand. Furthermore, cell development and activity are modulated by a microenvironment composed of cytokines and growth factors and of the extracellular matrix. Membrane transporters are a means for cells to interact with their environment. Within this study, the expression of proteins regulating cellular iron homeostasis in osteoclast-like cells grown from bone marrow-derived progenitors was compared to the expression of this set of proteins by monocyte/macrophage lineage cells. In differentiating osteoclasts, levels of transcripts encoding transferrin receptor 1 and divalent metal transporter 1 (Slc11A2) were increased, while levels of transcripts encoding ferroportin (Slc40A1) and natural resistance-associated macrophage protein 1 (Slc11A1) were decreased. Supplementation of the culture media with exogenous iron led to an increase in the proliferation of osteoclast progenitor cells and to the expression of a macrophage-like phenotype, while the development of osteoclasts was reduced. Upon transfer of mature OC onto a CaP substrate, iron depletion of the medium with the Fe(3+)-chelator Deferoxamine Mesylate decreased CaP dissolution by ~30 %, which could be restored by addition of exogenous iron. During the 24 h of the assay, no effects were observed on total TRAP activity. The data demonstrate transcriptional regulation of the components of cellular iron transporters during OC development and suggests that iron homeostasis may contribute to fine-tuning of the RANKL-induced OC development. PMID- 26615414 TI - Controlling the feed rate of propanol to optimize erythromycin fermentation by on line capacitance and oxygen uptake rate measurement. AB - The aim of the present study was to optimize the feeding proportion of glucose and propanol for erythromycin biosynthesis by real-time monitoring and exploring its limited ratio by the on-line multi-frequency permittivity measurement. It was found that the capacitance values were sensitive to the variation of biomass concentration and microbial morphology as well as the true state of cell growth. It was most favorable to both cell growth and secondary metabolism to keep the ratio of glucose to propanol at 4.3 (g/g). The specific growth rate calculated by the capacitance measurement correctly and accurately reflected the cell physiological state. An appropriate feed rate of propanol was crucial for cell growth and secondary metabolism, as well as to improve the quality of erythromycin-A. In addition, the erythromycin production titer (10,950 U/mL) was further enhanced by 4 % when the propanol feed was regulated by step-down strategy based on both OUR (oxygen uptake rate) and the on-line monitoring capacitance. PMID- 26615415 TI - Enhanced butanol production in a microbial electrolysis cell by Clostridium beijerinckii IB4. AB - Reducing power such as NADH is an essential factor for acetone/butanol/ethanol (ABE) fermentation using Clostridium spp. The objective of this study was to increase available NADH in Clostridium beijerinckii IB4 by a microbial electrolysis cell (MEC) with an electron carrier to enhance butanol production. First of all, a MEC was performed without electron carrier to study the function of cathodic potential applying. Then, various electron carriers were tested, and neutral red (NR)-amended cultures showed an increase of butanol concentration. Optimal NR concentration (0.1 mM) was used to add in a MEC. Electricity stimulated the cell growth obviously and dramatically diminished the fermentation time from 40 to 28 h. NR and electrically reduced NR improved the final butanol concentration and inhibited the acetone generation. In the MEC with NR, the butanol concentration, yield, proportion and productivity were increased by 12.2, 17.4, 7.2 and 60.3 %, respectively. To further understand the mechanisms of NR, cathodic potential applying and electrically reduced NR, NADH and NAD(+) levels, ATP levels and hydrogen production were determined. NR and electrically reduced NR also improved ATP levels and the ratio of NADH/NAD(+), whereas they decreased hydrogen production. Thus, the MEC is an efficient method for enhancing the butanol production. PMID- 26615416 TI - Do monkeys compare themselves to others? AB - Social comparisons are a fundamental characteristic of human behaviour, yet relatively little is known about their evolutionary foundations. Adapting the co acting paradigm from human research (Seta in J Pers Soc Psychol 42:281-291, 1982. doi: 10.1037//0022-3514.42.2.281), we examined how the performance of a partner influenced subjects' performance in long-tailed macaques (Macaca fascicularis). Using parallel testing in touch screen setups in which subjects had to discriminate familiar and novel photographs of men and women, we investigated whether accuracy and reaction time were influenced by partner performance and relationship quality (affiliate vs. non-affiliate). Auditory feedback about the alleged performance of the co-actor was provided via playback; partner performance was either moderately or extremely better or worse than subject performance. We predicted that subjects would assimilate to moderately different comparison standards as well as to affiliates and contrast away from extreme standards and non-affiliates. Subjects instantly generalized to novel pictures. While accuracy was not affected by any of the factors, long reaction times occurred more frequently when subjects were tested with a non-affiliate who was performing worse, compared to one who was doing better than them (80% quantile worse: 5.1, better: 4.3 s). For affiliate co-actors, there was no marked effect (worse: 4.4, better: 4.6 s). In a control condition with no auditory feedback, subjects performed somewhat better in the presence of affiliates (M = 77.8% correct) compared to non-affiliates (M = 71.1%), while reaction time was not affected. Apparently, subjects were sensitive to partner identity and performance, yet variation in motivation rather than assimilation and contrast effects may account for the observed effects. PMID- 26615417 TI - In Vitro Activities of Five Antifungal Drugs Against Opportunistic Agents of Aspergillus Nigri Complex. AB - Black aspergilli, particularly Aspergillus niger and A. tubingensis, are the most common etiological agents of otomycosis followed by onychomycosis, pulmonary aspergillosis and aspergilloma. However, so far there is no systematic study on their antifungal susceptibility profiles. A collection of 124 clinical and environmental species of black aspergilli consisted of A. niger, A. tubingensis, A. uvarum. A. acidus and A. sydowii were verified by DNA sequencing of the partial beta-tubulin gene. MICs of amphotericin B, itraconazole, voriconazole, posaconazole, and MECs of caspofungin were performed based on CLSI M38-A2. Posaconazole and caspofungin had the lowest MIC range (0.016-0.125 ug/ml and 0.008-0.031 ug/ml, respectively), followed by amphotericin B (0.25-4 ug/ml), voriconazole (0.125-16 ug/ml) and itraconazole (0.25 to >16) in an increasing order. Some strains of A. niger showed high MIC value for itraconazole and voriconazole (>16 ug/ml), in contrast only environmental isolates of A. tubingensis had high itraconazole MICs (>16 ug/ml). These results confirm that posaconazole and caspofungin are potential drugs for treatment of aspergillosis due to opportunistic agents of Aspergillus Nigri complex. However, in vivo efficacy remains to be determined. PMID- 26615418 TI - Association between interleukin 8 -251 A/T and +781 C/T polymorphisms and osteosarcoma risk in Chinese population: a case-control study. AB - Interleukin-8 (IL-8) is an angiogenic chemokine that plays a potent role in both development and progression of many human malignancies. However, there are no data about the role of IL-8 polymorphism in development of osteosarcoma. A hospital-based case-control study was conducted among 190 patients with osteosarcoma and 190 healthy controls to investigate the possible association between the IL-8 -251 A/T and +781 C/T polymorphisms, respectively, and the risk of osteosarcoma. Significant differences of genotype distribution were observed between osteosarcoma cases and controls at the IL-8 -251T/A genotypes. Compared with the IL-8 -251T/A homozygote TT, the heterozygous TA genotype was associated with significantly increased risk for osteosarcoma (odds ratio (OR) = 2.16, 95 % confidence interval (CI) = (1.38-4.52), P = 0.021); the AA genotype was associated with increased risk for osteosarcoma (OR = 1.94, 95 % CI = 1.31-3.83, P = 0.018). TA and AA combined variants were associated with increased risk for osteosarcoma compared with the TT genotype (OR = 1.72, 95 % CI = 1.45-4.41, P = 0.023). Moreover, the genotype AA of IL-8 -251T/A carried a higher risk of osteosarcoma metastasis and later Enneking stages, compared with the TT genotype. However, the genotype and allele frequencies of IL-8 +781 C/T polymorphisms in osteosarcoma patients were not significantly different from controls. Our results showed that the IL-8 -251 A/T genotype was associated with increased risk for development and metastasis of osteosarcoma in Chinese Han population. PMID- 26615419 TI - Association of FokI polymorphism of vitamin D receptor with urothelial bladder cancer in Tunisians: role of tobacco smoking and plasma vitamin D concentration. AB - The aim of the study was to test whether the VDR FokI polymorphism is associated with the risk of urothelial bladder cancer (UBC) in Tunisians. The study included 200 unrelated patients with UBC and 200 healthy controls. Genotyping of the VDR FokI polymorphism was determined by PCR-RFLP method. Plasma 25-hydroxyvitamin D concentrations were measured by immunoassay. Binary logistic regression model was applied to test how the association of VDR FokI polymorphism is independent of potential confounding factors. Genotype distribution (FF, 45 vs. 55 %; Ff, 52.1 vs. 47.9 %, and ff, 12 vs. 5.5 %, respectively) and allele frequencies (F, 66.5 vs. 74.8 % and f, 33.5 vs. 25.2 %, respectively) were significantly different between UBC patients and controls. The "ff" genotype [OR (95 % CI), 2.66 (1.24 5.73); p = 0.012] and "f" allele [1.49 (1.09-2.02); p = 0.010] were associated with increased risk of UBC. The association remained significant in multivariate analysis. Stratified analyses showed that VDR FokI polymorphism is only associated with UBC risk in ever-smokers, subjects exposed to chemical carcinogens and those with plasma 25-hydroxyvitamin D over 12 MUg/L. The "f" allele of VDR FokI polymorphism is associated with a higher risk of UBC in Tunisians, especially in smokers as well as subjects with occupational exposition and subjects without vitamin D deficiency. These results should be replicated in other ethnic groups and the influence of other genetic factors and environments on this association should be investigated. PMID- 26615420 TI - The alkyllysophospholipid edelfosine enhances TRAIL-mediated apoptosis in gastric cancer cells through death receptor 5 and the mitochondrial pathway. AB - The ether phospholipid edelfosine is the prototype of a group of synthetic antitumor alkyllysophospholipid (ALP) compounds that exert pro-apoptotic effects in various types of cancer cells through cell type-dependent mechanisms. In this study, we examined the antitumor effect of edelfosine in human gastric cancer cells. Edelfosine decreased cell viability and induced autophagic death at a moderate concentration (~30 MUM), whereas it induced apoptotic cell death at concentrations over 30 MUM. Interestingly, low concentrations of edelfosine (5-10 MUM) effectively enhanced recombinant human tumor necrosis factor (TNF)-related apoptosis-inducing ligand (rhTRAIL/TNFSF10)-induced apoptosis and clonogenicity in gastric cancer cells, including TRAIL-resistant AGS cells. Edelfosine upregulated the protein level of death receptor 5 (DR5/TNFRSF10B) and/or increased DR5 upregulation in lipid rafts. In addition, edelfosine-mediated rhTRAIL sensitization was regulated by the DR5 pathway. Edelfosine also activated p38MAPK (MAPK14), and edelfosine-mediated rhTRAIL sensitization was partially regulated by a p38-mediated decrease in mitochondrial membrane potential. This study suggests a novel therapeutic strategy targeting gastric cancer cells by using the combination of edelfosine and TRAIL. PMID- 26615421 TI - Functional characterization of the tumor suppressor CMTM8 and its association with prognosis in bladder cancer. AB - Previous research revealed that CMTM8 acts as a tumor suppressor gene in variety cancers. However, the role of CMTM8 in bladder cancer has never been reported. In this study, the expression profile of CMTM8 was examined in bladder cancer tissues and bladder cancer cell lines. The effects of CMTM8 on bladder cancer cell proliferation, apoptosis, migration, and invasion were examined. Bladder tumor tissues from 84 cases were examined for CMTM8 expression by immunohistochemistry. Disease-specific survival was investigated using a Kaplan Meier analysis, and Cox proportional hazards analysis was assessed. Our results showed that upregulation of CMTM8 in the T24 cell line could suppress T24 cells proliferation, migration and invasion and enhance the sensitivity to Epirubicin. Kaplan-Meier analysis revealed that the expression of CMTM8 was correlated with the survival time of bladder cancer patients. Altogether, our data suggested that CMTM8 is an important tumor suppressor gene in human bladder cancer and qualified as a useful prognostic indicator for patients with bladder cancer. PMID- 26615422 TI - 13-Oxyingenol dodecanoate, a cytotoxic ingenol derivative, induces mitochondrial apoptosis and caspase-dependent Akt decrease in K562 cells. AB - 13-Oxyingenol dodecanoate (13OD) is an ingenol derivative prepared from Chinese traditional medicine Euphorbia kansui without any report about its bioactivity. The present study demonstrated for the first time that 13OD displayed potent cytotoxicity against chronic myeloid leukemia K562 cells in vitro. 13OD inhibited proliferation, induced G2/M phase arrest, and exhibited potent apoptotic activity in K562 cells. In K562 cells, 13OD disrupted the mitochondrial membrane potential and induced high level of ROS, which played an indispensable role in 13OD-induced apoptosis. Further investigations on the molecular mechanisms revealed that total Akt protein level was decreased in a caspase-dependent way after treatment with 13OD; in addition, ERK was activated by 13OD, and this activation played a protective role in 13OD stimulation. Altogether, these results revealed that the cytotoxic ingenol derivative 13OD induced apoptosis with novel mechanisms for the proapoptotic function in cancer cells, and suggested that 13OD may serve as a lead template for rational drug design and for future anticancer agent development. PMID- 26615423 TI - Upregulation of centrosomal protein 55 is associated with unfavorable prognosis and tumor invasion in epithelial ovarian carcinoma. AB - Centrosomal protein 55 (CEP55) is a cell cycle regulator implicated in development of certain cancers. However, characteristics of CEP55 expression and its clinical/prognostic significance are unclear in human epithelial ovarian carcinoma (EOC). Therefore, we investigated the expression and clinicopathological significance of CEP55 in patients with EOC and its role in regulating invasion and metastasis of ovarian cell lines. CEP55 mRNA and protein expression levels were detected by quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemistry (IHC). Potential associations of CEP55 expression scores with clinical parameters and patient survival were evaluated. CEP55 function was investigated further using RNA interference, wound healing assay, transwell assay, immunofluorescence analysis, qRT-PCR, and Western blotting. CEP55 was significantly upregulated in ovarian cancer cell lines and lesions compared with normal cells and adjacent noncancerous ovarian tissues. In the 213 EOC samples, CEP55 protein levels were positively correlated with clinical stage (P < 0.001), lymph node metastasis (P < 0.001), intraperitoneal metastasis (P < 0.001), tumor recurrence (P < 0.001), differentiation grade (P < 0.001), residual tumor size (P < 0.001), ascites see tumor cells (P = 0.020), and serum CA153 level (P < 0.001). Moreover, patients with aberrant CEP55 protein expression showed tendencies to receive neoadjuvant chemotherapy (P < 0.001) and cytoreductive surgery (P = 0.020). By contrast, no significant correlation was detected between the protein levels and patient age, histological type, or serum CA125, CA199, CA724, NSE, CEA, and beta-HCG levels. Patients with high CEP55 protein expression had shorter overall survival and disease-free survival compared with those with low CEP55 expression. Multivariate analysis implicated CEP55 as an independent prognostic indicator for EOC patients. Additionally, downregulation of CEP55 in ovarian cancer cells remarkably inhibited cellular motility and invasion. Aberrant CEP55 expression may predict unfavorable clinical outcomes in EOC patients and play an important role in regulating invasion in ovarian cancer cells. Thus, CEP55 may serve as a prognostic marker and therapeutic target for EOC. PMID- 26615424 TI - MiR-145 suppresses cell proliferation and motility by inhibiting ROCK1 in hepatocellular carcinoma. AB - MicroRNAs (miRNAs) play key roles in cancer development and progression. In the present study, we investigated the role of miR-145 in the progression of hepatocellular carcinoma (HCC). Ten HCC cell lines and samples from 96 patients with HCC were analyzed for the expression of miR-145 by quantitative real-time polymerase chain reaction (qRT-PCR). Overexpression of miR-145 was established by transfecting mimics into HepG2 and QGY-7703 cells. Cell proliferation and cell migration were assessed by cell viability assay and transwell assay. Western blot was to verify ROCK1 as a novel target gene of miR-145. Our results showed that miR-145 was frequently downregulated in HCC tumors and cell lines. Overexpression of miR-145 in HCC cell lines significantly inhibited cell proliferation, migration, and invasion in vitro. ROCK1 was identified as a target of miR-145, and ectopic expression of miR-145 downregulated ROCK1. Together, these findings indicate that miR-145 acts as a tumor suppressor and its downregulation in tumor tissues may contribute to the progression and metastasis of HCC through a mechanism involving ROCK1, suggesting miR-145 as a potential new diagnostic and therapeutic target for the treatment of HCC. PMID- 26615425 TI - Isolation and characterization of heavy polycyclic aromatic hydrocarbon-degrading bacteria adapted to electrokinetic conditions. AB - Polycyclic aromatic hydrocarbon (PAH)-degrading bacteria capable of growing under electrokinetic conditions were isolated using an adjusted acclimation and enrichment procedure based on soil contaminated with heavy PAHs in the presence of an electric field. Their ability to degrade heavy PAHs under an electric field was individually investigated in artificially contaminated soils. The results showed that strains PB4 (Pseudomonas fluorescens) and FB6 (Kocuria sp.) were the most efficient heavy PAH degraders under electrokinetic conditions. They were re inoculated into a polluted soil from an industrial site with a PAH concentration of 184.95 mg kg(-1). Compared to the experiments without an electric field, the degradation capability of Pseudomonas fluorescens and Kocuria sp. was enhanced in the industrially polluted soil under electrokinetic conditions. The degradation extents of total PAHs were increased by 15.4 and 14.0% in the electrokinetic PB4 and FB6 experiments (PB4 + EK and FB6 + EK) relative to the PB4 and FB6 experiments without electrokinetic conditions (PB4 and FB6), respectively. These results indicated that P. fluorescens and Kocuria sp. could efficiently degrade heavy PAHs under electrokinetic conditions and have the potential to be used for the electro-bioremediation of PAH-contaminated soil, especially if the soil is contaminated with heavy PAHs. PMID- 26615426 TI - Chemical Strategies of the Beetle Metoecus Paradoxus, Social Parasite of the Wasp Vespula Vulgaris. AB - The parasitoid beetle Metoecus paradoxus frequently parasitizes colonies of the common wasp, Vespula vulgaris. It penetrates a host colony as a larva that attaches itself onto a foraging wasp's body and, once inside the nest, it feeds on a wasp larva inside a brood cell and then pupates. Avoiding detection by the wasp host is crucial when the beetle emerges. Here, we tested whether adult M. paradoxus beetles avoid detection by mimicking the cuticular hydrocarbon profile of their host. The beetles appear to be chemically adapted to their main host species, the common wasp, because they share more hydrocarbon compounds with it than they do with the related German wasp, V. germanica. In addition, aggression tests showed that adult beetles were attacked less by common wasp workers than by German wasp workers. Our results further indicated that the host-specific compounds were, at least partially, produced through recycling of the prey's hydrocarbons, and were not acquired through contact with the adult host. Moreover, the chemical profile of the beetles shows overproduction of the wasp queen pheromone, nonacosane (n-C29), suggesting that beetles might mimic the queen's pheromonal bouquet. PMID- 26615427 TI - Semantic annotation of 3D anatomical models to support diagnosis and follow-up analysis of musculoskeletal pathologies. AB - PURPOSE: While 3D patient-specific digital models are currently available, thanks to advanced medical acquisition devices, there is still a long way to go before these models can be used in clinical practice. The goal of this paper is to demonstrate how 3D patient-specific models of anatomical parts can be analysed and documented accurately with morphological information extracted automatically from the data. Part-based semantic annotation of 3D anatomical models is discussed as a basic approach for sharing and reusing knowledge among clinicians for next-generation CAD-assisted diagnosis and treatments. METHODS: We have developed (1) basic services for the analysis of 3D anatomical models and (2) a methodology for the enrichment of such models with relevant descriptions and attributes, which reflect the parameters of interest for medical investigations. The proposed semantic annotation is ontology-driven and includes both descriptive and quantitative labelling. Most importantly, the developed methodology permits to identify and annotate also parts-of-relevance of anatomical entities. RESULTS: The computational tools for the automatic computation of qualitative and quantitative parameters have been integrated in a prototype system, the SemAnatomy3D framework, which demonstrates the functionalities needed to support effective annotation of 3D patient-specific models. From the first evaluation, SemAnatomy3D appears as an effective tool for clinical data analysis and opens new ways to support clinical diagnosis. CONCLUSIONS: The SemAnatomy3D framework integrates several functionalities for 3D part-based annotation. The idea has been presented and discussed for the case study of rheumatoid arthritis of carpal bones; however, the framework can be extended to support similar annotations in different clinical applications. PMID- 26615428 TI - A novel platform for electromagnetic navigated ultrasound bronchoscopy (EBUS). AB - PURPOSE: Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) of mediastinal lymph nodes is essential for lung cancer staging and distinction between curative and palliative treatment. Precise sampling is crucial. Navigation and multimodal imaging may improve the efficiency of EBUS-TBNA. We demonstrate a novel EBUS-TBNA navigation system in a dedicated airway phantom. METHODS: Using a convex probe EBUS bronchoscope (CP-EBUS) with an integrated sensor for electromagnetic (EM) position tracking, we performed navigated CP-EBUS in a phantom. Preoperative computed tomography (CT) and real-time ultrasound (US) images were integrated into a navigation platform for EM navigated bronchoscopy. The coordinates of targets in CT and US volumes were registered in the navigation system, and the position deviation was calculated. RESULTS: The system visualized all tumor models and displayed their fused CT and US images in correct positions in the navigation system. Navigating the EBUS bronchoscope was fast and easy. Mean error observed between US and CT positions for 11 target lesions (37 measurements) was [Formula: see text] mm, maximum error was 5.9 mm. CONCLUSION: The feasibility of our novel navigated CP-EBUS system was successfully demonstrated. An EBUS navigation system is needed to meet future requirements of precise mediastinal lymph node mapping, and provides new opportunities for procedure documentation in EBUS-TBNA. PMID- 26615429 TI - Automatic 3D reconstruction of electrophysiology catheters from two-view monoplane C-arm image sequences. AB - PURPOSE: Catheter guidance is a vital task for the success of electrophysiology interventions. It is usually provided through fluoroscopic images that are taken intra-operatively. The cardiologists, who are typically equipped with C-arm systems, scan the patient from multiple views rotating the fluoroscope around one of its axes. The resulting sequences allow the cardiologists to build a mental model of the 3D position of the catheters and interest points from the multiple views. METHOD: We describe and compare different 3D catheter reconstruction strategies and ultimately propose a novel and robust method for the automatic reconstruction of 3D catheters in non-synchronized fluoroscopic sequences. This approach does not purely rely on triangulation but incorporates prior knowledge about the catheters. In conjunction with an automatic detection method, we demonstrate the performance of our method compared to ground truth annotations. RESULTS: In our experiments that include 20 biplane datasets, we achieve an average reprojection error of 0.43 mm and an average reconstruction error of 0.67 mm compared to gold standard annotation. CONCLUSIONS: In clinical practice, catheters suffer from complex motion due to the combined effect of heartbeat and respiratory motion. As a result, any 3D reconstruction algorithm via triangulation is imprecise. We have proposed a new method that is fully automatic and highly accurate to reconstruct catheters in three dimensions. PMID- 26615430 TI - Estimating needle tip deflection in biological tissue from a single transverse ultrasound image: application to brachytherapy. AB - PURPOSE: This paper proposes a method to predict the deflection of a flexible needle inserted into soft tissue based on the observation of deflection at a single point along the needle shaft. METHODS: We model the needle-tissue as a discretized structure composed of several virtual, weightless, rigid links connected by virtual helical springs whose stiffness coefficient is found using a pattern search algorithm that only requires the force applied at the needle tip during insertion and the needle deflection measured at an arbitrary insertion depth. Needle tip deflections can then be predicted for different insertion depths. RESULTS: Verification of the proposed method in synthetic and biological tissue shows a deflection estimation error of [Formula: see text]2 mm for images acquired at 35 % or more of the maximum insertion depth, and decreases to 1 mm for images acquired closer to the final insertion depth. We also demonstrate the utility of the model for prostate brachytherapy, where in vivo needle deflection measurements obtained during early stages of insertion are used to predict the needle deflection further along the insertion process. CONCLUSION: The method can predict needle deflection based on the observation of deflection at a single point. The ultrasound probe can be maintained at the same position during insertion of the needle, which avoids complications of tissue deformation caused by the motion of the ultrasound probe. PMID- 26615431 TI - Mechanisms of Apoptosis. AB - Nearly 15 types of programmed cell death (PCD) have been identified to date. Among them, apoptosis is the most common and well-studied type of PCD. In this review, we discuss different apoptotic pathways in which plasma membrane and membrane organelles, such as mitochondria, endoplasmic reticulum, Golgi apparatus, lysosomes, and nucleus play the pivotal role. Data concerning caspase cascades involved in these mechanisms are described. Various apoptosis induction mechanisms are analyzed and compared. The close relations between them and the possibility of switching from one pathway to another are demonstrated. In most cases, the result of these pathways is mitochondrial membrane permeabilization and/or caspase activation. These two events are closely linked and serve as the central point of integration of the apoptotic cell death pathways. PMID- 26615432 TI - Aging Epigenetics: Accumulation of Errors or Realization of a Specific Program? AB - Aging in mammals is known to be accompanied by a progressive loss of methylated cytosines from DNA. This loss is tissue-specific to a certain extent and affects mainly repeated sequences, transposable elements, and intergenic genome parts. Age-dependent DNA hypomethylation is correlated with and perhaps partly caused by a diminished activity of DNA methyltransferases. Along with the global DNA demethylation during aging, hypermethylation of certain genes occurs. On the whole-genome scale, an age-dependent hypermethylation is typical for genes associated with promoter CG islands, whereas hypomethylation mostly affects CG poor genes, besides the repeated sequences, transposable elements, and intergenic genome parts mentioned above. The methylation levels of certain CG sites display strict correlation to age and thus could be used as a molecular marker to predict biological age of cells, tissues, and organisms. Epigenetic cell reprogramming, such as induced pluripotent stem cell production, leads to complete resetting of their epigenetic age. PMID- 26615433 TI - Mitochondrial Matrix Processes. AB - Mitochondria possess their own genome that, despite its small size, is critically important for their functioning, as it encodes several dozens of RNAs and proteins. All biochemical processes typical for bacterial and nuclear DNA are described in mitochondrial matrix: replication, repair, recombination, and transcription. Commonly, their mechanisms are similar to those found in bacteria, but they are characterized by several unique features. In this review, we provide an overall description of mitochondrial matrix processes paying special attention to the typical features of such mechanisms. PMID- 26615434 TI - Small Noncoding 6S RNAs of Bacteria. AB - Small noncoding RNAs (ncRNAs) are non-translated transcripts with lengths below 300 nucleotide residues. Regulation of cellular processes under the influence of these ncRNAs is the most various in eukaryotic cells, but numerous ncRNAs are also found in bacteria. One of the best-known small prokaryotic ncRNAs is 6S RNA it has been detected in all branches of bacteria. Due to their conserved secondary structure including a large central "loop" flanked by long double helical arms, 6S RNAs can bind holoenzymes of RNA polymerase (RNAP) and inhibit their activity. This inhibits transcription of many genes. According to data of comparative transcriptome analysis, the 6S RNA-dependent regulation of transcription affects the expression level of hundreds of genes involved in various cellular processes. 6S RNA has the unique feature of serving as a transcription template for the synthesis of short product RNAs (pRNAs) complementary to the central part of the molecule. The length and abundance of pRNAs vary depending on the physiological status of the cell. The synthesis of pRNAs is of great importance because it releases RNAP and provides reversibility of the inhibition. A similar mechanism has been described for the noncoding mouse B2 RNA that inhibits the activity of RNAP II. This finding can be taken as evidence for the common evolutionary origin of the ncRNA-dependent regulation of RNAP and its immense significance for cells. This review summarizes the state of knowledge about the main features and functions of 6S RNAs from various bacterial species with a special focus on the peculiarities of pRNA synthesis. The majority of functional insights on 6S RNAs have been gained for E. coli 6S RNA as the best studied model system. PMID- 26615435 TI - Regulation of Flagellar Gene Expression in Bacteria. AB - The flagellum of a bacterium is a supramolecular structure of extreme complexity comprising simultaneously both a unique system of protein transport and a molecular machine that enables the bacterial cell movement. The cascade of expression of genes encoding flagellar components is closely coordinated with the steps of molecular machine assembly, constituting an amazing regulatory system. Data on structure, assembly, and regulation of flagellar gene expression are summarized in this review. The regulatory mechanisms and correlation of the process of regulation of gene expression and flagellum assembly known from the literature are described. PMID- 26615436 TI - Mitochondrial Fission and Fusion. AB - Mitochondria are key cellular organelles responsible for many different functions. The molecular biology of mitochondria is continuously subject to comprehensive studies. However, detailed mechanisms of mitochondrial biogenesis are still unclear. Fusion and fission are among the most enigmatic processes connected with mitochondria. On the other hand, it has been shown that these events are of great biological importance for functioning of living cells. In this review, we summarize existing molecular data on mitochondrial dynamics and discuss possible biological functions of fusion and fission of these organelles. PMID- 26615437 TI - StructAlign, a Program for Alignment of Structures of DNA-Protein Complexes. AB - Comparative analysis of structures of complexes of homologous proteins with DNA is important in the analysis of DNA-protein recognition. Alignment is a necessary stage of the analysis. An alignment is a matching of amino acid residues and nucleotides of one complex to residues and nucleotides of the other. Currently, there are no programs available for aligning structures of DNA-protein complexes. We present the program StructAlign, which should fill this gap. The program inputs a pair of complexes of DNA double helix with proteins and outputs an alignment of DNA chains corresponding to the best spatial fit of the protein chains. PMID- 26615438 TI - Stages of Cell Cannibalism--Entosis--in Normal Human Keratinocyte Culture. AB - Entosis is a type of cell cannibalism during which one cell penetrates into another cell and usually dies inside it. Researchers mainly pay attention to initial and final stages of entosis. Besides, tumor cells in suspension are the primary object of studies. In the present study, we investigated morphological changes of both cells-participants of entosis during this process. The substrate dependent culture of human normal keratinocytes HaCaT was chosen for the work. A combination of light microscopy and scanning electron microscopy was used to prove that one cell was completely surrounded by the plasma membrane of another cell. We investigated such "cell-in-cell" structures and described the structural and functional changes of both cells during entosis. The outer cell nucleus localization and shape were changed. Gradual degradation of the inner cell nucleus and of the junctions between the inner and the outer cells was revealed. Moreover, repeated redistribution of the outer cell membrane organelles (Golgi apparatus, lysosomes, mitochondria, and autophagosomes), rearrangement of its cytoskeleton, and change in the lysosomal, autophagosomal, and mitochondrial state in both entotic cells were observed during entosis. On the basis of these data, we divided entosis into five stages that make it possible to systematize description of this type of cell death. PMID- 26615439 TI - A Rapid and Cost-Effective Method for DNA Extraction from Archival Herbarium Specimens. AB - Here we report a rapid and cost-effective method for the extraction of total DNA from herbarium specimens up to 50-90-year-old. The method takes about 2 h, uses AMPure XP magnetic beads diluted by PEG-8000- containing buffer, and does not require use of traditional volatile components like chloroform, phenol, and liquid nitrogen. It yields up to 4 ug of total nucleic acid with high purity from about 30 mg of dry material. The quality of the extracted DNA was tested by PCR amplification of 5S rRNA and rbcL genes (nuclear and chloroplast DNA markers) and compared against the traditional chloroform/isoamyl alcohol method. Our results demonstrate that the use of the magnetic beads is crucial for extraction of DNA suitable for subsequent PCR from herbarium samples due to the decreasing inhibitor concentrations, reducing short fragments of degraded DNA, and increasing median DNA fragment sizes. PMID- 26615440 TI - Structure of Intergenic Spacer IGS1 of Ribosomal Operon from Schistidium Mosses. AB - The structure of the intergenic spacer 1 (IGS1) of the ribosomal operon from 12 species of Schistidium mosses was studied. In the IGS1 sequences of these species, three conserved regions and two areas of GC- and A-enriched repeats were identified. All of the studied mosses have a conserved pyrimidine-enriched motif at the 5'-end of IGS1. Species-specific nucleotide substitutions and insertions were found in the conserved areas. The repeated units contain single nucleotide substitutions that make unique the majority of repeated units. The positions of such repeats in IGS1 are species-specific, but their number can vary within the species and among operons of the same specimen. The comparison of IGS1 sequences from the Schistidium species and from representatives of ten other moss genera revealed the presence of common conserved motifs with similar localization. Presumably, these motifs are elements of termination of the pre-rRNA transcription and processing of rRNA. PMID- 26615441 TI - Primary Structure of 28S rRNA Gene Confirms Monophyly of Free-Living Heterotrophic and Phototrophic Apicomplexans (Alveolata). AB - Phylogenetic analysis of large subunit ribosomal RNA (LSU rRNA or 28S rRNA) gene sequences from free-living predatory flagellates Colpodella angusta, Voromonas pontica, and Alphamonas edax (Apicomplexa) confirms their close relationship with chromerids Chromera velia and Vitrella brassicaformis, which possess a functional photosynthetic plastid. Together these organisms form a sister group to parasitic apicomplexans (coccidians and gregarines, or sporozoans sensu lato). This result agrees with the previous conclusion on monophyly of colpodellids and chromerids (chrompodellids) based on phylogenomic data. The revealed relationships demonstrate a complex pattern of acquisition, loss, or modification of plastids and transition to parasitism during alveolate evolution. PMID- 26615442 TI - Modeling Interactions of Erythromycin Derivatives with Ribosomes. AB - Using a method of static simulation, a series of erythromycin A analogs was designed with aldehyde functions introduced instead of one of the methyl substituents in the 3'-N-position of the antibiotic that was potentially capable of forming a covalent bond with an amino group of one of the nucleotide residues of the 23S rRNA in the ribosomal exit tunnel. Similar interaction is observed for antibiotics of the tylosin series, which bind tightly to the large ribosomal subunit and demonstrate high antibacterial activity. Binding of novel erythromycin derivatives with the bacterial ribosome was investigated with the method of fluorescence polarization. It was found that the erythromycin analog containing a 1-methyl-3-oxopropyl group in the 3'-N-position demonstrates the best binding. Based on the ability to inhibit protein biosynthesis, it is on the same level as erythromycin, and it is significantly better than desmethyl erythromycin. Molecular dynamic modeling of complexes of the derivatives with ribosomes was conducted to explain the observed effects. PMID- 26615443 TI - Induction of Secondary Carotenogenesis in New Halophile Microalgae from the Genus Dunaliella (Chlorophyceae). AB - We report on the effects of high light irradiance (480 umol quanta/(m(2).s)) and salinity (160 and 200 g/liter NaCl) on culture growth as well as on cell lipid pigment and fatty acid (FA) composition in three novel strains of halophile microalga from the genus Dunaliella. Based on the ITS1-5.8S rRNA-ITS2 sequence and on the capability of accumulation of secondary (uncoupled from the photosynthetic apparatus) beta-carotene, the strains Dunaliella sp. BS1 and BS2 were identified as D. salina and Dunaliella sp. R5 as D. viridis. Under conditions optimal for growth, chlorophylls and primary carotenoids (mainly lutein) dominated the pigment profile of all investigated strains. The main FA were represented by unsaturated C18 FA typical of thylakoid membrane structural lipids. In all studied cells, stressors caused a decline in chlorophylls and an increase in unsaturated C16 and C18 FA associated with reserve lipids. The carotenogenic species D. salina demonstrated 10-fold increase in carotenoids accompanied by a decline in lutein and a drastic increase in beta-carotene (up to 75% of total carotenoids). In D. viridis, only 1.5-fold increase in carotenoid content took place, the ratio of major carotenoids remaining essentially unchanged. The role of the carotenogenic response in mechanisms of protection against photooxidative damage is discussed in view of halophile microalgae stress tolerance and application of the new Dunaliella strains for biotechnological production of beta-carotene. PMID- 26615444 TI - Metagenomic Analyses of White Sea Picoalgae: First Data. AB - Picoalgae (defined as cells smaller than 2-3 um) include members of diverse taxonomic groups. They are an important constituent of marine plankton and ice biota and play a significant ecological role in biogeochemical cycles. Despite their importance, the true extent of their diversity has only recently been uncovered by molecular surveys. The diversity of picoeukaryotes has not yet been studied in the White Sea, which is a unique marine environment combining features of temperate and Arctic seas. Here, we investigated the taxonomic composition of eukaryotic picoalgae in ice and under-ice water at a station located in the Kandalaksha Bay of the White Sea. We applied metagenomic survey using Illumina sequencing. Eight main algae phyla, namely, Chlorophyta, Katablepharidophyta, Haptophyta, Dinophyta, Cercozoa, Bacillariophyta, Cryptophyta, and Ochrophyta were identified. The genera Paraphysomonas and Micromonas and the order Pedinellales were most numerous in plankton; the genera Paraphysomonas, Micromonas, and Metopion were most abundant in ice. The number of "rare" phylotypes was 80 in under-ice water and 112 in ice. Some taxa of nano- and microalgae are identified for the first time in the White Sea phytoplankton. Our data provide a basis for further research of tiny phototrophs in the Russian Arctic. PMID- 26615445 TI - Moss Phylogeny Reconstruction Using Nucleotide Pangenome of Complete Mitogenome Sequences. AB - Stability of composition and sequence of genes was shown earlier in 13 mitochondrial genomes of mosses (Rensing, S. A., et al. (2008) Science, 319, 64 69). It is of interest to study the evolution of mitochondrial genomes not only at the gene level, but also on the level of nucleotide sequences. To do this, we have constructed a "nucleotide pangenome" for mitochondrial genomes of 24 moss species. The nucleotide pangenome is a set of aligned nucleotide sequences of orthologous genome fragments covering the totality of all genomes. The nucleotide pangenome was constructed using specially developed new software, NPG-explorer (NPGe). The stable part of the mitochondrial genome (232 stable blocks) is shown to be, on average, 45% of its length. In the joint alignment of stable blocks, 82% of positions are conserved. The phylogenetic tree constructed with the NPGe program is in good correlation with other phylogenetic reconstructions. With the NPGe program, 30 blocks have been identified with repeats no shorter than 50 bp. The maximal length of a block with repeats is 140 bp. Duplications in the mitochondrial genomes of mosses are rare. On average, the genome contains about 500 bp in large duplications. The total length of insertions and deletions was determined in each genome. The losses and gains of DNA regions are rather active in mitochondrial genomes of mosses, and such rearrangements presumably can be used as additional markers in the reconstruction of phylogeny. PMID- 26615447 TI - Giant fibroepithelial polyp of the perineum: Giant fibroepithelial polyp. AB - INTRODUCTION: Fibroepitheial polyps (FEP) are among the most common benign skin lesions and definitive histology is often needed to exclude malignancy. These polyps are usually less than 5cm in size and are often seen in genito-urinary sites including the perineum. A small number can reach a significant size. PRESENTATION OF CASE: A 46-year-old female patient presented with a pedunculated mass measuring 18cm in diameter, localized to the left perineum. The lesion was excised and the histopathological diagnosis was fibroepithelial polyp. CONCLUSION: We present this case as the third largest FEP recorded in the available literature. PMID- 26615446 TI - Effectiveness of neoadjuvant chemotherapy with cisplatin and irinotecan followed by surgery on small-cell carcinoma of the esophagus: A case report. AB - INTRODUCTION: Small-cell carcinoma of the esophagus (SCCE) is a rare disease with aggressive progression and a poor prognosis. A standard treatment strategy for SCCE is yet to be established. PRESENTATION OF CASE: A 40-year-old woman with dysphagia was admitted to our hospital. A clinical diagnosis of SCCE (T3N1N0 stage IIIA) was established. She was initially treated with chemotherapy using cisplatin (CDDP) and irinotecan (CPT-11). After two courses of treatment, the primary lesion in the esophagus was not detectable by esophageal endoscopy. Likewise, swelling of the right recurrent nerve lymph node present prior to treatment could not be detected. The chemotherapy resulted in a complete response. One month after the conclusion of chemotherapy, radical esophagectomy with three-field lymph node dissection was performed. Histopathological examination of the excised specimen revealed no residual tumor or lymph node metastasis. The patient was discharged from hospital 29 days after surgery with no complications. The patient is alive and has remained cancer-free for 48 months after the surgery. DISCUSSION: Systemic chemotherapy for SCCE in combination with surgery was treated after surgery in most reports. Neoadjuvant chemotherapy is advantageous from three viewpoints, namely achievement of downstaging, increasing complete resection rates, and a better completion of treatment compared with postoperative chemotherapy. Neoadjuvant chemotherapy following esophagectomy could be a useful treatment option for patients with limited disease (LD) of SCCE. CONCLUSION: We report a case of SCCE achieving a pathologically complete response with neoadjuvant chemotherapy using CDDP and CPT-11, and long-term survival followed by surgery. PMID- 26615448 TI - Population pharmacokinetic and pharmacodynamic modeling of epinephrine administered using a mobile inhaler. AB - Inhaled epinephrine is a potential alternative to self-administered intramuscular epinephrine in imminent anaphylactic reactions. The objective was to develop a pharmacokinetic-pharmacodynamic model describing exposure and effects on heart rate of inhaled epinephrine. Data from a 4-phase cross-over clinical trial in 9 healthy volunteers including 0.3 mg intramuscular epinephrine, two doses of inhaled epinephrine (4 mg/mL solution administered during [mean] 18 and 25 min, respectively) using a mobile pocket inhaler, and an inhaled placebo were analyzed using mixed-effects modeling. Inhaled epinephrine was available almost immediately and more rapidly than via the intramuscular route (absorption half live 29 min). Epinephrine plasma concentrations declined rapidly after terminating inhalation (elimination half-life 4.1 min) offering the option to stop exposure in case of adverse events. While the expected maximum concentration was higher for inhaled epinephrine, this was not associated with safety concerns due to only moderate additional hemodynamic effects compared to intramuscular administration. Bioavailability after inhalation (4.7%) was subject to high interindividual and interoccasional variability highlighting that training of inhalation would be essential for patients. The proposed model suggests that the use of a highly concentrated epinephrine solution via inhalation may offer an effective treatment option in anaphylaxis, while efficacy in patients remains to be shown. PMID- 26615449 TI - Genome wide classification and characterisation of CpG sites in cancer and normal cells. AB - This study identifies common methylation patterns across different cancer types in an effort to identify common molecular events in diverse types of cancer cells and provides evidence for the sequence surrounding a CpG to influence its susceptibility to aberrant methylation. CpG sites throughout the genome were divided into four classes: sites that either become hypo or hyper-methylated in a variety cancers using all the freely available microarray data (HypoCancer and HyperCancer classes) and those found in a constant hypo (Never methylated class) or hyper-methylated (Always methylated class) state in both normal and cancer cells. Our data shows that most CpG sites included in the HumanMethylation450K microarray remain unmethylated in normal and cancerous cells; however, certain sites in all the cancers investigated become specifically modified. More detailed analysis of the sites revealed that majority of those in the never methylated class were in CpG islands whereas those in the HyperCancer class were mostly associated with miRNA coding regions. The sites in the Hypermethylated class are associated with genes involved in initiating or maintaining the cancerous state, being enriched for processes involved in apoptosis, and with transcription factors predicted to bind to these genes linked to apoptosis and tumourgenesis (notably including E2F). Further we show that more LINE elements are associated with the HypoCancer class and more Alu repeats are associated with the HyperCancer class. Motifs that classify the classes were identified to distinguish them based on the surrounding DNA sequence alone, and for the identification of DNA sequences that could render sites more prone to aberrant methylation in cancer cells. This provides evidence that the sequence surrounding a CpG site has an influence on whether a site is hypo or hyper methylated. PMID- 26615450 TI - Concept learning set-size functions for Clark's nutcrackers. AB - Same/Different abstract-concept learning by Clark's nutcrackers (Nucifraga columbiana) was tested with novel stimuli following learning of training set expansion (8, 16, 32, 64, 128, 256, 512, and 1024 picture items). The resulting set-size function was compared to those from rhesus monkeys (Macaca mulatta), capuchin monkeys (Cebus apella), and pigeons (Columba livia). Nutcrackers showed partial concept learning following initial eight-item set learning, unlike the other species (Magnotti, Katz, Wright, & Kelly, 2015). The mean function for the nutcrackers' novel-stimulus transfer increased linearly as a function of the logarithm of training set size, which intersected its baseline function at the 128-item set size. Thus, nutcrackers on average achieved full concept learning (i.e., transfer statistically equivalent to baseline performance) somewhere between set sizes of 64 to 128 items, similar to full concept learning by monkeys. Pigeons required a somewhat larger training set (256 items) for full concept learning, but results from other experiments (initial training and transfer with 32- and 64-item set sizes) suggested carryover effects with smaller set sizes may have artificially prolonged the pigeon's full concept learning. We find it remarkable that these diverse species with very different neural architectures can fully learn this same/different abstract concept, and (at least under some conditions) do so with roughly similar sets sizes (64-128 items) and numbers of training exemplars, despite initial concept learning advantages (nutcrackers), learning disadvantages (pigeons), or increasing baselines (monkeys). PMID- 26615451 TI - Fire on cruise ships - An underestimated risk in travel medicine. PMID- 26615452 TI - The use of artificial neural network for modelling of phycoremediation of toxic elements As(III) and As(V) from wastewater using Botryococcus braunii. AB - In the present study, a thorough investigation has been done on the removal efficiency of both As(III) and As (V) from synthetic wastewater by phycoremediation of Botryococcus braunii algal biomass. Artificial neural networks (ANNs) are practised for predicting % phycoremediation efficiency of both As(III) and As(V) ions. The influence of several parameters for example initial pH, inoculum size, contact time and initial arsenic concentration (either As(III) or As(V)) was examined systematically. The maximum phycoremediation of As(III) and As(V) was found to be 85.22% and 88.15% at pH9.0, equilibrium time of 144h by using algal inoculum size of 10% (v/v) and initial arsenic concentration of 50mg/L. The data acquired from laboratory scale experimental set up was utilized for training a three-layer feed-forward back propagation (BP) with Levenberg-Marquardt (LM) training algorithm having 4:5:1 architecture. A comparison between the experimental data and model outputs provided a high correlation coefficient (R(2)all_ANN equal to 0.9998) and exhibited that the model was capable for predicting the phycoremediation of both As(III) and As(V) from wastewater. The network topology was optimized by changing number of neurons in hidden layers. ANNs are efficient to model and simulate highly non-liner multivariable relationships. Absolute error and Standard deviation (SD) with respect to experimental output were calculated for ANN model outputs. The comparison of phycoremediation efficiencies of both As(III) and As(V) between experimental results and ANN model outputs exhibited that ANN model can determine the behaviour of As(III) and As(V) elimination process under various circumstances. PMID- 26615453 TI - Assessing posttraumatic stress related impairment and well-being: The Posttraumatic Stress Related Functioning Inventory (PRFI). AB - Posttraumatic stress symptoms are associated with poorer social and occupational functioning and quality of life. However, general assessments of functioning do not determine the extent to which these difficulties are directly related to PTSD symptoms. This study examines the psychometric properties of a self-report measure, the 27-item Posttraumatic Stress Related Functioning Inventory (PRFI), which was developed to provide a self-report tool for clinicians and researchers to better understand the perceived impact of PTSD symptoms on functioning. The psychometric properties of the PRFI were examined utilizing data collected within a larger study examining quality of life and functioning in 251 veterans who had served in OEF/OIF/OND and endorsed the presence of subsyndromal or greater levels of PTSD symptoms at screening. One-year test-retest reliability of the measure was examined in a subset of the baseline sample who received a second administration of the PRFI (n = 109). Higher levels of PTSD symptoms were associated with poorer functioning in all domains. The PRFI demonstrated convergent validity with a measure of PTSD symptoms and was less correlated with measures of alcohol and drug use, good internal consistency and test-retest reliability from baseline to one-year follow-up. The PRFI provides self-report information regarding several domains of functioning. This initial examination of psychometric properties of the scale indicated that it may be useful for efficiently eliciting information about the ways in which PTSD symptoms in veterans impact everyday functioning. PMID- 26615454 TI - Multidetector CT angiography in the diagnosis and classification of carotid cavernous fistula. AB - AIM: To evaluate the performance of multidetector computed tomography angiography (MDCTA) in identifying and classifying carotid-cavernous fistulas (CCFs). MATERIALS AND METHODS: The neuro-interventional database was searched for patients with CCFs at four different institutions and for normal controls at one of the four institutions. Thirty-four patients were divided into the case group (direct type, n=8; indirect type, n=8) and the control group (n=18). Two readers retrospectively evaluated thin-section CTA images for the presence and laterality of four findings: (1) engorged ophthalmic vein, (2) engorged cavernous sinus, (3) similar enhancement of the cavernous sinus (CS) and internal carotid artery (ICA), and (4) greater enhancement of the CS than the transverse sinus (TS). Dehiscent ICA for the direct type was assessed only in the case group. Sensitivity, specificity, and inter-reader agreement were determined. Attenuation differences between the ICA and CS and between the CS and TS were compared across groups. RESULTS: The sensitivity/specificity for two engorgement and two enhancement findings were 81%/100%, 88%/94%, 100%/100%, and 88%/100%, respectively, for Reader 1, and 75%/100%, 75%/100%, 88%/100%, and 88%/100%, respectively, for Reader 2. Agreement between readers was excellent for all findings (kappa>0.80). Dehiscent ICA identified the direct type with a sensitivity/specificity of 100%/75% for Reader 1 and 100%/88% for Reader 2 (kappa=0.871). In the case group, the difference between ICA and CS attenuation values was significantly lower (180.1+/-76.6 versus 7.5+/-23.7; ?<0.001) and that between CS and TS were higher (-31.2+/-69 versus 102.6+/-59.3; ?<0.001). The area under the curve for the latter values was 0.95. CONCLUSION: The engorgement and enhancement categories in MDCTA may perform comparably in identifying CCFs and measurements of vessel attenuation differences may be of high diagnostic value. Dehiscent ICA can greatly aid in identifying the direct type. PMID- 26615455 TI - Risk factors and indication for dissection of right paraesophageal lymph node metastasis in papillary thyroid carcinoma. AB - BACKGROUND: Right paraesophageal lymph nodes (RPELNs) are located behind right recurrent laryngeal nerve which often ignored in central compartment lymph nodes (LNs) dissection of papillary thyroid carcinoma (PTC) patients. The aim of this study was to identify the risk factors for RPELN metastasis and indications for RPELN dissection. METHODS: Medical record of 246 consecutive PTC patients (194 female, 52 male), who underwent total thyroidectomy (244 patients) or right lobectomy (2 patients) with central compartment LN dissection (13 ipsilateral and 233 bilateral), were reviewed. The RPELNs were kept separately during the operation. The clinical pathology data was collected and analyzed. RESULTS: RPELN metastasis was confirmed in 33 patients (13.4%) and were discovered in 18.5% (31/168) of right lesion, 34.4% (31/90) of right central group LN (rCLN) metastasis, 33.3% (18/54) of lateral compartment LN (LLN) metastasis, 25.7% (9/35) of local recurrent patients respectively. The ultrasound suspected metastatic LNs, tumor diameter, tumor number, tumor location, and numbers of metastatic Delphian LNs, central group LNs (CLNs), rCLNs, and LLNs between patients with and without RPELN metastasis showed significant differences in univariate analysis (P < 0.05). In multivariate analysis, number of metastatic rCLNs (1-2: OR 13.6, 95% CI, 2.7-67.5; ?3: OR39.4, 95% CI, 7.7-200.9), right side tumor (OR 6.4, 95% CI, 1.1-35.6), and three or more metastatic LLNs (OR 3.5, 95% CI, 1.2-10.2) were independent risk factors for RPELN metastasis. CONCLUSIONS: PTC patients with right lobe lesions, especially with potential rCLN metastasis, are at considerable risk of RPELN metastasis. RPELN dissection should be considered in these patients. PMID- 26615456 TI - Update on monitoring the spread of KPC carbapenemase-producing Klebsiella spp. in South Brazil. PMID- 26615457 TI - Evaluation of patient-held carbapenemase-producing Enterobacteriaceae (CPE) alert card. AB - Public Health England recommends patient-held cards for those colonized with carbapenemase-producing Enterobacteriaceae (CPE). Alert cards were provided to 104 CPE-positive inpatients, with follow-up at six months. Excluding those who died, the response rate was 39%. Sixteen patients (46%) recalled receiving the card; 13 (81%) of these retained it, most (64%) of whom reported using it. This is the first evaluation of a patient-held alert card for any antimicrobial resistant (AMR) bacteria in the UK. This study demonstrated that, when retained, CPE alert cards can be an effective communication tool. Further work is required to evaluate effectiveness and improve retention. PMID- 26615458 TI - Gastrointestinal colonization with multiple New Delhi metallo-beta-lactamase producing Enterobacteriaceae isolates in the same patient: a potential challenge in outbreak investigation. PMID- 26615459 TI - Risk factors for carbapenemase-producing Enterobacteriaceae colonization of asymptomatic carriers on admission to an Italian rehabilitation hospital. AB - The spread of carbapenemase-producing Enterobacteriaceae (CPE) has become a worldwide problem. Early identification and isolation of asymptomatic carriers are important for infection prevention and control measures. All inpatients (N=1427) admitted to 'Fondazione Santa Lucia' Rehabilitation Hospital in 2014 were screened by rectal swab; 10.2% of them were CPE-colonized. The multivariate analysis on anamnestic data showed that both previous admission to an intensive care unit (odds ratio: 4.04; 95% confidence interval: 2.20-7.44; P<0.001) or post acute care hospitals (2.88; 1.74-4.77; P<0.001) and presence of a central venous catheter (2.19; 1.34-3.59; P<0.001) were significant risk factors. PMID- 26615460 TI - Characterization of NDM-1- and OXA-23-producing Acinetobacter baumannii isolates from inanimate surfaces in a hospital environment in Algeria. AB - BACKGROUND: Investigation of several outbreaks of multidrug-resistant Acinetobacter baumannii infection has demonstrated that contamination of the inanimate hospital environment could be implicated in the spread of these multidrug-resistant strains. AIM: To investigate the occurrence of carbapenem resistant A. baumannii on inanimate surfaces and possible dissemination in the hospital environment in Algeria as a potential source of infection in humans. METHODS: A. baumannii strains were isolated from the hospital environment and identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Antimicrobial susceptibility was determined using disc diffusion and E-test methods. Carbapenemase activity was detected using microbiological tests, including modified Hodge test, modified Carba NP test, and EDTA test. Carbapenem resistance determinants were studied by polymerase chain reaction (PCR) and sequencing. Clonal relatedness was determined using multi locus sequence typing (MLST). RESULTS: A total of 67 A. baumannii isolates were obtained from 868 environmental samples and identified by MALDI-TOF MS. Among them, 61 isolates were resistant to imipenem with minimum inhibitory concentration >32 MUg/mL and positive by the modified Hodge test and modified Carba NP test. In addition, the activity of carbapenemase was inhibited by EDTA in 32 strains. PCR and sequencing showed the presence of blaOXA-23 gene in 29 strains, and the blaNDM-1 gene in 32 isolates. MLST demonstrated the presence of five types of ST (ST19, ST2, ST85, ST98, and ST115). CONCLUSION: Our study demonstrated the dissemination of carbapenemase-producing A. baumannii strains recovered from inanimate surfaces in a hospital environment, surrounding patients, healthcare workers and visitors, in Algeria as a potential source for nosocomial infection. PMID- 26615461 TI - Epidemiological transition and distribution of stroke incidence in Tianjin, China, 1988-2010. AB - OBJECTIVES: To examine the trends in epidemiological transition of stroke over the last two decades in Tianjin, and investigate the subtypes of stroke. STUDY DESIGN: A population-based epidemiological study using data from the Stroke Incidence Surveillance System of the Tianjin Centres for Disease Control and Prevention from 1988 to 2010. METHODS: Almost 500,000 cases were analysed to examine changes in the incidence of stroke between 1988 and 2010 by age, sex, subtype, year and urban/rural status. RESULTS: The incidence of stroke amongst males increased from 136.8/100,000 in 1988 to 387.0/100,000 in 2010, and the incidence amongst females increased from 65.9/100,000 in 1988 to 249.7/100,000 in 2010. Over the study period, the proportion of haemorrhagic strokes decreased and the proportion of ischaemic strokes increased sharply in both men and woman; the differences were significant. CONCLUSION: The distribution of stroke subtypes changed dramatically over the study period. Changes in trend and subtypes of stroke have raised new challenges and there is a need for adjustment for stroke prevention in Tianjin. PMID- 26615462 TI - Spinal surgery for degenerative lumbar spine disease: Predictors of outcome. AB - OBJECTIVES: Identify predictors of outcomes for results in Degenerative Lumbar Spine Disease (DLSD). PATIENTS AND METHODS: A retrospective analysis of 164 patients who underwent surgery for DLSD was performed. The study duration was 24 months (January 2013-December 2014). The patients were first evaluated and were assessed for their results regarding the extent of surgery in four groups: patients undergoing surgery for treatment of one segment, two segments, three segments, and four or more segments of DLS. Posteriorly, the same group of patients was divided based on the presence or absence of Dural Tear (DT) during surgery. In addition, the relationship between elderlies and the incidence of surgical site infection (SSI) and reoperation was also analyzed. RESULTS: A total of 193 surgeries were performed on 164 patients (74 males/90 females), with a mean age of 53.18 years old (53.18 +/- 17.54). SSI occurred in 7.31% of cases and re-operations due to SSI or because of complications resulting from the first procedure occurred in 11,58% of cases. Results statistically significant were found regarding the incidence of SSI (P=0.05) and the rate of re-operation (p=0.003) in surgeries involving more than three segments. DT is directly related to the rate of re-operation (p=0.0172) and SSI (p=0.0002). Elderly patients were not a predictor of poor outcome, neither to incidence of SSI (p=0.2), nor chance of re-operation (p=0.36). CONCLUSION: Surgeries involving more than three segments are directly related to SSI, incidence of accidental DT and chance of re operation. The presence of DT during the procedure is presented as a predictor of postoperative SSI and an increase in re-operation rate. Furthermore, elderly patients are not related to a higher risk for SSI and re-operations. PMID- 26615463 TI - Surgical complications following malignant brain tumor surgery: An analysis of 2002-2011 data. AB - OBJECTIVES: To estimate the incidence of surgical complications and associated in hospital morbidity and mortality following surgery for malignant brain tumors. PATIENTS AND METHODS: The Nationwide Inpatient Sample (NIS) database was queried from 2002 to 2011. All adult patients who underwent elective brain surgery for a malignant brain tumor were included. Surgical complications included wrong side surgery, retention of a foreign object, iatrogenic stroke, meningitis, hemorrhage/hematoma complicating a procedure, and neurological complications. A regression model was conducted to estimate the odds ratios (OR) with their 95% confidence intervals (95% CI) of in-hospital mortality for each surgical complication. RESULTS: A total of 16,530 admissions were analyzed, with 601 (36.2 events per 1000 cases) surgical complications occurring in 567 patients. Over the examined 10-year period, the overall incidence of surgical complications did not change (P=0.061) except for iatrogenic strokes, which increased in incidence from 14.1 to 19.8 events per 1000 between 2002 and 2011 (P=0.023). Patients who developed a surgical complication had significantly longer lengths of stay, total hospital costs, and higher rates of other complications. Patients who experienced an iatrogenic stroke had a significantly increased risk of mortality (OR 9.6; 95% 6.3-14.8) and so were patients with a hemorrhage/hematoma (OR 3.3; 95% CI 1.6 6.6). CONCLUSION: In this study of an administrative database, patients undergoing surgery for a malignant brain tumor who suffered from a surgical complication had significantly longer lengths of stay, total hospital charges, and complication rates. Having a surgical complication was also an independent risk factor for in-hospital mortality. Nonetheless, it is unclear whether all surgical complications were clinically relevant, and further research is encouraged. PMID- 26615464 TI - Clinical efficacy of deep brain stimulation for the treatment of medically refractory epilepsy. AB - Epilepsy affects 50 million people worldwide and about 30% of these patients will not be adequately controlled with antiepileptic drugs (AEDs) alone. For patients where resective surgery is not indicated, deep brain stimulation (DBS) may be an effective alternative. The majority of available literature targets the thalamic nuclei (anterior; centromedian), subthalamic nucleus, hippocampus, and cerebellum. Here, we review patient outcomes and adverse events related to DBS to these various targets. Data show DBS may be a safe and effective treatment option for refractory epilepsy. PMID- 26615465 TI - Laparotomy vs minimally invasive laparoscopic ventriculoperitoneal shunt placement for hydrocephalus: A systematic review and meta-analysis. AB - Ventriculoperitoneal shunt (VPS) surgery is the most commonly used method for the treatment of hydrocephalus. Traditionally, distal catheters in the VPS surgery have been placed either through a standard small open laparotomy or via a laparoscopic technique. Although there are many studies demonstrating the benefits of a minimally invasive approach, limited research has directly compared the two techniques used in VPS surgery. The present meta-analysis aims to provide the first comprehensive review of all published observational studies and randomized controlled trials reporting outcomes of laparotomy and laparoscopy in VPS. Electronic searches were performed using six databases from their inception to February 2015. Relevant studies comparing conventional laparotomy and a laparoscopic video-guided approach in VPS were included. Data were extracted and analyzed according to predefined clinical endpoints. A total of ten studies were identified for inclusion in the present analysis. Results indicated that the laparoscopic technique was associated with a slight but significant reduction in operating time (~ 10 min), a significantly lower rate of abdominal malposition, distal obstruction and distal shunt failure. There was no difference between the laparotomic and laparoscopic approaches in the length of hospital stay, complication rate, proximal shunt failure or infection rate. The present systematic review and meta-analysis demonstrated that the laparoscopic technique in VPS surgery is associated with reduced shunt failure and abdominal malposition compared to the open laparotomy technique, with no significant difference in rates of infection or other complications. The lack of studies with high levels of evidence may contribute to bias in our conclusions and the long-term relative merits require validation by further prospective, randomized studies. PMID- 26615466 TI - Preschoolers understand the normativity of cooperatively structured competition. AB - Human institutional practices often involve competition within a cooperative structure of mutually accepted rules. In a competitive game, for instance, we not only expect adherence to the rules of the game but also expect an opponent who tries to win and, thus, follows a rational game-playing strategy. We had 3- and 5 year-olds (N=48) play for a prize against an opponent (a puppet) who played either rationally (trying to win) or irrationally (helping the children to win) while either following or breaking the rules of the game. Both age groups performed costly protest against an opponent who followed the rules but played irrationally by helping the children to win. When facing a rule-breaking opponent, 3-year-olds protested only the rule breaches of an irrational opponent but not irrational play. Five-year-olds also protested the rule breaches of a rational opponent, but in contrast to the 3-year-olds, they protested irrational behavior even in the context of rule breaches. Moreover, many children, in particular 3-year-olds, refrained from protesting. These findings suggest that 5 year-olds, but not 3-year-olds, fully understand the dual-level normative structure of cooperatively regulated competition. PMID- 26615467 TI - Modeling the relationship between rapid automatized naming and literacy skills across languages varying in orthographic consistency. AB - The purpose of this study was twofold: (a) to contrast the prominent theoretical explanations of the rapid automatized naming (RAN)-reading relationship across languages varying in orthographic consistency (Chinese, English, and Finnish) and (b) to examine whether the same accounts can explain the RAN-spelling relationship. In total, 304 Grade 4 children (102 Chinese-speaking Taiwanese children, 117 English-speaking Canadian children, and 85 Finnish-speaking children) were assessed on measures of RAN, speed of processing, phonological processing, orthographic processing, reading fluency, and spelling. The results of path analysis indicated that RAN had a strong direct effect on reading fluency that was of the same size across languages and that only in English was a small proportion of its predictive variance mediated by orthographic processing. In contrast, RAN did not exert a significant direct effect on spelling, and a substantial proportion of its predictive variance was mediated by phonological processing (in Chinese and Finnish) and orthographic processing (in English). Given that RAN predicted reading fluency equally well across languages and that phonological/orthographic processing had very little to do with this relationship, we argue that the reason why RAN is related to reading fluency should be sought in domain-general factors such as serial processing and articulation. PMID- 26615468 TI - Highly predictive support vector machine (SVM) models for anthrax toxin lethal factor (LF) inhibitors. AB - Anthrax is a highly lethal, acute infectious disease caused by the rod-shaped, Gram-positive bacterium Bacillus anthracis. The anthrax toxin lethal factor (LF), a zinc metalloprotease secreted by the bacilli, plays a key role in anthrax pathogenesis and is chiefly responsible for anthrax-related toxemia and host death, partly via inactivation of mitogen-activated protein kinase kinase (MAPKK) enzymes and consequent disruption of key cellular signaling pathways. Antibiotics such as fluoroquinolones are capable of clearing the bacilli but have no effect on LF-mediated toxemia; LF itself therefore remains the preferred target for toxin inactivation. However, currently no LF inhibitor is available on the market as a therapeutic, partly due to the insufficiency of existing LF inhibitor scaffolds in terms of efficacy, selectivity, and toxicity. In the current work, we present novel support vector machine (SVM) models with high prediction accuracy that are designed to rapidly identify potential novel, structurally diverse LF inhibitor chemical matter from compound libraries. These SVM models were trained and validated using 508 compounds with published LF biological activity data and 847 inactive compounds deposited in the Pub Chem BioAssay database. One model, M1, demonstrated particularly favorable selectivity toward highly active compounds by correctly predicting 39 (95.12%) out of 41 nanomolar level LF inhibitors, 46 (93.88%) out of 49 inactives, and 844 (99.65%) out of 847 Pub Chem inactives in external, unbiased test sets. These models are expected to facilitate the prediction of LF inhibitory activity for existing molecules, as well as identification of novel potential LF inhibitors from large datasets. PMID- 26615469 TI - Docking, molecular dynamics and QM/MM studies to delineate the mode of binding of CucurbitacinE to F-actin. AB - CucurbitacinE (CurE) has been known to bind covalently to F-actin and inhibit depolymerization. However, the mode of binding of CurE to F-actin and the consequent changes in the F-actin dynamics have not been studied. Through quantum mechanical/molecular mechanical (QM/MM) and density function theory (DFT) simulations after the molecular dynamics (MD) simulations of the docked complex of F-actin and CurE, a detailed transition state (TS) model for the Michael reaction is proposed. The TS model shows nucleophilic attack of the sulphur of Cys257 at the beta-carbon of Michael Acceptor of CurE producing an enol intermediate that forms a covalent bond with CurE. The MD results show a clear difference between the structure of the F-actin in free form and F-actin complexed with CurE. CurE affects the conformation of the nucleotide binding pocket increasing the binding affinity between F-actin and ADP, which in turn could affect the nucleotide exchange. CurE binding also limits the correlated displacement of the relatively flexible domain 1 of F-actin causing the protein to retain a flat structure and to transform into a stable "tense" state. This structural transition could inhibit depolymerization of F-actin. In conclusion, CurE allosterically modulates ADP and stabilizes F-actin structure, thereby affecting nucleotide exchange and depolymerization of F-actin. PMID- 26615470 TI - The framework of polysaccharide monooxygenase structure and chemistry. AB - Polysaccharide monooxygenases, or PMOs (also known as lytic PMOs or LPMOs), are a group of enzymes discovered in recent years to catalyze the oxidative degradation of carbohydrate polymers. The PMO catalytic domain has a beta-sandwich fold that bears a strong resemblance to both immunoglobulin (Ig) and fibronectin type III (FnIII) domains. PMOs are secreted by fungi and bacteria, and there is recent evidence for their roles in pathogenesis, in addition to biomass processing. This review addresses the biological origins and functions of emerging PMO families, as well as describes the aspects of PMO structure that support the chemistry of copper-catalyzed, oxidative polysaccharide degradation. PMID- 26615471 TI - Interrogating the architecture of protein assemblies and protein interaction networks by cross-linking mass spectrometry. AB - Proteins are involved in almost all processes of the living cell. They are organized through extensive networks of interaction, by tightly bound macromolecular assemblies or more transiently via signaling nodes. Therefore, revealing the architecture of protein complexes and protein interaction networks is crucial to understand their function. Towards this aim, cross-linking mass spectrometry (XL-MS), which allows the elucidation of structures and interactions of proteins at low-resolution, has emerged as a valuable technology. Especially in recent years, the substantial development of cross-linking approaches and MS based technologies, has led to noteworthy advances in the analysis of purified/in vitro reconstituted very large (megaDa) protein assemblies and various endogenous protein complexes in cells. Here we review the advances of XL-MS technologies and highlight some of the most recent studies. They clearly indicate that current XL MS methodologies are ideally positioned to bridge the gap between proteomic-based interactome studies and high-resolution structural biology-based technologies. PMID- 26615472 TI - Prospective longitudinal study of testosterone and incident depression in older men: The Health In Men Study. AB - BACKGROUND: Depression in older men has been associated with low circulating testosterone concentration but data from prospective studies are limited. METHODS: We conducted a prospective longitudinal study in a community representative cohort of 3179 older men free of clinically significant depressive symptoms at baseline. The main objective of this study was to determine if low serum testosterone, dihydrotestosterone and estradiol concentrations are associated with the development of depressive symptoms. Incident depression was assessed with the Patient Health Questionnaire and via an electronic health record database (The West Australian Data Linkage System). The main exposures of interest were serum testosterone, dihydrotestosterone and estradiol measured by liquid chromatography-mass spectrometry and calculated free testosterone in baseline blood samples (collected between 2001 and 2004). RESULTS: One hundred and thirty five men (4.2%) developed depression over a median follow up time of 9.4 years (range 8.4-10.9). Men with incident depression were older (median age 77.7 vs 76.1 years, z=-3.82, p=0<0.001) and were more likely to have cardiovascular disease (43.0% vs 32.6%, chi(2)=6.32, p=0.012) and diabetes (22.2% vs 13.2%, chi(2)=8.95, p=0.003). Low serum total testosterone (<6.4 nmol/L) was associated with incident depression (HR 2.07, 95%CI 1.17-3.68) and this remained significant after adjustment for relevant potential confounding factors (HR 1.86, 95%CI 1.05-3.31). Low serum dihydrotestosterone, estradiol and calculated free testosterone were not associated with risk of depression. CONCLUSIONS: Low serum total testosterone, but not calculated free testosterone, was associated with incident depression in this sample of older men. PMID- 26615474 TI - Highly efficient automated extraction of DNA from old and contemporary skeletal remains. AB - We optimised the automated extraction of DNA from old and contemporary skeletal remains using the AutoMate Express system and the PrepFiler BTA kit. 24 Contemporary and 25 old skeletal remains from WWII were analysed. For each skeleton, extraction using only 0.05 g of powder was performed according to the manufacturer's recommendations (no demineralisation - ND method). Since only 32% of full profiles were obtained from aged and 58% from contemporary casework skeletons, the extraction protocol was modified to acquire higher quality DNA and genomic DNA was obtained after full demineralisation (FD method). The nuclear DNA of the samples was quantified using the Investigator Quantiplex kit and STR typing was performed using the NGM kit to evaluate the performance of tested extraction methods. In the aged DNA samples, 64% of full profiles were obtained using the FD method. For the contemporary skeletal remains the performance of the ND method was closer to the FD method compared to the old skeletons, giving 58% of full profiles with the ND method and 71% of full profiles using the FD method. The extraction of DNA from only 0.05 g of bone or tooth powder using the AutoMate Express has proven highly successful in the recovery of DNA from old and contemporary skeletons, especially with the modified FD method. We believe that the results obtained will contribute to the possibilities of using automated devices for extracting DNA from skeletal remains, which would shorten the procedures for obtaining high-quality DNA from skeletons in forensic laboratories. PMID- 26615475 TI - Enhanced retention of drop vertical jump landing technique: A randomized controlled trial. AB - External focus instructions have been shown to result in superior motor performance compared to internal focus instructions. Using an EF may help to optimize current anterior cruciate ligament (ACL) injury prevention programs. The purpose of the current study was to investigate the effects of instructions on landing technique and performance by comparing an external focus (EF), internal focus (IF), video (VI) and control (CTRL) group. Subjects (age 22.50+/-1.62years, height 179.70+/-10.43cm, mass 73.98+/-12.68kg) were randomly assigned to IF (n=10), EF (n=10), VI (n=10) or CTRL group (n=10). Landing was assessed from a drop vertical jump (DVJ) in five sessions: pretest, two training blocks (TR1 and TR2) and directly after the training sessions (post test) and retention test 1week later. Group specific instructions were offered in TR1 and TR2. Landing technique was assessed with the Landing Error Scoring System (LESS) and jump height was taken as performance measure. The results show that males in the VI group and females both in the VI and EF groups significantly improved jump landing technique. Retention was achieved and jump height was maintained for males in the VI group and females both in the VI and EF groups. It is therefore concluded that EF and VI instructions have great potential in ACL injury prevention. PMID- 26615473 TI - Oxytocin in the nucleus accumbens shell reverses CRFR2-evoked passive stress coping after partner loss in monogamous male prairie voles. AB - Loss of a partner can have severe effects on mental health. Here we explore the neural mechanisms underlying increased passive stress-coping, indicative of depressive-like behavior, following the loss of the female partner in the monogamous male prairie vole. We demonstrate that corticotropin-releasing factor receptor 2 (CRFR2) in the nucleus accumbens shell mediates social loss-induced passive coping. Further, we show that partner loss compromises the oxytocin system through multiple mechanisms. Finally, we provide evidence for an interaction of the CRFR2 and oxytocin systems in mediating the emotional consequences of partner loss. Our results suggest that chronic activation of CRFR2 and suppression of striatal oxytocin signaling following partner loss result in an aversive emotional state that may share underlying mechanisms with bereavement. We propose that the suppression of oxytocin signaling is likely adaptive during short separations to encourage reunion with the partner and may have evolved to maintain long-term partnerships. Additionally, therapeutic strategies targeting these systems should be considered for treatment of social loss-mediated depression. PMID- 26615476 TI - Relationships between match activities and peak power output and Creatine Kinase responses to professional reserve team soccer match-play. AB - The specific movement demands of soccer that are linked to post-match recovery and readiness to train are unclear. Therefore, we examined the relationship between Global Positioning System (GPS) variables and the change (Delta; from baseline) in Creatine Kinase (CK) concentrations and peak power output (PPO; during the countermovement jump) at 24h and 48h post-match. Fifteen English Premier League reserve team players were examined over 1-4 matches. Measurements of CK and PPO were taken before (24h prior to match-play) and after (+24h and +48h) each game during which movement demands were quantified using 10Hz GPS data. High intensity distance covered (r=0.386, p=0.029; r=-0.349; p=0.050), high intensity distance covered?min(-1) (r=0.365, p=0.040; r=-0.364, p=0.040), high speed running distance (r=0.363, p=0.041; r=-0.360, p=0.043) and the number of sprints?min(-1) (r=0.410, p=0.020; r=-0.368, p=0.038) were significantly related to DeltaCK and DeltaPPO at +24h post-match, respectively. No relationships were observed between any match variables and DeltaCK and DeltaPPO after +48h of recovery. These findings highlight that high intensity match activities are related to DeltaCK and DeltaPPO in the 24h, but not 48h, following soccer match play. Such information is likely of interest to those responsible for the design of soccer player's training schedules in the days following a match. PMID- 26615477 TI - Effect of active arm swing to local dynamic stability during walking. AB - Arm swing is an essential component in regulating dynamic stability of the whole body during walking, while the contribution of active arm swing to local dynamic stability of different motion segments remains unclear. This study investigated the effects of arm swing under natural arm swing condition and active arm swing condition on local dynamic stability and gait variability of the trunk segments (C7 and T10 joint) and lower extremity joints (hip, knee and ankle joint). The local divergence exponents (lambdas) and mean standard deviation over strides (MeanSD) of 24 young healthy adults were calculated while they were walking on treadmill with two arm swing conditions at their preferred walking speed (PWS). We found that in medial-lateral direction, both lambdas and MeanSD values of the trunk segments (C7 and T10 joint) in active arm swing condition were significantly lower than those in natural arm swing condition (p<0.05), while no significant difference of lambdas or MeanSD in lower extremity joints (hip, knee and ankle joint) was found between two arm swing conditions (p>0.05, respectively). In anterior-posterior and vertical direction, neither lambdas nor MeanSD values of all body segments showed significant difference between two arm swing conditions (p>0.05, respectively). These findings indicate that active arm swing may help to improve the local dynamic stability of the trunk segments in medial-lateral direction. PMID- 26615478 TI - Effect of SPL (Spent Pot Liner) and its main components on root growth, mitotic activity and phosphorylation of Histone H3 in Lactuca sativa L. AB - Spent Pot Liner (SPL) is a solid waste from the aluminum industry frequently disposed of in industrial landfills; it can be leached and contaminate the soil, sources of drinking water and plantations, and thus may pose a risk to human health and to ecosystems. Its composition is high variable, including cyanide, fluoride and aluminum salts, which are highly toxic and environmental pollutants. This study evaluated the effect of SPL and its main components on root growth and the mitosis of Lactuca sativa, by investigating the mechanisms of cellular and chromosomal alterations with the aid of immunolocalization. To this end, newly emerged roots of L. sativa were exposed to SPL and its main components (solutions of cyanide, fluoride and aluminum) and to calcium chloride (control) for 48h. After this, root length was measured and cell cycle was examined by means of conventional cytogenetics and immunolocalization. Root growth was inhibited in the treatments with SPL and aluminum; chromosomal and nuclear alterations were observed in all treatments. The immunolocalization evidenced normal dividing cells with regular temporal and spatial distribution of histone H3 phosphorylation at serine 10 (H3S10ph). However, SPL and its main components inhibited the phosphorylation of histone H3 at serine 10, inactivated pericentromeric regions and affected the cohesion of sister chromatids, thus affecting the arrangement of chromosomes in the metaphase plate and separation of chromatids in anaphase. In addition, these substances induced breaks in pericentromeric regions, characterized as fragile sites. PMID- 26615480 TI - Mobile technology and clinical practice in resource-poor settings. PMID- 26615479 TI - Integrated micro-biochemical approach for phytoremediation of cadmium and lead contaminated soils using Gladiolus grandiflorus L cut flower. AB - The potential of vermicompost, elemental sulphur, Thiobacillus thiooxidans and Pseudomonas putida for phytoremediation is well known individually but their integrated approach has not been discovered so far. The present work highlights the consideration of so far overlooked aspects of their integrated treatment by growing the ornamental plant, Gladiolus grandiflorus L in uncontaminated and sewage-contaminated soils (sulphur-deficient alluvial Entisols, pH 7.6-7.8) for phytoremediation of cadmium and lead under pot experiment. Between vermicompost and elemental sulphur, the response of vermicompost was higher towards improvement in the biometric parameters of plants, whereas the response of elemental sulphur was higher towards enhanced bioaccumulation of heavy metals under soils. The integrated treatment (T7: vermicompost 6g and elemental sulphur 0.5gkg(-1) soil and co-inoculation of the plant with T. thiooxidans and P. putida) was found superior in promoting root length, plant height and dry biomass of the plant. The treatment T7 caused enhanced accumulation of Cd up to 6.96 and 6.45mgkg(-1) and Pb up to 22.6 and 19.9mgkg(-1) in corm and shoot, respectively at the contaminated soil. T7 showed maximum remediation efficiency of 0.46% and 0.19% and bioaccumulation factor of 2.92 and 1.21 and uptake of 6.75 and 21.4mgkg(-1) dry biomass for Cd and Pb respectively in the contaminated soil. The integrated treatment T7 was found significant over the individual treatments to promote plant growth and enhance phytoremediation. Hence, authors conclude to integrate vermicompost, elemental sulphur and microbial co-inoculation for the enhanced clean-up of Cd and Pb-contaminated soils. PMID- 26615481 TI - Autonomic nervous system functioning associated with psychogenic nonepileptic seizures: Analysis of heart rate variability. AB - OBJECTIVE: Psychogenic nonepileptic seizures (PNESs) resemble epileptic seizures but originate from psychogenic rather than organic causes. Patients with PNESs are often unable or unwilling to reflect on underlying emotions. To gain more insight into the internal states of patients during PNES episodes, this study explored the time course of heart rate variability (HRV) measures, which provide information about autonomic nervous system functioning and arousal. METHODS: Heart rate variability measures were extracted from double-lead electrocardiography data collected during 1-7days of video-electroencephalography monitoring of 20 patients with PNESs, in whom a total number of 118 PNESs was recorded. Heart rate (HR) and HRV measures in time and frequency domains (standard deviation of average beat-to-beat intervals (SDANN), root mean square of successive differences (RMSSD), high-frequency (HF) power, low-frequency (LF) power, and very low-frequency (VLF) power) were averaged over consecutive five minute intervals. Additionally, quantitative analyses of Poincare plot parameters (SD1, SD2, and SD1/SD2 ratio) were performed. RESULTS: In the five-minute interval before PNES, HR significantly (p<0.05) increased (d=2.5), whereas SDANN (d=-0.03) and VLF power (d=-0.05) significantly decreased. During PNES, significant increases in HF power (d=0.0006), SD1 (d=0.031), and SD2 (d=0.016) were observed. In the five-minute interval immediately following PNES, SDANN (d=0.046) and VLF power (d=0.073) significantly increased, and HR (d=-5.1) and SD1/SD2 ratio (d=-0.14) decreased, compared to the interval preceding PNES. CONCLUSION: The results suggest that PNES episodes are preceded by increased sympathetic functioning, which is followed by an increase in parasympathetic functioning during and after PNES. Future research needs to identify the exact nature of the increased arousal that precedes PNES. PMID- 26615482 TI - New insight into the correlations between land use and water quality in a coastal watershed of China: Does point source pollution weaken it? AB - Uncovering the associations between land use and river water quality is useful for managing land-based pollution in the catchment-coast continuum. However, it is not clear how land use affects water quality in the context of simultaneous point source (PS) pollution. In this study, we develop a self-organizing map (SOM)-based approach to explore the relationship between land use and water quality in the Minjiang River Watershed, Southeast China. Water samples from 139 headwater sub-watersheds were associated with six land use categories, namely, Woodland, Agriculture, Orchard, Built-up, Unused land and Water. Sampling sites are delineated into six clusters based on six water quality parameters: ammonium N, nitrate-N, total nitrogen, soluble reactive phosphate, total phosphate and potassium permanganate index. Local relationships between land use and water quality among four clusters that have sufficient sample sizes are further identified. There is no significant land use-water quality correlation in one of the four clusters (including 37 sub-watersheds). And the greater the PS pollution is, the less significant the land use-water quality correlations are in clusters. The results demonstrate how PS pollution weakens the land use-water quality correlation. Our method can help to determine whether non-point source or PS pollution exerts greater influence on the quality of the water coming from watershed. PMID- 26615483 TI - The effect of lignite on nitrogen mobility in a low-fertility soil amended with biosolids and urea. AB - Lignite has been proposed as a soil amendment that reduces nitrate (NO3(-)) leaching from soil. Our objective was to determine the effect of lignite on nitrogen (N) fluxes from soil amended with biosolids or urea. The effect of lignite on plant yield and elemental composition was also determined. Batch sorption and column leaching experiments were followed by a lysimeter trial where a low fertility soil was amended with biosolids (400 kg N/ha equivalent) and urea (200 kg N/ha equivalent). Treatments were replicated three times, with and without lignite addition (20 t/ha equivalent). Lignite did not reduce NO3(-) leaching from soils amended with either biosolids or urea. While lignite decreased NO3(-) leaching from an unamended soil, the magnitude of this effect was not significant in an agricultural context. Furthermore, lignite increased cumulative N2O production from soils receiving urea by 90%. Lignite lessened the beneficial growth effects of adding biosolids or urea to soil. Further work could investigate whether coating urea granules with lignite may produce meaningful environmental benefits. PMID- 26615484 TI - Radiotelemetry and wildlife: Highlighting a gap in the knowledge on radiofrequency radiation effects. AB - Radio transmitters and associated devices may induce negative effects that can bias the results of ongoing research. The main documented effects of radio transmitters on animals include reduced survival, decreased productivity, changes in behaviour and movement patterns and a biased sex ratio. The only factors that have claimed responsibility for these possible damages are the weight of the radio transmitter and associated devices, and the attachment type. The electromagnetic radiation produced by radio transmitters has not been considered so far in research. There have been no studies evaluating the effects of non ionising electromagnetic radiation (radiofrequency signals) necessary for tracking, although the problems found were significantly associated with the length of time that animals had been carrying their radio transmitters. Similar problems as those in radiotracked animals have been found in numerous studies with animals exposed to radiofrequency radiation for a sufficient amount of time. Laboratory scientists investigating the orientation of animals know they have to shield the place where experiments are performed to prevent interference from man made radiation, as anthropogenic signals may distort the results. It is paradoxical that, at the same time, field scientists investigating the movements and other aspects of animal biology are providing animals with radio transmitters that emit the same type of radiation, since this may affect the results concerning their orientation and movement. This paper identifies gaps in the knowledge that should be investigated in-depth. The possibility that the radiofrequency radiation from radiotracking devices is responsible for the findings should be considered. Considering this factor may allow researchers to best understand the long-term effects found. PMID- 26615485 TI - Ozone attributed to Madrid and Barcelona on-road transport emissions: Characterization of plume dynamics over the Iberian Peninsula. AB - Despite the ~30% emission decrease of the main tropospheric ozone (O3) precursors in Spain in the 2001-2012 period, the O3 concentration in summer still exceeds the target value for the protection of the human health of the Air Quality Directive (2008/50/EC). On-road transport is the main anthropogenic contributor to O3 precursor's emissions in Madrid and Barcelona metropolitan areas (65%/59% of NOx, 40%/33% of NMVOC, and 67%/85% of CO emissions) but this contribution to O3 formation is not well understood. The present work aims at increasing the understanding on the role of on-road transport emissions from main Spanish urban areas in O3 dynamics over Spain under typical circulation types. For that purpose, the Integrated Source Apportionment Method is used within the CALIOPE modelling system (WRF/CMAQ/HERMES/BSC-DREAM8b). The results indicate that the daily maximum O3 concentration attributed to the on-road transport emissions from Madrid (O3T-MAD) and Barcelona metropolitan areas (O3T-BCN) contribute up to 24% and 8% to total O3 concentration, respectively, within an area of influence of 200 km. The contribution of O3T-MAD and O3T-BCN is particularly significant (up to 80-100 MUg m(-3) in an hour) to the O3 concentration peak during the central hours of the day in the high O3 concentration season (April-September). The maximum O3T-MAD concentration is calculated within the metropolitan area of Madrid but the plume, channelled by the Tajo and the Henares valleys, affects large areas of the Iberian Peninsula. The O3T-BCN plume is more driven by sea land and mountain-valley breezes than by the synoptic advection and its maximum concentration is usually registered over the Mediterranean Sea. The O3 concentration transported long-range to the Iberian Peninsula is significant in the area of influence of Madrid and Barcelona, being maxima under cold (70-96%) and minima in warm circulation types (35-70%). PMID- 26615486 TI - Analysis of the uncertainty in the monetary valuation of ecosystem services--A case study at the river basin scale. AB - Ecosystem services provide multiple benefits to human wellbeing and are increasingly considered by policy-makers in environmental management. However, the uncertainty related with the monetary valuation of these benefits is not yet adequately defined or integrated by policy-makers. Given this background, our aim was to quantify different sources of uncertainty when performing monetary valuation of ecosystem services, in order to provide a series of guidelines to reduce them. With an example of 4 ecosystem services (i.e., water provisioning, waste treatment, erosion protection, and habitat for species) provided at the river basin scale, we quantified the uncertainty associated with the following sources: (1) the number of services considered, (2) the number of benefits considered for each service, (3) the valuation metrics (i.e. valuation methods) used to value benefits, and (4) the uncertainty of the parameters included in the valuation metrics. Results indicate that the highest uncertainty was caused by the number of services considered, as well as by the number of benefits considered for each service, whereas the parametric uncertainty was similar to the one related to the selection of valuation metric, thus suggesting that the parametric uncertainty, which is the only uncertainty type commonly considered, was less critical than the structural uncertainty, which is in turn mainly dependent on the decision-making context. Given the uncertainty associated to the valuation structure, special attention should be given to the selection of services, benefits and metrics according to a given context. PMID- 26615487 TI - Evaluation of three full-scale stormwater treatment systems with respect to water yield, pathogen removal efficacy and human health risk from faecal pathogens. AB - In this study, three full-scale, operational stormwater harvesting systems located in Melbourne, Australia were evaluated with respect to water yields; pathogen removal performance by analysis of native surrogate data (Escherichiacoli, somatic coliphages and Clostridium perfringens); and potential human health risk associated with exposures to faecal pathogens using Quantitative Microbial Risk Assessment (QMRA). The water yield assessment confirmed variation between design and measured yields. Faecal contamination of urban stormwater was site specific and variable. Different treatment removal performance was observed between each of the microbial surrogates and varied between event and baseline conditions, with negligible removal of viruses during event conditions. Open storages that provide a habitat for waterfowl may lead to elevated risk due to the potential for zoonotic transmission. Nevertheless, in the Australian urban setting studied, the potential for human faecal contamination of the separated stormwater system was a critical driver of risk. If the integrity of the sewerage system can be ensured, then predicted health risks are dramatically reduced. PMID- 26615488 TI - Ecotoxicological assessment of solar cell leachates: Copper indium gallium selenide (CIGS) cells show higher activity than organic photovoltaic (OPV) cells. AB - Despite the increasing use of photovoltaics their potential environmental risks are poorly understood. Here, we compared ecotoxicological effects of two thin film photovoltaics: established copper indium gallium selenide (CIGS) and organic photovoltaic (OPV) cells. Leachates were produced by exposing photovoltaics to UV light, physical damage, and exposure to environmentally relevant model waters, representing mesotrophic lake water, acidic rain, and seawater. CIGS cell leachates contained 583 MUg L(-1) molybdenum at lake water, whereas at acidic rain and seawater conditions, iron, copper, zinc, molybdenum, cadmium, silver, and tin were present up to 7219 MUg L(-1). From OPV, copper (14 MUg L(-1)), zinc (87 MUg L(-1)) and silver (78 MUg L(-1)) leached. Zebrafish embryos were exposed until 120 h post-fertilization to these extracts. CIGS leachates produced under acidic rain, as well as CIGS and OPV leachates produced under seawater conditions resulted in a marked hatching delay and increase in heart edema. Depending on model water and solar cell, transcriptional alterations occurred in genes involved in oxidative stress (cat), hormonal activity (vtg1, ar), metallothionein (mt2), ER stress (bip, chop), and apoptosis (casp9). The effects were dependent on the concentrations of cationic metals in leachates. Addition of ethylenediaminetetraacetic acid protected zebrafish embryos from morphological and molecular effects. Our study suggests that metals leaching from damaged CIGS cells, may pose a potential environmental risk. PMID- 26615489 TI - Bioaccumulation of perfluorinated carboxylates and sulfonates and polychlorinated biphenyls in laboratory-cultured Hexagenia spp., Lumbriculus variegatus and Pimephales promelas from field-collected sediments. AB - Polychlorinated biphenyls (PCBs) and perfluorinated carboxylates and sulfonates (PFASs) are persistent pollutants in sediment that can potentially bioaccumulate in aquatic organisms. The current study investigates variation in the accumulation of PCBs and PFASs in laboratory-cultured Hexagenia spp., Lumbriculus variegatus and Pimephales promelas from contaminated field-collected sediment using 28-day tests. BSAF(lipid) (lipid-normalized biota-sediment accumulation factor) values for total concentration of PCBs were greater in Hexagenia spp. relative to L. variegatus and P. promelas. The distribution of congeners contributing to the total concentration of PCBs in tissue varied among the three species. Trichlorobiphenyl congeners composed the greatest proportion of the total concentration of PCBs in L. variegatus while tetra- and pentabiphenyl congeners dominated in Hexagenia spp. and P. promelas. Perfluorooctane sulfonate (PFOS) was present in all three species at concentrations greater than all other PFASs analyzed. Hexagenia spp. also produced the greatest BSAF(lipid) and BSAF(ww) (non-lipid-normalized biota-sediment accumulation factor) values for PFOS relative to the other two species. However, this was not the case for all PFASs. The trend of BSAF values and number of carbon atoms in the perfluoroalkyl chain of perfluorinated carboxylates varied among the three species but was similar for perfluorinated sulfonates. Differences in the dominant pathways of exposure (e.g., water, sediment ingestion) likely explain a large proportion of the variation in accumulation observed across the three species. PMID- 26615490 TI - Contribution of aluminas and aluminosilicates to the formation of PCDD/Fs on fly ashes. AB - Chlorinated aromatics undergo surface-mediated reactions with metal oxides to form Environmentally Persistent Free Radicals (EPFRs) which can further react to produce polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). Previous work using laboratory-made fly ash surrogates composed of transition metal oxides deposited on silica powder has confirmed their ability to mimic fly ash in the production of PCDD/Fs. However, little is known about the propensity of aluminas and aluminosilicates, other components of fly ash, to form PCDD/Fs. A fly ash sample containing both alumina and mullite, an aluminosilicate, was tested for PCDD/F formation ability and compared to PCDD/F yields from the thermal degradation of 2-monochlorophenol (2-MCP) precursor over gamma-alumina, alpha alumina, and mullite. A packed-bed flow reactor was used to investigate the thermal degradation of 2-MCP over the various catalysts at 200-600 degrees C. Fly ash gave similar PCDD/F yields to surrogates made with similar transition metal content. gamma-alumina, which is thermodynamically unfavorable, was very catalytically active and gave low PCDD/F yields despite a high destruction of 2 MCP. Mullite and alpha-alumina, the thermodynamically favorable form of alumina, yielded higher concentrations of dioxins and products with a higher degree of chlorine substitution than gamma-alumina. The data suggest that certain aluminas and aluminosilicates, commonly found in fly ash, are active catalytic surfaces in the formation of PCDD/Fs in the post-flame cool zones of combustion systems and should be considered as additional catalytic surfaces active in the process. PMID- 26615491 TI - Pyrethroids in indoor air during application of various mosquito repellents: Occurrence, dissipation and potential exposure risk. AB - Commercial mosquito repellents (MRs) are generally applied as mosquito coils, electric vaporizers (liquid and solid) or aerosol spray, with pyrethroids often being the active ingredients. Four types of MRs were applied individually in a 13 m(2) bedroom to study the occurrence, dissipation and risk of pyrethroids in indoor environments. Total air concentrations (in gas and particle phases) of allethrin, cypermethrin, dimefluthrin and tetramethrin during MR applications were three to six orders of magnitude higher than indoor levels before the applications, and allethrin emitted from a vaporizing mat reached the highest concentration measured during the current study (18,600 +/- 4980 ng m(-3)). The fate of airborne pyrethroids was different when the four MRs were applied. Particle-associated allethrin accounted for 95% of its total concentration from the aerosol spray, and was significantly higher than the vaporizing mat (67%), suggesting that the released phase of MRs and size distribution of pyrethroid carrying particles played important roles in the gas-particle partitioning process. In addition, air exchange through open windows more effectively reduced the levels of indoor pyrethroids than ventilation using an air conditioner. The inhalation risk quotients (RQ) for allethrin derived from application of the vaporizing mat ranged from 1.04 +/- 0.40 to 1.98 +/- 0.75 for different age subgroups of the population, suggesting potential exposure risk. Special attention should be given concerning indoor exposure of pyrethroids to these vulnerable groups. PMID- 26615492 TI - Pathway fraction of bromate formation during O3 and O3/H2O2 processes in drinking water treatment. AB - Ozone process has been widely used for drinking water treatment recently. In the oxidation process, bromate is formed by three pathways, i.e., the direct pathway, the direct-indirect pathway and the indirect-direct pathway. This study developed a method to calculate the percentage of these three pathways for bromate formation during O3 process and O3/H2O2 process. Two kinds of water, distilled water containing bromide (DW) and surface water from the Yellow River (SW) were selected as raw rater. The result showed that in natural water systems, the direct-indirect pathway was dominant for bromate formation during the oxidation process. When 3 mg L(-1) O3 was used as the only oxidant, nearly 26% of bromide ion was transferred into bromate in two kinds of water after 80 min. The dominant pathway in DW was the direct pathway (48.5%) and the direct-indirect pathway (46.5%), while that was the direct-indirect pathway (68.9%) in SW. When O3/H2O2 were used as oxidants, as the H2O2 dosage increased, the fractions of bromate formation by direct pathway and direct-indirect pathway decreased, while that by indirect-direct pathway increased. The conversion ratio from bromide to bromate first kept stable or increased, then decreased and reached its minimum when [H2O2]/[O3] ratio was 1.0 in DW and 1.5 in SW. Under this condition the indirect direct pathway took the largest fraction of 70.7% in DW and 64.0% in SW, respectively. PMID- 26615493 TI - Endoplasmic reticulum stress and disturbed calcium homeostasis are involved in copper-induced alteration in hepatic lipid metabolism in yellow catfish Pelteobagrus fulvidraco. AB - The present study was conducted to investigate the effect of Cu exposure on ER stress and Ca(2+) homeostasis, and explore the underlying mechanism of the ER stress and disturbed Ca(2+) homeostasis in the regulation of hepatic lipid metabolism in yellow catfish Pelteobagrus fulvidraco. To this end, three experiments were conducted. In experiment 1, P. fulvidraco were exposed to three waterborne Cu concentrations for 56 days. Waterborne Cu exposure evoked ER stress and SREBP-1c activation and resulted in dysregulation of hepatic lipid metabolism in liver of P. fulvidraco in a time-dependent manner. In experiment 2, specific inhibitors 2-APB (IP3 receptor inhibitor) and dantrolene (RyR receptor inhibitor) were used to explore whether Ca(2+) release from ER was involved in the Cu induced ER stress change. Dantrolene and 2-APB prevented Cu-induced intracellular Ca(2+) elevation, demonstrating that the release of Ca(2+) from the ER, mediated by both RyR and IP3R, contributed to dysregulation of lipid metabolism. In experiment 3, a chemical chaperone (PBA) was used to demonstrate whether Cu induced alteration in lipid metabolism was suppressed through the attenuation of ER stress. PBA attenuated the Cu-induced elevation of mRNA expression of SREBP 1c, SCAP, ACC, FAS, GRP78/BiP, GRP94, CRT, eIF2alpha and XBP-1, and alleviated the Cu-induced downregulation of Insig-1. Based on these observations, these results reveal a link between ER stress and the change of lipid metabolism induced by Cu, which will help to understand the Cu-induced toxicity on cellular and molecular level, and provide some novel insights into the regulation of lipid metabolism in fish. PMID- 26615494 TI - A multivariate spatial crash frequency model for identifying sites with promise based on crash types. AB - Many studies have proposed the use of a systemic approach to identify sites with promise (SWiPs). Proponents of the systemic approach to road safety management suggest that it is more effective in reducing crash frequency than the traditional hot spot approach. The systemic approach aims to identify SWiPs by crash type(s) and, therefore, effectively connects crashes to their corresponding countermeasures. Nevertheless, a major challenge to implementing this approach is the low precision of crash frequency models, which results from the systemic approach considering subsets (crash types) of total crashes leading to higher variability in modeling outcomes. This study responds to the need for more precise statistical output and proposes a multivariate spatial model for simultaneously modeling crash frequencies for different crash types. The multivariate spatial model not only induces a multivariate correlation structure between crash types at the same site, but also spatial correlation among adjacent sites to enhance model precision. This study utilized crash, traffic, and roadway inventory data on rural two-lane highways in Pennsylvania to construct and test the multivariate spatial model. Four models with and without the multivariate and spatial correlations were tested and compared. The results show that the model that considers both multivariate and spatial correlation has the best fit. Moreover, it was found that the multivariate correlation plays a stronger role than the spatial correlation when modeling crash frequencies in terms of different crash types. PMID- 26615495 TI - Evaluation of Temperature and Stress Distribution on 2 Different Post Systems Using 3-Dimensional Finite Element Analysis. AB - BACKGROUND The mouth is exposed to thermal irritation from hot and cold food and drinks. Thermal changes in the oral cavity produce expansions and contractions in tooth structures and restorative materials. The aim of this study was to investigate the effect of temperature and stress distribution on 2 different post systems using the 3-dimensional (3D) finite element method. MATERIAL AND METHODS The 3D finite element model shows a labio-lingual cross-sectional view of the endodontically treated upper right central incisor and supporting periodontal ligament with bone structures. Stainless steel and glass fiber post systems with different physical and thermal properties were modelled in the tooth restored with composite core and ceramic crown. We placed 100 N static vertical occlusal loading onto the center of the incisal surface of the tooth. Thermal loads of 0 degrees C and 65 degrees C were applied on the model for 5 s. Temperature and thermal stresses were determined on the labio-lingual section of the model at 6 different points. RESULTS The distribution of stress, including thermal stress values, was calculated using 3D finite element analysis. The stainless steel post system produced more temperature and thermal stresses on the restorative materials, tooth structures, and posts than did the glass fiber reinforced composite posts. CONCLUSIONS Thermal changes generated stresses in the restorative materials, tooth, and supporting structures. PMID- 26615496 TI - Electrical stimulation on biodegradation of phenol and responses of microbial communities in conductive carriers supported biofilms of the bioelectrochemical reactor. AB - Conductive carbon felts (Cf) were used as biofilm carriers in bioelectrochemical reactors to enhance the electrical stimulation on treatment of phenol-containing synthetic wastewater. In batch test, phenol biodegradation was accelerated under an optimum direct current (DC), which was 2mA for Cf biofilm carriers, lower than that for non-conductive white foam carriers. The stimulation effect was consistent with Adenosine Triphosphate contents in biofilms. The long-term operation further demonstrated that a high and stable phenol removal efficiency could be achieved with applied DC of 2mA, and intermittent DC application was better than continuous one, with phenol removal efficiency of over 97%. Although the quantities of whole microbial communities kept at a high level under all conditions, special microorganisms related with genera of Zoogloea and Desulfovibrio were distinctively enriched under intermittent applied DC pattern. This study shows that the electrical stimulation is potentially effective for biofilm reactors treating phenol-containing wastewater. PMID- 26615497 TI - Simultaneous saccharification and co-fermentation for improving the xylose utilization of steam exploded corn stover at high solid loading. AB - Simultaneous saccharification and co-fermentation (SSCF) of steam exploded corn stover (SECS) was investigated at 5-25% solid loadings compared with other conversion processes. SECS was washed with a 15-fold excess of deionized water to remove inhibitors of hydrolysis and fermentation. The concentration, yield, and productivity of ethanol was 34.3g/L, 90.0%, 2.61g/L/h in the co-fermentation of 60g/L glucose and 10g/L xylose by Saccharomyces cerevisiae IPE003. Ethanol concentration and productivity increased with increasing solid loading while ethanol yield decreased in all conversion processes of SECS. Glucan and xylan conversion was 82.0% and 82.1% in SSCF at 20% solid loading, respectively, while the concentration, yield and productivity of ethanol was 60.8g/L, 75.3% and 0.63g/L/h. The feeding strategy of SECS addition within 24h improved the SSCF performance. Therefore, SSCF increased ethanol productivity and was an effective conversion process for ethanol production at high solid loading. PMID- 26615498 TI - Bioethanol production from taro waste using thermo-tolerant yeast Kluyveromyces marxianus K21. AB - In the present study, evaluation and optimization of taro waste (TW), which was mainly composed of taro peels that contain many starch residues, as the main carbon source in medium were studied. The flask studies showed the optimal medium was using 170g/L of TW which is about 100g/L of glucose and 9g/L of CGM as alternative nitrogen source. Simultaneous saccharification and fermentation (SSF) exhibited higher bioethanol productivity toward separation hydrolysis and fermentation (SHF). The optimal condition of SSF was 5% of Kluyveromyces marxianus K21 inoculum at 40 degrees C resulting in the maximum ethanol concentration (48.98g/L) and productivity (2.23g/L/h) after 22h of cultivation. The scaling up experiment in a 5L bioreactor demonstrated that K21 can still maintain its capability. After 20h of cultivation, 43.78g/L of ethanol (2.19g/L/h of productivity) was achieved corresponding to a 94.2% theoretical ethanol yield. PMID- 26615499 TI - Love moderates the relationship between partner type and condom use among women engaging in transactional vaginal sex. AB - Background Relationship characteristics and day-to-day variation in affective state have been associated with HIV risk behaviour. However, no research has assessed the impact of these factors on event-level condom use among women engaging in transactional sex. METHODS: Twenty-six women engaging in transactional sex were enrolled in a prospective study of their sexual health. They completed diaries about multi-level predictors of condom use during vaginal sex twice, daily. RESULTS: Over 4 weeks, 18 participants reported 87 paid/traded vaginal intercourse events. Of these, 51.7% were condom protected. The majority of paid/traded events (81.5%) occurred with a non-romantic partner. After controlling for partner type, feeling in love on a given day was associated with higher odds of condom use during paid/traded sexual events, while having sex on the weekend and at night were associated with lower odds of condom use (all P<=0.05). There was a significant interaction between being in love and using condoms during transactional sex (P<0.01). In paid/traded sexual events with romantic partners, the frequency of condom use was 71.4% (5/7) when women did not report love and 40% (4/10) when love was reported. In sexual events with non romantic partners, the frequency of condom use was 43.8% (14/32) when women did not report love and 59.5% (22/37) when love was reported. CONCLUSIONS: Women were less likely to report protected sex with romantic partners and more likely to report protected sex with non-romantic partners when they are in love. Interventions focusing on the link between day-to-day variation in affective state on condom use may help women with risk management across partner types. PMID- 26615500 TI - Implicit sequence learning in ring-tailed lemurs (Lemur catta). AB - Implicit learning involves picking up information from the environment without explicit instruction or conscious awareness of the learning process. In nonhuman animals, conscious awareness is impossible to assess, so we define implicit learning as occurring when animals acquire information beyond what is required for successful task performance. While implicit learning has been documented in some nonhuman species, it has not been explored in prosimian primates. Here we ask whether ring-tailed lemurs (Lemur catta) learn sequential information implicitly. We tested lemurs in a modified version of the serial reaction time task on a touch screen computer. Lemurs were required to respond to any picture within a 2 * 2 grid of pictures immediately after its surrounding border flickered. Over 20 training sessions, both the locations and the identities of the images remained constant and response times gradually decreased. Subsequently, the locations and/or the identities of the images were disrupted. Response times indicated that the lemurs had learned the physical location sequence required in original training but did not learn the identity of the images. Our results reveal that ring-tailed lemurs can implicitly learn spatial sequences, and raise questions about which scenarios and evolutionary pressures give rise to perceptual versus motor-implicit sequence learning. PMID- 26615501 TI - TlR expression profile of human gingival margin-derived stem progenitor cells. AB - BACKGROUND: Gingival margin-derived stem/progenitor cells (G-MSCs) show remarkable periodontal regenerative potential in vivo. During regeneration, G MSCs may interact with their inflammatory environment via toll-like-receptors (TLRs). The present study aimed to depict the G-MSCs TLRs expression profile. MATERIAL AND METHODS: Cells were isolated from free gingival margins, STRO-1 immunomagnetically sorted and seeded to obtain single colony forming units (CFUs). G-MSCs were characterized for CD14, CD34, CD45, CD73, CD90, CD105, CD146 and STRO-1 expression, and for multilineage differentiation potential. Following G-MSCs' incubation in basic or inflammatory medium (IL-1beta, IFN-gamma, IFN alpha, TNF-alpha) a TLR expression profile was generated. RESULTS: G-MSCs showed all stem/progenitor cells' characteristics. In basic medium G-MSCs expressed TLRs 1, 2, 3, 4, 5, 6, 7, and 10. The inflammatory medium significantly up-regulated TLRs 1, 2, 4, 5, 7 and 10 and diminished TLR 6 (p<=0.05, Wilcoxon-Signed-Ranks Test). CONCLUSIONS: The current study describes for the first time the distinctive TLRs expression profile of G-MSCs under uninflamed and inflamed conditions. PMID- 26615502 TI - Survey of Spanish dentists on the prescription of antibiotics and antiseptics in surgery for impacted lower third molars. AB - BACKGROUND: This study explored the attitude of registered dentists in Biscay towards prescribing antibiotics and/or antiseptics to prevent potential infections after surgical extraction of completely bone-impacted third molars in otherwise healthy individuals, with no history of infection. MATERIAL AND METHOD: We sent letters to 931 registered dentists in Biscay, with an explanation of the study objectives, description of a case of lower third molar impaction, including a panoramic radiograph, and a questionnaire. The questionnaire asked whether they would prescribe antibiotics and/or antiseptics, in the hypothetical case of lower third molar extraction surgery presented, and if so, when, what type, at what dose and how long for. RESULTS: The questionnaire was completed by 261 dentists (28%), with a mean age of 44.3 years old (SD 11.05) and mean of 18.7 years working as a dentist (SD 9). A total of 216 dentists (82.7%) considered it necessary to prescribe antibiotics. Of these, 126 (58.3%) would prescribe amoxicillin and 74 (34.5%) amoxicillin/clavulanic acid, while 129 dentists (59%) would prescribe antibiotics both before and after surgery and 10 (4.6%) only after surgery. The most common doses were amoxicillin 500 mg or 750 mg every 8 hours, and amoxicillin/clavulanic acid 875/125 mg every 8 hours, in both cases for a mean of 7 days. Further, 74 dentists (28%) said they would use immediate post-extraction socket irrigation with chlorhexidine, while 211 (81%) would prescribe antiseptics in the postoperative period, of whom 97% recommended chlorhexidine. We did not find significant differences in the use of antibiotics or antiseptics by dentist age (ANOVA p=0.22 and p=0.53, respectively), or professional experience (ANOVA p=0.45 and p=0.62). CONCLUSIONS: In our sample, the prophylactic prescription of antibiotics and/or chlorhexidine is widespread in clinical practice, in most cases amoxicillin and amoxicillin/clavulanic acid for a week, starting the treatment before surgery. PMID- 26615503 TI - Antibacterial suture vs silk for the surgical removal of impacted lower third molars. A randomized clinical study. AB - BACKGROUND: The aim of this study was to evaluate the clinical and microbiological impact of an antibacterial suture (Monocryl(r) Plus) in the surgical removal of I3M. MATERIAL AND METHODS: A "split-mouth", prospective pilot clinical study was designed involving 20 patients programmed for the surgical removal of I3M. Each side was randomly sutured with Monocryl(r) Plus or silk suture and removed for microbiological study 72 hours and 7 days after surgery. Presence of SSI, wound bleeding and the degree of discomfort associated with each type of suture material (scored by means of a visual analog scale) were evaluated. The level of contamination of each material was observed under the scanning electron microscope. RESULTS: Wound bleeding upon suture removing was slightly greater after 72 hours and 7 days with black silk suture, though the differences were not statistically significant (p=0.752 and p=0.113, respectively). Patient discomfort was very similar with both types of suture material (p=0.861). Only one case of SSI was recorded with black silk suture after 72 hours. Microbiologically, the antibacterial suture showed a lesser presence of microorganisms (p<0.001, at 72h and p=0.033 at 7th day, respectively). The most common bacterial species included grampositive cocci (Streptococcus viridans group, Neisseria spp., Coagulasenegative Staphylococcus and Peptostreptococcus), gramnegative cocci (Veillonella), grampositive Bacilli (Lactobacillus), and gramnegative Bacilli (Prevotella). CONCLUSIONS: The greatest antibacterial effect of Monocryl Plus suture was observed after 72 hours. According to most authors, there is no doubt that this antibacterial suture can provide little safety in the control of SSI. PMID- 26615504 TI - Impact of crestal and subcrestal implant placement in peri-implant bone: A prospective comparative study. AB - BACKGROUND: To assess the influence of the crestal or subcrestal placement of implants upon peri-implant bone loss over 12 months of follow-up. MATERIAL AND METHODS: Twenty-six patients with a single hopeless tooth were recruited in the Oral Surgery Unit (Valencia University, Valencia, Spain). The patients were randomized into two treatment groups: group A (implants placed at crestal level) or group B (implants placed at subcrestal level). Control visits were conducted by a trained clinician at the time of implant placement and 12 months after loading. A previously established standard protocol was used to compile general data on all patients (sex and age, implant length and diameter, and brushing frequency). Implant success rate, peri-implant bone loss and the treatment of the exposed implant surface were studied. The level of statistical significance was defined as 5% (alpha=0.05). RESULTS: Twenty-three patients (8 males and 15 females, mean age 49.8+/-11.6 years, range 28-75 years) were included in the final data analyses, while three were excluded. All the included subjects were non-smokers with a brushing frequency of up to twice a day in 85.7% of the cases. The 23 implants comprised 10 crestal implants and 13 subcrestal implants. After implant placement, the mean bone position with respect to the implant platform in group A was 0.0 mm versus 2.16+/-0.88 mm in group B. After 12 months of follow up, the mean bone positions were -0.06+/-1.11 mm and 0.95+/-1.50 mm, respectively - this representing a bone loss of 0.06+/-1.11 mm in the case of the crestal implants and of 1.22+/-1.06 mm in the case of the subcrestal implants (p=0.014). Four crestal implants and 5 subcrestal implants presented peri-implant bone levels below the platform, leaving a mean exposed treated surface of 1.13 mm and 0.57 mm, respectively. The implant osseointegration success rate at 12 months was 100% in both groups. CONCLUSIONS: Within the limitations of this study, bone loss was found to be greater in the case of the subcrestal implants, though from the clinical perspective these implants presented bone levels above the implant platform after 12 months of follow-up. PMID- 26615505 TI - Dental anomalies inside the cleft region in individuals with nonsyndromic cleft lip with or without cleft palate. AB - BACKGROUND: Individuals with nonsyndromic cleft lip with or without cleft palate (NSCL+/-P) present high frequency of dental anomalies, which may represent complicating factors for dental treatment. The aim of this study was to investigate the prevalence of dental anomalies inside cleft area in a group of Brazilians with NSCL+/-P. MATERIAL AND METHODS: Retrospective analysis of 178 panoramic radiographs of patients aged from 12 to 45 years old and without history of tooth extraction or orthodontic treatment was performed. Association between cleft type and the prevalence of dental anomalies was assessed by chi square test with a significance level set at p<= 0.05. RESULTS: Dental anomalies were found in 88.2% (n=157) of the patients. Tooth agenesis (47.1%), giroversion (20%) and microdontia (15.5%) were the most common anomalies. Individuals with unilateral complete cleft lip and palate (CLP, p<0.0001), bilateral complete CLP (p=0.0002) and bilateral incomplete CLP (p< 0.0001) were more affected by tooth agenesis than individuals with other cleft types. The maxillary lateral incisors were the most affected teeth (p<0.0001). CONCLUSIONS: The present study revealed a high frequency of dental anomalies inside cleft region in NSCL+/-P patients, and further demonstrated that patients with unilateral complete CLP and bilateral incomplete CLP were frequently more affected by dental anomalies. Moreover, our results demonstrate that dental anomalies should be considered during dental treatment planning of individuals affected by NSCL+/-P. PMID- 26615506 TI - Apoptosis and apoptotic pathway in actinic prurigo by immunohistochemistry. AB - BACKGROUND: Actinic prurigo (AP) is an idiopathic photodermatosis, this entity requires exposure to UV-B and -A to develop lesions. Apoptosis is a physiological death program that can be initiated by a permanently active mechanism (extrinsic pathway) or irreparable damage (intrinsic pathway). MATERIAL AND METHODS: Descriptive study, the sample size comprised 64 paraffin blocks of tissue with a diagnosis of AP. In H&E-stained slides, the diagnosis of AP was corroborated, and 1-um-thick sections were processed for immunohistochemistry (IHC). A database was constructed with SPSS version 20, Inc., Chicago, IL, USA, and descriptive statistics were analyzed by X2 test and comparison of means. RESULTS: A total of 64 cases were processed, of which 40 (62.5%) were cheilitis AP and 24 (37.5%) were AP in the skin. Of the 40 cheilitis samples, 27 were positive for Bcl-2 and caspase 3 (67.5%), p53 was expressed in 30 (75%). Of the skin lesions, p53 and caspase 3 were expressed in 18 of 24 cases (75%), and 13 were positive for Bcl-2 (54%). CONCLUSIONS: We propose that apoptosis is the last step in the type IV subtype a-b hypersensitivity response-activation of the intrinsic pathway indicates that external factors, such as UV-A and -B are the trigger. PMID- 26615507 TI - Can palpation-induced muscle pain pattern contribute to the differential diagnosis among temporomandibular disorders, primary headaches phenotypes and possible bruxism? AB - BACKGROUND: The evaluation of possible differences in the distribution or characteristics of palpation-induced pain in the masticatory muscles could be valuable in terms of diagnostic assessment. The aim of this study was to evaluate the impact of different combinations of anterior temporalis (AT) and masseter palpation-induced pain in the diagnostic of temporomandibular disorder (TMD), primary headaches and bruxism. MATERIAL AND METHODS: A total of 1200 dental records of orofacial pain adult patients were analyzed. The outcomes were dichotomously classified (presence/absence) as following: a) AT and/or masseter palpation-induced pain; b) myogenous TMD; c) temporomandibular joint (TMJ) arthralgia (arthrogenous TMD); d) migraine; e) tension-type headache (TTH); f) self-reported bruxism. Binomial logistic regression model (alpha = 5%) was applied to the data considering the palpation-induced muscle pain as the dependent variable. RESULTS: Mean age (SD) were 35.7 years (13.4) for 635 included dental records (83% females). Myogenous and arthrogenous TMD, migraine, TTH and bruxism were mainly associated with, respectively, masseter palpation induced pain (p<0.001 - OR=5.77, 95%CI 3.86-8.62), AT or masseter palpation induced pain (p<0.001 - OR=2.39, 95%CI 1.57-3.63), bilateral AT palpation-induced pain (p<0.001 - OR=2.67, 95%CI 1.64-4.32), masseter and AT palpation-induced pain (p=0.009 - OR=1.62, 95%CI 1.12-2.33) and bilateral masseter palpation-induced pain (p=0.01 - OR=1.74, 95%CI 1.13-2.69). CONCLUSIONS: Palpation-induced pain in the masticatory muscles may play a role in the differential diagnosis among painful TMD, primary headaches and bruxism. PMID- 26615508 TI - Prevalence of the different Axis I clinical subtypes in a sample of patients with orofacial pain and temporomandibular disorders in the Andalusian Healthcare Service. AB - BACKGROUND: The main objective of this paper is to analyze the prevalence of each of the different clinical subtypes of temporomandibular disorders (TMD) in a sample of patients with this pathology. In addition, a second objective was to analyze their distribution according to gender. MATERIAL AND METHODS: To this end, the results of 1603 patients who went to the Unit of Temporomandibular Disorders in the Cordoba Healthcare District because they suffered from this pathology were analyzed. In order to diagnose them, the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) were applied, analyzing the different Axis I subtypes (myopathy, discopathy and arthropathy) and obtaining the combined Axis I for each patient and the relation of all these variables according to gender. The null-hypothesis test confirmed the lack of connection between the gender variable and the different subtypes in the clinical analysis, and between the former and the combined Axis I of the RDC/TMD. RESULTS: The prevalence was high for the muscle disorders subtype in general, showing an 88.7% prevalence, while the presence of discopathies or arthropathies was much lower. Among discopathies, the most frequent ones were disc displacements with reduction, with 39.7% and 42.8% for the left and right temporomandibular joints (TMJ), respectively, while the prevalence of arthropathies was 26.3% for the right TMJ and 32.9% for the left TMJ. The bivariate analysis on the connection with gender reveals a p>= 0.05 value for the muscle and arthralgia subtypes. CONCLUSIONS: The patients seen at the TMD Unit where mostly middle-aged women whose main clinical axis subtype was the muscle disorder subtype. For their part, both discopathies and arthropathies, although present, are much less prevalent. PMID- 26615509 TI - Single dose of diclofenac or meloxicam for control of pain, facial swelling, and trismus in oral surgery. AB - BACKGROUND: Postoperative pain associated with removal of mandibular third molars has been documented from moderate to severe during the first 24 hours after surgery, with pain peaking between 6 and 8 hours when a conventional local anesthetic is used. Dental pain is largely inflammatory, and evidence-based medicine has shown that nonsteroidal anti-inflammatory drugs are the best analgesics for dental pain. The aim of this study was to compare the analgesic, anti-inflammatory and anti-trismus effect of a single dose of diclofenac and meloxicam after mandibular third molar extraction. MATERIAL AND METHODS: A total of 36 patients were randomized into two treatment groups, each with 18 patients, using a series of random numbers: Group A, was administered 100 mg of diclofenac; and Group B, 15 mg of meloxicam. Drugs were administered orally 1 hour prior to surgery. We evaluated pain intensity, analgesic consumption, swelling, as well as trismus. RESULTS: The results of this study showed that patients receiving 15 mg of meloxicam had less postoperative pain (P=0.04) and better aperture than those receiving 100 mg of diclofenac (P=0.03). The meloxicam group presented less swelling than diclofenac group; however, significant statistical differences were not observed. CONCLUSIONS: Data of this double-blind, randomized, parallel-group clinical trial demonstrated that patients receiving 15 mg of preoperative meloxicam had a better postoperative analgesia and anti-trismus effect compared with who were given 100 mg of diclofenac after third molar extractions. PMID- 26615510 TI - Management of oral Graft versus Host Disease with topical agents: A systematic review. AB - BACKGROUND: Oral Graft-versus-Host Disease (oGvHD) is a common complication of haematopoietic stem cell transplantation. Choosing the right topical application to be used intra orally can be a challenge. Consequently, the aim of this work is to review the effectiveness and safety of topical agents currently used in the management of the inflammatory mucosal lesions encountered in oGVHD. MATERIAL AND METHODS: We carried out electronic searches of publications up to May 2015 of the databases Pubmed, National Library of Medicine's Medline, Embase and the Cochrane Central Register of Controlled Clinical trials to identify potentially relevant studies (keywords: "oral", "graft", "versus", "host", "disease" and "treatment"). The main inclusion criterion was the reported use of a topical agent which was not intentionally swallowed when used for the treatment of oGVHD. A 3-point grading system, described by the Swedish Council on Technology Assessment in Health Care and the Centre for Reviews and Dissemination, University of York, was used to rate the methodological quality of the papers. RESULTS: From the 902 entries identified in the search, 7 studies qualifying for inclusion were analysed. Overall, there is limited evidence with regards to the effectiveness of topical steroids for oGVHD. However, the studies showed some effect of Budesonide alone and when combined with dexamethasone. Topical tacrolimus also appears to have some effect and clobetasol propionate mouthwash had a significantly better clinical response than dexamethasone mouthwash in treating oGVHD. CONCLUSIONS: As the number of clinical trials conducted is limited, there is little evidence to support the use of topical therapies to treat the inflammatory mucosal lesions found in oGVHD. High quality randomised control trials are needed in order to measure the effectiveness of any topical application for the treatment of the inflammatory mucosal lesions found in oGVHD. PMID- 26615511 TI - Preparation of Pd/Fe3O4 nanoparticles by use of Euphorbia stracheyi Boiss root extract: A magnetically recoverable catalyst for one-pot reductive amination of aldehydes at room temperature. AB - We describe a method for supporting palladium nanoparticles on magnetic nanoparticles using Euphorbia stracheyi Boiss root extract as the natural source of reducing and stabilizing agent. The progress of the reaction was monitored using UV-visible spectroscopy. The nanocatalyst was characterized by FE-SEM, TEM, XRD, EDS, FT-IR spectroscopy and ICP. The nanocatalyst was applied as an efficient, magnetically recoverable, highly reusable and heterogeneous catalyst for one-pot reductive amination of aldehydes at room temperature. The nanocatalyst was easily recovered by applying an external magnet and reused several times without considerable loss of activity. PMID- 26615512 TI - A single-step aerosol process for in-situ surface modification of nanoparticles: Preparation of stable aqueous nanoparticle suspensions. AB - HYPOTHESIS: Surface modification of nanoparticles during aerosol or gas-phase synthesis, followed by direct transfer into liquid media can be used to produce stable water-dispersed nanoparticle suspensions. EXPERIMENT: This work investigates a single-step, aerosol process for in-situ surface-modification of nanoparticles. Previous studies have used a two-step sublimation-condensation mechanism following droplet drying, for surface modification, while the present process uses a liquid precursor containing two solutes, a matrix lipid and a surface modifying agent. A precursor solution in chloroform, of stearic acid lipid, with 4 %w/w of surface-active, physiological molecules [1,2-dipalmitoyl-sn glycero-3-phosphocholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac glycerol)-sodium salt (DPPG) or 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine N-[methoxy (polyethylene glycol) 2000]-ammonium salt (DPPE-PEG)] was processed in an aerosol reactor at a low gas temperatures. The surface modified nanoparticles were characterized for morphology, surface composition and suspension properties. FINDINGS: Spherical, surface-modified lipid nanoparticles with median mobility diameters in the range of 105-150nm and unimodal size distributions were obtained. Fourier transform infra-red spectroscopy (FTIR) measurements confirmed the presence of surface-active molecules on external surfaces of modified lipid nanoparticles. Surface modified nanoparticles exhibited improved suspension stability, compared to that of pure lipid nanoparticles for a period of 30days. Lowest aggregation was observed in DPPE-PEG modified nanoparticles from combined electrostatic and steric effects. The study provides a single-step aerosol method for in-situ surface modification of nanoparticles, using minimal amounts of surface active agents, to make stable, aqueous nanoparticle suspensions. PMID- 26615513 TI - Self-powered supercapacitive microbial fuel cell: The ultimate way of boosting and harvesting power. AB - In this work, for the first time, we demonstrate a supercapacitive microbial fuel cell which integrates the energy harvesting function of a microbial fuel cell (MFC) with the high-power operation of an internal supercapacitor. The pursued strategies are: (i) the increase of the cell voltage by the use of high potential cathodes like bilirubin oxidase (BOx) or iron-aminoantipyrine (Fe-AAPyr); (ii) the use of an additional capacitive electrode (additional electrode, AdE) which is short-circuited with the MFC cathode and coupled with the MFC anode (MFC-AdE). The high working potential of BOx cathode and the low impedances of the additional capacitive electrode and the MFC anode permitted to achieve up to 19 mW (84.4 Wm(-2), 152 Wm(-3)), the highest power value ever reported for MFCs. Exploiting the supercapacitive properties of the MFC electrodes allows the system to be simpler, cheaper and more efficient without additional electronics management added with respect to an MFC/external supercapacitor coupling. The use of the AdE makes it possible to decouple energy and power and to achieve recharge times in the order of few seconds making the system appealing for practical applications. PMID- 26615514 TI - Highly sensitive electrochemical sensing platform for lead ion based on synergetic catalysis of DNAzyme and Au-Pd porous bimetallic nanostructures. AB - In this work, a sensitive and specific electrochemical biosensor for lead ion (Pb(2+)) detection was developed by coupling with synergetic catalysis of porous Au-Pd bimetallic nanoparticles and hemin/G-quadruplex-based DNAzyme. In the presence of target Pb(2+), the substrate strand was cleaved and the enzyme strand was released. Subsequently, G-rich DNA-labeled Au-Pd bimetallic nanoparticle was linked with the released enzyme strand through the helper DNA. Upon addition of hemin, a large number of hemin/G-quadruplex-based DNAzyme molecules were formed on the electrode to serve as nicotinamide adenine dinucleotide hydrogen (NADH) oxidase and peroxidase mimics. DNAzyme could catalyzed the reduction of H2O2, generated from NADH in the presence of O2, to produce an electrochemical signal when using thionine as the electron mediator. Introduction of porors Au-Pd bimetallic nanoparticles could enhance the detectable signal and cause the increase in the sensitivity. Experimental results showed that the variations (?I) in the cathodic peak currents of the biosensor were linearly dependent on target Pb(2+) concentrations from 1.0 pM to 100 nM with a detection limit (LOD) of 0.34 pM. The excellent performance of the sensing platform indicated its promising prospect as a valuable tool for simple and cost-effective Pb(2+) detection in practical application. PMID- 26615515 TI - Similar stimulus features control visual classification in orangutans and rhesus monkeys. AB - Many species classify images according to visual attributes. In pigeons, local features may disproportionately control classification, whereas in primates global features may exert greater control. In the absence of explicitly comparative studies, in which different species are tested with the same stimuli under similar conditions, it is not possible to determine how much of the variation in the control of classification is due to species differences and how much is due to differences in the stimuli, training, or testing conditions. We tested rhesus monkeys (Macaca mulatta) and orangutans (Pongo pygmaeus and Pongo abelii) in identical tests in which images were modified to determine which stimulus features controlled classification. Monkeys and orangutans were trained to classify full color images of birds, fish, flowers, and people; they were later given generalization tests in which images were novel, black and white, black and white line drawings, or scrambled. Classification in these primate species was controlled by multiple stimulus attributes, both global and local, and the species behaved similarly. PMID- 26615516 TI - Esmolol reduces anesthetic requirements thereby facilitating early extubation; a prospective controlled study in patients undergoing intracranial surgery. AB - BACKGROUND: Adequate cerebral perfusion pressure with quick and smooth emergence from anesthesia is a major concern of the neuroanesthesiologist. Anesthesia techniques that minimize anesthetic requirements and their effects may be beneficial. Esmolol, a short acting hyperselective beta-adrenergic blocker is effective in blunting adrenergic response to several perioperative stimuli and so it might interfere in the effect of the anesthetic drugs on the brain. This study was designed to investigate the effect of esmolol on the consumption of propofol and sevoflurane in patients undergoing craniotomy. METHOD: Forty-two patients that underwent craniotomy for aneurysm clipping or tumour dissection were randomly divided in two groups (four subgroups). Anesthesia was induced with propofol, fentanyl and a single dose of cis-atracurium, followed by continuous infusion of remifentanil and either propofol or sevoflurane. Patients in the esmolol group received 500 mcg/kg of esmolol bolus 10 min before induction of anesthesia, followed by additional 200 mcg/kg/min of esmolol. Monitoring of the depth of anesthesia was also performed using the Bispectral Index-BIS and cardiac output. The inspired concentration of sevoflurane and the infusion rate of propofol were adjusted in order to maintain a BIS value between 40-50. Intraoperative emergence was detected by the elevation of BIS value, HR or MAP. RESULTS: The initial and the intraoperative doses of propofol and sevoflurane were 18-50 mcg/kg/min and 0.2-0.5 MAC respectively in the esmolol group, whereas in the control group they where 100-150 mcg/kg/ and 0.9-2.0 MAC respectively (p = 0.000 for both groups). All procedures were anesthesiologically uneventful with no episodes of intraoperative emerge. CONCLUSIONS: Esmolol is effective not only in attenuating intraoperative hemodynamic changes related to sympathetic overdrive but also in minimizing significant propofol and sevoflurane requirements without compromising the hemodynamic status. ClinicalTrials.gov Identifier: NCT02455440 . Registered 26 May 2015. PMID- 26615517 TI - Covert enaction at work: Recording the continuous movements of visuospatial attention to visible or imagined targets by means of Steady-State Visual Evoked Potentials (SSVEPs). AB - Whereas overt visuospatial attention is customarily measured with eye tracking, covert attention is assessed by various methods. Here we exploited Steady-State Visual Evoked Potentials (SSVEPs) - the oscillatory responses of the visual cortex to incoming flickering stimuli - to record the movements of covert visuospatial attention in a way operatively similar to eye tracking (attention tracking), which allowed us to compare motion observation and motion extrapolation with and without eye movements. Observers fixated a central dot and covertly tracked a target oscillating horizontally and sinusoidally. In the background, the left and the right halves of the screen flickered at two different frequencies, generating two SSVEPs in occipital regions whose size varied reciprocally as observers attended to the moving target. The two signals were combined into a single quantity that was modulated at the target frequency in a quasi-sinusoidal way, often clearly visible in single trials. The modulation continued almost unchanged when the target was switched off and observers mentally extrapolated its motion in imagery, and also when observers pointed their finger at the moving target during covert tracking, or imagined doing so. The amplitude of modulation during covert tracking was ~25-30% of that measured when observers followed the target with their eyes. We used 4 electrodes in parieto-occipital areas, but similar results were achieved with a single electrode in Oz. In a second experiment we tested ramp and step motion. During overt tracking, SSVEPs were remarkably accurate, showing both saccadic-like and smooth pursuit-like modulations of cortical responsiveness, although during covert tracking the modulation deteriorated. Covert tracking was better with sinusoidal motion than ramp motion, and better with moving targets than stationary ones. The clear modulation of cortical responsiveness recorded during both overt and covert tracking, identical for motion observation and motion extrapolation, suggests to include covert attention movements in enactive theories of mental imagery. PMID- 26615518 TI - Repetition suppression to faces in the fusiform face area: A personal and dynamic journey. AB - I review a number of fMRI studies that investigate the effects of repeating faces on responses in the fusiform face area (FFA). These studies show that repetition suppression (RS), as well as repetition enhancement (RE), are sensitive to multiple factors, including pre-existing stimulus representations, cognitive task, lag between repetitions and spatial attention. Parallel EEG studies provide additional constraints on the timing of these repetition effects. Together, the results suggest that RS is not a unitary phenomenon, but likely subsumes multiple mechanisms that operate under different conditions. These mechanisms of course need to relate to single-cell data and known physiological mechanisms; but to make further progress, I believe we need dynamical neural network models that relate these mechanisms to the properties of neural populations that are measured by fMRI and EEG data. One example model is sketched, in which RS reflects an acceleration of neural dynamics, owing to reduced prediction error within a recurrent visual processing hierarchy. PMID- 26615520 TI - Human umbilical vein endothelial cells promote the inhibitory activation of CD4(+)CD25(+)Foxp3(+) regulatory T cells via PD-L1. AB - BACKGROUND: Atherosclerosis (AS) is a chronic inflammation characterized by massive infiltration of inflammatory cells in arterial wall plaques. Programmed death ligand-1 (PD-L1), a co-stimulatory molecule, plays a vital role in regulating immune responses. We investigated the role and mechanisms of PD-L1 expressed on oxidized low-density lipoprotein (ox-LDL)-impaired human umbilical vein endothelial cells (HUVECs) in promoting activation and cytokine production of CD4(+)CD25(+) forkhead box P3 (FoxP3) regulatory T cells (Tregs). METHODS AND RESULTS: Tregs were incubated alone, with HUVECs or HUVECs pre-stimulated with ox LDL in the presence of anti-CD3 monoclonal antibodies (mAbs) for 48 h. HUVECs were shown to upregulate the immune phenotypic markers of Tregs, such as glucocorticoid-induced TNF receptor (GITR), cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 protein (PD-1). Moreover, HUVECs modulated cytokine production of Tregs (e.g., interleukin-10 (IL-10) and transforming growth factor-beta1 (TGF-beta1)). HUVECs treated with anti-PD-L1 mAbs were unable to regulate the surface expression and cytokine production of Tregs. The Transwell culture system suggested that interaction between HUVECs and Tregs via PD-L1 requires cell-to-cell contact. CONCLUSION: Expression of the negative co stimulatory molecule PD-L1 on HUVECs may upregulate the inhibitory activation and cytokine production of CD4(+)CD25(+)Foxp3(+) regulatory T cells in AS. PMID- 26615521 TI - Mixed Streptococcus pneumoniae and Streptococcus pyogenes meningitis in an immunocompromised adult patient: a case report. AB - INTRODUCTION: Community-acquired meningitis is a monomicrobial infection caused by either viruses or bacteria in the vast majority of patients. We report here one exceptional case of a patient with mixed bacterial meningitis due to Streptococcus pneumoniae and Streptococcus pyogenes. CASE PRESENTATION: We report the case of a 68-year-old immunocompromised Caucasian man suffering from otitis and then meningitis caused by Streptococcus pneumoniae and Streptococcus pyogenes. Bacteria were undistinguishable by direct microscopic examination of the cerebrospinal fluid. He responded well to treatment with cefotaxime and dexamethasone, with no sequelae observed at the 4-month follow-up. CONCLUSIONS: This first reported case of mixed S. pneumoniae and S. pyogenes meningitis illustrates the life-threatening consequences of barotrauma in immunocompromised patients suffering from otorhinolaryngeal infections. PMID- 26615522 TI - Factors Associated with Low Flow in Aortic Valve Stenosis. AB - BACKGROUND: Low-flow low-gradient aortic stenosis (AS) is a predictor of worse outcome compared with normal-flow AS. Although depressed left ventricular ejection fraction (LVEF) is associated with low flow, there is less evidence to support the role of other indices of cardiac structure and function. METHODS: Clinical and echocardiographic data from patients with native AS and valve areas <= 1.0 cm(2) were retrospectively analyzed to identify characteristics that are associated with low-flow low-gradient AS. RESULTS: In total, 941 patients were included. On multivariate analysis, factors independently associated with low flow (stroke volume index < 35 mL/m(2)) included worse right ventricular systolic function, atrial fibrillation, lower LVEF, and higher left ventricular mass, with moderate or severe mitral regurgitation independently associated with low flow in the 694 patients (74%) with preserved LVEFs. CONCLUSIONS: Right ventricular dysfunction and atrial fibrillation are independently associated with low-flow low-gradient AS, while moderate or severe MR is independently associated with low flow in patients with preserved LVEF. These associations with low flow in AS are clinically important to recognize, to avoid underestimation of AS severity. PMID- 26615519 TI - A systematic review of predictive models for asthma development in children. AB - BACKGROUND: Asthma is the most common pediatric chronic disease affecting 9.6 % of American children. Delay in asthma diagnosis is prevalent, resulting in suboptimal asthma management. To help avoid delay in asthma diagnosis and advance asthma prevention research, researchers have proposed various models to predict asthma development in children. This paper reviews these models. METHODS: A systematic review was conducted through searching in PubMed, EMBASE, CINAHL, Scopus, the Cochrane Library, the ACM Digital Library, IEEE Xplore, and OpenGrey up to June 3, 2015. The literature on predictive models for asthma development in children was retrieved, with search results limited to human subjects and children (birth to 18 years). Two independent reviewers screened the literature, performed data extraction, and assessed article quality. RESULTS: The literature search returned 13,101 references in total. After manual review, 32 of these references were determined to be relevant and are discussed in the paper. We identify several limitations of existing predictive models for asthma development in children, and provide preliminary thoughts on how to address these limitations. CONCLUSIONS: Existing predictive models for asthma development in children have inadequate accuracy. Efforts to improve these models' performance are needed, but are limited by a lack of a gold standard for asthma development in children. PMID- 26615523 TI - Can housing improvements cure or prevent the onset of health conditions over time in deprived areas? AB - BACKGROUND: There is a need for more evidence linking particular housing improvements to changes in specific health conditions. Research often looks at generic works over short periods. METHODS: We use a longitudinal sample (n = 1933) with a survey interval of 2-5 years. Multivariate logistic regression is used to calculate the odds ratios of developing or recovering from six health conditions according to receipt of four types of housing improvements. RESULTS: Receipt of fabric works was associated with higher likelihood of recovery from mental health problems and circulatory conditions. Receipt of central heating was also associated with higher likelihood of recovery form circulatory conditions. No evidence was found for the preventative effects of housing improvements. CONCLUSIONS: Health gain from housing improvements appears most likely when targeted at those in greatest health need. The health impacts of area-wide, non targeted housing improvements are less clear in our study. PMID- 26615524 TI - Polyomavirus large T antigen is prevalent in urothelial carcinoma post-kidney transplant. AB - Viral pathogens have been associated with both infectious disease and neoplasia in transplant recipients. Polyomavirus is emerging as a potential causative agent for genitourinary tract cancer in post-kidney transplant patients. Human papillomavirus (HPV) has a proven role in squamous cancers, but has not been studied in genitourinary malignancies in transplantation. Of 2345 kidney transplants performed at our center over the past 20 years, we identified 16 patients with 20 genitourinary cancers (0.7%), including 13 bladder/ureter carcinomas, 5 renal cell carcinomas (RCCs), and 2 prostate carcinomas. We performed immunohistochemical staining for polyomavirus large T antigen and p16, followed by in situ hybridization for HPV in p16+ cases. Four cases of high-grade invasive urothelial bladder carcinomas were positive for large T. Large T+ urothelial carcinomas developed at least 8 years posttransplant in young men, 3 with history of BK polyoma viremia, 2 of whom had native kidney failure due to reflux/obstruction. In situ hybridization for high-risk HPV was negative in all tested cases. Overall, 3 patients died of carcinoma. All 5 RCCs were negative for both large T and p16; 2 prostate cancers were p16 negative and p16+/HPV negative, respectively. Thus, our study shows a relatively high prevalence of large T antigen in urothelial carcinoma in kidney transplant patients (31%), but not in RCC. Although sample size is small, young patients with obstructive disease may be at particular risk for developing large T-positive urothelial carcinoma. Overall, our data further support the necessities of long-term cancer surveillance for renal transplant patients. PMID- 26615526 TI - Highlight report: acetaminophen hepatotoxicity. PMID- 26615525 TI - Angle and Base of Gait Long Leg Axial and Intraoperative Simulated Weightbearing Long Leg Axial Imaging to Capture True Frontal Plane Tibia to Calcaneus Alignment in Valgus and Varus Deformities of the Rearfoot and Ankle. AB - The long leg axial view is primarily used to evaluate the frontal plane alignment of the calcaneus in relation to the long axis of the tibia when standing. This view allows both angular measurement and assessment for the apex of varus and valgus deformity of the rearfoot and ankle with clinical utility in the preoperative, intraoperative, and postoperative settings. The frontal plane alignment of the calcaneus to the long axis of the tibia is rarely fixed in the varus or valgus position because of the inherent flexibility of the foot and ankle, which makes patient positioning critical to obtain accurate and reproducible images. Inconsistent patient positioning and imaging techniques are commonly encountered with the long leg axial view for a variety of reasons, including the lack of a standardized or validated protocol. This angle and base of gait imaging protocol involves positioning the patient to align the tibia with the long axis of the foot, which is represented by the second metatarsal. Non weightbearing long leg axial imaging is commonly performed intraoperatively, which requires a modified patient positioning technique to capture simulated weightbearing long leg axial images. A case series is presented to demonstrate our angle and base of gait long leg axial and intraoperative simulated weightbearing long leg axial imaging protocols that can be applied throughout all phases of patient care for various foot and ankle conditions. PMID- 26615527 TI - Highlight report: redox-metals in toxicology. PMID- 26615528 TI - The ultra-slow NAT2*6A haplotype is associated with reduced higher cognitive functions in an elderly study group. AB - N-Acetyltransferase 2 (NAT2) genotype is associated with age-related declines in basic sensory hearing functions. However, the possible modulatory role of NAT2 for higher cognitive functions has not yet been studied. We tested auditory goal directed behavior and attentional control in 120 NAT2 genotyped subjects (63-88 years), using an auditory distraction paradigm in which participants responded to the duration of long and short tone stimuli. We studied involuntary shifts in attention to task-irrelevant deviant stimuli and applied event-related potentials (ERPs) to examine which cognitive subprocesses are affected by NAT2 status on a neurophysiological level. Relative to the standard stimuli, deviant stimuli decreased performance in the recently described ultra-slow acetylators (NAT2*6A and *7B): The increase in error-corrected reaction times (a combined measure of response speed and accuracy) in ultra-slow acetylators (254 ms increase) was more than twice as high as in the rapid acetylator reference group (111 ms increase; p < 0.01). The increase was still higher than in the other slow acetylators (149 ms increase, p < 0.05). In addition, clear differences were found in the ERP results: Ultra-slow acetylators showed deficits specifically in the automatic detection of changes in the acoustic environment as evidenced by reduced mismatch negativity (MMN, p < 0.005 compared to rapid acetylators). Refocussing of attention after a distracting event was also impaired in the ultra-slow acetylators as evidenced by a reduced re-orienting negativity (RON, p < 0.01 compared to rapid acetylators). In conclusion, the ultra-slow acetylation status was associated with reduced higher cognitive functions. PMID- 26615529 TI - Mutual invadability near evolutionarily singular strategies for multivariate traits, with special reference to the strongly convergence stable case. AB - Over the last two decades evolutionary branching has emerged as a possible mathematical paradigm for explaining the origination of phenotypic diversity. Although branching is well understood for one-dimensional trait spaces, a similarly detailed understanding for higher dimensional trait spaces is sadly lacking. This note aims at getting a research program of the ground leading to such an understanding. In particular, we show that, as long as the evolutionary trajectory stays within the reign of the local quadratic approximation of the fitness function, any initial small scale polymorphism around an attracting invadable evolutionarily singular strategy (ess) will evolve towards a dimorphism. That is, provided the trajectory does not pass the boundary of the domain of dimorphic coexistence and falls back to monomorphism (after which it moves again towards the singular strategy and from there on to a small scale polymorphism, etc.). To reach these results we analyze in some detail the behavior of the solutions of the coupled Lande-equations purportedly satisfied by the phenotypic clusters of a quasi-n-morphism, and give a precise characterisation of the local geometry of the set D in trait space squared harbouring protected dimorphisms. Intriguingly, in higher dimensional trait spaces an attracting invadable ess needs not connect to D. However, for the practically important subset of strongly attracting ess-es (i.e., ess-es that robustly locally attract the monomorphic evolutionary dynamics for all possible non-degenerate mutational or genetic covariance matrices) invadability implies that the ess does connect to D, just as in 1-dimensional trait spaces. Another matter is that in principle there exists the possibility that the dimorphic evolutionary trajectory reverts to monomorphism still within the reign of the local quadratic approximation for the invasion fitnesses. Such locally unsustainable branching cannot occur in 1- and 2-dimensional trait spaces, but can do so in higher dimensional ones. For the latter trait spaces we give a condition excluding locally unsustainable branching which is far stricter than the one of strong convergence, yet holds good for a relevant collection of published models. It remains an open problem whether locally unsustainable branching can occur around general strongly attracting invadable ess-es. PMID- 26615530 TI - The First Observation of Domoic Acid in Plankton Net Samples from the Sea of Marmara, Turkey. AB - This study reports the first evidence of domoic acid (DA), an algal neurotoxin produced by the genus Pseudo-nitzschia, from plankton net samples collected in the Sea of Marmara in December, 2010 and February, 2011. DA concentrations of plankton net samples were analyzed by high-performance liquid chromatography (HPLC), using the fluorenylmethoxycarbonyl fluorescence derivatization technique (detection limit 0.2 ng DA). The biotoxin concentrations in samples from coastal waters varied between 0.96 and 5.25 ug DA/mL. We also investigated possible correlations between physicochemical parameters and DA concentration. The DA levels appear to be correlated negatively with silica and nitrite concentrations for both sampling periods. These data may be used to evaluate the probability of finding similar conditions in coastal waters of the Sea of Marmara in order to determine the potential risks to local aquaculture and fisheries. PMID- 26615531 TI - Excessive Copper(II) and Zinc(II) Levels in Drinkable Water Sources in Areas Along the Lake Victoria Shorelines in Siaya County, Kenya. AB - Copper(II) and zinc(II) levels in drinkable water sources in the alluvium areas of the Lake Victoria Basin in Siaya County of Kenya were evaluated to assess the risk posed to resident communities by hydrogeological accumulation of toxic residues in the sedimentary regions of the lake basin. The levels of the metals in water were analyzed by atomic absorption spectroscopy. Metal concentrations ranged from 0.11 to 4.29 mg/L for Cu(II) and 0.03 to 1.62 mg/L for Zn(II), which were both higher than those normally recorded in natural waters. The Cu(II) levels also exceeded WHO guidelines for drinking water in 27% of the samples. The highest prevalence of excessive Cu(II) was found among dams and open pans (38%), piped water (33%) and spring water (25%). It was estimated that 18.2% of the resident communities in the current study area are exposed to potentially toxic levels of Cu(II) through their drinking water. PMID- 26615532 TI - Educating Engineers for the Public Good Through International Internships: Evidence from a Case Study at Universitat Politecnica de Valencia. AB - At Universitat Politecnica de Valencia, Meridies, an internship programme that places engineering students in countries of Latin America, is one of the few opportunities the students have to explore the implications of being a professional in society in a different cultural and social context. This programme was analyzed using the capabilities approach as a frame of reference for examining the effects of the programme on eight student participants. The eight pro-public-good capabilities proposed by Melanie Walker were investigated through semi-structured interviews. The internship is an environment in which students can put into practice the knowledge they have acquired in undergraduate studies and to find practical relevance in what they studied. Occasionally, this also entails a critical questioning of what they have learned, a greater awareness of the limits of the contents of their studies and of the way things were taught, and interest in less explored issues that are closely linked to social justice. However, tensions can arise between the pro-public-good oriented perspectives of this programme, and a more instrumental vision. One way to overcome these tensions is to foster consideration of reflexivity, that is, the dynamic relationship between technology and society. To do so, the programme must create space before and during the internship, and upon the return of the students, to discuss and collectively reflect upon their lived experience. Additionally, it ought to engage supervisors in this educational journey, both at the university and in the host institutions, and also involve socially committed organisations in this task. PMID- 26615535 TI - Study on the correlation of vertebral artery dominance, basilar artery curvature and posterior circulation infarction. AB - Vertebral artery dominance (VAD), which is a common congenital variation of vertebral artery, may be associated with an increased risk of cerebral posterior circulation infarction (PCI). The aims of this study were to investigate the correlation of VAD with incidence and laterality of PCI, and oblige the correlation of VAD and basilar artery (BA) curvature. Incidence of separate territory infarction in posterior circulation and incidence of BA curvature were compared between 78 VAD patients and 68 controls. VA dominance, laterality of BA curvature and separate territory infarction, and their directional relationships were observed in VAD group. The incidence of BA curvature in VAD group was significantly higher than that in controls (P = 0.000). 89.7 % (35/39) of patients had an opposite directional relationship between dominant VA and BA curvature. The total incidence of PCI in VAD group was significantly higher than that in controls (P = 0.001). The incidences of posterior inferior cerebellar artery (PICA) and BA territory infarction were both significantly higher than those in controls [11.5 % (9/78) vs. 1.5 % (1/68), P = 0.016; 20.5 % (16/78) vs. 7.4 % (5/68), P = 0.024]. No differences were found in superior cerebellar artery and posterior cerebral artery territory infarction between two groups. 77.8 % (7/9) of PICA infarction were on the opposite side of dominant VA. 75.0 % (12/16) of BA infarction were on the side of dominant VA. The incidence of PCI in BA curvature patients was significantly higher than that in BA straight patients. The incidence of BA curvature is higher in VAD patients, and BA usually bends to the opposite side of dominant VA. The incidence of PCI is higher in VAD patients, especially in PICA infarction and BA infarction patients. PMID- 26615533 TI - Mitotic kinase cascades orchestrating timely disjunction and movement of centrosomes maintain chromosomal stability and prevent cancer. AB - Centrosomes are microtubule-organizing centers that duplicate in S phase to form bipolar spindles that separate duplicated chromosomes faithfully into two daughter cells during cell division. Recent studies show that proper timing of centrosome dynamics, the disjunction and movement of centrosomes, is tightly linked to spindle symmetry, correct microtubule-kinetochore attachment, and chromosome segregation. Here, we review mechanisms that regulate centrosome dynamics, with emphasis on the roles of key mitotic kinases in the proper timing of centrosome dynamics and how aberrancies in these processes may cause chromosomal instability and cancer. PMID- 26615534 TI - Incidence of delayed ipsilateral intraparenchymal hemorrhage after stent-assisted coiling of intracranial aneurysms in a high-volume single center. AB - INTRODUCTION: Delayed ipsilateral intraparenchymal hemorrhage (IPH) has been reported following technically successful treatment of intracranial aneurysms using flow-diverting stents in up to 8.5% of patients. We report a similar, though less frequent phenomenon in the setting of stent-assisted coil embolization. METHODS: Institutional review board approval was obtained. A retrospective analysis of a prospective neurointerventional procedure registry was performed to review all IPHs that occurred in aneurysm patients within 90 days of endovascular treatment performed between November 2002 and November 2014 at one institution. Age, sex, hypertension, dual antiplatelet therapy, and technical details of the procedure were recorded. RESULTS: A total of 1697 patients underwent endovascular treatment of an intracranial aneurysm without a flow diverter at our institution during the study period. Among these, 138 patients underwent stent-assisted coiling (8.1%). Of these, three patients (2.2%) suffered a delayed IPH within the vascular territory distal to the treated lesion (one woman, median age 60 years). CONCLUSIONS: Recently described in the setting of flow diversion, delayed ipsilateral IPH is not limited to flow-diverting stents. Though less frequent, a potential for this complication may exist following any intracranial stenting procedure, possibly related to hemorrhagic conversion of microembolic phenomena in the setting of dual antiplatelet or anticoagulation therapy. PMID- 26615536 TI - Assessment of voice and speech symptoms in early Parkinson's disease by the Robertson dysarthria profile. AB - Changes in voice and speech are thought to involve 75-90% of people with PD, but the impact of PD progression on voice/speech parameters is not well defined. In this study, we assessed voice/speech symptoms in 48 parkinsonian patients staging <3 on the modified Hoehn and Yahr scale and 37 healthy subjects using the Robertson dysarthria profile (a clinical-perceptual method exploring all components potentially involved in speech difficulties), the Voice handicap index (a validated measure of the impact of voice symptoms on quality of life) and the speech evaluation parameter contained in the Unified Parkinson's Disease Rating Scale part III (UPDRS-III). Accuracy and metric properties of the Robertson dysarthria profile were also measured. On Robertson dysarthria profile, all parkinsonian patients yielded lower scores than healthy control subjects. Differently, the Voice Handicap Index and the speech evaluation parameter contained in the UPDRS-III could detect speech/voice disturbances in 10 and 75% of PD patients, respectively. Validation procedure in Parkinson's disease patients showed that the Robertson dysarthria profile has acceptable reliability, satisfactory internal consistency and scaling assumptions, lack of floor and ceiling effects, and partial correlations with UPDRS-III and Voice Handicap Index. We concluded that speech/voice disturbances are widely identified by the Robertson dysarthria profile in early parkinsonian patients, even when the disturbances do not carry a significant level of disability. Robertson dysarthria profile may be a valuable tool to detect speech/voice disturbances in Parkinson's disease. PMID- 26615537 TI - Assessing the risk: Scoring systems for outcome prediction in emergency laparotomies. AB - Emergency laparotomy is the commonest emergency surgical procedure in most hospitals and includes over 400 diverse surgical procedures. Despite the evolution of medicine and surgical practices, the mortality in patients needing emergency laparotomy remains abnormally high. Although surgical risk assessment first started with the ASA Physical Status score in 1941, efforts to find an ideal scoring system that accurately estimates the risk of mortality, continues till today. While many scoring systems have been developed, no single scoring system has been validated across multiple centers and geographical locations. While some scoring systems can predict the risk merely based upon preoperative findings and parameters, some rely on intra-operative assessment and histopathology reports to accurately stratify the risk of mortality. Although most scoring systems can potentially be used to compare risk-adjusted mortality across hospitals and amongst surgeons, only those which are based on preoperative findings can be used for risk prognostication and identify high-risk patients before surgery for an aggressive treatment. The recognition of the fact, that in the absence of outcome data in these patients, it would be impossible to evaluate the impact of quality improvement initiatives on risk-adjusted mortality, hospital groups and surgical societies have got together and started to pool data and analyze it. Appropriate scoring systems for emergency laparotomies would help in risk prognostication, risk-adjusted audit and assess the impact of quality improvement initiative in patient care across hospitals. Large multi-centric studies across varied geographic locations and surgical practices need to assess and validate the ideal and most apt scoring system for emergency laparotomies. While APACHE-II and P-POSSUM continue to be the most commonly used scoring system in emergency laparotomies,studies need to compare them in their ability to predict mortality and explore if either has a higher sensitivity and specificity than the other. PMID- 26615539 TI - Wound dressings - a review. AB - Wound healing is a dynamic and complex process which requires suitable environment to promote healing process. With the advancement in technology, more than 3000 products have been developed to treat different types of wounds by targeting various aspects of healing process. The present review traces the history of dressings from its earliest inception to the current status and also discusses the advantage and limitations of the dressing materials. PMID- 26615538 TI - Nutrition, psychoneuroimmunology and depression: the therapeutic implications of omega-3 fatty acids in interferon-alpha-induced depression. AB - The unmet need of current pharmacotherapy and the high occurrence of somatic symptoms and physical illness in depression imply that the 'monoamine hypothesis' is insufficient in approaching the aetiology of depression. Clinically, depressed patients manifest higher levels of inflammatory biomarkers, while proinflammatory cytokines induce neuropsychiatric symptoms (sickness behaviour) as well as major depressive episodes. Indeed, accumulating evidence suggests that inflammation dysregulation plays an important role in the pathophysiology of depression. Biological mechanisms that link inflammation to neuropsychiatric symptoms are vital in the understanding of the "mind-body" interface. IFN-alpha-induced depression is the most powerful support for the inflammation theory of depression. This clinical observation provides an excellent model for depression research. By comparing subjects with and without major depression induced by the cytokine treatment, statistical powers could be largely increased by reducing phenotypic variation (homogeneity in aetiological factors). In addition, the anti inflammatory pathway has recently become an important topic in looking for new antidepressant therapies. For example, anti-inflammatory compounds, omega-3 polyunsaturated fatty acids (omega-3 PUFAs or n-3 PUFAs), have been found to be associated with the development and treatment for depression in human and animal models. Here I review recent epidemiological studies, cross-sectional and longitudinal case-controlled studies, interventional clinical trials, as well as basic animal and cellular studies to prove the linkage among omega-3 PUFAs, inflammation, and depression. PMID- 26615540 TI - Influencing and moderating factors analyzed in the group art therapy of two schizophrenic inpatients. AB - Art therapy has been considered a guideline treatment for schizophrenia. Due to difficulty in the outcome measurement, the research is difficult and controversial. Here, we presented two schizophrenic patients receiving the regular art group therapy. We compared their characteristics and different outcome. Art therapy is difficult to quantify. However, we could qualify the improvement from the individual case. Further study might be focus on how to make appropriate qualification of art therapy and individualized difference instead of enrollment of huge data bank. PMID- 26615541 TI - "Personal Knowledge" in Medicine and the Epistemic Shortcomings of Scientism. AB - In this paper, we outline a framework for understanding the different kinds of knowledge required for medical practice and use this framework to show how scientism undermines aspects of this knowledge. The framework is based on Michael Polanyi's claim that knowledge is primarily the product of the contemplations and convictions of persons and yet at the same time carries a sense of universality because it grasps at reality. Building on Polanyi's ideas, we propose that knowledge can be described along two intersecting "dimensions": the tacit explicit and the particular-general. These dimensions supersede the familiar "objective-subjective" dichotomy, as they more accurately describe the relationship between medical science and medical practice. Scientism, we argue, excludes tacit and particular knowledge and thereby distorts "clinical reality" and impairs medical practice and medical ethics. PMID- 26615542 TI - The Race Idea in Reproductive Technologies: Beyond Epistemic Scientism and Technological Mastery. AB - This paper explores the limitations of epistemic scientism for understanding the role the concept of race plays in assisted reproductive technology (ART) practices. Two major limitations centre around the desire to use scientific knowledge to bring about social improvement. In the first case, undue focus is placed on debunking the scientific reality of racial categories and characteristics. The alternative to this approach is to focus instead on the way the race idea functions in ART practices. Doing so reveals how the race idea (1) helps to define the reproductive "problems" different groups of women are experiencing and to dictate when and how they should be "helped"; (2) helps to resolve tensions about who should be considered the real parents of children produced by reproductive technologies; and (3) is used to limit ART use where that use threatens to denaturalize the very sociopolitical landscape the race idea has created. In the second case, scientific knowledge regarding reproduction is thought to call for technological control over that reproduction. This leads to an overemphasis on personal responsibility and a depoliticization of racialized social inequalities. PMID- 26615543 TI - Culture, Truth, and Science After Lacan. AB - Truth and knowledge are conceptually related and there is a way of construing both that implies that they cannot be solely derived from a description that restricts itself to a set of scientific facts. In the first section of this essay, I analyse truth as a relation between a praxis, ways of knowing, and the world. In the second section, I invoke the third thing-the objective reality on which we triangulate as knowing subjects for the purpose of complex scientific endeavours like medical science and clinical care. Such praxes develop robust methods of "keeping in touch" with disease and illness (like biomarkers). An analysis drawing on philosophical semantics motivates the needed (anti scientistic) account of meaning and truth (and therefore knowledge) and underpins the following argument: (i) the formulation and dissemination of knowledge rests on language; (ii) language is selective in what it represents in any given situation; (iii) the praxes of a given (sub)culture are based on this selectivity; but (iv) human health and illness involve whole human beings in a human life-world; therefore, (v) medical knowledge should reflectively transcend, where required, biomedical science towards a more inclusive view. Parts three and four argue that a post-structuralist (Lacanian) account of the human subject can avoid both scientism and idealism or unconstrained relativism. PMID- 26615544 TI - Scientism and Pseudoscience: A Philosophical Commentary. AB - The term "scientism" is used in a variety of ways with both negative and positive connotations. I suggest that some of these uses are inappropriate, as they aim simply at dismissing without argument an approach that a particular author does not like. However, there are legitimate negative uses of the term, which I explore by way of an analogy with the term "pseudoscience." I discuss these issues by way of a recent specific example provided by a controversy in the field of bioethics concerning the value, or lack thereof, of homeopathy. I then frame the debate about scientism within the broader context of C.P. Snow's famous essay on the "two cultures." PMID- 26615545 TI - Scientism as a Social Response to the Problem of Suicide. AB - As one component of a broader social and normative response to the problem of suicide, scientism served to minimize sociopolitical and religious conflict around the issue. As such, it embodied, and continues to embody, a number of interests and values, as well as serving important social functions. It is thus comparable with other normative frameworks and can be appraised, from an ethical perspective, in light of these values, interests, and functions. This work examines the key values, interests, and functions of scientism in suicidology and argues that although scientism has had some social benefit, it primarily serves to maintain political and professional interests and has damaging implications for suicide research and prevention. PMID- 26615547 TI - The relevance of neutral arm positioning for true ap-view X-ray to provide true projection of the humeral head shaft angle. AB - INTRODUCTION: Textbooks commonly recommend using the true anterior-posterior (ap) view with the patient's arm in a sling and therefore in internal rotation (IR) for radiologic diagnostic assessment of the proximal humerus after trauma. However, IR or external rotation (ER) may affect the projection of the head shaft angle (HSA) and therefore bias the diagnostic conclusion significantly. We hypothesized that neutral rotation (NR) of the arm is mandatory for true ap-view to provide true projection of the HSA. MATERIALS AND METHODS: A simplified geometrical model of the proximal humerus was used to examine the influence of different arm positions and angulations of the central ray in relation to the projection of the HSA. RESULTS: Both ER and IR misleadingly suggested an increased valgus angle. Simulating the true ap-view with the central ray in cranio-caudal direction, IR changed the projection of the HSA substantially. CONCLUSION: In conclusion, standard fixation of the patient's arm in a shoulder sling in IR for true ap-view may result in an oblique projection, potentially leading to incorrect surgical implications. To prevent misdiagnosed valgus or varus angulation, NR of the arm should be obeyed when performing true ap-view X ray. We, therefore, highly recommend to overcome the traditionally arm position, ensuring the true amount of dislocation to assure correct surgical implications and comparable follow-up examinations. PMID- 26615546 TI - Delay in Presentation, Diagnosis and Treatment for Colorectal Cancer Patients in Jordan. AB - PURPOSE: Colorectal cancer (CRC) ranked first among cancers reported in males and second among cancers reported in females in Jordan in 2010. There has been no specific CRC-control programme in Jordan. Additionally, there has been no published study from Jordan or its neighbours on patient delays in presentation, diagnosis or treatment. Therefore, we conducted this study to assess these important quality indicators aiming to improve prognosis for CRC and to provide baseline data for future health promotion programmes for CRC in Jordan. METHODS: This project was a cross-sectional study on CRC patients at Al Bashir Hospital, Ministry of Health, and at the Military Oncology Centre of the Jordanian Royal Medical Services. RESULTS: The total number of participants was 189. The proportion of patients with presentation delay, diagnosis delay or treatment delay was 33.9, 68.1 and 32.6%, respectively. The main reasons reported for delay in presentation were lack of knowledge that symptoms were suggestive of cancer (58.5%), misdiagnosis by physicians or pharmacists (38.4%) or the patient did not want to visit a doctor (3.1%). Predictors of delay and mean time for presentation, diagnosis and treatment were identified. CONCLUSIONS: Our results revealed that CRC patients in Jordan experience delays in presentation, Powered by Editorial Manager(r) and ProduXion Manager(r) from Aries Systems Corporation diagnosis, and, to a lesser degree, in treatment. This could justify the advanced stages at diagnosis and poor outcomes for CRC patients. Our findings provide baseline information for future CRC-control programmes in Jordan. We recommend that CRC prevention programmes in Jordan focus on early detection of CRC and target both patients and physicians. PMID- 26615548 TI - Mortality and morbidity risks vary with birth weight standard deviation score in growth restricted extremely preterm infants. AB - OBJECTIVE: To assess whether the mortality and morbidity risks vary with birth weight standard deviation score (BWSDS) in growth restricted extremely preterm infants. STUDY DESIGN: This was a multicenter retrospective cohort study using the database of the Neonatal Research Network of Japan and including 9149 infants born between 2003 and 2010 at <28 weeks gestation. According to the BWSDSs, the infants were classified as: <-2.0, -2.0 to -1.5, -1.5 to -1.0, -1.0 to -0.5, and >=-0.5. Infants with BWSDS>=-0.5 were defined as non-growth restricted group. RESULTS: After adjusting for covariates, the risks of mortality and some morbidities were different among the BWSDS groups. Compared with non-growth restricted group, the adjusted odds ratio (aOR) for mortality [aOR, 1.69; 95% confidence interval (CI), 1.35-2.12] and chronic lung disease (CLD) (aOR, 1.28; 95% CI, 1.07-1.54) were higher among the infants with BWSDS -1.5 to <-1.0. The aOR for severe retinopathy of prematurity (ROP) (aOR, 1.36; 95% CI, 1.09-1.71) and sepsis (aOR, 1.72; 95% CI, 1.32-2.24) were higher among the infants with BWSDS -2.0 to <-1.5. The aOR for necrotizing enterocolitis (NEC) (aOR, 2.41; 95% CI, 1.64-3.55) was increased at a BWSDS<-2.0. CONCLUSION: Being growth restricted extremely preterm infants confer additional risks for mortality and morbidities such as CLD, ROP, sepsis and NEC, and these risks may vary with BWSDS. PMID- 26615549 TI - Measuring multimorbidity in a working population: the effect on incident sickness absence. AB - PURPOSE: Multimorbidity research typically focuses on chronic and common diseases in patient and/or older populations. We propose a multidimensional multimorbidity score (MDMS) which incorporates chronic conditions, symptoms, and health behaviors for use in younger, presumably healthier, working populations. METHODS: Cross-sectional study of 372,370 Spanish workers who underwent a standardized medical evaluation in 2006. We computed a MDMS (range 0-100) based on the sex specific results of a multicorrespondence analysis (MCA). We then used Cox regression models to assess the predictive validity of this MDMS on incident sickness absence (SA) episodes. RESULTS: Two dimensions in the MCA explained about 80% of the variability in both sexes: (1) chronic cardiovascular conditions and health behaviors, and (2) pain symptoms, in addition to sleep disturbances in women. More men than women had at least one condition (40 vs 15%) and two or more (i.e., multimorbidity) (12 vs 2%). The MDMS among those with multimorbidity ranged from 16.8 (SD 2.4) to 51.7 (SD 9.9) in men and 18.5 (SD 5.8) to 43.8 (SD 7.8) in women. We found that the greater the number of health conditions, the higher the risk of SA. A higher MDMS was also a risk factor for incident SA, even after adjusting for prior SA and other covariates. In women, this trend was less evident. CONCLUSIONS: A score incorporating chronic health conditions, behaviors, and symptoms provides a more holistic approach to multimorbidity and may be useful for defining health status in working populations and for predicting key occupational outcomes. PMID- 26615550 TI - Nucleotide sequence analysis of Vietnamese highly pathogenic porcine reproductive and respiratory syndrome virus from 2013 to 2014 based on the NSP2 and ORF5 coding regions. AB - A total of 34 highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) strains isolated from Vietnam during 2013-2014 were sequenced and analyzed. A partial sequence of ORF1a corresponding to the nonstructural protein 2 (Nsp2) coding region and the full sequence of open reading frame 5 (ORF5) gene was used for the analysis. The HP-PRRSV strains were isolated from pig herds that had never been vaccinated for PRRSV. Nucleotide sequence identities in the portions of ORF1a corresponding to the nonstructural protein 2 (Nsp2) coding region and ORF5 ranged from 96.4 to 100 % and 83.2 to 100 %, respectively. All of the 34 Vietnamese HP-PRRSV strains showed two discontinuous 30-amino-acid deletions in the Nsp2 coding region as a genetic marker of prototypic Chinese HP-PRRSV. The amino acid arginine (R) was present at positions 13 and 151 in ORF5 in 29 out of 34 Vietnamese HP-PRRSV isolates, as well as in the prototypic Chinese HP-PRRSV. Sequence analysis of the ORF5 genes of all Vietnamese HP-PRRSVs revealed six subgroups: Viet 1 to 4, JAX1-like, and VR-2332 like. Nucleotide and amino acid sequence analysis of 34 Vietnamese HP-PRRSV isolates from 2013-2014 indicated that Vietnamese HP-PRRSV has undergone rapid evolutionary changes in recent years when compared with Vietnamese HP-PRRSV isolated before 2012. PMID- 26615551 TI - Fish reovirus GCReV-109 VP33 protein elicits protective immunity in rare minnows. AB - Grass carp reovirus strain 109 (GCReV-109) was previously isolated from a grass carp (Ctenopharyngodon idellus) with hemorrhagic disease, and its complete genome has been sequenced. However, the infectivity of GCReV-109 has not been studied, and the viral protein VP33, encoded on genome segment S11, had no detectable sequence homology to other known reovirus proteins. In this study, we characterized GCReV-109 infections in vivo and in vitro, as well as the VP33 protein. Infectivity analysis showed that GCReV-109 caused severe hemorrhagic disease and 100% mortality at dilutions up to 10(-4) in rare minnows (Gobiocypris rarus) by 8 days postinfection, but no visible cytopathic effect was observed in GCReV-109-infected subcultured grass carp muscle (GCM) cells. To confirm that GCReV-109 could be propagated in GCM cells, three virus genome segments were detected by RT-PCR, and large numbers of virus particles were observed by transmission electron microscopy in samples from the infected GCM cells. The suspension of GCReV-109-infected GCM cells was pathogenic to rare minnows. VP33 protein was expressed and purified for generation of an anti-VP33 antiserum. In western blot analysis of purified GCReV-109 particles, the antiserum specifically recognized a protein band (approximately 33 kDa). This revealed that VP33 is a major structural protein of GCReV-109 that might have immunogenic properties. The protective efficacy of the anti-VP33 antiserum against GCReV-109 infection was tested. The death of infected fish was delayed and the mortality fell to 10% when fish were treated with the anti-VP33 antiserum, suggesting that it might be useful for the prevention and control of fish reoviral disease. PMID- 26615552 TI - Fetal growth of the anal sinus and sphincters, especially in relation to anal anomalies. AB - PURPOSE AND METHODS: The anal sinuses, small furrows above the pectinate line, sometimes form perianal abscesses in adults. We examined the pattern of fetal growth of the anal sinus and sphincters using 22 mid-term (8-18 weeks) and 6 late stage (30-38 weeks) fetuses. RESULTS: In mid-term fetuses, the external and internal sphincters gradually increased in thickness, depending on specimen size (from 0.2 to 1.5 mm), whereas the anteroposterior diameter of the anal canal at the epithelial junction was relatively stable (0.5-1.0 mm) irrespective of specimen size. Anal canal diameter increased less than twofold between mid-term and late-stage fetuses, from 0.5-1.0 to almost 2 mm, whereas sphincter thickness increased over tenfold, from 0.2-1.5 to almost 3.5 mm. The anal sinus often showed balloon-like enlargement when the sphincter muscle bundles were tightly packed in mid-term, but not in late-stage fetuses. CONCLUSIONS: Large concentric mechanical stress from the sphincters in late-stage fetuses apparently prevented the anal sinus from expanding in a balloon-like manner. Conversely, to avoid anal stenosis, the growing sinuses maintained a luminal space of the anal canal in response to stress from rapidly growing sphincters. The inferiorly extending sinus usually provided temporal double canals separated by a thick column. In the presence of double lumens, anal canal duplication is likely to develop without any abnormalities of the anal epithelium and sphincters. PMID- 26615553 TI - Early-onset stroke with moyamoya-like syndrome and extraneurological signs: a first reported paediatric series. AB - BACKGROUND: Moyamoya syndrome is characterised by an occlusion of the carotid terminations with the development of collateral vessels. Our objective is to describe a series of infants presenting early-onset moyamoya-like syndrome, which may constitute a distinct entity. METHODS: From a cohort of children with rare cerebral vascular pathologies, we studied eight infants (28 days-1 year) with early-onset moyamoya-like syndrome demonstrated by angiography. We retrospectively analysed the patterns on MRI and MRA, as well as all other available data. RESULTS: Median age at diagnosis was 7 months (IQR: 6-8) with arterial ischaemic stroke in the middle cerebral artery territory. All of the children experienced severe stroke recurrence within a median time of 11 months (IQR: 10-12), and all showed extraneurological symptoms. The anterior cerebral circulation was involved in all cases and the posterior circulation was involved in six. Two children died and all of the other children suffered permanent neurological deficits. CONCLUSIONS: The presence of extraneurological signs in cases of early-onset moyamoya syndrome is suggestive of a newly described systemic vasculopathy with predominantly cerebrovascular expression. Given its rapid progression marked by severe recurrent strokes and poor clinical outcome, early diagnosis could help in the decision to institute aggressive therapy. PMID- 26615554 TI - TrueFisp versus HASTE sequences in 3T cine MRI: Evaluation of image quality during phonation in patients with velopharyngeal insufficiency. AB - OBJECTIVE: To evaluate the image quality of two fast dynamic magnetic resonance imaging (MRI) sequences: True fast imaging with steady state precession (TrueFisp) was compared with half-Fourier acquired single turbo-spin-echo (HASTE) sequence for the characterization of velopharyngeal insufficiency (VPI) in repaired cleft palate patients. METHODS: Twenty-two patients (10 female and 12 male; mean age, 17.7 +/- 10.6 years; range, 9-31) with suspected VPI underwent 3 T MRI using TrueFisp and HASTE sequences. Imaging was performed in the sagittal plane at rest and during phonation of "ee" and "k" to assess the velum, tongue, posterior pharyngeal wall and a potential VP closure. The results were analysed independently by one radiologist and one orthodontist. RESULTS: HASTE performed better than TrueFisp for all evaluated items, except the tongue evaluation by the orthodontist during phonation of "k" and "ee". A statistically significant difference in favour of HASTE was observed in assessing the velum at rest and during phonation of "k" and "ee", and also in assessing VP closure in both raters (p < 0.05). TrueFisp imaging was twice as fast as HASTE (0.36 vs. 0.75 s/image). CONCLUSION: Dynamic HASTE images were of superior quality to those obtained with TrueFisp, although TrueFisp imaging was twice as fast. KEY POINTS: * Dynamic MRI is an invaluable tool for diagnosing VPI. * Dynamic HASTE images were of superior quality to those obtained with TrueFisp. * TrueFisp imaging was twice as fast as HASTE imaging. PMID- 26615555 TI - Multiparametric fully-integrated 18-FDG PET/MRI of advanced gastric cancer for prediction of chemotherapy response: a preliminary study. AB - OBJECTIVES: To investigate usefulness of multiparametric fully integrated 18-FDG PET/MRI in predicting treatment response after chemotherapy for unresectable advanced gastric cancers (AGCs). METHODS: Eleven patients with unresectable AGCs underwent multiparametric 18-FDG PET/MRI examinations prior to chemotherapy. Perfusion parameters obtained via dynamic contrast-enhanced MRI, apparent diffusion coefficient values from diffusion-weighted images, and maximum standardized uptake values (SUVmax) from 18-FDG PET were measured. For parameters obtained from 18-FDG PET/MRI data, interobserver agreement was obtained using intraclass correlation coefficients (ICC) and chemotherapy response relationship was evaluated using the Mann-Whitney test and receiver operating characteristic analysis. RESULTS: After chemotherapy, six patients were classified into the responder group and five patients into the non-responder group. For all parameters, moderate to nearly perfect agreement was achieved (ICC = 0.452 0.911). K (trans) values (P = 0.018) and initial area under the curves (iAUCs) (P = 0.045) of gastric cancers were significantly higher in responder group than in non-responder group. The area under the curve was 0.917 for K (trans) and 0.867 for iAUC. However, SUVmax values were not significantly different between the two groups. CONCLUSION: Multiparametric approach using fully integrated 18-FDG PET/MRI was shown to be feasible for patients with unresectable gastric cancers. In addition, K (trans) and iAUC values can be used as early predictive markers for chemotherapy response. KEY POINTS: * Multiparametric 18-FDG PET/MRI is feasible for patients with unresectable advanced gastric cancer * K (trans) and iAUC were significantly higher in the responder group of patients * K (trans) , iAUC can be utilized as early predictive markers for chemotherapeutic response. PMID- 26615556 TI - Acute extrahepatic infectious or inflammatory diseases are a cause of transient mosaic pattern on CT and MR imaging related to sinusoidal dilatation of the liver. AB - PURPOSE: To report the association of a mosaic enhancement pattern on contrast enhanced CT or MR imaging and hepatic sinusoidal dilatation (SD) with acute inflammatory conditions affecting extrahepatic organs. METHODS: From 2007 to 2012, patients with acute inflammatory diseases who underwent contrast-enhanced CT and/or MRI of the liver with a mosaic enhancement pattern were selected. Clinico-biological and other imaging features were collected at diagnosis and during follow-up. RESULTS: Sixteen patients were included (15 women, median age 27 years; range 18-68). Five women (33 %) were receiving oral contraceptives. Acute inflammatory diseases included pyelonephritis (n = 10), pancreatitis (n = 2), pneumonia (n = 1), septicemia (n = 1), active Crohn's disease (n = 1), and infectious colitis (n = 1). Median white blood cell count was 13,250 cells/MUL (range 11,500-18,000 cells/MUL) and CRP level 94 mg/L (range 60-121 mg/L). Mosaic enhancement pattern was present in the whole liver and was prominent in the subcapsular areas. Four patients underwent liver biopsy confirming SD. Eleven patients underwent follow-up imaging showing normalized aspect in 9/11 patients after a median of 2 months. CONCLUSION: Acute diseases of extrahepatic organs, associated with a marked systemic inflammatory syndrome should be added to the list of conditions causing a reversible hepatic sinusoidal dilatation as manifested by a mosaic enhancement pattern on contrast-enhanced CT or MR imaging. KEY POINTS: * Acute extrahepatic infectious/inflammatory diseases are a cause of transient MP. * In most patients, MP was seen during both arterial and portal venous phase. * In all patients, the mosaic enhancement pattern was diffuse, but more conspicuous in subcapsular areas. * MP was no longer seen after resolution of the acute disease. * No liver biopsy should be performed. PMID- 26615559 TI - Retraction Note to: Adipose stromal-vascular fraction-derived paracrine factors regulate adipogenesis. PMID- 26615557 TI - Evaluation of breast cancer using intravoxel incoherent motion (IVIM) histogram analysis: comparison with malignant status, histological subtype, and molecular prognostic factors. AB - PURPOSE: To examine heterogeneous breast cancer through intravoxel incoherent motion (IVIM) histogram analysis. MATERIALS AND METHODS: This HIPAA-compliant, IRB-approved retrospective study included 62 patients (age 48.44 +/- 11.14 years, 50 malignant lesions and 12 benign) who underwent contrast-enhanced 3 T breast MRI and diffusion-weighted imaging. Apparent diffusion coefficient (ADC) and IVIM biomarkers of tissue diffusivity (Dt), perfusion fraction (fp), and pseudo diffusivity (Dp) were calculated using voxel-based analysis for the whole lesion volume. Histogram analysis was performed to quantify tumour heterogeneity. Comparisons were made using Mann-Whitney tests between benign/malignant status, histological subtype, and molecular prognostic factor status while Spearman's rank correlation was used to characterize the association between imaging biomarkers and prognostic factor expression. RESULTS: The average values of the ADC and IVIM biomarkers, Dt and fp, showed significant differences between benign and malignant lesions. Additional significant differences were found in the histogram parameters among tumour subtypes and molecular prognostic factor status. IVIM histogram metrics, particularly fp and Dp, showed significant correlation with hormonal factor expression. CONCLUSION: Advanced diffusion imaging biomarkers show relationships with molecular prognostic factors and breast cancer malignancy. This analysis reveals novel diagnostic metrics that may explain some of the observed variability in treatment response among breast cancer patients. KEY POINTS: * Novel IVIM biomarkers characterize heterogeneous breast cancer. * Histogram analysis enables quantification of tumour heterogeneity. * IVIM biomarkers show relationships with breast cancer malignancy and molecular prognostic factors. PMID- 26615558 TI - Disrupted white matter structure underlies cognitive deficit in hypertensive patients. AB - OBJECTIVES: Hypertension is considered a risk factor of cognitive impairments and could result in white matter changes. Current studies on hypertension-related white matter (WM) changes focus only on regional changes, and the information about global changes in WM structure network is limited. METHODS: We assessed the cognitive function in 39 hypertensive patients and 37 healthy controls with a battery of neuropsychological tests. The WM structural networks were constructed by utilizing diffusion tensor tractography and calculated topological properties of the networks using a graph theoretical method. The direct and indirect correlations among cognitive impairments, brain WM network disruptions and hypertension were analyzed with structural equation modelling (SEM). RESULTS: Hypertensive patients showed deficits in executive function, memory and attention compared with controls. An aberrant connectivity of WM networks was found in the hypertensive patients (P Eglob = 0.005, P Lp = 0.005), especially in the frontal and parietal regions. Importantly, SEM analysis showed that the decline of executive function resulted from aberrant WM networks in hypertensive patients (p = 0.3788, CFI = 0.99). CONCLUSIONS: These results suggest that the cognitive decline in hypertensive patients was due to frontal and parietal WM disconnections. Our findings highlight the importance of brain protection in hypertension patients. KEY POINTS: * Hypertension has a negative effect on the performance of the cognitive domains * Reduced efficiencies of white matter networks were shown in hypertension * Disrupted white matter networks are responsible for poor cognitive function in hypertension. PMID- 26615560 TI - Nationwide classification of forest types of India using remote sensing and GIS. AB - India, a mega-diverse country, possesses a wide range of climate and vegetation types along with a varied topography. The present study has classified forest types of India based on multi-season IRS Resourcesat-2 Advanced Wide Field Sensor (AWiFS) data. The study has characterized 29 land use/land cover classes including 14 forest types and seven scrub types. Hybrid classification approach has been used for the classification of forest types. The classification of vegetation has been carried out based on the ecological rule bases followed by Champion and Seth's (1968) scheme of forest types in India. The present classification scheme has been compared with the available global and national level land cover products. The natural vegetation cover was estimated to be 29.36% of total geographical area of India. The predominant forest types of India are tropical dry deciduous and tropical moist deciduous. Of the total forest cover, tropical dry deciduous forests occupy an area of 2,17,713 km(2) (34.80%) followed by 2,07,649 km(2) (33.19%) under tropical moist deciduous forests, 48,295 km(2) (7.72%) under tropical semi-evergreen forests and 47,192 km(2) (7.54%) under tropical wet evergreen forests. The study has brought out a comprehensive vegetation cover and forest type maps based on inputs critical in defining the various categories of vegetation and forest types. This spatially explicit database will be highly useful for the studies related to changes in various forest types, carbon stocks, climate-vegetation modeling and biogeochemical cycles. PMID- 26615561 TI - The Relationship Between Distance from Gambling Venues and Gambling Participation and Problem Gambling Among U.S. Adults. AB - In this article we examine the relationship between extent of gambling for U.S. adults and the distance from their residence to the nearest casino or track. We employ data from a telephone survey of U.S. adults conducted in 2011-2013. The chances that the respondents gambled in the past year, were frequent gamblers, or were problem gamblers were greater if they lived close to a casino. The chances that the respondents gambled in the past year or were frequent gamblers were greater if they lived close to a horse or dog track. The effects of closeness to a casino on the likelihood of past-year gambling, frequent gambling, and problem gambling, as well as the effect of closeness to a track on past-year gambling, extended to about 30 miles from the respondent's home. In addition, the concentration of casinos within 30 miles of the respondent's home was positively related to the respondents' chance of being a frequent or problem gambler. If a respondent had no casinos within 30 miles, he or she had a 2.7 % chance of being a problem gambler; if one casino, a 3.9 % chance; if six or more, a 6.2 % chance. The authors estimate that at least part of this effect is causal. PMID- 26615562 TI - Theoretical investigations on stability of pyridylpentazoles, pyridazylpentazoles, triazinylpentazoles, tetrazinylpentazoles, and pentazinylpentazole searching for a replacement of phenylpentazole as N5 (-) source. AB - Stabilities of pyridylpentazoles, pyridazylpentazoles, triazinylpentazoles, tetrazinylpentazoles, and pentazinylpentazole were studied using density functional theory to assess their potentials as the source of pentazole anion (N5 (-)) for replacement of phenylpentazole (PhN 5 ). Replacing the aryl group of PhN 5 by six-member heterocycle weakens pentazole ring. Compared to PhN 5 , title molecules have longer N-N bonds and lower activation energy (E a,1) needed for the N5 ring breaking. E a,1 decreases with the increasing number of nitrogen atoms of heterocycle. The ortho nitrogen of heterocycle most obviously lowers the stability of pentazole. The central C-N bond dissociation energies (BDEs) of title molecules are lower than that of PhN 5 . For the molecule with 0~1 ortho nitrogen, H rearrangement happens during the central C-N bond breaking. The energy (E a,2) required for H rearrangement is considerably smaller than the corresponding BDE. DeltaE a,2 (E a,2(PhN5) - E a,2 = 7.5~35.7 kJ mol(-1)) is larger than DeltaE a,1 (E a,2(PhN5) - E a,2 = 4.6~15.5 kJ mol(-1)), while DeltaE a,2/E a,2(PhN5) (2~9.5 %) is smaller than DeltaE a,1/E a,1(PhN5) ( 4.4~15.0 %). The larger DeltaE a,1/E a,1(PhN5) suggests that title molecules can not be the better N5 (-) than PhN 5 . PMID- 26615563 TI - Nucleolin overexpression is associated with an unfavorable outcome for ependymoma: a multifactorial analysis of 176 patients. AB - Ependymoma typically has a better overall survival rate than most gliomas. Only a few comprehensive clinical studies have been published, but these are mostly from Western countries and use small sample sizes. Histopathological classification is not sufficient to show variable outcomes, and fails to show prognostic markers of the diverse outcomes; hence, it is essential to understand biological mechanisms. In this study, 176 ependymoma samples (World Health Organization grade II and III) were reviewed at Huashan Hospital. Both children and adults were included. We performed multifactorial analyses of clinical prognostic factors and the biomolecular marker expressions of nucleolin, epidermal growth factor receptor (EGFR) and caveolae-associated protein caveolin-1 by immunohistochemistry. We identified the probabilities of progression-free survival and overall survival using univariate and multivariate statistical methods. The participants were diagnosed with ependymomas between 2002 and 2010, including distributions of tumor locations in intracranial and extracranial regions. Nucleolin was overexpressed in 67 % of our samples, demonstrating a subgroup with poor outcome; particularly infratentorial and anaplastic ependymomas. There was no significant correlation between the expression of EGFR and caveolin-1 and clinical outcomes. Clinically, inferior prognosis was observed with regard to age (<18 years), intracranial location, high grade ependymomas, and incomplete resection. We found that nucleolin was an unfavorable prognostic predictor for ependymomas. Moreover, our findings show a subset of aggravating outcomes in high-grade and posterior fossa tumors. PMID- 26615565 TI - Advances in discovering small molecules to probe protein function in a systems context. AB - High throughput screening (HTS) has historically been used for drug discovery almost exclusively by the pharmaceutical industry. Due to a significant decrease in costs associated with establishing a high throughput facility and an exponential interest in discovering probes of development and disease associated biomolecules, HTS core facilities have become an integral part of most academic and non-profit research institutions over the past decade. This major shift has led to the development of new HTS methodologies extending beyond the capabilities and target classes used in classical drug discovery approaches such as traditional enzymatic activity-based screens. In this brief review we describe some of the most interesting developments in HTS technologies and methods for chemical probe discovery. PMID- 26615564 TI - Breast cancer subtype as a predictor for outcomes and control in the setting of brain metastases treated with stereotactic radiosurgery. AB - We investigated effects of breast cancer subtype on overall survival (OS), local and distant control, and time from initial diagnosis to brain metastases (BM). We also investigated advances in graded prognostic assessment (GPA) scores. A cohort of 72 patients treated for BM from breast cancer with Gamma Knife stereotactic radiosurgery at our institution from 2000 to 2014 had subtyping available and were used for this study. Median follow up for OS was 12 months and for control was 6 months. OS for luminal, HER2, and triple negative subtypes were 26, 20, and 22 months. OS when stratified by Sperduto et al. (J Clin Oncol 30(4):419-425, 2012) and Subbiah et al. (J Clin Oncol 33(20):2239-2245, 2015) GPAs were similar (p = 0.087 and p = 0.063). KPS and treatment modality were significant for OS (p = 0.002; p = 0.034). On univariate analysis, triple negative subtype and >3 BM were trending and significant for decreased OS (p = 0.084; p = 0.047). On multivariable analysis HER2, triple negative, and >3 BM were significant for OS (p = 0.022; p = 0.040; p = 0.009). Subtype was significant for response on a per lesion basis (p = 0.007). Subtype was trending towards significance when analyzing time from initial diagnosis to BM treatment (p = 0.064). Breast cancer subtype is an important prognostic factor when stratifying breast cancer patients with BM. The addition of number of BM to the GPA is a useful addition and should be further investigated. Subtype has an effect on lesion response, and also on rate of development BM after initial diagnosis. PMID- 26615566 TI - Targeted mutations in Val101 and Arg27 interferon beta protein increase its transcriptional and translational activities. AB - Interferon beta (IFNbeta) is the most prescribed drug that has been used frequently for the treatment of multiple sclerosis (MS) patients. The aim of this study is to improve the production of IFNbeta by induction of site directed mutagenesis. Accordingly, recombinant constructs were designed in order to enhance the expression of IFNbeta mRNA and protein. The recombinant plasmids were transfected to the CHO cell line, following RNA extractions and cDNA synthesis. The effects of recombinant constructs were analyzed by real time PCR, ELISA and MTT assay. Transfected samples with either IFNbeta101 or IFNbeta101+27 have shown 11.55 and 2.26 fold elevation and over-expression compare to the wild type construct respectively. Our data also indicated that the IFNbeta101 and IFNbeta101+27 constructs increase IFNbeta protein expression more than 2.2 and 4.5 fold, respectively compared to the control group. It could be concluded that the substitution of Phe in the codon 101 position, which may increase the binding activity of IFNbeta with its receptors and introduction of an additional N glycosylation site (Asn-X-Thr) in the position 27 of IFNbeta protein may cause such an effect. The proliferative activity of transfected cells by a recombinant IFNbeta101 decreases in comparison to the wild type, although it was not statistically significant. Over-expression of IFNbeta in such a level is promising not only for the patients but also for the pharmaceutical industries. PMID- 26615567 TI - Effects of mechanical loading on the expression of pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta in a rat spinal deformity model. AB - Mechanical loading of the spine is a major causative factor of degenerative changes and causes molecular and structural changes in the intervertebral disc (IVD) and the vertebrae end plate (EP). Pleiotrophin (PTN) is a growth factor with a putative role in bone remodeling through its receptor protein tyrosine phosphatase beta/zeta (RPTPbeta/zeta). The present study investigates the effects of strain on PTN and RPTPbeta/zeta protein expression in vivo. Tails of eight weeks old Sprague-Dawley rats were subjected to mechanical loading using a mini Ilizarov external apparatus. Rat tails untreated (control) or after 0 degrees of compression and 10 degrees , 30 degrees and 50 degrees of angulation (groups 0, I, II and III respectively) were studied. PTN and RPTPbeta/zeta expression were evaluated using immunohistochemistry and Western blot analysis. In the control group, PTN was mostly expressed by the EP hypertrophic chondrocytes. In groups 0 to II, PTN expression was increased in the chondrocytes of hypertrophic and proliferating zones, as well as in osteocytes and osteoblast-like cells of the ossification zone. In group III, only limited PTN expression was observed in osteocytes. RPTPbeta/zeta expression was increased mainly in group 0, but also in group I, in all types of cells. Low intensity RPTPbeta/zeta immunostaining was observed in groups II and III. Collectively, PTN and RPTPbeta/zeta are expressed in spinal deformities caused by mechanical loading, and their expression depends on the type and severity of the applied strain. PMID- 26615568 TI - Inflammatory cytokines regulate secretion of VEGF and chemokines by human conjunctival fibroblasts: Role in dysfunctional tear syndrome. AB - Ocular surface inflammation is one of the primary mechanisms associated with dysfunctional tear syndrome (DTS), also known as dry eye disease. DTS, more prevalent in older populations, causes ocular discomfort and visual disturbance due to dryness on the surface layer in the eye. We used human conjunctival fibroblast cultures (HCJVF) to investigate the effects of inflammatory cytokines IFN-gamma, TNF-alpha and IL-1beta (ITI) on the secretions of VEGF and chemokines. Our results demonstrate the elevated secretion of angiogenic VEGF molecules by ITI without affecting anti-angiogenic molecules, PEDF, endostatin, thrombospondin and sVEGF-R1. The secretion of interferon-gamma inducible chemokines, CXCL9, -10, -11 by HCJVF were significantly enhanced by ITI. Our in vitro study supports previously reported observations of elevated VEGF and chemokines in tear fluids of DTS patients, reiterating the role of inflammatory reactions in DTS. PMID- 26615569 TI - IkappaBzeta: A key protein in the pathogenesis of psoriasis. AB - Psoriasis is an immune-mediated chronic inflammatory skin disease with a complex etiology. The proinflammatory cytokine IL-17A is known to play key role in the pathogenesis of psoriasis, and recently anti-IL-17A antibodies have been approved for psoriasis treatment. Here, we discuss our recent findings demonstrating that IkappaBzeta, a transcriptional co-activator, plays a crucial role in the development of psoriasis by mediating IL-17A-driven effects. These findings have significant implications as they uncover a novel crucial regulatory mechanism involved in psoriasis development, and identify IkappaBzeta as a possible future target in the treatment of psoriasis and other IL-17A-driven diseases. PMID- 26615570 TI - Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome. AB - Recently, differences in the levels of various chemokines and cytokines were reported in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as compared with controls. Moreover, the analyte profile differed between chronic ME/CFS patients of long duration versus patients with disease of less than 3years. In the current study, we measured the plasma levels of 34 cytokines, chemokines and growth factors in 100 chronic ME/CFS patients of long duration and in 79 gender and age-matched controls. We observed highly significant reductions in the concentration of circulating interleukin (IL)-16, IL-7, and Vascular Endothelial Growth Factor A (VEGF-A) in ME/CFS patients. All three biomarkers were significantly correlated in a multivariate cluster analysis. In addition, we identified significant reductions in the concentrations of fractalkine (CX3CL1) and monokine-induced-by-IFN-gamma (MIG; CXCL9) along with increases in the concentrations of eotaxin 2 (CCL24) in ME/CFS patients. Our data recapitulates previous data from another USA ME/CFS cohort in which circulating levels of IL-7 were reduced. Also, a reduced level of VEGF-A was reported previously in sera of patients with Gulf War Illness as well as in cerebral spinal fluid samples from a different cohort of USA ME/CFS patients. To our knowledge, we are the first to test for levels of IL-16 in ME/CFS patients. In combination with previous data, our work suggests that the clustered reduction of IL-7, IL-16 and VEGF-A may have physiological relevance to ME/CFS disease. This profile is ME/CFS-specific since measurement of the same analytes present in chronic infectious and autoimmune liver diseases, where persistent fatigue is also a major symptom, failed to demonstrate the same changes. Further studies of other ME/CFS and overlapping disease cohorts are warranted in future. PMID- 26615571 TI - The neurodevelopmental differences of increasing verbal working memory demand in children and adults. AB - Working memory (WM) - temporary storage and manipulation of information in the mind - is a key component of cognitive maturation, and structural brain changes throughout development are associated with refinements in WM. Recent functional neuroimaging studies have shown that there is greater activation in prefrontal and parietal brain regions with increasing age, with adults showing more refined, localized patterns of activations. However, few studies have investigated the neural basis of verbal WM development, as the majority of reports examine visuo spatial WM. We used fMRI and a 1-back verbal WM task with six levels of difficulty to examine the neurodevelopmental changes in WM function in 40 participants, twenty-four children (ages 9-15 yr) and sixteen young adults (ages 20-25 yr). Children and adults both demonstrated an opposing system of cognitive processes with increasing cognitive demand, where areas related to WM (frontal and parietal regions) increased in activity, and areas associated with the default mode network decreased in activity. Although there were many similarities in the neural activation patterns associated with increasing verbal WM capacity in children and adults, significant changes in the fMRI responses were seen with age. Adults showed greater load-dependent changes than children in WM in the bilateral superior parietal gyri, inferior frontal and left middle frontal gyri and right cerebellum. Compared to children, adults also showed greater decreasing activation across WM load in the bilateral anterior cingulate, anterior medial prefrontal gyrus, right superior lateral temporal gyrus and left posterior cingulate. These results demonstrate that while children and adults activate similar neural networks in response to verbal WM tasks, the extent to which they rely on these areas in response to increasing cognitive load evolves between childhood and adulthood. PMID- 26615572 TI - Efficacy of internet-delivered cognitive-behavioral therapy for insomnia - A systematic review and meta-analysis of randomized controlled trials. AB - Cognitive-behavioral therapy for insomnia (CBT-I) has been shown efficacious, but the challenge remains to make it available and accessible in order to meet population needs. Delivering CBT-I over the internet (eCBT-I) may be one method to overcome this challenge. The objective of this meta-analysis was to evaluate the efficacy of eCBT-I and the moderating influence of various study characteristics. Two researchers independently searched key electronic databases (1991 to June 2015), selected eligible publications, extracted data, and evaluated methodological quality. Eleven randomized controlled trials examining a total of 1460 participants were included. Results showed that eCBT-I improved insomnia severity, sleep efficiency, subjective sleep quality, wake after sleep onset, sleep onset latency, total sleep time, and number of nocturnal awakenings at post-treatment, with effect sizes (Hedges's g) ranging from 0.21 to 1.09. The effects were comparable to those found for face-to-face CBT-I, and were generally maintained at 4-48 wk follow-up. Moderator analyses showed that longer treatment duration and higher degree of personal clinical support were associated with larger effect sizes, and that larger study dropout in the intervention group was associated with smaller effect sizes. In conclusion, internet-delivered CBT-I appears efficacious and can be considered a viable option in the treatment of insomnia. PMID- 26615573 TI - Effect of oral antiseptic agents on phospholipase and proteinase enzymes of Candida albicans. AB - OBJECTIVE: Candida-associated denture stomatitis is the most prevalent form of oral candida infections among the denture wearers. Generally, antiseptic oral rinses used in the treatment of these infections are considered as an adjunct or alternative antifungal treatment. Studies have suggested that the intraoral concentrations of antiseptics decrease substantially to the sub-therapeutic levels on account of the dynamics of the oral cavity. This condition yields the question about the minimum antiseptic concentration that effect the character or pathogenesis of Candida during treatment. The extracellular phospholipase and proteinase enzymes of Candida albicans are regarded to have a crucial role in the pathogenesis of human fungal infections. Therefore, the aim of this study was to investigate the effect of different sub-therapeutic concentrations of chlorhexidine gluconate, hexetidine and triclosan on the production of these enzymes by C. albicans strains isolated from 20 patients with denture stomatitis. METHODS: Phospholipase test was done by using Sabouraud dextrose agar with egg yolk, proteinase test was done by using bovine serum albumin agar. METHODS: Phospholipase test was done by using Sabouraud dextrose agar with egg yolk, proteinase test was done by using bovine serum albumin agar. RESULTS: Exoenzyme production of 20 strains which were brief exposured to sub-therapeutic concentrations of three antiseptic agents decreased significantly compared with the strains that were not exposured with antiseptic values (p<0.05). There was significant difference between the sub-therapeutic concentrations of each of three antiseptics (p<0.05). When the same concentrations of each antiseptic was compared, there were no significant differences between enzymatic activities (p>0.05). CONCLUSIONS: The results of this study show that sub-therapeutic levels of each antiseptic may modulate candidal exoenzyme production, consequently suppressing pathogenicity of C. albicans. PMID- 26615574 TI - Farrerol inhibits IL-6 and IL-8 production in LPS-stimulated human gingival fibroblasts by suppressing PI3K/AKT/NF-kappaB signaling pathway. AB - OBJECTIVES: Farrerol, a new type of 2,3-dihydro-flavonoid isolated from rhododendron, has been shown to have anti-bacterial and anti-inflammatory activities. In the present study, we investigated the anti-inflammatory effects of farrerol on the production of IL-6 and IL-8 in human gingival fibroblasts (HGFs) treated with lipopolysaccharide (LPS). METHODS: The cytotoxicity of farrerol was determined using the MTT assay. The production of IL-6 and IL-8 was measured using ELISA and qRT-PCR. The effects of farrerol on PI3K, Akt phosphorylation, and NF-kappaB activation were detected using western blotting analyses. RESULTS: These results showed that farrerol inhibited LPS-induced IL-6 and IL-8 production in a dose dependent manner. LPS-induced NF-kappaB activation was suppressed by farrerol. Furthermore, farrerol suppressed LPS-induced PI3K and Akt phosphorylation, which are upstream molecules of NF-kappaB. CONCLUSION: These results indicated that farrerol attenuated IL-6 and IL-8 production by inhibition of PI3K and AKT phosphorylation, resulting in an inhibition of NF-kappaB activation. Farrerol may be a therapeutic agent for the treatment of periodontal disease. PMID- 26615575 TI - Appropriate real-time PCR reference genes for fluoride treatment studies performed in vitro or in vivo. AB - OBJECTIVE: Quantitative real-time PCR (qPCR) is routinely performed for experiments designed to identify the molecular mechanisms involved in the pathogenesis of dental fluorosis. Expression of reference gene(s) is expected to remain unchanged in fluoride-treated cells or in rodents relative to the corresponding untreated controls. The aim of this study was to select optimal reference genes for fluoride experiments performed in vitro and in vivo. DESIGN: Five candidate genes were evaluated: B2m, Eef1a1, Gapdh, Hprt and Tbp. For in vitro experiments, LS8 cells derived from mouse enamel organ were treated with 0, 1, 3 and/or 5mM sodium fluoride (NaF) for 6 or 18 h followed by RNA isolation. For in vivo experiments, six-week old rats were treated with 0 or 100 ppm fluoride as NaF for six weeks at which time RNA was isolated from enamel organs. RNA from cells and enamel organs were reverse-transcribed and stability of gene expression for the candidate reference genes was evaluated by qPCR in treated versus non-treated samples. RESULTS: The most stably expressed genes in vitro according to geNorm were B2m and Tbp, and according to Normfinder were Hprt and Gapdh. The most stable genes in vivo were Eef1a1 and Gapdh. Expression of Ddit3, a gene previously shown to be induced by fluoride, was demonstrated to be accurately calculated only when using an optimal reference gene. CONCLUSIONS: This study identifies suitable reference genes for relative quantification of gene expression by qPCR after fluoride treatment both in cultured cells and in the rodent enamel organ. PMID- 26615576 TI - Ultra-trace determination of methylmercuy in seafood by atomic fluorescence spectrometry coupled with electrochemical cold vapor generation. AB - A homemade electrochemical flow cell was adopted for the determination of methylmercury. The cold vapor of mercury atoms was generated from the surface of glassycarbon cathode through the method of electrolytic reduction and detected by atomic fluorescence spectroscopy subsequently. The operating conditions were optimized with 2 ng mL(-1) methylmercury standard solution. The caliberation curve was favorably linear when the concentrations of standard HgCH3(+) solutions were in the range of 0.2-5 ng mL(-1)(as Hg). Under the optimized conditions, the limit of detection (LOD) for methylmercury was 1.88*10(-3)ng mL(-1) and the precision evaluated by relative standard deviation was 2.0% for six times 2 ng mL(-1) standard solution replicates. The terminal analytical results of seafood samples, available from local market, showed that the methylmercury content ranged within 3.7-45.8 ng g(-1). The recoveries for methylmercury spiked samples were found to be in the range of 87.6-103.6% and the relative standard deviations below 5% (n=6) were acquired, which showed this method was feasible for real sample analysis. PMID- 26615577 TI - Clinical experience with adjunctive perampanel in adult patients with uncontrolled epilepsy: A UK and Ireland multicentre study. AB - PURPOSE: To derive clinically useful information about the efficacy and tolerability of adjunctive treatment with perampanel for refractory epilepsy in an outpatient setting. METHOD: We pooled retrospective casenotes data of adult patients with refractory epilepsy prescribed perampanel from 18 hospitals throughout UK and Ireland. RESULTS: Three hundred and ten patients were included (mean age 40.9 [SD=12.0], 50% women, 27.7% with learning disability). The mean duration of epilepsy was 26.7 years (range 2-67 years, SD=13.5) and 91.9% were taking two or more anti-epileptic drugs at the time of perampanel initiation. Mean retention was 6.9 months (range 1 day-22.3 months, SD=4.5). The retention was 86% at 3 months, 71% at 6 months, 47.6% at 12 months and 27% at 18 months. At final follow-up a >50% reduction in seizure frequency was reached in 57.5% of tonic-clonic seizures, 57.4% of complex partial seizures and 43.8% of simple partial seizures. Eleven patients (3.5%) became seizure free. Two hundred and nine patients (67.4%) experienced adverse effects and of these 67% withdrew treatment due to their effects. The most common were sedation, behaviour/mood disturbance, dizziness, and unsteadiness. CONCLUSION: Perampanel appears a safe and effective antiepileptic drug when used as adjunctive therapy in patients with uncontrolled partial epilepsy (including those with learning disability), although few patients achieved complete seizure control. Long-term retention was slightly lower than reported rates for other anti-epileptic drugs, potentially due to the highly refractory population. Monitoring for adverse effects on energy levels, mood and behaviour is recommended. PMID- 26615578 TI - A study of the impact of VNS on health care utilisation in England. AB - PURPOSE: To compare hospital service use before and after VNS therapy implantation in a sample of drug-resistant people with epilepsy. METHOD: The before and after study was performed using anonymised Hospital Episode Statistics (HES) data from one year before to 3 years after implantation in 321 patients from data collected between April 2009 to July 2011. Episodes relating to out patient clinic, Accident and Emergency (A&E) department attendance, hospital admissions and length of stay were collected and compared. Descriptive statistics are used to summarise patient demographics, patient pathways and resource usage before and after VNS implantation. Means and proportions were reported on continuous variables, proportion and frequency on categorical variables. Trends of activity over time were determined using before and after VNS comparisons and tested with the Wilcoxon Signed-rank (WSR) test. RESULTS: The summary statistics indicate a drop in resource use in terms of in-patient bed-days (21% decrease), elective in-patient episodes (7% decrease) and non-elective in-patient episodes (14% decrease). There was an increase in the quarterly average out-patient appointments by 12%. The A&E attendance outcome recorded a mean increase in quarterly attendances of 9% but a slight decrease when subject to a signed rank test. These contradictory results should therefore be treated with caution. CONCLUSION: VNS Therapy may be associated with an overall reduction in health service resource use. PMID- 26615579 TI - Color density spectral array of bilateral bispectral index system: Electroencephalographic correlate in comatose patients with nonconvulsive status epilepticus. AB - PURPOSE: to describe the characteristics of the color density spectral array (CDSA) of bilateral bispectral index (b-BIS) monitoring system in patients with comatose nonconvulsive status epilepticus (NCSE). We hypothesized that CDSA could be helpful for monitoring NCSE in critically subjects if continuous EEG (cEEG) is not available. METHODS: we retrospectively analyzed comatose patients admitted to our neurological intensive care unit (NICU) from 2011 to 2014 with a diagnosis of definitive NCSE that underwent b-BIS monitoring for at least 24h to guide anesthetic sedation. Clinical, electroencephalography and neuroimaging findings were analyzed. Moreover, all parameters from the b-BIS data including the CDSA were reviewed during periods of NCSE (NCSE pattern) and profound sedation (sedation pattern). RESULTS: 15 NCSE patients were included. The delay from the diagnosis of NCSE to the onset of b-BIS monitoring was 8 (0.5-31)h and total time of b-BIS monitoring 7.8+/-6.5 days. CDSA during NCSE pattern was characterized by continuous or intermittent red and dark red tones, spectral edge frequency (SEF) in the delta-theta range, with or without asymmetry and BIS number trend with significant variability. In contrast, CDSA during sedation revealed predominance of orange, yellow, green and occasionally blue tones, SEF in the alpha-beta range, absence of asymmetry and stability of BIS number. CONCLUSIONS: b-BIS monitoring system and, in particular, CDSA used by nonexpert NICU personnel may be helpful to follow-up episodes of NCSE, to detect recurrences of nonconvulsive seizures (NCSzs), and to monitor profound anesthetic therapy in comatose patients when cEEG is not available. PMID- 26615580 TI - Polymorphisms in the P1 promoter of the IGF-1 gene in children with growth disorders. AB - BACKGROUND/AIMS: The aim of this study was to associate children's growth disorders with polymorphisms detected in the P1 promoter region of IGF1 (including SNP and (CA) n microsatellite repeat polymorphism) and IGF1 and IGFPB3 levels. METHODS: IGF-1 gene P1 promoter polymorphism was analyzed in DNA obtained from the blood of 51 children with growth disorders and 50 healthy children without growth disorders by means of PCR-SSCP and sequencing. RESULTS: Among children with growth disorders and the control group we found previously described polymorphisms in the P1 promoter of the IGF-1 gene (rs35767, rs5742612) and different genotypes. The frequency of both detected polymorphisms was no significantly different in the study and the control groups. The CA repeat sequence within the group of children in the study ranged from 11 to 21. The most common were homozygote 19/19 (49.02%) and heterozygote 19/20 (27.45%). Our results did not show any association between polymorphisms in the P1 promoter and IGF-1 levels in the serum of children with growth disorders. CONCLUSIONS: This study demonstrated that SNP and (CA) n microsatellite repeat polymorphisms by themselves are not the primary regulatory elements of IGF-1 expression. However, our bioinformatics analysis has shown that the (CA) n microsatellite region in the P1 promoter of IGF-1 is able to form DNA loop structures which can modulate transcription. PMID- 26615581 TI - [Prevalence of chronic complications in patients with over 30-year history of type 1 diabetes depending on the age of onset of diabetes]. AB - ABSTRACT: The aim of this study was to evaluate the prevalence of chronic complications in patients with type 1 diabetes with more than 30 years of history of the disease, depending on the age of onset of diabetes. The criterion for inclusion in the study was over 30-year history of type 1 diabetes. The study group was divided into two subgroups according to the age of diagnosis of type 1 diabetes (either before or after 18 years of age). Anthropometric parameters, degree of metabolic control and the presence of markers of chronic diabetic micro and macrovascular complications were assessed. The study was performed in 215 type 1 diabetic patients with more than 30 years history of the disease, aged 54+/-10 years, 98 men, 117 women. In 110 patients (group I), type 1 diabetes was diagnosed before age of 18 years, in 105 patients (group II) after 18 years of age. Patients in group I were younger, with a longer duration of the disease, more often treated with intensive functional insulin. There were no differences in terms of metabolic control between the assessed groups. Patients in group I were significantly more often diagnosed with chronic diabetic kidney disease, in group II hypertension was more often observed. CONCLUSIONS: The diagnosis of type 1 diabetes before or after the age of 18 had no significant effect on the lack of chronic complications. Patients with diabetes diagnosed in childhood, after 30 years of disease, presented a higher incidence of diabetic kidney disease. PMID- 26615582 TI - [Sugar content in non-alcoholic beverages and dietary recemmendations for children and adolescents]. AB - INTRODUCTION: Increase the intake of sugars among the inhabitants of developed countries is related to, among others, increasing consumption of non-alcoholic beverages, for which the relationship with the epidemic of obesity, particularly among children and adolescents, has been proven. The most frequently cited are non-alcoholic beverages, sweetened glucose-fructose syrup, ie. colas, tonics, ice teas, lemonades. Fruit drinks, fruit juices and nectars are commonly cited as a healthy alternative to non-alcoholic beverages and, however, we do not pay attention to the high content of sugars in these products. OBJECTIVE: Determine the content of sugars in non-alcohollic beverages popular among children and adolescents. MATERIAL AND METHODS: 80 non-alcoholic beverages such as cola, tonic, lemonade, ice tea, flavored waters, fruit juices, fruit nectars and fruit drinks. Evaluation of the content of monosaccharides and sucrose was performed by high performance liquid chromatography method (HPLC). RESULTS: In the tested non alcohollic beverages, monosaccharides ie. glucose and fructose and the disaccharide sucrose were detected in different proportions. The product with the lowest content of the total sugars content was flavored water with lemon flavor based on the mineral water (2.72 g/100 ml). In the group of fruit juices, fruit nectars and fruit drinks highest sugars content have been reported (12.94 g/100 ml for aronia nectar and 12.76 g/100ml for the juice of pomegranate and grapes). CONCLUSIONS: Significant monosaccharides and sucrose content in the tested non alcohollic beverages tends to claim that their manufacturers should be obliged to place warnings on the labels addressed to patients suffering from disorders of carbohydrate metabolism. Educational programs for children and adolescents with diabetes should include information about the content of a large amount of sugars in fruit products: fruit juices, fruit drinks and fruit nectar. PMID- 26615583 TI - [Insulin-like growth factor-1 (IGF-1) - structure and the role in the human body]. AB - In the recent years, managed to broadly explore the structure and role of insulin like growth factors type 1 and 2 (IGF1 I 2). They belong to the structure of polypeptide hormones homologous to proinsulin. They are characterized by a wide range of activities. IGF-1 is a key mediator of most tissue effects of growth hormone (GH). In addition to effects on growth processes of the body, is also an important factor for cell homeostasis, is subject to both endocrine and tissue specific auto- and paracrine regulation. In this paper, the current, general knowledge on the structure, function and mechanism of biological effects of IGF-1 in the human body was presented. Attention was also drawn to the directions of use of IGf-1 in the treatment of other diseases than the diseases of the hypothalamic-pituitary and growth disorders in children. PMID- 26615584 TI - [Yeast-like fungi in the gastrointestinal tract in children and adolescents with diabetes type 1]. AB - In recent years the frequency of fungal infections in human populations has increased considerably. The most common type offungus attacking the human organism is Candida albicans. Yeast-like fungi occur naturally in the oral cavity, intestines, vagina, or skin, however in amounts not dangerous to human health. The studies so far have shown that patients with diabetes type 1 (T1DM) to a large degree are exposed to complications related to fungal infections. A substantial growth of fungi observed in diabetic patients may unfavorably affect metabolic compensation, and lead to increased demand for insulin, as well as to the difficult to cure symptom infections. The weaker the immune resistance in patients with diabetes, the greater the risk of ailments related to candidiasis. The article contains a review of recent literature regarding the problems related to occurrence of yeast-like fungi in digestive tract of children with diabetes type 1. PMID- 26615585 TI - Response to low dose indomethacin in two children with nephrogenic diabetes insipidus. AB - Two children with nephrogenic diabetes insipidus (NDI) were treated with oral indomethacin (0.75-1.2 mg/kg/day) three times a day for a mean duration of 3 yrs. Remission occurred in both patients in terms of achieving a normal fluid balance and body growth and the drug was withdrawn in one patient after 2 yrs. The treatment was well tolerated and no side effects were noted. The mean duration of follow-up was 6.5 yrs. These long-term observations of a favourable response to low dose indomethacin in 2 children with NDI need to be tested on larger number of patients. PMID- 26615586 TI - Communication and general concern criterion prior to activation of the rapid response team: a grounded theory. AB - Objective Patients commonly show signs and symptoms of deterioration for hours or days before cardiorespiratory arrest. Rapid response teams (RRT) were created to improve recognition and response to patient deterioration in these situations. Activation criteria include vital signs or 'general concern' by a clinician or family member. The general concern criterion for RRT activation accounts for nearly one-third of all RRT activity, and although it is well established that communication deficits between staff can contribute to poorer outcomes for patients, there is little evidence pertaining to communication and its effects on the general concern RRT activation. Thus, the aim of the present study was to develop a substantive grounded theory related to the communication process between clinicians that preceded the activation of an RRT when general concern criterion was used. Methods Qualitative grounded theory involved collection of three types of data details namely personal notes from participants in focus groups with white board notes from discussions and audio recordings of the focus groups sessions. Focus groups were conducted with participants exploring issues associated with clinician communication and how it related to the activation of an RRT using the general concern criterion. Results The three main phases of coding (i.e. open, axial and selective coding) analysis identified 322 separate open codes. The strongest theme contributed to a theory of ineffective communication and decreased psychological safety, namely that 'In the absence of effective communication there is a subsequent increase in anxiety, fear or concern that can be directly attributed to the activation of an RRT using the 'general concern' criterion'. The RRT filled cultural and process deficiencies in the compliance with an escalation protocol. Issues such as 'not for resuscitation documentation' and 'inability to establish communication with and between medical or nursing personnel' rated highly and contributed to the debate. Conclusions This study highlighted that in the surveillance and management of the deteriorating patient and in the absence of effective communication there is a subsequent increase in anxiety, fear or concern that can be directly attributed to the activation of an RRT for the 'general concern' calling criteria. What is known about the topic? Deficiencies in collaboration and communication between healthcare professionals (HCPs) increase the stress and anxiety of healthcare staff and correspond to poorer outcomes for patients. The RRT can be activated as a 'general concern RRT' without observation of physiological derangements if staff are concerned about a patient's condition, allowing for assistance from a skilled critical care team at the patient's bedside. There are limited data on how poor communication affects the frequency of activation of general concern RRTs. What does this paper add? This study shows that poor communication between health professionals increases staff levels of anxiety and concern. In addition, the RRT system is being used to fill deficiencies in many other hospital processes, including end-of-life discussions. The deficiencies in hospital processes contribute to poor communication and increased levels of concern with this study demonstrating a direct link between a clinician's level of anxiety/concern and the 'general concern' activation category for the RRT system. What are the implications for practitioners? The present study highlights the importance of effective communication strategies between HCPs to improve patient safety and quality of care. The study also highlights the expanding role of the RRT in hospitals, which has implications for hospital policy makers with regard to future funding and resource allocation. Finally, many of the concerns raised in the present study by the focus groups have been addressed by recent measures introduced through the Australian Commission on Safety and Quality in Health Care (e.g. rapid detection and response observation charts and Introduction, Situation, Background, Assessment and Recommendation [ISBAR] style of communication) with these measures supported by the findings of the present study. PMID- 26615587 TI - Population level usage of health services, and HIV testing and care, prior to decentralization of antiretroviral therapy in Agago District in rural Northern Uganda. AB - BACKGROUND: Decentralization of ART services scaled up significantly with the country wide roll out of option B plus in Uganda. Little work has been undertaken to examine population level access to HIV care particularly in hard to reach areas in rural Africa. Most work on ART scale up has been done at health facility level which omits people not accessing healthcare in the community. This study describes health service usage, particularly HIV testing and care in 2/6 parishes of Lapono sub-county of northern Uganda, prior to introduction of ART services in Lira Kato Health Centre (a local lower-level health centre III), as part of ART decentralization. METHODS: Household and individual questionnaires were administered to household members (aged 15-59 years). Logit random effects models were used to test for differences in proportions (allowing for clustering within villages). RESULTS: 2124 adults from 1351 households were interviewed (755 [36%] males, 1369 [64 %] females). 2051 (97%) participants reported seeking care locally for fever, most on foot and over half at Lira Kato Health Centre. 574 (76%) men and 1156 (84%) women reported ever-testing for HIV (P < 0.001 for difference); 34/574 (6%) men and 102/1156 (9%) women reported testing positive (P = 0.04). 818/850 (96%) women who had given birth in the last 5 years had attended antenatal care in their last pregnancy: 7 women were already diagnosed with HIV (3 on ART) and 790 (97%) reported being tested for HIV (34 tested newly positive). 124/136 (91%) HIV-positive adults were in HIV-care, 123/136 (90 %) were taking cotrimoxazole and 74/136 (54%) were on ART. Of adults in HIV-care, most were seen at Kalongo hospital (n = 87), Patongo Health Centre (n = 7) or Lira Kato Health Centre (n = 23; no ART services). 58/87, 5/7 and 20/23 individuals walked to Kalongo hospital (56 km round-trip, District Health Office information), Patongo Health Centre (76 km round-trip, District Health Office information) and Lira Kato Health Centre (local) respectively. 8 HIV-infected children were reported; only 2 were diagnosed aged <24 months: 7/8 were in HIV care including 3 on ART. CONCLUSIONS: Higher proportions of women compared to men reported ever-testing for HIV and testing HIV-positive, similar to other surveys. HIV-infected men and women travelled considerable distances for ART services. Children appeared to be under-accessing testing and referral for treatment. Decentralization of ART services to a local health facility would decrease travel time and transport costs, making care and treatment more easily accessible. PMID- 26615588 TI - The prognostic influence of intrapancreatic tumor location on survival after resection of pancreatic ductal adenocarcinoma. AB - BACKGROUND: The prognosis of pancreatic ductal adenocarcinoma (PDAC) is worse when the tumor is located in the pancreatic body or tail, compared to being located in the pancreatic head. However, for localized, resectable tumors survival seems to be at least similar. METHODS: We analyzed and compared the outcome after pancreatoduodenectomy (PD) and distal pancreatectomy (DP) for PDAC at our institution. Clinical, pathological and survival data from patients undergoing pancreatic resection for PDAC 1994-2014 were explored retrospectively, accessing a prospective pancreatic database. Patients receiving primary total pancreatectomy were excluded. RESULTS: Four hundred and thirteen patients were treated for PDAC: 347 (84%) underwent PD and 66 (16%) DP. Tumors located in the pancreatic body and tail were significantly larger than their counterparts located in the head (30.6 mm vs. 41.2 mm; p < 0.001). However, distal tumors had significantly less nodal involvement (71% vs. 57%; p = 0.03). Portal-vein resection (PVR) was performed more often in PD, multivisceral resection (MVR) was more frequent in DP (37% vs. 14% and 4% vs. 29%; p < 0.001). Rates for negative resection margins and tumor grading were similar. Postoperative complication rates including morbidity, rates of re-operation and mortality were comparable. Long-term outcome revealed no significant difference between PD and DP with 5 year survival rates of 17.8 and 22% respectively (p = 0.284). Multivariate analysis confirmed positive resection margin, positive nodal status, extended resection (PVR, MVR) and lack of adjuvant/additive chemotherapy as independent risk factors for poor survival after pancreatic resection. CONCLUSION: Patients with resectable pancreatic ductal adenocarcinoma located in the body and tail of the pancreas display a similar postoperative oncological outcome despite larger tumors when compared to patients with resectable tumors located in the pancreatic head. PMID- 26615589 TI - Fully automatic flow-based device for monitoring of drug permeation across a cell monolayer. AB - A novel flow-programming setup based on the sequential injection principle is herein proposed for on-line monitoring of temporal events in cell permeation studies. The permeation unit consists of a Franz cell with its basolateral compartment mixed under mechanical agitation and thermostated at 37 degrees C. The apical compartment is replaced by commercially available Transwell inserts with a precultivated cell monolayer. The transport of drug substances across epithelial cells genetically modified with the P-glycoprotein membrane transporter (MDCKII-MDR1) is monitored on-line using rhodamine 123 as a fluorescent marker. The permeation kinetics of the marker is obtained in a fully automated mode by sampling minute volumes of solution from the basolateral compartment in short intervals (10 min) up to 4 h. The effect of a P-glycoprotein transporter inhibitor, verapamil as a model drug, on the efficiency of the marker transport across the cell monolayer is thoroughly investigated. The analytical features of the proposed flow method for cell permeation studies in real time are critically compared against conventional batch-wise procedures and microfluidic devices. PMID- 26615590 TI - Responses to phosphate deprivation in yeast cells. AB - Inorganic phosphate is an essential nutrient because it is required for the biosynthesis of nucleotides, phospholipids and metabolites in energy metabolism. During phosphate starvation, phosphatases play a major role in phosphate acquisition by hydrolyzing phosphorylated macromolecules. In Saccharomyces cerevisiae, PHM8 (YER037W), a lysophosphatidic acid phosphatase, plays an important role in phosphate acquisition by hydrolyzing lysophosphatidic acid and nucleotide monophosphate that results in accumulation of triacylglycerol and nucleotides under phosphate limiting conditions. Under phosphate limiting conditions, it is transcriptionally regulated by Pho4p, a phosphate-responsive transcription factor. In this review, we focus on triacylglycerol metabolism in transcription factors deletion mutants involved in phosphate metabolism and propose a link between phosphate and triacylglycerol metabolism. Deletion of these transcription factors results in an increase in triacylglycerol level. Based on these observations, we suggest that PHM8 is responsible for the increase in triacylglycerol in phosphate metabolising gene deletion mutants. PMID- 26615592 TI - Eczematous dermatitis due to subcutaneous teriparatide injection. AB - Teriparatide, or recombinant human parathyroid hormone, is approved for the treatment of osteoporosis. Possible cutaneous adverse events of teriparatide are urticaria, injection site pain, swelling, bruising, and pruritus. However, there have been no reports of widespread eczematous reactions caused by teriparatide. A 47-year-old male was recently diagnosed with osteogenesis imperfecta and prior to teeth extractions, he was subcutaneously injected with teriparatide. The patient developed multiple pruritic erythematous papules and plaques on his abdomen, around the site of the injection. A skin biopsy was done, which showed mild spongiosis and superficial perivenular lymphocytic infiltration with a few eosinophils. Drug-related eczematous changes were most likely suspected and in addition to the discontinuation of the injection, topical steroid was prescribed, in which dramatic improvements were observed. We report the eczematous hypersensitivity reaction caused by teriparatide, which is an adverse reaction that has not been reported before. PMID- 26615591 TI - Unconstrained total knee arthroplasty in significant valgus deformity: a modified surgical technique to balance the knee and avoid instability. AB - PURPOSE: Correction of valgus deformity in total knee arthroplasty (TKA) is technically challenging and has produced variable results. A modified surgical technique involving adapting the distal femoral cut with minimal soft tissue release is proposed. The authors hypothesise that using this technique would result in satisfactory radiological and functional outcome. METHODS: The technique involves balancing the knee in extension by changing the distal femoral resection angle and confining soft tissue release to only the posterolateral capsule if required. Retrospective analysis of 276 consecutive TKAs performed using this technique under the care of a single surgeon in patients with valgus knee deformity >=10 degrees was undertaken. An unconstrained mobile bearing implant was used in all knees with a medial para-patellar approach, and outcome scores were collected prospectively. Ninety six percent of the knees were cementless. RESULTS: Mean coronal alignment of the lower limb was corrected from 15.6 degrees (+/-5.7 degrees ) to 3.8 degrees (+/-2.5 degrees ). 97.8 % knees had their coronal alignment restored to <=7 degrees . Seventy-eight knees (28 %) were balanced by only changing the distal femoral resection angle. One hundred and ninety-eight knees (72 %) had release of the posterolateral capsule. Sixteen knees (5.8 %) also had release of iliotibial band. Lateral patellar release was performed in 39 knees (14 %). 93.1 % had central patello-femoral alignment. At between 5.8 and 10.5 year follow-up, there has been one spinout, managed by closed reduction, and one revision of tibial tray for subsidence. The mean American Knee Society clinical score improved from 19.1 to 86.5 (+/-12.2). CONCLUSION: Adequate correction of valgus knee deformity was successfully achieved using this modified technique with satisfactory medium-term outcome and avoidance of instability. PMID- 26615593 TI - MRI T2 characteristics in somatotroph adenomas following somatostatin analog treatment in acromegaly. PMID- 26615594 TI - Family Functioning and Adolescent Psychological Maladjustment: The Mediating Role of Coping Strategies. AB - This study aims to analyze the mediating role of coping strategies in the relationship between family functioning and youth maladjustment. A community sample of 341 adolescents (M = 15.11 years old; SD = 1.71) completed self-report measures about such variables. Results showed that a perception of an inadequate family functioning was associated with the use of maladaptive coping strategies, as well as with youth psychological maladjustment. The results also revealed that rumination and support-seeking mediated the relationship between family functioning and internalizing behavior, and hostile expression of feelings played a mediating role between family functioning and externalizing behavior. No gender differences were found in the relationship between variables. This study emphasizes the importance of coping strategies used by adolescents to understand the relationship between family functioning and youth psychological maladjustment. PMID- 26615595 TI - The exposome for kidney stones. AB - The exposome is the assembly and measure of all the exposures of an individual in a lifetime. An individual's exposures begin before birth and include insults from environmental and occupational sources. The associated field is called exposomics, which relies on the application of internal and external exposure assessment methods. Exposomics has not yet been thoroughly applied to the study of kidney stones although much is known about how diet and fluid intake affect nephrolithiasis. Some other novel exposures that may contribute to kidney stones are discussed including use of antibiotics, urbanization and migration to urban heat islands, and occupation. People whose school and jobs limit their access to fluids and adequate bathroom facilities may have higher prevalence of stones. Examples include athletes, teachers, heathcare workers, and cab drivers. Occupational kidney stones have received scant attention and may represent a neglected, and preventable, type of stone. An exposomic-oriented history would include a careful delineation of occupation and activities. PMID- 26615596 TI - Correlation Between Flexible Fiberoptic Laryngoscopic and Polysomnographic Findings in Patients with Mucopolysaccharidosis Type VI. AB - This study aimed to compare flexible fiberoptic laryngoscopy (FFL) and polysomnography (PSG) findings in patients with mucopolysaccharidosis (MPS) type VI and to describe upper airway anatomical findings and abnormal PSG results in these patients. In this cross-sectional study, all MPS VI patients followed up at the genetic division of a hospital in southern Brazil were included. Overnight PSG was performed, and the results were classified as normal or mildly, moderately, or severely abnormal. FFL was performed between 7 days before and 7 days after PSG. FFL findings were classified as (1) no obstruction, (2) mild obstruction, (3) moderate obstruction, or (4) severe obstruction of the airways, using the highest score obtained in all the regions.Eleven patients with MPS VI were included. FFL detected severe airway obstruction in eight (72.7%) patients, moderate obstruction in two (18.2%), and mild obstruction in one (9.1%). PSG revealed obstructive sleep apnea syndrome (OSAS) in nine (81.8%) patients. Among these, mild OSAS was observed in five (45.5%) patients, moderate OSAS in three (27.2%), and severe OSAS in one (9.1%). Moderate to severe hypertrophy of the nasal turbinates was found in 81.8% of the patients, and 64% had severe infiltration in the supraglottic region. There was no association between FFL and PSG findings (p = 0.454; kappa = -0.09; 95%CI = -0.34 to 0.17), indicating no agreement between the two methods. In the present study, all patients with MPS showed some degree of airway obstruction. We suggest performing PSG in MPS patients to determine disease severity. PMID- 26615597 TI - Spectrum of Mutations in 60 Saudi Patients with Mut Methylmalonic Acidemia. AB - Defects in the human gene encoding methylmalonyl-CoA mutase enzyme (MCM) give rise to a rare autosomal recessive inherited disorder of propionate metabolism termed mut methylmalonic acidemia (MMA). Patients with mut MMA have been divided into two subgroups: mut0 with complete loss of MCM activity and mut- with residual activity in the presence of adenosylcobalamin (AdoCbl). The disease typically presents in the first weeks or months of life and is clinically characterized by recurrent vomiting, metabolic acidosis, hyperammonemia, lethargy, poor feeding, failure to thrive and neurological deficit. To better elucidate the spectrum of mutations causing mut MMA in Saudi patients, we screened a cohort of 60 Saudi patients affected by either forms of the disease for mutations in the MUT gene. A total of 13 different mutations, including seven previously reported missense changes and six novel mutations, were detected in a homozygous state except for two compound heterozygous cases. The six novel mutations identified herein consist of three nonsense, two missense and one frameshift, distributed throughout the whole protein. This study describes for the first time the clinical and mutational spectrum of mut MMA in Saudi Arabian patients. PMID- 26615598 TI - CoQ10 Deficiency Is Not a Common Finding in GLUT1 Deficiency Syndrome. AB - CoQ10 deficiency has been recently described in tissues of a patient with GLUT1 deficiency syndrome. Here, we investigated patients and mice with GLUT1 deficiency in order to determine whether low CoQ is a recurrent biochemical feature of this disorder, to justify CoQ10 supplementation as therapeutic option.CoQ10 levels were investigated in plasma, white blood cells, and skin fibroblasts of 16 patients and healthy controls and in the brain, cerebellum, liver, kidney, muscle, and plasma of 4-month-old GLUT1 mutant and control mice.CoQ10 levels in plasma did not show any difference compared with controls. Since most of the patients studied were on a ketogenic diet, which can alter CoQ10 content in plasma, we also analyzed white blood cells and cultured skin fibroblasts. Again, we found no differences. In mice, we found slightly reduced CoQ in the cerebellum, likely an epiphenomenon, and activity of the mitochondrial respiratory chain enzymes was normal.Our data from GLUT1 deficiency patients and from GLUT1 model mice fail to support CoQ10 deficiency as a common finding in GLUT1 deficiency, suggesting that CoQ deficiency is not a direct biochemical consequence of defective glucose transport caused by molecular defects in the SLC2A1 gene. PMID- 26615599 TI - The impact of fibromyalgia symptoms on brain morphometry. AB - Fibromyalgia (FMS) is a complex clinical syndrome that includes many symptoms beyond chronic pain. The studies that have addressed brain morphometry in FMS have had very heterogeneous results. Thus, the question of which specific FMS symptoms and clinical features-pain, but also psychological distress, sleep related problems, health status, and medication intake-impact on brain morphometry remains open. Here, we wanted to determine if brain changes in FMS are "symptom-related" more than "diagnostic-related". We performed an observational study of 46 premenopausal women (23 FMS patients and 23 age-matched healthy participants). Magnetic resonance images were analyzed using voxel-based morphometry and subcortical segmentation. We used multiple regression models to assess the associations between total and local brain volumes and FMS clinical characteristics. Furthermore, we calculated associations between subcortical structures' shapes and volumes and FMS clinical characteristics. Larger psychological distress, anxiety, and sleepiness, and higher analgesic consumption accounted for 38 % of FMS patients' smaller total gray matter volume (GMV). For both groups, local decrements of GMV in the medial orbitofrontal cortex were associated to larger psychological distress. Local increases of GMV were positively related to pain scores (superior frontal gyrus), psychological distress (cerebellum), anxiety (medial orbitofrontal cortex), and sleepiness (frontal superior medial cortex). FMS clinical characteristics were also associated to deformations in subcortical structures and volumes changes. This study reveals that total and local GMV changes in FMS go beyond the traditional "pain matrix" alterations. We demonstrated that brain morphology is altered by pain, but also by clinical characteristics that define the FMS experience. PMID- 26615600 TI - A case of gastric adenocarcinoma of fundic gland type resected by combination of laparoscopic and endoscopic approaches to neoplasia with non-exposure technique (CLEAN-NET). AB - A male in his eighties attended our hospital for further evaluation of gastric cancer. A gastroscopy revealed a whitish flat elevated lesion (Paris, 0-IIa) of 15 mm in diameter on the greater curvature of the proximal fornix. The preoperative diagnosis was intra-mucosal differentiated gastric cancer, and a novel therapeutic approach, combination of laparoscopic and endoscopic approaches to neoplasia with non-exposure technique (CLEAN-NET) was applied and the lesion was resected in a single piece without any complications. Histopathological findings revealed atypical glandular epithelium proliferated in the mucosa and shallow layer (300 MUm) of submucosa. These cells stained positive for pepsinogen I and the final diagnosis was gastric cancer of fundic gland type (GAFT). There was no lymph-vascular involvement and free horizontal and vertical margins were confirmed. CLEAN-NET could be a therapeutic option for GAFT at low risk of lymph node metastasis because it prevents excess wall defect and exposure of cancer cells into the peritoneal cavity. PMID- 26615601 TI - Abnormal miRNAs Targeting Chromosome Open Reading Frame Genes were Enriched in Microvesicles Derived from the Circulation of HCC. AB - In this study, we detected the expression profiles of microRNAs (miRNAs) packaged within microvesicles (MVs) from blood samples of HCC patients and healthy donors. Using microarray analysis, there were 83 down-regulated and 92 over-expressed miRNAs in HCC circulation-derived MVs relative to control group. Then potential functions of the dysregulated MVs miRNAs were investigated with bioinformatic tools. We found that 664 Corf genes were targeted by 72 altered MVs miRNAs and some of these target genes were reported to be associated with tumorous activities. Gene Ontology annotation demonstrated that biological roles of the target Corf genes mainly contained the regulation of growth, cell death, macromolecule metabolism, etc. As regulated by abnormal MVs miRNAs, functions of target Corf genes might be interrupted, which were much likely to contribute to HCC occurrence and progression. PMID- 26615602 TI - Metabolic syndrome in Greek women with polycystic ovary syndrome: prevalence, characteristics and associations with body mass index. A prospective controlled study. AB - PURPOSE: The aim of this study was to estimate the prevalence, to evaluate the characteristics of the metabolic syndrome (MetS) in Greek women with polycystic ovary syndrome (PCOS) and to investigate the correlation of MetS with body mass index (BMI). METHODS: In a prospective controlled study, 230 Greek female patients with PCOS and 155 age-matched healthy controls were enrolled. Diagnosis of PCOS was based on the revised criteria of Rotterdam. Both groups were examined for MetS. Diagnosis of MetS was based on the revised criteria of International Diabetes Federation (IDF). RESULTS: The prevalence of the MetS was 12.6 %, nearly sevenfold higher than the controls. Elevated fasting plasma glucose (7.0 vs. 1.9 %) and elevated triglycerides (10.4 vs. 3.2 %) were more frequent in the PCOS cohort (p < 0.05). Women with PCOS presented statistically higher BMI in comparison with the controls (p < 0.001). Subsequently, the prevalence of MetS was estimated in three groups: normal, overweight and obese subdivided according to BMI. The latter two groups showed significant differences compared with the healthy controls (24.5 vs. 8.8 %, p = 0.050). CONCLUSION: In conclusion, this study showed high prevalence of MetS and increased BMI in Greek PCOS women. In addition, it demonstrated the higher prevalence of MetS in obese PCOS women in comparison with the controls. These results are placing them at increased risk for cardiovascular disease and diabetes in the future and underline the necessity of periodic screening, appropriate diet and exercise program. PMID- 26615603 TI - A central mesencephalic reticular formation projection to the Edinger-Westphal nuclei. AB - The central mesencephalic reticular formation, a region associated with horizontal gaze control, has recently been shown to project to the supraoculomotor area in primates. The Edinger-Westphal nucleus is found within the supraoculomotor area. It has two functionally and anatomically distinct divisions: (1) the preganglionic division, which contains motoneurons that control both the actions of the ciliary muscle, which focuses the lens, and the sphincter pupillae muscle, which constricts the iris, and (2) the centrally projecting division, which contains peptidergic neurons that play a role in food and fluid intake, and in stress responses. In this study, we used neuroanatomical tracers in conjunction with immunohistochemistry in Macaca fascicularis monkeys to examine whether either of these Edinger-Westphal divisions receives synaptic input from the central mesencephalic reticular formation. Anterogradely labeled reticular axons were observed making numerous boutonal associations with the cholinergic, preganglionic motoneurons of the Edinger-Westphal nucleus. These associations were confirmed to be synaptic contacts through the use of confocal and electron microscopic analysis. The latter indicated that these terminals generally contained pleomorphic vesicles and displayed symmetric, synaptic densities. Examination of urocortin-1-positive cells in the same cases revealed fewer examples of unambiguous synaptic relationships, suggesting the centrally projecting Edinger-Westphal nucleus is not the primary target of the projection from the central mesencephalic reticular formation. We conclude from these data that the central mesencephalic reticular formation must play a here-to-for unexpected role in control of the near triad (vergence, lens accommodation and pupillary constriction), which is used to examine objects in near space. PMID- 26615604 TI - Rapid activation of catalase followed by citrate efflux effectively improves aluminum tolerance in the roots of chick pea (Cicer arietinum). AB - The present study demonstrates the comparative response of two contrasting genotypes (aluminum (Al) tolerant and Al sensitive) of chick pea (Cicer arietinum) against Al stress. The Al-tolerant genotype (RSG 974) showed lesser inhibition of root growth as well as lower oxidative damages, measured in terms of the accumulation of H2O2 and lipid peroxidation compared to the Al-sensitive genotype (RSG 945). The accumulation of Al by roots of both genotypes was almost equal at 96 and 144 h after Al treatment; however, it was higher in Al-tolerant than Al-sensitive genotype at 48 h after Al treatment. Further, the Al-mediated induction of superoxide dismutase (SOD) activity was significantly higher in Al tolerant than Al-sensitive genotype. Ascorbate peroxidase (APX) activity was almost similar in both genotypes. Al treatment promptly activated catalase activity in Al-tolerant genotype, and it was remarkably higher than that of Al sensitive genotype. As another important Al detoxification mechanism, citrate efflux was almost equal in both genotypes except at 1000 MUM Al treatment for 96 and 144 h. Further, citrate carrier and anion channel inhibitor experiment confirmed the contribution of citrate efflux in conferring Al tolerance in Al tolerant genotype. Based on the available data, the present study concludes that rapid activation of catalase (also SOD) activity followed by citrate efflux effectively improves Al tolerance in chick pea. PMID- 26615606 TI - The 9p21 polymorphism is linked with atrial fibrillation during acute phase of ST segment elevation myocardial infarction. AB - The aim of the study was to find whether patients carrying polymorphic allele of the rs10757278 polymorphism from 9p21 locus have changed risk of arrhythmia (atrial fibrillation, AF; sustained ventricular tachycardia or ventricular fibrillation, sVT/VF) during acute phase of myocardial infarction. Retrospective analysis of data collected prospectively from two independent centers was performed. The clinical data were pooled from two independent cardiac registries: (1) the Warsaw ACS genetic registry (STEMI and NSTEMI/UA patients hospitalized in the years 2008-2011; only STEMI patients were analyzed); (2) the Bialystok STEMI genetic registry (STEMI patients hospitalized in years 2001-2005, who survived the first 48 h from hospital admission). Data regarding sVT/VF and AF within first 24 h were analyzed. The patients were genotyped with rs10757278 polymorphism. 1083 patients were included in the analysis; 62 (5.7 %) patients had sVT/VF during acute phase and 78 (7.2 %) patients had AF, 46 (4.2 %) patients had new-onset AF. Minor allele frequency in all patients with AF was significantly different from those without AF (0.40 vs 0.51, p = 0.0096). When only new-onset AF was analyzed, the trend was the same, with significant protective effect in recessive model [OR 0.41 (95 % CI 0.17-0.97), p = 0.025]. The effect was independent of age and GRACE score. No relationship was found between sVT/VF and rs10757278. Patients with STEMI, who survived until hospitalization with polymorphic allele of 9p21 rs10757278 SNP have less AF during acute phase of STEMI. SNP rs10757278 is not linked with sVT/VF in acute phase of STEMI. PMID- 26615605 TI - Spot urine sodium excretion as prognostic marker in acutely decompensated heart failure: the spironolactone effect. AB - INTRODUCTION: Loop diuretic resistance characterized by inefficient sodium excretion complicates many patients with acutely decompensated heart failure (ADHF). Mineralocorticoid receptor antagonists (MRAs) in natriuretic doses may improve spot urine sodium excretion and outcomes. OBJECTIVE: Our primary aim was to assess the association of high-dose spironolactone with short-term spot urine sodium excretion, and our secondary aim was to determine if this higher short term spot urine sodium excretion is associated with reduction in the composite clinical outcome (of cardiovascular mortality and/or ADHF hospitalization) event rate at 180 days. METHODS: Single-centre, non-randomized, open-label study enrolling 100 patients with ADHF. Patients were treated with standard ADHF therapy alone (n = 50) or oral spironolactone 100 mg/day plus standard ADHF therapy (n = 50). Spot urine samples were collected at day 1 and day 3 of hospitalization. RESULTS: Spironolactone group had significantly higher spot urine sodium levels compared to standard care group at day 3 (84.13 +/- 28.71 mmol/L vs 70.74 +/- 34.43 mmol/L, p = 0.04). The proportion of patients with spot urinary sodium <60 mmol/L was lower in spironolactone group at day 3 (18.8 vs 45.7, p = 0.01). In multivariate analysis, spironolactone was independently associated with increased spot urinary sodium and urinary sodium/potassium ratio of >2 at day 3 (both, p < 0.05). Higher spot urine sodium levels were associated with a lower event rate [HR for urinary sodium >100 mmol/L = 0.16 (0.06-0.42), p < 0.01, compared to <60], and provided a significant prognostic gain measured by net reclassification indexes. CONCLUSION: Spot urinary sodium levels >60 mmol/L and urinary sodium/potassium ratio >2 measured at day 3 of hospitalization for ADHF are associated with improved mid-term outcomes. Spironolactone is associated with increased spot urinary sodium and sodium/potassium ratio >2. PMID- 26615607 TI - Clinical benefit of tolvaptan in patients with acute decompensated heart failure and chronic kidney disease. AB - Tolvaptan, a vasopressin type 2 receptor antagonist, has an aquaretic effect without affecting renal function. The effects of long-term tolvaptan administration in heart failure patients with renal dysfunction have not been clarified. Here, we assessed the clinical benefit of tolvaptan during a 6-month follow-up in acute decompensated heart failure (ADHF) patients with severe chronic kidney disease (CKD; estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m(2)). We compared 33 patients with ADHF and severe CKD who were administered tolvaptan in addition to loop diuretics (TLV group), with 36 patients with ADHF and severe CKD who were administered high-dose loop diuretics (>=40 mg) alone (LD group). Alterations in serum creatinine and eGFR levels from the time of hospital discharge to 6-month follow-up were significantly different between the groups, with those in the TLV group being more favorable. Furthermore, Kaplan-Meier analysis revealed that rehospitalization for heart failure (HF) was significantly lower in the TLV group compared with the LD group. In ADHF patients with severe CKD, tolvaptan use for 6 months reduced worsening of renal function and rehospitalization rates for HF when compared with conventional diuretic therapy. In conclusion, tolvaptan could be a safe and effective agent for long-term management of HF and CKD. PMID- 26615609 TI - Discourse/Conversation Analysis and Autism Spectrum Disorder. PMID- 26615610 TI - Enrichment for Repopulating Cells and Identification of Differentiation Markers in the Bovine Mammary Gland. AB - Elucidating cell hierarchy in the mammary gland is fundamental for understanding the mechanisms governing its normal development and malignant transformation. There is relatively little information on cell hierarchy in the bovine mammary gland, despite its agricultural potential and relevance to breast cancer research. Challenges in bovine-to-mouse xenotransplantation and difficulties obtaining bovine-compatible antibodies hinder the study of mammary stem-cell dynamics in this species. In-vitro indications of distinct bovine mammary epithelial cell populations, sorted according to CD24 and CD49f expression, have been provided. Here, we successfully transplanted these bovine populations into the cleared fat pads of immunocompromised mice, providing in-vivo evidence for the multipotency and self-renewal capabilities of cells that are at the top of the cell hierarchy (termed mammary repopulating units). Additional outgrowths from transplantation, composed exclusively of myoepithelial cells, were indicative of unipotent basal stem cells or committed progenitors. Sorting luminal cells according to E-cadherin revealed three distinct populations: luminal progenitors, and early- and late-differentiating cells. Finally, miR-200c expression was negatively correlated with differentiation levels in both the luminal and basal branches of the bovine mammary cell hierarchy. Together, these experiments provide further evidence for the presence of a regenerative entity in the bovine mammary gland and for the multistage differentiation process within the luminal lineage. PMID- 26615611 TI - Chronic arthritis in systemic lupus erythematosus: distinct features in 336 paediatric and 1830 adult patients. AB - The objectives of this study are to assess the frequency of chronic arthritis and compare the clinical and laboratory features in a large population of childhood onset systemic lupus erythematosus (cSLE) and adult-onset (aSLE) patients. This historical study evaluated 336 cSLE and 1830 aSLE patients. Chronic arthritis was defined as synovitis of at least 6 weeks of duration. Rhupus was characterised as the association of SLE and chronic inflammatory arthritis with erosion and positive rheumatoid factor. Jaccoud's arthropathy is a non-erosive subluxation leading to severe deformity of the hands and feet. Data were compared using Student's t test or the Mann-Whitney test for continuous variables. For categorical variables, differences were assessed by Fisher's exact test and Pearson chi-square. Frequencies of chronic arthritis were similar in cSLE and aSLE (2.4 vs. 3.8%, p = 0.261). The median time from disease onset to appearance of chronic arthritis was shorter in cSLE (0 vs. 10 years, p < 0.001), and the median of age at chronic arthritis diagnosis was [10.8 (4.2-14.6) vs. 40 (21-67), p < 0.001]. The children presented with more chronic polyarthritis than the adults (75 vs. 32%, p = 0.024), a higher median number of joints with arthritis [8.5 (1-18) vs. 3 (1-9), p = 0.017] and a higher number of joints with limitation [1.5(0-24) vs. 0(0-4), p = 0.004]. The chronic arthritis diagnosis frequencies of hepatomegaly (25 vs. 0%, p = 0.009), splenomegaly (25 vs. 0%, p = 0.009), pericarditis (25 vs. 0%, p = 0.009), nephritis (37 vs. 3% , p = 0.006), haematuria (37 vs. 1.4%, p = 0.002), lupus anticoagulant (40 vs. 1.6%, p = 0.012), anticardiolipin IgM (40 vs. 1.5%, p = 0.012) and median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) [10.5(1-20) vs. 6(4-16), p = 0.029] were higher in cSLE. Frequency of rhupus, (12 vs. 17%, p = 1.0), Jaccoud's arthropathy (0 vs. 17%, p = 0.343) and treatments were similar in cSLE and aSLE. We determined that chronic arthritis in SLE has distinct features in children, with very early onset, polyarticular involvement and association with active disease. We further demonstrated in this series that a proportion of chronic arthritis involvement in SLE is manifested as rhupus and Jaccoud's arthropathy. PMID- 26615612 TI - Relationship between disease activity and hearing impairment in patients with rheumatoid arthritis compared with controls. AB - The characteristics of hearing impairment (HI) in rheumatoid arthritis (RA) are still poorly understood, and their association with disease activity is based on conflicting information. This study compared HI between RA patients and controls and between active and remission RA groups using multi-frequency audiometry. This study enrolled 88 RA patients and 50 controls. The pure-tone hearing thresholds at 500 to 4000 Hz for air (AC) and bone (BC) conduction were compared between RA and controls as well as between active and remission RA patients using DAS28-CRP scores. The pure-tone hearing thresholds for AC and BC were significantly higher at high frequencies (2000 and 4000 Hz) in the RA group for both ears compared with controls. In addition, the BC threshold at 1000 Hz for the right ear was higher in the RA group than controls. When active and remission RA patients were compared, the thresholds were higher only at 4000 Hz for both ears for AC and BC in patients with active RA. The air-bone gap differed significantly at 2000 and 4000 Hz in both ears. This study demonstrated that patients with RA have a heightened risk of HI, and disease activity increases this risk, particularly at high frequencies. Clinicians who manage RA should be aware of HI and consider performing audiological evaluations in RA patients with active disease in particular. PMID- 26615613 TI - Kidney disease and psoriasis: novel evidences beyond old concepts. AB - Psoriasis is an immune-mediated inflammatory disease for a long time considered as a type of pathology characterized by an exclusive skin involvement. Recently it has been shown that patients affected by this disease have a higher risk of developing comorbidities such as cardiovascular diseases, arterial hypertension, diabetes mellitus, and metabolic syndrome. Even the kidneys can be affected by psoriasis through three different mechanisms: immune-mediated renal damage, drug related renal damage and chronic renal damage. Renal function should be monitored periodically to minimize the risk of renal adverse events. PMID- 26615614 TI - Obesity, metabolic abnormality, and health-related quality of life by gender: a cross-sectional study in Korean adults. AB - PURPOSE: This study sought to compare the association between health-related quality of life (HRQoL) and four body health types by gender. METHODS: The study included 6217 men and 8243 women over 30 years of age chosen from a population based survey. Participants were grouped by body mass index and metabolic abnormality into four types: metabolically healthy normal weight, metabolically abnormal but normal weight (MANW), metabolically healthy obesity (MHO), and metabolically abnormal obesity (MAO). HRQoL was measured using the EQ-5D health questionnaire. The outcomes encompassed five dimensions (mobility, self-care, usual activity, pain/discomfort, and anxiety/depression), and the impaired HRQoL dichotomized by the EQ-5D preference score. Complex sample multivariate binary logistic regression analyses were conducted to adjust for sociodemographic variables, lifestyle factors, and disease comorbidity. RESULTS: Among men, those in the MANW group presented worse conditions on all dimensions and the impaired HRQoL compared to other men. However, no significant effect remained after adjusting for relevant covariates. For women, those in the MAO group had the most adversely affected HRQoL followed by those females in the MHO group. The domain of mobility and impaired HRQoL variable of the MAO and MHO groups remained significant when controlling for all covariates in the model. CONCLUSIONS: The MANW is the least favorable condition of HRQoL for men, suggesting that metabolic health may associate with HRQoL more than obesity for males. In women, the MAO and MHO groups had the most adversely affected HRQoL, implying that MHO is not a favorable health condition and that obesity, in general, may be strongly associated with HRQoL in women. PMID- 26615616 TI - Using the Three-Step Test Interview to understand how patients perceive the St. George's Respiratory Questionnaire for COPD patients (SGRQ-C). AB - PURPOSE: The aim of this study was to assess the experiences of patients with chronic obstructive pulmonary disease (COPD) while they were completing the St. George's Respiratory Questionnaire for COPD patients (SGRQ-C), using qualitative research methods. METHODS: Twenty Dutch COPD patients were recruited through pulmonary physicians [13 women; mean age = 63.3 years (SD = 11.4)]. A trained interviewer applied the Three-Step Test Interview which allowed the interviewer to follow the thought process of the patient filling out the SGRQ-C. The official Dutch translation of the SGRQ-C was used. RESULTS: Patients missed a recall period for the Symptoms subscale; were uncertain how to interpret specific words and phrases like "good days", "games", and "housework"; were confused by long item stems that included a list of activities; and were frustrated by the dichotomous format used for the majority of SGRQ-C items (true/false). CONCLUSIONS: Overall, patients were satisfied with the SGRQ-C. Nevertheless, making minor adjustments could further increase its quality. This includes reintroducing a recall period in the first set of items such as used in the previous version and splitting up items consisting of multiple activities. Furthermore, we recommend using the same response format (4 or 5 response categories) for all items. PMID- 26615615 TI - Prognostic value of health-related quality of life in patients with metastatic pancreatic adenocarcinoma: a random forest methodology. AB - PURPOSE: Eastern Cooperative Oncology Group Performance Status (ECOG-PS) is currently an important parameter in the choice of treatment strategy for metastatic pancreatic adenocarcinoma (mPA) patients. However, previous research has shown that patients' self-reported health-related quality of life (HRQOL) scales provided additional prognostic information in homogeneous groups of patients with respect to ECOG-PS. The aim of this study was to identify HRQOL scales with independent prognostic value in mPA and to propose prognostic groups for these patients. METHODS: We analysed data from 98 chemotherapy-naive patients with histologically proven mPA recruited from 2007 to 2011 in the FIRGEM phase II study which aimed to compare the effectiveness of two chemotherapy regimen. HRQOL data were assessed with the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. A random survival forest methodology was used to impute missing data and to identify major prognostic factors for overall survival. RESULTS: Baseline HRQOL assessment was completed by 60 % of patients (59/98). Twelve prognostic variables were identified. The three most important prognostic variables were fatigue, appetite loss, and role functioning, followed by three laboratory variables. The model's discriminative power assessed by Harrell's C statistic was 0.65. Fatigue score explained almost all the survival variability. CONCLUSION: HRQOL scores have prognostic value for mPA patients with good ECOG-PS. Moreover, the patient's fatigue, appetite loss, and self-perception of daily activities were more reliable prognostic indicators than clinical and laboratory variables. These HRQOL scores, especially the fatigue symptom, should be urgently included for prognostic assessment of mPA patients (with good ECOG PS). PMID- 26615617 TI - Methodology guideline for clinical studies investigating traditional Chinese medicine and integrative medicine: executive summary. AB - This guideline aims to provide a methodological guidance for clinical studies in TCM and integrative medicine in terms of study design, execution, and reporting. The commonly used methods including experimental and observational methods were introduced in this guideline such as randomized clinical trials, cohort study, case-control study, case series, and qualitative method which can be incorporated into above quantitative methods. The guideline can be used for the evaluation of therapeutic effect of TCM therapies or their combination with conventional therapy. TCM therapy refers to one of the followings or their combination: herbal medicine, acupuncture, moxibustion, cupping, Taichi/Qigong, and Guasha,Tuina (therapeutic massage). It is also suitable for research and development of ethnopharmaceuticals or folk medicine. PMID- 26615618 TI - [Evaluation of the Antianginal Efficacy of Ivabradine In Patients With Ischemic Heart Disease Complicated by Heart Failure]. AB - Results of the multicenter open observational program NACHALO (evaluation of therapy in patients with combined coronary artery disease and heart failure as part of daily clinical practice), in which 569 doctors in 58 regions of the Russian Federation participated, were presented. The program included 2751 patients with ischemic heart disease, stable angina complicated by heart failure at the age from 25 to 94 years (mean age 62.6 +/- 9.3 years). The follow-up period was 3 months, during which two visits were carried out--after 4 weeks and a final visit--12 weeks after the initiation of therapy. Despite treatment, angina attacks (mean 6.7 6.1 per week), increased blood pressure (average 145.1 +/- 20.9/87.2 +/- 1.8 mm Hg) and heart rate (average 85.8 +/- 9.5 beats/min) were noted in patients before the inclusion in the program. The addition of ivabradine therapy resulted in a significant (p < 0.00001) reduction in heart rate to 73.2 +/- 8.7 (at visit 1) and down to 65.2 +/- 6.1 beats/min (at visit 2), the number of angina attacks per week to 3.8 (at visit 1) and 1.9 (at visit 2). There were significant (p < 0.00001) positive dynamics of the clinical wellness and the severity of symptoms in patients. Adverse effects that, according to doctors, were associated with the agent, were observed in only 0.15% of cases. Thus, in real clinical practice inhibitor of the if channels ivabradine has been shown to be highly effective in treatment of stable angina in patients with coronary artery disease complicated by heart failure. PMID- 26615619 TI - [First Open Study of Syndrome of Acute Decompensation of Heart Failure and Concomitant diseases in Russian Federation: Independent Registry ORAKUL]. AB - Aim of the study was to assess mortality and rate of repetitive hospital admissions on days 30, 90, 180, 360, of observation as well as prevalence of concomitant diseases in patients with congestive heart failure (CHF). The register was formed in 41 centers of 20 cities of Russian Federation. Number of included patients with signs of chronic heart failure (CHF) was 2498. Data on 2404 was available for final analysis. Rehospitalization rate was 31, 11, 11, and 9.5% during 30 days, and during periods 31-90, 91-180, 181-360 days after discharge from hospital, respectively. Hospital mortality was 9%, 30 days and 1 year total mortality was 13 and 43%, respectively. Risk of death was most strongly affected by pneumonia, liver cirrhosis, and chronic kidney disease (mortality 49.5, 45.7, and 47.2%, respectively). Prognostic value of factors was ranked in the following order (descending): age, body mass index < 19 kg/m2, systolic blood pressure < 100 mm Hg, heart rate (HR) > 70 bpm, body temperature < 36.5 C. Each predictor was assigned weight of 1 point. Score 5 meant that risk of death with a high degree of probability approached 100%. Patients included into ORAKUL compared with those included in Euro HF register were more severely ill: in ORAKUL ejection fraction < 40% was observed 1.89 times more often, and more patients had "wet-cold" profile. Patients in ORAKUL had greater HR, smaller ejection fraction, lower glomerular filtration rate, and worse compliance to scientifically based treatment. PMID- 26615620 TI - [The First Results of the Russian Register of Chronic Heart Failure]. AB - We present in this paper first results of the Russian registry of chronic heart failure (CHF) as well as comparative analysis of available registries and a number of randomized controlled trials and meta-analyses on CHF. PMID- 26615622 TI - [Blood Lipid Parameters In Populations of Russia, Poland And Czech Republic: The Hapiee Study]. AB - PURPOSE: to analyze population values of blood lipid parameters in general populations of Russia, Poland and Czech Republic. MATERIALS AND METHODS: In the frame of international project HAPIEE representative samples of general population were examined in Novosibirsk (Russia), Krakow (Poland) and six centers in the Czech Republic. The analysis included data of 25,469 men and women aged 45 69 years old. RESULTS: The average levels of total cholesterol (TC), non-high density lipoprotein cholesterol (non-HDL-C) and low density lipoprotein cholesterol (LDL-C) were found relatively high in all centers, though average levels of blood triglycerides (TG) and high-density lipoprotein (HDL) were within "normal" range. In Novosibirsk mean levels of blood TC and LDL-C in persons of both sexes were obtained the highest among the study participants: 6.3 mmol/ and 4.1 mmol/l, respectively (p < 0.001). But the level of blood triglycerides (1.5 mmol/l) in Novosibirsk was the lowest, and HDL-C (1.5 mmol/l) was the highest among three centres. There were clear trend of increasing concentration of blood TC, non-HDL-C,LDL-C and blood atherogenic indexes with increasing age in both sexes of all participating countries. In Czech Republic levels of blood TC, LDL C, HDL-C in both sexes were relatively low: 5.7 mmol/l, 3.5 mmol/l, 1.4 mmol/l, respectively, but the level of blood TG were higher, than in other centers (1.9 mmol/l). Women of all centers had more demonstrative age changes of the blood lipid profile, than men. CONCLUSIONS: The average levels of blood TC, non-HDL-C and LDL-C in men and women aged 45-69 years old in Russia (Novosibirsk) were higher and level of blood TG was lower than in Poland and the Czech Republic. PMID- 26615621 TI - [Prognostic Value of Central Aortic Pressure in Pregnant Women With Hypertension]. AB - Prognostic value of central aortic pressure and peripheral blood pressure in relation to the development of pre-eclampsia was assessed in pregnant women with different forms of hypertension. It was shown that development of pre-eclampsia was associated with higher mean 24-hour systolic blood pressure (BP), time index of systolic BP, variability of diastolic BP, and pulse BP measured on weeks 16-22 of gestation. Pregnant women with hypertension, especially those with pre eclampsia were characterized by absence of proper nocturnal BP lowering or BP elevation during night hours (non-dippers and night-peakers). Critical values for prediction of preeclampsia were daily average central (aortic) systolic BP higher than 115 mm Hg and a mean daily brachial systolic BP above 131 mm Hg. PMID- 26615623 TI - [Atrial Contractile Function in Patients With Paroxysmal Atrial Fibrillation]. AB - The aim of study was to investigate atrial contractile function in patients with paroxysmal atrial fibrillation (AF) in sinus rhythm using transthoracic echocardiography. METHODS: 35 patients with paroxysmal AF and arterial hypertension (mean age 62 +/- 10 years, 43% males) were enrolled in the study. Control group was composed of comparable patients with arterial hypertension without heart rhythm disturbances. We found significant depression of atrial contraction function in patients with AF in sinus rhythm expressed as decrease in left atrium EF, A' velocity and VTI, and increase in A/A' ratio, whereas peak a velocity was not affected. Patients with AF has markedly depressed atrial contractile function in sinus rhythm, to improve measurements accuracy we propose to use A/A' ratio as LA contractile function marker minimally dependent from LV diastolic function. PMID- 26615624 TI - [Adherence to Therapy as a Factor Determining Prognosis of Coronary Artery Bypass Grafting]. AB - AIM: to study the influence of the patients adherence to the recommended therapy after coronary artery bypass grafting (CABG) on prognosis of postoperative period. MATERIAL: We examined 197 consecutive patients with stable coronary artery disease (CAD) who had undergone CABG. Age of patients was 38-75 years. RESULTS: Assessment of modifiable cardiovascular risk factors showed that about half of patients had smoked before CABG and only a few gave up smoking after surgery. Number of patients with abdominal obesity increased by 8% after surgery. Number of patients involved in physical trainings remained unchanged. Adherence to drug therapy before CABG was low. Less than half of the patients took antiplatelet agents, beta-blockers, angiotensin-converting enzyme inhibitors, only 25% took statins. One year after CABG number of patients taking appropriate medications significantly increased. However, only half of patients managed to achieve the main objectives of secondary prevention. PMID- 26615625 TI - [The Relationship of Obesity to the Character of Nutrition]. AB - The aim of the investigation was to study pathogenesis of abdominal obesity on the model of experimental fatty dystrophy in rats; to assess the state of lipid and protein metabolism and to elucidate morpho-biochemical interrelations between pathogenesis of fatty liver dystrophy and character of nutrition. MATERIAL AND METHODS: Male Wistar rats (n = 42, weight 210 g) were object of the research. Three groups of animals were formed: rats of group 1 (control group, n = 15) received standard vivarium diet; rats of group 2 (n = 15) received hypercaloric fatty diet with allyl alcohol; rats of group 3 (with alloxan diabetes, n = 12) also received hypercaloric fatty diet with allyl alcohol. Rats were maintained on these diets for 90 days and were controlled every 30 days. RESULTS: Dynamics of body mass of animals after 90 days of feeding was: group 1--from 200 +/- 10 to 230 +/- 10, group 2--from 200 +/- 10 to 385 +/- 5, group 3--from 200 +/- 10 to 400 +/- 10 g. CONCLUSION: Dynamic development of obesity and liver dystrophy is caused by disturbances of lipid and protein metabolism at the background of imbalance of alimentary fat and metabolic changes. Lipid disorganization is caused by the deficiency of the hepatrophic factors. PMID- 26615626 TI - [Age-related Changes of Left Ventricular Diastolic Function, NT-proBNP Level and Their Association With Leukocyte Telomere Length]. AB - With advancing age the left ventricle (LV) undergoes structural and functional changes, thereby creating the substrate for the development of diseases. One possible mechanism of the ageing of the heart is cellular senescence. Leukocyte telomere length (LTL) is a marker of replicative ageing. The purpose of this study was to evaluate the diastolic function of LV and level of NT-proBNP in people of different ages free of cardiovascular diseases and to assess their relationship with LTL. Our data showed that old age is associated with diastolic dysfunction and increase in the levels of NT-proBNP. The group of older subjects had lower values of E/A (0.96 +/- 0.036 vs 1.27 +/- 0.03, p < 0.001), Em/Am (0.9 +/- 0.035 vs 1.5 +/- 0.066) and higher values of IVRT (81 +/- 1.56 vs 70 +/- 1.23 MS, p < 0.001), DT (198 +/- 3.98 vs 175 +/- 2.82 MS, p < 0.001), that reflected impairment of LV relaxation. NT-proBNP level was higher in the elderly (100.82 +/ 7.1 vs 48.47 +/- 6.7 omegag/ml, p < 0.01), but it did not correlate with LTL. The most sensitive to the age parameters of LV diastolic function (E/A and Em/Am ratio) were positively and independently of age associated with LTL (p < 0.001). Older individuals with shorter LTL had significantly lower values of E/A ratio. CONCLUSION: Telomere length appears to be a biomarker of myocardium ageing. PMID- 26615627 TI - [The Effectiveness of Russian Public Health Recommendations for Sanogennykh Behavior in the Heatwave]. AB - There is an urgent need to create adapted for the Russian population of the recommendations in order to improve the efficiency and automation of the process of informing patients about the correct (sanogennykh) behavior in the heat. The proposed health WHO recommendations in 2010 year are difficult to perception, understanding and subsequent patient use without consulting a doctor. THE GOAL: creating and testing adapted for the Russian population recommendations for sanogennykh behavior during the summer heat on the basis of the recommendations of the WHO in 2010. MATERIALS AND METHODS: 155 persons older than 30 years, 93 people were adapted recommendations (group 1), 62--"classic" WHO recommendations 2010 (group 2). The groups were comparable in terms of the main clinical and demographic characteristics. Results: in the summer 2014 heat waves observed 2: 4 and 10 days, the maximum temperature of 32.7 degrees C. On the "deterioration of health during a heat wave", complained 20.6% of patients receiving tailored recommendations, and 40%--classic (p = 0.008). The number of cardiovascular complications in group 1 was 0.0 (0.3, 1.4) in group 2--0.0 (0.6, 2.4; p = 0.000). Most effective recommendations noted patients with coronary heart disease and hypertension (87.5%; 9 of them were adapted recommendations 4--"classic") and chronic heart failure (80%; all they got adapted recommendations). CONCLUSION: customized recommendations sanogennykh behavior during heat waves can be recommended for use in clinical practice for patients with cardiovascular diseases. PMID- 26615628 TI - [Cognitive Disorders and Nootropic Therapy in the Practice of Internist and Cardiologist]. PMID- 26615629 TI - [Efficacy of Nitric Oxide, With or Without Continuing Antihypertensive Treatment, for Management of High Blood Pressure in Acute Stroke. Results of the ENOS study]. PMID- 26615630 TI - [Noninvasive Methods of Detection of Vulnerable Atherosclerotic Plaques in Coronary Arteries]. AB - In most cases direct cause of acute coronary syndrome and sudden death is an intracoronary thrombus formed on a surface of unstable atherosclerotic plaque (UAP). The following are main characteristics of UAP: active inflammation; large lipid rich nucleus occupying a40% of plaque volume; thin (< 65 mm) fibrous cap; erosions of intima over plaque; tear of plaque cap; superficially located calcium nodules; intraplaque hemorrhage. Visualization of UAP in coronary arteries is a very important direction in diagnostics. During recent years both invasive and noninvasive methods of detection of UAP have been actively developed. In this review we present main noninvasive techniques used for detection of UAP: multislice computed tomography, magnetic resonance tomography, positron emission tomography and single-photon emission computed tomography. In the review we have covered main advantages and limitations of each invasive method of UAP detection and delineated perspectives of development of this direction. PMID- 26615631 TI - [To the Problem of Selection of Antihypertensive Therapy Scheme From Position of Cost of Treatment]. AB - The article is devoted to pharmacoeconomic aspects of treatment of arterial hypertension including its combination with diabetes mellitus. Data of four studies of comparison of clinical and economical effectiveness of treatment with original enalapril and its fixed combination with hydrochlorothiazide with some generic preparations of enalapril are presented. It has been shown that original enalapril has advantages over generics and from position of treatment cost. It is stressed that data of pharmacoeconomic studies should be taken into consideration when determining scheme of treatment of patients with arterial hypertension. PMID- 26615632 TI - [Treatment of Hypertension in Patients With High Cardiovascular Risk in Light of Current Guidelines and the Results of Observational Studies]. PMID- 26615633 TI - [Brugada Syndrome: Possibilities of the Use of Noninvasive Electrocardiographic Mapping. A Case Report]. AB - Patient P., 50 years old, male, with type I Brugada syndrome was examined. The patient had aborted sudden death event (2006) in his clinical history, ICD Gem III VR was implanted in 2006, ICDLumax DR was reimplanted in 2012. The patient had coved type pattern in right precordial ECG-leads. The p.E553X mutation in SCN5A gene, whish encodes the sodium channel alpha-subunit, was found. Noninvasive electrocardiographic mapping was performed. Significant changes of local unipolar electrograms including QRS fragmentation, ST segment elevation and late ventricular potentials were identified in the epicardium of the right ventricle outflow tract. Thus, the presented case demonstrates that noninvasive electrocardiographic mapping methodology allows to determine and visualize arrhythmogenic substrate in patients with inherited channelopathies. PMID- 26615634 TI - [Main Cellular Redox Couples]. AB - Most of the living cells maintain the continuous flow of electrons, which provides them by energy. Many of the compounds are presented in a cell at the same time in the oxidized and reduced states, forming the active redox couples. Some of the redox couples, such as NAD+/NADH, NADP+/NADPH, oxidized/reduced glutathione (GSSG/GSH), are universal, as they participate in adjusting of many cellular reactions. Ratios of the oxidized and reduced forms of these compounds are important cellular redox parameters. Modern research approaches allow setting the new functions of the main redox couples in the complex organization of cellular processes. The following information is about the main cellular redox couples and their participation in various biological processes. PMID- 26615635 TI - [Solubilization Specificities Interferon beta-1b from Inclusion Bodies]. AB - A new solubilization method of recombinant interferon beta-1b (IFNbeta-1b) from the inclusion bodies was developed. This method allows to extract the target protein selectively in the solutions of different alcohols, such as ethanol, propanol and isopropanol. It was shown that the more effective IFNbeta-1b solubilization was achieved in the 55% propanol solution. This method allowed to extract the target protein from inclusion bodies around 85-90%, and significantly reduced Escherichia coli content in the solubilizate, in comparison with standard methods. PMID- 26615636 TI - [A New Simple Technique for Producing Labeled Monoclonal Antibodies for Antibody Pair Screening in Sandwich-ELISA]. AB - A simple and fast method for obtaining biotin-labeled monoclonal antibodies was developed usingcontent of hybridoma culture supernatant sufficient to select antibody pairs in sandwich ELISA. The method consists in chemical biotinylation of antigen-bound antibodies in a well of ELISA plate. Using as an example target Vaccinia virus A27L protein it was shown that the yield of biotinylated reactant is enough to set comprehensive sandwich ELISA for a moderate size panel of up to 25 monoclonal antibodies with an aim to determine candidate pairs. The technique is a cheap and effective solution since it avoids obtaining preparative amounts of antibodies. PMID- 26615637 TI - IDENTIFCATION AND VALIDATION OF NOVEL microRNA MOLECULE FROM THE PELODISCUS SINENSIS BY BIOINFORMATICS APPROACHES. AB - MicroRNAs (miRNAs) are a group of endogenous, short non-coding RNAs with the length of about 22 nt, which mediate gene expression at the post-transcriptional level through mRNA degradation or translational repression. Among them, some are highly evolutionally conserved in the animal kingdom; this provides a powerful strategy for identifying miRNAs in new species. The Chinese soft-shelled turtle (Pelodiscus sinensis) is one of the most important freshwater aquaculture reptilian species in China, but related miRNAs have not been identified up to now. In the present study, a total of 10 Pelodiscus sinensis miRNAs were identified according to Pelodiscus sinensis ESTs and GSSs information in NCBI database by bioinformatics approaches. The RT-PCR-based assays were performed and found that 10 Pelodiscus sinensis miRNAs were expressed. Using these miRNAs, 22 target genes were identified. These genes encode 22 proteins involved in metabolism, signal transduction, transcriptional regulation, and development. These miRNAs and their targets will serve as useful resources for their, functional analyses in miRNA-regulated processes in Pelodiscus sinensis breeding and genetic research. PMID- 26615638 TI - [ag1 Is Required for the Fin Regeneration in Danio rerio]. AB - In the current research, we have demonstrated that Ag1 protein is necessary for the fin regeneration in the fish Danio rerio. Robust activation of gene ag1 expression in cells of the wound epithelium is observed after caudal fin amputation. Besides, inhibition of translation of ag1 mRNA leads to retardation of the caudal tail fin regeneration. Results of our research are important because only lower vertebrates (fish and amphibians) with good regenerative capacity have ag1, whereas this gene is missing in higher vertebrates, which are not capable to effectively regenerate limbs. Our data confirm that reduction of the regenerative abilities in higher vertebrates, including human, could be explained by extinction of some genes essential for the regeneration, in particular, of ag1. PMID- 26615639 TI - [The Role of Extracellular Calcium Ions Reduction in T Cell Activation in Human Peripheral Blood]. AB - Calcium plays a fundamental role in many essential live functions. It is well known that many infections can lead to hypocalcaemia in humans. The importance of extracellular calcium concentration ([Ca2+]o) in T-cell activation is well recognized, but [Ca2+]o levels necessary for lymphocyte activation have not been investigated in detail. Whole blood from healthy donors was stimulated by immobilized anti-CD3 plus soluble co-stimulation anti-CD28 mAb and activation parameters have been analyzed. Interleukins-2 (IL-2), JL-4, IL-17A, interferon gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) production and CD4+CD69+, CD4+CD25+, CD4+(CYTOKINE)+ T cells were used as activation parameters. To change current [Ca2+]o values in PB we used EGTA. No EGTA influence on resting T cells was shown. Dependences of T-cell activation parameters on various [Ca2+]o were studied. These data indicate that extracellular Ca2+ chelation by EGTA leads to non-linear dependences of T-cell activation parameters on [Ca2+]o values. Obtained dependence of the number of CD4+CD69+ T cells from EGTA can be represented as a nonlinear curve with two distinct peaks. Cytokines production by activated Th1, Th2 and Th17 cells and CD4+(CYTOKINE)+ T cells have been analyzed in dependence on EGTA. The first peak is close to the norm-pathology border. The second peak is in the pathological [Ca2+]o values of PB. However, the local minimum between them is entirely in the "pathological" range. Obtained dependences can be represented as a nonlinear curve with two distinct peaks. All dependences shape have similar curve describing the influence of [EGTA] values on activated CD4+CD69+ T cells. Physiological significance of obtained data discussed. PMID- 26615640 TI - [The Analysis for Probable Reasons of Cd4+ T-Cell Activation Non-Linear Dependence on Extra Cellular Calcium Ion Concentration in Human Peripheral Blood in vitro]. AB - The analysis for probable reasons of CD4+ T-cell activation non-linear dependence on [Ca2+]o in HPB in vitro is the general aim of current work. At the beginning we pursued the analysis of receptor-dependent (the mixture of monoclonal antibodies (mAbs) to CD3 and CD28 molecules) and receptor-independent (phorbol myristate-acetate and ionomycin mixture) means to activate T cells in vitro with different [Ca2+]o in HPB. The key role of intracellular T-cell signaling systems in activated T cells in their non-similar sensitivity to calcium ions in the blood was shown. The analysis of differentiation next stages of CD4+ T-cell activation in vitro relatively [Ca2+]o in PHB demonstrates the key role of the earliest induction stages in non-similar sensitivity to calcium ions in CD4+ T cell activation in vitro. According to the pursued analysis; the non-similar sensitivity of CD4+ T-cell in vitro to activation is in no-way connected with pace differences on the primary stages of activation process. The comparison of CD4+ memory T cells with their naive T-cell precursors in the cell activation process in hypocalcemia conditions was made in the separate experimental series. The 1st maximum consists in average of 85% CD4+CD45R0high CD69+ memory T cells. Naive CD4+CD45RAlowCD69+ T cells constitute the remainder 15%. The 2nd maximum almost completely consists of CD4+CD45R0+CD69+ memory T cells. The ratio between CD4+CD69+ T cell maximums depends on donor ages and represents linear dependence with R = -0.981. The most probable candidate on the role of CD4+ T cell, being capable of activation in hypocalcemia conditions, are memory T lymphocytes, being resistant to ionomycin action (I R) subset. To check this assumption the mononuclear cells and their IR-fraction were prepared from donor PB. Then the mononuclear cells and their IR-fraction were activated by mAbs mixture at different [EGTA] values. For IR-fraction, enriched with CD4+CD45RA-CD45R0+ memory T cells, slightly seen 1st maximum and drastic 2nd maximum in the "pathology" [Ca2+] region was observed. Most likely, namely, at the 2nd maximum, there is IR CD4+CD45RA-CD45R0+ memory T cell majority, having changed intracellular calcium signaling system, to be activated. Hence, the existence for CD4+ T cell activation two maximums in hypocalcemia conditions is connected with the presence of two subsets of CD4+ memory T cells, differing in their calcium-dependent intracellular signaling system, in HPB. PMID- 26615641 TI - [Synthesis and Pharmacological Activity of N-Hetaryl-3(5)-Nitropyridines]. AB - Reacting a number chlorosubstituted 3(5)-nitropyridine with some diazoles or 3 chloropyridazin-6-one synthesized previously undescribed various 2-, 4- or 6 substituted hetaryl-3(5)-nitropyridines. Furthermore, pyrazolyl-3-nitropyridine prepared by cyclizing hydrazinopyridine resulting from the nucleophilic substitution of chlorine in chlorosubstituted 3-nitropyridine by hydrazine. It has been shown that these compounds have moderate antibacterial activity against some pathogenic Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Escherichia coli), as well as a strong effect on protistocidal action form Colpoda steinii, surpassing clinically used reference drugs. PMID- 26615642 TI - [Genotoxic and Mutagenic Properties of Synthetic Betulinic and Betulonic Acids]. AB - Synthesis of betulinic acid was performed from the birch bark extract (Betula pendula). Betulonic acid was intermediate of the synthesis. Both acids were isolated with purity 95%. Genotoxicity and mutagenicity of obtained compounds were analyzed by Ames test and SOS chromotest, none of these properties have been detected. PMID- 26615643 TI - SYNTHESIS AND EVALUATION OF NEW PHTHALAZINE SUBSTITUTED beta-LACTAM DERIVATIVES AS CARBONIC ANHYDRASE INHIBITORS. AB - A new series of phthalazine substituted beta-lactam derivatives were synthesized and their inhibitory effects on the activity of purified human carbonic anhydrase (hCA I and II) were evaluated. 2H-Indazolo[2,1-b]phthala- zine-trione derivative was prepared with 4-nitrobenzaldehyde, dimedone, and phthalhydrazide in the presence of TFA in DMF, and the nitro group was reduced to 13-(4-aminophenyl)-3,3 dimethyl-3,4-dihydro- 2H-indazolo[1,2-b]phthalazine-1,6,11(13H)-trione with SnCl2 . 2H2O. The reduced compound was re- acted with different aromatic aldehydes, and phthalazine substituted imines were synthesized. The imine compounds undergo (2+2) cycloaddition reactions with ketenes to produce 2H-indazolo[2,1-b]phthala zine-trione substituted beta-lactam derivatives. The beta-lactam compounds were tested as inhibitors of the CA isoenzyme activity. The results showed that all the synthesized compounds inhibited the CA isoenzyme activity. 1-(4-(3,3-dimethyl 1,6,1 1-trioxo-2,3,4,6,11,13-hexahydro-1H-indazolo[1,2-b]phthalazin-13- yl)phenyl)-2-oxo-4-p-tolylazetidin-3-yl acetate (IC50 = 6.97 uM for hCA I and 8.48 uM for hCA II) had the most inhibitory effect. PMID- 26615644 TI - SYNTHESIS AND REACTIVITY OF ENAMINONE OF NAPHTHO[B] 1,4-OXAZINE: ONE POT SYNTHESIS OF NOVEL ISOLATED AND HETEROCYCLE-FUSED DERIVATIVES WITH ANTIMICROBIAL AND ANTIFUNGAL ACTIVITIES. AB - The synthesis of the multifunctional, hitherto unreported 3-(3 (dimethylamino)acryloyl)-2H-naphtho[1,2- b] [1,4]oxazin-2-one was described and its utility as a versatile building block was demonstrated for the synthesis of some new pyrimidines, pyrazoles, isoxazoles, pyrazolo[a]pyrimidines, triazolo[a]pyrimidines, pyrido[d]pyrimidines, pyrido[d]pyrimidines, piperidines, pyrido[a]benzimidazoles, 2H-pyran-3-carboxamides, benzofurans, naphtho[b]furans and pyrazolo[c] [1,2,4]triazines of potential biological activities. The synthesized compounds were characterized by IR, 1H NMR, 13C NHR and mass spectral data. Some of the compounds were evaluated for antimicrobial activities. PMID- 26615645 TI - SYNTHESIS, REACTIONS, AND BIOLOGICAL ACTIVITY OF SOME TRIAZINE DERIVATIVES CONTAINING SULFA DRUG MOIETIES. AB - Thienyl-triazine-sulphonamide conjugates were prepared from their precursor amines using triethyl orthoformate or ethyl chloroformate as cross coupling reagents. The progress of these reactions was investigated by spectral (IR, NMR, MS) and microanalytical techniques. The synthesized compounds were in vitro screened for antibacterial, antifungal, antioxidant, and anticancer activity. 4 [({[3-Mercapto-5-oxo-6-[2-(2-thienyl)yinyl]-1,2,4-triazin- 4(5H) yl]imino}methyl)amino]-benzenesulfonamide turned out to be a powerful antibacterial agent, while all the compounds prepared were inactive against fungal species tested. 4-{[({8-Cyano-4-oxo-3-[2-(2-thienyl)vinyl- 4H,8H [1,2,4]triazino[3,4-b][1,3,4]thiadiazin-7 yl}amino)(ethoxy)methyl]amino}benzenesulfonamide displayed in vitro promising cytotoxicity against Ehrlich ascites carcinoma cell line with concurrent attenuation of malonodinitrile and it was unique among other compounds being unable to increase glutathione S-transferase and reduced glutathione S transferase activities. This compound exhibited also good antioxidant properties that together with its cytotoxicity nominated it for further investigation in cancer research. PMID- 26615646 TI - [The Development and Application of BODIPY-Labeled Oligonucleotides in Real-Time Polymerase Chain Reaction]. AB - A BODIPY-based (4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene, TMB) green fluorescent probe for quantitative real-time polymerase chain reaction (qPCR) was synthesized by azide-alkyne cycloaddition reaction. Comparative studies with analogous fluorescein-based probe were carryed out. We demonstrate that fluorescent probes with TMB fluorophore can be used in qPCR experiments as well. PMID- 26615647 TI - KEY ITEMS OF INNOVATION MANAGEMENT IN THE PRIMARY HEALTHCARE CENTRES CASE STUDY: FINLAND. AB - Trends such as aging populations, excess costs, rising public expectations, and progress in medical science and technologies point out the necessity of adaptation and development of innovation in the healthcare systems particularly in developed countries. The main objective of this article is to review diffusion of innovation in the healthcare sector. Different types of innovation, diffusion characteristics, and adoption mechanisms are the subjects that are discussed in the selected case study, Finland. Finally, the key items of innovation management in the Finnish health system are introduced. The results can be implemented in other countries as well. PMID- 26615648 TI - IMPACT OF COMORBIDITY AND SOCIOECONOMIC STATUS ON QUALITY OF LIFE IN PATIENTS WITH CHRONIC DISEASES WHO ATTEND PRIMARY HEALTH CARE CENTRES. AB - AIM: The aim of the study was to analyse the impact of chronic disease on the quality of life (QoL) and how QoL changes with comorbidity and socioeconomic status in persons who attend primary health care centres. METHODS: The group of participants comprised 2,560 people who contacted six primary health care centres in Ankara. The level of QoL was determined by the World Health Organization Quality of Life Questionnaire Abbreviated Version (WHOQOL-BREF). RESULTS: Mental disorders and diabetes-hypertension comorbidity had the most negative effect on the QoL. In the physical domain of the WHOQOL-BREF, the effect of diabetes hypertension comorbidity is greater than the additive effect of hypertension and diabetes individually. The co-occurrence of any disease with cardiovascular disease does not change QoL within any domain, except for the co-occurrence of any disease with musculoskeletal diseases which deteriorated QoL in the physical domain. The higher income and socioeconomic status corresponded to higher QoL. CONCLUSIONS: The effect of comorbidity on QoL can be different from the additive effects of the co-occurring diseases. Socioeconomic factors undoubtedly affect the relationship between chronic diseases and QoL, and this relationship points to health inequities among socioeconomic groups. PMID- 26615649 TI - FACTORS AND ESTIMATION OF RISK FOR CARDIOVASCULAR DISEASES AMONG PATIENTS IN PRIMARY HEALTH CARE IN CENTRAL SERBIA. AB - AIM: Cardiovascular diseases present major cause of morbidity and mortality in the world as well as in Central Serbia. The aim of this study is to analyze the frequency of risk factors and estimate risk for the development of cardiovascular diseases. METHODS: The database was collected from health records of the Health Centre in Kragujevac. The following parameters were observed: gender and age, smoking, anthropometrical measurements and Body Mass Index, the value of systolic and diastolic blood pressure, diabetes, levels of cholesterol, and triglycerids in blood serum. The estimation of risk for developing the fatal cardiovascular disease during the period of ten years is determined according to SCORE system model. The statistical package SPSS version 18.0 was used for the statistical analysis. RESULTS: The study sample consisted of 1,053 people, 505 men and 548 women. 68.8% of people were overweight and obese, arterial hypertension was noted in 72.6%, and diabetes type II in 13.3% of people. 67.6% of people had a high level of total cholesterol in blood serum and 39.6% of people had a high level of triglycerids in blood serum. The metabolic syndrome was noted in 44.3%, and 3 or more risk factors for cardiovascular disease were noted in 65% of the population. We determined a significant statistic difference for age, smoking, nutritional status, dyslipidemia, and diabetes. CONCLUSION: The high incidence of potentially modifiable risk factors for cardiovascular disease gives a possibility to apply prevention measures for promotion and preservation of health. PMID- 26615650 TI - ORGANIZED PHYSICAL ACTIVITY AND HEALTH IN PRESCHOOL AGE: A REVIEW. AB - AIM: The aim of this study was to investigate how organized Physical Activity (oPA) can contribute to the promotion of preschool aged children's health and specifically to health indicators such as adiposity, bone and skeletal health, cardiometabolic health, motor skill development, cognitive development, and psychosocial health. METHODS: A literature search of interventions aimed at improving health in preschool age was conducted in five electronic databases. Included in the review were only studies meeting the following criteria: published or accepted for publication studies; written in English; intervention with any type of oPA; 2-6 years old participants; pre- and post-objective assessments of the intervention effects; presence of a control group. RESULTS: The majority of studies that met the inclusion criteria (n = 13) considered the effect of oPA on children's motor development, while limited were those which examined the rest of the health indicators--adiposity (n = 4), bone and skeletal health (n = 2), cardiometabolic health (n = 0), cognitive development (n = 2), and psychosocial health (n = 4). CONCLUSIONS: The information about how oPA can influence preschoolers' health status, although promising in most cases, was deficient. Questions about the kind, intensity, amount or frequency of physical activity (PA) required so as children's health to be enhanced still remain. Further research into the relationship between oPA and health in preschool age is required in order to draw conclusions enabling the development of efficient PA programmes to promote children's health. PMID- 26615651 TI - PREVENTIVE TRAINING PROGRAMME FOR PATIENTS AFTER ACUTE CORONARY EVENT-- CORRELATION BETWEEN SELECTED PARAMETERS AND AGE GROUPS. AB - AIM: Interventional cardiovascular training programmes provide a prescription of optimal form and safe intensity. They are part of the second phase of cardiovascular rehabilitation which is a key point in the whole tertiary preventive care for patients with coronary artery disease. The patients are hemodynamically adapted to a normal physical load, their aerobic capacity is gradually increased, and they learn principles of regular aerobic-resistance exercise. The aim of this study is to assess the impact of modified aerobic resistance exercise on cardiorespiratory indicators in patients after acute coronary event, and evaluate the differences between monitored parameters in different age groups. METHODS: The study was conducted on a group of 106 patients (85% of men) of an average age of 60.4 +/- 10.9 years, with left ventricular ejec tion fraction of 57.4 +/- 7.2%. All subjects went through an acute coronary event. The time elapsed between the occurence of a coronary event and the beginning of the training programme was 35 +/- 8 days. In patients after coronary artery bypass grafting, the time passed was 50 +/- 16 days on average. All patients received a two-month aerobic-resistance training with a frequency of three times a week. The length of a training unit was set to 100 minutes (out of which 60 minutes were allocated to individual aerobic training). RESULTS: A significant negative correlation between age and average values of monitored parameters was observed. Even though the values of all parameters are decreasing with increasing age, a shift towards higher values in all parameters occurred after completing the training programme. The study reveals that there are interindividual differences between the parameter values. Asignificant difference in individual parameters was found between different age groups. The result of the study shows that a given parameter could characterize each age group. Completing the interventional training programme also led to a significant increase of exercise tolerance (1.8 +/- 0.3 vs. 2.0 +/- 0.4 W/kg; p < 0.001) and of peak oxygen consumption (22.8 +/- 4.5 vs. 25.9 +/- 5.5 ml/kg/min, p < 0.001). CONCLUSION: Interindividual differences between the parameter values have been identified. This could be helpful in methodological conception of preventive training programmes for patients suffering from cardiovascular disease. The mutual connection between the parameter values and age groups does not relate only to a safer training intensity determination, but also to a more precisely targeted application of different training modalities in order to achieve an optimal final training effect. PMID- 26615652 TI - PERSISTENT ORGANOCHLORINE POLLUTANTS IN OBESE WOMEN AFTER DIET INDUCED WEIGHT LOSS: FIVE YEARS FOLLOW UP STUDY. AB - AIM: Persistent organochlorine pollutants (POPs) from the environment are still bioaccumulating in human tissues. The aim of our study was to analyze the development of plasma POPs levels in obese women in relationship with their weight loss success in five year follow-up study. METHODS: 20 obese women aged 25 73 years were studied just before and after having completed a 3 month controlled low calorie diet (LCD) intervention (5 MJ daily), and again after 6 and 60 months since the beginning of the study. Body weight and plasma levels of 7 POPs were measured: polychlorinated biphenyls (PCB) 153, 138, 180; 2,2-bis(4-chlorophenyl) 1,1,1-trichloroethylene (p,p'-DDE); 2,2-bis(4-chlorophenyl)-1,1,1-trichloroethane (p,p'-DDT), hexachlorocyclobenzene (HCB), hexachlorocyclohexane beta (HCH beta). RESULTS: Data shows that after 3 months of a completely controlled restrictive diet regimen, the weight loss was associated with an increase in POP plasma levels. However, after a five year follow-up, there were no differences in POPs plasma levels between those who kept losing weight or maintained the initial weight (WL/M) and the group of weight gainers (WG), except for HCB where the WG had a significantly higher level (p < 0.05). CONCLUSIONS: These results suggest that contrary to the long-term weight gain, the long-term weight loss or weight maintenance caused by diet restriction is associated with lower plasma levels of HCB. PMID- 26615653 TI - HOW DO WE EVALUATE AND MANAGE MANY DIFFERENT VACCINATION SCHEDULES IN THE EU? AB - BACKGROUND: Vaccines are biologic medical products, the biological activity and characteristics of which are significantly different from common drugs and other medical products. The process of determining the dosing (vaccination) schedule for a particular vaccine is based on different principles and rules than other drugs. The dosing schedule for drugs is based on the essential pharmacological properties: pharmacokinetics and pharmacodynamics. When determining the schedule for vaccines, the pharmacokinetic and pharmacodynamic principles cannot be applied: sero-conversion and sero-protectivity of the biologically active component of the vaccine need to be applied. As opposed to drugs and medical products the dosing (vaccination) schedule in the Summary of Product Characteristics (SPC) is often provided in several versions, sometimes with a supplement referring to official (national) recommendations. In relation to the large variability vaccination schedules in the European Union (EU), it is not realistic to test each vaccination schedule in clinical studies. Requiring clinical trials for each vaccination schedule used only for the needs of regulators is more of an ethical issue than a scientific one. The European Centre for Disease Prevention and Control (ECDC), which is the Scientific Panel on Childhood Immunisation Schedule (SPACIS), accepts all the schedules used in EU countries as valid. METHODS AND RESULTS: A review of the literature on immunisation schedules for primary series and booster doses choosing the following key words: immunisation, vaccination schedule, primary, booster, timing, vaccination delay. PMID- 26615654 TI - THE AUSTRIAN VACCINATION PARADOX: TICK-BORNE ENCEPHALITIS VACCINATION VERSUS INFLUENZA VACCINATION. AB - This paper describes a paradoxical situation in Austria. The vaccination rate against tick-borne encephalitis (TBE) in the general population is 82%, which is the highest worldwide, whereas the vaccination rate against influenza is about 8% and is among the lowest worldwide. A high awareness of TBE among the Austrian population achieved by an annual social marketing programme and the wide use of effective and well-tolerated vaccines have led to a successful containment of that disease. The vaccination coverage increased from 6% in 1980 to 82% in 2013 and exceeds 90% in some high-risk areas. This has led to a steady decline in the number of TBE cases from several hundred cases to 50 to 100 cases per year. The situation in regard to influenza vaccination is the opposite. Although Austria has issued one of the most extensive recommendations for influenza vaccination worldwide, the vaccination rate of the general population is extremely low. The possible reasons for the failure in the implementation of recommendations are ignorance, lack of social marketing and the predominance of a distinct discordance within the health system in general, and the Austrian medical fraternity in particular. PMID- 26615655 TI - MATHEMATICAL MODELLING OF VARICELLA SPREAD IN SLOVAKIA. AB - AIM: Varicella is a highly contagious disease. In Slovakia, 15,000-30,000 cases are reported annually. However, vaccination against varicella is not widely used in Slovakia. The aim of this paper is to predict the influence of vaccination administrated in different ages on the disease occurrence in different age groups. METHODS: Deterministic, age-stratified SIR (susceptible-infected recovered) model with stable population was used for prediction of varicella spread in Slovakia. RESULTS: Vaccination of a group designated as 0 influences the proportion of susceptible and infected persons in all age groups, vaccination of 10 years old ones affects only the proportion of susceptible and infected individuals older than 10 years. CONCLUSION: The increase of vaccination coverage should have a positive impact on the incidence of varicella in Slovakia. In case of vaccination coverage of 0 group in the range of 30-75%, it is necessary to pay attention to the protection of older children and adults. PMID- 26615656 TI - PREVALENCE OF FALLS AND ASSOCIATED RISK FACTORS AMONG AGED POPULATION: COMMUNITY BASED CROSS-SECTIONAL STUDY FROM TURKEY. AB - AIM: The aim of the study was to examine the prevalence and risk factors of falls among persons aged 65 years and older in Qanakkale, Turkey. METHODS: A community based cross-sectional study was conducted between May-September 2013. A total of 1,001 elderly living in Canakkale city centre were included into our study. The research was carried out with face-to-face interviews and survey forms. The survey form consists of seven sections: demographic characteristics, significance of ageing, daily activities, quality of life and social network in old age, use of health services and health problems, bad habits, and the European Health Impact Scale. Data analysis was performed using the SPSS software version 19.0. For data investigation the chi-square and logistic regression analyses were used. RESULTS: The prevalence of falls at home or outside was 32.1% among elderly in the last six months period. The prevalence of falling for women at home as well as outside was statistically significantly higher than for men (p < 0.05). According to multivariate analysis results the risk of falling at home or outside was increased by 2.7 times in women (95% CI: 1.90-3.75), by. 2.1 times in those who cannot take care of themselves (95% Cl: 1.33-3.29), and by 1.7 times in those who have low quality of life (95% Cl: 1.24-2.43). CONCLUSIONS: This community based cross-sectional study showed that prevalence of falling was high in aged persons living in centre of Canakkale located in the western part of Turkey. Moreover, the risk was increased in women, those who cannot take care for themselves, and those with low standard of living. PMID- 26615657 TI - SICKNESS PRESENCE AND STRESSFUL LIFE EVENTS OF HEALTH CARE WORKERS. AB - AIM: The aim of the study is to investigate the relationship between sickness presence and stressful life events among health care workers. METHODS: Data were gathered from all health care workers at the University Medical Centre Ljubljana employed there in the period between 1 January 2010 and 31 December 2010. Each employee obtained a questionnaire composed of two standardized international questionnaires. RESULTS: There were 57% of sickness present health care workers among the participants. The sickness present reported to have more diseases of family member than the non-sickness present (OR = 1.5; 95% CI = 1.2-2.0), loan (OR = 1.4; 95% CI = 1.1-1.6), their partner lost job (OR = 1.4; 95% CI = 1.0 1.8), or they changed the place of living (OR = 1.4; 95% CI = 1.0-2.0). CONCLUSIONS: The results of the study indicate that stressful life events with economic consequences might have an important influence on sickness presence. PMID- 26615658 TI - LOW-BACK PAIN DISORDERS AS OCCUPATIONAL DISEASES IN THE CZECH REPUBLIC AND 22 EUROPEAN COUNTRIES: COMPARISON OF NATIONAL SYSTEMS, RELATED DIAGNOSES AND EVALUATION CRITERIA. AB - AIM: Low-back pain diseases (LBPD) belong to the most frequent diagnoses determined by general practitioners, and constitute one of the most common reasons for sick leave and permanent disability pension in the Czech Republic and other European countries. Epidemiological studies have shown a statistically significant association between LBPD and certain types of occupational burden. However, in the Czech Republic, LBPD caused by overload and/or whole-body vibrations have not yet been included in the list of occupational diseases. The aim of this study was to collect and compare the systems, criteria and diagnoses used to recognize LBPD as occupational diseases in other European countries. METHODS: A questionnaire focused on LBPD was distributed and answered by specialists in occupational diseases in European countries. It included items concerning LBPD in the national list of occupational diseases, and work-related and diagnostic criteria that need to be fulfilled for recognizing LBPD as occupational diseases and possible awarding compensations to the patients. RESULTS: In 13 countries out of the 23 countries studied, LBPD caused by overload can be recognized as occupational, providing that the diagnosis is sufficiently proven and exposure criteria and/or listed occupation are met and duration of exposure is confirmed (Belgium, Denmark, France, Germany, Hungary, Italy, Lithuania, Macedonia, Netherlands, Romania, Slovakia, Sweden, and Switzerland). LBPD due to vibrations can be also recognized as occupational in 14 countries. In 8 countries LBPD are not accepted as occupational unless they are caused by an injury at work. Specific criteria to evaluate occupational exposure of patients with LBPD were set in Belgium, Denmark, France, Germany, Lithuania, Macedonia, Netherlands, and Slovakia. In other countries, the evaluation is done at an individual basis. CONCLUSIONS: In practice, the assessment of occupational overload and its contribution to the development of LBPD as well as its inclusion in the compensation system are important for several reasons. Firstly, it may be considered essentially preventable. Secondly, cases with a significant contribution of occupational aetiology may be viewed as occupational diseases for which compensation may be claimed, as it is the case in many European countries. Importantly, inclusion of LBPD in the list of occupational diseases or another system of compensation may be viewed as a preventive measure as it increases the visibility of this problem not only for the workers, but especially for the employers. PMID- 26615659 TI - HOW IS CLASSMATE AND PE TEACHER SUPPORT ASSOCIATED WITH THE LEVEL OF PHYSICAL ACTIVITY IN YOUNG ADOLESCENTS FROM KOSOVO? THE ROLE OF GENDER AND AGE. AB - AIM: This study aimed to investigate how were the peer and physical education (PE) teacher variables associated with moderate-to-vigorous physical activity (MVPA) among Kosovar teenagers (13-15 years of age), and the role of age and gender in these associations. METHODS: Cross-sectional data was gathered through a study conducted in seven major municipalities of Kosovo. 632 girls (aged 14.3 +/- 0.8) and 664 boys (aged 14.2 +/- 0.8) were examined using the adjusted Classmate and Teacher Support Scale and the Physical Activity Screening measure. A three-way (support*age*gender) ANOVA was used to compare the individuals' MVPA level with the different levels of support they received, with different age in groups of girls and boys. RESULTS: Boys reported higher levels of MVPA than girls in all age categories. A higher level of MVPA was reported by boys receiving high or medium support from classmates. In case of PE teacher support, high, medium and even low support correlated with high MVPA in all age categories. In girls only 13 year olds reported receiving high levels of both classmate and PE teachers support which correlated with a higher level of MVPA. CONCLUSIONS: It appears that engagement in MVPA among young Kosovar adolescents is relatively high in boys, regardless of the level of classmate or PE teacher support, whereas in girls the level of MVPA decreased over their time at school. Support from both classmates and PE teachers turned out to be the most significant factor in 13 years old girls, before they moved from primary to secondary school. This issue requires more detailed insight, considering traditional ethnical and religious barriers to engagement of young female adolescents in physical activity. PMID- 26615660 TI - REFINING OF ASTHMA PREVALENCE SPATIAL DISTRIBUTION AND VISUALIZATION OF OUTDOOR ENVIRONMENT FACTORS USING GIS AND ITS APPLICATION FOR IDENTIFICATION OF MUTUAL ASSOCIATIONS. AB - AIM: This study presents a procedure of complex assessment of the environment impact on asthma prevalence. This approach is also applicable for any other disease which is supposed to be associated with the quality of the outdoor environment. METHODS: The input data included asthma prevalence values from the National Institute of Public Health (NIPH) cross-section questionnaire survey (13,456 children) and annual reports on activities of all paediatricians in the Czech Republic (2,072 surgeries); concentrations of PM10, PM2.5, NO2, SO2, O3, benzene, benzo(a)pyrene, As, Cd, Pb and Ni; emissions of total suspended particles, SO2, NOx, CO, VOC, NH3; traffic intensity; land cover (anthropogenic area, urban greenery, arable land, grassland, other agricultural land, forests); proportion of cultivation of individual agricultural crops (17 categories); and proportion of individual woods (15 categories). Using the Geographical Information Systems (GIS) analysis the integration of all source data through one spatial unit was achieved and complete data sets were compiled to be subjected to statistical analysis (combination of factor analysis with logistic/linear regression). RESULTS: In this study, the approach of combined use of GIS analyses and statistical evaluation of large input data sets was tested. The asthma prevalence demonstrated positive associations with the air pollution (PM10, PM2.5, benzene, benzo(a)pyren, SO2, Pb, Cd) and the rate of agricultural use of land (growing oats, rye, arable fodder crops). Conversely, there was a negative association with the occurrence of natural forests (ash, poplar, fir, beech, spruce, pine). No significant associations were observed with the distance from the road, traffic intensity and NO2 concentration. CONCLUSIONS: These findings suggest that the outdoor quality may be one of the crucial factors for asthma prevalence. PMID- 26615661 TI - EFFECT OF WATER ACTIVITY AND TITANIA P25 PHOTOCATALYST ON INACTIVATION OF PATHOGENIC FUNGI--CONTRIBUTION TO THE PROTECTION OF PUBLIC HEALTH. AB - AIM: The aim of this study was to determine the antifungal activity of titanium dioxide activated by indoor light on Czapek Yeast Agar (CYA). METHODS: The agar plate method was used and titania P25 (Evonik) was added to the medium in the amount of 20 g.dm(-3). The control experiments without titania were also carried out. The water activity (a(w)) of the basal media was adjusted to 0.999, 0.997, 0.975, 0.950, 0.900 and 0.850 with sodium chloride. The photoactivity of titania was tested for six strains of potentially pathogenic fungi: Aspergillus versicolor (WB130, W11), Stachybotrys chartarum (STA1), Pseudallescheria boydii (AP25), Pseudallescheria ellipsoidea (ZUT1 2), Scedosporium apiospermum (ZUT1 1), Scedosporium aurantiacum (ZUT4BIS). After inoculation with fungal spore suspensions, one part of CYA plates was incubated in dark, while another part was daily exposed to indoor light for 12 hours per day.The plates were incubated at 25 degrees C for 10 days. The daily growth rates (mm x day(-1)) were calculated from the linear regression equation. RESULTS: The CYA supplementation with titanium dioxide for different availability of water resulted in the decrease of fungal growth rates in dark and under irradiation. The lowest and the highest rates of daily growth were obtained in the presence and absence of titania for the low and high water activity (0.900 a(w) and 0.999 a(w)), respectively. CONCLUSIONS: Fungi did not grow on all examined media with the lowest water activity (a(w) <= 0.850) which confirmed necessity of water for their growth. The fungi Pseudallescheria-Scedosporium were the most sensitive to titania and water activity, while the strains of Aspergillus versicolor were the most resistant to the presence of titania and lack of water. It has been shown that the lack of accessible water resulted in the strongest action of titanium dioxide both in dark and under irradiation. For the lowest amount of accessible water irradiation of titania resulted in complete inhibition of fungal growth. While, under dark conditions, titania presence enhanced the growth of persistent fungi, i.e., Aspergillus versicolor. It is assumed that these fungi could obtain water from the water-rich titania surface. PMID- 26615662 TI - [Retrospective Study of Laryngeal Preservation Treatment for Hypopharyngeal Carcinoma with Transoral Resection or Induction Chemotherapy]. AB - We have performed transoral surgical resection for patients with T1/T2 hypopharyngeal cancer and induction chemotherapy with docetaxel for patients with T2/T3 disease. The patients were analyzed in order to determine the current situation of larynx preservation in patients with hypopharyngeal cancer. The data of a total of 83 patients with hypopharyngeal cancer were analyzed retrospectively. The primary subsites were : pyriform sinus (PS) in 61 patients, posterior wall (PW) in 13 patients, and postcricoid (PC) in 9 patients. The number of patients classified as having T1, T2, T3 and T4 disease were 14, 29, 23 and 17, respectively. The main therapies employed in the patients were as follows: transoral surgical resection plus radiation therapy for T1 disease, radiation therapy, induction chemotherapy, and partial resection for T2 disease, induction chemotherapy, radiation therapy, and pharyngo-laryngoesophagectomy for T3 disease, and pharyngo-laryngoesophagectomy plus induction chemotherapy for T4 disease. The 5-year larynx preservation rates in the patients with T1, T2, T3 and T4 disease were 100%, 73%, 39% and 35%, respectively. Our method was able to improve the larynx preservation rate without having any adverse effect on the survival rate. However, the strength of treatment for T 3 disease needs to be improved, because a large number of recurrences and deaths due to the primary disease were encountered in this patient group. PMID- 26615663 TI - [Oral Allergy Syndrome Following Soy Milk Ingestion in Patients with Birch Pollen Allergy]. AB - BACKGROUND: Persons allergic to birch pollen often report oral and pharyngeal hypersensitivity to fruit and vegetables, due to immunological cross-reactivity between pollen and foods. This phenomenon is referred to as the oral allergy syndrome (GAS). Such cross-reactive antigen reactions mainly involve Bet v 1, which is the major birch-pollen allergen, and partially involve birch-pollen profilin Bet v 2. Soybean contains Bet v 1-related antigen (Gly m 4), and soy milk often causes the OAS with severe symptoms such as precordial and abdominal burning sensation because soy milk undergoes little denaturation, and this water soluble liquid is consumed by most people rather quickly. We evaluated the frequency of the oAS after ingestion of soymilk and examined IgE antibodies to various allergens. METHODS: A total of 167 patients [122 women, 45 men; age range, 4-72 years (mean age, 32 years)], who had experienced GAS episodes and had IgE birch--pollen antibodies, were interviewed. Using the CAP system, we examined IgE antibodies to birch pollen and other allergens. Of 167 patients, 161 were examined for IgE antibodies to Bet v 1, Bet v 2, Gly m 4, and soybean. We evaluated the frequency of the GAS after soy milk ingestion based on reports by GAS patients with birch pollen allergy, and evaluated the positive rates of some of the IgE antibodies. RESULTS: Among the 167 patients with birch-pollen allergy and GAS on ingestion of any of the foods, there were 16 cases (10%) with OAS following soy milk ingestion. In addition, the foods that caused OAS most often were apples (123 cases, 74%), peaches (67%), and cherries (55%), followed by pears (37%) and kiwi (37%). A higher CAP class for birch pollen, Bet v 1, Gly m 4, and soybean was associated with a higher prevalence of OAS to soy milk. Of 15 patients who had GAS on ingestion of soy milk and had birch-pollen allergy, 47% (7cases) were CAP class 1 for soybean and only 7% (case) was CAP class c2, whereas 93% (14cases) were CAP class 1 for Gly m 4, and 87% (3cases) were CAP class >= 2 for Gly m 4. CONCLUSION: Among the birch-pollen allergic OAS patients, 10% had the OAS on ingestion of soy milk, and among these with birch-pollen allergy and the OAS on ingestion of soy milk, the positive rate for soy milk CAP was low, whereas that for Gly m 4 CAP was high. PMID- 26615664 TI - [Serological Study of Otitis Media with ANCA Associated Vasculitis (OMAAV)]. AB - Otitis media related with ANCA associated vasculitis is an intractable condition conditions that is resistant to conventional conservative treatment or surgical treatments. The name "otitis media with ANCA associated vasculitis (OMAAV)" has been proposed as a new concept for this disease. In the present study, we examined the clinical feature of 14 cases of OMAAV. We also investigated the usefulness of combined tests for ANCA detection. There were 11 females and 3 males, with a median age of 68.5 years. PR3-ANCA was positively detected in 4 (28.6%) patients, MPO-ANCA was detected in 6 (42.9%), and 4 (28.6%) were both ANCAs negative. During the course 6 patients developed pachymeningitis and 5 patients developed facial palsy. Plasma samples from 14 OMAAV patients were tested for the presence of ANCAs with five detection methods (3 PR 3-ANCA kits (direct ELISA, capture ELISA, anchor ELISA), 2 MPO-ANCA kits (direct ELISA, capture ELISA)) and the indirect immunofluorescence (II) technique. Six patients (42.9%) were positive for ANCA in clinical examination (single EIA method), while ANCA was positively detected in 9 patients (64.3%) with combined methods. In ANCA negative cases, ANCA should also be tested with a different technique such as new generation ELISA and IIF. PMID- 26615665 TI - [A Case of Oropharyngeal Large Cell Neuroendocrine Carcinoma]. AB - The large cell neuroendocrine carcinoma (LCNEC) of the lung was first reported in detail by Travis et al. in 1991. Extrapulmonary LCNEC rarely occurs, and only 22 cases have been reported in the head and neck mucosal regions. Today LCNEC of the larynx is contained in the moderately differentiated/Grade 2 category. However some authors advocate that LCNEC of the larynx should be separated from this category because of the difference in the clinical manifestations and pathological features. Standard treatment for head and neck mucosal LCNEC (M LCNEC) has not been confirmed. However we suggested the efficacy of postoperative chemotherapy for M-LCNEC. This report describes a case of an LCNEC of the oropharynx. The patient was a 64-year-old man. We treated him with surgery and chemoradiotherapy. He has been disease-free for 36 months after adjuvant chemotherapy. PMID- 26615666 TI - [A Case of the Relapsing Polychondritis Limited to the Trachea]. AB - A 62-year-old woman, who had dysesthesia in the throat, and polyposia the previous year, was admitted in a coma because of respiratory failure. Computed tomography scans demonstrated dilatation of the esophagus and stenosis of the trachea. After emergency intubation, extubation was not possible due to a collapsed trachea, so we performed a tracheostomy. The tracheoscopy from the stoma showed an esophagus-like trachea due to disappearance of the tracheal cartilage and the straight pattern on the membranous portion, and the lumen deformed with coughing. With the continuous dyspnea episode, the patient was diagnosed as having tracheomalacia. Anti-type II collagen antibody and pathological findings of the trachea led us to the diagnosis of Relapsing Polychondritis. PMID- 26615667 TI - Upside Down! Crystallographic and Spectroscopic Characterization of an [Fe IV(O syn)(TMC)]2+ Complex. AB - Fe(II)(TMC)(OTf)2 reacts with 2-(t)BuSO2-C6H4IO to afford an oxoiron(IV) product, 2, distinct from the previously reported [Fe(IV)(Oanti)(TMC)(NCMe)](2+). In MeCN, 2 has a blue-shifted near-IR band, a higher nu(Fe?O), a larger Mossbauer quadrupole splitting, and quite a distinct (1)H NMR spectrum. Structural analysis of crystals grown from CH2Cl2 reveals a complex with the formulation of [Fe(IV)(Osyn)(TMC)(OTf)](OTf) and the shortest Fe(IV)?O bond [1.625(4) A] found to date. PMID- 26615668 TI - Near-Infrared- and Visible-Light-Enhanced Metal-Free Catalytic Degradation of Organic Pollutants over Carbon-Dot-Based Carbocatalysts Synthesized from Biomass. AB - Cost-efficient nanoparticle carbocatalysts composed of fluorescent carbon dots (CDs) embedded in carbon matrix were synthesized via one-step acid-assisted hydrothermal treatment (200 degrees C) of glucose. These as-synthesized CD-based carbocatalysts have excellent photoluminescence (PL) properties over a broad range of wavelengths and the external visible or NIR irradiation on the carbocatalysts could produce electrons to form electron-hole (e(-)-h(+)) pairs on the surface of carbocatalysts. These restant electron-hole pairs will react with the adsorbed oxidants/reducers on the surface of the CD-based carbocatalysts to produce active radicals for reduction of 4-nitrophenol and degradation of dye molecules. Moreover, the local temperature increase over CD-based carbocatalyst under NIR irradiation can enhance the electron transfer rate between the organic molecules and CD-based carbocatalysts, thus obviously increase the catalytic activity of the CD-based carbocatalyst for the reduction of 4-nitrophenol and the degradation of dye molecules. Such a type of CD-based carbocatalysts with excellent properties and highly efficient metal-free photocatalytic activities is an ideal candidate as photocatalysts for the reduction of organic pollutants under visible light and NIR radiation. PMID- 26615669 TI - Coassembly of Photosystem II and ATPase as Artificial Chloroplast for Light Driven ATP Synthesis. AB - Adenosine triphosphate (ATP) is one of the most important energy sources in living cells, which can drive serial key biochemical processes. However, generation of a proton gradient for ATP production in an artificial way poses a great challenge. In nature, photophosphorylation occurring in chloroplasts is an ideal prototype of ATP production. In this paper we imitate the light-to-ATP conversion process occurring in the thylakoid membrane by construction of FoF1 ATPase proteoliposome-coated PSII-based microspheres with well-defined core@shell structures using molecular assembly. Under light illumination, PSII can split water into protons, oxygen, and electrons and can generate a proton gradient for ATPase to produce ATP. Thus, an artificially designed chloroplast for PSII-driven ATP synthesis is realized. This biomimetic system will help to understand the photophosphorylation process and may facilitate the development of ATP-driven devices by remote light control. PMID- 26615670 TI - Chemical constituents of the mangrove-associated fungus Capnodium sp. SZ-F22. A new eremophilane sesquiterpene. AB - A new eremophilane sesquiterpene, capnodiumone (1), along with five known eremophilane sesquiterpenes (2-6) and eight other compounds (7-14), have been isolated from a mangrove-associated fungus Capnodium sp. SZ-F22. The chemical structures were elucidated on the basis of extensive spectroscopic analysis. The broth extract of the fungus exhibited a good inhibitory effect on the mycelium growth against Fusarium graminearum at 100 MUg/mL, however, all the 14 compounds showed no expected antifungal activity. The probable reasons were discussed. PMID- 26615671 TI - Influence of combined CYP3A4 and CYP3A5 single-nucleotide polymorphisms on tacrolimus exposure in kidney transplant recipients: a study according to the post-transplant phase. AB - AIM: The present study investigated in Tunisian renal transplant patients, genetic polymorphisms of CYP3A4 -392A>G and CYP3A5 6986A>G and their influence on tacrolimus (Tac) pharmacokinetics during early and late post-transplant (PT) phases and established customized ranges of Tac doses matching the C0 target levels according to CYP3A4 and CYP3A5 genotype combination and the PT phase. PATIENTS & METHODS: We included adult Tunisian patients having received Tac for de novo kidney grafts and undergone a therapeutic drug monitoring of Tac by morning C0 monitoring during early (1 to 90 days) and late (over 90 days) PT phases. The genomic DNA was extracted from peripheral blood mononuclear cells using a salting-out procedure. CYP3A4 promoter (rs2740574; -392A>G) and CYP3A5 (rs776746; 6986A>G) SNP genotyping was analyzed using PCR-RFLP. RESULTS: Fifty two patients were enrolled in the study. During the early PT phase, the CYP3A5 polymorphism but not that of CYP3A4, correlates significantly with Tac dose normalized C0 (C0/D ratio). During the late PT phase, the effect of CYP3A4 polymorphism becomes significant and that of CYP3A5 becomes nonsignificant on Tac C0/D Tac. The mean daily doses (mg/kg) matching therapeutic C0, regardless of the CYP3A genotypes, were 0.16 +/- 0.05 and 0.10 +/- 0.05 during early and late PT phase, respectively. Carriers of the CYP3A4*1B allele require higher doses to maintain the C0 in the therapeutic range during the two PT phases. However, patients carrying the CYP3A5*1 require significant higher Tac doses, only during the early phase. CONCLUSION: Our data support a critical role of the CYP3A5 6986A>G and CYP3A4 -392A>G polymorphisms on the variation of Tac exposure during the early and the late PT phase, respectively. The establishment of customized Tac doses, according to CYP3A4/CYP3A5 genotype combination and the PT time, may allow preventing graft rejection and improving the safety profile of this drug. Further studies are needed to investigate this issue. PMID- 26615672 TI - ANXA5 level is linked to in vitro and in vivo tumor malignancy and lymphatic metastasis of murine hepatocarcinoma cell. AB - AIM: To investigate ANXA5 overexpression on in vitro and in vivo malignancies of murine Hca-P cells. MATERIALS & METHODS: Hca-P with low lymph node metastasis (LNM) potential was used as cell model. TEM, CCK-8 and Boyden transwell assays were performed for in vitro Hca-P behaviors. Hca-P-transplanted mouse model was established for in vivo experiment. RESULTS: ANXA5-overexpressing monoclonal Anxa5-Hca-P-1, Anxa5-Hca-P-2 and Anxa5-Hca-P-3 cells were obtained. ANXA5 upregulation alters the proliferation, morphology and rough endoplasmic reticulum of Hca-P cells, enhances in vitro migration and invasions of Hca-P, promotes in vivo malignant degree and LNM rate of Anxa5-Hca-P-3-transplanted mice. CONCLUSION: As a potential indicator for malignancy and lymphatic metastasis, ANXA5 overexpression increases in vitro migration and invasion of Hca-P cell, promotes in vivo malignancy, LNM rate and level of Hca-P-transplanted mice. PMID- 26615681 TI - Transition-State Theory, Dynamics, and Narrow Time Scale Separation in the Rate Promoting Vibrations Model of Enzyme Catalysis. AB - The power of transition-state theory (TST) for understanding enzymes is evidenced by its recent use in the design and synthesis of highly active de novo enzymes. However, dynamics can influence reaction kinetics, and some studies of rate promoting vibrations even claim that dynamical theories instead of TST are needed to understand enzymatic reaction mechanisms. For the rate-promoting vibration (RPV) model of enzyme catalysis [Antoniou et al., J. Chem. Phys. 2004, 121, 6442], a reactive flux correlation function analysis shows that dynamical effects do slow the kinetics. However, the RPV model also shows extremely long-lived correlations because the RPV and the bath are not directly coupled. Additionally, earlier studies of the RPV model show a narrow time scale separation due to a small 5kT barrier. Thus earlier findings based on the RPV model may have little bearing on the properties of real enzymes. The intrinsic reaction coordinate (IRC) reveals that the RPV is an important component of the reaction coordinate at early and late stages of the pathway, but the RPV is not an important component of the reaction coordinate direction at the transition state. The unstable eigenmode from harmonic TST (which coincides with the IRC at the saddle point) gives a larger transmission coefficient than the coordinate used in the correlation functions of Antoniou et al. Thus while TST cannot predict the transmission coefficient, the RPV model suggests that TST can provide mechanistic insights on elementary steps in enzyme catalysis. Finally, we propose a method for using the transition-state ensemble as predicted from harmonic TST to distinguish promoting vibrations from other more mundane bath variables. PMID- 26615682 TI - Proton Transfer Dynamics in Crystalline Maleic Acid from Molecular Dynamics Calculations. AB - The crystal structure of maleic acid, the cis conformer of HOOC-CH?CH-COOH has been investigated by Car-Parrinello molecular dynamics (CPMD) and path integral molecular dynamics (PIMD) simulations. The interesting feature of this compound, compared to the trans conformer, fumaric acid, is that both intra- and intermolecular hydrogen bonds are present. CPMD simulations at 100 K indicate that the energy barrier height for proton transfer is too high for thermal jumps over the barrier in both the intra- and intermolecular hydrogen bonds. Dynamics at 295 K reveal that the occupancy ratio of the proton distribution in both the intra- and intermolecular hydrogen bonds is 0.96/0.04. The time lag between the proton transfers in the intra- and intermolecular hydrogen bonds is in the range of 2-9 fs. This is slightly shorter than the time lag obtained previously for fumaric acid, where only intermolecular hydrogen bonds are present. It is also interesting to notice that in most cases the proton transfer process starts in the intramolecular hydrogen bond and subsequently follows in the intermolecular hydrogen bond. Vibrational spectra of the investigated system and its deuterated analogs HOOC-CH?CH-COOD and DOOC-CH?CH-COOD have been calculated and compared with experimental data. PMID- 26615683 TI - Trends in R-X Bond Dissociation Energies (R(*) = Me, Et, i-Pr, t-Bu, X(*) = H, Me, Cl, OH). AB - Trends for R-X bond dissociation energies have been examined with density functional methods of B3LYP, BMK, M06-2X, MC3MPW, B2PLYP, MCG3-MPW, and XYG3, as well as G3, MCG3/3, G3X, and G4 theories as functions of alkylation (i.e., R(*) = Me, Et, i-Pr, t-Bu) and X(*) substitution (i.e., X(*) = H, Me, Cl, OH). The results highlight the physical origin of success or failure of each method and demonstrate the good agreement with experimental results for G4, MCG3-MPW, and XYG3. The last holds great promise as a reliable method that is applicable to larger systems. PMID- 26615684 TI - Topological Analysis of the Fukui Function. AB - In this work an alternative to the analysis of the Fukui function will be presented and compared with the traditional condensed function. The topological analysis allows us to define basins corresponding to different regions of the space, and the numerical integration of the density over those volumes gives a number amenable of a chemical interpretation in line with the Fukui function applications. Various examples are shown, a series of small molecules, a couple of clusters, and aromatic molecules. They are discussed in comparison with other methodologies and with the experimental evidence. PMID- 26615685 TI - Bound Triplet Pairs in the Highest Spin States of Coinage Metal Clusters. AB - The work discusses bonding in coinage metal clusters, (n+1)Mn (M = Cu, Ag, Au), that have maximum spin without a single electron pair. It is shown that the bonding energy per atom, De/n, exhibits a strong nonadditive behavior; it grows rapidly with the cluster size and converges to values as large as 16-19 kcal/mol for Au and Cu. A valence bond (VB) analysis shows that this no-pair ferromagnetic bonding arises from bound triplet electron pairs that spread over all the close neighbors of a given atom in the clusters. The bound triplet pair owes its stabilization to the resonance energy provided by the mixing of the local ionic configurations, (3)M(??)(- )M(+) and M(+ 3)M(??)(-), and by the various excited covalent configurations (involving pz and dz(2) atomic orbitals) into the fundamental covalent structure (3)(M??M) with a s(1)s(1) electronic configuration. The VB model shows that a weak interaction in the dimer can become a remarkably strong binding force that holds together monovalent atoms without a single electron pair. PMID- 26615686 TI - Dual Grid Methods for Finding the Reaction Path on Reduced Potential Energy Surfaces. AB - Two new algorithms are presented for determining the minimum energy reaction path (MEP) on the reduced potential energy surface (RPES) starting with only the reactant. These approaches are based on concepts from the fast marching method (FMM), which expands points outward as a wavefront on a multidimensional grid from the reactant until the product is reached. The MEP is then traced backward to the reactant. Since the number of possible grid points that must be considered grows exponentially with increasing dimensionality of the RPES, interpolation is important for maintaining manageable computational costs. In this work, we use Shepard interpolation, which we have modified to resolve problems in overfitting. In contrast to FMM, which accurately locates the MEP, the new algorithms focus on locating the single rate-limiting transition state and provide only a rough estimate of the MEP. They do this by mapping out the RPES on a coarse grid and then refining a least action path on a finer grid. This is done so that the majority of the interpolation is done on the finer grid, which minimizes the amount of extrapolation inherent in an outward searching algorithm. The first method scans the entire PES before iteratively locating the transition state (TS) for the MEP on the lower bound estimate of the fine PES. The second method explores the coarse grid in a similar manner to FMM and then iteratively locates the rate-limiting TS in the same manner as the first method. Both methods are shown to be capable of rapidly obtaining (in less than 30 constrained optimization cycles) an approximation to the MEP and the rate limiting TS for three example systems: the 4-well potential, the molecule N-hydroxymethyl methylnitrosaminee (HMMN), and a cluster model of DNA-uracil glycosylase. PMID- 26615687 TI - Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field. AB - The accurate prediction of protein-ligand binding free energies is a primary objective in computer-aided drug design. The solvation free energy of a small molecule provides a surrogate to the desolvation of the ligand in the thermodynamic process of protein-ligand binding. Here, we use explicit solvent molecular dynamics free energy perturbation to predict the absolute solvation free energies of a set of 239 small molecules, spanning diverse chemical functional groups commonly found in drugs and drug-like molecules. We also compare the performance of absolute solvation free energies obtained using the OPLS_2005 force field with two other commonly used small molecule force fields general AMBER force field (GAFF) with AM1-BCC charges and CHARMm-MSI with CHelpG charges. Using the OPLS_2005 force field, we obtain high correlation with experimental solvation free energies (R(2) = 0.94) and low average unsigned errors for a majority of the functional groups compared to AM1-BCC/GAFF or CHelpG/CHARMm-MSI. However, OPLS_2005 has errors of over 1.3 kcal/mol for certain classes of polar compounds. We show that predictions on these compound classes can be improved by using a semiempirical charge assignment method with an implicit bond charge correction. PMID- 26615688 TI - Assessment of Functionals for TD-DFT Calculations of Singlet-Triplet Transitions. AB - The calculation of transition energies for electronically excited states remains a challenge in quantum chemistry, for which time-dependent density functional theory (TD-DFT) is often viewed as a balanced (computational effort/obtained accuracy) technique. In this study, we benchmark 34 DFT functionals in the specific framework of TD-DFT calculations for singlet-triplet transitions. The results are compared to accurate wave function data reported for the same set of 63 excited-states, and it turns out that, within the selected TD-DFT framework, BMK and M06-2X emerge as the most efficient hybrids. This investigation clearly illustrates that the conclusions drawn for singlet excited states do not necessarily hold for triplet states, even for similar molecular structures. PMID- 26615689 TI - Updated Branching Plane for Finding Conical Intersections without Coupling Derivative Vectors. AB - The conical intersections (CIs) form a (f-2)-dimensional hyperspace on which two diabatic potential energy surfaces (PESs) belonging to the same symmetry cross, where f is the internal degree of freedom. The branching plane (BP) is a (two dimensional) plane defined by the difference gradient vector (DGV) and the coupling derivative vector (CDV), and on the BP, the degeneracy of the two adiabatic PESs is lifted. The properties of the BP are often used in the exploration of the conical intersection hyperspace, such as determination of the minimum energy CI or the first-order saddle point in CI. Although both DGV and CDV are necessary to construct the BP in general, CDV is not always available depending on ab initio methods and programs. Therefore, we developed an approach for optimizing critical points on the CI hypersurface without CDV by using a BP updating method, which was shown to be accurate and very useful for minimum energy and saddle point optimization and for the minimum energy path following within the CI hypersurface in numerical tests for C6H6 and C5H8N(+). PMID- 26615690 TI - Benchmark of Electronically Excited States for Semiempirical Methods: MNDO, AM1, PM3, OM1, OM2, OM3, INDO/S, and INDO/S2. AB - Semiempirical configuration interaction (CI) calculations with eight different Hamiltonians are reported for a recently proposed benchmark set of 28 medium sized organic molecules. Vertical excitation energies and one-electron properties are computed using the same geometries as in our previous ab initio benchmark study on electronically excited states. The CI calculations for the standard methods (MNDO, AM1, PM3) and for the orthogonalization-corrected methods (OM1, OM2, OM3) include single, double, triple, and quadruple excitations (CISDTQ) using the graphical unitary group approach (GUGA) as implemented in the MNDO code. The CIS calculations for the established INDO/S method and the reparametrized INDO/S2 variant employ a modified version of the ZINDO program. As compared to the best theoretical reference data from the ab initio benchmark, all currently applied semiempirical methods tend to underestimate the vertical excitation energies, but the errors are much larger in the case of the standard methods (MNDO, AM1, PM3). Overall, the mean absolute deviations relative to the theoretical best estimates are lowest for OM3, and only slightly higher for OM1 and OM2 (in the range of 0.4-0.5 eV). INDO/S performs similar to OM2 for the vertical excitation energies of singlet states, but deteriorates considerably for triplet states. The INDO/S2 reparametrization for oxygen improves the results for low-lying singlet states of oxygen-containing compounds, but makes them worse for high-lying singlets as well as for triplets. The ab initio reference data for oscillator strengths and excited-state dipole moments are again best reproduced by the orthogonalization-corrected approaches (OM1, OM2, OM3), which thus emerge as the most favorable semiempirical methods overall for treating valence excited states of large organic chromophores. PMID- 26615691 TI - New Variational Method for the Ab Initio Study in Valence Coordinates of the Renner-Teller Effect in Tetra-Atomic Systems. AB - A new variational methodology for the treatment of the Renner-Teller effect in tetra-atomic molecules has been developed in valence coordinates. The kinetic energy operator of Bramley et al. [Mol. Phys. 1991, 73, 1183] for any sequentially bonded four-atom molecule, A-B-C-D, in the singlet nondegenerate electronic state has been adapted to the Renner-Teller and spin couplings by modifying the expression of the nuclear angular momentum. The total Schrodinger equation is solved by diagonalizing the Hamiltonian matrix in a three-step contraction scheme. The main advantage of this new theoretical development is the possibility of studying different isotopomers using the same potential-energy surfaces. This procedure has been tested on HCCH(+) and its deuterated derivatives DCCD(+) and DCCH(+). The calculated rovibronic band origins were compared with previous data deduced from the Jacobi coordinates methodology, dimensionality reduced variational treatment, and photoelectron spectra with a good global agreement. Rotational structures for these systems are also tackled. PMID- 26615692 TI - Convergence of Nuclear Magnetic Shieldings in the Kohn-Sham Limit for Several Small Molecules. AB - Convergence patterns and limiting values of isotropic nuclear magnetic shieldings were studied for several small molecules (N2, CO, CO2, NH3, CH4, C2H2, C2H4, C2H6, and C6H6) in the Kohn-Sham limit. Individual results of calculations using dedicated families of Jensen's basis sets (pcS-n and pcJ-n) were fitted toward the complete basis set limit (CBS) using a simple two-parameter formula. Several density functionals were used; calculated vibrational corrections (ZPV) applied; and, for comparison purposes, similar calculations performed using RHF, MP2, SOPPA, SOPPA(CCSD), and CCSD(T) methods and additionally, the aug-cc-pVTZ-J basis set. Finally, the CBS estimated results were critically compared with earlier reported literature data and experimental results. Among 42 studied DFT methods, the KTn and "pure" functionals produced the most accurate heavy atom isotropic nuclear shieldings. PMID- 26615693 TI - The Use of Anisotropic Potentials in Modeling Water and Free Energies of Hydration. AB - We propose a novel, anisotropic rigid-body intermolecular potential model to predict the properties of water and the hydration free energies of neutral organic solutes. The electrostatic interactions of water and the solutes are modeled using atomic multipole moments up to hexadecapole; these are obtained from distributed multipole analysis of the quantum mechanically computed charge densities and include average polarization effects in solution. The repulsion dispersion water-water interactions are modeled with a three-site, exp-6 model fitted to the experimental liquid water density and oxygen-oxygen radial distribution function at ambient conditions. The proposed water model reproduces well several water properties not used in its parametrization, including vapor liquid coexistence densities, the maximum in liquid water density at atmospheric pressure, the structure of ordered ice polymorphs, and the liquid water heat capacity. The model is used to compute the hydration free energy of 10 neutral organic solutes using explicit-solvent free energy perturbation. The solute solute repulsion-dispersion intermolecular potential is obtained from previous parametrizations on organic crystal structures. In order to calculate the free energies of hydration, water-solute repulsion-dispersion interactions are modeled using Lorenz-Berthelot combining rules. The root-mean-square error of the predicted hydration free energies is 1.5 kcal mol(-1), which is comparable to the error found using a continuum mean-field quantum mechanical approach parametrized using experimental free energy of hydration data. The results are also contrasted with explicit-solvent hydration free energies obtained with an atomic charge representation of the solute's charge density computed at the same level of theory used to compute the distributed multipoles. Replacing the multipole description of the solute's charge density with an atomic charge model changes the free energy of hydration by as much as 3 kcal mol(-1) and provides an estimate for the effect of the modeling quality of the intermolecular electrostatic forces in free energy of solvation calculations. PMID- 26615694 TI - Rapid Prediction of Solvation Free Energy. 1. An Extensive Test of Linear Interaction Energy (LIE). AB - The present study provides a comprehensive systematic analysis on the applicability of the linear interaction energy (LIE) approximation to the prediction of gas-to-water transfer (hydration) free energy. The study is based on molecular dynamics simulations in explicit solvent for an extensive and diverse hydration data set comprising 564 neutral compounds with measured hydration free energies, including a "traditional" data set and the more challenging drug-like SAMPL1 data set. A highly correlative LIE model was achieved without empirical scaling of the solute-solvent interaction energy terms along with a cavity term calibrated to the experiment. This model was particularly accurate for the "traditional" data set and of acceptable accuracy for the SAMPL1 data set, with mean-unsigned-errors below 1 kcal/mol and slightly above 2 kcal/mol, respectively. We have analyzed the sensitivity of the LIE model to several parameters such as continuum correction terms applied outside the explicit water shell, the impact of various charging methods, the applicability of single-conformer representation of the solute, and the inclusion of internal energy terms. The parameters with the greatest sensitivity are the charging methods used, with AM1BCC-SP (without AM1 geometry optimization) charges favored over AM1BCC-OPT and RESP charges. The inclusion of the change in intramolecular van der Waals and electrostatic energies between the solution and gas phases can also lead to improved prediction accuracies. Functional group based error analysis identified several chemical classes as minor outliers with systematic errors. A direct comparison of the LIE and free energy perturbation (FEP) approaches using the same force field and charging method shows that the LIE approximation is at least as accurate as the FEP approach with a reduction of computing time by at least 1 order of magnitude. PMID- 26615695 TI - Rapid Prediction of Solvation Free Energy. 2. The First-Shell Hydration (FiSH) Continuum Model. AB - Local ordering of water in the first hydration shell around a solute is different from isotropic bulk water. This leads to effects that are captured by explicit solvation models and missed by continuum solvation models which replace the explicit waters with a continuous medium. In this paper, we introduce the First Shell Hydration (FiSH) model as a first attempt to introduce first-shell effects within a continuum solvation framework. One such effect is charge asymmetry, which is captured by a modified electrostatic term within the FiSH model by introducing a nonlinear correction of atomic Born radii based on the induced surface charge density. A hybrid van der Waals formulation consisting of two continuum zones has been implemented. A shell of water restricted to and uniformly distributed over the solvent-accessible surface (SAS) represents the first solvation shell. A second region starting one solvent diameter away from the SAS is treated as bulk water with a uniform density function. Both the electrostatic and van der Waals terms of the FiSH model have been calibrated against linear interaction energy (LIE) data from molecular dynamics simulations. Extensive testing of the FiSH model was carried out on large hydration data sets including both simple compounds and drug-like molecules. The FiSH model accurately reproduces contributing terms, absolute predictions relative to experimental hydration free energies, and functional class trends of LIE MD simulations. Overall, the implementation of the FiSH model achieves a very acceptable performance and transferability improving over previously developed solvation models, while being complemented by a sound physical foundation. PMID- 26615696 TI - Mechanical Properties of Coarse-Grained Bilayers Formed by Cardiolipin and Zwitterionic Lipids. AB - Lipid shape and charge are connected with the physical properties and the biological function of membranes. Cardiolipin, a double phospholipid with four chains and the potential of changing its charge with pH, is crucially connected with mitochondrial inner membrane shape, and recent experiments suggest that local pH changes allow highly curved local geometries. Here, we use a coarse grained molecular dynamics model to investigate the mechanical properties of cardiolipin bilayers, systematically varying the headgroup charge and the composition in mixtures with zwitterionic 1,2-dioleoyl-glycero-3 phosphatidylcholine (DOPC) or 1,2-dioleoyl-glycero-3-phosphatidylethanolamine (DOPE). Low cardiolipin charge, corresponding to low pH, was found to induce bending moduli on the order of kBT and curved microdomains. On the length scale investigated, in contrast to continuum theoretical models, we found the area modulus and bending modulus to be inversely correlated for mixtures of cardiolipin and DOPC/DOPE, explainable by changes in the effective headgroup volume. PMID- 26615697 TI - The Calculation of NMR Chemical Shifts in Periodic Systems Based on Gauge Including Atomic Orbitals and Density Functional Theory. AB - We present here a method that can calculate NMR shielding tensors from first principles for systems with translational invariance. Our approach is based on Kohn-Sham density functional theory and gauge-including atomic orbitals. Our scheme determines the shielding tensor as the second derivative of the total electronic energy with respect to an external magnetic field and a nuclear magnetic moment. The induced current density due to a periodic perturbation from nuclear magnetic moments is obtained through numerical differentiation, whereas the influence of the responding perturbation in terms of the external magnetic field is evaluated analytically. The method is implemented into the periodic program BAND. It employs a Bloch basis set made up of Slater-type or numeric atomic orbitals and represents the Kohn-Sham potential fully without the use of effective core potentials. Results from calculations of NMR shielding constants based on the present approach are presented for isolated molecules as well as systems with one-, two- and three-dimensional periodicity. The reported values are compared to experiment and results from calculations on cluster models. PMID- 26615698 TI - On the Calculation of Vibrational Frequencies for Molecules in Solution Beyond the Harmonic Approximation. AB - We report some results on the calculation of vibrational spectra of molecules in condensed phase with accounting simultaneously for anharmonicity and solute solvent interactions, the latter being described by means of the polarizable continuum model (PCM). Density functional theory force fields are employed as well as a new implementation of the PCM cavity and its derivatives. The results obtained for formaldehyde and simple peptide prototypes show that our approach is able to yield a quantitative agreement with experiments for vacuo-to-solvent harmonic and anharmonic frequency shifts. PMID- 26615699 TI - Theoretical Study on the Redox Cycle of Bovine Glutathione Peroxidase GPx1: pKa Calculations, Docking, and Molecular Dynamics Simulations. AB - Three approaches of computational chemistry [quantum mechanics (QM) calculations, docking, and molecular dynamics (MD) simulations] were used to investigate the redox cycle of bovine erythrocyte glutathione peroxidase from class 1 (GPx1, EC 1.11.1.9). The pKa calculations for two redox states of the active-site selenocysteine of GPx1 (selenol, Sec45-SeH, and selenenic acid, Sec45-SeOH) were estimated using a bulk solvent model (B3LYP-IEFPCM and B3LYP-CPCM-COSMO-RS). The calculated pKa values of Sec45-SeH and Sec45-SeOH were corrected via a simple linear fit to a training set of organoselenium compounds, which consisted of aliphatic selenols and aromatic selenenic acids with available experimental pKa values. Based on docking calculations, binding sites for both molecules of the cofactor glutathione (GSH) are described. MD simulations on the dimer of GPx1 have been performed for all chemical states of the redox cycle: without GSH and with one or two molecules of GSH bound at the active site. Conformational analyses of MD trajectories indicate high mobility of the Arg177 and His79 residues. These residues can approach the vicinity of Sec45 and take part in the catalytic mechanism. On the basis of the calculated data, new atomistic details for a generally accepted mechanism of GPx1 are proposed. PMID- 26615700 TI - A Statistical Framework for Hierarchical Methods in Molecular Simulation and Design. AB - A statistical framework for performance analysis in hierarchical methods is described, with a focus on applications in molecular design. A theory is derived from statistical principles, describing the relationships between the results of each hierarchical level by a functional correlation and an error model for how values are distributed around the correlation curve. Two key measures are then defined for evaluating a hierarchical approach-completeness and excess cost conceptually similar to the sensitivity and specificity of dichotomous prediction methods. We demonstrate the use of this method using a simple model problem in conformational search, refining the results of an in vacuo search of glucose conformations with a continuum solvent model. Second, we show the usefulness of this approach when structural hierarchies are used to efficiently make use of large rotamer libraries with the Dead-end Elimination and A* algorithms for protein design. The framework described is applicable not only to the specific examples given but to any problem in molecular simulation or design that involves a hierarchical approach. PMID- 26615701 TI - A Coarse Grained Model for Atomic-Detailed DNA Simulations with Explicit Electrostatics. AB - Coarse-grain (CG) techniques allow considerable extension of the accessible size and time scales in simulations of biological systems. Although many CG representations are available for the most common biomacromolecules, very few have been reported for nucleic acids. Here, we present a CG model for molecular dynamics simulations of DNA on the multi-microsecond time scale. Our model maps the complexity of each nucleotide onto six effective superatoms keeping the "chemical sense" of specific Watson-Crick recognition. Molecular interactions are evaluated using a classical Hamiltonian with explicit electrostatics calculated under the framework of the generalized Born approach. This CG representation is able to accurately reproduce experimental structures, breathing dynamics, and conformational transitions from the A to the B form in double helical fragments. The model achieves a good qualitative reproduction of temperature-driven melting and its dependence on size, ionic strength, and sequence specificity. Reconstruction of atomistic models from CG trajectories give remarkable agreement with structural, dynamic, and energetic features obtained from fully atomistic simulation, opening the possibility to acquire nearly atomic detail data from CG trajectories. PMID- 26615702 TI - Ligand Affinities Estimated by Quantum Chemical Calculations. AB - We present quantum chemical estimates of ligand-binding affinities performed, for the first time, at a level of theory for which there is a hope that dispersion and polarization effects are properly accounted for (MP2/cc-pVTZ) and at the same time effects of solvation, entropy, and sampling are included. We have studied the binding of seven biotin analogues to the avidin tetramer. The calculations have been performed by the recently developed PMISP approach (polarizable multipole interactions with supermolecular pairs), which treats electrostatic interactions by multipoles up to quadrupoles, induction by anisotropic polarizabilities, and nonclassical interactions (dispersion, exchange repulsion, etc.) by explicit quantum chemical calculations, using a fragmentation approach, except for long-range interactions that are treated by standard molecular mechanics Lennard-Jones terms. In order to include effects of sampling, 10 snapshots from a molecular dynamics simulation are studied for each biotin analogue. Solvation energies are estimated by the polarized continuum model (PCM), coupled to the multipole-polarizability model. Entropy effects are estimated from vibrational frequencies, calculated at the molecular mechanics level. We encounter several problems, not previously discussed, illustrating that we are first to apply such a method. For example, the PCM model is, in the present implementation, questionable for large molecules, owing to the use of a surface definition that gives numerous small cavities in a protein. PMID- 26615703 TI - Active Site, Catalytic Cycle, and Iodination Reactions of Vanadium Iodoperoxidase: A Computational Study. AB - A combined computational study using molecular surfaces and Poisson-Boltzmann electrostatic potentials for proteins and quantum calculations on complexes representing the vanadate cofactor throughout the catalytic cycle is employed to study the activity of vanadium iodoperoxidase (VIPO) from alga Laminaria digitata . A model structure of VIPO is compared with available crystal structures of chloroperoxidases (VClPOs) and bromoperoxidases (VBrPOs) focusing on properties of the active site that concern halogen specificity. It is found that VIPO displays distinctive features regarding electrostatic potentials at the site cavity and the local topography of the cavity entrance. Quantum calculations on cofactor stages throughout the catalytic cycle reveal that, while steps involving binding of hydrogen peroxide and halide oxidization agree with available data on VBrPO, final formation and subsequent release of hypohalous acid could follow a different pathway consisting of His476-assisted protonation of bonded hypoiodite and further displacement by a water molecule. Ab initio free energies of reaction computed to explore iodination of organic substrates predict strongly exoergonic reactions with HOI, whereas other possible iodination reagents give thermodynamically disfavored reactions. PMID- 26615704 TI - ProMetCS: An Atomistic Force Field for Modeling Protein-Metal Surface Interactions in a Continuum Aqueous Solvent. AB - In order to study protein-inorganic surface association processes, we have developed a physics-based energy model, the ProMetCS model, which describes protein-surface interactions at the atomistic level while treating the solvent as a continuum. Here, we present an approach to modeling the interaction of a protein with an atomically flat Au(111) surface in an aqueous solvent. Protein gold interactions are modeled as the sum of van der Waals, weak chemisorption, and electrostatic interactions, as well as the change in free energy due to partial desolvation of the protein and the metal surface upon association. This desolvation energy includes the effects of water-protein, water-surface, and water-water interactions and has been parametrized using molecular dynamics (MD) simulations of water molecules and a test atom at a gold-water interface. The proposed procedure for computing the energy terms is mostly grid-based and is therefore efficient for application to long-time simulations of protein binding processes. The approach was tested for capped amino acid residues whose potentials of mean force for binding to a gold surface were computed and compared with those obtained previously in MD simulations with water treated explicitly. Calculations show good quantitative agreement with the results from MD simulations for all but one amino acid (Trp), as well as correspondence with available experimental data on the adhesion properties of amino acids. PMID- 26615705 TI - Antisecretory medication is associated with decreased Helicobacter pylori detection in gastric marginal zone lymphoma. AB - Helicobacter pylori status influences the prognosis and management of gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), so accurate determination of H pylori status is of clinical importance. The low rate of histologic H pylori positivity among gastric MALT lymphoma cases at our institution prompted investigation for possible causes. A case series of 24 patients as having gastric MALT lymphoma (with no diffuse large B-cell component) in a tertiary care setting between 1997 and 2010 was identified, and clinical records were reviewed. Immunohistochemical staining for H pylori and BCL10 was performed. This study received institutional review board approval (protocol number M13-033). Thirty-nine percent of cases (9/23) were H pylori positive by histology, and 4 additional patients had positive serologic results; overall, 57% of cases (13/23) were positive for H pylori. Treatment with antisecretory medications was associated with a lower likelihood of histologic positivity (13% among treated patients vs 75% among untreated; P = .04). Nuclear localization of BCL10 was seen in 2 cases and was not associated with H pylori status. Antisecretory medications decrease the likelihood of histologic detection of H pylori in gastric MALT lymphoma cases. Incorporation of results of serologic or other testing is needed to ensure correct classification with respect to H pylori status. PMID- 26615706 TI - Camphanic acid chloride: a powerful derivatization reagent for stereoisomeric separation and its DMPK applications. AB - BACKGROUND: Camphanic acid chloride has proven to be an efficient chiral derivatization reagent for determination of stereoisomers. RESULTS: The utility of chemical derivatization of various stereoisomers containing hydroxy functional groups with camphanic acid chloride in the presence or absence of a base is highlighted. This procedure is shown to be relatively simple, fast and a cost effective method of separating racemic drugs and stereoisomeric metabolites in biological matrices. Camphanic derivatives contain two additional chirogenic centers, which are found to enhance stereoisomeric separation on both traditional and chiral stationary phases. CONCLUSION: Four methodologies described herein for separation of multiple stereoisomers in biological samples confirm camphanic acid chloride to be a powerful chiral reagent for stereoisomeric resolution for drug metabolism and PK applications. PMID- 26615707 TI - Molecular-shape selectivity by naphthalimido-modified silica stationary phases: Insight into the substituents effect of naphthalene on shape recognition and pi pi interactions via electrostatic potential. AB - This report describes the molecular-shape selectivity of four naphthalimido modified silica (NIM) stationary phases. To investigate the selectivity, several alkylbenzenes and polycyclic aromatic hydrocarbons (PAHs) were tested using capillary electrochromatography (CEC) with each NIM stationary phase. Results revealed that nitro group-substituted NIM phases had outstanding molecular-shape recognition ability toward PAHs; a strong negative correlation existed between the k' value and L/B ratio that is opposite those observed for C18 phases, in addition, one possessed 10-fold greater molecular-shape recognition ability compared to existing stationary phases. In addition, the position of the nitro group on the naphthalimide moiety modulated the pi-stacking interaction due to steric hindrance. Furthermore, structure optimization and electrostatic potential (ESP) surfaces were used to clarify the mechanism of recognition. Based on this high recognition ability, separations of several positional isomers were examined. Results indicated that structure optimization and ESP maps could reveal the effect of functional groups on pi-pi interactions, which will aid in the design of new NIM stationary phases with shape selectivity, while taking advantage of electrostatic interactions. PMID- 26615708 TI - Introduction to "Implementations of two-dimensional liquid chromatography" by G. Guiochon, N. Marchetti, K. Mriziq, R.A. Shaliker [J. Chromatogr. A 1189 (2008) 109-168]. PMID- 26615709 TI - Evaluation of scale-up from analytical to preparative supercritical fluid chromatography. AB - An approach for reliable transfer from analytical to preparative scale supercritical fluid chromatography was evaluated. Here, we accounted for the conditions inside the columns as well as to the fact that most analytical instruments are volume-controlled while most preparative scale units are mass controlled. The latter is a particular problem when performing pilot scale experiments and optimizations prior to scaling up to production scale. This was solved by measuring the mass flow, the pressure and the temperature on the analytical unit using external sensors. Thereafter, it was revealed with a design of experiments approach that the methanol fraction and the pressure are the two most important parameters to control for preserved retention throughout the scale up; for preserved selectivity the temperature was most important in this particular system. Using this approach, the resulting chromatograms from the preparative unit agreed well with those from the analytical unit while keeping the same column length and particles size. A brief investigation on how the solute elution volume varies with the volumetric flow rate revealed a complex dependency on pressure, density and apparent methanol content. Since the methanol content is a parameter of great importance to control during the scale up, we must be careful when changing operational and column design conditions which generates deviations in pressure, density and methanol content between different columns. PMID- 26615710 TI - Effect of sodium chloride on solute-solvent interactions in aqueous polyethylene glycol-sodium sulfate two-phase systems. AB - Partition behavior of eight small organic compounds and six proteins was examined in poly(ethylene glycol)-8000-sodium sulfate aqueous two-phase systems containing 0.215M NaCl and 0.5M osmolyte (sorbitol, sucrose, TMAO) and poly(ethylene glycol) 10000-sodium sulfate-0.215M NaCl system, all in 0.01M sodium phosphate buffer, pH 6.8. The differences between the solvent properties of the coexisting phases (solvent dipolarity/polarizability, hydrogen bond donor acidity, and hydrogen bond acceptor basicity) were characterized with solvatochromic dyes using the solvatochromic comparison method. Differences between the electrostatic properties of the phases were determined by analysis of partitioning of sodium salts of dinitrophenylated (DNP-) amino acids with aliphatic alkyl side-chain. The partition coefficients of all compounds examined (including proteins) were described in terms of solute-solvent interactions. The results obtained in the study show that solute-solvent interactions of nonionic organic compounds and proteins in polyethylene glycol-sodium sulfate aqueous two-phase system change in the presence of NaCl additive. PMID- 26615711 TI - The 3D pore structure and fluid dynamics simulation of macroporous monoliths: High permeability due to alternating channel width. AB - Polymethacrylate-based monoliths have excellent flow properties. Flow in the wide channel interconnected with narrow channels is theoretically assumed to account for favorable permeability. Monoliths were cut into 898 slices in 50nm distances and visualized by serial block face scanning electron microscopy (SBEM). A 3D structure was reconstructed and used for the calculation of flow profiles within the monolith and for calculation of pressure drop and permeability by computational fluid dynamics (CFD). The calculated and measured permeabilities showed good agreement. Small channels clearly flowed into wide and wide into small channels in a repetitive manner which supported the hypothesis describing the favorable flow properties of these materials. This alternating property is also reflected in the streamline velocity which fluctuated. These findings were corroborated by artificial monoliths which were composed of regular (interconnected) cells where narrow cells followed wide cells. In the real monolith and the artificial monoliths with interconnected flow channels similar velocity fluctuations could be observed. A two phase flow simulation showed a lateral velocity component, which may contribute to the transport of molecules to the monolith wall. Our study showed that the interconnection of small and wide pores is responsible for the excellent pressure flow properties. This study is also a guide for further design of continuous porous materials to achieve good flow properties. PMID- 26615712 TI - In Vivo MRI Assessment of Experimental Schistosomiasis. AB - A new study using magnetic resonance imaging (MRI) evaluated successfully the transverse relaxation time T2 as a non-invasive imaging biomarker for monitoring hepatic fibrogenesis in schistosomiasis. However, there are some drawbacks that need special attention. This preliminary data opens new opportunities to understand and monitor liver fibrosis in schistosomiasis and other fibrogenic diseases. PMID- 26615713 TI - Wound-healing improvement by resurfacing split-thickness skin donor sites with thin split-thickness grafting. AB - INTRODUCTION: Split-thickness skin graft (STSG) donor site dressing has been controversial until now. Our study aimed to assess the patient comfort and wound healing efficacy with the application of thin split-thickness skin grafts regrafting on STSG donor sites. METHODS: One hundred ninety-two consecutive patients undergoing split-thickness skin grafting were included in the study, and the participants were randomly divided into the following three groups: group A was regrafted with thin STSGs and groups B and C were covered with occlusive hydrocellular dressing and paraffin gauze, respectively. The participants were compared according to the epithelialization time, pain and scar formation. RESULTS: The average time of epithelialization was 6.2 +/- 1.1 days in group A, 11.1 +/- 2.1 days in group B and 13.5 +/- 2.5 days in group C. The pain scores on days 2 and 5 after operation were 2.3 +/- 0.8 and 1.9 +/- 0.8 in group A, 2.5 +/- 1.1 and 3.9 +/- 1.3 in group B, and 3.8 +/- 1.4 and 5.9 +/- 2.1 in group C. The scar scores at half a year and one year after operation were 4.3 +/- 0.6 and 2.50 +/- 0.6 in group A, 7.4 +/- 0.6 and 6.2 +/- 0.6 in group B, and 11.8 +/- 0.4 and 10.9 +/- 1.0 in group C, separately. The difference in the three groups was significant. CONCLUSION: Utilizing thin STSGs regrafting on donor sites could significantly shorten the epithelialization time, reduce pain and prevent hyperplastic scar formulation. PMID- 26615714 TI - Differential acute and chronic effects of burn trauma on murine skeletal muscle bioenergetics. AB - Altered skeletal muscle mitochondrial function contributes to the pathophysiological stress response to burns. However, the acute and chronic impact of burn trauma on skeletal muscle bioenergetics remains poorly understood. Here, we determined the temporal relationship between burn trauma and mitochondrial function in murine skeletal muscle local to and distal from burn wounds. Male BALB/c mice (8-10 weeks old) were burned by submersion of the dorsum in water (~ 95 degrees C) to create a full thickness burn on ~ 30% of the body. Skeletal muscle was harvested spinotrapezius underneath burn wounds (local) and the quadriceps (distal) of sham and burn treated mice at 3h, 24h, 4d and 10d post injury. Mitochondrial respiration was determined in permeabilized myofiber bundles by high-resolution respirometry. Caspase 9 and caspase 3 protein concentration were determined by western blot. In muscle local to burn wounds, respiration coupled to ATP production was significantly diminished at 3h and 24h post-injury (P<0.001), as was mitochondrial coupling control (P<0.001). There was a 5- (P<0.05) and 8-fold (P<0.001) increase in respiration in response to cytochrome at 3h and 24h post burn, respectively, indicating damage to the outer mitochondrial membranes. Moreover, we also observed greater active caspase 9 and caspase 3 in muscle local to burn wounds, indicating the induction of apoptosis. Distal muscle mitochondrial function was unaltered by burn trauma until 10d post burn, where both respiratory capacity (P<0.05) and coupling control (P<0.05) were significantly lower than sham. These data highlight a differential response in muscle mitochondrial function to burn trauma, where the timing, degree and mode of dysfunction are dependent on whether the muscle is local or distal to the burn wound. PMID- 26615715 TI - Guiding principles of sublingual immunotherapy for allergic rhinitis in Japanese patients. AB - OBJECTIVE: Sublingual immunotherapy (SLIT) appears to offer practical advantages for the treatment of allergic rhinitis (AR). Based on a review of the scientific literature, we present recommendations as guiding principles to administer SLIT safely. METHODS: Clinical questions concerning SLIT were prepared. Literature published between January 2003 and December 2012 was searched from PubMed, the Cochrane Library, and Japana Centra Revuo Medicina. Qualified studies were analyzed and the results were evaluated, consolidated, and codified. We answered 17 clinical questions and, based on this, presented evidence-based recommendations. RESULTS: Sublingual immunotherapy improved symptoms (e.g., quality of life [QOL]) and reduced medication scores in seasonal AR and perennial AR. Most SLIT-induced adverse effects were local oral reactions, although systemic adverse effects such as gastrointestinal symptoms, urticaria, and asthma are occasionally reported. There have been no reports of lethal anaphylactic reactions by SLIT. When SLIT is continued for 3-4 years, its effect persists long after discontinuation. CONCLUSION: A correct diagnosis of AR and sufficient informed consent from patients are required before initiating SLIT. Sublingual immunotherapy should be continued for 3 years or longer. The initial administration of SLIT during the uptitration of an allergen vaccine and the general condition of patients are critical for the safe performance of SLIT. PMID- 26615717 TI - Cranial irradiation significantly reduces beta amyloid plaques in the brain and improves cognition in a murine model of Alzheimer's Disease (AD). AB - BACKGROUND AND PURPOSE: To investigate if cranial X-irradiation reduces amyloid beta (Abeta) plaques and influences cognitive function in a transgenic mouse model of AD. METHODS AND MATERIALS: B6.Cg-Tg (APPswePSEN1dE9)85Dbo/J AD-prone mice were given cranial X-irradiation. The number of Abeta plaques, along with expression of AD specific genes (84 genes: Mouse Alzheimer's Disease RT(2) Profiler), radiation-associated cytokines (Milliplex MAP Mouse Cytokine Chemokine Immunoassay) and immunohistochemistry (IL10, IL-1beta, Iba1 CD45) was assessed. Behavioral testing was performed to relate changes in Abeta burden to cognitive function using a Morris water-maze task. RESULTS: Single X-ray doses reduced the number (p=0.002) and size (p=0.01) of Abeta plaques. Low-dose fractionation produced greater 50.6% (1 Gy * 10), 72% (2 Gy * 5) and 78% (2 Gy * 10) reductions. Irradiation was associated with gene (Pkp4, 1.5-fold, p=0.004) and proteomic (MIP-2, 8-fold, p=0.0024) changes at 24-48 h. Microglia increased at 4 weeks post-irradiation (p=0.001). The reduction in Abeta burden (2 Gy * 5) was associated with cognitive improvement (p=0.012). CONCLUSION: This is the first report that a clinically relevant course of external beam irradiation (2 Gy * 5) produces a significant reduction in AD-associated amyloid-beta plaques with a subsequent improvement in cognitive function. However, longer-term studies are needed to define the precise underlying mechanism and longevity of this response. PMID- 26615718 TI - Functional crosstalk between DNA damage response proteins 53BP1 and BRCA1 regulates double strand break repair choice. AB - PURPOSE: The aim of this study was to elucidate the impact of DNA damage response (DDR) proteins 53BP1 and BRCA1 on the double-strand break (DSB)-repair choice. This is important not only in order to understand the underlying mechanisms of DSB-repair pathway regulation but also to determine the therapeutic implications for BRCA1-associated tumors. MATERIALS AND METHODS: Human tumor cell lines A549 and HeLa were used. Non-homologous end-joining (NHEJ) and homologous recombination (HR) were assessed using NHEJ and HR reporter constructs. Colocalization of HR-proteins RPA and RAD51 with 53BP1 was evaluated by confocal microscopy and 3D-analysis. RESULTS: We demonstrate a specific crosstalk between 53BP1 and BRCA1. While 53BP1 does not colocalize with RPA or RAD51 and prohibits the recruitment of BRCA1 to DSBs to stimulate NHEJ, BRCA1 promotes the 53BP1 displacement specifically in S/G2-phase to allow end-resection, initiating HR. HR efficiency was restored in BRCA1-depleted cells upon additional 53BP1-knockdown. Further, we found that 53BP1-mediated end protection precedes BRCA1-dependent end resection. CONCLUSION: These results demonstrate that the interplay between 53BP1/NHEJ and BRCA1/HR is of great relevance for tumor treatment, as the 53BP1 status would be highly important for the treatment response of BRCA1-associated tumors. PMID- 26615719 TI - Introduction to the Special Issue "What sets the limit? How thermal limits, performance and preference in ectotherms are influenced by water or energy balance". PMID- 26615716 TI - Impact of methods used to express levels of circulating fatty acids on the degree and direction of associations with blood lipids in humans. AB - Numerous studies have examined relationships between disease biomarkers (such as blood lipids) and levels of circulating or cellular fatty acids. In such association studies, fatty acids have typically been expressed as the percentage of a particular fatty acid relative to the total fatty acids in a sample. Using two human cohorts, this study examined relationships between blood lipids (TAG, and LDL, HDL or total cholesterol) and circulating fatty acids expressed either as a percentage of total or as concentration in serum. The direction of the correlation between stearic acid, linoleic acid, dihomo-gamma-linolenic acid, arachidonic acid and DHA and circulating TAG reversed when fatty acids were expressed as concentrations v. a percentage of total. Similar reversals were observed for these fatty acids when examining their associations with the ratio of total cholesterol:HDL-cholesterol. This reversal pattern was replicated in serum samples from both human cohorts. The correlations between blood lipids and fatty acids expressed as a percentage of total could be mathematically modelled from the concentration data. These data reveal that the different methods of expressing fatty acids lead to dissimilar correlations between blood lipids and certain fatty acids. This study raises important questions about how such reversals in association patterns impact the interpretation of numerous association studies evaluating fatty acids and their relationships with disease biomarkers or risk. PMID- 26615720 TI - Ken Bowler and the development of thermal biology. PMID- 26615721 TI - Linking energetics and overwintering in temperate insects. AB - Overwintering insects cannot feed, and energy they take into winter must therefore fuel energy demands during autumn, overwintering, warm periods prior to resumption of development in spring, and subsequent activity. Insects primarily consume lipids during winter, but may also use carbohydrate and proteins as fuel. Because they are ectotherms, the metabolic rate of insects is temperature dependent, and the curvilinear nature of the metabolic rate-temperature relationship means that warm temperatures are disproportionately important to overwinter energy use. This energy use may be reduced physiologically, by reducing the slope or elevation of the metabolic rate-temperature relationship, or because of threshold changes, such as metabolic suppression upon freezing. Insects may also choose microhabitats or life history stages that reduce the impact of overwinter energy drain. There is considerable capacity for overwinter energy drain to affect insect survival and performance both directly (via starvation) or indirectly (for example, through a trade-off with cryoprotection), but this has not been well-explored. Likewise, the impact of overwinter energy drain on growing-season performance is not well understood. I conclude that overwinter energetics provides a useful lens through which to link physiology and ecology and winter and summer in studies of insect responses to their environment. PMID- 26615722 TI - Reprint of: The effectiveness of common thermo-regulatory behaviours in a cool temperate grasshopper. AB - Behavioural thermoregulation has the potential to alleviate the short-term impacts of climate change on some small ectotherms, without the need for changes to species distributions or genetic adaptation. We illustrate this by measuring the effect of behaviour in a cool temperate species of grasshopper (Phaulacridium vittatum) over a range of spatial and temporal scales in laboratory and natural field experiments. Microhabitat selection at the site scale was tested in free ranging grasshoppers and related to changing thermal quality over a daily period. Artificial warming experiments were then used to measure the temperature at which common thermoregulatory behaviours are initiated and the subsequent reductions in body temperature. Behavioural means such as timing of activity, choice of substrates with optimum surface temperatures, shade seeking and postural adjustments (e.g. stilting, vertical orientation) were found to be highly effective at maintaining preferred body temperature. The maximum voluntarily tolerated temperature (MVT) was determined to be 44 degrees C +/- 0.4 degrees C, indicating the upper bounds of thermal flexibility in this species. Behavioural thermoregulation effectively enables small ectotherms to regulate exposure to changing environmental temperatures and utilize the spatially and temporally heterogeneous environments they occupy. Species such as the wingless grasshopper, although adapted to cool temperate conditions, are likely to be well equipped to respond successfully to coarse scale climate change. PMID- 26615723 TI - Reprint of: Seasonal changes in the composition of storage and membrane lipids in overwintering larvae of the codling moth, Cydia pomonella. AB - The codling moth (Cydia pomonella) is a major insect pest of apples worldwide. It overwinters as a diapausing fifth instar larva. The overwintering is often a critical part of the insect life-cycle in temperate zone. This study brings detailed analysis of seasonal changes in lipid composition and fluidity in overwintering larvae sampled in the field. Fatty acid composition of triacylglycerol (TG) depots in the fat body and relative proportions of phospholipid (PL) molecular species in biological membranes were analyzed. In addition, temperature of melting (Tm) in TG depots was assessed by using differential scanning calorimetry and the conformational order (fluidity) of PL membranes was analyzed by measuring the anisotropy of fluorescence polarization of diphenylhexatriene probe in membrane vesicles. We observed a significant increase of relative proportion of linoleic acid (C18:2n6) at the expense of palmitic acid (C16:0) in TG depots during the larval transition to diapause accompanied with decreasing melting temperature of total lipids, which might increase the accessibility of depot fats for enzymatic breakdown during overwintering. The fluidity of membranes was maintained very high irrespective of developmental mode or seasonally changing acclimation status of larvae. The seasonal changes in PL composition were relatively small. We discuss these results in light of alternative survival strategies of codling moth larvae (supercooling vs. freezing), variability and low predictability of environmental conditions, and other cold tolerance mechanisms such as extending the supercooling capacity and massive accumulation of cryoprotective metabolites. PMID- 26615724 TI - Reprint of: The ins and outs of water dynamics in cold tolerant soil invertebrates. AB - Many soil invertebrates have physiological characteristics in common with freshwater animals and represent an evolutionary transition from aquatic to terrestrial life forms. Their high cuticular permeability and ability to tolerate large modifications of internal osmolality are of particular importance for their cold tolerance. A number of cold region species that spend some or most of their life-time in soil are in more or less intimate contact with soil ice during overwintering. Unless such species have effective barriers against cuticular water-transport, they have only two options for survival: tolerate internal freezing or dehydrate. The risk of internal ice formation may be substantial due to inoculative freezing and many species rely on freeze-tolerance for overwintering. If freezing does not occur, the desiccating power of external ice will cause the animal to dehydrate until vapor pressure equilibrium between body fluids and external ice has been reached. This cold tolerance mechanism is termed cryoprotective dehydration (CPD) and requires that the animal must be able to tolerate substantial dehydration. Even though CPD is essentially a freeze avoidance strategy the associated physiological traits are more or less the same as those found in freeze tolerant species. The most well-known are accumulation of compatible osmolytes and molecular chaperones reducing or protecting against the stress caused by cellular dehydration. Environmental moisture levels of the habitat are important for which type of cold tolerance is employed, not only in an evolutionary context, but also within a single population. Some species use CPD under relatively dry conditions, but freeze tolerance when soil moisture is high. PMID- 26615725 TI - The effect of water temperature and velocity on barnacle growth: Quantifying the impact of multiple environmental stressors. AB - Organisms employ a wide array of physiological and behavioral responses in an effort to endure stressful environmental conditions. For many marine invertebrates, physiological and/or behavioral performance is dependent on physical conditions in the fluid environment. Although factors such as water temperature and velocity can elicit changes in respiration and feeding, the manner in which these processes integrate to shape growth remains unclear. In a growth experiment, juvenile barnacles (Balanus glandula) were raised in dockside, once-through flow chambers at water velocities of 2 versus 19 cm s(-1) and temperatures of 11.5 versus 14 degrees C. Over 37 days, growth rates (i.e., shell basal area) increased with faster water velocities and higher temperatures. Barnacles at high flows had shorter feeding appendages (i.e., cirri), suggesting that growth patterns are unlikely related to plastic responses in cirral length. A separate experiment in the field confirmed patterns of temperature- and flow dependent growth over 41 days. Outplanted juvenile barnacles exposed to the faster water velocities (32+/-1 and 34+/-1 cm s(-1); mean+/-SE) and warm temperatures (16.81+/-0.05 degrees C) experienced higher growth compared to individuals at low velocities (1+/-1 cm s(-1)) and temperatures (13.67+/-0.02 degrees C). Growth data were consistent with estimates from a simple energy budget model based on previously measured feeding and respiration response curves that predicted peak growth at moderate temperatures (15 degrees C) and velocities (20-30 cm s(-1)). Low growth is expected at both low and high velocities due to lower encounter rates with suspended food particles and lower capture efficiencies respectively. At high temperatures, growth is likely limited by high metabolic costs, whereas slow growth at low temperatures may be a consequence of low oxygen availability and/or slow cirral beating and low feeding rates. Moreover, these results advocate for approaches that consider the combined effects of multiple stressors and suggest that both increases and decreases in temperature or flow impact barnacle growth, but through different physiological and behavioral mechanisms. PMID- 26615726 TI - Thermal acclimation in the perch (Perca fluviatilis L.) immunity. AB - Fish immune systems must be able to cope with pathogens over a wide temperature range. Earlier research suggest that fish are more dependent on innate immune responses based on pattern recognition than acquired functions with specific recognition. If this applies to phagocytes, then opsonins (serum factors that augment phagocytosis e.g. immunoglobulins and complement proteins) attached on zymosan (Z) particles should be recognized better at higher temperatures than Z only. Z is recognized by glucan receptor representing pattern recognition. In this study perch were acclimated to 5 degrees C or 16 degrees C for 3-5 weeks. The recognition and activation of respiratory burst reaction of peripheral blood phagocytes was examined at seven different measurement temperatures (5, 10, 16, 20, 24 27, and 30 degrees C) when the cells were stimulated with Z and serum opsonized zymosan (OZ). Respiratory burst was measured as luminol chemiluminescence (CL) from diluted whole blood. OZ-induced CL per volume of blood was on average approximately 4.6 times higher in 16 degrees C acclimated fish than 5 degrees C acclimated perch (P<0.0001). Z-induced CL was approximately 3 times higher at lower temperatures in 16 degrees C acclimated perch than 5 degrees C acclimated fish and 6-9 times higher at 27 degrees C and 30 degrees C (P<0.001), respectively. CL reaction kinetics were faster in perch acclimated to 5 degrees C than 16 degrees C -acclimated fish, especially at low temperatures (P<0.001). Thermal acclimation caused a 3-4 degrees C shift in temperature response curves of CL towards the acclimation temperature (P<0.0001 and P<0.053 in Z and OZ-induced CL, respectively). Serum opsonins activated perch phagocytes substantially better at higher temperatures in both acclimation groups, which is consistent with an earlier study in rainbow trout (O. mykiss). However, opsonin recognition was significantly better in 16 degrees C acclimated perch than 5 degrees C acclimated fish, which was seen as higher CLs for OZ compared to Z, especially at higher temperatures. This is opposite to previously reported results in rainbow trout. Differences between rainbow trout and perch in opsonin recognition by blood phagocytes suggest that the living habits of perch, which prefers approximately a 10 degrees C higher temperature than rainbow trout, may be reflected in immune cell functions. Results of the present examination suggest that also in fish phagocytes pattern recognition is the prevailing system at low temperatures, and specific recognition is more effective at high temperatures. PMID- 26615727 TI - Is the temperature-size rule mediated by oxygen in aquatic ectotherms? AB - Temperature is an important environmental factor that influences key traits like body size, growth rate and maturity. Ectotherms reared under high temperatures usually show faster growth, but reach a smaller final size, a phenomenon known as the temperature-size rule (TSR). Oxygen may become a limiting resource at high temperatures, when demand for oxygen is high, especially in water as oxygen uptake is far more challenging under water than in air. Therefore, in aquatic ectotherms, the TSR might very well be mediated by temperature effects on oxygen availability and oxygen demand. To distinguish between the direct effects of temperature and oxygen mediated effects, growth rate and final size were measured in the aquatic ectotherm Asellus aquaticus (Linnaeus, 1758) reared under different temperature and oxygen conditions in a factorial design. Growth could be best described by a modified Von Bertalanffy growth function. Both temperature and oxygen affected age at maturity and growth. Growth responses to temperature were dependent on oxygen conditions (interactive effect of temperature and oxygen). Only under hypoxic conditions, when oxygen was most limiting, did we find a classic TSR. Moreover, when comparing treatments differing in temperature, but where the balance between oxygen demand and supply was similar, high temperature increased both growth rate and final size. Thus effects of oxygen may resolve the life-history puzzle of the TSR in aquatic ectotherms. PMID- 26615728 TI - Has contemporary climate change played a role in population declines of the lizard Ctenophorus decresii from semi-arid Australia? AB - Whilst contemporary climatic changes are small in magnitude compared to those predicted for the coming decades, they have already been linked to species range shifts and local extinctions. Elucidating the drivers behind species' responses to contemporary climate change will better inform management strategies for vulnerable and pest species alike. A recent proposal to explain worldwide local extinctions in lizards is that increasing maximum temperatures have constrained lizard activity time in the breeding season beyond extinction thresholds. Here we document a significant population decline and potential local extinction at the warm (northern) range margin of the tawny dragon, Ctenophorus decresii, a rock dwelling lizard from the Flinders Ranges in semi-arid Australia. We developed and tested a biophysical model of tawny dragon thermoregulatory behaviour and drove the model with daily weather data for the period 1990-2009 across the Flinders Ranges. Our results indicate that potential annual activity time has likely increased over this period throughout the historic range, with within-season declines only in the summer months at the northern range limit. However, populations that have declined since 2000 have also likely experienced higher active body temperatures and more stringent retreat-site requirements (deeper crevices) than have regions where the species remains common, during a period of declining rainfall. Our laboratory estimates of thermal preference in this species were insensitive to altered nutritional and hydric state. Thus it is possible that recent population declines are linked to desiccation stress driven by higher body temperatures and declining rainfall. Our study illustrates that simple indices of the impact of climate warming on animals, such as activity restriction, may in fact reflect a variety of potential mechanisms whose ultimate outcome will be contingent on other factors such as water and shelter availability. PMID- 26615729 TI - The Temperature-Size Rule in Lecane inermis (Rotifera) is adaptive and driven by nuclei size adjustment to temperature and oxygen combinations. AB - The evolutionary implications of the Temperature-Size Rule (TSR) in ectotherms is debatable; it is uncertain whether size decrease with temperature increase is an adaptation or a non-adaptive by-product of some temperature-dependent processes. We tested whether (i) the size of the rotifer Lecane inermis affects fecundity in a way that depends on the combination of low or high temperature and oxygen content and (ii) the proximate mechanism underlying TSR in this species is associated with nuclei size adjustment (a proxy of cell size). Small-type and large-type rotifers were obtained by culturing at different temperatures prior to the experiment and then exposed to combinations of two temperature and two oxygen conditions. Fecundity was estimated and used as a measure of fitness. Nuclei and body sizes were measured to examine the response to both environmental factors tested. The results show the following for L. inermis. (i) Body size affects fecundity in response to both temperature and oxygen, supporting a hypothesis regarding the contribution of oxygen in TSR. (ii) Large individuals are generally more fecund than small ones; however, under a combination of high temperature and poor oxygen conditions, small individuals are more fecund than large ones, in accordance with a hypothesis of the adaptive significance of TSR. (iii) The body size response to temperature is realised by nuclei size adjustment. (iv) Nuclei size changes in response to temperature and oxygen conditions, in agreement with hypotheses on the cellular mechanism underlying TSR and on a contribution of oxygen availability in TSR. These results serve as empirical evidence for the adaptive significance of TSR and validation of the cellular mechanism for the observed response. PMID- 26615730 TI - The roles of microclimatic diversity and of behavior in mediating the responses of ectotherms to climate change. AB - We analyze the effects of changing patterns of thermal availability, in space and time, on the performance of small ectotherms. We approach this problem by breaking it into a series of smaller steps, focusing on: (1) how macroclimates interact with living and nonliving objects in the environment to produce a mosaic of thermal microclimates and (2) how mobile ectotherms filter those microclimates into realized body temperatures by moving around in them. Although the first step (generation of mosaics) is conceptually straightforward, there still exists no general framework for predicting spatial and temporal patterns of microclimatic variation. We organize potential variation along three axes-the nature of the objects producing the microclimates (abiotic versus biotic), how microclimates translate macroclimatic variation (amplify versus buffer), and the temporal and spatial scales over which microclimatic conditions vary (long versus short). From this organization, we propose several general rules about patterns of microclimatic diversity. To examine the second step (behavioral sampling of locally available microclimates), we construct a set of models that simulate ectotherms moving on a thermal landscape according to simple sets of diffusion based rules. The models explore the effects of both changes in body size (which affect the time scale over which organisms integrate operative body temperatures) and increases in the mean and variance of temperature on the thermal landscape. Collectively, the models indicate that both simple behavioral rules and interactions between body size and spatial patterns of thermal variation can profoundly affect the distribution of realized body temperatures experienced by ectotherms. These analyses emphasize the rich set of problems still to solve before arriving at a general, predictive theory of the biological consequences of climate change. PMID- 26615731 TI - Temperature-dependent physiological and biochemical responses of the marine medaka Oryzias melastigma with consideration of both low and high thermal extremes. AB - This study aimed to investigate temperature effect on physiological and biochemical responses of the marine medaka Oryzias melastigma larvae. The fish were subjected to a stepwise temperature change at a rate of 1 degrees C/h increasing or decreasing from 25 degrees C (the control) to six target temperatures (12, 13, 15, 20, 28 and 32 degrees C) respectively, followed by a 7 day thermal acclimation at each target temperature. The fish were fed ad libitum during the experiment. The results showed that cumulative mortalities were significantly increased at low temperatures (12 and 13 degrees C) and at the highest temperature (32 degrees C). For the survivors, their growth profile closely followed the left-skewed 'thermal performance curve'. Routine oxygen consumption rates of fish larvae were significantly elevated at 32 degrees C but suppressed at 13 and 15 degrees C (due to a high mortality, larvae from 12 degrees C were not examined). Levels of heat shock proteins and activities of malate dehydrogenase and lactate dehydrogenase were also measured in fish larvae exposed at 15, 25 and 32 degrees C. The activities of both enzymes were significantly increased at both 15 and 32 degrees C, where the fish larvae probably suffered from thermal discomfort and increased anaerobic components so as to compensate the mismatch of energy demand and supply at these thermal extremes. Coincidently, heat shock proteins were also up-regulated at both 15 and 32 degrees C, enabling cellular protection. Moreover, the critical thermal maxima and minima of fish larvae increased significantly with increasing acclimation temperature, implying that the fish could develop some degrees of thermal tolerance through temperature acclimation. PMID- 26615732 TI - Flies developed smaller cells when temperature fluctuated more frequently. AB - Changes in cell size might be an important component of adaptation to thermal heterogeneity. Although Drosophila melanogaster develops smaller cells at fluctuating temperatures, we do not know whether this response depends on the frequency or amplitude of thermal change. In a laboratory experiment, we exposed flies to either frequent or infrequent fluctuations between 17 and 27 degrees C, while controlling the total exposure to each temperature. Flies emerged from these treatments with similar body sizes, but flies at more frequent fluctuations emerged earlier and had smaller epidermal cells for a given body size. Tissue built from small cells has more nuclei for transcription, shorter distances between cell compartments, and a larger surface area for transport across membranes. Therefore, we hypothesize that physiological effects of small cells reduce lags in metabolic activity and enhance performance of flies during warming. For plasticity of cell size to confer a fitness advantage, this hypothetical benefit must outweigh the cost of maintaining a greater area of plasma membrane. PMID- 26615733 TI - Survival of rapidly fluctuating natural low winter temperatures by High Arctic soil invertebrates. AB - The extreme polar environment creates challenges for its resident invertebrate communities and the stress tolerance of some of these animals has been examined over many years. However, although it is well appreciated that standard air temperature records often fail to describe accurately conditions experienced at microhabitat level, few studies have explicitly set out to link field conditions experienced by natural multispecies communities with the more detailed laboratory ecophysiological studies of a small number of 'representative' species. This is particularly the case during winter, when snow cover may insulate terrestrial habitats from extreme air temperature fluctuations. Further, climate projections suggest large changes in precipitation will occur in the polar regions, with the greatest changes expected during the winter period and, hence, implications for the insulation of overwintering microhabitats. To assess survival of natural High Arctic soil invertebrate communities contained in soil and vegetation cores to natural winter temperature variations, the overwintering temperatures they experienced were manipulated by deploying cores in locations with varying snow accumulation: No Snow, Shallow Snow (30 cm) and Deep Snow (120 cm). Air temperatures during the winter period fluctuated frequently between +3 and -24 degrees C, and the No Snow soil temperatures reflected this variation closely, with the extreme minimum being slightly lower. Under 30 cm of snow, soil temperatures varied less and did not decrease below -12 degrees C. Those under deep snow were even more stable and did not decline below -2 degrees C. Despite these striking differences in winter thermal regimes, there were no clear differences in survival of the invertebrate fauna between treatments, including oribatid, prostigmatid and mesostigmatid mites, Araneae, Collembola, Nematocera larvae or Coleoptera. This indicates widespread tolerance, previously undocumented for the Araneae, Nematocera or Coleoptera, of both direct exposure to at least -24 degrees C and the rapid and large temperature fluctuations. These results suggest that the studied polar soil invertebrate community may be robust to at least one important predicted consequence of projected climate change. PMID- 26615734 TI - Responses of invertebrates to temperature and water stress: A polar perspective. AB - As small bodied poikilothermic ectotherms, invertebrates, more so than any other animal group, are susceptible to extremes of temperature and low water availability. In few places is this more apparent than in the Arctic and Antarctic, where low temperatures predominate and water is unusable during winter and unavailable for parts of summer. Polar terrestrial invertebrates express a suite of physiological, biochemical and genomic features in response to these stressors. However, the situation is not as simple as responding to each stressor in isolation, as they are often faced in combination. We consider how polar terrestrial invertebrates manage this scenario in light of their physiology and ecology. Climate change is also leading to warmer summers in parts of the polar regions, concomitantly increasing the potential for drought. The interaction between high temperature and low water availability, and the invertebrates' response to them, are therefore also explored. PMID- 26615735 TI - Behavioral thermoregulation and critical thermal limits of giant keyhole limpet Megathura crenulata(Sowerby 1825) (Mollusca; Vetigastropoda). AB - The thermoregulatory behavior of the giant keyhole limpet Megathura crenulata was determined in a horizontal thermal gradient during the day at 18.9 degrees C and 18.3 degrees C for the night. The final preferendum determined for giant keyhole limpets was of 18.6+/-1.2 degrees C. Limpets' displacement velocity was 10.0+/ 3.9 cm h(-1) during the light phase and 8.4+/-1.6 cm h(-1) during the dark phase. The thermotolerance (measured as CTMax at 50%) was determined in a keyhole limpet in three acclimation temperatures 17, 20, and 23 degrees C. Limpets were subjected to water increasing temperatures at a rate of 1 degrees C every 30 min, until they detached from the substrate. The critical thermal maximum at 50% was 27.2, 27.9 and 28.3 degrees C respectively. PMID- 26615736 TI - Relationship between volume and in-hospital mortality in digestive oncological surgery. AB - INTRODUCTION: The results previously obtained in Spain in the study of the relationship between surgical caseload and in-hospital mortality are inconclusive. The aim of this study is to evaluate the volume-outcome association in Spain in the setting of digestive oncological surgery. METHODS: An analytical, cross-sectional study was conducted with data from patients who underwent surgical procedures with curative intent of esophageal, gastric, colorectal and pancreatic neoplasms between 2006-2009 with data from the Spanish MBDS. In hospital mortality was used as outcome variable. Control variables were patient, health care and hospital characteristics. Exposure variable was the number of interventions for each disease, dividing the hospitals in 3 categories: high volume (HV), mid volume (MV) and low volume (LV) according to the number of procedures. RESULTS: An inverse, statistically significant relationship between procedure volume and in-hospital mortality was observed for both volume categories in both gastric (LV: OR=1,50 [IC 95%: 1,28-1,76]; MV: OR=1,49 (IC 95%: 1,28-1,74)) and colorectal (LV: OR=1,44 [IC 95%: 1,33-1,55]; MV: OR=1,24 [IC 95%: 1,15-1,33]) cancer surgery. In pancreatic procedures, this difference was only statistically significant between LV and HV categories (LV: OR=1,89 [IC 95%: 1,29 2,75]; MV: OR=1,21 [IC 95%: 0,82-1,79]). Esophageal surgery also showed an inverse relationship, which was not statistically significant (LV: OR=1,89 [IC 95%: 0,98-3,64]; MV: OR=1,05 [IC 95%: 0,50-2,21]). CONCLUSIONS: The results of this study suggest the existence in Spain of an inverse relationship between caseload and in-hospital mortality in digestive oncological surgery for the procedures analyzed. PMID- 26615737 TI - A hemodynamic, metabolic and histopathological study of a heterotopic auxiliary swine liver graft with portal vein arterialization. AB - BACKGROUND: Auxiliary heterotopic liver transplantation with portal vein arterialization (AHLT-PVA) is a model that has been hardly studied, despite its therapeutic potential. METHODS: Hemodynamic and biochemical characterization was carried out during graft implantation, in a pig-to-pig model (n=15 AHLT-PVA). Furthermore a histopathological study was performed to establish microscopic alterations due to PVA. RESULTS: Reperfusion of the arterialized graft produced an increase in heart rate (HR) vs. baseline (P=.004) and vs. inferior vena cava clamping phase (P=.004); and a decrease in systemic vascular resistance vs. cava clamping phase (P=.021). At the end of implantation, cardiac output remained elevated (P=.001), likewise HR remained increased vs. baseline phase (P=.002). Mean arterial pressure decreased with cava clamping, but was not affected by the reperfusion of the graft, nor the skin closure. The histopathological study at 3, 10, and 21 days post-PVA revealed that functional liver structure was maintained although it is common to find foci of perilobular necrosis on day 3 (P=.049), and perilobular connective tissue proliferation at day 10 (P=.007), vs. native liver. CONCLUSIONS: The described arterialized liver graft model minimizes the number of vascular anastomoses vs. previously described models. It is hemodynamically and metabolically well tolerated and the double arterial vascularization of the graft does not cause significant changes in liver histology. PMID- 26615738 TI - The assessment of epiphytic yeast diversity in sugarcane phyllosphere in Thailand by culture-independent method. AB - The diversity of epiphytic yeasts from sugarcane (Saccharum officinarum Linn.) phyllospheres in Thailand was investigated by culture-independent method based on the analysis of the D1/D2 domains of the large subunit rRNA gene sequences. Forty five samples of sugarcane leaf were collected randomly from ten provinces in Thailand. A total of 1342 clones were obtained from 45 clone libraries. 426 clones (31.7 %) were closely related to yeast strains in the GenBank database, and they were clustered into 31 operational taxonomic units (OTUs) with a similarity threshold of 99 %. All OTU sequences were classified in phylum Basidiomycota which were closely related to 11 yeast species in seven genera including Cryptococcus flavus, Hannaella coprosmaensis, Rhodotorula taiwanensis, Jaminaea angkoreiensis, Malassezia restricta, Pseudozyma antarctica, Pseudozyma aphidis, Pseudozyma hubeiensis, Pseudozyma prolifica, Pseudozyma shanxiensis, and Sporobolomyces vermiculatus. The most predominant yeasts detected belonged to Ustilaginales with 89.4 % relative frequency and the prevalent yeast genus was Pseudozyma. However, the majority were unable to be identified as known yeast species and these sequences may represent the sequences of new yeast taxa. In addition, The OTU that closely related to P. prolifica was commonly detected in sugarcane phyllosphere. PMID- 26615739 TI - FvSO regulates vegetative hyphal fusion, asexual growth, fumonisin B1 production, and virulence in Fusarium verticillioides. AB - Hyphal anastomosis is a hallmark of filamentous fungi and plays vital roles including cellular homoeostasis, interhyphal communication and nutrient translocation. Here we identify a gene, FvSO, in Fusarium verticillioides, a filamentous ascomycete causing maize ear and stalk rot and producing fumonisin mycotoxins. FvSO, like its Neurospora crassa homologue SO, is required for vegetative hyphal fusion. It is also essential for normal vegetative growth, sporulation, and pathogenesis. FvSO encodes a predicted WW domain protein and shares 70 % protein sequence identity with N. crassa SO. FvSO deletion mutants (DeltaFvSO) had abnormal distribution of conidia size, and conidia of DeltaFvSO germinated much later and slower than wild type. DeltaFvSO was deficient in hyphal anastomosis, had slower radial growth and produced less fungal biomass than wild type. DeltaFvSO were unable to perform anastomosis, a key feature of filamentous fungi. Interestingly, production of fumonisin B1 by DeltaFvSO was significantly reduced compared to wild type. Additionally, DeltaFvSO was nonpathogenic to corn ears, stalks and seedlings, likely due to defective growth and development. In conclusion, FvSO is essential for vegetative hyphal fusion and is required for normal vegetative growth and sporulation, normal levels of fumonisin production and pathogenicity in F. verticillioides. The pleiotropic nature of DeltaFvSO phenotypes suggests that FvSO is likely involved in certain signalling pathways that regulate multiple cellular functions. PMID- 26615740 TI - Fungal communities in gardens of the leafcutter ant Atta cephalotes in forest and cabruca agrosystems of southern Bahia State (Brazil). AB - Leaf-cutting ants interact with several fungi in addition to the fungal symbiont they cultivate for food. Here, we assessed alien fungal communities in colonies of Atta cephalotes. Fungus garden fragments were sampled from colonies in the Atlantic Rainforest and in a cabruca agrosystem in the state of Bahia (Brazil) in two distinct periods to evaluate whether differences in nest habitat influence the diversity of fungi in the ant colonies. We recovered a total of 403 alien fungi isolates from 628 garden fragments. The prevalent taxa found in these samples were Escovopsis sp. (26 %), Escovopsioides nivea (24 %), and Trichoderma spirale (10.9 %). Fungal diversity was similar between the colonies sampled in both areas suggesting that ants focus on reducing loads of alien fungi in the fungus gardens instead of avoiding specific fungi. However, fungal taxa composition differed between colonies sampled in the two areas and between the sampling periods. These differences are likely explained by the availability of plant substrates available for foraging over habitats and periods. Ordination analysis further supported that sampling period was the main attribute for community structuring but also revealed that additional factors may explain the structuring of fungal communities in colonies of A. cephalotes. PMID- 26615741 TI - Phylogenetic analysis of fungal heterotrimeric G protein-encoding genes and their expression during dimorphism in Mucor circinelloides. AB - In fungi, heterotrimeric G proteins are key regulators of biological processes such as mating, virulence, morphology, among others. Mucor circinelloides is a model organism for many biological processes, and its genome contains the largest known repertoire of genes that encode putative heterotrimeric G protein subunits in the fungal kingdom: twelve Galpha (McGpa1-12), three Gbeta (McGpb1-3), and three Ggamma (McGpg1-3). Phylogenetic analysis of fungal Galpha showed that they are divided into four distinct groups as reported previously. Fungal Gbeta and Ggamma are also divided into four phylogenetic groups, and to our understanding this is the first report of a phylogenetic classification for fungal Gbeta and Ggamma subunits. Almost all genes that encode putative heterotrimeric G subunits in M. circinelloides are differentially expressed during dimorphic growth, except for McGpg1 (Ggamma) that showed very low mRNA levels at all developmental stages. Moreover, several of the subunits are expressed in a similar pattern and at the same level, suggesting that they constitute discrete complexes. For example, McGpb3 (Gbeta), and McGpg2 (Ggamma), are co-expressed during mycelium growth, and McGpa1, McGpb2, and McGpg2, are co-expressed during yeast development. These findings provide the conceptual framework to study the biological role of these genes during M. circinelloides morphogenesis. PMID- 26615742 TI - Characterization of oleaginous yeasts accumulating high levels of lipid when cultivated in glycerol and their potential for lipid production from biodiesel derived crude glycerol. AB - This study attempted to identify oleaginous yeasts and selected the strain that accumulated the largest quantity of lipid for lipid production from glycerol. Two step screening of 387 yeast strains revealed 23 oleaginous strains that accumulated quantities of lipid higher than 20 % of their biomass when cultivated in glycerol. These strains were identified to be four ascomycetous yeast species i.e. Candida silvae, Kodamaea ohmeri, Meyerozyma caribbica, and Pichia manshurica, and five basidiomycetous yeast species i.e. Cryptococcus cf. podzolicus, Cryptococcus laurentii, Rhodosporidium fluviale, Rhodotorula taiwanensis, and Sporidiobolus ruineniae. Rhodosporidium fluviale DMKU-RK253 accumulated the highest quantity of lipid equal to 65.2 % of its biomass (3.9 g L(-1) lipid and 6.0 g L(-1) biomass) by shaking flask cultivation in crude glycerol. The main fatty acids in the accumulated lipid of this strain consisted of oleic acid, linoleic acid, and palmitic acid. Therefore, R. fluviale DMKU RK253 has potential for producing lipid for biodiesel manufacturing using crude glycerol as a feedstock. PMID- 26615743 TI - Five new Pseudophialophora species from grass roots in the oligotrophic pine barrens ecosystem. AB - During our recent survey of fungi in the oligotrophic pine barrens ecosystem, five new Pseudophialophora species, Pseudophialophora angusta, P. dichanthii, P. magnispora, P. tarda, and P. whartonensis, were uncovered from the roots of switchgrass (Panicum virgatum) and tapered rosette grass (Dichanthelium acuminatum). The five new fungal species are described based on morphological characteristics and DNA sequences of SSU, ITS, LSU, MCM7, RPB1, and TEF1 genes. The 6-locus phylogeny indicates that Pseudophialophora species form a monophyletic clade in Magnaporthaceae of Magnaporthales. A key for all described species in Pseudophialophora is provided, including these five and three previously published species. Distinctions among the new species and other related species are discussed. The plant-fungal interaction experiment indicates that P. angusta, Pseudophialophora eragrostis, P. magnispora, Pseudophialophora schzachyrii, P. tarda, and P. whartonensis have negative effects on the growth of switchgrass. Runner hyphae were observed from the inoculated switchgrass roots, which are typical structures of root-infecting pathogens. PMID- 26615744 TI - Barrenia, a new genus associated with roots of switchgrass and pine in the oligotrophic pine barrens. AB - A new genus Barrenia is described based on multi-gene phylogenetic analyses and phenotypic and ecological characters. Isolated from roots of switchgrass and pitch pine in the acidic and oligotrophic New Jersey Pine Barrens in this study, Barrenia likely has a wide distribution because its internal transcribed spacer (ITS) sequence has high similarity with a number of GenBank sequences from various ecological studies. The majority of these matching samples were from roots of plants in acidic, nutrient-poor environments, as well as from managed sugarcane plantations. Phylogenetic analyses based on ITS, LSU, and RPB1 sequence data strongly support that Barrenia is a monophyletic clade in Helotiales, distinct from any known taxa. Barrenia is phylogenetically close to Acidomelania, Loramyces, Mollisia, and Phialocephala fortinii - Acephala applanata species complex (PAC), the dark septate endophytes. Barrenia can be distinguished from Loramyces and Mollisia by its association with living plant roots. Taxa in PAC also are root endophytes but they have complex phialid arrangements that appear to be lacking in Barrenia. Plant-fungal interaction experiments showed that Barrenia panicia and Acidomelania panicicola significantly promoted root hair growth in switchgrass. Results from this work will facilitate ecological and evolutionary studies on root-associated fungi. PMID- 26615745 TI - PP-O and PP-V, Monascus pigment homologues, production, and phylogenetic analysis in Penicillium purpurogenum. AB - The production of pigments as secondary metabolites by microbes is known to vary by species and by physiological conditions within a single strain. The fungus strain Penicillium purpurogenum IAM15392 has been found to produce violet pigment (PP-V) and orange pigment (PP-O),Monascus azaphilone pigment homologues, when grown under specific culture conditions. In this study, we analysed PP-V and PP-O production capability in seven strains of P. purpurogenum in addition to strain IAM15392 under specific culture conditions. The pigment production pattern of five strains cultivated in PP-V production medium was similar to that of strain IAM15392, and all violet pigments produced by these five strains were confirmed to be PP-V. Strains that did not produce pigment were also identified. In addition, two strains cultivated in PP-O production medium produced a violet pigment identified as PP-V. The ribosomal DNA (rDNA) internal transcribed spacer (ITS) region sequences from the eight P. purpurogenum strains were sequenced and used to construct a neighbor-joining phylogenetic tree. PP-O and PP-V production of P. purpurogenum was shown to be related to phylogenetic placement based on rDNA ITS sequence. Based on these results, two hypotheses for the alteration of pigment production of P. purpurogenum in evolution were proposed. PMID- 26615746 TI - Brown mushroom symptom expression following infection of an Agaricus bisporus crop with MVX associated dsRNAs. AB - Mushroom Virus X (MVX) is associated with a range of symptoms observed in mushroom crops. The most prominent symptom in Ireland is the occurrence of 'brown' or 'off-white' mushrooms in white strain crops. The browning symptoms are associated with the presence of four low molecular weight dsRNAs: MVX(0.6), MVX(0.8), MVX(1.8) and MVX(2.0), however viral dsRNAs also occur in non symptomatic mushrooms. Three virus-infected mushroom cultures containing MVX(1.8) and MVX(2.0) were used to infect experimental crops at different rates and at different times in the crop cycle to test the effect on symptom expression. Mushroom colour was measured by chromometer, and the DeltaE value calculated. RT PCR was used to test for the presence of MVX(1.8) dsRNA in harvested mushrooms. Results indicate that following infection, browning symptom expression is variable both within and between crops. Control mushrooms from 1st and 2nd flush had DeltaE values of 7-12, with most being <10. In contrast, 1st flush mushrooms from virus infected treatments had DeltaE values of 6-25, with most being >10 while 2nd flush mushrooms had DeltaE values similar to controls. Only mushrooms with DeltaE > 15 appeared visibly brown or off colour. The transient and inconsistent nature of MVX-associated browning symptoms is discussed. PMID- 26615747 TI - Genome-wide analysis of DNA methylation in the sexual stage of the insect pathogenic fungus Cordyceps militaris. AB - DNA methylation is a basic epigenetic mechanism found in eukaryotes, but its patterns and roles vary significantly among diverse taxa. In fungi, DNA methylation has various effects on diverse biological processes. However, its function in the sexual development of fungi remains unclear. Cordyceps militaris, readily performs sexual reproduction and thus provides a remarkably rich model for understanding epigenetic processes in sexual development. Here, we surveyed the methylome of C. militaris at single-base resolution to assess DNA methylation patterns during sexual development using genomic bisulfite sequencing (BS-Seq). The results showed that approximately 0.4 % of cytosines are methylated, similar to the DNA methylation level (0.39 %) during asexual development. Importantly, we found that DNA methylation in the fungi undergoes global reprogramming during fungal development. Moreover, RNA-Seq analysis indicated that the differentially methylated regions (DMRs) have no correlation with the genes that have roles during fungal sexual development in C. militaris. These results provide a comprehensive characterization of DNA methylation in the sexual development of C. militaris, which will contribute to future investigations of epigenetics in fungi. PMID- 26615748 TI - Thermophilic growth and enzymatic thermostability are polyphyletic traits within Chaetomiaceae. AB - Thermophilic fungi have the potential to produce industrial-relevant thermostable enzymes, in particular for the degradation of plant biomass. Sordariales is one of the few fungal orders containing several thermophilic taxa, of which many have been associated with the production of thermostable enzymes. The evolutionary affiliation of Sordariales fungi, especially between thermophiles and non thermophilic relatives, is however poorly understood. Phylogenetic analysis within the current study was based on sequence data, derived from a traditional Sanger and highly multiplexed targeted next generation sequencing approach of 45 isolates. The inferred phylogeny and detailed growth analysis rendered the trait 'thermophily' as polyphyletic within Chaetomiaceae (Sordariales, Sordariomycetes), and characteristic to: Myceliophthora spp., Thielavia terrestris, Chaetomium thermophilum, and Mycothermus thermophilus. Compared to mesophiles, the isolates within thermophilic taxa produced enzyme mixtures with the highest thermostability of known cellulase activities. Temperature profiles of the enzyme activities correlated strongly with the optimal growth temperatures of the isolates but not with their phylogenetic relationships. This strong correlation between growth and enzyme characteristics indicated that detailed analysis of growth does give predictive information on enzyme physiology. The variation in growth and enzyme characteristics reveals these fungi as an excellent platform to better understand fungal thermophily and enzyme thermostability. PMID- 26615749 TI - Heterologous expression of a Penicillium purpurogenum exo-arabinanase in Pichia pastoris and its biochemical characterization. AB - Arabinan is a component of pectin, which is one of the polysaccharides present in lignocelluose. The enzymes degrading the main chain of arabinan are the endo- (EC 3.2.1.99) and exo-arabinanases (3.2.1.-). Only three exo-arabinanases have been biochemically characterized; they belong to glycosyl hydrolase family 93. In this work, the cDNA of an exo-arabinanase (Arap2) from Penicillium purpurogenum has been heterologously expressed in Pichia pastoris. The gene is 1310 bp long, has three introns and codes for a protein of 380 amino acid residues; the mature protein has a calculated molecular mass of 39 823 Da. The heterologously expressed Arap2 has a molecular mass in the range of 60-80 kDa due to heterogeneous glycosylation. The enzyme is active on debranched arabinan with optimum pH of 4-5.5 and optimal temperature of 40 degrees C, and has an exo-type action mode, releasing arabinobiose from its substrates. The expression profile of arap2 in corncob and sugar beet pulp follows a different pattern and is not related to the presence of arabinan. This is the first exo-arabinanase studied from P. purpurogenum and the first expressed in yeast. The availability of heterologous Arap2 may be useful for biotechnological applications requiring acidic conditions. PMID- 26615750 TI - A fermentative approach towards optimizing directed biosynthesis of fumaric acid by Rhizopus oryzae 1526 utilizing apple industry waste biomass. AB - The present research account deals with the bioproduction of fumaric acid (FA) from apple pomace ultrafiltration sludge (APUS) and apple pomace (AP) through fermentation. The filamentous fungus Rhizopus oryzae 1526 was used as a biocatalyst and its morphological impact on FA production was analysed in detail. For submerged fermentation, 40 g L(-1) of total solids concentration of APUS, pH 6.0, 30 degrees C, 200 rpm flask shaking speed and 72 h of incubation were found to be optimum for FA production (25.2 +/- 1.0 g L(-1), 0.350 g (L(-1) h(-1))). Broth viscosity (cP), residual reducing sugar (g L(-1)) and ethanol (g L(-1)) produced as by-product, were also analysed. Plastic trays were used for solid state fermentation and at optimized level of moisture and incubation period, 52 +/- 2.67 g FA per kg dry weight of AP was obtained. Changes in the total phenolic content (mg g(-1) dry weight of AP) were monitored at regular intervals. Utilization of APUS and AP for the directed synthesis of the high-value platform chemical FA by the fungal strain R. oryzae 1526 was an excellent display of fungal physiological and morphological control over a fermentative product. PMID- 26615751 TI - Species diversity in the Antrodia crassa group (Polyporales, Basidiomycota). AB - Antrodia is a polyphyletic genus, comprising brown-rot polypores with annual or short-lived perennial resupinate, dimitic basidiocarps. Here we focus on species that are closely related to Antrodia crassa, and investigate their phylogeny and species delimitation using geographic, ecological, morphological and molecular data (ITS and LSU rDNA, tef1). Phylogenetic analyses distinguished four clades within the monophyletic group of eleven conifer-inhabiting species (five described herein): (1)A. crassa s. str. (boreal Eurasia), Antrodia cincta sp. nova (North America) and Antrodia cretacea sp. nova (holarctic), all three being characterized by inamyloid skeletal hyphae that dissolve quickly in KOH solution; (2) Antrodia ignobilis sp. nova, Antrodia sitchensis and Antrodia sordida from North America, and Antrodia piceata sp. nova (previously considered conspecific with A. sitchensis) from Eurasia, possessing amyloid skeletal hyphae; (3) Antrodia ladiana sp. nova from the southern part of the USA, Antrodia pinea from East Asia, and Antrodia ferox - so far known from subtropical North America, but here reported also from Eurasia. These three species have inamyloid hyphae and narrow basidiospores; (4) the North American Antrodia pini-cubensis, sharing similar morphological characters with A. pinea, forming a separate clade. The habitat data indicate that several species are threatened by intensive forestry. PMID- 26615752 TI - Accuracy of the high-throughput amplicon sequencing to identify species within the genus Aspergillus. AB - This study characterized the accuracy of high-throughput amplicon sequencing to identify species within the genus Aspergillus. To this end, we sequenced the internal transcribed spacer 1 (ITS1), beta-tubulin (BenA), and calmodulin (CaM) gene encoding sequences as DNA markers from eight reference Aspergillus strains with known identities using 300-bp sequencing on the Illumina MiSeq platform, and compared them with the BLASTn outputs. The identifications with the sequences longer than 250 bp were accurate at the section rank, with some ambiguities observed at the species rank due to mostly cross detection of sibling species. Additionally, in silico analysis was performed to predict the identification accuracy for all species in the genus Aspergillus, where 107, 210, and 187 species were predicted to be identifiable down to the species rank based on ITS1, BenA, and CaM, respectively. Finally, air filter samples were analysed to quantify the relative abundances of Aspergillus species in outdoor air. The results were reproducible across biological duplicates both at the species and section ranks, but not strongly correlated between ITS1 and BenA, suggesting the Aspergillus detection can be taxonomically biased depending on the selection of the DNA markers and/or primers. PMID- 26615753 TI - Identification of Scedosporium boydii catalase A1 gene, a reactive oxygen species detoxification factor highly expressed in response to oxidative stress and phagocytic cells. AB - Scedosporium boydii is an opportunistic filamentous fungus which may be responsible for a large variety of infections in both immunocompetent and immunocompromised individuals. This fungus belongs to the Scedosporium apiospermum species complex which usually ranks second among the filamentous fungi colonizing the airways of patients with cystic fibrosis (CF). Species of the S. apiospermum complex are able to chronically colonize the CF airways suggesting pathogenic mechanisms allowing persistence and growth of these fungi in the respiratory tract. Few putative virulence factors have been purified and characterized so far in the S. apiospermum complex including a cytosolic Cu,Zn superoxide dismutase (SOD) and a monofunctional catalase (catalase A1). Upon microbial infection, host phagocytes release reactive oxygen species (ROS), such as hydrogen peroxide, as part of the antimicrobial response. Catalases are known to protect pathogens against ROS by degradation of the hydrogen peroxide. Here, we identified the S. boydii catalase A1 gene (CATA1) and investigated its expression in response to the environmental conditions encountered in the CF airways and to the oxidative stress. Results showed that S. boydii CATA1 gene expression is not affected by hypoxia, hypercapnia or pH changes. In contrast, CATA1 gene was overexpressed in response to a chemically induced oxidative stress with a relative gene expression 37-fold higher in the presence of 250 MUM H(2)O(2), 20-fold higher with 250 MUM menadione and 5-fold higher with 2 mM paraquat. Moreover, S. boydii CATA1 gene expression progressively increased upon exposure to activated THP-1-derived macrophages, reaching a maximum after 12 h (26 fold). Activated HL60-derived neutrophils and activated human peripheral blood neutrophils more rapidly induced S. boydii CATA1 gene overexpression, a maximum gene expression level being reached at 75 min (17 fold) and 60 min (15 fold), respectively. In contrast expression of the gene encoding the Cu,Zn-SOD (SODC gene) was not affected by H(2)O(2), menadione, paraquat or in co-culture with phagocytic cells. These results suggest that S. boydii CATA1 gene is highly stimulated by the oxidative burst response whereas SODC gene is constitutively expressed. PMID- 26615754 TI - Erinacine C: A novel approach to produce the secondary metabolite by submerged cultivation of Hericium erinaceus. AB - Erinacine C is a cyathane scaffold-based secondary metabolite, which is naturally produced by the filamentous fungus Hericium erinaceus and has a high potential to treat nervous diseases such as Alzheimer's disease. The investigated approach consists of combining an optimised precultivation of H. erinaceus with an enhanced erinacine C production by developing a suitable main cultivation medium enabling the utilisation of high biomass contents. The final erinacine C production medium is buffered by 100 mM HEPES to ensure a stable pH value of 7.5 during main cultivation at inoculation ratios of up to 5:10 (v/v). The medium components, such as 5.0 g L(-1) oatmeal, 1.5 g L(-1) calcium carbonate, and 0.5 g L(-1) Edamin((r)) K are crucial for an increased erinacine C production. Besides, different carbon to nitrogen ratios of 25, 64, and 103 do not affect the erinacine C synthesis. The investigated approach enables the production of 2.73 g erinacine C per litre main cultivation broth, which is tenfold higher than published data. In addition, erinacine C biosynthesis is determined to occur mainly in the first six days of main cultivation. PMID- 26615755 TI - Long term storage of Pleurotus ostreatus and Trametes versicolor isolates using different cryopreservation techniques and its impact on laccase activity. AB - The strain Pleurotus ostreatus Florida f6, its 45 basidiospore-derived isolates (both monokaryons and dikaryons prepared in our laboratory), Trametes versicolor strain CCBAS 614 and 22 other T. versicolor isolates obtained from the sporocarps collected in distant localities were successfully preserved for 12 y using perlite and straw cryopreservation protocols. All tested isolates survived a 12 year storage in liquid nitrogen (LN) and their laccase production and Poly B411 decolorization capacity was preserved. Also mycelium extension rate and the types of colony appearance of individual isolates remained unchanged. Different cryopreservation techniques were also tested for the short time (24 h) and the long time (6 m) storage of the culture liquid with extracellular laccase produced by T. versicolor strain CCBAS 614. The results showed that 10 % glycerol was the most suitable cryopreservant. The absence of the cryopreservant did not cause high loss of laccase activity in the samples; the presence of DMSO (5 or 10 %) in LN-stored samples caused mostly a decrease of laccase activity. For the preservation of laccase activity in the liquid culture the storage in the freezer at -80 degrees C is more convenient than the storage in liquid nitrogen. PMID- 26615756 TI - Characterisation of the large-scale production process of oyster mushroom (Pleurotus ostreatus) with the analysis of succession and spatial heterogeneity of lignocellulolytic enzyme activities. AB - Oyster mushroom (Pleurotus ostreatus) lignocellulolytic enzyme activity pattern and variation was investigated in a large-scale facility from spawning until the end of the second flush. In the first cultivation cycle laccase production reached its peak during vegetative growth stage, while manganese-peroxidase showed the highest activity during fruiting body induction. Cellulose and hemicellulose degrading enzymes had maximal activity at the beginning of flush and harvest stage. The enzyme activities showed similar tendencies among five different mushroom substrate blocks representing a production house. The spatial variability analysis of enzyme activities pointed out the within substrate block heterogeneity as the main source if variation. This result was confirmed by Combined Cluster and Discriminant Analysis (CCDA) method showing minimal among block heterogeneity considering the whole investigation period; furthermore in the first cultivation cycle all blocks were grouped into one cluster. PMID- 26615757 TI - Chronology of endocrine differentiation and beta-cell neogenesis. AB - Diabetes is a chronic and incurable disease, which results from absolute or relative insulin insufficiency. Therefore, pancreatic beta cells, which are the only type of cell that expresses insulin, is considered to be a potential target for the cure of diabetes. Although the findings regarding beta-cell neogenesis during pancreas development have been exploited to induce insulin-producing cells from non-beta cells, there are still many hurdles towards generating fully functional beta cells that can produce high levels of insulin and respond to physiological signals. To overcome these problems, a solid understanding of pancreas development and beta-cell formation is required, and several mouse models have been developed to reveal the unique features of each endocrine cell type at distinct developmental time points. Here I review our understanding of pancreas development and endocrine differentiation focusing on recent progresses in improving temporal cell labeling in vivo. PMID- 26615758 TI - Clinical coaching in primary care: Capable of improving control in patients with type 2 diabetes mellitus? AB - AIMS: Few clinical coaching studies are both endorsed by real cases and focused on reducing suboptimal diabetes control. We evaluated the effectiveness of coaching on improving type 2 diabetes goals after 3 years of implementation in primary care. METHODS: A cross-sectional study with follow up was conducted during 2008-2011. Coaching consisted of guiding family doctors to improve their clinical abilities, and it was conducted by a medical doctor trained in skill building, experiential learning, and goal setting. Effectiveness was assessed by means of fasting plasma glucose and glycosylated hemoglobin outcomes. The main analysis consisted of 1*3 and 2*3 repeated measures ANOVAs. RESULTS: A significant coaching*time interaction was observed, indicating that the difference in glucose between primary care units with and without coaching increased over time (Wilks' lambda multivariate test, P<0.0001). Coaching increased 1.4 times (95%CI 1.3, 1.5) the possibility of reaching the fasting glucose goal after controlling for baseline values. There was also a significant improvement in glycosylated hemoglobin (Bonferroni-corrected p-value for pairwise comparisons, P<0.0001). CONCLUSIONS: A correctible and even preventable contributing component in diabetes care corresponds to physicians' performance. After 3 years of implementation, coaching was found to be worth the effort to improve type 2 diabetes control in primary care. PMID- 26615760 TI - Antimalarial diterpenoid dimers of a new carbon skeleton from Aphanamixis grandifolia. AB - Chemical investigation into the minor constituents of Aphanamixis grandifolia yielded three new diterpenoid dimers, aphadilactones E-G (1-3) featuring a new carbon skeleton. Their structures and absolute configurations were fully established by comprehensive spectroscopic data analysis and ECD calculation. Discovery of another two new dimers (4 and 5) suggested the structure of recently reported aphanamene A to be re-investigated. Compounds 1-5 showed moderate antimalarial activities with low micromolar IC50 values. PMID- 26615759 TI - M1 of Murine Gamma-Herpesvirus 68 Induces Endoplasmic Reticulum Chaperone Production. AB - Viruses rely on host chaperone network to support their infection. In particular, the endoplasmic reticulum (ER) resident chaperones play key roles in synthesizing and processing viral proteins. Influx of a large amount of foreign proteins exhausts the folding capacity in ER and triggers the unfolded protein response (UPR). A fully-executed UPR comprises signaling pathways that induce ER folding chaperones, increase protein degradation, block new protein synthesis and may eventually activate apoptosis, presenting both opportunities and threats to the virus. Here, we define a role of the MHV-68M1 gene in differential modulation of UPR pathways to enhance ER chaperone production. Ectopic expression of M1 markedly induces ER chaperone genes and expansion of ER. The M1 protein accumulates in ER during infection and this localization is indispensable for its function, suggesting M1 acts from the ER. We found that M1 protein selectively induces the chaperon-producing pathways (IRE1, ATF6) while, interestingly, sparing the translation-blocking arm (PERK). We identified, for the first time, a viral factor capable of selectively intervening the initiation of ER stress signaling to induce chaperon production. This finding provides a unique opportunity of using viral protein as a tool to define the activation mechanisms of individual UPR pathways. PMID- 26615761 TI - Induction of differentiation of human embryonic stem cells into functional hair cell-like cells in the absence of stromal cells. AB - Sensorineural hearing loss and vestibular dysfunction have become the most common forms of sensory defects. Stem cell-based therapeutic strategies for curing hearing loss are being developed. Several attempts to develop hair cells by using chicken utricle stromal cells as feeder cells have resulted in phenotypic conversion of stem cells into inner ear hair-cell-like cells. Here, we induced the differentiation of human embryonic stem cells (hESCs) into otic epithelial progenitors (OEPs), and further induced the differentiation of OEPs into hair cell-like cells using different substrates. Our results showed that OEPs cultured on the chicken utricle stromal cells with the induction medium could differentiate into hair-cell-like cells with stereociliary bundles. Co-culture with stromal cells, however, may be problematic for subsequent examination of the induced hair-cell-like cells. In order to avoid the interference from stromal cells, we cultured OEPs on laminin with different induction media and examined the effects of the induction medium on the differentiation potentials of OEPs into hair-cell-like cells. The results revealed that the culture of OEPs on laminin with the conditioned medium from chicken utricle stromal cells supplemented with EGF and all-trans retinoic acid (RA) could promote the organization of cells into epithelial clusters displaying hair-cell-like cells with stereociliary bundles. These cells also displayed the expected electrophysiological properties. PMID- 26615762 TI - Hypoxic preconditioning decreases nuclear factor kappaB activity via Disrupted in Schizophrenia-1. AB - Nuclear factor kappaB is a key mediator of inflammation during conditions of hypoxia. Here, we used models of hypoxic pre-conditioning as mechanism to decrease nuclear factor kappaB activity induced by hypoxia. Our initial studies suggested that Disrupted in Schizophrenia-1 may be induced by hypoxic pre conditioning and possibly involved in the regulation of nuclear factor kappaB. In this study we used Disrupted in Schizophrenia-1 exogenous over-expression and knock-down to determine its effect on ataxia telangiectasia mutated--nuclear factor kappaB activation cascade. Our results demonstrated that hypoxic pre conditioning significantly increased the expression of Disrupted in Schizophrenia 1 at mRNA and protein levels both in vitro and in vivo. Over-expression of Disrupted in Schizophrenia-1 significantly attenuated the hypoxia-mediated ataxia telangiectasia mutated phosphorylation and prevented its cytoplasm translocation where it functions to activate nuclear factor kappaB. We further determined that Disrupted in Schizophrenia-1 activated the protein phosphatase 2A, preventing the phosphorylation of ataxia telangiectasia mutated serine-1981, the main regulatory site of ataxia telangiectasia mutated activity. Cellular levels of Disrupted in Schizophrenia-1 protein significantly decreased nuclear factor kappaB activation profiles and pro-inflammatory gene expression. Taken together, these results demonstrate that hypoxic pre-conditioning decreases the activation of nuclear factor kappaB through the transcriptional induction of Disrupted in Schizophrenia 1. PMID- 26615763 TI - Enhanced optoelectronic quality of perovskite thin films with hypophosphorous acid for planar heterojunction solar cells. AB - Solution-processed metal halide perovskite semiconductors, such as CH3NH3PbI3, have exhibited remarkable performance in solar cells, despite having non negligible density of defect states. A likely candidate is halide vacancies within the perovskite crystals, or the presence of metallic lead, both generated due to the imbalanced I/Pb stoichiometry which could evolve during crystallization. Herein, we show that the addition of hypophosphorous acid (HPA) in the precursor solution can significantly improve the film quality, both electronically and topologically, and enhance the photoluminescence intensity, which leads to more efficient and reproducible photovoltaic devices. We demonstrate that the HPA can reduce the oxidized I2 back into I(-), and our results indicate that this facilitates an improved stoichiometry in the perovskite crystal and a reduced density of metallic lead. PMID- 26615764 TI - A One-Pot Synthesis of Dibenzofurans from 6-Diazo-2-cyclohexenones. AB - A novel and efficient protocol for the rapid construction of dibenzofuran motifs from 6-diazo-2-cyclohexenone and ortho-haloiodobenzene has been developed. The process involves one-pot Pd-catalyzed cross-coupling/aromatization and Cu catalyzed Ullmann coupling. PMID- 26615765 TI - Modulation of brain network parameters associated with subclinical psychotic symptoms. AB - OBJECTIVE: Static deficits in small-world properties of brain networks have been described in clinical psychosis, but task-related modulation of network properties has been scarcely studied. Our aim was to assess the modulation of those properties and its association with subclinical psychosis and cognition in the general population. METHOD: Closeness centrality and small-worldness were compared between pre-stimulus baseline and response windows of an odd-ball task in 200 healthy individuals. The correlation between modulation of network parameters and clinical (scores in the Community Assessment of Psychological Experiences) and cognitive measures (performance in the dimensions included in the Brief Assessment of Cognition in Schizophrenia battery) was analyzed, as well as between these measures and the corresponding network parameters during baseline and response windows during task performance. RESULTS: In the theta band, closeness centrality decreased and small-worldness increased in the response window. Centrality and small-worldness modulation were, respectively, directly and inversely associated with subclinical symptoms. CONCLUSIONS: A widespread modulation of network properties in theta band was observed, with a transient increase of small-worldness during the response window, compatible with a transiently more integrated cortical activity associated to cognition. This supports the relevance of electroencephalography to study of normal and altered cognition and its substrates. A relative deficit in the ability to reorganize brain networks may contribute to subclinical psychotic symptoms. PMID- 26615766 TI - High-mesembrine Sceletium extract (TrimesemineTM) is a monoamine releasing agent, rather than only a selective serotonin reuptake inhibitor. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Extracts from and alkaloids contained in plants in the genus Sceletium have been reported to inhibit ligand binding to serotonin transporter. From this, the conclusion was made that Sceletium products act as selective serotonin-reuptake inhibitors. However, other mechanisms which may similarly result in the anxiolytic or anti-depressant effect ascribed to Sceletium, such as monoamine release, have not been investigated. AIMS OF THE STUDY: The current study investigated simultaneously and at two consecutive time points, the effect of high-mesembrine Sceletium extract on both monoamine release and serotonin reuptake into both human astrocytes and mouse hippocampal neurons, as well as potential inhibitory effects on relevant enzyme activities. MATERIALS AND METHODS: Human astrocytes and mouse hippocampal cells were treated with citalopram or Sceletium extract for 15 and 30min, after which protein expression levels of serotonin transporter (SERT) and vesicular monoamine transporter-2 (VAMT-2) was assessed using fluorescent immunocytochemistry and digital image analysis. Efficacy of inhibition of acetylcholinesterase (AChE) and monoamine oxidate-A (MAO-A) activity were assessed using the Ellman and Olsen methods (and appropriate controls) respectively. RESULTS: We report the first investigation of mechanism of action of Sceletium extract in the context of serotonin transport, release and reuptake in a cellular model. Cell viability was not affected by Sceletium treatment. High-mesembrine Sceletium extract down-regulated SERT expression similarly to citalopram. In addition, VMAT-2 was upregulated significantly in response to Sceletium treatment. The extract showed only relatively mild inhibition of AChE and MAO-A. CONCLUSIONS: We conclude that the serotonin reuptake inhibition activity ascribed to the Sceletium plant, is a secondary function to the monoamine-releasing activity of high-mesembrine Sceletium extract (Trimesemine(TM)). PMID- 26615767 TI - Poor reproducibility of the MRI measurement of distal femoral torsion. AB - Recent publications on patient-specific instrumentation for total knee arthroplasty have reported considerable variability in the axial positioning of the cutting guides for the femoral component. These personalized cutting guides are manufactured based on bone shape data, generated from magnetic resonance imaging (MRI) or computed tomography (CT). The goal of this study was to compare the reproducibility and accuracy of distal femoral torsion (DFT) values measured using these two imaging modalities. We hypothesized that MRI does not reproducibly and consistently measure DFT and is not as accurate as CT scan. METHODS: Anonymized radiology records from 54 patients that included MRI and CT scans of the knee were read in random order by two observers, on two separate occasions. These records were from patients being considered for a meniscal or osteochondral graft and who had their knee explored, but who had not undergone femoral or tibial surgery and were free of osteoarthritis. The DFT was estimated using the posterior condylar angle (PCA), using both its anatomical and surgical definitions. The intra- and inter-observer reproducibility of the MRI and the differences relative to CT scan measurements were analysed. RESULTS: The average intra-observer difference for the MRI evaluation of the anatomical PCA was 0.8+/ 1.2 degrees ; it was 0.4+/-0.9 degrees for the surgical PCA. More than 1 degrees difference from the average was found in 8 cases (14%) using the anatomical PCA measurement and 4 cases (7.4%) when using the surgical PCA (P=0.4). The intraclass correlation coefficients (ICCs) were 0.67 (95% CI: 0.33-0.85) and 0.74 (95% CI: 0.47-0.89) for the anatomical and surgical PCA, respectively. The average inter-observer difference for the MRI evaluation of the anatomical PCA was 1.6+/-1.4 degrees ; it was 1.5+/-1.0 degrees for the surgical PCA. More than 1 degrees difference from the average was found in 27 cases (50%) using the anatomical PCA measurement and 22 cases (40%) when using the surgical PCA (P=0.4). The ICCs were 0.31 (95% CI: 0.14-0.65) and 0.48 (95% CI: 0.06-0.75) for the anatomical and surgical PCA, respectively. The average differences between the CT and MRI measurements were 1.4+/-1.1 degrees (0.2-5 degrees ) and 1.1+/ 0.8 degrees (0-3.6 degrees ) for the anatomical and surgical PCA, respectively. Greater than 1 degrees difference between CT and MRI was found in 29 records (54%) for the anatomical PCA and in 18 records (33%) for the surgical PCA (P=0.03). CONCLUSION: DFT measurement on MRI is more reproducible and consistent when using the surgical PCA. MRI measurements differed by more than 1 degrees relative to CT measurements in more than one-third of cases. CASE CONTROL STUDY: Level III. PMID- 26615768 TI - Diaphyseal tibiofibular synostosis in professional athletes: Report of 2 cases. AB - Anterior leg pain is common in professional athletes and tibiofibular synostosis is reported to be a rare cause of anterior compartment pain or ankle pain related to sports activities. The management and appropriate treatment of this condition in professional athletes is controversial and the literature on the topic is sparse. Distal synostosis is usually related to ankle sprain and syndesmotic ligament injury, and proximal synostosis has been linked to leg length discrepancy and exostosis. Mid-shaft synostosis is even less common than proximal and distal forms. We present the treatment of mid-shaft tibiofibular synostosis in 2 cases of professional athletes (soccer and basketball player), along with a review of the literature. When diaphyseal synostosis is diagnosed, first-line conservative treatment, including ultrasound-guided steroid injection is recommended. However, if it does not respond to conservative management, surgical resection may be indicated to relieve symptoms. PMID- 26615770 TI - Solvent-dependent dual-mode photochromism between T- and P-types in a dipyrrinone derivative. AB - A newly synthesized dipyrrinone derivative bearing an ethoxycarbonyl group at the pyrrolic-alpha position exhibited solvent-dependent dual-mode photochromism between T- and P-types. While this molecule underwent thermally reversible (T type) photoresponsive reaction in chloroform, it became a thermally irreversible (P-type) system in methanol. PMID- 26615769 TI - Impact of donor and recipient hepatitis C status in lung transplantation. AB - BACKGROUND: Studies of lung transplantation in the setting of donors or recipients with hepatitis C virus (HCV) have been limited but have raised concerns about outcomes associated with this infection. METHODS: Lung transplant cases in the United Network for Organ Sharing (UNOS) database from 1994 to 2011 were analyzed for the HCV status of both donor and recipient. First, among HCV negative recipients, those who received a lung from an HCV-positive donor (HCV(+) D) were compared with those who received an HCV-negative lung (HCV(-) D). Donor, recipient and operative characteristics as well as outcomes were compared between groups, and overall survival was compared after adjustment for confounders. In a second analysis, HCV-positive recipients (HCV(+) R) were compared with HCV negative recipients (HCV(-) R). The analysis was stratified by era (1994 to 1999 and 2000 to 2011) and long-term survival was compared. RESULTS: Of 16,604 HCV negative patients in the UNOS database, 28 (0.2%) received a lung from an HCV(+) D, with use of HCV(+) D decreasing significantly over time. Overall survival (OS) was shorter in the HCV(+) D group (median survival: 1.3 vs 5.1 years; p = 0.002). Results were confirmed in adjusted analyses. After inclusion criteria were met, 289 (1.7%) of the lung transplant recipients were HCV(+) R. These patients appeared similar to their HCV(-) R counterparts, except they were older and had more limited functional status. OS was significantly lower in HCV-positive individuals during the early era (median survival: 1.7 vs 4.5 years; p = 0.004), but not the recent era (median survival: 4.4 vs 5.4 years; p = 0.100). Again, results were confirmed by adjusted analysis. CONCLUSIONS: HCV-positive status is a rare problem when considering both lung recipients and donors. Current data demonstrate significantly worse outcomes for HCV-negative patients receiving an HCV(+) lung; however, since 2000, HCV(+) recipients undergoing lung transplantation appear to have survival approximating that of HCV(-) recipients, an improvement from previous years. Recent medical advances in treatment for HCV may further improve outcomes in these groups. PMID- 26615771 TI - Biochemical conversion of sugarcane straw hemicellulosic hydrolyzate supplemented with co-substrates for xylitol production. AB - Biotechnological production of xylitol is an attractive route to add value to a sugarcane biorefinery, through utilization of the hemicellulosic fraction of sugarcane straw, whose availability is increasing in Brazil. Herein, supplementation of the sugarcane straw hemicellulosic hydrolyzate (xylose 57gL( 1)) with maltose, sucrose, cellobiose or glycerol was proposed, and their effect as co-substrates on xylitol production by Candida guilliermondii FTI 20037 was studied. Sucrose (10gL(-1)) and glycerol (0.7gL(-1)) supplementation led to significant increase of 8.88% and 6.86% on xylose uptake rate (1.11gL(-1)h(-1) and 1.09gL(-1)), respectively, but only with sucrose, significant increments of 12.88% and 8.69% on final xylitol concentration (36.11gL(-1)) and volumetric productivity (0.75gL(-1)h(-1)), respectively, were achieved. Based on these results, utilization of complex sources of sucrose, derived from agro-industries, as nutritional supplementation for xylitol production can be proposed as a strategy for improving the yeast performance and reducing the cost of this bioprocess by replacing more expensive nutrients. PMID- 26615772 TI - Level of evidence, sponsorship, conflict of interest policy and commercial impact of PubMed-listed clinical urolithiasis-related trials in 2014. AB - OBJECTIVES: To evaluate published trials on urolithiasis regarding level of evidence, type of sponsorship and declared conflicts of interest (COIs), and to elucidate a potential commercial impact. MATERIALS AND METHODS: We performed a systematic PubMed((r)) literature search using a predefined Boolean search term to identify PubMed-listed clinical research studies on urolithiasis in 2014 (fourth quarter). All authors screened the results for eligibility criteria and two independent reviewers evaluated and performed data extraction of predefined endpoints, including level of evidence, declaration of COI and sponsorship/funding (as indicated in the published print version), and commercial impact. RESULTS: A total of 110 clinical trials in urolithiasis listed in PubMed met the inclusion criteria. Levels of evidence 1, 2, 3 and 4 were found in 15%, 14%, 21% and 51% of trials, respectively. A COI was indicated in a total of 90% of publications, 93% of which declared no existing conflict of interest. Sponsorship was indicated in 36% of publications, 55% of which stated public funding, 33% institutional funding, 10% industrial funding and 2% both public and industrial funding. A total of 11% of the published trials were rated as having a high commercial impact. CONCLUSION: The present study provides evidence of increasing levels of evidence for published clinical trials on urolithiasis in 2014 (as compared with earlier data). Ninety percent of publications indicated conflicts of interest, whereas sponsoring of studies was declared only by one third. A considerable number of trials involved issues of high commercial impact. Recently established legal programmes and voluntary acts on self-reporting of financial relationships will enhance transparency in the future; however, increased public funding will be needed to further promote the quality of trials on urolithiasis. PMID- 26615773 TI - Undergraduate student nurses' lived experiences of anxiety during their first clinical practicum: A phenomenological study. AB - BACKGROUND: The Fundamental Nursing clinical practicum is an essential module for nursing students. Some feel stress or anxiety about attending this first placement; however, evidence demonstrates that it is rare to explore the feelings of anxiety felt by the nursing students concerning their first clinical practicum. OBJECTIVE: This study was designed to explore student nurses' experiences of anxiety felt regarding their initial clinical practicum while studying for their University degree. DESIGN: A phenomenological approach was used. SETTINGS: A university in Southern Taiwan. PARTICIPANTS: A purposive sampling of fifteen student nurses with anxiety reactions who had completed their first clinical practicum. METHODS: Data were collected using a semi-structured guide and deep interview. Data were analyzed using Colaizzi's seven-step phenomenological method. RESULTS: Three themes surfaced in the findings. The first theme was anxiety around their first clinical practicum, which stirred up anxiety about: self-doubt, worry and fear; difficulty coping with the learning process; worry hampered establishing therapeutic relationships with patients; the progress of the patients' illness could not be predicted; and anxiety felt about lecturer-student interactions. The second theme was three phases of anxiety reactions, which included increasing anxiety before clinical practicum; exacerbated anxiety during clinical practicum, and relief of anxiety after clinical practicum. The third theme was coping behaviors. This comprised: self reflection in preparation for clinical practicum; finding ways to release emotions; distractions from the anxiety; and, also facing their difficulties head on. CONCLUSION: The findings could help raise the awareness of lecturers and students by understanding student nurses' anxiety experiences and facilitating a healthy preparation for their initial clinical practicum, consequently proactively helping reduce potential anxiety experiences. PMID- 26615774 TI - Drug target prioritization by perturbed gene expression and network information. AB - Drugs bind to their target proteins, which interact with downstream effectors and ultimately perturb the transcriptome of a cancer cell. These perturbations reveal information about their source, i.e., drugs' targets. Here, we investigate whether these perturbations and protein interaction networks can uncover drug targets and key pathways. We performed the first systematic analysis of over 500 drugs from the Connectivity Map. First, we show that the gene expression of drug targets is usually not significantly affected by the drug perturbation. Hence, expression changes after drug treatment on their own are not sufficient to identify drug targets. However, ranking of candidate drug targets by network topological measures prioritizes the targets. We introduce a novel measure, local radiality, which combines perturbed genes and functional interaction network information. The new measure outperforms other methods in target prioritization and proposes cancer-specific pathways from drugs to affected genes for the first time. Local radiality identifies more diverse targets with fewer neighbors and possibly less side effects. PMID- 26615775 TI - A conceptual framework for navigating the superficial territories of the face: Relevant anatomic points for the dermatologic surgeon. AB - Recent publications in the dermatologic surgery literature have sparked a re emergence of interest in anatomy relevant for the Mohs surgeon necessitating a re visit of under-appreciated concepts, regarding the topography of the face and its visceral contents from a surgically relevant perspective. This paper presents a pre-operative review and a conceptual framework for intra-operative planning for Mohs micrographic surgery and reconstruction. The key concepts presented are based on a series of (1) reviews regarding clinically significant points aimed at improving outcomes for reconstructive surgery, (2) anatomical dissections of fresh frozen cadavers, and (3) surgical experience of the authors. Basic anatomical concepts have been assimilated, surgically evaluated and re-directed toward the dermatologic surgeon in the hope that improved anatomic competence will reduce surgical hesitance. PMID- 26615776 TI - Gray cases of child abuse: Investigating factors associated with uncertainty. AB - Research in child abuse pediatrics has advanced clinicians' abilities to discriminate abusive from accidental injuries. Less attention, however, has been paid to cases with uncertain diagnoses. These uncertain cases - the "gray" cases between decisions of abuse and not abuse - represent a meaningful challenge in the practice of child abuse pediatricians. In this study, we describe a series of gray cases, representing 17% of 134 consecutive children who were hospitalized at a single pediatric hospital and referred to a child abuse pediatrician for concerns of possible abuse. Gray cases were defined by scores of 3, 4, or 5 on a 7-point clinical judgment scale of the likelihood of abuse. We evaluated details of the case presentation, including incident history, patient medical and developmental histories, family social histories, medical studies, and injuries from the medical record and sought to identify unique and shared characteristics compared with abuse and accidental cases. Overall, the gray cases had incident histories that were ambiguous, medical and social histories that were more similar to abuse cases, and injuries that were similar to accidental injuries. Thus, the lack of clarity in these cases was not attributable to any single element of the incident, history, or injury. Gray cases represent a clinical challenge in child abuse pediatrics and deserve continued attention in research. PMID- 26615777 TI - Testing the sexually abused-sexual abuser hypothesis: A prospective longitudinal birth cohort study. AB - The sexually abused-sexual abuser hypothesis posits that persons, especially males, who are sexually abused as children are at particular risk of sexually abusing others later in life. We tested this hypothesis by prospectively examining associations between maltreatment and offending in a birth cohort of 38,282 males with a maltreatment history and/or at least one finalized offense. We examined these associations within the context of the wider birth population. Proportionally few boys were the subject of official notifications for sexual abuse (14.8% of maltreated boys, and 1.4% of the birth population); proportionally very few of these sexually abused boys (3%) went on to become sexual offenders; and, contrary to findings typically reported in retrospective clinical studies, proportionally few sexual offenders (4%) had a confirmed history of sexual abuse. Poly-victimization (exposure to multiple types of maltreatment) was significantly associated with sexual offending, violent offending, and general (nonsexual, nonviolent) offending. We found no specific association between sexual abuse and sexual offending, and nor did we find any association between sexual abuse and sexual offending specifically within the poly-victimized group. The total number of sexual abuse notifications did make a small unique contribution to the variance in sexual offending compared to other offending. Implications concerning maltreated boys and male sexual offenders are discussed. PMID- 26615778 TI - 'The darkest times of my life': Recollections of child abuse among forced migrants persecuted because of their sexual orientation and gender identity. AB - Numerous studies demonstrate that lesbian, gay, bisexual, and transgender (LGBT) children and youth are likely to experience abuse by peers, parents, and other adults and that these experiences correlate with a host of mental health problems. However, there is little understanding of the experiences of LGBT children and youth living in countries where social and legal protections for sexual and gender minorities are limited or nonexistent. This qualitative study used thematic analysis to explore the child and adolescent abuse experiences and their impact on the pre-migration mental health of LGBT forced migrants. We analyzed 26 interviews with individuals who obtained refugee or asylee status in the United States or Canada on the basis of sexual orientation or gender identity. Participants originated from countries in Asia, Africa, the Caribbean, Eastern Europe, Latin America, and the Middle East. Analysis revealed the following themes: abuse by parents and caregivers, abuse by peers and school personnel, having nowhere to turn, and dealing with psychological distress. Findings indicate that participants experienced severe verbal, physical, and sexual abuse throughout childhood and adolescence and that this abuse occurred at home, in school, and in the community. Furthermore, there were no resources or sources of protection available to them. Participants linked their abuse to subjective experiences of depression, anxiety, and traumatic stress, as well as suicidal ideation and suicide attempts. We conclude with implications for refugee adjudication practices, mental health care, and international policy. PMID- 26615779 TI - A Case of Barotrauma-Induced Post-Traumatic Headache With a Cluster Headache Phenotype. PMID- 26615781 TI - Involvement of platelets in tumor cell metastasis. AB - Extensive experimental evidence indicates that platelets contribute to tumor cell proliferation and metastasis through direct interactions and secreted bioactive proteins. Activated platelets release secretory factors that promote growth factors, chemokines, proangiogenic regulatory proteins, proteolytic enzymes and microparticles within the microenvironment to promote tumor cell growth and invasion. Furthermore, the formation of platelet-tumor cell heteroaggregates by integrin alphaIIbbeta3 (glycoprotein IIb/IIIa) bridging plays an important role in tumor survival by forming a physical shield around tumor cells, and thereby protecting circulating tumor cells from immune-mediated lysis by natural killer (NK) cells. Tumor cells directly activate platelets by enhancing expression of surface integrins, selectins and secretion of granules, which amplify platelet aggregation. In addition to the physical coating of tumor cells, platelets release transforming growth factor-beta1 (TGF-beta1) that induces phenotypic changes of epithelial to mesenchymal-like transition of tumor cells, thereby facilitating their extravasation and dissemination to distant sites during metastasis. Thus, there is a complex interplay between platelet-induced tumor growth and tumor cell-induced platelet activation, with the involvement of multiple components within the tumor microenvironment that enhance metastasis. This review describes the intimate reciprocal cross-talk between platelets and tumor cells, and the various signaling pathways involved in tumor amplification, which may be potential therapeutic targets to disrupt the platelet-tumor loop to reduce metastatic processes. PMID- 26615780 TI - DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice. AB - Maintaining DNA integrity is vital for all cells and organisms. Defective DNA repair may contribute to neurological disorders, including Alzheimer's disease (AD). We found reduced levels of BRCA1, but not of other DNA repair factors, in the brains of AD patients and human amyloid precursor protein (hAPP) transgenic mice. Amyloid-beta oligomers reduced BRCA1 levels in primary neuronal cultures. In wild-type mice, knocking down neuronal BRCA1 in the dentate gyrus caused increased DNA double-strand breaks, neuronal shrinkage, synaptic plasticity impairments, and learning and memory deficits, but not apoptosis. Low levels of hAPP/Amyloid-beta overexpression exacerbated these effects. Physiological neuronal activation increased BRCA1 levels, whereas stimulating predominantly extrasynaptic N-methyl-D-aspartate receptors promoted the proteasomal degradation of BRCA1. We conclude that BRCA1 is regulated by neuronal activity, protects the neuronal genome, and critically supports neuronal integrity and cognitive functions. Pathological accumulation of Abeta depletes neuronal BRCA1, which may contribute to cognitive deficits in AD. PMID- 26615782 TI - Liquid biopsies for solid tumors: Understanding tumor heterogeneity and real time monitoring of early resistance to targeted therapies. AB - In the era of personalized medicine detection of the molecular drivers of tumors and of specific DNA mutations predicting response or resistance to targeted agents has become routine practice in clinical oncology. The tumor biopsy depicts only a single timeframe from a single site, and might be inadequate to characterize a tumor because of intratumoral and intermetastatic heterogeneity. Circulating tumor DNA offers a "real time" tool for serially monitoring tumor genomes in a non-invasive manner providing accessible genetic biomarkers for cancer diagnosis, prognosis, and response to therapy. The liquid biopsy can be used for a variety of clinical and investigational applications. Future development will have to provide a cost effective analysis mainly identifying the genes known to be recurrently mutated in each tumor. Therefore, developing standardized methodologies for DNA analyses and validation in large prospective clinical studies is mandatory to implement the 'liquid biopsy' approach in the clinical management of cancer patients. In our review, we will focus on the clinical applications of liquid biopsies and on the recent findings in this field. PMID- 26615783 TI - Complement-fixing antibodies against denatured HLA and MICA antigens are associated with antibody mediated rejection. AB - BACKGROUND: We have found antibodies against denatured HLA class I antigens in the serum of allograft recipients which were not significantly associated with graft failure. It is unknown whether transplant recipients also have denatured HLA class II and MICA antibodies. The effects of denatured HLA class I, class II, and MICA antibodies on long-term graft outcome were further investigated based on their ability to fix complement c1q. MATERIALS AND METHODS: In this 4-year retrospective cohort study, post-transplant sera from 975 kidney transplant recipients were tested for antibodies against denatured HLA/MICA antigens and these antibodies were further classified based on their ability to fix c1q. RESULTS: Thirty percent of patients had antibodies against denatured HLA class I, II, or MICA antigens. Among them, 8.5% and 21.5% of all patients had c1q-fixing and non c1q-fixing antibodies respectively. There was no significant difference on graft survival between patients with or without antibodies against denatured HLA/MICA. However, when these antibodies were further classified according to their ability to fix c1q, patients with c1q-fixing antibodies had a significantly lower graft survival rate than patients without antibodies or patients with non c1q-fixing antibodies (p=0.008). In 169 patients who lost renal grafts, 44% of them had c1q-fixing antibodies against denatured HLA/MICA antigens, which was significantly higher than that in patients with functioning renal transplants (25%, p<0.0001). C1q-fixing antibodies were more significantly associated with graft failure caused by AMR (72.73%) or mixed AMR/CMR (61.9%) as compared to failure due to CMR (35.3%) or other causes (39.2%) (p=0.026). CONCLUSIONS: Transplant recipients had antibodies against denatured HLA class I, II, and MICA antigens. However, only c1q-fixing antibodies were associated with graft failure which was related to antibody mediated rejection. PMID- 26615784 TI - The Contribution of Whole Gene Deletions and Large Rearrangements to the Mutation Spectrum in Inherited Tumor Predisposing Syndromes. AB - Heterozygous whole gene deletions (WGDs), and intragenic microdeletions, account for a significant proportion of mutations underlying cancer predisposition syndromes. We analyzed the frequency and genotype-phenotype correlations of microdeletions in 12 genes (BRCA1, BRCA2, TP53, MSH2, MLH1, MSH6, PMS2, NF1, NF2, APC, PTCH1, and VHL) representing seven tumor predisposition syndromes in 5,897 individuals (2,611 families) from our center. Overall, microdeletions accounted for 14% of identified mutations. As expected, smaller deletions or duplications were more common (12%) than WGDs (2.2%). Where a WGD was identified in the germline in NF2, the mechanism of somatic second hit was not deletion, as previously described for NF1. For neurofibromatosis type 1 and 2, we compared the mechanism of germline deletion. Unlike NF1, where three specific deletion sizes account for most germline WGDs, NF2 deletion breakpoints were different across seven samples tested. One of these deletions was 3.93 Mb and conferred a severe phenotype, thus refining the region for a potential NF2 modifier gene to a 2.04 Mb region on chromosome 22. The milder phenotype of NF2 WGDs may be due to the apparent absence of chromosome 22 loss as the second hit. These observations of WGD phenotypes will be helpful for interpreting incidental findings from microarray analysis and next-generation sequencing. PMID- 26615785 TI - Drug-symptom networking: Linking drug-likeness screening to drug discovery. AB - Understanding the relationships between drugs and symptoms has broad medical consequences, yet a comprehensive description of the drug-symptom associations is currently lacking. Here, 1441 FDA-approved drugs were collected, and PCA was used to extract 122 descriptors which explained 91% of the variance. Then, a k-means++ method was employed to partition the drug dataset into 3 clusters, and 3 corresponding SVDD models (drug-likeness screening models) were constructed with an overall accuracy of up to 95.6%. Furthermore, 6878 herbal molecules from the TcmSPTM database were screened by the above 3 SVDD model to obtain 5309 candidate drug molecules with highly accept classification of 77.19%. To assess the accuracy of the SVDD models, 8559 herbal molecule-symptom co-occurrences were mined from Pubmed abstracts, involving 697 herbal molecules and 314 symptoms. Most of the 697 herbal molecules could be found in the accepted SVDD data (5309 molecules), showing the potential of the SVDD for the screening of drug candidates. Moreover, a herbal molecule-herbal molecule network and a herbal molecule-symptom were constructed. Overall, the results provided a new drug likeness screening approach independent to abnormal training data, and the comprehensive collection of herbal molecule-symptom associations formed a new data resource for systematic characterization of the symptom-oriented medicines. PMID- 26615786 TI - Pediatric Intraneural Ganglia: The Value of a Systematic Review for "Orphan" Conditions. PMID- 26615787 TI - The Retrosigmoid Petrosal Fissure Transpeduncular Approach to Central Pontine Lesions. AB - BACKGROUND: The advent of improved surgical instruments and neuronavigation and descriptions of safe-entry zones have allowed neurosurgeons to resect brainstem lesions with an acceptable morbidity. The authors describe the technique of petrosal fissure dissection to the lateral transpeduncular safe-entry zone at the middle cerebellar peduncle (MCP) for resection of deep-seated central pontine pathologies. This approach allows the surgeon to obtain less cerebellar retraction and a more direct, more shallow, and shorter approach compared with the approach without opening this fissure. METHODS: An illustrative case is used to highlight the technique of dissecting the petrosal fissure to obtain a direct surgical corridor to the MCP. Anatomic dissections are used to define better the relative relationships of this fissure to the MCP and adjacent structures. RESULTS: Dissection of the petrosal fissure provides a direct trajectory to the lateral transpeduncular entry zone at the MCP and can enhance exposure of this structure, while minimizing morbidity to the corticospinal tract and cerebellum during approaches to central pontine pathologies. CONCLUSIONS: For resection of lesions within the pons via the retrosigmoid craniotomy, dissection of the petrosal fissure allows for a more direct and shorter route to the central pontine and lateral pontine lesion compared with an approach without expansion of this potential space. PMID- 26615788 TI - Human Immunodeficiency Virus-Associated Cerebral Aneurysmal Vasculopathy: A Systematic Review. AB - BACKGROUND: Human immunodeficiency virus (HIV)-associated cerebral aneurysmal vasculopathy is a rare complication of HIV affecting pediatric and adult patients and has been the subject of many case reports and case series. METHODS: We performed a systematic literature search of PubMed, EMBASE, Scopus, Web of Science, Science Direct, and Google Scholar up to April 10, 2015. Our inclusion criteria encompassed all reported original case series and reports of HIV associated cerebral aneurysms diagnosed radiologically. We analyzed the clinical characteristics and management of the reported cases. RESULTS: We identified 61 patients reported in the literature (45 pediatric and 16 adult patients). The median age was 9.8 years for pediatric patients and 36.5 years for adult patients. Weakness was the most common presenting symptom in adult and pediatric patients. The most common affected artery was the middle cerebral artery. Approximately 87.2% of pediatric patients and 42.9% of adult patients were on antiretroviral therapy (ART) at presentation. The mortality rate was 60% and 35.7% among pediatric and adult patients, respectively. The optimal management is not well established. Variable response to ART was reported with possible survival benefits when ART was initiated early. CONCLUSIONS: HIV-associated cerebral aneurysmal arteriopathy is associated with high mortality. The optimal management is not well established, but early initiation of ART may improve the survival rate. PMID- 26615789 TI - Carotid-Anterior Cerebral Artery Anastomosis Associated with Paraclinoid Aneurysm and Ophthalmic Artery Originating From Middle Meningeal Artery: Case Report and Consideration of Terminology. AB - BACKGROUND: We summarized 63 cases of anterior cerebral artery (ACA) anomaly with an infraoptic course reported in the literature including abstracts written in English. All cases were reported individually, with a maximum of 3 cases. This report describes our findings in another case and opinions regarding the terminology. CASE DESCRIPTION: A 78-year-old woman presented with subarachnoid hemorrhage. A carotid angiogram showed a right paraclinoid aneurysm with an anomaly of the ACA. The right ACA originated from the internal carotid artery at the level of the ophthalmic segment intradurally with an infraoptic course. The right ophthalmic artery originated from the ipsilateral middle meningeal artery. We performed an emergent endovascular coil embolization with balloon assistance, and the patient recovered well. CONCLUSIONS: Use of the terminology "infraoptic course of the ACA" versus "carotid-ACA anastomosis" was discussed. Based on the literature reports, at least one third of the cases have a normal-positioned ACA rather than the infraoptic ACA. Also, based on embryogenesis, it is thought that the infraoptic ACA is not a misplaced A1 segment, but rather persistence of an embryologic vessel. Therefore, based on the literature and embryology, we prefer the term "carotid-ACA anastomosis" rather than "infraoptic ACA." However, as a morphologic and positional description, the term "infraoptic ACA" has value. To the best of our knowledge, the present case of a carotid-ACA anastomosis associated with a paraclinoid aneurysm and ophthalmic artery originating from the middle meningeal artery is the first to appear in the literature. PMID- 26615791 TI - Spinal Orthoses for Vertebral Osteoporosis and Osteoporotic Vertebral Fracture: A Systematic Review. AB - OBJECTIVE: To systematically review the evidence of effectiveness of spinal orthoses for adults with vertebral osteoporosis. DATA SOURCES: We conducted a systematic literature search using the databases of PubMed, MEDLINE, EMBASE, AMED, CINAHL, PEDro, and the Cochrane Library from January 1995 to October 2014. STUDY SELECTION: Two reviewers evaluated eligibility. Randomized controlled trials (RCTs), pilot RCTs, and prospective nonrandomized controlled studies of spinal orthoses for people with vertebral osteoporosis or osteopenia with and without osteoporotic vertebral fracture (OVF) that examined outcomes related to fracture consolidation, pain, strength, posture, balance, physical function, quality of life, and complications were eligible. DATA EXTRACTION: Two reviewers independently extracted data and evaluated methodological quality using a domain based risk-of-bias approach. DATA SYNTHESIS: Twelve studies were included: 8 RCTs or pilot RCTs and 4 nonrandomized studies involving 626 participants. Three studies (n=153) evaluated orthoses after acute OVF; none were of high quality. Complications were highest with rigid orthoses. Evidence that orthoses could affect vertebral deformity was lacking. Nine studies (n=473) of varying quality considered orthoses in subacute and longer rehabilitation. Three suggested a semirigid backpack thoracolumbar orthosis (TLO) could benefit strength, pain, posture, and quality of life. One found a weighted kypho-orthosis (WKO) improved balance. CONCLUSIONS: The limited evidence about orthoses after acute OVF is inconclusive; better evidence of efficacy is needed, particularly when considering complications. The promising evidence regarding the backpack TLO and WKO needs to be explored further in studies of sufficient size and quality that include men. PMID- 26615790 TI - Anaplastic Lymphoma Kinase-Negative Anaplastic Large Cell Lymphoma Manifesting as a Scalp Hematoma After an Acute Head Injury-a Case Report and Literature Review. AB - BACKGROUND: Anaplastic large cell lymphoma (ALCL) is a malignant non-Hodgkin lymphoma, typically associated with anaplastic lymphoma kinase (ALK) expression. In some cases, lack of ALK translocation correlated with a more unfavorable prognosis. CASE DESCRIPTION: We describe a case of ALK(-) ALCL that manifested as a progressive, enlarged, swollen mass on the scalp after an acute head injury in an 84-year-old man. Neither palpable lymph nodes nor any B symptoms were noted on admission. Brain computed tomography showed a hematoma in the right posterior occipital region of the scalp as the only remarkable finding. Debridement and biopsy were performed. Histologic and immunohistochemical analysis of the specimen revealed an ALK(-) ALCL of the scalp. The lymphoma was resistant to bendamustine-containing chemotherapies, ultimately leading to the patient's death within 2 months. CONCLUSIONS: This case report highlights the importance of recognizing the possibility of an ALCL manifesting as a focal inflammatory swelling mass on the scalp. PMID- 26615792 TI - Lower Limb Strength Is Significantly Impaired in All Muscle Groups in Ambulatory People With Chronic Stroke: A Cross-Sectional Study. AB - OBJECTIVE: To measure the strength of the major muscle groups of the affected and intact lower limbs in people with stroke compared with age-matched controls. DESIGN: Cross-sectional study. SETTING: University laboratory. PARTICIPANTS: Ambulatory stroke survivors (n=60; mean age, 69+/-11y), who had had a stroke between 1 and 6 years previously, and age-matched controls (n=35; mean age, 65+/ 9y) (N=95). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The maximum isometric strength of 12 muscle groups (hip flexors and extensors, hip adductors and abductors, hip internal rotators and external rotators, knee flexors and extensors, ankle dorsiflexors and plantarflexors, ankle invertors and evertors) of both lower limbs was measured using handheld dynamometry. All strength measurements were taken in standardized positions by 1 rater. RESULTS: The affected lower limb of the participants with stroke was significantly weaker than that of the control participants for all muscle groups (P<.01). Strength (adjusted for age, sex, and body weight) was 48% (range, 34%-62%) of that of the control participants. The most severely affected muscle groups were hip extensors (34% of controls), ankle dorsiflexors (35%), and hip adductors (38%), and the least severely affected muscle groups were ankle invertors (62%), ankle plantarflexors (57%), and hip flexors (55%). The intact lower limb of the participants with stroke was significantly weaker than that of the control participants for all muscle groups (P<.05) except for ankle invertors (P=.25). Strength (adjusted for age, sex, and body weight) was 66% (range, 44%-91%) of that of the control participants. The most severely affected muscle groups were hip extensors (44% of controls), ankle dorsiflexors (52%), and knee flexors (54%). CONCLUSIONS: Ambulatory people with chronic stroke have a marked loss of strength in most of the major muscle groups of both lower limbs compared with age matched controls. PMID- 26615794 TI - Dislocation-driven growth of porous CdSe nanorods from CdSe.(ethylenediamine)(0.5) nanorods. AB - Porous CdSe nanorods having a novel flute-like morphology have been prepared facilely via the hydrothermal treatment of CdSe.(en)0.5 (en = ethylenediamine) nanorods as sacrificial templates. During the hydrothermal process, various crystalline imperfections such as stacking faults and twinning planes appear due to lattice mismatches between orthorhombic CdSe.(en)0.5 and hexagonal wurtzite porous CdSe nanorods and subsequently disappear to release mismatched strains. In the self-healing process of defects, due to the imbalance of in-and-out atomic diffusion, point defects of atomic vacancies are heavily generated in CdSe nanorods to produce volume defects of voids eventually. The photoluminescence of CdSe nanorods shifts to the red region and decreases in intensity with the increase of the hydrolysis time as surface states and selenium vacancies increase. The mean lifetime of photoluminescence increases with the increase of the hydrothermal-treatment time as the fractional amplitude of the surface-state related component increases. PMID- 26615793 TI - Effects of hydroxyurea treatment for patients with hemoglobin SC disease. AB - Although hemoglobin SC (HbSC) disease is usually considered less severe than sickle cell anemia (SCA), which includes HbSS and HbS/beta(0) -thalassemia genotypes, many patients with HbSC experience severe disease complications, including vaso-occlusive pain, acute chest syndrome, avascular necrosis, retinopathy, and poor quality of life. Fully 20 years after the clinical and laboratory efficacy of hydroxyurea was proven in adult SCA patients, the safety and utility of hydroxyurea treatment for HbSC patients remain unclear. Recent NHLBI evidence-based guidelines highlight this as a critical knowledge gap, noting HbSC accounts for ~30% of sickle cell patients within the United States. To date, only 5 publications have reported short-term, incomplete, or conflicting laboratory and clinical outcomes of hydroxyurea treatment in a total of 71 adults and children with HbSC. We now report on a cohort of 133 adult and pediatric HbSC patients who received hydroxyurea, typically for recurrent vaso-occlusive pain. Hydroxyurea treatment was associated with a stable hemoglobin concentration; increased fetal hemoglobin (HbF) and mean corpuscular volume (MCV); and reduced white blood cell count (WBC), absolute neutrophil count (ANC), and absolute reticulocyte count (ARC). Reversible cytopenias occurred in 22% of patients, primarily neutropenia and thrombocytopenia. Painful events were reduced with hydroxyurea, more in patients >15 years old. These multicenter data support the safety and potentially salutary effects of hydroxyurea treatment for HbSC disease; however, a multicenter, placebo-controlled, Phase 3 clinical trial is needed to determine if hydroxyurea therapy has efficacy for patients with HbSC disease. PMID- 26615796 TI - HLA-DRB1 gene polymorphisms and its associations with rheumatoid arthritis in Chinese Han women of Shaanxi province, northwest of China. AB - Rheumatoid arthritis (RA) is a common chronic autoimmune disease characterized by symmetric polyarthritis. This study was designed to investigate the associations between HLA-DRB1 gene polymorphisms and RA in the Chinese Han population of Shaanxi province, northwest of China. In total, we identified 31 high-resolution HLA-DRB1 alleles in 109 patients with RA. Compared with the controls, the AF of HLA-DRB1*04:05 (P = 0.000, Pc = 0.007, OR = 3.462, 95%CI: 1.749-6.852) was significantly higher in patients with RA. In addition, the patients with RA had higher allele frequency (AF) of the HLA-DRB1*04:03 (P = 0.030, Pc = NS, OR = 4.737, 95%CI: 1.012-22.180); DRB1*04:06 (P = 0.018, Pc = NS, OR = 5.288, 95%CI: 1.145-24.422) and the shared epitope (SE) alleles (P = 0.004, Pc = NS, OR = 2.166, 95%CI: 1.279-3.667), respectively. Moreover, positive possibilities of RF and anti-CCP were significant higher in SE-positive patients compared to SR negative patients (OR = 4.787, 95%CI: 1.101-20.824; OR = 3.775, 95%CI: 1.106 12.876, respectively). Our results indicated that HLA-DRB1*04:05, *04:03, *04:06 and SE alleles might be susceptibility allele for RA in Chinese Han population of Shaanxi province, northwest of China. PMID- 26615795 TI - Improved spectral resolution and high reliability of in vivo (1) H MRS at 7 T allow the characterization of the effect of acute exercise on carnosine in skeletal muscle. AB - The aims of this study were to observe the behavior of carnosine peaks in human soleus (SOL) and gastrocnemius (GM) muscles following acute exercise, to determine the relaxation times and to assess the repeatability of carnosine quantification by (1) H MRS at 7 T. Relaxation constants in GM and SOL were measured by a stimulated echo acquisition mode (STEAM) localization sequence. For T1 measurement, an inversion recovery sequence was used. The repeatability of the measurement and the absolute quantification of carnosine were determined in both muscles in five healthy volunteers. For absolute quantification, an internal water reference signal was used. The effect of acute exercise on carnosine levels and resonance lines was tested in eight recreational runners/cyclists. The defined carnosine measurement protocol was applied three times - before and twice after (approximately 20 and 40 min) a 1-h submaximal street run and additional toe-hopping. The measured T1 relaxation times for the C2-H carnosine peak at 7 T were 2002 +/- 94 and 1997 +/- 259 ms for GM and SOL, respectively, and the T2 times were 95.8 +/- 9.4 and 81.0 +/- 21.8 ms for GM and SOL, respectively. The coefficient of variation of the carnosine quantification measurement was 9.1% for GM and 6.3% for SOL, showing high repeatability, and the intraclass correlation coefficients (ICCs) of 0.93 for GM and 0.98 for SOL indicate the high reliability of the measurement. Acute exercise did not change the concentration of carnosine in the muscle, but affected the shape of the resonance lines, in terms of the shifting and splitting into doublets. Carnosine measurement by (1) H MRS at 7 T in skeletal muscle exhibits high repeatability and reliability. The observed effects of acute exercise were more prominent in GM, probably as a result of the larger portion of glycolytic fibers in this muscle and the more pronounced exercise-induced change in pH. Our results support the application of the MRS based assessment of carnosine for pH measurement in muscle compartments. PMID- 26615797 TI - Sonocatalyzed decolorization of synthetic textile wastewater using sonochemically synthesized MgO nanostructures. AB - The present study focused on the synthesis of nanostructured MgO via sonochemical method and its application as sonocatalyst for the decolorization of Basic Red 46 (BR46) dye under ultrasonic irradiation. The sonocatalyst was characterized using X-ray diffraction (XRD) and field emission scanning electron microscopy (FE-SEM) equipped with energy dispersive X-ray microanalysis (EDX). In the following, the sonocatalytic removal of the dye under different operational conditions was evaluated kinetically on the basis of pseudo first-order kinetic model. The reaction rate of sonocatalyzed decolorization using MgO nanostructures (12.7 * 10(-3) min(-1)) was more efficient than that of ultrasound alone (2.0 * 10(-3) min(-1)). The increased sonocatalyst dosage showed better sonocatalytic activity but the application of excessive dosage should be avoided. The presence of periodate ions substantially increased the decolorization rate from 14.76 * 10( 3) to 33.4 * 10(-3) min(-1). Although the application of aeration favored the decolorization rate (17.8 * 10(-3) min(-1)), the addition of hydrogen peroxide resulted in a considerable decrease in the decolorization rate (9.5 * 10(-3) min( 1)) due to its scavenging effects at specific concentrations. Unlike alcoholic compounds, the addition of phenol had an insignificant scavenging effect on the sonocatalysis. A mineralization rate of 7.4 * 10(-3) min(-1) was obtained within 120 min. The intermediate byproducts were also detected using GC-MS analysis. PMID- 26615798 TI - Photophysics of Auramine-O: electronic structure calculations and nonadiabatic dynamics simulations. AB - Diphenylmethane dyes are very useful photoinduced molecular rotors; however, their photophysical mechanisms are still elusive until now. In this work, we adopted combined static electronic structure calculations (MS-CASPT2//CASSCF) and trajectory-based surface-hopping dynamics simulations (OM2/MRCI) to study the S1 excited-state relaxation mechanism of a representative diphenylmethane dye Auramine-O. On the basis of the optimized S1 minima and the computed emission bands, we have for the first time assigned experimentally proposed three transient states (i.e. S1-LE, S1-I1 or S1-I2, and S1-II). Mechanistically, upon irradiation to the S1 state, the system first relaxes to the locally excited S1 minimum (S1-LE). Starting from this point, there exist two kinds of relaxation paths to S1-II. In the sequential path, the system first evolves into S1-I1 or S1 I2 and then runs into S1-II; in the concerted one, the system, bypassing S1-I1 and S1-I2, directly runs into S1-II. In addition, the system can decay to the S0 state in the vicinity of three S1/S0 conical intersections i.e. S1S0-I1, S1S0-I2, and S1S0-II. In the S1 dynamic simulations, 54% trajectories decay to the S0 state via S1S0-II; the remaining trajectories are de-excited to the S0 state via S1S0-I1 (11%) and S1S0-I2 (35%). Our present theoretical investigation does not support the experimentally proposed S1 excited-state hypothesis that the intramolecular rotation of the two dimethyl groups around the C-N bond is responsible for the rapid decay of the emission band at about 500 nm; instead, it should be heavily interrelated with the rotation of the two dimethylanilino groups. Finally, this work provides important mechanistic insights into similar diphenylmethane dyes. PMID- 26615799 TI - Electrospun interconnected Fe-N/C nanofiber networks as efficient electrocatalysts for oxygen reduction reaction in acidic media. AB - One-dimensional electrospun nanofibers have emerged as a potential candidate for high-performance oxygen reduction reaction (ORR) catalysts. However, contact resistance among the neighbouring nanofibers hinders the electron transport. Here, we report the preparation of interconnected Fe-N/C nanofiber networks (Fe N/C NNs) with low electrical resistance via electrospinning followed by maturing and pyrolysis. The Fe-N/C NNs show excellent ORR activity with onset and half wave potential of 55 and 108 mV less than those of Pt/C catalyst in 0.5 M H2SO4. Intriguingly, the resulting Fe-N/C NNs exhibit 34% higher peak current density and superior durability than generic Fe-N/C ones with similar microstructure and chemical compositions. Additionally, it also displays much better durability and methanol tolerance than Pt/C catalyst. The higher electroactivity is mainly due to the more effective electron transport between the interconnected nanofibers. Thus, our findings provide a novel insight into the design of functional electrospun nanofibers for the application in energy storage and conversion fields. PMID- 26615800 TI - Femtosecond laser rapid fabrication of large-area rose-like micropatterns on freestanding flexible graphene films. AB - We developed a simple, scalable and high-throughput method for fabrication of large-area three-dimensional rose-like microflowers with controlled size, shape and density on graphene films by femtosecond laser micromachining. The novel biomimetic microflower that composed of numerous turnup graphene nanoflakes can be fabricated by only a single femtosecond laser pulse, which is efficient enough for large-area patterning. The graphene films were composed of layer-by-layer graphene nanosheets separated by nanogaps (~10-50 nm), and graphene monolayers with an interlayer spacing of ~0.37 nm constituted each of the graphene nanosheets. This unique hierarchical layering structure of graphene films provides great possibilities for generation of tensile stress during femtosecond laser ablation to roll up the nanoflakes, which contributes to the formation of microflowers. By a simple scanning technique, patterned surfaces with controllable densities of flower patterns were obtained, which can exhibit adhesive superhydrophobicity. More importantly, this technique enables fabrication of the large-area patterned surfaces at centimeter scales in a simple and efficient way. This study not only presents new insights of ultrafast laser processing of novel graphene-based materials but also shows great promise of designing new materials combined with ultrafast laser surface patterning for future applications in functional coatings, sensors, actuators and microfluidics. PMID- 26615801 TI - A designed room-temperature triplet ligand from pyridine-2,6-diyl bis(tert-butyl nitroxide). AB - The magnetic study on newly developed 4-mesitylpyridine-2,6-diyl bis(tert-butyl nitroxide) shows that almost the whole population has a ground triplet state at room temperature, and the ability of complex formation as a tridentate triplet ligand was proven with a diamagnetic yttrium(iii) ion. PMID- 26615802 TI - Structural basis of the Inv compartment and ciliary abnormalities in Inv/nphp2 mutant mice. AB - The primary cilium is a hair like structure protruding from most mammalian cells. The basic design of the primary cilium consists of a nine microtubule doublet structure (the axoneme). The Inv compartment, a distinct proximal segment of the ciliary body, is defined as the region in which the Inv protein is localized. Inv gene is a responsible gene for human nephronophthisis type2 (NPHP2). Here, we show that renal cilia have a short proximal microtubule doublet region and a long distal microtubule singlet region. The length of the Inv compartment was similar to that of the microtubule doublet region, suggesting a possibility that the doublet region is the structural basis of the Inv compartment. Respiratory cilia of inv mouse mutants had ciliary rootlet malformation and showed reduced ciliary beating frequency and ciliary beating angle, which may explain recurrent bronchitis in NPHP2 patients. In multiciliated tracheal cells, most Inv proteins were retained in the basal body and did not accumulate in the Inv compartment. These results suggest that the machinery to transport and retain Inv in cilia is different between renal and tracheal cilia and that Inv may function in the basal body of tracheal cells. PMID- 26615803 TI - The Lumipulse G HBsAg-Quant assay for screening and quantification of the hepatitis B surface antigen. AB - Qualitative HBsAg assay is used to screen HBV infection for decades. The utility of quantitative assay is also rejuvenated recently. We aimed to evaluate and compare the performance of a novel ultra-sensitive and quantitative assay, the Lumipulse assay, with the Architect and Elecsys assays. As screening methods, specificity was compared using 2043 consecutive clinical routine samples. As quantitative assays, precision and accuracy were assessed. Sera from 112 treatment-naive chronic hepatitis B patients, four patients undergoing antiviral therapy and one patient with acute infection were tested to compare the correlations. Samples with concurrent HBsAg/anti-HBs were also quantified. The Lumipulse assay precisely quantified ultra-low level of HBsAg (0.004 IU/mL). It identified additional 0.98% (20/2043) clinical samples with trance amount of HBsAg. Three assays displayed excellent linear correlations irrespective of genotypes and S-gene mutations (R(2)>0.95, P<0.0001), while minor quantitative biases existed. The Lumipulse assay did not yield higher HBsAg concentrations in samples with concomitant anti-HBs. Compared with other assays, the Lumipulse assay is sensitive and specific for detecting HBsAg. The interpretation of the extremely low-level results, however, is challenging. Quantitative HBsAg results by different assays are highly correlated, but they should be interpreted interchangeably only after conversion to eliminate the biases. PMID- 26615804 TI - VeroNectin-4 is a highly sensitive cell line that can be used for the isolation and titration of Peste des Petits Ruminants virus. AB - Peste des Petits Ruminants virus (PPRV) is a member of the Morbillivirus subgroup of the family Paramyxoviridae, and is one of the most contagious diseases of small ruminants throughout Africa and the rest of the world. Different cell lines have previously been used to isolate PPRV but with limited success. Thus, to improve the isolation of Morbilliviruses, human, canine, and goat homologues of the lymphocyte receptor signaling lymphocyte activation molecule (SLAM) have been introduced into cells that can support virus replication. However, the amino acid sequence of SLAM varies between species, and often requires adaptation of a particular virus to different versions of the receptor. The protein sequence of Nectin-4 is highly conserved between different mammals, which eliminate the need for receptor adaptation by the virus. Cell lines expressing Nectin-4 have previously been used to propagate measles and canine distemper viruses. In this study, we compared infections in Vero cells expressing canine SLAM (VeroDogSLAM) to those in Vero cells expressing Nectin-4 (VeroNectin-4), following inoculations with wild-type strains of PPRV. Virus isolation using VeroNectin-4 cells was successful with 23% of swabbed samples obtained from live infected animals, and was 89% effective using post-mortem tissues of infected sheep. By contrast, only 4.5% efficiency was observed from swab samples and 67% efficiency was obtained in virus isolation from post-mortem tissues using VeroDogSLAM cells. The average incubation period for virus recovery from post-mortem tissues was 3.4 days using VeroNectin-4 cells, compared with 5.5 days when using VeroDogSLAM cells. The virus titers of PPRV obtained from VeroNectin-4 cells were also higher than those derived from VeroDogSLAM cells. A comparison of the growth kinetics for PPRV in the two cell lines confirmed the superiority of VeroNectin-4 cells for PPR diagnostic purposes and vaccine virus titration. PMID- 26615805 TI - Protection against influenza A virus by vaccination with a recombinant fusion protein linking influenza M2e to human serum albumin (HSA). AB - The highly conserved extracellular domain of M2 protein (M2e) of influenza A viruses has limited immunogenicity on its own. Hence, aiming to enhance immunogenicity of M2e protein, optimal approaches remain to be established. In this study, we created recombinant fusion protein vaccines by linking M2e consensus sequence of influenza A viruses with C-terminal domain of human serum albumin (HSA). Then HSA/M2e recombinant fusion protein was studied. Our results showed that HSA/M2e could induce strong anti-M2e specific humoral immune responses in the established mice model. Administration of HSA/M2e with Freund's adjuvant resulted in a higher number of IFN-gamma-producing cells compared to HSA/M2e or M2e peptide emulsified in Freund's adjuvant. Furthermore, HSA/M2e was able to reduce viral load in the mice lungs and provide significant protection against lethal challenge with an H1N1 or an H3N2 virus compared to controls. In conclusion, this study has demonstrated a potential vaccine that could provide protection in preventing the threat of influenza outbreak because of rapid variation of the influenza virus. PMID- 26615807 TI - Novel multiplex PCR assay using locked nucleic acid (LNA)-based universal primers for the simultaneous detection of five swine viruses. AB - A novel multiplex PCR assay using non-homologous oligonucleotides with locked nucleic acid (LNA) modifications as universal primers was developed and validated for the simultaneous detection of five swine viruses. The assay utilizes five virus-specific primer pairs modified at the 5' end through the addition of the universal primer sequence. In the reaction, small amounts of target templates with the 5' tail were generated and subsequently amplified through the extension of a LNA universal primer set. To validate the specificity of this assay, 27 viral target strains and 12 non-target pathogens were tested. The lower limit of detection of viral nucleic acids was 1.1-1.9 pg per reaction or 11-32 pg in a five-plex viral nucleic acid mixture. The LNA mPCR assay displayed higher analytical sensitivity and efficiency for the detection of plasmid standards compared with the conventional assay, which uses standard primers without the 5' tail. A total of 207 field samples were tested using both assays. The LNA mPCR assay provided numerically higher detection rates for all pathogens in independent samples. Moreover, the LNA mPCR assay had significantly higher detection rates in independent samples compared with the conventional assay. PMID- 26615806 TI - Evaluation of a novel chemiluminescent microplate enzyme immunoassay for hepatitis B surface antigen detection. AB - Hepatitis B virus surface antigen (HBsAg) is an important biomarker used in the diagnosis of hepatitis B virus (HBV) infection, but false-negative results are still reported in the detection of HBsAg using commercial assays. In this study, we evaluated the qualitative properties of a novel HBsAg chemiluminescence enzyme immunoassay (CLEIA) assay--WTultra. WHO standard sample dilution series and samples from low-level HBsAg carriers (<1 ng/mL) were used to evaluate the sensitivity of the WTultra assay. Boston Biomedica, Inc. (BBI) hepatitis B seroconversion panels were used to assess the ability of the WTultra assay to detect the window period. In addition, dilution series of 22 serum samples with different genotypes, serotypes and HBsAg mutations were used to assess the WTultra assay, and these were compared with other commercial assays. The lower detection limit of the WTultra assay was 0.012 IU/mL, and it showed a high sensitivity (97.52%, 95% CI, 94.95-99.00) in the detection of 282 low-level HBsAg carriers (<1 ng/mL). In samples with various HBV genotypes, serotypes and HBsAg mutations, the WTultra assay yielded 117 positive results in 132 samples, which was significantly higher than the results with the other four commercial assays (89, 83, 65 and 45, respectively, p<0.01). In the assays of mutant strains, the WTultra assay detected 82 positive results in 90 samples, which was significantly better than the results for the Hepanostika HBsAg Ultra (58 positive) and Architect (55 positive) (p<0.01) assays, which in turn were significantly better than the Murex V.3 (41 positive, p=0.026) and AxSYM V2 (29 positive, p<0.01) assays. However, in the detection of 42 samples of wild-type strains with various genotypes and serotypes, no significant differences were observed among the WTultra (35 positive), Architect (28 positive) and Hepanostika HBsAg Ultra (31 positive) assays. However, the WTultra assay detected significantly more samples than the Murex V.3 (24 positive, p<0.01) and AxSYM V2 (16 positive, p<0.01) assays. In conclusion, the WTultra HBsAg assay has a high detection sensitivity and presents excellent results for the detection of mutants. PMID- 26615808 TI - Anti-HCV immunoassays based on a multiepitope antigen and fluorescent lanthanide chelate reporters. AB - There is a need for simple to produce immunoassays for hepatitis C virus (HCV) antibody capable of detecting all genotypes worldwide. Current commonly used third generation immunoassays use three to six separate recombinant proteins or synthetic peptides. We have developed and expressed in Escherichia coli a single recombinant antigen incorporating epitopes from different HCV proteins. This multiepitope protein (MEP) was used to develop two types of HCV antibody immunoassays: a traditional antibody immunoassay using a labeled secondary antibody (indirect assay) and a double-antigen assay with the same MEP used as capture binder and labeled binder. The secondary antibody assay was evaluated with 171 serum/plasma samples and double-antigen assay with 148 samples. These samples included an in-house patient sample panel, two panels of samples with different HCV genotypes and a seroconversion panel. The secondary antibody immunoassay showed 95.6% sensitivity and 100% specificity while the double antigen assay showed 91.4% sensitivity and 100% specificity. Both assays detected samples from all six HCV genotypes. The results showed that combining a low-cost recombinant MEP binder antigen with a high sensitivity fluorescent lanthanide reporter can provide a sensitive and specific immunoassay for HCV serology. The results also showed that the sensitivity of HCV double-antigen assays may suffer from the low avidity immune response of acute infections. PMID- 26615809 TI - Psychometric properties of Malay neuropsychiatry unit cognitive assessment tool among Alzheimer's disease patients in comparison to Malay Montreal Cognitive Assessment. AB - This study aims to establish psychometric properties of the Malay Neuropsychiatry Unit Cognitive Assessment Tool (Malay NuCOG) in Alzheimer's disease. NuCOG was translated to Malay language and compared with Montreal Cognitive Assessment Tool on 80 individuals. The Malay NuCOG showed good internal consistency and reliability (Cronbach's alpha = 0.895). It demonstrated 100% sensitivity and 87.5% specificity at the cutoff score of 78.50/100. The Malay NuCOG is a valid and reliable cognitive instrument that is sensitive and specific for the detection of dementia and has clinical advantages in its ability to examine individual cognitive domains. PMID- 26615810 TI - A two-stage treatment of lentigo maligna using ablative laser therapy followed by imiquimod: excellent cosmesis, but frequent recurrences on the nose. PMID- 26615811 TI - s-Block amidoboranes: syntheses, structures, reactivity and applications. AB - Metal amidoborane compounds of the alkali- and alkaline earth metals have in recent years found applications in diverse disciplines, notably as hydrogen storage materials, as reagents for the reduction of organic functional groups and as catalysts and intermediates in dehydrocoupling reactions. These functions are connected by the organometallic chemistry of the MNR2BH3 group. This review focusses on central aspects of the s-block amidoborane compounds - their syntheses, structures and reactivity. Well-defined amidoborane complexes of group 2 metals are now available by a variety of solution-phase routes, which has allowed a more detailed analysis of this functional group, which was previously largely confined to solid-state materials chemistry. Structures obtained from X ray crystallography have begun to provide increased understanding of the fundamental steps of key processes, including amine-borane dehydrocoupling and hydrogen release from primary and secondary amidoboranes. We review structural parameters and reactivity to rationalise the effects of the metal, nitrogen substituents and supporting ligands on catalytic performance and dehydrogenative decomposition routes. Mechanistic features of key processes involving amidoborane compounds as starting materials or intermediates are discussed, alongside emerging applications such as the use of group 1 metal amidoboranes in synthesis. Finally, the future prospects of this vibrant branch of main group chemistry are evaluated. PMID- 26615812 TI - Multimedia in the informed consent process for endoscopic sinus surgery: A randomized control trial. AB - OBJECTIVES/HYPOTHESIS: To determine patient recall of specific risks associated with endoscopic sinus surgery and whether an adjunct multimedia education module is an effective patient tool in enhancing the standard informed consent process. STUDY DESIGN: Prospective, randomized, controlled trial. METHODS: Fifty consecutive adult patients scheduled for endoscopic sinus surgery at a rhinology clinic of a tertiary care hospital were recruited for this study. Informed consent was studied by comparing the number of risks recalled when patients had a verbal discussion in conjunction with a 6-minute interactive module or the verbal discussion alone. Early recall was measured immediately following the informed consent process, and delayed recall was measured 3 to 4 weeks after patient preference details were also collected. RESULTS: Early risk recall in the multimedia group was significantly higher than the control group (P = .0036); however, there was no difference between the groups in delayed risk recall. Seventy-six percent of participants expressed interest in viewing the multimedia module if available online between the preoperative and procedural day. Sixty eight percent of patients preferred having the multimedia module as an adjunct to the informed consent process as opposed to the multimedia consent process alone. CONCLUSIONS: There is an early improvement in overall risk recall in patients who complete an interactive multimedia module, with a clear patient preference for this method. Here we emphasize the well-known challenges of patient education and demonstrate the effectiveness of integrating technology into clinical practice in order to enhance the informed consent process. LEVEL OF EVIDENCE: 1b Laryngoscope, 126:1273-1278, 2016. PMID- 26615813 TI - (18)F-FDG PET/CT imaging of breast cancer in a lactating woman. PMID- 26615814 TI - Exquisite 1D Assemblies Arising from Rationally Designed Asymmetric Donor Acceptor Architectures Exhibiting Aggregation-Induced Emission as a Function of Auxiliary Acceptor Strength. AB - One-dimensional nanostructures with aggregation-induced emission (AIE) properties have been fabricated to keep the pace with growing demand from optoelectronics applications. The compounds 2-[4-(4-methylpiperazin-1 yl)benzylidene]malononitrile (PM1), 2-{4-[4-(pyridin-2-yl)piperazin-1-yl] benzylidene}malononitrile (PM2), and 2-{4-[4-(pyrimidin-2-yl)piperazin-1 yl]benzylidene}malononitrile (PM3) have been designed and synthesized by melding piperazine and dicyanovinylene to investigate AIE in an asymmetric donor-acceptor (D-A) construct of A'-D-pi-A- topology. The synthetic route has been simplified by using phenylpiperazine as a weak donor (D), dicyanovinylene as an acceptor (A), and pyridyl/pyrimidyl groups (PM2/PM3) as auxiliary acceptors (A'). It has been established that A' plays a vital role in triggering AIE in these compounds because the same D-A construct led to aggregation-caused quenching upon replacing A' with an electron-donating ethyl group (PM1). Moreover, the effect of restricted intramolecular rotation and twisted intramolecular charge transfer on the mechanism of AIE has also been investigated. Furthermore, it has been clearly shown that the optical disparities of these A'-D-pi-A architectures are a direct consequence of comparative A' strength. Single-crystal X-ray analyses provided justification for role of intermolecular interactions in aggregate morphology. Electrochemical and theoretical studies affirmed the effect of the A' strength on the overall properties of the A'-D-pi-A system. PMID- 26615815 TI - Optimization of crude oil degradation by Dietzia cinnamea KA1, capable of biosurfactant production. AB - The aim of this study was isolation and characterization of a crude oil degrader and biosurfactant-producing bacterium, along with optimization of conditions for crude oil degradation. Among 11 isolates, 5 were able to emulsify crude oil in Minimal Salt Medium (MSM) among which one isolate, named KA1, showed the highest potency for growth rate and biodegradation. The isolate was identified as Dietzia cinnamea KA1 using morphological and biochemical characteristics and 16S rRNA gene sequencing. The optimal conditions were 510 mM NaCl, pH 9.0, 35 degrees C, and minimal requirement of 46.5 mM NH4 Cl and 2.10 mM NaH2 PO4 . Gravimetric test and Gas chromatography-Mass spectroscopy technique (GC-MS) showed that Dietzia cinnamea KA1 was able to utilize and degrade 95.7% of the crude oil after 5 days, under the optimal conditions. The isolate was able to grow and produce biosurfactant when cultured in MSM supplemented with crude oil, glycerol or whey as the sole carbon sources, but bacterial growth was occurred using molasses with no biosurfactant production. This is the first report of biosurfactant production by D. cinnamea using crude oil, glycerol and whey and the first study to report a species of Dietzia degrading a wide range of hydrocarbons in a short time. PMID- 26615816 TI - In situ fabrication of high-performance Ni-GDC-nanocube core-shell anode for low temperature solid-oxide fuel cells. AB - A core-shell anode consisting of nickel-gadolinium-doped-ceria (Ni-GDC) nanocubes was directly fabricated by a chemical process in a solution containing a nickel source and GDC nanocubes covered with highly reactive {001} facets. The cermet anode effectively generated a Ni metal framework even at 500 degrees C with the growth of the Ni spheres. Anode fabrication at such a low temperature without any sintering could insert a finely nanostructured layer close to the interface between the electrolyte and the anode. The maximum power density of the attractive anode was 97 mW cm(-2), which is higher than that of a conventional NiO-GDC anode prepared by an aerosol process at 55 mW cm(-2) and 600 degrees C, followed by sintering at 1300 degrees C. Furthermore, the macro- and microstructure of the Ni-GDC-nanocube anode were preserved before and after the power-generation test at 700 degrees C. Especially, the reactive {001} facets were stabled even after generation test, which served to reduce the activation energy for fuel oxidation successfully. PMID- 26615817 TI - Pathological study of chronic pulmonary toxicity induced by intratracheally instilled Asian sand dust (Kosa): possible association of fibrosis with the development of granulomatous lesions. AB - INTRODUCTION: Exposure to Asian sand dust (ASD) is associated with enhanced pulmonary morbidity and mortality, and the reporting of such cases has rapidly increased in East Asia since 2000. The purpose of the study was to assess chronic lung toxicity induced by ASD. MATERIAL AND METHODS: A total of 174 ICR mice were randomly divided into 5 control and 17 exposure groups. Suspensions of low dose (0.2, 0.4 mg) and high dose (3.0 mg) of ASD particles in saline were intratracheally instilled into ICR mice, followed by sacrifice at 24 hours, 1 week, and 1, 2, 3 and 4 months after instillation. Paraffin sections of lung tissues were stained with hematoxylin and eosin and by immunohistochemistry to detect alpha-smooth muscle actin, collagen III, matrix metalloproteinase-9 (MMP 9), tissue inhibitor of metalloproteinases-1 (TIMP-1), CD3, CD20, immunoglobulin G, interleukin-1beta and inducible nitric oxide synthase. RESULTS: A lung histological examination revealed similar patterns in the lesions of the groups treated with high (3.0 mg) or low dose (0.4 mg) of ASD. Acute inflammation was observed 24 h after treatment and subsided after 1 week; persistent granulomatous changes were observed at 2 months, focal lymphocytic infiltration at 3 months, and granuloma formation at 4 months. An increase in the size of granulomatous lesions was observed over time and was accompanied by collagen deposition in the lesions. The cytoplasm of macrophages in inflammatory lesions showed positive immunolabeling for MMP-9 at 24 h, 1 and 2 months after instillation of 3.0 mg of ASD. Positive immunolabeling for TIMP-1 was demonstrated in the cytoplasm of macrophages at 2 and 4 months after instillation of 3.0 mg of ASD. These findings suggest association between the expression of MMP-9 and TIMP-1 with the development of lung granulomatous lesions. CONCLUSIONS: These findings suggest that collagen deposition resulting from the altered regulation of extracellular matrix is associated with granuloma formation in the lungs of mice treated with ASD. PMID- 26615819 TI - Renal anomalies in patients with turner syndrome: Is scintigraphy superior to ultrasound? AB - Renal anomalies are present in up to 30% of patients with Turner syndrome (TS). Renal ultrasound (U/S) detects anatomical renal anomalies only while renal scintigraphy detects anomalies, detects early renal malfunction, and estimates glomerular filtration rate (GFR). Thus, we aimed to assess frequency of renal abnormalities detected by scintigraphy in comparison to renal U/S in TS patients. Ninety TS patients were subjected to auxological assessment, measurement of serum creatinine; and renal U/S and scintigraphy. Renal U/S detected renal anomalies in 22.22% of patients versus 17.78 % detected by scintigraphy (P = 0.035). Scintigraphy detected renal functional abnormalities in 44.44% of patients in the form of subnormal total GFR, abnormal renogram curve pattern, improper tracer handling and perfusion; and difference in split renal function >10% between both kidneys. Patients with a 45,X karyotype had more renal functional abnormalities (56%) than those with mosaic karyotype (33.33%), P = 0.04. In conclusion, renal scintigraphy is not superior to U/S in detection of renal anomalies but is a reliable method for early detection of renal malfunction in TS patients especially those with 45,X to ensure early management to offer a better quality of life. PMID- 26615818 TI - Mulberry fruit prevents LPS-induced NF-kappaB/pERK/MAPK signals in macrophages and suppresses acute colitis and colorectal tumorigenesis in mice. AB - Here, we investigated the impact of mulberry fruit (MBF) extracts on lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 macrophages, and the therapeutic efficacy of MBF diet in mice with dextran sulfate sodium (DSS)-induced acute colitis and MUC2(-/-) mice with colorectal cancer. In vitro, LPS-induced nitric oxide (NO) production was significantly inhibited by MBF extracts via suppressing the expression of proinflammatory molecules, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-beta) and IL-6. Particularly, a dose-dependent inhibition on LPS-induced inflammatory responses was observed following treatment with MBF dichloromethane extract (MBF-DE), in which linoleic acid and ethyl linolenate were identified as two active compounds. Moreover, we elucidated that MBF-DE attenuated LPS-induced inflammatory responses by blocking activation of both NF-kappaB/p65 and pERK/MAPK pathways. In vivo, DSS-induced acute colitis was significantly ameliorated in MBF fed mice as gauged by weight loss, colon morphology and histological damage. In addition, MBF-fed MUC2(-/-) mice displayed significant decrease in intestinal tumor and inflammation incidence compared to control diet-fed group. Overall, our results demonstrated that MBF suppressed the development of intestinal inflammation and tumorgenesis both in vitro and in vivo, and supports the potential of MBF as a therapeutic functional food for testing in human clinical trials. PMID- 26615820 TI - Lowering N2O emissions from soils using eucalypt biochar: the importance of redox reactions. AB - Agricultural soils are the primary anthropogenic source of atmospheric nitrous oxide (N2O), contributing to global warming and depletion of stratospheric ozone. Biochar addition has shown potential to lower soil N2O emission, with the mechanisms remaining unclear. We incubated eucalypt biochar (550 degrees C)--0, 1 and 5% (w/w) in Ferralsol at 3 water regimes (12, 39 and 54% WFPS)--in a soil column, following gamma irradiation. After N2O was injected at the base of the soil column, in the 0% biochar control 100% of expected injected N2O was released into headspace, declining to 67% in the 5% amendment. In a 100% biochar column at 6% WFPS, only 16% of the expected N2O was observed. X-ray photoelectron spectroscopy identified changes in surface functional groups suggesting interactions between N2O and the biochar surfaces. We have shown increases in -O C = N /pyridine pyrrole/NH3, suggesting reactions between N2O and the carbon (C) matrix upon exposure to N2O. With increasing rates of biochar application, higher pH adjusted redox potentials were observed at the lower water contents. Evidence suggests that biochar has taken part in redox reactions reducing N2O to dinitrogen (N2), in addition to adsorption of N2O. PMID- 26615821 TI - Serving Neuroscience, serving IBRO, serving neuroscientists. PMID- 26615822 TI - The consequences of human actions on risks for infectious diseases: a review. AB - The human population is growing, requiring more space for food production, and needing more animals to feed it. Emerging infectious diseases are increasing, causing losses in both human and animal lives, as well as large costs to society. Many factors are contributing to disease emergence, including climate change, globalization and urbanization, and most of these factors are to some extent caused by humans. Pathogens may be more or less prone to emergence in themselves, and rapidly mutating viruses are more common among the emerging pathogens. The climate-sensitive vector-borne diseases are likely to be emerging due to climate changes and environmental changes, such as increased irrigation. This review lists the factors within pathogens that make them prone to emergence, and the modes of transmission that are affected. The anthropogenic changes contributing to disease emergence are described, as well as how they directly and indirectly cause either increased numbers of susceptible or exposed individuals, or cause increased infectivity. Many actions may have multiple direct or indirect effects, and it may be difficult to assess what the consequences may be. In addition, most anthropogenic drivers are related to desired activities, such as logging, irrigation, trade, and travelling, which the society is requiring. It is important to research more about the indirect and direct effects of the different actions to understand both the benefits and the risks. PMID- 26615824 TI - Recent changes in the features of hypertrophic pyloric stenosis. AB - BACKGROUND: Hypertrophic pyloric stenosis (HPS) is a rare cause of non-bilious vomiting in young infants; the condition requires surgical management. Diagnosis is based on clinical, laboratory, and radiological findings. In the present study, we evaluate recent changes in the features of HPS. METHOD: We retrospectively reviewed the demographic, clinical, and laboratory data on 56 HPS patients who underwent pyloromyotomy between 1996 and 2015. Patients were divided into two groups according to date of operation (group 1, 1996-2006; group 2, 2007 2015). RESULTS: Group 1 consisted of 30 patients and group 2, 26. The age at diagnosis was longer in group 2 (43.3 +/- 13.1 days) than group 1 (37.4 +/- 17.7 days). All diagnoses were confirmed on ultrasonography. Pyloromyotomy was performed on all 56 patients (48 boys, 8 girls). Significant between-group differences were evident in terms of age at onset of vomiting; rate of dehydration; development of palpable olive-shaped abdominal mass; serum urea and creatinine; acid-base status; and air distribution pattern on abdominal radiography (all P < 0.05). CONCLUSION: The frequency of olive-shaped abdominal mass evident on physical examination decreased significantly over time, and was lower than published values. Early diagnosis triggers timely support and surgical intervention, and may thus prevent development of the classical clinical and laboratory findings of late-stage HPS. The remarkable recent advances in ultrasonography and techniques allow HPS to be diagnosed earlier than formerly. PMID- 26615823 TI - Making green infrastructure healthier infrastructure. AB - Increasing urban green and blue structure is often pointed out to be critical for sustainable development and climate change adaptation, which has led to the rapid expansion of greening activities in cities throughout the world. This process is likely to have a direct impact on the citizens' quality of life and public health. However, alongside numerous benefits, green and blue infrastructure also has the potential to create unexpected, undesirable, side-effects for health. This paper considers several potential harmful public health effects that might result from increased urban biodiversity, urban bodies of water, and urban tree cover projects. It does so with the intent of improving awareness and motivating preventive measures when designing and initiating such projects. Although biodiversity has been found to be associated with physiological benefits for humans in several studies, efforts to increase the biodiversity of urban environments may also promote the introduction and survival of vector or host organisms for infectious pathogens with resulting spread of a variety of diseases. In addition, more green connectivity in urban areas may potentiate the role of rats and ticks in the spread of infectious diseases. Bodies of water and wetlands play a crucial role in the urban climate adaptation and mitigation process. However, they also provide habitats for mosquitoes and toxic algal blooms. Finally, increasing urban green space may also adversely affect citizens allergic to pollen. Increased awareness of the potential hazards of urban green and blue infrastructure should not be a reason to stop or scale back projects. Instead, incorporating public health awareness and interventions into urban planning at the earliest stages can help insure that green and blue infrastructure achieves full potential for health promotion. PMID- 26615825 TI - Depletion interactions and modulation of DNA-intercalators binding: Opposite behavior of the "neutral" polymer poly(ethylene-glycol). AB - In this work we have investigated the role of high molecular weight poly(ethylene glycol) 8000 (PEG 8000) in modulating the interactions of the DNA molecule with two hydrophobic compounds: Ethidium Bromide (EtBr) and GelRed (GR). Both compounds are DNA intercalators and are used here to mimic the behavior of more complex DNA ligands such as chemotherapeutic drugs and proteins whose domains intercalate DNA. By means of single-molecule stretching experiments, we have been able to show that PEG 8000 strongly shifts the binding equilibrium between the intercalators and the DNA even at very low concentrations (1% in mass). Additionally, microcalorimetry experiments were performed to estimate the strength of the interaction between PEG and the DNA ligands. Our results suggest that PEG, depending on the system under study, may act as an "inert polymer" with no enthalpic contribution in some processes but, on the other hand, it may as well be an active (non-neutral) osmolyte in the context of modulating the activity of the reactants and products involved in DNA-ligand interactions. PMID- 26615826 TI - Understanding and confronting snakebite envenoming: The harvest of cooperation. AB - During 45 years, the Instituto Clodomiro Picado (ICP, University of Costa Rica) has developed an ambitious scientific, technological, productive, and social program aimed at providing a better understanding of snakes and their venoms, contributing to the development, production and distribution of antivenoms, improving the prevention and management of snakebite envenomings, and strengthening human resources in science and technology. Among other topics, its research agenda has focused on the local tissue alterations induced by viperid snake venoms, i.e. myonecrosis, hemorrhage, dermonecrosis, extracellular matrix degradation, lymphatic vessel damage, and inflammation. In addition, the preclinical efficacy of antivenoms has been thoroughly investigated, together with the technological development of novel antivenoms. ICP's project has been based on a philosophical frame characterized by: (a) An integrated approach for confronting the problem of snakebites, involving research, production, extension activities, and teaching; (b) a cooperative and team work perspective in the pursuit of scientific, technological, productive, and social goals; (c) a search for excellence and continuous improvement in the quality of its activities; and (d) a vision of solidarity and compassion, based on the realization that snakebite envenomings mostly affect impoverished vulnerable populations in the rural settings of developing countries. A key aspect in this program has been the consolidation of international partnerships with groups of all continents, within a frame of academic and social cooperation, some of which are described in this review. PMID- 26615827 TI - Systematic detection of BMAA (beta-N-methylamino-l-alanine) and DAB (2,4 diaminobutyric acid) in mollusks collected in shellfish production areas along the French coasts. AB - The neurotoxin beta-N-methylamino-l-alanine (BMAA) is naturally present in some microalgal species in the marine environment. The accumulation of BMAA has widely been observed in filter-feeding bivalves that are known to consume primary producers constituting the base of complex aquatic food webs. This study was performed to assess the occurrence of BMAA and isomers in mollusks collected from nine representative shellfish production areas located on the three French coasts (Channel, Atlantic and Mediterranean sites). The use of a highly selective and sensitive HILIC-MS/MS method, with D5DAB as internal standard, revealed the systematic detection of BMAA and DAB, in concentrations ranging from 0.20 to 6.7 MUg g(-1) dry weight of digestive gland tissues of mollusks. While we detected BMAA in four strains of diatoms in a previous study, here BMAA was only detected in one diatom species previously not investigated out of the 23 microalgal species examined (belonging to seven classes). The concentrations of BMAA and DAB in mussels and oysters were similar at different sampling locations and despite the high diversity of phytoplankton populations that mollusks feed on at these locations. Only small variations of BMAA and DAB levels were observed and these were not correlated to any of the phytoplankton species reported. Therefore, extensive research should be performed on both origin and metabolism of BMAA in shellfish. The levels observed in this study are similar to those found in other studies in France or elsewhere. A previous study had related such levels to a cluster of Amyotrophic Lateral Sclerosis in the South of France; hence the widespread occurrence of BMAA in shellfish from all coasts in France found in this study suggests the need for further epidemiological and toxicological studies to establish the levels that are relevant for a link between the consumption of BMAA-containing foodstuffs and neurodegenerative diseases. PMID- 26615828 TI - Bufadienolides from parotoid gland secretions of Cuban toad Peltophryne fustiger (Bufonidae): Inhibition of human kidney Na(+)/K(+)-ATPase activity. AB - Parotoid gland secretions of toad species are a vast reservoir of bioactive molecules with a wide range of biological properties. Herein, for the first time, it is described the isolation by preparative reversed-phase HPLC and the structure elucidation by NMR spectroscopy and/or mass spectrometry of nine major bufadienolides from parotoid gland secretions of the Cuban endemic toad Peltophryne fustiger: psi-bufarenogin, gamabufotalin, bufarenogin, arenobufagin, 3-(N-suberoylargininyl) marinobufagin, bufotalinin, telocinobufagin, marinobufagin and bufalin. In addition, the secretion was analyzed by UPLC-MS/MS which also allowed the identification of azelayl arginine. The effect of arenobufagin, bufalin and psi-bufarenogin on Na(+)/K(+)-ATPase activity in a human kidney preparation was evaluated. These bufadienolides fully inhibited the Na(+)/K(+)-ATPase in a concentration-dependent manner, although arenobufagin (IC50 = 28.3 nM) and bufalin (IC50 = 28.7 nM) were 100 times more potent than psi bufarenogin (IC50 = 3020 nM). These results provided evidence about the importance of the hydroxylation at position C-14 in the bufadienolide skeleton for the inhibitory activity on the Na(+)/K(+)-ATPase. PMID- 26615829 TI - Osteopenia is associated with glycemic levels and blood pressure in Chinese postmenopausal women: a cross-sectional study. AB - The aim of present study was to explore the relationships between osteopenia and dyslipidemia, glycemic levels or blood pressure in postmenopausal Chinese women. A total of 4080 women aged 42-85 years were enrolled in this cross-sectional study, which was nested in an ongoing longitudinal (REACTION) study. Calcaneus quantitative ultrasound (QUS) was performed and QUS T score was calculated to assess bone mineral density. Osteopenia was defined as a T score <=-1.0. The relationship between osteopenia and dyslipidemia, glycemic levels or blood pressure was investigated. The prevalence of osteopenia was significantly lower in subjects with systolic blood pressure (SBP) >=140 mmHg, fasting blood glucose (FBG) >=8.0 mmol/L, postprandial blood glucose (PBG) >=15.0 mmol/L, hemoglobin A1c (HbA1C) 6.5-7.5 %, HbA1C >=7.5 %. These relationships remained significant after controlling for multiple factors. Moreover, significant trend between osteopenia and SBP, FBG, PBG and HbA1C was observed in women. In contrast, no significant associations between osteopenia and diastolic blood pressure (DBP), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) were found, and no significant trend relationship between osteopenia and DBP, TC, TG, HDL-C, LDL-C was found in postmenopausal Chinese women. The present study showed a relationship between SBP, FBG, PBG, HbA1C and osteopenia in postmenopausal Chinese women, while no significant relationship was observed between dyslipidemia, DBP and osteopenia, even after controlling for multiple confounding factors. PMID- 26615830 TI - Effects of the Particulate Matter2.5 (PM2.5) on Lipoprotein Metabolism, Uptake and Degradation, and Embryo Toxicity. AB - Particulate matter2.5 (PM2.5) is notorious for its strong toxic effects on the cardiovascular, skin, nervous, and reproduction systems. However, the molecular mechanism by which PM2.5 aggravates disease progression is poorly understood, especially in a water-soluble state. In the current study, we investigated the putative physiological effects of aqueous PM2.5 solution on lipoprotein metabolism. Collected PM2.5 from Seoul, Korea was dissolved in water, and the water extract (final 3 and 30 ppm) was treated to human serum lipoproteins, macrophages, and dermal cells. PM2.5 extract resulted in degradation and aggregation of high-density lipoprotein (HDL) as well as low-density lipoprotein (LDL); apoA-I in HDL aggregated and apo-B in LDL disappeared. PM2.5 treatment (final 30 ppm) also induced cellular uptake of oxidized LDL (oxLDL) into macrophages, especially in the presence of fructose (final 50 mM). Uptake of oxLDL along with production of reactive oxygen species was accelerated by PM2.5 solution in a dose-dependent manner. Further, PM2.5 solution caused cellular senescence in human dermal fibroblast cells. Microinjection of PM2.5 solution into zebrafish embryos induced severe mortality accompanied by impairment of skeletal development. In conclusion, water extract of PM2.5 induced oxidative stress as a precursor to cardiovascular toxicity, skin cell senescence, and embryonic toxicity via aggregation and proteolytic degradation of serum lipoproteins. PMID- 26615832 TI - Hydrogen-Bonding Network and OH Stretch Vibration of Cellulose: Comparison of Computational Modeling with Polarized IR and SFG Spectra. AB - Hydrogen bonds play critical roles in noncovalent directional interactions determining the crystal structure of cellulose. Although diffraction studies accurately determined the coordinates of carbon and oxygen atoms in crystalline cellulose, the structural information on hydrogen atoms involved in hydrogen bonding is still elusive. This could be complemented by vibrational spectroscopy; but the assignment of the OH stretch peaks has been controversial. In this study, we performed calculations using density functional theory with dispersion corrections (DFT-D2) for the cellulose Ibeta crystal lattices with the experimentally determined carbon and oxygen coordinates. DFT-D2 calculations revealed that the OH stretch vibrations of cellulose are highly coupled and delocalized through intra- and interchain hydrogen bonds involving all OH groups in the crystal. Additionally, molecular dynamics (MD) simulations of a single cellulose microfibril showed that the conformations of OH groups exposed at the microfibril surface are not well-defined. Comparison of the computation results with the experimentally determined IR dichroism of uniaxially aligned cellulose microfibrils and the peak positions of various cellulose crystals allowed unambiguous identification of OH stretch modes observed in the vibrational spectra of cellulose. PMID- 26615831 TI - Direct Regulation of TLR5 Expression by Caveolin-1. AB - Toll-like receptor 5 (TLR5) is a specific receptor for microbial flagellin and is one of the most well-known receptors in the TLR family. We reported previously that TLR5 signaling is well maintained during aging and that caveolin-1 may be involved in TLR5 signaling in aged macrophages through direct interactions. Therefore, it is important to clarify whether caveolin-1/TLR5 interactions affect TLR5 expression during aging. To assess the effect of caveolin-1 on TLR5, we analyzed TLR5 expression in senescent fibroblasts and aged tissues expressing high levels of caveolin-1. As expected, TLR5 mRNA and protein expression was well maintained in senescent fibroblasts and aged tissues, whereas TLR4 mRNA and protein were diminished in those cells and tissues. To determine the mechanism of caveolin-1-dependent TLR5 expression, we examined TLR5 expression in caveolin-1 deficient mice. Interestingly, TLR5 mRNA and protein levels were decreased dramatically in tissues from caveolin-1 knockout mice. Moreover, overexpressed caveolin-1 in vitro enhanced TLR5 mRNA through the MAPK pathway and prolonged TLR5 protein half-life through direct interaction. These results suggest that caveolin-1 may play a crucial role in maintaining of TLR5 by regulating transcription systems and increasing protein half-life. PMID- 26615833 TI - Role of the Electron Spin Polarization in Water Splitting. AB - We show that in an electrochemical cell, in which the photoanode is coated with chiral molecules, the overpotential required for hydrogen production drops remarkably, as compared with cells containing achiral molecules. The hydrogen evolution efficiency is studied comparing seven different organic molecules, three chiral and four achiral. We propose that the spin specificity of electrons transferred through chiral molecules is the origin of a more efficient oxidation process in which oxygen is formed in its triplet ground state. The new observations are consistent with recent theoretical works pointing to the importance of spin alignment in the water-splitting process. PMID- 26615834 TI - Effect of Sb Segregation on Conductance and Catalytic Activity at Pt/Sb-Doped SnO2 Interface: A Synergetic Computational and Experimental Study. AB - Antimony-doped tin dioxide (ATO) is considered a promising support material for Pt-based fuel cell cathodes, displaying enhanced stability over carbon-based supports. In this work, the effect of Sb segregation on the conductance and catalytic activity at Pt/ATO interface was investigated through a combined computational and experimental study. It was found that Sb-dopant atoms prefer to segregate toward the ATO/Pt interface. The deposited Pt catalysts, interestingly, not only promote Sb segregation, but also suppress the occurrence of Sb(3+) species, a charge carrier neutralizer at the interface. The conductivity of ATO was found to increase, to a magnitude close to that of activated carbon, with an increment of Sb concentration before reaching a saturation point around 10%, and then decrease, indicating that Sb enrichment at the ATO surface may not always favor an increment of the electric current. In addition, the calculation results show that the presence of Sb dopants in ATO has little effect on the catalytic activity of deposited three-layer Pt toward the oxygen reduction reaction, although subsequent alloying of Pt and Sb could lower the corresponding catalytic activity. These findings help to support future applications of ATO/Pt-based materials as possible cathodes for proton exchange membrane fuel cell applications with enhanced durability under practical applications. PMID- 26615835 TI - Synthesis and Characterization of Palladium(II) Complexes of meso-Substituted [14]Tribenzotriphyrin(2.1.1). AB - Metalation of 6,13,20,21-tetrakis-aryl-22H-[14]tribenzotriphyrin(2.1.1) (TriPs) with PdCl2 provides Pd(II)-TriP complexes in 45-56% yields. The complexes were characterized by mass spectrometry, and UV-visible absorption, magnetic circular dichroism, and (1)H NMR spectroscopy. A single crystal X-ray analysis reveals that the Pd(II)-TriPs adopts a deeply saddled conformation. The palladium(II) ion is coordinated by two pyrrole nitrogen atoms and two chloride ions to form the square-planar coordination environment. The redox properties of the Pd(II)-TriPs were studied by cyclic voltammetry. Each compound undergoes one irreversible and two reversible one-electron reductions. There is a marked red-shift of the main spectral bands, relative to those of the free-base TriP ligand, due to a marked relative stabilization of the LUMO upon coordination by PdCl2. PMID- 26615836 TI - A Chromogenic Assay Suitable for High-Throughput Determination of Limit Dextrinase Activity in Barley Malt Extracts. AB - Twenty-four malt samples were assayed for limit dextrinase activity using a chromogenic assay developed recently in our group. The assay utilizes a small soluble chromogenic substrate which is hydrolyzed selectively by limit dextrinase in a coupled assay to release the chromophore 2-chloro-4-nitrophenol. The release of the chromophore, corresponding to the activity of limit dextrinase, can be followed by measuring the UV absorption at 405 nm. The 24 malt samples represented a wide variation of limit dextrinase activities, and these activities could be clearly differentiated by the assay. The results obtained were comparable with the results obtained from a commercially available assay, Limit Dextrizyme from Megazyme International Ireland. Furthermore, the improved assay uses a soluble substrate. That makes it well suited for high-throughput screening as it can be handled in a 96-well plate format. PMID- 26615837 TI - Integrated Photonic Nanofences: Combining Subwavelength Waveguides with an Enhanced Evanescent Field for Sensing Applications. AB - Photonic nanofences consisting of high aspect ratio polymeric optical subwavelength waveguides have been developed for their application into photonic sensing devices. They are up to millimeter long arrays of 250 nm wide and 6 MUm high ridges produced by an advanced lithography process on a silicon substrate enabling their straightforward integration into complex photonic circuits. Both simulations and experimental results show that the overlap of the evanescent fields propagating from each photonic nanofence allows for the formation of an effective waveguide that confines the overall evanescent field within its limits. This permits a high interaction with the surrounding medium which can be larger than 90% of the total guided light intensity (approximately 20000 times larger than the evanescent field of a standard waveguide with equivalent dimensions). In this work, we not only investigate the photonic properties of these structures but also demonstrate their successful integration into a photonic sensor. An absorbance-based sensor for the determination of lead in water samples is therefore achieved by the combination of the photonic nanofences with an ion sensitive optical membrane. The experimental results for lead detection in water show a sensitivity of 0.102 AU/decade, and a linear range between 10(-6) M and 10(-2) M Pb(II). A detection limit as low as 7.3 nM has been calculated according to IUPAC for a signal-to-noise ratio of 3. PMID- 26615838 TI - Hydrogen Bonding Cooperativity in polyQ beta-Sheets from First Principle Calculations. AB - Polyglutamine beta-sheet aggregates are associated with the derangement of Huntington's disease. The effect of cooperativity of the H-bond network formed by both backbone and side chain groups is expected to be important for the structure and energetics of the aggregates. So far, no direct description and/or quantification of the effect is yet available. By performing DFT and hybrid DFT/MM simulations of polyglutamine beta-sheet structures in vacuo and in aqueous solution, we observe that the cooperativity of glutamine side chains affects both the directions perpendicular and parallel to the backbone. This behavior is not usually observed in beta sheets and may provide significant extra-stabilization together with explaining some of the unique properties of polyglutamine aggregation. PMID- 26615840 TI - Molecular Dynamics with Multiple Time Scales: How to Avoid Pitfalls. AB - Multiple time scale methodologies have gained widespread use in molecular dynamics simulations and are implemented in a variety of ways across numerous packages. However, performance of the algorithms depends upon the details of the implementation. This is particularly important in the way in which the nonbonded interactions are partitioned. In this work, we show why some previous implementations give rise to energy drifts, and how this can be corrected. We also provide a recipe for using multiple time step methods to generate stable trajectories in large scale biomolecular simulations, where long trajectories are needed. PMID- 26615839 TI - Theoretical Investigation of Solvent Effects on Glycosylation Reactions: Stereoselectivity Controlled by Preferential Conformations of the Intermediate Oxacarbenium-Counterion Complex. AB - The mechanism of solvent effects on the stereoselectivity of glycosylation reactions is investigated using quantum-mechanical (QM) calculations and molecular dynamics (MD) simulations, considering a methyl-protected glucopyranoside triflate as a glycosyl donor equivalent and the solvents acetonitrile, ether, dioxane, or toluene, as well as gas-phase conditions (vacuum). The QM calculations on oxacarbenium-solvent complexes do not provide support to the usual solvent-coordination hypothesis, suggesting that an experimentally observed beta-selectivity (alpha-selectivity) is caused by the preferential coordination of a solvent molecule to the reactive cation on the alpha-side (beta-side) of the anomeric carbon. Instead, explicit-solvent MD simulations of the oxacarbenium-counterion (triflate ion) complex (along with corresponding QM calculations) are compatible with an alternative mechanism, termed here the conformer and counterion distribution hypothesis. This new hypothesis suggests that the stereoselectivity is dictated by two interrelated conformational properties of the reactive complex, namely, (1) the conformational preferences of the oxacarbenium pyranose ring, modulating the steric crowding and exposure of the anomeric carbon toward the alpha or beta face, and (2) the preferential coordination of the counterion to the oxacarbenium cation on one side of the anomeric carbon, hindering a nucleophilic attack from this side. For example, in acetonitrile, the calculations suggest a dominant B2,5 ring conformation of the cation with preferential coordination of the counterion on the alpha side, both factors leading to the experimentally observed beta selectivity. Conversely, in dioxane, they suggest a dominant (4)H3 ring conformation with preferential counterion coordination on the beta side, both factors leading to the experimentally observed alpha selectivity. PMID- 26615841 TI - Conjugated Molecules Described by a One-Dimensional Dirac Equation. AB - Starting from the Huckel Hamiltonian of conjugated hydrocarbon chains (ethylene, allyl radical, butadiene, pentadienyl radical, hexatriene, etc.), we perform a simple unitary transformation and obtain a Dirac matrix Hamiltonian. Thus already small molecules are described exactly in terms of a discrete Dirac equation, the continuum limit of which yields a one-dimensional Dirac Hamiltonian. Augmenting this Hamiltonian with specially adapted boundary conditions, we find that all the orbitals of the unsaturated hydrocarbon chains are reproduced by the continuous Dirac equation. However, only orbital energies close to the highest occupied molecular orbital/lowest unoccupied molecular orbital energy are accurately predicted by the Dirac equation. Since it is known that a continuous Dirac equation describes the electronic structure of graphene around the Fermi energy, our findings answer the question to what extent this peculiar electronic structure is already developed in small molecules containing a delocalized pi electron system. We illustrate how the electronic structure of small polyenes carries over to a certain class of rectangular graphene sheets and eventually to graphene itself. Thus the peculiar electronic structure of graphene extends to a large degree to the smallest unsaturated molecule (ethylene). PMID- 26615842 TI - Using Nonempirical Semilocal Density Functionals and Empirical Dispersion Corrections to Model Dative Bonding in Substituted Boranes. AB - Dative bonds to substituted boranes represent a challenge for the approximate exchange-correlation functionals typically used in density functional theory (DFT). Accurately modeling these bonds with DFT has usually required highly parametrized functionals, large admixtures of exact exchange, or computationally expensive double hybrids. This work shows that the nonempirical semilocal PBEsol functional, and the nonempirical semilocal PBE and TPSS functionals augmented with empirical interatomic dispersion corrections, accurately treat several representative problems in dative bonding. These methods typically surpass the MPW1K "kinetics" global hybrid previously recommended for dative bonds. This work also provides additional insights into the accuracy of the parametrized M06 functionals and indicates some deficiencies of the B97-D functional relative to PBE-D and TPSS-D. Applications to frustrated Lewis pairs illustrate the potential of these methods. PMID- 26615843 TI - Localized Orbitals for Incremental Evaluations of the Correlation Energy within the Domain-Specific Basis Set Approach. AB - A modified version of the Boys localization method is proposed in order to make the domain-specific basis set approach in the framework of the incremental scheme (J. Chem. Phys. 2008, 129, 244105) generally applicable. The method optimizes the molecular orbitals in one atomic orbital basis set to be similar to localized molecular orbitals in a second atomic orbital basis set under the constraint that the molecular orbitals stay orthonormal. The procedure is tested for RI-MP2 incremental correlation energy expansions for aromatic systems like naphthalene, anthracene, and tetracene as well as for conjugated hydrocarbon chains like C20H2, C20H22, or p-quaterphenyle. For all investigated systems, a rapid convergence of the incrementally expanded correlation energies to the exact RI MP2 energies is found. Furthermore, the systematic improvability of the approach is demonstrated. PMID- 26615844 TI - A Subsystem TDDFT Approach for Solvent Screening Effects on Excitation Energy Transfer Couplings. AB - We present a QM/QM approach for the calculation of solvent screening effects on excitation-energy transfer (EET) couplings. The method employs a subsystem time dependent density-functional theory formalism [J. Chem. Phys. 2007, 126, 134116] and explicitly includes solvent excited states to account for the environmental response. It is investigated how the efficiency of these calculations can be enhanced in order to treat systems with very large solvation shells while fully including the environmental response. In particular, we introduce a criterion to select solvent excited states according to their approximate contribution weight to the environmental polarization. As a model system, we investigate the perylene diimide dimer in a water cluster in comparison to a recent polarizable QM/MM method for EET couplings in the condensed phase [J. Chem. Theory Comput. 2009, 5, 1838]. A good overall agreement in the description of the solvent screening is found. Deviations can be observed for the effect of the closest water molecules, whereas the screening introduced by outer solvation shells is very similar in both methods. Our results can thus be helpful to determine at which distance from a chromophore environmental response effects may safely be approximated by classical models. PMID- 26615845 TI - Systematic Derivation of AMBER Force Field Parameters Applicable to Zinc Containing Systems. AB - Metal ions are indispensable for maintaining the structural stability and catalytic activity of metalloproteins. Molecular modeling studies of such proteins with force fields, however, are often hampered by the "missing parameter" problem. In this study, we have derived bond-stretching and angle bending parameters applicable to zinc-containing systems which are compatible with the AMBER force field. A total of 18 model systems were used to mimic the common coordination configurations observed in the complexes formed by zinc containing metalloproteins. The Hessian matrix of each model system computed at the B3LYP/6-311++G(2d,2p) level was then analyzed by Seminario's method to derive the desired force constants. These parameters were validated extensively in structural optimizations and molecular dynamics simulations of four selected model systems as well as one protein-ligand complex formed by carbonic anhydrase II. The best performance was achieved by a bonded model in combination with the atomic partial charges derived by the restrained electrostatic potential method. After some minor optimizations, this model was also able to reproduce the vibrational frequencies computed by quantum mechanics. This study provides a comprehensive set of force field parameters applicable to a variety of zinc containing molecular systems. In principle, our approach can be applied to other molecular systems with missing force field parameters. PMID- 26615846 TI - Merging Implicit with Explicit Solvent Simulations: Polyethylene Glycol. AB - We constructed an accurate polyether force field for implicit solvent (IS) molecular dynamics (MD) simulations that matches local and global conformations of 1,2-dimethoxy-ethane (DME) and polyethylene glycol (PEG), respectively. To make appropriate force field adjustments for IS models of PEG, we used long-term MD simulation data of 1 MUs in explicit solvent (ES) based on the most recent CHARMM35 ether force field that includes adjustments for PEG in explicit water. In IS models, competition of attractive van der Waals (vdW) interactions between solute-solute and solute-solvent atom pairs is often not considered explicitly. As a consequence, the attractive vdW interactions between solute atom pairs that remain in IS models explicitly can yield equilibrium structures that are too compact. This behavior was observed in the present study comparing MD simulation data of the DME and PEG ES model with corresponding IS models that use generalized Born (GB) electrostatics combined with positive surface energy terms favoring compact structures. To regain balance of attractive vdW interactions for IS models, we considered the IS generalized Born with simple switching (GBSW) model in detail, where we turned off surface energy terms and reduced attractive vdW interactions to 90%, or we used alternatively even slightly negative surface energies. However, to obtain quantitatively the same local and global distributions of PEG conformers as in ES, we needed additional force field adjustments involving torsion potentials and 1-4 and 1-5 atom pair Coulomb interactions. This CHARMM ether force field, specifically optimized for IS simulation conditions, is equally valid for dimeric and polymeric ethylene glycol. To explore the conformational space of PEG with MD simulations, an IS GBSW model requires 2 orders of magnitude less CPU time than the corresponding ES model. About a factor of 5 of this gain in efficiency is due to the lack of solvent viscosity in IS models. PMID- 26615847 TI - Accurate Estimates of Free Energy Changes in Charge Mutations. AB - The ability to determine the effect of charge changes on the free energy is necessary for fundamental studies of the electrostatic contribution to protein binding and stability. Currently, calculations of differences in free energy for charge mutations carried out in systems with periodic boundary conditions must include an approximate self-energy correction that can be on the same order of magnitude as the calculated free energy change. Here, a new method for accurately calculating the free energy change associated with any alchemical mutation, regardless of charge, is presented. In this method, paired mutations of opposite charge exactly cancel the self-energy term because of its quadratic charge dependence. Since the self-energy term implicitly cancels within the method, a correction never needs to be applied, and the statistical uncertainty associated is thereby removed. An implementation procedure is described and applied to the free energy of ionic hydration and a charged amino acid mutation. PMID- 26615848 TI - Magnetic Exchange Couplings with Range-Separated Hybrid Density Functionals. AB - We investigate the effect of Hartree-Fock range-separation on the calculation of magnetic exchange couplings in a set of nine bimetallic transition-metal complexes containing 3d elements (V, Cr, Mn, and Cu). To this end, we have compared magnetic exchange couplings calculated as self-consistent energy differences using two global hybrid functionals, B3LYP (Becke 3-parameter exchange and Lee-Yang-Parr correlation) and PBEh (hybrid Perdew-Burke-Ernzerhof) with the short-range separated HSE (Heyd-Scuseria-Ernzerhof) and the long-range corrected LC-omegaPBE. Our results show that, although there is no clear superiority of any of these functionals when compared with experimental data, the LC-omegaPBE provides a better description of the magnetization on the metallic centers, yielding self-consistent solutions that mimic more closely a Heisenberg like behavior. PMID- 26615849 TI - Evaluations of the Absolute and Relative Free Energies for Antidepressant Binding to the Amino Acid Membrane Transporter LeuT with Free Energy Simulations. AB - The binding of ligands to protein receptors with high affinity and specificity is central to many cellular processes. The quest for the development of computational models capable of accurately evaluating binding affinity remains one of the main goals of modern computational biophysics. In this work, free energy perturbation/molecular dynamics simulations were used to evaluate absolute and relative binding affinity for three different antidepressants to a sodium dependent membrane transporter, LeuT, a bacterial homologue of human serotonin and dopamine transporters. Dysfunction of these membrane transporters in mammals has been implicated in multiple diseases of the nervous system, including bipolar disorder and depression. Furthermore, these proteins are key targets for antidepressants including fluoxetine (aka Prozac) and tricyclic antidepressants known to block transport activity. In addition to being clinically relevant, this system, where multiple crystal structures are readily available, represents an ideal testing ground for methods used to study the molecular mechanisms of ligand binding to membrane proteins. We discuss possible pitfalls and different levels of approximation required to evaluate binding affinity, such as the dependence of the computed affinities on the strength of constraints and the sensitivity of the computed affinities to the particular partial charges derived from restrained electrostatic potential fitting of quantum mechanics electrostatic potential. Finally, we compare the effects of different constraint schemes on the absolute and relative binding affinities obtained from free energy simulations. PMID- 26615851 TI - Implementation and Performance of DFT-D with Respect to Basis Set and Functional for Study of Dispersion Interactions in Nanoscale Aromatic Hydrocarbons. PMID- 26615850 TI - Characterization of the BNNO Radical. AB - The cyclic, trans, and cis BNNO molecules and the two isomerization reactions on their doublet electronic states potential energy surface (PES) are systematically investigated. Ab initio self-consistent field, complete active space self consistent field, coupled cluster with single and double excitations (CCSD), and CCSD including perturbative triple excitations [CCSD(T)] quantum mechanical techniques are employed, in conjunction with Dunning's correlation consistent polarized valence basis sets (cc-pVXZ and aug-cc-pVXZ, where X = D, T, and Q). All stationary points located on the doublet PES lie within 19 kcal mol(-1) of the global minimum cyclic isomer at the aug-cc-pVQZ CCSD(T) level of theory. The cyclic and trans minima are separated by 2.4 kcal mol(-1) with an interconversion barrier (cyclic -> TS2 -> trans) of 18.3 kcal mol(-1); the trans and cis isomers are separated by 10.4 kcal mol(-1) with a barrier (trans -> TS1 -> cis) of 10.4 kcal mol(-1). The dissociation energies BNNO (X (2)A') -> B ((2)Pu) + NNO (X (1)Sigma(+)) for the cyclic, trans, and cis isomers are predicted to be 39.7, 37.3, and 27.0 kcal mol(-1), respectively. The diatomic fragment dissociation energies BNNO (X (2)A') -> BN (X (3)Pi) + NO (X (2)Sigma(+)) for the three isomers are determined to be 50.7, 48.4, and 38.0 kcal mol(-1), respectively. Additionally, fundamental vibrational frequencies are computed for the cyclic and trans isomers through application of second-order vibrational perturbation theory (VPT2) at the cc-pCVTZ CCSD(T) level of theory. Comparison of the resulting vibrational frequencies and their isotopic shifts with those determined experimentally by Wang and Zhou yields the surprising result that the B ((2)Pu) + NNO (X (1)Sigma(+)) reaction leads to formation of the trans isomer. The latter structure is not the global minimum, rather the second lowest lying isomer. This apparent disparity is rationalized by detailed examination of the PES describing this reaction. PMID- 26615852 TI - An overview of prodrug technology and its application for developing abuse deterrent opioids. AB - The Centers for Disease Control and Prevention has classified prescription drug abuse and overdose deaths as an epidemic. Prescription drug overdose is now the leading cause of injury death, with rates that have more than doubled since 1999. This crisis has developed concurrently with the increased prescribing and availability analgesic drugs, especially opioids, resulting from an effort on the part of clinicians to address a critical need for improved pain assessment and treatment. Clinicians have recognized that oftentimes, opioid analgesics are one of the few remaining options for patients who suffer with severe pain. A 2015 fact sheet issued by the Office of National Drug Policy stated: "While we must ensure better access to prescription medications to alleviate suffering, it is also vital that we do all we can to reduce the diversion and abuse of pharmaceuticals." The US Food and Drug Administration has issued guidance that encourages the research and development of abuse-deterrent formulation of opioids which have the potential to curtail abuse. Included among the recommended formulations for development of abuse-deterrent opioids are prodrugs. Prodrugs are chemically modified versions of pharmacological agents that must undergo a biochemical conversion following administration, often by enzymatic cleavage, to free the active drug. Prodrugs may be inherently abuse-deterrent because they are inactive or significantly less active until conversion to the active drug. This requirement for conversion in the GI tract can modify the pharmacokinetic profile and eliminate or reduce the euphoria when abusers change the route of administration. Abusers often attempt to extract the active drug for injection or insufflation. Prodrugs can be designed to be resistant to crushing or dissolving. In this article, we review the concept of prodrugs and introduce and examine the potential of abuse-deterrent opioid prodrugs. PMID- 26615853 TI - In vitro fermentation of prebiotic carbohydrates by intestinal microbiota in the presence of Lactobacillus amylovorus DSM 16998. AB - The aim of this study was to evaluate the assimilation of the prebiotics fructooligosaccharides (FOS), galactooligosaccharides (GOS), and Konjac glucomannan oligosaccharides (KGMO) by three human (H1, H2 and H3) and pig (P1, P2 and P3) faecal microbiotas in the presence of the potentially probiotic strain Lactobacillus amylovorus DSM 16698, using an in vitro batch fermentation model. Total bacteria and L. amylovorus populations were quantified using qPCR and biochemical features (pH, production of short chain fatty acids (SCFA), lactate, ammonia, and carbohydrate assimilation) were determined. L. amylovorus did not have a competitive advantage under in vitro conditions, reflected by its reduced relative abundance during fermentation despite the carbohydrate sources added. Pig microbiota sustained more stable probiotic counts. Intermittently produced lactate was possibly assimilated by the microbiota and converted to other SCFA as the carbohydrates were assimilated, with H3 probably having a methanogenic metabolism with high lactate and acetate consumption except in the presence of FOS, which assimilation resulted in the highest total SCFA for this volunteer. Addition of FOS also resulted in lower pH and ammonia, which might have been used as nitrogen source by pig microbiota. KGMO needed longer fermentation periods to be completely assimilated by both human and porcine faecal microbiotas. Overall, our results reinforce the notion that care must be taken when generalising the effects claimed for a given probiotic or potentially probiotic strain, including the combination with different prebiotic substrates, since they may vary considerably among individuals, which is important when studying potentially pro- and prebiotic combinations for application as functional foods and feed ingredients. PMID- 26615854 TI - Probiotic effect on calves infected with Salmonella Dublin: haematological parameters and serum biochemical profile. AB - The aim of this study was to evaluate the effect of a probiotic/lactose inoculum on haematological and immunological parameters and renal and hepatic biochemical profiles before and during a Salmonella Dublin DSPV 595T challenge in young calves. Twenty eight calves, divided into a control and probiotic group were used. The probiotic group was supplemented with 100 g lactose/calf/d and 1010 cfu/calf/d of each strain of a probiotic inoculum composed of Lactobacillus casei DSPV318T, Lactobacillus salivarius DSPV315T and Pediococcus acidilactici DSPV006T throughout the experiment. The pathogen was administered on day 11 of the experiment, at an oral dose of 109 cfu/animal (LD50). Aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), urea, red blood cells, haemoglobin, haematocrit, mean cell haemoglobin (MCH), mean corpuscular volume, mean corpuscular haemoglobin concentration (MCHC), white blood cells, lymphocytes, neutrophils, band neutrophils, monocytes, eosinophils, basophils and the neutrophils/lymphocytes ratio were measured on days 1, 10, 20 and 27 of the experiment. In addition, animals were necropsied to evaluate immunoglobulin A (IgA) production in the jejunal mucosa. The most significant differences caused by the administration of the inoculum/lactose were found during the acute phase of Salmonella challenge (9 days after challenge), when a difference between groups in neutrophils/lymphocytes ratio were detected. These results suggest that the probiotic/lactose inoculum administration increases the calf's ability to respond to the disease increasing the systemic immune response specific. No differences were found in haemoglobin, haematocrit, MCH, MCHC, AST, urea, GGT, band neutrophils, eosinophils, monocytes and IgA in the jejunum between the two groups of calves under the experimental conditions of this study. Further studies must be conducted to evaluate different probiotic/pathogens doses and different sampling times, to achieve a greater understanding of the effects of this inoculum on intestinal infections in young calves and of its mechanism of action. PMID- 26615855 TI - Enhancement of bifidobacteria survival by Williopsis saturnus var. saturnus in milk. AB - The viability of three strains of probiotic Bifidobacterium lactis that were inoculated into UHT milk was examined with and without the presence of the yeast, Williopsis saturnus var. saturnus NCYC 22, in polypropylene tubes at 30 degrees C. The B. lactis viable cell count for strains HN019 and BB-12 remained above 6.0 Log cfu/ml, while strain B94 had 5.7 Log cfu/ml after six weeks of incubation in the presence of the co-inoculated yeast. Incubating the bifidus milk without added yeast under anaerobic condition did not improve the survival of B. lactis HN019, indicating that oxygen removal may not be responsible for W. saturnus NCYC 22's viability enhancing property. The addition of yeast supernatant or non viable yeast also did not show any stabilising effects, suggesting that physical contact and/or interaction between viable W. saturnus and B. lactis plays an important role in sustaining the viability of the probiotic. W. saturnus NCYC 22 could increase the survival of B. lactis in bifidus milk under ambient temperature regardless of the initial concentration of yeast cells inoculated due to yeast growth. This study demonstrated the viability enhancing effect of viable W. saturnus NCYC 22 on B. lactis HN019, which could help towards extending the shelf-life of dairy beverages containing probiotic bifidobacteria. PMID- 26615856 TI - Next steps in preventing Ewing sarcoma progression. PMID- 26615857 TI - Significant effect of VEGFA polymorphisms on the clinical outcome of metastatic colorectal cancer patients treated with FOLFIRI-cetuximab. AB - AIM: The efficacy of a cetuximab-based regimen used to treat metastatic colorectal cancer (mCRC) could be influenced by VEGFA polymorphisms. MATERIALS & METHODS: We studied the effects of five polymorphisms in the VEGFA gene ( 2549D/I, -1154G/A, -460T/C, +405G/C and +936C/T) on the outcome of 98 mCRC patients treated with FOLFIRI plus cetuximab. RESULTS: Patients homozygous for the -2549D, -1154G and -460T alleles did exhibit higher response rates to treatment and longer progression-free survival compared with others. In addition, the DGTGC and IGCGC haplotypes were significantly associated with a lower risk of disease progression. CONCLUSION: These findings suggest that VEGFA genetic variations might influence response/resistance of FOLFIRI plus cetuximab treatment in mCRC patients. PMID- 26615865 TI - Antileishmanial diterpenoid alkaloids from Aconitum spicatum (Bruhl) Stapf. AB - The crude extracts of tubers of Aconitum spicatum (Bruhl) Stapf were investigated for in vitro antileishmanial activity against Leishmania major. The dichloromethane extract at pH 2.5 showed antileishmanial activity with IC50 value of 27.10 +/- 0.0 MUg/mL. Chromatographic purification of the dichloromethane extract led to isolation of three C-19 norditerpenoid alkaloids indaconitine (1), chasmaconitine (2) and ludaconitine (3). Compounds 3 and 2 showed antileishmanial activity with IC50 = 36.10 +/- 3.4 and 56.30 +/- 2.1 MUg/mL, respectively. Compound 1 was less effective (IC50 > 100 MUg/mL). The cytotoxicity of compounds 1, 2 and 3 studied against MCF7, HeLa and PC3 cancer cell lines and 3T3 normal fibroblast cell line did not show cytotoxicity at 30 MUM. PMID- 26615866 TI - Anatomical variation of arterial supply to the rabbit stomach. AB - Gastric stasis is common in rabbits, and gastrotomy may be performed to cure this pathological condition. Detailed descriptions of the arterial supply to the stomach are essential for this surgical operation, but published descriptions are limited. Here, we investigated anatomical variations of the arterial supply to the stomach in 43 New Zealand White rabbits by injecting colored latex into arteries. We observed that the left gastric artery that arose as the second branch from the celiac artery provided 1-3 parietal and 1-3 visceral branches to the stomach, with various branching patterns depending on the case. In 34 of 43 cases, the left gastric artery ended upon entering the gastric wall at the lesser curvature, whereas in the remaining cases, the artery continued as the hepatic artery without entering the gastric wall. The right gastric artery that branched off from the gastroduodenal artery also supplied the lesser curvature sinistrally but did not anastomose with the left gastric artery. In 40 cases, the hepatic artery provided 1-4 pyloric branches. In the fundic region, the short gastric arteries arose from the splenic artery and varied in number from 2 to 6. The right and left gastroepiploic arteries anastomosed to give 2-7 branches to the greater curvature. The results showed that many variations occurred in the arteries supplying the rabbit stomach, suggesting that such variations should be considered when performing veterinary surgical treatments in rabbits. PMID- 26615868 TI - Effect of Roux-en-Y gastric bypass-induced weight loss on the transcriptomic profiling of subcutaneous adipose tissue. AB - BACKGROUND: The changes in the transcriptomic profiling of subcutaneous adipose tissue (SAT) when weight loss stabilizes after a Roux-en-Y gastric bypass (RYGB) are still largely unknown. OBJECTIVES: To investigate the changes produced in SAT gene expression of morbidly obese women when their weight loss stabilizes 2 years after RYGB. SETTING: University hospital. METHODS: SAT biopsies of the periumbilical area were taken before and 2 years after RYGB. Gene expression levels were assessed by microarray analysis and significant differences in gene expression were validated by real-time quantitative polymerase chain reaction. The findings were also confirmed in an independent population of morbidly obese women. RESULTS: Microarray analysis revealed that the overexpressed differentially expressed genes have a prominent role in the pathways involved in biosynthetic processes, especially lipid or carboxylic ones (stearoyl-Coenzyme A desaturase-1, fatty acid desaturase-1, fatty acid elongase-6, ATP citrate lyase, fatty acid synthase, lipin-1, monoacylglycerol O-acyltransferase, patatin-like phospholipase domain containing-3, phosphate cytidylyltransferase-2, cholesteryl ester transfer protein, transmembrane 7 superfamily member 2, pyruvate carboxylase, and glycogen synthase 2). Most of the underexpressed differentially expressed genes are related with immune system and inflammation processes (immune responses, response to stress, cell death, regulation of biological quality, immune effector process, the response to endogenous stimulus, and the response to other types of stimulus). CONCLUSION: An improvement of the SAT inflammatory and immune profile and an induction of genes involved in the regulation of lipid metabolism are shown when weight loss stabilizes 2 years after RYGB. Most of the genes shown are clearly linked to obesity and other metabolic disorders. PMID- 26615869 TI - Population genetic structure and migration patterns of Liriomyza sativae in China: moderate subdivision and no Bridgehead effect revealed by microsatellites. AB - While Liriomyza sativae (Diptera: Agromyzidae), an important invasive pest of ornamentals and vegetables has been found in China for the past two decades, few studies have focused on its genetics or route of invasive. In this study, we collected 288 L. sativae individuals across 12 provinces to explore its population genetic structure and migration patterns in China using seven microsatellites. We found relatively low levels of genetic diversity but moderate population genetic structure (0.05 < F ST < 0.15) in L. sativae from China. All populations deviated significantly from the Hardy-Weinberg equilibrium due to heterozygote deficiency. Molecular variance analysis revealed that more than 89% of variation was among samples within populations. A UPGMA dendrogram revealed that SH and GXNN populations formed one cluster separate from the other populations, which is in accordance with STRUCTURE and GENELAND analyses. A Mantel test indicated that genetic distance was not correlated to geographic distance (r = -0.0814, P = 0.7610), coupled with high levels of gene flow (M = 40.1-817.7), suggesting a possible anthropogenic influence on the spread of L. sativae in China and on the effect of hosts. The trend of asymmetrical gene flow was from southern to northern populations in general and did not exhibit a Bridgehead effect during the course of invasion, as can be seen by the low genetic diversity of southern populations. PMID- 26615870 TI - Parameters and pitfalls to consider in the conduct of food additive research, Carrageenan as a case study. AB - This paper provides guidance on the conduct of new in vivo and in vitro studies on high molecular weight food additives, with carrageenan, the widely used food additive, as a case study. It is important to understand the physical/chemical properties and to verify the identity/purity, molecular weight and homogeneity/stability of the additive in the vehicle for oral delivery. The strong binding of CGN to protein in rodent chow or infant formula results in no gastrointestinal tract exposure to free CGN. It is recommended that doses of high Mw non-caloric, non-nutritive additives not exceed 5% by weight of total solid diet to avoid potential nutritional effects. Addition of some high Mw additives at high concentrations to liquid nutritional supplements increases viscosity and may affect palatability, caloric intake and body weight gain. In in vitro studies, the use of well-characterized, relevant cell types and the appropriate composition of the culture media are necessary for proper conduct and interpretation. CGN is bound to media protein and not freely accessible to cells in vitro. Interpretation of new studies on food additives should consider the interaction of food additives with the vehicle components and the appropriateness of the animal or cell model and dose-response. PMID- 26615871 TI - A novel quinazolinone chalcone derivative induces mitochondrial dependent apoptosis and inhibits PI3K/Akt/mTOR signaling pathway in human colon cancer HCT 116 cells. AB - We have synthesized a novel quinazolinone chalcone derivative (QC) and first time reported its in-vitro and in-vivo anticancer potential. It inhibited the cell proliferation of different cancer cell lines like PC-3, Panc-1, Mia-Paca-2, A549, MCF-7 and HCT-116. It induces apoptosis as measured by several biological endpoints such as apoptotic body formation, evident by Hoechst and scanning electron microscopy, enhanced annexinV-FITC binding of the cells, increased sub G0 cell fraction, loss of mitochondrial membrane potential (Deltapsim), reduction of Bcl-2/Bax ratio, activation of caspase-9, caspase-3 and PARP-1 (poly-ADP Ribose polymerase) cleavage in HCT-116 cells. In spite of apoptosis, QC significantly hammers the downstream and upstream signaling cascade of PI3K/Akt/mTOR pathway and cell cycle regulator Skp-2, p21 and p27. Interestingly, QC induces the S and G2/M phase of HCT-116 cells at experimental doses. QC inhibits the tumor growth of Ehrlich ascites carcinoma (EAC), Ehrlich tumor (ET, solid) and sarcoma-180(solid) mice models. Furthermore, it was found to be non toxic as no animal mortality (0/7) occurred during experimental doses. The present study provides an insight of anticancer potential of QC, which may be useful in managing and treating cancer. PMID- 26615872 TI - Molecular identification and characterization of Anaplasma platys and Ehrlichia canis in dogs in Mexico. AB - The tick-borne pathogens Ehrlichia canis and Anaplasma platys are the causative agents of canine monocytic ehrlichiosis (CME) and canine cyclic thrombocytopenia (CCT). Although molecular evidence of E. canis has been shown, phylogenetic analysis of this pathogen has not been performed and A. platys has not been identified in Mexico, where the tick vector Rhipicephalus sanguineus sensu lato (s.l.) is common. The aim of this research was to screen, identify and characterize E. canis and A. platys by PCR and phylogenetic analysis in dogs from La Comarca Lagunera, a region formed by three municipalities, Torreon, Gomez Palacio and Lerdo, in the Northern states of Coahuila and Durango, Mexico. Blood samples and five engorged R. sanguineus s.l. ticks per animal were collected from 43 females and 57 male dogs presented to veterinary clinics or lived in the dog shelter from La Comarca Lagunera. All the sampled dogs were apparently healthy and PCR for Anaplasma 16S rRNA, Ehrlichia 16S rRNA, and E. canis trp36 were performed. PCR products were sequenced and used for phylogenetic analysis. PCR products were successfully amplified in 31% of the samples using primers for Anaplasma 16S rRNA, while 10% and 4% amplified products using primers for Ehrlichia 16S rRNA and E. canis trp36 respectively. Subsequent sequencing and phylogenetic analyses of these products showed that three samples corresponded to A. platys and four to E. canis. Based on the analysis of trp36 we confirmed that the E. canis strains isolated from Mexico belong to a conservative clade of E. canis and are closely related to strains from USA. In conclusion, this is the first molecular identification of A. platys and the first molecular characterization and phylogenetic study of both A. platys and E. canis in dogs in Mexico. PMID- 26615873 TI - Genetic variations of four immunodominant antigens of Babesia gibsoni isolated from dogs in southwest Japan. AB - Babesia gibsoni is a tick-borne apicomplexan parasite of dogs that often causes fever and hemolytic anemia. Previous reports have shown that the apical membrane antigen 1 (BgAMA1), the 50 kDa surface antigen (BgP50), the secreted antigen 1 (BgSA1), and the thrombospondin-related adhesive protein (BgTRAP) are promising diagnostic antigens and vaccine candidates against B. gibsoni. In the present study, we investigated the genetic polymorphisms and natural selection of these four genes of B. gibsoni isolated from dogs in southwest Japan. The prediction B cell epitopes showed high antigenic score in the insert and indel regions of BgSA1 and BgTRAP. Sequence analyses have revealed that BgAMA1 had the highest nucleotide diversity, followed by BgP50, BgSA1 and BgTRAP. Meanwhile, the Tajima's D value test suggested balancing selection for BgAMA1 and BgP50. However, BgSA1 and BgTRAP have purifying selection making them potential vaccine candidate and diagnostic antigens since they are highly conserved. Our findings provide the genetic basis for designing and testing the efficacy of diagnostic antigens as well as vaccine candidates against B. gibsoni. PMID- 26615874 TI - How can we improve teaching of ECG interpretation skills? Findings from a prospective randomised trial. AB - BACKGROUND: There is an ongoing debate on how ECG interpretation should be taught during undergraduate medical training. This study addressed the impact of teaching format, examination consequences and student motivation on skills retention. METHODS: A total of 493 fourth-year medical students participated in a six-group, partially randomised trial. Students received three levels of teaching intensity: self-directed learning (2 groups), lectures (2 groups) or small-group peer-teaching (2 groups). On each level of teaching intensity, end-of-course written examinations (ECG exit exam) were summative in one group and formative in the other. Learning outcome was assessed in a retention test two months later. RESULTS: Retention test scores were predicted by summative assessments (adjusted beta 4.08; 95% CI 1.39-6.78) but not by the type of teaching. Overall performance levels and motivation did not predict performance decrease or skills retention. CONCLUSIONS: Summative assessments increase medium-term retention of ECG interpretation skills, irrespective of instructional format. PMID- 26615875 TI - Deletion of sphingosine kinase 1 ameliorates hepatic steatosis in diet-induced obese mice: Role of PPARgamma. AB - Sphingolipid metabolites have emerged playing important roles in the pathogenesis of nonalcoholic fatty liver disease, whereas the underlying mechanism remains largely unknown. In the present study, we provide both in vitro and in vivo evidence showing a pathogenic role of sphingosine kinase 1 (SphK1) in hepatocellular steatosis. We found that levels of SphK1 expression were significantly increased in steatotic hepatocytes. Enforced overexpression of SphK1 or treatment with sphingosine 1-phosphate (S1P) markedly enhanced hepatic lipid accumulation. In contrast, the siRNA-mediated knockdown of SphK1 or S1P receptors, S1P2 and S1P3, profoundly inhibited lipid accumulation in hepatocytes. Moreover, Sphk1(-/-) mice exhibited a significant amelioration of hepatosteatosis under diet-induced obese (DIO) conditions, compared to wild-type littermates. In addition, DIO-induced up-regulation of PPARgamma and its target genes were significantly reduced by SphK1 deficiency. Furthermore, treatment of hepatocytes with S1P induces a dose-dependent increase in PPARgamma expression at the transcriptional level. Blockage of S1P receptors and the Akt-mTOR signaling profoundly inhibited S1P-induced PPARgamma expression. Notably, down-regulation of PPARgamma by using its siRNA significantly diminished the pro-steatotic effect of SphK1/S1P. Thus, the study demonstrates a new pathway connecting SphK1 and PPARgamma involved in the pathogenesis of hepatocellular steatosis. PMID- 26615876 TI - The added value of SPECT/spiral CT in patients with equivocal bony metastasis from hepatocellular carcinoma. AB - The aim of this study was to evaluate the incremental value provided by single photon emission computed tomography (SPECT)/spiral computed tomography (CT) over SPECT alone for the evaluation of equivocal bone lesions in patients with hepatocellular carcinoma (HCC). PATIENTS, METHODS: This was a retrospective study of 65 patients (61 men and 4 women; mean age, 53.1 +/- 10.1 years; age range, 31 78 years) with HCC confirmed by pathology who underwent planar whole body scintigraphy and SPECT/CT. Each lesion was scored visually using a 5-point scale (0, negative; 1, benign; 2, likely benign; 3, likely bone metastasis; 4, bone metastasis). Lesions in which diagnostic confidence was scored as 3 or 4 were categorized into metastases.The final diagnosis of each lesion was based on pathological confirmation or follow-up by whole body scintigraphy and SPECT/spiral CT conducted two or more times. The diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of SPECT alone and SPECT/CT were computed. RESULTS: The diagnostic accuracy, sensitivity, specificity, PPV, and NPV of SPECT alone were 78.4, 70.9%, 94.9%, 96.8% and 59.7%, respectively. Moreover, for agreement of SPECT alone and the final results, the kappa value was 0.567 (p < 0.001), which was considered to be moderate agreement. The diagnostic accuracy, sensitivity, specificity, PPV, and NPV of SPECT/CT were 99.2%, 100%, 97.4%, 98.9% and 100 %, respectively. Furthermore, for agreement of SPECT/CT and the final results, the kappa value was 0.981 (p < 0.001), which was considered to be nearly perfect agreement. CONCLUSIONS: SPECT/spiral CT is more accurate and valuable than SPECT alone in the differential diagnosis of equivocal bone lesions in patients with HCC. PMID- 26615877 TI - [Schritte auf dem Weg in die Zukunft. Transparent, initiativ und nachhaltig]. PMID- 26615878 TI - Postural challenge affects motor cortical activity in young and old adults. AB - When humans voluntarily activate a muscle, intracortical inhibition decreases. Such a decrease also occurs in the presence of a postural challenge and more so with increasing age. Here, we examined age-related changes in motor cortical activity during postural and non-postural contractions with varying levels of postural challenge. Fourteen young (age 22) and twelve old adults (age 70) performed three conditions: (1) voluntary contraction of the soleus muscle in sitting and (2) leaning forward while standing with and (3) without being supported. Subthreshold transcranial magnetic stimulation was applied to the soleus motor area suppressing ongoing EMG, as an index of motor cortical activity. The area of EMG suppression was ~60% smaller (p<0.05) in unsupported vs. supported leaning and sitting, with no difference between these latter two conditions (p>0.05). Even though in absolute terms young compared with old adults leaned farther (p=0.018), there was no age effect or an age by condition interaction in EMG suppression. Leaning closer to the maximum without support correlated with less EMG suppression (rho=-0.44, p=0.034). We conclude that the critical factor in modulating motor cortical activity was postural challenge and not contraction aim or posture. Age did not affect the motor control strategy as quantified by the modulation of motor cortical activity, but the modulation appeared at a lower task difficulty with increasing age. PMID- 26615881 TI - Impacts of IOD, ENSO and ENSO Modoki on the Australian Winter Wheat Yields in Recent Decades. AB - Impacts of the Indian Ocean Dipole (IOD), two different types of El Nino/Southern Oscillation (ENSO): canonical ENSO and ENSO Modoki, on the year-to-year winter wheat yield variations in Australia have been investigated. It is found that IOD plays a dominant role in the recent three decades; the wheat yield is reduced (increased) by -28.4% (12.8%) in the positive (negative) IOD years. Although the canonical ENSO appears to be responsible for the wheat yield variations, its influences are largely counted by IOD owing to their frequent co-occurrence. In contrast, the ENSO Modoki may have its distinct impacts on the wheat yield variations, but they are much smaller compared to those of IOD. Both the observed April-May and the predicted September-November IOD indices by the SINTEX-F ocean atmosphere coupled model initialized on April 1st just before the sowing season explain ~15% of the observed year-to-year wheat yield variances. The present study may lead to a possible scheme for predicting wheat yield variations in Australia in advance by use of simple climate mode indices. PMID- 26615879 TI - Acetaminophen hepatotoxicity in mice: Effect of age, frailty and exposure type. AB - Acetaminophen is a commonly used analgesic that can cause severe hepatotoxicity in overdose. Despite old age and frailty being associated with extensive and long term utilization of acetaminophen and a high prevalence of adverse drug reactions, there is limited information on the risks of toxicity from acetaminophen in old age and frailty. This study aimed to assess changes in the risk and mechanisms of hepatotoxicity from acute, chronic and sub-acute acetaminophen exposure with old age and frailty in mice. Young and old male C57BL/6 mice were exposed to either acute (300 mg/kg via oral gavage), chronic (100 mg/kg/day in diet for six weeks) or sub-acute (250 mg/kg, t.i.d., for three days) acetaminophen, or saline control. Pre-dosing mice were scored for the mouse clinical frailty index, and after dosing serum and liver tissue were collected for assessment of toxicity and mechanisms. There were no differences with old age or frailty in the degree of hepatotoxicity induced by acute, chronic or subacute acetaminophen exposure as assessed by serum liver enzymes and histology. Age related changes in the acetaminophen toxicity pathways included increased liver GSH concentrations, increased NQO1 activity and an increased pro- and anti inflammatory response to acetaminophen in old age. Frailty-related changes included a negative correlation between frailty index and serum protein, albumin and ALP concentrations for some mouse groups. In conclusion, although there were changes in some pathways that would be expected to influence susceptibility to acetaminophen toxicity, there was no overall increase in acetaminophen hepatotoxicity with old age or frailty in mice. PMID- 26615880 TI - Metallothioneins, longevity and cancer: Comment on "Deficiency of metallothionein 1 and -2 genes shortens the lifespan of the 129/Sv mouse strain". PMID- 26615882 TI - Graphene and graphene oxide for desalination. AB - There is a huge scope for graphene-based materials to be used as membranes for desalination. A very recent study has confirmed that 100% salt rejection can be achieved for commonly used ions by utilizing single layer nonporous graphene. However, the cost effective fabrication procedure for graphene oxide membranes with precise control of pore size can offer a practical solution for filtration if one can achieve 100% percent salt rejection. PMID- 26615884 TI - The first organically templated open-framework metal-sulfites with layered and three-dimensional diamondoid structures. AB - The crystallographic signatures and characterization data of two novel organically templated open-framework zinc-sulfites (NH3CH2CH2NH3)[Zn3(SO3)4], 1, and (CN3H6)2[Zn(SO3)2], 2, are reported for the first time, synthesized under hydrothermal conditions using different amines, namely, ethylenediamine and guanidine, to generate 2D (for 1) and 3D (for 2) assemblies with 4-, 6-, 8- and 12-membered rings. PMID- 26615883 TI - Unsuppressed lipolysis in adipocytes is linked with enhanced gluconeogenesis and altered bile acid physiology in Insr(P1195L/+) mice fed high-fat-diet. AB - High-fat diet (HFD) triggers insulin resistance and diabetes mellitus, but their link remains unclear. Characterization of overt hyperglycemia in insulin receptor mutant (Insr(P1195L/+)) mice exposed to HFD (Insr(P1195L/+)/HFD mice) revealed increased glucose-6-phosphatase (G6pc) expression in liver and increased gluconeogenesis from glycerol. Lipolysis in white adipose tissues (WAT) and lipolysis-induced blood glucose rise were increased in Insr(P1195L/+)/HFD mice, while wild-type WAT transplantation ameliorated the hyperglycemia and the increased G6pc expression. We found that the expressions of genes involved in bile acid (BA) metabolism were altered in Insr(P1195L/+)/HFD liver. Among these, the expression of Cyp7a1, a BA synthesis enzyme, was insulin-dependent and was markedly decreased in Insr(P1195L/+)/HFD liver. Reduced Cyp7a1 expression in Insr(P1195L/+)/HFD liver was rescued by WAT transplantation, and the expression of Cyp7a1 was suppressed by glycerol administration in wild-type liver. These findings suggest that unsuppressed lipolysis in adipocytes elicited by HFD feeding is linked with enhanced gluconeogenesis from glycerol and with alterations in BA physiology in Insr(P1195L/+)/HFD liver. PMID- 26615885 TI - Addressing cytotoxicity of 1,4-biphenyl amide derivatives: Discovery of new potent and selective 17beta-hydroxysteroid dehydrogenase type 2 inhibitors. AB - Four different classes of new 17beta-hydroxysteroid dehydrogenase type 2 (17beta HSD2) inhibitors were synthesized, in order to lower the cytotoxicity exhibited by the lead compound A, via disrupting the linearity and the aromaticity of the biphenyl moiety. Compounds 3, 4, 7a and 8 displayed comparable or better inhibitory activity and selectivity, as well as a lower cytotoxic effect, compared to the reference compound A. The best compound 4 (IC50=160nM, selectivity factor=168, LD50~25MUM) turned out as new lead compound for inhibition of 17beta-HSD2. PMID- 26615886 TI - Synthesis and biological evaluation of a novel artesunate-podophyllotoxin conjugate as anticancer agent. AB - A novel conjugate of artesunate-podophyllotoxin was prepared and evaluated for its cytotoxicity against diverse normal and multidrug resistance human cancer cell lines by CCK-8 assay. The conjugate exhibited good cytotoxicity on all the cell lines with IC50 values of 0.453+/-0.156-3.011+/-0.272MUM and reduced the resistant factor. The conjugate was further found to disrupt the microtubule network and induce G2/M cell cycle arrest in multidrug resistance K562/ADR cells. Meanwhile, Hoechst staining analysis suggested that conjugate induced cell death by apoptosis. Furthermore, conjugate could downregulate the levels of P glycoprotein (P-gp) in P-gp overexpressing K562/ADR cells. PMID- 26615887 TI - Synthesis of the biotinylated anti-HIV compound BMMP and the target identification study. AB - BMMP [2-(benzothiazol-2-ylmethylthio)-4-methylpyrimidine], an inhibitor of HIV-1 replication, was linked to biotin to study the interaction with the presumed target, HIV-1 Pr55(Gag) or CA, by means of surface plasmon resonance. The synthesized Biotin-BMMP inhibited HIV-1 replication to a similar extent as BMMP alone, but did not interact with Pr55(Gag) or CA, suggesting that BMMP exerts its activity by a different mechanism. PMID- 26615888 TI - ent-Abietane-type diterpenoids from the roots of Euphorbia ebracteolata with their inhibitory activities on LPS-induced NO production in RAW 264.7 macrophages. AB - Ten ent-abietane diterpenoids (1-10), including four new (1-4) and six known ones (5-10) were isolated from the roots of Euphorbia ebracteolata. Their structures were determined by 1D, 2D NMR, and HRESIMS. Compounds 2, 4, and 7 exhibited significant inhibitory activities on lipopolysaccharide (LPS)-induced nitric oxide production in RAW 264.7 macrophages with IC50 values of 0.69, 1.97, and 0.88MUM, respectively. A primary structure-activity relationship was also discussed. PMID- 26615889 TI - Modulation of in vivo distribution through chelator: Synthesis and evaluation of a 2-nitroimidazole-dipicolylamine-(99m)Tc(CO)3 complex for detecting tumor hypoxia. AB - Previous studies have clearly demonstrated strong correlation between in vivo distribution and blood clearance of radiopharmaceuticals for the detection of hypoxia. Present study describes an attempt to improve the in vivo distribution of a previously reported 2-nitroimidazole-(99m)Tc(CO)3 complex by tuning its blood clearance pattern through structural modification of the ligand. Herein, a 2-nitroimidazole-dipicolylamine ligand (2-nitroimidazole-DPA) was synthesized in a two-step procedure and radiolabeled with (99m)Tc(CO)3 core. Subsequently, the complex was evaluated in Swiss mice bearing fibrosarcoma tumor. As intended by its design, 2-nitroimidazole-DPA-(99m)Tc(CO)3 complex was more lipophilic than previously reported 2-nitroimidazole-DETA-(99m)Tc(CO)3 complex (DETA diethylenetriamine) and showed slower blood clearance. Consequently it showed higher tumor uptake than 2-nitroimidazole-DETA-(99m)Tc(CO)3 complex. Significantly, despite structural modifications, other parameters such as the tumor to blood ratio and tumor to muscle ratio of the 2-nitroimidazole-DPA (99m)Tc(CO)3 complex remained comparable to that of 2-nitroimidazole-DETA (99m)Tc(CO)3 complex. Present study demonstrates the feasibility of structural modifications for improving in vivo tumor uptake of hypoxia detecting radiopharmaceuticals. This might encourage researchers to improve suboptimal properties of a potential radiopharmaceuticals rather than ignoring it altogether. PMID- 26615890 TI - Total synthesis and cytotoxic activities of longamide B, longamide B methyl ester, hanishin, and their analogues. AB - The marine alkaloids, longamide B (1), longamide B methyl ester (2), hanishin (3), and a series of non-naturally occurring analogues were synthesized in an efficient manner from inexpensive commercially available dl-aspartic acid dimethyl ester. The cytotoxicities of these natural products (1-3) and their analogues (9-15) were evaluated against human lung adenocarcinoma (A549) and human prostate cancer (PC3) cells. This is the first evaluation of the cytotoxicities of these alkaloids in these cancer cell lines and it revealed that analogue 15 had comparable cytotoxic activity to its natural parent compound, (+/ )-hanishin (3). This study provides useful information for further structural modification of these alkaloids in order to develop novel antitumor agents. PMID- 26615891 TI - Industrial arsenic contamination causes catastrophic changes in freshwater ecosystems. AB - Heavy metal pollution is now widely recognized to pose severe health and environmental threats, yet much of what is known concerning its adverse impacts on ecosystem health is derived from short-term ecotoxicological studies. Due to the frequent absence of long-term monitoring data, little is known of the long tem ecological consequences of pollutants such as arsenic. Here, our dated sediment records from two contaminated lakes in China faithfully document a 13.9 and 21.4-fold increase of total arsenic relative to pre-1950 background levels. Concurrently, coherent responses in keystone biota signal pronounced ecosystem changes, with a >10-fold loss in crustacean zooplankton (important herbivores in the food webs of these lake systems) and a >5-fold increase in a highly metal tolerant alga. Such fundamental ecological changes will cascade through the ecosystem, causing potentially catastrophic consequences for ecosystem services in contaminated regions. PMID- 26615892 TI - Socio-economic analysis of the risk management of hexabromocyclododecane (HBCD) in China in the context of the Stockholm Convention. AB - Socio-economic analysis (SEA) plays an important role in decision-making on risk management actions for certain chemicals under Multilateral Environmental Agreements (MEAs) in developing countries. This paper showed the first holistic and quantitative SEA case study on that by developing a country-specific SEA framwork and methodologies and applying the case of HBCD phase-out in China under the Stockholm Convention on Persistent Organic Pollutants (POPs). The study indicates that, under the possible scenarios of 10 years and 5 years , the economic costs of HBCD phase-out in China would be between 9.032 and 19.021 billion RMB. Although the total economic costs seems to be significant, it would only have a marginal impact on the house building industry with a likely cost increase by about 0.070/00-0.140/00. Meanwhile, the HBCD phase-out may render significant environmental and health benefits, including about 23-29 tons of HBCD release prevented to the environment, 1.142-1.469 million tons of potentially HBCD contained hazardous wastes avoided, along with significant reduction from 58% up to almost 100% in local environmental concentrations of HBCD, and about 0.0996-0.128 million workers at risk avoided and at least 3.067-4.033 billion RMB of the health care savings. While the scenario of phasing out HBCD over 10 years would be less costly than the scenario of that over 5 years, the later scenario suggested much greater environmental and health benefits for China. PMID- 26615893 TI - Adaptive immunity increases the pace and predictability of evolutionary change in commensal gut bacteria. AB - Co-evolution between the mammalian immune system and the gut microbiota is believed to have shaped the microbiota's astonishing diversity. Here we test the corollary hypothesis that the adaptive immune system, directly or indirectly, influences the evolution of commensal species. We compare the evolution of Escherichia coli upon colonization of the gut of wild-type and Rag2(-/-) mice, which lack lymphocytes. We show that bacterial adaptation is slower in immune compromised animals, a phenomenon explained by differences in the action of natural selection within each host. Emerging mutations exhibit strong beneficial effects in healthy hosts but substantial antagonistic pleiotropy in immune deficient mice. This feature is due to changes in the composition of the gut microbiota, which differs according to the immune status of the host. Our results indicate that the adaptive immune system influences the tempo and predictability of E. coli adaptation to the mouse gut. PMID- 26615894 TI - Effects of Paroxetine,a CYP2D6 Inhibitor, on the Pharmacokinetic Properties of Hydrocodone After Coadministration With a Single-entity,Once-daily, Extended release HydrocodoneTablet. PMID- 26615895 TI - Contrasting diel hysteresis between soil autotrophic and heterotrophic respiration in a desert ecosystem under different rainfall scenarios. AB - Diel hysteresis occurs often between soil CO2 efflux (R(S)) and temperature, yet, little is known if diel hysteresis occurs in the two components of R(S), i.e., autotrophic respiration (R(A)) and heterotrophic respiration (R(H)), and how diel hysteresis will respond to future rainfall change. We conducted a field experiment in a desert ecosystem in northern China simulating five different scenarios of future rain regimes. Diel variations of soil CO2 efflux and soil temperature were measured on Day 6 and Day 16 following the rain addition treatments each month during the growing season. We found contrasting responses in the diel hysteresis of R(A) and R(H) to soil temperature, with a clockwise hysteresis loop for R(H) but a counter-clockwise hysteresis loop for R(A). Rain addition significantly increased the magnitude of diel hysteresis for both R(H) and R(A) on Day 6, but had no influence on either on Day 16 when soil moisture was much lower. These findings underline the different roles of biological (i.e. plant and microbial activities) and physical-chemical (e.g. heat transport and inorganic CO2 exchange) processes in regulating the diel hysteresis of R(A) and R(H), which should be considered when estimating soil CO2 efflux in desert regions under future rainfall regime. PMID- 26615896 TI - Mitigation of Corrosion on Magnesium Alloy by Predesigned Surface Corrosion. AB - Rapid corrosion of magnesium alloys is undesirable in structural and biomedical applications and a general way to control corrosion is to form a surface barrier layer isolating the bulk materials from the external environment. Herein, based on the insights gained from the anticorrosion behavior of corrosion products, a special way to mitigate aqueous corrosion is described. The concept is based on pre-corrosion by a hydrothermal treatment of Al-enriched Mg alloys in water. A uniform surface composed of an inner compact layer and top Mg-Al layered double hydroxide (LDH) microsheet is produced on a large area using a one-step process and excellent corrosion resistance is achieved in saline solutions. Moreover, inspired by the super-hydrophobic phenomenon in nature such as the lotus leaves effect, the orientation of the top microsheet layer is tailored by adjusting the hydrothermal temperature, time, and pH to produce a water-repellent surface after modification with fluorinated silane. As a result of the trapped air pockets in the microstructure, the super-hydrophobic surface with the Cassie state shows better corrosion resistance in the immersion tests. The results reveal an economical and environmentally friendly means to control and use the pre corrosion products on magnesium alloys. PMID- 26615897 TI - Sulfurized metal borohydrides. AB - The reactions between metal borohydrides and elemental sulfur are investigated in situ during thermal treatment and are found to be highly exothermic (up to 700 J g(-1)). These reactions are exceptionally rapid, occurring below 200 degrees C, also resulting in the sudden release of substantial quantities of hydrogen gas. For NaBH4 this hydrogen release is pure, with no detectable levels of H2S or B2H6. The reaction results in the formation of an array of metal-boron-sulfur compounds. These MBH4-S compounds are interesting for possible uses in high energy applications (fuels or explosives), hydrogen generation, and metal-boron sulfur precursors. PMID- 26615898 TI - The MILLER banding procedure as a treatment alternative for dialysis access steal syndrome: a single institutional experience. AB - OBJECTIVE: To describe a single institutional experience with minimally invasive limited ligation endoluminal-assisted revision (MILLER) for treatment of dialysis access steal syndrome (DASS). MATERIALS AND METHODS: Twenty patients were retrospectively identified that underwent 30 MILLER band procedures for DASS at our institution from March 2010 to December 2014. Technical success was defined by successful creation of MILLER band with preservation of flow for hemodialysis. Clinical success was defined as complete resolution of signs and symptoms with preservation of dialysis access in a 1-month postprocedural period. Primary MILLER band patency, postintervention-assisted primary access patency, and postprocedure secondary access patency are reported. RESULTS: Technical success was achieved in all patients. Clinical success was achieved in 75% of patients after one banding procedure and in 95% of patients after two banding procedures. One patient experienced access thrombosis following the initial banding procedure which was subsequently treated and did not lead to loss of access. MILLER band patency was 83% at 1 month and 77% at 6 months. Postintervention-assisted primary patency was 95%, 93%, and 92% at 3 months, 6 months, and 1 year, respectively. Postintervention secondary patency was 86%, 68%, and 59% at 3 months, 6 months, and 1 year, respectively. CONCLUSIONS: MILLER banding offers a less-invasive alternative to surgical therapy that appears to be safe and permits preservation of dialysis access. PMID- 26615900 TI - Influence of paternal age on ongoing pregnancy rate at eight weeks' gestation in assisted reproduction. AB - A retrospective cohort study was performed with the followings aims: to evaluate the influence of paternal age on best embryo quality available for embryo transfer on the third day; biochemical pregnancy rate; miscarriage rate and ongoing pregnancy rate at 8 weeks' gestational age, after IVF or intracytoplasmic sperm injection (ICSI) treatment, respectively, including treatment with non ejaculated spermatozoa. In total, 7051 first IVF/ICSI cycles in Radboud university medical center, between 1 January 2001 and 1 June 2013 were included in this study. A statistical model was used to analyse the effect of paternal age and maternal age. No statistically significant differences between the paternal age groups were found with respect to the probability of an ongoing pregnancy after the first cycle (35-44 years: odds ratio [OR] = 0.97 [95% confidence interval [CI]: 0.86 to 1.10] and >=45 years: OR = 1.01 [95% CI: 0.82 to 1.26]), respectively, compared with <35 years of age (control). Similar results were found with respect to paternal age and the availability of a top quality embryo for transfer, biochemical pregnancy and miscarriage. However, live birth was not taken into account. In conclusion, paternal age did not affect ongoing pregnancy rates in first IVF/ICSI cycles. PMID- 26615899 TI - What do we know about brain contrast enhancement patterns in neuromyelitis optica? AB - Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system that usually presents with acute myelitis and/or optic neuritis. Recently, some brain magnetic resonance imaging findings have been described in NMO that are important in the differential diagnosis. Pencil-thin, leptomeningeal, and cloud-like enhancement may be specific to NMO. These patterns are usually seen during relapses. Recognizing these lesions and enhancement patterns may expedite the diagnosis and allows early effective treatment. The purpose of this article is to review the latest knowledge and to share our experience with the contrast enhancement patterns of NMO brain lesions. PMID- 26615901 TI - GnRH agonist trigger does not always cause luteolysis: a case report. AB - This study reports an IVF patient with excessive ovarian response, who received gonadotrophin-releasing hormone agonist (GnRHa) triggering. Fourteen oocytes were retrieved, and one embryo transferred 2 days later. Although no further luteal support was given, close follow-up showed consistently high oestradiol and progesterone concentrations, so no exogenous luteal support was given. A clinical pregnancy was achieved without signs or symptoms of ovarian hyperstimulation syndrome. This case report highlights the importance of individual follow-up post agonist trigger. PMID- 26615902 TI - Association between leukaemia inhibitory factor gene polymorphism and pregnancy outcomes after assisted reproduction techniques. AB - Certain gene polymorphisms are associated with implantation failure and pregnancy loss. Studies of leukaemia inhibitory factor (LIF) gene polymorphisms are scarce. The LIF single nucleotide polymorphism (SNP) thymine (T)/guanine (G) (rs929271) was studied in women to determine whether an association existed with pregnancy outcomes after intracytoplasmic sperm injection (ICSI); 411 women who underwent ICSI were recruited. DNA was extracted from the peripheral blood, and the LIF gene SNP T/G (rs929271) was genotyped using real-time polymerase chain reaction. Participants were divided into three groups according to their LIF genotype: T/T (n = 168), T/G (n = 202) and G/G (n = 41). All IVF and ICSI procedures were carried out under the same clinical and laboratory conditions. The ICSI cumulative results (from fresh plus frozen cycles) of each genotype group were analysed. The G/G genotype in women was associated with a higher implantation rate (T/T: 15.9%, T/G: 16.2%, G/G: 27.0%; P < 0.05), ongoing pregnancy rate/patient (T/T: 31.5%, T/G: 36.1%, G/G: 53.7%; P < 0.05) and ongoing pregnancy rate/transfer (T/T: 18.5%, T/G: 20.2%, G/G: 36.7%; P < 0.05). LIF SNP T/G (rs929271) seems to be a susceptibility biomarker capable of predicting implantation efficiency and pregnancy outcomes. PMID- 26615903 TI - The endocrine function of human placenta: an overview. AB - During pregnancy, several tightly coordinated and regulated processes take place to enable proper fetal development and gestational success. The formation and development of the placenta is one of these critical pregnancy events. This organ plays essential roles during gestation, including fetal nourishment, support and protection, gas exchange and production of several hormones and other mediators. Placental hormones are mainly secreted by the syncytiotrophoblast, in a highly and tightly regulated way. These hormones are important for pregnancy establishment and maintenance, exerting autocrine and paracrine effects that regulate decidualization, placental development, angiogenesis, endometrial receptivity, embryo implantation, immunotolerance and fetal development. In addition, because they are released into maternal circulation, the profile of their blood levels throughout pregnancy has been the target of intense research towards finding potential robust and reliable biomarkers to predict and diagnose pregnancy-associated complications. In fact, altered levels of these hormones have been associated with some pathologies, such as chromosomal anomalies or pre eclampsia. This review proposes to revise and update the main pregnancy-related hormones, addressing their major characteristics, molecular targets, function throughout pregnancy, regulators of their expression and their potential clinical interest. PMID- 26615904 TI - Family physicians and HIV infection. AB - OBJECTIVE: We aimed to describe the current and desired involvement of family physicians (FPs) in the treatment of HIV patients (screening practices, potential training and patient follow-up) to reduce the duration and frequency of their hospital treatment. MATERIAL AND METHODS: We conducted a descriptive cross sectional survey between 2011 and 2012 with the support of COREVIH (Regional Coordinating Committee on HIV). We sent a self-assessment questionnaire to all FPs of the Pays de la Loire region to enquire about their HIV screening practices and expectations for the management of HIV patients. RESULTS: A total of 871 FPs completed the questionnaire (response rate: 30.4%). A total of 54.2% said to provide care to HIV patients; the mean number of HIV patients per FP was estimated at 1.4. With regard to HIV screening, 12.2% systematically suggest an HIV serology to their patients and 72.7% always suggest it to pregnant women. About 45.4% of responding FPs said to be willing to manage HIV patients (clinical and biological monitoring, compliance checks and prescription renewal). FPs mainly reported the lack of training and the low number of HIV patients as a barrier to their further involvement in the management of HIV patients. CONCLUSION: The responding FPs provide care to very few HIV patients. They are, however, willing to be more involved in the routine care of these patients. Medical training provided by COREVIH would help improve HIV screening. The management of HIV patients could thus be handed over to willing FPs. PMID- 26615905 TI - Psychosocial factors associated with adherence to non-insulin antidiabetes treatments. AB - AIMS: To discern psychosocial factors of non-insulin antidiabetes drug (NIAD) adherence. METHODS: A cross-sectional study based on the theory of planned behavior (TPB). Adults with type 2 diabetes (T2D) who were members of Diabete Quebec, a provincial association of persons with diabetes, and were prescribed at least one NIAD were invited to complete a web-based questionnaire. We measured variables ascertaining TPB constructs and other factors potentially associated with NIAD adherence (e.g., habit, social support, and mental health). NIAD adherence was assessed using the 8-item Morisky Medication Adherence Scale. Factors were identified using a multivariate logistic regression model. RESULTS: In our study, 901 participants (373 women; 515 retired; mean age: 62.7 years) with T2D for a mean of 10 years, completed the questionnaire. Participants exhibited a high intention to adhere to their NIAD treatment (mean score=5.8/6), positive attitudes toward adherence (mean score=5.5/6), and elevated perceived behavioral control in taking their medication (mean score=5.7/6). Only 405 (45%) participants reported high adherence (score=8/8). Perceived behavioral control, habit, older age, no perceived side effects, a longer period since T2D diagnosis and a lower number of NIAD daily doses were significantly associated with adherence (p<0.05). CONCLUSION: We identified several factors that may be modified for NIAD adherence and thereby provided insight into future adherence enhancing intervention targets. PMID- 26615906 TI - The association between antidepressant use and glycemic control in the Southern Community Cohort Study (SCCS). AB - INTRODUCTION: Among people with diabetes, comorbid depression has been associated with suboptimal health outcomes. However, the independent impact of antidepressant use on glycemic control (A1C) has not been well understood. RESEARCH DESIGN AND METHODS: The Southern Community Cohort Study collected self reported antidepressant use and measured continuous A1C in a sample of racially diverse adults with and without diabetes who visited community health clinics serving low-income families in the southeastern United States (N=2445). Crude and adjusted linear regression models were used to examine the relationships between using specific antidepressant subclasses and continuous A1C. RESULTS: Although use of any single antidepressant subclass was not a significant predictor of A1C level, there was a significant association between using multiple antidepressant subclasses and higher A1C, specifically among individuals with diabetes (standardized effect size=.12, p=.04). CONCLUSION: Among adults with diabetes, the use of multiple antidepressant subclasses may be a risk factor for suboptimal glycemic control. Prospective studies are needed to confirm the direction of this observation, as the present study was limited by a cross-sectional design and small sample size. PMID- 26615907 TI - Ventral pallidal coding of a learned taste aversion. AB - The hedonic value of a sweet food reward, or how much a taste is 'liked', has been suggested to be encoded by neuronal firing in the posterior ventral pallidum (VP). Hedonic impact can be altered by psychological manipulations, such as taste aversion conditioning, which can make an initially pleasant sweet taste become perceived as disgusting. Pairing nausea-inducing LiCl injection as a Pavlovian unconditioned stimulus (UCS) with a novel taste that is normally palatable as the predictive conditioned stimulus (CS+) suffices to induce a learned taste aversion that changes orofacial 'liking' responses to that sweet taste (e.g., lateral tongue protrusions) to 'disgust' reactions (e.g., gapes) in rats. We used two different sweet tastes of similar initial palatability (a sucrose solution and a polycose/saccharin solution, CS +/- assignment was counterbalanced across groups) to produce a discriminative conditioned aversion. Only one of those tastes (arbitrarily assigned and designated as CS+) was associatively paired with LiCl injections as UCS to form a conditioned aversion. The other taste (CS-) was paired with mere vehicle injections to remain relatively palatable as a control sweet taste. We recorded the neural activity in VP in response to each taste, before and after aversion training. We found that the safe and positively hedonic taste always elicited excitatory increases in firing rate of VP neurons. By contrast, aversion learning reversed the VP response to the 'disgusting' CS+ taste from initial excitation into a conditioned decrease in neuronal firing rate after training. Such neuronal coding of hedonic impact by VP circuitry may contribute both to normal pleasure and disgust, and disruptions of VP coding could result in affective disorders, addictions and eating disorders. PMID- 26615908 TI - Semisynthetic UbH2A reveals different activities of deubiquitinases and inhibitory effects of H2A K119 ubiquitination on H3K36 methylation in mononucleosomes. AB - Using a genetically incorporated azidonorleucine for ubiquitin installation, we prepared multi-milligram quantities of H2AK119ub (ubH2A). With a native isopeptide linkage, the synthetic ubH2A was used to study the activity of deubiquitinases and crosstalk between H2A ubiquitination and H3K36 methylation in the context of chemically defined mononucleosomes. PMID- 26615909 TI - Integrated care delivery and health care seeking by chronically-ill patients - a case-control study of rural Henan province, China. AB - OBJECTIVE: This study examined the impact of an Integrated Care Delivery intervention on health care seeking and outcomes for chronically-ill patients in Henan province, China. METHODS: A case-control study was carried out in six health care organizations from two counties in Henan province, China. 371 patients aged 50 years or over with hypertension or diabetes who visited either community health centers or hospitals in the Intervention or Control Counties were systematically selected and surveyed on health care seeking behavior, quality of care, and pathway of care for their major chronic condition. Bivariate analyses were performed to compare quality and value of care indicators between patients from the Intervention and Control Counties. Multivariate analyses were used to confirm these associations after controlling for patients' demographic and health characteristics. RESULTS: Patients in both the Intervention and Control Counties chose their current health care providers primarily out of concern for quality of care (provider expertise and adequate medical equipment) and patient-centered care. Compared with the patients from the Control County, those from the Intervention County performed significantly better on almost all the quality and value of care indicators even after controlling for patients' demographic and health characteristics. Significant associations between types of health care facilities and quality as well as value of care were also observed. CONCLUSION: The study showed that the Integrated Care Delivery Model was critical in guiding patients' health care seeking behavior and associated with improved accessibility, continuity, coordination and comprehensiveness of care, as well as reducing health inequities and mitigating disparities for older patients with chronic conditions. PMID- 26615911 TI - Confirmation of co-denitrification in grazed grassland. AB - Pasture-based livestock systems are often associated with losses of reactive forms of nitrogen (N) to the environment. Research has focused on losses to air and water due to the health, economic and environmental impacts of reactive N. Di nitrogen (N2) emissions are still poorly characterized, both in terms of the processes involved and their magnitude, due to financial and methodological constraints. Relatively few studies have focused on quantifying N2 losses in vivo and fewer still have examined the relative contribution of the different N2 emission processes, particularly in grazed pastures. We used a combination of a high (15)N isotopic enrichment of applied N with a high precision of determination of (15)N isotopic enrichment by isotope-ratio mass spectrometry to measure N2 emissions in the field. We report that 55.8 g N m(-2) (95%, CI 38 to 77 g m(-2)) was emitted as N2 by the process of co-denitrification in pastoral soils over 123 days following urine deposition (100 g N m(-2)), compared to only 1.1 g N m(-2) (0.4 to 2.8 g m(-2)) from denitrification. This study provides strong evidence for co-denitrification as a major N2 production pathway, which has significant implications for understanding the N budgets of pastoral ecosystems. PMID- 26615910 TI - A distributed cell division counter reveals growth dynamics in the gut microbiota. AB - Microbial population growth is typically measured when cells can be directly observed, or when death is rare. However, neither of these conditions hold for the mammalian gut microbiota, and, therefore, standard approaches cannot accurately measure the growth dynamics of this community. Here we introduce a new method (distributed cell division counting, DCDC) that uses the accurate segregation at cell division of genetically encoded fluorescent particles to measure microbial growth rates. Using DCDC, we can measure the growth rate of Escherichia coli for >10 consecutive generations. We demonstrate experimentally and theoretically that DCDC is robust to error across a wide range of temperatures and conditions, including in the mammalian gut. Furthermore, our experimental observations inform a mathematical model of the population dynamics of the gut microbiota. DCDC can enable the study of microbial growth during infection, gut dysbiosis, antibiotic therapy or other situations relevant to human health. PMID- 26615912 TI - Vitamin D deficiency in non-alcoholic fatty liver disease: The chicken or the egg? AB - BACKGROUND & AIMS: Serum vitamin D concentration is reduced in patients with non alcoholic fatty liver disease (NAFLD). Although the mechanism of vitamin D deficiency in liver disease is not fully understood, a few reports have suggested the beneficial effects of vitamin D supplements. The present study investigated changes in serum 25-hydroxy vitamin D level and clinical parameters after total calorie restriction with vitamin D intake reduction in NAFLD patients. METHODS: Newly diagnosed NAFLD patients with elevated aminotransferase levels were chosen for a calorie restriction and weight-reduction program. A total of 82 patients received nutritional education from nutritionists every 2 weeks for 2 months. Serum 25-hydroxy vitamin D level, amount of vitamin D intake, and physical activity were thoroughly investigated. RESULTS: The mean serum 25-hydroxy vitamin D concentration was 13.0 ng/ml. Twenty-nine patients (35.4%) had severe vitamin D deficiency. Patients with a 25-hydroxy vitamin D concentration <10 ng/ml had an increased risk of abdominal obesity (72.4% vs. 47.2%, P = 0.023) and a higher prevalence of metabolic syndrome (69% vs. 42.2%, P = 0.015) compared with patients with 25-hydroxy vitamin D levels >10 ng/ml. Although total energy and vitamin D intake were reduced during the program, serum 25-hydroxy vitamin D levels increased in patients with NAFLD (P < 0.001). Liver enzymes and metabolic parameters also improved, even as vitamin D intake decreased. Serum vitamin D concentration increased with body weight and intrahepatic fat reduction, independent of decreases in vitamin D intake. CONCLUSIONS: Weight loss per increased serum vitamin D level without vitamin D supplementation and improved metabolic parameters in NAFLD. PMID- 26615913 TI - Meta-analysis is not enough: The critical role of pathophysiology in determining optimal care in clinical nutrition. AB - Evidence based medicine has preferably been based on prospective randomized controlled trials (PRCT's) and subsequent meta-analyses in many fields including nutrition and metabolism. These meta-analyses often yield convincing, contradictory or no proof of effectiveness. Consequently recommendations and guidelines of varying validity and quality have been published, often failing to convince the medical, insurance and government worlds to support nutritional care. Causes for lack of adequate proof of effectiveness are manifold. Many studies and meta-analyses lacked pathophysiological depth in design and interpretation. Study populations were not homogenous and endpoints not always clearly defined. Patients were included not at nutritional risk, unlikely to benefit from nutritional intervention. Others received nutrients in excess of requirements or tolerance due to organ failure. To include all available studies in a meta-analysis, study quality and homogeneity were only assessed on the basis of formal study design and outcome rather than on patient characteristics. Consequently, some studies showed benefit but included patients suffering harm, other studies were negative but contained patients that benefited. Recommendations did not always emphasize these shortcomings, confusing the medical and nutritional community and creating the impression that nutritional support is not beneficial. Strong reliance on meta-analyses and guidelines shifts the focus of education from studying clinical and nutritional physiology to memorizing guidelines. To prevent or improve malnutrition more physiological knowledge should be acquired to personalize nutritional practices and to more correctly value and evaluate the evidence. This also applies to the design and interpretation of PRCT's and meta-analyses. PMID- 26615914 TI - Genome-wide expression analysis offers new insights into the origin and evolution of Physcomitrella patens stress response. AB - Changes in the environment, such as those caused by climate change, can exert stress on plant growth, diversity and ultimately global food security. Thus, focused efforts to fully understand plant response to stress are urgently needed in order to develop strategies to cope with the effects of climate change. Because Physcomitrella patens holds a key evolutionary position bridging the gap between green algae and higher plants, and because it exhibits a well-developed stress tolerance, it is an excellent model for such exploration. Here, we have used Physcomitrella patens to study genome-wide responses to abiotic stress through transcriptomic analysis by a high-throughput sequencing platform. We report a comprehensive analysis of transcriptome dynamics, defining profiles of elicited gene regulation responses to abiotic stress-associated hormone Abscisic Acid (ABA), cold, drought, and salt treatments. We identified more than 20,000 genes expressed under each aforementioned stress treatments, of which 9,668 display differential expression in response to stress. The comparison of Physcomitrella patens stress regulated genes with unicellular algae, vascular and flowering plants revealed genomic delineation concomitant with the evolutionary movement to land, including a general gene family complexity and loss of genes associated with different functional groups. PMID- 26615916 TI - Ceramides with a pentadecasphingosine chain and short acyls have strong permeabilization effects on skin and model lipid membranes. AB - The composition and organization of stratum corneum lipids play an essential role in skin barrier function. Ceramides represent essential components of this lipid matrix; however, the importance of the individual structural features in ceramides is not fully understood. To probe the structure-permeability relationships in ceramides, we prepared analogs of N-lignoceroylsphingosine with shortened sphingosine (15 and 12 carbons) and acyl chains (2, 4 and 6 carbons) and studied their behavior in skin and in model lipid membranes. Ceramide analogs with pentadecasphingosine (15C) chains were more barrier-perturbing than 12C- and 18C-sphingosine ceramides; the greatest effects were found with 4 to 6C acyls (up to 15 times higher skin permeability compared to an untreated control and up to 79 times higher permeability of model stratum corneum lipid membranes compared to native very long-chain ceramides). Infrared spectroscopy using deuterated lipids and X-ray powder diffraction showed surprisingly similar behavior of the short ceramide membranes in terms of lipid chain order and packing, phase transitions and domain formation. The high- and low-permeability membranes differed in their amide I band shape and lamellar organization. These skin and membrane permeabilization properties of some short ceramides may be explored, for example, for the rational design of permeation enhancers for transdermal drug delivery. PMID- 26615915 TI - Disrupted lymphocyte homeostasis in hepatitis-associated acquired aplastic anemia is associated with short telomeres. AB - Hepatitis-associated aplastic anemia (HAA) is a variant of acquired aplastic anemia (AA) in which immune-mediated bone marrow failure (BMF) develops following an acute episode of seronegative hepatitis. Dyskeratosis congenita (DC) is an inherited BMF syndrome characterized by the presence of short telomeres, mucocutaneous abnormalities, and cancer predisposition. While both conditions may cause BMF and hepatic impairment, therapeutic approaches are distinct, making it imperative to establish the correct diagnosis. In clinical practice, lymphocyte telomere lengths (TL) are used as a first-line screen to rule out inherited telomeropathies before initiating treatment for AA. To evaluate the reliability of TL in the HAA population, we performed a retrospective analysis of TL in 10 consecutively enrolled HAA patients compared to 19 patients with idiopathic AA (IAA). HAA patients had significantly shorter telomeres than IAA patients (P = 0.009), including four patients with TL at or below the 1st percentile for age matched controls. HAA patients had no clinical features of DC and did not carry disease-causing mutations in known genes associated with inherited telomere disorders. Instead, short TLs were significantly correlated with severe lymphopenia and skewed lymphocyte subsets, features characteristic of HAA. Our results indicate the importance of caution in the interpretation of TL measurements in HAA, because, in this patient population, short telomeres have limited specificity. PMID- 26615917 TI - Small molecule pinocytosis and clathrin-dependent endocytosis at the intestinal brush border: Two separate pathways into the enterocyte. AB - Pinocytosis at the small intestinal brush border was studied in postweaned porcine cultured mucosal explants, using the fluorescent polar probes Alexa hydrazide (AH, MW 570), Texas red dextran (TRD, MW ~ 3000), and Cascade blue dextran (CBD, MW ~ 10,000). Within 1 h, AH appeared in a string of subapical punctae in enterocytes, indicative of an ongoing constitutive pinocytosis. By comparison, TRD was taken up less efficiently into the same compartment, and no intracellular labeling of CBD was detectable, indicating that only small molecules are pinocytosed from the postweaned gut lumen. AH remained in the terminal web region in EEA-1-positive endosomes ("TWEEs") for at least 2 h, implying that the pinocytic uptake does not proceed towards a transcytic pathway. Like AH, cholera toxin B subunit (CTB) was readily internalized, but the two probes appeared in completely non-overlapping subapical compartments, indicating the existence of two different uptake mechanisms operating simultaneously at the brush border. CTB is internalized by clathrin-dependent receptor mediated endocytosis, but surprisingly the toxin also caused a rapid disappearance from the apical cell surface of two major brush border enzymes, alkaline phosphatase and aminopeptidase N, demonstrating the disruptive effect of this pathway. By immunofluorescence, caveolin-1 was hardly detectable in enterocytes, arguing against a caveolae-mediated uptake of AH, whereas the pinocytosis/phagocytosis inhibitors dimethyl amiloride and cytochalasin D both arrested AH uptake. We propose that the constitutive pinocytic mechanism visualized by AH contributes to maintenance of membrane homeostasis and to enrich the contents of lipid raft constituents at the brush border. PMID- 26615918 TI - Two-peptide bacteriocin PlnEF causes cell membrane damage to Lactobacillus plantarum. AB - Biologically active, artificially synthesized two-peptide bacteriocin PlnEF was used to study its mode of action on sensitive bacteria Lactobacillus plantarum pl2. The data obtained showed that PlnEF induced membrane permeabilization, allowing for the efflux of electrolytes, which was evidenced by the increased extracellular conductivity, the dissipation of transmembrane electrical potential and pH gradient, and rapid intracellular ATP depletion after L. plantarum pl2 cells were treated with PlnEF for minutes. Laser confocal microscopy showed that PlnEF accumulated very quickly in L. plantarum pl2 cells and the accumulation of PlnEF caused damage to cell membrane. Scanning electron microscopy and transmission electron microscopy further showed that PlnEF induced morphological changes and structure disruption to L. plantarum pl2 cells, such as the formation of blebs, microspheres, membrane deformation and cell lysis. In summary, the data obtained show that PlnEF caused cell membrane damage to L. plantarum pl2 cells. Our study reveals the antimicrobial mechanism of two-peptide bacteriocin PlnEF against L. plantarum. PMID- 26615920 TI - In silico verification and parallel reaction monitoring prevalidation of potential prostate cancer biomarkers. AB - PURPOSE: Targeted proteomics of potential biomarkers is often challenging. Hence, we developed an intermediate workflow to streamline potential urinary biomarkers of prostate cancer (PCa). MATERIALS & METHODS: Using previously discovered potential PCa biomarkers; we selected proteotypic peptides for targeted validation. Preliminary in silico immunohistochemical and single reaction monitoring (SRM) verification was performed. Successful PTPs were then prevalidated using parallel reaction monitoring (PRM) and reconfirmed in 15 publicly available databases. RESULTS: Stringency-based targetable potential biomarkers were shortlisted following in silico screening. PRM reveals top 12 potential biomarkers including the top ranking seven in silico verification-based biomarkers. Database reconfirmation showed differential expression between PCa and benign/normal prostatic urine samples. CONCLUSION: The pragmatic penultimate screening step, described herein, would immensely improve targeted proteomics validation of potential disease biomarkers. PMID- 26615919 TI - The modified fluorescence based vesicle fluctuation spectroscopy technique for determination of lipid bilayer bending properties. AB - Lipid bilayer is the main constitutive element of biological membrane, which confines intracellular space. The mechanical properties of biological membranes may be characterized by various parameters including membrane stiffness or membrane bending rigidity, which can be measured using flicker noise spectroscopy. The flicker noise spectroscopy exploits the spontaneous thermal undulations of the membrane. The method is based on the quantitative analysis of a series of microscopic images captured during thermal membrane fluctuations. Thus, measured bending rigidity coefficient depends on the image quality as well as the selection of computational tools for image processing and mathematical model used. In this work scanning and spinning disc confocal microscopies were used to visualize fluctuating membranes of giant unilamellar vesicles. The bending rigidity coefficient was calculated for different acquisition modes, using different fluorescent probes and different image processing methods. It was shown that both imaging approaches gave similar bending coefficient values regardless of acquisition time. Using the developed methodology the effect of fluorescent probe type and aqueous phase composition on the value of the membrane bending rigidity coefficient was measured. Specifically it was found that the bending rigidity coefficient of DOPC bilayer in water is smaller than that determined for POPC membrane. It has been found that the POPC and DOPC bending rigidities coefficient in sucrose solution was lower than that in water. Fluorescence imaging makes possible the quantitative analysis of membrane mechanical properties of inhomogeneous membrane. PMID- 26615921 TI - Ab Initio Protein Folding Using a Cooperative Swarm of Molecular Dynamics Trajectories. AB - The use of atomistic simulation techniques to directly resolve the protein tertiary structure from the primary amino acid sequence is hindered by the rough topology of the protein free energy surface and the resulting simulation time scales required. We explore here the use of a molecular dynamics technique based on swarm intelligence to identify the native states of two peptides and a Trp cage miniprotein. In all cases, the presence of cooperative swarm interactions significantly enhanced the efficiency of molecular dynamics simulations in predicting the native conformation. PMID- 26615922 TI - How Different are Electron-Rich and Electron-Deficient pi Interactions? AB - The intermolecular interaction driven structural change is vital to molecular architecturing. In the Cambridge Structural Database (CSD), we find that the preference for geometrical conformations of electron-deficient pi systems is different from those of electron-rich pi systems. Indeed, ab initio calculations find that electron-deficient pi ring systems should involve different structures and energetics, consistent with the CSD search, due to the electric multipole moments and the decrease in the spatial extent of pi-electron density. PMID- 26615923 TI - Optimal Weights in Serial Generalized-Ensemble Simulations. AB - In serial generalized-ensemble simulations, the sampling of a collective coordinate of a system is enhanced through non-Boltzmann weighting schemes. A popular version of such methods is certainly the simulated tempering technique, which is based on a random walk in temperature ensembles to explore the phase space more thoroughly. The most critical aspect of serial generalized-ensemble methods with respect to their parallel counterparts, such as replica exchange, is the difficulty of weight determination. Here we propose an adaptive approach to update the weights on the fly during the simulation. The algorithm is based on generalized forms of the Bennett acceptance ratio and of the free energy perturbation. It does not require intensive communication between processors and, therefore, is prone to be used in distributed computing environments with modest computational cost. We illustrate the method in a series of molecular dynamics simulations of a model system and compare its performances to two recent approaches, one based on adaptive Bayesian-weighted histogram analysis and the other based on initial estimates of weight factors obtained by potential energy averages. PMID- 26615924 TI - Assessment of DFT and DFT-D for Potential Energy Surfaces of Rare Gas Trimers Implementation and Analysis of Functionals and Extrapolation Procedures. AB - Given the recent developments in methodology associated with the accurate computation of molecular systems with weak interactions, it is of particular interest to revisit systems that are notoriously challenging for determining reliable potential energy surface (PES) descriptions. Additionally, challenges associated with carrying out complete basis set extrapolation procedures and treatment of basis set superposition error (BSSE) are of importance in these descriptions. In this work, investigation into the ability to accurately predict the potential energy surfaces of the main Rg3 molecules (Rg = He, Ne, Ar) is made across a range of wave function types and large basis sets, including the use of several established extrapolation procedures and counterpoise corrections. Wave function types span most classes of density functional types, including the newest DFT-D schemes, and are benchmarked against high accuracy CCSD(T)/CBS methodology. Study of such systems is valuable, as they serve as simple models for many complex properties, most importantly n-body weak interaction energies. PMID- 26615925 TI - A Comparison of Three Variants of the Generalized Davidson Algorithm for the Partial Diagonalization of Large Non-Hermitian Matrices. AB - The solution of the equation of motion coupled cluster singles and doubles problem, that is finding the lowest lying electronic transition energies and properties, is fundamentally a large non-Hermitian matrix diagonalization problem. We implemented and compared three variants of the widely diffuse generalized Davidson algorithm, which iteratively finds the lowest eigenvalues and eigenvectors of such a matrix. Our numerical tests, based on different molecular systems, basis sets, state symmetries, and reference functions, demonstrate that the separate evaluation of the left- and right-hand eigenvectors is the most efficient strategy to solve this problem considering storage, numerical stability, and convergence rate. PMID- 26615926 TI - Arbitrary-Order Density Functional Response Theory from Automatic Differentiation. AB - We demonstrate how the functional derivatives appearing in perturbative time dependent density functional theory can be calculated using automatic differentiation. The approach starts from a computer implementation of the exchange-correlation energy functional, from which arbitrary-order derivatives are generated automatically. Automatic differentiation is shown to provide an accurate, general, and efficient implementation of higher-order exchange correlation functional derivatives that is easy to maintain. When used in combination with an arbitrary-order response solver, the methodology allows us to generate arbitrary-order response functions from time-dependent density functional theory. PMID- 26615927 TI - Approximate Multiconfigurational Treatment of Spin-Coupled Metal Complexes. AB - The weak interaction between unpaired electrons in polynuclear transition-metal complexes is often described by exchange and spin polarization mechanisms. The resulting intrinsic multiconfigurational electronic structure for such complexes may be calculated with wave function-based methods (e.g., complete active space configuration interaction and complete active space self-consistent field), but computations become extremely demanding and even unfeasible for polynuclear complexes with a large number of open-shells. Here, several levels of selection of configurations and symmetry considerations that still capture the essential physics of exchange and spin polarization mechanisms are presented. The proposed approximations result in significantly smaller configuration interaction expansions and are equally valid for ab initio and semiempirical methods. Tests are performed in simple molecular systems and in small transition-metal complexes that cover a range of valence and charge states. In particular, superexchange contributions can be calculated to good accuracy using only single ionic excitations. Further reduction in the size of the configuration expansions is possible but restricts the description to low-lying spin ladders. The proposed configuration interaction schemes may be used to resolve space and spin symmetries in the calculation of electronic structures, exchange coupling constants, and other properties pertinent to polynuclear transition-metal complexes. PMID- 26615928 TI - A System-Dependent Density-Based Dispersion Correction. AB - Density functional approximations fail to provide a consistent description of weak molecular interactions arising from small electron density overlaps. A simple remedy to correct for the missing interactions is to add a posteriori an attractive energy term summed over all atom pairs in the system. The density dependent energy correction, presented herein, is applicable to all elements of the periodic table and is easily combined with any electronic structure method, which lacks the accurate treatment of weak interactions. Dispersion coefficients are computed according to Becke and Johnson's exchange-hole dipole moment (XDM) formalism, thereby depending on the chemical environment of an atom (density, oxidation state). The long-range ~R(-6) potential is supplemented with higher order correction terms (~R(-8) and ~R(-10)) through the universal damping function of Tang and Toennies. A genuine damping factor depending on (iterative) Hirshfeld (overlap) populations, atomic ionization energies, and two adjustable parameters specifically fitted to a given DFT functional is also introduced. The proposed correction, dDXDM, dramatically improves the performance of popular density functionals. The analysis of 30 (dispersion corrected) density functionals on 145 systems reveals that dDXDM largely reduces the errors of the parent functionals for both inter- and intramolecular interactions. With mean absolute deviations (MADs) of 0.74-0.84 kcal mol(-1), PBE-dDXDM, PBE0-dDXDM, and B3LYP-dDXDM outperform the computationally more demanding and most recent functionals such as M06-2X and B2PLYP-D (MAD of 1.93 and 1.06 kcal mol(-1), respectively). PMID- 26615929 TI - Ring Current Model and Anisotropic Magnetic Response of Cyclopropane. PMID- 26615930 TI - Sparkle/PM6 Parameters for all Lanthanide Trications from La(III) to Lu(III). AB - PM6 is the first semiempirical method to be released already parametrized for the elements of the periodic table, from hydrogen to bismuth (Z = 83), with the exception of the lanthanides from cerium (Z = 58) to ytterbium (Z = 70). In order to fill this gap, we present in this article a generalization of our Sparkle Model for the quantum chemical semiempirical calculation of lanthanide complexes to PM6. Accordingly, we present Sparkle/PM6 parameters for all lanthanide trications from La(III) to Lu(III). The validation procedure again considered only high-quality crystallographic structures and included 633 complexes. Sparkle/PM6 unsigned mean errors UME(Ln-L)s, corresponding to all the interatomic distances between the lanthanide ion and the atoms directly coordinated to it, range from 0.066 to 0.086 A for Gd(III) and Ce(III), respectively. These minimum and maximum UME(Ln-L)s across the lanthanide series are comparable to the Sparkle/AM1 values of 0.054 and 0.085 A for Ho(III) and Pr(III), respectively, as well as to the values for Sparkle/PM3 of 0.064 and 0.093 A for Gd(III) and Pr(III), respectively. Moreover, for all 15 lanthanide ions, these interatomic distance deviations follow a gamma distribution within a 95% level of confidence, indicating that these errors appear to be random around a mean, freeing the model of systematic errors, at least within the validation set. Sparkle/PM6 presented here, therefore, broadens the range of applicability of PM6 to the coordination compounds of the rare earth metals. PMID- 26615931 TI - Generalized Moller-Plesset Partitioning in Multiconfiguration Perturbation Theory. AB - Two perturbation (PT) theories are developed starting from a multiconfiguration (MC) zero-order function. To span the configuration space, the theories employ biorthogonal vector sets introduced in the MCPT framework. At odds with previous formulations, the present construction operates with the full Fockian corresponding to a principal determinant, giving rise to a nondiagonal matrix of the zero-order resolvent. The theories provide a simple, generalized Moller Plesset (MP) second-order correction to improve any reference function, corresponding either to a complete or incomplete model space. Computational demand of the procedure is determined by the iterative inversion of the Fockian, similarly to the single reference MP theory calculated in a localized basis. Relation of the theory to existing multireference (MR) PT formalisms is discussed. The performance of the present theories is assessed by adopting the antisymmetric product of strongly orthogonal geminal (APSG) wave functions as the reference function. PMID- 26615932 TI - Eigenspace Update for Molecular Geometry Optimization in Nonredundant Internal Coordinate. AB - An eigenspace update method is introduced in this article for molecular geometry optimization. This approach is used to obtain the nonredundant internal coordinate space and diagonalize the Hessian matrix. A select set of large molecules is tested and compared with the conventional method of direct diagonalization in redundant space. While all methods considered herein take on similar optimization pathways for most molecules tested, the eigenspace update algorithm becomes much more computationally efficient with increasing size of the molecular system. A factor of 3 speed-up in overall computational cost is observed in geometry optimization of the 25-alanine chain molecule. The contributing factors to the computational savings are the reduction to the much smaller nonredundant coordinate space and the O(N(2)) scaling of the algorithm. PMID- 26615933 TI - Significant van der Waals Effects in Transition Metal Complexes. AB - There is, in general, very good experience using hybrid DFT to study mechanisms of enzyme reactions containing transition metals. For redox reactions, the B3LYP* functional, which has 15% exact exchange, has been shown to be particularly accurate. Still, there are some cases which have turned out to be quite difficult with large errors. In the present study, the effects of van der Waals interaction have been investigated for these cases, using the empirical formula of Grimme. The results are encouraging. PMID- 26615934 TI - Equipartition and the Calculation of Temperature in Biomolecular Simulations. AB - Since the behavior of biomolecules can be sensitive to temperature, the ability to accurately calculate and control the temperature in molecular dynamics (MD) simulations is important. Standard analysis of equilibrium MD simulations-even constant-energy simulations with negligible long-term energy drift-often yields different calculated temperatures for different motions, however, in apparent violation of the statistical mechanical principle of equipartition of energy. Although such analysis provides a valuable warning that other simulation artifacts may exist, it leaves the actual value of the temperature uncertain. We observe that Tolman's generalized equipartition theorem should hold for long stable simulations performed using velocity-Verlet or other symplectic integrators, because the simulated trajectory is thought to sample almost exactly from a continuous trajectory generated by a shadow Hamiltonian. From this we conclude that all motions should share a single simulation temperature, and we provide a new temperature estimator that we test numerically in simulations of a diatomic fluid and of a solvated protein. Apparent temperature variations between different motions observed using standard estimators do indeed disappear when using the new estimator. We use our estimator to better understand how thermostats and barostats can exacerbate integration errors. In particular, we find that with large (albeit widely used) time steps, the common practice of using two thermostats to remedy so-called hot solvent-cold solute problems can have the counterintuitive effect of causing temperature imbalances. Our results, moreover, highlight the utility of multiple-time step integrators for accurate and efficient simulation. PMID- 26615935 TI - On the Performances of the M06 Family of Density Functionals for Electronic Excitation Energies. AB - We assessed the accuracy of the four members of the M06 family of functionals (M06-L, M06, M06-2X, and M06-HF) for the prediction of electronic excitation energies of main-group compounds by time-dependent density functional theory. This is accomplished by comparing the predictions both to high-level theoretical benchmark calculations and some experimental data for gas-phase excitation energies of small molecules and to experimental data for midsize and large chromogens in liquid-phase solutions. The latter comparisons are carried out using implicit solvation models to include the electrostatic effects of solvation. We find that M06-L is one of the most accurate local functionals for evaluating electronic excitation energies, that M06-2X outperforms BHHLYP, and that M06-HF outperforms HF, although in each case, the compared functionals have the same or a similar amount of Hartree-Fock exchange. For the majority of investigated excited states, M06 emerges as the most accurate functional among the four tested, and it provides an accuracy similar to the best of the other global hybrids such as B3LYP, B98, and PBE0. For 190 valence excited states, 20 Rydberg states, and 16 charge transfer states, we try to provide an overall assessment by comparing the quality of the predictions to those of time-dependent Hartree-Fock theory and nine other density functionals. For the valence excited states, M06 yields a mean absolute deviation (MAD) of 0.23 eV, whereas B3LYP, B98, and PBE0 have MADs in the range 0.19-0.22 eV. Of the functionals tested, M05 2X, M06-2X, and BMK are found to perform best for Rydberg states, and M06-HF performs best for charge transfer states, but no single functional performs satisfactorily for all three kinds of excitation. The performance of functionals with no Hartree-Fock exchange is of great practical interest because of their high computational efficiency, and we find that M06-L predicts more accurate excitation energies than other such functionals. PMID- 26615936 TI - Can Range-Separated and Hybrid DFT Functionals Predict Low-Lying Excitations? A Tookad Case Study. AB - The spectral properties of Tookad (Pd-bacteriopheophorbide, Pd-BPheid), an effective photosensitizer that targets mainly prostate tumors, and metal-free BPheid have been studied using time-dependent density functional theory (TD-DFT). The well-established B3LYP functional, which is known to overestimate excitation energies, was included in the study along with recently introduced range separated and meta hybrid DFT functionals CAM-B3LYP, M06, M06-2X, M06HF, omegaB97XD, omegaB97X, omegaB97, LC-omegaPBE, and PBE0 (PBE1PBE). The main focus is the performance of the new functionals in predicting low-lying excitations (>600 nm), to explore their potential roles in drug development for photodynamic therapy. The data suggests that omegaB97XD overall performs best for the Qy transition band (the red-most absorption), followed by CAM-B3LYP. LC-omegaPBE, omegaB97, B3LYP, and PBE1PBE all generated the Qy band far from the experimental position. The error in absorption energy for the Qy band was found to be at most 0.05 eV for omegaB97XD, compared to 0.15-0.19 eV for B3LYP. The use of different basis sets used in excited-state calculations was shown to be of less importance as was the use of either B3LYP or M06 in geometry optimizations. PMID- 26615937 TI - A Fourier Transform Method for Generation of Anharmonic Vibrational Molecular Spectra. AB - Accurate computations of vibrational energies and vibrational spectra of molecules require inclusion of the anharmonic forces. In standard computational protocols, this leads to a large vibrational Hamiltonian matrix that needs to be diagonalized. Spectral intensities are calculated for individual transitions separately. In this work, an alternate direct generation of the spectral curves is proposed, based on a temporal propagation of a trial vibrational wave function followed by the Fourier transformation (FT). The method was applied to model water dimer and fenchone molecules. Arbitrary resolutions could be achieved by longer-time propagations, although a smaller integration time step (~0.02 fs) was needed for accurate peak frequencies than previously found for similar time dependent applications within the harmonic approximation. Acceptably accurate relative vibrational spectra intensities were obtained when many random vectors used in the propagations were averaged. For a model fenchone Hamiltonian, simulated Raman and Raman optical activity (ROA) spectral shapes compared well with those obtained by the classical approach. The algorithm is amendable to parallelization. The lack of the lengthy and computer-memory-demanding diagonalization thus makes the FT procedure especially convenient for spectral simulations of larger molecules. PMID- 26615938 TI - Singlet-Triplet States Interaction Regions in DNA/RNA Nucleobase Hypersurfaces. AB - The present study provides new insight into the intrinsic mechanisms for the population of the triplet manifold in DNA nucleobases by determining, at the multiconfigurational CASSCF/CASPT2 level, the singlet-triplet states crossing regions and the main decay paths for their lowest singlet and triplet states after near-UV irradiation. The studied singlet-triplet interacting regions are accessible along the minimum energy path of the initially populated singlet bright (1)pipi* state. In particular, all five natural DNA/RNA nucleobases have, at the end of the main minimum energy path and near a conical intersection of the ground and (1)pipi* states, a low-energy, easily accessible, singlet-triplet crossing region directly connecting the lowest singlet and triplet pipi* excited states. Adenine, thymine, and uracil display additional higher-energy crossing regions related to the presence of low-lying singlet and a triplet npi* state. These funnels are absent in guanine and cytosine, which have the bright (1)pipi* state lower in energy and less accessible npi* states. Knowledge of the location and accessibility of these regions, in which the singlet-triplet interaction is related to large spin-orbit coupling elements, may help to understand experimental evidence such as the wavelength dependence measured for the triplet formation quantum yield in nucleobases and the prevalence of adenine and thymine components in the phosphorescence spectra of DNA. PMID- 26615939 TI - Harmonic and Anharmonic Vibrational Frequency Calculations with the Double-Hybrid B2PLYP Method: Analytic Second Derivatives and Benchmark Studies. AB - This work aims to provide reliable benchmark data on the accuracy of harmonic and anharmonic vibrational frequencies computed with the B2PLYP double-hybrid density functional method. The exchange-correlation contributions required for the B2PLYP analytical second derivatives are presented here, which allow for the effective calculation of harmonic frequency as well as cubic and semidiagonal quartic force fields. The latter, in turn, are necessary to compute the anharmonic vibrational frequencies with the perturbative approach (VPT2). The quality of harmonic vibrational frequencies computed in conjunction with basis sets of double- to quadruple-zeta quality has been checked against reference data from the F38 benchmark set. Then, for an additional set of small closed- and open-shell systems, both harmonic frequencies and anharmonic contributions computed at the B2PLYP/N07D and the B2PLYP/aug-cc-pVTZ levels have been compared to their CCSD(T) counterparts. Moreover, for selected medium-size molecules (furan, pyrrole, thiophene, uracil, anisole, phenol, and pyridine), anharmonic frequencies have been compared to well established experimental results. Such benchmark studies have shown that the B2PLYP/N07D model provides good quality harmonic frequencies and describes correctly anharmonic contributions, the latter being of similar accuracy to their B3LYP/N07D counterparts, but obtained at significantly larger computational cost. Additionally, increased accuracy can be obtained by adopting hybrid models where the B2PLYP/N07D anharmonic contributions are combined with harmonic frequencies computed with more accurate quantum mechanical (QM) approaches or by B2PLYP with larger basis sets. This work confirmed also that most of the recently developed density functionals are significantly less suited for vibrational computations, while the B2PLYP method can be recommended for spectroscopic studies where a good accuracy of vibrational properties is required. PMID- 26615940 TI - Formation Enthalpies of Ions: Routine Prediction Using Atom Equivalents. AB - In view of identifying routine procedures to estimate formation enthalpies of ionic systems such as energetic salts or ionic liquids on the basis of density functional theory (DFT), various combinations of atom equivalent (AE) schemes, functionals, and basis sets are compared, using a specially designed training set to parametrize the models. After correction, none of the functionals considered proves significantly more reliable than B3LYP. A small but systematic improvement is noted as AE values are allowed to depend on the atomic environment. However, AE parameters fail to make up for basis set limitations, in constrast to previous observations for neutrals. Finally, a good trade-off between reliability and cost is obtained for ions using B3LYP/6-31++G** energies. PMID- 26615941 TI - Ligand Entropy in Gas-Phase, Upon Solvation and Protein Complexation. Fast Estimation with Quasi-Newton Hessian. AB - A method of rapid entropy estimation for small molecules in vacuum, solution, and inside a protein receptor is proposed. We show that the Hessian matrix of second derivatives built by a quasi-Newton optimizer during geometry optimization of a molecule with a classical molecular potential in these three environments can be used to predict vibrational entropies. We also show that a simple analytical solvation model allows for no less accurate entropy estimation of molecules in solution than a physically rigorous but computationally more expensive model based on Poisson's equation. Our work also suggests that scaled particle theory more precisely estimates the hydrophobic part of solvation entropy than the using a simple surface area term. PMID- 26615942 TI - A New Empirical Correction to the AM1 Method for Macromolecular Complexes. AB - Modeling systems that are governed by van der Waals (dispersion) interactions using empirically corrected DFT methods is becoming increasingly popular due to the promise of a CCSD(T) level accuracy at the computational cost of DFT. Although, DFT methods are computationally efficient in comparison to the CCSD(T) method, currently, structural optimizations using DFT methods are generally only feasible for systems of less than a few hundred atoms. We seek a method applicable to macromolecular complexes. In order to model such large systems, empirically corrected semiempirical methods appear to be an attractive alternative. As with most common DFT methods, the popular semiempirical methods (e.g., AM1) also do not model long-range dispersion (and therefore an empirical correction term is desirable), but this is not their only shortcoming. For weakly interacting systems, hydrogen bonding also poses a concern. A new empirically corrected AM1 method that uses two empirical correction terms, one for dispersion and one for hydrogen bonding interactions, is presented and termed AM1-FS1. This new empirically corrected AM1 method has been parametrized to a diverse training set of 66 complexes that includes nonequilibrium structures and yields sub kilocalorie accuracy in the prediction of intermolecular interaction energies. More significantly, AM1-FS1 achieves this result with substantially less parametrization than existing empirically corrected semiempirical methods and without modification of the original AM1 parameters so that it retains both the computational efficiency and predictive power for thermo-chemical quantities of the original AM1 Hamiltonian. The performance of AM1-FS1 is also tested on several carbon nanostructure complexes and pseudorotaxanes and is found to produce results in very good agreement with the best first-principles calculations. PMID- 26615943 TI - Molecular Dynamics in Physiological Solutions: Force Fields, Alkali Metal Ions, and Ionic Strength. AB - The monovalent ions Na(+) and K(+) and Cl(-) are present in any living organism. The fundamental thermodynamic properties of solutions containing such ions is given as the excess (electro-)chemical potential differences of single ions at finite ionic strength. This quantity is key for many biological processes, including ion permeation in membrane ion channels and DNA-protein interaction. It is given by a chemical contribution, related to the ion activity, and an electric contribution, related to the Galvani potential of the water/air interface. Here we investigate molecular dynamics based predictions of these quantities by using a variety of ion/water force fields commonly used in biological simulation, namely the AMBER (the newly developed), CHARMM, OPLS, Dang95 with TIP3P, and SPC/E water. Comparison with experiment is made with the corresponding values for salts, for which data are available. The calculations based on the newly developed AMBER force field with TIP3P water agrees well with experiment for both KCl and NaCl electrolytes in water solutions, as previously reported. The simulations based on the CHARMM-TIP3P and Dang95-SPC/E force fields agree well for the KCl and NaCl solutions, respectively. The other models are not as accurate. Single cations excess (electro-)chemical potential differences turn out to be similar for all the force fields considered here. In the case of KCl, the calculated electric contribution is consistent with higher level calculations. Instead, such agreement is not found with NaCl. Finally, we found that the calculated activities for single Cl(-) ions turn out to depend clearly on the type of counterion used, with all the force fields investigated. The implications of these findings for biomolecular systems are discussed. PMID- 26615944 TI - Starting-Condition Dependence of Order Parameters Derived from Molecular Dynamics Simulations. AB - We have studied how backbone N-H S(2) order parameters calculated from molecular dynamics simulations depend on the method used to calculate them, the starting conditions, and the length of the simulations. Using the carbohydrate binding domain of galectin-3 in the free and lactose-bound states as a test case, we compared the calculated order parameters with experimental data from NMR relaxation. The results indicate that the sampling can be improved by using several starting structures, taking into account conformational heterogeneity reported in crystal structures. However, the improvement is rather limited, and for 93% of the dihedrals that have alternative conformations in the crystal structures, the conformational space is well sampled even if a single conformation is used as the starting structure. Moreover, the agreement with experimental data is improved when using several short simulations, rather than a single long simulation. In the present case, we find that ~10 independent simulations provide sufficient sampling, and the ideal length of the simulations is ~10 ns, which is ~25% longer than the global correlation time for rotational diffusion. On the other hand, the equilibration time appears to be less important, and our results suggest that an equilibration time of 0.25 ns is sufficient. We have also compared four different methods to extract the order parameters from the simulations, namely, the autocorrelation function and isotropic reorientational eigenmode dynamics using three different window sizes. Overall, the four methods yield comparable results, but large differences between the methods may serve to pinpoint cases for which the calculated parameters are unreliable. PMID- 26615945 TI - Energy Matrix of Structurally Important Side-Chain/Side-Chain Interactions in Proteins. AB - The interactions between amino acid side chains in proteins are generally considered to be the most important stabilizing factor controlling the precise arrangement of the polypeptide chain into a well-defined spatial structure. We used the RI-DFT-D method to calculate the full 20 * 20 matrix of interaction energies between all pairs of amino acid side chains. For each pair, we used a representative 3D conformation extracted from an analysis of known protein structures from Protein Data Bank (PDB). The representative comes from the largest cluster of relative orientations of the two side chains. We find that all of the calculated interaction energies between selected pairs of amino acids are attractive in the gas phase with the exception of side chain pairs having the same total charge. We compared these data with those calculated by the parm03 and OPLS-AA/L force fields to investigate the reliability of simple methods in modeling biomolecules and their behavior. The force fields yield good overall interaction energies for our set but have problems in evaluation of some particular interactions which could be of principal importance for protein stability. We then looked in detail at the 20 side chain interactions involving tryptophan. The histograms of interaction energies showed that the distributions of the interaction energies are neither normal nor Boltzmann-like and that our representative geometries correspond mostly to the minimum energy geometry which is rather poorly populated in the whole pairwise energy distribution. We concluded that cluster representatives obtained by the clusterization algorithm based on geometry criteria cannot be considered as a typical interaction for the whole side chain/side chain interaction distribution. They seem to epitomize the strongest interactions in a protein and are often functionally or structurally important. PMID- 26615946 TI - Interdomain Conformations in the Full-Length MMP-2 Enzyme Explored by Protein Protein Docking Calculations Using pyDock. AB - Current understanding of the collagenolytic activity performed by the matrix metalloproteinases (MMPs) assumes some degree of relative motion between their catalytic and hemopexin-like domains, according to evidence from low-resolution techniques for some of the MMP family members. Herein, we employ protein-protein docking calculations to investigate the structure in aqueous solution of the full length MMP-2 enzyme in its active form, for which there is not yet experimental evidence of interdomain movement. After docking the domains as free rigid-body subunits, the linker region connecting the catalytic and hemopexin-like domains is taken into account a posteriori by merely adding an empiric energy term computed from expected end-to-end distance to the scoring function. Finally, full length MMP-2 structures are generated by model building the linker residues in the most stable docking poses. The results add support to the hypothesis that the interdomain dynamics of a single MMP-2 molecule in aqueous solution can result in a manifold of conformations, with some preferred orientations. Globally, this structural information could be helpful in future experimental or computational studies aimed to elucidate the dynamical behavior of the MMP-2 enzyme in solution. PMID- 26615947 TI - Halogen-Ionic Bridges: Do They Exist in the Biomolecular World? AB - If considering that the pronouncedly charged halide anions are ubiquitous in the biological world, then it is interesting to ask whether the halogen-ionic bridges this term is named by us to describe the interaction motif of a nonbonded halogen ion with two or more electrophiles simultaneously-commonly exist in biomolecules and how they contribute to the stability and specificity of biomolecular folding and binding? To address these problems, we herein present a particularly systematic investigation on the geometrical profile and the energy landscape of halogen ions interacting with and bridging between polar and charged molecular moieties in small model systems and real crystal structures, by means of ab initio calculation, database survey, continuum electrostatic analysis, and hybrid quantum mechanics/molecular mechanics examination. All of these unequivocally demonstrate that this putative halide motif is broadly distributed in biomolecular systems (>6000) and can confer a substantial stabilization for the architecture of proteins and their complexes with nucleic acids and small ligands. This stabilization energy is estimated to be generally more than 100 kcal.mol(-1) for gas-phase states or about 20 kcal.mol(-1) for solution conditions, which is much greater than that found in sophisticated water-mediated (<10 kcal.mol(-1)) and salt (~ 3.66 kcal.mol(-1)) bridges. In this respect, we would expect that the proposed halogen-ionic bridge, which has long been unrecognized in the arena of biological repertoires, could be appreciated in chemistry and biology communities and might be exploited as a new and versatile tool for rational drug design and bioengineering. PMID- 26615949 TI - Clinical decision-making described by Swedish prehospital emergency care nurse students - An exploratory study. AB - AIM: The purpose of this study was to explore the PECN students' clinical decision-making during a seven-week clinical rotation in the ambulance services. INTRODUCTION: Developing expertise in prehospital emergency care practices requires both theoretical and empirical learning. A prehospital emergency care nurse (PECN) is a Registered Nurse (RN) with one year of additional training in emergency care. There has been little investigation of how PECN students describe their decision-making during a clinical rotation. METHODS: A qualitative study design was used, and 12 logbooks written by the Swedish PECN students were analysed using content analysis. FINDINGS: The students wrote about 997 patient encounters - ambulance assignments during their clinical rotation. Four themes emerged as crucial for the students' decision-making: knowing the patient, the context-situation awareness in the ambulance service, collaboration, and evaluation. Based on the themes, students made decisions on how to respond to patients' illnesses. CONCLUSION: The PECN students used several variables in their decision-making. The decision- making was an on-going process during the whole ambulance assignment. The university has the responsibility to guide the students during their transition from an RN to a PECN. The findings of the study can support the educators and clinical supervisors in developing the programme of study for becoming a PECN. PMID- 26615950 TI - Anterior chamber migration of dexamethasone intravitreal implant (Ozurdex(r)) through basal iridectomy (Ando) in a pseudophakic patient. AB - PURPOSE: Intravitreal implantation of dexamethasone implant (Ozurdex(r)) is being widely used for the treatment of macular edema (ME) after branch or central retinal vein occlusion, diabetic ME, and persistent ME associated with uveitis or Irvine-Gass syndrome. We describe a complication: migration of the dexamethasone implant into the anterior chamber through basal iridectomy (Ando) in a pseudophakic patient with development of corneal edema and secondary high intraocular pressure. METHODS: This is a case report of migration of Ozurdex(r) through basal iridectomy in a pseudophakic patient with iris claw lens. CONCLUSIONS: Pseudophakic patients, with a history of vitrectomy, even those with a basal iridectomy (Ando), are at high risk for migration of the Ozurdex(r) into the anterior chamber and development of corneal edema. PMID- 26615951 TI - Reply to: A study aiming to define pupil dilation effect in biometry. PMID- 26615948 TI - Making better scar: Emerging approaches for modifying mechanical and electrical properties following infarction and ablation. AB - Following myocardial infarction (MI), damaged myocytes are replaced by collagenous scar tissue, which serves an important mechanical function - maintaining integrity of the heart wall against enormous mechanical forces - but also disrupts electrical function as structural and electrical remodeling in the infarct and borderzone predispose to re-entry and ventricular tachycardia. Novel emerging regenerative approaches aim to replace this scar tissue with viable myocytes. Yet an alternative strategy of therapeutically modifying selected scar properties may also prove important, and in some cases may offer similar benefits with lower risk or regulatory complexity. Here, we review potential goals for such modifications as well as recent proof-of-concept studies employing specific modifications, including gene therapy to locally increase conduction velocity or prolong the refractory period in and around the infarct scar, and modification of scar anisotropy to improve regional mechanics and pump function. Another advantage of scar modification techniques is that they have applications well beyond MI. In particular, ablation treats electrical abnormalities of the heart by intentionally generating scar to block aberrant conduction pathways. Yet in diseases such as atrial fibrillation (AF) where ablation can be extensive, treating the electrical disorder can significantly impair mechanical function. Creating smaller, denser scars that more effectively block conduction, and choosing the location of those lesions by balancing their electrical and mechanical impacts, could significantly improve outcomes for AF patients. We review some recent advances in this area, including the use of computational models to predict the mechanical effects of specific lesion sets and gene therapy for functional ablation. Overall, emerging techniques for modifying scar properties represents a potentially important set of tools for improving patient outcomes across a range of heart diseases, whether used in place of or as an adjunct to regenerative approaches. PMID- 26615952 TI - Interleukin-17 and its correlation with vascular endothelial growth factor expression in ocular surface pathologies: a histologic study. AB - PURPOSE: Interleukin-17 (IL-17), a cytokine that was recently associated with various inflammatory processes, was evaluated in ocular surface inflammatory pathologies, namely pterygium and inflamed juvenile conjunctival nevus (IJCN). Its expression was examined in correlation with vascular endothelial growth factor (VEGF) expression. METHODS: Expression of IL-17 and VEGF was immunohistochemically evaluated in 50 pterygia and 9 IJCN specimens. The pattern of IL-17 and VEGF expression was studied as well as the correlation between the 2 cytokines. RESULTS: Interleukin-17 was expressed in all IJCN samples and in 84% of pterygia (Fisher exact test, p<0.002). In pterygium, it was expressed mainly in the basal layer of the epithelial cells, in the perivascular tissues, and in the vascular endothelial cells. In IJCN, it was mainly expressed in the inflammatory infiltrate. In normal conjunctival epithelium, it was barely detected and was positive in only 11%. Vascular endothelial growth factor was expressed in all IJCN samples and in 92% of pterygia (Fisher exact test, p<0.002). It was expressed in the surface epithelial layers of the pterygium and in the vascular endothelium. In IJCN, it was again seen in the vascular endothelial cells and in the inflammatory infiltrate. Vascular endothelial growth factor expression was noted in 67% of normal conjunctival sections. CONCLUSIONS: The present study describes the expression of IL-17 in pterygium and in IJCN. These findings provide new insights into pterygium and IJCN pathogenesis. Interleukin-17 blockade may have a potential role in management of pterygium and IJCN or preventing pterygium recurrence. PMID- 26615953 TI - Sensitive detection of cancer cells using light-mediated apta-PCR. AB - Apta-PCR is an ultrasensitive assay in which aptamers are exploited not only as biomolecular recognition elements, but also as reporter labels for amplification via real-time PCR. This methodology has been successfully applied to the detection of proteins, achieving limits of detection in the picomolar range. The introduction of caged aptamers that bear photo-labile groups, so called cages, at strategic positions so that their tertiary structure and thus their binding properties can be controlled by light, facilitates a more robust and attractive assay in terms of sample conservation and reusability. In this work, we report for the first time the use of caged aptamers for cell detection in an apta-PCR assay. Specifically, a sandwich format is used combining the capture of B-cells by an antibody with the specific detection of Burkitt's lymphoma cancer cells by a caged aptamer, acting as a reporter probe. Elution of the aptamer bound to the cancer cells is performed by light and the number of cells is then correlated with the amount of eluted caged aptamer using real-time PCR analysis. The reported technique shows an excellent sensitivity, achieving detection of as few as 77 cells, and due to the inherent robustness of the assay, this detection platform can be reused for further analyses, demonstrating potential applicability in proteomics and clinical diagnostics. PMID- 26615954 TI - Current covalent modification methods for detecting RNA in fixed and living cells. AB - Labeling RNAs is of particular interest for elucidating localization, transport, and regulation of specific transcripts, ideally in living cells. Numerous methods have been developed ranging from hybridizing probes to genetically encoded reporters and chemo-enzymatic approaches. This review focuses on covalent labeling approaches that rely on the introduction of a small reactive group into the nascent or completed transcript followed by bioorthogonal click chemistry. State of the approaches for labeling RNA in fixed and living cells will be presented and emerging strategies with great potential for application in the complex cellular environment will be discussed. PMID- 26615955 TI - RNA FISH for detecting expanded repeats in human diseases. AB - RNA fluorescence in situ hybridization (FISH) is a widely used technique for detecting transcripts in fixed cells and tissues. Many variants of RNA FISH have been proposed to increase signal strength, resolution and target specificity. The current variants of this technique facilitate the detection of the subcellular localization of transcripts at a single molecule level. Among the applications of RNA FISH are studies on nuclear RNA foci in diseases resulting from the expansion of tri-, tetra-, penta- and hexanucleotide repeats present in different single genes. The partial or complete retention of mutant transcripts forming RNA aggregates within the nucleoplasm has been shown in multiple cellular disease models and in the tissues of patients affected with these atypical mutations. Relevant diseases include, among others, myotonic dystrophy type 1 (DM1) with CUG repeats, Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3) with CAG repeats, fragile X-associated tremor/ataxia syndrome (FXTAS) with CGG repeats, myotonic dystrophy type 2 (DM2) with CCUG repeats, amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) with GGGGCC repeats and spinocerebellar ataxia type 32 (SCA32) with GGCCUG. In this article, we summarize the results obtained with FISH to examine RNA nuclear inclusions. We provide a detailed protocol for detecting RNAs containing expanded CAG and CUG repeats in different cellular models, including fibroblasts, lymphoblasts, induced pluripotent stem cells and murine and human neuronal progenitors. We also present the results of the first single-molecule FISH application in a cellular model of polyglutamine disease. PMID- 26615956 TI - Hydrogen-bonded 4H-1-benzopyrane-4-thione-water complexes properties in the S2 excited state: the mechanism and dynamics of deactivation. AB - Unexpected results of spectral emission and photophysical study of S2-excited 4H 1-benzopyrane-4-thione (BPT) in water solution were explained by intermolecular hydrogen bonding. There are at least two types of BPT-water complexes that participate in the S2-fluorescence similarly as in S0-> S2 absorption. They both deactivate with high efficiency in internal conversion S2-> S1 and in intersystem crossing S1-> T1 processes. PMID- 26615957 TI - The role of mast cell in tissue morphogenesis. Thymus, duodenum, and mammary gland as examples. AB - Mast cells (MCs) are strategically located at host/environment interfaces like skin, airways, and gastro-intestinal and uro-genital tracts. MCs also populate connective tissues in association with blood and lymphatic vessels and nerves. MCs are absent in avascular tissues, such as mineralized bone, cartilage, and cornea. MCs have various functions and different functional subsets of MCs are encountered in different tissues. However, we do not' know exactly what is the physiological function of MC. Most of these functions are not essential for life, as various MC-deficient strains of mice and rats seems to have normal life spans. In this review article, we have reported and discussed the literature data concerning the role of MCs in tissue morphogenesis, and in particular their role in the development of thymus, duodenum, and mammary gland. PMID- 26615958 TI - Biomechanical insult switches PEA-15 activity to uncouple its anti-apoptotic function and promote erk mediated tissue remodeling. AB - Biomechanical insult contributes to many chronic pathological processes, yet the resulting influences on signal transduction mechanisms are poorly understood. The retina presents an excellent mechanotransduction model, as mechanical strain on sensitive astrocytes of the optic nerve head (ONH) is intimately linked to chronic tissue remodeling and excavation by matrix metalloproteinases (MMPs), and apoptotic cell death. However, the mechanism by which these effects are induced by biomechanical strain is unclear. We previously identified the small adapter protein, PEA-15 (phosphoprotein enriched in astrocytes), through proteomic analyses of human ONH astrocytes subjected to pathologically relevant biomechanical insult. Under resting conditions PEA-15 is regulated through phosphorylation of two key serine residues to inhibit extrinsic apoptosis and ERK1/2 signaling. However, we surprisingly observed that biomechanical insult dramatically switches PEA-15 phosphorylation and function to uncouple its anti apoptotic activity, and promote ERK1/2-dependent MMP-2 and MMP-9 secretion. These results reveal a novel cell autonomous mechanism by which biomechanical strain rapidly modifies this signaling pathway to generate altered tissue injury responses. PMID- 26615959 TI - Characterization of nitrogen species incorporated into graphite using low energy nitrogen ion sputtering. AB - The electronic structures of nitrogen species incorporated into highly oriented pyrolytic graphite (HOPG), prepared by low energy (200 eV) nitrogen ion sputtering and subsequent annealing at 1000 K, were investigated by X-ray photoelectron spectroscopy (XPS), angle-dependent X-ray absorption spectroscopy (XAS), and Raman spectroscopy. An additional peak was observed at higher binding energy of 401.9 eV than 400.9 eV for graphitic1 N (graphitic N in the basal plane) in N 1s XPS, where graphitic2 N (graphitic N in the zigzag edge and/or vacancy sites) has been theoretically expected to appear. N 1s XPS showed that graphitic1 N and graphitic2 N were preferably incorporated under low nitrogen content doping conditions (8 * 10(13) ions cm(-2)), while pyridinic N and graphitic1 N were dominantly observed under high nitrogen content doping conditions. In addition, angle-dependent N 1s XAS showed that the graphitic N and pyridinic N atoms were incorporated into the basal plane of HOPG and thus were highly oriented. Furthermore, Raman spectroscopy revealed that low energy sputtering resulted in almost no fraction of the disturbed graphite surface layers under the lowest nitrogen doping condition. The suitable nitrogen doping condition was discovered for realizing the well-controlled nitrogen doped HOPG. The electrochemical properties for the oxygen reduction reaction of these samples in acidic solution were examined and discussed. PMID- 26615960 TI - Single nucleotide polymorphisms in AGTR1, TFAP2B, and TRAF1 are not associated with the incidence of patent ductus arteriosus in Japanese preterm infants. AB - BACKGROUND: Persistent patent ductus arteriosus (PDA) is a frequent complication in preterm infants. Single nucleotide polymorphisms (SNP) in several genes, including angiotensin II receptor, type 1 (AGTR1), transcription factor AP-2 beta (TFAP2B) and tumor necrosis factor receptor-associated factor 1 (TRAF1), have been reported to be associated with PDA in preterm infants. The aim of this study was to evaluate the relationships between PDA in preterm infants and polymorphisms in AGTR1, TFAP2B and TRAF1 in the Japanese population. METHODS: The subjects consisted of 107 preterm infants with gestational age <32 weeks. Extremely low-birthweight infants were treated with prophylactic indomethacin during the first 24 h after birth. Five SNP, namely, rs5186 in AGTR1, rs987237 and rs6930924 in TFAP2B, and rs1056567 and rs10985070 in TRAF1, were genotyped using TaqMan SNP genotyping assays. RESULTS: There were no significant differences in the distributions of the genotypes and allele frequencies of all studied SNP between the PDA group (n = 46) and the non-PDA group (n = 61). CONCLUSIONS: There were no significant associations between the studied SNP and the incidence of PDA in Japanese preterm infants. These SNP may not be clinically important predisposing factors for PDA in Japanese preterm infants. PMID- 26615961 TI - Cyclam Derivatives with a Bis(phosphinate) or a Phosphinato-Phosphonate Pendant Arm: Ligands for Fast and Efficient Copper(II) Complexation for Nuclear Medical Applications. AB - Cyclam derivatives bearing one geminal bis(phosphinic acid), -CH2PO2HCH2PO2H2 (H2L(1)), or phosphinic-phosphonic acid, -CH2PO2HCH2PO3H2 (H3L(2)), pendant arm were synthesized and studied as potential copper(II) chelators for nuclear medical applications. The ligands showed good selectivity for copper(II) over zinc(II) and nickel(II) ions (log KCuL = 25.8 and 27.7 for H2L(1) and H3L(2), respectively). Kinetic study revealed an unusual three-step complex formation mechanism. The initial equilibrium step leads to out-of-cage complexes with Cu(2+) bound by the phosphorus-containing pendant arm. These species quickly rearrange to an in-cage complex with cyclam conformation II, which isomerizes to another in-cage complex with cyclam conformation I. The first in-cage complex is quantitatively formed in seconds (pH ~5, 25 degrees C, Cu:L = 1:1, cM ~ 1 mM). At pH >12, I isomers undergo nitrogen atom inversion, leading to III isomers; the structure of the III-[Cu(HL(2))] complex in the solid state was confirmed by X ray diffraction analysis. In an alkaline solution, interconversion of the I and III isomers is mutual, leading to the same equilibrium isomeric mixture; such behavior has been observed here for the first time for copper(II) complexes of cyclam derivatives. Quantum-chemical calculations showed small energetic differences between the isomeric complexes of H3L(2) compared with analogous data for isomeric complexes of cyclam derivatives with one or two methylphosphonic acid pendant arm(s). Acid-assisted dissociation proved the kinetic inertness of the complexes. Preliminary radiolabeling of H2L(1) and H3L(2) with (64)Cu was fast and efficient, even at room temperature, giving specific activities of around 70 GBq of (64)Cu per 1 MUmol of the ligand (pH 6.2, 10 min, ca. 90 equiv of the ligand). These specific activities were much higher than those of H3nota and H4dota complexes prepared under identical conditions. The rare combination of simple ligand synthesis, very fast copper(II) complex formation, high thermodynamic stability, kinetic inertness, efficient radiolabeling, and expected low bone tissue affinity makes such ligands suitably predisposed to serve as chelators of copper radioisotopes in nuclear medicine. PMID- 26615962 TI - A Simultaneous Metabolic Profiling and Quantitative Multimetabolite Metabolomic Method for Human Plasma Using Gas-Chromatography Tandem Mass Spectrometry. AB - For the first time it is possible to simultaneously collect targeted and nontargeted metabolomics data from plasma based on GC with high scan speed tandem mass spectrometry (GC-MS/MS). To address the challenge of getting broad metabolome coverage while quantifying known biomarker compounds in high throughput GC-MS metabolomics, we developed a novel GC-MS/MS metabolomics method using a high scan speed (20 000 Da/second) GC-MS/MS that enables simultaneous data acquisition of both nontargeted full scan and targeted quantitative tandem mass spectrometry data. The combination of these two approaches has hitherto not been demonstrated in metabolomics. This method allows reproducible quantification of at least 37 metabolites using multiple reaction monitoring (MRM) and full mass spectral scan-based detection of 601 reproducible metabolic features from human plasma. The method showed good linearity over normal concentrations in plasma (0.06-343 to 0.86-4800 MUM depending on the metabolite) and good intra- and interbatch precision (0.9-16.6 and 2.6-29.6% relative standard deviation). Based on the parameters determined for this method, targeted quantification using MRM can be expanded to cover at least 508 metabolites while still collecting full scan data. The new simultaneous targeted and nontargeted metabolomics method enables more sensitive and accurate detection of predetermined metabolites and biomarkers of interest, while still allowing detection and identification of unknown metabolites. This is the first validated GC-MS/MS metabolomics method with simultaneous full scan and MRM data collection, and clearly demonstrates the utility of GC-MS/MS with high scanning rates for complex analyses. PMID- 26615963 TI - Effects of Two Surfactants and Beta-Cyclodextrin on Beta-Cypermethrin Degradation by Bacillus licheniformis B-1. AB - The biodegradation efficiency of beta-cypermethrin (beta-CY) is low especially at high concentrations mainly due to poor contact between this hydrophobic pesticide and microbial cells. In this study, the effects of two biodegradable surfactants (Tween-80 and Brij-35) and beta-cyclodextrin (beta-CD) on the growth and cell surface hydrophobicity (CSH) of Bacillus licheniformis B-1 were studied. Furthermore, their effects on the solubility, biosorption, and degradation of beta-CY were investigated. The results showed that Tween-80 could slightly promote the growth of the strain while Brij-35 and beta-CD exhibited little effect on its growth. The CSH of strain B-1 and the solubility of beta-CY were obviously changed by using Tween-80 and Brij-35. The surfactants and beta-CD could enhance beta-CY biosorption and degradation by the strain, and the highest degradation was obtained in the presence of Brij-35. When the surfactant or beta CD concentration was 2.4 g/L, the degradation rate of beta-CY in Brij-35, Tween 80, and beta-CD treatments was 89.4%, 50.5%, and 48.1%, respectively. The half life of beta-CY by using Brij-35 was shortened by 69.1 h. Beta-CY content in the soil with both strain B-1 and Brij-35 decreased from 22.29 mg/kg to 4.41 mg/kg after incubation for 22 d. This work can provide a promising approach for the efficient degradation of pyrethroid pesticides by microorganisms. PMID- 26615964 TI - Balancing spatially regulated beta-actin translation and dynamin-mediated endocytosis is required to assemble functional epithelial monolayers. AB - Regulating adherens junction complex assembly/disassembly is critical to maintaining epithelial homeostasis in healthy epithelial tissues. Consequently, adherens junction structure and function is often perturbed in clinically advanced tumors of epithelial origin. Some of the most studied factors driving adherens junction complex perturbation in epithelial cancers are transcriptional and epigenetic down-regulation of E-cadherin expression. However, numerous reports demonstrate that post-translational regulatory mechanisms such as endocytosis also regulate early phases of epithelial-mesenchymal transition and metastatic progression. In already assembled healthy epithelia, E-cadherin endocytosis recycles cadherin-catenin complexes to regulate the number of mature adherens junctions found at cell-cell contact sites. However, following de novo epithelial cell-cell contact, endocytosis negatively regulates adherens junction assembly by removing E-cadherin from the cell surface. By contrast, following de novo epithelial cell-cell contact, spatially localized beta-actin translation drives cytoskeletal remodeling and consequently E-cadherin clustering at cell cell contact sites and therefore positively regulates adherens junction assembly. In this report we demonstrate that dynamin-mediated endocytosis and beta-actin translation-dependent cadherin-catenin complex anchoring oppose each other following epithelial cell-cell contact. Consequently, the final extent of adherens junction assembly depends on which of these processes is dominant following epithelial cell-cell contact. We expressed beta-actin transcripts impaired in their ability to properly localize monomer synthesis (Delta3'UTR) in MDCK cells to perturb actin filament remodeling and anchoring, and demonstrate the resulting defect in adherens junction structure and function is rescued by inhibiting dynamin mediated endocytosis. Therefore, we demonstrate balancing spatially regulated beta-actin translation and dynamin-mediated endocytosis regulates epithelial monolayer structure and barrier function. PMID- 26615965 TI - Elective induction of labour and maternal request: a national population-based study. AB - OBJECTIVE: To estimate the rate of elective inductions in France and the proportion of them that were maternally requested, and to study the factors associated with elective inductions that were or were not requested by women. DESIGN: Cross-sectional population-based study. SETTING: All maternity units in France. POPULATION: About 14 681 women from the 2010 French National Perinatal Survey of a representative sample of births. METHODS: Inductions were classified as elective based on their indications and maternal and fetal characteristics, collected from medical records. Elective inductions requested by women were identified from the mother's postpartum interviews. Polytomous logistic regression analysis was used to study the determinants of inductions that were or were not maternally requested. Women with spontaneous labour served as the comparison group. MAIN OUTCOME MEASURE: Rate of elective inductions. RESULTS: The induction rate was 22.6, 13.9% elective. Among elective inductions, 47.3% were requested by women. The characteristics of mothers, pregnancies, and maternity units were similar in both groups of elective inductions. The main associated factors were parity 2 or more [adjusted odds ratio (OR) 4.7, 95% confidence interval (CI) 3.1-7.2 for maternally requested inductions and aOR of 1.8 (95% CI1.2-2.7) for unrequested inductions, compared with parity 0] and private hospital status [aOR 4.5 95% (CI 3.3-6.0) for maternally requested inductions and aOR 3.7 (95% CI 2.8-4.9) for inductions not requested by the mother]. We found no association between maternal social characteristics and type of elective induction. CONCLUSION: Parity and organisational factors appear to influence the decision about elective inductions. It would be interesting to determine how obstetricians and women make this decision and for what reasons. TWEETABLE ABSTRACT: About 13.9% of inductions of labour were elective in France, 47.3% of these requested by women. PMID- 26615966 TI - Elevated plasma oxytocin levels in children with Prader-Willi syndrome compared with healthy unrelated siblings. AB - Prader-Willi syndrome (PWS) is a rare genetic disorder associated with distinct abnormal behaviors including hyperphagia, profound social deficits, and obsessive compulsive tendencies. PWS males showed reduced oxytocin receptor (OTR) gene expression and density in the hypothalamic paraventricular nucleus that may play a role in PWS psychopathology. Oxytocin is an anorexigenic neuropeptide similar to vasopressin that is associated with social cognition and obsessive-compulsive behavior. To evaluate oxytocin biology in PWS, we examined overnight fasting plasma oxytocin levels in 23 children with PWS (mean +/- SD age: 8.2 +/- 2.0 year) having genetic confirmation and 18 age matched healthy unrelated siblings without PWS (mean +/- SD age: 8.2 +/- 2.3 year) and a similar gender ratio under the same clinical assessments, specimen processing and laboratory conditions. Multiplex immune assays were carried out using the Milliplex Human Neuropeptide Magnetic panel and the Luminex system. Natural log-transformed oxytocin levels were analyzed using general linear model adjusting for diagnosis, gender, age and body mass index (BMI). Oxytocin plasma levels were significantly elevated in children with PWS (168 +/- 121 pg/ml) compared with unrelated and unaffected siblings without the diagnosis of PWS (64.8 +/- 83.8 pg/ml, F = 8.8, P < 0.01) and the diagnosis of PWS predicted oxytocin level (F = 9.5, P < 0.003) in controlled regression analysis with an overall model fit R(2) = 0.33 (P < 0.01). The symptoms of hyperphagia, anxiety and repetitive behaviors classically seen in PWS may be related to the disruption of oxytocin responsivity or feedback in the hypothalamic paraventricular nucleus possibly influencing vasopressin signaling. Further study is needed to characterize oxytocin function in PWS. PMID- 26615967 TI - A decrease in the permeability of aquaporin zero as a possible cause for presbyopia. AB - The crystalline lens appears to be a simple organ with the sole role of focusing light upon the retina. However, numerous studies have underscored its dynamic nature with a host of compartmentalized physiological processes. As the individual ages, the normal lens develops two inescapable processes, presbyopia and cataracts. Yet, to date, there is no uniform explanation for presbyopia and many factors have been proposed as contributors including continuous enlargement of the lens, loss of power of the ciliary muscle and hardening of the lens fibers. Proposed explanations are incomplete and need experimental confirmation. This paper analyzes the possible causes for presbyopia and proposes a new one for it: a decrease in the permeability of aquaporin zero (AQP-0) also known as major intrinsic protein (MIP). Based on original findings of our laboratory, this paper proposes that a fluid flow exists inside the avascular lens. This fluid enters and leaves the lens during the accommodation process. We believe that for this to occur the lens utilizes the permeability of aquaporin zero which is abundant in the membrane of the fiber cells. Volume change due to fluid traversing the surface of the lens occurs during accommodation. We present the hypothesis that increasing the permeability of AQP-0 would facilitate accommodation. Therefore, defects in AQP-0 permeability may be a cause for presbyopia. We would also like to propose that it is possible to visualize and measure the fluid volume lost during un-accommodation and determine if the fluid is lost across the anterior, posterior or both surfaces. An age-related loss in lens water permeability could reduce fluid fluxes during the shape changes of accommodation potentially contributing to presbyopia. PMID- 26615968 TI - Site-selective chemical modification of chymotrypsin using peptidyl derivatives bearing optically active diphenyl 1-amino-2-phenylethylphosphonate: Stereochemical effect of the diphenyl phosphonate moiety. AB - Diphenyl (alpha-aminoalkyl)phosphonates act as mechanism-based inhibitors against serine proteases by forming a covalent bond with the hydroxy group of the active center Ser residue. Because the covalent bond was found to be broken and replaced by 2-pyridinaldoxime methiodide (2PAM), we employed a peptidyl derivative bearing diphenyl 1-amino-2-phenylethylphosphonate moiety (Phe(p) (OPh)2 ) to target the active site of chymotrypsin and to selectively anchor to Lys175 in the vicinity of the active site. Previously, it was reported that the configuration of the alpha-carbon of phosphorus in diphenyl (alpha-aminoalkyl)phosphonates affects the inactivation reaction of serine proteases, i.e., the (R)-enantiomeric diphenyl phosphonate is comparable to l-amino acids and it effectively reacts with serine proteases, whereas the (S)-enantiomeric form does not. In this study, we evaluated the stereochemical effect of the phosphonate moiety on the selective chemical modification. Epimeric dipeptidyl derivatives, Ala-(R or S)-Phe(p) (OPh)2 , were prepared by separation with RP-HPLC. A tripeptidyl (R)-epimer (Ala Ala-(R)-Phe(p) (OPh)2 ) exhibited a more potent inactivation ability against chymotrypsin than the (S)-epimer. The enzyme inactivated by the (R)-epimer was more effectively reactivated with 2PAM than the enzyme inactivated by the (S) epimer. Finally, N-succinimidyl (NHS) active ester derivatives, NHS-Suc-Ala-Ala- (R or S)-Phe(p) (OPh)2 , were prepared, and we evaluated their action when modifying Lys175 in chymotrypsin. We demonstrated that the epimeric NHS derivative that possessed the diphenyl phosphonate moiety with the (R) configuration effectively modified Lys175 in chymotrypsin, whereas that with the (S)-configuration did not. These results demonstrate the utility of peptidyl derivatives that bear an optically active diphenyl phosphonate moiety as affinity labeling probes in protein bioconjugation. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 521-530, 2016. PMID- 26615969 TI - Oral Spindle Cell Lipoma in a Rare Location: A Differential Diagnosis. AB - BACKGROUND: Spindle cell lipoma (SCL) is an uncommon and histologically distinct variant of lipoma. It usually occurs as a solitary, subcutaneous, and well circumscribed lesion in the posterior neck, shoulders, and back of older men. SCL of the oral cavity is rare. We present the clinical-pathologic features of the third case of SCL located on the hard palate and discuss the histological differential diagnosis with other fusiform neoplasms. CASE REPORT: A 56-year-old man was evaluated for an asymptomatic swelling on the right side of the hard palate. The intraoral examination showed a 25*20 mm sessile and circumscribed tumor, underlying an apparently healthy mucosa of normal color. The lesion revealed a floating consistency during palpation. Excisional biopsy was carried out based on a clinical diagnosis of lipoma or a benign minor salivary gland tumor. The histopathology demonstrated a well-circumscribed but unencapsulated proliferation of bland spindle cells admixed with mature adipocytes in a collagenous/myxoid stroma. The spindle cells were uniform, exhibiting elongated nuclei and narrow cytoplasmic processes without atypia. They were positive to CD34 and negative to factor VIII, alpha-smooth muscle actin, S100, cytokeratin, and actin. Mitotic activity was low, as confirmed by Ki-67 immunostaining. No lipoblastic activity was found. The diagnosis of SCL was therefore established. CONCLUSIONS: Oral spindle cell lipoma is a rare benign lipomatous tumor. The histologic picture shows a range of variations and the observation of morphological features is important to distinguish this lesion from other fusiform tumors. Immunohistochemistry should be helpful in this differentiation. PMID- 26615971 TI - Recognizing the same face in different contexts: Testing within-person face recognition in typical development and in autism. AB - Unfamiliar face recognition follows a particularly protracted developmental trajectory and is more likely to be atypical in children with autism than those without autism. There is a paucity of research, however, examining the ability to recognize the same face across multiple naturally varying images. Here, we investigated within-person face recognition in children with and without autism. In Experiment 1, typically developing 6- and 7-year-olds, 8- and 9-year-olds, 10- and 11-year-olds, 12- to 14-year-olds, and adults were given 40 grayscale photographs of two distinct male identities (20 of each face taken at different ages, from different angles, and in different lighting conditions) and were asked to sort them by identity. Children mistook images of the same person as images of different people, subdividing each individual into many perceived identities. Younger children divided images into more perceived identities than adults and also made more misidentification errors (placing two different identities together in the same group) than older children and adults. In Experiment 2, we used the same procedure with 32 cognitively able children with autism. Autistic children reported a similar number of identities and made similar numbers of misidentification errors to a group of typical children of similar age and ability. Fine-grained analysis using matrices revealed marginal group differences in overall performance. We suggest that the immature performance in typical and autistic children could arise from problems extracting the perceptual commonalities from different images of the same person and building stable representations of facial identity. PMID- 26615972 TI - Behavioral avoidance of contagion in childhood. AB - Although there is a large literature on children's reasoning about contagion, there has been no empirical research on children's avoidance of contagious individuals. This study is the first to investigate whether children avoid sick individuals. Participants (4- to 7-year-old children) were invited to play with two confederates-one of whom was "sick." Afterward, their knowledge of contagion was assessed. Overall, children avoided proximity to and contact with the sick confederate and her toys, but only 6- and 7-year-olds performed above chance. The best predictor of avoidance behavior was not age but rather children's ability to make predictions about illness outcomes. This provides the first evidence of behavioral avoidance of contagious illness in childhood and suggests that causal knowledge underlies avoidance behavior. PMID- 26615973 TI - Structural insights of homotypic interaction domains in the ligand-receptor signal transduction of tumor necrosis factor (TNF). AB - Several members of tumor necrosis factor receptor (TNFR) superfamily that these members activate caspase-8 from death-inducing signaling complex (DISC) in TNF ligand-receptor signal transduction have been identified. In the extrinsic pathway, apoptotic signal transduction is induced in death domain (DD) superfamily; it consists of a hexahelical bundle that contains 80 amino acids. The DD superfamily includes about 100 members that belong to four subfamilies: death domain (DD), caspase recruitment domain (CARD), pyrin domain (PYD), and death effector domain (DED). This superfamily contains key building blocks: with these blocks, multimeric complexes are formed through homotypic interactions. Furthermore, each DD-binding event occurs exclusively. The DD superfamily regulates the balance between death and survival of cells. In this study, the structures, functions, and unique features of DD superfamily members are compared with their complexes. By elucidating structural insights of DD superfamily members, we investigate the interaction mechanisms of DD domains; these domains are involved in TNF ligand-receptor signaling. These DD superfamily members play a pivotal role in the development of more specific treatments of cancer. [BMB Reports 2016; 49(3): 159-166]. PMID- 26615974 TI - Corosolic acid ameliorates acute inflammation through inhibition of IRAK-1 phosphorylation in macrophages. AB - Corosolic acid (CA), a triterpenoid compound isolated from Lagerstroemia speciosa L. (Banaba) leaves, exerts anti-inflammatory effects by regulating phosphorylation of interleukin receptor-associated kinase (IRAK)-2 via the NF kappaB cascade. However, the protective effect of CA against endotoxic shock has not been reported. LPS (200 ng/mL, 30 min) induced phosphorylation of IRAK-1 and treatment with CA (10 MUM) significantly attenuated this effect. In addition, CA also reduced protein levels of NLRP3 and ASC which are the main components of the inflammasome in BMDMs. LPS-induced inflammasome assembly through activation of IRAK-1 was down-regulated by CA challenge. Treatment with Bay11-7082, an inhibitor of IkappaB-alpha, had no effect on CA-mediated inhibition of IRAK-1 activation, indicating that CA-mediated attenuation of IRAK-1 phosphorylation was independent of NF-kappaB signaling. These results demonstrate that CA ameliorates acute inflammation in mouse BMDMs and CA may be useful as a pharmacological agent to prevent acute inflammation. [BMB Reports 2016; 49(5): 276-281]. PMID- 26615975 TI - Selective Killing of Breast Cancer Cells by Doxorubicin-Loaded Fluorescent Gold Nanoclusters: Confocal Microscopy and FRET. AB - Fluorescent gold nanoclusters (AuNCs) capped with lysozymes are used to deliver the anticancer drug doxorubicin to cancer and noncancer cells. Doxorubicin-loaded AuNCs cause the highly selective and efficient killing (90 %) of breast cancer cells (MCF7) (IC50 =155 nm). In contrast, the killing of the noncancer breast cells (MCF10A) by doxorubicin-loaded AuNCs is only 40 % (IC50 =4500 nm). By using a confocal microscope, the fluorescence spectrum and decay of the AuNCs were recorded inside the cell. The fluorescence maxima (at ~490-515 nm) and lifetime (~2 ns), of the AuNCs inside the cells correspond to Au10-13 . The intracellular release of doxorubicin from AuNCs is monitored by Forster resonance energy transfer (FRET) imaging. PMID- 26615976 TI - It's harder for boys? Children's representations of their HIV/AIDS-affected peers in Zimbabwe. AB - This study examines whether children in rural Zimbabwe have differing representations of their HIV/AIDS-affected peers based on the gender of those peers. A group of 128 children (58 boys, 70 girls) aged 10-14 participated in a draw-and-write exercise, in which they were asked to tell the story of either an HIV/AIDS-affected girl child, or an HIV/AIDS-affected boy child. Stories were inductively thematically coded, and then a post hoc statistical analysis was conducted to see if there were differences in the themes that emerged in stories about girls versus stories about boys. The results showed that boys were more often depicted as materially deprived, without adult and teacher support, and heavily burdened with household duties. Further research is needed to determine whether the perceptions of the children in this study point to a series of overlooked challenges facing HIV/AIDS-affected boys, or to a culture of gender inequality facing HIV/AIDS-affected girls - which pays more attention to male suffering than to female suffering. PMID- 26615977 TI - A reappraisal of pediatric abdominal surface anatomy utilizing in vivo cross sectional imaging. AB - Despite being integral to medical and surgical practice, pediatric anatomy has remained relatively neglected except for a few landmark works. Neonatal and pediatric anatomy differs structurally and functionally from adult anatomy in many ways. The aim of the current study was to reappraise common abdominal surface landmarks of important structures in infants and children. After cases with related pathologies had been excluded, computer tomography scans of 90 children were divided into three age groups and systematically analyzed. The vertebral levels of the unpaired branches of the abdominal aorta (AA) were recorded. The vertebral level and relationship to the midline of the bifurcation of the AA and the formation of the inferior vena cava were measured. The renal long axes, costal relationships, renal artery vertebral levels, and hilar vertebral levels were measured. The splenic long axis and relationship to the mid axillary line were also measured. The renal length was disproportionately large in the youngest age group and increased less with age (7.12 cm, 7.85 cm, 8.86 cm). The renal artery was consistently found around L1; the left kidney was related to the 11th and 12th ribs posteriorly, the right kidney only to the 12th rib. The AA bifurcated to the right of the midline in 10% of children. The unpaired visceral branches of the aorta were commonly found at T12 (celiac artery), L1 (superior mesenteric artery), and L3 (inferior mesenteric artery). The current study provides age-standardized surface landmarks and measurements for major abdominal vascular structures and solid organs in normal children. The clinical applications of these data are multiple and diverse. PMID- 26615978 TI - Core/Shell Structured TiO2/CdS Electrode to Enhance the Light Stability of Perovskite Solar Cells. AB - In this work, enhanced light stability of perovskite solar cell (PSC) achieved by the introduction of a core/shell-structured CdS/TiO2 electrode and the related mechanism are reported. By a simple solution-based process (SILAR), a uniform CdS shell was coated onto the surface of a TiO2 layer, suppressing the activation of intrinsic trap sites originating from the oxygen vacancies of the TiO2 layer. As a result, the proposed CdS-PSC exhibited highly improved light stability, maintaining nearly 80% of the initial efficiency after 12 h of full sunlight illumination. From the X-ray diffraction analyses, it is suggested that the degradation of the efficiency of PSC during illumination occurs regardless of the decomposition of the perovskite absorber. Considering the light-soaking profiles of the encapsulated cells and the OCVD characteristics, it is likely that the CdS shell had efficiently suppressed the undesirable electron kinetics, such as trapping at the surface defects of the TiO2 and preventing the resultant charge losses by recombination. This study suggests that further complementary research on various effective methods for passivation of the TiO2 layer would be highly meaningful, leading to insight into the fabrication of PSCs stable to UV-light for a long time. PMID- 26615979 TI - Serpin A1 C-Terminal Peptides as Collagen Turnover Modulators. AB - The modulation of collagen turnover can be a relevant pharmacological target in the context of treating either pathological or pathophysiological conditions, such as collagen-related diseases and skin aging. Our recent work has focused on the search for short-chain peptides as lead compounds for further development of compounds that enhance the production of type I collagen. In this study we selected and synthesized overlapping peptides of the C-terminal portion of serpin A1 (residues 393-418), the impact of which on collagen production has been reported previously, in order to identify shorter and still active fragments and to provide insight on the mechanisms involved. The biological activity of each fragment was evaluated with cultured normal human dermal fibroblasts, and changes in the amounts of collagen were monitored in collected culture media by a sandwich ELISA technique developed in house. Interestingly, we identified a decapeptide, termed SA1-III (Ac-MGKVVNPTQK-NH2 ), as a promising candidate for our purposes; it is able to induce a significant increase in type I collagen levels in the culture medium of treated cells at micromolar concentrations. PMID- 26615980 TI - Cool and hot executive function as predictors of aggression in early childhood: Differentiating between the function and form of aggression. AB - Executive function (EF) has been implicated in childhood aggression. Understanding of the role of EF in aggression has been hindered, however, by the lack of research taking into account the function and form of aggression and the almost exclusive focus on cool EF. This study examined the role of cool and hot EF in teacher reported aggression, differentiating between reactive and proactive as well as physical and relational aggression. Children (N = 106) completed laboratory tasks measuring cool (inhibition, planning, working memory) and hot EF (affective decision-making, delay of gratification). Cool, but not hot, EF significantly contributed to understanding of childhood aggression. Inhibition was a central predictor of childhood aggression. Planning and working memory, in contrast, were significant independent predictors of proactive relational aggression only. Added to this, prosocial behaviour moderated the relationship between working memory and reactive relational aggression. This study therefore suggests that cool EF, particularly inhibition, is associated with childhood aggression across the different functions and forms. PMID- 26615981 TI - Degeneracy in model parameter estimation for multi-compartmental diffusion in neuronal tissue. AB - The ultimate promise of diffusion MRI (dMRI) models is specificity to neuronal microstructure, which may lead to distinct clinical biomarkers using noninvasive imaging. While multi-compartment models are a common approach to interpret water diffusion in the brain in vivo, the estimation of their parameters from the dMRI signal remains an unresolved problem. Practically, even when q space is highly oversampled, nonlinear fit outputs suffer from heavy bias and poor precision. So far, this has been alleviated by fixing some of the model parameters to a priori values, for improved precision at the expense of accuracy. Here we use a representative two-compartment model to show that fitting fails to determine the five model parameters from over 60 measurement points. For the first time, we identify the reasons for this poor performance. The first reason is the existence of two local minima in the parameter space for the objective function of the fitting procedure. These minima correspond to qualitatively different sets of parameters, yet they both lie within biophysically plausible ranges. We show that, at realistic signal-to-noise ratio values, choosing between the two minima based on the associated objective function values is essentially impossible. Second, there is an ensemble of very low objective function values around each of these minima in the form of a pipe. The existence of such a direction in parameter space, along which the objective function profile is very flat, explains the bias and large uncertainty in parameter estimation, and the spurious parameter correlations: in the presence of noise, the minimum can be randomly displaced by a very large amount along each pipe. Our results suggest that the biophysical interpretation of dMRI model parameters crucially depends on establishing which of the minima is closer to the biophysical reality and the size of the uncertainty associated with each parameter. PMID- 26615982 TI - MCM3AP and POMP Mutations Cause a DNA-Repair and DNA-Damage-Signaling Defect in an Immunodeficient Child. AB - Immunodeficiency patients with DNA repair defects exhibit radiosensitivity and proneness to leukemia/lymphoma formation. Though progress has been made in identifying the underlying mutations, in most patients the genetic basis is unknown. Two de novo mutated candidate genes, MCM3AP encoding germinal center associated nuclear protein (GANP) and POMP encoding proteasome maturation protein (POMP), were identified by whole-exome sequencing (WES) and confirmed by Sanger sequencing in a child with complex phenotype displaying immunodeficiency, genomic instability, skin changes, and myelodysplasia. GANP was previously described to promote B-cell maturation by nuclear targeting of activation-induced cytidine deaminase (AID) and to control AID-dependent hyperrecombination. POMP is required for 20S proteasome assembly and, thus, for efficient NF-kappaB signaling. Patient derived cells were characterized by impaired homologous recombination, moderate radio- and cross-linker sensitivity associated with accumulation of damage, impaired DNA damage-induced NF-kappaB signaling, and reduced nuclear AID levels. Complementation by wild-type (WT)-GANP normalized DNA repair and WT-POMP rescued defective NF-kappaB signaling. In conclusion, we identified for the first time mutations in MCM3AP and POMP in an immunodeficiency patient. These mutations lead to cooperative effects on DNA recombination and damage signaling. Digenic/polygenic mutations may constitute a novel genetic basis in immunodeficiency patients with DNA repair defects. PMID- 26615983 TI - The Sphenopalatine Ganglion: Anatomy, Pathophysiology, and Therapeutic Targeting in Headache. AB - The sphenopalatine ganglion (SPG) has attracted the interest of practitioners treating head and face pain for over a century because of its anatomical connections and role in the trigemino-autonomic reflex. In this review, we discuss the anatomy of the SPG, as well as what is known about its role in the pathophysiology of headache disorders, including cluster headache and migraine. We then address various therapies that target the SPG, including intranasal medication delivery, new SPG blocking catheter devices, neurostimulation, chemical neurolysis, and ablation procedures. PMID- 26615984 TI - Orienting versus inhibition in the Concealed Information Test: Different cognitive processes drive different physiological measures. AB - The Concealed Information Test (CIT) provides a valid tool for psychophysiological detection of concealed knowledge. However, its precise theoretical underpinnings remain a matter of debate. The differential physiological responses elicited by concealed, relevant items, relative to control items, were traditionally explained as reflecting an orienting response (OR). According to an alternative account, these responses reflect attempts to inhibit arousal. The present study examined whether and to what extent CIT detection efficiency is affected by instructions aimed at manipulating arousal inhibition (AI). One hundred and forty-eight undergraduate students completed a CIT, while electrodermal, cardiac, and respiratory measures were recorded. Half of the participants were requested to imagine that they are suspected of committing a crime and were motivated to avoid detection (presumably eliciting both OR and AI), while the other half were requested to imagine that they are witnesses of a crime and were motivated to be detected (presumably eliciting OR only). All participants were further requested to remain silent throughout the test. In both conditions, concealed items led to a similar increase in skin conductance as compared to the control items. However, the typically observed heart rate deceleration and respiratory suppression were found in suspects, but not in witnesses. These data imply that different mechanisms drive the responding of different psychophysiological measures used in the CIT, with skin conductance reflecting OR, and heart rate and respiration primarily reflecting AI. PMID- 26615985 TI - Static craniofacial measurements and dynamic airway collapse patterns associated with severe obstructive sleep apnoea: a sleep MRI study. AB - OBJECTIVES: Using sleep MRI, we aimed to identify static craniofacial measurements and dynamic upper airway collapse patterns associated with severe obstructive sleep apnoea (OSA) during natural sleep in age and BMI-matched patients. DESIGN: Nested case-control study. SETTING: Sleep MRI images (3.0 Tesla scanner) and synchronised acoustic recording were used to observe patterns of dynamic airway collapse in subjects with mild and severe OSA. Midsagittal images were also used for static craniofacial measurements. PARTICIPANTS: Fifteen male subjects with severe OSA (mean AHI 70.3 +/- 23 events/h) were matched by age and BMI to 15 subjects with mild OSA (mean AHI 7.8 +/- 1.4 events/h). Subjects were selected from a consecutive sleep MRI study cohort. MAIN OUTCOME MEASURES: Static craniofacial measurements selected a priori included measurements that represent maxillomandibular relationships and airway morphology. Axial, sagittal and coronal views of the airway were rated for dynamic collapse at retropalatal, retroglossal and lateral pharyngeal wall regions by blinded reviewers. Bivariate analysis was used to correlate measures associated with severity of OSA using AHI. Statistical significance was set at P < 0.01. RESULTS: Lateral pharyngeal wall collapse from dynamic sleep MRI (beta = 51.8, P < 0.001) and upper airway length from static MRI images (beta = 27.2, P < 0.001) positively correlated with severity of OSA. CONCLUSIONS: Lateral pharyngeal wall collapse and upper airway length are significantly associated with severe OSA based on sleep MRI. Assessment of these markers can be readily translated to routine clinical practice, and their identification may direct targeted surgical treatment. PMID- 26615987 TI - Design, Synthesis, and Structural Analysis of Divalent N(I) Compounds and Identification of a New Electron-Donating Ligand. AB - The dative-bond representation (L->E) in compounds with main group elements (E) has triggered extensive debate in the recent past. The scope and limits of this nonclassical coordination bond warrant comprehensive exploration. Particularly compounds with (L->N<-L')(+) arrangement are of special interest because of their therapeutic importance. This work reports the design and synthesis of novel chemical species with the general structural formula (L->N<-L')(+) carrying the unusual ligand cyclohexa-2,5-diene-4-(diaminomethynyl)-1-ylidene. Four species belonging to the (L->N<-L')(+) class carrying this unconventional ligand were synthesized. Quantum chemical and X-ray diffraction analyses showed that the electronic and geometric parameters are consistent with those of already reported divalent N(I) compounds. The molecular orbital analysis, geometric parameters, and spectral data clearly support the L->N and N<-L' interactions in these species. The newly identified ligand has the properties of a reactive carbene and high nucleophilicity. PMID- 26615986 TI - Structure, function and evolution of the animal mitochondrial replicative DNA helicase. AB - The mitochondrial replicative DNA helicase is essential for animal mitochondrial DNA (mtDNA) maintenance. Deleterious mutations in the gene that encodes it cause mitochondrial dysfunction manifested in developmental delays, defects and arrest, limited life span, and a number of human pathogenic phenotypes that are recapitulated in animals across taxa. In fact, the replicative mtDNA helicase was discovered with the identification of human disease mutations in its nuclear gene, and based upon its deduced amino acid sequence homology with bacteriophage T7 gene 4 protein (T7 gp4), a bi-functional primase-helicase. Since that time, numerous investigations of its structure, mechanism, and physiological relevance have been reported, and human disease alleles have been modeled in the human, mouse, and Drosophila systems. Here, we review this literature and draw evolutionary comparisons that serve to shed light on its divergent features. PMID- 26615988 TI - BRAF in metastatic colorectal cancer: the future starts now. AB - BRAF mutations are detectable in about 5-15% of metastatic colorectal cancer (mCRC) patients and represent a clear negative prognostic factor. While in BRAF mutated (BRAFmt) metastatic melanoma TKI target therapies (BRAF and MEK inhibitor), both alone or in combination, have shown significant efficacy, in BRAFmt CRC single-agent BRAF-inhibitors as well as chemotherapy seem to be ineffective. The critical role of EGFR in CRC and its multiple downstreaming pathways seem to be involved in this lack of response. In recent years, preclinical investigations and retrospective studies slowly increased our knowledge on BRAFmt CRC. This review analyses preclinical data and discusses several clinical trials in order to explore new therapeutic strategies targeting BRAFmt mCRC. PMID- 26615999 TI - Nanopipette-Based Electroplated Nanoelectrodes. AB - Here, we report a nanopipette-based electrochemical approach to prepare metal nanoelectrodes with excellent control over electrode size, shape, and thickness of the insulation wall. Nanoelectrodes are prepared by electrochemical plating in a laser-pulled quartz nanopipette tip immersed in a liquid gallium/indium alloy electrode, which not only protects the ultrasmall quartz tip but also starts electrodeposition from the tip orifice. This versatile approach enables reproducible fabrication of electrodes of several different metals, including gold, platinum, silver, and copper. Moreover, nanoelectrodes with varying sizes can be easily prepared by focused ion-beam milling. A unique aspect of this method is the control over the thickness of quartz insulation walls relative to the size of the electroactive surface enabling control of the RG (defined as the radius of the insulating sheath over the radius of the active metal electrode). As such, these nanoelectrodes may be especially attractive as useful nanoprobes in high-resolution imaging applications, such as scanning electrochemical microscopy. PMID- 26616000 TI - Anti-tumor effect of bevacizumab on a xenograft model of feline mammary carcinoma. AB - Feline mammary carcinomas are characterized by rapid progression and metastases. Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis, proliferation and metastasis. The present study aimed to investigate the effects of a single drug therapy of bevacizumab on a xenograft model of feline mammary carcinoma expressing VEGF protein. Bevacizumab treatment suppressed tumor growth by inhibiting angiogenesis and enhancing apoptosis; however, it did not affect the tumor proliferation index. Thus, bevacizumab had anti-tumor effects on a xenograft model, and this may be useful for the treatment of feline mammary carcinoma. PMID- 26616001 TI - Effect size comparison of ketorolac nasal spray and commonly prescribed oral combination opioids for pain relief after third molar extraction surgery. AB - OBJECTIVE: Opioids are frequently used for treatment of moderate to severe short term pain, but concerns exist about this treatment approach. Ketorolac tromethamine nasal spray, a nonsteroidal anti-inflammatory, is indicated for the short-term management of moderate to moderately severe pain requiring analgesia at the opioid level. However, there are no direct comparison studies between ketorolac nasal spray and opioids. The objective of this study was to use an effect size analysis to compare the effectiveness of ketorolac nasal spray with oral combination opioid formulations in treating moderate to severe short-term pain. METHODS: An effect size analysis of three randomized, double-blind, placebo controlled studies of third molar extraction surgery compared pain relief with ketorolac nasal spray and commonly prescribed combination opioids including hydrocodone/acetaminophen (APAP), oxycodone/APAP, oxycodone/ibuprofen and tramadol HCl/APAP. Effect size comparisons were made using total pain relief scores (TOTPAR6 or TOTPAR8; the weighted sum of pain relief scores through 6 or 8 h). Pain relief was measured using a five-point categorical rating scale (0 = none; 4 = complete). The effect size equivalent correlation, r, was determined using an online effect size calculator. The treatment effect size r compared with placebo was classified using established criteria (small = 0.20-0.49, moderate = 0.50-0.79 and large = >= 0.80). RESULTS: TOTPAR6 data indicated a moderate effect size for ketorolac nasal spray 31.5 mg (0.51) and oxycodone/ibuprofen 5/400 mg (0.64) and a small effect size for hydrocodone/APAP 7.5/500 mg (0.24) and oxycodone/APAP 5/325 mg (0.32). TOTPAR8 data indicated small effect sizes for ketorolac nasal spray (0.48), hydrocodone/APAP 10/650 mg (0.43), tramadol HCl/APAP 75/650 mg (0.35) and tramadol HCl/APAP 37.5/325 mg (0.17). CONCLUSION: The treatment effect sizes of ketorolac nasal spray were similar to or higher than the opioid comparators after third molar surgery, a well-accepted pain model. These results support ketorolac nasal spray as an effective treatment for moderate to moderately severe short-term pain. PMID- 26616002 TI - Developing the "Informed" of "Informed Mindfulness" One Step at a Time. PMID- 26616003 TI - Evaluating equality in psoriasis healthcare: a cohort study of the impact of age on prescription of biologics. AB - BACKGROUND: Inequality in healthcare has been identified in many contexts. To the best of our knowledge, this is the first study investigating age inequality in the form of prescription patterns of biologics in psoriasis care. OBJECTIVES: To determine whether patients with psoriasis have equal opportunities to receive biological medications as they age. If patients did not receive equal treatment, a subsequent objective was to determine the magnitude of the disparity. METHODS: A cohort of biologic-naive patients with psoriasis was analysed using Cox proportional hazards models to measure the impact of each additional year of life on the likelihood of initiating biological treatment, after controlling for sex, body mass index, comorbidities, disease activity and educational level. A supporting analysis used a nonparametric graphical method to study the proportion of patients initiating biological treatment as age increased, after controlling for the same covariates. RESULTS: The Cox proportional hazards model resulted in hazard ratios of a 1-year increase in age of 0.96-0.97 depending on calendar-year stratification, which implies that an increase in age of 30 years corresponds to a reduced likelihood of initiating biological treatment by 61.3-67.6%. The estimated proportion of patients initiating biological medication always decreased as age increased, at a statistically significant level. CONCLUSIONS: Patients with psoriasis have fewer opportunities to access biological medications as they age. This result was shown to be applicable at all stages in a patient's life course and was not only restricted to the elderly, although it implies greater disparities as the age difference between patients increases. These results show that inequality in access to biological treatments due to age is prevalent in clinical practice today. Further research is needed to investigate the extent to which this result is influenced by patient preferences. PMID- 26616004 TI - A comprehensive study of sensitivity in measuring oscillatory magnetic fields using rotary saturation pulse sequences. AB - Detecting the oscillatory currents with a specific frequency distribution may have the potential to make neuronal current MRI (ncMRI) come true. The phase shift or dephasing induced by both positive and negative episodes of oscillatory neuronal currents is likely to be canceled out over the echo time in typical BOLD contrast fMRI experiments. Based on the contrast of rotary saturation, both of the recently developed spin-locked oscillatory excitation (SLOE) and stimulus induced rotary saturation (SIRS) pulse sequences have been demonstrated to be able to detect weak oscillatory magnetic fields in phantoms with 3T MR scanners. In this report, through Bloch equation simulation as well as water phantom and anesthetic rats experiments, we comprehensively evaluate and compare the sensitivities of these two methods (SLOE and SIRS) in detecting the oscillatory magnetic fields for both high (100 Hz) and low (10 Hz) oscillation frequencies, while using their respective optimal imaging parameters. In agreement with the theoretical predications, both the simulated and experimental results showed that the SLOE method features a much higher detection sensitivity of weak magnetic fields than that of the SIRS method. SLOE was able to detect applied oscillatory magnetic fields as low as 0.1 nT in a water phantom and 0.5 nT in rat brains and the deteriorated noise levels in rat data may account for the reduced sensitivity in vivo. These promising results form the foundation for direct detection of in vivo neuronal currents using MRI. PMID- 26616006 TI - Specific detection of the cleavage activity of mycobacterial enzymes using a quantum dot based DNA nanosensor. AB - We present a quantum dot based DNA nanosensor specifically targeting the cleavage step in the reaction cycle of the essential DNA-modifying enzyme, mycobacterial topoisomerase I. The design takes advantages of the unique photophysical properties of quantum dots to generate visible fluorescence recovery upon specific cleavage by mycobacterial topoisomerase I. This report, for the first time, demonstrates the possibility to quantify the cleavage activity of the mycobacterial enzyme without the pre-processing sample purification or post processing signal amplification. The cleavage induced signal response has also proven reliable in biological matrices, such as whole cell extracts prepared from Escherichia coli and human Caco-2 cells. It is expected that the assay may contribute to the clinical diagnostics of bacterial diseases, as well as the evaluation of treatment outcomes. PMID- 26616007 TI - DHEA-induced modulation of renal gluconeogenesis, insulin sensitivity and plasma lipid profile in the control- and dexamethasone-treated rabbits. Metabolic studies. AB - In view of antidiabetic and antiglucocorticoid effects of dehydroepiandrosterone (DHEA) both in vitro and in vivo studies were undertaken: (i) to elucidate the mechanism of action of both dexamethasone phosphate (dexP) and DHEA on glucose synthesis in primary cultured rabbit kidney-cortex tubules and (ii) to investigate the influence of DHEA on glucose synthesis, insulin sensitivity and plasma lipid profile in the control- and dexP-treated rabbits. Data show, that in cultured kidney-cortex tubules dexP significantly stimulated gluconeogenesis by increasing flux through fructose-1,6-bisphosphatase (FBPase). DexP-induced effects were dependent only upon glucocorticoid receptor. DHEA decreased glucose synthesis via inhibition of glucose-6-phosphatase (G6Pase) and suppressed the dexP-induced stimulation of renal gluconeogenesis. Studies with the use of inhibitors of DHEA metabolism in cultured renal tubules showed for the first time that DHEA directly affects renal gluconeogenesis. However, in view of analysis of glucocorticoids and DHEA metabolites levels in urine, it seems likely, that testosterone may also contribute to DHEA-evoked effects. In dexP-treated rabbits, plasma glucose level was not altered despite increased renal and hepatic FBPase and G6Pase activities, while a significant elevation of both plasma insulin and HOMA-IR was accompanied by a decline of ISI index. It thus appears that increased insulin levels were required to maintain normoglycaemia and to compensate the insulin resistance. DHEA alone affected neither plasma glucose nor lipid levels, while it increased insulin sensitivity and diminished both renal and hepatic G6Pase activities. Surprisingly, DHEA co-administrated with dexP did not alter insulin sensitivity, while it partially suppressed the dexP-induced elevation of renal G6Pase activity and plasma cholesterol and triglyceride contents. As (i) gluconeogenic pathway in rabbit is similar to that in human, and (ii) DHEA counteracts several dexP-evoked effects, it seems likely, that its supplementation might be beneficial to patients treated with glucocorticoids. PMID- 26616008 TI - Structural basis for substrate specificity of Helicobacter pylori M17 aminopeptidase. AB - The M17 aminopeptidase from the carcinogenic gastric bacterium Helicobacter pylori (HpM17AP) is an important housekeeping enzyme involved in catabolism of endogenous and exogenous peptides. It is implicated in H. pylori defence against the human innate immune response and in the mechanism of metronidazole resistance. Bestatin inhibits HpM17AP and suppresses H. pylori growth. To address the structural basis of catalysis and inhibition of this enzyme, we have established its specificity towards the N-terminal amino acid of peptide substrates and determined the crystal structures of HpM17AP and its complex with bestatin. The position of the D-phenylalanine moiety of the inhibitor with respect to the active-site metal ions, bicarbonate ion and with respect to other M17 aminopeptidases suggested that this residue binds to the S1 subsite of HpM17AP. In contrast to most characterized M17 aminopeptidases, HpM17AP displays preference for L-Arg over L-Leu residues in peptide substrates. Compared to very similar homologues from other bacteria, a distinguishing feature of HpM17AP is a hydrophilic pocket at the end of the S1 subsite that is likely to accommodate the charged head group of the L-Arg residue of the substrate. The pocket is flanked by a sodium ion (not present in M17 aminopeptidases that show preference for L Leu) and its coordinating water molecules. In addition, the structure suggests that variable loops at the entrance to, and in the middle of, the substrate binding channel are important determinants of substrate specificity of M17 aminopeptidases. PMID- 26616005 TI - CAP2 in cardiac conduction, sudden cardiac death and eye development. AB - Sudden cardiac death kills 180,000 to 450,000 Americans annually, predominantly males. A locus that confers a risk for sudden cardiac death, cardiac conduction disease, and a newly described developmental disorder (6p22 syndrome) is located at 6p22. One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics. To determine the role of CAP2 in vivo, we generated knockout (KO) mice. cap2(-)/cap2(-) males were underrepresented at weaning and ~70% died by 12 weeks of age, but cap2(-)/cap2(-) females survived at close to the expected levels and lived normal life spans. CAP2 knockouts resembled patients with 6p22 syndrome in that mice were smaller and they developed microphthalmia and cardiac disease. The cardiac disease included cardiac conduction disease (CCD) and, after six months of age, dilated cardiomyopathy (DCM), most noticeably in the males. To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes. We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias. These studies establish a direct role for CAP2 and actin dynamics in sudden cardiac death and cardiac conduction disease. PMID- 26616009 TI - Functional and structural evaluation of bovine heart cytochrome c oxidase incorporated into bicelles. AB - Bilayered long- and short-chain phospholipid assemblies, known as bicelles, have been widely used as model membranes in biological studies. However, to date, there has been no demonstration of structural or functional viability for the fundamental mitochondrial electron transport complexes reconstituted into or interacting with bicelles. In the present work, bicelles were formed from the mixture of long- and short-chain phospholipids, specifically 14:0 and 6:0 phosphatidylcholines (1,2-dimyristoyl-sn-glycero-3-phosphocholine, (DMPC) and 1,2 dihexanoyl-sn-glycero-3-phosphocholine, (DHPC)). Isolated from bovine heart, cytochrome c oxidase was successfully incorporated into bicelles. Bicelles and cytochrome c oxidase incorporated into bicelles ("proteobicelles") were characterized by absorption spectroscopy, dynamic light scattering, atomic force microscopy, sedimentation velocity and differential scanning calorimetry. It was demonstrated that at total concentration of phospholipids CL = 24 mM and the molar ratio (q) of long-chain DMPC over short-chain DHPC equal to 0.4, the diameter of bicelles formed at neutral pH is in the range of 30-60 nm with the thickness of bicelles of about 4 nm. Adding cytochrome c oxidase to bicelles unified the size of the resulting proteobicelles to about 160 nm. Cytochrome c oxidase in bicelles was fully reducible by artificial donors of electrons, exhibited "normal" reaction with external ligands, and was fully active. Both, sedimentation velocity analysis and temperature-induced denaturation indicated that enzyme in bicelles is monomeric. We concluded that cytochrome c oxidase in bicelles maintains its structural and functional integrity, and that bicelles can be used for more comprehensive investigation of cytochrome c oxidase and most likely other mitochondrial electron transfer complexes. PMID- 26616010 TI - Anti-angiogenic activities of CRBGP from buccal glands of lampreys (Lampetra japonica). AB - Cysteine-rich secretory proteins (CRISPs), characterized by 16 conserved cysteines, are distributed in a wide range of organisms, such as secernenteas, amphibians, reptiles and mammals. In the previous studies, a novel CRISP family member (cysteine-rich buccal gland protein, CRBGP) was separated from the buccal gland of lampreys (Lampetra japonica, L. japonica). Lamprey CRBGP could not only suppress depolarization-induced contraction of rat tail arterial smooth muscle, but also block voltage-gated sodium channels (VGSCs). In the present study, the anti-angiogenic activities of lamprey CRBGP were investigated using endothelial cells and chick chorioallantoic membrane (CAM) models. In vitro assays, lamprey CRBGP is able to induce human umbilical vein endothelial cells (HUVECs) apoptosis by disturbing the calcium homeostasis and mitochondria functions. In addition, lamprey CRBGP could inhibit proliferation, adhesion, migration, invasion and tube formation of HUVECs by affecting the organization of F-actin and expression level of matrix metallo-proteinase 2 (MMP-2), matrix metallo-proteinase 9 (MMP-9) and vascular endothelial growth factor A (VEGFA) which are related to angiogenesis. In vivo assays, lamprey CRBGP could suppress the blood vessel formation in CAM models. Therefore, lamprey CRBGP is an important protein present in the buccal gland of lampreys and might help lampreys suppress the contraction of blood vessels, nociceptive responses and wound healing of host fishes during their feeding time. In addition, lamprey CRBGP might have the potential to act as an effective anti-angiogenic factor for the treatment of abnormal angiogenesis induced diseases. PMID- 26616011 TI - Comparison study of distinguishing cancerous and normal prostate epithelial cells by confocal and polarization diffraction imaging. AB - Accurate classification of malignant cells from benign ones can significantly enhance cancer diagnosis and prognosis by detection of circulating tumor cells (CTCs). We have investigated two approaches of quantitative morphology and polarization diffraction imaging on two prostate cell types to evaluate their feasibility as single-cell assay methods toward CTC detection after cell enrichment. The two cell types have been measured by a confocal imaging method to obtain their three-dimensional morphology parameters and by a polarization diffraction imaging flow cytometry (p-DIFC) method to obtain image texture parameters. The support vector machine algorithm was applied to examine the accuracy of cell classification with the morphology and diffraction image parameters. Despite larger mean values of cell and nuclear sizes of the cancerous prostate cells than the normal ones, it has been shown that the morphologic parameters cannot serve as effective classifiers. In contrast, accurate classification of the two prostate cell types can be achieved with high classification accuracies on measured data acquired separately in three measurements. These results provide strong evidence that the p-DIFC method has the potential to yield morphology-related "fingerprints" for accurate and label free classification of the two prostate cell types. PMID- 26616012 TI - Novel Measure of Opioid Dose and Costs of Care for Diabetes Mellitus: Opioid Dose and Health Care Costs. AB - Diabetes mellitus (DM) has well known costly complications but we hypothesized that costs of care for chronic pain treated with opioid analgesic (OA) medications would also be substantial. In a statewide, privately insured cohort of 29,033 adults aged 18 to 64 years with DM and noncancer pain who filled OA prescription(s) from 2008 to 2012, our outcomes were costs for specific health care services and total costs per 6-month intervals after the first filled OA prescription. Average daily OA dose (4 categories) and total dose (quartiles) in morphine-equivalent milligrams were calculated per 6-month interval after the first OA prescription and combined into a novel OA dose measure. Associations of OA measures with costs of care (n = 126,854 6-month intervals) were examined using generalized estimating equations adjusted for clinical conditions, psychotherapeutic drugs, and DM treatment. Incremental costs for each type of health care service and total cost of care increased progressively with average daily and total OA dose versus no OAs. The combined OA measure identified the highest incremental total costs per 6-month interval that were increased by $8,389 for 50- to 99-mg average daily dose plus >900 mg total dose and, by $9,181 and $9,958 respectively, for >=100 mg average daily dose plus 301- to 900-mg or >900 mg total dose. In this statewide DM cohort, total health care costs per 6 month interval increased progressively with higher average daily OA dose and with total OA dose but the greatest increases of >$8,000 were distinguished by combinations of higher average daily and total OA doses. PERSPECTIVE: The higher costs of care for opioid-treated patients appeared for all types of services and likely reflects multiple factors including morbidity from the underlying cause of pain, care and complications related to opioid use, and poorer control of diabetes as found in other studies. PMID- 26616013 TI - Controlling the Electronic Structures and Properties of in-Plane Transition-Metal Dichalcogenides Quantum Wells. AB - In-plane transition-metal dichalcogenides (TMDs) quantum wells have been studied on the basis of first-principles density functional calculations to reveal how to control the electronic structures and the properties. In collection of quantum confinement, strain and intrinsic electric field, TMD quantum wells offer a diverse of exciting new physics. The band gap can be continuously reduced ascribed to the potential drop over the embedded TMD and the strain substantially affects the band gap nature. The true type-II alignment forms due to the coherent lattice and strong interface coupling suggesting the effective separation and collection of excitons. Interestingly, two-dimensional quantum wells of in-plane TMD can enrich the photoluminescence properties of TMD materials. The intrinsic electric polarization enhances the spin-orbital coupling and demonstrates the possibility to achieve topological insulator state and valleytronics in TMD quantum wells. In-plane TMD quantum wells have opened up new possibilities of applications in next-generation devices at nanoscale. PMID- 26616014 TI - Zinc Chloride and Zinc Acetate Injected into the Neostriatum Produce Opposite Effect on Locomotor Behavior of Rats. AB - Zinc chloride and zinc acetate solutions injected in a dose of 1 MUg into the rostral neostriatum produced opposite effect on locomotor behavior of rats. Zink chloride disturbed conditioned avoidance and reduced spontaneous motor activity. Zink acetate virtually did not modify avoidance behavior and stimulated motor activity with elements of motor stereotypy. It was hypothesized that important factors here were the relationship between the effect and the level of metal released after salt dissociation and different reactivity of the synaptic substrate of the neostriatum to the presence of zinc ions. PMID- 26616015 TI - Palladium-catalyzed C-H bond carboxylation of acetanilides: an efficient usage of N,N-dimethyloxamic acid as the carboxylate source. AB - N,N-Dimethyloxamic acid can be successfully employed as a carboxylate precursor in the palladium-catalyzed direct C-H carboxylation of acetanilides. The reaction proceeds smoothly under mild conditions over a broad range of substrates with high functional group tolerance, affording substituted N-acyl anthranilic acids in moderate to high yields. PMID- 26616016 TI - Employee engagement, boredom and frontline construction workers feeling safe in their workplace. AB - Systems thinking is a philosophy currently prevalent within construction safety literature that is applied to understand and improve safety in sociotechnical systems. Among systems, the site-project organizational system is of particular interest to this paper. Using focus group and survey feedback research to learn about how safety incidents effect levels of construction workers engagement this paper reveals how a safety incident provides an opportunity to create a potential quality (productivity) upgrade within an organization. The research approach involved a qualitative study involving 27 frontline supervisors and a follow-up survey completed by 207 frontline workers in the Australian Asphalt and Pavement Industry. The focus group interviews supported the articulation of the concepts of tacit safety, explicit safety, situational awareness, foresight ability, practical intelligence and crew synergy. Our findings indicate that having regular shift changes and other job site workers being fatigued are influential on perceptions of tacit safety. An individual's foresight ability was found to be the most potent predictor of worker perceptions of work engagement. The paper explains that relatively small improvements in worker perceptions of safety can bring about significant improvements in employee engagement and productivity. PMID- 26616017 TI - Do night naps impact driving performance and daytime recovery sleep? AB - Short, nighttime naps are used as a fatigue countermeasure in night shift work, and may offer protective benefits on the morning commute. However, there is a concern that nighttime napping may impact upon the quality of daytime sleep. The aim of the current project was to investigate the influence of short nighttime naps (<30min) on simulated driving performance and subsequent daytime recovery sleep. Thirty-one healthy subjects (aged 21-35 y; 18 females) participated in a 3 day laboratory study. After a 9-h baseline sleep opportunity (22:00h-07:00h), subjects were kept awake the following night with random assignment to: a 10-min nap ending at 04:00h plus a 10-min nap at 07:00h; a 30-min nap ending at 04:00h; or a no-nap control. A 40-min driving simulator task was administered at 07:00h and 18:30h post-recovery sleep. All conditions had a 6-h daytime recovery sleep opportunity (10:00h-16:00h) the next day. All sleep periods were recorded polysomnographically. Compared to control, the napping conditions did not significantly impact upon simulated driving lane variability, percentage of time in a safe zone, or time to first crash on morning or evening drives (p>0.05). Short nighttime naps did not significantly affect daytime recovery total sleep time (p>0.05). Slow wave sleep (SWS) obtained during the 30-min nighttime nap resulted in a significant reduction in SWS during subsequent daytime recovery sleep (p<0.05), such that the total amount of SWS in 24-h was preserved. Therefore, short naps did not protect against performance decrements during a simulated morning commute, but they also did not adversely affect daytime recovery sleep following a night shift. Further investigation is needed to examine the optimal timing, length or combination of naps for reducing performance decrements on the morning commute, whilst still preserving daytime sleep quality. PMID- 26616019 TI - A Negative Feedback Loop Controlling bHLH Complexes Is Involved in Vascular Cell Division and Differentiation in the Root Apical Meristem. AB - Controlling cell division and differentiation in meristems is essential for proper plant growth. Two bHLH heterodimers consisting of LONESOME HIGHWAY (LHW) and TARGET OF MONOPTEROS 5 (TMO5)/TMO5-LIKE1 (T5L1) regulate periclinal cell division in vascular cells in the root apical meristem (RAM). In this study, we further investigated the functions of LHW-T5L1, finding that in addition to controlling cell division, this complex regulates xylem differentiation in the RAM via a novel negative regulatory system. LHW-T5L1 upregulated the thermospermine synthase gene ACAULIS5 (ACL5), as well as SUPPRESSOR OF ACAULIS5 LIKE3 (SACL3), which encodes a bHLH protein, in the RAM. The SACL3 promoter sequence contains a conserved upstream open reading frame (uORF), which blocked translation of the main SACL3 ORF in the absence of thermospermine. Thermospermine eliminated the negative effect of uORF and enhanced SACL3 production. Further genetic and molecular biological analyses indicated that ACL5 and SACL3 suppress the function of LHW-T5L1 through a protein-protein interaction between LHW and SACL3. Finally, we showed that a negative feedback loop consisting of LHW-T5L1, ACL5, SACL3, and LHW-SACL3 contributes to maintain RAM size and proper root growth. These findings suggest that a negative feedback loop regulates the LHW-T5L1 output level to coordinate cell division and differentiation in a cell-autonomous manner. PMID- 26616018 TI - Probing Origin of Binding Difference of inhibitors to MDM2 and MDMX by Polarizable Molecular Dynamics Simulation and QM/MM-GBSA Calculation. AB - Binding abilities of current inhibitors to MDMX are weaker than to MDM2. Polarizable molecular dynamics simulations (MD) followed by Quantum mechanics/molecular mechanics generalized Born surface area (QM//MM-GBSA) calculations were performed to investigate the binding difference of inhibitors to MDM2 and MDMX. The predicted binding free energies not only agree well with the experimental results, but also show that the decrease in van der Walls interactions of inhibitors with MDMX relative to MDM2 is a main factor of weaker bindings of inhibitors to MDMX. The analyses of dihedral angles based on MD trajectories suggest that the closed conformation formed by the residues M53 and Y99 in MDMX leads to a potential steric clash with inhibitors and prevents inhibitors from arriving in the deep of MDMX binding cleft, which reduces the van der Waals contacts of inhibitors with M53, V92, P95 and L98. The calculated results using the residue-based free energy decomposition method further prove that the interaction strength of inhibitors with M53, V92, P95 and L98 from MDMX are obviously reduced compared to MDM2. We expect that this study can provide significant theoretical guidance for designs of potent dual inhibitors to block the p53-MDM2/MDMX interactions. PMID- 26616020 TI - Primary digestive melanoma in association with tubular adenoma: a case report illustrating the distinction from metastatic colonic melanoma. AB - We report here an exceptional pattern of atypical lentiginous melanocytic proliferation within an adenoma, leading to focal lamina propria infiltration and pulmonary metastasis, which was considered as primary colonic mucosal melanoma (MM) in a Caucasian patient. Such case illustrates the diagnosis criteria required to differentiate primary MM from colonic metastasis of melanoma, including the absence of past history of other primary melanoma, a unique colonic and abdominal lesion with predominant features of in situ lentiginous MM and a very focal and unique invasive area without other digestive tract or abdominal localization. This tumor displayed a KIT exon 11 mutation leading to a unique combination of p.I571M and p.D572G deleterious amino acid changes. Such pattern also favors the diagnosis as KIT appears as a master oncogenic player in MM oncogenesis. PMID- 26616021 TI - SUMOylation of AMPKalpha1 by PIAS4 specifically regulates mTORC1 signalling. AB - AMP-activated protein kinase (AMPK) inhibits several anabolic pathways such as fatty acid and protein synthesis, and identification of AMPK substrate specificity would be useful to understand its role in particular cellular processes and develop strategies to modulate AMPK activity in a substrate specific manner. Here we show that SUMOylation of AMPKalpha1 attenuates AMPK activation specifically towards mTORC1 signalling. SUMOylation is also important for rapid inactivation of AMPK, to allow prompt restoration of mTORC1 signalling. PIAS4 and its SUMO E3 ligase activity are specifically required for the AMPKalpha1 SUMOylation and the inhibition of AMPKalpha1 activity towards mTORC1 signalling. The activity of a SUMOylation-deficient AMPKalpha1 mutant is higher than the wild type towards mTORC1 signalling when reconstituted in AMPKalpha deficient cells. PIAS4 depletion reduced growth of breast cancer cells, specifically when combined with direct AMPK activator A769662, suggesting that inhibiting AMPKalpha1 SUMOylation can be explored to modulate AMPK activation and thereby suppress cancer cell growth. PMID- 26616022 TI - [Recurrence of cutaneous sarcoidosis during immune reconstitution syndrome in an HIV-infected patient]. AB - BACKGROUND: Association of sarcoidosis and HIV can occur in the context of immune reconstitution syndrome (IRS) after initiation of antiretroviral therapy (ART). Herein we report a case of cutaneous sarcoidosis in remission in an HIV-infected patient but relapsing during IRS associated with initiation of ART. PATIENTS AND METHODS: A 33-year-old female HIV-infected patient from Cameroon was treated with triple therapy with good efficacy. The patient previously had a small nodular lesion on her left cheek which disappeared spontaneously 2 months before the diagnosis of HIV infection. Three months after initiation of triple ART, the patient consulted again for recurrence of the lesion, which had gradually increased in size. Clinical examination revealed a purplish-red nodular plaque of lupoid appearance under vitropression, located between the inner corner of the eye, the nasal wing and the left cheek. A skin biopsy revealed giant-cell epithelioid dermal granulomas without caseous necrosis. Blood angiotensin converting enzyme levels were elevated and intradermal reaction to tuberculin was negative. A diagnosis was made of cutaneous sarcoidosis. The patient was treated with chloroquine 200mg/day for 3 months, resulting in total subsidence of the lesions. No recurrence was observed at 1 year. DISCUSSION: Introduction of ART has changed the dermatological aspect of HIV infection. In addition to specific dermatological signs specific to HIV and to immunosuppression, there are the cutaneous adverse effects of antiretroviral drugs and skin disorders indicating reconstituted immunity during IRS. Schematically, three forms of IRS may be distinguished: the paradoxical form, the infectious form, and the inflammatory form. The latter corresponds to the onset or exacerbation of inflammatory conditions or autoimmune diseases after the start of ART. Thirty cases of association between sarcoidosis and HIV have been described, of which two-thirds occurred during IRS. The central role of CD4 in sarcoidosis explains its occurrence in HIV patients during reconstitution of the CD4 count. CONCLUSION: In HIV-infected patients treated with anti-retroviral treatment, certain skin diseases such as sarcoidosis may be related to IRS. PMID- 26616023 TI - [South American furuncular myiasis in a returning traveler]. PMID- 26616025 TI - Alkanols inhibit voltage-gated K(+) channels via a distinct gating modifying mechanism that prevents gate opening. AB - Alkanols are small aliphatic compounds that inhibit voltage-gated K(+) (K(v)) channels through a yet unresolved gating mechanism. K(v) channels detect changes in the membrane potential with their voltage-sensing domains (VSDs) that reorient and generate a transient gating current. Both 1-Butanol (1-BuOH) and 1-Hexanol (1 HeOH) inhibited the ionic currents of the Shaker K(v) channel in a concentration dependent manner with an IC50 value of approximately 50 mM and 3 mM, respectively. Using the non-conducting Shaker-W434F mutant, we found that both alkanols immobilized approximately 10% of the gating charge and accelerated the deactivating gating currents simultaneously with ionic current inhibition. Thus, alkanols prevent the final VSD movement(s) that is associated with channel gate opening. Applying 1-BuOH and 1-HeOH to the Shaker-P475A mutant, in which the final gating transition is isolated from earlier VSD movements, strengthened that neither alkanol affected the early VSD movements. Drug competition experiments showed that alkanols do not share the binding site of 4-aminopyridine, a drug that exerts a similar effect at the gating current level. Thus, alkanols inhibit Shaker-type K(v) channels via a unique gating modifying mechanism that stabilizes the channel in its non-conducting activated state. PMID- 26616026 TI - Surgical exploration of 71 free flaps in crisis following head and neck reconstruction. AB - The medical records of patients who had undergone a free flap reconstruction after radical resection of oral cancer between January 2009 and December 2013 at the study hospital in China were reviewed retrospectively. Of the 1550 patients who underwent free flap reconstructions, 71 were explored for suspected flap compromise caused by postoperative thrombosis. Patient demographic data, clinicopathological data of the tumour, details of the free flaps, and operative findings were assessed, and the medical records were analyzed to identify the reasons for intervention and the outcomes. Of the 71 flaps in crisis, 47 (66.2%) were salvaged. Free flap failure was 6.2-times more likely to develop in patients undergoing surgical exploration after 72 h (95% confidence interval 2.090-18.197, P=0.001). Of the 19 flaps identified as subject to delayed exploration, 14 failed and three had partial necrosis. Free flap failure was 3.4-times more likely to develop in patients with perforator flaps (95% confidence interval 1.222-9.719, P=0.019). The early detection of free flap failure is critical to flap salvage. The salvage success rate decreases significantly at >72 h after the initial operation. It appears to be more difficult to salvage a perforator flap. PMID- 26616027 TI - Stability of treatments for recurrent temporomandibular joint luxation: a systematic review. AB - Temporomandibular joint luxation (TMJ) is the excessive anterior translation of the mandibular condyle out of its normal range of movement and away from the glenoid fossa. Once dislocation occurs, the abnormal condylar position generates reflex contractions of the masticatory muscles, which in turn hinder movement of the condyle back to its resting position. Frequent luxation episodes characterize a condition referred to as recurrent TMJ luxation. While there are several surgical and conservative therapeutic options available for recurrent TMJ luxation, a robust, evidence-based rationale for choosing one technique over another is missing. Thus, a systematic review based on the PRISMA statement was proposed in an attempt to determine which therapeutic option results in the longest time to relapse. There is no good quality evidence on which treatment options guarantee the long-term elimination of recurrent TMJ luxation. In cases of post-surgical relapse, eminectomy has often been used as a 'rescue procedure', which may mean that surgeons empirically consider this treatment to be the 'gold standard' for addressing recurrent TMJ luxation. PMID- 26616028 TI - Upper airway dimensions in patients undergoing orthognathic surgery: a systematic review and meta-analysis. AB - The objective of this systematic review was to evaluate the effect of different types of orthognathic surgery on the dimensions of the upper airways assessed using three-dimensional images. An electronic search was performed in Cochrane Library, Medline, Scopus, VHL, Web of Science, and the System for Information on Grey Literature in Europe, ending January 2015. Inclusion criteria encompassed clinical studies in humans, patient age >15 years, patients submitted to maxillary or mandibular advancement or setback surgery, isolated or in combination, and presentation of airway measures, specifically volume and/or minimum cross-sectional area (CSA), obtained from computed tomography or magnetic resonance imaging. Additional searches were conducted on the references of included articles and in the NLM catalogue. An assessment of the risk of bias was performed. A total of 1180 studies were retrieved, of which 28 met the eligibility criteria; one was later excluded as it presented a high risk of bias. A meta-analysis was performed. There is moderate evidence to conclude that the upper airway minimum CSA increases significantly (124.13 mm(2)) after maxillomandibular advancement (MMA); the total volume increases significantly after MMA (7416.10mm(3)) and decreases significantly after maxillary advancement+mandibular setback (-1552.90 mm(3)) and isolated mandibular setback ( 1894.65 mm(3)). PMID- 26616029 TI - Genotyping of 28 blood group alleles in blood donors from Mali: Prediction of rare phenotypes. AB - We determined the frequencies of clinically relevant blood group alleles in 300 blood donors from Mali. Multiplex test based on xMAP technology was used to investigate six blood group systems (RH, KEL, MNS, FY, JK, DO, HPA) and complementary analysis were conducted for MNS and RH systems. Polymorphisms that affect the specificity of molecular tests leading to discrepant genotype results are discussed. Antigen expressions were predicted showing that 50% of donors expressed at least one traditional low prevalence antigen, and 11.6% lacked the ability to express at least one high prevalence antigen compatible with Dob-, HPA1a-, S-s-U-, Jsb-, RH:-31 and/or RH:-34 phenotypes. PMID- 26616031 TI - Time to Cost-Effectiveness Following Stroke Reduction Strategies in AF: Warfarin Versus NOACs Versus LAA Closure. AB - BACKGROUND: Left atrial appendage closure (LAAC) and nonwarfarin oral anticoagulants (NOACs) have emerged as safe and effective alternatives to warfarin for stroke prophylaxis in patients with nonvalvular atrial fibrillation (AF). OBJECTIVES: This analysis assessed the cost-effectiveness of warfarin, NOACs, and LAAC with the Watchman device (Boston Scientific, Marlborough, Massachusetts) for stroke risk reduction in patients with nonvalvular AF at multiple time points over a lifetime horizon. METHODS: A Markov model was developed to assess the cost-effectiveness of LAAC, NOACs, and warfarin from the perspective of the Centers for Medicare & Medicaid Services over a lifetime (20 year) horizon. Patients were 70 years of age and at moderate risk for stroke and bleeding. Clinical event rates, stroke outcomes, and quality of life information were drawn predominantly from PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) 4-year data and meta analyses of warfarin and NOACs. Costs for stroke risk reduction therapies, treatment of associated acute events, and long-term care following disabling stroke were presented in 2015 U.S. dollars. RESULTS: Relative to warfarin, LAAC was cost-effective at 7 years ($42,994/quality-adjusted life-years [QALY]), and NOACs were cost-effective at 16 years ($48,446/QALY). LAAC was dominant over NOACs by year 5 and warfarin by year 10. At 10 years, LAAC provided more QALYs than warfarin and NOACs (5.855 vs. 5.601 vs. 5.751, respectively). In sensitivity analyses, LAAC remained cost-effective relative to warfarin ($41,470/QALY at 11 years) and NOACs ($21,964/QALY at 10 years), even if procedure costs were doubled. CONCLUSIONS: Both NOACs and LAAC with the Watchman device were cost effective relative to warfarin, but LAAC was also found to be cost-effective and to offer better value relative to NOACs. The results of this analysis should be considered when formulating policy and practice guidelines for stroke prevention in AF. PMID- 26616032 TI - Left Atrial Appendage Closure for Stroke Prevention in AF: The Quest for the Holy Grail. PMID- 26616030 TI - Medical Therapy With Versus Without Revascularization in Stable Patients With Moderate and Severe Ischemia: The Case for Community Equipoise. AB - All patients with stable ischemic heart disease (SIHD) should be managed with guideline-directed medical therapy (GDMT), which reduces progression of atherosclerosis and prevents coronary thrombosis. Revascularization is also indicated in patients with SIHD and progressive or refractory symptoms, despite medical management. Whether a strategy of routine revascularization (with percutaneous coronary intervention or coronary artery bypass graft surgery as appropriate) plus GDMT reduces rates of death or myocardial infarction, or improves quality of life compared to an initial approach of GDMT alone in patients with substantial ischemia is uncertain. Opinions run strongly on both sides, and evidence may be used to support either approach. Careful review of the data demonstrates the limitations of our current knowledge, resulting in a state of community equipoise. The ongoing ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) is being performed to determine the optimal approach to managing patients with SIHD, moderate-to-severe ischemia, and symptoms that can be controlled medically. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522). PMID- 26616033 TI - Exploring the Relationship Between Stereotype Perception and Residents' Well Being. AB - BACKGROUND: Medicine has historically been a male-dominated field, and there remains a stereotype that men are better physicians than women. For female residents, and in particular female surgical residents, chronically contending with this stereotype can exact a toll on their psychological health. The objective of this study was to determine the relationship between women surgeons' psychological health and their perception of other people's endorsement of the stereotype (stereotype perception). STUDY DESIGN: This is a correlational study based on survey data collected from 14 residency programs at one medical center from September 2010 to March 2011. The participants were 384 residents (representing an 80% response rate). The main survey measures were the Dupuy Psychological General Well-Being Scale and the Maslach Burnout Inventory. RESULTS: Among female surgical residents, we found that those with higher degrees of stereotype perception had poorer psychological health than those with lower degrees of stereotype perception (beta = -0.44, p = 0.002). For men, there was no relationship between stereotype perception and psychological health (beta = 0.015; p = 0.92). Among nonsurgeons, there was no relationship between stereotype perception and psychological health for either women or men (beta = -0.016; p = 0.78; beta = -0.0050; p = 0.97, respectively). CONCLUSIONS: The data suggest that women in surgical training, but not men, can face a stressor--stereotype perception--that is negatively associated with their psychological health. This same relationship does not seem to exist for women in nonsurgical training programs. Efforts should be made to further understand this relationship and investigate possible interventions to level the playing field for male and female surgical trainees. PMID- 26616034 TI - Surveillance and Early Management of Deep Vein Thrombosis Decreases Rate of Pulmonary Embolism in High-Risk Trauma Patients. AB - BACKGROUND: Venous duplex ultrasound (VDU) is the modality of choice for surveillance of venous thromboembolism (VTE), but there is controversy about its appropriate implementation as a screening method. We hypothesize that VDU surveillance in trauma patients at high risk for VTE decreases the rate of pulmonary embolism (PE). STUDY DESIGN: One thousand two hundred and eighty-two trauma ICU admissions were screened with Greenfield's Risk Assessment Profile from August 2011 to September 2014. Four hundred and two patients were identified as high risk for VTE (Risk Assessment Profile >=10). Those who received weekly VDU to evaluate for deep vein thrombosis (n = 259 [64%]) were compared with those who did not (n = 143 [36%]). Parametric data are reported as mean +/- SD and nonparametric data are reported as median (interquartile range). Statistical significance was determined at an alpha level of 0.05. RESULTS: The overall study population was 47 +/- 19 years old and 75% were male, 78% of injuries were blunt mechanism, Injury Severity Score was 28 +/- 13, Risk Assessment Profile was 14 +/ 4, and mortality was 14.3%. Deep vein thrombosis rate was 11.6% (n = 30) in the surveillance group vs 2.1% (n = 3) in the non-surveillance group (p < 0.001). Deep vein thromboses detected in the surveillance group were managed with systemic anticoagulation (43%) or with IVC filter placement (57%). In the surveillance group, the PE rate was 1.9% (n = 5) vs 7.0% (n = 10) in the non surveillance group (p = 0.014). CONCLUSIONS: Trauma patients at high risk for VTE and who received VDU surveillance and early management of deep vein thrombosis have decreased rates of pulmonary embolism. PMID- 26616036 TI - Enantioselective palladium-catalyzed arylation of N-tosylarylimines with arylboronic acids using a chiral 2,2'-bipyridine ligand. AB - With the aid of an axially chiral 2,2'-bipyridine ligand, we have successfully developed a palladium-catalyzed method for the enantioselective arylation of N tosylarylimines, furnishing the chiral diarylmethamines with high yields and enantioselectivities under very mild conditions. An exogenous base was avoided and imine hydrolysis was inhibited in this transformation. PMID- 26616035 TI - Why do peroxisomes associate with the cytoskeleton? AB - Attachment of peroxisomes to cytoskeleton and movement along microtubular filaments and actin cables are essential and highly regulated processes enabling metabolic efficiency, biogenesis, maintenance and inheritance of this dynamic cellular compartment. Several peroxisome-associated proteins have been identified, which mediate interaction with motor proteins, adaptor proteins or other constituents of the cytoskeleton. It appears that there is a species specific complexity of protein-protein interactions required to control directional movement and arresting. An open question is why some proteins with a specific role in peroxisomal protein import have an additional function in the regulation of cytoskeleton binding and motility of peroxisomes. PMID- 26616037 TI - Estimating dynamic transmission model parameters for seasonal influenza by fitting to age and season-specific influenza-like illness incidence. AB - Dynamic transmission models are essential to design and evaluate control strategies for airborne infections. Our objective was to develop a dynamic transmission model for seasonal influenza allowing to evaluate the impact of vaccinating specific age groups on the incidence of infection, disease and mortality. Projections based on such models heavily rely on assumed 'input' parameter values. In previous seasonal influenza models, these parameter values were commonly chosen ad hoc, ignoring between-season variability and without formal model validation or sensitivity analyses. We propose to directly estimate the parameters by fitting the model to age-specific influenza-like illness (ILI) incidence data over multiple influenza seasons. We used a weighted least squares (WLS) criterion to assess model fit and applied our method to Belgian ILI data over six influenza seasons. After exploring parameter importance using symbolic regression, we evaluated a set of candidate models of differing complexity according to the number of season-specific parameters. The transmission parameters (average R0, seasonal amplitude and timing of the seasonal peak), waning rates and the scale factor used for WLS optimization, influenced the fit to the observed ILI incidence the most. Our results demonstrate the importance of between-season variability in influenza transmission and our estimates are in line with the classification of influenza seasons according to intensity and vaccine matching. PMID- 26616038 TI - One versus two doses: What is the best use of vaccine in an influenza pandemic? AB - Avian influenza A (H7N9), emerged in China in April 2013, sparking fears of a new, highly pathogenic, influenza pandemic. In addition, avian influenza A (H5N1) continues to circulate and remains a threat. Currently, influenza H7N9 vaccines are being tested to be stockpiled along with H5N1 vaccines. These vaccines require two doses, 21 days apart, for maximal protection. We developed a mathematical model to evaluate two possible strategies for allocating limited vaccine supplies: a one-dose strategy, where a larger number of people are vaccinated with a single dose, or a two-dose strategy, where half as many people are vaccinated with two doses. We prove that there is a threshold in the level of protection obtained after the first dose, below which vaccinating with two doses results in a lower illness attack rate than with the one-dose strategy; but above the threshold, the one-dose strategy would be better. For reactive vaccination, we show that the optimal use of vaccine depends on several parameters, with the most important one being the level of protection obtained after the first dose. We describe how these vaccine dosing strategies can be integrated into effective pandemic control plans. PMID- 26616039 TI - Ten-year performance of Influenzanet: ILI time series, risks, vaccine effects, and care-seeking behaviour. AB - Recent public health threats have propelled major innovations on infectious disease monitoring, culminating in the development of innovative syndromic surveillance methods. Influenzanet is an internet-based system that monitors influenza-like illness (ILI) in cohorts of self-reporting volunteers in European countries since 2003. We investigate and confirm coherence through the first ten years in comparison with ILI data from the European Influenza Surveillance Network and demonstrate country-specific behaviour of participants with ILI regarding medical care seeking. Using regression analysis, we determine that chronic diseases, being a child, living with children, being female, smoking and pets at home, are all independent predictors of ILI risk, whereas practicing sports and walking or bicycling for locomotion are associated with a small risk reduction. No effect for using public transportation or living alone was found. Furthermore, we determine the vaccine effectiveness for ILI for each season. PMID- 26616040 TI - Kinetics of antibody response to Coxiella burnetii infection (Q fever): Estimation of the seroresponse onset from antibody levels. AB - BACKGROUND: From 2007 to 2009, the Netherlands experienced a major Q fever epidemic. Long-term serological follow-up of acute Q fever patients enabled the investigation of longitudinal antibody responses and estimating the onset of the seroresponse in individual patients. METHODS: All available IgG and IgM phase I and II antibody measurements determined by immunofluorescence assay at month 3, 6, 12, and 48 from 2321 acute Q fever patients were retrospectively analyzed. Characteristic features of the antibody response were calculated. To model the seroresponse onset, serological data from patients diagnosed with a positive C. burnetii PCR test (n=364), and therefore with a known time of infection, were used as reference. RESULTS: In 9083 IgG samples and 3260 IgM samples large heterogeneity in shape and magnitude of antibody responses was observed. Phase II reached higher levels than phase I, and IgG antibodies were more persistent than IgM. The estimated seroresponse latency allowed for determining the time since start of the seroresponse from the concentrations of the different antibodies against C. burnetii. CONCLUSIONS: The extraordinary large serological dataset provides new insight into the kinetics of the immunoglobulins against C. burnetii antigens. This knowledge is useful for seroprevalence studies and helps to better understand infection dynamics. PMID- 26616042 TI - The effects of demographic change on disease transmission and vaccine impact in a household structured population. AB - The demographic structure of populations in both more developed and less developed countries is changing: increases in life expectancy and declining fertility have led to older populations and smaller households. The implications of these demographic changes for the spread and control of infectious diseases are not fully understood. Here we use an individual based model with realistic and dynamic age and household structure to demonstrate the marked effect that demographic change has on disease transmission at the population and household level. The decline in fertility is associated with a decrease in disease incidence and an increase in the age of first infection, even in the absence of vaccination or other control measures. Although large households become rarer as fertility decreases, we show that there is a proportionate increase in incidence of disease in these households as the accumulation of susceptible clusters increases the potential for explosive outbreaks. By modelling vaccination, we provide a direct comparison of the relative importance of demographic change and vaccination on incidence of disease. We highlight the increased risks associated with unvaccinated households in a low fertility setting if vaccine behaviour is correlated with household membership. We suggest that models that do not account for future demographic change, and especially its effect on household structure, may potentially overestimate the impact of vaccination. PMID- 26616041 TI - Phylodynamic analysis of HIV sub-epidemics in Mochudi, Botswana. AB - Southern Africa continues to be the epicenter of the HIV/AIDS epidemic. This HIV 1 subtype C epidemic has a predominantly heterosexual mode of virus transmission and high (>15%) HIV prevalence among adults. The epidemiological dynamics of the HIV-1C epidemic in southern Africa are still poorly understood. Here, we aim at a better understanding of HIV transmission dynamics by analyzing HIV-1 subtype C sequences from Mochudi, a peri-urban village in Botswana. HIV-1C env gene sequences (gp120 V1C5) were obtained through enhanced household-based HIV testing and counseling in Mochudi. More than 1200 sequences were generated and phylogenetically distinct sub-epidemics within Mochudi identified. The Bayesian birth-death skyline plot was used to estimate the effective reproductive number, R, and the timing of virus transmission, to classify sub-epidemics as "acute" (those with recent viral transmissions) or "historic" (those without recent viral transmissions). We identified two of the 15 sub-epidemics as "acute." The median estimates of R among the clusters ranged from 0.72 to 1.77. The majority of HIV lineages, 11 out of 15 clusters with 5+ members, appear to have been introduced to Mochudi between 1996 and 2002. The median peak duration of viral transmissions was 7.1 years (range 2.9-9.7 years). The median life span of identified HIV sub epidemics, i.e., the time between the inferred epidemic origin and its most recent sample, was 13.1 years (range 10.2-22.1 years). Most viral transmissions within the sub-epidemics occurred between 1997 and 2007. The time period during which infected people are infectious appears to have decreased since the introduction of the national ART program in Botswana. Real-time HIV genotyping and breaking down local HIV epidemics into phylogenetically distinct sub epidemics may help to reveal the structure and dynamics of HIV transmission networks in communities, and aid in the design of targeted interventions for members of the acute sub-epidemics that likely fuel local HIV/AIDS epidemics. PMID- 26616043 TI - Seasonality of absolute humidity explains seasonality of influenza-like illness in Vietnam. AB - BACKGROUND: Experimental and ecological studies have shown the role of climatic factors in driving the epidemiology of influenza. In particular, low absolute humidity (AH) has been shown to increase influenza virus transmissibility and has been identified to explain the onset of epidemics in temperate regions. Here, we aim to study the potential climatic drivers of influenza-like illness (ILI) epidemiology in Vietnam, a tropical country characterized by a high diversity of climates. We specifically focus on quantifying and explaining the seasonality of ILI. METHODS: We used 18 years (1993-2010) of monthly ILI notifications aggregated by province (52) and monthly climatic variables (minimum, mean, maximum temperatures, absolute and relative humidities, rainfall and hours of sunshine) from 67 weather stations across Vietnam. Seasonalities were quantified from global wavelet spectra, using the value of the power at the period of 1 year as a measure of the intensity of seasonality. The 7 climatic time series were characterized by 534 summary statistics which were entered into a regression tree to identify factors associated with the seasonality of AH. Results were extrapolated to the global scale using simulated climatic times series from the NCEP/NCAR project. RESULTS: The intensity of ILI seasonality in Vietnam is best explained by the intensity of AH seasonality. We find that ILI seasonality is weak in provinces experiencing weak seasonal fluctuations in AH (annual power <17.6), whereas ILI seasonality is strongest in provinces with pronounced AH seasonality (power >17.6). In Vietnam, AH and ILI are positively correlated. CONCLUSIONS: Our results identify a role for AH in driving the epidemiology of ILI in a tropical setting. However, in contrast to temperate regions, high rather than low AH is associated with increased ILI activity. Fluctuation in AH may be the climate factor that underlies and unifies the seasonality of ILI in both temperate and tropical regions. Alternatively, the mechanism of action of AH on disease transmission may be different in cold-dry versus hot-humid settings. PMID- 26616044 TI - Exploring the phase diagram of the two-impurity Kondo problem. AB - A system of two exchange-coupled Kondo impurities in a magnetic field gives rise to a rich phase space hosting a multitude of correlated phenomena. Magnetic atoms on surfaces probed through scanning tunnelling microscopy provide an excellent platform to investigate coupled impurities, but typical high Kondo temperatures prevent field-dependent studies from being performed, rendering large parts of the phase space inaccessible. We present a study of pairs of Co atoms on insulating Cu2N/Cu(100), which each have a Kondo temperature of only 2.6 K. The pairs are designed to have interaction strengths similar to the Kondo temperature. By applying a sufficiently strong magnetic field, we are able to access a new phase in which the two coupled impurities are simultaneously screened. Comparison of differential conductance spectra taken on the atoms to simulated curves, calculated using a third-order transport model, allows us to independently determine the degree of Kondo screening in each phase. PMID- 26616045 TI - Design of exceptionally strong and conductive Cu alloys beyond the conventional speculation via the interfacial energy-controlled dispersion of gamma-Al2O3 nanoparticles. AB - The development of Cu-based alloys with high-mechanical properties (strength, ductility) and electrical conductivity plays a key role over a wide range of industrial applications. Successful design of the materials, however, has been rare due to the improvement of mutually exclusive properties as conventionally speculated. In this paper, we demonstrate that these contradictory material properties can be improved simultaneously if the interfacial energies of heterogeneous interfaces are carefully controlled. We uniformly disperse gamma Al2O3 nanoparticles over Cu matrix, and then we controlled atomic level morphology of the interface gamma-Al2O3//Cu by adding Ti solutes. It is shown that the Ti dramatically drives the interfacial phase transformation from very irregular to homogeneous spherical morphologies resulting in substantial enhancement of the mechanical property of Cu matrix. Furthermore, the Ti removes impurities (O and Al) in the Cu matrix by forming oxides leading to recovery of the electrical conductivity of pure Cu. We validate experimental results using TEM and EDX combined with first-principles density functional theory (DFT) calculations, which all consistently poise that our materials are suitable for industrial applications. PMID- 26616047 TI - Flow cytometric quantification of neutrophil extracellular traps: Limitations of the methodological approach. PMID- 26616024 TI - The power of single molecule real-time sequencing technology in the de novo assembly of a eukaryotic genome. AB - Second-generation sequencers (SGS) have been game-changing, achieving cost effective whole genome sequencing in many non-model organisms. However, a large portion of the genomes still remains unassembled. We reconstructed azuki bean (Vigna angularis) genome using single molecule real-time (SMRT) sequencing technology and achieved the best contiguity and coverage among currently assembled legume crops. The SMRT-based assembly produced 100 times longer contigs with 100 times smaller amount of gaps compared to the SGS-based assemblies. A detailed comparison between the assemblies revealed that the SMRT-based assembly enabled a more comprehensive gene annotation than the SGS-based assemblies where thousands of genes were missing or fragmented. A chromosome-scale assembly was generated based on the high-density genetic map, covering 86% of the azuki bean genome. We demonstrated that SMRT technology, though still needed support of SGS data, achieved a near-complete assembly of a eukaryotic genome. PMID- 26616048 TI - Community health centers and primary care access and quality for chronically-ill patients - a case-comparison study of urban Guangdong Province, China. AB - OBJECTIVE: Reform of the health care system in urban areas of China has prompted concerns about the utilization of Community Health Centers (CHC). This study examined which of the dominant primary care delivery models, i.e., the public CHC model, the 'gate-keeper' CHC model, or the hospital-owned CHC models, was most effective in enhancing access to and quality of care for patients with chronic illness. METHODS: The case-comparison design was used to study nine health care organizations in Guangzhou, Dongguan, and Shenzhen cities within Guangdong province, China. 560 patients aged 50 or over with hypertension or diabetes who visited either CHCs or hospitals in these three cities were surveyed by using face-to-face interviews. Bivariate analyses were performed to compare quality and value of care indicators among subjects from the three cities. Multivariate analyses were used to assess the association between type of primary care delivery and quality as well as value of chronic care after controlling for patients' demographic and health status characteristics. RESULTS: Patients from all three cities chose their current health care providers primarily out of concern for quality of care (both provider expertise and adequate medical equipment), patient-centered care, and insurance plan requirement. Compared with patients from Guangzhou, those from Dongguan performed significantly better on most quality and value of care indicators. Most of these indicators remained significantly better even after controlling for patients' demographic and health status characteristics. The Shenzhen model (hospital-owned and -managed CHC) was generally effective in enhancing accessibility and continuity. However, coordination suffered due to seemingly duplicating primary care outpatients at the hospital setting. Significant associations between types of health care facilities and quality of care were also observed such that patients from CHCs were more likely to be satisfied with traveling time and follow-up care by their providers. CONCLUSION: The study suggested that the Dongguan model (based on insurance mandate and using family practice physicians as 'gate-keepers') seemed to work best in terms of improving access and quality for patients with chronic conditions. The study suggested adequately funded and well-organized primary care system can play a gatekeeping role and has the potential to provide a reasonable level of care to patients. PMID- 26616049 TI - Stimulation of nuclear receptor REV-ERBs regulates tumor necrosis factor-induced expression of proinflammatory molecules in C6 astroglial cells. AB - Under physiological conditions, astrocytes maintain homeostasis in the CNS. Following inflammation and injury to the CNS, however, activated astrocytes produce neurotoxic molecules such as cytokines and chemokines, amplifying the initial molecular-cellular events evoked by inflammation and injury. Nuclear receptors REV-ERBalpha and REV-ERBbeta (REV-ERBs) are crucial in the regulation of inflammation- and metabolism-related gene transcription. The current study sought to elucidate a role of REV-ERBs in rat C6 astroglial cells on the expression of inflammatory molecules following stimulation with the neuroinflammatory cytokine tumor necrosis factor (TNF). Stimulation of C6 cells with TNF (10 ng/ml) significantly increased the mRNA expression of CCL2, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and matrix metalloprotease (MMP)-9, but not fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (COX-2) and MMP-2. Treatment with either REV-ERB agonists GSK4112 or SR9009 significantly blocked TNF-induced upregulation of CCL2 mRNA and MMP-9 mRNA, but not IL-6 mRNA and iNOS mRNA expression. Furthermore, treatment with RGFP966, a selective histone deacetylase 3 (HDAC3) inhibitor, potently reversed the inhibitory effects of GSK4112 on TNF-induced expression of MMP-9 mRNA, but not CCL2 mRNA. Expression of Rev-erbs mRNA in C6 astroglial cells, primary cultured rat cortical and spinal astrocytes was confirmed by reverse transcription polymerase chain reaction. Together, the findings demonstrate an anti-inflammatory effect, downregulating of MMP-9 and CCL2 transcription, of astroglial REV-ERBs activation through HDAC3-dependent and HDAC3-independent mechanisms. PMID- 26616050 TI - DNT cell inhibits the growth of pancreatic carcinoma via abnormal expressions of NKG2D and MICA in vivo. AB - This research aimed to investigate the effects of natural killer group 2 member D (NKG2D) and its ligands major histocompatibility complex class I chain-related molecules A(MICA) in DNT cell killing pancreatic carcinoma. Antibodies adsorption was used to separate DNT cell from human peripheral blood. Human pancreatic tumor models were established via implanting BXPC-3 cells into nude mice. Then randomly divided mice into blank group, gemcitabine group and DNT group. Mice weights and mice tumor volumes were measured every 5 days. 50 days later mice were euthanized at cervical dislocation method. Tumor weights were measured. Relative tumor volume and tumor inhibition rate were calculated. Western blot and qPCR were used to detect the expressions of NKG2D and MICA in the transplanted tumors of the three groups. DNT cell significantly increased over time. The blank group tumor volume and weight were significantly larger than the other groups (p < 0.001, p < 0.001), but there were no significantly difference between DNT group and gemcitabine group (p > 0.05). Gemcitabine and DNT cell tumor inhibition rate were 40.4% and 35.5%. Western blot and qPCR showed that MICA mRNA and protein levels in blank group were significantly higher than DNT group (p = 0.001, p = 0.003). NKG2D mRNA and protein levels in blank group were significantly lower than DNT cells group (p < 0.001, p = 0.001). In conclusion DNT cell can significantly inhibit the growth of pancreatic carcinoma in vivo, and the mechanism may be involved in abnormal expressions of MICA and NKG2D. PMID- 26616051 TI - Vaccination with liposome-coupled glypican-3-derived epitope peptide stimulates cytotoxic T lymphocytes and inhibits GPC3-expressing tumor growth in mice. AB - Because therapeutic manipulation of immunity can induce tumor regression, anti cancer immunotherapy is considered a promising treatment modality. We previously reported that glypican-3 (GPC3), an oncofetal antigen overexpressed in hepatocellular carcinoma (HCC), is a useful target for cytotoxic T lymphocyte (CTL)-mediated cancer immunotherapy, and we have performed clinical trials using the GPC3-derived peptide vaccine. Although vaccine-induced GPC3-peptide-specific CTLs were often tumor reactive in vitro and were correlated with overall survival, no complete response was observed. In the current study, we synthesized liposome-coupled GPC3-derived CTL epitope peptide (pGPC3-lipsome) and investigated its antitumor potential. Vaccination with pGPC3-liposome induced peptide-specific CTLs at a lower dose than conventional vaccine emulsified in incomplete Freund's adjuvant. Coupling of pGPC3 to liposomes was essential for effective priming of GPC3-specific CTLs. In addition, immunization with pGPC3 liposome inhibited GPC3-expressing tumor growth. Thus, vaccination with tumor associated antigen-derived epitope peptides coupled to the surfaces of liposomes may be a novel therapeutic strategy for cancer. PMID- 26616053 TI - Identification of the T-complex protein as a binding partner for newly synthesized cytoplasmic dynein intermediate chain 2. AB - Cytoplasmic dynein is a macromolecular motor complex with diverse functions in eukaryotic cells. Dynein plays essential roles in intracellular transport of organelles and mitosis, mediated in part by interactions between the dynein intermediate chain 2 (IC-2) subunits and adapter proteins that bind specific cargos. In experiments to identify phosphorylation-dependent binding partners for IC-2 we instead identified a phosphorylation-independent binding partner, the cytosolic chaperonin containing T complex protein 1 (CCT). CCT consists of eight subunits (CCT1-8) and facilitates folding of a subset of newly synthesized proteins. We confirmed interactions between IC-2 and CCT5 and CCT8 in co immunoprecipitation experiments and determined that the C-terminal half of IC-2 is necessary and sufficient to bind CCT8. Interestingly, co-immunoiprecipitation of IC-2 and CCT is abolished by prior cycloheximide treatment of cells, suggesting that CCT participates in folding of nascent IC-2. In vitro translation experiments employing recombinant CCT complex demonstrated that CCT is able to bind newly synthesized IC-2 after release from the ribosome consistent with a role in folding of IC-2. PMID- 26616052 TI - Effects of vimentin disruption on the mechanoresponses of articular chondrocyte. AB - Human articular cartilage is subjected to repetitive mechanical loading during life time. As the only cellular component of articular cartilage, chondrocytes play a key role in the mechanotransduction within this tissue. The mechanoresponses of chondrocytes are largely determined by the cytoskeleton. Vimentin intermediate filaments, one of the major cytoskeletal components, have been shown to regulate chondrocyte phenotype. However, the contribution of vimentin in chondrocyte mechanoresponses remains less studied. In this study, we seeded goat articular chondrocytes on a soft polyacrylamide gel, and disrupted the vimentin cytoskeleton using acrylamide. Then we applied a transient stretch or compression to the cells, and measured the changes of cellular stiffness and traction forces using Optical Magnetic Twisting Cytometry and Traction Force Microscopy, respectively. In addition, to study the effects of vimentin disruption on the intracellular force generation, we treated the cells with a variety of reagents that are known to increase or decrease cytoskeletal tension. We found that, after a compression, the contractile moment and cellular stiffness were not affected in untreated chondrocytes, but were decreased in vimentin disrupted chondrocytes; after a stretch, vimentin-disrupted chondrocytes showed a lower level of fluidization-resolidification response compared to untreated cells. Moreover, vimentin-disrupted chondrocytes didn't show much difference to control cells in responding to reagents that target actin and ROCK pathway, but showed a weaker response to histamine and isoproterenol. These findings confirmed chondrocyte vimentin as a major contributor in withstanding compressive loading, and its minor role in regulating cytoskeletal tension. PMID- 26616054 TI - The catalytic mechanism of decarboxylative hydroxylation of salicylate hydroxylase revealed by crystal structure analysis at 2.5 A resolution. AB - The X-ray crystal structure of a salicylate hydroxylase from Pseudomonas putida S 1 complexed with coenzyme FAD has been determined to a resolution of 2.5 A. Structural conservation with p- or m-hydroxybenzoate hydroxylase is very good throughout the topology, despite a low amino sequence identity of 20-40% between these three hydroxylases. Salicylate hydroxylase is composed of three distinct domains and includes FAD between domains I and II, which is accessible to solvent. In this study, which analyzes the tertiary structure of the enzyme, the unique reaction of salicylate, i.e. decarboxylative hydroxylation, and the structural roles of amino acids surrounding the substrate, are considered. PMID- 26616055 TI - Bacillus cereus AR156 activates PAMP-triggered immunity and induces a systemic acquired resistance through a NPR1-and SA-dependent signaling pathway. AB - Induced resistance responses play a potent role in plant defense system against pathogen attack. Bacillus cereus AR156 is a plant growth promoting rhizobacterium (PGPR) that installs induced systemic resistance (ISR) to Pseudomonas syringae pv. tomato (Pst) in Arabidopsis. Here, we show that AR156 leaf infiltration enhances disease resistance in Arabidopsis through the activation of a systemic acquired resistance (SAR). PR1 protein expression and reactive oxygen species (ROS) burst are strongly induced in plants treated with AR156 and inoculated with Pst than that in plants inoculated with Pst only. Moreover, AR156 can trigger SAR in jar1 or ein2 mutants, but not in the NahG transgenic and NPR1 mutant plants. Our results indicate that AR156-induced SAR depends on SA-signaling pathway and NPR1, but not JA and ET. Also, AR156-treated plants are able to rapidly activate MAPK signaling and FRK1 gene expression, which are involved in pathogen associated molecular pattern (PAMP)-triggered immunity (PTI). Altogether, our results indicate that AR156 can induce SAR by the SA-signaling pathways in an NPR1-dependent manner and involves multiple PTI components. PMID- 26616056 TI - Insulin dependent apolipoprotein B degradation and phosphatidylinositide 3-kinase activation with microsomal translocation are restored in McArdle RH7777 cells following serum deprivation. AB - Previous studies in rat hepatocytes demonstrated that insulin-dependent apolipoprotein (apo) B degradation (IDAD) is lost when cells are maintained for 3 d under enriched culture conditions. Loss of IDAD correlates with increased expression of protein tyrosine phosphatase 1B (PTP1B) known to be associated with resistance to insulin signaling in the liver. McArdle RH7777 hepatoma (McA) cells cultured in serum containing medium are resistant to IDAD; demonstrate a 30% increase in apo B secretion, and express increased levels of PTP1B protein and mRNA. In addition, insulin-stimulated Class I phosphatidylinositide 3-kinase (PI3K) activity of anti-pY immunoprecipitates is severely blunted. IDAD resistance in McA cells correlates with diminished translocation of insulin stimulated pY-IRS1 to intracellular membranes. Incubation of McA cells with RK682, a protein tyrosine phosphatase inhibitor, is sufficient to restore IDAD in resistant McA cells. Overall, results further support the importance of Class I PI3K activity in IDAD, and suggest that loss of this activity is sufficient to cause resistance. Although other factors are involved in downstream events including sortilin binding to apo B, autophagy, and lysosomal degradation, loss of signal generation and reduced localization of Class I PI3K to intracellular membranes plays a significant role in IDAD resistance. PMID- 26616057 TI - Annexin A2 inhibits the migration of PASMCs stimulated with HPS rat serum by down regulating the expression of paxillin. AB - Hepatopulmonary syndrome (HPS) has been classically associated with intrapulmonary vasodilatation (IPVD) and pulmonary vascular remodelling (PVR), which are the key pathophysiological components of HPS and concerned frequently in the studies of HPS. Little is known about the relevance of pulmonary artery smooth muscle cells (PASMCs) migration or the molecular mechanisms of PVR in HPS. Annexin A2 (ANXA2) plays crucial role in HPS-associated PVR and might activate the activity of paxillin which as a regulatory protein participates in the regulation of PASMCs function in PVR. In addition, it has been identified that ANXA2 could influence the cells migration by some important signaling pathways in many diseases, including lung cancer, pulmonary hypertensionand and liver cancer. In this study, we performed scratch wound motility assay, modified boyden chamber, reverse transcription PCR, western blot and co-immunoprecipitation to determine the role of ANXA2 on HPS-associated PVR. We found that HPS rat serum from a common bile duct ligation (CBDL) rat model enhanced the migration of PASMCs and increased the expression of ANXA2 in PASMCs. We reported that ANXA2 and paxillin could form a co-immunoprecipitation. After silencing ANXA2 with siRNA, we found that the up-regulation of paxillin expression, induced by the HPS rat serum, was reversed. Additionally, we found that down-regulation of ANXA2 could significantly inhibit the migration of PASMCs. These findings indicated that down-regulation of ANXA2 by siRNA results in the inhibition of the aberrant dysregulation of paxillin and migration of PASMCs, which suggesting a potential therapeutic effect on HPS-associated PVR. PMID- 26616046 TI - The fish diversity in the upper reaches of the Salween River, Nujiang River, revealed by DNA barcoding. AB - Nujiang River (NR), an essential component of the biodiversity hotspot of the Mountains of Southwest China, possesses a characteristic fish fauna and contains endemic species. Although previous studies on fish diversity in the NR have primarily consisted of listings of the fish species observed during field collections, in our study, we DNA-barcoded 1139 specimens belonging to 46 morphologically distinct fish species distributed throughout the NR basin by employing multiple analytical approaches. According to our analyses, DNA barcoding is an efficient method for the identification of fish by the presence of barcode gaps. However, three invasive species are characterized by deep conspecific divergences, generating multiple lineages and Operational Taxonomic Units (OTUs), implying the possibility of cryptic species. At the other end of the spectrum, ten species (from three genera) that are characterized by an overlap between their intra- and interspecific genetic distances form a single genetic cluster and share haplotypes. The neighbor-joining phenogram, Barcode Index Numbers (BINs) and Automatic Barcode Gap Discovery (ABGD) identified 43 putative species, while the General Mixed Yule-coalescence (GMYC) identified five more OTUs. Thus, our study established a reliable DNA barcode reference library for the fish in the NR and sheds new light on the local fish diversity. PMID- 26616059 TI - Characterization and sub-cellular localization of GalNAc-binding proteins isolated from human hepatic stellate cells. AB - Although the expression levels of total GalNAc-binding proteins (GNBPs) were up regulated significantly in human hepatic stellate cells (HSCs) activated with transforming growth factor-beta1(TGF-beta1), yet little is known about the precise types, distribution and sub-cellular localization of the GNBPs in HSCs. Here, 264 GNBPs from the activated HSCs and 257 GNBPs from the quiescent HSCs were identified and annotated. A total of 46 GNBPs were estimated to be significantly up-regulated and 40 GNBPs were estimated to be significantly down regulated in the activated HSCs. For example, the GNBPs (i.e. BTF3, COX17, and ATP5A1) responsible for the regulation of protein binding were up-regulated, and those (i.e. FAM114A1, ENO3, and TKT) responsible for the regulation of protein binding were down-regulated in the activated HSCs. The motifs of the isolated GNBPs showed that Proline residue had the maximum preference in consensus sequences. The western blotting showed the expression levels of COX17, and PRMT1 were significantly up-regulated, while, the expression level of CLIC1(B5) was down-regulated in the activated HSCs and liver cirrhosis tissues. Moreover, the GNBPs were sub-localized in the Golgi apparatus of HSCs. In conclusion, the precision alteration of the GNBPs referred to pathological changes in liver fibrosis/cirrhosis may provide useful information to find new molecular mechanism of HSC activation and discover the biomarkers for diagnosis of liver fibrosis/cirrhosis as well as development of new anti-fibrotic strategies. PMID- 26616058 TI - Targeting HIF-1alpha is a prerequisite for cell sensitivity to dichloroacetate (DCA) and metformin. AB - Recently, targeting deregulated energy metabolism is an emerging strategy for cancer therapy. In the present study, combination of DCA and metformin markedly induced cell death, compared with each drug alone. Furthermore, the expression levels of glycolytic enzymes including HK2, LDHA and ENO1 were downregulated by two drugs. Interestingly, HIF-1alpha activation markedly suppressed DCA/metformin induced cell death and recovered the expressions of glycolytic enzymes that were decreased by two drugs. Based on these findings, we propose that targeting HIF 1alpha is necessary for cancer metabolism targeted therapy. PMID- 26616060 TI - Anti-adipogenic effects of sesamol on human mesenchymal stem cells. AB - Human mesenchymal stem cells (hMSCs) from adult bone marrow are able to differentiate into adipocytes, osteoblasts, chondrocytes and neuronal cells. Adipocytes in bone marrow are primarily responsible for the maintenance of bone structure by maintaining cell number balance with other stromal cells. However, the number of adipocytes in the bone marrow increases with age, leading to an imbalance of the bone marrow microenvironment, which results in a disruption of bone structure. In addition, the excessive number of adipocytes in bone marrow can cause diseases, such as osteoporosis or anemia. In this study, we investigated the effect of sesamol, a major natural phenolic compound of sesame oil, on the adipogenic differentiation of hMSCs. Numerous studies have reported the anti-oxidant property of sesamol, but its effect on cell differentiation has not yet been shown. We first found that sesamol treatment during adipogenic differentiation of hMSCs reduced intracellular lipid accumulation, which was unrelated to lipolysis. Interestingly, sesamol diminished the expression of genes responsible for adipogenesis, but increased the expression of osteogenic genes. In addition, sesamol decreased the expression of genes necessary for adipocyte maturation without affecting the expression of hMSC-specific genes. Studies concerning intracellular signaling in hMSCs showed that the extracellular signal regulated kinase 1/2 (ERK1/2) was decreased by sesamol, which was similar with the effect of an ERK1/2 inhibitor. Overall, this study demonstrates that sesamol can attenuate the adipogenic differentiation of hMSCs without affecting its characteristics through the inhibition of ERK1/2 pathway. Herein, this study reports for the first time the effect of sesamol on hMSC differentiation and suggests the possibility of using sesamol as a therapeutic agent to treat intraosseous disruption triggered by the excessive adipogenesis of hMSCs. PMID- 26616061 TI - Radiotherapy with BRAF inhibitor therapy for melanoma: progress and possibilities. AB - The introduction of small molecule BRAF(V600) kinase inhibitors represents a milestone in the targeted therapy of patients with metastatic melanoma by a significant increase in therapeutic efficacy in terms of overall and progression free survival compared with conventional chemotherapy. Beside BRAF(V600) inhibitor treatment, radiotherapy is a further mainstay for the therapy of metastatic melanoma and thus a concomitant or sequential application of BRAF(V600) inhibitors and radiotherapy is inevitable. Recent reports show a significant radiosensitization of the irradiated healthy tissue in patients with melanoma after the combination of radiotherapy and BRAF(V600) inhibitors, evoking concern in clinical practice. We review interactions of BRAF(V600) inhibitors and radiation with regard to antitumor effects and an increased radiotoxicity in the healthy tissue. PMID- 26616062 TI - Rigid-Body Molecular Dynamics of Fullerene-Based Nanocars on Metallic Surfaces. AB - Methodical problems of coarse-grained-type molecular dynamics, namely, rigid-body molecular dynamics (RB MD), are studied by investigating the dynamics of nanosized molecular vehicles called nanocars that move on gold and silver surfaces. Specifically, we analyzed the role of thermostats and the effects of temperature, couplings, and correlations between rigid fragments of the nanocar molecule in extensive RB MD simulations. It is found that the use of the Nose Poincare thermostat does not introduce systematic errors, but the time trajectories might be required to be limited to not accumulate large numerical integration errors. Correlations in the motion of different fragments of the molecules are also analyzed. Our theoretical computations also point to the importance of temperature, interfragment interactions, and interactions with surfaces and to the nature of the surface for understanding mechanisms of motion of single-molecule transporters. PMID- 26616063 TI - Water's Contribution to the Energetic Roughness from Peptide Dynamics. AB - Water plays a very important role in the dynamics and function of proteins. Apart from protein-protein and protein-water interactions, protein motions are accompanied by the formation and breakage of hydrogen-bonding network of the surrounding water molecules. This ordering and reordering of water also adds to the underlying roughness of the energy landscape of proteins and thereby alters their dynamics. Here, we extract the contribution of water to the ruggedness (in terms of an energy scale epsilon) of the energy landscape from molecular dynamics simulations of a peptide substrate analogue of prolyl cis-trans isomerases. In order to do so, we develop and implement a model based on the position space analog of the Ornstein-Uhlenbeck process and Zwanzig's theory of diffusion on a rough potential. This allows us to also probe an important property of the widely used atomistic simulation water models that directly affects the dynamics of biomolecular systems and highlights the importance of the choice of the water model in studying protein dynamics. We show that water contributes an additional roughness to the energy landscape. At lower temperatures this roughness, which becomes comparable to kBT, can considerably slow down protein dynamics. These results also have much broader implications for the function of some classes of enzymes, since the landscape topology of their substrates may change upon moving from an aqueous environment into the binding site. PMID- 26616064 TI - Enhanced Conformational Sampling in Molecular Dynamics Simulations of Solvated Peptides: Fragment-Based Local Elevation Umbrella Sampling. AB - A new method, fragment-based local elevation umbrella sampling (FB-LEUS), is proposed to enhance the conformational sampling in explicit-solvent molecular dynamics (MD) simulations of solvated polymers. The method is derived from the local elevation umbrella sampling (LEUS) method [ Hansen and Hunenberger , J. Comput. Chem. 2010 , 31 , 1 - 23 ], which combines the local elevation (LE) conformational searching and the umbrella sampling (US) conformational sampling approaches into a single scheme. In LEUS, an initial (relatively short) LE build up (searching) phase is used to construct an optimized (grid-based) biasing potential within a subspace of conformationally relevant degrees of freedom, which is then frozen and used in a (comparatively longer) US sampling phase. This combination dramatically enhances the sampling power of MD simulations but, due to computational and memory costs, is only applicable to relevant subspaces of low dimensionalities. As an attempt to expand the scope of the LEUS approach to solvated polymers with more than a few relevant degrees of freedom, the FB-LEUS scheme involves an US sampling phase that relies on a superposition of low dimensionality biasing potentials optimized using LEUS at the fragment level. The feasibility of this approach is tested using polyalanine (poly-Ala) and polyvaline (poly-Val) oligopeptides. Two-dimensional biasing potentials are preoptimized at the monopeptide level, and subsequently applied to all dihedral angle pairs within oligopeptides of 4, 6, 8, or 10 residues. Two types of fragment-based biasing potentials are distinguished: (i) the basin-filling (BF) potentials act so as to "fill" free-energy basins up to a prescribed free-energy level above the global minimum; (ii) the valley-digging (VD) potentials act so as to "dig" valleys between the (four) free-energy minima of the two-dimensional maps, preserving barriers (relative to linearly interpolated free-energy changes) of a prescribed magnitude. The application of these biasing potentials may lead to an impressive enhancement of the searching power (volume of conformational space visited in a given amount of simulation time). However, this increase is largely offset by a deterioration of the statistical efficiency (representativeness of the biased ensemble in terms of the conformational distribution appropriate for the physical ensemble). As a result, it appears difficult to engineer FB-LEUS schemes representing a significant improvement over plain MD, at least for the systems considered here. PMID- 26616065 TI - Ball-and-Stick Local Elevation Umbrella Sampling: Molecular Simulations Involving Enhanced Sampling within Conformational or Alchemical Subspaces of Low Internal Dimensionalities, Minimal Irrelevant Volumes, and Problem-Adapted Geometries. AB - A new method, ball-and-stick local elevation umbrella sampling (B&S-LEUS), is proposed to enhance the sampling in computer simulations of (bio)molecular systems. It enables the calculation of conformational free-energy differences between states (or alchemical free-energy differences between molecules), even in situations where the definition of these states relies on a conformational subspace involving more than a few degrees of freedom. The B&S-LEUS method consists of the following steps: (A) choice of a reduced conformational subspace; (B) representation of the relevant states by means of spheres ("balls"), each associated with a biasing potential involving a one-dimensional radial memory based term and a radial confinement term; (C) definition of a set of lines ("sticks") connecting these spheres, each associated with a biasing potential involving a one-dimensional longitudinal memory-based term and a transverse confinement term; (D) unification of the biasing potentials corresponding to the union of all of the spheres and lines (active subspace) into a single biasing potential according to the enveloping distribution sampling (EDS) scheme; (E) build-up of the memory using the local elevation (LE) procedure, leading to a biasing potential enabling a nearly uniform sampling (radially within the spheres, longitudinally within the lines) of the active subspace; (F) generation of a biased ensemble of configurations using this preoptimized biasing potential, following an umbrella sampling (US) approach; and (G) calculation of the relative free energies of the states via reweighting and state assignment. The main characteristics of this approach are: (i) a low internal dimensionality, that is, the memory only involves one-dimensional grids (acceptable memory requirements); (ii) a minimal irrelevant volume, that is, the conformational volume opened to sampling includes a minimal fraction of irrelevant regions in terms of the free energy of the physical system or of user-specified metastable states (acceptable build-up duration requirements, high statistical efficiency); and (iii) a problem adapted geometry (a priori specification of the conformational regions considered as relevant or irrelevant). In particular, the use of lines to connect the spheres ensures both a minimal irrelevant volume and a sufficient number of transitions between the states. As an illustration, the B&S-LEUS method is applied here to three test systems: (i) a solvated (blocked) alanine monopeptide (two-dimensional conformational subspace), used as a toy system to illustrate the versatility of the method in promoting the sampling of arbritrary regions of the Ramachandran map; (ii) a solvated polyalanine decapeptide (nine-dimensional conformational subspace), to evaluate the relative free energies of three different types of helices (pi, alpha, and 310) based on a single simulation; and (iii) a solvated artifical hexopyranose, termed the "mother" of all d hexopyranoses and constructed as a hybrid of all d-hexopyranose stereoisomers, where the method is applied (seven-dimensional mixed alchemical and conformational subspace) to calculate the relative free energies of the corresponding 32 isomers, anomers, and chair conformers, based on a single simulation. PMID- 26616066 TI - G4-SP, G4(MP2)-SP, G4-sc, and G4(MP2)-sc: Modifications to G4 and G4(MP2) for the Treatment of Medium-Sized Radicals. AB - The G4-SP and G4(MP2)-SP procedures are introduced, as alternatives to G4 and G4(MP2), to overcome shortcomings associated with the treatment of spin polarization (SP) in large open-shell systems. The new methods employ a converging SP term, to replace the diverging A' treatment used in the G4 and G4(MP2) formulations. The G4-SP and G4(MP2)-SP procedures have mean absolute deviations (MADs) from experimental energies of 3.49 and 4.37 kJ mol(-1), respectively, for the G3/05 test set, which are comparable to the MAD values for G4 and G4(MP2) but eliminate the problem of a diverging A' term. For energies involving larger radicals, G4(MP2)-SP performs better than standard G4(MP2). Alternative methods, including G4-5H, G4(MP2)-5H, G4-sc, and G4(MP2)-sc, are also introduced to avoid the problem of an indefinitely increasing SP correction in standard G4 or G4(MP2) for reactions involving larger open-shell systems. PMID- 26616067 TI - A Parallel Iterative Method for Computing Molecular Absorption Spectra. AB - We describe a fast parallel iterative method for computing molecular absorption spectra within TDDFT linear response and using the LCAO method. We use a local basis of "dominant products" to parametrize the space of orbital products that occur in the LCAO approach. In this basis, the dynamic polarizability is computed iteratively within an appropriate Krylov subspace. The iterative procedure uses a matrix-free GMRES method to determine the (interacting) density response. The resulting code is about 1 order of magnitude faster than our previous full-matrix method. This acceleration makes the speed of our TDDFT code comparable with codes based on Casida's equation. The implementation of our method uses hybrid MPI and OpenMP parallelization in which load balancing and memory access are optimized. To validate our approach and to establish benchmarks, we compute spectra of large molecules on various types of parallel machines. The methods developed here are fairly general, and we believe they will find useful applications in molecular physics/chemistry, even for problems that are beyond TDDFT, such as organic semiconductors, particularly in photovoltaics. PMID- 26616068 TI - Electric Field Gradients Calculated from Two-Component Hybrid Density Functional Theory Including Spin-Orbit Coupling. AB - An implementation of a four-component density corrected approach for calculations of nuclear electric field gradients (EFGs) in molecules based on the two component relativistic zeroth-order regular approximation (ZORA) is reported. The program module, which is part of the NWChem package, allows for scalar and spin orbit relativistic computations of EFGs. Benchmark density functional calculations are reported for a large set of main group diatomic molecules, a set of Cu and Au diatomics, several Ru and Nb complexes, the free uranyl ion, and two uranyl carbonate complexes. Data obtained from nonhybrid as well as fixed and range-separated hybrid functionals are compared. To allow for a chemically intuitive interpretation of the results, a breakdown of the EFGs of selected systems in terms of localized molecular orbitals is given. For CuF, CuCl, AuCl, UO2(2+), and a uranyl carbonate complex, the localized orbital decomposition demonstrates in particular the role of the valence metal d and f shells, respectively, and leads to rather compact analyses. For f orbitals, a Townes Dailey-like model is set up to assist the analysis. PMID- 26616069 TI - pi Interactions Studied with Electronic Structure Methods: The Ethyne Methyl Isocyanide Complex and Thioanisole. AB - Two molecular systems for which previous studies had found qualitative differences in the results from calculations with the B3LYP and MP2 methods are investigated with a range of different electronic structure methods, including meta and double hybrid density functionals and DFT-D (DFT augmented with an empirical dispersion term). The performance of the different methods is assessed by comparison to estimated CCSD(T)/CBS (complete basis set) results. The first molecular system studied is the ethyne methyl isocyanide complex (CH3NC-C2H2), which exhibits pi hydrogen bonds involving the C=C and N=C triple bonds. Earlier work on this system had shown that B3LYP predicts significantly longer hydrogen bond distances than MP2. Here, we show that this is likely due to missing dispersion in the B3LYP calculations. On the basis of the CCSD(T) results, the ethyne methyl isocyanide interaction energy is estimated to be 12 +/- 1 kJ/mol. B3LYP significantly underestimates the stability of the complex, whereas MP2 slightly overestimates. M05-2X, B3LYP-D, and (CP-corrected) mPW2-PLYP-D give results in close proximity to the CCSD(T) reference values. The second molecule investigated is thioanisole (C6H6SCH3), which can adopt two different conformations (thiomethyl group either planar or perpendicular with respect to the benzene ring). Potential energy curves for rotation around the C(sp(2))-S bond are computed and compared to the estimated CCSD(T)/CBS curve. CCSD(T) predicts the planar conformation to be the global minimum, with a plateau region near the perpendicular conformation (~4 kJ/mol higher in energy than the planar conformation). The shape of the curve, and location of minima and barriers, is very dependent on the method and basis set employed. MP2, B3LYP, M05-2X, mPW2 PLYP, and mPW2-PLYP-D (employing basis sets of double- or triple-zeta quality) give results in reasonable agreement with the CCSD(T) results, whereas B3LYP-D and M06-L give vastly overestimated barriers at the perpendicular conformation. PMID- 26616070 TI - Scalar and Spin-Orbit Relativistic Corrections to the NICS and the Induced Magnetic Field: The case of the E12(2-) Spherenes (E = Ge, Sn, Pb). AB - Can relativistic effects modify the NICS and the B(ind) values? In this manuscript we evaluate the relativistic corrections incorporated via the zeroth order regular approximation to the calculations of nucleus-independent chemical shifts and the induced magnetic field (B(ind)) in the E12(2-) spherenes (E = Ge, Sn, Pb). We found that both electron delocalization descriptors are strongly affected by the relativistic corrections. For instance, for plumbaspherene, the difference in values from the nonrelativistic to the relativity-included calculation is almost 40 ppm! Our results show that the changes observed in the NICS and B(ind) values in the title cages are a consequence of the treatment of the relativistic effects. If these effects are included as scalar or spin-orbit calculations, then we can establish the next trend: Ge12(2-) is a nonaromatic species, Sn12(2-) is a low aromatic species, and Pb12(2-) is strongly aromatic, according to calculated NICS and B(ind) values. Thus, any prediction of electron delocalization in molecules containing heavy elements without considering an adequate treatment for relativistic effects may lead to an erroneous chemical interpretation. PMID- 26616071 TI - Solving the Independent-Particle Model via Nonunitary Transformation Based on Variational Coupled Cluster Singles. AB - We propose an alternative new approach to obtain the Slater determinant ground state solution within an independent-particle approximation using the exponential ansatz for the wave function (Thouless theorem) and exact treatment in terms of variational coupled cluster singles. Although the resulting nonlinear equations formally represent nonterminating expansions, these can be reformulated to finite expansions in terms of the density matrix correction. The latter can be exactly calculated using a very simple recurrence relation within the occupied-occupied block, while the complementary occupied-virtual and virtual-virtual blocks are related and trivially obtained by subsequent matrix multiplications involving the amplitudes of the single-excitation operator. The density matrix is naturally idempotent in any step of the iterative procedure. Blocks of the density matrix are without any further change, apart from the sign, used in the orbital transformation matrix. The latter is not a unitary one, hence leading to nonorthogonal and unnormalized molecular orbitals. These are, however, biorthogonal and can be easily orthonormalized per blocks, if needed in the post SCF calculations. Formulation is diagonalization free, and the implementation can be easily parallelized. Finally, the formulation provides a challenging way to the solution with "a priori" localized orbitals, a way toward a linear scaling algorithm. PMID- 26616072 TI - Multiple Solutions to the Single-Reference CCSD Equations for NiH. AB - It is typically assumed that once a Hartree-Fock (HF) reference wave function is determined, the correlated wave function obtained from that HF wave function describes the same electronic state. In this paper, we report the appearance of multiple CCSD solutions obtained from the UHF reference wave function for the known ground state of a chemically interesting molecule, NiH. To determine a correspondence between the computed CCSD solutions and the physical electronic states, we consider several characteristics of the CCSD wave functions, e.g., potential energy curves, spin density isovalue plots, and excited state studies via EOM-CCSD calculations. Finally, the use of Brueckner orbitals is encouraged as a way to avoid some of the problems highlighted here for HF-based coupled cluster calculations in such challenging systems. PMID- 26616073 TI - Benchmark Calculations of Absolute Reduction Potential of Ferricinium/Ferrocene Couple in Nonaqueous Solutions. AB - High-level ab initio molecular orbital theory is used to obtain benchmark values for the ferricenium/ferrocene (Fc(+)/Fc) couple, the IUPAC recommended reference electrode for nonaqueous solution. The gas-phase ionization energy of ferrocene is calculated using the high-level composite method, G3(MP2)-RAD, and two higher level variants of this method. These latter methods incorporate corrections for core correlation and, in the case of the highest level considered, use (RO)CCSD(T)/6-311+G(d,p) in place of (RO)CCSD(T)/6-31G(d) as the base level of theory. All methods provide good agreement with one another and the corresponding experimental values. Solvation energies have been calculated using PCM, CPCM, SMD, and COSMO-RS. Using G3(MP2)-RAD-Full-TZ gas-phase energies and COSMO-RS solvation energies, the absolute redox potentials of the Fc(+)/Fc couple have been calculated as 4.988, 4.927, and 5.043 V in acetonitrile, 1,2-dichloroethane, and dimethylsulfoxide solutions, respectively. PMID- 26616074 TI - Describing Anions by Density Functional Theory: Fractional Electron Affinity. AB - It is shown that the majority of commonly used exchange-correlation potentials in Kohn-Sham density functional theory describe anions as having only a fraction of the extra electron bound, while the remaining fraction drifts off to infinity when sufficiently flexible basis sets are employed. For systems with both cationic and anionic sites, this leads to fractional electron transfer, even when standard basis sets are used, and thus a qualitative incorrect description of the electronic structure. Exchange functionals without Hartree-Fock exchange display the largest effects, but hybrid functionals also show the phenomenon, except for strongly bound anions. The source of the error is the incorrect long-range behavior of the exchange potential and can be avoided by employing the long-range correction method. The results have consequences for density functional descriptions of systems with localized anionic or strong electron donor sites for almost all of the commonly employed exchange-correlation functionals. PMID- 26616075 TI - Electron Localization Function at the Correlated Level: A Natural Orbital Formulation. AB - In this work we present a 2-fold approximation for the calculation of the electron localization function (ELF) which avoids the use of the two-particle density (2-PD). The first approximation is used for the calculation of the ELF itself and the second one is used to approximate pair populations integrated in the ELF basins. Both approximations only need the natural orbitals and their occupancies, which are available for most methods used in electronic structure calculations. In this way, methods such as CCSD and MP2 can be used for the calculation of the ELF despite the lack of a pertinent definition of the 2-PD. By avoiding the calculation of the 2-PD, the present formulation provides the means for routine calculations of the ELF in medium-size molecules with correlated methods. The performance of this approximation is shown in a number of examples. PMID- 26616076 TI - On the Dissociation of Ground State trans-HOOO Radical: A Theoretical Study. AB - The hydrotrioxyl radical (HOOO(*)) plays a crucial role in atmospheric processes involving the hydroxyl radical (HO(*)) and molecular oxygen (O2). The equilibrium geometry of the electronic ground state (X (2)A'') of the trans conformer of HOOO(*) and its unimolecular dissociation into HO(*) (X (2)Pi) and O2 (X (3)Sigmag(-)) have been studied theoretically using CASSCF and CASPT2 methodologies with the aug-cc-pVTZ basis set. On the one hand, CASSCF(19,15) calculations predict for trans-HOOO(*) (X (2)A'') an equilibrium structure showing a central O-O bond length of 1.674 A and give a classical dissociation energy De = 1.1 kcal/mol. At this level of theory, it is found that the dissociation proceeds through a transition structure involving a low energy barrier of 1.5 kcal/mol. On the other hand, CASPT2(19,15) calculations predict for trans-HOOO(*) (X (2)A'') a central O-O bond length of 1.682 A, which is in excellent agreement with the experimental value of 1.688 A, and give De = 5.8 kcal/mol. Inclusion of the zero-point energy correction (determined from CASSCF(19,15)/aug-cc-pVTZ harmonic vibrational frequencies) in this De leads to a dissociation energy at 0 K of D0 = 3.0 kcal/mol. This value of D0 is in excellent agreement with the recent experimentally determined D0 = 2.9 +/- 0.1 kcal/mol of Le Picard et al. (Science 2010, 328, 1258-1262). At the CASPT2 level of theory, we did not find for the dissociation of trans-HOOO(*) (X (2)A'') an energetic barrier other than that imposed by the endoergicity of the reaction. This prediction is in accordance with the experimental findings of Le Picard et al., indicating that the reaction of HO(*) with O2 yielding HOOO(*) is a barrierless association process. PMID- 26616077 TI - How Well Can Kohn-Sham DFT Describe the HO2 + O3 Reaction? AB - In a previous work (J. Chem. Theory Comput. 2010, 6, 412) we reported an ab initio investigation of the reaction between ozone and the hydroperoxyl radical. The studies on this atmospheric reaction are here continued with an evaluation of different exchange-correlation functionals (all rungs of "Jacob's ladder" of density functional approximations are represented) in Kohn-Sham DFT calculations. We focus on the comparison between the barrier heights of the oxygen- and hydrogen-abstraction mechanisms here calculated with the ones previously obtained at the CASPT2(11,11)/AVTZ level. The comparison is also extended to the remaining stationary points. Additionally, a relation between the fraction of exact exchange of one-parameter hybrid functionals and the imaginary frequency of a saddle point is developed, originating three new functionals that are also used in the present benchmark calculations. PMID- 26616078 TI - Understanding the Mechanism for Ribonucleotide Reductase Inactivation by 2'- Deoxy-2'-methylenecytidine-5'-diphosphate. AB - Ribonucleotide reductase (RNR) is the key enzyme in the biosynthesis of deoxyribonucleotides. The enzyme has thus an attractive target for chemotherapies that fight proliferation-based diseases. 2'-Deoxy-2'methylenecytidine-5' diphosphate (CH2dCDP) is a potent mechanism-based inhibitor of the enzyme RNR, which decomposes to an active alkylating furanone specie. The details of the inhibition mechanism are unknown, and experimental studies have indicated that some properties of the inactivation are dissimilar to those observed with a number of 2'-substituted 2'-deoxynucleotides mechanism-based inhibitors. To disclose the mechanism involved in RNR inactivation by CH2dCDP we explored the potential-energy surface in two different models of the system with different objectives in mind. In order to conveniently explore the reactional space, i.e. to study the possible reactions between the CH2dCDP and the RNR, we used a small model representing the active site of RNR with CH2dCDP using DFT. To provide further insights and efficiently account for the long-range RNR-CH2dCDP interactions and the stereochemical strain imposed by the protein scaffold we performed theoretical calculations on the more promising reactions using hybrid QM/MM calculations on a larger model system. We used quantum mechanics for the active-site region (CH2dCDP and active-site residues) and molecular mechanics for the surroundings (6373 atoms of the R1 monomer). The results obtained led us to understand the correct mechanism for RNR inactivation by CH2dCDP, and the furanone species formed presumably explains the dissimilarities observed with a number of 2'-substituted 2'-deoxynucleotides. PMID- 26616079 TI - Gold(I)-Catalyzed Hydration of 1,2-Diphenylacetylene: Computational Insights. AB - A DFT investigation of 1,2-diphenylacetilene hydration mediated by the [(Ph3P)Au](+) complex has been carried out to shed light on the mechanistic details of such process with the support of the experimental observations and mechanistic proposal. Computational analysis proves that the first inner-sphere attack of water occurs with gold acting as a proton shuttle to transfer the migrating hydrogen in cis position with respect to OH group. From the formed E isomer of the enol the Z one could be formed by rotation around the C-C bond. The addition of the second water molecule to give the ketone final product occurs favorably with the assistance of the catalyst and involves coordination of water followed by a second hydrogen shift from oxygen to carbon. If the E isomer is involved, gold directly participates in the reaction assisting the hydrogen transfer, whereas if the product is obtained starting from the Z isomer, gold is not directly involved. The elimination of a water molecule and the release of the catalyst close the catalytic cycle. Calculations show that the intervention of a third water molecule lowers the energy barrier for the elimination of water and formation of the pi carbonyl bond. PMID- 26616080 TI - Effective Approximation of Molecular Volume Using Atom-Centered Dielectric Functions in Generalized Born Models. AB - The generalized Born (GB) theory is a prime choice for implicit treatment of solvent that provides a favorable balance between efficiency and accuracy for reliable simulation of protein conformational equilibria. In GB, the dielectric boundary is a key physical property that needs to be properly described. While it is widely accepted that the molecular surface (MS) should provide the most physical description, most existing GB models are based on van der Waals (vdW) like surfaces for computational simplicity and efficiency. A simple and effective approximation to molecular volume is explored here using atom-centered dielectric functions within the context of a generalized Born model with simple switching (GBSW). The new model, termed GBSW/MS2, is as efficient as the original vdW-like surface-based GBSW model, but is able to reproduce the Born radii calculated from the "exact" Poisson-Boltzmann theory with a correlation of 0.95. More importantly, examination of the potentials of mean force of hydrogen-bonding and charge-charge interactions demonstrates that GBSW/MS2 correctly captures the first desolvation peaks, a key signature of true MS. Physical parameters including atomic input radii and peptide backbone torsion were subsequently optimized on the basis of solvation free energies of model compounds, potentials of mean force of their interactions, and conformational equilibria of a set of helical and beta-hairpin model peptides. The resulting GBSW/MS2 protein force field reasonably recapitulates the structures and stabilities of these model peptides. Several remaining limitations and possible future developments are also discussed. PMID- 26616081 TI - Exchange Often and Properly in Replica Exchange Molecular Dynamics. AB - Previous work by us showed that in replica exchange molecular dynamics, exchanges should be attempted extremely often, providing gains in efficiency and no undesired effects. Since that time some questions have been raised about the extendability of these claims to the general case. In this work, we answer this question in two ways. First, we perform a study measuring the effect of exchange attempt frequency in explicit solvent simulations including thousands of atoms. This shows, consistent with the previous assertion, that high exchange attempt frequency allows an optimal rate of exploration of configurational space. Second, we present an explanation of many theoretical and technical pitfalls when implementing replica exchange that cause "improper" exchanges resulting in erroneous data, exacerbated by high exchange attempt frequency. PMID- 26616082 TI - Calculation of One- and Two-Photon Absorption Spectra of Thiolated Gold Nanoclusters using Time-Dependent Density Functional Theory. AB - The one- (OPA) and two-photon (TPA) absorption spectra have been calculated for a gold dimer, for a monothiolated gold dimer anion, for a thiolated gold cluster [Au25(SH)18](-1), whose structure has been determined, and for a proposed cluster [Au12(SR)9](+1) using time-dependent density functional theory (TDDFT). Geometry optimization with different exchange-correlation (X-C) functionals yielded small differences which had significant consequences in the spectra calculations. The calculated excitation energies of Au25(SH)18(-1) are in excellent agreement with experiment when the local density approximation Xalpha-optimized geometry is used with the B3LYP X-C functional. The CAMB3LYP and mCAM functionals yielded OPA results in good agreement with experiment for the dimer systems and the larger clusters. The super-atom theory was useful in analyzing the electronic transitions in the larger clusters. TPA was dominated by resonance effects, and the calculated cross-sections displayed a strong X-C functional dependence. PMID- 26616083 TI - Scaling Factors and Uncertainties for ab Initio Anharmonic Vibrational Frequencies. AB - To predict the vibrational spectra of molecules, ab initio calculations are often used to compute harmonic frequencies, which are usually scaled by empirical factors as an approximate correction for errors in the force constants and for anharmonic effects. Anharmonic computations of fundamental frequencies are becoming increasingly popular. We report scaling factors, along with their associated uncertainties, for anharmonic (second-order perturbation theory) predictions from HF, MP2, and B3LYP calculations using the 6-31G(d) and 6 31+G(d,p) basis sets. Different scaling factors are appropriate for low- and high frequency vibrations. The method of analysis is based upon the Guide to the Expression of Uncertainty in Measurement, published by the International Organization for Standardization (ISO). The data used are from the Computational Chemistry Comparison and Benchmark Database (CCCBDB), maintained by the National Institute of Standards and Technology, which includes more than 3939 independent vibrations for 358 molecules. PMID- 26616084 TI - Sorting Out the Relative Contributions of Electrostatic Polarization, Dispersion, and Hydrogen Bonding to Solvatochromic Shifts on Vertical Electronic Excitation Energies. AB - Conventional polarized continuum model calculations of solvatochromic shifts on electronic excitation energies using popular quantum chemical programs (e.g., Gaussian or Turbomole) include the noninertial and inertial bulk-solvent polarization, which will be called electrostatics, but not dispersion interactions and specific effects like hydrogen bonding. For the n->pi* excitation of acetone in several solvents, we estimated the nonelectrostatic contributions in two ways: (i) the vertical excitation model (VEM) of Li et al. (Int. J. Quantum Chem. 2000, 77, 264), but updated to use TD-DFT corrected linear response with SMD atomic radii, and (ii) in the case of acetone in water, ensemble averaging over supermolecule calculations with up to 12 explicit solvent molecules selected from a molecular dynamics trajectory, with the explicit solvent surrounded by a continuum solvent. The TD-DFT VEM calculations carried out with the M06 density functional for 23 solvents result in a dispersion contribution to the red of 261-356 cm(-1) and a hydrogen-bonding contribution to the blue of up to 289 cm(-1). PMID- 26616085 TI - Understanding the Resonance Raman Scattering of Donor-Acceptor Complexes using Long-Range Corrected DFT. AB - The optical properties involving charge-transfer states of the donor-acceptor electron-transfer complexes carbazole/tetracyanoethylene (carbazole/TCNE) and hexamethylbenzene/tetracyanoethylene (HMB/TCNE) were investigated by utilizing the time-dependent theory of Heller to simulate absorbance and resonance Raman spectra. Excited-state properties were obtained using time-dependent density functional theory (TDDFT) using the global hybrid B3LYP and the long-range corrected LC- omegaPBE functionals and compared with experimental results. It is shown that, while reasonable simulations of the absorbance spectra can be made using B3LYP, the resonance Raman spectra for both complexes are poorly described. The LC-omegaPBE functional gives a more accurate representation of the excited state potential energy surfaces in the Franck-Condon region for charge-transfer states, as indicated by the good agreement with the experimental resonance Raman spectrum. For the carbazole/TCNE complex, which includes contributions from two overlapping excited states on its absorbance spectrum, interference effects are discussed, and it is found that detuning from resonance with an excited state results in interference along with other factors. Total vibrational reorganization energy for both complexes is discussed, and it is found that both B3LYP and LC-omegaPBE yield reasonable estimates of this quantity compared with experiment. PMID- 26616086 TI - Real-Time TD-DFT Simulations in Dye Sensitized Solar Cells: The Electronic Absorption Spectrum of Alizarin Supported on TiO2 Nanoclusters. AB - The structural and electronic properties of the alizarin dye supported on TiO2 nanoclusters have been examined by means of time-dependent density-functional (TD DFT) calculations performed in the time-domain framework. The calculated electronic absorption spectrum of free alizarin shows a first band centered at 2.67 eV that upon adsorption features a red shift by 0.31 eV, in agreement with both experimental and previous theoretical work. This red shift arises from a relative stabilization of the dye LUMO when adsorbed. To analyze the dependence of the electronic properties of the dye-support couple on the size of metal-oxide nanoparticles, different models of (TiO2)n nanoclusters have been used (with n = 1, 2, 3, 6, 9, 15, and 38). As a conclusion, the minimal model is good enough to theoretically reproduce the main feature in the spectrum (i.e., the energy shift of the main band upon binding to TiO2). However, it fails in creating intermediate states which could play a significant role under real experimental conditions (dynamics of the electronic transfer). Indeed, as the size of the nanocluster grows, the dye LUMO moves from the edge to well inside the conduction band (Ti 3d band). On the other hand, to assess the consistency of the time domain approach in the case of such systems, conventional (frequency-domain) TD DFT calculations have been carried out. It is found that, as far as the functional and basis set are equivalent, both approaches lead to similar results. While for small systems the standard TD-DFT is better suited, for medium to large sized systems, the real-time TD-DFT becomes competitive and more efficient. PMID- 26616087 TI - Computational Thermochemistry: Scale Factor Databases and Scale Factors for Vibrational Frequencies Obtained from Electronic Model Chemistries. AB - Optimized scale factors for calculating vibrational harmonic and fundamental frequencies and zero-point energies have been determined for 145 electronic model chemistries, including 119 based on approximate functionals depending on occupied orbitals, 19 based on single-level wave function theory, three based on the neglect-of-diatomic-differential-overlap, two based on doubly hybrid density functional theory, and two based on multicoefficient correlation methods. Forty of the scale factors are obtained from large databases, which are also used to derive two universal scale factor ratios that can be used to interconvert between scale factors optimized for various properties, enabling the derivation of three key scale factors at the effort of optimizing only one of them. A reduced scale factor optimization model is formulated in order to further reduce the cost of optimizing scale factors, and the reduced model is illustrated by using it to obtain 105 additional scale factors. Using root-mean-square errors from the values in the large databases, we find that scaling reduces errors in zero-point energies by a factor of 2.3 and errors in fundamental vibrational frequencies by a factor of 3.0, but it reduces errors in harmonic vibrational frequencies by only a factor of 1.3. It is shown that, upon scaling, the balanced multicoefficient correlation method based on coupled cluster theory with single and double excitations (BMC-CCSD) can lead to very accurate predictions of vibrational frequencies. With a polarized, minimally augmented basis set, the density functionals with zero-point energy scale factors closest to unity are MPWLYP1M (1.009), tauHCTHhyb (0.989), BB95 (1.012), BLYP (1.013), BP86 (1.014), B3LYP (0.986), MPW3LYP (0.986), and VSXC (0.986). PMID- 26616088 TI - Ab Initio Study of Water Polarization in the Hydration Shell of Aqueous Hydroxide: Comparison between Polarizable and Nonpolarizable Water Models. AB - Ab initio simulations of aqueous hydroxide are performed to study the structure and polarization of water molecules in the first solvation shell. Polarization is found to depend on the configuration of the hydrogen-bond (HB) donors. In the most common case of four HB donors, the dipole moment of water molecules is much larger than those in the first shell of monovalent ions. When there are only three HB donors, the water dipole moment exceeds even those in the first shell of a divalent cation. We also show that the dipole fluctuations in the first hydration shell of hydroxide are reduced compared to bulk water, which can provide a rationale for the propensity of hydroxide for interfaces with hydrophobes. Because of its unique properties, hydroxide provides a nontrivial test for benchmarking classical models. Comparison of the ab initio results with those obtained from the classical models indicates that the latter need to be further improved in order to yield reliable results. PMID- 26616089 TI - Quantum Mechanical and Quantum Mechanical/Molecular Mechanical Studies of the Iron-Dioxygen Intermediates and Proton Transfer in Superoxide Reductase. AB - Classical and quantum-chemical computations are employed to probe the reaction intermediates and proton-transfer processes in superoxide reductase (SOR) from Desulfoarculus baarsii. Ab initio studies of the SOR active site, as well as classical and QM/MM MD simulations on the overall enzymatic reaction, are performed. We explore the use of a Hubbard U correction to standard density functional theory (DFT) in order to obtain a better description of the strongly correlated d electrons in the transition-metal center. The results obtained from the standard and Hubbard-U-corrected DFT approaches are compared with those obtained using different hybrid-DFT functionals. We show that the Hubbard U correction gives a significant improvement in the description of the structural, energetic, and electronic properties of SOR. We establish that adopting the Hubbard U correction in the QM/MM approach leads to increased accuracy with essentially no additional computational cost. Our results suggest that Lys(48) is one of the likely sources of the first proton donation to the superoxide, either directly or through an interstitial water molecule. Our QM/MM calculations highlight the important role of the interactions and hydrogen-bond network created by the imidazole rings of the His ligands and the internal water molecules. Whereas the hydrogen-bonding pattern due to internal waters can facilitate the protonation event, the interactions with the His ligands and the hydrogen bonds with water can stabilize the dioxygen ligand in a side-on conformation, which, in turn, prevents the immediate proton transfer from Lys(48), as indicated by recent experimental studies. PMID- 26616090 TI - Approaching Elastic Network Models to Molecular Dynamics Flexibility. AB - Elastic network models (ENMs) are coarse-grained descriptions of proteins as networks of coupled harmonic oscillators. However, despite their widespread application to study collective movements, there is still no consensus parametrization for the ENMs. When compared to molecular dynamics (MD) flexibility in solution, the ENMs tend to disperse the important motions into multiple modes. We present here a new ENM, trained against a database of atomistic MD trajectories. The role of residue connectivity, the analytical form of the force constants, and the threshold for interactions were systematically explored. We found that contacts between the three nearest sequence neighbors are crucial determinants of the fundamental motions. We developed a new general potential function including both the sequential and spatial relationships between interacting residue pairs which is robust against size and fold variations. The proposed model provides a systematic improvement compared to standard ENMs: Not only do its results match the MD results-even for long time scales-but also the model is able to capture large X-ray conformational transitions as well as NMR ensemble diversity. PMID- 26616091 TI - Structural Fluctuations in Enzyme-Catalyzed Reactions: Determinants of Reactivity in Fatty Acid Amide Hydrolase from Multivariate Statistical Analysis of Quantum Mechanics/Molecular Mechanics Paths. AB - The effects of structural fluctuations, due to protein dynamics, on enzyme activity are at the heart of current debates on enzyme catalysis. There is evidence that fatty acid amide hydrolase (FAAH) is an enzyme for which reaction proceeds via a high-energy, reactive conformation, distinct from the predominant enzyme-substrate complex (Lodola et al. Biophys. J. 2007, 92, L20-22). Identifying the structural causes of differences in reactivity between conformations in such complex systems is not trivial. Here, we show that multivariate analysis of key structural parameters can identify structural determinants of barrier height by analysis of multiple reaction paths. We apply a well-tested quantum mechanics/molecular mechanics (QM/MM) method to the first step of the acylation reaction between FAAH and oleamide substrate for 36 different starting structures. Geometrical parameters (consisting of the key bond distances that change during the reaction) were collected and used for principal component analysis (PCA), partial least-squares (PLS) regression analysis, and multiple linear regression (MLR) analysis. PCA indicates that different "families" of enzyme-substrate conformations arise from QM/MM molecular dynamics simulation and that rarely sampled, catalytically significant conformational states can be identified. PLS and MLR analyses allowed the construction of linear regression models, correlating the calculated activation barriers with simple geometrical descriptors. These analyses reveal the presence of two fully independent geometrical effects, explaining 78% of the variation in the activation barrier, which are directly correlated with transition-state stabilization (playing a major role in catalysis) and substrate binding. These results highlight the power of statistical approaches of this type in identifying crucial structural features that contribute to enzyme reactivity. PMID- 26616092 TI - Dynamics-Based Discovery of Allosteric Inhibitors: Selection of New Ligands for the C-terminal Domain of Hsp90. AB - The study of allosteric functional modulation in dynamic proteins is attracting increasing attention. In particular, the discovery of new allosteric sites may generate novel opportunities and strategies for drug development, overcoming the limits of classical active-site oriented drug design. In this paper, we report on the results of a novel, ab initio, fully computational approach for the discovery of allosteric inhibitors based on the physical characterization of signal propagation mechanisms in proteins and apply it to the important molecular chaperone Hsp90. We first characterize the allosteric "hot spots" involved in interdomain communication pathways from the nucleotide-binding site in the N domain to the distal C-domain. On this basis, we develop dynamic pharmacophore models to screen drug libraries in the search for small molecules with the functional and conformational properties necessary to bind these "hot spot" allosteric sites. Experimental tests show that the selected moelcules bind the Hsp90 C-domain, exhibit antiproliferative activity in different tumor cell lines, while not affecting proliferation of normal human cells, destabilize Hsp90 client proteins, and disrupt association with several cochaperones known to bind the N- and M-domains of Hsp90. These results prove that the hits alter Hsp90 function by affecting its conformational dynamics and recognition properties through an allosteric mechanism. These findings provide us with new insights on the discovery and development of new allosteric inhibitors that are active on important cellular pathways through computational biology. Though based on the specific case of Hsp90, our approach is general and can readily be extended to other target proteins and pathways. PMID- 26616093 TI - Coarse-Grained Representations of Large Biomolecular Complexes from Low Resolution Structural Data. AB - High-resolution atomistic structures of many large biomolecular complexes have not yet been solved by experiments, such as X-ray crystallography or NMR. Often however low-resolution information is obtained by alternative techniques, such as cryo-electron microscopy or small-angle X-ray scattering. Coarse-grained (CG) models are an appropriate choice to computationally study these complexes given the limited resolution experimental data. One of the important questions therefore is how to define CG representations from these low-resolution density maps. This work provides a space-based essential dynamics coarse-graining (ED-CG) method to define a CG representation from a density map without detailed knowledge of its underlying atomistic structure and primary sequence information. This method is demonstrated on G-actin (both the atomic structure and its density map). It is then applied to the density maps of the Escherichia coli 70S ribosome and the microtubule. The results indicate that the method can define highly CG models that still preserve functionally important dynamics of large biomolecular complexes. PMID- 26616094 TI - Reconstruction of Pelvic Fracture Urethral Injuries With Sparing of the Bulbar Arteries. AB - OBJECTIVE: To present a novel reconstruction technique for patients with pelvic fracture urethral injuries (PFUI) with bulbar artery sparing. MATERIALS AND METHODS: We modified the traditional technique for PFUI reconstruction to preserve the proximal arterial inflow to the bulb. Since 2008, 26 consecutive patients have undergone this technique at our institution. The bulbar arteries are located using a Doppler ultrasound stethoscope and then the bulb is mobilized from one side only, without detachment from the perineum. The artery from that side is sacrificed to preserve the contralateral one; sometimes both arteries can be spared. Removal of the scar and end-to-end anastomosis is performed as usual. Successful arterial preservation was verified by postanastomosis Doppler auscultation. RESULTS: Mean age was 37 years (15 to 70). Median time from trauma to urethral reconstruction was 11 weeks and mean stenosis length was 2.3 cm (1 to 4.5 cm). The left bulbar artery was preserved in 14 cases, the right in 4, and both arteries were spared in seven; an accidental injury of the artery to be preserved occurred in the remaining case. At a mean follow-up of 20 months (2 69), all patients are voiding normally stricture free. CONCLUSION: Preservation of proximal arterial blood supply to the bulb during PFUI reconstruction is feasible and safe. A well-perfused reconstruction should heal better and theoretically our technique may avoid ischemic failure of the urethroplasty. A larger series and replication of our results in other centers are necessary to validate our technique's potential benefits. PMID- 26616095 TI - The Relationship Between Testosterone-Replacement Therapy and Lower Urinary Tract Symptoms: A Systematic Review. AB - OBJECTIVE: To systematically review prospective trials evaluating the clinical effects of testosterone-replacement therapy on lower urinary tract symptoms and prostate volume. MATERIALS AND METHODS: We performed a literature review through PubMed, Embase, and Cochrane Library from 1994 to 2015 for prospective trials of hypogonadal men with benign prostatic hyperplasia or lower urinary tract symptoms treated with testosterone-replacement therapy. We evaluated the abstracts for outcomes related to International Prostate Symptom Score, prostate volume, and urodynamic parameters. RESULTS: An original cohort of 3079 abstracts was reviewed. Thirty-five trials were selected for inclusion. The majority of trials reviewed found no significant prostate growth due to testosterone-replacement therapy. Studies of men with baseline mild lower urinary tract symptoms demonstrated either no change or an improvement in symptoms after treatment. There was a lack of relevant urodynamic studies. Trials of men with the metabolic syndrome demonstrated uniform improvement in lower urinary tract symptoms. Forty six percent of all the trials identified included exclusion criteria for baseline severe-range lower urinary tract symptoms or other signs of obstructive lower urinary tract symptoms. CONCLUSION: The current literature demonstrates scant support for a causative relationship between testosterone-replacement therapy, de novo or worsening lower urinary tract symptoms, and prostate volume. Furthermore, our review found an absence of high quality evidence that would support guideline recommendations that testosterone-replacement therapy is relatively contraindicated in men with severe-range lower urinary tract symptoms. Future clinical trials with more inclusive voiding criteria are needed. PMID- 26616096 TI - Congenital Mesoblastic Nephroma Presenting With Hematuria in a Neonate: A Case Report. AB - Congenital mesoblastic nephroma (CMN) is the most frequent renal neoplasm of newborns and young infants. Four cases presenting with hemorrhagic manifestations have been reported in the English literature (Hu et al, 2006; Bolande et al, 1967). We report the unusual clinical and radiographic findings of a 2-day-old neonate with hematuria secondary to a CMN. The first ultrasound was equivocal. Repeat ultrasound followed by magnetic resonance imaging confirmed the diagnosis. He underwent a right nephroureterectomy with histopathology revealing a cellular variant of CMN without classical translocation (t12:15). Neonates presenting with hematuria require close follow-up and serial imaging to rule out occult renal tumors. Classical translocation may not be demonstrable in all the cases. PMID- 26616097 TI - [PRETAGREF study: Prevalence of tobacco use and factors associated with smoking cessation in kidney transplant recipients]. AB - INTRODUCTION: Tobacco use increases the risk of mortality, cancers and cardiovascular diseases in transplanted patients. Transplanted patients are encouraged to quit tobacco use before and after renal transplantation. This study was carried out to evaluate the prevalence of tobacco consumption in transplanted patients in one French region. This survey was also conducted to identify factors associated with failure in smoking cessation. MATERIALS AND METHOD: A questionnaire was sent by mail to transplanted patients followed in our center between the 1/01/95 and the 31/12/10. A second mail was sent to increase the response rate. RESULTS: During the study period, 544 questionnaires were sent to kidney transplant recipients. Among these 544 patients, there were 362 responders. Of these 362 patients, 121 patients (33.4%) were past smokers, and 21 (5.8%) were active smokers. Among the smokers, 20% were exposed to second-hand smoke, 48% had criteria for tobacco moderate to high dependency, and 13.4% were addicted to alcohol. In the multivariate analysis, exposure to second-hand smoke and living alone at home were associated with failure in smoking cessation. CONCLUSION: This study shows that the prevalence of tobacco use is not high in transplanted patients. Only 6% of our patients report tobacco use at the study time. Environmental factors are associated with failure in tobacco cessation. Living alone and exposure to second-hand smoke are associated with smoking. Therefore, in transplantation centers, programs devoted to tobacco cessation should be implemented and should take care of patients' lifestyle. PMID- 26616098 TI - Transcription analysis of pyranose dehydrogenase from the basidiomycete Agaricus bisporus and characterization of the recombinantly expressed enzyme. AB - Agaricus bisporus is a litter degrading basidiomycete commonly found in humic rich environments. It is used as model organism and cultivated in large scale for food industry. Due to its ecological niche it produces a variety of enzymes for detoxification and degradation of humified plant litter. One of these, pyranose dehydrogenase, is thought to play a role in detoxification and lignocellulose degradation. It is a member of the glucose-methanol-choline family of flavin dependent enzymes and oxidizes a wide range of sugars with concomitant reduction of electron acceptors like quinones. In this work, transcription of pdh in A. bisporus was investigated with real-time PCR revealing influence of the carbon source on pdh expression levels. The gene was isolated and heterologously expressed in Pichia pastoris. Characterization of the recombinant enzyme showed a higher affinity towards disaccharides compared to other tested pyranose dehydrogenases from related Agariceae. Homology modeling and sequence alignments indicated that two loops of high sequence variability at substrate access site could play an important role in modulating these substrate specificities. PMID- 26616099 TI - Single-step affinity and cost-effective purification of recombinant proteins using the Sepharose-binding lectin-tag from the mushroom Laetiporus sulphureus as fusion partner. AB - Previous research showed that a lectin from the mushroom Laetiporus sulphureus, designed LSL, bound to Sepharose and could be eluted by lactose. In this study, by taking advantage of the strong affinity of LSL-tag for Sepharose, we developed a single-step purification method for LSL-tagged fusion proteins. We utilized unmodified Sepharose-4B as a specific adsorbent and 0.2 M lactose solution as an elution buffer. Fusion proteins of LSL-tag and porcine circovirus capsid protein, designated LSL-Cap was recovered with purity of 90 +/- 4%, and yield of 87 +/- 3% from crude extract of recombinant Escherichia coli. To enable the remove of LSL tag, tobacco etch virus (TEV) protease recognition sequence was placed downstream of LSL-tag in the expression vector, and LSL-tagged TEV protease, designated LSL TEV, was also expressed in E. coli., and was recovered with purity of 82 +/- 5%, and yield of 85 +/- 2% from crude extract of recombinant E. coli. After digestion of LSL-tagged recombinant proteins with LSL-TEV, the LSL tag and LSL-TEV can be easily removed by passing the digested products through the Sepharose column. It is of worthy noting that the Sepharose can be reused after washing with PBS. The LSL affinity purification method enables rapid and inexpensive purification of LSL-tagged fusion proteins and scale-up production of native proteins. PMID- 26616100 TI - The vibrational spectroscopy of the coordinated azide anion; a theoretical study. AB - The vibrational behaviour of the azide anion in a variety of environments has been examined by DFT methods. The frequency is sensitive to polar, dipolar and quadrupolar fields. The frequency is also dependent on the metal to which it is bonded and thus to the details of that bonding. Several azides within one molecule can be strongly vibrationally coupled, a coupling which carries with it a transfer of spectral activity. It is suggested that whilst absolute vibrational frequencies carry little immediately accessible information, a combination of infrared and Raman data for the antisymmetric stretch region might give limited structural insights. PMID- 26616102 TI - Central olfactory processing in patients with disorders of consciousness. AB - BACKGROUND AND PURPOSE: Previous studies have demonstrated that individuals suffering from disorder of consciousness (DOC) maintain some minor neural processing of percepts mediated by senses that early in their pathway intersect the thalamus, a key dysfunctional area in DOC patients. Here the degree of sensory preservation within the olfactory system, a system that lacks an obligatory thalamic relay, and its relationship to the consciousness level in DOC patients of various etiologies was assessed. METHODS: Clinical Coma Recovery Scale - Revised (CRS-R) as well as cerebral responses to odors by means of functional magnetic resonance were obtained in a group of vegetative state/unresponsive wakefulness syndrome (n = 26) patients, minimally conscious state (n = 7) patients and healthy controls (n = 25). RESULTS: A majority of vegetative state/unresponsive wakefulness syndrome patients (58%) and 100% of minimally conscious state patients demonstrated a significant preservation of olfactory neural processing, manifested by activation within the piriform cortex, an area considered as a primary olfactory region. Degree of preservation of olfactory processing differed linearly in line with the patients' etiologies where groups demonstrating greater conscious awareness demonstrated more significant processing. Viewed over all DOC patients, there was a significant negative association between odor-related activity in the orbitofrontal cortex and CRS-R scores. CONCLUSIONS: It is demonstrated that DOC patients exhibit a significant preservation of olfactory neural processing with a clear relationship to etiopathologies and clinical measures even years after of chronification of DOC. PMID- 26616101 TI - Tracking the fate of her4 expressing cells in the regenerating retina using her4:Kaede zebrafish. AB - The Basic-Helix-Loop-Helix-Orange (bHLH-O) transcription factor Hairy-related 4 (her4) is a downstream effector of Notch-Delta signaling that represses expression of typically pro-neural genes in proliferative domains of the central nervous system. Notch-Delta signaling in the retina has been shown to increase in response to injury and influences neuroprotective properties of Muller glia. In contrast to mammals, teleost fish are able to regenerate retinal neurons in response to injury. In zebrafish, her4 is upregulated in the regenerating neural retina in response to both acute and chronic photoreceptor damage, but the contribution of her4 expressing cells to neurogenesis following acute or chronic retinal damage has remained unexplored. Here we investigate the role of her4 in the regenerating retina in a background of chronic, rod-specific degeneration as well as following acute light damage. We demonstrate that her4 is expressed in the persistently neurogenic ciliary marginal zone (CMZ), as well as in small subsets of slowly proliferating Muller glia in the inner nuclear layer (INL) of the central retina. We generated a transgenic line of zebrafish that expresses the photoconvertible Kaede reporter driven by a her4 promoter and validated that expression of the transgene faithfully recapitulates endogenous her4 expression. Lineage tracing analysis revealed that her4-expressing cells in the INL contribute to the rod lineage, and her4 expressing cells in the CMZ are capable of generating any retinal cell type except rod photoreceptors. Our results indicate that her4 is involved in a replenishing pathway that maintains populations of stem cells in the central retina, and that the magnitude of the her4-associated proliferative response mirrors the extent of retinal damage. PMID- 26616103 TI - Syntheses of Diphenylaminodiazidophosphane and Diphenylaminofluoroazidophosphane. AB - Diphenylaminodiazidophosphane (C6H5)2NP(N3)2 was synthesized from the corresponding dihalides (C6H5)2NPX2 (X = F, Cl) and (CH3)3SiN3, and was characterized by vibrational and multinuclear NMR spectroscopy. The intermediate compound (C6H5)2NPF(N3) was also observed by NMR spectroscopy in solution. Some physical properties and reactions of all these compounds are discussed. PMID- 26616104 TI - Comparative Proteomic Analysis Reveals the Effects of Exogenous Calcium against Acid Rain Stress in Liquidambar formosana Hance Leaves. AB - Acid rain (AR) impacts forest health by leaching calcium (Ca) away from soils and plants. Ca is an essential element and participates in various plant physiological responses. In the present study, the protective role of exogenous Ca in alleviating AR stress in Liquidambar formosana Hance at the physiological and proteomic levels was examined. Our results showed that low Ca condition resulted in the chlorophyll content and photosynthesis decreasing significantly in L. formosana leaves; however, these effects could be reversed by high Ca supplementation. Further proteomic analyses successfully identified 81 differentially expressed proteins in AR-treated L. formosana under different Ca levels. In particular, some of the proteins are involved in primary metabolism, photosynthesis, energy production, antioxidant defense, transcription, and translation. Moreover, quantitative real time polymerase chain reaction (qRT-PCR) results indicated that low Ca significantly increased the expression level of the investigated Ca-related genes, which can be reversed by high Ca supplementation under AR stress. Further, Western blotting analysis revealed that exogenous Ca supply reduced AR damage by elevating the expression of proteins involved in the Calvin cycle, reactive oxygen species (ROS) scavenging system. These findings allowed us to better understand how woody plants respond to AR stress at various Ca levels and the protective role of exogenous Ca against AR stress in forest tree species. PMID- 26616106 TI - Ciliary metachronal wave propagation on the compliant surface of Paramecium cells. AB - Ciliary movements in protozoa exhibit metachronal wave-like coordination, in which a constant phase difference is maintained between adjacent cilia. It is at present generally thought that metachronal waves require hydrodynamic coupling between adjacent cilia and the extracellular fluid. To test this hypothesis, we aspirated a Paramecium cell using a micropipette which completely sealed the surface of the cell such that no fluid could pass through the micropipette. Thus, the anterior and the posterior regions of the cell were hydrodynamically decoupled. Nevertheless, we still observed that metachronal waves continued to propagate from the anterior to the posterior ends of the cell, suggesting that in addition to hydrodynamic coupling, there are other mechanisms that can also transmit the metachronal waves. Such transmission was also observed in computational modeling where the fluid was fully decoupled between two partitions of a beating ciliary array. We also imposed cyclic stretching on the surface of live Paramecium cells and found that metachronal waves persisted in the presence of cyclic stretching. This demonstrated that, in addition to hydrodynamic coupling, a compliant substrate can also play a critical role in mediating the propagation of metachronal waves. PMID- 26616105 TI - Analysis of the Photodegradation of the Imidazolinone Herbicides Imazamox, Imazapic, Imazaquin, and Imazamethabenz-methyl in Aqueous Solution. AB - The photodegradation of the imidazolinone herbicides imazamox, imazapic, imazaquin, and imazamethabenz-methyl has been investigated in phosphate-buffered solutions and buffered solutions containing natural organic matter (NOM). The hydrolysis of imazamethabenz-methyl, the only imidazolinone herbicide susceptible to hydrolysis, was also examined. The rate of hydrolysis of imazamethabenz-methyl increased with increasing pH, with the para isomer degrading more rapidly than the meta isomer. All photodegradation rate constants increased with pH and plateaued after pH 5.2. All imidzaolinones degraded more quickly under 253.7 nm lamps as compared to degradation under 310 nm lamps. Imazamox and imazapic degraded more rapidly than imazaquin at all pH values and had higher quantum yields. In addition, imazamox and imazapic quantum yields increased as a function of pH, whereas imazaquin quantum yields showed no trend as a function of pH. Photodegradation reaction rate constants decreased as the concentration of NOM was increased in the solutions due to the effect of light screening. Formulas for the proposed photoproducts for imazamox, imazapic, and imazaquin in pH 7 phosphate buffers were identified, and structures for the photoproducts are proposed. PMID- 26616109 TI - Safe energy use in the operating room. PMID- 26616111 TI - Disorder-specific genetic factors in obsessive-compulsive disorder: A comprehensive meta-analysis. AB - Much remains to be learned about the etiology of obsessive-compulsive disorder (OCD). Twin studies suggest that it arises from both disorder-specific and non specific genetic factors. To understand the etiology of OCD per se, it is necessary to identify disorder-specific factors. Previous research shows that OCD is associated with serotonin-related polymorphisms (5-HTTLPR coded as triallelic and HTR2A rs6311/rs6313) and, in males, a polymorphism involved in catecholamine modulation; COMT (rs4680). The present study is the first comprehensive meta analysis to investigate whether these polymorphisms are specific to OCD. A meta analysis was conducted for genetic association studies of OCD or any other psychiatric disorder, published in any language, in any country. A total of 551 studies were examined, of which 290 were included, consisting of 47,358 cases and 68,942 controls from case control studies, and 2,443 trios from family based studies. The main meta-analysis was limited to those disorders in which there were at least five datasets (studies or sub-studies) per disorder. Results confirmed that OCD is associated with polymorphisms of 5-HTTLPR, HTR2A, and, in males only, COMT. These polymorphisms were not associated with almost all other forms of psychopathology, including unipolar mood disorders, bipolar disorder, panic disorder, schizophrenia, and alcohol dependence. OCD, compared to most other disorders, had a significantly stronger association with particular alleles of each of the polymorphisms. Results did not differ across ancestral groups (Asian vs. Caucasian), designs (case control vs. family based), or diagnostic systems. Results suggest that the polymorphisms investigated in this study are relatively specific to OCD. PMID- 26616110 TI - Using measures of single-cell physiology and physiological state to understand organismic aging. AB - Genetically identical organisms in homogeneous environments have different lifespans and healthspans. These differences are often attributed to stochastic events, such as mutations and 'epimutations', changes in DNA methylation and chromatin that change gene function and expression. But work in the last 10 years has revealed differences in lifespan- and health-related phenotypes that are not caused by lasting changes in DNA or identified by modifications to DNA or chromatin. This work has demonstrated persistent differences in single-cell and whole-organism physiological states operationally defined by values of reporter gene signals in living cells. While some single-cell states, for example, responses to oxygen deprivation, were defined previously, others, such as a generally heightened ability to make proteins, were, revealed by direct experiment only recently, and are not well understood. Here, we review technical progress that promises to greatly increase the number of these measurable single cell physiological variables and measureable states. We discuss concepts that facilitate use of single-cell measurements to provide insight into physiological states and state transitions. We assert that researchers will use this information to relate cell level physiological readouts to whole-organism outcomes, to stratify aging populations into groups based on different physiologies, to define biomarkers predictive of outcomes, and to shed light on the molecular processes that bring about different individual physiologies. For these reasons, quantitative study of single-cell physiological variables and state transitions should provide a valuable complement to genetic and molecular explanations of how organisms age. PMID- 26616112 TI - Manganese superoxide dismutase (MnSOD) is a malignant astrocytoma specific biomarker and associated with adverse prognosis in p53 expressing glioblastoma. AB - BACKGROUND: Manganese super oxide dismutase (MnSOD) has been previously identified as one of the top regulated genes associated with poor survival in glioblastoma (GBM) patients. In the current study we have evaluated the protein expression of MnSOD across various grades of astrocytoma, studied its influence on survival of GBM patients and following recurrence. METHODS: The protein expression of MnSOD was analyzed on tumor tissue sections by immunohistochemistry on 30 diffuse astrocytomas (DA), 50 anaplastic astrocytomas (AA), 30 paired (primary and recurrent) GBM samples and 30 non-tumor brain tissues. The protein expression among the different grades of diffusely infiltrating astrocytoma (DIA) was evaluated by Kruskal-Wallis one-way ANOVA followed by post hoc test. Wilcoxon matched pair test was employed to assess MnSOD protein expression across 30 paired GBM samples (primary and recurrent). The prognostic impact of MnSOD protein expression individually and following stratification with p53 expression was evaluated in a cohort of 123 GBM patients. Both over-all survival (OS) and progression free survival (PFS) analysis were performed by employing Cox regression analysis and Kaplan-Meier survival analysis on GBM patients. RESULTS: A significantly increased protein expression of MnSOD was observed among malignant astrocytomas (GBM and AA) in comparison with either DA or non-tumor brain tissues (p<0.05). Among the GBM cases it was noted that the IDH1 immunopositive tumors (R132H mutant protein; n=17) had a low MnSOD expression as opposed to IDH1 immunonegative tumors (n=106), which had high expression of MnSOD (p=0.0307). Further, a statistically significant increase (p=0.010) in extent of MnSOD protein expression was also noted in GBM tumors following recurrence. Protein expression of MnSOD was associated with both poor OS (HR: 1.021; p=0.011) and early PFS (HR: 1.022; p=0.006) on univariate analysis. Multivariate Cox regression analysis as well as Kaplan-Meier survival analysis demonstrated similar poor prognostic association. Stratification of GBM cases based on p53 expression status revealed a strong association of MnSOD with OS (HR: 1.042; p=0.002) and PFS (HR: 1.044; p=0.001) in p53 positive tumor tissue samples. Similar findings were noted on multivariate Cox regression analysis and K-M survival analysis, while no such association was noted in tumor tissues staining negative for p53 expression. CONCLUSIONS: Our study shows an increased expression of MnSOD in anaplastic astrocytoma and GBM compared to low grade astrocytoma and control brain. An increase in MnSOD expression following GBM tumor recurrence strengthens its putative role in tumor aggressiveness. Further, MnSOD emerges as a poor prognostic biomarker in p53 expressing GBMs, rendering this molecule as a potential therapeutic target in such patients. PMID- 26616113 TI - Morphologic shift associated with aberrant cytokeratin expression in a GIST patient after tyrosine kinase inhibitors therapy. A case report with a brief review of the literature. AB - After an initial benefit from tyrosine kinase inhibitors (TKI), most gastrointestinal stromal tumors (GISTs) eventually develop disease progression or secondary resistance. An altered tumor (immune)phenotype with anaplasia and morphological changes secondary to therapy have occasionally been described in the literature. We present a 52-year old patient, diagnosed with high risk, spindle-cell, GIST (CD117 positive, Pankeratin negative) in 2003, showing a c-Kit exon 11 mutation. After TKI therapy, he developed drug resistance and disease progression. Pathological assessment of the last surgical specimen showed a pure epithelioid/clear cell histology, without evidence of cellular anaplasia. Tumor cells were CD117 positive, DOG1 positive but also E-cadherin positive and Pankeratin positive, whereas molecular analysis confirmed the presence of the c Kit exon 11 mutation, with no additional mutations. We describe an unusual case of GIST showing peculiar (immuno)phenotypic changes under therapy, different from the vast majority of therapy-driven changes, which include marked cellular pleomorphisms and KIT immunonegativity. Possible molecular explanations to understand these phenomena and a brief review of the literature are also addressed. PMID- 26616114 TI - Prognostic factors in advanced breast cancer: Race and receptor status are significant after development of metastasis. AB - Prognostic factors are well established in early-stage breast cancer (BC), but less well-defined in advanced disease. We analyzed 323 BC patients who had distant relapse during follow-up from 1997 to 2010 to determine the significant clinicopathologic factors predicting survival outcomes. By univariate analysis, race, tumor grade, estrogen and progesterone receptors (ER/PR) and HER2 status were significantly associated with overall survival (OS) and post-metastasis survival (PMS). Applying a Cox regression model revealed that all these factors remained significant for PMS, while race, tumor grade and HER2 were independent factors for OS. Tumor grade was the only significant factor for metastasis-free survival by univariate and multivariate analyses. Our findings demonstrated that being Caucasian, hormonal receptor positive (HR+) and HER2 positive (HER2+) were all associated with a decreased hazard of death and that patients with HR+/HER2+ tumors had superior outcomes to those with HR+/HER2- disease. Further, PR status held a prognostic value over ER, thus reflecting the biologic mechanism of the importance of the functional ER pathway and the heterogeneity in the response to endocrine therapy. These observations indicate that the patients' genetic makeup and the intrinsic nature of the tumor principally govern BC progression and prognosticate the long-term outcomes in advanced disease. PMID- 26616115 TI - Metabolic engineering of Corynebacterium glutamicum for efficient production of 5 aminolevulinic acid. AB - 5-Aminolevulinic acid (5-ALA) has recently attracted attention for its potential applications in the fields of medicine and agriculture. In this study, Corynebacterium glutamicum was firstly engineered for 5-ALA production via the C4 pathway. HemA encoding 5-aminolevulinic acid synthase from Rhodobacter sphaeroides was codon optimized and expressed in C. glutamicum ATCC13032, resulting in accumulation of 5-ALA. Deletion of all known genes responsible for the formation of acetate and lactate further enhanced production of 5-ALA. Overexpression of ppc gene encoding phoenolpyruvate carboxylase resulted in an accumulation of 5-ALA up to 2.06 +/- 0.05 g/L. Furthermore, deletion of high molecular-weight penicillin-binding proteins (HMW-PBPs) genes pbp1a, pbp1b, and pbp2b led to an increase in 5-ALA production of 13.53%, 29.47%, and 22.22%, respectively. Finally, 5-ALA production was enhanced to 3.14 +/- 0.02 g/L in shake flask by heterologously expressing rhtA encoding threonine/homoserine exporter, and 86.77% of supplemented glycine was channeled toward 5-ALA production in shake flask. The engineered C. glutamicum ALA7 strain produced 7.53 g/L 5-ALA in a 5 L bioreactor. This study demonstrated the potential utility of C. glutamicum as a platform for metabolic production of 5-ALA. Change of cell permeability by metabolic engineering HMW-PBPs may provide a new strategy for biochemicals production in Corynebacterium glutamicum. Biotechnol. Bioeng. 2016;113: 1284-1293. (c) 2015 Wiley Periodicals, Inc. PMID- 26616116 TI - Low LKB1 Expression Results in Unfavorable Prognosis in Prostate Cancer Patients. AB - BACKGROUND The present study aimed to compare the expression of liver kinase B1 (LKB1) in prostate cancer (PCa) tissues and the paired adjacent tissues, then to evaluate the statistical relationship between LKB1 expression and prognosis of PCa patients. MATERIAL AND METHODS The relative expression of LKB1 at mRNA level was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of LKB1 at protein level was measured by immunohistochemistry (IHC) method. The relationship between LKB1 expression and clinicopathologic characteristics was estimated by chi-square test. Kaplan-Meier method was used to analyze the overall survival of PCa patients with different LKB1 expression. Cox regression analysis was performed to estimate the significance of LKB1 expression and clinicopathologic characteristics in the prognosis of PCa patients. RESULTS The relative expression of LKB1 at mRNA level was significantly lower in PCa tissues than in the normal tissues (P<0.001). The LKB1 expression was proved to be affected by clinical stage (P=0.019) and PSA concentration (P=0.031) of PCa patients. Moreover, patients with negative LKB1 expression had shorter survival than those with positive expression. Cox regression analysis confirmed that LKB1 could be regarded as a prognostic biomarker for PCa patients (P=0.001, HR=3.981, 95% CI=1.698-9.336). CONCLUSIONS The expression of LKB1 was lower in PCa tissues and might be a predictor for the prognosis of PCa patients. PMID- 26616117 TI - Maternal and perinatal outcome of eclampsia over a decade at a tertiary hospital in Kuwait. AB - AIMS: To determine maternal and perinatal outcome of eclampsia patients over a decade. METHODS: Analysis of case records of all eclampsia cases from January 2005 to December 2014. RESULTS: There were 30 cases of eclampsia. The most significant risk factors for developing pre-eclampsia are unbooked cases (97%), nulliparity, young age, marriage <=4 months, history of pre-eclampsia in previous pregnancy, remarriage, preexisting diabetes mellitus, interval between pregnancies >=10 years, positive family history. The incidence of eclampsia was 0.05%, antepartum eclampsia 15 (50%), intrapartum 6 (20%) and postpartum 9 (30%) with no maternal deaths, and 1 perinatal death. Perinatal mortality was 33.3/1000. 22 (73%) patients received magnesium sulphate (MgSO4) and 8 patients (27%) received Diazepam, of which 1 had recurrence of convulsions. All 15 antepartum cases were delivered by cesarean section as were 2 intrapartum. 13 (43%) of women delivered vaginally. Only 6 (20%) patients were of low socio economic status and were primary school educated. Severe maternal complications occurred in 8 (27%), with abruptio placentae being the most common 3 (38%). CONCLUSIONS: Incidence of eclampsia was low, with no maternal deaths. MgSO4 was found to be highly effective. Lack of antenatal care is a major risk factor. PMID- 26616118 TI - Gene expression during gonocyte transformation into spermatogonial stem cells is not androgen dependent. AB - BACKGROUND/AIMS: Early germ cell development is deranged in undescended testis, potentially leading to infertility and cancer. Androgens are proposed to regulate gonocyte transformation into stem cells during human 'minipuberty' at 3-12months. We studied genes expressed in germ cells, Sertoli cells, and other somatic cells to determine whether androgen mediates gonocyte transformation. METHODS: Testes from androgen-receptor knockout (ARKO) and wild-type (WT) littermates were collected at postnatal day P0 (birth), P4, P8 for real-time PCR to measure gene expression of mouse VASA homolog (Mvh), anti-Mullerian hormone (Amh), kit oncogene (c-Kit), matrix metalloproteinase-1 (Mt1-mmp), zinc finger, and BTB domain-containing 16 (Plzf) and octamer-binding protein 4 (Oct4). Data were normalized to ribosomal protein L32 (Rpl32), and reproductive homeobox gene 5 (Rhox5) was a positive control for androgenic response. Changes in gene expression were calculated with GraphPad Prism 5.02. RESULTS: There were no statistical differences (p>0.05) in Mvh, Oct4, c-Kit, Plzf, Amh and Mt1-mmp expression between WT and ARKO testes from P0 to P8. CONCLUSION: These results show that androgen did not influence gene expression in postnatal mouse testis, which coincides with human 'minipuberty'. The results are consistent with gonocyte transformation being independent of androgens, and that nonandrogenic regulators need to be identified. PMID- 26616119 TI - Behaviour change techniques: the development and evaluation of a taxonomic method for reporting and describing behaviour change interventions (a suite of five studies involving consensus methods, randomised controlled trials and analysis of qualitative data). AB - BACKGROUND: Meeting global health challenges requires effective behaviour change interventions (BCIs). This depends on advancing the science of behaviour change which, in turn, depends on accurate intervention reporting. Current reporting often lacks detail, preventing accurate replication and implementation. Recent developments have specified intervention content into behaviour change techniques (BCTs) - the 'active ingredients', for example goal-setting, self-monitoring of behaviour. BCTs are 'the smallest components compatible with retaining the postulated active ingredients, i.e. the proposed mechanisms of change. They can be used alone or in combination with other BCTs' (Michie S, Johnston M. Theories and techniques of behaviour change: developing a cumulative science of behaviour change. Health Psychol Rev 2012;6:1-6). Domain-specific taxonomies of BCTs have been developed, for example healthy eating and physical activity, smoking cessation and alcohol consumption. We need to build on these to develop an internationally shared language for specifying and developing interventions. This technology can be used for synthesising evidence, implementing effective interventions and testing theory. It has enormous potential added value for science and global health. OBJECTIVE: (1) To develop a method of specifying content of BCIs in terms of component BCTs; (2) to lay a foundation for a comprehensive methodology applicable to different types of complex interventions; (3) to develop resources to support application of the taxonomy; and (4) to achieve multidisciplinary and international acceptance for future development. DESIGN AND PARTICIPANTS: Four hundred participants (systematic reviewers, researchers, practitioners, policy-makers) from 12 countries engaged in investigating, designing and/or delivering BCIs. Development of the taxonomy involved a Delphi procedure, an iterative process of revisions and consultation with 41 international experts; hierarchical structure of the list was developed using inductive 'bottom-up' and theory-driven 'top-down' open-sort procedures (n = 36); training in use of the taxonomy (1-day workshops and distance group tutorials) (n = 161) was evaluated by changes in intercoder reliability and validity (agreement with expert consensus); evaluating the taxonomy for coding interventions was assessed by reliability (intercoder; test-retest) and validity (n = 40 trained coders); and evaluating the taxonomy for writing descriptions was assessed by reliability (intercoder; test-retest) and by experimentally testing its value (n = 190). RESULTS: Ninety-three distinct, non-overlapping BCTs with clear labels and definitions formed Behaviour Change Technique Taxonomy version 1 (BCTTv1). BCTs clustered into 16 groupings using a 'bottom-up' open-sort procedure; there was overlap between these and groupings produced by a theory driven, 'top-down' procedure. Both training methods improved validity (both p < 0.05), doubled the proportion of coders achieving competence and improved confidence in identifying BCTs in workshops (both p < 0.001) but did not improve intercoder reliability. Good intercoder reliability was observed for 80 of the 93 BCTs. Good within-coder agreement was observed after 1 month (p < 0.001). Validity was good for 14 of 15 BCTs in the descriptions. The usefulness of BCTTv1 to report descriptions of observed interventions had mixed results. CONCLUSIONS: The developed taxonomy (BCTTv1) provides a methodology for identifying content of complex BCIs and a foundation for international cross-disciplinary collaboration for developing more effective interventions to improve health. Further work is needed to examine its usefulness for reporting interventions. FUNDING: This project was funded by the Medical Research Council Ref: G0901474/1. Funding also came from the Peninsula Collaboration for Leadership in Applied Health Research and Care. PMID- 26616120 TI - What's in the telling? Understanding social, psychological and clinical aspects of HIV disclosure. PMID- 26616121 TI - Characteristics of HIV-infected adolescents enrolled in a disclosure intervention trial in western Kenya. AB - Knowledge of one's own HIV status is essential for long-term disease management, but there are few data on how disclosure of HIV status to infected children and adolescents in sub-Saharan Africa is associated with clinical and psychosocial health outcomes. We conducted a detailed baseline assessment of the disclosure status, medication adherence, HIV stigma, depression, emotional and behavioral difficulties, and quality of life among a cohort of Kenyan children enrolled in an intervention study to promote disclosure of HIV status. Among 285 caregiver child dyads enrolled in the study, children's mean age was 12.3 years. Caregivers were more likely to report that the child knew his/her diagnosis (41%) compared to self-reported disclosure by children (31%). Caregivers of disclosed children reported significantly more positive views about disclosure compared to caregivers of non-disclosed children, who expressed fears of disclosure related to the child being too young to understand (75%), potential psychological trauma for the child (64%), and stigma and discrimination if the child told others (56%). Overall, the vast majority of children scored within normal ranges on screenings for behavioral and emotional difficulties, depression, and quality of life, and did not differ by whether or not the child knew his/her HIV status. A number of factors were associated with a child's knowledge of his/her HIV diagnosis in multivariate regression, including older age (OR 1.8, 95% CI 1.5 2.1), better WHO disease stage (OR 2.5, 95% CI 1.4-4.4), and fewer reported caregiver-level adherence barriers (OR 1.9, 95% CI 1.1-3.4). While a minority of children in this cohort knew their HIV status and caregivers reported significant barriers to disclosure including fears about negative emotional impacts, we found that disclosure was not associated with worse psychosocial outcomes. PMID- 26616122 TI - HIV knowledge, stigma, and illness beliefs among pediatric caregivers in Ghana who have not disclosed their child's HIV status. AB - The majority of HIV-infected children in sub-Saharan Africa have not been informed of their HIV status. Caregivers are reluctant to disclose HIV status to their children because of concern about the child's ability to understand, parental sense of guilt, and fear of social rejection and isolation. We hypothesized that the low prevalence of pediatric HIV disclosure in Ghana is due to lack of accurate HIV information and high HIV stigma among caregivers. This is a preliminary analysis of baseline data of an HIV pediatric disclosure intervention study in Ghana ("Sankofa"). "Sankofa" - is a two-arm randomized controlled clinical trial comparing disclosure intervention plus usual care (intervention arm) vs usual care (control arm) at Korle-Bu Teaching Hospital (KBTH; control arm) and Komfo-Anokye Teaching Hospital (KATH; intervention arm). We enrolled HIV-infected children, ages 7-18 years who do not know their HIV status, and their caregivers. Baseline data of caregivers included demographic characteristics; Brief HIV Knowledge Questionnaire (HIV-KQ-18); Brief Illness Perception Questionnaire; and HIV Stigma Scale. Simple and multivariable linear regression analyses were used to assess the relationship between caregiver characteristics and HIV knowledge, stigma, and illness perception. Two hundred and ninety-eight caregivers were enrolled between January 2013 and July 2014 at the two study sites; KBTH (n = 167) and KATH (n = 131). The median age of caregivers was 41 years; 80.5% of them were female and about 60% of caregivers were HIV-positive. Seventy-eight percent of caregivers were self-employed with low household income. In both unadjusted and adjusted analyses, HIV negative status and lower level of education were associated with poor scores on HIV-KQ. HIV positive status remained significant for higher level of stigma in the adjusted analyses. None of the caregiver's characteristics predicted caregiver's illness perception. Intensification of HIV education in schools and targeted community campaigns are needed. PMID- 26616123 TI - The role of enacted stigma in parental HIV disclosure among HIV-infected parents in China. AB - Existing studies have delineated that HIV-infected parents face numerous challenges in disclosing their HIV infection to the children ("parental HIV disclosure"), and practices of parental HIV disclosure vary with individual characteristics, family contexts, and social environment. Using cross-sectional data from 1254 HIV-infected parents who had children aged 5-16 years in southwest China, the current study examined the association of parental HIV disclosure with mental health and medication adherence among parents and explored the possible effect of enacted stigma on such association. Multivariate analysis of variance revealed that parents who had experienced disclosure to children reported higher level enacted stigma, worse mental health conditions, and poorer medication adherence. Enacted stigma partially mediated the associations between disclosure and both mental health and medication adherence after controlling basic background characteristics. Our findings highlight the importance of providing appropriate disclosure-related training and counseling service among HIV-infected parents. In a social setting where HIV-related stigma is still persistent, disclosure intervention should address and reduce stigma and discrimination in the practice of parental HIV disclosure. PMID- 26616124 TI - Factors influencing social self-disclosure among adolescents living with HIV in Eastern Africa. AB - Adolescents living with HIV (ALHIV) face many psychosocial challenges, including HIV disclosure to others. Given the importance of socialization during the adolescent transition process, this study investigated the psychological and social factors influencing self-disclosure of own HIV status to peers. We examined social HIV self-disclosure to peers, and its relationship to perceived HIV-related stigma, self-efficacy to disclose, self-esteem, and social support among a sample of n = 582 ALHIV aged 13-17 years in Kampala, Uganda, and Western Kenya. Data were collected between February and April 2011. Among them, 39% were double orphans. We conducted a secondary data analysis to assess the degree of social disclosure, reactions received, and influencing factors. Interviewer administered questionnaires assessed medical, socio-demographic, and psychological variables (Rosenberg self-esteem scale; self-efficacy to disclose to peers), HIV-related stigma (10-item stigma scale), and social support (family life and friends). Descriptive, bivariate, and logistic regression analyses were performed with social self-disclosure to peers with gender as covariates. Almost half of ALHIV had told nobody (except health-care providers) about their HIV status, and about 18% had disclosed to either one of their friends, schoolmates, or a boy- or girlfriend. Logistic regression models revealed that having disclosed to peers was significantly related to being older, being a paternal orphan, contributing to family income, regular visits to the HIV clinic, and greater social support through peers. Low self-efficacy to disclose was negatively associated to the outcome variable. While social self-disclosure was linked to individual factors such as self-efficacy, factors relating to the social context and adolescents' access to psychosocial resources play an important role. ALHIV need safe environments to practice disclosure skills. Interventions should enable them to make optimal use of available psychosocial resources even under constraining conditions such as disruptive family structures. PMID- 26616125 TI - Sex and secrecy: How HIV-status disclosure affects safe sex among HIV-positive adolescents. AB - HIV-positive adolescents who engage in unsafe sex are at heightened risk for transmitting or re-acquiring HIV. Disclosure of HIV-status to sexual partners may impact on condom use, but no study has explored the effects of (i) adolescent knowledge of one's HIV-status, (ii) knowledge of partner status and (iii) disclosure to partners, on safer sex behaviour. This study aimed to identify whether knowledge of HIV-status by HIV-positive adolescents and partners was associated with safer sex. Eight fifty eight HIV-positive adolescents (10-19 years old, 52% female, 68.1% vertically infected) who had ever initiated antiretroviral treatment in 41 health facilities in the Eastern Cape, South Africa, were interviewed using standardised questionnaires. Quantitative analyses used multivariate logistic regressions, controlling for confounders. Qualitative research included interviews, focus group discussions and observations with 43 HIV-positive teenagers and their healthcare workers. N = 128 (14.9%) of the total sample had ever had sex, while N = 109 (85.1%) of sexually active adolescents had boy/girlfriend. In total, 68.1% of the sample knew their status, 41.5% of those who were sexually active and in relationships knew their partner's status, and 35.5% had disclosed to their partners. For adolescents, knowing one's status was associated with safer sex (OR = 4.355, CI 1.085-17.474, p = .038). Neither knowing their partner's status, nor disclosing one's HIV-status to a partner, were associated with safer sex. HIV-positive adolescents feared rejection, stigma and public exposure if disclosing to sexual and romantic partners. Counselling by healthcare workers for HIV-positive adolescents focused on benefits of disclosure, but did not address the fears and risks associated with disclosure. These findings challenge assumptions that disclosure is automatically protective in sexual and romantic relationships for HIV-positive adolescents, who may be ill equipped to negotiate safer sex. There is a pressing need for effective interventions that mitigate the risks of disclosure and provide HIV-positive adolescents with skills to engage in safe sex. PMID- 26616126 TI - HIV serostatus disclosure in the treatment cascade: evidence from Northern Tanzania. AB - HIV serostatus disclosure plays an important role in HIV transmission risk reduction and is positively associated with HIV medication adherence and treatment outcomes. However, to date, no study has quantified the role of disclosure across the HIV treatment cascade, particularly in Sub-Saharan Africa. We used data from a cohort of HIV-infected adults in Northern Tanzania to describe associations between disclosure and engagement and retention in the HIV treatment cascade. Between 2008 and 2009, the Coping with HIV/AIDS in Tanzania (CHAT) study enrolled 260 clients newly diagnosed with HIV and 492 HIV-infected patients in established HIV care in two large HIV care and treatment centers in Northern Tanzania. Participants aged 18 and older completed annual clinical assessments and twice-annual in-person interviews for 3.5 years. Using logistic regression models, we assessed sociodemographic correlates of HIV serostatus disclosure to at least one household member, and associations between this disclosure measure and linkage to care, evaluation for antiretroviral therapy (ART) eligibility, ART coverage, and rates of undetectable HIV RNA levels during the follow-up period. Married individuals and those diagnosed earlier were more likely to have disclosed their HIV infection to at least one household member. During follow-up, HIV serostatus disclosure was associated with higher rates of linkage to care, evaluation for ART eligibility, and ART coverage. No significant association was observed with rates of undetectable viral loads. Marginal effects estimates suggest that a 10 percentage-point lower probability of linkage to care for those who did not disclose their HIV serostatus (86% vs. 96%; p = 0.035) was compounded by an 18 percentage-point lower probability of ever receiving a CD4 count (62% vs. 80%; p = .039), and a 20 percentage-point lower probability of ever receiving ART (55% vs. 75%; p = .029). If causal, these findings suggest an important role for disclosure assistance efforts across the HIV treatment cascade. PMID- 26616127 TI - Living with HIV, disclosure patterns and partnerships a decade after the introduction of HIV programmes in rural South Africa. AB - Prevention of mother-to-child Transmission and HIV Treatment programmes were scaled-up in resource-constrained settings over a decade ago, but there is still much to be understood about women's experiences of living with HIV and their HIV disclosure patterns. This qualitative study explored women's experiences of living with HIV, 6-10 years after being diagnosed during pregnancy. The area has high HIV prevalence, and an established HIV treatment programme. Participants were enrolled in a larger intervention, "Amagugu", that supported women (n = 281) to disclose their HIV status to their children. Post-intervention we conducted individual in-depth interviews with 20 randomly selected women, stratified by clinic catchment area, from the total sample. Interviews were entered into ATLAS.ti computer software for coding. Most women were living with their current sexual partner and half were still in a relationship with the child's biological father. Household exposure to HIV was high with the majority of women knowing at least one other HIV-infected adult in their household. Eighteen women had disclosed their HIV status to another person; nine had disclosed to their current partner first. Two main themes were identified in the analyses: living with HIV and the normalisation of HIV treatment at a family level; and the complexity of love relationships, in particular in long-term partnerships. A decade on, most women were living positively with HIV, accessing care, and reported experiencing little stigma. However, as HIV became normalised new challenges arose including concerns about access to quality care, and the need for family-centred care. Women's sexual choices and relationships were intertwined with feelings of love, loyalty and trust and the important supportive role played by partners and families was acknowledged, however, some aspects of living with HIV presented challenges including continuing to practise safe sex several years after HIV diagnosis. PMID- 26616128 TI - Using communication privacy management theory to examine HIV disclosure to sexual partners/spouses among PLHIV in Guangxi. AB - The current study employed Communication Privacy Management (CPM) theory to examine the factors associated with disclosure of HIV infection to sexual partners or spouses as well as gender differences in these associations among a sample of people living with HIV (PLHIV) in China. A total of 1254 PLHIV who had 5-16 years old children were invited to answer the questions related to disclosure of HIV infection to sexual partners/spouses. Prevalence of HIV disclosure was reported. Key variables related to CPM theory (such as motivations for disclosure and nondisclosure, HIV-related stigma, and relational factors) were compared between females and males. Logistic regression was employed to determine the factors of influencing whether or not the participants disclosed their HIV status to spouses/partners for the male, the female and the combined samples. Fear of rejection was a significant predictor of HIV nondisclosure for the male, the female and the combined samples. Concern about privacy was a significant factor in not disclosing to sexual partners/spouses only in the male sample. The endorsement of duty to inform/educate was the only motivation factor that was significantly related to HIV disclosure for the three samples. The motivation to establish a close/supportive relationship with intimate partners/spouses was found to be associated with HIV disclosure for the combined and male samples. The current study confirmed the utilities of CPM in studying HIV disclosure to sexual partners/spouse. The findings have theoretical and practical implications for HIV disclosure interventions among PLHIV in Guangxi. PMID- 26616129 TI - Truth-telling to the patient, family, and the sexual partner: a rights approach to the role of healthcare providers in adult HIV disclosure in China. AB - Patients' rights are central in today's legislation and social policies related to health care, including HIV care, in not only Western countries but around the world. However, given obvious socio-cultural differences it is often asked how or to what extent patients' rights should be respected in non-Western societies such as China. In this paper, it is argued that the patients' rights framework is compatible with Chinese culture, and that from the perspective of contemporary patient rights healthcare providers have a duty to disclose truthfully the diagnosis and prognosis to their patients, that the Chinese cultural practice of involving families in care should - with consent from the patient - be promoted out of respect for patients' rights and well-being, and that healthcare providers should be prepared to address the issue of disclosing a patient's HIV status to sexual partner(s). Legally, the provider should be permitted to disclose without consent from the patient but not obliged to in all cases. The decision to do this should be taken with trained sensitivity to a range of ethically relevant considerations. Post-disclosure counseling or psychological support should be in place to address the concerns of potentially adverse consequences of provider initiated disclosure and to maximize the psychosocial and medical benefits of the disclosure. There is an urgent need for healthcare providers to receive training in ethics and disclosure skills. This paper concludes also with some suggestions for improving the centerpiece Chinese legislation, State Council's "Regulations on AIDS Prevention and Control" (2006), to further safeguard the rights and well being of HIV patients. PMID- 26616130 TI - The need to know: HIV status disclosure expectations and practices among non-HIV positive gay and bisexual men in Australia. AB - Although there is evidence of increasing overall rates of HIV status disclosure among gay and bisexual men, little is known about men's disclosure expectations and practices. In this study, we investigate the importance non-HIV-positive men in Australia vest in knowing the HIV status of their sexual partners, and the extent to which they restrict sex to partners of the same HIV status, and their HIV disclosure expectations. Data were collected through a national, online self report survey. Of the 1044 men included in the study, 914 were HIV negative and 130 were untested. Participants completed the assessment of socio-demographic characteristics, HIV status preferences, and disclosure expectations and practices. Participants also completed reliable multi-item measures of perceived risk of HIV transmission, expressed HIV-related stigma, and engagement with the gay community and the community of people living with HIV. A quarter (25.9%) of participants wanted to know the HIV status of all sexual partners, and one-third (37.2%) restricted sex to partners of similar HIV status. Three quarters (76.3%) expected HIV-positive partners to disclosure their HIV status before sex, compared to 41.6% who expected HIV-negative men to disclose their HIV status. Less than half (41.7%) of participants reported that they consistently disclosed their HIV status to sexual partners. Multivariate linear regression analysis identified various covariates of disclosure expectations and practices, in particular of disclosure expectations regarding HIV-positive men. Men who expected HIV-positive partners to disclose their HIV status before sex more often lived outside capital cities, were less educated, were less likely to identify as gay, perceived more risk of HIV transmission from a range of sexual practices, were less engaged with the community of people living with HIV, and expressed more stigma towards HIV-positive people. These findings suggest that an HIV status divide is emerging or already exists among gay men in Australia. HIV negative and untested men who are most likely to sexually exclude HIV-positive men are less connected to the HIV epidemic and less educated about HIV risk and prevention. PMID- 26616131 TI - Sankofa pediatric HIV disclosure intervention cyber data management: building capacity in a resource-limited setting and ensuring data quality. AB - Prevalence of pediatric HIV disclosure is low in resource-limited settings. Innovative, culturally sensitive, and patient-centered disclosure approaches are needed. Conducting such studies in resource-limited settings is not trivial considering the challenges of capturing, cleaning, and storing clinical research data. To overcome some of these challenges, the Sankofa pediatric disclosure intervention adopted an interactive cyber infrastructure for data capture and analysis. The Sankofa Project database system is built on the HUBzero cyber infrastructure ( https://hubzero.org ), an open source software platform. The hub database components support: (1) data management - the "databases" component creates, configures, and manages database access, backup, repositories, applications, and access control; (2) data collection - the "forms" component is used to build customized web case report forms that incorporate common data elements and include tailored form submit processing to handle error checking, data validation, and data linkage as the data are stored to the database; and (3) data exploration - the "dataviewer" component provides powerful methods for users to view, search, sort, navigate, explore, map, graph, visualize, aggregate, drill down, compute, and export data from the database. The Sankofa cyber data management tool supports a user-friendly, secure, and systematic collection of all data. We have screened more than 400 child-caregiver dyads and enrolled nearly 300 dyads, with tens of thousands of data elements. The dataviews have successfully supported all data exploration and analysis needs of the Sankofa Project. Moreover, the ability of the sites to query and view data summaries has proven to be an incentive for collecting complete and accurate data. The data system has all the desirable attributes of an electronic data capture tool. It also provides an added advantage of building data management capacity in resource limited settings due to its innovative data query and summary views and availability of real-time support by the data management team. PMID- 26616132 TI - Perceptions towards aqua-based exercise among older adults with osteoarthritis who have discontinued participation in this exercise mode. AB - AIM: This study aimed to investigate reasons for ceasing participation in aqua based exercise among older adults with osteoarthritis (OA). METHODS: Eleven adults over 60 years of age with OA participated in one of two focus groups, during which they discussed barriers to aqua-based exercise and the potential benefits of this exercise mode. Each focus group was audiotaped, transcribed and then analysed using the general inductive thematic approach. The investigators reached a consensus on all coding categories and then identified themes. RESULTS: Key barriers identified were: a lack of suitable classes; insufficient instructor knowledge, which often led to increased pain; cold water and the changing facilities. Key perceived benefits included increased physical ability in water and social interaction. CONCLUSIONS: A greater understanding of reasons for ceasing participation in aqua-based exercise among older adults with OA may help facilitate development of suitable exercise programs that minimise barriers for this group. PMID- 26616134 TI - Assessment of etanercept efficacy in the treatment of psoriatic arthritis: ultrasonography of Achilles tendon. PMID- 26616135 TI - Flexible and Patterned Thin Film Polarizer: Photopolymerization of Perylene-based Lyotropic Chromonic Reactive Mesogens. AB - A perylene-based reactive mesogen (DAPDI) forming a lyotropic chromonic liquid crystal (LCLC) phase was newly designed and synthesized for the fabrication of macroscopically oriented and patterned thin film polarizer (TFP) on the flexible polymer substrates. The anisotropic optical property and molecular self-assembly of DAPDI were investigated by the combination of microscopic, scattering and spectroscopic techniques. The main driving forces of molecular self-assembly were the face-to-face pi-pi intermolecular interaction among aromatic cores and the nanophase separation between hydrophilic ionic groups and hydrophobic aromatic cores. Degree of polarization for the macroscopically oriented and photopolymerized DAPDI TFP was estimated to be 99.81% at the lambdamax = 491 nm. After mechanically shearing the DAPDI LCLC aqueous solution on the flexible polymer substrates, we successfully fabricated the patterned DAPDI TFP by etching the unpolymerized regions selectively blocked by a photomask during the photopolymerization process. Chemical and mechanical stabilities were confirmed by the solvent and pencil hardness tests, and its surface morphology was further investigated by optical microscopy, atomic force microscopy, and three dimensional surface nanoprofiler. The flexible and patterned DAPDI TFP with robust chemical and mechanical stabilities can be a stepping stone for the advanced flexible optoelectronic devices. PMID- 26616136 TI - Effect of NaCl Salts on the Activation Energy of Excited-State Proton Transfer Reaction of Coumarin 183. AB - Coumarin 183 (C183) was used as a photoacid to study excited-state proton transfer (ESPT) reactions. Here, we studied the effect of ions on the ESPT of C183 in aqueous NaCl solutions using a steady-state fluorescence spectroscopy and time-correlated single photon counting (TCSPC) method. The acid dissociation equilibrium of excited-state C183 and the activation energy for the ESPT of C183 were determined as a function of NaCl concentration. The change in the equilibrium constant was found to be correlated with the solvation energy of deprotonated C183. Frequency-resolved TCSPC signals measured at several temperatures were analyzed by using a global fitting analysis method which enabled us to extract all the rate constants involving the ESPT reaction and the spectra of individual species. The activation energy for the ESPT reaction of C183 was highly dependent on NaCl concentration. Quantum chemical calculations were used to calculate the local hydrogen-bond (H-bond) configurations around C183 in aqueous NaCl solutions. It was found that the activation energy for the ESPT was determined by the local H-bond configurations around C183 which were significantly influenced by the dissolved ions. PMID- 26616137 TI - Parenteral Nutrition Is One of the Most Significant Risk Factors for Nosocomial Infections in a Pediatric Cardiac Intensive Care Unit. AB - BACKGROUND: Nosocomial infections (NIs) are associated with significant morbidity and mortality and increased healthcare costs. We aimed to assess the NI epidemiology and associated risk factors in a pediatric cardiac intensive care unit (PCICU). MATERIALS AND METHODS: Prospective observational study on 1106 patients admitted to a PCICU from January 1, 2012, to October 31, 2013. NIs were defined and recorded weekly by a multidisciplinary team. Independent risk factors for NIs were assessed by logistic regression analysis in the overall cohort, in cardiac surgical patients, and in those who had cardiopulmonary bypass (CPB). RESULTS: Ninety-two patients (8.3%) had NIs. Overall mortality was 2% but 8.3% in children with NIs ( P < .001). The most frequent NIs were pneumonia (19.6%), bacteremia of unknown origin (16.3%), and catheter-associated bloodstream infection (14.1%) caused mainly by Staphylococcus aureus and Pseudomonas aeruginosa. In the overall cohort, independent risk factors for NIs were number of days of parenteral nutrition (PN), days of invasive and noninvasive ventilation, ward before PCICU admission, and days of PCICU stay; in the cardiac surgical patients, the risk factors were days of PN and days of invasive and noninvasive ventilation; in children who had undergone CPB, the risk factors for NIs were days of PN, delayed sternal closure, reintervention, length of CPB, younger age, and days of invasive ventilation. CONCLUSION: Mortality was significantly higher in patients with NIs. The use of PN was one of the most significant predictors for NIs in the overall cohort of PCICU patients, cardiac surgical patients, and those who required CPB. PMID- 26616138 TI - Fecal Transplantation Successfully Treats Recurrent D-Lactic Acidosis in a Child With Short Bowel Syndrome. AB - D-lactic acidosis can occur in patients with short bowel syndrome (SBS) when excessive malabsorbed carbohydrate (CHO) enters the colon and is metabolized by colonic bacteria to D-lactate. D-lactate can be absorbed systemically, and increased serum levels are associated with central nervous system toxicity manifested by confusion, ataxia, and slurred speech. Current therapy, usually directed toward suppressing intestinal bacterial overgrowth and limiting ingested CHO, is not always successful. Fecal transplantation, the infusion of donor feces into a recipient's intestinal tract, has been used for decades to treat recurrent Clostridium difficile infection, and case reports document its use in the successful treatment of constipation, diarrhea, and abdominal pain. The exact mechanism of action is unknown, but it is surmised that the alteration of the intestinal microbiome, as well as the reintroduction of potential beneficial microbes, helps mediate disease. Here we present the case of a child with SBS and recurrent, debilitating D-lactic acidosis, which was successfully treated with fecal transplantation. PMID- 26616139 TI - Molecular detection and characterization of noroviruses in river water in Thailand. AB - Norovirus (NoV) generally exists as a mixture of multiple genotype variants in nature. However, there has been no published report monitoring NoV in natural settings in Thailand. To obtain information on mixed presence of the NoV RNA genome, we conducted viral genome analysis of 15 water specimens collected from five sites in a river near Bangkok between August 2013 and August 2014. The number of viral RNA copies per specimen declined progressively from the most upstream to the most downstream site. Following direct nucleotide sequencing of the PCR products, we obtained three partial genome sequences of the NoV GI strain and 13 partial genome sequences of the NoV GII strains. Phylogenetic analysis indicated the presence of four GII.4 variant groups pro-circulated after the Den Haag_2006b, New Orleans_2009 and Sydney_2012 outbreaks. On the other hand, only GI.4 was observed from the specimens collected on April, 2014. These results indicated that multiple genogroups and genotypes of noroviruses are present and are circulating in the natural environment in Thailand as in other countries. Our study provides comprehensive information on the occurrence of new variants. SIGNIFICANCE AND IMPACT OF THE STUDY: Our study is the first paper that multiple genogroups and genotypes of norovirus exist, and are circulating in the river water near Bangkok, Thailand. Phylogenetic analysis indicated the presence of four GII.4 variant groups pro-circulated after the Den Haag_2006b, New Orleans_2009 and Sydney_2012 that caused outbreaks in the world. Continued research will be essential for understanding the natural history of NoV and the control of future outbreaks. PMID- 26616140 TI - Identification of Small-Molecule Inhibitors of the Antiapoptotic Protein Myeloid Cell Leukaemia-1 (Mcl-1). AB - Protein-protein interactions (PPIs) control many cellular processes in cancer and tumour growth. Of significant interest is the role PPIs play in regulating apoptosis. The overexpression of the antiapoptosis regulating Bcl-2 family of proteins is commonly observed in several cancers, leading to resistance towards both radiation and chemotherapies. From this family, myeloid cell leukemia-1 (Mcl 1) has proven the most difficult to target, and one of the leading causes of treatment resistance. Exploiting the selective PPI between the apoptosis regulating protein Noxa and Mcl-1, utilising a fluorescence polarization assay, we have identified four small molecules with the ability to modulate Mcl-1. The identified compounds were computationally modelled and docked against the Mcl-1 binding interface to obtain structural information about their binding sites allowing for future analogue design. When examined for their activity towards pancreatic cell lines that overexpress Mcl-1 (MiaPaCa-2 and BxPC-3), the identified compounds demonstrated growth inhibition, suggesting effective Mcl-1 modulation. PMID- 26616141 TI - Erythropoietin-enhanced endothelial progenitor cell recruitment in peripheral blood and renal vessels during experimental acute kidney injury in rats. AB - Beneficial effects of erythropoietin (EPO) have been reported in acute kidney injury (AKI) when administered prior to induction of AKI. We studied the effects of EPO administration on renal function shortly after ischemic AKI. For this purpose, rats were subjected to renal ischemia for 30 min and EPO was administered at a concentration of 500 U/kg either i.v. as a single shot directly after ischemia or with an additional i.p. dose until 3 days after surgery. The results were compared with AKI rats without EPO application and a sham-operated group. Renal function was assessed by measurement of serum biochemical markers, histological grading, and using an isolated perfused kidney (IPK) model. Furthermore, we performed flow cytometry to analyze the concentration of endothelial progenitor cells (EPCs) in the peripheral blood and renal vessels. Following EPO application, there was only a statistically non-significant tendency of serum creatinine and urea to improve, particularly after daily EPO application. Renal vascular resistance and the renal perfusion rate were not significantly altered. In the histological analysis, acute tubular necrosis was only marginally ameliorated following EPO administration. In summary, we could not demonstrate a significant improvement in renal function when EPO was applied after AKI. Interestingly, however, EPO treatment resulted in a highly significant increase in CD133- and CD34-positive EPC both in the peripheral blood and renal vessels. PMID- 26616142 TI - Activation of autophagy by unfolded proteins during endoplasmic reticulum stress. AB - Endoplasmic reticulum stress is defined as the accumulation of unfolded proteins in the endoplasmic reticulum, and is caused by conditions such as heat or agents that cause endoplasmic reticulum stress, including tunicamycin and dithiothreitol. Autophagy, a major pathway for degradation of macromolecules in the vacuole, is activated by these stress agents in a manner dependent on inositol-requiring enzyme 1b (IRE1b), and delivers endoplasmic reticulum fragments to the vacuole for degradation. In this study, we examined the mechanism for activation of autophagy during endoplasmic reticulum stress in Arabidopsis thaliana. The chemical chaperones sodium 4-phenylbutyrate and tauroursodeoxycholic acid were found to reduce tunicamycin- or dithiothreitol induced autophagy, but not autophagy caused by unrelated stresses. Similarly, over-expression of BINDING IMMUNOGLOBULIN PROTEIN (BIP), encoding a heat shock protein 70 (HSP70) molecular chaperone, reduced autophagy. Autophagy activated by heat stress was also found to be partially dependent on IRE1b and to be inhibited by sodium 4-phenylbutyrate, suggesting that heat-induced autophagy is due to accumulation of unfolded proteins in the endoplasmic reticulum. Expression in Arabidopsis of the misfolded protein mimics zeolin or a mutated form of carboxypeptidase Y (CPY*) also induced autophagy in an IRE1b-dependent manner. Moreover, zeolin and CPY* partially co-localized with the autophagic body marker GFP-ATG8e, indicating delivery to the vacuole by autophagy. We conclude that accumulation of unfolded proteins in the endoplasmic reticulum is a trigger for autophagy under conditions that cause endoplasmic reticulum stress. PMID- 26616143 TI - A Review of Cardiovascular Autonomic Control in Cluster Headache. AB - OBJECTIVE: This review aims to evaluate existing literature concerning cardiovascular autonomic function and CH. Suggestions about future research are offered and known difficulties in investigating the autonomic nervous system in cluster headache are discussed. BACKGROUND: Little is known of the pathophysiological mechanisms behind cluster headache. Cranial autonomic features are an inherent and diagnostic feature; however, a number of studies and clinical observations support the involvement of systemic autonomic control in its pathophysiology. Further, cluster headache attacks are apparently more easily triggered during periods of parasympathetic dominance. A better understanding of this interaction may provide insight into central autonomic regulation and its role in cluster headache. METHODS: A PubMed search was performed in April 2015 using the search terms "cluster headache," "cardiovascular," "autonomic nervous system," and "cardiac." References of identified articles were also searched for relevant articles. Studies were included if they contained data on cardiovascular or autonomic responses to autonomic tests, induced or spontaneous attacks. RESULTS: In total, 22 studies investigating cardiac autonomic control in cluster headache were identified. Three overall categories of investigations exist: (1) Those studying changes in heart rate, blood pressure, and electrocardiographic changes; (2) those employing various clinical autonomic tests; and finally (3) those using spectral and nonlinear analysis of heart rate variability. Although not completely congruent, overall, results suggest ictal hyperactivation of the parasympathetic branch and a sympathetic deficit. Subclinical autonomic dysregulation is also present in the pain-free state. CONCLUSION: Cardiac autonomic control is subclinically affected in cluster headache. The changes could be attributed to the suggested central dysregulation present in this disorder. PMID- 26616144 TI - The influence of alternative pathways of respiration that utilize branched-chain amino acids following water shortage in Arabidopsis. AB - During dark-induced senescence isovaleryl-CoA dehydrogenase (IVDH) and D-2 hydroxyglutarate dehydrogenase (D-2HGDH) act as alternate electron donors to the ubiquinol pool via the electron-transfer flavoprotein/electron-transfer flavoprotein:ubiquinone oxidoreductase (ETF/ETFQO) pathway. However, the role of this pathway in response to other stresses still remains unclear. Here, we demonstrated that this alternative pathway is associated with tolerance to drought in Arabidopsis. In comparison with wild type (WT) and lines overexpressing D-2GHDH, loss-of-function etfqo-1, d2hgdh-2 and ivdh-1 mutants displayed compromised respiration rates and were more sensitive to drought. Our results demonstrated that an operational ETF/ETFQO pathway is associated with plants' ability to withstand drought and to recover growth once water becomes replete. Drought-induced metabolic reprogramming resulted in an increase in tricarboxylic acid (TCA) cycle intermediates and total amino acid levels, as well as decreases in protein, starch and nitrate contents. The enhanced levels of the branched-chain amino acids in loss-of-function mutants appear to be related to their increased utilization as substrates for the TCA cycle under water stress. Our results thus show that mitochondrial metabolism is highly active during drought stress responses and provide support for a role of alternative respiratory pathways within this response. PMID- 26616145 TI - Circulating RNA: looking at the liver through a frosted glass. AB - CONTEXT: The evaluation of the liver condition, based on serum enzymatic activity and biopsies, is insufficient. Therefore, it is a priority to find a correlation between circulating RNAs and liver damage. METHODS: Publications were retrieved by the search terms "circulating RNA AND liver". RESULTS: Although differences exist between studies, a profile of RNAs that repeatedly appeared as indicators of liver damage was identified. DISCUSSION: We highlight those circulating RNAs useful to diagnostic, and discuss the transport mechanisms. CONCLUSION: Several studies have proven that circulating RNAs are useful to establish a diagnostic and a prognosis of liver diseases. PMID- 26616147 TI - Kidney injury biomarkers and urinary creatinine variability in nominally healthy adults. AB - Environmental exposure diagnostics use creatinine concentrations in urine aliquots as the internal standard for dilution normalization of all other excreted metabolites when urinary excretion rate data are not available. This is a reasonable approach for healthy adults as creatinine is a human metabolite that is continually produced in skeletal muscles and presumably excreted in the urine at a stable rate. However, creatinine also serves as a biomarker for glomerular filtration rate (efficiency) of the kidneys, so undiagnosed kidney function impairment could affect this commonly applied dilution calculation. The United States Environmental Protection Agency (US EPA) has recently conducted a study that collected approximately 2600 urine samples from 50 healthy adults, aged 19 50 years old, in North Carolina in 2009-2011. Urinary ancillary data (creatinine concentration, total void volume, elapsed time between voids), and participant demographic data (race, gender, height, and body weight) were collected. A representative subset of 280 urine samples from 29 participants was assayed using a new kidney injury panel (KIP). In this article, we investigated the relationships of KIP biomarkers within and between subjects and also calculated their interactions with measured creatinine levels. The aims of this work were to document the analytical methods (procedures, sensitivity, stability, etc.), provide summary statistics for the KIP biomarkers in "healthy" adults without diagnosed disease (distribution, fold range, central tendency, variance), and to develop an understanding as to how urinary creatinine level varies with respect to the individual KIP proteins. Results show that new instrumentation and data reduction methods have sufficient sensitivity to measure KIP levels in nominally healthy urine samples, that linear regression between creatinine concentration and urinary excretion explains only about 68% of variability, that KIP markers are poorly correlated with creatinine (r(2) ~ 0.34), and that statistical outliers of KIP markers are not random, but are clustered within certain subjects. In addition, we interpret these new adverse outcome pathways based in vivo biomarkers for their potential use as intermediary chemicals that may be diagnostic of kidney adverse outcomes to environmental exposure. PMID- 26616146 TI - A Japanese cross-sectional multicentre study of biomarkers associated with cardiovascular disease in smokers and non-smokers. AB - We performed a cross-sectional, multicentre study in Japan to detect the differences in biomarkers of exposure and cardiovascular biomarkers between smokers and non-smokers. Several clinically relevant cardiovascular biomarkers differed significantly between smokers and non-smokers, including lipid metabolism (high-density lipoprotein cholesterol concentrations - lower in smokers), inflammation (fibrinogen and white blood cell count - both higher in smokers), oxidative stress (8-epi-prostaglandin F2alpha - higher in smokers) and platelet activation (11-dehydro-thromboxane B2 - higher in smokers) (p <= 0.0001). These results provide further evidence showing that cardiovascular biomarkers can discriminate smokers from non-smokers, and could be used to evaluate the risks associated with tobacco products. PMID- 26616148 TI - Adiponectin gene polymorphisms are associated with increased susceptibility to diabetic peripheral neuropathy. AB - BACKGROUND: Adiponectin (ADP) polymorphisms associated with diabetes mellitus in several populations. However, no previous studies have investigated its association with diabetic peripheral neuropathy (DPN). Our study examined the association between ADP-linked SNPs and DPN susceptibility. METHODS: We randomly recruited 160 diabetes mellitus (DM) patients and 80 healthy individuals. RESULTS: The C allele of rs3821799 increased DPN susceptibility. In normal individuals, GG of rs3774261 carriers had 7.1 times higher DPN susceptibility than AA carriers. The haplotype analyzes indicated CGG might increase DPN susceptibility. CONCLUSION: Our study demonstrated that ADP gene polymorphisms are associated with the susceptibility to DPN. PMID- 26616149 TI - Effects of perioperative blood transfusion on the prognosis in hereditary and sporadic colon cancer. AB - We investigated the effects of perioperative blood transfusion in the prognosis of hereditary and sporadic colon cancer. There are 1075 colon cancer patients, including 936 sporadic colon cancer and 139 with hereditary colon cancer undergoing surgery at our hospital. All patients underwent 10 years of follow-up. In the sporadic group, mortality, local recurrence rate and distant metastases rate of transfused patients were significantly higher than non-transfused patients. The 10-year survival rates were significantly lower in patients receiving blood transfusions compared to non-transfused patients. In the hereditary group, mortality was higher in transfused patients compared to non transfused patients. PMID- 26616150 TI - Meta-analysis of transforming growth factor beta receptor I 6A/9A gene polymorphism and breast cancer risk: the picture remains murky. AB - Breast cancer is currently the second most common cancer worldwide and the most frequent malignant tumor among women. However, the exact contribution of various allelic alterations remains unclear. This meta-analysis was conducted to evaluate the association of the transforming growth factor beta receptor I 6A/9A (TbetaR-I 6A/9A) gene polymorphism with breast cancer risk. Relevant studies were identified from PubMed and Cochrane Library on 1 October 2013, and eligible reports were recruited and synthesized. Eleven reports that included a total of 12 studies were recruited into this meta-analysis for the association of the TbetaR-I 6A/9A gene polymorphism and breast cancer risk. The results indicated that overall the TbetaR-I 6A allele was associated with breast cancer risk (OR = 1.33, 95% CI: 1.02-1.73, p = 0.04). However, the TbetaR-I 6A/6A and 9A/9A genotypes were not associated with an increased risk of developing breast cancer (6A/6A: OR = 1.71, 95% CI: 0.95-3.08, p = 0.07; 9A/9A: OR = 0.82, 95% CI: 0.66 1.02, p = 0.08). In the Caucasian population, no such association could be established. In conclusion, the TbetaR-I 6A allele might represent a risk factor for breast cancer risk, but significantly larger data sets from a larger number of studies, including studies that allow ethnicity, subgroup analysis and environmental impact evaluation, are required to maximize statistical significance and meta-analysis robustness. PMID- 26616151 TI - Symmetry-Driven Strategy for the Assembly of the Core Tetracycle of (+) Ryanodine: Synthetic Utility of a Cobalt-Catalyzed Olefin Oxidation and alpha Alkoxy Bridgehead Radical Reaction. AB - Ryanodine (1) is a potent modulator of intracellular calcium release channels, designated as ryanodine receptors. The exceptionally complex molecular architecture of 1 comprises a highly oxygenated pentacyclic system with eleven contiguous stereogenic centers, which makes it a formidable target for organic synthesis. We identified the embedded C2 -symmetric tricyclic substructure within 1. This specific recognition permitted us to design a concise synthetic route to enantiopure tricycle 9 by utilizing a series of pairwise functionalizations. The four tetrasubstituted carbon centers of 9 were effectively constructed by three key reactions, a dearomatizing Diels-Alder reaction, the kinetic resolution of the obtained racemic 14 through asymmetric methanolysis, and the transannular aldol reaction of the eight-membered diketone 10. A new combination of cobalt catalyzed hydroperoxidation and NfF-promoted elimination enabled conversion of the hindered olefin of 9 into the corresponding ketone, thus realizing the desymmetrization. Finally, the tetrasubstituted carbon was stereospecifically installed by utilizing the alpha-alkoxy bridgehead radical to deliver the core tetracycle 7 with the six contiguous tetrasubstituted carbon centers. Consequently, the present work not only accomplishes efficient assembly of four out of the five fused rings of 1, but also develops two new powerful methodologies: two-step ketone formation and bridgehead radical reaction. PMID- 26616153 TI - Advances in Sample Extraction. PMID- 26616152 TI - The role of ADME pharmacogenomics in early clinical trials: perspective of the Industry Pharmacogenomics Working Group (I-PWG). AB - Genetic polymorphisms in metabolizing enzymes and drug transporters have been shown to significantly impact the exposure of drugs having a high dependence on a single mechanism for their absorption, distribution or clearance, such that genotyping can lead to actionable steps in disease treatment. Recently, global regulatory agencies have provided guidance for assessment of pharmacogenomics during early stages of drug development, both in the form of formal guidance and perspectives published in scientific journals. The Industry Pharmacogenomics Working Group (I-PWG), conducted a survey among member companies to assess the practices relating to absorption, distribution, metabolism, excretion pharmacogenomics) during early stages of clinical development, to assess the impact of the recent Regulatory Guidance issued by the US FDA and EMA on Industry practices. PMID- 26616155 TI - A case report of suspected hepatopulmonary syndrome secondary to ductal plate malformation with chronic active hepatitis in a dog. AB - Hepatopulmonary syndrome (HPS) is a respiratory complication of hepatic disease, that is well recognized in humans and defined by the presence of 1) liver disease, 2) hypoxemia and/or high alveolar-arterial oxygen gradient (AaDO2) and 3) intrapulmonary vasodilatation. The present report describes a similar case of HPS in a dog. A six-month-old Papillon was diagnosed with ductal plate malformation with chronic active hepatitis and showed progressive increases in AaDO2 over the course of the following six months. The presence of intrapulmonary vasodilatation was confirmed by agitated saline contrast transthoracic echocardiography. Also, the absence of congenital cardiac defect was confirmed by transthoracic echocardiography. From these results, we suspected that this dog had HPS. This is the first description of suspected canine HPS. PMID- 26616156 TI - Development of a novel detection system for microbes from bovine diarrhea by real time PCR. AB - Diarrhea in cattle is one of the most economically costly disorders, decreasing milk production and weight gain. In the present study, we established a novel simultaneous detection system using TaqMan real-time PCR designed as a system for detection of microbes from bovine diarrhea using real-time PCR (referred to as Dembo-PCR). Dembo-PCR simultaneously detects a total of 19 diarrhea-causing pathogens, including viruses, bacteria and protozoa. Specific primer-probe sets were newly designed for 7 pathogens and were synthesized on the basis of previous reports for 12 pathogens. Assays were optimized to react under the same reaction conditions. The PCR efficiency and correlation coefficient (R(2)) of standard curves for each assay were more than 80% and 0.9766, respectively. Furthermore, the sensitivity of Dembo-PCR in fecal sample analysis was measured with feces spiked with target pathogens or synthesized DNA that included specific nucleotide target regions. The resulting limits of detection (LOD) for virus-spiked samples, bacteria and DNA fragments were 0.16-1.6 TCID50 (PFU/reaction), 1.3-13 CFU/reaction and 10-100 copies/reaction, respectively. All reactions showed high sensitivity in pathogen detection. A total of 8 fecal samples, collected from 6 diarrheic cattle, 1 diarrheic calf and 1 healthy cow, were tested using Dembo-PCR to validate the assay's clinical performance. The results revealed that bovine coronavirus had infected all diarrheic adult cattle and that bovine torovirus had infected the diarrheic calf. These results suggest that Dembo-PCR may be a powerful tool for diagnosing infectious agents in cattle diarrhea. PMID- 26616157 TI - Impact of moisture and magnesium stearate functionality on manufacturability of wet granulated metformin tablets. AB - During the development of a wet granulated 850 mg metformin hydrochloride tablet formulation, the tablets exhibited high friability (>3% w/w) irrespective of the source of extra-granular magnesium stearate (MgSt). High friability values indicated that an anti-bonding effect of MgSt was too high to be overcome by 3.3% w/w povidone as a binder in the formulation with 1.5% w/w residual granule moisture. Increasing the povidone concentration up to 7% w/w showed limited improvement in friability, with tablets showing variable friability depending on MgSt source. Characterization of MgSt indicated differences in crystallinity, surface area and particle morphology between different vendors. In addition, a new bulk yield strength test, which determines the MgSt fragmentation tendency, was found to be indicative of the MgSt performance in the tablet formulation. To improve bonding properties of granules, residual granule moisture was increased to 2% w/w at different povidone concentrations. At 2% w/w residual granule moisture content, regardless of MgSt source, the tablets showed significant improvement in friability (~0.6% w/w) even at the lowest povidone concentration (3.3% w/w). The bonding power of higher residual granule moisture had a greater impact than higher povidone concentration in overcoming the anti-bonding effects of magnesium stearate. PMID- 26616158 TI - Editorial overview: Virus-vector interactions. PMID- 26616159 TI - Trials and tribulations with electronic medication adherence monitoring in kidney transplantation. AB - Medication adherence in kidney transplantation is critical to prevent graft rejection. Testing interventions designed to support patients to take their prescribed medications following a kidney transplant require an accurate measure of medication adherence. In research, the available methods for measuring medication adherence include self-report, pill counts, prescription refill records, surrogate measures of medication adherence and medication bottles with a microchip-embedded cap to record bottle openings. Medication bottles with a microchip-embedded cap are currently regarded as the gold standard measure. This commentary outlines the challenges in measuring medication adherence using electronic medication monitoring of kidney transplant patients recruited from five sites. The challenges included obtaining unanimous stakeholder support for using this method, agreement on an index medication to measure, adequate preparation of the patient and training of pharmacy staff, and how to analyze data when periods of time were not recorded using the electronic adherence measure. Provision of this information will enable hospital and community pharmacists to implement approaches that promote the effective use of this adherence measure for optimal patient outcomes. PMID- 26616160 TI - Premenstrual flares of pyoderma gangrenosum controlled with use of a combined oral contraceptive and antiandrogen (ethinyl estradiol/drospirenone). AB - The effect of sex hormones on pyoderma gangrenosum (PG) has not been reported. We report the case of a 34-year-old woman with chronic PG leg ulcers who was found to have recurring, premenstrual flares of PG. Her PG flares were controlled with the use of ethinyl estradiol/drospirenone. PMID- 26616162 TI - Morphology evolution of single-crystalline hematite nanocrystals: magnetically recoverable nanocatalysts for enhanced facet-driven photoredox activity. AB - We have developed a new green chemical approach for the shape-controlled synthesis of single-crystalline hematite nanocrystals in aqueous medium. FESEM, HRTEM and SAED techniques were used to determine the morphology and crystallographic orientations of each nanocrystal and its exposed facets. PXRD and HRTEM techniques revealed that the nanocrystals are single crystalline in nature; twins and stacking faults were not detected in these nanocrystals. The structural, vibrational, and electronic spectra of these nanocrystals were highly dependent on their shape. Different shaped hematite nanocrystals with distinct crystallographic planes have been synthesized under similar reaction conditions, which can be desired as a model for the purpose of properties comparison with the nanocrystals prepared under different reaction conditions. Here we investigated the photocatalytic performance of these different shaped-nanocrystals for methyl orange degradation in the presence of white light (lambda > 420 nm). In this study, we found that the density of surface Fe(3+) ions in particular facets was the key factor for the photocatalytic activity and was higher on the bitruncated dodecahedron shape nanocrystals by coexposed {104}, {100} and {001} facets, attributing to higher catalytic activity. The catalytic activity of different exposed facet nanocrystals were as follows: {104} + {100} + {001} (bitruncated dodecahedron) > {101} + {001} (bitruncated-octahedron) > {001} + {110} (nanorods) > {012} (nanocuboid) which provided the direct evidence of exposed facet-driven photocatalytic activity. The nanocrystals were easily recoverable using an external magnet and reused at least six times without significant loss of its catalytic activity. PMID- 26616161 TI - Zeolite Nanoparticles for Selective Sorption of Plasma Proteins. AB - The affinity of zeolite nanoparticles (diameter of 8-12 nm) possessing high surface area and high pore volume towards human plasma proteins has been investigated. The protein composition (corona) of zeolite nanoparticles has been shown to be more dependent on the plasma protein concentrations and the type of zeolites than zeolite nanoparticles concentration. The number of proteins present in the corona of zeolite nanoparticles at 100% plasma (in vivo state) is less than with 10% plasma exposure. This could be due to a competition between the proteins to occupy the corona of the zeolite nanoparticles. Moreover, a high selective adsorption for apolipoprotein C-III (APOC-III) and fibrinogen on the zeolite nanoparticles at high plasma concentration (100%) was observed. While the zeolite nanoparticles exposed to low plasma concentration (10%) exhibited a high selective adsorption for immunoglobulin gamma (i.e. IGHG1, IGHG2 and IGHG4) proteins. The zeolite nanoparticles can potentially be used for selectively capture of APOC-III in order to reduce the activation of lipoprotein lipase inhibition during hypertriglyceridemia treatment. The zeolite nanoparticles can be adapted to hemophilic patients (hemophilia A (F-VIII deficient) and hemophilia B (F-IX deficient)) with a risk of bleeding, and thus might be potentially used in combination with the existing therapy. PMID- 26616163 TI - Cronobacter sakazakii clinical isolates overcome host barriers and evade the immune response. AB - Cronobacter sakazakii is the most frequently clinically isolated species of the Cronobacter genus. However the virulence factors of C. sakazakii including their ability to overcome host barriers remains poorly studied. In this study, ten clinical isolates of C. sakazakii were assessed for their ability to invade and translocate through human colonic carcinoma epithelial cells (Caco-2) and human brain microvascular endothelial cells (HBMEC). Their ability to avoid phagocytosis in human macrophages U937 and human brain microglial cells was investigated. Additionally, they were tested for serum sensitivity and the presence of the Cronobacter plasminogen activation gene (cpa) gene, which is reported to confer serum resistance. Our data showed that the clinical C. sakazakii strains invaded and translocated through Caco-2 and HBMEC cell lines and some strains showed significantly higher levels of invasion and translocation. Moreover, C. sakazakii was able to persist and even multiply in phagocytic macrophage and microglial cells. All strains, except one, were able to withstand human serum exposure, the single serum sensitive strain was also the only one which did not encode for the cpa gene. These results demonstrate that C. sakazakii clinical isolates are able to overcome host barriers and evade the host immune response indicating their capacity to cause diseases such as necrotizing enterocolitis (NEC) and meningitis. Our data showed for the first time the ability of C. sakazakii clinical isolates to survive and multiply within human microglial cells. Additionally, it was shown that C. sakazakii clinical strains have the capacity to translocate through the Caco-2 and HBMEC cell lines paracellularly. PMID- 26616164 TI - Correlation between nerve growth factor and tissue expression of IL-17 in leprosy. AB - Leprosy is a serious public health problem in peripheral and developing countries. Leprosy is a chronic infectious-contagious disease caused by the intracellular, bacillus Mycobacterium leprae, which causes tissue damage and demyelination of peripheral nerves. Recent studies have demonstrated the participation of new subtype's cytokines profile in the inflammatory response of leprosy. Since nerve functions are affected by inflammatory response during the course of leprosy, changes in the production of NGF and its receptor (NGF R) may be directly associated with disability and sensory loss. Skin biopsies were collected and submitted to immunohistochemistry using specific antibodies to IL 17, NGF and NGF R. Quantitative analysis of NGF, NGFR and IL-17 immunostaining showed a significant difference between the clinical forms, with higher expression of NGF and NGFR in lepromatous leprosy and IL-17 in tuberculoid leprosy. The present study showed that IL-17, in addition to stimulating an inflammatory response, negatively regulates the action of NGF and NGF R in the polar forms of the disease. PMID- 26616165 TI - Differential induction of innate defense antimicrobial peptides in primary nasal epithelial cells upon stimulation with inflammatory cytokines, Th17 cytokines or bacterial conditioned medium from Staphylococcus aureus isolates. AB - To date it is incompletely understood why half of the human population is intrinsically resistant to Staphylococcus aureus colonization whereas the other half is intermittently or permanently colonized. Nasal colonization represents the primary niche for S. aureus. We therefore investigated whether primary nasal epithelial cells (HNEC) express antimicrobial peptides (AMPs) upon stimulation by inflammatory cytokines or bacterial conditioned medium (BCM) of different colonizing and invasive staphylococci. Stimulation with classical cytokines (IL 1beta, TNF-alpha, IFN-gamma) potently induced hBD-3 and RNase7 in HNEC. Th17 cytokines (IL-17A, IL-17F, IL-22) yielded comparably weak hBD-3 and RNase7 induction and no synergistic effects with classical cytokines. BCM of S. aureus and Staphylococcus epidermidis isolates moderately induced hBD3 and RNase7 mRNA expression without significant differences when comparing colonizing vs. invasive isolates. Our results indicate that HNEC contribute to the innate defense by secretion of an AMP-containing chemical defense shield along the nasal mucosa i.e. within the primary colonization niche of S. aureus. Further studies are needed to investigate whether a deficient AMP expression in the nasal mucosa may be related to different S. aureus carrier states. AMPs or AMP-inducing agents may be promising candidates for future topical decolonization regimens that aim to prevent invasive S. aureus infections. PMID- 26616166 TI - Biological and immunological characterization of norovirus major capsid proteins from three different genotypes. AB - Noroviruses (NoVs) are the leading cause of non-bacterial acute gastroenteritis worldwide. Due to a lack of cell culture system and animal model, our understanding of NoVs has been lagging behind. In this study, NoV major capsid proteins (VP1) from three different genotypes (GI.2, GII.3 and GII.4) were expressed by using recombinant baculovirus expression system and which led to successful assembly of virus-like particles (VLPs). The receptor binding patterns of three kinds of VLPs were characterized by using synthetic and salivary HBGA VLP binding assay. Cross-reactivity and cross-blocking activity of rabbit hyperimmune sera against these VLPs were determined by ELISA/Western blot analysis and saliva-VLP binding blockade assay, respectively. Expression of the major capsid proteins from three genotypes all led to smaller VLPs in dominance when sf9 cells were cultured in suspension, which was in consistence with our previous report. These smaller VLPs were used for in vitro synthetic and salivary HBGA-VLP binding and binding blockade assays. VLPs from GII.3 strain exhibited no binding to all synthetic HBGAs and saliva samples tested while VLPs from GI.2 and GII.4 strain showed similar binding pattern and bound to all salivary HBGAs tested. Rabbit anti-GII.3 VLPs hyperimmune serum didn't block the binding of GI.2 and GII.4 VLPs to salivary HBGAs while rabbit anti-GI.2 VLP hyperimmune serum blocked the binding of GII.4 VLPs to salivary HBGAs but not vice versa. Our results provide further evidence indirectly in support of presence of other factors involved in receptor binding other than HBGAs for NoVs, and demonstrate poor cross-blocking activities of antibodies against VLPs within or across genogroups. PMID- 26616167 TI - The degree of virulence does not necessarily affect MRSA biofilm strength and response to photodynamic therapy. AB - Biofilm formation transforms infections from acute to chronic, increasing patient mortality and significantly increasing healthcare costs. We are studying the prevalence of some virulence genes among methicillin resistant Staphylococcus aureus (MRSA) isolates relative to biofilm formation and the potential of photoactivated hypericin to treat these infections. Isolates were collected from three Egyptian governorates over seven months in 2011, 100 isolates were identified as MRSA. Biofilm formation was established using crystal violet staining and 2,3,5-triphenyl tetrazolium chloride reduction. Twenty two percent of the isolates formed biofilms, of which 68.2% were moderate to strong. The virulence genes were detected using polymerase chain reaction. spaX (x-region of protein A) was most prevalent. All biofilm-formers lacked cap5 (capsular polysaccharide 5), the other genes were: nuc (thermonuclease) > clfA (clumping factor) > spaIgG (IgG binding site of protein A), fnbA (fibronectin protein A), cap8 (capsular polysaccharide 8), agr (accessory-gene-regulator locus) > fnbB (fibronectin protein B). agr-locus was only found in 22.22% of moderate biofilm formers, the remaining genes were almost equally prevalent among biofilm-formers and negative controls. Photoactivated hypericin efficiently inhibited 92.2-99.9% of biofilm viability, irrespective of the number of virulence genes. To conclude, biofilm formation, and treatment might be affected by a myriad of virulence factors rather than a single gene, however, photoactivated hypericin remains a potential antibiofilm approach. PMID- 26616168 TI - Endotracheal intubation in newly born infants in the light of new resuscitation guidelines. PMID- 26616169 TI - Progressive quadriparesis caused by anterior odontoid screw upward migration in rheumatoid arthritis. PMID- 26616170 TI - Multiple vertebral metastases of the renal cell carcinoma presenting with back pain. PMID- 26616171 TI - Incidence and risk factors for pneumonia following anterior cervical decompression and fusion procedures: an ACS-NSQIP study. AB - BACKGROUND CONTEXT: Postoperative pneumonia has important clinical consequences for both patients and the health-care system. Few studies have examined pneumonia following anterior cervical decompression and fusion (ACDF) procedures. PURPOSE: This study aimed to determine the incidence and risk factors for development of pneumonia following ACDF procedures. STUDY DESIGN/SETTING: A retrospective cohort study of data collected prospectively by the American College of Surgeons National Surgical Quality Improvement Program was carried out. PATIENT SAMPLE: This study comprised 11,353 patients undergoing ACDF procedures during 2011-2013. OUTCOME MEASURES: The primary outcome was diagnosis of pneumonia in the first 30 postoperative days. METHODS: Independent risk factors for the development of pneumonia were identified using multivariate regression. Readmission rates were compared between patients who did and did not develop pneumonia using multivariate regression that adjusted for all demographic, comorbidity, and procedural characteristics. RESULTS: The incidence of pneumonia was 0.45% (95% confidence interval=0.33%-0.57%). In the multivariate analysis, independent risk factors for the development of pneumonia were greater age (p<.001), dependent functional status (relative risk [RR]=5.3, p<.001), chronic obstructive pulmonary disease (RR=4.4, p<.001), and greater operative duration (p=.020). Patients who developed pneumonia following discharge had a higher readmission rate than other patients (72.7% vs. 2.4%, adjusted RR=24.5, p<.001). In total, 10.2% of all readmissions were caused by pneumonia. CONCLUSIONS: Pneumonia occurs in approximately 1 in 200 patients following ACDF procedures. Patients who are older, are functionally dependent, or have chronic obstructive pulmonary disease are at greater risk. These patients should be counseled, monitored, and targeted with preventative interventions accordingly. Greater operative duration is also an independent risk factor. Approximately three in four patients who develop pneumonia following hospitalization for ACDF procedures are readmitted. This elevated readmission rate has implications for bundled payments and hospital performance reports. PMID- 26616172 TI - Sucrose metabolism gene families and their biological functions. AB - Sucrose, as the main product of photosynthesis, plays crucial roles in plant development. Although studies on general metabolism pathway were well documented, less information is available on the genome-wide identification of these genes, their expansion and evolutionary history as well as their biological functions. We focused on four sucrose metabolism related gene families including sucrose synthase, sucrose phosphate synthase, sucrose phosphate phosphatase and UDP glucose pyrophosphorylase. These gene families exhibited different expansion and evolutionary history as their host genomes experienced differentiated rates of the whole genome duplication, tandem and segmental duplication, or mobile element mediated gene gain and loss. They were evolutionarily conserved under purifying selection among species and expression divergence played important roles for gene survival after expansion. However, we have detected recent positive selection during intra-species divergence. Overexpression of 15 sorghum genes in Arabidopsis revealed their roles in biomass accumulation, flowering time control, seed germination and response to high salinity and sugar stresses. Our studies uncovered the molecular mechanisms of gene expansion and evolution and also provided new insight into the role of positive selection in intra-species divergence. Overexpression data revealed novel biological functions of these genes in flowering time control and seed germination under normal and stress conditions. PMID- 26616173 TI - Alcohol exposure in utero is associated with decreased gray matter volume in neonates. AB - Neuroimaging studies have indicated that prenatal alcohol exposure is associated with alterations in the structure of specific brain regions. However, the temporal specificity of such changes and their behavioral consequences are less known. Here we explore the brain structure of infants with in utero exposure to alcohol shortly after birth. T2 structural MRI images were acquired from 28 alcohol-exposed infants and 45 demographically matched healthy controls at 2-4 weeks of age on a 3T Siemens Allegra system as part of large birth cohort study, the Drakenstein Child Health Study (DCHS). Neonatal neurobehavior was assessed at this visit; early developmental outcome assessed on the Bayley Scales of Infant Development III at 6 months of age. Volumes of gray matter regions were estimated based on the segmentations of the University of North Carolina neonatal atlas. Significantly decreased total gray matter volume was demonstrated for the alcohol exposed cohort compared to healthy control infants (p < 0.001). Subcortical gray matter regions that were significantly different between groups after correcting for overall gray matter volume included left hippocampus, bilateral amygdala and left thalamus (p < 0.01). These findings persisted even when correcting for infant age, gender, ethnicity and maternal smoking status. Both early neurobehavioral and developmental adverse outcomes at 6 months across multiple domains were significantly associated with regional volumes primarily in the temporal and frontal lobes in infants with prenatal alcohol exposure. Alcohol exposure during the prenatal period has potentially enduring neurobiological consequences for exposed children. These findings suggest the effects of prenatal alcohol exposure on brain growth is present very early in the first year of life, a period during which the most rapid growth and maturation occurs. PMID- 26616175 TI - Evaluation and Management of Hip and Pelvis Injuries. AB - Injuries to the hip and pelvis among runners can be among the most challenging to treat. Advances in the understanding of running biomechanics as it pertains to the lumbopelvic and hip regions have improved the management of these conditions. Conservative management with an emphasis on activity modification and neuromuscular exercises should comprise the initial plan of care, with injection therapies used in a supportive manner. PMID- 26616174 TI - Metformin suppressed the proliferation of LoVo cells and induced a time-dependent metabolic and transcriptional alteration. AB - Metformin is a widely used anti-diabetic drug with potential anti-tumor activity. However, little is known about its global metabolic and transcriptional impacts on tumor cells. In current study, we performed a metabolic profiling on human derived colon cancer LoVo cells treated by 10 mM metformin for 8, 24 and 48 h. An obvious time-dependent metabolic alteration was observed from 8 to 48 h, prior to the reduction of cell viability. A total of 47, 45 and 66 differential metabolites were identified between control and metformin-treated cells at three time points. Most of the metabolites were up-regulated at 8 h, but down-regulated at 24 and 48 h by metformin. These metabolites were mainly involved in carbohydrates, lipids, amino acids, vitamins and nucleotides metabolism pathways. Meanwhile, the transcirptomic profile revealed 134 and 3061 differentially expressed genes at 8 and 24 h by metformin. In addition to the cancer signaling pathways, expression of genes involved in cell energy metabolism pathways was significantly altered, which were further validated with genes in glucose metabolism pathway. Altogether, our current data indicate that metformin suppressed the proliferation of LoVo cells, which may be due to the modulation on cell energy metabolism at both metabolic and transcriptional levels in a time dependent way. PMID- 26616176 TI - Patellofemoral Pain. AB - Patellofemoral pain is characterized by insidious onset anterior knee pain that is exaggerated under conditions of increased patellofemoral joint stress. A variety of risk factors may contribute to the development of patellofemoral pain. It is critical that the history and physical examination elucidate those risk factors specific to an individual in order to prescribe an appropriate and customized treatment plan. This article aims to review the epidemiology, risk factors, diagnosis, and management of patellofemoral pain. PMID- 26616177 TI - Iliotibial Band Syndrome in Runners: Biomechanical Implications and Exercise Interventions. AB - Iliotibial band syndrome (ITBS) has known biomechanical factors with an unclear explanation based on only strength and flexibility deficits. Neuromuscular coordination has emerged as a likely reason for kinematic faults guiding research toward motor control. This article discusses ITBS in relation to muscle performance factors, fascial considerations, epidemiology, functional anatomy, strength deficits, kinematics, iliotibial strain and strain rate, and biomechanical considerations. Evidence-based exercise approaches are reviewed for ITBS, including related methods used to train the posterior hip muscles. PMID- 26616178 TI - Running Injuries: The Infrapatellar Fat Pad and Plica Injuries. AB - When considering knee pain in runners, clinicians differentiate sources of symptoms and determine their cause. Knee problems arise when a runner increases the amount/frequency of the loading through the lower limb. The way the loading is distributed through the knee determines which tissues are abnormally loaded. Knee problems cannot be considered in isolation, requiring a thorough investigation of static and dynamic lower limb mechanics, and footwear and surfaces. This article examines potential sources of knee pain and explores the role of the infrapatellar fat pad and synovial plica in the mechanics of the knee and its involvement in knee symptoms. PMID- 26616179 TI - Exertional Leg Pain. AB - Exertional leg pain is a common condition seen in runners and the general population. Given the broad differential diagnosis of this complaint, this article focuses on the incidence, anatomy, pathophysiology, clinical presentation, diagnostic evaluation, and management of common causes that include medial tibial stress syndrome, tibial bone stress injury, chronic exertional compartment syndrome, arterial endofibrosis, popliteal artery entrapment syndrome, and entrapment of the common peroneal, superficial peroneal, and saphenous nerves. Successful diagnosis of these conditions hinges on performing a thorough history and physical examination followed by proper diagnostic testing and appropriate management. PMID- 26616180 TI - Foot and Ankle Injuries in Runners. AB - Foot and ankle injuries account for nearly one-third of running injuries. Achilles tendinopathy, plantar fasciopathy, and ankle sprains are 3 of the most common types of injuries sustained during training. Other common injuries include other tendinopathies of the foot and ankle, bone stress injuries, nerve conditions including neuromas, and joint disease including osteoarthritis. This review provides an evidence-based framework for the evaluation and optimal management of these conditions to ensure safe return to running participation and reduce risk for future injury. PMID- 26616181 TI - Bone Stress Injuries in Runners. AB - Bone stress injuries (BSIs) are common running injuries and may occur at a rate of 20% annually. Both biological and biomechanical risk factors contribute to BSI. Evaluation of a runner with suspected BSI includes completing an appropriate history and physical examination. MRI grading classification for BSI has been proposed and may guide return to play. Management includes activity modification, optimizing nutrition, and addressing risk factors, including the female athlete triad. BSI prevention strategies include screening for risk factors during preparticipation evaluations, optimizing nutrition (including adequate caloric intake, calcium, and vitamin D), and promoting ball sports during childhood and adolescence. PMID- 26616182 TI - Health Considerations in Female Runners. AB - Female participation in running is at a historical high. Special consideration should be given to this population, in whom suboptimal nutritional intake, menstrual irregularity, and bone stress injury are common. Immature athletes should garner particular attention. Advances in the understanding of the Triad and Triad-related conditions have largely informed the approach to the health of this population. Clinicians should be well versed in the identification of Triad related risk factors. A multidisciplinary team may be necessary for the optimal treatment of at-risk runners. Nonpharmacologic strategies to increase energy availability in athletes should be used as first-line treatment. PMID- 26616183 TI - Running Injuries During Adolescence and Childhood. AB - The popularity of running among young athletes has significantly increased over the past few decades. As the number of children who participate in running increases, so do the potential number of injuries to this group. Proper care of these athletes includes a thorough understanding of the unique physiology of the skeletally immature athlete and common injuries in this age group. Treatment should focus on athlete education, modification of training schedule, and correction of biomechanical deficits contributing to injury. Early identification and correction of these factors will allow a safe return to running sports. PMID- 26616184 TI - Injuries and Health Considerations in Ultramarathon Runners. AB - Ultramarathon runners are a relatively small and unique group of distance runners with somewhat different medical issues than other distance runners. This article outlines some of those differences so that clinicians caring for these runners in the clinic or at competitions might be better prepared. PMID- 26616186 TI - Malalignment Syndrome in Runners. AB - More than 80% of runners are out of alignment. The standard back examination should include assessment of pelvic alignment. An awareness of pelvic malalignment and the the malalignment syndrome is essential to allow one to provide proper care of a runner. The 3 most common presentations usually respond to a supervised, progressive treatment program. The validity of any research into the biomechanics of running should be questioned if the study has failed to look at whether pelvic malalignment was present and whether the altered, asymmetrical biomechanical changes attributable to the malalignment itself could have affected the results of the study. PMID- 26616185 TI - An Evidence-Based Videotaped Running Biomechanics Analysis. AB - Running biomechanics play an important role in the development of injuries. Performing a running biomechanics analysis on injured runners can help to develop treatment strategies. This article provides a framework for a systematic video based running biomechanics analysis plan based on the current evidence on running injuries, using 2-dimensional (2D) video and readily available tools. Fourteen measurements are proposed in this analysis plan from lateral and posterior video. Identifying simple 2D surrogates for 3D biomechanic variables of interest allows for widespread translation of best practices, and have the best opportunity to impact the highly prevalent problem of the injured runner. PMID- 26616187 TI - Core and Lumbopelvic Stabilization in Runners. AB - Core muscles provide stability that allows generation of force and motion in the lower extremities, as well as distributing impact forces and allowing controlled and efficient body movements. Imbalances or deficiencies in the core muscles can result in increased fatigue, decreased endurance, and injury in runners. Core strengthening should incorporate the intrinsic needs of the core for flexibility, strength, balance, and endurance, and the function of the core in relation to its role in extremity function and dysfunction. Specific exercises are effective in strengthening the core muscles. PMID- 26616189 TI - Supporting a Running Lifestyle. PMID- 26616188 TI - Gait Retraining: Altering the Fingerprint of Gait. AB - In terms of running, there is evidence that links mechanics with injury. This evidence provides the justification for altering these mechanics. Increased hip adduction and vertical impact loading have been most commonly associated with injury. More work is needed in order to understand the optimal way to retrain gait patterns in runners. The human body has a considerable ability to adapt. To provide individuals with the ability to alter faulty movement patterns in ways that can reduce injury risk is a powerful tool. PMID- 26616190 TI - Running Injuries. PMID- 26616191 TI - Photochemical H2 evolution from water catalyzed by a dichloro(diphenylbipyridine)platinum(ii) derivative tethered to multiple viologen acceptors. AB - A new single-component photocatalyst for the reduction of water to H2, a dichloro(dpbpy)platinum(ii) derivative (dpbpy = 4,4'-diphenyl-2,2'-bipyridine) tethered to four pendant viologen acceptors (1), is shown to exhibit twice higher photocatalytic efficiency than the previously reported dichloro(bpy)-platinum(ii) analog (; bpy = 2,2'-bipyridine), consistent with the higher absorptivity of at the metal-to-ligand charge transfer ((1)MLCT) band due to the larger pi conjugation in dpbpy relative to bpy. PMID- 26616192 TI - Regulation of Microtubule Growth and Catastrophe: Unifying Theory and Experiment. AB - Recent studies have found that microtubule-associated proteins (MAPs) can regulate the dynamical properties of microtubules in unexpected ways. For most MAPs, there is an inverse relationship between their effects on the speed of growth and the frequency of catastrophe, the conversion of a growing microtubule to a shrinking one. Such a negative correlation is predicted by the standard GTP cap model, which posits that catastrophe is due to loss of a stabilizing cap of GTP-tubulin at the end of a growing microtubule. However, many other MAPs, notably Kinesin-4 and combinations of EB1 with XMAP215, contradict this general rule. In this review, we show that a more nuanced, but still simple, GTP-cap model, can account for the diverse regulatory activities of MAPs. PMID- 26616194 TI - The glassy random laser: replica symmetry breaking in the intensity fluctuations of emission spectra. AB - The behavior of a newly introduced overlap parameter, measuring the correlation between intensity fluctuations of waves in random media, is analyzed in different physical regimes, with varying amount of disorder and non-linearity. This order parameter allows to identify the laser transition in random media and describes its possible glassy nature in terms of emission spectra data, the only data so far accessible in random laser measurements. The theoretical analysis is performed in terms of the complex spherical spin-glass model, a statistical mechanical model describing the onset and the behavior of random lasers in open cavities. Replica Symmetry Breaking theory allows to discern different kinds of randomness in the high pumping regime, including the most complex and intriguing glassy randomness. The outcome of the theoretical study is, eventually, compared to recent intensity fluctuation overlap measurements demonstrating the validity of the theory and providing a straightforward interpretation of qualitatively different spectral behaviors in different random lasers. PMID- 26616193 TI - AMPK: An Energy-Sensing Pathway with Multiple Inputs and Outputs. AB - AMP-activated protein kinase (AMPK) is a key regulator of energy balance expressed ubiquitously in eukaryotic cells. Here we review the canonical adenine nucleotide-dependent mechanism that activates AMPK when cellular energy status is compromised, as well as other, noncanonical activation mechanisms. Once activated, AMPK acts to restore energy homeostasis by promoting catabolic pathways, resulting in ATP generation, and inhibiting anabolic pathways that consume ATP. We also review the various hypothesis-driven and unbiased approaches that have been used to identify AMPK substrates and have revealed substrates involved in both metabolic and non-metabolic processes. We particularly focus on methods for identifying the AMPK target recognition motif and how it can be used to predict new substrates. PMID- 26616195 TI - LOB Domain Proteins: Beyond Lateral Organ Boundaries. AB - LATERAL ORGAN BOUNDARIES DOMAIN (LBD) proteins defined by a conserved LATERAL ORGAN BOUNDARIES (LOB) domain are key regulators of plant organ development. Recent studies have expanded their functional diversity beyond the definition of lateral organ boundaries to pollen development, plant regeneration, photomorphogenesis, pathogen response, and specific developmental functions in non-model plants, such as poplar and legumes. The identification of a range of upstream regulators, protein partners, and downstream targets of LBD family members has unraveled the molecular networks of LBD-dependent processes. Moreover, it has been demonstrated that LBD proteins have essential roles in integrating developmental changes in response to phytohormone signaling or environmental cues. As we discuss here, these novel discoveries of LBD functions and their molecular contexts promote a better understanding of this plant specific transcription factor family. PMID- 26616196 TI - Aurora Kinases Throughout Plant Development. AB - Aurora kinases are evolutionarily conserved key mitotic determinants in all eukaryotes. Yeasts contain a single Aurora kinase, whereas multicellular eukaryotes have at least two functionally diverged members. The involvement of Aurora kinases in human cancers has provided an in-depth mechanistic understanding of their roles throughout cell division in animal and yeast models. By contrast, understanding Aurora kinase function in plants is only starting to emerge. Nevertheless, genetic, cell biological, and biochemical approaches have revealed functional diversification between the plant Aurora kinases and suggest a role in formative (asymmetric) divisions, chromatin modification, and genome stability. This review provides an overview of the accumulated knowledge on the function of plant Aurora kinases as well as some major challenges for the future. PMID- 26616197 TI - Fatty Acid and Lipid Transport in Plant Cells. AB - Fatty acids (FAs) and lipids are essential - not only as membrane constituents but also for growth and development. In plants and algae, FAs are synthesized in plastids and to a large extent transported to the endoplasmic reticulum for modification and lipid assembly. Subsequently, lipophilic compounds are distributed within the cell, and thus are transported across most membrane systems. Membrane-intrinsic transporters and proteins for cellular FA/lipid transfer therefore represent key components for delivery and dissemination. In addition to highlighting their role in lipid homeostasis and plant performance, different transport mechanisms for land plants and green algae - in the model systems Arabidopsis thaliana, Chlamydomonas reinhardtii - are compared, thereby providing a current perspective on protein-mediated FA and lipid trafficking in photosynthetic cells. PMID- 26616199 TI - Molecular evolution: Regulatory runaways. PMID- 26616200 TI - Lamellipodial tension, not integrin/ligand binding, is the crucial factor to realise integrin activation and cell migration. AB - The molecular clutch (MC) model proposes that actomyosin-driven force transmission permits integrin-dependent cell migration. To investigate the MC, we introduced diverse talin (TLN) and integrin variants into Flp-InTM T-RexTM HEK293 cells stably expressing uPAR. Vitronectin variants served as substrate providing uPAR-mediated cell adhesion and optionally integrin binding. This particular system allowed us to selectively analyse key MC proteins and interactions, effectively from the extracellular matrix substrate to intracellular f-actin, and to therewith study mechanobiological aspects of MC engagement also uncoupled from integrin/ligand binding. With this experimental approach, we found that for the initial PIP2-dependent membrane/TLN/f-actin linkage and persistent lamellipodia formation the C-terminal TLN actin binding site (ABS) is dispensable. The establishment of an adequate MC-mediated lamellipodial tension instead depends predominantly on the coupling of this C-terminal TLN ABS to the actomyosin-driven retrograde actin flow force. This lamellipodial tension is crucial for full integrin activation eventually determining integrin-dependent cell migration. In the integrin/ligand-independent condition the frictional membrane resistance participates to these processes. Integrin/ligand binding can also contribute but is not necessarily required. PMID- 26616201 TI - Cardiac involvement in antiphospholipid syndrome: The diagnostic role of noninvasive cardiac imaging. AB - OBJECTIVES: The antiphospholipid syndrome (APS) is an autoimmune disorder of acquired hypercoagulability characterized by vascular thrombosis, increased pregnancy morbidity, and elevated levels of antiphospholipid antibodies. Cardiac involvement in APS may be presented as heart valve disease affecting approximately a third of patients or less frequently as intracardial thombosis, pulmonary hypertension, right or left ventricular dysfunction, micro-vascular thrombosis, coronary artery, or micro-vascular disease with overt or silent clinical presentation. METHODS: Noninvasive cardiovascular imaging plays a crucial role in the evaluation of heart involvement in APS. Transthoracic or transoesophageal echocardiography enable early, accurate diagnosis and severity assessment of HVD as well as of ventricular dysfunction and pulmonary hypertension. Studies by echocardiography and nuclear imaging have detected abnormalities in myocardial perfusion in approximately 30% of primary APS. CT scan is the technique of choice for the assessment of pulmonary embolism and can effectively detect intracardiac thrombi. Myocardial perfusion defects have been detected by 13N-ammonia PET in 40% of APS. Cardiovascular magnetic resonance (CMR) has identified an unexpectedly high prevalence of occult myocardial scarring and endomyocardial fibrosis in APS, and is the technique of choice, if quantification of heart valve disease and stress myocardial perfusion-fibrosis is needed. RESULTS: Noninvasive, nonradiating imaging techniques, such as echocardiography and CMR are superior to CT or nuclear techniques and are of great value for the diagnosis and follow-up of both clinically overt and silent cardiac disease in APS. CONCLUSIONS: The high incidence of cardiac involvement in APS demands early diagnosis/treatment and multimodality cardiovascular imaging is of great importance. PMID- 26616198 TI - Evolution of vertebrate sex chromosomes and dosage compensation. AB - Differentiated sex chromosomes in mammals and other vertebrates evolved independently but in strikingly similar ways. Vertebrates with differentiated sex chromosomes share the problems of the unequal expression of the genes borne on sex chromosomes, both between the sexes and with respect to autosomes. Dosage compensation of genes on sex chromosomes is surprisingly variable - and can even be absent - in different vertebrate groups. Systems that compensate for different gene dosages include a wide range of global, regional and gene-by-gene processes that differ in their extent and their molecular mechanisms. However, many elements of these control systems are similar across distant phylogenetic divisions and show parallels to other gene silencing systems. These dosage systems cannot be identical by descent but were probably constructed from elements of ancient silencing mechanisms that are ubiquitous among vertebrates and shared throughout eukaryotes. PMID- 26616202 TI - Tracking live cell response to cadmium (II) concentrations by scanning electrochemical microscopy. AB - The biological chemistry of toxic heavy metals, such as Cd (II), has become an active area of research due to connections with increased oxidative stress, cytotoxicity, and human/animal carcinogenicity. In this study, scanning electrochemical microscopy (SECM) was used as a noninvasive technique to monitor membrane permeability of single live human bladder cancer cells (T24) subjected to exposure of Cd (II) at various concentrations. The addition of a membrane permeable redox mediator, ferrocenemethanol (FcMeOH), in combination with depth scan imaging provided probe approach curves (PACs) to reveal changes in membrane homeostasis. To demonstrate the strength of SECM as a bioanalytical technique for cell physiology and pathology, we tested responses of live cells after 1h incubations with various concentrations of Cd (II). For the first time, a trend in membrane permeability of Cd (II) treated live T24 cells was discovered. Dependent on the incubation concentration, the trend displayed an initial decrease in membrane permeability coefficient from 75MUm/s for control cells to 25MUm/s for cells incubated with 75MUM Cd (II). This was followed by an eventual return to the permeability coefficient of control cells (75MUm/s) with further increases in Cd (II) exposure. The cells were found to respond at as little as 10MUM Cd (II) concentrations. This work further demonstrates the use of SECM as a bioanalytical technique to monitor cell physiology and topography. A greater insight into the complex mechanisms behind Cd (II) toxicity is anticipated. PMID- 26616203 TI - Environmentally friendly method to grow wide-bandgap semiconductor aluminum nitride crystals: Elementary source vapor phase epitaxy. AB - Aluminum nitride (AlN) has attracted increasing interest as an optoelectronic material in the deep ultraviolet spectral range due to its wide bandgap of 6.0 eV (207 nm wavelength) at room temperature. Because AlN bulk single crystals are ideal device substrates for such applications, the crystal growth of bulky AlN has been extensively studied. Two growth methods seem especially promising: hydride vapor phase epitaxy (HVPE) and sublimation. However, the former requires hazardous gases such as hydrochloric acid and ammonia, while the latter needs extremely high growth temperatures around 2000 degrees C. Herein we propose a novel vapor-phase-epitaxy-based growth method for AlN that does not use toxic materials; the source precursors are elementary aluminum and nitrogen gas. To prepare our AlN, we constructed a new growth apparatus, which realizes growth of AlN single crystals at a rate of ~18 MUm/h at 1550 degrees C using argon as the source transfer via the simple reaction Al + 1/2N2 -> AlN. This growth rate is comparable to that by HVPE, and the growth temperature is much lower than that in sublimation. Thus, this study opens up a novel route to achieve environmentally friendly growth of AlN. PMID- 26616204 TI - Water resistance profile as a marker of skin barrier damage in atopic dermatitis patients. PMID- 26616205 TI - Acefylline activates filaggrin deimination by peptidylarginine deiminases in the upper epidermis. AB - BACKGROUND: Peptidylarginine deiminases (PADs) catalyze deimination (or citrullination), a calcium-dependent post-translational modification involved in several physiological processes and human diseases, such as rheumatoid arthritis and cancer. Deimination of filaggrin (FLG) by PAD1 and PAD3 during the last steps of keratinocyte differentiation is a crucial event for the epidermis function and homeostasis. This allows the complete degradation of FLG, leading to the production of free amino acids and their derivatives that are essential for epidermal photoprotection and moisturizing of the stratum corneum. OBJECTIVE: To increase the flux of this catabolic pathway, we searched for activators of PADs. METHODS: A large chemical library was screened first in silico and then by using an automated assay based on an indirect colorimetric measurement of recombinant human PAD activity. Potential activators were then confirmed using a recombinant human FLG as a substrate, and secondly after topical application at the surface of three-dimensional reconstructed human epidermis. RESULTS: The data obtained after the library screening pointed to xanthine derivatives as potential PAD activators. Among seven xanthine derivatives tested at 50-300MUM, caffeine, theobromine and acefylline proved to be the most potent enhancers of in vitro deimination of FLG by PAD1 and PAD3. After topical application of a gel formulation containing 3% acefylline at the surface of reconstructed epidermis, immunoblotting analysis showed an increase in the total amount of deiminated proteins, and confocal microscopy showed an enhanced deimination in the stratum corneum. This demonstrated the activation of PADs in living cells. CONCLUSION: As a PAD activator, acefylline will be useful to study the role of deimination and could be proposed to increase or correct the hydration of the cornified layers of the epidermis. PMID- 26616206 TI - Cost-effectiveness of national mandatory screening of all admissions to English National Health Service hospitals for meticillin-resistant Staphylococcus aureus: a mathematical modelling study. AB - BACKGROUND: In December, 2010, National Health Service (NHS) England introduced national mandatory screening of all admissions for meticillin-resistant Staphylococcus aureus (MRSA). We aimed to assess the effectiveness and cost effectiveness of this policy, from a regional or national health-care decision makers' perspective, compared with alternative screening strategies. METHODS: We used an individual-based dynamic transmission model parameterised with national MRSA audit data to assess the effectiveness and cost-effectiveness of admission screening of patients in English NHS hospitals compared with five alternative strategies (including no screening, checklist-activated screening, and high-risk specialty-based screening), accompanied by patient isolation and decolonisation, over a 5 year time horizon. We evaluated strategies for different NHS hospital types (acute, teaching, and specialist), MRSA prevalence, and transmission potentials using probabilistic sensitivity analyses. FINDINGS: Compared with no screening, mean cost per quality-adjusted life-year (QALY) of screening all admissions was L89,000-148,000 (range L68,000-222,000), and this strategy was consistently more costly and less effective than alternatives for all hospital types. At a L30,000/QALY willingness-to-pay threshold and current prevalence, only the no-screening strategy was cost effective. The next best strategies were, in acute and teaching hospitals, targeting of high-risk specialty admissions (30 40% chance of cost-effectiveness; mean incremental cost-effectiveness ratios [ICERs] L45,200 [range L35,300-61,400] and L48,000/QALY [L34,600-74,800], respectively) and, in specialist hospitals, screening these patients plus risk factor-based screening of low-risk specialties (a roughly 20% chance of cost effectiveness; mean ICER L62,600/QALY [L48,000-89,400]). As prevalence and transmission increased, targeting of high-risk specialties became the optimum strategy at the NHS willingness-to-pay threshold (L30,000/QALY). Switching from screening all admissions to only high-risk specialty admissions resulted in a mean reduction in total costs per year (not considering uncertainty) of L2.7 million per acute hospital, L2.9 million per teaching, and L474,000 per specialist hospital for a minimum rise in infections (about one infection per year per hospital). INTERPRETATION: Our results show that screening all admissions for MRSA is unlikely to be cost effective in England at the current NHS willingness-to-pay threshold, and our findings informed modified guidance to NHS England in 2014. Screening admissions to high-risk specialties is likely to represent better resource use in terms of cost per QALY gained. FUNDING: UK Department of Health. PMID- 26616207 TI - Making sense of universal screening for MRSA. PMID- 26616208 TI - Closed reduction of anterior shoulder dislocation in the super obese. PMID- 26616209 TI - After Detection: The Improved Accuracy of Lung Cancer Assessment Using Radiologic Computer-aided Diagnosis. AB - RATIONALE AND OBJECTIVES: The aim of this study was to evaluate the improved accuracy of radiologic assessment of lung cancer afforded by computer-aided diagnosis (CADx). MATERIALS AND METHODS: Inclusion/exclusion criteria were formulated, and a systematic inquiry of research databases was conducted. Following title and abstract review, an in-depth review of 149 surviving articles was performed with accepted articles undergoing a Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-based quality review and data abstraction. RESULTS: A total of 14 articles, representing 1868 scans, passed the review. Increases in the receiver operating characteristic (ROC) area under the curve of .8 or higher were seen in all nine studies that reported it, except for one that employed subspecialized radiologists. CONCLUSIONS: This systematic review demonstrated improved accuracy of lung cancer assessment using CADx over manual review, in eight high-quality observer-performance studies. The improved accuracy afforded by radiologic lung-CADx suggests the need to explore its use in screening and regular clinical workflow. PMID- 26616212 TI - Enhanced visible and near infrared emissions via Ce(3+) to Ln(3+) energy transfer in Ln(3+)-doped CeF3 nanocrystals (Ln = Nd and Sm). AB - We report the enhancement of both visible and near infrared (NIR) emissions from Nd(3+) ions via Ce(3+) sensitization in colloidal nanocrystals for the first time. This is achieved in citrate capped Nd(3+)-doped CeF3 nanocrystals under ultraviolet (UV) irradiation (lambdaex = 282 nm). The lasing transition ((4)F3/2 > (4)I11/2) at 1064 nm from Nd(3+)-doped CeF3 nanocrystals has much higher emission intensity via Ce(3+) ion sensitization compared to the direct excitation of Nd(3+) ions. The nanocrystals were prepared using a simple microwave irradiation route. Moreover, the study has been extended to Sm(3+)-doped CeF3 nanocrystals which show strong characteristic emissions of Sm(3+) ions via energy transfer from Ce(3+) ions. The energy transfer mechanism from Ce(3+) to Nd(3+) and Sm(3+) ions is proposed. PMID- 26616210 TI - Single-molecule spectroscopy and imaging over the decades. AB - As of 2015, it has been 26 years since the first optical detection and spectroscopy of single molecules in condensed matter. This area of science has expanded far beyond the early low temperature studies in crystals to include single molecules in cells, polymers, and in solution. The early steps relied upon high-resolution spectroscopy of inhomogeneously broadened optical absorption profiles of molecular impurities in solids at low temperatures. Spectral fine structure arising directly from the position-dependent fluctuations of the number of molecules in resonance led to the attainment of the single-molecule limit in 1989 using frequency-modulation laser spectroscopy. In the early 1990s, a variety of fascinating physical effects were observed for individual molecules, including imaging of the light from single molecules as well as observations of spectral diffusion, optical switching and the ability to select different single molecules in the same focal volume simply by tuning the pumping laser frequency. In the room temperature regime, researchers showed that bursts of light from single molecules could be detected in solution, leading to imaging and microscopy by a variety of methods. Studies of single copies of the green fluorescent protein also uncovered surprises, especially the blinking and photoinduced recovery of emitters, which stimulated further development of photoswitchable fluorescent protein labels. All of these early steps provided important fundamentals underpinning the development of super-resolution microscopy based on single molecule localization and active control of emitting concentration. Current thrust areas include extensions to three-dimensional imaging with high precision, orientational analysis of single molecules, and direct measurements of photodynamics and transport properties for single molecules trapped in solution by suppression of Brownian motion. Without question, a huge variety of studies of single molecules performed by many talented scientists all over the world have extended our knowledge of the nanoscale and many microscopic mechanisms previously hidden by ensemble averaging. PMID- 26616213 TI - Convection associated with exclusion zone formation in colloidal suspensions. AB - The long-range repulsion of colloids from various interfaces has been observed in a wide range of studies from different research disciplines. This so-called exclusion zone (EZ) formation occurs near surfaces such as hydrogels, polymers, or biological tissues. It was recently shown that the underlying physical mechanism leading to this long-range repulsion is a combination of ion-exchange at the interface, diffusion of ions, and diffusiophoresis of colloids in the resulting ion concentration gradients. In this paper, we show that the same ion concentration gradients that lead to exclusion zone formation also imply that diffusioosmosis near the walls of the sample cell must occur. This should lead to convective flow patterns that are directly associated with exclusion zone formation. We use multi-particle tracking to study the dynamics of particles during exclusion zone formation in detail, confirming that indeed two pronounced vortex-like convection rolls occur near the cell walls. These dramatic flow patterns persist for more than 4 hours, with the typical velocity decreasing as a function of time. We find that the flow velocity depends strongly on the surface properties of the sample cell walls, consistent with diffusioosmosis being the main physical mechanism that governs these convective flows. PMID- 26616211 TI - Current disease modifying approaches to treat Parkinson's disease. AB - Parkinson's disease (PD is a progressive neurological disorder characterized by the degeneration and death of midbrain dopamine and non-dopamine neurons in the brain leading to motor dysfunctions and other symptoms, which seriously influence the quality of life of PD patients. The drug L-dopa can alleviate the motor symptoms in PD, but so far there are no rational therapies targeting the underlying neurodegenerative processes. Despite intensive research, the molecular mechanisms causing neuronal loss are not fully understood which has hampered the development of new drugs and disease-modifying therapies. Neurotrophic factors are by virtue of their survival promoting activities attract candidates to counteract and possibly halt cell degeneration in PD. In particular, studies employing glial cell line-derived neurotrophic factor (GDNF) and its family member neurturin (NRTN), as well as the recently described cerebral dopamine neurotrophic factor (CDNF) and the mesencephalic astrocyte-derived neurotrophic factor (MANF) have shown positive results in protecting and repairing dopaminergic neurons in various models of PD. Other substances with trophic actions in dopaminergic neurons include neuropeptides and small compounds that target different pathways impaired in PD, such as increased cell stress, protein handling defects, dysfunctional mitochondria and neuroinflammation. In this review, we will highlight the recent developments in this field with a focus on trophic factors and substances having the potential to beneficially influence the viability and functions of dopaminergic neurons as shown in preclinical or in animal models of PD. PMID- 26616215 TI - An antenatal prediction model for adverse birth outcomes in an urban population: The contribution of medical and non-medical risks. AB - OBJECTIVES: in the Netherlands the perinatal mortality rate is high compared to other European countries. Around eighty percent of perinatal mortality cases is preceded by being small for gestational age (SGA), preterm birth and/or having a low Apgar-score at 5 minutes after birth. Current risk detection in pregnancy focusses primarily on medical risks. However, non-medical risk factors may be relevant too. Both non-medical and medical risk factors are incorporated in the Rotterdam Reproductive Risk Reduction (R4U) scorecard. We investigated the associations between R4U risk factors and preterm birth, SGA and a low Apgar score. DESIGN: a prospective cohort study under routine practice conditions. SETTING: six midwifery practices and two hospitals in Rotterdam, the Netherlands. PARTICIPANTS: 836 pregnant women. INTERVENTIONS: the R4U scorecard was filled out at the booking visit. MEASUREMENTS: after birth, the follow-up data on pregnancy outcomes were collected. Multivariate logistic regression was used to fit models for the prediction of any adverse outcome (preterm birth, SGA and/or a low Apgar score), stratified for ethnicity and socio-economic status (SES). FINDINGS: factors predicting any adverse outcome for Western women were smoking during the first trimester and over-the-counter medication. For non-Western women risk factors were teenage pregnancy, advanced maternal age and an obstetric history of SGA. Risk factors for high SES women were low family income, no daily intake of vegetables and a history of preterm birth. For low SES women risk factors appeared to be low family income, non-Western ethnicity, smoking during the first trimester and a history of SGA. KEY CONCLUSIONS: the presence of both medical and non-medical risk factors early in pregnancy predict the occurrence of adverse outcomes at birth. Furthermore the risk profiles for adverse outcomes differed according to SES and ethnicity. IMPLICATIONS FOR PRACTICE: to optimise effective risk selection, both medical and non-medical risk factors should be taken into account in midwifery and obstetric care at the booking visit. PMID- 26616214 TI - The epigenomic landscape of African rainforest hunter-gatherers and farmers. AB - The genetic history of African populations is increasingly well documented, yet their patterns of epigenomic variation remain uncharacterized. Moreover, the relative impacts of DNA sequence variation and temporal changes in lifestyle and habitat on the human epigenome remain unknown. Here we generate genome-wide genotype and DNA methylation profiles for 362 rainforest hunter-gatherers and sedentary farmers. We find that the current habitat and historical lifestyle of a population have similarly critical impacts on the methylome, but the biological functions affected strongly differ. Specifically, methylation variation associated with recent changes in habitat mostly concerns immune and cellular functions, whereas that associated with historical lifestyle affects developmental processes. Furthermore, methylation variation--particularly that correlated with historical lifestyle--shows strong associations with nearby genetic variants that, moreover, are enriched in signals of natural selection. Our work provides new insight into the genetic and environmental factors affecting the epigenomic landscape of human populations over time. PMID- 26616216 TI - CMOS integration of inkjet-printed graphene for humidity sensing. AB - We report on the integration of inkjet-printed graphene with a CMOS micro-electro mechanical-system (MEMS) microhotplate for humidity sensing. The graphene ink is produced via ultrasonic assisted liquid phase exfoliation in isopropyl alcohol (IPA) using polyvinyl pyrrolidone (PVP) polymer as the stabilizer. We formulate inks with different graphene concentrations, which are then deposited through inkjet printing over predefined interdigitated gold electrodes on a CMOS microhotplate. The graphene flakes form a percolating network to render the resultant graphene-PVP thin film conductive, which varies in presence of humidity due to swelling of the hygroscopic PVP host. When the sensors are exposed to relative humidity ranging from 10-80%, we observe significant changes in resistance with increasing sensitivity from the amount of graphene in the inks. Our sensors show excellent repeatability and stability, over a period of several weeks. The location specific deposition of functional graphene ink onto a low cost CMOS platform has the potential for high volume, economic manufacturing and application as a new generation of miniature, low power humidity sensors for the internet of things. PMID- 26616218 TI - Structural Modifications of Benzimidazoles via Multi-Step Synthesis and Their Impact on Sirtuin-Inhibitory Activity. AB - Benzimidazole derivatives have been shown to possess sirtuin-inhibitory activity. In the continuous search for potent sirtuin inhibitors, systematic changes on the terminal benzene ring were performed on previously identified benzimidazole-based sirtuin inhibitors, to further investigate their structure-activity relationships. It was demonstrated that the sirtuin activities of these novel compounds followed the trend where meta-substituted compounds possessed markedly weaker potency than ortho- and para-substituted compounds, with the exception of halogenated substituents. Molecular docking studies were carried out to rationalize these observations. Apart from this, the methods used to synthesize the interesting compounds are also discussed. PMID- 26616217 TI - Short-term hyperoxia does not exert immunologic effects during experimental murine and human endotoxemia. AB - Oxygen therapy to maintain tissue oxygenation is one of the cornerstones of critical care. Therefore, hyperoxia is often encountered in critically ill patients. Epidemiologic studies have demonstrated that hyperoxia may affect outcome, although mechanisms are unclear. Immunologic effects might be involved, as hyperoxia was shown to attenuate inflammation and organ damage in preclinical models. However, it remains unclear whether these observations can be ascribed to direct immunosuppressive effects of hyperoxia or to preserved tissue oxygenation. In contrast to these putative anti-inflammatory effects, hyperoxia may elicit an inflammatory response and organ damage in itself, known as oxygen toxicity. Here, we demonstrate that, in the absence of systemic inflammation, short-term hyperoxia (100% O2 for 2.5 hours in mice and 3.5 hours in humans) does not result in increased levels of inflammatory cytokines in both mice and healthy volunteers. Furthermore, we show that, compared with room air, hyperoxia does not affect the systemic inflammatory response elicited by administration of bacterial endotoxin in mice and man. Finally, neutrophil phagocytosis and ROS generation are unaffected by short-term hyperoxia. Our results indicate that hyperoxia does not exert direct anti-inflammatory effects and temper expectations of using it as an immunomodulatory treatment strategy. PMID- 26616219 TI - Involvement of pregnane X receptor in the impaired glucose utilization induced by atorvastatin in hepatocytes. AB - Accumulating evidences demonstrated that statins impaired glucose utilization. This study was aimed to investigate whether PXR was involved in the atorvastatin impaired glucose utilization. Rifampicin/PCN served as PXR activator control. Glucose utilization, glucose uptake, protein levels of GLUT2, GCK, PDK2, PEPCK1 and G6Pase in HepG2 cells were measured. PXR inhibitors, PXR overexpression and PXR siRNA were applied to verify the role of PXR in atorvastatin-impaired glucose utilization in cells. Hypercholesterolemia rats induced by high fat diet feeding, orally received atorvastatin (5 and 10 mg/kg), pravastatin (10 mg/kg) for 14 days, or intraperitoneally received PCN (35 mg/kg) for 4 days. Results showed that glucose utilization was markedly inhibited by atorvastatin, simvastatin, pitavastatin, lovastatin and rifampicin. Neither rosuvastatin nor pravastatin showed the similar effect. Atorvastatin and pravastatin were selected for the following study. Atorvastatin and rifampicin significantly inhibited glucose uptake and down-regulated GLUT2 and GCK expressions. Similarly, overexpressed PXR significantly down-regulated GLUT2 and GCK expressions and impaired glucose utilization. Ketoconazole and resveratrol attenuated the impaired glucose utilization by atorvastatin and rifampicin in both parental and overexpressed PXR cells. PXR knockdown significantly up-regulated GLUT2 and GCK proteins and abolished the decreased glucose consumption and uptake by atorvastatin and rifampicin. Animal experiments showed that atorvastatin and PCN significantly elicited postprandial hyperglycemia, leading to increase in glucose AUC. Expressions of GLUT2 and GCK in rat livers were markedly down-regulated by atorvastatin and PCN. In conclusion, atorvastatin impaired glucose utilization in hepatocytes via repressing GLUT2 and GCK expressions, which may be partly due to PXR activation. PMID- 26616220 TI - Identification of new highly selective inhibitors of the human ADP/ATP carriers by molecular docking and in vitro transport assays. AB - Mitochondrial carriers are proteins that shuttle a variety of metabolites, nucleotides and coenzymes across the inner mitochondrial membrane. The mitochondrial ADP/ATP carriers (AACs) specifically translocate the ATP synthesized within mitochondria to the cytosol in exchange for the cytosolic ADP, playing a key role in energy production, in promoting cell viability and regulating mitochondrial permeability transition pore opening. In Homo sapiens four genes code for AACs with different tissue distribution and expression patterns. Since AACs are dysregulated in several cancer types, the employment of known and new AAC inhibitors might be crucial for inducing mitochondrial-mediated apoptosis in cancer cells. Albeit carboxyatractyloside (CATR) and bongkrekic acid (BKA) are known to be powerful and highly selective AAC inhibitors, able to induce mitochondrial dysfunction at molecular level and poisoning at physiological level, we estimated here for the first time their affinity for the human recombinant AAC2 by in vitro transport assays. We found that the inhibition constants of CATR and BKA are 4 nM and 2.0 MUM, respectively. For finding new AAC inhibitors we also performed a docking-based virtual screening of an in-house developed chemical library and we identified about 100 ligands showing high affinity for the AAC2 binding region. By testing 13 commercially available molecules, out of the 100 predicted candidates, we found that 2 of them, namely suramin and chebulinic acid, are competitive AAC2 inhibitors with inhibition constants 0.3 MUM and 2.1 MUM, respectively. We also demonstrated that chebulinic acid and suramin are "highly selective" AAC2 inhibitors, since they poorly inhibit other human mitochondrial carriers (namely ORC1, APC1 and AGC1). PMID- 26616221 TI - Low dose tunicamycin enhances atherosclerotic plaque stability by inducing autophagy. AB - After decades of indolent progression, atherosclerosis may cause unheralded events, such as myocardial infarction, acute coronary syndrome and stroke due to sudden rupture of atherosclerotic plaques, and pharmacologically modulating plaque stability would reduce the risk of cardiovascular diseases. Endoplasmic reticulum stress (ERS) is responsible for the vulnerability of plaques. However, the underlying mechanism has not been fully elucidated. In this work, ApoE(-/-) mice underwent perivascular carotid collar placement surgeries or sham operations were given higher (3.0mg/kg) and lower (0.3mg/kg) doses of tunicamycin (TM), and plaque stability was evaluated. It was shown that lower TM-treated animals exhibited reduced plaque areas and necrotic cores as well as fibrous cap thickness accompanied by a lower percentage of infiltrates and foam cells than the sham-operated and higher TM treated animals. Lower TM had a profound inhibitory effect on plasma inflammatory response and lipid profile in atherosclerotic ApoE(-/-) mice. In addition, we found that the ApoE(-/-) mice presented higher autophagy activity in response to lower TM administration while apoptosis was reduced. An in vitro study in murine macrophages revealed that lower TM could markedly reduce lipid uptake and accumulation and cell apoptosis while significantly upregulated the expression of Atg7. However, higher TM had adverse effects. Finally, mild induction of ERS by lower TM inhibits AKT-TSC-mTOR cascades to increase cellular autophagy. However, high TM failed to enhance autophagy and equilibrate elevated CHOP-mediated cell death in spite of the inhibition of AKT-TSC-mTOR signaling. In conclusion, lower TM stabilized plaques by activating autophagy through AKT-TSC-mTOR signaling. PMID- 26616222 TI - Olaparib recommendations for ovarian cancer patients. AB - Peter Johnson speaks to Gemma Westcott, Commissioning Editor: Peter Johnson is Professor of Medical Oncology at the University of Southampton and Chief Clinician for Cancer Research UK. He graduated from Cambridge University and St Thomas's Medical School (UK). He trained in oncology at St Bartholomew's Hospital, London, where he was an Imperial Cancer Research Fund (ICRF) Clinical Research Fellow and completed his doctoral research on the Bcl-2 gene, its potential as a therapeutic target in lymphoma and the effects of CD40 ligation on the B-cell surface. He was subsequently a Senior Lecturer in Medical Oncology in the ICRF Cancer Medicine Research Unit, Leeds and took up the Chair of Medical Oncology in Southampton (UK) in 1998. He is responsible for bringing together a broad multidisciplinary group of basic, translational and clinical researchers, and linking the research of the academic unit to the extensive clinical practice in cancer treatment in the Southampton Cancer Centre. His research interests are in applied immunology and immunotherapy, lymphoma biology and clinical trials. He is Chief Investigator for lymphoma trials ranging from first in man novel antibody therapeutics to international randomized studies, and for the Cancer Research UK Stratified Medicine Programme. He was Chair of the UK National Cancer Research Institute Lymphoma Group from 2005 to 2011 and has been a member of national trials committees for the Medical Research Council, Cancer Research UK and Leukaemia and Lymphoma Research. PMID- 26616223 TI - A pilot study of pNGVL4a-CRT/E7(detox) for the treatment of patients with HPV16+ cervical intraepithelial neoplasia 2/3 (CIN2/3). AB - OBJECTIVE: The purpose of this study was to evaluate the safety, efficacy, and immunogenicity of a plasmid vaccine, pNGVL4a-CRT-E7(detox), administered either intradermally, intramuscularly, or directly into the cervical lesion, in patients with HPV16-associated CIN2/3. METHODS: Eligible patients with HPV16(+) CIN2/3 were enrolled in treatment cohorts evaluating pNGVL4a-CRT-E7(detox), administered by either particle-mediated epidermal delivery (PMED), intramuscular injection (IM), or cervical intralesional injection, at study weeks 0, 4, and 8. Patients were monitored for local injection site and systemic toxicity. A standard therapeutic resection was performed at week 15. The primary endpoints were safety and tolerability. Secondary endpoints included histologic regression and change in cervical HPV viral load. Exploratory endpoints included immune responses in the blood and in the target tissue. RESULTS: Thirty-two patients with HPV16(+) CIN2/3 were enrolled onto the treatment phase of the study, and were vaccinated. Twenty-two of 32 patients (69%) experienced vaccine-specific related adverse events. The most frequent vaccine-related events were constitutional and local injection site in nature, and were grade 1 or less in severity. Histologic regression to CIN 1 or less occurred in 8 of 27 (30%) patients who received all vaccinations and underwent LEEP. In subject-matched comparisons, intraepithelial CD8+ T cell infiltrates increased after vaccination in subjects in the intralesional administration cohort. CONCLUSION: pNGVL4a-CRT-E7(detox) was well tolerated, elicited the most robust immune response when administered intralesionally, and demonstrated preliminary evidence of potential clinical efficacy. PMID- 26616224 TI - A phase II study of paclitaxel for the treatment of ovarian stromal tumors: An NRG Oncology/ Gynecologic Oncology Group Study. AB - OBJECTIVE: To estimate the probability of complete clinical response and toxicity of paclitaxel as second-line chemotherapy in measurable disease patients with malignant tumors of the ovarian stroma, and to evaluate the value of inhibin for predicting response. METHODS: Thirty-one patients with histologically confirmed ovarian stromal tumor were enrolled from 2000 to 2013. Patients were required to have measurable recurrent disease, and to have received only one prior chemotherapy regimen. Paclitaxel 175 mg/m2 was administered over a 3 hour infusion, cycling every 21 days. Inhibin levels were drawn within two weeks of initiation of treatment. RESULTS: Of 31 women enrolled, there was only one complete response (3.2%), and partial response in eight of 31 cases (25.8%). The pretreatment inhibin level for the single patient who had complete response was 88 pg/mL. Median progression-free survival was 10.0 months and overall survival was 73.6 months. Myelosuppression was common with 12 of 31 patients (38.7%) suffering grade 3 or 4 neutropenia, leukopenia, or anemia. CONCLUSION: There were too few complete responses to warrant continued evaluation of paclitaxel as a single agent treatment for women with recurrent malignant ovarian stromal tumors with measurable disease according to the primary objective of the study. Toxicity of the regimen was acceptable. Pretreatment inhibin is not a reliable tumor marker as it was not elevated in the majority of patients. PMID- 26616226 TI - MUC20 promotes aggressive phenotypes of epithelial ovarian cancer cells via activation of the integrin beta1 pathway. AB - OBJECTIVE: Mucin (MUC) 20 has recently been implicated to play a role in human carcinogenesis. However, the role of MUC20 in epithelial ovarian cancer (EOC) remains to be elucidated. METHODS: MUC20 expression was assessed in tissue microarray and tumor specimens of EOC patients by immunohistochemistry. Effects of MUC20 on cell viability, adhesion, migration, and invasion were analyzed in MUC20 overexpressing or knockdown EOC cells. Western blotting was performed to analyze signaling pathways modulated by MUC20. RESULTS: MUC20 was overexpressed in EOC samples compared with benign tissues. High MUC20 expression was significantly associated with poor overall survival in patients with advanced stage disease. MUC20 overexpression significantly enhanced EOC cell migration and invasion, but not viability. Mechanistic investigations showed that MUC20 increased cell adhesion to extracellular matrix (ECM) proteins and enhanced activation of integrin beta1 and phosphorylation of focal adhesion kinase (FAK). The enhancement of cell motility and the integrin beta1 signaling by MUC20 was significantly suppressed by integrin beta1 blocking antibody. Furthermore, these effects of MUC20 on EOC cells were also demonstrated in MUC20 knockdown cells. CONCLUSIONS: Our results suggest that MUC20 enhances aggressive behaviors of EOC cells by activating integrin beta1 signaling and provide novel insights into the role of MUC20 in ovarian cancer metastasis. PMID- 26616225 TI - A phase I trial of pegylated liposomal doxorubicin (PLD), carboplatin, bevacizumab and veliparib in recurrent, platinum-sensitive ovarian, primary peritoneal, and fallopian tube cancer: An NRG Oncology/Gynecologic Oncology Group study. AB - OBJECTIVE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of veliparib combined with PLD and carboplatin (CD) in patients with recurrent, platinum-sensitive epithelial ovarian cancer. To determine the tolerability at the MTD combined with bevacizumab. METHODS: Patients received PLD (30mg/m(2), IV) and carboplatin (AUC 5, IV) on day 1 with veliparib on days 1-7 (intermittent) or days 1-28 (continuous). Standard 3+3 design was used in the dose escalation phase with DLTs based on the first cycle. Once the MTDs were determined, cohorts of 6 patients were enrolled to each regimen with bevacizumab (10mg/kg on days 1 and 15) to assess feasibility. DLTs were based on the first 4cycles of treatment in the bevacizumab cohorts. RESULTS: In the dose-escalation phase, 27 patients were treated at 3 dose levels with DLTs noted in 6 patients including grade 4 thrombocytopenia (n=4), and prolonged neutropenia >7days (n=3). At the MTD of veliparib (80mg p.o. b.i.d. for both dosing arms), myelosuppression was the DLT. At MTD, 12 additional patients were treated with bevacizumab with 9 patients experiencing DLTs including grade 4 thrombocytopenia (n=4), prolonged neutropenia >7days (n=1), grade 3 hypertension (n=5), and grade 5 sepsis (n=1). CONCLUSIONS: The MTD of veliparib combined with CD is 80mg p.o. b.i.d. in women with recurrent, platinum-sensitive ovarian cancer. With bevacizumab, DLTs were noted in 9 out of 12 patients. Lower doses of veliparib will need to be considered when given in combination with platinum-based therapies. PMID- 26616227 TI - Oculopharyngeal muscular dystrophy or oculopharyngeal distal myopathy: case report. PMID- 26616229 TI - Ki-67 labeling index can be used as a prognostic marker in gastrointestinal stromal tumor: a systematic review and meta-analysis. AB - PURPOSE: The aim of this study was to investigate the prognostic relevance of the Ki-67 labeling index (LI) in gastrointestinal stromal tumor (GIST) through a systematic review, meta-analysis and diagnostic test accuracy review. METHOD: The study included 1,967 GIST cases from 24 eligible studies. We investigated the correlation between high Ki-67 LI and survival and the proper criteria for high Ki-67 LI. In addition, a diagnostic test accuracy review was conducted to evaluate the predictive role of high Ki-67 LI for higher risk of tumor recurrence. RESULTS: A high Ki-67 LI was significantly correlated with worse disease-free survival (DFS) (hazard ratio [HR] 3.658, 95% confidence interval [CI] 2.687-4.979, p<0.001) and overall survival (OS) (HR 3.730, 95% CI 2.819 4.936, p<0.001). With regard to DFS and OS, the subgroup with a cutoff value of >4% for high Ki-67 LI had a higher HR than the subgroup with a <=4% cutoff. In the diagnostic test accuracy review, a high Ki-67 LI was significantly correlated with higher risk of tumor recurrence (pooled sensitivity = 0.44, pooled specificity = 0.87, area under the curve on the summary receiver operating characteristic curve = 0.656). CONCLUSIONS: Our results showed that a high Ki-67 LI was significantly correlated with worse prognosis and higher risk of tumor recurrence in GIST. Further prospective studies of the prognostic role of Ki-67 LI are necessary prior to application in clinical practice. PMID- 26616228 TI - Does a pay-for-performance program for primary care physicians alleviate health inequity in childhood vaccination rates? AB - INTRODUCTION: Childhood vaccination rates in Manitoba populations with low socioeconomic status (SES) fall significantly below the provincial average. This study examined the impact of a pay-for-performance (P4P) program called the Physician Integrated Network (PIN) on health inequity in childhood vaccination rates. METHODS: The study used administrative data housed at the Manitoba Centre for Health Policy. We included all children born in Manitoba between 2003 and 2010 who were patients at PIN clinics receiving P4P funding matched with controls at non-participating clinics. We examined the rate of completion of the childhood primary vaccination series by age 2 across income quintiles (Q1-Q5). We estimated the distribution of income using the Gini coefficient, and calculated concentration indices for vaccination to determine whether the P4P program altered SES-related differences in vaccination completion. We compared these measures between study cohorts before and after implementation of the P4P program, and over the course of the P4P program in each cohort. RESULTS: The PIN cohort included 6,185 children. Rates of vaccination completion at baseline were between 0.53 (Q1) and 0.69 (Q5). Inequality in income distribution was present at baseline and at study end in PIN and control cohorts. SES-related inequity in vaccination completion worsened in non-PIN clinics (difference in concentration index 0.037; 95 % CI 0.013, 0.060), but remained constant in P4P-funded clinics (difference in concentration index 0.006; 95 % CI 0.008, 0.021). CONCLUSIONS: The P4P program had a limited impact on vaccination rates and did not address health inequity. PMID- 26616230 TI - SYNJ2 variant rs9365723 is associated with colorectal cancer risk in Chinese Han population. AB - PURPOSE: Colorectal cancer (CRC) is the third most common cancer and fourth leading cause of cancer mortality, and twin studies have shown that approximately 35% of the variation in susceptibility to CRC involves inherited genetic differences. We sought to investigate potential genetic associations between some single nucleotide polymorphisms (SNPs) and the risk of CRC in the Chinese Han population. METHODS: We conducted a case-control study including 269 cases and 309 controls. Sixteen SNPs associated with CRC risk were selected from previous genome-wide association studies and genotyped using Sequenom MassARRAY technology. Odds ratios and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusting for age and gender. RESULTS: Using the chi-squared test we found that rs9365723 was associated with CRC risk (p = 0.012). With genetic model analysis, the genotype A/G-G/G (OR = 1.50; 95% CI 1.02 2.21; p = 0.038) of rs9365723 showed an increased risk of CRC in the dominant model. Furthermore, we found that rs9365723 was associated with an increased risk only for colon cancer but not rectal cancer (p = 0.009 and p = 0.414, respectively). CONCLUSIONS: Our results, combined with previous studies, suggest that rs9365723, located on SYNJ2, is associated with the risk of CRC in a Chinese population. Thus, SYNJ2 may play a role in the development of CRC, especially colon cancer. PMID- 26616231 TI - Organisation for oncology and translational research newsletter. PMID- 26616232 TI - Telomerase activity as a marker for differential diagnosis of pancreatic adenocarcinoma: a systematic review and meta-analysis. AB - BACKGROUND: Studies evaluating the role of telomerase activity in pancreatic adenocarcinoma are inconsistent and a systemic review of the available literature may shed new light on this issue. OBJECTIVE: To systematically review the usefulness of telomerase activity in distinguishing pancreatic cancer from other pancreatic diseases. METHODS: A comprehensive search of the PubMed and Embase databases was conducted to identify eligible studies. Only studies evaluating telomerase activity in patients with suspected or previously diagnosed pancreatic adenocarcinomas versus nonpancreatic adenocarcinomas and published in English with a sufficient number of cases were included. The hierarchical summary receiver operating characteristic (HSROC) model was used to establish the potential value of telomerase activity in the diagnosis of pancreatic adenocarcinoma. RESULTS: A total of 19 studies qualified for this meta-analysis. In distinguishing pancreatic adenocarcinoma from benign diseases, the pooled sensitivity and specificity of telomerase activity were 0.81 (95% CI, 0.68-0.90) and 0.97 (95% CI, 0.93-0.98), respectively; the diagnostic odds ratio (DOR) was 126.62 (95% CI, 49.94-320.99); beta was -1.16 (95% CI, -3.62-1.29), Z was -0.93, p was 0.35>0.1, and lambda was 6.86 (95% CI, 1.01-12.70). In distinguishing pancreatic adenocarcinoma from chronic pancreatitis, the pooled sensitivity and specificity of telomerase activity were 0.77 (95% CI, 0.61-0.88) and 0.97 (95% CI, 0.91-0.99), respectively; DOR was 117.28 (95% CI, 32.25-426.53); beta was 0.38 (95% CI, -1.89-1.13), Z was -0.49, p was 0.62>0.1, and lambda was 5.30 (95% CI, 3.37-7.24). CONCLUSIONS: The present meta-analysis demonstrates that telomerase activity could be a useful biomarker for the differential diagnosis of pancreatic adenocarcinoma and benign pancreatic diseases. PMID- 26616233 TI - Polypharmacy, MRPs, PIMs and deprescribing. PMID- 26616234 TI - Haemocyanin content of shrimp (Fenneropenaeus chinensis) associated with white spot syndrome virus and Vibrio harveyi infection process. AB - Haemocyanin (Hc) is frequently reported to vary significantly by physiological status and environmental stress in Crustaceans. In this paper, the shrimp Fenneropenaeus chinensis was infected with different concentrations of white spot syndrome virus (WSSV) and Vibrio harveyi. Then, the variation of Hc and total protein content of the haemolymph (TPCH) were investigated using the established double antibody sandwich enzyme linked immunosorbent assay (DAS-ELISA) and Coomassie brilliant blue method, respectively. The results showed that the Hc content peaked at 12 h post-infection (PI) in the 10(-2), 10(-4) and 10(-6) viral supernatant (VS) groups, and the maximum was 93.03 +/- 2.55 mg ml(-1), 77.57 +/- 6.02 mg ml(-1) and 70.25 +/- 3.96 mg ml(-1), respectively. TPCH reached the maximum of 108.18 +/- 1.36 mg ml(-1) and 103.49 +/- 1.33 mg ml(-1) at 12 h PI in the 10(-2) and 10(-4) VS groups, respectively. The maximum was 96.94 +/- 1.06 mg ml(-1) at 24 h PI in the 10(-6) VS group. In the V. harveyi infection groups, the Hc content reached a maximum of 87.97 +/- 4.39 mg ml(-1) at 36 h PI in the 10(6) CFU ml(-1) group, 73.74 +/- 4.38 mg ml(-1) and 72.47 +/- 2.09 mg ml(-1) at 12 h PI in the 10(7) and 10(8) CFU ml(-1) groups, respectively. TPCH reached a maximum of 111.16 +/- 0.86 mg ml(-1) at 36 h PI in the 10(6) CFU ml(-1) group, 100.41 +/- 0.51 mg ml(-1) and 101.94 +/- 0.47 mg ml(-1) at 12 h PI in the 10(7) and 10(8) CFU ml(-1) groups, respectively. These data showed that both Hc content and TPCH varied as the same extent after infection. The up-regulation of the Hc content at 6-36 h PI might be a reference threshold for shrimp infection. PMID- 26616236 TI - Proton transfer in acetylacetone and its alpha-halo derivatives. AB - A two-dimensional potential energy surface was utilized to treat the proton transfer in acetylacetone (AA) and its alpha-halo derivatives: alpha-fluoro (FAA), alpha-chloro-(ClAA), and alpha-bromo-acetylacetone (BrAA). This potential energy function, which couples O-H stretching and in-plane bending vibrations, was acquired through ab initio calculations for a fixed skeleton geometry. The resulting potential energy surfaces were then used to calculate the proton tunneling frequencies and proton transfer barrier heights. The barrier heights (the energy difference between the saddle point and the minima) calculated at the MP2/6-31G(2d,p) level of theory for proton transfers in AA, FAA, ClAA, and BrAA are 7.2, 9.4, 6.3, and 5.9 kcal mol(-1), respectively. The theoretically predicted proton transfer barrier heights exhibit excellent linear correlations with geometrical, electronic structural, and topological parameters evaluated by the atoms-in-molecule (AIM) and natural bond orbital (NBO) analyses. PMID- 26616237 TI - Polaron spin filtering in an organic ferromagnetic polymer: a dynamics simulation. AB - We present a model study of the dynamic properties of a polaron in an organic ferromagnetic polymer by focusing on the spin correlation between the polymer backbone and the side radicals. The simulations are performed by using a tight binding description coupled with a nonadiabatic dynamics method. We find that, in the presence of an external electric field, the polarons with both up and down spins can get trapped near the side radicals of the polymer chain unless the electric field is stronger than a critical field. However, the magnitudes of the critical electric field vary quite differently for the spin-up and spin-down polarons as a function of the number of side radicals in the polymer, leading to the exponential change of the range of the electric field within which the spin filtering takes place. The range of the electric field increases nearly in a linear manner with the strength of the electron-lattice coupling as a result of the increase of the polaron binding energy. The impact of the strength of the spin correlation between the backbone and the side radicals on the polaron spin filtering is also discussed. These findings are expected to be useful for the design of organic-based spin filters. PMID- 26616235 TI - Molecular cloning and expression analysis of small ubiquitin-like modifier (SUMO) genes from grouper (Epinephelus coioides). AB - Small ubiquitin-like modifier (SUMO) is a group of proteins binding to lysine residues of target proteins and thereby modifying their stability, activity and subcellular localization. In the present study, two SUMO homolog genes (EcSUMO1 and EcSUMO2) from grouper (Epinephelus coioides) were cloned and characterized. The full-length sequence of EcSUMO1 was 749 bp in length and contained a predicted open reading frame of 306 bp encoding 101 amino acids with a molecular mass of 11.34 kDa. The full-length sequence of EcSUMO2 was 822 bp in length and contained a predicted open reading frame of 291 bp encoding 96 amino acids with a molecular mass of 10.88 kDa EcSUMO1 shares 44.55% identity with EcSUMO2. EcSUMO1 shares 99%, 90%, and 88% identity with those from Oreochromis niloticus, Danio rerio, and Homo sapiens, respectively. EcSUMO2 shares 98%, 93%, and 96% identity with those from Anoplopoma fimbria, D.rerio, and H. sapiens, respectively. Quantitative real-time PCR analysis indicated that EcSUMO1 and EcSUMO2 were constitutively expressed in all of the analyzed tissues in healthy grouper, but the expression of EcSUMO2 was higher than that of EcSUMO1. EcSUMO1 and EcSUMO2 were identified as a remarkably (P < 0.01) up-regulated responding to poly(I:C) and Singapore grouper iridovirus (SGIV) stimulation in head kidney of groupers. EcSUMO1 and EcSUMO2 were distributed in both cytoplasm and nucleus in GS cells. Over-expressed EcSUMO1 and EcSUMO2 enhanced SGIV and Red-spotted grouper nervous necrosis virus (RGNNV) replication during viral infection in vitro. Our study was an important attempt to understand the SUMO pathway in fish, which may provide insights into the regulatory mechanism of viral infection in E.coioides under farmed conditions. PMID- 26616238 TI - Disrupting protein tyrosine phosphatase sigma does not prevent sympathetic axonal dieback following myocardial infarction. AB - The neuronal receptor protein tyrosine phosphatase receptor sigma (PTPsigma) inhibits axonal extension upon binding to chondroitin sulfate proteoglycans (CSPGs) in scar tissue. We recently demonstrated that modulating or deleting PTPsigma promoted re-innervation of the CSPG-containing cardiac scar after ischemia-reperfusion (I-R). However, it remains unknown if the lack of PTPsigma or early treatment with the PTPsigma modulator, intracellular sigma peptide (ISP), prevents the initial injury-induced axonal dieback. To address this, we carried out I-R in PTPsigma -/- mice or control littermates treated with ISP or vehicle immediately at the time of I-R, and then assessed sympathetic innervation of the scar and surrounding myocardium 3days later. Vehicle-treated WT controls displayed sympathetic denervation within the scar and viable tissue adjacent to the scar, as well as distal myocardium farther from the scar. PTPsigma -/- and ISP-treated animals also displayed denervation of the scar and adjacent tissue, but regions distal to the scar were innervated normally. This suggests that PTPsigma does not mediate axonal dieback but its disruption enhances axonal regrowth in the heart. CSPG digestion alters the macrophage response to prevent axonal dieback in spinal neurons, so we investigated whether targeting PTPsigma might alter the macrophage response in the heart. The macrophage response after I R was similar in vehicle and ISP-treated groups. Mice lacking PTPsigma trended toward an increased M2 response, but were not significantly different than the other groups. These data suggest that PTPsigma is not involved in axonal dieback or the early macrophage response following cardiac I-R. PMID- 26616239 TI - Interneurons in the human olfactory system in Alzheimer's disease. AB - The principal olfactory structures display Alzheimer's disease (AD) related pathology at early stages of the disease. Consequently, olfactory deficits are among the earliest symptoms. Reliable olfactory tests for accurate clinical diagnosis are rarely made. In addition, neuropathological analysis postmortem of olfactory structures is often not made. Therefore, the relationship between the clinical features and the underlying pathology is poorly defined. Traditionally, research into Alzheimer's disease has focused on the degeneration of cortical temporal projection neurons and cholinergic neurons. Recent evidence has demonstrated the neurodegeneration of interneuron populations in AD. This review provides an updated overview of the pathological involvement of interneuron populations in the human olfactory system in Alzheimer's disease. PMID- 26616241 TI - Whole-Visible-Light Absorption of a Mixed-Valence Silver Vanadate Semiconductor Stemming from an Assistant Effect of d-d Transition. AB - Wide-light absorption is important to semiconductors exploited in many applications such as photocatalysts, photovoltaic devices, and light-emitting diodes, which can effectively improve solar energy utilization. Especially for photocatalysts, the development and design of new semiconductors that harvest the whole-visible-light region (lambda = 400-800 nm) is rarely reported, which is still a tremendous challenge up to now. Here we realize whole-visible-light absorption up to 900 nm for a semiconductor by means of construction of a mixed valence Ag0.68V2O5, which results from an assistant effect of d-d transition. Ag0.68V2O5 serving as a photocatalyst obviously exhibits photoelectrochemical and photocatalytic properties. Our results provide a brand-new feasible design strategy to broaden the light absorption of semiconductors and highlight a route to further make the best use of the full solar spectrum. PMID- 26616240 TI - Can carbon emissions from tropical deforestation drop by 50% in 5 years? AB - Halving carbon emissions from tropical deforestation by 2020 could help bring the international community closer to the agreed goal of <2 degree increase in global average temperature change and is consistent with a target set last year by the governments, corporations, indigenous peoples' organizations and non-governmental organizations that signed the New York Declaration on Forests (NYDF). We assemble and refine a robust dataset to establish a 2001-2013 benchmark for average annual carbon emissions from gross tropical deforestation at 2.270 Gt CO2 yr(-1). Brazil did not sign the NYDF, yet from 2001 to 2013, Brazil ranks first for both carbon emissions from gross tropical deforestation and reductions in those emissions - its share of the total declined from a peak of 69% in 2003 to a low of 20% in 2012. Indonesia, an NYDF signatory, is the second highest emitter, peaking in 2012 at 0.362 Gt CO2 yr(-1) before declining to 0.205 Gt CO2 yr(-1) in 2013. The other 14 NYDF tropical country signatories were responsible for a combined average of 0.317 Gt CO2 yr(-1) , while the other 86 tropical country non signatories were responsible for a combined average of 0.688 Gt CO2 yr(-1). We outline two scenarios for achieving the 50% emission reduction target by 2020, both emphasizing the critical role of Brazil and the need to reverse the trends of increasing carbon emissions from gross tropical deforestation in many other tropical countries that, from 2001 to 2013, have largely offset Brazil's reductions. Achieving the target will therefore be challenging, even though it is in the self-interest of the international community. Conserving rather than cutting down tropical forests requires shifting economic development away from a dependence on natural resource depletion toward recognition of the dependence of human societies on the natural capital that tropical forests represent and the goods and services they provide. PMID- 26616242 TI - SFINX: Straightforward Filtering Index for Affinity Purification-Mass Spectrometry Data Analysis. AB - Affinity purification-mass spectrometry is one of the most common techniques for the analysis of protein-protein interactions, but inferring bona fide interactions from the resulting data sets remains notoriously difficult. We introduce SFINX, a Straightforward Filtering INdeX that identifies true-positive protein interactions in a fast, user-friendly, and highly accurate way. SFINX outperforms alternative techniques on two benchmark data sets and is available via the Web interface at http://sfinx.ugent.be/. PMID- 26616243 TI - Neutralizing salivary pH by mouthwashes after an acidic challenge. AB - AIM: The aim of the present study was to test the neutralizing effect of mouthwashes on salivary pH after an acidic challenge. METHODS: Twelve participants were recruited for three visits, one morning per week. Resting saliva was collected at baseline and after 2-min swishing with 20 mL orange juice as an acidic challenge. Participants then rinsed their mouth for 30 s with 20 mL water (control), an over-the-counter mouthwash (Listerine), or a two-step mouthwash, randomly assigned for each visit. Saliva was collected immediately, 15, and 45 min after rinsing. The pH values of the collected saliva were measured and analyzed with anova, followed by Student-Newman-Keuls post-hoc test (significance level: 0.05). RESULTS: Orange juice significantly lowered salivary pH. Immediately after rinsing, Listerine and water brought pH back to baseline values, with the pH significantly higher in the Listerine group. The two-step mouthwash raised pH significantly higher than Listerine and water, and higher than the baseline value. Salivary pH returned to baseline and was not significantly different among groups at 15 and 45 min post-rinsing. CONCLUSIONS: Mouth rinsing after an acidic challenge increased salivary pH. The tested mouthwashes raised pH higher than water. Mouthwashes with a neutralizing effect can potentially reduce tooth erosion from acid exposure. PMID- 26616245 TI - Prognostic factors for trabeculectomy failure in a Cuban population. AB - OBJECTIVE: To identify the prognostic factors for mid-term trabeculectomy failure. METHOD: A prospective cohort study was conducted on 113 eyes (113 patients) that had undergone a trabeculectomy for primary open or closed angle, pigmentary, or juvenile glaucoma. Surgical failure was defined if intraocular pressure was equal or more than 18mmHg with medication (two or more drops), after 1-4 postoperative years. The relative risk was calculated and a logistic regression analysis was performed. RESULTS: Previous trabeculectomy, preoperative intraocular pressure >= 31mmHg, black race, and advanced glaucoma increased the failure risk by 7.9 times (P=.036), 5.3 times (P=.011) and 4.7 times (P=.028, and P=.027), respectively. The addition of two or more factors increased the risk by 6.4 times (P<.001). It was not affected by age, sex, pre-operative drops, or surgical complication. CONCLUSIONS: Previous trabeculectomy, pre-operative intraocular pressure >= 31mmHg, black race, and advanced glaucoma are prognostic factors for trabeculectomy failure, in decreasing order of their association with surgical failure. The addition of two or more factors increased the risk of failure. In those situations, the use of trans- operative anti-metabolites is suggested. PMID- 26616244 TI - The Immp2l mutation causes age-dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment. AB - Reactive oxygen species are implicated in age-associated neurodegeneration, although direct in vivo evidence is lacking. We recently showed that mice with a mutation in the Inner Mitochondrial Membrane Peptidase 2-like (Immp2l) gene had elevated levels of mitochondrial superoxide, impaired fertility and age associated phenotypes, including kyphosis and ataxia. Here we show that ataxia and cerebellar hypoplasia occur in old mutant mice (> 16 months). Cerebellar granule neurons (CGNs) are significantly underrepresented; Purkinje cells and cells in the molecular layer are not affected. Treating mutant mice with the mitochondria-targeted antioxidant SkQ1 from 6 weeks to 21 months protected cerebellar granule neurons. Apoptotic granule neurons were observed in mutant mice but not in age-matched normal control mice or SkQ1-treated mice. Old mutant mice showed increased serum protein carbonyl content, cerebellar 4-hydroxynonenal (HNE), and nitrotyrosine modification compared to old normal control mice. SOD2 expression was increased in Purkinje cells but decreased in granule neurons of old mutant mice. Mitochondrial marker protein VDAC1 also was decreased in CGNs of old mutant mice, suggesting decreased mitochondrial number. SkQ1 treatment decreased HNE and nitrotyrosine modification, and restored SOD2 and VDAC1 expression in CGNs of old mutant mice. Neuronal expression of nitric oxide synthase was increased in cerebella of young mutant mice but decreased in old mutant mice. Our work provides evidence for a causal role of oxidative stress in neurodegeneration of Immp2l mutant mice. The Immp2l mutant mouse model could be valuable in elucidating the role of oxidative stress in age-associated neurodegeneration. PMID- 26616246 TI - Improving the activity of Trichoderma reesei cel7B through stabilizing the transition state. AB - Trichoderma reesei (Tr.) cellulases, which convert cellulose to reducing sugars, are a promising catalyst used in the lignocellulosic biofuel production. Improving Tr. cellulases activity, though very difficult, is highly desired due to the recalcitrance of lignocellulose. Meanwhile, it is preferable to enhance the cellulase's promiscuity so that substrates other than cellulose can also be hydrolyzed. In this work, an attempt is made to improve the catalytic activity of a major endogluanase Tr. Cel7B against xylan which crosslinks with cellulose in lignocellulose. By using quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations, the transition state of the xylo-oligosaccharide hydrolysis is identified. Then, mutations are introduced and their effect on the transition state stabilization is ranked based on the free energy calculations. Seven top ranked mutants are evaluated experimentally. Three mutants A208Q, A222D, and G230R show a higher activity than the wild-type Tr. Cel7B in the hydrolysis of xylan (by up to 47%) as well as filter paper (by up to 50%). The combination of the single mutants can further improve the enzyme activity. Our work demonstrates that the free energy method is effective in engineering the Tr. Cel7B activity against xylan and cellulose, and thus may also be useful for improving the activity of other Tr. cellulases. Biotechnol. Bioeng. 2016;113: 1171-1177. (c) 2015 Wiley Periodicals, Inc. PMID- 26616247 TI - Treatment algorithms for patients with (sub)acute type B aortic dissections. AB - Aortic dissection is the most common acute aortic syndrome and constitutes a potentially catastrophic cardiovascular condition. Traditionally, complicated acute type B dissection has been considered an indication for surgical treatment, whereas patients with uncomplicated dissection have been treated medically. In recent years, there has been a clear paradigm shift towards endovascular treatment of complicated type B dissection. This is founded in numerous reviews and meta-analyses demonstrating a lower perioperative mortality and morbidity for TEVAR in comparison to open surgical repair. In uncomplicated patients, treatment options are still a matter of debate. Best medical therapy shows acceptable early results with respect to in-hospital mortality and morbidity but fails to address the issue of late aortic expansion and aortic-related adverse events in a significant number of patients. There is increasing evidence that early TEVAR promotes false lumen thrombosis, induces remodeling of the aortic wall and should be considered preventively in selected patients with suitable anatomy. This report gives an overview of current literature on treatment options and optimal time of intervention, and finally proposes a treatment algorithm for acute type B aortic dissection. PMID- 26616248 TI - Mental Health in Pregnant Adolescents: Focus on Psychopharmacology. PMID- 26616249 TI - The Financial and Emotional Impact of Atopic Dermatitis on Children and Their Families. AB - OBJECTIVE: To examine the personal financial impact of atopic dermatitis (AD) and attempt to correlate cost of AD with emotional impact. STUDY DESIGN: Between March 2011 and December 2013, 82 caretakers of children 6 months to 12 years of age with moderate-to-severe AD were recruited at the time of dermatology clinic visits in Cleveland, Ohio, to complete surveys. The response rate was >95%. Participants were asked questions about direct expenses (medical visits, medications, and other products) and indirect expenses (time missed from work, childcare costs) related to AD in the past 4 weeks. Emotional impact was measured by the Childhood Atopic Dermatitis Impact Scale. RESULTS: The mean monthly personal cost of AD in the month before the office visit was $274 (median $114; IQR $29, $276), with $75 from direct costs (median $45; IQR $20, $110) and $199 from indirect costs (median $0; IQR $0, $208). An average of 34.8% of available monthly money was spent on AD care in the month before the office visit. For patients with Medicaid, there was a significant correlation between monthly adjusted personal cost and Childhood Atopic Dermatitis Impact Scale score (r = 0.548; P < .001); however, this correlation did not exist for patients who had commercial insurance (r = 0.269; P = .166). CONCLUSIONS: Our results illustrate the high emotional and financial burden of childhood AD and provide insight into spending patterns. In addition, our study correlate costs with emotional burden of AD for lower-income patients. PMID- 26616250 TI - Developing a Predictive Score for Chronic Arthritis among a Cohort of Children with Musculoskeletal Complaints--The Chronic Arthritis Score Study. AB - OBJECTIVE: To explore if features obtained from a carefully taken medical history can be predictors of the final diagnosis in children with musculoskeletal complaints. STUDY DESIGN: We collected detailed clinical information on 178 children referred to our Pediatric Immunology and Rheumatology Unit by their primary care pediatrician for musculoskeletal complaints; a univariate logistic analysis was performed to identify variables correlated with the diagnosis of chronic arthritis. The variables identified were combined in a linear score that indicates the probability for a patient with musculoskeletal pain to receive the diagnosis of chronic arthritis. RESULTS: The joint swelling pattern (P < .0001), the precipitating factors of pain (P = .001), the duration of morning stiffness (P < .0001) and the frequency of pain (P < .0001), were found to be independently correlated with the diagnosis of chronic arthritis and were used to develop a diagnostic score. This score had a sensitivity of 90.9% and specificity of 95.3%. CONCLUSIONS: We developed a score that could be useful in the daily clinical routine to correctly direct the differential diagnosis in a child with musculoskeletal complaints, rationalizing time and resources necessary to reach a definitive diagnosis. PMID- 26616251 TI - Pediatric Achalasia in the Netherlands: Incidence, Clinical Course, and Quality of Life. AB - OBJECTIVE: To assess incidence and clinical course of Dutch patients with achalasia diagnosed before 18 years of age as well as their current symptoms and quality of life (QoL). STUDY DESIGN: Retrospective medical chart review and a cross-sectional study assessing current clinical status using the Eckardt score and reflux disease questionnaire. General QoL was measured using Kidscreen-52 for patients <18 years of age or to 36-Item Short Form Health Survey for patients >=18 years of age. RESULTS: Between 1990 and 2013, 87 children (mean age 11.4 +/- 3.4 years, 60% male) diagnosed with achalasia in the Netherlands were included. Mean incidence was 0.1/100,000/y (range 0.03-0.21). Initial treatment was pneumodilation (PD) in 68 (79%) patients and Heller myotomy (HM) in 18 (21%) patients. Retreatment was required more often after initial PD compared with initial HM (88% vs 22%; P < .0001). More complications of initial treatment occurred after HM compared with PD (55.6% vs 1.5%; P < .0001). Three esophageal perforations were seen after HM (16.7%), 1 after PD (1.5%). Sixty-three of 87 (72%) patients were prospectively contacted. Median Eckardt score was 3 (IQR 2 5), with 32 patients (44.5%) having positive scores suggesting active disease. Reflux disease questionnaire scores were higher after initial HM vs PD (1.71 [0.96-2.90] vs 0.58 [0-1.56]; P = .005). The 36-Item Short Form Health Survey (n = 52) was lower compared with healthy population norms for 7/8 domains. Kidscreen 52 (n = 20) was similar to population norms. CONCLUSIONS: Pediatric achalasia is rare and relapse rates are high after initial treatment, especially after pneumodilation, but with more complications after HM. Symptoms often persist into adulthood, without any clinical follow-up. QoL in adulthood was decreased. PMID- 26616252 TI - Fever, Hepatosplenomegaly, and a Typical Skin Lesion. PMID- 26616253 TI - A strategy to reposition the South Australian health system for quality and value. AB - Clinical commissioning was introduced in South Australia in 2012 to support implementation of the South Australian Health Care Plan and to achieve the desired transformation and efficiency gains required for a sustainable health system. This paper describes how the South Australian Commissioning Model was established and the process of developing the necessary culture, governance arrangements and performance management structures. Commissioning has played a key role in improving appropriateness and quality of clinical practice, resulting in reduced hospital inpatient growth and average length of stay. Despite early successes, there remain many challenges that need to be faced before value can be demonstrated consistently across the whole system. PMID- 26616254 TI - Maximising research value in the field of hearing implantation: A call for 'big data'. PMID- 26616255 TI - Future of family support: Projected living arrangements and income sources of older people in Hong Kong up to 2030. AB - AIM: The study aims to project future trends in living arrangements and access to children's cash contributions and market income sources among older people in Hong Kong. METHOD: A cell-based model was constructed by combining available population projections, labour force projections, an extrapolation of the historical trend in living arrangements based on national survey datasets and a regression model on income sources. RESULTS: Under certain assumptions, the proportion of older people living with their children may decline from 59 to 48% during 2006-2030. Although access to market income sources may improve slightly, up to 20% of older people may have no access to either children's financial support or market income sources, and will not live with their children by 2030. CONCLUSION: Family support is expected to contract in the next two decades. Public pensions should be expanded to protect financially vulnerable older people. PMID- 26616256 TI - The significance of structured parental educational intervention on childhood atopic dermatitis: a randomized controlled trial. AB - BACKGROUND: Parental education is important in managing childhood chronic diseases. OBJECTIVES: The aim of the study was to evaluate the effects of a short term structured educational programme for parents of children with moderate to severe atopic dermatitis ( AD), aged 3 months to 7 years, on the clinical course of AD, parental stress, anxiety and the quality of family life. METHODS: One hundred thirty-four parents with AD children were recruited in a randomized controlled clinical trial at the Outpatient Unit of Pediatric Dermatology, Children's Hospital in Zagreb. The primary outcome was change in the severity of eczema measured using SCORing AD (SCORAD) and Patient Oriented (PO) SCORAD index, changes of symptom scores for pruritus and sleep disturbance. Secondary outcomes included change in stress level according to the Perceived Stress Scale (PSS); change in anxiety level according to State Trait Anxiety Inventory (STAI) and change in the quality of family life according to the Croatian version of the Family Dermatology Life Quality Index (FDLQI). RESULTS: Participants in the intervention group had a significantly lower SCORAD (P = 0.000), PO SCORAD (P = 0.000) index, pruritus (P = 0.000), sleep disturbance (P = 0.001), level of perceived stress (P = 0.024) and anxiety as a state (P = 0.42) than those in the control group at the second visit. After the educational programme, participants in the intervention group had a significantly lower impact of AD on the total quality of family life (P = 0.006). We found a statistically significant difference between the two groups with respect to additional education received between the visits. The control group had acquired significantly more additional education (P = 0.007). There was no significant difference between groups in the amount of corticosteroid used. CONCLUSION: Our structured educational programme had a positive effect on AD severity, quality of family life, parental stress and anxiety. PMID- 26616257 TI - Significance of prostate cancer missed on needle biopsy tools for retrieving missed cancer. AB - BACKGROUND: Prostate needle biopsy (PNB) is required for the diagnosis of prostate cancer (PCa), but little is known about the frequency and clinical implication of false-negative results. OBJECTIVE: To investigate the incidence and clinical impact of minute PCa missed on routine haematoxylin and eosin (H&E) slides, but retrieved by alpha-methylacyl-CoA-racemase (AMACR) immunohistochemistry. METHODS: AMACR immunohistochemistry was used to detect PCa missed on H&E slides in a series of consecutive 1,672 PNB including 1,003 patients without evidence of PCa, and 669 patients with PCa meeting pathological criteria for active surveillance (PCAS) under current clinical investigation, including Gleason score <=7 (3 + 4), <33% of biopsies involved by cancer, <50% of any core involved by cancer. Using improved multicore (pre-) embedding techniques a single AMACR immunostain/patient was sufficient to detect missed lesions. RESULTS: In patients without histological evidence of PCa, AMACR immunohistochemistry retrieved minute PCa in 33 of 1,003 patients (3.29%) and atypical small acinar proliferations (ASAP) in 17 of 1,003 patients (1.69%). Among 116 of 669 (17.34%) PCa patients meeting PCAS, detection of additional core(s) involved by cancer was found responsible for disease reclassification in 63 of 116 of patients (54.31%). Limitations include the single-institutional design of the study. CONCLUSIONS: PCa missed on routine H&E histology was retrieved by AMACR in 8.91% of PNB, including 17.34% of PCa patients meeting PCAS. 54.31% of them have finally lost their eligibility for active surveillance after detecting additional cores involved by cancer. Underdiagnosis of limited adenocarcinoma on PNB is a matter of concern, but can be prevented by a single AMACR immunostain/patient if improved multicore (pre-) embedding techniques are used. PMID- 26616259 TI - The Lysosomal Protein Saposin B Binds Chloroquine. AB - Chloroquine (CQ) has been widely used in the treatment of malaria since the 1950s, though toxicity and resistance is increasingly limiting its use in the clinic. More recently, CQ is also becoming recognized as an important therapeutic compound for the treatment of autoimmune disorders and has shown activity as an anticancer agent. However, the full extent of CQ pharmacology in humans is still unclear. Herein, we demonstrate that the lysosomal protein saposin B (sapB), critical for select lipid degradation, binds CQ with implications for both CQ function and toxicity. Using isothermal titration calorimetry (ITC) and fluorescence quenching experiments, CQ was shown to bind to the dimeric form of sapB at both pH 5.5 and pH 7.4 with an average binding affinity of 2.3*10(4) m( 1). X-ray crystallography confirmed this, and the first complete crystal structure of sapB with a bound small molecule (CQ) is reported. The results suggest that sapB might play a role in mitigating CQ-based toxicity and that sapB might itself be overwhelmed by CQ causing impaired lipid degradation. PMID- 26616260 TI - Insulin Sensitivity Determines Effects of Insulin and Meal Ingestion on Systemic Vascular Resistance in Healthy Subjects. AB - OBJECTIVE: In addition to insulin's metabolic actions, insulin can dilate arterioles which increase blood flow to metabolically active tissues. This effect is blunted in insulin-resistant subjects. Insulin's effect on SVR, determined by resistance arterioles, has, however, rarely been examined directly. We determined the effects of both hyperinsulinemia and a mixed meal on SVR and its relationship with insulin sensitivity. METHODS: Thirty-seven lean and obese women underwent a hyperinsulinemic-euglycemic clamp, and 24 obese volunteers underwent a mixed-meal test. SVR was assessed using CPP before and during hyperinsulinemia as well as before and 60 and 120 minutes after a meal. RESULTS: SVR decreased significantly during hyperinsulinemia (-13%; p < 0.001) and after the meal (-11%; p < 0.001). Insulin decreased SVR more strongly in insulin-sensitive individuals (standardized beta: -0.44; p = 0.01). In addition, SVR at 60 minutes after meal ingestion was inversely related to the Matsuda index (beta: -0.39; p = 0.04) and the change in postprandial SVR was directly related to postprandial glycemia (beta: 0.53; p < 0.01). CONCLUSIONS: Hyperinsulinemia and meal ingestion decrease SVR, which is directly associated with metabolic insulin resistance. This suggests that resistance to insulin-induced vasodilatation contributes to regulation of vascular resistance. PMID- 26616261 TI - Is it necessary to diagnose levator avulsion on pelvic floor muscle contraction? AB - OBJECTIVE: Avulsion of the levator ani muscle commonly occurs at vaginal birth. This condition is usually diagnosed by translabial ultrasound (TLUS) during pelvic floor muscle contraction (PFMC). Some patients are unable to achieve a satisfactory PFMC and in these cases avulsion is assessed at rest. The aim of this study was to validate the diagnosis of levator avulsion by means of TLUS at rest. METHODS: This was a retrospective study of 233 women seen at a tertiary urogynecological center. All women underwent four-dimensional TLUS in the supine position and after voiding. Volumes were obtained on maximal PFMC and at rest. Analysis of the volumes was performed with the observer blinded against all clinical data. Avulsion was defined as an abnormal levator ani muscle insertion that was visible in at least three consecutive axial plane slices, at and above the level of minimal hiatal dimensions, at 2.5-mm intervals. We examined the correlation between both assessment methods using Cohen's kappa coefficient and tested the association of each method with female pelvic organ prolapse on clinical examination, organ descent on ultrasound and hiatal ballooning. RESULTS: In total, datasets from 202 women were available for analysis. The correlation between a diagnosis of avulsion in volumes obtained at rest and those on PFMC was moderate, with a kappa value of 0.583 (95% CI, 0.484-0.683). Agreement for defects visualized on single slices was moderate, with a kappa value of 0.556 (95% CI, 0.520-0.591). When avulsion diagnoses at rest and on PFMC were tested against symptoms of prolapse, and prolapse on clinical examination and on ultrasound, neither of the two methods was superior. CONCLUSION: Although tomographic ultrasound imaging during PFMC enhances tissue discrimination, this may not translate to superior diagnostic performance. Hence, volumes obtained at rest may be used in women unable to contract their pelvic floor. The diagnosis of levator avulsion by tomographic pelvic floor ultrasound is equally valid when performed at rest or on PFMC. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26616262 TI - Diabetes, metformin and incidence of and death from invasive cancer in postmenopausal women: Results from the women's health initiative. AB - Findings from studies of metformin use with risk of cancer incidence and outcome provide mixed results; with few studies examined associations by recency of diabetes diagnosis or duration of medication use. Thus, in the Women's Health Initiative, we examined these associations and further explored whether associations differ by recency of diabetes and duration of metformin use. Cox regression models were used to estimate hazard ratios (HR) and their 95% confidence intervals. Diabetes was associated with higher risk of total invasive cancer (HR, 1.13; p < 0.001) and of several site-specific cancers (HR, 1.2-1.4, and up to over twofold). Diabetes was also associated with higher risk of death from cancer (HR, 1.46; p < 0.001). There was no overall difference in cancer incidence by diabetes therapy (p = 0.66). However, there was a lower risk of death from cancer for metformin users, compared to users of other medications, relative to women without diabetes, overall (HRs, 1.08 vs. 1.45; p = 0.007) and for breast cancer (HRs, 0.50 vs. 1.29; p = 0.05). Results also suggested that lower cancer risk associated with metformin may be evident only for a longer duration of use in certain cancer sites or subgroup populations. We provide further evidence that postmenopausal women with diabetes are at higher risk of invasive cancer and cancer death. Metformin users, particularly long-term users, may be at lower risk of developing certain cancers and dying from cancer, compared to users of other anti-diabetes medications. Future studies are needed to determine the long-term effect of metformin in cancer risk and survival from cancer. PMID- 26616263 TI - A novel approach for preparation of the antisera reagent for potency determination of inactivated H7N9 influenza vaccines. AB - BACKGROUND: The potency of inactivated influenza vaccines is determined using a single-radial immunodiffusion (SRID) assay and requires standardized reagents consisting of a Reference Antigen and an influenza strain-specific antiserum. Timely availability of reagents is a critical step in influenza vaccine production, and the need for backup approaches for reagent preparation is an important component of pandemic preparedness. OBJECTIVES: When novel H7N9 viruses emerged in China in 2013, candidate inactivated H7N9 influenza vaccines were developed for evaluation in clinical trials, and reagents were needed to measure vaccine potency. METHODS: We previously described an alternative approach for generating strain-specific potency antisera, utilizing modified vaccinia virus Ankara vectors to produce influenza hemagglutinin (HA)-containing virus-like particles (VLPs) for immunization. Vector-produced HA antigen is not dependent upon the success of the traditional bromelain-digestion and HA purification. RESULTS: Antiserum for H7N9 vaccines, produced after immunization of sheep with preparations of bromelain-HA (br-HA), was not optimal for the SRID assay, and the supply of antiserum was limited. However, antiserum obtained from sheep boosted with VLPs containing H7 HA greatly improved the ring quality in the SRID assay. Importantly, this antiserum worked well with both egg- and cell-derived antigen and was distributed to vaccine manufacturers. CONCLUSIONS: Utilizing a previously developed approach for preparing vaccine potency antiserum, we have addressed a major bottleneck encountered in preparation of H7N9 vaccine reagents. The combination of br-HA and mammalian VLPs for sequential immunization represents the first use of an alternative approach for producing an influenza vaccine potency antiserum. PMID- 26616265 TI - Asymmetric Total Synthesis of (+)-Ryanodol and (+)-Ryanodine. AB - (+)-Ryanodine (1) is the ester derivative of 1H-pyrrole-2-carboxylic acid and the complex terpenoid (+)-ryanodol (2), which possesses eleven contiguous stereogenic centers on the ABCDE-ring system. Compound 1 is known to be a potent modulator of intracellular calcium release channels, whereas the activity of 2 is significantly weaker. To chemically construct 1, the multiple oxygen functional groups must be installed on the fused pentacycle in stereoselective fashions and the extremely hindered C3-hydroxy group must be acylated in a site-selective manner. First, the total synthesis of 2 was accomplished by introducing the five stereocenters from the previously prepared enantiopure ABDE-ring 7. Stereoselective construction of the C3-secondary, C2- and C6-tertiary alcohols was achieved by three nucleophilic reactions. The C9- and C10-trisubstituted carbon centers were regio- and stereoselectively introduced by hydroboration/oxidation of the six-membered C-ring, which was formed by the ring closing metathesis reaction. Direct esterification of the C3-alcohol with pyrrole 2-carboxylic acid proved unsuccessful; therefore, we developed a new, two-step protocol for attachment of the pyrrole moiety. The C3-hydroxy group was first converted into the less sterically cumbersome glycine ester, which was then transformed into the pyrrole ring through condensation with 1,3 bis(dimethylamino)allylium tetrafluoroborate. This procedure resulted in the first total synthesis of 1. PMID- 26616266 TI - Susceptibility of N-acetyltransferase 2 slow acetylators to antituberculosis drug induced liver injury: a meta-analysis. AB - AIM: This study aimed to evaluate the association between N-acetyltransferase 2 (NAT2) gene polymorphisms and the risk of antituberculosis drug-induced liver injury (ATLI). MATERIALS & METHODS: A meta-analysis was performed including 27 studies with 1289 cases and 5462 controls. Odds ratio with 95% CI was used to evaluate the strength of association. RESULTS: Our meta-analysis found that NAT2 slow acetylators were associated with increased risk of ATLI compared with fast and intermediate acetylators when standard dose of isoniazid was administrated (odds ratio: 3.08; 95% CI: 2.29-4.15). CONCLUSION: Individuals with NAT2 slow acetylators may have increased risk of ATLI when standard dose of isoniazid was used. Detection of NAT2 genotype may benefit to the prevention of ATLI. PMID- 26616267 TI - Water Analysis: Emerging Contaminants and Current Issues. PMID- 26616271 TI - Glucose Uptake Is Decreased in Affected Lower Leg Muscles of Hemiparetic Persons during Level Walking. AB - Stroke patients suffer from gait disturbance due to altered leg muscle actions. Many kinesiological studies have investigated muscle actions, but the metabolic activity of muscles in stroke patients remains to be investigated. We therefore evaluated energy consumption in lower extremity muscles during level walking in hemiparetic individuals. Glucose uptake was measured by positron emission tomography (PET) using (18)F-fluorodeoxyglucose ((18)F-FDG) in eight hemiparetic (mean age: 56 years) and 11 healthy (mean age: 26 years) participants. Standardized uptake ratio (SUR) was computed in each muscle to express the (18)F FDG-uptake level. SUR was compared across gluteal, thigh, and lower leg muscles and across individual muscles within each muscle group. For each muscle, SUR was compared among the paretic limb of hemiparetic participants, the non-paretic limb of hemiparetic participants, and the right limb of healthy participants. In paretic limbs, mean SUR did not differ between the three muscle groups, or between individual muscles within each muscle group. SURs of paretic lower leg muscles and gluteus minimus muscle were significantly smaller than those of non paretic limb and healthy participants (p < 0.05). In the non-paretic limb of hemiparetic participants, SUR of the lower leg muscles was larger than that of the thigh muscles (p < 0.05). Unexpectedly, SURs of medial hamstring and posterior tibial muscles were larger in the non-paretic limb of hemiparetic participants, compared to the right limb of healthy participants (p < 0.05). (18)F-FDG PET is useful to evaluate energy consumption levels of lower extremity muscles during level walking in hemiparetic individuals. PMID- 26616272 TI - Induction of Memory Deficit in Mice with Chronic Exposure to Cerebrospinal Fluid from Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis. AB - Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is now widely recognized and the patients with this disease show prominent psychiatric symptoms followed by seizures, respiratory failure, involuntary movement, autonomic instability, and amnesia. The anti-NMDAR antibody titer coincides with disease activity, and antibody-deprivation treatment ameliorates neurological symptoms. Previous studies have shown that clusters of NMDARs on the neuronal surface decrease in density upon incubation with the cerebrospinal fluid from patients (NMDAR-CSF), and that the induction of long-term potentiation, a cellular mechanism underlie learning and memory processes, was suppressed with NMDAR-CSF. In this study, we exposed mice to NMDAR-CSF in an attempt to reproduce the human symptoms in mice. CSF was continuously administered via a cannula placed in the lateral ventricle of the mouse that connected to an osmotic pump transplanted in the back of the mouse. From day 8-18, we evaluated the behavior of the mice using standardized tests that were performed serially. Mice exposed to NMDAR-CSF showed impaired spatial memory, as detected with the Morris water maze test. Brain tissue from mice with memory disturbances had decreased content of NMDAR protein in the hippocampal area shown by immunohistochemistry, which is consistent with the anti NMDAR antibodies affect the expression and function of NMDARs, resulting in anti NMDAR encephalitis-like symptoms. Also, the mice treated with the NMDAR-CSF did not show inflammatory cell infiltration or neuron loss in their brain tissue and this lack of nervous tissue destruction is encouraging as it is consistent with the idea that this disease can be treated through immunotherapy. PMID- 26616273 TI - Preparation and in vitro evaluation of 5-fluorouracil-loaded PCL nanoparticles for colon cancer treatment. AB - Nanoparticles loaded with 5-fluorouracil (5-FU) for colon cancer therapies were prepared using the solvent evaporation technique, which involved lyophilization by freeze-drying. Formulations produced a substantially high encapsulation efficiency of approximately 93%. A positive correlation was seen when increasing polycaprolactone (PCL) and/or PVA concentrations and the size of nanoparticles produced. Increasing PCL concentration had a considerable influence on PDI while increasing PVA concentration had a lesser effect. All nanoparticles possessed a negative zeta potential, particularly in formulations with low polymer and polymer emulsifier concentrations. The formulation with the lowest PCL and PVA concentration was characterized by the most optimal properties; which accounts for the desirable delayed release profile of the active drug in dissolution testing indicating an improved targeting capability and enhanced bioavailability at the action site. Cytotoxicity studies showed that 5-FU loaded PCL nanoparticles had higher antiproliferative effect than free 5-FU on Caco-2 cell line (p < 0.05). The encouraging results obtained offer reasons for optimism regarding the future of 5-FU nanoparticles as a promising drug delivery system which could be further improved by including either enteric coating or encapsulating the nanoparticles onto microparticles to overcome unanticipated degradation. PMID- 26616275 TI - Tuning the surface oxygen concentration of {111} surrounded ceria nanocrystals for enhanced photocatalytic activities. AB - For oxide semiconductors, the morphology, particle size and oxygen vacancies are usually considered as key influential parameters for photocatalytic degradation of organic pollutants/dyes. It is widely accepted that cation doping not only modifies their phase and microstructures but also introduces variations in oxygen vacancy concentration. Herein, we report the fabrication of sub-10 nm sized pure and indium doped CeO2 nanocrystals (NCs) via a facile, green hydrothermal method for the investigation of photocatalytic activities. X-ray diffraction and transmission electron microscopy were employed to examine the crystal phase and morphology of the as-prepared nanocrystals. Raman and X-ray photoelectron spectroscopy techniques were implemented to investigate the presence and variations in oxygen vacancy concentration in un-doped and indium doped CeO2 nanocrystals. The photocatalytic activity results revealed that 10 at% doping is the optimal indium doping level to demonstrate superior dye removal efficiency (~40%) over un-doped and doped CeO2 NCs. Moreover, the 10% In-doped CeO2 nanocrystals expressed excellent cycling stability and superior photocatalytic performance toward other dye pollutants. Finally, on the basis of our findings, a possible photocatalytic mechanism in which indium doping can generate more surface oxygen vacancies in the ceria lattice which delay the electron-hole recombination rates, thus increasing the lifetime of electron-hole separation for enhanced photocatalytic performances was proposed. PMID- 26616274 TI - Temporal changes in the current practice of primary angioplasty: a real life experience of a single high-volume center. AB - BACKGROUND: In the last years, new techniques, drugs and devices have been introduced in the current practice of primary angioplasty (PPCI) and validated by pivotal studies The objective of our study was to evaluate if these studies have led to significant changes on the current practice of primary PCI in our center. METHODS: From March 2003 to December 2013 1980 patients with ST-segment elevation myocardial infarction underwent PPCI within 12-hours of onset of symptoms. We considered 2 periods of our activity: from 2003 to 2009 (P1) with 1078 patients and from 2010 to 2013 (P2) with 902 patients, and compared them in terms of pharmacological and arterial access strategies and of devices utilization. RESULTS: In P2 there was a significant increase of radial access (34.1% vs. 1.5, p<0.001), as well as of the use of bivalirudin (22.7% vs. 0.5%, p<0.001) and of new antiplatelet drugs (prasugrel or ticagrelor) (18.3% vs. 0%, p<0.001) whereas the use of GP IIb-IIIa and of intraaortic balloon pump significantly decreased (from 82.3% to 52%, p<0.001 and from 17% to 7.5%, p<0.001 respectively). In the P2 there was a significant increase of the procedural efficacy (97.2% vs. 95.1%, p=0.01) that persisted after the logistic regression adjustment (OR 2.09, CI 95%, 1.04-4.21). CONCLUSIONS: Our study shows that in the last years, in a high-PCI center, after the publication of pivotal randomized trial and nationwide registries, there were significant changes in the PPCI current practice that could have had an impact on procedural efficacy. PMID- 26616276 TI - Importance of teamwork, communication and culture on failure-to-rescue in the elderly. AB - BACKGROUND: Surgical mortality increases significantly with age. Wide variations in mortality rates across hospitals suggest potential levers for improvement. Failure-to-rescue has been posited as a potential mechanism underlying these differences. METHODS: A review was undertaken of the literature evaluating surgery, mortality, failure-to-rescue and the elderly. This was followed by a review of ongoing studies and unpublished work aiming to understand better the mechanisms underlying variations in surgical mortality in elderly patients. RESULTS: Multiple hospital macro-system factors, such as nurse staffing, available hospital technology and teaching status, are associated with differences in failure-to-rescue rates. There is emerging literature regarding important micro-system factors associated with failure-to-rescue. These are grouped into three broad categories: hospital resources, attitudes and behaviours. Ongoing work to produce interventions to reduce variations in failure to-rescue rates include a focus on teamwork, communication and safety culture. Researchers are using novel mixed-methods approaches and theories adapted from organizational studies in high-reliability organizations in an effort to improve the care of elderly surgical patients. CONCLUSION: Although elderly surgical patients experience failure-to-rescue events at much higher rates than their younger counterparts, patient-level effects do not sufficiently explain these differences. Increased attention to the role of organizational dynamics in hospitals' ability to rescue these high-risk patients will establish high-yield interventions aimed at improving patient safety. PMID- 26616277 TI - A cost-effective system for differentiation of intestinal epithelium from human induced pluripotent stem cells. AB - The human intestinal epithelium is a useful model for pharmacological studies of absorption, metabolism, drug interactions, and toxicology, as well as for studies of developmental biology. We established a rapid and cost effective system for differentiation of human induced pluripotent stem (iPS) cells into definitive endoderm (DE) cells. In the presence of dimethyl sulfoxide (DMSO), a low concentration of Activin at 6.25 ng/ml is sufficient to give a similar differentiation efficiency with that using Activin at 100 ng/ml at the presence of Wnt activator. In the presence of DMSO, Activin at low concentration triggered hiPS cells to undergo differentiation through G1 arrest, reduce apoptosis, and potentiate activation of downstream targets, such as SMAD2 phosphorylation and SOX17 expression. This increased differentiation into CDX2 + SOX17 + DE cells. The present differentiation procedure therefore permits rapid and efficient derivation of DE cells, capable of differentiating into intestinal epithelium upon BIO and DAPT treatment and of giving rise to functional cells, such as enterocytes. PMID- 26616278 TI - Propylparaben-induced disruption of energy metabolism in human HepG2 cell line leads to increased synthesis of superoxide anions and apoptosis. AB - The effect of propylparaben (in final concentrations 0.4 ng/ml, 2.3 ng/ml and 4.6 ng/ml) on the energy metabolism of HepG2 hepatocytes, superoxide anion synthesis, apoptosis and necrosis is described. Propylparaben can be toxic to liver cells due to the increased production of superoxide anions, which can contribute to a reduced concentration of superoxide dismutase in vivo and impairment of the body's antioxidant mechanisms. Finally, a further reduction in the mitochondrial membrane potential and uncoupling of the respiratory chain resulting in a reduction in ATP concentration as a result of mitochondrial damage may lead to cell death by apoptosis. PMID- 26616279 TI - Antimitotic activity of the pyrimidinone derivative py-09 on sea urchin embryonic development. AB - Chemotherapy is the main cancer treatment and consists of drug administration that interferes with several metabolic pathways, leading to tumor cell death. Antimitotic drugs have a relevant role in chemotherapy. This study aimed to investigate the effect of a pyrimidinone derivative (6-(p-Anisyl)-2-(p chlorophenyl)-4-oxo-3,4-dihydropyrimidine-5-carbonitrile, Py-09) on sea urchin embryonic development model. The effects of the compound were analyzed on fertilization, embryonic development, mitochondrial membrane potential (DeltaPsim), production of reactive oxygen species (ROS) and ABC transporter activity. Py-09 inhibited the fertilization and the embryonic development in a time and dose-dependent pattern, with the maximum effect at 50 MUM (EC50=12.5 MUM). Py-09 induced the loss of DeltaPsim without altering ROS intracellular levels. Morphological changes were observed in the pattern of embryo cleavage (unequal cleavage) and at larval stages (fissures of spicules and pigment cell leakage). We also demonstrated that Py-09 is not an ABC transporter substrate and the derivative does not circumvent the MXR phenomenon. Our study reports--for the first time--the antimitotic activity of Py-09 and stimulates new research on the potential of Py-09 as a pharmacological tool for in vitro studies, as well as its use as a new anticancer drug. PMID- 26616280 TI - Oxidative stress-responsive transcription factor NRF2 is not indispensable for the human hepatic Flavin-containing monooxygenase-3 (FMO3) gene expression in HepG2 cells. AB - The flavin-containing monooxygenases (FMOs) are important for the oxidation of a variety of endogenous compounds and xenobiotics. The hepatic expression of FMO3 is highly variable and until recently, it was thought to be uninducible. In this study, human FMO3 gene regulation by the oxidative stress transcription factor, nuclear factor (erythroid-derived 2)-like 2 (NRF2) was examined. Constitutive FMO3 gene expression is repressed in HepG2 cells, thus this cell can be a good model for FMO3 gene regulation studies. Over-expression of NRF2 in HepG2 cells increased NRF2 target gene expression, heme oxygenase-1 (HMOX1) and NAD(P)H: quinone oxidoreductase-1 (NQO1), but did not alter FMO3 gene expression. Co transfection studies with NRF2 or its cytosolic regulatory protein, Kelch-like ECH-associated protein 1 (KEAP1), expression vectors, along with FMO3 promoter luciferase reporter constructs of various lengths (5kb or 6kb), did not change FMO3 reporter gene activity significantly. Furthermore, treatment with tert-butyl hydroperoxide (tBHP) and tert-butyl hydroquinone (tBHQ) did not alter FMO3 reporter construct activity. In summary, in vitro results suggest that the transcriptional regulation of FMO3 might not involve the NRF2-KEAP1 regulatory pathway. PMID- 26616281 TI - Alkaloids derived from flowers of Senna spectabilis, (-)-cassine and (-) spectaline, have antiproliferative activity on HepG2 cells for inducing cell cycle arrest in G1/S transition through ERK inactivation and downregulation of cyclin D1 expression. AB - Cancer is one of the most critical problems of public health in the world and one of the main challenges for medicine in this century. Unfortunately, most patients are diagnosed at advanced stage, when the treatment options are palliative. Consequently, the search for novel therapeutic options is imperative. In the context, the plants represent an important source for discovering of novel compounds with pharmacological potential including antineoplastic agents. Herein, we aimed to investigate in vitro antiproliferative and cytotoxic potentials of an alkaloid mixture derived from Senna spectabilis, (-)-cassine (1) and (-) spectaline (2). These alkaloids reduced cell viability in a concentration dependent manner of six tumor cell lines. From initial screening, HepG2 cells were selected for further investigations. We show that alkaloids 1/2 have an important antiproliferative activity on HepG2 cells due to their ability in inducing cell cycle arrest in G1/S transition. This effect was associated to ERK inactivation and down-regulation of cyclin D1 expression. In addition, we evidenced a disruption of the microfilaments and microtubules in a consequence of the treatment. Taken together, the data showed by the first time that alkaloids 1/2 strongly inhibit cell proliferation of hepatocellular carcinoma cells. Therefore, they represent promise antitumor compounds against liver cancer and should be considered for further anticancer in vivo studies. PMID- 26616282 TI - Human CD34(+) progenitor hematopoiesis in liquid culture for in vitro assessment of drug-induced myelotoxicity. AB - Utilization of validated CFU-GM assays for myelotoxicity screening is hampered by its labor-intensive and low-throughput nature. Herein, we transformed the defined CFU-GM assay conditions and IC90 endpoint into a higher throughput format. Human CD34(+) hematopoietic progenitors were cultured in a 96-well plate for 14 days with the same cytokine (rhGM-CSF) used in the CFU-GM assay. Expansion and differentiation toward myeloid lineages were manifested by characteristic changes in nuclear and cytoplasmic morphology and by temporal expression patterns of CD34, CD11b and CD13 markers. Inhibition of CD34(+) cell myelopoiesis by 12 anticancer drugs known to induce myelotoxicity in the clinic was quantifiable using either general cytotoxicity endpoints (cell growth area or total nucleus count) or lineage specific readouts (count of cells expressing CD11b and/or CD13). The IC50 and IC90 values derived from the concentration-response curves of 14-day drug exposure in CD34(+) cell culture were highly correlated with those from the international validation study of the CFU-GM assay, demonstrating capability to assess general cytotoxicity, cell proliferation and myelopoiesis simultaneously. These results suggest that this human CD34(+) hematopoietic progenitor cell assay can be used as a direct replacement for the validated, low throughput CFU-GM assay, and could expand application of in vitro myelotoxicity testing. PMID- 26616283 TI - Boolean modeling identifies Greatwall/MASTL as an important regulator in the AURKA network of neuroblastoma. AB - Aurora Kinase A (AURKA) is often overexpressed in neuroblastoma (NB) with poor outcome. The causes of AURKA overexpression in NB are unknown. Here, we describe a gene regulatory network consisting of core regulators of AURKA protein expression and activation during mitosis to identify potential causes. This network was transformed to a dynamic Boolean model. Simulated activation of the serine/threonine protein kinase Greatwall (GWL, encoded by MASTL) that attenuates the pivotal AURKA inhibitor PP2A, predicted stabilization of AURKA. Consistent with this notion, gene set enrichment analysis showed enrichment of mitotic spindle assembly genes and MYCN target genes in NB with high GWL/MASTL expression. In line with the prediction of GWL/MASTL enhancing AURKA, elevated expression of GWL/MASTL was associated with NB risk factors and poor survival of patients. These results establish Boolean network modeling of oncogenic pathways in NB as a useful means for guided discovery in this enigmatic cancer. PMID- 26616284 TI - An architecture for a continuous, user-driven, and data-driven application of clinical guidelines and its evaluation. AB - OBJECTIVES: Design, implement, and evaluate a new architecture for realistic continuous guideline (GL)-based decision support, based on a series of requirements that we have identified, such as support for continuous care, for multiple task types, and for data-driven and user-driven modes. METHODS: We designed and implemented a new continuous GL-based support architecture, PICARD, which accesses a temporal reasoning engine, and provides several different types of application interfaces. We present the new architecture in detail in the current paper. To evaluate the architecture, we first performed a technical evaluation of the PICARD architecture, using 19 simulated scenarios in the preeclampsia/toxemia domain. We then performed a functional evaluation with the help of two domain experts, by generating patient records that simulate 60 decision points from six clinical guideline-based scenarios, lasting from two days to four weeks. Finally, 36 clinicians made manual decisions in half of the scenarios, and had access to the automated GL-based support in the other half. The measures used in all three experiments were correctness and completeness of the decisions relative to the GL. RESULTS: Mean correctness and completeness in the technical evaluation were 1+/-0.0 and 0.96+/-0.03 respectively. The functional evaluation produced only several minor comments from the two experts, mostly regarding the output's style; otherwise the system's recommendations were validated. In the clinically oriented evaluation, the 36 clinicians applied manually approximately 41% of the GL's recommended actions. Completeness increased to approximately 93% when using PICARD. Manual correctness was approximately 94.5%, and remained similar when using PICARD; but while 68% of the manual decisions included correct but redundant actions, only 3% of the actions included in decisions made when using PICARD were redundant. CONCLUSIONS: The PICARD architecture is technically feasible and is functionally valid, and addresses the realistic continuous GL-based application requirements that we have defined; in particular, the requirement for care over significant time frames. The use of the PICARD architecture in the domain we examined resulted in enhanced completeness and in reduction of redundancies, and is potentially beneficial for general GL-based management of chronic patients. PMID- 26616285 TI - QUANTITY: An Isobaric Tag for Quantitative Glycomics. AB - Glycan is an important class of macromolecules that play numerous biological functions. Quantitative glycomics--analysis of glycans at global level--however, is far behind genomics and proteomics owing to technical challenges associated with their chemical properties and structural complexity. As a result, technologies that can facilitate global glycan analysis are highly sought after. Here, we present QUANTITY (Quaternary Amine Containing Isobaric Tag for Glycan), a quantitative approach that can not only enhance detection of glycans by mass spectrometry, but also allow high-throughput glycomic analysis from multiple biological samples. This robust tool enabled us to accomplish glycomic survey of bioengineered Chinese Hamster Ovary (CHO) cells with knock-in/out enzymes involved in protein glycosylation. Our results demonstrated QUANTITY is an invaluable technique for glycan analysis and bioengineering. PMID- 26616287 TI - Enantioselective targeting left-handed Z-G-quadruplex. AB - Herein, we report the first example where an M-enantiomer of a chiral metal complex can selectively stabilize a left-handed G-quadruplex, but its P enantiomer cannot. The interactions between the chiral metal complexes and the left-handed G-quadruplex were evaluated by UV melting, circular dichroism, isothermal titration calorimetry, gel electrophoresis and NMR titrations. PMID- 26616286 TI - Thickness-Induced Metal-Insulator Transition in Sb-doped SnO2 Ultrathin Films: The Role of Quantum Confinement. AB - A thickness induced metal-insulator transition (MIT) was firstly observed in Sb doped SnO2 (SnO2:Sb) epitaxial ultrathin films deposited on sapphire substrates by pulsed laser deposition. Both electrical and spectroscopic studies provide clear evidence of a critical thickness for the metallic conductivity in SnO2:Sb thin films and the oxidation state transition of the impurity element Sb. With the shrinkage of film thickness, the broadening of the energy band gap as well as the enhancement of the impurity activation energy was studied and attributed to the quantum confinement effect. Based on the scenario of impurity level pinning and band gap broadening in quantum confined nanostructures, we proposed a generalized energy diagram to understand the thickness induced MIT in the SnO2:Sb system. PMID- 26616288 TI - Singlet oxygen oxidation products of biliverdin IXalpha dimethyl ester. AB - Biliverdin IXalpha is a naturally occurring linear tetrapyrrolic product of the enzymatic oxidative ring cleavage of heme. Evidence is mounting that biliverdin possesses antioxidant properties in mammals but its mode of action is unclear. We present the single crystal X-ray structure analysis of two regioisomeric biladien 1,19-diones-ab that are derived from biliverdin IXalpha dimethyl ester by addition of two vicinal trans-methoxy groups to the 4,5- or 15,16-double bonds, respectively. The compounds were likely formed by photosensitized singlet oxygen addition, followed by Lewis acid-catalyzed methanol-induced ring-opening of the intermediate epoxide, and OH-to-OMe substitution. We thus present structural evidence for a possible reaction mechanism by which biliverdin can act as an antioxidant. PMID- 26616289 TI - Identification of dual PPARalpha/gamma agonists and their effects on lipid metabolism. AB - The three peroxisome proliferator-activated receptor (PPAR) isoforms; PPARalpha, PPARgamma and PPARdelta, play central roles in lipid metabolism and glucose homeostasis. Dual PPARalpha/gamma agonists, which stimulate both PPARalpha and PPARgamma isoforms to similar extents, are gaining popularity as it is believed that they are able to ameliorate the unwanted side effects of selective PPARalpha and PPARgamma agonists; and may also be used to treat dyslipidemia and type 2 diabetes mellitus simultaneously. In this study, virtual screening of natural product libraries, using both structure-based and ligand-based drug discovery approaches, identified ten potential dual PPARalpha/gamma agonist lead compounds (9-13 and 16-20). In vitro assays confirmed these compounds to show no statistically significant toxicity to cells, with the exception of compound 12 which inhibited cell growth to 74.5%+/-3.5 and 54.1%+/-3.7 at 50MUM and 100MUM, respectively. In support of their potential as dual PPARalpha/gamma agonists, all ten compounds upregulated the expression of cholesterol transporters ABCA1 and ABCG1 in THP-1 macrophages, with indoline derivative 16 producing the greatest elevation (2.3-fold; 3.3-fold, respectively). Furthermore, comparable to the activity of established PPARalpha and PPARgamma agonists, compound 16 stimulated triacylglycerol accumulation during 3T3-L1 adipocyte differentiation as well as fatty acid beta-oxidation in HuH7 hepatocytes. PMID- 26616291 TI - Risk factors of gangrenous cholecystitis. PMID- 26616290 TI - Crystal structure of CobK reveals strand-swapping between Rossmann-fold domains and molecular basis of the reduced precorrin product trap. AB - CobK catalyzes the essential reduction of the precorrin ring in the cobalamin biosynthetic pathway. The crystal structure of CobK reveals that the enzyme, despite not having the signature sequence, comprises two Rossmann fold domains which bind coenzyme and substrate respectively. The two parallel beta-sheets have swapped their last beta-strands giving a novel sheet topology which is an interesting variation on the Rossmann-fold. The trapped ternary complex with coenzyme and product reveals five conserved basic residues that bind the carboxylates of the tetrapyrrole tightly anchoring the product. A loop, disordered in both the apoenzyme and holoenzyme structures, closes around the product further tightening binding. The structure is consistent with a mechanism involving protonation of C18 and pro-R hydride transfer from NADPH to C19 of precorrin-6A and reveals the interactions responsible for the specificity of CobK. The almost complete burial of the reduced precorrin product suggests a remarkable form of metabolite channeling where the next enzyme in the biosynthetic pathway triggers product release. PMID- 26616292 TI - Murine macrophage response from peritoneal cavity requires signals mediated by chemokine receptor CCR-2 during Staphylococcus aureus infection. AB - C-C chemokine receptor-2 (CCR-2) is a cognate receptor for monocyte chemotactic protein-1 (MCP-1), and recent studies revealed that MCP-1-CCR-2 signaling is involved in several inflammatory diseases characterized by macrophage infiltration. Currently, there is no study on the involvement of CCR-2 in the killing of S. aureus by macrophages of Swiss albino mice, and its substantial role in host defense against S. aureus infection in murine macrophages is still unclear. Therefore, the present study was aimed to investigate the functional and interactive role of CCR-2 and MCP-1 in regulating peritoneal macrophage responses with respect to acute S. aureus infection. We found that phagocytosis of S. aureus can serve as an important stimulus for MCP-1 production by peritoneal macrophages, which is dependent directly or indirectly on cytokines, reactive oxygen species and nitric oxide. Neutralization of CCR-2 in macrophages leads to increased production of IL-10 and decreased production of IFN-gamma and IL-6. In CCR-2 blocked macrophages, pretreatment with specific blocker of NF-kappaB or p38 MAPK causes elevation in MCP-1 level and subsequent downregulation of CCR-2 itself. We speculate that CCR-2 is involved in S. aureus-induced MCP-1 production via NF-kappaB or p38-MAPK signaling. We also hypothesized that unnaturally high level of MCP-1 that build up upon CCR-2 neutralization might allow promiscuous binding to one or more other chemokine receptors, a situation that would not occur in CCR-2 non-neutralized condition. This may be the plausible explanation for such observed Th-2 response in CCR-2 blocked macrophages infected with S. aureus in the present study. PMID- 26616293 TI - Increased expression of long noncoding RNAs LOC100652951 and LOC100506036 in T cells from patients with rheumatoid arthritis facilitates the inflammatory responses. AB - The aim of this study was to evaluate whether the presence of aberrantly expressed lncRNAs could promote T cell inflammatory responses in patients with RA. The expression levels of 10 potential aberrantly expressed lncRNAs were evaluated in T cells from 39 patients with RA and 17 controls using real-time reverse transcription polymerase chain reaction. The aberrantly expressed lncRNAs were measured in Jurkat cells co-cultured with or without ionomycin and phorbol 12-myristate 13-acetate. Transfection studies using small interfering RNA (siRNA) were conducted for biological functions, and microarray analysis was performed to search for target genes of specific lncRNAs. We confirmed that the expression levels of LOC100652951 and LOC100506036 were higher in RA T cells compared with controls. RA patients treated with biologic agents had lower expression levels of LOC100652951, and female RA patients had lower LOC100506036 expression levels after multivariate analysis. After activation, the expression levels of LOC100506036, but not LOC100652951, increased in Jurkat cells. Transfection of siRNA targeting LOC100506036 inhibited interferon gamma production and the expression of nuclear factor of activated T cells in activated Jurkat cells. After the microarray analysis with validation, inhibition of LOC100506036 expression by siRNA leaded to the decreased expression of sphingomyelin phosphodiesterase 1 (SMPD1). In conclusion, the expression levels of LOC100652951 and LOC100506036 were increased in RA T cells. Treatment with biologic agents could lower the expression of LOC100652951 in RA T cells. LOC100506036 could regulate the expression of SMPD1 and NFAT1 and could contribute to the inflammatory responses in RA. PMID- 26616294 TI - Atrial natriuretic peptide down-regulates LPS/ATP-mediated IL-1beta release by inhibiting NF-kB, NLRP3 inflammasome and caspase-1 activation in THP-1 cells. AB - Atrial natriuretic peptide (ANP) is an hormone/paracrine/autocrine factor regulating cardiovascular homeostasis by guanylyl cyclase natriuretic peptide receptor (NPR-1). ANP plays an important role also in regulating inflammatory and immune systems by altering macrophages functions and cytokines secretion. Interleukin-1beta (IL-1beta) is a potent pro-inflammatory cytokine involved in a wide range of biological responses, including the immunological one. Unlike other cytokines, IL-1beta production is rigorously controlled. Primarily, NF-kB activation is required to produce pro-IL-1beta; subsequently, NALP3 inflammasome/caspase-1 activation is required to cleave pro-IL-1beta into the active secreted protein. NALP3 is a molecular platform capable of sensing a large variety of signals and a major player in innate immune defense. Due to their pleiotropism, IL-1beta and NALP3 dysregulation is a common feature of a wide range of diseases. Therefore, identifying molecules regulating IL 1beta/NALP3/caspase-1 expression is an important step in the development of new potential therapeutic agents. The aim of our study was to evaluate the effect of ANP on IL-1beta/NALP3/caspase-1 expression in LPS/ATP-stimulated human THP1 monocytes. We provided new evidence of the direct involvement of ANP/NPR-1/cGMP axis on NF-kB/NALP3/caspase-1-mediated IL-1beta release and NF-kB-mediated pro-IL 1beta production. In particular, ANP inhibited both NF-kB and NALP3/caspase-1 activation leading to pro- and mature IL-1beta down-regulation. Our data, pointing out a modulatory role of this endogenous peptide on IL-1beta release and on NF-kB/NALP3/caspase-1 activation, indicate an important anti-inflammatory and immunomodulatory effect of ANP via these mechanisms. We suggest a possible employment of ANP for the treatment of inflammatory/immune-related diseases and IL-1beta/NALP3-associated disorders, affecting millions of people worldwide. PMID- 26616296 TI - Oxytocin and Social Adaptation: Insights from Neuroimaging Studies of Healthy and Clinical Populations. AB - Adaptation to the social environment is critical for human survival. The neuropeptide oxytocin (OT), implicated in social cognition and emotions pivotal to sociality and well-being, is a promising pharmacological target for social and emotional dysfunction. We suggest here that the multifaceted role of OT in socio affective processes improves the capability for social adaptation. We review OT effects on socio-affective processes, with a focus on OT-neuroimaging studies, to elucidate neuropsychological mechanisms through which OT promotes social adaptation. We also review OT-neuroimaging studies of individuals with social deficits and suggest that OT ameliorates impaired social adaptation by normalizing hyper- or hypo-brain activity. The social adaption model (SAM) provides an integrative understanding of discrepant OT effects and the modulations of OT action by personal milieu and context. PMID- 26616295 TI - HIV-1-exposed seronegative individuals show alteration in TLR expression and pro inflammatory cytokine production ex vivo: An innate immune quiescence status? AB - Pattern recognition receptors (PRRs) are involved in direct recognition of viruses, promoting cellular activation and the production of pro-inflammatory cytokines. However, despite the reduced systemic immune activation described in HIV-1-exposed seronegatives (HESNs), few studies have focused on determining the relationship between PRR expression and cytokine production. We have aimed here to evaluate the expression level of PRRs and cytokines in HESNs, HIV-1 patients and healthy donors. Basal PRR expression levels in PBMCs, dendritic cells (DCs) and monocytes, and plasma cytokine levels as well as the PRR ligand-induced cytokine productions were determined by flow cytometry, qPCR and ELISA. Higher TLR2/4 expression in DCs and monocytes from HESNs was observed. Nevertheless, TLR4/8, NOD2 and RIG-I mRNA levels were lower in PBMCs from HESNs than HIV-1 infected patients. Comparable IL-1beta, IL-18 and TNF-alpha mRNA levels were observed among the groups examined; however, at the protein level, production of IL-1beta, IL-6 and IL-10 was significantly lower in plasma from HESNs than from HIV-1-infected patients. Our results suggest that exposure to HIV-1 without infection could be associated with reduced basal pro-inflammatory responses. Further studies are required to define the cell subsets responsible for these differences and the role of PRRs on protection against HIV-1 infection. PMID- 26616297 TI - Immune tolerance: A window of opportunity. PMID- 26616298 TI - [Tolerability and short-term efficacy of the Ozurdex(r) dexamethasone intravitreal implant for treatment of uveitic cystoid macular edema: A retrospective study of 52 injections performed at the Clermont-Ferrand teaching hospital]. AB - Macular edema is the main cause of decreased visual acuity in uveitis and determines the visual prognosis. We retrospectively analyzed the tolerability and efficacy of the dexamethasone intravitreal implant in the management of uveitis. Twenty-five patients with uveitic cystoid macular edema were all treated with the Ozurdex((r)) dexamethasone intravitreal implant from January 2012 to August 2014. The main outcome measures were visual acuity recovery, changes in macular thickness and resolution of the vitritis. Thirty-two eyes of 25 patients received 52 injections of Ozurdex((r)). Both complete regression of the macular edema and resolution of the vitritis occurred in 100 % patients. Visual acuity improved in 62 % of patients: the mean reduction in macular thickness was 252 (+/-171MUm); the mean time between injections was 6.7 (+/-3.8) months. Secondary ocular hypertension was seen in 33 % of patients. No patient required secondary surgery although a selective laser trabeculoplasty was required for one patient. The dexamethasone intravitreal implant Ozurdex((r)) resulted in continuous and complete regression of uveitic cystoid macular edema. It allows evaluation of the potential visual recovery of treated eyes. The tolerability and duration of action provide a rationale for considering Ozurdex((r)) as a first-line therapy for uveitis which remains uncontrolled despite optimal systemic treatment. PMID- 26616299 TI - [Case of a bilateral MALT lymphoma of the lacrimal sac treated only medically]. PMID- 26616300 TI - [Subconjunctival migration of a Loa Loa parasite]. PMID- 26616301 TI - Acquired von Willebrand factor deficiency caused by LVAD is ADAMTS-13 and platelet dependent. AB - INTRODUCTION: The high shear rates induced by left ventricular assist devices cause acquired von Willebrand disease (aVWD). We hypothesised that an ex vivo model could be established to study whether mechanical shear stress alone causes aVWD or whether this process depends also on the VWF cleavage protein ADAMTS-13 and on platelets. MATERIALS AND METHODS: Healthy volunteers and two patients with congenital ADAMTS-13 deficiency donated blood. In vitro closed extracorporeal circuits were established using medically approved left ventricular assist devices (LVAD). VWF multimers were quantified by gel electrophoresis; VWF antigen, ristocetin cofactor activity (VWF:RCo), ADAMTS-13 levels and platelet function were assessed. RESULTS: The high shear stress in the extracorporeal circulation rapidly decreased VWF:RCo and thereby the VWF:RCo/VWF:Ag ratio by 47% (p<0.01) to pathologically low values. Concomitantly, high molecular weight multimers (HMWM) decreased: up to 14-15 mers were visible on the gels at baseline, which were reduced by a maximum of 6-7 mers, corresponding to an average 68% lower densitometry signal of HMWM (p<0.001). This was accompanied by marked reduction of aggregation by various agonists (p<0.005). In contrast, the two patients with congenital thrombocytopenic purpura with virtually complete deficiency of ADAMTS-13 activity had only a minimal or no decrease in multimers (p<0.005 vs. healthy controls). Similarly, no or minimal depletion of large multimers occurred, when normal plasma circulated without platelets. CONCLUSION: An in vitro model for LVAD associated aVWD demonstrated that ADAMTS-13 and platelets contribute to the depletion of HMWM of VWF. PMID- 26616303 TI - Acute reduction in anxiety after deep transcranial magnetic stimulation (DTMS) in unipolar major depression- a systematic review and meta-analysis. AB - The current study investigated the anxiolytic properties of the deep transcranial magnetic stimulation (DTMS) in unipolar major depression using a systematic literature review and meta-analysis. Compared to baseline, large anxiolytic and antidepressant outcomes were obtained after 20 daily sessions of high-frequency DTMS according to data from six open-label studies with 95 patients. Unlike the antidepressant effect, the anxiolytic effect was more heterogeneous among studies and did not depend on concurrent treatment with antidepressants. PMID- 26616302 TI - Therapeutic effect of baicalin on experimental autoimmune encephalomyelitis is mediated by SOCS3 regulatory pathway. AB - Natural compounds derived from medicinal plants have long been considered a rich source of novel therapeutic agents. Baicalin (Ba) is a bioactive flavonoid compound derived from the root of Scutellaria baicalensis, an herb widely used in traditional medicine for the treatment of various inflammatory diseases. In this study, we investigate the effects and mechanism of action of Ba in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Ba treatment effectively ameliorated clinical disease severity in myelin oligodendrocyte glycoprotein (MOG)35-55 peptide-induced EAE, and reduced inflammation and demyelination of the central nervous system (CNS). Ba reduced infiltration of immune cells into the CNS, inhibited expression of proinflammatory molecules and chemokines, and prevented Th1 and Th17 cell differentiation via STAT/NFkappaB signaling pathways. Further, we showed that SOCS3 induction is essential to the effects of Ba, given that the inhibitory effect of Ba on pathogenic Th17 responses was largely abolished when SOCS3 signaling was knocked down. Taken together, our findings demonstrate that Ba has significant potential as a novel anti-inflammatory agent for therapy of autoimmune diseases such as MS. PMID- 26616304 TI - The association between prolonged sleep onset latency and heart rate dynamics among young sleep-onset insomniacs and good sleepers. AB - A blunting of heart rate (HR) reduction during sleep has been reported to be associated with increased all-cause mortality. An increased incident of cardiovascular events has been observed in patients with insomnia but the relationship between nighttime HR and insomnia remains unclear. Here we investigated the HR patterns during the sleep onset period and its association with the length of sleep onset latency (SOL). Nineteen sleep-onset insomniacs (SOI) and 14 good sleepers had their sleep analyzed. Linear regression and nonlinear Hilbert-Huang transform (HHT) of the HR slope were performed in order to analyze HR dynamics during the sleep onset period. A significant depression in HR fluctuation was identified among the SOI group during the sleep onset period when linear regression and HHT analysis were applied. The magnitude of the HR reduction was associated with both polysomnography-defined and subjective SOL; moreover, we found that the linear regression and HHT slopes of the HR showed great sensitivity with respect to sleep quality. Our findings indicate that HR dynamics during the sleep onset period are sensitive to sleep initiation difficulty and respond to the SOL, which indicates that the presence of autonomic dysfunction would seem to affect the progress of falling asleep. PMID- 26616305 TI - Comparison of patients who were violent, victimized and violent-victimized during the first year after discharge from emergency psychiatry. AB - This prospective observational study included 345 (70%) of 489 patients discharged from an emergency psychiatric hospital during one year. Episodes of offending and victimization were recorded during first year after discharge. Forty-eight persons (14%) committed violent offenses only, 27 persons (8%) were violence victims only, and 42 persons (12%) were both offenders and victims. Significant differences in demographic and clinical variables were found between the three groups. The results pointed to two distinct groups of victims: one group with a robust offender-victim overlap and another group without offender victim overlap. The latter group was difficult to distinguish from other discharged patients. PMID- 26616306 TI - Racial/Ethnic Differences in Unintended Pregnancy: Evidence From a National Sample of U.S. Women. AB - INTRODUCTION: Racial and ethnic minorities experience greater burden of unintended pregnancy in the U.S. This study examined the factors associated with racial and ethnic disparities in unintended pregnancy among women in the U.S. using the social ecological model. METHODS: This study utilized the National Survey of Family Growth data from 2006 to 2010. Data were analyzed in Autumn 2014 and Winter 2015. Decomposition analyses examined which intrapersonal, interpersonal, institutional, community, and public policy factors explained racial and ethnic disparities in unintended pregnancy. RESULTS: Unadjusted analyses found that black and Hispanic women had a greater likelihood of unintended pregnancy compared with white women. Decomposition models explained 51% of the disparity in unintended pregnancy between black and white women and 73% of that between Hispanic and white women. Factors contributing to the disparity between black and white women included age, relationship status, respondent's mother's age at first birth, Federal Poverty Level, and insurance status. Between Hispanic and white women, these factors included age, U.S.-born status, education, and relationship status. CONCLUSIONS: Given that the results showed factors at different levels of the social ecological model contribute to racial and ethnic disparities in unintended pregnancy, interventions that aim to reduce these disparities should target at-risk groups of women such as younger, unmarried, lower-income, less-educated, non-U.S. born women and uninsured or publicly insured women. PMID- 26616308 TI - Xenophilus feline species goes human.-Watch out for neglected zoonotic pathogens when treating animal bites. PMID- 26616309 TI - Uepaa! - 24 h safety - An app that works like a Guardian Angel in remote areas (A seasonal gift for the trekker ...). PMID- 26616307 TI - Drinking water treatment with ultraviolet light for travelers -- Evaluation of a mobile lightweight system. AB - BACKGROUND: The SteriPEN((r)) is a handheld device for disinfecting water with ultraviolet (UV) radiation. The manufacturer claims a reduction of at least 99.9% of bacteria, viruses, and protozoa. The present study intends to verify the general effectiveness of the device. Furthermore, the influence of bottle geometry and water movement is examined and the issue of user safety with regard to UV-C radiation is addressed. METHODS: The device was applied on water containing a known number of microorganisms (Escherichia coli, Staphylococcus aureus, and the spore of Geobacillusstearothermophilus) and the survival rate was examined. Three different types of bottles commonly used among travelers served as test containers. All tests were conducted with and without agitating the water during irradiation. Furthermore, a spectral analysis was performed on the light of the device. RESULTS: The SteriPEN((r)) reached a mean reduction of more than 99.99% of bacteria and 99.57% of the spores when applied correctly. However, the results of the trials without agitating the water only yielded a 94.98% germ reduction. The device's maximal radiation intensity lies at 254 nm which is the wavelength most efficient in inactivating bacteria. The UV-C fraction is filtered out completely by common bottle materials. However, when applied in larger containers a portion of the UV-C rays exits the water surface. CONCLUSIONS: If applied according to the instructions the device manages a satisfactory inactivation of bacteria. However, it bears the danger of user errors relevant to health. Therefore, education on the risks of incorrect application should be included in the travel medical consultation. Also there are still aspects that need to be subject to further independent research. PMID- 26616310 TI - Mixed anionic surfactant-templated mesoporous silica nanoparticles for fluorescence detection of Fe(3.). AB - This work demonstrates a novel method for the synthesis of large pore mesoporous silica nanoparticles (MSNs) with a pore diameter of 10.3 nm and a particle diameter of ~50 nm based on the incorporation of mixed anionic surfactants sodium dodecyl benzene sulfonate (SDBS) and sodium dodecyl sulphate (SDS) as the template in the synthesis process. The dispersity, morphology, pore structure and size of mesoporous nanoparticles were adjusted by changing the molar ratio of two anionic surfactants, the concentration of the co-structure-directing agent (3 aminopropyltrimethoxysilane) and the reaction temperature. The results of synthesis experiments suggested that the formation of large pore MSNs involved a nucleation and growth process. MSNs were post-grafted with a Schiff base moiety for fluorescence sensing of Fe(3+) in water. The applicability of functionalized MSNs was demonstrated by selective fluorescence detection of Fe(3+) in aqueous media. PMID- 26616311 TI - Neuromusculoskeletal models based on the muscle synergy hypothesis for the investigation of adaptive motor control in locomotion via sensory-motor coordination. AB - Humans and animals walk adaptively in diverse situations by skillfully manipulating their complicated and redundant musculoskeletal systems. From an analysis of measured electromyographic (EMG) data, it appears that despite complicated spatiotemporal properties, muscle activation patterns can be explained by a low dimensional spatiotemporal structure. More specifically, they can be accounted for by the combination of a small number of basic activation patterns. The basic patterns and distribution weights indicate temporal and spatial structures, respectively, and the weights show the muscle sets that are activated synchronously. In addition, various locomotor behaviors have similar low dimensional structures and major differences appear in the basic patterns. These analysis results suggest that neural systems use muscle group combinations to solve motor control redundancy problems (muscle synergy hypothesis) and manipulate those basic patterns to create various locomotor functions. However, it remains unclear how the neural system controls such muscle groups and basic patterns through neuromechanical interactions in order to achieve adaptive locomotor behavior. This paper reviews simulation studies that explored adaptive motor control in locomotion via sensory-motor coordination using neuromusculoskeletal models based on the muscle synergy hypothesis. Herein, the neural mechanism in motor control related to the muscle synergy for adaptive locomotion and a potential muscle synergy analysis method including neuromusculoskeletal modeling for motor impairments and rehabilitation are discussed. PMID- 26616312 TI - Quantum optics, molecular spectroscopy and low-temperature spectroscopy: general discussion. PMID- 26616313 TI - Thriving With Thankfulness. PMID- 26616314 TI - Faith: A Foundational Companion to Hope. PMID- 26616315 TI - Results of the 2015 AORN Salary and Compensation Survey. AB - AORN conducted its 13th annual compensation survey for perioperative nurses in June and July 2015. A multiple regression model was used to examine how a number of variables, including job title, education level, certification, experience, and geographic region, affect nurse compensation. Comparisons between the 2015 data and data from previous years are presented. The effects of other forms of compensation (eg, on-call compensation, overtime, bonuses, shift differentials, benefits) on base compensation rates also are examined. Additional analyses explore the effect of the economic downturn on the perioperative work environment. PMID- 26616316 TI - Overview of Key Infection Prevention Issues and Advances. PMID- 26616317 TI - Patient-Centered Care--Enhanced Recovery After Surgery and Population Health Management. PMID- 26616318 TI - The OR Environment--Hand Hygiene, Cleaning, and Clostridium difficile. PMID- 26616319 TI - Sterilization and High-Level Disinfection Update. PMID- 26616320 TI - Looking Forward--Infection Prevention in 2016. PMID- 26616321 TI - Ghost Surgery: A Frank Look at the Issue and How to Address It. AB - Ghost surgery occurs when a physician assistant, a surgical assistant, an RN first assistant, a resident, or another surgeon assists on or performs an operative or other invasive procedure without the patient's knowledge, regardless of whether the surgeon who obtained the consent was scrubbed in or not. This practice denies patients important information, eliminates their ability to provide informed consent, and represents an ethical issue that nurses must deal with when working with peers and patients. The American Nurses Association developed the Code of Ethics for Nurses to help guide nursing practice, and the provisions within the code embody the ethical issues that should guide nurses' practice in advocating for patients. PMID- 26616322 TI - Quality and Patient Safety Teams in the Perioperative Setting. AB - Quality and patient safety teams in the perioperative setting can provide perioperative personnel with a safety net to prevent avoidable errors, which is a necessity in today's complex surgical world. The primary goal of the quality and patient safety team should be to develop and implement a perioperative quality and patient safety strategic plan. The mission of the plan can be developed by surveying facility employees, choosing a quality methodology, and using an evidence-based approach to develop and implement quality programs and processes. To create and sustain a quality and patient safety team, it is important to select a heterogeneous group; define team roles; identify day-to-day, weekly, and monthly team responsibilities; actively participate in facility committees, meetings, and new employee orientation; conduct audits; and schedule project time. PMID- 26616323 TI - Guideline Implementation: Radiation Safety. AB - Because radiologic technology is used in a variety of perioperative procedures and settings, it is essential for perioperative RNs to be knowledgeable of the risks related to radiation and the ways to adequately protect patients and health care providers from unintended radiation exposure. The updated AORN "Guideline for radiation safety" provides guidance on preventing injury from ionizing radiation exposure during therapeutic, diagnostic, and interventional procedures. This article focuses on key points of the guideline to help perioperative personnel practice radiation safety. The key points address the requirements for an organization's radiation safety program, measures used to keep radiation exposure as low as reasonably achievable, proper handling and testing of radiation protection devices, and considerations for protecting employees and patients who are pregnant and who will be exposed to radiation. Perioperative RNs should review the complete guideline for additional information and for guidance when writing and updating policies and procedures. PMID- 26616324 TI - Getting Ready for Emerging Perioperative Technologies. PMID- 26616325 TI - Guiding Novice Learners in the OR. PMID- 26616326 TI - Fostering a Culture of Safety: The OR Huddle. PMID- 26616328 TI - CVC Removal: A Procedure Like Any Other. PMID- 26616329 TI - Free Flap Procedures for Reconstruction After Head and Neck Cancer. AB - Patients with head and neck cancer are seeking improved surgical procedures to avoid severe defects that result from head and neck cancer resection. Free flap reconstruction provides vascularized tissue that has been transferred from a distant donor site on a patient's body to a recipient site, markedly improving wound closure and protecting structures of the head and neck. This article discusses free flap procedures for reconstruction after head and neck cancer resection, including the following procedure phases: airway protection and neck dissections, tumor resection, flap harvest, microvascular anastomosis of the flap, and reconstruction and closure. The article also explains specific risk factors for patients undergoing free flap procedures that have been identified in the literature and include procedure length, hypothermia, and pressure injuries. Each of these factors is discussed regarding its specific effect on this patient population, and the nursing interventions to reduce these risks are identified. PMID- 26616330 TI - Hand Contamination, Cross-Transmission, and Risk-Associated Behaviors: An Observational Study of Team Members in ORs. AB - Team members in ORs have frequent hand contact with many surfaces and sites during high workload, thus increasing the risk for microorganism cross transmission. This study aimed at identifying risks for hand contamination and microorganism cross-transmission during invasive procedures in ORs. We carried out observations during 22 daytime sessions and analyzed data using qualitative content analysis. The results revealed that clinicians' hands may be contaminated by self-contamination, via objects, or by touching the patient. Contamination may occur before, during, or directly after performing an invasive procedure requiring the use of aseptic technique, which risks cross-transmitting microorganisms. The results of the study contribute detailed knowledge about risk associated activities and behaviors in relation to performing invasive procedures in the OR. This knowledge provides clinicians, managers, and educators with specific information that can be used in nursing and medical education and in quality improvement projects aimed at improving hand hygiene routines and enhancing aseptic technique. PMID- 26616331 TI - Alternative splicing of Drosophila Nmnat functions as a switch to enhance neuroprotection under stress. AB - Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved enzyme in the NAD synthetic pathway. It has also been identified as an effective and versatile neuroprotective factor. However, it remains unclear how healthy neurons regulate the dual functions of NMNAT and achieve self-protection under stress. Here we show that Drosophila Nmnat (DmNmnat) is alternatively spliced into two mRNA variants, RA and RB, which translate to protein isoforms with divergent neuroprotective capacities against spinocerebellar ataxia 1-induced neurodegeneration. Isoform PA/PC translated from RA is nuclear-localized with minimal neuroprotective ability, and isoform PB/PD translated from RB is cytoplasmic and has robust neuroprotective capacity. Under stress, RB is preferably spliced in neurons to produce the neuroprotective PB/PD isoforms. Our results indicate that alternative splicing functions as a switch that regulates the expression of functionally distinct DmNmnat variants. Neurons respond to stress by driving the splicing switch to produce the neuroprotective variant and therefore achieve self-protection. PMID- 26616332 TI - Isolation and Identification of Post-Transcriptional Gene Silencing-Related Micro RNAs by Functionalized Silicon Nanowire Field-effect Transistor. AB - Many transcribed RNAs are non-coding RNAs, including microRNAs (miRNAs), which bind to complementary sequences on messenger RNAs to regulate the translation efficacy. Therefore, identifying the miRNAs expressed in cells/organisms aids in understanding genetic control in cells/organisms. In this report, we determined the binding of oligonucleotides to a receptor-modified silicon nanowire field effect transistor (SiNW-FET) by monitoring the changes in conductance of the SiNW FET. We first modified a SiNW-FET with a DNA probe to directly and selectively detect the complementary miRNA in cell lysates. This SiNW-FET device has 7-fold higher sensitivity than reverse transcription-quantitative polymerase chain reaction in detecting the corresponding miRNA. Next, we anchored viral p19 proteins, which bind the double-strand small RNAs (ds-sRNAs), on the SiNW-FET. By perfusing the device with synthesized ds-sRNAs of different pairing statuses, the dissociation constants revealed that the nucleotides at the 3'-overhangs and pairings at the terminus are important for the interactions. After perfusing the total RNA mixture extracted from Nicotiana benthamiana across the device, this device could enrich the ds-sRNAs for sequence analysis. Finally, this bionanoelectronic SiNW-FET, which is able to isolate and identify the interacting protein-RNA, adds an additional tool in genomic technology for the future study of direct biomolecular interactions. PMID- 26616333 TI - Interaction of the hepatitis B virus X protein with the lysine methyltransferase SET and MYND domain-containing 3 induces activator protein 1 activation. AB - Hepatitis B virus (HBV) is a widespread human pathogen that often causes chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The detailed mechanisms underlying HBV pathogenesis remain poorly understood. The HBV X protein (HBx) is a multifunctional regulator that modulates viral replication and host cell functions, such as cell cycle progression, apoptosis and protein degradation through interaction with a variety of host factors. Recently, the nonstructural protein 5A (NS5A) of hepatitis C virus has been reported to interact with methyltransferase SET and MYND domain-containing 3 (SMYD3), which is implicated in chromatin modification and development of cancer. Because HBx shares fundamental regulatory functions concerning viral replication and pathogenesis with NS5A, it was decided to examine whether HBx interacts with SMYD3. In the present study, it was demonstrated by co-immunoprecipitation analysis that HBx interacts with both ectopically and endogenously expressed SMYD3 in Huh-7.5 cells. Deletion mutation analysis revealed that the C-terminal region of HBx (amino acids [aa] 131-154) and an internal region of SMYD3 (aa 269-288) are responsible for their interaction. Immunofluorescence and proximity ligation assays showed that HBx and SMYD3 co-localize predominantly in the cytoplasm. Luciferase reporter assay demonstrated that the interaction between HBx and SMYD3 activates activator protein 1 (AP-1) signaling, but not that of nuclear factor kappa B (NF-kappaB). On the other hand, neither overexpression nor knockdown of SMYD3 altered production of HBV transcripts and HBV surface antigen (HBsAg). In conclusion, a novel HBx-interacting protein, SMYD3, was identified, leading to proposal of a novel mechanism of AP-1 activation in HBV-infected cells. PMID- 26616334 TI - Bullous Pemphigoid With a Dual Pattern of Glomerular Immune Complex Disease. AB - A 75-year-old man presented with a blistering skin disease and nephrotic syndrome. Bullous pemphigoid was diagnosed by linear immunoglobulin G (IgG) and C3 staining along the basement membrane zone of a skin biopsy specimen and by the presence of circulating IgG recognizing the 180-kDa bullous pemphigoid antigen (BP180; type XVII collagen). A kidney biopsy specimen showed endocapillary inflammation without crescents. Direct immunofluorescence showed strong IgG and C3 staining in a combined granular and linear pattern along the glomerular basement membrane. Electron microscopy showed subepithelial deposits. In serum, no antibodies against the Goodpasture antigen (type IV collagen) or phospholipase A2 receptor were detected. Indirect immunofluorescence studies using the patient's serum showed a strikingly linear but not granular IgG pattern along the epithelial basement membranes of monkey esophagus and kidney. Although type XVII collagen was recently identified in the glomerulus, the patient's serum did not produce a 180-kDa band on immunoblot of kidney tissue and still stained glomeruli of BP180 knockout mice by indirect immunofluorescence. The patient was treated with prednisone and azathioprine, which resulted in complete remission of skin and kidney manifestations. Although bullous pemphigoid has been reported previously in association with anti-glomerular basement membrane disease or membranous nephropathy, this case demonstrates both elements in 1 patient. This concurrence and the linear pattern on indirect immunofluorescence support the possibility of cross-reactive or parallel autoantibodies to basement membranes with a secondary membranous component. PMID- 26616335 TI - New Options for Iron Supplementation in Maintenance Hemodialysis Patients. AB - End-stage renal disease results in anemia caused by shortened erythrocyte survival, erythropoietin deficiency, hepcidin-mediated impairment of intestinal absorption and iron release, recurrent blood loss, and impaired responsiveness to erythropoiesis-stimulating agents (ESAs). Iron malabsorption renders oral iron products generally ineffective, and intravenous (IV) iron supplementation is required in most patients receiving maintenance hemodialysis (HD). IV iron is administered at doses far exceeding normal intestinal iron absorption. Moreover, by bypassing physiologic safeguards, indiscriminate use of IV iron overwhelms transferrin, imposing stress on the reticuloendothelial system that can have long term adverse consequences. Unlike conventional oral iron preparations, ferric citrate has recently been shown to be effective in increasing serum ferritin, hemoglobin, and transferrin saturation values while significantly reducing IV iron and ESA requirements in patients treated with HD. Ferric pyrophosphate citrate is a novel iron salt delivered by dialysate; by directly reaching transferrin, its obviates the need for storing administered iron and increases transferrin saturation without increasing serum ferritin levels. Ferric pyrophosphate citrate trials have demonstrated effective iron delivery and stable hemoglobin levels with significant reductions in ESA and IV iron requirements. To date, the long-term safety of using these routes of iron administration in patients receiving HD has not been compared to IV iron and therefore awaits future investigations. PMID- 26616336 TI - Development of Clinical Practice Guidelines in the Care of People With Kidney Disease: Core Curriculum 2016. PMID- 26616337 TI - Implementing GFR Estimation Guidelines Using Cystatin C: A Quality Improvement Project. PMID- 26616338 TI - Was millennial scale climate change during the Last Glacial triggered by explosive volcanism? AB - The mechanisms responsible for millennial scale climate change within glacial time intervals are equivocal. Here we show that all eight known radiometrically dated Tambora-sized or larger NH eruptions over the interval 30 to 80 ka BP are associated with abrupt Greenland cooling (>95% confidence). Additionally, previous research reported a strong statistical correlation between the timing of Southern Hemisphere volcanism and Dansgaard-Oeschger (DO) events (>99% confidence), but did not identify a causative mechanism. Volcanic aerosol-induced asymmetrical hemispheric cooling over the last few hundred years restructured atmospheric circulation in a similar fashion as that associated with Last Glacial millennial-scale shifts (albeit on a smaller scale). We hypothesise that following both recent and Last Glacial NH eruptions, volcanogenic sulphate injections into the stratosphere cooled the NH preferentially, inducing a hemispheric temperature asymmetry that shifted atmospheric circulation cells southward. This resulted in Greenland cooling, Antarctic warming, and a southward shifted ITCZ. However, during the Last Glacial, the initial eruption-induced climate response was prolonged by NH glacier and sea ice expansion, increased NH albedo, AMOC weakening, more NH cooling, and a consequent positive feedback. Conversely, preferential SH cooling following large SH eruptions shifted atmospheric circulation to the north, resulting in the characteristic features of DO events. PMID- 26616339 TI - Effects of propofol on glycinergic neurotransmission in a single spinal nerve synapse preparation. AB - The effects of the intravenous anesthetic, propofol, on glycinergic transmission and on glycine receptor-mediated whole-cell currents (IGly) were examined in the substantia gelatinosa (SG) neuronal cell body, mechanically dissociated from the rat spinal cord. This "synaptic bouton" preparation, which retains functional native nerve endings, allowed us to evaluate glycinergic inhibitory postsynaptic currents (IPSCs) and whole-cell currents in a preparation in which experimental solution could rapidly access synaptic terminals. Synaptic IPSCs were measured as spontaneous (s) and evoked (e) IPSCs. The eIPSCs were elicited by applying paired pulse focal electrical stimulation, while IGly was evoked by a bath application of glycine. A concentration-dependent enhancement of IGly was observed for >=10uM propofol. Propofol (>=3uM) significantly increased the frequency of sIPSCs and prolonged the decay time without altering the current amplitude. However, propofol (>=3uM) also significantly increased the mean amplitude of eIPSCs and decreased the failure rate (Rf). A decrease in the paired-pulse ratio (PPR) was noted at higher concentrations (>=10uM). The decay time of eIPSCs was prolonged only at the maximum concentration tested (30uM). Propofol thus acts at both presynaptic glycine release machinery and postsynaptic glycine receptors. At clinically relevant concentrations (<1MUM) there was no effect on IGly, sIPSCs or eIPSCs suggesting that at anesthetic doses propofol does not affect inhibitory glycinergic synapses in the spinal cord. PMID- 26616340 TI - In situ enzymatic activity of transglutaminase isoforms on brain tissue sections of rodents: A new approach to monitor differences in post-translational protein modifications during neurodegeneration. AB - Mammalian transglutaminases (TGs) catalyze the irreversible post-translational modifications of proteins, the most prominent of which is the calcium-dependent formation of covalent acyl transfers between the gamma-carboxamide group of glutamine and the epsilon-amino-group of lysine (GGEL-linkage). In the central nervous system, at least four TG isoforms are present and some of them are differentially expressed under pathological conditions in human patients. However, the precise TG-isoform-dependent enzymatic activities in the brain as well as their anatomical distribution are unknown. Specificity of the used biotinylated peptides was analyzed using an in vitro assay. Isoform-specific TG activity was evaluated in in vitro and in situ studies, using brain extracts and native brain tissue obtained from rodents. Our method allowed us to reveal in vitro and in situ TG-isoform-dependent enzymatic activity in brain extracts and tissue of rats and mice, with a specific focus on TG6. In situ activity of this isoform varied between BACHD mice in comparison to their wt controls. TG isozyme specific activity can be detected by isoform-specific biotinylated peptides in brain tissue sections of rodents to reveal differences in the anatomical and/or subcellular distribution of TG activity. Our findings yield the basis for a broader application of this method for the screening of pathological expression and activity of TGs in a variety of animal models of human diseases, as in the case of neurodegenerative conditions such as Huntington's, Parkinson's and Alzheimer's, where protein modification is involved as a key mechanism of disease progression. PMID- 26616343 TI - Physical activity advice could become part of routine care for colorectal cancer survivors. PMID- 26616342 TI - In quest for method of insulin resistance assessment in everyday clinical practice-Insulin resistance indices. AB - Insulin resistance (IR) a state of decreased sensitivity of target tissues to insulin is suspected usually in obese so can be overlooked in normal weight subjects thus it is important to find optimal method of IR assessment in clinical practice. AIMS: METHODS: HOMA, HOMA2, QUICKI, Matsuda index were calculated using data obtained from medical history of 130 female subjects - patients of the Department of Endocrinology and Metabolic Diseases, in whom oral glucose tolerance test (OGTT) with parallel insulin concentrations assessment was performed. RESULTS: IR correlated positively with body mass index (BMI) in the entire study group, regardless which of four analyzed IR indices was used. Insulin resistance occurred in the obese as well as in normal weight and underweight subjects. The incidences of IR in the study group varied, depending upon chosen method and adopted cut-off values. CONCLUSIONS: The need for quantitative assessment of IR in clinical practice is apparent. Proper selection of the best method of IR assessment remains a problem. HOMA appears the method of first choice for clinical use. There is an urgent need to establish universal or, at least, national standard cut-off values for IR, to introduce IR assessment in clinical practice. PMID- 26616341 TI - Influence of maternal care on the developing brain: Mechanisms, temporal dynamics and sensitive periods. AB - Variation in maternal care can lead to divergent developmental trajectories in offspring with implications for neuroendocrine function and behavioral phenotypes. Study of the long-term outcomes associated with mother-infant interactions suggests complex mechanisms linking the experience of variation in maternal care and these neurobiological consequences. Through integration of genetic, molecular, cellular, neuroanatomical, and neuroendocrine approaches, significant advances in our understanding of these complex pathways have been achieved. In this review, we will consider the impact of maternal care on male and female offspring development with a particular focus on the issues of timing and mechanism. Identifying the period of sensitivity to maternal care and the temporal dynamics of the molecular and neuroendocrine changes that are a consequence of maternal care represents a critical step in the study of mechanism. PMID- 26616344 TI - Model-based total evidence phylogeny of Neotropical electric knifefishes (Teleostei, Gymnotiformes). AB - This study provides the most comprehensive Model-Based Total Evidence (MBTE) phylogenetic analyses of the clade Gymnotiformes to date, reappraising relationships using a dataset comprised of six genes (5277bp) and 223 morphological characters, and an ingroup taxon sample including 120 of 212 valid species representing 34 of the 35 extant genera. Our MBTE analyses indicate the two main gymnotiform clades are Gymnotidae and Sternopygoidei, the latter comprised of Rhamphichthyoidea (Rhamphichthyidae+Hypopomidae) and Sinusoidea (Sternopygidae+Apteronotidae). Within Gymnotidae, Electrophorus and Gymnotus are sister taxa, and Gymnotus includes the following six clades: (i) G. pantherinus clade, (ii) G. coatesi clade, (iii) G. anguillaris clade, (iv) G. tigre clade, (v) G. cylindricus clade, and (vi) G. carapo clade. Within Rhamphichthyoidea, Steatogenae (Steatogenys+Hypopygus) is a member of Rhamphichthyidae, and Hypopomidae includes the following clades: (i) Akawaio, (ii) Hypopomus, (iii) Microsternarchini, and (iv) Brachyhypopomus. Within Sternopygidae, Sternopygus and Eigenmanninae are sister groups, Rhabdolichops is the sister to other Eigenmanninae, Archolaemus+Distocyclus is the sister to Eigenmannia, and Japigny is nested within Eigenmannia. Within Apteronotidae, Sternarchorhamphinae (Sternarchorhamphus+Orthosternarchus) is the sister to Apteronotinae, Adontosternarchus is the sister group to other Apteronotinae, Sternarchorhynchini (Sternarchorhynchus+Platyurosternarchus) is the sister to Navajini, and species assigned to Apteronotus are members of two separate clades: (i) A. sensu stricto in the Apteronotini, and (ii) the "A." bonapartii clade in the Navajini. PMID- 26616345 TI - Structural, electronic, magnetic and chemical properties of B-, C- and N-doped MgO(001) surfaces. AB - Doping of simple oxide materials can give rise to new exciting physical and chemical properties and open new perspectives for a variety of possible applications. Here we use density functional theory calculations to investigate the B-, C- and N-doped MgO(001) surfaces. We have found that the investigated dopants induce magnetization of the system amounting to 3, 2 and 1 MUB for B, C and N, respectively. The dopants are found to be in the X(2-) state and tend to segregate to the surface. These impurity sites also present the centers of altered chemical reactivity. We probe the chemisorption properties of the doped MgO(001) surfaces with the CO molecule and atomic O. The adsorption of CO is much stronger on B- and C-doped MgO(001) compared to pure MgO(001) as the impurity sites serve as potent electron donors. The situation is similar to the case of atomic oxygen, for which we find the adsorption energy of -8.78 eV on B-doped MgO(001). The surface reactivity changes locally around the dopant atom, which is mainly restricted to its first coordination shell. The presented results suggest doped MgO as a versatile multifunctional material with possible use as an adsorbent or a catalyst. PMID- 26616346 TI - The impact of primary healthcare reform on equity of utilization of services in the province of Quebec: a 2003-2010 follow-up. AB - INTRODUCTION: In 2003, the Quebec government made important changes in its primary healthcare (PHC) system. This reform included the creation of new models of PHC, Family Medicine Groups (e.g. multidisciplinary health teams with extended opening hours and enrolment of patients) and Network Clinics (clinics providing access to investigation and specialist services). Considering that equity is one of the guiding principles of the Quebec health system, our objectives are to assess the impact of the PHC reform on equity by examining the association between socio-economic status (SES) and utilization of healthcare services between 2003 and 2010; and to determine how the organizational model of PHC facilities impacts utilization of services according to SES. METHODS: We held population surveys in 2005 (n = 9206) and 2010 (n = 9180) in the two most populated regions of Quebec province, relating to utilization and experience of care during the preceding two years, as well as organizational surveys of all PHC facilities. We performed multiple logistical regression analyses comparing levels of SES for different utilization variables, controlling for morbidity and perceived health; we repeated the analyses, this time including type of PHC facility (older vs newer models). RESULTS: Compared with the lowest SES, highest SES is associated with less emergency room visits (OR 0.80) and higher likelihood of at least one visit to a PHC facility (OR 2.17), but lower likelihood of frequent visits to PHC (OR 0.69), and higher affiliation to a family doctor (OR 2.04). Differences remained stable between the 2005 and 2010 samples except for likelihood of visit to PHC source which deteriorated for the lowest SES. Greater improvement in affiliation to family doctor was seen for the lowest SES in older models of PHC organizations, but a deterioration was seen for that same group in newer models. CONCLUSIONS: Differences favoring the rich in affiliation to family doctor and likelihood of visit to PHC facility likely represent inequities in access to PHC which remained stable or deteriorated after the reform. New models of PHC organizations do not appear to have improved equity. We believe that an equity-focused approach is needed in order to address persisting inequities. PMID- 26616347 TI - Haemoproteus tartakovskyi (Haemoproteidae): Complete sporogony in Culicoides nubeculosus (Ceratopogonidae), with implications for avian haemoproteid experimental research. AB - Numerous recent studies have addressed the molecular characterization, distribution and genetic diversity of Haemoproteus spp. (Haemoproteidae). Some species of these blood parasites cause severe disease in birds, and heavy infections are often lethal in biting midges (Ceratopogonidae) and other blood sucking insects. However, information about the vectors of haemoproteids is scarce. This presents an obstacle for better understanding the mechanisms of host parasite interactions and the epidemiology of haemoproteosis. Here we investigated the sporogonic development of Haemoproteus tartakovskyi, a widespread bird parasite, in experimentally infected biting midges, Culicoides nubeculosus. These biting midges are widespread in the Europe. The insects were cultivated under laboratory conditions. Unfed females were allowed to take blood meals on wild caught siskins Carduelis spinus naturally infected with H. tartakovskyi (lineage hSISKIN1). Engorged females were maintained at 22-23 degrees C, dissected at intervals, and examined for sporogonic stages. Mature ookinetes of H. tartakovskyi were seen in the midgut content between 6 and 48 h post infection, oocysts were observed in the midgut wall 3-4 days post infection (dpi). Sporozoites were first reported in the salivary gland preparations 7 dpi. In accordance with microscopy data, polymerase chain reaction amplification and sequencing confirmed presence of the corresponding parasite lineage in experimentally infected biting midges. This study indicates that C. nubeculosus willingly takes blood meals on birds and is a vector of H. tartakovskyi. These biting midges are readily amenable to cultivation under laboratory conditions. Culicoides nubeculosus transmits Haemoproteus parasites infecting parrots, owls and siskins, birds belonging to different families and orders. Thus, this vector provides a convenient model for experimental research with avian haemoproteids. PMID- 26616348 TI - Photoelectrochemical evidence of nitrogen incorporation during anodizing sputtering--deposited Al-Ta alloys. AB - Anodic films were grown to 20 V on sputtering-deposited Al-Ta alloys in ammonium biborate and borate buffer solutions. According to glow discharge optical emission spectroscopy, anodizing in ammonium containing solution leads to the formation of N containing anodic layers. Impedance measurements did not evidence significant differences between the dielectric properties of the anodic films as a function of the anodizing electrolyte. Photoelectrochemical investigation allowed evidencing that N incorporation induces a red-shift in the light absorption threshold of the films due to the formation of allowed localized states inside their mobility gap. The estimated Fowler threshold for the internal photoemission processes of electrons resulted to be independent of the anodizing electrolyte confirming that N incorporation does not appreciably affect the density of states distribution close to the conduction band mobility edge. The transport of photogenerated carriers has been rationalized according to the Pai Enck model of geminate recombination. PMID- 26616350 TI - Risk factors for the progression of periodontal disease in a Greek adult population. AB - AIM: The purpose of the present study was to investigate the progression risk factors of periodontal disease by individual characteristics at baseline in a Greek adult population. METHODS: The study sample consisted of 854 individuals. All participants were clinically examined and answered questions regarding sex, smoking status, socioeconomic status, low educational level, frequency of dental follow up, and oral hygiene habits. Serum levels of disease markers were investigated, and attachment levels were clinically recorded. For the assessment of periodontal disease progression, additional clinical attachment loss (CAL) was used if one or more sites showed a 3 mm or more increase in probing attachment level over a 2-year period. Statistical analysis was performed by using a modified multiple Poisson's analysis model. RESULTS: A total of 74% of the participants exhibited additional CAL over a 2-year period. Significant associations were observed between additional CAL and smoking (relative risk [RR] = 0.78, 95% confidence level [CI] = 0.65-0.92), attachment level of 5 mm or more at baseline (RR = 0.89, 95% CI = 0.75-1.05), educational level (RR = 0.90, 95% CI = 0.76-1.07), socioeconomic status (RR = 0.86, 95% CI = 0.59-1.14), and irregular dental follow up (RR = 1.23, 95% CI = 1.04-1.45). CONCLUSIONS: Smoking, baseline attachment level of 5 mm or more, low educational level, low socioeconomic status, and irregular dental follow up could be considered risk factors for further CAL. PMID- 26616349 TI - Differential effects of sex in a West African cohort of HIV-1, HIV-2 and HIV-1/2 dually infected patients: men are worse off. AB - OBJECTIVES: Several studies have reported conflicting effects of sex on HIV-1 infection. We describe differences in baseline characteristics and assess the impact of sex on HIV progression among patients at a clinic with many HIV-2 and HIV-1/2 dually infected patients. METHODS: This study utilised a retrospective cohort of treatment-naive adults at the largest HIV clinic in Guinea-Bissau from 6 June 2005 to 1 December 2013. Baseline characteristics were assessed and the patients followed until death, transfer, loss to follow-up, or 1 June 2014. We estimated the time from the first clinic visit until initiation of ART, death or loss to follow-up using Cox proportional hazard models. RESULTS: A total of 5694 patients were included in the study, 3702 women (65%) and 1992 men (35%). Women were more likely than men to be infected with HIV-2 (19% vs. 15%, P < 0.01) or dually infected with HIV-1/2 (11% vs. 9%, P = 0.02). For all HIV types, women were younger (median 35 vs. 40 years), less likely to have schooling (55% vs. 77%) or to be married (46% vs. 67%), and had higher baseline CD4 cell counts (median 214 vs. 178 cells/MUl). Men had a higher age-adjusted mortality rate (hazard rate ratio (HRR) 1.29, 95% confidence interval (CI) 1.09-1.52) and were more often lost to follow-up (HRR 1.27, 95% CI 1.17-1.39). CONCLUSION: Significant differences exist between HIV-infected men and women regardless of HIV type. Men seek treatment at a later stage and, despite better socio-economic status, have higher mortality and loss to follow-up than women. PMID- 26616351 TI - A Stochastic Algorithm for the Isobaric-Isothermal Ensemble with Ewald Summations for All Long Range Forces. AB - We present an algorithm termed COMPEL (COnstant Molecular Pressure with Ewald sum for Long range forces) to conduct simulations in the NPT ensemble. The algorithm combines novel features recently proposed in the literature to obtain a highly efficient and accurate numerical integrator. COMPEL exploits the concepts of molecular pressure, rapid stochastic relaxation to equilibrium, exact calculation of the contribution to the pressure of long-range nonbonded forces with Ewald summation, and the use of Trotter expansion to generate a robust, highly stable, symmetric, and accurate algorithm. Explicit implementation in the MOIL program and illustrative numerical examples are discussed. PMID- 26616352 TI - Adaptation of Skyline for Targeted Lipidomics. AB - In response to the urgent need for analysis software that is capable of handling data from targeted high-throughput lipidomics experiments, we here present a systematic workflow for the straightforward method design and analysis of selected reaction monitoring data in lipidomics based on lipid building blocks. Skyline is a powerful software primarily designed for proteomics applications where it is widely used. We adapted this tool to a "Plug and Play" system for lipid research. This extension offers the unique capability to assemble targeted mass spectrometry methods for complex lipids easily by making use of building blocks. With simple yet tailored modifications, targeted methods to analyze main lipid classes such as glycerophospholipids, sphingolipids, glycerolipids, cholesteryl-esters, and cholesterol can be quickly introduced into Skyline for easy application by end users without distinct bioinformatics skills. To illustrate the benefits of our novel strategy, we used Skyline to quantify sphingolipids in mesenchymal stem cells. We demonstrate a simple method building procedure for sphingolipids screening, collision energy optimization, and absolute quantification of sphingolipids. In total, 72 sphingolipids were identified and absolutely quantified at the fatty acid scan species level by utilizing Skyline for data interpretation and visualization. PMID- 26616353 TI - Sofosbuvir-based regimens in clinical practice achieve SVR rates closer to clinical trials: results from ERCHIVES. AB - BACKGROUND & AIMS: Sofosbuvir is widely prescribed for treatment of HCV infection. We compared the sustained virologic response rates (SVR12) and the haematologic toxicity of various sofosbuvir-based regimens in routine clinical practice. METHODS: We used ERCHIVES (Electronically Retrieved Cohort of HCV infected Veterans) to identify HCV-infected persons initiated on sofosbuvir-based regimens. Treatment duration and regimen were defined as per labelling guidelines. We excluded persons with HIV, positive hepatitis-B surface antigen, hepatocellular carcinoma and missing HCV RNA. RESULTS: Among 4257 sofosbuvir treated persons, sofosbuvir/simeprevir (30%), sofosbuvir/ledipasvir (29%) and sofosbuvir/ribavirin (23%) were the most common combinations prescribed. The mean age (SD) was 60.22 (6.3) years, 96% were male, 22.4% were black, 37.2% had cirrhosis, 29.7% were treatment-experienced; baseline mean HCV RNA was 6.73 log lIU/ml. Comorbidities included: 40.2% alcohol abuse or dependence, 39.7% drug abuse or dependence, 25.1% diabetes and 14.4% stage 3-5 chronic kidney disease. Overall, 86.7% completed a full course of treatment. Overall, SVR12 rates were 88 98% in the sofosbuvir/simeprevir group and 93-98% in the sofosbuvir/ledipasvir group and did not vary based on previous treatment history or cirrhosis at baseline. For genotype 2/3 patients treated with sofosbuvir/ribavirin, SVR12 rates ranged from 69 to 87% with lowest rates in treatment-experienced cirrhotics. For the sofosbuvir/simeprevir and sofosbuvir/ledipasvir groups, grade3/4 haematologic adverse events were uncommon; these trended back close to baseline values after completion of treatment. CONCLUSIONS: Sofosbuvir-based regimens in clinical practice are associated with SVR rates comparable to those seen in clinical trials and low rates of grade 3/4 haematological adverse events. PMID- 26616354 TI - Anti-inflammatory and anti-chemotactic effects of dietary flaxseed oil on CD8(+) T cell/adipocyte-mediated cross-talk. AB - SCOPE: CD8(+) T cell/adipocyte paracrine interactions represent a critical step in the development of the obese inflammatory phenotype that is disrupted by long chain n-3 PUFA. Our objective was to determine the effect of flaxseed-derived n-3 PUFA (alpha-linolenic acid) on these paracrine interactions. METHODS AND RESULTS: C57BL/6 mice were fed 3.5% flaxseed oil (FX) + 3.5% corn oil diet w/w or an isocaloric 7% corn oil w/w control diet (CON) for 3 wk. 3T3-L1 adipocytes and purified primary splenic CD8(+) T cells were cocultured at an obese cellular ratio (10% CD8(+) T cells) and LPS-stimulated (10 ng/mL mimicking obese circulating endotoxin levels) for 24 h. FX cocultures reduced (i) secreted IL-6, tumor necrosis factor alpha (TNF-alpha), macrophage chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1alpha (MIP-1alpha), and RANTES (regulated on activation, normal T cell expressed and secreted) levels; (ii) activation of inflammatory transcription factors NFkappaB (nuclear factor kappa light-chain-enhancer of activated B cell) p65 and signal transducer and activator of transcription-3 (STAT3); and (iii) RAW264.7 macrophage chemotaxis versus CON (p <= 0.05). Coculture of pre-inflamed adipocytes (10 ng/mL LPS, 24 h prior to CD8(+) T-cell addition) resulted in reduced secretion of IL-6, IL-1beta, MCP-1, MCP-3, MIP-1beta, and RANTES in FX cocultures versus CON (p <= 0.05). CONCLUSION: FX exerts an anti-chemotactic and anti-inflammatory effect on CD8(+) T cell/adipocyte paracrine interactions (cross-talk), which has the potential to mitigate macrophage chemotaxis which drives components of the obese phenotype. PMID- 26616355 TI - [Training of future instructors to teach obstetrics and gynecology by simulation in Phnom Penh, Cambodia]. PMID- 26616356 TI - Comparison of three transposons for the generation of highly productive recombinant CHO cell pools and cell lines. AB - Several naturally occurring vertebrate transposable elements have been genetically modified to enable the transposition of recombinant genes in mammalian cells. We compared three transposons-piggyBac, Tol2, and Sleeping Beauty-for their ability to generate cell pools (polyclonal cultures of recombinant cells) and clonal cell lines for the large-scale production of recombinant proteins using Chinese hamster ovary cells (CHO-DG44) as the host. Transfection with each of the dual-vector transposon systems resulted in cell pools with volumetric yields of tumor necrosis factor receptor-Fc fusion protein (TNFR:Fc) that were about ninefold higher than those from cell pools generated by conventional plasmid transfection. On average, the cell pools had 10-12 integrated copies of the transgene per cell. In the absence of selection, the volumetric productivity of the cell pools decreased by 50% over a 2-month cultivation period and then remained constant. The average volumetric TNFR:Fc productivity of clonal cell lines recovered from cell pools was about 25 times higher than that of cell lines generated by conventional transfection. In 14-day fed-batch cultures, TNFR:Fc levels up to 900 mg/L were obtained from polyclonal cell pools and up to 1.5 g/L from clonal cell lines using any of the three transposons. Biotechnol. Bioeng. 2016;113: 1234-1243. (c) 2015 Wiley Periodicals, Inc. PMID- 26616357 TI - Measuring participation when combining subjective and objective variables: the development of the Ghent Participation Scale (GPS). AB - BACKGROUND: The ICF reflects a bio-psycho-social paradigm and is increasingly used in outpatients rehabilitation settings. The component of participation is in the ICF the manifestation of a bio-psycho-social reasoning. Different participation measures have already been developed and were operationalized through objective and/or a limited set of subjective variables, but keeping them as separate concepts. There is still need for a generic participation instrument including both objective and all relevant subjective variables resulting in one participation score. AIM: To develop a generic participation measure based on objective and subjective aspects and leading to one final score; the Ghent Participation Scale (GPS). Additionally it was the aim to explore whether the GPS has a good internal validity by means of factorial validity and homogeneity and whether the GPS is feasible and interpretable. DESIGN: Cross-sectional study. SETTING: Outpatient rehabilitation centre. POPULATION: One hundred thirty former rehabilitation outpatients with various conditions. METHODS: Item derivation for the GPS was based on qualitative research. The participants administered the GPS in the third week after discharge from the Ghent University Hospital. An exploratory factor analysis was performed to determine underlying dimensions. Statistical coherence was expressed in both item-total correlations and in Cronbach's alpha coefficient. RESULTS: An exploratory factor analysis showed 3 underlying dimensions within the GPS: 1) performing activities according to preferred choices and wishes; 2) social appreciation and acceptance by performing activities; and 3) the need to delegate activities explaining 55.8% of the total variance. The results show a good to strong homogeneity (item-total ranged from 0.58 to 0.80) and a strong internal consistency (Cronbach's alpha ranged from 0.76-0.92). CONCLUSIONS: The results of this preliminary validation study suggest that the GPS appears to be a valid measure to rate participation. CLINICAL REHABILITATION IMPACT: Further research and more and more powerful psychometric models such as Rash Analysis or Item Response models are needed to establish a psychometrically sound instrument. PMID- 26616358 TI - Recovery of personal neglect. AB - BACKGROUND: Extrapersonal unilateral spatial neglect after stroke is associated to a poor rehabilitation outcome. Minor attention has been paid to the recovery of personal neglect, to its relationship with the recovery of extrapersonal neglect and of independency in activities of daily living. AIM: The present study aims at evaluating whether there is an association between recovery of extrapersonal and personal neglect. The secondary aim was to investigate if personal neglect may affect the effectiveness of neurorehabilitation in patients with subacute stroke. DESIGN: Observational study. SETTING: Neurorehabilitation Hospital in Rome, Italy, inpatients. POPULATION: A sample of 49 patients with unilateral spatial neglect resulting from right ischemic cerebral infarction was enrolled in this study, divided into three subgroups according to the presence and the degree of personal neglect, and evaluated pre and postneurorehabilitation. METHODS: Personal neglect was evaluated using Zoccolotti and Judica's Scale, extrapersonal neglect using Letter Cancellation Test, Barrage Test, Sentence Reading Test and Wundt-Jastrow Area Illusion Test. Barthel Index (BI), Rivermead Mobility Index, and Canadian Neurological Scale were also administered. RESULTS: Results showed the following: 1) recovery of personal neglect was not significantly correlated with that of extrapersonal neglect, despite both the disorders were ameliorated after a "non-specific" rehabilitation treatment; 2) personal neglect per se was not an additional negative prognostic factor in the rehabilitation findings. CONCLUSIONS: Our results suggested that the recoveries of the two types of neglect are independent from each other, and that the presence of personal neglect does not imply significant additional problems to the functional outcomes. CLINICAL REHABILITATION IMPACT: Our study highlighted the need of novel tools to assess the presence and to improve the recovery of personal neglect. PMID- 26616360 TI - Comment on: 'Efficacy of topical tacrolimus for oral lichen planus: real-life experience in a retrospective cohort of patients with a review of the literature' by Ribero et al. (2015). PMID- 26616359 TI - Pain severity and mobility one year after spinal cord injury: a multicenter, cross-sectional study. AB - BACKGROUND: Following a spinal cord injury, patients are often burdened by chronic pain. Preliminary research points to activation of the motor cortex through increased mobility as a potential means of alleviating postinjury chronic pain. AIM: The aim of this study was to assess the relationship between pain severity and mobility among patients who have sustained a traumatic spinal cord injury while controlling for clinically-relevant covariates. DESIGN: A multi center, cross-sectional study. SETTING: The SCIMS is composed of 14 centers, all located in the United States and funded by the National Institute on Disability and Rehabilitation Research (NIDRR). POPULATION: The study cohort included 1980 patients who completed the one-year SCIMS follow-up assessment between October 2000- December 2013. METHODS: A multi-center, cross-sectional study was performed to assess the impact of mobility on self-reported pain using information from 1980 subjects who sustained a traumatic spinal cord injury and completed a year one follow-up interview between October 2000 and December 2013. Patient information was acquired using the Spinal Cord Injury National Database, compiled by the affiliated Spinal Cord Injury Model Systems. Analyses included a multivariable linear regression of patients' self-reported pain scores on mobility, quantified using the CHART-SF mobility total score, and other clinically relevant covariates. RESULTS: After controlling for potential confounders, a significant quadratic relationship between mobility and patients' self-reported pain was observed (P=0.016). Furthermore, female gender, "unemployed" occupational status, paraplegia, and the presence of depressive symptoms were associated with significantly higher pain scores (P<0.02 for all variables). Statistically significant quadratic associations between pain scores and age at injury, life satisfaction total score, and the CHART-SF occupational total subscale were also observed (P<=0.03 for all variables). CONCLUSIONS: Among patients with moderate to high levels of mobility, pain scores decreased with increasing mobility. CLINICAL REHABILITATION IMPACT: Enhancing a patient's physical activity by increasing his or her mobility may reduce neuropathic pain if begun shortly after a spinal cord injury. PMID- 26616361 TI - Sociodemographic correlates of smoking in pregnancy and antenatal-care attendance in Indigenous and non-Indigenous women in South Australia. AB - Smoking in pregnancy is a key health issue in Australia, particularly among Indigenous women. However, few studies have examined the sociodemographic factors associated with smoking in pregnancy or the predictors of antenatal-care attendance among Indigenous and non-Indigenous Australian women who smoke. Data from the South Australian perinatal statistics collection of all births from 2000 2010 (n=197538) were analysed separately by Indigenous status to determine the sociodemographic factors associated with smoking in pregnancy and antenatal-care attendance by women who smoke. For Indigenous and non-Indigenous women, smoking in pregnancy was significantly independently associated with socioeconomic disadvantage, residing in regional or remote areas, increased parity, unemployment, being a public patient and attending fewer antenatal care visits. Smoking in pregnancy was associated with younger age and not being partnered only for non-Indigenous women. For Indigenous and non-Indigenous pregnant women who smoked, antenatal-care attendance was lower among women who were of younger age, higher parity, unemployed and not partnered. Differences in attendance within sociodemographic factors were greater for Indigenous women. Therefore, while sociodemographic correlates of smoking in pregnancy and antenatal-care attendance are largely similar for Indigenous and non-Indigenous women, tailored cessation and antenatal-care programs that reflect the differences in sociodemographic groups most at risk may be beneficial. PMID- 26616362 TI - The role of self-regulation in health and illness. PMID- 26616363 TI - Psychosocial factors significantly predict driving self-regulation in Australian older adults. AB - AIMS: This study aimed to investigate: (i) whether attitudes and beliefs about driving predict older adults' driving self-regulation, and how much variance in self-regulation can be explained by these factors; and (ii) if driving confidence is controlled, whether attitudes and beliefs remain significant independent predictors of driving self-regulation. METHOD: The present study examined the psychosocial factors that underlie driving self-regulation in 277 older adults within Australia. Participants completed standardised questionnaires about their driving, attitudes, belief and use of driving self-regulation. RESULTS: Driving confidence, affective and instrumental attitude, and perceived behavioural control were all significant predictors of driving self-regulation. The combination of these factors accounted for 56% of the variance in driving self regulation. CONCLUSION: Driving self-regulation is a complex behaviour influenced by a wide range of psychosocial factors. Improved understanding of these factors could inform strategies to improve older driver safety and influence the advice that people receive. PMID- 26616364 TI - Prediction of Spin Orientations in Terms of HOMO-LUMO Interactions Using Spin Orbit Coupling as Perturbation. AB - For most chemists and physicists, electron spin is merely a means needed to satisfy the Pauli principle in electronic structure description. However, the absolute orientations of spins in coordinate space can be crucial in understanding the magnetic properties of materials with unpaired electrons. At low temperature, the spins of a magnetic solid may undergo long-range magnetic ordering, which allows one to determine the directions and magnitudes of spin moments by neutron diffraction refinements. The preferred spin orientation of a magnetic ion can be predicted on the basis of density functional theory (DFT) calculations including electron correlation and spin-orbit coupling (SOC). However, most chemists and physicists are unaware of how the observed and/or calculated spin orientations are related to the local electronic structures of the magnetic ions. This is true even for most crystallographers who determine the directions and magnitudes of spin moments because, for them, they are merely the parameters needed for the diffraction refinements. The objective of this article is to provide a conceptual framework of thinking about and predicting the preferred spin orientation of a magnetic ion by examining the relationship between the spin orientation and the local electronic structure of the ion. In general, a magnetic ion M (i.e., an ion possessing unpaired spins) in a solid or a molecule is surrounded with main-group ligand atoms L to form an MLn polyhedron, where n is typically 4-6, and the d states of MLn are split because the antibonding interactions of the metal d orbitals with the p orbitals of the surrounding ligands L depend on the symmetries of the orbitals involved.1 The magnetic ion M of MLn has a certain preferred spin direction because its split d states interact among themselves under SOC.2,3 The preferred spin direction can be readily predicted on the basis of perturbation theory in which the SOC is taken as perturbation and the split d states as unperturbed states by inspecting the magnetic quantum numbers of its d orbitals present in the HOMO and LUMO of the MLn polyhedron. This is quite analogous to how chemists predict whether a chemical reaction is symmetry-allowed or symmetry-forbidden in terms of the HOMO LUMO interactions by simply inspecting the symmetries of the frontier orbitals.4,5 Experimentally, the determination of the preferred spin orientations of magnetic ions requires a sophisticated level of experiments, for example, neutron diffraction measurements for magnetic solids with an ordered spin state at a very low temperature. Theoretically, it requires an elaborate level of electronic structure calculations, namely, DFT calculations including electron correlation and SOC. We show that the outcomes of such intricate experimental measurements and theoretical calculations can be predicted by a simple perturbation theory analysis. PMID- 26616365 TI - Low serum dehydroepiandrosterone examined by liquid chromatography-tandem mass spectrometry correlates with poor prognosis in hormone-naive prostate cancer. AB - BACKGROUND: There is no consensus on blood adrenal androgen concentrations in men with different stages and pathological grades of prostate cancer. In this study, dehydroepiandrosterone (DHEA) concentrations in blood were examined by ultrasensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS). We analyzed the correlation between DHEA concentrations in blood and clinicopathological findings of prostate cancer. METHODS: We analyzed 196 men (mean age 70 years) with prostate cancer. The patients underwent systematic needle biopsy, and peripheral blood sampling was conducted for measurement of DHEA. DHEA concentrations in blood were determined using LC-MS/MS method. Patient age, serum prostate-specific antigen, prostate volume measured by ultrasound, and DHEA levels in blood were compared with Gleason score and clinical stage by multivariate analyses. RESULTS: Median value of PSA and prostate volume were 11.5 ng/ml and 27.7 ml, respectively. Median concentration of DHEA in blood was 1,506.4 pg/ml. There was no correlation between serum DHEA and clinical variables such as age, serum PSA, and prostate volume. In multivariate analysis, low serum DHEA levels in prostate cancer patients were significantly related to high Gleason score and advanced clinical stage. Serum PSA levels in prostate cancer patients were also significantly associated with high Gleason score and advanced clinical stage. High serum PSA and low serum DHEA levels were significantly associated with poor prognosis factors in men with hormone-naive prostate cancer. CONCLUSIONS: DHEA concentrations in blood were examined by newly developed ultrasensitive LC-MS/MS. We confirmed that low serum DHEA levels in prostate cancer patients were related to high Gleason score and advanced clinical stage. These results suggest that serum DHEA level may be a useful prognostic factor in prostate cancer patients. PMID- 26616366 TI - Mass spectrometry based translational proteomics for biomarker discovery and application in colorectal cancer. AB - Colorectal cancer (CRC) is a leading cause of cancer-related death in the world. Clinically, early detection of the disease is the most effective approach to tackle this tough challenge. Discovery and development of reliable and effective diagnostic tools for the assessment of prognosis and prediction of response to drug therapy are urgently needed for personalized therapies and better treatment outcomes. Among many ongoing efforts in search for potential CRC biomarkers, MS based translational proteomics provides a unique opportunity for the discovery and application of protein biomarkers toward better CRC early detection and treatment. This review updates most recent studies that use preclinical models and clinical materials for the identification of CRC-related protein markers. Some new advances in the development of CRC protein markers such as CRC stem cell related protein markers, SRM/MRM-MS and MS cytometry approaches are also discussed in order to address future directions and challenges from bench translational research to bedside clinical application of CRC biomarkers. PMID- 26616367 TI - The Nitric Oxide Prodrug JS-K Induces Ca(2+)-Mediated Apoptosis in Human Hepatocellular Carcinoma HepG2 Cells. AB - Hepatocellular carcinoma is one of the most common and deadly forms of human malignancies. JS-K, O(2)-(2, 4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazin-1 yl] diazen-1-ium-1, 2-diolate, has the ability to induce apoptosis of tumor cell lines. In the present study, JS-K inhibited the proliferation of HepG2 cells in a time- and concentration-dependent manner and significantly induced apoptosis. JS K enhanced the ratio of Bax-to-Bcl-2, released of cytochrome c (Cyt c) from mitochondria and the activated caspase-9/3. JS-K caused an increasing cytosolic Ca(2+) and the loss of mitochondrial membrane potential. Carboxy-PTIO (a NO scavenger) and BAPTA-AM (an intracellular Ca(2+) chelator) significantly blocked an increasing cytosolic Ca(2+) in JS-K-induced HepG2 cells apoptosis, especially Carboxy-PTIO. Meanwhile, Carboxy-PTIO and BAPTA-AM treatment both attenuate JS-K induced apoptosis through upregulation of Bcl-2, downregulation of Bax, reduction of Cyt c release from mitochondria to cytoplasm and inactivation of caspase-9/3. In summary, JS-K induced HepG2 cells apoptosis via Ca(2+)/caspase-3-mediated mitochondrial pathway. PMID- 26616368 TI - Potential cost-effectiveness of supervised injection facilities in Toronto and Ottawa, Canada. AB - BACKGROUND AND AIMS: Supervised injection facilities (legally sanctioned spaces for supervised consumption of illicitly obtained drugs) are controversial public health interventions. We determined the optimal number of facilities in two Canadian cities using health economic methods. DESIGN: Dynamic compartmental model of HIV and hepatitis C transmission through sexual contact and sharing of drug use equipment. SETTING: Toronto and Ottawa, Canada. PARTICIPANTS: Simulated population of each city. INTERVENTIONS: Zero to five supervised injection facilities. MEASUREMENTS: Direct health-care costs and quality-adjusted life years (QALYs) over 20 years, discounted at 5% per year; incremental cost effectiveness ratios. FINDINGS: In Toronto, one facility cost $4.1 million and resulted in a gain of 385 QALYs over 20 years, for an incremental cost effectiveness ratio (ICER) of $10,763 per QALY [95% credible interval (95CrI): cost-saving to $278,311]. Establishing one facility in Ottawa had an ICER of $6127 per QALY (95CrI: cost-saving to $179,272). At a $50,000 per QALY threshold, three facilities would be cost-effective in Toronto and two in Ottawa. The probability that establishing three, four, or five facilities in Toronto was cost effective was 17, 21, and 41%, respectively. Establishing one, two, or three facilities in Ottawa was cost-effective with 13, 35, and 41% probability, respectively. Establishing no facility was unlikely to be the most cost-effective option (14% in Toronto and 10% in Ottawa). In both cities, results were robust if the reduction in needle-sharing among clients of the facilities was at least 50% and fixed operating costs were less than $2.0 million. CONCLUSIONS: Using a $50,000 per quality-adjusted life-years threshold for cost-effectiveness, it is likely to be cost-effective to establish at least three legally sanctioned spaces for supervised injection of illicitly obtained drugs in Toronto, Canada and two in Ottawa, Canada. PMID- 26616369 TI - Metabolic response to subacute and subchronic iron overload in a rat model. AB - One of the common causes of iron overload is excessive iron intake in cases of iron-poor anemia, where iron saccharate complex (ISC) is routinely used to optimize erythropoiesis. However, non-standardized ISC administration could entail the risk of iron overload. To induce iron overload, Wistar rats were intraperitoneally injected with subacute (0.2 mg kg-1) and subchronic (0.1 mg kg 1) overdoses of ISC for 2 and 4 weeks, respectively. Iron status was displayed by an increase in transferrin saturation (up to 332%) and serum and liver iron burden (up to 19.3 MUmol L-1 and 13.2 MUmol g-1 wet tissue, respectively) together with a drop in total and unsaturated iron binding capacities "TIBC, UIBC" as surrogate markers of transferrin activity. Iron-induced leukocytosis (up to 140%), along with the decline in serum transferrin markers (up to 43%), respectively, mark positive and negative acute phase reactions. Chemical stress was demonstrated by a significant rise (p > 0.05) in indices of the hemogram (erythrocytes, hemoglobin, hematocrit, leukocytes) and stress metabolites [corticosterone (CORT) and lactate]. Yet, potential causes of the unexpected decline in serum activities of ALT, AST and LDH (p > 0.05) might include decreased hepatocellular enzyme production and/or inhibition or reduction of the enzyme activities. The current findings highlight the toxic role of elevated serum and liver iron in initiating erythropoiesis and acute phase reactions, modifying iron status and animal organ function, changing energy metabolism and bringing about accelerated glycolysis and impaired lactate clearance supposedly by decreasing anaerobic threshold and causing premature entering to the anaerobic system. PMID- 26616370 TI - Biological potential of marine macroalgae of the genus Cystoseira. AB - In the present investigation the acetone extracts of three macroalgae, Cystoseira amentacea, Cystoseira barbata and Cystoseira compressa, were tested for antioxidant, antimicrobial and cytotoxic potential. As a result of the study, C. amentacea extract had more potent free radical scavenging activity (IC50 = 409.81 MUg/mL) than C. barbata and C. compressa extracts. For reducing power, measured values of absorbance varied from 0.0352 to 0.8873. The IC50 values for superoxide anion scavenging activity for different extracts were 521.45-976.62 MUg/mL. Total phenol and flavonoid contents in extracts were 39.96-81.28 MUg PE/mg and 20.85 64.58 MUg RE/mg respectively. Further, all three Cystoseira species exhibited a similar antimicrobial activity. The lowest MIC value (0.312 mg/mL) was shown in the extract obtained from C. compressa against Bacillus subtilis. Finally, extract of C. amentacea expressed the strongest cytotoxic activity toward tested cell lines with IC50 values ranging from 94.72 to 186.55 MUg/mL. Based on these results, it can be stated that the tested macroalgae can be used as potential natural antioxidants and antimicrobial and cytotoxic agents. PMID- 26616371 TI - Study of in vitro antimicrobial and antiproliferative activities of selected Saharan plants. AB - The aim of the present study was the evaluation of the antimicrobial and antiproliferative activities of selected Saharan species, which are applied in the traditional medicine but not studied thoroughly from chemical and pharmacological point of view. The studied plants, namely Anthyllis henoniana, Centropodia forskalii, Cornulaca monacantha, Ephedra alata var. alenda, Euphorbia guyoniana, Helianthemum confertum, Henophyton deserti, Moltkiopsis ciliata and Spartidium saharae were collected from remote areas of North Africa, especially from the Tunisian region of Sahara. After drying and applying the appropriate extraction methods, the plant extracts were tested in antimicrobial screening assay, performed on 19 Gram-positive and -negative strains of microbes. The inhibition zones produced by plant extracts were determined by disc-diffusion method. Remarkable antibacterial activities were exhibited by extracts of Ephedra alata var. alenda and Helianthemum confertum against B. subtilis, M. catarrhalis and methicillin-resistant and non-resistant S. aureus. Minimum inhibitory concentrations of these two species were also determined. Antiproliferative effects of the extracts were evaluated against 4 human adherent cell lines (HeLa, A431, A2780 and MCF7). Notable cell growth inhibition was found for extract of Helianthemum confertum and Euphorbia guyoniana. Our results provided data for selection of some plant species for further detailed pharmacological and phytochemical examinations. PMID- 26616372 TI - In vitro biological activity of secondary metabolites from Seseli rigidum Waldst. et Kit. (Apiaceae). AB - The antioxidant, antimicrobial activity, total phenolic content and flavonoid concentration of Seseli rigidum Waldst. et Kit. were evaluated. Five different extracts of the aboveground plant parts were obtained by extraction with distilled water, methanol, acetone, ethyl acetate and petroleum ether. Total phenols were determined using the Folin-Ciocalteu's reagent, with the highest values obtained in the acetone extract (102.13 mg GAE/g). The concentration of flavonoids, determined by using a spectrophotometric method with aluminum chloride and expressed in terms of rutin equivalent, was also highest in the acetone extracts (291.58 mg RUE/g). The antioxidant activity was determined in vitro using DPPH reagent. The greatest antioxidant activity was expressed in the aqueous extract (46.15 MUg/ml). In vitro antimicrobial activities were determined using a microdilution analysis method; minimum inhibitory concentration (MIC) and minimum microbicidal concentration (MMC) were determined. Methanolic extract had the greatest influence on bacilli (MIC at 0.0391 mg/ml), but the best antimicrobial effect had acetone and ethyl acetate extracts considering their broad impact on bacteria. According to our research, S. rigidum can be regarded as promising candidate for natural plant source with high value of biological compounds. PMID- 26616373 TI - The role of Arabidopsis glutathione transferase F9 gene under oxidative stress in seedlings. AB - Arabidopsis thaliana contains 54 soluble glutathione transferases (GSTs, EC 2.5.1.18), which are thought to play major roles in oxidative stress responses, but little is known about the function of individual isoenzymes. The role of AtGST phi 9 (GSTF9) in the salt- and salicylic acid response was investigated using 2-week-old Atgstf9 and wild type (Wt) plants. Atgstf9 mutants accumulated more ascorbic acid (AsA) and glutathione (GSH) and had decreased glutathione peroxidase (GPOX) activity under control conditions. Treatment of 2-week-old seedlings with 10-7 M salicylic acid (SA) for 48 h resulted in elevated H2O2level and enhanced GST activity in Atgstf9 plants, 10-5 M SA treatment enhanced the malondialdehyde and dehydroascorbate contents compared to Wt. 50 and 150 mM NaCl increased the GST activity, AsA and GSH accumulation in Atgstf9 seedlings more pronounced than in Wt plants. We found that the Atgstf9 mutants had altered redox homeostasis under control and stress conditions, in which elevated AsA and GSH levels and modified GST and GPOX activities may play significant role. The half cell potential values calculated from the concentration of GSH and GSSG indicate that this GST isoenzyme has an important role in the salt stress response. PMID- 26616375 TI - Chitinase production by Bacillus subtilis ATCC 11774 and its effect on biocontrol of Rhizoctonia diseases of potato. AB - Stem canker and black scurf of potato, caused by Rhizoctonia solani, can be serious diseases causing an economically significant damage. Biocontrol activity of Bacillus subtilis ATCC 11774 against the Rhizoctonia diseases of potato was investigated in this study. Chitinase enzyme was optimally produced by B. subtilis under batch fermentation conditions similar to those of the potato growing soil. The maximum chitinase was obtained at initial pH 8 and 30 degrees C. In vitro, the lytic action of the B. subtilis chitinase was detected releasing 355 MUg GlcNAc ml-1 from the cell wall extract of R. solani and suggesting the presence of various chitinase enzymes in the bacterial filtrate. In dual culture test, the antagonistic behavior of B. subtilis resulted in the inhibition of the radial growth of R. solani by 48.1% after 4 days. Moreover, the extracted B. subtilis chitinase reduced the growth of R. solani by 42.3% when incorporated with the PDA plates. Under greenhouse conditions, application of a bacterial suspension of B. subtilis at 109 cell mL-1 significantly reduced the disease incidence of stem canker and black scurf to 22.3 and 30%, respectively. In addition, it significantly improved some biochemical parameters, growth and tubers yield. Our findings indicate two points; firstly, B. subtilis possesses a good biocontrol activity against Rhizoctonia diseases of potato, secondly, the harmonization and suitability of the soil conditions to the growth and activity of B. subtilis guaranteed a high controlling capacity against the target pathogen. PMID- 26616374 TI - Morphological and physiological changes in esterase and lipid peroxidation of two bean cultivars pre-soaked with potassium nitrate under salt stress. AB - Two broad bean cultivars (Vicia faba CV Nobaria3 and Vicia faba CV Sakha3) were obtained from Mallwi Agriculture Research Center, El Minia Governorate, Egypt. The seeds were divided into two groups, the first group soaked with distilled water, while the second group were soaked with 3 mM KNO3, respectively, for 4 hours. Seeds were sown and left to grow for 3 weeks then treated with different concentrations of NaCl (0.0, 40, 80, 120 and 160 mM) by top irrigation, then they left to grow further for 65 days from sowing. Plant samples were collected for some measurements: leaf area, plant height, root length, fresh and dry weight, photosynthetic pigments, carotenoids, soluble sugars, soluble proteins, total free amino acids, esterase enzyme, as well as MDA (malondialdehyde) content. Salinity reduced both fresh and dry weight in two broad bean cultivars, this reduction were more pronounced in Sakha3 than Nobaria3. Seed pre-soaking with KNO3resulted in enhancement of fresh and dry weight production in both cultivars especially at 40 mM NaCl. Photosynthetic pigments were substantially affected by salt treatment while the carotenoids were increased, seed pre-soaking with KNO3improved these components. The soluble sugars, amino acids as well as soluble proteins showed various responses with increasing salinity in the cultivars, seed pre-soaking with KNO3has improved these parameters to some extent. The shoots of two cultivars exhibited significant accumulation of MDA, compared to roots exposed to the highest salinity levels. Pre-soaking seeds with KNO3did not improve MDA in shoots but enhanced it in roots, however, in most cases still lower than the absolute control. The assessment of the esterase isozyme profiles on 7.5% native polyacrylamide gel revealed the presence of 13 isoforms in two faba bean plants in response to KNO3pre-soaking and treatments with different concentrations of NaCl. PMID- 26616376 TI - Characteristics and biodiversity of endophytic phosphorus- and potassium solubilizing bacteria in Moso Bamboo (Phyllostachys edulis). AB - Endophytic phosphorus- and potassium-solubilizing bacteria were screened from the root, rhizome, stem, and leaves of Moso Bamboo, and their diversity was analyzed using their 16S rDNA sequences. Twenty endophytic phosphorus and potassium solubilizing bacteria were screened from 82 bamboo plants, among which the CT-B09 2, WYS-A01-1 and JL-B06 had higher activities in decomposing organophosphates. The three species showed a decomposition diameter/colony diameter (D/d) of 5.05, 4.19 and 2.95, respectively, and a solubilizing activity of 81.77 mg/L, 77.85 mg/L and 63.69 mg/L, respectively. JL-B06, WYS-A01-1 and CT-B09-2 had higher activities in decomposing inorganic phosphorus, with a decomposition diameter/colony diameter (D/d) of 2.34, 2.12 and 1.82, respectively, and a solubilizing activity of 30.58 mg/L, 38.89 mg/L and 48.35 mg/L, respectively. CT B21, WYS-A03-1 and JL-B06 had higher activities in decomposing potassium, with a decomposition diameter/colony diameter (D/d) of 3.37, 4.84 and 4.33, respectively, and a solubilizing activity of 2.81 mg/L, 2.54 mg/L and 2.46 mg/L, respectively. The 16S rDNA sequence analysis showed that the 20 phosphorus- and potassium-solubilizing bacteria belong to 14 species from 10 genera, and mainly consist of Alcaligenes spp., Enterobacter spp. and Bacillus spp. Our results demonstrate the abundant diversity of endophytic phosphorus- and potassiumsolubilizing bacteria in Moso Bamboo. PMID- 26616377 TI - Genotoxic effect of Lythrum salicaria extract determined by the mussel micronucleus test. AB - A wide range of aquatic plants have been proven to release allelochemicals, of them phenolics and tannin are considered rather widely distributed. Tannins, however, have been demonstrated to have genotoxic capacity. In our study genotoxic potential of Lythrum salicaria L. (Purple Loosestrife, family Lythraceae) was assessed by the mussel micronucleus test, using Unio pictorum. In parallel, total and hydrolysable tannin contents were determined. Results clearly show that the extract had a high hydrolysable tannin content and significant mutagenic effect. As L. salicaria has been long used in traditional medicine for chronic diarrhoea, dysentery, leucorrhoea and blood-spitting, genotoxic potential of the plant should be evaluated not only with regard to potential effects in the aquatic ecosystem, but also assessing its safe use as a medicinal herb. PMID- 26616378 TI - First phytochemical investigation of secondary metabolites of Euphorbia davidii Subils. and antiproliferative activity of its extracts. AB - The present work is the first phytochemical investigation of Euphorbia davidii Subils. After multistep separation process, three flavonoid glycosides were obtained from the ethyl acetate soluble fraction of the methanol extract of the whole plant. The structures of the isolated compounds were determined as kaempferol 3-O-rhamnoside, myricetin 3-O-rhamnoside, and quercetin 3-O rhamnoside. Aqueous and organic extracts of the plant were screened in vitro for antiproliferative activity against HeLa (cervix epithelial adenocarcinoma), A431 (skin epidermoid carcinoma), A2780 (ovarian carcinoma) and MCF7 (breast epithelial adenocarcinoma) cells, using the MTT assay. n-Hexane and chloroform extracts demonstrated moderately dose-dependent cell growth inhibitory activity against all four cell lines. PMID- 26616379 TI - Women are not less field independent than men-the role of stereotype threat. AB - Prior research has shown that females are less field independent (FI) than males. However, when gender identity is salient, performance on tests assessing constructs similar to FI may be hindered, because of stereotype threat. This study examined the impact of stereotype threat on gender differences in FI. We expected that (a) reporting one's own gender prior to FI testing and (b) having an opposite-gender experimenter would activate stereotype threat, and in turn result in lower performance on a test of FI among females. Overall, 170 participants were randomly assigned to one of eight conditions in a between participants design varying the participant's gender, experimenter's gender and timing of the gender question (before vs. after test). Results showed that reporting one's gender before the FI test led to lower FI performance among females. Furthermore, females achieved higher FI when experimenters were females and gender questions were administered after the FI test. PMID- 26616380 TI - McLean OnTrack: a transdiagnostic program for early intervention in first-episode psychosis. AB - AIMS: Most programs specializing in the treatment of first-episode psychosis in the United States focus on schizophrenia. However, many early psychosis patients do not fit into this diagnostic category. Here we describe McLean OnTrack, an intensive outpatient treatment program that accepts all comers with first-episode psychosis. METHODS: We assessed baseline characteristics of patients in the 2.5 years since program initiation. We examined how initial referral diagnoses compare with current diagnoses, calculating the proportion of diagnostic changes. RESULTS: At 2.5 years, patients in McLean OnTrack consist of 30 (33.0%) individuals with primary psychotic disorder, 40 (44.0%) with affective psychosis, 19 (20.9%) with psychotic disorder not otherwise specified (NOS) who do not meet full criteria for either category and two (2.2%) individuals with no psychosis. Although patients with affective psychosis had higher pre-morbid functioning, all three categories of psychosis had similar rates of prior hospitalizations and substance use. The retention rate in the psychotic disorder NOS group was lower than that in affective and primary psychotic disorders. Finally, diagnoses changed over the course of treatment in 50.5% of patients. CONCLUSIONS: Diagnostic heterogeneity appears to be the norm among patients with first-episode psychosis, and diagnoses commonly evolve over the illness course. Baseline indices of illness severity were similar across categories and suggest the need for early intervention, irrespective of specific diagnosis. We discuss the benefits and challenges of a transdiagnostic approach to early intervention in first-episode psychosis, treating patients who share many but not all characteristics. PMID- 26616386 TI - On the role of oxytocin in borderline personality disorder. AB - OBJECTIVES: Interpersonal dysfunction is central to borderline personality disorder (BPD). Recent research has focused on the role of oxytocin (OT) in BPD, particularly regarding associations of OT activity with symptoms, genetic polymorphisms of the oxytocin receptor coding gene (OXTR) in BPD, and experimental modification of interpersonal core problems of patients with BPD such as hypervigilance towards threat detection, mistrust, and non-verbal behaviour during social interaction by intranasal application of OT. METHODS: A literature ('medline') review was performed using the keywords 'oxytocin' and 'borderline personality disorder'. Secondary literature on trauma and attachment in relation to OT was also considered relevant. RESULTS: Together, findings suggest that in BPD OT is associated with enhanced defensive mechanisms and avoidance behaviour. Moreover, gene-environment interaction concerning polymorphic variations of the OXTR gene and childhood adversity in BPD suggests that these genes convey developmental flexibility or 'differential susceptibility' to environmental contingencies, whereby BPD resides at the poor outcome end of the spectrum. CONCLUSIONS: In view of the conflicting literature, it needs to be studied carefully whether OT can serve as a therapeutic agent given adjunct to psychotherapy in BPD. More research about the role of OT is also required with regard to the prevention of the non-genetic intergenerational transmission of BPD. Clarifying the role of OT in BPD may also benefit from research in non-human animals targeting the interaction between early adversity and OT availability more directly. PRACTITIONER POINTS: The study of oxytocin can contribute to the understanding of the neurobiology of borderline personality disorder. Oxytocin is critically involved in attachment security, and methylation of the oxytocin receptor may play a role in the epigenetic modulation of early adversity. The intranasal application of oxytocin may be a useful therapeutic adjunct to psychotherapy. Insecure attachment and childhood adversity may produce differential neurobiological effects on the oxytocinergic system in borderline personality disorder. There is insufficient knowledge of how oxytocin interacts with vasopressin, testosterone, dopamine, and serotonin, which are also important key players in the experience of social reward and stress responsivity. It is unclear whether or not oxytocin could be beneficial in preventing the intergenerational (non-genetic) transmission of borderline personality traits. PMID- 26616387 TI - Human Granulocyte Macrophage Colony-Stimulating Factor Enhances Antibiotic Susceptibility of Pseudomonas aeruginosa Persister Cells. AB - Bacterial persister cells are highly tolerant to antibiotics and cause chronic infections. However, little is known about the interaction between host immune systems with this subpopulation of metabolically inactive cells, and direct effects of host immune factors (in the absence of immune cells) on persister cells have not been studied. Here we report that human granulocyte macrophage colony stimulating factor (GM-CSF) can sensitize the persister cells of Pseudomonas aeruginosa PAO1 and PDO300 to multiple antibiotics including ciprofloxacin, tobramycin, tetracycline, and gentamicin. GM-CSF also sensitized the biofilm cells of P. aeruginosa PAO1 and PDO300 to tobramycin in the presence of biofilm matrix degrading enzymes. The DNA microarray and qPCR results indicated that GM-CSF induced the genes for flagellar motility and pyocin production in the persister cells, but not the normal cells of P. aeruginosa PAO1. Consistently, the supernatants from GM-CSF treated P. aeruginosa PAO1 persister cell suspensions were found cidal to the pyocin sensitive strain P. aeruginosa PAK. Collectively, these findings suggest that host immune factors and bacterial persisters may directly interact, leading to enhanced susceptibility of persister cells to antibiotics. PMID- 26616389 TI - Cyclic Tetramers of Zinc Chlorophylls as a Coupled Light-Harvesting Antenna Charge-Separation System. AB - A coupled light-harvesting antenna-charge-separation system, consisting of self assembled zinc chlorophyll derivatives that incorporate an electron-accepting unit, is reported. The cyclic tetramers that incorporated an electron acceptor were constructed by the co-assembly of a pyridine-appended zinc chlorophyll derivative, ZnPy, and a zinc chlorophyll derivative further decorated with a fullerene unit, ZnPyC60 . Comprehensive steady-state and time-resolved spectroscopic studies were conducted for the individual tetramers of ZnPy and ZnPyC60 as well as their co-tetramers. Intra-assembly singlet energy transfer was confirmed by singlet-singlet annihilation in the ZnPy tetramer. Electron transfer from the singlet chlorin unit to the fullerene unit was clearly demonstrated by the transient absorption of the fullerene radical anion in the ZnPyC60 tetramer. Finally, with the co-tetramer, a coupled light-harvesting and charge-separation system with practically 100 % quantum efficiency was demonstrated. PMID- 26616388 TI - Shotgun Analysis of Rough-Type Lipopolysaccharides Using Ultraviolet Photodissociation Mass Spectrometry. AB - Detailed structural characterization of intact rough-type lipopolysaccharides (R LPS) was accomplished using a multi-stage mass spectrometry (MS(3)) strategy consisting of collision-induced dissociation (CID) followed by 193 ultraviolet photodissociation (UVPD) implemented on an Orbitrap Fusion mass spectrometer. Complex mixtures of R-LPS from either Escherichia coli or Salmonella enterica were directly infused into the mass spectrometer using static source nanoelectrospray ionization (nanoESI). An initial CID event performed on an R-LPS precursor produced spectra with abundant ions corresponding to the lipid A and core oligosaccharide (OS) substructures. Comparison of CID spectra of R-LPS ions with varying lipid A and core OS structures verifies that lipid A and core OS ions are consistently produced in high abundance. The resulting lipid A and core OS ions were subsequently activated by CID, high-energy collision-induced dissociation (HCD), or UVPD. For both the lipid A and core OS substructures, HCD and UVPD produced highly informative complementary spectra, with UVPD of the core OS producing an extensive array of cross-ring cleavage fragments. Successful discernment of E. coli R-LPS structures with isomeric core structures confirmed the degree to which subtle structural differences could be determined using this method. PMID- 26616390 TI - Gellan gum microspheres crosslinked with trivalent ion: effect of polymer and crosslinker concentrations on drug release and mucoadhesive properties. AB - Gellan gum microspheres were obtained by ionotropic gelation technique, using the trivalent ion Al(3+). The percentage of entrapment efficiency ranged from 48.76 to 87.52% and 2(2) randomized full factorial design demonstrated that both the increase of polymer concentration and the decrease of crosslinker concentration presented a positive effect in the amount of encapsulated drug. Microspheres size and circularity ranged from 700.17 to 938.32 MUm and from 0.641 to 0.796 MUm, respectively. The increase of polymer concentration (1-2%) and crosslinker concentration (3-5%) led to the enlargement of particle size and circularity. However, the association of increased crosslinker concentration and reduced polymer content made the particles more irregular. In vitro and ex vivo tests evidenced the high mucoadhesiveness of microspheres. The high liquid uptake ability of the microspheres was demonstrated and the pH variation did not affect this parameter. Drug release was pH dependent, with low release rates in acid pH (42.40% and 44.93%) and a burst effect in phosphate buffer pH (7.4). The Weibull model had the best correlation with the drug release data, demonstrating that the release process was driven by a complex mechanism involving the erosion and swelling of the matrix or by non-Fickian diffusion. PMID- 26616391 TI - Making the elderly fit for surgery. PMID- 26616392 TI - President's page - understanding risk prior to treating-the ongoing story of coronary artery calcium scoring. PMID- 26616393 TI - Electrophoretic deposition of fluorescent Cu and Au sheets for light-emitting diodes. AB - Electrophoretic deposition (EPD) is a conventional method for fabricating film materials from nanometer-sized building blocks, and exhibits the advantages of low-cost, high-efficiency, wide-range thickness adjustment, and uniform deposition. Inspired by the interest in the application of two-dimensional (2D) nanomaterials, the EPD technique has been recently extended to building blocks with 2D features. However, the studies are mainly focused on simplex building blocks. The utilization of multiplex building blocks is rarely reported. In this work, we demonstrate a controlled EPD of Cu and Au sheets, which are 2D assemblies of luminescent Cu and Au nanoclusters. Systematic investigations reveal that both the deposition efficiency and the thickness are determined by the lateral size of the sheets. For Cu sheets with a large lateral size, a high zeta-potential and strong face-to-face van der Waals interactions facilitate the deposition with high efficiency. However, for Au sheets, the small lateral size and zeta-potential limit the formation of a thick film. To solve this problem, the deposition dynamics are controlled by increasing the concentration of the Au sheets and adding acetone. This understanding permits the fabrication of a binary EPD film by the stepwise deposition of Cu and Au sheets, thus producing a luminescent film with both Cu green emission and Au red emission. A white light emitting diode prototype with color coordinates (x, y) = (0.31, 0.36) is fabricated by employing the EPD film as a color conversion layer on a 365 nm GaN clip and further tuning the amount of deposited Cu and Au sheets. PMID- 26616394 TI - NES1/KLK10 gene represses proliferation, enhances apoptosis and down-regulates glucose metabolism of PC3 prostate cancer cells. AB - The normal epithelial cell-specific-1 (NES1) gene, also named as KLK10, is recognised as a novel putative tumour suppressor in breast cancer, but few studies have focused on the function of KLK10 in human prostate cancer. Our study confirms that the expression of KLK10 in prostate cancer tissue and cell lines (PC3, DU145, and LNCaP clone FGC) is low. Given that the androgen-independent growth characteristic of the PC3 cell line is more similar to clinical castration resistant prostate cancer, we studied the role of KLK10 in PC3. In vitro and in vivo assays showed that over-expressing KLK10 in PC3 could decelerate tumour proliferation, which was accompanied with an increase in apoptosis and suppression of glucose metabolism. The related proteins, such as Bcl-2 and HK-2, were down-regulated subsequently. Furthermore, by up-regulating Bcl-2 or HK-2 respectively in the PC3-KLK10 cell line, we observed a subsequent increase of cell proliferation and a synchronous up-regulation of HK-2 and Bcl-2. Besides, KLK10 expression was also increased by Bcl-2 and HK-2, which suggests that there is a negative feedback loop between KLK10 and Bcl-2/HK-2. Thus, our results demonstrated that KLK10 may function as a tumour suppressor by repressing proliferation, enhancing apoptosis and decreasing glucose metabolism in PC3 cells. PMID- 26616395 TI - The Associations Between Smoking Habits and Serum Triglyceride or Hemoglobin A1c Levels Differ According to Visceral Fat Accumulation. AB - BACKGROUND: Whether smokers and former smokers have worse lipid profiles or glucose levels than non-smokers remains unclear. METHODS: The subjects were 1152 Japanese males aged 42 to 81 years. The subjects were divided according to their smoking habits (nonsmokers, former smokers, and current smokers) and their visceral fat area (VFA) (<100 cm(2) and >=100 cm(2)). RESULTS: The serum triglyceride (TG) levels of 835 males were assessed. In the VFA >=100 cm(2) group, a significantly greater proportion of current smokers (47.3%) exhibited TG levels of >=150 mg/dL compared with former smokers (36.4%) and non-smokers (18.8%). The difference in TG level distribution between former smokers and non smokers was also significant. However, among the subjects with VFA of <100 cm(2), the TG levels of the three smoking habit groups did not differ. The serum hemoglobin A1c (HbA1c) levels of 877 males were also assessed. In the VFA <100 cm(2) group, significantly higher proportions of current smokers (17.9%) and former smokers (14.9%) demonstrated HbA1c levels of >=5.6% compared with non smokers (6.3%). In contrast, in the VFA >=100 cm(2) group, significantly fewer former smokers displayed HbA1c levels of >=5.6% compared with non-smokers and current smokers. Furthermore, the interaction between smoking habits and VFA was associated with the subjects' TG and HbA1c concentrations, and the associations of TG and HbA1c concentrations and smoking habits varied according to VFA. CONCLUSIONS: Both smoking habits and VFA exhibited associations with TG and HbA1c concentrations. The associations between smoking habits and these parameters differed according to VFA. PMID- 26616396 TI - Body Mass Index and Kidney Stones: A Cohort Study of Japanese Men. AB - BACKGROUND: In Japan, the incidence of kidney stones has increased markedly in recent decades. Major causes of kidney stones remain unclear, and limited data are available on the relationship between overweight/obesity and the incidence of kidney stones. We therefore evaluated body mass index (BMI) and the incidence of kidney stones in Japanese men. METHODS: Of the workers at a gas company, 5984 males aged 20-40 years underwent a medical examination in 1985 (baseline). This study includes 4074 of the men, who were free of kidney stones at baseline and underwent a second medical examination performed between April 2004 and March 2005. BMI was calculated from measured height and weight in 1985, and men were categorized into tertiles. The development of kidney stones during follow-up was based on self-reports from questionnaires at the second medical examination. RESULTS: The average duration of follow-up was 19 years, with 258 participants developing kidney stones during this period. Using the lowest BMI (1st tertile) group as a reference, the hazard ratios (95% confidence intervals [CIs]) for the 2nd and 3rd BMI tertiles were: 1.26 (95% CI, 0.92-1.73) and 1.44 (95% CI, 1.06 1.96), respectively (P for trend = 0.019). After additionally adjusting for potential confounders, such as age, systolic blood pressure, cardiorespiratory fitness, cigarette smoking, and alcohol consumption, the hazard ratios were 1.28 (95% CI, 0.93-1.76) and 1.41 (95% CI, 1.02-1.97), respectively (P for trend = 0.041). CONCLUSIONS: These results suggest that increased BMI is a risk factor for kidney stones in Japanese men. PMID- 26616397 TI - Evaluation of periodontitis in hospital outpatients with major depressive disorder. A focus on gingival and circulating cytokines. AB - An imbalance in stimulated cytokine production is associated with the etiopathogenesis of numerous diseases such as major depressive disorder (MDD) and periodontal disease. Increased cytokine levels have been reported in the gingival crevicular fluid (GCF) of patients with MDD. Thirty-six outpatients with MDD participated in this study. Each outpatient was age-matched (+/- 3 years) with a healthy control (n=36). The patients were controlled for race and smoking habits. Unstimulated and stimulated interleukin 6 (IL-6), interleukin 1beta (IL-1beta), and interferon-gamma (INF-gamma) production in whole blood culture (WBC) and IL-6 and IL-1beta levels in the GCF were evaluated. Circulating levels of IL-6 and IL 1beta (unstimulated) as well as GCF IL-1beta were modestly lower in MDD patients, compared to the levels in age-matched controls (Mann-Whitney, p=0.002, 0.0075, ANCOVA, p=0.025, respectively). In the unstimulated group, there was no correlation between the levels of circulating IL-6 and GCF IL-6 (r=0.07, p=0.67), and between the levels of circulating IL-1beta and the IL-1beta level in the CGF (r=-0.08, p=0.63). In the LPS stimulation group, there was no correlation between the levels of circulating levels of IL-6 and GCF IL-6 (r=0. 02, p=0.91) or between the circulating IL-1beta and GCF IL-1beta (r=0.13, p=0.42). We observed modest immunosuppression in MDD patients (evaluated by no stimulation whole blood culture [WBC]), especially in patients with melancholic depression, chronic depression, and severe depression. PMID- 26616399 TI - Polymeric behavior evaluation of PVP K30-poloxamer binary carrier for solid dispersed nisoldipine by experimental design. AB - CONTEXT: High melting point polymeric carrier without plasticizer is unacceptable for solid dispersion (SD) by melting method. Combined polymer-plasticizer carrier significantly affects drug solubility and tableting property of SD. OBJECTIVE: To evaluate and optimize the combined effect of a binary carrier consisting PVP K30 and poloxamer 188, on nisoldipine solubility and tensile strength of amorphous SD compact (SDcompact) by experimental design. MATERIALS AND METHODS: SD of nisoldpine (SDnisol) was prepared by melt mixing with different PVP K30 and poloxamer amount. A 32 factorial design was employed using nisoldipine solubility and tensile strength of SDcompact as response variables. Statistical optimization by design expert software, and SDnisol characterization using ATR FTIR, DSC and microscopy were done. RESULTS: PVP K30:poloxamer, at a ratio of 3.73:6.63, was selected as the optimized combination of binary polymeric carrier resulting nisoldipine solubility of 115 MUg/mL and tensile strength of 1.19 N/m2. DISCUSSION: PVP K30 had significant positive effect on both responses. Increase in poloxamer concentration after a certain level decreased nisoldipine solubility and tensile strength of SDcompact. CONCLUSION: An optimized PVP K30-poloxamer binary composition for SD carrier was developed. Tensile strength of SDcompact can be considered as a response for experimental design to optimize SD. PMID- 26616398 TI - Associations of childhood adversity and adulthood trauma with C-reactive protein: A cross-sectional population-based study. AB - Mounting evidence highlights specific forms of psychological stress as risk factors for ill health. Particularly strong evidence indicates that childhood adversity and adulthood trauma exposure increase risk for physical and psychiatric disorders, and there is emerging evidence that inflammation may play a key role in these relationships. In a population-based sample from the Health and Retirement Study (n=11,198, mean age 69 +/- 10), we examine whether childhood adversity, adulthood trauma, and the interaction between them are associated with elevated levels of the systemic inflammatory marker high sensitivity C-reactive protein (hsCRP). All models were adjusted for age, gender, race, education, and year of data collection, as well as other possible confounds in follow-up sensitivity analyses. In our sample, 67% of individuals had experienced at least one traumatic event during adulthood, and those with childhood adversity were almost three times as likely to have experienced trauma as an adult. Childhood adversities and adulthood traumas were independently associated with elevated levels of hsCRP (beta=0.03, p=0.01 and beta=0.05, p<0.001, respectively). Those who had experienced both types of stress had higher levels of hsCRP than those with adulthood trauma alone, Estimate=-0.06, 95% CI [-0.003, -0.12], p=0.04, but not compared to those with childhood adversity alone, Estimate=-0.06, 95% CI [0.03, -0.16], p=0.19. There was no interaction between childhood and adulthood trauma exposure. To our knowledge, this is the first study to examine adulthood trauma exposure and inflammation in a large population-based sample, and the first to explore the interaction of childhood adversity and adulthood trauma with inflammation. Our study demonstrates the prevalence of trauma-related inflammation in the general population and suggests that childhood adversity and adulthood trauma are independently associated with elevated inflammation. PMID- 26616400 TI - Prediction of sudden cardiac death with automated high-throughput analysis of heterogeneity in standard resting 12-lead electrocardiograms. AB - BACKGROUND: Heterogeneity of depolarization and repolarization underlies the development of lethal arrhythmias. OBJECTIVE: We investigated whether quantification of spatial depolarization and repolarization heterogeneity identifies individuals at risk for sudden cardiac death (SCD). METHODS: Spatial R , J-, and T-wave heterogeneity (RWH, JWH, and TWH, respectively) was analyzed using automated second central moment analysis of standard digital 12-lead electrocardiograms in 5618 adults (2588, 46% men; mean +/- SEM age 50.9 +/- 0.2 years), who took part in the epidemiological Health 2000 Survey as representative of the entire Finnish adult population. RESULTS: During the follow-up period of 7.7 +/- 0.2 years, a total of 72 SCDs occurred (1.3%), with an average yearly incidence rate of 0.17% per year. Increased RWH, JWH, and TWH in left precordial leads (V4-V6) were univariately associated with SCD (P < .001 for each). When adjusted with standard clinical risk markers, JWH and TWH remained independent predictors of SCD. Increased TWH (>=102 uV) was associated with a 1.7-fold adjusted relative risk for SCD (95% confidence interval [CI] 1.0-2.9; P = .048) and increased JWH (>=123 uV) with a 2.0-fold adjusted relative risk for SCD (95% CI 1.2-3.3; P = .006). When both TWH and JWH were above the threshold, the adjusted relative risk for SCD was 2.9-fold (95% CI 1.5-5.7; P = .002). When RWH (>=470 uV), JWH, and TWH were all above the threshold, the adjusted relative risk for SCD was 3.2-fold (95% CI 1.4-7.1; P = .009). CONCLUSION: Second central moment analysis of standard resting 12-lead electrocardiographic morphology provides an ultrarapid means for the automated measurement of spatial RWH, JWH, and TWH, enabling analysis of high subject volumes and screening for SCD risk in the general population. PMID- 26616401 TI - Inhibition of insulin fibrillation by osmolytes: Mechanistic insights. AB - We have studied here using a number of biophysical tools the effects of osmolytes, betaine, citrulline, proline and sorbitol which differ significantly in terms of their physical characteristics such as, charge distribution, polarity, H-bonding abilities etc, on the fibrillation of insulin. Among these, betaine, citrulline, and proline are very effective in decreasing the extent of fibrillation. Proline also causes a substantial delay in the onset of fibrillation in the concentration range (50-250 mM) whereas such an effect is seen for citrulline only at 250 mM, and in case of betaine this effect is not seen at all in the whole concentration range. The enthalpies of interaction at various stages of fibrillation process have suggested that the preferential exclusion of the osmolyte and its polar interaction with the protein are important in inhibition. The results indicate that the osmolytes are most effective when added prior to the elongation stage of fibrillation. These observations have significant biological implications, since insulin fibrillation is known to cause injection amyloidosis and our data may help in designing lead drug molecules and development of potential therapeutic strategies. PMID- 26616402 TI - Sexually transmitted infections and viral hepatitides in patients presenting for non-occupational HIV post-exposure prophylaxis: results of a prospective cohort study. AB - Data evaluating the screening practices for viral hepatitides and sexually transmitted infections (STIs) in patients presenting for non-occupational HIV post-exposure prophylaxis (nPEP) care are limited. Screening practices and prevalences of viral hepatitides and STIs were evaluated in 126 patients presenting to a dedicated HIV prevention clinic for HIV nPEP. Three patients (2.4%) were diagnosed with chronic hepatitis C infection, 28 (22.2%) did not have surface antibodies in sufficient quantity to confer immunity to hepatitis B, and six (4.8%) were diagnosed with an STI. A multivariate regression model did not predict any demographic or clinical features predictive of HBV non-immunity. Beyond screening for HIV infection, evaluation for viral hepatitides and STIs is an important feature in the care of patients presenting for HIV nPEP. PMID- 26616403 TI - Analysis of the protective effects of a neuronal Cav2.1 calcium channel in brain injury. AB - We previously reported that rolling Nagoya mice carrying a mutation in the alpha1 subunit of the Cav2.1 channel protective from ischemia- and kainate-induced neuronal damage. However, the protective effect of this mutation and its relationship to brain injury recovery have not been examined. To examine the relationship between Cav2.1 channel function and brain injury, we induced cryogenic brain damage in homozygous rolling Nagoya (rol/rol), control wild-type (+/+), omega-agatoxin IVA-pretreated +/+ (omega-aga +/+), and omega-agatoxin IVA post-treated +/+ (omega-aga-post-treated +/+) mice. We measured the lesion area, blood brain-barrier permeability and performed immunohistochemistry and western blot analysis. The lesions of rol/rol and omega-aga +/+ mice were significantly smaller than those observed in +/+ mice at both day 1 and day 7 after injury. Similar results were shown in blood-brain barrier permeability. We observed more reactive astrogliosis in +/+ mice than in rol/rol or omega-aga +/+ mice. rol/rol and omega-aga +/+ mice had fewer degenerating cells due to cryogenic injury than did +/+ mice at both day 1 and day 7. omega-Aga-post-treated +/+ mice 24h after injury were sacrificed on day 7. The lesions were smaller in omega-aga-post treated +/+ mice than those in vehicle-treated +/+ mice. We also examined phosphorylated p38 (pp38) at the injured site. omega-Aga-post-treated +/+ mouse brain slices showed weak pp38 signal; vehicle-treated +/+ mouse brain slices were pp38-positive. These findings demonstrate that the mutant Cav2.1 channel exerts a protective effect against cryogenic brain injury in rolling Nagoya mice. Our results indicate that inhibitors of the Cav2.1-dependent p38 signaling cascade would be useful as therapeutic agents in the treatment of brain injury. PMID- 26616404 TI - The diameter-dependent photoelectrochemical performance of silicon nanowires. AB - We demonstrate the first systematic study of the diameter-dependent photoelectrochemical performance of single silicon nanowires within a broad size range from 200 to 2000 nm. SiNWs with a diameter of 1415 nm exhibit the highest solar energy conversion efficiency, which can be mainly traced to their diameter dependent light absorption properties. PMID- 26616405 TI - Establishment of a new pull-out strength testing method to quantify early osseointegration-An experimental pilot study. AB - OBJECTIVES: The animal study aims to evaluate a new experimental model for measuring sole the influence of the surface characteristics independent from implant macro-design on the level of osseointegration by registering the pull-out strength needed for removal of experimental devices with different surfaces from artificial defects. MATERIAL AND METHODS: Seventy-two test bodies (36 with the FRIADENT((r)) plus surface, 36 with the P15/HAp biofunctionalized surface) were inserted in six adult domestic pigs with artificial calvarial defects. The experimental devices were designed to fit in the defects leaving a gap between the test body and the local bone. After 21 days of healing, the animals were sacrificed and the test bodies were pulled out with a standardised reproducible pull-out device measuring the pull-out strength. The pull-out strength for both groups was compared. RESULTS: Twenty-one days after insertion a mean force of 412 +/- 142 N for the P15/HAp group and 183 +/- 105 N for the FRIADENT((r)) plus group was measured for the removal of the specimens from the calvarial bone. The difference between the groups was statistically significant (p < 0.0001). CONCLUSION: The experimental set-up seems to be a suitable method when measuring the impact of implant surfaces on the early stage of osseointegration. PMID- 26616406 TI - How users adopt healthcare information: An empirical study of an online Q&A community. AB - OBJECTIVES: The emergence of social media technology has led to the creation of many online healthcare communities, where patients can easily share and look for healthcare-related information from peers who have experienced a similar problem. However, with increased user-generated content, there is a need to constantly analyse which content should be trusted as one sifts through enormous amounts of healthcare information. This study aims to explore patients' healthcare information seeking behavior in online communities. METHODS: Based on dual process theory and the knowledge adoption model, we proposed a healthcare information adoption model for online communities. This model highlights that information quality, emotional support, and source credibility are antecedent variables of adoption likelihood of healthcare information, and competition among repliers and involvement of recipients moderate the relationship between the antecedent variables and adoption likelihood. Empirical data were collected from the healthcare module of China's biggest Q&A community-Baidu Knows. Text mining techniques were adopted to calculate the information quality and emotional support contained in each reply text. A binary logistics regression model and hierarchical regression approach were employed to test the proposed conceptual model. RESULTS: Information quality, emotional support, and source credibility have significant and positive impact on healthcare information adoption likelihood, and among these factors, information quality has the biggest impact on a patient's adoption decision. In addition, competition among repliers and involvement of recipients were tested as moderating effects between these antecedent factors and the adoption likelihood. Results indicate competition among repliers positively moderates the relationship between source credibility and adoption likelihood, and recipients' involvement positively moderates the relationship between information quality, source credibility, and adoption decision. CONCLUSIONS: In addition to information quality and source credibility, emotional support has significant positive impact on individuals' healthcare information adoption decisions. Moreover, the relationships between information quality, source credibility, emotional support, and adoption decision are moderated by competition among repliers and involvement of recipients. PMID- 26616408 TI - The Society of Thoracic Surgeons Adult Cardiac Surgery Database: 2016 Update on Outcomes and Quality. AB - The Society of Thoracic Surgeons Adult Cardiac Database is one of the longest standing, largest, and most highly regarded clinical data registries in health care. It serves as the foundation for all quality measurement and improvement activities of The Society of Thoracic Surgeons. This report summarizes current aggregate national outcomes in adult cardiac surgery and reviews database-related activities in the areas of quality measurement and performance improvement. PMID- 26616407 TI - P311 promotes renal fibrosis via TGFbeta1/Smad signaling. AB - P311, a gene that was identified in 1993, has been found to have diverse biological functions in processes such as cell proliferation, migration and differentiation. However, its role in fibrosis is unknown. We previously observed that P311 is highly expressed in skin hypertrophic scars. In this study, P311 over-expression was detected in a subset of tubular epithelial cells in clinical biopsy specimens of renal fibrosis; this over-expression, was found concurrent with alpha-smooth muscle actin (alpha-SMA) and transforming growth factor beta1 (TGFbeta1) expression. Subsequently, these results were verified in a mouse experimental renal fibrosis model induced by unilateral ureteral obstruction. The interstitial deposition of collagen, alpha-SMA and TGF-beta1 expression, and macrophage infiltration were dramatically decreased when P311 was knocked out. Moreover, TGFbeta/Smad signaling had a critical effect on the promotion of renal fibrosis by P311. In conclusion, this study demonstrate that P311 plays a key role in renal fibrosis via TGFbeta1/Smad signaling, which could be a novel target for the management of renal fibrosis. PMID- 26616409 TI - Effect of Zinc Supplementation on Early Outcome of Neonatal Sepsis--A Randomized Controlled Trial. AB - OBJECTIVE: To find the effect of zinc supplementation on the outcome of neonatal sepsis at one month of age. METHODS: This randomized controlled trial was conducted in a tertiary care neonatal unit, enrolling neonates with clinical features of sepsis and positive blood culture or positive sepsis screening tests. The treatment group received 3 mg/kg/twice a day of zinc sulfate monohydrate orally for 10 d along with standard antibiotic therapy. The control group received standard antibiotic treatment without zinc. Samples were collected from both the groups before and after the treatment. Babies were monitored till discharge and followed up as out-patients till one month of age. RESULTS: Demographic characteristics were similar between the cases and controls. After 10 d of treatment, the mean serum zinc level between the two groups was 737.09 +/- 219.97 vs. 801.26 +/- 405.56, (p = 0.20). Outcome measures like days of hospital stay (15 vs. 15; p = 0.69) and mortality rate (4.5% vs. 13.6%; p = 0.27) were not found to be significantly different between the groups. At one month of age, more number of control neonates had abnormal neurological findings as compared to the zinc supplemented group [(P = 0.02); RR (95%CI) = 0.28 (0.11-0.73)]. CONCLUSIONS: Zinc supplementation in neonates with sepsis improves the neurological status at one month of age although the mortality reduction was not statistically significant. PMID- 26616410 TI - Incidence of Clostridium difficile infection in patients receiving high-risk antibiotics with or without a proton pump inhibitor. AB - BACKGROUND: Considering the incidence and severity of Clostridium difficile infection (CDI), risk reduction strategies are crucial. Prior studies suggest that proton pump inhibitor (PPI) use can increase the risk of CDI over antibiotics alone; however, data and guidelines have been conflicting. AIM: The aim was to compare CDI incidence in patients receiving high-risk antibiotics, comparing rates in those prescribed a PPI versus those without overlapping PPI exposure. METHODS: This retrospective cohort study assessed the incidence of CDI in veterans receiving high-risk antibiotics over an approximately three-year period. High-risk antibiotics were defined as: ciprofloxacin, levofloxacin, moxifloxacin, clindamycin, ceftriaxone, cefotaxime, ceftazidime, or cefixime. FINDINGS: We identified subjects who were prescribed any high-risk antibiotic, finding 3513 on a concomitant PPI and 6149 not taking a PPI. Of these subjects, 111 were diagnosed with CDI and met inclusion criteria. Baseline characteristics, CDI severity, length of hospitalization and antibiotic therapy prior to infection were similar in both groups. The incidence of CDI was significantly higher in patients prescribed a PPI (odds ratio: 2.2; 95% confidence interval: 1.52-3.23; P=0.0001). A strong association was found between concurrent PPI use with fluoroquinolones (P=0.005) and clindamycin (P=0.045). CONCLUSION: The use of PPIs together with high-risk antibiotics was associated with a significantly higher incidence of CDI. Our study provides further support for the CDI prevention strategy of judicious PPI use, especially in patients receiving high-risk antibiotics. Prudent avoidance of PPIs may reduce the incidence of CDI, a major cause of morbidity and mortality worldwide. PMID- 26616411 TI - Novel use of fluorescent gel to ensure that cleaning does not take place. PMID- 26616412 TI - Response to Antonelli et al.: 'Association between nosocomial pneumonia and non invasive ventilation: what plays a role in clinical practice?'. PMID- 26616413 TI - Extensively drug-resistant Acinetobacter baumannii in a Lebanese intensive care unit: risk factors for acquisition and determination of a colonization score. AB - BACKGROUND: Acinetobacter baumannii (AB) has emerged as an important nosocomial pathogen causing worldwide hospital outbreaks. It has become a prototype of extensively drug-resistant (XDR) organisms. AIM: To identify risk factors for acquisition of XDR-AB and to develop a colonization risk score in intensive care unit (ICU) patients in a Lebanese tertiary care centre where XDR-AB causes intermittent outbreaks. METHODS: This retrospective study included 257 patients with baseline negative screening cultures for XDR-AB admitted to a seven-bed ICU from July 2012 to July 2013. Patients' demographic data and clinical characteristics were collected from the hospital's electronic medical records. Univariate analysis of potential risk factors was performed followed by multivariate analysis to determine parameters to be included in the colonization risk score. FINDINGS: The rate of XDR-AB acquisition was 15.6%. Multivariate analysis identified urinary catheter placement >6 days (odds ratio: 16.98; 95% confidence interval: 3.96-49.56; P<0.0001), ICU contact pressure for >4 days (2.38; 1.48-3.57; P=0.001), presence of gastrostomy tube (5.44; 1.43-20.68; P=0.013), and previous use of carbapenems or piperacillin-tazobactam (4.20; 1.65 11.81; P=0.002) as parameters to be included in the colonization score. The risk of XDR-AB acquisition was 0, 5.6%, 17.2%, 56.8%, and 80% in the presence of a score of 0, 1, 2, 3, and 4 respectively. A score of 4 indicates high probability of XDR-AB acquisition, suggesting that patient isolation is required; zero indicates a low probability of XDR-AB acquisition. CONCLUSION: Risk factors could be used to develop a score to decide which patients need isolation to limit the spread of XDR-AB. PMID- 26616414 TI - Association between nosocomial pneumonia and non-invasive ventilation: what plays a role in clinical practice? PMID- 26616415 TI - Norovirus outbreak management: how much cohorting is necessary? AB - For the control of norovirus outbreaks, it is widely recommended that exposed but asymptomatic patients should be cohorted separately from unexposed patients and from symptomatic patients. The frequency of subsequent symptomatic norovirus infection in contact patients has not been investigated systematically. We retrospectively investigated the development of typical norovirus symptoms in contact patients during seven norovirus outbreaks affecting 57 patients between November 2014 and May 2015. Only one of 14 contact patients developed typical norovirus symptoms, calling into question current recommendations to isolate contact patients. PMID- 26616416 TI - Defining the user role in infection control. AB - BACKGROUND: Health policy initiatives continue to recognize the valuable role of patients and the public in improving safety, advocating the availability of information as well as involvement at the point of care. In infection control, there is a limited understanding of how users interpret the plethora of publicly available information about hospital performance, and little evidence to support strategies that include reminding healthcare staff to adhere to hand hygiene practices. AIM: To understand how users define their own role in patient safety, specifically in infection control. METHODS: Through group interviews, self completed questionnaires and scenario evaluation, user views of 41 participants (15 carers and 26 patients with recent experience of inpatient hospital care in London, UK) were collected and analysed. In addition, the project's patient representative performed direct observation of the research event to offer inter rater reliability of the qualitative analysis. FINDINGS: Users considered evidence of systemic safety-related failings when presented with hospital choices, and did not discount hospitals with high ('red' flagged) rates of meticillin-resistant Staphylococcus aureus. Further, users considered staff satisfaction within the workplace over and above user satisfaction. Those most dissatisfied with the care they received were unlikely to ask staff, 'Have you washed your hands?' CONCLUSION: This in-depth qualitative analysis of views from a relatively informed user sample shows 'what matters', and provides new avenues for improvement initiatives. It is encouraging that users appear to take a holistic view of indicators. There is a need for strategies to improve dimensions of staff satisfaction, along with understanding the implications of patient satisfaction. PMID- 26616417 TI - HIV reservoirs: what, where and how to target them. AB - One of the main challenges in the fight against HIV infection is to develop strategies that are able to eliminate the persistent viral reservoir that harbours integrated, replication-competent provirus within host cellular DNA. This reservoir is resistant to antiretroviral therapy (ART) and to clearance by the immune system of the host; viruses originating from this reservoir lead to rebound viraemia once treatment is stopped, giving rise to new rounds of infection. Several studies have focused on elucidating the cells and tissues that harbour persistent virus, the true size of the reservoir and how best to target it, but these topics are the subject of ongoing debate. In this Viewpoint article, several experts in the field discuss the constitution of the viral reservoir, how best to measure it and the best ways to target this source of persistent infection. PMID- 26616418 TI - [Niemann-Pick disease mistaken for miliary tuberculosis]. PMID- 26616420 TI - Analyzing depression tendency of web posts using an event-driven depression tendency warning model. AB - OBJECTIVE: The Internet has become a platform to express individual moods/feelings of daily life, where authors share their thoughts in web blogs, micro-blogs, forums, bulletin board systems or other media. In this work, we investigate text-mining technology to analyze and predict the depression tendency of web posts. METHODS: In this paper, we defined depression factors, which include negative events, negative emotions, symptoms, and negative thoughts from web posts. We proposed an enhanced event extraction (E3) method to automatically extract negative event terms. In addition, we also proposed an event-driven depression tendency warning (EDDTW) model to predict the depression tendency of web bloggers or post authors by analyzing their posted articles. RESULTS: We compare the performance among the proposed EDDTW model, negative emotion evaluation (NEE) model, and the diagnostic and statistical manual of mental disorders-based depression tendency evaluation method. The EDDTW model obtains the best recall rate and F-measure at 0.668 and 0.624, respectively, while the diagnostic and statistical manual of mental disorders-based method achieves the best precision rate of 0.666. The main reason is that our enhanced event extraction method can increase recall rate by enlarging the negative event lexicon at the expense of precision. Our EDDTW model can also be used to track the change or trend of depression tendency for each post author. The depression tendency trend can help doctors to diagnose and even track depression of web post authors more efficiently. CONCLUSIONS: This paper presents an E3 method to automatically extract negative event terms in web posts. We also proposed a new EDDTW model to predict the depression tendency of web posts and possibly help bloggers or post authors to early detect major depressive disorder. PMID- 26616419 TI - Genetic dosage and position effect of small supernumerary marker chromosome (sSMC) in human sperm nuclei in infertile male patient. AB - Chromosomes occupy specific distinct areas in the nucleus of the sperm cell that may be altered in males with disrupted spermatogenesis. Here, we present alterations in the positioning of the human chromosomes 15, 18, X and Y between spermatozoa with the small supernumerary marker chromosome (sSMC; sSMC(+)) and spermatozoa with normal chromosome complement (sSMC(-)), for the first time described in the same ejaculate of an infertile, phenotypically normal male patient. Using classical and confocal fluorescent microscopy, the nuclear colocalization of chromosomes 15 and sSMC was analyzed. The molecular cytogenetic characteristics of sSMC delineated the karyotype as 47,XY,+der(15)(pter >p11.2::q11.1->q11.2::p11.2->pter)mat. Analysis of meiotic segregation showed a 1:1 ratio of sSMC(+) to sSMC(-) spermatozoa, while evaluation of sperm aneuploidy status indicated an increased level of chromosome 13, 18, 21 and 22 disomy, up to 7 * (2.7 - 15.1). Sperm chromatin integrity assessment did not reveal any increase in deprotamination in the patient's sperm chromatin. Importantly, we found significant repositioning of chromosomes X and Y towards the nuclear periphery, where both chromosomes were localized in close proximity to the sSMC. This suggests the possible influence of sSMC/XY colocalization on meiotic chromosome division, resulting in abnormal chromosome segregation, and leading to male infertility in the patient. PMID- 26616422 TI - Synthesis and characterization of ML and ML2 metal complexes with amino acid substituted bis(2-picolyl)amine ligands. AB - Metal complexes with ML or ML2 stoichiometry have been isolated in the reaction of Zn(NO3)2, ZnBr2 or M(NO3)2/NaBF4, M = Zn(ii), Co(ii) or Ni(ii), with either amino acid or amine substituted tridentate nitrogen ligands based on bis(2 picolyl)amine (bpa) or bis(2-quinaldyl)amine (bqa). The stoichiometry (M : L = 1 : 1 or 1 : 2) and stereochemistry (mer, trans-fac or cis-fac) of the products have been studied by NMR and IR spectroscopy, X-ray single crystal analysis and quantum-chemical calculations with an implicit SMD solvation model. PMID- 26616421 TI - Folate metabolic pathway single nucleotide polymorphisms: a predictive pharmacogenetic marker of methotrexate response in Indian (Asian) patients with rheumatoid arthritis. AB - AIM: We evaluated the pharmacogenetic influence of genetic polymorphisms in folate pathway genes in Indian rheumatoid arthritis patients receiving methotrexate (MTX). PATIENTS & METHODS: Twelve polymorphisms within nine folate pathway genes were analyzed for association with MTX response in 322 Indian rheumatoid arthritis (RA) patients and MTX pharmacokinetics in 94 RA patients. RESULTS: Polymorphisms in GGH, SHMT1 and TS were associated with MTX-related adverse events while SNPs in MTHFR and RFC1/SLC19A1 were associated with MTX efficacy. TS5'UTR and SHMT1 polymorphisms were associated with higher plasma levels of MTX. CONCLUSION: Polymorphisms in folate-MTX pathway genes contribute to MTX response and affect MTX concentrations in Indian RA patients. A toxicogenetic index could identify patients who develop adverse events to MTX. PMID- 26616423 TI - Engineering wild-type robust Pediococcus acidilactici strain for high titer L- and D-lactic acid production from corn stover feedstock. AB - Pediococcus acidilactici TY112 producing L-lactic acid and P. acidilactici ZP26 producing D-lactic acid, were engineered from the wild-type P. acidilactici DQ2 by ldhD or ldh gene disruption, and the robustness of the wild-type strain to the inhibitors derived from lignocellulose pretreatment was maintained well. In simultaneous saccharification and fermentation (SSF), 77.66 g L(-1) of L-lactic acid and 76.76 g L(-1) of D-lactic acid were obtained at 25% (w/w) solids content of dry dilute acid pretreated and biodetoxified corn stover feedstock. L- and D Lactic acid yield and productivity were highly dependent on the inhibitor removal extent due to the significant down-regulation on the expressions of ldh and ldhD encoding lactate dehydrogenase by inhibitor, especially syringaldehyde and vanillin at the low concentrations. This study provided a prototype of industrial process for high titer L- and D-lactic acid production from lignocellulose feedstock. PMID- 26616424 TI - Occurrence and characterization of inducible clindamycin resistance in canine methicillin-resistant Staphylococcus pseudintermedius. AB - This study aimed to detect inducible clindamycin (iCLI) resistance in Staphylococcus pseudintermedius isolated from dogs in Thailand using D-zone testing. Strains that were iCLI-resistant were characterized by molecular typing and antibiogram and were detected in 10/200 S. pseudintermedius isolates (5%) from 7/41 dogs (17%). All were methicillin-resistant S. pseudintermedius (MRSP) and demonstrated multidrug resistance. The iCLI-resistant MRSP contained erm(B) and had identical or closely related DNA fingerprint patterns by pulsed-field gel electrophoresis. All iCLI-resistant MRSP strains belonged to the same clonal complex 112 (sequence types 111 and 112) by multilocus sequence typing. To avoid misinterpretation of clindamycin susceptibility, D-zone testing is recommended to promote rational antimicrobial selection and limit the clonal expansion of multidrug resistant bacteria. PMID- 26616425 TI - Using the incidence and impact of health conditions in guide dogs to investigate healthy ageing in working dogs. AB - This study aimed to use retirement data from working guide dogs to investigate healthy ageing in dogs and the demographic factors that influence ageing. Using a dataset of 7686 dogs spanning 20 years, dogs withdrawn for health reasons before they reached retirement were identified. Cases of retirement for old age, rather than for health reasons, were also recorded, as was the length of working life for all dogs. Specific health reasons were grouped into 14 different health categories. The influence of purebred or crossbreed, breed, and sex on the incidence of these health categories and the length of working life within each health category was considered. The majority (n = 6465/7686; 84%) of working guide dogs were able to function as guide dogs until they had worked for 8.5 years, when they retired. This working life might constitute a reference for the different breeds considered, with the exception of the German shepherd dog, which had a shorter working life. The most common reason for health withdrawals was musculoskeletal conditions (n = 387/1362; 28%), mostly arthritis. Skin conditions (mostly comprised of cases of atopic dermatitis) reduced working life most commonly (mean, approximately 5 years). Nervous sensory conditions (35% of which were cases of epilepsy) reduced working life by 3 years. PMID- 26616426 TI - Superresolution techniques, biophysics with nanostructures, and fluorescence energy transfer: general discussion. PMID- 26616427 TI - EM?IM: software for relating ion mobility mass spectrometry and electron microscopy data. AB - We present EM?IM, software that allows the calculation of collision cross sections from electron density maps obtained for example by means of transmission electron microscopy. This allows the assessment of structures other than those described by atomic coordinates with ion mobility mass spectrometry data, and provides a new means for contouring and validating electron density maps. EM?IM thereby facilitates the use of data obtained in the gas phase within structural biology studies employing diverse experimental methodologies. PMID- 26616428 TI - Nonlinear elasticity of disordered fiber networks. AB - Disordered biopolymer gels have striking mechanical properties including strong nonlinearities. In the case of athermal gels (such as collagen-I) the nonlinearity has long been associated with a crossover from a bending dominated to a stretching dominated regime of elasticity. The physics of this crossover is related to the existence of a central-force isostatic point and to the fact that for most gels the bending modulus is small. This crossover induces scaling behavior for the elastic moduli. In particular, for linear elasticity such a scaling law has been demonstrated [Broedersz et al. Nat. Phys., 2011 7, 983]. In this work we generalize the scaling to the nonlinear regime with a two-parameter scaling law involving three critical exponents. We test the scaling law numerically for two disordered lattice models, and find a good scaling collapse for the shear modulus in both the linear and nonlinear regimes. We compute all the critical exponents for the two lattice models and discuss the applicability of our results to real systems. PMID- 26616429 TI - The Western South Atlantic Ocean in a High-CO2 World: Current Measurement Capabilities and Perspectives. AB - An international multi-disciplinary group of 24 researchers met to discuss ocean acidification (OA) during the Brazilian OA Network/Surface Ocean-Lower Atmosphere Study (BrOA/SOLAS) Workshop. Fifteen members of the BrOA Network (www.broa.furg.br) authored this review. The group concluded that identifying and evaluating the regional effects of OA is impossible without understanding the natural variability of seawater carbonate systems in marine ecosystems through a series of long-term observations. Here, we show that the western South Atlantic Ocean (WSAO) lacks appropriate observations for determining regional OA effects, including the effects of OA on key sensitive Brazilian ecosystems in this area. The impacts of OA likely affect marine life in coastal and oceanic ecosystems, with further social and economic consequences for Brazil and neighboring countries. Thus, we present (i) the diversity of coastal and open ocean ecosystems in the WSAO and emphasize their roles in the marine carbon cycle and biodiversity and their vulnerabilities to OA effects; (ii) ongoing observational, experimental, and modeling efforts that investigate OA in the WSAO; and (iii) highlights of the knowledge gaps, infrastructure deficiencies, and OA-related issues in the WSAO. Finally, this review outlines long-term actions that should be taken to manage marine ecosystems in this vast and unexplored ocean region. PMID- 26616430 TI - Modeling Agricultural Watersheds with the Soil and Water Assessment Tool (SWAT): Calibration and Validation with a Novel Procedure for Spatially Explicit HRUs. AB - Applications of the Soil and Water Assessment Tool (SWAT) model typically involve delineation of a watershed into subwatersheds/subbasins that are then further subdivided into hydrologic response units (HRUs) which are homogeneous areas of aggregated soil, landuse, and slope and are the smallest modeling units used within the model. In a given standard SWAT application, multiple potential HRUs (farm fields) in a subbasin are usually aggregated into a single HRU feature. In other words, the standard version of the model combines multiple potential HRUs (farm fields) with the same landuse/landcover, soil, and slope, but located at different places of a subbasin (spatially non-unique), and considers them as one HRU. In this study, ArcGIS pre-processing procedures were developed to spatially define a one-to-one match between farm fields and HRUs (spatially unique HRUs) within a subbasin prior to SWAT simulations to facilitate input processing, input/output mapping, and further analysis at the individual farm field level. Model input data such as landuse/landcover (LULC), soil, crop rotation, and other management data were processed through these HRUs. The SWAT model was then calibrated/validated for Raccoon River watershed in Iowa for 2002-2010 and Big Creek River watershed in Illinois for 2000-2003. SWAT was able to replicate annual, monthly, and daily streamflow, as well as sediment, nitrate and mineral phosphorous within recommended accuracy in most cases. The one-to-one match between farm fields and HRUs created and used in this study is a first step in performing LULC change, climate change impact, and other analyses in a more spatially explicit manner. PMID- 26616431 TI - Toward Better Animal Models for Molecular Psychiatry. PMID- 26616432 TI - From Synapses to Behavior: What Rodent Models Can Tell Us About Neuropsychiatric Disease. PMID- 26616433 TI - There Is Much to Be Learned From Animal Models of Obsessive-Compulsive Disorder. PMID- 26616434 TI - Electric-field-assisted formation of an interfacial double-donor molecule in silicon nano-transistors. AB - Control of coupling of dopant atoms in silicon nanostructures is a fundamental challenge for dopant-based applications. However, it is difficult to find systems of only a few dopants that can be directly addressed and, therefore, experimental demonstration has not yet been obtained. In this work, we identify pairs of donor atoms in the nano-channel of a silicon field-effect transistor and demonstrate merging of the donor-induced potential wells at the interface by applying vertical electric field. This system can be described as an interfacial double donor molecule. Single-electron tunneling current is used to probe the modification of the potential well. When merging occurs at the interface, the gate capacitance of the potential well suddenly increases, leading to an abrupt shift of the tunneling current peak to lower gate voltages. This is due to the decrease of the system's charging energy, as confirmed by Coulomb blockade simulations. These results represent the first experimental observation of electric-field-assisted formation of an interfacial double-donor molecule, opening a pathway for designing functional devices using multiple coupled dopant atoms. PMID- 26616435 TI - An endoscope with integrated transparent bioelectronics and theranostic nanoparticles for colon cancer treatment. AB - The gastrointestinal tract is a challenging anatomical target for diagnostic and therapeutic procedures for bleeding, polyps and cancerous growths. Advanced endoscopes that combine imaging and therapies within the gastrointestinal tract provide an advantage over stand-alone diagnostic or therapeutic devices. However, current multimodal endoscopes lack the spatial resolution necessary to detect and treat small cancers and other abnormalities. Here we present a multifunctional endoscope-based interventional system that integrates transparent bioelectronics with theranostic nanoparticles, which are photoactivated within highly localized space near tumours or benign growths. These advanced electronics and nanoparticles collectively enable optical fluorescence-based mapping, electrical impedance and pH sensing, contact/temperature monitoring, radio frequency ablation and localized photo/chemotherapy, as the basis of a closed-loop solution for colon cancer treatment. In vitro, ex vivo and in vivo experiments highlight the utility of this technology for accurate detection, delineation and rapid targeted therapy of colon cancer or precancerous lesions. PMID- 26616436 TI - Stimulation of neuronal cells by culture supernatant of T lymphocytes triggered by anti-CD3 mAb followed by propagation in the presence of interleukin-2. AB - Performance status (PS) frequently improves occurs in cancer patients who have been infused with their own lymphokine-activated killer T cells (LAK-T). In the present study, a culture supernatant of LAK-T (LAK-T sup) administered to 8-week old rats caused neurogenesis as evidenced by increased 5-ethynyl-2'-deoxyuridine staining of brain tissues. Intravenous injection of granulocyte-macrophage colony stimulating factor (GM-CSF), a major cytokine in LAK-T sup, had a similar effect. Furthermore, LAK-T sup induced Ca(++) increase in rat hippocampal brain slices that was detected in neuronal cells by emission of Fluo-8 NW at 520 nm. The same effect was observed with an rGM-CSF solution. GM-CSF may activate neuronal cells by stimulating the glial cells that surround and attach to them. If so, GM-CSF and LAK-T sup may improve the motor neurons of patients with amyotrophic lateral sclerosis. The neurogenerative effect of GM-CSF in LAK-T sup may also help improve brain function in aged adults including those with dementia such as Alzheimer's disease. PMID- 26616437 TI - Individuals' experiences and opinions of psychological therapies for psychosis: A narrative synthesis. AB - Beliefs, attitudes and expectations about therapy are likely to influence engagement, adherence and outcomes in psychological therapy but despite increased research interest in this area, the evidence has not been systematically reviewed or synthesised. This review is the first to explore service user beliefs by synthesising existing quantitative and qualitative research in order to develop a comprehensive understanding of beliefs about psychological therapy in people with psychosis and to identify gaps in the literature. Thirty-five papers were included in this review and synthesised. Themes and subthemes of both service user expectations (including outcomes, process and barriers) and experiences (including satisfaction, outcomes, process and therapist characteristics) are described. High levels of satisfaction and positive regard towards therapy for psychosis were found. However, many clients refuse, do not attend or withdraw from psychological therapy. Data were primarily limited to people who have completed therapy. Expectations about therapy have not been adequately addressed and warrant further exploration. Understanding and managing expectations, including consideration of fears, misconceptions, and potential challenges, could promote engagement. Exploration of beliefs, particularly in those who refuse or terminate therapy, is essential to further our understanding of factors affecting services users' decision-making processes, as well as the efficacy of therapy. PMID- 26616438 TI - Angiotensin II type 2 receptor is expressed in human sperm cells and is involved in sperm motility. AB - OBJECTIVE: To investigate the presence of angiotensin II type 2 receptor (AT2R) in human spermatozoa and its implication in sperm fertility status. DESIGN: We carried out expression assays for AT2R by reverse transcription-polymerase chain reaction, Western blot, immunofluorescence, and flow cytometry techniques in human sperm cells. Percentage of AT2R-positive sperm cells was analyzed by flow cytometry. SETTING: Assisted reproduction unit and academic research laboratory. PATIENT(S): Ninety-seven human semen samples from the Clinica IVI Bilbao. INTERVENTION(S): All samples were examined and classified according to World Health Organization guidelines. Spermatozoa were isolated from semen on discontinuous colloidal silica gradient (45%-90%) and swim-up techniques. MAIN OUTCOME MEASURE(S): Presence and location of the AT2R in spermatozoa and percentage of AT2R-positive sperm cells measured by flow cytometry. RESULT(S): We demonstrated the existence of AT2R and its transcript in human sperm by Western blot and reverse transcription-polymerase chain reaction. Immunofluorescence studies showed that AT2R is mainly located at the equatorial segment of the sperm head. The AT2R levels were associated with sperm motility parameters. Particularly, we found a significant positive correlation between AT2R and spermatozoa with progressive motility grade and a significant negative correlation with immotile spermatozoa, both in fresh semen samples and in prepared sperm cells. Regarding pathologic studies, the levels of AT2R measured by flow cytometry were lower in spermatozoa of asthenozoospermic men than in normozoospermic controls. CONCLUSION(S): Angiotensin II type 2 receptor is present in human semen and may be involved in the control of sperm motility. In depth understanding of the proteins involved in sperm motility can help to elucidate the role of these proteins in male infertility as well as to establish new biomarkers for male infertility. PMID- 26616439 TI - Time-lapse deselection model for human day 3 in vitro fertilization embryos: the combination of qualitative and quantitative measures of embryo growth. AB - OBJECTIVE: To present a time-lapse deselection model involving both qualitative and quantitative parameters for assessing embryos on day 3. DESIGN: Retrospective cohort study and prospective validation. SETTING: Private IVF center. PATIENT(S): A total of 270 embryos with known implantation data (KID) after day 3 transfer from 212 IVF/intracytoplasmic sperm injection (ICSI) cycles were retrospectively analyzed for building the proposed deselection model, followed by prospective validation using an additional 66 KID embryos. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Morphological score on day 3, embryo morphokinetic parameters, abnormal cleavage patterns, and known implantation results. RESULT(S): All included embryos were categorized either retrospectively or prospectively into 7 grades (A+, A, B, C, D, E, F). Qualitative deselection parameters included poor conventional day 3 morphology, abnormal cleavage patterns identified via time-lapse monitoring, and <8 cells at 68 hours postinsemination. Quantitative parameters included time from pronuclear fading (PNF) to 5-cell stage and duration of 3-cell stage. KID implantation rates of embryos graded from A+ to F were 52.9%, 36.1%, 25.0%, 13.8%, 15.6%, 3.1%, and 0 respectively (area under the curve [AUC] = 0.762; 95% confidence interval [CI], 0.701-0.824), and a similar pattern was seen in either IVF (AUC = 0.721; 95% CI, 0.622-0.821) or ICSI embryos (AUC = 0.790; 95% CI, 0.711-0.868). Preliminary prospective validation using 66 KID embryos also showed statistically significant prediction in Medicult (AUC = 0.750; 95% CI, 0.588-0.912) and Vitrolife G-Series (AUC = 0.820; 95% CI, 0.671-0.969) suites of culture media. CONCLUSION(S): The proposed model involving both qualitative and quantitative deselection effectively predicts day 3 embryo implantation potential and is applicable to all IVF embryos regardless of insemination method by using PNF as the reference starting time point. PMID- 26616440 TI - Assessing new terminal body and facial hair growth during pregnancy: toward developing a simplified visual scoring system for hirsutism. AB - OBJECTIVE: To study the distribution and progression of terminal hair growth in pregnant women and to determine the feasibility of a simplified scoring system for assessing hirsutism. DESIGN: Prospective follow-up observational study. SETTING: Academic hospital. PATIENT(S): A total of 115 pregnant women (discovery cohort) and 1,159 women with polycystic ovary syndrome (PCOS) (validation cohort). INTERVENTION(S): Facial and body terminal hair growth assessed by modified Ferriman and Gallwey score system (mFG score), and total testosterone (TT) level detected by liquid chromatography with tandem mass spectrometry. MAIN OUTCOME MEASURE(S): Degree of facial and body terminal hair growth. RESULT(S): The serum TT level and mFG score increased as pregnancy progressed. Both the prospective study and receiver operating characteristics curve indicated that the body areas with the greatest contribution to hirsutism (defined as an mFG score >=5) with new terminal hair growth were the upper lip, lower back, lower abdomen, and thigh. A simplified mFG scoring system (sFG) was developed, and a cutoff value of >=3 was defined as hirsutism. Pregnant hirsute women were distinguished from nonhirsute women with an accuracy of 95.2%, sensitivity of 96.8%, and specificity of 94.3% for detecting hirsutism. This was further validated in the PCOS population with a sensitivity, specificity, and positive predictive value of 97.6%, 96.4%, and 96.4%, respectively. CONCLUSION(S): This study suggests that the upper lip, lower back, lower abdomen, and thigh may be an effective simplified combination of the mFG system for the evaluation of excess hair growth in Chinese women. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-OCH-14005012. PMID- 26616441 TI - Evaluation of the antiproliferative, proapoptotic, and antiangiogenic effects of a double-stranded RNA mimic complexed with polycations in an experimental mouse model of leiomyoma. AB - OBJECTIVE: To assess the antiproliferative, proapoptotic, and antiangiogenic effects of the double-stranded RNA mimic polyinosine-polycytidylic acid (pIC) complexed with polyethylenimine [pIC(PEI)] in xenografted human leiomyomas. DESIGN: Heterologous leiomyoma mouse model. SETTING: University-affiliated infertility center. ANIMAL(S): Ovariectomized and hormone-replaced nude mice (n = 16) who received human leiomyoma fragment transplantation. INTERVENTION(S): Leiomyoma fragments placed in the peritoneum of 5-week-old nude female mice and treated with the vehicle (n = 8) or 0.6 mg/kg [pIC(PEI)] (n = 8) for 4 weeks. MAIN OUTCOME MEASURE(S): The size of the leiomyoma implants, and cellular proliferation (Ki67), vascularization (PECAM), and apoptosis (OH-ends) assessed by quantitative immunohistochemical/immunofluorescent analysis of the recovered implants. RESULT(S): No significant differences were observed in the size of the leiomyoma implants between groups. Vascularization and proliferation were significantly decreased, and apoptosis was increased in the [pIC(PEI)]-treated group versus control. CONCLUSION(S): We hypothesize that the antiangiogenic and apoptotic effects exerted by [pIC(PEI)] might lead to a decrease in lesion size in this animal model if the compound is administered for longer periods of time. This study provides promising data on [pIC(PEI)] as a potential novel therapeutic agent against human leiomyoma. PMID- 26616442 TI - The future of reproductive medicine centers. PMID- 26616443 TI - Assessing the Bonding Properties of Individual Molecular Orbitals. AB - Molecular orbitals (MOs), while one of the most widely used representations of the electronic structure of a system, are often too complex to intuit properties. Aside from the simplest of cases, it is not necessarily possible to visually tell which orbitals are bonding or antibonding along particular directions, especially in cases of highly delocalized and nontrivial bonding like metal clusters or solids. We propose a method for easily assessing and comparing the relative bonding contributions of MOs, by calculating their response to stress (e.g., compression). We find that this approach accurately describes relative bonding or antibonding character in both the simplest cases and provides new insight in more complex cases. We test the approach on four systems: H2, Am2, benzene, and the Pt4 cluster. In exploring this methodology, a scheme became elucidated, for predicting changes in the ground electronic configuration upon compression, including changes in bonding order, angular momenta of occupied MOs, and trends in MO ordering. We note that the applications of this work go beyond simple molecules and could be straightforwardly extended to, for example, solids and their response to stress along the specific crystallographic plane. Additionally, predictions of structures and properties of chemical systems under stress could result from the emerging intuition about changes in the electronic structure. PMID- 26616444 TI - Acute and additive toxicity of ten photosystem-II herbicides to seagrass. AB - Photosystem II herbicides are transported to inshore marine waters, including those of the Great Barrier Reef, and are usually detected in complex mixtures. These herbicides inhibit photosynthesis, which can deplete energy reserves and reduce growth in seagrass, but the toxicity of some of these herbicides to seagrass is unknown and combined effects of multiple herbicides on seagrass has not been tested. Here we assessed the acute phytotoxicity of 10 PSII herbicides to the seagrass Halophila ovalis over 24 and/or 48 h. Individual herbicides exhibited a broad range of toxicities with inhibition of photosynthetic activity (?F/F(m)') by 50% at concentrations ranging from 3.5 MUg l(-1) (ametryn) to 132 MUg l(-1) (fluometuron). We assessed potential additivity using the Concentration Addition model of joint action for binary mixtures of diuron and atrazine as well as complex mixtures of all 10 herbicides. The effects of both mixture types were largely additive, validating the application of additive effects models for calculating the risk posed by multiple PSII herbicides to seagrasses. This study extends seagrass ecotoxicological data to ametryn, metribuzin, bromacil, prometryn and fluometuron and demonstrates that low concentrations of PSII herbicide mixtures have the potential to impact ecologically relevant endpoints in seagrass, including ?F/F(m)'. PMID- 26616445 TI - beta-cell regenerative efficacy of a polysaccharide isolated from methanolic extract of Tinospora cordifolia stem on streptozotocin -induced diabetic Wistar rats. AB - The use of herbal supplements either as extracts or plant-derived individual molecules has significantly increased in the process of drug discovery and development for their potential efficacy or reduced risk in treating human disorders. Tinospora cordifolia (T. cordifolia) is a widely used herbal source to treat various human ailments, including diabetes mellitus. The present study was aimed on evaluating the antidiabetic property of a novel polysaccharide isolated from the methanolic extract of T. cordifolia stem. Bioassay guided fractionation was followed to isolate a compound from the methanol extract. The compound was administered orally at a dose of 20 mg/kg.b.wt for 60 days to control and STZ induced diabetic male Wistar rats. It was found that plasma glucose was significantly (p < 0.05) reduced compared to normal. Oral administration of the compound significantly decreased HBA1c, triglycerides and total cholesterol and at the same time markedly increased hemoglobin, tissue glycogen and HDL cholesterol. Also the compounds restored the altered carbohydrate metabolizing enzymes, insulin, C-peptide, (14)C-glucose oxidation levels to near normal. In addition, the histological studies revealed that there was regeneration of beta cells in the pancreatic sections. The expression of Glut-4 mRNA and protein in the gasrtocnemius muscle were significantly enhanced after the compound treatment. These results confirm that the novel polysaccharide possesses hypoglycemic, glucose oxidizing, hypolipidemic and beta-cell regenerative properties and hence it could be developed into potential oral hypoglycemic drug with lesser side effects. PMID- 26616446 TI - Improvement of physiological parameters of rats subjected to hypercaloric diet, with the use of Pereskia grandifolia (Cactaceae) leaf flour. AB - OBJECTIVE: The aim of the present study was to investigate the anti-obesity effects of Pereskia grandifolia leaf flour on rats fed a hypercaloric diet. METHODS: After a hypercaloric diet for 10 weeks, 21 animals were divided into the following groups and were fed the following diets for 4 weeks: control (CH), hypercaloric diet with P. grandifolia flour (PGF) 5%, and hypercaloric diet with PGF 10%. Several measurements were performed including body weight, food consumption, body mass index, Lee index, liver weight, liver and body moisture content, and body and hepatic lipid level. Data were analyzed by Tukey's test at 5% probability. RESULTS: Rats fed PGF diet had decreased food consumption and body weight and showed lower body mass and Lee indices compared to control group. At week 2, weight of the PGF 10% group was statistically lower than the control group (CH). At week 4, the PGF 10% group demonstrated the highest body weight loss compared to the other two groups. There were no significant difference in total lipids and moisture level between the groups; however, rats fed PGF diet had lower hepatic lipids levels than control group and reduced liver weight. CONCLUSION: This suggests that PGF induced weight loss and decreased hepatic lipid level and may be effective in treating obesity and related metabolic diseases. PMID- 26616447 TI - Contribution of primary care to health: an individual level analysis from Tibet, China. AB - INTRODUCTION: There have been significant improvements in health outcomes in Tibet, health disparities between Tibet and the rest of China has been greatly reduced. This paper tests whether there was a positive association between good primary care and better health outcomes in Tibet. METHOD: A validated Tibetan version of the Primary Care Assessment Tool (PCAT-T) was used to collect data on 1386 patients aged over 18 years old accessing primary care. Self-rated health (SRH) was employed to measure health outcomes. A multiple binary logistic regression model was used to explore the association between primary care quality and self-rated health status after controlling for socio-demographic and lifestyle variables. RESULTS: This study found that primary care quality had a significant positive association with self-rated health status. Among the nine domains of PCAT-T, family centeredness domain had the highest Odds Ratio (OR = 1.013) with SRH. Patients located in rural area, with higher education levels, without depression, and less frequent drinking were more likely to self-rate as "good health" compared with the reference group. CONCLUSIONS: In Tibet, higher quality primary care was associated with better self-rated health status. Primary care should be much strengthened in future health system reform in Tibet. PMID- 26616448 TI - Fabrication of PEG-carboxymethylcellulose hydrogel by thiol-norbornene photo click chemistry. AB - Both poly(ethylene glycol) (PEG) and carboxymethylcellulose (CMC) are biocompatible polymers, which have been widely utilized in biomedical fields. In this study, we demonstrated the fabrication of pH-sensitive PEG-CMC hydrogels based on thiol-norbornene photo-click reaction and characterized their properties, such as swelling ratio, stiffness, degradation, and protein drug release. For the hydrogel fabrication, tetra-arm PEG and CMC were functionalized with norbornene groups and thiol groups, respectively. The hydrogels fabricated with varying concentration (0-3%) of CMCSH and a fixed concentration (4%) of PEG4NB by orthogonal step-growth photopolymerization showed high gel fractions (~0.85). The presence of CMCSH in hydrogel did not affected gel point (~4 s) but significantly prolonged completion time of gelation. Swelling ratios of PEG-CMC increased from ~32 to ~60 and the shear elastic modulus decreased from ~3000 to ~600 Pa with an increase of CMCSH content (0-3%). PEG-CMC hydrogel containing more CMCSH not only underwent slower hydrolytic bulk degradation but also showed a slower BSA release in acidic condition. These results indicate thiol-norbornene PEG-CMC hydrogel has potential as pH-sensitive protein drug carrier. PMID- 26616449 TI - Use of thiol-ene click chemistry to modify mechanical and thermal properties of polyhydroxyalkanoates (PHAs). AB - In order to diversify the number of applications for poly[(R)-3 hydroxyalkanoates] (PHAs), methods must be developed to alter their physical properties so they are not limited to aliphatic polyesters. Recently we developed Escherichia coli LSBJ as a living biocatalyst with the ability to control the repeating unit composition of PHA polymers, including the ability to incorporate unsaturated repeating units into the PHA polymer at specific ratios. The incorporation of repeating units with terminal alkenes in the side chain of the polymer allowed for the production of random PHA copolymers with defined repeating unit ratios that can be chemically modified for the purpose of tailoring the physical properties of these materials beyond what are available in current PHAs. In this study, unsaturated PHA copolymers were chemically modified via thiol-ene click chemistry to contain an assortment of new functional groups, and the mechanical and thermal properties of these materials were measured. Results showed that cross-linking the copolymer resulted in a unique combination of improved strength and pliability and that the addition of polar functional groups increased the tensile strength, Young's modulus, and hydrophilic profile of the materials. This work demonstrates that unsaturated PHAs can be chemically modified to extend their physical properties to distinguish them from currently available PHA polymers. PMID- 26616450 TI - Improvement in physical and biological properties of chitosan/soy protein films by surface grafted heparin. AB - A series of chitosan/soy protein isolate (SPI) composite films (CS-n, n=0, 10 and 30, corresponding to SPI content in the composites) were prepared. Heparin was grafted onto the surface of CS-n to fabricate a series of heparinized films (HCS n). CS-n and HCS-n were characterized by ATR-Fourier transform infrared spectroscopy and water contact angle. The surface heparin density was measured by toluidine blue assay. The results showed that heparin has been successfully grafted onto the surface of CS-n. Heparin evenly distributed on the surface of the films and the heparin content increased with the increase of SPI content, and the hydrophilicity of the films was enhanced due to the grafted heparin. The cytocompatibility and hemocompatibility of CS-n and HCS-n were evaluated by cell culture (MTT assay, live/dead assay, cell morphology and cell density observation), platelet adhesion test, plasma recalcification time (PRT) measurement, hemolysis assay and thrombus formation test. HCS-n showed higher cell adhesion rate and improved cytocompatibility compared to the corresponding CS-n. HCS-n also exhibited lower platelet adhesion, longer PRT, higher blood anticoagulant indexes (BCI) and lower hemolysis rate than the corresponding CS-n. The improved cytocompatibility and hemocompatibility of HCS-n would shed light on the potential applications of chitosan/soy protein-based biomaterials that may come into contact with blood. PMID- 26616451 TI - Synthesis of potential antioxidants by synergy of ultrasound and acidic graphene nanosheets as catalyst in water. AB - Efficient synthesis of a set of bisphenolic compounds, resulting from the incorporation of 2,4-dialkylphenols and aromatic or aliphatic aldehydes, allowed the discovery of new bisphenols with relative modest to good antioxidant activity. Bisphenolic compounds were prepared via easy and simple approach under ultrasound irradiation in water. Sulfonated graphene nanosheets were employed as a catalyst for the synthesis of bisphenolic compounds. These compounds were obtained in high to excellent yields (88-98%) and relatively short reaction times (4-20 min). Moreover, some of the synthetic compounds were investigated and revealed outstanding antioxidant activity, when examined by a 1,1-diphenyl-2 picrylhydrazyl radical (DPPH) decolorization assay system. The proposed method has a novel viewpoint in the preparation of potential antioxidant compounds. PMID- 26616452 TI - Comparative insight into surfactants mediated amyloidogenesis of lysozyme. AB - Electrostatic and hydrophobic interactions have an important role in the protein aggregation. In this study, we have investigated the effect of charge and hydrophobicity of oppositely charged surfactants i.e., anionic (AOT and SDS) and cationic (CTAB and DTAB) on hen egg white lysozyme at pH 9.0 and 13.0, respectively. We have employed various methods such as turbidity measurements, Rayleigh light scattering, ThT, Congo red and ANS dye binding assays, far-UV CD, atomic force microscopy, transmission electron and fluorescence microscopy. At lower molar ratio, both anionic and cationic surfactants promote amyloid fibril formation in lysozyme at pH 9.0 and 13.0, respectively. The aggregation was proportionally increased with respect to protein concentration and hydrophobicity of surfactant. The morphology of aggregates at both the pH was fibrillar in structure, as visualized by dye binding and microscopic imaging techniques. Initially, the interaction between surfactants and lysozyme was electrostatic and then hydrophobic as investigated by ITC. This study demonstrates the crucial role of charge and hydrophobicity during amyloid fibril formation. PMID- 26616453 TI - Establishment of correlation between in-silico and in-vitro test analysis against Leishmania HGPRT to inhibitors. AB - Hypoxanthine Phosphoribosyltransferase (HGPRT; EC 2.4.2.8) is a central enzyme in the purine recycling pathway of all protozoan parasites. Protozoan parasites cannot synthesize purine bases (DNA/RNA) which is essential for survival as lack of de-novo pathway. Thus its good target for drug design and discovery as inhibition leads to cessation of replication. PRTase (transferase enzyme) has common PRTase type I folding pattern domain for its activities. Genomic studies revealed the sequence pattern and identified highly conserved residues that catalyzed the reaction in protozoan parasites. A recombinant protein has 24 kDa molecular mass (rLdHGPRT) was cloned, expressed and purified for testing of guanosine monophosphate (GMP) analogous compounds in-vitro by spectroscopically to the rLdHGPRT, lysates protein and MTT assay on Leishmania donovani. The predicted inhibitors of different libraries were screen into FlexX. The reported inhibitors were tested in-vitro. The 2'-deoxyguanosine 5'-diphosphate (DGD) (IC50 value 12.5 MUM) is two times more effective when compared to guanosine-5' diphosphate sodium (GD). Interestingly, LdHGPRT complex has shown stable after 24 ns in molecular dynamics simulation with interacting amino acids are Glu125, Ile127, Lys87 and Val186. QSAR studies revealed the correlation between predicted and experimental values has shown R2 0.998. Concludes that inversely proportional to their docked score with activities. PMID- 26616454 TI - Interference of salts used on aqueous two-phase systems on the quantification of total proteins. AB - In this study the interference of potassium phosphate, sodium citrate, sodium chloride and sodium nitrate salts on protein quantification by Bradford's method was assessed. Potassium phosphate and sodium citrate salts are commonly used in aqueous two-phase systems for enzyme purification. Results showed that the presence of potassium phosphate and sodium citrate salts increase the absorbance of the samples, when compared with the samples without any salt. The increase in absorptivity of the solution induces errors on protein quantification, which are propagated to the calculations of specific enzyme activity and consequently on purification factor. The presence of sodium chloride and sodium nitrate practically did not affect the absorbance of inulinase, probably the metals present in the enzyme extract did not interact with the added salts. PMID- 26616455 TI - Separation, characterization and anticancer activities of a sulfated polysaccharide from Undaria pinnatifida. AB - The purpose of this paper was to investigate separation, characterization and anticancer activities of a sulfated polysaccharide (SPUP) from Undaria pinnatifida. Firstly, polysaccharide from U. pinnatifida was separated by DEAE-52 cellulose and Sephacryl S-400 column chromatography. As results, SPUP was obtained with the yield of 19.42%. Then, SPUP was characterized using chemical analysis, gas chromatography, size-exclusion HPLC chromatography, UV-vis spectra and FT-IR spectrum. The content of total sugar, uronic acid, protein and sulfate radical were 80.48%, 3.21%, 7.12% and 29.14%, respectively. SPUP was a heteropolysaccharide composed of fucose, glucose and galactose in a molar percentage of 27.15:19.34:53.51 with molecular weight of 97.9 kDa. Finally, the strongly against breast cancer activity of SPUP was confirmed by DMBA-induced breast cancer rats model. AS results, SPUP can significantly restrain breast abnormal enlargement, prolong tumor latency and reduced tumor incidence. Immunomodulatory activity and regulating abnormal sex hormones level might contribute to its anticancer activities. PMID- 26616456 TI - Effects of phycocyanin on INS-1 pancreatic beta-cell mediated by PI3K/Akt/FoxO1 signaling pathway. AB - The level of methylglyoxal (MG), which is a side-product of metabolic pathways, particularly in glycolysis, is elevated in diabetes. Notably, the accumulation of MG causes a series of pathological changes. Phycocyanin (PC) has been demonstrated to show insulin-sensitizing effect, however, the underlying molecular mechanism remains elusive. The aim of this study was to investigate the protective effects of PC on INS-1 rat insulinoma beta-cell against MG-induced cell dysfunction, as well as the underlying mechanisms. PC was preliminarily verified to time-dependently activate PI3-kinase (PI3K) pathway, but the PI3K specific inhibitor Wortmannin blocked the effect of PC. Glucose-stimulated insulin secretion (GSIS) was impaired in MG-treated INS-1 cells. Furthermore, MG induced dephosphorylation of Akt and FoxO1, resulting in nuclear localization and transactivation of FoxO1. Nevertheless, these effects were all effectively attenuated by PC. The ameliorated insulin secretion was related to the changes of FoxO1 mediated by PC, which demonstrated by RNA interference. And, the dosage used in the above experiments did not affect beta-cell viability and apoptosis, although long-term MG induced cell apoptosis and mitochondrial dysfunction. In conclusion, PC was capable to protect INS-1 pancreatic beta-cell against MG induced cell dysfunction through modulating PI3K/Akt pathway and the downstream FoxO1. PMID- 26616457 TI - Should we diagnose and treat minimal and mild endometriosis before medically assisted reproduction? AB - The treatment of minimal or mild endometriosis prior to assisted reproduction (ranging from intrauterine insemination to in vitro fertilization [IVF]) to improve the likelihood of success is controversial. Ovulation suppression is commonly used in endometriosis to decrease pain, however, there is little evidence to suggest improvements in fertility associated with this technique. Moreover, current evidence is sparse and does not support ovarian suppression prior to intrauterine insemination with or without ovulation induction, while there is some evidence favoring ovarian suppression with gonadotropin releasing hormone agonists prior to IVF to improve pregnancy rates. However, the majority of studies were performed in women with moderate to severe endometriosis. There is currently conflicting evidence regarding surgical ablation or removal of endometriomas prior to IVF, and its outcome on pregnancy rates. This review highlights the paucity of data in the management of endometriosis prior to assisted reproductive technologies and suggests that further studies are needed. PMID- 26616458 TI - Coronary and peripheral stenting in aorto-ostial protruding stents: The balloon assisted access to protruding stent technique. AB - Treatment of aorto-ostial in-stent restenosis lesions represents a challenge for interventional cardiologists. Excessive protrusion of the stent into the aorta may lead to multiple technical problems, such as difficult catheter reengagement of the vessel ostium or inability to re-wire through the stent lumen in repeat interventions. We describe a balloon assisted access to protruding stent technique in cases where conventional coaxial engagement of an aorto-ostial protruding stent with the guide catheter or passage of the guide wire through the true lumen is not feasible. This technique is applicable both in coronary and peripheral arteries. PMID- 26616459 TI - Feasibility and safety of laparoscopic nephrectomy in uremic patients with end stage renal disease. AB - INTRODUCTION: The purpose of this study was to analyse the feasibility and safety of laparoscopic radical nephrectomy (LRN) vs. open radical nephrectomy (ORN), in terms of perioperative and postoperative outcomes, in uremic patients. METHODS: Between September 2007 and December 2013, 19 patients with end-stage renal disease (ESRD), who underwent LRN or ORN for chronic pyelonephritis, renal calculi, hydronephrosis, renal tumors, complicated cyst, or associated polycystic kidney, were retrospectively analysed. All patients with complete preoperative clinical and intraoperative parameters, including age at surgery, gender, body mass index (BMI), American Society of Anesthesiologists (ASA) score, surgical technique, operation time, complications, were available for further analyses. The 30-day complication rate in both groups was retrospectively review and graded according to the modified Clavien System in five grades. RESULTS: Overall, nine (47.3%) vs. 10 (52.7%) patients underwent LRN vs. ORN, respectively. The mean ASA score (2.7 +/- 0.8 vs. 2.9 +/- 0.7) did not show statistically significant differences in both groups (p = 0.632). None of the patients in G1 was converted to open surgery for intraoperative complications or CO2 retention. The estimated blood loss was 223 +/- 155 mL in G1 and 455 +/- 134 mL in G2 (p<0.005). Both groups were comparable with regard to mean operation time. The mean hospital stay was 5.95 +/- 1.85 days in G1 and 8.10 +/- 1.67 days in G2 (p<0.001). CONCLUSIONS: The present study revealed that laparoscopic surgery in uremic patients might be performed safely under the expertise of an experienced laparoscopic team. This surgical technique is a minimally invasive treatment, reduces blood loss, shortens postoperative hospital stay, minimizes wound pain, and encourages an earlier return to normal activity. PMID- 26616460 TI - Rare complication after a transrectal ultrasound guided prostate biopsy: a giant retroperitoneal hematoma. AB - Common complications related to transrectal ultrasound (TRUS) guided prostatic needle biopsy are hematuria, hematospermia, and hematochezia. To the best of our knowledge, we report the second case of a very large hematoma extending from the pelvis into the retroperitoneal space in literature.A 66-year-old man with a serum prostate-specific antigen (PSA) of 5.4 ng/ml was admitted to our department for a TRUS-guided prostatic needle biopsy. Laboratory values on the day before biopsy, including coagulation studies, were all normal. The patients did not take any anticoagulant drugs. No immediate complications were encountered. Nevertheless, 7 hours after the biopsy, the patient reached our emergency department with severe diffuse abdominal pain, hypotension, tachycardia, and confusional state. He underwent an ultrasonography and then a computed tomography (CT) scan that showed "a blood collection in the pelvis that extending to the lower pole of left kidney associated with a focus of active contrast extravasation, indicating active ongoing prostate bleeding." Consequently, he underwent a diagnostic angiography that showed no more contrast extravasation, without the need of embolization. Management of hematoma has been conservative and hematoma was completely reabsorbed 4 months later. PMID- 26616461 TI - Intravesical BCG therapy as cause of miliary pulmonary tuberculosis. AB - Immunotherapy with intravesical bacillus Calmette-Guerin (BCG) is considered the most effective adjuvant to endoscopic resection of bladder urothelial carcinoma in the therapeutic management of non-muscle invasive (NMIBC) at intermediate and high risk of recurrence and progression (pTa - pT1 and high-grade carcinoma in situ, CIS). Despite its proven efficacy, this type of treatment can determine local and systemic side effects of moderate or severe gravity, with the histological diagnosis of epithelioid granulomas in different organs, even in the absence of microbiological positivity of BCG. The immunotherapy with BCG is usually well tolerated and the virulence of the attenuated BCG is very low in immuno-competent patients, although only 16% of patients are able to receive all the instillations of the maintenance period (3 years) of treatment provided by the protocols, precisely because of side effects. Minor side effects usually resolve within a few hours or days. They develop in 3-5% of patients and usually consist of local infectious complications. Manifestations of BCG dissemination, such as vascular and ocular complications, are much less common, while BCG disseminated infections, with granulomatous pneumonia or hepatitis present, are quite rare, representing 0.5-2% of the complications recorded. We present the clinical case of granulomatous lung and possibly liver infection caused by BCG in a patient aged 56 years being treated for several weeks with intravesical BCG for NIMBC pT1 high grade associated with CIS. PMID- 26616462 TI - Optimizing the utilization of kidneys from small pediatric deceased donors under 15 kg by choosing pediatric recipients. AB - Currently, most kidneys from small pediatric deceased donors are transplanted into adult recipients (i.e., PTA). However, due to the weight mismatch, there is a high discard rate and a high ratio of EBKTs if adopting PTA. Here, we sought both to optimize utilization of these challenging but scarce donor grafts by selecting pediatric recipients and to characterize the feasibility and efficacy of this PTP allocation strategy. From February 2012 to October 2014, kidneys from 27 infant donors <= 15 kg were procured and distributed to 38 pediatric candidates in our center. The grafts were utilized for EBKT if the donor weighed 2.5-5 kg and for SKT if the donor weighed 5-15 kg, leading to 10 EBKTs and 28 SKTs. The overall utilization rate from small pediatric deceased donors was 94.12%. After a follow-up of 3-26 months, the graft survival rate was 89.47%, with four graft losses due to vascular thrombosis. Kidneys from low-body-weight donors should be applied to pediatric recipients, and the kidneys from infant donors >= 5 kg can be used in single-kidney-transplant procedures at experienced centers to optimize utilization. PMID- 26616463 TI - Antibiotic prophylaxis in cardiac surgery: If some is good, how come more is not better? PMID- 26616464 TI - Mitral valve repair for endocarditis can be performed 3 days after repair of a bleeding mycotic brain aneurysm. PMID- 26616465 TI - Inter-tube adhesion mediates a new pearling mechanism. AB - A common mechanism for intracellular transport is the controlled shape transformation, also known as pearling, of membrane tubes. Exploring how tube pearling takes place is thus of quite importance to not only understand the bio functions of tubes, but also promote their potential biomedical applications. While the pearling mechanism of one single tube is well understood, both the pathway and the mechanism of pearling of multiple tubes still remain unclear. Herein, by means of computer simulations we show that the tube pearling can be mediated by the inter-tube adhesion. By increasing the inter-tube adhesion strength, each tube undergoes a discontinuous transition from no pearling to thorough pearling. The discontinuous pearling transition is ascribed to the competitive variation between tube surface tension and the extent of inter-tube adhesion. Besides, the final pearling instability is also affected by tube diameter and inter-tube orientation. Thinner tubes undergo inter-tube lipid diffusion before completion of pearling. The early lipid diffusion reduces the extent of inter-tube adhesion and thus restrains the subsequent pearling. Therefore, only partial or no pearling can take place for two thinner tubes. For two perpendicular tubes, the pearling is also observed, but with different pathways and higher efficiency. The finite size effect is discussed by comparing the pearling of tubes with different lengths. It is expected that this work will not only provide new insights into the mechanism of membrane tube pearling, but also shed light on the potential applications in biomaterials science and nanomedicine. PMID- 26616467 TI - Male irradiation affects female remating behavior in Anastrepha serpentina (Diptera: Tephritidae). AB - Female remating in target pest species can affect the efficacy of control methods such as the Sterile Insect Technique (SIT) but very little is known about the postcopulatory mating behavior of these pests. In this study, we investigated the remating behavior of female Anastrepha serpentina (Diptera: Tephritidae), an oligophagous pest of Sapotaceae. First, we tested how long the sexual refractory period of females lasted after an initial mating. Second, we tested the effect of male and female sterility, female ovipositing opportunities and male density on female propensity to remate. Lastly, we tested if the amount of sperm stored by females was correlated to the likelihood of females to remate. We found that receptivity of mass-reared A. serpentina females had a bimodal response, with up to 16% of mass-reared A. serpentina females remating five days after the initial copulation, decreasing to 2% at 10 and 15 days and increasing to 13% after 20 days. Compared to fertile males, sterile males were less likely to mate and less likely to inhibit females from remating. Copula duration of sterile males was shorter compared to fertile males. Remating females were less likely to mate with a sterile male as a second mate. Sterile females were less likely to mate or remate compared to fertile females. Opportunity to oviposit and male density had no effect on female remating probability. Sperm numbers were not correlated with female likelihood to remate. Information on the post-copulatory behavior of mass reared A. serpentina will aid fruit fly managers in improving the quality of sterile males. We discuss our results in terms of the differences this species presents in female remating behavior compared to other tephritids. PMID- 26616466 TI - TAS-102: a novel antimetabolite for the 21st century. AB - TAS-102, a novel antimetabolite combination chemotherapy agent, consists of a rediscovered antimetabolite agent, trifluorothymidine (trifluridine) combined with the metabolic inhibitor of thymidine phosphorylase, tipiracil, in a 1:0.5 molar ratio. Mechanism of action studies suggest that this agent works by incorporation into DNA. Both preclinical and clinical studies demonstrate that this agent is noncross-resistant with 5-fluorouracil. Tipiracil may also have antiangiogenic effects through inhibition of thymidine phosphorylase. Recent randomized Phase II and III trials demonstrate clinical activity (improved progression-free survival, time to decrease in performance status, prolonged overall survival) in metastatic colorectal cancer refractory to all standard agents. Monotherapy with TAS-102 has now been approved for this indication in Japan and in the USA. PMID- 26616468 TI - Incidence and outcomes after bariatric surgery in older patients: a state-wide data-linked cohort study. AB - BACKGROUND: The burgeoning problem of obesity is seen most profoundly in older populations. Despite the dramatic increase in bariatric surgery rates over the last 20 years, weight reduction surgery is largely restricted to younger patients. METHODS: This retrospective, longitudinal, self-matched, population based cohort study assessed the incidence and outcomes of all patients undergoing bariatric surgery who were >=55 years old in Western Australia between 2007 and 2011. The mean preoperative and post-operative follow-up periods were 2.5 years and 3.4 years, respectively. RESULTS: Of the 12 062 bariatric surgical operations recorded during the study period, 2179 (18.1%) were performed in patients aged >=55 years old. Older bariatric patients were statistically more likely to require longer hospital admissions (2.85 versus 2.65 days, P < 0.001), have post operative complications (12.0 versus 6.3%, P < 0.001) and require intensive care admissions (8.2 versus 4.3%, P = 0.001) compared to patients <55 years old. However, both 30-day (no deaths in the older cohort) and long-term mortality rates (1.07 versus 0.42 deaths per 1000 patient-years, P = 0.10) remained relatively low. All-cause long-term hospitalization rates were also significantly reduced (P < 0.001) after bariatric surgery for patients who were older than 55 years compared to before surgery. CONCLUSION: Despite older age being associated with a higher risk of complications and longer hospital stays, there was a reduction in subsequent overall hospitalizations for older patients after bariatric surgery, suggesting that bariatric surgery may still confer health benefits to carefully selected obese older patients who cannot achieve weight loss by other means. PMID- 26616469 TI - Is uremic pruritus still an important clinical problem in maintenance hemodialysis patients? PMID- 26616470 TI - Mortality Patterns of Hydro-Geomorphologic Disasters. AB - Social impacts caused by floods and landslides in Portugal in the period of 1865 2010 are gathered in the DISASTER database. This database contains 1,902 hydro geomorphologic cases that caused 1,248 fatalities (81% and 19% associated with floods and landslides, respectively). The use of the DISASTER database allowed for: (i) the analysis of the frequency and the temporal evolution of fatal floods and landslides; (ii) the analysis of the spatio-temporal distribution of fatalities; (iii) the identification of the most deadly flood and landside types; (iv) the verification of gender tendencies in mortalities; and (v) the evaluation of individual and societal risk. The highest number of flood and landslide cases and related mortalities occurred in the period of 1935-1969. After this period, the number of flood and landslide mortalities decreased, although landslide fatalities remained higher than those registered in the period of 1865-1934. The occurrence of flood fatalities was widespread in the country, with an important cluster in the Lisbon region and in the Tagus valley, while fatalities caused by landslides mainly occurred in the north of the Tagus valley. Flash floods caused the majority of fatalities associated with floods, while falls and flows were responsible for the highest number of fatalities associated with landslides. Males were found to have the highest frequency of fatalities. In the case of floods, the majority of fatalities were found both outdoors and inside of buildings in rural areas while fatalities inside buildings were dominant in landslide cases, mostly in rural areas. PMID- 26616471 TI - Liposome-Loaded Cell Backpacks. AB - Cell backpacks, or micron-scale patches of a few hundred nanometers in thickness fabricated by layer-by-layer (LbL) assembly, are potentially useful vehicles for targeted drug delivery on the cellular level. In this work, echogenic liposomes (ELIPs) containing the anticancer drug doxorubicin (DOX) are embedded into backpacks through electrostatic interactions and LbL assembly. Poly(allylamine hydrochloride)/poly(acrylic acid) (PAH/PAA)n , and poly(diallyldimethylammonium chloride)/poly(styrene sulfonate) (PDAC/SPS)n film systems show the greatest ELIP incorporation of the films studied while maintaining the structural integrity of the vesicles. The use of ELIPs for drug encapsulation into backpacks facilitates up to three times greater DOX loading compared to backpacks without ELIPs. Cytotoxicity studies reveal that monocyte backpack conjugates remain viable even after 72 h, demonstrating promise as drug delivery vehicles. Because artificial vesicles can load many different types of drugs, ELIP containing backpacks offer a unique versatility for broadening the range of possible applications for cell backpacks. PMID- 26616472 TI - Advances in crop proteomics: PTMs of proteins under abiotic stress. AB - Under natural conditions, crop plants are frequently subjected to various abiotic environmental stresses such as drought and heat wave, which may become more prevalent in the coming decades. Plant acclimation and tolerance to an abiotic stress are always associated with significant changes in PTMs of specific proteins. PTMs are important for regulating protein function, subcellular localization and protein activity and stability. Studies of plant responses to abiotic stress at the PTMs level are essential to the process of plant phenotyping for crop improvement. The ability to identify and quantify PTMs on a large-scale will contribute to a detailed protein functional characterization that will improve our understanding of the processes of crop plant stress acclimation and stress tolerance acquisition. Hundreds of PTMs have been reported, but it is impossible to review all of the possible protein modifications. In this review, we briefly summarize several main types of PTMs regarding their characteristics and detection methods, review the advances in PTMs research of crop proteomics, and highlight the importance of specific PTMs in crop response to abiotic stress. PMID- 26616473 TI - Different versions of the Alcohol Use Disorders Identification Test (AUDIT) as screening instruments for underage binge drinking. AB - BACKGROUND: The changes experienced in recent years in the conceptualization of binge drinking (BD) make it necessary to revise the usefulness of the existing instruments for its detection among minors. The AUDIT and its abbreviated versions have shown their utility in different populations and consumption ranges, but there has been little research into their use in the detection of BD among adolescents. This study tests the capacity of the AUDIT, AUDIT-C and AUDIT 3 to identify BD adolescents, indicating the optimal cut-off points for each sex. METHODS: High school students self-administered the AUDIT and completed a weekly self-report of their alcohol intake. BD is classified into different groups according to parameters like the quantity consumed and its frequency in the past six months, adjusting the cut-off points for each case. RESULTS: The results obtained with a sample of 634 adolescents (15-17 years old/52.2% female) indicate that cut-off points of 4 on the AUDIT and 3 on the AUDIT-C show the best fit. Dividing the sample by sexes, the AUDIT and the AUDIT-C would detect BD males with scores of 5 and 4, respectively (with the AUDIT-C being more sensitive), and BD females with a score of 3 on both (the more sensitive being the AUDIT). CONCLUSIONS: All three versions are adequate to classify BD adolescents but none of them made it possible to safely differentiate binge drinkers with different consumption intensities. PMID- 26616475 TI - Molecular Dynamics Force-Field Refinement against Quasi-Elastic Neutron Scattering Data. AB - Quasi-elastic neutron scattering (QENS) is one of the experimental techniques of choice for probing the dynamics at length and time scales that are also in the realm of full-atom molecular dynamics (MD) simulations. This overlap enables extension of current fitting methods that use time-independent equilibrium measurements to new methods fitting against dynamics data. We present an algorithm that fits simulation-derived incoherent dynamical structure factors against QENS data probing the diffusive dynamics of the system. We showcase the difficulties inherent to this type of fitting problem, namely, the disparity between simulation and experiment environment, as well as limitations in the simulation due to incomplete sampling of phase space. We discuss a methodology to overcome these difficulties and apply it to a set of full-atom MD simulations for the purpose of refining the force-field parameter governing the activation energy of methyl rotation in the octa-methyl polyhedral oligomeric silsesquioxane molecule. Our optimal simulated activation energy agrees with the experimentally derived value up to a 5% difference, well within experimental error. We believe the method will find applicability to other types of diffusive motions and other representation of the systems such as coarse-grain models where empirical fitting is essential. Also, the refinement method can be extended to the coherent dynamic structure factor with no additional effort. PMID- 26616476 TI - Anti-TNF-alpha therapies for the treatment of Crohn's disease: the past, present and future. AB - INTRODUCTION: Anti-TNF-alpha therapy is a novel approach that has transformed the way moderate-to-severe Crohn's disease (CD) is treated and has significantly improved clinical outcomes of patients with enhanced remission induction and maintenance efficacies. As a result, anti-TNF-alpha agents have become the primary cost driver in the treatment of CD, as the frequency of hospitalizations and surgical interventions have been drastically reduced. AREAS COVERED: In the review, the authors cover current anti-TNF-alpha treatments for CD including efficacy, mechanisms of action, pharmacokinetics and safety. In addition, the authors discuss future anti-TNF-alpha agents currently in the development pipeline including biosimilars, golimumab, oral AVX-470, TNF-alpha-kinoid vaccine, and non-biologic HMPL-004. EXPERT OPINION: While new therapeutics are in the pipeline like anti-integrin and anti-interleukin therapeutics, anti-TNF-alpha therapy remains at the forefront of CD treatment due to its long-term efficacy and safety profiles. The next horizon for new anti-TNF-alpha agents is biosimilars, which offer comparable safety and effectiveness to the originator molecules. Biosimilars promise to expand accessibility to anti-TNF-alpha therapy while significantly reducing the cost burden to patients and healthcare systems. PMID- 26616477 TI - So you think your assay is robust? PMID- 26616474 TI - In Vivo Linking of Membrane Lipids and the Anion Transporter Band 3 with Thiourea modified Amphiphilic Lipid Probes. AB - Membrane proteins interact with membrane lipids for their structural stability and proper function. However, lipid-protein interactions are poorly understood at a molecular level especially in the live cell membrane, due to current limitations in methodology. Here, we report that amphiphilic lipid probes can be used to link membrane lipids and membrane proteins in vivo. Cholesterol and a phospholipid were both conjugated to a fluorescent tag through a linker containing thiourea. In the erythrocyte, the cholesterol probe fluorescently tagged the anion transporter band 3 via thiourea. Tagging by the cholesterol probe, but not by the phospholipid probe, was competitive with an anion transporter inhibitor, implying the presence of a specific binding pocket for cholesterol in this ~100 kDa protein. This method could prove an effective strategy for analyzing lipid-protein interactions in vivo in the live cell membrane. PMID- 26616478 TI - Insulin-like growth factor binding protein-2 as a novel biomarker for disease activity and renal pathology changes in lupus nephritis. AB - Lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus. Invasive renal biopsy remains the gold standard for the diagnosis and management of LN. The objective of this study is to validate serum insulin like growth factor binding protein-2 (IGFBP-2) as a novel biomarker for clinical disease and renal pathology in LN. Eighty-five biopsy-proven lupus nephritis patients, 18 chronic kidney disease (CKD) patients and 20 healthy controls were recruited for enzyme-linked immunosorbent assay (ELISA) testing of serum IGFBP-2 levels. Compared to CKD patients of origins other than lupus or healthy controls, serum IGFBP-2 levels were elevated significantly in LN patients. Serum IGFBP-2 was able to discriminate LN patients from the other two groups of patients [area under the curve (AUC) = 0.65, 95% confidence interval (CI) = 0.52-0.78; P = 0.043 for LN versus CKD; 0.97, 95% CI = 0.93-1.00; P < 0.0001 for LN versus healthy controls]. Serum IGFBP-2 was a potential indicator of both global disease activity and renal disease activity in LN patients, correlated with serum creatinine levels (r = 0.658, P < 0.001, n = 85) and urine protein-to-creatinine levels (r = 0.397, P < 0.001, n = 85). More importantly, in 19 concurrent patient samples, serum IGFBP-2 correlated with the chronicity index of renal pathology (r = 0.576, P = 0.01, n = 19) but not renal pathological classification. In conclusion, serum IGFBP-2 is a promising biomarker for lupus nephritis, reflective of disease activity and chronicity changes in renal pathology. PMID- 26616479 TI - Iron casein succinylate-chitosan coacervate for the liquid oral delivery of iron with bioavailability and stability enhancement. AB - Iron casein succinylate (ICS) liquid oral preparation as iron supplement has uncomfortable taste after a long period of storage because of its stability, and poor bioavailability of iron compared to any other iron preparations. To improve the chemical stability of ICS and enhance the bioavailability of iron, chitosan ICS nanoparticles (NPs) were prepared by complex coacervation method and stabilized with polyethylene glycol (PEG) 400. NPs were spherical (mean diameter of 830-1070 nm) with positive charge (+30-60 mV) depending on the composition of NPs. Addition of PEG400 (2 w/v %) increased the zeta potential (26-50 %) and physical stability of chitosan-ICS NPs suspension. Also, NPs decreased iron release compared to ICS after 7-weeks of storage at 4 degrees C. NPs markedly increased the permeability of iron in Caco-2 cell up to 32-38-fold compared to ICS, while physical mixture of chitosan and ICS increased the iron permeability only 2.5-fold. In summary, NPs improved the physicochemical stability and enhanced the transport of iron compared to other iron preparations in Caco-2 cell model. Thus, chitosan-ICS coacervate might be a promising candidate as a liquid oral iron delivery system for iron deficiency patients with stability and bioavailability enhancement. PMID- 26616480 TI - Correction to Formation of a Stacked Dimeric G-Quadruplex Containing Bulges by the 5'-Terminal Region of Human Telomerase RNA (hTERC). PMID- 26616481 TI - The functional-cognitive framework for psychological research: Controversies and resolutions. AB - The scientific goals, values and assumptions of functional and cognitive researchers have propelled them down two very different scientific pathways. Many have, and continue to argue, that these differences undermine any potential communication and collaboration between the two traditions. We explore a different view on this debate. Specifically, we focus on the Functional-Cognitive (FC) framework, and in particular, the idea that cognitive and functional researchers can and should interact to the benefit of both. Our article begins with a short introduction to the FC framework. We sweep aside misconceptions about the framework, present the original version as it was outlined by De Houwer (2011) and then offer our most recent thoughts on how it should be implemented. Thereafter, we reflect on its strengths and weaknesses, clarify the functional (effect-centric vs. analytic-abstractive) level and consider its many implications for cognitive research and theorising. In the final section, we briefly review the articles contained in this Special Issue. These contributions provide clear examples of the conceptual, empirical and methodological developments that can emerge when cognitive, clinical, personality and neuroscientists fully engage with the functional-cognitive perspective. PMID- 26616482 TI - [A case of orbital apex syndrome due to aspergillus infection that avoided loss of visual acuity by optic canal decompression]. AB - A 71-year-old woman was admitted to our hospital complaining of left orbital pain, headache, diplopia and left-sided ptosis, which she had suffered for two months. On examination, the patient had loss of visual acuity, left-sided ptosis, lateral gaze disturbance, and was diagnosed as having left orbital apex syndrome. An abnormal signal to the left orbital cone was detected on MRI. Serum beta-D glucan was increased, and serum Aspergillus antigen and antibody were both positive. Although antifungal drugs (voriconazole and liposomal amphotericin B) were administered, the symptoms deteriorated. The patient then underwent optic nerve decompression surgery and was treated with intravenous methylprednisolone, which gradually improved the patient's symptoms, Aspergillus hyphae were confirmed by pathological examination. To obtain good prognosis for patients with orbital apex syndrome associated with Aspergillus infection, optic nerve decompression surgery should be considered. PMID- 26616483 TI - [A case of Gerstmann-Straussler-Scheinker disease presented with numbness in the lower extremities]. AB - We report a patient of 68-year-old woman who developed numbness of feet in 2008. Ataxic gait disturbance, truncal ataxia, muscle weakness of lower limbs have gradually appeared and she couldn't walk without assistance in 2013. Her cognitive function declined subacutely in 2014. When she was admitted to our hospital, it was difficult to fully evaluate her neurological symptoms and cognitive function. The tendon reflex were absent and Babinski reflex showed positive in both sides of the lower limbs. Diffusion weighted image of MRI showed high intensity in cerebrocortical area, and variation P102L prion protein gene mutation was detected. We diagnosed her with Gerstmann-Straussler-Scheinker (GSS) disease. Cerebellar symptom such as ataxic gait occurs as the initial manifestation in 90% of patients with GSS disease. Her initial symptom was numbness of lower limbs and cerebellar symptom gradually appeared during the course of disease. In addition, her cognitive function declined six years after the onset. This case presented atypical clinical course as described above. Consequently, it led to diagnostic delay in GSS disease. PMID- 26616484 TI - [Cryptococcal meningoencephalitis presenting with treatable cognitive impairment and involuntary movement]. AB - The patient is a 72-year-old Japanese woman. Seven years prior to admission, multiple nodules in her left lung were found. Bronchoscopic biopsy of the nodules did not provide a confirmative diagnosis, and probable diagnosis of cryptococcosis was made. Follow-up CT scan of the chest revealed reduction in size of the lung nodules. She was admitted to our hospital due to progressive cognitive impairment and difficulty in walking that lasted for 5 months. On admission, athetotic involuntary movement was observed in her lower extremities, predominantly in the right side. Blood and cerebrospinal fluid culture of the patient were positive for Cryptococcus neoformans. Antifungal drugs resolved the cognitive impairment, the difficulty in walking, and the involuntary movement. We assessed the cognitive impairment and observed the clinical improvement of the patient, with the use of neuropsychological examinations. To our knowledge, there has been only a few reported case of cryptococcal meningoencephalitis presenting with treatable cognitive impairment and involuntary movement. PMID- 26616485 TI - [An autopsy case of progressive generalized muscle atrophy over 14 years due to post-polio syndrome]. AB - We report the case of a 72-year-old man who had contracted acute paralytic poliomyelitis in his childhood. Thereafter, he had suffered from paresis involving the left lower limb, with no relapse or progression of the disease. He began noticing slowly progressive muscle weakness and atrophy in the upper and lower extremities in his 60s. At the age of 72, muscle weakness developed rapidly, and he demonstrated dyspnea on exertion and dysphagia. He died after about 14 years from the onset of muscle weakness symptoms. Autopsy findings demonstrated motoneuron loss and glial scars not only in the plaque-like lesions in the anterior horns, which were sequelae of old poliomyelitis, but also throughout the spine. No Bunina bodies, TDP-43, and ubiquitin inclusions were found. Post-polio syndrome is rarely fatal due to rapid progressive dyspnea and dysphagia. Thus, the pathological findings in the patient are considered to be related to the development of muscle weakness. PMID- 26616486 TI - [A case of Marchiafava-Bignami disease suggesting vasogenic edema]. AB - A 61-year-old alcoholic man was admitted to our hospital because of disturbance of consciousness. He also exhibited external ophthalmoplegia, diplopia and mild rigidity, but tendon reflex was normal. On brain MRI, diffusion weighted images (DWI) and apparent diffusion coefficient (ADC) map depicted high intensity in the splenium of the corpus callosum. DWI showed high intensity, but ADC map depicted iso-intensity in bilateral precentral gyri. Marchiafava-Bignami disease (MBD) was diagnosed. After intravenous drip of vitamin, his symptoms improved rapidly and the abnormal MRI findings in the splenium of the corpus callosum and bilateral precentral gyri disappeared gradually. MBD is pathologically characterized by demyelination and necrosis in the corpus callosum, which are generally caused by cytotoxic edema. Our case suggests that vasogenic edema may occur at the early stage of the MBD. PMID- 26616487 TI - [Ophthalmoplegia without severe painful eyelid swelling in acute dacryoadenitis: a case report]. AB - Here, we present a case of right eyelid drooping in a 79-year-old man. Neurological examination revealed ptosis of the right eye without severe painful eyelid swelling and redness. An ocular motility examination of the right eye revealed upward limitation and downward overshoot. The results of routine blood examinations were within normal limits, and no autoantibodies were detected. Orbital magnetic resonance images revealed mild right eyelid swelling and lacrimal gland enlargement, indicating orbital inflammation. The ocular discharge was positive for Staphylococcus hominis by culture and the patient was diagnosed as having acute dacryoadenitis. Treatment with topical and systemic administration of antibiotics rapidly improved symptoms. Ocular infection is not usually suspected in the absence of local severe painful swelling and redness, and painless acute dacryoadenitis presenting as ophthalmoplegia and ptosis may be misdiagnosed. Orbital inflammation may rapidly progress to orbital cellulitis with treatment delay, which may also lead to aggravation of ophthalmic prognosis. Therefore, neurologists should be aware of the possibility of acute dacryoadenitis occurring without the local severe inflammatory findings mimicking neurological diseases, and acute dacryoadenitis should be considered in patients with ophthalmoplegia even in the absence of severe painful eyelid swelling and redness. PMID- 26616488 TI - [A case of dural arteriovenous fistula at the craniocervical junction, which spinal MRI findings reveals increased intensity signal in Th3-medullary cone]. AB - A 60-year-old woman had transient weakness of the legs and urinary retention for six weeks. She presented with a gait disorder and was admitted to the hospital. She showed symptoms of paraplegia, tingling in the lower extremities, dysuria. She underwent an MRI, and T2-weighted images showed an enlargement of the thoracolumbar spinal cord and high intensity signal from Th3 to the medullary cone, and a contrast-enhanced T1-weighted image showed abnormal vessels anterior to the spine cord. Cervical and spinal angiography documented a dural arteriovenous fistula at the craniocervical junction that was fed by the right vertebral artery and the right ascending pharyngeal arteries and drained into the perimedullary veins. Surgical therapy improved her symptoms and MRI images. Craniocervical junction DAVF with thoracic-medullary cones lesion is rare. PMID- 26616489 TI - [Malignant lymphoma presented as recurrent multiple cranial nerve palsy after spontaneous regression of oculomotor nerve palsy: A case report]. AB - We report the case of a 62-year-old man who presented with malignant lymphoma as recurrent multiple cranial nerve palsy after spontaneous regression of oculomotor nerve palsy. He developed ptosis and diplopia due to right oculomotor nerve palsy. Brain MRI/MRA showed no abnormality, and he recovered with conservative medical management. Three months later, he showed diplopia due to right abducens nerve palsy and facial pain and trigeminal sensory loss. Neurological examination revealed multiple cranial nerve palsy involved cranial nerve III, V, IX, and X of the right side. Serum soluble interleukin-2 receptor levels were normal, and cerebrospinal fluid examination was unremarkable. Steroid and subsequent intravenous immunoglobulin therapy didn't improve his symptoms. Six weeks after his admission, he showed rapid enlargement of the cervical lymph node and the right tonsil, and post-contrast T1-weighted MRI showed enlargement and enhancement of the left infraorbital nerve, the bilateral cavernous sinus, the bilateral facial nerves, and the left trigeminal nerve. The histopathologic examination of the tonsil biopsy revealed diffuse large B cell lymphoma. The cause of these symptoms was thought to be infiltrating the cavernous sinus, and adjacent nerves. Spontaneous regression of malignant lymphoma is an exceptional event, but this possibility should be considered so as to the correct diagnosis and proper treatment. PMID- 26616490 TI - The role of interparticle interaction and environmental coupling in a two particle open quantum system. AB - The effects of bath coupling on an interacting two-particle quantum system are studied using tools from information theory. Shannon entropies of the one (reduced) and two-particle distribution functions in position, momentum and separable phase-space are examined. Results show that the presence of the bath leads to a delocalization of the distribution functions in position space, and a localization in momentum space. This can be interpreted as a loss of information in position space and a gain of information in momentum space. The entropy sum of the system, in the presence of a bath, is shown to be dependent on the strength of the interparticle potential and also on the strength of the coupling to the bath. The statistical correlation between the particles, and its dependence on the bath and interparticle potential, is examined using mutual information. A stronger repulsive potential between particles, in the presence of the bath, yields a smaller correlation between the particles positions, and a larger one between their momenta. PMID- 26616491 TI - Recombination reduction on lead halide perovskite solar cells based on low temperature synthesized hierarchical TiO2 nanorods. AB - Intensive research on the electron transport material (ETM) has been pursued to improve the efficiency of perovskite solar cells (PSCs) and decrease their cost. More importantly, the role of the ETM layer is not yet fully understood, and research on new device architectures is still needed. Here, we report the use of three-dimensional (3D) TiO2 with a hierarchical architecture based on rutile nanorods (NR) as photoanode material for PSCs. The proposed hierarchical nanorod (HNR) films were synthesized by a two-step low temperature (180 degrees C) hydrothermal method, and consist of TiO2 nanorod trunks with optimal lengths of 540 nm and TiO2 nanobranches with lengths of 45 nm. Different device configurations were fabricated with TiO2 structures (compact layer, NR and HNR) and CH3NH3PbI3, using different synthetic routes, as the active material. PSCs based on HNR-CH3NH3PbI3 achieved the highest power conversion efficiency compared to PSCs with other TiO2 structures. This result can be ascribed mainly to lower charge recombination as determined by impedance spectroscopy. Furthermore, we have observed that the CH3NH3PbI3 perovskite deposited by the two-step route shows higher efficiency, surface coverage and infiltration within the structure of 3D HNR than the one-step CH3NH3PbI(3-x)Cl(x) perovskite. PMID- 26616492 TI - Immigrants' outcome after a first-episode psychosis. AB - AIM: Immigration is a risk factor for psychosis emergence, and previous studies show that immigrants are less likely to engage in treatment for psychosis. However, the literature on outcome is scant and heterogeneous. This study was designed to compare first-generation (FGI) and second-generation immigrants (SGI) to non-immigrants' symptomatic and functional outcomes 2 years after a first episode psychosis (FEP). METHODS: A 2-year prospective longitudinal study of 223 FEP patients between 18 and 30 years took place in two early intervention services (EIS) in Montreal, Canada. RESULTS: Forty-two per cent of the sample were immigrants (FGI (n = 56), SGI (n = 38)). Compared with non-immigrants, immigrants had similar symptomatic and functioning profiles at baseline, 1 and 2 years, except that fewer SGI had a history of homelessness and more were living with their families. FGI were less likely to have a substance use disorder but more likely to pursue their studies and to present depressive symptoms. CONCLUSIONS: Even if immigrants are known to be at greater risk of developing psychosis, probably secondary to stress related to immigration, their symptomatic and functional outcomes, once engaged in EIS treatment, are similar to or sometimes better than non-immigrants' outcomes. Because immigrants tend to be less engaged in their follow-up, understanding why they disengage from treatment is crucial to develop better therapeutic approaches to better engage them as EIS treatment can improve their outcomes effectively. PMID- 26616493 TI - Engineering Cel7A carbohydrate binding module and linker for reduced lignin inhibition. AB - Non-productive binding of cellulases to lignin inhibits enzymatic hydrolysis of biomass, increasing enzyme requirements and the cost of biofuels. This study used site-directed mutagenesis of the Trichoderma Cel7A carbohydrate binding module (CBM) and linker to investigate the mechanisms of adsorption to lignin and engineer a cellulase with increased binding specificity for cellulose. CBM mutations that added hydrophobic or positively charged residues decreased the specificity for cellulose, while mutations that added negatively charged residues increased the specificity. Linker mutations that altered predicted glycosylation patterns selectively impacted lignin affinity. Beneficial mutations were combined to generate a mutant with 2.5-fold less lignin affinity while fully retaining cellulose affinity. This mutant was uninhibited by added lignin during hydrolysis of Avicel and generated 40% more glucose than the wild-type enzyme from dilute acid-pretreated Miscanthus. Biotechnol. Bioeng. 2016;113: 1369-1374. (c) 2015 Wiley Periodicals, Inc. PMID- 26616494 TI - Polydatin Induces Apoptosis and Inhibits Growth of Acute Monocytic Leukemia Cells. AB - Polydatin (PD), a component isolated from Polygonum cuspidatum, has various activities such as inhibiting platelet aggregation, lowering level of blood lipid, reducing lipid peroxidation, and so on. However, the antitumor activity of PD has been poorly reported. In the present study, effect of PD on cell proliferation was evaluated by Cell Counting Kit-8, and cell cycle and apoptosis were investigated by flow cytometry. Meanwhile, the protein expression level of Bc1-2, Bax, cyclin A, cyclin B, and cyclin D1, which associated with apoptosis and cell cycle were analyzed by Western blotting. Results show that PD could effectively inhibit the growth, arrest cells in S phase, and induce apoptosis of acute monocytic leukemia cell line THP-1; meanwhile, expression of cyclin D1 and Bc1-2 decreased significantly, and expression of Bax and cyclin A increased notably. All results suggest that PD maybe a potential therapeutic strategy for acute monocytic leukemia. PMID- 26616495 TI - Increased collagen cross-linking is a signature of dystrophin-deficient muscle. AB - INTRODUCTION: Collagen cross-linking is a key parameter in extracellular matrix (ECM) maturation, turnover, and stiffness. We examined aspects of collagen cross linking in dystrophin-deficient murine, canine, and human skeletal muscle. METHODS: DMD patient biopsies and samples from mdx mice and golden retriever muscular dystrophy dog samples (with appropriate controls) were analyzed. Collagen cross-linking was evaluated using solubility and hydroxyproline assays. Expression of the cross-linking enzyme lysyl oxidase (LOX) was determined by real time polymerase chain reaction, immunoblotting, and immunofluorescence. RESULTS: LOX protein levels are increased in dystrophic muscle from all species evaluated. Dystrophic mice and dogs had significantly higher cross-linked collagen than controls, especially in the diaphragm. Distribution of intramuscular LOX was heterogeneous in all samples, but it increased in frequency and intensity in dystrophic muscle. CONCLUSION: These findings implicate elevated collagen cross linking as an important component of the disrupted ECM in dystrophic muscles, and heightened cross-linking is evident in mouse, dog, and man. Muscle Nerve 54: 71 78, 2016. PMID- 26616496 TI - The Gore Global Registry for Endovascular Aortic Treatment: Objectives and Design. AB - BACKGROUND: The Global Registry for Endovascular Aortic Treatment (GREAT) is a prospective observational multicenter cohort registry that was initiated in November 2011. The aim of the GREAT is to collect contemporary real-world data on the performance of all Gore aortic endografts in the treatment of multiple aortic pathologies. The primary and secondary objectives, design, and future directions of the GREAT are described. METHODS: The GREAT aims to enroll 5000 consecutive patients with Gore thoracic and abdominal aortic endografts from multiple centers throughout the world. The GREAT has broad inclusion criteria with minimal exclusion criteria to reflect real-world practice such as including off-label use, nonstandard indications and devices deployed outside instruction for use. Follow-up will extend to 10 years providing major insights into the long-term durability and behavior of Gore aortic endografts. Primary end points include the incidence and timing of (1) endoleak of any type, (2) endograft migration and/or stent fracture, (3) endograft explantation, and (4) aortic rupture. Secondary end points include the following: (1) incidence of serious device events by pathology, (2) incidence of serious device events by aortic segment (ascending aorta, arch of aorta, descending thoracic aorta, abdominal aorta), (3) long-term survival by pathology, and (4) aorta-related mortality by pathology. RESULTS: As of June 2015, 2960 patients have been enrolled into the GREAT from 78 centers in Europe, the United States, Australia, New Zealand, and Brazil. The majority of patients and centers are from Europe and the United States. Completion of enrollment is anticipated to be in 2017 with interim results planned to be published during enrollment and on follow-up. CONCLUSIONS: Upon completion, the GREAT will be among the largest clinical registry to date of abdominal and thoracic aortic devices manufactured by a single sponsor. It will provide valuable real-world data on the use and durability of Gore aortic endografts in the treatment of a variety of aortic pathologies and devices deployed within and outside instruction for use. PMID- 26616497 TI - Proposal for Classification of the Great Saphenous Vein Aplasia by the B-mode Ultrasound. AB - BACKGROUND: The lack of the great saphenous vein (GSV) in its compartment is rarely mentioned in literature, although it happens in individuals with or without insufficiency of it. With the help of the B-mode ultrasound examination this vein can be easily identified. The aim of this study was to propose a classification for the findings. METHODS: Prospective study carried out for a period of 6 months in a sample of 2,665 lower limbs with ages ranging from 17 to 85, being that 1,286 patients are female. These patients underwent B-mode ultrasound examination as recommended by the literature. This evaluation determined whether there was a GSV aplasia by the analysis of its location in the saphenous compartment. RESULTS: After images were taken they were classified as: type I-aplasia only along the thigh, type II-aplasia only along the calf, type III-aplasia in the distal section of the thigh and proximal calf, type IV-vein in the saphenous compartment in the thigh and aplasia in the whole calf, type V-vein in the saphenous compartment only in a short segment in the proximal thigh, and type VI-vein with short segment in the saphenous compartment in the distal calf. From the total of 2,665 limbs, aplasia was found in 442 (16.6%). CONCLUSIONS: These anatomic findings attain an important role in daily practice, influencing the surgical decision, particularly with the arrival of endovascular procedures, such as the use of laser and thermoablation. PMID- 26616498 TI - Open versus Endovascular Repair of Arch and Descending Thoracic Aneurysms: A Retrospective Comparison. AB - BACKGROUND: Thoracic aortic aneurysms (TAAs) contribute significant mortality if left untreated, but surgical repair has historically carried substantial risks. METHODS: We sought to observe trends and outcomes of open and endovascular thoracic endovascular aneurysm repair thoracic aortic repairs, so conducted a retrospective review of all patients who presented for management of TAAs from 2003 to 2013 at 2 hospitals in Sydney, Australia. RESULTS: A total of 179 patients presented with TAAs over the study period, including 5 ruptures. Fifty two were treated nonoperatively, with 127 surgically repaired. Operative duration was significantly shorter in endovascular than open repair of arch (193 +/- 108 vs. 396 +/- 98 min, P = 0.0001) and descending aneurysms (242 +/- 116 vs. 422.5 +/- 161 min, P = 0.003). There were no differences in mortality or complication rates (including paraplegia), duration of hospital or intensive care unit stay, or transfusion requirements between endovascular and open TAA repairs. CONCLUSIONS: Apart from reduced surgical duration, this study revealed no benefits of endovascular over open TAA repair. Overall morbidity and mortality were low, even in elderly patients. PMID- 26616499 TI - Hemodialysis Access in the Elderly: Outcomes among Patients Older than Seventy. AB - BACKGROUND: Arteriovenous fistulae (AVF) are the preferred access for hemodialysis, however, there continues to be limited data guiding the surgical management of primary dialysis access creation in elderly end-stage renal disease patients. METHODS: This is an 8-year retrospective institutional study evaluating the operative and clinical characteristics of patients 70 years or above who underwent primary, first-ever, AVF or arteriovenous graft (AVG) creation. RESULTS: There was no overall significant difference in AVF and AVG primary (P = 0.127) and secondary (P = 0.870) patency. AVG had higher graft loss secondary to infection (P = 0.0002) and thrombosis (P = 0.0213). Survival was less than 50% at 2 years for AVF and AVG patients. An equal number of AVF and AVG patients who died had functional access at the time of death (P = 1.0000) with more AVG patients using their graft (initiating dialysis) before death (P = 0.0118). CONCLUSIONS: Elderly patient patency rates for AVF and AVG are satisfactory and support surgical access creation; however, overall 2-year survival is low. An equal number of AVF and AVG patients died with functioning surgical access, however, more AVG patients initiated dialysis and successfully used their access. Accordingly, special consideration needs to be given with regard to estimated timing until dialysis and predicted patient longevity. Delaying access creation until dialysis is needed and proceeding with AVG creation appears to be justified. PMID- 26616500 TI - Moderate to Deep Hypothermia in Patients Undergoing Thoracoabdominal Aortic Repair. AB - BACKGROUND: The aim of this study was to determine early and mid-term outcomes after open repair of thoracoabdominal aortic aneurysm, with moderate to deep hypothermia as part of proximal aortic management. METHODS: Between April 2009 and March 2015, 44 patients underwent thoracoabdominal aortic repair by total cardiopulmonary bypass at our institute. Our strategy was to use deep (<25 degrees C) hypothermic circulatory arrest when open proximal anastomosis is necessary (n = 18). Otherwise, proximal anastomosis with an aortic clamp was performed with moderate (25-30 degrees C) hypothermia without circulatory arrest (n = 26). Early and mid-term outcomes were assessed in all patients. RESULTS: In hospital mortality was observed in 1 patient (2.3%). Stroke was observed in 2 (4.5%) patients and a spinal cord ischemic injury in 4 (9.1%). Renal failure requiring new hemodialysis was observed in 5 patients (11.4%). There were 9 patients (20.5%) with early major adverse events (in-hospital death, stroke, spinal cord ischemic injury, renal failure requiring new hemodialysis, and prolonged intubation). Multivariable logistic regression analysis demonstrated that a history of abdominal aortic aneurysm repair (odds ratio 17.711, 95% confidence interval 1.274-246.426, P = 0.032) was the only independent predictor of early major adverse events. Deep hypothermic circulatory arrest was not an independent predictor of early major adverse events. At 5 years, overall freedom from death was 89.4 +/- 6.1%. CONCLUSION: Moderate to deep hypothermia as a constituent of proximal aortic management was safe and effective in patients undergoing open repair of thoracoabdominal aortic aneurysm. PMID- 26616501 TI - Preoperative Predictors of 30-Day Mortality and Prolonged Length of Stay after Above-Knee Amputation. AB - BACKGROUND: The above-knee amputation (AKA) is an operation of last resort with high postoperative morbidity and mortality. This study identifies preoperative risk factors predictive of both 30-day mortality and extended length of stay (LOS) in AKA patients. METHODS: Two hundred ninety-five AKA patients from 2004 to 2013 from a single institution were retrospectively reviewed using a deidentified electronic medical record. Rationally selected factors potentially influencing 30 day mortality and LOS were chosen, including demographics, etiologies, vascular surgical history, lifestyle factors, comorbidities, and laboratory values. Variables trending with one of the end points on bivariate analysis (P <= 0.10) were entered into multivariate forward stepwise regression models to determine independence as a risk factor (P <= 0.05). Subgroup analysis of AKA patients without a traumatic, burn, or malignant etiology was similarly conducted. RESULTS: Within the 295 patient cohort, 60% of the patients were male, 18% were African American, mean age was 58 years and mean body mass index was 28 kg/m(2). The 30-day mortality rate was 9%, and mean postoperative LOS of discharged patients was 9.3 days. Upon logistic regression, thrombocytopenia (platelet count < 250 * 10(6)/mL, P < 0.001, odds ratio 6.1) and preoperative septic shock (P = 0.02, odds ratio 5.1) were identified as independent risk factors for 30-day mortality. Upon linear regression, burn etiology (P < 0.001, B = 15.8 days), leukocytosis (white blood cell count > 12 * 10(6)/mL, P < 0.001, B = 6.2 days), and guillotine amputation (P < 0.001, B = 7.6 days) were independently associated with prolonged LOS. Excluding patients with AKAs due to trauma, burn, or malignancy, only thrombocytopenia (platelet count < 250 * 10(6)/mL, P < 0.001, odds ratio 10.2) and leukocytosis (white blood cell count > 12 * 10(6)/mL, P = 0.01, B = 5.2 days) were independent risk factors for in-hospital mortality and prolonged LOS, respectively. CONCLUSIONS: Preoperative septic shock and thrombocytopenia are independent risk factors for 30-day mortality after AKA, while burn etiology, leukocytosis, and guillotine amputation contribute to prolonged LOS. Awareness of these risk factors may help enhance both preoperative decision making and expectations of the hospital admission. PMID- 26616502 TI - Use of Tapered Balloons to Recanalize Occluded Below-the-Knee Arteries in Diabetic Patients with Critical Limb Ischemia. AB - BACKGROUND: The aim of this study was to evaluate the outcome of tapered balloon use in recanalization of long occlusions of below-the-knee (BTK) arteries in diabetic patients with critical limb ischemia (CLI). METHODS: Forty-nine occluded BTK arteries in 35 diabetic patients with CLI were revascularized in our Diabetic Foot Center between January and September 2014 using tapered balloons. Twelve month outcomes were evaluated in terms of healing of the lesions, survival, limb salvage, primary patency, primary assisted patency, and secondary patency. RESULTS: The patients were predominantly male (27/35, 77.1%) with a mean age of 70.9 years (+/-10.3 standard deviation [SD]). During the follow-up (mean duration 12.4 months +/- 4 SD), healing of the lesions was obtained in 27 of the 35 cases (77.1%). Estimated 12-month survival and limb salvage were 85.7% and 91.1%, respectively. Estimated 12-month primary patency, primary assisted patency, and secondary patency were 78.3%, 79%, and 88.9%, respectively. Univariate analysis demonstrated that the presence of chronic renal failure affected survival (P = 0.005), and assignment to Rutherford class 6 affected limb salvage (P = 0.005), primary patency (P < 0.001), and primary assisted patency (P < 0.001). Furthermore, the presence of coronary artery disease affected primary patency (P = 0.001) and primary assisted patency (P = 0.05). CONCLUSIONS: Tapered balloons are a safe and effective means to recanalize long occlusions of BTK arteries in diabetic patients with CLI. Outcomes are poorer in patients with major tissue loss and with a history of coronary artery disease. Further experience with larger groups is needed to validate these outcomes. PMID- 26616503 TI - Trends in Procedure Type, Morbidity and In-Hospital Outcomes of Patients with Peripheral Artery Disease: Data from the Brazilian Public Health System. AB - BACKGROUND: The prevalence of peripheral artery disease (PAD) is rising worldwide, with considerable impact on health care systems. METHODS: We aimed to characterize the trends in therapeutic procedures and outcomes of PAD in the Brazilian Public Health System Database (DataSUS) between 2008 and 2012. RESULTS: The number of hospitalizations remained stable from 2008 to 2012, although there was a significant change in the proportions of treatment modalities. In 2008, surgical revascularization (SR) = 8,001 (29%), endovascular revascularization (EVR) = 3,207 (11%), and clinical treatment (CT) = 16,887 (60%); and in 2012, SR = 7,882 (28%), EVR = 5,044 (18%), and CT = 15,225 (54%); P < 0.001, a 57% increase in EVR, and 9.8% decrease in CT. Total costs raised 37% (US $18.2-24.9 million, P < 0.001), with a marked 92% increase in EVR costs (US $5.1-9.8 million), compared with SR (11%) and CT (30%). Mortality decreased for EVR (2.0 1.4%, P = 0.048), increased for CT (5.1-5.8%, P = 0.002) and remained stable for SR. A nonsignificant increase was observed in total mortality (5.7-5.9%, P = NS). CONCLUSIONS: Our analysis depicts the high-PAD mortality in Brazil emphasizing the need of preventing and controlling cardiovascular risk factors. The impact of PAD in costs increased, mainly because of costs related to EVR. PMID- 26616504 TI - Failures and Lessons in the Endovascular Treatment of Symptomatic Isolated Dissection of the Superior Mesenteric Artery. AB - BACKGROUND: To discuss failures and lessons in the endovascular treatment of symptomatic isolated dissection of the superior mesenteric artery (SIDSMA). METHODS: Data from 33 patients with SIDSMA treated between July 2007 and September 2013 were retrospectively collected. The technical failures in and lessons from endovascular management were analyzed in terms of causes and prophylaxis. RESULTS: Eighteen patients were successfully treated medically, 13 underwent stent placement, 1 underwent a hybrid procedure, and 1 had open fenestration. Full follow-ups (37 +/- 21 months) were achieved in 28 patients. Failures to cannulate the true lumen occurred in 8 patients. Among these patients, femoral and brachial approaches were taken in 6 and 2 patients, respectively, and a 2-sided Fisher's exact test revealed no significant differences (P = 0.204). Among the 6 femoral failures, the true lumina were cannulated after conversion to the brachial approach in 3 cases. The perfusion of the distal SMA was not improved until the second stent was distally placed to cover the entire expanded false lumen in 1 case. Numerous branches originating from the false lumen were overlooked in 1 patient and were apparently compromised after stenting. Consequently, the patient died of intestinal necrosis. In a patient with a huge dissecting aneurysm, a stent was misplaced across the false lumen. Fortunately, a remarkable aneurysmal thrombosis formed at 3 months. In a patient who received a hybrid procedure, the stent was occluded at 2 weeks, most likely because the thrombus protruded into the stent. CONCLUSIONS: Difficulty in cannulating the true lumen is not uncommon in the endovascular treatment of SIDSMA, and the selection of the arterial approach would benefit from being based on the morphology of the SMA arch. The lengths and branches of the involvement of the false lumen should be evaluated beforehand. Covered stents would be a reasonable option for lumina that contain thrombi. PMID- 26616505 TI - Costs of Real-Life Endovascular Treatment of Critical Limb Ischemia: Report from Poland-A European Union Country with a Low-Budget Health Care System. AB - BACKGROUND: To analyze the costs of inhospital, percutaneous treatment of patients with critical limb ischemia (CLI) carried out in Poland, a European Union country with a low-budget national health system. METHODS: A retrospective analysis of prospectively collected data on all patients admitted to a tertiary care hospital for endovascular treatment of CLI over 1 year. SETTING: A single, large volume, tertiary angiology center located in Southern Poland. PARTICIPANTS: CLI patients due to aortoiliac, femoropopliteal, or infrapopliteal arterial stenoses or occlusions with indications for first-line endovascular therapy or similar patients who refused open surgical procedure despite having primary indications for vascular surgery. INTERVENTIONS: Direct stenting using bare-metal stents was the primary mode of treatment for lesions located within the aortoiliac and femoropopliteal arterial segments. Plain old balloon angioplasty (POBA) was the second most commonly used technique. For below-the-knee arteries, POBA was the mainstay of treatment, which was occasionally supported by drug eluting stent angioplasty. Directional atherectomy, scoring balloon angioplasty, or local fibrinolysis was used infrequently. Drug-eluting balloon percutaneous transluminal angioplasty was not used. MAIN OUTCOME MEASURES: The main outcome measures were the mean reimbursement of costs provided by the Polish National Health Fund (NHF) for inhospital treatment of patients for whom endovascular procedures were performed as initial treatment for CLI and the inhospital costs of endovascular treatment calculated by the caregiver in the 2 years since the first procedure. The average total number of days spent in hospital, amputation free survival (AFS), overall survival (OS), and limb salvage rate (LSR) according to a life-table method were also calculated for the 2 years. RESULTS: In the first year, there were 496 endovascular and 15 surgical hospitalizations for revascularization procedures to treat 340 limbs in 327 patients, with a further 53 revascularization procedures in the second year. There were an additional 90 hospitalizations over the first year and 38 over the second year for CLI associated cardiovascular comorbidities. The mean reimbursement for hospitalizations of patients included into observation, provided by the NHF, was $4901.94 per patient for the first year and $833.57 per patient alive to the second year. The mean cost of hospitalization for percutaneous revascularization treatment was $3804.25 per patient for the first year and $3340.30 per patient requiring revascularization within the second year. All costs were calculated in constant 2011 USD. The average total number of days spent in hospital was 8.4 days for the first year and 1.97 days per patient alive to the second year. At 1 and 2 years, the AFS was 76.8% and 66.6%, the OS was 86.5% and 77.3%, and the LSR was 89.4% and 86%, respectively. CONCLUSIONS: Endovascular therapy using the currently available techniques can be performed in almost all patients suffering from CLI at relatively low costs, and satisfactory results can be obtained. Physicians play a pivotal role in ensuring quality of treatment and the reduction of treatment cost in these patients. PMID- 26616506 TI - Reimbursement Policies for Carotid Duplex Ultrasound that are Based on International Classification of Diseases Codes May Discourage Testing in High Yield Groups. AB - BACKGROUND: To curb increasing volumes of diagnostic imaging and costs, reimbursement for carotid duplex ultrasound (CDU) is dependent on "appropriate" indications as documented by International Classification of Diseases (ICD) codes entered by ordering physicians. Historically, asymptomatic indications for CDU yield lower rates of abnormal results than symptomatic indications, and consensus documents agree that most asymptomatic indications for CDU are inappropriate. In our vascular laboratory, we perceived an increased rate of incorrect or inappropriate ICD codes. We therefore sought to determine if ICD codes were useful in predicting the frequency of abnormal CDU. We hypothesized that asymptomatic or nonspecific ICD codes would yield a lower rate of abnormal CDU than symptomatic codes, validating efforts to limit reimbursement in asymptomatic, low-yield groups. MATERIAL AND METHODS: We reviewed all outpatient CDU done in 2011 at our institution. ICD codes were recorded, and each medical record was then reviewed by a vascular surgeon to determine if the assigned ICD code appropriately reflected the clinical scenario. CDU findings categorized as abnormal (>50% stenosis) or normal (<50% stenosis) were recorded. Each individual ICD code and group 1 (asymptomatic), group 2 (nonhemispheric symptoms), group 3 (hemispheric symptoms), group 4 (preoperative cardiovascular examination), and group 5 (nonspecific) ICD codes were analyzed for correlation with CDU results. RESULTS: Nine hundred ninety-four patients had 74 primary ICD codes listed as indications for CDU. Of assigned ICD codes, 17.4% were deemed inaccurate. Overall, 14.8% of CDU were abnormal. Of the 13 highest frequency ICD codes, only 433.10, an asymptomatic code, was associated with abnormal CDU. Four symptomatic codes were associated with normal CDU; none of the other high frequency codes were associated with CDU result. Patients in group 1 (asymptomatic) were significantly more likely to have an abnormal CDU compared to each of the other groups (P < 0.001, P < 0.001, P = 0.020, P = 0.002) and to all other groups combined (P < 0.001). CONCLUSIONS: Asymptomatic indications by ICD codes yielded higher rates of abnormal CDU than symptomatic indications. This finding is inconsistent with clinical experience and historical data, and we suggest that inaccurate coding may play a role. Limiting reimbursement for CDU in low-yield groups is reasonable. However, reimbursement policies based on ICD coding, for example, limiting payment for asymptomatic ICD codes, may impede use of CDU in high-yield patient groups. PMID- 26616507 TI - Treatment of High Flow Arteriovenous Fistulas after Successful Renal Transplant Using a Simple Precision Banding Technique. AB - BACKGROUND: Observation versus ligation of a functional arteriovenous fistula (AVF) after successful renal transplantation (SRT) has been a controversial topic of debate. Congestive heart failure and pulmonary hypertension are common in dialysis patients, and more frequent when vascular access flow is excessive. Renal transplant failure may occur in up to 34% of patients after 5 years, therefore maintaining a moderate flow AVF appears warranted. We review SRT patients with high flow-AVFs (HF-AVF) and clinical signs of heart failure where a modified precision banding procedure was used for access flow reduction. METHODS: Patients referred for HF-AVF evaluation after SRT were identified and records reviewed retrospectively. In addition to recording clinical signs of heart failure, each patient had ultrasound AVF flow measurement before and after temporary AVF occlusion of the access by digital compression. Pulse rate and the presence or absence of a cardiac murmur was noted before and after AVF compression. Adequacy of access flow restriction was evaluated intraoperatively using ultrasound flow measurements, adjusting the banding diameter in 0.5 mm increments to achieve the targeted AVF flow. RESULTS: Twelve patients were evaluated over a 19-month period. Eight (66%) were male and one (8%) obese. Ages were 15-73 years (mean = 42). The AVFs were established 24-86 months previously. The mean pulse rate declined after AVF compression from 90/min to 72/min (range 110-78). Six patients had a precompression cardiac flow murmur that disappeared with temporary AVF compression. One patient with poor cardiac function underwent immediate AVF ligation with dramatic improvement in cardiac status. All other patients underwent a precision banding procedure with real-time flow monitoring. Mean access flow was 2,280 mL/min (1,148-3,320 mL/min) before access banding and was 598 mL/min (481-876) after flow reduction. The clinical signs of heart failure disappeared in all patients. All AVFs remained patent although one individual later requested ligation for cosmesis. Two patients had renal transplant failure and later successfully used the AVF. Follow-up postbanding was 1-18 months (mean = 12). CONCLUSIONS: Patients with successful renal transplants and HF-AVFs had resolution of heart failure findings and maintenance of access patency using a modified precision banding procedure. Flow reduction in symptomatic renal transplant patients with elevated access flow is recommended. Further study is warranted to substantiate these recommendations and clarify the appropriate thresholds for such interventions. PMID- 26616508 TI - Targeting BRAF aberrations in advanced colorectal carcinoma: from bench to bedside. AB - Colorectal cancer (CRC) is a global health problem with profound mortality and morbidity effects particularly in the advanced/metastatic setting. Because of the recent understanding of the biology of this disease, many candidate targets have come into light for therapeutic evaluation. The current review is about evaluating the preclinical and clinical aspects of BRAF as a therapeutic target in this disease. The available clinical results suggest that while the use of unselective RAF inhibitors (e.g., sorafenib) has been ineffective in the management of advanced CRC patients with KRAS mutation, combination of selective BRAF inhibitors plus EGFR inhibitors may represent a good therapeutic strategy in BRAF-mutant CRC. PMID- 26616514 TI - Validity of the alcohol purchase task: a meta-analysis. AB - BACKGROUND AND AIMS: Behavioral economists assess alcohol consumption as a function of unit price. This method allows construction of demand curves and demand indices, which are thought to provide precise numerical estimates of risk for alcohol problems. One of the more commonly used behavioral economic measures is the Alcohol Purchase Task (APT). Although the APT has shown promise as a measure of risk for alcohol problems, the construct validity and incremental utility of the APT remain unclear. This paper presents a meta-analysis of the APT literature. METHODS: Sixteen studies were included in the meta-analysis. Studies were gathered via searches of the PsycInfo, PubMed, Web of Science and EconLit research databases. Random-effects meta-analyses with inverse variance weighting were used to calculate summary effect sizes for each demand index-drinking outcome relationship. Moderation of these effects by drinking status (regular versus heavy drinkers) was examined. Additionally, tests of the incremental utility of the APT indices in predicting drinking problems above and beyond measuring alcohol consumption were performed. RESULTS: The APT indices were correlated in the expected directions with drinking outcomes, although many effects were small in size. These effects were typically not moderated by the drinking status of the samples. Additionally, the intensity metric demonstrated incremental utility in predicting alcohol use disorder symptoms beyond measuring drinking. CONCLUSIONS: The Alcohol Purchase Task appears to have good construct validity, but limited incremental utility in estimating risk for alcohol problems. PMID- 26616515 TI - Cytochromes c': Structure, Reactivity and Relevance to Haem-Based Gas Sensing. AB - Cytochromes c' are a group of class IIa cytochromes with pentacoordinate haem centres and are found in photosynthetic, denitrifying and methanotrophic bacteria. Their function remains unclear, although roles in nitric oxide (NO) trafficking during denitrification or in cellular defence against nitrosoative stress have been proposed. Cytochromes c' are typically dimeric with each c-type haem-containing monomer folding as a four-alpha-helix bundle. Their hydrophobic and crowded distal sites impose severe restrictions on the binding of distal ligands, including diatomic gases. By contrast, NO binds to the proximal haem face in a similar manner to that of the eukaryotic NO sensor, soluble guanylate cyclase and bacterial analogues. In this review, we focus on how structural features of cytochromes c' influence haem spectroscopy and reactivity with NO, CO and O2. We also discuss the relevance of cytochrome c' to understanding the mechanisms of gas binding to haem-based sensor proteins. PMID- 26616516 TI - Bridging Theory and Experiment to Address Structural Properties of Truncated Haemoglobins: Insights from Thermobifida fusca HbO. AB - In this chapter, we will discuss the paradigmatic case of Thermobifida fusca (Tf trHb) HbO in its ferrous and ferric states and its behaviour towards a battery of possible ligands. This choice was dictated by the fact that it has been one of the most extensively studied truncated haemoglobins, both in terms of spectroscopic and molecular dynamics studies. Tf-trHb typifies the structural properties of group II trHbs, as the active site is characterized by a highly polar distal environment in which TrpG8, TyrCD1, and TyrB10 provide three potential H-bond donors in the distal cavity capable of stabilizing the incoming ligands. The role of these residues in key topological positions, and their interplay with the iron-bound ligands, has been addressed in studies carried out on the CO, F(-), OH(-), CN(-), and HS(-) adducts formed with the wild-type protein and a combinatorial set of mutants, in which the distal polar residues, TrpG8, TyrCD1, and TyrB10, have been singly, doubly, or triply replaced by a Phe residue. In this context, such a complete analysis provides an excellent benchmark for the investigation of the relationship between protein structure and function, allowing one to translate physicochemical properties of the active site into the observed functional behaviour. Tf-trHb will be compared with other members of the group II trHbs and, more generally, with members of the other trHb subgroups. PMID- 26616517 TI - Structural Biology of Bacterial Haemophores. AB - Iron plays a key role in a wide range of metabolic and signalling functions representing an essential nutrient for almost all forms of life. However, the ferric form is hardly soluble, whereas the ferrous form is highly toxic. Thus, in biological fluids, most of the iron is sequestered in iron- or haem-binding proteins and the level of free iron is low, making haem and iron acquisition a challenge for pathogenic bacteria during infections. Although toxic to the host, free haem is a major and readily available source of iron for several pathogenic microorganisms. Both Gram-positive and Gram-negative bacteria have developed several strategies to acquire free haem-Fe and protein-bound haem-Fe. Haemophores are a class of secreted and cell surface-exposed proteins promoting free-haem uptake, haem extraction from host haem proteins, and haem presentation to specific outer-membrane receptors that internalize the metal-porphyrins. Here, structural biology of bacterial haemophores is reviewed focusing on haem acquisition, haem internalization, and haem-degrading systems. PMID- 26616518 TI - The Haemoglobins of Algae. AB - In the last few years, advances in algal research have identified the participation of haemoglobins in nitrogen metabolism and the management of reactive nitrogen and oxygen species. This chapter summarises the state of knowledge concerning algal haemoglobins with a focus on the most widely used model system, namely, Chlamydomonas reinhardtii. Genetic, physiologic, structural, and chemical information is compiled to provide a framework for further studies. PMID- 26616519 TI - The Challenging World of Biofilm Physiology. AB - Worldwide, infectious diseases are one of the leading causes of death among children. At least 65% of all infections are caused by the biofilm mode of bacterial growth. Bacteria colonise surfaces and grow as multicellular biofilm communities surrounded by a polymeric matrix as a common survival strategy. These sessile communities endow bacteria with high tolerance to antimicrobial agents and hence cause persistent and chronic bacterial infections, such as dental caries, periodontitis, otitis media, cystic fibrosis and pneumonia. The highly complex nature and the rapid adaptability of the biofilm population impede our understanding of the process of biofilm formation, but an important role for oxygen-binding proteins herein is clear. Much research on this bacterial lifestyle is already performed, from genome/proteome analysis to in vivo antibiotic susceptibility testing, but without significant progress in biofilm treatment or eradication. This review will present the multiple challenges of biofilm research and discuss possibilities to cross these barriers in future experimental studies. PMID- 26616520 TI - Avoid Excessive Oxygen Levels in Experiments with Organisms, Tissues and Cells. AB - O2 levels encountered in vivo in cells and tissues are almost always at least an order of magnitude less than atmospheric pO2 because of sensing, signalling and bioenergetic demand. Although deleterious reactions are minimized by protective mechanisms (residual toxic products scavenged and detoxified) ambient levels should be mimicked in experiments with whole organisms, their isolated organs, tissues or cells and also with cultures of cell lines. These are also important issues for microorganisms inhabiting low O2 niches within higher organisms and their cells. Here, we highlight the importance of optimization of micro-aerobic conditions for experimentation and the deleterious consequences of not doing so. PMID- 26616521 TI - Preface. PMID- 26616523 TI - Isolation of exosomes by differential centrifugation: Theoretical analysis of a commonly used protocol. AB - Exosomes, small (40-100 nm) extracellular membranous vesicles, attract enormous research interest because they are carriers of disease markers and a prospective delivery system for therapeutic agents. Differential centrifugation, the prevalent method of exosome isolation, frequently produces dissimilar and improper results because of the faulty practice of using a common centrifugation protocol with different rotors. Moreover, as recommended by suppliers, adjusting the centrifugation duration according to rotor K-factors does not work for "fixed angle" rotors. For both types of rotors--"swinging bucket" and "fixed-angle"--we express the theoretically expected proportion of pelleted vesicles of a given size and the "cut-off" size of completely sedimented vesicles as dependent on the centrifugation force and duration and the sedimentation path-lengths. The proper centrifugation conditions can be selected using relatively simple theoretical estimates of the "cut-off" sizes of vesicles. Experimental verification on exosomes isolated from HT29 cell culture supernatant confirmed the main theoretical statements. Measured by the nanoparticle tracking analysis (NTA) technique, the concentration and size distribution of the vesicles after centrifugation agree with those theoretically expected. To simplify this "cut off"-size-based adjustment of centrifugation protocol for any rotor, we developed a web-calculator. PMID- 26616524 TI - Towards holistic dual diagnosis care: physical health screening in a Victorian community-based alcohol and drug treatment service. AB - The poorer health outcomes experienced by people with mental illness have led to new directions in policy for routine physical health screening of service users. By contrast, little attention has been paid to the physical health needs of consumers of alcohol and other drug (AOD) services, despite a similar disparity in physical health outcomes compared with the general population. The majority of people with problematic AOD use have comorbid mental illness, known as a dual diagnosis, likely to exacerbate their vulnerability to poor physical health. With the potential for physical health screening to improve health outcomes for AOD clients, a need exists for systematic identification and management of common health conditions. Within the current health service system, those with a dual diagnosis are more likely to have their physical health surveyed and responded to if they present for treatment in the mental health system. In this study, a physical health screening tool was administered to clients attending a community based AOD service. The tool was administered by a counsellor during the initial phase of treatment, and referrals to health professionals were made as appropriate. Findings are discussed in terms of prevalence, types of problems identified and subsequent rates of referral. The results corroborate the known link between mental and physical ill health, and contribute to developing evidence that AOD clients present with equally concerning physical ill health to that of mental health clients and should equally be screened for such when presenting for AOD treatment. PMID- 26616525 TI - Metastatic melanoma treatment: Combining old and new therapies. AB - Metastatic melanoma is an aggressive form of cancer characterised by poor prognosis and a complex etiology. Until 2010, the treatment options for metastatic melanoma were very limited. Largely ineffective dacarbazine, temozolamide or fotemustine were the only agents in use for 35 years. In recent years, the development of molecularly targeted inhibitors in parallel with the development of checkpoint inhibition immunotherapies has rapidly improved the outcomes for metastatic melanoma patients. Despite these new therapies showing initial promise; resistance and poor duration of response have limited their effectiveness as monotherapies. Here we provide an overview of the history of melanoma treatment, as well as the current treatments in development. We also discuss the future of melanoma treatment as we go beyond monotherapies to a combinatorial approach. Combining older therapies with the new molecular and immunotherapies will be the most promising way forward for treatment of metastatic melanoma. PMID- 26616526 TI - Classification of portal vein tributaries in Thai cadavers including a new type V. AB - PURPOSE: To compare portal vein tributaries in Thai with Thompson classification. METHODS: In 211 Thai cadavers, abdominal regions were dissected to identify the portal veins and their tributaries. The subjects were classified into types based on modes of drainage of the left gastric and inferior mesenteric veins. Percentages of all types of venous drainage were counted. RESULTS: There are four types of portal tributaries as defined by Thompson, type I_47.87 %, type II_13.27 %, type III_7.58 %, and type IV_29.86 %. There were 1.42 % of whose inferior mesenteric veins entered the joining angle of the superior mesenteric and splenic veins, and were classified as type V. The left gastric vein mostly drained into the portal vein in 79.15 %, while the inferior mesenteric vein emptied into the splenic vein mainly in 55.45 %. CONCLUSIONS: A new variance of portal tributaries in Thai cadavers is reported. The variations of portal vein formations are critical for liver surgery and interventional radiological procedures. PMID- 26616527 TI - Association of plasminogen activator inhibitor-1 gene polymorphism and type 2 diabetic nephropathy. AB - BACKGROUND: We investigated the relationship between plasminogen activator inhibitor-1 (PAI-1) 4G/5G insertion/deletion polymorphism and prevalence of diabetic nephropathy (DN) in Chinese patients. METHODS: A total of 107 patients with type 2 diabetes were randomly recruited in the study, and 102 healthy subjects were selected as Control. Patients were divided into three groups according to their urinary albumin-creatinine ratio (UACR). Group A (n = 44), had patients without DN (serum creatinine <106 umol/L and UACR <30 ug/mg); Group B (n = 30), had patients with micro-albuminuria (UACR 30-299 ug/mg), and Group C (n = 33), had patients with macro-albuminuria (UACR >=300 ug/mg and creatinine <200 umol/L). Plasma level of PAI-1 was measured by ELISA. PAI-1 polymorphism was determined by a polymerase chain reaction (PCR) method and DNA sequencing. RESULTS: (1) The plasma PAI-1 levels of group A (60.39 +/- 17.01 ng/L), group B (68.76 +/- 17.81 ng/L) and group C and (68.63 +/- 18.30 ng/L) are higher than that of controls (46.26 +/- 26.04 ng/L); (2) Patients with genotype 4G/4G tended to exhibit higher PAI-1 level; (3) The distribution frequency of genotype 4G/4G in group C was significantly higher than in group A (42.4% vs. 28.7%, p < 0.05) and (4) In type 2 diabetic patients, the occurrence of diabetes nephropathy in genotype 4G/4G, 4G/5G and 5G/5G is 35.0%, 30.2% and 21.4%, respectively. CONCLUSIONS: (1) Plasma PAI-1 level was elevated in Type 2 diabetic patients; (2) The level of plasma PAI-1 is closely related to PAI-1 gene 4G/5G polymorphism and (3) PAI-1 4G/5G polymorphism is associated with the development and progression of predominant proteinuria diabetes nephropathy. PMID- 26616528 TI - The role of Drosophila mismatch repair in suppressing recombination between diverged sequences. AB - DNA double-strand breaks (DSBs) must be accurately repaired to maintain genomic integrity. DSBs can be repaired by homologous recombination (HR), which uses an identical sequence as a template to restore the genetic information lost at the break. Suppression of recombination between diverged sequences is essential to the repair of DSBs without aberrant and potentially mutagenic recombination between non-identical sequences, such as Alu repeats in the human genome. The mismatch repair (MMR) machinery has been found to suppress recombination between diverged sequences in murine cells. To test if this phenomenon is conserved in whole organisms, two DSB repair systems were utilized in Drosophila melanogaster. The DR-white and DR-white.mu assays provide a method of measuring DSB repair outcomes between identical and diverged sequences respectively. msh6(-/-) flies, deficient in MMR, were not capable of suppressing recombination between sequences with 1.4% divergence, and the average gene conversion tract length did not differ between msh6(-/+) and msh6(-/-)flies. These findings suggest that MMR has an early role in suppressing recombination between diverged sequences that is conserved in Drosophila. PMID- 26616529 TI - Porphyrin-based mixed-valent Ag(i)/Ag(ii) and Cu(i)/Cu(ii) networks as efficient heterogeneous catalysts for the azide-alkyne "click" reaction and promising oxidation of ethylbenzene. AB - By using a new porphyrin-based linker, two unusual mixed-valent Ag(i,ii)- and Cu(i,ii)-organic networks were synthesized. Most strikingly, 1 and 2 exhibit highly efficient catalytic activities for the azide-alkyne "click" reaction and oxidation of ethylbenzene. PMID- 26616530 TI - Chemical Exchange Saturation Transfer (CEST) Agents: Quantum Chemistry and MRI. AB - Diamagnetic chemical exchange saturation transfer (CEST) contrast agents offer an alternative to Gd(3+) -based contrast agents for MRI. They are characterized by containing protons that can rapidly exchange with water and it is advantageous to have these protons resonate in a spectral window that is far removed from water. Herein, we report the first results of DFT calculations of the (1) H nuclear magnetic shieldings in 41 CEST agents, finding that the experimental shifts can be well predicted (R(2) =0.882). We tested a subset of compounds with the best MRI properties for toxicity and for activity as uncouplers, then obtained mice kidney CEST MRI images for three of the most promising leads finding 16 (2,4 dihydroxybenzoic acid) to be one of the most promising CEST MRI contrast agents to date. Overall, the results are of interest since they show that (1) H NMR shifts for CEST agents-charged species-can be well predicted, and that several leads have low toxicity and yield good in vivo MR images. PMID- 26616531 TI - Tempol prevents chronic sleep-deprivation induced memory impairment. AB - Sleep deprivation is associated with oxidative stress that causes learning and memory impairment. Tempol is a nitroxide compound that promotes the metabolism of many reactive oxygen species (ROS) and has antioxidant and neuroprotective effect. The current study investigated whether chronic administration of tempol can overcome oxidative stress and prevent learning and memory impairment induced by sleep deprivation. Sleep deprivation was induced in rats using multiple platform model. Tempol was administered to rats via oral gavages. Behavioral studies were conducted to test the spatial learning and memory using radial arm water maze. The hippocampus was dissected; antioxidant biomarkers (GSH, GSSG, GSH/GSSG ratio, GPx, SOD, and catalase) were assessed. The result of this project revealed that chronic sleep deprivation impaired both short and long term memory (P<0.05), while tempol treatment prevented such effect. Furthermore, tempol normalized chronic sleep deprivation induced reduction in the hippocampus activity of catalase, GPx, and SOD (P<0.05). Tempol also enhanced the ratio of GSH/GSSG in chronically sleep deprived rats treated with tempol as compared with only sleep deprived rats (P<0.05). In conclusion chronic sleep deprivation induced memory impairment, and treatment with tempol prevented this impairment probably through normalizing antioxidant mechanisms in the hippocampus. PMID- 26616532 TI - Integrating traditional indigenous medicine and western biomedicine into health systems: a review of Nicaraguan health policies and miskitu health services. AB - Throughout the world, indigenous peoples have advocated for the right to retain their cultural beliefs and traditional medicine practices. In 2007, the more than 370 million people representing 5000 distinct groups throughout the world received global recognition with the adoption of the United Nations Declaration on the Rights of Indigenous Peoples (UNDRIP). UNDRIP Article 24 affirms the rights of indigenous peoples to their traditional medicines and health practices, and to all social and health services. Although not a legally binding agreement, UNDRIP encourages nation states to comply and implement measures to support and uphold its provisions. Within the context of indigenous health and human rights, Nicaragua serves as a unique case study for examining implementation of UNDRIP Article 24 provisions due to the changes in the Nicaraguan Constitution that strive for the overarching goal of affirming an equal right to health for all Nicaraguans and supporting the integration of traditional medicine and biomedicine at a national and regional level. To explore this subject further, we conducted a review of the policy impact of UNDRIP on health services accessible to the Miskitu indigenous peoples of the North Atlantic Autonomous Region (RAAN). We found that although measures to create therapeutic cooperation are woven into Nicaraguan health plans at the national and regional level, in practice, the delivery of integrated health services has been implemented with varying results. Our review suggests that the method of policy implementation and efforts to foster intercultural collaborative approaches involving respectful community engagement are important factors when attempting to assess the effectiveness of UNDRIP implementation into national health policy and promoting traditional medicine access. In response, more study and close monitoring of legislation that acts to implement or align with UNDRIP Article 24 is necessary to ensure adequate promotion and access to traditional medicines and health services for indigenous populations in Nicaragua and beyond. PMID- 26616533 TI - Advances of Molecular Imaging for Monitoring the Anatomical and Functional Architecture of the Olfactory System. AB - The olfactory system of organisms serves as a genetically and anatomically model for studying how sensory input can be translated into behavior output. Some neurologic diseases are considered to be related to olfactory disturbance, especially Alzheimer's disease, Parkinson's disease, multiple sclerosis, and so forth. However, it is still unclear how the olfactory system affects disease generation processes and olfaction delivery processes. Molecular imaging, a modern multidisciplinary technology, can provide valid tools for the early detection and characterization of diseases, evaluation of treatment, and study of biological processes in living subjects, since molecular imaging applies specific molecular probes as a novel approach to produce special data to study biological processes in cellular and subcellular levels. Recently, molecular imaging plays a key role in studying the activation of olfactory system, thus it could help to prevent or delay some diseases. Herein, we present a comprehensive review on the research progress of the imaging probes for visualizing olfactory system, which is classified on different imaging modalities, including PET, MRI, and optical imaging. Additionally, the probes' design, sensing mechanism, and biological application are discussed. Finally, we provide an outlook for future studies in this field. PMID- 26616534 TI - Transcriptome analysis of human OXR1 depleted cells reveals its role in regulating the p53 signaling pathway. AB - The oxidation resistance gene 1 (OXR1) is crucial for protecting against oxidative stress; however, its molecular function is unknown. We employed RNA sequencing to examine the role of human OXR1 for genome wide transcription regulation. In total, in non-treated and hydrogen peroxide exposed HeLa cells, OXR1 depletion resulted in down-regulation of 554 genes and up-regulation of 253 genes. These differentially expressed genes include transcription factors (i.e. HIF1A, SP6, E2F8 and TCF3), antioxidant genes (PRDX4, PTGS1 and CYGB) and numerous genes of the p53 signaling pathway involved in cell-cycle arrest (i.e. cyclin D, CDK6 and RPRM) and apoptosis (i.e. CytC and CASP9). We demonstrated that OXR1 depleted cells undergo cell cycle arrest in G2/M phase during oxidative stress and increase protein expression of the apoptosis initiator protease CASP9. In summary, OXR1 may act as a sensor of cellular oxidative stress to regulate the transcriptional networks required to detoxify reactive oxygen species and modulate cell cycle and apoptosis. PMID- 26616536 TI - Managing Urolithiasis. PMID- 26616535 TI - A virtual reality intervention (Second Life) to improve weight maintenance: Rationale and design for an 18-month randomized trial. AB - Despite the plethora of weight loss programs available in the US, the prevalence of overweight and obesity (BMI>=25kg/m(2)) among US adults continues to rise at least, in part, due to the high probability of weight regain following weight loss. Thus, the development and evaluation of novel interventions designed to improve weight maintenance are clearly needed. Virtual reality environments offer a promising platform for delivering weight maintenance interventions as they provide rapid feedback, learner experimentation, real-time personalized task selection and exploration. Utilizing virtual reality during weight maintenance allows individuals to engage in repeated experiential learning, practice skills, and participate in real-life scenarios without real-life repercussions, which may diminish weight regain. We will conduct an 18-month effectiveness trial (6 months weight loss, 12 months weight maintenance) in 202 overweight/obese adults (BMI 25 44.9kg/m(2)). Participants who achieve >=5% weight loss following a 6month weight loss intervention delivered by phone conference call will be randomized to weight maintenance interventions delivered by conference call or conducted in a virtual environment (Second Life(r)). The primary aim of the study is to compare weight change during maintenance between the phone conference call and virtual groups. Secondarily, potential mediators of weight change including energy and macronutrient intake, physical activity, consumption of fruits and vegetables, self-efficacy for both physical activity and diet, and attendance and completion of experiential learning assignments will also be assessed. PMID- 26616537 TI - Renal injury: Preventing organ dysfunction--is preconditioning still an option? PMID- 26616539 TI - Ternary SnS(2-x)Se(x) Alloys Nanosheets and Nanosheet Assemblies with Tunable Chemical Compositions and Band Gaps for Photodetector Applications. AB - Ternary metal dichalcogenides alloys exhibit compositionally tunable optical properties and electronic structure, and therefore, band gap engineering by controllable doping would provide a powerful approach to promote their physical and chemical properties. Herein we obtained ternary SnS(2-x)Se(x) alloys with tunable chemical compositions and optical properties via a simple one-step solvothermal process. Raman scattering and UV-vis-NIR absorption spectra reveal the composition-related optical features, and the band gaps can be discretely modulated from 2.23 to 1.29 eV with the increase of Se content. The variation tendency of band gap was also confirmed by first-principles calculations. The change of composition results in the difference of crystal structure as well as morphology for SnS(2-x)Se(x) solid solution, namely, nanosheets assemblies or nanosheet. The photoelectrochemical measurements indicate that the performance of ternary SnS(2-x)Se(x) alloys depends on their band structures and morphology characteristics. Furthermore, SnS(2-x)Se(x) photodetectors present high photoresponsivity with a maximum of 35 mA W(-1) and good light stability in a wide range of spectral response from ultraviolet to visible light, which renders them promising candidates for a variety of optoelectronic applications. PMID- 26616540 TI - Comparison of taurine and pantoyltaurine as antioxidants in vitro and in the central nervous system of diabetic rats. AB - This study has comparatively evaluated the antiradical and antilipid peroxidizing actions of taurine (TAU) and its N-pantoyl analog pantoyltaurine (PTAU) in vitro, and has determined the extent to which these findings agree with the in vivo ability of these compounds to prevent changes in plasma glucose and in indices of oxidative stress in the plasma, brain and spinal cord induced by the diabetogen streptozotocin (STZ) in Sprague-Dawley rats. Using free radical-generating and oxidizing systems, PTAU was found more effective than TAU in scavenging DPPH, hydroxyl, peroxyl, and superoxide anion radicals and peroxynitrite, and in preventing lipid peroxidation of a brain homogenate by iron (III)-dopamine and the oxidation of dopamine by iron (III). On the other hand, when administered intraperitoneally (i.p.) at a 1.2mM/kg dose, 75min and 45min before a single i.p., 60mg/kg, dose of (STZ), TAU was about equipotent with PTAU in attenuating STZ-induced increases in glucose, malondialdehyde (MDA) and nitric oxide (NO), and the loss of reduced glutathione (GSH) in plasma collected at 24h post STZ. Moreover, the analysis of concurrently collected brain and spinal cords samples revealed that both TAU and PTAU were able to equally reverse the increases in MDA and NO concentrations and to effectively counteract the decrease in the GSH/GSSG ratio caused by STZ. Likewise, both compounds were very effective in preventing the losses of tissue catalase, glutathione peroxidase and superoxide dismutase activities. A comparison of the results for spinal cord and for brain parts such as the cerebellum, cortex and brain stem suggested the existence of regional differences in antioxidant potency between TAU and PTAU, especially in terms of antioxidant enzymes. In general, differences in antiradical and antioxidant potencies between TAU and PTAU derived from in vitro test are not reliable indicators of the antioxidant potencies these compounds may subsequently manifest in a living organism. PMID- 26616541 TI - The brain injury case management taxonomy (BICM-T); a classification of community based case management interventions for a common language. AB - BACKGROUND: Case management is a complex intervention. Complexity arises from the interaction of different components: the model (theoretical basis), implementation context (service), population and health condition, focus for the intervention (client and/or their family), case manager's actions (interventions) and the target of case management (integrated care and support, client's community participation). There is a lack of understanding and a common language. To our knowledge there is no classification (taxonomy) for community-based case management. OBJECTIVE: To develop a community-based case management in brain injury taxonomy (BICM-T), as a common language and understanding of case management for use in quality analysis, policy, planning and practice. METHODS: The mixed qualitative methods used multiple sources of knowledge including scoping, framing and a nominal group technique to iteratively develop the Beta version (draft) of the taxonomy. A two part developmental evaluation involving case studies and mapping to international frameworks assessed the applicability and acceptability (feasibility) before finalization of the BICM-T. RESULTS: The BICM-T includes a definition of community-based case management, taxonomy trees, tables and a glossary. The interventions domain tree has 9 main actions (parent category): engagement, holistic assessment, planning, education, training and skills development, emotional and motivational support, advising, coordination, monitoring; 17 linked actions (children category); 8 related actions; 63 relevant terms defined in the glossary. CONCLUSIONS: The BICM-T provides a knowledge map with the definitions and relationships between the core actions (interventions domain). Use of the taxonomy as a common language will benefit practice, quality analysis, evaluation, policy, planning and resource allocation. PMID- 26616538 TI - The gut microbiome, diet, and links to cardiometabolic and chronic disorders. AB - Cardiometabolic diseases (CMDs) have been associated with changes in the composition of the gut microbiota, with links between the host environment and microbiota identified in preclinical models. High-throughput sequencing technology has facilitated in-depth studies of the gut microbiota, bacterial derived metabolites, and their association with CMDs. Such strategies have shown that patients with CMDs frequently exhibit enrichment or depletion of certain bacterial groups in their resident microbiota compared to healthy individuals. Furthermore, the ability to transfer resident gut microbiota from mice or humans into germ-free mouse models, or between human patients, has enabled researchers to characterize the causative role of the gut microbiota in CMDs. These approaches have helped identify that dietary intake of choline, which is metabolized by the gut microbiota, is associated with cardiovascular outcomes in mice and humans. Trimethylamine N-oxide (TMAO) - a metabolite derived from the gut microbiota - is also associated with poor cardiovascular outcomes in patients with cardiovascular disease and is elevated in patients with chronic kidney disease (CKD). TMAO might represent a biomarker that links the environment and microbiota with CKD. This Review summarizes data suggesting a link between the gut microbiota and derived metabolites with food intake patterns, metabolic alterations, and chronic CMDs. PMID- 26616544 TI - Extracellular matrix for repair of type IV laryngotracheo-esophageal cleft. AB - Type IV laryngotracheo-esophageal cleft (LTEC) extending to the level of the carina presents unique challenges to operative repair, particularly with respect to soft tissue durability. This is the first report of CorMatrix((r)) extra cellular matrix (ECM) material use as an interposition graft in a four-layered LTEC repair. At day seven post-operatively, there was epithelialization along the surface of the trachea. At 3 months, she was stable for tracheotomy. At 6 months, the posterior wall resembled completely native tissue. CorMatrix((r)) ECM((r)) use intra-operatively and post-operative outcome were both highly satisfactory. No adverse reaction was seen in this case through 12-month follow up. PMID- 26616542 TI - Cost-effectiveness of non-vitamin K antagonist oral anticoagulants for atrial fibrillation in Portugal. AB - INTRODUCTION AND OBJECTIVES: Recently, three novel non-vitamin K antagonist oral anticoagulants received approval for reimbursement in Portugal for patients with non-valvular atrial fibrillation (AF). It is therefore important to evaluate the relative cost-effectiveness of these new oral anticoagulants in Portuguese AF patients. METHODS: A Markov model was used to analyze disease progression over a lifetime horizon. Relative efficacy data for stroke (ischemic and hemorrhagic), bleeding (intracranial, other major bleeding and clinically relevant non-major bleeding), myocardial infarction and treatment discontinuation were obtained by pairwise indirect comparisons between apixaban, dabigatran and rivaroxaban using warfarin as a common comparator. Data on resource use were obtained from the database of diagnosis-related groups and an expert panel. Model outputs included life years gained, quality-adjusted life years (QALYs), direct healthcare costs and incremental cost-effectiveness ratios (ICERs). RESULTS: Apixaban provided the most life years gained and QALYs. The ICERs of apixaban compared to warfarin and dabigatran were ?5529/QALY and ?9163/QALY, respectively. Apixaban was dominant over rivaroxaban (greater health gains and lower costs). The results were robust over a wide range of inputs in sensitivity analyses. Apixaban had a 70% probability of being cost-effective (at a threshold of ?20 000/QALY) compared to all the other therapeutic options. CONCLUSIONS: Apixaban is a cost-effective alternative to warfarin and dabigatran and is dominant over rivaroxaban in AF patients from the perspective of the Portuguese national healthcare system. These conclusions are based on indirect comparisons, but despite this limitation, the information is useful for healthcare decision-makers. PMID- 26616543 TI - A composite fibre optic catheter for monitoring peristaltic transit of an intra luminal bead. AB - A fibre optic motion sensor has been developed for monitoring the proximity and direction of motion of a ferrous bead travelling axial to the sensor. By integrating an array of these sensors into our previously developed fibre optic manometry catheters we demonstrate simultaneous detection of peristaltic muscular activity and the associated motion of ferrous beads through a colonic lumen. This allows the motion of solid content to be temporally and spatially related to pressure variations generated by peristaltic contractions without resorting to videoflouroscopy to track the motion of a radio opaque bolus. The composite catheter has been tested in an in-vitro animal preparation consisting of excised sections of rabbit colon. Cut-away image of the fibre optic motion sensor showing the location of the fibre Bragg gratings and the rare earth magnet. PMID- 26616545 TI - Auditory cortical activity to different voice onset times in cochlear implant users. AB - OBJECTIVE: Voice onset time (VOT) is a critical temporal cue for perception of speech in cochlear implant (CI) users. We assessed the cortical auditory evoked potentials (CAEPs) to consonant vowels (CVs) with varying VOTs and related these potentials to various speech perception measures. METHODS: CAEPs were recorded from 64 scalp electrodes during passive listening in CI and normal-hearing (NH) groups. Speech stimuli were synthesized CVs from a 6-step VOT /ba/-/pa/ continuum ranging from 0 to 50 ms VOT in 10-ms steps. Behavioral measures included the 50% boundary point for categorical perception ("ba" to "pa") from an active condition task. RESULTS: Behavioral measures: CI users with poor speech perception performance had prolonged 50% VOT boundary points compared to NH subjects. The 50% boundary point was also significantly correlated to the ability to discriminate consonants in quiet and noise masking. Electrophysiology: The most striking difference between the NH and CI subjects was that the P2 response was significantly reduced in amplitude in the CI group compared to NH. N1 amplitude did not differ between NH and CI groups. P2 latency increased with increases in VOT for both NH and CI groups. P2 was delayed more in CI users with poor speech perception compared to NH subjects. N1 amplitude was significantly related to consonant perception in noise while P2 latency was significantly related to vowel perception in noise. When dipole source modelling in auditory cortex was used to characterize N1/P2, more significant relationships were observed with speech perception measures compared to the same N1/P2 activity when measured at the scalp. N1 dipole amplitude measures were significantly correlated with consonants in noise discrimination. Like N1, the P2 dipole amplitude was correlated with consonant discrimination, but additional significant relationships were observed such as sentence and word identification. CONCLUSIONS: P2 responses to a VOT continuum stimulus were different between NH subjects and CI users. P2 responses show more significant relationships with speech perception than N1 responses. SIGNIFICANCE: The current findings indicate that N1/P2 measures during a passive listening task relate to speech perception outcomes after cochlear implantation. PMID- 26616546 TI - Whole body heat stress increases motor cortical excitability and skill acquisition in humans. AB - OBJECTIVE: Vigorous systemic exercise stimulates a cascade of molecular and cellular processes that enhance central nervous system (CNS) plasticity and performance. The influence of heat stress on CNS performance and learning is novel. We designed two experiments to determine whether passive heat stress (1) facilitated motor cortex excitability and (2) improved motor task acquisition compared to no heat stress. METHODS: Motor evoked potentials (MEPs) from the first dorsal interosseus (FDI) were collected before and after 30 min of heat stress at 73 degrees C. A second cohort of subjects performed a motor learning task using the FDI either following heat or the no heat condition. RESULTS: Heat stress increased heart rate to 65% of age-predicted maximum. After heat, mean resting MEP amplitude increased 48% (p<0.05). MEP stimulus-response amplitudes did not differ according to stimulus intensity. In the second experiment, heat stress caused a significant decrease in absolute and variable error (p<0.05) during a novel movement task using the FDI. CONCLUSIONS: Passive environmental heat stress (1) increases motor cortical excitability, and (2) enhances performance in a motor skill acquisition task. SIGNIFICANCE: Controlled heat stress may prime the CNS to enhance motor skill acquisition during rehabilitation. PMID- 26616547 TI - Case report: Remote neuromodulation with direct electrical stimulation of the brain, as evidenced by intra-operative EEG recordings during wide-awake neurosurgery. PMID- 26616549 TI - Photosensitized H2 generation from "one-pot" and "two-pot" assemblies of a zinc porphyrin/platinum nanoparticle/protein scaffold. AB - We report photosensitized H2 generation using a protein scaffold that nucleates formation of platinum nanoparticles (Pt NPs) and contains "built-in" photosensitizers. The photosensitizers, zinc-protoporphyrin IX or zinc mesoporphyrin IX (ZnP) were incorporated in place of the naturally occurring heme in the 24-subunit iron storage protein bacterioferritin (Bfr) when the ZnPs were added to the E. coli expression medium. We engineered a stable dimeric Bfr variant with two protein subunits sandwiching a ZnP. Ten glycines were also substituted in place of residues surrounding the vinyl side of the porphyrin in order increase access of solvent and/or redox agents. An optimized "one-pot" reaction of this glycine-substituted ZnMP-Bfr dimer with a Pt(iv) salt and borohydride resulted in a ~50 : 50 mixture of protein in the form of Pt-free glycine-substituted ZnP-Bfr dimers and re-assembled 24-mers surrounding Pt NPs formed in situ. H2 production occurred upon visible light irradiation of this "one-pot" product when combined with triethanolamine as sacrificial electron donor and methyl viologen as electron relay. An analogous "two-pot" system containing mixtures of separately prepared Pt-free glycine-substituted ZnP-Bfr dimer and porphyrin-free Pt NP@Bfr 24-mer also showed robust photosensitized H2 generation. The glycine-substituted-ZnP-Bfr dimer thus served as photosensitizer for catalytic reduction of methyl viologen by triethanolamine, and the reduced methyl viologen was able to transfer electrons across the Bfr 24-mer protein shell to generate H2 at the enclosed Pt NP in a "dark" reaction. Our results demonstrate that Bfr is a readily manipulatable and versatile scaffold for photosensitized redox chemistry. PMID- 26616548 TI - Effects of preincubation of eggs and activation medium on the percentage of eyed embryos in ide (Leuciscus idus), an externally fertilizing fish. AB - Standardization of fertilization protocols is crucial for improving reproductive techniques for externally fertilizing fish in captive breeding. Therefore, the objectives of this study were to determine the effects of preincubation of eggs and activation medium on the percentage of eyed embryos for ide (Leuciscus idus). Pooled eggs from five females were preincubated in three different activating media for 0, 30, 60, 90, and 120 seconds and then fertilized by pooled sperm from five males. At the eyed-egg stage, the percentage of viable embryos was later calculated. Results showed that preincubation time was significant for the freshwater activation medium (P < 0.001), such that the percentage of eyed embryos declined across the preincubation time gradient. Additionally, there was an effect on the percentage of eyed embryos when eggs were incubated with Woynarovich solution (P < 0.001), such that a decline was detected at 90 seconds, whereas no effect was detected for the saline water medium. Activating medium had a significant effect on the percentage of eyed embryos for each preincubation time (P < 0.05). More precisely, freshwater produced the lowest percentage of eyed embryos at all preincubation times (ranged from 1.9% at 120 seconds to 43.6% at 0 seconds), whereas saline water and Woynarovich solution produced the highest percentage of eyed embryos at 0 seconds and 30 seconds before incubation. Woynarovich solution produced the highest percentage of eyed embryos at 60 seconds (65.26%), whereas saline water produced the highest percentage at 90 seconds (68.37%). No difference was detected between saline water and Woynarovich solution at 120 seconds. Examination of sperm traits showed no impact of activating medium on computer assisted sperm analysis parameters. Together, these results suggest that saline water or Woynarovich solution improve fertilization rate in ide during IVF; thus, these media are useful for standardizing fertilization protocols and controlled reproduction for this species. PMID- 26616550 TI - Brucella abortusDeltacydCDeltacydD and DeltacydCDeltapurD double-mutants are highly attenuated and confer long-term protective immunity against virulent Brucella abortus. AB - We constructed double deletion (DeltacydCDeltacydD and DeltacydCDeltapurD) mutants from virulent Brucella abortus biovar 1 field isolate (BA15) by deleting the genes encoding an ATP-binding cassette-type transporter (cydC and cydD genes) and a phosphoribosylamine-glycine ligase (purD). Both BA15DeltacydCDeltacydD and BA15DeltacydCDeltapurD double-mutants exhibited significant attenuation of virulence when assayed in murine macrophages or in BALB/c mice. Both double mutants were readily cleared from spleens by 4 weeks post-inoculation even when inoculated at the dose of 10(8) CFU per mouse. Moreover, the inoculated mice showed no splenomegaly, which indicates that the mutants are highly attenuated. Importantly, the attenuation of in vitro and in vivo growth did not impair the ability of these mutants to confer long-term protective immunity in mice against challenge with B. abortus strain 2308. Vaccination of mice with either mutant induced humoral and cell-mediated immune responses, and provided significantly better protection than commercial B. abortus strain RB51 vaccine. These results suggest that highly attenuated BA15DeltacydCDeltacydD and BA15DeltacydCDeltapurD mutants can be used effectively as potential live vaccine candidates against bovine brucellosis. PMID- 26616551 TI - Maternal immunization with respiratory syncytial virus fusion protein formulated with a novel combination adjuvant provides protection from RSV in newborn lambs. AB - Respiratory syncytial virus (RSV) is the causative agent of serious upper and lower respiratory tract infections in newborns and infants. Protection from RSV is crucial for neonates, and maternal immunization is one approach that holds promise for providing immediate protection to young infants against severe RSV infection. We previously reported efficacy of a subunit vaccine consisting of the fusion (F) protein formulated with a novel adjuvant (DeltaF/TriAdj) in neonates. The goal of the current study was to evaluate the DeltaF/TriAdj as a maternal vaccine. Pregnant ewes were vaccinated intramuscularly with DeltaF/TriAdj or PBS six weeks prior to lambing, and re-vaccinated four weeks later, which resulted in transfer of maternal antibodies (MatAbs) to the newborn lambs through the colostrum. Significantly higher levels of RSV DeltaF-specific serum IgG were detected in vaccinated pregnant ewes and their lambs when compared to control animals, which revealed that MatAbs were passively transferred to the offspring. All newborn lambs were challenged with RSV at three days of age. After RSV challenge, virus production and lung pathology were significantly lower in lambs that had received passively transferred antibodies than in control animals. These results indicate that maternal immunization with DeltaF/TriAdj might be an alternative, safe and effective approach to provide protection against RSV in newborn and young infants. PMID- 26616552 TI - Evaluation of the first oral rabies vaccination campaign of the red foxes in Greece. AB - Following the late 2012 recurrence of rabies in wild foxes (Vulpes vulpes) in central and north-western Greece, the first oral fox vaccination campaign co financed by the European Union (EU) and the Greek state budget, was implemented. Initially, it involved 24 regional units of the Greek territory during the period October-December 2013. Vaccine-baits were aerially distributed by fixed-wing aircrafts. Vaccines were scattered along parallel flight paths 500m apart in order to optimize aerial missions and achieve homogeneous distribution. A geographical information system was used to objectively evaluate bait distribution. This system identified areas of inadequate bait density that would require additional flights. A total number of 1,504,821 baits were distributed covering an area of 54,584.29km(2). To assess the effectiveness of oral vaccination campaign a monitoring program was introduced, which entailed examination of serum samples and canine teeth derived from red foxes collected in the field. The laboratory analysis revealed 60% seropositivity and detection of tetracycline biomarker in 70% of the foxes tested. PMID- 26616553 TI - Enhancing cellular immunogenicity of MVA-vectored vaccines by utilizing the F11L endogenous promoter. AB - Modified vaccinia virus Ankara (MVA)-vectored vaccines against malaria, influenza, tuberculosis and recently Ebola virus are in clinical development. Although this vector is safe and immunogenic in humans, efforts remain on-going to enhance immunogenicity through various approaches such as using stronger promoters to boost transgene expression. We previously reported that endogenous MVA promoters such as pB8 and pF11 increased transgene expression and immunogenicity, as compared to the conventional p7.5 promoter. Here, we show that both promoters also rivalled the mH5 promoter in enhancing MVA immunogenicity. We investigated the mechanisms behind this improved immunogenicity and show that it was a result of strong early transgene expression in vivo, rather than in vitro as would normally be assessed. Moreover, keeping the TK gene intact resulted in a modest improvement in immunogenicity. Utilizing pB8 or pF11 as ectopic promoters at the TK locus instead of their natural loci also increased transgene expression and immunogenicity. In addition to a reporter antigen, the pF11 promoter was tested with the expression of two vaccine antigens for which cellular immunogenicity was significantly increased as compared to the p7.5 promoter. Our data support the use of the pF11 and pB8 promoters for improved immunogenicity in future MVA-vectored candidate vaccines. PMID- 26616554 TI - Perceptions of Hong Kong Chinese women toward influenza vaccination during pregnancy. AB - INTRODUCTION: Pregnant women are the highest priority group for seasonal influenza vaccination. However, their vaccination uptake remains suboptimal. The purpose of this study is to explore Hong Kong women's perceptions of the threat of influenza infection during pregnancy, the risks and benefits of influenza vaccination, and their decision-making processes. METHODS: We used a qualitative descriptive design and recruited women who had just given births to a live infant from April to June 2011. Participants were recruited from a large teaching hospital in Hong Kong and were interviewed in the immediate postpartum period. RESULTS: A total of 32 postpartum women were interviewed, and two had been vaccinated during pregnancy. Following thematic analysis, three themes emerged: perceived risk of influenza infection, perceived risk of influenza vaccine, and decision-making cues. Overall, participants held negative impressions about influenza vaccination during pregnancy, and they underestimated the threat of influenza to themselves and their fetus. They were also confused about the safety and efficacy of the influenza vaccine and the differences between preventive strategies and treatment for influenza. Most participants reported that their health care providers (HCPs) did not offer or recommend vaccination. Because of negative media reports about vaccination, participants were hesitant to receive the vaccine. Motivating forces for vaccine acceptance were a perceived high prevalence of circulating influenza during their pregnancy and HCP recommendations and reassurances that the vaccination was safe, effective, and beneficial for the fetus. CONCLUSION: Vaccination promotion strategies need to focus on encouraging HCPs to take the initiative to discuss vaccination with their pregnant clients and provide accurate and unbiased information about the risks of influenza and the benefits of vaccination. PMID- 26616555 TI - Lovastatin blocks Kv1.3 channel in human T cells: a new mechanism to explain its immunomodulatory properties. AB - Lovastatin is a member of Statins, which are beneficial in a lot of immunologic cardiovascular diseases and T cell-mediated autoimmune diseases. Kv1.3 channel plays important roles in the activation and proliferation of T cells, and have become attractive target for immune-related disorders. The present study was designed to examine the block effect of Lovastatin on Kv1.3 channel in human T cells, and to clarify its new immunomodulatory mechanism. We found that Lovastatin inhibited Kv1.3 currents in a concentration- and voltage-dependent manner, and the IC50 for peak, end of the pulse was 39.81 +/- 5.11, 6.92 +/- 0.95 MUM, respectively. Lovastatin also accelerated the decay rate of current inactivation and negatively shifted the steady-state inactivation curves concentration-dependently, without affecting the activation curve. However, 30 MUM Lovastatin had no apparent effect on KCa current in human T cells. Furthermore, Lovastatin inhibited Ca(2+) influx, T cell proliferation as well as IL-2 production. The activities of NFAT1 and NF-kappaB p65/50 were down-regulated by Lovastatin, too. At last, Mevalonate application only partially reversed the inhibition of Lovastatin on IL-2 secretion, and the siRNA against Kv1.3 also partially reduced this inhibitory effect of Lovastatin. In conclusion, Lovastatin can exert immunodulatory properties through the new mechanism of blocking Kv1.3 channel. PMID- 26616556 TI - Deformability measurement of red blood cells using a microfluidic channel array and an air cavity in a driving syringe with high throughput and precise detection of subpopulations. AB - Red blood cell (RBC) deformability has been considered a potential biomarker for monitoring pathological disorders. High throughput and detection of subpopulations in RBCs are essential in the measurement of RBC deformability. In this paper, we propose a new method to measure RBC deformability by evaluating temporal variations in the average velocity of blood flow and image intensity of successively clogged RBCs in the microfluidic channel array for specific time durations. In addition, to effectively detect differences in subpopulations of RBCs, an air compliance effect is employed by adding an air cavity into a disposable syringe. The syringe was equally filled with a blood sample (V(blood) = 0.3 mL, hematocrit = 50%) and air (V(air) = 0.3 mL). Owing to the air compliance effect, blood flow in the microfluidic device behaved transiently depending on the fluidic resistance in the microfluidic device. Based on the transient behaviors of blood flows, the deformability of RBCs is quantified by evaluating three representative parameters, namely, minimum value of the average velocity of blood flow, clogging index, and delivered blood volume. The proposed method was applied to measure the deformability of blood samples consisting of homogeneous RBCs fixed with four different concentrations of glutaraldehyde solution (0%-0.23%). The proposed method was also employed to evaluate the deformability of blood samples partially mixed with normal RBCs and hardened RBCs. Thereafter, the deformability of RBCs infected by human malaria parasite Plasmodium falciparum was measured. As a result, the three parameters significantly varied, depending on the degree of deformability. In addition, the deformability measurement of blood samples was successfully completed in a short time (~10 min). Therefore, the proposed method has significant potential in deformability measurement of blood samples containing hematological diseases with high throughput and precise detection of subpopulations in RBCs. PMID- 26616557 TI - Enzymatically triggered rupture of polymersomes. AB - Polymersomes are robust vesicles made from amphiphilic block co-polymers. Large populations of uniform giant polymersomes with defined, entrapped species can be made by templating of double-emulsions using microfluidics. In the present study, a series of two enzymatic reactions, one inside and the other outside of the polymersome, were designed to induce rupture of polymersomes. We measured how the kinetics of rupture were affected by altering enzyme concentration. These results suggest that protocells with entrapped enzymes can be engineered to secrete contents on cue. PMID- 26616559 TI - Sonographic assessment of liver and spleen size based on age, height, and weight: evaluation of jordanian children. AB - AIM: The growth of the liver and spleen is a dynamic process in children, and is related to the somatic parameters of the child, and may be affected by many diseases in children. It is of paramount importance to have standard reference values for the size of these organs for diagnostic and prognostic purposes. The aim of our study was to provide practical and reliable normal reference values for the size of the liver and spleen in children and to correlate the values with age, height, and weight. METHODS: 315 children (142 boys and 173 girls) were prospectively examined by ultrasound due to problems unrelated to the liver or spleen. All of the subjects had normal sonographic appearance of their organs. The ages of the subjects ranged from newborns to 14 years. The liver and spleen size was correlated with age, height, and weight. The spleen size was compared with previous internationally published data. RESULTS: There was no statistical significant difference in the size of the liver and spleen between boys and girls (P>0.05). There was steady increase in the size of the liver and spleen, with good correlation with age and all the somatic parameters. The spleen size was in close proximity to those previously reported in the literature. CONCLUSION: Standard spleen and liver size reference values were obtained by ultrasound for Jordanian children and were in concordance with international values. PMID- 26616558 TI - Diabetes Management and Education in Older Adults: The Development of a National Consensus of Key Research Priorities. AB - OBJECTIVES: Diabetes in older adults is increasing in its prevalence and complexity. To date, little research has been done to inform current diabetes management, including education and support, in older adults in Canada. The objective of this interactive national workshop was to develop key research priorities for future research related to diabetes in older adults. METHODS: Workshop participants comprised interprofessional healthcare providers, decision makers and policy makers from across Canada. Approximately 30 individuals attended an interactive 2-day meeting that included expert presentations and group consensus building using an electronic meeting system as well as nominal group techniques. RESULTS: The results of the 2-day meeting found more than 50 ideas that were summarized into 5 overall themes, with 14 subquestions, reflecting areas such as 1) identifying relevant outcomes for patients, providers and decision makers; 2) diabetes prevention; 3) the impact of diabetes on older adults and informal caregivers; 4) risk assessment tools and 5) effective models of care across a variety of healthcare settings. CONCLUSIONS: To date, this workshop is the first of its kind and follows suit with other international working groups and associations. The research priorities developed through consensus from this workshop set forward a research agenda for diabetes in older adults in Canada. PMID- 26616560 TI - Women's experiences of having a Bachelor of Midwifery student provide continuity of care. AB - BACKGROUND: The Australian national midwifery education standards require students to complete a number of continuity of care (COC) experiences. There is increasing evidence outlining the value of this experience to the student, but there is limited research examining women's experiences of having a COC midwifery student. This study aimed to investigates the woman's experiences. METHODS: A retrospective descriptive cohort design was used. A paper-based survey was posted to all women cared for by a midwifery student in 2013 (n=698). Descriptive statistics were used to explore the proportion, mean score, standard deviation and range of the variables. Construct validity of the Satisfaction and Respect Scales was tested using exploratory factor analysis. Free text responses were analysed using latent content analysis. RESULT: One-third of women returned a completed survey (n=237/698, 34%). There was a significant positive correlation (p<0.05) between the number of AN/PN visits a midwifery student attended and women's levels of satisfaction. Women were very satisfied with having a student midwife provide continuity. The qualitative data provided additional insight demonstrating that most women had a positive relationship with the midwifery student that enhanced their childbearing experience. CONCLUSION: The women in this study valued continuity of midwifery care and were able to form meaningful relationships with their midwifery student. Programs leading to registration as a midwife should privilege continuity of care experiences. Not only does this benefit women but provides the future midwifery workforce with a clear understanding of models that best meet women's individual and the benefits of working in these models. PMID- 26616561 TI - Young student's motivations to choose an undergraduate midwifery program. AB - BACKGROUND: Within the context of an ageing health workforce it is important to gain a greater understanding of the motivations of young people (aged less than 21 years) to choose a career in midwifery. AIM: To explore the reasons why young students decided to study midwifery and enrol in one Australian Bachelor of Midwifery program. METHOD: A descriptive exploratory qualitative design was used. Eleven midwifery students aged less than 21 years on enrollment participated in a semi-structured tape-recorded interview. The transcribed interviews were analysed using thematic analysis. FINDINGS: Direct and indirect exposure to positive constructions of childbirth as well as the midwives role fuelled young student's fascination with midwifery and drove their desire to enrol. While some young students entered midwifery studies as a result of their 'love of babies' others took a more pragmatic 'wait and see' approach about their career choice. Many young students however clearly distinguished midwifery from nursing demonstrating an intention to be a midwife rather than a nurse. This decision often took place within the context of opposition from within their family, school and social networks where the public discourse continued to reinforce nursing as the preferred pathway to midwifery. CONCLUSION: Creating opportunities for young people to be exposed to positive constructions of childbirth as well as midwifery role models may increase the number of young students entering midwifery. There is also a need for information to be provided to school careers officers to assist them to understand the distinction between midwifery and nursing. PMID- 26616562 TI - Micellar dipole potential is sensitive to sphere-to-rod transition. AB - Structural transitions involving shape changes play an important role in cellular physiology. Charged micelles offer a convenient model system in which structural transitions can be suitably induced by increasing the ionic strength of the medium. In this paper, we have explored sphere-to-rod transition in charged micelles of SDS and CTAB by monitoring micellar dipole potential using the dual wavelength ratiometric approach utilizing the potential-sensitive membrane probe di-8-ANEPPS. Our results show that micellar dipole potential is sensitive to sphere-to-rod transition in charged micelles. Micellar dipole potential exhibited increase with increasing ionic strength (salt), irrespective of the nature of micellar charge, implying considerable dipolar reorganization underlying structural transitions. We interpret the increase in dipole potential due to sphere-to-rod transition because of an increase in the population of confined (nonrandom) dipoles induced by micellar organizational change. This is due to the fact that dipole potential arises due to the nonrandom arrangement of micellar dipoles and water molecules at the micelle interface. Our results constitute one of the first reports describing drastic dipolar reorganization due to micellar shape (and size) change. We envision that dipole potential measurements could provide novel insights into micellar processes that are associated with dipolar reorganization. PMID- 26616563 TI - Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci. AB - Genome-wide association studies have been tremendously successful in identifying genetic variants associated with complex diseases. The majority of association signals are intergenic and evidence is accumulating that a high proportion of signals lie in enhancer regions. We use Capture Hi-C to investigate, for the first time, the interactions between associated variants for four autoimmune diseases and their functional targets in B- and T-cell lines. Here we report numerous looping interactions and provide evidence that only a minority of interactions are common to both B- and T-cell lines, suggesting interactions may be highly cell-type specific; some disease-associated SNPs do not interact with the nearest gene but with more compelling candidate genes (for example, FOXO1, AZI2) often situated several megabases away; and finally, regions associated with different autoimmune diseases interact with each other and the same promoter suggesting common autoimmune gene targets (for example, PTPRC, DEXI and ZFP36L1). PMID- 26616564 TI - An invertebrate signal transducer and activator of transcription 5 (STAT5) ortholog from the disk abalone, Haliotis discus discus: Genomic structure, early developmental expression, and immune responses to bacterial and viral stresses. AB - Signal transducer and activator of transcription (STAT) family members are key signaling molecules that transduce cellular responses from the cell membrane to the nucleus upon Janus kinase (JAK) activation. Although seven STAT members have been reported in mammals, very limited information on STAT genes in molluscans is available. In this study, we identified and characterized a STAT paralog that is homologous to STAT5 from the disk abalone, Haliotis discus discus, and designated as AbSTAT5. Comparison of the deduced amino acid sequence for AbSTAT5 (790 amino acids) with other counterparts revealed conserved residues important for functions and typical domain regions, including the N-terminal domain, coiled coil domain, DNA-binding domain, linker domain, and Src homology 2 (SH2) domains as mammalian counterparts. Analysis of STAT phylogeny revealed that AbSTAT5 was clustered with the molluscan subgroup in STAT5 clade with distinct evolution. According to the genomic structure of AbSTAT5, the coding sequence was distributed into 20 exons with 19 introns. Immunologically essential transcription factor-binding sites, such as GATA-1, HNF, SP1, C/EBP, Oct-1, AP1, c-Jun, and Sox-2, were predicted at the 5'-proximal region of AbSTAT5. Expression of AbSTAT5 mRNA was detected in different stages of embryonic development and observed at considerably higher levels in the morula and late veliger stages. Tissue-specific expressional studies revealed that the highest level of AbSTAT5 transcripts was detected in hemocytes, followed by gill tissues. Temporal expressions of AbSTAT5 were analyzed upon live bacterial (Vibrio parahemolyticus and Listeria monocytogenes), viral (viral hemorrhagic septicemia virus), and pathogen-associated molecular pattern (lipopolysaccharides and Poly I:C) stimulations, and significant elevations indicated immune modulation. These results suggest that AbSTAT5 may be involved in maintaining innate immune responses from developmental to adult stages in the disk abalone. Further, this study provides a basis for structural and functional exploration of STAT members in the invertebrate JAK/STAT signaling pathway. PMID- 26616565 TI - Emerging immunotherapy in pediatric lymphoma. AB - Hodgkin and non-Hodgkin lymphoma collectively are the third most common cancer diagnosed in children each year. For children who relapse or have refractory disease, outcomes remain poor. Immunotherapy has recently emerged as a novel approach to treat hematologic malignancies. The field has been rapidly expanding over the past few years broadening its armamentarium which now includes monoclonal antibodies, antibody-drug conjugates and cellular therapies including bispecific T-cell engagers and chimeric antigen receptor-engineered T cells. Many of these agents are in their infancy stages and only beginning to make their mark on lymphoma treatment while others have begun to show promising efficacy in relapsed disease. In this review, the authors provide an overview of current and emerging immunotherapies in the field of pediatric lymphoma. PMID- 26616567 TI - Characterization of Pseudomonas aeruginosa phage KPP21 belonging to family Podoviridae genus N4-like viruses isolated in Japan. AB - Bacteriophages (phages) belonging to the family Podoviridae genus N4-like viruses have been used as therapeutic agent in phage therapy against Pseudomonas aeruginosa infections. P. aeruginosa phage KPP21 was isolated in Japan, and phylogenetically investigated the phages belonging to this viral genus. Morphological and genetic analyses confirmed that phage KPP21 belongs to the family Podoviridae genus N4-like viruses. Moreover, phylogenetic analyses based on putative DNA polymerase and major virion protein showed that P. aeruginosa phages belonging to the genus N4-like viruses are separated into two lineages and that phage KPP21 is in the same clade as phage LUZ7. PMID- 26616568 TI - Reactivation of Mycobacterium bovis infection and tumor necrosis factor inhibitors. A Mexican case. PMID- 26616566 TI - Environmental Surveillance of Genogroup I and II Noroviruses in Shandong Province, China in 2013. AB - Noroviruses are the most common cause of epidemic gastroenteritis. However, the case-based surveillance is limited in China. In this study, we analyzed the results of environmental surveillance conducted in two cities of Shandong Province, China from January to December in 2013. Twenty-four sewage samples were collected and concentrated via membrane absorption/elution method. After reverse transcription-PCR, cloning and sequencing on ORF2 region, norovirus nucleic acid was detected in all 24 sewage samples. A total of 403 norovirus sequences of 16 genotypes were detected, among which GII.3 (22.6%), GI.2 (17.1%), GI.5 (13.4%), GI.3 (11.9%), GII.4 (7.7%), and GII.6 (6.7%) were the 6 most common genotypes. Phylogenetic analysis revealed multiple lineages within most common genotypes, especially in GI.3, whereas all GII.4 sequences belonged to Sydney 2012 strain. Recombination events were observed in 5 GI and 4 GII sequences within or near the ORF1/ORF2 overlap. This is the first report on systematic environmental surveillance on norovirus in China. The data presented here reveal co-circulation and high genetic diversity of multiple norovirus genotypes in the two cities, and suggest continued environmental surveillance can provide valuable information on norovirus circulation in the population. PMID- 26616569 TI - Undiagnosed myotonic dystrophy type 1 in a patient with synchronous thymoma and thyroid cancer. PMID- 26616570 TI - Reply. PMID- 26616571 TI - Reply. PMID- 26616572 TI - Is Autoimmunity More Predominant in Nonceliac Wheat Sensitivity Than Celiac Disease? PMID- 26616573 TI - Methodology, Not Concept of Fecal Microbiota Transplantation, Affects Clinical Findings. PMID- 26616574 TI - High False-Negative Rate for Nonalcoholic Steatohepatitis in Extreme Obesity. PMID- 26616575 TI - Reply. PMID- 26616576 TI - Complications during retrograde approach for chronic coronary total occlusion: Sub-analysis of Japanese multicenter registry. AB - OBJECTIVES: This study was performed to determine the complications occurring during retrograde percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) based on analysis of the multicenter, prospective, nonrandomized Retrograde Summit registry. BACKGROUND: Retrograde PCI for CTO has improved treatment success rates, but several complications related to the retrograde approach have been reported, including collateral channel injury and donor artery injury due to their use as retrograde roots. METHODS: This registry included data from 1,166 patients who underwent retrograde PCI for CTO in 28 Japanese centers between January 2009 and December 2011. RESULTS: Overall procedure success and retrograde procedure success were achieved in 985 (84.5%) and 838 (71.9%) of the 1,166 patients, respectively. In-hospital major adverse cardiac and cerebrovascular events (MACCE) occurred in 18 (1.5%) of the 1,166 patients. With regard to complications related to the retrograde approach, channel injury occurred in 111 (9.5%) of the 1,166 patients, but treatment was required in only 24 (2.1%) patients and subsequent cardiac tamponade occurred in only 4 (0.3%) patients. Donor artery problems occurred in only 10 (0.9%) of the 1,166 patients. In sub-analysis regarding the types of collateral channels, the septal channel was significantly safer than epicardial channel because of the lower frequency of non-Q-wave myocardial infarction (non-QMI) and channel injury requiring treatment. CONCLUSIONS: The MACCE rate during retrograde PCI for CTO determined from the Retrograde Summit registry was low and the frequency of complications related to the retrograde approach was acceptable. (c) 2015 Wiley Periodicals, Inc. PMID- 26616577 TI - Photobleaching and stabilization of carbon nanodots produced by solvothermal synthesis. AB - In this work we performed a detailed investigation of the photostability of bottom-up produced carbon nanodots (CDs) prepared from citric acid and urea by solvothermal synthesis. Analytical ultracentrifugation (AUC) reveals that the CDs have a hydrodynamic diameter of <1 nm and a very narrow size distribution. In the community it is widely assumed that CDs are photo-stable. In contrast, we found that CDs exposed to UV-irradiation exhibit noteworthy fluorescence degeneration compared to freshly prepared CDs or CDs stored in the dark, indicating that fluorescence bleaching is caused by a photochemical process. We found that fluorescence intensity decay due to exposure to UV-irradiation is accelerated in the presence of oxygen and identified the surface status of CDs as the decisive factor of fluorescence bleaching of CDs. Based on a discussion on the underlying mechanisms we show how to avoid photobleaching of CDs. PMID- 26616580 TI - We Have Skin in the Game: Not the Headline You Expected to See. PMID- 26616578 TI - The Impact of Donor and Recipient Renal Dysfunction on Cardiac Allograft Survival: Insights Into Reno-Cardiac Interactions. AB - BACKGROUND: Renal dysfunction (RD) is a potent risk factor for death in patients with cardiovascular disease. This relationship may be causal; experimentally induced RD produces findings such as myocardial necrosis and apoptosis in animals. Cardiac transplantation provides an opportunity to investigate this hypothesis in humans. METHODS AND RESULTS: Cardiac transplantations from the United Network for Organ Sharing registry were studied (n = 23,056). RD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m(2). RD was present in 17.9% of donors and 39.4% of recipients. Unlike multiple donor characteristics, such as older age, hypertension, or diabetes, donor RD was not associated with recipient death or retransplantation (age-adjusted hazard ratio [HR] = 1.00, 95% confidence interval [CI] 0.94-1.07, P = .92). Moreover, in recipients with RD the highest risk for death or retransplantation occurred immediately posttransplant (0-30 day HR = 1.8, 95% CI 1.54-2.02, P < .001) with subsequent attenuation of the risk over time (30-365 day HR = 0.92, 95% CI 0.77 1.09, P = .33). CONCLUSIONS: The risk for adverse recipient outcomes associated with RD does not appear to be transferrable from donor to recipient via the cardiac allograft, and the risk associated with recipient RD is greatest immediately following transplant. These observations suggest that the risk for adverse outcomes associated with RD is likely primarily driven by nonmyocardial factors. PMID- 26616579 TI - From CONSENSUS to SAVE: The Early Development of Inhibition of the Renin Angiotensin System in the Treatment of Chronic Heart Failure. PMID- 26616581 TI - Anti-BP180 mucous membrane pemphigoid associated with acquired haemophilia A in a patient who suffered from life-threatening mucosal bleeding. PMID- 26616582 TI - Tacrolimus-Induced Cardiomyopathy in an Adult Renal Transplant Recipient. AB - Tacrolimus-induced cardiomyopathy (TICM) is a rare but serious adverse effect of tacrolimus, which has been described primarily in pediatric non-renal transplant recipients. We describe a case of TICM in an adult renal transplant recipient that resulted in allograft dysfunction and multiple hospital admissions for heart failure exacerbation. Prompt and complete reversal of TICM occurred after tacrolimus discontinuation. Although tacrolimus-induced cardiomyopathy is reversible, availability of alternative immunosuppressants is limited, particularly in the setting of renal dysfunction. Available studies and patient specific factors must be considered when determining an alternative maintenance immunosuppression regimen. We chose to use belatacept as alternative immunosuppression in this patient with TICM. Over the next 3 years, the patient remained free of hospital admissions and acute rejection, and demonstrated superior renal allograft function than was observed before her first heart failure admission. We believe that belatacept is an acceptable alternative to tacrolimus therapy for resolution of TICM. PMID- 26616583 TI - TD-DFT Study of the Double Excited-State Intramolecular Proton Transfer Mechanism of 1,3-Bis(2-pyridylimino)-4,7-dihydroxyisoindole. AB - The 1,3-bis(2-pyridylimino)-4,7-dihydroxyisoindole (BPD) is chosen to investigate the excited-state double proton transfer process (ESDPT). The IR spectra, bond distance, and angle analyses show that the two intramolecular hydrogen bonds in the BPD molecule, formed between hydroxyl group and pyridine-type nitrogen atom, are significantly strengthened in the S1 state. The potential energy surfaces in both S0 and S1 states are scanned with varying O-H bond lengths to visually investigate the double proton transfer mechanism. Compared with previous investigations, the proton transfer process can be interpreted in more detail. The hydrogen bond strengthening promotes the proton transfer in the S1 state effectively. The large Stocks shift observed in the experiment can be explained more comprehensively according to the ESDPT mechanism. PMID- 26616584 TI - In situ protein-SIP highlights Burkholderiaceae as key players degrading toluene by para ring hydroxylation in a constructed wetland model. AB - In constructed wetlands, organic pollutants are mainly degraded via microbial processes. Helophytes, plants that are commonly used in these systems, provide oxygen and root exudates to the rhizosphere, stimulating microbial degradation. While the treatment performance of constructed wetlands can be remarkable, a mechanistic understanding of microbial degradation processes in the rhizosphere is still limited. We investigated microbial toluene removal in a constructed wetland model system combining 16S rRNA gene sequencing, metaproteomics and (13) C-toluene in situ protein-based stable isotope probing (protein-SIP). The rhizospheric bacterial community was dominated by Burkholderiales and Rhizobiales, each contributing about 20% to total taxon abundance. Protein-SIP data revealed that the members of Burkholderiaceae, the proteins of which showed about 73% of (13) C-incorporation, were the main degraders of toluene in the planted system, while the members of Comamonadaceae were involved to a lesser extent in degradation (about 64% (13) C-incorporation). Among the Burkholderiaceae, one of the key players of toluene degradation could be assigned to Ralstonia pickettii. We observed that the main pathway of toluene degradation occurred via two subsequent monooxygenations of the aromatic ring. Our study provides a suitable approach to assess the key processes and microbes that are involved in the degradation of organic pollutants in complex rhizospheric ecosystems. PMID- 26616585 TI - Elements That Regulate the DNA Damage Response of Proteins Defective in Cockayne Syndrome. AB - Cockayne syndrome (CS) is a premature aging disorder characterized by developmental defects, multisystem progressive degeneration and sensitivity to ultraviolet light. CS is divided into two primary complementation groups, A and B, with the CSA and CSB proteins presumably functioning in DNA repair and transcription. Using laser microirradiation and confocal microscopy, we characterized the nature and regulation of the CS protein response to oxidative DNA damage, double-strand breaks (DSBs), angelicin monoadducts and trioxsalen interstrand crosslinks (ICLs). Our data indicate that CSB recruitment is influenced by the type of DNA damage and is most rapid and robust as follows: ICLs>DSBs>monoadducts>oxidative lesions. Transcription inhibition reduced accumulation of CSB at sites of monoadducts and ICLs, but it did not affect recruitment to (although slightly affected retention at) oxidative damage. Inhibition of histone deacetylation altered the dynamics of CSB assembly, suggesting a role for chromatin status in the response to DNA damage, whereas the proteasome inhibitor MG132 had no effect. The C-terminus of CSB and, in particular, its ubiquitin-binding domain were critical to recruitment, while the N-terminus and a functional ATPase domain played a minor role at best in facilitating protein accumulation. Although the absence of CSA had no effect on CSB recruitment, CSA itself localized at sites of ICLs, DSBs and monoadducts but not at oxidative lesions. Our results reveal molecular components of the CS protein response and point to a major involvement of complex lesions in the pathology of CS. PMID- 26616587 TI - Effects of Bile Salt Sodium Glycodeoxycholate on the Self-Assembly of PEO-PPO-PEO Triblock Copolymer P123 in Aqueous Solution. AB - A comprehensive experimental study on the interaction between the PEO-PPO-PEO block copolymer P123 (EO20PO68EO20) and the anionic bile salt sodium glycodeoxycholate (NaGDC) in water has been performed. The work was aimed at investigating the suitability of using P123 as bile salt sequestrant beside the fundamental aspects of PEO-PPO-PEO block copolymer-bile salt interactions. Various experimental techniques including dynamic and static light scattering, small-angle X-ray scattering, and differential scanning calorimetry (DSC) were employed in combination with electrophoretic mobility measurements. The system was investigated at a constant P123 concentration of 1.74 mM and with varying bile salt concentrations up to approximately 250 mM NaGDC (or a molar ratio n(NaGDC)/n(P123) = 144). In the mixed P123-NaGDC solutions, the endothermic process related to the self-assembly of P123 was observed to gradually decrease in enthalpy and shift to higher temperatures upon progressive addition of NaGDC. To explain this effect, the formation of NaGDC micelles carrying partly dehydrated P123 unimers was proposed and translated into a stoichiometric model, which was able to fit the experimental DSC data. In the mixtures at low molar ratios, NaGDC monomers associated with the P123 micelle forming a charged "P123 micelle-NaGDC" complex with a dehydrated PPO core. These complexes disintegrated upon increasing NaGDC concentration to form small "NaGDC-P123" complexes visualized as bile salt micelles including one or a few P123 copolymer chains. PMID- 26616586 TI - Correct Assembly of the Bacteriophage T5 Procapsid Requires Both the Maturation Protease and the Portal Complex. AB - The 90-nm-diameter capsid of coliphage T5 is organized with T=13 icosahedral geometry and encloses a double-stranded DNA genome that measures 121kbp. Its assembly follows a path similar to that of phage HK97 but yielding a larger structure that includes 775 subunits of the major head protein, 12 subunits of the portal protein and 120 subunits of the decoration protein. As for phage HK97, T5 encodes the scaffold function as an N-terminal extension (?-domain) to the major head protein that is cleaved by the maturation protease after assembly of the initial prohead I form and prior to DNA packaging and capsid expansion. Although the major head protein alone is sufficient to assemble capsid-like particles, the yield is poor and includes many deformed structures. Here we explore the role of both the portal and the protease in capsid assembly by generating constructs that include the major head protein and a combination of protease (wild type or an inactive mutant) and portal proteins and overexpressing them in Escherichia coli. Our results show that the inactive protease mutant acts to trigger assembly of the major head protein, probably through binding to the ? domain, while the portal protein regulates assembly into the correct T=13 geometry. A cryo-electron microscopy reconstruction of prohead I including inactivated protease reveals density projecting from the prohead interior surface toward its center that is compatible with the ?-domain, as well as additional internal density that we assign as the inactivated protease. These results reveal complexity in T5 beyond that of the HK97 system. PMID- 26616588 TI - Manifestations of type 2 diabetes in corneal endothelial cell density, corneal thickness and intraocular pressure. AB - We sought to evaluate central corneal thickness (CCT), corneal endothelial cell density (ECD) and intraocular pressure (IOP) in patients with type 2 diabetes mellitus (DM) and to associate potential differences with diabetes duration and treatment modality in a prospective, randomized study. We measured ECD, CCT and IOP of 125 patients with type 2 DM (mean age 57.1+/-11.5 years) and compared them with 90 age-matched controls. Measured parameters were analyzed for association with diabetes duration and glucose control modalities (insulin injection or oral medication) while controlling for age. In the diabetic group, the mean ECD (2511+/-252 cells/mm2), mean CCT (539.7+/-33.6 MUm) and mean IOP (18.3+/-2.5 mmHg) varied significantly from those the control group [ECD: 2713+/-132 cells/mm2 (P<0.0001), CCT: 525.0+/-45.3 MUm (P=0.003) and IOP: 16.7+/-1.8 mmHg (P<0.0001)]. ECD was significantly reduced by about 32 cell/mm2 for diabetics with duration of >10 years when compared with those with duration of <10 years (P<0.05). CCT was thicker and IOP was higher for diabetics with duration of >10 years than those with duration of <10 years (P>0.05). None of the measured parameters was significantly associated with diabetes duration and treatment modality (P>0.05). In conclusion, subjects with type 2 DM exhibit significant changes in ECD, IOP and CCT, which, however, are not correlated with disease duration or if the patients receive on insulin injection or oral medications. PMID- 26616590 TI - The Level of Autoantibodies Targeting Eukaryote Translation Elongation Factor 1 alpha1 and Ubiquitin-Conjugating Enzyme 2L3 in Nondiabetic Young Adults. AB - BACKGROUND: The prevalence of novel type 1 diabetes mellitus (T1DM) antibodies targeting eukaryote translation elongation factor 1 alpha 1 autoantibody (EEF1A1 AAb) and ubiquitin-conjugating enzyme 2L3 autoantibody (UBE2L3-AAb) has been shown to be negatively correlated with age in T1DM subjects. Therefore, we aimed to investigate whether age affects the levels of these two antibodies in nondiabetic subjects. METHODS: EEF1A1-AAb and UBE2L3-AAb levels in nondiabetic control subjects (n=150) and T1DM subjects (n=101) in various ranges of age (18 to 69 years) were measured using an enzyme-linked immunosorbent assay. The cutoff point for the presence of each autoantibody was determined based on control subjects using the formula: [mean absorbance+3*standard deviation]. RESULTS: In nondiabetic subjects, there were no significant correlations between age and EEF1A1-AAb and UBE2L3-AAb levels. However, there was wide variation in EEF1A1-AAb and UBE2L3-AAb levels among control subjects <40 years old; the prevalence of both EEF1A1-AAb and UBE2L3-AAb in these subjects was 4.4%. When using cutoff points determined from the control subjects <40 years old, the prevalence of both autoantibodies in T1DM subjects was decreased (EEFA1-AAb, 15.8% to 8.9%; UBE2L3 AAb, 10.9% to 7.9%) when compared to the prevalence using the cutoff derived from the totals for control subjects. CONCLUSION: There was no association between age and EEF1A1-AAb or UBE2L3-AAb levels in nondiabetic subjects. However, the wide variation in EEF1A1-AAb and UBE2L3-AAb levels apparent among the control subjects <40 years old should be taken into consideration when determining the cutoff reference range for the diagnosis of T1DM. PMID- 26616589 TI - Emerging targets for glioblastoma stem cell therapy. AB - Glioblastoma multiforme (GBM), designated as World Health Organization (WHO) grade IV astrocytoma, is a lethal and therapy-resistant brain cancer comprised of several tumor cell subpopulations, including GBM stem cells (GSCs) which are believed to contribute to tumor recurrence following initial response to therapies. Emerging evidence demonstrates that GBM tumors are initiated from GSCs. The development and use of novel therapies including small molecule inhibitors of specific proteins in signaling pathways that regulate stemness, proliferation and migration of GSCs, immunotherapy, and non-coding microRNAs may provide better means of treating GBM. Identification and characterization of GSC specific signaling pathways would be necessary to identify specific therapeutic targets which may lead to the development of more efficient therapies selectively targeting GSCs. Several signaling pathways including mTOR, AKT, maternal embryonic leucine zipper kinase (MELK), NOTCH1 and Wnt/beta-catenin as well as expression of cancer stem cell markers CD133, CD44, Oct4, Sox2, Nanog, and ALDH1A1 maintain GSC properties. Moreover, the data published in the Cancer Genome Atlas (TCGA) specifically demonstrated the activated PI3K/AKT/mTOR pathway in GBM tumorigenesis. Studying such pathways may help to understand GSC biology and lead to the development of potential therapeutic interventions to render them more sensitive to chemotherapy and radiation therapy. Furthemore, recent demonstration of dedifferentiation of GBM cell lines into CSC-like cells prove that any successful therapeutic agent or combination of drugs for GBM therapy must eliminate not only GSCs, but the differentiated GBM cells and the entire bulk of tumor cells. PMID- 26616591 TI - Non-Association between rs7903146 and rs12255372 Polymorphisms in Transcription Factor 7-Like 2 Gene and Type 2 Diabetes Mellitus in Jahrom City, Iran. AB - BACKGROUND: Transcription factor 7-like 2 (TCF7L2) is a transcription factor in the Wnt signaling pathway. High levels of TCF7L2 have been reported in most human tissues, including the heart, lung, brain, liver, kidney, placenta, adipose tissues, and pancreatic beta-cells. The purpose of this study was to assess the association between TCF7L2 polymorphisms (rs12255372 and rs7903146) and type 2 diabetes mellitus in the city of Jahrom, Iran. METHODS: This case-control study was conducted with 200 patients referred to Diabetes Clinics and 200 healthy subjects in Jahrom City. Biochemical characteristics were first determined. TCF7L2 rs1255372 and rs7903146 polymorphisms were then genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: T-allele frequencies of both single nucleotide polymorphisms (SNPs) were significantly higher in diabetic patients than in normal glucose-tolerant subjects (rs12255372: 20.3% vs. 14.5%; rs7903146: 28.5% vs. 22.25%). The rs12255372 (G/T) polymorphism analysis showed an odds ratio of 0.473 (95% confidence interval [CI], 0.170 to 1.314; P=0.151) for the TT genotype and 0.646 (95% CI, 0.410 to 1.019; P=0.060) for the TG genotype, compared with the GG genotype. The rs7903146 (C/T) polymorphism odds ratios for TT and TC genotypes were 0.564 (95% CI, 0.280 to 1.135; P=0.109) and 0.751 (95% CI, 0.487 to 1.157; P=0.194) compared with the CC genotype, respectively. CONCLUSION: The rs12255372 and rs7903146 SNPs of the TCF7L2 gene were not associated with insulin resistance in the evaluated population. PMID- 26616592 TI - Is an Oral Glucose Tolerance Test Still Valid for Diagnosing Diabetes Mellitus? AB - BACKGROUND: We evaluated the diagnostic rate of diabetes using fasting plasma glucose (FPG), 2-hour plasma glucose (2h PG) after 75 g oral glucose tolerance test (OGTT), and glycosylated hemoglobin (HbA1c) levels, and we elucidated the pathophysiologic characteristics and risk factors that give rise to diabetes in patients with prediabetes. METHODS: The data of 236 patients who had the OGTT at Konkuk University Hospital were analyzed. Fasting, 30, and 120 minutes blood glucose levels and insulin levels were measured. The diagnostic rate of diabetes was assessed using FPG, 2h PG, and HbA1c levels. The clinical data and insulin resistance and secretion evaluations were compared using indexes according to the fasting glucose level. RESULTS: Among 236 subjects, 97 (41.1%) were diabetics and 102 (43.2%) were prediabetics. The rate of diabetes diagnosis by one of the individual criteria was 56.7%, 53.6%, and 84.5% for FPG, HbA1c, and 2h PG, respectively. When two criteria were used to diagnose diabetes, 72.2% of the diabetic patients were identified by FPG and HbA1c, while 100% were identified by FPG and 2h PG, and 91.7% were identified by 2h PG and HbA1c. The HbA1c cut-off value for 2h PG >=200 mg/dL was 6.1%, and the FPG cut-off value was 115 mg/dL. In impaired fasting glucose subjects, the HbA1c level, Matsuda index, and insulinogenic index were associated with risk of occurrence of overt diabetes (P<0.01). CONCLUSION: This study suggests that performing additional OGTT for patients with FPG >=110 mg/dL or HbA1c >=6.1% is helpful to reclassify their glucose tolerance status and evaluate their potential for progressing to overt diabetes. PMID- 26616593 TI - The Usefulness of the Glycosylated Hemoglobin Level for the Diagnosis of Gestational Diabetes Mellitus in the Korean Population. AB - BACKGROUND: An oral glucose tolerance test (OGTT) is the current method used for screening and diagnosis of gestational diabetes mellitus (GDM). OGTT is a relatively complicated procedure and is expensive. Thus, new strategies that do not require fasting or more than a single blood draw may improve the diagnosis of GDM and increase the rate of GDM testing. We investigated the utility of monitoring glycosylated hemoglobin (HbA1c) levels for the diagnosis of GDM. METHODS: The data from 992 pregnant women with estimated gestational ages ranging from 24 to 28 weeks were retrospectively reviewed. There were 367 women with plasma glucose levels >=140 mg/dL 1 hour after a 50-g OGTT. GDM was diagnosed according to the Carpenter-Coustan criteria for a 3-hour 100 g OGTT. A HbA1c assessment was performed at the same time. RESULTS: We enrolled 343 women in this study, and there were 109 women with GDM. The area under the curve the receiver operating characteristic curve for HbA1c detection of GDM was 0.852 (95% confidence interval, 0.808 to 0.897). A HbA1c cutoff value >=5.35% had maximal points on the Youden index (0.581). The sensitivity was 87.2% and the specificity was 70.9% for diagnosing GDM. A threshold value >=5.35% indicated that 163 patients had GDM and that 68 (41.7%) were false positive. The positive predictive value was 58.3% at this threshold value. CONCLUSION: Despite substantial progress in methodology, HbA1c values cannot replace OGTT for the diagnosis of GDM. PMID- 26616594 TI - Insulin Initiation in Insulin-Naive Korean Type 2 Diabetic Patients Inadequately Controlled on Oral Antidiabetic Drugs in Real-World Practice: The Modality of Insulin Treatment Evaluation Study. AB - BACKGROUND: The Modality of Insulin Treatment Evaluation (MOTIV) study was performed to provide real-world data concerning insulin initiation in Korean type 2 diabetes mellitus (T2DM) patients with inadequate glycemic control with oral hypoglycemic agents (OHAs). METHODS: This multicenter, non-interventional, prospective, observational study enrolled T2DM patients with inadequate glycemic control (glycosylated hemoglobin [HbA1c] >=7.0%) who had been on OHAs for >=3 months and were already decided to introduce basal insulin by their physician prior to the start of the study. All treatment decisions were at the physician's discretion to reflect real-world practice. RESULTS: A total of 9,196 patients were enrolled, and 8,636 patients were included in the analysis (mean duration of diabetes, 8.9 years; mean HbA1c, 9.2%). Basal insulin plus one OHA was the most frequently (51.0%) used regimen. After 6 months of basal insulin treatment, HbA1c decreased to 7.4% and 44.5% of patients reached HbA1c <7%. Body weight increased from 65.2 kg to 65.5 kg, which was not significant. Meanwhile, there was significant increase in the mean daily insulin dose from 16.9 IU at baseline to 24.5 IU at month 6 (P<0.001). Overall, 17.6% of patients experienced at least one hypoglycemic event. CONCLUSION: In a real-world setting, the initiation of basal insulin is an effective and well-tolerated treatment option in Korean patients with T2DM who are failing to meet targets with OHA therapy. PMID- 26616595 TI - Clinical Characteristics and Metabolic Predictors of Rapid Responders to Dipeptidyl Peptidase-4 Inhibitor as an Add-on Therapy to Sulfonylurea and Metformin. AB - BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitor add-on therapy is a new option for patients with inadequately controlled type 2 diabetes who are taking combined metformin and sulfonylurea (SU). We evaluated the efficacy and safety of this triple therapy and the characteristics of rapid responders and hypoglycemia prone patients. METHODS: We included 807 patients with type 2 diabetes who were prescribed a newly added DPP-4 inhibitor to ongoing metformin and SU in 2009 to 2011. Glycemia and other metabolic parameters at baseline, 12, 24, and 52 weeks, as well as episodes of hypoglycemia were analyzed. Rapid responders were defined as patients with >=25% reduction in glycosylated hemoglobin (HbA1c) within 12 weeks. RESULTS: At baseline, while on the submaximal metformin and SU combination, the mean HbA1c level was 8.4%. Twelve weeks after initiation of DPP 4 inhibitor add-on, 269 patients (34.4%) achieved an HbA1c level <=7%. Sixty-six patients (8.2%, 47 men) were rapid responders. The duration of diabetes was shorter in rapid responders, and their baseline fasting plasma glucose (FPG), HbA1c, C-peptide, and homeostasis model assessment of insulin resistance were significantly higher. Patients who experienced hypoglycemia after taking DPP-4 inhibitor add-on were more likely to be female, to have a lower body weight and lower triglyceride and FPG levels, and to have higher homeostasis model assessment of beta-cells. CONCLUSION: An oral hypoglycemic triple agent combination including a DPP-4 inhibitor was effective in patients with uncontrolled diabetes. Proactive dose reduction of SU should be considered when a DPP-4 inhibitor is added for rapid responders and hypoglycemia-prone patients. PMID- 26616596 TI - The Association of Serum Cystatin C with Glycosylated Hemoglobin in Korean Adults. AB - BACKGROUND: Cystatin C has been known to be associated not only with early renal impairment but also with the incidence of diabetic conditions (prediabetes plus diabetes). However, it is not clear whether cystatin C levels are associated with the prevalence of diabetic conditions in Asian populations. We evaluated this association using glycosylated hemoglobin (HbA1c) levels as the definition of diabetes in Korean adults. METHODS: We analyzed data from 1,559 Korean adults (937 men and 622 women) with available serum cystatin C and HbA1c values. RESULTS: The serum cystatin C levels in subjects with prediabetes and diabetes were significantly increased (0.91+/-0.14 mg/L in prediabetes and 0.91+/-0.17 mg/L in diabetes vs. 0.88+/-0.13 mg/L in patients with normal glucose levels, P=0.001). At increasing cystatin C levels, the prevalence of subjects with prediabetes (30.2% vs. 14.6%, P<0.001) and those with diabetes (10.6% vs. 8.0%, P<0.001) significantly increased in the group with the highest cystatin C levels. The group with the highest cystatin C levels had a significantly increased odds ratio (OR) for the presence of diabetic conditions compared to the group with the lowest values in total subjects (OR, 2.35; 95% confidence interval [CI], 1.54 to 3.58; P<0.001) and in women (OR, 4.13; 95% CI, 1.97 to 8.65; P<0.001), though there was no significant increase after adjusting for multiple variables. CONCLUSIONS: Higher levels of serum cystatin C are associated with an increased prevalence of diabetic conditions in Korean adults. Our findings may extend the positive association of cystatin C with diabetes incidence to an Asian population. PMID- 26616597 TI - Effect of Atorvastatin on Growth Differentiation Factor-15 in Patients with Type 2 Diabetes Mellitus and Dyslipidemia. AB - BACKGROUND: Elevated serum levels of growth differentiation factor-15 (GDF-15) are associated with type 2 diabetes. Therefore, the effects of atorvastatin on metabolic parameters and GDF-15 levels in patients with type 2 diabetes and dyslipidemia were evaluated. METHODS: In this prospective randomized trial from February 2013 to March 2014, 50 consecutive type 2 diabetic patients with a low density lipoprotein cholesterol (LDL-C) levels >=100 mg/dL were enrolled. The patients were divided into two groups based on the amount of atorvastatin prescribed, 10 mg/day (n=23) or 40 mg/day (n=27). The effect of atorvastatin on metabolic parameters, including lipid profiles and GDF-15 levels, at baseline and after 8 weeks of treatment were compared. RESULTS: The baseline metabolic parameters and GDF-15 levels were not significantly different between the two groups. After 8 weeks of treatment, the total cholesterol (TC) and LDL-C levels were significantly decreased in both groups. The mean changes in TC and LDL-C levels were more significant in the 40 mg atorvastatin group. The GDF-15 level was decreased in the 10 mg atorvastatin group, from 1,460.6+/-874.8 to 1,451.0+/ 770.8 pg/mL, and was increased in the 40 mg atorvastatin group, from 1,271.6+/ 801.0 to 1,341.4+/-855.2 pg/mL. However, the change in the GDF-15 level was not statistically significant in the 10 or 40 mg atorvastatin group (P=0.665 and P=0.745, respectively). CONCLUSION: The GDF-15 levels were not significantly changed after an 8-week treatment with atorvastatin in type 2 diabetic patients. PMID- 26616598 TI - Spectral library searching in proteomics. AB - Spectral library searching has become a mature method to identify tandem mass spectra in proteomics data analysis. This review provides a comprehensive overview of available spectral library search engines and highlights their distinct features. Additionally, resources providing spectral libraries are summarized and tools presented that extend experimental spectral libraries by simulating spectra. Finally, spectrum clustering algorithms are discussed that utilize the same spectrum-to-spectrum matching algorithms as spectral library search engines and allow novel methods to analyse proteomics data. PMID- 26616599 TI - Altered pathogenicity of a tl/CH/LDT3/03 genotype infectious bronchitis coronavirus due to natural recombination in the 5'- 17kb region of the genome. AB - An infectious bronchitis coronavirus, designated as ck/CH/LGX/130530, was isolated from an IBV strain H120-vaccinated chicken in this study. Analysis of the S1 gene showed that isolate ck/CH/LGX/130530 was a tl/CH/LDT3/03-like virus, with a nucleotide sequence similarity of 99%. However, a complete genomic sequence analysis showed that ck/CH/LGX/130530 was more closely related to a Massachusetts type strain (95% similarity to strain H120) than to the tl/CH/LDT3/03 strain (86%), suggesting that recombination might have occurred during the origin of the virus. A SimPlot analysis of the complete genomic sequence confirmed this hypothesis, and it showed that isolate ck/CH/LGX/130530 emerged from a recombination event between parental IBV H120 strain and pathogenic tl/CH/LDT3/03-like virus. The results obtained from the pairwise comparison and nucleotide similarity showed that the recombination breakpoint was located in the nsp14 gene at nucleotides 17055-17083. In line with the high S1 gene sequence similarity, the ck/CH/LGX/130530 isolate was serotypically close to that of the tl/CH/LDT3/03 strain (73% antigenic relatedness). Furthermore, vaccination with the LDT3-A vaccine, which was derived from the tl/CH/LDT3/03 strain by serial passaging in chicken eggs, provided good protection against challenge with the tl/CH/LDT3/03 strain, in contrast to the poor protection offered with the H120 vaccine. Interestingly, isolate ck/CH/LGX/130530 exhibited low pathogenicity toward specific-pathogen-free chickens compared with the nephropathogenic tl/CH/LDT3/03 strain, which was likely due to natural recombination in the 5' 17-kb region of the genome. Our results also indicate that the replicase gene of IBV isolate ck/CH/LGX/130530 is associated with viral pathogenicity. PMID- 26616600 TI - Detection of atypical Chlamydiaceae in roe deer (Capreolus capreolus). AB - Investigations on fecal samples, vaginal swabs and sera from roe deer (Capreolus capreolus) in south-western France led to the detection of a non-classified Chlamydiaceae strain. A total of 85 vaginal swabs were sampled from roe deer that had been captured in 2012 (n=42) and 2013 (n=43). Using a Chlamydiaceae family specific real-time PCR, only one vaginal swab out of the 42 samples done in 2012 tested positive and was subsequently identified as Chlamydia (C.) psittaci. In contrast, 6/43 vaginal swab samples were positive in 2013. Four of these positive samples came from a single group of roe deer, captured in the Fabas plain. Fecal samples from this group of 9 females were subsequently analyzed, with 6 of them testing positive with the Chlamydiaceae-specific PCR. All positive samples collected in 2013 were negative when re-tested with C. abortus-, C. pecorum- and C. suis-specific real-time PCR assays. Sera from this group of 9 females were analyzed with two immunoassays (recomLine and ELISA). Whereas intense positive reactions with C. pneumoniae antigens were observed for all sera when tested with the recomLine test, none was positive with the C. abortus specific ELISA test. Comparative sequence analysis of the 16S, 23S rRNA and ompA gene sequences from 3 animals, as well as the MLST analysis from 2 animals, showed that this roe deer group likely harbored the same bacterium related to members of the family Chlamydiaceae. Notably, the roe deer strain formed a separate entity different from the currently recognized chlamydial species, with C. trachomatis, C. suis and C. muridarum appearing as its closest relatives. PMID- 26616601 TI - Impact of colistin sulfate treatment of broilers on the presence of resistant bacteria and resistance genes in stored or composted manure. AB - The application of manure may result in contamination of the environment with antimicrobials, antimicrobial-resistant bacteria, resistance genes and plasmids. The aim of this study was to investigate the impact of the administration of colistin and of manure management on (i) the presence of colistin-resistant Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa and (ii) the prevalence of various antimicrobial resistance genes in feces and in composted or stored manure. One flock of chickens was treated with colistin at the recommended dosage and a second flock was kept as an untreated control. Samples of feces, litter and stored or composted manure from both flocks were collected for isolation and determination of the colistin-susceptibility of E. coli, K. pneumoniae and P. aeruginosa and quantification of genes coding for resistance to different antimicrobials. The persistence of plasmids in stored or composted manure from colistin-treated broilers was also evaluated by plasmid capturing experiments. Results revealed that colistin administration to chickens had no apparent impact on the antimicrobial resistance of the dominant Enterobacteriaceae and P. aeruginosa populations in the chicken gut. Composting stimulated an apparently limited decrease in genes coding for resistance to different antimicrobial families. Importantly, it was shown that even after six weeks of composting or storage, plasmids carrying antimicrobial resistance genes could still be transferred to a recipient E. coli. In conclusion, composting is insufficient to completely eliminate the risk of spreading antimicrobial resistance through chicken manure. PMID- 26616602 TI - A Novel Self-Assembling Al-based Composite Powder with High Hydrogen Generation Efficiency. AB - In this study, a novel self-assembling hydrogen generation powder comprised of 80Al-10Bi-10Sn wt.% was prepared using the gas atomization method and then collected in an air environment. The morphological and hydrolysis properties of the powders were investigated. The results indicated that the powders formed unique core/shell microstructures with cracked surfaces and (Bi, Sn)-rich phases distributed on the Al grain boundaries. The powders exhibited good oxidation resistance and reacted violently with distilled water at temperatures as low as 0 degrees C. Furthermore, at 30 degrees C, the powders exhibited a hydrogen conversion yield of 91.30% within 16 minutes. The hydrogen produced by this powder could be directly used in proton exchange membrane fuel cells. The mechanisms of the hydrolysis reactions were also analyzed. PMID- 26616603 TI - Tracing the Entropy along a Reactive Pathway: The Energy As a Generalized Reaction Coordinate. AB - By using metadynamics at a temperature T0 we reconstruct the free energy FT0(E,s) as a function of the potential energy E and of a geometrical variable s. We show here that from FT0(E,s) one can estimate the free energy also at a different temperature. This allows tracing the entropy and characterizing the properties of molecular systems at all temperatures by a single simulation. We validate this approach on the water dimer dissociation. PMID- 26616604 TI - A Collective Variable for the Efficient Exploration of Protein Beta-Sheet Structures: Application to SH3 and GB1. AB - We introduce a new class of collective variables which allow forming efficiently beta-sheet structures in all-atom explicit-solvent simulations of proteins. By this approach we are able to systematically fold a 16-residue beta hairpin using metadynamics on a single replica. Application to the 56-residue SH3 and GB1 proteins show that, starting from extended states, in ~100 ns tens of structures containing more than 30% beta-sheet are obtained, including parts of the native fold. Using these variables may allow folding moderate size proteins with an accurate explicit solvent description. Moreover, it may allow investigating the presence of misfolded states that are relevant for diseases (e.g., prion and Alzheimer) and studying beta-aggregation (amyloid diseases). PMID- 26616605 TI - Peptide Partitioning and Folding into Lipid Bilayers. AB - The folding and partitioning of WALP peptides into lipid bilayers is characterized using atomic detail molecular dynamics simulations on microsecond time scales. Elevated temperatures are used to increase sampling, and their suitability is validated via circular dichroism experiments. A new united atom parametrization of lipids is employed, adjusted for consistency with the OPLS all atom force field. In all simulations secondary structure forms rapidly, culminating in the formation of the native trans-membrane helix, which is demonstrated to have the lowest free energy. Partitioning simulations show that peptide insertion into the bilayer is preceded by interfacial folding. These results are in excellent agreement with partitioning theory. In contrast, previous simulations observed unfolded insertion pathways and incorrectly report stable extended configurations inside the membrane. This highlights the importance of accurately tuning and experimentally verifying force field parameters against microsecond time scale phenomena. PMID- 26616606 TI - Improved Hydrogen Bonding at the NDDO-Type Semiempirical Quantum Mechanical/Molecular Mechanical Interface. AB - A semiempirical quantum mechanical (QM)/molecular mechanical (MM) potential with reformulated QM core-MM charge interactions is introduced, specifically to more accurately model hydrogen bonding at the QM/MM interface. Application of this potential using the PM3 Hamiltonian shows improved prediction of geometry and interaction energy for hydrogen bonded small molecule complexes typical of biomolecular interactions, without significantly impacting the modeling of other interaction types. Using this potential, more quantitative prediction of interaction energies is also found at a protein-ligand interface. PMID- 26616607 TI - Toward a Practical Method for Adaptive QM/MM Simulations. AB - We present an accurate adaptive multiscale molecular dynamics method that will enable the detailed study of large molecular systems that mimic experiment. The method treats the reactive regions at the quantum mechanical level and the inactive environment regions at lower levels of accuracy, while at the same time molecules are allowed to flow across the border between active and environment regions. Among many other things, this scheme affords accurate investigation of chemical reactions in solution. A scheme like this ideally fulfills the key criteria applicable to all molecular dynamics simulations: energy conservation and computational efficiency. Approaches that fulfill both criteria can, however, result in complicated potential energy surfaces, creating rapid energy changes when the border between regions is crossed. With the difference-based adaptive solvation potential, a simple approach is introduced that meets the above requirements and reduces fast fluctuations in the potential to a minimum. In cases where none of the current adaptive QM/MM potentials are able to properly describe the system under investigation, we use a continuous force scheme instead, which, while no longer energy conserving, still retains a related conserved quantity along the trajectory. We show that this scheme does not introduce a significant temperature drift on time scales feasible for QM/MM simulations. PMID- 26616608 TI - Heavy Halogen Atom Effect on (13)C NMR Chemical Shifts in Monohalo Derivatives of Cyclohexane and Pyran. Experimental and Theoretical Study. AB - As a first step, a qualitative analysis of the spin-orbit operator was performed to predict the kind of organic compounds, where it could be expected that the SO/FC (spin-orbit/Fermi contact) and SO/SD (spin-orbit/spin dipolar) yield unusually small contributions to the "heavy atom effect" on (13)C SCSs (substituent chemical shifts). This analysis led to the conclusion that compounds presenting strong hyperconjugative interactions involving the sigma*C-X orbital (X = halogen) are good examples where such effects can be expected to take place. On the basis of such results, the following set of model compounds was chosen: 2 eq-halocyclohexane (2-eq), 2-ax-halocyclohexane (2-ax), and 2-ax-halopyran (3), to measure (13)C SCSs. Such experimental values, as well as those of methane and halomethanes taken from the literature, were compared to calculated values at a nonrelativistic approach using B3LYP, and at a relativistic approach with BP86 using scalar ZORA, spin-orbit ZORA, scalar PAULI, and spin-orbit PAULI. Results from relativistic calculations are in agreement with the trends predicted by the qualitative model discussed in this work. PMID- 26616609 TI - All-Electron Scalar Relativistic Basis Sets for the Lanthanides. AB - Segmented all-electron relativistically contracted (SARC) basis sets are constructed for the elements 57La-71Lu and optimized for density functional theory (DFT) applications. The basis sets are intended for use in combination with the DKH2 or ZORA scalar relativistic Hamiltonians for which individually optimized contractions are provided. Significant computational advantages can be realized owing to the loose contraction of the SARC basis sets compared to generally contracted basis sets, while their compact size allows them to replace effective core potentials for routine studies of lanthanide complexes. The new basis sets are evaluated in DFT calculations of the first four ionization energies of the lanthanides. They yield results that accurately reproduce the experimental trends, confirming a balanced treatment of different electronic configurations. The performance of the basis sets is further assessed in molecular systems with a comprehensive study of the lanthanide trihalides. Despite their compact size, the SARC basis sets demonstrate consistent, efficient, and reliable performance and will be especially useful in calculations of molecular properties that require explicit treatment of the core electrons. PMID- 26616610 TI - An Ab Initio Study of the Structures and Selected Properties of 1,2-Dihydro-1,2 azaborine and Related Molecules. AB - An ab initio study has been carried out to investigate the effect of replacing [HC-CH]n linkages in benzene by the isoelectronic [HN-BH]n linkages for n = 1, 2, and 3. Such replacements give rise to azaborine, a set of diazaborines, borazine, and pseudoborazine. These replacements lead to significant rearrangements of electron densities in these molecules due primarily to the introduction of the polar B-N bond. As a result, azaborine and diazaborines exhibit much more localized structures than that of benzene. They are also less aromatic than benzene but have a higher degree of aromaticity than borazine. The bonding patterns can be related to the relative stabilities of the diazaborines. Among these molecules, the most stable isomer contains an N-B-N-B linkage, while the two least stable isomers have either a B-B or a N-N bond. Changes in bonding patterns are also reflected in changes in the N1-B2 coupling constant. When N1 and B2 are bonded to the less electronegative atoms C and B, (1)J(N1-B2) increases relative to borazine, but when either N1 or B2 is bonded to N, (1)J(N1 B2) decreases. Computed NMR chemical shifts and coupling constants are in good agreement with available experimental data. PMID- 26616611 TI - Phenylalanyl-Glycyl-Phenylalanine Tripeptide: A Model System for Aromatic Aromatic Side Chain Interactions in Proteins. AB - The performance of a wide range of quantum chemical calculations for the ab initio study of realistic model systems of aromatic-aromatic side chain interactions in proteins (in particular those pi-pi interactions occurring between adjacent residues along the protein sequence) is here assessed on the phenylalanyl-glycyl-phenylalanine (FGF) tripeptide. Energies and geometries obtained at different levels of theory are compared with CCSD(T)/CBS benchmark energies and RI-MP2/cc-pVTZ benchmark geometries, respectively. Consequently, a protocol of calculation alternative to the very expensive CCSD(T)/CBS is proposed. In addition to this, the preferred orientation of the Phe aromatic side chains is discussed and compared with previous results on the topic. PMID- 26616612 TI - Quantitative Assessment of Electrostatic Embedding in Density Functional Theory Calculations of Biomolecular Systems. AB - We evaluate the accuracy of density functional theory quantum calculations of biomolecular subsystems using a simple electrostatic embedding scheme. Our scheme is based on dividing the system of interest into a primary and secondary subsystem. A finite difference discretization of the Kohn-Sham equations is used for the primary subsystem, while its electrostatic environment is modeled with a simple one-electron potential. Force-field atomic partial charges are used to generate smeared Gaussian charge densities and to model the secondary subsystem. We illustrate the utility of this approach with calculations of truncated dipeptide chains. We analyze quantitatively the accuracy of this approach by calculating atomic forces and comparing results with full QM calculations. The impact of the choice made in terminating dangling bonds at the frontier of the QM region is also investigated. PMID- 26616613 TI - Theoretical Study of the Structure and Electronic Properties of Si3On(-) and Si6On(-) (n = 1-6) Clusters. Fragmentation and Formation Patterns. AB - A theoretical study of two series of small clusters, Si3On(-) and Si6On(-) (n = 1 6), has been carried out. The minimum energy structures were produced adding an electron to neutral species followed by relaxation at the B3LYP-6-311G(2d) level. The vertical ionization energies (VIEs) were computed using the electron propagator theory (EPT) in two approximations, Unrestricted Outer Valence Green Functions (UOVGF) and partial third-order approximation (P3). In the series Si3On(-) the theoretical VIEs of the minimum energy structures agree well with experimental data. For the second series there are not experimental VIEs, and the theoretical results are predictions. The performance of EPT methodologies in conjunction with all-electron or pseudopotentials (PP) calculations is analyzed. The conjunction of P3 and PP approximation proves to be the most efficient and economical methodology to calculate the VIEs of small anionic silicon oxide clusters. In the series Si6On(-) different channels of fragmentation have been calculated. The results suggest that the fragments do not have drastic geometric changes and the anionic fragment corresponds to the atoms where the spin density of the initial large cluster is localized. The Fukui function calculated over selected optimized fragments predicts adequately the interaction between them to form large stable clusters. PMID- 26616614 TI - Characterization of the Chemical Behavior of the Low Excited States through a Local Chemical Potential. AB - Exploiting the locality of the chemical potential of an excited state when it is evaluated using the ground-state density functional theory (DFT), a new descriptor for excited states has been proposed. This index is based on the assumption that the relaxation of the electronic density drives the chemical reactivity of excited states. The sign of the descriptor characterizes the electrophilic or nucleophilic behavior of the atomic regions. A relation between the new descriptor and the dual descriptor is derived and provides a posteriori justification of its use to rationalize the Woodward-Hoffmann rules for photochemical reactions within the conceptual DFT. Finally, the descriptor is successfully applied to some [2 + 2] photocycloadditions, like Paterno-Buchi reactions. PMID- 26616615 TI - Solvent Dependence of (14)N Nuclear Magnetic Resonance Chemical Shielding Constants as a Test of the Accuracy of the Computed Polarization of Solute Electron Densities by the Solvent. AB - Although continuum solvation models have now been shown to provide good quantitative accuracy for calculating free energies of solvation, questions remain about the accuracy of the perturbed solute electron densities and properties computed from them. Here we examine those questions by applying the SM8, SM8AD, SMD, and IEF-PCM continuum solvation models in combination with the M06-L density functional to compute the (14)N magnetic resonance nuclear shieldings of CH3CN, CH3NO2, CH3NCS, and CH3ONO2 in multiple solvents, and we analyze the dependence of the chemical shifts on solvent dielectric constant. We examine the dependence of the computed chemical shifts on the definition of the molecular cavity (both united-atom models and models based on superposed individual atomic spheres) and three kinds of treatments of the electrostatics, namely the generalized Born approximation with the Coulomb field approximation, the generalized Born model with asymmetric descreening, and models based on approximate numerical solution schemes for the nonhomogeneous Poisson equation. Our most systematic analyses are based on the computation of relative (14)N chemical shifts in a series of solvents, and we compare calculated shielding constants relative to those in CCl4 for various solvation models and density functionals. While differences in the overall results are found to be reasonably small for different solvation models and functionals, the SMx models SM8, and SM8AD, using the same cavity definitions (which for these models means the same atomic radii) as those employed for the calculation of free energies of solvation, exhibit the best agreement with experiment for every functional tested. This suggests that in addition to predicting accurate free energies of solvation, the SM8 and SM8AD generalized Born models also describe the solute polarization in a manner reasonably consistent with experimental (14)N nuclear magnetic resonance spectroscopy. Models based on the nonhomogeneous Poisson equation show slightly reduced accuracy. Scaling the intrinsic Coulomb radii to larger values (as has sometimes been suggested in the past) does not uniformly improve the results for any kind of solvent model; furthermore it uniformly degrades the results for generalized Born models. Use of a basis set that increases the outlying charge diminishes the accuracy of continuum models that solve the nonhomogeneous Poisson equation, which we ascribe to the inability of the numerical schemes for approximately solving the nonhomogeneous Poisson equation to fully account for the effects of electronic charge outside the solute cavity. PMID- 26616616 TI - High Accuracy ab Initio Calculations on Reactions of OH with 1-Alkenes. The Case of Propene. AB - The energetics of terminal, central OH-additions as well as allylic H abstractions by OH in its reaction with propene was studied as proxies for the 1 alkenes + OH reactions using several single and multireference ab initio techniques with basis set extrapolation where possible. Selection of the localized occupied orbitals forming the active space for multireference methods is discussed. Initial geometries of the reactants, prereaction complex (pi complex), and transition states were determined at the [5,5]-CASPT2/cc-pVTZ level of theory. Frequency analysis was also carried out at this level with the introduction of a scale factor. Analyzing the results, it will be concluded that multireference effects are negligible, and from the various single reference models we will opt for UCCSD(T)/cc-pVTZ for final geometry optimizations and vibrational frequency analysis. These results will be compared with those from approximate models yielding information on the reliability of the latter. Triples contributions are found to be very important, except for the pi-complex, which has a UCCSD(T)/CBS relative enthalpy of -10.56 kJ/mol compared to infinitely separated propene + OH. The addition transition states are found to have relative enthalpies of -9.93 kJ/mol for the central and -9.84 kJ/mol for the terminal case. Allylic abstraction mechanisms, although lying significantly higher, still have only slightly positive barriers - a value of 3.21 kJ/mol for the direct and 1.67 kJ/mol for the consecutive case. Conventional transition state theory was used as a rough estimation for determining rate constants and turned out to agree well with experimental data. PMID- 26616618 TI - An Implementation of the Smooth Particle Mesh Ewald Method on GPU Hardware. AB - The smooth particle mesh Ewald summation method is widely used to efficiently compute long-range electrostatic force terms in molecular dynamics simulations, and there has been considerable work in developing optimized implementations for a variety of parallel computer architectures. We describe an implementation for Nvidia graphical processing units (GPUs) which are general purpose computing devices with a high degree of intrinsic parallelism and arithmetic performance. We find that, for typical biomolecular simulations (e.g., DHFR, 26K atoms), a single GPU equipped workstation is able to provide sufficient performance to permit simulation rates of ~50 ns/day when used in conjunction with the ACEMD molecular dynamics package (1) and exhibits an accuracy comparable to that of a reference double-precision CPU implementation. PMID- 26616617 TI - Capturing the Trans Influence in Low-Spin d(8) Square-Planar Platinum(II) Systems using Molecular Mechanics. AB - Molecular modeling of coordination complexes continues to present challenges for force field methods. Implicit or explicit treatment of the significant d electron effects is mandatory. Ligand field molecular mechanics is designed for coordination complexes by explicitly including the ligand field stabilization energy (LFSE) and it is applied here to model the trans influence in tetracoordinate Pt(II) complexes of general formulas PtX4, PtX3Y, cis-PtX2Y2, and trans-PtX2Y2, where X and Y are OH2, H(-), Cl(-), Br(-), PR3, SH2, NR3, and pyridine. Parameters have been developed within the Merck molecular force field using DFT structures and energies as reference data. Both geometric changes and relative energies are generally well-reproduced although PH3 and H(-) complexes show deviations. However, for phosphine complexes, replacing PH3 with PMe3 resolves all bar one of these. The LFSE associated with the low-spin d(8) configuration ensures planar coordination and provides an electronic connection between all the ligands, thus enabling a correct description of the trans influence. The parameters developed for NR3 and PR3 with R = H work well for R = Me and Et and, in agreement with experimental and/or DFT structures, display either a tetrahedral distortion or even ligand dissociation. PMID- 26616619 TI - Theoretical Study of the X2NO Systems (X = F, Cl, Br, I): Effects of Halogen Substitution on Structural and Spectroscopic Properties. AB - Structural and spectroscopic properties of the X2 NO series of radicals, with X = F, Cl, Br, I, have been computed by the coupled cluster ansatz in conjunction with hierarchical series of basis sets, accounting for, in most cases, core correlation effects and extrapolation to the complete basis set limit. Namely, equilibrium structures, vibrational frequencies, and hyperfine coupling constants have been considered. Methods rooted into the density functional theory have been used to estimate anharmonic and, in conjunction with the polarizable continuum model, environmental effects. The remarkable agreement with the available experimental data, limited to the lighter member of the series, confirms the reliability of our computational approach and suggests that the data for heavier species represent reliable benchmarks for future experimental data and/or cheaper computational methods devised for larger systems. PMID- 26616620 TI - Molecular Dynamics and Room Temperature Vibrational Properties of Deprotonated Phosphorylated Serine. AB - The local structure of phosphorylated residues in peptides and proteins may have a decisive role on their functional properties. Recent IRMPD experiments have started to provide spectroscopic signatures of such structural details; however, a proper modeling of these signatures beyond the harmonic approximation, taking into account temperature and entropic effects, is still lacking. In order to bridge this gap, DFT-based Car-Parrinello molecular dynamics simulations have been carried out for the first time on a phosphorylated amino acid, gaseous deprotonated phosphoserine. It is found that all vibrational signatures are successfully reproduced, and new deconvolution techniques enable the assignment of the vibrational spectrum directly from the dynamics results and the comparison of vibrational modes at several temperatures. The lowest energy structure is found to involve a strong hydrogen bond between the deprotonated phosphate and the acid with relatively small free energy barriers to proton transfer; however, we find that proton shuttling between the two sites does not occur frequently. Anharmonicities turn out to be important to reproduce the frequencies and shapes of several experimental bands. Comparison of room temperature and 13 K, effectively harmonic dynamics, allows insight to be obtained into vibrational anharmonicities. In particular, a significant blue-shift and broadening of the C?O stretching frequency from 13 to 300 K can be ascribed to intrinsic anharmonicity rather than to anharmonic coupling to other modes. On the other hand, significant couplings are found for the stretching motions of the hydrogen bonded P-O bond and of the free P-OH bond, mainly with modes within the phosphate group. PMID- 26616621 TI - Excited State Potential Energy Surfaces of Polyenes and Protonated Schiff Bases. AB - The potential energy surface of the (1)Bu and (1)A' states of all-trans-polyenes and the corresponding protonated Schiff bases have been studied at density functional theory and coupled cluster levels. Linear polyenes and protonated Schiff bases with 4 to 12 heavy atoms have been investigated. The calculations show remarkable differences in the excited state potential energy surfaces of the polyenes and the protonated Schiff bases. The excited states of the polyenes exhibit high torsion barriers for single-bond twists and low torsion barriers for double-bond twists. The protonated Schiff bases, on the other hand, are very flexible molecules in the first excited state with low or vanishing torsion barriers for both single and double bonds. Calculations at density functional theory and coupled cluster levels yield qualitatively similar potential energy surfaces. However, significant differences are found for some single-bond torsions in longer protonated Schiff bases, which indicate a flaw of the employed time-dependent density functional theory methods. The close agreement between the approximate second and third order coupled cluster levels indicates that for these systems calculations at second order coupled cluster level are useful in the validation of results based on time-dependent density functional theory. PMID- 26616622 TI - Singlet-Triplet Transitions in Real-Time Time-Dependent Hartree-Fock/Density Functional Theory. AB - Real-time time-dependent Hartree-Fock (TDHF)/density functional theory (TDDFT) has been gaining in popularity because of its ability to treat phenomena beyond the linear response and because it has the potential to be more computationally powerful than frequency domain TDHF/TDDFT. Within real-time TDHF/TDDFT, we present a method that gives the excited state triplet energies starting from a singlet ground state. Using a spin-dependent field, we break the spin-symmetry of the alpha and beta density matrices, which incorporates a triplet contribution into the superposition state. The alpha electron density follows the applied field, and the beta electron density responds to the perturbation from the changing alpha electron density. We examine the individual alpha/beta responses during the electron density propagation. Singlet-triplet transitions appear as 'dark' states: they are present in the alpha/beta responses but are absent from the total electron density response. PMID- 26616623 TI - Extensive TD-DFT Benchmark: Singlet-Excited States of Organic Molecules. AB - Extensive Time-Dependent Density Functional Theory (TD-DFT) calculations have been carried out in order to obtain a statistically meaningful analysis of the merits of a large number of functionals. To reach this goal, a very extended set of molecules (~500 compounds, >700 excited states) covering a broad range of (bio)organic molecules and dyes have been investigated. Likewise, 29 functionals including LDA, GGA, meta-GGA, global hybrids, and long-range-corrected hybrids have been considered. Comparisons with both theoretical references and experimental measurements have been carried out. On average, the functionals providing the best match with reference data are, one the one hand, global hybrids containing between 22% and 25% of exact exchange (X3LYP, B98, PBE0, and mPW1PW91) and, on the other hand, a long-range-corrected hybrid with a less rapidly increasing HF ratio, namely LC-omegaPBE(20). Pure functionals tend to be less consistent, whereas functionals incorporating a larger fraction of exact exchange tend to underestimate significantly the transition energies. For most treated cases, the M05 and CAM-B3LYP schemes deliver fairly small deviations but do not outperform standard hybrids such as X3LYP or PBE0, at least within the vertical approximation. With the optimal functionals, one obtains mean absolute deviations smaller than 0.25 eV, though the errors significantly depend on the subset of molecules or states considered. As an illustration, PBE0 and LC omegaPBE(20) provide a mean absolute error of only 0.14 eV for the 228 states related to neutral organic dyes but are completely off target for cyanine-like derivatives. On the basis of comparisons with theoretical estimates, it also turned out that CC2 and TD-DFT errors are of the same order of magnitude, once the above-mentioned hybrids are selected. PMID- 26616624 TI - 1-Octanol/Water Partition Coefficients of n-Alkanes from Molecular Simulations of Absolute Solvation Free Energies. AB - The 1-octanol/water partition coefficient is an important thermodynamic variable usually employed to understand and quantify the partitioning of solutes between aqueous and organic phases. It finds widespread use in many empirical correlations to evaluate the environmental fate of pollutants as well as in the design of pharmaceuticals. The experimental evaluation of 1-octanol/water partition coefficients is an expensive and time-consuming procedure, and thus, theoretical estimation methods are needed, particularly when a physical sample of the solute may not yet be available, such as in pharmaceutical screening. 1 Octanol/water partition coefficients can be obtained from Gibbs free energies of solvation of the solute in both the aqueous and the octanol phases. The accurate evaluation of free energy differences remains today a challenging problem in computational chemistry. In order to study the absolute solvation Gibbs free energies in 1-octanol, a solvent that can mimic many properties of important biological systems, free energy calculations for n-alkanes in the range C1-C8 were performed using molecular simulation techniques, following the thermodynamic integration approach. In the first part of this paper, we test different force fields by evaluating their performance in reproducing pure 1-octanol properties. It is concluded that all-atom force fields can provide good accuracy but at the cost of a higher computational time compared to that of the united-atom force fields. Recent versions of united-atom force fields, such as Gromos and TraPPE, provide satisfactory results and are, thus, useful alternatives to the more expensive all-atom models. In the second part of the paper, the Gibbs free energy of solvation in 1-octanol is calculated for several n-alkanes using three force fields to describe the solutes, namely Gromos, TraPPE, and OPLS-AA. Generally, the results obtained are in excellent agreement with the available experimental data and are of similar accuracy to commonly used QSPR models. Moreover, we have estimated the Gibbs free energy of hydration for the different compounds with the three force fields, reaching average deviations from experimental data of less than 0.2 kcal/mol for the case of the Gromos force field. Finally, we systematically compare different strategies to obtain the 1-octanol/water partition coefficient from the simulations. It is shown that a fully predictive method combining the Gromos force field in the aqueous phase and the OPLS AA/TraPPE force field for the organic phase can give excellent predictions for n alkanes up to C8 with an absolute average deviation of 0.1 log P units to the experimental data. PMID- 26616625 TI - Universal Solvation Model Based on the Generalized Born Approximation with Asymmetric Descreening. AB - We present a new self-consistent reaction field continuum solvation model based on the generalized Born (GB) approximation for the bulk electrostatic contribution to the free energy of solvation. The new model improves on the earlier SM8 model by using the asymmetric descreening algorithm of Grycuk to treat dielectric descreening effects rather than the Coulomb field approximation; it will be called Solvation Model 8 with asymmetric descreening (SM8AD). The SM8AD model is applicable to any charged or uncharged solute in any solvent or liquid medium for which a few key descriptors are known, in particular dielectric constant, refractive index, bulk surface tension, and acidity and basicity parameters. It does not require the user to assign molecular mechanics types to an atom or a group; all parameters are unique and continuous functions of geometry. This model employs a single set of parameters (solvent acidity dependent intrinsic Coulomb radii for the treatment of bulk electrostatics and solvent description-dependent atomic surface tensions coefficients for the treatment of nonelectrostatic and short-range electrostatic effects). The SM8AD model was optimized over 26 combinations of theoretical levels including various basis sets (MIDI!, 6-31G*, 6-31+G*, 6-31+G**, 6-31G**, cc-pVDZ, DZVP, 6-31B*) and electronic structure methods (M05-2X, M05, M06-2X, M06, M06-HF, M06-L, mPW1PW, mPWPW, B3LYP, HF). It may be used with confidence with any level of electronic structure theory as long as self-consistently polarized Charge Model 4 or other self-consistently polarized charges compatible with CM4 charges are used, for example, CM4M charges can be used. With M05-2X/6-31G*, the SM8AD model achieves a mean unsigned error of 0.6 kcal/mol on average over 2 560 solvation free energies of tested aqueous and nonaqueous neutral solutes and a mean unsigned error of 3.9 kcal/mol on average over 332 solvation free energies of aqueous and nonaqueous ions. PMID- 26616626 TI - Coarse-Grained MD Simulations and Protein-Protein Interactions: The Cohesin Dockerin System. AB - Coarse-grained molecular dynamics (CG-MD) may be applied as part of a multiscale modeling approach to protein-protein interactions. The cohesin-dockerin interaction provides a valuable test system for evaluation of the use of CG-MD, as structural (X-ray) data indicate a dual binding mode for the cohesin-dockerin pair. CG-MD simulations (of 5 MUs duration) of the association of cohesin and dockerin identify two distinct binding modes, which resemble those observed in X ray structures. For each binding mode, ca. 80% of interfacial residues are predicted correctly. Furthermore, each of the binding modes identified by CG-MD is conformationally stable when converted to an atomistic model and used as the basis of a conventional atomistic MD simulation of duration 20 ns. PMID- 26616627 TI - Computational Screening of Rhodopsin Mutations Associated with Retinitis Pigmentosa. AB - Retinitis pigmentosa (RP) refers to a group of debilitating, hereditary disorders that cause severe visual impairment in as many as 1.5 million patients worldwide. Rhodopsin mutations account for >25% of the autosomal dominant form of the disease (ADRP). Forty artificial and ADRP-associated mutations located in the second extracellular loop (EL2) that folds into a twisted beta-hairpin were screened through replica exchange molecular dynamics (REMD) simulations using the FACTS implicit solvent model. According to in vitro experiments, ADRP-linked mutants fail to express at the plasma membrane and/or to reconstitute with 11-cis retinal, indicative of variable defects in protein folding and/or stability. The computational protocol was first probed on the protein G C-terminal beta-hairpin, proving the effectiveness of the implicit solvent model in reproducing the free energy landscape of beta-hairpin formation. Eight out of the 40 EL2 mutants resulted in misfolding effects on the native beta-hairpin structure, consistent with in vitro evidence that they all share severe impairments in folding/expression. Five mutants displayed moderate misfolding attitudes, whereas the remaining 27 mutants, overall characterized by milder effects on rhodopsin expression, did not perturb significantly the conformational behavior of the native beta-hairpin but are expected to exert variably disturbing effects on the native interactions of the loop with the chromophore and/or the surrounding receptor domains. Collectively, the results of this study add structural insight to the poorly resolved biochemical behavior of selected class II ADRP mutations, a fundamental step toward an understanding of the atomistic causes of the disease. PMID- 26616628 TI - Assembly of Viral Membrane Proteins. AB - The generation of computational models is an alternative route to obtain reliable structures for the oligomeric state of membrane proteins. A strategy has been developed to search the conformational space of all possible assemblies in a reasonable time, taking symmetry considerations into account. The methodology tested on M2 from influenza A, shows an excellent agreement with established structures. For Vpu from HIV-1 a series of conformational distinct structures are proposed. For the first time a structural model for a fully assembled transmembrane part of 3a from SARS-CoV is proposed. PMID- 26616629 TI - Single Stranded Loops of Quadruplex DNA As Key Benchmark for Testing Nucleic Acids Force Fields. AB - We have carried out a set of explicit solvent molecular dynamics (MD) simulations on two DNA quadruplex (G-DNA) molecules, namely the antiparallel d(G4T4G4)2 dimeric quadruplex with diagonal loops and the parallel-stranded human telomeric monomolecular quadruplex d[AGGG(TTAGGG)3] with three propeller loops. The main purpose of the paper was testing of the capability of the MD simulation technique to describe single-stranded topologies of G-DNA loops, which represent a very challenging task for computational methods. The total amount of conventional and locally enhanced sampling (LES) simulations analyzed in this study exceeds 1.5 MUs, while we tested several versions of the AMBER force field (parm99, parmbsc0, and a version with modified glycosidic chi torsion profile) and the CHARMM27 force field. Further, we compared minimal salt and excess salt simulations. Postprocessing MM-PBSA (Molecular Mechanics, Poisson-Boltzmann, Surface Area) free energy calculations are also reported. None of the presently available force fields is accurate enough in describing the G-DNA loops. The imbalance is best seen for the propeller loops, as their experimental structure is lost within a few ns of standard simulations with all force fields. Among them, parmbsc0 provides results that are clearly closest to the experimental target values but still not in full agreement. This confirms that the improvement of the gamma torsional profile penalizing the gamma trans substates in the parmbsc0 parametrization was a step in the right direction, albeit not sufficient to treat all imbalances. The modified chi parametrization appears to rigidify the studied systems but does not change the ultimate outcome of the present simulations. The structures obtained in simulations with the modified chi profile are predetermined by its combination with either parm99 or parmbsc0. Experimental geometries of diagonal loops of d(G4T4G4)2 are stable in standard simulations on the ~10 ns time scale but are becoming progressively lost in longer and LES simulations. In addition, the d(G4T4G4)2 quadruplex contains, besides the three genuine binding sites for cations in the channel of its stem, also an ion binding site at each stem-loop junction. This arrangement of five cations in the quadruplex core region is entirely unstable in all 24 simulations that we attempted. Overall, our results confirm that G-DNA loops represent one of the most difficult targets for molecular modeling approaches and should be considered as reference structures in any future studies aiming to develop or tune nucleic acids force fields. PMID- 26616630 TI - Combining an Elastic Network With a Coarse-Grained Molecular Force Field: Structure, Dynamics, and Intermolecular Recognition. AB - Structure-based and physics-based coarse-grained molecular force fields have become attractive approaches to gain mechanistic insight into the function of large biomolecular assemblies. Here, we study how both approaches can be combined into a single representation, that we term ELNEDIN. In this representation an elastic network is used as a structural scaffold to describe and maintain the overall shape of a protein and a physics-based coarse-grained model (MARTINI-2.1) is used to describe both inter- and intramolecular interactions in the system. The results show that when used in molecular dynamics simulations ELNEDIN models can be built so that the resulting structural and dynamical properties of a protein, including its collective motions, are comparable to those obtained using atomistic protein models. We then evaluate the behavior of such models in (1) long, microsecond time-scale, simulations, (2) the modeling of very large macromolecular assemblies, a viral capsid, and (3) the study of a protein-protein association process, the reassembly of the ROP homodimer. The results for this series of tests indicate that ELNEDIN models allow microsecond time-scale molecular dynamics simulations to be carried out readily, that large biological entities such as the viral capsid of the cowpea mosaic virus can be stably modeled as assemblies of independent ELNEDIN models, and that ELNEDIN models show significant promise for modeling protein-protein association processes. PMID- 26616631 TI - Docking Ligands on Protein Surfaces: The Case Study of Prion Protein. AB - Molecular docking of ligands targeting proteins undergoing fibrillization in neurodegenerative diseases is difficult because of the lack of deep binding sites. Here we extend standard docking methods with free energy simulations in explicit solvent to address this issue in the context of the prion protein surface. We focus on a specific ligand (2-pyrrolidin-1-yl-N-[4-[4-(2-pyrrolidin-1 yl-acetylamino)-benzyl]-phenyl]-acetamide), which binds to the structured part of the protein as shown by NMR (Kuwata, K. et al. Proc Natl Acad Sci U.S.A. 2007, 104, 11921-11926). The calculated free energy of dissociation (7.8 +/- 0.9 kcal/mol) is in good agreement with the value derived by the experimental dissociation constant (Kd = 3.9 MUM, corresponding to DeltaG(0) = -7.5 kcal/mol). Several binding poses are predicted, including the one reported previously. Our prediction is fully consistent with the presence of multiple binding sites, emerging from NMR measurements. Our molecular simulation-based approach emerges, therefore, as a useful tool to predict poses and affinities of ligand binding to protein surfaces. PMID- 26616632 TI - Intramolecular Basis Set Superposition Error Effects on the Planarity of DNA and RNA Nucleobases. AB - Molecules of utmost importance like DNA and RNA nucleobases are predicted to be nonplanar by a typical ab initio method, such as second order Moller-Plesset perturbation theory (MP2) combined with standard Pople's basis sets. Similarly to the case of other planar aromatic systems, these pitfalls can be explained in terms of intramolecular basis set superposition error (BSSE) effects, induced by local basis set deficiencies. We demonstrate that conventional BSSE correction techniques such as the Counterpoise method can account for this wrong behavior and provide proper correction whenever spurious results occur, mainly in case of thymine, uracil and guanine but also to lower extent for adenine and cytosine. We also show that special care must be taken when assessing the BSSE by means of ghost-orbital calculations for strongly overlapping fragments. Often molecular orbitals in the isolated fragment calculation have a different orientation as in the ghost-orbital calculation. This can lead to bogus derivatives of the CP correction term, essential to account for geometry and vibrational BSSE effects. PMID- 26616633 TI - Oseltamivir for influenza infection in children: risks and benefits. AB - Influenza is a common disease affecting many children each year. In a number of cases, particularly in children <2 years old and in those with severe chronic underlying disease, influenza can be complicated by lower respiratory tract infections, acute otitis media, rhinosinusitis, febrile seizures, dehydration or encephalopathy. Oseltamivir is the influenza virus drug that is most commonly studied in children for both the treatment and prevention of influenza. To avoid the risk that children with mild influenza or patients suffering from different viral infections receive oseltamivir, oseltamivir treatment should be recommended only in severe influenza cases, especially if confirmed by reliable laboratory tests. However, therapy must be initiated considering the risk of complications and the presence of severe clinical manifestations at age- and weight-appropriate doses. Because the vaccine remains the best option for preventing influenza and its complications, prophylaxis using oseltamivir should only be considered in select patients. PMID- 26616634 TI - Influence of sample handling conditions on drug partitioning in blood: a major problem in PK studies? PMID- 26616635 TI - Burke-Fahn-Marsden dystonia severity, Gross Motor, Manual Ability, and Communication Function Classification scales in childhood hyperkinetic movement disorders including cerebral palsy: a 'Rosetta Stone' study. AB - AIM: Hyperkinetic movement disorders (HMDs) can be assessed using impairment based scales or functional classifications. The Burke-Fahn-Marsden Dystonia Rating Scale-movement (BFM-M) evaluates dystonia impairment, but may not reflect functional ability. The Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), and Communication Function Classification System (CFCS) are widely used in the literature on cerebral palsy to classify functional ability, but not in childhood movement disorders. We explore the concordance of these three functional scales in a large sample of paediatric HMDs and the impact of dystonia severity on these scales. METHOD: Children with HMDs (n=161; median age 10y 3mo, range 2y 6mo-21y) were assessed using the BFM-M, GMFCS, MACS, and CFCS from 2007 to 2013. This cross-sectional study contrasts the information provided by these scales. RESULTS: All four scales were strongly associated (all Spearman's rank correlation coefficient rs >0.72, p<0.001), with worse dystonia severity implying worse function. Secondary dystonias had worse dystonia and less function than primary dystonias (p<0.001). A longer proportion of life lived with dystonia is associated with more severe dystonia (rs =0.42, p<0.001). INTERPRETATION: The BFM-M is strongly linked with the GMFCS, MACS, and CFCS, irrespective of aetiology. Each scale offers interrelated but complementary information and is applicable to all aetiologies. Movement disorders including cerebral palsy can be effectively evaluated using these scales. PMID- 26616636 TI - siRNA-Loaded Polyion Complex Micelle Decorated with Charge-Conversional Polymer Tuned to Undergo Stepwise Response to Intra-Tumoral and Intra-Endosomal pHs for Exerting Enhanced RNAi Efficacy. AB - Small interfering RNA (siRNA) needs an efficient delivery vehicle to reach the cytoplasm of target cells for successful RNA interference (RNAi) therapy. This study aimed to develop an siRNA-loaded polyion complex (PIC) micelle equipped with a smart polymeric shell featuring tumor targetability and endosome escapability for enhanced RNAi activity in cancer cells. To this end, an acidic pH-responsive polypeptide was designed to exert a stepwise change in its charged state from negative to modestly positive and highly positive in response to slightly acidic environment of tumor (pH ~6.7) and further lowered-pH condition of late endosomal compartments (pH ~5.0), respectively, for selective binding to cancer cell surface and subsequent endosome disruption. This polypeptide, termed PAsp(DET-CDM/DBCO), was synthesized by introducing acid-labile carboxydimethyl maleate (CDM) and dibenzylcyclooctyne (DBCO) moieties into a polyaspartamide derivative bearing two-repeated aminoethylene side chains (PAsp(DET)). Then, PAsp(DET-CDM/DBCO) was installed on the surface of disulfide cross-linked PIC micelles prepared from cholesterol-modified siRNA (Chol-siRNA) and azide poly(ethylene glycol)-b-poly[(3-mercaptopropylamidine)-L-lysine] (N3-PEG-b PLys(MPA)) through the copper-free click reaction. Successful PAsp(DET-CDM/DBCO) coverage of PIC micelles was confirmed by a significant decrease in zeta potential as well as a narrowly distributed size of 40 nm. The PAsp(DET-CDM/DBCO) installed micelles significantly improved the gene-silencing efficiency in cultured lung cancer cells, compared with nonmodified control micelles, especially after incubation at pH 6.7. This improved silencing activity was nicely correlated with the facilitated cellular uptake of siRNA payloads at the acidic pH and the efficient endosomal escape. These results demonstrate that the acidic pH-responsive polypeptide shell is a promising design strategy for tumor targeted siRNA delivery. PMID- 26616637 TI - Maternal perinatal mental health and offspring academic achievement at age 16: the mediating role of childhood executive function. AB - BACKGROUND: Elucidating risk pathways for under-achieving at school can inform strategies to reduce the number of adolescents leaving school without passing grades in core subjects. Maternal depression can compromise the quality of parental care and is associated with multiple negative child outcomes. However, only a few small studies have investigated the association between perinatal maternal depression and poor academic achievement in adolescence. The pathways to explain the risks are also unclear. METHOD: Prospective observational data from 5,801 parents and adolescents taking part in a large UK population cohort (Avon Longitudinal-Study-of-Parents-and-Children) were used to test associations between maternal and paternal depression and anxiety in the perinatal period, executive function (EF) at age 8, and academic achievement at the end of compulsory school at age 16. RESULTS: Adolescents of postnatally depressed mothers were 1.5 times (1.19, 1.94, p = .001) as likely as adolescents of nondepressed mothers to fail to achieve a 'pass' grade in math; antenatal anxiety was also an independent predictor of poor math. Disruption in different components of EF explained small but significant proportions of these associations: attentional control explained 16% (4%, 27%, p < .001) of the association with postnatal depression, and working memory explained 17% (13%, 30%, p = .003) of the association with antenatal anxiety. A similar pattern was seen for language grades, but associations were confounded by maternal education. There was no evidence that paternal factors were independently associated with impaired child EF or adolescent exams. CONCLUSION: Maternal postnatal depression and antenatal anxiety are risk factors for adolescents underachieving in math. Preventing, identifying, and treating maternal mental health in the perinatal period could, therefore, potentially increase adolescents' academic achievement. Different aspects of EF partially mediated these associations. Further work is needed, but if these pathways are causal, improving EF could reduce underachievement in math. PMID- 26616638 TI - Isolation and morphological characterization of ovine amniotic fluid mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are one of the most promising cell populations for tissue engineering and regenerative medicine. Of utmost importance to MSC research is identification of MSC sources that are easily obtainable and stable. Several studies have shown that MSCs can be isolated from amniotic fluid. The sheep is one of the main types of farm animal, and it has many biophysical and biochemical similarities to humans. Here, we obtained MSCs from ovine amniotic fluid and determined the expansion capacity, surface and intracellular marker expression, karyotype, and multilineage differentiation ability of these ovine amniotic fluid mesenchymal stem cells (oAF-MSCs). Moreover, expression levels of differentiation markers were measured using reverse transcription-qPCR (RT-qPCR). Our phenotypic analysis shows that the isolated oAF-MSCs are indeed MSCs. PMID- 26616639 TI - Peritoneal dialysate effluent and serum CA125 concentrations in stable peritoneal dialysis patients. AB - INTRODUCTION: CA125 in peritoneal dialysis (PD) effluent dialysate has been used as a surrogate biomarker for the health of the peritoneum in PD patients. However CA125 is synthesised by epithelial cells and as such is not specific for the peritoneum, and most studies have only measured peritoneal CA125, without serum CA125 values. As such we wished to determine the factors which influenced PD effluent CA125 in a large contemporaneous cohort. METHODS: We measured dialysate effluent CA125 in PD patients attending for routine assessment of peritoneal membrane function with a peritoneal equilibration test (PET), with corresponding serum CA125. RESULTS: Serum and dialysate CA125 were measured in 205 PD patients; 59.0 +/- 16.8 years, median PD treatment 3 (2-20) months, 59 % male, 42.4 % diabetic, with 31.2 % treated by continuous ambulatory peritoneal dialysis, 22 % by automated overnight peritoneal dialysis cycler (APD) and 46.8 % by APD with a day time exchange. The median serum CA125 was 21 (13-38) U/ml, with an effluent 4 h PD PET effluent of 20 (11.5-36.5) U/ml. PET PD effluent dialysate was associated with PET dialysate total protein (beta 12.9, p < 0.001), serum CA125 (beta 0.109, p = 0.002), residual renal function (beta 0.53, p = 0.018) and age (beta 0.145, p = 0.042) and negatively with the number of PD cycles/day (beta 2.19, p = 0.001). There was no association with prior peritonitis episodes. CONCLUSION: PD effluent CA125 concentrations were associated with peritoneal protein losses and increased by the usage of higher glucose dialysates to compensate for loss of residual renal function. PMID- 26616640 TI - Rotational spectroscopy of the atmospheric photo-oxidation product o-toluic acid and its monohydrate. AB - o-Toluic acid, a photo-oxidation product in the atmosphere, and its monohydrate were characterized in the gas phase by pure rotational spectroscopy. High resolution spectra were measured in the range of 5-14 Hz using a cavity-based molecular beam Fourier-transform microwave spectrometer. Possible conformers were identified computationally, at the MP2/6-311++G(2df,2pd) level of theory. For both species, one conformer was identified experimentally, and no methyl internal rotation splittings were observed, indicative of relatively high barriers to rotation. In the monomer, rocking of the carboxylic acid group is a large amplitude motion, characterized by a symmetrical double-well potential. This and other low-lying out-of-plane vibrations contribute to a significant (methyl top corrected) inertial defect (-1.09 amu A(2)). In the monohydrate, wagging of the free hydrogen atom of water is a second large amplitude motion, so the average structure is planar. As a result, no c-type transitions were observed. Water tunneling splittings were not observed, because the water rotation coordinate is characterized by an asymmetrical double-well potential. Since the minima are not degenerate, tunneling is precluded. Furthermore, a concerted tunneling path involving simultaneous rotation of the water moiety and rocking of the carboxylic acid group is precluded, because the hilltop along this coordinate is a virtual, rather than a real, saddle-point. Inter- and intramolecular non-covalent bonding is discussed in terms of the quantum theory of atoms in molecules. The percentage of o-toluic acid hydrated in the atmosphere is estimated to be about 0.1% using statistical thermodynamics. PMID- 26616641 TI - Epitaxial patterning of nanometer-thick Y3Fe5O12 films with low magnetic damping. AB - Magnetic insulators such as yttrium iron garnet, Y3Fe5O12, with extremely low magnetic damping have opened the door for low power spin-orbitronics due to their low energy dissipation and efficient spin current generation and transmission. We demonstrate here reliable and efficient epitaxial growth and nanopatterning of Y3Fe5O12 thin-film based nanostructures on insulating Gd3Ga5O12 substrates. In particular, our fabrication process is compatible with conventional sputtering and lift-off, and does not require aggressive ion milling which may be detrimental to the oxide thin films. Their structural and magnetic properties indicate good qualities, in particular low magnetic damping of both films and patterned structures. The dynamic magnetic properties of the nanostructures are systematically investigated as a function of the lateral dimension. By comparing with ferromagnetic nanowire structures, a distinct edge mode in addition to the main mode is identified by both experiments and simulations, which also exhibit cross-over with the main mode upon varying the width of the wires. The non-linear evolution of dynamic modes over nanostructural dimensions highlights the important role of size confinement to their material properties in magnetic devices where Y3Fe5O12 nanostructures serve as the key functional component. PMID- 26616642 TI - Evaluating hazardous waste generation in for-profit outpatient haemodialysis centres. AB - BACKGROUND: "Green" haemodialysis management to reduce the environmental impact of haemodialysis is growing. OBJECTIVES: Dealing with hazardous waste production could heighten healthcare professionals' awareness of this problem, and improve their healthcare involvement in environmental sustainability and environmental friendliness. DESIGN AND MEASUREMENTS: A list of for-profit outpatient haemodialysis centres in the Valencian Community (E Spain) was compiled. Data on their hazardous waste production from 2008 to 2012 through the annual waste reports issued by official organisations competent in environmental issues were collected. RESULTS: There are 22 for-profit dialysis centres, that managed the treatment for 69.1% of all dialysis patients in the region. Data were collected from 16 centres that collectively offer 350 dialysis places (33.8% of all the places in this region). Mean annual hazardous waste production per dialysis session increased by 14% during the study period: 0.640 kg per session in 2008 vs. 0.740 kg in 2012. DISCUSSION AND CONCLUSIONS: As hazardous waste production is high, we must examine the reasons why it is growing. Information about haemodialysis waste production and management is scarce and difficult to access. Having an evaluation of its production would motivate further research, especially as end-stage kidney disease is increasing, and whose main long-term treatment, haemodialysis, produces hazardous waste and employs substantial natural resources. Minimising its environmental impact is not mission impossible. PMID- 26616643 TI - Development and validation of a new dynamic computer-controlled model of the human stomach and small intestine. AB - For ethical, regulatory, and economic reasons, in vitro human digestion models are increasingly used as an alternative to in vivo assays. This study aims to present the new Engineered Stomach and small INtestine (ESIN) model and its validation for pharmaceutical applications. This dynamic computer-controlled system reproduces, according to in vivo data, the complex physiology of the human stomach and small intestine, including pH, transit times, chyme mixing, digestive secretions, and passive absorption of digestion products. Its innovative design allows a progressive meal intake and the differential gastric emptying of solids and liquids. The pharmaceutical behavior of two model drugs (paracetamol immediate release form and theophylline sustained release tablet) was studied in ESIN during liquid digestion. The results were compared to those found with a classical compendial method (paddle apparatus) and in human volunteers. Paracetamol and theophylline tablets showed similar absorption profiles in ESIN and in healthy subjects. For theophylline, a level A in vitro-in vivo correlation could be established between the results obtained in ESIN and in humans. Interestingly, using a pharmaceutical basket, the swelling and erosion of the theophylline sustained release form was followed during transit throughout ESIN. ESIN emerges as a relevant tool for pharmaceutical studies but once further validated may find many other applications in nutritional, toxicological, and microbiological fields. Biotechnol. Bioeng. 2016;113: 1325-1335. (c) 2015 Wiley Periodicals, Inc. PMID- 26616644 TI - Comparison of dexmedetomidine and chloral hydrate sedation for transthoracic echocardiography in infants and toddlers: a randomized clinical trial. AB - BACKGROUND: Procedural sedation using chloral hydrate is used in many institutions to improve the quality of transthoracic echocardiograms (TTE) in infants and young children. Chloral hydrate has limited availability in some countries, creating the need for alternative effective sedatives. OBJECTIVE: The aim of our study was to compare the effectiveness of two doses of intranasal dexmedetomidine vs oral chloral hydrate sedation for transthoracic echocardiography. METHODS: This is a randomized, prospective study of 150 children under the age of 3 years with known or suspected congenital heart disease scheduled for transthoracic echocardiography with sedation. Group CH received oral chloral hydrate 70 mg . kg(-1), group DEX2 received 2 MUg . kg(-1) intranasal dexmedetomidine, and group DEX3 received 3 MUg . kg(-1) intranasal dexmedetomidine. Acceptance of drug administration, sedation onset and duration, heart rate, and oxygen saturation, sonographer and parent satisfaction were recorded. RESULTS: All patients were successfully sedated for TTE. A second sedative dose (rescue) for failed single-dose sedation was required for 4% of patients after CH, none of the patients after DEX2, and 4% of patients after DEX3. Patients in group CH had an average heart rate decline of 22% during sedation, while group DEX2 decreased 27%, and group DEX3 23% (P = 0.2180). Mean time from administration of the sedative to final patient discharge was 96 min after CH, 83 min after DEX2, and 94 min after DEX3 (P = 0.1826). CONCLUSION: Intranasal dexmedetomidine 2 and 3 MUg . kg(-1) were found to be as effective for TTE sedation as oral chloral hydrate with similar sedation onset and recovery time and heart rate changes in this study population. PMID- 26616645 TI - CCR9 AND CCR7 are overexpressed in CD4- CD8- thymocytes of myasthenia gravis patients. AB - INTRODUCTION: Chemokine CC motif receptors 9 and 7 (CCR9 and CCR7) play a major role in the migration of T-cell precursors to the thymus to initiate T thymopoiesis. However, their role in development of T-cells in myasthenia gravis (MG) patients has not been fully elucidated. METHODS: Expression and distribution of CCR9+ and CCR7+ cells were detected by flow cytometry and immunofluorescence. Real-time polymerase chain reaction was used to check the adhesion molecules on CD4- CD8- double-negative (DN) thymocytes. RESULTS: CCR9 and CCR7 expression by DN thymocytes increased in the MG thymus; the levels of CCR9, CCR7, interleukin 7R mRNA increased, and CXCR4 levels decreased compared with levels in the non-MG thymus. More CCR7 and CCR9 double-positive (DP) thymocytes were gathered near the subcapsular region in MG thymus. CONCLUSIONS: Enhanced expression of CCR9 and CCR7 may complicate the differentiation of DP thymocytes from the DN stage in MG thymus. Muscle Nerve, 2016 Muscle Nerve 55: 84-90, 2017. PMID- 26616646 TI - The myeloperoxidase-derived oxidant hypothiocyanous acid inhibits protein tyrosine phosphatases via oxidation of key cysteine residues. AB - Phosphorylation of protein tyrosine residues is critical to cellular processes, and is regulated by kinases and phosphatases (PTPs). PTPs contain a redox sensitive active site Cys residue, which is readily oxidized. Myeloperoxidase, released from activated leukocytes, catalyzes thiocyanate ion (SCN(-)) oxidation by H2O2 to form hypothiocyanous acid (HOSCN), an oxidant that targets Cys residues. Dysregulated phosphorylation and elevated MPO levels have been associated with chronic inflammatory diseases where HOSCN can be generated. Previous studies have shown that HOSCN inhibits isolated PTP1B and induces cellular dysfunction in cultured macrophage-like cells. The present study extends this previous work and shows that physiologically-relevant concentrations of HOSCN alter the activity and structure of other members of the wider PTP family (including leukocyte antigen-related PTP, PTP-LAR; T-cell PTP, TC-PTP; CD45 and Src homology phosphatase-1, Shp-1) by targeting Cys residues. Isolated PTP activity, and activity in lysates of human monocyte-derived macrophages (HMDM) was inhibited by 0-100 uM HOSCN with this being accompanied by reversible oxidation of Cys residues, formation of sulfenic acids or sulfenyl-thiocyanates (detected by Western blotting, and LC-MS as dimedone adducts), and structural changes. LC-MS/MS peptide mass-mapping has provided data on the modified Cys residues in PTP-LAR. This study indicates that inflammation-induced oxidants, and particularly myeloperoxidase-derived species, can modulate the activity of multiple members of the PTP superfamily via oxidation of Cys residues to sulfenic acids. This alteration of the balance of PTP/kinase activity may perturb protein phosphorylation and disrupt cell signaling with subsequent induction of apoptosis at sites of inflammation. PMID- 26616648 TI - Assessing safety and feasibility of minimally invasive surgical approaches for advanced gastric cancer. PMID- 26616653 TI - Spermatozoa in the Peak District. PMID- 26616647 TI - HERPUD1 protects against oxidative stress-induced apoptosis through downregulation of the inositol 1,4,5-trisphosphate receptor. AB - Homocysteine-inducible, endoplasmic reticulum (ER) stress-inducible, ubiquitin like domain member 1 (HERPUD1), an ER resident protein, is upregulated in response to ER stress and Ca(2+) homeostasis deregulation. HERPUD1 exerts cytoprotective effects in various models, but its role during oxidative insult remains unknown. The aim of this study was to investigate whether HERPUD1 contributes to cytoprotection in response to redox stress and participates in mediating stress-dependent signaling pathways. Our data showed that HERPUD1 protein levels increased in HeLa cells treated for 30 min with H2O2 or angiotensin II and in aortic tissue isolated from mice treated with angiotensin II for 3 weeks. Cell death was higher in HERPUD1 knockdown (sh-HERPUD1) HeLa cells treated with H2O2 in comparison with control (sh-Luc) HeLa cells. This effect was abolished by the intracellular Ca(2+) chelating agent BAPTA-AM or the inositol 1,4,5-trisphosphate receptor (ITPR) antagonist xestospongin B, suggesting that the response to H2O2 was dependent on intracellular Ca(2+) stores and the ITPR. Ca(2+) kinetics showed that sh-HERPUD1 HeLa cells exhibited greater and more sustained cytosolic and mitochondrial Ca(2+) increases than sh-Luc HeLa cells. This higher sensitivity of sh-HERPUD1 HeLa cells to H2O2 was prevented with the mitochondrial permeability transition pore inhibitor cyclosporine A. We concluded that the HERPUD1-mediated cytoprotective effect against oxidative stress depends on the ITPR and Ca(2+) transfer from the ER to mitochondria. PMID- 26616654 TI - Heat-labile enterotoxin of Escherichia coli promotes intestinal colonization of Salmonella enterica. AB - Enterotoxigenic Escherichia coli (ETEC) is an important cause of infantile and travellers' diarrhoea, which poses a serious health burden, especially in developing countries. In addition, ETEC bacteria are a major cause of illness and death in neonatal and recently weaned pigs. The production of a heat-labile enterotoxin (LT) promotes the colonization and pathogenicity of ETEC and may exacerbate co-infections with other enteric pathogens such as Salmonella enterica. We showed that the intraintestinal presence of LT dramatically increased the intestinal Salmonella Typhimurium load in experimentally inoculated pigs. This could not be explained by direct alteration of the invasion or survival capacity of Salmonella in enterocytes, in vitro. However, we demonstrated that LT affects the enteric mucus layer composition in a mucus secreting goblet cell line by significantly decreasing the expression of mucin 4. The current results show that LT alters the intestinal mucus composition and aggravates a Salmonella Typhimurium infection, which may result in the exacerbation of the diarrhoeal illness. PMID- 26616655 TI - Dietary Bacillus subtilis FPTB13 and chitin, single or combined, modulate systemic and cutaneous mucosal immunity and resistance of catla, Catla catla (Hamilton) against edwardsiellosis. AB - Effects of dietary administration of Bacillus subtilis FPTB13 and chitin, single or combined, on the systemic immunity, mucosal immunity and resistance of catla (Catla catla) against Edwardsiella tarda infection were investigated. The probiotic attributes of B. subtilis was tested by conducting antagonism study, safety in catla, in vitro immunomodulation and dietary immunomodulation. Results of these studies indicated the probiotic potential of the strain. From the preliminary dietary immunomodulation study, a dose of 10(9) B. subtilis cells g( 1) was selected for inclusion into diets for subsequent experiments. Experimental diets were prepared by adding B. subtilis (10(9) cells g(-1)), chitin (2%) and their combination to the basal diet. Different systemic and mucosal immunological parameters viz. oxygen radical production, myeloperoxidase content, lysozyme activity, total protein content and alkaline phosphatase activity showed significant enhancement (p<0.05) after 2 weeks of feeding with the combined diet. B. subtilis and chitin alone also significantly elevated most of the immune responses. All the diets significantly increased the resistance of catla against E. tarda challenge. The highest post-challenge survival was observed in combined group (i.e. 63.33%). In conclusion, B. subtilis and chitin, alone or combined, had a health ameliorating effect in catla. The results also collectively suggest the usefulness of applying a combined probiotic and immunostimulant supplemented diet to achieve greater benefits. PMID- 26616656 TI - Butyrylcholinesterase as a marker of inflammation and liver injury in the acute and subclinical phases of canine ehrlichiosis. AB - The aim of this study was to evaluate the role of butyrylcholinesterase (BChE) as a marker of inflammation and liver injury in the acute and subclinical phases of canine ehrlichiosis. Forty-two serum samples of dogs naturally infected with Ehrlichia canis were used, of which 24 were from animals with the acute phase of the disease and 18 with subclinical disease. In addition, sera from 17 healthy dogs were used as negative controls. The hematocrit, BChE activity, hepatic injury (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), nitric oxide, and cytokines levels were evaluated. The BChE activity was significantly elevated (P<0.05) in dogs with the acute phase of the disease when compared to healthy animals. However, there was a reduction on BChE activity on dogs with subclinical disease compared to the other two groups. AST and ALT levels were significantly higher (P<0.05) in the acute phase, as well as the inflammatory mediators (NOx, TNF-alpha, INF-gamma, IL-4, IL-6) when compared to the control group. On the other hand, IL-10 levels were lower in the acute phase. Based on these results, we are able to conclude that the acute infection caused by E. canis in dogs leads to an increase on seric BChE activity and some inflammatory mediators. Therefore, this enzyme might be used as a marker of acute inflammatory response in dogs naturally infected by this bacterium. PMID- 26616657 TI - Epidemiological survey of zoonotic pathogens in feral pigeons (Columba livia var. domestica) and sympatric zoo species in Southern Spain. AB - A cross-sectional study was carried out to determine the prevalence of pathogenic zoonotic agents (flaviviruses, avian influenza viruses (AIVs), Salmonella spp. and Toxoplasma gondii) in feral pigeons and sympatric zoo animals from Cordoba (Southern Spain) between 2013 and 2014. Antibodies against flaviviruses were detected in 7.8% out of 142 (CI95%: 3.7-11.8) pigeons, and 8.2% of 49 (CI95%: 0.9 15.4) of zoo animals tested. Antibodies with specificity against West Nile virus (WNV) and Usutu virus (USUV) were confirmed both in pigeons and in zoo birds. Even though seropositivity to AIVs was not detected in any of the analyzed pigeons, 17.9% of 28 (CI95%: 3.7-32.0) zoo birds tested showed positive results. Salmonella spp. was not isolated in any of 152 fecal samples collected from pigeons, while 6.8% of 44 zoo animals were positive. Antibodies against T. gondii were found in 9.2% of 142 (CI95%: 4.8-13.6) feral pigeons and 26.9% of 108 (CI95%: 19.6-34.1) zoo animals. This is the first study on flaviviruses and T. gondii in feral pigeons and captive zoo species in Spain. Antibodies against WNV and USUV detected in non-migratory pigeons and captive zoo animals indicate local circulation of these emerging pathogens in the study area. T. gondii was widespread in species analyzed. This finding could be of importance for Public Health and Conservation of endangered species present in zoo parks. Pigeons and zoo animals may be included as sentinel species for monitoring zoonotic pathogens in urban areas. PMID- 26616658 TI - Identification of Hsp90 as a species independent H5N1 avian influenza A virus PB2 interacting protein. AB - The avian influenza polymerase protein PB2 subunit is an important mediator of cross species adaptation and adaptation to mammalian cells is strongly but not exclusively associated with an adaptive mutation of the codon at position 627 of the PB2 protein which alters the glutamate normally found at this position to a lysine. This study sought to identify host cell factors in both mammalian and avian cells that interacted in a species specific or species independent manner. Two PB2 fusion proteins differing only in codon 627 were generated and transfected into mammalian and avian cells and interacting proteins identified through co-immunoprecipitation. A number of proteins including Hsp90 were identified and further investigation showed that Hsp90 interacted with both isoforms of PB2 in both mammalian and avian cells. Hsp90 is thus identified as a species independent interacting protein, further confirming that this protein may be a suitable target for anti-influenza drug development. PMID- 26616659 TI - Dysbiotic gut microbiome: A key element of Crohn's disease. AB - Since the first publication on "regional ileitis", the relevance of this chronic inflammatory disease condition termed finally as Crohn's disease is continuously increasing. Although we are beginning to comprehend certain aspects of its pathogenesis, many facets remain unexplored. Host's gut microbiota is involved in a wide range of physiological and pathological processes including immune system development, and pathogen regulation. Further, the microbiome is thought to play a key role in Crohn's disease. The presence of Crohn's-associated variants of NOD2 and ATG16L genes appears to be associated not only with alterations of mucosal barrier functions, and bacterial killing, but the gut microbiota, as well, reflecting a potential relationship between the host's genotype and intestinal dysbiosis, involved in disease etiology. This review aims to characterize some exciting new aspect of Crohn's disease pathology, focusing mainly on the role of intestinal microbes, and their interplay with the immune system of the host. PMID- 26616660 TI - Diversity and molecular characterization of novel hemoplasmas infecting wild rodents from different Brazilian biomes. AB - Although hemoplasma infection in domestic animals has been well documented, little is known about the prevalence and genetic diversity of these bacteria in wild rodents. The present work aimed to investigate the occurrence of hemotrophic mycoplasmas in wild rodents from five Brazilian biomes, assessing the 16S rRNA phylogenetic position of hemoplasma species by molecular approach. Spleen tissues were obtained from 500 rodents, comprising 52 different rodent species trapped between 2000 and 2011. DNA samples were submitted to previously described PCR protocols for amplifying Mycoplasma spp. based on 16S rRNA, followed by sequencing and phylogenetic inferences. Among 457 rodent spleen samples showing absence of inhibitors, 100 (21.9%) were PCR positive to Mycoplasma spp. The occurrence of hemotropic mycoplasmas among all sampled rodents was demonstrated in all five biomes and ranged from 9.3% (7/75) to 26.2% (38/145). The Blastn analysis showed that amplified sequences had a percentage of identity ranging from 86 to 99% with other murine hemoplasmas. The ML phylogenetic analysis of 16S rRNA gene of 24 positive randomly selected samples showed the presence of ten distinct groups, all clustering within the Mycoplasma haemofelis. The phylogenetic assessment suggests the circulation of novel hemoplasma species in rodents from different biomes in Brazil. PMID- 26616661 TI - Serological evidence of Rickettsia and Coxiella burnetii in humans of Buenos Aires, Argentina. AB - In Buenos Aires city (Argentina), the circulation of these agents has been detected mainly in vectors and animals, few human cases having been described. The aim of our study was to determine the seroprevalence of Rickettsia (spotted fever--SFG--and typhus--TG--groups) and Coxiella burnetii (Q fever agent) in residents of Buenos Aires city. The study involved 99 participants. Rickettsia IgG antibodies against SFG and TG were detected by IFA in 28.3% and 16.2% of serum samples, respectively. SFG titers were mostly 1/64 (53.6%) with a maximum of 1/512 (3.5%) whereas TG titers ranged between 1/64 (62.5%) and 1/256 (6.3%). Only one sample showed a titer of 1/32 for C. burnetii (phases I and II). The circulation of these pathogens in urban areas such as the city of Buenos Aires should be considered by health services, especially at the primary care level. PMID- 26616663 TI - 12 is bigger and better than 6 - Moving to monthly issues. PMID- 26616662 TI - Escherichia coli Nissle 1917 enhances bioavailability of serotonin in gut tissues through modulation of synthesis and clearance. AB - Accumulating evidence shows indigenous gut microbes can interact with the human host through modulation of serotonin (5-HT) signaling. Here we investigate the impact of the probiotic Escherichia coli Nissle 1917 (EcN) on 5-HT signalling in gut tissues. Ex-vivo mouse ileal tissue sections were treated with either EcN or the human gut commensal MG1655, and effects on levels of 5-HT, precursors, and metabolites, were evaluated using amperometry and high performance liquid chromatography with electrochemical detection (HPLC-EC). Exposure of tissue to EcN cells, but not MG1655 cells, was found to increase levels of extra-cellular 5 HT. These effects were not observed when tissues were treated with cell-free supernatant from bacterial cultures. In contrast, when supernatant recovered from untreated ileal tissue was pre-incubated with EcN, the derivative cell-free supernatant was able to elevate 5-HT overflow when used to treat fresh ileal tissue. Measurement of 5-HT precursors and metabolites indicated EcN also increases intracellular 5-HTP and reduces 5-HIAA. The former pointed to modulation of tryptophan hydroxylase-1 to enhance 5-HT synthesis, while the latter indicates an impact on clearance into enterocytes through SERT. Taken together, these findings show EcN is able to enhance 5-HT bioavailability in ileal tissues through interaction with compounds secreted from host tissues. PMID- 26616664 TI - Soluble Delta-like ligand 1 alters human endometrial epithelial cell adhesive capacity. AB - The endometrium undergoes substantial morphological and functional changes to become receptive to embryo implantation and to enable establishment of a successful pregnancy. Reduced Delta-like ligand 1 (DLL1, Notch ligand) in the endometrium is associated with infertility. DLL1 can be cleaved by 'a disintegrin and metalloprotease' (ADAM) proteases to produce a soluble ligand that may act to inhibit Notch signalling. We used an enzyme-linked immunosorbent assay to quantify soluble DLL1 in uterine lavages from fertile and infertile women in the secretory phase of the menstrual cycle. We also determined the cellular location and immunostaining intensity of ADAM12 and 17 in human endometrium throughout the cycle. Functional effects of soluble DLL1 in receptivity were analysed using in vitro adhesion and proliferation assays and gene expression analysis of Notch signalling targets. Soluble DLL1 was significantly increased in uterine lavage samples of infertile women compared with fertile women in the secretory phase of the menstrual cycle. This coincided with significantly increased ADAM17 immunostaining detected in the endometrial luminal epithelium in the mid secretory phase in infertile women. Soluble DLL1 significantly inhibited the adhesive capacity of endometrial epithelial cells via downregulation of helix loop-helix and hairy/enhancer of split family member HES1 mRNA. Thus, soluble DLL1 may serve as a suitable target or potential biomarker for receptivity. PMID- 26616667 TI - Chiral phosphoric acid catalyzed enantioselective 1,3-dipolar cycloaddition reaction of azlactones. AB - The first chiral phosphoric acid catalyzed highly diastereo- and enantioselective 1,3-dipolar cycloaddition reaction of azlactones and methyleneindolinones was disclosed. By using a BINOL-derived chiral phosphoric acid as the catalyst, azlactones were activated as chiral anti N-protonated 1,3-dipoles to react with methyleneindolinones to yield biologically important 3,3'-pyrrolidonyl spirooxindole scaffolds in high yields, with good-to-excellent diastereo- and enantioselectivity. PMID- 26616665 TI - Immunological contributions to adipose tissue homeostasis. AB - Adipose tissue is composed of many functionally and developmentally distinct cell types, the metabolic core of which is the adipocyte. The classification of "adipocyte" encompasses three primary types - white, brown, and beige - with distinct origins, anatomic distributions, and homeostatic functions. The ability of adipocytes to store and release lipids, respond to insulin, and perform their endocrine functions (via secretion of adipokines) is heavily influenced by the immune system. Various cell populations of the innate and adaptive arms of the immune system can resist or exacerbate the development of the chronic, low-grade inflammation associated with obesity and metabolic dysfunction. Here, we discuss these interactions, with a focus on their consequences for adipocyte and adipose tissue function in the setting of chronic overnutrition. In addition, we will review the effects of diet composition on adipose tissue inflammation and recent evidence suggesting that diet-driven disruption of the gut microbiota can trigger pathologic inflammation of adipose tissue. PMID- 26616666 TI - Quantitative Profiling of the Effects of Vanoxerine on Human Cardiac Ion Channels and its Application to Cardiac Risk. AB - Vanoxerine has been in clinical trials for Parkinsonism, depression and cocaine addiction but lacked efficacy. Although a potent blocker of hERG, it produced no serious adverse events. We attributed the unexpected result to offsetting Multiple Ion Channel Effects (MICE). Vanoxerine's effects were strongly frequency dependent and we repositioned it for treatment of atrial fibrillation and flutter. Vanoxerine terminated AF/AFL in an animal model and a dose-ranging clinical trial. Reversion to normal rhythm was associated with QT prolongation yet absent proarrhythmia markers for Torsade de Pointes (TdP). To understand the QT/TdP discordance, we used quantitative profiling and compared vanoxerine with dofetilide, a selective hERG-blocking torsadogen used for intractable AF, verapamil, a non-torsadogenic MICE comparator and bepridil, a torsadogenic MICE comparator. At clinically relevant concentrations, verapamil blocked hCav1.2 and hERG, as did vanoxerine and bepridil both of which also blocked hNav1.5. In acute experiments and simulations, dofetilide produced early after depolarizations (EADs) and arrhythmias, whereas verapamil, vanoxerine and bepridil produced no proarrhythmia markers. Of the MICE drugs only bepridil inhibited hERG trafficking following overnight exposure. The results are consistent with the emphasis on MICE of the CiPA assay. Additionally we propose that trafficking inhibition of hERG be added to CiPA. PMID- 26616668 TI - Synergistic Ternary Composite (Carbon/Fe3 O4 @Graphene) with Hollow Microspherical and Robust Structure for Li-Ion Storage. AB - The electrode materials with hollow structure and/or graphene coating are expected to exhibit outstanding electrochemical performances in energy-storage systems. 2D graphene-wrapped hollow C/Fe3 O4 microspheres are rationally designed and fabricated by a novel facile and scalable strategy. The core@double-shell structure SPS@FeOOH@GO (SPS: sulfonated polystyrene, GO: graphene oxide) microspheres are first prepared through a simple one-pot approach and then transformed into C/Fe3 O4 @G (G: graphene) after calcination at 500 degrees C in Ar. During calcination, the Kirkendall effect resulting from the diffusion/reaction of SPS-derived carbon and FeOOH leads to the formation of hollow structure carbon with Fe3 O4 nanoparticles embedded in it. In the rationally constructed architecture of C/Fe3 O4 @G, the strongly coupled C/Fe3 O4 hollow microspheres are further anchored onto 2D graphene networks, achieving a strong synergetic effect between carbon, Fe3 O4 , and graphene. As an anode material of Li-ion batteries (LIBs), C/Fe3 O4 @G manifests a high reversible capacity, excellent rate behavior, and outstanding long-term cycling performance (1208 mAh g(-1) after 200 cycles at 100 mA g(-1) ). PMID- 26616670 TI - Evaluation of the Two-Dimensional Performances of Low Activity Planar Catalysts: Development and Validation of a True Scanning Reactor. AB - The development of a scanning reactor for planar catalysts is presented here. With respect to other existing models, this reactor is able to scan catalysts even with low turnover frequencies with a minimum sensed circular area of approximately 6 mm in diameter. The downstream gas analysis is performed with a quaprupole mass spectrometer. The apparatus performances are presented for two different reactions: the hydrogenation of butadiene over palladium films and the oxidation of CO over a gold/titania catalyst. With the final setup, true scans in both X and Y directions (or even in a previously defined complex directional pattern) are possible within a scan speed ranging from 0.1 to 5.0 mm/min. Finally, this apparatus aims at becoming a valuable tool for high throughput and combinatorial experimentation to test patterned active surfaces and catalytic libraries. PMID- 26616671 TI - Polyphasic Characterization of Lysobacter maris sp. nov., a Bacterium Isolated from Seawater. AB - A strictly aerobic, Gram-negative, apricot-pigmented, non-motile, rod-shaped strain designated KMU-14(T) was isolated from seawater collected from the coastal zone of Yokji Island, Gyeongsangnam-do, Republic of Korea. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that the novel isolate was affiliated with the genus Lysobacter within the class Gammaproteobacteria and that it showed the highest sequence similarity (97.1 %) to Lysobacter concretionis Ko07(T). The hybridization value for DNA-DNA relatedness between the strains of KMU-14(T) and L. concretionis Ko07(T) was 34.8 %, which was lower than 70 %, the recommended delineation value for differentiation of species. The DNA G+C content of strain KMU-14(T) was 64.9 mol%. The major respiratory quinone was ubiquinone 8 (Q-8), and iso-C15:0, iso-C16:0, and 10-methyl C16:0 and/or iso C17:1 omega9c were the major (>10 %) cellular fatty acids. A polar lipid profile was present consisting of diphosphatidylglycerol, phosphatidylethanolamine, an unidentified phosphoglycolipid, two unidentified aminophospholipids, and two unidentified phospholipids. From the distinct phylogenetic position and combination of genotypic and phenotypic characteristics, the strain is considered to represent a novel species for which the name Lysobacter maris sp. nov. is proposed. The type strain of L. maris sp. nov. is KMU-14(T) (=KCTC 42381(T) =NBRC 110750(T)). PMID- 26616669 TI - Peginterferon plus Ribavirin for HIV-infected Patients with Treatment-Naive Acute or Chronic HCV Infection in Taiwan: A Prospective Cohort Study. AB - Data are limited on the effectiveness and safety of peginterferon plus ribavirin in HIV-infected Asian patients with acute or chronic HCV infection. HIV-infected Taiwanese patients with acute HCV infection received peginterferon plus weight based ribavirin for 24 weeks (n = 24), and those with chronic HCV genotype 1 or 6 (HCV-1/6) and HCV genotype 2 or 3 (HCV-2/3) infection received response-guided therapy for 12-72 and 24-48 weeks, respectively (n = 92). The primary endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA 24 weeks off-therapy. The SVR rates were 83% and 72% in patients with acute and chronic HCV infection (p = 0.30), and 68% and 72% in patients with chronic HCV-1/6 and HCV-2/3 infection (p = 0.48), respectively. While no factors predicted SVR in acute HCV and chronic HCV-2/3 infection, age (odds ratio [OR] per 1-year increase: 0.88, 95% confidence interval [CI]: 0.78-0.99, p = 0.04), HCV RNA (OR per 1-log10 increase: 0.18, 95% CI: 0.03-0.98, p = 0.03), IL28B genotype (OR: 5.52, 95% CI: 1.55-12.2, p = 0.02), and RVR (OR: 9.62, 95% CI: 3.89-15.3, p = 0.007) predicted SVR in chronic HCV-1/6 infection. In conclusion, the SVR rates of peginterferon plus ribavirin for 24 weeks and for response-guided 12-72 weeks are satisfactory in HIV-infected Taiwanese patients with acute and chronic HCV infection. PMID- 26616672 TI - Detection and discrimination of complex sounds by pigeons (Columba livia). AB - Auditory scene analysis is the process by which sounds are separated and identified from each other and from the background to make functional auditory objects. One challenge in making these psychological units is that complex sounds often continuously differ in composition over their duration. Here we examined the acoustic basis of complex sound processing in four pigeons by evaluating their performance in an ongoing same/different (S/D) task. This provided an opportunity to investigate avian auditory processing in a non-vocal learning, non songbird. These pigeons were already successfully discriminating 18.5 s sequences of all different 1.5 s sounds (ABCD...) from sequences of one sound repeating (AAAA..., BBBB..., etc.) in a go/no-go procedure. The stimuli for these same/different sequences consisted of 504 tonal sounds (36 chromatic notes*14 different instruments), 36 pure tones, and 72 complex sounds. Not all of these sounds were equally effective in supporting S/D discrimination. As identified by a stepwise regression modeling of ten acoustic properties, tonal and complex sounds with intermediate levels of acoustic content tended to support better discrimination. The results suggest that pigeons have the auditory and cognitive capabilities to recognize and group continuously changing sound elements into larger functional units that can serve to differentiate long sequences of same and different sounds. PMID- 26616673 TI - Territoriality evidenced by asymmetric intruder-holder motivation in an amblypygid. AB - Territoriality has an extensive and thorough history of research, but has been difficult to impossible to test empirically in most species. We offer a method for testing for territoriality by measuring the motivation of territory intruders to win contests in controlled trials. We demonstrated this approach by staging paired trials of the Amblypygi Phrynus longipes (Chelicerata: Arachnida). Amblypygids engaged in agonistic interactions after the opportunity to establish a putative territory on one side of an arena. We found that intruders of putative territories had lower motivation to win contests, thus evidencing territoriality. Physical components of individuals (i.e. energy stores) increased the probability of winning the contest for holders but not intruders, thereby providing insight into the differing decision rules opponents use in territory contests. We discuss why alternative hypotheses, including loser-initiator covariation and home field bourgeois advantage, fail empirical tests. We demonstrated that analyzing animal motivation in territorial contests is tractable even for animals where territories are inconspicuous and cues are outside the normal perceptions of researchers. PMID- 26616675 TI - Comparative analysis of the Shiga toxin converting bacteriophage first detected in Shigella sonnei. AB - Here we report the first complete nucleotide sequence of a Shiga toxin (Stx) converting phage from a Shigella sonnei clinical isolate that harbors stx1 operon, first identified in the chromosome of Shigella dysenteriae type 1. The phage named Shigella phage 75/02 Stx displayed Podoviridae morphology. It proved to be transferable to Escherichia coli K-12 strains, and cytotoxicity of the lysogenized strains was demonstrated in Vero cell cultures. Genomic analysis revealed that the prophage genome is circular and its size is 60,875 nt that corresponds to 76 ORFs. The genome of Shigella phage 75/02 Stx shows a great degree of mosaic structure and its architecture is related to lambdoid phages. All the deduced proteins, including the 37 hypothetical proteins showed significant homologies to Stx phage proteins present in databases. The phage uniformly inserted into the ynfG oxidoreductase gene framed by phage integrase and antirepressor genes in parental S. sonnei and in the three lysogenized K-12 strains C600, DH5alpha and MG1655. The Stx1 prophage proved to be stable in its bacterial hosts and remained inducible. PMID- 26616674 TI - Association between the TLR2 Arg753Gln polymorphism and the risk of sepsis: a meta-analysis. AB - INTRODUCTION: Recently, researchers in a number of studies have explored the association between the Toll-like receptor 2 (TLR2) Arg753Gln polymorphism and sepsis risk. However, the results were conflicting. In this meta-analysis, we aimed to confirm the effect of the TLR2 Arg753Gln polymorphism on sepsis risk. METHODS: Relevant records up to 1 June 2015 were retrieved from the PubMed, Embase, and Web of Knowledge databases. The odds ratios with their corresponding 95 % confidence intervals were used to assess the association between the TLR2 Arg753Gln polymorphism and sepsis risk. The selection of a fixed or random effects model was made according to a heterogeneity test in total and subgroup analyses. Sensitivity analysis and publication bias test were performed to ensure the reliability of our results. RESULTS: A total of 12 studies with aggregate totals of 898 cases and 1517 controls met our inclusion criteria for meta analysis. There were significant associations between the TLR2 Arg753Gln polymorphism and sepsis risk in overall analyses under two genetic models (the allele comparison and the dominant model). In addition, subgroup analyses based on age group, ethnicity, sepsis type, and source of control also showed a significant effect of the TLR2 Arg753Gln polymorphism on sepsis risk. CONCLUSIONS: Our present meta-analysis supports a direct effect of the TLR2 Arg753Gln polymorphism on sepsis risk, especially in Europeans. The TLR2 Arg753Gln polymorphism might be used as a relevant risk estimate for the development of sepsis. Studies with larger sample sizes and homogeneous groups of patients with sepsis are required for further analysis. PMID- 26616676 TI - Genetic and phylogenetic characterization of novel bocaparvovirus infecting chimpanzee. AB - Primate bocaparvoviruses were first described in 2005, since then further human and gorilla bocaparvoviruses have been identified. To uncover diversity of non human primates' bocaparvoviruses, their phylogenetic relationship and potential to cross the host species barrier, we tested 153 fecal samples from 17 captive primate species. The only one captive female of central chimpanzee (coded CPZh2) has been identified as bocaparvovirus positive. Based on the full genome phylogenetic analyses, CPZh2 strain shows close relationship to HBoV3 and GBoV. Further recombination analysis confirmed expected mosaic origin of CPZh2 strain. According the phylogenetic position, following the ICTV recommendations, we propose a novel genotype within the Primate bocaparvovirus 1 species infecting chimpanzee. PMID- 26616677 TI - Targeted gold-coated iron oxide nanoparticles for CD163 detection in atherosclerosis by MRI. AB - CD163 is a membrane receptor expressed by macrophage lineage. Studies performed in atherosclerosis have shown that CD163 expression is increased at inflammatory sites, pointing at the presence of intraplaque hemorrhagic sites or asymptomatic plaques. Hence, imaging of CD163 expressing macrophages is an interesting strategy in order to detect atherosclerotic plaques. We have prepared a targeted probe based on gold-coated iron oxide nanoparticles vectorized with an anti-CD163 antibody for the specific detection of CD163 by MRI. Firstly, the specificity of the targeted probe was validated in vitro by incubation of the probe with CD163(+) or (-) macrophages. The probe was able to selectively detect CD163(+) macrophages both in human and murine cells. Subsequently, the targeted probe was injected in 16 weeks old apoE deficient mice developing atherosclerotic lesions and the pararenal abdominal aorta was imaged by MRI. The accumulation of probe in the site of interest increased over time and the signal intensity decreased significantly 48 hours after the injection. Hence, we have developed a highly sensitive targeted probe capable of detecting CD163-expressing macrophages that could provide useful information about the state of the atheromatous lesions. PMID- 26616678 TI - Effects of doxycycline on local and systemic inflammation in stable COPD patients, a randomized clinical trial. AB - Neutrophilic inflammation plays a causal role in Chronic Obstructive Pulmonary Disease (COPD). Neutrophil derived myeloperoxidase(MPO) matrix metalloproteinases(MMP's), and elastases are thought to contribute to the perpetuation of the disease. The tetracycline analogue doxycycline has been shown to inhibit neutrophil-mediated inflammation. It was thus reasoned that doxycycline may attenuate neutrophil-mediated inflammation in COPD. METHODS: In this double blind randomized controlled trial the effect of a 3-week course of doxycycline on sputum and systemic inflammatory parameters was evaluated in stable COPD patients. In order to exclude inflammation by bacterial colonisation patients must have 2 negative sputum cultures in the previous year. The effect of doxycycline treatment on inflammatory markers (TNF-alpha, IL-1beta and IL-6) and neutrophil specific markers in sputum (MPO, MMP's, and IL-8) and serum C-reactive protein was evaluated. Sputum was obtained by sputum induction with hypertonic saline. RESULTS: A total of 41 patients were included. Ten patients were excluded as they were not able to produce sputum at the first or second visit. Baseline characteristics were similar in the two groups. In the remaining patients doxycycline did not influence sputum MPO concentrations. Also MMP-8 and 9, IL-6 and IL-8 concentrations as well as lung function parameters were not affected by doxycycline. Systemic inflammation by means of CRP was also not influenced by doxycycline. CONCLUSION: A three week course of doxycycline did not influence MPO sputum levels nor any of the other inflammatory sputum and systemic markers. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00857038 URL: clinicaltrials.gov. PMID- 26616679 TI - Colorimetric monitoring of formaldehyde in indoor environment using built-in camera on mobile phone. AB - A simple monitoring system of indoor air pollution is proposed by integrating a novel colorimetric detector of formaldehyde (HCHO) and a function of a built-in camera on mobile phone. The colorimetric detector employs a solid phase colorimetric reagent made from 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole, ZnO, KIO4 and agar, and changes colour from white to purple by exposure to HCHO gas. The degree of colour changes expressed in Red, Green and Blue model model responded to the HCHO concentration levels both in air and from building materials. Limit of quantitation of the detector with 24 h-exposure resulted in 0.011 mg/m(3) of air concentration which meets a requirement of methodology to detect indoor air quality guideline level of HCHO set by World Health Organization. The detector is also applicable to classify HCHO-emitting materials at least into Type 1, whose emission flux is greater than 120 MUg/m(2)/h, and others. Then, variation of the acquired photo images was investigated by using various mobile phones and changing conditions of photography. As a result, the calibration of the measured colour intensity with a colour standard reduced the variation of the results and gave a significant output when the auto-focused images were taken under the condition of common indoor environment. PMID- 26616682 TI - Development of a Steel-Slag-Based, Iron-Functionalized Sorbent for an Autothermal Carbon Dioxide Capture Process. AB - We propose a new class of autothermal CO2 -capture process that relies on the integration of chemical looping combustion (CLC) into calcium looping (CaL). In the new process, the heat released during the oxidation of a reduced metallic oxide is utilized to drive the endothermic calcination of CaCO3 (the regeneration step in CaL). Such a process is potentially very attractive (both economically and technically) as it can be applied to a variety of oxygen carriers and CaO is not in direct contact with coal (and the impurities associated with it) in the calciner (regeneration step). To demonstrate the practical feasibility of the process, we developed a low-cost, steel-slag-based, Fe-functionalized CO2 sorbent. Using this material, we confirm experimentally the feasibility to heat integrate CaCO3 calcination with a Fe(II)/Fe(III) redox cycle (with regards to the heat of reaction and kinetics). The autothermal calcination of CaCO3 could be achieved for a material that contained a Ca/Fe ratio of 5:4. The uniform distribution of Ca and Fe in a solid matrix provides excellent heat transfer characteristics. The cyclic CO2 uptake and redox stability of the material is good, but there is room for further improvement. PMID- 26616683 TI - Long-Range pi-Conjugation in Phenothiazine-containing Donor-Acceptor Dyes for Application in Dye-Sensitized Solar Cells. AB - Four organic donor-pi-bridge-acceptor dyes containing phenothiazine as a spacer and cyanoacrylic acid as an acceptor were synthesized and tested as sensitizers in dye-sensitized solar cells (DSCs). The influence of iodide- and cobalt-based redox electrolytes on the photovoltaic device performance was investigated. In these new dyes, systematic pi-conjugation was extended by inserting one or two phenothiazine moieties and investigated within the context of the resulting photoinduced charge-transfer properties. A detailed investigation, including transient absorption spectroscopy and quantum chemical methods, provided important information on the role of extended pi-conjugation on the photophysical properties and photovoltaic device performance. Overall, the results showed that the extension of pi-conjugation by one phenothiazine unit resulted in the best device performance owing to reduced recombination rates, whereas extension by two phenothiazine units reduced dye adsorption on TiO2 probably owing to the increase in molecular size. The performance of the dyes in DSCs was found to be a complex interaction between dye structure and size. PMID- 26616684 TI - Non-small cell lung cancer in young patients--a retrospective analysis of 10 years in a tertiary university hospital. PMID- 26616685 TI - Role and Image of Nursing in Children's Literature: A Qualitative Media Analysis. AB - Nurses' role and image as portrayed in young children's literature were described and analyzed. DESIGN AND METHODS: A total of 30 children's books (pre kindergarten through grade two audience) written in English were chosen using progressive theoretical sampling. Included were books, both fiction and non fiction and with varying years of publication, that mentioned nurses and/or were about general healthcare topics. The books were analyzed using the method of qualitative media analysis which is derived from the theoretical framework of symbolic interactionism. RESULTS: Nurses were generally portrayed positively but simply and inaccurately in this sample of children's literature. The seven themes discovered were labeled as nurse characters using traits evident in the sample: nurse unlikely, nurse minimal, nurse caring, nurse subordination, nurse skillful, nurse diversity, and nurse obvious. CONCLUSION: The image of nursing is socially and culturally constructed, and accurate portrayals of nurses and their roles are necessary in all media. Thus, better representation of nurses in children's books is needed as young children's literature is an important first exposure to the art and science of nursing. PRACTICE IMPLICATIONS: Future children's books authored by nurses may more closely reflect accurate contemporary nursing practice and contribute to an improved image of the nursing profession. PMID- 26616687 TI - Microbiome of titanium and zirconia dental implants abutments. AB - OBJECTIVES: This study employed culture-independent molecular techniques to extend the characterization of the microbial diversity of biofilm associated with either titanium or zirconia implant-abutments, including not-yet-cultivated bacteria species, and to identify and quantify species recovered from peri implantar/periodontal sulci, supragingival biofilm and the internal parts of implants. Probing depth, clinical attachment level, bleeding on probing, and marginal bone level were also evaluated over time and correlated with biofilm formation. METHODS: Twenty healthy participants were analyzed. DNA-Checkerboard and 16S-rDNA-Pyrosequencing were used to quantify and determine species identity. RESULTS: 161 bacterial taxa representing 12 different phylotypes were found, of which 25% were non-cultivable. Species common to all sites belonged to genera Fusobacterium, Prevotella, Actinomyces, Porphyromonas, Veillonella and Streptococcus. While some species were subject-specific and detected in most sites, other species were site-specific. Moderate to higher levels of unclassified species were found colonizing titanium-related sites. Pathogenic and non-pathogenic species were detected colonizing oral sites in both materials. Titanium-related sites presented the highest total microbial count and higher counts of pathogenic species. CONCLUSIONS: Our results revealed differences regarding microbial diversity and microorganisms counts in oral biofilm associated with titanium or zirconia. The obtained data suggests a possible relation between microbiological findings and clinical outcomes. SIGNIFICANCE: Next-generation methods of detection have provided new insights on complex microbiota colonizing different sites of oral cavity. The present study demonstrates relevant differences in the communities and microbial counts colonizing different tested substrates with consequent significant differences in the clinical-outcomes, suggesting a probably different mechanism for specific bacterial adhesion. PMID- 26616686 TI - Grid Cells and Place Cells: An Integrated View of their Navigational and Memory Function. AB - Much has been learned about the hippocampal/entorhinal system, but an overview of how its parts work in an integrated way is lacking. One question regards the function of entorhinal grid cells. We propose here that their fundamental function is to provide a coordinate system for producing mind-travel in the hippocampus, a process that accesses associations with upcoming positions. We further propose that mind-travel occurs during the second half of each theta cycle. By contrast, the first half of each theta cycle is devoted to computing current position using sensory information from the lateral entorhinal cortex (LEC) and path integration information from the medial entorhinal cortex (MEC). This model explains why MEC lesions can abolish hippocampal phase precession but not place fields. PMID- 26616689 TI - Autologous blood injection for treatment of lateral epicondylosis: A meta analysis of randomized controlled trials. AB - OBJECTIVES: To appraise existing evidence of autologous blood injection in treating lateral epicondylosis. DESIGN: Meta-analysis of randomized controlled trials. SETTING: A comprehensive search of the PubMed, Cochrane, SCOPUS, and CINAHL databases was performed to identify randomized controlled trials that reported the efficacy of autologous blood injection in treating lateral epicondylosis. The selected studies were subjected to a meta-analysis and risk of bias assessment. PARTICIPANTS: Patients with lateral epicondylosis. MAIN OUTCOME MEASURES: Pain-related measurement in each selected randomized controlled trial was pooled into meta-analysis. RESULTS: Nine randomized controlled trials were included in the analysis. The results of the meta-analysis including the pain scores indicated that autologous blood injection is more effective compared with corticosteroid injection (standard mean difference: -0.75; 95% confidence interval: -1.14 to -0.37) but not more effective compared with platelet-rich plasma injection (standard mean difference: 0.09; 95% confidence interval: -0.66 to 0.84). The risk of bias assessment indicated that all the included trials exhibited a moderate to high risk of bias. CONCLUSION: Autologous blood injection is more effective than corticosteroid injection but not more effective than platelet-rich plasma injection in treating lateral epicondylosis. However, this evidence is limited by the potential risk of bias. PMID- 26616688 TI - Tris(trimethylsilyl)silane as a co-initiator for dental adhesive: Photo polymerization kinetics and dynamic mechanical property. AB - OBJECTIVES: The purpose of this study was to evaluate the polymerization behavior of a model dentin adhesive with tris(trimethylsilyl)silane (TTMSS) as a co initiator, and to investigate the polymerization kinetics and mechanical properties of copolymers in dry and wet conditions. METHODS: A co-monomer mixture based on HEMA/BisGMA (45/55, w/w) was used as a model dentin adhesive. The photoinitiator system included camphorquinone (CQ) as the photosensitizer and the co-initiator was ethyl-4-(dimethylamino) benzoate (EDMAB) or TTMSS. Iodonium salt, diphenyliodonium hexafluorophosphate (DPIHP) serving as a catalyst, was selectively added into the adhesive formulations. The control and the experimental formulations were characterized with regard to the degree of conversion (DC) and dynamic mechanical properties under dry and wet conditions. RESULTS: In two-component photoinitiator system (CQ/TTMSS), with an increase of TTMSS concentration, the polymerization rate and DC of CC double bond increased, and showed a dependence on the irradiation time and curing light intensity. The copolymers that contained the three-component photoinitiator system (CQ/TTMSS/DPIHP) showed similar dynamic mechanical properties, under both dry and wet conditions, to the EDMAB-containing system. SIGNIFICANCE: The DC of formulations using TTMSS as co-initiator showed a strong dependence on irradiation time. With the addition of TTMSS, the maximum polymerization rate can be adjusted and the network structure became more homogenous. The results indicated that the TTMSS could be used as a substitute for amine-type co initiator in visible-light induced free radical polymerization of methacrylate based dentin adhesives. PMID- 26616690 TI - Surface Aesthetics and Analysis. AB - Surface aesthetics of an attractive nose result from certain lines, shadows, and highlights with specific proportions and breakpoints. Analysis emphasizes geometric polygons as aesthetic subunits. Evaluation of the complete nasal surface aesthetics is achieved using geometric polygons to define the existing deformity and aesthetic goals. The relationship between the dome triangles, interdomal triangle, facet polygons, and infralobular polygon are integrated to form the "diamond shape" light reflection on the nasal tip. The principles of geometric polygons allow the surgeon to analyze the deformities of the nose, define an operative plan to achieve specific goals, and select the appropriate operative technique. PMID- 26616691 TI - Open and Closed Rhinoplasty. AB - Most surgeons recognize the broad utility of both endonasal and external rhinoplasty approaches. Most understand that there are situations when a given approach offers advantages and may be considered preferable. In this article, the anatomy, incisions, and approaches that are available to the surgeon are reviewed. General indications are discussed for the external and endonasal approaches. The pros and cons of each approach are discussed, and further thoughts on the decision-making process are provided. PMID- 26616692 TI - Surgical Treatment of Nasal Obstruction in Rhinoplasty. AB - The key to a successful septorhinoplasty includes an understanding of nasal anatomy and physiology. This allows the surgeon the ability to properly address both form and function during the operation. History and physical examination are paramount in diagnosing and subsequently treating the epicenter of obstruction, which is commonly found among the internal and external nasal valve, the septum, or the turbinates. Treatment of each of these areas is nuanced and multiple approaches are discussed to provide an understanding of the current surgical techniques that allow for excellent functional and cosmetic rhinoplasty results. PMID- 26616693 TI - Surgical Management of Nasal Airway Obstruction. AB - The management and diagnosis of nasal airway obstruction requires an understanding of the form and function of the nose. Nasal airway obstruction can be structural, physiologic, or a combination of both. Anatomic causes of airway obstruction include septal deviation, internal nasal valve narrowing, external nasal valve collapse, and inferior turbinate hypertrophy. Thus, the management of nasal air obstruction must be selective and carefully considered. The goal of surgery is to address the deformity and not just enlarge the nasal cavity. PMID- 26616694 TI - Dorsal Hump Reduction and Osteotomies. AB - This article discusses the technique for planning, executing, and troubleshooting dorsal hump reduction for the cosmetic rhinoplasty patient. Details of the discussion include the necessary elements of the preoperative consultation with the patient, the specific instruments used to effectively and reproducibly create osteotomies, the anatomic and patient variables that require special attention, and the necessary measures to guard against potential complications. PMID- 26616695 TI - Management of the Nasal Dorsum: Construction and Maintenance of a Barrel Vault. AB - Rhinoplasty is not so much an art, but rather an architectural undertaking: a methodical approach to reconfiguring the nasal components to give a proportionate nose that both pleases the eye and satisfies functional requirements. The dorsum and dorsal esthetic lines are some of the most important components of the nose in terms of esthetics and function. The middle vault is the critical portion of the nose that will guide the management of the bony vault and the tip. The role of the spreader flap and its extension into the bony vault is stressed to re create the barrel vaultlike nasal architecture. PMID- 26616696 TI - Nasal Bone Osteotomies with Nonpowered Tools. AB - Controlling the shape of the nasal bones has long been a frustrating problem. Conventional osteotomies are associated with bleeding, loss of reduction, inability to achieve the desired alignment, improperly placed osteotomy sites, and spicule formation. A nonpowered osteotomy method empirically provided the safest and most controlled technique to achieve the desired anatomic result. The nasal bones should be thought of as 2 thin nasal plates that can be released from their medial and lateral attachments to become mobile units that can affect the dorsal width and bony base independently. There is a learning curve to osteotomies. PMID- 26616697 TI - Surgical Treatment of the Middle Nasal Vault. AB - The middle nasal vault is a sensitive region of the nose from both an esthetic and a functional perspective. It is critical for the rhinoplasty surgeon to properly evaluate and identify abnormalities of the middle vault when considering patients for primary or secondary surgery. This article addresses the surgical management of the cosmetic deformities and functional deficits of the middle vault and provides guidance for avoiding complications in this structurally critical region of the nose. PMID- 26616698 TI - Surgical Treatment of the Twisted Nose. AB - The twisted nose is a challenging procedure in rhinoplasty. The goal of surgery is to realign the nasal skeleton to create symmetry in the face and restore nasal patency. Key in the surgical procedure is that all structures of the nasal skeleton be dissected free, mobilized, repositioned, and stabilized. Important surgical steps are intermediate osteotomies on the contralateral side of the deviation for the upper nasal third; for the mid nasal third, a unilateral spreader graft or splint on the nondeviated side, and for the lower nasal third, fixation of the caudal septum to the anterior nasal spine. PMID- 26616699 TI - The Crooked Nose. AB - Correction of a crooked nose is one of the most common requests from patients presenting for rhinoplasty. Both esthetic and functional issues are typically present in patients with this deformity. Rhinoplasty for the crooked nose is particularly challenging because multiple nasal structures, both external and internal, are commonly involved. A major septal deformity is almost always a component of severely deviated noses. The crooked nose results from extrinsic and intrinsic forces that produce distortion of the nasal structures and nasal deviation. The open approach is particularly useful and is the focus of this article. PMID- 26616700 TI - Reshaping of the Broad and Bulbous Nasal Tip. AB - This article presents a contemporary overview of tip suturing and tip structural grafting techniques used to refine the wide nasal tip. Previous reductive techniques have proved to produce unnatural results over time. It is imperative to correctly evaluate the nose and assess all possible pitfalls during the preoperative period before outlining a surgical plan. Intraoperatively, an algorithmic approach helps obtain a reproducible and refined yet properly narrowed domal tip region with graceful contours that extend laterally to the alar lobule with proper shadowing. PMID- 26616701 TI - Alar Rim Deformities. AB - The alar rim plays an important role in nasal harmony. Alar rim flaws are common following the initial rhinoplasty. Classification of the deformities helps with diagnosis and successful surgical correction. Diagnosis of the deformity requires careful observation of the computerized or life-sized photographs. Techniques for treatment of these deformities can easily be learned with attention to detail. PMID- 26616702 TI - Nasal Tip Deficiency. AB - Nasal tip deficiency can be congenital or secondary to previous nasal surgeries. Underdeveloped medial crura usually present with underprojected tip and lack of tip definition. Weakness or malposition of lateral crura causes alar rim retraction and lateral nasal wall weakness. Structural grafting of alar cartilages strengthens the tip framework, reinforces the disrupted support mechanisms, and controls the position of the nasal tip. In secondary cases, anatomic reconstruction of the weakened or interrupted alar cartilages and reconstitution of a stable nasal tip tripod must be the goal for a predictable outcome. PMID- 26616703 TI - Projection and Deprojection Techniques in Rhinoplasty. AB - Projection of the nasal tip is among the most important aspects of the nose. In this article, a wide spectrum of techniques are presented that allow the rhinoplasty surgeon to decrease, maintain, or increase nasal tip projection. Rhinoplasty surgeons must be adept with suture techniques, lower lateral cartilage overlay techniques, and structural grafting to be able to achieve excellent long-term results. PMID- 26616704 TI - The Short Nose. AB - The causes of the short nose deformity vary greatly, from congenital malformations to acquired deformities. Despite this degree of variation, key commonalities exist, namely, a shortened nasal length, overrotation of the nasal tip, and increased nostril show. This article is designed to help the reader identify precise causes of the short nose, outline associated anatomy, and discuss reliable surgical techniques to correct this deformity. PMID- 26616705 TI - Revision Rhinoplasty. AB - Revision rhinoplasty is one of the most challenging operations the facial plastic surgeon performs given the complex 3-dimensional anatomy of the nose and the psychological impact it has on patients. The intricate interplay of cartilages, bone, and soft tissue in the nose gives it its aesthetic and function. Facial harmony and attractiveness depends greatly on the nose given its central position in the face. In the following article, the authors review common motivations and anatomic findings for patients seeking revision rhinoplasty based on the senior author's 30-year experience with rhinoplasty and a review of the literature. PMID- 26616706 TI - Pyriform Aperture Augmentation as An Adjunct to Rhinoplasty. AB - Skeletal deficiency in the central midface impacts nasal aesthetics. This lack of lower face projection can be corrected by alloplastic augmentation of the pyriform aperture. Creating convexity in the deficient midface will make the nose seem less prominent. Augmentation of the pyriform aperture is, therefore, often a useful adjunct during the rhinoplasty procedure. Augmenting the skeleton in this area can alter the projection of the nasal base, the nasolabial angle, and the vertical plane of the lip. The implant design and surgical techniques described here are extensions of others' previous efforts to improve paranasal aesthetics. PMID- 26616707 TI - Harvesting Rib Cartilage in Primary and Secondary Rhinoplasty. AB - Satisfactory and consistent long-term results in primary and secondary rhinoplasty rely on adequately resupporting or reconstructing the nasal osseocartilagenous framework. Autogenous rib cartilage has been our graft material of choice for major nasal reconstruction when sufficient septal cartilage is not available. The rib provides the most abundant source of cartilage for graft fabrication and is the most reliable when structural support is needed. PMID- 26616708 TI - Costal Cartilage Grafts in Rhinoplasty. AB - Cartilage grafts are regularly used in rhinoplasty. Septal and auricular donor sites are commonly used. Many situations compel the surgeon to use other alternative donor sites, including revision rhinoplasty and trauma. Many patients have a small amount of native septal cartilage and are unable to provide adequate septal cartilage to be used for frequently performed rhinoplasty maneuvers. The rib cage provides an enormous reserve of costal cartilage that can be carved into a variety of necessary grafts. A description of the technique of harvesting costal cartilage, a review of complications and management, and illustrative cases examples are included. PMID- 26616709 TI - The Cleft Lip Nose: Primary and Secondary Treatment. AB - This article presents an overview of the cleft lip nasal deformity and its treatment. The complex pathologic changes to normal nasal anatomy are described, and treatment strategies for both unilateral and bilateral cleft lip patients are presented. The surgical technique for management of the cleft lip nasal deformity is discussed as it pertains to both primary and secondary correction. PMID- 26616711 TI - Rhinoplasty in Latino Patients. AB - Rhinoplasty is the main facial plastic procedure performed in Latin America. Mestizo or Latino patients tend to have noses with thick skin, bulbous tips with poor projection, and flimsy osteocartilaginous underlying frameworks. A technique is presented in which structural grafts are used to strengthen support structures of the nose. A gradual approach is used to obtain tip definition, rotation, and projection using sutures and grafts. Simple techniques are used initially, progressing to more aggressive and less predictable ones in patients who require greater changes. The result should be noses that look more refined, with greater definition, but without looking bigger. PMID- 26616710 TI - Cleft Lip Nose. AB - All patients with a cleft lip deformity have an associated nasal deformity that varies in degree of severity. A three-dimensional understanding of the anatomy of the cleft nose aids surgeons in selecting the proper technique for repair. Analysis and performance of orthognathic surgery should be done before nasal surgery to optimize the overall result. Goals of the secondary rhinoplasty include relief of nasal obstruction, creation of symmetry and definition of the nasal base and tip, and management of nasal scarring and webbing. Septal reconstruction in the cleft nose is a key maneuver in cleft rhinoplasty. PMID- 26616712 TI - Rhinoplasty in the African American Patient: Anatomic Considerations and Technical Pearls. AB - There are several anatomic considerations as well as variations in patients of African heritage. The goal of improvement in aesthetics and functionality must be in balance with racial preservation. Preoperative counseling must discuss patient expectations and surgical limitations based on patients' skin and cartilage. Dorsal augmentation, increased tip projection, and rotation are often needed. Understanding the thick, sebaceous skin often seen in African Americans assists in postoperative management of swelling. PMID- 26616713 TI - Rhinoplasty in the Asian Patient. AB - The ubiquitous goal of rhinoplasty is to make a natural-looking and attractive nose that blends harmoniously with the face. Rhinoplasty among Asians includes characteristics that distinguish the procedure from its white counterpart. Anatomic differences of the Asian nose coupled with differences in aesthetic standards demand they be approached in a unique way. In this article, peculiar aspects of Asian rhinoplasty are addressed with emphasis on surgical techniques used to obtain reliable results. PMID- 26616715 TI - Chin Advancement, Augmentation, and Reduction as Adjuncts to Rhinoplasty. AB - Chin deformities are commonly encountered defects in patients seeking rhinoplasty. Careful preoperative evaluation may identify patients who could benefit from concurrent augmentation or reduction mentoplasty. Alloplastic chin implants and sliding genioplasty represent the main accepted methods of chin augmentation. Although both procedures may be used for retrognathia or microgenia, the sliding genioplasty may also be used in chin asymmetry, prognathia, and vertical height discrepancies. This article outlines the methods to analyze the chin, and discusses the treatment options available for correction of chin deformities as an adjunct to rhinoplasty. PMID- 26616714 TI - Rhinoplasty in Middle Eastern Patients. AB - Rhinoplasty in patients of Middle Eastern origin requires complete understanding of nasal morphology and an individualized approach to create a racially congruent and aesthetically pleasing outcome. In this article, common anatomic features and characteristics and detailed steps, surgical techniques, and operative maneuvers that can lead to predictable outcome in rhinoplasty of Middle Eastern patients are discussed. PMID- 26616716 TI - Use of Fillers in Rhinoplasty. AB - Surgical rhinoplasty is the one of the most common cosmetic procedures in Asians. But there are limitations, such as down time, high cost, and a steep learning curve. Most complications are implant related. A safer and less invasive procedure is rhinoplasty using fillers. Good knowledge of the nasal anatomy is essential for rhinoplasty using fillers. Knowledge of nerves, blood supply, and injection plane allows avoiding complications. There are several planes in the nose. The deep fatty layer is recommended for injection, because it is wide and loose and there are less important neurovascular structures. Botulinum toxin also can be used for noninvasive rhinoplasty. PMID- 26616718 TI - New Pd(II) hemichelates devoid of incipient bridging COPd interactions. AB - In organometallic chemistry the commonly known Sidgwick-Langmuir 18 electron rule is constantly being probed for further discovery of molecular compounds that arise as exceptions. The present study examines the formation and the structure of three novel hemichelates of Pd(ii) derived from the reaction of in situ-formed indene and hydrophenanthrene-based organometallic anions with three different MU chloro-bridged palladacycles. Electronic structure and interaction behavior have been calculated with methods of the density functional theory at the (ZORA) MetaGGA-D TPSS-D3(BJ), GGA-D PBE-D3(BJ), and hybrid PBE0-dDsC dispersion corrected levels, all with the implementation of all electron triple zeta single polarization basis set. A particular focus of the theoretical investigation was made on the nature of the interaction between the [Cr(CO)3] moiety and the Pd(ii) centers, which according to X-ray diffraction analyses lack significant incipient bridging COPd character. Structures were further assessed - Natural Bonding Orbitals (NBO), Quantum Theory of Atoms in Molecules (QTAIM), and Extended Transition State with Natural Orbitals for Chemical Valence (ETS-NOCV) analysis methods. As a result, intramolecular interactions of interest, primarily around the Pd atom, were analyzed as a measure of natural atomic orbital (NAO) contributions to the natural bonding orbital (NBO) formation, QTAIM analysis with special attention to the bonding critical points (BCPs), as well as energetic analysis of intramolecular interaction forces by Energy Decomposition Analysis (EDA). Theoretical analyses confirm that attractive electrostatics dominate the stabilization of Pd(ii) hemichelates. In the case of complexes , and we expand the known amount of 14 electron transition metal complexes that can be synthesized via reliable synthetic methods. However, complex presented some means of stability but was more reactive to moisture and air under laboratory conditions and escaped thorough analytical characterization. PMID- 26616719 TI - Porous VO(x)N(y) nanoribbons supported on CNTs as efficient and stable non-noble electrocatalysts for the oxygen reduction reaction. AB - Novel nanocomposites of carbon nanotubes supported porous VO(x)N(y) nonoribbons (VO(x)N(y)-CNTs) have been synthesized by the annealing of the sol-gel mixture of CNTs and V2O5 under NH3 atmosphere as well as the ageing process in air. Besides the morphological and structural characterizations revealed by TEM, SEAD, EDS, XRD and XPS measurements, typical electrochemical tests including cyclic voltammetry (CV), rotating disk electrode (RDE) and chronoamperometry have been employed to determine the oxygen reduction reaction (ORR) performance of VO(x)N(y)-CNTs. Inspiringly, the results indicate that VO(x)N(y)-CNTs catalyst exhibits a 0.4 mA/cm(2) larger diffusion-limited current density, a 0.10 V smaller onset potential value, a 10.73% less of ORR current decay and an excellent methanol-tolerance compared with commercial Pt/C catalyst. Therefore, we have reasonable grounds to believe that this new VO(x)N(y)-CNTs nanocomposites can be regarded as a promising non-precious methanol-tolerant ORR catalyst candidate for alkaline fuel cells. PMID- 26616720 TI - FTIR imaging of the 3D extracellular matrix used to grow colonies of breast cancer cell lines. AB - Infrared imaging was applied to investigate a reconstituted basement membrane, known as Matrigel, in three-dimensional cell cultures. Matrigel, in the vicinity of the colonies, was examined for four breast cancer cell lines presenting different 3D colony morphologies. MCF-7 and T-47D present mass colonies, SKBR-3 grape-like colonies and MDA-MB-231 stellate colonies associated with a more invasive phenotype. The edge of the cell colonies was found to be significantly depleted in Matrigel. Except in a limited number of cases, Matrigel appeared to be thinner at the edges of the colonies but not completely destroyed or torn off as it would be for a purely mechanical effect. When a PCA was run on the spectra of one or several colonies, the score images on PC#3 and PC#4 presented structures in the Matrigel areas which appeared as fringes, lines, dots or regular patterns. This effect represents a very small fraction of the total variance but is reproducible for all the 4 cell lines. PC#4 presents systematically a maximum near 1624 cm(-1) and a minimum around 1700 cm(-1). When spectra are normalized, the effect is less marked but does not disappear. The nature of the variations that exist in the Matrigel layer is therefore not solely related to thickness but also to the chemical composition. At this stage, the weakness of the effect prevents a thorough investigation. PMID- 26616721 TI - Low-grade metastases in high-grade clear cell renal cell carcinomas: A clinicopathologic study of 4 cases with an insight into the role of mesenchymal to-epithelial transition process. AB - Clear cell renal cell carcinoma (CCRCC) frequently develops distant metastases. However, high-grade primary CCRCC rarely leads to low-grade metastases. Cellular changes occurring during neoplastic progression known as epithelial-to mesenchymal and mesenchymal-to-epithelial transitions explain this apparent contradiction. Four high-grade CCRCCs, which lead to low-grade metastases, are analyzed in this study, with the focus on epithelial-to-mesenchymal and mesenchymal-to-epithelial processes. Clinicopathologic data have been collected retrospectively and immunohistochemistry has been performed with E-cadherin, N cadherin, vimentin, and WT-1. Three cases had organ-confined disease (2 pT2 and 1 pT1b). Three cases were G3 and 1 case was G4. Lung (3 cases), bone (2 cases), and pancreas (1 case) were the metastatic organs (2 patients developed multiple metastases). Metastases were G1 in all the cases. Average elapsed time between the primary tumor and the metastasis was 35.5 months. Three patients died of disease after 36, 120, and 180 months of follow-up, respectively. One patient is alive without disease after 75 months of follow-up. E-cadherin and N-cadherin showed concordant immunostaining patterns between primaries and metastases but inverse when correlated with Fuhrman grade. Hence, E-cadherin was positive in G3 cases and negative in G4, whereas N-cadherin was negative in G3 and positive in G4. Vimentin was positive in primaries and metastases only in 2 cases. WT-1 was consistently negative in all cases. In conclusion, pathologists must remember that high-grade CCRCC may develop low-grade metastases. Cadherin switching seems to be related to Fuhrman grade in this group of cases. This preliminary observation must be confirmed in longer studies. PMID- 26616722 TI - Distinctive immunostaining of claudin-4 in spiradenomas. AB - The intercellular bridges are essential structures in maintaining the histologic organization of the epithelium, while providing a very efficient way to exchange molecules between cells and transduction of the cell-to-cell and matrix-to-cell signals. Derangement in those important structures' physical integrity and/or function, which can be assessed by the presence or absence of several intercellular bridge proteins including claudin-4, E-cadherin, and beta-catenin, was found to be related to several phenomena in the path to the neoplastic transformation. However, these proteins have not been studied in the wide variety of the skin neoplasms, in detail. Herein, we immunohistochemically assessed the expression patterns of these 3 intercellular bridge proteins on a total of 86 epidermal and eccrine adnexal tumors including basal cell carcinoma, squamous cell carcinoma, poroma, spiradenoma, syringoma, and hidradenoma. We observed a selective and distinct claudin-4 expression in the ductal-type cells of all cases of spiradenomas. Similarly, in the poromas, syringomas, and hidradenomas, claudin 4 was only positive in the luminal cells of microcystic structures, although not as conspicuous as in the spiradenomas. On the other hand, E-cadherin and beta catenin were positive in almost all types of the tumors, in a way which was not contributory to differentiate from each other. In conclusion, we think that claudin-4 can be helpful at least in making a reliable differential diagnosis of spiradenoma when overlapping morphologic features do not allow to further subclassification in the overwhelming variety of the adnexal tumors. PMID- 26616723 TI - Editorial. PMID- 26616724 TI - Nature versus design: synthetic biology or how to build a biological non-machine. AB - The engineering ideal of synthetic biology presupposes that organisms are composed of standard, interchangeable parts with a predictive behaviour. In one word, organisms are literally recognized as machines. Yet living objects are the result of evolutionary processes without any purposiveness, not of a design by external agents. Biological components show massive overlapping and functional degeneracy, standard-free complexity, intrinsic variation and context dependent performances. However, although organisms are not full-fledged machines, synthetic biologists may still be eager for machine-like behaviours from artificially modified biosystems. PMID- 26616725 TI - Endoscopic electronic medical record systems. PMID- 26616726 TI - Breast cancer in pregnancy: A brief clinical review. AB - As global wealth increases and demographic changes similar to Europe and North America start affecting other societies, the global breast cancer epidemic will coincide with a delayed maternal age during first and subsequent pregnancies. Breast cancer in pregnancy will continue to increase, and standardized treatment strategies are required to be developed. This study will review current diagnostic and treatment approaches. PMID- 26616727 TI - Adiponectin downregulation is associated with volume overload-induced myocyte dysfunction in rats. AB - AIM: Adiponectin has been reported to exert protective effects during pathological ventricular remodeling, but the role of adiponectin in volume overload-induced heart failure remains unclear. In this study we investigated the effect of adiponectin on cardiac myocyte contractile dysfunction following volume overload in rats. METHODS: Volume overload was surgically induced in rats by infrarenal aorta-vena cava fistula. The rats were intravenously administered adenoviral adiponectin at 2-, 6- and 9-weeks following fistula. The protein expression of adiponectin, adiponectin receptors (AdipoR1/R2 and T-cadherin) and AMPK activity were measured using Western blot analyses. Isolated ventricular myocytes were prepared at 12 weeks post-fistula to examine the contractile performance of myocytes and intracellular Ca(2+) transient. RESULTS: A-V fistula resulted in significant reductions in serum and myocardial adiponectin levels, myocardial adiponectin receptor (AdipoR1/R2 and T-cadherin) levels, as well as myocardial AMPK activity. Consistent with these changes, the isolated myocytes exhibited significant depression in cell shortening and intracellular Ca(2+) transient. Administration of adenoviral adiponectin significantly increased serum adiponectin levels and prevented myocyte contractile dysfunction in fistula rats. Furthermore, pretreatment of isolated myocytes with recombinant adiponectin (2.5 MUg/mL) significantly improved their contractile performance in fistula rats, but had no effects in control or adenoviral adiponectin-administered rats. CONCLUSION: These results demonstrate a positive correlation between adiponectin downregulation and volume overload-induced ventricular remodeling. Adiponectin plays a protective role in volume overload-induced heart failure. PMID- 26616729 TI - The no-reflow phenomenon: State of the art. AB - Primary percutaneous coronary intervention (PCI) is the best available reperfusion strategy for acute ST-segment elevation myocardial infarction (STEMI), with nearly 95% of occluded coronary vessels being reopened in this setting. Despite re-establishing epicardial coronary vessel patency, primary PCI may fail to restore optimal myocardial reperfusion within the myocardial tissue, a failure at the microvascular level known as no-reflow (NR). NR has been reported to occur in up to 60% of STEMI patients with optimal coronary vessel reperfusion. When it does occur, it significantly attenuates the beneficial effect of reperfusion therapy, leading to poor outcomes. The pathophysiology of NR is complex and incompletely understood. Many phenomena are known to contribute to NR, including leukocyte infiltration, vasoconstriction, activation of inflammatory pathways and cellular oedema. Vascular damage and haemorrhage may also play important roles in the establishment of NR. In this review, we describe the pathophysiological mechanisms of NR and the tools available for diagnosing it. We also describe the microvasculature and the endothelial mechanisms involved in NR, which may provide relevant therapeutic targets for reducing NR and improving the prognosis for patients. PMID- 26616728 TI - Cancer predisposition genes: molecular mechanisms and clinical impact on personalized cancer care: examples of Lynch and HBOC syndromes. AB - Up to 10% of cancers occur through the inherited mutation of a group of genes called cancer predisposition genes. Individuals who carry a mutant allele of these genes have an increased susceptibility to cancer. A growing number of cancer susceptibility genes are being identified, and the physiopathology of germline mutation-based cancer development is also being elucidated with accumulating clinical and molecular data. More importantly, the identification of familial mutations has become routine practice, which is a perfect example of bench-to-bed translational medicine. Recently, other clinical applications of predisposition genes have been exploited, especially as efficient biomarkers predicting prognosis or response to treatment. Thus, it appears interesting to give an overview of the advances and impacts of predisposition genes in personalized cancer care by taking representative and common cancer syndromes as examples: Lynch syndrome for the first example, which is related to cancer susceptibility, and breast and ovary cancer syndrome for the second example, which involves BRCA deficiency-related targeted therapy. PMID- 26616730 TI - Subfraction analysis of circulating lipoproteins in a patient with Tangier disease due to a novel ABCA1 mutation. AB - Tangier disease, characterized by low or absent high-density lipoprotein (HDL), is a rare hereditary lipid storage disorder associated with frequent, but not obligatory, severe premature atherosclerosis due to disturbed reverse cholesterol transport from tissues. The reasons for the heterogeneity in atherogenicity in certain dyslipidemias have not been fully elucidated. Here, using high performance liquid chromatography with a gel filtration column (HPLC-GFC), we have studied the lipoprotein profile of a 17-year old male patient with Tangier disease who to date has not developed manifest coronary atherosclerosis. The patient was shown to be homozygous for a novel mutation (Leu1097Pro) in the central cytoplasmic region of ATP-binding cassette transporter A1 (ABCA1). Serum total and HDL-cholesterol levels were 59mg/dl and 2mg/dl, respectively. Lipoprotein electrophoretic analyses on agarose and polyacrylamide gels showed the presence of massively abnormal lipoproteins. Further analysis by HPLC-GFC identified significant amounts of lipoproteins in low-density lipoprotein (LDL) subfractions. The lipoprotein particles found in the peak subfraction were smaller than normal LDL, were rich in triglycerides, but poor in cholesterol and phospholipids. These findings in an adolescent Tangier patient suggest that patients in whom these triglyceride-rich, cholesterol- and phospholipid-poor LDL type particles accumulate over time, would experience an increased propensity for developing atherosclerosis. PMID- 26616731 TI - Cut-off values to rule out urinary tract infection should be gender-specific. AB - The diagnosis of urinary tract infection (UTI) by urine culture is an expensive and time-consuming procedure. Using a screening method, to identify negative samples, would improve the procedure and reduce costs. In this study, urine flow cytometry, of over 7000 urine samples, was assessed by retrospective analysis. With a cut-off value of >200bacteria/MUl, we obtained a sensitivity of 93.0%, a specificity of 63.5%, and a negative predictive value (NPV) of 96.2%. As a result the culturing of 49% of all samples could be avoided. In addition, the data was retrospectively analyzed to determine if the introduction of gender-specific cut off values could improve screening results. The obtained receiver operator curves are indeed significantly different when gender specific cut-offs were used. When a NPV of 95% is considered acceptable the unisex cut-off value of >200bacteria/MUl can be used for women (NPV 94.9%), but the cut-off value for men could be raised to >400bacteria/MUl without diminishing the NPV (NPV 95.0%). PMID- 26616732 TI - The Joint Committee for Traceability in Laboratory Medicine (JCTLM) - its history and operation. AB - The Joint Committee for Traceability in Laboratory Medicine (JCTLM) was formed to bring together the sciences of metrology, laboratory medicine and laboratory quality management. The aim of this collaboration is to support worldwide comparability and equivalence of measurement results in clinical laboratories for the purpose of improving healthcare. The JCTLM has its origins in the activities of international metrology treaty organizations, professional societies and federations devoted to improving measurement quality in physical, chemical and medical sciences. The three founding organizations, the International Committee for Weights and Measures (CIPM), the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and the International Laboratory Accreditation Cooperation (ILAC) are the leaders of this activity. The main service of the JCTLM is a web-based database with a list of reference materials, reference methods and reference measurement services meeting appropriate international standards. This database allows manufacturers to select references for assay traceability and provides support for suppliers of these services. As of mid 2015 the database lists 295 reference materials for 162 analytes, 170 reference measurement procedures for 79 analytes and 130 reference measurement services for 39 analytes. There remains a need for the development and implementation of metrological traceability in many areas of laboratory medicine and the JCTLM will continue to promote these activities into the future. PMID- 26616733 TI - Assessing hazardous risks of indoor airborne polycyclic aromatic hydrocarbons in the kitchen and its association with lung functions and urinary PAH metabolites in kitchen workers. AB - BACKGROUND: Indoor air pollution is associated with decreased pulmonary function but the relative impact of pollution from kitchen sources on health risks in kitchen workers is not well-known or studied. A study was conducted to measure the kitchen indoor air quality including PAHs estimation and risk assessment based on reported PAHs in indoor air in a central kitchen at North India. METHODS: A cross sectional study was undertaken to assess the lung function status using spirometer and urinary PAH metabolite measurements using GC-MS/MS among 94 male kitchen workers and their corresponding controls. Assessment of the indoor air quality levels was evaluated using standard methods. RESULTS: All the indoor air pollutants were within the recommended guidelines except CO, TVOC and PAH emission in the kitchen. Incremental life time cancer risk (ICLR) based on indoor air PAH measurements indicates potential for carcinogenic risk. Significant lung function decline was observed among kitchen workers as compared to controls after adjusting for smoking habits. Urinary PAH metabolites were detected in kitchen workers and measured concentrations were comparatively higher than control subjects. CONCLUSION: The decline in lung functions after adjustment for confounders and detection of urinary PAH metabolites in kitchen workers can be associated with higher concentrations of PAHs, CO and TVOCs in kitchen indoor air. PMID- 26616735 TI - Rethinking psychopharmacotherapy: The role of treatment context and brain plasticity in antidepressant and antipsychotic interventions. AB - Emerging evidence indicates that treatment context profoundly affects psychopharmacological interventions. We review the evidence for the interaction between drug application and the context in which the drug is given both in human and animal research. We found evidence for this interaction in the placebo response in clinical trials, in our evolving knowledge of pharmacological and environmental effects on neural plasticity, and in animal studies analyzing environmental influences on psychotropic drug effects. Experimental placebo research has revealed neurobiological trajectories of mechanisms such as patients' treatment expectations and prior treatment experiences. Animal research confirmed that "enriched environments" support positive drug effects, while unfavorable environments (low sensory stimulation, low rates of social contacts) can even reverse the intended treatment outcome. Finally we provide recommendations for context conditions under which psychotropic drugs should be applied. Drug action should be steered by positive expectations, physical activity, and helpful social and physical environmental stimulation. Future drug trials should focus on fully controlling and optimizing such drug*environment interactions to improve trial sensitivity and treatment outcome. PMID- 26616734 TI - p38- and MK2-dependent signalling promotes stress-induced centriolar satellite remodelling via 14-3-3-dependent sequestration of CEP131/AZI1. AB - Centriolar satellites (CS) are small granular structures that cluster in the vicinity of centrosomes. CS are highly susceptible to stress stimuli, triggering abrupt displacement of key CS factors. Here we discover a linear p38-MK2-14-3-3 signalling pathway that specifically targets CEP131 to trigger CS remodelling after cell stress. We identify CEP131 as a substrate of the p38 effector kinase MK2 and pinpoint S47 and S78 as critical MK2 phosphorylation sites in CEP131. Ultraviolet-induced phosphorylation of these residues generates direct binding sites for 14-3-3 proteins, which sequester CEP131 in the cytoplasm to block formation of new CS, thereby leading to rapid depletion of these structures. Mutating S47 and S78 in CEP131 is sufficient to abolish stress-induced CS reorganization, demonstrating that CEP131 is the key regulatory target of MK2 and 14-3-3 in these structures. Our findings reveal the molecular mechanism underlying dynamic CS remodelling to modulate centrosome functions on cell stress. PMID- 26616736 TI - Neurophysiology of action anticipation in athletes: A systematic review. AB - The purpose of this study was to provide a systematic review of action anticipation studies using functional neuroimaging or brain stimulation during a sport-specific anticipation task. A total of 15 studies from 2008 to 2014 were evaluated and are reported in four sections: expert-novice samples, action anticipation tasks, neuroimaging and stimulation techniques, and key findings. Investigators examined a wide range of action anticipation scenarios specific to eight different sports and utilized functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), and transcranial magnetic stimulation (TMS). Expert novice comparisons were commonly used to investigate differences in action anticipation performance and neurophysiology. Experts tended to outperform novices, and an extensive array of brain structures were reported to be involved differently for experts and novices during action anticipation. However, these neurophysiological findings were generally inconsistent across the studies reviewed. The discussion focuses on strengths and four key limitations. The conclusion posits remaining questions and recommendations for future research. PMID- 26616737 TI - Updates from the Neuro-Oncology Section of the 2015 American Neurological Association Annual Meeting. AB - American Neurological Association Annual Meeting, Chicago, IL, USA, 27-29 September 2015 The American Neurological Association (ANA) held its annual meeting in Chicago, IL, USA on 27-29 September 2015. The Scientific Programming Advisory Committee was chaired by Dr. S Pleasure from the University of California-San Francisco (CA, USA). The Neuro-Oncology session, chaired by Dr. A Pruitt from the University of Pennsylvania (PA, USA) and cochaired by Dr. J Laterra from Johns Hopkins University (MD, USA), was held on 27 September 2015. Speakers included Dr. D Wainwright (Northwestern University, IL, USA), Dr. N Kolb (University of Utah, UT, USA), Dr. A Nath (NINDS/NIH, MD, USA), Dr. D Franz (Cincinnati Children's Hospital, OH, USA) and Dr. R Lukas (University of Chicago, IL, USA). A summary of key presentations from the Neuro-Oncology section of the 2015 American Neurological Association annual meeting is reported. Preclinical and clinical advances in the use of immunotherapies for the treatment of primary and metastatic CNS tumors are covered. Particular attention is paid to the enzyme indoleamine dioxygenase and the immune checkpoints CTLA4 and PD1 and their ligands. Specific nervous system toxicities associated with novel immunotherapies are also discussed. The recent success of targeting the mTOR pathway in the neurocutaneous syndrome tuberous sclerosis is detailed. Finally, important early steps in our understanding of the common toxicity of chemotherapy induced neuropathy are reviewed. PMID- 26616739 TI - Fatherhood in a New Country: A Qualitative Study Exploring the Experiences of Afghan Men and Implications for Health Services. AB - BACKGROUND: Fathers of refugee background are dealing with multiple, interrelated stressors associated with forced migration and establishing their lives in a new country. This has implications for the role of men in promoting the health and well-being of their families. METHODS: Afghan community researchers conducted interviews with 30 Afghan women and men who had recently had a baby in Australia. Interviews and focus groups were conducted with health professionals working with families of refugee background. RESULTS: Fourteen men, 16 women, and 34 health professionals participated. Afghan men reported playing a major role in supporting their wives during pregnancy and postnatal care, accompanying their wives to appointments, and providing language and transport support. Although men embraced these roles, they were rarely asked by health professionals about their own concerns related to their wife's pregnancy, or about their social circumstances. Perinatal health professionals queried whether it was their role to meet the needs of men. CONCLUSION: There are many challenges for families of refugee background navigating maternity services while dealing with the challenges of settlement. There is a need to move beyond a narrow conceptualization of antenatal and postnatal care to encompass a broader preventive and primary care approach to supporting refugee families through the period of pregnancy and early years of parenting. Pregnancy and postnatal care needs to be tailored to the social and psychological needs of families of refugee background, including men, and incorporate appropriate language support, in order to improve child and family health outcomes. PMID- 26616740 TI - Efficacy of a Juncus effusus extract on grapevine and apple plants against Plasmopara viticola and Venturia inaequalis, and identification of the major active constituent. AB - BACKGROUND: There is growing demand to replace chemical pesticides with alternatives owing to concerns related to impacts on human health and the environment. Plant-derived plant protection products could provide sustainable and environmentally friendly alternatives to chemical products. The aim of this study was to identify plant and fungal extracts with so far unknown activity against important plant pathogens by in vitro screening of a library of more than 3000 extracts. RESULTS: Several plant extracts with promising in vitro fungicidal activity (MIC100 <= 50 ug mL(-1) ) towards one or several of the investigated pathogens (Venturia ineaqualis, Phytophthora infestans, Plasmopara viticola) were identified by the screening. One of the hits, an ethyl acetate extract of Juncus effusus L. medulla, was further investigated, and dehydroeffusol (DHEF) was identified as its main active constituent. On susceptible grapevine and apple seedlings, efficacies of up to 100% were reached with the extract (EC50 123 or 156 ug mL(-1) ) and with DHEF (EC50 18 or 21 ug mL(-1) ) against P. viticola and V. inaequalis respectively. CONCLUSIONS: Our results demonstrate that plants can provide promising alternatives for integrated and organic farming. J. effusus shows high efficacy at low concentrations and, as an abundant perennial species, is an interesting candidate for the development of a novel plant protection product. (c) 2015 Society of Chemical Industry. PMID- 26616741 TI - Possible interstellar formation of glycine from the reaction of CH2=NH, CO and H2O: catalysis by extra water molecules through the hydrogen relay transport. AB - "How the fundamental life elements are created in the interstellar medium (ISM)?" is one of the intriguing questions related to the genesis of life. Using computational calculations, we have discussed the reaction of CH2=NH, CO and H2O for the formation of glycine, the simplest life element. This reaction proceeds through a concerted mechanism with reasonably large barriers for the cases with one and two water molecules as reactants. For the two water case we found that the extra water molecule exhibits some catalytic role through the hydrogen transport relay effect and the barrier height is reduced substantially compared to the case with one water molecule. These two cases can be treated as ideal cases for the hot-core formation of the interstellar glycine. With an increasing number of water molecules as the reactants, we found that when the numbers of water molecules are three or more than three, the barrier height reduced so drastically that the transition states were more stable than the reactants. Such a situation gives a clear indication that with excess water molecules as the reactants, this reaction will be feasible even under the low temperature conditions existing in the cold interstellar clouds and the exothermic nature of the reaction will be the driving force. PMID- 26616738 TI - Conjunctival fibrosis and the innate barriers to Chlamydia trachomatis intracellular infection: a genome wide association study. AB - Chlamydia trachomatis causes both trachoma and sexually transmitted infections. These diseases have similar pathology and potentially similar genetic predisposing factors. We aimed to identify polymorphisms and pathways associated with pathological sequelae of ocular Chlamydia trachomatis infections in The Gambia. We report a discovery phase genome-wide association study (GWAS) of scarring trachoma (1090 cases, 1531 controls) that identified 27 SNPs with strong, but not genome-wide significant, association with disease (5 * 10(-6) > P > 5 * 10(-8)). The most strongly associated SNP (rs111513399, P = 5.38 * 10(-7)) fell within a gene (PREX2) with homology to factors known to facilitate chlamydial entry to the host cell. Pathway analysis of GWAS data was significantly enriched for mitotic cell cycle processes (P = 0.001), the immune response (P = 0.00001) and for multiple cell surface receptor signalling pathways. New analyses of published transcriptome data sets from Gambia, Tanzania and Ethiopia also revealed that the same cell cycle and immune response pathways were enriched at the transcriptional level in various disease states. Although unconfirmed, the data suggest that genetic associations with chlamydial scarring disease may be focussed on processes relating to the immune response, the host cell cycle and cell surface receptor signalling. PMID- 26616742 TI - Genotype-Directed Dosing Leads to Optimized Voriconazole Levels in Pediatric Patients Receiving Hematopoietic Stem Cell Transplantation. AB - Invasive fungal infections are a significant cause of morbidity and mortality in recipients of hematopoietic stem cell transplantation (HSCT), warranting antifungal prophylaxis as a standard of care in these patients. Voriconazole is commonly used in this setting because of its broad-spectrum activity and available dosage forms. There is wide well-known inter- and intrapatient variability in voriconazole concentrations, in part because concentrations are affected by common CYP2C19 polymorphisms. In 2 successive studies we have optimized voriconazole dosing to achieve target voriconazole serum concentrations using a genotype-specific dosing algorithm for antifungal prophylaxis in the post HSCT period. In our pilot study all patients undergoing HSCT who received voriconazole antifungal prophylaxis were prospectively followed. Voriconazole concentrations were monitored weekly and doses adjusted until concentrations reached between 1 and 5.5 MUg/L. The most common CYP2C19 polymorphisms were determined and correlated with voriconazole dose and time required to reach the target concentration range. In the subsequent study patients receiving voriconazole prophylaxis were dosed based on their CYP2C19 genotype and followed prospectively. In the pilot study 25 patients received voriconazole as antifungal prophylaxis for a median of 49 days (range, 15 to 196 days). The median time to reach the target concentration was 34 days for extensive metabolizers and 11 days for poor metabolizers. Three patients were genotyped as intermediate metabolizers; they reached the target concentration in a median of 56 days. Similarly, 2 patients who were genotyped as ultrarapid metabolizers reached the target range in 18 and 25 days. The time and dose required to reach the adequate concentration showed a trend toward correlation with individual CYP2C19 genotype, although voriconazole concentrations showed large interpatient variability in wild-type patients (extensive metabolizers). In our follow-up study, 20 patients received voriconazole prophylaxis prospectively dosed based on their CYP2C19 genotype. The median times to reach the target concentration using genotype guided dosing were 9, 6.5, and 4 days for ultrarapid, extensive, and intermediate metabolizers, respectively. Overall, the median time to reach the target concentration with genotype-guided dosing was 6.5 days compared with a median time of 29 days when all patients were started on the same dose regardless of CYP2C19 genotype (P < .001). Our data show that traditional voriconazole dosing does not lead to timely achievement of target levels for fungal prophylaxis. However, a genotype-directed dosing algorithm allows patients to reach the voriconazole target range significantly sooner, providing better prophylaxis against fungal infections in the immediate post-transplant period. PMID- 26616743 TI - Silicon- and Tin-Containing Open-Chain and Eight-Membered-Ring Compounds as Bicentric Lewis Acids toward Anions. AB - Herein, we report the syntheses of silicon- and tin-containing open-chain and eight-membered-ring compounds Me2 Si(CH2 SnMe2 X)2 (2, X=Me; 3, X=Cl; 4, X=F), CH2 (SnMe2 CH2 I)2 (7), CH2 (SnMe2 CH2 Cl)2 (8), cyclo-Me2 Sn(CH2 SnMe2 CH2 )2 SiMe2 (6), cyclo-(Me2 SnCH2 )4 (9), cyclo-Me(2-n) Xn Sn(CH2 SiMe2 CH2 )2 SnXn Me(2-n) (5, n=0; 10, n=1, X=Cl; 11, n=1, X=F; 12, n=2, X=Cl), and the chloride and fluoride complexes NEt4 [cyclo- Me(Cl)Sn(CH2 SiMe2 CH2 )2 Sn(Cl)Me?F] (13), PPh4 [cyclo-Me(Cl)Sn(CH2 SiMe2 CH2 )2 Sn(Cl)Me?Cl] (14), NEt4 [cyclo-Me(F)Sn(CH2 SiMe2 CH2 )2 Sn(F)Me?F] (15), [NEt4 ]2 [cyclo-Cl2 Sn(CH2 SiMe2 CH2 )2 SnCl2 ?2 Cl] (16), M[Me2 Si(CH2 Sn(Cl)Me2 )2 ?Cl] (17 a, M=PPh4 ; 17 b, M=NEt4 ), NEt4 [Me2 Si(CH2 Sn(Cl)Me2 )2 ?F] (18), NEt4 [Me2 Si(CH2 Sn(F)Me2 )2 ?F] (19), and PPh4 [Me2 Si(CH2 Sn(Cl)Me2 )2 ?Br] (20). The compounds were characterised by electrospray mass-spectrometric, IR and (1) H, (13) C, (19) F, (29) Si, and (119) Sn NMR spectroscopic analysis, and, except for 15 and 18, single-crystal X-ray diffraction studies. PMID- 26616744 TI - Distribution, sources and ecological risk assessment of PAHs in surface sediments from the Luan River Estuary, China. AB - The distribution, sources and risk assessment of 16 polycyclic aromatic hydrocarbons (PAHs) of surface sediments in the Luan River Estuary, China, have been investigated in the research. The results indicated that the total concentrations of 16 PAHs in surface sediments of the Luan River Estuary ranged from 5.1 to 545.1 ng g(-1)dw with a mean value of 120.8 ng g(-1)dw, which is relatively low in comparison with other estuaries around the world. The PAHs in the study area were mainly originated from pyrogenic sources. Besides, PAHs may be contaminated by petrogenic PAHs as indicated by the selected ratios of PAHs, the 2-tailed Pearson correlation analysis and principal components analysis at different sites. The result of the ecological risk assessment shows little negative effect for most individual PAHs in surface sediments of the Luan River Estuary, China. PMID- 26616745 TI - Anthropogenic waste indicators (AWIs), particularly PAHs and LABs, in Malaysian sediments: Application of aquatic environment for identifying anthropogenic pollution. AB - Polycyclic aromatic hydrocarbons (PAHs) and linear alkylbenzenes (LABs) were used as anthropogenic markers of organic chemical pollution of sediments in the Selangor River, Peninsular Malaysia. This study was conducted on sediment samples from the beginning of the estuary to the upstream river during dry and rainy seasons. The concentrations of ?PAHs and ?LABs ranged from 203 to 964 and from 23 to 113 ng g(-1) dry weight (dw), respectively. In particular, the Selangor River was found to have higher sedimentary levels of PAHs and LABs during the wet season than in the dry season, which was primarily associated with the intensity of domestic wastewater discharge and high amounts of urban runoff washing the pollutants from the surrounding area. The concentrations of the toxic contaminants were determined according to the Sediment Quality Guidelines (SQGs). The PAH levels in the Selangor River did not exceed the SQGs, for example, the effects range low (ERL) value, indicating that they cannot exert adverse biological effects. PMID- 26616746 TI - A metabolomic study on the biological effects of metal pollutions in oysters Crassostrea sikamea. AB - Metal pollution has become a great threat to organisms in the estuaries in South China. In the present study, the oysters Crassostrea sikamea were collected from one clean (Jiuzhen) and five metal polluted sites (Baijiao, Fugong, Gongqian, Jinshan and Songyu). The tissue metal concentrations in oysters indicated that the five metal sites were polluted by several metals, including Cr, Ni, Co, Cu, Zn, Ag, Cd and Pb with different patterns. Especially, Cu and Zn were the major contaminants in Baijiao, Fugong and Jinshan sites. The metabolic responses in oysters C. sikamea indicated that the metal pollutions in BJ, FG, JS and SY sites induced disturbances in osmotic regulation and energy metabolism via different metabolic pathways. However, the metal pollution in GQ site mainly influenced the osmotic regulation in the oysters C. sikamea. This study demonstrates that NMR based metabolomics is useful to characterize metabolic responses induced by metal pollution. PMID- 26616747 TI - Nanosized IrO(x)-Ir Catalyst with Relevant Activity for Anodes of Proton Exchange Membrane Electrolysis Produced by a Cost-Effective Procedure. AB - We have developed a highly active nanostructured iridium catalyst for anodes of proton exchange membrane (PEM) electrolysis. Clusters of nanosized crystallites are obtained by reducing surfactant-stabilized IrCl3 in water-free conditions. The catalyst shows a five-fold higher activity towards oxygen evolution reaction (OER) than commercial Ir-black. The improved kinetics of the catalyst are reflected in the high performance of the PEM electrolyzer (1 mg(Ir) cm(-2)), showing an unparalleled low overpotential and negligible degradation. Our results demonstrate that this enhancement cannot be only attributed to increased surface area, but rather to the ligand effect and low coordinate sites resulting in a high turnover frequency (TOF). The catalyst developed herein sets a benchmark and a strategy for the development of ultra-low loading catalyst layers for PEM electrolysis. PMID- 26616748 TI - Secular trends in parent-reported television viewing among children in the United States, 2001-2012. AB - OBJECTIVE: Examine trends in parent-reported television (TV) viewing among preschoolers (2-5 years) and children (6-11 years) between 2001 and 2012. METHODS: Data from the 2001-2012 National Health and Nutrition Examination Survey (NHANES) were used. The analytic sample included 5724 preschoolers and 7104 children. Parent proxy of TV viewing at each of the six 2-year cycles was assessed. RESULTS: Statistically significant decreases in mean TV viewing between 2001 and 2012 were observed for preschoolers of nearly all gender, race-ethnicity and poverty combinations (exception of Mexican American boys), with the largest decrease occurring among non-Hispanic white boys (29% decrease; 2.24 h/day in 2001-2002 to 1.59 h/day in 2011-2012; P = .01). There was evidence of progressive decrease in mean TV viewing among children, but not to the extent that occurred among the preschool population. Across the six respective cycles for the entire preschool sample, the proportion watching <2 h/day of TV was: 34.9, 34.2, 43.9, 43.4, 39.1 and 49.2 (P(trend) < .001). For children, the respective proportions were: 32.9, 25.2, 38.2, 36.5, 38.1 and 36.6 (P(trend) = .01). CONCLUSIONS: Statistically significant decreases in mean TV viewing between 2001 and 2012 were observed for preschoolers and children. However, a relatively large proportion of parents report their children watching 2 or more hours/day of TV. PMID- 26616749 TI - Conceptual Basis for Understanding C-C Bond Activation in Ethane by Second Row Transition Metal Carbides. AB - It has been suggested that the addition of carbon to Mo and W may improve their catalytic properties and even grant these metal carbides behaviors similar to those of late transition metals such as Pd and Pt. First-principles studies on the C-C bond activation of ethane by 4d transition metal (TM) atoms and TMC molecules have been carried out to develop a conceptual model underlying the changes. We find that the addition of carbon to TM atoms leads to large variations in the activation barrier depending on the metal, and that MoC indeed reveals a pronounced reduction in the C-C bond activation energy. A critical examination of molecular orbitals shows that the changes in reactivity are not linked to a dramatic increase in the filling of 4d states as implied by the analogy with Pd. The reactivity is governed by the location and filling of the 5s and 4d orbitals, with the different orbitals controlling different facets of reactivity. The 5s state controls the initial binding of ethane, with a strong anticorrelation between the ethane binding energy and the 5s occupation, while the location of the 4dz(2) orbital controls the reaction barrier that controls the activation energy for cleaving the C-C bond. PMID- 26616750 TI - Ecology and physiology of anaerobic ammonium oxidizing bacteria. AB - Anaerobic ammonium oxidation (anammox) is a microbial process in which NH4 (+) is oxidized to N2 gas with NO2 (-) as an electron acceptor. The anammox process is mediated by bacterial members affiliated with the phylum Planctomycetes, which are ubiquitously detected from anoxic natural and man-made ecosystems and a key player in the global nitrogen cycle. In the past two decades, phylogenetically different anammox bacteria have been recognized in natural and synthetic ecosystems (i.e. 'Candidatus Kuenenia', 'Candidatus Brocadia', 'Candidatus Jettenia', 'Candidatus Anammoxoglobus' and 'Candidatus Scalindua' genera), and the geographic distributions of these anammox bacteria indicate that they have genus-specific or species-specific habitats. Recently, we revealed the physiological characteristics of 'Ca. Jettenia' in addition to 'Ca. Kuenenia', 'Ca. Brocadia' and 'Ca. Scalindua', and, as a result, it is possible to compare the physiological characteristics of the anammox bacteria and discuss their niche partitioning. Therefore, we summarize the current knowledge of anammox bacterial ecology and physiology in this review to assess the potential ecological niche partitioning of anammox bacteria in natural and synthetic ecosystems. PMID- 26616751 TI - Protection against renal ischemia-reperfusion injury through hormesis? Dietary intervention versus cold exposure. AB - AIM: Dietary restriction (DR) and fasting (FA) induce robust protection against the detrimental effects of renal ischemia-reperfusion injury (I/RI). Several mechanisms of protection have been proposed, such as hormesis. Hormesis is defined as a life-supporting beneficial effect resulting from the cellular responses to single or multiple rounds of (mild) stress. The cold exposure (CE) model is a stress model similar to DR, and has been shown to have hormetic effects and has proved to increase longevity. CE is considered to be the most robust method to increase metabolism through activation of brown adipocytes. BAT has been considered important in etiology of obesity and its metabolic consequences. MATERIALS AND METHODS: Since DR, FA, and CE models are proposed to work through hormesis, we investigated physiology of adipose tissue and effect on BAT in these models and compared them to ad libitum (AL) fed mice. We also studied the differential effect of these stress models on immunological changes, and effect of CE on renal I/RI. KEY FINDINGS: We show similar physiological changes in adiposity in male C57Bl/6 mice due to DR, FA and CE, but the CE mice were not protected against renal I/RI. The immunophenotypic changes observed in the CE mice were similar to the AL animals, in contrast to FA mice, that showed major immunophenotypic changes in the B and T cell development stages in primary and secondary lymphoid organs. SIGNIFICANCE: Our findings thus demonstrate that DR, FA and CE are hormetic stress models. DR and FA protect against renal I/IR, whereas CE could not. PMID- 26616752 TI - Roughness and microhardness of composites after different bleaching techniques. AB - BACKGROUND: The aim of this study was to evaluate the roughness and microhardness of SonicFillTM (Kerr), and compare it with FiltekTM Supreme XTE (3M ESPE) after 2 bleaching regimens. METHODS: Sixty cylindrical specimens (10 * 2 mm) of each of the 2 composites were prepared and divided into 6 groups (n = 20): groups 1, 2: no treatment; groups 3, 4: 10% carbamide peroxide (CP); and groups 5, 6: 35% hydrogen peroxide (HP) plus LED. After treatments, specimens were thermocycled (500 cycles, 5 degrees C/55 degrees C, dwell time 30 minutes). A mechanical roughness tester was employed to measure the surface roughness parameters and the Vickers test to measure microhardness. One-way ANOVA, Tukey and Bonferroni methods with a significance level of 5% were used for the statistical analysis. RESULTS: For SonicFillTM, there was no statistically significant difference in microhardness between the control group (no. 1) and the bleached groups (nos. 3, 5), but there was difference between CP and HP treatments; for FiltekTM Supreme XTE, there was no significant difference in microhardness among all groups. There was no significant difference in average roughness (Ra) and the root mean square of the roughness (Rq) among all groups. The mean roughness depth (Rz) parameter showed no statistically significant differences among all groups for SonicFillTM, but in FiltekTM Supreme XTE, there was a significant increase between control and bleaching treatments; roughness skewness (Rsk) showed no statistically significant differences among all groups for SonicFillTM and FiltekTM Supreme XTE, except for nos. 2 and 4, where the Rsk increased with CP. CONCLUSIONS: The microhardness of FiltekTM Supreme XTE is less affected by bleaching than that of SonicFillTM. Both bleaching treatments affect Rz in FiltekTM Supreme XTE in contrast to SonicFillTM, but only the CP treatment affects the Rsk of FiltekTM Supreme XTE, with no significant effect of SonicFillTM. PMID- 26616753 TI - Penetration of titanium dioxide nanoparticles through slightly damaged skin in vitro and in vivo. AB - PURPOSE: Titanium dioxide nanoparticles (TiO2-NPs) have been widely developed for versatile use, but the potential risk form their skin exposure is still unclear. To evaluate this risk, the skin penetration of TiO2-NPs is necessary to be understood first. The aims of this study are to investigated the penetration of TiO2-NPs through slightly damaged skin and intact skin in vitro and in vivo. METHODS: TiO2-NPs with a diameter of 20 nm was labeled with 125I.The skin of rat was treated with 2% SLS solution and obtained as slightly damaged skin. The 125I labeled TiO2-NPs (125I-TiO2-NPs)solution and 0.9% PS solution were added into the donor chamber and receptor chamber of static diffusion cells which clamped the skin at the middle of two half-cells, respectively. During 24 hours, samples were extracted from the receptor chamber and counted for 1 min using gamma-counter to detect the radioactivity. The skin penetration of TiO2-NPs in vitro was expressed as the percentage of radioactivity of receptor chamber solution compared with total radioactivity in the donor chamber. Thereafter, the 125I-TiO2-NPs was exposed to the rats. After 1 day and 3 days, the blood and tissues of rats were harvested, weighed and counted for 1 min using gamma-counter to detect the tissue radioactivity. The skin penetration of TiO2-NPs in vivo was expressed as the percentage dose per gram tissue (% dose/g). RESULTS: In the skin penetration experiment in vitro, the radioactivity of receptor chamber solution through damaged skin was higher than that of through intact skin and was about 2% radioactivity of donor chamber on 24 h. In the skin penetration experiment in vivo, the radioactivity of blood and tissues of rats after exposing to 125I-TiO2 NPs solution though damaged skin or intact skin were less than 0.05% dose/g on 1 d and quickly declined on 3 d. The skin penetration rates of TiO2-NPs through slightly damaged skin and intact skin in vitro and vivo were lower than the rate of free 125I in the TiO2-NPs solution. CONCLUSIONS: The TiO2-NPs could not penetrate through the damaged skin or intact skin both in vitro and in vivo. It suggested that the TiO2-NPs should be safe when it was applied and contacted with skin. PMID- 26616754 TI - Development of a microscale red blood cell-shaped pectin-oligochitosan hydrogel system using an electrospray-vibration method: preparation and characterization. AB - PURPOSE: To develop and characterize a microscale pectin-oligochitosan hydrogel microcapsule system that could be applied in such biological fields as drug delivery, cell immobilization/encapsulation, and tissue engineering. METHODS: Microscale pectin-oligochitosan hydrogel microcapsules were prepared by using the vibration/electrostatic spray method. The morphology and chemistry of the hydrogel microcapsules were characterized by using scanning electron microscope (SEM) and Fourier Transform Infrared Spectroscopy (FTIR), respectively. The designed hydrogel microcapsule system was then used to study the responsiveness of the microcapsules to different simulated human body fluids as well as cell encapsulation. RESULTS: The designed hydrogel microcapsule system exhibited a large surface area-to-volume ratio (red blood cell-shaped) and great pH/enzymatic responsiveness. In addition, this system showed the potential for controlled drug delivery and three-dimensional cell culture. CONCLUSION: This system showed a significant potential not only for bioactive-agent delivery, especially to the lower gastrointestinal (GI) tract, but also as a three-dimensional niche for cell culture. In particular, the hydrogel microcapsule system could be used to create artificial red-blood-cells as well as blood substitutes. PMID- 26616755 TI - Does insect mother know under what conditions it will make their offspring live? AB - According to the optimal oviposition theory, the larval success of insects depends on the oviposition site selection by females. Females are expected to choose a site with many resources and few competitors or predators to allow the best performance for their progeny, assuming that "mother knows best." However, this is not systematically observed. The Aphidoletes aphidimyza larvae are generalist aphid predators and females consequently lay their eggs near or inside aphid colonies. The goal of this study was to investigate the impact of intraspecific competition on oviposition behavior of A. aphidimyza females. First, we counted the number of eggs laid by a female on a leaf with 20 aphids, in the presence of 0, 2, 4, or 6 conspecific eggs or in the absence of eggs but in presence of 3 virgin females. The same experiment was also performed under choice condition with 2 oviposition sites. Our results show that the presence of low densities of conspecific eggs, or the presence of conspecific females, have no significant impact on the number of eggs laid by A. aphidimyza females. One of the hypotheses advanced to explain these results is the advantages of conspecifics presence. At low densities, the presence of eggs on an oviposition site can indicate the suitability of the site for the females. The conspecific presence can also insure a dilution effect against predator and increase the presence of potential mating partners for this monogenic species. PMID- 26616756 TI - Chromatin modification and NBS1: their relationship in DNA double-strand break repair. AB - The importance of chromatin modification, including histone modification and chromatin remodeling, for DNA double-strand break (DSB) repair, as well as transcription and replication, has been elucidated. Phosphorylation of H2AX to gamma-H2AX is one of the first responses following DSB detection, and this histone modification is important for the DSB damage response by triggering several events, including the accumulation of DNA damage response-related proteins and subsequent homologous recombination (HR) repair. The roles of other histone modifications such as acetylation, methylation and ubiquitination have also been recently clarified, particularly in the context of HR repair. NBS1 is a multifunctional protein that is involved in various DNA damage responses. Its recently identified binding partner RNF20 is an E3 ubiquitin ligase that facilitates the monoubiquitination of histone H2B, a process that is crucial for recruitment of the chromatin remodeler SNF2h to DSB damage sites. Evidence suggests that SNF2h functions in HR repair, probably through regulation of end resection. Moreover, several recent reports have indicated that SNF2h can function in HR repair pathways as a histone remodeler and that other known histone remodelers can also participate in DSB damage responses. On the other hand, information about the roles of such chromatin modifications and NBS1 in non homologous end joining (NHEJ) repair of DSBs and stalled fork-related damage responses is very limited; therefore, these aspects and processes need to be further studied to advance our understanding of the mechanisms and molecular players involved. PMID- 26616757 TI - Recent progress in research on DNA damage responses in animals and plants. PMID- 26616758 TI - The distinctive cellular responses to DNA strand breaks caused by a DNA topoisomerase I poison in conjunction with DNA replication and RNA transcription. AB - Camptothecin (CPT) inhibits DNA topoisomerase I (Top1) through a non-catalytic mechanism that stabilizes the Top1-DNA cleavage complex (Top1cc) and blocks the DNA re-ligation step, resulting in the accumulation in the genome of DNA single strand breaks (SSBs), which are converted to secondary strand breaks when they collide with the DNA replication and RNA transcription machinery. DNA strand breaks mediated by replication, which have one DNA end, are distinct in repair from the DNA double-strand breaks (DSBs) that have two ends and are caused by ionizing radiation and other agents. In contrast to two-ended DSBs, such one ended DSBs are preferentially repaired through the homologous recombination pathway. Conversely, the repair of one-ended DSBs by the non-homologous end joining pathway is harmful for cells and leads to cell death. The choice of repair pathway has a crucial impact on cell fate and influences the efficacy of anticancer drugs such as CPT derivatives. In addition to replication-mediated one ended DSBs, transcription also generates DNA strand breaks upon collision with the Top1cc. Some reports suggest that transcription-mediated DNA strand breaks correlate with neurodegenerative diseases. However, the details of the repair mechanisms of, and cellular responses to, transcription-mediated DNA strand breaks still remain unclear. In this review, combining our recent results and those of previous reports, we introduce and discuss the responses to CPT-induced DNA damage mediated by DNA replication and RNA transcription. PMID- 26616759 TI - Homoeologous copy-specific expression patterns of MADS-box genes for floral formation in allopolyploid wheat. AB - The consensus model for floral organ formation in higher plants, the so-called ABCDE model, proposes that floral whorl-specific combinations of class A, B, C, D, and E genes specify floral organ identity. Class A, B, C, D and E genes encode MADS-box transcription factors; the single exception being the class A gene APETALA2. Bread wheat (Triticum aestivum) is a hexaploid species with a genome constitution AABBDD; the hexaploid originated from a cross between tetraploid T. turgidum (AABB) and diploid Aegilops tauschii (DD). Tetraploid wheat is thought to have originated from a cross between the diploid species T. urartu (AA) and Ae. speltoides (BB). Consequently, the hexaploid wheat genome contains triplicated homoeologous copies (homoeologs) of each gene derived from the different ancestral diploid species. In this study, we examined the expression patterns of homoeologs of class B, C and D MADS-box genes during floral development. For the class B gene wheat PISTILLATA2 (WPI2), the homoeologs from the A and D genomes were expressed, while expression of the B genome homoeolog was suppressed. For the class C gene wheat AGAMOUS1 (WAG1), the homoeologs on the A and B genomes were expressed, while expression of the D genome homoeolog was suppressed. For the class D gene wheat SEEDSTICK (WSTK), the B genome homoeolog was preferentially expressed. These differential patterns of homoeolog expression were consistently observed among different hexaploid wheat varieties and synthetic hexaploid wheat lines developed by artificial crosses between tetraploid wheat and Ae. tauschii. These results suggest that homoeolog-specific regulation of the floral MADS-box genes occurs in allopolyploid wheat. PMID- 26616760 TI - Increased local delivery of antagomir therapeutics to the rodent myocardium using ultrasound and microbubbles. AB - Recent developments in microRNA (miRNA) research have identified these as important mediators in the pathophysiological response upon myocardial infarction (MI). Specific miRNAs can inhibit the translation of entire groups of mRNAs, which are involved in specific processes in the pathophysiology after MI, e.g. the fibrotic, apoptotic or angiogenic response. By modulating miRNAs in the heart, these processes can be tuned to improve cardiac function. Antagomirs are effective miRNA-inhibitors, but have a low myocardial specificity and cardiac antagomir treatment therefore requires high doses, which causes side effects. In the present study, ultrasound-triggered microbubble destruction (UTMD) was studied to increase specific delivery of antagomir to the myocardium. Healthy control mice were treated with UTMD and sacrificed at 30min, 24h and 48h, after which antagomir delivery in the heart was analyzed, both qualitatively and quantitatively. Additionally, potential harmful effects of treatment were analyzed by monitoring ECG, analyzing neutrophil invasion and cell death in the heart, and measuring troponin I after treatment. Finally, UTMD was tested for delivery of antagomir in a model of ischemia-reperfusion (I/R) injury. We found that UTMD can significantly increase local antagomir delivery to the non-ischemic heart with modest side-effects like neutrophil invasion without causing apoptosis. Delivered antagomirs enter cardiomyocytes within 30min after treatment and remains there for at least 48h. Interestingly, after I/R injury antagomir already readily enters the infarcted zone and we observed no additional benefit of UTMD for antagomir delivery. This study is the first to explore cardiac antagomir delivery using UTMD. In addition, it is the first to study tissue distribution of short RNA based therapeutics (~22 base pairs) at both the cellular and organ levels after UTMD to the heart in general. In summary, UTMD provides a myocardial delivery strategy for non-vascular permeable cardiac conditions later in the I/R response or chronic conditions like cardiac hypertrophy. PMID- 26616762 TI - Second-Nearest-Neighbor Correlations from Connection of Atomic Packing Motifs in Metallic Glasses and Liquids. AB - Using molecular dynamics simulations, we have studied the atomic correlations characterizing the second peak in the radial distribution function (RDF) of metallic glasses and liquids. The analysis was conducted from the perspective of different connection schemes of atomic packing motifs, based on the number of shared atoms between two linked coordination polyhedra. The results demonstrate that the cluster connections by face-sharing, specifically with three common atoms, are most favored when transitioning from the liquid to glassy state, and exhibit the stiffest elastic response during shear deformation. These properties of the connections and the resultant atomic correlations are generally the same for different types of packing motifs in different alloys. Splitting of the second RDF peak was observed for the inherent structure of the equilibrium liquid, originating solely from cluster connections; this trait can then be inherited in the metallic glass formed via subsequent quenching of the parent liquid through the glass transition, in the absence of any additional type of local structural order. Increasing ordering and cluster connection during cooling, however, may tune the position and intensity of the split peaks. PMID- 26616761 TI - pH-responsive and enzymatically-responsive hydrogel microparticles for the oral delivery of therapeutic proteins: Effects of protein size, crosslinking density, and hydrogel degradation on protein delivery. AB - Two potential platform technologies for the oral delivery of protein therapeutics were synthesized and tested. pH-responsive poly(itaconic acid-co-N-vinyl-2 pyrrolidone) (P(IA-co-NVP)) hydrogel microparticles were tested in vitro with model proteins salmon calcitonin, urokinase, and rituximab to determine the effects of particle size, protein size, and crosslinking density on oral delivery capability. Particle size showed no significant effect on overall delivery potential but did improve percent release of encapsulated protein over the micro scale particle size range studied. Protein size was shown to have a significant impact on the delivery capability of the P(IA-co-NVP) hydrogel. We show that when using P(IA-co-NVP) hydrogel microparticles with 3 mol% tetra(ethylene glycol) dimethacrylate crosslinker, a small polypeptide (salmon calcitonin) loads and releases up to 45 MUg/mg hydrogel while the mid-sized protein urokinase and large monoclonal antibody rituximab load and release only 19 and 24 MUg/mg hydrogel, respectively. We further demonstrate that crosslinking density offers a simple method for tuning hydrogel properties to variously sized proteins. Using 5 mol% TEGDMA crosslinker offers optimal performance for the small peptide, salmon calcitonin, whereas lower crosslinking density of 1 mol% offers optimal performance for the much larger protein rituximab. Finally, an enzymatically degradable hydrogels of P(MAA-co-NVP) crosslinked with the peptide sequence MMRRRKK were synthesized and tested in simulated gastric and intestinal conditions. These hydrogels offer ideal loading and release behavior, showing no degradative release of encapsulated salmon calcitonin in gastric conditions while yielding rapid and complete release of encapsulated protein within 1h in intestinal conditions. PMID- 26616763 TI - Same same but different: analyzing hyperkinetic movement disorders. PMID- 26616764 TI - A comparison of calisthenic and cycle exercise training in chronic obstructive pulmonary disease patients: a randomized controlled trial. AB - AIM: To compare the effects of calisthenic and cycle exercises with no exercise in chronic obstructive pulmonary disease patients. METHOD: Forty-seven participants were allocated to either a cycle or calisthenic exercise or control group. Outcome measures, including Saint George Respiratory Questionnaire, pulmonary functions, cardiopulmonary exercise testing, Fitness Testing, and Hospital Anxiety-Depression, Modified Medical Research Council Dyspnea, Fatigue Severity, Fatigue Impact Scales, were performed before and after the intervention. RESULTS: The change in VE/VCO2 significantly differed (p = 0.01) between two exercise groups. Physical fitness, quality of life, anxiety depression, dyspnea and fatigue changed significantly in exercise groups, with no between-group differences. There were no significant improvements in control group. CONCLUSION: Calisthenics are as safe and effective as cycle exercise and could be included in comprehensive treatment programs. PMID- 26616765 TI - Structural Dynamics of Thrombin-Binding DNA Aptamer d(GGTTGGTGTGGTTGG) Quadruplex DNA Studied by Large-Scale Explicit Solvent Simulations. AB - The thrombin-binding aptamer (15-TBA) is a 15-mer DNA oligonucleotide with sequence d(GGTTGGTGTGGTTGG). 15-TBA folds into a quadruplex DNA (G-DNA) structure with two planar G-quartets connected by three single-stranded loops. The arrangement of the 15-TBA-thrombin complex is unclear, particularly with respect to the precise 15-TBA residues that interact with the thrombin structure. Our present understanding suggests either the 15-TBA single stranded loops containing sequential thymidines (TT) or alternatively a single-stranded loop, containing a guanine flanked by 2 thymidines (TGT), physically associates with thrombin protein. In the present study, the explicit solvent molecular dynamics (MD) simulation method was utilized to further analyze the 15-TBA-thrombin three dimensional structure. Functional annotation of the loop residues was made with long simulations in the parmbsc0 force field. In total, the elapsed time of simulations carried out in this study exceeds 12 microseconds, substantially surpassing previous G-DNA simulation reports. Our simulations suggest that the TGT-loop function is to stabilize the structure of the aptamer, while the TT loops participate in direct binding to thrombin. The findings of the present report advance our understanding of the molecular structure of the 15-TBA thrombin structure further enabling the construction of biosensors for aptamer bases and the development of anticoagulant agents. PMID- 26616766 TI - Direct Dynamics Implementation of the Least-Action Tunneling Transmission Coefficient. Application to the CH4/CD3H/CD4 + CF3 Abstraction Reactions. AB - We present two new direct dynamics algorithms for calculating transmission coefficients of polyatomic chemical reactions by the multidimensional least action tunneling approximation. The new algorithms are called the interpolated least-action tunneling method based on one-dimensional interpolation (ILAT1D) and the double interpolated least-action tunneling (DILAT) method. The DILAT algorithm, which uses a one-dimensional spline under tension to interpolate both of the effective potentials along the nonadiabatic portions of tunneling paths and the imaginary action integrals as functions of tunneling energies, was designed for the calculation of multidimensional LAT transmission coefficients for very large polyatomic systems. The performance of this algorithm has been tested for the CH4/CD3H/CD4 + CF3 hydrogen abstraction reactions with encouraging results, i.e., when the fitting is performed using 13 points, the algorithm is about 30 times faster than the full calculation with deviations that are smaller than 5%. This makes direct dynamics least-action tunneling calculations practical for larger systems, higher levels of electron correlation, and/or larger basis sets. PMID- 26616767 TI - Adaptive Steered Molecular Dynamics of the Long-Distance Unfolding of Neuropeptide Y. AB - Neuropeptide Y (NPY) has been found to adopt two stable conformations in vivo: (1) a monomeric form called the PP-fold in which a polyproline tail is folded onto an alpha-helix via a beta-turn and (2) a dimeric form of the unfolded proteins in which the alpha-helices interact with each other via side chains. The transition pathway and rates between the two conformations remain unknown and are important to the nature of the binding of the protein. Toward addressing this question, the present work suggests that the unfolding of the PP-fold is too slow to play a role in NPY monomeric binding unless the receptor catalyzes it to do so. Specifically, the dynamics and structural changes of the unfolding of a monomeric NPY protein have been investigated in this work. Temperature accelerated molecular dynamics (MD) simulations at 500 K under constant (N,V,E) conditions suggests a hinge-like unraveling of the tail rather than a random unfolding. The free energetics of the proposed unfolding pathway have been described using an adaptive steered MD (SMD) approach at various temperatures. This approach generalizes the use of Jarzynski's equality through a series of stages that allows for better convergence along nonlinear and long-distance pathways. Results acquired using this approach provide a potential of mean force (PMF) with narrower error bars and are consistent with some of the earlier reports on the qualitative behavior of NPY binding. PMID- 26616768 TI - Efficient Multistate Reactive Molecular Dynamics Approach Based on Short-Range Effective Potentials. AB - Nonbonded interactions between molecules usually include the van der Waals force and computationally expensive long-range electrostatic interactions. This article develops a more efficient approach: the effective-interaction multistate empirical-valence-bond (EI-MS-EVB) model. The EI-MS-EVB method relies on a mapping of all interactions onto a short-range and thus, computationally efficient effective potential. The effective potential is tabulated by matching its force to known trajectories obtained from the full-potential empirical multistate empirical-valence-bond (MS-EVB) model. The effective pairwise interaction depends on and is uniquely determined by the atomic configuration of the system, varying only with respect to the hydrogen-bonding topology. By comparing the EI-MS-EVB and full MS-EVB calculations of several equilibrium and dynamic properties important to hydrated excess proton solvation and transport, we show that the EI-MS-EVB model produces very accurate results for the specific system in which the tabulated potentials were generated. The EI-MS-EVB potential also transfers reasonably well to similar systems with different temperatures and box sizes. The EI-MS-EVB method also reduces the computational cost of the nonbonded interactions by about 1 order of magnitude in comparison with the full algorithm. PMID- 26616769 TI - A Graphics Processing Unit Implementation of Coulomb Interaction in Molecular Dynamics. AB - We report a GPU implementation in HOOMD Blue of long-range electrostatic interactions based on the orientation-averaged Ewald sum scheme, introduced by Yakub and Ronchi (J. Chem. Phys. 2003, 119, 11556). The performance of the method is compared to an optimized CPU version of the traditional Ewald sum available in LAMMPS, in the molecular dynamics of electrolytes. Our GPU implementation is significantly faster than the CPU implementation of the Ewald method for small to a sizable number of particles (~10(5)). Thermodynamic and structural properties of monovalent and divalent hydrated salts in the bulk are calculated for a wide range of ionic concentrations. An excellent agreement between the two methods was found at the level of electrostatic energy, heat capacity, radial distribution functions, and integrated charge of the electrolytes. PMID- 26616770 TI - Lowest-Lying Conformers of Alanine: Pushing Theory to Ascertain Precise Energetics and Semiexperimental Re Structures. PMID- 26616771 TI - Antisymmetric Magnetic Interactions in Oxo-Bridged Copper(II) Bimetallic Systems. AB - The antisymmetric magnetic interaction is studied using correlated wave-function based calculations in oxo-bridged copper bimetallic complexes. All of the anisotropic multispin Hamiltonian parameters are extracted using spin-orbit state interaction and effective Hamiltonian theory. It is shown that the methodology is accurate enough to calculate the antisymmetric terms, while the small symmetric anisotropic interactions require more sophisticated calculations. The origin of the antisymmetric anisotropy is analyzed, and the effect of geometrical deformations is addressed. PMID- 26616772 TI - Asymmetry and Electronegativity in the Electron Capture Activation of the Se-Se Bond: sigma*(Se-Se) vs sigma*(Se-X). AB - The effects of electron capture on the structure of XSeSeX' diselenide derivatives in which the substituents attached to the selenium atoms have different electronegativities have been investigated at different levels of theory, namely, DFT, MP2, CCSD, G2, and CASSCF/CASPT2. An analysis of the bonding changes upon electron attachment shows that when the diselenides bear low electronegativity substituents, the Se-Se bond becomes activated upon electron capture, as previous studies have shown. However, this is no longer the case for very electronegative substituents, where this bond remains practically unaltered and is the Se-X bond the one which becomes strongly activated through a preferential population of the sigma*(Se-X) antibonding orbital rather than the sigma*(Se-Se) one. When this is the case, several anionic species are also encountered, namely, stretched, bent, and book structures. The present findings are similar to those obtained for a series of analogous disulfide compounds, which points out that these results are not unique and could be extrapolated to a wider range of compounds than the ones covered here. The Se-Se (Se-X) linkage in CH3SeSeOH, CH3SeSeF, FSeSeOH, and FSeSeF bears some of the characteristics of the so-called charge-shift bonds, with a clear charge fluctuation between both selenium atoms. This is more evident in their anions where the bonding reflects the important contribution of the ionic resonant forms Se-Se(-) <-> (-)Se-Se vs the covalent component Se?Se. This resonance changes with the nature of the substituents but also depends on the asymmetry of the substitution. PMID- 26616773 TI - Relativistic Effects on Metal-Metal Bonding: Comparison of the Performance of ECP and Scalar DKH Description on the Picture of Metal-Metal Bonding in Re2Cl8(2.). AB - This paper reports a systematic comparison of the performance of alternative methods of including relativistic effects on the nature of metal-metal bonding in the Re2Cl8(2-) anion. The comparison involved the description using a scalar relativistic Douglas-Kroll-Hess (DKH2) Hamiltonian with all-electron basis sets and the relativistic effective core potential (ECP) basis sets. The impact of the above methods on the picture of the bonding was analyzed using the so-called domain averaged Fermi holes (DAFH). Besides comparing the impact on the picture of the bonding of the two above methods, the focus was also put on the systematic comparison of the "exact" AIM generalized form of DAFH analysis with the approximate Mulliken-like approach used in an earlier DAFH study of ReRe bonding. It has been shown that in contrast to descriptions using ECP basis sets where the differences in the picture of the bonding emerging from the approximate and "exact" DAFH analysis are only marginal, the approximate DAFH approach has been found to dramatically fail in the case of all-electron basis sets required for the description in terms of the Douglas-Kroll-Hess (DKH2) Hamiltonian. PMID- 26616774 TI - Anharmonic Vibrational Analysis for the Propadienylidene Molecule (H2C?C?C:). AB - Maier et al. found that photolysis of singlet cyclopropenylidene (1S) in a matrix yields triplet propargylene (2T), which upon further irradiation is converted to singlet propadienylidene (vinylidenecarbene, 3S). Their discovery was followed by interstellar identification of 3S by Cernicharo et al. An accurate quartic force field for propadienylidene (3S) has been determined employing the ab initio coupled-cluster (CC) with single and double excitations and perturbative triple excitations [CCSD(T)] method and the correlation-consistent core-valence quadruple-zeta (cc-pCVQZ) basis set. Utilizing vibrational second-order perturbation theory (VPT2), vibration-rotation coupling constants, rotational constants, centrifugal distortion constants, vibrational anharmonic constants, and fundamental vibrational frequencies are determined. The predicted fundamental frequencies for 3S as well as its (13)C and deuterium isotopologues are in good agreement with experimental values. The theoretical zero-point vibration corrected rotational constants B0 are consistent with experimental values within 0.3% of errors. The isotopic shifts of B0 are in close to exact agreement with experimental observations. The mean absolute deviation between theoretical anharmonic and experimental fundamental vibrational frequencies for 24 modes (excluding CH2 s-str.) is only 2.6 cm(-1). The isotopic shifts of the vibrational frequencies are also in excellent agreement with the available experimental values. However, a large discrepancy is observed for the CH2 symmetric stretch, casting doubt on the experimental assignment for this mode. PMID- 26616775 TI - Charge Transfer Across ONIOM QM:QM Boundaries: The Impact of Model System Preparation. AB - The inability to describe charge redistribution from regions I to II at the high level of theory imposes limitations on the general applicability of the our own N layered integrated molecular orbital and molecular mechanics (ONIOM) method. In this report, we exploit the most inexpensive components of an ONIOM QM:QM calculation to provide a new method which has the ability to describe such charge transfer effects with only a nominal increase in computational effort. Central to this method is the model system preparation step, in which an one-electron potential is optimized to shift density into or out of a defined buffer region. In this initial effort, we treat the link atoms on the model subsystem as the electron buffer region and swell or diminish the link-atom nuclear charges to shift electron density into or out of the buffer region. Due to the relatively small computational cost of the model-low calculation, this procedure can be iteratively optimized to produce a charge distribution equal to the real-low calculation. Initial results for a test set of 20 reaction energies and 8 different combinations of high and low levels of theory show improvements of more than 35% over the standard ONIOM QM:QM approach, with improvements of up to 50% for some high and low combinations. PMID- 26616776 TI - A Local Pair Natural Orbital Coupled Cluster Study of Rh Catalyzed Asymmetric Olefin Hydrogenation. AB - The recently developed local pair natural orbital coupled cluster theory with single and double excitations (LPNO-CCSD) was used to study the rhodium-catalyzed asymmetric hydrogenation of two prochiral enamides. The method was carefully calibrated with respect to its accuracy. According to calculations on a truncated model system, the effects of perturbative triples (T) on the reaction energetics are very limited, the LPNO approximation is accurate, and complete basis set extrapolation (CBS) causes only minor changes in the relative energies computed with a standard basis set (def2-TZVP). The results for the full system are thus believed to be within 1-2 kcal/mol of the CCSD(T)/CBS limit for the present systems. Relativistic effects were treated by a scalar relativistic Hamiltonian using the zeroth order regular approximation (ZORA). The results of the study were compared to density functional calculations on the same systems and with calculations available in the literature. All calculations predict the correct stereochemical outcome of the reaction that is determined by the relative energies of the transition states in the early stages of the catalytic cycle. In general, DFT calculations using the B3LYP functional are in reasonable agreement with the LPNO-CCSD results, although deviations of 3-5 kcal/mol exist that are also not entirely systematic in the minor and major reaction branches. The present case study thus demonstrates that catalytic reactions, which are well described by single-reference electronic structure theory, can now be routinely studied with confidence in systems with 50-100 atoms applying local correlation methods that are as easy to use as DFT methods. PMID- 26616777 TI - Density Functional Calculations of E2 and SN2 Reactions: Effects of the Choice of Method, Algorithm, and Numerical Accuracy. AB - Herein we provide a detailed account on how the potential energy surfaces of the E2 and SN2 reactions of X(-) + CH3CH2X (X = F, Cl) depend on various methodological and technical choices in density functional calculations. We cover a choice of density functionals (OLYP, various M06-types, and the new SSB-D), basis sets (up to quintuple- and quadruple-zeta for Gaussian- and Slater-type orbitals, respectively, plus polarization and diffuse functions), and other aspects of the computations (among others: nonrelativistic versus zeroth-order regular approximation relativistic; numerical integration accuracy; all-electron versus frozen core; self-consistent field (SCF) versus post-SCF). The program codes ADF and NWChem are used for calculations with Slater- and Gaussian-type basis sets, respectively. The fluoride systems (X = F) appear to not only depend extremely sensitively on the basis set size (especially the presence of diffuse functions) but also on other technical settings, especially in the case of hybrid meta-generalized gradient approximation functionals. This work complements a recent contribution (Y. Zhao, D. G. Truhlar, J. Chem. Theory Comput. 2010, 6, 1104) and provides recommendations for density functionals, basis sets, and technical settings. PMID- 26616778 TI - Using Electronic Energy Derivative Information in Automated Potential Energy Surface Construction for Vibrational Calculations. AB - The availability of an accurate representation of the potential energy surface (PES) is an essential prerequisite in an anharmonic vibrational calculation. At the same time, the high dimensionality of the fully coupled PES and the adverse scaling properties with respect to the molecular size make the construction of an accurate PES a computationally demanding task. In the past few years, our group tested and developed a series of tools and techniques aimed at defining computationally efficient, black-box protocols for the construction of PESs for use in vibrational calculations. This includes the definition of an adaptive density-guided approach (ADGA) for the construction of PESs from an automatically generated set of evaluation points. Another separate aspect has been the exploration of the use of derivative information through modified Shepard (MS) interpolation/extrapolation procedures. With this article, we present an assembled machinery where these methods are embedded in an efficient way to provide both a general machinery as well as concrete computational protocols. In this framework we introduce and discuss the accuracy and computational efficiency of two methods, called ADGA[2gx3M] and ADGA[2hx3M], where the ADGA recipe is used (with MS interpolation) to automatically define modest sized grids for up to two mode couplings, while MS extrapolation based on, respectively, gradients only and gradients and Hessians from the ADGA determined points provides access to sufficiently accurate three-mode couplings. The performance of the resulting potentials is investigated in vibrational coupled cluster (VCC) calculations. Three molecular systems serve as benchmarks: a trisubstituted methane (CHFClBr), methanimine (CH2NH), and oxazole (C3H3NO). Furthermore, methanimine and oxazole are addressed in accurate calculations aiming to reproduce experimental results. PMID- 26616779 TI - A Theoretical Study of Brominated Porphycenes: Electronic Spectra and Intersystem Spin-Orbit Coupling. AB - In this paper, a time-dependent density functional theoretical study (TDDFT) has been carried out for brominated 2,7,12,17-tetra-n-propylporphycenes. Their potential therapeutic use in photodynamic therapy (PDT), a noninvasive medical treatment of cancer diseases, is due to the strong absorbance in the red part of the visible spectrum and the presence of heavy atoms (bromine). The prediction of electronic spectra for photosensitizer molecules can be a valuable tool in the design of drugs for application in PDT. Singlet and triplet vertical excitation energies have been calculated by means of the nonempirical hybrid functional PBE0 in conjunction with a split valence basis set (SVP), on previously optimized, at the density functional level of theory, ground state geometries. In particular, the quantum-chemical simulation of their absorption electronic spectra, both in vacuo and in solvent environments (dichloromethane and bromobenzene), has evidenced the red shift maxima wavelengths for the Q bands (or lower energy bands) with an increasing number of bromine atoms, in agreement with experimental results. The mean absolute deviation for the Q-electronic bands is about 0.3 eV. Calculated vertical triplet energies are between 1.04 (for tetra-brominated derivative) and 1.20 eV (for dibrominated derivative). The influence of bromine atoms on intersystem spin crossing has been investigated by applying a computational code which calculates spin-orbit matrix elements between singlet and triplet excited state wave functions weighted by the TDDFT transition coefficients. PMID- 26616780 TI - Structure, Stabilities, Thermodynamic Properties, and IR Spectra of Acetylene Clusters (C2H2)n=2-5. AB - There are no clear conclusions over the structures of the acetylene clusters. In this regard, we have carried out high-level calculations for acetylene clusters (C2H2)2-5 using dispersion-corrected density functional theory (DFT-D), Moller Plesset second-order perturbation theory (MP2); and coupled-cluster theory with single, double, and perturbative triple excitations [CCSD(T)] at the complete basis set limit. The lowest energy structure of the acetylene dimer has a T shaped structure of C2v symmetry, but it is nearly isoenergetic to the displaced stacked structure of C2h symmetry. We find that the structure shows the quantum statistical distribution for configurations between the T-shaped and displaced stacked structures for which the average angle (|theta|) between two acetylene molecules would be 53-78 degrees , close to the T-shaped structure. The trimer has a triangular structure of C3h symmetry. The tetramer has two lowest energy isomers of S4 and C2h symmetry in zero-point energy (ZPE)-uncorrected energy (DeltaEe), but one lowest energy isomer of C2v symmetry in ZPE-corrected energy (DeltaE0). For the pentamer, the global minimum structure is C1 symmetry with eight sets of T-type pi-H interactions and a set of pi-pi interactions. Our high level ab initio calculations are consistent with available experimental data. PMID- 26616781 TI - Calculation of Dipole Transition Matrix Elements and Expectation Values by Vibrational Coupled Cluster Method. AB - An effective operator approach based on the coupled cluster method is described and applied to calculate vibrational expectation values and absolute transition matrix elements. Coupled cluster linear response theory (CCLRT) is used to calculate excited states. The convergence pattern of these properties with the rank of the excitation operator is studied. The method is applied to a water molecule. Arponen-type double similarity transformation in extended coupled cluster (ECCM) framework is also used to generate an effective operator, and the convergence pattern of these properties is compared to the normal coupled cluster (NCCM) approach. It is found that the coupled cluster method provides an accurate description of these quantities for low lying vibrational excited states. The ECCM provides a significant improvement for the calculation of the transition matrix elements. PMID- 26616782 TI - Effects of Discrete Charge Clustering in Simulations of Charged Interfaces. AB - A system of counterions between charged surfaces is investigated, with the surfaces represented by uniform charged planes and three different arrangements of discrete surface charges - an equispaced grid and two different clustered arrangements. The behaviors of a series of systems with identical net surface charge density are examined, with particular emphasis placed on the long ranged corrections via the method of "charged slabs" and the effects of the simulation cell size. Marked differences are observed in counterion distributions and the osmotic pressure dependent on the particular representation of the charged surfaces; the uniformly charged surfaces and equispaced grids of discrete charge behave in a broadly similar manner, but the clustered systems display a pronounced decrease in osmotic pressure as the simulation size is increased. The influence of the long ranged correction is shown to be minimal for all but the very smallest of system sizes. PMID- 26616783 TI - Toward a Coarse Graining/All Atoms Force Field (CG/AA) from a Multiscale Optimization Method: An Application to the MCM-41 Mesoporous Silicates. AB - Many interesting physical phenomena occur on length and time scales that are not accessible by atomistic molecular simulations. By introducing a coarse graining of the degrees of freedom, coarse-grained (CG) models allow ther study of larger scale systems for longer times. Coarse-grained force fields have been mostly derived for large molecules, including polymeric materials and proteins. By contrast, there exist no satisfactory CG potentials for mesostructured porous solid materials in the literature. This issue has become critical among a growing number of studies on confinement effects on fluid properties, which require both long time and large scale simulations and the conservation of a sufficient level of atomistic description to account for interfacial phenomena. In this paper, we present a general multiscale procedure to derive a hybrid coarse grained/all atoms force field CG/AA model for mesoporous systems. The method is applied to mesostructured MCM-41 molecular sieves, while the parameters of the mesoscopic interaction potentials are obtained and validated from the computation of the adsorption isotherm of methanol by grand canonical molecular dynamic simulation. PMID- 26616784 TI - Defining Condensed Phase Reactive Force Fields from ab Initio Molecular Dynamics Simulations: The Case of the Hydrated Excess Proton. AB - In this report, a general methodology is presented for the parametrization of a reactive force field using data from a condensed phase ab initio molecular dynamics (AIMD) simulation. This algorithm allows for the creation of an empirical reactive force field that accurately reproduces the underlying ab initio reactive surface while providing the ability to achieve long-time statistical sampling for large systems not possible with AIMD alone. In this work, a model for the hydrated excess proton is constructed where the hydronium cation and proton hopping portions of the model are statistically force-matched to the results of Car-Parrinello Molecular Dynamics (CPMD) simulations. The flexible nature of the algorithm also allows for the use of the more accurate classical simple point-charge flexible water (SPC/Fw) model to describe the water water interactions while utilizing the ab initio data to create an overall multistate molecular dynamics (MS-MD) reactive model of the hydrated excess proton in water. The resulting empirical model for the system qualitatively reproduces thermodynamic and dynamic properties calculated from the ab initio simulation while being in good agreement with experimental results and previously developed multistate empirical valence bond (MS-EVB) models. The present methodology, therefore, bridges the AIMD technique with the MS-MD modeling of reactive events, while incorporating key strengths of both. PMID- 26616785 TI - Effect of Water Polarizability on the Properties of Solutions of Polyvalent Ions: Simulations of Aqueous Sodium Sulfate with Different Force Fields. AB - We show that aqueous sodium sulfate solutions exhibit an unrealistically large degree of ion pairing and clustering when modeled using nonpolarizable force fields, with clusters resembling precipitate readily forming in a 0.5 m solution at ambient conditions. This aggregation behavior was found to be persistent in nonpolarizable water for a range of parameters of the sulfate anion. In contrast, a polarizable potential performs satisfactorily, producing a well dissolved salt with a degree of association that is consistent with activity data for real solutions. Most of this improvement is due to polarization of water molecules in the vicinity of the divalent sulfate anion, which enhances its solvation. PMID- 26616786 TI - Temperature Effects on Donor-Acceptor Couplings in Peptides. A Combined Quantum Mechanics and Molecular Dynamics Study. AB - We report a quantum chemistry and molecular dynamics study on the temperature dependence of electronic coupling in two short model oligopeptides. Ten nanoseconds replica exchange molecular dynamics was performed on Trp-(Pro)3-Trp and Trp-(Pro)6-Trp peptides in the gas phase in combination with computation of the energy and electronic coupling for thermal hole transfer between Trp residues. The electron transfer parameters were estimated by using the semiempirical INDO/S method together with the charge fragment difference scheme. Conformational analysis of the derived trajectories revealed that the electronic coupling becomes temperature dependent when incorporating structural dynamics of the system. We demonstrate that Trp-(Pro)3-Trp, having only few degrees of freedom, results in relatively weak couplings at low and high temperature and a strong peak at 144 K, whereas the more flexible system Trp-(Pro)6-Trp shows monotonically decreased coupling. Only a few conformations with strong donor acceptor couplings are shown to be crucial for the overall ET rates. Our results introduce the question whether the T dependence of ET coupling can also be found in large biological systems. PMID- 26616787 TI - Fast Proton Titration Scheme for Multiscale Modeling of Protein Solutions. AB - Proton exchange between titratable amino acid residues and the surrounding solution gives rise to exciting electric processes in proteins. We present a proton titration scheme for studying acid-base equilibria in Metropolis Monte Carlo simulations where salt is treated at the Debye-Huckel level. The method, rooted in the Kirkwood model of impenetrable spheres, is applied on the three milk proteins alpha-lactalbumin, beta-lactoglobulin, and lactoferrin, for which we investigate the net-charge, molecular dipole moment, and charge capacitance. Over a wide range of pH and salt conditions, excellent agreement is found with more elaborate simulations where salt is explicitly included. The implicit salt scheme is orders of magnitude faster than the explicit analog and allows for transparent interpretation of physical mechanisms. It is shown how the method can be expanded to multiscale modeling of aqueous salt solutions of many biomolecules with nonstatic charge distributions. Important examples are protein-protein aggregation, protein-polyelectrolyte complexation, and protein-membrane association. PMID- 26616788 TI - Simulating POPC and POPC/POPG Bilayers: Conserved Packing and Altered Surface Reactivity. AB - Molecular dynamics (MD) simulation is a popular technique to study bilayer structural properties, but it has not been widely used in mixed bilayers of neutral and charged lipids. Here, we present results from constant temperature and pressure MD simulations of a 2-oleoyl-1-pamlitoyl-sn-glyecro-3-phosphocholine (POPC) bilayer containing 23% 2-oleoyl-1-pamlitoyl-sn-glyecro-3-glycerol (POPG). The simulations were performed using the recently updated CHARMM force field and involved two bilayers of 104 and 416 lipids. A control simulation of a pure POPC bilayer of 128 lipids yielded equilibrium structural properties that compare very well with experimental data. The average equilibrium properties of the mixed bilayer systems were very similar to those of the pure POPC. However, nearly one half of all the POPG lipids were found to be involved in hydrogen bonding with POPC lipids. Furthermore, the hydration of the mixed bilayer is different from that of the pure POPC, with the former inducing ordering of water molecules at longer distances. Thus, a phospholipid bilayer with ~23% negative charge content in the liquid crystalline phase differs from its neutral counterpart only at the headgroup. PMID- 26616789 TI - Activating the Prolactin Receptor: Effect of the Ligand on the Conformation of the Extracellular Domain. AB - The prolactin receptor resides on the surface of the cell as a preformed dimer. This suggests that cell signaling is triggered by conformational changes within the extracellular domain of the receptors. Here, by using atomistic molecular dynamics simulations, we show that the removal of the ligand placental lactogen from the dimeric form of the prolactin receptor results in a relative reorientation of the two extracellular domains by 20-30 degrees , which corresponds to a clockwise rotation of the domains with respect to each other. Such a mechanism of activation for the prolactin receptor is similar to that proposed previously in the case of the growth hormone receptor. In addition to the effect of the removal of the ligand, the mechanical coupling between the extracellular and transmembrane domains within a model membrane was also examined. PMID- 26616790 TI - Respiratory Intervention in Patients With Chronic Heart Failure. PMID- 26616791 TI - Application of a high-throughput, parallel HPLC system for quantitative chiral analysis of pantoprazole. AB - BACKGROUND: Chromatographic separation of enantiomers is considered a task in analytical chemistry particularly for high sample throughput. This paper describes a high-throughput parallel HPLC-MS/MS method for the determination of pantoprazole enantiomers. RESULTS: Baseline separation of pantoprazole enantiomers was achieved on a Chiralcel OZ-RH column in a run time of 4.5 min. Assays for enantiomers were linear with satisfactory intra- and inter-day precision and accuracy. The assay was suitable for high-throughput analysis as shown by its successful application to a chiral PK study in beagle dog. CONCLUSION: A high-throughput parallel HPLC-MS/MS assay for pantoprazole has been developed and validated. This method provides nearly twofold increased sample throughput, and was shown to be suitable for application in PK studies. PMID- 26616792 TI - Parenting behavior at 2 years predicts school-age performance at 7 years in very preterm children. AB - BACKGROUND: Parenting influences child development, but it is unclear whether early parenting behavior can influence school-age outcomes in very preterm (VPT) children, and/or if certain groups of VPT children may be more affected by early parenting behavior. These research questions were examined. METHODS: Participants were 147 children born <30 weeks' gestation or birth weight <1250 g and their primary caregiver. At term corrected age (CA), magnetic resonance imaging (MRI) was used to determine presence and severity of brain abnormality and medical data collected. High medical risk was defined as the presence of at least one of sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, moderate to severe white matter abnormality on MRI, or postnatal corticosteroids. At 2 years CA, parent-child interaction was assessed, and at 7 years CA, general intelligence (IQ), language, executive function, academic skills, and social-emotional functioning were assessed. RESULTS: Higher levels of parent-child synchrony, and parent facilitation, sensitivity and positive affect at 2 years were associated with better child outcomes at 7 years, while higher levels of intrusiveness and negative affect were associated with poorer outcomes. Many of these relationships remained after controlling for early child cognitive development. Interactions between child medical risk (higher/lower) and parenting were limited to child reading, math, and executive functioning outcomes, with stronger relationships for lower medical risk children. CONCLUSIONS: The contribution of early parenting to VPT children's school-age performance is significant, with stronger effects for lower medical risk children in some outcomes. These findings support the premise that parenting strategies should be included in the NICU and early interventions programs for VPT infants. PMID- 26616793 TI - PNIPAm(x)-PPO(36)-PNIPAm(x) thermo-sensitive triblock copolymers: chain conformation and adsorption behavior on a hydrophobic gold surface. AB - The chain conformations and adsorption behaviors of four thermo-sensitive poly(N isopropylacrylamide)x-poly(propylene oxide)36-poly(N-isopropylacrylamide)x (PNIPAmx-PPO36-PNIPAmx) triblock copolymers with x values of 15, 33, 75, and 117 in dilute aqueous solutions were investigated by combined techniques of micro differential scanning calorimetry (micro-DSC), static and dynamic light scattering (SLS & DLS), and the quartz crystal microbalance (QCM). PNIPAm15-PPO36 PNIPAm15 only exhibited the lower critical solution temperature (LCST) of the PPO block, i.e. 25 degrees C, because the PNIPAm block with x = 15 was too short to maintain its own LCST. With middle lengths x of 33 and 75, the LCSTs of PPO and PNIPAm blocks were observed, respectively. For the longest PNIPAm block with x = 117, only LCST of PNIPAm block dominated, i.e. 32.3 degrees C. DLS results revealed that the four PNIPAmx-PPO36-PNIPAmx triblock copolymers formed "associate" structures in their dilute aqueous solutions at 20 degrees C, which was well below the LCSTs of the PPO and PNIPAm blocks. QCM results indicated that the adsorption time constant decreased with increasing adsorption temperature but tended to increase with increasing length x of the PNIPAm block. A complex adsorption behavior with large adsorption amounts was only observed at the corresponding LCST of the PNIPAm block for PNIPAmx-PPO36-PNIPAmx with longer PNIPAm blocks with x = 33, 75, and 117. Furthermore, the adsorbed PNIPAmx-PPO36 PNIPAmx layers obtained at 20 degrees C were rigid with less energy dissipation. PMID- 26616794 TI - Isomerization of 5-Hydroxy-5-methylhydantoin 2'-Deoxynucleoside into alpha Furanose, beta-Furanose, alpha-Pyranose, and beta-Pyranose Anomers. AB - Oxidative damage is one of the most frequent types of DNA damage resulting from biologically generated oxygen or nitrogen reactive species. Hydroxyl radicals, one electron oxidants, and various chemical oxidants, such as permanganate and ozone, react with pyrimidine bases in DNA, cytosine and thymine, to produce 5 hydroxyhydantoin derivatives. 5-Hydroxyhydantoin modifications are interesting because they undergo ring-chain tautomerism into a pair of diastereomers via an open chain carbonyl intermediate. Here, we show that purified diastereomers of N1 (2-deoxy-beta-D-erythro-pentofuranosyl)-5-hydroxy-5-methylhydantoin not only undergo isomerization into a mixture of 5R and 5S diastereomers of the hydantoin ring but also into three additional pairs of diastereomers, in which the sugar moiety transforms into alpha-furanose, beta-pyranose, and alpha-pyranose anomers. The novel 5-hydroxy-5-methylhydantoin derivatives were characterized by extensive NMR analyses. Further studies indicate that isomerization is greatly suppressed at pH 6 compared to that at higher pH. A novel mechanism of isomerization is proposed to account for the formation of nucleoside anomers at neutral pH, which involves ring-chain tautomerism of both the hydantoin and sugar moieties. Last, the isomerization of beta-furanose into the corresponding alpha-furanose is shown to take place in purified DNA, albeit to a slower extent than that in solution. The ability of 5-hydroxyhydantoin nucleosides to undergo isomerization may complicate the biological processing of this damage in cellular DNA. PMID- 26616795 TI - [Mutual influence and development between Gastrointestinal surgery and hernia and abdominal wall surgery]. AB - The aim of this article is to expound on the crossing and influence each other of gastrointestinal surgery and abdominal wall hernia surgery. Although these two departments are independent respectively, but due to the existence of association among anatomy, physiology and pathology, so they are also overlapping. First of all, the abdominal wall and digestive tract are interdependent, and the abdominal wall provides "protection" for gut. In case of large abdominal wall defect, intra abdominal viscera, breathing, circulation system and spine will change accordingly. In addition, when intra-abdominal pressure increases due to various reasons, laparotomy is an effective way. But laparotomy is not an easy case, but a crisis. One of the most difficult problems is "enteroatmospheric fistulae". Therefore, to avoid serious complications after laparotomy, the concept of planned ventral hernia is proposed. When life safety is threatened by inter abdominal hypertension, planned abdominal wall hernia is the style to save life. This is a kind of concept of innovation, and is the concrete practice of the theory of damage control surgery. For a planned abdominal wall hernia patient, it is better to wait and watch, and after making a comprehensive assessment, multidisciplinary collaboration mode should be applied to ensure the safety of surgery. PMID- 26616796 TI - [Basic principle and standard procedure of hernia surgery]. AB - The basic principle of the hernia surgery is to find the hernia sac, reduce the contents, find the hernia ring and repair the abdominal wall defect. In recent years, the field of hernia surgery has a rapid development and the basic principle of hernia surgery has an obvious change in specific details. The standard procedure of hernia surgery is the guide of our work in practice to determine whether patients need surgical treatment. If operation is available, suitable method should be chosen and surgeons should pay attention to the special problems of hernia surgery in the perioperative period. According to the standard operation procedure in practice, the lowest morbidity of intraoperative complication may occur and patients will have the maximal gain. PMID- 26616797 TI - [Surgical treatment of large incisional hernia]. AB - Treatment of large incisional hernia (LIH) is still a challenge to most of the abdominal wall surgeons. Mesh reinforcement is essential for treatment of LIH, component separation technique(CST) provides significant assistances for the close of abdominal wall defect. The use of mesh reinforcement with CST during LIH repair displayed the best results. Understanding and choosing the correct procedure is very important for LIH repair which significantly decreases both the recurrence rate and morbidity postoperatively after LIH repair. PMID- 26616798 TI - [Clinical study of argon plasma coagulation combined with laparoscopic hiatal hernia repair and fundoplication in the treatment of hiatal hernia with Barrett esophagus]. AB - OBJECTIVE: To investigate the clinical efficacy of argon plasma coagulation (APC) combined with laparoscopic hiatal hernia repair and fundoplication in the treatment of hiatal hernia associated with Barrett esophagus. METHODS: A total of 61 cases of hiatal hernias with Barrett esophagus from June 2010 to January 2014 in the Department of Minimal Invasive Surgery, Hernia and Abdominal wall Surgery, People's Hospital of Xinjiang Uyhur Autonomous Region were prospectively enrolled and were randomly allocated into two groups by computer system. Twenty-nine patients received esomeprazole 40 mg/d after APC treatment for 8 weeks (APC with medicine group). Thirty-two patients underwent laparoscopic hiatal hernia repair and Nissen fundoplication after APC treatment (APC with surgery group). All the patients were reviewed by gastroscope and pathologic examination at half a year and one year after operation respectively. Differences of disease improvement and recurrence between the two groups were evaluated. RESULTS: In APC with medicine group, the Barrett's esophagus was relieved after one or two times of APC treatment, however, gastroscope and pathology revealed recurrence of Barrett's esophagus in 7 cases at half a year, and cumulative 16 cases of recurrences were detected after one year follow-up(16/29, 55.2%). In APC with surgery group, only one patient had recurrent Barrett's esophagus at half a year, and a total of two at one year follow-up by gastroscope examination(2/32, 6.3%). Significantly low recurrence rate of Barrett's esophagus was observed in APC with surgery group compared to APC with medicine group(P<0.01). Furthermore, recurrent hiatal hernia was detected in only one case in APC with surgery group. No esophageal cancer was found in both groups during follow-up. CONCLUSION: APC combined with laparoscopic hiatal hernia repair and fundoplication is an ideal method for patients with hiatal hernia and Barrett's esophagus. PMID- 26616799 TI - [Efficacy comparison of laparoscopic versus open tension-free hernia repair using biologic mesh for inguinal strangulated hernia]. AB - OBJECTIVE: To compare the efficacy of laparoscopic versus open tension-free mesh repair using biologic mesh for inguinal strangulated hernia. METHODS: Clinical data of 27 patients with inguinal strangulated hernia in the Shanxi Provincial People's Hospital between January 2012 and April 2014 were analyzed retrospectively. All the patients underwent one-stage tension-free repair using biological mesh, including laparoscopic(n=13) and open procedures(n=14). RESULTS: As compared with the open group, the laparoscopic group had shorter operative time [(90.8+/-11.6) min vs. (130.8+/-32.5) min, P<0.01], lower rates of hematoma/seroma and wound infection[(7.7% vs. 42.9%) and (0 vs. 28.6%) respectively, both P<0.05], faster recovery of bowel function [(2.5+/-0.3) d vs. (3.8+/-1.4) d, P<0.01], and shorter hospital stay [(6.3+/-1.8) d vs. (9.8+/-3.2) d, P<0.01]. The mean follow-up was 5.7 months (ranged from 2 to 12 months), and no recurrence or serious complications occurred. CONCLUSION: Laparoscopic tension free hernia repair using biological mesh for inguinal strangulated hernia has significant advantage versus open operation. PMID- 26616800 TI - [Diagnosis and treatment of pelvic wall and bowel fibrosis with bowel obstruction induced by neoadjuvant chemoradiotherapy for rectal carcinoma]. AB - OBJECTIVE: To introduce the diagnosis and the treatment of the long-segment bowel stenosis above the anastomosis and bowel obstruction caused by the radiation induced pelvic wall and bowel fibrosis. METHODS: Between January 2008 and June 2014, 468 patients with rectal carcinoma underwent sphincter-preserving operation after neoadjuvant chemoradiotherapy in Fujian Medical University Union Hospital. Among 241 patients without postoperative anastomotic leakage, anastomosis stenosis, local recurrence and small bowel obstruction, severe pelvic and bowel fibrosis with obstruction during follow-up was found in 14 patients(SFO group). Associated data of these 14 patients were retrospectively collected. Clinical and image characteristics, and treatment outcomes of these 14 patients were analyzed and compared to those of other 227 patients without fibrosis and obstruction (control group). RESULTS: Compared to control group, SFO group had lower BMI(19.7+/-2.3 vs. 22.5+/-3.2, P=0.000), higher ratio of male (92.9% vs. 63.9%, P=0.039) and smoking patients(78.6% vs. 32.2%, P=0.001), shorter preoperative distance from lower edge of tumor to anal verge [(4.9+/-0.7) cm vs. (5.7+/-1.4) cm, P=0.043), and longer time from the end of radiation to operation [(9.4+/-2.3) week vs. (8.1+/-1.7) week, P=0.024). The largest thickness of the bilateral obturator internus increased significantly after chemoradiotherapy (left side: P=0.030, right side: P=0.020) as compared to pre-chemoradiotherapy on MR image. Patients of SFO group received corresponding treatments according to the status of bowel stricture, and the outcomes were all satisfactory. CONCLUSIONS: Reconstructed rectum stricture can be caused by the radiation-induced fibrosis of pelvic wall soft tissue and proximal colon. Severe stricture can be treated with corresponding methods to relieve symptoms. PMID- 26616801 TI - [Risk factor analysis of early recurrence after resection of colorectal liver metastasis]. AB - OBJECTIVE: To explore the role of repeat liver resection in colorectal liver metastasis (CRLM) with early recurrence and to analyze the risk factors of early recurrence. METHODS: Clinicopathological and follow-up data of 303 CRLM patients undergoing liver resection in our department between January 2000 and August 2014 were analyzed retrospectively. The 5-year overall survivals between early recurrence(within postoperative 1 year) and non-early recurrence were compared. The impact of repeat liver resection on 5-year survival of early recurrence was analyzed. Clinicopathological features which might be associated with early recurrence were investigated using univariate and multivariate analyses. RESULTS: Among 303 patients, 192(63.4%) patients had recurrence, including 145 patients of early recurrence and 47 of non-early recurrence. The 5-year overall survival of early recurrence patients was significantly lower compared with non-early recurrence ones(16.0% vs. 63.9%, P=0.000). Among 145 early recurrence patients, 80 were evaluated as resectable, of whom 22 received repeat liver resection. Compared with other 58 patients receiving conservative treatment, above 22 patients receiving repeat liver resection had a significantly higher 5-year overall survival(27.1% vs. 0%, P=0.033). Multivariate analysis revealed T-stage of primary tumor, lymph node metastasis, and larger size(> 5 cm) of metastatic liver focus were independent risk factors of early recurrence, and good efficacy of neo-adjuvant chemotherapy was independent protective factor of early recurrence(all P<0.05). Repeat liver resection was associated with better long term survival. CONCLUSIONS: The prognosis of early recurrence after liver resection in CRLM patients is poor, while repeat resection for resectable lesions in recurrence patients can obviously prolong the survival. For those with late T stage, lymph node metastasis, and larger metastatic liver focus, actively preoperative neo-adjuvant chemotherapy should be considered. PMID- 26616802 TI - [Application of beta-shaped intracorporeal Roux-en-y reconstruction in totally laparoscopic distal gastrectomy]. AB - OBJECTIVE: To explore the technical feasibility, safety, and clinical efficacy of beta-shaped Roux-en-Y reconstruction(beta reconstruction) in totally laparoscopic distal gastrectomy (TLDG). METHODS: Clinical data of 21 patients with gastric cancer undergoing TLDG with beta reconstruction from January 2014 to May 2014 were retrospectively analyzed. RESULTS: TLDG with beta reconstruction was successfully performed in all the patients. The mean time of operation and beta reconstruction was (229.0+/-18.7) min and (27.5+/-4.2) min. The blood loss was (91.0+/-38.3) ml and number of dissected lymph node was 33.2+/-4.6 per patient. The length of upper and lower segment of resection from lesion was (5.9+/-0.4) cm and (3.2+/-0.8) cm. The average time to resume fluid diet, time to restore flatus and hospital stay were (2.1+/-0.8) d, (3.1+/-0.9) d and (5.9+/-2.4) d, respectively. CONCLUSION: The beta reconstruction is a safe and feasible procedure for TLDG and provides satisfactory short-term efficacy. PMID- 26616803 TI - [Differences between colorectal cancer patients and healthy people in fecal microbiota and metabolites]. AB - OBJECTIVE: To compare fecal microbiota and metabolites between colorectal cancer (CRC) patients and healthy population. METHODS: Feces from fifteen CRC patients and twelve normal people were analyzed by using pyrosequencing and gas chromatography mass spectrometry(GC/MS). RESULTS: There were no significant differences in the overall microbial community structure associated with the disease state, but 18 bacterial genera were underrepresented or overrepresented in the CRC samples. GC-MS profiling revealed higher concentrations for 9 kinds of amino acids and metabolites of short-chain fatty acids, lower concentrations for 3 kinds of unsaturated fatty acids and 2 kinds of glycerin and ursodeoxycholic acid in stool samples from CRC patients. Correlative analysis between the combined datasets revealed some potential relationships between stool metabolites and certain bacterial species. CONCLUSIONS: There are significant differences in fecal metabolites and the relative abundance of certain types of bacteria between CRC patients and healthy people, which can provide insight into microbial functions occurring in a cancer environment and will help direct future mechanism studies. PMID- 26616804 TI - [Association between RIPK4 relative copy number and prognosis of colorectal cancer patient after oxaliplatin-based chemotherapy]. AB - OBJECTIVE: To investigate the association between receptor-interacting kinase protein 4 (RIPK4) relative copy number (RCN) and prognosis of stage III( colorectal cancer (CRC) patients treated with oxaliplatin-based chemotherapy. METHODS: RIPK4 RCN was determined by real-time PCR and then dichotomized into high RIPK4 RCN group(n=35) and low RIPK4 RCN group (n=104) using the third quartile as the cut-off point. Overall survival (OS) and recurrence-free survival (RFS) were compared between high and low RIPK4 RCN groups. The subgroup prognostic analysis was also conducted based on tumor site. RESULTS: The median follow-up period was 49 months (ranged 4 to 98 months). Patients with high RIPK4 RCN had poorer OS than those with low RIPK4 RCN, which reached marginal significance(median OS, 43.0 months vs. 53.5 months, P=0.074). Meanwhile there was no significant difference of RFS between two groups (P=0.352). In colon cancer subgroup, high RIPK4 RCN was significantly associated with poor OS (median OS, 31.5 months vs. 56.6 months, P=0.015) but not with RFS (P=0.135). In rectal cancer subgroup, RIPK4 RCN was not associated with both OS and RFS (P=0.981, P=0.738). Multivariate analysis revealed that high RIPK4 RCN was an independent prognostic factor of OS in stage III( CRC patients treated with oxaliplatin-based chemotherapy (HR=2.903, 95% CI: 1.275 to 6.610). CONCLUSION: RIPK4 RCN is significantly associated with OS in stage III( colon cancer patients receiving oxaliplatin-based chemotherapy and may be a novel biomarker that can predict the efficacy of oxaliplatin in colon cancer patients. PMID- 26616805 TI - [Prognostic analysis of different treatments for synchronous colorectal liver metastasis]. AB - OBJECTIVE: To evaluate the effects of different treatments on the prognosis of patients with synchronous colorectal liver metastasis(CLM). METHODS: Clinicopathological data of 121 patients with synchronous CLM in The First Affiliated Hospital of Xinjiang Medical University between January 2010 and December 2014 were retrospectively analyzed. According to the metastatic lesions, patients were divided into simple operation group(22 patients, receiving operation only), simple chemotherapy group(43 patients, receiving chemotherapy only), and combination group(56 patients, receiving chemotherapy based on operation). The prognosis of patients in three groups was investigated. Univariate and multivariate analyses were performed through the long-rank test and Cox model to evaluate the related factors affecting prognosis. RESULTS: The median survival time was 10(3-39) months in simple operation group, 7(3-36) months in simple chemotherapy group, and 18 (4-66) months in combination group. The differences among groups were all statistically significant (all P<0.05). Extent of lymph node metastasis, number of liver metastatic lesion, size of liver metastatic lesion, resection edge extent of liver metastatic lesion, and treatment method were independent factors of synchronous CLM(all P<0.05). CONCLUSION: Combination therapy of a variety of treatment can prolong the survival of patients with synchronous CLM. PMID- 26616806 TI - [Comparative study of laparoscopic and open surgery for gastric gastrointestinal stromal tumors]. AB - OBJECTIVE: To investigate the feasibility and short-term efficacy of laparoscopic resection of primary localized gastric gastrointestinal stromal tumors (GIST) by comparing with open surgery. METHODS: Clinicopathological data of 167 gastric GIST patients undergoing operation in Zhongshan Hospital from June 2008 to December 2013 were retrospectively analyzed, among whom 55 received laparoscopic surgery and 112 underwent open surgery for primary local gastric GIST. Efficacy of different size and different location of GIST was compared between laparoscopic and open groups. RESULTS: There was no conversion to open surgery in laparoscopy group. Compared with open surgery, laparoscopic resection for gastric GIST smaller than 5 cm or located at anterior wall, greater curvature, lesser curvature, was associated with similar operation time(P>0.05), but less blood loss, shorter post-hospital stay or flatus time(all P<0.05). The operative outcomes were similar between laparoscopic and open resection for gastric GIST bigger than or equal to 5 cm or located at posterior wall(all P>0.05), except the longer operation time in laparoscopy group(P<0.05). The incidence of postoperative complication did not differ between two groups. Laparoscopic group had 2 patients with gastroparesis and open group had 2 gastroparesis, 2 pulmonary infection, and 1 poor wound healing(all P>0.05), which all recovered after conservative treatment. During 7 to 84 months(median 35) of follow-up, no recurrence or hepatic metastasis was found in laparoscopy group, and 3 hepatic metastases in open group. There was no significant difference of recurrence-free survival between two groups(P>0.05). CONCLUSION: Laparoscopic resection for gastric GIST is safe and effective in selected patients, especially for those with tumors smaller than 5 cm, or located at anterior wall, greater curvature, lesser curvature, whose short-term outcomes are better than open resection. PMID- 26616807 TI - [Efficacy analysis of laparoscopic radical right hemicolectomy using caudal-to cranial approach]. AB - OBJECTIVE: To investigate the safety and feasibility of laparoscopic radical right hemicolectomy using caudal-to-cranial approach (yellow-white borderline between right mesostenium and retroperitoneal is firstly cut as the entry to dissect the fusion fascial space between the visceral and parietal peritoneum, which is called caudal-to-cranial approach for right hemicolectomy). METHODS: From January 2014 to May 2015, 76 consecutive patients with right side colon cancer underwent laparoscopic radical right hemicolectomy using caudal-to-cranial approach. The baseline characteristics, intraoperative and postoperative outcomes were prospective collected and reviewed retrospectively. RESULTS: All the 76 patients completed operations successfully, and one patient (1.3%) was converted to open surgery because of intraoperative bleeding due to unexpected injury of ileocolic artery. The mean operative time was (152.8+/-42.1) min with a mean estimated blood loss of (70.4+/-43.5) ml. The mean time of first flatus was (49.3+/-22.9) h and mean liquid oral intake was (58.5+/-17.6) h. The postoperative complications appeared in 7 patients (9.2%), including one (1.3%) of pulmonary infection, one(1.3%) of urinary system infection, two (2.6%) of wound infection, two (2.6%) of inflammatory bowel obstruction and one (1.3%) of lymphatic fistula, and they were all cured with conservative treatments. The postoperative hospital stay was (7.8+/-5.4) d. The mean number of harvested lymph node was 34.2+/-10.9, among which 4.1+/-2.8 was positive. CONCLUSIONS: Laparoscopic radical right hemicolectomy using caudal-to-cranial approach is safe and feasible. PMID- 26616808 TI - [Clinicopathological factor analysis of positive cells in peritoneal lavage of gastric carcinoma]. AB - OBJECTIVE: To explore the clinicopathological factors affecting positive cells in peritoneal lavage of gastric carcinoma. METHODS: Clinicopathological data of 163 patients undergoing radical operation for gastric carcinoma and receiving cytology examination of peritoneal lavage (1000 ml normal saline) in our department from June 2013 to May 2014 were analyzed retrospectively. Pathology and immunohistochemistry were performed for resected lesions and harvested lymph nodes. Affecting factors of peritoneal lavage cytology were evaluated with univariate and multivariate logistic analyses. RESULTS: The positive rate of exfoliative carcinoma cells was 9.2%(15/163). Univariate analysis showed that pathologic staging, depth of invasion, N staging, lymph node metastasis, station of positive lymph node, metastatic rate of lymph node, metastatic rate of the second station of lymph node, and carcinoma differentiation degree were associated with the positive rate of peritoneal lavage cytology (all P<0.05). Multivariate analysis revealed only the metastatic rate of the second station of lymph node was independent risk factor of positive exfoliative cells in peritoneal lavage. CONCLUSION: The metastatic rate of the second station of lymph node is an independent risk factor of positive exfoliative cells in peritoneal lavage for gastric cancer patients. PMID- 26616809 TI - [Effect of ligation level of inferior mesenteric artery on postoperative defecation function in patients with rectal cancer]. AB - OBJECTIVE: To investigate the effect of ligation level of inferior mesenteric artery (IMA) on postoperative defecation function in patients with rectal cancer. METHODS: A total of 128 rectal cancer patients who were planned to undergo low anterior resection in the First Hospital of Zibo City between January 1, 2012 and December 31, 2013 were prospectively enrolled and randomly divided into IMA high ligation group(63 cases, cutting distance of 1.0 to 1.5 cm to the root of IMA) and low ligation group(65 cases, cutting distance of 0.5 to 1.0 cm to the root of left colic artery originated from IMA). The efficacy, especially the defecation function, was observed and compared 3 months and 1 year after surgery between the two groups. RESULTS: No significant difference was found in the number of harvested lymph nodes between two groups[8(1-30) vs. 7(2-28), P=0.125], but high ligation group had greater number of metastatic lymph nodes[1(0-9) vs. 0(0-8), P=0.041]. Frequency of defecation in high ligation group was significantly higher than that in low ligation group during postoperative 3-month follow-up[5(2-10)/d vs. 3(1-8)/d, P=0.035], whereas other indexes of defecation function were not significantly different(all P>0.05). The proportion of patients needing laxatives in high ligation group was higher than that in low ligation group during postoperative 1-year follow-up [11.3%(6/53) vs. 1.7%(1/58), P=0.038], whereas other indexes of defecation function were not significantly different as well (all P>0.05). Three cases and 2 cases showed recurrence in high ligation group and low ligation group respectively during postoperative 1-year follow-up without significant difference(P=0.623). CONCLUSION: Low ligation of IMA in low anterior resection for rectal cancer is beneficial to the protection against defecation function. PMID- 26616810 TI - [Diagnostic value of endoscopic ultrasonography for submucosal tumors of upper gastrointestinal tract]. AB - OBJECTIVE: To evaluate the diagnostic value of endoscopic ultrasonography (EUS) for submucosal tumors (SMTs) of upper gastrointestinal tract. METHODS: A retrospective analysis was made based on clinical data of 206 upper gastrointestinal SMTs patients from January 2009 to July 2013 in The First Affiliated Hospital of Soochow University. Preoperative EUS findings were compared with postoperative pathological diagnosis, and the sensitivity, specificity and accuracy of EUS diagnosis in property and layer origin of SMTs were calculated. RESULTS: The sensitivity, specificity and accuracy of EUS diagnosis in SMTs property were 60.2%, 67.1% and 61.2%. The sensitivity, specificity and accuracy of EUS diagnosis in layer origin of SMTs were 98.0%, 98.2% and 98.1%. CONCLUSION: EUS has limited value in the diagnosis of property of SMT, and has high accuracy of identifying the origin layer, which is helpful to choose therapeutic schedule of SMT under endoscopy. PMID- 26616811 TI - [Relationship of preoperative and postoperative myeloid-derived suppressor cells percentage with the prognosis in rectal cancer patients]. AB - OBJECTIVE: To observe the change of myeloid-derived suppressor cells (MDSCs) percentage in peripheral blood after operation in rectal cancer patients and to examine its association with the prognosis. METHODS: Blood samples of pre operation and postoperative 21-day from 64 stage I(-III( rectal cancer patients who underwent surgery in Department of General Surgery, The Affiliated Cancer Hospital, Zhengzhou University between January and December 2009 were collected. MDSCs percentage was detected by flow cytometry. Its association with the prognosis of patients was analyzed. RESULTS: MDSCs percentage of postoperative 21 day decreased significantly compared with pre-operation (P<0.01). When local recurrence or distant metastasis presented, MDSCs percentage increased again (all P<0.01) and reached the preoperative level(P>0.05). All the patients were further divided into two groups based on median MDSCs percentage. Patients with higher MDSCs percentage before operation (>3.78%) and after operation (>2.11%) had significantly lower 5-year overall survival(OS) (58.1% and 62.1%) and 5-year disease-free survival (DFS)(54.8% and 58.6%) as compared to those with lower MDSCs percentage(5-year OS 87.9% and 84.8%; 5-year DFS 82.8% and 80.0%, all P<0.05). Multivariate analysis showed that preoperative MDSCs percentage was an independent prognostic factor of rectal cancer(HR:4.065, 95% CI:1.026 to 16.108, P=0.04). CONCLUSIONS: Preoperative increased MDSCs percentage may be an important predictor of poor OS in rectal cancer patients. Dynamic change of MDSCs percentage can reflect the disease development. PMID- 26616812 TI - [Does bariatric surgery decrease the risk of obesity-related tumor: a meta analysis]. AB - OBJECTIVE: To explore whether bariatric surgery can decrease the incidence of obesity-related tumors in obesity patients. METHODS: Relevant studies comparing the incidence of obesity-related tumors in obesity patients between bariatric surgery and non- bariatric surgery were identified by search of PubMed, Medline, EBSCO, High Wire Press, OVID, EMbase, China hownet (CNKI) and Wanfang databases since the self-built database. In strict accordance with the standard after the screening, literature quality and extracted data were evaluated. Review manager 5.2 software was used to perform meta-analysis and sensitivity analysis. Inverted funnel chart was used to investigate the publication bias. RESULTS: Five articles including 108 954 patients were enrolled in the analysis. Among them, 26 218 cases were bariatric surgery group, and 82 736 cases of non-surgical weight loss were the control group. Meta analysis showed that bariatric surgery could obviously decrease the incidence of postoperative obesity-related tumor(RR=0.60, 95% CI:0.45-0.80, P=0.0005). Subgroup analysis showed that cancer risk difference of obesity-related tumor in male patients was not significant between two group, while the postoperative incidence of obesity-related tumor of female patients in bariatric surgery group was significantly lower compared to those female patients in control group(RR=0.68, 95% CI:0.61-0.77, P<0.01). During follow-up of 1 to 10 years, the incidence of obesity-related tumor in bariatric surgery group was significantly lower than that in control group(P<0.05). When follow-up was more than 10 years, the incidence of obesity-related tumors was similar between two groups(P=0.70). CONCLUSION: Bariatric surgery can decrease the overall risk of obesity-related cancer, especially for female patients, but with the prolongation of time, such effect of bariatric surgery is not obvious. PMID- 26616813 TI - [Screening and diagnostic value of the molecular markers of DNA methylation in colorectal neoplasma]. AB - OBJECTIVE: To screen the molecular markers of DNA methylation with potential diagnostic value, and to explore their methylation features in Chinese colorectal neoplasma in order to find out ones with higher diagnostic value. METHODS: Tissue samples of colorectal cancer and normal adjacent mucosa(>10 cm distance to tumors) from 10 colorectal cancer patients undergoing operation, and tissue samples of colorectal adenoma from 10 patients undergoing endoscopic resection in our center from June to August 2013 were collected respectively. Methylation status of 8 genes, such as SNCA, MAL, INA, SPG20, FBN1, CNRIP1, TFPI2, OSMR, was detected by BSP and qMSP to screen genes with potential diagnostic valua. ROC curve was drawn to analyze its diagnostic value. RESULTS: BSP measurement showed that the rate of DNA methylation of SNCA, SPG20 and FBN1 was 100% in colorectal cancer and adenoma, while no methylation was found in normal adjacent mucosa. The other 5 genes expressed in different extent in cancer, adenoma and normal adjacent mucosa. Among 10 cancer tissues and normal adjacent mucosa detected by qMSP method, positive SNCA methylation was found in 5 cases and 1 case respectively; positive SPG20 in 8 cases and 1 case respectively; positive FBN1 in 7 cases and 0 cases respectively, whose differences were significant (P=0.070, P=0.003 and P=0.007). The area under curve(AUC) of SNCA, SPG20, and FBN1 methylation for diagnosing colorectal cancer was 0.890, 0.730 and 0.880 respectively. CONCLUSION: SNCA, SPG20 and FBN1 are potential genes with screening value for colorectal neoplasma. PMID- 26616814 TI - [Expression of transcriptional coactivator with PDZ-binding motif (TAZ) in colon cancer tissues and its clinical significance]. AB - OBJECTIVE: To investigate the expression of transcriptional coactivator with PDZ binding motif(TAZ) in colon cancer tissues and its association with clinicopathological parameters and prognosis of patients. METHODS: The expression of TAZ protein was detected in 56 resected colon cancer tissues and matched tumor adjacent tissues using immunohistochemistry. The positive expression rate of TAZ was compared between patients with different clinicopathological features. The association between TAZ expression and prognosis was analyzed. RESULTS: Expression of TAZ protein located in the nucleolus. The positive expression rate of TAZ in colon cancer tissues was significantly higher than that in matched tumor-adjacent tissues(73.2% vs. 12.5%, P=0.000). Clinicopathological evaluation suggested that the expression of TAZ protein was associated with tumor size(P=0.009), depth of infiltration(P=0.026), lymph node metastasis (P=0.007) and TNM staging(P=0.004). Colon cancer patients with negative expression of TAZ showed a better 5-year survival as compared with those with positive expression of TAZ (66.7% vs. 22.9%, P=0.0017). Multivariate Cox regression analysis revealed that positive TAZ expression was an independent factor for predicting poor prognosis in colon cancer (HR:3.532, 95% CI: 1.3-9.9, P=0.016). CONCLUSION: The expression of TAZ protein is up-regulated in colon cancer tissues and its high expression is associated with poor prognosis of colon cancer patients. PMID- 26616815 TI - [Location of bone marrow mesenchymal stem cells in rats after small intestinal transplantation]. AB - OBJECTIVE: To study the bone marrow mesenchymal stem cells (MSC) settled in rats after small intestinal transplantation. METHODS: Bone marrow MSCs were taken from 1-month male Lewis rats, isolated and cultured by density gradient centrifugation and differential adherent culture. The surface antigens (CD29, CD90, CD34 and CD45) of MSC were identified by flow cytometry. Final concentration of 5 MUg/L CFSE was used to mark the third generation of MSCs. Adult male inbred line F344 rats were used as donor and adult male Lewis rats as acceptor. A heterotopic intestinal transplant rat model was established by F344 to Lewis. Labeled MSCs were injected into model rats through vena dorsalis penis after operation. Tissues at postoperative 7-day were collected for frozen pathology to reveal the location of transplanted MSCs under fluorescence microscope. RESULTS: MSCs were successfully isolated from rat bone marrow. The average positive expression rates of surface antigens CD29, CD90, CD34 and CD45 were 96.48%, 99.77%, 2.41% and 1.39% respectively. MSCs were successfully and effectively marked with CFSE. Seven days after operation, a large number of green fluorescence could be observed in transplanted intestine, spleen and thymus. Autograft intestinal tissues only showed trace fluorescence, and the heart, liver and lung tissue basically did not present the green fluorescence. CONCLUSION: Bone marrow MSCs can settle in transplanted small intestine of rat. PMID- 26616816 TI - [Efficacy comparison between endoscopic resection and tradition surgery in the treatment of early gastric cancer]. AB - Endoscopic resection (ER) has been a preferred treatment for early gastric cancer (EGC) based on the guidelines. In recent years the technique is developing rapidly. Surgical operation, a traditional treatment, still has its advantages such as complete tumor removal and low recurrence rate. In this review, a long term outcome comparison of these two methods in EGC is discussed. PMID- 26616817 TI - [Predictive factors for locally recurrent rectal cancer after primary curative surgery]. AB - Local recurrence is a major clinical challenge after primary rectal cancer surgery. Although there is a possibility that R0 resection can be achieved, the outcome is still not favorable due to the low R0 resection rate and complexity of the surgery. Therefore prevention has a higher priority over treatment afterwards. As TME principle is accepted worldwide, the local recurrence rate has been reduced dramatically. And there are other factors associated with local recurrence including CRM, operation type, staging and PNI. Proper chemoradiotherapy may reduce the risk, however benefit always comes with side effect, therefore risk stratification is important. PMID- 26616818 TI - [Research progress of Lgr4 in gastrointestinal carcinomas]. AB - Gastrointestinal carcinomas, whose incidence increases in recent years, are among the malignancies with highest morbidity and mortality. Many patients are always advanced stages when having diagnosis. So far, there are no any reliable tumor biomarkers which are able to screen people with high risk of developing cancer. Studies have shown that the expression level of Lgr4 is high in gastrointestinal carcinomas and Lgr4 is useful in diagnosis, differential diagnosis and prognosis judgment of these carcinomas. Lgr4 belongs to the G-protein-coupled receptors family. Its function is to potentiate Wnt signaling and plays an important role in the development of multiple organs. Recent studies find that Lgr4 has close relationship with the development of many gastrointestinal carcinomas, such as gastric cancer and colorectal cancer(CRC). In this article we review recent progress in understanding the relationship between Lgr4 and gastrointestinal carcinomas. PMID- 26616819 TI - MicroRNA expression profiling in peritoneal fibrosis. AB - Peritoneal fibrosis (PF) is an intractable complication leading to peritoneal membrane failure in peritoneal dialysis (PD). The aim of this study was to identify microRNAs (miRNAs) involved in PF. Peritoneal tissue from a PF rat model was screened for miRNA expression using microarray analysis. The expression levels of differentially expressed miRNAs were evaluated in serum and drained dialysate and associated with peritoneal membrane functions, as measured by the peritoneal equilibrium test in 33 PD patients. Furthermore, an miRNA inhibitor (anti-miRNA-21-5p locked nucleic acid (LNA): anti-miRNA-21-LNA) was intraperitoneally injected to PF model mice to investigate its effects on PF. The initial profiling study of PF rat peritoneal tissue identified 6 miRNAs (miRNA 142-3p, miRNA-21-5p, miRNA-221-3p, miRNA-223-3p, miRNA-34a-5p, and miRNA-327) whose expression was increased more than 2-fold and no miRNAs whose expression was decreased more than half. Among them, serum levels of miRNA-21-5p, miRNA-221 3p, and miRNA-327 and drained dialysate levels of miRNA-221-3p and miRNA-34a-5p were significantly correlated with peritoneal membrane functions in PD patients. Anti-miRNA-21-LNA significantly inhibited miRNA-21-5p expression in the PF mouse peritoneum, inhibited peritoneal fibrous thickening, and maintained peritoneal membrane functions. These results suggest that several miRNAs are involved in PF and that they may be useful as novel diagnostic biomarkers and therapeutic targets for PF. PMID- 26616821 TI - Self-assembly of like-charged nanoparticles into microscopic crystals. AB - Like-charged nanoparticles, NPs, can assemble in water into large, faceted crystals, each made of several million particles. These NPs are functionalized with mixed monolayers comprising ligands terminating in carboxylic acid group ligands as well as positively charged quaternary ammonium ligands. The latter groups give rise to electrostatic interparticle repulsions which partly offset the hydrogen bonding between the carboxylic acids. It is the balance between these two interactions that ultimately enables self-assembly. Depending on the pH, the particles can crystallize, form aggregates, remain unaggregated or even - in mixtures of two particle types - can "choose" whether to crystallize with like charged or oppositely charged particles. PMID- 26616822 TI - Pickering emulsions based on cyclodextrins: A smart solution for antifungal azole derivatives topical delivery. AB - Surfactants are usually used for the preparation of emulsions. Potential drawbacks on the human body or on the environment can be observed for some of them(e.g. skin irritation, hemolysis, protein denaturation, etc.). However, it is possible to use biocompatible emulsifiers such as native cyclodextrins (CDs). The mixture of oil (paraffin oil or isopropyl myristate), water and native CDs results in the formation of Pickering emulsions. The emulsion properties were investigated by ternary phase diagrams elaboration, multiple light scattering, optical and transmission microscopies. The results prove that these Pickering emulsions were very stable against coalescence due to the dense film format the oil/water interface. The rheological behavior has shown that these emulsions remain compatible for topical applications. This kind of emulsions (biocompatibility, stability and surfactant free) has been used to obtain sustainable formulations for antifungal econazole derivatives delivery. Our results prove that these new formulations are at least as active as commercially available formulations. PMID- 26616823 TI - Vibrational spectroscopic, molecular docking and density functional theory studies on 2-acetylamino-5-bromo-6-methylpyridine. AB - Conformational and molecular docking analysis of 2-acetylamino-5-bromo-6 methylpyridine molecule was carried out and the vibrational spectral analysis was also carried out using experimental and theoretical methods. The calculated and experimentally observed vibrational frequencies of the molecule were assigned and compared. The pyridine ring CH stretching and CH3 stretching vibrational modes were shifted towards higher wavenumber (blue shift). The C=O stretching vibrational frequency was shifted towards lower wavenumber (red shift). Ultraviolet-visible spectrum of the molecule simulated theoretically was further validated experimentally. Molecular reactivity and stability were investigated using the frontier molecular orbital analysis and the related quantum chemical molecular properties. Natural bond orbital analysis and the structure activity relations were also studied to confirm the bioactivity of the molecule. Anticancer activity was examined based on molecular docking analysis and it has been identified that the AABMP molecule can act as a good inhibitor against lung cancer. PMID- 26616824 TI - Single Amino Acid Switch between a Flavin-Dependent Dehalogenase and Nitroreductase. AB - A single mutation within a flavoprotein is capable of switching the catalytic activity of a dehalogenase into a nitroreductase. This change in function correlates with a destabilization of the one-electron-reduced flavin semiquinone that is differentially expressed in the nitro-FMN reductase superfamily during redox cycling. The diversity of function within such a superfamily therefore has the potential to arise from rapid evolution, and its members should provide a convenient basis for developing new catalysts with an altered specificity of choice. PMID- 26616826 TI - Comparison of differential gene expression to water stress among bacteria with relevant pollutant-degradation properties. AB - Resistance to semi-dry environments has been considered a crucial trait for superior growth and survival of strains used for bioaugmentation in contaminated soils. In order to compare water stress programmes, we analyse differential gene expression among three phylogenetically different strains capable of aromatic compound degradation: Arthrobacter chlorophenolicus A6, Sphingomonas wittichii RW1 and Pseudomonas veronii 1YdBTEX2. Standardized laboratory-induced water stress was imposed by shock exposure of liquid cultures to water potential decrease, induced either by addition of solutes (NaCl, solute stress) or by addition of polyethylene glycol (matric stress), both at absolute similar stress magnitudes and at those causing approximately similar decrease of growth rates. Genome-wide differential gene expression was recorded by micro-array hybridizations. Growth of P. veronii 1YdBTEX2 was the most sensitive to water potential decrease, followed by S. wittichii RW1 and A. chlorophenolicus A6. The number of genes differentially expressed under decreasing water potential was lowest for A. chlorophenolicus A6, increasing with increasing magnitude of the stress, followed by S. wittichii RW1 and P. veronii 1YdBTEX2. Gene inspection and gene ontology analysis under stress conditions causing similar growth rate reduction indicated that common reactions among the three strains included diminished expression of flagellar motility and increased expression of compatible solutes (which were strain-specific). Furthermore, a set of common genes with ill-defined function was found between all strains, including ABC transporters and aldehyde dehydrogenases, which may constitute a core conserved response to water stress. The data further suggest that stronger reduction of growth rate of P. veronii 1YdBTEX2 under water stress may be an indirect result of the response demanding heavy NADPH investment, rather than the presence or absence of a suitable stress defence mechanism per se. PMID- 26616825 TI - Clinical and patient-reported outcomes of Chinese patients undergoing haemodialysis in hospital or in the community: A 1-year longitudinal study. AB - AIM: Little is known about the effect of haemodialysis (HD) setting on outcomes of patients with end stage renal disease (ESRD). The study aimed at comparing clinical outcomes and patient-reported outcomes (PRO) of patients on community based (CBHD) and hospital-based haemodialysis (HBHD). METHODS: A prospective cohort of Chinese ESRD patients receiving HBHD (n = 89) or CBHD (n = 117) in Hong Kong were followed up for 12 months. Subjects were assessed on clinical outcomes of dialysis adequacy (Kt/V) and blood haemoglobin and PRO of health-related quality of life (SF-12v2), general health condition (Global Rating Scale (GRS)) and confidence to cope with their illness (Patient Enablement Instrument (PEI)). Differences between groups were analyzed by independent t-tests for the SF-12v2, GRS and PEI scores. chi(2) tests were used to analyze the difference in proportion of patients reaching the targets of Kt/V and blood haemoglobin and with GRS > 0 and PEI > 0. Multiple linear and logistic regressions were performed to assess the adjusted difference-in-difference estimation. RESULTS: The mean PEI and GRS scores of CBHD patients at 12 months were significantly higher than those of HBHD patients. CBHD patients had significantly greater improvement in self efficacy and were more likely to be enabled after 12 months than the HBHD patients. CONCLUSION: The study showed similar clinical outcomes and PRO between CBHD and HBHD but CBHD was more effective than HBHD in promoting patient enablement over a 12-month period. The results suggest added value for patients receiving CBHD and support the transfer of HD care from the hospital to the community. PMID- 26616827 TI - [Post-partum iron deficiency anaemia]. AB - Post-partum anaemia is an important global health issue. It is associated with increased maternal morbidity and mortality. This article focuses on the prevalence, causes and consequences of post-partum anaemia in Western countries. There is a need for national/international guidelines concerning the diagnosis, prevention and treatment of anaemia after delivery. In order to improve the mother's health status and quality of life, we suggest an increased awareness of diagnosing post-partum anaemia and use of evidence-based treatment options including oral and intravenous iron therapy. PMID- 26616828 TI - [When muscle relaxants have unexpected prolonged duration during anaesthesia]. AB - Muscle relaxation facilitates tracheal intubation and improves surgical conditions during anaesthesia. However, unexpected prolonged muscle relaxation may occur. This article describes important causes of prolonged muscle relaxation and gives suggestions for its prevention. Drug interactions, incomplete reversal, co-morbidity, inaccurate neuromuscular monitoring and critical illness may prolong the effect of muscle relaxants. The anaesthetist must titrate the muscle relaxants using objective neuromuscular monitoring and proper reversal of the blockade when needed. PMID- 26616829 TI - [Rheumatic fever in a four-year-old girl]. AB - Rheumatic fever (RF) is a systemic autoimmune response 2-4 weeks after a tonsillopharyngitis with group A beta-haemolytic Streptococcus. The disease may cause arthritis, carditis, chorea, erythema marginatum and subcutaneous noduli. Due to improved hygiene, living conditions and use of antibiotics, RF is a rare disease in Denmark today. The variable symptoms and low incidence is a diagnostic challenge. In this article, we present a case of RF in a four-year-old girl and provide an overview of diagnostic criteria and treatment. PMID- 26616830 TI - [Children can present with liver disease without elevation of liver-specific enzymes]. AB - In children, liver diseases are rarely suspected without elevated levels of liver transaminases. We describe two cases of portal hypertension of children who presented with gastrointestinal bleeding, splenomegaly and cytopenia. Both cases had normal levels of liver transaminases; thus haematological conditions initially were suspected. An elevated alanine aminotransferase level should always lead to further examination to detect liver diseases in early stages, in order to limit development of cirrhosis. PMID- 26616831 TI - [Regret of female sterilization]. AB - Regret of sterilization is inversely correlated to age at the time of sterilization. The minimum age for legal sterilization in Denmark has recently been lowered to 18 years. In Denmark surgical refertilization has almost completely been replaced by in vitro fertilization (IVF). In recent literature pregnancy results after surgical refertilization are easily comparable to IVF. Refertilization may in some cases be advantageous to IVF treatment. Women requesting reversal of sterilization should be offered individualized evaluation and differentiated treatment. It is recommended that surgical refertilization is performed at very few centres. PMID- 26616832 TI - [Cutaneous sinus tract due to an asymptomatic dental infection]. AB - Pyogenic cutaneous lesions of the cervicofacial region may have a variety of causes but one possibility that should be considered is a cutaneous sinus tract (CST) of dental origin. Correct diagnosis is based on a high index of suspicion and radiologic evidence of a dental pathology. Patients with odontogenic CST should be referred to a dentist and the treatment consists of either endodontic therapy or extraction of the involved tooth. We present a case report with misdiagnosis of CST of dental origin. PMID- 26616833 TI - Synthesis of Three-Dimensional Butterfly Slit-Cyclobisazaanthracenes and Hydrazinobisanthenes through One-Step Cyclodimerization and Their Properties. AB - New three-dimensional (3D) pi-conjugated molecules, butterfly-shaped slit cyclobisazaanthracenes, were synthesized in high yields by Ni-mediated one-step cyclodimerization of dibromoazaanthracenes with a dimethylacridine, phenothiazine, or acridone skeleton. The 3D slit butterfly shape was formed by folded azaanthracene skeletons. Closure of the slit via N?N bond formation afforded hydrazinobisanthenes with an embedded hydrazine structure in a bisanthene skeleton, which exhibited a 3D butterfly or a 2D plane structure depending on the type of heterocycle used. Extensive study of the stereoselective chemical reactivity of the butterfly shape, X-ray analysis, DFT calculations, electrochemical/chemical oxidations, and photophysical measurements revealed that the properties of these materials included stereoselective oxidation, a rigid or flexible butterfly shape, dynamic conformational behavior, unique crystal-packing structures, excellent electron donation with low oxidation potential, a radical cation, a long absorption wavelength, and fluorescence property. PMID- 26616834 TI - Induction of targeted, heritable mutations in barley and Brassica oleracea using RNA-guided Cas9 nuclease. AB - BACKGROUND: The RNA-guided Cas9 system represents a flexible approach for genome editing in plants. This method can create specific mutations that knock-out or alter target gene function. It provides a valuable tool for plant research and offers opportunities for crop improvement. RESULTS: We investigate the use and target specificity requirements of RNA-guided Cas9 genome editing in barley (Hordeum vulgare) and Brassica oleracea by targeting multicopy genes. In barley, we target two copies of HvPM19 and observe Cas9-induced mutations in the first generation of 23 % and 10 % of the lines, respectively. In B. oleracea, targeting of BolC.GA4.a leads to Cas9-induced mutations in 10 % of first generation plants screened. In addition, a phenotypic screen identifies T0 plants with the expected dwarf phenotype associated with knock-out of the target gene. In both barley and B. oleracea stable Cas9-induced mutations are transmitted to T2 plants independently of the T-DNA construct. We observe off-target activity in both species, despite the presence of at least one mismatch between the single guide RNA and the non-target gene sequences. In barley, a transgene-free plant has concurrent mutations in the target and non-target copies of HvPM19. CONCLUSIONS: We demonstrate the use of RNA-guided Cas9 to generate mutations in target genes of both barley and B. oleracea and show stable transmission of these mutations thus establishing the potential for rapid characterisation of gene function in these species. In addition, the off-target effects reported offer both potential difficulties and specific opportunities to target members of multigene families in crops. PMID- 26616835 TI - ICD Therapy--Can We Make a Life-Saving Device Less Lethal? PMID- 26616836 TI - The Tinel sign has no diagnostic value for nerve entrapment or neuropathy in the legs. AB - INTRODUCTION: The presence of a Tinel sign in leg nerves has been proposed as a criterion for decompressive surgery in polyneuropathy. We investigated the diagnostic yield of the Tinel sign for nerve entrapment and for distal symmetrical peripheral neuropathy (DSPN). METHODS: We prospectively tested for the Tinel sign at 3 sites of possible nerve entrapment per leg in 91 patients. Entrapment was defined using nerve conduction data. We also investigated whether the number of sites at which the Tinel sign was present identified patients with DSPN. RESULTS: Sensitivity of the Tinel sign for nerve entrapment was low (29%, 44%, and 17%) for the 3 sites, and specificity was moderate (86%, 75%, and 81%). In the subgroup with DSPN, sensitivity was extremely low (0%, 20%, and 8%), and specificity was moderate (91%, 79%, and 73%). The number of sites with a Tinel sign did not identify patients with DSPN. CONCLUSION: The Tinel sign does not reliably indicate nerve entrapment or DSPN. Muscle Nerve 54: 25-30, 2016. PMID- 26616837 TI - Exploring possible association between DbetaH genotype (C1021T), early onset of conduct disorder and psychopathic traits in juvenile delinquents. AB - Early onset of conduct disorder (CD) with callous-unemotional traits has been linked to low levels of dopamine beta-hydroxylase (DbetaH), an enzyme involved in dopamine turnover. The C1021T polymorphism in the DbetaH gene is a major quantitative-trait locus, regulating the level of DbetaH. In this study of juvenile delinquents from Northern Russia (n = 180), the polymorphism at -1021 was associated neither with early-onset CD nor with psychopathic traits. Association was found between psychopathic traits and early-onset CD, ADHD and mania. PMID- 26616838 TI - [Not Available]. PMID- 26616839 TI - Aborted sudden death during a marathon race. PMID- 26616840 TI - Recurrence rate of lentigo maligna after micrographically controlled staged surgical excision. AB - BACKGROUND: Lentigo maligna is a slowly growing melanoma in situ. Current guidelines advise wide local excision with a margin of 5 mm as the treatment of first choice, which has recurrence rates ranging from 6% to 20%. OBJECTIVES: To determine retrospectively the recurrence rate of lentigo maligna after staged surgical excision. METHODS: Records of all patients with lentigo maligna treated with our method of staged surgical excision between 2002 and 2011 were retrieved. To identify recurrences we used the computer program Sympathy, which is linked to PALGA, a nationwide network and registry of histo- and cytopathology in the Netherlands. RESULTS: We identified 100 patients, who were treated with staged surgical excision with 100% immunohistopathological control of lateral margins. Digital pictures were used to facilitate orientation during the several stages of surgery. After a mean follow-up of 60 months, four patients had a recurrence, after 37, 58, 74 and 77 months of follow-up. CONCLUSIONS: Staged surgical excision is superior in clearance and recurrence rates to wide local excision for lentigo maligna and should be considered as the treatment of first choice in national and international guidelines. PMID- 26616841 TI - WITHDRAWN: Versatility of different melting temperature (Tm) calculator software for robust PCR and Real-time PCR oligonucleotide design: A practical guide. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26616842 TI - Periodontal Microorganisms and Cardiovascular Risk Markers in Youth With Type 1 Diabetes and Without Diabetes. AB - BACKGROUND: A subset of periodontal microorganisms has been associated with cardiovascular disease (CVD), which is the leading complication of type 1 diabetes (t1DM). The authors therefore evaluated the association between periodontal microorganism groups and early markers of CVD in youth with t1DM. METHODS: A cross-sectional analysis was conducted among youth aged 12 to 19 years at enrollment; 105 had t1DM for >=5 years and were seeking care at the Barbara Davis Center, University of Colorado, from 2009 to 2011, and 71 did not have diabetes. Subgingival plaque samples were assessed for counts of 41 periodontal microorganisms using DNA-DNA hybridization. Microorganisms were classified using cluster analysis into four groups named red-orange, orange-green, blue/other, and yellow/other, modified from Socransky's color scheme for periodontal microorganisms. Subsamples (54 with t1DM and 48 without diabetes) also received a periodontal examination at the University of Colorado School of Dental Medicine. RESULTS: Participants were ~15 years old on average, and 74% were white. Mean periodontal probing depth was 2 mm (SE 0.02), and 17% had bleeding on probing. In multivariable analyses, glycated hemoglobin (HbA1c) was inversely associated with the yellow/other cluster (microorganisms that are not associated with periodontal disease) among youth with t1DM. Blood pressure, triglycerides, low-density lipoprotein, high-density lipoprotein, and total cholesterol were not associated with microorganism clusters in this group. HbA1c was not associated with periodontal microorganism clusters among youth without diabetes. CONCLUSION: Among youth with t1DM who had good oral health, periodontal microorganisms were not associated with CVD risk factors. PMID- 26616843 TI - Accuracy of core needle biopsy for the diagnosis of osteosarcoma: A retrospective analysis of 73 patients. AB - PURPOSE: The goals of this retrospective study were to evaluate the accuracy of core needle biopsy (CNB) for the diagnosis of osteosarcoma and to identify criteria that may predict failed CNB. MATERIALS AND METHODS: From 2002 to 2012, 73patients with a total of 73osteosarcomas underwent CNB. Patients demographics and procedure details were recorded, including tumor size, tumor characteristics (hemorrhagic or not, lytic, sclerotic [>50% bone condensation], or mixed), the type of anesthesia, the number of tissue samples, the size of the biopsy needle and pathology report. Procedures were analyzed in terms of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: A diagnosis was not made in 5/73patients (6.8%) with an overall sensitivity of 93.1%, a specificity of 100%, a PPV of 100% and a NPV of 99.9%. No complications due to CNB were observed. No criteria were identified as predictors of CNB failure. CONCLUSION: Even in the presence of sclerotic tumors, CNB should be the first line diagnostic test for suspected osteosarcomas, pending performance by a well-trained radiologist and reading by a specialized pathologist. LEVEL OF EVIDENCE: IV. PMID- 26616844 TI - The Role of Platelet-Activating Factor in Chronic Inflammation, Immune Activation, and Comorbidities Associated with HIV Infection. AB - With the advent of highly effective antiretroviral therapy, cardiovascular disease has become an important cause of morbidity and mortality among people with treated HIV-1, but the pathogenesis is unclear. Platelet-activating factor is a potent lipid mediator of inflammation that has immunomodulatory effects and a pivotal role in the pathogenesis of inflammatory disorders and cardiovascular disease. Limited scientific evidence suggests that the platelet-activating factor pathway may be a mechanistic link between HIV-1 infection, systemic inflammation, and immune activation that contribute to pathogenesis of chronic HIV-related comorbidities, including cardiovascular disease and HIV-associated neurocognitive disorders. In this review, we examine the mechanisms by which the cross-talk between HIV-1, immune dysregulation, inflammation, and perturbations in the platelet-activating factor pathway may directly affect HIV-1 immunopathogenesis. Understanding the role of platelet-activating factor in HIV-1 infection may pave the way for further studies to explore therapeutic interventions, such as diet, that can modify platelet-activating factor activity and use of platelet activating factor inhibitors that might improve the prognosis of HIV-1 infected patients. PMID- 26616846 TI - News on HIV-HCV Coinfection: Update From the 2015 GEHEP Conference. AB - New therapeutic options for the treatment of HCV infection are highly effective, possess minimal side effects, and allow for a shortened course of therapy, presenting a favorable scenario to treat and cure all patients chronically infected with HCV. However, there are still many challenges to advancement towards HCV eradication, not only related to the cost and the availability of the drugs, but also pertaining to epidemiologic, diagnostic, and treatment issues that remain to be resolved. Advances in the knowledge of all these topics are essential for the optimization of diagnostic and treatment strategies to fight again HCV infection. The latest data presented at the I Conference of the Group for the Study of Viral Hepatitis (GEHEP) (23-26 September, Spain) highlights relevant progress on many of these fronts for an overview of HCV infection at present. This review summarizes some of the major findings presented and discussed during the conference. PMID- 26616847 TI - Cutaneous tuberculosis overview and current treatment regimens. AB - Tuberculosis is one of the oldest diseases known to humankind and it is currently a worldwide threat with 8-9 million new active disease being reported every year. Among patients with co-infection of the human immunodeficiency virus (HIV), tuberculosis is ultimately responsible for the most deaths. Cutaneous tuberculosis (CTB) is uncommon, comprising 1-1.5% of all extra-pulmonary tuberculosis manifestations, which manifests only in 8.4-13.7% of all tuberculosis cases. A more accurate classification of CTB includes inoculation tuberculosis, tuberculosis from an endogenous source and haematogenous tuberculosis. There is furthermore a definite distinction between true CTB caused by Mycobacterium tuberculosis and CTB caused by atypical mycobacterium species. The lesions caused by mycobacterium species vary from small papules (e.g. primary inoculation tuberculosis) and warty lesions (e.g. tuberculosis verrucosa cutis) to massive ulcers (e.g. Buruli ulcer) and plaques (e.g. lupus vulgaris) that can be highly deformative. Treatment options for CTB are currently limited to conventional oral therapy and occasional surgical intervention in cases that require it. True CTB is treated with a combination of rifampicin, ethambutol, pyrazinamide, isoniazid and streptomycin that is tailored to individual needs. Atypical mycobacterium infections are mostly resistant to anti-tuberculous drugs and only respond to certain antibiotics. As in the case of pulmonary TB, various and relatively wide-ranging treatment regimens are available, although patient compliance is poor. The development of multi-drug and extremely drug-resistant strains has also threatened treatment outcomes. To date, no topical therapy for CTB has been identified and although conventional therapy has mostly shown positive results, there is a lack of other treatment regimens. PMID- 26616848 TI - Impact of EGFR mutations and KRAS amino acid substitution on the response to radiotherapy for brain metastasis of non-small-cell lung cancer. AB - BACKGROUND: Our study aimed to evaluate response rate (RR) to brain metastasis radiotherapy (RT), depending on the genomic status of non-small-cell lung cancer. MATERIAL & METHODS: We retrospectively reviewed 1971 non-small-cell lung cancer files of patients with EGFR and KRAS testing and focused on 157 patients who had undergone RT for brain metastasis. RESULTS: A total of 16 patients (10.2%) harbored EGFR mutations (mEGFR) and 45 patients (28.7%) KRAS (mKRAS). In univariate analysis, RR was significantly higher for mEGFR compared with wild type EGFR/KRAS (odds ratio [OR]: 4.96; p = 0.05) or mKRAS (OR: 1.81; p = 0.03). In multivariate analysis, KRAS G12V or G12C status was associated with both poor RR (OR: 0.1; p < 0.0001) and overall survival (OR: 3.41; p < 0.0001). CONCLUSION: mEGFR are associated with higher RR to brain RT than wild-type EGFR/RAS or mKRAS. PMID- 26616849 TI - Salutogenesis: Contextualising place and space in the policies and politics of recovery from drug dependence. AB - This commentary seeks to make a contribution to applied and academic debates concerning recovery from drug dependence. This involves a discussion of various commonalities relating to the places and spaces of substance use/treatment; the identification of various tensions relating to 'structure and agency' in current service provision and the way in which environmentally disparate settings may be synthesised to establish enabling environments of recovery. At the centre of this discussion is Aaron Antonovsky's (1984) model of 'salutogenesis' (and 'salutogenic environments') and how this conceptual framework may be considered and/or applied in the field of recovery from dependent substance use. Whereas public health, clinical intervention and epidemiology each attempt to identify the underlying causation of illness and ill health, salutogenesis is an agency led concept that seeks to identify the factors and mechanisms that foster good health and the principles of 'keeping well'. It is suggested that a salutogenic approach to recovery options would draw upon the guiding principles of the framework towards advancing, individual level, recovery capital. These principles being (i) the development of social/cultural capital within socially-constructed environments; in which (ii) individual action (or agency) seeks to (iii) manage ill health; recognise the challenges underlying illness and identify the resources that are available to improve health. The author suggests that opportunities for a more 'salutogenic approach' to recovery may be noted within a grassroots model burgeoning throughout parts of the UK (and known as Recovery Cafes). This design is in stark contrast to the State's more structurally-focused treatment options that may not fully appreciate the influence of agency (and the role of place) in attempts to garner recovery capital. In order to demonstrate the academic and applied value of the proposed salutogenic framework to the issue of recovery from dependence (including the centrality of space and place in debate surrounding substance use/treatment), the author draws upon empirical research as well as theoretical and hypothetical frameworks from the discipline of sociology to illustrate throughout. PMID- 26616845 TI - The Burden of Neglected HIV-2 and HTLV-1 Infections in Spain. AB - HIV-2 and HTLV-1 infections are globally less frequent than those produced by HIV 1, the classical AIDS agent. In Spain and up to the end of 2014, a total of 310 cases of HIV-2, 274 of HTLV-1, and 776 of HTLV-2 infections had been reported. No cases of HTLV-3 or HTLV-4 infections have been identified so far in Spain. Most persons infected with HIV-2 or HTLV-1 acknowledge epidemiological risk factors for contagion, such as originating from or living in endemic regions and/or having had sexual partners from those areas. However, risk factors could not be recognized in up to 20-25% of carriers in Spain. Thus, it seems worth keeping a high level of clinical suspicion in order to identify earlier these neglected human retroviral infections, since diagnostic procedures and antiviral treatment are specific for each of these agents. In this article we summarize the major contributions reported at the meeting of the Spanish Group for HIV-2/HTLV held in Madrid in December 2014. PMID- 26616850 TI - Structure of Mycobacterium thermoresistibile GlgE defines novel conformational states that contribute to the catalytic mechanism. AB - GlgE, an enzyme of the pathway that converts trehalose to alpha-glucans, is essential for Mycobacterium tuberculosis. Inhibition of GlgE, which transfers maltose from a maltose-1-phosphate donor to alpha-glucan/maltooligosaccharide chain acceptor, leads to a toxic accumulation of maltose-1-phosphate that culminates in cellular death. Here we describe the first high-resolution mycobacterial GlgE structure from Mycobacterium thermoresistibile at 1.96 A. We show that the structure resembles that of M. tuberculosis and Streptomyces coelicolor GlgEs, reported before, with each protomer in the homodimer comprising five domains. However, in M. thermoresistibile GlgE we observe several conformational states of the S domain and provide evidence that its high flexibility is important for enzyme activity. The structures here reported shed further light on the interactions between the N-terminal domains and the catalytic domains of opposing chains and how they contribute to the catalytic reaction. Importantly this work identifies a useful surrogate system to aid the development of GlgE inhibitors against opportunistic and pathogenic mycobacteria. PMID- 26616851 TI - An outbreak of artemisinin resistant falciparum malaria in Eastern Thailand. AB - Artemisinin resistant falciparum malaria is an increasing problem in Southeast Asia, but has not been associated with increased transmission of the disease, yet. During a recent outbreak in 2014 in Ubon Ratchatani, Eastern Thailand, parasites from 101 patients with falciparum malaria were genotyped for antimalarial drug resistance markers. Mutations in the Kelch13 marker for artemisinin resistance were present in 93% of samples, mainly C580Y from 2 major clusters as identified by microsatellite typing. Resistance markers for antifolates and chloroquine were also highly prevalent. Most strains (91%) carried single copy number PfMDR1, suggesting sustained sensitivity to mefloquine, the partner drug in the local first-line artemisinin combination therapy (ACT). The high prevalence of artemisinin resistance in this recent malaria outbreak suggests but does not prove a causative role in increased transmission. Careful monitoring of ACT efficacy and additional genetic epidemiological studies are warranted to guide the public health response to the outbreak. PMID- 26616852 TI - Ageing and the telomere connection: An intimate relationship with inflammation. AB - Telomeres are the heterochromatic repeat regions at the ends of eukaryotic chromosomes, whose length is considered to be a determinant of biological ageing. Normal ageing itself is associated with telomere shortening. Here, critically short telomeres trigger senescence and eventually cell death. This shortening rate may be further increased by inflammation and oxidative stress and thus affect the ageing process. Apart from shortened or dysfunctional telomeres, cells undergoing senescence are also associated with hyperactivity of the transcription factor NF-kappaB and overexpression of inflammatory cytokines such as TNF-alpha, IL-6, and IFN-gamma in circulating macrophages. Interestingly, telomerase, a reverse transcriptase that elongates telomeres, is involved in modulating NF kappaB activity. Furthermore, inflammation and oxidative stress are implicated as pre-disease mechanisms for chronic diseases of ageing such as neurodegenerative diseases, cardiovascular disease, and cancer. To date, inflammation and telomere shortening have mostly been studied individually in terms of ageing and the associated disease phenotype. However, the interdependent nature of the two demands a more synergistic approach in understanding the ageing process itself and for developing new therapeutic approaches. In this review, we aim to summarize the intricate association between the various inflammatory molecules and telomeres that together contribute to the ageing process and related diseases. PMID- 26616853 TI - CD99 regulates neural differentiation of Ewing sarcoma cells through miR-34a Notch-mediated control of NF-kappaB signaling. AB - Sarcomas are mesenchymal tumors characterized by blocked differentiation process. In Ewing sarcoma (EWS) both CD99 and EWS-FLI1 concur to oncogenesis and inhibition of differentiation. Here, we demonstrate that uncoupling CD99 from EWS FLI1 by silencing the former, nuclear factor-kappaB (NF-kappaB) signaling is inhibited and the neural differentiation program is re-established. NF-kappaB inhibition passes through miR-34a-mediated repression of Notch pathway. CD99 counteracts EWS-FLI1 in controlling NF-kappaB signaling through the miR-34a, which is increased and secreted into exosomes released by CD99-silenced EWS cells. Delivery of exosomes from CD99-silenced cells was sufficient to induce neural differentiation in recipient EWS cells through miR-34a inhibition of Notch NF-kappaB signaling. Notably, even the partial delivery of CD99 small interfering RNA may have a broad effect on the entire tumor cell population owing to the spread operated by their miR-34a-enriched exosomes, a feature opening to a new therapeutic option. PMID- 26616854 TI - PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo. AB - Glioblastoma (GBM) remains the most common and lethal intracranial tumor. In a comparison of gene expression by A2B5-defined tumor-initiating progenitor cells (TPCs) to glial progenitor cells derived from normal adult human brain, we found that the F2R gene encoding PAR1 was differentially overexpressed by A2B5-sorted TPCs isolated from gliomas at all stages of malignant development. In this study, we asked if PAR1 is causally associated with glioma progression. Lentiviral knockdown of PAR1 inhibited the expansion and self-renewal of human GBM-derived A2B5(+) TPCs in vitro, while pharmacological inhibition of PAR 1 similarly slowed both the growth and migration of A2B5(+) TPCs in culture. In addition, PAR1 silencing potently suppressed tumor expansion in vivo, and significantly prolonged the survival of mice following intracranial transplantation of human TPCs. These data strongly suggest the importance of PAR1 to the self-renewal and tumorigenicity of A2B5-defined glioma TPCs; as such, the abrogation of PAR1 dependent signaling pathways may prove a promising strategy for gliomas. PMID- 26616855 TI - Diacerein-mediated inhibition of IL-6/IL-6R signaling induces apoptotic effects on breast cancer. AB - Interleukin-6 (IL-6) signaling network has been implicated in oncogenic transformations making it attractive target for the discovery of novel cancer therapeutics. In this study, potent antiproliferative and apoptotic effect of diacerein were observed against breast cancer. In vitro apoptosis was induced by this drug in breast cancer cells as verified by increased sub-G1 population, LIVE/DEAD assay, cell cytotoxicity and presence of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, as well as downregulation of antiapoptotic proteins Bcl-2 and Bcl-xL and upregulation of apoptotic protein Bax. In addition, apoptosis induction was found to be caspase dependent. Further molecular investigations indicated that diacerein instigated apoptosis was associated with inhibition of IL-6/IL-6R autocrine signaling axis. Suppression of STAT3, MAPK and Akt pathways were also observed as a consequence of diacerein-mediated upstream inhibition of IL-6/IL-6R. Fluorescence study and western blot analysis revealed cytosolic accumulation of STAT3 in diacerein treated cells. The docking study showed diacerein/IL-6R interaction that was further validated by competitive binding assay and isothermal titration calorimetry. Most interestingly, it was found that diacerein considerably suppressed tumor growth in MDA-MB-231 xenograft model. The in vivo antitumor effect was correlated with decreased proliferation (Ki-67), increased apoptosis (TUNEL) and inhibition of IL-6/IL-6R-mediated STAT3, MAPK and Akt pathway in tumor remnants. Taken together, diacerein offered a novel blueprint for cancer therapy by hampering IL-6/IL-6R/STAT3/MAPK/Akt network. PMID- 26616856 TI - Spontaneous tumor development in bone marrow-rescued DNA-PKcs(3A/3A) mice due to dysfunction of telomere leading strand deprotection. AB - Phosphorylation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) at the Thr2609 cluster is essential for its complete function in DNA repair and tissue stem cell homeostasis. This phenomenon is demonstrated by congenital bone marrow failure occurring in DNA-PKcs(3A/3A) mutant mice, which require bone marrow transplantation (BMT) to prevent early mortality. Surprisingly, an increased incidence of spontaneous tumors, especially skin cancer, was observed in adult BMT-rescued DNA-PKcs(3A/3A) mice. Upon further investigation, we found that spontaneous gammaH2AX foci occurred in DNA-PKcs(3A/3A) skin biopsies and primary keratinocytes and that these foci overlapped with telomeres during mitosis, indicating impairment of telomere replication and maturation. Consistently, we observed significantly elevated frequencies of telomere fusion events in DNA-PKcs(3A/3A) cells as compared with wild-type and DNA-PKcs-knockout cells. In addition, a previously identified DNA-PKcs Thr2609Pro mutation, found in breast cancer, also induces a similar impairment of telomere leading-end maturation. Taken together, our current analyses indicate that the functional DNA PKcs T2609 cluster is required to facilitate telomere leading strand maturation and prevention of genomic instability and cancer development. PMID- 26616857 TI - Oncogenic PTEN functions and models in T-cell malignancies. AB - PTEN is a protein phosphatase that is crucial to prevent the malignant transformation of T-cells. Although a numerous mechanisms regulate its expression and function, they are often altered in T-cell acute lymphoblastic leukaemias and T-cell lymphomas. As such, PTEN inactivation frequently occurs in these malignancies, where it can be associated with chemotherapy resistance and poor prognosis. Different Pten knockout models recapitulated the development of T-cell leukaemia/lymphoma, demonstrating that PTEN loss is at the center of a complex oncogenic network that sustains and drives tumorigenesis via the activation of multiple signalling pathways. These aspects and their therapeutic implications are discussed in this review. PMID- 26616858 TI - Inactivating mutations in GNA13 and RHOA in Burkitt's lymphoma and diffuse large B-cell lymphoma: a tumor suppressor function for the Galpha13/RhoA axis in B cells. AB - G proteins and their cognate G protein-coupled receptors (GPCRs) function as critical signal transduction molecules that regulate cell survival, proliferation, motility and differentiation. The aberrant expression and/or function of these molecules have been linked to the growth, progression and metastasis of various cancers. As such, the analysis of mutations in the genes encoding GPCRs, G proteins and their downstream targets provides important clues regarding how these signaling cascades contribute to malignancy. Recent genome wide sequencing efforts have unveiled the presence of frequent mutations in GNA13, the gene encoding the G protein Galpha13, in Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL). We found that mutations in the downstream target of Galpha13, RhoA, are also present in Burkitt's lymphoma and DLBCL. By multiple complementary approaches, we now show that that these cancer-specific GNA13 and RHOA mutations are inhibitory in nature, and that the expression of wild-type Galpha13 in B-cell lymphoma cells with mutant GNA13 has limited impact in vitro but results in a remarkable growth inhibition in vivo. Thus, although Galpha13 and RhoA activity has previously been linked to cellular transformation and metastatic potential of epithelial cancers, our findings support a tumor suppressive role for Galpha13 and RhoA in Burkitt's lymphoma and DLBCL. PMID- 26616859 TI - STAT3 selectively interacts with Smad3 to antagonize TGF-beta signalling. AB - Smad and STAT proteins are critical signal transducers and transcription factors in controlling cell growth and tumorigenesis. Here we report that the STAT3 signaling pathway attenuates transforming growth factor-beta (TGF-beta)-induced responses through a direct Smad3-STAT3 interplay. Activated STAT3 blunts TGF-beta mediated signaling. Depletion of STAT3 promotes TGF-beta-mediated transcriptional and physiological responses, including cell cycle arrest, apoptosis and epithelial-to-mesenchymal transition. STAT3 directly interacts with Smad3 in vivo and in vitro, resulting in attenuation of the Smad3-Smad4 complex formation and suppression of DNA-binding ability of Smad3. The N-terminal region of DNA-binding domain of STAT3 is responsible for the STAT3-Smad3 interaction and also indispensable for STAT3-mediated inhibition of TGF-beta signaling. Thus, our finding illustrates a direct crosstalk between the STAT3 and Smad3 signaling pathways that may contribute to tumor development and inflammation. PMID- 26616860 TI - ALK inhibitor resistance in ALK(F1174L)-driven neuroblastoma is associated with AXL activation and induction of EMT. AB - The crizotinib-resistant ALK(F1174L) mutation arises de novo in neuroblastoma (NB) and is acquired in ALK translocation-driven cancers, lending impetus to the development of novel anaplastic lymphoma kinase (ALK) inhibitors with different modes of action. The diaminopyrimidine TAE684 and its derivative ceritinib (LDK378), which are structurally distinct from crizotinib, are active against NB cells expressing ALK(F1174L). Here we demonstrate acquired resistance to TAE684 and LDK378 in ALK(F1174L)-driven human NB cells that is linked to overexpression and activation of the AXL tyrosine kinase and epithelial-to-mesenchymal transition (EMT). AXL phosphorylation conferred TAE684 resistance to NB cells through upregulated extracellular signal-regulated kinase (ERK) signaling. Inhibition of AXL partly rescued TAE684 resistance, resensitizing these cells to this compound. AXL activation in resistant cells was mediated through increased expression of the active form of its ligand, GAS6, that also served to stabilize the AXL protein. Although ectopic expression of AXL and TWIST2 individually in TAE684-sensitive parental cells led to the elevated expression of mesenchymal markers and invasive capacity, only AXL overexpression induced resistance to TAE684 as well. TAE684-resistant cells showed greater sensitivity to HSP90 inhibition than did their parental counterparts, with downregulation of AXL and AXL-mediated ERK signaling. Our studies indicate that aberrant AXL signaling and development of an EMT phenotype underlie resistance of ALK(F1174L)-driven NB cells to TAE684 and its derivatives. We suggest that the combination of ALK and AXL or HSP90 inhibitors be considered to delay the emergence of such resistance. PMID- 26616861 TI - Critical role of mitochondria-mediated apoptosis for JNJ-26481585-induced antitumor activity in rhabdomyosarcoma. AB - JNJ-26481585 is a second-generation histone deacetylase inhibitor with broad range efficacy and improved pharmacodynamic properties. In the present study, we investigated the therapeutic potential of JNJ-26481585 and its molecular mechanisms of action in rhabdomyosarcoma (RMS). Here, we report that JNJ- 26481585's anticancer activity critically depends on an intact mitochondrial pathway of apoptosis. JNJ-26481585 induces apoptosis and also inhibits long-term clonogenic survival of several RMS cell lines at nanomolar concentrations that cause histone acetylation. Importantly, JNJ-26481585 significantly suppresses tumor growth in vivo in two preclinical RMS models, that is, the chorioallantoic membrane model and a xenograft mouse model. Mechanistically, we identify activation of the mitochondrial pathway of apoptosis as a key event that is critically required for JNJ-26481585-mediated cell death. JNJ-26481585 upregulates expression levels of several BH3-only proteins including Bim, Puma and Noxa, which all contribute to JNJ-26481585-mediated apoptosis, as knockdown of Bim, Puma or Noxa significantly inhibits cell death. This shift toward proapoptotic Bcl-2 proteins promotes activation of Bax and Bak as a critical event, as genetic silencing of Bax or Bak protects against JNJ-26481585-induced apoptosis. Intriguingly, rescue experiments reveal that JNJ-26481585 triggers Bax/Bak activation independently of caspase activation and activates caspase-9 as the initiator caspase in the cascade, as Bcl-2 overexpression, but not the broad range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) blocks JNJ-26481585-induced Bax/Bak activation and caspase-9 cleavage. In conclusion, JNJ-26481585 exerts potent antitumor activity against RMS in vitro and in vivo by engaging mitochondrial apoptosis before caspase activation and represents a promising therapeutic for further investigation in RMS. PMID- 26616863 TI - Affinity-based release of polymer-binding peptides from hydrogels with the target segments of peptides. AB - Peptides with affinities for the target segments of polymer hydrogels were identified by biological screening using phage-displayed peptide libraries, and these peptides exhibited an affinity-based release capability from hydrogels. The results from cell culture assays demonstrated the sustained anticancer effects of the drug-conjugated peptides that were released from the hydrogels. PMID- 26616862 TI - Regulation of oncogenic KRAS signaling via a novel KRAS-integrin-linked kinase hnRNPA1 regulatory loop in human pancreatic cancer cells. AB - Integrin-linked kinase (ILK) is a mediator of aggressive phenotype in pancreatic cancer. On the basis of our finding that knockdown of either KRAS or ILK has a reciprocal effect on the other's expression, we hypothesized the presence of an ILK-KRAS regulatory loop that enables pancreatic cancer cells to regulate KRAS expression. This study aimed to elucidate the mechanism by which this regulatory circuitry is regulated and to investigate the translational potential of targeting ILK to suppress oncogenic KRAS signaling in pancreatic cancer. Interplay between KRAS and ILK and the roles of E2F1, c-Myc and heterogeneous nuclear ribonucleoprotein as intermediary effectors in this feedback loop was interrogated by genetic manipulations through small interfering RNA/short hairpin RNA knockdown and ectopic expression, western blotting, PCR, promoter-luciferase reporter assays, chromatin immunoprecipitation and pull-down analyses. In vivo efficacy of ILK inhibition was evaluated in two murine xenograft models. Our data show that KRAS regulated the expression of ILK through E2F1-mediated transcriptional activation, which, in turn, controlled KRAS gene expression via hnRNPA1-mediated destabilization of the G-quadruplex on the KRAS promoter. Moreover, ILK inhibition blocked KRAS-driven epithelial-mesenchymal transition and growth factor-stimulated KRAS expression. The knockdown or pharmacological inhibition of ILK suppressed pancreatic tumor growth, in part, by suppressing KRAS signaling. These studies suggest that this KRAS-E2F1-ILK-hnRNPA1 regulatory loop enables pancreatic cancer cells to promote oncogenic KRAS signaling and to interact with the tumor microenvironment to promote aggressive phenotypes. This regulatory loop provides a mechanistic rationale for targeting ILK to suppress oncogenic KRAS signaling, which might foster new therapeutic strategies for pancreatic cancer. PMID- 26616864 TI - A tool for determining duration of mortality events in archaeological assemblages using extant ungulate microwear. AB - The seasonality of human occupations in archaeological sites is highly significant for the study of hominin behavioural ecology, in particular the hunting strategies for their main prey-ungulates. We propose a new tool to quantify such seasonality from tooth microwear patterns in a dataset of ten large samples of extant ungulates resulting from well-known mass mortality events. The tool is based on the combination of two measures of variability of scratch density, namely standard deviation and coefficient of variation. The integration of these two measurements of variability permits the classification of each case into one of the following three categories: (1) short events, (2) long-continued event and (3) two separated short events. The tool is tested on a selection of eleven fossil samples from five Palaeolithic localities in Western Europe which show a consistent classification in the three categories. The tool proposed here opens new doors to investigate seasonal patterns of ungulate accumulations in archaeological sites using non-destructive sampling. PMID- 26616865 TI - Increased interleukin-6 correlates with myelin oligodendrocyte glycoprotein antibodies in pediatric monophasic demyelinating diseases and multiple sclerosis. AB - Acquired demyelinating syndromes (ADS) in children evolve either as a monophasic disease diagnosed as acute demyelinating encephalomyelitis (ADEM), transverse myelitis (TM) or optic neuritis (ON), or a multiphasic one with several relapses most often leading to the diagnosis of multiple sclerosis (MS) or neuromyelitis optica (NMO). These neuroinflammatory disorders are increasingly associated with autoantibodies against proteins such as aquaporin-4 in rare instances, and more frequently against myelin oligodendrocyte glycoprotein (MOG). Recently, in adult NMO patients, C5a levels were shown to be elevated in cerebrospinal fluid (CSF) during acute exacerbation. We investigated the CSF levels of anaphylatoxins and pro-inflammatory cytokines, and plasma MOG antibodies in onset samples from children with ADS. Thirty four children presenting with a first episode of ADS, 17 with monophasic ADS (9 with ADEM, 4 with TM and 4 with ON) and 17 with MS, who had paired blood and CSF samples at onset were included and compared to 12 patients with other non-inflammatory neurological disorders (OND). Cytokines and anaphylatoxins in CSF were measured by Cytometric Bead Array immunoassay. MOG antibody titers in plasma were tested by flow cytometry using a stable cell line expressing full-length human MOG. We found a significant increase in C5a levels in the CSF of patients with monophasic ADS (n=17) compared to OND (n=12, p=0.0036) and to MS (n=17, p=0.0371). The C5a levels in MS were higher than in OND without reaching significance (p=0.2). CSF IL-6 levels were significantly increased in monophasic ADS compared to OND (p=0.0027) and to MS (p=0.0046). MOG antibody plasma levels were significantly higher in monophasic ADS (p<0.0001) and, to a lesser extent, in MS compared to OND (p=0.0023). Plasma MOG antibodies and CSF IL-6 levels were significantly correlated (r=0.51, p=0.018). CSF C5a and IL-6 levels are increased in monophasic ADS but not in MS when compared to OND, suggesting that these markers may help to predict monophasic or relapsing fate of ADS at onset. MOG antibody titers, which were higher in monophasic ADS than in MS, correlated with IL-6 levels, but not with C5a, suggesting an association between MOG antibodies and neuroinflammation in pediatric ADS. PMID- 26616866 TI - Anti-aquaporin-4 autoantibodies in systemic lupus erythematosus persist for years and induce astrocytic cytotoxicity but not CNS disease. AB - Anti-aquaporin-4 autoantibodies are specific for the neuromyelitis optica spectrum disorders (NMOSD) and they have also been described in patients with systemic lupus erythematosus (SLE) with neurological signs consistent with NMOSD. Our objective was to test for the presence and pathogenicity of anti-AQP4 antibodies in SLE patients without neurological disease. Sera from 89 non-CNS-SLE patients were screened for anti-AQP4 autoantibodies. Two of the 89 patients were positive. Archived samples dating back 11 years were also positive. A brain and spinal cord MRI did not reveal any NMOSD-compatible lesions. An in vitro cytotoxicity assay showed that either sera or purified IgG from these patients induced a complement-mediated damage in cultured astrocytes comparable to antibodies obtained from typical NMO patients. We conclude that AQP4-antibodies can be present in SLE patients and persist for many years, without concurrent clinical or radiological NMOSD signs. It is unclear why the anti-AQP4 antibodies did not induce CNS disease. PMID- 26616867 TI - Molecular dynamics and intracellular signaling of the TNF-R1 with the R92Q mutation. AB - The tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A) gene encodes the TNF-R1, one of the main TNF receptors that mediates its inflammatory actions. In a recent study, serum levels of the soluble TNF-R1 and mRNA levels of the full length receptor were found to be significantly increased in multiple sclerosis (MS) patients carrying the R92Q mutation. Interestingly, R92Q-mutated patients were younger at disease onset and progressed slower as compared to non-carriers. Building on these previous findings, here we aimed to investigate by means of both in silico and in vitro approaches the mechanisms relating the R92Q substitution with functional changes of the receptor and their potential effects modulating MS disease course. Models of the extracellular domains of the human TNF-R1 and human TNF-R1 carrying the R92Q mutation, alone or bound to TNF, were constructed and submitted to molecular dynamics. TRAF2 and CASP3 mRNA expression levels were determined by real-time PCR in peripheral blood mononuclear cells (PBMC) from 61 MS patients, 9 R92Q carriers and 52 non-carriers (CT and CC genotypes for SNP rs4149584, respectively). Molecular dynamic studies revealed that the R92Q mutation increased the contact area between receptor and TNF (1070 and 1388A(2) for native and mutated receptor) and decreased the distance between them (28.7 to 27.9A), while Van der Waals and electrostatic interaction energies were increased. In PBMC from MS patients carrying the R92Q mutation, CASP3 mRNA expression levels were significantly increased compared to non-carriers, whereas a trend was observed for TRAF2. These data suggest that the R92Q mutation gives rise to a stronger interaction between the receptor and its ligand, which results in the potentiation of TNF-mediated pathways. Although further studies are needed, these functional changes may be related with the modulation in disease course reported in MS patients carrying the R92Q mutation. PMID- 26616868 TI - Leishmania infection and neuroinflammation: Specific chemokine profile and absence of parasites in the brain of naturally-infected dogs. AB - Visceral leishmaniasis is a chronic disease caused by Leishmania infantum. We aimed to detect the parasite in the brain of fifteen naturally-infected dogs using in situ hybridization and immunohistochemistry, and the gene expression of selected chemokines by RT-qPCR. We detected no parasite in the brain, but perivascular deposition of parasite DNA and IgG in the choroid plexus. We noticed up-regulation of CCL-3, CCL-4 and CCL-5, coherent with T lymphocyte accumulation, stating the brain as a pro-inflammatory environment. Indeed, not necessarily the parasite itself, but rather its DNA seems to act as a trigger to promote brain inflammation during visceral leishmaniasis. PMID- 26616869 TI - Histamine 4 receptor promotes expression of costimulatory B7.1/B7.2 molecules, CD28 signaling and cytokine production in stress-induced immune responses. AB - Recently, the expression of histamine 4 receptor (H4R) on neurons was reported, however its function in cells within the central nervous system (CNS) remains poorly understood. To this end, we used the H4R agonist, 4-methylhistamine (4 MeH), and the H4R antagonist, JNJ77777120 (JNJ), to investigate the function of H4R signaling in immune cells in a murine model of chronic stress. Treatment of stressed mice with 4-MeH resulted in an increase in the proportion of lymphocyte subsets (CD3(+), CD8(+), CD28(+), and CD4(+)CD28(+)) and cells expressing the co stimulatory molecules CD80(+) (B7.1) and CD86(+) (B7.2) in heparinized blood as compared to normal control (NC) and stressed control (SC) groups. We also observed that as compared to NC and SC mice, 4-MeH-treated mice showed greater production of IL-2(+), IL-6(+), IL-9(+), IL-21(+), and IL-27(+) cytokines in the spleen and by splenic CD4(+) T cells. Furthermore, 4-MeH treatment of stressed mice led to an increase in the levels of serum Th1/Th17 cytokines and corticosterone, and a decrease in Th2 cytokines. Treatment of chronically stressed mice with 4-MeH also augmented expression of IL-6, IL-21, NF-kappaB p65, and STAT3 mRNA. Moreover, Western blot analyses confirmed increased protein expression of NF-kappaB, iNOS, and STAT3 expression following 4-MeH treatment of chronically-stressed mice as compared to controls. These proteins provide a novel relevant targets for the manipulation of chronic stress induced immune regulation. In striking contrast, treatment of stressed mice with the H4R antagonist, JNJ, resulted in a substantial reduction in all of the aforementioned effects upon immune cell percentages and cytokine production. PMID- 26616870 TI - Berberine is a dopamine D1- and D2-like receptor antagonist and ameliorates experimentally induced colitis by suppressing innate and adaptive immune responses. AB - Berberine is an herbal alkaloid with various biological activities, including anti-inflammatory and antidepressant effects. Here, we examined the effects of berberine on dopamine receptors and the ensuing anti-inflammatory responses. Berberine was found to be an antagonist at both dopamine D1- and D2-like receptors and ameliorates the development of experimentally induced colitis in mice. In lipopolysaccharide-stimulated immune cells, berberine treatment modified cytokine levels, consistent with the effects of the dopamine receptor specific antagonists SCH23390 and L750667. Our findings indicate that dopamine receptor antagonists suppress innate and adaptive immune responses, providing a foundation for their use in combatting inflammatory diseases. PMID- 26616871 TI - The poor recovery of neuromyelitis optica spectrum disorder is associated with a lower level of CXCL12 in the human brain. AB - Neuromyelitis optica spectrum disorders (NMOSDs) are blindness-causing neuritis. In NMOSD patients, NMO-IgG evokes astrocytopathy that in turn causes demyelination. While measurement of NMO-IgG titer will help neurologists make the diagnosis of NMOSDs, it is not sufficient to evaluate the severity of astrocytopathy. In this study, we compared the different levels of an astrocyte biomarker in cerebrospinal fluid of NMOSD patients with good or poor recovery, and then linked their differences to the changes in remyelinating promoter (CXCL12) levels. Our results indicate that NMO-IgG down-regulated CXCL12 and impaired the remyelinating process, this may be a mechanism contributing to the poor recovery of NMOSDs. PMID- 26616872 TI - Clinical significance of the number of oligoclonal bands in patients with clinically isolated syndromes. AB - CSF oligoclonal bands (OCBs) in patients with clinically isolated syndromes (CIS) are a risk factor for clinically definite multiple sclerosis (CDMS). We aimed to address the relevance of the number of OCBs in the prognosis of CIS patients. 219 CIS patients were included in the study, and 42% of them developed the disease during follow-up (median: 5.04 years). Patients with a high number of CSF OCBs (third quartile, 8-12 OCBs) had 2.5-fold increase in CDMS risk, while no further increase in the HR of disease was observed for patients with more than 12 OCBs. The results did not change after adjustment for additional correlates of CDMS development. This association may be due to the epitope-spreading phenomenon and may reflect the stage of the disease at the time of the examination. PMID- 26616874 TI - Sickness behavior is accentuated in rats with metabolic disorders induced by a fructose diet. AB - This study investigated behavioral responses to an immune challenge among animals with fructose-induced metabolic disorders. Adult male Wistar rats were provided either water or a fructose solution (10%) for 5 weeks. Sickness behaviors were assessed 2h following the injection of either a lipopolysaccharide (LPS) or vehicle. The rats were subjected to an open field test, a social interaction test, a food intake test and a fever evaluation. Cytokine expression was assessed in both adipose tissue and hypothalamus samples. The neural response was assessed in the forebrain immunohistochemistry for c-Fos. Compared with the control group, the fructose diet induced dyslipidemia and significantly higher plasma total cholesterol, HDL-cholesterol, triglyceride, and glucose levels as well as both epididymal and retroperitoneal adiposity. Furthermore, in response to LPS (1 mg/kg), the rats subjected to a fructose diet exhibited exacerbated sickness behaviors and accentuated febrile responses. LPS induced Fos protein expression in several areas of the brains of the control rats; however, higher numbers of Fos-positive cells were observed in the brains of the rats that were fed a fructose diet. Moreover, larger increases in cytokine expression were observed in both the hypothalamus and the adipose tissue of the obese rats compared with the control rats in response to LPS. In this study, fructose diets played an important role in both the induction of metabolic disorders and the modulation of sickness behaviors in response to an immunological challenge, most likely through the induction of cytokines in the hypothalamus. PMID- 26616875 TI - Jerking & confused: Leucine-rich glioma inactivated 1 receptor encephalitis. AB - This is a case of autoimmune encephalitis with features of faciobrachial dystonic seizures (FBDS) pathognomonic for Leucine Rich Glioma inactivated (LGI)1 antibody encephalitis. This voltage-gated potassium channel complex encephalitis is marked by rapid onset dementia, FBDS and hyponatremia, which is sensitive to management with immunotherapy including steroids, IVIG and other agents. In this case report we review the clinical features, imaging and management of this condition. PMID- 26616873 TI - Lipoic acid reduces inflammation in a mouse focal cortical experimental autoimmune encephalomyelitis model. AB - Cortical lesions are a crucial part of MS pathology and it is critical to determine that new MS therapies have the ability to alter cortical inflammatory lesions given the differences between white and gray matter lesions. We tested lipoic acid (LA) in a mouse focal cortical EAE model. Brain sections were stained with antibodies against CD4, CD11b and galectin-3. Compared with vehicle, treatment with LA significantly decreased CD4+ and galectin-3+ immune cells in the brain. LA treated mice had fewer galectin-3+ cells with no projections indicating decrease in the number of infiltrating monocytes. LA significantly reduces inflammation in a focal cortical model of MS. PMID- 26616876 TI - Scavenger receptor SRA attenuates TLR4-induced microglia activation in intracerebral hemorrhage. AB - Scavenger receptor A (SRA) has been shown to participate in the pattern recognition of pathogen infection. However, its role in intracerebral hemorrhage has not been well defined. In this study, we detected SRA and TLR4 expression and inflammatory response of microglia treated with erythrocyte lysate in vitro, and observed the cerebral water content and neurological deficit of ICH mice in vivo. We found that SRA deficiency leads to greater sensitivity to erythrocyte lysate induced inflammatory response. SRA down-regulated inflammatory response expression in microglia by suppressing TLR4-induced activation. Collectively, we have identified the molecular linkage between SRA and the TLR4 signaling pathways in ICH. And our results reveal that SRA has important clinical implications for TLR-targeted immunotherapeutical strategy in ICH. PMID- 26616877 TI - Safety and efficacy of fingolimod in clinical practice: The experience of an academic center in the Middle East. AB - BACKGROUND: Few published studies addressed real-world clinical experience with fingolimod especially in the Middle East region. OBJECTIVE: To review our clinical experience with fingolimod at a specialized academic MS center in Lebanon. METHODS: All patients treated with fingolimod at the MS Center between October 2011 and January 2015 were retrospectively identified. RESULTS: A total of 122 patients were included. The first dose observation was uneventful in 98.8% of patients. Annualized relapse rate decreased from 1.16 pre-treatment to 0.29 post-treatment representing a relative risk reduction of 75% (p<0.0001). The proportion of patients with no new T2 or enhancing lesions was 66.3%. Seventy-six (62.3%) patients experienced adverse events with lymphopenia, increase liver enzymes, urinary tract infections and fatigue being the most common. CONCLUSION: Our cohort confirms the effectiveness and safety of fingolimod in a real world setting. PMID- 26616878 TI - N-adamantyl-4-methylthiazol-2-amine suppresses lipopolysaccharide-induced brain inflammation by regulating NF-kappaB signaling in mice. AB - We report that N-adamantyl-4-methylthiazol-2-amine (KHG26693), a novel thiazole derivative, can prevent lipopolysaccharide (LPS)-induced brain inflammation in mice. In this LPS-induced model of brain inflammation, administration of KHG26693 effectively prevented increases in the levels of IL-1beta, TNF-alpha, prostaglandin E2, malondialdehyde, and nitric oxide, and mitigated reductions in the levels of superoxide dismutase in the hippocampus. KHG26693 also prevented reductions in the levels of hippocampal brain-derived neurotrophic factors. Furthermore, pretreatment with KHG26693 prior to LPS treatment dramatically attenuated the elevation of inducible nitric oxide synthase and cyclooxygenase-2 protein levels. Moreover, pretreatment with KHG26693 significantly suppressed LPS induced phosphorylation of NF-kappaB and IkappaBalpha through the inactivation of IKKbeta. Additionally, KHG26693 caused the downregulation of LPS-induced cystathionine-b-synthase gene expression in the brain. Although the clinical relevance of our findings remains to be determined, our data suggest that KHG26693 might prevent neuronal cell injury via the reduction of inflammation and oxidative stress in the brain. PMID- 26616879 TI - Pertussis toxin promotes relapsing-remitting experimental autoimmune encephalomyelitis in Lewis rats. AB - Animal models simulate different aspects of human diseases and are essential to get a better understanding of the disease, studying treatments and producing new drugs. Experimental autoimmune encephalomyelitis (EAE) is a preferred model in multiple sclerosis research. Common EAE model in Lewis rats is induced using MBP peptide as a myelin antigen which results in a monophasic disease course. In the present study, EAE was induced in Lewis rats by homogenized guinea pig spinal cord along with or without pertussis toxin (PT). When PT was used, EAE turned into remitting-relapsing form and worsen the clinical symptoms. Higher inflammation and oxidative stress marker gene expression was observed when PT was administrated. PMID- 26616880 TI - Innate and adaptive immune response in stroke: Focus on epigenetic regulation. AB - Inflammation and immune response play a pivotal role in the pathophysiology of ischemic stroke giving their contribution to tissue damage and repair. Emerging evidence supports the involvement of epigenetic mechanisms such as methylation, histone modification and miRNAs in the pathogenesis of stroke. Interestingly, epigenetics can influence the molecular events involved in ischemic injury by controlling the switch from pro- to anti-inflammatory response, however, this is still a field to be fully explored. The knowledge of epigenetic processes could to allow for the discovery of more sensitive and specific biomarkers for risk, onset, and progression of disease as well as further novel tools to be used in both primary prevention and therapy of stroke. Indeed, studies performed in vitro and in small animal models seem to suggest a neuroprotective role of HDAC inhibitors (e.g. valproic acid) and antagomir (e.g. anti-miR-181a) in ischemic condition by modulation of both immune and inflammatory pathways. Thus, the clinical implications of altered epigenetic mechanisms for the prevention of stroke are very promising but clinical prospective studies and translational approaches are still warranted. PMID- 26616881 TI - Identification and characterization of natural antibodies against tau protein in an intravenous immunoglobulin product. AB - The latest therapeutic approaches to Alzheimer disease are using intravenous immunoglobulin (IVIG) products. Therefore, the detailed characterization of target-specific antibodies naturally occurring in IVIG products is beneficial. We have focused on characterization of antibodies isolated against tau protein, a biomarker of Alzheimer's disease, from Flebogamma IVIG product. The analysis of IgG subclass distribution indicated skewing toward IgG3 in anti-tau-enriched IgG fraction. The evaluation of their reactivity and avidity with several recombinant tau forms was performed by ELISA and blotting techniques. Truncated non phosphorylated tau protein (amino acids 155-421) demonstrated the highest reactivity and avidity index. We provide the first detailed insight into the reactivity of isolated natural antibodies against tau protein. PMID- 26616882 TI - IL-10 derived from CD1dhiCD5+ B cells regulates experimental autoimmune myasthenia gravis. AB - IL-10-competent subset within CD1d(hi)CD5(+) B cells, also known as B10 cells, has been shown to regulate autoimmune diseases. In our previous study, adoptive transfer of CD1d(hi)CD5(+) B cells expanded in vivo by GM-CSF prevented and suppressed experimental autoimmune myasthenia gravis (EAMG). The goal of this study was to further examine the role and mechanism of IL-10 in the regulatory function of B10 cells in EAMG. We found that only IL-10 competent CD1d(hi)CD5(+) B cells sorted from WT mice, but not IL-10 deficient CD1d(hi)CD5(+) B cells exhibited regulatory function in vitro and in vivo. Adoptive transfer of IL-10 competent CD1d(hi)CD5(+) B cells led to higher frequency of Tregs and B10 cells, and low levels of proinflammatory cytokines and autoantibody production. We conclude that IL-10 production within CD1d(hi)CD5(+) B cells plays an important role in immune regulation of EAMG. PMID- 26616883 TI - Exome and regulatory element sequencing of neuromyelitis optica patients. AB - Neuromyelitis optica (NMO) is rare in Finland. To identify rare genetic variants contributing to NMO risk we performed whole exome, HLA and regulatory region sequencing in all ascertained cases during 2005-2013 (n=5) in a Southern Finnish population of 1.6 million. There were no rare variant shared by all patients. Four missense variants were shared by two patients in C3ORF20, PDZD2, C5ORF47 and ZNF606. Another PDZD2 variant was found in a third patient. In the non-coding sequence two predictably functional rare variants were shared by two patients. Our results do not support a homogeneous genetic etiology of NMO in Finland. PMID- 26616884 TI - Lipopolysaccharide preconditioning prevents acceleration of kindling epileptogenesis induced by traumatic brain injury. AB - 10-20% of symptomatic epilepsies are post-traumatic. We examined effect of LPS preconditioning on epileptogenesis after controlled cortical impact (CCI). LPS (0.01, 0.1 and 0.5 mg/kg) was injected i.p. to rats 5 days before induction of CCI to parieto-temporal cortex. Kindling started 24h after CCI by i.p. injection of 30 mg/kg of pentylenetetrazole every other day until manifestation of 3 consecutive generalized seizures. CCI injury accelerated the rate of kindled seizures acquisition. LPS (0.1 and 0.5 mg/kg) prevented the acceleration of kindling. LPS preconditioning significantly decreased IL-1beta and TNF-alpha over expression and the number of damaged neurons in the hippocampus of traumatic rats. PMID- 26616885 TI - Oxytocin-secreting system: A major part of the neuroendocrine center regulating immunologic activity. AB - Interactions between the nervous system and immune system have been studied extensively. However, the mechanisms underlying the neural regulation of immune activity, particularly the neuroendocrine regulation of immunologic functions, remain elusive. In this review, we provide a comprehensive examination of current evidence on interactions between the immune system and hypothalamic oxytocin secreting system. We highlight the fact that oxytocin may have significant effects in the body, beyond its classical functions in lactation and parturition. Similar to the hypothalamo-pituitary-adrenal axis, the oxytocin-secreting system closely interacts with classical immune system, integrating both neurochemical and immunologic signals in the central nervous system and in turn affects immunologic defense, homeostasis, and surveillance. Lastly, this review explores therapeutic potentials of oxytocin in treating immunologic disorders. PMID- 26616886 TI - Elevated plasma inflammatory mediators in post-polio syndrome: No association with long-term functional decline. AB - A key feature of post-polio syndrome (PPS) is progressive loss of muscle strength. In other chronic diseases systemic inflammation has been linked to muscle wasting. In this study plasma TNF-alpha, IL-6, IL-8, and leptin levels were significantly increased in PPS-patients compared to healthy controls. There was however no association between these raised systemic levels of inflammatory mediators and long-term decline in quadriceps strength or other clinical parameters. In conclusion, there is evidence for systemic inflammation in PPS, yet the relationship with clinical deterioration remains tenuous. PMID- 26616887 TI - Guillain Barre syndrome (GBS): new insights in the molecular mimicry between C. jejuni and human peripheral nerve (HPN) proteins. AB - Profile and immunoreactivity of proteins from HPN tissue, and from Campylobacter jejuni (O:19) were investigated. Proteins were extracted, separated by SDS-PAGE, their cross reactivity monitored by Western blotting, and identified by nHPLC nESI-HRMS analysis. Proteins from C. jejuni, at Mw ~70 KDa were chaperone/co chaperone proteins (GroEL, DnaK and HtpG). In the corresponding HPN band were serum albumin, neurofilament light peptide, cytoskeletal keratins and one HSP 70 and one HSP60. These chaperones reciprocally share high primary sequence homology and conservation of their known epitopes. These findings suggest that HSP chaperones may be suitable candidates involved in the molecular mimicry triggering GBS. PMID- 26616888 TI - Clinical outcome of generalized myasthenia gravis in Hong Kong Chinese. AB - BACKGROUND: Myasthenia gravis (MG) is an organ-specific autoimmune disease characterized by autoantibody-mediated impairment of skeletal muscle neuromuscular transmission. MG causes significant morbidity and even mortality. We studied the long-term clinical outcome of generalized MG (gMG) patients. METHODS: Records of Chinese gMG patients managed in Queen Mary Hospital from 1997 to 2012 were reviewed. Clinical, serological and radiological characteristics were studied for independent predictors of good long-term clinical outcome. RESULTS: A total of 123 Chinese gMG patients were studied. Their mean onset age was 44.8 years (range 7-83 years), 87 (70.7%) were female, and median follow-up duration was 114 months (interquartile range 67-188 months). Thymoma were detected in 45 patients (36.6%). Acetylcholine receptor autoantibodies were detected in 99 patients (87.6%). Ninety-three patients (75.6%) received immunosuppressant therapy (corticosteroid 75.6%, azathioprine 58.5%, mycophenolate mofetil 5.7%, cyclosporin 5.7%) and 77 (62.6%) received thymectomy. Thirty-five (28.5%) patients experienced MG crisis and two died. Ninety-six (78.0%) patients had good outcome defined by Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) of complete stable remission (CSR), pharmacological remission (PR) or minimal manifestation (MM) at latest follow-up, whereas 24 patients (19.5%) had intermediate outcome defined by MGFA PIS of Improved (I); 3 patients (2.4%) had poor prognosis defined by MGFA PIS of unchanged (U), worse (W), exacerbation (E) or died of MG (D). Azathioprine therapy was the only independent predictor of good outcome (OR 3.57, 95% CI 1.05 12.10, p=0.042). CONCLUSION: 78.0% of gMG patients had good long-term clinical outcome. Azathioprine therapy independently predicted good clinical outcome. PMID- 26616889 TI - Autoantibody-mediated cytotoxicity in paediatric opsoclonus-myoclonus syndrome is dependent on ERK-1/2 phophorylation. AB - Paediatric opsoclonus-myoclonus syndrome (OMS) is in 50% of the cases associated with a neuroblastoma as a paraneoplastic syndrome and is associated with surface binding antibodies against cerebellar granular neurons (CGN). To evaluate possible pathogenic effects of these autoantibodies on CGN we examined their influence on the MAPKinase enzymes ERK-1/2 and p38 using flow cytometry and phospho-specific antibodies. OMS IgG but not IgG from neuroblastoma without OMS or healthy controls induced phosphorylation of ERK-1/2 in cerebellar granular neurons (p<0.01). No effect on p38 phosphorylation or on HEK293 control cell line could be detected. IgG-mediated phosphorylation of ERK-1/2 was associated with an increased cytotoxicity of CGN, which could be blocked by ERK-1/2 pathway inhibitor U0126. We here show that IgG-mediated anti-neuronal cytotoxicity in OMS is mediated by ERK-1/2 phosphorylation in CGN. PMID- 26616890 TI - Ustekinumab-induced drug eruption resembling lymphocytic infiltration (of Jessner Kanof) and lupus erythematosus tumidus. PMID- 26616891 TI - Water based scale-up of CPO-27 synthesis for nitric oxide delivery. AB - The applicability of water-based reflux and room temperature synthesis processes for the production of CPO-27 MOFs, suitable for NO delivery applications, is investigated. NO adsorption, storage and release performance of products obtained under reflux conditions are comparable to those of equivalent samples synthesised from traditional solvothermal methods at small scale. Products obtained from room temperature processes show lower NO release capability, although the quantities that are released are still more than adequate for biomedical applications. Results also reveal differences for the first time in NO uptake, storage and release depending on whether Zn, Ni or Mg is employed. The results indicate that while the crystallinity of CPO-27(Zn) and CPO-27(Mg) is not affected by moving to lower temperature methods, the crystallinity of CPO-27(Ni) is reduced. Particle morphology and size is also affected. The low temperature processes are successfully demonstrated at 20 L and 100 L scale and the main problems encountered during scale-up are outlined. The 100 L scale is in itself an appropriate production scale for some niche biomedical products. Indeed, results indicate that this synthesis approach is suitable for commercial production of MOFs for this application field. We also confirm that BET surface area from nitrogen adsorption at 77 K is not a good indicator for successful adsorption of NO. PMID- 26616892 TI - Solid-Phase Synthesis of 1,3,7,8-Tetrasubstituted Xanthine Derivatives on Traceless Solid Support. AB - Traceless solid-phase synthesis of 1,3,7,8-tetrasubstituted xanthine (1,3,7,8 tetrasubstituted 1H-purine-2,6(3H,7H)-dione) derivatives has been developed. The solid-phase synthetic route began on a solid supported N'-cyano-N-substituted carbamimidothioate, which was prepared from cyanamide, isothiocyanate, and Merrifield resin. After N-alkylation of carbamimidothioate resin with ethyl 2 bromoacetate, an imidazole ring is introduced by Thorpe-Ziegler-type cyclization. The resulting imidazole resin is converted to 1,3,7-trisubstituted xanthine resin using sequential reactions, such as Lewis acid-catalyzed urea formation, pyrimidine ring cyclization, and N-alkylation. After oxidation of sulfides to sulfones, traceless cleavage with amine or thiol nucleophiles afforded the desired 1,3,7,8-tetrasubstituted xanthines in good purities and overall yields (eight-steps; 36 examples). This efficient solid-phase synthesis enables the incorporation of four diversity points into the preparation of the 1,3,7,8 tetrasubstituted xanthines. PMID- 26616893 TI - Setting up the Pediatric Endoscopy Unit. AB - As pediatric gastrointestinal endoscopy continues to develop and evolve, pediatric gastroenterologists are more frequently called on to develop and direct a pediatric endoscopy unit. Lack of published literature and focused training in fellowship can render decision making about design, capacity, operation, equipment purchasing, and staffing challenging. To help guide management decisions, we distributed a short survey to 18 pediatric gastroenterology centers throughout the United States and Canada. This article provides practical guidance by summarizing available expert opinions on the topic of setting up a pediatric endoscopy unit. PMID- 26616894 TI - Training and Assessment in Pediatric Endoscopy. AB - A key aspect of pediatric gastroenterology practice is the ability to perform endoscopy procedures safely, effectively, and efficiently. Similar to adult endoscopy, performance of pediatric endoscopy requires the acquisition of related technical, cognitive, and integrative competencies to effectively diagnose and manage gastrointestinal disorders in children. However, the distinctive requirements of pediatric patients and their families and the differential spectrum of disease highlight the need for a pediatric-specific training curriculum and assessment framework to ensure endoscopic procedures are performed safely and successfully in children. This review outlines the current state of evidence as it pertains to pediatric endoscopy training and assessment. PMID- 26616895 TI - Informed Consent for Pediatric Endoscopy. AB - Informed consent and refusal for pediatric procedures involves a process in which the provider, child, and parents/guardians participate. In pediatric gastroenterology, many procedures are considered elective and the process generally begins with an office visit and ends with the signing of the consent document. If the process is emergent then this occurs more expeditiously and a formal consent may not be required. Information about the procedure should be shared in a way that allows a decision-making process to occur for both the parent/guardian and the child, if of assenting age. PMID- 26616896 TI - Measuring Quality in Pediatric Endoscopy. AB - Measuring quality in endoscopy includes the assessment of appropriateness of a procedure and the skill with which it is performed. High-quality pediatric endoscopy is safe and efficient, used effectively to make proper diagnoses, is useful for excluding other diagnoses, minimizes adverse events, and is accompanied by appropriate documentation from beginning through end of the procedure. There are no standard quality metrics for pediatric endoscopy, but proposed candidates are both process and outcomes oriented. Both are likely to be used in the near future to increase transparency about patient outcomes, as well as to influence payments for the procedure. PMID- 26616897 TI - Management of Upper Gastrointestinal Bleeding in Children: Variceal and Nonvariceal. AB - Upper gastrointestinal (UGI) bleeding is generally defined as bleeding proximal to the ligament of Treitz, which leads to hematemesis. There are several causes of UGI bleeding necessitating a detailed history to rule out comorbid conditions, medications, and possible exposures. In addition, the severity, timing, duration, and volume of the bleeding are important details to note for management purposes. Despite the source of the bleeding, acid suppression with a proton-pump inhibitor has been shown to be effective in minimizing rebleeding. Endoscopy remains the interventional modality of choice for both nonvariceal and variceal bleeds because it can be diagnostic and therapeutic. PMID- 26616898 TI - Lower Gastrointestinal Bleeding in Children. AB - This article provides an overview of the evaluation and management of lower gastrointestinal bleeding (LGIB) in children. The common etiologies at different ages are reviewed. Conditions with endoscopic importance for diagnosis or therapy include solitary rectal ulcer syndrome, polyps, vascular lesions, and colonic inflammation and ulceration. Diagnostic modalities for identifying causes of LGIB in children include endoscopy and colonoscopy, cross-sectional and nuclear medicine imaging, video capsule endoscopy, and enteroscopy. Pre-endoscopic preparation and decision-making unique to pediatrics is highlighted. The authors conclude with a summary of current and emerging therapeutic hemostatic techniques that can be used in pediatric patients. PMID- 26616899 TI - Button Battery Ingestion in Children: A Paradigm for Management of Severe Pediatric Foreign Body Ingestions. AB - Gastrointestinal injuries secondary to button battery ingestions in children have emerged as a dangerous and difficult management problem for pediatricians. Implementation of a multidisciplinary team approach, with rapid and coordinated care, is paramount to minimize the risk of negative outcomes. In addition to providing a comprehensive review of the topic, this article outlines the authors' referral center's experience with patients with severe battery ingestion, highlighting the complications, outcomes, and important lessons learned from their care. The authors also propose an algorithm for clinical care that may be useful for guiding best management of pediatric button battery ingestion. PMID- 26616900 TI - Pediatric Considerations in Endoscopic Retrograde Cholangiopancreatography. AB - Endoscopic retrograde cholangiopancreatography is a technically challenging endoscopic technique that provides a minimally invasive way of evaluating and treating pathologic abnormality in the bile ducts and pancreas. Its utilization in children is increasing rapidly, broadening the understanding of its pediatric indications, clinical utility, and technical limitations. This article updates providers about specific considerations of endoscopic retrograde cholangiopancreatography in children as they relate to appropriate indications, patient preparation, available equipment, as well as expected technical and clinical outcomes following the procedure in pediatric populations. PMID- 26616901 TI - Role of Endoscopic Ultrasound in Pediatric Disease. AB - The application of endoscopic ultrasound (EUS) in children is growing, with studies demonstrating a positive impact of EUS in the management of childhood diseases. EUS has shown to be useful in the evaluation and management of a spectrum of childhood diseases including pancreaticobiliary disease, congenital anomalies, submuocsal lesions, biliary stones disease, inflammatory bowel disease, and eosinophilic esophagitis. Its diagnostic capabilities with fine needle aspiration and core-needle biopsy are shown to be technically successful, safe, and effective in several pediatric studies. Therapeutic EUS procedures include endoscopic cystgastrostomy, celiac plexus neurolysis, and biliary access. This article discusses the role of EUS for diagnostic and therapeutic purposes in pediatrics. PMID- 26616902 TI - Advances in Pediatric Small Bowel Imaging. AB - Technological advances for visualizing the small bowel have significantly grown over the past few decades. Balloon-assisted enteroscopy has come to the forefront of these innovations, and has been found to be safe and effective in children with small bowel ailments. The expanding body of research into balloon-assisted enteroscopy will continue to refine the current knowledge base of this technique, along with a growing assessment of the long-term benefits of such interventions. PMID- 26616903 TI - Advances in Pediatric Gastrostomy Placement. AB - Placement of gastrostomy tubes in infants and children has become increasingly commonplace. A historical emphasis on use of open gastrostomy has been replaced by less invasive methods of placement, including percutaneous endoscopic gastrostomy and laparoscopically assisted gastrostomy procedures. Various complications, ranging from minor to the more severe, have been reported with all methods of placement. Many pediatric patients who undergo gastrostomy tube placement will require long-term enteral therapy. Given the prolonged time pediatric patients may remain enterally dependent, further quality improvement and education initiatives are needed to improve long-term care and outcomes of these patients. PMID- 26616905 TI - Endoscopic Management of Anastomotic Esophageal Strictures Secondary to Esophageal Atresia. AB - The reported incidence of anastomotic stricture after esophageal atresia repair has varied in case series from as low as 9% to as high as 80%. The cornerstone of esophageal stricture treatment is dilation with either balloon or bougie. The goal of esophageal dilation is to increase the luminal diameter of the esophagus while also improving dysphagia symptoms. Once a stricture becomes refractory to esophageal dilation, there are several treatment therapies available as adjuncts to dilation therapy. These therapies include intralesional steroid injection, mitomycin C, esophageal stent placement, and endoscopic incisional therapy. PMID- 26616906 TI - Pediatric Gastrointestinal Endoscopy: A Mature Subspecialty. PMID- 26616904 TI - Role of Endoscopy in Diagnosis and Management of Pediatric Eosinophilic Esophagitis. AB - Eosinophilic esophagitis (EoE) is a chronic allergic (immune-mediated) disease that leads to esophageal dysfunction and feeding disorders in children. Foods, and possibly environmental triggers, cause an inflammatory response in the esophagus, leading to esophageal inflammation, eosinophilic infiltration, and esophageal dysmotility, which may progress to dysphagia, food impaction, and esophageal stricture. Endoscopy with biopsy and histologic evaluation is currently the only method to diagnose EoE. Once diagnosed with EoE, children undergo follow-up endoscopy after therapy initiation and adjustments to ensure remission. Furthermore, children with food impactions or strictures may require endoscopic intervention such as foreign body removal and/or esophageal dilation. PMID- 26616907 TI - Pediatric Endoscopy. PMID- 26616908 TI - Engineering anastomosis between living capillary networks and endothelial cell lined microfluidic channels. AB - This paper reports a method for generating an intact and perfusable microvascular network that connects to microfluidic channels without appreciable leakage. This platform incorporates different stages of vascular development including vasculogenesis, endothelial cell (EC) lining, sprouting angiogenesis, and anastomosis in sequential order. After formation of a capillary network inside the tissue chamber via vasculogenesis, the adjacent microfluidic channels are lined with a monolayer of ECs, which then serve as the high-pressure input ("artery") and low pressure output ("vein") conduits. To promote a tight interconnection between the artery/vein and the capillary network, sprouting angiogenesis is induced, which promotes anastomosis of the vasculature inside the tissue chamber with the EC lining along the microfluidic channels. Flow of fluorescent microparticles confirms the perfusability of the lumenized microvascular network, and minimal leakage of 70 kDa FITC-dextran confirms physiologic tightness of the EC junctions and completeness of the interconnections between artery/vein and the capillary network. This versatile device design and its robust construction methodology establish a physiological transport model of interconnected perfused vessels from artery to vascularized tissue to vein. The system has utility in a wide range of organ-on-a-chip applications as it enables the physiological vascular interconnection of multiple on-chip tissue constructs that can serve as disease models for drug screening. PMID- 26616909 TI - Gemcitabine-resistant pancreatic cancer: a second-line option. PMID- 26616911 TI - Behavioral toxicity and physiological changes from repeated exposure to fluorene administered orally or intraperitoneally to adult male Wistar rats: A dose response study. AB - Fluorene is one of the most abundant polycyclic aromatic hydrocarbons (PAHs) in the environment by reason of its high volatility. Demonstrated to be a neurotoxicant through inhalation, it was also identified as a contributive PAH to food contamination. Since no data are available on its oral neurotoxicity, the purpose of the present study was to assess the behavioral and physiological toxicity of repeated oral administration of fluorene to adult Wistar male rats. Animals were daily treated with fluorene at 1, 10 or 100mg/kg/day for 28 consecutive days. Administration was intraperitoneal (i.p.) or oral (p.o.) to evaluate the influence of the route of exposure on fluorene toxicity. Following this period of treatment, animals in both groups were subjected to similar cognitive evaluations, namely anxiety (elevated-plus maze), locomotor activity (open-field) and learning and memory abilities (eight-arm maze and avoidance test of an aversive light stimulus), as well as physiological measurements. The behavioral testing occurred from the 28th to the 60th day of the experiment during which fluorene treatment continued uninterrupted. At the end of this period, the concentration levels of fluorene and of three of its monohydroxylated metabolites in blood and brain were determined using a GC-MS/MS method. The results demonstrated a reduction in rat anxiety level at the lowest doses administered (1 and 10mg/kg/day) regardless of the treatment route, whereas locomotor activity and learning abilities remained unchanged. Moreover, a less significant weight gain was noticed in animals i.p.- and p.o.-treated with 100mg/kg/day during the 28-day period of treatment, which, upon comparison with the three other groups, induced a body weight gap that was maintained throughout the experiment. Significant increases in relative liver weight were also observed in a dose-dependent manner in orally treated rats and only in animal treated i.p. with 100mg/kg/day. According to the dose, higher concentration levels of fluorene and its monohydroxylated metabolites were measured in blood and brain compartments of i.p.-treated rats compared to p.o.-treated animals. In conclusion, fluorene reduced the anxiety level of rats related to dose, treatment route, duration of exposure and blood concentration levels of metabolites. PMID- 26616912 TI - The effects of preweaning manganese exposure on spatial learning ability and p CaMKIIalpha level in the hippocampus. AB - BACKGROUND: The effects and mechanisms of preweaning Manganese (Mn) exposure on cognitive dysfunction remain unclear. OBJECTIVE: This study evaluated the effects of preweaning Mn exposure on spatial learning and memory as well as the protein expression of CaMKIIalpha and p-CaMKIIalpha. METHODS: We treated neonate rats with Mn(2+) doses of 0 (control group), 10, 20 and 30mg of Mn(2+) per kg body weight (Mn-exposed groups) over postnatal day (PND) 1-21 by intraperitoneal injection. The ability of spatial learning and memory was tested on PND 22 using the Morris water maze (MWM), while the protein expressions of CaMKIIalpha and p CaMKIIalpha in the hippocampus were evaluated by Western blotting. The levels of Mn in the blood and hippocampus were measured by inductively coupled plasma-mass spectrometry (ICP-MS). RESULTS: The rats in Mn-exposed groups showed a significant delay in spatial learning ability on the third day of the MWM without dose-dependent differences, but there was no effect on the spatial memory ability. p-CaMKIIalpha, but not CaMKIIalpha protein expression significantly reduced in the Mn-exposed group. CONCLUSION: These findings suggested that the inhibition of p-CaMKIIalpha could be one of the mechanisms involved in the occurrence of Mn-induced cognitive impairments. PMID- 26616910 TI - Delayed effects of developmental exposure to low levels of the aryl hydrocarbon receptor agonist 3,3',4,4',5-pentachlorobiphenyl (PCB126) on adult zebrafish behavior. AB - Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants. The most toxic PCBs are the non-ortho-substituted ("dioxin-like") congeners that act through the aryl hydrocarbon receptor (AHR) pathway. In humans, perinatal exposure to dioxin-like PCBs is associated with neurodevelopmental toxicity in children. Yet, the full potential for later-life neurobehavioral effects that result from early-life low level exposure to dioxin-like PCBs is not well understood. The objective of this study was to determine the effects of developmental exposure to low levels of dioxin-like PCBs on early- and later-life behavioral phenotypes using zebrafish as a model system. We exposed zebrafish embryos to either vehicle (DMSO) or low concentrations of PCB126 (0.3, 0.6, 1.2nM) for 20h (4-24h post fertilization), and then reared them to adulthood in clean water. Locomotor activity was tested at two larval stages (7 and 14 days post fertilization). Adult fish were tested for anxiety-related behavior using the novel tank and shoaling assays. Adult behavioral assays were repeated several times on the same group of fish and effects on intra- and inter-trial habituation were determined. While there was no effect of PCB126 on larval locomotor activity in response to changes in light conditions, developmental exposure to PCB126 resulted in impaired short- and long-term habituation to a novel environment in adult zebrafish. Cyp1a induction was measured as an indicator for AHR activation. Despite high induction at early stages, cyp1a expression was not induced in the brains of developmentally exposed adult fish that showed altered behavior, suggesting that AHR was not activated at this stage. Our results demonstrate the effectiveness of the zebrafish model in detecting subtle and delayed behavioral effects resulting from developmental exposure to an environmental contaminant. PMID- 26616914 TI - Analysis of trichothecenes in laboratory rat feed by gas chromatography-tandem mass spectrometry. AB - A method for the determination of seven trichothecenes, neosolaniol (NEO), diacetoxyscirpenol (DAS), deoxynivalenol (DON), nivalenol (NIV), fusarenon-X (FUS X), 3-acetyldeoxynivalenol (3-ADON) and 15-acetyldeoxynivalenol (15-ADON), in laboratory rat feed by GC-MS/MS was developed. Sample extraction and purification was performed by an acidified mixture of acetonitrile/water (80-20% v/v). Limits of quantitation (LOQs) were between 1 and 10 MUg kg(-1) for all studied trichothecenes. Eight concentration levels between the LOQ and 100 * LOQ were used for the calibration curves. Matrix-matched calibration was used for quantitation purposes to compensate the detector signal enhancement obtained for all the analytes. The method accuracy was evaluated by recovery assays at three concentration levels, 25, 50 and 100 MUg kg(-1) (n = 9). Recoveries ranged from 62% to 97% and precision, expressed as intra- and inter-day relative standard deviations, was evaluated for all compounds. The validated method was successfully applied to the analysis of 35 laboratory rat feed samples showing mycotoxin contamination in 66% of the samples. DON was the most prevalent trichothecene followed by 15-ADON, NIV and 3-ADON. The maximum DON concentration reached in real samples was 2156 +/- 4.3 MUg kg(-1), while NEO, DAS and FUS-X were not detected in any sample. Multi-contamination by at least two mycotoxins was observed in 17% of the analysed feed samples. PMID- 26616913 TI - Brain abscess mimicking brain metastasis in breast cancer. AB - 61 year old female presented with chief complaints of headache for 30 days, fever for 10 days, altered behavior for 10 days and convulsion for 2 days. She was diagnosed and treated as a case of carcinoma of left breast 5 years ago. MRI brain showed a lobulated lesion in the left frontal lobe. She came to our hospital for whole brain radiation as a diagnosed case of carcinoma of breast with brain metastasis. Review of MRI brain scan, revealed metastasis or query infective pathology. MR spectroscopy of the lesion revealed choline: creatinine and choline: NAA (N-Acetylaspartate) ratios of ~1.6 and 1.5 respectively with the presence of lactate within the lesion suggestive of infective pathology. She underwent left fronto temporal craniotomy and evacuation of abscess and subdural empyema. Gram stain showed gram positive cocci. After 1 month of evacuation and treatment she was fine. This case suggested a note of caution in every case of a rapidly evolving space-occupying lesion independent of the patient's previous history. PMID- 26616915 TI - DNA replication stress and cancer: cause or cure? AB - There is an extensive and growing body of evidence that DNA replication stress is a major driver in the development and progression of many cancers, and that these cancers rely heavily on replication stress response pathways for their continued proliferation. This raises the possibility that the pathways that ordinarily protect cells from the accumulation of cancer-causing mutations may actually prove to be effective therapeutic targets for a wide range of malignancies. In this review, we explore the mechanisms by which sustained proliferation can lead to replication stress and genome instability, and discuss how the pattern of mutations observed in human cancers is supportive of this oncogene-induced replication stress model. Finally, we go on to consider the implications of replication stress both as a prognostic indicator and, more encouragingly, as a potential target in cancer treatment. PMID- 26616916 TI - Construction of a smart temperature-responsive GPx mimic based on the self assembly of supra-amphiphiles. AB - Glutathione peroxidase (GPx) is a major defense against hydroperoxides as a kind of seleno-enzyme that protects cells from oxidative damage. A supramolecular vesicle with controllable GPx activity and morphology has been successfully constructed by the self-assembly of supra-amphiphiles formed by host-guest recognition between cyclodextrin and adamantane derivatives. By introducing thermosensitive poly(N-isopropylacrylamide) (PNIPAM) scaffolds and the catalytic moiety selenium into adamantane and cyclodextrin, respectively, the complex of catalysis-functionalized cyclodextrin with thermosensitivity-functionalized adamantane directed the formation of a supramolecular vesicle which acted as a GPx mimic at 37 degrees C. The self-assembled nanoenzyme exhibited an obvious temperature responsive characteristic and high GPx-like catalytic activity promoting the reduction of hydrogen peroxide (H2O2) with glutathione (GSH) as the reducing substrate at 37 degrees C. However, the vesicle disassembled when the temperature decreased to 25 degrees C due to the transition of PNIPAM between the coil and the globule. Interestingly, the catalytic activity changed along with the transformation of morphologies. The vesicle structure self-assembled at 37 degrees C provided the favorable microenvironment for the enzymatic reaction, hence we successfully developed a temperature-responsive nanoenzyme model. Moreover, the catalytic activity of the thermosensitive GPx mimic exhibited excellent reversibility and typical saturation kinetics behaviour similar to a natural enzyme catalyst. It is assumed that the proposed GPx model not only has remarkable advantages such as easy functionalization and facile preparation but also provided a new way to develop intelligent responsive materials. PMID- 26616917 TI - Phenolic content, antioxidant activity and effective compounds of kumquat extracted by different solvents. AB - The total phenolic and flavonoid content of extracts from peel of kumquat were higher than those from pulp, and those extracted from immature kumquat were higher than those from mature kumquat. The highest levels of phenolic and flavonoid content were obtained in hot water extracts. The flavonoids of kumquat extracted from hot water were mainly soluble conjugated compounds, including C glycosides, such as 3',5'-di-C-beta-glucopyranosylphloretin (DGPP), acacetin 8-C neohesperidoside (margaritene), acacetin 6-C-neohesperidoside (isomargaritene), apigenin 8-C-neohesperidoside, and O-glycosides, such as acacetin 7-O neohesperidoside (fortunellin), isosakuranetin 7-O-neohesperidoside (poncirin) and apigenin 7-O-neohesperidoside (rhoifolin). A positive relationship existed between total phenolic content and DPPH scavenging potency (p<0.001). Total flavonoid content showed a similar correlation (p<0.001) to DPPH scavenging potency. The effective flavonoids contributing to antioxidant activity were DGPP and apigenin 8-C-neohesperidoside, which could be extracted in high amounts, by hot water at 90 degrees C, from immature kumquat peel. PMID- 26616918 TI - On-line restricted access molecularly imprinted solid phase extraction of ivermectin in meat samples followed by HPLC-UV analysis. AB - A new restricted access molecularly imprinted polymer coated with bovine serum albumin (RAMIP-BSA) was synthesized, characterized and used for direct analysis of ivermectin from bovine meat samples, in a two-dimensional liquid chromatography system with UV detection. Ivermectin, 4-vynilpiridine and ethylene glycol dimethacrylate were employed as template, functional monomer and cross linker, respectively. A BSA layer was cross-linked around the polymer, resulting in a biocompatible chemical barrier able to eliminate about 100% of protein from the samples. Ivermectin was extracted from the minced meat samples through a solvent extraction using methanol:water (70:30, v:v), and the extracts were directly injected into the two-dimensional liquid chromatography system, without any other treatment. Samples, fortified with ivermectin from 50 to 500 MUg kg( 1), were used to build the analytical calibration curve (r=0.996). The limit of quantification was 50 MUg kg(-1). Precision and accuracy presented variation coefficients, as well as relative errors lower than 17.0% and within -18.5% and 22.0%, respectively. PMID- 26616919 TI - Effect of theanine and polyphenols enriched fractions from decaffeinated tea dust on the formation of Maillard reaction products and sensory attributes of breads. AB - The antiglycoxidative properties of theanine (TEF) and polyphenols enriched fractions (PEF) prepared from tea dust were tested in a model system composed of bovine serum albumin (BSA) and methylglyoxal (MGO). PEF caused a decrease in available free amino groups of BSA in presence and absence of MGO, suggesting the simultaneous occurrence of glycoxidation reaction and phenols-protein interaction. The presence of PEF and TEF inhibited formation of fluorescent advanced glycation end-products (AGEs). Moreover, theanine (TB) and polyphenol enriched bread (PB) were formulated. A significant increase in free amino groups was observed in TBs with a dose-response effect, while addition of PEF in bread produced a significant decrease (p<0.05). PEF efficiently reduced fluorescent AGE formation in breads compared with TEF. The results are in line with the simplified model systems. PEF used as food ingredient allows obtaining a tasty food possessing health promoting properties and lower content of potential harmful compounds (AGEs). PMID- 26616920 TI - Multiple headspace-solid phase microextraction for the determination of migrants coming from a self-stick label in fresh sausage. AB - Most fresh sausages are sold with a self-stick adhesive label stuck directly on it. Because of that, the substances in the adhesive could migrate into the fresh sausage. In this work, the multiple headspace-solid-phase microextraction technique has been optimized to quantify the migrants found in the fresh sausage. All the compounds could be analyzed by this technique since its concentration decay exponentially with the number of extractions with good correlation coefficients (0.8258-0.9987). Then, migration assays were carried out and an evaluation of the potential risk for the human health was undertaken with the conclusion that the migration of the compounds from the label does not endanger human health. The results were compared those obtained in migration to casing filled with isooctane used as fat food simulant by Canellas et al. (2014). The values obtained for isooctane (10-600 ng/g) were much higher than the migration values found in the meat stuffed in casing expressed as ng/g of fat content (ranged from 0.02 to 3.3 ng/g of fat content). This finding shows that in some scenarios, it is difficult to simulate the intended contact of materials used in food packaging with simulants. PMID- 26616921 TI - Legume seeds and colorectal cancer revisited: Protease inhibitors reduce MMP-9 activity and colon cancer cell migration. AB - MMP-9 activity is strongly related to cancer growth and metastization. This study aimed at assessing the inhibitory potential of the major seed protein fractions from eight selected legume species towards MMP-9 activity in colon carcinoma cells. Albumin and globulin fractions were screened for MMP-9 inhibitors, using a fluorometric assay and gelatin zymography. Their effect on HT29 cell proliferation and cell migration was tested, as well as on the corresponding intrinsic cellular MMP-9 activities. Seed proteins include potent inhibitors of MMP-9, particularly low molecular mass proteins. Their effectiveness differs greatly among species, with a positive correlation detected between their inhibitory activity and the reduction in cell migration. Lupin seeds contain the most efficient MMP-9 inhibitors of all legume seeds analyzed, inhibiting both gelatinases and HT29 migration and growth, while pea seeds showed no effect. Results reveal legume protein MMPIs as novel metalloproteinase inhibitors with possible pharmacological interest. This may be important for selecting leguminous species with potential use in anti-cancer diets. PMID- 26616922 TI - Anthocyanin copigmentation and color of wine: The effect of naturally obtained hydroxycinnamic acids as cofactors. AB - Copigmentation of anthocyanins accounts for over 30% of fresh red wine color, while during storage, the color of polymeric pigments formed between anthocyanins and proanthocyanidins predominates. Rosmarinic acid and natural extracts rich in hydroxycinnamic acids, obtained from aromatic plants (Origanum vulgare and Satureja thymbra), were examined as cofactors to fresh Merlot wine and the effect on anthocyanin copigmentation and wine color was studied during storage for 6months. An increase of the copigmented anthocyanins that enhanced color intensity by 15-50% was observed, confirming the ability of complex hydroxycinnamates to form copigments. The samples with added cofactors retained higher percentages of copigmented anthocyanins and higher color intensity, compared to the control wine, up to 3 months. However, the change in the equilibrium between monomeric and copigmented anthocyanins that was induced by added cofactors, did not affect the rate of polymerization reactions during storage. PMID- 26616923 TI - Influence of postharvest UV-B treatment and fermentation on secondary plant compounds in white cabbage leaves. AB - The influence of postharvest UV-B on its own and in combination with fermentation (e.g. sauerkraut production) on formation and degradation of bioactive compounds was investigated in white cabbage, processed according to traditional Chinese fermentation methods. The pattern of polyphenols was affected by postharvest UV B: Newly formed coumaroylglycoside, feruloylglycoside, caffeoylglycoside (up to 1 mg/g dry matter; 4 days) and quercetintriglycoside (0.4-0.5 mg/gdm; 4 days) might be related to postharvest increase in enzyme activity in the biosynthesis. Decreasing contents were observed for the glucosinolates glucobrassicin and 4 methoxyglucobrassicin, but the formation of the degradation products dihydroascorbigen and dihydro-4-methoxyascorbigen, which might be related to cell shrinking as mechanical damage. Fermentation resulted in deglycosidation of hydroxycinnamic acids. Newly generated cinnamic acid from coumaric acid aglycone was detected in fermented plant material combined with UV-B (50 MUg/g). Glucosinolates and dihydroascorbigens were completely degraded. This study shows exemplary UV-B as a supplemental step to improve the nutritional quality of processed plants. PMID- 26616924 TI - Effect of feeding CLA on plasma and granules fatty acid composition of eggs and prepared mayonnaise quality. AB - Eggs rich in trans, trans conjugated linoleic acid (CLA) are significantly more viscous, have more phospholipids containing linoleic acid (LA), and more saturated triacylglycerol species than control eggs. However, the fatty acid (FA) composition of yolk plasma and granule fractions are unreported. Furthermore, there are no reports of mayonnaise rheological properties or emulsion stability by using CLA-rich eggs. Therefore, the objectives were (1) compare the FA composition of CLA-rich yolk granules and plasma, relative to standard control and LA-rich control yolks, (2) compare the rheological properties of mayonnaise prepared with CLA-rich eggs to control eggs and (3) compare the emulsion stability of CLA-yolk mayonnaise. CLA-rich eggs and soy control eggs were produced by adding 10% CLA-rich soy oil or 10% of control unmodified soy oil to the hen's diet. The eggs were used in subsequent mayonnaise preparation. CLA-yolk mayonnaise was more viscous, had greater storage modulus, resisted thinning, and was a more stable emulsion, relative to mayonnaise prepared with control yolks or soy control yolks. PMID- 26616925 TI - Perception of bitterness, sweetness and liking of different genotypes of lettuce. AB - Lettuce is an important leafy vegetable, consumed across the world, containing bitter sesquiterpenoid lactone (SL) compounds that may negatively affect consumer acceptance and consumption. We assessed liking of samples with differing absolute abundance and different ratios of bitter:sweet compounds by analysing recombinant inbred lines (RILs) from an interspecific lettuce mapping population derived from a cross between a wild (L. serriola acc. UC96US23) and domesticated lettuce (L. sativa, cv. Salinas). We found that the ratio of bitter:sweet compounds was a key determinant of bitterness perception and liking. We were able to demonstrate that SLs, such as 8-deoxylactucin-15-sulphate, contribute most strongly to bitterness perception, whilst 15-p-hydroxylphenylacetyllactucin-8-sulphate does not contribute to bitter taste. Glucose was the sugar most highly correlated with sweetness perception. There is a genetic basis to the biochemical composition of lettuce. This information will be useful in lettuce breeding programmes in order to produce leaves with more favourable taste profiles. PMID- 26616926 TI - Bactericidal action mechanism of negatively charged food grade clove oil nanoemulsions. AB - Clove oil (CO) anionic nanoemulsions were prepared with varying ratios of CO to canola oil (CA), emulsified and stabilized with purity gum ultra (PGU), a newly developed succinylated waxy maize starch. Interfacial tension measurements showed that CO acted as a co-surfactant and there was a gradual decrease in interfacial tension which favored the formation of small droplet sizes on homogenization until a critical limit (5:5% v/v CO:CA) was reached. Antimicrobial activity of the negatively charged CO nanoemulsion was determined against Gram positive GPB (Listeria monocytogenes and Staphylococcus aureus) and Gram negative GNB (Escherichia coli) bacterial strains using minimum inhibitory concentration (MIC) and a time kill dynamic method. Negatively charged PGU emulsified CO nanoemulsion showed prolonged antibacterial activities against Gram positive bacterial strains. We concluded that negatively charged CO nanoemulsion droplets self assemble with GPB cell membrane, and facilitated interaction with cellular components of bacteria. Moreover, no electrostatic interaction existed between negatively charged droplets and the GPB membrane. PMID- 26616927 TI - Controlling the taste receptor accessible structure of rebaudioside A via binding to bovine serum albumin. AB - We illustrate a method that uses bovine serum albumin (BSA) to control the receptor-accessible part of rebaudioside A (Reb A). The critical micelle concentration (CMC) of Reb A was found to be 4.5 mM and 5 mM at pH 3 and 6.7 respectively. NMR studies show that below its CMC, Reb A binds weakly to BSA to generate a Reb A-protein complex ("RPC"), which is only modestly stable under varying conditions of pH (3.0-6.7) and temperature (4-40 degrees C) with its binding affinities determined to be in the range of 5-280 mM. Furthermore, saturation transfer difference (STD) NMR experiments confirm that the RPC has fast exchange of the bitterness-instigating diterpene of Reb A into the binding sites of BSA. Our method can be used to alter the strength of Reb A-receptor interaction, as a result of binding of Reb A to BSA, which may ultimately lead to moderation of its taste. PMID- 26616928 TI - Biguanide-functionalized mesoporous SBA-15 silica as an efficient solid catalyst for interesterification of vegetable oils. AB - The biguanide-functionalized SBA-15 materials were fabricated by grafting of organic biguanide onto the SBA-15 silica through covalent attachments, and then this organic-inorganic hybrid material was employed as solid catalysts for the interesterification of triacylglycerols for the modification of vegetable oils. The prepared catalyst was characterized by FTIR, XRD, SEM, TEM, nitrogen adsorption-desorption and elemental analysis. The biguanide base was successfully tethered onto the SBA-15 silica with no damage to the ordered mesoporous structure of the silica after the organo-functionalization. The solid catalyst had stronger base strength and could catalyze the interesterification of triacylglycerols. The fatty acid compositions and triacylglycerol profiles of the interesterified products were noticeably varied following the interesterification. The reaction parameters, namely substrate ratio, reaction temperature, catalyst loading and reaction time, were investigated for the interesterification of soybean oil with methyl decanoate. The catalyst could be reused for at least four cycles without significant loss of activity. PMID- 26616929 TI - Antimicrobial activity of syringic acid against Cronobacter sakazakii and its effect on cell membrane. AB - Syringic acid (SA) has been reported to exhibit antibacterial ability against various microorganisms, but little work has been done on its effect on Cronobacter sakazakii. In this study, minimum inhibitory concentrations (MICs) of SA against various C. sakazakii strains were determined. Moreover, changes in intracellular ATP concentration, intracellular pH (pHin), membrane potential and membrane integrity were measured to evaluate the influence of SA on cell membrane. Finally, field emission scanning electron microscope (FESEM) was used to assess the morphological changes of bacterial cells caused by SA. It was shown that the MICs of SA against all tested C. sakazakii strains were 5mg/mL. SA retarded bacterial growth, and caused cell membrane dysfunction, which was evidenced by intracellular ATP concentration decrease, pHin reduction, cell membrane hyperpolarization and changes in cellular morphology. These findings indicated that SA has potential to be developed as a natural preservative to control C. sakazakii in foods associated with this pathogen and prevent related infections. PMID- 26616930 TI - Determination of some metal ions in various meat and baby food samples by atomic spectrometry. AB - In this paper, we report a simple and rapid solid phase extraction system for the separation/preconcentration and determination of Cd(II), Co(II), Cu(II), Fe(III), Cr(III), Pb(II), and Zn(II) ions by flame atomic absorption spectrometry (FAAS). This method is based upon the retention of metal ions on a column packed with poly[N-(3-methyl-1H-indole-1-yl)]-2-methacrylamide-co-2-acrylamido-2-methyl-1 propane sulphonic acid-co divinylbenzene] (MMAD) resin as a solid-phase extraction (SPE) sorbent at pH 8. At the optimized conditions, the limits of detection (3 s/b) between 0.12 and 1.6 MUg L(-1), preconcentration factor of 100, and the relative standard deviation of ?1.8% were achieved (n=10). The accuracy of the method was verified by analyzing certified reference materials (CRMs) and performing recovery experiments. The developed method was successfully applied to the various natural water, meat products and baby food samples. The recoveries of analyte ions were found in added real samples and CRMs from 95% to 102%. PMID- 26616931 TI - Effect of enzymatic (thermostable alpha-amylase) treatment on the physicochemical and antioxidant properties of extruded rice incorporated with soybean flour. AB - In order to determine the effect of enzymatic extrusion on the physicochemical and antioxidant properties of rice/soybean mixture, different mass ratios (100/0, 95/5, 85/15, 70/30, 50/50 and 25/75%, w/w) were treated with thermostable alpha amylase. The reduced special mechanical energy and the enhanced product temperature were closely and regularly linked with the increase of soybean content. The bulk density and water solubility index increased, and the water absorption index and viscosities decreased remarkably after enzymatic extrusion, however, the modification caused by alpha-amylase were dramatically eliminated with the increase of soybean content to ~50%. Moreover, the addition of enzyme exhibited an improvement of the total phenolic/flavonoid content (TPC/TFC) and antioxidant capacities compared to traditional extrusion. The TPC/TFC retention of extrudate (ratios of 85/15 and 70/30%) attained over 90%, but dramatically decreased (72.91 and 67.81%, respectively) with soybean added to 75%, probably due to the great reduction of starch substrate for enzymatic hydrolysis. PMID- 26616932 TI - Variability of chemical composition and antioxidant activity of essential oils between Myrtus communis var. Leucocarpa DC and var. Melanocarpa DC. AB - Essential oils (EOs) from several individuals of Myrtus communis L. (M. communis) growing in different habitats in Sardinia have been studied. The analyses were focused on four groups of samples, namely cultivated and wild M. communis var. melanocarpa DC, characterized by red/purple berries, and cultivated and wild M. communis var. leucocarpa DC, characterized by white berries. Qualitative and quantitative analyses demonstrated different EO fingerprints among the studied samples: cultivated and wild leucocarpa variety differs mainly from the melanocarpa variety by a high amount of myrtenyl acetate (>200 mg/mL and 0.4 mg/mL in leucocarpa and melanocarpa varieties respectively). Conversely, the wild group is characterized by a higher amount, compared with the cultivated species, of linalool (about 110 mg/mL and 20 mg/mL respectively), linalyl acetate (about 24 mg/mL and about 6 mg/mL respectively) whereas EOs of the cultivated plants were rich in pinocarveol-cis compared with wild plants (about 2 mg/mL and about 0.5 mg/mL respectively). Principal component analysis applied to the chromatographic data confirm a differentiation and classification of EOs from the four groups of M. communis plants. Finally, antioxidant activity of the studied EOs shows differences between the various categories of samples. PMID- 26616933 TI - Vine-shoot waste aqueous extract applied as foliar fertilizer to grapevines: Effect on amino acids and fermentative volatile content. AB - The aim of this work was to study the influence of foliar applications of different wood aqueous extracts on the amino acid content of musts and wines from Airen variety; and to study their relationship with the volatile compounds formed during alcoholic fermentation. For this purpose, the foliar treatments proposed were a vine-shoot aqueous extract applied in one and two times, and an oak extract which was only applied once. Results obtained show the potential of Airen vine-shoot waste aqueous extracts to be used as foliar fertilizer, enhancing the wine amino acid content especially when they were applied once. Similar results were observed with the aqueous oak extract. Regarding wine fermentative volatile compounds, there is a close relationship between musts and their wines amino acid content allowing us to discuss about the role of proline during the alcoholic fermentation and the generation of certain volatiles. PMID- 26616934 TI - Acidic electrolyzed water efficiently improves the flavour of persimmon (Diospyros kaki L. cv. Mopan) wine. AB - The ability of acidic (AcW) and alkaline electrolyzed waters (AlW) to improve the flavour of persimmon (Diospyros kaki L.) wine was evaluated. Wines made with AcW (WAcW) were significantly better than wines made with AlW or pure water (PW) in aroma, taste, and colour. Volatile analysis showed that WAcW has high alcohol and ester contents, including 2-phenylethanol, isopentanol, isobutanol, ethyl dodecanoate, phenethyl acetate, and butanedioic acid diethyl ester. The total amino acid content of persimmon slurry soaked with AcW reached 531.2 mg/l, which was much higher than those of the slurries soaked in AlW (381.3 mg/l) and PW (182.7 mg/l). The composition of major amino acids in the AcW-soaked slurry may contribute to the strong ester flavour of WAcW. This is the first report to suggest that electrolyzed functional water (EFW) can be used to improve wine flavour, leading to the possible use of EFW in food processing. PMID- 26616935 TI - Colour stabilities of sour cherry juice concentrates enhanced with gallic acid and various plant extracts during storage. AB - Gallic acid (GA) and pomegranate rind extract (PRE), cherry stem extract (CSE) and green tea extract (GTE) were added to sour cherry juice concentrates (SCJCs) to enhance the colour. Effects of these copigment sources on anthocyanins, colour and turbidity were investigated during storage at -20, 4 and 20 degrees C for 110 days. Cyanidin-3-glucosylrutinoside (cyd-3-glu-rut, 75%) was the major anthocyanin, followed by cyanidin-3-rutinoside (cyd-3-rut, 23%) and cyanidin-3 sophoroside (cyd-3-soph, 2%). While GA (37-53%), PRE (27-77%) and GTE (44-119%) increased the stabilities of cyd-3-rut and cyd-3-glu-rut, CSE reduced (12-24%) the stabilities of all anthocyanins. Polymeric colour and turbidity values increased after the addition of all extracts and GA. The lowest turbidity value after 110 days of storage at 20 degrees C was determined in the SCJC enhanced with PRE. We recommend the addition of PRE to SCJC for the enhancement of anthocyanin stability and colour intensity, and the reduction in turbidity. PMID- 26616936 TI - Brewing and volatiles analysis of three tea beers indicate a potential interaction between tea components and lager yeast. AB - Green tea, oolong tea and black tea were separately introduced to brew three kinds of tea beers. A model was designed to investigate the tea beer flavour character. Comparison of the volatiles between the sample of tea beer plus water mixture (TBW) and the sample of combination of tea infusion and normal beer (CTB) was accomplished by triangular sensory test and HS-SPME GC-MS analysis. The PCA of GC-MS data not only showed a significant difference between volatile features of each TBW and CTB group, but also suggested some key compounds to distinguish TBW from CTB. The results of GC-MS showed that the relative concentrations of many typical tea volatiles were significantly changed after the brewing process. More interestingly, the behaviour of yeast fermentation was influenced by tea components. A potential interaction between tea components and lager yeast could be suggested. PMID- 26616937 TI - Effects of partial hydrolysis and subsequent cross-linking on wheat gluten physicochemical properties and structure. AB - The rheological behavior and thermal properties of wheat gluten following partial hydrolysis using Alcalase and subsequent microbial transglutaminase (MTGase) cross-linking were investigated. The wheat gluten storage modulus (G') and thermal denaturation temperature (Tg) were significantly increased from 2.26 kPa and 54.43 degrees C to 7.76 kPa and 57.69 degrees C, respectively, by the combined action of partial hydrolysis (DH 0.187%) and cross-linking. The free SH content, surface hydrophobicity, and secondary structure analysis suggested that an appropriate degree of Alcalase-based hydrolysis allowed the compact wheat gluten structure to unfold, increasing the beta-sheet content and surface hydrophobicity. This improved its molecular flexibility and exposed additional glutamine sites for MTGase cross-linking. SEM images showed that a compact 3D network formed, while SDS-PAGE profiles revealed that excessive hydrolysis resulted in high-molecular-weight subunits degrading to smaller peptides, unsuitable for cross-linking. It was also demonstrated that the combination of Alcalase-based partial hydrolysis with MTGase cross-linking might be an effective method for modifying wheat gluten rheological behavior and thermal properties. PMID- 26616938 TI - Multi-response optimisation of the extraction solvent system for phenolics and antioxidant activities from fermented soy flour using a simplex-centroid design. AB - A simplex-centroid design comprising three solvents (water, ethanol and methanol) was used to optimise the extraction mixture for phenolics and antioxidant activities from defatted soy flour fermented with Monascus purpureus or Aspergillus oryzae. Total phenolics were more efficiently extracted using only water for both samples. The highest antioxidant activities by the DPPH and ABTS methods were obtained using extraction mixtures containing at least 75 wt% water. Specific water:ethanol:methanol ratios promoted the joint optimisation of the total phenolic and isoflavone contents as well as antioxidant activities: 0.5:0.375:0.125 (wt/wt/wt) and 0.5:0.3:0.2 (wt/wt/wt) from defatted soy flour fermented with M. purpureus or A. oryzae, respectively. However, a water:ethanol ratio of 0.5:0.5 (wt/wt) was deemed optimal because it is comprised of green solvents and yielded results that were greater than 90% of the multi-response maximum values. Both the solvents and the sample matrix strongly influenced the extractability of total phenolics and isoflavones. PMID- 26616939 TI - Characterization of polyphenol oxidase from Cape gooseberry (Physalis peruviana L.) fruit. AB - Cape gooseberry (Physalis peruviana) is an exotic fruit highly valued, however it is a very rich source of polyphenol oxidase (PPO). In this study, Cape gooseberry PPO was isolated and biochemically characterized. The enzyme was extracted and purified using acetone and aqueous two-phase systems. The data indicated that PPO had the highest substrate affinity for chlorogenic acid, 4-methylcatechol and catechol. Chlorogenic acid was the most suitable substrate (Km=0.56+/-0.07 mM and Vmax=53.15+/-2.03 UPPO mL(-1) min(-1)). The optimal pH values were 5.5 for catechol and 4-methylcatechol and 5.0 for chlorogenic acid. Optimal temperatures were 40 degrees C for catechol, 25 degrees C for 4-methylcatechol and 20 degrees C for chlorogenic acid. In inhibition tests, the most potent inhibitor was found to be ascorbic acid followed by L-cysteine and quercetin. This study shows possible treatments that can be implemented during the processing of Cape gooseberry fruits to prevent browning. PMID- 26616940 TI - Some microbial, chemical and sensorial properties of gamma irradiated sesame (Sesamum indicum L.) seeds. AB - The effect on microbial, chemical and sensorial properties of sesame seeds was determined after irradiation and storage. The sesame seeds were analyzed before and after irradiation with 3, 6 and 9 kGy of gamma irradiation, and after 6 and 12 months of storage. The results showed that gamma irradiation had no significant (p>0.05) effect on the moisture, ash and fat content on sesame seeds. While, small differences, but sometimes significant (p<0.05), on protein and sugar contents were recorded between irradiated and non-irradiated samples. Total acidity percentage decreased significantly (p<0.05), while total volatile basic nitrogen (TVBN) increased significantly (p<0.05) due to irradiation. During storage, total acidity increased (p<0.05) and TVBN decreased (p<0.05). Gamma irradiation reduced the microorganisms of sesame seeds. Samples treated with 3 kGy or more remained completely free of fungi throughout the storage. While, only the samples treated with 9 kGy remained completely free of bacteria at the end of storage period (after 12 months). The scores for taste, flavor, color and texture of irradiated samples were higher, but not significantly (p>0.05) than those of non-irradiated samples. PMID- 26616941 TI - Fluorescence sensor array for identification of commercial milk samples according to their thermal treatments. AB - Identification of processed milk is of importance for commercial and legal concerns. The fluorescence response patterns induced by fluorophore/protein interactions allow a possible discrimination of processed milk samples corresponding to their thermal treatment. The fluorescence responses of 4 fluorophores upon addition of commercial milk samples in 96-well plate are measured in the range of 400-600 nm using the excitation wavelength at 375 nm. The pattern recognition of the 53,126 fluorescence responses (4 fluorophores*41 wavelengths*4 thermally processed milks*3 brands*3 lots*3 bottles*3 repeats) are analyzed by multivariate statistical methods. Linear discriminant analysis (LDA) successfully recognizes the milk samples according to their thermal processing, i.e. pasteurized milk, sterilized milk, UHT fresh milk and recombined milk (UHT milk having milk powder), with 100% classification accuracy in a cross validation using a leave-one-out technique. PMID- 26616942 TI - Inhibitory effects of Na7PMo11CuO40 on mushroom tyrosinase and melanin formation and its antimicrobial activities. AB - Keggin-type Cu-substituted phosphomolybdic acid (Na7PMo11CuO40, abbreviated as PMo11Cu) was synthesized and characterized. The inhibitory effects of PMo11Cu on mushroom tyrosinase and melanin formation in B16 melanoma cells were studied. The results showed that PMo11Cu could strongly inhibit the activity of tyrosinase, and it was reversible and competitive inhibitor. The IC50 value was estimated to be 0.48 mM for diphenolase activity. PMo11Cu also exhibited inhibitory effects on cell viability, cellular tyrosinase activity and melanin formation in B16 melanoma cells at concentrations ranging from 0 to 200 MUM for 24 h. Furthermore, the antimicrobial activities of PMo11Cu against Sarcina lutea, Staphylococcus aureus, Bacillus subtilis and Escherichia coli were investigated. The results showed that PMo11Cu had an obvious antimicrobial activities, and it was more effective against two kinds of coccus than two kinds of bacillus. This study may provide theoretical basis for designing novel effective mushroom tyrosinase inhibitors and extend the use of polyoxometalates in the fields of food preservation and depigmentation. PMID- 26616943 TI - Preparation, characterization and functional properties of flax seed protein isolate. AB - Flaxseed protein isolate (FPI) was extracted from flaxseeds, and its amino acid composition and functional properties (solubility, thermal stability, emulsifying properties and electrostatic charge density, water holding and fat absorption capacities) were determined. The highest purity of FPI (90.6%) was achieved by extraction at 60 degrees C. FPI had a low lysine to arginine ratio of 0.25, which is desired in heart-healthy foods and infant formulas. The denaturation temperature of FPI was 105 degrees C. FPI had the highest emulsion activity index (375.51 m(2)/g), highest emulsion stability index (179.5 h) and zeta potential ( 67.4 mV) when compared to those of other commonly used proteins, such as sodium caseinate (SC), whey protein isolate (WPI), gelatin (Gel) and soy protein isolate (SPI). The average emulsion droplet size of emulsions stabilized by these proteins was in the order SCblack raspberry>blueberry. Amongst fractions, the order was insoluble bound>esterified>free. These trends were the same as those found against copper induced LDL-cholesterol oxidation and supercoiled plasmid DNA strand breakage inhibition induced by both peroxyl and hydroxyl radicals. Extracts were found to contain various levels of phenolic compounds that were specific to each berry seed meal type. Berry seed meals should be considered as a good source of phenolics with potential health benefits. Their full exploitation may be helpful for the food industry and consumers. PMID- 26616945 TI - Effects of calcium chelators on calcium distribution and protein solubility in rennet casein dispersions. AB - This study investigated the effects of calcium chelating salts on calcium-ion activity (ACa(++)), calcium distribution, and protein solubility in model CaCl2 solutions (50 mmol L(-1)) or rennet casein dispersions (15 g/100 g). Disodium phosphate and trisodium citrate at concentrations of 10 and 30 mmol L(-1) and at ratios of 1:0, 2:1, 1:1, 1:2 and 0:1 were added to both systems. The CaCl2 system, despite its simplicity, was a good indicator of chelating salt-calcium interactions in rennet casein dispersions. Adding trisodium citrate either alone or as part of a mixed chelating salt system resulted in high levels of dispersed "chelated" calcium; conversely, disodium phosphate addition resulted in lower levels, while the ACa(++) decreased with increasing concentration of both chelating salts. Neither chelating salt produced high levels of soluble protein. Thus calcium chelating salts may play a more subtle role in modulating hydration during manufacture of casein-based matrices than simply solubilising calcium or protein. PMID- 26616947 TI - Green and biodegradable composite films with novel antimicrobial performance based on cellulose. AB - In order to obtain a safe and biodegradable material with antimicrobial properties from cellulose for food packaging, we presented a facile way to graft chitosan onto the oxidized cellulose films. The obtained films had a high transparent property of above 80% transmittance, excellent barrier properties against oxygen and antimicrobial properties against Escherichia coli and Staphylococcus aureus. The antimicrobial properties, mechanical properties, and water vapor permeability of composites are essential characteristics in determining their applicability as food-packaging materials. Moreover, using a sausage model, it was shown that the composites exhibited better performance than traditional polyethylene packaging material and demonstrated good potential as food packaging materials. The results presented a new insight into the development of green materials for food packaging. PMID- 26616946 TI - Characterization, antioxidative and bifidogenic effects of polysaccharides from Pleurotus eryngii after heat treatments. AB - Polysaccharides were extracted from freeze-dried-, oven-dried- and boiling treated Pleurotus eryngii (FDPEPS, ODPEPS and BTPEPS). Yield of FDPEPS and its total carbohydrates, total polysaccharides, reducing sugars, phenolics and protein content were higher than ODPEPS and BTPEPS. High performance liquid chromatography (HPLC) identified that FDPEPS, ODPEPS, and BTPEPS were composed of mannose (5.75%, 5.52%, 6.97%), glucose (88.90%, 89.31%, 87.68%) and galactose (5.34%, 5.17%, 5.35%). All three polysaccharides showed typical saccharic absorption bands in FT-IR. The FDPEPS showed the highest antioxidant activities in ferric reducing antioxidant power (FRAP), ABTS, superoxide anion and hydroxyl radical scavenging tests. Denser aggregates and larger serum pores were observed in confocal micrographs of soymilk added with ODPEPS. Viability of Bifidobacterium longum in soymilk added with polysaccharides was significantly higher (p<0.01) than those without polysaccharides during fermentation. Heat treatments applied before extraction affected the properties, composition and microstructures of FDPEPS, ODPEPS and BTPEPS. PMID- 26616948 TI - Prediction of total volatile basic nitrogen contents using wavelet features from visible/near-infrared hyperspectral images of prawn (Metapenaeus ensis). AB - A visible/near-infrared hyperspectral imaging (HSI) system (400-1000 nm) coupled with wavelet analysis was used to determine the total volatile basic nitrogen (TVB-N) contents of prawns during cold storage. Spectral information was denoised by conducting wavelet analysis and uninformative variable elimination (UVE) algorithm, and then three wavelet features (energy, entropy and modulus maxima) were extracted. Quantitative models were established between the wavelet features and the reference TVB-N contents by using three regression algorithms. As a result, the LS-SVM model with modulus maxima features was considered as the best model for determining the TVB-N contents of prawns, with an excellent RP(2) of 0.9547, RMSEP=0.7213 mg N/100g and RPD=4.799. Finally, an image processing algorithm was developed for generating a TVB-N distribution map. This study demonstrated the possibility of applying the HSI imaging system in combination with wavelet analysis to the monitoring of TVB-N values in prawns. PMID- 26616949 TI - Conventional, ultrasound-assisted, and accelerated-solvent extractions of anthocyanins from purple sweet potatoes. AB - Purple sweet potatoes (PSPs) are rich in anthocyanins. In this study, we investigated the extraction efficiency of anthocyanins from PSPs using conventional extraction (CE), ultrasound-assisted extraction (UAE), and accelerated-solvent extraction (ASE). Additionally, the effects of these extraction methods on antioxidant activity and anthocyanin composition of PSP extracts were evaluated. In order of decreasing extraction efficiency, the extraction methods were ASE>UAE>CE for anthocyanins (218-244 mg/100 g DW) and CE>UAE>ASE for total phenolics (631-955 mg/100 g DW) and flavonoids (28-40 mg/100 g DW). Antioxidant activities of PSP extracts were CE~UAE>ASE for ORAC (766-1091 mg TE/100 g DW) and ASE>CE~UAE for FRAP (1299-1705 mg TE/100 g DW). Twelve anthocyanins were identified. ASE extracts contained more diacyl anthocyanins and less nonacyl and monoacyl anthocyanins than CE and ASE extracts (P<0.05). PMID- 26616951 TI - Development and validation of a simple high performance thin layer chromatography method combined with direct 1,1-diphenyl-2-picrylhydrazyl assay to quantify free radical scavenging activity in wine. AB - The aim of this study was to: (a) develop a simple, high performance thin layer chromatographic (HPTLC) method combined with direct 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay to rapidly assess and compare free radical scavenging activity or anti-oxidant activity for major classes of polyphenolics present in wines; and (b) to investigate relationship between free radical scavenging activity to the total polyphenolic content (TPC) and total antioxidant capacity (TAC) in the wine samples. The most potent free radical scavengers that we tested for in the wine samples were found to be resveratrol (polyphenolic non-flavonoid) and rutin (flavonoid), while polyphenolic acids (caffeic acid and gallic acid) although present in all wine samples were found to be less potent free radical scavengers. Therefore, the total antioxidant capacity was mostly affected by the presence of resveratrol and rutin, while total polyphenolic content was mostly influenced by the presence of the less potent free radical scavengers gallic and caffeic acids. PMID- 26616950 TI - Peptidomic analysis reveals proteolytic activity of kefir microorganisms on bovine milk proteins. AB - SCOPE: The microorganisms that make up kefir grains are well known for lactose fermentation, but the extent to which they hydrolyze and consume milk proteins remains poorly understood. Peptidomics technologies were used to examine the proteolytic activity of kefir grains on bovine milk proteins. METHODS AND RESULTS: Gel electrophoresis revealed substantial digestion of milk proteins by kefir grains, with mass spectrometric analysis showing the release of 609 protein fragments and alteration of the abundance of >1500 peptides that derived from 27 milk proteins. Kefir contained 25 peptides identified from the literature as having biological activity, including those with antihypertensive, antimicrobial, immunomodulatory, opioid and anti-oxidative functions. 16S rRNA and shotgun metagenomic sequencing identified the principle taxa in the culture as Lactobacillus species. CONCLUSION: The model kefir sample contained thousands of protein fragments released in part by kefir microorganisms and in part by native milk proteases. PMID- 26616952 TI - Resistant starch content among several sorghum (Sorghum bicolor) genotypes and the effect of heat treatment on resistant starch retention in two genotypes. AB - The resistant starch (RS) contents in 49 sorghum genotypes and the effects of heat treatment using dry and wet heat on the grain and flour from two sorghum genotypes were investigated. The results showed a wide variation in the RS contents of the genotypes analyzed. The RS mean values were grouped into six distinct groups and ranged from 0.31+/-0.33 g/100 g to 65.66+/-5.46 g/100 g sorghum flour on dry basis. Dry heat causes minor losses in the RS content with retentions of up to 97.19+/-1.92% of this compound, whereas wet heat retained at most 6.98+/-0.43% of the RS. The SC 59 and (SSN76)FC6608 RED KAFIR BAZINE (ASA N23) cultivars, which have an average RS content of 65.51 g/100 g, were appropriate for human consumption, and the use of dry heat is presented as a better alternative for the preservation of RS in heat-treated grains. PMID- 26616953 TI - Physicochemical properties of whey protein, lactoferrin and Tween 20 stabilised nanoemulsions: Effect of temperature, pH and salt. AB - Oil-in-water nanoemulsions were prepared by emulsification and solvent evaporation using whey protein isolate (WPI), lactoferrin and Tween 20 as emulsifiers. Protein-stabilised nanoemulsions showed a decrease in particle size with increasing protein concentration from 0.25% to 1% (w/w) level with Z-average diameter between 70 and 90 nm. However, larger droplets were produced by Tween 20 (120-450 nm) especially at concentration above 0.75% (w/w). The stability of nanoemulsions to temperature (30-90 degrees C), pH (2-10) and ionic strength (0 500 mM NaCl or 0-90 mM CaCl2) was also tested. Tween 20 nanoemulsions were unstable to heat treatment at 90 degrees C for 15 min. WPI-stabilised nanoemulsions exhibited droplet aggregation near the isoelectric point at pH 4.5 and 5 and they were also unstable at salt concentration above 30 mM CaCl2. These results indicated that stable nanoemulsions can be prepared by careful selection of emulsifiers. PMID- 26616954 TI - Sorghum-cowpea composite porridge as a functional food, Part II: Antioxidant properties as affected by simulated in vitro gastrointestinal digestion. AB - The effect of compositing red non-tannin sorghum with brownish-cream cowpea and in vitro gastrointestinal digestion on total phenolic and flavonoid contents and antioxidant properties of a sorghum-cowpea composite porridge was studied. Maize soybean composite porridge was used as a reference sample. Antioxidant properties were studied using radical scavenging activities against the 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulphonic acid), peroxyl and NO radicals as well as inhibition of low density lipoprotein (LDL) oxidation and oxidative damage of vector DNA. Hydroperoxide content of the samples was also measured. All the samples demonstrated radical scavenging activity. Simulated duodenal digests of the porridges had hydroperoxides and therefore caused LDL oxidation. The undigested porridges and simulated gastric digests inhibited LDL oxidation. Compositing the cereals with legumes increased total phenolic and flavonoid contents and NO scavenging activity of their porridges. In vitro gastrointestinal digestion of the porridges increased their total phenolic and flavonoid contents, radical scavenging activities and LDL oxidation inhibitory activity. PMID- 26616955 TI - Diversity in quality traits amongst Indian wheat varieties II: Paste, dough and muffin making properties. AB - The relationship between protein molecular weight (MW) distribution, quality characteristics and muffin making properties amongst Indian wheat varieties were evaluated. Flours from varieties with higher grain weight showed lower proportion of fine particles. Lactic acid solvent retention capacity (LASRC), sedimentation value (SV) and dough stability (DS) correlated with the proportion of 0-55 MUm size particles. Paste peak viscosity and breakdown viscosity showed positive correlation with polymeric protein and negatively with monomeric protein, alpha amylase activity and sodium carbonate solvent retention capacity (NaSRC). Gluten strength indicators such as DS, dough development time (DDT), LASRC and gluten index (GI) were positively related to polymeric protein and negatively to monomeric protein. Both G' and G" were correlated significantly with GI, LASRC, DS and DDT. The varieties that possesses high MW glutenin subunits combinations of 91 kDa + 84 kDa + 78 kDa + 74 kDa showed lower G' and G". Muffin volume was positively correlated with gluten content and LASRC. PMID- 26616956 TI - Carotenoid and polyphenol bioaccessibility and cellular uptake from plum and cabbage varieties. AB - Plum and cabbage are rich in carotenoids and polyphenols. However, their bioactivity depends on their release and intestinal uptake. Four varieties of Brassicaceae (Duchy, Scots Kale, Kale, Kalorama) and Prunus (Cherry Plum, Plum 620, Ersinger, Italian Plum) were studied; bioaccessibility following in vitro digestion, cellular uptake (Caco-2 vs. co-culture cell model: Caco-2:HT-29-MTX (90:10%) and colonic fermentation were determined for carotenoids/polyphenols; the influence of certain kitchen preparations was likewise studied. Carotenoids were non-significantly influenced by the latter, while for polyphenols, boiling and steaming significantly reduced total phenolics (p<0.05). Carotenoid bioaccessibility did not differ significantly between Prunus vs. Brassicaceae varieties, but xanthophyll was higher than carotene bioaccessibility (p<0.01). Polyphenol bioaccessibility was low (<10%), possibly compromised by the cream containing test meal. Total carotenoid cellular uptake varied between varieties (0.3-4.1%), being higher for carotenes (4.1%) than for xanthophylls (1.6%, p<0.01), and were higher for the co-culture cell model compared to Caco-2 cells (p<0.01). Total carotenoid recovery in the colonic fraction varied from 4% to 25%. Lower bioaccessibility of carotenes thus appeared to be somewhat counterbalanced by higher cellular uptake. The potential positive role of the mucus layer for cellular uptake and the fate of the colonic digesta deserve further attention in the future. PMID- 26616957 TI - Contribution of polyamines metabolism and GABA shunt to chilling tolerance induced by nitric oxide in cold-stored banana fruit. AB - Effect of exogenous nitric oxide (NO) on polyamines (PAs) catabolism, gamma aminobutyric acid (GABA) shunt, proline accumulation and chilling injury of banana fruit under cold storage was investigated. Banana fruit treated with NO sustained lower chilling injury index than the control. Notably elevated nitric oxide synthetase activity and endogenous NO level were observed in NO-treated banana fruit. PAs contents in treated fruit were significantly higher than control fruit, due to the elevated activities of arginine decarboxylase and ornithine decarboxylase. NO treatment increased the activities of diamine oxidase, polyamine oxidase and glutamate decarboxylase, while reduced GABA transaminase activity to lower levels compared with control fruit, which resulted the accumulation of GABA. Besides, NO treatment upregulated proline content and significantly enhanced the ornithine aminotransferase activity. These results indicated that the chilling tolerance induced by NO treatment might be ascribed to the enhanced catabolism of PAs, GABA and proline. PMID- 26616958 TI - Postmortem changes in actomyosin dissociation, myofibril fragmentation and endogenous enzyme activities of grass carp (Ctenopharyngodon idellus) muscle. AB - The changes of actomyosin, proteolytic activities and myofibril fragmentation during the postmortem aging of grass carp were studied. The study revealed dramatically increased actomyosin dissociation within 6 h of storage postmortem in grass carp, and it was associated with the drop of pH from 6.9 to 6.7, while liberated actin remained almost unchanged after 6 h postmortem. The myofibril fragmentation also increased significantly with the storage time in 6 h, and a highly positive correlation (P<0.01) existed between MFI and cathepsin B, D, H activities. The study indicated both actomyosin dissociation and cathepsin B, D, H played a role in postmortem tenderization and textural changes in grass carp. PMID- 26616959 TI - Effect of roasting on physicochemical, functional and antioxidant properties of arrowhead (Sagittaria sagittifolia L.) flour. AB - Arrowhead tubers with protein, lipid and ash content of 4.60%, 2.27% and 6.15%, respectively were subjected to pan and microwave roasting, converted to flour and studied for physicochemical, functional and antioxidant properties. The lightness 'L' of flour decreased significantly (p?0.05) from 83.01 to 72.21 while significant increase in 'a' and 'b' color values was observed from -0.27 to 2.49 and 15.49 to 25.35 on roasting. Light transmittance decreased significantly upon roasting and the lowest value (0.80) was showed by pan roasted sample. Significant decrease in pasting properties like peak (963.0-147.7 cP), setback (172.0-97.67 cP) and final viscosity (861.67-202.66 cP) was also recorded on roasting. However, roasting led to increase in pasting temperature from 78.53 to 95.23 degrees C. The water (1.49-2.03 g/g) and oil (1.65-1.85 g/g) absorption capacity increased, while significant decrease was observed in foaming and emulsion properties upon roasting. The total phenolic content, antioxidant activity and reducing power enhanced upon pan and microwave roasting from 1.02 to 2.42 mg/g (GAE); 44.30% to 46.61%; 74.59% to 76.23%, respectively. Thermal parameters like onset temperature (To) and DeltaH decreased while peak temperature (Tp) increased on roasting. PMID- 26616960 TI - The effect of vacuum frying on starch gelatinization and its in vitro digestibility in starch-gluten matrices. AB - Starch digestibility in a food matrix depends on processing conditions that may affect its physical state and microstructure. Starch gelatinization is one critical change that takes place during frying which could be affected during low pressure processing. This study assessed the effect of vacuum frying on starch gelatinization and its in vitro digestibility. Laminated dough was made of a reconstituted blend of wheat starch (88% d.b.) and gluten (12% d.b.). Samples were fried under vacuum (6.5 kPa, Twater-boiling-point=38 degrees C) or atmospheric conditions up to bubble-end point, maintaining a thermal driving force of 70 degrees C (Toil-Twater-boiling-point=70 degrees C). Vacuum fried samples showed less starch gelatinization (28%), less rapidly available glucose (27%), and more unavailable glucose (70%) than their atmospheric counterparts (which presented 99% starch gelatinization, 40% rapidly available glucose, and 46% unavailable glucose), and the values were close to those of raw dough. These results show how vacuum processing may be used to control the degree of starch gelatinization and related digestibility. PMID- 26616961 TI - Highly sensitive and simultaneous detection of melamine and aflatoxin M1 in milk products by multiplexed planar waveguide fluorescence immunosensor (MPWFI). AB - Mycotoxins and industrial chemicals, such as aflatoxin M1 and melamine, now commonly exist in milk and cause potential health risks. This study presents an indirect competitive immunoassay through multiplex planar waveguide fluorescence immunosensor (MPWFI) for rapid, sensitive, and simultaneous detection and quantification of aflatoxin M1 and melamine by applying the principle of immunoreaction and total internal reflect fluorescent. Double-channel standard curves with appropriate logistic correlation (R(2)>0.99) were plotted, respectively. The working ranges (0.073-0.400 ng/mL and 26.38-270.00 ng/mL, respectively) were calculated, as well as the limit of detection (0.045 and 13.37 ng/mL, respectively), when two analytes were simultaneously detected. Both results satisfied the requirements for the maximum amount set by the WHO, which illustrated that the current method was better than some other standard methods. The recovery rates in the actual samples ranged from 85% to 103%, with relative standard deviations between 1.3% and 6.5%, which indicated high accuracy and repeatability. PMID- 26616962 TI - The influence of fermentation condition on production and molecular mass of EPS produced by Streptococcus thermophilus 05-34 in milk-based medium. AB - The yield of exopolysaccharide (EPS) produced by Streptococcus thermophilus 05-34 reached up to 250 mg/L under the optimal fermentation condition, which was 4.2 fold higher than that produced under the non-optimal fermentation condition. Structure analysis showed that EPS produced under the optimal fermentation condition was composed of galactose and glucose in a molar ratio of 1.0:0.8. This EPS was with a molecular mass of 4.7*10(5) Da, which was increased by 9 times compared with that in the non-optimal fermentation condition, while monosaccharide composition did not change. Furthermore, real-time quantitative PCR showed that the transcription level of epsC, which is responsible for chain length determination, was up-regulated by 2.7-fold, suggesting that the increased molecular mass of EPS was resulted from improving polymerization degree of monosaccharide. These findings demonstrated that the optimized fermentation condition can improve EPS molecular mass, and may consequently modify the rheological properties of EPS. PMID- 26616963 TI - Selection of aroma compounds for the differentiation of wines obtained by fermenting musts with starter cultures of commercial yeast strains. AB - Nine wines obtained by fermenting Aligote musts with individual starter cultures of eight Saccharomyces cerevisiae yeast strains and with the indigenous microbiota were compared in terms of their composition in minor volatile aroma compounds. An easy handle methodology Stir-Bar-Sorptive-Adsorption, Gas Chromatography-Mass Spectrometry based, permits the identification of 49 aroma compounds. The rearrangement of these aroma compounds in six chemical families permits the establishment of a finger printing for each wine. Eighteen aroma compounds that exhibit a high differentiation power (p?0.05) were selected for chemometric analysis. The Principal Component Analysis carried out with these aroma compounds reveal that the first two principal components explain 53.8% and 17.2% of the total variance, respectively, allowing the establishment of nine different groups, in accordance with the wine types obtained. These results reveal analytical differences among the wines that are not recognized by sensorial analysis. PMID- 26616964 TI - Selenium bioaccessibility in stomach, small intestine and colon: Comparison between pure Se compounds, Se-enriched food crops and food supplements. AB - Selenium (Se) is an essential nutrient for humans as it plays an important role in glutathione peroxidase (GPx) activity. Moreover, it may reduce cancer risks. The objective of this work was to examine in vitro the bioaccessibility of Se in three different Se-enriched food supplements and two different Se-enriched food crops, with reference to two pure Se standards, and changes in its speciation during intestinal digestion. Selenate was found to be stable throughout the entire digestion, whereas incubation of selenomethionine resulted in the chemical and microbial production of minor metabolites. The bioaccessibility of Se in Se enriched food supplements and food crops was found to be highest in the small intestine. Compared to SelenoPrecise and Se-ACE tablets, a yoghurt-based supplement exhibited a much lower Se bioaccessibility, possibly due to the presence of nano- or microparticles of elemental Se. Colon microbiota were found to primarily affect Se bioaccessibility in the colon environment, with the presence of inactivated microbiota resulting in a higher bioaccessibility. A higher potential of Se to reach the colon and become accessible in this phase may result in beneficial effects on the colon health. PMID- 26616965 TI - A simplified determination of total concentrations of Ca, Fe, Mg and Mn in addition to their bioaccessible fraction in popular instant coffee brews. AB - A direct analysis of instant coffee brews with HR-CS-FAAS spectrometry to determine the total Ca, Fe, Mg and Mn content has been developed and validated. The proposed method is simple and fast; it delivers good analytical performance; its accuracy being within -3% to 3%, its precision--2-3% and detection limits- 0.03, 0.04, 0.004 and 0.01 mg l(-1) for Ca, Fe, Mg and Mn, respectively. In addition, Ca, Fe, Mg and Mn bioaccessibility in instant coffee brews was measured by means of the in vitro gastrointestinal digestion with the use of simulated gastric and intestinal juice solutions. Absorption of metals in intestinal villi was simulated by means of ultrafiltration over semi-permeable membrane with a molecular weight cut-off of 5 kDa. Ca, Fe, Mg and Mn concentrations in permeates of instant coffee gastrointestinal incubates were measured with HR-CS-FAA spectrometry. PMID- 26616966 TI - A silver nanorod resonance rayleigh scattering-energy transfer analytical platform for trace tea polyphenols. AB - The stable silver nanorod (AgNR) sol in red was prepared by the two-step procedure of NaBH4-H2O2 and citrate heating reduction, and it exhibited a strong resonance Rayleigh scattering (RRS) peak at 346 nm. In pH 3.8 HAc-NaAc buffer solution, tea polyphenols (TP) reacted with ammonium molybdate (AM) to form yellow organic molybdate (OM) as receptor that was closed to the donor of AgNR, the RRS energy transfer (RRS-ET) takes place, owing to the overlapping between the AgNR RRS spectra and OM absorption spectra. When TP concentration increased, the RRS intensity decreased due to the RRS-ET increasing. So, a simple and sensitive AgNR surface plasmon RRS-ET analytical platform was fabricated to detect trace TP in the range of 0.05-0.85 MUg/mL, with a detection limit of 0.03 MUg/mL TP. The TP in tea samples was analyzed by this RRS-ET analysis platform, with satisfactory results. PMID- 26616967 TI - Determination of seleno-amino acids bound to proteins in extra virgin olive oils. AB - An analytical method has been developed to determine seleno-amino acids in proteins extracted from extra virgin olive oils (EVOOs). Different aqueous/organic solvents were tested to isolate proteins, an acetone:n-hexane combination being the best protein precipitant. In a first dimension chromatography, extracted proteins were analysed by size exclusion chromatography (SEC) coupled to inductively coupled plasma mass spectrometry (ICP-MS) to identify S and Se associations as proteins marker. Two fractions of 66 kDa (A) and 443 kDa (B) were identified. These fractions were submitted to microwave assisted acid hydrolysis (MAAH) to release seleno-amino acids. In a second dimension chromatography seleno-amino acids were determined by reversed-phase chromatography (RPC) coupled to ICP-MS. Seleno-methylselenocysteine was determined with values ranging from 1.03-2.03+/-0.2 MUg kg(-1) and selenocysteine at a concentration of 1.47+/-0.1 MUg kg(-1). Variations of protein and seleno amino acid concentrations were observed between EVOO varieties, contributing to EVOO cultivar differentiation. PMID- 26616968 TI - Enzymatic generation of galactose-rich oligosaccharides/oligomers from potato rhamnogalacturonan I pectic polysaccharides. AB - Potato pulp by-product rich in galactan-rich rhamnogalacturonan I (RG I) was investigated as a new source of oligosaccharides with potential prebiotic properties. The efficiency of selected monocomponent enzymes and multi-enzymatic preparations to generate oligosaccharides/oligomers from potato RG I was evaluated. These overall results of yield were dependent on the activity profile of the multi-enzymatic preparations. Highest oligo-RG I yield of 93.9% was achieved using multi-enzymatic preparation (Depol 670L) with higher hydrolytic activity toward side chains of RG I as compared to its backbone. Main oligo-RG I products were oligosaccharides with DP of 2-12 (79.8-100%), while the oligomers with DP of 13-70 comprised smaller proportion (0.0-20.2%). Galactose (58.9-91.2%, w/w) was the main monosaccharide of oligo-RG I, while arabinose represented 0.0 12.1%. An understanding of the relationship between the activity profile of multi enzymatic preparations and the yield/DP of oligo-RG I was achieved. This is expected to provide the capability to generate galacto- and galacto(arabino) oligosaccharides and their corresponding oligomers from an abundant by-product. PMID- 26616969 TI - Targeted acylation for all the hydroxyls of (+)-catechin and evaluation of their individual contribution to radical scavenging activity. AB - The reactivity profile of all the hydroxyl groups in (+)-catechin towards acylation and their respective contribution to radical scavenging activity were systematically explored in this work. Selective acylation of the hydroxyls on different rings was carried out employing either a basic or acidic activation strategy. Monoacylation of B ring was achieved effectively with the aid of dimethyltin dichloride. Monoacylation of A ring was accomplished by sequential protection and deprotection of B and C rings. Based on specific acylation of all the individual hydroxyls of (+)-catechins, the structure radical scavenging activity relationship of each hydroxyl of (+)-catechin was established. It was demonstrated that the vicinal phenolic hydroxyls on B ring played the most important role in the ABTS radical scavenging activity and those on A and C rings made a much smaller contribution. This study has laid solid groundwork for further modification of the catechins and improvement of their properties. PMID- 26616970 TI - POD promoted oxidative gelation of water-extractable arabinoxylan through ferulic acid dimers. Evidence for its negative effect on malt filterability. AB - As a major component of non-starch polysaccharide in barley, arabinoxylan (AX) plays an important role in quality traits of malt and the final beer product. The Chinese barley malt has encountered filterability problems for a long time. The main reason caused by barley cultivar has been accepted in the malting and brewing industries. In our previous proteomic study, the peroxidase (POD) BP1 was found to be in quite high abundant in the filterability defect Chinese barley malt. Therefore, the present study tried to verify its negative effect on filterability, by surveying its activity in different malt samples and detecting effects of POD on AX gelation and filterability. The results showed that the activity of POD, as well as the content of AX bounded ferulic acid, were both negatively correlated with filterability, while the feruloyl esterase activity was positively correlated with it. In addition, AX gelation catalyzed by POD caused worse filterability, and the natural inhibitor of POD, vitamin C, could blocked the cross linking catalyzed by POD and thus improve the filterability. These results all suggested the great negative effect of POD on malt filterability. PMID- 26616971 TI - Relationship between bran characteristics and bran starch of selected soft wheats grown in Michigan. AB - The aims of this study were to investigate differences among chosen wheat varieties in their bran starch (the starch adherent to bran particles after a dry milling process) quantity, bran particle size, and milled bran thickness, and to investigate the relationship between bran characteristics and bran starch content. The neutral saccharide profile of the wheat bran was dominated by arabinose, xylose, and glucose, whereas mannose and galactose were present in small amounts. Bran thickness was found to have a positive correlation with bran starch content. Bound ferulic acid to xylose ratio showed positive correlations with percent large bran particles, and negative correlations with bran starch content. Bran characteristics can explain the variation seen in bran starch content and percent large bran particles of various wheat varieties. Bound ferulic acid to xylose ratio and bran thickness could both play roles in the mechanical properties of bran, and therefore change the percent of large bran particles produced during milling. PMID- 26616972 TI - Effect of plasma activated water on the postharvest quality of button mushrooms, Agaricus bisporus. AB - Non-thermal plasma is a new approach to improving microbiological safety while maintaining the sensory attributes of the treated foods. Recent research has reported that plasma activated water (PAW) can also efficiently inactivate a wide variety of microorganisms. This study invested the effects of plasma-activated water soaking on the postharvest preservation of button mushrooms (Agaricus bisporus) over seven days of storage at 20 degrees C. Plasma activated water reduced the microbial counts by 1.5 log and 0.5 log for bacteria and fungi during storage, respectively. Furthermore, the corresponding physicochemical and biological properties were assessed between plasma activated water soaking groups and control groups. The results for firmness, respiration rate and relative electrical conductivity suggested that plasma activated water soaking can delay mushroom softening. Meanwhile, no significant change was observed in the color, pH, or antioxidant properties of A. bisporus treated with plasma activated water. Thus, plasma activated water soaking is a promising method for postharvest fresh keeping of A. bisporus. PMID- 26616973 TI - Extraction of nickel from edible oils with a complexing agent prior to determination by FAAS. AB - In the present work, a new extraction method for separation of nickel from edible oils and determination by FAAS is reported. This method is based on extraction of Ni(II) ions from the oil to aqueous phase with N,N'-bis(4-methoxysalicylidene) ethylenediamine (MSE) and determination by FAAS. Properties of the complex formed between MSE and Ni(II) were investigated spectrophotometrically. Central composite design (CCD) was utilized for optimization of MSE to oil, stirring time and temperature, which were 0.97 mL g(-1), 15.4 min, and 29.7 degrees C, respectively. The developed method was tested with an oil-based metal standard and the recovery was 93.8+/-3.9%. The proposed method was applied with five different edible oils. PMID- 26616974 TI - Reverse micellar extraction of bromelain from pineapple peel--Effect of surfactant structure. AB - Pineapple peel is generally disposed or used as compost. This study was focused on extracting bromelain from pineapple peel by using reverse micelles. It was found that gemini surfactant C12-8-C12.2Br (octamethylene-alpha,omega bis(dimethyldodecylammonium bromide)) showed distinctive advantage over its monomeric counterpart DTAB (dodecyl trimethyl ammonium bromide); under optimized condition, the bromelain extracted with C12-8-C12.2Br reverse micelle had an activity recovery of 163% and a purification fold of 3.3, while when using DTAB reverse micelle, the activity recovery was 95% and the purification fold was 1.7. Therefore, the spacer of gemini surfactant should play a positive role in bromelain extraction and may suggest the potential of gemini surfactant in protein separation since it has been so far rarely used in relative experiments or technologies. PMID- 26616975 TI - Determination of vitamin A and vitamin E esters in infant formulae and fortified milk powders by HPLC: Use of internal standardisation. AB - An HPLC method is described using normal phase conditions with an unbonded silica column to determine concentrations of supplementary vitamin A and vitamin E esters and beta-carotene in infant formulae. The method utilises selective dual channel fluoresence for vitamins A and E and visible absorbance for beta carotene. An attribute of the method is the use of retinol propionate, alpha tocopheryl propionate and all-E-beta-apo-8'-carotenoic acid ethyl ester internal standards to compensate for analytical variations associated with these labile vitamins. Extraction is performed without saponification, with the aid of protease to remove vitamin encaspsulation and facilitate vitamin partition into hydrocarbon solvent. Figures of merit indicate the method is suitable for its intended purpose in the highly regulated infant formula environment, including liquid formulations. The method is extendable to whole milk powders where total vitamin A content data can be calculated by summing the innate long-chain vitamin A esters with the added esters. PMID- 26616976 TI - Influence of heat treatment on antioxidant capacity and (poly)phenolic compounds of selected vegetables. AB - The impact of cooking heat treatments (frying in olive oil, frying in sunflower oil and griddled) on the antioxidant capacity and (poly)phenolic compounds of onion, green pepper and cardoon, was evaluated. The main compounds were quercetin and isorhamnetin derivates in onion, quercetin and luteolin derivates in green pepper samples, and chlorogenic acids in cardoon. All heat treatments tended to increase the concentration of phenolic compounds in vegetables suggesting a thermal destruction of cell walls and sub cellular compartments during the cooking process that favor the release of these compounds. This increase, specially that observed for chlorogenic acids, was significantly correlated with an increase in the antioxidant capacity measured by DPPH (r=0.70). Griddled vegetables, because of the higher temperature applied during treatment in comparison with frying processes, showed the highest amounts of phenolic compounds with increments of 57.35%, 25.55% and 203.06% compared to raw onion, pepper and cardoon, respectively. PMID- 26616977 TI - Biochemical characterization of an acidophilic beta-mannanase from Gloeophyllum trabeum CBS900.73 with significant transglycosylation activity and feed digesting ability. AB - Acidophilic beta-mannanases have been attracting much attention due to their excellent activity under extreme acidic conditions and significant industrial applications. In this study, a beta-mannanase gene of glycoside hydrolase family 5, man5A, was cloned from Gloeophyllum trabeum CBS900.73, and successfully expressed in Pichia pastoris. Purified recombinant Man5A was acidophilic with a pH optimum of 2.5 and exhibited great pH adaptability and stability (>80% activity over pH 2.0-6.0 and pH 2.0-10.0, respectively). It had a high specific activity (1356 U/mg) against locust bean gum, was able to degrade galactomannan and glucomannan in a classical four-site binding mode, and catalyzed the transglycosylation of mannotetrose to mannooligosaccharides with higher degree of polymerization. Besides, it had great resistance to pepsin and trypsin and digested corn-soybean meal based diet in a comparable way with a commercial beta mannanase under the simulated gastrointestinal conditions of pigs. This acidophilic beta-mannanase represents a valuable candidate for wide use in various industries, especially in the feed. PMID- 26616978 TI - Assessment of Pb and Cd in seed oils and meals and methodology of their extraction. AB - Oil seed, which is a secondary product in phytoremediation, contaminated with heavy metals should be disposed of in an appropriate fashion. In this study, heavy metal concentrations found in oilseed rape and peanut oils were below 0.1 mg kg(-1) after extractions, being found most of the heavy metals in meals rather in oils. Extraction experiments were carried out to determine the optimum methodology for the removal of Pb and Cd from seed meals using K3C6H5O7, K2C4H4O6 and (NH4)2EDTA. The highest extraction of the Pb and Cd in the seed meals was achieved using 30 mM extractant solutions at 30 degrees C for 24 h and a three step extraction procedure. K3C6H5O7 and K2C4H4O6 had less impact on the removal of nutrients than (NH4)2EDTA. PMID- 26616979 TI - In situ formation of the amino sugars 1-amino-1-deoxy-fructose and 2-amino-2 deoxy-glucose under Maillard reaction conditions in the absence of ammonia. AB - Replacing amino acids with their binary metal complexes during the Maillard reaction can initiate various processes, including the oxidative degradation of their glucose conjugates, generating 1-amino-1-deoxy-fructose and its derivatives. These reactive amino sugars are not easily accessible under Maillard reaction conditions and are only formed in the presence of ammonia. To explore the generality of this observation and to study in particular the ability of fructose to generate glucosamine, the amino acid-metal complexes were heated in aqueous solutions with three aldohexoses and two ketohexoses at 110 degrees C for 2 h and the dry residues were analysed by ESI/qTOF/MS/MS. All the sugars generated relatively intense ions at [M+H](+) 180 (C6H14NO5); those ions originating from ketohexoses exhibited MS/MS fragmentations identical to glucosamine and those originating form aldohexoses showed ions identical to fructosamine. Furthermore, the amino sugars were found to form fructosazine, react with other sugars and undergo dehydration reactions. PMID- 26616980 TI - Characterization of omega-3 tablets. AB - Omega-3 nutraceuticals are extensively used as health supplements worldwide. Various administration forms for delivery of omega-3 are available. However, the niche omega-3 tablets have so far remained unexplored. In this work tablets containing 25-40% (w/w) omega-3 oil as triglycerides or ethyl esters were prepared utilizing a direct compaction grade powder with beta-cyclodextrin as encapsulating agent. It was found that powders with up to 35% (w/w) triglyceride oil and 30% (w/w) ethyl ester oil, respectively, can be directly compressed into tablets of excellent quality. Physical properties of omega-3 containing powders and tablets are described. The powder X-ray diffractograms of the powders and crushed tablets show evidence of the formation of new crystalline phases not present in beta-cyclodextrin. In addition, (1)H NMR data suggest that the ethyl esters form inclusion complexes with beta-cyclodextrin. Compaction of other, commercially available, omega-3 powders was performed as a comparison and deemed unsuccessful. PMID- 26616981 TI - Flow injection analysis of nitrate and nitrite in commercial baby foods. AB - Commercial baby foods are an easy alternative to home-made meals especially for working parents in a nuclear family therefore it is imperative to determine the nitrate and nitrite content in commercially available baby foods varieties marketed in Fiji. A total of 108 baby food samples were analyzed for nitrate and nitrite using our standardized flow injection analysis (FIA) technique with colorimetric detection technique employing sulfanilamide and N-(1 naphthyl)ethylenediamine dihydrochloride as color reagents where the samples throughput was 38 h(-1). The commercial baby food varieties chosen comprised of vegetables, cereals, fruits and milk. The study shows that the nitrate content of the baby foods studied ranges from 2.10 to 220.67 mg kg(-1) whereas the nitrite content ranges from 0.44 to 3.67 mg kg(-1). Typical recoveries of spiked nitrate residues ranged from 92% to 106%. The study shows that the average nitrate content of commercially available baby foods in Fiji descends below the maximum level proposed by the European Union Legislation. PMID- 26616982 TI - Improving green enrichment of virgin olive oil by oregano. Effects on antioxidants. AB - This work is about improvement of a maceration method in order to achieve a green process for the enrichment of virgin olive oil (VOO) with natural antioxidants, specifically from oregano leaves. This goal was accomplished after evaluating different mechanical methods, i.e. magnetic stirring, sonication, vertical stirring and sonication in combination with vertical stirring, for promoting the extraction of the antioxidants from oregano. The results obtained indicated that the best extraction procedure was vertical stirring at 1000 r.p.m. for 3 h. Therefore, these conditions were selected to enrich VOO with phenolic acids (mainly rosmarinic acid) and endogenous antioxidants (o-coumaric and vanillic acids), and further determine their stability at room temperature or under temperature stress (50 degrees C) during 45 days. Quantitative analysis of rosmarinic, o-coumaric and vanillic acids was carried out by an off-line, solid phase extraction, capillary zone, electrophoresis method combined with diode array detector (SPE-CE-DAD). PMID- 26616983 TI - Salt stress increases content and size of glutenin macropolymers in wheat grain. AB - Addition of salt solution in making wheat dough improves viscoelasticity. However, the effect of native salt fortification on dough quality is unclear. Here, wheat plants were subjected to post-anthesis salt stress to modify salt ion content in grains. The contents of Na(+) and K(+), high-molecular-weight glutenin subunits (HMW-GS), glutenin macropolyers (GMP) and amino acids in mature grains were measured. As NaCl concentration in soil increased, grain yield decreased while Na(+) and K(+) contents increased. The contents of amino acids, HMW-GS and GMP in grains also increased, especially when NaCl concentration exceeded 0.45%. Fraction of GMP larger than 10 MUm was also increased. Na(+) and K(+) contents were significantly positively correlated to GMP and total HMW-GS contents, and to large GMP fraction. PMID- 26616984 TI - Comparison of polyphenol, anthocyanin and antioxidant capacity in four varieties of Lonicera caerulea berry extracts. AB - Four varieties of Lonicera caerulea berries--'Wild', 'Beilei', 'No. 1', and 'No. 2'--were compared with respect to extraction yield, fruit weight, total soluble solids, polyphenol and anthocyanin contents, oxygen radical absorbance capacity (ORAC), and anthocyanin composition. Sixteen individual anthocyanins were identified in the selected varieties. Acylated anthocyanins, cyanidin 3 acetylhexoside and peonidin 3-acetylhexoside, were identified in L. caerulea berries for the first time. Cyanidin-3-glucoside was the most prominent anthocyanin in all four tested varieties. Wild type of L. caerulea fruit ('Wild'), with the highest polyphenol content, contained 14 anthocyanins and the highest ORAC value. Eleven anthocyanins were found in 'Beilei' berries, which had a higher ORAC value than 'No. 1' and 'No. 2'. The highest total soluble solid content and extraction yield were found in 'No. 2' and 'Wild' berries, respectively. PMID- 26616985 TI - Nitrogen split dose fertilization, plant age and frost effects on phytochemical content and sensory properties of curly kale (Brassica oleracea L. var. sabellica). AB - We investigated how concentrations of sensory relevant compounds: glucosinolates (GLSs), flavonoid glycosides, hydroxycinnamic acid derivatives and sugars in kale responded to split dose and reduced nitrogen (N) fertilization, plant age and controlled frost exposure. In addition, frost effects on sensory properties combined with N supply were assessed. Seventeen week old kale plants showed decreased aliphatic GLSs at split dose N fertilization; whereas reduced N increased aliphatic and total GLSs. Ontogenetic effects were demonstrated for all compounds: sugars, aliphatic and total GLSs increased throughout plant development, whereas kaempferol and total flavonoid glycosides showed higher concentrations in 13 week old plants. Controlled frost exposure altered sugar composition slightly, but not GLSs or flavonoid glycosides. Reduced N supply resulted in less bitterness, astringency and pungent aroma, whereas frost exposure mainly influenced aroma and texture. N treatment explained most of the sensory variation. Producers should not rely on frost only to obtain altered sensory properties. PMID- 26616986 TI - The digestion of kiwifruit (Actinidia deliciosa) fibre and the effect of kiwifruit on the digestibility of other dietary nutrients. AB - The effect of dietary kiwifruit inclusion level on the digestibility of kiwifruit fibre and dietary nutrients was studied. Ileal cannulated pigs (50+/-1.9 kg) were fed a fibre-free diet for seven days (n=14) followed by kiwifruit-containing diets (133 or 266 g kiwifruit/kg dry matter) (n=7) for 44 days followed by the fibre-free diet (n=14) for seven days. Faecal and ileal samples were collected on days 5, 11, 21, 35, 49 and 56. The soluble kiwifruit fibre was highly digested in the foregut (80%), and the insoluble fibre in the hindgut (95%). Increasing the kiwifruit inclusion level decreased the apparent ileal and faecal digestibilities of several nutrients (P<0.05), including the faecal digestibility of insoluble kiwifruit fibre and led to higher ileal and faecal concentrations of short-chain fatty acids (P<0.05). The decreased digestibility was explained by the lower digestibility of kiwifruit itself. The duration of kiwifruit consumption per se did not affect dietary nutrient digestibility (P>0.05). PMID- 26616987 TI - Effect of divalent minerals on the bioaccessibility of pure carotenoids and on physical properties of gastro-intestinal fluids. AB - During digestion, high concentrations of divalent minerals (DMs) can lead to insoluble lipid-soap complex formation, hampering carotenoid bioaccessibility. The effect of varying concentrations (0-1000 mg/L) of calcium, magnesium, zinc and sodium (control) on the bioaccessibility of lutein, neoxanthin, lycopene and beta-carotene, following in vitro gastro-intestinal digestion (GI), was investigated systematically and coupled with physical measurements of the digesta. Addition of DMs significantly decreased (p<0.001) carotenoid bioaccessibility, up to 100% in the case of calcium. Mean half maximal inhibitory concentrations (EC50) for calcium, magnesium and zinc were 270+/-18, 253+/-75 and 420+/-322 mg/L respectively. Increased DM concentrations correlated with decreased viscosity (r>0.9) and decreased carotenoid bioaccessibility. Surface tension of digesta correlated inversely (p<0.05) with the bioaccessibility of carotenoids. This correlation was mineral and carotenoid dependent. Although based on in vitro findings, it is plausible that similar interactions occur in vivo, with DMs affecting the bioaccessibility and bioavailability of carotenoids and other lipophilic micronutrients and phytochemicals. PMID- 26616988 TI - Extraction of phenolic compounds from virgin olive oil by deep eutectic solvents (DESs). AB - Deep eutectic solvents (DESs) are "green" solvents, applied in this study for the extraction of phenolic compounds from virgin olive oil (VOO). Different combinations of DES consisting of choline chloride (ChCl) in various mixing ratios with sugars, alcohols, organic acids, and urea, as well as a mixture of three sugars were used. The yields of the DES extractions were compared with those from conventional 80% (v/v) methanol/water. DES showed a good solubility of phenolic compounds with different polarities. The two most abundant secoiridoid derivatives in olive oil, oleacein and oleocanthal, extracted with ChCl/xylitol and ChCl/1,2-propanediol showed an increase of 20-33% and 67.9-68.3% with respect to conventional extraction, respectively. To our knowledge, this is the first time that phenolic compounds have been extracted from VOO oil using DES. Our results suggest that DES offers an efficient, safe, sustainable, and cost effective alternative to methanol for extraction of bioactive compounds from VOO. PMID- 26616989 TI - Phosphatidylcholine, an edible carrier for nanoencapsulation of unstable thiamine. AB - Lipid nanoparticles have been used for carrying different therapeutic agents because of the advantage in improved absorption, bioavailability, targeted deliveries and reduction in the quantity of drugs required. The aim of the study was to prepare and characterize nanoliposomes containing thiamine hydrochloride and study their physicochemical stability as this vitamin is highly unstable. Phosphatidylcholine (PC) was used as an edible encapsulant. The average size of nanoliposomes was found to be 150 nm and zeta potential was -34 mV. The encapsulation efficiency was 97%. Atomic force microscopy (AFM) and scanning electron microscopy (SEM) confirmed the size, spherical nature and smooth surface of the nanoliposomes. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) evidenced that the nanoliposomes were stable up to 300 degrees C. The functional groups present were determined by Fourier transformed infrared spectroscopy (FTIR) and the presence of vitamin was confirmed in final formulation by biochemical analysis. The crystalline nature of thiamine was analyzed by X-ray diffraction studies. Storage studies indicated that the nanoliposomes were highly stable up to 3 months at different temperatures. Thus, phosphatidylcholine can be used as carrier vehicle of nutrients especially vitamins, as it can form stable nanoliposomes with 97% encapsulation efficiency. PMID- 26616990 TI - Multiresidue method for the simultaneous determination of veterinary medicinal products, feed additives and illegal dyes in eggs using liquid chromatography tandem mass spectrometry. AB - A multiclass method was developed for the simultaneous determination of 120 analytes in fresh eggs. The method covers the analytes from the groups of tetracyclines (6), fluoroquinolones (11), sulphonamides (17), nitroimidazoles (9), amphenicols (2), cephalosporins (7), penicillins (8), macrolides (8), benzimidazoles (20), coccidiostats (14), insecticides (3), dyes (12) and others (3). Samples were extracted using 0.1% formic acid in acetonitrile:water (8:2) with the addition of EDTA and cleaned using solid phase extraction with Hybrid SPE cartridges. The chromatographic separation was achieved on C8 column using mobile phase consisting of (A) methanol:acetonitrile (8:2) - (B) 0.1% formic acid in a gradient mode. Validation results according to the Commission Decision 2002/657/EC are as follows: linearity (r?0.99), recovery (75-108%), repeatability (CV 1.60-15.9%), reproducibility (CV 2.60-15%), decision limit (CCalpha 2.25-1156 MUg/kg) and detection capability (CCbeta 2.04-1316 MUg/kg). The presented method was used for analysis of 150 real eggs samples taken from monitoring control program. PMID- 26616991 TI - Toward shrimp consumption without chemicals: Combined effects of freezing and modified atmosphere packaging (MAP) on some quality characteristics of Giant Red Shrimp (Aristaeomorpha foliacea) during storage. AB - The combined effects of freezing and modified atmosphere packaging (MAP) (100% N2 and 50% N2+50% CO2) on some quality characteristics of Giant Red Shrimp (GRS) (Aristaeomorpha foliacea) was studied during 12-month storage. In particular, the quality characteristics determined proximal and gas compositions, melanosis scores, pH, total volatile basic-nitrogen (TVB-N), thiobarbituric acid (TBA) as well as free amino acid (FAA). In addition, the emergent data were compared to those subject to vacuum packaging as well as conventional preservative method of sulphite treatment (SUL). Most determined qualities exhibited quantitative differences with storage. By comparisons, while pH and TVB-N statistically varied between treatments (P<0.05) and TBA that ranged between ~0.15 and 0.30 mg MDA/kg appeared least at end of storage for 100% N2 treated-group, the latter having decreased melanosis scores showed such treatments with high promise to keep the colour of GRS sample hence, potential replacement for SUL group. By comparisons also, while some individual FAA values showed increases especially at the 100% N2 treated group, the total FAAs statistically differed with storage (P<0.05). The combination of freezing and MAP treatments as preservative treatment method shows high promise to influence some quality characteristics of GRS samples of this study. PMID- 26616992 TI - Preparation of tyrosinase inhibitors and antibrowning agents using green technology. AB - Chalcones and their derivatives have attracted great interests in recent years for their comprehensive biological activities. In this study, 2,4,2',4' tetrahydroxychalcone and its two derivatives, 1,3,5-tris-(2,4-dihydroxy phenyl)pentane-1,5-dione (new compound) and 7,2',4'-trihydroxyflavanone, were synthesized through one-pot green procedure catalyzed by boric acid in polyethylene glycol 400. Their structures were identified by ESI-MS and NMR spectral. Tyrosinase inhibitory activity and antibrowning test results showed that compounds 1-3 exhibited strong tyrosinase inhibitory activities and significant antibrowning effects on the fresh-cut lotus root slices at room temperature in 48 h. Among them, 0.01% 1,3,5-tris-(2,4-dihydroxy-phenyl)pentane 1,5-dione combined with 0.5% VC showed the best antibrowning ability. In brief, this study offers a protocol for one-pot green synthesis of high efficiency tyrosinase inhibitors which may be suitable as antibrowning agents for fresh-cut vegetables. More important, this study developed a new type of 1,5-dione derivative which may serve as new lead structures for novel tyrosinase inhibitors discovery. PMID- 26616993 TI - Nutrient composition and antioxidant activity of gonads of sea urchin Stomopneustes variolaris. AB - The study investigated, for the first time, proximate nutritional composition and antioxidant activity of gonads from the sea urchin, Stomopneustes variolaris, inhabiting the coastal area of Visakhapatnam (India). Moisture, ash, proteins, lipids and carbohydrate content were 77.53%+/-0.80, 3.76%+/-0.25, 12.10%+/-0.41, 4.98%+/-0.36 and 1.63%+/-0.18, respectively, based on dry weight. The gonads were rich in essential amino acids (ca. 32.1% of total amino acids) with the most predominant being phenylalanine, lysine and valine. The essential to non essential amino acid ratio was 0.5. Polyunsaturated fatty acids (PUFA) constituted 22.01%+/-2.2 of total fatty acids. The omega6:omega3 ratio was 0.94. Total phenol content of the gonad was 9.90+/-0.01 mg GAE/g and the IC50 of the extract, using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay, was 57.81 MUg/ml. PMID- 26616994 TI - Inhibitory effect of microwaved thinned nectarine extracts on polyphenol oxidase activity. AB - By-products from agricultural practices or from the fruit processing industry are a source of bioactive compounds that could be used in the food industry. Such by products include thinned fruits, which are expected to contain high quantities of interesting compounds. One possible application of this fruits is the prevention of the enzymatic browning suffered by fruits and vegetables after minimal processing. The aim of this study is to determine the in vitro and in vivo activity of microwaved extracts obtained from thinned nectarines. It has been observed that in vitro the extracts obtained after the application of high microwave power levels (500, 1000 and 1500 W) are mixed type inhibitors of polyphenoloxidase enzyme, showing an irreversible inactivation. This inhibition could be attributed to the Maillard reaction products formed during the microwave treatment. In vivo, a solution of 2% of the extract obtained at 1500 W inhibited the enzymatic browning in minimally processed peaches for 8 days of storage. PMID- 26616995 TI - Biocatalytic conversion of poultry processing leftovers: Optimization of hydrolytic conditions and peptide hydrolysate characterization. AB - Peptide hydrolysate (PH) was produced by deep controllable bioconversion of poultry processing leftovers (broiler necks), by means of a multienzyme composition, containing four commercially available enzyme preparations (Alcalase, Neutrase, Flavourzyme, Protamex). The design of multienzyme composition (MEC) was applied to yield a hydrolysate with adjusted properties, including minimized antigenicity and bitterness. The protein recovery was optimized using Box-Behnken response surface design. The individual and interactive effects of hydrolysis conditions (time, hydromodule and MEC dosage) were studied. The experimental data were analyzed by ANOVA method and a well predictive, second order polynomial model was developed using multiple regression analysis. Optimal hydrolysis conditions were found to be: hydrolysis time 3 h, hydromodule 2.25 l/kg and dosage of MEC 0.25%. The corresponding predicted value for protein recovery was 75.34%, 2 times higher compared to traditional long-term heating hydrolysis. The PH obtained is a low allergenic product with high antioxidant capacity. PMID- 26616996 TI - Case study of a commercial sheep flock under extensive mountain grazing: Pasture derived lipid compounds in milk and cheese. AB - Terpenoid, fat-soluble antioxidant and fatty acid (FA) composition of pasture as well as those of milk and cheese from a commercial sheep flock managed under extensive mountain grazing in the east region of the Cantabrian mountain (Northern Spain) was investigated. The grazing period lasted for 2 months and ewes were at late lactation stage. Plants, feces, bulk milk and cheese samples were collected on two sampling dates. The abundance of the dominating botanical families in the mountain pasture prevailed in the sheep diet of the commercial flock. Major terpenoids and tocols in the pasture appeared as major ones in milk and cheese, whereas C18 unsaturated FAs in milk and cheese were derived from the intake of C18 polyunsaturated FAs which were prevalent in the pasture. No carotene was detected in the dairy samples but retinol (free or esterified), derived from the intake of beta-carotene present in pasture plants, was found in milk and cheese. PMID- 26616997 TI - Changes in wheat kernel proteins induced by microwave treatment. AB - Wheat kernels were subjected to microwave treatment, and the proteins were characterized by size exclusion high-performance liquid chromatography (SE-HPLC) and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). Using this process, the proteins polymerize, forming intermolecular bonds among the same classes of proteins. Furthermore, the polymerization occurs only through disulphide bonds. Although SDS-PAGE did not show any differences for either the number or intensity of protein bands between flour samples before and after microwave treatment, gliadins from treated flours showed significantly reduced cross-reactivity with the R5 antibody. Moreover, the gluten became soluble in an aqueous saline solution, and it was not possible to isolate it using the Glutomatic apparatus. However, the treated flour, in the presence of water, was able to form dough and leaven and produce bread. PMID- 26616998 TI - Thermal inactivation kinetics of proteases and polyphenoloxidase in brown shrimp (Crangon crangon). AB - To optimize product quality of the cooked brown shrimp (Crangon crangon), quantitative data on the influence of all relevant process parameters (treatment time and temperature) on several quality attributes is required. Surprisingly, kinetic data and models on heat induced inactivation of important endogenous spoilage enzymes of the brown shrimp are not available today. In this study the thermal inactivation kinetics of the most important spoilage enzymes, proteases and polyphenoloxidase (PPO), were determined from isothermal heat treatments of enzyme extracts of the cephalothorax. For both enzymes, inactivation kinetics showed first order decay(s). Proteases showed two distinct stability fractions. A labile fraction, representing 42+/-2% of the total activity with kl,60 degrees C=0.94+/-0.14 min(-1) and Ea,l=178+/-8.5 kJ/mol, and a stable fraction, representing 58+/-2%, with ks,60 degrees C=0.020+/-0.002 min(-1) and Ea,s=155+/ 7.0 kJ/mol. PPO showed a single fraction with k60 degrees C=1.58+/-0.02 min(-1) and Ea=161+/-2.2 kJ/mol. Based on these results, the proteolytic activity, in particular the thermostable fraction, should be considered as a target in thermal processing of brown shrimp in relation to enzyme induced product quality changes during storage. PMID- 26616999 TI - Gastrointestinal digested Sambucus nigra L. fruit extract protects in vitro cultured human colon cells against oxidative stress. AB - Elderberry (EDB) Sambucus nigra L. is one of the oldest medicinal plants which is useful for therapeutic and nutritional purposes due to a large amount of biologically active constituents, including compounds with a high antioxidant capacity. The present study focused on the antioxidant potential of the colon available EDB fruit extract, derived from the artificial gastrointestinal tract, with regard to human colonic mucosa cells cultured in vitro. Despite the significant loss of EDB bioactive compounds due to the digestion process, the colon-digested extract was able to reduce the excessive intracellular ROS production (22%) and oxidative DNA damage (46%) in the colon cells at a dose of 1 mg of freeze-dried EDB powder/ml. Moreover, the colon-digested EDB extract inhibited oxidant-induced mutagenicity (26%) in the Salmonella typhimurium TA102 strain, as determined by the Ames test. In conclusion, the current in vitro study confirmed that the fruits of S. nigra are capable of protecting colonic cells against the detrimental effects of oxidative stress. PMID- 26617000 TI - Comparative analysis of the in vitro cytotoxicity of the dietary biogenic amines tyramine and histamine. AB - Tyramine and histamine, the most toxic biogenic amines (BA), are often found in high concentrations in certain foods. Prompted by the limited knowledge of BA toxicity, and increasing awareness of the risks associated with high intakes of dietary BA, the in vitro cytotoxicity of tyramine and histamine was investigated. Tyramine and histamine were toxic for HT29 intestinal cell cultures at concentrations commonly found in BA-rich food, as determined by real-time cell analysis. Surprisingly, tyramine had a stronger and more rapid cytotoxic effect than histamine. Their mode of action was also different, while tyramine caused cell necrosis, histamine induced apoptosis. To avoid health risks, the BA content of foods should be reduced and legal limits established for tyramine. PMID- 26617001 TI - Lactulose production from cheese whey using recyclable catalyst ammonium carbonate. AB - Ammonium carbonate ((NH4)2CO3) was used as an alkaline catalyst of lactulose production from cheese whey. Maximum yield of 29.6% was obtained at reaction time of 28.44 min, (NH4)2CO3 of 0.76% at 97 degrees C. During reaction, (NH4)2CO3 was fully decomposed to NH3 and CO2, and these gases were recovered. To boost up NH3 recovery, various methods such as heating, aeration, and pH adjustment were applied. The optimal condition for the purpose of NH3 retrieval was temperature of up to 60 degrees C alongside aeration. Easy separation and recovery make (NH4)2CO3 a catalyst alternative to common alkaline chemicals especially for the weak alkaline reaction. PMID- 26617002 TI - Novel DNPH-based method for determination of protein carbonylation in muscle and meat. AB - Protein oxidation is considered an ongoing deteriorative process during storage of fresh and processed meat. Carbonyl compounds have traditionally been detected spectrophotometrically after derivatization with 2,4-dinitrophenylhydrazine (DNPH) to form protein-bound hydrazones with absorbance at 370 nm. Here we describe a novel DNPH-based method to quantify protein carbonylation in muscle and meat. The additional steps of the novel method aimed at increasing the protein solubility and inducing protein unfolding before labeling with DNPH. Compared to the traditional method, the new procedure reflected an increased protein carbonylation level measuring overall two to fourfold more carbonyls in muscles from different species as well as in soluble, salt-soluble and insoluble protein fractions. The study suggested that protein unfolding is a more important phenomenon than solubilization for increased DNPH labeling. The novel method resulted in three to fourfold larger carbonyl content determined in chicken, pork and beef (2.8, 3.6 and 3.1 nmol/mg of protein, respectively). PMID- 26617003 TI - Molecular interactions of a model bile salt and porcine bile with (1,3:1,4)-beta glucans and arabinoxylans probed by (13)C NMR and SAXS. AB - Two main classes of interaction between soluble dietary fibres (SDFs), such as (1,3:1,4)-beta-D-glucan (betaG) and arabinoxylan (AX) and bile salt (BS) or diluted porcine bile, were identified by (13)C NMR and small angle X-ray scattering (SAXS). Small chemical shift differences of BS NMR resonances were consistent with effective local concentration or dilution of BS micelles mostly by betaG, suggesting dynamic interactions; whilst the reduced line widths/intensities observed were mostly caused by wheat AX and the highest molecular size and concentrations of betaG. SAXS showed evidence of changes in betaG but not AX in the presence of BS micelles, at >13 nm length scale consistent with molecular level interactions. Thus intermolecular interactions between SDF and BS depend on both SDF source and its molecular weight and may occur alone or in combination. PMID- 26617004 TI - Yeast influence on the formation of stable pigments in red winemaking. AB - The anthocyanin profile of a wine greatly varies over time depending on many factors. In addition to color modifications due to changes in the chemical composition of wine, there may be some influence of the yeast strain used in fermentation. The main aim of this study is to identify and quantify the different ways in which yeast may influence on wine color and its stability, during red winemaking. Hydroxycinnamate decarboxylase activity was measured by the ability to transform the p-coumaric acid (HPLC-DAD). Acetaldehyde (GC-FID) and pyruvic acid (Y15 enzymatic autoanalyser) contents were monitored along fermentation. Stable pigments formation, including vitisins, vinylphenolic pyranoanthocyanins and flavanols-anthocyanins adducts, were analyzed by HPLC DAD/ESI-MS. Moreover, the ability of adsorbing color molecules by yeasts' cell walls was assessed. It could be concluded that the strain used has substantial influence on the formation of stable pigments, and therefore, proper yeast selection is important to ensure the stability of the wine coloring matter. PMID- 26617005 TI - A novel reductive amination method with isotopic formaldehydes for the preparation of internal standard and standards for determining organosulfur compounds in garlic. AB - Garlic (Allium sativum) is a long-cultivated plant that is widely utilized in cooking and has been employed as a medicine for over 4000 years. In this study, we fabricated standards and internal standards (ISs) for absolute quantification via reductive amination with isotopic formaldehydes. Garlic has four abundant organosulfur compounds (OSCs): S-allylcysteine, S-allylcysteinine sulfoxide, S methylcysteine, and S-ethylcysteine are abundant in garlic. OSCs with primary amine groups were reacted with isotopic formaldehydes to synthesize ISs and standards. Cooked and uncooked garlic samples were compared, and we utilized tandem mass spectrometry equipped with a selective reaction monitoring technique to absolutely quantify the four organosulfur compounds. PMID- 26617006 TI - Heat-induced interaction between egg white protein and wheat gluten. AB - Some wheat-based food systems, such as cakes and cookies, include mixtures of gluten and egg white protein (EWP) and are processed under heating conditions. Changes in these proteins during processing can affect the quality of the end product. This study investigated protein polymerization during heating of (mixtures of) wheat gluten and EWP. Chemical changes were studied by size exclusion high performance liquid chromatography (SE-HPLC), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), thiol (SH) measurement and Fourier transform infrared (FTIR). During heating, protein polymerization was observed in the mixtures of gluten, glutenin, gliadin and EWP according to SE HPLC profiles and results of SDS-extractable protein. The results of SDS-PAGE profiles of different proteins were in accordance with SE-HPLC. The number of SH groups in the majority of proteins showed a significant decrease, implying that disulfide (SS) bonds contributed to the extractability loss. In addition, changes of secondary structure tested by FTIR indicated protein aggregation. PMID- 26617007 TI - Characterization of lipid oxidation in plant oils by micro-calorimetry. AB - A new experimental device was developed, based on the measurement of the heat flux dissipated during chemical reactions. The technique was exploited for real time monitoring of lipid oxidation in plant oils. The thermopiles were used in adiabatic configuration in order to measure the entire heat flux and improve sensitivity. Measurements were operated with a resolution of few MUW as required to follow low exothermic reactions like oxidation. The validation of the device was performed by correlating conjugated diene concentrations measured by spectrophotometry and the heat flux dissipated by oxidation reactions. Our experimental approach involved several plant oils analyzed in isothermal conditions. This novel technique provides a versatile, sensitive, solvent-free and yet low-cost method to assess lipid oxidation stability, particularly suitable for the fast screening of plant oils. PMID- 26617008 TI - Effects of different drying methods on the product quality and volatile compounds of whole shiitake mushrooms. AB - Various drying methods play important roles in the preservation of foods. However, how the different drying methods affect the quality of some foods is not clear. This paper evaluates the effects of hot air, vacuum, microwave, and microwave vacuum drying techniques on important qualities and volatile compounds of whole shiitake (Lentinus edodes) mushrooms. These four drying methods resulted in a significantly (p<0.05) increase in the content of total free amino acids and the relative content of sulfur compounds of dried products. Microwave vacuum drying helped to maintain larger amounts of taste-active amino acids, and improved nutrient retention and color attributes. Furthermore, the uniform honeycomb network created by microwave vacuum drying along with a less collapsed structure of dried samples can be used to explain the observed high rehydration ratio. Therefore, microwave vacuum drying should be a potential method for obtaining high-quality dried mushrooms. PMID- 26617009 TI - Label-free surface-enhanced Raman scattering strategy for rapid detection of penicilloic acid in milk products. AB - A label-free surface-enhanced Raman scattering (SERS) strategy based on silver coated gold nanoparticles (Au@Ag NPs) was developed for rapid detection of penicilloic acid (PA) in milk products. It has been demonstrated that core size and shell thickness of Au@Ag NPs are two critical variants affecting enhancement of Raman signals by coupling of two plasma resonance absorption. The Au@Ag NPs with 26-nm core and 9-nm Ag shell exhibit excellent Raman enhancement, in particular, upon the formation of hot spots through NPs aggregation induced by interaction between target molecules and Au@Ag NPs. Compared to the early studies limited to laboratory settings, our analytical approach is simple (without sample pretreatment), less time-consuming (within ~3 min) and inexpensive. The limit of detection of PA is 3.00 ppm, 3.00 ppm and 4.00 ppm in liquid milk, yogurt and milk powder, respectively. The label-free SERS technique offers a potential for the on-site monitoring of chemical contaminants in milk products. PMID- 26617010 TI - Residue determination of glufosinate in plant origin foods using modified Quick Polar Pesticides (QuPPe) method and liquid chromatography coupled with tandem mass spectrometry. AB - A sensitive and specific method for the determination of glufosinate in plant origin foods was developed. The method involves extraction using modified QuPPe method, clean-up by multi-walled carbon nanotubes (MWCNTs), derivatization with 9 fluorenylmethyl chloroformate (FMOC-Cl) and detection with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The method was validated on twelve matrices spiked at 10 or 20, 100 and 500 MUg/kg. The recovery ranged from 80% to 108% with intra-day RSDs (n=5) of 0.6-9.8% and inter-day RSDs (n=15) of 3.0-9.4%. Good linearities (R(2)?0.9991) were obtained for all matrices. The limit of detection (LOD) and limit of quantification (LOQ) for the selected matrices ranged from 0.3 to 3.3 MUg kg(-1) and from 1 to 10 MUg kg(-1), respectively. The method was demonstrated to be reliable and sensitive for the routine monitoring of glufosinate in plant origin foods. PMID- 26617011 TI - The role of ascorbate peroxidase, guaiacol peroxidase, and polysaccharides in cassava (Manihot esculenta Crantz) roots under postharvest physiological deterioration. AB - This study aimed to investigate the role of ascorbate peroxidase (APX), guaiacol peroxidase (GPX), polysaccharides, and protein contents associated with the early events of postharvest physiological deterioration (PPD) in cassava roots. Increases in APX and GPX activity, as well as total protein contents occurred from 3 to 5 days of storage and were correlated with the delay of PPD. Cassava samples stained with Periodic Acid-Schiff (PAS) highlighted the presence of starch and cellulose. Degradation of starch granules during PPD was also detected. Slight metachromatic reaction with toluidine blue is indicative of increasing of acidic polysaccharides and may play an important role in PPD delay. Principal component analysis (PCA) classified samples according to their levels of enzymatic activity based on the decision tree model which showed GPX and total protein amounts to be correlated with PPD. The Oriental (ORI) cultivar was more susceptible to PPD. PMID- 26617012 TI - Validation of analytical conditions for determination of polycyclic aromatic hydrocarbons in roasted coffee by gas chromatography-mass spectrometry. AB - Polycyclic aromatic hydrocarbons (PAHs) are of significant interest due to their genotoxicity in humans. PAHs quantification in coffee is complex since some of its compounds interfere in the chromatographic analysis, which hinders the reliable determination of the PAHs. Analytical conditions for the ultrasound extraction, purification and quantification of 16 PAHs in roasted coffee were studied. The better extraction efficiency of benzo[a]pyrene (68%) from ground roasted coffee was achieved with a solvent ratio of Hex:MC (9:1 v/v) and three extraction periods of 20 min, followed by alkaline saponification and purification of the extracts. The detection limits were 0.85-39.32 ng mL(-1), and the quantification limits from 2.84 to 131.05 ng mL(-1), obtained for fluoranthene and chrysene, respectively. The extraction was effective for most of the analytes, with recoveries of 39.8% dibenzo[ah]anthracene and 69.0% benzo[b]fluoranthene. For coffee roasted in a spouted bed reactor, the summation of the 16 PAHs ranged from 3.5 to 16.4 MUg kg(-1). PMID- 26617013 TI - Application of ionic liquid-based dispersive liquid phase microextraction for highly sensitive simultaneous determination of three endocrine disrupting compounds in food packaging. AB - Ionic liquid (IL) dispersive liquid-liquid microextraction (DLLME) method was successfully developed for extracting three endocrine disrupting compounds (EDCs) (bisphenol A, bisphenol AF and bisphenol AP) from the food packaging. 1-Octyl-3 methylimidazoliumhexafluorophosphate ([C8MIM][PF6]) was selected as extraction solution. The extraction procedure did not require a dispersive solvent. Three EDCs extraction kinetics were found to be very fast and the equilibrium was attained within 3.0 min following the pseudo-first-order model. The H-bonding and hydrophobic interactions play an important role in the partitioning of EDCs into IL from aqueous solution. The recovered IL could be reused for three runs without significant loss of extraction efficiencies. The spiked recoveries of three targets in food packaging were in the range of 97.8-103.1%. The limits of detection ranged from 0.50 to 1.50 ng mL(-1) (S/N=3). As a result, this method has been successfully applied for the sensitive detection of three EDCs in real samples. PMID- 26617014 TI - Beta-glucan-depleted, glycopeptide-rich extracts from Brewer's and Baker's yeast (Saccharomyces cerevisiae) lower interferon-gamma production by stimulated human blood cells in vitro. AB - Regulation of the human immune system requires controlled pro- and anti inflammatory responses for host defence against infection and disease states. Yeasts (Saccharomyces cerevisiae), as used in brewing and baking, are mostly known for ability to stimulate the human immune-system predominantly reflecting the pro-inflammatory cell wall beta-glucans. However, in this study, using food compatible processing methods, glycopeptide-enriched and beta-glucan-depleted products were each prepared from Brewer's and Baker's yeasts, which suppressed production of interferon-gamma (IFN-gamma) in human whole blood cell assay, signifying that anti-inflammatory factors are also present in yeast. Anti inflammatory bioactivities of products prepared from Brewer's and Baker's yeast were compared with the commercial yeast product, Epicor(r). While unfractionated Epicor was inactive, the C18 resin-binding fractions of Brewer's and Baker's yeast products and Epicor dose-dependently lowered IFN-gamma, demonstrating that Epicor also contained both pro-inflammatory (beta-glucans) and anti-inflammatory components. Anti-inflammatory activity was attributed to C18 resin-binding species glyco-peptides in Epicor and experimental yeast products. This study demonstrated that pro- and anti-inflammatory factors could be resolved and enriched in yeasts by suitable processing, with potential to improve specific activities. PMID- 26617015 TI - Investigations on the effect of antioxidant type and concentration and model system matrix on acrylamide formation in model Maillard reaction systems. AB - The formation of acrylamide in model Maillard reaction systems containing phenolic compounds was examined, with regards to phenolic type, concentration, and model system matrix. In dry glyoxal/asparagine waxy maize starch (WMS) systems, 9 out of 10 examined phenolics demonstrated an inhibiting effect, with the most significant reductions (55-60%) observed for caffeoylquinic acids. In WMS glucose/asparagine systems, examination of three different concentrations (0.1, 0.5 and 1 MUmol/g WMS) suggested a 'minimum effective concentration' for epicatechin and caffeic acid, whilst addition of caffeoylquinic acids resulted in dose-dependent acrylamide reduction (25-75%). The discordant results of further studies utilising different matrices (dry and wet-to-dry) indicated that, apart from the nature and chemical reactivity, the matrix and the physical state of the reactants might be important for acrylamide formation. PMID- 26617017 TI - An investigation into the fatty acid content of selected fish-based commercial infant foods in the UK and the impact of commonly practiced re-heating treatments used by parents for the preparation of infant formula milks. AB - The importance of dietary lipids during infancy is paramount for rapid growth and development. Linoleic acid (LA), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) were quantified using RP-HPLC with charged aerosol detection in a range of complementary infant foods and formula milk. Total daily intake of fatty acids for infants aged 6-9 months was calculated based on the consumption of complementary infant foods and formula milk. Total daily intakes of ALA, AA and DHA were below, whereas LA was above the recommended intake. This provides scope for product optimisation, to improve the nutritive value of commercial infant food products. The impact of re heating treatments by parents on fatty acid content of formula milk was investigated and statistically significant changes were observed. Furthermore, the transparency of the labelling information declared by the manufacturers was within recommendations despite a degree of significant variation. PMID- 26617016 TI - Genotypic variation in phenolic acids, vitamin E and fatty acids in whole grain rice. AB - The genetic diversity of phenolic content (PC), individual phenolic acids, vitamin E isomers (VE) and fatty acids (FA) in the whole grain rice were investigated. The most abundant phenolic acid was ferulic acid ranging from 155.6 to 271.1 MUg/g and comprising approximately 40-57% of total phenolic acid (TPA). The predominant tocopherols (T) and tocotrienols (T3) were alpha-T (6.43-12.67 MUg/g) and gamma-T3 (12.88-32.75 MUg/g). The unsaturated fractions of FAs accounted for 74-81% of the total FAs in rice. Most of the phytochemicals among phenolics and VEs showed significant differences between white and red rice, with red rice demonstrating significantly higher levels. However, white rice had higher content of oleic, linolenic, eicosenoic and total fatty acids than red rice. The wide genetic diversity in whole grain rice allows food processors to have a good selection for producing rice products, and breeders to have new rice lines that can be bred for high nutrient levels. PMID- 26617018 TI - Changes in the microbiological and chemical characteristics of white bread during storage in paper packages modified with Ag/TiO2-SiO2, Ag/N-TiO2 or Au/TiO2. AB - Microbiological and chemical characteristics of white bread during storage in paper-packages modified with Ag/TiO2-SiO2, Ag/N-TiO2 or Au/TiO2 were investigated. The whiteness and the water retention of the modified packages were slightly superior to those exhibited by the reference sample, as the color of the composite was lighter. The water retention was very good especially for the Ag/TiO2-SiO2-paper. These improvements can be associated with the high specific surface area and with the low agglomeration tendency of Ag nanoparticles in comparison with the Au ones. The preservation activity of the composites for the bread storage is positively influenced by photoactivity and presence of nano-Ag. Packages Ag/TiO2-SiO2-paper and Ag/N-TiO2-paper can find their applicability for extending the shelf life of bread by 2 days as compared with the unmodified paper package. No influence of the Au/TiO2 on the extending the shelf life of bread was observed. PMID- 26617019 TI - The major proteins of the seed of the fruit of the date palm (Phoenix dactylifera L.): Characterisation and emulsifying properties. AB - Proteins were extracted from the seeds of the fruit of the date palm. Proteomic analysis and SDS-PAGE electrophoresis of the extracted proteome suggested it is composed predominantly of the storage proteins glycinin and beta-conglycinin, although over 300 proteins were detected, 91 of which were identified with confidence. In terms of protein type, the largest numbers of proteins were associated, not unexpectedly, with metabolism and energy functions, which reflected the requirements of the germinating and growing embryonic plant. The emulsifying properties of the extracted proteins were determined. Date seed protein exhibited a lower emulsifying activity than either whey protein concentrate or soy protein isolate, at each of the pH values tested. However, the stability of the emulsions produced with all three proteins was very similar at the different pH values. This combination of large emulsion droplet size and high emulsion stability properties suggested that the date proteins may adsorb as large protein oligomers. PMID- 26617020 TI - Radical scavenging activities of Tyr-, Trp-, Cys- and Met-Gly and their protective effects against AAPH-induced oxidative damage in human erythrocytes. AB - Radical scavenging activities of Tyr-, Trp-, Cys- and Met-Gly and their protective effects against AAPH-induced oxidative damage in erythrocytes were evaluated in this study. This damage includes hemolysis, oxidation of hemoglobin, formation of MDA and the depletion of glutathione (GSH) and catalase (CAT). Results showed that Tyr- and Trp-Gly could quench the radicals effectively in ABTS and ORAC assays with TE (Trolox equivalent) values of more than 1.0 MUmol TE/MUmol, followed by Cys- and Met-Gly. All these dipeptides could protect erythrocytes against AAPH-induced hemolysis in a dose-dependent manner. They could also significantly (p<0.05) retard the oxidation of hemoglobin and depletion of GSH in erythrocytes. The protective effects of these dipeptides decreased in the following order: Trp-Gly>Tyr-Gly>Met-Gly>Cys-Gly, which were consistent with their peroxyl radical scavenging activities. It suggested that these dipeptides might protect erythrocytes against AAPH-induced oxidative damage, mainly by acting as the direct radical scavengers. PMID- 26617021 TI - Element distribution and morphology of spotted golden goatfish fish scales as affected by demineralisation. AB - Scales of spotted golden goatfish were subjected to non-collagenous protein removal followed by demineralisation with hydrochloric acid at different concentrations (0.25, 0.5, 0.75 and 1 M) for various times (30, 60 and 90 min). The morphology and element composition/distribution of scales from spotted golden goatfish as influenced by demineralisation conditions were determined. The appropriate demineralisation was pertained using 0.75 M hydrochloric acid for 30 min, in which the ash content was 0.62% (dry weight basis). The scales having non collagenous protein removal with, and without, subsequent demineralisation were analysed for element content using X-ray fluorescence spectrometer. Images of different scales were determined using scanning electron microscopy (SEM) and scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX). Based on the images, an external layer rich in inorganic elements was removed. Most of Ca and P were eliminated with the coincidental increases in organic substances (C, N and O) after demineralisation. Demineralisation therefore mainly removed the external layer of scales, which facilitated the further extraction of collagen or gelatin. PMID- 26617022 TI - Development and validation of an indirect competitive enzyme-linked immunosorbent assay for monitoring organoarsenic compounds in edible chicken and pork and feed. AB - For the first time in this study, we used molecular modelling to design a suitable hapten (arsanilic acid, ASA) and produced a broad-specificity monoclonal antibody (mAb). This mAb exhibited the IC50 for ASA was 913.7 MUg L(-1) and showed the cross-reactivity to ASA (100%), carbarsone (849.2%), and nitarsone (1159.5%), respectively. Based on this mAb, an optimised indirect competitive enzyme linked immunosorbent assay (ic-ELISA) protocol was developed to monitor organoarsenic compounds (OAs) in edible chicken and pork and feed, which the detection limit for OAs in a muscle matrix ranged from 74.2 MUg kg(-1) to 143.3 MUg kg(-1) and in a feed matrix ranged from 7.4 mg kg(-1) to 11.8 mg kg(-1), the recoveries were 61.3-109.6% with a coefficient of variation of less than 10.8%. These data demonstrated that the developed ic-ELISA is a reliable and useful tool for screening OAs in edible chicken and pork and feed. PMID- 26617023 TI - Protective effects of five allium derived organosulfur compounds against mutation and oxidation. AB - In this study, we examined the ability of five allium-derived organosulfur compounds to protect cells against mutation and oxidation. The compounds tested were 1-propylmercaptan (PM), dimethyl disulfide (DMDS), diallyl disulfide (DADS), propyl disulfide (PDS), and 2,5-dimethylthiophene (DMT). Our results showed that when used at concentrations of 100-400 MUmol/l, the five compounds inhibited the mutagenicity of 4-nitroquinoline-N-oxide, a direct mutagen, and benzo[a]pyrene, an indirect mutagen, toward Salmonella typhimurium TA 98 and TA 100. Furthermore, at these concentrations, all five of the compounds protected HepG2 cells against tert-butyl hydroperoxide-induced oxidative cytotoxicity. The compounds likely enhanced cell viability by suppressing the formation of reactive oxygen species and the depletion of glutathione depletion in cells. DMT and PM inhibited mutation and oxidation to a greater extent than DMDS, DADS, and PDS. These results demonstrate for the first time that DMT and PM can contribute to the antimutagenic and the antioxidative property of Allium vegetables. PMID- 26617024 TI - Identification of products from canthaxanthin oxidation. AB - Canthaxanthin is a carotenoid that lacks pro-vitamin A activity but is known to have antioxidant activity. The products of its oxidation in oxygen were found to be mainly substituted apo-carotenals and apo-carotenones. The product profile resembles that obtained in the oxidation of beta-carotene, except that with canthaxanthin these products are the 4-oxo-beta-apo-carotenals and 4-oxo-beta-apo carotenones. Epoxides and diepoxides were clearly identified from beta-carotene oxidation but in contrast, with canthaxanthin, apart from 5,6-epoxy canthaxanthin, which was detected at the early stage of oxidation and minor quantities of 5,6-epoxy-beta-ionone and 5,6-epoxy-4-oxo-beta-apo-11-carotenal, no other epoxides were detected. The identities of these products lead us to suggest that the mechanism of canthaxanthin oxidation bears significant similarity to that of beta-carotene. PMID- 26617025 TI - Polydiacetylene/triblock copolymer nanoblend applied as a sensor for micellar casein: A thermodynamic approach. AB - Polydiacetylene (PDA) and triblock copolymer nanoblends were synthesized to detect micellar casein (MC), the main milk protein and an indicator of milk quality. UV-Vis spectrum showed that MC induced blue-to-red transition in nanoblends. When nanoblends and MC were separated by dialysis membrane colorimetric response (CR) was similar, whereas a remarkable CR reduction was noticed after addition of dialyzed-MC, suggesting that small molecules present in MC (salts) caused PDA color change. Interaction enthalpy variation between nanoblends and MC showed an abrupt increase that coincided with MC concentration when colorimetric transition occurred. Copolymer hydrophobic/hydrophilic balance and presence of other molecules in the system affected nanoblends CR. MC salts were found to interact with nanoblends leading to color changes. MC concentration, MC salt release, copolymer hydrophobic/hydrophilic balance, and presence of other molecules in the system affected responses of the sensors. These results contribute to future applications of PDA/copolymer nanosensors to dairy models. PMID- 26617026 TI - Spectral absorption index in hyperspectral image analysis for predicting moisture contents in pork longissimus dorsi muscles. AB - Spectral absorption index was proposed to extract the morphological features of the spectral curves in pork meat samples (longissimus dorsi) under the conditions including fresh, frozen-thawed, heated-dehydrated and brined-dehydrated. Savitzky Golay (SG) smoothing and multiplicative scatter correction (MSC) were used for calibrating both the spectral reflectance and absorbance values. The absorption values were better than the reflectance values and the calibrated spectra by MSC were better than the raw and SG smoothing corrected spectra in building moisture content predictive models. The optimized partial least square regression (PLSR) model attained good results with the MSC calibrated spectral absorption values based on the spectral absorption index features (R(2)P=0.952, RMSEP=1.396) and the optimal wavelengths selected by regression coefficients (R(2)P=0.966, RMSEP=0.855), respectively. The models proved spectral absorption index was promising in spectral analysis to predict moisture content in pork samples using HSI techniques for the first time. PMID- 26617027 TI - Combining the genetic algorithm and successive projection algorithm for the selection of feature wavelengths to evaluate exudative characteristics in frozen thawed fish muscle. AB - The potential use of feature wavelengths for predicting drip loss in grass carp fish, as affected by being frozen at -20 degrees C for 24 h and thawed at 4 degrees C for 1, 2, 4, and 6 days, was investigated. Hyperspectral images of frozen-thawed fish were obtained and their corresponding spectra were extracted. Least-squares support vector machine and multiple linear regression (MLR) models were established using five key wavelengths, selected by combining a genetic algorithm and successive projections algorithm, and this showed satisfactory performance in drip loss prediction. The MLR model with a determination coefficient of prediction (R(2)P) of 0.9258, and lower root mean square error estimated by a prediction (RMSEP) of 1.12%, was applied to transfer each pixel of the image and generate the distribution maps of exudation changes. The results confirmed that it is feasible to identify the feature wavelengths using variable selection methods and chemometric analysis for developing on-line multispectral imaging. PMID- 26617028 TI - Quercetin/beta-cyclodextrin inclusion complex embedded nanofibres: Slow release and high solubility. AB - Electrospinning of polyacrylic acid (PAA) nanofibres (NF) incorporating beta cyclodextrin inclusion complex (beta-CD-IC) of quercetin (QU) was performed. Here, beta-CD was used as not only the crosslinking agent for PAA nanofibres but also as a host molecule for inclusion of QU. The phase solubility test showed enhanced solubility of QU due to the inclusion complexation; in addition, the stoichiometry of QU/beta-CD-IC was determined to be 1:1. Computational modelling studies confirmed that 1:1 and 1:2 complex formation are desirable; 1:1 complex formation was chosen to have higher weight loading of QU. SEM images showed that PAA/QU/beta-CD-IC-NF were bead-free and uniform. XRD indicated that PAA/QU/beta CD-IC-NF were amorphous in nature without the crystalline peaks of QU. Comparative results revealed that the release profile of QU from PAA/QU/beta-CD IC-NF was much slower but greater in total than from PAA/QU/beta-CD-IC-film. Moreover, high antioxidant activity and photostability of QU was achieved in PAA/QU/beta-CD-IC-NF. PMID- 26617029 TI - On the use of differential solubility in aqueous ethanol solutions to narrow the DP range of food-grade starch hydrolysis products. AB - Considerable research is focused on understanding the functionality of starch hydrolysis products (SHP) consisting of glucose, maltose, maltooligosaccharides (MOS), and maltopolysaccharides (MPS). A confounding factor in this research is the high molecular dispersity of commercially available SHP. The study presented herein characterizes a flexible fractionation approach for lowering the dispersity of such products. This was accomplished by fractionating a corn syrup solids (CSS) preparation based on the differential solubility of its component saccharides in aqueous-ethanol solutions. Products obtained from selected fractionations were characterized with respect to degree of polymerization (DP; liquid chromatography), dextrose equivalency (reducing sugar assays), and prevalence of branching (NMR). Glucose and maltose were preferentially removed from CSS using high (?90%) ethanol extractants. Preparations with relatively narrow ranges of MOS, lower DP MPS, and higher DP MPS were obtained through repetitive 70%-ethanol extractions. Linear, as opposed to branched, MOS and MPS were preferentially extracted under all conditions tested. PMID- 26617030 TI - Effect of drying method on volatile compounds, phenolic profile and antioxidant capacity of guava powders. AB - We studied the chemical composition of oven and freeze dried guava powders for future use as antioxidant-rich flavour enhancers. Among thirty-one volatiles in guava powders, terpenes were predominant, even after both drying processes. In contrast, esters and aldehydes, volatiles characteristic of fresh guava fruit, appeared to have been decreased by drying. Insoluble phenolics were predominant and among the sixteen compounds identified, quercetin-3-O-rutinoside and naringenin corresponded to 56% of total phenolics. Drying processes decreased total phenolics contents by up to 44%. Oven drying promoted the release of insoluble flavonoids, generating mainly quercetin. Antioxidant capacity also decreased due to both drying processes, but guava powders still presented similar antioxidant capacity in comparison to other tropical fruit powders. Our results suggest that oven drying is a viable option for the production of a functional ingredient that would improve the phenolic content of cereal foods while adding desirable guava flavour. PMID- 26617031 TI - Effects of enzymatic dephosphorylation on infant in vitro gastrointestinal digestibility of milk protein concentrate. AB - This study investigated the effects of dephosphorylation extent on infant in vitro gastric clotting property and gastrointestinal digestibility of milk protein concentrate. Dephosphorylation was affected by phosphatase type and incubation pH. A series of milk protein concentrate with 0-69% dephosphorylation were obtained by incubation with calf intestinal alkaline phosphatase at pH 6.5 for 0-420 min. Both beta- and alphas1-caseins in the modified milk protein concentrate showed multiply dephosphorylated isoforms with different numbers of phosphate groups depending on the extent of dephosphorylation. With increased dephosphorylation of milk protein concentrate, the gastric clotting extent decreased and the gastrointestinal digestibility increased under infant in vitro conditions. These results suggested the potential of developing a dephosphorylated milk protein concentrate, with improved gastric clotting property and gastrointestinal digestibility, to simulate the multiply phosphorylated patterns of human casein and hence to further the humanization of infant formula on a molecular level. PMID- 26617032 TI - Molar absorptivity (epsilon) and spectral characteristics of cyanidin-based anthocyanins from red cabbage. AB - Red cabbage extract contains mono and di-acylated cyanidin (Cy) anthocyanins and is often used as food colorants. Our objectives were to determine the molar absorptivity (epsilon) of different red cabbage Cy-derivatives and to evaluate their spectral behaviors in acidified methanol (MeOH) and buffers pH 1-9. Major red cabbage anthocyanins were isolated using a semi-preparatory HPLC, dried and weighed. Pigments were dissolved in MeOH and diluted with either MeOH (0.1% HCl) or buffers to obtain final concentrations between 5*10(-5) and 1*10(-3) mol/L. Spectra were recorded and epsilon calculated using Lambert-Beer's law. The epsilon in acidified MeOH and buffer pH 1 ranged between ~16,000-30,000 and ~13,000-26,000 L/mol cm, respectively. Most pigments showed higher epsilon in pH 8 than pH 2, and lowest epsilon between pH 4 and 6. There were bathochromic shifts (81-105 nm) from pH 1 to 8 and hypsochromic shifts from pH 8 to 9 (2-19 nm). Anthocyanins molecular structures and the media were important variables which greatly influenced their epsilon and spectral behaviors. PMID- 26617033 TI - Multi-class methodology to determine pesticides and mycotoxins in green tea and royal jelly supplements by liquid chromatography coupled to Orbitrap high resolution mass spectrometry. AB - A multi-class methodology was developed to determine pesticides and mycotoxins in food supplements. The extraction was performed using acetonitrile acidified with formic acid (1%, v/v). Different clean-up sorbents were tested, and the best results were obtained using C18 and zirconium oxide for green tea and royal jelly, respectively. The compounds were determined using ultra high performance liquid chromatography (UHPLC) coupled to Exactive-Orbitrap high resolution mass spectrometry (HRMS). The recovery rates obtained were between 70% and 120% for most of the compounds studied with a relative standard deviation <25%, at three different concentration levels. The calculated limits of quantification (LOQ) were <10 MUg/kg. The method was applied to green tea (10) and royal jelly (8) samples. Nine (eight of green tea and one of royal jelly) samples were found to be positive for pesticides at concentrations ranging from 10.6 (cinosulfuron) to 47.9 MUg/kg (paclobutrazol). The aflatoxin B1 (5.4 MUg/kg) was also found in one of the green tea samples. PMID- 26617034 TI - A simple liposome assay for the screening of zinc ionophore activity of polyphenols. AB - An efficient liposomal system for screening the zinc ionophore activity of a selected library consisting of the most relevant dietary polyphenols is presented. The zinc ionophore activity was demonstrated by exploring the use of zinc-specific fluorophore FluoZin-3 loaded liposomes as simple membrane tools that mimic the cell membrane. The zinc ionophore activity was demonstrated as the capacity of polyphenols to transport zinc cations across the liposome membrane and increase the zinc-specific fluorescence of the encapsulated fluorophore FluoZin-3. In addition, the zinc chelation strength of the polyphenols was also tested in a competition assay based on the fluorescence quenching of zinc dependent fluorescence emitted by zinc-FluoZin-3 complex. Finally, the correlation between the chelation capacity and ionophore activity is demonstrated, thus underlining the sequestering or ionophoric activity that the phenolic compounds can display, thus, providing better knowledge of the importance of the structural conformation versus their biological activity. Furthermore, the assays developed can be used as tools for rapid, high-throughput screening of families of polyphenols towards different biometals. PMID- 26617035 TI - Effect of sugarcane molasses extract on the formation of 2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine (PhIP) in a model system. AB - Molasses, the main by-product of sugar production, is a well-known source of antioxidants. In this study, sugarcane molasses extract was investigated for its total phenolic content and in vitro antioxidant capacity. The experimental total phenolic content was 101.3 mg of gallic acid equivalent (GAE) in 1 g of extract, IC50 of Trolox and sugarcane molasses extract were 125.33 MUg/ml and 126.0 MUg/ml, respectively. A chemical model system showed that the sugarcane molasses extract effectively reduced the formation of phenylacetaldehyde and the aldol condensation product, meanwhile, the amount of 2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine (PhIP) also decreased. This could be due to the reaction between the phenolic compounds of sugarcane molasses extract and the carbonyl group of phenylacetaldehyde inhibiting the aldol condensation product formation, and this would suppress the formation of PhIP. A pathway that phenolic compounds inhibited the formation of PhIP is proposed. This pathway also suggested a mechanism for how the sugarcane affects the formation of PHIP. PMID- 26617036 TI - Detection of meat-borne trimethylamine based on nanoporous colorimetric sensor arrays. AB - Trimethylamine (TMA) is a key measurement indicator for meat spoilage. In order to develop simple, cheap, and sensitive sensors for TMA detection, a nanoporous colorimetric sensor array (NCSA) was developed. A sol-gel method has been used to obtain TiO2 nanoporous film as substrate material to improve the sensitivity and stability of the CSA. The sensor enabled the visual detection of TMA gas from the permissible exposure limits (PEL) 10 ppm to 60 ppb concentrations with significant response. Principal component analysis (PCA) was used to characterize the functional relationship between the color difference data and TMA concentrations. Furthermore, the NCSA was used to predict the presence of TMA in Yao-meat. A partial least square (PLS) prediction model was obtained with the correlation coefficients of 0.896 and 0.837 in calibration and prediction sets, respectively. This research suggested that the NCSA offers a useful technology for quality evaluation of TMA in meat. PMID- 26617037 TI - The bio refinery; producing feed and fuel from grain. AB - It is both possible and practicable to produce feed and fuel from grain. Using the value of grain to produce renewable energy for transport, while using the remaining protein content of the grain as a valuable protein source for livestock and for fish, can be seen as a complimentary and optimal use of all the grain constituents. Consideration must be given to maximise the value of the yeast components, as substantial yeast is generated during the fermentation of the grain starch to produce ethanol. Yeast is a nutritionally rich feed ingredient, with potential for use both as feed protein and as a feed supplement with possible immunity and gut health enhancing properties. Bioprocessing, with the consequent economies of scale, is a process whereby the value of grain can be optimised in a way that is traditional, natural and sustainable for primarily producing protein and oil for feed with a co-product ethanol as a renewable fuel. PMID- 26617039 TI - Fermentation and dry fractionation increase bioactivity of cloudberry (Rubus chamaemorus). AB - Phenolic composition and bioactivity of cloudberry was modified by bioprocessing, and highly bioactive fractions were produced by dry fractionation of the press cake. During fermentation polymeric ellagitannins were partly degraded into ellagic acid derivatives. Phenolic compounds were differentially distributed in seed coarse and fine fractions after dry fractionation process. Tannins concentrated in fine fraction, and flavonol derivatives were mainly found in coarse fraction. Ellagic acid derivatives were equally distributed between the dry fractions. Fermentation and dry fractionation increased statistically significantly anti-adhesion and anti-inflammatory activity of cloudberry. The seed fine fraction showed significant inhibition of P fimbria-mediated haemagglutination assay of uropathogenic Escherichia coli. The seed coarse fraction significantly reduced NO and IL-6 production and iNOS expression in activated macrophages. Fermentation did not affect antimicrobial activity, but slight increase in activity was detected in dry fractions. The results indicate the potential of cloudberry in pharma or health food applications. PMID- 26617038 TI - Rapid preparation of expanded graphite by microwave irradiation for the extraction of triazine herbicides in milk samples. AB - In this study, we proposed a rapid and efficient method for the preparation of the expanded graphite (EG). The exfoliation process was accelerated by microwave irradiation, and the preparation time was greatly shortened. The obtained EG was worm-like in shape and exhibits well exfoliated structure. It was successfully applied as solid-phase extraction (SPE) adsorbent to extract and clean up the triazine herbicides in milk, followed by liquid chromatography tandem mass spectrometry (LC-MS) analysis. The parameters affecting the performance of extraction and LC-MS analysis were evaluated. Under the optimal conditions, the detection limits of triazines are in the range of 0.03-0.12 ng mL(-1). At the spiked level (0.4 ng mL(-1)), the recoveries of triazines are in the range of 82.5+/-2.5% to 97.5+/-7.5%. The proposed method was successfully applied to determine six triazines in six milk samples. PMID- 26617040 TI - Stability indicating simplified HPLC method for simultaneous analysis of resveratrol and quercetin in nanoparticles and human plasma. AB - Resveratrol and quercetin are well-known polyphenolic compounds present in common foods, which have demonstrated enormous potential in the treatment of a wide variety of diseases. Owing to their exciting synergistic potential and combination delivery applications, we developed a simple and rapid RP-HPLC method based on isosbestic point detection. The separation was carried out on phenomenex Synergi 4MU Hydro-RP 80A column using methanol: acetonitrile (ACN): 0.1% phosphoric acid (60:10:30) as mobile phase. The method was able to quantify nanograms of analytes simultaneously on a single wavelength (269 nm), making it highly sensitive, rapid as well as economical. Additionally, forced degradation studies of resveratrol and quercetin were established and the method's applicability was evaluated on PLGA nanoparticles and human plasma. The analytes peaks were found to be well resolved in the presence of degradation products and excipients. The simplicity of the developed method potentializes its suitability for routine in vitro and in vivo analysis of resveratrol and quercetin. PMID- 26617041 TI - Biosynthesis of 2-acetyl-1-pyrroline in rice calli cultures: Demonstration of 1 pyrroline as a limiting substrate. AB - The role of 1-pyrroline was studied via feeding experiments using rice calli cultures to gain further insight into the key steps of 2-acetyl-1-pyrroline (2AP) biosynthesis in rice. The origin of the acetyl donor was also studied through stable isotope labelled substrates. Incubation of fresh calli from a fragrant rice variety (Aychade) and a non-fragrant variety (Gladio*Fidji K2) with 1 pyrroline led to a significant increase in 2AP in both varieties. Importantly, the amount of 2AP in the non-fragrant variety could be greatly enhanced by this supplementation. When rice calli were fed with increasing levels of 1-pyrroline, 2AP levels increased accordingly. Our data show that 1-pyrroline is a limiting factor for 2AP synthesis in rice. Heat treatment of calli suggested that 1 pyrroline might be enzymatically acetylated. The presence of labelled 2AP in calli supplemented with [U-(13)C]glucose, sodium acetate (1,2-(13)C2) and sodium octanoate (1,2,3,4-(13)C4) suggested that these compounds are possible candidates for acetyl group-donors of 2AP, predominately in the form of intact labelled (13)C2-units. PMID- 26617042 TI - Thin-film amperometric multibiosensor for simultaneous determination of lactate and glucose in wine. AB - An amperometric multi-biosensor based on lactate and glucose oxidases has been developed for determination of lactate and glucose in wine. Gold thin-film amperometric electrodes were used as multi-transducers. Analytical characteristics of the multi-biosensor developed were studied. The minimum detectable concentration was 5*10(-6) mol/l for both glucose and lactate. High reproducibility and storage stability of the multi-biosensor are demonstrated in this paper. Lactate and glucose were determined in wine, and a good correlation was obtained with concentrations determined using high-performance liquid chromatography (correlation coefficient for glucose R(2)=0.998, for lactate R(2)=0.718). PMID- 26617043 TI - Effect of chitosan-lemon essential oil coatings on volatile profile of strawberries during storage. AB - Chitosan coatings containing lemon essential oils were described as effective at controlling fruit fungal decay at 20 degrees C during 7 days. In this work, GC-MS was used to characterise the volatile compounds of strawberries during cold storage in order to analyse the influence of fruit coatings with chitosan, containing or not containing lemon essential oil, on the volatile profile of the fruits. The coatings affected the metabolic pathways and volatile profile of the fruits. Pure chitosan promoted the formation of esters and dimethyl furfural in very short time after coating, while coatings containing lemon essential oil incorporated terpenes (limonene, gamma-terpinene, p-cymene and alpha-citral) to the fruit volatiles and enhanced the fermentative process, modifying the typical fruit aroma composition. No effect of chitosan coatings was sensorially perceived, the changes induced by lemon essential oil were notably appreciated. PMID- 26617044 TI - Evaluation of the antioxidant capacity of natural polyphenolic compounds using a macrocyclic Ni-(II) complex-catalysed Briggs-Rauscher reaction. AB - This paper reports a method for evaluating antioxidant capacity based on the inhibitory effects of a macrocyclic Ni(II) complex-catalysed Briggs-Rauscher reaction. The macrocyclic Ni(II) complex NiL(ClO4)2, in which L is 5,7,7,12,14,14 hexamethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene, is a porphyrin-like compound, the structure of which can be found in certain enzymes. The experiments indicated that three natural compounds could temporarily quench the oscillations for a period of time prior to regeneration of oscillations. The inhibition time was related to the compound type and concentration; thus, procedures for evaluating the antioxidant activities of polyphenolic compounds were successfully established. Three polyphenolic compounds were tested to evaluate their antioxidant activities: protocatechuic acid, rutin hydrate and procyanidin. Of these three naturally occurring compounds, procyanidin was found to be the most efficient antioxidant. We have also discussed the reaction of the antioxidant with the hydroperoxyl radical (HOO) present in the oscillating system. PMID- 26617046 TI - Microemulsion-based lycopene extraction: Effect of surfactants, co-surfactants and pretreatments. AB - Lycopene is a potent antioxidant that has received extensive attention recently. Due to the challenges encountered with current methods of lycopene extraction using hazardous solvents, industry calls for a greener, safer and more efficient process. The main purpose of present study was application of microemulsion technique to extract lycopene from tomato pomace. In this respect, the effect of eight different surfactants, four different co-surfactants, and ultrasound and enzyme pretreatments on lycopene extraction efficiency was examined. Experimental results revealed that application of combined ultrasound and enzyme pretreatments, saponin as a natural surfactant, and glycerol as a co-surfactant, in the bicontinuous region of microemulsion was the optimal experimental conditions resulting in a microemulsion containing 409.68+/-0.68 MUg/glycopene. The high lycopene concentration achieved, indicates that microemulsion technique, using a low-cost natural surfactant could be promising for a simple and safe separation of lycopene from tomato pomace and possibly from tomato industrial wastes. PMID- 26617045 TI - Carotenoid profile and retention in yellow-, purple- and red-fleshed potatoes after thermal processing. AB - This research aimed to investigate the effect of thermal processing on carotenoid profile, quantity and stability in 22 colour-fleshed potato cultivars grown in the Czech Republic. The total of nine carotenoids was analysed by HPLC using a C30 column and PDA detection. The total carotenoid content for all cultivars ranged from 1.44 to 40.13 MUg/g DM. Yellow cultivars showed a much higher average total carotenoid content (26.22 MUg/g DM) when compared to red/purple-fleshed potatoes (5.69 MUg/g DM). Yellow cultivars were dominated by antheraxanthin, whereas neoxanthin was the main carotenoid in red/purple cultivars. Thermal processing significantly impacted all potato cultivars. Boiling decreased the total carotenoids by 92% compared to baking (88%). Lutein was the most stable carotenoid against thermal processing (decreased by 24-43%) followed by beta carotene (decreased by 78-83%); other carotenoids were degraded nearly completely. Increased formation of (Z)-isomers by thermal processing has not been confirmed. PMID- 26617047 TI - Selective separation and concentration of antihypertensive peptides from rapeseed protein hydrolysate by electrodialysis with ultrafiltration membranes. AB - Rapeseed protein isolate was subjected to alcalase digestion to obtain a protein hydrolysate that was separated into peptide fractions using electrodialysis with ultrafiltration membrane (EDUF) technology. The EDUF process (6h duration) led to isolation of three peptide fractions: anionic (recovered in KCl-1 compartment), cationic (recovered in KCl-2 compartment), and those that remained in the feed compartment, which was labeled final rapeseed protein hydrolysate (FRPH). As expected the KCl-1 peptides were enriched in negatively-charged (43.57%) while KCl-2 contained high contents of positively-charged (28.35%) amino acids. All the samples inhibited angiotensin converting enzyme (ACE) and renin activities in dose-dependent manner with original rapeseed protein hydrolysate having the least ACE-inhibitory IC50 value of 0.0932+/-0.0037 mg/mL while FRPH and KCl-2 had least renin-inhibitory IC50 values of 0.47+/-0.05 and 0.55+/-0.06 mg/mL, respectively. Six hours after oral administration (100 mg/kg body weight) to spontaneously hypertensive rats, the FRPH produced the maximum systolic blood pressure reduction of -51 mmHg. PMID- 26617048 TI - beta-Lactoglobulin as nanotransporter--Part I: Binding of organosulfur compounds. AB - The binding reaction of allicin and diallyl disulfide with beta-lactoglobulin and the influence of pH value and protein denaturation on this reaction have been examined in the present study. Regardless of the structural similarity of both the organosulfur compounds, their binding behavior was significantly different. Both ligands were covalently bound by the free thiol group of the protein, whereas the affinity for allicin was significantly higher. In addition, diallyl disulfide was non-covalently bound. The binding reaction of both ligands was very sensitive to the pH value during incubation. The optimal pH range was between pH 8.0 and 9.0. Protein denaturation increased the reaction rate and reduced the number of binding sites for allicin, whereas the number of non-covalent binding sites increased for diallyl disulfide. Based on these findings, it can be proposed that the covalent modification of beta-lactoglobulin functions as a specific transporter stabilizing allicin or diallyl disulfide. PMID- 26617049 TI - beta-Lactoglobulin as nanotransporter--Part II: Characterization of the covalent protein modification by allicin and diallyl disulfide. AB - The whey protein beta-lactoglobulin has been proposed as a transporter for covalent bound bioactive compounds in order to enhance their stability and reduce their sensory perception. The garlic derived compounds allicin and diallyl disulfide were bound covalently to the native and heat denatured protein. The binding site and the influence of the modification on the digestibility were determined by mass spectrometric analysis of the modified beta-lactoglobulin. Further, the conformation of the modified protein was assessed by circular dichroism and dynamic light scattering. The free thiol group of Cys(121) turned out to be the major binding site. After proteolysis with trypsin at pH 7 but not with pepsin at pH 2, a limited transfer to other cysteinyl residues was observed. The covalently bound ligands did not mask any proteolytic cleavage sites of pepsin, trypsin or chymotrypsin. The modified beta-lactoglobulin showed a native like conformation, besides a moderate loosening of protein folding. The covalent binding of organosulfur compounds to beta-lactoglobulin provides a bioactive ingredient without impairing the digestibility and functional properties of the protein. PMID- 26617051 TI - Sjogren SER: National registry of the Spanish Society of Rheumatology of patients with primary Sjogren syndrome: Objectives and methodology. AB - OBJECTIVE: To describe the objectives and methods of the Spanish Society of Rheumatology primary Sjogren syndrome (pSS) registry (SJOGREN-SER) METHODS: This is a multicenter descriptive transversal study of a cohort of pSS patients fulfilling European/American consensus criteria collected from Rheumatology clinics all over Spain. Patients were included by randomisation from an anonymised list provided by every department. Data were collected by reviewing clinical records and an interviewing the patients. Two hundred and ninety eight variables were investigated: epidemiological, clinical, serological characteristics, treatments and complications. Informed consent was obtained and local ethics committees approved the study. Variables were analysed by descriptive statistical methods, using means, medians, and rates, with their deviations and interquartile ranges (p25-p75). RESULTS: A total of 3 rheumatology departments participated in the registry. A total of 437 patients were included. And 95% of them were women, with a median age of 58. Median age at pSS 's diagnosis was 50 years. Dryness symptoms (95%) were the most frequent complaint and anti-Ro/SS-A were present in 94% of the cases. Only 27% of the patients fulfilled the new 2012 SICCA-ACR classification criteria. CONCLUSIONS: SJOGREN SER has been designed in order to characterize a representative pSS Spanish cohort, in clinical daily practice, to analyze the magnitude and distribution of its manifestations, activity, accumulated damage and therapeutic management of the disease. This will allow broadening the knowledge of this disease and plan strategies of action in pSS. PMID- 26617050 TI - A tunable artificial circadian clock in clock-defective mice. AB - Self-sustaining oscillations are essential for diverse physiological functions such as the cell cycle, insulin secretion and circadian rhythms. Synthetic oscillators using biochemical feedback circuits have been generated in cell culture. These synthetic systems provide important insight into design principles for biological oscillators, but have limited similarity to physiological pathways. Here we report the generation of an artificial, mammalian circadian clock in vivo, capable of generating robust, tunable circadian rhythms. In mice deficient in Per1 and Per2 genes (thus lacking circadian rhythms), we artificially generate PER2 rhythms and restore circadian sleep/wake cycles with an inducible Per2 transgene. Our artificial clock is tunable as the period and phase of the rhythms can be modulated predictably. This feature, and other design principles of our work, might enhance the study and treatment of circadian dysfunction and broader aspects of physiology involving biological oscillators. PMID- 26617052 TI - SAPHO syndrome in the differential diagnosis of metastasis. AB - SAPHO syndrome was proposed in the late 80s in order to group different osteoarticular manifestations with specific radiological findings such as the hyperostosis of the front part of the chest wall. Prevalence, etiology and pathogenesis of the disease are unknown, while diagnosis is made both clinically and by the specific gammagraphic image of "bull horn" in the sternoclavicular joint. The following case of a 64-year-old woman diagnosed with infiltrating ductal carcinoma of the right breast pT1N0Mx is reported. When studying the extent of the disease, a gammagraphic image of diffuse blast injury in the sterna manubrium was evidenced, which allowed the suspicion of Paget's disease or metastatic injury. Study was completed with a chest CT in which manubrium sclerosis was evidenced, suggesting metastasis. Res ults of the studies pointed out SAPHO syndrome as the most likely diagnostic option. The low tumor stage of the patient prompted the idea of possible alternative diagnoses. A deeper knowledge of this clinical condition may be crucial to avoid mistakes when classifying a subject in more advanced tumor stages, and consequently, to prevent the use of more aggressive chemotherapy and radiotherapy treatments. PMID- 26617053 TI - Corporate giants provide fertility benefits: have they got it wrong? PMID- 26617054 TI - Sample storage-induced changes in the quantity and quality of soil labile organic carbon. AB - Effects of sample storage methods on the quantity and quality of labile soil organic carbon are not fully understood even though their effects on basic soil properties have been extensively studied. We studied the effects of air-drying and frozen storage on cold and hot water soluble organic carbon (WSOC). Cold- and hot-WSOC in air-dried and frozen-stored soils were linearly correlated with those in fresh soils, indicating that storage proportionally altered the extractability of soil organic carbon. Air-drying but not frozen storage increased the concentrations of cold-WSOC and carbohydrate in cold-WSOC, while both increased polyphenol concentrations. In contrast, only polyphenol concentration in hot-WSOC was increased by air-drying and frozen storage, suggesting that hot-WSOC was less affected by sample storage. The biodegradability of cold- but not hot-WSOC was increased by air-drying, while both air-drying and frozen storage increased humification index and changed specific UV absorbance of both cold- and hot-WSOC, indicating shifts in the quality of soil WSOC. Our results suggest that storage methods affect the quantity and quality of WSOC but not comparisons between samples, frozen storage is better than air-drying if samples have to be stored, and storage should be avoided whenever possible when studying the quantity and quality of both cold- and hot-WSOC. PMID- 26617055 TI - Letter to the Editor. PMID- 26617056 TI - Sexual dimorphism in the facial morphology of adult humans: A three-dimensional analysis. AB - The objective of this study was to demonstrate sexual dimorphism in the entire three-dimensional facial surface form of adult humans. The sample consisted of female and male groups (n=200; age range, 18-35 years). Three-dimensional images of each participant's face at rest were recorded. A total of 185 variables that described facial surface configuration features were extracted from each image. The variables were compared between the groups using t-tests, and those exhibiting P-values <0.0001 were entered into a stepwise discriminant function analysis for sex determination. Wire mesh fitting was also performed on each image to examine the facial surface morphology. The mean node coordinates of the fitted mesh were compared between the groups using t-tests. Sixty-seven of the 185 variables differed significantly between the groups, and 11 qualified for inclusion in the stepwise analysis. The female group exhibited a greater vertical height of the eye fissure, shorter postero-anterior height of the nasal tip, vertically greater supraorbital ridge, shorter lower face height relative to the total upper anterior face height, more prominent cheeks in the infraorbital region, less prominent cheeks in the buccal region, shorter vertical height of the subnasal region, a smaller nasal hump, and a smaller alar. The discriminant function analysis was 96.5% accurate overall. The wire mesh fitting results showed that the eyes, forehead, and chin were in vertically higher positions in the female group than in the male group. The cheeks and nose were more protuberant in the female group and male group, respectively. PMID- 26617057 TI - Calcified Mesenteric Lymphangioma Mimicking a Teratoma in a 4-Year-Old Child. PMID- 26617058 TI - A novel approach to the consecutive extraction of drugs with different properties via on chip electromembrane extraction. AB - In the present research, for the first time, a consecutive on chip electromembrane extraction coupled with high performance liquid chromatography was introduced for the analysis of betaxolol (Bet), naltrexone (Nalt) and nalmefene (Nalm) as model analytes with different chemical properties from biological samples. The chip consists of two polymethyl methacrylate (PMMA) parts where two microfluidic channels are carved in each part. These channels were used as a flow path for the sample solution and a thin compartment for the acceptor phase. A porous polypropylene sheet membrane impregnated with an organic solvent was placed between two parts of the chip device in order to separate the channels. Two platinum electrodes were bent at the bottom of these channels that are connected to a power supply providing the electrical driving force for migration of ionized analytes from the sample solution through the porous sheet membrane into the acceptor phase. The new setup provides effective and reproducible extractions by using a low volume of sample solution. Efficient parameters on consecutive electromembrane extraction of the model analytes were optimized by using the one variable at a time method. Under the optimized conditions, the new setup offered a good linearity in the range of 10.0-500 MUg L(-1) with coefficient of determination (R(2)) higher than 0.9932. The relative standard deviation (RSD%) and LOD values were less than 6.8% based on four replicate measurements and 10.0 MUg L(-1) for the model analytes, respectively. The preconcentration factors higher than 15.6-fold were obtained. Finally, the proposed method was successfully applied for determination and quantification of the model analytes in biological samples. PMID- 26617059 TI - Ultrafast Electronic Energy Transfer Beyond the Weak Coupling Limit in a Proximal but Orthogonal Molecular Dyad. AB - Electronic energy transfer (EET) from a donor to an acceptor is an important mechanism that controls the light harvesting efficiency in a wide variety of systems, including artificial and natural photosynthesis and contemporary photovoltaic technologies. The detailed mechanism of EET at short distances or large angles between the donor and acceptor is poorly understood. Here the influence of the orientation between the donor and acceptor on EET is explored using a molecule with two nearly perpendicular chromophores. Very fast EET with a time constant of 120 fs is observed, which is at least 40 times faster than the time predicted by Coulombic coupling calculations. Depolarization of the emission signal indicates that the transition dipole rotates through ca. 64 degrees , indicating the near orthogonal nature of the EET event. The rate of EET is found to be similar to structural relaxation rates in the photoexcited oligothiophene donor alone, which suggests that this initial relaxation brings the dyad to a conical intersection where the excitation jumps to the acceptor. PMID- 26617061 TI - Hemoglobin Hirose: A rare beta chain variant causing falsely low HbA1c by HPLC. AB - OBJECTIVES: To investigate the underlying cause of unexpectedly low HbA1c results (3.3-3.5%) obtained by HPLC in three siblings undergoing routine screening for type 2 diabetes mellitus. DESIGN AND METHODS: HbA1c was measured using an alternate method based on a different analytical principle (the Siemens DCA 2000+ immunoassay). Hemoglobin fractionation was performed by HPLC on the BioRad Variant II, gel electrophoresis at acid and alkaline pH on the Sebia Hydrasys 2, and capillary electrophoresis on the Sebia Capillarys 2. Sequencing of the beta globin gene was also conducted. RESULTS: HbA1c analysis by immunoassay gave significantly higher results, ranging from 5.2-5.5%. Hemoglobin fractionation by HPLC showed an abnormal peak comprising approximately 43% of total hemoglobin, suggesting the presence of a beta chain hemoglobin variant. Gel electrophoresis at alkaline pH revealed a very unusual pattern, with 3 abnormal bands migrating with Hb F, between Hb F and Hb S, and slightly cathodal to Hb S. A single band in the Hb A position was seen on gel electrophoresis at acid pH. Capillary electrophoresis revealed two abnormal peaks, comprising 42% and 5% of total hemoglobin. Sequencing of the beta globin gene showed heterozygosity for Hb Hirose (beta 37(C3) Trp>Ser), an extremely rare variant with a substitution at the alpha1beta2 interface. CONCLUSIONS: We describe the chromatographic and electrophoretic properties of Hb Hirose, and demonstrate that this rare variant causes falsely low HbA1c results on the BioRad variant II Turbo 2.0. Recognition of this interference is crucial in order to prevent reporting erroneous results. PMID- 26617060 TI - Fragmented mitochondrial genomes in two suborders of parasitic lice of eutherian mammals (Anoplura and Rhynchophthirina, Insecta). AB - Parasitic lice (order Phthiraptera) infest birds and mammals. The typical animal mitochondrial (mt) genome organization, which consists of a single chromosome with 37 genes, was found in chewing lice in the suborders Amblycera and Ischnocera. The sucking lice (suborder Anoplura) known, however, have fragmented mt genomes with 9-20 minichromosomes. We sequenced the mt genome of the elephant louse, Haematomyzus elephantis - the first species of chewing lice investigated from the suborder Rhynchophthirina. We identified 33 mt genes in the elephant louse, which were on 10 minichromosomes. Each minichromosome is 3.5-4.2 kb in size and has 2-6 genes. Phylogenetic analyses of mt genome sequences confirm that the elephant louse is more closely related to sucking lice than to the chewing lice in the Amblycera and Ischnocera. Our results indicate that mt genome fragmentation is shared by the suborders Anoplura and Rhynchophthirina. Nine of the 10 mt minichromosomes of the elephant louse differ from those of the sucking lice (Anoplura) known in gene content and gene arrangement, indicating that distinct mt karyotypes have evolved in Anoplura and Rhynchophthirina since they diverged ~92 million years ago. PMID- 26617062 TI - Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO defined essential thrombocythemia. PMID- 26617063 TI - An abnormal secretion of soluble mediators contributes to the hematopoietic-niche dysfunction in low-risk myelodysplastic syndrome. PMID- 26617064 TI - Exploring the charging mechanisms in non-aqueous multiphase surfactant solutions, emulsions and colloidal systems via conductivity behaviors predicted with eyring's rate process theory. AB - The common charging agents and charging mechanisms in non-aqueous multiphase systems available in the literature are analyzed, and the conductivity equations derived on the basis of the charging mechanisms with the Eyring's rate process theory are compared with experimental observations. The popular charging mechanisms in non-aqueous systems, such as the ion preferential absorption, ion pair dissociation, and micelle disproportionation/fluctuation models, are found to be incapable of explaining all experimental evidences. Particularly, the ion pair dissociation and micelle disproportionation/fluctuation models apparently suffer a major drawback: how charges are separated and most importantly how charging entities are stabilized in non-aqueous systems, are not adequately addressed; in low dielectric constant non-aqueous media separated ions tend to bind together rather than stay separately. A new charging mechanism incorporating an electric field internally available or externally applied into the charging process is proposed to explain charge separations and stabilizations. The conductivity equations derived on the basis of this new mechanism predict that conductivity should linearly increase with both the electric field and the concentrations of inverse micelles in very low concentration regions, which is consistent with experimental evidences. PMID- 26617065 TI - Metabolic engineering of Pseudomonas putida for production of docosahexaenoic acid based on a myxobacterial PUFA synthase. AB - Long-chain polyunsaturated fatty acids (LC-PUFAs) can be produced de novo via polyketide synthase-like enzymes known as PUFA synthases, which are encoded by pfa biosynthetic gene clusters originally discovered from marine microorganisms. Recently similar gene clusters were detected and characterized in terrestrial myxobacteria revealing several striking differences. As the identified myxobacterial producers are difficult to handle genetically and grow very slowly we aimed to establish heterologous expression platforms for myxobacterial PUFA synthases. Here we report the heterologous expression of the pfa gene cluster from Aetherobacter fasciculatus (SBSr002) in the phylogenetically distant model host bacteria Escherichia coli and Pseudomonas putida. The latter host turned out to be the more promising PUFA producer revealing higher production rates of n-6 docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA). After several rounds of genetic engineering of expression plasmids combined with metabolic engineering of P. putida, DHA production yields were eventually increased more than threefold. Additionally, we applied synthetic biology approaches to redesign and construct artificial versions of the A. fasciculatus pfa gene cluster, which to the best of our knowledge represents the first example of a polyketide-like biosynthetic gene cluster modulated and synthesized for P. putida. Combination with the engineering efforts described above led to a further increase in LC-PUFA production yields. The established production platform based on synthetic DNA now sets the stage for flexible engineering of the complex PUFA synthase. PMID- 26617066 TI - Synthesis of Supported Ultrafine Non-noble Subnanometer-Scale Metal Particles Derived from Metal-Organic Frameworks as Highly Efficient Heterogeneous Catalysts. AB - The properties of supported non-noble metal particles with a size of less than 1 nm are unknown because their synthesis is a challenge. A strategy has now been created to immobilize ultrafine non-noble metal particles on supports using metal organic frameworks (MOFs) as metal precursors. Ni/SiO2 and Co/SiO2 catalysts were synthesized with an average metal particle size of 0.9 nm. The metal nanoparticles were immobilized uniformly on the support with a metal loading of about 20 wt%. Interestingly, the ultrafine non-noble metal particles exhibited very high activity for liquid-phase hydrogenation of benzene to cyclohexane even at 80 degrees C, while Ni/SiO2 with larger Ni particles fabricated by a conventional method was not active under the same conditions. PMID- 26617067 TI - Field-evolved resistance to insecticides in the invasive western flower thrips Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae) in China. AB - BACKGROUND: To understand the current status of insecticide resistance of the invasive western flower thrips, Frankliniella occidentalis, in China, the responses of six field populations to six commonly used insecticides, i.e. spinosad, spinetoram, cyantraniliprole, imidacloprid, acetamiprid and pyriproxyfen, were evaluated in comparison with a susceptible laboratory strain. RESULTS: Field populations tended to be less susceptible than the laboratory strain. The population from Shouguang, Shandong Province, showed the lowest levels of susceptibility. A 15.64-fold and 17.29-fold resistance to spinosad and spinetoram was detected in the Shouguang population. A 11.74-fold and 13.64-fold resistance to cyantraniliprole was detected in populations from Daxing in the Beijing area and Shouguang. All populations showed a low level of resistance to imidacloprid, acetamiprid and pyriproxyfen, except for the Shouguang population, which was 127.58-fold more resistant to pyriproxyfen. CONCLUSION: Variations in resistance to the tested insecticides were observed among the sampled population. Spinosad and spinetoram were the most efficient insecticides and are recommended for use in an integrated management programme. Resistance management strategies should be implemented to reduce the potential for resistance evolving. (c) 2015 Society of Chemical Industry. PMID- 26617068 TI - From Dark to Light to Fluorescence Resonance Energy Transfer (FRET): Polarity Sensitive Aggregation-Induced Emission (AIE)-Active Tetraphenylethene-Fused BODIPY Dyes with a Very Large Pseudo-Stokes Shift. AB - The work presented herein is devoted to the fabrication of large Stokes shift dyes in both organic and aqueous media by combining dark resonance energy transfer (DRET) and fluorescence resonance energy transfer (FRET) in one donor acceptor system. In this respect, a series of donor-acceptor architectures of 4,4 difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dyes substituted by one, two, or three tetraphenylethene (TPE) luminogens were designed and synthesised. The photophysical properties of these three chromophore systems were studied to provide insight into the nature of donor-acceptor interactions in both THF and aqueous media. Because the generation of emissive TPE donor(s) is strongly polarity dependent, due to its aggregation-induced emission (AIE) feature, one might expect the formation of appreciable fluorescence emission intensity with a very large pseudo-Stokes shift in aqueous media when considering FRET process. Interestingly, similar results were also recorded in THF for the chromophore systems, although the TPE fragment(s) of the dyes are non-emissive. The explanation for this photophysical behaviour lies in the DRET. This is the first report on combining two energy-transfer processes, namely, FRET and DRET, in one polarity-sensitive donor-acceptor pair system. The accuracy of the dark-emissive donor property of the TPE luminogen is also presented for the first time as a new feature for AIE phenomena. PMID- 26617069 TI - Letter to the Editor. PMID- 26617070 TI - Tryptophan availability for kynurenine pathway metabolism across the life span: Control mechanisms and focus on aging, exercise, diet and nutritional supplements. AB - Tryptophan (Trp) availability for the kynurenine pathway (KP) across the life span is discussed. Free (non-albumin-bound) plasma Trp is the major determinant of the flux of Trp down the KP. Flux is the major determinant of kynurenine metabolite formation and is more effective than induction of hepatic Trp 2,3 dioxygenase (TDO) or extrahepatic indoleamine 2,3-dioxygenase (IDO). Flux is better expressed using the sum of plasma kynurenine and its metabolites, rather than kynurenine only. Under normal conditions, TDO controls Trp flux in liver and availability in plasma and can supply kynurenine for the extrahepatic pathway. Under certain pathological conditions associated with immune activation, IDO assumes the major role in control of Trp availability. Plasma Trp availability is increased during pregnancy, at birth, and by exercise, high protein and fat intake. Aging does not seem to exert a major effect on plasma Trp. Assessment of plasma Trp availability in health and disease requires measurement of concentrations of both free and total [Trp] in the first instance, followed, if necessary, by those of albumin and the physiological displacers of albumin-bound Trp, non-esterified fatty acids. Additional measures should include cortisol, cytokines, kynurenine and its metabolites. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'. PMID- 26617072 TI - Functional metagenomic selection of ribulose 1, 5-bisphosphate carboxylase/oxygenase from uncultivated bacteria. AB - Ribulose 1,5-bisphosphate carboxylase/oxygenase (RubisCO) is a critical yet severely inefficient enzyme that catalyses the fixation of virtually all of the carbon found on Earth. Here, we report a functional metagenomic selection that recovers physiologically active RubisCO molecules directly from uncultivated and largely unknown members of natural microbial communities. Selection is based on CO2 -dependent growth in a host strain capable of expressing environmental deoxyribonucleic acid (DNA), precluding the need for pure cultures or screening of recombinant clones for enzymatic activity. Seventeen functional RubisCO encoded sequences were selected using DNA extracted from soil and river autotrophic enrichments, a photosynthetic biofilm and a subsurface groundwater aquifer. Notably, three related form II RubisCOs were recovered which share high sequence similarity with metagenomic scaffolds from uncultivated members of the Gallionellaceae family. One of the Gallionellaceae RubisCOs was purified and shown to possess CO2 /O2 specificity typical of form II enzymes. X-ray crystallography determined that this enzyme is a hexamer, only the second form II multimer ever solved and the first RubisCO structure obtained from an uncultivated bacterium. Functional metagenomic selection leverages natural biological diversity and billions of years of evolution inherent in environmental communities, providing a new window into the discovery of CO2 -fixing enzymes not previously characterized. PMID- 26617071 TI - State-dependent alterations in sleep/wake architecture elicited by the M4 PAM VU0467154 - Relation to antipsychotic-like drug effects. AB - Accumulating evidence indicates direct relationships between sleep abnormalities and the severity and prevalence of other symptom clusters in schizophrenia. Assessment of potential state-dependent alterations in sleep architecture and arousal relative to antipsychotic-like activity is critical for the development of novel antipsychotic drugs (APDs). Recently, we reported that VU0467154, a selective positive allosteric modulator (PAM) of the M4 muscarinic acetylcholine receptor (mAChR), exhibits robust APD-like and cognitive enhancing activity in rodents. However, the state-dependent effects of VU0467154 on sleep architecture and arousal have not been examined. Using polysomnography and quantitative electroencephalographic recordings from subcranial electrodes in rats, we evaluated the effects of VU0467154, in comparison with the atypical APD clozapine and the M1/M4-preferring mAChR agonist xanomeline. VU0467154 induced state dependent alterations in sleep architecture and arousal including delayed Rapid Eye Movement (REM) sleep onset, increased cumulative duration of total and Non Rapid Eye Movement (NREM) sleep, and increased arousal during waking periods. Clozapine decreased arousal during wake, increased cumulative NREM, and decreased REM sleep. In contrast, xanomeline increased time awake and arousal during wake, but reduced slow wave activity during NREM sleep. Additionally, in combination with the N-methyl-d-aspartate subtype of glutamate receptor (NMDAR) antagonist MK 801, modeling NMDAR hypofunction thought to underlie many symptoms in schizophrenia, both VU0467154 and clozapine attenuated MK-801-induced elevations in high frequency gamma power consistent with an APD-like mechanism of action. These findings suggest that selective M4 PAMs may represent a novel mechanism for treating multiple symptoms of schizophrenia, including disruptions in sleep architecture without a sedative profile. PMID- 26617073 TI - Visualization of Bacterial Microcompartment Facet Assembly Using High-Speed Atomic Force Microscopy. AB - Bacterial microcompartments (BMCs) are proteinaceous organelles widespread among bacterial phyla. They compartmentalize enzymes within a selectively permeable shell and play important roles in CO2 fixation, pathogenesis, and microbial ecology. Here, we combine X-ray crystallography and high-speed atomic force microscopy to characterize, at molecular resolution, the structure and dynamics of BMC shell facet assembly. Our results show that preformed hexamers assemble into uniformly oriented shell layers, a single hexamer thick. We also observe the dynamic process of shell facet assembly. Shell hexamers can dissociate from and incorporate into assembled sheets, indicating a flexible intermolecular interaction. Furthermore, we demonstrate that the self-assembly and dynamics of shell proteins are governed by specific contacts at the interfaces of shell proteins. Our study provides novel insights into the formation, interactions, and dynamics of BMC shell facets, which are essential for the design and engineering of self-assembled biological nanoreactors and scaffolds based on BMC architectures. PMID- 26617074 TI - First trimester serum tests for Down's syndrome screening. AB - BACKGROUND: Down's syndrome occurs when a person has three, rather than two copies of chromosome 21; or the specific area of chromosome 21 implicated in causing Down's syndrome. It is the commonest congenital cause of mental disability and also leads to numerous metabolic and structural problems. It can be life-threatening, or lead to considerable ill health, although some individuals have only mild problems and can lead relatively normal lives. Having a baby with Down's syndrome is likely to have a significant impact on family life.Noninvasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing. However, no test can predict the severity of problems a person with Down's syndrome will have. OBJECTIVES: The aim of this review was to estimate and compare the accuracy of first trimester serum markers for the detection of Down's syndrome in the antenatal period, both as individual markers and as combinations of markers. Accuracy is described by the proportion of fetuses with Down's syndrome detected by screening before birth (sensitivity or detection rate) and the proportion of women with a low risk (normal) screening test result who subsequently had a baby unaffected by Down's syndrome (specificity). SEARCH METHODS: We conducted a sensitive and comprehensive literature search of MEDLINE (1980 to 25 August 2011), Embase (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), The Database of Abstracts of Reviews of Effectiveness (The Cochrane Library 25 August 2011), MEDION (25 August 2011), The Database of Systematic Reviews and Meta-Analyses in Laboratory Medicine (25 August 2011), The National Research Register (Archived 2007), Health Services Research Projects in Progress database (25 August 2011). We did forward citation searching ISI citation indices, Google Scholar and PubMed 'related articles'. We did not apply a diagnostic test search filter. We also searched reference lists and published review articles. SELECTION CRITERIA: We included studies in which all women from a given population had one or more index test(s) compared to a reference standard (either chromosomal verification or macroscopic postnatal inspection). Both consecutive series and diagnostic case-control study designs were included. Randomised trials where individuals were randomised to different screening strategies and all verified using a reference standard were also eligible for inclusion. Studies in which test strategies were compared head-to-head either in the same women, or between randomised groups were identified for inclusion in separate comparisons of test strategies. We excluded studies if they included less than five Down's syndrome cases, or more than 20% of participants were not followed up. DATA COLLECTION AND ANALYSIS: We extracted data as test positive or test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria. We used hierarchical summary ROC meta analytical methods or random-effects logistic regression methods to analyse test performance and compare test accuracy as appropriate. Analyses of studies allowing direct and indirect comparisons between tests were undertaken. MAIN RESULTS: We included 56 studies (reported in 68 publications) involving 204,759 pregnancies (including 2113 with Down's syndrome). Studies were generally of good quality, although differential verification was common with invasive testing of only high-risk pregnancies. We evaluated 78 test combinations formed from combinations of 18 different tests, with or without maternal age; ADAM12 (a disintegrin and metalloprotease), AFP (alpha-fetoprotein), inhibin, PAPP-A (pregnancy-associated plasma protein A, ITA (invasive trophoblast antigen), free betahCG (beta human chorionic gonadotrophin), PlGF (placental growth factor), SP1 (Schwangerschafts protein 1), total hCG, progesterone, uE3 (unconjugated oestriol), GHBP (growth hormone binding protein), PGH (placental growth hormone), hyperglycosylated hCG, ProMBP (proform of eosinophil major basic protein), hPL (human placental lactogen), (free alphahCG, and free betahCG to AFP ratio. Direct comparisons between two or more tests were made in 27 studies.Meta-analysis of the nine best performing or frequently evaluated test combinations showed that a test strategy involving maternal age and a double marker combination of PAPP-A and free betahCG significantly outperformed the individual markers (with or without maternal age) detecting about seven out of every 10 Down's syndrome pregnancies at a 5% false positive rate (FPR). Limited evidence suggested that marker combinations involving PAPP-A may be more sensitive than those without PAPP-A. AUTHORS' CONCLUSIONS: Tests involving two markers in combination with maternal age, specifically PAPP-A, free betahCG and maternal age are significantly better than those involving single markers with and without age. They detect seven out of 10 Down's affected pregnancies for a fixed 5% FPR. The addition of further markers (triple tests) has not been shown to be statistically superior; the studies included are small with limited power to detect a difference.The screening blood tests themselves have no adverse effects for the woman, over and above the risks of a routine blood test. However some women who have a 'high risk' screening test result, and are given amniocentesis or chorionic villus sampling (CVS) have a risk of miscarrying a baby unaffected by Down's. Parents will need to weigh up this risk when deciding whether or not to have an amniocentesis or CVS following a 'high risk' screening test result. PMID- 26617075 TI - Effect of Omeprazole and Dextromethorphan on the Urinary Metabolic Ratio of Flurbiprofen. PMID- 26617076 TI - SOG1: a master regulator of the DNA damage response in plants. AB - The DNA damage response (DDR) is a critical mechanism to maintain the genome stability of an organism upon exposure to endogenous and exogenous DNA-damaging factors. The DDR system is particularly important for plants as these organisms, owing to their intrinsic immobility, are inevitably exposed to environmental stress factors, some of which induce DNA damage. Arabidopsis thaliana has orthologs of several DDR factors that are present in animals; however, some of the important animal regulators, such as the tumor suppressor p53 and the DDR kinases CHK1 and CHK2, have not been found in plants. These observations imply a unique DDR system in plants. The present review focuses on recent advances in our understanding of the DDR in A. thaliana and, in particular, on the function and role of SUPPRESSOR OF GAMMA RESPONSE 1 (SOG1), a plant-specific transcription factor that regulates the DDR. The most obvious response to DNA damage in A. thaliana is a rapid and robust change in the transcriptional regulation of numerous genes, in which SOG1 is an essential regulatory factor. Mutation of SOG1 causes various defects in the activation of cell cycle arrest, programmed cell death, and endoreduplication in response to DNA damage. These observations indicate that SOG1 is a master regulator of the DDR. Phylogenetic analyses of SOG1 reveal that orthologs of this crucial transcription factor are present not only in angiosperms but also in gymnosperms, suggesting that the SOG1 system is conserved across spermatophytes. Finally, future prospects for SOG1 research are also discussed. PMID- 26617077 TI - Human gut endogenous proteins as a potential source of angiotensin-I-converting enzyme (ACE-I)-, renin inhibitory and antioxidant peptides. AB - It is well known that endogenous bioactive proteins and peptides play a substantial role in the body's first line of immunological defence, immune regulation and normal body functioning. Further, the peptides derived from the luminal digestion of proteins are also important for body function. For example, within the peptide database BIOPEP (http://www.uwm.edu.pl/biochemia/index.php/en/biopep) 12 endogenous antimicrobial and 64 angiotensin-I-converting enzyme (ACE-I) inhibitory peptides derived from human milk and plasma proteins are listed. The antimicrobial peptide database (http://aps.unmc.edu/AP/main.php) lists over 111 human host-defence peptides. Several endogenous proteins are secreted in the gut and are subject to the same gastrointestinal digestion processes as food proteins derived from the diet. The human gut endogenous proteins (GEP) include mucins, serum albumin, digestive enzymes, hormones, and proteins from sloughed off epithelial cells and gut microbiota, and numerous other secreted proteins. To date, much work has been carried out regarding the health altering effects of food-derived bioactive peptides but little attention has been paid to the possibility that GEP may also be a source of bioactive peptides. In this review, we discuss the potential of GEP to constitute a gut cryptome from which bioactive peptides such as ACE-I inhibitory, renin inhibitory and antioxidant peptides may be derived. PMID- 26617079 TI - Migratory Restlessness and the Role of Androgen for Increasing Behavioral Drive in the Spawning Migration of the Japanese eel. AB - Migratory restlessness refers to a type of locomotor activity observed just before the onset of a migration. This behavior is primarily known in birds, where it is considered to be an indicator of the urge for migration. In contrast, little is known about migratory restlessness in fishes. To confirm migratory restlessness in a fish, we measured the locomotor activity of the Japanese eel, Anguilla japonica during its migration season. Migratory-phase silver eels showed higher locomotor activity in aquaria than yellow eels at the non-migratiory growth-phase. Silver eels stayed outside of their shelters for longer durations in dark periods than yellow eels and were active even in light periods when yellow eels were inactive in the shelters. Silver eels had higher levels of the androgen hormone 11-ketotestosterone at the end of experiment than yellow eels. Administration of 11-ketotesosterone to yellow eels induced higher levels of locomotor activity than that observed in non-treated controls. These findings suggest that anguillid eels exhibit migratory restlessness just before their spawning migration and that 11-ketotestosterone may be involved in the onset of this behavior. PMID- 26617078 TI - Reproductive characteristics of the Yangtze vole (Microtus fortis calamorum) under laboratory feeding conditions. AB - The reproductive characteristics of a laboratory population of the vole Microtus fortis calamorum were examined. Voles were allowed to breed under laboratory feeding conditions. Over a period of 3 months, 61.82% of the 110 vole pairs examined produced 3 or 4 litters. There were 1-9 voles in each litter and the mean litter size was 4.67+/-0.28 (mean+/-SE). Most litters included 3-7 young voles, accounting for 83.62% of all litters. The mean farrowing interval was 25.9 days (range from 19 to 95 days), and the most farrowing intervals were 20-25 days, accounting for 79.9% of the total. When based on litter size, the reproductive index was 6.23, but was 3.42 when based on pup survival. The survival rate of offspring to weaning was 55.03%. The high rate of infanticide that occurred after removal of males from cages indicates that, in the laboratory, both parents need to be present prior to weaning. PMID- 26617080 TI - Caregiver perceptions of mental health problems and treatment utilisation in siblings of children with mental health problems. AB - BACKGROUND: Siblings of children with mental health problems (MHPs) have been found to have higher rates of psychopathology and impaired psychosocial functioning compared to control children. It is not yet known how these siblings are managed within the clinical service context (e.g., are they assessed for mental health problems? Do they receive appropriate psychological treatment?). AIMS: The following brief report describes a pilot study which aimed to explore (a) the rate of caregiver-identified MHPs in siblings and (b) the proportion of siblings receiving psychiatric or psychosocial treatment or support (i.e., treatment utilisation). METHODS: Eighty-five caregivers of children receiving treatment at CAMHS were interviewed about the mental health and treatment utilisation of their siblings. RESULTS: The findings revealed a high rate of caregiver-identified MHPs in siblings (34.1%) and a high rate of treatment utilisation (85.7%). CONCLUSIONS: The findings suggest that, for the vast majority, when siblings of children with MHPs are identified by their caregivers as having MHPs, they are receiving some kind of support and treatment. Implications for mental health service costs are discussed and recommendations for future research are outlined. PMID- 26617081 TI - How the mode of action affects evidence of planning and movement kinematics in aging: End-state comfort in older adults. AB - Motor deficits are commonly observed with age; however, it has been argued that older adults are more adept when acting in natural tasks and do not differ from young adults in these contexts. This study assessed end-state comfort and movement kinematics in a familiar task to examine this further. Left- and right handed older adults picked up a glass (upright or overturned) as if to pour water in four modes of action (pantomime, pantomime with image/cup as a guide, actual grasping). With increasing age, a longer deceleration phase (in pantomime without a stimulus) and less end-state comfort (in pantomime without a stimulus and image as a guide) was displayed as the amount of contextual information available to guide movement decreased. Changes in movement strategies likely reflect an increased reliance on feedback control and demonstration of a more cautious movement. A secondary aim of this study was to assess hand preference and performance, considering conflicting reports of manual asymmetries with age. Performance differences in the Grooved Pegboard place task indicate left handers may display a shift towards right handedness in some, but not all cases. Summarizing, this study supports age-related differences in planning and control processes in a familiar task, and changes in manual asymmetries with age in left handers. PMID- 26617082 TI - Pyruvate dehydrogenase as a therapeutic target for obesity cardiomyopathy. AB - INTRODUCTION: Obesity cardiomyopathy is a major public health problem with few specific therapeutic options. Abnormal cardiac substrate metabolism with reduced pyruvate dehydrogenase (PDH) activity is associated with energetic and functional cardiac impairment and may be a therapeutic target. AREAS COVERED: This review summarizes the changes to cardiac substrate and high energy phosphorus metabolism that occur in obesity and describes the links between abnormal metabolism and impairment of cardiac function. The available evidence for the currently available pharmacological options for selective metabolic therapy in obesity cardiomyopathy is reviewed. EXPERT OPINION: Pharmacological restoration of PDH activity is in general associated with favourable effects upon cardiac substrate metabolism and function in both animal models and small scale human studies, supporting a potential role as a therapeutic target. PMID- 26617083 TI - Simulating Lattice Spin Models on Graphics Processing Units. AB - Lattice spin models are useful for studying critical phenomena and allow the extraction of equilibrium and dynamical properties. Simulations of such systems are usually based on Monte Carlo (MC) techniques, and the main difficulty is often the large computational effort needed when approaching critical points. In this work, it is shown how such simulations can be accelerated with the use of NVIDIA graphics processing units (GPUs) using the CUDA programming architecture. We have developed two different algorithms for lattice spin models, the first useful for equilibrium properties near a second-order phase transition point and the second for dynamical slowing down near a glass transition. The algorithms are based on parallel MC techniques, and speedups from 70- to 150-fold over conventional single-threaded computer codes are obtained using consumer-grade hardware. PMID- 26617084 TI - Magnetizabilities at Self-Interaction-Corrected Density Functional Theory Level. AB - Using a recent high-quality ab initio coupled cluster benchmark set for magnetizabilities, we assess the performance of a set of density functionals, representing different levels of complexity, from the local density approximation (LDA), via generalized gradient approximations (GGA's) to kinetic energy density including meta-GGA's. The effect of self-interaction correction (SIC) is remarkable and, in most cases, leads to a significant error reduction, revealing the sensitivity of magnetizability toward a physically sound exchange-correlation potential. PMID- 26617085 TI - Transferability of Atomic Properties in Molecular Partitioning: A Comparison. AB - For a given choice of fragmentation of a molecule, Partition Density Functional Theory (PDFT) provides fragment densities that add up to the correct molecular density, and produce the-in principle exact-molecular energy. Using a simple model system of a heteronuclear diatomic molecule, we investigate the transferability of the resulting PDFT fragment densities by examining how their shapes and dipoles are preserved as the environment changes, and compare with other partitioning schemes. Our results show that (1) the transferability of PDFT densities is about an order of magnitude higher than that of real-space partitioning schemes, and (2) the PDFT dipoles are about an order of magnitude more transferable than Hirshfeld dipoles in regions of chemical relevance. PMID- 26617086 TI - Investigation of Self-Interaction Corrections for an Exactly Solvable Model System: Orbital Dependence and Electron Localization. AB - A systematic investigation of two approximate self-interaction corrections (SICs), Perdew-Zunger SIC and Lundin-Eriksson SIC, and the local-density approximation (LDA) is performed for a model Hamiltonian whose exact many-body solution and exact LDA are known. Both SICs as well as LDA are applied in the calculation of ground-state energies, ground-state densities, energy gaps, and impurity densities of one-dimensional Hubbard chains differing in size, particle number, and interaction strength. The orbital-dependent potentials arising from either SIC are treated within the optimized-effective potential method, which we reformulate for the Hubbard model. The delocalization tendency of LDA is confronted with the localization tendency of SIC. A statistical analysis of the resulting data set sheds light on the role of SIC for weakly and strongly interacting particles and allows one to assess the performance of each methodology. PMID- 26617087 TI - Including Charge Penetration Effects in Molecular Modeling. AB - Electrostatic effects are often the dominant component of intermolecular interactions, but they are often modeled without accounting for charge penetration effects due to the finite extent of electronic orbitals. Here, we propose a new scheme to include charge penetration effects in electrostatic modeling, and we parametrize it and illustrate it by employing the electronically embedded combined quantum mechanical and molecular mechanical (QM/MM) method. It can also be extended to other molecular modeling approximations that include electrostatic effects. The method, which is based on introduction of a single parameter for each element, is simple in concept and implementation, modest in cost, and easily incorporated into existing codes. In the new scheme, the MM atomic charge density of an atom in a molecule is represented by a screened charge rather than by a point charge. The screened charge includes a point charge for the nucleus, core electrons, and inner valence electrons, and a smeared charge for the outer valence electron density, which is distributed in a Slater type orbital representing the outer part of the atomic charge distribution such that the resulting pairwise interactions are still analytic central potentials. We optimize the exponential parameters of the Slater-type orbitals for 10 elements, in particular H, C, N, O, F, Si, P, S, Cl, and Br, to minimize the mean unsigned error (MUE) of the QM/MM electrostatic and induction energies with respect to the Hartree-Fock electrostatic energies and the sum of induction and induction-exchange energies calculated by symmetry-adapted perturbation theory (SAPT). The resulting optimized exponential parameters are very physical, which allows one to assign parameters to all nonmetal elements (except rare gases) with atomic number less than or equal to 35. For a test set of complexes, the improved description of MM charge densities reduces the error of electrostatic interactions between QM and MM regions in the QM/MM method from 8.1 to 2.8 kcal/mol and reduces the error of induction interactions from 1.9 to 1.4 kcal/mol. PMID- 26617088 TI - Relative Weights of sigma and pi Ring Currents in a Few Simple Monocycles. AB - By partitioning the bond current strength (current susceptibility) into plane symmetric and plane antisymmetric contributions, it is shown that 91% of the diatropic ring current of benzene is transported by the pi electrons and the remaining non-negligible 9% is sustained by the sigma electrons. In planar cyclooctatetraene 94% (6%) of the paratropic ring current is transported by the pi (sigma) electrons. In cyclopropane 95% (5%) of the diatropic ring current is transported by the sigma (pi-like) electrons. The 85% fraction of the diatropic ring current of Al4(2-) is transported by the sigma valence electrons and 15% by the pi valence electrons. In the nonaromatic borazine system the nitrogen centered pi electron circulations are surrounded by a weak diatropic "ring current" 6.5 times smaller than that of benzene. PMID- 26617089 TI - Geometry Optimization with Multilayer Methods Using Least-Squares Minimization. AB - In this article, we introduce a least-squares minimization scheme for optimizing molecular structures with mixed quantum mechanics (QM) and molecular mechanics (MM) multilayer models. A mixed-coordinate optimization framework was developed. The QM and MM regions are modeled with redundant internal coordinates and Cartesian coordinates, respectively. Within this mixed-coordinate system, a least squares minimization method using the quasi-Newton step as the evaluation of error is constructed. The couplings between layers are treated rigidly in accordance with the mechanical embedding approach, and the MM Hessian is approximated as a scalar constant of the root-mean-square QM Hessian eigenvalues. Both two-layer and three-layer models were tested. The performance of the method developed herein shows consistently stable and fast convergence. PMID- 26617090 TI - Toward a General Formulation of Dispersion Effects for Solvation Continuum Models. AB - We revised the quantum model of Amovilli and Mennucci (J. Phys. Chem. B 1997, 101, 1051) to include the dispersion contribution to the solvation free energy within the framework of continuum models. Our revised formulation makes use of a single adjustable solvent-dependent parameter, and it can be readily generalized to different quantum mechanical descriptions. In particular, we made use of DFT and applied the model to investigate dispersion effects on vertical excitation energies within a time-dependent DFT framework. Our findings show that dispersion effects constitute a significant component of the absolute solvent effect but when relative solvent-solvent shifts are considered a cancellation effect is observed. PMID- 26617091 TI - On the Electronic Structure of H-Ng-Ng-F (Ng = Ar, Kr, Xe) and the Nonlinear Optical Properties of HXe2F. AB - The electronic ground state of H-Ng-Ng-F (Ng = Ar, Kr, Xe) has been studied theoretically by employing the ab initio complete active space valence bond (CASVB) and multi-state complete active space perturbation theory (MS-CASPT2) methods. Both levels of theory confirm the diradicaloid character (DC) of the HNg2F ground state, increasing in the order Ar > Kr > Xe. The very significant effect of the first and, even more, the second Xe atom on the (hyper)polarizabilities has been shown and interpreted. Thus, the present results demonstrate a mechanism for producing very large (hyper)polarizabilities. PMID- 26617092 TI - PACE Force Field for Protein Simulations. 1. Full Parameterization of Version 1 and Verification. AB - A further parametrization of a united-atom protein model coupled with coarse grained water has been carried out to cover all amino acids (AAs). The local conformational features of each AA have been fitted on the basis of restricted coil-library statistics of high-resolution X-ray crystal structures of proteins. Potential functions were developed on the basis of combined backbone and side chain rotamer conformational preferences, or rotamer Ramachandran plots (phi, Psi, chi1). Side chain-side chain and side chain-backbone interaction potentials were parametrized to fit the potential mean forces of corresponding all-atom simulations. The force field has been applied in molecular dynamics simulations of several proteins of 56-108 AA residues whose X-ray crystal and/or NMR structures are available. Starting from the crystal structures, each protein was simulated for about 100 ns. The Calpha RMSDs of the calculated structures are 2.4 4.2 A with respect to the crystal and/or NMR structures, which are still larger than but close to those of all-atom simulations (1.1-3.6 A). Starting from the PDB structure of malate synthase G of 723 AA residues, the wall-clock time of a 30 ns simulation is about three days on a 2.65 GHz dual-core CPU. The RMSD to the experimental structure is about 4.3 A. These results implicate the applicability of the force field in the study of protein structures. PMID- 26617093 TI - PACE Force Field for Protein Simulations. 2. Folding Simulations of Peptides. AB - We present the application of our recently developed PACE force field to the folding of peptides. These peptides include alpha-helical (AK17 and Fs), beta sheet (GB1m2 and Trpzip2), and mixed helical/coil (Trp-cage) peptides. With replica exchange molecular dynamics (REMD), our force field can fold the five peptides into their native structures while maintaining their stabilities reasonably well. Our force field is also able to capture important thermodynamic features of the five peptides that have been observed in previous experimental and computational studies, such as different preferences for a helix-turn-helix topology for AK17 and Fs, the relative contribution of four hydrophobic side chains of GB1p to the stability of beta-hairpin, and the distinct role of a hydrogen bond involving Trp-Hepsilon and a D9/R16 salt bridge in stabilizing the Trp-cage native structure. Furthermore, multiple folding and unfolding events are observed in our microsecond-long normal MD simulations of AK17, Trpzip2, and Trp cage. These simulations provide mechanistic information such as a "zip-out" pathway of the folding mechanism of Trpzip2 and the folding times of AK17 and Trp cage, which are estimated to be about 51 +/- 43 ns and 270 +/- 110 ns, respectively. A 600 ns simulation of the peptides can be completed within one day. These features of our force field are potentially applicable to the study of thermodynamics and kinetics of real protein systems. PMID- 26617094 TI - Spectroscopic Properties of Formaldehyde in Aqueous Solution: Insights from Car Parrinello and TDDFT/CASPT2 Calculations. AB - We present Car-Parrinello and Car-Parrinello/molecular mechanics simulations of the structural, vibrational, and electronic properties of formaldehyde in water. The calculated properties of the molecule reproduce experimental values and previous calculations. The n -> pi* excitation energy, calculated with TDDFT and CASPT2, agrees with experimental data. In particular, it shows a blue shift on going from the gas phase to aqueous solution. Temperature and wave function polarization contributions have been disentangled. PMID- 26617095 TI - Position Isomerism on One and Two Photon Absorption in Multibranched Chromophores: A TDDFT Investigation. AB - Recently, branching and click chemistry strategies have been combined to design a series of optically active chromophores built from triazole moieties. These triazole-based multipolar chromophores have been shown to be promising candidates for two-photon absorption (TPA) transparency optimization in perspective of optical limiting in the visible region. In this work, the nature of one- and two photon absorption properties in a family of triazole-based chromophores has been investigated using hybrid time-dependent density functional theory (TD-DFT). We use recent extensions of TD-DFT to determine nonlinear optical responses and natural transition orbitals to analyze the underlying electronic processes. Our results are also interpreted in the framework of the Frenkel exciton model. In agreement with experimental data, we found that introducing a triazole moiety into multibranched chromophores substantially modifies their optical behavior due to changes in electronic delocalization and charge-transfer properties between donating end groups and the branching center that can be controlled by the triazole ring. Structural conformations via modulation of the torsion between phenyl and triazole rings significantly alter the excited state electronic structure. Moreover, isomer positioning also greatly influences both linear and nonlinear optical responses such as TPA. Our theoretical findings allow elucidation of these differences and contribute to the general understanding of structure-property relations. Consequently, the interplay of donor/acceptor strength, triazole regioisomerism, and branching are shown to provide flexible means allowing for precise tuning of both linear and nonlinear optical responses, thus opening new perspectives toward synergic TPA architectures. PMID- 26617096 TI - Stability of Hydrocarbons of the Polyhedrane Family Containing Bridged CH Groups: A Case of Failure of the Colle-Salvetti Correlation Density Functionals. AB - DFT-computed energies of polyhedric hydrocarbons, such as dodecahedrane C20H20, its smaller analogs C16H16 and C12H12, and the larger C24H24, estimated in comparison with corresponding isomeric hydrocarbons, vary widely with the choice of the density functional. In particular, large discrepancies were observed with the functionals that are based on the B88 (as well as G96, B86) exchange and the LYP (as well as OP) correlation parts. The problem is not related to the presence of the smaller cyclopropane rings in the C12H12 polyhedrane, for its hydrogenated products do show similar errors; moreover, the larger dodecahedrane that is free from the Bayer strain shows a similar trend. DFT-D corrections that are very useful in fixing long- and medium-range correlation issues with GGA DFT do not help in this case either. We show that these errors stem from the B88 (G96, B86) exchange functionals and are not compensated by Colle-Salvetti-based GGA correlation functionals such as LYP, OP, TCA, etc. However, they can be corrected by the PBE correlation functional based on the PW92 uniform electron gas (UEG) parametrization. Range-separated hybrids (Iikura and Hirao's LC-BOP, LC-BLYP) perform much better than the parent GGAs. Comparisons of polyhedranes with a well studied system of similar size, the set of CnHn cyclophanes, reveal a completely different performance for the latter-for instance, RHF results are the poorest, and LC-type functionals do not give any improvement, but dispersion-corrected BLYP-D performs very well. We conclude that, while for polyhedranes medium-range delocalization errors from exchange dominate, for cyclophanes, the correlation/overlap-dispersion interactions are more important. The OPTX exchange functional shows significantly lower errors compared to B88 and G96; its combinations like OLYP and especially KT3 perform well for both test sets. The OPTX-based double hybrid, O2PLYP, also outperforms the corresponding B88-based B2PLYP functional for polyhedranes. Our computations also suggest that the (CH)16 and (CH)24 polyhedranes could be possible synthetic targets. PMID- 26617097 TI - The Dissociated Amorphous Silica Surface: Model Development and Evaluation. AB - At pH 7, amorphous silica has a characteristic negative charge due to the deprotonation of silanol groups on the surface. Electrokinetic phenomena and transport of biomolecules in devices depend sensitively on the surface morphology, distribution of ions and solvent, and adsorption properties of solutes close to the surface in the electrical double layer region. Hence, simulation of these phenomena requires detailed atomistic models of the double layer region. In this Article, we extend our undissociated silica surface model [J. Phys. Chem. B 2007, 111, 11181-11193] to include dissociated Si-O(-) groups, which interact with both water and salt (Na(+) and Cl(-)). We have also conducted ab initio molecular dynamics (AIMD) simulations of a smaller system consisting of a hydrated silica slab. The radial distribution functions predicted by the empirical model are in qualitative agreement with those from the AIMD simulations. The hydrophobic and hydrophilic nature of silanol-poor and silanol rich regions of the amorphous silica surface observed in our empirical model is reproduced in the AIMD simulations of the smaller slab. In the initial stages of our AIMD simulations, we observe various chemical processes that represent different hydroxylation mechanisms of the surface. PMID- 26617098 TI - Automatic Structure Analysis in High-Throughput Characterization of Porous Materials. AB - Inspection of the structure and the void space of a porous material is a critical step in most computational studies involving guest molecules. Some sections of the void space, like inaccessible pockets, have to be identified and blocked in molecular simulations. These pockets are typically detected by visual analysis of the geometry, potential or free energy landscapes, or a histogram of an initial molecular simulation. Such visual analysis is time-consuming and inhibits characterization of large sets of materials required in studies focused on identification of the best materials for a given application. We present an automatic approach that bypasses manual visual analysis of this kind, thereby enabling execution of molecular simulations in an unsupervised, high-throughput manner. In our approach, we used a partial differential equations-based front propagation technique to segment out channels and inaccessible pockets of a periodic unit cell of a material. We cast the problem as a path planning problem in 3D space representing a periodic fragment of porous material, and solve the resulting Eikonal equation by using Fast Marching Methods. One attractive feature of this approach is that the to-be-analyzed data can be of varying types, including, for example, a 3D grid representing the distance to the material's surface, the potential or free energy of a molecule inside the material, or even a histogram (a set of snapshots) from a molecular simulation showing areas which were visited by the molecule during the simulation. PMID- 26617099 TI - Theoretical Design by First Principles Molecular Dynamics of a Bioinspired Electrode-Catalyst System for Electrocatalytic Hydrogen Production from Acidified Water. AB - Bacterial di-iron hydrogenases produce hydrogen efficiently from water. Accordingly, we have studied by first-principles molecular-dynamics simulations (FPMD) electrocatalytic hydrogen production from acidified water by their common active site, the [FeFe]H cluster, extracted from the enzyme and linked directly to the (100) surface of a pyrite electrode. We found that the cluster could not be attached stably to the surface via a thiol link analogous to that which attaches it to the rest of the enzyme, despite the similarity of the (100) pyrite surface to the Fe4S4 cubane to which it is linked in the enzyme. We report here a systematic sequence of modifications of the structure and composition of the cluster devised to maintain the structural stability of the pyrite/cluster complex in water throughout its hydrogen production cycle, an example of the molecular design of a complex system by FPMD. PMID- 26617100 TI - Computational Study of the DNA-Binding Protein Helicobacter pylori NikR: The Role of Ni(2.). AB - An integrated approach, combining atomistic molecular dynamics simulations, coarse-grained models, and solution NMR, was used to characterize the internal dynamics of HpNikR, a Ni-dependent transcription factor. Specifically, these methods were used to ascertain how the presence of bound Ni(2+) ions affects the stability of the known open, cis, and trans forms observed in the crystal structures of this protein as well as their interconversion capability. The consensus picture emerging from all the collected data hints at the interconversion of NikR among the three types of conformations, regardless of the content of bound Ni(2+). On the basis of atomistic and coarse-grained simulations, we deduce that the interconversion capability is particularly effective between the cis and the open forms and appreciably less so between the trans conformer and the other two forms. The presence of the bound Ni(2+) ions does, however, affect significantly the degree of the correlations on the two DNA binding domains of NikR, which is significantly suppressed as compared to the apo form. Overall, the findings suggest that the binding of HpNikR to DNA occurs through a sophisticated multistep process involving both a conformational selection and an induced fit. PMID- 26617101 TI - Electric Field Effects on Short Fibrils of Abeta Amyloid Peptides. AB - Amyloid fibrils are highly ordered protein aggregates, which are associated with many neurodegenerative diseases. The assembling dynamics of monomeric beta amyloid peptides, Abeta, into small aggregates (and then into long fibrils) is still debated and has become a hot topic. In this study, we conducted molecular dynamics simulations in explicit water of small Abeta protofibrils (from monomer to pentamer) under the perturbation of an externally applied electric field with the aim of investigating the fundamental molecular interactions involved in the aggregation mechanism. Dynamics of small adducts of Abeta(16-42) in the presence of an electric field, which was shown before to accelerate the conformational change of a single molecule, indicate that the structural resilience increases with the number of molecules in the aggregate. In particular, for 50 ns, the pentamer shows an enhanced stability in secondary structure, number of hydrogen bonds, and number of salt bridges, even in the presence of the field perturbation. The resilience to the field perturbation is linked to the variation of the induced dipole moment of the aggregates that tends to level off very rapidly with the growing number of molecules, thereby reducing the energy available per molecule to produce structural changes. The results also show that in the presence of the field the stability of the hydrophobic second beta-sheet (beta2, residues 31-42) is higher than that of the first one (beta1, residues 18 26). In particular, we identify Gly33, Gly37, and Met35 as the most important residues that stabilize the intermolecular packing and may act as nucleation sites for fibrillization. Furthermore, dynamics of the full-length Abeta(1-42) pentameric aggregate, which include the highly charged random coil residues 1-15, confirmed the key role of the second hydrophobic core in the protofibril structure. PMID- 26617102 TI - Nonpolar Solvation Free Energies of Protein-Ligand Complexes. AB - Recent investigations have indicated that different solvation methods give qualitatively different results for the nonpolar solvation contribution to ligand binding affinities. Therefore, we have calculated the nonpolar solvation contribution to the free energy of benzene binding to the T4 lysozyme Leu99Ala mutant using thermodynamic integration (TI) and three approximate methods. The total binding free energy was calculated with TI and then decomposed into contributions from the solvent and the solute. The nonpolar contribution from the solute was compared to approximate methods within the framework of the molecular mechanics and generalized Born with surface area method (MM/GBSA). First, the nonpolar solvation energy was calculated with a linear relation to the solvent accessible surface area (SASA). Second, a recent approach that divides the nonpolar solvation energy into cavity and dispersion parts was used, and third, the nonpolar solvation energy was calculated with the polarized continuum model (PCM). Surprisingly, the simple SASA estimate reproduces the TI results best. However, the reason for this is that all continuum methods assume that the benzene cavity is filled with water for the free protein, contrary to both experimental and simulation results. We present a method to avoid this assumption and then, PCM provides results that are closest to the results obtained with TI. PMID- 26617103 TI - Explicit Water Models Affect the Specific Solvation and Dynamics of Unfolded Peptides While the Conformational Behavior and Flexibility of Folded Peptides Remain Intact. AB - Conventional molecular dynamics simulations on 50 ns to 1 MUs time scales were used to study the effects of explicit solvent models on the conformational behavior and solvation of two oligopeptide solutes: alpha-helical EK-peptide (14 amino acids) and a beta-hairpin chignolin (10 amino acids). The widely used AMBER force fields (ff99, ff99SB, and ff03) were combined with four of the most commonly used explicit solvent models (TIP3P, TIP4P, TIP5P, and SPC/E). Significant differences in the specific solvation of chignolin among the studied water models were identified. Chignolin was highly solvated in TIP5P, whereas reduced specific solvation was found in the TIP4P, SPC/E, and TIP3P models for kinetic, thermodynamic, and both kinetic and thermodynamic reasons, respectively. The differences in specific solvation did not influence the dynamics of structured parts of the folded peptide. However, substantial differences between TIP5P and the other models were observed in the dynamics of unfolded chignolin, stability of salt bridges, and specific solvation of the backbone carbonyls of EK peptide. Thus, we conclude that the choice of water model may affect the dynamics of flexible parts of proteins that are solvent-exposed. On the other hand, all water models should perform similarly for well-structured folded protein regions. The merits of the TIP3P model include its high and overestimated mobility, which accelerates simulation processes and thus effectively increases sampling. PMID- 26617104 TI - Simulation of Coarse-Grained Protein-Protein Interactions with Graphics Processing Units. AB - We report a hybrid parallel central and graphics processing units (CPU-GPU) implementation of a coarse-grained model for replica exchange Monte Carlo (REMC) simulations of protein assemblies. We describe the design, optimization, validation, and benchmarking of our algorithms, particularly the parallelization strategy, which is specific to the requirements of GPU hardware. Performance evaluation of our hybrid implementation shows scaled speedup as compared to a single-core CPU; reference simulations of small 100 residue proteins have a modest speedup of 4, while large simulations with thousands of residues are up to 1400 times faster. Importantly, the combination of coarse-grained models with highly parallel GPU hardware vastly increases the length- and time-scales accessible for protein simulation, making it possible to simulate much larger systems of interacting proteins than have previously been attempted. As a first step toward the simulation of the assembly of an entire viral capsid, we have demonstrated that the chosen coarse-grained model, together with REMC sampling, is capable of identifying the correctly bound structure, for a pair of fragments from the human hepatitis B virus capsid. Our parallel solution can easily be generalized to other interaction functions and other types of macromolecules and has implications for the parallelization of similar N-body problems that require random access lookups. PMID- 26617106 TI - A Novel Murine Candidiasis Model with Severe Colonization in the Stomach Induced by N-acetylglucosamine-treatment and Its Scoring System Based on Local Characteristic Stomach Symptoms. AB - We developed a novel murine candidiasis model of the gastrointestinal tract using N-acetylglucosamine ( GlcNAc ) as a tool to aggravate symptoms. Forty-eight hours after intragastrically inoculating Candida albicans cells to immunosuppressed and GlcNAc-treated mice, vigorously accumulating patchy whitish plaques were observed on their inner stomach surface. Candida cells colonizing the plaques consisted of both yeast and mycelia, and were directly stained with Calcofluor White M2R. Aggravation of the candidiasis symptoms was dependent on GlcNAc concentration in drinking water, wherein administration of 50 mM GlcNAc not only severely worsened stomach symptoms, but also significantly increased Candida cell number in the stomach and small intestine. The aggravation effect of GlcNAc was enhanced by addition of sedative chemical chlorpromazine chloride after inoculation. In order to semi-quantitatively assess colonization by Candida in the stomach, we devised a new symptom scoring system that represents the extent of the patchy whitish plaques on the mucosal epithelium of the stomach. Histochemical analysis of Candida-infected tissues revealed not only a large amount of thick Candida mycelia invading mucosal epithelial stomach tissues but also infiltrating inflammatory cells. These results suggest that this murine gastrointestinal candidiasis model could serve as a useful tool for evaluating the protective activity of antifungal agents, probiotics, or functional foods against gastrointestinal candidiasis. Furthermore, from another point of view, this novel murine model could also be used to analyze the pathological mechanisms behind the translocation of C. albicans across intestinal barriers, which results in systemic Candida dissemination and infection. PMID- 26617105 TI - Cutaneous Pseudallescheria boydii/Scedosporium apiospermum Complex (Molecular type: Scedosporium apiospermum [Clade 4]) Infection: A Case Report and Literature Review of Cases from Japan. AB - We report a case of subcutaneous Pseudallescheria boydii/Scedosporium apiospermum complex infection occurring in a 77-year-old Japanese female farmer suffering from interstitial pneumonia. Seven months prior to the current presentation, she noticed nodes on her right forearm after pulling up weeds, and the nodes grew larger. Two soft dome-shaped, protruded nodes ( 15 mm and 30 mm in size ) had fused together on the extensor surface of the right forearm. Yellowish-white, rice-grain-sized pustules clustered on the surface. Histopathological examination of the skin specimen showed large and small abscesses surrounded by epithelioid granuloma; separate branching hyphae within the granulation tissue were stained with PAS. No grains were observed. Fungal culture yielded fast-growing, grayish white, fluffy colonies which were identified as Scedosporium apiospermum (Clade 4) using sequence analysis of the beta-tubulin gene. We also reviewed 28 previously reported Japanese cases of P. boydii or S. apiospermum infection presenting with skin manifestations. PMID- 26617107 TI - [A Case of Cutaneous Phaeohyphomycosis Caused by Exophiala lecanii-corni Showing a Seasonal Fluctuation of Skin Lesions]. AB - A 56-year-old Japanese female presented to our hospital in March complaining of asymptomatic skin lesions on both cheeks for the past few years. She had been receiving treatment for phlebosclerotic colitis and gastroesophageal reflux disease. We identified subcutaneous nodules with scale, erosion, and necrotic crusts on the surface, with one on the right cheek and two on the left. The patient said that the eruptions almost disappeared every summer but always recurred in winter, a phenomenon that we confirmed. Histopathology revealed pseudoepitheliomatous hyperplasia and marked infiltration from various inflammatory cells with a granulomatous reaction in the dermis. Brown fungal elements were scattered around the epidermis and dermis in the form of single spore or toruloid hyphae. We identified the fungus as Exophiala lecanii-corni based on morphological and physiological characteristics, as well as rRNA gene analysis. The strain grew well at 27 C, but growth was remarkably suppressed at 33 C and not observed at all at 37 C. Treatment with itraconazole 200 mg / day for 6 months resulted in complete remission of the lesions. PMID- 26617108 TI - [Antifungal susceptibility and drug-resistant mechanism of Trichosporon]. AB - Most cases of deep-seated trichosporonosis develop in patients with neutropenia, but it has recently been reported that breakthrough infections with Trichosporon species can develop during the use of candin family of antifungal agents. This is due to the primary resistance of the causal fungus, Trichosporon asahii (T. asahii), to the candin agents. On the other hand, there has been a case report of infection with Trichosporon that presented high-level resistance to the azole family of antifungal agents. Therefore, the possibility that the frequent use of azole agents may lead to secondary resistance to these agents is a cause for concern. Since trichosporonosis is a relatively rare infectious disease, there has been no established breakpoint for this fungus to various antifungal agents, wherein we cannot precisely confirm its sensitivity or resistance to the agents. However, our experiment demonstrated one of the processes for acquired drug resistance, wherein the minimal inhibitory concentration of fluconazole for T. asahii was markedly elevated after its long-term in vitro exposure to the drug. Although the mechanisms for drug-resistance of Trichosporon species are unknown, it is supposed that they are the same as the mechanisms found in Candida and Aspergillus species, namely, modification of target molecules or decrease of access to the molecules. Since cases of trichosporonosis are likely to increase in the future, we believe that there is an urgent need to establish the breakpoint for T. asahii based on large-scale drug sensitivity tests, as well as to elucidate its drug-resistance mechanisms. PMID- 26617109 TI - [2011 Epidemiological Survey of Dermatomycoses in Japan]. AB - An epidemiological survey of dermatomycoses and their causative fungus flora in Japan for 2011 was conducted in accordance with methods and criteria of the past four surveys. The survey covered a total number of 36,052 outpatients who visited 12 dermatological clinics throughout Japan. The results were as follows. 1)Dermatophytosis was the most prevalent cutaneous fungal infection (2,980 cases) seen in these clinics, followed by candidiasis (378 cases) and then Malassezia infections (152 cases). 2)Among dermatophytoses, tinea pedis was the most frequent (1,930 cases : male, 980 ; female, 950), then in decreasing order, tinea unguium (780 cases : male, 409 ; female, 371), tinea corporis (203 cases : male, 132 ; female, 71), tinea cruris (112 cases : male, 86 ; female, 26), tinea manuum (43 cases : male, 25 ; female, 18), and tinea capitis including kerion (16 cases : male, 13 ; female, 3). 3)Tinea pedis and tinea unguium were seen to increase in the summer season and occur mostly among the aged population. Compared to the last survey, by clinical form, there was a marked decrease in dermatophytosis patients. 4)As the causative dermatophyte species, Trichophyton rubrum was the most frequently isolated at about 80 % among all dermatophyte infections excluding tinea capitis. T. mentagrophytes was about 10 %. Microsporum canis was isolated in five cases. M. gypseum was isolated in three cases, and Epidermophyton floccosum was isolated in only one case. T. tonsurans was isolated in 13 cases. 5)Cutaneous candidiasis was seen in 378 cases (305, male ; 537, female). Intertrigo (298 cases) was the most frequent clinical form, followed by diaporcandidiasis (79 cases), erosion interdigitalis (62 cases), genital candidiasis (46 cases). 6)Tinea versicolor was seen in 97 cases. Malassezia folliculitis was isolated in 55 cases. PMID- 26617110 TI - Deep-seated mycosis. Aspergillus lentulus. PMID- 26617111 TI - [Term 8]. PMID- 26617112 TI - Clinical and Pharmaceutical Solutions through Analysis (CPSA BRASIL 2015): on the way to innovation - pharmaceutical/analytical technology, regulation and knowledge management. AB - Clinical and Pharmaceutical Solutions through Analysis, Sao Paulo, Brazil, 3-5 August 2015 The 2nd Annual Symposium on Clinical and Pharmaceutical Solutions through Analysis was held on 3-5 August 2015 at Club Transatlantico, Sao Paulo, Brazil. This annual meeting began in 2014 and was the first industry-led event in Brazil to focus on the specific needs of industry researchers while bringing together technology and regulators. The goal of CPSA is to provide an in-depth review of innovative technology and industry practices through open discussion of industry-related issues and needs. Education and specialized training are the foundation of all CPSA events. As the industry has evolved so has CPSA. The CPSA annual meeting thrived with high quality scientific content, open interaction from industry opinion leaders and a collegial environment. PMID- 26617113 TI - Adsorption of O2 on anionic silver clusters: spins and electron binding energies dominate in the range up to nano sizes. AB - Exploring the reactivity of metal clusters is an important task in cluster science, while only a few previous studies involve the reactions of nano-sized ones. Here we report a kinetic measurement on reactions of Ag(n)(-) (n = 6-69) with O2 using a flow reactor running at 120 K. Their relative rates were obtained by fitting decay processes of parent ions at different O2 flow rates. Comparing the variations of the kinetic rates and the photodetachment energies of Ag(n)(-) (i.e. the binding energies of their excess electrons), we distinguished the separate effect of clusters' spins or their electron binding strength. This work firstly shows that reactions of O2 and Ag(n)(-) up to nano sizes are still dominated by the clusters' global electronic properties. This conclusion is conceptually important for understanding the reaction mechanisms on silver based nanocatalysts. PMID- 26617114 TI - Attenuation of cerebral ischemic injury in interferon regulatory factor 3 deficient rat. AB - Interferon regulatory factor 3 (IRF3) is a transcription factor that plays a central role in the innate immune response, apoptosis, and oncogenesis. Previous studies have shown that endogenous IRF3 does not affect stroke in mice; however, paradoxically, elevated IRF3 expression was observed in the rat brains following cerebral ischemia/reperfusion (I/R) injury, indicating that IRF3 may have different functions during stroke in rats than in mice. A clear and comprehensive study of the effect of IRF3 on stroke in rats has been hampered by the lack of an IRF3-knockout rat strain. In this study, a novel IRF3 knockout rat strain and a transgenic rat strain with neuronal-specific IRF3 over-expression (IRF3-TG) were created. Subsequently, the generated IRF3-knockout rats, the neuronal-specific IRF3 over-expressing rats and their corresponding controls were subjected to transient middle cerebral artery occlusion and followed by reperfusion, to investigate the exact role of IRF3 in cerebral I/R in rats. In contrast to the results in mice, IRF3 deficiency in rats provided significant protection against cerebral I/R injury and inhibited neuronal apoptosis, inflammation, and oxidative stress after cerebral I/R injury; the opposite patterns were observed in neuronal specific IRF3 over-expressing rats. Taken together, these data demonstrate that IRF3 plays a negative regulatory role in cerebral I/R in rats, and IRF3 may be an attractive therapeutic target for preventing stroke. In the present study, we discovered that the transcription factor IRF3, which plays a central role in the innate immune response, apoptosis, and oncogenesis, could exacerbate cerebral ischemia/reperfusion (I/R) injury via activating caspase-dependent neuronal apoptosis, inducing inflammation and oxidative stress. These findings suggest that IRF3 may be an attractive therapeutic target for the prevention of stroke. PMID- 26617115 TI - [Recent advances in bladder urothelial carcinogenesis]. AB - Bladder cancer is the sixth cause of cancer mortality in France and prognosis of muscle-invasive tumors remains poor due to lack of effective treatments. Recent advances in molecular biology applied to tumors and results of recent genome-wide studies have brought a important impact on the understanding of bladder carcinogenesis. Main molecular alterations concern FGFR3, TP53 and HER2, and it is now possible to distinguish three subgroups of tumors according to molecular profile. This paper proposes a review of different genetic and epigenetic alterations in bladder cancer, their potential role as theranostic markers in clinical oncology and new targeted therapies according to the concept of personalized medicine. PMID- 26617116 TI - [FGF/FGFR blockade: New insights in endometrial cancer]. PMID- 26617128 TI - Electrophoretic mobility shift in native gels indicates calcium-dependent structural changes of neuronal calcium sensor proteins. AB - In proteins of the neuronal calcium sensor (NCS) family, changes in structure as well as function are brought about by the binding of calcium. In this article, we demonstrate that these structural changes, solely due to calcium binding, can be assessed through electrophoresis in native gels. The results demonstrate that the NCS proteins undergo ligand-dependent conformational changes that are detectable in native gels as a gradual decrease in mobility with increasing calcium but not other tested divalent cations such as magnesium, strontium, and barium. Surprisingly, such a gradual change over the entire tested range is exhibited only by the NCS proteins but not by other tested calcium-binding proteins such as calmodulin and S100B, indicating that the change in mobility may be linked to a unique NCS family feature--the calcium-myristoyl switch. Even within the NCS family, the changes in mobility are characteristic of the protein, indicating that the technique is sensitive to the individual features of the protein. Thus, electrophoretic mobility on native gels provides a simple and elegant method to investigate calcium (small ligand)-induced structural changes at least in the superfamily of NCS proteins. PMID- 26617129 TI - Next-generation sequencing-based 5' rapid amplification of cDNA ends for alternative promoters. AB - Mammalian genomes contain many unknown alternative first exons and promoters. Thus, we have modified the existing 5'RACE (5' rapid amplification of cDNA ends) approach into a next-generation sequencing (NGS)-based new protocol that can identify these alternative promoters. This protocol has incorporated two main ideas: (i) 5'RACE starting from the known second exons of genes and (ii) NGS based sequencing of the subsequent cDNA products. This protocol also provides a bioinformatics strategy that processes the sequence reads from NGS runs. This protocol has successfully identified several alternative promoters for an imprinted gene, PEG3. Overall, this NGS-based 5'RACE protocol is a sensitive and reliable method for detecting low-abundant transcripts and promoters. PMID- 26617130 TI - The Anatomy of the Posterior Commissure. AB - AIM: The connections of posterior commissure are defined. Its fibers mediate the consensual light reflex by interconnecting the pretectal nuclei. The fiber connections from the thalamic, pretectal, superior colliculus and the habenular nuclei are known, but they have not been shown anatomically. The present study is a fiber dissection study to define the anatomy of the posterior commissure. MATERIAL AND METHODS: Twenty formalin-fixed sheep heads were used in the study. The specimens were fixed in 10% formalin solution for 3 weeks. The arachnoidal and vascular structures were removed by using a surgical microscope magnification (x6-x40) and brains were again fixed for 4 weeks at -20 degrees C. The fiber dissections were performed at Marmara University, Rhoton Laboratory. Also, a radiological tractographic study was carried on five healthy volunteers to see the posterior commissure cortical connections. RESULTS: In fifteen sheep brains, the dimensions of the posterior commissure were measured as 1.36 mm (range 0.5 2.5 mm) width, and as 4.6 mm (range 3-6 mm) length. In the dissection study, a frontotemporooccipital fascicle was observed to connect with the fibers of the posterior commissure. Diffusion tensor imaging scans showed the frontotemporooccipital tract to extend to posterior commissural region. CONCLUSION: To our knowledge, this is the first anatomical and tractographic study regarding the posterior commissure. However, further human cadaveric studies are necessary. PMID- 26617131 TI - The Paracondylar Skull Base: Anatomical Variants and Their Clinical Implications. AB - AIM: The knowledge of the vasculature around the paracondylar region is important in neurosurgical procedures such as the paracondylar and lateral supracondylar approaches. The objectives of the present study were to determine the prevalence of paracondylar emissary foramina in the adult skull bases and to study the morphology of condylar canals and hypoglossal canals. MATERIAL AND METHODS: The present study included 48 adult human skulls that were obtained from the gross anatomy laboratory of our institution. The paracondylar region was macroscopically observed for the variant foramina, canals and grooves. RESULTS: It was observed that the paracondylar emissary foramen was present in 16 skulls (33.3%). The foramen was found bilaterally in 7 skulls (14.6%) and unilaterally in 9 skulls (18.7%). The hypoglossal canal was single in 35 (72.9%) skulls, double in 11 skulls (22.9%), and triple in 2 skulls (4.2%). The paracondylar process (2.1%) and the paracondylar groove (2.1%) were seen in 1 skull each. The posterior condylar canal was found to be patent in 19 (39.6%) skulls. CONCLUSION: The present study observed that, the paracondylar emissary vein is not rare in occurrence as it is observed in 33.3% of cases. The identification of the paracondylar emissary veins and accessory vessels is important to avoid dangerous bleeding during the surgery. The morphological knowledge of the foramina around the paracondylar region is enlightening to the chiropractors, neurosurgeons and radiologists. PMID- 26617132 TI - Effect of Statins on Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis of Randomized Controlled Trials. AB - AIM: The role of statins for treating aneurysmal subarachnoid hemorrhage (aSAH) remains uncertain. In this study, the relevance of different end points was evaluated in order to clarify the action and efficacy of statins. MATERIAL AND METHODS: A systematic literature retrieval was carried out to obtain randomized controlled trials (RCTs) from before March 2013 on the use of statins for aSAH. Data extraction and quality evaluation of the studies were performed by 2 investigators. A meta-analysis was performed using Review Manager (RevMan) software version 5.2.3. RESULTS: Seven randomized controlled trials comprising 347 patients that met the inclusion criteria were included in this meta-analysis. Results showed that, in aSAH, statins did not reduce vasospasm on transcranial Doppler (RR=0.80; 95% CI, 0.53-1.21; p=0.29) or improve outcomes (RR=0.92; 95% CI, 0.71-1.20; p=0.54). However, statins were able to decrease delayed ischemic neurological deficits (RR=0.56; 95% CI, 0.41-0.75; p=0.0001) and mortality (RR=0.54; 95% CI, 0.32-0.91; p=0.02) compared with placebo. CONCLUSION: Acute statin treatment might not be a good choice for cerebral vasospasm after aSAH. Further large-scale, well-designed RCTs on this topic are still needed. PMID- 26617133 TI - Factors Influencing Intraoperative Rupture of Intracranial Aneurysms. AB - AIM: The study deals with intraoperative rupture of intracranial aneurysms (IOR) during microsurgery, analyzing factors that may be connected with IOR. MATERIAL AND METHODS: During the three-year period (2006-2008), 934 patients were operated for aneurysms at the Institute of Neurosurgery, CCS, Belgrade. In total, 536 patients were observed. RESULTS: IOR occurred in 14.7%. Male gender, seizures and timing of surgery proved to be risk factors for IOR. All other tested features had no significance. Localization {IOR rate 11.93% in ACM, 17.06% in ACA and 17.26% in ACI) and size (small: IOR in 68/439 (15.49%), large: 8/74 (10.8%), and very large: 3/23 (13.04%)} of aneurysm seemed to have an influence, but this could not be proved. The majority of IORs (58.23%) occurred in early surgery. Early operated patients: IOR occurred in 46/167 (27.54%), intermediary: 25/103 (24.27%), and delayed: 8/266 (3%) - with highly significant differences. CONCLUSION: Age, hypertension, diabetes mellitus, cardiomyopathy, pregnancy, higher Fisher score, previous IOR, or the presence of vomiting and headache did not affect the occurrence of IOR, whereas the timing of surgery, male gender and epileptic seizures increased the risk. Localization and size of aneurysm tend to have an influence but statistical significance was not proved in this study. PMID- 26617134 TI - The Volume Embolization Ratio of Intraaneurysmal Embolization Using Guglielmi Detachable Coils. AB - AIM: To analyse the relationship between the Volume Embolization Ratio (VER), aneurysmal morphological characteristics, and intracranial aneurysm embolization results. MATERIAL AND METHODS: Using the clinical and radiological data of 57 cerebral aneurysms treated with detachable coils, VERs were calculated. The relationship between the VER and aneurysm embolization was analysed. RESULTS: We observed that the mean VERs of the small, medium, large, and giant aneurysms were 40.8+/-26.5%, 18.6+/-16.1%, 2.3+/-2.1% and 0.4+/-0.1%, respectively and the differences were statistically significant (F=7.091, P=0.000). The mean VERs of the wide- and small-necked aneurysms were 27.5+/-23.1% and 29.4+/-26.6%, respectively. There was no significant difference between these values. The mean VERs of aneurysms causing complete occlusion, neck residual and partial embolization were 41.8+/-29.3%, 31.4+/-21.2%, 12.3+/-15.1%, respectively, and the differences were statistically significant (F=7.97, p=0.001). CONCLUSION: The VER is an objective index with which to evaluate aneurysm embolization and is a significant predictor of the efficacy of intracranial aneurysm embolization. PMID- 26617135 TI - Enteral Nutritional Support in Patients with Head Injuries After Craniocerebral Surgery. AB - AIM: To explore the effect of early enteral (EN) and parenteral nutritional (PN) support on head-injured patients after craniocerebral surgery. MATERIAL AND METHODS: We randomly divided 120 head trauma patients into two groups: those receiving EN and those receiving PN support (60 patients each). Physiological and biochemical indices, monitoring time and cost, and the incidence of complications were compared between the two groups. RESULTS: More patients presented with complications in the PN than the EN group, and this difference was statistically significant (P < 0.05). One week after surgery, albumin (ALB), alanine aminotransferase (ALT), and blood glucose (GLU) levels were 39.6 +/- 3.3 U/L, 51.4 +/- 5.6 U/L, and 9.6 +/- 5.2 mmol/L, respectively, in the EN group, and monitoring time and cost were 4.0 +/- 1.2 days and 1.2 +/- 1.0 thousand yuan, respectively. In the PN group, ALB, ALT, and GLU levels were 34.3 +/- 3.4 U/L, 65.5 +/- 6.1 U/L, and 15.1 +/- 4.0 mmol/L, respectively, and monitoring time and cost were 6.2 +/- 1.5 days and 1.8 +/- 2.0 thousand yuan, respectively. We detected significant differences between the two groups (P < 0.05). CONCLUSION: Early EN support is superior to PN support in head-injured patients after craniocerebral surgery. PMID- 26617136 TI - Retrospective Analysis of Prognostic Factors of Severe Traumatic Brain Injury in a University Hospital in Turkey. AB - AIM: To examine the use of prognostic factors such as age, Glasgow Coma Scale (GCS) score, pupil reactivity and computerized tomography (CT) findings for predicting the prognosis of severe traumatic brain injury (TBI) patients in Turkey. MATERIAL AND METHODS: We retrospectively evaluated TBI patients who were accepted to Akdeniz University Intensive Care Unit between 1 January 2007 and 31 December 2009. Patient data were collected from the hospital information system. Marshall CT classification was performed and CT findings were noted. The Glasgow outcome scale (GOS) score of patients was calculated according to their 6-months follow up. RESULTS: A total of 101 patients with severe TBI were studied. The mean age of the patients was 34.7 +/- 14.1 years. Of these, male patients (81.2%) were dominant and road accidents (83.2%) were the most common mechanism of TBI development. In addition, poor neurological outcome was detected in 58.4% of the patients and 29 patients (28.7%) died. The mechanism of injury (p = 0.34), gender (p = 0.64) or age (p = 0.34) did not lead to a difference in neurologic outcomes while the GCS score (p = 0.01), pupillary reactivity (p = 0.000), Marshall CT classification (p = 0.01) and the presence of traumatic subarachnoid haemorrhage (p = 0.04) affected the GOS scores. CONCLUSION: In our study, GCS score, CT findings and pupil reactivity were prominent as prognostic factors, but a relationship between age and prognosis was not observed. PMID- 26617137 TI - Endoscopic Endonasal Transsphenoidal Pituitary Surgery: Experience of 80 Cases. AB - AIM: Surgical approaches to the pituitary have undergone numerous refinements over the last 100 years. The fully endoscopic transsphenoidal approach has gained widespread use all around the world. We report the results of a consecutive series of patients who underwent pituitary surgery using a pure endoscopic endonasal approach and the results of the evaluation of the efficacy and safety of this procedure. MATERIAL AND METHODS: We retrospectively reviewed the hospital database of 80 consecutive pituitary adenomas that were resected with the purely endoscopic endonasal transsphenoidal technique. RESULTS: The preoperative clinical condition of the patients, hormone profile, visual field, computed tomography and magnetic resonance imaging findings, and the Hardy-Vezina and Knosp scores were evaluated and revealed the importance of the parameters for surgery. Surgical technique, postoperative clinical condition of the patients, hormone profile, complications and follow-up period were reviewed. CONCUSION: Endonasal endoscopic pituitary surgery is a safe and effective surgical technique. PMID- 26617138 TI - Reconstruction of Tissue Defects Developing After Excision of Non-Melanoma Malignant Skin Tumors in Scalp and Forehead Regions. AB - AIM: The scalp and forehead are the anatomical regions where non-melanoma malignant skin tumors are commonly seen due to direct sun exposure. After surgery for non-melanoma malignant skin tumors located in the scalp and forehead, many complex defects can develop, ranging from sole skin defects to deep defects in which bone and dura mater are opened. MATERIAL AND METHODS: This study examined 43 patients who presented to the Department of Plastic Surgery in Ankara Numune Training and Research Hospital and were diagnosed with non-melanoma malignant tumors of scalp and forehead between 2006 and 2013. The number of operations, the operation techniques applied, the number and type of complications (if any) of free tissue transplantation were also investigated. Various techniques are used for reconstruction of scalp and forehead region following resection of non melanoma skin tumors. RESULTS: In order to accomplish satisfactory results these patients have to be carefully assessed with specific parameters while performing the reconstruction of the defect and reconstruction should be planned. Patients with local invasion may need adjuvant radiotherapy postoperatively and reconstruction with free flaps is reliable in the prevention of the possible comorbid problems due to radiotherapy. CONCLUSION: Multidisciplinary approach is needed and the treatment should be managed with neurosurgical team, radiation oncologists and medical oncologists. PMID- 26617139 TI - The Role of Sulfadiazine for the Treatment of Refractory Intracranial Infection. AB - AIM: Sulfadiazine (SD) is a classic antibiotic for intracranial infection. Due to the medical market policy, SD has not been chosen as an essential drug in all the hospitals in China. However, its therapeutic effect is definite and cannot be substituted. The aim of this study was to evaluate the therapeutic and economic value of SD compared to other popular antibiotics in patients with refractory intracranial infection. MATERIAL AND METHODS: A retrospective single-center study was performed from January 2011 until December 2012. Thirteen patients diagnosed with refractory intracranial infection were treated with SD. The clinical effects were reviewed. RESULTS: Treatment was successful for 12 of the patients (cure rate=92.3%). One patient died of secondary epilepsy, respiratory complications, and multiple organ failure. Only one patient was allergic to SD, and there were no drug-related liver or kidney side effects. CONCLUSION: SD is a safe, effective, and economical antibiotic, and is used by our neurosurgical department. It should be offered as an option for the patients with refractory intracranial infection, especially for patients with lower ability to pay. PMID- 26617140 TI - Epilepsy Surgery in Children with Lesional Partial Epilepsies. AB - AIM: Surgery for epilepsy is a significant treatment alternative with favorable outcomes in the pediatric age group. In this study we present the surgical outcomes of pediatric population referred to our center. MATERIAL AND METHODS: The clinical data of 126 patients (<=18 years) with lesional partial epilepsies operated in our center between 1995- 2011 were evaluated retrospectively. Parameters investigated were gender, age at seizure onset, duration of epilepsy, etiology, type and location of operation and outcome. Seizure outcome was classified according to Engel's classification. RESULTS: The study group consisted of 70 males (55,6%) and 56 females (44.4%). The most common etiology was malformation of cortical development followed by tumors and hippocampal sclerosis. Overall 73.8% of patients had Engel I, 13.5% Engel II and 11.9% Engel III+IV postoperative seizure outcome. CONCLUSION: The results of our pediatric patients who underwent surgery were similar to previous reports in the literature. The seriousness of the clinical picture should tempt physicians to refer the patients as soon as possible to avoid long term complications like epileptic encephalopathies and the side effects of antiepileptic drugs during the development of the young brains. PMID- 26617141 TI - Presurgical Evaluation and Epilepsy Surgery in MRI Negative Resistant Epilepsy of Childhood with Good Outcome. AB - Magnetic resonance imaging (MRI)-negative epilepsy may be successfully solved with a multidisciplinary approach using invasive recordings, image and signal analysis. The whole methodology used by the epilepsy surgery team is systematically described based on an resistant epilepsy case with all steps and rationale of choosing different investigation methods from surface electroencephalography (EEG) to invasive recordings. Due to negative MRI and non concordant ictal surface EEG with clinical semiology, the patient was investigated with stereo- EEG (SEEG), aiming to delimitate epileptogenic and eloquent cerebral areas. Implantation strategy, seizures recordings, stimulation, resection planning using quantitative EEG analysis, and the surgery plan are presented. The patient has been seizure-free for 14 months so far, with improved behavior and daily life quality. Post-operative examination revealed focal cortical dysplasia type II B. PMID- 26617142 TI - Three-Dimensional Microsurgical Anatomy of the Choroid Plexus Using the Volume Rendering Technique. AB - AIM: The choroid plexus (CP) is a specific anatomical structure producing cerebrospinal fluid into the ventricular space. The three-dimensional anatomical structure of the choroid plexus located within the lateral ventricle may be evaluated by using the three dimensional volume rendering technique (3D-VRT) from acquired two-dimensional contrast enhanced computerized tomographic images. MATERIAL AND METHODS: The raw data of Three-dimensional Computerized Tomography Angiography (3D-CTA) were transferred into the computer and recorded in a software program. These images were evaluated in terms of anatomical shape, borders, extensions length and dimensions. RESULTS: The patient group consisted of 57 (27 female and 30 male) patients. The mean age of the patients was 55+/-9 years. In male individuals, the distance of the superior tip from Frazier's point was 7.96+/-0.71 centimeters at the right side. In males, the distance of the inferior tip of the CP was estimated as 1.93+/-0.26 centimeters posterior-lateral from the anterior clinoid process, 1.64+/-0.23 centimeters posterior-lateral from the bifurcation of internal carotid artery, and 2.86+/-0.23 centimeters posterior medial from the bifurcation of middle cerebral artery on the right side. CONCLSION: The results of this study showed us that this technique could be used in the three-dimensional evaluation of some anatomical structures such as the choroid plexus. PMID- 26617143 TI - Tethered Cord Syndrome in Adults: Experience of 56 Patients. AB - AIM: The aim of this study was to describe the results of surgery performed in a group of adult patients with tethered cord syndrome with their outcomes. MATERIAL AND METHODS: This retrospective study included 56 patients. There were 38 females and 18 males. All patients were older than 18 years. RESULTS: The mean age at referral was 36 years and 1 month. The mean follow-up period was 10 months 27 days. 95% of all patients with back and leg pains improved and 5% remained the same. Three patients with motor deficits remained the same in the postoperative period. Of the 16 patients with urological complaints, 10 improved, 5 unchanged and 1 patient died in the postoperative first day due to pulmonary embolism. CONCLUSION: The syndrome of tethered cord may be a situation to be treated even in the elderly in case of normal level conus medullaris and filum terminale with a normal appearance as well as a low-lying conus and thick filum. To prevent overlooking the diagnosis of tethered cord and/or unnecessary spinal surgeries, the tethered cord syndrome should be remembered in the differential diagnosis list in the presence of back and leg pains, neurological deficits or urological complaints. PMID- 26617144 TI - Effect of Carvedilol on Secondary Damage in Experimental Spinal Cord Injury in Rats. AB - AIM: Previous studies have shown that carvedilol has a neuroprotective effect in animal models of brain ischemia and brain oxidative damage in vitro. This study was perfomed to investigate the effect of carvedilol on the secondary damage in experimental spinal cord injury (SCI). MATERIAL AND METHODS: Twenty-four Wistar albino rats were divided into three groups. Group 1 underwent laminectomy alone. Group 2 underwent laminectomy followed by SCI and received carvedilol. Group 3 underwent laminectomy followed by SCI and received no medication. The neurological functions were assessed by Tarlov's motor scale at the first and 24th hours. Oxidative stress status was assessed by MDA, SOD, MPO, GSH activities. A TUNEL-based apoptosis kit was used for evaluating apoptosis in the spinal cord samples and hematoxylinand eosin-stained specimens were used for light microscopic examination. RESULTS: Carvedilol reduced apoptosis and regulated oxidant and antioxidant status by increasing SOD and GSH levels and reducing MPO and MDA levels in the spinal tissue homogenate. Neurological examination of rats revealed statistically significant improvement 24 hours after the trauma. CONCLUSION: Carvedilol has a statistically significant therapeutic effect, especially on functional recovery, and we found that carvedilol reduced secondary damage by inhibiting apoptosis and regulating the oxidant and antioxidant status. PMID- 26617145 TI - Metastatic Adenocarcinoma of Unknown Primary in the Bilateral Cerebellopontine Angles: Case Report and Review of the Literature. AB - Metastatic adenocarcinoma in bilateral cerebellopontine angles (CPA) is rare. We report a case and review the current literature in order to enhance recognition of metastatic adenocarcinoma in the cerebellopontine angle. A 44-year-old man was referred to the hospital with rightsided diminished hearing for 7 weeks, left sided facial palsy for 2 weeks, and left-sided sensorineural hearing loss for 1 week. On Magnetic Resonance Imaging (MRI) two tumors in bilateral CPAs were detected. The left-sided tumor was resected and histopathological examination revealed an adenocarcinoma. Many investigations could not find the primary tumor. One should be careful with middle-aged or elderly patients with sudden progressive deficits in the VIII < sup > th < /sup > or VII < sup > th < /sup > cranial nerves, particularly in bilateral CPA. PMID- 26617146 TI - Intradural Cement Leakage After Percutaneous Vertebroplasty. AB - Intradural cement leakage after percutaneous vertebroplasty (PV) is a rare clinical picture. We report a 64-year-old woman with osteoporotic compression fracture of the L2 vertebral body developing monoparesis and monoparesthesia after PV. The diagnosis of intradural cement collection with spinal cord damage was evidenced by clinical and neuroradiographic investigation. After decompressive surgery, the patient showed gradual improvement. This report highlights the postulated mechanism of intradural cement collection after PV and advocates some intraoperative skills to avoid this complication. In order to get a satisfactory clinical outcome, we suggest early decompressive surgery for those patients having symptomatic intradural cement leakage after PV. PMID- 26617147 TI - Cervical Primary Ewing's Sarcoma in Intradural and Extramedullary Location and Skip Metastasis to Cauda Equina. AB - Ewing's Sarcoma (ES) is a rare malignant tumor that commonly arises from skeletal bone but rarely has an extraskeletal origin. Intradural ES is rare in childhood and adulthood. Intradural metastasis is very rarely encountered in clinical observations. There are only two reports of intradural ES skip metastasis in the literature to date. Here we present the case of a 39-year-old female who was admitted to our hospital with complaints of left upper limb pain and numbness for one year. Cervical magnetic resonance imaging showed a C4-C6 primary intradural and extramedullary Ewing's sarcoma. Skip metastasis to cauda equina was observed three years following the first surgery and chemoradiotherapy. PMID- 26617148 TI - Macrocerebellum: Volumetric and Diffusion Tensor Imaging Analysis. AB - Macrocerebellum is a rare entity characterized by an enlarged cerebellum. We describe a case of a 48-month-old child with macrocerebellum. We performed serial volumetric analysis [total brain volume (TBV) and cerebellar volume] over a period of 4 years. We analyzed the white matter microstructure in the cerebellum using diffusion tensor imaging (DTI). In our patient, we found higher fractional anisotropy (FA) and lower mean diffusivity (MD) in the cerebellar white matter compared to age-matched controls. Our results may represent accelerated myelination secondary to the abnormal cerebellar development. PMID- 26617149 TI - Tophaceous Gout of the Lumbar Spine: Case Report and Review of the Literature. AB - Tophaceous gout has classically been described as an affliction of the extremities. It has however been reported as early as 1947 to involve the spinal column. We report a 63-year-old male, previously scheduled for Anterior Cervical Discectomy and Fusion to correct an existing cervical myelopathy at the C3-C4 spinal level, who presented to the emergency room with progressive weakness of the lower extremities and inability to ambulate for three days. Physical examination suggested a possible worsening of his cervical myelopathy but magnetic resonance imaging (MRI) findings remained unchanged from comparison studies. On the day of surgery, he became febrile and complained of excruciating back pain and we therefore initiated an infectious etiology workup and obtained a lumbar spine MRI. Results of imaging suggested a lumbar epidural abscess with effacement of the thecal sac. Emergent L4-L5 decompression led to an evacuation of a "chalky" substance, which was sent for pathology evaluation. This patient was diagnosed with tophaceous gout of the lumbar spine upon final pathological review. We aim to present the management of this case and review the literature associated with this diagnosis with the goal of improving the approach taken to diagnose and treat this pathology. PMID- 26617150 TI - Cerebral Hemodynamic Evaluation of Parent Artery Occlusion for Giant Intracranial Aneurysm in Patients who Tolerated Balloon Test Occlusion: Two Case Reports. AB - Parent artery occlusion is an effective treatment for giant intracranial aneurysms that cannot be clipped directly by surgery in patients who tolerate balloon test occlusion. However, concern remains that impaired hemodynamics after parent artery occlusion may cause delayed ischemic events in the ipsilateral hemisphere. We used computed tomography perfusion studies to evaluate the cerebral hemodynamics before and after parent artery occlusion in two patients with giant intracranial aneurysms who tolerated balloon test occlusion. In the first case, significant vortex flow in the aneurysm cavity prevented distal vascular engorgement and caused severe ischemic changes. After parent artery occlusion, the vortex flow was eliminated, circle of Willis compensatory flow was restored, and cerebral hemodynamics were significantly improved. In the second case, cerebral hemodynamics were normal on preoperative computed tomography perfusion. After parent artery occlusion, the time-to-peak was prolonged in the cerebral hemisphere on the occluded side compared with the contralateral hemisphere. PMID- 26617151 TI - Endovascular Stenting of an Extracranial-Intracranial Bypass Stenosis: A Technical Note. AB - The use of an extracranial-intracranial (EC-IC) bypass has been a choice to improve the safety of parent vessel occlusion during the management of aneurysm. However, the prognosis and subsequent patency of bypass graft are variable and have seldom been managed by endovascular treatment. A 38-year-old gentleman presented to our hospital with intermittent headache. Subarachnoid hemorrhage caused by an internal carotid artery aneurysm was disclosed on the subsequent examination. He received an EC-IC bypass later. However, graft stenosis was found during follow-up. To solve the stenosis, an endovascular stent was inserted by us. There is seldom report of endovascular treatment of the graft. Here we share our experience under such circumstances. PMID- 26617152 TI - Malignant Peripheral Nerve Sheath Tumor Manifesting as Severe Buttock Pain. AB - A 28-year-old woman presented with complaints of severe buttock pain exacerbating for 2 weeks. Physical examination found numerous cafe-au-lait macules and axillary freckles. Neurological examination revealed sensory loss at the S3-S5 dermatome and significant vesicorectal dysfunction. Magnetic resonance imaging revealed an enhanced intraspinal mass at S1-S2, with bony erosion on the dorsal aspect of the sacrum. Intraoperatively, the rostral part of the tumor was found to involve a filament of the cauda equina. The tumor protruded extraspinally through an irregular-shaped defect in the dorsal dura and bony erosion. Total resection was achieved. The histological appearance was consistent with malignant peripheral nerve sheath tumor and loss of neurofibromin. Malignant peripheral nerve sheath tumor should be included in the differential diagnosis of spinal tumor in a patient with neurofibromatosis type 1. PMID- 26617153 TI - Foramen Magnum Dural Arteriovenous Fistula Treated by a Microsurgical Technique Combined with a Feeder Occlusion Using Transarterial Coil Embolization. AB - The treatment of dural arteriovenous fistulas (DAVFs) at the foramen magnum remains controversial by reason that DAVFs appearing from the foramen magnum represent only a minority of spinal DAVFs. We present our treatment for an asymptomatic patient suffering from a foramen magnum DAVF. A 53-year-old man presented to our hospital with the complaint of a floating sensation. Although there was no subarachnoid hemorrhage or cerebral infarction on magnetic resonance imaging, a magnetic resonance angiography revealed a number of dilated veins and a large varix surrounding the medulla oblongata. Cerebral digital subtraction angiography (DSA) showed a foramen magnum DAVF fed by the neuromeningeal branch of the left ascending pharyngeal artery and occipital artery, draining into the posterior spinal vein. Occlusion of the fistula was achieved by a microsurgical technique combined with a feeder occlusion using transarterial coil embolization, without complications. We verified the complete occlusion on post-operative cerebral DSA. While this combined therapy was already established for the treatment of DAVFs, there were no reports of the combined therapy for foramen magnum DAVFs. This treatment was considered to be useful for foramen magnum DAVFs, especially those DAVFs at the foramen magnum with a number of dilated veins and a large varix. PMID- 26617155 TI - Cerebral Venous Sinus Thrombosis with Internal Jugular Venous Thrombosis in a Male Patient with Nephrotic Syndrome. AB - Cerebral venous sinus thrombosis with internal jugular vein thrombosis is not reported as a complication in nephrotic syndrome. We report a 40-year-old male with nephrotic syndrome, who had headache during his hospitalization. Conventional diagnostic tests showed extensive thrombosis at the proximal part of superior sagittal sinus, left cortical vein, left sigmoid-transverse sinus and left internal jugular vein. The patient underwent medical treatment and was discharged in good health after 2 weeks. The aim of this study is to report a novel case of cerebral venous sinus thrombosis with internal jugular venous thrombosis in a male patient with nephrotic syndrome. PMID- 26617154 TI - Intrasellar Clear Cell Meningioma Mimicking Invasive Pituitary Adenoma: A Case Report and Review of the Literature. AB - The authors report on a 55-year-old man with complaints of intermittent pulsatile headache for 6 months, vision loss of the right eye and diplopia for 2 months. A magnetic resonance image (MRI) showed a large heterogeneously enhanced intrasellar mass lesion, occupying the entire hypophyseal fossa and extending into the sphenoid sinus. The patient underwent microscopic transsphenoidal surgery for removal of the tumor. Microscopic examination with hematoxylin&eosin and immunohistochemical staining of the tumor specimen was performed and confirmed the diagnosis of clear cell meningioma (CCM). Though postoperative MRI indicated gross total resection of the tumor, rapid recurrence was detected at 4 months after surgery. Gamma knife radiotherapy was administered. To the authors' knowledge, the present case is the first case of transsphenoidal removal of CCM. We reviewed the current literature on this rare histological type of meningioma in the sellar region. PMID- 26617156 TI - Solitary Fibrous Tumor of the Orbit: A Case Report and Review of the Literature. AB - Solitary fibrous tumor (SFT) is a rare, benign, spindle cell tumor that is most commonly found in the visceral pleura. The orbit is one of the most common extrapleural sites of occurrence. Though they can be seen in any age, they typically present in adults with proptosis as the prominent symptom. They show no significant gender predominance. Orbital solitary fibrous tumors routinely exhibit a benign course, but malignant forms with an increased propensity for local recurrence have been reported. Histopathologically, they share similar features with hemangiopericytoma, which is much more common. The diagnosis of SFT depends on the diffuse and intense positivity of CD34 staining by immunohistochemistry (14). Here, we report a case of SFT, which presented with proptosis and double vision on lateral gaze. We describe the clinical, radiographic, histopathological, and immunohistochemical findings. We also provide a discussion on its origin and differential diagnosis in the light of relevant literature. PMID- 26617157 TI - Morphological differences in adipose tissue and changes in BDNF/Trkb expression in brain and gut of a diet induced obese zebrafish model. AB - Obesity is a multifactorial disease generated by an alteration in balance between energy intake and expenditure, also dependent on genetic and non-genetic factors. Moreover, various nuclei of the hypothalamus receive and process peripheral stimuli from the gastrointestinal tract, controlling food intake and therefore energy balance. Among anorexigenic molecules, brain-derived neurotrophic factor (BDNF) acts through the tyrosine-kinase receptor TrkB. Numerous data demonstrate that the BDNF/TrkB system has a fundamental role in the control of food intake and body weight. Quantitative PCR and immunohistochemistry for both BDNF and TrkB were used to determine changes in levels in the brain and gastro-intestinal tract of an experimental zebrafish model of diet-induced obesity. Overfed animals showed increased weight and body mass index as well as accumulation of adipose tissue in the visceral, subcutaneous and hepatic areas. These changes were concomitant with decreased levels of BDNF mRNA in the gastro-intestinal tract and increased expression of TrkB mRNA in the brain. Overfeeding did not change the density of cells displaying immunoreactivity for BDNF or TrkB in the brain although both were significantly diminished in the gastro-intestinal tract. These results suggest an involvement of the BDNF/TrkB system in the regulation of food intake and energy balance in zebrafish, as in mammals. PMID- 26617158 TI - Multiple gingival recession coverage with an allogeneic biostatic fascia lata graft using the tunnel technique--A histological assessment. AB - BACKGROUND: Autogenous connective tissue graft (CTG) that can be safely harvested from the palatal mucosa is limited. Often a multi-stage surgical procedure is needed to cover multiple gingival recessions (MGR). To address this problem, efforts are being made to explore substitutes suitable in size to ensure surgical treatment in a single visit.The objective of the present study was the histological evaluation of tissue in the recipient site after augmentation with a hydrated biostatic Fascia Lata Allograft (FLA) in conjunction with MGR coverage at different healing stages. MATERIAL AND METHODS: Twelve patients needing bilateral multiple gingival recession coverage participated in this study. On the test side, the tunnel technique with FLA was used, while CTG, harvested from the palatal mucosa, was used to cover MGR on the control side. Histological assessment was performed 3, 6, 9 and 12 months after augmentation. RESULTS: FLA was well tolerated by the host tissue. During all investigation periods histological images of all patients in the test side revealed a slow process of incorporation of the material grafted in the host connective tissue, showing a colonization of the graft with host fibroblasts and formation of new blood vessels. After 12 months, the graft had fully remodeled into connective tissue of the host gingiva. CONCLUSION: Apart from the limitations of the present study, we conclude that the FLA may serve as a substitute for autogenous CTG harvested from the palatal mucosa and can be applied as a technique for covering MGR in a single visit. PMID- 26617159 TI - The morphological substrate for Renal Denervation: Nerve distribution patterns and parasympathetic nerves. A post-mortem histological study. AB - BACKGROUND: Renal Denervation as a possible treatment for hypertension has been studied extensively, but knowledge on the distribution of nerves surrounding the renal artery is still incomplete. While sympathetic and sensory nerves have been demonstrated, there is no mention of the presence of parasympathetic nerve fibers. OBJECTIVES: To provide a description of the distribution patterns of the renal nerves in man, and, in addition, provide a detailed representation of the relative contribution of the sympathetic, parasympathetic and afferent divisions of the autonomic nervous system. METHODS: Renal arteries of human cadavers were each divided into four longitudinal segments and immunohistochemically stained with specific markers for afferent, parasympathetic and sympathetic nerves. Nerve fibers were semi-automatically quantified by computerized image analysis, and expressed as cross-sectional area relative to the distance to the lumen. RESULTS: A total of 3372 nerve segments were identified in 8 arteries of 7 cadavers. Sympathetic, parasympathetic and afferent nerves contributed for 73.5% (95% CI: 65.4-81.5%), 17.9% (10.7-25.1%) and 8.7% (5.0-12.3%) of the total cross-sectional nerve area, respectively. Nerves are closer to the lumen in more distal segments and larger bundles that presumably innervate the kidney lie at 1-3.5mm distance from the lumen. The tissue-penetration depth of the ablation required to destroy 50% of the nerve fibers is 2.37 mm in the proximal segment and 1.78 mm in the most distal segments. CONCLUSION: Sympathetic, parasympathetic and afferent nerves exist in the vicinity of the renal artery. The results warrant further investigation of the role of the parasympathetic nervous system on renal physiology, and may contribute to refinement of the procedure by focusing the ablation on the most distal segment. PMID- 26617160 TI - Cocaine- and amphetamine-regulated transcript and calcium binding proteins immunoreactivity in the subicular complex of the guinea pig. AB - In this study we present the distribution and colocalization pattern of cocaine- and amphetamine-regulated transcript (CART) and three calcium-binding proteins: calbindin (CB), calretinin (CR) and parvalbumin (PV) in the subicular complex (SC) of the guinea pig. The subiculum (S) and presubiculum (PrS) showed higher CART-immunoreactivity (-IR) than the parasubiculum (PaS) as far as the perikarya and neuropil were concerned. CART- IR cells were mainly observed in the pyramidal layer and occasionally in the molecular layer of the S. In the PrS and PaS, single CART-IR perikarya were dispersed, however with a tendency to be found only in superficial layers. CART-IR fibers were observed throughout the entire guinea pig subicular neuropil. Double-labeling immunofluorescence showed that CART-IR perikarya, as well as fibers, did not stain positively for any of the three CaBPs. CART-IR fibers were only located near the CB-, CR-, PV-IR perikarya, whereas CART-IR fibers occasionally intersected fibers containing one of the three CaBPs. The distribution pattern of CART was more similar to that of CB and CR than to that of PV. In the PrS, the CART, CB and CR immunoreactivity showed a laminar distribution pattern. In the case of the PV, this distribution pattern in the PrS was much less prominent than that of CART, CB and CR. We conclude that a heterogeneous distribution of the CART and CaBPs in the guinea pig SC is in keeping with findings from other mammals, however species specific differences have been observed. PMID- 26617161 TI - Chemical Pathways Connecting Lead(II) Iodide and Perovskite via Polymeric Plumbate(II) Fiber. AB - Despite tremendous progress in optoelectronic devices using lead perovskite (CH3NH3(+)PbI3(-)), there has been a paucity of mechanistic information on how photoactive micron-sized crystals of lead perovskite grow from a mixture of a layered crystal of lead(II) iodide and methylammonium iodide mediated by a polar solvent, DMSO or DMF. We report here that the whole process of the lead perovskite synthesis consists of a series of equilibria driven by reversible solvent participation involving a polymeric strip of plumbate(II) oligomer as a key intermediate. A significant finding includes quick decomposition of perovskite crystal upon exposure to DMSO or DMF at room temperature, where the solvent molecules act as a base to remove acidic ammonium iodide from the perovskite crystal. This observation accounts for the difficulty in controlling perovskite solar cell fabrication. Overall, the polar solvent is indispensible first to degrade a 2-D sheet of crystals of lead(II) iodide into 1-D fibrous intermediates and then to promote Oswald ripening of perovskite crystals. The detailed chemical information provided here will help to rationalize the photovoltaic device studies that have so far remained empirical and to open a new venue to a developing field of microscale lead perovskite devices, as illustrated by fabrication of photovoltaic devices and photodetectors. PMID- 26617162 TI - Outcomes of hepatitis B surface antigenaemia in patients with incident end-stage renal disease. AB - AIM: Hepatitis B virus (HBV) infection is an important risk factor for morbidity and mortality in the general population. However, limited data are available on the progression of HBV infection in patients with end-stage renal disease (ESRD), and available data are controversial. Therefore, we investigated the association between hepatitis B surface antigen (HBsAg) seropositivity and mortality in patients with incident ESRD. METHODS: All adult patients (>=18 years of age) starting dialysis for ESRD from January 2000 to December 2011 were included. A total of 1090 patients with ESRD were analyzed. HBsAg-positive patients were paired 1:6 with HBsAg-negative patients using propensity score matching. RESULTS: Eighty one (7.4%) patients were HBsAg positive. No differences in the survival rates of the HBsAg-positive and HBsAg-negative patients with ESRD were detected in either the entire cohort or the propensity score matched cohort. No differences in survival were detected between the groups of HBsAg-positive patients based on the hepatitis B envelope antigen, hepatitis B envelope antibody, HBV DNA status, or use of antiviral agents. No difference in mortality was found between the haemodialysis (HD) and peritoneal dialysis (PD) subgroups among HBsAg-positive patients. CONCLUSION: Our results suggest that hepatitis B surface antigenaemia is not related to increased mortality in patients with incident ESRD. Survival of HBsAg-positive patients undergoing PD was comparable to that of patients undergoing HD. PMID- 26617163 TI - The marine bacteria Shewanella frigidimarina NCIMB400 upregulates the type VI secretion system during early biofilm formation. AB - Shewanella sp. are facultative anaerobic Gram-negative bacteria, extensively studied for their electron transfer ability. Shewanella frigidimarina has been detected and isolated from marine environments, and in particular, from biofilms. However, its ability to adhere to surfaces and form a biofilm is poorly understood. In this study, we show that the ability to adhere and to form a biofilm of S. frigidimarina NCIMB400 is significantly higher than that of Shewanella oneidensis in our conditions. We also show that this strain forms a biofilm in artificial seawater, whereas in Luria-Bertani, this capacity is reduced. To identify proteins involved in early biofilm formation, a proteomic analysis of sessile versus planktonic membrane-enriched fractions allowed the identification of several components of the same type VI secretion system gene cluster: putative Hcp1 and ImpB proteins as well as a forkhead-associated domain containing protein. The upregulation of Hcp1 a marker of active translocation has been confirmed using quantitative reverse transcription polymerase chain reaction. Our data demonstrated the presence of a single and complete type VI secretion system in S. frigidimarina NCIMB400 genome, upregulated in sessile compared with planktonic conditions. The fact that three proteins including the secreted protein Hcp1 have been identified may suggest that this type VI secretion system is functional. PMID- 26617164 TI - Bifunctional Furfuryl Cations Strategy: Three-Component Synthesis of Enamidyl Triazoles. AB - A new multicomponent synthesis of functionalized enamidyl triazoles starting from simple and readily available starting materials is described. A simple treatment of a dichloromethane solution of an azide, amine, and 5-bromo-2-furylcarbinol with a Lewis acid provides the enamidyl triazole in good to high yield. A triple domino sequence, formal [3+2] cycloaddition/ring-opening/amidation, is involved in this new skeleton-generating reaction. PMID- 26617165 TI - [In Process Citation]. PMID- 26617166 TI - [In Process Citation]. PMID- 26617167 TI - [In Process Citation]. PMID- 26617168 TI - [Post-partum posterior reversible encephalopathy syndrome]. AB - Posterior reversible encephalopathy syndrome (PRES) is a complex clinical condition with vasogenic subcortical oedema caused by hypertension. Oedema is often seen on magnetic resonance imaging. The wide clinical spectrum ranges from headaches to vision loss and even death. Early diagnosis and treatment is important for the reversibility of the condition. In this case report we emphasize the importance of blood pressure control in a post-partum woman, who had a rather complicated pregnancy. The symptoms of PRES were not recognized immediately because of failure to use and acknowledge a blood pressure test. PMID- 26617169 TI - [Cirrhosis and liver fibrosis are potentially reversible]. AB - Cirrhosis is the end result of most chronic liver diseases. Contrary to the general view of liver fibrosis and cirrhosis being irreversible, recent findings have revealed that liver fibrosis can decrease if the cause(s) for the fibrosis formation can be weakened or eliminated. Thus, liver fibrosis and cirrhosis are potentially reversible. This paper reviews current evidence of reversibility in cirrhosis of varying aetiology and the consequence for therapeutic strategies. PMID- 26617170 TI - [Breast implant-associated anaplastic large-cell lymphoma]. AB - Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare entity. Due to the lack of awareness of BIA-ALCL, patients with prior history of breast implants who present with non-specific implant-related complications might experience a delay in diagnosis and appropriate treatment of this distinct condition. There are still no evidence-based guidelines on how this condition should be diagnosed, treated or followed because of the rarity of available data. We review current literature in order to raise awareness and discuss management options of this unique clinical entity. PMID- 26617171 TI - [Misophonia is a neglected disorder]. AB - A 14-year-old girl, who was diagnosed with OCD when she was 11-year-old, experienced emotional reactions and autonomic arousal in response to specific human-made sounds. At first she thought that these symptoms were part of her OCD, but it became clear to her that she suffered from misophonia - a disorder not yet classified. PMID- 26617172 TI - [The patient's team and the responsible doctor as a condition for efficient patient courses]. AB - In the healthcare system in The North Denmark Region the patient's team has been implemented in order to create and ensure efficient patient courses. Each patient has his or her own team, which is responsible for the entire patient course. As part of the team there is one doctor, who has the ultimate responsibility for the patient's treatment and pathway within the healthcare system. The patient's team is implemented in 2015-2017 in the healthcare system in The North Denmark Region. PMID- 26617173 TI - [Post-exposure prophylaxis against measles]. AB - This review article deals with the newest guidelines in post-exposure prophylaxis against measles and puts forward recommendations on how this prophylaxis should be handled with regards to children in all ages, both immunosuppressed and competent. PMID- 26617174 TI - Assessment of Short-term Blood Pressure Variability in Patients With Ascending Aortic Dilatation. AB - BACKGROUND: Blood pressure variability (BPV) is a novel parameter related to adverse cardiovascular findings and events, especially in hypertensive patients. The aim of the present study was to investigate the relationship between short term BPV and ascending aortic dilatation (AAD). HYPOTHESIS: Hypertensive patients with AAD may exhibit higher short-term BPV compared to hypertensive patients with normal diameter ascending aorta and BPV may be correlated with aortic sizes. METHODS: Seventy-six hypertensive patients with AAD and 181 hypertensive patients with a normal-diameter ascending aorta were retrospectively enrolled in the study. Clinical data, echocardiographic characteristics, and 24-hour ambulatory blood pressure monitoring characteristics were compared between the 2 groups. Standard deviation (SD) and Delta of BP were used as parameters of BPV. RESULTS: Although 24-hour mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) were similar between the 2 groups, the SD of SBP and SD of DBP values were significantly higher in AAD patients (17.2 +/- 6.8 vs 13.8 +/- 3.5, P < 0.01; and 12.1 +/- 5.1 vs 10.7 +/- 3.1, P = 0.02, respectively). Daytime SD of SBP values were higher in AAD patients, whereas nighttime SD of SBP values did not differ between groups. In multivariate linear regression analysis, 24-hour SD of SBP, 24 hour Delta SBP, daytime SD of SBP, daytime Delta SBP, and left ventricular mass index were independently correlated with aortic size index. CONCLUSIONS: Our study revealed higher levels of short-term BPV in hypertensive patients with AAD. This conclusion warrants further study. PMID- 26617175 TI - Implication of Left Bundle Branch Block-Related Cardiac Memory in the Initiation of Torsades de Pointes. PMID- 26617176 TI - Progressive multifocal leukoencephalopathy in an immunocompetent patient. PMID- 26617177 TI - CCR6(+) Th cell populations distinguish ACPA positive from ACPA negative rheumatoid arthritis. AB - INTRODUCTION: Patients with rheumatoid arthritis (RA) can be separated into two major subpopulations based on the absence or presence of serum anti-citrullinated protein antibodies (ACPAs). The more severe disease course in ACPA(+) RA and differences in treatment outcome between these subpopulations suggest that ACPA(+) and ACPA(-) RA are different disease subsets. The identification of T helper (Th) cells specifically recognizing citrullinated peptides, combined with the strong association between HLA-DRB1 and ACPA positivity, point toward a pathogenic role of Th cells in ACPA(+) RA. In this context we recently identified a potential pathogenic role for CCR6(+) Th cells in RA. Therefore, we examined whether Th cell population distributions differ by ACPA status. METHODS: We performed a nested matched case-control study including 27 ACPA(+) and 27 ACPA(-) treatment-naive early RA patients matched for disease activity score in 44 joints, presence of rheumatoid factor, sex, age, duration of complaints and presence of erosions. CD4(+)CD45RO(+) (memory) Th cell distribution profiles from these patients were generated based on differential chemokine receptor expression and related with disease duration. RESULTS: ACPA status was not related to differences in total CD4(+) T cell or memory Th cell proportions. However, ACPA(+) patients had significantly higher proportions of Th cells expressing the chemokine receptors CCR6 and CXCR3. Similar proportions of CCR4(+) and CCR10(+) Th cells were found. Within the CCR6(+) cell population, four Th subpopulations were distinguished based on differential chemokine receptor expression: Th17 (CCR4(+)CCR10(-)), Th17.1 (CXCR3(+)), Th22 (CCR4(+)CCR10(+)) and CCR4/CXCR3 double-positive (DP) cells. In particular, higher proportions of Th22 (p = 0.02), Th17.1 (p = 0.03) and CCR4/CXCR3 DP (p = 0.01) cells were present in ACPA(+) patients. In contrast, ACPA status was not associated with differences in Th1 (CCR6(-)CXCR3(+); p = 0.90), Th2 (CCR6(-)CCR4(+); p = 0.27) and T-regulatory (CD25(hi)FOXP3(+); p = 0.06) cell proportions. Interestingly, CCR6(+) Th cells were inversely correlated with disease duration in ACPA(-) patients (R(2) = 0.35; p < 0.01) but not in ACPA(+) (R(2) < 0.01; p = 0.94) patients. CONCLUSIONS: These findings demonstrate that increased peripheral blood CCR6(+) Th cells proportions distinguish ACPA(+) RA from ACPA(-) RA. This suggests that CCR6(+) Th cells are involved in the differences in disease severity and treatment outcome between ACPA(+) and ACPA(-) RA. PMID- 26617178 TI - Optical coherence tomography angiography in patients with polypoidal choroidal vasculopathy. AB - PURPOSE: To report the characteristics of polypoidal choroidal vasculopathy (PCV) based on optical coherence tomography angiography (OCTA) results. METHOD: A retrospective, cross-sectional case series was conducted. Patients treated for PCV were evaluated with the OCTA system. The OCTA images of these patients were compared with those from indocyanine green angiography (ICGA). All eyes of consecutive patients with PCV were included. RESULTS: The mean age of the patients (five men and two women) was 67.86 +/- 14.02 years. The mean number of anti-vascular endothelial growth factor injections was 10.43 +/- 10.01. OCTA demonstrated branched vascular networks, which were detected by ICGA; however, polyps were not revealed consistently by OCTA. A total of 24 polyps were detected in seven eyes from seven patients by hyper-fluorescence on ICGA. However, only 12 polyps (50 %) were hyper-reflective on OCTA. CONCLUSION: PCV polyps were not detected as consistently by OCTA as by ICGA. This suggests that the polyps were detected differently by OCTA depending on blood flow in the polyp. PMID- 26617179 TI - Lack of effect of nitroglycerin on the diameter response of larger retinal arterioles in normal persons during hypoxia. AB - PURPOSE: Retinal hypoxia with consequent changes in blood flow play a role in a number of vision-threatening diseases, such as diabetic retinopathy. Previous studies have shown that the inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX) products are involved in the diameter regulation of the retinal vessels during hypoxia. Therefore, the aim of the present study was to examine the effects of an NO donor combined with COX inhibition on the diameter regulation of retinal vessels during hypoxia in normal persons. METHODS: Twenty normal persons aged 21-47 years were examined. The Dynamic Vessel Analyzer (DVA) was used to measure retinal vessel diameters at rest, during isometric exercise, and during flicker stimulation. The measurements were performed during normoxia and hypoxia before and after sublingual administration of the NO donor nitroglycerin, and were repeated on a second study day after topical administration of the COX-inhibitor diclofenac. RESULTS: The resting diameter of arterioles and venules increased significantly during hypoxia (p < 0.0001). Hypoxia also significantly reduced the arteriolar constriction during isometric exercise, and the dilatation of the arterioles and venules during flicker stimulation (p < 0.0001). Diclofenac further reduced the arteriolar constriction induced by isometric exercise during hypoxia (p = 0.005). However, the NO-donor nitroglycerin had no effect on vascular diameters. CONCLUSION: Diameter regulation of retinal vessels during hypoxia in normal persons can be influenced by the inhibition of COX products, but not by increasing the NO concentration. The findings suggest that the vasoactive effects of NO on retinal arterioles during hypoxia are saturated in normal persons. PMID- 26617180 TI - Systemic treatments in childhood psoriasis: a French multicentre study on 154 children. PMID- 26617181 TI - How Do Scores on the ADAS-Cog, MMSE, and CDR-SOB Correspond? AB - OBJECTIVE: Clinicians and researchers who measure cognitive dysfunction often use the Alzheimer's Disease Assessment Scale--Cognitive Subscale (ADAS-Cog), the Mini Mental State Examination (MMSE), or the Clinical Dementia Rating scale (CDR-SOB). But, the use of different measures can make it difficult to compare data across patients or studies. What is needed is a simple chart that shows how scores on these three important measures correspond to each other. METHODS: Using data from 1709 participants from the Alzheimer's Disease Neuroimaging Initiative and item response theory-based statistics, we analyzed how scores on each measure, the ADAS-Cog, the MMSE, and the CDR-SOB, correspond. RESULTS: Results indicated multiple inflections in CDR-SOB and ADAS-Cog scores within a given MMSE score, suggesting that the CDR-SOB and ADAS-Cog are more precise in measuring the severity of cognitive dysfunction than the MMSE. CONCLUSIONS: This study shows how scores on these three popular measures of cognitive dysfunction correspond to each other, which is very useful information for both researchers and clinicians. PMID- 26617182 TI - Delayed onset of electromyographic activity of the vastus medialis relative to the vastus lateralis may be related to physical activity levels in females with patellofemoral pain. AB - The aims of this study were to examine group differences in muscle activation onset of the vastus medialis (VM) in relation to the vastus lateralis (VL) and pain level during stair ascent in females with patellofemoral pain (PFP) who maintain high and moderate levels of physical activity; to determine the association between physical activity level and muscle activation onset. Forty three females with PFP and thirty-eight pain-free females were recruited and divided into four groups based on their level of physical activity: females with PFP (n=26) and pain-free females (n=26) who practiced a moderate level of physical activity and females with PFP (n=17) and pain-free females (n=12) who practiced an intense amount of physical activity. Participants were asked to ascend a seven-step staircase and the VM and VL activation onset was determined. Females with PFP who practiced high level of physical activity demonstrated delayed onset of VM (4.06ms) compared to healthy females (-14.4ms). Conversely, females with PFP who practiced moderate level of physical activity did not present VM delay (-2.48ms) in comparison to healthy females (-9.89ms). Furthermore, physical activity significantly correlated to the muscle activation onset difference (p=0.005; R=0.60). These findings may explain why controversial results regarding VM and VL muscle activation onset have been found. PMID- 26617183 TI - Lactobacillus rhamnosus GG supernatant promotes intestinal barrier function, balances Treg and TH17 cells and ameliorates hepatic injury in a mouse model of chronic-binge alcohol feeding. AB - Impaired intestinal barrier function plays a critical role in alcohol-induced hepatic injury, and the subsequent excessive absorbed endotoxin and bacterial translocation activate the immune response that aggravates the liver injury. Lactobacillus rhamnosus GG supernatant (LGG-s) has been suggested to improve intestinal barrier function and alleviate the liver injury induced by chronic and binge alcohol consumption, but the underlying mechanisms are still not clear. In this study, chronic-binge alcohol fed model was used to determine the effects of LGG-s on the prevention of alcoholic liver disease in C57BL/6 mice and investigate underlying mechanisms. Mice were fed Lieber-DeCarli diet containing 5% alcohol for 10 days, and one dose of alcohol was gavaged on Day 11. In one group, LGG-s was supplemented along with alcohol. Control mice were fed isocaloric diet. Nine hours later the mice were sacrificed for analysis. Chronic binge alcohol exposure induced an elevation in liver enzymes, steatosis and morphology changes, while LGG-s supplementation attenuated these changes. Treatment with LGG-s significantly improved intestinal barrier function reflected by increased mRNA expression of tight junction (TJ) proteins and villus-crypt histology in ileum, and decreased Escherichia coli (E. coli) protein level in liver. Importantly, flow cytometry analysis showed that alcohol reduced Treg cell population while increased TH17 cell population as well as IL-17 secretion, which was reversed by LGG-s administration. In conclusion, our findings indicate that LGG-s is effective in preventing chronic-binge alcohol exposure-induced liver injury and shed a light on the importance of the balance of Treg and TH17 cells in the role of LGG-s application. PMID- 26617185 TI - Resources for Building a Diverse and Culturally Competent Workforce in the Dietetics Profession. PMID- 26617184 TI - Toxicity of nanosilver in intragastric studies: Biodistribution and metabolic effects. AB - The unique physicochemical properties of silver nanoparticles explain their extensive application in consumer goods, food, and medicinal products. However, the biological effects of nanosilver after peroral exposure of mammals are still debatable. This study describes the biodistribution and biological action of 12nm non-coated silver nanoparticles intragastrically administered to male rats after acute (single exposure) and sub-acute (multiple exposures over 30 days) toxicity experiments. The daily doses were 2000 and 250mg/kg of body weight for single and multiple administrations, respectively. Silver tissue detection was conducted by elemental analysis with the help of atomic absorption spectroscopy. An estimation of the state of exposed animals was made and the dynamics of hematological and biochemical parameters of rats was studied. It was demonstrated that single and multiple administrations resulted in silver accumulation in the liver, kidneys, spleen, stomach, and small intestine. After both one- and repeated-dose exposures, the highest Ag contents were detected in the liver (0.87+/-0.37MUg/g of organ) and kidneys (0.24+/-0.02MUg/g of organ). The concentrations of silver detected in tissues were far smaller than the administered doses (<99%), indicating its efficient excretion from the organism. Acute and sub-acute exposures caused no animal mortality or signs of toxicity, manifested as changes in outward appearance or notable deviations in behavior or locomotor activity. Postmortem study revealed no visible pathomorphological abnormalities of internal organs. Hematological indices and biochemical parameters of the treated rats did not differ from those of the vehicle control animals. Overall, it can be concluded that nanosilver is able to be absorbed from the gastrointestinal tract into the bloodstream and accumulate in the secondary organs of rats. It showed no distinct toxicity under the experimental conditions of this study. PMID- 26617186 TI - Canned Vegetable and Fruit Consumption Is Associated with Changes in Nutrient Intake and Higher Diet Quality in Children and Adults: National Health and Nutrition Examination Survey 2001-2010. AB - BACKGROUND: Canned vegetables and fruit (CV+CF) are ubiquitous throughout the food supply. Yet information regarding their specific contribution to nutrient intake and health measures is lacking. OBJECTIVE: The objective of this study was to examine the association of CV+CF with nutrient intake, diet quality, anthropometric indicators of overweight/obesity, and blood pressure in a nationally representative population. DESIGN AND PARTICIPANTS: A secondary analysis of cross-sectional data from 17,344 children and 24,807 adults in the National Health and Nutrition Examination Survey 2001-2010 was conducted. A dataset was developed that distinguished CV+CF consumers from nonconsumers. MAIN OUTCOME MEASURES: Diet quality was calculated using the Healthy Eating Index 2010. STATISTICAL ANALYSES: Regression analysis determined differences between groups. RESULTS: About 11% of the population consumed CV+CF on a given day. Compared with nonconsumers, child (n=2,066) and adult (n=2,746) CV+CF consumers ate more energy, and energy adjusted dietary fiber, total sugar, choline, and potassium, and less fat and saturated fat. Child consumers also ate more energy adjusted protein, vitamin A, calcium, and magnesium. Child and adult consumers and nonconsumers had comparable energy adjusted sodium and added sugar intakes. Compared with nonconsumers, the total Healthy Eating Index 2010 score was higher (P<0.001) in child (45.8+/-0.5 vs 43.3+/-0.3) and adult (49.0+/-0.4 vs 47.4+/ 0.3) consumers. Covariate adjusted body weight, body mass index, waist circumference, and blood pressure were comparable in both of the child and adult groups. CONCLUSIONS: Results suggest CV+CF consumption was associated with higher intake of select nutrients, a higher-quality diet, and comparable adiposity measures and blood pressure. PMID- 26617187 TI - Erratum: (4Z)-4-Benzyl-idene-2-phenyl-1,3-oxazol-5(4H)-one. Corrigendum. AB - In the paper by Asiri et al. [Acta Cryst. (2012), E68, o1154], the title and the chemical name of one of the reagents used in the synthesis are corrected.[This corrects the article DOI: 10.1107/S1600536812011579.]. PMID- 26617188 TI - Clinical management of metastatic kidney cancer: the role of new molecular drugs. AB - Over the last few years, the most recent advances of the molecular mechanisms involved in renal cell carcinoma have led to the use of new drugs targeting VEGF, such as bevacizumab plus interferon, sorafenib, sunitinib, pazopanib, and axitinib, or the mTOR, such as temsirolimus and everolimus. The purpose of this review is to analyze the results of Phase III trial with these targeted agents, and on the management of the treatment and, in particular, when to start and to stop therapy and the use of alternative schedule of sunitinib. Recent developments in immunotherapy are also discussed. PMID- 26617189 TI - CeO2 nanocrystallines ensemble-on-nitrogen-doped graphene nanocomposites: one pot, rapid synthesis and excellent electrocatalytic activity for enzymatic biosensing. AB - Ceria nanomaterials for heterogeneous catalysis have attracted much attention due to their excellent properties and have been extensively applied in recent years. But the poor electron conductivity and the aggregation behavior severely affect their electrocatalytic performances. In this paper, we prepared a novel catalyst based on CeO2 nanocrystallines (CeO2 NCs) ensemble-on-nitrogen-doped graphene (CeO2-NG) nanocomposites through a one-step heat-treatment without the need of the precursor. The results confirmed that the high dispersion of CeO2 NCs with the uniform size distribution of about 5nm on the surface of nitrogen-doped graphene (NG) sheets could be easily obtained via the one-step procedure and the resultant CeO2-NG nanocomposites were an excellent electrode material possessing outstanding electrochemical features for electron transfer. Luminol, an important electroactive substance, was further chosen to inspect the electrocatalytic properties of the as-prepared CeO2-NG nanocomposites. The studies showed that the presence of the NG in CeO2-NG nanocomposites could facilitate the electrochemical redox process of luminol. Compared with pristine CeO2 NCs, the synthesized CeO2 NG nanocomposites can enhance the electrochemiluminescence (ECL) intensity by 3.3 fold and decrease the onset ECL potential for about 72mV in the neutral condition. Employing above superiority, selecting cholesterol oxidase (ChOx) as the model oxidase, a facile ECL method for cholesterol detection with the CeO2-NG nanocomposites as the matrix to immobilize enzyme ChOx was developed. The results demonstrated CeO2-NG nanocomposites exhibited excellent performances in terms of sensitivity and catalytic activities, indicating that NG-based nanomaterials have great promise in electrocatalytic and enzymatic biosensing fields. PMID- 26617190 TI - Compact Shielding of Graphene Monolayer Leads to Extraordinary SERS-Active Substrate with Large-Area Uniformity and Long-Term Stability. AB - Surface-enhanced Raman scattering (SERS) can significantly boost the inherently weak Raman scattering signal and provide detailed structural information and binding nature of the molecules on the surface. Despite the long history of this technology, SERS has yet to become a sophisticated analytical tool in practical applications. A major obstacle is the absence of high-quality and stable SERS active substrate. In this work, we report a monolayer graphene-shielded periodic metallic nanostructure as large-area uniform and long-term stable SERS substrate. The monolayer graphene acting as a corrosion barrier, not only greatly enhanced stability, but also endowed many new features to the substrate, such as alleviating the photo-induced damages and improving the detection sensitivity for certain analytes that are weakly adsorbed on the conventional metallic substrates. Besides, our fabrication strategy were also capable of fabricating the reproducible SERS sensing spots array, which may serve as a promising high throughput or multi-analyte sensing platform. Taken together, the graphene shielded SERS substrate holds great promise both in fundamental studies of the SERS effect and many practical fields. PMID- 26617191 TI - Compact Optical Fiber 3D Shape Sensor Based on a Pair of Orthogonal Tilted Fiber Bragg Gratings. AB - In this work, a compact fiber-optic 3D shape sensor consisting of two serially connected 2 degrees tilted fiber Bragg gratings (TFBGs) is proposed, where the orientations of the grating planes of the two TFBGs are orthogonal. The measurement of the reflective transmission spectrum from the pair of TFBGs was implemented by Fresnel reflection of the cleaved fiber end. The two groups of cladding mode resonances in the reflection spectrum respond differentially to bending, which allows for the unique determination of the magnitude and orientation of the bend plane (i.e. with a +/- 180 degree uncertainty). Bending responses ranging from -0.33 to + 0.21 dB/m(-1) (depending on orientation) are experimentally demonstrated with bending from 0 to 3.03 m(-1). In the third (axial) direction, the strain is obtained directly by the shift of the TFBG Bragg wavelengths with a sensitivity of 1.06 pm/MUepsilon. PMID- 26617192 TI - Antimicrobial photodynamic therapy (aPDT) induction of biofilm matrix architectural and bioadhesive modifications. AB - BACKGROUND: Dental implants are commonly used today for the treatment of partially and fully edentulous patients. Despite the high success rate they are not resistant to complications and failure due to a variety of problems including peri-implantitis or peri-mucositis due to bacterial biofilm formation on the implant surface. The use of non-surgical and surgical treatment procedure to promote healing in cases with peri-implantitis have limited efficacy. Here we studied the ability of photodynamic therapy to destroy a known bacterial pathogen and the extracellular matrix architecture of biofilm attached to titanium plates and germanium prisms. METHODS: Titanium plates or germanium prisms were incubated for 24h with Fusobacterium nucleatum a fusiform, gram-negative bacterium was used to enable biofilm formation. Photodynamic therapy was carried out by incubating the biofilm samples on each substrata with porfimer sodium. Treatment was carried out using a diode laser at 630nm, 150mW/cm(2) for light doses ranging from 25 100J/cm(2). Evaluation of killing efficacy was done by counting colony forming units compared to controls. Multiple attenuated internal reflection-infrared spectroscopy (MAIR-IR) and SEM were used to analyze the samples pre and post PDT for validation. RESULTS: F. nucleatum was significantly reduced in a dose dependent manner by treatment with PDT. Changes in biofilm components and strength of bioadhesion were examined with MAIR-IR following jet impingement using calibrated water jets. SEM demonstrates significant morphological alterations in the bacteria, consistent with damage associated with exposure to reactive oxygen species. CONCLUSION: The results are indicative that aPDT is a method that can be used to eradicate micro-organisms associated with biofilm in peri-implantitis on relevant substrata. Data shows that the slime layer of the biofilm is removed and that further methods need to be employed to completely remove weakened or destroyed biofilm matrix components. Reactive oxygen species (ROS) mediated oxidative damage results in morphologic changes as a consequence of changes in cell membrane integrity. PMID- 26617193 TI - Long-period ocean-bottom motions in the source areas of large subduction earthquakes. AB - Long-period ground motions in plain and basin areas on land can cause large scale, severe damage to structures and buildings and have been widely investigated for disaster prevention and mitigation. However, such motions in ocean-bottom areas are poorly studied because of their relative insignificance in uninhabited areas and the lack of ocean-bottom strong-motion data. Here, we report on evidence for the development of long-period (10-20 s) motions using deep ocean-bottom data. The waveforms and spectrograms demonstrate prolonged and amplified motions that are inconsistent with attenuation patterns of ground motions on land. Simulated waveforms reproducing observed ocean-bottom data demonstrate substantial contributions of thick low-velocity sediment layers to development of these motions. This development, which could affect magnitude estimates and finite fault slip modelling because of its critical period ranges on their estimations, may be common in the source areas of subduction earthquakes where thick, low-velocity sediment layers are present. PMID- 26617194 TI - trans-cis Configuration regulated supramolecular polymer gels and chirality transfer based on a bolaamphiphilic histidine and dicarboxylic acids. AB - Supramolecular polymer gels based on the co-assembly of bolaamphiphilic l histidine(BolaHis) and dicarboxylic acids are dependent on the molar ratios, flexibility and cis-trans configuration of acid molecules. Thus, oligomerized rigid cis-maleic acid or flexible trans-cyclohexane dicarboxylic acid can form chiral supramolecular polymer gels with l-BolaHis. PMID- 26617195 TI - Mortality Benefits of Antibiotic Computerised Decision Support System: Modifying Effects of Age. AB - Antibiotic computerised decision support systems (CDSSs) are shown to improve antibiotic prescribing, but evidence of beneficial patient outcomes is limited. We conducted a prospective cohort study in a 1500-bed tertiary-care hospital in Singapore, to evaluate the effectiveness of the hospital's antibiotic CDSS on patients' clinical outcomes, and the modification of these effects by patient factors. To account for clustering, we used multilevel logistic regression models. One-quarter of 1886 eligible inpatients received CDSS-recommended antibiotics. Receipt of antibiotics according to CDSS's recommendations seemed to halve mortality risk of patients (OR 0.54, 95% CI 0.26-1.10, P = 0.09). Patients aged <=65 years had greater mortality benefit (OR 0.45, 95% CI 0.20-1.00, P = 0.05) than patients that were older than 65 (OR 1.28, 95% CI 0.91-1.82, P = 0.16). No effect was observed on incidence of Clostridium difficile (OR 1.02, 95% CI 0.34-3.01), and multidrug-resistant organism (OR 1.06, 95% CI 0.42-2.71) infections. No increase in infection-related readmission (OR 1.16, 95% CI 0.48 2.79) was found in survivors. Receipt of CDSS-recommended antibiotics reduced mortality risk in patients aged 65 years or younger and did not increase the risk in older patients. Physicians should be informed of the benefits to increase their acceptance of CDSS recommendations. PMID- 26617197 TI - Tuning the structure, dimensionality and luminescent properties of lanthanide metal-organic frameworks under ancillary ligand influence. AB - This manuscript addresses the synthesis, structural characterization and optical properties of a 1D coordination polymer (CPs) and 2D and 3D Metal-Organic Frameworks (MOFs) obtained from lanthanide metals, 3-hydroxinaftalene-2,7 disulfonic acid (3-OHNDS) and two different phenanthroline derivates as ancillary ligands. The first is a family of 2D compounds with formula [Ln(3-OHNDS)(H2O)2], where Ln = La(), Pr(), Nd() and Sm(). The addition of 1,10-phenanthroline (phen) in the reaction produces 1D compounds with general formula [Ln(3 OHNDS)(phen)(H2O)].3H2O, where Ln = La(), Pr(), Nd() and Sm(). Finally, the synthesis with 3,4,7,8-tetramethyl-1,10-phenanthroline (3,4,7,8-TMPhen) as an ancillary ligand results in the formation of the 3D [La(3-OHNDS)(3,4,7,8 TMphen)(H2O)] () compound. The photoluminescence (PL) properties of 1D and 2D compounds were fully investigated in comparison with the 3-OHNDS ligand. One of the most important results was the obtaining of a white-light single-emitter without adding dopant atoms in the structure. With all these results in mind it was possible to establish structure-property relationships. PMID- 26617196 TI - Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on Delta(9) tetrahydrocannabinol challenge tests. AB - AIM: The severe psychiatric side effects of cannabinoid receptor type 1 (CB1 ) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of different CB1 antagonists in Delta(9) -tetrahydrocannabinol (THC) challenge tests in healthy volunteer were constructed. METHODS: The pharmacokinetic models of THC and four CB1 antagonists were built separately. THC-induced effects on heart rate and the visual analogue scale of feeling high in healthy volunteers and inhibitive effects of CB1 antagonists on THC-induced effects were modelled in PD models linked to the PK models. Simulations were then applied to evaluate the reduction rate of each antagonist on the reversal of the THC-induced effect in a unified simulation scenario. RESULTS: The final PK model of THC and antagonists was a two compartment model. An Emax model and logistic regression model were used for effect measures and the antagonist effect was added in these models in a competitive binding manner. t1/2ke0 ranged from 0.00462 to 63.7 h for heart rate and from 0.964 to 150 h for VAS. IC50 ranged from 6.42 to 202 ng ml(-1) for heart rate and from 12.1 to 376 ng ml(-1) for VAS. Benchmark simulation showed different dose-efficacy profiles of two efficacy measures for each CB1 antagonist. CONCLUSIONS: PK/PD modelling and simulation approach was suitable for describing and predicting heart rate and feeling high for CB1 antagonists in THC challenge tests. Direct comparison of four antagonists based on simulated efficacy profiles might be of benefit to guide future studies. PMID- 26617198 TI - Mechanically Tunable Dielectric Resonator Metasurfaces at Visible Frequencies. AB - Devices that manipulate light represent the future of information processing. Flat optics and structures with subwavelength periodic features (metasurfaces) provide compact and efficient solutions. The key bottleneck is efficiency, and replacing metallic resonators with dielectric resonators has been shown to significantly enhance performance. To extend the functionalities of dielectric metasurfaces to real-world optical applications, the ability to tune their properties becomes important. In this article, we present a mechanically tunable all-dielectric metasurface. This is composed of an array of dielectric resonators embedded in an elastomeric matrix. The optical response of the structure under a uniaxial strain is analyzed by mechanical-electromagnetic co-simulations. It is experimentally demonstrated that the metasurface exhibits remarkable resonance shifts. Analysis using a Lagrangian model reveals that strain modulates the near field mutual interaction between resonant dielectric elements. The ability to control and alter inter-resonator coupling will position dielectric metasurfaces as functional elements of reconfigurable optical devices. PMID- 26617199 TI - A multiplexed miRNA and transgene expression platform for simultaneous repression and expression of protein coding sequences. AB - Knockdown of single or multiple gene targets by RNA interference (RNAi) is necessary to overcome escape mutants or isoform redundancy. It is also necessary to use multiple RNAi reagents to knockdown multiple targets. It is also desirable to express a transgene or positive regulatory elements and inhibit a target gene in a coordinated fashion. This study reports a flexible multiplexed RNAi and transgene platform using endogenous intronic primary microRNAs (pri-miRNAs) as a scaffold located in the green fluorescent protein (GFP) as a model for any functional transgene. The multiplexed intronic miRNA - GFP transgene platform was designed to co-express multiple small RNAs within the polycistronic cluster from a Pol II promoter at more moderate levels to reduce potential vector toxicity. The native intronic miRNAs are co-transcribed with a precursor GFP mRNA as a single transcript and presumably cleaved out of the precursor-(pre) mRNA by the RNA splicing machinery, spliceosome. The spliced intron with miRNA hairpins will be further processed into mature miRNAs or small interfering RNAs (siRNAs) capable of triggering RNAi effects, while the ligated exons become a mature messenger RNA for the translation of the functional GFP protein. Data show that this approach led to robust RNAi-mediated silencing of multiple Renilla Luciferase (R-Luc)-tagged target genes and coordinated expression of functional GFP from a single transcript in transiently transfected HeLa cells. The results demonstrated that this design facilitates the coordinated expression of all mature miRNAs either as individual miRNAs or as multiple miRNAs and the associated protein. The data suggest that, it is possible to simultaneously deliver multiple negative (miRNA or shRNA) and positive (transgene) regulatory elements. Because many cellular processes require simultaneous repression and activation of downstream pathways, this approach offers a platform technology to achieve that dual manipulation efficiently. In conclusion, the current platform technology offers a miRNA/shRNA scaffold for the expression of combinations of native or synthetic intronic miRNAs as singletons or polycistrons for combinatorial multiplexed RNAi silencing or RNA-based gene therapy applications. PMID- 26617200 TI - Catalytic Activity and Impedance Behavior of Screen-Printed Nickel Oxide as Efficient Water Oxidation Catalysts. AB - We report that films screen printed from nickel oxide (NiO) nanoparticles and microballs are efficient electrocatalysts for water oxidation under near-neutral and alkaline conditions. Investigations of the composition and structure of the screen-printed films by X-ray diffraction, X-ray absorption spectroscopy, and scanning electron microscopy confirmed that the material was present as the cubic NiO phase. Comparison of the catalytic activity of the microball films to that of films fabricated by using NiO nanoparticles, under similar experimental conditions, revealed that the microball films outperform nanoparticle films of similar thickness owing to a more porous structure and higher surface area. A thinner, less-resistive NiO nanoparticle film, however, was found to have higher activity per Ni atom. Anodization in borate buffer significantly improved the activity of all three films. X-ray photoelectron spectroscopy showed that during anodization, a mixed nickel oxyhydroxide phase formed on the surface of all films, which could account for the improved activity. Impedance spectroscopy revealed that surface traps contribute significantly to the resistance of the NiO films. On anodization, the trap state resistance of all films was reduced, which led to significant improvements in activity. In 1.00 m NaOH, both the microball and nanoparticle films exhibit high long-term stability and produce a stable current density of approximately 30 mA cm(-2) at 600 mV overpotential. PMID- 26617201 TI - S-1 versus taxanes for HER2-negative metastatic breast cancer. PMID- 26617203 TI - Introduction: The Changing Spectrum of Breast Cancer. PMID- 26617204 TI - Breast Cancer Risk Assessment: Moving Beyond BRCA 1 and 2. AB - The National Cancer Institute estimates that 12.3% of all women (about 1 in 8) would be diagnosed with breast cancer throughout their lifetime. In 2015, a projected 231,840 new cases are expected in the United States, accompanied by 40,290 deaths. Presently, breast cancer is responsible for 6.8% of all cancer deaths, and roughly 30% of all cancers in women. Since the discovery of the BRCA gene in 1994, efforts have been made to develop effective screening methods for breast cancer detection. Although the BRCA gene certainly opened the door to breast cancer genetics, a wide variety of new genes have recently been linked to breast cancer risk, and the tools to screen for genes beyond just BRCA1 and BRCA2 are available. However, the indications for both screening and prevention of inherited predispositions beyond BRCA1 and BRCA2 are not entirely clear, and as a result, much of the ongoing work is aimed at determining the role of broader genetic screening in women deemed at sufficiently high risk for breast cancer based on family history. On this topic, we provide a brief overview of the genes associated with breast cancer risk as well as the technological platforms available to patients. We conclude by discussing recommendations of expert groups and what they practically mean for patients. PMID- 26617205 TI - Molecular Phenotype, Multigene Assays, and the Locoregional Management of Breast Cancer. AB - Molecular profiling has revealed that breast cancer is not a single disease entity, but rather a class of heterogeneous subtypes, each with its own inherent biology and natural history. As a result, different treatment approaches have been optimized for the various subtypes and, in turn, the ability to identify subtypes has become a critical element in the management of breast cancer. Comprehensive transcriptional profiling studies have revealed at least 4 principal subtypes that, in practice, are often distinguished by immunohistochemical staining of the estrogen receptor (ER), progesterone receptor (PR), and HER2, along with a determination of histologic grade or Ki-67 staining: luminal A (ER+/HER2-/grade 1 or 2), luminal B (ER+/HER2-/grade 3), HER2 enriched (any HER2+ tumor), and basal like (ER-/PR-/HER2-). Although these immunohistochemically derived subtypes show robust prognostic and predictive ability, there remain many cases that demand profiling that more closely approximates the original transcriptionally derived definitions of the intrinsic subtypes. The need for improved prognostication and risk stratification has led to the development of several multigene assays in breast cancer. Although there is little molecular overlap between current assays, they all rely heavily on quantifying the transcriptional output of ER signaling and proliferation-related genes. These data are typically then used in multivariate prediction models that incorporate other canonical risk factors such as the tumor size, lymph node involvement, and patient demographic parameters, among others. Indeed, the advent of scalable molecular profiling technologies has brought a number of assays into routine clinical use for optimizing risk prediction and treatment assignment. The landscape of these assays and the clinical utility of contemporary molecular profiles are the main focus of this overview. In addition to the clinical advances in transcriptional subtyping, recent reports have characterized the most common genomic and epigenomic alterations that are likely to drive certain breast cancers. The identification of these "driver" lesions has heralded an era of precision medicine in which vulnerable oncogenic pathways may be targeted to disrupt the etiologic lesion(s) of a specific tumor. A number of such early targeted approaches have yielded success in treating breast cancer, demonstrating the critical need for molecular diagnostics in this disease. PMID- 26617206 TI - Incorporating Imaging Into the Locoregional Management of Breast Cancer. AB - Although some breast cancers present as palpable masses or with other clinical findings, many are detected at screening. Most screening is currently done with digital mammography, but high-risk patients or those with dense breast tissue may undergo additional screening examinations with magnetic resonance imaging or ultrasound. Additionally, digital breast tomosynthesis, contrast-enhanced mammography, and molecular breast imaging are newer technologies available at some sites. Optimal usage of breast imaging technologies remains controversial, both in screening and diagnostic settings following a new diagnosis of breast cancer. This article will review well established and newer, alternative breast imaging technologies as well as recent data regarding their role in optimizing patient care. PMID- 26617207 TI - New Insights into the Surgical Management of Breast Cancer. AB - William Halstead is considered by many as the father of modern breast surgery. He popularized the notion that breast cancer progresses in an orderly fashion and that appropriately timed radical surgery can interrupt this progression to save lives. This view dominated for nearly 100 years and still persists to one extent or another in the minds of physicians and patients alike. Rapid advances in breast cancer biology have highlighted the heterogeneity of breast cancer and paradigm-shifting clinical trials have successfully challenged prevailing wisdom to effect a seed change in breast cancer surgery. Advances in radiation and systemic therapies permit more limited surgery for most patients. Recurrence rates of all kinds are on the decline; yet, paradoxically, use of bilateral mastectomy is increasing. PMID- 26617208 TI - Management of the Regional Lymph Nodes in Early-Stage Breast Cancer. AB - The management of regional nodes in early-stage invasive breast cancer continues to evolve. Improved systemic therapy has contributed to better local regional control, and at the same time it has drawn more attention to its importance. Axillary dissections have decreased, in part because of the increased efficacy of systemic therapy, and also because adjuvant therapy decisions are increasingly driven by biologic characterization of the tumor rather than pathologic nodal information. The trend toward less axillary surgery and a shift toward increased reliance on systemic and radiation therapy to address nodal disease has created interesting questions that were subsequently addressed in recent trials. We review the controversies in regional nodal management, the benefits of current treatment paradigms, the balance between less surgery and more radiation, and the potential tradeoffs vs toxicity. PMID- 26617202 TI - Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. AB - BACKGROUND: Oral fluoropyrimidines are used for the first-line treatment of metastatic breast cancer to avoid severe adverse effects, although firm supporting evidence is lacking. We aimed to establish whether S-1 is non-inferior to taxanes in this setting. METHODS: We did an open-label, non-inferiority, phase 3 trial at 154 hospitals in Japan. We enrolled individuals who had HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease, and who were resistant to endocrine treatment. Patients were randomly assigned (1:1) either to taxane (docetaxel 60-75 mg/m(2) at intervals of 3-4 weeks; paclitaxel 80-100 mg/m(2) weekly for 3 of 4 weeks; or paclitaxel 175 mg/m(2) at intervals of 3-4 weeks) or to S-1 (40-60 mg twice daily for 28 consecutive days, followed by a 14-day break). Randomisation was done centrally with the minimisation method, with stratification by institution, liver metastasis, oestrogen and progesterone receptor status, previous treatment with taxanes or oral fluorouracil, and time from surgery to recurrence. The primary endpoint was overall survival, with a prespecified non-inferiority margin of 1.333 for the hazard ratio (HR). The primary efficacy analysis was done in the full analysis set, which consisted of all patients who took at least one study treatment and who had all data after randomisation. This trial is registered with the University Hospital Medical Information Network, Japan (protocol ID C000000416). FINDINGS: Between Oct 27, 2006, and July 30, 2010, we enrolled 618 patients (309 assigned to taxane; 309 assigned to S-1). The full analysis set consisted of 286 patients in the taxane group and 306 in the S-1 group. Median follow-up was 34.6 months (IQR 17.9-44.4). Median overall survival was 35.0 months (95% CI 31.1 39.0) in the S-1 group and 37.2 months (33.0-40.1) in the taxane group (HR 1.05 [95% CI 0.86-1.27]; pnon-inferiority=0.015). The most common grade 3 or worse adverse events were neutropenia (20 [7%] of 307 patients in the S-1 group vs nine [3%] of 290 patients in the taxane group), fatigue (ten [3%] vs 12 [4%]), and oedema (one [<1%] vs 12 [4%]). Treatment-related deaths were reported in two patients in the taxane group. INTERPRETATION: S-1 is non-inferior to taxane with respect to overall survival as a first-line treatment for metastatic breast cancer. S-1 should be considered a new option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. FUNDING: Comprehensive Support Project for Oncology Research of the Public Health Research Foundation, Japan; Taiho. PMID- 26617209 TI - Novel and Highly Compressed Schedules for the Treatment of Breast Cancer. AB - Our thinking about radiotherapy (RT) for early-stage breast cancer has evolved considerably over the last several years. Increasingly patients and physicians together are making the decision to use altered fractionation rather than standard 6-7 weeks of conventional whole breast treatment plus lumpectomy bed boost. Adjuvant hypofractionated whole breast irradiation is now viewed as a preferred strategy for many eligible women, and can be completed in 3-4 weeks. Adjuvant accelerated partial breast irradiation is another alternative that is typically delivered in 8-10 fractions over 4-5 days. With improvements in delivery techniques, there has been renewed interest in shortening treatment times even further, with novel intraoperative approaches and ultrashort courses of external beam RT. This article provides a summary of the status and future directions in intraoperative and ultrashort course RT schedules used in the treatment of breast cancer. Outlined are the benefits as well as the drawbacks of these techniques for abbreviated breast RT. PMID- 26617210 TI - The Role of Postmastectomy Radiation Therapy in Patients With Breast Cancer Responding to Neoadjuvant Chemotherapy. AB - When surgery is the first line of breast cancer treatment, numerous randomized clinical trials and meta-analyses have demonstrated that postmastectomy radiation therapy (PMRT) improves locoregional control and survival for many women with axillary lymph node-positive disease. In contrast, there are no randomized data regarding the use of PMRT in women who receive neoadjuvant chemotherapy (NAC) first followed by mastectomy. This has led to controversy regarding which patient with breast cancer will benefit from PMRT after NAC, particularly in women with clinically node-positive axillary disease that responds well and is down staged to pathologically negative disease at surgery (ypN0). We review the current evidence on this topic, which forms the underlying basis for the ongoing phase III clinical trial-National Surgical Adjuvant Breast and Bowel Project (NSABP) B51/RTOG 1304-that is examining the role of regional nodal irradiation in patients with clinical N1 disease that responds to NAC and becomes ypN0 at surgery. PMID- 26617211 TI - Advances in Medical Management of Early Stage and Advanced Breast Cancer: 2015. AB - Standard management of early stage and advanced breast cancer has been improved over the past few years by knowledge gained about the biology of the disease, results from a number of eagerly anticipated clinical trials and the development of novel agents that offer our patients options for improved outcomes or reduced toxicity or both. This review highlights recent major developments affecting the systemic therapy of breast cancer, broken down by clinically relevant patient subgroups and disease stage, and briefly discusses some of the ongoing controversies in the treatment of breast cancer and promising therapies on the horizon. PMID- 26617212 TI - Contemporary Breast Radiotherapy and Cardiac Toxicity. AB - Long-term cardiac effects are an important component of survivorship after breast radiotherapy. The pathophysiology of cardiotoxicity, history of breast radiotherapy, current methods of cardiac avoidance, modern outcomes, context of historical outcomes, quantifying cardiac effects, and future directions are reviewed in this article. Radiation-induced oxidative stress induces proinflammatory cytokines and is a process that potentiates late effects of fibrosis and intimal proliferation in endothelial vasculature. Breast radiation therapy has changed substantially in recent decades. Several modern technologies exist to improve cardiac avoidance such as deep inspiration breath hold, gating, accelerated partial breast irradiation, and use of modern 3-dimensional planning. Modern outcomes may vary notably from historical long-term cardiac outcomes given the differences in cardiac dose with modern techniques. Methods of quantifying radiation-related cardiotoxicity that correlate with future cardiac risks are needed with current data exploring techniques such as measuring computed tomography coronary artery calcium score, single-photon emission computed tomography imaging, and biomarkers. Placing historical data, dosimetric correlations, and relative cardiac risk in context are key when weighing the benefits of radiotherapy in breast cancer control and survival. Estimating present day cardiac risk in the modern treatment era includes challenges in length of follow-up and the use of confounding cardiotoxic agents such as evolving systemic chemotherapy and targeted therapies. Future directions in both multidisciplinary management and advancing technology in radiation oncology may provide further improvements in patient risk reduction and breast cancer survivorship. PMID- 26617213 TI - Surgical Management of de novo Stage IV Breast Cancer. AB - The natural history of stage IV breast cancer is changing, with diagnosis when the disease burden is lower and better drugs translating into longer survival. Nevertheless, a small but constant fraction of women present with de novo stage IV disease and an intact primary tumor. The management of the primary site in this setting has classically been determined by the presence of symptoms, but this approach has been questioned based on multiple retrospective reviews reported over the past decade that suggested a survival advantage for women whose intact primary tumor is resected. These reviews are necessarily biased, as younger women with lower disease burden and more favorable biological features were offered surgery, but they led to several randomized trials to test the value of local therapy for the primary tumor in the face of distant disease. Preliminary results from 2 of these do not support a significant survival benefit, although local control benefits may exist. Completion of ongoing trials is needed to reach a definitive conclusion regarding the merit of primary tumor resection for local control and survival. Until unbiased data are available, local therapy for asymptomatic primary tumors cannot be recommended in the expectation of a survival benefit. PMID- 26617214 TI - Certolizumab treatment during late pregnancy in patients with rheumatic diseases: Low drug levels in cord blood but possible risk for maternal infections. A case series of 13 patients. AB - OBJECTIVE: Due to reduction of immune-suppressive drugs, patients with rheumatic diseases can experience an increase in disease activity during pregnancy. In such cases, TNF-inhibitors may be prescribed. However, monoclonal antibodies with the Fc moiety are actively transported across the placenta, resulting in therapeutic drug levels in the newborn. As certolizumab (CZP) lacks the Fc moiety, it may bear a lower risk for the child. METHOD: We report a case series of thirteen patients (5 with rheumatoid arthritis and 8 with spondyloarthritis) treated with CZP during late pregnancy to control disease activity. RESULT: CZP measured in cord blood of eleven infants ranged between undetectable levels and 1MUg/mL whereas the median CZP level of maternal plasma was 32.97MUg/mL. Three women developed an infection during the third trimester, of whom one had a severe infection and one had an infection that resulted in a pre-term delivery. During the postpartum period, 6 patients remained on CZP while breastfeeding. CZP levels in the breast milk of two breastfeeding patients were undetectable. CONCLUSION: The lack of the active transplacental transfer of CZP gives the possibility to treat inflammatory arthritis during late gestation without potential harm to the newborn. However, in pregnant women treated with TNF-inhibitors and prednisone, attention should be given to the increased susceptibility to infections, which might cause prematurity. CZP treatment can be continued while breastfeeding. PMID- 26617215 TI - New therapeutic opportunities for 5-HT2C receptor ligands in neuropsychiatric disorders. AB - The 5-HT2C receptor (R) displays a widespread distribution in the CNS and is involved in the action of 5-HT in all brain areas. Knowledge of its functional role in the CNS pathophysiology has been impaired for many years due to the lack of drugs capable of discriminating among 5-HT2R subtypes, and to a lesser extent to the 5-HT1B, 5-HT5, 5-HT6 and 5-HT7Rs. The situation has changed since the mid 90s due to the increased availability of new and selective synthesized compounds, the creation of 5-HT2C knock out mice, and the progress made in molecular biology. Many pharmacological classes of drugs including antipsychotics, antidepressants and anxiolytics display affinities toward 5-HT2CRs and new 5-HT2C ligands have been developed for various neuropsychiatric disorders. The 5-HT2CR is presumed to mediate tonic/constitutive and phasic controls on the activity of different central neurobiological networks. Preclinical data illustrate this complexity to a point that pharmaceutical companies developed either agonists or antagonists for the same disease. In order to better comprehend this complexity, this review will briefly describe the molecular pharmacology of 5-HT2CRs, as well as their cellular impacts in general, before addressing its central distribution in the mammalian brain. Thereafter, we review the preclinical efficacy of 5-HT2C ligands in numerous behavioral tests modeling human diseases, highlighting the multiple and competing actions of the 5-HT2CRs in neurobiological networks and monoaminergic systems. Notably, we will focus this evidence in the context of the physiopathology of psychiatric and neurological disorders including Parkinson's disease, levodopa-induced dyskinesia, and epilepsy. PMID- 26617216 TI - Low attentive and high impulsive rats: A translational animal model of ADHD and disorders of attention and impulse control. AB - Many human conditions such as attention deficit hyperactivity disorder (ADHD), schizophrenia and drug abuse are characterised by deficits in attention and impulse control. Carefully validated animal models are required to enhance our understanding of the pathophysiology of these disorders, enabling development of improved pharmacotherapy. Recent models have attempted to recreate the psychopathology of these conditions using chemical lesions or genetic manipulations. In a diverse population, where the aetiology is not fully understood and is multifactorial, these methods are restricted in their ability to identify novel targets for drug discovery. Two tasks of visual attention and impulsive action typically used in rodents and based on the human continuous performance task (CPT) include, the well-established 5 choice serial reaction time task (5C-SRTT) and the more recently validated, 5 choice continuous performance task (5C-CPT) which provides enhanced translational value. We suggest that separating animals by behavioural performance into high and low attentive and impulsivity cohorts using established parameters in these tasks offers a model with enhanced translational value. In this review, methods to separate animals are compared and the results discussed to highlight advantages over more constrained models, in addition to potential future directions for enhanced validation. Advantages include reliability, flexibility and enhanced translation to clinical conditions, all important considerations in modelling ADHD, schizophrenia and drug abuse, conditions with multifactorial aetiology. Based on the existing evidence, we suggest that future studies should incorporate an element of behavioural separation when studying the constructs of visual attention and impulsive action of relevance to human disorders. PMID- 26617217 TI - Nrf2-ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases. AB - Neurodegenerative diseases (NDDs) are predicted to be the biggest health concern in this century and the second leading cause of death by 2050. The main risk factor of these diseases is aging, and as the aging population in Western societies is increasing, the prevalence of these diseases is augmenting exponentially. Despite the great efforts to find a cure, current treatments remain ineffective or have low efficacy. Increasing lines of evidence point to exacerbated oxidative stress, mitochondrial dysfunction and chronic neuroinflammation as common pathological mechanisms underlying neurodegeneration. We will address the role of the nuclear factor E2-related factor 2 (Nrf2) as a potential target for the treatment of NDDs. The Nrf2-ARE pathway is an intrinsic mechanism of defence against oxidative stress. Nrf2 is a transcription factor that induces the expression of a great number of cytoprotective and detoxificant genes. There are many evidences that highlight the protective role of the Nrf2 ARE pathway in neurodegenerative conditions, as it reduces oxidative stress and neuroinflammation. Therefore, the Nrf2 pathway is being increasingly considered a therapeutic target for NDDs. Herein we will review the deregulation of the Nrf2 pathway in different NDDs and the recent studies with Nrf2 inducers as "proof-of concept" for the treatment of those devastating pathologies. PMID- 26617218 TI - Pharmacological models and approaches for pathophysiological conditions associated with hypoxia and oxidative stress. AB - Hypoxia is the failure of oxygenation at the tissue level, where the reduced oxygen delivered is not enough to satisfy tissue demands. Metabolic depression is the physiological adaptation associated with reduced oxygen consumption, which evidently does not cause any harm to organs that are exposed to acute and short hypoxic insults. Oxidative stress (OS) refers to the imbalance between the generation of reactive oxygen species (ROS) and the ability of endogenous antioxidant systems to scavenge ROS, where ROS overwhelms the antioxidant capacity. Oxidative stress plays a crucial role in the pathogenesis of diseases related to hypoxia during intrauterine development and postnatal life. Thus, excessive ROS are implicated in the irreversible damage to cell membranes, DNA, and other cellular structures by oxidizing lipids, proteins, and nucleic acids. Here, we describe several pathophysiological conditions and in vivo and ex vivo models developed for the study of hypoxic and oxidative stress injury. We reviewed existing literature on the responses to hypoxia and oxidative stress of the cardiovascular, renal, reproductive, and central nervous systems, and discussed paradigms of chronic and intermittent hypobaric hypoxia. This systematic review is a critical analysis of the advantages in the application of some experimental strategies and their contributions leading to novel pharmacological therapies. PMID- 26617220 TI - Extracellular vesicles: Pharmacological modulators of the peripheral and central signals governing obesity. AB - Obesity and its metabolic resultant dysfunctions such as insulin resistance, hyperglycemia, dyslipidemia and hypertension, grouped as the "metabolic syndrome", are chronic inflammatory disorders that represent one of the most severe epidemic health problems. The imbalance between energy intake and expenditure, leading to an excess of body fat and an increase of cardiovascular and diabetes risks, is regulated by the interaction between central nervous system (CNS) and peripheral signals in order to regulate behavior and finally, the metabolism of peripheral organs. At present, pharmacological treatment of obesity comprises actions in both CNS and peripheral organs. In the last decades, the extracellular vesicles have emerged as participants in many pathophysiological regulation processes. Whether used as biomarkers, targets or even tools, extracellular vesicles provided some promising effects in the treatment of a large variety of diseases. Extracellular vesicles are released by cells from the plasma membrane (microvesicles) or from multivesicular bodies (exosomes) and contain lipids, proteins and nucleic acids, such as DNA, protein coding, and non-coding RNAs. Owing to their composition, extracellular vesicles can (i) activate receptors at the target cell and then, the subsequent intracellular pathway associated to the specific receptor; (ii) transfer molecules to the target cells and thereby change their phenotype and (iii) be used as shuttle of drugs and, thus, to carry specific molecules towards specific cells. Herein, we review the impact of extracellular vesicles in modulating the central and peripheral signals governing obesity. PMID- 26617219 TI - Bisphosphonates for cancer treatment: Mechanisms of action and lessons from clinical trials. AB - A growing body of evidence points toward an important anti-cancer effect of bisphosphonates, a group of inexpensive, safe, potent, and long-term stable pharmacologicals that are widely used as osteoporosis drugs. To date, they are already used in the prevention of complications of bone metastases. Because the bisphosphonates can also reduce mortality in among other multiple myeloma, breast, and prostate cancer patients, they are now thoroughly studied in oncology. In particular, the more potent nitrogen-containing bisphosphonates have the potential to improve prognosis. The first part of this review will elaborate on the direct and indirect anti-tumoral effects of bisphosphonates, including induction of tumor cell apoptosis, inhibition of tumor cell adhesion and invasion, anti-angiogenesis, synergism with anti-neoplastic drugs, and enhancement of immune surveillance (e.g., through activation of gammadelta T cells and targeting macrophages). In the second part, we shed light on the current clinical position of bisphosphonates in the treatment of hematological and solid malignancies, as well as on ongoing and completed clinical trials investigating the therapeutic effect of bisphosphonates in cancer. Based on these recent data, the role of bisphosphonates is expected to further expand in the near future outside the field of osteoporosis and to open up new avenues in the treatment of malignancies. PMID- 26617221 TI - Polysaccharide-based freestanding multilayered membranes exhibiting reversible switchable properties. AB - The design of self-standing multilayered structures based on biopolymers has been attracting increasing interest due to their potential in the biomedical field. However, their use has been limited due to their gel-like properties. Herein, we report the combination of covalent and ionic cross-linking, using natural and non cytotoxic cross-linkers, such as genipin and calcium chloride (CaCl2). Combining both cross-linking types the mechanical properties of the multilayers increased and the water uptake ability decreased. The ionic cross-linking of multilayered chitosan (CHI)-alginate (ALG) films led to freestanding membranes with multiple interesting properties, such as: improved mechanical strength, calcium-induced adhesion and shape memory ability. The use of CaCl2 also offered the possibility of reversibly switching all of these properties by simple immersion in a chelate solution. We attribute the switch-ability of the mechanical properties, shape memory ability and the propensity for induced-adhesion to the ionic cross-linking of the multilayers. These findings suggested the potential of the developed polysaccharide freestanding membranes in a plethora of research fields, including in biomedical and biotechnological fields. PMID- 26617222 TI - Studies on stable isotopic composition of daily rainfall from Kozhikode, Kerala, India. AB - The stable isotopic compositions of all major daily rain fall samples (n = 113) collected from Kozhikode station in Kerala, India, for the year 2010 representing the pre-monsoon, southwest and northeast monsoon seasons are examined. The isotopic variations delta(18)O, delta(2)H and d-excess in daily rainfall ranged from delta(18)O: -4.4 to 2 0/00, delta(2)H: -25.3 to 13.8 0/00, and d-excess: 2.4 to 15.3 0/00; delta(18)O: -9.7 to -0.6 0/00, delta(2)H: -61.7 to 5.3 0/00, and d-excess 5.8 to 17.4 0/00; delta(18)O -11.3 to -1.4 0/00, delta(2)H: -75.3 to 0.9 0/00, and d-excess: 8.8 to 21.3 0/00 during the pre-, southwest and northeast monsoon periods, respectively. Thus, daily rainfall events during two monsoon periods had a distinct range of isotopic variations. The daily rain events within the two monsoon seasons also exhibited periodic variations. The isotopic composition of rain events during pre-monsoon and a few low-intensity events during the southwest monsoon period had imprints of secondary evaporation. This study analysing the stable isotopic characteristics of individual rain events in southern India, which is influenced by dual monsoon rainfall, will aid in a better understanding of its mechanism. PMID- 26617223 TI - Allergen Immunotherapy: History and Future Developments. AB - Allergen immunotherapy (AIT) was introduced in clinical practice more than 100 years ago. The clinical effectiveness in allergic rhinitis (and asthma) and in hymenoptera allergy was apparent early on but it was not until the mid-1900s that randomized placebo-controlled trials proved its efficacy. In the 1980s, sublingual immunotherapy (SLIT) was accepted in official guidelines. The availability of safer routes, such as SLIT, prompted increasing investigation of AIT for food allergy. The introduction of molecular-based diagnosis introduced the possibility of better targeted prescription of AIT. Other approaches are being explored, such as immunogenic peptides, recombinant allergens, and adjuvants. PMID- 26617224 TI - Subcutaneous Immunotherapy and Sublingual Immunotherapy: Comparative Efficacy, Current and Potential Indications, and Warnings--United States Versus Europe. AB - Subcutaneous immunotherapy and sublingual immunotherapy are effective for allergic rhinitis and allergic asthma and with some support for use in selected patients with atopic dermatitis. The sequence of immunologic responses is the same, irrespective of the route of administration, and similar disease modification has been demonstrated. However, there are differences between the two approaches. The most important is the greatly reduced likelihood of sublingual immunotherapy producing systemic reactions. There are major drawbacks for sublingual immunotherapy in regard to dosing. Finally, there is the question of relative clinical efficacy, with the currently available data favoring subcutaneous immunotherapy. PMID- 26617225 TI - Novel Delivery Routes for Allergy Immunotherapy: Intralymphatic, Epicutaneous, and Intradermal. AB - Current allergy immunotherapy protocols suffer from two main problems: long treatment duration and systemic allergic side effects of the allergen administrations. The immunologic effects of allergen administration could be enhanced and the number of allergen administrations and treatment duration reduced by choosing a tissue for administration that contains a high density of antigen-presenting cells. Local side effects could be reduced by choosing a route characterized by a low density of mast cells, and systemic side effects could be reduced by administration to nonvascularized tissues, so that inadvertent systemic distribution of the allergen and consequent systemic allergic side effects are minimized. PMID- 26617226 TI - Advances in the Treatment of Food Allergy: Sublingual and Epicutaneous Immunotherapy. AB - Food allergies continue to increase in prevalence. Standard care is a strict elimination diet, but life-threatening reactions still occur. Allergen immunotherapy has the most potential in treating food allergy. Subcutaneous immunotherapy has not been adopted into food allergy therapy. Oral immunotherapy has a high rate of adverse reactions. Sublingual immunotherapy (SLIT) uses the tolerogenic environment of the oral mucosa and epicutaneous immunotherapy (EPIT) uses the immune cells of the epidermis to transport antigens to afferent lymph nodes to activate immune responses. SLIT and EPIT can successfully desensitize patients. More research is needed to define optimal doses and administration protocols. PMID- 26617227 TI - Oral Immunotherapy for Food Allergy. AB - Food allergy is a potentially life-threatening condition with no approved therapies, apart from avoidance and injectable epinephrine for acute allergic reactions. Oral immunotherapy (OIT) is an experimental treatment in which food allergic patients consume gradually increasing quantities of the food to increase their threshold for allergic reaction. This therapy carries significant risk of allergic reactions. The ability of OIT to desensitize patients to particular foods is well-documented, although the ability to induce tolerance has not been established. This review focuses on recent studies for the treatment of food allergies such as cow's milk, hen's egg, and peanut. PMID- 26617228 TI - Mechanisms of Aeroallergen Immunotherapy: Subcutaneous Immunotherapy and Sublingual Immunotherapy. AB - Allergen immunotherapy (AIT) is an effective way to treat allergic disorders, targeting the underlying mechanisms and altering the disease course by inducing a long-lasting clinical and immune tolerance to allergens. Although sublingual and subcutaneous routes are used in daily practice, many novel ways to decrease side effects and duration and increase efficacy have been pursued. Further studies are needed to develop biomarkers for the identification of AIT responder patients and also to use the developed knowledge in allergy prevention studies. Future directions in AIT include treatments for autoimmune diseases, chronic infections, organ transplantation, and breaking immune tolerance to cancer cells. PMID- 26617229 TI - Mechanisms Underlying Induction of Tolerance to Foods. AB - Oral tolerance refers to a systemic immune nonresponsiveness to antigens first encountered by the oral route, and a failure in development of this homeostatic process can result in food allergy. Clinical tolerance induced by allergen immunotherapy is associated with alterations in immune mechanisms relevant to the allergic response, including reduction of basophil reactivity, induction of IgG4, loss of effector Th2 cells, and induction of Tregs. The relative contribution of these immune changes to clinical tolerance to foods, and the duration of these immune changes after termination of immunotherapy, remains to be identified. PMID- 26617230 TI - Allergen Immunotherapy: Vaccine Modification. AB - There is a need for newer therapeutic agents that improve the safety of allergen immunotherapy, provide ease of delivery to patients that fosters compliance and allows access to a greater proportion of the allergic population who could benefit from this disease-modifying treatment, and achieve an acceptable therapeutic benefit for patients committing to the treatment. The advances in sublingual allergen immunotherapy are encouraging, as this offers patients a noninjectable form of treatment of inhalant allergies. The continued research and development of the novel therapeutic constructs discussed in this article holds the promise of accomplishing the aforementioned goals in the future. PMID- 26617231 TI - The Use of Adjuvants for Enhancing Allergen Immunotherapy Efficacy. AB - One key approach to increase the efficacy and the safety of immunotherapy is the use of adjuvants. However, many of the adjuvants currently in use can cause adverse events, raising concerns regarding their clinical use, and are geared toward productive immune responses but not necessarily tolerogenic responses. Thus, novel adjuvants for immunotherapy are needed and are being developed. Essential is their potential to boost appropriate tolerogenic adaptive immune responses to allergens while limiting side effects. This review provides an overview of adjuvants currently in clinical use or under development and discusses their therapeutic effect in enhancing allergen-induced tolerance. PMID- 26617232 TI - Baked Milk and Egg Diets for Milk and Egg Allergy Management. AB - In baked form, cow's milk and egg are less allergenic and are tolerated by most milk- and egg-allergic children. Not only may including baked milk and egg in the diets of children who are tolerant improve nutrition and promote more social inclusion but there is also evidence that inclusion may accelerate the resolution of unheated milk and egg allergy. Further research is needed on biomarkers that can predict baked milk or egg reactivity; however, data suggest casein- and ovomucoid-specific immunoglobulin E levels may be useful. Physician-supervised introduction of baked milk and egg is recommended because anaphylaxis has occurred. PMID- 26617233 TI - Biomarkers for Allergen Immunotherapy: A "Panoromic" View. AB - Biomarkers (BMKs) are biological parameters that can be measured to predict or monitor disease severity or treatment efficacy. The induction of regulatory dendritic cells (DCs) concomitantly with a downregulation of proallergic DC2s (ie, DCs supporting the differentiation of T-helper lymphocyte type 2 cells) in the blood of patients allergic to grass pollen has been correlated with the early onset of allergen immunotherapy efficacy. The combined use of omics technologies to compare biological samples from clinical responders and nonresponders is being implemented in the context of nonhypothesis-driven approaches. Such comprehensive "panoromic" strategies help identify completely novel candidate BMKs, to be subsequently validated as companion diagnostics in large-scale clinical trials. PMID- 26617234 TI - Allergen Immunotherapy Outcomes and Unmet Needs: A Critical Review. AB - Allergen immunotherapy (AIT) has been evaluated throughout several studies over the last years. A position paper from the European Academy of Allergy and Clinical Immunology highlighted the total combined symptoms score as the method to record the primary end point in AIT studies for allergic rhinitis, but this score still needs to be formally validated and more work done for other allergic diseases. These aspects still seem to be the main unmet need in the evaluation of AIT clinical outcomes in clinical trials. PMID- 26617235 TI - Allergy Work-Up Including Component-Resolved Diagnosis: How to Make Allergen Specific Immunotherapy More Specific. AB - Symptoms are recorded by obtaining a clinical history. Allergen sensitization is demonstrated by skin prick test or allergen-specific IgE serology. IgE sensitizations to allergen sources can be identified knowing the relationship between major aeroallergens and homologous allergen families. Some develop allergic sensitization to pan-allergens. Allergen extracts do not allow definitive separation of the sources. IgE antibody analysis of the major allergenic molecules facilitates differentiation of sensitizing allergen sources. IgE sensitizations to inhalant allergens are only relevant in the case of corresponding symptoms. In questionable cases, conjunctival or nasal provocation tests help induce confirmatory symptoms and identify relevant allergens for immunotherapy. PMID- 26617236 TI - Solving the Problem of Nonadherence to Immunotherapy. AB - Allergen immunotherapy (AIT) can improve allergic response by modifying the underlying disease. Many patients are nonadherent, and do not achieve full benefit. Numerous studies reveal that fewer than 10% of patients complete a full course and that most abandon treatment in the first year. The development and testing of interventions to improve AIT are emerging. Data from adherence interventions in other chronic conditions provide guidance to allergists/immunologists. Evidence-based communication strategies-patient centered care, motivational interviewing, and shared-decision making-underscore the importance of taking time to establish trust, understand patient concerns and priorities, and involve the patient in decisions regarding AIT. PMID- 26617237 TI - Allergen Immunotherapy--An Old Friend Coming of Age. PMID- 26617238 TI - Allergen-specific Immunotherapy--Turning the Tables on the Immune System. PMID- 26617240 TI - Risk of death in patients with post-traumatic cerebrospinal fluid leakage- analysis of 1773 cases. AB - BACKGROUND: Post-traumatic cerebrospinal fluid (CSF) leakage is one of the most troublesome conditions associated with head trauma. CSF fistulae, meningitis/central nervous infection, or even death may accompany it. Few studies have discussed post-traumatic CSF leakage as a risk factor in mortality following head trauma. We conducted this cohort study to examine the issue. METHODS: We reviewed the records in the Taiwan Traumatic Brain Injury (TBI) Registry System between 1993 and 2008. The study group included patients with acute TBI and post traumatic CSF leakage, and the control group included cases with TBI but without CSF leakage, selected randomly at a 5:1 ratio with respect to the study group. The demographic data, Glasgow Coma Scale, brain computerized tomography, association of skull fractures and intracranial lesions, and 1-year mortality rates between these two cohorts were reviewed meticulously and analyzed statistically. RESULTS: Of 174,236 cases, 1773 with post-traumatic CSF leakage were included in the study group, and 8865 cases in the control group. Of the total 10,638 sampled cases, 406 (3.8%) died during the 1-year follow-up period, 159 (9.0%) cases in the CSF leakages group, and 247 (2.8%) in the control group. The patients with CSF leakage had a significantly higher mortality rate within 1 year (adjusted hazard ratio = 1.44, p < 0.001) than those without. We divided the CSF leakage group into three subgroups: otorrhea (n = 568), rhinorrhea (n = 302), and tension pneumocephalus (n = 903). The mortality rates were 8.5% (48/568) in the otorrhea subgroup, 10.9% (33/302) in the rhinorrhea subgroup, and 8.6% (78/903) in the tension pneumocephalus subgroup. The cases with CSF rhinorrhea had a significantly higher mortality rate than the other two subgroups (p < 0.05). All three subgroups had significantly higher mortality rates than the control group during the 1-year follow-up period (adjusted hazard ratios = 2.29, 1.35, and 1.32 in the rhinorrhea, tension pneumocephalus, and otorrhea subgroups, respectively). CONCLUSION: Post-traumatic CSF leakages had higher mortality rates than those without CSF leakages in TBI cases, and the cases with CSF rhinorrhea had worse outcomes compared with CSF leakages with pneumocephalus or otorrhea. PMID- 26617239 TI - Endothelial Gata5 transcription factor regulates blood pressure. AB - Despite its high prevalence and economic burden, the aetiology of human hypertension remains incompletely understood. Here we identify the transcription factor GATA5, as a new regulator of blood pressure (BP). GATA5 is expressed in microvascular endothelial cells and its genetic inactivation in mice (Gata5-null) leads to vascular endothelial dysfunction and hypertension. Endothelial-specific inactivation of Gata5 mimics the hypertensive phenotype of the Gata5-null mice, suggestive of an important role for GATA5 in endothelial homeostasis. Transcriptomic analysis of human microvascular endothelial cells with GATA5 knockdown reveals that GATA5 affects several genes and pathways critical for proper endothelial function, such as PKA and nitric oxide pathways. Consistent with a role in human hypertension, we report genetic association of variants at the GATA5 locus with hypertension traits in two large independent cohorts. Our results unveil an unsuspected link between GATA5 and a prominent human condition, and provide a new animal model for hypertension. PMID- 26617241 TI - N-Acetyltransferase 2 (NAT2) genetic variation and the susceptibility to noncardiac gastric adenocarcinoma in Taiwan. AB - BACKGROUND: N-Acetyltransferase (NAT) is an important enzyme with the capacity to metabolize carcinogenic aromatic amines. However, it remains controversial whether the encoded functional NAT2 genetic polymorphism is related to the risk of gastric adenocarcinoma (GA). The aim of this study was to evaluate the association between NAT2 genetic variation and gastric adenocarcinoma (GA), with special reference to the gastric noncardiac adenocarcinoma (GNA). METHODS: Peripheral white blood cell DNA from 368 GA patients and 368 age- and sex-matched controls were genotyped for NAT2 by a polymerase chain reaction method. The lifestyle habits of the participants were assessed using a semiquantitative food frequency questionnaire. NAT2 genotype, interaction with lifestyle habits, and the risk of GA and GNA were analyzed by logistic regression. RESULTS: GA patients were more likely to have a smoking habit, ate more salted foods, and consumed more well-done meat than the controls. There was no association between the NAT2 genotypes and susceptibility to GA. However, if patients with gastric cardiac adenocarcinoma (GCA; n = 42) were excluded, the NAT2 slow acetylators (without rapid acetylator allele) had a higher risk of GA than intermediate and rapid acetylators (odds ratio = 1.53; 95% confidence interval, 1.05-2.23, p = 0.027). In addition, there was a synergic effect of NAT2 slow acetylator and well-done meat intake to the development of GNA (odds ratio = 3.83; 95% confidence interval, 1.68-8.76, p = 0.001). CONCLUSION: NAT2 slow acetylators have a higher risk of GNA than intermediate and rapid acetylators have in a Taiwanese population. The intake of well-done meat, an additive to the acetylator status, may contribute to the incidence of gastric carcinogenesis. PMID- 26617242 TI - Influence of Guided Waves in Tibia on Non-linear Scattering of Contrast Agents. AB - The aim of this study was to elucidate the linear and non-linear responses of ultrasound contrast agent (UCA) to frequency-dispersive guided waves from the tibia cortex, particularly two individual modes, S0 (1.23 MHz) and A1 (2.06 MHz). The UCA responses to guided waves were illustrated through the Marmottant model derived from measured guided waves, and then verified by continuous infusion experiments in a vessel-tibia flow phantom. These UCA responses were further evaluated by the enhanced ratio of peak values and the resolutions of UCA backscattered echoes. Because of the individual modes S0 and A1 in the tibia, the peak values of the UCA backscattered echoes were enhanced by 83.57 +/- 7.35% (p < 0.05) and 80.77 +/- 6.60% (p < 0.01) in the UCA subharmonic frequency and subharmonic imaging, respectively. However, corresponding resolutions were 0.78 +/- 0.07 (p < 0.05) and 0.72 +/- 0.12 (p < 0.01) times those without guided wave disturbances, respectively. Even though the resolution was partly degenerated, the subharmonic detection sensitivity of UCA was improved by the guided waves. Thus, UCA responses to the double-frequency guided waves should be further explored to benefit the detection of capillary perfusion in tissue layers near the bone cortex, particularly for perfusion imaging in the free flaps and skeletal muscles. PMID- 26617244 TI - Shear Wave Elastography in Head and Neck Lymph Node Assessment: Image Quality and Diagnostic Impact Compared with B-Mode and Doppler Ultrasonography. AB - The aim of this study was to assess the diagnostic performance of shear wave elastography (SWE) in comparison to B-mode and Doppler ultrasonography in differentiating benign from malignant head and neck lymph nodes (HNLNs). Sixty two HNLNs from 56 patients were prospectively examined using B-mode, Doppler and SWE. The standard of reference was histopathology or cytology and follow-up. Qualitative malignant criteria (hilum infiltration, cortical hypo-echogenicity, irregular margins, abnormal vessels) were assessed on a five-point scale. Four quantitative parameters were obtained: long axis length, short axis length, short axis/long axis ratio, resistive index and maximum shear elasticity modulus (MUmax). Diagnostic performance was analyzed with special emphasis on the sub centimeter HNLN subgroup. Thirty HNLNs were malignant (48%). MUmax intra-observer reproducibility was 0.899 (0.728 in sub-centimeter subgroup). Malignant HNLNs were stiffer (MUmax = 72.4 +/- 59.0 kPa) compared with benign nodes (MUmax = 23.3 +/- 25.3 kPa) (p < 0.001). Among the quantitative criteria, MUmax had the highest diagnostic accuracy (area under the curve = 0.903 +/- 0.042), especially in the sub-centimeter subgroup (area under the curve = 0.929 +/- 0.045; p < 0.001) in which the area under the curve was significantly higher compared with the other quantitative criteria (p < 0.05). The additional use of SWE combined with B-mode tended to improve diagnostic accuracy (p > 0.05). SWE is a promising reproducible quantitative tool with which to predict malignant HNLNs, especially sub centimeter nodes. PMID- 26617243 TI - Safety Validation of Repeated Blood-Brain Barrier Disruption Using Focused Ultrasound. AB - The purpose of this study was to investigate the effects on the brain of multiple sessions of blood-brain barrier (BBB) disruption using focused ultrasound (FUS) in combination with micro-bubbles over a range of acoustic exposure levels. Six weekly sessions of FUS, using acoustical pressures between 0.66 and 0.80 MPa, were performed under magnetic resonance guidance. The success and degree of BBB disruption was estimated by signal enhancement of post-contrast T1-weighted imaging of the treated area. Histopathological analysis was performed after the last treatment. The consequences of repeated BBB disruption varied from no indications of vascular damage to signs of micro-hemorrhages, macrophage infiltration, micro-scar formations and cystic cavities. The signal enhancement on the contrast-enhanced T1-weighted imaging had limited value for predicting small-vessel damage. T2-weighted imaging corresponded well with the effects on histopathology and could be used to study treatment effects over time. This study demonstrates that repeated BBB disruption by FUS can be performed with no or limited damage to the brain tissue. PMID- 26617246 TI - Letter to the Editor. PMID- 26617245 TI - Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation. AB - Nupr1 is a chromatin protein, which cooperates with Kras(G12D) to induce PanIN formation and pancreatic cancer development in mice, though the molecular mechanisms underlying this effect remain to be fully characterized. In the current study, we report that Nupr1 acts as a gene modifier of the effect of Kras(G12D)-induced senescence by regulating Dnmt1 expression and consequently genome-wide levels of DNA methylation. Congruently, 5-aza-2'-deoxycytydine, a general inhibitor of DNA methylation, reverses the Kras(G12D)-induced PanIN development by promoting senescence. This requirement of Nupr1 expression, however, is not restricted to the pancreas since in lung of Nupr1(-/-) mice the expression of Kras(G12D) induces senescence instead of transformation. Therefore, mechanistically this data reveals that epigenetic events, at least at the level of DNA methylation, modulate the functional outcome of common genetic mutations, such as Kras(G12D), during carcinogenesis. The biomedical relevance of these findings lies in that they support the rational for developing similar therapeutic interventions in human aimed at controlling either the initiation or progression of cancer. PMID- 26617247 TI - The role of childbirth research simulators in clinical practice. PMID- 26617248 TI - A clinical evaluation of bleeding patterns, adverse effects, and satisfaction with the subdermal etonogestrel implant among postpartum and non-postpartum users. PMID- 26617249 TI - Association of bacteria in diabetic and non-diabetic foot infection - An investigation in patients from Bangladesh. AB - The microbial community on a host relies on its immune status and pathophysiological condition. Diabetes mellitus is a metabolic disorder associated with a 25% increased risk of developing foot infection. The pathophysiological differences between diabetic foot infection (DFI) and non-DFI patients may alter the microbial composition in infections. The present study aims to comparatively analyze the microbes colonized in DFI and non-DFI patients in Bangladesh. Pus specimens were collected from 67 DFI and 12 non-DFI patients to investigate the bacteria associated with foot infection. For this investigation, an array of microbiological, molecular biological and immunological approaches were performed. Common bacteria detected in both DFI/non DFI samples were Pseudomonas spp. (22/29%), Bacillus spp. (12/3%), Enterobacter spp. (22/7%), Staphylococcus spp. (13/13%) and Acinetobacter spp. (10/10%). Enterococcus spp. (9%) and Klebsiella spp. (8%) occurred only in DFI patients, whereas Citrobacter spp. (29%) was only detected in non-DFI samples. The rate of occurrence of three organisms, namely, Enterococcus spp. |Z|=2.2125, Klebsiella spp. |Z|=1.732, Bacillus spp. |Z|=1.9034, were also statistically significant. Most of the isolates from DFI patients were commonly resistant to the cephalosporin (Ceftazidime, Ceftriazone, Cefurozime) and monobactam (Aztreonam) groups of antibiotics. DFI patients had comparatively higher C-reactive protein (CRP) levels than non-DFI patients, and a positive correlation was observed between multi-antibiotic resistance and CRP levels (one of the markers of chronic subclinical inflammation). The present investigation implicated a complex association of the bacterial population in DFI compared with non-DFI with different antimicrobial resistance properties, which was linked with CRP levels. PMID- 26617250 TI - Prevalence of multidrug resistant uropathogenic bacteria in pediatric patients of a tertiary care hospital in eastern India. AB - Today, because systemic infections such as urinary tract infection (UTI) affect even pediatric patients, antibiotic resistant bacteria have become a constant clinical challenge. In the present study, a total of 1054 urine samples were collected from pediatric patients over 18 months. From these samples, 510 isolates of pathogenic bacteria were collected using HiCrome UTI agar. Antibiotic sensitivity tests of isolates were performed using the Kirby-Bauer method. Two Gram-positive bacteria (Enterococcus faecalis and Staphylococcus aureus) and 7 Gram-negative bacteria (Citrobacter freundii, Enterobacter aerogenes, Escherichia coli, Klebsiella oxytoca, K. pneumoniae, Proteus vulgaris and Pseudomonas aeruginosa) were isolated. Antibiograms of isolated bacteria were ascertained using antibiotics of 4 classes: aminoglycosides, beta-lactams, fluoroquinolones and 2 stand-alones (co-trimoxazole and nitrofurantoin). Based on percent values of antibiotic resistance, isolated bacteria were (in decreasing order of number of isolated isolates): E. coli (109)>S. aureus (65)>E. faecalis (82)>E. aerogenes (64)>C. freundii (41)>P. aeruginosa (32)>K. pneumoniae (45)>K. oxytoca (50)>P. vulgaris (22). Surveillance results show that MDR isolates of 9 pathogenic bacteria were prevalent in the environment around the hospital. Thus, revisions to the antimicrobial stewardship program in this area of the country are required to increase clinician confidence in empiric therapy, which is often used for UTI cases. PMID- 26617251 TI - Sensing protein antigen and microvesicle analytes using high-capacity biopolymer nano-carriers. AB - Lab-on-a-chip systems with molecular motor driven transport of analytes attached to cytoskeletal filament shuttles (actin filaments, microtubules) circumvent challenges with nanoscale liquid transport. However, the filaments have limited cargo-carrying capacity and limitations either in transportation speed (microtubules) or control over motility direction (actin). To overcome these constraints we here report incorporation of covalently attached antibodies into self-propelled actin bundles (nanocarriers) formed by cross-linking antibody conjugated actin filaments via fascin, a natural actin-bundling protein. We demonstrate high maximum antigen binding activity and propulsion by surface adsorbed myosin motors. Analyte transport capacity is tested using both protein antigens and microvesicles, a novel class of diagnostic markers. Increased incubation concentration with protein antigen in the 0.1-100 nM range (1 min) reduces the fraction of motile bundles and their velocity but maximum transportation capacity of >1 antigen per nm of bundle length is feasible. At sub nanomolar protein analyte concentration, motility is very well preserved opening for orders of magnitude improved limit of detection using motor driven concentration on nanoscale sensors. Microvesicle-complexing to monoclonal antibodies on the nanocarriers compromises motility but nanocarrier aggregation via microvesicles shows unique potential in label-free detection with the aggregates themselves as non-toxic reporter elements. PMID- 26617252 TI - Isomerization and Fragmentation of Cyclohexanone in a Heated Micro-Reactor. AB - The thermal decomposition of cyclohexanone (C6H10?O) has been studied in a set of flash-pyrolysis microreactors. Decomposition of the ketone was observed when dilute samples of C6H10?O were heated to 1200 K in a continuous flow microreactor. Pyrolysis products were detected and identified by tunable VUV photoionization mass spectroscopy and by photoionization appearance thresholds. Complementary product identification was provided by matrix infrared absorption spectroscopy. Pyrolysis pressures were roughly 100 Torr, and contact times with the microreactors were roughly 100 MUs. Thermal cracking of cyclohexanone appeared to result from a variety of competing pathways, all of which open roughly simultaneously. Isomerization of cyclohexanone to the enol, cyclohexen-1 ol (C6H9OH), is followed by retro-Diels-Alder cleavage to CH2?CH2 and CH2?C(OH) CH?CH2. Further isomerization of CH2?C(OH)-CH?CH2 to methyl vinyl ketone (CH3CO CH?CH2, MVK) was also observed. Photoionization spectra identified both enols, C6H9OH and CH2?C(OH)-CH?CH2, and the ionization threshold of C6H9OH was measured to be 8.2 +/- 0.1 eV. Coupled cluster electronic structure calculations were used to establish the energetics of MVK. The heats of formation of MVK and its enol were calculated to be DeltafH298(cis-CH3CO-CH?CH2) = -26.1 +/- 0.5 kcal mol(-1) and DeltafH298(s-cis-1-CH2?C(OH)-CH?CH2) = -13.7 +/- 0.5 kcal mol(-1). The reaction enthalpy DeltarxnH298(C6H10?O -> CH2?CH2 + s-cis-1-CH2?C(OH)-CH?CH2) is 53 +/- 1 kcal mol(-1) and DeltarxnH298(C6H10?O -> CH2?CH2 + cis-CH3CO-CH?CH2) is 41 +/- 1 kcal mol(-1). At 1200 K, the products of cyclohexanone pyrolysis were found to be C6H9OH, CH2?C(OH)-CH?CH2, MVK, CH2CHCH2, CO, CH2?C?O, CH3, CH2?C?CH2, CH2?CH-CH?CH2, CH2?CHCH2CH3, CH2?CH2, and HC=CH. PMID- 26617253 TI - Differential proteome association study of freeze-thaw damage in ram sperm. AB - In this study proteomics analysis was performed to investigate damage caused to ram sperm by the freeze-thaw process. Sperm motility, viability, reactive oxygen species (ROS) and adenosine triphosphate (ATP) content were measured to evaluate sperm quality. Compared with fresh groups, motility, viability and ATP content were all lower in freeze-thawed sperm (P < 0.001), and ROS content was higher (P < 0.001). Moreover, 25 differential protein spots were detected in two dimensional gels using PDQuest 8.0 software and the corresponding proteins were identified using matrix-assisted laser desorption/ionization tandem time-of flight mass spectrometry (MALDI-TOF-TOF MS) coupled with searching of the NCBI protein sequence database. Among these proteins, hexokinase1 (HXK1), the enzyme that catalyzes the first step of glycolysis in the sperm glycolytic pathway, is known to be associated with sperm motility. Casein kinase II subunit alpha (CSNK2A2), a serine/threonine-selective protein kinase, is associated with sperm apoptosis. We used immunoblotting and immunofluorescence to analyze the expression and localization of these two proteins. HXK1 and CSNK2A2 expression levels in fresh sperm were significantly higher than that in freeze-thawed sperm (P < 0.001). HXK1 and CSNK2A2 were detected in the main part of the sperm flagellum, and the immunofluorescence signal from these proteins was weakened in the freeze-thawed group. Decreased expression of HXK1 and CSNK2A2 may be associated with decreased sperm motility and viability following freeze-thawing. PMID- 26617255 TI - Dopant morphology as the factor limiting graphene conductivity. AB - Graphene's low intrinsic carrier concentration necessitates extrinsic doping to enhance its conductivity and improve its performance for application as electrodes or transparent conductors. Despite this importance limited knowledge of the doping process at application-relevant conditions exists. Employing in situ carrier transport and Raman characterization of different dopants, we here explore the fundamental mechanisms limiting the effectiveness of doping at different doping levels. Three distinct transport regimes for increasing dopant concentration could be identified. First the agglomeration of dopants into clusters provides a route to increase the graphene conductivity through formation of ordered scatterers. As the cluster grows, the charge transfer efficiency between graphene and additional dopants decreases due to emerging polarization effects. Finally, large dopant clusters hinder the carrier motion and cause percolative transport that leads to an unexpected change of the Hall effect. The presented results help identifying the range of beneficial doping density and guide the choice of suitable dopants for graphene's future applications. PMID- 26617256 TI - The influence of cations on lithium ion coordination and transport in ionic liquid electrolytes: a MD simulation study. AB - The dynamical and structural properties in two ionic liquid electrolytes (ILEs) based on 1-ethyl-3-methylimidazolium bis-(trifluoromethanesulfonyl)-imide ([emim][TFSI]) and N-methyl-N-propylpyrrolidinium bis (trifluoromethanesulfonyl)imide([pyr13][TFSI]) were compared as a function of lithium bis-(trifluoromethanesulfonyl)-imide (LiTFSI) salt concentrations using atomistic molecular dynamics (MD) simulations. The many-body polarizable APPLE&P force field has been utilized. The influence of anion polarization on the structure of the first coordination shell of Li(+) was examined. In particular, the reduction of the oxygen of the TFSI anion (OTFSI) polarizability from 1.36 A(3) to 1.00 A(3) resulted in an increased fraction of the TFSI anion bidentate coordination to the Li(+). While the overall dynamics in [pyr13][TFSI]-based ILEs was slower than in [emim][TFSI]-based ILEs, the exchange of TFSI anions in and out of the first coordination shell of Li(+) was found to be faster in pyr13 based systems. The Li(+) ion transference number is higher for these systems as well. These trends can be related to the difference in interaction of TFSI with the IL cation which is stronger for pyr13 than for emim. PMID- 26617254 TI - Physical activity intensity and type 2 diabetes risk in overweight youth: a randomized trial. AB - BACKGROUND: The chronic effects of high-intensity endurance training on metabolic health outcomes in overweight adolescents remains poorly understood. OBJECTIVE: To test the hypothesis that high-intensity endurance training (ET) is superior to moderate-intensity ET for improving risk factors for type 2 diabetes in overweight adolescents. DESIGN AND METHODS: In this randomized trial, 106 overweight and obese adolescents (15.2 years; 76% female; 62% Caucasian) were randomly assigned to high-intensity ET (70-85% of heart rate reserve, n=38), moderate-intensity ET (40-55% heart rate reserve; n=32) or control for 6 months (n=36). The primary and secondary outcome measures were insulin sensitivity assessed using a frequently sampled intravenous glucose tolerance test and hepatic triglyceride content with magnetic resonance spectroscopy. Exploratory outcomes were cardiorespiratory fitness, physical activity and MRI and dual x-ray absorptiometry-derived measures of adiposity. RESULTS: The study had 96% retention and attendance was 61+/-21% and 55+/-24% in the high- and moderate intensity ET arms. Intention-to-treat analyses revealed that, at follow-up, insulin sensitivity was not different between high-intensity (-1.0 mU kg(-1) min( 1); 95% confidence interval (CI): -1.6, +1.4 mU kg(-1) min(-1)) and moderate intensity (+0.26 mU kg(-1) min(-1); 95% CI: -1.3, +1.8 mU kg(-1) min(-1)) ET arms compared with controls (interaction, P=0.97). Similarly, hepatic triglyceride at follow-up was not different in high-intensity (-1.7% fat/water (F/W); 95% CI: 7.0, +3.6% F/W) and moderate-intensity (-0.40% FW; 95% CI: -6.0, +5.3% F/W) ET compared with controls. Both high intensity (+4.4 ml per kg-FFM (fat-free mass) per minute; 95% CI: 1.7, 7.1 ml kg-FFM(-1) min(-1)) and moderate intensity (+4.4 ml kg-FFM(-1) min(-1); 95% CI: 1.6, 7.3 ml kg-FFM(-1) min(-1)) increased cardiorespiratory fitness, relative to controls (interaction P<0.001). CONCLUSIONS: ET improves cardiorespiratory fitness among obese adolescents; however, owing to lack of compliance, the influence of exercise intensity on insulin sensitivity and hepatic triglycerides remains unclear. PMID- 26617257 TI - Strongyloidiasis in a young French woman raises concern about possible ongoing autochthonous transmission in Spain. AB - Strongyloidiasis is one of the most common geohelminth infections in tropical and subtropical areas. Accurate diagnosis remains challenging, leading to an overall underestimation of strongyloidiasis prevalence. The possibility of ongoing autochthonous transmission in some temperate areas and especially in southern Europe is still debated, and data supporting this hypothesis are scarce. The case of a young French woman, who had travelled frequently to Spain and had acquired Strongyloides stercoralis infection as revealed by gastrointestinal symptoms and hypereosinophilia, is reported here. Physicians should keep in mind the risk of being infected in some areas of southern Europe, even if low, in order to avoid the life-threatening manifestations of strongyloidiasis favoured by pathological or therapeutic immunosuppression. PMID- 26617258 TI - Conferring Phosphorogenic Properties on Iridium(III)-Based Bioorthogonal Probes through Modification with a Nitrone Unit. AB - The use of bioorthogonal probes that display fluorogenic or phosphorogenic properties is advantageous to the labeling and imaging of biomolecules in live cells and organisms. Herein we present the design of three iridium(III) complexes containing a nitrone moiety as novel phosphorogenic bioorthogonal probes. These probes were non-emissive owing to isomerization of the C=N group but showed significant emission enhancement upon cycloaddition reaction with strained cyclooctynes. Interestingly, the connection of the nitrone ligand to the cationic iridium(III) center led to accelerated reaction kinetics. These nitrone complexes were also identified as phosphorogenic bioorthogonal labels and imaging reagents for cyclooctyne-modified proteins. These findings contribute to the development of phosphorogenic bioorthogonal probes and imaging reagents. PMID- 26617259 TI - Uterine sarcoma vs adenocarcinoma: can MRI distinguish between them? AB - OBJECTIVE: To analyze the MRI characteristics of uterine sarcomas (mainly carcinosarcomas) and to compare them with those of adenocarcinomas to define the findings that would be useful for the differential diagnosis. MATERIALS AND METHODS: We retrospectively reviewed the MRI studies of 13 patients with histologically diagnosed uterine sarcoma. We analyzed tumor size, signal in T2 weighted, unenhanced and gadolinium-enhanced T1-weighted, and diffusion-weighted sequences. We compared the data obtained with those of another series of 30 consecutive cases of adenocarcinomas studied with MRI. RESULTS: The sarcomas (> 9cm in 77% of cases) were considerably larger than the adenocarcinomas (p<0.001). There were no differences in FIGO staging by MRI or surgery: both tumor types were diagnosed in early stages. The signal intensity in T2-weighted images differed significantly between the two tumor types: all the sarcomas were heterogeneous and predominantly hyperintense with respect to the myometrium in T2 weighted sequences (p<0.001). In postcontrast studies, all the sarcomas showed enhancement greater than or equal to the myometrium; this finding was significantly different from the adenocarcinomas (p<0.001). In diffusion-weighted sequences, we found no significant differences in ADC values in the areas with greatest restriction, but the ADC map was more heterogeneous in the sarcomas. CONCLUSION: Uterine sarcomas do not have specific characteristics on MRI, but some findings can indicate the diagnosis. In our study, we found significant differences between sarcomas and adenocarcinomas. Sarcomas were larger, had more hyperintense and heterogeneous signal intensity in T2-weighted sequences, and enhanced more than or at least as much as the myometrium. PMID- 26617260 TI - [Is magnetic resonance imaging absolutely necessary for musculotendinous disease?]. AB - Disorders of the musculoskeletal system are very prevalent in our society, especially those involving muscles and tendons, above all related to sports and work. These conditions are normally diagnosed and treated according to their clinical symptoms and signs, but a precise diagnosis is often necessary. The most widely used techniques for diagnosing these conditions are ultrasonography and magnetic resonance imaging. In this article, we propose ultrasonography as the technique of choice for diagnosing the most prevalent musculotendinous diseases, because it is accurate, versatile, dynamic, and effective. PMID- 26617261 TI - Field-evolved resistance to Cry1Ab maize by Spodoptera frugiperda in Brazil. AB - BACKGROUND: The first Bt maize in Brazil was launched in 2008 and contained the MON 810 event, which expresses Cry1Ab protein. Although the Cry1Ab dose in MON 810 is not high against fall armyworm (FAW), Spodoptera frugiperda (J.E. Smith), MON 810 provided commercial levels of control. To support insect resistance management in Brazil, the baseline and ongoing susceptibility of FAW was examined using protein bioassays, and the level of control and life history parameters of FAW were evaluated on MON 810 maize. RESULTS: Baseline diet overlay assays with Cry1Ab (16 ug cm(-2) ) caused 76.3% mortality to field FAW populations sampled in 2009. Moderate mortality (48.8%) and significant growth inhibition (88.4%) were verified in leaf-disc bioassays. In greenhouse trials, MON 810 had significantly less damage than non-Bt maize. The surviving FAW larvae on MON 810 (22.4%) had a 5.5 day increase in life cycle time and a 24% reduction in population growth rate. Resistance monitoring (2010-2015) showed a significant reduction in Cry1Ab susceptibility of FAW over time. Additionally, a significant reduction in the field efficacy of MON 810 maize against FAW was observed in different regions from crop season 2009 to 2013. CONCLUSIONS: The decrease in susceptibility to Cry1Ab was expected, but the specific contributions to this resistance by MON 810 maize cannot be distinguished from cross-resistance to Cry1Ab caused by exposure to Cry1F maize. Technologies combining multiple novel insecticidal traits with no cross-resistance to the current Cry1 proteins and high activity against the same target pests should be pursued in Brazil and similar environments. (c) 2015 Society of Chemical Industry. PMID- 26617262 TI - Engaging Copper(III) Corrole as an Electron Acceptor: Photoinduced Charge Separation in Zinc Porphyrin-Copper Corrole Donor-Acceptor Conjugates. AB - An electron-deficient copper(III) corrole was utilized for the construction of donor-acceptor conjugates with zinc(II) porphyrin (ZnP) as a singlet excited state electron donor, and the occurrence of photoinduced charge separation was demonstrated by using transient pump-probe spectroscopic techniques. In these conjugates, the number of copper corrole units was varied from 1 to 2 or 4 units while maintaining a single ZnP entity to observe the effect of corrole multiplicity in facilitating the charge-separation process. The conjugates and control compounds were electrochemically and spectroelectrochemically characterized. Computational studies revealed ground state geometries of the compounds and the electron-deficient nature of the copper(III) corrole. An energy level diagram was established to predict the photochemical events by using optical, emission, electrochemical, and computational data. The occurrence of charge separation from singlet excited zinc porphyrin and charge recombination to yield directly the ground state species were evident from the diagram. Femtosecond transient absorption spectroscopy studies provided spectral evidence of charge separation in the form of the zinc porphyrin radical cation and copper(II) corrole species as products. Rates of charge separation in the conjugates were found to be of the order of 10(10) s(-1) and increased with increasing multiplicity of copper(III) corrole entities. The present study demonstrates the importance of copper(III) corrole as an electron acceptor in building model photosynthetic systems. PMID- 26617263 TI - From mind wandering to involuntary retrieval: Age-related differences in spontaneous cognitive processes. AB - The majority of studies that have investigated the effects of healthy aging on cognition have focused on age-related differences in voluntary and deliberately engaged cognitive processes. Yet many forms of cognition occur spontaneously, without any deliberate attempt at engaging them. In this article we review studies that have assessed age-related differences in four such types of spontaneous thought processes: mind-wandering, involuntary autobiographical memory, intrusive thoughts, and spontaneous prospective memory retrieval. These studies suggest that older adults exhibit a reduction in frequency of both mind wandering and involuntary autobiographical memory, whereas findings regarding intrusive thoughts have been more mixed. Additionally, there is some preliminary evidence that spontaneous prospective memory retrieval may be relatively preserved in aging. We consider the roles of age-related differences in cognitive resources, motivation, current concerns and emotional regulation in accounting for these findings. We also consider age-related differences in the neural correlates of spontaneous cognitive processes. PMID- 26617264 TI - Impaired acquisition of new words after left temporal lobectomy despite normal fast-mapping behavior. AB - Word learning has been proposed to rely on unique brain regions including the temporal lobes, and the left temporal lobe appears to be especially important. In order to investigate the role of the left temporal lobe in word learning under different conditions, we tested whether patients with left temporal lobectomies (N=6) could learn novel words using two distinct formats. Previous research has shown that word learning in contrastive fast mapping conditions may rely on different neural substrates than explicit encoding conditions (Sharon et al., 2011). In the current investigation, we used a previously reported word learning task that implemented two distinct study formats (Warren and Duff, 2014): a contrastive fast mapping condition in which a picture of a novel item was displayed beside a picture of a familiar item while the novel item's name was presented aurally ("Click on the numbat."); and an explicit encoding (i.e., control) condition in which a picture of a novel item was displayed while its name was presented aurally ("This is a numbat."). After a delay, learning of the novel words was evaluated with memory tests including three-alternative forced choice recognition, free recall, cued recall, and familiarity ratings. During the fast-mapping study condition both the left temporal lobectomy and healthy comparison groups performed well, but at test only the comparison group showed evidence of novel word learning. Our findings indicate that unilateral resection of the left temporal lobe including the hippocampus and temporal pole can severely impair word learning, and that fast-mapping study conditions do not promote subsequent word learning in temporal lobectomy populations. PMID- 26617265 TI - Effect of Statin Treatment on Plasma 4beta-Hydroxycholesterol Concentrations. AB - The endogenous oxysterol 4beta-hydroxycholesterol may be used as a marker for the drug-metabolizing enzymes cytochrome P450 3A (CYP3A). The primary aim of this study was to investigate the effect of statin treatment on plasma 4beta hydroxycholesterol concentrations. Plasma samples from a previously performed clinical study where gallstone patients had been treated with placebo (n = 6), 20 mg fluvastatin (n = 9) or 80 mg atorvastatin (n = 9) daily for 4 weeks were analysed. Hepatic CYP3A mRNA levels had previously been shown to be unchanged in all three treatment groups. Plasma 4beta-hydroxycholesterol did not change significantly (p = 0.92) in the placebo group, but treatment with low-dose fluvastatin or high-dose atorvastatin resulted in reductions in plasma concentration of 10.7% (p < 0.05) and 36.5% (p < 0.01), respectively. However, the 4beta-hydroxycholesterol/cholesterol ratio did not change significantly for the patients receiving placebo or patients receiving low-dose fluvastatin. The ratio for patients receiving high-dose atorvastatin increased by 12% (p < 0.05). In conclusion, the total plasma cholesterol level is an important determinant for the plasma 4beta-hydroxycholesterol level. PMID- 26617266 TI - Knockout mutations of insulin-like peptide genes enhance sexual receptivity in Drosophila virgin females. AB - In the fruitfly Drosophila melanogaster, females take the initiative to mate successfully because they decide whether to mate or not. However, little is known about the molecular and neuronal mechanisms regulating sexual receptivity in virgin females. Genetic tools available in Drosophila are useful for identifying molecules and neural circuits involved in the regulation of sexual receptivity. We previously demonstrated that insulin-producing cells (IPCs) in the female brain are critical to the regulation of female sexual receptivity. Ablation and inactivation of IPCs enhance female sexual receptivity, suggesting that neurosecretion from IPCs inhibits female sexual receptivity. IPCs produce and release insulin-like peptides (Ilps) that modulate various biological processes such as metabolism, growth, lifespan and behaviors. Here, we report a novel role of the Ilps in sexual behavior in Drosophila virgin females. Compared with wild type females, females with knockout mutations of Ilps showed a high mating success rate toward wild-type males, whereas wild-type males courted wild-type and Ilp-knockout females to the same extent. Wild-type receptive females retard their movement during male courtship and this reduced female mobility allows males to copulate. Thus, it was anticipated that knockout mutations of Ilps would reduce general locomotion. However, the locomotor activity in Ilp-knockout females was significantly higher than that in wild-type females. Thus, our findings indicate that the high mating success rate in Ilp-knockout females is caused by their enhanced sexual receptivity, but not by improvement of their sex appeal or by general sluggishness. PMID- 26617267 TI - Generation of artificial drooping leaf mutants by CRISPR-Cas9 technology in rice. AB - CRISPR-Cas9 technology, which uses an RNA-guided nuclease, has been developed as an efficient and versatile genome-editing method to induce mutations in genes of interest. To examine the feasibility of this method in developmental studies of a model monocot, rice (Oryza sativa), we introduced the construct gDL-1, which produced a guide RNA targeting the DROOPING LEAF (DL) gene. DL regulates midrib formation in the leaf and carpel specification in the flower. Because loss of function of DL causes the drooping leaf phenotype in regenerated seedlings, the effect of gene disruption should be easily detected. In transgenic plants carrying gDL-1, the DL gene was disrupted at high efficiency: seven out of nine plants examined had bi-allelic mutations. All transgenic plants with the bi allelic mutation showed the drooping leaf phenotype. Observation of cross sections of the leaf blade clearly indicated that these transgenic plants failed to make midrib structures, and were comparable to the severe dl mutant dl-sup1. Thus, CRISPR-Cas9 technology can be a useful and efficient tool in developmental studies in rice. PMID- 26617268 TI - The uremic toxin indoxyl sulfate exacerbates reactive oxygen species production and inflammation in 3T3-L1 adipose cells. AB - Inflammation and oxidative stress are common features of patients with chronic kidney disease (CKD) and many uremic solutes retained in these patients could be involved in these processes, among which protein-bound solutes such as indoxyl sulfate (IS). White adipose tissue recently gained attention as an important source of inflammation and oxidative stress. To examine the effect of IS on adipocytes, 3T3-L1 adipose cells were incubated with IS to mimic the conditions encountered in uremic patients. Incubation of adipose cells with IS increased reactive oxygen species production generated mainly through activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase since it was prevented by the NADPH oxidase inhibitor apocynin. Exposure to IS furthermore exacerbated the secretion of tumor necrosis factor-alpha and interleukin-6 by adipose cells. This inflammatory response was prevented by NADPH oxidase inhibition pinpointing the pivotal role of intracellular oxidative stress. IS induces adipocyte perturbation and promotes inflammatory state mainly through induction of oxidative stress. IS, a uremic toxin, accumulates in CKD patients could, therefore, be an important mediator of adipocyte dysfunction in these patients. PMID- 26617269 TI - Scopariusicides, Novel Unsymmetrical Cyclobutanes: Structural Elucidation and Concise Synthesis by a Combination of Intermolecular [2 + 2] Cycloaddition and C H Functionalization. AB - Scopariusicides A (1) and B (2), two novel immunosuppressive unsymmetrical cyclobutane derivatives, were isolated from the aerial parts of Isodon scoparius. Moreover, based on the results of phytochemical investigation, a concise stereocontrolled synthesis of scopariusicide A and its analogues with enhanced biological activities was efficiently achieved using the main diterpenoid (3) isolated from this plant as a readily available starting material. A crossed intermolecular [2 + 2] photocycloaddition and a Pd-catalyzed sp(3) C-H bond beta arylation were used synergistically to access the highly congested unsymmetrical cyclobutane core with four contiguous stereocenters. PMID- 26617270 TI - Resonances of nanoparticles with poor plasmonic metal tips. AB - The catalytic and optical properties of metal nanoparticles can be combined to create platforms for light-driven chemical energy storage and enhanced in-situ reaction monitoring. However, the heavily damped plasmon resonances of many catalytically active metals (e.g. Pt, Pd) prevent this dual functionality in pure nanostructures. The addition of catalytic metals at the surface of efficient plasmonic particles thus presents a unique opportunity if the resonances can be conserved after coating. Here, nanometer resolution electron-based techniques (electron energy loss, cathodoluminescence, and energy dispersive X-ray spectroscopy) are used to show that Au particles incorporating a catalytically active but heavily damped metal, Pd, sustain multiple size-dependent localized surface plasmon resonances (LSPRs) that are narrow and strongly localized at the Pd-rich tips. The resonances also couple with a dielectric substrate and other nanoparticles, establishing that the full range of plasmonic behavior is observed in these multifunctional nanostructures despite the presence of Pd. PMID- 26617271 TI - Effect of Foeniculum vulgare (fennel) vaginal cream on vaginal atrophy in postmenopausal women: A double-blind randomized placebo-controlled trial. AB - OBJECTIVE: Vaginal atrophy is one of the main concerns of postmenopausal women. The aim of the present study was to investigate the effect of fennel vaginal cream on vaginal atrophy in postmenopausal women in Ahvaz, Iran. MATERIALS AND METHODS: This double-blind randomized controlled trial was conducted on 60 postmenopausal women (45-65 years of age) in Ahvaz, Iran. The study participants were randomly divided into one of two groups, receiving either a placebo (n=30) or fennel 5% vaginal cream (n=30) administered as one application per day (5g/day) for 8 weeks. MAIN OUTCOME: The vaginal pH and maturation vaginal index (MVI) were measured at baseline and 8 weeks after the intervention, while the vaginal atrophy symptoms was measured at baseline and at 2, 4, and 8 weeks after the intervention. The data were analyzed using the independent t-test, chi-square test, paired sample t-test, and the generalized estimating equation. RESULTS: The number of superficial cells increased significantly in the fennel group after 8 weeks compared to the control group (76.1+/-15.3 vs. 11.8+/-8, p<0.001). The number of intermediate and parabasal cells decreased significantly in the fennel group compared to the control group (p<0.001). The vaginal pH decreased significantly at the 8-week follow-up in the fennel group compared to the control group (100% vs. 7.4%, p<0.001). All women in the fennel group had an MVI of 65 100 at the 8-week follow-up, whereas almost half (40.7%) of the women in the control group had an MVI of 50-64 (p<0.001). CONCLUSION: According to results of this study, fennel is an effective means to manage the symptoms of vaginal atrophy in postmenopausal women and is devoid of side effects. Larger studies are necessary to confirm the positive impact of fennel for vaginal conditions occurring among postmenopausal women. PMID- 26617272 TI - Awareness of breast cancer and barriers to breast screening uptake in Bangladesh: A population based survey. AB - OBJECTIVES: To investigate the awareness of breast cancer (BCa) and BCa screening amongst women at midlife in Bangladesh. METHODS: A nationally representative cross-sectional survey of women aged 30-59 years was conducted in 7 districts of the 7 divisions in Bangladesh, using a multistage cluster sampling technique. The factors associated with the awareness of BCa and breast assessment of asymptomatic women were investigated separately, using multivariable logistic regression. RESULTS: Of the 1590 participants, mean age 42.3 (+/-8.0) years, 81.9% had ever heard of BCa and 64.2% of any methods of BCa screening, respectively. Awareness of BCa was associated with being aged 40-49 years (adjusted OR 2.04, 95% CI 1.46-2.84), aged 49-59 years (1.96, 1.32-2.91), being overweight (1.46, 1.07-2.01) and obesity (1.62, 1.01-2.62), while inversely associated with rural dwelling (0.37, 0.22-0.61), primary education (0.44, 0.27 0.70), having no education (0.23, 0.14-0.36) and parity (0.62, 0.44-0.87). Of the 750 women who were aware of clinical breast examination (CBE) or mammography, reasons provided for not undergoing screening included that they had no symptoms (92%) and that they did not know screening was needed (40%). 8% of women reported CBE. Women with no education were less likely to have undergone CBE (0.38, 0.141.04; p=0.059). CONCLUSION: Lack of understanding of the assessment of asymptomatic women is the key obstacle to BCa screening uptake in Bangladesh. Health education programs, especially BCa awareness programs, have the potential to increase BCa awareness and down-staging of the disease. PMID- 26617273 TI - Intracellular periodontal pathogen exploits recycling pathway to exit from infected cells. AB - Although human gingival epithelium prevents intrusions by periodontal bacteria, Porphyromonas gingivalis, the most well-known periodontal pathogen, is able to invade gingival epithelial cells and pass through the epithelial barrier into deeper tissues. We previously reported that intracellular P. gingivalis exits from gingival epithelial cells via a recycling pathway. However, the underlying molecular process remains unknown. In the present study, we found that the pathogen localized in early endosomes recruits VAMP2 and Rab4A. VAMP2 was found to be specifically localized in early endosomes, although its localization remained unclear in mammalian cells. A single transmembrane domain of VAMP2 was found to be necessary and sufficient for localizing in early endosomes containing P. gingivalis in gingival epithelial cells. VAMP2 forms a complex with EXOC2/Sec5 and EXOC3/Sec6, whereas Rab4A mediates dissociation of the EXOC complex followed by recruitment of RUFY1/Rabip4, Rab4A effector, and Rab14. Depletion of VAMP2 or Rab4A resulted in accumulation of bacteria in early endosomes and disturbed bacterial exit from infected cells. It is suggested that these novel dynamics allow P. gingivalis to exploit fast recycling pathways promoting further bacterial penetration of gingival tissues. PMID- 26617274 TI - Bioanalytical approaches to assess the proteolytic stability of therapeutic fusion proteins. AB - Therapeutic fusion proteins (TFPs) are designed to improve the therapeutic profile of an endogenous protein or protein fragment with a limited dose frequency providing the desired pharmacological activity in vivo. Fusion of a therapeutic protein to a half-life extension or targeting domain can improve the disposition of the molecule or introduce a novel mechanism of action. Prolonged exposure and altered biodistribution of an endogenous protein through fusion technology increases the potential for local protein unfolding during circulation increasing the chance for partial proteolysis of the therapeutic domain. Characterizing the proteolytic liabilities of a TFP can guide engineering efforts to inhibit or hinder partial proteolysis. This review focuses on considerations and techniques for evaluating the stability of a TFP both in vivo and in vitro. PMID- 26617275 TI - A prospective observational study of maternal oxygenation during remifentanil patient-controlled analgesia use in labour. AB - Numerous studies of remifentanil patient-controlled analgesia during labour have shown high levels of maternal satisfaction, but concerns remain, especially over the side-effects of sedation and respiratory depression. We conducted a prospective observational study of maternal oxygen desaturation during remifentanil patient-controlled analgesia. Pulse oximetry values were recorded every eight s and later downloaded for analysis. A desaturation episode was defined as oxygen saturation < 90%. We collected 148 h of data in 61 women, during which we observed 176 desaturation episodes. These episodes occurred in 43 (70%) women. The median (IQR [range]) of the lowest saturation during each episode was 87 (85-89 [68-89])% with duration 16 (8-24 [8-104]) s. Supplementary oxygen reduced the time per hour spent with saturation < 90%, but not the depth or duration of individual episodes. Desaturation episodes were twice as common during the second stage of labour as compared with the first stage. Prior opioid administration, bolus size and use of nitrous oxide during patient-controlled analgesia use were not found to influence frequency, depth or duration of desaturation episodes. Although these findings suggest desaturation occurs more frequently during remifentanil patient-controlled analgesia than previously reported, the results are comparable with earlier oximetry studies of women who received nitrous oxide and pethidine during labour. PMID- 26617276 TI - The magnetocaloric effect with critical behavior of a periodic Anderson-like organic polymer. AB - We study the magnetocaloric effect and the critical behavior of a periodic Anderson-like organic polymer using Green's function theory, in which the localized f orbitals hybridize with the conduction orbitals at even sites. The field-induced metal-insulator transitions with the magnetic Gruneisen parameter showing |Gammah|~T(-1) power-law critical behaviour are revealed, which provides a new thermodynamic means for probing quantum phase transitions. It is found that the competition of up-spin and down-spin hole excitations is responsible for the double peak structure of magnetic entropy change (-DeltaS) for the dominant Kondo coupling case, implying a double magnetic cooling process via demagnetization, which follows a power law dependence of the magnetic field h: -DeltaS~h(n). The local exponent n tends to 1 and 2 below and above TC, while has a minimum of 0.648 at TC, which is in accordance with the experimental observation of perovskite manganites Pr0.55Sr0.45MnO3 and Nd0.55Sr0.45MnO3 (J. Y. Fan et al., Appl. Phys. Lett., 2011, 98, 072508; Europhys. Lett., 2015, 112, 17005) corresponding to the conventional ferromagnets within the mean field theory DeltaS~h(2/3). At TC, the -DeltaS~h curves with a convex curvature superpose each other for small V values, which are separated by the large V case, distinguishing the RKKY interaction and Kondo coupling explicitly. Furthermore, the critical scaling law n(TC) = 1 + (beta- 1)/(beta + gamma) = 1 + 1/delta(1 - 1/beta) is related to the critical exponents (beta, gamma, and delta) extracted from the Arrott-Noakes equation of state and the Kouvel-Fisher method, which fulfill the Widom scaling relation delta = 1 + gammabeta(-1), indicating the self-consistency and reliability of the obtained results. In addition, based on the scaling hypothesis through checking the scaling analysis of magnetization, the M-T-h curves collapse into two independent universal branches below and above TC. PMID- 26617277 TI - Phenotypic differentiation of gastrointestinal microbes is reflected in their encoded metabolic repertoires. AB - BACKGROUND: The human gastrointestinal tract harbors a diverse microbial community, in which metabolic phenotypes play important roles for the human host. Recent developments in meta-omics attempt to unravel metabolic roles of microbes by linking genotypic and phenotypic characteristics. This connection, however, still remains poorly understood with respect to its evolutionary and ecological context. RESULTS: We generated automatically refined draft genome-scale metabolic models of 301 representative intestinal microbes in silico. We applied a combination of unsupervised machine-learning and systems biology techniques to study individual and global differences in genomic content and inferred metabolic capabilities. Based on the global metabolic differences, we found that energy metabolism and membrane synthesis play important roles in delineating different taxonomic groups. Furthermore, we found an exponential relationship between phylogeny and the reaction composition, meaning that closely related microbes of the same genus can exhibit pronounced differences with respect to their metabolic capabilities while at the family level only marginal metabolic differences can be observed. This finding was further substantiated by the metabolic divergence within different genera. In particular, we could distinguish three sub-type clusters based on membrane and energy metabolism within the Lactobacilli as well as two clusters within the Bifidobacteria and Bacteroides. CONCLUSIONS: We demonstrate that phenotypic differentiation within closely related species could be explained by their metabolic repertoire rather than their phylogenetic relationships. These results have important implications in our understanding of the ecological and evolutionary complexity of the human gastrointestinal microbiome. PMID- 26617278 TI - A temperate river estuary is a sink for methanotrophs adapted to extremes of pH, temperature and salinity. AB - River Tyne (UK) estuarine sediments harbour a genetically and functionally diverse community of methane-oxidizing bacteria (methanotrophs), the composition and activity of which were directly influenced by imposed environmental conditions (pH, salinity, temperature) that extended far beyond those found in situ. In aerobic sediment slurries methane oxidation rates were monitored together with the diversity of a functional gene marker for methanotrophs (pmoA). Under near in situ conditions (4-30 degrees C, pH 6-8, 1-15 g l(-1) NaCl), communities were enriched by sequences affiliated with Methylobacter and Methylomonas spp. and specifically a Methylobacter psychrophilus-related species at 4-21 degrees C. More extreme conditions, namely high temperatures >= 40 degrees C, high >= 9 and low <= 5 pH, and high salinities >= 35 g l(-1) selected for putative thermophiles (Methylocaldum), acidophiles (Methylosoma) and haloalkaliphiles (Methylomicrobium). The presence of these extreme methanotrophs (unlikely to be part of the active community in situ) indicates passive dispersal from surrounding environments into the estuary. PMID- 26617279 TI - Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury. AB - Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 degrees C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation. PMID- 26617282 TI - Mitochondrial genome of Megaphragma amalphitanum (Hymenoptera: Trichogrammatidae). AB - The mitochondrial genome of the parasitic wasp Megaphragma amalphitanum is published in this paper. The mitochondrial DNA (mtDNA) is 15 041 base pairs (bp) in length and contained 13 protein-coding genes, 2 rRNA genes and 22 tRNA genes. The overall base composition of the genome in descending order was 45.67% A, 8.71% C, 39.63% T and 5.99% G, with a significant AT bias of 85.30%. PMID- 26617284 TI - An economic evaluation of the ketogenic diet versus care as usual in children and adolescents with intractable epilepsy: An interim analysis. AB - OBJECTIVES: To gain insight into the cost-effectiveness of the ketogenic (KD) diet compared with care as usual (CAU) in children and adolescents with intractable epilepsy, we conducted an economic evaluation from a societal perspective, alongside a randomized controlled trial. METHODS: Participants from a tertiary epilepsy center were randomized into KD (intervention) group or CAU (control) group. Seizure frequency, quality adjusted life years (QALYs), health care costs, production losses of parents and patient, and family costs were assessed at baseline and during a 4-month study period and compared between the intervention and control groups. The incremental cost-effectiveness ratios (ICERs) (i.e., cost per QALY and cost per responder), and cost-effectiveness acceptability curves (CEACs) were calculated and presented. RESULTS: In total, 48 children were included in the analyses of this study (26 KD group). At 4 months, 50% of the participants in the KD group had a seizure reduction >=50% from baseline, compared with 18.2 of the participants in the CAU group. The mean costs per patient in the CAU group were ?15,245 compared to ?20,986 per patient in the KD group, resulting in an ICER of ?18,044 per responder. We failed, however, to measure any benefits in terms of QALYs and therefore, the cost per QALY rise high above any acceptable ceiling ratio. It might be that the quality of life instruments used in this study were not sufficiently sensitive to detect changes, or it might be that being a clinical responder is not sufficient to improve a patient's quality of life. Univariate and multivariate sensitivity analyses and nonparametric bootstrapping were performed and demonstrated the robustness of our results. SIGNIFICANCE: The results show that the KD reduces seizure frequency. The study did not find any improvements in quality of life and, therefore, unfavorable cost per QALY ratio's resulted. PMID- 26617280 TI - Sorting out release, uptake and processing of alpha-synuclein during prion-like spread of pathology. AB - Parkinson's disease is a progressive neurological disorder that is characterized by the formation of intracellular protein inclusion bodies composed primarily of a misfolded and aggregated form of the protein alpha-synuclein. There is growing evidence that supports the prion-like hypothesis of alpha-synuclein progression. This hypothesis postulates that alpha-synuclein is a prion-like pathological agent and is responsible for the progression of Parkinson pathology in the brain. Potential misfolding or aggregation of alpha-synuclein that might occur in the peripheral nervous system as a result of some insult, environmental or genetic (or more likely a combination of both) that might spread into the midbrain, eventually causing degeneration of the neurons in the substantia nigra. As the disease progresses further, it is likely that alpha-synuclein pathology continues to spread throughout the brain, including the cortex, leading to deterioration of cognition and higher brain functions. While it is unknown why alpha-synuclein initially misfolds and aggregates, a great deal has been learned about how the cell handles aberrant alpha-synuclein assemblies. In this review, we focus on these mechanisms and discuss them in an attempt to define the role that they might play in the propagation of misfolded alpha-synuclein from cell-to-cell. The prion-like hypothesis of alpha-synuclein pathology suggests a method for the transmission of misfolded alpha-synuclein from one neuron to another. This hypothesis postulates that misfolded alpha-synuclein becomes aggregation prone and when released and taken up by neighboring cells, seeds further misfolding and aggregation. In this review we examine the cellular mechanisms that are involved in the processing of alpha-synuclein and how these may contribute to the prion like propagation of alpha-synuclein pathology. This article is part of a special issue on Parkinson disease. PMID- 26617281 TI - TGF-beta in tolerance, development and regulation of immunity. AB - The TGF-beta superfamily is an ancient metazoan protein class which cuts across cell and tissue differentiation, developmental biology and immunology. Its many members are regulated at multiple levels from intricate control of gene transcription, post-translational processing and activation, and signaling through overlapping receptor structures and downstream intracellular messengers. We have been interested in TGF-beta homologues firstly as key players in the induction of immunological tolerance, the topic so closely associated with Ray Owen. Secondly, our interests in how parasites may manipulate the immune system of their host has also brought us to study the TGF-beta pathway in infections with longlived, essentially tolerogenic, helminth parasites. Finally, within the spectrum of mammalian TGF-beta proteins is an exquisitely tightly-regulated gene, anti-Mullerian hormone (AMH), whose role in sex determination underpins the phenotype of freemartin calves that formed the focus of Ray's seminal work on immunological tolerance. PMID- 26617286 TI - Hypoxia and GABA shunt activation in the pathogenesis of Alzheimer's disease. AB - We have previously observed that the conversion of mild cognitive impairment to definitive Alzheimer's disease (AD) is associated with a significant increase in the serum level of 2,4-dihydroxybutyrate (2,4-DHBA). The metabolic generation of 2,4-DHBA is linked to the activation of the gamma-aminobutyric acid (GABA) shunt, an alternative energy production pathway activated during cellular stress, when the function of Krebs cycle is compromised. The GABA shunt can be triggered by local hypoperfusion and subsequent hypoxia in AD brains caused by cerebral amyloid angiopathy. Succinic semialdehyde dehydrogenase (SSADH) is a key enzyme in the GABA shunt, converting succinic semialdehyde (SSA) into succinate, a Krebs cycle intermediate. A deficiency of SSADH activity stimulates the conversion of SSA into gamma-hydroxybutyrate (GHB), an alternative route from the GABA shunt. GHB can exert not only acute neuroprotective activities but unfortunately also chronic detrimental effects which may lead to cognitive impairment. Subsequently, GHB can be metabolized to 2,4-DHBA and secreted from the brain. Thus, the activation of the GABA shunt and the generation of GHB and 2,4-DHBA can have an important role in the early phase of AD pathogenesis. PMID- 26617288 TI - Charting Frontotemporal Dementia: From Genes to Networks. AB - Frontotemporal dementia (FTD) is a genetically and clinically heterogeneous syndrome that is characterized by overlapping clinical symptoms involving behavior, personality, language and/or motor functions and degeneration of the frontal and temporal lobes. The term frontotemporal lobar degeneration (FTLD) is used to describe the proteinopathies associated with clinical FTD. Emerging evidence from network-based neuroimaging studies, such as resting state functional MRI and diffusion tensor MRI studies, have implicated specific large scale brain networks in the pathogenesis of FTD syndromes, suggesting a new paradigm for explaining the distributed and heterogeneous spreading patterns of pathological proteins in FTLD. In this review, we overview recent research on the study of FTD syndromes as connectivity disorders in symptomatic patients as well as genotype-specific changes in asymptomatic FTD-related gene mutation carriers. Characterizing brain network breakdown in these subjects using neuroimaging may help anticipate the diagnosis and perhaps prevent the devastating impact of FTD. PMID- 26617287 TI - The fucomic potential of mosquitoes: Fucosylated N-glycan epitopes and their cognate fucosyltransferases. AB - Fucoconjugates are key mediators of protein-glycan interactions in prokaryotes and eukaryotes. As examples, N-glycans modified with the non-mammalian core alpha1,3-linked fucose have been detected in various organisms ranging from plants to insects and are immunogenic in mammals. The rabbit polyclonal antibody raised against plant horseradish peroxidase (anti-HRP) is able to recognize the alpha1,3-linked fucose epitope and is also known to specifically stain neural tissues in the fruit fly Drosophila melanogaster. In this study, we have detected and localized the anti-HRP cross-reactivity in another insect species, the malaria mosquito vector Anopheles gambiae. We were able to identify and structurally elucidate fucosylated N-glycans including core mono- and difucosylated structures (responsible for anti-HRP cross reactivity) as well as a Lewis-type antennal modification on mosquito anionic N-glycans by applying enzymatic and chemical treatments. The three mosquito fucosyltransferase open reading frames (FucT6, FucTA and FucTC) required for the in vivo biosynthesis of the fucosylated N-glycan epitopes were identified in the Anopheles gambiae genome, cloned and recombinantly expressed in Pichia pastoris. Using a robust MALDI-TOF MS approach, we characterised the activity of the three recombinant fucosyltransferases in vitro and demonstrate that they share similar enzymatic properties as compared to their homologues from D. melanogaster and Apis mellifera. Thus, not only do we confirm the neural reactivity of anti-HRP in a mosquito species, but also demonstrate enzymatic activity for all its alpha1,3- and alpha1,6-fucosyltransferase homologues, whose specificity matches the results of glycomic analyses. PMID- 26617289 TI - Incremental Tuning Up of Fluorous Phenazine Acceptors. AB - In a simple, one-step direct trifluoromethylation of phenazine with CF3 I we prepared and characterized nine (poly)trifluoromethyl derivatives with up to six CF3 groups. The electrochemical reduction potentials and gas-phase electron affinities show a direct, strict linear relation to the number of CF3 groups, with phenazine(CF3)6 reaching a record-high electron affinity of 3.24 eV among perfluoroalkylated polyaromatics. PMID- 26617290 TI - [Diagnosis of inherited thrombocytopenia]. AB - Inherited thrombocytopenias are rare, heterogenous and probably under-diagnosed because often classified as autoimmune thrombocytopenia. About 20 genes were described responsible for these thrombocytopenias. Precise diagnosis is necessary because the prognosis is different and some of them can evolve into hemopathies. First of all, it is important to gather a body of evidence to orientate towards an inherited cause: presence of the thrombocytopenia since childhood and of other family cases is a strong argument. Secondly, it is difficult to target the genetic investigations that settle the precise diagnosis. Genetic variants responsible for inherited thrombocytopenias affect different stage during megakaryocytopoiesis and cause thrombocytopenias with distinct characteristics. Presence of extra-hematological features, platelets' size measurement and evaluation of bone marrow megakaryocyte morphology when it is possible allow a primary orientation. We propose a diagnostic approach considering extra hematological features, mode of inheritance, morphology, molecular and functional platelets' studies and bone marrow megakaryocyte morphology in order to better target genetic study. Nevertheless, despite this approach, some inherited thrombocytopenias remain still unexplained and could benefit from new methods of new generation sequencing in the future. PMID- 26617291 TI - [Atopic dermatitis of the adult]. AB - Atopic dermatitis (AD) of the adult is a common skin disease. Its prevalence has greatly increased during the past decades. AD is commonly associated with other atopic disorders. Its impact on quality of life is often underestimated. Various immunopathologic mechanisms are involved in AD: innate epidermal barrier dysfunction due to filaggrin gene mutations, innate and adaptative abnormalities of the immune system (an initial Th2 phase precedes a chronic Th1 phase), intestinal and cutaneous microbiomes dysbiosis, and environmental factors. Diagnosis of AD is clinical and there is no predictive biomarker of future severity. The main differential diagnoses are: scabies, psoriasis, cutaneous adverse reaction, cutaneous T cell lymphoma, primary immunodeficiency, and Netherton's syndrome. Therapeutic management is challenging and should integrate a therapeutic education program. Topical corticosteroids are the first line treatment, including a preliminary assessment of possible topical corticosteroids phobia. Systemic treatments are recommended in severe, chronic and resistant AD, after careful evaluation in a reference centre. Dupilumab, an IL4/IL13 inhibitor, might be the first effective targeted therapy in AD, whereas therapies that specifically target the mechanisms of pruritus represent an exciting perspective. PMID- 26617292 TI - [Issues and difficulties in the relationship between patients and caregivers in painful sickle cell vaso-occlusive crisis]. AB - Sickle cell patients in acute pain situation experiment cognitive, behavioral and emotional changes that can accentuate their pain and disrupt communication with caregivers. On the other hand, caregivers have to face pain assessment difficulties and their own psychological reactions to their patient's pain. The gap between the patient's experience and caregiver's evaluation can lead to conflict and non-adherence treatment, and have a direct impact on the sickle cell disease prognosis. There is nothing inevitable about these phenomena, whose knowledge allows the action and opens up prospects for improving the management of sickle cell disease pain. This article is a narrative review updating the interactions between acute pain and some configurations, such as the inability to discern emotions, catastrophizing, post-traumatic stress or feeling ostracized. The overestimation of patient's addiction by caregivers also influences the pain itself. Open communication, as well as some treatments, medicated or not, a consistent institutional organization and a multidisciplinary approach altogether have an analgesic role by acting on pain cognitive and emotional components. PMID- 26617294 TI - Influence of Strong Electron Correlation on Magnetism in Transition-Metal Doped Si Nanocrystals. AB - We studied the influence of strong electron correlation on magnetic properties of Si nanocrystals doped with the transition metal (TM) atoms Mn and Fe. Different approaches to describe exchange and correlation (XC) effects are compared within a density-functional framework. Beside a semilocal treatment, two different methods to include the influence of electron correlation on the localized TM 3d states are studied. They are based on XC functionals with the inclusion of on site Coulomb repulsion or short-range screened exchange. We demonstrate a strong dependence of both electronic structure and magnetization on the used XC functional. The inclusion of strong correlation drastically changes position and occupation of the TM or TM-Si-bond-derived levels as well as the total magnetic moments. PMID- 26617293 TI - Interaction of the serine hydrolase KIAA1363 with organophosphorus agents: Evaluation of potency and kinetics. AB - Oxons are bioactive metabolites of organophosphorus insecticides (OPs) that covalently inactivate serine hydrolases. KIAA1363 is one of the most abundant serine hydrolases in mouse brain. Although the physiological consequences related to the inhibition of KIAA1363 due to environmental exposures to OPs are poorly understood, the enzyme was previously shown to have a role in the detoxification of oxons. Here, we overexpressed human KIAA1363 and CES1 in COS7 cells and compared the potency of inhibition (IC50s, 15 min) of KIAA1363 and CES1 by chlorpyrifos oxon (CPO), paraoxon (PO), and methyl paraoxon (MPO). The order of potency was CPO > PO >> MPO for both enzymes. We also determined the bimolecular rate constants (kinact/Ki) for reactions of CPO and PO with KIAA1363 and CES1. KIAA1363 and CES1 were inactivated by CPO at comparable rates (4.4 * 10(6) s(-1) M(-1) and 6.7 * 10(6) s(-1) M(-1), respectively), whereas PO inactivated both enzymes at slower rates (0.4 * 10(6) s(-1) M(-1) and 1.5 * 10(6) s(-1) M(-1), respectively). Finally, the reactivation rate of KIAA1363 following inhibition by CPO was evaluated. Together, the results define the kinetics of inhibition of KIAA1363 by active metabolites of agrochemicals and indicate that KIAA1363 is highly sensitive to inhibition by these compounds. PMID- 26617295 TI - Combined Quantum Mechanical and Molecular Mechanical Methods for Calculating Potential Energy Surfaces: Tuned and Balanced Redistributed-Charge Algorithm. AB - The combined quantum mechanical and molecular mechanical (QM/MM) method is one of the most powerful approaches for including correlation and polarization effects in simulations of large and complex systems, and the present article is concerned with the systematics of treating a QM/MM boundary that passes through a covalent bond, especially a polar covalent bond. In this study, we develop a new algorithm to treat such boundaries; the new method is called the balanced redistributed charge (balanced RC or BRC) scheme with a tuned fluorine link atom. The MM point charge on the MM boundary atom is modified to conserve the total charge of the entire system, and the modified charge is redistributed to the midpoints of the bonds between an MM boundary atom and its neighboring MM atoms. A pseudopotential is added to the fluorine link atom to reproduce the partial charge of the uncapped portion of the QM subsystem. We select proton affinities as the property used to validate the new method because the energy change associated with the addition of an entire charge (proton) to the QM system is very sensitive to the treatment of electrostatics at the boundary; we apply the new method to calculate proton affinities of 25 molecules with 13 different kinds of bonds being cut. The average proton affinity in the test set is 373 kcal/mol, and the test set provides a more challenging test than those usually used for testing QM/MM methods. For this challenging test set, common unbalanced schemes give a mean unsigned error (MUE) of 15-21 kcal/mol for H link atoms or 16-24 kcal/mol for F link atoms, much larger than the 5 kcal/mol obtained by simply omitting the MM region with either kind of link atom. Balancing the charges reduces the error to 5-7 kcal/mol for H link atoms and 4-6 kcal/mol for F link atoms. Balancing the charges and also tuning an F link atom lowers the MUE to 1.3-4 kcal/mol, with the best result for the balanced RC scheme. We conclude that properly tuning the link atom and correctly treating the point charges near the QM/MM boundary significantly improves the accuracy of the calculated proton affinities. PMID- 26617296 TI - Electronic Transition Energies: A Study of the Performance of a Large Range of Single Reference Density Functional and Wave Function Methods on Valence and Rydberg States Compared to Experiment. AB - This work reports a comparison among wave function and DFT single reference methods for vertical electronic transition energy calculations toward singlet states, valence and Rydberg in nature. A series of 11 small organic molecules are used as test cases, where accurate experimental data in gas phase are available. We compared CIS, RPA, CIS(D), EOM-CCSD, and 28 multipurpose density functionals of the type LSDA, GGA, M-GGA, H-GGA, HM-GGA and with separated short and long range exchange. The list of functionals is obviously not complete, but it spans more than 20 years of DFT development and includes functionals which are commonly used in the computation of a variety of molecular properties. Large differences in the results were found between the various functionals. The aim of this work is therefore to shed some light on the performance of the plethora of functionals available and compare them with some traditional wave function based methods on a molecular property of large interest as the transition energy. PMID- 26617297 TI - An Efficient Parallel All-Electron Four-Component Dirac-Kohn-Sham Program Using a Distributed Matrix Approach. AB - We show that all-electron relativistic four-component Dirac-Kohn-Sham (DKS) computations, using G-spinor basis sets and state-of-the-art density fitting algorithms, can be efficiently parallelized and applied to large molecular systems, including large clusters of heavy atoms. The performance of the parallel implementation of the DKS module of the program BERTHA is illustrated and analyzed by some test calculations on several gold clusters up to Au32, showing that calculations with more than 25 000 basis functions (i.e., DKS matrices on the order of 10 GB) are now feasible. As a first application of this novel implementation, we investigate the interaction of the atom Hg with the Au20 cluster. PMID- 26617298 TI - HO2 + O3 Reaction: Ab Initio Study and Implications in Atmospheric Chemistry. AB - We report a theoretical investigation on the reaction between ozone and the hydroperoxyl radical, which is part of the ozone depletion cycle. This reaction represents a great challenge to the state of the art ab initio methods, while its mechanism remains unclear to both experimentalists and theoreticians. In this work we calculated the relative energies of the stationary points along the reaction coordinate of the oxygen- and hydrogen-abstraction mechanisms using different levels of theory and extrapolating some of the results to the complete one-electron basis set limit. Oxygen abstraction is shown to be preceded by formation of hydrogen-bonded complexes, while hydrogen abstraction shows a lower energy barrier than oxygen abstraction. Both mechanisms lead to formation of HO3 + O2 in a very troublesome region of the potential-energy surface that is not correctly described by single-reference methods. The implications of the results on reaction dynamics are discussed. PMID- 26617299 TI - QM/MM Studies on the beta-Galactosidase Catalytic Mechanism: Hydrolysis and Transglycosylation Reactions. AB - Carbohydrates perform a wide range of crucial functions in biological systems and are of great interest for the food and pharmaceutical industries. beta Galactosidase from Escherichia coli catalyzes both the hydrolytic breaking of the very stable glycosidic bond of lactose and a series of transglycosylation reactions. These reactions are crucial for the development of new carbohydrate molecules, as well as the optimization of their syntheses. In this work we have used computational methods to study the catalytic mechanism of hydrolysis and a set of distinct transglycosylation reactions of a retaining galactosidase, with atomic detail, with lactose as the natural substrate. The ONIOM method (BB1K:AMBER//B3LYP:AMBER calculations) was employed to address such a large enzymatic system. Such a methodology can efficiently account for the stereochemistry of the reactive residues, as well as the long-range enzyme substrate interactions. The possible importance of the magnesium ion in the catalytic reaction was investigated, and it was found that, indeed, the magnesium ion catalyzes the transformation, lowering the activation barrier by 14.9 kcal/mol. The calculations indicate that the formation of beta(1-3) glycosidic linkages is thermodynamically very unfavorable. In contrast, the formation of beta(1-6) glycosidic bonds is the most favored, in complete agreement with the enantioselectivity observed experimentally. The data also clearly show the importance of the enzyme scaffold beyond the first-shell amino acids in the stabilization of the transition states. It is fundamental to include the enzyme explicitly in computational studies. PMID- 26617300 TI - Problems with Some Current Water Models for Close Pair Interactions That Are Not Near the Minimum Energy. AB - The ability of an empirical, polarizable model of water to predict a thermal ensemble of molecular configurations at ambient conditions was examined using first-principle quantum mechanics. The empirical model of water selected for this evaluation was the TTM2-F model. The quantum mechanical methodology selected was the second-order Moller-Plesset model (MP2). Only pairwise interaction energies were considered. Significant deviations from the empirical model were found. Similar results were found for ad-hoc comparisons with several other common water models including the TIP3P, TIP4P, TIP4P-FQ, TIP5P, TTM2.1-F, TTM2.2-F, TTM3-F, and POL5/QZ potential models. Our results show that spatially close dimer configurations with interaction energies notably above the potential well minimum (but are still thermally accessible at ambient conditions) are the source of the largest deviations. To assist others in future water model parametrizations we report the MP2 near complete basis set limit energies for 840 water dimer configurations sampled from an approximate thermal ensemble at ambient conditions. PMID- 26617301 TI - Implementation of the CHARMM Force Field in GROMACS: Analysis of Protein Stability Effects from Correction Maps, Virtual Interaction Sites, and Water Models. AB - CHARMM27 is a widespread and popular force field for biomolecular simulation, and several recent algorithms such as implicit solvent models have been developed specifically for it. We have here implemented the CHARMM force field and all necessary extended functional forms in the GROMACS molecular simulation package, to make CHARMM-specific features available and to test them in combination with techniques for extended time steps, to make all major force fields available for comparison studies in GROMACS, and to test various solvent model optimizations, in particular the effect of Lennard-Jones interactions on hydrogens. The implementation has full support both for CHARMM-specific features such as multiple potentials over the same dihedral angle and the grid-based energy correction map on the phi, psi protein backbone dihedrals, as well as all GROMACS features such as virtual hydrogen interaction sites that enable 5 fs time steps. The medium-to-long time effects of both the correction maps and virtual sites have been tested by performing a series of 100 ns simulations using different models for water representation, including comparisons between CHARMM and traditional TIP3P. Including the correction maps improves sampling of near native state conformations in our systems, and to some extent it is even able to refine distorted protein conformations. Finally, we show that this accuracy is largely maintained with a new implicit solvent implementation that works with virtual interaction sites, which enables performance in excess of 250 ns/day for a 900 atom protein on a quad-core desktop computer. PMID- 26617302 TI - Explicit Hydrogen-Bond Potentials and Their Application to NMR Scalar Couplings in Proteins. AB - Hydrogen bonds (H bonds) are fundamental for the stability, structure, and dynamics of chemically and biologically relevant systems. One of the direct means to detect H bonds in proteins is NMR spectroscopy. As H bonds are dynamic in nature, atomistic simulations offer a meaningful way to characterize and analyze properties of hydrogen bonds, provided a sufficiently accurate interaction potential is available. Here, we use explicit H-bond potentials to investigate scalar coupling constants (h3)JNC' and characterize the conformational ensemble for increasingly accurate intermolecular potentials. By considering a range of proteins with different overall topology a general procedure to improve the hydrogen-bonding potential ("morphing potentials") based on experimental information is derived. The robustness of this approach is established through explicit simulations in full solvation and comparison with experimental results. The H-bond potentials used here lead to more directional H bonds than conventional electrostatic representations employed in molecular mechanics potentials. It is found that the optimized potentials lead to H-bond geometries in remarkable agreement with previous ab initio and knowledge-based approaches to H bonds in model systems and in proteins. This suggests that, by combining theory, computation, and experimental data, H-bonding potentials can be improved and are potentially useful to better study coupling, energy transfer, and allosteric communication in proteins. PMID- 26617303 TI - Performance of the Empirical Dispersion Corrections to Density Functional Theory: Thermodynamics of Hydrocarbon Isomerizations and Olefin Monomer Insertion Reactions. AB - Most of the commonly used approximate density functionals have systematic errors in the description of the stability of hydrocarbons. This poses a challenge for the realistic modeling of reactions involving hydrocarbons, such as olefin polymerization. Practical remedies have been proposed, including the application to usual black-box DFT of additional empirical correction CR(-6) terms for the van der Waals interaction (termed DFT-D), or introducing additional pseudopotentials that introduce some medium-to-long-range attraction (C-Pot). In this Article, we use the DFT-D scheme as realized in our BOptimize package to evaluate the performance of a range of commonly used DFT functionals (combinations of xPBE, B88, OPTX with LYP and cPBE GGAs and hybrids) for the modeling of the thermodynamics of reactions of the growth of common polyolefins. We also review and reproduce some of the previously done benchmarks in the area: alkane branching and relative stability of C12H12 and C10H16 isomers. In addition to the common DFT methods, computations with correlated wave function methods (MP2) and the new functionals B97-D and M06-L were performed. The performance of the special density functionals B97-D and M06-L is, in general, similar to the best DFT-D corrected regular functionals (BPBE-D and PBE-D). The results show that (1) the DFT-D correction is sufficient to describe alkane branching, but its performance depends on the parametrization; (2) inclusion of the correction is essential for a proper description of the thermodynamics of reactions of polymer growth; and (3) not all approximate density functionals perform effectively for the description of hydrocarbons even with the correction. The C-Pot method for the B3LYP functional shows quantitatively correct results for our test cases. The enthalpies of hydrocarbon reactions were analyzed in terms of the repulsion characteristics of a given DFT method. PBE is the least repulsive, while OLYP is the most. However, there are cases where the failure of a DFT method cannot be correlated with its repulsive character. A striking example is the performance of B3LYP and BLYP for caged molecules with small carbocycles, such as the [D3d] octahedrane. The stability of [D3d]-octahedrane is underestimated by the B3LYP, BLYP, and B97-D functionals, but not by DFT methods that contain either B88 exchange or LYP correlation functionals separately. While DFT-D cannot amend the performance of the former functionals for the octahedrane, C-Pot for B3LYP does. PMID- 26617304 TI - Computation of Nonretarded London Dispersion Coefficients and Hamaker Constants of Copper Phthalocyanine. AB - A time-dependent density functional theory (TDDFT) scheme has been validated for predictions of the dispersion coefficients of five molecules (H2O, NH3, CO2, C6H6, and pentane) and for predictions of the static dipole polarizabilities of three organometallic compounds (TiCl4, OsO4, and Ge(CH3)4). The convergence of grid spacing has been examined, and two types of pseudopotentials and 13 density functionals have been tested. The nonretarded Hamaker constants A11 are calculated by employing a semiempirical parameter a along with the standard Hamaker constant equation. The parameter a is optimized against six accurate Hamaker constants obtained from the full Lifshitz theory. The dispersion coefficients of copper phthalocyanine CuPc and CuPc-SO3H are then computed. Using the theoretical densities of rho1 = 1.63 and 1.62 g/cm(3), the Hamaker constants A11 of crystalline alpha-CuPc and beta-CuPc are found to be 14.73 * 10(-20) and 14.66 * 10(-20) J, respectively. Using the experimentally derived density of rho1 = 1.56 g/cm(3) for a commercially available beta-CuPc (nanoparticles of ~90 nm hydrodynamic diameter), A11 = 13.52 * 10(-20) J is found. Its corresponding effective Hamaker constant in water (A121) is calculated to be 3.07 * 10(-20) J. All computed A11 values for CuPc are noted to be higher than those reported previously. PMID- 26617305 TI - Bulk and Surface Properties of Rutile TiO2 from Self-Consistent-Charge Density Functional Tight Binding. AB - Bulk rutile TiO2 and its (110) surface have been investigated with a computationally efficient semiempirical tight binding method: self-consistent charge density functional tight binding (SCC-DFTB). Comparisons of energetic, mechanical, and electronic properties are made to density functional theory (DFT) and to experiment to characterize the accuracy of SCC-DFTB for bulk rutile TiO2 and TiO2(110). Despite the fact that the SCC-DFTB parameters for Ti, Ti-Ti, and Ti-O were developed in the context of small biologically relevant Ti containing compounds, SCC-DFTB predicts many properties of bulk TiO2 and the TiO2(110) surface with accuracy similar to local and gradient-corrected DFT. In particular, SCC-DFTB predicts a direct band gap of TiO2 of 2.46 eV, which is in better agreement with experiment, 3.06 eV, than DFT utilizing the local density approximation (LDA), 2.0 eV. SCC-DFTB also performs similar in terms of accuracy as LDA-DFT for the phonon frequencies of the bulk lattice and for the relaxed geometry of the TiO2(110) surface. SCC-DFTB does, however, overestimate the surface energy of TiO2(110) compared to LDA-DFT. Nevertheless, the overall accuracy of SCC-DFTB, which is substantially more computationally efficient than DFT, is encouraging for bulk rutile TiO2 and TiO2(110). PMID- 26617306 TI - Diffusion of Hydrides in Palladium Nanoclusters. A Ring-Polymer Molecular Dynamics Study of Quantum Finite Size Effects. AB - The diffusion kinetics of hydrogen in bulk palladium and in Pd nanoclusters containing up to 512 atoms has been theoretically investigated at 3% loading using ring-polymer molecular dynamics simulations. The electronic ground-state energy surfaces are modeled using an explicit many-body potential fitted to reproduce the properties of bulk palladium and palladium hydrides. The diffusion constant, calculated by integration of the velocity autocorrelation function, shows Arrhenius behavior with inverse temperature. In addition, both the prefactor and activation energy are found to exhibit approximately linear variations with inverse cluster radius for sizes exceeding 128 Pd atoms. Vibrational delocalization generally enhances diffusion, this effect being stronger in clusters than in bulk. An inherent structure analysis from the positions of the centroids was used to characterize the diffusion mechanisms. Quantum effects lead to not only a higher coordination of hydrogen atoms both in bulk (fcc) palladium and in clusters but also favor further softening of the outer layers. PMID- 26617307 TI - Tautomerism in Reduced Pyrazinacenes. AB - Monoprotic and diprotic NH tautomerism in reduced oligoazaacenes, the pyrazinacenes, was studied by using first principles simulations. Stepwise reductions in the metadynamics-sampled free energy profile were observed during consecutive monoprotic tautomerizations, with energy barriers gradually reducing with increasing proton separation during monoprotic processes. This is accompanied by an increasing contribution from the quinoidal electronic structure, as evidenced by the computed highest occupied molecular orbital (HOMO) structure. An unusual odd-even effect in the free energy profiles is also observed upon changing the length of the pyrazinacene. Calculated HOMO structures reveal an increasing tendency for delocalization of pyrazine lone pairs with an increasing number of ring annelations. The influence of tautomerism on the pyrazine lone pair delocalization was also observed. Tautomers with protons situated centrally on the pyrazinacene backbone are predicted to be more stable due to a combination of (enamine) delocalization and a loss of Clar sextet resonance stabilization in tautomers with protons at terminal pyrazine rings. Experimental evidence suggesting the structure of pyrazinacene tautomers is included and discussed as a support to the calculation. PMID- 26617308 TI - Coarse-Grained Computer Simulations of Polymer/Fullerene Bulk Heterojunctions for Organic Photovoltaic Applications. AB - We develop coarse-grained (CG) computer simulation models of poly(3 hexylthiophene) (P3HT) and P3HT/fullerene-C60 mixtures, in which collections of atoms from a physically accurate atomistic model are mapped onto a smaller number of "superatoms". These CG models allow much larger systems to be simulated for longer durations than is achievable atomistically, making it possible to study in molecular detail the morphology of polymer/fullerene bulk heterojunctions at length and time scales relevant to organic photovoltaic devices. We demonstrate that our CG models, parametrized at two state points, accurately capture the structure of atomistic systems at other points in the mixture phase diagram. Finally, we use our CG models to study the dynamic evolution of the microstructure of a P3HT/C60 bulk heterojunction in a system approaching the device scale. PMID- 26617309 TI - Interaction Analysis of the Native Structure of Prion Protein with Quantum Chemical Calculations. AB - We examined the solvent interaction and intramolecular interaction of the native structure of prion protein (PrP) using quantum chemical calculations based on the fragment molecular orbital (FMO) method. The influence due to the geometrical fluctuation was taken into account by performing calculations on forty different conformations. Each FMO calculation was carried out at the MP2 level of theory with the cc-pVDZ in which the resolution of the identity approximation was employed to reduce the computational cost. The solvent interaction energies obtained from the calculations provided information about the hydrophilicity of the three alpha-helices. We examined the roles of the charged residues in retaining the native structure of PrP with the calculated intramolecular interaction energies. The analysis, focused on van der Waals interaction, showed that the hydrophobic residues were important for the stability of the native structure. Our results were also discussed in relation to the identified pathogenetic mutations of prion diseases. Additionally, we examined the distribution of the calculated values with 40 structures, in which we demonstrated the influence of geometrical fluctuations on quantum chemical calculations. PMID- 26617310 TI - Magnetostructural Dynamics from Hubbard-U Corrected Spin-Projection: [2Fe-2S] Complex in Ferredoxin. AB - A Hubbard-corrected spin-projected two-determinant approach, EBS+Uscf, is introduced to treat low-spin ground states of antiferromagnetically coupled transition metal complexes. In addition to providing access to total energies, forces, and ab initio simulations, it allows one to readily compute Heisenberg's exchange coupling J(t) on the fly. By studying the binuclear [2Fe-2S] cofactor in a metalloprotein, Anabaena Fd, within this consistent nonempirical procedure in combination with a QM/MM framework, it is illustrated that spin-projection, self interaction corrections, thermal fluctuations, and protein matrix shifts are crucial in obtaining ?J? close to the experiment. PMID- 26617311 TI - Performance of CASPT2 and DFT for Relative Spin-State Energetics of Heme Models. AB - The accuracy of the relative spin-state energetics of three small Fe(II) or Fe(III) heme models from multiconfigurational perturbation theory (CASPT2) and density functional theory with selected functionals (including the recently developed M06 and M06-L functionals) was assessed by comparing with recently available coupled cluster results. While the CASPT2 calculations of spin-state energetics were found to be very accurate for the studied Fe(III) complexes (including FeP(SH), a model of the active site of cytochrome P450 in its resting state), there is a strong indication of a systematic error (around 5 kcal/mol) in favor of the high-spin state for the studied Fe(II) complexes (including FeP(Im), a model of the active site of myoglobin). A larger overstabilization of the high spin states was observed for the M06 and M06-L functionals, up to 22 and 11 kcal/mol, respectively. None of the tested density functionals consistently provides a better accuracy than CASPT2 for all model complexes. PMID- 26617312 TI - Electrokinetic injection of samples into a short electrophoretic capillary controlled by piezoelectric micropumps. AB - Electrokinetic sample injection using two piezoelectric micropumps has been proposed for electrophoresis in short capillaries. The sample is brought to the injection end of the capillary using one of them. Then, the high-voltage source is turned on and the sample is injected electrokinetically for a defined time. The injection is terminated by removal of the sample zone by the flowing separation electrolyte pumped by the second piezoelectric micropump. The RSD value, expressing the repeatability of the injection, does not exceed 4%. The injection apparatus does not contain any mobile mechanical components, there is no movement of the capillary and both its ends remain constantly in the solution during both the sample injection and separation. Thus, the micropumps replace the six-way injection valve and linear pump in similar types of injection apparatuses. The injection was tested in the separation and determination of ammonium and potassium ions in two samples of mineral fertilizers. The separation was performed in background electrolyte containing 500 mM of acetic acid + 20 mM Tris + 2 mM 18-crown-6 (pH 3.3) in a capillary with id 50 MUm and total length/length to the contactless conductivity detector of 10.5/8 cm. The injection and separation took place at a voltage of 5 kV and the separation time equaled 20 s. The measured values of the analyte contents corresponded to the value declared by the manufacturer within the reliability interval, where RSD equaled between 3.5 and 4.7%. PMID- 26617313 TI - Alitretinoin: treatment for refractory palmoplantar keratoderma. PMID- 26617314 TI - Enhanced delivery of Paclitaxel using electrostatically-conjugated Herceptin bearing PEI/PLGA nanoparticles against HER-positive breast cancer cells. AB - We have developed a novel nanoparticle delivery system fabricated from polyethylenimine (PEI) and poly(d,l-lactide-co-glycolide) (PLGA), which were able to deliver the chemotherapeutic agent Paclitaxel, while the biomacromolecule Herceptin acted as a targeting ligand that was conjugated onto the surfaces of the nanoparticles via electrostatic interactions. In this study, these electrostatically-conjugated Herceptin-bearing PEI/PLGA nanoparticles (eHER-PPNs) were optimized and employed as vectors to target HER2-positive breast cancer cells. The eHER-PPNs had an average diameter of ~ 280 nm and a neutral surface charge (1.00 +/- 0.73 mV), which remained stable under physiological conditions. The anticancer effects of eHER-PPNs were investigated in HER2-positive BT474 cells and HER2-negative MCF7 cells. The eHER-PPNs showed enhanced cytotoxicity that was dependent on the receptor expression levels and the incubation time. These conjugated nanoparticles deliver Paclitaxel more efficiently (p<0.001) than unmodified PPNs, Herceptin and the combined effects of these two monotherapies. Furthermore, the chemically-conjugated Herceptin-bearing PEI/PLGA nanoparticles (cHER-PPNs) were fabricated as a comparison. The eHER-PPNs exhibited lower cell viability (46.7%) than that of cHER-PPNs (65.1%). The targeting ability of eHER PPNs was demonstrated through confocal microscopy images and flow cytometry, which showed that eHER-PPNs displayed higher cellular uptake efficiency (p<0.001) in comparison with cHER-PPNs. Therefore, eHER-PPNs could provide promising platforms for the delivery of therapeutic drugs against HER2-positive breast cancers. PMID- 26617315 TI - Lipoamino acid-based micelles as promising delivery vehicles for monomeric amphotericin B. AB - Lipoamino acid-based micelles have been developed as delivery vehicles for the hydrophobic drug amphotericin B (AmB). The micellar solubilisation of AmB by a gemini lipoamino acid (LAA) derived from cysteine and its equimolar mixtures with the bile salts sodium cholate (NaC) and sodium deoxycholate (NaDC), as well as the aggregation sate of the drug in the micellar systems, was studied under biomimetic conditions (phosphate buffered-saline, pH 7.4) using UV-vis spectroscopy. Pure surfactant systems and equimolar mixtures were characterized by tensiometry and important parameters were determined, such as critical micelle concentration (CMC), surface tension at the CMC (gammaCMC), maximum surface excess concentration (Gammamax), and minimum area occupied per molecule at the water/air interface (Amin). Rheological behaviour from viscosity measurements at different shear rates was also addressed. Solubilisation capacity was quantified in terms of molar solubilisation ratio (chi), micelle-water partition coefficient (KM) and Gibbs energy of solubilisation (DeltaGs degrees ). Formulations of AmB in micellar media were compared in terms of drug loading, encapsulation efficiency, aggregation state of AmB and in vitro antifungal activity against Candida albicans. The LAA-containing micellar systems solubilise AmB in its monomeric and less toxic form and exhibit in vitro antifungal activity comparable to that of the commercial formulation Fungizone. PMID- 26617316 TI - Stability hierarchy between Piracetam forms I, II, and III from experimental pressure-temperature diagrams and topological inferences. AB - The trimorphism of the active pharmaceutical ingredient piracetam is a famous case of polymorphism that has been frequently revisited by many researchers. The phase relationships between forms I, II, and III were ambiguous because they seemed to depend on the heating rate of the DSC and on the history of the samples or they have not been observed at all (equilibrium II-III). In the present paper, piezo-thermal analysis and high-pressure differential thermal analysis have been used to elucidate the positions of the different solid-solid and solid-liquid equilibria. The phase diagram, involving the three solid phases, the liquid phase and the vapor phase, has been constructed. It has been shown that form III is the high-pressure, low-temperature form and the stable form at room temperature. Form II is stable under intermediary conditions and form I is the low pressure, high temperature form, which possesses a stable melting point. The present paper demonstrates the strength of the topological approach based on the Clapeyron equation and the alternation rule when combined with high-pressure measurements. PMID- 26617317 TI - Continuous production of controlled release dosage forms based on hot-melt extruded gum arabic: Formulation development, in vitro characterization and evaluation of potential application fields. AB - Controlled release matrices based on gum arabic are prepared by applying a continuous hot-melt extrusion technology: the pre-mixture consisting of gum arabic and the incorporated API is plasticized by a co-rotating twin-screw extruder, an intermediate strand is formed by a round nozzle. Single dosed matrices are prepared by cutting the semi elastic strand with a rotary fly cutter. Paracetamol and phenazone are used as model drug substances. High drug loadings up to 70% can be realized. Matrices are characterized concerning their crystalline structure, in vitro dissolution, disintegration time and various physical parameters including glass transition temperature (Tg). Release characteristic behavior is mainly influenced by erosion of the matrices. At higher drug loadings also diffusion based transport gain importance. The solubility of the API shows an influence on the erosion rate of the matrix and should therefore be considered during formulation development. Tg is mainly influenced by the solubility of the API in the surrounding matrix. High soluble phenazone shows a decrease, whereas paracetamol addition has nearly no influence on the Tg of the polymeric system. Activation energy (EA) of the glass transition is determined via dynamic mechanical analysis. The addition of APIs leads to a reduction of EA indicating an increased molecular movement at Tg region compared to placebo extrudates. X-ray diffraction is used to determine the crystalline state of the extruded matrices and interaction between matrix and incorporated APIs. The production of thin layer matrices is an interesting option to provide a fast drug delivery to the oral cavity. High mechanical strength combined with fast disintegration times can be a great advantage for the development of oro dispersible tablets. A great benefit of the evaluated processing technology is the simple adaption of the final dose by varying either the cutting length or the diameter of the nozzle resulting in a cost-effective production of single dosed matrices without modification of the base formula. PMID- 26617319 TI - An automated learning apparatus for classical conditioning of Lymnaea stagnalis. AB - BACKGROUND: The pond snail Lymnaea stagnalis is capable of taste avoidance classical conditioning (TAC) with sucrose as the conditional stimulus (CS) and mechanical prodding as the unconditional stimulus (US). After successful training, feeding behavior is significantly suppressed in response to CS presentation. NEW METHOD: An automated apparatus is described for the training of multiple snails up to 10 snails at the same time. The new apparatus employs an electrical shock obtained from a 9-V dry cell to deliver a consistent and effective current amplitude of 0.4MUA (i.e., the US). RESULTS: Using this apparatus, 10 snails can be conditioned simultaneously. We found that the optimal parameters to result in both short (STM) and long-term memory (LTM) were 15 paired presentations of the CS and US with a 5-min inter-trial interval (ITI) and 0.2-s current duration. However, both STM and LTM were observed with other ITIs tested. Successful TAC with only a single pairing of the CS-US occurred with a CS of 100mM sucrose solution for 60s followed by a US of 9V with 0.4MUA for 5s. COMPARISON WITH EXISTING METHOD: The use of automated training apparatus for TAC will enable us to better examine the relationship between strength of CS and US. PMID- 26617320 TI - Chronic, intermittent convection-enhanced delivery devices. AB - BACKGROUND: Intraparenchymal convection-enhanced delivery (CED) of therapeutics directly into the brain has long been endorsed as a medium through which meaningful concentrations of drug can be administered to patients, bypassing the blood brain barrier. The translation of the technology to clinic has been hindered by poor distribution not previously observed in smaller pre-clinical models. In part this was due to the larger volumes of target structures found in humans but principally the poor outcome was linked to reflux (backflow) of infusate proximally along the catheter track. Over the past 10 years, improvements have been made to the technology in the field which has led to a small number of commercially available devices containing reflux inhibiting features. NEW METHOD: While these devices are currently suitable for acute or short term use, several indications would benefit from longer term repeated, intermittent administration of therapeutics (Parkinson's, Alzheimer's, Amyotrophic lateral sclerosis, Brain tumours such as Glioblastoma Multiforme (GBM) and Diffuse intrinsic Pontine Glioma (DIPG), etc.). RESULTS: Despite the need for a chronically accessible platform for such indications, limited experience exists in this part of the field. COMPARISON WITH EXISTING METHOD(S): At the time of writing no commercially available clinical platform, indicated for chronic, intermittent or continuous delivery to the brain exists. CONCLUSIONS: Here we review the improvements that have been made to CED devices over recent years and current state of the art for chronic infusion systems. PMID- 26617318 TI - Characterization and comparison of two novel nanosystems associated with siRNA for cellular therapy. AB - To direct stem cell fate, a delicate control of gene expression through small interference RNA (siRNA) is emerging as a new and safe promising strategy. In this way, the expression of proteins hindering neuronal commitment may be transiently inhibited thus driving differentiation. Mesenchymal stem cells (MSC), which secrete tissue repair factors, possess immunomodulatory properties and may differentiate towards the neuronal lineage, are a promising cell source for cell therapy studies in the central nervous system. To better drive their neuronal commitment the repressor Element-1 silencing transcription (REST) factor, may be inhibited by siRNA technology. The design of novel nanoparticles (NP) capable of safely delivering nucleic acids is crucial in order to successfully develop this strategy. In this study we developed and characterized two different siRNA NP. On one hand, sorbitan monooleate (Span((r))80) based NP incorporating the cationic components poly-l-arginine or cationized pullulan, thus allowing the association of siRNA were designed. These NP presented a small size (205 nm) and a negative surface charge (-38 mV). On the other hand, lipid nanocapsules (LNC) associating polymers with lipids and allowing encapsulation of siRNA complexed with lipoplexes were also developed. Their size was of 82 nm with a positive surface charge of +7 mV. Both NP could be frozen with appropriate cryoprotectors. Cytotoxicity and transfection efficiency at different siRNA doses were monitored by evaluating REST expression. An inhibition of around 60% of REST expression was observed with both NP when associating 250 ng/mL of siRNA-REST, as recommended for commercial reagents. Span NP were less toxic for human MSCs than LNCs, but although both NP showed a similar inhibition of REST over time and the induction of neuronal commitment, LNC-siREST induced a higher expression of neuronal markers. Therefore, two different tailored siRNA NP offering great potential for human stem cell differentiation have been developed, encouraging the pursuit of further in vitro and in vivo in studies. PMID- 26617322 TI - Notch in T Cell Differentiation: All Things Considered. AB - Differentiation of naive T cells into effector cells is required for optimal protection against different classes of microbial pathogen and for the development of immune memory. Recent findings have revealed important roles for the Notch signaling pathway in T cell differentiation into all known effector subsets, raising the question of how this pathway controls such diverse differentiation programs. Studies in preclinical models support the therapeutic potential of manipulating the Notch pathway to alleviate immune pathology, highlighting the importance of understanding the mechanisms through which Notch regulates T cell differentiation and function. We review these findings here, and outline both unifying principles involved in Notch-mediated T cell fate decisions and cell type- and context-specific differences that may present the most suitable points for therapeutic intervention. PMID- 26617321 TI - Phase-locked loop for precisely timed acoustic stimulation during sleep. AB - BACKGROUND: A brain-computer interface could potentially enhance the various benefits of sleep. NEW METHOD: We describe a strategy for enhancing slow-wave sleep (SWS) by stimulating the sleeping brain with periodic acoustic stimuli that produce resonance in the form of enhanced slow-wave activity in the electroencephalogram (EEG). The system delivers each acoustic stimulus at a particular phase of an electrophysiological rhythm using a phase-locked loop (PLL). RESULTS: The PLL is computationally economical and well suited to follow and predict the temporal behavior of the EEG during slow-wave sleep. COMPARISON WITH EXISTING METHODS: Acoustic stimulation methods may be able to enhance SWS without the risks inherent in electrical stimulation or pharmacological methods. The PLL method differs from other acoustic stimulation methods that are based on detecting a single slow wave rather than modeling slow-wave activity over an extended period of time. CONCLUSIONS: By providing real-time estimates of the phase of ongoing EEG oscillations, the PLL can rapidly adjust to physiological changes, thus opening up new possibilities to study brain dynamics during sleep. Future application of these methods hold promise for enhancing sleep quality and associated daytime behavior and improving physiologic function. PMID- 26617323 TI - Differential proteome profile of skin mucus of gilthead seabream (Sparus aurata) after probiotic intake and/or overcrowding stress. AB - Gilthead seabream (Sparus aurata L.) is the major cultured fish species in the Mediterranean area. High density stocking causes stress and increases the impact of diseases leading to economic losses. Probiotics could represent a solution to prevent diseases through several mechanisms such as improving the immune status and/or mucosal microbiota or competing with pathogens. The probiotic Shewanella putrefaciens, also known as Pdp11, was firstly isolated from the skin of healthy gilthead seabream. Our study focuses on the skin mucus proteome after dietary probiotic Pdp11 intake in fish maintained under normal or overcrowding conditions. 2-DE of skin mucus followed by LC-MS/MS analysis was done for each experimental group and differentially expressed proteins were identified. The results showed differentially expressed proteins especially involved in immune processes, such as lysozyme, complement C3, natural killer cell enhancing factor and nonspecific cytotoxic cell receptor protein 1, whose transcript profiles were studied by qPCR. A consistency between lysozyme protein levels in the mucus and lysozyme mRNA levels in skin was found. Further research is necessary to unravel the implications of skin mucosal immunity on fish welfare and disease. BIOLOGICAL SIGNIFICANCE: The present work reveals the proteomic changes, which are taking place in the skin mucus of stressed and non-stressed gilthead seabream after Pdp11 probiotic intake. The study contributes to improving the knowledge on skin mucosal immunology of this relevant farmed fish species. Furthermore, the paper shows for the first time how a suitable proteomic methodology, in this case 2-DE followed by LC-MS/MS is useful to perform a comparative study with a non-invasive technique of skin mucus of gilthead seabream. PMID- 26617324 TI - Oxacalix[2]arene[2]triazine based ion-pair transporters. AB - Heteracalixaromatics are a new generation of macrocyclic hosts showing a unique structure and versatile recognition properties towards various guests. Amazingly, the application of heteracalixaromatics as membrane transporters or ion channels has never been explored. We reported herein the elaborated design of a series of oxacalix[2]arene[2]triazine-based derivatives 1-10 and their ion transport properties. Among these compounds, 3, 8-10 can mediate the transport of chloride across the lipid bilayer of EYPC with activity (EC50) ranging from 0.43 to 8.23 MUM. These compounds serve as ion carriers during the transport process, and the transport activity is both anion- and cation-dependent, suggesting a Cl(-)/M(+) ion-pair transport model. Structure-activity studies indicate that hydrogen bonding, electron deficiency of the triazine rings, lipophilicity and macrocyclic frameworks are essential for ion transport. PMID- 26617325 TI - Assessing the reactivity of sodium alkyl-magnesiates towards quinoxaline: single electron transfer (SET) vs. nucleophilic alkylation processes. AB - By exploring the reactivity of sodium butyl-magnesiate (1) supported by the bulky chelating silyl(bisamido) ligand {Ph2Si(NAr*)2}(2-) (Ar* = 2,6-iPr2-C6H3) towards Quinoxaline (Qx), the ability of this bimetallic system to effectively promote SET processes has been disclosed. Thus 1 executes the single-electron reduction of Qx affording complex (2) whose structure in the solid state contains two quinaxolyl radical anions Qx stabilised within a dimeric magnesiate framework. Combining multinuclear NMR and EPR measurements with DFT calculations, new insights into the constitution of 2 in solution and its magnetic behaviour have been gained. Further evidence on the SET reactivity of 1 was found when it was reacted with nitroxyl radical TEMPO which furnished contacted ion pair sodium magnesiate [(Ph2Si(NAr*)2)Mg(TEMPO(-))Na(THF)3] (4) where both metals are connected by an alkoxide bridge, resulting from reduction of TEMPO. The role that the different ligands present in 1 can play in these new SET reactions has also been assessed. Using an amination approach, the Bu group in 1 can be replaced by the more basic amide TMP allowing the isolation of (3) which was characterised by multinuclear NMR and X-ray crystallography. (1)H NMR monitoring of the reaction of 3 with Qx showed its conversion to 2, leaving the hydrogen atoms of the heterocycle untouched. Contrastingly, using sodium homoalkyl magnesiate [NaMg(CH2SiMe3)3] (5) led to the chemoselective C2 alkylation of this heterocycle, suggesting that the presence of the steric stabiliser {Ph2Si(NAr*)2}(2-) on the mixed-metal reagent is required in order to facilitate the Qx reduction. PMID- 26617326 TI - The Correlation between Depression, Balance, and Physical Functioning Post Stroke. AB - BACKGROUND AND OBJECTIVE: Depression, imbalance, and physical disability are among the serious stroke sequels. The objective of this study was to examine the correlation between depression, balance, and self-reported physical performance in patients post stroke. METHODS: The Arabic versions of the Beck Depression Inventory (BDI), Dynamic Gait Index (A-DGI), and physical Stroke Impact Scale-16 version 3 were administered to a convenience sample of patients post stroke. The correlation between the mentioned measures was calculated using the Pearson coefficient. Additionally, the Kruskal-Wallis test was used to find out if the distribution of measurement scores differs among BDI levels of depression intensity or among Orpington Prognostic Scale (OPS) levels of stroke severity. RESULTS: Sixty-one patients with stroke (mean age [standard deviation] = 64 [12] years, 39 male) were recruited. Significant moderate correlations were found between BDI and A-DGI, BDI and Stroke Impact Scale (SIS), and A-DGI and physical SIS. Additionally, the distribution of the A-DGI and the physical SIS scores showed significant differences among BDI levels of depression intensity. Moreover, the distribution of the BDI, A-DGI, and physical SIS scores showed significant differences among OPS levels of stroke severity. CONCLUSIONS: Depressive symptoms were found frequent among people post stroke and were associated with balance and self-reported physical performance. PMID- 26617328 TI - Telemedicine as a special case of machine translation. AB - Machine translation is evolving quite rapidly in terms of quality. Nowadays, we have several machine translation systems available in the web, which provide reasonable translations. However, these systems are not perfect, and their quality may decrease in some specific domains. This paper examines the effects of different training methods when it comes to Polish-English Statistical Machine Translation system used for the medical data. Numerous elements of the EMEA parallel text corpora and not related OPUS Open Subtitles project were used as the ground for creation of phrase tables and different language models including the development, tuning and testing of these translation systems. The BLEU, NIST, METEOR, and TER metrics have been used in order to evaluate the results of various systems. Our experiments deal with the systems that include POS tagging, factored phrase models, hierarchical models, syntactic taggers, and other alignment methods. We also executed a deep analysis of Polish data as preparatory work before automatized data processing such as true casing or punctuation normalization phase. Normalized metrics was used to compare results. Scores lower than 15% mean that Machine Translation engine is unable to provide satisfying quality, scores greater than 30% mean that translations should be understandable without problems and scores over 50 reflect adequate translations. The average results of Polish to English translations scores for BLEU, NIST, METEOR, and TER were relatively high and ranged from 7058 to 8272. The lowest score was 6438. The average results ranges for English to Polish translations were little lower (6758 7897). The real-life implementations of presented high quality Machine Translation Systems are anticipated in general medical practice and telemedicine. PMID- 26617327 TI - Gender and Time to Arrival among Ischemic Stroke Patients in the Greater Cincinnati/Northern Kentucky Stroke Study. AB - BACKGROUND: Some studies of stroke patients report longer prehospital delays in women, but others conflict; studies vary in their inclusion of factors including age and stroke severity. We aimed to investigate the relationship between gender and time to emergency department (ED) arrival and the influence of age and stroke severity on this relationship. METHODS: Ischemic stroke patients 20 years old or older who presented to 15 hospitals within a 5-county region of Greater Cincinnati/Northern Kentucky during 2010 were included. Time from symptom onset to ED arrival and covariates were abstracted by study nurses and reviewed by study physicians. Data were analyzed using logistic regression with time to arrival dichotomized at 3 hours or less in the overall sample and then stratified by National Institutes of Health Stroke Scale (NIHSS) and age. RESULTS: 1991 strokes (55% women) were included. Time to arrival was slightly longer in women (geometric mean 337 minutes [95% confidence interval {CI} 307-369] versus 297 [95% CI 268-329], P = .05), and 24% of women versus 27% of men arrived within 3 hours (P = .15). After adjusting for age, race, NIHSS, living situation, and other covariates, gender was not associated with delayed time to arrival (OR = 1.00, 95% CI .78-1.28). This did not change across age or NIHSS categories. CONCLUSIONS: After adjusting for factors including age, NIHSS score, and living alone, women and men with ischemic stroke had similar times to arrival. Arrival time is not likely a major contributor to differences in outcome between men and women. PMID- 26617329 TI - Clinical evaluation of the use of an intracardiac electrocardiogram to guide the tip positioning of peripherally inserted central catheters. AB - The use of peripherally inserted central catheters (PICCs) provides important central venous accesses for clinical treatments, tests and monitoring. Compared with the traditional methods, intracardiac electrocardiogram (ECG)-guided method has the potential to guide more accurate tip positioning of PICCs. This study aimed to clinically evaluate the effectiveness of an intracardiac ECG to guide the tip positioning by monitoring characteristic P-wave changes. In this study, eligible patients enrolled September 2011 to May 2012 according to the inclusion and exclusion criteria received the catheterization monitored by intracardiac ECG. Then chest radiography was performed to check the catheter position. The results revealed that, with 117 eligible patients, all bar one patient who died (n = 116) completed the study, including 60 males and 56 females aged 51.2 +/- 15.1 years. Most (n = 113, > 97%) had characteristic P-wave changes. The intracardiac ECG-guided positioning procedure achieved correct placement for 112 patients (96.56%), demonstrating 99.12% sensitivity and 100% specificity. In conclusion, the intracardiac ECG can be a promising technique to guide tip positioning of PICCs. However, since the sample size in this study is limited, more experience and further study during clinical practice are needed to demonstrate achievement of optimal catheterization outcomes. PMID- 26617330 TI - Evaluation of Two Lyophilized Molecular Assays to Rapidly Detect Foot-and-Mouth Disease Virus Directly from Clinical Samples in Field Settings. AB - Accurate, timely diagnosis is essential for the control, monitoring and eradication of foot-and-mouth disease (FMD). Clinical samples from suspect cases are normally tested at reference laboratories. However, transport of samples to these centralized facilities can be a lengthy process that can impose delays on critical decision making. These concerns have motivated work to evaluate simple to-use technologies, including molecular-based diagnostic platforms, that can be deployed closer to suspect cases of FMD. In this context, FMD virus (FMDV) specific reverse transcription loop-mediated isothermal amplification (RT-LAMP) and real-time RT-PCR (rRT-PCR) assays, compatible with simple sample preparation methods and in situ visualization, have been developed which share equivalent analytical sensitivity with laboratory-based rRT-PCR. However, the lack of robust 'ready-to-use kits' that utilize stabilized reagents limits the deployment of these tests into field settings. To address this gap, this study describes the performance of lyophilized rRT-PCR and RT-LAMP assays to detect FMDV. Both of these assays are compatible with the use of fluorescence to monitor amplification in real-time, and for the RT-LAMP assays end point detection could also be achieved using molecular lateral flow devices. Lyophilization of reagents did not adversely affect the performance of the assays. Importantly, when these assays were deployed into challenging laboratory and field settings within East Africa they proved to be reliable in their ability to detect FMDV in a range of clinical samples from acutely infected as well as convalescent cattle. These data support the use of highly sensitive molecular assays into field settings for simple and rapid detection of FMDV. PMID- 26617331 TI - Evolving molecular era of childhood medulloblastoma: time to revisit therapy. AB - Currently medulloblastoma is treated with a uniform therapeutic approach based on histopathology and clinico-radiological risk stratification, resulting in unpredictable treatment failure and relapses. Improved understanding of the biological, molecular and genetic make-up of these tumors now clearly identifies it as a compendium of four distinct subtypes (WNT, SHH, group 3 and 4). Advances in utilization of the genomic and epigenomic machinery have now delineated genetic aberrations and epigenetic perturbations in each subgroup as potential druggable targets. This has resulted in endeavors to profile targeted therapy. The challenge and future of medulloblastoma therapeutics will be to keep pace with the evolving novel biological insights and translating them into optimal targeted treatment regimens. PMID- 26617332 TI - Incidental observations on "Clinical importance of incidental findings reported on small-volume dental cone beam computed tomography scans focused on impacted maxillary canine teeth". PMID- 26617334 TI - Bioart. AB - Bioart is a creative practice that adapts scientific methods and draws inspiration from the philosophical, societal, and environmental implications of recombinant genetics, molecular biology, and biotechnology. Some bioartists foster inter- disciplinary relationships that blur distinctions between art and science. Others emphasize critical responses to emerging trends in the life sciences. Since bioart can be combined with realistic views of scientific developments, it may help inform the public about science. Artistic responses to biotechnology also integrate cultural commentary resembling political activism. Art is not only about 'responses', however. Bioart can also initiate new science and engineer- ing concepts, foster openness to collaboration and increasing scientific literacy, and help to form the basis of artists' future relationships with the communities of biology and the life sciences. PMID- 26617333 TI - Intratumor molecular heterogeneity in pleomorphic adenoma of the salivary glands. AB - OBJECTIVE: To assess intratumor molecular heterogeneity in salivary gland pleomorphic adenoma (PA) and to investigate if intratumor molecular heterogeneity is associated with cell proliferation or apoptotic indexes. STUDY DESIGN: Nine formalin-fixed paraffin-embedded samples of PA of salivary glands were included in the study. Cell proliferation was estimated by using Ki-67 immunohistochemistry, and apoptotic index was achieved by combining terminal deoxynucleotidyl transferase dUTP nick end-labeling with morphology. A minimum of two different tumor areas of each sample was microdissected, and DNA was extracted. DNA extracted from the tumor capsule was used as normal matched control. Different tumor areas were at least 4 mm from one another and comprised tumor cell-rich areas. Loss of heterozygosity was assessed by a panel of six polymorphic microsatellite markers located at chromosomes 3 (D3 S1029), 9 (D9 S162 and D9 S157), 11 (D11 S1369), and 17 (P53 and AFM238 WF2). RESULTS: Six of nine samples showed intratumor heterogeneity on the basis of the loss of heterozygosity findings. Intratumor molecular heterogeneity did not show association with cell proliferation or apoptotic indexes (P > .05). CONCLUSIONS: Our findings point to the existence of intratumor molecular heterogeneity in salivary gland PA. This is an advance in the efforts to clarify PA molecular pathogenesis, showing that this characteristic is not exclusive to malignant solid tumors. PMID- 26617335 TI - Phospha-fluorescein: a red-emissive fluorescein analogue with high photobleaching resistance. AB - Phospha-fluorescein (POF), a phosphine oxide-containing analogue of fluorescein, was synthesized and its photophysical properties were examined. Compared with fluorescein and sila-fluorescein, POF displayed significantly red-shifted absorption and fluorescence as well as superior photobleaching resistance, while retaining the pH-responsive characteristics of fluorescein dyes. PMID- 26617337 TI - Local structure of human hair spatially resolved by sub-micron X-ray beam. AB - Human hair has three main regions, the medulla, the cortex, and the cuticle. An existing model for the cortex suggests that the alpha-keratin- based intermediate filaments (IFs) align with the hair's axis, but are orientationally disordered in plane. We found that there is a new region in the cortex near the cuticle's boundary in which the IFs are aligned with the hair's axis, but additionally, they are orientationally ordered in-plane due to the presence of the cuticle/hair boundary. Further into the cortex, the IF arrangement becomes disordered, eventually losing all in-plane orientation. We also find that in the cuticle, a key diffraction feature is absent, indicating the presence of the beta-keratin rather than that of the alpha-keratin phase. This is direct structural evidence that the cuticle contains beta-keratin sheets. This work highlights the importance of using a sub-micron x-ray beam to unravel the structures of poorly ordered, multi-phase systems. PMID- 26617336 TI - Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis. AB - Ras is phosphorylated on a conserved tyrosine at position 32 within the switch I region via Src kinase. This phosphorylation inhibits the binding of effector Raf while promoting the engagement of GTPase-activating protein (GAP) and GTP hydrolysis. Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. In comparison to normal astrocytes, SHP2 activity is elevated in astrocytes isolated from glioblastoma multiforme (GBM)-prone H-Ras(12V) knock-in mice as well as in glioma cell lines and patient-derived GBM specimens exhibiting hyperactive Ras. Pharmacologic inhibition of SHP2 activity attenuates cell proliferation, soft-agar colony formation and orthotopic GBM growth in NOD/SCID mice and decelerates the progression of low-grade astrocytoma to GBM in a spontaneous transgenic glioma mouse model. These results identify SHP2 as a direct activator of Ras and a potential therapeutic target for cancers driven by a previously 'undruggable' oncogenic or hyperactive Ras. PMID- 26617338 TI - Effects of a discoloration-resistant calcium aluminosilicate cement on the viability and proliferation of undifferentiated human dental pulp stem cells. AB - Discoloration-resistant calcium aluminosilicate cement has been formulated to overcome the timely problem of tooth discoloration reported in the clinical application of bismuth oxide-containing hydraulic cements. The present study examined the effects of this experimental cement (Quick-Set2) on the viability and proliferation of human dental pulp stem cells (hDPSCs) by comparing the cellular responses with commercially available calcium silicate cement (white mineral trioxide aggregate; WMTA) after different aging periods. Cell viability and proliferation were examined using assays that examined plasma membrane integrity, leakage of cytosolic enzyme, caspase-3 activity for early apoptosis, oxidative stress, mitochondrial metabolic activity and intracellular DNA content. Results of the six assays indicated that both Quick-Set2 and WMTA were initially cytotoxic to hDPSCs after setting for 24 h, with Quick-Set2 being comparatively less cytotoxic than WMTA at this stage. After two aging cycles, the cytotoxicity profiles of the two hydraulic cements were not significantly different and were much less cytotoxic than the positive control (zinc oxide-eugenol cement). Based on these results, it is envisaged that any potential beneficial effect of the discoloration-resistant calcium aluminosilicate cement on osteogenesis by differentiated hDPSCs is more likely to be revealed after outward diffusion and removal of its cytotoxic components. PMID- 26617340 TI - The UK National Flap Registry (UKNFR): A National Database for all pedicled and free flaps in the UK. AB - The UK National Flap Registry (UKNFR) is a cross-speciality National Clinical Audit with participation by the British Association of Plastic Reconstructive and Aesthetic Surgeons (BAPRAS), British Association of Head and Neck Oncologists (BAHNO), British Association of Oral and Maxillofacial Surgeons (BAOMS) and Association of Breast Surgery (ABS). The aim of UKNFR is to collect information about all major pedicled and free flap operations carried out in the UK and through that, assess the quality of care we provide for patients. This audit will allow appropriate comparison of clinical performance with national standards and provide useful data on changing trends. Participation in audit is integral to appraisal and revalidation in the UK. PMID- 26617341 TI - R.I.P. the "Re:" Letter to the Editor. PMID- 26617339 TI - Application of pharmacometric approaches to evaluate effect of weight and renal function on pharmacokinetics of alogliptin. AB - AIMS: The aims of the study were to characterize the pharmacokinetics (PK) of alogliptin in healthy and type 2 diabetes mellitus (T2DM) subjects using a population PK approach and to assess the influence of various covariates on alogliptin exposure. METHODS: Plasma concentration data collected from two phase 1 studies and one phase 3 study following administration of alogliptin (12.5-400 mg) were used for the PK model development. One- and two-compartment models were evaluated as base structural PK models. The impact of selected covariates was assessed using stepwise forward selection and backward elimination procedures. The predictability and robustness of the final model was evaluated using visual predictive check and bootstrap analyses. The final model was used to perform simulations and guide appropriate dose adjustments. RESULTS: A two-compartment model with first-order absorption and elimination best described the alogliptin concentration vs. time profiles. Creatinine clearance and weight had a statistically significant effect on the oral clearance (CL/F) of alogliptin. The model predicted a lower CL/F (17%, 35%, 80%) and a higher systemic exposure (56%, 89%, 339%) for subjects with mild, moderate and severe renal impairment, respectively, compared with healthy subjects. Effect of weight on CL/F was not considered clinically relevant. Simulations at different doses of alogliptin support the approved doses of 12.5 mg and 6.25 mg for patients with moderate and severe renal impairment, respectively. CONCLUSIONS: The PK of alogliptin was well characterized by the model. The analysis suggested an alogliptin dose adjustment for subjects with moderate-to-severe renal impairment and no dose adjustments based on weight. PMID- 26617342 TI - Rational design of inorganic dielectric materials with expected permittivity. AB - Techniques for rapid design of dielectric materials with appropriate permittivity for many important technological applications are urgently needed. It is found that functional structure blocks (FSBs) are helpful in rational design of inorganic dielectrics with expected permittivity. To achieve this, coordination polyhedra are parameterized as FSBs and a simple empirical model to evaluate permittivity based on these FSB parameters is proposed. Using this model, a wide range of examples including ferroelectric, high/low permittivity materials are discussed, resulting in several candidate materials for experimental follow-up. PMID- 26617343 TI - Observed deep energetic eddies by seamount wake. AB - Despite numerous surface eddies are observed in the ocean, deep eddies (a type of eddies which have no footprints at the sea surface) are much less reported in the literature due to the scarcity of their observation. In this letter, from recently collected current and temperature data by mooring arrays, a deep energetic and baroclinic eddy is detected in the northwestern South China Sea (SCS) with its intensity, size, polarity and structure being characterized. It remarkably deepens isotherm at deep layers by the amplitude of ~120 m and induces a maximal velocity amplitude about 0.18 m/s, which is far larger than the median velocity (0.02 m/s). The deep eddy is generated in a wake when a steering flow in the upper layer passes a seamount, induced by a surface cyclonic eddy. More observations suggest that the deep eddy should not be an episode in the area. Deep eddies significantly increase the velocity intensity and enhance the mixing in the deep ocean, also have potential implication for deep-sea sediments transport. PMID- 26617344 TI - X-ray Lithography on Perovskite Nanocrystals Films: From Patterning with Anion Exchange Reactions to Enhanced Stability in Air and Water. AB - Films of colloidal CsPbX3 (X = I, Br or Cl) nanocrystals, prepared by solution drop-casting or spin-coating on a silicon substrate, were exposed to a low flux of X-rays from an X-ray photoelectron spectrometer source, causing intermolecular C?C bonding of the organic ligands that coat the surface of the nanocrystals. This transformation of the ligand shell resulted in a greater stability of the film, which translated into the following features: (i) Insolubility of the exposed regions in organic solvents which caused instead complete dissolution of the unexposed regions. This enabled the fabrication of stable and strongly fluorescent patterns over millimeter scale areas. (ii) Inhibition of the irradiated regions toward halide anion exchange reactions, when the films were exposed either to halide anions in solution or to hydrohalic vapors. This feature was exploited to create patterned regions of different CsPbIxBryClz compositions, starting from a film with homogeneous CsPbX3 composition. (iii) Resistance of the films to degradation caused by exposure to air and moisture, which represents one of the major drawbacks for the integration of these materials in devices. (iv) Stability of the film in water and biological buffer, which can open interesting perspectives for applications of halide perovskite nanocrystals in aqueous environments. PMID- 26617345 TI - Letter to the Editor. PMID- 26617346 TI - Bovine xenograft application for treatment of a metatarsal nonunion fracture in an alpaca (Vicugna pacos). AB - CASE HISTORY: A 15-year-old female huacaya alpaca (Vicugna pacos) was referred because of a non-weight-bearing lameness (4/4) in the left pelvic limb caused by a grade three open metatarsal fracture. The referring veterinarian treated the fracture with conservative management using bandages, but it progressively evolved to a non-union. CLINICAL FINDINGS AND DIAGNOSIS: Clinical examination revealed external wounds on the medial and lateral surfaces of the metatarsus. Radiographs confirmed an open, nonarticular, displaced, diaphyseal fracture of the left metatarsus. TREATMENT AND OUTCOME: Cancellous bone was sourced from bovine proximal and distal femur epiphyses, followed by a thermal shock procedure to achieve decellularisation, to produce a xenograft. Open reduction and internal fixation of the fracture using locking plates was performed. Alignment of the fracture fragments was corrected and the xenograft was placed at the debrided fracture site to stimulate and harness osteogenesis in situ. Clinical and radiographic follow-up was performed up to 40 weeks postoperatively. Clinical evaluations revealed that the alpaca gradually increased weight bearing following bandage removal 10 days after surgery. Serial radiographs showed correct alignment of the left metatarsus, progressive bone modelling and, complete bone union at 12 weeks. Ten months postoperatively the alpaca showed no signs of lameness and resumed normal activity. CLINICAL RELEVANCE: For management of a metatarsal non-union, a combination of bovine xenograft application and angular stable internal fixation progressed toward an excellent long-term recovery. PMID- 26617347 TI - There's an App for That: Creating a Coronary CT Angiography Learning Module for the iPad. PMID- 26617348 TI - Charging C60 islands with the AFM tip. AB - We show that electrons can be transferred on demand from an AFM tip into single bulk-like C60 islands, which are supported on the insulating NaCl(001) surface. We exemplify this by controlled charge-manipulation experiments conducted in ultrahigh vacuum by noncontact AFM (nc-AFM), electrostatic force microscopy (EFM) and Kelvin probe force microscopy (KPFM). KPFM shows a homogeneous contrast at the islands, which is a signature for an equal distribution of the electrons in the T1u band. The charge dissipates during half a day due to an interaction of the charged C60 islands with defects in the near surface region of NaCl. Our results open the perspective in photo-voltaics to study charge attachment, stability and charge exchange with the environment of any C60 bulk-like system. PMID- 26617349 TI - Antimicrobial susceptibility and molecular characteristics of methicillin resistant Staphylococcus aureus in a Japanese secondary care facility. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is prevalent in Japan, and the Staphylococcus cassette chromosome mec (SCCmec) type II is common among hospital acquired MRSA isolates. Information pertaining to MRSA characteristics is limited, including SCCmec types, in primary or secondary care facilities. A total of 128 MRSA isolates (90 skin and soft tissue isolates and 38 blood isolates) were collected at a secondary care facility, Kawatana Medical Center, from 2005 to 2011. Antimicrobial susceptibility testing for anti-MRSA antibiotics and molecular testing for SCCmec and virulence genes (tst, sec, etb, lukS/F-PV) were performed. Strains positive for lukS/F-PV were analyzed by multilocus sequence typing and phage open-reading frame typing. SCCmec typing in skin and soft tissue isolates revealed that 65.6% had type IV, 22.2% had type II, 8.9% had type I, and 3.3% had type III. In blood isolates, 50.0% had type IV, 47.4% had type II, and 2.6% had type III. Minimum inhibitory concentrations, MIC(50)/MIC(90), against vancomycin, teicoplanin, linezolid, and arbekacin increased slightly in SCCmec II isolates from skin and soft tissue. MICs against daptomycin were similar between sites of isolation. SCCmec type II isolates possess tst and sec genes at a greater frequently than SCCmec type IV isolates. Four lukS/F-PV-positive isolates were divided into two clonal patterns and USA300 was not included. In conclusion, SCCmec type IV was dominant in blood, skin, and soft tissue isolates in a secondary care facility in Japan. Because antimicrobial susceptibility varies with the SCCmec type, SCCmec typing of clinical isolates should be monitored in primary or secondary care facilities. PMID- 26617350 TI - Keratinocyte growth factor-2 inhibits bacterial infection with Pseudomonas aeruginosa pneumonia in a mouse model. AB - To determine protective effects of concurrent administration of Keratinocyte growth factor-2 (KGF-2) with Pseudomonas aeruginosa (P. aeruginosa) inoculation on the induced pneumonia. KGF-2 (5 mg/kg) was concurrently administered into the left lobe of 55 mice with P. aeruginosa PAO1 (5 * 10(6) CFU, half-lethal dose); 55 mice in the control group were concurrently administered PBS with the PAO1. We detected and analyzed: body temperature; amount of P. aeruginosa in homogenates; count of total number of nucleated cells and of mononuclear macrophages; protein concentration in bronchoalveolar lavage fluid (BALF); lung wet-to-dry weight ratio; cytokines in BALF and blood; and lung morphology. To study survival rate, concurrent administration of KGF-2 (experimental group) versus PBS (control) with a lethal dose of PAO1 (1 * 10(7) CFU was performed, and survivorship was documented for 7 days post-inoculation. The bacterial CFU in lung homogenates was significantly decreased in the KGF-2 group compared to the control group. There were significantly more mononuclear macrophages in the BALF from the KGF-2 group than from the control group (p < 0.05). KGF-2 increased the surfactant protein and GM-CSF mRNA in lung at 6 h and 72 h after inoculation. Significant reduction of lung injury scores, protein concentrations, lung wet-to-dry weight ratio, and IL-6 and TNF-alpha levels was noted in the KGF-2 treated rats at 72 h after inoculation (p < 0.05). The 7-day survival rate of the KGF-2 group was significantly higher than that of the control group (p < 0.05). Concurrent administration of KGF-2 facilitates the clearance of P. aeruginosa from the lungs, attenuates P. aeruginosa-induced lung injury, and extends the 7-day survival rate in mice model with P. aeruginosa pneumonia. PMID- 26617351 TI - Diagnosing Hidradenitis Suppurativa. AB - Three diagnostic criteria must be met for hidradenitis suppurativa: typical lesions, occurrence in one or more of the predilection areas, and that it is chronic and/or recurrent. Several outcome measures are used, including patient reported pain and itch scales, Dermatology Life Quality Index, and Skindex. Hidradenitis suppurativa is associated with significant comorbidities that must be addressed in the evaluation of the patients. PMID- 26617353 TI - The Handicap of Hidradenitis Suppurativa. AB - Hidradenitis suppurativa (HS) is a chronic skin disease, with painful, foul smelling, recurring inflammation, leading to a diminished quality of life. Patients with HS also often suffer from depression, have an impaired sexual health, and may have difficulty performing their work duties. PMID- 26617352 TI - Prevalence, Risk Factors, and Comorbidities of Hidradenitis Suppurativa. AB - It is challenging to estimate a true prevalence of hidradenitis suppurativa (HS) because it is underdiagnosed and misdiagnosed. Prevalences have been reported from 0.00033% to 4.1%. The incidence seems to be rising. In addition to dermatologic symptoms, HS is associated with metabolic syndrome, and increased cardiovascular risk. The majority of HS patients are smokers. Additional somatic comorbidities complicating HS include autoimmune conditions, follicular syndromes, rheumatologic conditions, and malignancies. HS patients are troubled by psychological comorbidities. When treating HS patients it is imperative not only to treat the skin symptoms, but also address the screening and treatment of possible comorbidities. PMID- 26617354 TI - The Genetics of Hidradenitis Suppurativa. AB - A family history of hidradenitis suppurativa (HS) is reported by about one-third of patients, and the pattern of inheritance suggests a single gene disorder inherited as an autosomal dominant trait. Several gamma-secretase gene mutations were identified in 6 Han Chinese families with multiple affected family members. Several of the Han Chinese patients had a severe disease phenotype, with involvement of nonflexural skin locations such as the back and chest. These findings have been repeated in other populations, but gamma-secretase mutations have been found only in a minority of patients with HS. PMID- 26617355 TI - The Microbiology of Hidradenitis Suppurativa. AB - Although the clinical presentation of Hidradenitis Suppurativa (HS) is strongly reminiscent of bacterial infection, the role of bacteria remains controversial. Studies have isolated an array of different bacterial specimens as well as biofilm formation in lesional HS skin. Consistent findings of Gram-positive cocci and -rods including Staphylococus aureus, Coagulase-negative staphylococci (CoNS) and Corynebacterium species (spp) in deep tissue samples have been demonstrated in HS. Although efficacy of antibiotics, i.e., rifampicin, clindamycin or tetracycline may support a microbial role in disease pathogenesis, the most often isolated bacterial specimens are commensal bacteria (CoNS). PMID- 26617356 TI - The Role of Mechanical Stress in Hidradenitis Suppurativa. AB - Mechanical stress can act as a possible trigger in the development of hidradenitis suppurativa (HS). The mechanical stress has been supported by (1) the special biomechanical conditions in the typically topographic areas of HS; (2) the indirect proof of similar findings in associated follicular occlusion diseases such as acne mechanica and pilonidal sinus disease, and in limb amputees after expression of mechanical forces; (3) pathohistologic, ultrasonography, and immunologic findings; and (4) overweight patients seem to be most susceptible to the effects of mechanical stress. PMID- 26617357 TI - Endocrinologic Aspects of Hidradenitis Suppurativa. AB - Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder of unknown etiology. The role of hormones in HS remains unclear, but the observation of premenstrual flares, female predominance, and improvement during pregnancy suggest a hormonal/metabolic background. The reported positive effects of antiandrogen therapy supports a possible role of androgens. The predominant onset of the disease years after puberty may indicate a metabolic disorder. Obesity contributes significantly to HS pathogenesis; diabetes, dyslipidemia, the metabolic syndrome, and polycystic ovarian syndrome are among the commonest comorbidities. More studies are required to clarify a potential hormonal dysregulation in HS. PMID- 26617358 TI - Inflammatory Mechanisms in Hidradenitis Suppurativa. AB - Hidradenitis suppurativa (HS) is a chronic relapsing disease of follicular occlusion that causes immense clinical and psychosocial morbidity when refractory to treatment. HS is no longer considered a disease of primary infectious etiology, although bacteria play a role. There is increasing evidence that HS is associated with immune dysregulation, based on its clinical association with other immune-mediated disorders, by its response to biologic therapy in the clinical arena, and from molecular research. This article summarizes what is known in relation to the inflammatory pathways in HS. PMID- 26617359 TI - Imaging of Hidradenitis Suppurativa. AB - Hidradenitis suppurativa is a complex disease of chronic evolution and difficult management. Imaging, particularly color Doppler ultrasound, has demonstrated a wide range of subclinical anatomic abnormalities, allowing modification of the clinical assessment of severity of the disease and therefore management of patients. Sonography supports early and more precise diagnosis and staging by providing critical objective information in real time. The richness of these data can also support assessment of the pathogenesis of the disease, allow monitoring of patients, and contribute to clinical trials. MRI can support the diagnosis of extensive anogenital and deep lesions. PMID- 26617360 TI - Randomized Controlled Trials for the Treatment of Hidradenitis Suppurativa. AB - Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent, debilitating skin disease. Several treatment modalities are available, but most of them lack high-quality evidence. A systematic search was performed to identify all randomized controlled trials for the treatment of HS in order to review and evaluate the evidence. Recommendations for future randomized controlled trials include using validated scores, inclusion of patient rated outcomes, and thorough report of side effects. Evidence for long-term treatment and benefit/risk ratio of available treatment modalities is needed in order to enhance evidence-based treatment in daily clinical practice. Combining surgery with antiinflammatory treatment warrants further investigation. PMID- 26617361 TI - Antibiotic Treatment of Hidradenitis Suppurativa. AB - Although hidradenitis suppurativa (HS) is not primarily an infectious disease, antibiotics are widely used to treat HS. Recent microbiological data show that HS suppurating lesions are associated with a polymorphous anaerobic flora, including actinomycetes and milleri group streptococci, and can therefore be considered as polymicrobial soft tissue and skin infections. Analysis of the literature provides little information on the efficacy of antibiotics in HS but suggests a beneficial effect of certain antimicrobial treatments, depending on the clinical severity of the disease. Patients must be informed and should agree with the treatment strategy before starting antibiotic treatments. PMID- 26617362 TI - Medical Treatments of Hidradenitis Suppurativa: More Options, Less Evidence. AB - Hidradenitis suppurativa is a common debilitating skin disease that has been neglected by science. The disease is getting more and more attention, reflected by the rising number of scientific publications. There is a clear need for effective treatment. We are still at the beginning of improving care for these patients as demonstrated by the low levels of evidence for the medical treatments. Many of these therapies showed promising results, but are still waiting to be validated in randomized, controlled trials. Much more research is needed to strengthen the Level of Evidence for these therapies and thus improve patient care. PMID- 26617363 TI - Surgical Procedures in Hidradenitis Suppurativa. AB - Hidradenitis suppurativa is difficult to treat owing to its complex pathomechanism; beside the extensive inflammation with abscesses and inflammatory nodules, there is also an architectural loss with sinus tract formation and in severe cases with extensive scarring. Therefore, surgery is mandatory in moderate and severe HS. PMID- 26617364 TI - Lasers and Intense Pulsed Light Hidradenitis Suppurativa. AB - Lasers and intense pulsed light (IPL) treatment are useful for the treatment of hidradenitis suppurativa (HS). Carbon dioxide lasers are used for cutting or vaporization of the affected area. It is a effective therapy for the management of severe and recalcitrant HS with persistent sinus tract and scarring, and can be performed under local anesthesia. HS has a follicular pathogenesis. Lasers and IPL targeting the hair have been found useful in treating HS by reducing the numbers of hairs in areas with HS. The methods have few side effects, but the studies are preliminary and need to be repeated. PMID- 26617365 TI - BRAF Mutations in Erdheim-Chester Disease. PMID- 26617366 TI - The Secret Scourge. PMID- 26617367 TI - Effects of the mas-related gene (Mrg) C receptor agonist BAM6-22 on nociceptive reflex activity in naive, monoarthritic and mononeuropathic rats after intraplantar and intrathecal administration. AB - MrgC receptors are selectively expressed on peripheral and central terminals of small calibre nociceptive fibres. Peptide agonists of the MrgC receptor were reported to modulate nociceptive transmission exerting either pro- or antinociceptive effects depending on site of action and pain model used. Here, we investigated the effect of intraplantar and intrathecal administration of the selective MrgC receptor agonist BAM6-22 on mechanically and electrically evoked nociceptive reflex activity as a uniform readout measure in naive, monoarthritic and mononeuropathic rats. In naive rats, intraplantar BAM6-22 enhanced, whereas intrathecal BAM6-22 did not modulate mechanically-evoked nociceptive reflex activity. In monoarthritic rats, intraplantar BAM6-22 had no effect, whereas intrathecal BAM6-22 inhibited mechanically evoked nociceptive reflex activity. In mononeuropathic rats, BAM6-22 reduced mechanically evoked nociceptive reflex activity after both intraplantar and intrathecal administration. BAM6-22 did not modulate electrically evoked nociceptive reflex activity in any condition. Thus, the results of the present investigation confirm and add to previous studies demonstrating that site of action, (patho)-physiological state and stimulus modality determine the effect quality of MrgC receptor agonists. It still needs to be explored how concurrent activation of peripheral and spinal MrgC receptors modulates nociceptive processing under conditions of both acute and chronic pain to evaluate the therapeutic potential of putative small molecule MrgC receptor agonists as innovative analgesics. PMID- 26617368 TI - Three-dimensional stiffness of the carpal arch. AB - The carpal arch of the wrist is formed by irregularly shaped carpal bones interconnected by numerous ligaments, resulting in complex structural mechanics. The purpose of this study was to determine the three-dimensional stiffness characteristics of the carpal arch using displacement perturbations. It was hypothesized that the carpal arch would exhibit an anisotropic stiffness behavior with principal directions that are oblique to the conventional anatomical axes. Eight (n=8) cadavers were used in this study. For each specimen, the hamate was fixed to a custom stationary apparatus. An instrumented robot arm applied three dimensional displacement perturbations to the ridge of trapezium and corresponding reaction forces were collected. The displacement-force data were used to determine a three-dimensional stiffness matrix using least squares fitting. Eigendecomposition of the stiffness matrix was used to identify the magnitudes and directions of the principal stiffness components. The carpal arch structure exhibited anisotropic stiffness behaviors with a maximum principal stiffness of 16.4+/-4.6N/mm that was significantly larger than the other principal components of 3.1+/-0.9 and 2.6+/-0.5N/mm (p<0.001). The principal direction of the maximum stiffness was pronated within the cross section of the carpal tunnel which is accounted for by the stiff transverse ligaments that tightly bind distal carpal arch. The minimal principal stiffness is attributed to the less constraining articulation between the trapezium and scaphoid. This study provides advanced characterization of the wrist's three-dimensional structural stiffness for improved insight into wrist biomechanics, stability, and function. PMID- 26617369 TI - Computational study of the fluid-dynamics in carotids before and after endarterectomy. AB - In this work, we provide a computational study of the effects of carotid endarterectomy (CEA) on the fluid-dynamics at internal carotid bifurcations. We perform numerical simulations in real geometries of the same patients before and after CEA, using patient-specific boundary data obtained by Echo-Color Doppler measurements. We analyze four patients with a primary closure and other four where a patch was used to close arteriotomies. The results show that (i) CEA is able to restore physiological fluid-dynamic conditions; (ii) among the post operative cases, the presence of patch leads to local hemodynamic conditions which might imply a higher risk of restenosis in comparison with the cases without patch. PMID- 26617370 TI - The ground reaction force thresholds for detecting postural stability in participants with and without flat foot. AB - Foot mobility commonly contributes to injury via altered motion of the lower extremities. However, there is a lack of understanding of sensitive kinetic changes with flat foot. The purpose of this study was to investigate the threshold that best distinguishes between participants with and without flat foot. The kinetic stability index was developed based on the three-dimensional data from the ground reaction force (GRF) during one leg standing. In total, 34 control participants and 30 participants with flat foot were asked to maintain one leg standing for 25s with the contra lateral hip and knee flexed approximately 90 degrees . The various thresholds (3, 7, 15, 30, 50, and 200N) were analyzed by the kinetic stability index. The standing time was not significantly different between groups (t=1.07, p=0.28); however, there were significant differences on threshold level (F=369.23, p=0.001) as well as group interactions with threshold (F=6.72, p=0.01). The post hoc test indicated that less than 15N was the best to detect the kinetic stability index between the groups. Clinicians need to understand sensitive threshold settings to differentiate the participants with and without flat foot. The threshold changes might be altered to detect postural deficits by the kinetic stability index. PMID- 26617371 TI - Preparticipation Evaluation of the Wilderness Athlete and Adventurer. PMID- 26617372 TI - Setting, Structure, and Timing of the Preparticipation Examination: The Wilderness Adventure Consultation. AB - Patients pursue wilderness experiences throughout the entire life cycle, and while outdoor pursuits are relatively safe, injuries do occur. Many of these adverse events can be anticipated, identified, and prevented through a wilderness preparticipation examination (PPE). To accomplish this, it is incumbent on the physician to assess the extrinsic and intrinsic factors faced by the patient and attempt to correct them to ensure an enjoyable experience in the outdoors. This article outlines the goals of the PPE along with identification of various risk factors that can influence a trip. Most injuries and rescues occur from underestimating the risks from extrinsic, environmental factors, and/or overestimating one's intrinsic skills. By matching the patient's fitness and skill level to the environment, the physician can help reduce the risk of serious injury. PMID- 26617373 TI - Ethical, Legal, and Administrative Considerations for Preparticipation Evaluation for Wilderness Sports and Adventures. AB - Preparticipation evaluations (PPEs) are common in team, organized, or traditional sports but not common in wilderness sports or adventures. Regarding ethical, legal, and administrative considerations, the same principles can be used as in traditional sports. Clinicians should be trained to perform such a PPE to avoid missing essential components and to maximize the quality of the PPE. In general, participants' privacy should be observed; office-based settings may be best for professional and billing purposes, and adequate documentation of a complete evaluation, including clearance issues, should be essential components. Additional environmental and personal health issues relative to the wilderness activity should be documented, and referral for further screening should be made as deemed necessary, if unable to be performed by the primary clinician. Travel medicine principles should be incorporated, and recommendations for travel or adventure insurance should be made. PMID- 26617374 TI - General Consideration in the History, Physical Examination, and Safety Determination. AB - A thorough medical history is perhaps the most important aspect when evaluating an athlete before wilderness adventure. A physical examination should follow focusing on conditions that may be affected by changes in atmospheric pressure, extremes of temperature, or altitude. This information can then be used to make safety recommendations ensuring that adventurers are able to safely enjoy participation in the wilderness pursuit of their choice. PMID- 26617375 TI - General Medical Considerations for the Wilderness Adventurer: Medical Conditions That May Worsen With or Present Challenges to Coping With Wilderness Exposure. AB - Participation in wilderness and adventure sports is on the rise, and as such, practitioners will see more athletes seeking clearance to participate in these events. The purpose of this article is to describe specific medical conditions that may worsen or present challenges to the athlete in a wilderness environment. PMID- 26617376 TI - Risk Stratification for Athletes and Adventurers in High-Altitude Environments: Recommendations for Preparticipation Evaluation. AB - High-altitude athletes and adventurers face a number of environmental and medical risks. Clinicians often advise participants or guiding agencies before or during these experiences. Preparticipation evaluation (PPE) has the potential to reduce risk of high-altitude illnesses in athletes and adventurers. Specific conditions susceptible to high-altitude exacerbation also important to evaluate include cardiovascular and lung diseases. Recommendations by which to counsel individuals before participation in altitude sports and adventures are few and of limited focus. We reviewed the literature, collected expert opinion, and augmented principles of a traditional sport PPE to accommodate the high-altitude wilderness athlete/adventurer. We present our findings with specific recommendations on risk stratification during a PPE for the high-altitude athlete/adventurer. PMID- 26617377 TI - Preparticipation Evaluation for Climbing Sports. AB - Climbing is a popular wilderness sport among a wide variety of professional athletes and amateur enthusiasts, and many styles are performed across many environments. Potential risks confront climbers, including personal health or exacerbation of a chronic condition, in addition to climbing-specific risks or injuries. Although it is not common to perform a preparticipation evaluation (PPE) for climbing, a climber or a guide agency may request such an evaluation before participation. Formats from traditional sports PPEs can be drawn upon, but often do not directly apply. The purpose of this article was to incorporate findings from expert opinion from professional societies in wilderness medicine and in sports medicine, with findings from the literature of both climbing epidemiology and traditional sports PPEs, into a general PPE that would be sufficient for the broad sport of climbing. The emphasis is on low altitude climbing, and an overview of different climbing styles is included. Knowledge of climbing morbidity and mortality, and a standardized approach to the PPE that involves adequate history taking and counseling have the potential for achieving risk reduction and will facilitate further study on the evaluation of the efficacy of PPEs. PMID- 26617378 TI - Medical Clearance for Desert and Land Sports, Adventure, and Endurance Events. AB - Endurance events are increasing in popularity in wilderness and remote settings, and participants face a unique set of potential risks for participation. The purpose of this article is to outline these risks and allow the practitioner to better guide the wilderness adventurer who is anticipating traveling to a remote or desert environment. PMID- 26617379 TI - Pre-Participation Medical Evaluation for Adventure and Wilderness Watersports. AB - A request for a preparticipation medical evaluation for wilderness watersports may be made by guiding agencies, instructional camps, or by patients presenting for an annual visit. Although guidelines have been published regarding preparticipation physical evaluation for traditional competitive high school and collegiate sports, little has been written about medical evaluations for those wishing to engage in wilderness and adventure watersports. in this article, we offer guidance based on literature review and expert opinion. Watersports are among the most common recreational activities in the United states and are generally safe. Drowning, however, is a significant risk, particularly in small, self-propelled craft, and among children. Medical counseling before participation in watersports should include screening for medical conditions which may impair swimming ability, including a history of seizures, heart disease, and lung disease. Physicians should also promote preventive health measures such as use of lifejackets and sun protection, as well as alcohol avoidance. Swim testing tailored to specific activities should be strongly considered for children and those with questionable swimming ability. PMID- 26617380 TI - Medical Evaluation for Exposure Extremes: Cold. AB - Risk of injury in cold environments is related to a combination of athlete preparedness, preexisting medical conditions, and the body's physiologic response to environmental factors, including ambient temperature, windchill, and wetness. The goal of this section is to decrease the risk of hypothermia, frostbite, and nonfreezing cold injuries as well as to prevent worsening of preexisting conditions in cold environments using a preparticipation screening history, examination, and counseling. Cold weather exercise can be done safely with education, proper preparation, and appropriate response to changing weather conditions. PMID- 26617381 TI - Medical Evaluation for Exposure Extremes: Heat. AB - Exertional heat illness can be a serious consequence of sports or exercise in hot environments. Participants can possess intrinsic or face extrinsic risk factors that may increase their risk for heat-related illness. Knowledge of the physiology and pathology of heat illness, identification of risk factors, and strategies to combat heat accumulation will aid both the practitioner and the participant in preparing for activities that occur in hot environments. Through preparation and mitigation of risk, safe and enjoyable wilderness adventure can be pursued. PMID- 26617382 TI - Wilderness Preparticipation Evaluation and Considerations for Special Populations. AB - Children, older adults, disabled and special needs athletes, and female athletes who participate in outdoor and wilderness sports and activities each face unique risks. For children and adolescents traveling to high altitude, the preparticipation physical evaluation should focus on risk assessment, prevention strategies, early recognition of altitude-related symptoms, management plans, and appropriate follow-up. As the risk and prevalence of chronic disease increases with age, both older patients and providers need to be aware of disease and medication-specific risks relative to wilderness sport and activity participation. Disabled and special needs athletes benefit from careful pre-event planning for the potential medical issues and equipment modifications that may affect their health in wilderness environments. Issues that demand special consideration for female adventurers include pregnancy, contraceptive use, menses, and ferritin levels at altitude. A careful preparticipation evaluation that factors in unique, population- specific risks will help special populations stay healthy and safe on wilderness adventures. The PubMed and SportDiscus databases were searched in 2014 using both MeSH terms and text words and include peer-reviewed English language articles from 1977 to 2014. Additional information was accessed from Web-based sources to produce this narrative review on preparticipation evaluation for special populations undertaking wilderness adventures. Key words include children, adolescent, pediatric, seniors, elderly, disabled, special needs, female, athlete, preparticipiation examination, wilderness medicine, and sports. PMID- 26617383 TI - Counseling for the Wilderness Athlete and Adventurer During a Preparticipation Evaluation for Preparation, Safety, and Injury Prevention. AB - Wilderness sports and adventures continue to increase in popularity. Counseling is an essential element of the preparticipation evaluation (PPE) for athletes in traditional sports. This approach can be applied to and augmented for the wilderness athlete and adventurer. The authors reviewed the literature on counseling during PPEs and gathered expert opinion from medical professionals who perform such PPEs for wilderness sports enthusiasts. The objective was to present findings of this review and make recommendations on the counseling component of a wilderness sports/adventure PPE. The counseling component of a PPE for wilderness sports/adventures should take place after a basic medical evaluation, and include a discussion on sport or activity-specific injury prevention, personal health, travel recommendations, and emergency event planning. Counseling should be individualized and thorough, and involve shared decision making. This should take place early enough to allow ample time for the athlete or adventurer to further prepare as needed based on the recommendations. Resources may be recommended for individuals desiring more information on selected topics. PMID- 26617384 TI - A green and efficient photocatalytic route for the highly-selective oxidation of saturated alpha-carbon C-H bonds in aromatic alkanes over flower-like Bi2WO6. AB - A green and efficient route for the highly-selective oxidation of saturated alpha carbon C-H bonds in aromatic alkanes under visible-light irradiation and solvent free conditions is developed using flower-like Bi2WO6 microspheres as catalysts. PMID- 26617386 TI - Quantum-enabled temporal and spectral mode conversion of microwave signals. AB - Electromagnetic waves are ideal candidates for transmitting information in a quantum network as they can be routed rapidly and efficiently between locations using optical fibres or microwave cables. Yet linking quantum-enabled devices with cables has proved difficult because most cavity or circuit quantum electrodynamics systems used in quantum information processing can only absorb and emit signals with a specific frequency and temporal envelope. Here we show that the temporal and spectral content of microwave-frequency electromagnetic signals can be arbitrarily manipulated with a flexible aluminium drumhead embedded in a microwave circuit. The aluminium drumhead simultaneously forms a mechanical oscillator and a tunable capacitor. This device offers a way to build quantum microwave networks using separate and otherwise mismatched components. Furthermore, it will enable the preparation of non-classical states of motion by capturing non-classical microwave signals prepared by the most coherent circuit quantum electrodynamics systems. PMID- 26617385 TI - The burden of HIV-associated neurocognitive disorder (HAND) in the Asia-Pacific region and recommendations for screening. AB - BACKGROUND: HIV-associated neurocognitive disorder incurs a significant burden on HIV patients in Asia-Pacific countries; however, the incidence is difficult to estimate due to a lack of local epidemiological data. The impact of neurocognitive impairment in HIV patients is often underestimated due to a lack of education and awareness, and there are consequently gaps in the provision of screening and diagnosis to enable earlier intervention to limit neurocognitive impairment. METHOD: This review seeks to redress the imbalance by promoting awareness and education among physicians concerning the neurovirulence of HIV and thereby increase screening efforts to improve diagnosis rates and clinical outcomes for underserved patients in this region. The Asia, Australia, and Middle East (AAME) HAND Advisory Board convened expert regional representatives to review current practice and recommend appropriate measures related to the implementation of standardised screening programmes and treatment recommendations to curb the developing HAND epidemic in the region. In particular, we recommend basic neuropsychological testing protocols that could be efficiently introduced into clinical practice for routine screening. RESULT: We also propose simple guidelines for the management of HAND. We believe that HAND is a significant and under-reported diagnosis in HIV patients that warrants both greater recognition and further clinical investigation of the underlying pathophysiology and the impact of HIV disease progression, with HAND being associated with worse medication adherence and therefore possibly increased risk of ARV treatment failure. DISCUSSION: Widespread screening will lead to greater recognition of HAND and earlier intervention, which may lead to improved management strategies in the future. PMID- 26617387 TI - Comparative study of aromatic compounds in fruit wines from raspberry, strawberry, and mulberry in central Shaanxi area. AB - BACKGROUND: Although grape wines have firmly dominated the production and consumption markets of fruit wines, raspberry, strawberry, and mulberry have been utilized to make wines because of their joyful aroma and high contents of polyphenolic phytochemicals and essential fatty acids. However, little is known about aromatic compounds of the wines produced from these three fruits. METHODS: The aromatic composition of fruit wines produced from raspberry, strawberry, mulberry, and red grape was analyzed by GC-MS. Odor activity values (OAVs) and relative odor contributions (ROCs) were used to estimate the sensory contribution of the aromatic compounds to the overall flavor of the wines. RESULTS: In strawberry, raspberry, and mulberry wines, 27, 30, and 31 odorants were detected, respectively. Alcohols formed the most abundant group, followed by esters and acids. The grape wine contained a wider variety (16 types) of alcohols, and 4 methyl-2-pentanol and 2,3-butanediol were not present in the three fruit wines. The quantity of esters in raspberry (1.54%) and mulberry wines (2.08%) were higher than those of strawberry wine (0.78%), and mulberry wine contained more types of esters. There were no significant differences of acids between the three fruit wines and the control wine. In addition, 2-heptanone, 2-octanone, 2 nonanone, and 2-undecanone were unique to raspberry wine, and nonanal was present only in mulberry wine. The indistinguishable aroma of the three fruit wines was attributed to the dominance of fruity and floral odor components derived from ethyl esters of fatty acids and their contributions to the global aroma of the three fruit wines. CONCLUSION: The present study demonstrated that there were significant differences in the volatile components of fruit wines made from raspberry, strawberry, and mulberry. The aroma compounds were more abundant in the raspberry and mulberry wines than in the strawberry wine, but the quality of strawberry wine was superior to raspberry and mulberry wines. PMID- 26617389 TI - Enhancing Energetic Properties and Sensitivity by Incorporating Amino and Nitramino Groups into a 1,2,4-Oxadiazole Building Block. AB - A single nitrogen-rich heterocyclic ring with many energetic groups is expected to exhibit excellent detonation performance. We report an effective approach for the synthesis of 3-amino-5-nitramino-1,2,4-oxadiazole, which has nitramino and amino groups in the same building block. The single-crystal X-ray structure shows layered hydrogen-bonding pairs as well as the presence of a water molecule which ensure insensitivity. Through incorporation of a cation, the hydrazinium or hydroxylammonium salts exhibit good energetic performance and acceptable sensitivities. PMID- 26617388 TI - Foetal cord blood contains higher portions of n-3 and n-6 long-chain PUFA but lower portions of trans C18:1 isomers than maternal blood. AB - BACKGROUND/OBJECTIVE: An adequate supply of long-chain polyunsaturated fatty acids (LC PUFA) promotes foetal health and development, whereas generally, trans fatty acids (tFA) are considered to negatively interfere with LC PUFA metabolism. Nevertheless, to date, limited data concerning separate trans C18:1, such as t9 and t11, are available for maternal and foetal blood. Therefore, in this study the portions of individual trans C18:1, LC n-6, and n-3 PUFA in lipids of maternal and foetal plasma and erythrocyte membranes of German mother and child pairs (n=40) were analysed. RESULTS: Portions of linoleic acid and alpha linolenic acid as LC precursors were lower (~0.4-fold); whereas the metabolites arachidonic acid (AA, n-6) and docosahexaenoic acid (DHA, n-3) were significantly higher (~2-fold) in foetal than in maternal plasma and erythrocytes. The main tFA in maternal and foetal blood were elaidic acid (C18:1t9; t9) and vaccenic acid (C18:1t11; t11). Portions of t9, t10, t11, and t12 in foetal blood lipids were lower (~0.5-fold) compared with maternal blood. In foetal lipids, t9 was higher than t11. The t9 correlated negatively with eicosapentaenoic acid (n-3) and AA in maternal and foetal lipids; whereas t11 correlated negatively only with foetal total LC n-6 (plasma and erythrocytes) and n-3 PUFA (erythrocytes). No correlation between maternal tFA and foetal PUFA was observed. CONCLUSIONS: 'Biomagnification' of LC n-6 and n-3 PUFA AA and DHA in foetal blood was confirmed, whereas single trans isomers were lower compared with maternal blood. Nevertheless, tFA intake, especially from industrial sources, should be as low as possible. PMID- 26617390 TI - Gas-phase structure of 2,2,2-trichloroethyl chloroformate studied by electron diffraction and quantum-chemical calculations. AB - The molecular structure and conformational properties of 2,2,2-trichloroethyl chloroformate, ClC(O)OCH2CCl3 were determined experimentally using gas-phase electron diffraction (GED) and theoretically based on quantum-chemical calculations at the MP2 and DFT levels of theory. Further experimental measurements such as UV-visible, IR and Raman spectroscopy were complemented with the corresponding theoretical studies. All experimental results and calculations confirm the presence of two conformers namely anti-gauche (C1 symmetry) and anti anti (Cs symmetry). The conformational preference was rationalised by NBO and AIM analyses. Molecular properties such as ionisation potential, electronegativity, chemical potential, chemical hardness and softness were deduced from HOMO-LUMO analyses. The TD-DFT approach was applied to assign the electronic transitions observed in the UV-visible spectrum. A detailed interpretation of the infrared and Raman spectra of the title compound are reported. Using calculated frequencies as a guide, IR and Raman spectra also provide evidence for the presence of both C1 and Cs conformers. PMID- 26617391 TI - Microenvironmental hypoxia regulates FLT3 expression and biology in AML. AB - Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase constitutively expressed by acute myeloid leukaemia (AML) blasts. In addition, 25% of AML patients harbour a FLT3-ITD mutation, associated with inferior outcome due to increased relapse rate. Relapse might be propagated by interactions between AML blasts and the bone marrow microenvironment. Besides cellular elements of the microenvironment (e.g. mesenchymal stromal cells), bone marrow hypoxia has emerged as an additional crucial component. Hence, effects of hypoxia on FLT3 expression and biology could provide novel insight into AML biology. Here we show that 25% of AML patients down-regulate FLT3 expression on blasts in response to in vitro hypoxia (1% O2), which was independent of its mutational state. While virtually no AML cell lines regulate FLT3 in response to hypoxia, the down regulation could be observed in Ba/F3 cells stably transfected with different FLT3 mutants. Hypoxia-mediated down-regulation was specific for FLT3, reversible and proteasome-dependent; with FLT3 half-life being significantly shorter at hypoxia. Also, PI-3K inhibition could partially abrogate down-regulation of FLT3. Hypoxia-mediated down-regulation of FLT3 conferred resistance against cytarabine in vitro. In conclusion, FLT3 expression in AML is dependent on the oxygen partial pressure, but response to hypoxia differs. PMID- 26617392 TI - Development of germ cell neoplasia in situ in chinchilla rabbits. AB - The present study was designed to describe the development of germ cell neoplasia in situ in Chinchilla rabbit by administration of estradiol. The study was performed in rabbits distributed into two groups: control and 17 beta-estradiol. The determination of histological alterations and POU5F1 and c-kit proteins employed as biomarkers for the diagnosis of this neoplasia was carried out. Testicular descent and complete spermatogenesis were observed in the control group. The protein biomarkers were negative. However, in the rabbits treated with estradiol, the testes remained undescended with the gonocytes undifferentiated to spermatogonia. There were histological lesions owing to germ cell neoplasia in situ and positive to POU5F1 and c-kit proteins. These findings indicate that the chinchilla rabbit is an ideal model to study this neoplasia in which the histological characteristics and biomarkers of the disease could be clearly observed. Using this model we suggested that the persisting gonocytes could be responsible for the development of germ cell neoplasia in situ. PMID- 26617393 TI - Structural Effects in Visible-Light-Responsive Metal-Organic Frameworks Incorporating ortho-Fluoroazobenzenes. AB - The ability to control the interplay of materials with low-energy photons is important as visible light offers several appealing features compared to ultraviolet radiation (less damaging, more selective, predominant in the solar spectrum, possibility to increase the penetration depth). Two different metal organic frameworks (MOFs) were synthesized from the same linker bearing all visible ortho-fluoroazobenzene photoswitches as pendant groups. The MOFs exhibit different architectures that strongly influence the ability of the azobenzenes to isomerize inside the voids. The framework built with Al-based nodes has congested 1D channels that preclude efficient isomerization. As a result, local light-heat conversion can be used to alter the CO2 adsorption capacity of the material on exposure to green light. The second framework, built with Zr nodes, provides enough room for the photoswitches to isomerize, which leads to a unique bistable photochromic MOF that readily responds to blue and green light. The superiority of green over UV irradiation was additionally demonstrated by reflectance spectroscopy and analysis of digested samples. This material offers promising perspectives for liquid-phase applications such as light-controlled catalysis and adsorptive separation. PMID- 26617394 TI - Nebivolol Ameliorates Cisplatin-Induced Nephrotoxicity in Rats. AB - Treatment with cisplatin is associated with dose-limiting side effects, mainly nephrotoxicity. On the other hand, nebivolol, a beta1 -adrenoceptor antagonist, exhibits vasodilatory and antioxidative properties. This study aimed to determine whether nebivolol possesses a protective effect against cisplatin nephrotoxicity and explore many mechanisms underlying this potential effect. Nephrotoxicity was induced in Wistar rats by a single intraperitoneal injection of cisplatin (6 mg/kg) on day 2. Nebivolol (10 mg/kg) was administered orally for 7 consecutive days. Nebivolol showed a nephroprotective effect as demonstrated by the significant reduction in the elevated levels of serum creatinine and urea as well as renal levels of malondialdehyde, nitric oxide products (nitrite/nitrate), inducible nitric oxide synthase, tumour necrosis factor-alpha, caspase-3, angiotensin II and endothelin-1 with a concurrent increase in renal levels of reduced glutathione and endothelial nitric oxide synthase compared to untreated rats. Histopathological examination confirmed the nephroprotective effect of nebivolol. Pre-treatment with Nomega -nitro-L-arginine methyl ester, the non specific nitric oxide synthase inhibitor, partially altered the protection afforded by nebivolol. In conclusion, nebivolol protects rats against cisplatin induced nephrotoxicity that is most likely through its antioxidant, anti inflammatory and antiapoptotic effects as well as by abrogation of the augmented angiotensin II and endothelin-1 levels. PMID- 26617395 TI - Potential of neuropeptide Y for preventing or treating post-traumatic stress disorder. AB - There is extensive evidence that NPY in the brain can modulate the responses to stress and play a critical role in resistance to, or recovery from, harmful effects of stress. Development of PTSD and comorbid depression following exposure to traumatic stress are associated with low NPY. This review discusses putative mechanisms for NPY's anti-stress actions. Recent preclinical data indicating potential for intranasal delivery of NPY to brain as a promising non-invasive strategy to prevent a variety of neuroendocrine, molecular and behavioral impairments in PTSD model are summarized. PMID- 26617396 TI - Scalable production of graphene with tunable and stable doping by electrochemical intercalation and exfoliation. AB - Graphene's unique semimetallic band structure yields carriers with widely tunable energy levels that enable novel electronic devices and energy generators. To enhance the potential of this feature, a scalable synthesis method for graphene with adjustable Fermi levels is required. We here show that the electrochemical intercalation of FeCl3 and subsequent electrochemical exfoliation produces graphene whose energy levels can be finely tuned by the intercalation parameters. X-ray photoelectron spectroscopy reveals that a gradual transition in the bonding character of the intercalant is the source of this behavior. The intercalated graphene exhibits a significantly increased work function that can be varied between 4.8 eV and 5.2 eV by the intercalation potential. Transparent conducting electrodes produced by these graphene flakes exhibit a threefold improvement in performance and the doping effect was found to be stable for more than a year. These findings open up a new route for the scalable production of graphene with adjustable properties for future applications. PMID- 26617397 TI - Ehrlichia's molecular tricks to manipulate their host cells. AB - Ehrlichia is a large genus of obligate intracellular Gram-negative bacteria transmitted by ticks that cause several emerging infectious diseases in humans and are pathogenic on rodents, ruminants, and dogs. Ehrlichia spp. invade and replicate either in endothelial cells, white blood cells, or within midgut cells and salivary glands of their vector ticks. In this review, we discuss the insights that functional studies are providing on how this group of bacteria exploits their host by subverting host innate immunity and hijacking cellular processes. PMID- 26617398 TI - Trials and tribulations of a meta-analyst. PMID- 26617399 TI - Accessing the Long-Lived Triplet Excited States in Transition-Metal Complexes: Molecular Design Rationales and Applications. AB - Transition-metal complex triplet photosensitizers are versatile compounds that have been widely used in photocatalysis, photovoltaics, photodynamic therapy (PDT) and triplet-triplet annihilation (TTA) upconversion. The principal photophysical processes in these applications are the intermolecular energy transfer or electron transfer. One of the major challenges facing these triplet photosensitizers is the short triplet-state lifetime, which is detrimental to the above-mentioned photophysical processes. In order to address this challenge, transition-metal complexes showing long-lived triplet excited states are highly desired. This review article summarizes the development of this fascinating area, including the molecular design rationales, the principal photophysical properties, and the applications of these complexes in PDT and TTA upconversion. PMID- 26617400 TI - Salvia divinorum: An overview of the usage, misuse, and addiction processes. AB - Salvia divinorum, a sage plant with leaves that can produce a psychoactive high, has been used for hundreds of years for its psycho-mimetic effects in religious rituals in South America. Salvia has now become popular mainly with adolescents and young adults for the short-lived relatively pleasant experiences many consider a "legal high" and its ready availability through Internet purchases. The main (psycho)active compound in salvia is Salvinorin A, a potent kappa-opioid agonist and although the short and long-term effects have not been examined in sufficient detail, it is widely believed to have low addictive potential and low toxicity. Recent findings, however, seem to suggest that Salvinorin A can precipitate psychiatric symptoms and negatively affect cognition. Its ready availability and increasingly widespread use requires clinicians to have knowledge and awareness of its effects. PMID- 26617402 TI - No effects of ingesting or rinsing sucrose on depleted self-control performance. AB - Self-control tasks appear to deplete a limited resource resulting in reduced subsequent self-control performance; a state of ego depletion. Evidence of reduced peripheral glucose by exertion of self-control, and attenuation of ego depletion by carbohydrate metabolism underpins the proposition that this macronutrient provides the energetic source of self-control. However, the demonstration of positive, non-metabolic effects on ego depletion when merely sensing carbohydrates orally contradicts this hypothesis. Recent studies have also failed to support both metabolic and non-metabolic accounts. The effects of ingesting or rinsing a carbohydrate (sucrose) and an artificially sweetened (sucralose) solution on capillary blood and interstitial glucose, and depleted self-control performance were examined in older adults. Forty, healthy, adults (50-65years) ingested and rinsed sucrose and sucralose solutions in a 2 (method)*2 (source), fully counterbalanced, repeated measures, crossover design. Capillary blood and interstitial glucose responses were assayed. Depleted self control performance (induced by the Bakan visual processing task) on an attention switch task was assessed under each study condition. Ego depletion had no consistent effects on peripheral glucose levels and no significant effects of ingesting or rinsing sucrose on self-control were observed. The act of rinsing the solutions, independent of energetic content, resulted in a small, non significant enhancement of performance on the attention switch task relative to ingesting the same solutions (RT: p=.05; accuracy: p=.09). In conclusion, a metabolic account of self-control was not supported. Whilst a positive effect of rinsing on depleted self-control performance was demonstrated, this was independent of energetic content. Findings suggest glucose is an unlikely physiological analogue for self-control resources. PMID- 26617403 TI - Reproducibility of 3D kinematics and surface electromyography measurements of mastication. AB - The aim of this study was to determine the measurement reproducibility for a procedure evaluating the mastication process and to estimate the smallest detectable differences of 3D kinematic and surface electromyography (sEMG) variables. Kinematics of mandible movements and sEMG activity of the masticatory muscles were obtained over two sessions with four conditions: two food textures (biscuit and bread) of two sizes (small and large). Twelve healthy adults (mean age 29.1 years) completed the study. The second to the fifth chewing cycle of 5 bites were used for analyses. The reproducibility per outcome variable was calculated with an intraclass correlation coefficient (ICC) and a Bland-Altman analysis was applied to determine the standard error of measurement relative error of measurement and smallest detectable differences of all variables. ICCs ranged from 0.71 to 0.98 for all outcome variables. The outcome variables consisted of four bite and fourteen chewing cycle variables. The relative standard error of measurement of the bite variables was up to 17.3% for 'time-to swallow', 'time-to-transport' and 'number of chewing cycles', but ranged from 31.5% to 57.0% for 'change of chewing side'. The relative standard error of measurement ranged from 4.1% to 24.7% for chewing cycle variables and was smaller for kinematic variables than sEMG variables. In general, measurements obtained with 3D kinematics and sEMG are reproducible techniques to assess the mastication process. The duration of the chewing cycle and frequency of chewing were the best reproducible measurements. Change of chewing side could not be reproduced. The published measurement error and smallest detectable differences will aid the interpretation of the results of future clinical studies using the same study variables. PMID- 26617401 TI - Red clover (Trifolium pratense L.) draft genome provides a platform for trait improvement. AB - Red clover (Trifolium pratense L.) is a globally significant forage legume in pastoral livestock farming systems. It is an attractive component of grassland farming, because of its high yield and protein content, nutritional value and ability to fix atmospheric nitrogen. Enhancing its role further in sustainable agriculture requires genetic improvement of persistency, disease resistance, and tolerance to grazing. To help address these challenges, we have assembled a chromosome-scale reference genome for red clover. We observed large blocks of conserved synteny with Medicago truncatula and estimated that the two species diverged ~23 million years ago. Among the 40,868 annotated genes, we identified gene clusters involved in biochemical pathways of importance for forage quality and livestock nutrition. Genotyping by sequencing of a synthetic population of 86 genotypes show that the number of markers required for genomics-based breeding approaches is tractable, making red clover a suitable candidate for association studies and genomic selection. PMID- 26617404 TI - Cholesterol-rich lipid rafts are involved in neuropeptide FF anti nociceptin/orphanin FQ effect. AB - The participation of a signaling platform to the anti-nociceptin/orphanin FQ (N/OFQ) effect of neuropeptide FF (NPFF) receptors was investigated in both acutely dissociated neurons and SH-SY5Y human neuroblastoma cells. The NPFF anti N/OFQ, not anti-MU opioid effect, on the Ca2+ transient triggered by depolarization was reversed by methyl-beta-cyclodextrin which depletes cholesterol from cell membranes. While the inactive alpha-cyclodextrin had no effect. By using [35 S]GTPgammaS binding assay, a significant 20% decrease in the activity of nociceptin/orphanin FQ peptide receptors induced by the NPFF analog 1DMe was observed in detergent-resistant membranes, but not in total membranes of SH-SY5Y cells. Moreover, siRNA knock-down of G-protein-coupled receptor kinase 2 indicated that G-protein-coupled receptor kinase 2, but not protein kinase C, acted as the mediator in the NPFF anti-N/OFQ process. These data indicate that cholesterol-rich lipid rafts play an important role in the anti-N/OFQ effect of NPFF receptors. We proposed the participation of a signaling platform to the anti Nociceptin/Orphanin FQ (N/OFQ) effect of Neuropeptide FF (NPFF) receptors both in mouse neurons and SH-SY5Y cells, with GRK2 protein acting as the mediator in this process. These findings should provide a more precise way to understand the anti opioid effect of NPFF. NOP, Nociceptin/Orphanin FQ peptide. PMID- 26617405 TI - Guideline of guidelines: follow-up after nephrectomy for renal cell carcinoma. AB - The purpose of this article was to review and compare the international guidelines and surveillance protocols for post-nephrectomy renal cell carcinoma (RCC). PubMed database searches were conducted, according to the PRISMA statement for reporting systematic reviews, to identify current international surveillance guidelines and surveillance protocols for surgically treated and clinically localized RCC. A total of 17 articles were reviewed. These included three articles on urological guidelines, three on oncological guidelines and 11 on proposed strategies. Guidelines and strategies varied significantly in relation to follow-up, specifically with regard to the frequency and timing of radiological imaging. Although there is currently no consensus within the literature regarding surveillance protocols, various guidelines and strategies have been developed using both patient and tumour characteristics. PMID- 26617406 TI - It is time to beelieve the CD1a hype! AB - Conventional T cells have historically been linked to exacerbating allergy. By efficiently generating primarily TH 2 cells, allergens skew the immune response to produce IL-4, IL-13, and IgE. Previously, CD1a-responsive T cells were shown to functionally respond to bee and wasp venom allergens. In this issue of the European Journal of Immunology, Subramaniam et al. [Eur. J. Immunol. 2016. 46: 242-252] show that more functionally active CD1a-restricted cells are present in bee venom-allergic patients than in healthy patients. Additionally, the authors show that these cells are not as frequently found in individuals receiving venom immunotherapy. Consequently, this study implicates CD1a-reactive cells as the primary responders to venom allergy, which considerably regulate the downstream immune response. PMID- 26617407 TI - Evaluation of genotoxic and apoptotic potential of Hypericum adenotrichum Spach. in vitro. AB - Hypericum adenotrichum Spach. is an endemic plant from Turkey that is also used in folk medicine. In this study, following analyses of its chemical composition, the genotoxic/antigenotoxic effects of the methanol extract of H. adenotrichum in human lymphocyte culture were investigated using in vitro sister chromatid exchange, micronucleus and comet assays. In addition, the anti-growth effect of the extract was investigated in human breast cancer cell lines (MCF-7 and MDA-MB 231) using MTT and ATP viability assays. The mode of cell death was determined using fluorescence microscopy and biochemical methods. We found that the H. adenotrichum extract demonstrated cytotoxic and genotoxic effects in a cell type dependent manner. At selected doses (125-500 MUg/ml), the H. adenotrichum extract exhibited significant genotoxic activity in human lymphocytes, whereas it showed anti-growth effects on cancer cell lines between 0.2 and 100 MUg/ml concentrations. The mode of cell death in cancer cells was shown to be apoptosis due to the presence of pyknotic nuclei, the cleavage of poly-(ADP-ribose) polymerase (PARP) and/or the activation of caspase-3. These results suggest that H. adenotrichum might show both cytotoxic and genotoxic effects depending on the cell type. This should be taken into account in its use for therapeutic purposes. PMID- 26617408 TI - In vivo micronucleus studies with 6 titanium dioxide materials (3 pigment-grade & 3 nanoscale) in orally-exposed rats. AB - Six pigment-grade (pg) or ultrafine (uf)/nanoscale (anatase and/or rutile) titanium dioxide (TiO2) particulates were evaluated for in vivo genotoxicity (OECD 474 Guidelines) in male and female rats by two different laboratories. All test materials were robustly characterized. The BET surface areas of the pg and uf samples ranged from 7 to 17 m(2)/g and 50 to 82 m(2)/g respectively. The materials were assessed for induction of micronuclei and toxicity in bone marrow by analyzing peripheral blood reticulocytes (RETs) by flow cytometry. Single oral gavage doses of 500, 1000 or 2000 mg/kg body weight (bw) of each material were implemented with concurrent negative (water) and positive controls (cyclophosphamide). Approximately 48 and 72 h after exposure, blood samples were collected and 20,000 RETs per animal were analyzed. For each of the six tests, there were no biologically or toxicologically relevant increases in the micronucleated RET frequency in any TiO2 exposed group at either time point at any dose level. In addition, there were a lack of biologically relevant decreases in %RETs among total erythrocytes. All six TiO2 test substances were negative for in vivo genotoxicity effects; however, it is noted that the exposure to target tissues was likely negligible. One pigment grade and one ultrafine material each were evaluated for potential systemic exposure/uptake from the gastrointestinal tract by analysis of TiO2 into blood and liver. No significant increases in TiO2 over controls were measured in blood (48 or 72 h) or liver (72 h) following exposures to 2000 mg/kg bw TiO2. These data indicate that there was no absorption of the test material from the gastrointestinal tract into the blood circulation and the lack of genotoxic effects is therefore attributed to a lack of exposure due to the inability of the test material to migrate from the gastrointestinal tract into the blood and then into target tissues. PMID- 26617409 TI - Evaluation of the safety of primary metabolites of cyadox: Acute and sub-chronic toxicology studies and genotoxicity assessment. AB - Cyadox (CYA) is a synthetic antimicrobial agent, belonging to quinoxaline (QdNO) family. Cy1 (bidesoxy cyadox), Cy2 (N4-desoxycyadox) and Cy10 (N1-desoxycyadox) are the primary metabolites of CYA. In our present study, an acute toxicity test, a sub-chronic toxicity test, and a battery of three genotoxicity tests were carried out according to standard protocols. The LD50 of the metabolites were above 5000 mg/kg b.w. The maximum tolerated dose (MTD) of Cy1 and Cy-M (mixture of Cy2 and Cy10) in rats, and the MTD of Cy1, Cy2 and Cy10 in mice were above 6000 mg/kg b.w./day. In subchronic study, rats were separately administered Cy1 and Cy-M at the dose levels of 0, 50, 150 and 2500 mg/kg diet for 90 days, with CYA (2500 mg/kg) as a control. Significant decreases in body weight and changes in clinical serum biochemistry were observed in the high-dose group of Cy1 and Cy M, as well as CYA. Significant changes in relative weights of organs at 150 and 2500 mg/kg diet of Cy1 and CYA were noted. Additionally, the high-dose groups of Cy1, Cy-M and CYA showed pathological changes near the hepatic portal area. There was no evidence for genotoxic activity of any of the three metabolites in the bacterial reverse mutation test, mouse bone marrow micronucleus assay or an in vitro assay for clastogenicity. Based on the subchronic study, the target organ of the primary metabolites was the liver, and the no-observed-adverse-effect level for Cy1 and Cy-M was 150 mg/kg diet. PMID- 26617410 TI - Characterization of potential impurities and degradation products in electronic cigarette formulations and aerosols. AB - E-cigarettes are gaining popularity in the U.S. as well as in other global markets. Currently, limited published analytical data characterizing e-cigarette formulations (e-liquids) and aerosols exist. While FDA has not published a harmful and potentially harmful constituent (HPHC) list for e-cigarettes, the HPHC list for currently regulated tobacco products may be useful to analytically characterize e-cigarette aerosols. For example, most e-cigarette formulations contain propylene glycol and glycerin, which may produce aldehydes when heated. In addition, nicotine-related chemicals have been previously reported as potential e-cigarette formulation impurities. This study determined e-liquid formulation impurities and potentially harmful chemicals in aerosols of select commercial MarkTen((r)) e-cigarettes manufactured by NuMark LLC. The potential hazard of the identified formulation impurities and aerosol chemicals was also estimated. E-cigarettes were machine puffed (4-s duration, 55-mL volume, 30-s intervals) to battery exhaustion to maximize aerosol collection. Aerosols analyzed for carbonyls were collected in 20-puff increments to account for analyte instability. Tobacco specific nitrosamines were measured at levels observed in pharmaceutical grade nicotine. Nicotine-related impurities in the e cigarette formulations were below the identification and qualification thresholds proposed in ICH Guideline Q3B(R2). Levels of potentially harmful chemicals detected in the aerosols were determined to be below published occupational exposure limits. PMID- 26617411 TI - Examples of how the pharmaceutical industries distort the evidence of drug safety: the case of pioglitazone and the bladder cancer issue. PMID- 26617412 TI - Non-Pincer-Type Mononuclear Scandium Alkylidene Complexes: Synthesis, Bonding, and Reactivity. AB - The first non-pincer-type mononuclear scandium alkylidene complexes were synthesized and structurally characterized. These complexes exhibited short Sc-C bond lengths and even one of the shortest reported to date (2.1134(18) A). The multiple character of the Sc-C bond was highlighted by a DFT calculation. This was confirmed by experimental reactivity study where the complex underwent [2+1] cycloaddition with elemental selenium and [2+2] cycloaddition with imine. DFT calculation also revealed a strong nucleophilic behavior of the alkylidene complex that was experimentally demonstrated by the C-H bond activation of phenylacetylene. PMID- 26617413 TI - Retracted: Bacteria diversity overview and endoglucanase assessment from Himalayan Tapovan geothermal spring. AB - The above article from the Journal of Basic Microbiology, published online on 25 August 2015 in Wiley Online Library as Early View (http://onlinelibrary.wiley.com/doi/10.1002/jobm.201500135/pdf), has been retracted by agreement between Naveen Kumar Navani and Ranjana Pathania, the Editor-in-Chief and Wiley-VCH GmbH & Co. KGaA. The retraction has been agreed because the article has been submitted and approved for publication by Jitendra Kumar Sahoo without consent in any form by the named co-authors Naveen Kumar Navani and Ranjana Pathania. PMID- 26617414 TI - Re-Emergence of Bluetongue Virus Serotype 8 in France, 2015. AB - At the end of August 2015, a ram located in central France (department of Allier) showed clinical signs suggestive of BTV (Bluetongue virus) infection. However, none of the other animals located in the herd showed any signs of the Bluetongue disease. Laboratory analyses identified the virus as BTV serotype 8. The viro and sero prevalence intraherd were 2.4% and 8.6% in sheep and 18.3% and 42.9% in cattle, respectively. Phylogenetic studies showed that the sequences of this strain are closely related to another BTV-8 strain that has circulated in France in 2006-2008. The origin of the outbreak is unclear but it may be assumed that the BTV-8 has probably circulated at very low prevalence (possibly in livestock or wildlife) since its first emergence in 2007-2008. PMID- 26617415 TI - Prevalence of small for gestational age (SGA) and short stature in children born SGA who qualify for growth hormone treatment at 3 years of age: Population-based study. AB - BACKGROUND: To treat children born small for gestational age (SGA) with severe short stature, treatment with growth hormone (GH) has been approved in the USA, Europe, and Japan, but no population-based studies have reported their prevalence. The aims of this study were to investigate the prevalence of SGA and short stature in children born SGA who qualify for GH treatment at 3 years of age in a Japanese population. METHODS: A population-based study was conducted in Kobe, Japan with 27 228 infants who were born between 2006 and 2008 and followed until 3 years of age. Prevalence of birthweight (BW) or birth length (BL) <= -2.0 standard deviation scores (SDS) for gestational age (GA; definition of SGA) was calculated. Short children born SGA who qualify for GH treatment at 3 years of age were estimated using the following criteria: BW and BL below the 10th percentile for GA, BW or BL <= -2.0 SDS for GA, and 2.5 SDS below the mean height for age. RESULTS: The prevalence of SGA was 3.5%. The estimated prevalence of short stature in children born SGA who met the criteria for GH treatment was 0.06%. The prevalence in infants born <34 weeks (0.39%) was significantly higher than that in infants born 34-41 weeks GA (0.05%, P = 0.02). CONCLUSIONS: The prevalence of SGA and short stature in children born SGA who qualify for GH treatment is approximately 1 of 30 infants and 1 of 1800 children, respectively. The risk is increased when children are born <34 weeks GA. PMID- 26617416 TI - Association of Cole disease with novel heterozygous mutations in the somatomedin B domains of the ENPP1 gene: necessary, but not always sufficient. PMID- 26617417 TI - From Bench to Bedside: A communal utility value intervention to enhance students' biomedical science motivation. AB - Motivating students to pursue science careers is a top priority among many science educators. We add to the growing literature by examining the impact of a utility value intervention to enhance student's perceptions that biomedical science affords important utility work values. Using an expectancy-value perspective we identify and test two types of utility value: communal (other oriented) and agentic (self-oriented). The culture of science is replete with examples emphasizing high levels of agentic value, but communal values are often (stereotyped as) absent from science. However, people in general want an occupation that has communal utility. We predicted and found that an intervention emphasizing the communal utility value of biomedical research increased students' motivation for biomedical science (Studies 1-3). We refined whether different types of communal utility value (working with, helping, and forming relationships with others) might be more or less important, demonstrating that helping others was an especially important predictor of student motivation (Study 2). Adding agentic utility value to biomedical research did not further increase student motivation (Study 3). Furthermore, the communal value intervention indirectly impacted students' motivation because students believed that biomedical research was communal and thus subsequently more important (Studies 1-3). This is key, because enhancing student communal value beliefs about biomedical research (Studies 1-3) and science (Study 4) was associated both with momentary increases in motivation in experimental settings (Studies 1-3) and increased motivation over time among students highly identified with biomedicine (Study 4). We discuss recommendations for science educators, practitioners, and faculty mentors who want to broaden participation in science. PMID- 26617419 TI - Controlled Atmosphere Electrospinning of Organic Nanofibers with Improved Light Emission and Waveguiding Properties. AB - Electrospinning in controlled nitrogen atmosphere is developed for the realization of active polymer nanofibers. Fibers electrospun under controlled atmospheric conditions are found to be smoother and more uniform than samples realized by conventional electrospinning processes performed in air. In addition, they exhibit peculiar composition, incorporating a greatly reduced oxygen content during manufacturing, which favors enhanced optical properties and increases emission quantum yield. Active waveguides with optical losses coefficients lowered by 10 times with respect to fibers spun in air are demonstrated through this method. These findings make the process very promising for the highly controlled production of active polymer nanostructures for photonics, electronics and sensing. PMID- 26617418 TI - Have superfetation and matrotrophy facilitated the evolution of larger offspring in poeciliid fishes? AB - Superfetation is the ability of females to simultaneously carry multiple broods of embryos, with each brood at a different developmental stage. Matrotrophy is the post-fertilization maternal provisioning of nutrients to developing embryos throughout gestation. Several studies have demonstrated that, in viviparous fishes, superfetation and matrotrophy have evolved in a correlated way, such that species capable of bearing several simultaneous broods also exhibit advanced degrees of post-fertilization provisioning. The adaptive value of the concurrent presence of both reproductive modes may be associated with the production of larger newborns, which in turn may result in enhanced offspring fitness. In this study, we tested two hypotheses: (1) species with superfetation and moderate or extensive matrotrophy give birth to larger offspring compared to species without superfetation or matrotrophy; (2) species with higher degrees of superfetation and matrotrophy (i.e. more simultaneous broods and increased amounts of post fertilization provisioning) give birth to larger offspring compared to species with relatively low degrees of superfetation and matrotrophy (i.e. fewer simultaneous broods and lesser amounts of post-fertilization provisioning). Using different phylogenetic comparative methods and data on 44 species of viviparous fishes of the family Poeciliidae, we found a lack of association between offspring size and the combination of superfetation and matrotrophy. Therefore, the concurrent presence of superfetation and moderate or extensive matrotrophy has not facilitated the evolution of larger offspring. In fact, these traits have evolved differently. Superfetation and matrotrophy have accumulated gradual changes that largely can be explained by Brownian motion, whereas offspring size has evolved fluidly, experiencing changes that likely resulted from selective responses to the local conditions. PMID- 26617420 TI - CONTESTED DOMAINS, VERBAL 'AMPLIFIERS,' AND INTIMATE PARTNER VIOLENCE IN YOUNG ADULTHOOD. AB - We draw on structured and qualitative data to examine relationship dynamics associated with intimate partner violence (IPV) that occurs during the young adult period. Relying on a symbolic interactionist perspective, we identify specific contested domains associated with what has been called 'situational couple violence,' and explore the degree to which certain forms of communication about contested areas ('verbal amplifiers') exacerbate the risk of violence. Consistent with this relational focus, measures index respondent as well as partner concerns and use of these negative forms of communication. Results of analyses of interview data from a large, diverse sample of young adults show that net of family background, history of antisocial behavior, and other controls, concerns about the partner's or individual's own economic viability, disagreements about time spent with friends, and issues of infidelity are significantly related to IPV perpetration. Yet the analyses indicate that infidelity is particularly central as a source of conflict associated with violence, and the use of verbal amplifiers explained additional variance. Further, while research has highlighted important differences in the meaning and consequences of male and female IPV, findings point to some areas of overlap in the relationship concerns and communication processes associated with variations in self-reports of the use of violence. In-depth "relationship history narratives" elicited from a subset of respondents and a sample of their partners support the quantitative results, but also highlight variations within the sample, the sequencing of these interrelated processes, and ways in which gender may have influenced respondents' perspectives and behavior. PMID- 26617422 TI - Compact low-cost detection electronics for optical coherence imaging. AB - A compact and low-cost detection electronics scheme for optical coherence imaging is demonstrated. The performance of the designed electronics is analyzed in comparison to a commercial lock-in amplifier of equal bandwidth. Images of a fresh-onion sample are presented for each detection configuration. PMID- 26617421 TI - High dimensional data analysis using multivariate generalized spatial quantiles. AB - High dimensional data routinely arises in image analysis, genetic experiments, network analysis, and various other research areas. Many such datasets do not correspond to well-studied probability distributions, and in several applications the data-cloud prominently displays non-symmetric and non-convex shape features. We propose using spatial quantiles and their generalizations, in particular, the projection quantile, for describing, analyzing and conducting inference with multivariate data. Minimal assumptions are made about the nature and shape characteristics of the underlying probability distribution, and we do not require the sample size to be as high as the data-dimension. We present theoretical properties of the generalized spatial quantiles, and an algorithm to compute them quickly. Our quantiles may be used to obtain multidimensional confidence or credible regions that are not required to conform to a pre-determined shape. We also propose a new notion of multidimensional order statistics, which may be used to obtain multidimensional outliers. Many of the features revealed using a generalized spatial quantile-based analysis would be missed if the data was shoehorned into a well-known probabilistic configuration. PMID- 26617423 TI - Qualitative and quantitative analysis of solar hydrogen generation literature from 2001 to 2014. AB - Solar hydrogen generation is one of the new topics in the field of renewable energy. Recently, the rate of investigation about hydrogen generation is growing dramatically in many countries. Many studies have been done about hydrogen generation from natural resources such as wind, solar, coal etc. In this work we evaluated global scientific production of solar hydrogen generation papers from 2001 to 2014 in any journal of all the subject categories of the Science Citation Index compiled by Institute for Scientific Information (ISI), Philadelphia, USA. Solar hydrogen generation was used as keywords to search the parts of titles, abstracts, or keywords. The published output analysis showed that hydrogen generation from the sun research steadily increased over the past 14 years and the annual paper production in 2013 was about three times 2010-paper production. The number of papers considered in this research is 141 which have been published from 2001 to this date. There are clear distinctions among author keywords used in publications from the five most high-publishing countries such as USA, China, Australia, Germany and India in solar hydrogen studies. In order to evaluate this work quantitative and qualitative analysis methods were used to the development of global scientific production in a specific research field. The analytical results eventually provide several key findings and consider the overview hydrogen production according to the solar hydrogen generation. PMID- 26617424 TI - IsoDOT Detects Differential RNA-isoform Expression/Usage with respect to a Categorical or Continuous Covariate with High Sensitivity and Specificity. AB - We have developed a statistical method named IsoDOT to assess differential isoform expression (DIE) and differential isoform usage (DIU) using RNA-seq data. Here isoform usage refers to relative isoform expression given the total expression of the corresponding gene. IsoDOT performs two tasks that cannot be accomplished by existing methods: to test DIE/DIU with respect to a continuous covariate, and to test DIE/DIU for one case versus one control. The latter task is not an uncommon situation in practice, e.g., comparing the paternal and maternal alleles of one individual or comparing tumor and normal samples of one cancer patient. Simulation studies demonstrate the high sensitivity and specificity of IsoDOT. We apply IsoDOT to study the effects of haloperidol treatment on the mouse transcriptome and identify a group of genes whose isoform usages respond to haloperidol treatment. PMID- 26617425 TI - Behavior problems, foster home integration, and evidence-based behavioral interventions: What predicts adoption of foster children? AB - OBJECTIVES: Adoption is particularly important for foster children with special mental health needs who are unable to return home, as adoption increases parental support often critically needed by youth with mental health issues. Unfortunately, significant behavior problems frequently inhibit foster parents from adopting, and little is known about factors that predict adoption when a child has behavior problems. Previous research suggests that foster parent behavioral training could potentially increase rates of successful adoptions for pre-school-aged foster children with behavior problems (Fisher, Kim, & Pears, 2009), but this has not been previously tested in older samples. In older children, effective treatment of behavior problems might also increase adoption by reducing the interference of behavior problems and strengthening the child's foster home integration. This pilot study focused on this question by testing associations between behavior problems, foster home integration, an evidence based foster parent intervention, and adoption likelihood. METHODS: This study used an intent-to-treat design to compare foster home integration and adoption likelihood for 31 foster children with histories of abuse and neglect whose foster parents received a foster behavioral parenting intervention (see Chamberlain, 2003) or usual services. Random effect regression analyses were used to estimate outcomes across four time points. RESULTS: As expected, externalizing behavior problems had a negative effect on both integration and adoption, and foster home integration had an independent positive effect on adoption. Internalizing behavior problems (e.g., depression/anxiety) were not related to adoption or integration. However, the intervention did not have a direct effect on either foster home integration or adoption despite its positive effect on behavior problems. CONCLUSIONS: Results from this preliminary study provide further evidence of the negative effect of externalizing behavior problems on adoption. Its findings also suggest that foster home integration is an important dimension of foster home adaptation that appears particularly relevant to chances for adoption. While behavior problems appear to weaken foster home integration, integration is also an independent predictor of adoption likelihood. If these results are replicated in a larger study, consideration of foster home integration in case planning and future intervention studies focused on increasing permanency could potentially improve outcomes for foster children with behavior problems. PMID- 26617426 TI - Correlates of Emotional Support and Negative Interaction Among African Americans and Caribbean Blacks. AB - This study explores the relationship of family and demographic factors to the frequency of receiving emotional support and the frequency of engaging in negative interactions with family members (i.e., criticism, burden, and being taken advantage of). The study uses the ambivalence framework and data from the National Survey of American Life, a national sample of African Americans and Caribbean Blacks (Caribbean Blacks). Overall, no significant differences were found between African Americans and Caribbean Blacks in the frequency of emotional support or negative interaction; several significant correlates (e.g., age, family closeness) were found for both groups. However, a number of unique associations were also demonstrated (e.g., marital status, frequency of family contact), indicating differences in the ways that these variables operate within the two populations. These and other findings are discussed in relation to the ambivalence framework and subgroup differences in family phenomena within the Black population. PMID- 26617427 TI - Assessing and analyzing change in attitudes in the classroom. AB - We explore three analytic methods that can be used to quantify and qualify changes in attitude and similar outcomes that may be encountered in the educational context. These methods can be used or adapted whenever the outcome of interest is change in a generally unmeasurable attribute, such as attitude. The analyses we describe focus on: (1) change in total 'attitude score'; (2) item level changes in attitudes towards different topics; and (3) 'attitude shift' that is defined based on a qualified change algorithm. In our example data, the total-score approach gives a general index to the level of positive attitude; the item-level approach gives the median level of positive attitude and indicates items with the most positive/negative attitude (i.e., items to target in future iterations). The qualified change approach provides an objective measure of whether a shift in attitude has occurred. Each analysis is described with its advantages and disadvantages using the data from a survey of 70 preclinical first and second year medical students before and after an elective 11-week interactive seminar (22 contact hours) which introduced elements of complementary and alternative medicine (CAM) into programmed medical school training. When assessing changes that are more qualitative than quantitative, any of these methods can be employed to derive either descriptive or inferential statistics. The methods are straightforward and are appropriate when measurements are imperfect, ratings are subjective and differences are not necessarily absolute. PMID- 26617428 TI - An electric-field induced dynamical state in dispersions of highly charged colloidal rods: comparison of experiment and theory. AB - Concentrated dispersions of highly charged rod-like colloids (fd-virus particles) in isotropic-nematic coexistence exhibit a dynamical state when subjected to low frequency electric fields [Soft Matter, 2010, 6, 273]. This dynamical state consists of nematic domains which persistently melt and form on time scales typically of the order of seconds. The origin of the dynamical state has been attributed to a field-induced, cyclic dissociation and association of condensed ions [Soft Matter, 2014, 10, 1987, Soft Matter, 2015, 11, 2893]. The ionic strength increases on dissociation of condensed ions, rendering the nematic domains unstable, while the subsequent decrease of the ionic strength due to association of condensed ions leads to a recurrent stabilization of the nematic state. The role of dissociation/association of condensed ions in the phase/state behaviour of charged colloids in electric fields has not been addressed before. The electric field strength that is necessary to dissociate sufficient condensed ions to render a nematic domain unstable, depends critically on the ambient ionic strength of the dispersion without the external field, as well as the rod concentration. The aim of this paper is to compare experimental results for the location of transition lines and the dynamics of melting and forming of nematic domains at various ionic strengths and rod-concentrations with the ion dissociation/association model. Phase/state diagrams in the field-amplitude versus frequency plane at two different ambient ionic strengths and various rod concentrations are presented, and compared to the theory. The time scale on which melting and forming of the nematic domains occurs diverges on approach of the transition line where the dynamical state appears. The corresponding critical exponents have been measured by means of image time-correlation spectroscopy [Eur. Phys. J. E, 2009, 30, 333], and are compared to the theoretical values predicted by the ion-dissociation/association model. PMID- 26617429 TI - Characterization of protein adsorption onto silica nanoparticles: influence of pH and ionic strength. AB - The adsorption of lysozyme and beta-lactoglobulin onto silica nanoparticles (diameter 21 nm) was studied in the pH range 2-11 at three different ionic strengths. Since the two proteins have a widely different isoelectric point (pI), electrostatic interactions with the negative silica surface lead to a different dependence of adsorption on pH. For lysozyme (pI ~ 11), the adsorption level increases with pH and reaches a value corresponding to about two close-packed monolayers at pH = pI. In the multilayer adsorption region near pI, added electrolyte causes a decrease in adsorption, which is attributed to the screening of attractive interactions between protein molecules in the first and second adsorbed layer. For beta-lactoglobulin (pI ~ 5), a pronounced maximum of the adsorbed amount is found at pH 4 in the absence of salt. It is attributed to the adsorption of oligomers of the protein that exist in the solution at this pH. An inversion in the influence of salt on the adsorbed amount occurs at pH > pI, where the protein and the surface are both negatively charged. This inversion is attributed to the screening of the repulsive protein-surface and protein-protein interactions. The adsorption isotherms were analyzed with the Guggenheim-Anderson De Boer (GAB) model, which allows for two adsorption states (strongly and weakly bound protein). PMID- 26617430 TI - Interpersonal Psychotherapy With a Parenting Enhancement Adapted for In-Home Delivery in Early Head Start. AB - Formidable barriers prevent low-income mothers from accessing evidence-based treatment for depressive symptoms that compromise their ability to provide sensitive, responsive parenting for their infant or toddler. Interpersonal psychotherapy (IPT), an evidence-based psychotherapy for depression, was tailored for in-home delivery to mothers navigating economic hardship and other intense stressors, and for Latina mothers with limited English language proficiency. Psychiatric-mental health nurses delivered the adapted IPT in randomized clinical trials that were conducted in partnership with Early Head Start (EHS). The authors discuss the results of these studies and the impacts on EHS staff members and programs, and they provide additional implications for current early childhood-focused programs. PMID- 26617431 TI - Cumulative Disadvantage and Youth Well-Being: A Multi-Domain Examination with Life Course Implications. AB - PURPOSE: The accumulation of disadvantage has been shown to increase psychosocial stressors that impact life course well-being. This study tests for significant differences, based on disadvantage exposure, on youths' emotional and physical health, as well as family supports, peer assets, and academic success, which hold potential for resilience and amelioration of negative health outcomes. METHODS: A 12 item cumulative disadvantage summed index derived from surveys of a racially and socioeconomically diverse sample of urban high school seniors (n=9,658) was used to distinguish youth at low, moderate, and high levels. RESULTS: Findings supported hypothesized stepped patterns such that as multiple disadvantages accumulate, a concomitant decline is evident across the assessed outcome variables (except positive academic identity). Post-hoc tests indicated a pattern of groups being significantly different from one another. DISCUSSION: Overall, results lend support for an additive stress load associated with stacked disadvantage, with implications for continuing trends into adulthood as well as preventive interventions. PMID- 26617432 TI - A Group Contingency Plus Self-Management Intervention Targeting At-Risk Secondary Students' Class-Work and Active Engagement. AB - The purpose of the present study is to show that an independent group contingency (GC) combined with self-management strategies and randomized-reinforcer components can increase the amount of written work and active classroom responding in high school students. Three remedial reading classes and a total of 15 students participated in this study. Students used self-management strategies during independent reading time to increase the amount of writing in their reading logs. They used self-monitoring strategies to record whether or not they performed expected behaviors in class. A token economy using points and tickets was included in the GC to provide positive reinforcement for target responses. The results were analyzed through visual inspection of graphs and effect size computations and showed that the intervention increased the total amount of written words in the students' reading logs and overall classroom and individual student academic engagement. PMID- 26617433 TI - Profiles of Intimate Partner Violence Victimization, Substance Misuse, and Depression Among Female Caregivers Involved with Child Protective Services. AB - Intimate partner violence (IPV) victimization, substance misuse, and depression are highly prevalent among female caregivers involved with child protective services (CPS). Understanding heterogeneity in the occurrence of these problems is essential to improving pathways to intervention for women in this population. Latent class analysis was employed to determine whether there exist homogeneous subgroups of female caregivers who experience different patterns of IPV victimization, substance misuse, and depression. A restricted three-class solution best fit the data, suggesting high risk, moderate risk, and no risk subgroups. A substantial number of female caregivers comprise the high-risk subgroup (33%) in which caregivers reported very high rates of IPV victimization, substance misuse, and depression. Only a very small proportion comprised the no risk subgroup (9%). Findings emphasize the heterogeneity among subgroups of female caregivers based on these risk factors, which may have implications for practitioners, such as CPS caseworkers, and researchers alike. PMID- 26617434 TI - Nanoscale Transformations in Covellite (CuS) Nanocrystals in the Presence of Divalent Metal Cations in a Mild Reducing Environment. AB - We studied the structural and compositional transformations of colloidal covellite (CuS) nanocrystals (and of djurleite (Cu1.94S) nanocrystals as a control) when exposed to divalent cations, as Cd2+ and Hg2+, at room temperature in organic solvents. All the experiments were run in the absence of phosphines, which are a necessary ingredient for cation exchange reactions involving copper chalcogenides, as they strongly bind to the expelled Cu+ ions. Under these experimental conditions, no remarkable reactivity was indeed seen for both CuS and Cu1.94S nanocrystals. On the other hand, in the covellite structure 2/3 of sulfur atoms form covalent S-S bonds. This peculiarity suggests that the combined presence of electron donors and of foreign metal cations can trigger the entry of both electrons and cations in the covellite lattice, causing reorganization of the anion framework due to the rupture of the S-S bonds. In Cu1.94S, which lacks S-S bonds, this mechanism should not be accessible. This hypothesis was proven by the experimental evidence that adding ascorbic acid increased the fraction of metal ions incorporated in the covellite nanocrystals, while it had no noticeable effect on the Cu1.94S ones. Once inside the covellite particles, Cd2+ and Hg2+ cations engaged in exchange reactions, pushing the expelled Cu+ ions toward the not-yet exchanged regions in the same particles, or out to the solution, from where they could be recaptured by other covellite nanoparticles/domains. Because no good solvating agent for Cu ions was present in solution, they essentially remained in the nanocrystals. PMID- 26617435 TI - Gene flow, population growth and a novel substitution rate estimate in a subtidal rock specialist, the black-faced blenny Tripterygion delaisi (Perciformes, Blennioidei, Tripterygiidae) from the Adriatic Sea. AB - Population histories depend on the interplay between exogeneous and endogeneous factors. In marine species, phylogeographic and demographic patterns are often shaped by sea level fluctuations, water currents and dispersal ability. Using mitochondrial control region sequences (n = 120), we infer phylogeographic structure and historic population size changes of a common littoral fish species, the black-faced blenny Tripterygion delaisi (Perciformes, Blennioidei, Tripterygiidae) from the north-eastern Adriatic Sea. We find that Adriatic T. delaisi are differentiated from conspecific populations in the remaining Mediterranean, but display little phylogeographic structure within the Adriatic basin. The pattern is consistent with passive dispersal of planktonic larvae along cyclonic currents within the Adriatic Sea, but limited active dispersal of adults. Demographic reconstructions are consistent with recent population expansion, probably triggered by rising sea levels after the last glacial maximum (LGM). Placing the onset of population growth between the LGM and the warming of surface waters (18 000-13 000 years BP) and employing a novel expansion dating approach, we inferred a substitution rate of 2.61-3.61% per site per MY. Our study is one of only few existing investigations of the genetic structure of animals within the Adriatic basin and is the first to provide an estimate for mitochondrial control region substitution rates in blennioid fishes. PMID- 26617436 TI - Maresin 1 Inhibits TRPV1 in Temporomandibular Joint-Related Trigeminal Nociceptive Neurons and TMJ Inflammation-Induced Synaptic Plasticity in the Trigeminal Nucleus. AB - In the trigeminal system, disruption of acute resolution processing may lead to uncontrolled inflammation and chronic pain associated with the temporomandibular joint (TMJ). Currently, there are no effective treatments for TMJ pain. Recently, it has been recognized that maresin 1, a newly identified macrophage-derived mediator of inflammation resolution, is a potent analgesic for somatic inflammatory pain without noticeable side effects in mice and a potent endogenous inhibitor of transient receptor potential vanilloid 1 (TRPV1) in the somatic system. However, the molecular mechanisms underlying the analgesic actions of maresin 1 on TMJ pain are unclear in the trigeminal system. Here, by performing TMJ injection of a retrograde labeling tracer DiI (a fluorescent dye), I showed that maresin 1 potently inhibits capsaicin-induced TRPV1 currents and neuronal activity via Galphai-coupled G-protein coupled receptors in DiI-labeled trigeminal nociceptive neurons. Further, maresin 1 blocked TRPV1 agonist-evoked increases in spontaneous excitatory postsynaptic current frequency and abolished TMJ inflammation-induced synaptic plasticity in the trigeminal nucleus. These results demonstrate the potent actions of maresin 1 in regulating TRPV1 in the trigeminal system. Thus, maresin 1 may serve as a novel endogenous inhibitor for treating TMJ-inflammatory pain in the orofacial region. PMID- 26617437 TI - DMA(V) in Drinking Water Activated NF-kappaB Signal Pathway and Increased TGF beta and IL-1beta Expressions in Bladder Epithelial Cells of Rats. AB - Dimethylarsinic acid (DMA(V)) is the main product of arsenic methylation metabolism in vivo and is rat bladder carcinogen and tumor promoting agent. In this study, we measured the expressions of mRNA and proteins of NF-kappaB pathway members, IKKalpha, IKKbeta, p65, and p50 in rat bladder epithelium by qRT-PCR and immunohistochemical analysis after rats received drinking water containing 100 and 200 ppm DMA(V) for 10 weeks. Transforming growth factor-beta (TGF-beta) immunoexpression in rat bladder epithelium and urine level of IL-1beta also were determined. We found that DMA(V) dramatically increased the mRNA levels of NF kappaB p50 and IKKalpha in the bladder epithelium of rats compared to the control group. Immunohistochemical examinations showed that DMA(V) increased immunoreactivities of IKKalpha, IKKbeta, and phospho-NF-kappaB p50 in the cytoplasm and phospho-NF-kappaB p50 and p65 in nucleus of rat urothelial cells. In addition, DMA(V) treated rats exhibited significantly increased inflammatory factor TGF-beta immunoreactivity in bladder epithelium and IL-1beta secretion in urine. These data suggest that DMA(V) could activate NF-kappaB signal pathway and increase TGF-beta and IL-1beta expressions in bladder epithelial cells of rats. PMID- 26617438 TI - A Traditional Chinese Medicine Xiao-Ai-Tong Suppresses Pain through Modulation of Cytokines and Prevents Adverse Reactions of Morphine Treatment in Bone Cancer Pain Patients. AB - Treating cancer pain continues to possess a major challenge. Here, we report that a traditional Chinese medicine Xiao-Ai-Tong (XAT) can effectively suppress pain and adverse reactions following morphine treatment in patients with bone cancer pain. Visual Analogue Scale (VAS) and Quality of Life Questionnaire (EORTC QLQ C30) were used for patient's self-evaluation of pain intensity and evaluating changes of adverse reactions including constipation, nausea, fatigue, and anorexia, respectively, before and after treatment prescriptions. The clinical trials showed that repetitive oral administration of XAT (200 mL, bid, for 7 consecutive days) alone greatly reduced cancer pain. Repetitive treatment with a combination of XAT and morphine (20 mg and 30 mg, resp.) produced significant synergistic analgesic effects. Meanwhile, XAT greatly reduced the adverse reactions associated with cancer and/or morphine treatment. In addition, XAT treatment significantly reduced the proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha and increased the endogenous anti-inflammatory cytokine interleukin-10 in blood. These findings demonstrate that XAT can effectively reduce bone cancer pain probably mediated by the cytokine mechanisms, facilitate analgesic effect of morphine, and prevent or reduce the associated adverse reactions, supporting a use of XAT, alone or with morphine, in treating bone cancer pain in clinic. PMID- 26617439 TI - Intra-group Stigma: Examining Peer Relationships Among Women in Recovery for Addictions. AB - This grounded theory study explores how women with histories of addiction perceive stigma while in treatment. In-depth interviews were conducted with 30 women participating in a residential drug treatment center. Previous research has found that support from peers during recovery can be critical to managing illnesses. In fact, researchers have postulated that peers can be a more effective form of support than even family. This study extends existing literature indicating that peer support systems can be supportive, however they can also can be perceived as negative support that impose stigmas. Findings reveal that women perceive stigmas due to how various types of drug use violate societal expectations and conflict with notions of deservingness. Specifically, the "hard users" (i.e., women who use heroin or crack cocaine) perceive stigmas regarding how their drug use violates norms of womanhood. Moreover, the "soft users" (i.e., those who use alcohol or marijuana) perceive stigmas that their drug use is considered undeserving of support. This paper explores the factors that contribute to stigma amongst populations who potentially face marginalization from larger society. Implications for treatment and group work are discussed. PMID- 26617441 TI - EDITOR'S NOTE--About This Supplement. PMID- 26617440 TI - Patient Outcomes in Association With Significant Other Responses to Chronic Fatigue Syndrome: A Systematic Review of the Literature. AB - Social processes have been suggested as important in the maintenance of chronic fatigue syndrome (also known as myalgic encephalomyelitis; CFS/ME), but the specific role of close interpersonal relationships remains unclear. We reviewed 14 articles investigating significant other responses to close others with CFS/ME and the relationships between these responses and patient outcomes. Significant other beliefs attributing patient responsibility for the onset and ongoing symptoms of CFS/ME were associated with increased patient distress. Increased symptom severity, disability, and distress were also associated with both solicitous and negative significant other responses. Specific aspects of dyadic relationship quality, including high Expressed Emotion, were identified as important. We propose extending current theoretical models of CFS/ME to include two potential perpetuating interpersonal processes; the evidence reviewed suggests that the development of significant other-focused interventions may also be beneficial. PMID- 26617442 TI - Dr. LEE Jong-wook-Seoul Project--Successful Korean Version of Minnesota Project- Could Be a Model of Partner in the Field of Medicine. PMID- 26617443 TI - Measles Elimination Activities in the Western Pacific Region: Experience from the Republic of Korea. AB - We describe the global status of measles control and elimination, including surveillance and vaccination coverage data provided by the World Health Organization (WHO). Since 2000, two doses of measles vaccine (MCV2) became recommended globally and the achievement of high vaccination coverage has led to dramatic decrease in the measles incidence. Our finding indicates that, in the Western Pacific Region (WPR), substantial progress has been made to control measles transmission in some countries; however, the measles virus continues to circulate, causing outbreaks. The Republic of Korea (ROK) experienced a series of resurgence of measles due to the importation and healthcare-associated transmission in infants, however overall incidence and surveillance indicators met the WHO criteria for measles elimination. The ROK was verified to be measles free along with Australia, Mongolia, and Macau, China in 2014. One of the effective elimination activities was the establishment of solid keep-up vaccination system in school settings. The lessons learnt from the measles elimination activities in Korea may contribute to enhancing the surveillance schemes and strengthening of vaccination programs in member countries and areas of WPR. PMID- 26617444 TI - Who Neglects Neglected Tropical Diseases? - Korean Perspective. AB - Neglected tropical diseases (NTDs) are a group of tropical infectious diseases of poorest people. Of 17 NTDs managed by WHO, two, guinea worm disease (by 2015) and yaws (by 2020) are targeted for eradication, and four (blinding trachoma, human African trypanosomiasis, leprosy, and lymphatic filariasis) for elimination by 2020. The goals look promising but 11 others are still highly prevalent. Soil transmitted helminths (STHs) are one NTD which prevail over the world including temperate zones. They had been highly prevalent in Korea but are mostly disappearing at present through systematic and sustainable control activity. The successful experience of STH control enables Korean experts to develop many programs of NTD control in developing countries. Several programs of both official development aid and non-governmental organizations are now targeting NTDs. Most NTDs are low in health priority compared to their health threats because they are chronic, insidious, and of low mortality. No one, including the victims, raised priority of NTD control with a loud voice in the endemic field of the diseases. After the millennium development goals declared disease control over the world, NTDs are becoming less neglected globally. Even with limited resources, beginning a sustainable national program is the key for the control and elimination of NTDs. No more neglect, especially no more self-neglect, can eliminate diseases and upgrade quality of life of the neglected people. PMID- 26617445 TI - Limits to Economic Growth: Why Direct Investments Are Needed to Address Child Undernutrition in India. AB - About two of every five undernourished young children of the world live in India. These high levels of child undernutrition have persisted in India for several years, even in its relatively well-developed states. Moreover, this pattern was observed during a period of rapid economic growth. Evidence from India and other developing countries suggests that economic growth has little to no impact on reducing child undernutrition. We argue that a growth-mediated strategy is unlikely to be effective in tackling child undernutrition unless growth is pro poor and leads to investment in programs addressing the root causes of this persistent challenge. PMID- 26617446 TI - Patterns of Health Expenditures and Financial Protections in Vietnam 1992-2012. AB - Health financing has been considered as an important building block of a health system and has a key role in promoting universal health coverage in the Vietnam. This paper aims to describe the pattern of health expenditure, including total health expenditure and composition of health expenditure, over the last two decades in Vietnam. The paper mainly uses the data from Vietnam National Health Account and Vietnam Living Standards Survey. We also included data from other relevant published literature, reports and statistics about health care expenditure in Vietnam. The per capita health expenditure in Vietnam increased from US$ 14 in 1995 to US$ 86 in 2012. The total health expenditure as a share of GDP also rose from 5.2% in 1995 to 6.9% in 2012. Public health expenditure as percentage of government expenditure rose from 7.4% in 1995 to nearly 10% in 2012. The coverage of health insurance went up from 10% in 1995 to 68.5% in 2012. However, health financing in Vietnam was depending on private expenditures (57.4% in 2012). As a result, the proportion of households with catastrophic expenditure in 2012 was 4.2%. The rate of impoverishment in 2012 was 2.5%. To ensure equity and efficient goal of health system, policy actions for containing the health care out-of-pocket payments and their poverty impacts are urgently needed in Vietnam. PMID- 26617447 TI - Development-assistance Strategies for Stroke in Low- and Middle-income Countries. AB - While communicable diseases still pose a serious health threat in developing countries, previously neglected health issues caused by non-communicable diseases such as stroke are rapidly becoming a major burden to these countries. In this review we will discuss the features and current status of stroke in low- and middle-income countries (LMICs). Overall the global burden of hemorrhagic stroke is larger than ischemic stroke, with a disproportionately greater burden, measured in incidence and disability-adjusted life-years, regionally localized in LMICs. Patients in poorer countries suffer due to insufficient primary care needed to control risk factors such as hypertension, and inadequate emergency care systems through which sudden events should be managed. In light of these situations, we emphasize two strategic points for development assistance. First, assistance should be provided for bolstering, integrating, and coordinating both the primary health and emergency care systems, in order to prevent stroke and strengthen stroke management, respectively. Second, the assistance needs to focus on programs at the community level, to reduce life-style risks of stroke in a more sustainable manner, and to improve stroke outcomes more effectively. PMID- 26617448 TI - A New Approach of Measuring Hospital Performance for Low- and Middle-income Countries. AB - Efficiency of the hospitals affects the price of health services. Health care payments have equity implications. Evidence on hospital performance can support to design the policy; however, the recent literature on hospital efficiency produced conflicting results. Consequently, policy decisions are uncertain. Even the most of evidence were produced by using data from high income countries. Conflicting results were produced particularly due to differences in methods of measuring performance. Recently a management approach has been developed to measure the hospital performance. This approach to measure the hospital performance is very useful from policy perspective to improve health system from cost-effective way in low and middle income countries. Measuring hospital performance through management approach has some basic characteristics such as scoring management practices through double blind survey, measuring hospital outputs using various indicators, estimating the relationship between management practices and outputs of the hospitals. This approach has been successfully applied to developed countries; however, some revisions are required without violating the fundamental principle of this approach to replicate in low- and middle-income countries. The process has been clearly defined and applied to Nepal. As the results of this, the approach produced expected results. The paper contributes to improve the approach to measure hospital performance. PMID- 26617449 TI - Republic of Korea's Health Aid Governance: Perspectives from Partner Countries. AB - The Republic of Korea (ROK) has a remarkable development history, including its status as the first country to transition from aid recipient to member of the Organization for Economic Cooperation and Development Development Assistance Committee (DAC). However, since becoming a donor country, the ROK has struggled to achieve internationally accepted agreements related to aid effectiveness and several evaluations have identified the ROK as being one of the weakest DAC member countries at providing good aid. A survey was conducted to assess partner countries' perceptions of the ROK's governance of health official development assistance (ODA). The survey was administered to government officials based in partner countries' Ministries of Health and therefore presents the unique perspective of ODA recipients. The survey questions focused on governance principles established in the internationally-accepted Paris Declaration on Aid Effectiveness. The total response rate was 13 responses out of 26 individuals who received the email request (50%). The survey results indicate that progress has been made since earlier international evaluations but the ROK has not overcome all areas of concern. This confirms that the ROK is continuing to develop its capacity as a good donor but has yet to achieve all governance-related targets. The results of this survey can be used to inform a future aid strategy. PMID- 26617450 TI - Horizontal Inequity in Elderly Health Care Utilization: Evidence from India. AB - Against the backdrop of population aging, this paper presents the analysis of need-standardised health care utilization among elderly in India. Based on nationally representative morbidity and health care survey 2004, we demonstrate that the need for health care utilization is indeed pro-poor in nature. However, the actual health care utilization is concentrated among richer sections of the population. Further, the decomposition analysis reveals that income has a very strong role in shifting the distribution of health care away from the poor elderly. The impact of income on utilization is well-demonstrated even at the ecological-level as states with higher per capita incomes have higher elderly health care utilization even as the levels of need-predicted distribution across these states are similar. We also find that the distribution of elderly across social groups and their educational achievements favours the rich and significantly contributes to overall inequality. Nevertheless, contribution of need-related self-assessed health clearly favours pro-poor inequality. In concluding, we argue that to reduce such inequities in health care utilization it is necessary to increase public investments in health care infrastructure including geriatric care particularly in rural areas and underdeveloped regions to enhance access and quality of health care for the elderly. PMID- 26617451 TI - Factor Configurations with Governance as Conditions for Low HIV/AIDS Prevalence in HIV/AIDS Recipient Countries: Fuzzy-set Analysis. AB - This paper aims to investigate whether good governance of a recipient country is a necessary condition and what combinations of factors including governance factor are sufficient for low prevalence of HIV/AIDS in HIV/AIDS aid recipient countries during the period of 2002-2010. For this, Fuzzy-set Qualitative Comparative Analysis (QCA) was used. Nine potential attributes for a causal configuration for low HIV/AIDS prevalence were identified through a review of previous studies. For each factor, full membership, full non-membership, and crossover point were specified using both author's knowledge and statistical information of the variables. Calibration and conversion to a fuzzy-set score were conducted using Fs/QCA 2.0 and probabilistic tests for necessary and sufficiency were performed by STATA 11. The result suggested that governance is the necessary condition for low prevalence of HIV/AIDS in a recipient country. From sufficiency test, two pathways were resulted. The low level of governance can lead to low level of HIV/AIDS prevalence when it is combined with other favorable factors, especially, low economic inequality, high economic development and high health expenditure. However, strengthening governance is a more practical measure to keep low prevalence of HIV/AIDS because it is hard to achieve both economic development and economic quality. This study highlights that a comprehensive policy measure is the key for achieving low prevalence of HIV/AIDS in recipient country. PMID- 26617452 TI - Cost of Hospitalization for Foodborne Diarrhea: A Case Study from Vietnam. AB - Vietnam is undergoing a rapid social and economic developments resulting in speedy urbanization, changes in methods for animal production, food marketing systems, and food consumption habits. These changes will have major impacts on human exposures to food poisoning. The present case study aimed to estimate hospitalization costs of foodborne diarrhea cases in selected health facilities in Vietnam. This is a facility-based cost-of-illness study conducted in seven health facilities in Northern Vietnam. All suspect cases of foodborne diarrhea, as diagnosed by doctors, who admitted to the studied health facilities during June-August, 2013 were selected. Costs associated with hospitalization for foodborne diseases were estimated from societal perspective using retrospective approach. We included direct and indirect costs of hospitalization of foodborne diarrhea cases. During the study period, 87 foodborne diarrhea cases were included. On average, the costs per treatment episode and per hospitalization day for foodborne diarrhea case were US$ 106.9 and US$ 33.6 respectively. Indirect cost (costs of times to patient, their relatives due to the patient's illness) made up the largest share (51.3%). Direct medical costs accounted for 33.8%; direct non-medical costs (patient and their relatives) represented 14.9%. Cost levels and compositions varied by level of health facilities. More attentions should be paid on prevention, control of foodborne diarrhea cases in Vietnam. Ensuring safety of food depends on efforts of everyone involved in food chain continuum, from production, processing, and transport to consumption. PMID- 26617453 TI - Implementation of a self-monitoring application to improve on-task behavior: A high school pilot study. AB - Technological innovations offer promise for improving intervention implementation in secondary, inclusive classrooms. A withdrawal design was employed with two high school students in order to assess the effectiveness of a technologically delivered, self-monitoring intervention in improving on-task behavior in a science classroom. Two students ages 14 and 15 with diagnoses of specific learning disability (student 1) and attention deficit hyperactivity disorder (ADHD: student 2) were selected by case manager referral due to difficulties with on-task behavior despite long-term administration of psychostimulant medication. After baseline data were collected, both students were trained in the use of a self-monitoring application (I-Connect) delivered via a handheld tablet. On-task prompts were delivered at five min intervals in an ABAB withdrawal design. The intervention resulted in positive, stable improvements in the primary dependent variable of on-task behavior for both students and less clear improvement in the generalization variable of disruptive behavior. PMID- 26617455 TI - Accelerating Fuzzy-C Means Using an Estimated Subsample Size. AB - Many algorithms designed to accelerate the Fuzzy c-Means (FCM) clustering algorithm randomly sample the data. Typically, no statistical method is used to estimate the subsample size, despite the impact subsample sizes have on speed and quality. This paper introduces two new accelerated algorithms, GOFCM and MSERFCM, that use a statistical method to estimate the subsample size. GOFCM, a variant of SPFCM, also leverages progressive sampling. MSERFCM, a variant of rseFCM, gains a speedup from improved initialization. A general, novel stopping criterion for accelerated clustering is introduced. The new algorithms are compared to FCM and four accelerated variants of FCM. GOFCM's speedup was 4-47 times that of FCM and faster than SPFCM on each of the six datasets used in experiments. For five of the datasets, partitions were within 1% of those of FCM. MSERFCM's speedup was 5 26 times that of FCM and produced partitions within 3% of those of FCM on all datasets. A unique dataset, consisting of plankton images, exposed the strengths and weaknesses of many of the algorithms tested. It is shown that the new stopping criterion is effective in speeding up algorithms such as SPFCM and the final partitions are very close to those of FCM. PMID- 26617454 TI - Family Economic Stress, Quality of Paternal Relationship, and Depressive Symptoms among African American Adolescent Fathers. AB - This study examined the association between perceived family economic stress, quality of father-son relationships, and depressive symptoms among African American adolescent fathers. Data were collected during pregnancy from 65 African American adolescents who were first-time fathers, ages 14-19. Results from multiple regression analyses indicated that higher paternal relationship satisfaction was associated with fewer depressive symptoms among adolescent fathers. Additionally, depressive symptoms were higher among adolescent fathers who reported experiencing higher levels of conflict with their fathers. Further, paternal conflict moderated the effect of perceived family economic stress on depressive symptoms. That is, among adolescent fathers experiencing low levels of conflict with their fathers, high perceived family economic stress was associated with more depressive symptoms. Study findings suggest that the risk for depressive symptoms is highest among adolescent fathers experiencing low family economic stress and highly conflictual relations with their fathers. These results highlight the complexities of paternal relationships and perceived economic stressors on depressive symptoms during pregnancy for African American adolescent fathers. The importance of expanding research on influential familial relationships and economic stressors on adolescent African American fathers is discussed. PMID- 26617456 TI - The Use of Protease Inhibitors in Pregnancy: Maternal and Fetal Considerations. AB - BACKGROUND: Previous studies examining protease inhibitor use in pregnancy and the rate of preterm and small-for-gestational-age infants have yielded conflicting results. METHODS: This was a retrospective study of HIV-infected women who delivered singleton infants at our institution between 1984 and 2014. Women with protease inhibitor use were compared to women on regimens without a protease inhibitor as well as those who received no antepartum antiretroviral therapy. Infants were considered preterm if less than 37 completed weeks of gestation and small-for-gestational-age if less than 10th percentile. RESULTS: During the study period 1,004 pregnancies met inclusion criteria. Of those, 597 received a protease inhibitor as part of their regimen, 230 ART without a protease inhibitor, and 177 no ART. There was no difference in the rate of preterm birth between groups who received ART with or without a protease inhibitor, 14% versus 13%. There was no difference in the rate of small-for gestational-age infants between the three groups. Use of a protease inhibitor was associated with a greater fall in viral load during pregnancy, p < 0.001. CONCLUSION: In this population with access to prenatal care and ART, treatment with protease inhibitors was associated with a greater fall in viral load, but not an increase in small or preterm infants. PMID- 26617457 TI - ADAPTIVE SMALL-ANIMAL SPECT/CT. AB - We are exploring the concept of adaptive multimodality imaging, a form of non linear optimization where the imaging configuration is automatically adjusted in response to the object. Preliminary studies suggest that substantial improvement in objective, task-based measures of image quality can result. We describe here our work to add motorized adjustment capabilities and a matching CT to our existing FastSPECT II system to form an adaptive small-animal SPECT/CT. PMID- 26617458 TI - Method of Calibrating Response Statistics for ML Estimation of 3D Interaction Position in a Thick-Detector Gamma Camera. AB - High-energy photon detectors are often made thick in order to improve their photon-detection efficiency. To avoid issues of parallax and increased signal variance that result from random interaction depth, we must determine the 3D interaction position in the imaging detector. With this goal in mind, we examine a method of calibrating response statistics of a thick-detector gamma camera to produce a maximum- likelihood estimate of 3D interaction position. We parameterize the mean detector response as a function of 3D position and estimate the parameters by maximizing their likelihood given prior knowledge of the pathlength distribution and a complete list of camera signals for an ensemble of gamma-ray interactions. Demonstrating this calibration method with simulated gamma-camera data, we show that the resulting calibration is accurate and can be used to produce unbiased estimates of 3D interaction position. PMID- 26617459 TI - Screening Analogs of beta-OG Pocket Binder as Fusion Inhibitor of Dengue Virus 2. AB - Dengue is an infectious disease caused by dengue virus (DENV) and transmitted between human hosts by mosquitoes. Recently, Indonesia was listed as a country with the highest cases of dengue by the Association of Southeast Asian Nations. The current treatment for dengue disease is supportive therapy; there is no antiviral drug available in the market against dengue. Therefore, a research on antiviral drug against dengue is very important, especially to prevent outbreak explosion. In this research, the development of dengue antiviral is performed through the inhibition of n-octyl-beta-D-glucoside (beta-OG) binding pocket on envelope protein of DENV by using analogs of beta-OG pocket binder. There are 828 compounds used in this study, and all of them were screened based on the analysis of molecular docking, pharmacological character prediction of the compounds, and molecular dynamics simulation. The result of these analyses revealed that the compound that can be used as an antiviral candidate against DENV is 5-(3,4 dichlorophenyl)-N-[2-(p-tolyl) benzotriazol-5-yl]furan-2-carboxamide. PMID- 26617460 TI - Educating Future Environmental Health Professionals. AB - Future environmental health problems will require a new generation of educated and trained professionals. Efforts to enhance the environmental public health workforce have been promoted by several organizations. While progress has been measured by these organizations, many environmental health academic programs are experiencing budget reductions and lower enrollments. One of the reasons for this trend is the so-called higher education crisis. We argue that training is not equivalent to education in the environmental health sciences, albeit the two terms are often used interchangeably. Organizations involved with the education, training, and credentialing of environmental health professionals must work together to ensure the viability and effectiveness of environmental health academic programs. PMID- 26617461 TI - Human and Environmental Toxicity of Sodium Lauryl Sulfate (SLS): Evidence for Safe Use in Household Cleaning Products. AB - Environmental chemical exposure is a major concern for consumers of packaged goods. The complexity of chemical nomenclature and wide availability of scientific research provide detailed information but lends itself to misinterpretation by the lay person. For the surfactant sodium lauryl sulfate (SLS), this has resulted in a misunderstanding of the environmental health impact of the chemical and statements in the media that are not scientifically supported. This review demonstrates how scientific works can be misinterpreted and used in a manner that was not intended by the authors, while simultaneously providing insight into the true environmental health impact of SLS. SLS is an anionic surfactant commonly used in consumer household cleaning products. For decades, this chemical has been developing a negative reputation with consumers because of inaccurate interpretations of the scientific literature and confusion between SLS and chemicals with similar names. Here, we review the human and environmental toxicity profiles of SLS and demonstrate that it is safe for use in consumer household cleaning products. PMID- 26617462 TI - Apolipoprotein-E genotype and human immunodeficiency virus-associated neurocognitive disorder: the modulating effects of older age and disease severity. AB - BACKGROUND: The apolipoprotein-E (APOE) epsilon4 allele is a risk factor for vascular dementia and Alzheimer's disease. Recent studies are equivocal with regards to whether or not the epsilon4 allele confers increased risk for the development of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND), but suggest that age and/or disease severity may be modulating factors. The aim of this study was to assess the interactions and contributions of APOE genotype, age, and HIV disease severity as risk factors for HAND in HIV infected adults. METHODS: Participants were 259 HIV-positive individuals who underwent APOE genotyping, a standardized neurological evaluation, a comprehensive neuropsychological evaluation, and laboratory testing. RESULTS: Older epsilon4 carriers showed a higher frequency of HAND compared with age matched non-epsilon4 carriers. Analysis by discrete neurocognitive domain revealed that advanced age modulated the effect of the epsilon4 allele, such that older epsilon4 allele carriers showed reduced executive functioning and information processing speed. Exploratory analyses assessing the relationship between epsilon4 and disease severity in the overall sample revealed that disease severity modulated the effect of the epsilon4 allele on cognition. Lower absolute CD4+ cell count among epsilon4 allele carriers was associated with poorer working memory ability. CONCLUSION: Advancing age and degree of immunosuppression may influence the association between APOE epsilon4 allele status and HAND. These two factors need to be taken into account in future research. PMID- 26617463 TI - Glioblastoma Stem Cells as a New Therapeutic Target for Glioblastoma. AB - Primary and secondary glioblastomas (GBMs) are two distinct diseases. The genetic and epigenetic background of these tumors is highly variable. The treatment procedure for these tumors is often unsuccessful because of the cellular heterogeneity and intrinsic ability of the tumor cells to invade healthy tissues. The fatal outcome of these tumors promotes researchers to find out new markers associated with the prognosis and treatment planning. In this communication, the role of glioblastoma stem cells in tumor progression and the malignant behavior of GBMs are summarized with attention to the signaling pathways and molecular regulators that are involved in maintaining the glioblastoma stem cell phenotype. A better understanding of these stem cell-like cells is necessary for designing new effective treatments and developing novel molecular strategies to target glioblastoma stem cells. We discuss hypoxia as a new therapeutic target for GBM. We focus on the inhibition of signaling pathways, which are associated with the hypoxia-mediated maintenance of glioblastoma stem cells, and the knockdown of hypoxia-inducible factors, which could be identified as attractive molecular target approaches for GBM therapeutics. PMID- 26617464 TI - Soil contamination with silver nanoparticles reduces Bishop pine growth and ectomycorrhizal diversity on pine roots. AB - Soil contamination by silver nanoparticles (AgNP) is of potential environmental concern but little work has been carried out on the effect of such contamination on ectomycorrhizal fungi (EMF). EMF are essential to forest ecosystem functions as they are known to enhance growth of trees by nutrient transfer. In this study, soil was experimentally contaminated with AgNP (0, 350 and 790 mg Ag/kg) and planted with Bishop pine seedlings. The effect of AgNP was subsequently measured, assessing variation in pine growth and ectomycorrhizal diversity associated with the root system. After only 1 month, the highest AgNP level had significantly reduced the root length of pine seedlings, which in turn had a small effect on above ground plant biomass. However, after 4 months growth, both AgNP levels utilised had significantly reduced both pine root and shoot biomass. For example, even the lower levels of AgNP (350 mg Ag/kg) soil, reduced fresh root biomass by approximately 57 %. The root systems of the plants grown in AgNP-contaminated soils lacked the lateral and fine root development seen in the control plants (no AgNP). Although, only five different genera of EMF were found on roots of the control plants, only one genus Laccaria was found on roots of plants grown in soil containing 350 mg AgNP/kg. At the higher levels of AgNP contamination, no EMF were observed. Furthermore, extractable silver was found in soils containing AgNP, indicating potential dissolution of silver ions (Ag+) from the solid AgNP. PMID- 26617465 TI - A breath of fresh air: a quality-improvement study comparing an air-circulating technique versus conventional technique to prevent nasogastric tube dysfunction. AB - BACKGROUND: Nasogastric tubes are an important component of care in patients with gastrointestinal obstructions. However, they are prone to malfunction despite conventional flushing techniques, with potentially severe consequences. There is no widely accepted, gold-standard way to ensure that a nasogastric tube succeeds in maintaining an empty stomach following flushing. METHODS: We have developed a flushing technique to better ensure successful tube function. We compared this technique to conventional flushing both in vitro (using a plastic stomach model) and in vivo (in a pig model), and we provide a didactic video. RESULTS: The mean gastric residual volume following our novel flushing technique is nearly 25-fold lower than following conventional flushing (13 mL vs. 330 mL). CONCLUSIONS: Our simple technique is more effective than conventional techniques in maintaining nasogastric tube function and therefore should prevent dangerous vomiting and aspiration pneumonia better than conventional techniques. PMID- 26617466 TI - Fatigue in adults with post-infectious fatigue syndrome: a qualitative content analysis. AB - BACKGROUND: Fatigue is a major problem among individuals with post-infectious fatigue syndrome (PIFS), also known as chronic fatigue syndrome or myalgic encephalomyelitis. It is a complex phenomenon that varies across illnesses. From a nursing perspective, knowledge and understanding of fatigue in this illness is limited. Nurses lack confidence in caring for these patients and devalue their professional role. The aim of this study was to explore in-depth the experiences of fatigue among individuals with PIFS. A detailed description of the phenomenon of fatigue is presented. Increased knowledge would likely contribute to more confident nurses and improved nursing care. METHODS: A qualitative study with open interviews was employed. In-depth interviews with patients were fully transcribed and underwent a qualitative content analysis. A maximum variation sample of 26 affected adults between 26-59 years old was recruited from a population diagnosed at a fatigue outpatient clinic. RESULTS: The fatigue was a post-exertional, multidimensional, fluctuating phenomenon with varying degrees of severity and several distinct characteristics and was accompanied by concomitant symptoms. Fatigue was perceived to be an all-pervasive complex experience that substantially reduced the ability to function personally or professionally. A range of trigger mechanisms evoked or worsened the fatigue, but the affected were not always aware of what triggered it. There was an excessive increase in fatigue in response to even minor activities. An increase in fatigue resulted in the exacerbation of other concomitant symptoms. The term fatigue does not capture the participants' experiences, which are accompanied by a considerable symptom burden that contributes to the illness experience and the severe disability. CONCLUSIONS: Although some aspects of the fatigue experience have been reported previously, more were added in our study, such as the dimension of awakening fatigue and the characteristic beyond time, when time passes unnoticed. We also identified trigger mechanisms such as emotional, neurological, social, financial, and pressure on oneself or from others. This in-depth exploration of fatigue in PIFS provides an overview of the dimensions, characteristics, and trigger mechanisms of fatigue, thus making better clinical observations, early recognition, improved communication with patients and more appropriate nursing interventions possible. PMID- 26617467 TI - STAT1 inhibits human hepatocellular carcinoma cell growth through induction of p53 and Fbxw7. AB - BACKGROUND: Aberrant STAT1 signaling is observed in human hepatocellular carcinoma (HCC) and has been associated with the modulation of cell proliferation and survival. However, the role of STAT1 signaling in HCC and its underlying mechanism remain elusive. METHODS: We transiently transfected pcDNA3.1-STAT1 and STAT1 siRNA into SMMC7721 and HepG2 cells. Western blot and qRT-PCR examined the expression of protein and RNA of target genes. Cell viability was assessed using MTT assay, and cell cycle and apoptosis were analyzed by flow cytometry. RESULTS: We found that STAT1 overexpression increased protein expression of p53 and Fbxw7, and downregulated the expression of cyclin A, cyclin D1, cyclin E, CDK2, Hes-1 and NF-kappaB p65. These changes led to growth inhibition and induced G0/G1 cell cycle arrest and apoptosis in SMMC7721 and HepG2 cells. Conversely, ablation of STAT1 had the opposite effect on p53, Fbxw7, Hes-1, NF-kappaB p65, cyclin A, cyclin D1, cyclin E and CDK2, and improved the viability of SMMC7721 and HepG2 cells. CONCLUSIONS: Our data indicate that STAT1 exerts tumor-suppressive effects in hepatocarcinogenesis through induction of G0/G1 cell cycle arrest and apoptosis, and may provide a basis for the design of new therapies for the intervention of HCC in the clinic. PMID- 26617468 TI - Differential abundance analysis of mesocarp protein from high- and low-yielding oil palms associates non-oil biosynthetic enzymes to lipid biosynthesis. AB - BACKGROUND: The oil palm Elaeis guineensis Jacq. which produces the highest yield per unit land area of the oil crops is the most important commercial oil crop in South East Asia. The fleshy mesocarp of oil palm fruit, where oil is mostly derived from, contains up to 90 % dry weight of oil (one of the most concentrated in plant tissues). Hence, there is attention given to gain insights into the processes of oil deposition in this oil rich tissue. For that purpose, two dimensional differential gel electrophoresis (DIGE) coupled with western assays, were used here to analyze differential protein levels in genetically-related high and low-yielding oil palm mesocarps. RESULTS: From the DIGE comparative analysis in combination with western analysis, 41 unique differentially accumulated proteins were discovered. Functional categorization of these proteins placed them in the metabolisms of lipid, carbohydrate, amino acids, energy, structural proteins, as well as in other functions. In particular, higher abundance of fructose-1,6-biphosphate aldolase combined with reduced level of triosephosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase may be indicative of important flux balance changes in glycolysis, while amino acid metabolism also appeared to be closely linked with oil yield. CONCLUSIONS: Forty-one proteins in several important biological pathways were identified as exhibiting differential in abundance at critical oil production stages. These confirm that oil yield is a complex trait involving the regulation of genes in multiple biological pathways. The results also provide insights into key control points of lipid biosynthesis in oil palm and can assist in the development of genetic markers for use in oil palm breeding programmes. PMID- 26617469 TI - The Physical Health of Patients with Advanced Pancreatic Cancer and the Psychological Health of their Family Caregivers When Newly Enrolled in Hospice. PMID- 26617470 TI - Innovative Methods in the Science of Parent-Child Relations. PMID- 26617471 TI - Barriers to Psychosocial Services among Homeless Women Veterans. AB - Veterans comprise a disproportionate fraction of the nation's homeless population, with women veterans up to four times more likely to be homeless than non-veteran women. This paper provides a grounded description of barriers to psychosocial services among homeless women veterans. Three focus groups were held in Los Angeles, CA, with a total of 29 homeless women veterans. These women described three primary, proximal (current) barriers: lack of information about services, limited access to services, and lack of coordination across services. Compared to non-veteran homeless women, women veterans potentially face additional challenges of trauma exposure during military service, post-military readjustment issues, and few services specific to women veterans. Understanding their service needs and experiences is critical to the development of relevant and appropriate services that move homeless women veterans away from vulnerability, into safety. PMID- 26617472 TI - The Dog narratives: Benefits of the human-animal bond for women with HIV. AB - INTRODUCTION: Companion animals play important roles in the lives of people managing the many symptoms associated with a chronic illness such as HIV. This study explored meaningful examples of pets, particularly dogs, and their place in support networks among women living with AIDS/HIV. METHOD: Data were collected via focus group, as part of a larger Photovoice project. Qualitative analysis discovered three key related themes. RESULTS: Emerging themes included pet as spiritual custodian, pet as unconditional source of support, and pet providing a sense of purpose. DISCUSSION: The comments these participants made about their dogs allowed us to explore culturally embedded notions about animal companionship; the ability to know when one is sick, frightened, emotionally upset, or facing a spiritual crisis. The women. PMID- 26617473 TI - 'Packages' of Risk: Implications for Determining the Effect of Maternal Incarceration on Child Wellbeing. PMID- 26617474 TI - Cultural Acceptability of a Smoking Relapse Prevention Intervention for Pregnant Women in Puerto Rico: Providers' Feedback. AB - Hispanic women are more likely than non-Hispanic women to quit smoking during pregnancy, indicating that relapse-prevention interventions may benefit this population. We conducted qualitative interviews with health care providers in Puerto Rico who serve pregnant women regarding the cultural acceptability of Libres Para Siempre Por Mi Bebe y Por Mi (transcreated from the English version, Forever Free for Baby and Me), a smoking relapse-prevention booklet series. Providers praised the overall quality of the content, interactive activities, vignettes, and partner booklet. Recommendations included condensing the content, and distributing the booklets during one-on-one counseling and via "charlas"(community themed presentations). Overall, these smoking relapse prevention materials are culturally acceptable among health care providers, yet there is a need to attend to local cultural preferences for delivering the intervention. PMID- 26617475 TI - Toward Formulating Evidence-Based Principles of LGB-Affirmative Psychotherapy. AB - In this commentary, we review eight potential LGB-affirmative psychotherapy principles for improving minority stress coping among sexual minority clients. We illustrate these principles with examples from both Mandel's (2014) treatment approach and our clinical research team's recent attempt to create and test the efficacy of a treatment employing these principles in an ongoing randomized controlled trial. These principles are grounded in empirical research regarding the mechanisms through which minority stress compromises the mental health of sexual minority individuals and are supported by clinical expert consensus. The specific principles that we review include: 1) normalizing the mental health impact of minority stress, 2) facilitating emotion awareness, regulation, and acceptance, 3) decreasing avoidance, 4) restructuring minority stress cognitions, 5) empowering sexual minority clients to communicate assertively, 6) validating sexual minority individuals' unique strengths, 7) building supportive relationships, and 8) affirming healthy, rewarding expressions of sexuality. We believe that Mandel's skillful approach to helping her hybrid client Adam cope with minority stressors, such as internalized homophobia, and associated mental health problems such as substance abuse and depression, to form a healthy identity as a gay man represents an exemplary demonstration of these principles in action. PMID- 26617476 TI - The United Nations Probabilistic Population Projections: An Introduction to Demographic Forecasting with Uncertainty. AB - The United Nations publishes projections of populations around the world and breaks these down by age and sex. Traditionally, they are produced with standard demographic methods based on assumptions about future fertility rates, survival probabilities, and migration counts. Such projections, however, were not accompanied by formal statements of uncertainty expressed in probabilistic terms. In July 2014 the UN for the first time issued official probabilistic population projections for all countries to 2100. These projections quantify uncertainty associated with future fertility and mortality trends worldwide. This review article summarizes the probabilistic population projection methods and presents forecasts for population growth over the rest of this century. PMID- 26617477 TI - Treatment Individualization in Colorectal Cancer. AB - Colorectal cancer has been characterized as a genetically heterogeneous disease, with a large diversity in molecular pathogenesis resulting in differential responses to therapy. However, the currently available validated biomarkers KRAS, BRAF, and microsatellite instability do not sufficiently cover this extensive heterogeneity and are therefore not suitable to successfully guide personalized treatment. Recent studies have focused on novel targets and rationally designed combination strategies. Furthermore, a more comprehensive analysis of the underlying biology of the disease revealed distinct phenotypic differences within subgroups of patients harboring the same genetic driver mutation with both prognostic and predictive relevance. Accordingly, patient stratification based on molecular intrinsic subtypes rather than on single gene aberrations holds promise to improve the clinical outcome of patients with colorectal cancer. PMID- 26617478 TI - Global metabolomics reveals metabolic dysregulation in ischemic retinopathy. AB - Proliferative diabetic retinopathy (PDR) is the most severe form of diabetic retinopathy and, along with diabetic macular edema, is responsible for the majority of blindness in adults below the age of 65. Therapeutic strategies for PDR are ineffective at curtailing disease progression in all cases; however a deeper understanding of the ocular metabolic landscape in PDR through metabolomic analysis may offer new therapeutic targets. Here, global and targeted mass spectrometry-based metabolomics were used to investigate metabolism. Initial analyses on vitreous humor from patients with PDR (n = 9) and non-diabetic controls (n = 11) revealed an increase of arginine and acylcarnitine metabolism in PDR. The oxygen-induced-retinopathy (OIR) mouse model, which exhibits comparable pathological manifestations to human PDR, revealed similar increases of arginine and other metabolites in the urea cycle, as well as downregulation of purine metabolism. We validated our findings by targeted multiple reaction monitoring and through the analysis of a second set of patient samples [PDR (n = 11) and non-diabetic controls (n = 20)]. These results confirmed a predominant and consistent increase in proline in both the OIR mouse model and vitreous samples from patients with PDR, suggesting that over activity in the arginine-to proline pathway could be used as a therapeutic target in diabetic retinopathy. PMID- 26617479 TI - Novel application of heuristic optimisation enables the creation and thorough evaluation of robust support vector machine ensembles for machine learning applications. AB - Today's researchers have access to an unprecedented range of powerful machine learning tools with which to build models for classifying samples according to their metabolomic profile (e.g. separating diseased samples from healthy controls). However, such powerful tools need to be used with caution and the diagnostic performance of models produced by them should be rigorously evaluated if their output is to be believed. This involves considerable processing time, and has hitherto required expert knowledge in machine learning. By adopting a constrained nonlinear simplex optimisation for the tuning of support vector machines (SVMs) we have reduced SVM training times more than tenfold compared to a traditional grid search, allowing us to implement a high performance R package that makes it possible for a typical bench scientist to produce powerful SVM ensemble classifiers within a reasonable timescale, with automated bootstrapped training and rigorous permutation testing. This puts a state-of-the-art open source multivariate classification pipeline into the hands of every metabolomics researcher, allowing them to build robust classification models with realistic performance metrics. PMID- 26617480 TI - The effects of smoking on obesity: evidence from Indonesian panel data. AB - BACKGROUND: It has been known that smoking is negatively related to weight related outcomes. However, it has been difficult to determine whether the relationship is causal, and if so, how strong it is. We attempted to estimate the approximately causal effects of smoking on weight, body mass index (BMI), and obesity. METHODS: The Indonesian Family Life Survey provided a sample of over 9000 men aged 15-55 years-each of them was observed in 1993, 1997, 2000 and 2007. The preferred method was a fixed effects model; that is, we related changes in smoking status or smoking intensity to changes in weight-related outcomes, while controlling for time-varying covariates. We also compared these results to those estimated by ordinary least squares and assessed the importance of controlling for time invariant individual heterogeneity. RESULTS: Although the effects of smoking were precisely estimated in a statistical sense, their size was minuscule: a quitter would gain weight by at most 1 kg, or a smoker would lose weight by the same amount. The results were similar for BMI and obesity. When we did not control for time invariant individual heterogeneity, the size of the relationship was overestimated at least three times. CONCLUSIONS: Smoking exerted little influence on weight, and it was important to control for bias stemming from time invariant individual heterogeneity. PMID- 26617481 TI - Hypoxia Affects Neprilysin Expression Through Caspase Activation and an APP Intracellular Domain-dependent Mechanism. AB - While gene mutations in the amyloid precursor protein (APP) and the presenilins lead to an accumulation of the amyloid beta-peptide (Abeta) in the brain causing neurodegeneration and familial Alzheimer's disease (AD), over 95% of all AD cases are sporadic. Despite the pathologies being indistinguishable, relatively little is known about the mechanisms affecting generation of Abeta in the sporadic cases. Vascular disorders such as ischaemia and stroke are well established risk factors for the development of neurodegenerative diseases and systemic hypoxic episodes have been shown to increase Abeta production and accumulation. We have previously shown that hypoxia causes a significant decrease in the expression of the major Abeta-degrading enzyme neprilysin (NEP) which might deregulate Abeta clearance. Abeta itself is derived from the transmembrane APP along with several other biologically active metabolites including the C-terminal fragment (CTF) termed the APP intracellular domain (AICD), which regulates the expression of NEP and some other genes in neuronal cells. Here we show that in hypoxia there is a significantly increased expression of caspase-3, 8, and 9 in human neuroblastoma NB7 cells, which can degrade AICD. Using chromatin immunoprecipitation we have revealed that there was also a reduction of AICD bound to the NEP promoter region which underlies the decreased expression and activity of the enzyme under hypoxic conditions. Incubation of the cells with a caspase-3 inhibitor Z-DEVD-FMK could rescue the effect of hypoxia on NEP activity protecting the levels of AICD capable of binding the NEP promoter. These data suggest that activation of caspases might play an important role in regulation of NEP levels in the brain under pathological conditions such as hypoxia and ischaemia leading to a deficit of Abeta clearance and increasing the risk of development of AD. PMID- 26617482 TI - Depression-like Behavior Induced by Nesfatin-1 in Rats: Involvement of Increased Immune Activation and Imbalance of Synaptic Vesicle Proteins. AB - Depression is a multicausal disorder and has been associated with metabolism regulation and immuno-inflammatory reaction. The anorectic molecule nesfatin-1 has recently been characterized as a potential mood regulator, but its precise effect on depression and the possible mechanisms remain unknown, especially when given peripherally. In the present study, nesfatin-1 was intraperitoneally injected to the rats and the depression-like behavior and activity of the hypothalamic-pituitary-adrenal (HPA) axis were evaluated. The plasma concentrations of nesfatin-1, interleukin 6 (IL-6), and C-reactive protein (CRP); and the hypothalamic expression levels of nesfatin-1, synapsin I, and synaptotagmin I mRNA were evaluated in nesfatin-1 chronically treated rats. The results showed that both acute and chronic administration of nesfatin-1 increased immobility in the forced swimming test (FST), and resulted in the hyperactivity of HPA axis, as indicated by the increase of plasma corticosterone concentration and hypothalamic expression of corticotropin-releasing hormone (CRH) mRNA. Moreover, after chronic nesfatin-1 administration, the rats exhibited decreased activity and exploratory behavior in the open field test (OFT) and increased mRNA expression of synapsin I and synaptotagmin I in the hypothalamus. Furthermore, chronic administration of nesfatin-1 elevated plasma concentrations of IL-6 and CRP, which were positively correlated with despair behavior, plasma corticosterone level, and the hypothalamic mRNA expression of synapsin I and synaptotagmin I. These results indicated that exogenous nesfatin-1 could induce the immune-inflammatory activation, which might be a central hug linking the depression-like behavior and the imbalanced mRNA expression of synaptic vesicle proteins in the hypothalamus. PMID- 26617483 TI - Nucleation and Dynamics of Golgi-derived Microtubules. AB - Integrity of the Golgi apparatus requires the microtubule (MT) network. A subset of MTs originates at the Golgi itself, which in this case functions as a MT organizing center (MTOC). Golgi-derived MTs serve important roles in post-Golgi trafficking, maintenance of Golgi integrity, cell polarity and motility, as well as cell type-specific functions, including neurite outgrowth/branching. Here, we discuss possible models describing the formation and dynamics of Golgi-derived MTs. How Golgi-derived MTs are formed is not fully understood. A widely discussed model implicates that the critical step of the process is recruitment of molecular factors, which drive MT nucleation (gamma-tubulin ring complex, or gamma-TuRC), to the Golgi membrane via specific scaffolding interactions. Based on recent findings, we propose to introduce an additional level of regulation, whereby MT-binding proteins and/or local tubulin dimer concentration at the Golgi helps to overcome kinetic barriers at the initial nucleation step. According to our model, emerging MTs are subsequently stabilized by Golgi-associated MT stabilizing proteins. We discuss molecular factors potentially involved in all three steps of MT formation. To preserve proper cell functioning, a balance must be maintained between MT subsets at the centrosome and the Golgi. Recent work has shown that certain centrosomal factors are important in maintaining this balance, suggesting a close connection between regulation of centrosomal and Golgi-derived MTs. Finally, we will discuss potential functions of Golgi-derived MTs based on their nucleation site location within a Golgi stack. PMID- 26617484 TI - Neuroinflammation is not a Prerequisite for Diabetes-induced Tau Phosphorylation. AB - Abnormal phosphorylation and aggregation of tau is a key hallmark of Alzheimer's disease (AD). AD is a multifactorial neurodegenerative disorder for which Diabetes Mellitus (DM) is a risk factor. In animal models for DM, the phosphorylation and aggregation of tau is induced or exacerbated, however the underlying mechanism is unknown. In addition to the metabolic dysfunction, DM is characterized by chronic low-grade inflammation. This was reported to be associated with a neuroinflammatory response in the hypothalamus of DM animal models. Neuroinflammation is also implicated in the development and progression of AD. It is unknown whether DM also induces neuroinflammation in brain areas affected in AD, the cortex and hippocampus. Here we investigated whether neuroinflammation could be the mechanistic trigger to induce tau phosphorylation in the brain of DM animals. Two distinct diabetic animal models were used; rats on free-choice high-fat high-sugar (fcHFHS) diet that are insulin resistant and streptozotocin-treated rats that are insulin deficient. The streptozotocin treated animals demonstrated increased tau phosphorylation in the brain as expected, whereas the fcHFHS diet fed animals did not. Remarkably, neither of the diabetic animal models showed reactive microglia or increased GFAP and COX-2 levels in the cortex or hippocampus. From this, we conclude: 1. DM does not induce neuroinflammation in brain regions affected in AD, and 2. Neuroinflammation is not a prerequisite for tau phosphorylation. Neuroinflammation is therefore not the mechanism that explains the close connection between DM and AD. PMID- 26617485 TI - Alpha-synuclein Toxicity in the Early Secretory Pathway: How It Drives Neurodegeneration in Parkinsons Disease. AB - Alpha-synuclein is a predominant player in the pathogenesis of Parkinson's Disease. However, despite extensive study for two decades, its physiological and pathological mechanisms remain poorly understood. Alpha-synuclein forms a perplexing web of interactions with lipids, trafficking machinery, and other regulatory factors. One emerging consensus is that synaptic vesicles are likely the functional site for alpha-synuclein, where it appears to facilitate vesicle docking and fusion. On the other hand, the dysfunctions of alpha-synuclein are more dispersed and numerous; when mutated or over-expressed, alpha-synuclein affects several membrane trafficking and stress pathways, including exocytosis, ER-to-Golgi transport, ER stress, Golgi homeostasis, endocytosis, autophagy, oxidative stress, and others. Here we examine recent developments in alpha synuclein's toxicity in the early secretory pathway placed in the context of emerging themes from other affected pathways to help illuminate its underlying pathogenic mechanisms in neurodegeneration. PMID- 26617486 TI - Alteration of Golgi Structure by Stress: A Link to Neurodegeneration? AB - The Golgi apparatus is well-known for its role as a sorting station in the secretory pathway as well as for its role in regulating post-translational protein modification. Another role for the Golgi is the regulation of cellular signaling by spatially regulating kinases, phosphatases, and GTPases. All these roles make it clear that the Golgi is a central regulator of cellular homeostasis. The response to stress and the initiation of adaptive responses to cope with it are fundamental abilities of all living cells. It was shown previously that the Golgi undergoes structural rearrangements under various stress conditions such as oxidative or osmotic stress. Neurodegenerative diseases are also frequently associated with alterations of Golgi morphology and many stress factors have been described to play an etiopathological role in neurodegeneration. It is however unclear whether the stress-Golgi connection plays a role in neurodegenerative diseases. Using a combination of bioinformatics modeling and literature mining, we will investigate evidence for such a tripartite link and we ask whether stress-induced Golgi arrangements are cause or consequence in neurodegeneration. PMID- 26617488 TI - REST-Governed Gene Expression Profiling in a Neuronal Cell Model Reveals Novel Direct and Indirect Processes of Repression and Up-Regulation. AB - The role of REST changes in neurons, including the rapid decrease of its level during differentiation and its fluctuations during many mature functions and diseases, is well established. However, identification of many thousand possible REST-target genes, mostly based on indirect criteria, and demonstration of their operative dependence on the repressor have been established for only a relatively small fraction. In the present study, starting from our recently published work, we have expanded the identification of REST-dependent genes, investigated in two clones of the PC12 line, a recognized neuronal cell model, spontaneously expressing different levels of REST: very low as in neurons and much higher as in most non-neural cells. The molecular, structural and functional differences of the two PC12 clones were shown to depend largely on their different REST level and the ensuing variable expression of some dependent genes. Comprehensive RNA Seq analyses of the 13,700 genes expressed, validated by parallel RT-PCR and western analyses of mRNAs and encoded proteins, identified in the high-REST clone two groups of almost 900 repressed and up-regulated genes. Repression is often due to direct binding of REST to target genes; up-regulation to indirect mechanism(s) mostly mediated by REST repression of repressive transcription factors. Most, but not all, genes governing neurosecretion, excitability, and receptor channel signaling were repressed in the high REST clone. The genes governing expression of non-channel receptors (G protein-coupled and others), although variably affected, were often up-regulated together with the genes of intracellular kinases, small G proteins, cytoskeleton, cell adhesion, and extracellular matrix proteins. Expression of REST-dependent genes governing functions other than those mentioned so far were also identified. The results obtained by the parallel investigation of the two PC12 clones revealed the complexity of the REST molecular and functional role, deciphering new aspects of its participation in neuronal functions. The new findings could be relevant for further investigation and interpretation of physiological processes typical of neurons. Moreover, they could be employed as tools in the study of neuronal diseases recently shown to depend on REST for their development. PMID- 26617487 TI - Use of Genetically Encoded Calcium Indicators (GECIs) Combined with Advanced Motion Tracking Techniques to Examine the Behavior of Neurons and Glia in the Enteric Nervous System of the Intact Murine Colon. AB - Genetically encoded Ca(2+) indicators (GECIs) have been used extensively in many body systems to detect Ca(2+) transients associated with neuronal activity. Their adoption in enteric neurobiology has been slower, although they offer many advantages in terms of selectivity, signal-to-noise and non-invasiveness. Our aims were to utilize a number of cell-specific promoters to express the Ca(2+) indicator GCaMP3 in different classes of neurons and glia to determine their effectiveness in measuring activity in enteric neural networks during colonic motor behaviors. We bred several GCaMP3 mice: (1) Wnt1-GCaMP3, all enteric neurons and glia; (2) GFAP-GCaMP3, enteric glia; (3) nNOS-GaMP3, enteric nitrergic neurons; and (4) ChAT-GCaMP3, enteric cholinergic neurons. These mice allowed us to study the behavior of the enteric neurons in the intact colon maintained at a physiological temperature, especially during the colonic migrating motor complex (CMMC), using low power Ca(2+) imaging. In this preliminary study, we observed neuronal and glial cell Ca(2+) transients in specific cells in both the myenteric and submucous plexus in all of the transgenic mice variants. The number of cells that could be simultaneously imaged at low power (100-1000 active cells) through the undissected gut required advanced motion tracking and analysis routines. The pattern of Ca(2+) transients in myenteric neurons showed significant differences in response to spontaneous, oral or anal stimulation. Brief anal elongation or mucosal stimulation, which evokes a CMMC, were the most effective stimuli and elicited a powerful synchronized and prolonged burst of Ca(2+) transients in many myenteric neurons, especially when compared with the same neurons during a spontaneous CMMC. In contrast, oral elongation, which normally inhibits CMMCs, appeared to suppress Ca(2+) transients in some of the neurons active during a spontaneous or an anally evoked CMMC. The activity in glial networks appeared to follow neural activity but continued long after neural activity had waned. With these new tools an unprecedented level of detail can be recorded from the enteric nervous system (ENS) with minimal manipulation of tissue. These techniques can be extended in order to better understand the roles of particular enteric neurons and glia during normal and disordered motility. PMID- 26617489 TI - Force Generation by Molecular-Motor-Powered Microtubule Bundles; Implications for Neuronal Polarization and Growth. AB - The heavily cross-linked microtubule (MT) bundles found in neuronal processes play a central role in the initiation, growth and maturation of axons and dendrites; however, a quantitative understanding of their mechanical function is still lacking. We here developed computer simulations to investigate the dynamics of force generation in 1D bundles of MTs that are cross-linked and powered by molecular motors. The motion of filaments and the forces they exert are investigated as a function of the motor type (unipolar or bipolar), MT density and length, applied load, and motor connectivity. We demonstrate that only unipolar motors (e.g., kinesin-1) can provide the driving force for bundle expansion, while bipolar motors (e.g., kinesin-5) oppose it. The force generation capacity of the bundles is shown to depend sharply on the fraction of unipolar motors due to a percolation transition that must occur in the bundle. Scaling laws between bundle length, force, MT length and motor fraction are presented. In addition, we investigate the dynamics of growth in the presence of a constant influx of MTs. Beyond a short equilibration period, the bundles grow linearly in time. In this growth regime, the bundle extends as one mass forward with most filaments sliding with the growth velocity. The growth velocity is shown to be dictated by the inward flux of MTs, to inversely scale with the load and to be independent of the free velocity of the motors. These findings provide important molecular-level insights into the mechanical function of the MT cytoskeleton in normal axon growth and regeneration after injury. PMID- 26617491 TI - Multiple Independent Oscillatory Networks in the Degenerating Retina. AB - During neuronal degenerative diseases, microcircuits undergo severe structural alterations, leading to remodeling of synaptic connectivity. This can be particularly well observed in the retina, where photoreceptor degeneration triggers rewiring of connections in the retina's first synaptic layer (e.g., Strettoi et al., 2003; Haq et al., 2014), while the synaptic organization of inner retinal circuits appears to be little affected (O'Brien et al., 2014; Figures 1A,B). Remodeling of (outer) retinal circuits and diminishing light driven activity due to the loss of functional photoreceptors lead to spontaneous activity that can be observed at different retinal levels (Figure 1C), including the retinal ganglion cells, which display rhythmic spiking activity in the degenerative retina (Margolis et al., 2008; Stasheff, 2008; Menzler and Zeck, 2011; Stasheff et al., 2011). Two networks have been suggested to drive the oscillatory activity in the degenerating retina: a network of remnant cone photoreceptors, rod bipolar cells (RBCs) and horizontal cells in the outer retina (Haq et al., 2014), and the AII amacrine cell-cone bipolar cell network in the inner retina (Borowska et al., 2011). Notably, spontaneous rhythmic activity in the inner retinal network can be triggered in the absence of synaptic remodeling in the outer retina, for example, in the healthy retina after photo-bleaching (Menzler et al., 2014). In addition, the two networks show remarkable differences in their dominant oscillation frequency range as well as in the types and numbers of involved cells (Menzler and Zeck, 2011; Haq et al., 2014). Taken together this suggests that the two networks are self-sustained and can be active independently from each other. However, it is not known if and how they modulate each other. In this mini review, we will discuss: (i) commonalities and differences between these two oscillatory networks as well as possible interaction pathways; (ii) how multiple self-sustained networks may hamper visual restoration strategies employing, for example, microelectronic implants, optogenetics or stem cells, and briefly; and (iii) how the finding of diverse (independent) networks in the degenerative retina may relate to other parts of the neurodegenerative central nervous system. PMID- 26617490 TI - Synaptic Impairment in Layer 1 of the Prefrontal Cortex Induced by Repeated Stress During Adolescence is Reversed in Adulthood. AB - Chronic stress is a risk factor for the development of psychiatric disorders, some of which involve dysfunction of the prefrontal cortex (PFC). There is a higher prevalence of these chronic stress-related psychiatric disorders during adolescence, when the PFC has not yet fully matured. In the present work we studied the effect of repeated stress during adolescence on synaptic function in the PFC in adolescence and adulthood. To this end, adolescent Sprague-Dawley rats were subjected to seven consecutive days of restraint stress. Afterward, both synaptic transmission and short- and long-term synaptic plasticity were evaluated in layer 1 of medial-PFC (mPFC) slices from adolescent and adult rats. We found that repeated stress significantly reduced the amplitude of evoked field excitatory post-synaptic potential (fEPSP) in the mPFC. Isolation of excitatory transmission reveled that lower-amplitude fEPSPs were associated with a reduction in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor mediated transmission. We also found that repeated stress significantly decreased long-term depression (LTD). Interestingly, AMPA/kainate receptor-mediated transmission and LTD were recovered in adult animals that experienced a three week stress-free recovery period. The data indicates that the changes in synaptic transmission and plasticity in the mPFC induced by repeated stress during adolescence are reversed in adulthood after a stress-free period. PMID- 26617492 TI - Chronic Intermittent Ethanol Regulates Hippocampal GABA(A) Receptor Delta Subunit Gene Expression. AB - Chronic ethanol consumption causes structural and functional reorganization in the hippocampus and induces alterations in the gene expression of gamma aminobutyric acid type A receptors (GABAARs). Distinct forced intermittent exposure models have been used previously to investigate changes in GABAAR expression, with contrasting results. Here, we used repeated cycles of a Chronic Intermittent Ethanol paradigm to examine the relationship between voluntary, dependence-associated ethanol consumption, and GABAAR gene expression in mouse hippocampus. Adult male C57BL/6J mice were exposed to four 16-h ethanol vapor (or air) cycles in inhalation chambers alternated with limited-access two-bottle choice between ethanol (15%) and water consumption. The mice exposed to ethanol vapor showed significant increases in ethanol consumption compared to their air matched controls. GABAAR alpha4 and delta subunit gene expression were measured by qRT-PCR at different stages. There were significant changes in GABAAR delta subunit transcript levels at different time points in ethanol-vapor exposed mice, while the alpha4 subunit levels remained unchanged. Correlated concurrent blood ethanol concentrations suggested that GABAAR delta subunit mRNA levels fluctuate depending on ethanol intoxication, dependence, and withdrawal state. Using a vapor-based Chronic Intermittent Ethanol procedure with combined two-bottle choice consumption, we corroborated previous evidences showing that discontinuous ethanol exposure affects GABAAR delta subunit expression but we did not observe changes in alpha4 subunit. These findings indicate that hippocampal GABAAR delta subunit expression changes transiently over the course of a Chronic Intermittent Ethanol paradigm associated with voluntary intake, in response to ethanol mediated disturbance of GABAergic neurotransmission. PMID- 26617494 TI - Editorial: Quantitative Analysis of Neuroanatomy. PMID- 26617495 TI - Corrigendum: (1) Some OFF Bipolar Cell Types Make Contact With Both Rods and Cones in Macaque and Mouse Retinas; (2) OFF Bipolar Cells in Macaque Retina: Type specific Connectivity in the Outer and Inner Synaptic Layers. AB - [This corrects the article on p. 105 in vol. 8, PMID: 25309346.][This corrects the article on p. 122 in vol. 9, PMID: 26500507.]. PMID- 26617493 TI - Control of Sleep by Dopaminergic Inputs to the Drosophila Mushroom Body. AB - The Drosophila mushroom body (MB) is an associative learning network that is important for the control of sleep. We have recently identified particular intrinsic MB Kenyon cell (KC) classes that regulate sleep through synaptic activation of particular MB output neurons (MBONs) whose axons convey sleep control signals out of the MB to downstream target regions. Specifically, we found that sleep-promoting KCs increase sleep by preferentially activating cholinergic sleep-promoting MBONs, while wake-promoting KCs decrease sleep by preferentially activating glutamatergic wake-promoting MBONs. Here we use a combination of genetic and physiological approaches to identify wake-promoting dopaminergic neurons (DANs) that innervate the MB, and show that they activate wake-promoting MBONs. These studies reveal a dopaminergic sleep control mechanism that likely operates by modulation of KC-MBON microcircuits. PMID- 26617496 TI - Philosophy of the Spike: Rate-Based vs. Spike-Based Theories of the Brain. AB - Does the brain use a firing rate code or a spike timing code? Considering this controversial question from an epistemological perspective, I argue that progress has been hampered by its problematic phrasing. It takes the perspective of an external observer looking at whether those two observables vary with stimuli, and thereby misses the relevant question: which one has a causal role in neural activity? When rephrased in a more meaningful way, the rate-based view appears as an ad hoc methodological postulate, one that is practical but with virtually no empirical or theoretical support. PMID- 26617497 TI - Two is More Than One: How to Combine Brain Stimulation Rehabilitative Training for Functional Recovery? AB - A number of studies have shown that non-invasive brain stimulation has an additional effect in combination with rehabilitative therapy to enhance functional recovery than either therapy alone. The combination enhances use dependent plasticity induced by repetitive training. The neurophysiological mechanism of the effects of this combination is based on associative plasticity. However, these effects were not reported in all cases. We propose a list of possible strategies to achieve an effective association between rehabilitative training with brain stimulation for plasticity: (1) control of temporal aspect between stimulation and task execution; (2) the use of a shaped task for the combination; (3) the appropriate stimulation of neuronal circuits where use dependent plastic changes occur; and (4) phase synchronization between rhythmically patterned brain stimulation and task-related patterned activities of neurons. To better utilize brain stimulation in neuro-rehabilitation, it is important to develop more effective techniques to combine them. PMID- 26617498 TI - Editorial: The Vestibular System in Cognitive and Memory Processes in Mammalians. PMID- 26617499 TI - Infusion of D1 Dopamine Receptor Agonist into Medial Frontal Cortex Disrupts Neural Correlates of Interval Timing. AB - Medial frontal cortical (MFC) dopamine is essential for the organization of behavior in time. Our prior work indicates that blocking D1 dopamine receptors (D1DR) attenuates temporal processing and low-frequency oscillations by MFC neuronal networks. Here we investigate the effects of focal infusion of the D1DR agonist SKF82958 into MFC during interval timing. MFC D1DR agonist infusion impaired interval timing performance without changing overall firing rates of MFC neurons. MFC ramping patterns of neuronal activity that reflect temporal processing were attenuated following infusion of MFC D1DR agonist. MFC D1DR agonist infusion also altered MFC field potentials by enhancing delta activity between 1 and 4 Hz and attenuating alpha activity between 8 and 15 Hz. These data support the idea that the influence of D1-dopamine signals on frontal neuronal activity adheres to a U-shaped curve, and that cognition requires optimal levels of dopamine in frontal cortex. PMID- 26617501 TI - Conditional Reduction of Adult Born Doublecortin-Positive Neurons Reversibly Impairs Selective Behaviors. AB - Adult neurogenesis occurs in the adult mammalian subventricular zone (SVZ) along the walls of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus. While a burgeoning body of research implicates adult neurogenesis in olfactory bulb (OB)- and hippocampal-related behaviors, the precise function continues to elude. To further assess the behavioral importance of adult neurogenesis, we herein generated a novel inducible transgenic mouse model of adult neurogenesis reduction where mice with CreER(T2) under doublecortin (DCX) promoter control were crossed with mice where diphtheria toxin A (DTA) was driven by the Rosa26 promoter. Activation of DTA, through the administration of tamoxifen (TAM), results in a specific reduction of DCX+ immature neurons in both the hippocampal dentate gyrus and OB. We show that the decrease of DCX+ cells causes impaired social discrimination ability in both young adult (from 3 months) and middle aged (from 10 months) mice. Furthermore, these animals showed an age-independent altered coping behavior in the Forced Swim Test without clear changes in anxiety-related behavior. Notably, these behavior changes were reversible on repopulating the neurogenic zones with DCX+ cells on cessation of the TAM treatment, demonstrating the specificity of this effect. Overall, these results support the notion that adult neurogenesis plays a role in social memory and in stress coping but not necessarily in anxiety-related behavior. PMID- 26617503 TI - Editorial: Further Understanding of Serotonin 7 Receptors' Neuro-psycho pharmacology. PMID- 26617502 TI - Environmental Enrichment Increases Glucocorticoid Receptors and Decreases GluA2 and Protein Kinase M Zeta (PKMzeta) Trafficking During Chronic Stress: A Protective Mechanism? AB - Environmental enrichment (EE) housing paradigms have long been shown beneficial for brain function involving neural growth and activity, learning and memory capacity, and for developing stress resiliency. The expression of the alpha-amino 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA2, which is important for synaptic plasticity and memory, is increased with corticosterone (CORT), undermining synaptic plasticity and memory. Thus, we determined the effect of EE and stress on modulating GluA2 expression in Sprague-Dawley male rats. Several markers were evaluated which include: plasma CORT, the glucocorticoid receptor (GR), GluA2, and the atypical protein kinase M zeta (PKMzeta). For 1 week standard-(ST) or EE-housed animals were treated with one of the following four conditions: (1) no stress; (2) acute stress (forced swim test, FST; on day 7); (3) chronic restraint stress (6 h/day for 7 days); and (4) chronic + acute stress (restraint stress 6 h/day for 7 days + FST on day 7). Hippocampi were collected on day 7. Our results show that EE animals had reduced time immobile on the FST across all conditions. After chronic + acute stress EE animals showed increased GR levels with no change in synaptic GluA2/PKMzeta. ST housed animals showed the reverse pattern with decreased GR levels and a significant increase in synaptic GluA2/PKMzeta. These results suggest that EE produces an adaptive response to chronic stress allowing for increased GR levels, which lowers neuronal excitability reducing GluA2/PKMzeta trafficking. We discuss this EE adaptive response to stress as a potential underlying mechanism that is protective for retaining synaptic plasticity and memory function. PMID- 26617500 TI - The Role of the Medial Prefrontal Cortex in the Conditioning and Extinction of Fear. AB - Once acquired, a fearful memory can persist for a lifetime. Although learned fear can be extinguished, extinction memories are fragile. The resilience of fear memories to extinction may contribute to the maintenance of disorders of fear and anxiety, including post-traumatic stress disorder (PTSD). As such, considerable effort has been placed on understanding the neural circuitry underlying the acquisition, expression, and extinction of emotional memories in rodent models as well as in humans. A triad of brain regions, including the prefrontal cortex, hippocampus, and amygdala, form an essential brain circuit involved in fear conditioning and extinction. Within this circuit, the prefrontal cortex is thought to exert top-down control over subcortical structures to regulate appropriate behavioral responses. Importantly, a division of labor has been proposed in which the prelimbic (PL) and infralimbic (IL) subdivisions of the medial prefrontal cortex (mPFC) regulate the expression and suppression of fear in rodents, respectively. Here, we critically review the anatomical and physiological evidence that has led to this proposed dichotomy of function within mPFC. We propose that under some conditions, the PL and IL act in concert, exhibiting similar patterns of neural activity in response to aversive conditioned stimuli and during the expression or inhibition of conditioned fear. This may stem from common synaptic inputs, parallel downstream outputs, or cortico-cortical interactions. Despite this functional covariation, these mPFC subdivisions may still be coding for largely opposing behavioral outcomes, with PL biased towards fear expression and IL towards suppression. PMID- 26617504 TI - Response: Commentary: Chronic SSRI Stimulation of Astrocytic 5-HT2B Receptors Change Multiple Gene Expressions/Editings and Metabolism of Glutamate, Glucose and Glycogen: A Potential Paradigm Shift. PMID- 26617505 TI - The Effects of Repeated Testing, Simulated Malingering, and Traumatic Brain Injury on High-Precision Measures of Simple Visual Reaction Time. AB - Simple reaction time (SRT), the latency to respond to a stimulus, has been widely used as a basic measure of processing speed. In the current experiments, we examined clinically-relevant properties of a new SRT test that presents visual stimuli to the left or right hemifield at varying stimulus onset asynchronies (SOAs). Experiment 1 examined test-retest reliability in 48 participants who underwent three test sessions at weekly intervals. In the first test, log transformed (log-SRT) z-scores, corrected for the influence of age and computer use, were well predicted by regression functions derived from a normative population of 189 control participants. Test-retest reliability of log-SRT z scores was measured with an intraclass correlation coefficient (ICC = 0.83) and equaled or exceeded those of other SRT tests and other widely used tests of processing speed that are administered manually. No significant learning effects were observed across test sessions. Experiment 2 investigated the same participants when instructed to malinger during a fourth testing session: 94% showed abnormal log-SRT z-scores, with 83% producing log-SRT z-scores exceeding a cutoff of 3.0, a degree of abnormality never seen in full-effort conditions. Thus, a log-SRT z-score cutoff of 3.0 had a sensitivity (83%) and specificity (100%) that equaled or exceeded that of existing symptom validity tests. We argue that even expert malingerers, fully informed of the malingering-detection metric, would be unable to successfully feign impairments on the SRT test because of the precise control of SRT latencies that would be required. Experiment 3 investigated 26 patients with traumatic brain injury (TBI) tested more than 1 year post-injury. The 22 patients with mild TBI showed insignificantly faster SRTs than controls, but a small group of four patients with severe TBI showed slowed SRTs. Simple visual reaction time is a reliable measure of processing speed that is sensitive to the effects of malingering and TBI. PMID- 26617506 TI - On the Role of Mentalizing Processes in Aesthetic Appreciation: An ERP Study. AB - We used event-related brain potentials to explore the impact of mental perspective taking on processes of aesthetic appreciation of visual art. Participants (non-experts) were first presented with information about the life and attitudes of a fictitious artist. Subsequently, they were cued trial-wise to make an aesthetic judgment regarding an image depicting a piece of abstract art either from their own perspective or from the imagined perspective of the fictitious artist [i.e., theory of mind (ToM) condition]. Positive self referential judgments were made more quickly and negative self-referential judgments were made more slowly than the corresponding judgments from the imagined perspective. Event-related potential analyses revealed significant differences between the two tasks both within the preparation period (i.e., during the cue-stimulus interval) and within the stimulus presentation period. For the ToM condition we observed a relative centro-parietal negativity during the preparation period (700-330 ms preceding picture onset) and a relative centro parietal positivity during the stimulus presentation period (700-1100 ms after stimulus onset). These findings suggest that different subprocesses are involved in aesthetic appreciation and judgment of visual abstract art from one's own vs. from another person's perspective. PMID- 26617507 TI - Cognitive Control of Episodic Memory in Schizophrenia: Differential Role of Dorsolateral and Ventrolateral Prefrontal Cortex. AB - BACKGROUND: Dorsal (DLPFC) and ventral (VLPFC) subregions in lateral prefrontal cortex play distinct roles in episodic memory, and both are implicated in schizophrenia. We test the hypothesis that schizophrenia differentially impairs DLPFC versus VLPFC control of episodic encoding. METHODS: Cognitive control was manipulated by requiring participants to encode targets and avoid encoding non targets based upon stimulus properties of test stimuli. The more automatic encoding response (target versus non-target) was predicted to engage VLPFC in both groups. Conversely, having to overcome the prepotent encoding response (non targets versus targets) was predicted to produce greater DLPFC activation in controls than in patients. Encoding occurred during event-related fMRI in a sample of 21 individuals with schizophrenia and 30 healthy participants. Scanning was followed by recognition testing outside the scanner. RESULTS: Patients were less successful differentially remembering target versus non-target stimuli, and retrieval difficulties correlated with more severe disorganized symptoms. As predicted, the target versus non-target contrast activated the VLPFC and correlated with retrieval success in both groups. Conversely, the non-target versus target contrast produced greater DLPFC activation in controls than in patients, and DLPFC activation correlated with performance only in controls. CONCLUSION: Individuals with schizophrenia can successfully engage the VLPFC to provide control over semantic encoding of individual items, but are specifically impaired at engaging the DLPFC to main context for task-appropriate encoding and thereby generate improved memory for target versus non-target items. This extends previous cognitive control models based on response selection tasks to the memory domain. PMID- 26617509 TI - Editorial: Turning the Mind's Eye Inward: The Interplay Between Selective Attention and Working Memory. PMID- 26617508 TI - Apathy in Frontotemporal Degeneration: Neuroanatomical Evidence of Impaired Goal directed Behavior. AB - BACKGROUND: Apathy, the major manifestation of impaired goal-directed behavior (GDB), is the most common neuropsychiatric syndrome associated with behavioral variant frontotemporal degeneration (bvFTD). The behavioral and biological mechanisms of apathy, however, are not well understood. We hypothesized that GDB has multiple components-including at least initiation, planning and motivation and that GDB is supported by a network of multiple frontal brain regions. In this study, we examined this hypothesis by evaluating the selective breakdown of GDB in bvFTD, and relating these deficits to gray matter (GM) atrophy and white matter (WM) integrity. METHODS: Eighteen apathetic bvFTD participants and 17 healthy controls completed the Philadelphia Apathy Computerized Test (PACT). This test quantifies each of three components of GDB hypothesized to contribute to apathy. We then used regression analyses to relate PACT scores to GM atrophy and reduced white matter (WM) fractional anisotropy (FA) in bvFTD. RESULTS: Compared to controls, bvFTD participants demonstrated significant impairments in each of the three hypothesized components of GDB that contribute to apathy. Regression analyses related each component to disease in specific GM structures and associated WM tracts. Poor initiation thus was related to GM atrophy in anterior cingulate and reduced FA in the cingulum. Planning impairment was related to GM atrophy in dorsolateral prefrontal cortex and reduced FA in superior longitudinal fasciculus. Poor motivation was related to GM atrophy in orbitofrontal cortex (OFC) and reduced FA in uncinate fasciculus (UNC). CONCLUSIONS: bvFTD patients have difficulty with initiation, planning and motivation components of GDB. These findings are consistent with the hypotheses that GDB encompasses at least three processes, that these are supported by a large-scale neural network within specific portions of the frontal lobe, and that degradation of any one of these prefrontal regions in bvFTD may contribute to apathy. PMID- 26617510 TI - Toward a Wireless Open Source Instrument: Functional Near-infrared Spectroscopy in Mobile Neuroergonomics and BCI Applications. AB - Brain-Computer Interfaces (BCIs) and neuroergonomics research have high requirements regarding robustness and mobility. Additionally, fast applicability and customization are desired. Functional Near-Infrared Spectroscopy (fNIRS) is an increasingly established technology with a potential to satisfy these conditions. EEG acquisition technology, currently one of the main modalities used for mobile brain activity assessment, is widely spread and open for access and thus easily customizable. fNIRS technology on the other hand has either to be bought as a predefined commercial solution or developed from scratch using published literature. To help reducing time and effort of future custom designs for research purposes, we present our approach toward an open source multichannel stand-alone fNIRS instrument for mobile NIRS-based neuroimaging, neuroergonomics and BCI/BMI applications. The instrument is low-cost, miniaturized, wireless and modular and openly documented on www.opennirs.org. It provides features such as scalable channel number, configurable regulated light intensities, programmable gain and lock-in amplification. In this paper, the system concept, hardware, software and mechanical implementation of the lightweight stand-alone instrument are presented and the evaluation and verification results of the instrument's hardware and physiological fNIRS functionality are described. Its capability to measure brain activity is demonstrated by qualitative signal assessments and a quantitative mental arithmetic based BCI study with 12 subjects. PMID- 26617511 TI - The Eye is Listening: Music-Induced Arousal and Individual Differences Predict Pupillary Responses. AB - Pupillary responses are a well-known indicator of emotional arousal but have not yet been systematically investigated in response to music. Here, we measured pupillary dilations evoked by short musical excerpts normalized for intensity and selected for their stylistic uniformity. Thirty participants (15 females) provided subjective ratings of music-induced felt arousal, tension, pleasantness, and familiarity for 80 classical music excerpts. The pupillary responses evoked by these excerpts were measured in another thirty participants (15 females). We probed the role of listener-specific characteristics such as mood, stress reactivity, self-reported role of music in life, liking for the selected excerpts, as well as of subjective responses to music, in pupillary responses. Linear mixed model analyses showed that a greater role of music in life was associated with larger dilations, and that larger dilations were also predicted for excerpts rated as more arousing or tense. However, an interaction between arousal and liking for the excerpts suggested that pupillary responses were modulated less strongly by arousal when the excerpts were particularly liked. An analogous interaction was observed between tension and liking. Additionally, males exhibited larger dilations than females. Overall, these findings suggest a complex interplay between bottom-up and top-down influences on pupillary responses to music. PMID- 26617512 TI - Models of Metaplasticity: A Review of Concepts. AB - Part of hippocampal and cortical plasticity is characterized by synaptic modifications that depend on the joint activity of the pre- and post-synaptic neurons. To which extent those changes are determined by the exact timing and the average firing rates is still a matter of debate; this may vary from brain area to brain area, as well as across neuron types. However, it has been robustly observed both in vitro and in vivo that plasticity itself slowly adapts as a function of the dynamical context, a phenomena commonly referred to as metaplasticity. An alternative concept considers the regulation of groups of synapses with an objective at the neuronal level, for example, maintaining a given average firing rate. In that case, the change in the strength of a particular synapse of the group (e.g., due to Hebbian learning) affects others' strengths, which has been coined as heterosynaptic plasticity. Classically, Hebbian synaptic plasticity is paired in neuron network models with such mechanisms in order to stabilize the activity and/or the weight structure. Here, we present an oriented review that brings together various concepts from heterosynaptic plasticity to metaplasticity, and show how they interact with Hebbian-type learning. We focus on approaches that are nowadays used to incorporate those mechanisms to state-of-the-art models of spiking plasticity inspired by experimental observations in the hippocampus and cortex. Making the point that metaplasticity is an ubiquitous mechanism acting on top of classical Hebbian learning and promoting the stability of neural function over multiple timescales, we stress the need for incorporating it as a key element in the framework of plasticity models. Bridging theoretical and experimental results suggests a more functional role for metaplasticity mechanisms than simply stabilizing neural activity. PMID- 26617513 TI - Mechanical Stimulation (Pulsed Electromagnetic Fields "PEMF" and Extracorporeal Shock Wave Therapy "ESWT") and Tendon Regeneration: A Possible Alternative. AB - The pathogenesis of tendon degeneration and tendinopathy is still partially unclear. However, an active role of metalloproteinases (MMP), growth factors, such as vascular endothelial growth factor (VEGF) and a crucial role of inflammatory elements and cytokines was demonstrated. Mechanical stimulation may play a role in regulation of inflammation. In vitro studies demonstrated that both pulsed electromagnetic fields (PEMF) and extracorporeal shock wave therapy (ESWT) increased the expression of pro-inflammatory cytokine such as interleukin (IL-6 and IL-10). Moreover, ESWT increases the expression of growth factors, such as transforming growth factor beta(TGF-beta), (VEGF), and insulin-like growth factor 1 (IGF1), as well as the synthesis of collagen I fibers. These pre clinical results, in association with several clinical studies, suggest a potential effectiveness of ESWT for tendinopathy treatment. Recently PEMF gained popularity as adjuvant for fracture healing and bone regeneration. Similarly to ESWT, the mechanical stimulation obtained using PEMFs may play a role for treatment of tendinopathy and for tendon regeneration, increasing in vitro TGF beta production, as well as scleraxis and collagen I gene expression. In this manuscript the rational of mechanical stimulations and the clinical studies on the efficacy of extracorporeal shock wave (ESW) and PEMF will be discussed. However, no clear evidence of a clinical value of ESW and PEMF has been found in literature with regards to the treatment of tendinopathy in human, so further clinical trials are needed to confirm the promising hypotheses concerning the effectiveness of ESWT and PEMF mechanical stimulation. PMID- 26617514 TI - Early Shifts of Brain Metabolism by Caloric Restriction Preserve White Matter Integrity and Long-Term Memory in Aging Mice. AB - Preservation of brain integrity with age is highly associated with lifespan determination. Caloric restriction (CR) has been shown to increase longevity and healthspan in various species; however, its effects on preserving living brain functions in aging remain largely unexplored. In the study, we used multimodal, non-invasive neuroimaging (PET/MRI/MRS) to determine in vivo brain glucose metabolism, energy metabolites, and white matter structural integrity in young and old mice fed with either control or 40% CR diet. In addition, we determined the animals' memory and learning ability with behavioral assessments. Blood glucose, blood ketone bodies, and body weight were also measured. We found distinct patterns between normal aging and CR aging on brain functions - normal aging showed reductions in brain glucose metabolism, white matter integrity, and long-term memory, resembling human brain aging. CR aging, in contrast, displayed an early shift from glucose to ketone bodies metabolism, which was associated with preservations of brain energy production, white matter integrity, and long term memory in aging mice. Among all the mice, we found a positive correlation between blood glucose level and body weight, but an inverse association between blood glucose level and lifespan. Our findings suggest that CR could slow down brain aging, in part due to the early shift of energy metabolism caused by lower caloric intake, and we were able to identify the age-dependent effects of CR non invasively using neuroimaging. These results provide a rationale for CR-induced sustenance of brain health with extended longevity. PMID- 26617516 TI - Study of GABA in Healthy Volunteers: Pharmacokinetics and Pharmacodynamics. AB - Preclinical studies show that GABA exerts anti-diabetic effects in rodent models of type 1 diabetes. Because little is known about its absorption and effects in humans, we investigated the pharmacokinetics and pharmacodynamics of GABA in healthy volunteers. Twelve subjects were subjected to an open-labeled, three period trial involving sequential oral administration of placebo, 2 g GABA once, and 2 g GABA three times/day for 7 days, with a 7-day washout between each period. GABA was rapidly absorbed (Tmax: 0.5 ~ 1 h) with the half-life (t1/2) of 5 h. No accumulation was observed after repeated oral GABA administration for 7 days. Remarkably, GABA significantly increased circulating insulin levels in the subjects under either fasting (1.6-fold, single dose; 2.0-fold, repeated dose; p < 0.01) or fed conditions (1.4-fold, single dose; 1.6-fold, repeated dose; p < 0.01). GABA also increased glucagon levels only under fasting conditions (1.3 fold, single dose, p < 0.05; 1.5-fold, repeated dose, p < 0.01). However, there were no significant differences in the insulin-to-glucagon ratio and no significant change in glucose levels in these healthy subjects during the study period. Importantly, GABA significantly decreased glycated albumin levels in the repeated dosing period. Subjects with repeated dosing showed an elevated incidence of minor adverse events in comparison to placebo or the single dosing period, most notably transient discomforts such as dizziness and sore throat. However, there were no serious adverse events observed throughout the study. Our data show that GABA is rapidly absorbed and tolerated in human beings; its endocrine effects, exemplified by increasing islet hormonal secretion, suggest potential therapeutic benefits for diabetes. PMID- 26617515 TI - Advancing Cardiovascular, Neurovascular, and Renal Magnetic Resonance Imaging in Small Rodents Using Cryogenic Radiofrequency Coil Technology. AB - Research in pathologies of the brain, heart and kidney have gained immensely from the plethora of studies that have helped shape new methods in magnetic resonance (MR) for characterizing preclinical disease models. Methodical probing into preclinical animal models by MR is invaluable since it allows a careful interpretation and extrapolation of data derived from these models to human disease. In this review we will focus on the applications of cryogenic radiofrequency (RF) coils in small animal MR as a means of boosting image quality (e.g., by supporting MR microscopy) and making data acquisition more efficient (e.g., by reducing measuring time); both being important constituents for thorough investigational studies on animal models of disease. This review attempts to make the (bio)medical imaging, molecular medicine, and pharmaceutical communities aware of this productive ferment and its outstanding significance for anatomical and functional MR in small rodents. The goal is to inspire a more intense interdisciplinary collaboration across the fields to further advance and progress non-invasive MR methods that ultimately support thorough (patho)physiological characterization of animal disease models. In this review, current and potential future applications for the RF coil technology in cardiovascular, neurovascular, and renal disease will be discussed. PMID- 26617517 TI - Apolipoprotein A-I and Cancer. AB - High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I), the predominant protein in plasma HDL, have long been the focus of intense studies in the field of atherosclerosis and cardiovascular disease. ApoA-I, in large part, is responsible for HDL assembly and its main atheroprotective function, that of shuttling excess cholesterol from peripheral tissues to the liver for excretion (reverse cholesterol transport). Recently, a protective role for HDL in cancer was suggested from several large clinical studies where an inverse relationship between plasma HDL-cholesterol (HDL-C) levels and risk of developing cancer was noted. This notion has now been tested and found to be supported in mouse tumor studies, where increasing levels of apoA-I/HDL were discovered to protect against tumor development and provision of human apoA-I was therapeutic against established tumors. This mini-review discusses the emerging role of apoA-I in tumor biology and its potential as cancer therapeutic. PMID- 26617518 TI - The Spatiotemporal Regulation of cAMP Signaling in Blood Platelets-Old Friends and New Players. AB - Atherothrombosis, the pathology underlying numerous cardiovascular diseases, is a major cause of death globally. Hyperactive blood platelets play a key role in the atherothrombotic process through the release of inflammatory mediators and formation of thrombi. In healthy blood vessels, excessive platelet activation is restricted by endothelial-derived prostacyclin (PGI2) through cyclic adenosine-5' monophosphate (cAMP) and protein kinase A (PKA)-dependent mechanisms. Elevation in intracellular cAMP is associated with the control of a number of distinct platelet functions including actin polymerisation, granule secretion, calcium mobilization and integrin activation. Unfortunately, in atherosclerotic disease the protective effects of cAMP are compromised, which may contribute to pathological thrombosis. The cAMP signaling network in platelets is highly complex with the presence of multiple isoforms of adenylyl cyclase (AC), PKA, and phosphodiesterases (PDEs). However, a precise understanding of the relationship between specific AC, PKA, and PDE isoforms, and how individual signaling substrates are targeted to control distinct platelet functions is still lacking. In other cells types, compartmentalisation of cAMP signaling has emerged as a key mechanism to allow precise control of specific cell functions. A-kinase anchoring proteins (AKAPs) play an important role in this spatiotemporal regulation of cAMP signaling networks. Evidence of AKAP-mediated compartmentalisation of cAMP signaling in blood platelets has begun to emerge and is providing new insights into the regulation of platelet function. Dissecting the mechanisms that allow cAMP to control excessive platelet activity without preventing effective haemostasis may unleash the possibility of therapeutic targeting of the pathway to control unwanted platelet activity. PMID- 26617519 TI - Cytotoxicity of the Sesquiterpene Lactones Neoambrosin and Damsin from Ambrosia maritima Against Multidrug-Resistant Cancer Cells. AB - Multidrug resistance is a prevailing phenomenon leading to chemotherapy treatment failure in cancer patients. In the current study two known cytotoxic pseudoguaianolide sesquiterpene lactones; neoambrosin (1) and damsin (2) that circumvent MDR were identified. The two cytotoxic compounds were isolated using column chromatography, characterized using 1D and 2D NMR, MS, and compared with literature values. The isolated compounds were investigated for their cytotoxic potential using resazurin assays and thereafter confirmed with immunoblotting and in silico studies. MDR cells overexpressing ABC transporters (P-glycoprotein, BCRP, ABCB5) did not confer cross-resistance toward (1) and (2), indicating that these compounds are not appropriate substrates for any of the three ABC transporters analyzed. Resistance mechanisms investigated also included; the loss of the functions of the TP53 and the mutated EGFR. The HCT116 p53(-/-) cells were sensitive to 1 but resistant to 2. It was interesting to note that resistant cells transfected with oncogenic DeltaEGFR exhibited hypersensitivity CS toward (1) and (2) (degrees of resistances were 0.18 and 0.15 for (1) and (2), respectively). Immunoblotting and in silico analyses revealed that 1 and 2 silenced c-Src kinase activity. It was hypothesized that inhibition of c-Src kinase activity may explain CS in EGFR-transfected cells. In conclusion, the significant cytotoxicity of 1 and 2 against different drug-resistant tumor cell lines indicate that they may be promising candidates to treat refractory tumors. PMID- 26617520 TI - Microglial Inhibitory Mechanism of Coenzyme Q10 Against Abeta (1-42) Induced Cognitive Dysfunctions: Possible Behavioral, Biochemical, Cellular, and Histopathological Alterations. AB - RATIONALE: Alzheimer's disease (AD) is a debilitating disease with complex pathophysiology. Amyloid beta (Abeta) (1-42) is a reliable model of AD that recapitulates many aspects of human AD. OBJECTIVE: The intent of the present study was to investigate the neuroprotective potential of Coenzyme Q10 (CoQ10) and its modulation by minocycline (microglial inhibitor) against Abeta (1-42) induced cognitive dysfunction in rats. METHOD: Intrahippocampal (i.h.) Abeta (1 42) (1 MUg/MUl; 4MUl/site) were administered followed by drug treatment with galantamine (2 mg/kg), CoQ10 (20 and 40 mg/kg), minocycline (50 and 100 mg/kg) and their combinations for a period of 21 days. Various neurobehavioral parameters followed by biochemical, acetylcholinesterase (AChE) level, proinflammatory markers (TNF-alpha), mitochondrial respiratory enzyme complexes (I-IV) and histopathological examinations were assessed. RESULTS: Abeta (1-42) administration significantly impaired cognitive performance in Morris water maze (MWM) performance test, causes oxidative stress, raised AChE level, caused neuroinflammation, mitochondrial dysfunction and histopathological alterations as compared to sham treatment. Treatment with CoQ10 (20 and 40 mg/kg) and minocycline (50 and 100 mg/kg) alone for 21 days significantly improved cognitive performance as evidenced by reduced transfer latency and increased time spent in target quadrant (TSTQ), reduced AChE activity, oxidative damage (reduced LPO, nitrite level and restored SOD, catalase and GHS levels), TNF-alpha level, restored mitochondrial respiratory enzyme complex (I, II, III, IV) activities and histopathological alterations as compared to Abeta (1-42) treated animals. Further, combinations of minocycline (50 and 100 mg/kg) with CoQ10 (20 and 40 mg/kg) significantly modulates the protective effect of CoQ10 dose dependently as compared to their effect alone. CONCLUSION: The present study suggests that the neuroprotective effect of CoQ10 could be due to its microglia inhibitory mechanism along with its mitochondrial restoring and anti-oxidant properties. PMID- 26617521 TI - Luminal Conversion and Immunoregulation by Probiotics. AB - Beneficial microbes are responsible for the synthesis of nutrients and metabolites that are likely important for the maintenance of mammalian health. Many nutrients and metabolites derived from the gut microbiota by luminal conversion have been implicated in the development, homeostasis and function of innate and adaptive immunity. These factors clearly suggest that intestinal microbiota may influence host immunity via microbial metabolite-dependent mechanisms. We describe how intestinal microbes including probiotics generate microbial metabolites that modulate mucosal and systemic immunity. PMID- 26617523 TI - The Matricellular Receptor LRP1 Forms an Interface for Signaling and Endocytosis in Modulation of the Extracellular Tumor Environment. AB - The membrane protein low-density lipoprotein receptor related-protein 1 (LRP1) has been attributed a role in cancer. However, its presumably often indirect involvement is far from understood. LRP1 has both endocytic and signaling activities. As a matricellular receptor it is involved in regulation, mostly by clearing, of various extracellular matrix degrading enzymes including matrix metalloproteinases, serine proteases, protease inhibitor complexes, and the endoglycosidase heparanase. Furthermore, by binding extracellular ligands including growth factors and subsequent intracellular interaction with scaffolding and adaptor proteins it is involved in regulation of various signaling cascades. LRP1 expression levels are often downregulated in cancer and some studies consider low LRP1 levels a poor prognostic factor. On the contrary, upregulation in brain cancers has been noted and clinical trials explore the use of LRP1 as cargo receptor to deliver cytotoxic agents. This mini-review focuses on LRP1's role in tumor growth and metastasis especially by modulation of the extracellular tumor environment. In relation to this role its diagnostic, prognostic and therapeutic potential will be discussed. PMID- 26617524 TI - Bacteriocins as Potential Anticancer Agents. AB - Cancer remains one of the leading causes of deaths worldwide, despite advances in its treatment and detection. The conventional chemotherapeutic agents used for the treatment of cancer have non-specific toxicity toward normal body cells that cause various side effects. Secondly, cancer cells are known to develop chemotherapy resistance in due course of treatment. Thus, the demand for novel anti-cancer agents is increasing day by day. Some of the experimental studies have reported the therapeutic potential of bacteriocins against various types of cancer cell lines. Bacteriocins are ribosomally-synthesized cationic peptides secreted by almost all groups of bacteria. Some bacteriocins have shown selective cytotoxicity toward cancer cells as compared to normal cells. This makes them promising candidates for further investigation and clinical trials. In this review article, we present the overview of the various cancer cell-specific cytotoxic bacteriocins, their mode of action and efficacies. PMID- 26617522 TI - Counteracting Protein Kinase Activity in the Heart: The Multiple Roles of Protein Phosphatases. AB - Decades of cardiovascular research have shown that variable and flexible levels of protein phosphorylation are necessary to maintain cardiac function. A delicate balance between phosphorylated and dephosphorylated states of proteins is guaranteed by a complex interplay of protein kinases (PKs) and phosphatases. Serine/threonine phosphatases, in particular members of the protein phosphatase (PP) family govern dephosphorylation of the majority of these cardiac proteins. Recent findings have however shown that PPs do not only dephosphorylate previously phosphorylated proteins as a passive control mechanism but are capable to actively control PK activity via different direct and indirect signaling pathways. These control mechanisms can take place on (epi-)genetic, (post )transcriptional, and (post-)translational levels. In addition PPs themselves are targets of a plethora of proteinaceous interaction partner regulating their endogenous activity, thus adding another level of complexity and feedback control toward this system. Finally, novel approaches are underway to achieve spatiotemporal pharmacologic control of PPs which in turn can be used to fine tune misleaded PK activity in heart disease. Taken together, this review comprehensively summarizes the major aspects of PP-mediated PK regulation and discusses the subsequent consequences of deregulated PP activity for cardiovascular diseases in depth. PMID- 26617525 TI - Molecular Regulation of Toll-like Receptors in Asthma and COPD. AB - Asthma and chronic obstructive pulmonary disease (COPD) have both been historically associated with significant morbidity and financial burden. These diseases can be induced by several exogenous factors, such as pathogen-associated molecular patterns (PAMPs) (e.g., allergens and microbes). Endogenous factors, including reactive oxygen species, and damage-associated molecular patterns (DAMPs) recognized by toll-like receptors (TLRs), can also result in airway inflammation. Asthma is characterized by the dominant presence of eosinophils, mast cells, and clusters of differentiation (CD)4(+) T cells in the airways, while COPD typically results in the excessive formation of neutrophils, macrophages, and CD8(+) T cells in the airways. In both asthma and COPD, in the respiratory tract, TLRs are the primary proteins of interest associated with the innate and adaptive immune responses; hence, multiple treatment options targeting TLRs are being explored in an effort to reduce the severity of the symptoms of these disorders. TLR-mediated pathways for both COPD and asthma have their similarities and differences with regards to cell types and the pro-inflammatory cytotoxins present in the airway. Because of the complex TLR cascade, a variety of treatments have been used to minimize airway hypersensitivity and promote bronchodilation. Although unsuccessful at completely alleviating COPD and severe asthmatic symptoms, new studies are focused on possible targets within the TLR cascade to ameliorate airway inflammation. PMID- 26617526 TI - Resistin, an Adipokine with Non-Generalized Actions on Sympathetic Nerve Activity. AB - The World Health Organization has called obesity a global epidemic. There is a strong association between body weight gain and blood pressure. A major determinant of blood pressure is the level of activity in sympathetic nerves innervating cardiovascular organs. A characteristic of obesity, in both humans and in animal models, is an increase in sympathetic nerve activity to the skeletal muscle vasculature and to the kidneys. Obesity is now recognized as a chronic, low level inflammatory condition, and pro-inflammatory cytokines are elevated including those produced by adipose tissue. The most well-known adipokine released from fat tissue is leptin. The adipokine, resistin, is also released from adipose tissue. Resistin can act in the central nervous system to influence the sympathetic nerve activity. Here, we review the effects of resistin on sympathetic nerve activity and compare them with leptin. We build an argument that resistin and leptin may have complex interactions. Firstly, they may augment each other as both are excitatory on sympathetic nerves innervating cardiovascular organs; In contrast, they could antagonize each other's actions on brown adipose tissue, a key metabolic organ. These interactions may be important in conditions in which leptin and resistin are elevated, such as in obesity. PMID- 26617527 TI - Simulated Firefighting Task Performance and Physiology Under Very Hot Conditions. AB - PURPOSE: To assess the impact of very hot (45 degrees C) conditions on the performance of, and physiological responses to, a simulated firefighting manual handling task compared to the same work in a temperate environment (18 degrees C). METHODS: Ten male volunteer firefighters performed a 3-h protocol in both 18 degrees C (CON) and 45 degrees C (VH). Participants intermittently performed 12 * 1-min bouts of raking, 6 * 8-min bouts of low-intensity stepping, and 6 * 20-min rest periods. The area cleared during the raking task determined work performance. Core temperature, skin temperature, and heart rate were measured continuously. Participants also periodically rated their perceived exertion (RPE) and thermal sensation. Firefighters consumed water ad libitum. Urine specific gravity (USG) and changes in body mass determined hydration status. RESULTS: Firefighters raked 19% less debris during the VH condition. Core and skin temperature were 0.99 +/- 0.20 and 5.45 +/- 0.53 degrees C higher, respectively, during the VH trial, and heart rate was 14-36 beats.min(-1) higher in the VH trial. Firefighters consumed 2950 +/- 1034 mL of water in the VH condition, compared to 1290 +/- 525 in the CON trial. Sweat losses were higher in the VH (1886 +/- 474 mL) compared to the CON trial (462 +/- 392 mL), though both groups were hydrated upon protocol completion (USG < 1.020). Participants' average RPE was higher in the VH (15.6 +/- 0.9) compared to the CON trial (12.6 +/- 0.9). Similarly, the firefighers' thermal sensation scores were significantly higher in the VH (6.4 +/- 0.5) compared to the CON trial (4.4 +/- 0.4). CONCLUSIONS: Despite the decreased work output and aggressive fluid replacement observed in the VH trial, firefighters' experienced increases in thermal stress, and exertion. Fire agencies should prioritize the health and safety of fire personnel in very hot temperatures, and consider the impact of reduced productivity on fire suppression efforts. PMID- 26617528 TI - Complex Coordination of Cell Plasticity by a PGC-1alpha-controlled Transcriptional Network in Skeletal Muscle. AB - Skeletal muscle cells exhibit an enormous plastic capacity in order to adapt to external stimuli. Even though our overall understanding of the molecular mechanisms that underlie phenotypic changes in skeletal muscle cells remains poor, several factors involved in the regulation and coordination of relevant transcriptional programs have been identified in recent years. For example, the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a central regulatory nexus in the adaptation of muscle to endurance training. Intriguingly, PGC-1alpha integrates numerous signaling pathways and translates their activity into various transcriptional programs. This selectivity is in part controlled by differential expression of PGC-1alpha variants and post translational modifications of the PGC-1alpha protein. PGC-1alpha-controlled activation of transcriptional networks subsequently enables a spatio-temporal specification and hence allows a complex coordination of changes in metabolic and contractile properties, protein synthesis and degradation rates and other features of trained muscle. In this review, we discuss recent advances in our understanding of PGC-1alpha-regulated skeletal muscle cell plasticity in health and disease. PMID- 26617529 TI - Intercellular Odontoblast Communication via ATP Mediated by Pannexin-1 Channel and Phospholipase C-coupled Receptor Activation. AB - Extracellular ATP released via pannexin-1 channels, in response to the activation of mechanosensitive-TRP channels during odontoblast mechanical stimulation, mediates intercellular communication among odontoblasts in dental pulp slice preparation dissected from rat incisor. Recently, odontoblast cell lines, such as mouse odontoblast lineage cells, have been widely used to investigate physiological/pathological cellular functions. To clarify whether the odontoblast cell lines also communicate with each other by diffusible chemical substance(s), we investigated the chemical intercellular communication among cells from mouse odontoblast cell lines following mechanical stimulation. A single cell was stimulated using a glass pipette filled with standard extracellular solution. We measured intracellular free Ca(2+) concentration ([Ca(2+)]i) by fura-2 in stimulated cells, as well as in cells located nearby. Direct mechanical stimulation to a single odontoblast increased [Ca(2+)]i, which showed sensitivity to capsazepine. In addition, we observed increases in [Ca(2+)]i not only in the mechanically stimulated odontoblast, but also in nearby odontoblasts. We could observe mechanical stimulation-induced increase in [Ca(2+)]i in a stimulated human embryo kidney (HEK) 293 cell, but not in nearby HEK293 cells. The increase in [Ca(2+)]i in nearby odontoblasts, but not in the stimulated odontoblast, was inhibited by adenosine triphosphate (ATP) release channel (pannexin-1) inhibitor in a concentration- and spatial-dependent manner. Moreover, in the presence of phospholipase C (PLC) inhibitor, the increase in [Ca(2+)]i in nearby odontoblasts, following mechanical stimulation of a single odontoblast, was abolished. We could record some inward currents evoked from odontoblasts near the stimulated odontoblast, but the currents were observed in only 4.8% of the recorded odontoblasts. The results of this study showed that ATP is released via pannexin-1, from a mechanically stimulated odontoblast, which transmits a signal to nearby odontoblasts by predominant activation of PLC-coupled nucleotide receptors. PMID- 26617530 TI - The Role of Kruppel-like Factor 4 in Renal Fibrosis. AB - Chronic kidney disease (CKD) caused by renal fibrosis is an important public health concern. It is therefore necessary to understand the molecular pathogenesis of renal fibrosis in order to develop novel therapeutic strategies. KLF4 is the most extensively studied factor among the various members of the Kruppel-like factor (KLF) family of zinc finger-containing transcription factors. Many studies have demonstrated that KLF4 inhibits the activation of myofibroblasts and exerts an inhibitory effect on fibrosis. However, other studies have indicated that KLF4 may promote renal fibrosis. These controversial results suggest that KLF4 may be crucially involved in the development of renal fibrosis, although the underlying mechanism(s) remain unclear. Here, we summarize the recent progress made in understanding the role of KLF4 in renal fibrosis. Together, these findings suggest that KLF4 may participate in the development of renal fibrosis, but that its inhibition of fibrosis is greater than its promotion of the condition, which suggests that KLF4 may serve as a novel therapeutic target for renal fibrosis. PMID- 26617531 TI - Cytoglobin as a Marker of Hepatic Stellate Cell-derived Myofibroblasts. AB - Myofibroblasts play important roles in inflammation, fibrosis and tumorigenesis in chronically inflamed liver. Liver myofibroblasts originate from hepatic stellate cells, portal fibroblasts or mesothelial cells, and they are localized in and around fibrotic septum and portal tracts. Liver myofibroblasts are the source of extracellular matrix materials, including type I collagen and multiple fibrogenic growth factors, such as transforming growth factor-beta and vascular endothelial growth factor. Although a detailed characterization of the function of individual myofibroblasts has not been conducted, owing to the lack of appropriate cell markers, recent lineage-tracing technology has revealed the limited contribution of myofibroblasts that are derived from portal fibroblasts to various types of liver fibrosis, as compared with the contribution of hepatic stellate cells. In addition, cytoglobin, which is the fourth globin in mammals and function as a local gas sensor, provides a new perspective on the involvement of stellate cells in fibrosis and carcinogenesis, possibly through its anti oxidative properties and is a promising new marker that discriminates between myofibroblasts derived from stellate cells and those from portal fibroblasts. PMID- 26617532 TI - A New Perspective on Delusional States - Evidence for Claustrum Involvement. AB - Delusions are a hallmark positive symptom of schizophrenia, although they are also associated with a wide variety of other psychiatric and neurological disorders. The heterogeneity of clinical presentation and underlying disease, along with a lack of experimental animal models, make delusions exceptionally difficult to study in isolation, either in schizophrenia or other diseases. To date, no detailed studies have focused specifically on the neural mechanisms of delusion, although some studies have reported characteristic activation of specific brain areas or networks associated with them. Here, we present a novel hypothesis and extant supporting evidence implicating the claustrum, a relatively poorly understood forebrain nucleus, as a potential common center for delusional states. PMID- 26617533 TI - Joint Coupling of Awake EEG Frequency Activity and MRI Gray Matter Volumes in the Psychosis Dimension: A BSNIP Study. AB - BACKGROUND: Many studies have examined either electroencephalogram (EEG) frequency activity or gray matter volumes (GMV) in various psychoses [including schizophrenia (SZ), schizoaffective (SZA), and psychotic bipolar disorder (PBP)]. Prior work demonstrated similar EEG and gray matter abnormalities in both SZ and PBP. Integrating EEG and GMV and jointly analyzing the combined data fully elucidates the linkage between the two and may provide better biomarker- or endophenotype-specificity for a particular illness. Joint exploratory investigations of EEG and GMV are scarce in the literature and the relationship between the two in psychosis is even less explored. We investigated a joint multivariate model to test whether the linear relationship or linkage between awake EEG (AEEG) frequency activity and GMV is abnormal across the psychosis dimension and if such effects are also present in first-degree relatives. METHODS: We assessed 607 subjects comprising 264 probands [105 SZ, 72 SZA, and 87 PBP], 233 of their first degree relatives [82 SZ relatives (SZR), 71 SZA relatives (SZAR), and 80 PBP relatives (PBPR)], and 110 healthy comparison subjects (HC). All subjects underwent structural MRI (sMRI) and EEG scans. Frequency activity and voxel-based morphometric GMV were derived from EEG and sMRI data, respectively. Seven AEEG frequency and gray matter components were extracted using Joint independent component analysis (jICA). The loading coefficients (LC) were examined for group differences using analysis of covariance. Further, the LCs were correlated with psychopathology scores to identify relationship with clinical symptoms. RESULTS: Joint ICA revealed a single component differentiating SZ from HC (p < 0.006), comprising increased posterior alpha activity associated with decreased volume in inferior parietal lobe, supramarginal, parahippocampal gyrus, middle frontal, inferior temporal gyri, and increased volume of uncus and culmen. No components were aberrant in either PBP or SZA or any relative group. No significant association was identified with clinical symptom measures. CONCLUSION: Our data suggest that a joint EEG and GMV model yielded a biomarker specific to SZ, not abnormal in PBP or SZA. Alpha activity was related to both increased and decreased volume in different cortical structures. Additionally, the joint model failed to identify endophenotypes across psychotic disorders. PMID- 26617534 TI - Voluntary self-touch increases body ownership. AB - Experimental manipulations of body ownership have indicated that multisensory integration is central to forming bodily self-representation. Voluntary self touch is a unique multisensory situation involving corresponding motor, tactile and proprioceptive signals. Yet, even though self-touch is frequent in everyday life, its contribution to the formation of body ownership is not well understood. Here we investigated the role of voluntary self-touch in body ownership using a novel adaptation of the rubber hand illusion (RHI), in which a robotic system and virtual reality allowed participants self-touch of real and virtual hands. In the first experiment, active and passive self-touch were applied in the absence of visual feedback. In the second experiment, we tested the role of visual feedback in this bodily illusion. Finally, in the third experiment, we compared active and passive self-touch to the classical RHI in which the touch is administered by the experimenter. We hypothesized that active self-touch would increase ownership over the virtual hand through the addition of motor signals strengthening the bodily illusion. The results indicated that active self-touch elicited stronger illusory ownership compared to passive self-touch and sensory only stimulation, and show an important role for active self-touch in the formation of bodily self. PMID- 26617536 TI - Analyzing Statistical Mediation with Multiple Informants: A New Approach with an Application in Clinical Psychology. AB - Testing mediation models is critical for identifying potential variables that need to be targeted to effectively change one or more outcome variables. In addition, it is now common practice for clinicians to use multiple informant (MI) data in studies of statistical mediation. By coupling the use of MI data with statistical mediation analysis, clinical researchers can combine the benefits of both techniques. Integrating the information from MIs into a statistical mediation model creates various methodological and practical challenges. The authors review prior methodological approaches to MI mediation analysis in clinical research and propose a new latent variable approach that overcomes some limitations of prior approaches. An application of the new approach to mother, father, and child reports of impulsivity, frustration tolerance, and externalizing problems (N = 454) is presented. The results showed that frustration tolerance mediated the relationship between impulsivity and externalizing problems. The new approach allows for a more comprehensive and effective use of MI data when testing mediation models. PMID- 26617535 TI - Is the Motor System Necessary for Processing Action and Abstract Emotion Words? Evidence from Focal Brain Lesions. AB - Neuroimaging and neuropsychological experiments suggest that modality preferential cortices, including motor- and somatosensory areas, contribute to the semantic processing of action related concrete words. Still, a possible role of sensorimotor areas in processing abstract meaning remains under debate. Recent fMRI studies indicate an involvement of the left sensorimotor cortex in the processing of abstract-emotional words (e.g., "love") which resembles activation patterns seen for action words. But are the activated areas indeed necessary for processing action-related and abstract words? The current study now investigates word processing in two patients suffering from focal brain lesion in the left frontocentral motor system. A speeded Lexical Decision Task on meticulously matched word groups showed that the recognition of nouns from different semantic categories - related to food, animals, tools, and abstract-emotional concepts - was differentially affected. Whereas patient HS with a lesion in dorsolateral central sensorimotor systems next to the hand area showed a category-specific deficit in recognizing tool words, patient CA suffering from lesion centered in the left supplementary motor area was primarily impaired in abstract-emotional word processing. These results point to a causal role of the motor cortex in the semantic processing of both action-related object concepts and abstract-emotional concepts and therefore suggest that the motor areas previously found active in action-related and abstract word processing can serve a meaning-specific necessary role in word recognition. The category-specific nature of the observed dissociations is difficult to reconcile with the idea that sensorimotor systems are somehow peripheral or 'epiphenomenal' to meaning and concept processing. Rather, our results are consistent with the claim that cognition is grounded in action and perception and based on distributed action perception circuits reaching into modality-preferential cortex. PMID- 26617537 TI - Children's Spatial Representations: 3- and 4-Year-Olds are Affected by Irrelevant Peripheral References. AB - Children as young as 3 years can remember an object's location within an arrangement and can retrieve it from a novel viewpoint (Nardini et al., 2006). However, this ability is impaired if the arrangement is rotated to compensate for the novel viewpoint, or, if the arrangement is rotated and children stand still. There are two dominant explanations for this phenomenon: self-motion induces an automatic spatial updating process which is beneficial if children move around the arrangement, but misleading if the children's movement is matched by the arrangement and not activated if children stand still and only the arrangement is moved (see spatial updating; Simons and Wang, 1998). Another explanation concerns reference frames: spatial representations might depend on peripheral spatial relations concerning the surrounding room instead on proximal relations within the arrangement, even if these proximal relations are sufficient or more informative. To evaluate these possibilities, we rotated children (N = 120) aged between 3 and 6 years with an occluded arrangement. When the arrangement was in misalignment to the surrounding room, 3- and 4-year-olds' spatial memory was impaired and 5-year-olds' was lightly impaired suggesting that they relied on peripheral references of the surrounding room for retrieval. In contrast, 6-years olds' spatial representation seemed robust against misalignment indicating a successful integration of spatial representations. PMID- 26617538 TI - Development and Validation of the Computerized Family Relations Test for Children. AB - The aim of the present study was to develop and investigate the psychometric properties of the Computerized Family Relations Test (CFRT) for children. This test assesses the quality of family relationships with the mother and father from a child's perspective. The CFRT consists of six scales relating to control (Restrictiveness and Justice), and support (Affection, Vulnerability, Acknowledgment, and Trust) within the family relationships. CFRT is an innovative approach to the Dutch Nijmegen Family Relations Test (NFRT) developed by Oud and Welzen (1989). The administration of the test has been computerized and graphical representations of female and male silhouettes were included to facilitate the child's parental identification. In total, 404 primary school children, aged 8 to 13 years (M = 11.0; SD = 1.17), took part in this study. The CFRT's reliability was assessed by McDonald's omega coefficients, and ranged from 0.71 to 0.86, except for Vulnerability which achieved the lowest reliability 0.57 for mothers' ratings and 0.56 for fathers' ratings. The test-retest procedure revealed higher stability for the ratings on father-child relationships of 0.71 compared to mother-child relationships of 0.67. Confirmatory factor analysis indicated that a six-factor model provided an adequate fit. Measurement invariance across the children's assessments of the quality of family relationships was achieved. The construct validity of CFRT was assessed by examining differences in the child's ratings of the relationships with the mother and father, the child's gender, and associations of CFRT scales with other variables such as depression, anxiety symptoms, and prosocial behavior. PMID- 26617539 TI - Reconstruction of a Real World Social Network using the Potts Model and Loopy Belief Propagation. AB - The scope of this paper is to test the adoption of a statistical model derived from Condensed Matter Physics, for the reconstruction of the structure of a social network. The inverse Potts model, traditionally applied to recursive observations of quantum states in an ensemble of particles, is here addressed to observations of the members' states in an organization and their (anti)correlations, thus inferring interactions as links among the members. Adopting proper (Bethe) approximations, such an inverse problem is showed to be tractable. Within an operational framework, this network-reconstruction method is tested for a small real-world social network, the Italian parliament. In this study case, it is easy to track statuses of the parliament members, using (co)sponsorships of law proposals as the initial dataset. In previous studies of similar activity-based networks, the graph structure was inferred directly from activity co-occurrences: here we compare our statistical reconstruction with such standard methods, outlining discrepancies and advantages. PMID- 26617541 TI - If We Build It Comparative Psychologists Will Come. Commentary: A Crisis in Comparative Psychology: Where Have All the Undergraduates Gone? PMID- 26617540 TI - Differential Neural Correlates Underlie Judgment of Learning and Subsequent Memory Performance. AB - Judgment of learning (JOL) plays a pivotal role in self-regulated learning. Although the JOLs are in general accurate, important deviations from memory performance are often reported, especially when the JOLs are made immediately after learning. Nevertheless, existing studies have not clearly dissociated the neural processes underlying subjective JOL and objective memory. In the present study, participants were asked to study a list of words that would be tested 1 day later. Immediately after learning an item, participants predicted how likely they would remember that item. Critically, the JOL was performed on only half of the studied items to avoid its contamination on subsequent memory. We found that during encoding, compared to items later judged as "will be forgotten," those judged as "will be remembered" showed stronger activities in the default-mode network, including the ventromedial prefrontal cortex (PFC) and posterior cingulate cortex, as well as weaker functional connectivity between the left dorsolateral PFC and the visual cortex. The exact opposite pattern was found when comparing items that were actually remembered with those that were later forgotten. These important neural dissociations between JOL and memory performance shed light on the neural mechanisms of human metamemory bias. PMID- 26617542 TI - Exploration of Functional Connectivity During Preferred Music Stimulation in Patients with Disorders of Consciousness. AB - Preferred music is a highly emotional and salient stimulus, which has previously been shown to increase the probability of auditory cognitive event-related responses in patients with disorders of consciousness (DOC). To further investigate whether and how music modifies the functional connectivity of the brain in DOC, five patients were assessed with both a classical functional connectivity scan (control condition), and a scan while they were exposed to their preferred music (music condition). Seed-based functional connectivity (left or right primary auditory cortex), and mean network connectivity of three networks linked to conscious sound perception were assessed. The auditory network showed stronger functional connectivity with the left precentral gyrus and the left dorsolateral prefrontal cortex during music as compared to the control condition. Furthermore, functional connectivity of the external network was enhanced during the music condition in the temporo-parietal junction. Although caution should be taken due to small sample size, these results suggest that preferred music exposure might have effects on patients auditory network (implied in rhythm and music perception) and on cerebral regions linked to autobiographical memory. PMID- 26617544 TI - Americans Still Overestimate Social Class Mobility: A Pre-Registered Self Replication. AB - Kraus and Tan (2015) hypothesized that Americans tend to overestimate social class mobility in society, and do so because they seek to protect the self. This paper reports a pre-registered exact replication of Study 3 from this original paper and finds, consistent with the original study, that Americans substantially overestimate social class mobility, that people provide greater overestimates when made while thinking of similar others, and that high perceived social class is related to greater overestimates. The current results provide additional evidence consistent with the idea that people overestimate class mobility to protect their beliefs in the promise of equality of opportunity. Discussion considers the utility of pre-registered self-replications as one tool for encouraging replication efforts and assessing the robustness of effect sizes. PMID- 26617543 TI - Measuring Verbal Psychotherapeutic Techniques-A Systematic Review of Intervention Characteristics and Measures. AB - Language is one of the most important "tools" of psychotherapists. The working mechanisms of verbal therapeutic techniques, however, are still marginally understood. In part, this is due to the lack of a generally acknowledged typology as well as a gold standard for the assessment of verbal techniques, which limits the possibility of conducting studies focusing this topic. The present study reviews measures used in clinical research which assess directly observable dimensions of verbal interventions in a reliable manner. All measures were evaluated with respect to their theoretical foundation, research goals, assessment modes, and various psychometric properties. A systematic search in databases (PubMed, PsycInfo, PsycArticles, PSYNDEX, Web of Science, Embase) followed by an additional "snowballing" search covering the years 1940-2013 yielded n = 179 publications eligible for review. Within these publications, 34 measures were identified showing great heterogeneity regarding the aspects under study. Only two measures reached the highest psychometric standards and can be recommended for clinical use without any reservation. Central problems include deficiencies in the systematization of techniques as well as their partly ambiguous and inconsistent definitions. To promote this field of research, it will be important to achieve a consensus concerning the terminology, conceptions and measures of verbal interventions. PMID- 26617545 TI - Working Memory Training is Associated with Long Term Attainments in Math and Reading. AB - Training working memory (WM) using computerized programs has been shown to improve functions directly linked to WM such as following instructions and attention. These functions influence academic performance, which leads to the question of whether WM training can transfer to improved academic performance. We followed the academic performance of two age-matched groups during 2 years. As part of the curriculum in grade 4 (age 9-10), all students in one classroom (n = 20) completed Cogmed Working Memory Training (CWMT) whereas children in the other classroom (n = 22) received education as usual. Performance on nationally standardized tests in math and reading was used as outcome measures at baseline and two years later. At baseline both classes were normal/high performing according to national standards. At grade 6, reading had improved to a significantly greater extent for the training group compared to the control group (medium effect size, Cohen's d = 0.66, p = 0.045). For math performance the same pattern was observed with a medium effect size (Cohen's d = 0.58) reaching statistical trend levels (p = 0.091). Moreover, the academic attainments were found to correlate with the degree of improvements during training (p < 0.053). This is the first study of long-term (>1 year) effects of WM training on academic performance. We found performance on both reading and math to be positively impacted after completion of CWMT. Since there were no baseline differences between the groups, the results may reflect an influence on learning capacity, with improved WM leading to a boost in students' capacity to learn. This study is also the first to investigate the effects of CWMT on academic performance in typical or high achieving students. The results suggest that WM training can help optimize the academic potential of high performers. PMID- 26617546 TI - Genetic Factors of Individual Differences in Decision Making in Economic Behavior: A Japanese Twin Study using the Allais Problem. AB - Why does decision making differ among individuals? People sometimes make seemingly inconsistent decisions with lower expected (monetary) utility even when objective information of probabilities and reward are provided. It is noteworthy, however, that a certain proportion of people do not provide anomalous responses, choosing the alternatives with higher expected utility, thus appearing to be more "rational." We investigated the genetic and environmental influences on these types of individual differences in decision making using a classical Allais problem task. Participants were 1,199 Japanese adult twins aged 20-47. Univariate genetic analysis revealed that approximately a third of the Allais problem response variance was explained by genetic factors and the rest by environmental factors unique to individuals and measurement error. The environmental factor shared between families did not contribute to the variance. Subsequent multivariate genetic analysis clarified that decision making using the expected utility theory was associated with general intelligence and that the association was largely mediated by the same genetic factor. We approach the mechanism underlying two types of "rational" decision making from the perspective of genetic correlations with cognitive abilities. PMID- 26617547 TI - The Application of Timing in Therapy of Children and Adults with Language Disorders. AB - A number of evidence revealed a link between temporal information processing (TIP) and language. Both literature data and results of our studies indicated an overlapping of deficient TIP and disordered language, pointing to the existence of an association between these two functions. On this background the new approach is to apply such knowledge in therapy of patients suffering from language disorders. In two studies we asked the following questions: (1) can the temporal training reduce language deficits in aphasic patients (Study 1) or in children with specific language impairment (SLI, Study 2)? (2) can such training ameliorate also the other cognitive functions? Each of these studies employed pre training assessment, training application, post-training and follow-up assessment. In Study 1 we tested 28 patients suffering from post-stroke aphasia. They were assigned either to the temporal training (Group A, n = 15) in milliseconds range, or to the non-temporal training (Group B, n = 13). Following the training we found only in Group A improved TIP, accompanied by a transfer of improvement to language and working memory functions. In Study 2 we tested 32 children aged from 5 to 8 years, affected by SLI who were classified into the temporal training (Group A, n = 17) or non-temporal training (Group B, n = 15). Group A underwent the multileveled audio-visual computer training Dr. Neuronowski ((r)), recently developed in our laboratory. Group B performed the computer speech therapy exercises extended by playing computer games. Similarly as in Study 1, in Group A we found significant improvements of TIP, auditory comprehension and working memory. These results indicated benefits of temporal training for amelioration of language and other cognitive functions in both aphasic patients and children with SLI. The novel powerful therapy tools provide evidence for future promising clinical applications. PMID- 26617548 TI - Studying Musical and Linguistic Prediction in Comparable Ways: The Melodic Cloze Probability Method. AB - Prediction or expectancy is thought to play an important role in both music and language processing. However, prediction is currently studied independently in the two domains, limiting research on relations between predictive mechanisms in music and language. One limitation is a difference in how expectancy is quantified. In language, expectancy is typically measured using the cloze probability task, in which listeners are asked to complete a sentence fragment with the first word that comes to mind. In contrast, previous production-based studies of melodic expectancy have asked participants to sing continuations following only one to two notes. We have developed a melodic cloze probability task in which listeners are presented with the beginning of a novel tonal melody (5-9 notes) and are asked to sing the note they expect to come next. Half of the melodies had an underlying harmonic structure designed to constrain expectations for the next note, based on an implied authentic cadence (AC) within the melody. Each such 'authentic cadence' melody was matched to a 'non-cadential' (NC) melody matched in terms of length, rhythm and melodic contour, but differing in implied harmonic structure. Participants showed much greater consistency in the notes sung following AC vs. NC melodies on average. However, significant variation in degree of consistency was observed within both AC and NC melodies. Analysis of individual melodies suggests that pitch prediction in tonal melodies depends on the interplay of local factors just prior to the target note (e.g., local pitch interval patterns) and larger-scale structural relationships (e.g., melodic patterns and implied harmonic structure). We illustrate how the melodic cloze method can be used to test a computational model of melodic expectation. Future uses for the method include exploring the interplay of different factors shaping melodic expectation, and designing experiments that compare the cognitive mechanisms of prediction in music and language. PMID- 26617549 TI - Editorial: An Open Book: What and How Young Children Learn from Picture and Story Books. PMID- 26617551 TI - Model of Love, Hate, and Anxiety Scripts in Psychopathic Individuals. PMID- 26617552 TI - Beliefs as Self-Sustaining Networks: Drawing Parallels Between Networks of Ecosystems and Adults' Predictions. AB - In this paper, we argue that beliefs share common properties with the self sustaining networks of complex systems. Matching experiences are said to couple with each other into a mutually reinforcing network. The goal of the current paper is to spell out and develop these ideas, using our understanding of ecosystems as a guide. In Part 1 of the paper, we provide theoretical considerations relevant to this new conceptualization of beliefs, including the theoretical overlap between energy and meaning. In Part 2, we discuss the implications of this new conceptualization on our understanding of belief emergence and belief change. Finally, in Part 3, we provide an analytical mapping between beliefs and the self-sustaining networks of ecosystems, namely by applying to behavioral data a measure developed for ecosystem networks. Specifically, average accuracies were subjected to analyses of uncertainty (H) and average mutual information. The ratio between these two values yields degree of order, a measure of how organized the self-sustained network is. Degree of order was tracked over time and compared to the amount of explained variance returned by a categorical non-linear principal components analysis. Finding high correspondence between the two measures of order, together with the theoretical groundwork discussed in Parts 1 and 2, lends preliminary validity to our theory that beliefs have important similarities to the structural characteristics of self-sustaining networks. PMID- 26617550 TI - A Serious Videogame as an Additional Therapy Tool for Training Emotional Regulation and Impulsivity Control in Severe Gambling Disorder. AB - BACKGROUND: Gambling disorder (GD) is characterized by a significant lack of self control and is associated with impulsivity-related personality traits. It is also linked to deficits in emotional regulation and frequently co-occurs with anxiety and depression symptoms. There is also evidence that emotional dysregulation may play a mediatory role between GD and psychopathological symptomatology. Few studies have reported the outcomes of psychological interventions that specifically address these underlying processes. OBJECTIVES: To assess the utility of the Playmancer platform, a serious video game, as an additional therapy tool in a CBT intervention for GD, and to estimate pre-post changes in measures of impulsivity, anger expression and psychopathological symptomatology. METHOD: The sample comprised a single group of 16 male treatment-seeking individuals with severe GD diagnosis. Therapy intervention consisted of 16 group weekly CBT sessions and, concurrently, 10 additional weekly sessions of a serious video game. Pre-post treatment scores on South Oaks Gambling Screen (SOGS), Barratt Impulsiveness Scale (BIS-11), I7 Impulsiveness Questionnaire (I7), State Trait Anger Expression Inventory 2 (STAXI-2), Symptom Checklist-Revised (SCL-90 R), State-Trait Anxiety Inventory (STAI-S-T), and Novelty Seeking from the Temperament and Character Inventory-Revised (TCI-R) were compared. RESULTS: After the intervention, significant changes were observed in several measures of impulsivity, anger expression and other psychopathological symptoms. Dropout and relapse rates during treatment were similar to those described in the literature for CBT. CONCLUSION: Complementing CBT interventions for GD with a specific therapy approach like a serious video game might be helpful in addressing certain underlying factors which are usually difficult to change, including impulsivity and anger expression. PMID- 26617553 TI - From Crisis to Crowd Control. Commentary: A Crisis in Comparative Psychology: Where Have All the Undergraduates Gone? PMID- 26617554 TI - Editorial: What can Neuroscience Learn from Contemplative Practices? PMID- 26617555 TI - Motivational Interviewing in Childhood Obesity Treatment. AB - Obesity is one of today's most diffused and severe public health problems worldwide. It affects both adults and children with critical physical, social, and psychological consequences. The aim of this review is to appraise the studies that investigated the effects of motivational interviewing techniques in treating overweight and obese children. The electronic databases PubMed and PsychINFO were searched for articles meeting inclusion criteria. The review included studies based on the application of motivational interviewing (MI) components and having the objective of changing body mass index (BMI) in overweight or obese children from age 2 to age 11. Six articles have been selected and included in this review. Three studies reported that MI had a statistically significant positive effect on BMI and on secondary obesity-related behavior outcomes. MI can be applicable in the treatment of overweight and obese children, but its efficacy cannot be proved given the lack of studies carried out on this specific sample. PMID- 26617556 TI - Unitary Transformations in the Quantum Model for Conceptual Conjunctions and Its Application to Data Representation. AB - Quantum models of concept combinations have been successful in representing various experimental situations that cannot be accommodated by traditional models based on classical probability or fuzzy set theory. In many cases, the focus has been on producing a representation that fits experimental results to validate quantum models. However, these representations are not always consistent with the cognitive modeling principles. Moreover, some important issues related to the representation of concepts such as the dimensionality of the realization space, the uniqueness of solutions, and the compatibility of measurements, have been overlooked. In this paper, we provide a dimensional analysis of the realization space for the two-sector Fock space model for conjunction of concepts focusing on the first and second sectors separately. We then introduce various representation of concepts that arise from the use of unitary operators in the realization space. In these concrete representations, a pair of concepts and their combination are modeled by a single conceptual state, and by a collection of exemplar-dependent operators. Therefore, they are consistent with cognitive modeling principles. This framework not only provides a uniform approach to model an entire data set, but, because all measurement operators are expressed in the same basis, allows us to address the question of compatibility of measurements. In particular, we present evidence that it may be possible to predict non commutative effects from partial measurements of conceptual combinations. PMID- 26617557 TI - Auditory Contagious Yawning in Humans: An Investigation into Affiliation and Status Effects. AB - While comparative research on contagious yawning has grown substantially in the past few years, both the interpersonal factors influencing this response and the sensory modalities involved in its activation in humans remain relatively unknown. Extending upon previous studies showing various in-group and status effects in non-human great apes, we performed an initial study to investigate how the political affiliation (Democrat vs. Republican) and status (high vs. low) of target stimuli influences auditory contagious yawning, as well as the urge to yawn, in humans. Self-report responses and a subset of video recordings were analyzed from 118 undergraduate students in the US following exposure to either breathing (control) or yawning (experimental) vocalizations paired with images of former US Presidents (high status) and their respective Cabinet Secretaries of Commerce (low status). The overall results validate the use of auditory stimuli to prompt yawn contagion, with greater response in the experimental than the control condition. There was also a negative effect of political status on self reported yawning and the self-reported urge to yawn irrespective of the condition. In contrast, we found no evidence for a political affiliation bias in this response. These preliminary findings are discussed in terms of the existing comparative evidence, though we highlight limitations in the current investigation and we provide suggestions for future research in this area. PMID- 26617559 TI - How Does the Effort Spent to Hold a Door Affect Verbal Thanks and Reciprocal Help? AB - When someone holds a door for us we often respond with a verbal "thanks." But given such a trivial favor, our feelings can vary considerably depending on how the door is held. Studies have shown that verbal thanking increases in relation to door-holding effort. However, it is unclear how such a favor can lead to verbal thanks in addition to reciprocal help. We examined how holding a door in an effortful or non-effortful manner relates to verbal thanking and reciprocal helping. We measured: (1) whether participants verbally thanked the experimenter, (2) whether they agreed to help another person by taking a survey, and (3) whether they helped pick up objects (pens) that the door-holder subsequently dropped. Participants in the effortful condition were more likely to offer verbal thanks, to help pick up the pens, and to walk a greater distance to pick them up. Participants who thanked the door-holder, however, were not more likely to provide help. PMID- 26617558 TI - Commentary: Is the Frontal Lobe Involved in Conscious Perception? PMID- 26617560 TI - Is It Attachment Style or Socio-Demography: Singlehood in a Representative Sample. AB - Since the percentage of single adults is steadily increasing, the reasons for this development have become a matter of growing interest. Hereby, an individual's attachment style may have a connection to the partnership status. In the following analysis, attachment style, gender, age, education, and income were compared in regard to the partnership status. Furthermore, an analysis of variance was computed to compare the attachment style within different groups. In 2012, a sample of 1,676 representative participants was used. The participants were aged 18 to 60 (M = 41.0, SD = 12.3); 54% of the sample were female, and 40% were single. Attachment-related attitudes were assessed with the German version of the adult attachment scale (AAS). Single adult males did not show a more anxious attachment style than single adult females or females in relationships. Younger, i.e., 18 to 30 years old, paired individuals showed greater attachment anxiety than single individuals, whereby single individuals between the ages of 31 to 45 showed greater attachment anxiety than individuals in relationships. In addition, single individuals more frequently had obtained their high school diploma in contrast to individuals in relationships. Concerning attachment style, the individuals who had not completed their high school diploma showed less faith in others independent of singlehood or being in a relationship. Concerning age, older single individuals, i.e., 46 to 60 years, felt less comfortable in respect to closeness and showed less faith in others compared to paired individuals. Logistic regression showed that individuals were not single if they did not mind depending on others, showed high attachment anxiety, were older, and had lower education. An income below ? 2000/month was linked to a nearly 13-fold increase of likelihood of being single. In sum, the attachment style had a differential age-dependent association to singlehood versus being in a relationship. Education played also a role, exclusively concerning faith in others. PMID- 26617561 TI - An Alternative Approach to Analyze Ipsative Data. Revisiting Experiential Learning Theory. AB - The ritualistic use of statistical models regardless of the type of data actually available is a common practice across disciplines which we dare to call type zero error. Statistical models involve a series of assumptions whose existence is often neglected altogether, this is specially the case with ipsative data. This paper illustrates the consequences of this ritualistic practice within Kolb's Experiential Learning Theory (ELT) operationalized through its Learning Style Inventory (KLSI). We show how using a well-known methodology in other disciplines compositional data analysis (CODA) and log ratio transformations-KLSI data can be properly analyzed. In addition, the method has theoretical implications: a third dimension of the KLSI is unveiled providing room for future research. This third dimension describes an individual's relative preference for learning by prehension rather than by transformation. Using a sample of international MBA students, we relate this dimension with another self-assessment instrument, the Philosophical Orientation Questionnaire (POQ), and with an observer-assessed instrument, the Emotional and Social Competency Inventory (ESCI-U). Both show plausible statistical relationships. An intellectual operating philosophy (IOP) is linked to a preference for prehension, whereas a pragmatic operating philosophy (POP) is linked to transformation. Self-management and social awareness competencies are linked to a learning preference for transforming knowledge, whereas relationship management and cognitive competencies are more related to approaching learning by prehension. PMID- 26617562 TI - Commentary "A Crisis in Comparative Psychology: Where have all the Undergraduates Gone?" Collaborating with Behavior Analysts Could Avert a Crisis in Comparative Psychology. PMID- 26617563 TI - What is the Value of Embedding Artificial Emotional Prosody in Human-Computer Interactions? Implications for Theory and Design in Psychological Science. AB - In computerized technology, artificial speech is becoming increasingly important, and is already used in ATMs, online gaming and healthcare contexts. However, today's artificial speech typically sounds monotonous, a main reason for this being the lack of meaningful prosody. One particularly important function of prosody is to convey different emotions. This is because successful encoding and decoding of emotions is vital for effective social cognition, which is increasingly recognized in human-computer interaction contexts. Current attempts to artificially synthesize emotional prosody are much improved relative to early attempts, but there remains much work to be done due to methodological problems, lack of agreed acoustic correlates, and lack of theoretical grounding. If the addition of synthetic emotional prosody is not of sufficient quality, it may risk alienating users instead of enhancing their experience. So the value of embedding emotion cues in artificial speech may ultimately depend on the quality of the synthetic emotional prosody. However, early evidence on reactions to synthesized non-verbal cues in the facial modality bodes well. Attempts to implement the recognition of emotional prosody into artificial applications and interfaces have perhaps been met with greater success, but the ultimate test of synthetic emotional prosody will be to critically compare how people react to synthetic emotional prosody vs. natural emotional prosody, at the behavioral, socio cognitive and neural levels. PMID- 26617564 TI - The Evolution of Empathy and Women's Precarious Leadership Appointments. AB - Glass cliffs describe situations in which women are promoted to executive roles in declining organizations. To explain them, some authors suggest that people tend to "think crisis-think female." However, the root cause of this association remains elusive. Using several subfields of evolutionary theory, we argue that biology and culture have shaped the perception of women as being more empathic than men and, consequently, as capable of quelling certain crises. Some crises are more intense than others and, whereas some brew within organizations, others originate from the external environment. We therefore propose that women will be selected to lead whenever a crisis is minimal to moderate and stems primarily from within the organization. Men, on the other hand, will be chosen as leaders whenever the crisis threatens the very existence of the firm and its source is an external threat. Leadership is a highly stressful experience, and even more so when leaders must scale glass cliffs. It is imperative that we understand what gives rise to them not only because they place women and potentially other minorities in positions where the likelihood of failure is high, but also because they help propagate stereotypes that undermine their true leadership ability. PMID- 26617565 TI - Frequency of Direct Funduscopy Upon Initial Encounters for Patients with Headaches, Altered Mental Status, and Visual Changes: A Pilot Study. AB - OBJECTIVE: To determine the performance of direct funduscopy (DF) as part of the initial clinical assessment among different faculty physicians and residents from internal medicine, emergency medicine, and neurology (N). METHODS: Retrospective study of 163 randomly reviewed charts of patients (>18 years) presenting either to the ED, inpatient units, or outpatient clinics from January 2001 to July 2013, with corresponding ICD-9 codes for headaches, altered mental status, and visual changes. RESULTS: Although the Neurology Service was the one who performed most DF upon initial evaluation, DF is infrequently done throughout services independent of inpatient or outpatient location. Two thirds of the patients (66%) presenting with visual symptoms had evaluation done by Ophthalmology, which in some instances contributed to the final diagnosis. CONCLUSION: A more robust teaching of DF should be included among the basic clinical competencies during Medical School and Neurology Residency training. PMID- 26617566 TI - Effects of Auditory Rhythm and Music on Gait Disturbances in Parkinson's Disease. AB - Gait abnormalities, such as shuffling steps, start hesitation, and freezing, are common and often incapacitating symptoms of Parkinson's disease (PD) and other parkinsonian disorders. Pharmacological and surgical approaches have only limited efficacy in treating these gait disorders. Rhythmic auditory stimulation (RAS), such as playing marching music and dance therapy, has been shown to be a safe, inexpensive, and an effective method in improving gait in PD patients. However, RAS that adapts to patients' movements may be more effective than rigid, fixed tempo RAS used in most studies. In addition to auditory cueing, immersive virtual reality technologies that utilize interactive computer-generated systems through wearable devices are increasingly used for improving brain-body interaction and sensory-motor integration. Using multisensory cues, these therapies may be particularly suitable for the treatment of parkinsonian freezing and other gait disorders. In this review, we examine the affected neurological circuits underlying gait and temporal processing in PD patients and summarize the current studies demonstrating the effects of RAS on improving these gait deficits. PMID- 26617567 TI - Plasma 24-metabolite Panel Predicts Preclinical Transition to Clinical Stages of Alzheimer's Disease. AB - We recently documented plasma lipid dysregulation in preclinical late-onset Alzheimer's disease (LOAD). A 10 plasma lipid panel, predicted phenoconversion and provided 90% sensitivity and 85% specificity in differentiating an at-risk group from those that would remain cognitively intact. Despite these encouraging results, low positive predictive values limit the clinical usefulness of this panel as a screening tool in subjects aged 70-80 years or younger. In this report, we re-examine our metabolomic data, analyzing baseline plasma specimens from our group of phenoconverters (n = 28) and a matched set of cognitively normal subjects (n = 73), and discover and internally validate a panel of 24 plasma metabolites. The new panel provides a classifier with receiver operating characteristic area under the curve for the discovery and internal validation cohort of 1.0 and 0.995 (95% confidence intervals of 1.0-1.0, and 0.981-1.0), respectively. Twenty-two of the 24 metabolites were significantly dysregulated lipids. While positive and negative predictive values were improved compared to our 10-lipid panel, low positive predictive values provide a reality check on the utility of such biomarkers in this age group (or younger). Through inclusion of additional significantly dysregulated analyte species, our new biomarker panel provides greater accuracy in our cohort but remains limited by predictive power. Unfortunately, the novel metabolite panel alone may not provide improvement in counseling and management of at-risk individuals but may further improve selection of subjects for LOAD secondary prevention trials. We expect that external validation will remain challenging due to our stringent study design, especially compared with more diverse subject cohorts. We do anticipate, however, external validation of reduced plasma lipid species as a predictor of phenoconversion to either prodromal or manifest LOAD. PMID- 26617569 TI - Brain Injury Impairs Working Memory and Prefrontal Circuit Function. AB - More than 2.5 million Americans suffer a traumatic brain injury (TBI) each year. Even mild to moderate TBI causes long-lasting neurological effects. Despite its prevalence, no therapy currently exists to treat the underlying cause of cognitive impairment suffered by TBI patients. Following lateral fluid percussion injury (LFPI), the most widely used experimental model of TBI, we investigated alterations in working memory and excitatory/inhibitory synaptic balance in the prefrontal cortex. LFPI impaired working memory as assessed with a T-maze behavioral task. Field excitatory postsynaptic potentials recorded in the prefrontal cortex were reduced in slices derived from brain-injured mice. Spontaneous and miniature excitatory postsynaptic currents onto layer 2/3 neurons were more frequent in slices derived from LFPI mice, while inhibitory currents onto layer 2/3 neurons were smaller after LFPI. Additionally, an increase in action potential threshold and concomitant decrease in firing rate was observed in layer 2/3 neurons in slices from injured animals. Conversely, no differences in excitatory or inhibitory synaptic transmission onto layer 5 neurons were observed; however, layer 5 neurons demonstrated a decrease in input resistance and action potential duration after LFPI. These results demonstrate synaptic and intrinsic alterations in prefrontal circuitry that may underlie working memory impairment caused by TBI. PMID- 26617570 TI - A Broad G Protein-Coupled Receptor Internalization Assay that Combines SNAP-Tag Labeling, Diffusion-Enhanced Resonance Energy Transfer, and a Highly Emissive Terbium Cryptate. AB - Although G protein-coupled receptor (GPCR) internalization has long been considered as a major aspect of the desensitization process that tunes ligand responsiveness, internalization is also involved in receptor resensitization and signaling, as well as the ligand scavenging function of some atypical receptors. Internalization thus contributes to the diversity of GPCR-dependent signaling, and its dynamics and quantification in living cells has generated considerable interest. We developed a robust and sensitive assay to follow and quantify ligand induced and constitutive-induced GPCR internalization but also receptor recycling in living cells. This assay is based on diffusion-enhanced resonance energy transfer (DERET) between cell surface GPCRs labeled with a luminescent terbium cryptate donor and a fluorescein acceptor present in the culture medium. GPCR internalization results in a quantifiable reduction of energy transfer. This method yields a high signal-to-noise ratio due to time-resolved measurements. For various GPCRs belonging to different classes, we demonstrated that constitutive and ligand-induced internalization could be monitored as a function of time and ligand concentration, thus allowing accurate quantitative determination of kinetics of receptor internalization but also half-maximal effective or inhibitory concentrations of compounds. In addition to its selectivity and sensitivity, we provided evidence that DERET-based internalization assay is particularly suitable for characterizing biased ligands. Furthermore, the determination of a Z'-factor value of 0.45 indicates the quality and suitability of DERET-based internalization assay for high-throughput screening (HTS) of compounds that may modulate GPCRs internalization. PMID- 26617568 TI - Recovery Potential After Acute Stroke. AB - In acute stroke, the major factor for recovery is the early use of thrombolysis aimed at arterial recanalization and reperfusion of ischemic brain tissue. Subsequently, neurorehabilitative training critically improves clinical recovery due to augmention of postlesional plasticity. Neuroimaging and electrophysiology studies have revealed that the location and volume of the stroke lesion, the affection of nerve fiber tracts, as well as functional and structural changes in the perilesional tissue and in large-scale bihemispheric networks are relevant biomarkers of post-stroke recovery. However, associated disorders, such as mood disorders, epilepsy, and neurodegenerative diseases, may induce secondary cerebral changes or aggravate the functional deficits and, thereby, compromise the potential for recovery. PMID- 26617571 TI - Biodegradable Polymeric Microsphere-Based Drug Delivery for Inductive Browning of Fat. AB - Brown and beige adipocytes are potent therapeutic agents to increase energy expenditure and reduce risks of obesity and its affiliated metabolic symptoms. One strategy to increase beige adipocyte content is through inhibition of the evolutionarily conserved Notch signaling pathway. However, systemic delivery of Notch inhibitors is associated with off-target effects and multiple dosages of application further faces technical and translational challenges. Here, we report the development of a biodegradable polymeric microsphere-based drug delivery system for sustained, local release of a Notch inhibitor, DBZ. The microsphere based delivery system was fabricated and optimized using an emulsion/solvent evaporation technique to encapsulate DBZ into poly(lactide-co-glycolide) (PLGA), a commonly used biodegradable polymer for controlled drug release. Release studies revealed the ability of PLGA microspheres to release DBZ in a sustained manner. Co-culture of white adipocytes with and without DBZ-loaded PLGA microspheres demonstrated that the released DBZ retained its bioactivity, and effectively inhibited Notch and promoted browning of white adipocytes. Injection of these DBZ-loaded PLGA microspheres into mouse inguinal white adipose tissue depots resulted in browning in vivo. Our results provide the encouraging proof-of principle evidence for the application of biodegradable polymers as a controlled release platform for delivery of browning factors, and pave the way for development of new translational therapeutic strategies for treatment of obesity. PMID- 26617572 TI - GILZ as a Mediator of the Anti-Inflammatory Effects of Glucocorticoids. AB - Glucocorticoid-induced leucine zipper (GILZ) is a dexamethasone-inducible gene that mediates glucocorticoid (GC) actions in a variety of cell types, including many cells of immune system. In particular, GILZ can control T cell activities, such as activation and differentiation, mainly through its ability to homo- and hetero-dimerize with partner proteins, such as NF-kappaB, Ras, and C/EBP. These protein-protein interactions control the regulation of pro-inflammatory target genes. A number of in vitro and in vivo studies using mouse models of inflammatory diseases demonstrate an anti-inflammatory role for GILZ. Here, authors summarize the studies that make GILZ eligible as an anti-inflammatory protein through which GCs can act. These findings permit the future development of pharmacological tools that mimic the therapeutic effects of GCs while avoiding the detrimental ones. PMID- 26617573 TI - Early-Life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats. AB - Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH) neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinizing hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic-GnIH neuronal system using enhanced green fluorescent protein (EGFP)-tagged GnIH transgenic rats. Socially isolated rats were observed for anxious and depressive behaviors. Using immunohistochemistry, we examined c-Fos protein expression in EGFP-GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group housing. We also inspected serotonergic fiber juxtapositions in EGFP-GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviors. The total number of EGFP-GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fiber juxtapositions on EGFP-GnIH neurons were also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early-life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure. PMID- 26617575 TI - Viral Impact on Prokaryotic and Microalgal Activities in the Microphytobenthic Biofilm of an Intertidal Mudflat (French Atlantic Coast). AB - This is the first report on viriobenthos activity within the microbial biofilm located at the top-surface of the intertidal mudflat during emersion in Marennes Oleron Bay (France). By combining in situ and ex situ approaches, the viral production (VP) was linked to the dynamics of prokaryotes and microphytobenthos (MPB). VP averaged 2-4 * 10(8) viruses ml(-1) h(-1). VP correlated positively with the Virus to Prokaryote Ratio, and both were correlated negatively with the water content. The virus-induced mortality of prokaryotes was lower in winter than in summer (6.8 vs. 39.7% of the production) and the C-shunting may supply 2 12% of their Carbon Demand, respectively. VP accounted for 79% of loss in Prokaryotes but the response was delayed compared to the increase in VP suggesting a simultaneous release of viruses of MPB origin. This hypothesis is supported by capsid-sizing of virions by transmission electronic microscopy and bioassays. Harvesting and ex situ maintenance of top-surface sediments was carried out to monitor the dynamics of viruses, prokaryotes and MPB after inoculation with benthic or planktonic viruses. Benthic viruses modified the prokaryotic and MPB dynamics and decreased the photosynthesis efficiency in contrast to planktonic viruses that impacted MPB but not the prokaryotes. PMID- 26617574 TI - Parasitic diarrheal disease: drug development and targets. AB - Diarrhea is the manifestation of gastrointestinal infection and is one of the major causes of mortality and morbidity specifically among the children of less than 5 years age worldwide. Moreover, in recent years there has been a rise in the number of reports of intestinal infections continuously in the industrialized world. These are largely related to waterborne and food borne outbreaks. These occur by the pathogenesis of both prokaryotic and eukaryotic organisms like bacteria and parasites. The parasitic intestinal infection has remained mostly unexplored and under assessed in terms of therapeutic development. The lack of new drugs and the risk of resistance have led us to carry out this review on drug development for parasitic diarrheal diseases. The major focus has been depicted on commercially available drugs, currently synthesized active heterocyclic compounds and unique drug targets, that are vital for the existence and growth of the parasites and can be further exploited for the search of therapeutically active anti-parasitic agents. PMID- 26617576 TI - Modulation of Host Biology by Pseudomonas aeruginosa Quorum Sensing Signal Molecules: Messengers or Traitors. AB - Bacterial cells sense their population density and respond accordingly by producing various signal molecules to the surrounding environments thereby trigger a plethora of gene expression. This regulatory pathway is termed quorum sensing (QS). Plenty of bacterial virulence factors are controlled by QS or QS mediated regulatory systems and QS signal molecules (QSSMs) play crucial roles in bacterial signaling transduction. Moreover, bacterial QSSMs were shown to interfere with host cell signaling and modulate host immune responses. QSSMs not only regulate the expression of bacterial virulence factors but themselves act in the modulation of host biology that can be potential therapeutic targets. PMID- 26617577 TI - Synergism Between Bacterial GAPDH and OMVs: Disparate Mechanisms but Co-Operative Action. PMID- 26617578 TI - Resistance of Undisturbed Soil Microbiomes to Ceftriaxone Indicates Extended Spectrum beta-Lactamase Activity. AB - Emergence and spread of antibiotic resistance, and specifically resistance to third generation cephalosporins associated with extended spectrum beta-lactamase (ESBL) activity, is one of the greatest epidemiological challenges of our time. In this study we addressed the impact of the third generation cephalosporin ceftriaxone on microbial activity and bacterial community composition of two physically and chemically distinct undisturbed soils in highly regulated microcosm experiments. Surprisingly, periodical irrigation of the soils with clinical doses of ceftriaxone did not affect their microbial activity; and only moderately impacted the microbial diversity (alpha and beta) of the two soils. Corresponding slurry experiments demonstrated that the antibiotic capacity of ceftriaxone rapidly diminished in the presence of soil, and ~70% of this inactivation could be explained by biological activity. The biological nature of ceftriaxone degradation in soil was supported by microcosm experiments that amended model Escherichia coli strains to sterile and non-sterile soils in the presence and absence of ceftriaxone and by the ubiquitous presence of ESBL genes (blaTEM, blaCTX-M, and blaOXA) in soil DNA extracts. Collectively, these results suggest that the resistance of soil microbiomes to ceftriaxone stems from biological activity and even more, from broad-spectrum beta-lactamase activity; raising questions regarding the scope and clinical implications of ESBLs in soil microbiomes. PMID- 26617579 TI - Metagenome and Metatranscriptome Revealed a Highly Active and Intensive Sulfur Cycle in an Oil-Immersed Hydrothermal Chimney in Guaymas Basin. AB - The hydrothermal vent system is a typical chemosynthetic ecosystem in which microorganisms play essential roles in the geobiochemical cycling. Although it has been well-recognized that the inorganic sulfur compounds are abundant and actively converted through chemosynthetic pathways, the sulfur budget in a hydrothermal vent is poorly characterized due to the complexity of microbial sulfur cycling resulting from the numerous parties involved in the processes. In this study, we performed an integrated metagenomic and metatranscriptomic analysis on a chimney sample from Guaymas Basin to achieve a comprehensive study of each sulfur metabolic pathway and its hosting microorganisms and constructed the microbial sulfur cycle that occurs in the site. Our results clearly illustrated the stratified sulfur oxidation and sulfate reduction at the chimney wall. Besides, sulfur metabolizing is closely interacting with carbon cycles, especially the hydrocarbon degradation process in Guaymas Basin. This work supports that the internal sulfur cycling is intensive and the net sulfur budget is low in the hydrothermal ecosystem. PMID- 26617580 TI - Biogenesis, Function, and Applications of Virus-Derived Small RNAs in Plants. AB - RNA silencing, an evolutionarily conserved and sequence-specific gene inactivation system, has a pivotal role in antiviral defense in most eukaryotic organisms. In plants, a class of exogenous small RNAs (sRNAs) originating from the infecting virus called virus-derived small interfering RNAs (vsiRNAs) are predominantly responsible for RNA silencing-mediated antiviral immunity. Nowadays, the process of vsiRNA formation and the role of vsiRNAs in plant viral defense have been revealed through deep sequencing of sRNAs and diverse genetic analysis. The biogenesis of vsiRNAs is analogous to that of endogenous sRNAs, which require diverse essential components including dicer-like (DCL), argonaute (AGO), and RNA-dependent RNA polymerase (RDR) proteins. vsiRNAs trigger antiviral defense through post-transcriptional gene silencing (PTGS) or transcriptional gene silencing (TGS) of viral RNA, and they hijack the host RNA silencing system to target complementary host transcripts. Additionally, several applications that take advantage of the current knowledge of vsiRNAs research are being used, such as breeding antiviral plants through genetic engineering technology, reconstructing of viral genomes, and surveying viral ecology and populations. Here, we will provide an overview of vsiRNA pathways, with a primary focus on the advances in vsiRNA biogenesis and function, and discuss their potential applications as well as the future challenges in vsiRNAs research. PMID- 26617581 TI - The Membrane Proteins Involved in Virulence of Cronobacter sakazakii Virulent G362 and Attenuated L3101 Isolates. AB - Cronobacter sakazakii is an opportunistic foodborne pathogen and the virulence differences were previously documented. However, information about membranous proteins involved in virulence differences was not available. In this study, virulent characterization such as biofilm formation and flagella motility between virulent C. sakazakii isolate G362 and attenuated L3101 were determined. Then, two-dimensional gel electrophoresis (2-DE) technology was used to preliminarily reveal differential expression of membranous proteins between G362 and L3101. On the mass spectrometry (MS) analysis and MASCOT research results, fourteen proteins with differential expression were successfully identified. At the threshold of twofold changes, five out of eight membranous proteins were up regulated in G362. Using RT-PCR, the expression abundance of the protein (enzV, ompX, lptE, pstB, and OsmY) genes at mRNA levels was consistent with the results by 2-DE method. The findings presented here provided novel information and valuable knowledge for revealing pathogenic mechanism of C. sakazakii. PMID- 26617582 TI - Antimicrobial Resistance and Genotypic Diversity of Campylobacter Isolated from Pigs, Dairy, and Beef Cattle in Tanzania. AB - Foodborne Campylobacter infections pose a serious threat to public health worldwide. However, the occurrence and characteristics of Campylobacter in food animals and products remain largely unknown in Tanzania. The objective of this study was to determine the prevalence, antibiotic resistance, and genetic profiles (sequence types, STs) of Campylobacter isolated from feces of pigs and dairy and beef cattle in Tanzania. Overall, 259 (~30%) of 864 samples were positive for Campylobacter spp, which were detected in 32.5, 35.4, and 19.6% of the pig, dairy, and beef cattle samples, respectively. Multiplex PCR analysis identified 64.5 and 29.3% of the Campylobacter isolates as C. coli and C. jejuni, respectively. The majority (91.9%) of the isolates from pig samples were identified as C. coli, while C. jejuni accounted for 65.5% of the isolates from cattle. Antimicrobial susceptibility testing using the disk diffusion assay and the broth microdilution method revealed resistance to: ampicillin (Amp) (70.3% and 75.7%, respectively), gentamicin (Gen) (1.8% and 12.6%), streptomycin (Str) (65.8 and 74.8%), erythromycin (Ery) (41.4 and 48.7%), tetracycline (Tet) (18.9 and 23.4%), and ciprofloxacin (Cip) (14.4 and 7.2%). Resistance to nalidixic acid (Nal) (39.6%), azithromycin (Azm) (13.5%), and chloramphenicol (Chl) (4.5%) was determined using the disk diffusion assay only, while resistance to tylosin (Tyl) (38.7%) was quantified using the broth microdilution method. Multilocus sequence typing of 111 Campylobacter isolates resulted in the identification of 48 STs (26 C. jejuni and 22 C. coli) of which seven were novel (six C. jejuni and one C. coli). Taken together, this study revealed the high prevalence, genetic diversity and antimicrobial resistance of Campylobacter in important food animals in Tanzania, which highlights the urgent need for the surveillance and control of Campylobacter in this country. PMID- 26617583 TI - Heat Shock Protein 90 (Hsp90) as a Molecular Target for the Development of Novel Drugs Against the Dermatophyte Trichophyton rubrum. AB - Treatment of fungal infections is difficult due to several reasons, such as side effects of drugs, emergence of resistant strains, and limited number of molecular targets for the drug compounds. In fungi, heat shock proteins (Hsps) have been implicated in several processes with the conserved molecular chaperone Hsp90 emerging as a potential target for antifungal therapy. It plays key cellular roles by eliciting molecular response to environmental changes, morphogenesis, antifungal resistance, and fungal pathogenicity. Here, we evaluated the transcription profiles of hsp genes of the most prevalent dermatophyte Trichophyton rubrum in response to different environmental challenges including nutrient availability, interaction with cells and molecules of the host tissue, and drug exposure. The results suggest that each Hsp responds to a specific stress condition and that the cohort of Hsps facilitates fungal survival under various environmental challenges. Chemical inhibition of Hsp90 resulted in increased susceptibility of the fungus to itraconazole and micafungin, and decreased its growth in human nails in vitro. Moreover, some hsp and related genes were modulated by Hsp90 at the transcriptional level. We are suggesting a role of Hsp90 in the pathogenicity and drug susceptibility of T. rubrum as well as the regulation of other Hsps. The synergism observed between the inhibition of Hsp90 and the effect of itraconazole or micafungin in reducing the fungal growth is of great interest as a novel and potential strategy to treat dermatophytoses. PMID- 26617584 TI - Inside the Envelope: Endogenous Retrovirus-K Env as a Biomarker and Therapeutic Target. AB - Due to multiple ancestral human retroviral germ cell infections, the modern human genome is strewn with relics of these infections, termed endogenous retroviruses (ERVs). ERV expression has been silenced due to negative selective pressures and genetic phenomena such as mutations and epigenetic silencing. Nonetheless, select ERVs have retained the capacity to be damaging to their host when reawakened. Much of the current research on the ERVK Env protein strongly suggests a causal or contributive role in the pathogenesis of various cancers, autoimmune and infectious diseases. Additionally, there is a small body of research suggesting that ERVK Env has been domesticated for use in placental development, akin to the ERVW syncytin. Though much is left to ascertain, the innate immune response to ERVK Env expression has been partially characterized and appears to be due to a region located in the transmembrane domain of the Env protein. In this review, we aim to highlight ERVK Env as a biomarker for inflammatory conditions and explore its use as a future therapeutic target for cancers, HIV infection and neurological disease. PMID- 26617585 TI - Evaluation of Fungal Laccase Immobilized on Natural Nanostructured Bacterial Cellulose. AB - The aim of this work was to assess the possibility of using native bacterial nanocellulose (BC) as a carrier for laccase immobilization. BC was synthesized by Gluconacetobacter xylinus, which was statically cultivated in a mannitol-based medium and was freeze-dried to form BC sponge after purification. For the first time, fungal laccase from Trametes versicolor was immobilized on the native nanofibril network-structured BC sponge through physical adsorption and cross linking with glutaraldehyde. The properties including morphologic and structural features of the BC as well as the immobilized enzyme were thoroughly investigated. It was found that enzyme immobilized by cross-linking exhibited broader pH operation range of high catalytic activity as well as higher running stability compared to free and adsorbed enzyme. Using ABTS as substrate, the optimum pH value was 3.5 for the adsorption-immobilized laccase and 4.0 for the crosslinking-immobilized laccase. The immobilized enzyme retained 69% of the original activity after being recycled seven times. Novel applications of the BC immobilized enzyme tentatively include active packaging, construction of biosensors, and establishment of bioreactors. PMID- 26617586 TI - The Helicase Activity of Hyperthermophilic Archaeal MCM is Enhanced at High Temperatures by Lysine Methylation. AB - Lysine methylation and methyltransferases are widespread in the third domain of life, archaea. Nevertheless, the effects of methylation on archaeal proteins wait to be defined. Here, we report that recombinant sisMCM, an archaeal homolog of Mcm2-7 eukaryotic replicative helicase, is methylated by aKMT4 in vitro. Mono methylation of these lysine residues occurs coincidently in the endogenous sisMCM protein purified from the hyperthermophilic Sulfolobus islandicus cells as indicated by mass spectra. The helicase activity of mini-chromosome maintenance (MCM) is stimulated by methylation, particularly at temperatures over 70 degrees C. The methylated MCM shows optimal DNA unwinding activity after heat-treatment between 76 and 82 degrees C, which correlates well with the typical growth temperatures of hyperthermophilic Sulfolobus. After methylation, the half life of MCM helicase is dramatically extended at 80 degrees C. The methylated sites are located on the accessible protein surface, which might modulate the intra- and inter- molecular interactions through changing the hydrophobicity and surface charge. Furthermore, the methylation-mimic mutants of MCM show heat resistance helicase activity comparable to the methylated MCM. These data provide the biochemical evidence that posttranslational modifications such as methylation may enhance kinetic stability of proteins under the elevated growth temperatures of hyperthermophilic archaea. PMID- 26617587 TI - Fusarium Oxysporum Volatiles Enhance Plant Growth Via Affecting Auxin Transport and Signaling. AB - Volatile organic compounds (VOCs) have well-documented roles in plant-plant communication and directing animal behavior. In this study, we examine the less understood roles of VOCs in plant-fungal relationships. Phylogenetically and ecologically diverse strains of Fusarium oxysporum, a fungal species complex that often resides in the rhizosphere of assorted plants, produce volatile compounds that augment shoot and root growth of Arabidopsis thaliana and tobacco. Growth responses of A. thaliana hormone signaling mutants and expression patterns of a GUS reporter gene under the auxin-responsive DR5 promoter supported the involvement of auxin signaling in F. oxysporum volatile-mediated growth enhancement. In addition, 1-naphthylthalamic acid, an inhibitor of auxin efflux, negated F. oxysporum volatile-mediated growth enhancement in both plants. Comparison of the profiles of volatile compounds produced by F. oxysporum strains that differentially affected plant growth suggests that the relative compositions of both growth inhibitory and stimulatory compounds may determine the degree of plant growth enhancement. Volatile-mediated signaling between fungi and plants may represent a potentially conserved, yet mostly overlooked, mechanism underpinning plant-fungus interactions and fungal niche adaption. PMID- 26617589 TI - Characterization of a CTX-M-15 Producing Klebsiella Pneumoniae Outbreak Strain Assigned to a Novel Sequence Type (1427). AB - Extended-spectrum -lactamase producing Klebsiella pneumoniae have emerged as one of the major nosocomial pathogens. Between July and September 2012, a CTX-M-15 producing K. pneumoniae caused an outbreak in a university hospital in the Netherlands. The outbreak isolates were characterized and assigned to a novel sequence type (ST1427). An epidemiological link between affected patients was supported by patient contact tracing and whole-genome phylogenetic analysis. Intra-strain polymorphism was detected among multiple isolates obtained from different body sites of the index patient, which may relate to antibiotic treatment and/or host adaptation. Environmental contamination caused by the outbreak clone was found in the patient rooms even on medical equipment. The novel clone was not closely related to any known endemic/epidemic clone, but carried a set of a plasmid-borne resistance genes [bla CTX-M-15, bla TEM-1, bla OXA-1, aac(6')-Ib-cr, qnrB1, tetA(A), aac(3)-II]. Analysis of its virulence factors revealed a previously uncharacterized capsular biosynthesis region and two uncharacterized fimbriae gene clusters, and suggested that the new clone was not hypervirulent. To our knowledge, this is the first outbreak report of K. pneumoniae ST1427, and our study could be of help to understand the features of this newly emerging clone. PMID- 26617588 TI - Genotypic and Antimicrobial Susceptibility of Carbapenem-resistant Acinetobacter baumannii: Analysis of is Aba Elements and bla OXA-23-like Genes Including a New Variant. AB - Carbapenem-resistant Acinetobacter baumannii (CR-AB) causes serious nosocomial infections, especially in ICU wards of hospitals, worldwide. Expression of bla OXA genes is the chief mechanism of conferring carbapenem resistance among CR-AB. Although some bla OXA genes have been studied among CR-AB isolates from Iran, their bla OXA-23-like genes have not been investigated. We used a multiplex-PCR to detect Ambler class A, B, and D carbapenemases of 85 isolates, and determined that 34 harbored bla OXA-23-like genes. Amplified fragment length polymorphism (AFLP) genotyping, followed by DNA sequencing of bla OXA-23-like amplicons of CR AB from each AFLP group was used to characterize their bla OXA-23-like genes. We also assessed the antimicrobial susceptibility pattern of CR-AB isolates, and tested whether they harbored insertion sequences ISAba1 and ISAba4. Sequence comparison with reference strain A. baumannii (NCTC12156) revealed five types of mutations in bla OXA-23-like genes; including one novel variant and four mutants that were already reported from China and the USA. All of the bla OXA-23-like genes mutations were associated with increased minimum inhibitory concentrations (MICs) against imipenem. ISAba1 and ISAba4 sequences were detected upstream of bla OXA-23 genes in 19 and 7% of isolates, respectively. The isolation of CR-AB with new bla OXA-23 mutations including some that have been reported from the USA and China highlights CR-AB pervasive distribution, which underscores the importance of concerted national and global efforts to control the spread of CR AB isolates worldwide. PMID- 26617590 TI - Assessment of Culturable Tea Rhizobacteria Isolated from Tea Estates of Assam, India for Growth Promotion in Commercial Tea Cultivars. AB - In the present study, 217 rhizobacterial isolates were obtained from six different tea estates of Assam, India and subjected to preliminary in vitro plant growth promotion (PGP) screening for indole acetic acid (IAA) production, phosphate solubilization, siderophore production and ammonia production. Fifty isolates showed all the PGP traits and five isolates did not exhibit any PGP traits. These 50 potential isolates were further analyzed for quantitative estimation of the PGP traits along with the aminocyclopropane-1-carboxylate (ACC) deaminase, protease and cellulose production. After several rounds of screening, four rhizobacteria were selected based on their maximum ability to produce in vitro PGP traits and their partial 16S rRNA gene sequence analysis revealed that they belong to Enterobacter lignolyticus strain TG1, Burkholderia sp. stain TT6, Bacillus pseudomycoides strain SN29 and Pseudomonas aeruginosa strain KH45. To evaluate the efficacy of these four rhizobacteria as plant growth promoters, three different commercially important tea clones TV1, TV19, and TV20 plants were inoculated with these rhizobacteria in greenhouse condition and compared to the uninoculated control plants. Though, all the rhizobacterial treatments showed an increase in plant growth compared to control but the multivariate PCA analysis confirmed more growth promotion by TG1 and SN29 strains than the other treatments in all three clones. To validate this result, the fold change analysis was performed and it revealed that the tea clone TV19 plants inoculated with the E. lignolyticus strain TG1 showed maximum root biomass production with an increase in 4.3-fold, shoot biomass with increase in 3.1-fold, root length by 2.2-fold and shoot length by 1.6-fold. Moreover, two way ANOVA analysis also revealed that rhizobacterial treatment in different tea clones showed the significant increase (P < 0.05) in growth promotion compared to the control. Thus, this study indicates that the potential of these indigenous plant growth promoting rhizobacteria isolates to use as microbial inoculation or biofertilizer for growth promotion of tea crops. PMID- 26617592 TI - On the (Un)greenness of Biocatalysis: Some Challenging Figures and Some Promising Options. AB - Biocatalysis is generally regarded as a "green" technology. This statement is justified by the mild reaction conditions, the use of aqueous reaction media-with water as the paradigm of green solvents-, and the renewable nature of the biocatalysts. However, researchers making these statements frequently do not take into account the entire picture of their processes. Aspects like water consumption, wastewater production, titers, and metrics of the (diluted?) biocatalytic processes are important as well. With those figures at hand, many biocatalytic reactions do not appear so green anymore. This article critically discusses some common wrong assumptions given for biocatalytic approaches, with regard to their environmental impact, and actual greenness. Some promising biocatalytic approaches, such as the use of biphasic systems involving biogenic solvents, deep-eutectic-solvents (and biogenic ionic liquids), water-free media, solvent-free processes, are briefly introduced, showing that enzyme catalysis can actually be a robust sustainable alternative for chemical processes. PMID- 26617591 TI - On the Ancestral UDP-Glucose Pyrophosphorylase Activity of GalF from Escherichia coli. AB - In bacteria, UDP-glucose is a central intermediate in carbohydrate metabolism. The enzyme responsible for its synthesis is encoded by the galU gene and its deletion generates cells unable to ferment galactose. In some bacteria, there is a second gene, galF, encoding for a protein with high sequence identity to GalU. However, the role of GalF has been contradictory regarding its catalytic capability and not well understood. In this work we show that GalF derives from a catalytic (UDP-glucose pyrophosphorylase) ancestor, but its activity is very low compared to GalU. We demonstrated that GalF has some residual UDP-glucose pyrophosphorylase activity by in vitro and in vivo experiments in which the phenotype of a galU (-) strain was reverted by the over-expression of GalF and its mutant. To demonstrate its evolutionary path of "enzyme inactivation" we enhanced the catalysis by mutagenesis and showed the importance of the quaternary structure. This study provides important information to understand the structural and functional evolutionary origin of the protein GalF in enteric bacteria. PMID- 26617593 TI - Quasispecies Analyses of the HIV-1 Near-full-length Genome With Illumina MiSeq. AB - Human immunodeficiency virus type-1 (HIV-1) exhibits high between-host genetic diversity and within-host heterogeneity, recognized as quasispecies. Because HIV 1 quasispecies fluctuate in terms of multiple factors, such as antiretroviral exposure and host immunity, analyzing the HIV-1 genome is critical for selecting effective antiretroviral therapy and understanding within-host viral coevolution mechanisms. Here, to obtain HIV-1 genome sequence information that includes minority variants, we sought to develop a method for evaluating quasispecies throughout the HIV-1 near-full-length genome using the Illumina MiSeq benchtop deep sequencer. To ensure the reliability of minority mutation detection, we applied an analysis method of sequence read mapping onto a consensus sequence derived from de novo assembly followed by iterative mapping and subsequent unique error correction. Deep sequencing analyses of aHIV-1 clone showed that the analysis method reduced erroneous base prevalence below 1% in each sequence position and discarded only < 1% of all collected nucleotides, maximizing the usage of the collected genome sequences. Further, we designed primer sets to amplify the HIV-1 near-full-length genome from clinical plasma samples. Deep sequencing of 92 samples in combination with the primer sets and our analysis method provided sufficient coverage to identify >1%-frequency sequences throughout the genome. When we evaluated sequences of pol genes from 18 treatment naive patients' samples, the deep sequencing results were in agreement with Sanger sequencing and identified numerous additional minority mutations. The results suggest that our deep sequencing method would be suitable for identifying within-host viral population dynamics throughout the genome. PMID- 26617595 TI - In situ Detection of Microbial Life in the Deep Biosphere in Igneous Ocean Crust. AB - The deep biosphere is a major frontier to science. Recent studies have shown the presence and activity of cells in deep marine sediments and in the continental deep biosphere. Volcanic lavas in the deep ocean subsurface, through which substantial fluid flow occurs, present another potentially massive deep biosphere. We present results from the deployment of a novel in situ logging tool designed to detect microbial life harbored in a deep, native, borehole environment within igneous oceanic crust, using deep ultraviolet native fluorescence spectroscopy. Results demonstrate the predominance of microbial-like signatures within the borehole environment, with densities in the range of 10(5) cells/mL. Based on transport and flux models, we estimate that such a concentration of microbial cells could not be supported by transport through the crust, suggesting in situ growth of these communities. PMID- 26617594 TI - RNA-seq de novo Assembly Reveals Differential Gene Expression in Glossina palpalis gambiensis Infected with Trypanosoma brucei gambiense vs. Non-Infected and Self-Cured Flies. AB - Trypanosoma brucei gambiense (Tbg), causing the sleeping sickness chronic form, completes its developmental cycle within the tsetse fly vector Glossina palpalis gambiensis (Gpg) before its transmission to humans. Within the framework of an anti-vector disease control strategy, a global gene expression profiling of trypanosome infected (susceptible), non-infected, and self-cured (refractory) tsetse flies was performed, on their midguts, to determine differential genes expression resulting from in vivo trypanosomes, tsetse flies (and their microbiome) interactions. An RNAseq de novo assembly was achieved. The assembled transcripts were mapped to reference sequences for functional annotation. Twenty four percent of the 16,936 contigs could not be annotated, possibly representing untranslated mRNA regions, or Gpg- or Tbg-specific ORFs. The remaining contigs were classified into 65 functional groups. Only a few transposable elements were present in the Gpg midgut transcriptome, which may represent active transpositions and play regulatory roles. One thousand three hundred and seventy three genes differentially expressed (DEGs) between stimulated and non-stimulated flies were identified at day-3 post-feeding; 52 and 1025 between infected and self-cured flies at 10 and 20 days post-feeding, respectively. The possible roles of several DEGs regarding fly susceptibility and refractoriness are discussed. The results provide new means to decipher fly infection mechanisms, crucial to develop anti-vector control strategies. PMID- 26617596 TI - Identification of Genetic Modules Mediating the Jekyll and Hyde Interaction of Dinoroseobacter shibae with the Dinoflagellate Prorocentrum minimum. AB - The co-cultivation of the alphaproteobacterium Dinoroseobacter shibae with the dinoflagellate Prorocentrum minimum is characterized by a mutualistic phase followed by a pathogenic phase in which the bacterium kills aging algae. Thus it resembles the "Jekyll-and-Hyde" interaction that has been proposed for other algae and Roseobacter. Here, we identified key genetic components of this interaction. Analysis of the transcriptome of D. shibae in co-culture with P. minimum revealed growth phase dependent changes in the expression of quorum sensing, the CtrA phosphorelay, and flagella biosynthesis genes. Deletion of the histidine kinase gene cckA which is part of the CtrA phosphorelay or the flagella genes fliC or flgK resulted in complete lack of growth stimulation of P. minimum in co-culture with the D. shibae mutants. By contrast, pathogenicity was entirely dependent on one of the extrachromosomal elements of D. shibae, the 191 kb plasmid. The data show that flagella and the CtrA phosphorelay are required for establishing mutualism and prove a cell density dependent killing effect of D. shibae on P. minimum which is mediated by an unknown factor encoded on the 191 kb plasmid. PMID- 26617597 TI - High Prevalence of Hyper-Aerotolerant Campylobacter jejuni in Retail Poultry with Potential Implication in Human Infection. AB - Campylobacter jejuni is a leading cause of foodborne illnesses around the world. Since C. jejuni is microaerophilic and sensitive to oxygen, aerotolerance is important in the transmission of C. jejuni to humans via foods under aerobic conditions. In this study, 70 C. jejuni strains were isolated from retail raw chicken meats and were subject to multilocus sequence typing (MLST) analysis. In the aerotolerance testing by aerobic shaking at 200 rpm, 50 (71.4%) isolates survived after 12 h (i.e., aerotolerant), whereas 20 (28.6%) isolates did not (i.e., aerosensitive). Interestingly, further aerobic cultivation showed that 25 (35.7%) isolates still survived even after 24 h of vigorous aerobic shaking (i.e., hyper-aerotolerant). Compared to aerosensitive strains, the hyper aerotolerant strains exhibited increased resistance to oxidative stress, both peroxide and superoxide. A mutation of ahpC in hyper-aerotolerant strains significantly impaired aerotolerance, indicating oxidative stress defense plays an important role in hyper-aerotolerance. The aerotolerant and hyper-aerotolerant strains were primarily classified into MLST clonal complexes (CCs)-21 and -45, which are known to be the major CCs implicated in human gastroenteritis. Compared to the aerosensitive strains, CC-21 was more dominant than CC-45 in aerotolerant and hyper-aerotolerant strains. The findings in this study revealed that hyper aerotolerant C. jejuni is highly prevalent in raw chicken meats. The enhanced aerotolerance in C. jejuni would impact human infection by increasing possibilities of the foodborne transmission of C. jejuni under aerobic conditions. PMID- 26617598 TI - Identification and Partial Characterization of Potential FtsL and FtsQ Homologs of Chlamydia. AB - Chlamydia is amongst the rare bacteria that lack the critical cell division protein FtsZ. By annotation, Chlamydia also lacks several other essential cell division proteins including the FtsLBQ complex that links the early (e.g., FtsZ) and late (e.g., FtsI/Pbp3) components of the division machinery. Here, we report chlamydial FtsL and FtsQ homologs. Ct271 aligned well with Escherichia coli FtsL and shared sequence homology with it, including a predicted leucine-zipper like motif. Based on in silico modeling, we show that Ct764 has structural homology to FtsQ in spite of little sequence similarity. Importantly, ct271/ftsL and ct764/ftsQ are present within all sequenced chlamydial genomes and are expressed during the replicative phase of the chlamydial developmental cycle, two key characteristics for a chlamydial cell division gene. GFP-Ct764 localized to the division septum of dividing transformed chlamydiae, and, importantly, over expression inhibited chlamydial development. Using a bacterial two-hybrid approach, we show that Ct764 interacted with other components of the chlamydial division apparatus. However, Ct764 was not capable of complementing an E. coli FtsQ depletion strain in spite of its ability to interact with many of the same division proteins as E. coli FtsQ, suggesting that chlamydial FtsQ may function differently. We previously proposed that Chlamydia uses MreB and other rod-shape determining proteins as an alternative system for organizing the division site and its apparatus. Chlamydial FtsL and FtsQ homologs expand the number of identified chlamydial cell division proteins and suggest that Chlamydia has likely kept the late components of the division machinery while substituting the Mre system for the early components. PMID- 26617599 TI - Comparative Genomic Insights into Ecophysiology of Neutrophilic, Microaerophilic Iron Oxidizing Bacteria. AB - Neutrophilic microaerophilic iron-oxidizing bacteria (FeOB) are thought to play a significant role in cycling of carbon, iron and associated elements in both freshwater and marine iron-rich environments. However, the roles of the neutrophilic microaerophilic FeOB are still poorly understood due largely to the difficulty of cultivation and lack of functional gene markers. Here, we analyze the genomes of two freshwater neutrophilic microaerophilic stalk-forming FeOB, Ferriphaselus amnicola OYT1 and Ferriphaselus strain R-1. Phylogenetic analyses confirm that these are distinct species within Betaproteobacteria; we describe strain R-1 and propose the name F. globulitus. We compare the genomes to those of two freshwater Betaproteobacterial and three marine Zetaproteobacterial FeOB isolates in order to look for mechanisms common to all FeOB, or just stalk forming FeOB. The OYT1 and R-1 genomes both contain homologs to cyc2, which encodes a protein that has been shown to oxidize Fe in the acidophilic FeOB, Acidithiobacillus ferrooxidans. This c-type cytochrome common to all seven microaerophilic FeOB isolates, strengthening the case for its common utility in the Fe oxidation pathway. In contrast, the OYT1 and R-1 genomes lack mto genes found in other freshwater FeOB. OYT1 and R-1 both have genes that suggest they can oxidize sulfur species. Both have the genes necessary to fix carbon by the Calvin-Benson-Basshom pathway, while only OYT1 has the genes necessary to fix nitrogen. The stalk-forming FeOB share xag genes that may help form the polysaccharide structure of stalks. Both OYT1 and R-1 make a novel biomineralization structure, short rod-shaped Fe oxyhydroxides much smaller than their stalks; these oxides are constantly shed, and may be a vector for C, P, and metal transport to downstream environments. Our results show that while different FeOB are adapted to particular niches, freshwater and marine FeOB likely share common mechanisms for Fe oxidation electron transport and biomineralization pathways. PMID- 26617600 TI - Survival with a Helping Hand: Campylobacter and Microbiota. AB - Campylobacteriosis is the most important bacterial food-borne disease in the developed world. Consumption of chicken meat, beef or raw milk, direct contact with ruminants and exposure to contaminated surface water or even consumption of tap water have been identified as risk factors for human disease. However, the most important risk factor is consumption of and/or handling contaminated chicken. Campylobacter spp. are fastidious microorganisms but must somehow survive outside the host, especially in food and agricultural environments and also resist the innate and humoral immune responses inside the host. In this paper we hypothesize that other microorganisms in mixed populations with Campylobacter may act to improve survival outside the host and may also protect the pathogen against the intestinal immune system. Our evidence for this hypothesis is based on: 1. newly generated microbial community analysis; 2. the prolonged survival of Campylobacter in mixed species biofilms and in co-culture with environmental bacteria; 3. improved survival in amoebae and rumen fluid; 4. sulfur release and iron uptake systems within the intestinal lumen. This would make Campylobacter an exceptional food-borne pathogen. With this in mind, new strategies are necessary to combat Campylobacter along the total food chain. PMID- 26617601 TI - On-Demand Isolation of Bacteriophages Against Drug-Resistant Bacteria for Personalized Phage Therapy. AB - Bacteriophages are bacterial viruses, capable of killing even multi-drug resistant bacterial cells. For this reason, therapeutic use of phages is considered as a possible alternative to conventional antibiotics. However, phages are very host specific in comparison to wide-spectrum antibiotics and thus preparation of phage-cocktails beforehand against pathogens can be difficult. In this study, we evaluate whether it may be possible to isolate phages on-demand from environmental reservoir. We attempted to enrich infectious bacteriophages from sewage against nosocomial drug-resistant bacterial strains of different medically important species in order to evaluate the probability of discovering novel therapeutic phages. Stability and host-range were determined for the acquired phages. Our results suggest that on-demand isolation of phages is possible against Pseudomonas aeruginosa, Salmonella and extended spectrum beta lactamase Escherichia coli and Klebsiella pneumoniae. The probability of finding suitable phages was less than 40% against vancomycin resistant Enterococcus and Acinetobacter baumannii strains. Furthermore, isolation of new phages against methicillin resistant Staphylococcus aureus strains was found to be very difficult. PMID- 26617602 TI - Slow and Fast Evolving Endosymbiont Lineages: Positive Correlation between the Rates of Synonymous and Non-Synonymous Substitution. AB - The availability of complete genome sequences of bacterial endosymbionts with strict vertical transmission to the host progeny opens the possibility to estimate molecular evolutionary rates in different lineages and understand the main biological mechanisms influencing these rates. We have compared the rates of evolution for non-synonymous and synonymous substitutions in nine bacterial endosymbiont lineages, belonging to four clades (Baumannia, Blochmannia, Portiera, and Sulcia). The main results are the observation of a positive correlation between both rates with differences among lineages of up to three orders of magnitude and that the substitution rates decrease over long endosymbioses. To explain these results we propose three mechanisms. The first, variations in the efficiencies of DNA replication and DNA repair systems, is unable to explain most of the observed differences. The second, variations in the generation time among bacterial lineages, would be based on the accumulation of fewer DNA replication errors per unit time in organisms with longer generation times. The third, a potential control of the endosymbiont DNA replication and repair systems through the transfer of nuclear-encoded proteins, could explain the lower rates in long-term obligate endosymbionts. Because the preservation of the genomic integrity of the harbored obligate endosymbiont would be advantageous for the insect host, biological mechanisms producing a general reduction in the rates of nucleotide substitution per unit of time would be a target for natural selection. PMID- 26617603 TI - Antimicrobial and Anti-Virulence Activity of Capsaicin Against Erythromycin Resistant, Cell-Invasive Group A Streptococci. AB - Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the active component of Capsicum plants (chili peppers), which are grown as food and for medicinal purposes since ancient times, and is responsible for the pungency of their fruit. Besides its multiple pharmacological and physiological properties (pain relief, cancer prevention, and beneficial cardiovascular, and gastrointestinal effects) capsaicin has recently attracted considerable attention because of its antimicrobial and anti-virulence activity. This is the first study of its in vitro antibacterial and anti-virulence activity against Streptococcus pyogenes (Group A streptococci, GAS), a major human pathogen. The test strains were previously characterized, erythromycin-susceptible (n = 5) and erythromycin resistant (n = 27), cell-invasive pharyngeal isolates. The MICs of capsaicin were 64-128 MUg/mL (the most common MIC was 128 MUg/mL). The action of capsaicin was bactericidal, as suggested by MBC values that were equal or close to the MICs, and by early detection of dead cells in the live/dead assay. No capsaicin resistant mutants were obtained in single-step resistance selection studies. Interestingly, growth in presence of sublethal capsaicin concentrations induced an increase in biofilm production (p <= 0.05) and in the number of bacteria adhering to A549 monolayers, and a reduction in cell-invasiveness and haemolytic activity (both p <= 0.05). Cell invasiveness fell so dramatically that a highly invasive strain became non-invasive. The dose-response relationship, characterized by opposite effects of low and high capsaicin doses, suggests a hormetic response. The present study documents that capsaicin has promising bactericidal activity against erythromycin-resistant, cell-invasive pharyngeal GAS isolates. The fact that sublethal concentrations inhibited cell invasion and reduced haemolytic activity, two important virulence traits of GAS, is also interesting, considering that cell-invasive, erythromycinresistant strains can evade beta-lactams by virtue of intracellular location and macrolides by virtue of resistance, thus escaping antibiotic treatment. By inhibiting intracellular invasion and haemolytic activity, capsaicin could thus prevent both formation of a difficult to eradicate intracellular reservoir, and infection spread to deep tissues. PMID- 26617604 TI - Tolerogenic Dendritic Cells for Regulatory T Cell Induction in Man. AB - Dendritic cells (DCs) are highly specialized professional antigen-presenting cells that regulate immune responses, maintaining the balance between tolerance and immunity. Mechanisms via which they can promote central and peripheral tolerance include clonal deletion, the inhibition of memory T cell responses, T cell anergy, and induction of regulatory T cells (Tregs). These properties have led to the analysis of human tolerogenic DCs as a therapeutic strategy for the induction or re-establishment of tolerance. In recent years, numerous protocols for the generation of human tolerogenic DCs have been developed and their tolerogenic mechanisms, including induction of Tregs, are relatively well understood. Phase I trials have been conducted in autoimmune disease, with results that emphasize the feasibility and safety of treatments with tolerogenic DCs. Therefore, the scientific rationale for the use of tolerogenic DCs therapy in the fields of transplantation medicine and allergic and autoimmune diseases is strong. This review will give an overview on efforts and protocols to generate human tolerogenic DCs with focus on IL-10-modulated DCs as inducers of Tregs and discuss their clinical applications and challenges faced in further developing this form of immunotherapy. PMID- 26617605 TI - Bacterial Exotoxins and the Inflammasome. AB - The inflammasomes are intracellular protein complexes that play an important role in innate immune sensing. Activation of inflammasomes leads to activation of caspase-1 and maturation and secretion of the pro-inflammatory cytokines interleukin (IL)-1beta and IL-18. In certain myeloid cells, this activation can also lead to an inflammatory cell death (pyroptosis). Inflammasome sensor proteins have evolved to detect a range of microbial ligands and bacterial exotoxins either through direct interaction or by detection of host cell changes elicited by these effectors. Bacterial exotoxins activate the inflammasomes through diverse processes, including direct sensor cleavage, modulation of ion fluxes through plasma membrane pore formation, and perturbation of various host cell functions. In this review, we summarize the findings on some of the bacterial exotoxins that activate the inflammasomes. PMID- 26617606 TI - Cigarette Smoke Amplifies Inflammatory Response and Atherosclerosis Progression Through Activation of the H1R-TLR2/4-COX2 Axis. AB - Emerging evidence suggests that infection and persistent inflammation are key players in the pathogenesis of atherosclerotic cardiovascular disease (CVD). Although it is well established that cigarette smoke (CS) promotes atherosclerotic CVD, very little is known about the potential impact of the collective effects of CS and intermittent or chronic subclinical infection on atherosclerosis. Our previous studies demonstrated that mast cell-derived histamine and lipopolysaccharide (LPS) synergistically enhance endothelial cell inflammatory response. We further noted that the synergy between histamine and LPS was due to reciprocal upregulation of histamine receptor and Toll-like receptor 4 (TLR4) expression and functions. These results suggest that the combined and persistent effects of mast cell mediators and bacterial agents on the vasculature are risk factors of CVD. Our recent data demonstrated that CS extract enhances histamine- and LPS-induced expression of cyclooxygenase-2 (COX 2) in endothelial cells, suggesting that CS and mast cell mediators may collectively amplify inflammatory response in the vessel wall. We hypothesize that CS enhances histamine-mediated upregulation of TLR2/TLR4 signaling in the endothelium and promotes progression of atherosclerosis. This article presents our perspective on the modulatory effects of CS and nicotine on the "histamine TLR-COX-2 axis." PMID- 26617607 TI - Activating KIRs and NKG2C in Viral Infections: Toward NK Cell Memory? AB - Natural killer (NK) cells are important players in the immune defense against viral infections. The contribution of activating killer immunoglobulin-like receptors (KIRs) and CD94/NKG2C in regulating anti-viral responses has recently emerged. Thus, in the hematopoietic stem cell transplantation setting, the presence of donor activating KIRs (aKIRs) may protect against viral infections, while in HIV-infected individuals, KIR3DS1, in combination with HLA-Bw4-I80, results in reduction of viral progression. Since, studies have been performed mainly at the genetic or transcriptional level, the effective size, the function, and the "licensing" status of NK cells expressing aKIRs, as well as the nature of their viral ligands, require further investigation. Certain viral infections, mainly due to Human cytomegalovirus (HCMV), can deeply influence the NK cell development and function by inducing a marked expansion of mature NKG2C(+) NK cells expressing self-activating KIRs. This suggests that NKG2C and/or aKIRs are involved in the selective proliferation of this subset. The persistent, HCMV induced, imprinting suggests that NK cells may display unexpected adaptive immune traits. The role of aKIRs and NKG2C in regulating NK cell responses and promoting a memory-like response to certain viruses is discussed. PMID- 26617608 TI - A SOCS1/3 Antagonist Peptide Protects Mice Against Lethal Infection with Influenza A Virus. AB - We have developed an antagonist to suppressor of cytokine signaling 1 (SOCS1), pJAK2(1001-1013), which corresponds to the activation loop of the Janus kinase JAK2, which is the binding site for the kinase inhibitory region (KIR) of SOCS1. Internalized pJAK2(1001-1013) inhibits SOCS1 and SOCS3. SOCS1 has been shown to be an influenza virus-induced virulence factor that enhances infection of cells. The antagonist was protective in cell culture and in influenza virus PR8 lethally infected C57BL/6 mice. The SOCS antagonist also prevented adverse morbidity as assessed by parameters, such as weight loss and drop in body temperature, and showed potent induction of both the cellular and humoral immune responses to the influenza virus candidate universal antigen matrix protein 2 (M2e). The SOCS antagonist, thus, protected mice against lethal influenza virus infection and possessed potent adjuvancy against the M2e candidate influenza virus universal vaccine antigen. PMID- 26617610 TI - A 6-Year-Long Manipulation with Soil Warming and Canopy Nitrogen Additions does not Affect Xylem Phenology and Cell Production of Mature Black Spruce. AB - The predicted climate warming and increased atmospheric inorganic nitrogen deposition are expected to have dramatic impacts on plant growth. However, the extent of these effects and their interactions remains unclear for boreal forest trees. The aim of this experiment was to investigate the effects of increased soil temperature and nitrogen (N) depositions on stem intra-annual growth of two mature stands of black spruce [Picea mariana (Mill.) BSP] in Quebec, QC, Canada. During 2008-2013, the soil around mature trees was warmed up by 4 degrees C with heating cables during the growing season and precipitations containing three times the current inorganic N concentration were added by frequent canopy applications. Xylem phenology and cell production were monitored weekly from April to October. The 6-year-long experiment performed in two sites at different altitude showed no substantial effect of warming and N-depositions on xylem phenological phases of cell enlargement, wall thickening and lignification. Cell production, in terms of number of tracheids along the radius, also did not differ significantly and followed the same patterns in control and treated trees. These findings allowed the hypothesis of a medium-term effect of soil warming and N depositions on the growth of mature black spruce to be rejected. PMID- 26617609 TI - MIF: Implications in the Pathoetiology of Systemic Lupus Erythematosus. AB - Macrophage migration Inhibitory factor (MIF) was one of the earliest pro inflammatory cytokines to be identified. Increasing interest in this cytokine in recent decades has followed the cloning of human MIF and the generation of Mif(-/ ) mice. Deepening understanding of signaling pathways utilized by MIF and putative receptor mechanisms have followed. MIF is distinct from all other cytokines by virtue of its unique induction by and counter regulation of glucocorticoids (GCs). MIF is further differentiated from other cytokines by its structural homology to specific tautomerase and isomerase enzymes and correlative in vitro enzymatic functions. The role of MIF in immune and inflammatory states, including a range of human autoimmune diseases, is now well established, as are the relationships between MIF polymorphisms and a number of inflammatory diseases. Here, we review the known pleiotropic activities of MIF, in addition to novel functions of MIF in processes including autophagy and autophagic cell death. In addition, recent developments in the understanding of the role of MIF in systemic lupus erythematosus (SLE) are reviewed. Finally, we discuss the potential application of anti-MIF strategies to treat human diseases such as SLE, which will require a comprehensive understanding of the unique and complex activities of this ubiquitously expressed cytokine. PMID- 26617612 TI - Variation for N Uptake System in Maize: Genotypic Response to N Supply. AB - An understanding of the adaptations made by plants in their nitrogen (N) uptake systems in response to reduced N supply is important to the development of cereals with enhanced N uptake efficiency (NUpE). Twenty seven diverse genotypes of maize (Zea mays, L.) were grown in hydroponics for 3 weeks with limiting or adequate N supply. Genotypic response to N was assessed on the basis of biomass characteristics and the activities of the nitrate ([Formula: see text]) and ammonium ([Formula: see text]) high-affinity transport systems. Genotypes differed greatly for the ability to maintain biomass with reduced N. Although, the N response in underlying biomass and N transport related characteristics was less than that for biomass, there were clear relationships, most importantly, lines that maintained biomass at reduced N maintained net N uptake with no change in size of the root relative to the shoot. The root uptake capacity for both [Formula: see text] and [Formula: see text] increased with reduced N. Transcript levels of putative [Formula: see text] and [Formula: see text] transporter genes in the root tissue of a subset of the genotypes revealed that predominately ZmNRT2 transcript levels responded to N treatments. The correlation between the ratio of transcripts of ZmNRT2.2 between the two N levels and a genotype's ability to maintain biomass with reduced N suggests a role for these transporters in enhancing NUpE. The observed variation in the ability to capture N at low N provides scope for both improving NUpE in maize and also to better understand the N uptake system in cereals. PMID- 26617611 TI - Population Structure, Genetic Variation, and Linkage Disequilibrium in Perennial Ryegrass Populations Divergently Selected for Freezing Tolerance. AB - Low temperature is one of the abiotic stresses seriously affecting the growth of perennial ryegrass (Lolium perenne L.), and freezing tolerance is a complex trait of major agronomical importance in northern and central Europe. Understanding the genetic control of freezing tolerance would aid in the development of cultivars of perennial ryegrass with improved adaptation to frost. The plant material investigated in this study was an experimental synthetic population derived from pair-crosses among five European perennial ryegrass genotypes, representing adaptations to a range of climatic conditions across Europe. A total number of 80 individuals (24 of High frost [HF]; 29 of Low frost [LF], and 27 of Unselected [US]) from the second generation of the two divergently selected populations and an unselected (US) control population were genotyped using 278 genome-wide SNPs derived from perennial ryegrass transcriptome sequences. Our studies investigated the genetic diversity among the three experimental populations by analysis of molecular variance and population structure, and determined that the HF and LF populations are very divergent after selection for freezing tolerance, whereas the HF and US populations are more similar. Linkage disequilibrium (LD) decay varied across the seven chromosomes and the conspicuous pattern of LD between the HF and LF population confirmed their divergence in freezing tolerance. Furthermore, two F st outlier methods; finite island model (fdist) by LOSITAN and hierarchical structure model using ARLEQUIN, both detected six loci under directional selection. These outlier loci are most probably linked to genes involved in freezing tolerance, cold adaptation, and abiotic stress. These six candidate loci under directional selection for freezing tolerance might be potential marker resources for breeding perennial ryegrass cultivars with improved freezing tolerance. PMID- 26617613 TI - Transformation and Evaluation of Cry1Ac+Cry2A and GTGene in Gossypium hirsutum L. AB - More than 50 countries around the globe cultivate cotton on a large scale. It is a major cash crop of Pakistan and is considered "white gold" because it is highly important to the economy of Pakistan. In addition to its importance, cotton cultivation faces several problems, such as insect pests, weeds, and viruses. In the past, insects have been controlled by insecticides, but this method caused a severe loss to the economy. However, conventional breeding methods have provided considerable breakthroughs in the improvement of cotton, but it also has several limitations. In comparison with conventional methods, biotechnology has the potential to create genetically modified plants that are environmentally safe and economically viable. In this study, a local cotton variety VH 289 was transformed with two Bt genes (Cry1Ac and Cry2A) and a herbicide resistant gene (cp4 EPSPS) using the Agrobacterium mediated transformation method. The constitutive CaMV 35S promoter was attached to the genes taken from Bacillus thuringiensis (Bt) and to an herbicide resistant gene during cloning, and this promoter was used for the expression of the genes in cotton plants. This construct was used to develop the Glyphosate Tolerance Gene (GTGene) for herbicide tolerance and insecticidal gene (Cry1Ac and Cry2A) for insect tolerance in the cotton variety VH 289. The transgenic cotton variety performed 85% better compared with the non-transgenic variety. The study results suggest that farmers should use the transgenic cotton variety for general cultivation to improve the production of cotton. PMID- 26617614 TI - isomiRs: Increasing Evidences of isomiRs Complexity in Plant Stress Functional Biology. PMID- 26617615 TI - Contrasting Changes Caused by Drought and Submergence Stresses in Bermudagrass (Cynodon dactylon). AB - In this study, we investigated the mechanisms by which bermudagrass withstands the drought and submergence stresses through physiological, proteomic and metabolomic approaches. The results showed that significant physiological changes were observed after drought treatment, while only slight changes after submergence treatment, including compatible solute contents, ROS levels and antioxidant enzyme activities. Proteomics results showed that 81 proteins regulated by drought or submergence treatment were identified by MALDI-TOF-MS. Among them, 76 proteins were modulated by drought stress with 46 increased abundance and 30 decreased abundance. Forty-five showed abundance changes after submergence treatment with 10 increased and 35 decreased. Pathway enrichment analysis revealed that pathways of amino acid metabolism and mitochondrial electron transport/ATP synthesis were only enriched by drought treatment, while other pathways including photosynthesis, biodegradation of xenobiotics, oxidative pentose phosphate, glycolysis and redox were commonly over-represented after both drought and submergence treatments. Metabolomic analysis indicated that most of the metabolites were up-regulated by drought stress, while 34 of 40 metabolites contents exhibited down-regulation or no significant changes when exposed to submergence stress, including sugars and sugar alcohols. These data indicated that drought stress extensively promoted photosynthesis and redox metabolisms while submergence stress caused declined metabolisms and dormancy in Cynodon dactylon. Taken together, the quiescence strategy with retarded growth might allow bermudagrass to be adaptive to long-term submerged environment, while activation of photosynthesis and redox, and accumulation of compatible solutes and molecular chaperones increased bermudagrass tolerance to drought stress. PMID- 26617616 TI - (1)H NMR Metabolic Fingerprinting to Probe Temporal Postharvest Changes on Qualitative Attributes and Phytochemical Profile of Sweet Cherry Fruit. AB - Sweet cherry fruits (Prunus avium cvs. 'Canada Giant', 'Ferrovia') were harvested at commercial maturity stage and analyzed at harvest and after maintenance at room temperature (storage at ~20 degrees C, shelf life) for 1, 2, 4, 6, and 8 days, respectively. Fruit were initially analyzed for respiration rate, qualitative attributes and textural properties: 'Canada Giant' fruit were characterized by higher weight losses and stem browning index, being more intense over the late stages of shelf life period; meanwhile 'Ferrovia' possessed appreciably better performance even after extended shelf life period. A gradual decrease of respiration rate was monitored in both cultivars, culminated after 8 days at 20 degrees C. The sweet cherry fruit nutraceutical profile was monitored using an array of instrumental techniques (spectrophotometric assays, HPLC, (1)H NMR). Fruit antioxidant capacity was enhanced with the progress of shelf life period, concomitant with the increased levels of total anthocyanin and of phenolic compounds. 'Ferrovia' fruit presented higher contents of neochlorogenic acid and p-coumaroylquinic acid throughout the shelf life period. We further developed an (1)H-NMR method that allows the study of primary and secondary metabolites in a single running, without previous separation and isolation procedures. Diagnostic peaks were located in the aliphatic region for sugars and organic acids, in the aromatic region for phenolic compounds and at 8.2-8.6 ppm for anthocyanins. This NMR-based methodology provides a unifying tool for quantitative and qualitative characterization of metabolite changes of sweet cherry fruits; it is also expected to be further exploited for monitoring temporal changes in other fleshy fruits. PMID- 26617617 TI - Gravitropism and Lateral Root Emergence are Dependent on the Trans-Golgi Network Protein TNO1. AB - The trans-Golgi network (TGN) is a dynamic organelle that functions as a relay station for receiving endocytosed cargo, directing secretory cargo, and trafficking to the vacuole. TGN-localized SYP41-interacting protein (TNO1) is a large, TGN-localized, coiled-coil protein that associates with the membrane fusion protein SYP41, a target SNARE, and is required for efficient protein trafficking to the vacuole. Here, we show that a tno1 mutant has auxin transport related defects. Mutant roots have delayed lateral root emergence, decreased gravitropic bending of plant organs and increased sensitivity to the auxin analog 2,4-dichlorophenoxyacetic acid and the natural auxin 3-indoleacetic acid. Auxin asymmetry at the tips of elongating stage II lateral roots was reduced in the tno1 mutant, suggesting a role for TNO1 in cellular auxin transport during lateral root emergence. During gravistimulation, tno1 roots exhibited delayed auxin transport from the columella to the basal epidermal cells. Endocytosis to the TGN was unaffected in the mutant, indicating that bulk endocytic defects are not responsible for the observed phenotypes. Together these studies demonstrate a role for TNO1 in mediating auxin responses during root development and gravistimulation, potentially through trafficking of auxin transport proteins. PMID- 26617618 TI - JAZ Repressors: Potential Involvement in Nutrients Deficiency Response in Rice and Chickpea. AB - Jasmonates (JA) are well-known phytohormones which play important roles in plant development and defense against pathogens. Jasmonate ZIM domain (JAZ) proteins are plant-specific proteins and act as transcriptional repressors of JA responsive genes. JA regulates both biotic and abiotic stress responses in plants; however, its role in nutrient deficiency responses is very elusive. Although, JA is well-known for root growth inhibition, little is known about behavior of JAZ genes in response to nutrient deficiencies, under which root architectural alteration is an important adaptation. Using protein sequence homology and a conserved-domains approach, here we identify 10 novel JAZ genes from the recently sequenced Chickpea genome, which is one of the most nutrient efficient crops. Both rice and chickpea JAZ genes express in tissue- and stimuli specific manners. Many of which are preferentially expressed in root. Our analysis further showed differential expression of JAZ genes under macro (NPK) and micronutrients (Zn, Fe) deficiency in rice and chickpea roots. While both rice and chickpea JAZ genes showed a certain level of specificity toward type of nutrient deficiency, generally majority of them showed induction under K deficiency. Generally, JAZ genes showed an induction at early stages of stress and expression declined at later stages of macro-nutrient deficiency. Our results suggest that JAZ genes might play a role in early nutrient deficiency response both in monocot and dicot roots, and information generated here can be further used for understanding the possible roles of JA in root architectural alterations for nutrient deficiency adaptations. PMID- 26617620 TI - Breeding and Domesticating Crops Adapted to Drought and Salinity: A New Paradigm for Increasing Food Production. AB - World population is expected to reach 9.2 * 10(9) people by 2050. Feeding them will require a boost in crop productivity using innovative approaches. Current agricultural production is very dependent on large amounts of inputs and water availability is a major limiting factor. In addition, the loss of genetic diversity and the threat of climate change make a change of paradigm in plant breeding and agricultural practices necessary. Average yields in all major crops are only a small fraction of record yields, and drought and soil salinity are the main factors responsible for yield reduction. Therefore there is the need to enhance crop productivity by improving crop adaptation. Here we review the present situation and propose the development of crops tolerant to drought and salt stress for addressing the challenge of dramatically increasing food production in the near future. The success in the development of crops adapted to drought and salt depends on the efficient and combined use of genetic engineering and traditional breeding tools. Moreover, we propose the domestication of new halophilic crops to create a 'saline agriculture' which will not compete in terms of resources with conventional agriculture. PMID- 26617622 TI - Ethylene is Involved in Brassinosteroids Induced Alternative Respiratory Pathway in Cucumber (Cucumis sativus L.) Seedlings Response to Abiotic Stress. AB - Effects of brassinosteroids (BRs) on cucumber (Cucumis sativus L.) abiotic stresses resistance to salt, polyethylene glycol (PEG), cold and the potential mechanisms were investigated in this work. Previous reports have indicated that BRs can induce ethylene production and enhance alternative oxidase (AOX) pathway. The mechanisms whether ethylene is involved as a signal molecule which connected BR with AOX in regulating stress tolerance are still unknown. Here, we found that pretreatment with 1 MUM brassinolide (BL, the most active BRs) relieved stress caused oxidative damage in cucumber seedlings and clearly enhanced the capacity of AOX and the ethylene biosynthesis. Furthermore, transcription level of ethylene signaling biosynthesis genes including ripening-related ACC synthase1 (C S ACS1), ripening-related ACC synthase2 (C S ACS2), ripening-related ACC synthase3 (C S ACS3), 1-aminocyclopropane-1-carboxylate oxidase1 (C S ACO1), 1 aminocyclopropane-1-carboxylate oxidase2 (C S ACO2), and C S AOX were increased after BL treatment. Importantly, the application of the salicylhydroxamic acid (SHAM, AOX inhibitor) and ethylene biosynthesis inhibitor aminooxyacetic acid (AOA) decreased plant resistance to environmental stress by blocking BRs-induced alternative respiration. Taken together, our results demonstrated that ethylene was involved in BRs-induced AOX activity which played important roles in abiotic stresses tolerance in cucumber seedlings. PMID- 26617621 TI - Flg22-Triggered Immunity Negatively Regulates Key BR Biosynthetic Genes. AB - In plants, activation of growth and activation of immunity are opposing processes that define a trade-off. In the past few years, the growth-promoting hormones brassinosteroids (BR) have emerged as negative regulators of pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI), promoting growth at the expense of defense. The crosstalk between BR and PTI signaling was described as negative and unidirectional, since activation of PTI does not affect several analyzed steps in the BR signaling pathway. In this work, we describe that activation of PTI by the bacterial PAMP flg22 results in the reduced expression of BR biosynthetic genes. This effect does not require BR perception or signaling, and occurs within 15 min of flg22 treatment. Since the described PTI induced repression of gene expression may result in a reduction in BR biosynthesis, the crosstalk between PTI and BR could actually be negative and bidirectional, a possibility that should be taken into account when considering the interaction between these two pathways. PMID- 26617619 TI - Plant Survival in a Changing Environment: The Role of Nitric Oxide in Plant Responses to Abiotic Stress. AB - Nitric oxide in plants may originate endogenously or come from surrounding atmosphere and soil. Interestingly, this gaseous free radical is far from having a constant level and varies greatly among tissues depending on a given plant's ontogeny and environmental fluctuations. Proper plant growth, vegetative development, and reproduction require the integration of plant hormonal activity with the antioxidant network, as well as the maintenance of concentration of reactive oxygen and nitrogen species within a narrow range. Plants are frequently faced with abiotic stress conditions such as low nutrient availability, salinity, drought, high ultraviolet (UV) radiation and extreme temperatures, which can influence developmental processes and lead to growth restriction making adaptive responses the plant's priority. The ability of plants to respond and survive under environmental-stress conditions involves sensing and signaling events where nitric oxide becomes a critical component mediating hormonal actions, interacting with reactive oxygen species, and modulating gene expression and protein activity. This review focuses on the current knowledge of the role of nitric oxide in adaptive plant responses to some specific abiotic stress conditions, particularly low mineral nutrient supply, drought, salinity and high UV-B radiation. PMID- 26617623 TI - Cold Treatment Breaks Dormancy but Jeopardizes Flower Quality in Camellia japonica L. AB - Camellia japonica L. is an evergreen shrub whose cultivars are of great ornamental value. In autumn, after flower bud differentiation, dormancy is initiated. As in many other spring flowering woody ornamentals, winter low temperatures promote dormancy release of both flower and vegetative buds. However, warm spells during late autumn and winter can lead to unfulfilled chilling requirements leading to erratic and delayed flowering. We hypothesized that storing plants at no light and low temperature could favor dormancy breaking and lead to early and synchronized flowering in response to forcing conditions in C. japonica 'Nuccio's Pearl'. Plants with fully developed floral primordia were stored at dark, 7 degrees C, and RH > 90% for up to 8 weeks. To monitor endodormancy release during the storage, we evaluated the content of abscisic acid (ABA) in flower buds and the expression profiles of five putative genes related to dormancy and cold acclimation metabolism in leaves and flower buds. In addition, the expression of four anthocyanin biosynthesis pathway genes was profiled in flower buds to assess the effect of the treatment on flower pigment biosynthesis. At 0, 4, 6, and 8 weeks of cold treatment, 10 plants were transferred to the greenhouse and forced to flower. Forced plant flower qualities and growth were observed. The ABA content and the expression profiles of two dormancy-related genes (CjARP and CjDEH) suggested that dormancy breaking occurred after 6-8 weeks of cold treatment. Overall, plants treated for 6-8 weeks showed earlier vegetative sprouting, enhanced, and homogeneous flowering with reduced forcing time. Prolonged cold treatments also reduced flower size and longevity, anthocyanin content, and pigment biosynthesis-related gene transcripts. In conclusion, the cold treatment had a promotive effect on dormancy breaking but caused severe drawbacks on flower quality. PMID- 26617624 TI - A Genetically Modified Tobacco Mosaic Virus that can Produce Gold Nanoparticles from a Metal Salt Precursor. AB - We genetically modified tobacco mosaic virus (TMV) to surface display a characterized peptide with potent metal ion binding and reducing capacity (MBP TMV), and demonstrate that unlike wild type TMV, this construct can lead to the formation of discrete 10-40 nm gold nanoparticles when mixed with 3 mM potassium tetrachloroaurate. Using a variety of analytical physicochemical approaches it was found that these nanoparticles were crystalline in nature and stable. Given that the MBP TMV can produce metal nanomaterials in the absence of chemical reductants, it may have utility in the green production of metal nanomaterials. PMID- 26617625 TI - cDNA Library Screening Identifies Protein Interactors Potentially Involved in Non Telomeric Roles of Arabidopsis Telomerase. AB - Telomerase-reverse transcriptase (TERT) plays an essential catalytic role in maintaining telomeres. However, in animal systems telomerase plays additional non telomeric functional roles. We previously screened an Arabidopsis cDNA library for proteins that interact with the C-terminal extension (CTE) TERT domain and identified a nuclear-localized protein that contains an RNA recognition motif (RRM). This RRM-protein forms homodimers in both plants and yeast. Mutation of the gene encoding the RRM-protein had no detectable effect on plant growth and development, nor did it affect telomerase activity or telomere length in vivo, suggesting a non-telomeric role for TERT/RRM-protein complexes. The gene encoding the RRM-protein is highly expressed in leaf and reproductive tissues. We further screened an Arabidopsis cDNA library for proteins that interact with the RRM protein and identified five interactors. These proteins are involved in numerous non-telomere-associated cellular activities. In plants, the RRM-protein, both alone and in a complex with its interactors, localizes to nuclear speckles. Transcriptional analyses in wild-type and rrm mutant plants, as well as transcriptional co-analyses, suggest that TERT, the RRM-protein, and the RRM protein interactors may play important roles in non-telomeric cellular functions. PMID- 26617626 TI - Plant Innate Immunity Multicomponent Model. AB - Our understanding of plant-pathogen interactions is making rapid advances in order to address issues of global importance such as improving agricultural productivity and sustainable food security. Innate immunity has evolved in plants, resulting in a wide diversity of defense mechanisms adapted to specific threats. The postulated PTI/ETI model describes two perception layers of plant innate immune system, which belong to a first immunity component of defense response activation. To better describe the sophisticated defense system of plants, we propose a new model of plant immunity. This model considers the plant's ability to distinguish the feeding behavior of their many foes, such as a second component that modulates innate immunity. This hypothesis provides a new viewpoint highlighting the relevance of hormone crosstalk and primary metabolism in regulating plant defense against the different behaviors of pathogens with the intention to stimulate further interest in this research area. PMID- 26617627 TI - Development and Utilization of InDel Markers to Identify Peanut (Arachis hypogaea) Disease Resistance. AB - Peanut diseases, such as leaf spot and spotted wilt caused by Tomato Spotted Wilt Virus, can significantly reduce yield and quality. Application of marker assisted plant breeding requires the development and validation of different types of DNA molecular markers. Nearly 10,000 SSR-based molecular markers have been identified by various research groups around the world, but less than 14.5% showed polymorphism in peanut and only 6.4% have been mapped. Low levels of polymorphism limit the application of marker assisted selection (MAS) in peanut breeding programs. Insertion/deletion (InDel) markers have been reported to be more polymorphic than SSRs in some crops. The goals of this study were to identify novel InDel markers and to evaluate the potential use in peanut breeding. Forty eight InDel markers were developed from conserved sequences of functional genes and tested in a diverse panel of 118 accessions covering six botanical types of cultivated peanut, of which 104 were from the U.S. mini-core. Results showed that 16 InDel markers were polymorphic with polymorphic information content (PIC) among InDels ranged from 0.017 to 0.660. With respect to botanical types, PICs varied from 0.176 for fastigiata var., 0.181 for hypogaea var., 0.306 for vulgaris var., 0.534 for aequatoriana var., 0.556 for peruviana var., to 0.660 for hirsuta var., implying that aequatoriana var., peruviana var., and hirsuta var. have higher genetic diversity than the other types and provide a basis for gene functional studies. Single marker analysis was conducted to associate specific marker to disease resistant traits. Five InDels from functional genes were identified to be significantly correlated to tomato spotted wilt virus (TSWV) infection and leaf spot, and these novel markers will be utilized to identify disease resistant genotype in breeding populations. PMID- 26617629 TI - Development of a Susceptibility Index of Apple Cultivars for Codling Moth, Cydia pomonella (L.) (Lepidoptera: Tortricidae) Oviposition. AB - Codling moth (CM), Cydia pomonella (L.) (Lepidoptera: Tortricidae) is a major fruit feeding pest of apples. Understanding susceptibility differences of various apple cultivars to CM oviposition is an important step in developing resistant varieties as well as monitoring and management strategies for this pest in apple orchards planted with mixed-cultivars. In this context, oviposition preferences of CM for the fruits of different apple cultivars were studied in laboratory bioassays using a series of no-choice and multiple-choice tests in 2006, 2007, and 2008. In 2006 and 2007, 10 apple cultivars, viz., Arlet, Fuji, Gala, Golden Delicious, Honeycrisp, Pristine, Delicious, Stayman, Sunrise, and York Imperial were evaluated, while in the 2008 tests, Golden Delicious, Honeycrisp, and York Imperial were evaluated. During the 2006 tests, preferred apple cultivars for CM oviposition were Golden Delicious and Fuji, while the least preferred were Arlet, Pristine, Sunrise, and Honeycrisp. Similarly, during the 2007 tests, Golden Delicious, Fuji and Stayman remained the preferred cultivars, while Arlet, Honeycrisp, Pristine, and Sunrise remained the least preferred cultivars. In the 2008 tests, Golden Delicious and Honeycrisp were the most and least preferred cultivars, respectively. Based on the oviposition preferences from these bioassays, a susceptibility index for each cultivar was developed. This index may be used as a standard measure in cultivar evaluations in breeding programs, and may assist fruit growers and crop consultants to select the most appropriate cultivar(s) for monitoring and detecting the initial signs of fruit injury from CM in an apple orchard planted with mixed-cultivars. PMID- 26617628 TI - Gene Expression Reaction Norms Unravel the Molecular and Cellular Processes Underpinning the Plastic Phenotypes of Alternanthera Philoxeroides in Contrasting Hydrological Conditions. AB - Alternanthera philoxeroides is an amphibious invasive weed that can colonize both aquatic and terrestrial habitats. Individuals growing in different habitats exhibit extensive phenotypic variation but little genetic differentiation. Little is known about the molecular basis underlying environment-induced phenotypic changes. Variation in transcript abundance in A. philoxeroides was characterized throughout the time-courses of pond and upland treatments using RNA-Sequencing. Seven thousand eight hundred and five genes demonstrated variable expression in response to different treatments, forming 11 transcriptionally coordinated gene groups. Functional enrichment analysis of plastically expressed genes revealed pathway changes in hormone-mediated signaling, osmotic adjustment, cell wall remodeling, and programmed cell death, providing a mechanistic understanding of the biological processes underlying the phenotypic changes in A. philoxeroides. Both transcriptional modulation of environmentally sensitive loci and environmentally dependent control of regulatory loci influenced the plastic responses to the environment. Phenotypic responses and gene expression patterns to contrasting hydrological conditions were compared between A. philoxeroides and its alien congener Alternanthera pungens. The terricolous A. pungens displayed limited phenotypic plasticity to different treatments. It was postulated based on gene expression comparison that the interspecific variation in plasticity between A. philoxeroides and A. pungens was not due to environmentally-mediated changes in hormone levels but to variations in the type and relative abundance of different signal transducers and receptors expressed in the target tissue. PMID- 26617630 TI - Silicon as Versatile Player in Plant and Human Biology: Overlooked and Poorly Understood. AB - Silicon (Si) serves as bioactive beneficial element. Si is highly abundant in soil, and occurs ubiquitously in all organisms including plants and humans. During the last three decades, nutritional significance of Si for plant and human health has received increasing attention. Plant Si plays a pivotal role in growth and development, and this beneficial effect depends usually on accumulation in plant tissues, which are then protected from various forms of biotic and abiotic stresses. Likewise, human exposure to Si imparts health benefits and essentially occurs through plant-derived food products. Si bioavailability in human diet, e.g., strengthens bones and improves immune response, as well as neuronal and connective tissue health. Despite this empiric knowledge, the essentiality of Si still remains enigmatic. Thus the link between Si availability for plant development and its profound implication for human welfare should receive attention. This review aims to provide a broad perspective on Si as important element for plant and human nutrition and to define research fields for interdisciplinary research. PMID- 26617631 TI - Elevated Temperature Differentially Influences Effector-Triggered Immunity Outputs in Arabidopsis. AB - Pseudomonas syringae is a Gram-negative bacterium that infects multiple plant species by manipulating cellular processes via injection of type three secreted effectors (T3SEs) into host cells. Nucleotide-binding leucine-rich repeat (NLR) resistance (R) proteins recognize specific T3SEs and trigger a robust immune response, called effector-triggered immunity (ETI), which limits pathogen proliferation and is often associated with localized programmed cell death, known as the hypersensitive response (HR). In this study, we examine the influence of elevated temperature on two ETI outputs: HR and pathogen virulence suppression. We found that in the Arabidopsis thaliana accession Col-0, elevated temperatures suppress the HR, but have minimal influence on ETI-associated P. syringae virulence suppression, thereby uncoupling these two ETI responses. We also identify accessions of Arabidopsis that exhibit impaired P. syringae virulence suppression at elevated temperature, highlighting the natural variation that exists in coping with biotic and abiotic stresses. These results not only reinforce the influence of abiotic factors on plant immunity but also emphasize the importance of carefully documented environmental conditions in studies of plant immunity. PMID- 26617632 TI - Low-Temperature-Induced Expression of Rice Ureidoglycolate Amidohydrolase is Mediated by a C-Repeat/Dehydration-Responsive Element that Specifically Interacts with Rice C-Repeat-Binding Factor 3. AB - Nitrogen recycling and redistribution are important for the environmental stress response of plants. In non-nitrogen-fixing plants, ureide metabolism is crucial to nitrogen recycling from organic sources. Various studies have suggested that the rate-limiting components of ureide metabolism respond to environmental stresses. However, the underlying regulation mechanism is not well understood. In this report, rice ureidoglycolate amidohydrolase (OsUAH), which is a recently identified enzyme catalyzing the final step of ureide degradation, was identified as low-temperature- (LT) but not abscisic acid- (ABA) regulated. To elucidate the LT regulatory mechanism at the transcriptional level, we isolated and characterized the promoter region of OsUAH (P OsUAH ). Series deletions revealed that a minimal region between -522 and -420 relative to the transcriptional start site was sufficient for the cold induction of P OsUAH . Detailed analyses of this 103-bp fragment indicated that a C-repeat/dehydration-responsive (CRT/DRE) element localized at position -434 was essential for LT-responsive expression. A rice C-repeat-binding factors/DRE-binding proteins 1 (CBFs/DREB1s) subfamily member, OsCBF3, was screened to specifically bind to the CRT/DRE element in the minimal region both in yeast one-hybrid assays and in in vitro gel-shift analysis. Moreover, the promoter could be exclusively trans-activated by the interaction between the CRT/DRE element and OsCBF3 in vivo. These findings may help to elucidate the regulation mechanism of stress-responsive ureide metabolism genes and provide an example of the member-specific manipulation of the CBF/DREB1 subfamily. PMID- 26617634 TI - Carcinogenesis: alterations in reciprocal interactions of normal functional structure of biologic systems. AB - The evolution of biologic systems (BS) includes functional mechanisms that in some conditions may lead to the development of cancer. Using mathematical group theory and matrix analysis, previously, it was shown that normally functioning BS are steady functional structures regulated by three basis regulatory components: reciprocal links (RL), negative feedback (NFB) and positive feedback (PFB). Together, they form an integrative unit maintaining system's autonomy and functional stability. It is proposed that phylogenetic development of different species is implemented by the splitting of "rudimentary" characters into two relatively independent functional parts that become encoded in chromosomes. The functional correlate of splitting mechanisms is RL. Inversion of phylogenetic mechanisms during ontogenetic development leads cell differentiation until cells reach mature states. Deterioration of reciprocal structure in the genome during ontogenesis gives rise of pathological conditions characterized by unsteadiness of the system. Uncontrollable cell proliferation and invasive cell growth are the leading features of the functional outcomes of malfunctioning systems. The regulatory element responsible for these changes is RL. In matrix language, pathological regulation is represented by matrices having positive values of diagonal elements (TrA > 0) and also positive values of matrix determinant (detA > 0). Regulatory structures of that kind can be obtained if the negative entry of the matrix corresponding to RL is replaced with the positive one. To describe not only normal but also pathological states of BS, a unit matrix should be added to the basis matrices representing RL, NFB and PFB. A mathematical structure corresponding to the set of these four basis functional patterns (matrices) is a split quaternion (coquaternion). The structure and specific role of basis elements comprising four-dimensional linear space of split quaternions help to understand what changes in mechanism of cell differentiation may lead to cancer development. PMID- 26617635 TI - Is There Really Relationship between Androgenetic Alopecia and Metabolic Syndrome? AB - Background. There are several studies investigating the relationship between androgenetic alopecia (AGA) and metabolic syndrome (MS) with conflicting results. Objective. We sought to investigate whether there is a relationship between AGA and MS. Methods. A case-control study including 74 male patients with AGA and 42 male controls was conducted. Age, duration of AGA, AGA onset age, anthropometric measures, body mass index, lipid parameters, fasting blood glucose, blood pressure, and presence of MS were recorded. Results. Of the 74 male AGA patients (age range 20-50 years, mean 32.14), 24 were in stage 2, 26 were in stage 3, 17 were in stage 3V, 1 was in stage 5, and 6 were in stage 7. There was no significant difference in the rate of MS between AGA and control groups (P = 0.135). Among the evaluated parameters, only systolic blood pressure in AGA group was significantly higher than control group. Conclusion. In contrast to the most of the previous studies, our study does not support the link between AGA and MS. To exclude confounding factors such as advanced age and therefore metabolic disturbances, further studies are needed with large group of AGA patients including different age groups and varying severity. PMID- 26617636 TI - Flexible Ureteroscopy Can Be More Efficacious in the Treatment of Proximal Ureteral Stones in Select Patients. AB - Purpose. We aimed to compare and evaluate the outcomes and complications of two endoscopic treatment procedures, semirigid ureteroscopy (SR-URS) and flexible ureteroscopy (F-URS), in the treatment of proximal ureteral stones (PUS). Methods. SR-URS (group 1) was done on 68 patients whereas 64 patients underwent F URS (group 2) for the treatment of PUS. Success rate was defined as the absence of stone fragments or presence of asymptomatic insignificant residual fragments < 2 mm. Outcomes and complications were recorded. Results. The differences were statistically not significant in age, gender, body mass index (BMI), and stone characteristics between groups. Mean ureteral stone size was 9.1 +/- 0.4 mm and 8.9 +/- 0.5 mm for groups 1 and 2. Mean operative time was 34.1 +/- 1.5 min and 49.4 +/- 2.3 min for groups 1 and 2 (p = 0.001). SFRs were 76.5% and 87.5% for groups 1 and 2 (p = 0.078). Two major complications (ureteral avulsion and ureteral rupture) occurred in group 1. Conclusion. F-URS is safer and less invasive than SR-URS in patients with PUS. There is no statistically significant difference in the efficacy of either technique. Nonetheless we recommend F-URS in the management of PUS as a first-line treatment option in select cases of proximal ureteral calculi. PMID- 26617633 TI - Non-Coding RNA: Sequence-Specific Guide for Chromatin Modification and DNA Damage Signaling. AB - Chromatin conformation shapes the environment in which our genome is transcribed into RNA. Transcription is a source of DNA damage, thus it often occurs concomitantly to DNA damage signaling. Growing amounts of evidence suggest that different types of RNAs can, independently from their protein-coding properties, directly affect chromatin conformation, transcription and splicing, as well as promote the activation of the DNA damage response (DDR) and DNA repair. Therefore, transcription paradoxically functions to both threaten and safeguard genome integrity. On the other hand, DNA damage signaling is known to modulate chromatin to suppress transcription of the surrounding genetic unit. It is thus intriguing to understand how transcription can modulate DDR signaling while, in turn, DDR signaling represses transcription of chromatin around the DNA lesion. An unexpected player in this field is the RNA interference (RNAi) machinery, which play roles in transcription, splicing and chromatin modulation in several organisms. Non-coding RNAs (ncRNAs) and several protein factors involved in the RNAi pathway are well known master regulators of chromatin while only recent reports show their involvement in DDR. Here, we discuss the experimental evidence supporting the idea that ncRNAs act at the genomic loci from which they are transcribed to modulate chromatin, DDR signaling and DNA repair. PMID- 26617637 TI - Ecological Risk Assessment of Metal Pollution along Greater Cairo Sector of the River Nile, Egypt, Using Nile Tilapia, Oreochromis niloticus, as Bioindicator. AB - The present work aims to evaluate seasonal metal pollution along Greater Cairo sector of the River Nile, Egypt, using wild Nile tilapia, Oreochromis niloticus, as bioindicator and to conduct a risk assessment for human consumers. Greater Cairo is the largest populated area along the whole course of River Nile with a wide range of anthropogenic activities. Effects of metal pollution on fish body indices were studied using condition factor (CF) and scaled mass index (SMI). Metal pollution index (MPI) showed that the total metal load in fish organs followed the follwoing order: kidney > liver > gill > muscle which gives a better idea about the target organs for metal accumulation. Metal concentrations in fish muscle (edible tissue) showed the following arrangement: Fe > Zn > Cu > Mn > Pb > Cd. Metal's bioaccumulation factor (BAF) in fish muscle showed the following arrangement: Zn > Cu > Fe > Mn > Cd and Pb. The hazard index (HI) as an indicator of human health risks associated with fish consumption showed that adverse health effects are not expected to occur in most cases. However, the metals' cumulative risk effects gave an alarming sign specifically at high fish consumption rates. PMID- 26617638 TI - Photodegradation of Eosin Y Using Silver-Doped Magnetic Nanoparticles. AB - The purification of industrial wastewater from dyes is becoming increasingly important since they are toxic or carcinogenic to human beings. Nanomaterials have been receiving significant attention due to their unique physical and chemical properties compared with their larger-size counterparts. The aim of the present investigation was to fabricate magnetic nanoparticles (MNPs) using a coprecipitation method, followed by coating with silver (Ag) in order to enhance the photocatalytic activity of the MNPs by loading metal onto them. The fabricated magnetic nanoparticles coated with Ag were characterised using different instruments such as a scanning electron microscope (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray (EDAX) spectroscopy, and X-ray diffraction (XRD) analysis. The average size of the magnetic nanoparticles had a mean diameter of about 48 nm, and the average particle size changed to 55 nm after doping. The fabricated Ag-doped magnetic nanoparticles were used for the degradation of eosin Y under UV-lamp irradiation. The experimental results revealed that the use of fabricated magnetic nanoparticles coated with Ag can be considered as reliable methods for the removal of eosin Y since the slope of evaluation of pseudo-first-order rate constant from the slope of the plot between ln?(C o /C) and the irradiation time was found to be linear. Ag-Fe3O4 nanoparticles would be considered an efficient photocatalyst to degrade textile dyes avoiding the tedious filtration step. PMID- 26617639 TI - Decitabine Compared with Low-Dose Cytarabine for the Treatment of Older Patients with Newly Diagnosed Acute Myeloid Leukemia: A Pilot Study of Safety, Efficacy, and Cost-Effectiveness. AB - Introduction. The incidence of Acute Myeloid Leukemia (AML) increases progressively with age and its treatment is challenging. This prospective case control study was undertaken to compare the safety, efficacy, and cost effectiveness of decitabine with those of cytarabine in older patients with newly diagnosed AML who are not fit for intensive chemotherapy. Materials and Methods. 30 eligible patients above 60 years old with newly diagnosed AML were assigned to receive decitabine or cytarabine. The primary end point was overall survival (OS). The secondary objective was to compare adverse events and cost effectiveness of therapy in the two study groups. Results. In this study, 15 patients received decitabine and 15 patients received cytarabine. The median OS was 5.5 months for each of the treatment groups. The hazard ratio between the treatment groups was 0.811 with 95% CI of 0.390 to 1.687. Toxicity profile was similar in both groups. Cost per cycle of chemotherapy in INR was 24,200 for decitabine and 1,600 for low-dose cytarabine group. Median of simplified cost effectiveness ratio was 0.00022 for decitabine group and 0.0034 for low-dose cytarabine group. Conclusions. For elderly patients with AML, decitabine and low dose cytarabine should be chosen based on the patient's choice and affordability. Our study has shown that both of these agents have similar OS and toxicity. Low dose cytarabine scores over decitabine in developing countries as it is more cost effective. PMID- 26617640 TI - Resveratrol, Acetyl-Resveratrol, and Polydatin Exhibit Antigrowth Activity against 3D Cell Aggregates of the SKOV-3 and OVCAR-8 Ovarian Cancer Cell Lines. AB - Resveratrol has aroused significant scientific interest as it has been claimed that it exhibits a spectrum of health benefits. These include effects as an anti inflammatory and an antitumour compound. The purpose of this study was to investigate and compare any potential antigrowth effects of resveratrol and two of its derivatives, acetyl-resveratrol and polydatin, on 3D cell aggregates of the EGFR/Her-2 positive and negative ovarian cancer cell lines SKOV-3 and OVCAR 8, respectively. Results showed that resveratrol and acetyl-resveratrol reduced cell growth in the SKOV-3 and OVCAR-8 in a dose-dependant manner. The growth reduction was mediated by the induction of apoptosis via the cleavage of poly(ADP ribose) polymerase (PARP-1). At lower concentrations, 5 and 10 uM, resveratrol, acetyl-resveratrol, and polydatin were less effective than higher concentrations, 50 and 100 uM. In SKOV-3 line, at higher concentrations, resveratrol and polydatin significantly reduced the phosphorylation of Her-2 and EGFR and the expression of Erk. Acetyl-resveratrol, on the other hand, did not change the activation of Her-2 and EGFR. Resveratrol, acetyl-resveratrol, and polydatin suppressed the secretion of VEGF in a dose-dependant fashion. In the OVCAR-8 cell line, resveratrol and acetyl-resveratrol at 5 and 10 uM increased the activation of Erk. Above these concentrations they decreased activation. Polydatin did not produce this effect. This study demonstrates that resveratrol and its derivatives may inhibit growth of 3D cell aggregates of ovarian cancer cell lines via different signalling molecules. Resveratrol and its derivatives, therefore, warrant further in vivo evaluation to assess their potential clinical utility. PMID- 26617641 TI - Multiple Low Energy Long Bone Fractures in the Setting of Rothmund-Thomson Syndrome. AB - Rothmund-Thomson syndrome is a rare autosomal recessive genodermatosis characterized by a poikilodermatous rash starting in infancy as well as various skeletal anomalies, juvenile cataracts, and predisposition to certain cancers. Although Rothmund-Thomson syndrome is associated with diminished bone mineral density in addition to multiple skeletal abnormalities, there are few reports of the association with stress fractures or pathologic fractures in low energy trauma or delayed healing of fractures. Presented is a case of a young adult male with Rothmund-Thomson syndrome presenting with multiple episodes of long bone fractures caused by low energy trauma with one of the fractures exhibiting significantly delayed healing. The patient was also found to have an asymptomatic stress fracture of the lower extremity, another finding of Rothmund-Thomson syndrome rarely reported in the literature. A thorough review of the literature and comprehensive presentation of Rothmund-Thomson syndrome is provided in conjunction with our case. PMID- 26617642 TI - Ulcerative Colitis Presented as Fever and Bloody Diarrhea at Initiation of Dialysis in an Elderly Patient with End-Stage Kidney Disease. AB - Ulcerative colitis (UC) is a chronic inflammatory bowel disorder that mainly affects the colon and rectum. Immunological derangements are associated with the pathogenesis of UC. Many patients with UC also have chronic kidney disease, associated with immunological disorders and/or pharmacotherapy for UC. Some patients with UC may develop end-stage renal disease (ESRD) and require renal replacement therapy. However, little is known clinically about ESRD patients who develop UC or about patients with UC who develop ESRD. This report describes an elderly patient with ESRD who presented with fever and bloody diarrhea and was finally diagnosed as UC (pancolitis type) at dialysis initiation. The patient was successfully treated with a series of immunosuppressive agents. This report highlights the importance of considering UC as a potential cause of bloody stool and fever in patients with ESRD. PMID- 26617643 TI - EARLY DETECTION AND INTERVENTION FOR PSYCHOSIS: PERSPECTIVES FROM NORTH AMERICA. AB - Clinicians and researchers in Canada and the United States have established a number of early intervention programs and research sites on the early course of psychosis and the prodromal period that commonly precedes psychotic disorders. In Canada, early detection and treatment programs for psychosis have been established in many areas of the country, and typically serve specific catchment areas. Canadian research on early psychosis is often built on to these clinical sites, and covers a broad array of topics including interventions during the prodromal stage of the illness, treatment-seeking behaviors, and development of optimal pharmacological and psychosocial treatment approaches for early psychosis. In the United States, clinical programs for early intervention in psychosis are often located at academic programs with ongoing research on the early course of psychotic disorders. Researchers from sites across the United States offer a plethora of information, including neuroimaging studies, research on treatment response, and the development of standardized rating scales and research instruments. Researchers from sites in both countries have formed a consortium to launch the North American Prodrome Longitudinal Study, a multi-site collaboration to gain a better understanding of the prodromal period of the illness and prediction of conversion from the prodrome to psychosis. PMID- 26617644 TI - Consortium-Based Genetic Studies of Kawasaki Disease in Korea: Korean Kawasaki Disease Genetics Consortium. AB - In order to perform large-scale genetic studies of Kawasaki disease (KD) in Korea, the Korean Kawasaki Disease Genetics Consortium (KKDGC) was formed in 2008 with 10 hospitals. Since the establishment of KKDGC, there has been a collection of clinical data from a total of 1198 patients, and approximately 5 mL of blood samples per patient (for genomic deoxyribonucleic acid and plasma isolation), using a standard clinical data collection form and a nation-wide networking system for blood sample pick-up. In the clinical risk factor analysis using the collected clinical data of 478 KD patients, it was found that incomplete KD type, intravenous immunoglobulin (IVIG) non-responsiveness, and long febrile days are major risk factors for coronary artery lesions development, whereas low serum albumin concentration is an independent risk factor for IVIG non-responsiveness. In addition, we identified a KD susceptibility locus at 1p31, a coronary artery aneurysm locus (KCNN2 gene), and the causal variant in the C-reactive protein (CRP) promoter region, as determining the increased CRP levels in KD patients, by means of genome-wide association studies. Currently, this consortium is continually collecting more clinical data and genomic samples to identify the clinical and genetic risk factors via a single nucleotide polymorphism chip and exome sequencing, as well as collaborating with several international KD genetics teams. The consortium-based approach for genetic studies of KD in Korea will be a very effective way to understand the unknown etiology and causal mechanism of KD, which may be affected by multiple genes and environmental factors. PMID- 26617645 TI - Current Practices in Korea: Coronary Angiography and Intervention Using Radial Access. PMID- 26617646 TI - Radiation Exposure in Coronary Angiography: A Comparison of Cineangiography and Fluorography. AB - BACKGROUND AND OBJECTIVES: Coronary angiography (CAG) is the gold standard for diagnosing coronary artery disease. However, exposure to ionizing radiation delivered during CAG has various negative biological effects on humans. In this study, there was an evaluation of whether fluorography resulted in decreased radiation exposure, as compared with cineangiography. SUBJECTS AND METHODS: Fifty five patients were prospectively enrolled and divided into two CAG groups, in accordance with the operator's professional discretion: a conventional cineangiography group versus a fluorography group. Fluorography refers to the photography of fluoroscopic images that are retrospectively stored, e.g., using the "Store fluoro" function of the Siemens cardiac angiography system. The primary outcomes included the air kinetic energy released per unit mass {air kerma (AK) mGy} and the dose (kerma)-area product (DAP; uGy . m(2)), both measured using built-in software in the Siemens system. The secondary outcomes included the total procedure time and amount of contrast agent used with each CAG method. RESULTS: The total AK and DAP were significantly lower in the fluorography group (159.3+/-64.9 mGy and 1337.9+/-629.6 uGy . m(2), respectively) than in the cineangiography group (326.9+/-107.5 mGy and 2341.1+/-849.9 uGy . m(2), respectively; p=0.000 for both). The total procedure time (cineangiography vs. fluorography, 12.8+/-4.7 vs. 12.5+/-2.9 min; p=0.779) and contrast agent amount (136.1+/-28.3 vs. 126.3+/-25.7, p=0.214) were comparable between the two groups. CONCLUSION: Fluorography is a useful method to decrease the radiation exposure in selected patients requiring CAG. PMID- 26617647 TI - Current Practice of Transradial Coronary Angiography and Intervention: Results from the Korean Transradial Intervention Prospective Registry. AB - BACKGROUND AND OBJECTIVES: Although increasing evidence has indicated that radial access is a beneficial technique, few studies have focused on Korean subjects. The aim of this study was to evaluate current practice of coronary angiography (CAG) and percutaneous coronary intervention (PCI) using radial access in South Korea. SUBJECTS AND METHODS: A total of 6338 subjects were analyzed from Korean Transradial Intervention prospective registry that was conducted at 20 centers in Korea. After evaluating the initial access, subjects intended for radial access were assessed for their baseline, procedure-related, and complication data. Subjects were categorized into three groups: group of overall subjects (n=5554); group of subjects who underwent PCI (n=1780); and group of subjects who underwent primary percutaneous coronary intervention (PPCI) (n=167). RESULTS: The rate of radial artery as an initial access and the rate of access site crossover was 87.6% and 4.4%, respectively, in overall subjects. Those rates were 82.4% and 8.1%, respectively, in subjects who underwent PCI, and 60.1% and 4.8%, respectively, in subjects who underwent PPCI. For subjects who underwent CAG, a 6 F introducer sheath and a 5-F angiographic catheter was the most commonly used. During PCI, a 6-F introducer sheath (90.6%) and a 6-F guiding catheter were standardly used. CONCLUSION: The large prospective registry allowed us to present the current practice of CAG and PCI using radial access. These data provides evidence to achieve consensus on radial access in CAG and PCI in the Korean population. PMID- 26617648 TI - Prevalence of Gastrointestinal Diseases and Treatment Status in Noncardiac Chest Pain Patients. AB - BACKGROUND AND OBJECTIVES: We evaluated the prevalence of gastroesophageal reflux diseases (GERD) in noncardiac chest pain (NCCP) patients, risk factors for GERD, and status of prescriptions for GERD in Korean population. SUBJECTS AND METHODS: This was a retrospective non-interventional observational nation-wide 45-center study. Patients with a normal coronary angiogram (CAG) and upper gastroendoscopy within 2 years after CAG were enrolled. The prevalence of GERD was examined. Other gastrointestinal diseases including peptic ulcer diseases or gastritis were also examined. Risk factors for GERD were compared between the GERD group and non GERD group. The ratio of patients medicated for gastrointestinal diseases (antacids or proton-pump inhibitor) was also examined. RESULTS: Nine hundred four patients were enrolled. Among the NCCP patients, GERD was present in 436 (48.2%), peptic ulcer disease in 154 patients (17.0%), and gastritis in 659 (72.9%). There was no difference in risk factors for GERD between the GERD and non-GERD patients. Medications for GERD and other gastrointestinal diseases were prescribed in 742 (82.1%) patients. CONCLUSION: GERD was common (42.8%) in Korean NCCP patients and most (82.1%) received the prescription of gastrointestinal medications. No differences were evident in risk factors between GERD and non GERD patients. PMID- 26617650 TI - Comparison of Prolonged Atrial Electromechanical Delays with Different Definitions in the Discrimination of Patients with Non-Valvular Paroxysmal Atrial Fibrillation. AB - BACKGROUND AND OBJECTIVES: Previous studies have evaluated atrial electromechanical delays (AEMDs) with a number of different definitions to discriminate patients with paroxysmal atrial fibrillation (PAF) from controls without PAF. However, their discriminative values for PAF have not previously been directly compared. SUBJECTS AND METHODS: A total of 65 PAF patients and 130 control subjects matched for age, sex, history of hypertension, and diabetes mellitus were selected. The AEMDi and AEMDp were defined as the time intervals from the initiation of the P wave on the surface electrocardiogram to the initiation and peak of the late diastolic transmitral inflow on pulsed wave Doppler images, respectively. The AEMDim and AEMDpm were defined as the time intervals from the initiation of the P wave on the surface electrocardiogram to the initiation and peak of the late diastolic lateral mitral annular motion on tissue Doppler images, respectively. RESULTS: There were no significant differences in the clinical characteristics between the two groups. All 4 AEMDs were consistently longer in the PAF group, and proven effective to differentiate the PAF patients from the controls. The AEMDi measurement had a larger area under the curve (AUC) than the other AEMDs, left atrial volume index, and P wave amplitude. However, the AEMDp, AEMDim, and AEMDpm measurements had AUCs similar to those of the left atrial volume index and P wave amplitude. CONCLUSION: The findings suggest that the AEMDi is better than the other AEMDs for the discrimination of PAF patients from the controls. PMID- 26617649 TI - Impact of Impaired Renal Function on the Incidence of Atrial Fibrillation following Radiofrequency Ablation of Cavotricuspid Isthmus-Dependent Atrial Flutter. AB - BACKGROUND AND OBJECTIVES: Atrial fibrillation (AF) occurs frequently after successful radiofrequency ablation (RFA) of cavotricuspid isthmus-dependent atrial flutter (CTI-AFL). Renal impairment has been implicated in the development of AF. The purpose of this study is to clarify the impact of impaired renal function on the incidence of AF after RFA of CTI-AFL. SUBJECTS AND METHODS: Between January 2001 and December 2013, 240 non-dialysis patients with no prior history of AF {mean age 55.9+/-15.2 years old; male, 192 (80.0%)} who had undergone successful CTI-AFL ablation were included in the present study. The baseline estimated glomerular filtration rate was calculated, and patients were divided into those with impaired renal function (<60 mL/min/1.73 m(2)) and those with preserved renal function (>= 60 mL/min/1.73 m(2)). The incidence of AF was retrospectively analyzed. RESULTS: 69 (28.8%) patients experienced new onset AF during a median follow-up duration of 26 months (inter-quartile, 7-53). The incidence of AF was significantly higher in patients with impaired renal function than in those with preserved renal function {13/25 (52.0%) versus 56/215 (26.0%), log rank p=0.019}. Age, CHADS2 score, impaired renal function, and left atrial diameter were significantly associated with the incidence of AF in univariate Cox regression analysis. Multivariate analysis showed that age was the only significant predictor of AF incidence (hazard ratio, 1.024; 95% confidence interval, 1.004-1.044, p=0.020). CONCLUSION: Patients with impaired renal function may require careful attention for the incidence of new onset AF following successful RFA of CTI-AFL. PMID- 26617651 TI - The Clinical Impact of Bedside Contrast Echocardiography in Intensive Care Settings: A Korean Multicenter Study. AB - BACKGROUND AND OBJECTIVES: We assessed the ability of portable echocardiography (with contrasts) to clearly delineate the cardiac structure, and evaluated the impact of its use on the diagnosis and management of critically ill patients in Korea. SUBJECTS AND METHODS: We prospectively enrolled 123 patients (mean age 66+/-16 years), who underwent portable transthoracic echocardiography (with contrast) for image enhancement at 12 medical centers. The quality of the global left ventricular (LV) images, the number of the regional LV segments visualized, the ability to visualize the LV apex and the right ventricle (RV), and any changes in the diagnostic procedure and treatment strategy were compared before and after the contrast. RESULTS: Of the 123 patients, 52 (42%) were using mechanical ventilators. The amount of poor or uninterpretable images decreased from 48% to 5% (p<0.001), after the contrast. Before the contrast, 15.6+/-1.1 of 16 LV segments were seen, which improved to 15.9+/-0.6 segments (p=0.001) after the contrast. The ability to visualize the LV apex increased from 47% to 94% (p<0.001), while the inability to clearly visualize the RV decreased from 46% to 19% (p<0.001). Changes in the diagnostic procedure (for example, not requiring other types of imaging studies) were observed in 18% of the patients, and the treatment plan (medication) was altered in 26% of patients after the contrast echocardiography. CONCLUSION: The use of a contrast agent during the portable echocardiography, in intensive care settings, can improve the image quality and impact the diagnostic procedures and treatment for Korean patients. PMID- 26617652 TI - Prevalence and Trends of Isolated Systolic Hypertension among Korean Adults: the Korea National Health and Nutrition Examination Survey, 1998-2012. AB - BACKGROUND AND OBJECTIVES: Systolic and diastolic blood pressure may have different effects on cardiovascular disease, but limited data is available for hypertension subtypes in the Korean population. Thus, the prevalence, and absolute number of hypertension subtypes among Korean adults was estimated. SUBJECTS AND METHODS: The Korea National Health and Nutrition Examination Survey 1998-2012 was used to estimate the prevalence and absolute number of each hypertension subtype among Korean adults aged >=20 years. Hypertension was classified into four subtypes: treated hypertension (TH), isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), and combined systolic and diastolic hypertension (SDH). RESULTS: In 2012, approximately 9.5 million adults were estimated to have hypertension, which consists of 5675671 TH (60.0%), 954253 ISH (10.1%), 1649486 IDH (17.4%), and 1175506 SDH (12.4%). Between 2010 and 2012, the proportion of IDH steadily decreased with age, but ISH increased especially in older ages (>=40). Between 1998 and 2012, TH markedly increased from 1.4 million to 5.7 million while the number of untreated hypertension remained relatively constant. During the same time, the number of hypertensive elderlies increased from 507000 to 2822000 along with rapid ageing of the Korean population. Despite of significant improvement in treatment rate, there are still around 583000 elderlies with untreated hypertension (423000 ISH; 42000 IDH; 118000 SDH) as of 2012. CONCLUSION: Although the prevalence of hypertension has been constant over the last decades, absolute number of people with hypertension has been increasing. Along with the rapid population ageing, the number of elderly hypertension is increasing and the ISH is also becoming more prevalent. PMID- 26617654 TI - Early Detection of Kawasaki Disease in Infants. AB - BACKGROUND AND OBJECTIVES: This study aimed to investigate the clinical characteristics of infantile Kawasaki disease (KD), and to evaluate early diagnostic features of KD in febrile infants. SUBJECTS AND METHODS: We retrospectively reviewed the medical records of 64 KD patients from January 2010 to October 2014. There was an analysis of the clinical, laboratory data of the infants versus children groups. Furthermore, the clinical and laboratory data of infantile KD patients were compared with 16 infants who were admitted for other acute febrile diseases. RESULTS: A total of 64 patients with KD were identified; 20 (31.3%) were infants; 44 (68.8%) were >1 year old children. Incomplete KD was much more common in infants (n=13, 65.0%) than in children group (n=14, 31.8%) (p=0.013). The infants were characterized by significantly higher rates of inflammatory changes at the Bacille Calmett-Guerin (BCG) inoculation site (p<0.001), but lower rates of changes in the extremities (p=0.029) and cervical lymphadenopathy (p=0.006). The serum levels of platelet after 1 week (p=0.005), C reactive protein (p=0.038), and N-terminal pro-brain natriuretic peptide (NT proBNP) (p=0.026) were all significantly higher in the infants group. Comparing the infants with KD versus the other acute febrile diseases, there were significantly higher serum levels of erythrocyte sedimentation rate (p=0.002), C reactive protein (p=0.046) and NT-proBNP (p=0.001) for the infants with KD group. CONCLUSION: BCGitis and higher levels of NT-proBNP can be helpful for early diagnosis of the incomplete KD in infants, and may be a good predictor of KD in acute febrile infants, when combined with other acute phase reactants. PMID- 26617655 TI - T-Helper Cytokine Profiles in Patients with Kawasaki Disease. AB - BACKGROUND AND OBJECTIVES: Kawasaki disease is an acute systemic vasculitis of which pathogenesis suspected is caused by immune dysregulation. The goal of this study is to evaluate the activation pattern of T helper cell type 1 (Th1) and T helper cell type 2 (Th2) in patients with Kawasaki disease. SUBJECTS AND METHODS: Prospective study of 60 patients (male 36, female 24) with diagnosis of Kawasaki disease were enrolled. One hundred and eighty blood samples from these patients were collected according to the different clinical stages {before initial intravenous immunoglobulin (IVIG), 5 days after initial IVIG, 2 months after initial IVIG}. The plasma level of Th1 cytokines; interferon-gamma (IFN-gamma) & interleukin (IL)-2 and Th2 cytokines; IL-4 & IL-10 were measured by enzyme-liked immunosorbent assay. RESULTS: In all patients, the plasma level of Th1 cytokines (IFN-gamma, IL-2) and Th2 cytokines (IL-4 and IL-10) were markedly elevated during the acute stage of Kawasaki disease. Since then, the plasma level of all these cytokines decreased significantly along with the process of clinical stages. Regardless of the existence of coronary artery lesion or no response to initial IVIG treatment, there were no significant differences between them. CONCLUSION: These data suggest that both Th1 and Th2 cells may be activated simultaneously during the acute stage of Kawasaki disease. Further studies are therefore required to establish the difference of activation pattern of T helper cells between Kawasaki disease and other inflammatory diseases. PMID- 26617653 TI - A Novel Echocardiographic Method for Assessing Arterial Stiffness in Obstructive Sleep Apnea Syndrome. AB - BACKGROUND AND OBJECTIVES: Obstructive sleep apnea syndrome (OSAS) is associated with increased arterial stiffness and cardiovascular complications. The objective of this study was to assess whether the color M-mode-derived propagation velocity of the descending thoracic aorta (aortic velocity propagation, AVP) was an echocardiographic marker for arterial stiffness in OSAS. SUBJECTS AND METHODS: The study population included 116 patients with OSAS and 90 age and gender matched control subjects. The patients with OSAS were categorized according to their apnea hypopnea index (AHI) as follows: mild to moderate degree (AHI 5-30) and severe degree (AHI>=30). Aortofemoral pulse wave velocity (PWV), carotid intima-media thickness (CIMT), brachial artery flow-mediated dilatation (FMD), and AVP were measured to assess arterial stiffness. RESULTS: AVP and FMD were significantly decreased in patients with OSAS compared to controls (p<0.001). PWV and CIMT were increased in the OSAS group compared to controls (p<0.001). Moreover, AVP and FMD were significantly decreased in the severe OSAS group compared to the mild to moderate OSAS group (p<0.001). PWV and CIMT were significantly increased in the severe group compared to the mild to moderate group (p<0.001). AVP was significantly positively correlated with FMD (r=0.564, p<0.001). However, it was found to be significantly inversely related to PWV (r= 0.580, p<0.001) and CIMT (r=-0.251, p<0.001). CONCLUSION: The measurement of AVP is a novel and practical echocardiographic method, which may be used to identify arterial stiffness in OSAS. PMID- 26617656 TI - Femoropopliteal Artery Stent Fracture with Recurrent In-Stent Reocclusion and Aneurysm Formation: Successful Treatment with Self-Expandable Viabahn Endoprosthesis. AB - Primary stenting in femoropopliteal lesions of intermediate length has recently shown favorable outcomes. However, stent fractures are a concern after bare metal stent implantation. The incidence of stent fracture varies widely (ranging from 2% to 65%) depending on factors such as the treated lesions or stent type and may potentially lead to various complications. We reported a case of stent fracture with complete dislocation combined with recurrent in-stent reocclusion and aneurysm formation in a patient with occlusive disease of the femoropopliteal artery, which was successfully treated with self-expandable endovascular stent graft. PMID- 26617657 TI - Intramural Reentrant Ventricular Tachycardia in a Patient with Severe Hypertensive Left Ventricular Hypertrophy. AB - We describe the case of a patient with severe hypertensive left ventricular hypertrophy and sustained hemodynamically unstable ventricular tachycardia (VT). Entrainment was demonstrated in the electrophysiological study. Activation mapping and pacemapping identified the location of the intramural reentrant VT with the exit site close to the epicardium. However, VT persisted after ablation at the epicardial exit site. Successful ablation was performed endocardially at the corresponding position. PMID- 26617658 TI - A Rare Cause of Secondary Hypertension in A Young Adult. AB - Reninoma is a rare, renin-secreting, benign renal neoplasm that can cause secondary hypertension. We report a case of a 21-year-old man who suffered from progressively worsening headache for 2 months with a history of hypertension for 7 years. Laboratory studies showed normal potassium level, increased basal plasma renin activity, and normal serum aldosterone level. Abdominal computed tomography and magnetic resonance imaging revealed a small mass in the middle region of the right kidney. Partial nephrectomy was performed; immunohistochemical results demonstrated typical features of reninoma. Postoperatively, blood pressure and potassium level were normal at the 2-month follow-up. PMID- 26617659 TI - Takotsubo Cardiomyopathy related to Pheochromocytoma or Other Etiology Should Be Considered as Similar. PMID- 26617660 TI - Herbal Medicine after Interventional Therapy in Cardiovascular Diseases: Efficacy, Mechanisms, and Safety. PMID- 26617661 TI - The Roots of Atractylodes macrocephala Koidzumi Enhanced Glucose and Lipid Metabolism in C2C12 Myotubes via Mitochondrial Regulation. AB - The root of Atractylodes macrocephala Koidzumi (Atractylodis Rhizoma Alba, ARA) is a Traditional Korean Medicine and has been commonly used for weight control. Mitochondrial dysfunction appears to be a key contributor to insulin resistance, and therefore mitochondrial targeting drugs represent an important potential strategy for the treatment of insulin resistance and obesity. In this study, the authors investigated the regulatory effects of ARA on mitochondrial function with respect to the stimulation of glucose and lipid metabolism in C2C12 myotubes. After differentiating C2C12 myotubes, cells were treated with or without different concentrations (0.2, 0.5, and 1.0 mg/mL) of ARA extract. ARA extract significantly increased the expression of peroxisome proliferator-activated receptor coactivator 1 alpha (PGC1alpha) and the downregulations of its targets, nuclear respiratory factor-1 (NRF-1), transcription factor A (TFAM), and total ATP content in C2C12 myotubes. ARA extract also increased the expressions of PGC1alpha activator and of the metabolic sensors, AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase and sirtuin (SIRT) 1. Furthermore, it significantly increased glucose uptake by enhancing glucose consumption and subsequently decreased FFA contents and increased carnitine palmitoyltransferase (CPT) 1b expression. Our study indicates that ARA has a potential for stimulating mitochondrial function and energy metabolism in muscle. PMID- 26617662 TI - Neutrophilic Lung Inflammation Suppressed by Picroside II Is Associated with TGF beta Signaling. AB - Although acute lung injury (ALI) is a leading cause of death in intensive care unit, effective pharmacologic means to treat ALI patients are lacking. The rhizome of Picrorhiza scrophulariiflora used in a traditional herbal medicine in Asian countries has been shown to have anti-inflammatory function, and picroside II (PIC II) is known as a major constituent in the plant. Here, we examined whether PIC II has an anti-inflammatory activity, which is applicable for treating ALI. We found that although it is not significantly effective in suppressing proinflammatory factor NF-kappaB or in activating anti-inflammatory factor Nrf2, PIC II induced the phosphorylation of Smad 2, with concomitant increase of luciferase activity from SBE luciferase reporter in RAW 264.7 cells. H&E staining of lung, differential counting of cells in bronchoalveolar lavage fluid, and semiquantitative RT-PCR analyses of lung tissues show that an intratracheal (i.t.) spraying of PIC II suppressed neutrophilic inflammation and the expression of proinflammatory cytokine genes in the lung, which were elicited by an i.t. LPS instillation to the lung. In addition, PIC II treatment increased the phosphorylation of Smad 2 in the lung tissue. Together, our results suggest that PIC II plays a role as an anti-inflammatory constituent in P. scrophulariiflora, whose activity is associated at least in part with TGF-beta signaling. PMID- 26617663 TI - Virological outcome among HIV-1 infected patients on first-line antiretroviral treatment in semi-rural HIV clinics in Togo. AB - BACKGROUND: Access to antiretroviral treatment (ART) in resource-limited countries has increased significantly but scaling-up ART into semi-rural and rural areas is more recent. Information on treatment outcome in such areas is still very limited notably due to additional difficulties to manage ART in these areas. RESULTS: 387 HIV-1 infected adults (>=18 years) were consecutively enrolled when attending healthcare services for their routine medical visit at 12 or 24 months on first-line ART in five HIV care centers (four semi-rural and one rural). Among them, 102 patients were on first-line ART for 12 +/- 2 months (M12) and 285 for 24 +/- 2 months (M24). Virological failure was observed in 70 (18.1 %) patients ranging from 13.9 to 31.6 % at M12 and from 8.1 to 22.4 % at M24 across the different sites. For 67/70 patients, sequencing was successful and drug resistance mutations were observed in 65 (97 %). The global prevalence of drug resistance in the study population was thus at least 16.8 % (65/387). Moreover, 32 (8.3 %) and 27 (6.9 %) patients were either on a completely ineffective ART regime or with only a single drug active. Several patients accumulated high numbers of mutations and developed also cross-resistance to abacavir, didanosine or the new NNRTI drugs like etravirine and rilpivirine. CONCLUSION: The observations on ART treatment outcome from ART clinics in semi rural areas are close to previous observations in Lome, the capital city suggesting that national ART-programme management plays a role in treatment outcome. PMID- 26617666 TI - Higher breastfeeding performance index is associated with lower risk of illness in infants under six months in Ethiopia. AB - BACKGROUND: Breastfeeding performance index is an explanatory attempt to summarize key breastfeeding practices by summarizing the different dimensions of breastfeeding practices into a single summary variable. Breastfeeding performance index is used to assess optimal breastfeeding practices by constructing a single composite index that includes timely initiation of breastfeeding, prelacteal feeding, current breastfeeding status, bottle feeding, any liquid given(except medicine) in the last 24 h, formula given in the last 24 h, any solid food given in the last 24 h. This study aimed to assess optimal breastfeeding practices of 0 6 month infants using breastfeeding performance index (BPI) and its association with childhood illness in Ethiopia. METHODS: A secondary data analysis was carried out based on the Ethiopia Demographic and Health Survey (EDHS) 2011 data. The BPI was created using seven components by giving equal weight for all components during scoring. The data were described using descriptive statistics and analyzed using multivariable logistic regression. RESULTS: The prevalence of low, medium, and high BPI was 18.41, 57.96 and 23.63 % respectively. The mean BPI score was 4.38 (SD 1.25; 95 % CI 4.31, 4.45). Multivariable logistic regression analysis showed that those infants who had low BPI score were 2.22 times (AOR = 2.22; 95 % CI 1.20, 4.11) and medium BPI category had 2.15 times at higher odds (AOR = 2.15; 95 % CI 1.23, 3.75) of developing diarrhea compared to infants in the highest BPI category. Being in the lower BPI category was significantly associated with higher odds of having fever (AOR = 1.73; 95 % CI 1.06, 2.80). Being in the medium index category was also associated with higher odds of having short and rapid breaths (AOR = 2.02; 95 % CI 1.01, 4.04). CONCLUSION: More than 80 % of the infants did not receive optimal breastfeeding practices based on the Breastfeeding Performance Index. Lower BPI was statistically associated with diarrhea, fever and short and rapid breaths illness in the last 2 weeks. This study implicates the importance of optimal breastfeeding to reduce childhood illness. PMID- 26617665 TI - H5N1 influenza virulence, pathogenicity and transmissibility: what do we know? AB - Highly pathogenic influenza viruses of the H5N1 subtype have infected more than 600 people since 1997, resulting in the deaths of approximately 60% of those infected. Multiple studies have established the viral hemagglutinin (HA) surface glycoprotein as the major determinant of H5N1 virulence. HA mediates host specific virus binding to cells, and mutations that allow efficient binding to viral receptors on mammalian cells are critical (although not sufficient) for H5N1 transmissibility among mammals. The viral polymerase PB2 protein is also a critical virulence determinant, and adaptive mutations in this protein are crucial for efficient H5N1 virus replication in mammals. Additionally, viral proteins (such as NS1 and PB1-F2) with roles in innate immune responses also affect the virulence of highly pathogenic H5N1 viruses. PMID- 26617664 TI - Forebrain-Cerebellar Interactions During Learning. AB - The cerebral cortex and cerebellum are high level neural centers that must interact cooperatively to generate coordinated and efficient goal directed movements, including those necessary for a well-timed conditioned response. In this review we describe the progress made in utilizing the forebrain-dependent trace eyeblink conditioning paradigm to understand the neural substrates mediating cerebro-cerebellar interactions during learning and consolidation of conditioned responses. This review expands upon our previous hypothesis that the interaction occurs at sites that project to the pontine nuclei (Weiss & Disterhoft, 1996), by offering more details on the function of the hippocampus and prefrontal cortex during acquisition and the circuitry involved in facilitating pontine input to the cerebellum as a necessary requisite for trace eyeblink conditioning. Our discussion describes the role of the hippocampus, caudal anterior cingulate gyrus, basal ganglia, thalamus, and sensory cortex, including the benefit of utilizing the whisker barrel cortical system. We propose that permanent changes in the sensory cortex, along with input from the caudate and claustrum, and a homologue of the primate dorsolateral prefrontal cortex, serve to bridge the stimulus free trace interval and allow the cerebellum to generate a well-timed conditioned response. PMID- 26617667 TI - Optimizing technology for cervical cancer screening in high-resource settings. AB - Although historically successful in reducing the burden of cervical cancer, Papanicolaou (Pap) testing faces numerous limitations. A growing body of evidence suggests that modern screening practice will benefit from primary screening for high-risk human papillomavirus (HPV) infection, the causative agent of cervical cancer. Molecular tests detecting the presence of HPV nucleic acids consistently demonstrate high sensitivity relative to Pap testing, and provide reliable, dichotomous results. Pap cytology is ideally suited to triage HPV-positive cases owing to its high test specificity, and the accuracy of cytological readings will be maximized in high-prevalence conditions. This algorithm of primary HPV testing with Pap triage has been shown to maintain the high sensitivity of HPV testing without compromising Pap cytology's strong ability to rule out falsely positive diagnoses. Given the anticipated decline of high-risk HPV-16 and -18 infections in the emergent post-HPV vaccination era, highly sensitive primary HPV testing is especially warranted. Novel screening technologies that identify HPV viral gene expression continue to emerge and seek to complement current HPV testing by identifying those women who may be at risk of progressive disease. How to best incorporate these new technologies into clinical practice presents our next great challenge. Implementation of novel algorithms for cervical screening is not a trivial task. Avoidance of exceedingly complex screening algorithms is an important priority. PMID- 26617669 TI - The impact of teach-back on comprehension of discharge instructions and satisfaction among emergency patients with limited health literacy: A randomized, controlled study. AB - OBJECTIVE: Recommended as a 'universal precaution' for improving provider-patient communication, teach-back has a limited evidence base. Discharge from the emergency department (ED) to home is an important high-risk transition of care with potential for miscommunication of critical information. We examined whether teach-back improves: comprehension and perceived comprehension of discharge instructions and satisfaction among patients with limited health literacy (LHL) in the ED. METHODS: We performed a randomized, controlled study among adult patients with LHL, to teach-back or standard discharge instructions. Patients completed an audio-recorded structured interview evaluating comprehension and perceived comprehension of (1) diagnosis, (2) ED course, (3) post-ED care, and (4) reasons to return and satisfaction using four Consumer Assessment of Healthcare Providers and Systems questions. Concordance with the medical record was rated using a five-level scale. We analyzed differences between groups using multivariable ordinal logistic regression. RESULTS: Patients randomized to receive teach-back had higher comprehension of post-ED care areas: post-ED medication (P < 0.02), self-care (P < 0.03), and follow-up instructions (P < 0.0001), but no change in patient satisfaction or perceived comprehension. CONCLUSION: Teach-back appears to improve comprehension of post-ED care instructions but not satisfaction or perceived comprehension. Our data from a randomized, controlled study support the effectiveness of teach-back in a busy clinical setting. Further research is needed to test the utility and feasibility of teach-back for routine use including its impacts on distal outcomes. PMID- 26617668 TI - Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases. AB - Age-associated neurodegenerative disorders such as Alzheimer's disease are a major public health challenge, due to the demographic increase in the proportion of older individuals in society. However, the relatively few currently approved drugs for these conditions provide only symptomatic relief. A major goal of neurodegeneration research is therefore to identify potential new therapeutic compounds that can slow or even reverse disease progression, either by impacting directly on the neurodegenerative process or by activating endogenous physiological neuroprotective mechanisms that decline with ageing. This requires model systems that can recapitulate key features of human neurodegenerative diseases that are also amenable to compound screening approaches. Mammalian models are very powerful, but are prohibitively expensive for high-throughput drug screens. Given the highly conserved neurological pathways between mammals and invertebrates, Caenorhabditis elegans has emerged as a powerful tool for neuroprotective compound screening. Here we describe how C. elegans has been used to model various human ageing-associated neurodegenerative diseases and provide an extensive list of compounds that have therapeutic activity in these worm models and so may have translational potential. PMID- 26617670 TI - Sugar loss and enzyme inhibition due to oligosaccharide accumulation during high solids-loading enzymatic hydrolysis. AB - BACKGROUND: Accumulation of recalcitrant oligosaccharides during high-solids loading enzymatic hydrolysis of cellulosic biomass reduces biofuel yields and increases processing costs for a cellulosic biorefinery. Recalcitrant oligosaccharides in AFEX-pretreated corn stover hydrolysate accumulate to the extent of about 18-25 % of the total soluble sugars in the hydrolysate and 12-18 % of the total polysaccharides in the inlet biomass (untreated), equivalent to a yield loss of about 7-9 kg of monomeric sugars per 100 kg of inlet dry biomass (untreated). These oligosaccharides represent a yield loss and also inhibit commercial hydrolytic enzymes, with both being serious bottlenecks for economical biofuel production from cellulosic biomass. Very little is understood about the nature of these oligomers and why they are recalcitrant to commercial enzymes. This work presents a robust method for separating recalcitrant oligosaccharides from high solid loading hydrolysate in gramme quantities. Composition analysis, recalcitrance study and enzyme inhibition study were performed to understand their chemical nature. RESULTS: Oligosaccharide accumulation occurs during high solid loading enzymatic hydrolysis of corn stover (CS) irrespective of using different pretreated corn stover (dilute acid: DA, ionic liquids: IL, and ammonia fibre expansion: AFEX). The methodology for large-scale separation of recalcitrant oligosaccharides from 25 % solids-loading AFEX-corn stover hydrolysate using charcoal fractionation and size exclusion chromatography is reported for the first time. Oligosaccharides with higher degree of polymerization (DP) were recalcitrant towards commercial enzyme mixtures [Ctec2, Htec2 and Multifect pectinase (MP)] compared to lower DP oligosaccharides. Enzyme inhibition studies using processed substrates (Avicel and xylan) showed that low DP oligosaccharides also inhibit commercial enzymes. Addition of monomeric sugars to oligosaccharides increases the inhibitory effects of oligosaccharides on commercial enzymes. CONCLUSION: The carbohydrate composition of the recalcitrant oligosaccharides, ratios of different DP oligomers and their distribution profiles were determined. Recalcitrance and enzyme inhibition studies help determine whether the commercial enzyme mixtures lack the enzyme activities required to completely de-polymerize the plant cell wall. Such studies clarify the reasons for oligosaccharide accumulation and contribute to strategies by which oligosaccharides can be converted into fermentable sugars and provide higher biofuel yields with less enzyme. PMID- 26617671 TI - Ozone detoxification of steam-pretreated Norway spruce. AB - BACKGROUND: Pretreatment of lignocellulose for biochemical conversion commonly results in formation of by-products that inhibit microorganisms and cellulolytic enzymes. To make bioconversion processes more efficient, inhibition problems can be alleviated through conditioning. Ozone is currently commercially employed in pulp and paper production for bleaching, as it offers the desirable capability to disrupt unsaturated bonds in lignin through an ionic reaction known as ozonolysis. Ozonolysis is more selective towards lignin than cellulose, for instance, when compared to other oxidative treatment methods, such as Fenton's reagent. Ozone may thus have desirable properties for conditioning of pretreated lignocellulose without concomitant degradation of cellulose or sugars. Ozone treatment of SO2-impregnated steam-pretreated Norway spruce was explored as a potential approach to decrease inhibition of yeast and cellulolytic enzymes. This novel approach was furthermore compared to some of the most effective methods for conditioning of pretreated lignocellulose, i.e., treatment with alkali and sodium dithionite. RESULTS: Low dosages of ozone decreased the total contents of phenolics to about half of the initial value and improved the fermentability. Increasing ozone dosages led to almost proportional increase in the contents of total acids, including formic acid, which ultimately led to poor fermentability at higher ozone dosages. The decrease of the contents of furfural and 5 hydroxymethylfurfural was inversely proportional (R (2) > 0.99) to the duration of the ozone treatment, but exhibited no connection with the fermentability. Ozone detoxification was compared with other detoxification methods and was superior to treatment with Fenton's reagent, which exhibited no positive effect on fermentability. However, ozone detoxification was less efficient than treatment with alkali or sodium dithionite. High ozone dosages decreased the inhibition of cellulolytic enzymes as the glucose yield was improved with 13 % compared to that of an untreated control. CONCLUSIONS: Low dosages of ozone were beneficial for the fermentation of steam-pretreated Norway spruce, while high dosages decreased the inhibition of cellulolytic enzymes by soluble components in the pretreatment liquid. While clearly of interest for conditioning of lignocellulosic hydrolysates, future challenges include finding conditions that provide beneficial effects both with regard to enzymatic saccharification and microbial fermentation. PMID- 26617672 TI - Gender moderates the effect of exercise on anxiety sensitivity. AB - A moderate to vigorous intensity exercise program is emerging as a promising strategy for reducing anxiety sensitivity (AS). Initial evidence suggests that the effects of exercise on mental health outcomes may vary as a function of gender, with men benefitting more than women. Building upon this evidence, the present study tested the hypothesis that the effect of exercise on AS would vary as a function of gender, such that the effect would be stronger for men than for women. We tested this hypothesis using the data from a published study (Smits, Berry, Rosenfield, et al., 2008). In this study, participants (N = 60) with elevated levels of AS were randomly assigned to a two-week exercise intervention [EX] or a waitlist control condition [WL]. Results revealed that males showed significantly greater initial AS reductions relative to females (following 1 week of exercise). However, these gender differences were no longer evident at the end of the intervention. Possible mechanisms for the observed findings and directions for future research are discussed. PMID- 26617675 TI - Cavovarus deformity in Charcot-Marie-Tooth disease: is there a hindfoot equinus deformity that needs treatment? AB - BACKGROUND: Charcot-Marie-Tooth disease (CMT), one of the most common hereditary neurologic disorders, often results in debilitating cavovarus foot deformities. The deformities are still not fully understood, and the treatment recommendations are consequently heterogeneous, often including calf muscle or Achilles tendon lengthening. METHODS: We examined 40 patients (80 feet) with CMT and bilateral cavovarus deformities (19 men and 21 women, mean age 33.6 +/- 14.6 years) and the feet of a healthy control population of 13 individuals (7 men and 6 women, mean age 43.9 +/- 10.8 years). In all cases 3D instrumented gait analysis results with both conventional Plug-in-Gait analysis and the Heidelberg Foot Measurement Method (HFMM) were used to determine the sagittal plane kinematics, dorsi-plantar flexion (DPF), tibio-talar dorsiflexion (TTDF), and medial arch angle (MAA), and the results of patients and the control group were compared using the 2 methods. Decreased and increased dorsiflexion using TTDF was defined as 1 standard deviation below or above the mean of the control. Comparisons were done using descriptive statistics, the Pearson correlation coefficient and ANOVA. RESULTS: The TTDF was found to be decreased in 18 of the 80 feet examined (22.5 %), normal in 31 feet (38.75 %), and increased in 31 feet (38.75 %). The Pearson coefficient showed a positive correlation with R = 0.765, p < 0.001 between decreased TTDF values found by HFMM and decreased DPF values found with conventional Plug-in Gait analysis, but a very weak correlation in patients with normal TTDF (R = 0.118) and increased TTDF (R = 0.078). Also, in patients with decreased TTDF values, there was a weak to moderate correlation with the MAA (R = 0.335), but no correlation between the MAA and DPF (R = 0.023). CONCLUSIONS: The HFMM, unlike the conventional Plug-in-Gait analysis, distinguishes between the segments of the foot in foot deformities and facilitates evaluation of the hindfoot equinus component in patients with CMT and cavovarus deformity. Although there is a significant correlation between decreased TTDF with HFMM and decreased DPF with conventional Plug-in-Gait analysis, this correlation was not seen in patients with normal or increased TTDF values. Conventional Plug-in-Gait analysis alone does not indicate if an increased plantar flexion deformity is the result of either a cavus deformity or hindfoot equinus deformity, which limits its usefulness in assisting in treatment decision making. PMID- 26617673 TI - Genome-wide predictors of NF-kappaB recruitment and transcriptional activity. AB - BACKGROUND: Inducible transcription factors (TFs) mediate transcriptional responses to environmental cues. In response to multiple inflammatory signals active NF-kappaB dimers enter the nucleus and trigger cell-type-, and stimulus specific transcriptional programs. Although much is known about NF-kappaB inducing pathways and about locus-specific mechanisms of transcriptional control, it is poorly understood how the pre-existing chromatin landscape determines NF kappaB target selection and activation. Specifically, it is not known which epigenetic marks and pre-bound TFs serve genome-wide as positive (negative) cues for active NF-kappaB. RESULTS: We applied multivariate and combinatorial data mining techniques on a comprehensive dataset of DNA methylation, DNase I hypersensitivity, eight epigenetic marks, and 34 TFs to arrive at genome-wide patterns that predict NF-kappaB binding. Strikingly, we observed NF-kappaB recruitment to accessible and nucleosome-bound sites. Within nucleosomal DNA NF kappaB binding was primed by H3K4me1 and H2A.Z, but also hyper-methylated DNA outside of promoters and CpG-islands. Many of these predictors showed combinatorial cooperativity and statistically significant interactions. Recruitment to pre-accessible sites was more frequent and influenced by chromatin associated TFs. We observed that specific TF-combinations are greatly enriched for (or depleted of) NF-kappaB binding events. CONCLUSIONS: We provide evidence of NF-kappaB binding within genomic regions that lack classical marks of activity. These pioneer binding events are relatively often associated with transcriptional regulation. Further, our predictive models indicate that specific combinations of epigenetic marks and transcription factors predetermine the NF kappaB cistrome, supporting the feasibility of using statistical approaches to identify "histone codes". PMID- 26617674 TI - Increased production of piRNAs from euchromatic clusters and genes in Anopheles gambiae compared with Drosophila melanogaster. AB - BACKGROUND: Specific genomic loci, termed Piwi-interacting RNA (piRNA) clusters, manufacture piRNAs that serve as guides for the inactivation of complementary transposable elements (TEs). The piRNA pathway has been accurately detailed in Drosophila melanogaster, while it remains poorly examined in other insects. This pathway is increasingly recognized as critical for germline development and reproduction. Understanding of the piRNA functions in mosquitoes could offer an opportunity for disease vector control by the reduction of their reproductive potential. RESULTS: To analyze the similarities and differences in this pathway between Drosophila and mosquito, we performed an in-depth analysis of the genomic loci producing piRNAs and their targets in the African malaria vector Anopheles gambiae. We identified 187 piRNA clusters in the An. gambiae genome and 155 piRNA clusters in the D. melanogaster genome. We demonstrate that many more piRNA clusters in the mosquito compared with the fruit fly are uni-directionally transcribed and are located outside pericentromeric heterochromatin. About 11 % of the An. gambiae piRNA population map to gene transcripts. This is a noticeable increase compared with the ~6 % of the piRNA population mapped to genes in D. melanogaster. A subset of the piRNA-enriched genes in An. gambiae has functions related to reproduction and development. At least 24 and 65 % of the mapped piRNAs correspond to genomic TE sequences in An. gambiae and D. melanogaster, respectively. DNA transposons and non-LTR retrotransposons are more abundant in An. gambiae, while LTR retrotransposons are more abundant in D. melanogaster. Yet, piRNAs predominantly target LTR retrotransposons in both species, which may point to a distinct feature of these elements compared to the other classes of TEs concerning their silencing by the piRNA pathway. CONCLUSIONS: Here, we demonstrate that piRNA-producing loci have more ubiquitous distribution in the An. gambiae genome than in the genome of D. melanogaster. Also, protein-coding genes have an increased role in production of piRNAs in the germline of this mosquito. Genes involved in germline and embryonic development of An. gambiae generate a substantial portion of piRNAs, suggesting a role of the piRNA pathway in the epigenetic regulation of the reproductive processes in the African malaria vector. PMID- 26617676 TI - Identifying factors which enhance capacity to engage in clinical education among podiatry practitioners: an action research project. AB - BACKGROUND: Health profession students develop practical skills whilst integrating theory with practice in a real world environment as an important component of their training. Research in the area of practice placements has identified challenges and barriers to the delivery of effective placement learning. However, there has been little research in podiatry and the question of which factors impact upon clinical educators' capacity to engage with the role remains an under-researched area. This paper presents the second phase of an action research project designed to determine the factors that impact upon clinical educators' capacity to engage with the mentorship role. METHODS: An online survey was developed and podiatry clinical educators recruited through National Health Service (NHS) Trusts. The survey included socio-demographic items, and questions relating to the factors identified as possible variables influencing clinical educator capacity; the latter was assessed using the 'Clinical Educator Capacity to Engage' scale (CECE). Descriptive statistics were used to explore demographic data whilst the relationship between the CECE and socio-demographic factors were examined using inferential statistics in relation to academic profile, career profile and organisation of the placement. RESULTS: The survey response rate was 42 % (n = 66). Multiple linear regression identified four independent variables which explain a significant proportion of the variability of the dependent variable, 'capacity to engage with clinical education', with an adjusted R2 of 0.428. The four variables were: protected mentorship time, clinical educator relationship with university, sign-off responsibility, and volunteer status. CONCLUSION: The identification of factors that impact upon clinical educators' capacity to engage in mentoring of students has relevance for strategic planning and policy-making with the emphasis upon capacity-building at an individual level, so that the key attitudes and characteristics that are linked with good clinical supervision are preserved. PMID- 26617677 TI - Assessing the benefits and harms of low-dose computed tomography screening for lung cancer. AB - The concept of using low-dose computed tomography (LDCT) for lung cancer screening goes back almost 25 years. In 2011, the National Lung Screening Trial (NLST) reported that LDCT screening significantly reduced mortality from lung cancer in a high risk population. This article evaluates the benefits and harms of LDCT screening, based largely on evidence from randomized trials. Harms include false-positive screens and resultant diagnostic procedures, overdiagnosed cancers, and radiation exposure. Benefits can be expressed as the number needed to be screened to prevent one lung cancer death or as estimated overall reductions in lung cancer mortality assuming LDCT population screening as recommended by guidelines. Indirect metrics of benefit, such as lung cancer survival and stage distribution, as well as measures of harms, will be important to monitor in the future as LDCT screening disseminates in the population. PMID- 26617678 TI - Trends in mortality due to diabetes in Brazil, 1996-2011. AB - BACKGROUND: Over recent decades, Brazilian mortality registration has undergone increasing improvement in terms of completeness and quality in cause of death reporting. These improvements, however, complicate the description of mortality trends over this period. We aim to characterize the trend in diabetes mortality in Brazil and its five regions in adults (30-69 years), from 1996 to 2011 after corrections for underreporting of deaths and redistribution of ill-defined causes and "garbage codes". METHODS: Starting with official data from the Brazilian Mortality Information System (SIM) for adults aged 30-69 in the period 1996 to 2011 for diabetes (ICD-10 codes E10-14), we redistributed garbage codes using methods based on the Global Burden of Disease Study (2010), redistributed ill defined causes based on recent Brazilian investigations of similar cases and corrected for underreporting using official estimates of deaths. RESULTS: With these corrections, age-standardized mortality fell approximately 1.1 %/year for men and 2.2 %/year for women from 1996 to 2011. The rate of decline first accelerated and then decelerated, reaching stable rates in men and minimal declines in women from 2005 onward. Regional inequalities decreased during the period in both relative and absolute terms. CONCLUSION: Mortality due to diabetes declined in Brazil from 1996 to 2011, minimally in men and considerably in women. The lesser declines in recent years may reflect the increasing prevalence of diabetes, and suggest that current efforts to prevent diabetes and minimize the impact of its complications need to be reinforced to ensure that declines will continue. PMID- 26617679 TI - Electrophysiological Neuroimaging using sLORETA Comparing 22 Age Matched Male and Female Schizophrenia Patients. AB - INTRODUCTION: The purpose of this electrophysiological neuroimaging study was to provide a deeper mechanistic understanding of both olanzapine and risperidone pharmacodynamics relative to gender. In doing so, we age-matched 22 men and women and evaluated their resting-state EEG recordings and later used standard low resolution brain Electrotomography to visualize the differences in brain activity amongst the two patient groups. METHODS: In this investigation, electroencephalogram (EEG) data were analyzed from male and female schizophrenia patients treated with either olanzapine or risperidone, both atypical antipsychotics, during their in-patient stay at the Department of Psychiatry. Twenty-two males and females were age-matched and EEG recordings were analyzed from 19 Ag/AgCl electrodes. Thirty-seconds of resting EEG were spectrally transformed in standardized low resolution electromagnetic tomography (sLORETA). 3D statistical non-paramentric maps for the sLORETA Global Field Power within each band were finally computed. RESULTS: The results indicated that, relative to males patients, females schizophrenia patients had increased neuronal synchronization in delta frequency, slow-wave, EEG band located in the dorsolateral prefrontal cortex, within the middle frontal gyrus (t= -2.881, p < 0.03580). These findings suggest that females experience greater dopamine (D2) receptor and serotonin (5-HT2) receptor neuronal blockade relative to age-matched males. Further, our finding provided insight to the pharmacodynamics of second generation antipsychotics olanzapine and risperidone. CONCLUSION: When compared to male patients, female patients, suffering from schizophrenia, have D2 and 5 HT2 receptors that are blocked more readily than age-matched male schizophrenia patients. Clinically, this may translate into a quicker time to treatment response in females as compared to male patients. PMID- 26617680 TI - HTRF: a technology tailored for biomarker determination-novel analytical detection system suitable for detection of specific autoimmune antibodies as biomarkers in nanogram level in different body fluids. AB - BACKGROUND: Classical methods of gene product analysis such as binding assays (e.g., ELISA, protein chip technology) are generally time-consuming, lab intensive, less sensitive, and lack high-throughput capacity. In addition, all existing methods used to measure proteins necessitate multiple divisions of the original sample and individual tests carried out for each substance, with an associated cost for each test. METHOD: Together with a small biotech company, we developed a new and innovative analytical detection system based on homogenous time-resolved fluorescence (HTRF) technology. Our system facilitates the development of immune assays that measure selective different analytes such as selected biomarkers in a small sample volume at less than 20 min with a much higher sensitivity compared to common binding assay systems such as enzyme-linked immunosorbent assay (ELISA). Recent advances of the application of this novel detection system combine the power of miniaturization, microfluidics, better linear range, and faster quantification. RESULTS: The power of the HTRF technology offers great promise for point-of-care clinical testing and monitoring of many important analytes such as disease-specific biomarkers in the nanogram level in different human body fluids such as CSF, blood, serum, plasma, and saliva. The linear dynamical range of our HTRF assay was determined between 2.5 and 100 ng/mL. Precision and accuracy calculated for inter- as well as intra assays was less than +/- 10 %. Intra-assay and inter-assay precision for high, medium, and low analyte concentrations show mean CV values less than +/- 10 %. Intra- and inter-assay accuracy for all three concentrations show mean recovery values of 80-120 %. CONCLUSION: The aim of this work is to describe the development and establishment of this novel HTRF system that allows the very fast detection and quantification of biomarkers in different human body fluids. Furthermore, a specific antibody combination that assures a specific binding of the correct refolded autoimmune IgG is evaluated. PMID- 26617681 TI - Prediction using hierarchical data: Applications for automated detection of cervical cancer. AB - Although the Papanicolaou smear has been successful in decreasing cervical cancer incidence in the developed world, there exist many challenges for implementation in the developing world. Quantitative cytology, a semi-automated method that quantifies cellular image features, is a promising screening test candidate. The nested structure of its data (measurements of multiple cells within a patient) provides challenges to the usual classification problem. Here we perform a comparative study of three main approaches for problems with this general data structure: a) extract patient-level features from the cell-level data; b) use a statistical model that accounts for the hierarchical data structure; and c) classify at the cellular level and use an ad hoc approach to classify at the patient level. We apply these methods to a dataset of 1,728 patients, with an average of 2,600 cells collected per patient and 133 features measured per cell, predicting whether a patient had a positive biopsy result. The best approach we found was to classify at the cellular level and count the number of cells that had a posterior probability greater than a threshold value, with estimated 61% sensitivity and 89% specificity on independent data. Recent statistical learning developments allowed us to achieve high accuracy. PMID- 26617682 TI - Nickel-Oxide-Modified SrTiO3(110)-(4 * 1) Surfaces and Their Interaction with Water. AB - Nickel oxide (NiO), deposited onto the strontium titanate (SrTiO3) (110)-(4 * 1) surface, was studied using photoemission spectroscopy (PES), X-ray absorption near edge structure (XANES), and low-energy He+ ion scattering (LEIS), as well as scanning tunneling microscopy (STM). The main motivation for studying this system comes from the prominent role it plays in photocatalysis. The (4 * 1) reconstructed SrTiO3(110) surface was previously found to be remarkably inert toward water adsorption under ultrahigh-vacuum conditions. Nickel oxide grows on this surface as patches without any apparent ordered structure. PES and LEIS reveal an upward band bending, a reduction of the band gap, and reactivity toward water adsorption upon deposition of NiO. Spectroscopic results are discussed with respect to the enhanced reactivity toward water of the NiO-loaded surface. PMID- 26617683 TI - Graphene on Ni(111): Electronic Corrugation and Dynamics from Helium Atom Scattering. AB - Using helium atom scattering, we have studied the structure and dynamics of a graphene layer prepared in situ on a Ni(111) surface. Graphene/Ni(111) exhibits a helium reflectivity of ~20% for a thermal helium atom beam and a particularly small surface electron density corrugation ((0.06 +/- 0.02) A peak to peak height). The Debye-Waller attenuation of the elastic diffraction peaks of graphene/Ni(111) and Ni(111) was measured at surface temperatures between 150 and 740 K. A surface Debye temperature of thetaD = (784 +/- 14) K is determined for the graphene/Ni(111) system and thetaD = (388 +/- 7) K for Ni(111), suggesting that the interlayer interaction between graphene and the Ni substrate is intermediary between those for strongly interacting systems like graphene/Ru(0001) and weakly interacting systems like graphene/Pt(111). In addition we present measurements of low frequency surface phonon modes on graphene/Ni(111) where the phonon modes of the Ni(111) substrate can be clearly observed. The similarity of these findings with the graphene/Ru(0001) system indicates that the bonding of graphene to a metal substrate alters the dynamic properties of the graphene surface strongly and is responsible for the high helium reflectivity of these systems. PMID- 26617684 TI - Immune-phenotypical markers for the differential diagnosis of melanocytic lesions. AB - For specific subsets of melanocytic proliferations, there are morphologic limitations in the histological diagnosis, especially for borderline melanocytic tumors. In particular, Spitzoid proliferations can be difficult to diagnose. For these reasons, in the last years, clinic research has focused attention on discovery of new diagnostic markers. Published gene expression and proteomic profiling data indicate new candidate molecules involved in melanoma pathogenesis, and useful in differential diagnosis of difficult melanocytic lesions. Recently, the diagnostic power of galectin-3 was demonstrated in series of melanocytic lesions, with a strong increasing of expression in malignant lesions compared with benign lesions. Similarly, the accumulation of Collagen XVII antibody was detected in vertical melanoma fronts and associated with invasive phenotype. Moreover, overexpression of cyclin D1 and p21 was detected in Spitz nevi compared with non-spitzoid melanomas; Ki-67 appears highly expressed in deep areas of non-spitzoid melanomas. In this review, we overview of the main molecular markers that a useful tool for the differential diagnosis of benign, borderline and malignant melanocytic lesions, related to their biological behavior, useful also for predicting the evolution of the disease. PMID- 26617685 TI - Duodenal gangliocytic paraganglioma: report of two cases and review of literature. AB - We report two cases of Gangliocytic paraganglioma (GP), one of which was accompanied by lymph node metastasis. Histologically, the tumor was composed of three morphologically distinct cell populations: spindle cells, ganglion-like cells and epithelioid cells. The epithelioid cells were positive for cytokeratin (AE1/AE3), synaptophysin (Syn), chromogranin A (CgA), CD56 and progesterone receptor (PR). Ganglion-like cell types showed positive reactivity for Syn and CD56. In contrast, the spindle-shaped cells showed positive reactivity for S-100. The patient with lymph node metastasis has a good prognosis. Nonetheless, close surveillance is still necessary for patients with GP because a few cases of GP with regional lymph node metastasis and even distant metastasis have been published, including a malignant case of GP showing a lethal course. PMID- 26617686 TI - Expression of fibroblast growth factor receptor 1, fibroblast growth factor 2, phosphatidyl inositol 3 phosphate kinase and their clinical and prognostic significance in early and advanced stage of squamous cell carcinoma of the lung. AB - AIM: Non-small cell lung carcinoma is the leading cause of cancer related to death in the world. Squamous cell lung carcinoma (SqCLC) is the second most frequent histological subtype of lung carcinomas. Recently, growth factors, growth factor receptors, and signal transduction system-related gene amplifications and mutations are extensively under investigation to estimate the prognosis and to develop individualized therapies in SqCLC. In this study, besides the signal transduction molecule phosphatidyl inositol-3-phosphate kinase (IP3K) p110alpha, we explored the expressions of fibroblast growth factor 2 (FGF2) and receptor-1 (FGFR1) in tumor tissue and also their clinical and prognostic significance in patients with early/advanced SqCLC. MATERIALS AND METHODS: From 2005 to 2013, 129 patients (23 early, 106 advanced disease) with a histopathological SqCLC diagnosis were selected from the hospital files of Cukurova University Medical Faculty for this study. Two independent pathologists evaluated FGFR1, FGF2, and PI3K (p110alpha) expressions in both tumor and stromal tissues from 99 of the patients with sufficient tissue samples, using immunohistochemistry. Considering survival analysis separately for patients with both early and advanced stage diseases, the relationship between the clinical features of the patients and expressions were evaluated by univariate and multivariate analyses. RESULTS: FGFR1 expression was found to be low in 59 (60%) patients and high in 40 (40%) patients. For FGF2; 12 (12%) patients had high, 87 (88%) patients had low expression and for IP3K; 31 (32%) patients had high and 66 (68%) patients had low expressions. In univariate analysis, overall survival (OS) was significantly associated with stage of the disease and the performance status of the patient (P<0.0001 and P<0.001). There was no significant difference in OS of the patients with either low or high expressions of FGFR1, FGF2, and IP3K. When the patients with early or advanced stage disease were separately taken into consideration, the relationship did not differ, either. Any of FGFR1, FGF2 or IP3K expressions was not found predictive for the treatment of early or advanced staged patients. On the other hand, the expressions of both FGFR1 and FGF2 were significantly different with respect to smoking, scar of tuberculosis and scar of radiotherapy (P=0.002; P=0.06 and P=0.05, respectively). DISCUSSION: There has not been identified an effective individualized treatment for SqCLC yet. Therefore, in order to be able to develop such a treatment in the future, it is essential to identify the genetic abnormalities that are responsible for the biological behaviors and carcinogenesis of SqCLC. Although we could not show the prognostic and predictive significance of FGFR1, FGF2 and IP3K expressions in SqCLC, we determined the expression rates of FGFR1, FGF2 and IP3K as a reference for Turkish patients. In conclusion, we want to put some emphasis on the fact that, pulmonary fibrosis which is a late complication of radiotherapy at stage III disease, and the scar of tuberculosis could be associated with FGFR1 and FGF2 expressions. PMID- 26617687 TI - Association between well-known histopathological criteria and overall survival in invasive ductal carcinoma. AB - We investigated the effect of clinical features and well-known histomorphological parameters on survival of breast cancer. MATERIAL AND METHODS: 44 patients with invasive ductal carcinoma were included in this study. We investigated the effect of age, breast cancer location (right/left), histological grade, largest diameter of the tumor, lymphovascular and perineural invasion on patient survival. IBM SPSS (Statistical Package for Social Sciences) 20 program was used for statistics. Cox proportional hazard regression model for survival analysis, log log plot, life function graphs were used. Results were 95% confidence interval, significance (P < 0.05). RESULTS: In univariate analysis, the left breast localization, high histological grade, large tumor size, lymphovascular invasion, perineural invasion has been shown that reduced the overall survival (P < 0.05). In multivariate analysis, only high histological grade, large tumor size and perineural invasion were identified as parameters negatively associated with patient survival (P < 0.05). On univariate and multivariate analysis, age was not associated with survival. CONCLUSION: The above results should be considered in the follow-up and treatment planning of invasive ductal carcinoma patients. PMID- 26617688 TI - Subchondral bone changes and chondrogenic capacity of progenitor cells from subchondral bone in the collagenase-induced temporomandibular joints osteoarthritis rabbit model. AB - PURPOSE: The goals of this study were to characterize subchondral bone changes, and to determine biological activity characteristics of progenitor cell populations from subchondral bone in the collagenase-induced temporomandibular joint osteoarthritis (TMJOA) rabbit model. Greater understanding of such pathological changes occurring in TMJOA samples is critical in the future treatment modalities regarding cartilage protection and repair. Furthermore, the use of progenitor cell populations in various cartilage regeneration strategies proves to be a fruitful avenue for research and clinical applications. MATERIALS AND METHODS: Bone remodeling and anabolic activity of subchondral bone was evaluated by hematoxylin-eosin (H&E), Alcian blue-periodic acid-Schiff (AB-PAS) staining and immuohistochemical staining. The biological activity characteristics of progenitor cells were assessed by expressions of collagen type II, CD44, SOX-9 and MMP-9 by immunohistochemistry and Western blot analysis. RESULTS: In most of the specimens, cartilage of the digested area displayed a reaction characterized by thickening of the cartilage cellular structure with retraction structure formation in the subchondral bone. Most of the specimens focuses on chondroid metaplasia were observed in the subchondral bone, promoting its remodeling, which could develop to endochondral ossification and increasing subchondral bone size. Meanwhile, immunohistochemistry analysis revealed that CD44 expressions in subchondral bone were most significantly increased in TMJOA at 2 weeks group (P < 0.01). And, at 4, 6 and 8 weeks groups, the osteochondral junction had completely disappeared by active subchondral bone remodeling, and collagen type II, CD44, SOX-9 and MMP-9 expressions in active subchondral bone region were significantly increased in TMJOA (P < 0.05). In addition, western blot analysis revealed that CD44 expression significantly emerged in subchondral bone region at 2 weeks group (P < 0.01). Meanwhile, SOX-9 expression emerged in all group, and the intensity was increased in the experimental groups (P < 0.05). CONCLUSION: Our results suggest that the beneficial activation of progenitor cells and bone marrow stem cells in subchondral bone at early stage of TMJOA played an important role on renovation and remodeling of subchondral bone. PMID- 26617689 TI - Pathologic findings in patients with targeted magnetic resonance imaging-guided prostate needle core biopsies. AB - In contrast to the routine (non-targeted) sampling approach of transrectal ultrasound guided biopsies (TRUS-GB), targeted magnetic resonance imaging-guided biopsies (TMRI-GB) target regions of the prostate suspicious for prostate cancer (PCa), based on findings on multiparametric MRI. We sought to examine the pathologic findings identified on TMRI-GB, due to the fact that there are limited studies on this in the Pathology literature. A search was made through our Urologic Pathology files for prostate needle core biopsies that were obtained via TMRI-GB. Forty-six patients were identified. Mean patient (PT) age was 62 years (range: 50-78 years). Twenty one of 46 PTs (46%) had a history of PCa, 10/46 PTs (22%) had a history of negative TRUS-GB and rising PSA, and the remaining 15/46 PTs (32%) had never undergone biopsy. Cancer detection rate on TMRI-GB was 57% for PTs with a prior diagnosis of PCa, 50% for PTs with a history of benign biopsy, and 67% who were biopsy naive. An average of 3.16 cores were sampled from malignant lesions and an average of 2.74 were sampled from benign lesions (P=0.02). TMRI-GB has a higher cancer detection rate than TRUS-GB. TMRI-GB may have a critical role as a tool for active surveillance, tumor mapping, and primary detection of PCa, which will likely evolve as the ability to identify malignant lesions improve. The roles of pathologists and radiologists in the validation of this procedure will continue to be even more vital in the future. PMID- 26617690 TI - Up-regulation of AKAP13 and MAGT1 on cytoplasmic membrane in progressive hepatocellular carcinoma: a novel target for prognosis. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers and is associated with high mortality worldwide. The current gold standards for HCC surveillance are detection of serum alpha-fetoprotein (AFP) and ultrasonography; however, non-specificity of AFP and ultrasonography has frequently been reported. Therefore, alternative tools, especially novel specific tumor markers, are required. In this study, cytoplasmic membrane proteins were isolated from phorbol 12-myristate 13-acetate (PMA)-induced invasive HepG2 cells and identified using nano-scale liquid chromatographic tandem mass spectrometry (NLC-MS/MS) with comparison to non-treated controls. The results showed that two proteins, magnesium transporter protein 1 (MAGT1) and A-kinase anchor protein 13 (AKAP13), were highly expressed in PMA-treated HepG2 cells. This up-regulation was confirmed by real-time RT-PCR, western blot analysis, and immunofluorescent staining studies. Furthermore, evaluation of MAGT1 and AKAP13 expression in clinical HCC tissues by immunohistochemistry suggested that both proteins were strongly expressed in tumor tissues with significantly higher average immunoreactive scores of Remmele and Stegner (IRS) than in non-tumor tissues (P <= 0.005). In conclusion, the expression levels of MAGT1 and AKAP13 in HCC may be potential biomarkers for the diagnosis and prognosis of this cancer. PMID- 26617691 TI - A meta-analysis of the associations between the Q141K and Q126X ABCG2 gene variants and gout risk. AB - BACKGROUND: Gout is an inflammatory disease in which genetic factors play a role. ABCG2 is a urate transporter, and the Q141K and Q126X variants of ABCG2 have been associated with a risk of developing gout, though previous studies of these associations have been inconsistent. Therefore, we conducted a meta-analysis to explore the relationship between these genetic variants and gout. METHODS: We examined 8 electronic literature databases. In total, 9 eligible articles on the associations between the Q141K (rs2231142) and Q126X (rs72552713) variants and gout risk, including 11 case-control studies were selected. We used odds ratios (OR) and 95% confidence intervals (CI) to assess the strength of these relationships in dominant, recessive, and co-dominant models. RESULTS: This study included 6652 participants (2499 gout patients and 4153 controls). The Q141K variant was found to significantly increase the risk of gout in Asians (dominant model: OR=2.64, 95% CI=2.04-3.43, P=0.02 for heterogeneity; recessive model: OR=3.19, 95% CI=2.56-3.97, P=0.28 for heterogeneity; co-dominant model: OR=1.37, 95% CI=1.18-1.59, P=0.09 for heterogeneity) and other populations (dominant model: OR=1.85, 95% CI=1.20-2.85, P<0.0001 for heterogeneity; recessive model: OR=3.78, 95% CI=2.28-6.27, P=0.19 for heterogeneity; co-dominant model: OR=1.48, 95% CI=1.26-1.74, P=0.19 for heterogeneity). The Q126X variant also significantly increased the risk of gout in Asians (dominant model: OR=3.87, 95% CI=2.07-7.24, P=0.06 for heterogeneity). CONCLUSIONS: These results suggest associations between the rs2231142 and rs72552713 ABCG2 gene polymorphisms and gout risk, which led to unfavorable outcomes. However, studies with larger sample sizes and homogeneous populations should be performed to confirm these results. PMID- 26617692 TI - Poly (ADP-ribose) synthetase inhibitor has a heart protective effect in a rat model of experimental sepsis. AB - The aim of this study is to investigate whether PARP inhibitor could reduce cell apoptosis and injury in the heart during sepsis. MATERIALS AND METHODS: 60 healthy male Sprague-Dawley (SD) rats were randomly divided into 4 groups---sham group, modal group, 3-AB pretreatment group and 3-AB treatment group, 15 rats per group. The cecal ligation and puncture (CLP) model of sepsis was used. The following were determined--levels of malondialdehyde (MDA), ATP and nicotinamide adenine dinucleotide (NAD+), expression of PARP, Bcl-2, Bax, cytochrome C and caspase 3 activity in the myocardium tissue, levels of serum creatine kinase muscle brain (CK-MB) fraction and troponin I. RESULTS: Histological and molecular analyses showed that myocardial cells apoptosis were associated with mitochondria injury, with an increase in the amount of PARP and a decrease in ATP and NAD+ levels in model group. In addition, the levels of Bax, cytochrome C and caspase 3 activity, serum levels of CK-MB and troponin I increased, but levels of Bcl-2 significantly decreased. Inhibition of PARP upregulated the levels of ATP, NAD + and Bcl-2, and significantly reduced the activation of PARP and caspase 3, decreased the levels of MDA, cytochrome C, CK-MB and troponin I. As a result, apoptosis in the heart was attenuated. CONCLUSION: These results indicate that PARP activation may be involved in apoptosis in the heart induced by sepsis and 3 AB could improve it. PMID- 26617693 TI - Intermedin attenuates myocardial infarction through activation of autophagy in a rat model of ischemic heart failure via both cAMP and MAPK/ERK1/2 pathways. AB - Intermedin is a proopiomelanocortin-derived peptide before opioid promoting cortical hormone, its main function embodies in mononuclear macrophages and neutrophilic granulocytes to inhibit the proinflammatory cytokines. The aim of this study is to determine intermedin attenuates myocardial infarction and its related mechanisms in a rat model of ischemic heart failure. After rat model of ischemic heart failure was set up, myocardial infarction, blood levels of activities of creatine kinase (CK), the MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin T (cTnT) were effectively reduced by treatment with intermedin. Tumor necrosis factor (TNF-alpha) and interleukin-6 (IL-6) in a rat model of ischemic heart failure were recovered by pretreatment with intermedin. Administrate of intermedin availably promoted cAMP contents and suppressed caspase-3 protein in ischemic heart failure rat. ERK1/2 and LC3 protein expression were significantly activated and autophagy was significantly promoted by intermedin in a rat model of ischemic heart failure. These results indicate that intermedin protected rat heart, attenuates myocardial infarction from ischemic heart failure in the rat model. The underlying mechanisms may include upregulation of cAMP, ERK1/2 and LC3 protein expression and activating of autophagy. PMID- 26617694 TI - Aldosterone and TGF-beta1 synergistically increase PAI-1 expression in hepatic stellate cells of rats. AB - OBJECTIVE: Aldosterone is related to the fibrosis of several organs, but the specific mechanism underlying the aldosterone induced hepatic fibrosis is still unclear. METHODS: Separation, culture and identification of primary hepatic stellate cells (HSCs): The fluids and digestives used in the present study were able to completely remove blood cells, digest hepatocytes and matrix, and effectively separate HSCs. The in situ perfusion was performed at 2 steps: in situ perfusion with pre-perfusion fluid and ex vivo perfusion with enzyme containing perfusion fluid. Influence of Ald on PAI-1 and Smad expressions in HSCs: cells were divided into control group, Ald group (10(-6) M), spironolactone (SPI) group and Ald+SPI group, and the mRNA and protein expressions of PAI-1 and Smad were detected. Ald induced type I collagen expression in HSCs: Immunohistochemistry was performed to detect type I collagen expression in the supernatant of control group, Ald group (10(-6) M), TGF-beta1 group, and Ald+TGF beta1 group. Influence of Ald and TGF-beta1 on PAI-1 expression in HSCs: cells were divided into control group, Ald group (10(-6) M), TGF-beta1 group, and Ald+TGF-beta1 group, and the mRNA and protein expressions of PAI-1 were determined by RT-PCR and Western blot assay, respectively. Synergistic effect of Ald and TGF-beta1 on PAI-1 expression in HSCs: cells were divided into control group, Ald group (10(-6)), TGF-beta1 group, Ald (10(-6) M)+TGF-beta1 group, Ald (10(-7) M)+TGF-beta1 group and Ald (10(-8) M)+TGF-beta1 group, and the mRNA and protein expressions of PAI-1 were detected by RT-PCR and Western blot assay, respectively. RESULTS: The survival rate, purity, markers and activation of HSCs were determined after separation. Influence of Ald on PAI-1 expression in HSCs: PAI-1 expression increased in HSCs of Ald group, SPI group and Ald+API group, and the PAI-1 expression in Ald group and Ald+SPI group was significantly higher than in control group (P<0.01). Influence of Ald on Smad expression in HSCs: Smad expression in Ald group, TGF-beta1 group and ALD+TGF-beta1 group was markedly higher than in control group (P<0.05). Smad expression in ALD+TGF-beta1 group increased significantly when compared with Ald group (P<0.01). Ald induced type I collagen expression in HSCs: type I collagen expression in Ald group, TGF-beta1 group and ALd+TGF-beta1 group was dramatically higher than in control group (P<0.05), and it in ALd+TGF-beta1 group was also significantly different from that in Ald group and TGF-beta1 group (P<0.01). Synergistic effects of Ald and TGF-beta1 on PAI expression in HSCs: PAI-1 expression in treated cells was markedly higher than in control group (P<0.01). PAI-1 expression in 10(-6) M Ald+5 ng/ml TGF-beta1 group increased dramatically as compared to Ald group and TGF-beta1 group (P<0.01), but the increased PAI-1 expression reduced after SPI treatment. Ald at different concentrations exerts synergistic effect with TGF beta1 to increase PAI-1 expression in HSCs: PAI-1 expression in HSCs after different treatments increased markedly as compared to control group (P<0.01). Significant difference in PAI-1 expression was observed in 10(-6) M Ald+50 pg/ml TGF-beta1 group and 10(-6) M Ald group (P<0.01), PAI-1 expression in 10(-7) M Ald+50 pg/ml TGF-beta1 group was significantly higher than in 50 pg/ml TGF-beta1 group (P<0.01), but the PAI-1 expression in 10(-7) M Ald+50 pg/ml TGF-beta1 group was similar to that in 10(-6) M Ald group (P>0.05). CONCLUSION: Aldosterone is able to activate HSCs and increase PAI-1 expression during hepatic fibrosis, which may be inhibited by spironolactone. Aldosterone and TGF-beta1 may synergistically act on HSCs to increase PAI-1 expression as compared to treatment with aldosterone or TGF-beta1 alone. Aldosterone or TGF-beta1 alone may slightly increase PAI-1 expression in HSCs, which can be inhibited by spironolactone. PMID- 26617695 TI - Correlation between proinflammatory role of a lectin from Typhonium giganteum Engl. and macrophage. AB - PURPOSE: To analyze the correlation between proinflammatory effects of a lectin from Typhonium giganteum Engl. and macrophage. METHODS: T. giganteum lectin (TGL) was extracted from the tuber of T. giganteum and purified, and was then identified by using SDS-PAGE gel electrophoresis in combination with mass spectrometry. The morphologic changes of macrophage after being stimulated by TGL were observed with scanning electron microscopy. The influences of such stimulation on neutrophil migration were evaluated by establishing an in vitro macrophage-neutrophil co-culture migration model. By establishing a rat peritoneal macrophage in vitro cultured model, the effects of TGL stimulation on inflammatory factors TNF-alpha and IL-1beta released by macrophage were analyzed. With p65 as the index, the expressions of the NF-kappaB signaling pathway in the cytoplasm and nucleus were detected before and after TGL stimulation respectively. Furthermore, we also investigated whether the inhibitor for NF kappaB signaling pathway BAY11-7082 can block p65 nuclear translocation. RESULTS: After being stimulated by TGL, macrophage had increased volume, number of pseudopodia and gradually cracked cell membrane, accompanied by evidently induced migration of neutrophils due to released inflammatory factors. As the concentration of TGL varied, NF-kappaB's monomer p65 had different expression levels in the cytoplasm and nucleus, while BAY11-7082 can indeed block the nuclear translocation of p65. CONCLUSIONS: TGL-induced inflammation was closely related to macrophage mediation. PMID- 26617696 TI - Overexpression of Prdx1 in hilar cholangiocarcinoma: a predictor for recurrence and prognosis. AB - Prdx1 is an important member of peroxiredoxins (Prdxs) regulating various cellular signaling and differentiation. Prdx1 confers an aggressive survival phenotype of cancer cells and drug-resistance, yet its role in hilar cholangiocarcinoma is not fully investigated. In present study, we detected the expression profile of Prdx1 in 88 hilar cholangiocarcinoma by tissue arrays and immunohistochemistry. Prdx1 level was down-regulated by specific Prdx1-shRNA in vitro and the possible mechanism was investigated. Overexpression of Prdx1 was observed in 53 of 88 cases (60.2%). Prdx1 expression was significantly associated with tumor invasion, nodal metastasis, advanced disease stage. Down-regulation of Prdx1 inhibited cell proliferation and colony formation of QBC939 cells and reduced the level of SNAT1 expression. Patients with Prdx1 overexpression had a shorter disease-free survival and overall survival than those without Prdx1 expression. Multivariate analysis showed that Prdx1 was an independent prognostic factor for patients with hilar cholangiocarcinoma. The data indicate that Prdx1 may contribute to the development and progression of hilar cholangiocarcinoma, partially through regulating SNAT1 expression, and may be used as a biomarker in predicting the outcome of patients with hilar cholangiocarcinoma. PMID- 26617697 TI - Flk-1+Sca-1- mesenchymal stem cells: functional characteristics in vitro and regenerative capacity in vivo. AB - OBJECTIVES: Mesenchymal stem cells (MSCs) represent a powerful tool in regenerative medicine because of their differentiation and migration capacities. We aimed to investigate the possibility of Flk-1(+)Sca-1(-) mesenchymal stem cells (Flk-1(+)Sca-1(-) MSCs) transplantation to repair erectile function in patients suffering from diabetes mellitus (DM)-associated erectile dysfunction (ED). METHODS: In this study, we isolated Flk-1(+)Sca-1(-) MSCs from bone marrow (bMSCs). Then, newborn male rats were intraperitoneally injected with 5-ethynyl-2 deoxyuridine for the purpose of tracking endogenous Flk-1(+)Sca-1(-) MSCs. Eight weeks later, 8 of these rats were randomly chosen to serve as normal control (N group). The remaining rats were injected intraperitoneally with 60 mg/kg of streptozotocin (STZ) to induce DM. Eight of these rats were randomly chosen to serve as DM control (DM group) while another 8 rats were subject to Flk-1(+)Sca 1(-) MSCs treatment (DM+MSC group). All rats were evaluated for erectile function by intracavernous pressure (ICP) measurement. Afterward, their penile tissues were examined by histology. RESULTS: Flk-1(+)Sca-1(-) MSCs could differentiate into skeletal muscle cells and endothelial cells in vivo and in vitro. Engrafted Flk-1(+)Sca-1(-) MSCs were shown to home to injured muscle, participate in myofibers repair and could partially reconstitute the sarcolemmal expression of myocardin and ameliorate the level of related specific pathological markers. CONCLUSION: Flk-1(+)Sca-1(-) MSCs could be used in the treatment erectile function in diabetes mellitus associated erectile dysfunction by promoting regeneration of nNOS-positive nerves, endothelium, and smooth muscle in the penis. PMID- 26617698 TI - MicroRNA-96 plays an oncogenic role by targeting FOXO1 and regulating AKT/FOXO1/Bim pathway in papillary thyroid carcinoma cells. AB - MicroRNAs (miRNAs) are kind of small non-coding RNAs that negatively regulate gene expression at post-transcription level, and those non-coding RNAs appear to play a key role in tumorigenesis. The aim of this study was to investigate the biological role of miR-96 in papillary thyroid carcinoma (PTC) cell lines. We identified miR-96 to be up-regulated in PTC specimens in comparison to matched normal tissues by microRNA microarray and RT-qPCR analysis (P < 0.05). Next, to explore the potential function of miR-96, PTC cell lines K1 and TPC1 were transiently transfected with miR-96 mimics and inhibitor. Successful transfection being confirmed by RT-qPCR. Ectopic expression of miR-96 promoted proliferation and colony formation ability, and inhibited apoptosis of K1 and TPC1 cells, whereas down-regulated expression of miR-96 suppressed those functions when compared with the control cells. According to a computational prediction, FOXO1 maybe a potential target of miR-96. Luciferase assays revealed that miR-96 is directly targeted to both binding sites of FOXO1 3'-untranslated region (3'-UTR) and suppressed the FOXO1 expression, and subsequently inhibited the expression of Bim protein in PTC cells. Moreover, the expression of FOXO1 had an inverse correlation with expression of miR-96 in PTC specimens by RT-qPCR and western blot analysis. The data from the present study demonstrated that miR-96 can promote proliferation, and inhibit apoptosis in PTC cell lines K1 and TPC1, thus miR-96 may play an oncogenic role in PTC by inhibiting the FOXO1 and regulating AKT/FOXO1/Bim pathway, and it may serve as a novel therapeutic target for miRNA based PTC therapy. PMID- 26617699 TI - Reversal effect of GnT-V on the radioresistance of human nasopharyngeal carcinoma cells by alteration beta1, 6-GlcNAc branched N-glycans. AB - Radiotherapy is the primary treatment for human nasopharyngeal carcinoma (NPC), yet radioresistance remains a major obstacle to successful treatment in many cases. N-acetylglucosaminyltransferase V (GnT-V), which synthesizes beta1, 6 GlcNAc branched N-glycans, is closely related to the radiosensitivity of NPC cells. However, a better understanding of the functional role of GnT-V in NPC radioresistance and the related mechanisms is urgently needed. In the present study, a radioresistant NPC cell line, CNE-2R, was established by repeated gamma irradiation. We found that GnT-V levels, as well as beta1, 6-GlcNAc branched N glycans were significantly increased in the CNE-2R cells as compared with that in the parental cells. Meanwhile, knockdown of GnT-V in the CNE-2R cells enhanced cell radiosensitivity and inhibited the formation of beta1, 6-branched N-glycans. In addition, the regulated expression of GnT-V in the CNE-2R cells converted the heterogeneous N-glycosylated forms of CD147. Furthermore, swainsonine, an inhibitor of N-glycan biosynthesis, was also able to reverse the radioresistance of the CNE-2R cells. Taken together, the present study revealed a novel mechanism of GnT-V as a regulator of radioresistance in NPC cells, which may be useful for fully understanding the biological role of N-glycans in NPC radioresistance. PMID- 26617700 TI - Inhibition of the NF-kappaB pathway by R65 ribozyme gene via adeno-associated virus serotype 9 ameliorated oxidized LDL induced human umbilical vein endothelial cell injury. AB - OBJECTIVE: NF-kappaB signaling plays a central role in the regulation of inflammatory responses in atherosclerosis. R65 ribozyme gene suppresses activation of NF-kappaB pathway, therefore we studied whether R65 gene therapy can ameliorate oxidized low-density lipoprotein (ox-LDL) induced human umbilical vein endothelial cells (HUVECs) injury. METHODS AND RESULTS: Recombinant adeno associated virus serotype 9 (rAVV9) vector was used to transfect the R65 ribozyme gene (rAVV9-R65) into HUVECs then following ox-LDL stimulation, expression of NF kappaB p65 and p50 subunits, inflammatory mediators and cell apoptosis were examined. First, rAVV9-enhanced green fluorescent protein (eGFP)-R65 at 1*10(7) v.g./cell multiplicity of infection reached a long-lasting and significant increase in R65 gene expression. Second, ox-LDL treatment led to time- and dose dependent activation of NF-kappaB pathway, and enhanced inflammatory response and cell death evidenced by increased expression of nuclear NF-kappaB p65 and p50 subunits, greater production of tumor necrosis factor alpha, interleukin-6 and von willebrand factor and 20.57% increased apoptotic HUVECs. Third, over expression of R65 gene was 2-fold increased in HUVECs attenuated ox-LDL induced unclear accumulation and expression of p65 subunit and ameliorated inflammation and cell death (all P < 0.05). CONCLUSION: rAAV9-mediated R65 ribozyme gene transfection in cultured HUVECs effectively inhibits ox-LDL induced activation of NF-kappaB and production of inflammatory cytokines and prevents cell apoptosis. PMID- 26617701 TI - MicroRNA-200a inhibits epithelial-mesenchymal transition in human hepatocellular carcinoma cell line. AB - OBJECTIVE: Our study investigated the role of microRNA (miR)-200a and its molecular targets in hepatocellular carcinoma (HCC) cells. METHODS: An inhibitor of miR-200a was transiently transfected into the hepatocellular carcinoma cell line, MHCC-97L. The effect of this transfection on mRNA levels of epithelial mesenchymal transition (EMT)-related genes was measured by fluorescence-based quantitative real-time polymerase chain reaction (qRT-PCR). Further, protein levels of EMT-related genes, cell proliferation and apoptosis-related markers were assessed by Western blot analysis in these transfected cells. MTT and wound healing assay were used to evaluate the proliferation and migration of MHCC-97L cells in presence and in absence of miR-200a inhibitor. RESULTS: Compared with miR-NC control group, qRT-PCR results in anti-miR-200a group revealed a significant reduction in the mRNA levels of E-cadherin, with a concomitant increasing in vimentin mRNA level (all P < 0.05). Western blot results showed higher E-cadherin and Caspase-3 protein expressions in anti-miR-200a group compared to miR-NC group (P < 0.05). In addition, vimentin and Ki-67 protein expression was found sharply decreased in anti-miR-200a group compared to miR-NC group (P < 0.05). Consistent with this, wound-healing and MTT assay showed that migration and proliferation capacity of MHCC-97L cells in anti-miR-200a group is significantly increased compared with miR-NC group (both P < 0.05). CONCLUSION: Our study reveals an important role of miR-200a in inhibiting EMT, proliferation and migration in HCC cells, suggesting the possibility of miR-200a-based therapeutics in HCC. PMID- 26617702 TI - Expression of Robo protein in bladder cancer tissues and its effect on the growth of cancer cells by blocking Robo protein. AB - This study aimed to detect the expression of Slit signaling protein ligand Robo protein in human bladder cancer and para-carcinoma tissue, and observe the tumor cell survival and growth by inoculating the bladder cancer cells with the blocked signaling protein into the subcutaneous tissue of nude mice. The expression of Robo protein was detected in T24 cells in human bladder uroepithelium carcinoma and cultivated human bladder uroepithelium carcinoma confirmed by pathological diagnosis. The cultivated T24 cells were coated by the protein antibody and human bladder uroepithelium carcinoma T24 tumor-bearing mice model was established. The tumor cell survival and growth were observed in the antibody coating group and non-coating group. The tumor body size was measured. The immunohistochemical detection showed that Robo protein isoforms Robo1 and Robo 4 were expressed in T24 cells of cancer tissues, paracarcinoma tissues and cultured human uroepithelium carcinoma. The expression of Robo1 was significantly higher than that of Robo4 (P<0.05). The cancer cells could be detected in nodular tumor of mice in each group. The volume of the tumor-bearing mice in the nodular tumor of the non-coating group was larger than that of anti-Robol antibody coating group and the difference was statistically significant (P<0.01). There was no significant difference in tumor volume between anti-Robo4 antibody coating group and non-coating group (P>0.05); The difference was statistically significant compared with the anti-Robo1 antibody coating group (P<0.01). In conclusion, Robo protein isoforms Robo1 and Robo4 were expressed in human bladder cancer T24 cells. To block Robo4 signal protein had little effect on the survival and growth of the transplantation tumor and to block Robo1 signal protein would seriously affect the survival and growth of the transplantation tumor, suggesting that Robo1 might play an important role in the growth and metastasis of bladder cancer, and might become a new target for the treatment of human bladder cancer and drug research. PMID- 26617703 TI - Ischemia-reperfusion model in rat spinal cord: cell viability and apoptosis signaling study. AB - This work aimed at determining the ideal ischemia time in an in vitro ischemia reperfusion model of spinal cord injury. Rat spinal cord slices were prepared and then exposed or not to oxygen deprivation and low glucose (ODLG) for 30, 45, 60, 75 and 90 minutes. Cell viability was assessed by triphenyltetrazolium (TTC), lactate dehydrogenase (LDH) release, and fluorochrome dyes specific for cell dead (ethidium homodimer) using the apotome system. Glutamate release was enzymatically measured by a fluorescent method. Gene expression of apoptotic factors was assessed by real time RT-PCR. Whereas spinal cord slices exposed to ODLG exhibited mild increase in fluorescence for 30 minutes after the insult, the 45, 60, 75 and 90 minutes caused a 2-fold increase. ODLG exposure for 45, 60, 75 or 90 minutes, glutamate and LDH release were significantly elevated. nNOS mRNA expression was overexpressed for 45 minutes and moderately increased for 60 minutes in ODLG groups. Bax/bcl-xl ratio, caspase 9 and caspase 3 mRNA expressions were significantly increased for 45 minutes of ODLG, but not for 30, 60, 75 and 90 minutes. Results showed that cell viability reduction in the spinal cord was dependent on ischemic time, resulting in glutamate and LDH release. ODLG for 45 minutes was adequate for gene expression evaluation of proteins and proteases involved in apoptosis pathways. PMID- 26617704 TI - A classification of lesions around interventricular foramen and its clinical value. AB - OBJECTIVES: Lesions around interventricular foramen are difficult to remove for their important adjacent structures. We classify these tumors according their location on Magnetic Resonance Image (MRI) to help us resect these lesions. METHODS: Thirty-two tumors around the interventricular foramen were studied according their location and anatomic relations in MRI. RESULTS: Tumors around interventricular foramen were classified into three types. The first one mainly locates in lateral ventricle and the second one growth both in lateral ventricle, interventricular foramen and third ventricle, while the third one mainly in third ventricle. Different surgical approaches were adopted according their classification and the patients recovered well. CONCLUSION: This classification can help us to chose the surgical approach for these tumors. PMID- 26617705 TI - Antitumor effects of combining tumor radiation with the antivascular action of ultrasound stimulated microbubbles. AB - OBJECTIVE: More and more evidence indicates tumor vasculature plays an important role in tumor radiation response. In this study, we investigated ultrasound stimulated microbubbles to enhance the effects of radiation. METHODS: Human bladder cancer HT-1376 xenografts in severe combined immuno-deficient mice were used. High-frequency (25 MHz) ultrasound was used to image tumor responses caused by ultrasound-stimulated microbubbles in combination with radiation. Human bladder xenografts grown in severe combined immunodeficiency (SCID) mice were treated using microbubbles stimulated with ultrasound at 250, 570, or 750 kPa, and exposed to 0, 2, or 8 Gy of radiation. Tumors were imaged prior to treatment and 24 hours after treatment. Spectral analysis of images acquired from treated tumors revealed overall increases in ultrasound backscatter intensity and the spectral intercept parameter. RESULTS: There existed a synergistic effect in vivo with combined single treatments of ultrasound-stimulated microbubble vascular perturbation and radiation inducing an over 10-fold greater cell kill with combined treatments. We further demonstrate that induction of ceramide-related endothelial cell apoptosis, leading to vascular disruption, is a causative mechanism. In vivo experiments with ultrasound and bubbles permit radiation doses to be decreased significantly for comparable effect. CONCLUSION: We envisage this unique combined ultrasound-based vascular perturbation and radiation treatment method being used to enhance the effects of radiation in a tumor, leading to greater tumor eradication. PMID- 26617706 TI - Proteomic analysis of synovial fluid as an analytical tool to detect candidate biomarkers for knee osteoarthritis. AB - We conducted research to detect the proteomic profiles in synovial fluid (SF) from knee osteoarthritis (OA) patients to better understand the pathogenesis and aetiology of OA. Our long-term goal is to identify reliable candidate biomarkers for OA in SF. The SF proteins obtained from 10 knee OA patients and 10 non-OA patients (9 of whom were patients with a meniscus injury in the knee; 1 had a discoid meniscus in the knee, and all exhibited intact articular cartilage) were separated by two-dimensional electrophoresis (2-DE). The repeatability of the obtained protein spots regarding their intensity was tested via triplicate 2-DE of selected samples. The observed protein expression patterns were subjected to statistical analysis, and differentially expressed protein spots were identified via matrix-assisted laser desorption/ionisation-time of flight/time of flight mass spectrometry (MALDI-TOF/TOF MS). Our analyses showed low intrasample variability and clear intersample variation. Among the protein spots observed on the gels, there were 29 significant differences, of which 22 corresponded to upregulation and 7 to downregulation in the OA group. One of the upregulated protein spots was confirmed to be haptoglobin by mass spectrometry, and the levels of haptoglobin in SF are positively correlated with the severity of OA (r = 0.89, P < 0.001). This study showed that 2-DE could be used under standard conditions to screen SF samples and identify a small subset of proteins in SF that are potential markers associated with OA. Spots of interest identified by mass spectrometry, such as haptoglobin, may be associated with OA severity. PMID- 26617707 TI - Niflumic acid exhibits anti-tumor activity in nasopharyngeal carcinoma cells through affecting the expression of ERK1/2 and the activity of MMP2 and MMP9. AB - Niflumic acid (NFA) was known to inhibit cell proliferation or migration in several types of cancer. However, the function of NFA in human nasopharyngeal carcinoma (NPC) cells was not clarified. The proliferation of NPC cell line CNE 2Z cells with NFA treatment was detected using the cell counting kit-8 method and transwell assay was employed to assess the effect of NFA on the CNE-2Z cell migration and invasion. The activity of MMP2 and MMP9 was detected by Gelatin Zymography. Cell cycle distribution and apoptosis were detected using flow cytometry. In vitro pull-down assay, western blot, and computational technique were applied to investigate the NFA regulating signaling pathway. Our results indicated that the growth capacity and colony formation potential of CNE-2Z cells in soft agar were significantly suppressed by treatment with NFA. NFA inhibited the proliferation of CNE-2Z cells in a concentration and time-dependent manner. NFA exerted an S phase arrest on the CNE-2Z cells in a concentration-dependent manner, while promoting apoptosis in a dose-dependent manner. Migration and invasion potential of CNE-2Z cells were decreased by NFA treatment in vitro. In vitro pull-down assay and molecular modeling indicated that NFA directly bound with early respond kinase 1 (ERK1). Finally, the anti-tumor effect of NFA was suggested to be mediated by inhibiting early respond kinases (ERK) expression and the MMP2 and MMP9 activities. NFA has proliferation-inhibiting, invasion suppressing, cell cycle-blocking and apoptosis-promoting effects on CNE-2Z cells through regulation of ERK/MAPK and our results indicates that NFA may serve as a candidate of anticancer drug for NPC. PMID- 26617708 TI - Enhanced expression of Fas and FasL modulates apoptosis in the lungs of severe P. falciparum malaria patients with pulmonary edema. AB - Apoptosis mediated by Fas/FasL has been implicated in pulmonary disorders. However, little is known about the relationship between Fas and FasL in the process of lung injury during malaria infection. Paraffin-embedded lung tissues from malaria patients were divided into two groups: those with pulmonary edema (PE) and those without pulmonary edema (non-PE). Normal lung tissues were used as the control group. Cellular expression of Fas, FasL, and the markers of apoptotic caspases, including cleaved caspase-3 and cleaved caspase-8 in the lung tissues were investigated by the immunohistochemistry (IHC) method. Semi-quantitative analysis of IHC staining revealed that cellular expression of Fas, FasL, cleaved caspase-8, and cleaved caspase-3 were significantly increased in the lungs of patients with PE compared with the lungs of patients with non-PE and control groups (all P < 0.05). In addition, significant positive correlations were obtained between Fas and apoptosis (rs = 0.937, P < 0.001) and FasL and apoptosis (rs = 0.808, P < 0.001). Significant positive correlations were found between Fas and FasL expression (rs = 0.827, P < 0.001) and between cleaved caspase-8 and cleaved caspase-3 expression (rs = 0.823, P < 0.001), which suggests that Fas dependent initiator and effector caspases, including cleaved caspase-8 and caspase-3, are necessary for inducing apoptosis in the lungs of patients with severe P. falciparum malaria. The Fas/FasL system and downstream activation of caspases are important mediators of apoptosis and may be involved in the pathogenesis of pulmonary edema in severe P. falciparum malaria patients. The proper regulation of the Fas/FasL pathway can be a potential treatment for pulmonary complications in falciparum malaria patients. PMID- 26617709 TI - Lipopolysaccharide activated TLR4/NF-kappaB signaling pathway of fibroblasts from uterine fibroids. AB - Uterine fibroids (UF) are the most common benign tumor of the female reproductive tract. The aim of this study was to explore the role of lipopolysaccharide (LPS) induced activation of TLR4/NF-kappaB signaling pathway on stromal fibroblasts in the pathogenesis of UF. Here, TLR4/NF-kappaB signaling pathway was more activated in UF, and UF cells (UFC) and UF derived fibroblasts (TAF) than in smooth muscle tissues, smooth muscle cell (SMC) and myometrial fibroblasts (fib) respectively. After lipopolysaccharide (LPS) stimulation, the activity of fib was enhanced, characterized by the increased expression of fibroblast activation protein (FAP), and increased secretion of collagen I and transforming growth factor-beta (TGF beta). Moreover, TLR4 inhibitor (VIPER) and siTLR4 can represses LPS-activated fibroblasts and TLR4/NF-kappaB signaling transduction pathways in fib and UFC cells. Co-cultured with LPS-activated fibroblast enhanced fibroblast activation and TLR4/NF-kappaB signaling. In conclusion, LPS treatment activated TLR4/NF kappaB signaling pathway on fibroblasts, which may involve in the development of UF. Our study indicated reproductive tract infection may be associated with fibroid pathogenesis through TLR4/NF-kappaB signaling. Targeting NF-kappaB with inhibitors may hold promises of treating uterine fibroid. PMID- 26617710 TI - Impairment of mesenchymal stem cells derived from oral leukoplakia. AB - Oral leukoplakia is one of the common precancerous lesions in oral mucosa. To compare the biological characteristics and regenerative capacities of mesenchymal stem cells (MSCs) from oral leukoplakia (epithelial hyperplasia and dysplasia) and normal oral mucosa, MSCs were isolated by enzyme digestion. Then these cells were identified by the expression of MSC related markers, STRO-1, CD105 and CD90, with the absent for the hematopoietic stem cell marker CD34 by flow cytometric detection. The self-renewal ability of MSCs from oral leukoplakia was enhanced, while the multipotent differentiation was descended, compared with MSCs from normal oral mucosa. Fibrin gel was used as a carrier for MSCs transplanted into immunocompromised mice to detect their regenerative capacity. The regenerative capacities of MSCs from oral leukoplakia became impaired partly. Collagen IV (Col IV) and matrix metalloproteinases-9 (MMP-9) were selected to analyze the potential mechanism for the functional changes of MSCs from oral leukoplakia by immunochemical and western blot analysis. The expression of Col IV was decreased and that of MMP-9 was increased by MSCs with the progression of oral leukoplakia, especially in MSCs from epithelial dysplasia. The imbalance between regenerative and metabolic self-regulatory functions of MSCs from oral leukoplakia may be related to the progression of this premalignant disorder. PMID- 26617711 TI - Lentiviral vector-mediated over-expression of Sox9 protected chondrocytes from IL 1beta induced degeneration and apoptosis. AB - To explore whether the over-expression of Sry-related HMG box (Sox9) in degenerative chondrocytes is able to improve cell regeneration and protects cells from inflammation induced apoptosis, we generated a Sox9 over-expressing vector delivery system in which the Sox9 gene was inserted into a lentiviral vector. After infecting mouse chondrocytes with the Sox9-encoding vector, we observed a high level of gene transduction efficiency and achieved a high level of Sox9 expression in the infected chondrocytes. To explore whether over-expression of Sox9 is able to induce cell regeneration and improve cell survival, we induced Sox9 over-expression by lentiviral vector infection 48 hours before IL-1beta treatment. The cells were infected with the reporter gene GFP-encoded lentiviral vector as a negative control or left uninfected. 48-hours after IL-1beta treatment, the chrondrocytes treated with IL-1beta alone, underwent a degenerative process, with elevated expression of MMP-3, MMP-13, ADAMTS-5 and ALP, but the cell specific anabolic proteins collagen II and aggrecan were significantly suppressed. The cells infected with the GFP reporter vector had no increased regeneration after IL-1beta treatment. The results indicated that Sox9 is an important chondrocyte transcription factor, promoting chondrocyte regeneration and cell survival, which were mediated through affecting multiple cell differentiation as well as anti-apoptotic signaling pathways. PMID- 26617712 TI - MicroRNA-214 induces dendritic cell switching from tolerance to immunity by targeting beta-Catenin signaling. AB - MicroRNAs (miRNAs) are known to function as negative gene regulators. Recently, miRNAs have been shown to regulate immunity processes; however, the mechanism is unclear. The role of microRNA-214 (miR-214) in dendritic cell (DC) maturation has not been investigated. We found that the miR-214 level was correlated with the maturation of DCs and inflammatory cytokine secretion, as depressed miR-214 levels induced DC tolerance. We also identified beta-catenin as a target gene of miR-214 and demonstrated its association with Treg cell differentiation. MiR-214 regulates gene expression by binding to the 3'UTR of beta-catenin. The results suggest that beta-catenin is a critical regulator of tolerance in DCs via miR 214. The expression of miR-214 could be a potential therapeutic strategy in organ transplantation or autoimmunity patients. PMID- 26617713 TI - Anticancer activity of NOB1-targeted shRNA combination with TRAIL in epithelial ovarian cancer cells. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) based strategy is a promising targeted therapeutic approach for the treatment of ovarian cancer. However, the effectiveness of the treatment remains limited due to the inherent or acquired resistance of tumor cells to TRAIL. Our previously study demonstrated that downregulation of NOB1 (NIN1/RPN12 binding protein 1 homolog) expression by a lentiviral short hairpin RNA (shRNA) delivery system (Lv/sh-NOB1) suppressed ovarian cancer growth. Here, Lv/sh-NOB1 and TRAIL were combined and tested the effects of this combination on ovarian cancer cells to identify more effective therapeutics against ovarian cancer by several in vitro experiments. Tumor growth ability in SKVO3 xenograft nude mice was also determined to define this combination treatment effect in tumorigenesis in vivo. In vitro assay showed that Lv/sh-NOB1 in combination with TRAIL treatment in ovarian cancer cell synergistically suppressed the proliferation and colony formation, as well as induced cell apoptosis and increased the activity of caspase-3, -8 and -9. In vivo assay showed that Lv/sh-NOB1 combination with TRAIL synergistically suppressed tumor growth of nude mice model. Importantly, we found that downregulation of NOB1 could upregulate DR5 expression and active MAPK pathway, which might contribute to increase sensitivity TRAIL to ovarian cancer cells. These findings suggested that Lv/sh-NOB1 combination with TRAIL treatment may be a potential treatment approach for ovarian cancer. PMID- 26617714 TI - MicroRNA-299-3p promotes the sensibility of lung cancer to doxorubicin through directly targeting ABCE1. AB - MicroRNAs (miRNAs) are a class of endogenous, small non-coding RNAs which play important roles in various biological and cellular processes, including chemoresistance. The expression level of miR-299-3p was dysregulated in doxorubicin-resistance lung cancer cell lines. However, the exact role of miR-299 3p in doxorubicin-resistance is still unknown. In the present study, miR-299-3p was down-expressed in doxorubicin-resistant or -sensitive lung cancer samples and it was identified to directly targeted adenosine triphosphate binding cassette E1 (ABCE1) 3'-untranslated region (UTR) in lung cancer H69 cells by luciferase assay. After transfection of miR-299-3p mimics or ABCE1-siRNA, MTT assay confirmed that the H69/ADR cell proliferation was inhibited, as well as the enhanced cell inhibitory rate in the presence of doxorubicin. H69/ADR cell apoptosis rate was promoted after miR-299-3p or ABCE1-siRNA transfection. The results indicated that miR-299-3p promotes the sensibility of lung cancer to doxorubicin through suppression of ABCE1, at least partly. Therefore, the disordered decreased of miR-299-3p and resulting ABCE1 up-expression may contribute to chemoresistance of lung cancer, and miR-299-3p-ABCE1 may represent a new potential therapeutic target for the treatment of chemoresistance of lung cancer. PMID- 26617715 TI - Ectopic expressed long non-coding RNA H19 contributes to malignant cell behavior of ovarian cancer. AB - Recent studies have highlighted the role of long non-coding RNAs (lncRNAs) in carcinogenesis and have suggested that genes of this class might be used as biomarkers in cancer. However, whether lncRNAs are involved in ovarian cancer (OC) remains largely unknown. In the present study, we focused on lncRNAH19 and investigated the expression and functional role of H19 in OC. H19 expression was measured in 70 pairs of ovarian cancer tissue samples compared with normal controls by real-time quantitative RT-PCR. The effects of H19 on ovarian cancer cells were studied by RNA interference approach. Apoptosis and cell cycle were analyzed by flow cytometry. Cells viability was evaluated using cell counting Kit 8. Our results demonstrated that that H19 silencing inhibited OV90 and SKOV3 OC cell proliferation in vitro. Further investigation into the mechanisms responsible for the growth inhibitory effects by H19 silencing revealed that its knockdown resulted in the induction of cell cycle arrest and apoptosis through certain cell cycle-related and apoptosis-related proteins. Together, our data suggest that LncRNAH19 plays an important role in OC cell proliferation and contributes to a better understanding of the importance of dysregulated lncRNAs in OC progression. PMID- 26617716 TI - Inhibition of SALL4 suppresses carcinogenesis of colorectal cancer via regulating Gli1 expression. AB - BACKGROUND: SALL4 is a novel oncogene mediating tumorigenesis in multiple carcinomas. However, its actual role and mechanisms participating in the development of colorectal cancer remains unclear. METHODS: Immunohistochemical staining and Western blot were conducted to detect the expression of SALL4 and other molecules. siRNA of SALL4 was transfected to silence SALL4 expression in Caco-2 cell line. Flow cytometry was used for cell cycle and apoptosis analysis. Wound healing and transwell assay were used for invasion test. CCK-8 test was employed for cell proliferation and drug sensitivity assessment. RESULTS: By inhibition of SALL4 expression, the proliferation, invasiveness and drug resistance were dramatically reduced while apoptosis rate was up-regulated. Gli1 was found to decrease its expression in SALL4 silencing cells. Moreover, the inhibition on tumorigenesis of Caco-2 by SALL4 silencing was antagonized by Gli1 up-regulation, suggesting Gli1 as a downstream target of SALL4 in cancer development. CONCLUSION: SALL4 inhibition limited oncogenesis on colorectal cancer by reducing Gli1 expression. PMID- 26617717 TI - Expression of cystatin C and its effect on EC9706 cells in esophageal carcinoma. AB - OBJECTIVE: To investigate the expression of cystatin C gene and its effect on the proliferation, apoptosis and invasiveness of EC9706 cells in esophageal carcinoma. METHODS: 56 cases of esophageal carcinoma were randomly collected from our hospital. Samples of human esophageal carcinomas and matched normal esophageal mucosal epithelium were selected by resection operation from these patients. Expression of cathepsin B and cystatin C in these specimens were determined by immunohistochemistry and qRT-PCR. Next, lentiviral vectors of over expression and interference for cystatin C gene were constructed, and both were transfected into EC9706 cells, and then the levels of cystatin C mRNA and protein were detected by qRT-PCR and Western blot. The effect of over and low-expressed cystatin C on the proliferation, apoptosis and invasiveness of esophageal carcinoma cells were detected by MTT assay, flow cytometry and Transwell assay. RESULTS: Compared with normal esophageal epithelial tissues, mRNA and protein levels of cathepsin B and cystatin C in esophageal carcinoma tissues were significantly increased (P<0.05). Lentiviral vectors of over-expression and interference for cystatin C gene were successfully transfected into EC9706 cells. Over or low-expression cystatin C had no effect on EC9706 cells proliferation but had a reverse relationship with the apoptosis. However, cystatin C over expression significantly decreased tumor invasiveness (P<0.05) while the invasiveness of EC9706 cells was significantly enhanced by RNAi-mediated abrogation of cystatin C gene expression (P<0.05). CONCLUSION: Over-expressed cystatin C could inhibit the invasiveness of esophageal carcinoma cells. PMID- 26617718 TI - Luteolin improves the impaired nerve functions in diabetic neuropathy: behavioral and biochemical evidences. AB - Peripheral neuropathies are a major cause of morbidity in patients with diabetes mellitus. Up to now, drugs for improving the impaired nerve functions has been lacking for diabetic neuropathy. The antioxidant and neuroprotective effects of luteolin make it an attractive candidate for diabetic neuropathy. The present study was designed to investigate the putative beneficial effect of luteolin on diabetic neuropathy. Diabetic rats were intraperitoneally treated with daily luteolin (50 mg/kg, 100 mg/kg and 200 mg/kg) or vehicle for 3 weeks from the 28(th) day after streptozotocin injection. Behavioral, electrophysiological and biochemical studies were performed to evaluate the effect of luteolin on the impaired nerve functions in diabetic neuropathy. It was found that luteolin dose dependently alleviated abnormal sensation, improved nerve conduction velocities and nerve blood flow in diabetic rats. Biochanical analysis showed that luteolin significantly lowered the reactive oxygen species production and malondialdehyde level, as well as increased antioxidants activities in a dose dependent manner. In addition, luteolin significantly up-regulated the protein levels of nuclear factor-E2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) in diabetic nerves. Taken together, luteolin is capable of improving diabetes-induced deficit in motor and sensory functions, which could be attributable, at least in part, to its Nrf2-dependent antioxidant capacity. The findings in the present study highlight the therapeutic value of luteolin for diabetic neuropathy. PMID- 26617719 TI - 7,8-dihydroxycoumarin has a dual mechanism of action in hepatic ischemia reperfusion injury. AB - The present study was designed to investigate the protective effect of 7,8 dihydroxycoumarin on hepatic ischemia/reperfusion (I/R) injury in the rats. The rats were divided in three groups of 10 each; normal control, untreated and the 7,8-dihydroxycoumarin treatment groups. The rats in the treatment group received 7,8-dihydroxycoumarin at doses of 15 mg/kg body weight 1 h prior to ischemia and then daily for 2 days. The animals were sacrificed after 1, 12, 24, 36, and 48 h of reperfusion. The results revealed that 7,8-dihydroxycoumarin protected the liver against I/R injury via inhibition of inflammatory response at the early stage (0-24 h). However, in 7,8-dihydroxycoumarin treatment group autophagy was inhibited resulting in intensified I/R injury following 36 h of reperfusion. 7,8 dihydroxycoumarin treatment caused reduction in the level of serum aminotransferase, liver inflammatory cytokines and showed minor liver histopathologic alterations. However, after 36 h of reperfusion treatment group showed similar I/R injury as that of untreated group. It was observed that 7,8 dihydroxycoumarin enhanced the activation of mitogen-activated protein kinase, decreased nuclear release of high-mobility group box 1 and production of inflammatory cytokines. After 36 h 7,8-dihydroxycoumarin promoted hepatic injury through suppression of autophagy and induction of hepatic apoptosis. Therefore, 7,8-dihydroxycoumarin exhibits inhibitory effect on hepatic ischemia during 0-24 h but causes its promotion after 36 h. PMID- 26617720 TI - Decreased expression of SOX9 indicates a better prognosis and inhibits the growth of glioma cells by inducing cell cycle arrest. AB - Deregulation of SOX9 expression has been detected in various human cancer tissues; however, the functional role of SOX9 expression has not been fully elucidated in glioma. SOX9 expression in glioma tissues was analyzed using public tumor datasets and quantitative reverse transcription polymerase chain reaction. The association of SOX9 expression with clinical prognosis in glioma patients was analyzed by examining publically available microarray profiling datasets. The functional roles of SOX9 in glioma were examined using gene set enrichment analysis (GSEA). Cell growth was measured using soft agar colony formation assay, and the cell cycle was analyzed using flow cytometry. Our data showed that SOX9 expression was commonly upregulated in glioma tissues, and patients with high SOX9 levels had shorter survival times. GSEA identified that the gene sets regulating cell proliferation and cell cycle progression were significantly enriched in glioma cells with high SOX9 expression. SOX9 downregulation decreased cyclin D1, CDK4 expression and Rb phosphorylation, which correlated with a reduced population of cells in the S phase and suppressed growth. SOX9, as an oncogene, is highly expressed in gliomas and may be potential indicators of a poor prognosis in glioma patients. SOX9 knockdown may suppress cancer cell growth by inducing cell cycle arrest, which suggests that SOX9 is a potential therapeutic target in glioma. PMID- 26617721 TI - Baicalin ameliorates isoproterenol-induced acute myocardial infarction through iNOS, inflammation and oxidative stress in rat. AB - Baicalin belongs to glucuronic acid glycosides and after hydrolysis baicalein and glucuronic acid come into being. It has such effects as clearing heat and removing toxicity, anti-inflammation, choleresis, bringing high blood pressure down, diuresis, anti-allergic reaction and so on. In this study, we investigated whether baicalin ameliorates isoproterenol-induced acute myocardial infarction and its mechanism. Rat model of acute myocardial infarction was induced by isoproterenol. Casein kinase (CK), the MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH), cardiac troponin T (cTnT) and infarct size measurement were used to measure the protective effect of baicalin on isoproterenol-induced acute myocardial infarction. iNOS protein expression in rat was analyzed using western blot analysis. Tumor necrosis factor-alpha (TNF alpha), interleukin 6 (IL-6), malondialdehyde (MDA) and superoxide dismutase (SOD) and caspase-3 activation levels were explored using commercial ELISA kits. In the acute myocardial infarction experiment, baicalin effectively ameliorates the level of CK, CK-MB, LDH and cTnT, reduced infarct size in acute myocardial infarction rat model. Meanwhile, treatment with baicalin effectively decreased the iNOS protein expression, inflammatory factors and oxidative stresses in a rat model of acute myocardial infarction. However, baicalin emerged that anti apoptosis activity and suppressed the activation of caspase-3 in a rat model of acute myocardial infarction. The data suggest that the protective effect of baicalin ameliorates isoproterenol-induced acute myocardial infarction through iNOS, inflammation and oxidative stress in rat. PMID- 26617722 TI - MicroRNA-101 regulates the viability and invasion of cervical cancer cells. AB - BACKGROUND: Cervical cancer has the second highest morbidity and mortality rates of any malignancy in women worldwide, and it is one of the leading causes of death in Uygur women in Xinjiang China. MicroRNAs are involved in cancer development and progression. Previously, we found that miR-101 is significantly down-regulated in cervical cancer tissues from Uyghur women. The underlying pathophysiology and relevance to tumorigenesis of miR-101 is still largely unknown. The purpose of this study was to elucidate the molecular mechanisms of miR-101 regulation of cervical cancer cell viability and invasion. MATERIALS AND METHODS: The expression of miR-101 in cervical cancer cell line (SiHa) was detected by real-time PCR. A miR-101 mimic was overexpressed in SiHa cells, and MTT assays were performed to determine the impact on cell proliferation. Cell would heal assays and flow cytometry were used to detect migratory ability and cellular apoptosis, respectively. Immunohistochemistry was performed to assess protein expression of the miR-101 target gene COX-2. RESULTS: MiR-101 was endogenously expressed in SiHa cells, and alterations in its expression had profound effects on cellular migration and invasion efficiency. Overexpression of miR-101 decreased proliferation in the MTT assay (the mimics at 490 nm absorbance is lower 60% than normal, and decreased cellular motility in the cell would healing assay (transfected: 37 +/- 2 m, pre-transfected 184 +/- 2 m). Apoptosis rate was significantly higher with overexpression of miR-101 relative to control (transfected: 76.6%, pre-transfected: 3.5%) (P < 0.05). The expression of Cox-2 was decreased in transfected cells. CONCLUSIONS: MiR-101 likely acts as a tumor suppressor in cervical cancer. Overexpression of miR-101 decreased expression of its target gene Cox-2 and inhibited proliferation and invasion, and promoted apoptosis to suppress tumorigenicity. MiR-101 is a promising new target for the development of therapeutic strategies for the clinical treatment of cervical cancer. PMID- 26617723 TI - Heme oxygenase 1 plays role of neuron-protection by regulating Nrf2-ARE signaling post intracerebral hemorrhage. AB - The NF-E2 related factor 2 (Nrf2) could be activated in intracerebral hemorrhage (ICH), and trigger the expression of ARE regulated heme oxygenase 1 (HO-1) subsequently. This study aims to explore neuroprotection of HO-1 protein in regulating the Nrf2-ARE signaling pathway in ICH. In this study, the femoral artery injection method was used to establish the ICH model. The zinc porphyrin-9 (ZPP-IX) was used to inhibit the HO-1 expression in ICH rats. The ICH rats were randomly divided into 3 groups, ICH group, ZPP-IX (10 mg/kg) + ICH group and DMSO (10 mg/kg) + ICH group. Neurological scores were evaluated for the 3 groups. Double immunofluorescence staining method was employed to observe the co expression of HO-1, Nrf2, NF-kappaB and TNF-alpha and CD11b in glia cells. Western blot and RT-PCR assay were used to detect the total Nrf2, binding Nrf2, HO-1, NF-kappaB and TNF-alpha expression. The results indicated that ZPP-IX could aggravate the neurological dyafunstions of ICH rats. The HO-1 level in ZPP-IX group was significantly decreased compared to the ICH group (P < 0.05). The binding-Nrf2 protein was significantly increased in ZPP-IX group compared to ICH group (P < 0.05). The NF-kappaB and TNF-alpha level were significantly increased in ZPP-IX group compared to ICH group (P < 0.05). The ZPP-IX significantly inhibited the HO-1 and Nrf2, and enhanced NF-kappaB and TNF-alpha co-expressing with the CD11b compared to the ICH group (P < 0.05). In conclusion, HO-1 protein regulates the Nrf2-ARE pathway in ICH model by inhibiting the Nrf2 entering nucleus and activating the NF-kappaB and TNF-alpha expression. PMID- 26617724 TI - Expression of RKIP, E-cadherin and NF-kB p65 in esophageal squamous cell carcinoma and their correlations. AB - To detect the expression of RKIP, E-cadherin and NF-kB p65 in esophageal squamous cell carcinoma (ESCC) and study their correlations. Steptavidin-peroxidase (S-P) method was employed to detect the expressions of RKIP, E-cadherin and NF-kB p65 in ESCC tissues from 77 cases and paracancerous tissues from 77 cases. The correlations between their expressions and clinicopathological indices and between the expressions of these proteins themselves were analyzed. The expressions of RKIP and E-cadherin in ESCC tissues were obviously lower than those in the paracancerous tissues (P<0.01); the expressions in ESCC tissues from cases with lymph node metastasis were lower than those from cases without lymph node metastasis (P<0.01); the expression of RKIP was positively correlated with the expression of E-cadherin in ESCC tissues (P<0.01). The expression of NF-kB p65 in ESCC tissues was correlated with clinical staging, lymph node metastasis and tumor differentiation (P<0.01); the expression of RKIP was negatively correlated with the expression of NF-kB p65 in ESCC tissues (P<0.05). Downregulation or depletion of RKIP was related to the onset and progression of ESCC, and facilitated the invasion and metastasis of ESCC by downregulating E cadherin and upregulating NF-kB p65. PMID- 26617725 TI - Clinical, histopathological and genetic studies in a case of fatal familial insomnia with review of the literature. AB - To explore clinical, histopathological and genetic features of a case with fatal familial insomnia (FFI) and review the related literatures. A middle-aged woman who complained of "insomnia for 9 months and psychosis for 3 months" was suspicious of FFI. The clinical features of the patient were analyzed, and the dead patient was examined by autopsy and the brain tissues were obtained for histopathological studies, and the blood samples from the patient and some of her familial members were collected for the sequencing of prion protein gene (PRNP). The main clinical features included intractable insomnia, psychiatric symptoms and abnormal night sleep behavior, unsteady gait, difficulty swallowing, sudden death, and positive family history. The pathological studies showed neuronal loss and gliosis of multiple brain tissues in the proband, predominated with thalamus; and analysis of PRNP revealed gene D178N mutation, and linkage with 129 methionine (Met) allele in the proband and a relative. FFI patients may manifest as sudden death, and may have prominent psychiatric symptoms; the corresponding gene mutation could occur in the asymptomatic carriers; the data of autopsy and brain tissue pathology is helpful for further understanding of this disease. PMID- 26617726 TI - Squamous cell carcinoma resulting from chronic osteomyelitis: a retrospective study of 8 cases. AB - BACKGROUND: Squamous cell carcinoma is a severe malignant tumor but was rare in the chronic osteomyelitis. The purpose of this study was to present the results from a retrospective study the cases of squamous cell carcinoma arising from chronic osteomyelitis. MATERIAL AND METHODS: Between 1974 and 2010, eight cases of squamous cell carcinoma after chronic osteomyelitis were treated. The patients had an average age of 55 years (range 45 to 66 years), with a male predominance (6 men and 2 woman). We analyzed the time up to cancerization, localization and histopathological types of the carcinoma, and types and results of the treatment. RESULTS: The mean delay between the initial injury and the diagnosis of malignant transformation was 28 years (range 8 to 50 years). The carcinoma resulted from tibia osteomyelitis in six cases, femur in one case and ankle in one case. The pathological examination showed two cases of a well-differentiated squamous cell carcinoma with bone invasion and six cases of invasive squamous cell carcinoma. Curative amputation was performed in all patients but one who refused. No recurrence or metastasis occurred during follow-up time. CONCLUSION: Amputation appears to be an effective treatment method in squamous carcinoma secondary to chronic osteomyelitis. PMID- 26617727 TI - Effects of insulin-like growth factor 2 and its receptor expressions on corneal repair. AB - Limbal stem cell (LSC) on the basal layer of cornea plays an important role in the epithelial repair after corneal injury as it can proliferate, differentiate and migrate into injury sites under the direction of cytokines. This study explored the signaling pathway and cellular mechanism between corneal epithelial cells LSC, on a mouse model with mechanic corneal injury. Ipsilateral corneal mechanic injury model was prepared on mice using the contralateral eye as the control. Tissues from both central and peripheral regions of cornea were collected, cultured and quantified for expression of various cytokines including epidermal growth factor (EGF), fibroblast growth factor-beta (FGF-beta), heparin like growth factor (HGF), keratinocyte growth factor (KGF), transforming growth factor-beta1 (TGF-beta1), IGF-1 and IGF-2. The effects of these factors on the differentiation of LSC and fibroblasts were also studied. Most of those cytokines had elevated gene expressions after the corneal injury. Among those IGF-2 had significantly increased expression, along with the high expression of IGF-2 receptor in corneal peripheral cells. IGF-2 also induced the differentiation of LSC into keratin-12-positive cells. Further studies showed the prominent expression of alpha-actin in injured tissues, suggesting the potential transformation of fibroblasts into myofibroblasts. Both IGF-2 and its receptor had elevated expressions after corneal injury. They may facilitate the transformation of LSC into epithelial cells, in addition to the role in transformation from fibroblasts to myofibroblasts. PMID- 26617728 TI - FBXW12, a novel F box protein-encoding gene, is deleted or methylated in some cases of epithelial ovarian cancer. AB - Epithelial ovarian cancer is one of the most lethal of gynecological malignancies. Due to its lack of early symptoms, detection usually occurs when the tumor is no longer confined to the ovary. We previously identified Fbxw15, a gene encoding an F-box protein in the mouse ovary, and showed that its expression is developmentally regulated. Here we report the molecular analysis of its human homologue, FBXW12 in epithelial ovarian tumors. To search for FBXW12 gene mutations, we PCR-amplified and sequenced the coding region of FBXW12, the gene's 5-untranslated region and the proximal promoter in each of 30 EOC tumors. Promoter methylation was determined by DNA bisulfite conversion, followed by methylation specific PCR. FBXW12 intracellular localization was identified by means of immunohistochemistry. A complete deletion of the gene's coding region, the 5'-UTR and the proximal promoter, was observed in 3 EOC samples. Eight of the remaining 27, had a deletion of the 5'-UTR, and the proximal promoter. FBXW12 mRNA was detected in 2 of the 19 samples without deletions. The methylation specific PCR results demonstrated CpGs methylation in the FBXW12 proximal promoter. Immunohistochemistry assay revealed that within the normal ovary, FBXW12 has an oocyte specific expression, whereas in EOC samples it is present in the ovarian surface epithelium. Our results indicate that the FBXW12 gene is deleted in approximately ten percent of the EOC cases studied; such deletions comprised either the FBXW12 promoter or the mRNA-encoding region. Moreover, FBXW12 could be epigenetically silenced by CpGs methylation in some of these EOC cases. PMID- 26617729 TI - Activation of unfolded protein response protects osteosarcoma cells from cisplatin-induced apoptosis through NF-kappaB pathway. AB - The aim of this study was to uncover that unfolded protein response (UPR) contributed to the development of cisplatin resistance in osteosarcoma. MG-63 cells and SaOS-2 cells were exposed to cisplatin at presence or absence of 4 phenylbutyrayte (4-pba) and then analyzed by MTT assay and flow cytometry to determine the cell survival rates and apoptosis. Levels of glucose regulated protein 78KD (GRP78), C/EBP homologus protein (CHOP), cytoplasmic and nuclear NF kappaB were detected by Western blot. Further, MG-63 cells and SaOS-2 cells were subjected to cisplatin with or without Bay 11-7082, a well-known inhibitor of NF kappaB. After that, MTT assay and flow cytometry were used to determine the cell survival rates and apoptosis. Cisplatin and 4-PBA co-treatment significantly enhanced the cell apoptosis. Administration of cisplatin substantially increased the levels of GRP78 and CHOP. Moreover, mechanistic investigation uncovered that cisplatin promoted the levels of nuclear NF-kappaB whereas 4-PBA administration suppressed the cisplatin-induced accumulation of nuclear NF-kappaB level in osteosarcoma cells. Cisplatin combined with Bay 11-7082 obviously augmented MG-63 cells and SaOS-2 cells apoptosis when compared to that in osteosarcoma cells treated by cisplatin alone. Taken together, our data show that UPR protects osteosarcoma from cisplatin-mediated apoptosis through activation of NF-kappaB pathway. Therefore, targeting UPR may be a potential strategy to improve the osteosarcoma therapy. PMID- 26617730 TI - Ets-1 upregulation mediates angiotensin II-related cardiac fibrosis. AB - Ets-1, the prototypical member of the family of Ets transcription factors, has been shown to participate in tissue fibrotic remodeling. However, its role in cardiac fibrosis has not been established. The aim of this study was to investigate the role of Ets-1 in profibrotic actions of angiotensin II (Ang II) in cardiac fibroblasts (CFs) and in the in vivo heart. In growth-arrested CFs, Ang II induced Ets-1 expression in a time- and concentration-dependent manner. Pretreatment with Ang II type 1 receptor blocker losartan, protein kinase C inhibitor bisindolylmaleimide I, extracellular signal-regulated kinase (ERK) inhibitor PD98059, or c-Jun NH(2)-terminal kinase (JNK) inhibitor SP600125 partly inhibited this induction accompanied with impaired cell proliferation and production of plasminogen activator inhibitor-1 (PAI-1) and connective tissue growth factor (CTGF) protein, the two downstream targets of Ets-1. Knockdown of Ets-1 by siRNA significantly inhibited the inductive effects of Ang II on cell proliferation and expression of CTGF and PAI-1. Moreover, the levels of Ets-1, PAI-1 and CTGF protein were simultaneously upregulated in left ventricle of Ang II-infused rats in parallel with an increase in the activation of ERK and JNK. Our data suggest that Ets-1 may mediate Ang II-induced cardiac fibrotic effects. PMID- 26617731 TI - Changes of mesenchymal stromal cells mobilization and bone turnover in an experimental bone fracture model in ovariectomized mice. AB - OBJECTIVE: The aim of this study was to characterize the mesenchymal stromal cells (MSCs) and endothelial progenitor cells (EPCs) mobilization, and bone turnover in osteoporotic fracture healing in ovariectomized mice. METHODS: In total, 112 female C57/BL mice were divided into two groups. The first group was sham-operated (SO), and the other group was ovariectomized (OVX). After three weeks, the right femora of the mice were fractured under anesthesia and internally fixed with steel pin. Peripheral blood and bone marrow were was collected for flow cytometry analysis, at 0 hours (h), 12 h, 24 h, 72 h and 168 h after fracture. MSCs and EPCs levels were assessed using cell surface antigens in different combinations (CD44+ CD34-CD45-, and CD34+ KDR+CD45-) by flow cytometry. At 0, 14, 28 and 42 days after fracture, sera were assayed for circulating levels of procollagen type I-N-terminal propeptide (P1NP) and C-terminal telopeptide of type I-collagen (CTX) by ELISA. Femurs were harvested at 2 weeks and 6 weeks after fracture for X-ray radiography, micro-computed tomography (micro-CT) and histology. RESULTS: Our results showed that bone marrow and peripheral blood MSCs numbers of the OVX mice were significantly lower than the SO mice, at 12 h, 24 h and 72 h after fracture. In addition, circulating P1NP and CTX levels of the OVX mice were significantly higher than the SO mice, at 2 and 4 weeks. CONCLUSION: Results of the present study revealed disorders of bone marrow MSCs mobilization and bone turnover may partially account for the delay of osteoporotic fracture healing. PMID- 26617732 TI - Cardiac sodium/calcium exchanger preconditioning promotes anti-arrhythmic and cardioprotective effects through mitochondrial calcium-activated potassium channel. AB - BACKGROUND: Reverse-mode of the Na(+)/Ca(2+) exchanger (NCX) stimulation provides cardioprotective effects for the ischemic/reperfused heart during ischemic preconditioning (IP). This study was designed to test the hypothesis that pretreatment with an inhibitor of cardiac delayed-rectifying K(+) channel (IKr), E4031, increases reverse-mode of NCX activity, and triggers preconditioning against infarct size (IS) and arrhythmias caused by ischemia/reperfusion injury through mitoKCa channels. MATERIALS AND METHODS: In the isolated perfused rat heart, myocardial ischemia/reperfusion injury was created by occlusion of the left anterior descending coronary artery for 30 min followed by 120 min reperfusion. Two cycles of coronary occlusion for 5 min and reperfusion were performed, or pretreatment with E4031 or sevoflurane (Sevo) before the 30 min occlusion with the reversed-mode of NCX inhibitor (KB-R7943) or not. RESULTS: E4031 or Sevo preconditioning not only markedly decreased IS but also reduced arrhythmias, which was significantly blunted by KB-R7943. Furthermore, these effects of E4031 preconditioning on IS and arrhythmias were abolished by inhibition of the mitoKCa channels. Similarly, pretreatment with NS1619, an opener of the mitoKCa channels, for 10 min before occlusion reduced both the infarct size and arrhythmias caused by ischemia/reperfusion. However, these effects weren't affected by blockade of the NCX with KB-R7943. CONCLUSION: Taken together, these preliminary results conclude that pretreatment with E4031 reduces infarct size and produces anti-arrhythmic effect via stimulating the reverse-mode NCX, and that the mitoKCa channels mediate the protective effects. PMID- 26617733 TI - MicroRNA-370 directly targets FOXM1 to inhibit cell growth and metastasis in osteosarcoma cells. AB - MicroRNAs (miRNAs) are endogenous, non-coding, small RNAs, which play a critical role in regulating varieties of the biological and pathologic processes. Several reports have indicated that miR-370 acts as a tumor suppressor in varieties of tumors. However, the roles of miR-370 in osteosarcoma have not been reported. In this study, our objective was to explore the biological functions and its molecular mechanism of miR-370 in osteosarcoma cell lines, finding a therapeutic target of osteosarcoma. Our data demonstrated that miR-370 was evidently reduced in osteosarcoma cell lines, whereas FOXM1 expression was markedly increased. Up regulation of miR-370 suppressed proliferation, arrested cell cycle and induced apoptosis in osteosarcoma cells. Besides, invasion and EMT of osteosarcoma cells was also inhibited by introduction of miR-370. Next, we found that FOXM1 expression was significantly reduced by up-regulation of miR-370. Bioinformatics analysis predicted that the FOXM1 was a potential target gene of miR-370. Luciferase reporter assay further confirmed that miR-370 could directly target the 3' UTR of FOXM1. Overexpression of FOXM1 in osteosarcoma cells transfected with miR-370 mimic partially reversed the effects of miR-370. In conclusion, miR 370 inhibited cell growth and metastasis in osteosarcoma cells by down-regulation of FOXM1. PMID- 26617734 TI - Systemic BMSC homing in the regeneration of pulp-like tissue and the enhancing effect of stromal cell-derived factor-1 on BMSC homing. AB - Pulp regeneration caused by endogenous cells homing has become the new research spot in endodontics. However, the source of functional cells that are involved in and contributed to the reconstituting process has not been identified. In this study, the possible role of systemical BMSC in pulp regeneration and the effect of stromal cell-derived factor-1 (SDF-1) on stem cell recruitment and angiogenesis were evaluated. 54 mice were divided into three groups: SDF-1 group (subcutaneous pockets containing roots with SDF-1 absorbed neutralized collagen gel and the green fluorescent protein (GFP) positive BMSCs transplantation via the tail vein), SDF-1-free group (pockets containing roots with gel alone and GFP + BMSCs transplantation) and Control group (pockets containing roots with gel alone). The animals were sacrificed after the roots were implanted into subcutaneous pockets for 3 weeks. Histomorphometric analysis was performed to evaluate the regenerated tissue in the canal by hematoxylin and eosin (HE) staining. The homing of the transplanted BMSCs was monitored with a fluorescence microscope and immunohistochemical analysis. The expression of ALP in new formed tissue was detected immunohistochemically. Dental-pulp-like tissue and new vessels were regenerated and GFP-positive BMSCs and expression of ALP could be observed in both SDF-1 group and SDF-1-free group. Furthermore, more GFP+ cells, stronger expression of ALP and stronger angiogenesis were found in the SDF-1 group than in the SDF-1-free group. To conclude, systemic BMSC can home to the root canal and participate in dental-pulp-like tissue regeneration. Intracanal application of SDF-1 may enhance BMSC homing efficiency and angiogenesis. PMID- 26617735 TI - Down-regulation of ASICs current and the calcium transients by disrupting PICK1 protects primary cultured mouse cortical neurons from OGD-Rep insults. AB - Acid sensing ion channels (ASICs), activated by lowering extracellular pH, play an important role in normal synaptic transmission in brain and in the pathology of brain ischemia. ASICs activation involving in glutamate receptor-independent ischemic brain injury has been generally accepted, and PICK1 is recently shown to be one of partner proteins interacting with ASICs through its PDZ domain. Here we showed that ASICs and PICK1 played key roles in OGD-Rep process. In wild-type cultured cortical neurons, not only the amplitude of ASICs current and the calcium transients induced by acidosis were both increased after OGD-Rep, but also the total protein levels of ASIC1 and ASIC2a were up-regulated progressively after ischemia insults, indicating that ASICs play a vital role in neuronal ischemia. However, these activities were reversed with PICK1-knockout after OGD Rep, accompanied with the dramatically down-regulating the protein abundances of ASIC1 and ASIC2a, which suggested the neuroprotection activity in brain ischemia by PICK1-knockout. These results indicate that knocking-out PICK1 gene casts the neuroprotection effect by reducing ASICs current and the calcium transients in OGD-Rep neuronal cells, which will offer a promising strategy in the therapy of brain ischemia. PMID- 26617736 TI - The effects of early versus delayed castration targeting androgen on prolonging survival in a mouse model of bladder cancer. AB - OBJECTIVE: To compare the efficacy of early versus delayed surgical castration on prolonging survival and further to investigate the anticancer effect and potential value of targeting androgen in the therapeutic intervention of bladder cancer. MATERIALS AND METHODS: N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) was used to induce bladder cancer in male mice. Mice were randomly divided into three groups: the early castration group (on which castration was perform at 4 weeks after first time of BBN administration), the delayed castration group (on which castration was perform at 20 weeks after first time of BBN administration), and the sham-castrated group. Mice were monitored daily throughout their lifespan until cancer-related death or the progress of an obviously moribund appearance, at which time the mice were killed. Androgen receptor expression and cell proliferation and apoptosis analysis were also evaluated. RESULTS: The average lifespan in early castration, delayed castration and sham-castrated groups were 315.8 days, 300.1 days and 254.6 days, respectively. Early castration conferred a statistically significant survival advantage when compared with the sham castrated group (P < 0.05). However, the difference in the lifespan between the delayed castration group and the sham-castrated group was not statistically significant (P = 0.198). Both early and delayed castration significantly increased apoptosis of tumor cells when compared with the sham-castrated group (both P < 0.01), which was also accompanied by a significant decrease in cells proliferation (both P < 0.01). Prolonged survival of mice in early castration group was correlated with a lower G/B value (genitourinary tract weight/body weight) at death than the sham-castrated mice. CONCLUSION: Early castration had an overall survival benefit when compared with the sham-castrated treatment in BBN-induced bladder cancer mice. This finding may enhance the feasibility of androgen ablation treatment in patients with bladder cancer. PMID- 26617737 TI - Down-regulation of microRNA-135b inhibited growth of cervical cancer cells by targeting FOXO1. AB - More and more evidence has confirmed that dysregulation of microRNAs (miRNAs) can conduce to the progression of human cancers. Previous studied have shown that dysregulation of miR-135b is in varieties of tumors. However, the roles of miR 135b in cervical cancer remain unknown. Therefore, our aim of this study was to explore the biological function and molecular mechanism of miR-135b in cervical cancer cell lines, discussing whether it could be a therapeutic biomarker of cervical cancer in the future. The MTT assay and ELISA-Brdu assay were used to assess cell proliferation. Cell cycle was detected by flow cytometry. Real-time quantitative polymerase chain reaction (PCR) and Western blot analyses were used to detect expressions of cyclin D1, p21, p27 and FOXO1. In our study, we found that miR-135b is up-regulated in cervical cancer cell lines. Down-regulation of miR-135b evidently inhibited proliferation and arrested cell cycle in cervical cancer cells. Bioinformatics analysis predicted that the FOXO1 was a potential target gene of miR-135b. Besides, miR-135b inhibition significantly increased expressions of the cyclin-dependent kinase inhibitors, p21(/CIP1) and p27(/KIP1), and decreased expression of cyclin D1. However, the high level of miR-135b was associated with increased expression of FOXO1 in cervical cancer cells. Further study by luciferase reporter assay demonstrated that miR-135b could directly target FOXO1. Down-regulation of FOXO1 in cervical cancer cells transfected with miR-135b inhibitor partially reversed its inhibitory effects. In conclusion, down regulation of miR-135b inhibited cell growth in cervical cancer cells by up regulation of FOXO1. PMID- 26617738 TI - Acid-sensing ion channel 2 (asic 2) and trkb interrelationships within the intervertebral disc. AB - The cells of the intervertebral disc (IVD) have an unusual acidic and hyperosmotic microenvironment. They express acid-sensing ion channels (ASICs), gated by extracellular protons and mechanical forces, as well as neurotrophins and their signalling receptors. In the nervous tissues some neurotrophins regulate the expression of ASICs. The expression of ASIC2 and TrkB in human normal and degenerated IVD was assessed using quantitative-PCR, Western blot, and immunohistochemistry. Moreover, we investigated immunohistochemically the expression of ASIC2 in the IVD of TrkB-deficient mice. ASIC2 and TrkB mRNAs were found in normal human IVD and both increased significantly in degenerated IVD. ASIC2 and TrkB proteins were also found co-localized in a variable percentage of cells, being significantly higher in degenerated IVD than in controls. The murine IVD displayed ASIC2 immunoreactivity which was absent in the IVD of TrkB deficient mice. Present results demonstrate the occurrence of ASIC2 and TrkB in the human IVD, and the increased expression of both in pathological IVD suggest their involvement in IVD degeneration. These data also suggest that TrkB-ligands might be involved in the regulation of ASIC2 expression, and therefore in mechanisms by which the IVD cells accommodate to low pH and hypertonicity. PMID- 26617739 TI - Elevated expression of RIT1 correlates with poor prognosis in endometrial cancer. AB - RIT1, (Ras-like without CAAX1), the founding member of a novel branch of the Ras subfamily, mediates a wide variety of cellular functions, including cell proliferation, survival, and differentiation, and it may play crucial oncogenic role in human cancer. The purpose of the current study was to characterize the expression pattern of RIT1 and assess the clinical significance of RIT1 expression in endometrial cancer patients. The mRNA and protein expression of RIT1 was significantly overexpressed in 7 endometrial cancer cell lines by qPCR and Western blot, respectively. In addition, RIT1 mRNA expression was elevated in 36 freshly frozen endometrial cancer tissues compared to 21 non-cancerous endometrial tissue samples. Similar results were observed by analyzing GEO datasets. Immunohistochemistry was used to examine the protein expression of RIT1 in two tissue microarrays containing 257 cases of tumor and 31 non-tumor tissues, which showed that elevated expression of RIT1 was significantly correlated with pathological type, clinical stage, grade and vascular invasion. Importantly, Kaplan-Meier survival analysis indicated that RIT1 expression was associated with overall survival of endometrial cancer patients. Multivariate Cox regression analysis revealed that RIT1 expression was one of the independent prognostic factors for endometrial cancer patients. Furthermore, RIT1 combined with other clinicopathological risk factors was a more significant model in ROC curve comparison. In conclusion, elevated expression of RIT1 may contribute to the progression of endometrial cancer and thus may serve as a novel prognostic marker and a promising molecular target for the treatment of endometrial cancer. PMID- 26617740 TI - Overexpression of histone demethylase JMJD5 promotes metastasis and indicates a poor prognosis in breast cancer. AB - In this study, we showed the expression of JMJD5 was increased in breast cancer tissues and breast adenocarcinoma cell lines MCF-7 as well as triple negative breast cancer cell lines MDA-MB-231 compared with paired adjacent normal mammary tissues and normal mammary epithelial cell lines MCF-10A. The higher expression of JMJD5 was significantly corresponded with clinical stage, histological grade and lymph node metastasis. Overexpression of JMJD5 promoted cell invasion and induce EMT, while JMJD5 siRNA inhibits MDA-MB-231 cells invasion in vitro. Moreover, qChIP analysis revealed the Snail family proteins Snai1 was the direct target of JMJD5 in breast cancer cells. Luciferase reporter assays suggested that the overexpression of JMJD5 resulted in the activation of Snail1 promoter-driven luciferase reporter. The changes in the level of RNA and protein implied that the activation of Snail was the important mechanisms by which JMJD5 triggers metastasis. We also detected the higher expression of JMJD5 protein was an independent unfavorable biomarker for worse overall survival in breast cancer patients. Therefore, our results identified an important role for JMJD5 in breast cancer through the regulation of snail1. PMID- 26617741 TI - S-propranolol protected H9C2 cells from ischemia/reperfusion-induced apoptosis via downregultion of RACK1 Gene. AB - Ischemia-reperfusion (I/R) injury can lead to apoptotic death of heart cells and subsequently heart failure. Propranolol is widely used in the management of cardiovascular disorders, but the mechanism is still unclear. Our previous studies showed that activated protein kinase C1 (RACK1) was significantly down regulated in human umbilical vein endothelial cells by S-propranolol. RACK1 may be a target protein of S-propranolol during I/R. At present, we constructed a lentiviral expression vector for RNA interference (RNAi) of RACK1. The interference efficiency of the lentivirus was confirmed by RT-PCR and western blot. H9C2 cells infected with Lv-RACK1-shRNA or control were subjected to simulate I/R in the presence and absence of S-propranolol. The release of cytokines and chemokines was determined by ELISA assay. Flow cytometry was employed to determine mitochondrial membrane potential (MMP), Ca(2+) concentration, reactive oxygen species (ROS) production, and cell apoptosis. We found that RACK1 RNAi and S-propranolol treatment remarkably protected I/R injured cells from apoptosis via attenuating the release of cytokines and chemokines, Ca(2+) overload, ROS concentration, and MMP. Furthermore, RACK1 RNAi and S-propranolol, separately and in combination, significantly reduced caspase-3 activity, cytochrome c release and JNK activation. RACK 1 can be considered as a target for drug development. PMID- 26617742 TI - MicroRNA-126 acts as a tumor suppressor in glioma cells by targeting insulin receptor substrate 1 (IRS-1). AB - MicroRNA (miR-126) was reported to be downregulated and to act as a tumor suppressor in cancers of the lung, cervix, bladder, breast, liver and prostate. However, the precise roles and underling mechanisms of miR-126 in glioma remain largely unknown. This study is aimed to study the role of miR-126 in the progression of glioma and to elucidate underlying miR-126-mediated mechanisms in glioma. Our results revealed that miR-126 was downregulated in the collected glioma specimen, compared with non-cancerous brain tissues. Restored miR-126 expression inhibited cell proliferation, colony formation, migration and invasion, and induced cell cycle arrest at G0/G1 phase and cell apoptosis of U-87 MG glioma cells. Overexpression of miR-126 was also able to suppress the growth of U-87 MG glioma xenografts in mice. Furthermore, insulin receptor substrate 1 (IRS-1) were identified as a target of miR-126, and showed that it was negatively regulated by miR-126 in glioma cells. We also demonstrated that overexpression of miR-126 suppressed PI3K and AKT activation, which contribute to suppress tumor growth of glioma. Taken together, these findings showed that miR-126 functions as a tumor suppressor in glioma cells by targeting IRS-1 expression via the PI3K/AKT signaling pathways, suggesting that miR-126 might be a novel target for therapeutic strategies in glioma. PMID- 26617743 TI - Xanthatin, a novel potent inhibitor of VEGFR2 signaling, inhibits angiogenesis and tumor growth in breast cancer cells. AB - Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as an important tool for cancer treatment. In this study, we described a novel VEGFR2 inhibitor, xanthatin, which inhibits tumor angiogenesis and growth. The biochemical profiles of xanthatin were investigated using kinase assay, migration assay, tube formation, Matrigel plug assay, western blot, immunofluorescence and human tumor xenograft model. Xanthatin significantly inhibited growth, migration and tube formation of human umbilical vascular endothelial cell as well as inhibited vascular endothelial growth factor (VEGF) stimulated angiogenesis. In addition, it inhibited VEGF-induced phosphorylation of VEGFR2 and its downstream signaling regulator. Moreover, xanthatin directly inhibit proliferation of breast cancer cells MDA-MB-231. Oral administration of xanthatin could markedly inhibit human tumor xenograft growth and decreased microvessel densities (MVD) in tumor sections. Taken together, these preclinical evaluations suggest that xanthatin inhibits angiogenesis and may be a promising anticancer drug candidate. PMID- 26617744 TI - Muc-1 promotes migration and invasion of oral squamous cell carcinoma cells via PI3K-Akt signaling. AB - Muc-1 is a member of the carbohydrate-binding protein family that contributes to neoplastic transformation, tumor survival, angiogenesis, and metastasis. The aim of this study is to investigate the role of muc-1 in human oral squamous cell carcinoma progression. In this study, we tested our hypothesis that muc-1 regulate oral squamous cell carcinoma cells (SCC-9) malignant biological behaviors, and silencing muc-1 reduced SCC-9 cellular colony forming ability, migration and invasion. Moreover, silenced cells present defects in phosphatidylinositol 3-kinase (PI3K)-serine/threonine kinase (Akt) signaling, and reduced expression/activity of matrix metallopeptidase (MMP)-2/9. Furthermore, in muc-1 siRNA-transfected cells, we detected a decrease in signal transducer and activator of transcription 3 (STAT3) phosphorylation and nuclear translocation. In vivo, muc-1 siRNA cells inoculated subcutaneously in nude mice demonstrated decreased tumor growth and PI3K-Akt signaling inhibition. These results indicate that muc-1 is a key factor in SCC-9 tumor migration, invasion, and suggesting that muc-1 can be a novel therapeutic target in oral squamous cell carcinoma. PMID- 26617745 TI - MicroRNA 181b promotes vascular smooth muscle cells proliferation through activation of PI3K and MAPK pathways. AB - Vascular smooth muscle cells (VSMCs) hyperplasia is a common feature of pathologic cardiovascular event such as restenosis and atherosclerosis. The role and mechanisms of microRNAs (miRs) in VSMCs proliferation are poorly understood. Here, we report that miR-181b promotes VSMCs proliferation and migration. In an animal model, miR-181b was significantly increased in the rat carotid artery after balloon catheter injury. Delivery of miR-181b inhibitor to injured artery exhibited a marked inhibition of neointimal hyperplasia. Transfection of miR-181b with "mimics" to A10 cells accelerated cell proliferation, which was accompanied by an increase of cell migration. The induction of A10 cells proliferation by miR 181b appeared to be involved in activation of S and G2/M checkpoint, concomitant with decreases in cell-cycle inhibitors p21 and p27, and increases in cell-cycle activators CDK4 and cyclinD1. In contract, miR-181b inhibition attenuated A10 cells proliferation, inhibited cell migration and arrested cell cycle transition. Moreover, forced miR-181b expression elevated the phosphorylation levels of Akt and Erk1/2, whereas inhibition of miR-181b produced the opposite effects. Additionally, inhibition of PI3K and MAPK signaling pathways with specific inhibitors, but not inhibition of JNK pathway, significantly abolished the effects of miR-181b in promoting cell proliferation. These findings demonstrate that miR-181b enhances the proliferation and migration of VSMCs through activation of PI3K and MAPK pathways. PMID- 26617746 TI - EFEMP2 is upregulated in gliomas and promotes glioma cell proliferation and invasion. AB - Gliomas are the most common and aggressive form of primary brain tumor. Although EGF-containing fibulin-like extracellular matrix protein 2 (EFEMP2), an extracellular matrix (ECM) glycoprotein, is regarded as a candidate oncogene, little is known about the association of EFEMP2 and gliomas. Here, the expression of EFEMP2 was significantly increased in glioma tissues (n=60) compared to non tumorous brain tissues (n=25). Silencing of EFEMP2 expression through RNA interference in two glioma cell lines (U87 and U373) remarkably inhibited cell proliferation and G1/S transition. More importantly, EFEMP2 silencing significantly induced cell apoptosis via increasing the ratio of Bax and Bcl-2. Additionally, knockdown of EFEMP2 significantly inhibited the invasive ability of both glioma cells, which was associated with the downregulated expression of metalloproteinase-2 (MMP-2) and MMP-9. In conclusion, expression of EFEMP2 was associated with the oncogenic potential of gliomas and silencing of its expression can suppress cancer cell growth and metastasis. Inhibition of EFEMP2 may be a therapeutic strategy for gliomas. PMID- 26617747 TI - Knockdown of CUL4B inhibits proliferation and promotes apoptosis of colorectal cancer cells through suppressing the Wnt/beta-catenin signaling pathway. AB - Colorectal cancer is one of the leading causes of cancer related deaths worldwide. Cullin 4B (CUL4B) is over-expressed in diverse cancer types. However, the function and precise molecular mechanism of CUL4B in colorectal cancer remains largely unknown. Therefore, in this study, we examined the expression of CUL4B in colorectal cancer cell lines and its effects on cellular proliferation and apoptosis, and the underlying mechanism was also explored. Our results showed that CUL4B was significantly overexpressed in colorectal cancer cell lines. Silencing CUL4B obviously inhibited proliferation and tumorigenicity of colorectal cancer cells both in vitro and in vivo, and it also promoted the apoptosis of colorectal cancer cells. Moreover, knockdown of CUL4B inhibited the expression of beta-catenin, cyclin D1 and c-Myc in colorectal cancer cells. Taken together, these results showed that knockdown of CUL4B inhibit proliferation and promotes apoptosis of colorectal cancer cells through suppressing the Wnt/beta catenin signaling pathway. Therefore, CUL4B may represent a novel therapeutic target for colorectal cancer treatment. PMID- 26617748 TI - Triple-controlled oncolytic adenovirus expressing melittin to exert inhibitory efficacy on hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a highly malignant disease, and its outcome of routine therapies is poor. Comprehensive treatment including gene therapy is an important way to improve patients' prognosis and survival. In this study, we successfully constructed a triple-controlled cancer-selective oncolytic adenovirus, QG511-HA-Melittin, carrying melittin gene, in which the hybrid promoter, hypoxia-response element (HRE)-AFP promoter, was used to control viral E1a expression targeting AFP-positive cancer cells in hypoxia microenviroment, and the E1b-55 kDa gene was deleted in cancer cells with p53-deficiency. The cytological experiments found that the viral replication of QG511-HA-Melittin was increased to 12800-folds in Hep3B cells within 48 h, and 130-folds in SMMC-7721, but the virus did not replicate in L-02 cells. QG511-HA-Melittin had a strong inhibition effect on AFP-positive HCC cell proliferation, such as Hep3B and HepG2, whereas, there was low or no inhibition effect of QG511-HA-Melittin on AFP negative cancer cells SMMC-7721 and normal cells L-02. In the in vivo experiment, compared with the blank control group, QG511-HA-Melittin can significantly inhibit the growth of HCC xenografts (P<0.05). The survival of mice in QG511-HA Melittin group was much longer than that of the blank control group. Both in vitro and in vivo experiments manifested that QG511-HA-Melittin exerts an inhibitory effect on HCC cells, which may provide a new strategy for HCC biotherapy. PMID- 26617749 TI - Trefoil factor 1 elevates the malignant phenotype of mucinous ovarian cancer cell through Wnt/beta-catenin signaling. AB - Mucinous ovarian cancer accounts for almost 10% of epithelial ovarian cancer, though patients in the early stage have an excellent prognosis, patients with advanced disease have a poor outcome and the molecular mechanism remains unclear. In this study, we retrieved database and found a secretory protein TFF1, which plays a tumor suppressor role in gastric cancer, is highly expressed in mucinous ovarian cancer, not serous or any other kind of ovarian cancer. Furthermore, the highly expressed TFF1 indicates a poor clinical outcome. Further biological function analysis revealed that TFF1 not only promotes cell proliferation but also invasion and chemoresistance, and these oncogenic effects might through regulating the activity of Wnt/beta-catenin signaling and the level of Twist. Taken together, we found TFF1 plays an oncogenic role in mucinous ovarian cancer, unlike its suppressive role in gastric cancer. PMID- 26617750 TI - Knockdown of eIF3D inhibits breast cancer cell proliferation and invasion through suppressing the Wnt/beta-catenin signaling pathway. AB - eIF3D (eukaryotic translation initiation factor 3 subunit D) is one member of the eIF3 family and plays a critical role in translation initiation. Previous studies showed that it was involved in the development and progression of several tumors. However, the role of eIF3D in breast cancer and the underlying mechanism is still unclear. Therefore, this study set out to investigate the role of eIF3D in breast cancer. Our results demonstrated that eIF3D is up-regulated in breast cancer cells. Knockdown of eIF3D inhibited breast cancer cell proliferation and invasion. In addition, knockdown of eIF3D inhibited the expression of beta catenin, cyclin D1 and c-Myc in breast cancer cells. Taken together, our findings show that siRNA-eIF3D inhibits breast cancer cell proliferation and invasion through suppressing the Wnt/beta-catenin signaling pathway. Therefore, eIF3D may be a good molecular target for the prevention and treatment of breast cancer. PMID- 26617752 TI - Effects of that ATRA inhibits Nrf2-ARE pathway on glial cells activation after intracerebral hemorrhage. AB - Previous studies indicate that the Nrf2-ARE signaling pathway plays a neruo protective role in glia cell, however, the mechanism was also elusive. This study aims to explore the inhibitive function of all-trans-retinoic (ATRA) on Nrf2-ARE pathway in intracerebral hemorrhage (ICH), and investigate the mechanism. In this study, the femoral artery injection method was employed to establish ICH model. The model rats were randomly divided into four groups, including Sham group, ICH group, ATRA group and DMSO group. The neurological scores were evaluated for the four groups at different time points. Hematoxylin-Eosin staining was used to stain the CD11b positive glia cells. Double immunofluorescence staining method was utilized to observe the co-expression of HO-1, NF-kappaB, Nrf2 and TNF-alpha and CD11b marker in glia cells. Western blot assay was used to detect the Nrf2 protein (total and binding Nrf2), HO-1, NF-kappaB and TNF-alpha proteins in every group. The results indicated that neurologiclal scores were significantly decreased in ATRA group compared to ICH gorup (P < 0.05). The glia cells were significantly activated and accumulated in ICH rats. ATRA significantly decreased co-expression of Nrf2, HO-1 and CD11b, and increased co-expression of NF-kappaB, TNF-alpha and CD11b of glia cells. ATRA significantly decreased total Nrf2 expression and increased binding Nrf2 expression in ATRA group compared to ICH group (P < 0.05). ATRA decreased anti-oxygen protein Nrf2 and HO-1, and increases inflammatory factors NF-kappaB and TNF-alpha. In conclusion, the application of ATRA could inhibit the neuro-protective function effectively by blocking the Nrf2 ARE pathway in glia cells. PMID- 26617751 TI - Losartan alleviates hyperuricemia-induced atherosclerosis in a rabbit model. AB - OBJECTIVE: To investigate the mechanisms underlying the therapeutic effects of losartan on hyperuricemia-induced aortic atherosclerosis, in an experimental rabbit model. METHODS: Male rabbits (n = 48) were divided into control, hyperuricemia (HU), hypercholesterolemia + hyperuricemia (HC + HU) and high purine with 30-mg/kg/d losartan (HU + losartan) groups. Serum uric acid (UA) and plasma renin and angiotensin II activities were determined. Aortic tissue specimens were analyzed for histological changes and proliferating cell nuclear antigen (PCNA). Liver tissues were sampled for quantitative analyses of liver low density lipoprotein receptor (LDLR) mRNA and protein via reverse transcription polymerase chain reaction and western blotting. RESULTS: After 12 weeks, serum UA and plasma renin and plasma angiotensin II activities were enhanced in the HU and HU + HC groups (P < 0.001) compared to the control, whereas in the HU + losartan group plasma renin activity was not different and serum UA concentrations as well as plasma angiotensin II activity were moderately enhanced (P < 0.05). Smooth muscle cell (SMC) PCNA expression increased strongly in the HU and HU + HC groups (P < 0.001), but was less pronounced in the HU + losartan group. In contrast, transcription and expression of LDLR mRNA and protein were significantly higher in the control and HU + losartan groups compared to the HU and HU + HC groups. Both the HU and HU + HC groups had elevated intima thickness and intima areas compared to the control and HU + losartan groups. CONCLUSIONS: Losartan can alleviate experimental atherosclerosis induced by hyperuricemia. PMID- 26617753 TI - Role of MAPK7 in cell proliferation and metastasis in ovarian cancer. AB - AIM: To investigate the effect of mitogen-activated protein kinase 7 (MAPK7) in ovarian cancer metastasis and to explore its potential mechanism. METHODS: pcDNA MAPK7 and siRNA-MAPK7 vectors were transfected into the human ovarian cell line OVCAR-3 based on gene silencing and overexpression methods. Effects of MAPK7 overexpression and silencing on OVCAR-3 cells proliferation, cell invasion, and migration were analyzed using the MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5 diphenyl tetrazolium bromide) assay, Matrigel methods, and Markered methods respectively. In addition, effect of MAPK7 expression on extracellular matrix (ECM) associated protein was detected using Western blot. RESULTS: Compared with the controls, MAPK7 was up-regulated when cells were transfected with pcDNA-MAPK7 plasma, as well as MAPK7 was sliced when cells were transfected with siRNA-MAPK7 plasma (P<0.05). Besides, biological function analysis performed that overexpression of MAPK7 significantly increased OVCAR-3 cell proliferation, invasion, and migration (P<0.05), while these effects were inhibited by MAPK7 silencing (P<0.05). Additionally, MAPK7 overexpression increased type II collagen expression (P<0.05). However, there was no significant difference between MAPK7 expression and type I collagen expression (P>0.05). CONCLUSION: Our data implied the up-regulated MAPK7 might contribute to ovarian cancer metastasis through up regulating type II collagen expression and then were involved in cell biological processes such as cell proliferation, invasion, and migration. MAPK7 may be a potential therapeutic target in the clinical treatment for ovarian cancer. PMID- 26617754 TI - Apoptotic effect of mtrix metalloproteinases 9 in the development of diabetic retinopathy. AB - OBJECTIVE: To explore the potential regulatory mechanism of MMP9 in the development of DR. METHODS: Plasmids pcDNA-MMP9 and pcDNA-Ang2 were transfected into primary rat retinal Muller cells (RMCs) using Lipofectamine 2000. Cell viability and apoptosis were respectively determined by MTT assay and flow cytometry. Moreover, the interaction between MMP9 and Ang2 was explored. Besides, RMCs were treated with MMP-9 under normal glucose and high glucose condition for 2d. Besides, the expression levels of apoptotic proteins, like MMP9, Ang2, Bax2, Bcl2, cleaved PARP and cleaved caspase3 were determined by Western blot. RESULTS: The cell viability of siRNA-MMP9 group was significantly increased while decreased in MMP9 overexpression group when compared to control group, respectively. The apoptotic cells in MMP9 overexpression group significantly increased while decreased in siRNA-MMP9 group when compared with control group. MMP9 expression was significantly regulated by Ang2 whereas no significant changes occurred in Ang2 expression when MMP9 expression changed. Moreover, MMP9 expression in HG group significantly increased while there were no significant differences between NG group and control group. Besides, the expression of Bax2, Bcl2, cleaved PARP and cleaved caspase3 in HG group increased while there were no significant differences between NG group and control group. CONCLUSION: Our findings indicate that MMP9 may play an important role via inducing cell apoptosis in the development of DR via regulating by Ang2 or targeting apoptotic proteins, such as Bax2, Bcl2, cleaved PARP and cleaved caspase3. PMID- 26617755 TI - Expression of osteoprotegerin, RNAK and RANKL genes in femoral head avascular necrosis and related signaling pathway. AB - Femoral head avascular necrosis (AVN) causes the damage of hip joint and related dysfunctions, thus consisting of a clinical challenge. Osteoprotegerin (OPG), receptor activator of nuclear factor kappaB (RANK) and its ligand (RANKL) all regulate the formation of bones via gene transcriptional regulation for the balance between osteoblasts and osteoclasts. This study thus investigated the expressional profiles of OPG, RANK and RANKL genes in AVN patients, and explored related molecular mediating pathways. Real-time qPCR was used to measure the gene expression of OPG, RANK and RANKL genes in AVN femoral head tissue samples from 42 patients, along with normal tissues. Western blotting analysis was performed to quantify protein levels of OPG and RANKL. There was a trend but not statistically significant elevation of mRNA levels of OPG in femoral head AVN tissues compared to normal tissues (P>0.05). The expression of RNAK and RNAKL, however, was significantly elevated in necrotic tissues (P<0.05). No significant difference in protein levels of OPG or RANKL between groups. The expression of OPG, RANK and RANKL genes exert a crucial role in the progression of AVN, suggesting their roles in mediating bone homeostasis and potential effects on bone destruction. PMID- 26617756 TI - Expression of p53beta and Delta133p53 isoforms in different gastric tissues. AB - This study aims to detect the mRNA of p53beta and Delta133p53 isoforms in three gastric carcinoma cell lines and tissues of superficial gastritis, atrophic gastritis, gastric carcinoma, or paracancerous area. Nested reverse transcription PCR was used to detect the mRNA of p53beta and Delta133p53 isoforms in tissues of superficial gastritis, chronic atrophic gastritis, gastric cancer cell lines (SGC 7901, MKN45, KATO III), gastric adenocarcinoma, and paracancerous lesion. The amplified products were shown by agarose gel electrophoresis. The expression difference among various tissues was analyzed by x(2) tests. The positive rates of ?133p53 mRNA were 73.3% (11/15) in gastric adenocarcinoma and 20% (3/15) in paracancerous tissue, whereas the positive rates of p53beta mRNA were 20% (3/15) in gastric adenocarcinoma and 66.7% (10/15) in paracancerous tissue. The difference between adenocarcinoma and paracancerous tissues was significant (P<0.05). The positive rates of ?133p53 mRNA were 25% (5/20), 50% (15/30), and 75% (15/20), respectively, in superficial gastritis, atrophic gastritis, and gastric adenocarcinoma; the positive rates of p53beta mRNA were 65% (13/20), 33.3% (10/30), and 25% (5/20), respectively, in superficial gastritis, atrophic gastritis, and gastric adenocarcinoma. The difference between adenocarcinoma and superficial gastritis samples was significant (P<0.05). Both p53beta and ?133p53 mRNAs were positive in MKN45; only p53beta mRNA was detected in SGC7901; neither p53beta nor ?133p53 mRNA was detected in KATO III. ?133p53 and p53beta, which are possible indicators for the diagnosis and biological therapy of gastric carcinoma, were expressed differentially in different gastric tissues. PMID- 26617757 TI - Clinicopathological features of cryoglobulinemic glomerulonephritis associated with HBV infection: a retrospective analysis of 8 cases in China. AB - AIMS: We retrospectively analyzed clinicopathologic features of 8 cases of hepatitis B virus-associated glomerulonephritis with hyaline thrombi, to confirm the diagnosis of cryoglobulinemic glomerulonephritis (CRYGN) associated with HBV infection. METHODS: Retrospective analysis was carried out with demographic information, clinical manifestations, laboratory parameters, pathological and prognostic features. RESULTS: The median age of 8 patients was 30.5 years (range, 21-75 years), including 6 males and 2 femles (M:F = 3:1). One patient had Raynaud's syndrome. Cryoglobulin testing was performed in 4 cases of our series, and 3 cases had elevated cryocrit (>256). Serum C4 decreased in all detected cases. Histopathologically, all cases showed hyaline thrombi occluded in capillary lumina; Co-deposit of IgG, IgM, IgA, Fib, C3d, C4d, C1q, HBsAg and HBcAb were identified in hyaline deposit/hyaline thrombi with polyclonal Igkappa and Iglambda staining. Ultrastructural examination confirmed the hyaline thrombi to be huge electron-dense bodies, which were a homogeneous texture. CONCLUSIONS: The results suggest that 8 cases in the series are CRYGN associated with HBV infection. The incidence of CRYGN associated HBV was extremely low. Our series suggested that prognosis of CRYGN associated HBV was better in patients with mild symptoms, but it was poor in elder patients with severe vasculitis. PMID- 26617758 TI - Effect of miR-200b on retinal endothelial cell function under high glucose environment. AB - As one of the important complications of diabetes, diabetic retinopathy (DR) presented high incidence worldwide. Hyperglycemia is an important promoting factor for DR occurrence and development. It can damage retinal endothelial cell, resulting in retinal structure and function disorder. Studies have shown that miR 200b may involve in regulating DR occurrence and development, but its specific function and mechanism have not been elucidated. This study aimed to investigate miR-200b effect and mechanism on human retinal endothelial cells (hRECs) under high glucose environment. hRECs were cultured under high glucose or normal environment. Real time PCR was applied to detect miR-200b expression. MiR-200b was transfected to hRECs and MTT was used to detect its effect on hRECs proliferation under high glucose environment. Real time PCR and Western blot were performed to determine VEGF and TGFbeta1 expression in the retina endothelial cells. MiR-200b expression decreased significantly under high glucose environment, whereas hRECs proliferated obviously. Compared with normal control, VEGF and TGFbeta1 mRNA and protein expression increased markedly (P < 0.05). After miR-200b transfection, miR-200b expression increased, while VEGF and TGFbeta1 mRNA and protein expression decreased obviously. Compared with high glucose group, hRECs proliferation was inhibited (P < 0.05). MiR-200b can regulate RECs growth and proliferation by changing VEGF and TGFbeta1 expression to delay DR. PMID- 26617759 TI - Association of genetic polymorphisms on BTNL2 with susceptibility to and prognosis of dilated cardiomyopathy in a Chinese population. AB - BACKGROUND: Dilated cardiomyopathy (DCM) is one type of primary myocardial disease, partly caused by immunity dysfunctions. BTNL2 (butyrophilin-like 2) has already been confirmed to be involved in the etiology of autoimmune disorders and GWAS (genome wide association study) has also identified mutants of a SNP (single nucleotide polymorphism) near BTNL2 could modulate risk of coronary heart disease (also cardiomyopathy). The current study, therefore, was aimed to investigate whether polymorphisms within or around BTNL2 would be correlated with susceptibility to and prognosis of DCM. MATERIAL AND METHODS: Peripheral blood samples were gathered from 82 DCM patients and 75 healthy controls. Nine tag-SNPs within or near BTNL2 were obtained from HapMap Database and previously published studies. Eligible haplotypes were gained on the basis of SHesis software. Genotyping of SNPs was implemented with aid of Sequenom MassArray iPLEX platform and subsequently analyzed via MALDI-TOF mass spectrometry. The odd ratios and their 95% confidence interval (95% CI) were utilized to evaluate the correlations between SNPs/haplotypes and DCM risks. Finally, Cox proportional hazard models and Kaplan-Meier curves were performed to assess association of SNPs/haplotypes with prognosis of DCM patients. The statistical analyses were conducted with SPSS 19.0 software. RESULTS: Under the allelic model, rs3763313 (A > C), rs9268494 (C > A), rs9268492 (C > G) and rs9268402 (A > G) were remarkably associated with susceptibility to grade IV of DCM classified by NYHA (New York heart association) (OR = 0.43, 95% CI: 0.22-0.84; P = 0.018; OR = 0.49, 95% CI: 0.27-0.91; P = 0.024; OR = 0.50, 95% CI: 0.27-0.94; P = 0.035; OR = 0.53, 95% CI: 0.28-0.97; P = 0.048). Haplotype C-C-A-T (rs9268492, rs9268494, rs3763313 and rs3763317 synthesized) was also regarded as a protective factor for DCM patients compared with carriers of other haplotypes (OR = 0.50, 95% CI: 0.26-0.97, P = 0.038). Moreover, the univariate survival analysis and multivariate Cox regression analysis both indicated noticeable correlations between rs9268402 and haplotype C C-A-T and prognosis of DCM patients (NYHA IV), respectively (Long-Rank P = 0.029, HR: 0.241, 95% CI: 0.089-0.650, P = 0.005; Long-Rank P = 0.036; HR = 0.126, 95% CI: 0.035-0.457, P = 0.002). Nonetheless, rs3763313 was found only associated with prognosis of DCM patients (NYHA IV) expressed in the Kaplan-Meier curve (P = 0.009). CONCLUSION: The genetic mutations within or around BTNL2 (rs3763313, rs9268494, rs9268492 and rs9268402) could alter susceptibility to grade IV of DCM in a Chinese population, and the 2 SNPs (rs3763313 and rs9268402) therein added with haplotype C-C-A-T might separately predict the prognosis of DCM patients. However, additional studies regarding diverse ethnicities need to be furthered to validate our results. PMID- 26617760 TI - Tankyrase 1 polymorphism associated with an increased risk in developing non small cell lung cancer in a Chinese population: a proof-of-principle study. AB - OBJECTIVES: Tankyrase 1 (TNKS1), a poly (ADP-ribose) polymerase, regulates telomere length and apoptosis in cells, overexpression of which occurred in non small cell lung cancer (NSCLC). This study investigated TNKS1 single-nucleotide polymorphisms (SNPs) for association with a risk in NSCLC development in a Chinese population. METHODS: NSCLC cases and healthy controls of 500 each were recruited for genotyping of 24 TNKS1 SNPs. The association between genotype and NSCLC risk was evaluated by computing the odds ratio (OR) and 95% confidence interval (CI) with multivariate unconditional logistic regression analyses. Haploview software was to analyze association between haplotypes and NSCLC risk. RESULTS: TNKS1 rs6601328 A allele was associated with a lower risk in developing NSCLC and adenocarcinoma (ADC) (OR=0.71; 95% CI, 0.51-0.99 and OR=0.70; 95% CI, 0.50-0.99), whereas TNKS1 rs11991621 C allele (OR=1.44; 95% CI, 1.03-2.03), rs11991621 C/C (OR=1.44, 95% CI, 1.03-2.35; P=0.03), and rs10503380 G/G (OR= 1.56, 95% CI, 1.09-2.50, P=0.02) were associated with a higher risk in developing NSCLC or ADC in females and rs6601328 A/A major allele (OR=1.39; 95% CI, 1.00 1.92; P=0.047) and rs7015700 G/G (OR= 1.51, 95% CI, 1.04-2.21) was associated with an increased NSCLC or ADC risk in males but a reduced NSCLC risk (OR=0.63; 95% CI, 0.42-0.96) and ADC risk (OR=0.64; 95% CI, 0.42-0.97) in females. Haploview showed that there were three Haplotype Blocks associated with NSCLC risk. However, TNKS1 rs12541709 C/C was associated with protective effect against ADC (OR=0.75; 95% CI, 0.56-0.99; P=0.04) in this Chinese population. CONCLUSION: TNKS1 SNPs (rs11991621 rs10503380, and rs7015700) were associated with NSCLC risk, whereas rs6601328 and rs12541709 inversely associated with NSCLC or ADC risk in this Chinese population. PMID- 26617761 TI - Perfluorooctanoic acid enhances colorectal cancer DLD-1 cells invasiveness through activating NF-kappaB mediated matrix metalloproteinase-2/-9 expression. AB - OBJECTIVE: Perfluorooctanoic acid (PFOA) is widely used in consumer products and detected in human serum. Our study meant to elucidate the uncovered molecular mechanisms underlying the PFOA induced colorectal cancer cell DLD-1 invasion and matrix metalloproteinases (MMP) expression. METHODS AND RESULTS: Trans-well filter assay appeared that PFOA treatment stimulated DLD-1 cells invasion significantly. Meanwhile, the results of luciferase reporter, quantitative real time PCR, western blotting, and gelatin zymography showed that PFOA induced MMP 2/-9 expression and enzyme activation levels consistently (P < 0.05 each). Subsequently, western blotting and immunofluorescence assay demonstrated that PFOA could enhance nuclear factor kappaB (NF-kappaB) activity by stimulating NF kappaB translocation into nuclear in DLD-1 cells. Furthermore, JSH-23, a well known NF-kappaB inhibitor, could reverse the PFOA induced colorectal cancer cell invasion and MMP-2/-9 expression. CONCLUSIONS: Our study confirmed that PFOA could induce colorectal cancer cell DLD-1 invasive ability and MMP-2/-9 expression through activating NF-kappaB, which deserves more concerns on environmental pollutant-resulted public health risk. PMID- 26617762 TI - Variation in the expression levels of predictive chemotherapy biomarkers in histological subtypes of lung adenocarcinoma: an immunohistochemical study of tissue samples. AB - BACKGROUND: Lung adenocarcinoma is often composed of a complex and heterogeneous mixture of histological subtypes. Invasive adenocarcinomas are now classified by their predominant pattern, using the comprehensive histological subtyping of the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) classifications. This study aimed to determine whether the expression levels of predictive chemotherapy biomarkers are associated with the histological subtypes proposed by the IASLC/ATS/ERS classification. MATERIALS AND METHODS: We reviewed data on representative tissue samples from 27 patients who received surgical resection and the expression of excision repair cross complementation group 1 (ERCC1), class III beta-tubulin, thymidylate synthase (TS), ribonucleotide reductase M1 (RRM1), and c-Met were examined using immunostaining on tumor tissue slides. We assessed immunohistochemical H-scores, as calculated from the intensity and distribution of intratumor expression, according to the IASLC/ATS/ERS histological subtype. RESULTS: The expression levels of predictive chemotherapy biomarkers varied according to histological subtype. The H-scores of TS and class III beta-tubulin expression levels were higher in solid-type components than they were in lepidic-type components Tumors with solid predominant histology tended to recur earlier than non-solid predominant tumors. However, none of the H-scores in histologically predominant tissues was significantly associated with staging or overall survival. CONCLUSIONS: Immunohistochemical H-scores of the predictive chemotherapy biomarkers were strongly associated with histological subtype. The presence of a solid subtype, which was associated with poor outcomes, might be assessed by measuring these biomarkers in mixed subtype adenocarcinomas. PMID- 26617763 TI - Down-regualtion of miR-106b induces epithelial-mesenchymal transition but suppresses metastatic colonization by targeting Prrx1 in colorectal cancer. AB - Accumulating evidence identified that epithelial-mesenchymal transition (EMT) is acquired during progression to metastatic, but whether it is an absolute requirement is still controversial. MiR-106b has been confirmed to promote cancer cell proliferation; however few studies are available on its functions in EMT and metastasis in colorectal cancer (CRC). In this study, we found that knocking down miR-106b induced EMT conferring migratory and invasive properties. MiR-106b knockdown induced cytoskeletal reorganization through staining intracellular F actin. The expression of Rho GTPases (Rac1 and Cdc42) and Tiam1 was significantly enforced after miR-106b down-regulation. However, miR-106b knocking down could suppress metastatic colonization in vivo. Correspondingly, over expression of miR 106b obtained an opposite effect. We identified Prrx1 was a direct target of miR 106b through using target prediction algorithms and dual-Luciferase reporter assay. Moreover, Moreover, we also found TGF-beta1 could down-regulate miR-106b, and simultaneously miR-106b also influences the expression of TGF-beta1, establishing a negative feedback loop to regulate the expression of Prrx1 together. Taken together, these findings demonstrated that miR-106b knockdown could induce EMT which conferring cells migratory and invasive properties but could not accomplish distant metastatic colonization efficiently. PMID- 26617764 TI - E2F2 induction in related to cell proliferation and poor prognosis in non-small cell lung carcinoma. AB - E2F transcription factors regulate a wide range of biological processes, including cell cycle, apoptosis and DNA damage response. In the present study, we examined whether E2F2 is related to the poor prognosis of NSCLC and its role in progress of NSCLC. Firstly, we analyzed 86 NSCLC samples by immunohistochemistry and found that E2F2 expression was markedly increased in 62.8% (54/86) of all samples compared with the normal tissues. Further study showed that E2F2 expression was closely associated with clinical stage (P = 0.039) and tumor size (P = 0.045). Furthermore, Kaplan-Meier analysis indicated that high Bad expression was significantly correlated to overall survival (P = 0.045) but not disease-free survival (P = 0.288). In addition, our results showed that knockdown E2F2 expression could reduce cell viability and colony formation in NSCLC cells. The results in our study for the first time revealed that E2F2 act as an activator in tumor progress of NSCLC and could become a promising marker for the prognosis of patients with NSCLC. PMID- 26617765 TI - Bone marrow mesenchymal stromal cells with CD47 high expression via the signal transducer and activators of transcription signaling pathway preventing myocardial fibrosis. AB - This study was initiated to investigate the efficacy of myocardial fibrosis intervention via signal transducer and activators of transcription (STAT) signaling using bone marrow (BM) mesenchymal stromal cells (MSC) in which being over-expressed with the aid of bispecific antibody (BiAb) and ultrasound-mediated microbubbles (MB). BiAb was prepared and combined with isolated MSC with CD47 overexpression from male mice and trans-fused into female mice with isoproterenol induced myocardial fibrosis via the tail vein, followed by MB. This study included five groups. Five weeks after treatment, expression levels of the sex determining region of Y-chromosome (SRY), matrix metalloproteinases (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1 and vascular endothelial growth factor (VEGF) in myocardium were detected by fluorescent quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of signal transducer and activators of transcription (STAT) 1 and STAT 3 was detected by Western blot. RESULTS: The highest homing number of MSC was in the CD47 + MSC + BiAb + MB group, second highest in the CD47 + MSC + BiAb group, and lowest in MSC alone. Compared with the Control group, CD47 + MSC + BiAb + MB, CD47 + MSC + BiAb, CD47 + MSC and MSC groups had decreased levels of MMP-9, TIMP-1, STAT 1 and collagen deposition, and increased levels of STAT 3. Up regulated STAT 3 and down regulated TIMP-1 were significantly different in CD47 + MSC + BiAb + MB compared with CD47 + MSC or CD47 + MSC + BiAb. CONCLUSION: CD47 can enhance the homing rate and repairing efficacy of MSC. MSC can improve MMP-TIMP expression in injured myocardium and interfere with myocardial fibrosis after homing, a mechanism that may be related to the STAT-mediated signaling pathway. PMID- 26617766 TI - Quantitative real-time polymerase chain reaction is an alternative method for the detection of HER-2 amplification in formalin-fixed paraffin-embedded breast cancer samples. AB - Fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) are the most common methods that are used to quantify HER-2 gene and protein levels, respectively, in human breast cancer. However, due to bad sample quality, some samples are unable to be subjected to a FISH assay. We evaluated 71 formalin fixed paraffin-embedded (FFPE) breast carcinoma specimens by quantitative real time polymerase chain reaction (qPCR), IHC, and FISH. We also performed qPCR and FISH assays on delayed formalin-fixed (DDF) samples. The qPCR results were in complete concordance with the results of IHC and FISH. In regards to the DDF samples, the HER-2 fluorescent signal seemed decayed compared with that of the DDF samples after 1 h. However, the qPCR method still works well up to 12 hours. Our results indicated that qPCR was obviously superior to FISH in cases that were not fixed in a reasonable amount of time. However, qPCR can be an alternative method by which to perform HER2 amplification assays in breast cancer. PMID- 26617767 TI - Grb2-associated binder 2 silencing impairs growth and migration of H1975 cells via modulation of PI3K-Akt signaling. AB - Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death and often has a poor prognosis. Investigation of NSCLC cancer cell migration, invasion and development of strategies to block this process is essential to improve the disease prognosis. In this study, we tested our hypothesis that Grb2 associated binder 2 (Gab2) regulate NSCLC cancer cell H1975 malignant biological behaviors, and silencing Gab2 reduced H1975 cellular colony forming ability, migration and invasion. Moreover, silenced cells present defects in phosphatidylinositol 3-kinase (PI3K)-serine/threonine kinase (Akt) signaling, and reduced expression/activity of matrix metallopeptidase (MMP)-2/9. Furthermore, in Gab2 siRNA-transfected cells, we detected a decrease in signal transducer and activator of transcription 3 (STAT3) phosphorylation and nuclear translocation. In vivo, Gab2 siRNA cells inoculated subcutaneously in nude mice demonstrated decreased tumor growth and PI3K-Akt signaling inhibition. These results indicate that Gab2 is a key factor in H1975 tumor migration, invasion, suggesting that Gab2 can be a novel therapeutic target in NSCLC. PMID- 26617768 TI - Immunohistochemical evaluation of stem cell markers and signal transducer and activator of transcription 6 (STAT6) in solitary fibrous tumors. AB - Solitary fibrous tumors (SFT) are fibroblastic, ubiquitous mesenchymal tumors. Although several SFT studies have been conducted, the cell of origin of SFT remains controversial and reliable diagnostic markers are needed for SFT identification for proper prognosis and therapeutics. To analyze the immunophenotype of SFT for the identification of specific diagnostic markers and the cell of origin of this tumor, we performed an immunohistochemical study of stem cell markers [aldehyde dehydrogenase 1 (ALDH1), CD29, CD44, CD133, and nestin] and signal transducer and activator of transcription 6 (STAT6) in 18 cases of SFT. The results demonstrated that ALDH1 was present in 16 cases (16/18), STAT6 in 13 cases (13/18), CD44 in 8 cases (8/18), and CD29 in 1 case (1/18), whereas CD133 and nestin were absent in all cases (0/18). Our results indicate that combination with ALDH1 and STAT6 can improve the diagnostic value of CD34 for SFT. The immunohistochemical findings for stem cell surface markers indicate that SFT may originate from stem cells and that ALDH1 plays an important role in the development of SFT. PMID- 26617769 TI - Demethylation of miR-10b plays a suppressive role in ccRCC cells. AB - MicroRNAs have been implicated in cancer cells proliferation, migration and invasion, including clear-cell renal cell carcinoma (ccRCC). DNA methylation, a major epigenetic change associated with cancer, may lead to transcriptional silencing of tumor suppressor genes, including miRNAs, which may be a possible mechanism in carcinogenesis. In this study, we aim to investigate the role of miR 10b in ccRCC and its possible epigenetic mechanism. By qPCR and MSP, we found that miR-10b was significantly decreased in ccRCC tissues and cells, and exhibited heavy methylation on promoter. Upregulation of miR-10b by transfecting with lentivirus highly expressed miR-10b or by exogenous demethylation agents was capable of inhibiting cell proliferation, migration and invasion measured by CCK 8 cell proliferation assay, scratch assay, transwell assay, and flow cytometric analysis of the cell cycle. Our results suggest that miR-10b plays a tumor suppressive role in ccRCC. Demethylation of miR-10b may be therapeutically beneficial for ccRCC treatment. PMID- 26617770 TI - MicroRNA-133b inhibits proliferation and invasion of ovarian cancer cells through Akt and Erk1/2 inactivation by targeting epidermal growth factor receptor. AB - Aberrant expression of microRNA-133b (miR-133b) has been frequently reported in some cancers excluding ovarian cancer (OC). The role and its molecular mechanism of miR-133b in OC have not been reported. In this study, we explored the effects of miR-133b overexpression on proliferation and invasion in OC cells. The mRNA level of miR-133b in OC cell lines was determined by real-time PCR. The miR-133b mimic was transiently transfected into OC cells using LipofectamineTM 2000 reagent. Subsequently, cell proliferation and invasion were assessed by MTT, Brdu ELISA and Transwell assays. Moreover, the effects of miR-133b overexpression on the MAPK and PI3K/Akt signaling pathways were determined by Western blot. Protein level of EGFR was also measured by Western blotting. Meanwhile, luciferase assays were performed to validate EGFR as miR-133b target in OC cells. Our results showed that the mRNA level of miR-133b was remarkably decreased in OC cell lines compared with normal colon epithelium cells, whereas the protein expression of EGFR was significantly increased. Up-regulation of miR-133b inhibited the proliferation and invasion of OC cells. We also found that miR-133b overexpression evidently decreased the phosphorylation of Erk1/2 and Akt. Bioinformatics analysis predicted that the EGFR was a potential target gene of miR-133b. Luciferase reporter assay demonstrated that miR-133b could directly target EGFR. Altogether, our results indicated that miR-133b overexpression was shown to inhibit proliferation and invasion of OC cells through suppression of the MAPK and PI3K/Akt signaling pathways by targeting EGFR. PMID- 26617771 TI - Golgi phosphoprotein3 overexpression is associated with poor survival in patients with solid tumors: a meta-analysis. AB - Golgi phosphoprotein3 (GOLPH3) is known as an oncoprotein and may be a prognostic biomarker in various tumors. Here we performed a meta-analysis on the association of GOLPH3 expression and survival in solid tumors. All eligible studies were identified in Embase, PubMed and Web of Science Databases up to November 2014. Data about overall survival (OS), and disease-free survival (DFS) were extracted and pooled hazard ratios (HRs) of GOLPH3 for survival were calculated by using a random-effect model. Heterogeneity and publication bias were also assessed. A total of 15 eligible studies which comprised of 2529 cases were included in this global analysis: 14 were dealing with overall survival (OS) and 6 were with disease-free survival (DFS). We found that GOLPH3 overexpression was associated with shorter OS (HR 2.487, 95% CI 1.897-3.258, P < 0.001) and DFS (HR 1.911, 95% CI 1.245-2.932, P = 0.003) in general carcinomas. Importantly, subgroup analysis suggested that overexpression of GOLPH3 correlated with shorter OS in urogenital system cancers (HR 4.258, 95% CI 1.81-4.91, P < 0.001). Moreover, publication bias was not significant (P > 0.05). In conclusion, the present meta-analysis showed that overexpression of GOLPH3 predicts poor prognosis in solid tumors. PMID- 26617772 TI - MCPIP is induced by cholesterol and participated in cholesterol-caused DNA damage in HUVEC. AB - Hypercholesterolemia is an important risk factor for atherosclerosis and cholesterol treatment would cause multiple damages, including DNA damage, on endothelial cells. In this work, we have used human umbilical vein endothelial cell line (HUVEC) to explore the mechanism of cholesterol induced damage. We have found that cholesterol treatment on HUVEC could induce the expression of MCPIP1. When given 12.5 mg/L cholesterol on HUVEC, the expression of MCPIP1 starts to increase since 4 hr after treatment and at 24 hr after treatment it could reach to 10 fold of base line level. We hypothesis this induction of MCPIP1 may contribute to the damaging process and we have used siRNA of MCPIP1 in further research. This MCPIP1 siRNA (siMCPIP) could down regulate MCPIP1 by 73.4% and when using this siRNA on HUVECs, we could see the cholesterol induced DNA damage have been reduced. We have detected DNA damage by gammaH2AX foci formation in nuclear, gammaH2AX protein level and COMET assay. Compare to cholesterol alone group, siMCPIP group shows much less gammaH2AX foci formation in nuclear after cholesterol treatment, less gammaH2AX protein level in cell and also less tail moment detected in COMET assay. We have also seen that using siMCPIP1 could result in less reactive oxygen species (ROS) in cell after cholesterol treatment. We have also seen that using siMCPIP could reduce the protein level of Nox4 and p47(phox), two major regulators in ROS production. These results suggest that MCPIP1 may play an important role in cholesterol induced damage. PMID- 26617773 TI - Establishment of stable multiple myeloma cell line with overexpressed PDCD5 and its proapoptosis mechanism. AB - OBJECTIVE: The transfected multiple myeloma cell line showing a stable doxycycline (DOX)-induced expression of PDCD5 was established. PDCD5 overexpression in the transfected cell line was analyzed for its effect on the dexamethasone (DXM)-induced apoptosis along with a discussion on the mechanism. METHODS: (1) Lentiviral plasmid was used for the transfection of PDCD5 gene into the multiple myeloma cells. The screening was done by applying puromycin, and PDCD5 expression was induced by DOX. Real-time fluorescence quantitative PCR and Western Blot were performed to detect the expression levels of the target gene in the stable transfection group and the empty vector group; (2) The cell apoptosis rates of stable transfection group, blank group and empty vector group were measured by Annexin-APC/PI double staining flow cytometry; (3) Real-time fluorescence quantitative PCR and Western Blot were carried out to detect the expression levels of survivin, casepase-3 and Bcl-2 genes and proteins. RESULTS: PDCD5 expression was significantly increased in the stably tranfected multiple myeloma cells compared with blank group and empty vector group. The cells in the transfection group were more sensitive to DXM, and the proportion of apoptotic cells was obviously higher than that of the blank group and the empty vector group (P<0.05). Survivin and Bcl-2 were considerably downregulated in U266/PDCD5 cells and combined DXM group than in the single agent group. However, caspase-3 was significantly upregulated. CONCLUSION: Multiple myeloma cell line transfected with endogenous PDCD5 gene was established. The endogenous PDCD5 overexpression accelerated the cell apoptosis under DXM induction. The proapoptotic action of PDCD5 gene had the effect of activating casepase-3 and downregulating survivin and Bcl-2, which further promoted the apoptosis of multiple myeloma cells. PMID- 26617774 TI - Beclin 1 and p62 expression in non-small cell lung cancer: relation with malignant behaviors and clinical outcome. AB - Autophagy plays a complicated role in tumorigenesis in a variety of cancers. Recently, many studies report that some autophagy-related markers could be detected in several types of human tumors. However, fewer studies have been conducted to evaluate the relationship between autophagy and lung cancer, especially in non-small cell lung cancer (NSCLC). In this study, the expression levels of autophagy-related markers Beclin 1 and p62 were detected by Western blot analysis and cell immunofluorescence staining in three human NSCLC cell lines A549, H1299 and HCC827. Then, tissue microarray and immunohistochemical staining were used to determine Beclin 1 and p62 expression in 104 NSCLC specimens collected from patients. Beclin 1 and p62 were observed to primarily distribute in the cytoplasm of the cells. Beclin 1 was expressed more predominantly in male and heavy-smoker and its expression was significantly correlated with the differentiation and lymph node metastasis. p62 expression was negatively correlated with TNM stage and lymph node metastasis. Univariate Cox regression analysis revealed that low expression of Beclin 1 and high expression of p62 were significantly associated with shorter survival. Meanwhile, multivariate Cox regression analysis indicated that Beclin 1 and p62 were independent risk factors related to overall survival for patients with NSCLC. Collectively, our study suggests that Beclin 1 and p62 could serve as potential indicators for the prognosis of patients with NSCLC. PMID- 26617775 TI - Fenofibrate, a PPARalpha agonist, protect proximal tubular cells from albumin bound fatty acids induced apoptosis via the activation of NF-kB. AB - Albumin-bound fatty acids is the main cause of renal damage, PPARalpha is responsible in the metabolism of fatty acids. Previous study found that PPARalpha played a protective role in fatty acids overload associated tubular injury. The aim of the present study is to investigate whether fenofibrate, a PPARalpha ligands, could contribute to the renoprotective action in fatty acids overload proximal tubule epithelial cells. We observed in HK-2 cells that fenofibrate significantly inhibited fatty acids bound albumin (FA-BSA) induced up-regulation of MCP-1 and IL-8. Treatment with fenofibrate attenuated renal oxidative stress induced by FA-BSA as evidenced by decreased MDA level, increased SOD activity and catalase, GPx-1 expression. FA-BSA induced apoptosis of HK-2 cells were also obviously prevented by fenofibrate. Furthermore, fenofibrate significantly increased the expression of PPARalpha mRNA and protein in FA-BSA treated cells. Finally, the activation of NF-kB induced by FA-BSA was markedly suppressed by fenofibrate. Taken together, our study describes a renoprotective role of fenofibrate in fatty acids associated tubular toxicity, and the transcriptional activation of PPARalpha and suppression of NF-kB were at least partially involved. PMID- 26617776 TI - Ectopic expressed miR-203 contributes to chronic obstructive pulmonary disease via targeting TAK1 and PIK3CA. AB - MiRNA is a group of powerful short non-coding RNAs that suppress the expression of protein coding genes by targeting to the 3'UTRs of mRNAs. Some researchers have detected the miRNAs expression profile in tissue and blood samples of chronic obstructive pulmonary disease (COPD) patients recently. Several disturbed miRNAs were found to be related to COPD; however, the mechanisms were still well understood. In this study, we first detected the expression of 11 candidate miRNAs in the lung samples of COPD patients, non-COPD smokers and non-smock controls. We found that the expression of miR-181a, miR-203, miR-338, miR-1 and miR-199a was altered compared with control. Subsequently, we detected these five miRNAs expression in the blood samples of the participants. A significant higher expression of miR-203 was found in the blood samples of smokers and COPD patients. Predicted by bioinformatics tools and confirmed by luciferase assay and western blot, we demonstrated that TAK1 and PIK3CA are two direct targets of miR 203. Furthermore, we detected a lower p-IkappaBalpha and p-p65 level in the bronchial/tracheal epithelial cells from COPD patients compared with the cells from healthy controls, when stimulated by LPS. The concentration of TNF-alpha and IL-6 in the medium from bronchial/tracheal epithelial cells from COPD patients is also lower. Meanwhile, the miR-203 level was down-regulated significantly in the control cells, but non-significant change in the cells from COPD patients. miR 203 represses NF-kappaB signaling via targeting TAK1 and PI3KCA and miR-203 overexpression may contribute to the COPD initiation. PMID- 26617777 TI - Changes of ferrous iron and its transporters after intracerebral hemorrhage in rats. AB - OBJECTIVE: Ferrous iron is a major source inducing oxidative stress after intracerebral hemorrhage (ICH). Divalent metal transporter1 (DMT1) is the important and well-known plasma membrane transport protein which was proved to be involved in the transport of free ferrous iron in mammals. Ferroportin 1 (FPN1) is the unique exporter of ferrous iron from mammalian cells. The role of DMT1 and FPN1 in brain after ICH is still not elucidated. Therefore, we measure the expression of DMT1 and FPN1, to explore the correlations between ferrous iron and its specific transporters after ICH. METHODS: Ninety-six Sprague-Dawley rats received intra-striatal infusions of 0.5 U type IV collagenase to establish ICH model. Ferrous iron content in brain was determined using Turnbull's method. DMT1 and FPN1 expression were examined by immunohistochemical staining and Real-Time quantitative polymerase chain reaction (RT-PCR). With the use of confocal laser microscopy, we determined the colocalization of DMT1 and FPN1 at 1, 3, 7 and 14 days after ICH. RESULTS: Ferrous iron deposition was shown in the perihematomal zone as early as 1 day after ICH; it reached a peak after 7 days and was not elevated within 14 days following ICH. The expression of the DMT1 upregulated and reached to peak at day 7 after ICH. FPN1 reached a plateau at 3 days post-ICH. Expression levels of DMT1 and FPN1 were in parallel with ferrous iron deposition. There was a positive correlation between FPN1 and DMT1. DMT1 mainly localized in the cytoplasm of glias and neurons. FPN1 were mostly distributed on the membrane of endothelial cells and glias. Confocal microscope showed that DMT1 colocalized with FPN1. CONCLUSIONS: DMT1 and FPN1 are positively influenced by ferrous iron status in brain after ICH. DMT1 and FPN1 attenuate iron overload after ICH via increasing transmembrane iron export. PMID- 26617778 TI - Thymidine phosphorylase and hypoxia-inducible factor 1-alpha expression in clinical stage II/III rectal cancer: association with response to neoadjuvant chemoradiation therapy and prognosis. AB - The aim of this study was to determine whether pretreatment status of thymidine phosphorylase (TP), and hypoxia-inducible factor alpha (HIF-1alpha) could predict pathologic response to neoadjuvant chemoradiation therapy with oxaliplatin and capecitabine (XELOXART) and outcomes for clinical stage II/III rectal cancer patients. A total of 180 patients diagnosed with clinical stage II/III rectal cancer received XELOXART. The status of TP, and HIF-1alpha were determined in pretreatment biopsies by immunohistochemistry (IHC). Tumor response was assessed in resected regimens using the tumor regression grade system and TNM staging system. 5-year disease free survival (DFS) and 5-year overall survival (OS) were evaluated with the Kaplan-Meier method and were compared by the log-rank test. Over expression of TP and low expression of HIF-1alpha were associated with pathologic response to XELOXART and better outcomes (DFS and OS) in clinical stage II/III rectal cancer patients (P < 0.05). Our result suggested that pretreatment status of TP and HIF-1alpha were found to predict pathologic response and outcomes in clinical stage II/III rectal cancer received XELOXART. Additional well-designed, large sample, multicenter, prospective studies are needed to confirm the result of this study. PMID- 26617779 TI - Abnormal glutamate release in aged BTBR mouse model of autism. AB - Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. Most of the available research on autism is focused on children and young adults and little is known about the pathological alternation of autism in older adults. In order to investigate the neurobiological alternation of autism in old age stage, we compared the morphology and synaptic function of excitatory synapses between the BTBR mice with low level sociability and B6 mice with high level sociability. The results revealed that the number of excitatory synapse colocalized with pre- and post-synaptic marker was not different between aged BTBR and B6 mice. The aged BTBR mice had a normal structure of dendritic spine and the expression of Shank3 protein in the brain as well as that in B6 mice. The baseline and KCl-evoked glutamate release from the cortical synaptoneurosome in aged BTBR mice was lower than that in aged B6 mice. Overall, the data indicate that there is a link between disturbances of the glutamate transmission and autism. These findings provide new evidences for the hypothesis of excitation/inhibition imbalance in autism. Further work is required to determine the cause of this putative abnormality. PMID- 26617780 TI - Blockage of thymic stromal lymphopoietin signaling improves acute lung injury in mice by regulating pulmonary dendritic cells. AB - OBJECTIVES: To investigate the effects of blockage of thymic stromal lymphopoietin (TSLP) signaling by TSLP receptor (TSLPR)-immunoglobulin (Ig) on acute lung injury (ALI) induced by lipopolysaccharide (LPS). METHODS: C57BL/6 mice received TSLPR-Ig or controlled-Ig before being induced ALI. Lung wet/dry (W/D) weight ratio was recorded. Neutrophil number and albumin concentration of bronchoalveolar lavages fluids (BALF) were determined. Besides, bone marrow dendritic cells (BMDCs) were separated and cultured with medium, TSLP, TSLP plus TSLPR-Ig or TSLP plus controlled-Ig. Protein expression levels of TSLP in lung tissues, phosphorylation extracellular regulated protein kinases (pERK) 1/2, p38, and signal transducers and activators of transcription (STAT) 3 in BMDCs were analyzed using Western blotting. Expression of CD40, CD80 and CD86 on pulmonary DCs and BMDCs was determined using flow cytometry (FCM). RESULTS: The W/D ratio, neutrophil number and albumin concentration were significantly decreased in the TSLPR-Ig group compared with the controlled-Ig and model group. Moreover, there was a noticeable decrease in CD40, CD80 or CD86 expression by TSLPR-Ig on both pulmonary DCs and BMDCs. The protein levels of TSLP, pERK1 and STAT3 were significantly decreased by TSLPR-Ig. However, no significant differences were found in p38 and pERK2. CONCLUSION: These results suggest that TSLP may be involved in ALI, and blockage of TSLP signaling using TSLPR-Ig improves ALI at least in part by regulation of DCs functions. The underling downstream signaling mediated by TSLP might be associated with activating the ERK1 and STAT3 signaling pathway. PMID- 26617781 TI - USP17-mediated deubiquitination and stabilization of HDAC2 in cigarette smoke extract-induced inflammation. AB - Histone deacetylase HDAC2 regulates genes transcription via removing the acetyl group from histones. Glucocorticoids, the most potent anti-inflammatory treatment available for inflammatory diseases, inhibit the expression of inflammatory genes by recruiting HDAC2 to activated genes. In the lungs of patients who smoke and have chronic obstructive pulmonary disease (COPD) or asthma, glucocorticoids are not effective enough to suppress airway inflammation, which is so called "glucocorticoid resistance", due to decreased HDAC2 level caused by cigarette smoke. We report that the ubiquitin-specific protease USP17 interacts with HDAC2. USP17 deubiquitinates and stabilizes the protein level of HDAC2. In cigarette smoke extract-exposed airway epithelial cells and macrophages, HDAC2 is excessively ubiquitinated and degraded in the proteasome attributed to low expression of USP17. Furthermore, over-expression of USP17 blocks the destruction of HDAC2 induced by cigarette smoke extract. These results provide a new insight into the mechanisms of glucocorticoid resistance in airway inflammatory disease. Small molecules which can specifically induce the expression of USP17 might be useful in reversing glucocorticoid resistance. PMID- 26617782 TI - HOXD13 methylation status is a prognostic indicator in breast cancer. AB - Homeobox protein Hox-D13 is encoded by HOXD13 gene which is frequently methylated in cancer and has been recognized as a tumor suppressor in pancreatic cancer. In this study, we examined HOXD13 mRNA expression in 40 pairs of breast cancers and corresponding normal breast tissues. Bisulfite sequencing of HOXD13 promoter was performed in 6 pairs of breast tumors and corresponding normal breast tissues to examine the potential HOXD13 CpG methylated sites. HOXD13 DNA methylation frequency analysis was performed using MethyLight in 196 pairs of breast cancers and corresponding normal breast samples. DNA methylation status and clinico pathological features were investigated. Kaplan-Meier survival analysis and Cox proportional hazards models were utilized to assess the effect of methylation status on overall survival. We found that 60% (24/40) of breast cancers showed low HOXD13 mRNA expression when compared with corresponding normal breast tissue. The predicted CpG island was located in the -1325 bp to +675 bp region. Next, the -332 bp site in HOXD13 gene promoter was further examined and in 57.7% (113/196) samples methylation was detected at this site. HOXD13 methylation was correlated with larger tumor size (P = 0.004), but not with other clinico-pathological parameters. In addition, patients with methylated -HOXD13 promoter had worse overall survival (OS) (P = 0.005). Based on our results we conclude that HOXD13 methylation is a common event in primary breast cancer and is associated with poor survival of breast cancer patients. HOXD13 methylation could therefore potentially be used as a prognostic factor for breast cancer. PMID- 26617783 TI - MicroRNA-323 regulates ischemia/reperfusion injury-induced neuronal cell death by targeting BRI3. AB - PURPOSE: MicroRNA-323 (miR-323) has been reported to be upregulated in Ischemia/Reperfusion (I/R) injury-treated neuronal cell. However, the effect and underlying mechanism of miR-323 in I/R-induced neuronal cell death remains poorly understood. The current study was aim to investigate the role and molecular basis of miR-323 in I/R-induced neuronal cell. METHODS: An oxygen-glucose deprivation (OGD) model of hippocampal neuron I/R was produced in vitro. Cell apoptosis, cell survival, and the expression of miR-323 were determined after 6 h, 12 h and 24 h after OGD treatment. The up- or down-regulation of miR-323 was performed by miR 323 mimics or anti-miR-323, respectively. RESULTS: OGD induced apoptosis and suppressed survival in rat hippocampal neurons. And the expression levels of miR 323 were increased after OGD treatment. Furthermore, the up-regulation of miR-323 promoted apoptosis and suppressed survival, whereas the inhibition of miR-323 suppressed apoptosis and enhanced survival in OGD-treated neurons. Moreover, miR 323 could directly bind to BRI3 3'-UTR. Notably, the knockdown of BRI3 by BRI3 siRNA apparently abrogated cell survival and induced cell apoptosis in rat neurons. CONCLUSION: This study indicated that miR-323 might regulate ischemia/reperfusion-induced rat neuronal cell death via targeting BRI3. PMID- 26617785 TI - Correlation between congenital heart disease complicated with pulmonary artery hypertension and circulating endothelial cells as well as endothelin-1. AB - OBJECTIVE: To investigate changes in the level of circulating endothelial cells (CECs) and endothelin-1 (ET-1) in peripheral venous blood of the patients with congenital heart disease (CHD) complicated with pulmonary artery hypertension (PAH), and research on their effects in the onset and progress of CHD complicated with PAH. METHODS: A case-control study including 30 cases of healthy controls, 15 cases of left-to-right shunt CHD without PAH, 26 cases of CHD complicated with mild PAH, and 17 cases of CHD complicated with moderate-severe PAH was performed. We used flow cytometry to measure the percentage of CECs accounting for nucleated cells in whole blood, and enzyme linked immunosorbent assay (ELISA) to measure the level of ET-1 in serum. The differences of above-mentioned biomarkers between different groups were compared. RESULTS: (1) The level of CECs and ET-1in the group of moderate-severe PAH was significantly higher than those in the group of mild PAH and the group of CHD without PAH. Significantly difference was also observed between the level of CECs and ET-1 in the group of mild PAH and those in the group of CHD without PAH and the control group. Meanwhile, the level of CECs and ET-1 in the group of large shunt was significantly higher than those in the group few shunt and few-medium shunt. (2) Strong positive correlations were observed between pulmonary artery systolic pressure and percentage of CECs as well as ET-1 production. Mean pulmonary artery pressure also positively correlated with percentage of CECs as well as ET-1 production. (3) Arterial partial pressure of oxygen as well as arterial oxygen saturation negatively correlated with the level of CECs, whereas the volume of left-to-right shunt positively correlated with the level of ET-1. (4) The level of CECs and ET-1 were positively correlated as well in CHD patients. CONCLUSIONS: CHD complicated with PAH is associated with increased CEC counts and ET-1 production. This study suggests that CECs and ET-1 could be used as clinical biomarkers to define medical strategies for control of PAH. PMID- 26617784 TI - Piwil 2 gene transfection changes the autophagy status in a rat model of diabetic nephropathy. AB - This study aims to investigate effects of Piwil2 on autohpagy in a DN rat model. Sixty health SD rats were selected and divided into four group, including normal group, control, DN and Piwil2 therapy group. DN model (DN group) was established by injecting the streptozotocin (50 mg/kg) into rats. Piwil2 therapy group was injected with viral plasmid carrying Piwil2 mRNA to DN rats. The urinary protein concentrations were determined by placing the animals in individual metabolic cages for a timed urine collection every 8 weeks. Blood and soleus muscle samples were collected after animals were sacrificed. Blood glucose was examined by using commercial detection kits. Western blot assay was employed to examine expression of Beclin 1 and LC3 (LC3 I and LC3 II) protein. Results indicated that urinary protein levels were remarkably higher in DN group compared to Normal and Control group (P<0.05). Blood glucose values were also increased in DN group compared to Normal and Control group (P<0.05). Body weights decreased significantly in DN rats compared to Normal group and Control group (P<0.05). Expression of Beclin 1 protein and LC3 proteins was significantly decreased in DN group compared to Normal and Control group (P<0.05). However, Piwil2 transfection could enhance level of Beclin 1 and LC3 protein significantly compared to DN group. In conclusion, the Tiwil 2 mRNA transfection could obviously enhance the autophagy biomarker, including Beclin 1 and LC3 protein, which indicates that the Tiwil 2 treatment has improved the autophagy in diabetic nephropathy rats. PMID- 26617786 TI - Activation of alpha2 adrenoceptor attenuates lipopolysaccharide-induced hepatic injury. AB - Sepsis induces hepatic injury but whether alpha-2 adrenoceptor (alpha2-AR) modulates the severity of sepsis-induced liver damage remains unclear. The present study used lipopolysaccharide (LPS) to induce hepatic injury and applied alpha2-AR agonist dexmedetomidine (DEX) and/or antagonist yohimbine to investigate the contribution of alpha2-AR in LPS-induced liver injury. Our results showed that LPS resulted in histological and functional abnormality of liver tissue (ALT and AST transaminases, lactate), higher mortality, an increase in proinflammatory cytokines (IL-1beta, IL-6 & TNF-alpha), as well as a change in oxidative stress (MDA, SOD). Activation of alpha2-AR by dexmedetomidine (DEX) attenuated LPS-induced deleterious effects on the liver and block of alpha2-AR by yohimbine aggravated LPS-induced liver damage. Our data suggest that alpha2-AR plays an important role in sepsis-induced liver damage and activation of alpha2 AR with DEX could be a novel therapeutic avenue to protect the liver against sepsis-induced injury. PMID- 26617787 TI - RAC1 overexpression promotes the proliferation, migration and epithelial mesenchymal transition of lens epithelial cells. AB - Cataract is a main cause of blindness worldwide. RAC1 has been reported to have a close relationship with the proliferation and migration of cells. However, the relationship between RAC1 and cataract is not yet clear. The proliferation and migration of lens epithelial cells are key factors in the formation of cataract as well as in the complication of cataract surgery. In this study, the effect of RAC1 overexpression on the proliferation and migration of lens epithelial cells was explored. Results showed that RAC1 overexpression promoted the proliferation of lens epithelial cells and increased the protein level of proliferating cell nuclear antigen. RAC1 overexpression also promoted migration and invasion of lens epithelial cells and had an influence on the epithelial-mesenchymal transition process. These results indicate that RAC1 may become a therapeutic target of cataract and inhibition of RAC1 may become a promising way for the therapy of cataract. PMID- 26617788 TI - Long noncoding RNA AK056155 involved in the development of Loeys-Dietz syndrome through AKT/PI3K signaling pathway. AB - Loeys-Dietz syndrome (LDS) is an autosomal dominant genetic connective tissue disorder, and most of LDS patients will develop into aortic aneurysm. Unfortunately, there is no known cure, and a high risk of death from aortic aneurysm rupture. However the detailed mechanism is still unknown. In order to explore the mechanism, we firstly used bioinformatics to predict, and then verified with biology methods. Firstly, we found that LncRNA AK056155 was differentially expressed in peripheral blood circulating endothelial cells between normal patients and LDS patients by bioinformatics. Then we further verified that AK056155 was also overexpressed in aortic aneurysm patients by RT PCR. Moreover, we demonstrated that the expression of AK056155 can be enhanced by TGF-beta1 in a concentration or time depended manner in HUVECs by RT-PCR. Furthermore, the expression of AK056155 was reduced with treatment of PI3K inhibitor (LY294002) or AKT inhibitor (GDC-0068) in combination with TGF-beta1. These results indicate that AK056155 involved in the development of Loeys-Dietz syndrome through AKT/PI3K signaling pathway, it may provide a promising target gene to prevent LDS develop in to aortic aneurysm. PMID- 26617789 TI - MiR-374a promotes the proliferation of osteosarcoma cell proliferation by targeting Axin2. AB - BACKGROUND: MicroRNA-374a (miR-374a) has been implicated in several cancers. However, its role in osteosarcoma (OS) remains unclear. Thus the aim of this study was to investigate its expression and role in progression of OS. METHODS: Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of miR-374a in OS cell lines and tissues. To further understand its role, we restored expression of miR-374a in MG63 cell line by transfection with miR-374a mimics or inhibitors. Effects of miR-374a on cell proliferation on targets were also determined. RESULTS: In the present study, our results showed that miR-374a was significantly up-regulated in both OS cell lines and OS tissues. Over expression of miR-374a markedly accelerated proliferation of OS cells, while its inhibition significantly suppressed cell proliferation. Moreover, Axin2 was identified to be a functional downstream target of miR-374a, and decreased expression of Axin2 could promote OS cell proliferation. CONCLUSION: Our study suggested that miR-374a functions as an oncogene in OS, and the miR-374a/Axin2 axis might represent a potential therapeutic target for OS intervention. PMID- 26617790 TI - GM130 regulates epithelial-to-mesenchymal transition and invasion of gastric cancer cells via snail. AB - Gastric cancer is one of the most common causes of digestive tract tumor. Despite of recent advances in surgical techniques and development of adjuvant therapy, the underlying mechanisms of gastric cancer remain poorly understood and relevant insight into novel treatment strategies using gene target remains incomplete. Recently, several studies report that epithelial to mesenchymal transition (EMT) is a crucial process for the invasion and metastasis of epithelial tumors; however, the molecular mechanisms underlying this transition are unknown. As a cis-Golgi matrix protein, GM130 plays an important role in cell cycle progression and transport of protein in the secretory pathway. In this study, we found that GM130 expression has a positive correlation with the pathological differentiation and tumor node metastasis (TNM) stage of gastric cancer. High GM130 expression levels also predict shorter overall survival of gastric cancer patients. RNA interference-mediated knockdown of GM130 expression increased epithelial marker (E-cadherin) and decreased mesenchymal marker (N-cadherin and vimentin) expression in gastric cancer cells, suppressing cell invasion, and tumor formation. Furthermore, we found that GM130 upregulated expression of the key EMT regulator Snail (SNAI1), which mediated EMT activation and cell invasion by GM130. Taken together, our study indicates GM130 may be a promising therapeutic biomarker for gastric cancer. PMID- 26617791 TI - The regulation effect of ulinastatin on the expression of SSAT2 and AQP4 in myocardial tissue of rats after cardiopulmonary resuscitation. AB - OBJECTIVE: This study aims to investigate the regulation effects of ulinastatin (UT1) on the expression of spermidine/spermine -N1-acetyltransferase 2 (SSAT2) and aquaporin 4 (AQP4) in myocardial tissue of rats after cardiopulmonary resuscitation (CPR) and their correlations. METHODS: A total of 90 adult SD rats were divided into sham operation group (A, n=30), model group (B, n=30) and UT1 group (C, n=30). The cardiac arrest (CA) and CPR model was established by asphyxia method. Left ventricular fractional shortening (LVFS), left ventricular ejection fraction (LVEF) and E/A peak ratio of mitral valve in three groups were collected by ultrasonic echocardiography. Apoptosis of myocardial cells was detected by DAPI staining. The expression levels of SSAT2 and AQP4 were detected by RT-PCR, Western blotting and immunohistochemical methods. RESULTS: UT1 could significantly improve the levels of LVFS, LVEF and E/A ratio and decrease myocardial cell apoptosis. As compared with group B, the expression level of SSAT2 increased and the expression level of AQP4 decreased in group C (P<0.01). SSAT2 was the most in group A and the least in group B while AQP4 was the least in group A and the most in group B (P<0.01). There was positive correlation between SSAT2 and cardiac function in CRP model while there was negative correlation between AQP4 and cardiac function (P<0.01). The expression of SSAT2 and AQP4 protein in myocardial tissue was negatively correlated in CRP model (r= 0.920, P<0.01). CONCLUSIONS: UT1 can effectively reduce the cardiac function damage caused by CRP, which could be related with the increased SSAT2 and decreased AQP4. PMID- 26617792 TI - MiR-142-3p functions as a potential tumor suppressor directly targeting HMGB1 in non-small-cell lung carcinoma. AB - BACKGROUND: microRNAs (miRNAs) play a significant role in cancer development and progression by regulating the expression of oncogenes or tumor suppressor genes. Previous study using microarrays demonstrated that miR-142-3p was downregulated in patients with Non-small-cell lung carcinoma (NSCLC). However, the functional role of miR-142-3p in NSCLC is still unclear. MATERIAL AND METHOD: Real-time quantitative PCR was applied to evaluate the expression level of miRNA-142-3p in NSCLC and normal samples. The cell proliferation of NSCLC cells was analyzed by MTT and colony formation assay after miR-142-3p transfection. Luciferase activities assay, cotransfection and Western blot were used to reveal that the predicted target genes of miR-125b were direct and specific. RESULTS: In this study, we demonstrate miR-142-3p was downregulated in NSCLC tissues and cell lines. We demonstrated that the overexpression of miR-142-3p inhibits NSCLC cell proliferation and induced cell apoptosis. Furthermore, we demonstrate HMGB1 was a directly target of miR-142-3p in NSCLC cells, and confirmed the target specificity between miR-142-3p and the HMGB1 3'-untranslated region by luciferase reporter assay. CONCLUSIONS: These results suggest that miR-142-3p may be a tumor suppressor through the downregulation of HMGB1 in NSCLC. miR-142-3p may be a tumor suppressor and a potential therapeutic agent for patients with NSCLC. PMID- 26617793 TI - Effects of calcium-sensing receptors on apoptosis in rat hippocampus during hypoxia/reoxygenation through the ERK1/2 pathway. AB - OBJECTIVES: To explore the effects of calcium-sensing receptors (CaSR) on apoptosis in rat hippocampus during hypoxia/reoxygenation (H/R). METHODS: After rat hippocampus was isolated, the cultures were subjected to H/R, and meanwhile gadolinium chloride (GdCl3, agonist of CaSR) and NPS 2390 (antagonists of CaSR) were added to reperfusion solution. The number of hippocampal neuron, cell viability and apoptosis rate were determined by inverted microscope, 3-(4, 5 dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometer (FCM), respectively. Besides, caspase-3, Bax, cytochrome C (Cyt-c), extracellular signal-regulated protein kinase (ERK) 1/2, pERK1/2, P38 and pP38 were analyzed by Western blotting. RESULTS: The hippocampal neuron number and cell viability were significantly decreased during H/R, and were further significantly reduced when co-treatment with CaSR agonist GdCl3. But the effects of GdCl3 were attenuated by NPS-2390. Whereas, apoptosis rate, the expression level of caspase-3, Bax and Cyt c were all significantly increased under H/R condition, and was further significantly increased by GdCl3, but were reversed by NPS-2390 (P < 0.05). Moreover, there were no significant differences in expression of ERK1/2, P38 and pP38 among different groups. However, the expression of pERK1/2 was significantly increased during H/R, but was significantly reduced by NPS 2390 (P < 0.05). CONCLUSION: The results suggest that CaSR might play significant roles in the induction of hippocampus apoptosis in rat during H/R through phosphorylation of ERK1/2. PMID- 26617794 TI - Protective role of Osthole on myocardial cell apoptosis induced by doxorubicin in rats. AB - OBJECTIVE: To explore the effect of Osthole on protecting myocardial cell apoptosis induced by doxorubicin during cardiac failure in rats. METHODS: Myocardial cells isolated from the newborn SD rats were separated into three groups: cells treated with 1 MUmol doxorubicin, cells treated with Osthole at three concentrations of 10, 20, and 40 MUmol, cells treated neither with Osthole nor with doxorubicin were the control groups. Consequently, cell apoptosis of myocardial cells in each group was analyzed using TUNEL assay. Also, expressions of oxidase, NADPH, and ROS in myocardial cells were analyzed using different biological methods. Moreover, expressions of cell apoptosis associated proteins were analyzed using Western blotting. RESULTS: Compared with the controls, the results showed that cells received Osthole and doxorubicin treatments performed high percentage of cell apoptosis, suggesting that Osthole could anesis myocardial cell apoptosis induced by doxorubicin (P<0.05). Osthole of 10 MUmol depressed the expressions of cell apoptosis associated proteins including Caspase 3 and Cytc, and enhancing expression of Bcl-XL expression (P<0.05). Osthole of 20 MUmol significantly decreased the generation of intracellar superoxidase, NADPH, and NADPH activity in myocardial cells treated with doxorubicin (P<0.05). Moreover, Osthole of 20 MUmol could significantly increase phosphorylated elF2alpha level in cells. CONCLUSION: Our study suggested that Osthole may play a protective role in suppressing myocardial apoptosis induced by doxorubicin through inhibiting NADPH and superoxidase production and downstream phosphorylated elF2alpha. PMID- 26617795 TI - TMP21 modulates cell growth in papillary thyroid cancer cells by inducing autophagy through activation of the AMPK/mTOR pathway. AB - OBJECTIVE: To investigate the role of transmembrane protein (TMP) 21 in human thyroid cancer. METHODS: The recombinant expression vector pcDNA3.1 (+)-TMP21 and specific small interfering RNAs (siRNA) against TMP21 were transfected into a papillary thyroid cancer cell line (TPC1). After transfection, the expression of TMP21 was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Moreover, cell viability and apoptosis rate were respectively determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) colorimetric assay and flow cytometry (FCM). Additionally, Western blotting was performed to analyze the adenosine monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathways associated protein (P-AMPKalpha(Thr172), P-mTOR(Ser2448), light chain (LC)-II/LC3-I, and P S6K(Thr389)) after pre-treatment with AMPK inhibitor, compound C (Com C) and siTMP21. RESULTS: The TMP21 protein level and cell viability were significantly higher, but apoptotic rate was significantly lower by transfection with pcDNA3.1 TMP21 than those in control group (P < 0.05), and reverse results were obtained by transfection with siTMP21. However, qRT-PCR showed different results due to the feedback inhibition of mRNA. Besides, silencing of TMP21 significantly reduced the levels of P-mTOR(Ser2448) and P-S6K(Thr389) (P < 0.05), but significantly increased the levels of P-AMPKalpha(Thr172) and LC3-II/LC3-I compared with the control group (P < 0.01). Whereas, the levels of P AMPKalpha(Thr172) and LC3-II/LC3-I were significantly decreased by Com C compared with the control group (P < 0.05). CONCLUSION: TMP21 modulates cell growth in TPC1 cells by inducing autophagy, which may be associated with activation of AMPK/mTOR pathway. PMID- 26617796 TI - Platelet-derived microvesicles are involved in cardio-protective effects of remote preconditioning. AB - The ischemia-protective mechanism of remote precondition has been a mystery for a long time. Little was known about details of the inter-organ cardio-protective. Microvesicles, also known as microparticles (MPs), are small membrane-vesicles budding from the plasma membrane of cell. Recent studies have indicated MPs to be an important messenger in various biological processes. Our research mainly examined the hypothesis that remote ischemic conditioning can attenuate heart infarction in a rat after they were subjected to 30 min ischemia and 180 min reperfusion (I/R) by MPs. MPs were extracted from three groups of rat: 1) healthy rats, 2) healthy rats that underwent hindlimb ischemia-reperfusion preconditioning (RIPC) immediately, 3) healthy rats that underwent RIPC in 6 hours. Isolated MPs were transfused into rats that had undergone I/R without RIPC. The transfusion of MPs from rats that underwent RIPC immediately resulted in an increase in platelet-derived MPs in blood and reduction in infarction size, confirmed by 2-3-5-triphenyltetrazolium chloride staining. We further observed the contractile function in hearts after they were subjected to different treatments. However, no significant difference was observed in transfusion of MPs from rats that underwent RIPC in 6 hours. RIPC induces an increase in MPs, and platelet-derived MPs may confer at least part of the remote protective effect against cardiac ischemic-reperfusion injury. PMID- 26617797 TI - Down-regulation of TET2 in CD3+ and CD34+ cells of myelodysplastic syndromes and enhances CD34+ cells proliferation. AB - AIMS AND BACKGROUND: To investigate the expressions of TET2 mRNA in bone marrow CD3(+) and CD34(+) cells of the patients with myelodysplastic syndromes (MDS) and to study the effect of silencing TET2 by small interfering RNA (siRNA) on the biological characteristics of CD34(+) cells. METHODS: CD3(+) and CD34(+) cells were sorted by magnetic activated cell-sorting system from bone marrow of MDS patients and controls. The mRNA expressions of TET2 in bone marrow CD3(+) and CD34(+) cells of 28 MDS patients and 20 controls were detected by qPCR. The silencing effect of RNA interference (RNAi) on TET2 expression in CD34(+) bone marrow cells of normal control was identified by qPCR and Western blot analysis. The cell cycle kinetics and cell apoptosis were then detected by flow cytometry. RESULTS: The expression of TET2 mRNA in CD3(+) and CD34(+) cells was down regulated in MDS compared with that in controls [(0.16 +/- 0.11) vs. (1.05 +/- 0.32) (P<0.001); (0.58 +/- 0.26) vs. (1.25 +/- 0.94) (P<0.005)]. The siRNA targeting TET2 suppressed the expression of TET2 in normal CD34(+) cells. Meanwhile, the proliferation activity was significantly enhanced [G0/G1: (87.82 +/- 8.25)% vs. (92.65 +/-7.06)% and (93.60 +/- 5.54)%, P<0.05; S: (11.50 +/- 8.31)% vs. (6.92 +/- 7.04)% and (5.95 +/- 5.53)%, P<0.05] and the apoptosis rate was declined [(21.28 +/- 9.73)% vs. (26.17 +/- 9.88)% and (26.20 +/- 9.78)%] in the cells which transfected with TET2 siRNA as compared to those in the cells transfected with scrambled siRNA and control cells. CONCLUSIONS: The TET2 expression of in CD3(+) and CD34(+) cells of MDS patients was decreased. Suppression of TET2 expression renders the CD34(+) cells harboring more aggressive phenotype. This preliminary finding suggests that CD34(+) cells lowering expression of TET2 may play an oncogenic role on myeloid tumor and CD3(+) T cells of MDS patients may be derived from the malignant clone. PMID- 26617798 TI - MicroRNA-137 inhibits cell migration and invasion by targeting bone morphogenetic protein-7 (BMP7) in non-small cell lung cancer cells. AB - MicroRNA-137 (miR-137) was reported to be dysregulated in several human cancers. However, the function and mechanism of miR-137 in non-small cell lung cancer (NSCLC) is still unclear. In the current study, we explored the role of miR-137 in NSCLC progression. Using qRT-PCR, our data showed that miR-137 was significantly down-regulated in NSCLC tissues and cell lines. In vitro functional assay, we found that over-expression of miR-137 suppressed NSCLC cells proliferation, migration and invasion, indicating that miR-137 could act as a tumor suppressor in NSCLC progression. In addition, bone morphogenetic protein-7 (BMP7) was identified as a target of miR-137 in NSCLC cells, Luciferase reporter assay suggested that miR-137 directly targeted 3'-UTR of BMP7, and correlation analysis revealed that BMP7 inversely correlated with miR-137 in NSCLC tissues. Furthermore, Restoration of BMP7 remarkably reversed the tumor suppressive effects of miR-137 on NSCLC cell proliferation, migration, and invasion. Taken together, our findings suggested that miR-137/BMP7 axis could contribute to the progression of NSCLC, suggesting miR-137 as a potential therapeutic target for the treatment of NSCLC. PMID- 26617799 TI - Quercetin increases macrophage cholesterol efflux to inhibit foam cell formation through activating PPARgamma-ABCA1 pathway. AB - The accumulation of cholesterol in macrophages could induce the formation of foam cells and increase the risk of developing atherosclerosis. We wonder if quercetin, one of flavonoids with anti-inflammation functions in different cell types, could elevate the development of foam cells formation in atherosclerosis. We treated foam cells derived from oxLDL induced THP-1 cells with quercetin, and evaluated the foam cells formation, cholesterol content and apoptosis of the cells. We found that quercetin induced the expression of ABCA1 in differentiated THP-1 cells, and increased the cholesterol efflux from THP-1 cell derived foam cells. Eventually, cholesterol level and the formation of foam cell derived from THP-1 cells decreased after quercetin treatment. In addition, quercetin activated PPARgamma-LXRalpha pathway to upregulate ABCA1 expression through increasing protein level of PPARgamma and its transcriptional activity. Inhibition of PPARgamma activity by siRNA knockdown or the addition of chemical inhibitor, GW9662, abolished quercetin induced ABCA1 expression and cholesterol efflux in THP-1 derived macrophages. Our data demonstrated that quercetin increased cholesterol efflux from macrophages through upregulating the expressions of PPARgamma and ABCA1. Taken together, increasing uptake of quercetin or quercetin rich foods would be an effective way to lower the risk of atherosclerosis. PMID- 26617800 TI - Adipositas cordis sudden death: a series of 79 patients. AB - BACKGROUND: The principal aim of this study was to investigate the clinical, epidemiological and pathologic features for a series of 79 cases of adipositas cordis sudden death. METHODS: We analyzed clinical and autopsy pathological features of 79 patients (43 females and 36 males) with adipositas cordis who died suddenly between 1975 and 2010. Data were extracted from China National Knowledge Infrastructure and Wan Fang Database. RESULTS: The average age of the 79 cases was 36.6 +/- 1.4 years old ranging from 13 to 68, and 82.3% of them were between 20 to 50 years old. Sudden death was the first symptom in 62 (78.5%) of the cases, only 17 (21.5%) had a history of chest distress or dyspnea. More than 4/5 (87.3%) of the cases had no any past medical history. At autopsy, the subjects' heart weight was mild or moderately increased, and a large amount of fatty tissues but not fibrous or fibro fatty was accumulated underneath the epicardium and infiltrated toward the right ventricle walls, and even infiltrated to all layers of the cardiac walls. Regional epidemiological data showed that about 80% of cases were living north and only 20% were living south of the Yangzi River, but not any familial heredity. CONCLUSION: Adipositas cordis sudden death is a very severe disease, it occurs mostly in youth and middle-aged and sudden death is often the first symptom. There is a significant regional difference, but not any genetic correlation. The pathogenesis of adipositas cordis sudden death should to be further explored. PMID- 26617801 TI - MicroRNA-506 inhibits esophageal cancer cell proliferation via targeting CREB1. AB - MicroRNAs (miRNAs) act as key regulators of multiple cancers. MicroRNA-506 (miR 506) functions as a tumor suppressor in various types of cancers. However, its role in esophageal cancer remains unclear. In our study, we found that miR-506 was significantly down-regulated in esophageal cancer tissues and cell lines. In vitro assay, our results showed that ectopic over-expression of miR-506 inhibited esophageal cancer cells proliferation, meanwhile, cells proliferation was promoted by miR-506 inhibition. In exploring mechanisms underlying the inhibitive role, we found that miR-506 significantly decreased the expression and transcription activity of cAMP responsive element binding protein 1 (CREB1). CREB1, tumor oncogene, exhibited significantly promote effect on esophageal cancer cell proliferation. Taken together, our data identify a new role of miR 506 in esophageal cancer involving CREB1 suppression. PMID- 26617802 TI - Cold exposure stimulates lipid metabolism, induces inflammatory response in the adipose tissue of mice and promotes the osteogenic differentiation of BMMSCs via the p38 MAPK pathway in vitro. AB - This study was to explore the effect of long-term cold exposure on morphological changes of WAT and BAT, metabolic changes and inflammatory responses in vivo. We also investigated the effect of cold exposure on the osteogenic differentiation of BMMSCs and the mechanism involved in vitro. At the end of the animal experiments, WAT and BAT were isolated and analyzed by HE staining. The results showed that both temperature and exposure time were associated with the degree of WAT browning. Then, peripheral blood samples were collected and centrifuged to obtain serum. Serum biochemical analysis was performed. After exposure to cold air for 21 d, cyclic adenosine monophosphate (cAMP) level in BAT was greatly upregulated. cAMP in WAT and glycerol levels were slightly increased. Cold exposure decreased triglyceride (TG) level and increased the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Whereas, high density lipoprotein cholesterol (HDL-C) and free fatty acid (FFA) levels remains unchanged. Moreover, leptin and adiponectin (ADP) levels were remarkably downregulated. Tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 concentrations were significantly elevated. Furthermore, the results showed that cold exposure significantly elevated runt-related transcription factor 2 (Runx2), bone sialoprotein (BSP), osteopontin (OPN) and collagen I levels and promoted the phosphorylation of p38 MAPK. However, the inducing effects were greatly inhibited by p38 MAPK inhibitor SB203580. These data suggest that long-term cold exposure activate BAT, increase lipolysis rate and enhance inflammatory response in mice. Furthermore, cold exposure promoted the osteogenic differentiation of BMMSCs partially via the p38 MAPK pathway. PMID- 26617803 TI - Pituitary tumor transforming gene PTTG2 induces psoriasis by regulating vimentin and E-cadherin expression. AB - Psoriasis is a common and intractable skin disease affecting the physical and mental health of patients. This study focused on the roles of pituitary tumor transforming gene 2 (PTTG2) in psoriasis. Using real-time quantitative PCR and western blot, the expression patterns of PTTG2 were compared in psoriatic epidermis cells and normal cells, from both mRNA levels and protein levels. Knockdown of PTTG2 by siRNA was conducted in HaCaT cells to investigate the changes in cell viability and migration in vitro. Expression changes of vimentin and E-cadherin were also detected in the transfected cells. Results showed PTTG2 was significantly overexpressed in the psoriatic epidermis cells (P < 0.05). The cell viability and migration were inhibited by the knockdown of PTTG2. Besides, knockdown of PTTG2 resulted in down-regulation of vimentin and up-regulation of E cadherin, with significant differences compared to the siRNA control group (P < 0.05). This study indicated the involvement of PTTG2 in mediating epidermis cell viability and migration and in pathogenesis of psoriasis. PTTG2 might be a potential therapeutic target for psoriasis through inducing epithelial-to mesenchymal transition (EMT) via regulating the expression of vimentin and E cadherin. PMID- 26617804 TI - Programmed cell death 2 functions as a tumor suppressor in osteosarcoma. AB - OBJECTIVES: To investigate the role of programmed cell death 2 (PDCD2) in osteosarcoma (OS), along with correlations between PDCD2 and CD4(+)/CD8(+). METHODS: Sprague-Dawley (SD) rats were randomly assigned to control group and OS group. The OS group rats were subjected to induce models of OS by transplantation with UMR106 cells. Peripheral blood was collected to test the percentages of the CD4(+) and CD8(+) cell subsets using flow cytometry (FCM). Western blotting was performed to determine the PDCD2 protein level. The correlations between PDCD2 and CD4(+)/CD8(+) were analyzed by Pearson correlation coefficient. Besides, specific small interfering RNAs (siRNA) against PDCD2 and nonspecific (NS)-siRNA were transfected into UMR106 cells. Cell viability and invasive ability were determined after transfection. RESULTS: CD4(+) cells percentages were significantly decreased in the OS group, while CD8(+) cells were significantly increased (P < 0.05). The PDCD2 protein levels were markedly lower than that in the control group (P < 0.05). Additionally, PDCD2 was positively correlated with CD4(+) (R(2) = 0.66, P < 0.05), but was negatively correlated with CD8(+) (R(2) = -0.94, P < 0.05). Moreover, the cell viability and invasion ability were significantly higher than that in the control group and the NS siRNA group after transfection with PDCD2 siRNA (P < 0.05). CONCLUSION: These results suggest that PDCD2 is involved in the pathogenesis of OS, and PDCD2 may play an important role in tumor suppression. These mechanisms might be related to immune response induced by CD4(+) and CD8(+) T cells. PMID- 26617805 TI - MiR-19a targets suppressor of cytokine signaling 1 to modulate the progression of neuropathic pain. AB - PURPOSE: We aimed to investigate whether miR-19a is associated with neuropathic pain and elucidate the underlying regulatory mechanism. METHODS: We established a neuropathic pain model of bilateral chronic constriction injury (bCCI). Then bCCI rats were injected with mo-miR-19a, siR-SOCS1 or blank expression vector through a microinjection syringe via an intrathecal catheter on 3 day before surgery and after surgery. Behavioral tests, such as mechanical allodynia, thermal hyperalgesia and acetone induced cold allodynia, were performed to evaluate the pain threshold. Besides, quantitative real-time polymerase chain reaction (qRT PCR) was performed to determine the expression of miR-19a and western blotting was carried out to measure the expression of SOCS1. RESULTS: miR-19a expression levels were markedly increased in neuropathic pain models. Moreover, miR-19a significantly attenuated mechanical allodynia and thermal hyperalgesia, and similar results were obtained after knockdown of SOCS1 expression. However, miR 19a markedly increased the times that the rats appeared a sign of cold allodynia, and knockdown of SOCS1 expression had similar effects. Besides, the results of bioinformatics analysis and western blotting analysis were all confirmed that SOCS1 was a direct target of miR-19a in neuropathic pain models. CONCLUSIONS: Our finding indicate that SOCS1 is a direct target of miR-19a in neuropathic pain rats and miR-19a may play a critical role in regulating of neuropathic pain via targeting SOCS1. PMID- 26617806 TI - Nox2 contributes to cardiac fibrosis in diabetic cardiomyopathy in a transforming growth factor-beta dependent manner. AB - PURPOSE: This study aimed to investigate the effect of Nox2 on cardiac fibrosis and to elucidate the regulatory mechanism of Nox2 in the development of DCM. METHODS: We established normal and insulin-resistant cellular model using neonatal rat cardiac fibroblasts. Then Nox2-specific siRNA were transfected into cardiac fibroblasts with Lipofectamine (r) 2000 and crambled siRNA sequence was considered as control. Meanwhile, a part of cells were randomly selected to be treated with or without transforming growth factor-beta (TGF-beta). Moreover, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were respectively performed to determine the expression level of related molecules, such as Nox2, collagen type I and III (COL I and III) and PI3K/AKT and PKC/Rho signaling pathway-related proteins. RESULTS: TGF-beta stimulation significantly increased the expression level of Nox2 both in mRNA and protein levels. Suppression of the Nox2 markedly decreased the expression of COL I and COL III in normal and insulin-resistant cellular model with TGF-beta stimulation. Moreover, suppression of the Nox2 significantly decreased the expression of PI3K/AKT and PKC/Rho signaling pathway-related proteins in insulin-resistant cellular model with TGF-beta stimulation. However, suppression of Nox2 had no effects on these proteins without TGF-beta stimulation. CONCLUSIONS: Our finding reveals that Nox2 may promote synthesis of COL I and III via involved in PI3K/AKT and PKC/Rho signaling pathway in a TGF-beta dependent manner and consequently promote cardiac fibrosis in the development of DCM. PMID- 26617807 TI - Down-regulation of nectin-4 inhibits apoptosis in systemic lupus erythematous (SLE) through targeting Bcl-2/Bax pathway. AB - PURPOSE: The purpose of this study was to investigate the potential role of nectin-4 in systemic lupus erythematous (SLE) cell apoptosis during the disease development and its potential mechanism. METHODS: Human peripheral blood mononuclear cells (PBMCs) were obtained for the isolation of monocytes and T lymphocytes. siRNA-nectin-4 plasma was constructed for the transfection into T cells using Lipofectamine 2000 reagent. siRNA with no nectin-4 sequence was transfected into T cells for the control group. mRNA expression of nectin-4 in cells was analyzed using RT-PCR method. Effect of netin-4 expression on T cell apoptosis was analyzed with Annexin V-FITC cell apoptosis kit. Moreover, effects of nectin-4 expression on cell apoptotic-related proteins expressions were detected using western blotting analysis. RESULTS: Nectin-4 was significantly overexpressed in cells from SLE group compared with healthy control (HC) group (P<0.05). When T cells were transfected with sinectin-4, nectin-4 slicing increased cell apoptosis in HC group but significantly decreased apoptosis in SLE group (P<0.05). Nectin-4 slicing significantly decreased CD40L and CD17 expressions in SLE (P<0.05), but performed no effect on CD11a expression. Moreover, nectin-4 down-regulation could significantly decrease Bcl-2, Bcl-XL, and caspase-6 expressions but increase Bax level in SLE group. CONCLUSION: The data presented in this study suggested that nectin-4 may be a therapeutic target for SLE through affecting the cell apoptosis. PMID- 26617808 TI - MiR-338-3p inhibits the proliferation and migration of gastric cancer cells by targeting ADAM17. AB - BACKGROUND: MicroRNAs (miRNA) have been documented playing a critical role in cancer progression. Although miR-338-3p has been implicated in several cancers, its role in gastric cancer is still unknown. The aim of our study was to investigate the role of miR-338-3p in gastric cancer progression. METHODS: Expression levels of miR-338-3p in gastric cancer cell lines and tissues were determined by quantitative real-time PCR (qRT-PCR). The effect of miR-338-3p on proliferation was evaluated by MTT assay, cell migration and invasion were evaluated by transwell migration and invasion assays. Furthermore, luciferase reporter assay was conducted to confirm the target gene of miR-338-3p, and the results were validated in gastric cancer cells. RESULTS: In the present study, we found that miR-338-3p was down-regulated in both gastric cancer cell lines and tissues. Enforced expression of miR-338-3p inhibited proliferation, migration and invasion of gastric cancer cells in vitro. Moreover, we identified A disintegrin and metalloproteinase 17 (ADAM17) gene as potential target of miR-338-3p. Importantly, ADAM17 rescued the miR-338-3p mediated inhibition of cell proliferation, migration and invasion. CONCLUSIONS: Our study suggested that miR 338-3p is significantly decreased in gastric cancer, and inhibits cell proliferation, migration and invasion partially via the downregulation of ADAM17. Thus, miR-338-3p may represent a potential therapeutic target for gastric cancer intervention. PMID- 26617809 TI - Role of transcriptional factor Nrf2 in the acute lung injury of mice. AB - OBJECTIVE: This study aimed to investigate the expression and role of Nrf2 in the acute lung injury (ALI) of mice. METHODS: A total of 60 BABL/c mice were randomly divided into 2 groups: ALI group and control group. In ALI group, ALI was introduced by injection of LPS. Immunohistochemistry was performed to detect Nrf2 expression in the lung; Western blot assay was employed to detect the expression of Nrf2 in the lung homogenate; ELISA was conducted to detect the expression of Nrf2 in the lung homogenate and BALF. RESULTS: As compared to control group, ALI mice had a high Nrf2 expression in the lung as shown in immunohistochemistry, and the Nrf2 expression in the lung homogenate and BALF also increased markedly (P<0.05). CONCLUSION: The Nrf2 expression increases in the lung and BALF of ALI mice, suggesting that Nrf2 is involved in the inflammation during ALI and may serve as a new target in the therapy of ALI. PMID- 26617810 TI - Clear cell sarcoma of soft tissue in right parapharyngeal region: report of a rare case. AB - Clear cell sarcoma (CCS), initially named malignant melanoma of soft parts, is a rare malignant neoplasm typically involving deep soft tissue of the extremities, in close proximity to tendons and aponeuroses. Here we describe a case of clear cell sarcoma of the right parapharyngeal region in a young female aged 20 years. MRI detected a mass about 4.4 cm*3.4 cm*3.0 cm, located in the right parapharyngeal area and between the external pterygoid and the medial pterygoid. Microscopically, most of the tumor cells were epithelioid with palely eocinophilic cytoplasm arranged in sheets. Pleophorism of tumor cells were not marked. Immunohistochemical analysis shows that the tumor cells were positive for vimentin, S-100, HMB45 and MelanA, and negative for AE1/AE3, actin-sm, desmin, CD117, TFE-3, and P63. Ki67 index was about 5%. PMID- 26617811 TI - Experimental study of vein subvolution combined with neural stem cells to repair sciatic neurologic defects in rats. AB - This study aims to explore the effects of vein subvolution combined with neural stem cells on nerve regeneration. Animal model of sciatic nerve defects was established with SD rats. A total of 63 SD rats were divided into control group, vein subvolution group (treatment 1 group) and vein subvolution combined with neural stem cells group (treatment 2 group). The recovery of neurological function after 12 weeks was evaluated by nerve electrophysiological technique, histological observation and other methods. The recovery degree of sciatic nerve defect in treatment 2 group was better than that of other groups; The SFI values significantly decreased in treatment 2 group after 8 weeks; the regenerative nerve fiber numbers in treatment 2 group were significant higher than that of other groups; the recovery rates of treatment 1 and 2 groups were significant higher than that of control group. The effects of vein subvolution combined with neural stem cells on repairing peripheral nerve defects were better than that of vein subvolution method. PMID- 26617812 TI - Alterations of sympathetic nerve fibers in avascular necrosis of femoral head. AB - OBJECTIVES: Avascular necrosis of the femoral head (ANFH) was mainly due to alterations of bone vascularity. And noradrenaline (NA), as the neurotransmitter of the sympathetic nervous system (SNS), leads to the vasoconstriction by activating its alpha-Receptor. This study was to explore the nerve fiber density of the femoral head in the rabbit model of ANFH. METHODS: Twenty New Zealand white rabbits were used in this study. The rabbit model of ANFH was established by the injection of methylprednisolone acetate. The nerve fiber density and distribution in the femoral head was determined using an Olympus BH2 microscope. RESULTS: Significant fewer sympathetic nerve fibers was found in the ANFH intertrochanteric bone samples (P = 0.036) with osteonecrosis. The number of sympathetic nerve fibers was compared between the two groups. And less sympathetic nerve fibers were found in later stage ANFH samples in comparison with those of early stages. CONCLUSIONS: ANFH might be preceded by an inflammatory reaction, and an inflammatory response might lead to arthritic changes in tissue samples, which in turn reduces the number of sympathetic nerve fibers. PMID- 26617813 TI - Expression of NF-kappaB and PTEN in primary epithelial ovarian carcinoma and the correlation with chemoresistance. AB - The present study aims to investigate the relationship of NF-kappaB p65 and PTEN protein with chemotherapy resistance in ovarian cancer by measuring their expression in primary epithelial ovarian cancer, and to explore the correlation of the expression of these two proteins with ovarian carcinoma and their clinical significance. Ovarian cancer patients (n = 161) were divided into two groups: sensitive group (n = 82) and resistant group (n = 79). Expression of NF-kappaB p65 and PTEN protein in the ovarian cancer tissues was determined using immunohistochemistry to assess the relationship and correlation between the expression levels of these two proteins and chemotherapy resistance of ovarian carcinoma. The Cox model was used to analyze the independent risk factors associated with ovarian cancer prognosis. The expression of NF-kappaB p65 in the sensitive group (68.29%) was lower than that of the resistant group (94.94%). In contrast, the expression of PTEN protein in the sensitive group (50.00%) was higher than that of the resistant group (17.72%). Expression of NF-kappaB p65 was negatively correlated with that of PTEN protein in ovarian cancer tissue (rs = 0.246, P = 0.002). Expression of NF-kappaB p65 or PTEN protein and surgical stage of ovarian cancer were independent risk factors associated with chemoresistance (all P < 0.05). Low expression of PTEN and high expression of NF-kappaB are significant risk factors for chemotherapy resistance of ovarian cancer patients. PMID- 26617814 TI - Macrophages polarization is mediated by the combination of PRR ligands and distinct inflammatory cytokines. AB - Macrophages recognize microbes through Pattern Recognition Receptors (PRRs), and then release pro-inflammatory and anti-inflammatory cytokines. Recent studies have highlighted that collaboration between different PRRs. However, these studies have neglected the crosstalk between various PRRs on macrophages. In the present study, we investigated the interplay of nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) (NOD1, NOD2) and TLRs (TLR1, 2, 3, 4, 5, 6, 7, 8) in terms of macrophage activation, the expression and production of cytokines. The macrophages were stimulated with a single PRR ligand or a combination of TLR and NOD ligands. After 8 h of incubation, the mRNA expression of interleukin-1beta (IL-1beta), IL-4, IL-6, IL-10, IL-12p35, IL 12p40, IL-13, and interferon-gamma (IFN-gamma) was evaluated. The production of these cytokines was also measured. NOD2 synergized with TLR3 agonists on enhancement of IL-10 release. However, the combination of NOD1 with TLR3 ligands showed little effect on IL-10 production. Moreover, NOD2 inhibited the percentages of CD11b + F4/80 + cells activated by TLR3 agonist. PMID- 26617815 TI - Prognostic value of ISG15 mRNA level in drinkers with esophageal squamous cell cancers. AB - ISG15, the protein encoded by interferon (IFN)-stimulated gene 15, was the first identified ubiquitin-like protein, which could be strongly upregulated by type I interferons as a primary response to diverse microbial and cellular stress stimuli. Although the biological activities of ISG15 have yet to be fully elucidated, it is frequently overexpressed in various cancers. As the role of ISG15 in esophageal squamous cell cancer (ESCC) has not been well reported, the current study aimed to elucidate the role of ISG15 in predicting outcomes of ESCC patients. Samples were collected from 153 ESCC patients, including 54 pairs of tumor tissues and non-tumor tissues. Compared with the paired non-tumor tissues, higher expression of ISG15 mRNA were detected in ESCC tissues. The cut-off value 1.28 determined by ROC curve analysis divided the ESCC patients into high and low ISG15 mRNA expression group. High-ISG15 mRNA expression appeared with more frequency in ever-drinkers (P = 0.018). Kaplan-Meier analysis indicated that Low ISG15 mRNA expression group had a longer cancer-specific survival (CSS) compared with High-ISG15 mRNA expression group. Multivariate analysis revealed that ISG15 mRNA (P = 0.024; hazard ratio, 2.759, 95% CI, 1.841-4.134) as well as Pathological staging (P < 0.001; hazard ratio, 1.634, 95% CI, 1.065-2.505) were independent prognostic factors. Subgroup analysis revealed that the discernibility of ISG15 mRNA level on ESCC outcomes was only pronounced in ever drinkers (P = 0.026) not in never-drinkers (P = 0.138). ISG15 might serve as a novel prognostic biomarker in drinkers with ESCC. PMID- 26617816 TI - Circadian gene expression predicts patient response to neoadjuvant chemoradiation therapy for rectal cancer. AB - Preoperative neoadjuvant chemoradiation therapy may be useful in patients with operable rectal cancer, but treatment responses are variable. We examined whether expression levels of circadian clock genes could be used as biomarkers to predict treatment response. We retrospectively analyzed clinical data from 250 patients with rectal cancer, treated with neoadjuvant chemoradiation therapy in a single institute between 2011 and 2013. Gene expression analysis (RT-PCR) was performed in tissue samples from 20 patients showing pathological complete regression (pCR) and 20 showing non-pCR. The genes analyzed included six core clock genes (Clock, Per1, Per2, Cry1, Cry2 and Bmal1) and three downstream target genes (Wee1, Chk2 and c-Myc). Patient responses were analyzed through contrast-enhanced pelvic MRI and endorectal ultrasound, and verified by histological assessment. pCR was defined histologically as an absence of tumor cells. Among the 250 included patients, 70.8% showed regression of tumor size, and 18% showed pCR. Clock, Cry2 and Per2 expressions were significantly higher in the pCR group than in the non pCR group (P<0.05), whereas Per1, Cry1 and Bmal1 expressions did not differ significantly between groups. Among the downstream genes involved in cell cycle regulation, c-Myc showed significantly higher expression in the pCR group (P<0.05), whereas Wee1 and Chk2 expression did not differ significantly between groups. Circadian genes are potential biomarkers for predicting whether a patient with rectal cancer would benefit from neoadjuvant chemoradiation therapy. PMID- 26617818 TI - Decreased expression of mucin 18 is associated with unfavorable postoperative prognosis in patients with clear cell renal cell carcinoma. AB - BACKGROUND: MUC18 is correlated with tumor progression and metastasis in types of malignancy. But the role of MUC18 in clear cell renal cell carcinoma remains unclear. In this study, we aimed to investigate the expression of MUC18 and its correlation with clinical outcomes in clear cell renal cell carcinoma. PATIENTS AND METHODS: Immunohistochemical staining was performed in samples from 288 patients with clear cell renal cell carcinoma. We used Kaplan-Meier method and Cox proportional hazard models to value the association between MUC18 expression and clinical outcome. Nomogram was constructed to predict overall survival at 5 and 8 years after nephrectomy. RESULTS: MUC18 expression was significantly decreased in tumor compared to non-tumor tissue (P<0.001). Lower MUC18 expression in tumor predicted a shorter survival time (P=0.007). By multivariate cox analysis, MUC18 was defined as an independent prognostic factor (P=0.006). The nomogram performed better in predicting 5- and 8-year overall survival than the TNM stage alone in clear cell renal cell carcinoma. CONCLUSION: MUC18 is an independent prognostic factor for clear cell renal cell carcinoma and could be incorporated with the other parameters to predict 5- and 8-year overall survival for clear cell renal cell carcinoma patients. PMID- 26617817 TI - Prognostic value of TROP2 in human nasopharyngeal carcinoma. AB - BACKGROUND: There is increasing evidence demonstrating the role of human trophoblast cell surface antigen 2 (TROP2) in cancer development and progression. However, their prognostic value in Epstein-Barr virus (EBV) associated nasopharyngeal carcinoma (NPC) remains to be elucidated. METHOD: The prognostic significances of TROP2 and Ki-67 were determined by immunohistochemistry in 58 NPC samples. TROP2 mRNA expression level and biological functions were evaluated. The presence of EBV was assessed using in situ hybridization. Analyses were conducted on the association between each of these variables as well as clinical outcome. RESULTS: TROP2 was exhibited over expression in 64% of NPC samples and significantly associated with highly proliferative tumor cells (P = 0.05) and lymph node metastases (P = 0.03). Overexpression of TROP2 significantly correlated with worse overall survival (P = 0.026) and poor disease-free survival (P = 0.021). By univariate analysis, high expression of TROP2 significantly correlated with patients with distant metastases, Ki-67 and EBV infection. Multivariate analysis further revealed that TROP2 along with Ki-67 and distant metastasis are independent prognostic predictors for NPC patients. CONCLUSION: Our findings have demonstrated that overexpression of TROP2 appears to be an independent predictor for poor clinical outcome in NPC. The strong correlation of overexpression of TROP2 with Ki-67 and distant metastases indicates a potentially therapeutic strategies targeting TROP2 for NPC patients. PMID- 26617819 TI - Pathological characteristics of liver biopsies in eight patients with hepatic epithelioid hemangioendothelioma. AB - We aim to investigate the pathological characteristics of liver biopsies and their implications for the prognosis of hepatic epithelioid hemangioendothelioma (HEHE). Clinical data of eight patients (5 male, 3 female) with HEHE were analyzed retrospectively. Expression of CD34, FVIII, AE1/AE3, Hepa-par1, GPC3, CK19 and the proliferation index marker Ki-67 were determined by immunohistochemical staining. The clinical pathological features and effects of treatment on prognosis were investigated. Among the eight patients, four did not exhibit significant symptoms, while four showed symptoms such as abdominal distension, aversion to greasy food and mild fever. Two patients had single liver lesions, while multiple lesions were observed in six cases, in which the tumor cells exhibited spindle, irregular or epithelioid morphology, with scattered, streaked and nested distribution. Individual luminal cells were also visible, containing red cells and accompanied by mucoid or fibrous stroma. All cases were CD34 positive, one case was FVIII factor negative, two cases were AE1/AE3 positive, Ki-67 staining exceeded 15% in two cases, and nuclear fission was visible in two cases. Patients with nuclear fission and Ki-67 > 15% died within 2 years after artery embolization, liver transplantation without relapse was observed in two cases and one case survived with the tumor. The other patients without cellular atypia, without nuclear fission and with Ki-67 < 10% did not relapse during the 2-5 years of follow-up. HEHE can be diagnosed according to hematoxylin and eosin morphology and immunohistochemical characteristics in biopsies before treatment allowing the selection of different treatment protocols based on pathological characteristics. PMID- 26617820 TI - IMP3 expression in biopsy specimens of colorectal cancer predicts lymph node metastasis and TNM stage. AB - IMP3 is associated with lymph node metastasis and TNM stage and is a good independent prognostic biomarker for colorectal cancer (CRC). However, the expression status and clinical implication of IMP3 in biopsy specimens have not yet been studied. We aim to address whether the presence of IMP3 expression in preoperative biopsies of CRC could predict lymph node metastasis and TNM stage. In this study, we examined IMP3 expression in paired biopsy and resection specimens of 71 CRC and analyzed the correlation of IMP3 expression with clinicopathological parameters. In the biopsy specimens, IMP3 positive expression was observed in 56 of 71 cases (78.9%) whereas negative expression was observed in 15 of 71 cases (21.1%). In the resection specimens, IMP3 positive expression was detected in 83.1% cases (59/71) whereas negative expression was detected in 16.9% cases (12/71). The absolute concordance rate between biopsy and resection specimens was 90.1% (64/71). The Spearman correlation test documented the existence of a strong linear correlation between the percentage of IMP3-positive cells in the biopsy and resection specimen (r = 0.629; P < 0.001). IMP3 expression in resection specimens was significantly related to histological grade (P = 0.043), T classification (P = 0.035), lymph node metastasis (P = 0.023), TNM stage (P = 0.007), tumor border (P = 0.049) and tumor budding (P = 0.012). IMP3 expression in biopsy specimens was significantly related to lymph node metastasis (P = 0.004), TNM stage (P = 0.005) and tumor budding (P = 0.001). In conclusion, IMP3 expression in biopsy specimens could be used to predict lymph node metastasis and TNM stage in CRC patients. PMID- 26617821 TI - The prognostic factors in the elderly patients with small cell lung cancer: a retrospective analysis from a single cancer institute. AB - OBJECTIVES: We conducted a retrospective study to evaluate the prognostic factors of elderly patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: The records of elderly patients (>= 65 years) with histologically-proven SCLC were reviewed. The patients' information including demographic, clinical and laboratory parameters, staging status on the Veterans Administration Lung Study Group staging system, and treatment modalities were registered. Univariate and multivariate survival analysis was performed by the Kaplan-Meier method and Cox proportional hazards model, respectively. RESULTS: Between January 2004 and December 2012, 247 elderly patients with SCLC were analyzed, 129 patients initially presented with limited stage (LS) and 118 with extensive disease (ES). The median age of the patients was 70.7 years (range, 65-83 years). The median follow-up period for all patients was 22.0 months (range, 1.0-84.0 months) and 39.9 months for the surviving patients (range, 4.7-84.0 months). The median survival time (MST) was 17.3 months, and the 2-year and 3-year OS rates were 36.3% and 22.7%, respectively. The MST, 2-year and 3-year OS rates were 22 months, 45.0% and 30.5% in patients with limited stage, versus 13.4 months, 26.5% and 13.7% in patients having extensive diseases, respectively. Multivariate analysis revealed that disease extent (HR = 3.034; P < 0.001) and the number of chemotherapy cycles (HR = 0.486; P = 0.003) were independent prognostic factors for the OS. Additionally, a normal serum NSE level (HR = 0.447, P = 0.017) at the time of diagnosis was independent positive prognostic factors for patients with LS-SCLC, but not for ES-SCLC. CONCLUSION: Disease extent and the number of chemotherapy cycles were independent prognostic factors of elderly patients with SCLC. The fit cohort might benefit from positive treatment. PMID- 26617822 TI - DNA promoter hypermethylation contributes to down-regulation of galactocerebrosidase gene in lung and head and neck cancers. AB - Galactocerebrosidase (GALC) is a lysosomal enzyme responsible for glycosphingolipids degradation byproducts of which are important for synthesis of apoptosis mediator ceramide. Reduced expression of GALC has been identified in human malignancies; however, molecular mechanisms underlying down-regulation of GALC expression in cancer remain unknown. We performed methylation and expression analysis on GALC gene in a panel of head and neck cancer (HNC) and lung cancer cell lines, attempting to understand the regulation of GALC in human cancer. QRT PCR and western blot analysis were performed to detect the expression of GALC in HNC. Bisulfite DNA sequencing and real-time qMSP were used to detect the methylation of GALC in HNC and lung cancer cell lines. 5aza-dC treatment assay was used to analysis the functional effect of GALC methylation on GALC expression in HNC. Reduction or complete absence of GALC expression was observed in more than a half of the tested HNC cell lines (8/14). 7 out of 8 cell lines with down regulated expression harbored heavy CpG island methylation, while all cell lines with abundant expression of the gene contained no methylation. Hypermethylation was also found in primary HNC tumor tissues and lung cancer cell lines whereas absent in normal oral mucosa tissues. Demethylating treatment demonstrated that 5aza-dC significantly restored GALC expression in cell lines with methylated promoter while showed no effect on cell lines without promoter hypermethylation. Our findings for the first time demonstrated that promoter hypermethylation contributed to down-regulation of GALC Gene, implicating epigenetic inactivation of GALC may play a role in tumorigenesis of cancer. PMID- 26617823 TI - Single-stage posterior-only approach treating single-segment thoracic tubercular spondylitis. AB - There are quite a few controversies on surgical management of single-segment thoracic spinal tuberculosis (STB) with neurological deficits. The present study was to compare single-stage posterior-only transpedicular debridement, interbody fusion and posterior instrumentation (posterior-only surgery) with a combined posterior-anterior surgical approach for treatment of single-segment thoracic STB with neurological deficits and to determine the clinical feasibility and effectiveness of posterior-only surgical treatment. Sixty patients with single segment thoracic STB with neurological deficits were treated with one of two surgical procedures in our center from January 2003 to January 2013. Thirty patients were treated with posterior-only surgery (Group A) and thirty were treated with combined posterior-anterior surgery (Group B). The American Spinal Injury Association (ASIA) score system to evaluate the neurological deficits, the visual analogue scale (VAS) to assess the degree of pain, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to judge the activity of tuberculosis (TB), surgery duration, intraoperative blood loss, length of hospitalization, bony fusion rates, and kyphosis correction of the two groups were compared. The average follow-up period was 36.5 +/- 9.2 months for Group A and 34.6 +/- 10.2 months for Group B. Under the ASIA score system, all patients improved with treatment. STB was completely cured and grafted bones were fused within 5-11 months in all patients. There were no persistent or recurrent infections or obvious differences in radiological results between the groups. The kyphosis deformity was significantly corrected after surgical management. The average operative duration, blood loss, length of hospital stay, and postoperative complication rate of Group A were lower than those of Group B. In conclusions, posterior-only surgery is feasible and effective, resulting in better clinical outcomes than combined posterior-anterior surgeries, especially in surgical time, blood loss, hospital stay, and complications. PMID- 26617824 TI - MSH3 rs26279 polymorphism increases cancer risk: a meta-analysis. AB - Previous studies have investigated the association of mutS homolog 3 (MSH3) rs26279 G > A polymorphism with the risk of different types of cancers including colorectal cancer, breast cancer, prostate cancer, bladder cancer, thyroid cancer, ovarian cancer and oesophageal cancer. However, its association with cancer remains conflicting. We performed a comprehensive meta-analysis to derive a more precise estimation of the relationship between MSH3 rs26279 G > A polymorphism and cancer susceptibility. Systematically searching the PubMed and EMBASE databases yielded 11 publications with 12 studies of 3282 cases and 6476 controls. The strength of the association was determined by crude odds ratios (OR) and 95% confidence intervals (CI). Overall, pooled risk estimates demonstrated that MSH3 rs26279 G > A was significantly associated with an increased overall cancer risk under all the genetic models (GG vs. AA: OR = 1.27, 95% CI = 1.09-1.48, P = 0.002; AG vs. AA: OR = 1.10, 95% CI = 1.00-1.21, P = 0.045; GG vs. AG + AA: OR = 1.23, 95% CI = 1.06-1.42, P = 0.005; AG + GG vs. AA: OR = 1.13, 95% CI = 1.04-1.24, P = 0.006; G vs. A: OR = 1.13, 95% CI = 1.05-1.20, P = 0.001). The association was more evident for colorectal cancer and breast cancer. Moreover, the significant association was also observed in the following subgroups: Europeans, Asians, population-based studies, hospital-based studies, and studies comprising relatively large sample size (>= 200). Our meta-analysis results demonstrated that MSH3 rs26279 G > A polymorphism is associated with an increased risk of overall cancer, especially for the colorectal cancer and breast cancer. PMID- 26617825 TI - Histological validation of frequency domain optical coherence tomography for the evaluation of neointimal formation after a novel polymer-free sirolimus-eluting stent implantation. AB - Novel polymer-free drug-eluting stents have been developed to reduce polymer related adverse events. However, neointimal coverage after polymer-free DES implantation is unclear and validation between optical coherence tomography (OCT) and histology is required. Sixteen polymer-free sirolimus-eluting stents were randomly implanted into coronary arteries of 8 normal swine. OCT and histological measurement were conducted at 3 or 6 months after stent placement. For quantitative measures, lumen area, stent area, neointimal area and neointimal thickness were validated in every single OCT and histology matched cross-section. Moreover, for qualitative analysis, OCT signal patterns of neointimal tissue were classified as homogeneous, layered and heterogeneous patterns based on optical intensity and backscatter pattern and peri-strut inflammation was also determined by histology. In total, 70 OCT and histology matched cross-sections were analyzed. At quantitative analysis, good correlations and agreements were found in the measurement of lumen area (ICC = 0.67, P<0.001), neointimal area (ICC = 0.89, P<0.001) and neointimal thickness (ICC = 0.94, P<0.001) except for stent area (ICC 0.19, P = 0.13) between OCT and histology. At qualitative analysis, lymphocyte infiltrations of peri-strut were more frequently seen in heterogeneous sections than in homogeneous sections (10/14 sections, 71.4% vs. 12/50 sections, 24%; P = 0.003). In conclusion, OCT has proper correlation and agreement with histology in assessment of neointimal formation and heterogeneous neointima assessed by OCT may also be associated with peri-strut inflammation detected in histology after polymer-free sirolimus-eluting stents implantation, supporting the use of OCT to evaluate neointimal coverage after polymer-free stent implantation in clinical practice. PMID- 26617826 TI - Down-regulation of BRMS1 by DNA hypermethylation and its association with metastatic progression in triple-negative breast cancer. AB - Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene in several solid tumors. However, the expression and function of BRMS1 in triple negative breast cancer (TNBC) have not been reported. In this study, we found that BRMS1 was down-regulation in breast cancer cell lines and primary TNBC, while decreased expression of BRMS1 mRNA was significantly associated with lymph node metastasis. And this down-regulation was found to be in accordance with aberrant methylation of the gene. Hypermethylation of the gene was observed in 53.4% (62/116) of the TNBC primary breast carcinomas, while it was found in only 24.1% (28/116) of the corresponding nonmalignant tissues. In addition, BRMS1 expression was restored in MDA-MB-231 after treatment with the demethylating agent, 5-aza-2-deoxycytidine (5-Aza-dC), and demethylation of the highly metastatic cells MDA-MB-231 induced invasion suppression of the cells. Furthermore, the suppression of BRMS1 by siRNA transfection enhanced cancer cells invasion. Collectively, our results suggest that the aberrant methylation of BRMS1 frequently occurs in the down-regulation of BRMS1 in TNBC and that it may play a role in the metastasis of breast cancer. PMID- 26617827 TI - Programmed cell death ligand 1 (PD-L1) expression on gastric cancer and its relationship with clinicopathologic factors. AB - BACKGROUND: Targeting the immune checkpoints in solid tumors becomes hot recently. Programmed cell death ligand 1 (PD-L1) is ligand for programmed death 1 (PD-1), which is known to negatively regulate T-cell activation. In the present study, we investigated the expression of PD-L1 in tumor specimens of gastric cancer and its relationships with clinicopathological variables and survival. METHODS: The expression of PD-L1 in 132 surgically resected specimens of stage II and III gastric cancer was evaluated by immunohistochemistry in microarray tissue. RESULTS: Expression of PD-L1 was observed in 50.8% (67/132) of gastric cancer tumor specimens. Patients whose tumor size over 5cm had a higher positive rate of PD-L1 expression. There was no relationship between the expression of PD L1 and other clinicopathological variables including age, gender, clinical stage, location as well as histological differentiation. PD-L1 positive patients had significantly poorer survival than negative patients. The 5-year survival rates was 83.1% in those with PD-L1 negative patients and 50.7% for PD-L1 positive patients (P<0.001). The multivariate analysis indicated that both PD-L1 positive and Tumor-node-metastasis stage were independent prognostic factors in gastric cancer patients (P=0.001 and 0.025, respectively). CONCLUSIONS: The expression of PD-L1 was found in half of stages II and III gastric cancer patients. Positive of PD-L1 expression indicated poor survival in Chinese stages II and III gastric adenocarcinoma patients. These results may provide the clue for immunotherapy in the adjuvant treatment setting of gastric cancer patients. PMID- 26617828 TI - Elevated JMJD1A is a novel predictor for prognosis and a potential therapeutic target for gastric cancer. AB - Jumonji domain-containing protein 1A (JMJD1A) play a key role in the development and progression of several malignancies. The present study investigated the expression and clinical significance of JMJD1A in gastric cancer. JMJD1A was found to be upregulated in gastric cancer tissues and cell lines. Furthermore, the upregulated expression of JMJD1A was significantly correlated with the results of the invasion depth (P=0.006), lymph node metastatic status (P<0.001), and TNM stage (P<0.001). JMJD1A was also shown to be an independent prognostic predictor of overall survival (HR3.988; 95% CI 1.948-8.167; P<0.001) for patients with gastric cancer. In addition, in vitro experiment revealed that knockdown of JMJD1A expression inhibited the gastric cancer cell proliferation, and further study suggested that JMJD1A knockdown suppressed MAPK pathway via transcriptional downregulation the expression of long noncoding RNA MALAT1. Therefore, we speculated that JMJD1A-MALAT1-MAPK signaling might participate in the JMJD1A induced cell proliferation of gastric cancer. Collectively, our data demonstrate for the first time that JMJD1A gene has an important regulatory role in gastric carcinogenesis, and could function as a novel prognostic indicator and a potential therapeutic target for gastric cancer. PMID- 26617829 TI - IL-17 producing innate lymphoid cells 3 (ILC3) but not Th17 cells might be the potential danger factor for preeclampsia and other pregnancy associated diseases. AB - In pregnancy, the immunologic system plays an important role that ensures normal pregnancy development and can as well promote the development of complications. Pregnancy success appears to rely on a discrete balance between the Th cytokines, which are involved in fetal growth and development. Preeclampsia and gestational diabetes are known complications associated with pregnancy. However, the source of the increased IL-17 cytokine in preeclampsia and other pregnancy associated diseases still remains unclear amidst numerous inconsistencies. The recent identification of innate lymphoid cells (ILC) has raised more doubts about the sources of most of the Th associated cytokines. We investigated the source of peripheral IL-17 levels in preeclamptic, gestational diabetics and chronic diabetics compared to healthy pregnancy subjects. To evaluate the source of the increased IL-17 cytokine among preeclampsia, chronic diabetic and gestational diabetic patients we investigated the proportion of Th17 cell populations in peripheral blood mononuclear cells using flow cytometry as well as analyzing levels of IFN-gamma, IL-17, IL-1beta and HMGB1. This study found that the Th17 cell populations in peripheral blood of preeclamptic, gestational nor chronic diabetes during pregnancy did not correlate with the increased IL-17. We report that the increased IL-17 levels observed in patients with preeclampsia, gestational diabetes and chronic diabetes are associated with innate lymphoid cells 3 (ILC3) and may pose threats to the fetus if disregulated. PMID- 26617830 TI - Angiosarcoma (Stewart-Treves syndrome) in postmastectomy patients: report of 10 cases and review of literature. AB - AIMS: To study the clinicopathologic features of Stewart-Treves syndrome (STS) in postmastectomy patients including the epidemiology, presentation, morphology, differentiation, pathogenesis and therapeutic options. METHODS AND RESULTS: Ten cases of STS in postmastectomy patients were retrospectively identified in our archives, and immunohistochemistry for CD34, CD31, D2-40, HHV-8, CK, EMA and Ki 67 was performed. All ten patients presented with lymphedema after mastectomy as the first sign. Physical examination revealed multiple raised, pinkish-red papulo vesicular lesions or ulceration as the early evidence of tumor in the field where radiation therapy was introduced. Microscopic examination revealed infiltrative proliferation of vessels and the heteromorphic tumor cells expressed CD34, CD31 and D2-40. Despite the various treatment modalities, 5 patients died in an average of 19 months, 4 patients survived to the last follow-up (9-31 months), and 1 patient got lost. CONCLUSIONS: STS is a fatal complication of postmastectomy lymphedema. Patients with STS have very poor prognosis. The key to improve patient's survival is the early diagnosis through a high alert of this disease by primary care physicians and comprehensive physical examination of patients with pertinent history and suspicious clinical presentations followed by prompt biopsy for definitive diagnosis. PMID- 26617831 TI - Beneficial effects of polydatin on learning and memory in rats with chronic ethanol exposure. AB - The purpose of this paper is to examine the effects of polydatin on cognitive function in rats self-administered with chronic ethanol levels. The levels of cyclin-dependent kinase 5 (Cdk5) were also determined. In the in vivo study, adult male Sprague-Dawley rats were used to establish an ethanol-administered rat model. Cognitive function was measured using the Morris water maze and the level of Cdk5 expression was measured to evaluate the effect of polydatin treatment. Cdk5 kinase activity and cell survival rate in primary hippocampal neuron cultures treated with ethanol or ethanol and polydatin were measured in the in vitro study. Polydatin reversed the performance impairments in chronic ethanol treated rats in Morris water maze test, and decreased unregulated Cdk5 expression. Moreover, polydatin increased cell survival rate, and decreased Cdk5 activity in the ethanol-treated primary culture of hippocampal neurons. The study results suggest that polydatin exhibits neuroprotective potential for ethanol induced neurotoxicity, both in vivo and in vitro, which is most likely related to its ability to target Cdk5 in neurons. PMID- 26617832 TI - Tubulocystic renal cell carcinoma with poorly differentiated foci is indicative of aggressive behavior: clinicopathologic study of two cases and review of the literature. AB - Tubulocystic renal cell carcinoma (TCRCC) is a rare, recently characterized RCC subtype with distinctive clinicopathologic and genetic characterizations as well as typical behaviors in an indolent fashion. However, sporadic case reports in the literature have indicated that TCRCC with sarcomatoid differentiation or poorly differentiated (PD) foci could behave aggressively. Herein, we reported two cases of TCRCC with PD foci indentified from our consultative service. Both patients were male and aged 66 y and 47 y, respectively. The first patient experienced radical nephrectomy while the other was treated by partial nephrectomy. Macroscopically, both tumors were described as partly cystic and solid with the greatest diameter measuring of 12-cm and 4.5-cm, respectively. Histologically, both lesions had classic areas of TCRCC occupying most part of the tumor with small papillary RCC component. In case one, PD foci were scatteredly distributed and mixed with TCRCC and papillary RCC components, while in the other case the PD foci were adjacent to the areas of TCRCC. In both tumors, the PD foci were composed of irregular, often angulated, small tubules lined by atypical eosinophilic cells and surrounded by desmoplastic stroma, resembling collecting duct carcinoma. Immunohistochemistry, in both tumors, both TCRCC component and PD foci showed the similar immunoprofiles, i.e., labeling strongly and diffusely with PAX8, AMACR and Vimentin, and focally with CK34betaE12 but not with renal cell carcinoma marker or P63. In case one, the tumor invaded extensively into the adjacent renal parenchyma and focally into both renal sinusal and perirenal adipose tissues. The patient had metastasis in the pelvic cavity at the time of diagnosis and succumbed to the disease without further treatment 3 months later. The other case was organ confined but with focal positive renal parenchymal margin. The patient subsequently underwent radical nephrectomy and was in a good status without evidence of tumor recurrence or metastasis at a follow-up of 8 months. PMID- 26617833 TI - YAP is up-regulated in the bronchial airway smooth muscle of the chronic asthma mouse model. AB - Asthma is characterized by leukocytic infiltration and tissue remodeling with structural changes including subepithelial fibrosis and ASM cells proliferation. The Hippo pathway is a key regulatory point involved in cell proliferation, fibroblasts, and smooth muscle cell differentiation. In order to disclose the relation between asthma and the Hippo pathway, expression of the Yes-associated protein (YAP), a key gene in the Hippo pathway, in the bronchial smooth muscle of chronic asthma model (CAM) was studied. 40 mice were randomly divided into control (wide type) and experimental group to construct CAM using chicken ovalbumin (OVA). Pathological changes of the lung tissues were observed in the CAM mice compared with the control using HE staining method. Immunohistochemistry (IHC) was used to detect if YAP protein is expressed in the lung tissues. The pathological changes of the CAM group showed that a large number of inflammatory cells infiltration including mainly lymphocytes and a small amount of eosinophilic, with the presence of certain airway smooth muscle hyperplasia, was observed in comparison with the control. IHC results showed that the YAP protein was significantly increased compared with the control groups (P < 0.01). This result was further confirmed by quantitative real-time PCR (qPCR) assay which detected the up-regulation of the YAP gene (P < 0.01) and Western blot. In conclusion, the YAP protein was significantly expressed in the bronchial airway tissues of the CAM mice, and could be used as an indicator for asthma. PMID- 26617834 TI - Decitabine induces G2/M cell cycle arrest by suppressing p38/NF-kappaB signaling in human renal clear cell carcinoma. AB - OBJECTIVE: The anti-neoplastic effects of decitabine, an inhibitor of DNA promoter methylation, are beneficial for the treatment of renal cell carcinoma (RCC); however, the mechanism of action of decitabine is unclear. We analyzed gene expression profiling and identified specific pathways altered by decitabine in RCC cells. METHODS: Four human RCC cell lines (ACHN, Caki-1, Caki-1, and A498) were used in this study; growth suppression of RCC cells by decitabine was analyzed using the WST-1 assay. Apoptosis and cell cycle arrest were examined using flow cytometric analysis. Gene expression of RCC cells induced by decitabine was evaluated with cDNA microarray, and potential biological pathways were selected using Ingenuity Pathway Analysis. The activity of the p38-NF-kappaB pathway regulated by decitabine was confirmed by Western blotting. RESULTS: Decitabine suppresses the proliferation of RCC cells in vitro. Although decitabine did not significantly induce apoptosis, decitabine caused cell cycle arrest at G2/M in a dose-dependent manner. Gene expression regulated by decitabine in RCC cells was investigated using microarray analysis. Ubiquitin carboxyl terminal hydrolase 1 (UCHL1), interferon inducible protein 27 (IFI27), and cell division cycle-associated 2 (CDCA2) may be involved in growth suppression of RCC cells by decitabine. The phosphorylation of p38-NF-kappaB pathway was suppressed by decitabine in RCC cells. CONCLUSIONS: We investigated gene expression profiling and pathways modulated by decitabine in RCC cells. Decitabine was shown to suppress the growth of RCC cells via G2/M cell cycle arrest and the p38-NF-kappaB signaling pathway may play a role in the anti neoplastic effect of decitabine in RCC cells. PMID- 26617835 TI - Transplantation of olfactory ensheathing cells promotes partial recovery in rats with experimental autoimmune encephalomyelitis. AB - OBJECTIVE: This study was to investigate the efficacy of olfactory ensheathing cell (OEC) transplantation on experimental autoimmune encephalomyelitis (EAE). METHODS: EAE models were established by guinea pig spinal cord homogenate (GPSCH) immunization in Lewis rats. OECs were purified and cultured from the olfactory nerve layer of SD rats, and then transplanted to the EAE models through the vena caudalis (Group A) or into the lateral cerebral ventricle (Group B). Neurological function scores and body weights were daily recorded following transplantation, and histological analysis was performed to assess the pathological changes in EAE rats. RESULTS: Cultured cells mainly exhibited bipolar or tripolar morphology, and the majority of these cells were positive for NGFR p75 staining. Neurological function scoring and the body weight measurement showed that, OEC transplantation could significantly improve the performance of EAE rats, and similar results were observed for the transplantation through the vena caudalis and into the lateral cerebral ventricle. Moreover, the transplanted OECs accumulated to the lesions in the brains of EAE rats, in spite of the different transplantation approaches. However, no significant differences in histopathology (HE and LFB staining) were observed between the OEC-transplanted groups and the control group. CONCLUSION: OEC transplantation could exert beneficial effects in the treatment of EAE, no matter which the cells were transplanted through the vena caudalis or into the lateral cerebral ventricle. Our findings might provide evidence for the clinical treatment of multiple sclerosis with cell transplantation. PMID- 26617836 TI - Low expression of KLF17 is associated with tumor invasion in esophageal carcinoma. AB - PURPOSE: KLF17 belongs to the Sp/KLF zinc-finger protein family as a regulator in tumor development. However, its expression and biologic function has remained unclear in EC. METHODS: The esophageal carcinoma tissue samples and adjacent normal tissues were obtained from the Second Hospital of Hebei Medical University. Immunohistochemistry, Western blot, and transfection were applied to evaluate the expression and clinical significance of KLF17 in esophageal cancer. RESULTS: In this study, we showed that KLF17 was overexpressed in esophageal normal samples compared to the cancer. Moreover, KLF17 was upregulated at lymph node non-metastatic cancer tissues when compared to metastatic cancer tissues. KLF17 overexpression decreased EC cell proliferation, migration and invasion ability. In contrast, the knockdown of KLF17 increased EC cell proliferation, migration and invasion ability. CONCLUSION: These results suggest that KLF17 inhibits tumor development and may serve as a potential therapeutic target. PMID- 26617837 TI - The fusion of autophagosome with lysosome is impaired in L-arginine-induced acute pancreatitis. AB - BACKGROUND & AIMS: Acute pancreatitis is an inflammatory pancreatic disease that carries considerable morbidity and mortality. The pathogenesis of this disease remains poorly understood. We investigated the incidence of autophagy in mice following induction of acute pancreatitis. METHODS: Mice were received intraperitoneal injections of L-arginine (200 mg * 2/100 g BW), while controls were administered with saline. Pancreatic tissues were assessed by histology, electron microscopy and western blotting. RESULTS: Injection of L-arginine resulted in the accumulation of autophagosomes and a relative paucity of autolysosomes. Moreover, the autophagy marker p62 is significantly increased. However, the lysosomal-associated membrane protein-2 (Lamp-2), a protein that is required for the proper fusion of autophagosomes with lysosomes, is decreased in acute pancreatitis. These results suggest that a crucial role for autophagy and Lamp-2 in the pathogenesis of acute pancreatitis. CONCLUSIONS: Our data suggest that the autophagic flux is impaired in acute pancreatitis. The depletion of Lamp 2 may play a role in the pathogenesis of acute pancreatitis. PMID- 26617838 TI - Lymphangiogenesis in breast cancer is associated with non-sentinel lymph node metastases in sentinel node positive patients. AB - Axillary lymph node dissection (ALND) is not suggested in breast cancer patients with negative sentinel lymph node (SLN) biopsies, and SLN is the only positive node in 40-70% of the remaining cases. To distinguish a subgroup in which ALND would be omitted, we investigated the role of lymphangiogenesis in primary breast cancer as a risk factor for distal lymph node involvements in patients with positive SLNs. 86 patients were included in this study. The frequency of proliferative lymphatic endothelial cells (LECP%) was evaluated in each specimen after immunohistochemical double staining for D2-40 and Ki-67. Larger primary tumor size, increased number of positive SLNs, lymphatic vessel invasion and LECP% were significantly associated with non-SLN metastases in the univariate analysis, but only LECP% retained significance in the multivariate model. A positive correlation between LECP% and lymphatic vessel invasion was also revealed. Our study confirmed the important role of lymphangiogenesis in tumor spread, and suggested that LECP% is a promising predictor for additional axillary lymph node involvements. PMID- 26617839 TI - Low MiR-149 expression is associated with unfavorable prognosis and enhanced Akt/mTOR signaling in glioma. AB - MicroRNAs (miRs) play critical roles in the progression of glioma. Previous in vitro studies have described the anti-tumor role of miR-149 in cancer cells including glioma. In this study, we aimed to investigate whether miR-149 is associated with the prognosis of glioma patients. A total of 163 glioma patients who underwent tumor resection were included in our follow-up study. We found that the miR-149 expression was significantly lower in tumor tissues compared with that in normal tissues (P<0.05). Kaplan-Meier and analysis showed that the miR 149 expression status was significantly associated with the survival duration (logrank test, P<0.001), and multivariate Cox regression revealed that patients with low miR-149 expression were exposed to a 1.825 fold higher death risk (HR=1.825, 95% CI=1.031-3.229, P=0.039) compared with those with high miR-149 expression. Further study showed that Akt/mTOR signaling was hyperactive in low miR-149 expressing tissues. Our study thus demonstrates that miR-149 expression in glioma tissues is critically associated with the prognosis of patients, suggesting its potential clinical significance. PMID- 26617840 TI - SP-D, KL-6, and HTI-56 levels in children with mycoplasma pneumoniae pneumonia. AB - The study was aimed to evaluate the potential biomarkers from pulmonary surfactant protein D (SP-D), Krebs von den Lungen-6 (KL-6), and 56-kD a human type I protein (HTI-56) in serum and bronchoalveolar lavage fluid samples of children with Mycoplasma pneumoniae pneumonia. This retrospective study, self controlled study enrolled 34 Chinese children with M. pneumoniae pneumonia. The levels of SP-D, KL-6, and HTI-56 in bronchoalveolar lavage fluid samples were assessed and compared between patients with unilateral lung infection and contralateral lungs without any abnormal findings. Significant differences in the levels of SP-D, KL-6, and HTI-56 were observed in infected bronchoalveolar lavage fluid samples compared with uninfected samples (all P<0.05); however, there was no correlation between the serum level of SP-D, KL-6, and HTI-56 and their levels in infected and uninfected bronchoalveolar lavage fluid samples (P>0.05). CONCLUSION: The high levels of SP-D, KL-6, and HTI-56 in infected bronchoalveolar lavage fluid samples may reflect the injury of alveolar epithelium caused by M. pneumoniae. Instead of SP-D in uninfected bronchoalveolar lavage fluid samples obtained by invasive bronchoscopy, serum SP-D may serve as a convenient medium to distinguish lung infection caused by M. pneumoniae. PMID- 26617841 TI - Metastatic and prognostic factors in patients with alveolar echinococcosis. AB - BACKGROUND: Prognostic predictions in alveolar echinococcosis (AE) are usually based on relapse and metastasis. Thus, assessment of factors associated with metastasis and clinical outcomes in patients with alveolar echinococcosis are of significant important. The purpose of this study was to investigate the correlated factors for metastasis and prognosis for patients with AE. METHODS: We analyzed 159 AE patients who underwent curative surgery at the First Teaching Hospital of Xinjiang Medical University from February 2003 to December 2013 by hematoxylin and eosin (HE) staining. Immunohistochemistry (IHC) staining for CD44 was performed in 159 AE and adjacent normal liver specimens. The clinicopathological parameters were analyzed for metastasis and prognosis, including gender, age, size, calcification, necrosis, foreign body granuloma and CD44 protein level. RESULTS: The rate of metastasis was 22.1%. Chi-square test showed that low levels of CD44 was associated with metastasis (P = 0.004). However, multivariate analysis suggested that CD44 expression is not independent prognostic indicators for overall survival (P = 0.356). In addition, no correlations between prognosis and gender, age, size, calcification, necrosis, foreign body granulomatous, metastasis were identified. CONCLUSIONS: The finding that a low level of CD44 is associated with metastasis in AE patients. At present, it thus remains question whether CD44 expression is a valid prognostic marker for AE, further investigations are required. PMID- 26617842 TI - Electroacupuncture modulated the inflammatory reaction in MCAO rats via inhibiting the TLR4/NF-kappaB signaling pathway in microglia. AB - In this study, we aim to investigate the effects of electroacupuncture on the TLR4/NF-kappaB signaling pathway in microglia. Male Wistar rat of SPF grade (weighing 200 +/- 20 g) were randomly divided into (i): sham control group, which was subjected to sham operation (ii) vehicle group, which underwent the occlusion of middle cerebral artery; (iii-v): acupuncture groups, which were subjected to the occlusion of middle cerebral artery and treated with acupuncture on the Neiguan acupoint (P6), Quchi acupoint (LI11), and Diji acupoint (SP8), respectively. HE staining was performed to detect the necrotic rate of neurons. Mediators of inflammation were measured using ELISA. Immunofluorescence was performed to measure the expression of TLR4, HMGB1, TRAF6, IKKbeta and NF-kappaB p65 in microglia. Severe decrease was noticed in the neurological score, necrotic rates of neuron, expression of IL-1beta, IL-6, TLR4, HMGB1, TRAF6, IKKbeta and NF kappaB p65 in microglia. Compared with the vehicle group, significant decrease was revealed in the neurological score, necrotic rate, IL-1beta, TLR4, TRAF6, IKKbeta and NF-kappaB p65 in Neiguan group and Quchi group, respectively. In addition, remarkable decrease was observed in the expression of TNF-alpha and IL 6 in Quchi group. Compared with the Diji group, the necrotic rate of neurons in hippocampus region was significantly decreased in the Quchi group (P < 0.05). In Neiguan group, the expression of TLR4 and IKKbeta was significantly attenuated (P < 0.05). The expression of TRAF6 was remarkably decreased in the Neiguan group and Quchi group, respectively. Electroacupuncture on Neiguan and Quchi could improve the neurological injury, attenuate the inflammation, and inhibit the activity of TLR4/NF-kappaB signaling pathway in microglia. PMID- 26617843 TI - Role of E-selectin for diagnosis of myocardial injury in children of age up to 14 years. AB - BACKGROUND: Effects of myocardial injury on E-selectin remain unclear. Thus, we investigated the diagnostic value of E-selectin for myocardial injury in children of no more than 14 years of age, which determined the scoring method of myocardial injury. METHODS: In this prospective study, plasma E-selectin, cardiac troponin I (cTnI) and creatine kinase isoenzyme MB (CK-MB) concentrations in pediatric patients with myocardial injury (myocardial injury group, n=85) were measured. The control group comprised 80 patients without myocardial injury, and the case-control study method was selected at the same time. The definition of cardiac injury was based on cTnI and CK-MB (with or possibly without abnormal ECG evidence). Diagnostic value of E-selectin for myocardial injury was determined by analyzing receiver operating characteristic (ROC) curves. RESULTS: The differences between the two groups were of statistical significance (P<0.001). For the 85 patients with myocardial injury, the area under the ROC curve (AUC) value for plasma E-selectin levels was 0.945 with a 95% CI of 0.899-0.991 and the optimal diagnostic cut-off value 29.67 ng/ml (positive likelihood ratio (positive LR=72.5); AUC value for plasma cTnI level was 0.848 with a 95% CI: 0.737-0.960 and the optimal diagnostic cut-off value was 0.155 ug/L (positive LR=12.3); AUC value for plasma CK-MB levels was 0.946 with a 95% CI: 0.903-0.989 and the optimal diagnostic cut-off value 24.26 IU/L (positive LR=72.5). CONCLUSIONS: E selectin is more effective than cTnI in diagnosing myocardial injury as an important biological marker of myocardial injury- an important index of pediatric cardiac injury score. PMID- 26617844 TI - Multifocality predicts poor outcome of patients with insular thyroid cancer: a clinicopathological study. AB - Insular thyroid carcinoma (ITC) is a rare type of thyroid malignancy whose aggressiveness and propensity to local recurrence differentiate it from other thyroid malignancies. However, data pertaining to its clinical characteristics is still lacking. In this study, we retrospectively analyzed 10 ITC patients treated and followed in Tianjin Medical University Cancer Institute and Hospital during Apr 2007 to Aug 2010, and compared the clinical and pathological characteristics and long-term follow-up with 2220 patients with papillary thyroid carcinoma (PTC). These ten ITC cases comprised 7 women and 3 men, of whom 6 patients are multifocal ITC (mITC) and showed cervical lymph node metastasis to the lateral compartment, while the other 4 solitary ITC (sITC) had regional metastasis confined to level VI or even no cervical metastasis. The ITC group had more frequent retrosternal metastasis (40% vs. 7.5%), recurrent laryngeal nerve invasion (40% vs. 4.4%), esophageal invasion (50% vs. 1.9%), a higher proportion of distant metastasis (50% vs. 3.2%), and vascular invasion (50% vs. 1.0%). While the presence of lymph node metastasis showed no significant difference. Interestingly, although patients with ITC are lacking in number to perform survival analysis, we still noticed that all the four sITC patients (4/4, 100%) have survived much longer (at least 45 months) than those who have multinodularity (mITC, 5/6, 83.3%). Our results indicated that ITC is an aggressive disease and the presence of multifocality might be a risk factor for long time survival of ITC patients. PMID- 26617845 TI - Establishment of pancreatic cancer stem cells by flow cytometry and their biological characteristics. AB - To investigate the method of separating human pancreatic cancer stem cells by Hoechst 33342 labeled flow cytometry and to analyze the biological properties of pancreatic cancer stem cells. The human pancreatic cancer cell line PC-3 was divided into SP and non-SP cells by flow cytometry. The number of two cell clone spheres and nude mice tumor formation rates were compared by cultivating in serum free medium; The expression of CD133, Nestin mRNA and protein was analyzed by real-time fluorescence quantitative PCR and Western blot; The expression of two cell drug resistance genes (MDR1, ABCG2, ABCA2 and MRP1) was analyzed by real time fluorescent quantitative PCR. The number of the cloned spheres in SP cells in serum-free medium was significantly higher than that of non-SP cells (P<0.05). The incidence of SP cells in the tumor of immunodeficiency nude mice was significantly higher than that of non-SP cells, and the difference was statistically significant (P<0.05). Real-time fluorescence quantitative PCR analysis showed that the expression of CD133 and Nestin mRNA in SP cells was significantly higher than those of non-SP cells, and the expression of CD133 and Nestin protein in SP cells was also significantly higher than those of non-SP cells (P<0.05). In conclusion, SP side population pancreatic cancer cells by Hoechst 33342 separation have the stem cell characteristics, higher tumor formation rate and higher drug resistance, which may be related to chemotherapy resistance. PMID- 26617846 TI - MiR-223 inhibited cell metastasis of human cervical cancer by modulating epithelial-mesenchymal transition. AB - Accumulating evidence have emerged important roles for microRNAs (miRNAs) participating in epithelial-mesenchymal transition (EMT) process and are associated with metastasis in cervical cancer. We hypothesized that miR-223 played an important role in cell metastasis of cervical cancer. Here, we found miR-223 was downregulated in human cervical cancer cell lines and clinical tumor tissues. Result of wound healing and cell migration assays revealed that miR-223 inhibited cell migration, whereas miR-223-in showed the opposite effect. In terms of mechanism, miR-223 influenced the expression of the EMT-associated proteins by upregulating the epithelial markers E-cadherin and alpha-cadherin and downregulating the mesenchymal marker vimentin. In conclusion, miR-223 inhibited cell metastasis of human cervical cancer by modulating epithelial-mesenchymal transition. PMID- 26617847 TI - Nonspecific interstitial pneumonia overlaps organizing pneumonia in lung-dominant connective tissue disease. AB - Here, we reported two cases of nonspecific interstitial pneumonia overlap organizing pneumonia (NSIP/OP) with lung-dominant connective tissue disease (LD ILD). The first case is a patient with hands of chapped skin, right-sided pleuritic chest discomfort, weakness, positive ANA and antibodies to Ro/SS-A (+++) and Ro-52 (++). In the second case, there were Reynaud's disease, and nucleolus-ANA increased (1:800). Chest high resolution CT scan in both cases showed ground-glass opacifications, predominantly in basal and subpleural region and the pathologic manifestation were correlated with NSIP/OP, which were previously discovered in Sjogren syndrome, PM/DM and other rheumatic diseases. The two cases of NSIP/OP with LD-CTD we reported expand disease spectrum of NSIP/OP pathological types in ILD. However, it is necessary to process large scale studies. PMID- 26617848 TI - Role of GPER1, EGFR and CXCR1 in differentiating between malignant follicular thyroid carcinoma and benign follicular thyroid adenoma. AB - It is extremely difficult to discriminate between follicular thyroid carcinoma (FTC) and follicular thyroid adenoma (FTA) before surgery, because the morphologies of carcinoma cells and adenoma cells obtained by fine needle aspiration biopsy (FNAB) are similar. Molecular markers may be helpful on this issue. The purpose of this study was to assess the role of GPER1, EGFR and CXCR1 in differential diagnosis between FTC and FTA. GPER1, EGFR and CXCR1 mRNA expression levels were examined in 15 FTCs and 10 FTAs using real-time RT-PCR. FTC showed to have significantly increased mRNA levels of the three molecules compared to FTA (P < 0.001 for all the three molecules). GPER1, EGFR and CXCR1 protein expression in 106 FTCs and 128 FTAs were analyzed using immunohistochemistry. The rates of GPER1, EGFR and CXCR1 high expression were 73.6%, 72.6% and 70.8% in FTC and 30.5%, 28.1% and 27.3% in FTA, respectively. Statistical analysis showed that GPER1, EGFR and CXCR1 protein expression were correlated with one another in FTC and concomitant high expression of the three molecules had stronger correlation with the occurrence of FTC than did each alone. The positive predictive values (PPV) for concomitant high expression of the three molecules for discriminating between FTC and FTA were 91.0% for GPER1/EGFR, 93.8% for GPER1/CXCR1, 92.3% for EGFR/CXCR1 and 98.2% for GPER1/EGFR/CXCR1, respectively. These results indicated that the evaluation of GPER1, EGFR and CXCR1 concomitant high expression may be helpful in differential diagnosis between FTC and FTA. PMID- 26617849 TI - Expression of Yes-associated protein (YAP) in metastatic breast cancer. AB - The purpose of this study was to investigate the expression of Yes-associated protein (YAP) in different metastatic sites in metastatic breast cancer and to determine the clinical implications of these patterns. Immunohistochemical staining was used to investigate the expression of YAP and phospho-YAP in tissue microarrays from 122 cases of metastatic breast cancer (bone metastasis = 29, brain metastasis = 38, liver metastasis = 12, and lung metastasis = 43). The expression levels of YAP and phospho-YAP differed according to the metastatic site in metastatic breast cancer. Specifically, nuclear expression of phospho-YAP was high in brain metastasis but low in lung metastasis (P = 0.010). The effects of YAP and phospho-YAP expression on clinical outcomes were investigated by univariate analysis. This analysis showed that nuclear YAP positivity (P = 0.008) and nuclear phospho-YAP positivity (P = 0.003) were both associated with shorter overall survival. In conclusion, the level of YAP expression varies according to the metastatic site in metastatic breast cancer. Moreover, high YAP expression was correlated with poor prognosis. PMID- 26617851 TI - Extracapsular extension is a powerful prognostic factor in stage IIA-IIIA non small cell lung cancer patients with completely resection. AB - The purpose of this study is to evaluate the relationship between extracapsular extension (ECE) and clinicopathology, and its influence on the prognosis in non small cell lung cancer (NSCLC) patients. Clinical data from 388 stage IIA-IIIA NSCLC patients who underwent curative resection and confirmed ECE positive were reviewed. The Fisher's exact or Chi-square test was used to analyze the associations between ECE and the clinical pathology. The log-rank test and Cox regression model were used to evaluate the factors influencing disease-free survival (DFS) and overall survival (OS). ECE was detected in 85 (21.9%) patients, and it had a significant correlation with advanced T stage, pathological stage and histologic type of adenocarcinoma. For the whole population, the median OS was 39.0 months, and the 5-year OS rate was 33.9%. In multivariate analysis, both ECE status and postoperative chemotherapy were significant factors for OS. The median DFS for all patients was 26.0 months, and the 5-year DFS rate was 21.7%. In multivariate analysis, pathologic stage, ECE, and postoperative chemotherapy were the independent predictor factors for DFS. Further analysis found that the locoregional recurrence-free survival and the distant recurrence-free survival rates in ECE negative group were also significantly higher than in the ECE positive group. For NSCLC patients with lymph node metastasis, the presence of ECE occurs more frequently in advanced stage and histologic type of adenocarcinoma and it may be a powerful prognostic factor which reflects the aggressive biological behavior. PMID- 26617850 TI - ZEB1 promotes the progression and metastasis of cervical squamous cell carcinoma via the promotion of epithelial-mesenchymal transition. AB - OBJECTIVE: The process of epithelial-mesenchymal transition (EMT) clearly contributes to cancer metastasis. The aim of this study was to investigate the expression of the EMT-related transcription repressor ZEB1 and the expression of EMT-associated markers (E-cadherin, beta-catenin and N-cadherin) in cervical squamous cell carcinoma. In addition, the role of ZEB1 and these EMT-associated markers in the progression and metastasis of cervical squamous cell carcinoma was explored. METHODS: The expression of ZEB1, E-cadherin, beta-catenin and N cadherin was evaluated in 81 specimens of cervical squamous cell carcinoma by immunohistochemistry; the clinicopathological significance of these markers was then analyzed. RESULTS: 1) Of the 81 samples, 37 cases (45.7%) were positive for ZEB1, and nuclear expression of ZEB1 in tumor cells was positively associated with the differentiation status of the tumor tissue (P < 0.05), vascular invasion (P < 0.05) and lymph node metastasis (P < 0.05). 2) The loss of E-cadherin and beta-catenin expression in tumor cells and the acquisition of N-cadherin expression were positively associated with the differentiation status of the tumor tissue (P < 0.05) and with the occurrence of vascular invasion (P < 0.05). 3) A significant negative correlation was observed between ZEB1 and E-cadherin expression (Spearman = -0.636, P < 0.05) and between ZEB1 and beta-catenin expression (Spearman = -0.417, P < 0.05). Moreover, a significant positive correlation was observed between ZEB1 and N-cadherin expression (Spearman = 0.557, P < 0.05). CONCLUSIONS: These results emphasize the role of EMT in cervical squamous cell carcinoma. The upregulation of ZEB1 is associated with the abnormal expression of E-cadherin, beta-catenin and N-cadherin, which might promote the progression and metastasis of cervical squamous cell carcinoma. PMID- 26617852 TI - Predictive value of CD44 and CD24 for prognosis and chemotherapy response in invasive breast ductal carcinoma. AB - OBJECTIVE: Cells with unique phenotypes and stem cell-like properties have been found to exist in breast cancer. The aim of the present study was to study the relationship of CD24, CD44, CD44(+)/CD24(-/low) and CD44(-)/CD24(+) tumor phenotypes' with clinico-pathological features, chemotherapy response and with prognosis. METHODS: The study included paraffin-embedded tissues of 140 primary and secondary invasive ductal carcinoma samples. All the patients received routine chemotherapy. Expression of CD24, CD44, ER, PR, and Her2 were assayed immunohistochemically. We applied double-staining immunohistochemistry for the detection of CD44(+)/CD24(-/low), CD44(+)/CD24 (+), CD44(-)/CD24(-) and CD44( )/CD24(+) cells. The association between the proportions of CD44(+)/CD24(-/low) and CD44(-)/CD24(+) and clinicopathological features, chemotherapy response and with prognosis of these patients was evaluated. RESULTS: CD24 expression was not significantly associated with tumor characteristics, but was significantly associated with poor prognostic variables including ER-, PR-, HER2(+) and triple negative (TN) phenotype; There was no association of CD44 with nodal status, age or HER2 expression. In the correlation analysis, CD24 expression was positively associated with chemotherapy response (P = 0.018), however, CD44 expression was not associated with pathological response to chemotherapy When both markers are considered, the CD44(+)/CD24(-) phenotype had the poor prognosis. The proportion of CD44+/CD24- tumor cells was significantly associated with lymph node involvement, recurrent or metastatic tumors and ER/PR status. High CD44(+)/CD24( ) phenotype had poor response to chemotherapy. The median disease-free survival (DFS) of patients with and without CD44(+)/CD24(-/low) tumor cells were 19.8 +/- 2.6 months and 31.7 +/- 4.2 months, and the median overall survival (OS) of patients with and without CD44(+)/CD24(-/low) tumor cells were 33.5 +/- 2.8 months and 51.4 +/- 3.9 months, respectively, and with both univariate and multivariate analyses showing that the proportion of CD44(+)/CD24(-/low) tumor cells was strongly correlated with DFS and OS. However, the CD44(-)/CD24(+), CD44(+)/CD24(+), CD44(-)/CD24 (-) phenotype had no relation with prognosis. CONCLUSION: There was significant correlation between CD44(+)/CD24(-/low) tumor cell prevalence and tumor metastasis, prognosis and chemotherapy response. The CD44(+)/CD24(-) phenotype may be an important factor for malignant relapse following surgical resection and chemotherapy in patients with invasive ductal carcinoma. PMID- 26617853 TI - Grb7 gene amplification and protein expression by FISH and IHC in ovarian cancer. AB - OBJECTIVE: Overexpression of growth factor receptor-bound protein 7 (Grb7) has been found in numerous human cancers. The aim of this study was to evaluate the correlation between Grb7 gene amplification and protein expression in ovarian cancer (OC). METHODS: We use Tissue Microarray (TMA) respectively to detect the gene amplification and protein expression of Grb7 in 90 cases OC and 10 control specimens of normal ovarian tissues by IHC and FISH. RESULTS: The Grb7 protein expression by IHC analysis was observed in 52/90 (57.8%) OC with 3 cases (3.3%) scored 3(+) and 9 cases (10%) scored 2(+) Grb7 gene amplification by FISH analysis was successfully detectable in 6 specimens with a positive rate of 6.8% (6/88) in which immunostaining 3(+), 2(+) and negative (1(+)/0) expressions of Grb7 were 100.0% (3/3), 11.1% (1/9) and 2.6% (2/76), respectively. Our data exhibited that the IHC and FISH results had a good consistency between Grb7 gene amplification and Grb7 protein expression (Kappa = 0.651, P < 0.001). Both the results of IHC and FISH revealed that Grb7 did not seem to have a role in OC clinicopathology. CONCLUSION: There is a close relationship between Grb7 gene amplification and GRB7 protein overexpression in human OC. IHC might have limited diagnostic value especially in these tumors and especially in characterizing genetically diverse borderline cases, FISH could be superior to IHC. PMID- 26617854 TI - Ki-67 and caspase expression in breast carcinoma: does variance in locational sampling exist? AB - Ki-67 and caspase indices are two very important prognostic variables for breast cancer. The aim of this study was to compare the immunoexpressions of these two prognostic variables at the center, the periphery of the tumor in comparison with each other, and additional parameters in 53 breast cancer specimens. It has been shown that the increase of caspase immunoexpression either at the periphery or the center of the tumor correlated with the increase of Ki-67 immunoexpression at the same areas. There was no statistically significant difference between caspase and Ki-67 immunoexpression at the center or the periphery of the tumor. No statistically significant correlation was found between immunoexpressions of caspase and Ki-67 with the tumor grade, stage, lymph node metastasis, lymphovascular or perineural invasion. The two very important prognostic variables of breast cancer (caspase and Ki-67) were evenly distributed in the center and the periphery of the tumor. It is evident that there is no need for a specific locational sampling when these two variables are considered. In accordance with this information, the differences in sampling due to observer diversity may be prevented. PMID- 26617855 TI - Gene expression profiling of taxol-resistant nasopharyngeal carcinoma cells with siRNA-mediated FOLR1 downregulation. AB - OBJECTIVES: Our previous study has shown that downregulation of FOLR1 by siRNA partially reversed taxol-resistant phenotype in taxol-resistant nasopharyngeal carcinoma cell lines. We aim to gain further insight into the molecular mechanisms of this process and identify the differentially expressed genes after FOLR1 downregulation. METHOD: The global gene expression profile was identified and analyzed using the Affymetrix HG-U133 Plus 2.0 array. RESULTS: There was a significant dysregulation in the global gene expression of the FOLR1-suppressed taxol-resistant nasopharyngeal carcinoma cell lines. There were 41 upregulated genes and 109 downregulated genes. QRT-PCR validation of the selected differentially expressed genes demonstrated there was a good correlation with the microarray analysis. There was a significant deregulation of expression in the apoptosis-related genes such as BIRC3, PRKX, TNFRSF10A and involved in Viral carcinogenesis, MAPK signaling pathways after FOLR1 was downregulated. CONCLUSION: The suppression of FOLR1 by RNA interference altered gene expression profile of taxol-resistant nasopharyngeal carcinoma cell lines. The apoptosis related genes and the gene alterations in viral carcinogenesis, MAPK signaling pathways might be important in FOLR1 siRNA-induced taxol-resistant reversal. PMID- 26617856 TI - Differences in peritumoral pseudocapsule characteristics according to clinicopathological factors in clinical T1a renal tumors. AB - OBJECTIVES: To evaluate the status of peritumoral pseudocapsules in renal tumors and the effects of clinicopathological factors on their formation. METHODS: From January 2011 to December 2012, 258 patients with solitary clinical stage T1a renal tumors who underwent partial nephrectomy were analyzed. Status of pseudocapsule was re-evaluated by a pathologist. RESULTS: The mean long diameter (+/- SD) of the tumor and the width of the safety margin were 2.17 (+/- 0.94) cm and 3.2 (+/- 2.4) mm, respectively. A complete pseudocapsule was identified in 152 (58.9%) tumors, an incomplete pseudocapsule was identified in 69 (26.7%) tumors, and no pseudocapsule was identified in 37 (14.3%) tumors. Out of 152 tumors with complete pseudocapsules, 45 (29.6%) were confirmed to directly invade the renal parenchyma. In a multivariable analysis, age (odds ratio [OR], 1.045; 95% confidence interval [CI], 1.021-1.070, P < 0.001) and histologic subtype (chromophobe type: OR, 19.455; 95% CI, 4.233-89.471, P < 0.001; oncocytoma: OR, 11.307; 95% CI, 1.357-94.198, P = 0.025) were significant factors for an incomplete or absent pseudocapsule. CONCLUSIONS: Peritumoral pseudocapsules are absent or incomplete in a significant portion of renal tumors. Old age as well as chromophobe and oncocytoma histologic subtypes were significant risk factors for an incomplete or absent peritumoral pseudocapsule. PMID- 26617857 TI - Genetic association of the ApoB and ApoA1 gene polymorphisms with the risk for alcohol-induced osteonecrosis of femoral head. AB - Polymorphisms of apolipoprotein B (ApoB), apolipoprotein A1 (ApoA1) gene and ApoB/ApoA1 Ratio were associated with lipid metabolism disorders in previous reports. The aim of this study assess whether variation of ApoB, ApoA1 gene are associated or not with alcohol-induced osteonecrosis of femoral head (ONFH). In a case-control study, we genotyped 4 single-nucleotide polymorphisms (SNPs) in ApoB and ApoA1 genes in 209 alcohol-induced ONFH patients and 300 healthy control subjects in Han Chinese population using chi(2) test and genetic model analysis. The analysis revealed that the frequencies of ApoB and ApoA1 genotypes were significantly different in alcohol-induced ONFH patients than in controls. We identified rs1042034, rs676210 and rs673548 in ApoB gene were associated with decreased risk of alcohol-induced ONFH using recessive model analysis (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.19-0.99; P = 0.042), the OR, CI, P value of three SNPs were the same after adjusted for gender + age. We also identified rs632153 in ApoA1 gene was associated with increased risk of alcohol induced ONFH using allele model (OR, 1.83; 95% CI, 1.16-2.88; P = 0.008) and log additive model (adjusted OR, 1.77; 95% CI, 1.00-3.14; P = 0.046), analysis respectively. Haplotype analysis demonstrated no difference between ApoB and alcohol-induced ONFH. Polymorphisms of the ApoB and ApoA1 gene are associated with alcohol-induced ONFH in the Han Chinese population. PMID- 26617858 TI - Inhibition effect of Peg-IFNalpha-2b and Imatinib alone or combination on imatinib-resistant gastrointestinal stromal tumors cell lines. AB - To investigate the inhibition effect of polyethylene glycol interferon alpha-2b and imatinib alone or combination on imatinib-resistant GIST cell lines, and to explore the possible mechanism. Imatinib resistant GIST cell lines (GIST-R) were exposured to either Peg-IFNalpha-2b or imatinib alone or combination. The proliferative inhibition rates and the combination index (CI) values of GIST-R cells were detected by MTT assay. The apoptotic rates of GIST-R cells were detected by flow cytometry. The expression levels of phospho-mammalian target of rapamycin (p-mTOR), and Bcl-2 of GIST-R cells were analyzed by Western blot. GIST R cells presents remarkable resistance to imatinib, and the resistance index (RI) were (P<0.05). And The proliferative inhibition rate and the apoptotic rate of GIST-R cells in combination of Peg-IFNalpha2b and Imatinib group were higher than those in Peg-IFNalpha-2b or imatinib alone group (P<0.05). The CI value of Peg IFNalpha-2b and imatinib was less than each alone, which had a synergistic effect (CI=0.63). As compared with the control (GIST-R cells without any treatment), the expression levels of p-mTOR and Bcl-2 proteins of GIST-R cells in combination of Peg-IFNalpha-2b and imatinib group were decreased (P<0.01). The combination of Peg-IFNalpha-2b and imatinib generats a synergistic effect in GIST-R cells, and reversal of drug resistance. This effect may be related with apoptosis and down regulation of the expression of p-mTOR. PMID- 26617859 TI - Tumor-stroma ratio is an independent predictor for survival in NSCLC. AB - Tumor-stroma ratio (TSR) has been identified as a new and practicable prognostic factor in some solid tumors. The aim of the study is to evaluate the prognostic value of TSR in non-small cell lung cancer (NSCLC). A total of 404 patients who underwent surgery resection for NSCLC were included in this study. TSR was assessed visually on the hematoxylin-stained tissue sections of surgical specimens. Patients with more than 50% intratumor stroma were quantified as the stroma-rich group and those with less than 50% as the stroma-poor group. In 404 cases of tissue samples, 302 cases were included in the stroma-poor group, while 102 cases in stroma-rich group. The different expression of TSR in NSCLC tissue was not correlated with gender, age, smoking history, tumor diameter, histology, differentiation grade and pTNM staging. In the Cox univariate and multivariate analyses of the 5-year OS, the HRs of the TSR were 1.818 (95% CI; 1.323-2.497; P<0.001) and 1.748 (95% CI; 1.262-2.422; P<0.05), respectively. As for DFS, the HRs were 1.715 (95% CI; 1.249-2.354; P<0.001) and 1.570 (95% CI; 1.135-2.172; P<0.05). Stroma-rich tumors were associated with poor prognosis and an increased risk of relapse, which may serve as a new prognostic histological characteristic in NSCLC. PMID- 26617860 TI - Functional analysis of UMOD gene and its effect on inflammatory cytokines in serum of essential hypertension patients. AB - OBJECTIVE: The study aimed to investigate the function of uromodulin (UMOD) gene and its effect on inflammatory cytokines in serum of essential hypertension patients. METHODS: The online database and software of computer were used for bioinformatics analysis on UMOD gene as well as the structure and function of its encoding proteins. Moreover, radioimmunoassay and enzyme linked immunosorbent assay was adopted to validate the content of urine UMOD protein of essential hypertension patients and their serum inflammatory cytokines. RESULTS: As an alkaline and hydrophilic protein, UMOD has no transmembrane region, but it does have a signal peptide sequence. It is mainly located extracellularly, belonging to a secreted protein, whose secondary structure was based mainly on Random coil which account for 58.44%. According to function prediction, it is found that the UMOD protein has stress response which may be participate in the inflammatory reaction. It has been observed from the experiment which was designed on the basis of the correlation between inflammation reaction and essential hypertension that the content of urine UMOD protein of essential hypertension patients who is in stage I was (28.71 +/- 10.53) mg/24 h and when compared with the control group's content (30.15 +/- 14.10 mg/24 h), the difference was not obviously; The content of urine UMOD protein of essential hypertension patients who's in stage II and III was (18.24 +/- 6.12) mg/24 h and (9.43 +/- 3.16) mg/24 h, respectively, which were obviously lower than that of the control group (P<0.01). Additionally, the serum inflammatory cytokines, such as TNF-alpha, IL-6 and IL1 alpha content of essential hypertension patients were all markedly higher than that of control group (P<0.05). CONCLUSION: For essential hypertension patients, there's a close relationship between the expression level of UMOD gene and inflammatory cytokines, which were manifested as the negative correlation between the level of the gene's expression and inflammatory cytokines. That has certain reference value to realize the targeted treatment for essential hypertension through regulated blood pressure conversely in the view of expression level of inflammatory cytokines. PMID- 26617861 TI - Vitronectin significantly influences prognosis in osteosarcoma. AB - Vitronectin (Vn), a multifunctional adhesive protein, is found in association with tumor progression, angiogenesis and metastasis in a variety of (human) tumors. But no studies concerning its correlation to osteosarcoma prognosis were found. Hence, we aimed to investigate the prognostic value of Vitronectin (Vn) in osteosarcoma. Here, we studied the expression of VN in the tumor tissues from 67 patients with osteosarcoma and 20 patients with osteochondroma using immunohistochemistry and estimated the effects of VN expression in osteosarcoma on progression-free survival (PFS) and overall survival (OS) using the Kaplan Meier curve and COX proportional hazards regression model. Increased expression of VN in osteosarcoma tissue compared to no VN expression in osteochondroma tissue was shown in immunohistochemical assay. No associations were observed between VN expression and osteosarcoma patients' gender (P = 0.675), age (P = 0.813), tumor size (P = 0.436), histologic subtype (P = 0.0.543) or tumor location (P = 0.456). Univariate survival analysis demonstrated significant correlations of high VN expression with shorter PFS (P = 0.002) and OS (P = 0.001); multivariate survival analysis revealed high VN expression as a significant independent prognostic indicator for shorter PFS (HR 2.788, P = 0.003) and OS (HR2.817, P = 0.003). In conclusion, the high expression of VN in tumor cells independently indicated poor clinical prognosis in patients with osteosarcoma, other than large tumor size and non-neoadjuvant chemoradiotherapy, suggesting that VN may serve as a potential therapeutic target in osteosarcoma. PMID- 26617862 TI - MUM-1 expression differentiates AITL with HRS-like cells from cHL. AB - MUM1 is a member of the interferon regulatory factor family of transcription factors. It is normally expressed in plasma cells, late B cells, and activated T cells, and has been described in several B-cell malignancies and some T-cell neoplasms. The aim of our study was to evaluate the role of MUM-1/IRF4 protein in differentiating angioimmunoblastic T cell lymphoma (AITL) with Hodgkin/Reed Sternberg (HRS)-like cells from cHL. We identified 12 cases of AITL with HRS-like cells and 24 cases of cHL from March 2013 to November 2014. IHC for MUM-1/IRF4 protein was performed on the tissue of these cases and some relevant positive and negative controls. MUM-1 was expressed in HRS-like cells and some neoplastic T cells in AITL with HRS-like cells (12/12, 100%) and formed the rosettes around the HRS-like cells (12/12, 100%), expressed in HRS cells in classic Hodgkin Lymphoma (cHL) (24/24, 100%) and just one case formed rosettes around the HRS cells (1/24, 4.2%). Based on the results, MUM-1 could be a useful marker for the differential diagnosis between AITL with HRS-like cells and cHL. PMID- 26617863 TI - Diagnostic value of serum Golgi protein 73 for HBV-related primary hepatic carcinoma. AB - BACKGROUND: Alpha-fetoprotein (AFP) levels are routinely used for diagnosis and monitoring of hepatic diseases, but it has a limited value. Golgi protein 73 (GP73) has been suggested as a new marker for hepatic diseases. OBJECTIVE: To explore the clinical value of serum GP73 in different diseases associated with hepatitis B virus (HBV) infection. METHOD: Between January 2010 and August 2014, serum samples from 88 patients with chronic hepatitis B (CHB), 78 patients with HBV-related liver cirrhosis (LC), and 194 patients with HBV-related primary hepatic cancer (PHC) were collected. Serum samples from 30 healthy volunteers were used as controls. ELISA and microparticle enzyme immunoassay were used to measure serum GP73 and AFP levels. Receiver operating characteristic (ROC) curves were used to analyze the diagnostic value of serum GP73 and AFP for PHC. RESULTS: For the diagnosis of PHC, GP73 showed a sensitivity of 65.5% and specificity of 66.3%, while AFP levels showed sensitivity of 64.4% and specificity of 76.5%. Serial testing (both tests are positive) could increase the specificity (sensitivity of 45.9% and specificity of 85.5%) while parallel testing (any single positive test result) could increase the sensitivity (sensitivity of 84.0% and specificity of 57.2%). Serum GP73 and AFP levels were significantly different between Child-Pugh grades (P<0.001 for GP73 and P=0.044 for AFP). Significant differences in serum GP73 and AFP were found between TNM stages (all P<0.001). CONCLUSION: Serum GP73 had limited diagnostic value for HBV-related PHC. The combined use of serum GP73 and AFP levels improved the diagnostic efficacy. PMID- 26617864 TI - Clinicopathological significance of CD206-positive macrophages in patients with acute tubulointerstitial disease. AB - OBJECTIVE: To investigate the clinicopathological significance of CD206-positive macrophage expression in patients with acute tubulointerstitial disease, including acute tubular necrosis (ATN) and acute interstitial nephritis (AIN). METHODS: Renal tissue samples from patients with ATN (n=10), AIN (n=10), and minimal change disease (MCD, as disease control, n=8) as well as tissue from normal control kidneys (negative control, n=3) were included in this study. The expression of CD206 and CD68 in renal tissues was detected by immunohistochemistry or immunofluorescence. RESULTS: CD206-positive cells accumulated in areas around damaged tubular cells and regenerating tubules. Compared with AIN patients, ATN patients had lower serum albumin, lower proteinuria, lower urinary osmolality and higher plasma hemoglobin, (P=0.002; P=0.01; P<0.001; P=0.002, respectively). CD206-positive cells could also be observed in the tubular basement membrane and tubule lumen. Some CD206-positive cells infiltrated into the tubular cells in patients with AIN. Compared to patients with ATN, patients with AIN had more CD206-positive cells (P=0.005). In the ATN patients, there were more CD206-positive cells in ischemic tissue. CD206 positive cells were negatively correlated with hemoglobin (r=-0.565, P=0.009) and positively correlated with serum albumin (r=0.496, P=0.026), urinary osmolality (r=0.567, P=0.009) and proteinuria (r=0.460, P=0.041). There was no correlation between CD206-positive cells and eGFR. CONCLUSION: CD206-positive macrophages are involved in the pathogenesis of acute tubular necrosis and acute interstitial nephritis. PMID- 26617865 TI - Expression of pyruvate kinase M2 in human colorectal cancer and its prognostic value. AB - Reprogrammed metabolism is a hallmark of cancer cells. Pyruvate kinase isozyme type M2 (PKM2), which is frequently up-regulated in multiple human malignancies, has been demonstrated to play a critical function in glucose metabolism, gene transcription and tumorigenesis. However, limited knowledge is known about the expression pattern and prognostic value of PKM2 in colorectal cancer (CRC). In this study, we first observed that the mRNA level of PKM2 is commonly up regulated in CRC tissues compared with their normal counterparts as demonstrated by data derived from Oncomine database. Similar results were also found in 32 paired CRC tumor and non-tumor specimens in our cohort and 4 CRC cell lines. Furthermore, by a large scale of immunohistochemical analysis in a tissue microarray containing 345 cases of CRC specimens, we demonstrated that the protein expression of PKM2 expression is up-regulated in 79.4% (274/345) samples detected and elevated PKM2 expression is closely correlated with enhanced TNM stage and higher serum CEA level. Meanwhile, Kaplan-Meier survival analysis showed that CRC patients with a higher PKM2 expression have a poorer clinical outcome than those with a lower PKM2 expression. Multivariate Cox regression analysis revealed that PKM2 and TNM stage are two independent prognostic factors for overall survival rate of CRC patients. Taken together, our studies reveal the prognostic value of PKM2 in CRC and support that PKM2 may act as a molecular target for CRC treatment. PMID- 26617866 TI - Solid pseudopapillary neoplasms of the pancreas: clinical analysis of 45 cases. AB - AIMS: This study investigated the clinicopathological features and surgical management of solid pseudopapillary neoplasms (SPNs) at a single institution in China. METHODS: We investigated 45 patients who underwent surgery for pathologically confirmed SPNs between 1996 and 2014. RESULTS: The 45 cases included 44 female and 1 male patients, and the average age was 32.2 years. The tumor was located in the body and/or tail in 33 patients, the head in 9 patients and the neck in 3 patients. The median tumor size was 6.3 cm (range 1.5 to 16). All 45 patients had curative resections including 29 distal pancreatectomies, 9 pancreaticoduodenectomy, 5 central pancreatectomy and 2 enucleation. 2 patients required superior mesenteric vein resection due to local tumor invasion. Eight patients had malignant tumors. Ki-67 was detected positive in 5 patients with malignant potential. After a median follow-up of 51.7 months, one patient with malignant SPN had evidence of tumor recurrence. CONCLUSION: SPN is an infrequent tumor, typically affect young women with low malignant potential. Surgical resection is warranted even in the presence of local invasion or metastases as patients demonstrate excellent long-term survival. Positive immunoreactivity for Ki-67 may predict the malignant potential and poor outcome of SPNs. PMID- 26617867 TI - Prognostic significance of HOXD13 expression in human breast cancer. AB - Homeobox protein Hox-D13 has been recognized as a tumor suppressor in pancreatic cancer. To evaluate the function of HOXD13 in invasive breast cancer pathogenesis, we examined HOXD13 expression in 434 breast cancer tissues and 230 their counterpart normal breast tissues by immunohistochemistry using a tissue microarray (TMA). The association between HOXD13 expression and clinicopathological factors was analyzed by use of Chi-square test. Kaplan-Meier survival curves and log-rank tests were applied to analyze the survival status. Cox regression was applied for multivariate analysis of prognosis. We found that low HOXD13 expression accounts for 84.3% in breast cancer tissues. Low HOXD13 expression was significantly associated with large tumor size (P=0.038) and positive lymph node metastasis (LNM) (P=0.026). In Kaplan-Meier survival curves and log-rank tests, the patients with HOXD13-negative breast cancer showed significantly poorer outcomes (69.867 +/- 1.058 months) in terms of overall survival (OS) than positive-HOXD13-expression patients (76.248 +/- 1.069 months) (P=0.003). And in multivariate analysis, low level of HOXD13 expression was a significant unfavorable prognostic factor. So we conclude that down-regulation of HOXD13 might be a potentially useful prognostic marker for patients with breast cancer. PMID- 26617868 TI - Long non-coding RNA HOTTIP is up-regulated and associated with poor prognosis in patients with osteosarcoma. AB - Long non-coding RNAs (lncRNAs) have been shown to play key roles in cancer development and progression. In this study, we focused on lncRNA HOTTIP and investigated its expression pattern, clinical significance, and biological function in osteosarcoma (OS). In the present study, lncRNA HOTTIP expression in OS tissues was examined and its correlation with clinicopathological features and patient prognosis was analyzed. In vitro assays were performed to understand the biological roles of lncRNA HOTTIP in OS progression. In the study, we found that HOTTIP expression was up-regulated in OS tissues, and correlated with advanced clinical stage and distant metastasis. OS patients with high HOTTIP expression level had poorer overall survival than those with low HOTTIP expression. Multivariable Cox proportional hazards regression analysis suggested that increased HOTTIP expression was an independent prognostic factor of overall survival in OS patients. Moreover, the results of in vitro assays showed that the suppression of HOTTIP in OS cells significantly reduced cell proliferation, migration and invasion ability. Our study demonstrated that lncRNA HOTTIP play critical roles in OS progression and could represent a novel prognostic marker and potential therapeutic target in OS patients. PMID- 26617869 TI - Increased WNT6 expression in tumor cells predicts unfavorable survival in esophageal squamous cell carcinoma patients. AB - WNT proteins are a family of secreted, cysteine-rich proteins containing 19 members. Signaling through WNT proteins is reported to be involved in carcinogenesis and cancer progression of gastrointestinal tumors, such as gastric cancer and colon cancer. The expression status of WNT6 in ESCCs and their clinico prognostic significances remain to be elucidated. In this study, One-hundred and thirty-six patients with ESCC were explored. Paraffin-embedded tumor sections were stained with WNT6 antibody. The correlations between WNT6 expression and survival parameters were analyzed. The overall frequency of WNT6 over-expression was 50.7% (69/136) of advanced EC patients. For DMS and OS, over-expression of WNT6 remained the independent factor for worse prognosis (hazard ratio (HR), 2.425; 95% CI, 1.631-3.605; P < 0.001 for OS and HR, 2.238; 95% CI, 1.507-3.323; P < 0.001 for DMS, respectively). To conclude, our results support the concept that WNT6 may play a role in tumor progression. WNT6 over-expression inversely correlates with the poor long-term survival in ESCC patients. WNT6 can be considered as a predictor for recurrence. PMID- 26617870 TI - High expression of EphB6 protein in tongue squamous cell carcinoma is associated with a poor outcome. AB - EphB6 is a member in the receptor tyrosine kinase Eph family in that its kinase domain contains several alterations in conserved amino acids and is catalytically inactive. Although EphB6 is expressed both in a variety of embryonic and adult tissues, biological functions of this receptor are largely unknown. In this study, we examined the expression of EphB6 protein in 54 of tissue specimens of tongue squamous cell carcinoma by using a specific polyclonal anti-EphB6 antibody. The relationship between expression of EphB6 and clinical pathologic parameters was analyzed. The expression level of EphB6 in carcinoma cells from 34 out of 54 (63%) specimens was no alterative compared with normal squamous cells in same patient. The level of EphB6 protein staining was increased in carcinoma cells in 20 out of 54 (37%) specimens compared with normal squamous cells in same patient. The high-expression of EphB6 was significantly associated with age (P=0.021), tumor TNM stage (P=0.026) and lymph node metastasis (P=0.046). Patients with high expressed EphB6 protein had a high mortality (P=0.057). No significant relationship between expression of EphB6 and sex, tumor grade, HPV infection, relapse and smoke was found. We showed that patients with high expression of EphB6 had a significantly poor overall survival (OS) compared to patients with negative or weak expression (P=0.042). Our results indicated that EphB6 protein may be used as a new marker for prognosis for tongue squamous cell carcinoma. PMID- 26617871 TI - A De novo PAX8 mutation in a Chinese child with congenital thyroid dysgenesis. AB - BACKGROUND: Thyroid dysgenesis (TD) is the most frequent cause of congenital hypothyroidism (CH), but its pathogenesis remains unclear. As a thyroid transcription factor, paired box transcription factor 8 (PAX8) is essential for thyroid organogenesis and development. AIM: To screen PAX8 mutations and characterize the features of these mutations in Chinese TD patients. MATERIALS AND METHODS: Blood samples were collected from 63 TD patients in Shandong Province, China, and genomic DNA was extracted from peripheral blood leukocytes. Exon 3~4 of PAX8 were analyzed by PCR and direct sequencing. RESULTS: Direct sequencing of PAX8 revealed a heterozygous missense mutation (c.155G/C, P.Arg52Pro) in one child with agenesis. Genetic screening of the child's family revealed that the clinically unaffected parents do not carry the mutation, suggesting that the identified sequence change is a de novo mutation. CONCLUSION: We report a heterozygous missense de novo mutation in PAX8 in one out of 63 unrelated Chinese TD patients, showing that the PAX8 mutation rate is very low in TD patients in China. However, de novo mutation and epigenetic mechanisms need to be considered in the future study. PMID- 26617872 TI - High DBC1 (CCAR2) expression in gallbladder carcinoma is associated with favorable clinicopathological factors. AB - There have been several studies on gallbladder carcinogenesis, and mutations of the KRAS, TP53, and CDKN2A genes have been reported in gallbladder carcinoma. The DBC1 gene (deleted in breast cancer 1) was initially cloned from region 8p21, which was homozygously deleted in breast cancer. DBC1 has been implicated in cancer cell proliferation and death. The functional role of DBC1 in normal cells and the role of DBC1 loss in cancer are not entirely clear. And DBC1 expression and its clinical implications in gallbladder carcinoma have yet to be thoroughly elucidated. Therefore, we evaluated DBC1 expression in 104 gallbladder carcinoma tissues in relation to survival and other prognostic factors via immunohistochemical analysis. DBC1 expression was divided into two categories: high DBC1 expression was observed in 32/104 cases (30.8%) and low expression in 72/104 cases (69.2%). High DBC1 expression correlated significantly with favorable clinicopathologic variables. Furthermore, in survival analysis, the high-DBC1 expression group showed a better survival rate compared to the low-DBC1 expression group. In conclusion, high DBC1 expression is associated with several favorable clinicopathologic factors in gallbladder carcinoma. These findings suggest that loss of DBC1 expression plays a role in tumorigenesis and tumor progression in gallbladder carcinoma. PMID- 26617873 TI - Decreased expression of microRNA-20a promotes tumor progression and predicts poor prognosis of cutaneous squamous cell carcinoma. AB - BACKGROUND: MicroRNA-20a (miRNA-20a or miR-20a) plays a key role in tumorigenesis and progression. But the prognostic value of miR-20a in cutaneous squamous cell carcinoma (CSCC) remains unclear. The aim of this study was to identify the association of miR-20a and the prognosis of CSCC patients. METHODS: The miR-20a expression was detected using quantitative real-time polymerase chain reaction (qRT-PCR) in 152 CSCC tissues and matched adjacent normal tissues. Kaplan-Meier and Cox regression analysis were utilized to determine the association of miR-20a with overall survival as well as the prognosis of CSCC patients. RESULTS: The expression of miR-20a was lower in CSCC tissues compared with adjacent normal tissues (P=0.000). Moreover, the expression of miR-20a was closely correlated with TNM stage (P=0.013). Kaplan-Meier analysis showed that patients with low miR 20a expression had significantly poorer overall survival than those with high miR 20a expression (P<0.05). Multivariate analysis revealed that miR-20a expression (P=0.001, HR=3.262, 95% CI: 1.635-6.520) could influence the prognosis and might be an independent prognostic predictor in CSCC. CONCLUSIONS: Our results indicated that low miR-20a expression was associated with tumor stage of CSCC and suggested that miR-20a expression would be a novel biomarker for predicting clinical outcomes in CSCC patients. The inhibition of miR-20a might even become a new therapeutic method for the treatment of CSCC. PMID- 26617874 TI - Down-regulation of PAX6 by promoter methylation is associated with poor prognosis in non small cell lung cancer. AB - BACKGROUND: Promoter methylation is an alternative mechanism of gene silencing in human tumorigenesis. Although a number of methylated genes have been found in non small cell lung cancer (NSCLC), useful methylation markers for early prognostic evaluation of NSCLC remain largely unknown. METHODS: Using methylation-specific PCR (MSP), we examined promoter methylation status of PAX6 gene, and explored their association with clinical features in NSCLC via chi-square test. NSCLC patient survival was assessed by Kaplan-Meier analyses and a Cox proportional hazard model was employed for multivariate analyses. RESULTS: The methylation level of PAX6 gene was higher in tumor tissues than that in normal tissues. In addition, PAX6 promoter methylation showed a very significant correlation with differentiation (P = 0.002), distant metastasis (P = 0.024), and TNM stage (P = 0.002). PAX6 gene promoter hyper-methylation was found to be significantly associated with poor overall survival (P = 0.018) and to serve as an independent marker for prognosis using multivariate Cox regression analysis (HR: 2.254, 95% CI: 1.088-4.667, P = 0.029). CONCLUSION: We found that PAX6 gene was specifically methylated in NSCLC, and demonstrated the effect of promoter methylation of PAX6 gene on clinical outcome in NSCLC, indicating the methylated PAX6 may be useful biomarkers for prognostic evaluation in NSCLC. PMID- 26617875 TI - Association of long non-coding RNA HOTTIP with progression and prognosis in colorectal cancer. AB - Long non-coding RNA (lncRNA) has an important role in carcinoma progression and prognosis. However, little is known about the pathological role of lncRNA HOTTIP (HOXA transcript at the distal tip) in colorectal cancer (CRC) patients. This study attempted to investigate the association of lncRNA HOTTIP expression with progression and prognosis in CRC patients. LncRNA HOTTIP expression was measured in 156 CRC tissues and 21 adjacent non-malignant tissues using qRT-PCR. In present study, our results indicated that lncRNA HOTTIP was highly expressed in CRC compared with adjacent non-malignant tissues (P<0.001), and positively correlated with T stage (T1-2 vs. T3-4, P = 0.001), clinical stage (I-II stages vs. III-IV stages, P = 0.003), and distant metastasis (absent vs. present, P = 0.014) in CRC patients. Furthermore, we also observed that increased lncRNA HOTTIP expression was an unfavorable prognostic factor in CRC patients (P = 0.001), regardless of T stage, distant metastasis and clinical stage. Finally, overexpression of lncRNA HOTTIP was supposed to be an independent poor prognostic factor for CRC patients through multivariate analysis (P = 0.017). In conclusion, lncRNA HOTTIP overexpression maybe serves as an unfavorable prognosis predictor for CRC patients. However, a further larger sample size investigation is needed to support our results. PMID- 26617876 TI - Increased urinary angiotensinogen precedes the onset of albuminuria in normotensive type 2 diabetic patients. AB - It was previously reported that intrarenal renin angiotensin system (RAS) plays a pivotal role in the onset and progression of diabetic nephropathy (DN). Urinary angiotensinogen (UAGT) was employed as a special index of the intrarenal RAS status and enhanced significantly at a very early stage of chronic kidney disease and type 1 diabetes. On the basis of these findings, the present study was performed to test the hypothesis that UAGT levels are increase even before the development of DN in type 2 diabetic patients without hypertension. 102 patients with type 2 diabetes mellitus (T2DM) and 18 healthy volunteers were studied cross sectionally. Clinical data were collected and morning spot urine samples were obtained from all participants. UAGT levels were detected by an enzyme-linked immunosorbent assay (ELISA). As a result, UAGT to creatinine ratio (UAGT/Cr) was significantly enhanced in T2DM patients before the appearance of urinary albumin (UALB) and further increased to a greater degree in albuminuric patients. UAGT/Cr levels were positively correlated with Log (UALB to creatinine ratio) and diastolic blood pressure, but negatively correlated with estimated glomerular filtration rate. These data indicate that elevated UAGT levels precede the onset of albuminuria in normotensive T2DM patients. UAGT might potentially serve as an early marker to determine intrarenal RAS activity and predict progressive kidney disease in T2DM patients without hypertension. PMID- 26617877 TI - Effect of fosinopril on chemerin and VEGF expression in diabetic nephropathy rats. AB - As the most common and severe complication of diabetes, diabetic nephropathy (DN) has been known to be related with angiotensin converting enzyme inhibitor (ACEI), which can reduce proteinuria and protect renal function. This study analyzed the effect of ACEI analog-fosinopril-on the expression of chemerin and vascular epithelial growth factor (VEGF), in an attempt to reveal the mechanism of ACEI analog on renal protection. A total of 45 SD rats were induced by sreptozotocin for diabetes and were given fosinopril via intragastric cannulation for 12 weeks. After sacrifice, serum and renal chemerin and VEGF contents were quantified by enzyme linked immunosorbent assay (ELISA) and Western blot method, in addition to biochemical laboratory examinations. In diabetic model rats, blood glucose, creatinine, urea nitrogen, 24-hour urinary protein, chemerin and VEGF protein contents were all significantly elevated when compared to those in control group (P<0.05). After fosinopril treatment, blood creatinine, urea nitrogen, 24-hour urinary protein, Chemerin and VEGF protein concentrations were significantly depressed (P<0.05 compared to model group). Positive relationships existed between renal chemerin, VEGF and urea protein levels. Fosinopril may protect renal tissues in diabetes by suppressing chemerin and VEGF protein expression. PMID- 26617878 TI - Expression of vascular endothelial growth factor (VEGF) under hypoxia in placenta with intrahepatic cholestasis of pregnancy and its clinically pathological significance. AB - The expression of vascular endothelial growth factor (VEGF) under hypoxia in the placenta with intrahepatic cholestasis of pregnancy (ICP) was observed, and mechanisms of ICP fetal distress were discussed. METHODS: Different culturing times were established in hypoxia incubator, and protein expressions of VEGF in placental tissue were observed using immunohistochemical S-P method. RESULTS: After 4 h hypoxic culture, VEGF protein expression in ICP group was higher than the normal group with significant difference (P < 0.05). With the extension of hypoxic exposure, VEGF protein expression in both groups was suppressed, but no distinction in-between. Regression analyses indicated a noticeable effect of CG on VEGF expression, the higher the CG was, the lower the VEGF protein expression was (P < 0.05). CONCLUSIONS: Short term hypoxia induces up-regulation of VEGF expression in ICP placenta, and this adaptive change is probably a protective mechanism of fetus in ICP. PMID- 26617879 TI - Over-expression of lncRNA DANCR is associated with advanced tumor progression and poor prognosis in patients with colorectal cancer. AB - Despite advances made in the diagnosis and treatment of human colorectal cancer (CRC), the long-term survival for CRC remains poor. Long non-coding RNA anti differentiation ncRNA (lncRNA DANCR) was identified to be involved in carcinogenesis of hepatocellular carcinoma. While its expression in CRC and potential role in tumor progression is still unknown. In the present study, we investigated the expression level of lncRNA DANCR as well as its association with CRC progression and prognosis. The expression of lncRNA DANCR was detected by quantitative real-time PCR (qRT-PCR) in 104 CRC specimens. The prognostic value of lncRNA DANCR was further analysis. Our results showed that lncRNA DANCR expression was increased in CRC tissues compared with that in adjacent normal tissues (P<0.05). In addition, tumors with high lncRNA DANCR expression was correlated with TNM stage, histologic grade, and lymph node metastasis (P<0.05). Kaplan-Meier analysis showed that patients with high lncRNA DANCR expression had a shorter overall survival (OS) and disease-free survival (DFS) compared with the low lncRNA DANCR expression group (P<0.05). Moreover, in a multivariate Cox model, our results showed that lncRNA DANCR expression was an independent poor prognostic factor for both OS and DFS in CRC. Our data indicated that lncRNA DANCR expression might be a novel potential biomarker for CRC prognosis. PMID- 26617880 TI - TERT promoter mutated WHO grades II and III gliomas are located preferentially in the frontal lobe and avoid the midline. AB - The promoter region of telomerase reverse transcriptase (TERTp) and isocitrate dehydrogenase (IDH) have been regarded as biomarkers with distinct clinical and phenotypic features. Investigated the possible correlations between tumor location and genetic alterations would enhance our understanding of gliomagenesis and heterogeneity of glioma. We examined mutations of TERTp and IDH by direct sequencing and fluorescence in-situ hybridization in a cohort of 225 grades II and III diffuse gliomas. Correlation analysis between molecular markers and tumor locations was performed by Chi-square tests/Fisher's exact test and multivariate logistic regression analysis. We found gliomas in frontal lobe showed higher frequency of TERTp mutation (P=0.0337) and simultaneously mutations of IDH and TERTp (IDH (mut)-TERTp(mut)) (P=0.0281) than frequency of biomarkers mutation of tumors in no-Frontal lobes, while lower frequency of TERTp mutation (P<0.0001) and simultaneously wild type of IDH and TERTp (IDH (wt)-TERTp(wt)) (P<0.0001) in midline than no-midline lobes. Logistic regression analysis indicated that locations of tumors associated with TERTp mutation (OR=0.540, 95% CI 0.324-0.900, P=0.018) and status of combinations of IDH and TERTp (IDH (mut)-TERTp (mut) vs. IDH (wt)-TERTp (wt) OR=0.162, 95% CI 0.075-0.350, P<0.001). In conclusion, grades II and III gliomas harboring TERTp mutation were located preferentially in the frontal lobe and rarely in midline. Association of IDH-TERTp status and tumor location suggests their potential values in molecular classification of grades II and III gliomas. PMID- 26617881 TI - Decrease in circulating myeloid dendritic cell precursors in patients with intracranial large artery atherosclerosis. AB - Intracranial large artery atherosclerosis (ILAA) is a major cause of ischemic cerebrovascular disease. The aim of this study was to investigate whether the levels of circulating dendritic cell precursors (DCP) could reflect the severity of intracranial large artery atherosclerosis (ILAA). For this purpose, a series of angiography were taken to determine the severity and extent of coronary artery and intracranial large artery stenosis, and flow cytometry were taken to determine the levels of circulating mDC precursors and pDC precursors in patients with severe intracranial large artery atherosclerosis (ILAA) (n = 101) and mild intracranial large artery atherosclerosis (ILAA) (n = 123) according to the angiography. Circulating mDC precursors were lower in patients with severe intracranial large artery atherosclerosis (ILAA) than in mild intracranial large artery atherosclerosis (ILAA) (P < 0.05), but circulating pDC precursors were not significant differences (P > 0.05). According to these data, circulating mDC precursors could predict the severity of ILAA, which also could be able to reflect the severity of ILAA. PMID- 26617882 TI - Curcumin prevents the non-alcoholic fatty hepatitis via mitochondria protection and apoptosis reduction. AB - BACKGROUND: Non-alcoholic fatty hepatitis (NASH) is highly prevalent, mitochondria damage is the main pathophysiological characteristic of NASH. However, treatment for mitochondria damage is rarely reported. METHODS: NASH model was established in rats, the protective effects of curcumin were evaluated by histological observation; structure and function assessments of mitochondria; and apoptotic genes expression. RESULTS: NASH rats treated with curcumin displayed relatively slight liver damage when compared with NASH livers. The average mitochondrial length and width of NASH (12.0 +/- 3.2 and 5.1 +/- 1.1 micrometers) were significantly longer than that of normal (6.2 +/- 2.1 and 2.1 +/- 1.5 micrometers) and NASH treated with curcumin (7.4 +/- 1.2 and 3.2 +/- 1.5 micrometers) rats. The average malondialdehyde (MDA) and 4-hydroxy nonyl alcohol (HNE) levels in liver homogenates of NASH rats (4.23 +/- 0.22 and 19.23 +/- 2.3 nmol/Ml) were significantly higher than these in normal (1.32 +/- 0.12 and 3.52 +/- 0.43 nmol/mL) and NASH treated with curcumin (1.74 +/- 0.11 and 4.66 +/- 0.99 nmol/mL) rats. The expression levels of CytC, Casp3 and Casp8 of the NASH livers were significantly higher than normal and NASH treated with curcumin rats livers. CONCLUSION: Our data demonstrated that curcumin prevents the NASH by mitochondria protection and apoptosis reduction and provided a possible novel treatment for NASH. PMID- 26617884 TI - Radiological score for hemorrhage in the patients with portal hypertension. AB - GOAL: To analyze the risk factors from radiological indices for hemorrhage in the patients with portal hypertension and weight risk factors. METHOD: We retrospectively analyzed all cases of portal hypertension with hepatitis B from June 2008 to June 2014 in Nanjing Drum Tower hospital. Patients with hepatocellular carcinoma, portal vein thrombosis, or portal hypertension with other causes, such as autoimmune hepatitis, pancreatitis, or hematological diseases were excluded. RESULTS: Ninety-eight patients were recruited and divided into hemorrhage and non-hemorrhage groups. There were no statistical differences in clinical indexes such as age, prothrombin time, serum albumin, serum creatinine, serum sodium, hemameba, and blood platelet count. However, the differences were statistically significant in total bilirubin, hemoglobin, and liver function with the p values of 0.023, 0.000, and 0.039 respectively. For radiological indices, hemorrhage was correlated with diameter of inferior mesenteric vein (P=0.0528), posterior gastric vein (P=0.0283), and esophageal varices scores (P=0.0221). Logistic procedure was used to construct the model with stepwise selection and finally inferior mesenteric vein, posterior gastric vein, esophageal varices, and short gastric vein were enrolled into the model. These veins were scored according to the diameters and the rates of hemorrhage were increased with the score. We then validated the model with 26 patents from July 2014 to December 2014. The AUC value was 0.8849 in ROC curves for this radiological model. CONCLUSIONS: A risk model was constructed including inferior mesenteric vein, esophageal varices, posterior gastric vein, and short gastric vein. This radiological scoring model may be a valuable indicator for hemorrhage of portal hypertension. PMID- 26617883 TI - High CD4+ T cell density is associated with poor prognosis in patients with non muscle-invasive bladder cancer. AB - PURPOSE: The aim of this study was to investigate the clinical significance of CD4(+) T cells in non-muscle-invasive bladder cancer (NMIBC) tissues in situ. METHODS: Immunohistochemistry was used to examine the distribution of CD4(+) T cells in 131 NMIBC tissues. Kaplan-Meier analysis and Cox proportional hazards regression models were applied to estimate overall survival (OS) and recurrence free survival (RFS). RESULTS: NMIBC patients were divided into two groups based on the median frequency of CD4(+) T cells (median, 1/*400 high resolution). On univariate analysis, CD4(+) T cell density was inversely associated with overall survival (P = 0.01). In those patients with high CD4(+) T density, 5-year OS rates was only 77%, compared with 86% in those with low density, respectively. Although CD4(+) T cell density showed no prognostic significance for RFS (P = 0.36), 5-year RFS rates of patients with high CD4(+) T density (58%) was lower than those of patients with low CD4(+) T density (65%, respectively). By multivariate analysis, tumor infiltrating CD4(+) T cell density emerged as an independent prognostic factor for OS (HR, 2.75; P = 0.004). In addition, no association was found between CD4(+) T cell density and any clinicopathological variables (P > 0.05). CONCLUSION: Our findings suggest that CD4(+) T cells could potentially serve as a poor prognostic marker for patients with NMIBC. PMID- 26617885 TI - Deep sequencing identifies deregulation of microRNAs involved with vincristine drug-resistance of colon cancer cells. AB - BACKGROUND: Vincristine (VCR) is a chemical that is widely used in tumor therapy. While long-term use can make tumor cells resistant to VCR, the underlying mechanisms of this resistance are still unclear. OBJECTIVE: This study aimed at investigating the role of microRNA (miRNA) in colon cancer drug resistance. METHODS: HCT-8 colon carcinoma cells were cultured and treated with different VCR concentrations to establish an HCT-8/VCR resistant cell line. Whole-genome screens, HiSeq 2500 sequencing, and bioinformatics methods were used to detect and analyze differences in miRNA expression between the drug-resistant HCT-8/VCR cells and non-resistant HCT-8 cells. Differential expression profiles of miRNAs were constructed based on sequencing result. RESULTS: The HCT-8/VCR resistant colon carcinoma cell line was established. With regard to the difference in drug resistance between HCT-8/VCR and HCT-8 cells, 24 miRNAs showed statistically significant differences in their expression (fold change > 4), of which 17 were up-regulated. Seven miRNAs were down-regulated. CONCLUSION: As abnormal expression of miRNAs was associated with VCR resistance of colon carcinoma cells, differences in miRNA expression may play a key role in VCR resistance of colon cancer cells. PMID- 26617886 TI - Genetic polymorphisms in COL18A1 influence the development of osteosarcoma. AB - We conducted a case-control study to investigate the association of COL18A1 D104N polymorphism in the development of osteosarcoma in a Chinese population. Between May 2012 and May 2014, 141 patients with pathologically proven osteosarcoma and 341 were selected into this study. Genotyping of COL18A1 D104N was analyzed using polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). By logistic regression analysis, we found that individuals with the NN genotype of COL18A1 D104N were significantly associated with an increased risk of osteosarcoma when compared with the DD genotype (OR=20.97, 95% CI=2.74-933.42). In dominant model, the NN+DN genotype of COL18A1 D104N had a 1.99 fold risk of osteosarcoma when compared with the DD genotype. Moreover, the NN genotype was correlated with a 20.45 fold risk of osteosarcoma when compared with the DN+DD genotype in recessive model. However, we did not find significant interaction between COL18A1 D104N polymorphism and Enneking stage, histological subtype, tumor metastasis and tumor location of patients with osteosarcoma. In conclusion, our study suggests that the homozygous DN and NN genotypes of COL18A1 D104N were associated with the risk of osteosarcoma. PMID- 26617887 TI - Multidrug resistance protein and topoisomerase 2 alpha expression in non-small cell lung cancer are related with brain metastasis postoperatively. AB - The aim of this study was to investigate association between expressions of multidrug resistance protein (MRP) and topoisomerase 2 alpha expression in non small cell lung cancer (TOP2A) and brain metastasis operatively. The expression of MRP and TOP2A were performed using immunohistochemistry (IHC) staining, and the results were analyzed in correlation with clinicopathological data. A total of 286 NSCLC patients who underwent curative surgery between 2007 and 2013 were enrolled in this study. Positive expression of MRP and TOP2A were 62.2% and 37.8%. MRP positive expression in NSCLC was significantly correlated with tumor cell differentiation (P=0.028). TOP2A expression was significantly associated with patients' smoking status, tumor histological type (P<0.05). The positive MRP group had significantly inferior survival rates for 2-year BMFS than did the negative MRP group (79.0% vs. 93.4%, P=0.003) by the Kaplan-Meier method and a log-rank test. Similarly, the positive TOP2A expression was inversely correlated with 2-year BMFS (84.2% vs. 93.4%, P=0.030). Multivariate analysis showed that gender, MRP expression and TOP2A expression were independent prognostic factors for BMFS (P<0.05). Positive expressions of MRP and TOP2A in the tumor tissue are associated with increased risk of developing brain metastases in NSCLC. PMID- 26617888 TI - Pattern of primary tumors and tumor-like lesions of bone in children: retrospective survey of biopsy results. AB - BACKGROUND: Although primary bone tumors are relatively uncommon, they constitute the most important tumors in patients less than 20 years. We aimed to determine the frequencies of primary bone tumors and tumor-like lesions of bone and the anatomical sites of their occurrence. METHODS: A retrospective review of histopathology reports of all bone specimens received in a private pathology laboratory in Istanbul between 2009 and 2015. RESULTS: A total of 57 patients (aged 5 to 18 years) with a mean of 13.12 years were studied. Thirty five patients (61.4%) were males and 22 (38.6%) were females. Fifty five (94.4%) of the tumors were benign. Osteochondroma was the commonest tumor accounting for 31 cases (54.3%) followed by osteoid osteoma, 9 cases (15.7%). Chondrosarcoma observed in two patients and Ewing sarcoma in one patient as malignant tumors. Of the 57 bone tumors 13 (22.8%) occurred in the upper extremities, while 44 (77.2%) were in the lower extremities. Proximal humerus was the most commonly involved site in upper extremity tumors, with osteochondromas representing the most frequent type of tumor (4 patients; 7%). In the lower extremities again osteochondromas were the most common type of tumor (8 cases, 14%), with the femur being the most common site of involvement (18 patients, 31.5%). Of the patients with tumor-like lesions; four patients had fibrous dysplasia, 4 patients had non ossified fibromas, 4 patients had simple bone cysts and 3 had aneurismal bone cyst. CONCLUSION: This study showed that primary bone tumors were mainly benign, settled predominantly in the lower extremities mostly in the femur with a male preponderance. Osteochondroma was the most common benign bone tumor. We didn't observed osteosarcoma, which is the most frequent malignant bone tumor. PMID- 26617889 TI - Expression profile of mucin-associated sialyl-Tn antigen in Chinese patients with different colorectal lesions (adenomas, carcinomas). AB - BACKGROUND: The sialyl-Tn (sTn) antigen is a mucin-associated carbohydrate antigen expressed by numerous human carcinomas, and is also claimed to be a prognostic factor in colorectal cancer. But the associations between sTn and colorectal cancer remain elusive and controversial. Here, we investigated the expression profile of sTn antigen in a series of human colorectal tissue samples including normal colon, colorectal adenomas, and colorectal carcinomas (CRCs), with an aim to analyzing whether sTn plays a role in the progression and development of Chinese patients with CRCs. METHODS: Immunohistochemical staining of sTn antigen was performed in formalin-fixed, paraffin-embedded colonic sections from 4 healthy controls, 44 patients with colorectal adenomas, and 186 patients with primary CRCs. RESULTS: No sTn antigen was detected in normal colonic tissues. There were 41 of 44 patients with colorectal adenomas (93.2%), and 141 of 186 patients with CRCs (75.8%) found to express sTn antigen. The patterns of sTn localization were different in adenomas and carcinomas of colonic tissues. Colorectal adenomas showed predominant supranuclear distribution of sTn antigen, while carcinomas revealed apical membrane, mucin droplet and diffuse cytoplasmic localization. Notably, sTn was significantly associated with the degree of differentiation (P = 0.006) and perineural invasion (P = 0.041) of the tumors, but was independent of age, gender, tumor location, depth of penetration, status of lymph nodes, lymphovascular invasion and TNM stage. CONCLUSIONS: These results indicate that sTn may play a role in initiating colorectal carcinogenesis and promoting tumor progression. Determination of sTn expression and localization may assist in evaluating malignant status of colorectal lesions. PMID- 26617890 TI - Prevalence of the frequency of JAK2 (V617F) mutation in different myeloproliferative disorders in Egyptian patients. AB - BACKGROUND AND OBJECTIVES: Detection of chromosomal abnormalities in myeloproliferative disorders is important for proper diagnosis of these disorders. This study has investigated the presence of JAK2 mutation (V617F) in Egyptian patients with myeloproliferative disorders referred to National Cancer institute, Cairo University. METHODS: The study involved 110 cases of Philadelphia negative Myeloproliferative diseases (MPDs), 70 cases with Polycythemia Vera (PV), 24 cases with Essential Thrombocytosis (ET) and 16 cases with Idiopathic Myelofibrosis (IMF) and 20 cases as a control group which represented as; (10 cases with secondary erythrocytosis, 1 case with reactive thrombocytosis, 4 cases as normal control and 5 as Philadelphia positive Chronic Myeloid Leukemia cases), they were collected from National Cancer Institute (NCI) over 3 years. We used ARMS technique for mutation detection. RESULTS: The frequency of the V617F JAK2 mutation was highest in patients with PV where 56 out of 70 cases (80%) carried the mutation, followed by ET with 6 of 24 (25) and IMF with 2 of 16 (12.5%) . None of the cases with secondary Erythrocytosis, reactive thrombocytosis, the normal controls or Philadelphia positive CML cases carried the mutation. CONCLUSIONS: Our results are concordant with international published results for detection of this mutation. It is unequivocal now that V617F is met in many MPDs especially PRV. Finding this mutation in those patients is thought to have a big impact on the diagnosis and treatment of these disorders. PMID- 26617891 TI - Prognosis value of MGMT promoter methylation for patients with lung cancer: a meta-analysis. AB - The role of MGMT promoter methylation in lung cancer (LC) remains controversial. To clarify the association of MGMT promoter methylation with survival in LC, we performed a meta-analysis of the literature with meta-analysis. Trials were selected for further analysis if they provided an independent assessment of MGMT promoter methylation in LC and reported the survival data in the context of MGMT promoter methylation status. Subgroup analyses were conducted according to the study characteristic. A total of 9 trials, which comprised 859 patients, were included in the meta-analysis. The combined hazard ratio (HR) of 1.27 [95% CI 0.88-1.82; test for heterogeneity P = 0.027] suggests that MGMT promoter methylation has none impact on patient survival. In Stage I-III or younger populations, a significant association was found for MGMT promoter methylation in the prognosis of LC. In addition, the heterogeneity disappeared when the analysis was restricted to Stage I-III LC. Our analysis indicates that MGMT promoter methylation in stage I-III or younger patients was significantly correlated with wore survival. Further study is needed to determine these specific subgroups of LC patients. PMID- 26617892 TI - Application of IMF screws to assist internal rigid fixation of jaw fractures: our experiences of 168 cases. AB - Intermaxillary fixation (IMF) screws were first introduced to achieve IMF as a kind of bone borne appliance for jaw fractures in 1989. Because this method can overcome many disadvantages associated with tooth borne appliance, IMF screws have been popularly used for jaw fractures since then. From March 2011 to February 2014, we treated 168 cases with single or multiple jaw fractures by open reduction and a total of 705 IMF screws were intraoperatively applied in all the cases to achieve IMF and maintain dental occlusion as an adjuvant to open reduction. The numbers, implantation sites and complications of IMF screws were retrospectively analyzed. In our experience, we found that IMF screws were important to assist open reduction of jaw fractures but their roles should be objectively assessed and the reliability of open reduction and internal rigid fixation must be emphasized. Much attention should be paid when implanting. PMID- 26617893 TI - Polypoid lesions of the gallbladder: report of 160 cases with special reference to diagnosis and treatment in China. AB - BACKGROUND: The preoperative diagnosis of gallbladder polypoid lesions is difficult, justifying the lack of consensus on the appropriate treatment. OBJECTIVE: The aim of this study was to identify the characteristics of each type of polypoid lesion of the gallbladder and the indications for surgery. METHODS: Between January 1999 and December 2012, clinical data were retrospectively correlated with the histopathologic characteristics of polypoid lesions in 160 patients who underwent cholecystectomy. RESULTS: A total of 160 patients with benign polypoid lesions (including 49 tumor-like lesions and 75 adenomas) and 14 patients with malignant polypoid lesions (including 2 adenocarcinomas and 12 adenomas with malignant changes) were included in this study. One hundred and five (65.6%) of the patients had associated symptoms, and 70 (43.8%) had gallstones. Of the 49 patients with tumor-like lesions, 49 (100%) were correlated with chronic cholecystitis. A total of 72 (83.8%) patients with neoplasms had a single polyp compared with 25 (59.5%) of those with non-neoplastic polyps. The mean age of the patients with malignancy was 59.07 +/- 13.465 years, and 12 (85.7%) of these patients were over 50 years of age. The mean diameters of the benign and malignant polyps were 1.0 +/- 0.77 cm and 2.15 +/- 1.16 cm, respectively. Ten (100%) of the patients with malignancy had polyps of over 1 cm in size, as shown by ultrasound. CONCLUSION: Our findings indicate that tumor like lesions, adenomas, and adenocarcinomas are the most common polypoid lesions of the gallbladder. Cholecystecomy should be done in patients with symptoms. The risk of malignancy is high in patients over 50 years of age; those with polyps with diameters of greater than 10 mm; and those with single polypoid lesions. The remainder of PLG patients without cholecystectomy should be followed up at regular intervals. PMID- 26617894 TI - Association of single nucleotide polymorphisms of DNA repair genes in NER pathway and susceptibility to pancreatic cancer. AB - In our study, we conducted a case-control study to investigate the association of ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, XPA, XPC and DDB2 gene polymorphisms in the risk of pancreatic cancer. Between May 2012 and May 2014, a total of 246 patients with who were newly diagnosed with histopathologically confirmed primary pancreatic cancer and 246 controls were selected into our study. Genotyping of ERCC1 rs3212986 and rs11615, ERCC2 rs13181, ERCC3 rs4150441, ERCC4 rs6498486, ERCC5 rs873601, XPA rs2808668, XPC rs2228000, XPC rs2228001 and DDB2 rs2029298 were analyzed using polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). By conditional logistic regression analysis, individuals carrying with TT genotype of ERCC1 rs3212986 and GG genotype of ERCC2 rs13181 were associated with increased risk of pancreatic cancer when compared with wide-type genotype, and the adjusted ORs (95% CI) were 2.40 (1.29-4.52) and 2.27 (1.26-4.15), respectively. We found that individuals carrying with GT+TT genotype of ERCC1 rs3212986 and TG+GG genotype of ERCC2 rs1318 gene polymorphisms were correlated with higher risk of pancreatic cancer in smokers when compared with non-smokers, and the adjusted ORs (95% CI) were 1.89 (1.05-3.40) and 1.88 (1.06-3.34), respectively. In conclusion, our study suggests that ERCC1 rs3212986 and ERCC2 rs1318 gene polymorphisms contribute to the development of pancreatic cancer, especially in smokers. PMID- 26617895 TI - Serum cytokine, chemokine and hormone levels in Saudi adults with pre-diabetes: a one-year prospective study. AB - Approximately 5-10% of subjects with pre-diabetes eventually progress to diabetes every year. While inflammation is thought to be involved in the development of obesity-related type 2 diabetes mellitus (T2DM), the relation between inflammation and pre-diabetes remains largely unexplored. In this study we examined a comprehensive panel of 10 serum biomarkers involved in overweight and obese subjects with pre-diabetes. A total of 98 subjects (23 males, 75 females) were advised to reduce total intake of fat, increase fiber intake and physical activity. Serum cytokines, MCP and other hormones were assessed by multiplex cytokine profiling. Results show that CRP, IL-6, leptin, IL-10, MCP, resistin, serpin, and TNF-alpha were significantly lower after 12-months than baseline. Serum concentrations of other adipocytokines, including adipsin and leptin were modestly lower in the 12-month follow-up than baseline, but failed to reach statistical significance. Changes in HbA1c was found to be positively correlated with adipsin, CRP, IL-6, IL-10, resistin, serpin, and TNF-alpha. The results suggest that promotion of lifestyle changes for one year among overweight and obese subjects modestly changes several circulating inflammatory biomarkers which maybe favorable in reducing risk for T2DM progression. PMID- 26617896 TI - CCND1 G870A polymorphism is associated with toxicity of methotrexate in childhood acute lymphoblastic leukemia. AB - CCND1 plays a key role in cell cycle progression and may cause methotrexate (MTX) resistance, as well as its cytotoxicity. CCND1 870A variant allele is associated with altered transcripts of this gene. We hypothesized that this polymorphism may contribute to the elimination rate and hepatotoxicity of MTX in childhood acute lymphoblastic leukemia (ALL). We genotyped the CCND1 G870A polymorphism in 125 childhood ALL patients treated with HDMTX. We found no notable associations between G870A polymorphism and the risk of delayed MTX elimination. However, this polymorphism was significantly associated with an increased risk of MTX hepatotoxicity [adjusted odds ratio (OR) = 4.44, 95% confidence interval (CI) = 1.35-14.63 for AG versus GG and adjusted OR = 6.39, 95% CI = 1.82-22.43 for AA versus GG]. Our results indicated that the CCND1 G870A polymorphism may be involved in the hepatotoxicity of MTX and act as a biological marker. PMID- 26617897 TI - Polymorphism within the distal RAD51 gene promoter is associated with colorectal cancer in a Polish population. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers in developed countries. Annually, over one million of new cases in the world are recorded. Majority of CRCs occur sporadically with dominant phenotype of chromosomal instability (CIN). Permanent exposure to DNA damaging agents such as ionizing radiation result in DNA double-stranded breaks, which create favorable conditions for chromosomal aberration to arise. Homologous recombination repair (HRR) is the leading process engaged in maintaining of the genome integrity. RAD51 protein was recognized as crucial in HRR. Single nucleotide polymorphisms are the primary source of genetic variation which presence in the RAD51 promoter region can affect on its expression and consequently modulate HR efficiency. OBJECTIVES: The aim of this study was to analyze the distribution of genotypes and allele frequencies of -4791A/T and -4601A/G RAD51 gene polymorphisms, followed by an assessment of their relationship with the risk of CRC. MATERIAL AND METHODS: The study included 115 patients with confirmed CRC. Control group was consisted of 118 cancer-free individuals with a negative family history. The genotypes were identified by PCR-RFLP method. CONCLUSION: This study revealed statistically significant association between appearance of G/A genotype in position -4601 of RAD51 gene and CRC risk. PMID- 26617898 TI - Relationship between serologic response and clinical symptoms in children with enterovirus 71-infected hand-foot-mouth disease. AB - This study aimed to explore the correlation between clinical symptoms, including rash and fever, and serum antibody reaction to enterovirus 71 (EV71) infection in children hospitalized due to hand-foot-mouth disease (HFMD). From May 2014 to July 2014, a total of 547 children hospitalized due to HFMD in Children's Hospital of Fudan University were enrolled retrospectively. RNA levels of EV71 and CA16 in fecal, serum, and cerebrospinal fluid specimens were measured using quantitative real-time RT-PCR, and EV71-IgM antibody in the serum was detected using immune colloidal gold assays. Of the 547 fecal specimens, 296 were EV71 RNA positive, 109 were CA16 RNA positive, and 8 were positive for both EV71 RNA and CA16 RNA. The total positive rate for either EV71 or CA16 in feces was 72.58% (397/547). Additionally, 544 serum specimens were collected, and 409 were EV71 IgM positive (75.18%). The duration of rash and fever was found to be correlated to the positive rate of serum EV71-IgM, and the positive rate of serum EV71-IgM plus EV71 RNA in feces. The positive rates of serum EV71-IgM and serum EV71-IgM plus EV71 RNA in fecal collected at day 3 of fever were 79.7% and 52.8%, respectively. In conclusion, EV71 and CA16 were found to be the major pathogens responsible for the epidemics of HFMD in children during May to July 2014 in Shanghai, China. There is a close relationship between the positive rate of serum EV71-IgM and the duration of fever and rash. PMID- 26617899 TI - Association of NER pathway gene polymorphisms with susceptibility to laryngeal cancer in a Chinese population. AB - We systematically analyzed the association of nine SNPs of seven key NER pathway genes with the development of laryngeal cancer patients, and investigated whether NER pathway polymorphisms could serve as potential biomarkers for laryngeal cancer risk. 271 patients with pathologically proven laryngeal cancer and 271 control subjects were included in our study. Genotyping of ERCC1 rs11615 and rs2298881, ERCC2 rs13181 and rs50871, ERCC3 rs4150441, ERCC4 rs6498486, ERCC5 rs2094258, XPA rs2808668 and XPC rs2228001 were analyzed by polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). By conditional logistic regression analysis, individuals carrying the TT genotype of ERCC1 rs11615 were correlated with an increased risk of larynx cancer when compared with the CC genotype (OR=1.89, 95% CI=1.07-3.37; P value=0.02). Moreover, individuals with the GG genotype of ERCC2 rs50871 were associated with an elevated risk of larynx cancer when compare with the TT genotype (OR=2.03, 95% CI=1.15-3.63; P value=0.01). We found a significant interaction between ERCC2 rs50871 polymorphism and tobacco smoking in the risk of larynx cancer (P for interaction <0.05). In conclusion, our study showed that ERCC1 rs11615 and ERCC2 rs50871 polymorphisms could influence the risk of larynx cancer in Chinese population, particularly among smokers. PMID- 26617900 TI - Human recombinant-B-type natriuretic peptide protect ventricular function and structure in ST-elevation myocardial infarction. AB - BACKGROUND: ST-elevation myocardial infarction (STEMI) is the most serious clinical type of coronary artery disease (CAD), which will lead to a loss of contractile function asa result of adverse left ventricular (LV) remodeling. Post myocardial infarction remodeling is detrimental to the left ventricular function, which is strongly related to clinical outcome,including heart failure and cardiac death. And our study was designed to assess the efficacy of 72-hour IV infusion of rh-BNP therapy in STEMI patients with or without successful primary PCI, in preventing adverse LV remodeling and preserving LV function. METHODS: 100 patients diagnosed as STEMI combined with acute heart failure (Killip classification >= 2) were recorded. And they were divided into "rh-BNP treatment group" (n=50) and "control group" (n=50). In addition to conventional heart failure therapy, patients in the rh-BNP group received rh-BNP infusion for 72 hours. All patients were followed up at 3 month after discharge. Their medical history was taken, as well as the presence or absence of relevant symptoms. 6 minute walking test, as well as echocardiographic indexes were recorded to evaluate the improvement of cardiac function. RESULTS: The data analysis about demographic comparison, including those related complicated diseases among groups showed no significant difference. After the follow-up, the indicators were all better than baseline among four subgroups (all P<0.001). Results showed that rh BNP was able to significantly reduce the NT-pro BNP levels (P<0.001), decrease LVESD (P<0.01), and increase LVEF (P<0.05). The difference of 6WMT between two groups was significant (P<0.001). According to the classification of 6WMT, the multivariate Cox regression showed that the usage of rh-BNP was an independent predictor for 6WMT (OR 0.478, 95% CI, 0.290-0.787), while it may not for MACE (OR 1.762, 95% CI, 0.793-3.913). CONCLUSIONS: Although the use of rh-BNP was not an independent risk factor in prediction of MACE in our study, the current data still showed that rh-BNP is a useful prognosis factor of 6WMT in the STEMI patients. The protection of ventricular function and structure in STEMI patients is affirmative. PMID- 26617901 TI - Pattern of nodal involvement in papillary thyroid cancer: a challenge of quantitative analysis. AB - INTRODUCTION: Backgrounds of this study were to examine and analyse the relationship among the number of lymph nodes with metastases harvested in central and lateral compartments, the characteristics of tumours and patients, and the recurrences rate. METHODS: A retrospective review of 118 patients treated for a papillary thyroid cancer and underwent to neck dissection, including in all cases both central and lateral compartment, was realised. A quantitative analysis, on this homogeneous cohort of patients, was performed to hypothesize the minimum number of cervical lymph nodes to be necessarily excised in order to obtain an adequate management of these patients. RESULTS: The mean follow-up time was 75.9 months. Five-year overall survival was 96.6%. The correlation among the metastatic lymph node number of the ipsilateral central compartment, isolated or pooled with those of the ipsilateral lateral compartment, age of patient and tumour size revealed a statistical significance (P=0.01); both parameters, tumour size and age, may be considered as dependent predictor variables. CONCLUSION: We suppose, notwithstanding the limited number of patients, that the number of lymph nodes harvested to achieve an optimal cervical dissection may be superior to 8 and 11 in central and lateral compartments, and 6 and 10 in contralateral ones, respectively. Moreover we recommend the bilateral dissection of central nodes compartment in presence of tumour localised in the isthmus. PMID- 26617902 TI - COL8A1 rs13095226 polymorphism shows no association with neovascular age-related macular degeneration or polypoidal choroidal vasculopathy in Chinese subjects. AB - PURPOSE: Age-related macular degeneration (AMD) is the main cause of visual impairment and legal blindness in older individuals. COL8A1 rs13095226 variants have recently been implicated associated with neovascular age-related macular degeneration (nAMD) and Polypoidal Choroidal Vasculopathy (PCV) in American studies. The aim of this study was to investigate the association between the COL8A1 rs13095226 Polymorphism and neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) in Chinese people. METHODS: 900 Chinese subjects-300 cases with nAMD, 300 cases with PCV and 300 controls, were enrolled in a cross-sectional observational study. The diagnoses of nAMD and PCV were confirmed by Fundus photography, Fluorescence Fundus Angiography (FFA) and Indocyanine Green Angiography (ICGA). Genomic DNA was extracted from venous blood leukocytes and genotypes of rs13095226 were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Differences in allele distribution between cases and controls were tested by chi-square tests, with age and gender adjusted by logistic regression analysis. RESULT: The COL8A1 rs13095226 polymorphism was not statistically significantly different from the nAMD or PCV to the normal controls (P>0.05) in Chinese Population. The association remained insignificant after adjustment for age and gender differences (P>0.05). CONCLUSIONS: This case-control study indicated that the COL8A1 rs13095226 polymorphism is not associated with nAMD or PCV, which suggesting this gene maybe not a susceptibility gene locus for nAMD or PCV in Chinese subjects. PMID- 26617903 TI - Association between ERAP1 gene polymorphisms and ankylosing spondylitis susceptibility in Han population. AB - PURPOSES: The present study was designed to investigate the relationship between endoplasmic reticulum amino peptidase 1 (ERAP1) gene polymorphisms and ankylosing spondylitis (AS) in Han population of Shaanxi province. METHODS: 100 AS patients and 100 healthy people were enrolled in present study as case and control groups respectively, and the control group was matched with the case group by age and gender. ERAP1 gene rs27434 and rs7711564 polymorphisms were test by TaqMan probe genotyping method. SHEsis software was used to operate linkage disequilibrium (LD) and haplotype analysis between the two single nucleotide polymorphisms (SNPs). chi(2) test was employed to compare the differences of the genotype, allele and haplotype frequencies between the case and control groups. Relative risk of AS was represented by odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: In ERAP1 rs27434 and rs7711564 polymorphisms, the frequencies of AA and CC genotypes in case group were significantly higher compared to those in control group (P=0.036; P=0.039), and so were the frequencies of A and C alleles (OR=1.589, 95% CI=1.070-2.359, P=0.028; OR=1.535, 95% CI=1.021-2.308, P=0.050). Linkage disequilibrium test and haplotype analysis of the alleles of the two SNPs showed that the frequency of A-C haplotype was higher in case group than that in control group (P=0.005), which indicated that A-C might be the susceptible haplotype to AS. CONCLUSIONS: ERAP1 gene rs27434 and rs7711564 polymorphisms may increase the risk of AS. PMID- 26617904 TI - Association between matrix metalloproteinase gene polymorphisms and development of ischemic stroke. AB - We investigated the association between MMP2 rs243865, MMP3 rs3025058 and MMP9 rs3918242 polymorphisms and development of ischemic stroke in a Chinese population. Between January 2012 and May 2014, a total of 317 patients with ischemic stroke and 317 health control subjects were enrolled into our study. The MMP2 rs243865, MMP3 rs3025058 and MMP9 rs3918242 polymorphisms were analyzed using polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). By multivariate logistic regression analysis, we found that individuals carrying with the CC genotype and the TC+CC genotype of MMP9 rs3918242 were associated with a significantly increased risk of ischemic stroke when compared with the TT genotype, and the ORs (95% CI) was 5.47 (2.64-12.38) and 1.55 (1.08-2.24), respectively. The TC+CC genotype of MMP9 rs3918242 was associated with an elevated risk of ischemic stroke in tobacco smokers, and the OR (95% CI) was 2.03 (1.11-3.74). In conclusion, our study suggests that MMP9 rs3918242 polymorphism is correlated with an elevated risk of ischemic stroke, and this gene polymorphism has interaction with tobacco smoking in the risk of ischemic stroke. PMID- 26617905 TI - Association between interleukin-17 gene polymorphisms and risk of coronary artery disease. AB - We conducted a case-control study to estimate the association between IL-17A rs2275913, rs3819025 and rs3748067 polymorphisms and development of coronary artery disease. A total of 415 patients with coronary artery disease and 448 health controls were recruited during the period of March 2013 and October 2014. Genotyping of IL-17A rs2275913, rs3819025 and rs3748067 were analyzed by polymerase chain reaction coupled with restriction fragment length polymorphism. By logistic regression analysis, we found that individuals with the AA genotype (OR, 2.18; 95% CI, 1.35-3.56) and the GA+AA genotype (OR, 1.39, 95% CI, 1.06 1.84) of rs2275913 were associated with an increased risk of coronary artery disease when compared with the GG genotype. Individuals carrying the GA+AA genotype of rs2275913 were more likely to have a higher risk of coronary artery disease in those with hypertension and smoking habit, and the adjusted ORs (95% CI) were 3.92 (2.13-6.82) and 2.74 (1.71-4.40). In conclusion, we suggest that individuals with the AA genotype and the GA+AA genotype of rs2275913 are associated with an increased risk of coronary artery disease, especially in those with hypertension and smoking habit. PMID- 26617906 TI - Association between Interleukin-10 gene polymorphisms and risk of early-onset preeclampsia. AB - We conducted a case-control study to investigate the role of IL-10 -1082A/G (rs1800896), -819T/C (rs1800871), and -592A/C (rs1800872) polymorphisms in the development of early-onset preeclampsia. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay was applied to assess the polymorphisms of IL-10 -1082A/G (rs1800896), -819T/C (rs1800871), and -592A/C (rs1800872). The genotype distributions of IL-10 -1082A/G (rs1800896), -819T/C (rs1800871), and -592A/C (rs1800872) confirmed with HWE in the controls, and the P value for HWE was 0.41, 0.38 and 0.26, respectively. The results of the multivariate logistic regression analysis revealed that the association of individuals expressing the CC genotype and AC+CC of IL-10 -592A/C (rs1800872) with a significantly increased risk of early-onset preeclampsia in co-dominant and dominant models, compared to the AA genotype; the OR (95% CI) for these individuals was determined to be 2.09 (1.12-3.90) and 1.66 (1.03-2.71), respectively. In the recessive model, we found that CC genotype of IL-10 -592A/C (rs1800872) was associated with the increased risk of early-onset preeclampsia when compared with AA+AC genotype (OR = 1.67; 95% CI = 1.01-2.92). In conclusion, our study has indicated that IL-10 -592A/C (rs1800872) polymorphism was associated with an increased risk of early-onset preeclampsia in a Chinese population. PMID- 26617907 TI - Comparison of percutaneous microwave ablation and laparoscopic resection in the prognosis of liver cancer. AB - The effect of percutaneous microwave ablation and laparoscopic resection on the prognosis of liver cancer was investigated. Ninety patients with liver cancer treated at our hospital from March 2010 to March 2012 were divided into group A and group B (n=45) by using a random number table, and the surgical conditions and the prognosis were compared. The surgical conditions of patients in group A were significantly better than those in group B (P<0.05). The incidence of complications in group A was 6.67%, which was obviously lower than that of group B (P<0.05). The local recurrence rate of group A was 20.00%, and that of group B was 8.89%, which showed a significant difference (P<0.05). The two groups did not differ significantly in terms of either total recurrence rate (P>0.05) or 1-year, 2-year and 3-year survival (P>0.05). Both percutaneous microwave ablation and laparoscopic resection had a good long-term efficacy in liver cancer. However, percutaneous microwave ablation was superior as it caused less invasiveness, reduced the incidence of complications and improved prognosis of liver cancer. PMID- 26617908 TI - Association between XRCC3 Thr241Met polymorphism and risk of osteosarcoma in a Chinese population. AB - The aim of this study was to investigate whether XRCC3 Thr241Met polymorphism could affect the development of osteosarcoma in a Chinese population. A total of 152 osteosarcoma patients and 304 health control subjects were included in our study. Polymerase chain reaction restriction fragment length polymorphism (PCR RFLP) assay was applied to assess the XRCC3 Thr241Met gene polymorphism. By conditional logistic regression analysis, we found that TT genotype of XRCC3 Thr241Met was associated with increased risk of osteosarcoma in codominant model (OR = 2.53, 95% CI = 1.28-5.39). Moreover, XRCC3 Thr241Met gene polymorphism was correlated with an elevated increased risk of osteosarcoma in dominant (OR = 1.55, 95% CI = 1.03-2.34) and recessive models (OR = 2.30, 95% CI = 1.16-4.56). In conclusion, we found that XRCC3 Thr241Met gene polymorphism was associated with increased risk of osteosarcoma in codominant, dominant and recessive models. PMID- 26617909 TI - Genetic association between CD44 polymorphisms and chronic hepatitis B virus infection in a Chinese Han population. AB - AIMS: This article aimed at discussing the association of chronic hepatitis B virus (HBV) infection with CD44 polymorphisms in Chinese Han population; meanwhile, the interaction of polymorphisms was also analyzed based on chronic HBV infection. METHODS: The genotyping of CD44 polymorphisms was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 108 HBV infected and 130 healthy persons. The genotype distributions of CD44 rs187115, rs13347 in the control group were checked by Hardy-Weinberg equilibrium (HWE). The strength of the relevance between polymorphism and disease was measured by odds ratio (OR) with corresponding 95% confidence interval (CI) calculated by chi(2) test. The 2*4 crossover analysis method was used to conduct the interaction analysis of polymorphisms. RESULTS: The genotype distributions in controls conformed to HWE. GG genotype and G allele frequencies in rs187115 were obviously higher in cases than the controls (P=0.02, 0.04). Compared with the common genotype CC, individual who carried mutant genotypes (CT and TT) of rs13347 had a significantly high risk to suffer from HBV infection (OR=1.99, P=0.02 for CT; OR=3.56, P=3.00*10(-3) for TT), furthermore, CT+TT genotype also showed a high susceptibility (OR=2.27, P=2.00*10(-3)). Similarly, T allele of rs13347 increased 0.98 times risk in cases compared with controls (OR=1.98, 95% CI=1.34-2.92). The two polymorphisms in CD44 presented a positive interaction. CONCLUSION: CD44 polymorphisms are associated with chronic HBV infection as the risk factors, and the synergistic action is also found between the two polymorphisms. PMID- 26617910 TI - Association between interleukin-10 gene promoter polymorphisms and susceptibility to liver cirrhosis. AB - We conducted a case-control study to investigate the association between three common SNPs in IL-10 gene (rs1800896, rs1800871 and rs1800872) and the development of liver cirrhosis in a Chinese population. Between January 2013 and December 2014, a total of 318 patients with liver cirrhosis and 318 health control subjects were enrolled into our study. The IL-10 rs1800896, rs1800871 and rs1800872 polymorphisms were analyzed using polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). By multivariate logistic regression analysis, we found that individuals with the AA genotype and GA+AA genotype of IL-10 rs1800896 were more likely to have an increased risk of liver cirrhosis when compared with the GG genotype, and the ORs (95% CI) for the AA genotype and GA+AA genotype were 2.04 (1.20-3.50) and 1.41 (1.02-1.96), respectively. We found that the GA+AA genotype of IL-10 rs1800896 had higher risk of liver cirrhosis in individuals with chronic hepatitis B when compared with the GG genotype (OR = 1.95, 95% CI = 1.01-3.59). In conclusion, we found that IL-10 rs1800896 polymorphism was correlated with an increased risk of liver cirrhosis, especially in individuals with chronic hepatitis B. PMID- 26617911 TI - Primary mucosal CD30-positive T-cell lymphoproliferative disorders of the head and neck rarely involving epiglottis: clinicopathological, immunohistomchemical and genetic features of a case. AB - A case of primary mucosal CD30-positive T-cell lymphoproliferative disorder of the head and neck rarely involving epiglottis in a 59-year-old male was reported. Histologically, the ulcerative mucosa was affected by sheets of mixed inflammatory infiltration, with scattered large atypical lymphoid cells arranging in an individual or small clusters with focal epidermotropism. Immunohistochemically, tumor cells were uniformly immunoreactive to antibodies against CD2, CD3, CD7, CD43, CD4, TIA-1, with a heterogeneous expression of CD30, but negative for CD20, CD79a, CD21, CD8, CD56, ALK, EMA, granzyme B. Epstein-Barr virus encoded RNA (EBER) were detected. Genetically, T-cell receptor (TCR) gamma gene showed an oligoclonal rearrangement. This first case developing in epiglottis demonstrates mucosal CD30-positive T-cell lymphoproliferative disorders are characteristic of a broad clinicopathologic spectrum similar to the counterpart in the skin with a favorable prognosis. PMID- 26617912 TI - Solitary fibrous tumor of small bowel mesentery with postoperative bowel obstruction: a case report and review of literature. AB - Solitary fibrous tumor (SFT) which is an extremely rare clinical entity has been reported infrequently. Most commonly it is distinguished into pleural and extrapleural forms, with same morphological resemblance. There has been many literatures reported regarding extrapleural form of SFT but few cases of SFT originating from small bowel mesentery have been reported till now. We here report one case of SFT of small bowel mesentery with some eventful postoperative bowel obstruction and literature review. PMID- 26617913 TI - A case report on intermediate-grade malignant meningeal melanocytoma with elevated cell proliferation index. AB - Meningeal melanocytoma is a kind of extremely rare pigmented tumor of the central nervous system, which often occurs in the groove around the base of the brain and spinal pia mater. Age of onset is 40 to 50 years old, mostly presenting a benign course of disease and the prognosis is good. Case reports of partial invasion or metastasis from lesions are even rarer. This report described a case of 56-year old meningeal melanoma patient with partial skull and muscle invasion at the lantooccipital transition zone. Intraoperative histological examination showed moderate malignancy and Ki-67 index was 10%. PMID- 26617914 TI - Ectopic liver tissue in stomach paries: a case report. AB - Ectopic liver (EL) tissue is a rare entity which is reported to occur in several organs such as the gallbladder, pancreas and some other places. The EL tissue is usually detected incidentally during laparoscopy or autopsy, and several potential mechanisms may explain the development of liver ectopia. Although ectopic liver tissue is usually asymptomatic, it develops the same pathologic conditions as orthotopic liver. Although incidental ectopic livers rarely existing and do not have clinical importance, they should be looked for during electron microscope scan and histopathological examination should be carried out to rule out pathological changes since development of hepatocellular carcinoma is a possible issue. In this article, we presented an EL tissue in stomach of which only two cases were reported previously and this is the first reported case of a laparoscopically treated EL which lies to the bottom submucosal of the stomach. It would seem sensible to resect the ectopic tissue under endoscopic and the patient was well when seen for follow-up three months later. PMID- 26617915 TI - Intracranial benign fibrous histiocytoma mimicking parasagittal meningioma: report of two cases and review of literature. AB - Primary benign fibrous histiocytoma involving the central nervous system is an exceedingly rare tumor with most cases originating from the dura or parenchymal tissue. Diagnosis of primary benign fibrous histiocytoma is difficult due to its confusing histopathological characteristics. Two cases of primary intracranial benign fibrous histiocytoma mimicking parasagittal meningioma are presented in this report. Both tumors were gross totally resected and the patients showed no evidence of recurrence at follow-up of 12 months. The clinical features and prognosis of this rare tumor that were reported previously in the literature were also reviewed. Histopathological examination coupled with immunohistochemical staining is proved to be the convincing diagnostic method for the primary benign fibrous histiocytoma. Surgical resection is the recommendation for the therapy of the tumor. PMID- 26617917 TI - Synchronous primary breast cancer and hepatocellular carcinoma in a male patient: a case report. AB - Male breast cancer is a rare malignant disease characterized by hormonal imbalance. Hepatocellular carcinoma (HCC) is the most common neoplasm of the liver, and is generally correlated with hepatitis B or C virus-related cirrhosis. While to our knowledge a case with these two malignant diseases in a same male patient in the concomitant period is an exceptional event, rarely reported in literature. In this report, we present a case in which a Chinese patient with hepatitis B developed a tumor mass that originated from segment V of the liver and presented with right breast nodules at the same time. Synchronous mastectomy and hepatectomy were performed, and standard endocrine therapy and chemotherapy as adjuvant treatment were therefore followed. The diverse histogenesis of the two kinds of cancers highlights the need for us to investigate any common physiopathogenetic elements. PMID- 26617916 TI - A lethal mesenteric gastrointestinal stromal tumor: a case report and review of the literature. AB - Gastrointestinal stromal tumors (GISTs) arising from the mesentery are very rare. Here, we report a 53-year old man with a huge lobulated cystic-solid tumor in the left lower quadrant of the abdomen, which had been proved clinically and radiographically. Surgical resection showed that the large mass was noted at the mesentery of small intestine. Grossly, the largest diameter of the mass were measured up to 23 cm, and poorly circumscribed. Histological observation demonstrated it as a malignant GIST with positive CD117 (c-kit) staining. Mitotic figures were frequently observed up to 110 per 50 high power fields. Soon after the surgery, the patient experienced local recurrence with quick growth. The patient received targeted therapy (imatinib mesylate) but had no ideal effect. The patient died nine months after the operation because of rapid disease progression. PMID- 26617918 TI - Cysts in angiomyolipoma with epithelial cysts may be consisted of entrapped and dilated renal tubules: report of a case with additional immunohistochemical evidence to the pre-existing literature. AB - Angiomyolipoma with epithelial cysts (AMLEC) is a distinctive variant of angiomyolipoma characterized by grossly apparent epithelial cysts and a cellular, mullerian-like subepithelial stroma. Some authors suspect that the epithelial cysts mainly represent dilated entrapped native renal collecting duct epithelium, while other authors think that they represented true epithelial differentiation of the AML. Recently, it has been reported that obvious immunolabeling of melanocytic markers such as Melan A and HMB45, which are often immunolabeled in classical angiomyolipoma, are present in epithelial cysts in cases of AMLEC. Here, we report the case of a 43-year-old Japanese woman with AMLEC, and attempt to elucidate the significance of melanocytic marker immunolabeling in the cyst's epithelium. In the present case, Melan A was labeled in the cyst's epithelium, and was thought to reflect its labeling in renal tubules existing in the renal parenchyma outside the tumor. This finding may indicate that the cyst epithelium is derived from entrapped renal tubules inside the AML. Non-immunolabeling of the estrogen and progesterone receptors in the cyst epithelium may also suggest that the cyst epithelium is not neoplastic, in contrast to their labeling in neoplastic cells existing in cyst wall. Further examination, such as molecular analysis, is needed to determine whether these epithelial cysts is neoplastic or non-neoplastic. PMID- 26617919 TI - The first attempt in local excision of anorectal malignant melanoma using transanal endoscopic microsurgery. AB - Anorectal malignant melanoma (AMM) is an uncommon malignancy that is thought to arise from melanocytes in the mucosa around the anorectal junction. AMM is commonly misdiagnosed, and definitive preoperative diagnosis is often difficult. The prognosis of AMM is relatively poor. Although radical resection is required for AMM, there is still no consensus at this moment on which surgical approach is preferred. We herein report a rare case of AMM which was treated by transanal endoscopic microsurgery (TEM) in combination with radiotherapy, which resulted in complete excision of the lesion without complications. The successful treatment for this AMM using TEM emphasizes the need to broaden its application in the treatment of various rectal lesions while preserving organ function and decreasing recurrence. PMID- 26617920 TI - Rare coexistence of mediastinal hepatoid adenocarcinoma, idiopathic azoospermia and horseshoe kidney: a case report and review of the literature. AB - Hepatoid adenocarcinoma (HAC) is the term proposed for a special type of extrahepatic tumors, which is similar to the hepatocellular carcinoma (HCC) both in the histopathology and immunohistochemistry. HAC has been observed in the stomach, colon, pancreas, gall bladder, lung and female genital tract, but rarely in the mediastinum. Now we describe a case of a 28-year-old Chinese male with primary mediastinal HAC with lung and liver metastasis. In this patient, HAC was associated with horseshoe kidney and idiopathic nonobstructive azoospermia. It seemed derivation abnormalities during organogenesis in the embryo stage played a significant role in the pathogenesis of HAC, horseshoe kidney and idiopathic nonobstructive azoospermia. Even the pathogenesis was still unknown; it may merit consideration of HAC together with horseshoe kidney and idiopathic nonobstructive azoospermia as a syndrome rather than as a spectrum of coincidental diseases. Furthermore, we found the HAC is a neoplasm with unfavorable outcomes despite aggressive and multi-protocol strategies. The serum alpha fetoprotein (AFP) should be regarded as a useful marker for diagnostic purposes and therapeutic response evaluation of HAC. PMID- 26617921 TI - IgG4-related prostatitis progressed from localized IgG4-related lymphadenopathy. AB - Immunoglobulin G4-related disease (IgG4-RD) is a recently described inflammatory disease involving multiple organs. Prostate involvement with IgG4-RD is very rare. In this report, we describe a case of IgG4-related prostatitis progressed from localized IgG4-related lymphadenopathy. This patient was present with urine retention symptoms. MRI and CT examination revealed the prostatic enlargement and the multiple lymphadenopathy. Serum IgG4 levels were elevated. Prostatic tissue samples resected both this time and less than 1 year earlier showed the same histological type of prostatitis with histopathologic and immunohistochemical findings characteristic of IgG4-RD. The right submandibular lymph nodes excised 2 years earlier were eventually proven to be follicular hyperplasia-type IgG4 related lymphadenopathy. This is the first case of IgG4-RD that began as localized IgG4-related lymphadenopathy and progressed into a systemic disease involving prostate and multiple lymph nodes. This patient showed a good response to steroid therapy. This leads us to advocate a novel pathogenesis of prostatitis, and a novel therapeutic approach against prostatitis. Pathologists and urologists should consider this disease entity in the patients with elevated serum IgG4 levels and the symptoms of prostatic hyperplasia to avoid ineffective medical or unnecessary surgical treatment. PMID- 26617922 TI - Discordant intracellular and plasma D-2-hydroxyglutarate levels in a patient with IDH2 mutated angioimmunoblastic T-cell lymphoma. AB - OBJECTIVES: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma with mutations in genes encoding isocitrate dehydrogenase1 and 2 (IDH1 and IDH2). Mutant IDH generates the oncometabolite D-2-hydroxyglutarate (D 2HG). We report the first case of discordant intracellular and plasma D-2HG levels in a patient with IDH2 R172S mutated AITL. METHODS: An 87-year-old woman was diagnosed with AITL in the groin lymph node by morphologic and immunophenotypic analyses, and molecular studies by DNA sequencing. D-2HG was measured in both tumoral tissue and in pre-treatment plasma by liquid chromatography-tandem mass spectrometry. RESULTS: While D-2HG was markedly elevated in the tissue sample, its level in plasma was normal. We discuss this discordant D-2HG result within the context of previously reported discordant 2HG results in other IDH mutated tumors, and its implication for using circulating D 2HG as a biomarker of IDH mutation. In addition, this case also harbored mutations in RHOA, TET2, and TP53. The molecular pathogenesis is briefly discussed. CONCLUSION: While our case suggests that circulating D-2HG is not a reliable marker of IDH mutation in AITL, more cases need to be studied to arrive at a definite conclusion. PMID- 26617923 TI - Renal angiomyolipoma with epithelial cysts: a rare entity and review of literature. AB - Renal angiomyolipoma (AML) with epithelial cysts (AMLEC) is a comparatively rare benign renal tumor that is recently recognized as a distinct entity and there are relatively few reported cases in the English-language literature. To date 19 cases of AMLEC have been reported in 2 case series and a few case reports. AMLEC has been described as a cystic variant of AML. Herein we reported an AMLEC in a 25-year-old female patient, and to the best of our knowledge this is the first case report of AMLEC in Chinese. She was incidentally found to have a kidney occupying lesion during a routine medical examination for 1 month. CT examination demonstrated a multilocular cystic lesions arising from right-kidney lower pole. The patient underwent the partial nephrectomy. Histological examination of the tumor was composed of epithelial cysts, compact subepithelial mullerian-like stroma and muscle-predominant AML. Immunohistochemically, epithelial cysts were positive for CK but negative for ER, PR, CD10 and HMB-45; the subepithelial stroma and muscle-predominant AML were positive for ER, PR and HMB-45; the subepithelial stroma was negative for SMA, but muscle-predominant AML was positive for SMA. The final histopathological diagnosis was AMLEC. PMID- 26617924 TI - A case of gastric cancer with heterogeneous components of EB virus (+)/TP53 (+) and EB virus (-)/TP53 (-). AB - Epstein-Barr virus (EBV)-associated gastric adenocarcinoma is a histological subtype of gastric adenocarcinoma, in which all of the carcinoma cells are basically positive for EBV-encoded small RNA (EBER) by in situ hybridization. Although its typical histology has some overlap with gastric carcinoma with lymphoid stroma, absence of massive lymphoid infiltrate is sometimes observed either in whole or in part. EBV-associated adenocarcinoma is one of the four representative molecular pathological subtypes recently identified by comprehensive genomic analysis of gastric adenocarcinomas. According to the analysis, typical EBV-associated gastric adenocarcinoma constitutes an independent molecular pathological subgroup, which is mutually exclusive to TP53 mutated adenocarcinoma with chromosomal instability, another molecular pathological subtype in gastric adenocarcinomas. Here, we report a rare case of gastric cancer heterogeneously composed of EBER (+)/TP53 (+) and EBER (-)/TP53 ( ) portions. The EBER (+)/TP53 (+) component with massive lymphoid infiltrate surrounded the EBER (-)/TP53 (-) component showing well to moderately differentiated tubular adenocarcinoma. Although collision of two independent gastric cancers could be the simplest and most possible explanation for this situation, we discussed another possibility. In the case of gastric collision tumors, concurrent development of EBER (+) gastric adenocarcinomas and EBER (-) gastric adenocarcinomas in a single stomach is a rare incident. Since presence of the EBER (+)/TP53 (+) tumor component is atypical in itself, we also discussed the mechanism of development of the clone. PMID- 26617925 TI - Mixed epithelial and stromal tumor of the kidney: report of a rare case and review of literature. AB - Mixed epithelial and stromal tumor of the kidney (MESTK) is a rare benign tumor composed of epithelial and stromal cells. We report a rare male case with detailed clinicopathological data and follow-up information. The patient presented with gross hematuria. Computed tomography (CT) and magnetic resonance imaging study showed a 60 mm*40 mm cystic lesion with thickened septa and minimal contrast enhancement at the lower pole of the right kidney. The patient underwent nephron sparing surgery (NSS). Intraoperative frozen section showed benign histological features without significant cytologic atypia and mitosis. By additional immunohistochemistry investigations, the epithelial component was positive for cytokeratin-7, high molecular weight cytokeratin, and PAX-8. The stromal component showed strong positivity for vimentin and smooth-muscle actin. This case emphasizes that it is difficult to establish a precise diagnosis of MESTK preoperatively due to lack of any typical radiological features. Thus, intraoperative frozen section is of great clinical significance for NSS with preservation of kidney function. Additionally, regular follow-up is necessary for the MESTK with malignant potential. PMID- 26617926 TI - Ectopic hamartomatous thymoma: report of a case and review of literature. AB - Ectopic hamartomatous thymoma (EHT) is an exceedingly rare lesion that usually arises in the lower neck and mainly affects adult men. We present the clinicopathological features of a case of EHT in a 28-year-old Chinese male, together with a literature review. Ultrasound imaging and a computed tomography (CT) scan of the neck demonstrated a 3.0-cm well-defined nodule of heterogeneous density located within the left sternocleidomastoid muscle. The patient underwent a gross total resection of the tumor. Grossly, the well-demarcated, encapsulated mass had a predominantly solid and gray-white appearance admixed with microcystic foci filled with serous content and yellowish regions. The lesion consisted of an irregular admixture of spindle cells, epithelium, and mature adipose tissue. Immunohistochemistry showed that both the spindle cell and epithelial components were diffuse and had intense nuclear positivity for p63 and cytoplasmic reactivity for pan-cytokeratin, CK7, and CK19. The patient was followed for 18 months without any evidence of metastasis or recurrence. PMID- 26617927 TI - Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells: a rare case report and review of the literature. AB - Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCPOGC) is an extremely rare non-endocrine pancreatic tumor. To date, some cases have been reported, however, histogenesis and biologic behavior of UCPOGC remain controversial. We report a case of an UCPOGC in a 54-year-old female, who presented with a three-month history of recurrent abdominal pain without any incentive. Abdominal computed tomography (CT) revealed a large cystic mass of 10.5 * 9.3 cm in the body and tail of the pancreas compressing the adjacent bowel loop and stomach. The preliminary diagnosis was considered as a malignant tumor of body and tail of the pancreas. The patient had open distal pancreatic mass resection with splenectomy and according to the results of histopathological and immunohistochemical studies, the diagnosis of an UCPOGC was established. PMID- 26617928 TI - Overlap of microcystic stromal tumor and primary solid pseudopapillary neoplasm of the ovary. AB - Ovarian microcystic stromal tumors (MCSTs) and ovarian primary solid pseudopapillairy neoplasms (SPNs) are rare ovarian tumors, and recently classified as distinctive variant in the stromal category and miscellaneous tumors respectically in 2009 and 2010. Ever since, there were less then 10 MCSTs and ovarian primary SPNs reported in English literatures. Both of them had something in common, including microscopical morphology, immunohistochemical phenotype, even for the tumorigenesis pathway. Hence, is there any possible linkage between them? In addition to a thorough case description, the literature concerning this entity is reviewed and discussed. PMID- 26617929 TI - Gastric-type mucinous adenocarcinoma of the uterine cervix with neoadjuvant therapy mimicking clear cell carcinoma. AB - Gastric-type mucinous adenocarcinoma, an uncommon subtype of cervical carcinoma, is characterized by a distinct morphology and immunophenotype. Herein, we report a case of a 71-year-old woman who received neoadjuvant radiotherapy and chemotherapy after cervical biopsy revealed moderately differentiated invasive endocervical adenocarcinoma. Subsequently, the outside patient underwent radical hysterectomy with bilateral salpingo-oophorectomy. The post-neoadjuvant therapy hysterectomy specimen showed tumor cells with clear cytoplasm, hyperchromatic nuclei with irregular contours, which mimicked clear cell carcinoma. However, immunohistochemical staining showed that these tumor cells were positive for carcinoembryonic antigen, cytokeratin 7 (diffuse), and cytokeratin 20 (patchy), After review of the pretreatment cervical biopsy specimen, the tumor was favored to represent a gastric-type mucinous adenocarcinoma of the cervix. Pathologists should be aware of this rare tumor and its post-neoadjuvant therapy morphologic changes, which can make diagnosis more challenging. PMID- 26617930 TI - A subcutaneous pleomorphic hyalinizing angiectatic tumor of soft parts of the right chest wall: report of a rare case. AB - Pleomorphic hyalinizing angiectatic tumor of the soft parts is an extremely rare mesenchymal tumor consisting of spindled and pleomorphic tumor cells and clusters of ectatic, fibrin-lined vessels. It typically occurs in the subcutaneous tissues of the distal extremities, usually the ankles and feet. Here we present a case of pleomorphic hyalinizing angiectatic tumor of the soft parts of the right chest wall in a 51-year old female. The tumor was subcutaneous, nonencapsulated, and about 2.0 cm*1.0 cm. Microscopically, the tumor was composed of numerous ectatic, fibrin-filled, thin-walled blood vessels, surrounded by spindled or pleomorphic tumor cells arranged in sheet-like or fascicular architecture, or randomly. Mitotic activity of the tumor cells was low. Immunohistochemical analysis shows that the tumor cells were positive for CD34 and vimentin, but negative for CD31, CK, desmin, EMA, HMB45, Myo D1, P63 and S-100. Ki67 index was about 1%. PMID- 26617931 TI - IDH1 R132H mutation in a pilocytic astrocytoma: a case report. AB - We present the case of a 72-year old female with a right cerebellar pilocytic astrocytoma WHO grade I with an Isocitrate dehydrogenase 1 (IDH1) R132H mutation. The patient is recurrence-free 6 years after the initial diagnosis. Only one single case with strikingly similar clinicopathological features has been reported before. Otherwise, IDH1/2 mutations are not seen in pilocytic astrocytomas. The clinical implications of these findings are discussed. PMID- 26617933 TI - A rare case of xanthogranulomatous pyelonepheritis with hepatic angiomyolipoma. AB - Xantogranulomatous pyelonephritis (XGP) is a rare and chronic variant of pyelonephritis typically associated with obstruction and infection. Xantogranulomatous pyelonephritis can infiltrate liver and connect with hepatic dysfunction. Here we report on a 52-year-old female with a liver mass and a left renal mass detected by uitrasonography and magnetic resonance imaging. Right lobectomy and partial nephrectomy were successively performed. Subsequent pathologic examination indicated hepatic angiomyolipoma and xanthogranulomatous pyelonepheritis, respectively. To the best of our knowledge, this is the first case of such rare combination. PMID- 26617932 TI - Rare presentation of multi-organ abdominal echinococcosis: report of a case and review of literature. AB - Hydatid disease, which is also known as cystic echinococcosis, is a zoonotic infection caused by the cestode tapeworm Echinococcus granulosus and rarely by Echinococcus multilocularis. In this report we describe an unusual case of a 19 year-old woman who was admitted to our hospital for abdominal pain, nausea, and vomiting. Computed tomography revealed multi-organ abdominal echinococcosis. The patient recovered after undergoing surgery to excise the cyst. The diagnosis, clinical features, treatment, and prevention in this case of multi-organ abdominal echinococcosis are discussed, in light of the relevant literature. PMID- 26617934 TI - Squamous cell carcinoma of lung associated with osteoclast-like giant cells: report of a case. AB - Resently, we treated a 69-year-old patient with squamous cell carcinoma of lung with osteoclast-like giant cells which were similar with the giant cell tumor of bone. The clinical and pathological characteristics of this case were presented, and the literatures were reviewed. The tumor differed histologically from the pleomorphic carcinoma, which occurs most commonly in the lung and showed diverse pleomorphic manifestation with benign looking osteoclast-like multinucleated cells and bizarre giant cells. In addition, undifferentiated carcinoma with a sarcoma-like appearance containing small areas of papillary adenocarcinoma was evident in the tumor. Histological features and immunohistochemical staining could be helpful in differential diagnosis. PMID- 26617935 TI - Multiple organ dysfunction syndrome, an unusual complication of heroin intoxication: a case report and review of literature. AB - Multiple organ dysfunction syndrome (MODS) has rarely been described in patients with heroin intoxication. Here, we report a rare case of MODS involving six organs, due to heroin intoxication. The patient was a 32-year-old Chinese man with severe heroin intoxication complicated by acute pulmonary edema and respiratory insufficiency, shock, myocardial damage and cardiac insufficiency, rhabdomyolysis and acute renal insufficiency, acute liver injury and hepatic insufficiency, toxic leukoencephalopathy, and hypoglycemia. He managed to survive and was discharged after 10 weeks of intensive care. The possible pathogenesis and therapeutic measures of MODS induced by heroin intoxication and some suggestions for preventing and treating severe complications of heroin intoxication, based on clinical evidence and the pertinent literature, are discussed in this report. PMID- 26617936 TI - Two independent primary mucinous tumors involving the appendix and ovary accompanied with acellular pseudomyxoma peritonei. AB - We report a case of a 30-year-old woman who had complained of lower abdominal distension. She was noted to have a history of primary mucinous tumor of the left ovary (13.2 * 9.9 * 10.4 cm) that was removed surgically. Two years later she developed the same tumor on her left ovary (8.7 * 6.0 * 6.9 cm) and also had appendiceal mucinous tumor accompanied with acellular PMP. Final pathology revealed two truly independent primary mucinous tumors involving the appendix and ovary accompanied with acellular PMP. We recommend a minimum follow-up of 5 years for the patient to detect any development of mucinous tumors and the acellular pseudomyxoma peritonei. PMID- 26617937 TI - Oral bacteria in pancreatic cancer: mutagenesis of the p53 tumour suppressor gene. AB - Carcinoma of exocrine pancreas is the fourth leading cause of cancer deaths, worldwide. The prevalence of this disease is very high in patients with chronic pancreatitis. Orodigestive cancers are frequently seen in patients with periodontitis. These findings suggest that this type of cancer may have some bacterial origins. This study hypothesizes that the peptidyl arginine deaminase (PAD) enzymes found in oral bacteria may be responsible for the p53 point mutations that occur in patients with pancreatic cancer. Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia, and Treponema denticola possess the PAD enzyme, and p53 arginine mutations have been detected in patients with pancreatic cancer. Moreover, the Pro allele p53Arg72-Pro is a risk factor for the development of this cancer. Anti-P. gingivalis antibody titers have been found to be higher in patients with pancreatic cancer as compared to healthy controls. The hypothesis in question can be tested if the DNA of P. gingivalis or the antibodies against P. gingivalis can be detected in patients with the p53 arginine mutation.If this hypothesis is true, it could reveal the real cause of pancreatic cancer, which is a fatal disease. Further studies are necessary in order to confirm this hypothesis. PMID- 26617938 TI - TRAF4 enhances oral squamous cell carcinoma cell growth, invasion and migration by Wnt-beta-catenin signaling pathway. AB - Oral squamous cell carcinoma (OSCC) ranks as the fifth most common cancer worldwide with poor prognosis. Recently, tumor necrosis factor receptor associated factor 4 (TRAF4) has attracted increasing attenuation due to its overexpression in certain cancers. However, its function and underlying mechanism in OSCC remains elusive. In this study, the high expression of TRAF4 mRNA and protein levels was noted in OSCC cell lines. Its overexpression with pcDNA3.1 TRAF4 vector transfection dramatically promoted cell proliferation and inhibited cell apoptosis, indicating a pivotal role of TRAF4 in OSCC cell growth. Simultaneously, TRAF4 elevation also increased cell invasion and migration. Mechanism analysis confirmed that TRAF4 up-regulation induced the expression of beta-catenin and the downstream target molecules of cyclinD1, c-myc, Bcl-2, MMP-9 and MMP-2, indicating that TRAF4 could induce the activation of Wnt/beta-catenin pathway. After pretreatment with beta-catenin siRNA, the pathway was remarkably silenced. Simultaneously, cell growth, invasion and migration induced by TRAF4 were strikingly abrogated, suggesting that TRAF4 may promote OSCC cell growth, invasion and migration by Wnt/beta-catenin pathway. Together, this study confirmed that TRAF4 acts as an oncogene for the development and progression of OSCC. Therefore, our study may support a promising therapeutic target for the treatment of OSCC. PMID- 26617939 TI - Microenviromental change after synthetic E-selectins interfere in ischemia reperfusion in rats and its contribution to endogenetic/exogenous never stem cells. AB - OBJECTIVE: To explore the special significances in advantages of using anti inflammatory drugs, such as amelioration of growing conditions and the promotion of cell growth. METHODS: Utilizing anti-adhesive effects of synthetic E selectins, we observed the changes of inflammatory cytokines (TNF-alpha, IL 1beta) contented in brain tissues and rat serums in rats hind cerebral ischemia reperfusion models. Both growth and expression of endogenetic/exogenous neurological stem cells were detected after ameliorated local microenvironment. RESULTS: The contents of TNF-alpha and IL-1beta were decreased in brain tissues and rat serums after applying synthetic E-selectins. Expression of exogenous neurological stem cells was enhanced. Animal neurological functions improved. CONCLUSION: Anti-inflammatory therapy in early stage could enhance proliferation of stem cells so that it has vital significations in treating cerebrovascular diseases. PMID- 26617940 TI - MiR-185 acts as a tumor suppressor by targeting AKT1 in non-small cell lung cancer cells. AB - Increasing evidence has shown that microRNAs play critical roles in the initiation and progression of non-small cell lung cancer (NSCLC). miR-185 is deregulated in various cancers, whereas its functional mechanism in NSCLC is still unclear. Here, we confirmed that the expression of miR-185 was significantly down-regulated in NSCLC tissues and cell lines. miR-185 over expression caused significant suppression of in vitro cell proliferation, migration and invasion, and in vivo tumor growth. We subsequently identified that AKT1 was a target gene of miR-185. Re-expression of AKT1 could partially rescue the inhibitory effects of miR-185 on the capacity of NSCLC cell proliferation and motility. Collectively, we conclude that miR-185 has a critical function by blocking AKT1 in NSCLC cells, and it may be a novel therapeutic agent for miRNA based NSCLC therapy. PMID- 26617941 TI - Beta-3 adrenergic receptors could be significant factors for overactive bladder related symptoms. AB - The treatment failure often happens in overactive bladder (OAB) partly owing to its unknown pathogenesis. The purpose of this study is to find significant receptors or biological markers for OAB-related symptoms for establishment of potential order-made therapeutic strategies. The overactive bladder symptom scores (OABSS) and international prostate symptom scores (IPSS)/quality of life (QOL) were questioned in all the 18 patients with OAB diagnosis. Their bladder mucosal tissues were taken from the random biopsy of bladder cancer suspected patients without any finding such as inflammation or carcinoma in situ. They were investigated quantitatively by immunohistochemical (IHC) stainings for inflammatory or immune-system (Interleukin (IL)-6 and cyclooxygenase-2 (Cox-2)), Caspase-3 apoptosis markers, angiogenesis (CD-31), epithelial-mesenchymal transition (E-cadherin) and muscarinic receptor (Muscarine-2 (M)-2), adrenergic receptors (ARs) (alpha 1-d (alpha1-d) and beta-3 (beta-3)). The statistical correlation between the expressions of these 5 markers and 3 receptors and these symptom scores were examined under the comparison between OAB patients and control patients who had urgency score with less than 2 in OABSS. The OABSS and IPSS/QOL was 7.39 +/- 2.69 and 21.2 +/- 6.59/4.33 +/- 1.33, respectively but those of control patients were 2.00 +/- 1.41 and 10.1 +/- 9.52/2.14 +/- 1.46, respectively (P<0.05). Regarding the correlation of those markers' expressions and symptom scores, in OAB patients, OABSS total significantly correlated with beta-3 AR expressions (P=0.0457). IPSS post-voiding significantly correlated with beta-3 AR expressions (P=0.0308) but no significant relationship in control patients (P>0.05). In conclusion, this study demonstrated that beta-3 AR in our tested 8 markers or receptors was correlated strongly with OAB-related symptoms. These data may help elucidate the pathophysiology of OAB and offer possible strategy for its order-made therapies. PMID- 26617942 TI - Expression of long non-coding RNA ZEB1-AS1 in esophageal squamous cell carcinoma and its correlation with tumor progression and patient survival. AB - BACKGROUND: LncRNA ZEB1-AS1 has been identified as a tumor oncogene in hepatocellular carcinoma. However, the clinical significance in esophageal squamous cell carcinoma (ESCC) is still unknown. The aim of this study was to explore ZEB1-AS1 expression levels and evaluated its clinical significance in ESCC patients. METHODS: LNCRNA ZEB1-AS1 expression was determined by quantitative real-time PCR (QRT-PCR) in 87 pairs of ESCC specimens and adjacent non-tumor tissues. Then, the association of ZEB1-AS1 expression with clinicopathological factors or survival of ESCC patients were determined. RESULTS: LNCRNA ZEB1-AS1 was found up-regulated in ESCC tissues compared to adjacent non-tumor tissues. Increased lncRNA ZEB1-AS1 expression was significantly associated with tumor grade, depth of invasion, and lymph node metastasis. Kaplan-Meier analysis revealed that ESCC patients with high ZEB1-AS1 expression had a poorer overall survival and disease-free survival. Furthermore, multivariate analysis suggested that ZEB1-AS1 expression was identified as an independent prognostic factor in patients with ESCC. CONCLUSION: These results indicated that lncRNA ZEB1-AS1 was associated with tumor progression and could be an independent prognostic factor for ESCC patients. PMID- 26617943 TI - Decreased pretreatment serum cholesterol level is related with poor prognosis in resectable non-small cell lung cancer. AB - The cholesterol has been reported to be associated with cancer development. The aim of our study was to investigate the serum cholesterol level (TC) in non-small cell lung cancer (NSCLC) patients and their association with clinicopathologic parameters and the prognosis. The serum cholesterol levels were evaluated in 259 resected NSCLC patients and were correlated with clinicopathologic variables including age, gender, tumor size, regional lymph node metastasis, disease-free survival time and overall survival time. Preoperative serum TC level was significantly associated with gender (P=0.001), smoking history (P=0.016), tumor differentiation (P=0.027), pT stage (P<0.001) and pN stage (P=0.009). Multivariate analyses indicated that decreased serum TC level was an independent prognostic factor for worse outcome. The hazard ratio was 1.89 (95% confidence interval [CI] 1.09-3.26) for disease progression and 2.19 (95% CI 1.01-4.74) for death. Based on this finding, the pretreatment serum cholesterol level is a novel independent prognostic biomarker in resectable NSCLC. PMID- 26617944 TI - Essentials of oral cancer. AB - Oral cancer is one of the 10 most common cancers in the world, with a delayed clinical detection, poor prognosis, without specific biomarkers for the disease and expensive therapeutic alternatives. This review aims to present the fundamental aspects of this cancer, focused on squamous cell carcinoma of the oral cavity (OSCC), moving from its definition and epidemiological aspects, addressing the oral carcinogenesis, oral potentially malignant disorders, epithelial precursor lesions and experimental methods for its study, therapies and future challenges. Oral cancer is a preventable disease, risk factors and natural history is already being known, where biomedical sciences and dentistry in particular are likely to improve their poor clinical indicators. PMID- 26617945 TI - Expression and function of osteogenic genes runt-related transcription factor 2 and osterix in orthodontic tooth movement in rats. AB - OBJECTIVE: To investigate the expression and function of osteogenic genes osterix (OSX) and runt-related transcription factor 2 (RUNX2) in the rat periodontal tissues under orthodontic force for the remodeling of the periodontal tissues. METHODS: 24 Wistar rats were randomly divided into 4 groups of orthodontic tooth movements for 1, 3, and 7 days (experimental groups) and control group (without orthodontic force). The expression of RUNX2 and OSX in the periodontal tissues was analyzed using real time PCR for mRNA and Western blot analysis for protein. The data were also analyzed for involvement of the two genes in signal pathways using bioinformatics tools. RESULTS: The mRNA levels of RUNX2 and OSX increased in the periodontal tissues after subjected to the orthodontic force for 1 to 7 days, with the highest level occurring at day 7. The relative expression levels of RUNX2 and OSX mRNA were 1.85 +/- 0.12, 304 +/- 0.06 and 4.16 +/- 0.068, and 1.52 +/- 0.09, 1.83 +/- 0.03 and 2.56 +/- 0.06 at day 1, 3 and 7, respectively. The results of Western blot analysis were consistent with the mRNA results. CONCLUSION: In orthodontic tooth movement, the expression of RUNX2 and OSX was upregulated as a result of external stimulation, suggesting that the two genes is involved in periodontal tissue remodeling and plays an important role in periodontal tissue remodeling. PMID- 26617946 TI - Distribution of HPV genotypes in Shanghai women. AB - OBJECTIVE: To study the Distribution of HPV genotypes in Shanghai women. DESIGN: Cohort study. SETTING: Shanghai First Maternity and Infant Hospital affiliated with Tongji University. POPULATION: Patients those attended in the cervical disease diagnosis and treatment center of Shanghai First Maternity and Infant Hospital between January 2011 and December 2014. METHODS: HPV GenoArray test kit (HybriBio Ltd) was used to perform HPV genotyping and was also used in DNA amplification and HybriBio's proprietary flow-through hybridization technique. RESULTS: In this study, total patients analyzed were 4585. Among 4585 sample the HPV positive patients were 1460 i.e. 31.84% in total. On the basis of pathological report normal were 1358, with inflammation 2441, with low grade lesion were 399, high grade lesion were 353, CIN were 19 and cervical carcinoma were 15. Among normal HPV positive were 215 (15.8%), among inflammation HPV positive were 735 (30.11%). HPV positive in low grade lesion were 353 i.e. 59.77%. In high grade lesion 211 were HPV positive among 272 (68.17%). The percentage of HPV positive was 73.68% i.e. 14 out of 19 patient in cervical carcinoma in situ. 13 patient out of 15 i.e. 86.67% of Cervical carcinoma were HPV positive. Among all percentage of HPV positive was high among cervical carcinoma then cervical carcinoma in situ then high grade lesion in decreasing fashion to low grade lesion and in normal. Highest prevalence i.e. 22.67% is of HPV 52 subtype and HPV 16 has second highest prevalence with 17.67% among HPV positive cases. Sensitivity of TCT detection is 71.6%. Specificity of TCT detection is 79.6%. Sensitivity of HPV-DNA detection is 65.2%. Specificity of HPV DNA detection is 78.2%. CONCLUSION: HPV is one of major health concern in shanghai having high prevalence rate in comparison to other part of china and other part of world. This has implications for the future cervical cancer burden and the priority to be given to prevent cervical cancer in Shanghai, especially, given the promising efficacy of prophylactic vaccines against HPV52, 16 and 58. This study also shows high sensitivity and specificity of TCT and HPV-DNA detection. PMID- 26617947 TI - Downregulated protein expression of transcriptional activator ELK-1 in atrial myocardium of chronic AF patients. AB - BACKGROUND: The structural alterations in atrial myocytes appear to be an adaptive response of dedifferentiation during chronic atrial fibrillation (AF). Transcriptional activator ELK-1, one of the members of ETS family, has been shown to play an important role in regulating cell differentiation, It is reasonable to presume that ELK-1 participate in the molecular and structural remodeling by which AF is sustained. To prove this hypothesis, the expression of ELK-1 protein in chronically fibrillating atria compared to that in normal rhythmic atria was detected. METHODS: Right atrial myocardium were obtained from twenty-four patients undergoing valve replacement surgery, twelve patients were in chronic AF (>6 months), whereas the others were in sinus rhythm (SR). The protein expression level of ELK-1 was quantified by Western blot analysis, and the cellular localization and expression pattern of ELK-1 was examined by immunohistochemical staining and indirect immunofluorescence. RESULTS: Western blot analysis showed that the protein expression of ELK-1 was significantly reduced in the atrial tissue of chronic AF patients compared to that in the controls. Immunohistochemistry showed that ELK-1 immunostaining occurred in both cytosolic and nuclear compartments of atrial myocardium. Indirect immunofluorescence showed that the nuclei of normal rhythmic atrial cells were densely labeled, whereas the nuclei in chronically fibrillating atrial cells were very faintly labeled. CONCLUSIONS: Our results suggest that the downregulated expression of transcriptional activator ELK-1 may play an important role in the pathogenesis of AF. PMID- 26617948 TI - Significance of Fas and FasL protein expression in cardiac carcinoma and local lymph node tissues. AB - OBJECTIVE: To investigate the relation of Fas and Fas ligand (FasL) protein expression with carcinogenesis and metastasis of cardiac carcinoma. METHODS: Immunohistochemistry was used to detect Fas and FasL protein expression in 64 cardiac carcinoma tissue samples and 20 normal gastric tissue samples. Relation between FasL and Fas expression, age and gender of gastric cancer patients, and pathological subtype and lymph node metastasis of gastric cancer was analyzed. RESULTS: The Fas expression level was significantly higher in normal gastric tissue samples than in cardiac carcinoma tissue samples (85.0% vs. 25.0%, P<0.001), while the FasL expression level was significantly lower in normal gastric tissue samples than in cardiac carcinoma tissue samples (30.0% vs. 81.3%, P<0.001). The Fas expression level was significantly higher in invasive lymph nodes than in non-invasive lymph nodes (82.9% vs. 56.5%, P<0.003) and in well differentiated gastric carcinoma tissue samples than in poorly-differentiated cardiac carcinoma tissue samples (50.0% vs. 18.0%, P=0.015). The FasL expression level was significantly lower in well-differentiated cardiac carcinoma tissue samples than in poorly- differentiated cardiac carcinoma tissue samples (42.9% vs. 84.0%, P=0.021). The Fas and FasL expression levels (25.0% and 81.3%) were significantly different in cardiac carcinoma tissue samples (P<0.001), but had a non-linear correlation (P=0.575). CONCLUSION: Abnormal Fas and FasL expressions in cardiac carcinoma and lymph node tissues are involved in carcinogenesis and metastasis of gastric cancer. PMID- 26617950 TI - Analysis of susceptible genes and chromosome loci for lung cancers by automated gene prediction tools and genome scanning meta-analysis. AB - Genome-wide scanning of susceptible loci and genes for medical diseases is important in current post-genome era. To date, a variety of studies have been focused on the experimental validation or genome-wide linkage scans across multiple populations hunting for susceptibility genes in lung cancer. In the present study, we used two gene prediction tools (PROSPECTR and SUSPECTS, Gen Wanderer) to analyze eight previously identified susceptibility loci for lung tumors, which are selected from literature searching. Our results showed that there was a subset of 26 likely candidate susceptible genes related to lung cancer in each chromosomal region. For potential susceptible chromosome loci, the genome-wide scanning meta-analysis using bins of 60 cM width predicted a group of potential regions associated with lung cancer. Locus 15q21-26 (P=0.000606) is strongly evidenced, which has been confirmed in previous work. In contrast, another potential locus 10q11.2-q23.3 (P=0.0435223) is suggestively evidenced, which was never identified before. Ac compared to previous known regions, the latter one is the new detected one in our study. In conclusion, our study may be useful to contribute to further experimental tests of susceptibility genes/loci related to lung cancer. PMID- 26617949 TI - The rs5743708 gene polymorphism in the TLR2 gene contributes to the risk of tuberculosis disease. AB - BACKGROUND: It has been reported that one single nucleotide polymorphisms (SNPs) rs5743708 in TLR2 gene might be associated with the susceptibility to tuberculosis disease. Owing to mixed and inconclusive results, we conducted a meta-analysis to systematically summarize and clarify the association between the rs5743708 gene polymorphism in the TLR2 gene and the risk of tuberculosis disease. METHODS: A systematic search of studies on the association of the rs5743708 gene polymorphism in the TLR2 gene with susceptibility to tuberculosis disease was conducted in PubMed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to pool the effect size. RESULTS: A total of nineteen case control studies from 13 articles on rs2910164 and 3 studies on the rs5743708 gene polymorphism in the TLR2 gene and the risk of tuberculosis disease were included. A significant relationship between the rs5743708 gene polymorphism in the TLR2 gene and tuberculosis disease was discovered in an allelic genetic model (OR: 2.801, 95% CI: 2.130-3.683, P=0.000), a homozygote model (OR: 5.795, 95% CI: 1.982-16.941, P=0.001), a heterozygote model (OR: 2.628, 95% CI: 1.888-3.569, P=0.000), a dominant genetic model (OR: 2.786, 95% CI: 2.003-3.877, P=0.000) and a recessive genetic model OR: (5.568, 95% CI: 1.907-16.255, P=0.002). In sub group analysis base on ethnicity, significance was observed between the Caucasian group and the Asian group. CONCLUSIONS: The rs5743708 gene polymorphism in the TLR2 gene contributes to the risk of tuberculosis disease. Individuals with the rs5743708 gene polymorphism in the TLR2 gene are under a higher risk for tuberculosis disease. PMID- 26617951 TI - Annonaceous acetogenins reverses drug resistance of human hepatocellular carcinoma BEL-7402/5-FU and HepG2/ADM cell lines. AB - Hepatocellular carcinoma (HCC) is the most common tumor in worldwide and chemotherapy resistant is a severe obstacle in HCC treatment. Annonaceous acetogenins was a nature compound from Uvaria accuminata and it has show the anti tumor proliferation activity in many types cancer. In this study, we showed that annonaceous acetogenins is correlated with the drug resistance reversal in human hepatocellular carcinoma BEL-7402/5-FU and HepG2/ADM cell lines. We found that cell apoptosis was improved and cell cycle was arrested, further, multidrug resistance proteins such as MDR1, MRP1, Topo-IIalpha, GST-pi, cyclin D1, Survivin and bcl-2 are down-regulated, however, intracellular Rh-123 and caspase-3/8 was up-regulated by Annonaceous acetogenins treatment. We also found that there was a decreased activity of NF-kappaB and Akt in Annonaceous acetogenins treatment groups. Therefore, we demonstrate that Akt/NF-kappaB pathway was involved in Annonaceous acetogenins reverses drug resistance of human hepatocellular carcinoma cells. PMID- 26617952 TI - Signaling pathway and molecular subgroups of medulloblastoma. Int J Clin Exp Pathol. 2013; 6(7): 1211-22. AB - Medulloblastoma (MB) is the most common malignant brain tumor in children. Although multimodality treatment regimens including surgery, radiotherapy and chemotherapy have greatly improved disease outcome, about one-third of MB patient remains incurable, and many long-term survivors are suffered from deleterious effects due to aggressive treatment. Understanding the signaling pathways and the genetic mechanisms contributed to MB development would be the key to develop novel therapeutic treatment strategies for improving survival and outcome of MB. In this review, we discuss the biological signaling pathways involved in MB pathogenesis. We also go through the current international consensus of four core MB subgroups namely, SHH, WNT, Group 3 and Group 4. This is adopted based on the knowledge of genomic complexity of MB as analyzed by recent high-throughput genomic technology. We talk about immunohistochemistry assays established to determine molecular subgroup affiliation. In the last part of review, we discuss how identification of molecular subgroups is going to change our routine disease diagnosis and clinical management. PMID- 26617954 TI - Pretending to Play or Playing to Pretend: The Case of Autism. AB - An article by Angeline S. Lillard and others published in the January 2013 issue of Psychological Bulletin about the impact of pretend play on child development raised a number of issues about play studies and child psychology. They claimed that, contrary to current theories on the subject, the evidence of many studies does not support causal explanations of play's relationship to most childhood development. In this article, authors Kasari, Chang, and Patterson review these arguments about play and devlopment in relation to children with autism-children who show specific deficits in pretend play. They argue that the study of these children provides a unique opportunity to consider which elements in play are important and how play skills are associated with different periods of child development. They conclude that, because pretend play requires intervention for the majority of children with autism, improving pretense in these children may shed more light on the causal impact of pretense on later developing skills in children. Key words: child development and pretend play; children with autism; funtional play; intervention in play; symbol play. PMID- 26617953 TI - Anticoagulants and Statins As Pharmacological Agents in Free Flap Surgery: Current Rationale. AB - Microvascular free flaps are key components of reconstructive surgery, but despite their common use and usual reliability, flap failures still occur. Many pharmacological agents have been utilized to minimize risk of flap failure caused by thrombosis. However, the challenge of most antithrombotic therapy lies in providing patients with optimal antithrombotic prophylaxis without adverse bleeding effects. There is a limited but growing body of evidence suggesting that the vasoprotective and anti-inflammatory actions of statins can be beneficial for free flap survival. By inhibiting mevalonic acid, the downstream effects of statins include reduction of inflammation, reduced thrombogenicity, and improved vasodilation. This review provides a summary of the pathophysiology of thrombus formation and the current evidence of anticoagulation practices with aspirin, heparin, and dextran. In addition, the potential benefits of statins in the perioperative management of free flaps are highlighted. PMID- 26617955 TI - CORRECTING INHOMOGENEITY-INDUCED DISTORTION IN FMRI USING NON-RIGID REGISTRATION. AB - Magnetic field inhomogeneities in echo planar images (EPI) can cause large distortion in the phase encoding dimension. In functional MRI (fMRI), this distortion can shift activation loci, increase inter subject variability, and reduce statistical power during group analysis. Distortion correction methods that make use of acquired magnetic field maps have been developed, however, field maps are not always acquired or may not be available to researchers. An alternative approach, which we pursue in this paper, is to estimate the distortion retrospectively by spatially registering the EPI to a structural MRI. We describe a constrained non-linear registration method for correcting fMRI distortion that uses T1-weighted images and does not require field maps. We compared resting state results from uncorrected fMRI, fMRI data corrected with field maps, and fMRI data corrected with our proposed method in data from 20 subjects. The results show that the estimated field maps were similar to the acquired field maps and that the proposed method reduces the overall error in independent component location. PMID- 26617956 TI - The Sociocultural Context of Caregiving Experiences for Vietnamese Dementia Family Caregivers. AB - The goal of this qualitative study was to describe the beliefs and experiences of Vietnamese caregivers caring for a family member with dementia and to elicit their ideas about promising interventions. We recruited 10 caregivers from support groups, the Alzheimer's Association, and local community-based organizations in Northern California. We conducted semi-structured in-depth interviews with all caregivers, as well as a focus group to obtain ideas about supportive strategies. Several themes emerged from the data: (1) Filial piety was influential in caregiving; (2) A sense of loss/grief or trauma was pervasive; and (3) Caregivers had clear sources of stress and sources of support. An overarching theme underlying these three topics was that cultural beliefs, values, and expectations impacted the caregiving experience. Suggestions for promising interventions included education, language-congruent and/or telephone support groups, case management, inclusion of the care recipient in the intervention, and importance of credibility of the intervention. It also may be valuable to include an understanding of cultural values and promotion of spirituality and religion as key components. Findings highlight targets for dementia caregiver interventions to reduce burden and distress in an understudied population. PMID- 26617958 TI - Preparation of N-Phenyl-lactam Derivatives Capable of Stimulating Neurogenesis and Their Use in the Treatment of Neurological Disorders. PMID- 26617957 TI - Exploring Oxidovanadium(IV) Complexes as YopH Inhibitors: Mechanism of Action and Modeling Studies. AB - YopH tyrosine phosphatase, a virulence factor produced by pathogenic species of Yersinia, is an attractive drug target. In this work, three oxidovanadium(IV) complexes were assayed against recombinant YopH and showed strong inhibition of the enzyme in the nanomolar range. Molecular modeling indicated that their binding is reinforced by H-bond, cation-pi, and pi-pi interactions conferring specificity toward YopH. These complexes are thus interesting lead molecules for phosphatase inhibitor drug discovery. PMID- 26617959 TI - LpxC Inhibitors as Effective Therapy Against Multidrug Resistant Bacterial Infections. PMID- 26617960 TI - Therapeutic Potential of GPR120 Agonists for the Treatment of Type 2 Diabetes. PMID- 26617961 TI - Cytotoxic Activity of Salicylic Acid-Containing Drug Models with Ionic and Covalent Binding. AB - Three different types of drug delivery platforms based on imidazolium ionic liquids (ILs) were synthesized in high preparative yields, namely, the models involving (i) ionic binding of drug and IL; (ii) covalent binding of drug and IL; and (iii) dual binding using both ionic and covalent approaches. Seven ionic liquids containing salicylic acid (SA-ILs) in the cation or/and in the anion were prepared, and their cytotoxicity toward the human cell lines CaCo-2 (colorectal adenocarcinoma) and 3215 LS (normal fibroblasts) was evaluated. Cytotoxicity of SA-ILs was significantly higher than that of conventional imidazolium-based ILs and was comparable to the pure salicylic acid. It is important to note that the obtained SA-ILs dissolved in water more readily than salicylic acid, suggesting benefits of possible usage of traditional nonsoluble active pharmaceutical ingredients in an ionic liquid form. PMID- 26617962 TI - Design, Synthesis, and Identification of Silicon Incorporated Oxazolidinone Antibiotics with Improved Brain Exposure. AB - Therapeutic options for brain infections caused by pathogens with a reduced sensitivity to drugs are limited. Recent reports on the potential use of linezolid in treating brain infections prompted us to design novel compounds around this scaffold. Herein, we describe the design and synthesis of various oxazolidinone antibiotics with the incorporation of silicon. Our findings in preclinical species suggest that silicon incorporation is highly useful in improving brain exposures. Interestingly, three compounds from this series demonstrated up to a 30-fold higher brain/plasma ratio when compared to linezolid thereby indicating their therapeutic potential in brain associated disorders. PMID- 26617963 TI - Silicon Incorporated Morpholine Antifungals: Design, Synthesis, and Biological Evaluation. AB - Known morpholine class antifungals (fenpropimorph, fenpropidin, and amorolfine) were synthetically modified through silicon incorporation to have 15 sila analogues. Twelve sila-analogues exhibited potent antifungal activity against different human fungal pathogens such as Candida albicans, Candida glabrata, Candida tropicalis, Cryptococcus neoformans, and Aspergillus niger. Sila-analogue 24 (fenpropimorph analogue) was the best in our hands, which showed superior fungicidal potential than fenpropidin, fenpropimorph, and amorolfine. The mode of action of sila-analogues was similar to morpholines, i.e., inhibition of sterol reductase and sterol isomerase enzymes of ergosterol synthesis pathway. PMID- 26617964 TI - Total Syntheses and Biological Evaluation of (+/-)-Botryosphaeridione, (+/-) Pleodendione, 4-epi-Periconianone B, and Analogues. AB - The total syntheses of (+/-)-botryosphaeridione, (+/-)-pleodendione, (+/-) hoaensieremodione, 4-epi-periconianone B, and their analogues have been accomplished for the first time. All the synthesized target compounds were screened in neural anti-inflammatory assays using LPS induced microglia cells (N9). Among them, compounds 1 and 21 were identified as potential lead compounds for further profiling. PMID- 26617965 TI - Borrelidin Induces the Unfolded Protein Response in Oral Cancer Cells and Chop Dependent Apoptosis. AB - Oral squamous cell carcinoma (OSCC) is the most common cancer affecting the oral cavity, and US clinics will register about 30,000 new patients in 2015. Current treatment modalities include chemotherapy, surgery, and radiotherapy, which often result in astonishing disfigurement. Cancers of the head and neck display enhanced levels of glucose-regulated proteins and translation initiation factors associated with endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Previous work demonstrated that chemically enforced UPR could overwhelm these adaptive features and selectively kill malignant cells. The threonyl-tRNA synthetase (ThRS) inhibitor borrelidin and two congeners were discovered in a cell-based chemical genomic screen. Borrelidin increased XBP1 splicing and led to accumulation of phosphorylated eIF2alpha and UPR-associated genes, prior to death in panel of OSCC cells. Murine embryonic fibroblasts (MEFs) null for GCN2 and PERK were less able to accumulate UPR markers and were resistant to borrelidin. This study demonstrates that UPR induction is a feature of ThRS inhibition and adds to a growing body of literature suggesting ThRS inhibitors might selectively target cancer cells. PMID- 26617967 TI - Synthesis and Biological Activity of Mono- and Di-N-acylated Aminoglycosides. AB - Despite issues with oto/nephrotoxicity and bacterial resistance, aminoglycosides (AGs) remain an effective and widely used class of antibacterial agents. For decades now, efforts toward the development of novel AGs with potential to overcome some of these problems have been major research focuses. 1-N-Acylation, especially gamma-amino-beta-hydroxybutyrate (AHB) derivatization, has proven to be one of the most successful strategies for improving the overall properties of AGs, including their ability to avoid certain resistance mechanisms. More recently, 6'-N-acylation arose as another possible strategy to improve the properties of these drugs. In this study, we report on the glycinyl, carboxybenzyl, and AHB mono- and diderivatization at the 1-, 6'-, and/or 4''' amines of the AGs amikacin, kanamycin A, netilmicin, sisomicin, and tobramycin. We also present the antibacterial activities and the reduced reactivity of AG modifying enzymes (AMEs) toward these new AG derivatives, and identify the AMEs present in the bacterial strains tested. PMID- 26617966 TI - Discovery of an in Vivo Tool to Establish Proof-of-Concept for MAP4K4-Based Antidiabetic Treatment. AB - Recent studies in adipose tissue, pancreas, muscle, and macrophages suggest that MAP4K4, a serine/threonine protein kinase may be a viable target for antidiabetic drugs. As part of the evaluation of MAP4K4 as a novel antidiabetic target, a tool compound, 16 (PF-6260933) and a lead 17 possessing excellent kinome selectivity and suitable properties were delivered to establish proof of concept in vivo. The medicinal chemistry effort that led to the discovery of these lead compounds is described herein together with in vivo pharmacokinetic properties and activity in a model of insulin resistance. PMID- 26617968 TI - Design and Synthesis of a Focused Library of Diamino Triazines as Potential Mycobacterium tuberculosis DHFR Inhibitors. AB - We report design of a series of 2,4-diamino triazines as Mycobacterium tuberculosis (Mtb) dihydrofolate reductase inhibitors. The synthesized compounds were evaluated against Mtb (H37Rv and Dormant stage H37Ra), their cytotoxicity was assessed (HepG2 and A549 cell lines), and selectivity toward Mtb was evaluated by testing against other bacterial strains. Some derivatives showed promising activity along with low cytotoxicity. The most potent compound in the whole cell assay (MIC 0.325 MUM against H37Rv) showed selectivity in the enzyme assay and exhibited synergy with second line anti-TB agent p-amino salicylic acid. This study therefore provides promising molecules for further development as antituberculosis DHFR inhibitors. PMID- 26617969 TI - Trioxolane-Mediated Delivery of Mefloquine Limits Brain Exposure in a Mouse Model of Malaria. AB - Peroxidic antimalarial agents including the sequiterpene artemisinins and the synthetic 1,2,4-trioxolanes function via initial intraparasitic reduction of an endoperoxide bond. By chemically coupling this reduction to release of a tethered drug species it is possible to confer two distinct pharmacological effects in a parasite-selective fashion, both in vitro and in vivo. Here we demonstrate the trioxolane-mediated delivery of the antimalarial agent mefloquine in a mouse malaria model. Selective partitioning of the trioxolane-mefloquine conjugate in parasitized erythrocytes, combined with effective exclusion of the conjugate from brain significantly reduced brain exposure as compared to mice directly administered mefloquine. These studies suggest the potential of trioxolane mediated drug delivery to mitigate off-target effects of existing drugs, including the adverse neuropsychiatric effects of mefloquine use in therapeutic and chemoprophylactic settings. PMID- 26617970 TI - Discovery of New Acid Ceramidase-Targeted Acyclic 5-Alkynyl and 5-Heteroaryl Uracil Nucleosides. AB - A series of novel N-acyclic uracil analogs with linear, branched, aromatic, and cyclopropyl-alkynyl as well as heteroaryl moieties at C-5 were prepared using palladium catalyzed Sonogashira and Stille cross-coupling and evaluated against malignant tumor cell lines. C-5-Furan-2-yl uracil derivative 6 was shown to be more potent against MCF-7 than the reference drug 5-fluorouracil (5-FU), while C 5-alkynyl uracil derivatives 9c and 9e exhibited antibreast cancer activities comparable to 5-FU. Selected compounds induced cell death, partially due to apoptosis, of MCF-7 breast cancer cells. Abrogation of acid ceramidase (ASAH1) expression of 9c and 9e indicated that these compounds could perturb ASAH1 mediated sphingolipid signaling. The selective activity of 9c and 9e against breast cancer cells via the ASAH1-mediated signaling, as a molecular target, might have a great advantage for potential future therapeutic use. PMID- 26617971 TI - Thiol-Based Potent and Selective HDAC6 Inhibitors Promote Tubulin Acetylation and T-Regulatory Cell Suppressive Function. AB - Several new mercaptoacetamides were synthesized and studied as HDAC6 inhibitors. One compound, 2b, bearing an aminoquinoline cap group, was found to show 1.3 nM potency at HDAC6, with >3000-fold selectivity over HDAC1. 2b also showed excellent efficacy at increasing tubulin acetylation in rat primary cortical cultures, inducing a 10-fold increase in acetylated tubulin at 1 MUM. To assess possible therapeutic effects, compounds were assayed for their ability to increase T-regulatory (Treg) suppressive function. Some but not all of the compounds increased Treg function, and thereby decreased conventional T cell activation and proliferation in vitro. PMID- 26617972 TI - Phosphonate Pendant Armed Propylene Cross-Bridged Cyclam: Synthesis and Evaluation as a Chelator for Cu-64. AB - A propylene cross-bridged macrocyclic chelator with two phosphonate pendant arms (PCB-TE2P) was synthesized from cyclam. Various properties of the synthesized chelator, including Cu-complexation, Cu-complex stability, (64)Cu-radiolabeling, and in vivo behavior, were studied and compared with those of a previously reported propylene cross-bridged chelator (PCB-TE2A). PMID- 26617973 TI - From non-obese diabetic to Network for the Pancreatic Organ Donor with Diabetes: New heights in type 1 diabetes research. AB - Since the discovery of therapeutic insulin in 1922 and the development of the non obese diabetic spontaneous mouse model in 1980, the establishment of Network for the Pancreatic Organ Donor with Diabetes (nPOD) in 2007 is arguably the most important milestone step in advancing type 1 diabetes (T1D) research. In this perspective, we briefly describe how nPOD is transforming T1D research via procuring and coordinating analysis of disease pathogenesis directly in human organs donated by deceased diabetic and control subjects. The successful precedent set up by nPOD is likely to spread far beyond the confines of research in T1D to revolutionize biomedical research of other disease using high quality procured human cells and tissues. PMID- 26617974 TI - Simple calculator to estimate the medical cost of diabetes in sub-Saharan Africa. AB - AIM: To design a medical cost calculator and show that diabetes care is beyond reach of the majority particularly patients with complications. METHODS: Out-of pocket expenditures of patients for medical treatment of type-2 diabetes were estimated based on price data collected in Benin, Burkina Faso, Guinea and Mali. A detailed protocol for realistic medical care of diabetes and its complications in the African context was defined. Care components were based on existing guidelines, published data and clinical experience. Prices were obtained in public and private health facilities. The cost calculator used Excel. The cost for basic management of uncomplicated diabetes was calculated per person and per year. Incremental costs were also computed per annum for chronic complications and per episode for acute complications. RESULTS: Wide variations of estimated care costs were observed among countries and between the public and private healthcare system. The minimum estimated cost for the treatment of uncomplicated diabetes (in the public sector) would amount to 21%-34% of the country's gross national income per capita, 26%-47% in the presence of retinopathy, and above 70% for nephropathy, the most expensive complication. CONCLUSION: The study provided objective evidence for the exorbitant medical cost of diabetes considering that no medical insurance is available in the study countries. Although the calculator only estimates the cost of inaction, it is innovative and of interest for several stakeholders. PMID- 26617975 TI - Corrigendum: Determinants of Conductive Hearing Loss in Tympanic Membrane Perforation: Correction of the Sixth Author Name. AB - [This corrects the article on p. 92 in vol. 8, PMID: 26045905.]. PMID- 26617976 TI - Reimagining professional competence in physical education. AB - Physical educators have critical roles to play in assisting communities and schools to increase physical activity for all citizens. They can assist classroom teachers in increasing physical activity in the academic school day and can serve as school wellness directors to increase the amount of physical activity students and school staff members receive during the day. Additionally, physical educators can implement innovative approaches to physical education curricula to enhance students' opportunities to be active and to learn concepts to assist them to be physically active now and for a lifetime. When implementing evidence-based approaches to physical education, teachers need to teach the curriculum coherently and with fidelity. New programs such as Science, PE, & Me! and the Science of Healthful Living provide opportunities for students to examine the effects of exercise on their bodies in a physically active, learning-oriented approach to physical education. PMID- 26617978 TI - Cancer: see, reach, treat. AB - An academic-industry partnership between Johns Hopkins University School of Medicine and Philips has yielded quantitative methods to evaluate liver cancer. Their 3D visualisation technique offers a more accurate representation of the tumour and could radically improve treatment. PMID- 26617977 TI - Potential Medicinal Application and Toxicity Evaluation of Extracts from Bamboo Plants. AB - Bamboo plants play a significant role in traditional Asian medicine, especially in China and Japan. Biomedical investigations on the health-benefiting effects as well as toxicity of different parts and species of bamboo have been carried out worldwide since the 1960s, and documented a wide range of protective effects of bamboo-derived products, such as protection against oxidative stress, inflammation, lipotoxicity, cancer, and cardiovascular disease. Some of these products may interfere with male and female reproductive function, thyroid hormone metabolism, and hepatic xenobiotransformation enzymes. The diversity of bamboo species, parts of the plants available for medicinal use, and different extraction methods suggest that bamboo has great potential for producing a range of extracts with functional utility in medicine. PMID- 26617979 TI - Sexual transmission of hepatitis C: A rare event among heterosexual couples. PMID- 26617980 TI - Sex-specific regulation of chemokine Cxcl5/6 controls neutrophil recruitment and tissue injury in acute inflammatory states. AB - BACKGROUND: Tissue infiltration by neutrophils during acute inflammatory states causes substantial tissue injury. While the magnitude of tissue neutrophil accumulation in innate immune responses is profoundly greater in males than females, fundamental aspects of the molecular mechanisms underlying these sex differences remain largely unknown. METHODS: We investigated sex differences in neutrophil stimulation and recruitment in ischemia/reperfusion (I/R; mesenteric or renal) or carrageenan pleurisy in rats or mice, as well as skin injury in human volunteers. The induction of potent chemoattractive mediators (chemokines) and neutrophil adhesion molecules were measured by real-time PCR, flow cytometry, and protein assays. RESULTS: Mesenteric I/R in age-matched Wistar rats resulted in substantially more neutrophil accumulation and tissue injury at 2 h reperfusion in males than females. Using intravital microscopy, we show that the immediate (<30 min) neutrophil response to I/R is similar in males and females but that prolonged neutrophil recruitment occurs in males at sites local and distal to inflammatory insult partly due to an increase in circulating neutrophil populations with elevated surface expression of adhesion molecules. Sex differences in neutrophil kinetics were correlated with sustained induction of chemokine Cxcl5 in the tissue, circulation, and bone marrow of males but not females. Furthermore, blockade of Cxcl5 in males prior to ischemia resulted in neutrophil responses that were similar in magnitude to those in females. Conversely, administration of Cxcl5 to males in the absence of I/R was sufficient to increase levels of systemic neutrophils. Cxcl5 treatment of bone marrow neutrophils in vitro caused substantial induction of neutrophil-mobilizing cytokine granulocyte colony-stimulating factor (GCSF) and expression of beta2 integrin that accounts for sexual dimorphism in circulating neutrophil populations in I/R. Moreover, male Cxcl5-stimulated bone marrow neutrophils had an increased capacity to adhere to beta2 integrin ligand ICAM-1, implicating a greater sensitivity of male leukocytes to Cxcl5-mediated activation. Differential induction of Cxcl5 (human CXCL6) between the sexes was also evident in murine renal I/R, rat pleurisy, and human skin blisters and correlated with the magnitude of neutrophil accumulation in tissues. CONCLUSIONS: Our study reveals that sex-specific induction of chemokine Cxcl5/CXCL6 contributes to sexual dimorphism in neutrophil recruitment in diverse acute inflammatory responses partly due to increased stimulation and trafficking of bone marrow neutrophils in males. PMID- 26594322 TI - Biological network analysis with CentiScaPe: centralities and experimental dataset integration. AB - The growing dimension and complexity of the available experimental data generating biological networks have increased the need for tools that help in categorizing nodes by their topological relevance. Here we present CentiScaPe, a Cytoscape app specifically designed to calculate centrality indexes used for the identification of the most important nodes in a network. CentiScaPe is a comprehensive suite of algorithms dedicated to network nodes centrality analysis, computing several centralities for undirected, directed and weighted networks. The results of the topological analysis can be integrated with data set from lab experiments, like expression or phosphorylation levels for each protein represented in the network. Our app opens new perspectives in the analysis of biological networks, since the integration of topological analysis with lab experimental data enhance the predictive power of the bioinformatics analysis. PMID- 26617981 TI - Molecular classification of hepatocellular carcinoma: potential therapeutic implications. AB - Genomic profiling of hepatocellular carcinoma (HCC) tumors has elucidated recurrent molecular aberrations common or specific to disease etiology, patient race or geographic regions, allowing the classification of HCC tumors into subclasses sharing similar molecular and clinical characteristics. Previously reported transcriptome-based molecular subclasses have highlighted several common themes. Aggressive tumors are characterized by TP53 inactivation mutations and activation of pro-oncogenic signaling pathways, and further subclassified according to expression of stemness markers. The stemness marker-negative aggressive tumors display preferential TGF-beta activation. Another group of less aggressive tumors contains a subclass characterized by CTNNB1 mutations accompanied with overexpression of liver-specific WNT targets such as GLUL. Molecular therapies selectively targeting features of the HCC subclasses have suggested their utility in enriching potential responders in clinical trials and guiding therapeutic decision-making for HCC patients. PMID- 26617983 TI - De novo assembly of Dekkera bruxellensis: a multi technology approach using short and long-read sequencing and optical mapping. AB - BACKGROUND: It remains a challenge to perform de novo assembly using next generation sequencing (NGS). Despite the availability of multiple sequencing technologies and tools (e.g., assemblers) it is still difficult to assemble new genomes at chromosome resolution (i.e., one sequence per chromosome). Obtaining high quality draft assemblies is extremely important in the case of yeast genomes to better characterise major events in their evolutionary history. The aim of this work is two-fold: on the one hand we want to show how combining different and somewhat complementary technologies is key to improving assembly quality and correctness, and on the other hand we present a de novo assembly pipeline we believe to be beneficial to core facility bioinformaticians. To demonstrate both the effectiveness of combining technologies and the simplicity of the pipeline, here we present the results obtained using the Dekkera bruxellensis genome. METHODS: In this work we used short-read Illumina data and long-read PacBio data combined with the extreme long-range information from OpGen optical maps in the task of de novo genome assembly and finishing. Moreover, we developed NouGAT, a semi-automated pipeline for read-preprocessing, de novo assembly and assembly evaluation, which was instrumental for this work. RESULTS: We obtained a high quality draft assembly of a yeast genome, resolved on a chromosomal level. Furthermore, this assembly was corrected for mis-assembly errors as demonstrated by resolving a large collapsed repeat and by receiving higher scores by assembly evaluation tools. With the inclusion of PacBio data we were able to fill about 5 % of the optical mapped genome not covered by the Illumina data. PMID- 26617984 TI - Image processing for optical mapping. AB - Optical Mapping is an established single-molecule, whole-genome analysis system, which has been used to gain a comprehensive understanding of genomic structure and to study structural variation of complex genomes. A critical component of Optical Mapping system is the image processing module, which extracts single molecule restriction maps from image datasets of immobilized, restriction digested and fluorescently stained large DNA molecules. In this review, we describe robust and efficient image processing techniques to process these massive datasets and extract accurate restriction maps in the presence of noise, ambiguity and confounding artifacts. We also highlight a few applications of the Optical Mapping system. PMID- 26617985 TI - Co-delivery of camptothecin and curcumin by cationic polymeric nanoparticles for synergistic colon cancer combination chemotherapy. AB - Nanoparticle (NP)-based combination chemotherapy has been proposed as a potent strategy for enhancing intracellular drug concentrations and achieving synergistic effects in colon cancer therapy. Here, we fabricated a series of chitosan-functionalized camptothecin (CPT)/curcumin (CUR)-loaded polymeric NPs with various weight ratios of CPT to CUR. The resultant cationic spherical CPT/CUR-NPs had a desirable particle size (193-224 nm), relatively narrow size distribution, and slightly positive zeta-potential. These NPs exhibited a simultaneous sustained release profile for both drugs throughout the study period with a slight, initial burst release. Subsequent cellular uptake experiments demonstrated that the introduction of chitosan to the NP surface markedly increased cellular-uptake efficiency compared with other drug formulations, and thus increased the intracellular drug concentrations. Importantly, the combined delivery of CPT and CUR in a single NP enhanced synergistic effects of the two drugs. Among the five cationic CPT/CUR-NPs tested, NPs with a CPT/CUR weight ratio of 4:1 showed the highest anticancer activity, resulting in a combination index of approximately 0.46. In summary, our study represents the first report of combinational application of CPT and CUR with a one-step-fabricated co-delivery system for effective colon cancer combination chemotherapy. PMID- 26617986 TI - Characterization of saline dust emission resulted from Urmia Lake drying. AB - Compared with common dust storms, saline dust storms transport high concentrations of fine-grain saline and alkaline material. The saline dust storm differs from common dust storm, especially considering the sources of the suspended particulate matter (PM), chemical composition, grain size, and circulation processes. Atmospheric particulate matters (TSP, PM10, PM2.5, and PM1) and their water-soluble ions were concurrently measured at two sites located at north and southeast part of Urmia lake from January 2013 to September 2013. Particulate matters (PMs) were measured using high volume sampler and HAZ-DUST EPAM-5000 particulate air monitors. In both of the sampling sites, the highest concentration of PM was observed during the summer season (521.6, 329.1, 42.6, and 36.5 for TSP, PM10, PM2.5, and PM1, respectively). A total of 11 inorganic water-soluble ions in the TSP and PM10 were identified by ion chromatography (IC). No statistically significant difference was found between PM's ions concentrations of two sampling sites. The average of the total measured water soluble ions in the sampling sites was 28.75 +/- 12.9 MUg/m(3) (11.9 +/- 4.8% of total TSP mass) for TSP and 14.65 +/- 7.1MUg/m(3) (8.7 +/- 4.4 of total PM10 mass) for PM10. Among all detected ions, sulfate was the dominant constituent followed by nitrate and sodium. This study showed that the water soluble salts compose 3-20% of the total mass of TSP and PM10. The PCA analysis showed that saline particulates formed from Urmia lake bed were the dominant source (57.6 %) of TSP. In addition, saline particulates together with crustal materials resulted from resuspension were the main source (59.9%) of PM10. PMID- 26617987 TI - Obesity trends and risk factors in the South African adult population. AB - BACKGROUND: Obesity prevalence is increasing globally and contributes substantially to the burgeoning burden of non-communicable diseases. South Africa is particularly affected by this increasing trend and cross-sectional evidence suggests socioeconomic and behavioural variables as possible drivers. However, no large scale longitudinal study has attempted the direct identification of risk factors for progression towards obesity. METHODS: This study analysed data on 10,100 South African adults (18 years and over) randomly selected in 2008 and successfully recontacted in 2010 and 2012. Latent Growth Modelling was used to estimate the average rate of change in body mass index (BMI) during the study period, and to identify baseline characteristics associated with different trajectories. RESULTS: The overall rate of change in BMI during the study period was +1.57 kg/m(2) per decade (95 % CI: 0.93 -2.22), and it was higher among women (+ 1.82 kg/m(2) per decade, 95 % CI: 1.06 -2.58) than among men (+ 1.03 kg/m(2) per decade; 95 % CI: 0.14 -1.93). Female gender, younger age, larger waist circumference, white population group and higher household income per capita were baseline characteristics associated with higher rates of change. The association between tobacco use and obesity was complex. Smoking was associated with greater waist circumference at baseline but lower rates of increase in BMI during the study period. Quitting smoking was an independent predictor of BMI increase among subjects with normal weight at baseline. Among subjects with baseline BMI lower than 25 kg/m(2), rates of changes were higher in rural than urban areas, and inversely related to the frequency of physical exercise. CONCLUSIONS: A strong positive trend in BMI remains in South Africa and obesity prevalence is likely to increase. Trends are not homogeneous, and high risk groups (subjects with high socioeconomic status, rural dwellers, young women) and modifiable risk factors (physical inactivity) can be targeted. Subjects quitting smoking should receive additional weight-loss support in order that the numerous health benefits of cessation are not reduced by increasing BMI. Centrally obese subjects should be targeted in campaigns. PMID- 26617988 TI - Persistent Psychological Well-being Predicts Improved Self-Rated Health Over 9-10 Years: Longitudinal Evidence from MIDUS. AB - Psychological well-being has been linked with better health, but mostly with cross-sectional evidence. Using MIDUS, a national sample of U.S. adults (N = 4,963), longitudinal profiles of well-being were used to predict in cross-time change over a 9-10 years in self-reported health. Well-being was largely stable, although adults differed in whether they had persistently high versus persistently low or moderate levels of well-being. After adjusting for sociodemographic factors, those with persistently high well-being reported better health (subjective health, chronic conditions, symptoms, functional impairment) across time compared to those with persistently low well-being. Further, persistently high well-being was protective of improved health especially among the educationally disadvantaged. The findings underscore the importance of intervention and educational programs designed to promote well-being for greater segments of society. PMID- 26617989 TI - Individual protomers of a G protein-coupled receptor dimer integrate distinct functional modules. AB - Recent advances in proteomic technology reveal G-protein-coupled receptors (GPCRs) are organized as large, macromolecular protein complexes in cell membranes, adding a new layer of intricacy to GPCR signaling. We previously reported the alpha1D-adrenergic receptor (ADRA1D)-a key regulator of cardiovascular, urinary and CNS function-binds the syntrophin family of PDZ domain proteins (SNTA, SNTB1, and SNTB2) through a C-terminal PDZ ligand interaction, ensuring receptor plasma membrane localization and G-protein coupling. To assess the uniqueness of this novel GPCR complex, 23 human GPCRs containing Type I PDZ ligands were subjected to TAP/MS proteomic analysis. Syntrophins did not interact with any other GPCRs. Unexpectedly, a second PDZ domain protein, scribble (SCRIB), was detected in ADRA1D complexes. Biochemical, proteomic, and dynamic mass redistribution analyses indicate syntrophins and SCRIB compete for the PDZ ligand, simultaneously exist within an ADRA1D multimer, and impart divergent pharmacological properties to the complex. Our results reveal an unprecedented modular dimeric architecture for the ADRA1D in the cell membrane, providing unexpected opportunities for fine-tuning receptor function through novel protein interactions in vivo, and for intervening in signal transduction with small molecules that can stabilize or disrupt unique GPCR:PDZ protein interfaces. PMID- 26617990 TI - C-terminal domains of a histone demethylase interact with a pair of transcription factors and mediate specific chromatin association. AB - JmjC domain containing protein 14 (JMJ14) is an H3K4-specific histone demethylase that plays important roles in RNA-mediated gene silencing and flowering time regulation in Arabidopsis. However, how JMJ14 is recruited to its target genes remains unclear. Here, we show that the C-terminal FYRN and FYRC domains of JMJ14 are required for RNA silencing and flowering time regulation. Chromatin binding of JMJ14 is lost upon deletion of its FYRN and FYRC domains, and H3K4me3 is increased. FYRN and FYRC domains interact with a pair of NAC domain containing transcription factors, NAC050 and NAC052. Genome-wide ChIP analysis revealed that JMJ14 and NAC050/052 share a set of common target genes with CTTGNNNNNCAAG consensus sequences. Mutations in either NAC052 or NAC050 impair RNA-mediated gene silencing. Together, our findings demonstrate an important role of FYRN and FYRC domains in targeting JMJ14 through direct interaction with NAC050/052 proteins, which reveals a novel mechanism of histone demethylase recruitment. PMID- 26617991 TI - A Disposable Microfluidic Virus Concentration Device Based on Evaporation and Interfacial Tension. AB - We report a disposable and highly effective polymeric microfluidic viral sample concentration device capable of increasing the concentration of virus in a human nasopharyngeal specimen more than one order of magnitude in less than 30 min without the use of a centrifuge. The device is fabricated using 3D maskless xurography method using commercially available polymeric materials, which require no cleanroom operations. The disposable components can be fabricated and assembled in five minutes. The device can concentrate a few milliliters (mL) of influenza virus in solution from tissue culture or clinical nasopharyngeal swab specimens, via reduction of the fluid volume, to tens of microliters MUL). The performance of the device was evaluated by nucleic acid extraction from the concentrated samples, followed by a real-time quantitative polymerase chain reaction (qRT-PCR). The viral RNA concentration in each sample was increased on average over 10-fold for both cultured and patient specimens compared to the starting samples, with recovery efficiencies above 60% for all input concentrations. Highly concentrated samples in small fluid volumes can increase the downstream process speed of on-chip nucleic acid extraction, and result in improvements in the sensitivity of many diagnostic platforms that interrogate small sample volumes. PMID- 26617992 TI - Trypanosoma Infection Rates in Glossina Species in Mtito Andei Division, Makueni County, Kenya. AB - African Animal Trypanosomiasis (AAT) transmitted cyclically by tsetse fly (Glossina spp.) is a major obstacle to livestock production in the tropical parts of Africa. The objective of this study was to determine the infection rates of trypanosomes in Glossina species in Mtito Andei Division, Makueni County, Kenya. Tsetse fly species, G. longipennis and G. pallidipes, were trapped and DNA was isolated from their dissected internal organs (proboscis, salivary glands, and midguts). The DNA was then subjected to a nested PCR assay using internal transcribed spacer primers and individual trypanosome species were identified following agarose gel electrophoresis. Out of the 117 flies trapped in the area 39 (33.3%) were teneral while 78 (67%) were nonteneral. G. pallidipes constituted the largest percentage of 58% while G. longipennis were 42%. The overall trypanosomes infection rate in all nonteneral Glossina spp. was 11.53% with G. longipennis recording the highest infection rate of 23.08% while G. pallidipes had an infection rate of 5.77%. T. vivax was the most infectious (10.26%) compared to T. congolense (1.28%). Mean apparent densities were strongly positively correlated with infection rates (r = 0.95) confirming the importance of this parameter as an indicator of AAT transmission risk. PMID- 26617993 TI - In Vivo Antiplasmodial, Anti-Inflammatory, and Analgesic Properties, and Safety Profile of Root Extracts of Haematostaphis barteri Hook F. (Anacardiaceae). AB - Malaria is an endemic disease globally and the conundrum of drug resistance has led to the search for newer antimalarial agents. The root extract of H. barteri was evaluated for antimalarial, analgesic, and anti-inflammatory properties. The prophylactic effect of H. barteri on P. berghei was determined by pretreating mice with aqueous root extract of H. barteri (30-300 mg/kg), saline, and 1.2 mg/kg sulfadoxine/pyrimethamine for three days followed by 1 * 10(6) P. berghei inoculation. Parasite density was measured after 72 h. The curative antimalarial property of the extract was assessed by treating mice with extract, saline, and 1.14 : 6.9 mg/kg Artemether : Lumefantrine four days after 1 * 10(6) P. berghei inoculation. Selected organs were harvested for toxicity assessment. The anti inflammatory and analgesic effect of the extract was determined in the carrageenan and thermal tail withdrawal tests, respectively. The extract significantly reduced the parasite density in the prophylactic but not the curative study. The anti-inflammatory and analgesic activities of the extract were significant (P < 0.05) only at the highest doses employed. Regeneration of hepatocytes was also evident in the extract treated groups. The extract has prophylactic but not curative activity on P. berghei-induced malaria. The anti inflammatory and analgesic property of the extract occurred at the highest doses used. PMID- 26617994 TI - Wide-Field Landers Temporary Keratoprosthesis in Severe Ocular Trauma: Functional and Anatomical Results after One Year. AB - Purpose. To evaluate longitudinal functional and anatomical results after combined pars plana vitrectomy (PPV) and penetrating keratoplasty (PKP) using a wide-field Landers intraoperative temporary keratoprosthesis (TKP) in patients with vitreoretinal pathology and corneal opacity due to severe ocular trauma. Material and Methods. Medical records of 12 patients who had undergone PPV/PKP/KP due to severe eye trauma were analyzed. Functional (best-corrected visual acuity) and anatomic outcomes (clarity of the corneal graft, retinal attachment, and intraocular pressure) were assessed during the follow-up (mean 16 months). Results. Final visual acuities varied from NLP to CF to 2 m. Visual acuity improved in 7 cases, was unchanged in 4 eyes, and worsened in 1 eye. The corneal graft was transparent during the follow-up in 3 cases and graft failure was observed in 9 eyes. Silicone oil was used as a tamponade in all cases and retina was reattached in 92% of cases. Conclusions. Combined PPV and PKP with the use of wide-field Landers TKP allowed for surgical intervention in patients with vitreoretinal pathology coexisting with corneal wound. Although retina was attached in most of the cases, corneal graft survived only in one-fourth of patients and final visual acuities were poor. PMID- 26617995 TI - Management of Ocular Diseases Using Lutein and Zeaxanthin: What Have We Learned from Experimental Animal Studies? AB - Zeaxanthin and lutein are two carotenoid pigments that concentrated in the retina, especially in the macula. The effects of lutein and zeaxanthin on the prevention and treatment of various eye diseases, including age-related macular degeneration, diabetic retinopathy and cataract, ischemic/hypoxia induced retinopathy, light damage of the retina, retinitis pigmentosa, retinal detachment, and uveitis, have been studied in different experimental animal models. In these animal models, lutein and zeaxanthin have been reported to have beneficial effects in protecting ocular tissues and cells (especially the retinal neurons) against damage caused by different etiological factors. The mechanisms responsible for these effects of lutein and zeaxanthin include prevention of phototoxic damage by absorption of blue light, reduction of oxidative stress through antioxidant activity and free radical scavenging, and their anti inflammatory and antiangiogenic properties. The results of these experimental animal studies may provide new preventive and therapeutic procedures for clinical management of various vision-threatening diseases. PMID- 26617996 TI - The Safety and Efficacy of Routine Administration of Intracameral Vancomycin during Cataract Surgery. AB - Purpose. To evaluate the safety and efficacy of intracameral vancomycin during cataract surgery using a standardized dosage and delivery technique. Methods. The charts of 20,719 consecutive eyes that underwent phacoemulsification with intraocular lens implantation in a single ambulatory surgery center were retrospectively reviewed over a 5-year period. Results. The first 11,333 consecutive cases did not receive intracameral vancomycin, whereas the next 9,386 consecutive cases all received intracameral vancomycin. There were no significant differences in the baseline characteristics between the cohort of subjects who received intracameral vancomycin and the cohort of subjects that did not. There were a total of 11 subjects (0.97 cases per 1,000) that developed postoperative endophthalmitis in the group that did not receive intracameral vancomycin, whereas there were no cases of postoperative endophthalmitis in the group that received intracameral vancomycin (p = 0.0015). The overall rate of intraoperative and postoperative complications and the final postoperative visual acuities were similar among cohorts. There were no cases of toxic anterior segment syndrome occurring in either group during the study period. Conclusions. Routine administration of intracameral vancomycin during cataract surgery significantly decreased the incidence of postoperative endophthalmitis and was not associated with an increased incidence of postoperative adverse events. PMID- 26617998 TI - The Effect of Elevated Triglycerides on the Onset and Progression of Coronary Artery Disease: A Retrospective Chart Review. AB - Background. The American College of Cardiology and American Heart Association did not indicate a correlation between treating hypertriglyceridemia and reducing cardiovascular events. Objective. This study investigated whether patients with hypertriglyceridemia were more prone to worse outcomes during cardiac catheterization. Methods. Data collected over a one-year period analyzed lipid panels obtained at the time of cardiac catheterization. Triglyceride levels were categorized into three groups: <150 mg/dL, 150 mg/dL-300 mg/dL, and >300 mg/dL. Controlled variables included age, gender, the presence of hypertension, diabetes, hyperlipidemia, and history of coronary artery disease. Results. Subjects with a triglyceride level <150 mg/dL have a 54% likelihood of being treated medically compared to 38% and 41% in the 150 mg/dL-300 mg/dL and >300 mg/dL groups, respectively (p < 0.01). Subjects with a triglyceride level >300 mg/dL have a 20% percent chance of being treated with a coronary artery bypass graft compared to 12% and 15% in the <150 mg/dL and 150 mg/dL-300 mg/dL groups, respectively (p < 0.01). Subjects with a triglyceride level between 150 and 300 mg/dL have a 44% percent of being treated with a percutaneous coronary intervention compared to 34% and 43% in the <150 mg/dL and >300 mg/dL groups, respectively (p < 0.01). Conclusion. Hypertriglyceridemia was associated with worse outcomes in percutaneous coronary intervention or surgery. PMID- 26617997 TI - Urea Unfolding Study of E. coli Alanyl-tRNA Synthetase and Its Monomeric Variants Proves the Role of C-Terminal Domain in Stability. AB - E. coli alanyl-tRNA exists as a dimer in its native form and the C-terminal coiled-coil part plays an important role in the dimerization process. The truncated N-terminal containing the first 700 amino acids (1-700) forms a monomeric variant possessing similar aminoacylation activity like wild type. A point mutation in the C-terminal domain (G674D) also produces a monomeric variant with a fivefold reduced aminoacylation activity compared to the wild type enzyme. Urea induced denaturation of these monomeric mutants along with another alaRS variant (N461 alaRS) was studied together with the full-length enzyme using various spectroscopic techniques such as intrinsic tryptophan fluorescence, 1 anilino-8-naphthalene-sulfonic acid binding, near- and far-UV circular dichroism, and analytical ultracentrifugation. Aminoacylation activity assay after refolding from denatured state revealed that the monomeric mutants studied here were unable to regain their activity, whereas the dimeric full-length alaRS gets back similar activity as the native enzyme. This study indicates that dimerization is one of the key regulatory factors that is important in the proper folding and stability of E. coli alaRS. PMID- 26617999 TI - Depressive Symptoms: The Interaction between Rumination and Self-Reported Insomnia. AB - Objective. Prior research has found consistent support that rumination and insomnia are important risk factors for depressive symptoms. The aim of the present cross-sectional study is to examine the interaction between these two previously well-established risk factors (i.e., rumination and insomnia) in the explanation of depressive symptoms. Design. A total of 417 participants (277 women) with a mean age of 39 (SD = 17.59; range 18-85) completed a cross sectional survey. Main Outcome Measures. Participants filled out the Response Rumination Scale, the Athens Insomnia Scale, and the short version of the Center for Epidemiologic Studies Depression Scale. Results. It was predicted and found that self-reported insomnia moderated the relationship between rumination and depressive symptoms. We found that particularly participants who reported higher levels of rumination as well as insomnia had the highest depressive symptoms. Conclusion. This study is the first to suggest that particularly individuals exhibiting both self-reported insomnia and higher levels of rumination also report higher levels of depressive symptoms. Health professionals screening for mental problems should be aware of this specific combination of insomnia and rumination. Explanations for this moderation effect were discussed in light of study's limitations. PMID- 26618000 TI - Symptomatology and Coping Resources Predict Self-Care Behaviors in Middle to Older Age Patients with Heart Failure. AB - Background. Symptoms of heart failure (HF) and coping resources, such as social support and social problem-solving, may influence self-care behaviors. Research regarding the influence of HF symptomatology characteristics and components of social support and social problem-solving on self-care is limited. Objective. To identify predictors of HF self-care behaviors using characteristics of HF symptomatology, components of social support and social problem-solving, and demographic and clinical factors. Methods. Using a cross-sectional, correlational predictive design, a convenience sample (N = 201) of outpatients with HF answered self-report surveys. Multiple linear regression with stepwise variable selection was conducted. Results. Six predictors of HF self-care were identified: race, symptom frequency, symptom-related interference with enjoyment of life, New York Heart Association Class HF, rational problem-solving style, and social network (beta = 34.265, R (2) = 0.19, P = 0.001). Conclusions. Assessing the influence of race on self-care behaviors in middle to older age patients with HF is important. Clinical assessment that focuses on symptom frequency, symptom-related interference with enjoyment of life, and HF Class might also impact self-care behaviors in this population. Rational problem-solving skills used and evaluation of the size of and satisfaction with one's social network may be appropriate when assessing self-care. PMID- 26618002 TI - Why Do Parents Bring Their Children to the Emergency Department? A Systematic Inventory of Motives. AB - Parents frequently bring their children to general or pediatric emergency departments (EDs), even though many of these visits are judged by others to be "nonurgent" and inappropriate. This study examined the motives behind parents' decisions to take their children to a pediatric emergency department (PED). At a PED in Toulouse, France, 497 parents rated their level of agreement with each of 69 possible motives-representing all categories of human motivation-for coming to the PED that day. Exploratory and confirmatory factor analyses found evidence for six separable motives, called (in order of importance) (a) Seeking Quick Diagnosis, Treatment, and Reassurance; (b) PED as the Best Place to Go; (c) Empathic Concern for Child's Suffering; (d) Being Considered by Others as Responsible Parents; (e) External Factors; and (f) Dissatisfaction with Previous Consultation. Conclusions. Parents' motives in bringing their children to the PED are primarily serious and goal-oriented. They are also often emotion based, as would be expected in parents of ill children. The parents would be unlikely to agree that these visits were inappropriate. PMID- 26618003 TI - Montreal Cognitive Assessment and Modified Mini Mental State Examination in African Americans. AB - Background. Sparse data limit the interpretation of Montreal Cognitive Assessment (MoCA) scores, particularly in minority populations. Additionally, there are no published data on how MoCA scores compare to the widely used Modified Mini Mental State Examination (3MSE). We provide performance data on the MoCA in a large cohort of African Americans and compare 3MSE and MoCA scores, providing a "crosswalk" for interpreting scores. Methods. Five hundred and thirty African Americans with type 2 diabetes were enrolled in African American-Diabetes Heart Study-MIND, a cross-sectional study of cognition and structural and functional brain imaging. After excluding participants with possible cognitive impairment (n = 115), mean (SD) MoCA and 3MSE scores are presented stratified by age and education. Results. Participant mean age was 58.2 years (range: 35-83); 61% were female; and 64.9% had >12 years of education. Mean (SD) 3MSE and MoCA scores were 86.9 (8.2) and 19.8 (3.8), respectively. 93.5% of the cohort had a "positive" screen on the MoCA, scoring <26 (education-adjusted), compared with 47.5% on the 3MSE (cut-point < 88). A 3MSE score of 88 corresponded to a MoCA score of 20 in this population. Conclusion. The present data suggest the need for caution when applying proposed MoCA cutoffs to African Americans. PMID- 26618001 TI - Statins in Asthma: Potential Beneficial Effects and Limitations. AB - Asthma's sustenance as a global pandemic, across centuries, can be attributed to the lack of an understanding of its workings and the inability of the existing treatment modalities to provide a long lasting cure without major adverse effects. The discovery of statins boosted by a better comprehension of the pathophysiology of asthma in the past few decades has opened up a potentially alternative line of treatment that promises to be a big boon for the asthmatics globally. However, the initial excellent results from the preclinical and animal studies have not borne the results in clinical trials that the scientific world was hoping for. In light of this, this review analyzes the ways by which statins could benefit in asthma via their pleiotropic anti-inflammatory properties and explain some of the queries raised in the previous studies and provide recommendations for future studies in this field. PMID- 26618005 TI - Prevalence of Plasmid-Mediated Quinolone Resistance Genes among Extended-Spectrum beta -Lactamase-Producing Klebsiella pneumoniae Human Isolates in Iran. AB - The purpose of this study was to determine the prevalence and molecular characterization of plasmid-mediated quinolone resistance (PMQR) genes (qnrA, qnrB, qnrS, aac(6')-Ib-cr, and qepA) among ESBL-producing Klebsiella pneumoniae isolates in Kashan, Iran. A total of 185 K. pneumoniae isolates were tested for quinolone resistance and ESBL-producing using the disk diffusion method and double disk synergy (DDST) confirmatory test. ESBL-producing strains were further evaluated for the bla CTX-M genes. The PCR method was used to show presence of plasmid-mediated quinolone resistance genes and the purified PCR products were sequenced. Eighty-seven ESBL-producing strains were identified by DDST confirmatory test and majority (70, 80.5%) of which carried bla CTX-M genes including CTX-M-1 (60%), CTX-M-2 (42.9%), and CTX-M-9 (34.3%). Seventy-seven ESBL producing K. pneumoniae isolates harbored PMQR genes, which mostly consisted of aac(6')-Ib-cr (70.1%) and qnrB (46.0%), followed by qnrS (5.7%). Among the 77 PMQR-positive isolates, 27 (35.1%) and 1 (1.3%) carried 2 and 3 different PMQR genes, respectively. However, qnrA and qepA were not found in any isolate. Our results highlight high ESBL occurrence with CTX-M type and high frequency of plasmid-mediated quinolone resistance genes among ESBL-producing K. pneumoniae isolates in Kashan. PMID- 26618004 TI - Phytochemicals Mediated Remediation of Neurotoxicity Induced by Heavy Metals. AB - Almost all the environmental components including both the abiotic and biotic factors have been consistently threatened by excessive contamination of heavy metals continuously released from various sources. Different heavy metals have been reported to generate adverse effects in many ways. Heavy metals induced neurotoxicity and impairment in signalling cascade leading to cell death (apoptosis) has been indicated by several workers. On one hand, these metals are required by the cellular systems to regulate various biological functions of normal cells, while on the other their biomagnification in the cellular systems produces adverse effects. The mechanism by which the heavy metals induce neurotoxicity follows free radicals production pathway(s) specially the generation of reactive oxygen species and reactive nitrogen species. These free radicals produced in excess have been shown to create an imbalance between the oxidative and antioxidative systems leading to emergence of oxidative stress, which may cause necrosis, DNA damage, and many neurodegenerative disorders. This mini review summarizes the current knowledge available on the protective role of varied natural products isolated from different herbs/plants in imparting protection against heavy metals (cadmium, lead, arsenic, and mercury) mediated neurotoxicity. PMID- 26618007 TI - Influenza Induced Cardiomyopathy: An Unusual Cause of Hypoxemia. AB - Influenza has considerable burden on public health funds. The complications of influenza can be devastating. We present a case of a 42-year-old woman with history of asthma who presented to the emergency room in winter with shortness of breath and general malaise and was found to be in hypoxemic respiratory failure. She was diagnosed with influenza and workup revealed severely depressed systolic cardiac function (ejection fraction of 25%). She was treated with oseltamivir and diuresis and regained cardiac function within a week. We review the pathophysiology and management of influenza induced cardiomyopathy. PMID- 26618008 TI - Cystic Odontoma in a Patient with Hodgkin's Lymphoma. AB - Cystic odontoma is a rare entity, which is characterized by the association of a cyst with complex/compound odontoma. The aim of this study was to report the case of a 5-year-old male patient diagnosed previously with Hodgkin's lymphoma and treated successfully with chemotherapy and radiotherapy, who developed a mandibular odontogenic lesion. Physical examination revealed a swelling on the right side of the mandible. Radiographically, a well-defined radiolucent area surrounded by radiopaque material was observed. An incisional biopsy was performed and microscopic analysis showed a cystic lesion consisting of an atrophic epithelium comprising 2-3 cell layers and the absence of inflammation in the cystic capsule. The cyst was decompressed and the lesion was removed after 3 months of follow-up. Microscopic analysis of the surgical specimen showed a cystic hyperplastic epithelium surrounded by an intense chronic inflammatory cell infiltrate, which was in close contact with mineralized tissue resembling dentin and cementum. The final diagnosis was cystic odontoma. Since chemotherapy can affect the growth and development of infant teeth, a relationship between chemotherapy-associated adverse events and cystic odontoma is suggested in the present case. PMID- 26618006 TI - General Overview on Nontuberculous Mycobacteria, Biofilms, and Human Infection. AB - Nontuberculous mycobacteria (NTM) are emergent pathogens whose importance in human health has been growing. After being regarded mainly as etiological agents of opportunist infections in HIV patients, they have also been recognized as etiological agents of several infections on immune-competent individuals and healthcare-associated infections. The environmental nature of NTM and their ability to assemble biofilms on different surfaces play a key role in their pathogenesis. Here, we review the clinical manifestations attributed to NTM giving particular importance to the role played by biofilm assembly. PMID- 26618009 TI - Orocutaneous Fistula or Traumatic Infectious Skin Lesion: A Diagnostic Dilemma. AB - Orocutaneous fistula (OCF) (of dental origin) is an uncommon but well-described condition in the literature. These are often misdiagnosed by physicians and dentists. Careful selection of investigating modality is important in case of diagnostically challenging cases. A 19-year-old female came with a complaint of a lesion on the chin reported with h/o trauma with the impact on chin presented as diagnostic dilemma because of unusual case history and clinical examination. Commonly used radiographic investigations like IOPA and orthopantomograph did not resolve the dilemma whereas advanced imaging modality like CT scan, 3D volume imaging, and contrast enhanced CT played an important role in the diagnosis of OCF and selecting the treatment plan. PMID- 26618010 TI - Weekly Intramuscular Injection of Levothyroxine following Myxoedema: A Practical Solution to an Old Crisis. AB - An 82-year-old female with known hypothyroidism was admitted to hospital after being found on the floor. On examination, she was unkempt, confused, bradycardic, hypothermic, and barely arousable. Initial biochemistry revealed a thyroid stimulating hormone (TSH) of >100 mU/L and free thyroxine (FT4) level of 1.5 pmol/L which supported a diagnosis of myxoedema coma. She was resuscitated and commenced on liothyronine, levothyroxine, and hydrocortisone and some improvement was made. It became apparent that she was hiding and spitting out her oral levothyroxine including levothyroxine elixir. Given the need for prompt alternative control, we sought advice from international experts where intramuscular levothyroxine was recommended. She was managed from day 50 onwards with intramuscular levothyroxine 200 mcg once a week, which was subsequently increased to 500 mcg. Thyroid function normalized and she made continual cognitive and physical progress and was discharged to a rehabilitation hospital. Her intramuscular levothyroxine was stopped and she was subsequently restarted on oral levothyroxine, with a plan for on-going close monitoring of her thyroid function. This report highlights the potential to use intramuscular levothyroxine in individuals with severe hypothyroidism arising from poor compliance with levothyroxine treatment or other potential causes such as impaired absorption. PMID- 26618011 TI - Adrenal Lymphangioma Masquerading as a Catecholamine Producing Tumor. AB - Objective. To report the unusual case of an adrenal lymphangioma presenting in a patient with an adrenal cystic lesion and biochemical testing concerning for pheochromocytoma. The pertinent diagnostic and imaging features of adrenal lymphangiomas are reviewed. Methods. We describe a 59-year-old patient who presented with hyperhidrosis and a 2.2 by 2.2 cm left adrenal nodule. Biochemical evaluation revealed elevated plasma-free normetanephrine, urine normetanephrine, urine vanillylmandelic acid, and urine norepinephrine levels. Elevated plasma norepinephrine levels were not suppressed appropriately with clonidine administration. Results. Given persistent concern for pheochromocytoma, the patient underwent adrenalectomy. The final pathology was consistent with adrenal lymphangioma. Conclusions. Lymphangiomas are benign vascular lesions that can very rarely occur in the adrenal gland. Imaging findings are generally consistent with a cyst but are nonspecific. Excluding malignancy in patients presenting with adrenal cysts can be difficult. Despite its benign nature, the diagnosis of adrenal lymphangioma may ultimately require pathology. PMID- 26618012 TI - Case Report of Granulicatella adiacens as a Cause of Bacterascites. AB - Granulicatella adiacens is a Gram-positive coccus, formerly grouped with nutritionally variant Streptococcus, often found as commensal bacteria of the human oral cavity, urogenital tract, and gastrointestinal tract. Prior case reports have demonstrated Granulicatella spp. as a pathogen that can cause bacteremia and infective endocarditis particularly of prosthetic valves and pacemaker leads. Here, we report on a unique case of Granulicatella adiacens bacterascites in a 50-year-old male. PMID- 26618013 TI - First Report of Ventriculoperitoneal Shunt Infection due to Cyberlindnera fabianii. AB - Fungal infections in the central nervous system (CNS) are associated with significant morbidity and death. Transient fungemia in immunocompetent patients without any other risk factors for fungemia has been suggested as a possible mechanism that may lead to serious fungal ventriculoperitoneal (VP) shunt infections, but evidence is lacking. The clinical spectrum, diagnosis, and optimal therapy of Cyberlindnera fabianii infections remain to be determined. We describe the first case of CNS infection due to C. fabianii that occurred in an immunocompetent adult with a VP shunt. Spontaneous translocation with yeast that is not part of the normal gastrointestinal flora in the setting of ingestion of multiple servings of a fermentation product was the likely source from which Cyberlindnera fabianii gained entrance into the VP shunt system, causing meningitis in this patient. The authors conclude that, in view of the high morbidity associated with yeast infection of the CNS, long-term antifungal therapy should be strongly considered in cases where the VP shunt cannot be completely removed. Transient fungemia may lead to invasive disease in an immunocompetent host with VP shunt, even in the absence of any other risk factors for fungemia and even after remote placement of the VP shunt. PMID- 26618014 TI - Brainstem Tuberculoma in Pregnancy. AB - We report a case of a Somali refugee who presented in the second trimester of her first pregnancy with a four-week history of gradual right-sided sensomotoric hemisyndrome including facial palsy and left-sided paresis of the oculomotorius nerve causing drooping of the left eyelid and double vision. Cranial magnetic resonance imaging revealed a solitary brainstem lesion. Upon detection of hilar lymphadenopathy on chest X-ray (CXR), the diagnosis of disseminated tuberculosis with involvement of the central nervous system was confirmed by PCR and treatment induced with rifampicin, isoniazid, pyrazinamide, and ethambutol. The patient had a steady neurological improvement and a favorable pregnancy outcome. PMID- 26618015 TI - Ischemic Retinal Vasculitis Associated with Cataract Surgery and Intracameral Vancomycin. AB - Recently, there have been reports suggesting that intracameral vancomycin has been associated with retinal vasculitis; some have described this phenomenon as postoperative hemorrhagic occlusive retinal vasculitis. We present a case of a 65 year-old woman who underwent uncomplicated phacoemulsification and posterior chamber intraocular lens implantation followed by intracameral antibiotic prophylaxis. Unlike prior reports, this report demonstrates a case of mild visual reduction and minimal inflammation with subtle but complete unilateral peripheral retinal ischemia associated with cataract surgery and intracameral vancomycin, suggesting a spectrum of toxicity that may be underrecognized. PMID- 26618016 TI - Multifocal Osteonecrosis Secondary to Chronic Alcohol Ingestion. AB - Multifocal osteonecrosis is a relatively rare disorder with an estimated incidence of around 3% among patients diagnosed as having osteonecrosis. Multifocal osteonecrosis is caused by the several conditions including corticosteroid treatment, coagulation disorders, connective tissue disorders including systemic lupus erythematosus (SLE), inflammatory bowel disease, renal transplantation, and underlying malignancies. Alcohol abuse is one of the risk factors for osteonecrosis, and alcohol-induced osteonecrosis is 5% among all the osteonecrosis. Furthermore, the overall incidence of alcohol-induced multifocal osteonecrosis was approximately 6% among all the osteonecrosis induced by the alcohol. Therefore, here, we report an extremely rare case of alcohol-induced multifocal osteonecrosis involving three joints (two knees and one hip) and review the related literature. PMID- 26618017 TI - Rotator Interval Lesion and Damaged Subscapularis Tendon Repair in a High School Baseball Player. AB - In 2013, a 16-year-old baseball pitcher visited Nobuhara Hospital complaining of shoulder pain and limited range of motion in his throwing shoulder. High signal intensity in the rotator interval (RI) area (ball sign), injured subscapularis tendon, and damage to both the superior and middle glenohumeral ligaments were identified using magnetic resonance imaging (MRI). Repair of the RI lesion and partially damaged subscapularis tendon was performed in this pitcher. During surgery, an opened RI and dropping of the subscapularis tendon were observed. The RI was closed in a 90 degrees externally rotated and abducted position. To reconfirm the exact repaired state of the patient, arthroscopic examination was performed from behind. However, suture points were not visible in the >30 degrees externally rotated position, which indicates that the RI could not be correctly repaired with the arthroscopic procedure. One year after surgery, the patient obtained full function of the shoulder and returned to play at a national convention. Surgical repair of the RI lesion should be performed in exactly the correct position of the upper extremity. PMID- 26618018 TI - Undiagnosed Hepatocellular Carcinoma Presenting as Nasal Metastases. AB - Hepatocellular carcinoma (HCC) is a primary malignancy of the liver with up to half of cases suffering from extrahepatic metastasis in the later stages of the disease. Commonly reported and encountered metastatic sites include the lymph nodes, lung, bone, and adrenal glands. This is an effort to throw a spotlight on a rare case of metastatic HCC which presented to us as two distinct lesions in the nose. It focuses on the presentation and the steps that were taken to reach this rare and unusual diagnosis. It sparks interest from a clinical and histopathology perspective. Our cynosure is the findings of the case coupled with a probe on the possible routes of spread of HCC to sinonasal region. PMID- 26618019 TI - Tuberculous Abscess of the Chest Wall Simulate Pyogenic Abscess. AB - The chest wall tuberculosis abscesses is rare. We present a case of a 27-year-old immunocompetent male who presented chest wall abscesses. Imaging (chest radiographic, ultrasound, and computed tomography) and Ziehl-Neelsen staining demonstrated chest wall tuberculosis abscesses. PMID- 26618020 TI - Massive Hemothorax Caused by a Single Intercostal Artery Bleed Ten Days after Solitary Minimally Displaced Rib Fracture. AB - Delayed hemothorax (DHX) following blunt thoracic trauma is a rare occurrence with an extremely variable incidence and time to diagnosis that is generally associated with clinically insignificant blood loss. In this report, we present a case of acute onset DHX ten days after a relatively mild traumatic event that resulted in a single minimally displaced rib fracture. The patient awoke from sleep suddenly with acute onset dyspnea and chest pain and reported to the emergency department (ED). The patient lost over six and a half liters of blood during the first 9 hours of his admission, the largest volume yet reported in the literature for DHX, which was eventually found to be due to a single intercostal artery bleed. Successful management in this case entailed two emergent thoracotomies and placement of multiple thoracostomy tubes to control blood loss. The patient was discharged home on postoperative day 5. PMID- 26618021 TI - Repeat Minimally Invasive Mitral Valve Replacement for Recurrent Mitral Stenosis after OMC in Patients Who Decline Blood Product Transfusion for Religious Reasons. AB - Cardiac surgery for Jehovah's Witness (JW) patients is considered to be high risk because of patients' refusal to receive blood transfusion. We report a successful mitral valve replacement for recurrent mitral stenosis after OMC with minimally invasive right thoracotomy, without any transfusion of allogeneic blood or blood products. This minimally invasive mitral valve replacement through right thoracotomy was an excellent approach for JW patients. PMID- 26618022 TI - Isolated Renal Metastasis from Non-Small-Cell Lung Cancer: Report of 2 Cases. AB - Renal metastasis from non-small-cell lung cancer is rather uncommon; isolated metastasis especially is rare. Herein we report 2 cases who developed a solitary renal metastasis after undergoing a curative resection for non-small-cell lung cancer. They received nephrectomy. PMID- 26618023 TI - A Useful Strategy to Evaluate the Quality Consistency of Traditional Chinese Medicines Based on Liquid Chromatography and Chemometrics. AB - Evaluation of the batch consistency of traditional Chinese medicines (TCMs) is essential for the promotion of the development and quality control of TCMs. The aim of the present work was to develop a useful strategy via liquid chromatography and chemometrics to evaluate the batch consistency of TCM preparations. Xin-Ke-Shu (XKS) tablet was chosen as a model for this method development. Four types of chromatographic fingerprint approaches were compared by using similarity analysis based on cosine of angel or correlation coefficient. Differences in the fingerprints of 71 batches of XKS tablet were illustrated by hierarchical cluster analysis. Then, Mahalanobis distance was employed for estimating the probability level (P < 0.05) of the differences mentioned above. Additionally, t-test was applied to find out the chromatographic peaks which had significant differences. For XKS tablet, the maximum wavelength fingerprint had the largest range and dispersion degree of similarity as compared with the other three ones. There were two clear clusters in all the batches of samples. And we clearly arrived at the conclusion that higher similarity does not exactly indicate small Mahalanobis distance, while lower similarity indicated larger Mahalanobis distance. Finally, a useful strategy was proposed for evaluation of the batch consistency of XKS tablet. PMID- 26618024 TI - Impacts of Different Tree Species of Different Sizes on Spatial Distribution of Herbaceous Plants in the Nigerian Guinea Savannah Ecological Zone. AB - This study was aimed at finding the impacts of different tree species and individual trees of different sizes on species richness, diversity, and composition of the herbaceous layer. All the three tree species have greatly increased species richness and diversity both within and outside their crown zones compared with the open grassland. Both species richness and diversity were found to be higher under all the three tree species than outside their crowns, which was in turn higher than the open field. Daniella oliveri has the highest species richness and diversity both within and outside its crown zone followed by Vitellaria paradoxa and then Parkia biglobosa. The result also revealed that the same tree species with different sizes leads to different herbaceous species richness, diversity, and composition under and around the trees' crowns. P. biglobosa and V. paradoxa trees with smaller sizes showed higher species richness and diversity under their crowns than the bigger ones. The dissimilarity of species composition differs between the inside and outside crown zones of the individuals of the same tree species and among the different trees species and the open field. PMID- 26618025 TI - High Time to Discuss Future-Oriented Telemedicine. PMID- 26618027 TI - Geriatric Telemedicine: Background and Evidence for Telemedicine as a Way to Address the Challenges of Geriatrics. AB - OBJECTIVES: The global population of elderly people is increasing at a remarkable rate, which may be expected to continue for some time. Older patients require more care, and with the current model of care delivery, the costs may be expected to rise, although higher cost is unsustainable. For this reason, a new pattern of practice is needed. Telemedicine will be presented as a highly effective and necessary tool in geriatrics. METHODS: This review will present some of the background and evidence for telemedicine as a way to address the challenges of geriatrics through geriatric telemedicine. Some of the evidence for the value of telemedicine as a tool for physicians and healthcare systems is presented. RESULTS: Telemedicine offers many means to address the problems of geriatric care in creative ways. The use of electronic medicine, telecommunications, and information management has now found its way into the very fabric of health care. The use of telemedicine is a fait accompli in much of the world, and it continues to have an increasing role deeply imbedded in our electronic practices coupled with social media. CONCLUSIONS: The evidence for successful incorporation of telemedicine into practice is abundant and continues to accrue. This is a great opportunity for medical practice to evolve to new levels of engagement with patients and new levels of attainment in terms of quality care. PMID- 26618026 TI - Recent Directions in Telemedicine: Review of Trends in Research and Practice. AB - OBJECTIVES: Healthcare is now routinely delivered by telecommunications-based services in all developed countries and an increasing number of developing countries. Telemedicine is used in many clinical specialities and across numerous healthcare settings, which range from mobile patient-centric applications to complex interactions amongst clinicians in tertiary referral hospital settings. This paper discusses some recent areas of significant development and progress in the field with the purpose of identifying strong trends in both research and practice activities. METHODS: To establish the breadth of new ideas and directions in the field, a review of literature was made by searching PubMed for recent publications including terms (telemedicine OR telehealth) AND (challenge OR direction OR innovation OR new OR novel OR trend), for all searchable categories. 3,433 publications were identified that have appeared since January 1, 2005 (2,172 of these since January 1, 2010), based on a search conducted on June 1, 2015. RESULTS: The current interest areas in these papers span both synchronous telemedicine, including intensive care, emergency medicine, and mental health, and asynchronous telemedicine, including wound and burns care, dermatology and ophthalmology. CONCLUSIONS: It is concluded that two major drivers of contemporary tele medicine development are a high volume demand for a particular clinical service, and/or a high criticality of need for clinical exper tise to deliver the service. These areas offer promise for further study and enhancement of applicable telemedicine methods and have the potential for large scale deployments internationally, which would contribute significantly to the advancement of healthcare. PMID- 26618028 TI - Evaluation Framework for Telemedicine Using the Logical Framework Approach and a Fishbone Diagram. AB - OBJECTIVES: Technological advances using telemedicine and telehealth are growing in healthcare fields, but the evaluation framework for them is inconsistent and limited. This paper suggests a comprehensive evaluation framework for telemedicine system implementation and will support related stakeholders' decision-making by promoting general understanding, and resolving arguments and controversies. METHODS: This study focused on developing a comprehensive evaluation framework by summarizing themes across the range of evaluation techniques and organized foundational evaluation frameworks generally applicable through studies and cases of diverse telemedicine. Evaluation factors related to aspects of information technology; the evaluation of satisfaction of service providers and consumers, cost, quality, and information security are organized using the fishbone diagram. RESULTS: It was not easy to develop a monitoring and evaluation framework for telemedicine since evaluation frameworks for telemedicine are very complex with many potential inputs, activities, outputs, outcomes, and stakeholders. A conceptual framework was developed that incorporates the key dimensions that need to be considered in the evaluation of telehealth implementation for a formal structured approach to the evaluation of a service. The suggested framework consists of six major dimensions and the subsequent branches for each dimension. CONCLUSIONS: To implement telemedicine and telehealth services, stakeholders should make decisions based on sufficient evidence in quality and safety measured by the comprehensive evaluation framework. Further work would be valuable in applying more comprehensive evaluations to verify and improve the comprehensive framework across a variety of contexts with more factors and participant group dimensions. PMID- 26618029 TI - Current Status and Progress of Telemedicine in Korea and Other Countries. AB - OBJECTIVES: The purpose of this study was to review the current telemedicine of the Korea and the telemedicine of the other countries. METHODS: This study reviewed several documents on telemedicine and summarized the documents on the initiation of the telemedicine of the Korea, the recent regulations of the government, the analytical research results, and the telemedicine of foreign countries. RESULTS: One of recent demonstration trials of telemedicine began in July 2015 in the Korea. The plan was to conduct an emergency telemedical treatment trial among the cooperative medical service centers until the end of February 2016. No telemedical services were provided at the level of local primary care clinics, and there was 1.2% provision at the hospital level. The Europe Union and the United States had more active telemedical services in comparison to the Korea. CONCLUSIONS: The introduction and usage of telemedicine in the Korea was behind those of other countries. It is necessary to develop a proactive support policy for telemedicine through a government implemented trial. PMID- 26618031 TI - Prerequisites for Effective Implementation of Telemedicine: Focusing on Current Situations in Korea. AB - OBJECTIVES: The practice of telemedicine requires social interventions and systems for efficient implementation. Further, it requires sufficient discussions among related parties because the purpose of telemedicine is diagnosis and treatment, and the participation of medical specialists is essential. Based on the characteristics of the healthcare structure of Korea, which has a low proportion of public healthcare and most patients are taken care of by a few large tertiary care hospitals, the fundamental issues need to be discussed. METHODS: A comparison was conducted with overseas cases to discuss the prerequisites for the effective implementation of telemedicine in South Korea under the current situation. We also examined the structural characteristics of the Korean medical community. RESULTS: The current paper recommends that an in depth analysis and studies are conducted on the following aspects: a search for telemedicine services focused on public healthcare, a search of services for illnesses that impose high levels of burden on households, and the development and implementation of a telemedicine system for follow-up management at primary and secondary care hospitals after the patient undergoes surgery or treatment at tertiary care hospitals. CONCLUSIONS: As the technology develops, the focus should also be on factors such as safety, usefulness, availability, and how the functions will be realized in order to enable user communication. A clear system should be established to regulate and manage the lack of sufficient discussions. In addition, seeking projects and systems that reflect the characteristics of each country will facilitate the efficient implementation of telemedicine. PMID- 26618032 TI - Proposal on the Establishment of Telemedicine Guidelines for Korea. AB - OBJECTIVES: An official guideline must be prepared for legalizing the doctor patient telemedicine system based on the evaluations of the ongoing telemedicine demonstration project performed by the Korean government. In this study, critical items of the Korean telemedicine guideline are suggested based on the guidelines of developed countries. METHODS: To investigate the telemedicine guidelines of developed countries, a keyword of 'telemedicine guidelines' was used for Google search to find out US, Australian, and Japanese guidelines. The common items included in two or more of the followings were screened: US Core Operational Guidelines for Telehealth Services Involving Provider-Patient Interactions, the Australian New South Wales (NSW) Agency for Clinical Innovation Guidelines for the use of Telehealth for Clinical and Non Clinical Settings in NSW, and the Japanese Guidelines for the practice of home telemedicine. RESULTS: A total of 22 common items of the following four domains, which could be used for the Korean guideline were screened: the common features in overall considerations (6 items), the common features in clinical considerations (6 items), the common features in technical considerations (5 items), and the common features in privacy considerations (5 items). These 22 items were suggested as the critical items of the Korean telemedicine guideline. CONCLUSIONS: The screened 22 items of the telemedicine guideline must be further organized for details. Additional studies and professional opinions on the telemedicine cases and on the guidelines of developed countries are required to establish the Korean guideline in the near future. PMID- 26618030 TI - Current Clinical Status of Telehealth in Korea: Categories, Scientific Basis, and Obstacles. AB - OBJECTIVES: Through telehealth, medical services have expanded beyond spatial boundaries and are now available in living spaces outside of hospitals. It can also contribute to patient medical knowledge improvement because patients can access their hospital records and data from home. However, concepts of telehealth are rather vague in Korea. METHODS: We refer to several clinical reports to determine the current clinical status of and obstacles to telehealth in Korea. RESULTS: Patients' health conditions are now reported regularly to doctors remotely, and patients can receive varied assistance. Self-improvement based on minute details that are beyond medical staff's reach is another possible benefit that may be realized with the help of a variety of medical equipment (sensors). The feasibility, clinical effect, and cost-benefit of telehealth have been verified by scientific evidence. CONCLUSIONS: Patients will be able to improve their treatment adherence by receiving help from various professionals, such as doctors, nurses, nutritionists, and sports therapists. This means that the actual treatment time per patient will increase as well. Ultimately, this will increase the quality of patients' self-administration of care to impede disease progression and prevent complications. PMID- 26618033 TI - Innovation Network Development Model in Telemedicine: A Change in Participation. AB - OBJECTIVES: This paper introduces a telemedicine innovation network and reports its implementation in Tehran University of Medical Sciences. The required conditions for the development of future projects in the field of telemedicine are also discussed; such projects should be based on the common needs and opportunities in the areas of healthcare, education, and technology. METHODS: The development of the telemedicine innovation network in Tehran University of Medical Sciences was carried out in two phases: identifying the beneficiaries of telemedicine, and codification of the innovation network memorandum; and brainstorming of three workgroup members, and completion and clustering ideas. The present study employed a qualitative survey by using brain storming method. Thus, the ideas of the innovation network members were gathered, and by using Freeplane software, all of them were clustered and innovation projects were defined. RESULTS: In the services workgroup, 87 and 25 ideas were confirmed in phase 1 and phase 2, respectively. In the education workgroup, 8 new programs in the areas of telemedicine, tele-education and teleconsultation were codified. In the technology workgroup, 101 and 11 ideas were registered in phase 1 and phase 2, respectively. CONCLUSIONS: Today, innovation is considered a major infrastructural element of any change or progress. Thus, the successful implementation of a telemedicine project not only needs funding, human resources, and full equipment. It also requires the use of innovation models to cover several different aspects of change and progress. The results of the study can provide a basis for the implementation of future telemedicine projects using new participatory, creative, and innovative models. PMID- 26618034 TI - Service-Oriented Security Framework for Remote Medical Services in the Internet of Things Environment. AB - OBJECTIVES: Remote medical services have been expanding globally, and this is expansion is steadily increasing. It has had many positive effects, including medical access convenience, timeliness of service, and cost reduction. The speed of research and development in remote medical technology has been gradually accelerating. Therefore, it is expected to expand to enable various high-tech information and communications technology (ICT)-based remote medical services. However, the current state lacks an appropriate security framework that can resolve security issues centered on the Internet of things (IoT) environment that will be utilized significantly in telemedicine. METHODS: This study developed a medical service-oriented frame work for secure remote medical services, possessing flexibility regarding new service and security elements through its service-oriented structure. First, the common architecture of remote medical services is defined. Next medical-oriented secu rity threats and requirements within the IoT environment are identified. Finally, we propose a "service oriented security frame work for remote medical services" based on previous work and requirements for secure remote medical services in the IoT. RESULTS: The proposed framework is a secure framework based on service-oriented cases in the medical environment. A com parative analysis focusing on the security elements (confidentiality, integrity, availability, privacy) was conducted, and the analysis results demonstrate the security of the proposed framework for remote medical services with IoT. CONCLUSIONS: The proposed framework is service oriented structure. It can support dynamic security elements in accordance with demands related to new remote medical services which will be diversely generated in the IoT environment. We anticipate that it will enable secure services to be provided that can guarantee confidentiality, integrity, and availability for all, including patients, non-patients, and medical staff. PMID- 26618035 TI - Fifteen-year Experience with Telemedicine Services in Gangwon Province in Korea. AB - OBJECTIVES: This study attempted to identify the factors that contribute to successful telemedicine service. This was done by analyzing the operational state of successful telemedicine services offered in Gangwon Province of Korea and their outcome for the last fifteen years. METHODS: A comparative analysis was made based on reports and a thesis on the satisfaction rate of patients and providers, patient compliance to treatment, and economic assessment of Gangwon telemedicine service, which were carried out in three periods: the years 2006, 2010, and 2012. RESULTS: The satisfaction surveys in all three periods showed similar results for patients (4.46+/-0.70 point) and healthcare practitioners, including nurses (3.82+/-0.62 point) and physicians (3.60+/-0.56 point), in decreasing order from the year 2012. Through the survey of patients' compliance with treatment, it was confirmed that telemedicine services increased patients' compliance with drug administration, facilitated improvement of lifestyle habits, improved glycated hemoglobin for patients with diabetes mellitus, and enhanced the rate of blood pressure control. In the survey conducted on patients' willingness to pay for telemedicine services in 2007, it was found that those patients were willing to pay about $3.5 for services. CONCLUSIONS: The telemedicine services of Gangwon Province increased patients' compliance with drug administration, improved blood glucose control, enhanced blood pressure control for patients with hypertension, and provided economic advantage. PMID- 26618036 TI - Early Experiences with Mobile Electronic Health Records Application in a Tertiary Hospital in Korea. AB - OBJECTIVES: Recent advances in mobile technology have opened up possibilities to provide strongly integrated mobile-based services in healthcare and telemedicine. Although the number of mobile Electronic Health Record (EHR) applications is large and growing, there is a paucity of evidence demonstrating the usage patterns of these mobile applications by healthcare providers. This study aimed to illustrate the deployment process for an integrated mobile EHR application and to analyze usage patterns after provision of the mobile EHR service. METHODS: We developed an integrated mobile application that aimed to enhance the mobility of healthcare providers by improving access to patient- and hospital-related information during their daily medical activities. The study included mobile EHR users who accessed patient healthcare records between May 2013 and May 2014. We performed a data analysis using a web server log file analyzer from the integrated EHR system. Cluster analysis was applied to longitudinal user data based on their application usage pattern. RESULTS: The mobile EHR service named M UMIS has been in service since May 2013. Every healthcare provider in the hospital could access the mobile EHR service and view the medical charts of their patients. The frequency of using services and network packet transmission on the M-UMIS increased gradually during the study period. The most frequently accessed service in the menu was the patient list. CONCLUSIONS: A better understanding regarding the adoption of mobile EHR applications by healthcare providers in patient-centered care provides useful information to guide the design and implementation of future applications. PMID- 26618037 TI - Evaluation of Mobile Health Applications Developed by a Tertiary Hospital as a Tool for Quality Improvement Breakthrough. AB - OBJECTIVES: To evaluate the mobile health applications (apps) developed by a single tertiary hospital in Korea with a particular focus on quality and patient safety. METHODS: Twenty-three mobile health apps developed by Asan Medical Center were selected for analysis after exclusion of the apps without any relationship with healthcare or clinical workflow, the apps for individual usage, and the mobile Web apps. Two clinical informaticians independently evaluated the apps with respect to the six aims for quality improvement suggested by the United States Institute of Medicine. All discrepancies were resolved after discussion by the two reviewers. The six aims observed in the apps were reviewed and compared by target users. RESULTS: Eleven apps targeted patients, the other 12 were designed for healthcare providers. Among the apps for patients, one app also had functions for healthcare providers. 'My cancer diary' and 'My chart in my hand' apps matched all the six aims. Of the six aims, Timeliness was the most frequently observed (20 apps), and Equity was the least observed (6 apps). Timeliness (10/11 vs. 10/12) and Patient safety (10/11 vs. 9/12) were frequently observed in both groups. In the apps for patients, Patient-centeredness (10/11 vs. 2/12) and Equity (6/11 vs. 0/12) were more frequent but Efficiency (5/11 vs. 10/12) was less frequent. CONCLUSIONS: Most of the six aims were observed in the apps, but the extent of coverage varied. Further studies, evaluating the extent to which they improve quality are needed. PMID- 26618038 TI - Chronic Heart Failure Follow-up Management Based on Agent Technology. AB - OBJECTIVES: Monitoring heart failure patients through continues assessment of sign and symptoms by information technology tools lead to large reduction in re hospitalization. Agent technology is one of the strongest artificial intelligence areas; therefore, it can be expected to facilitate, accelerate, and improve health services especially in home care and telemedicine. The aim of this article is to provide an agent-based model for chronic heart failure (CHF) follow-up management. METHODS: This research was performed in 2013-2014 to determine appropriate scenarios and the data required to monitor and follow-up CHF patients, and then an agent-based model was designed. RESULTS: Agents in the proposed model perform the following tasks: medical data access, communication with other agents of the framework and intelligent data analysis, including medical data processing, reasoning, negotiation for decision-making, and learning capabilities. CONCLUSIONS: The proposed multi-agent system has ability to learn and thus improve itself. Implementation of this model with more and various interval times at a broader level could achieve better results. The proposed multi-agent system is no substitute for cardiologists, but it could assist them in decision-making. PMID- 26618039 TI - Are Currently Available Wearable Devices for Activity Tracking and Heart Rate Monitoring Accurate, Precise, and Medically Beneficial? AB - OBJECTIVES: The new wave of wireless technologies, fitness trackers, and body sensor devices can have great impact on healthcare systems and the quality of life. However, there have not been enough studies to prove the accuracy and precision of these trackers. The objective of this study was to evaluate the accuracy, precision, and overall performance of seventeen wearable devices currently available compared with direct observation of step counts and heart rate monitoring. METHODS: Each participant in this study used three accelerometers at a time, running the three corresponding applications of each tracker on an Android or iOS device simultaneously. Each participant was instructed to walk 200, 500, and 1,000 steps. Each set was repeated 40 times. Data was recorded after each trial, and the mean step count, standard deviation, accuracy, and precision were estimated for each tracker. Heart rate was measured by all trackers (if applicable), which support heart rate monitoring, and compared to a positive control, the Onyx Vantage 9590 professional clinical pulse oximeter. RESULTS: The accuracy of the tested products ranged between 79.8% and 99.1%, while the coefficient of variation (precision) ranged between 4% and 17.5%. MisFit Shine showed the highest accuracy and precision (along with Qualcomm Toq), while Samsung Gear 2 showed the lowest accuracy, and Jawbone UP showed the lowest precision. However, Xiaomi Mi band showed the best package compared to its price. CONCLUSIONS: The accuracy and precision of the selected fitness trackers are reasonable and can indicate the average level of activity and thus average energy expenditure. PMID- 26618040 TI - Correction: Value of Analog in Medicine: Digital Compromise to Teach Old-Timer New Trick. AB - [This corrects the article on p. 141 in vol. 21, PMID: 26279949.]. PMID- 26618041 TI - Optimal Sampling-Based Motion Planning under Differential Constraints: the Driftless Case. AB - Motion planning under differential constraints is a classic problem in robotics. To date, the state of the art is represented by sampling-based techniques, with the Rapidly-exploring Random Tree algorithm as a leading example. Yet, the problem is still open in many aspects, including guarantees on the quality of the obtained solution. In this paper we provide a thorough theoretical framework to assess optimality guarantees of sampling-based algorithms for planning under differential constraints. We exploit this framework to design and analyze two novel sampling-based algorithms that are guaranteed to converge, as the number of samples increases, to an optimal solution (namely, the Differential Probabilistic RoadMap algorithm and the Differential Fast Marching Tree algorithm). Our focus is on driftless control-affine dynamical models, which accurately model a large class of robotic systems. In this paper we use the notion of convergence in probability (as opposed to convergence almost surely): the extra mathematical flexibility of this approach yields convergence rate bounds - a first in the field of optimal sampling-based motion planning under differential constraints. Numerical experiments corroborating our theoretical results are presented and discussed. PMID- 26618042 TI - Limb Ischemic Perconditioning Attenuates Blood-Brain Barrier Disruption by Inhibiting Activity of MMP-9 and Occludin Degradation after Focal Cerebral Ischemia. AB - Remote ischemic perconditioning (PerC) has been proved to have neuroprotective effects on cerebral ischemia, however, the effect of PerC on the BBB disruption and underlying mechanisms remains largely unknown. To address these issues, total 90 adult male Sprague Dawley (SD) rats were used. The rats underwent 90-min middle cerebral artery occlusion (MCAO), and the limb remote ischemic PerC was immediately applied after the onset of MCAO. We found that limb remote PerC protected BBB breakdown and brain edema, in parallel with reduced infarct volume and improved neurological deficits, after MCAO. Immunofluorescence studies revealed that MCAO resulted in disrupted continuity of claudin-5 staining in the cerebral endothelial cells with significant gap formation, which was significantly improved after PerC. Western blot analysis demonstrated that expression of tight junction (TJ) protein occludin was significantly increased, but other elements of TJ proteins, claudin-5 and ZO-1, in the BBB endothelial cells were not altered at 48 h after PerC, compared to MCAO group. The expression of matrix metalloproteinase (MMP-9), which was involved in TJ protein degradation, was decreased after PerC. Interestingly, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), an upstream of MMP-9 signaling, was significantly reduced in the PerC group. Our data suggest that PerC inhibits MMP-9-mediated occludin degradation, which could lead to decreased BBB disruption and brain edema after ischemic stroke. PMID- 26618043 TI - Cortisol Supplement Combined with Psychotherapy and Citalopram Improves Depression Outcomes in Patients with Hypocortisolism after Traumatic Brain Injury. AB - Depression is one of the most prevalent psychiatric disorders in people with Traumatic brain injury (TBI). Depression after TBI is closely related with social and psychological factors and hypothalamic-pituitary -adrenal (HPA) axis dysfunction. However, there is a lack of evidence regarding effective treatment approaches for depression. A total of 68 patients with depression following closed TBI were recruited. Glasgow Coma Scale score (GCS) was employed to demonstrate the severity of neurological deficits and Glasgow Outcome Scale (GOS) was employed to measure functional outcome after TBI. The severity of depression was quantified using the Beck Depression Inventory-II (BDI-II) in line with DSM IV. Citalopram and Prednisone were administered to subjects with normal cortisol levels or hypocortisolism separately, based on psychotherapeutic interventions. We investigated the relationship between degree of depression of TBI patients and the severity and progression of TBI with the therapeutic effects of Citalopram in combination with psychotherapeutic and Prednisone in depressed patients. There was no relationship between the severity of depression and the severity and progression of TBI. The basic treatment of psychotherapeutic interventions could partially relieve depressive symptoms. Combination of psychotherapeutic support and Citalopram significantly improved depressive symptoms in patients with normal cortisol levels, but not in hypocortisolic patients. Combination of Prednisone administration with psychotherapeutic treatment and Citalopram significantly improved depression outcome in hypocortisolic patients after TBI. Hypocortisolism after TBI may regulate depression. Combination of Prednisone with psychotherapeutic treatment and Citalopram may provide better therapeutic effects in depression patients with hypocortisolism after TBI. PMID- 26618044 TI - Low Cerebral Glucose Metabolism: A Potential Predictor for the Severity of Vascular Parkinsonism and Parkinson's Disease. AB - This study explored the association between cerebral metabolic rates of glucose (CMRGlc) and the severity of Vascular Parkinsonism (VP) and Parkinson's disease (PD). A cross-sectional study was performed to compare CMRGlc in normal subjects vs. VP and PD patients. Twelve normal subjects, 22 VP, and 11 PD patients were evaluated with the H&Y and MMSE, and underwent 18F-FDG measurements. Pearson's correlations were used to identify potential associations between the severity of VP/PD and CMRGlc. A pronounced reduction of CMRGlc in the frontal lobe and caudate putamen was detected in patients with VP and PD when compared with normal subjects. The VP patients displayed a slight CMRGlc decrease in the caudate putamen and frontal lobe in comparison with PD patients. These decreases in CMRGlc in the frontal lobe and caudate putamen were significantly correlated with the VP patients' H&Y, UPDRS II, UPDRS III, MMSE, cardiovascular, and attention/memory scores. Similarly, significant correlations were observed in patients with PD. This is the first clinical study finding strong evidence for an association between low cerebral glucose metabolism and the severity of VP and PD. Our findings suggest that these changes in glucose metabolism in the frontal lobe and caudate putamen may underlie the pathophysiological mechanisms of VP and PD. As the scramble to find imaging biomarkers or predictors of the disease intensifies, a better understanding of the roles of cerebral glucose metabolism may give us insight into the pathogenesis of VP and PD. PMID- 26618045 TI - Topography of Cortical Microbleeds in Alzheimer's Disease with and without Cerebral Amyloid Angiopathy: A Post-Mortem 7.0-Tesla MRI Study. AB - Cortical microbleeds (CMBs) detected on T2*-weighted gradient-echo (GRE) magnetic resonance imaging (MRI) are considered as a possible hallmark of cerebral amyloid angiopathy (CAA). The present post-mortem 7.0-tesla MRI study investigates whether topographic differences exist in Alzheimer's brains without (AD) and with CAA (AD-CAA). The distribution of CMBs in thirty-two post-mortem brains, consisting of 12 AD, 8 AD-CAA and 12 controls, was mutually compared on T2*-GRE MRI of six coronal sections of a cerebral hemisphere. The mean numbers of CMBs were determined in twenty-two different gyri. As a whole there was a trend of more CMBs on GRE MRI in the prefrontal section of the AD, the AD-CAA as well as of the control brains. Compared to controls AD brains had significantly more CMBs in the superior frontal, the inferior temporal, the rectus and the cinguli gyrus, and in the insular cortex. In AD-CAA brains CMBs were increased in all gyri with exception of the medial parietal gyrus and the hippocampus. AD-CAA brains showed a highly significant increase of CMBs in the inferior parietal gyrus (p value: 0.001) and a significant increase in the precuneus and the cuneus (p value: 0.01) compared to the AD brains. The differences in topographic distribution of CMBs between AD and AD-CAA brains should be further investigated on MRI in clinically suspected patients. PMID- 26618046 TI - Inflammatory Cytokines Induce Expression of Chemokines by Human Retinal Cells: Role in Chemokine Receptor Mediated Age-related Macular Degeneration. AB - Chemokine reeptor-3 (CCR-3) was shown to be associated with choroidal neovascularization (CNV) in age-related macular degeneration (AMD). AMD is a vision threatening retinal disease that affects the aging population world-wide. Retinal pigment epithelium and choroid in the posterior part of the retina are the key tissues targeted in the pathogenesis of CNV in AMD. We used human retinal pigment epithelial (HRPE) and choroidal fibroblast (HCHF) cells, prepared from aged adult human donor eyes, to evaluate the expression of major CCR-3 ligands, CCL-5, CCL -7, CCL-11,CCL-24 and CCL-26. Microarray analysis of gene expression in HRPE cells treated with inflammatory cytokine mix (ICM= IFN-gamma+TNF-alpha+IL 1beta) revealed 75 and 23-fold increase in CCL-5 and CCL-7 respectively, but not CCL-11, CCL-24 and CCL-26. Chemokine secretion studies of the production of CCL5 and CCL7 by HRPE corroborated with the gene expression analysis data. When the HRPE cells were treated with either individual cytokines or the ICM, both CCL-5 and CCL-7 were produced in a dose dependent manner. Similar to the gene expression data, the ICM did not enhance HRPE production of CCL-11, CCL-24 and CCL-26. CCL-11 and CCL-26 were increased with IL-4 treatment and this HRPE production was augmented in the presence of TNF-alpha and IL1beta. When HCHF cells were treated with either individual cytokines or the ICM, both CCL-5 and CCL-7 were produced in a dose dependent fashion. IL-4 induced low levels of CCL 11 and CCL-26 in HCHF and this production was significantly enhanced by TNF alpha. Under these conditions, neither HRPE nor HCHF were demonstrated to produce CCL-24. These data demonstrate that chronic inflammation triggers CCL-5 and CCL-7 release by HRPE and HCHF and the subsequent interactions with CCR3 may participate in pathologic processes in AMD. PMID- 26618047 TI - Genistein, the Isoflavone in Soybean, Causes Amyloid Beta Peptide Accumulation in Human Neuroblastoma Cell Line: Implications in Alzheimer's Disease. AB - The isoflavone, genistein, present in soybean is being actively investigated for its potential beneficial effect against Alzheimer's disease. Our data, however, show that in SHSY5Y cells genistein causes increased expression (mRNA and protein) of amyloid precursor protein (APP), increased mRNA expression and activity of beta-secretase and diminished level of insulin degrading enzyme (IDE) which also degrades amyloid beta peptide. These effects of genistein lead to enhanced accumulation of amyloid beta peptide (Abeta42) in SHSY5Y cells. The results do not support the view that genistein could be a putative drug against AD and instead strengthen the epidemiological study which implies that genistein content of soybean food product (Tofu) leads to cognitive impairment. PMID- 26618048 TI - Influence of Pulmonary Rehabilitation on Lung Function Changes After the Lung Resection for Primary Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease. AB - Influence of physiotherapy on the outcome of the lung resection is still controversial. Study aim was to assess the influence of physiotherapy program on postoperative lung function and effort tolerance in lung cancer patients with chronic obstructive pulmonary disease (COPD) that are undergoing lobectomy or pneumonectomy. The prospective study included 56 COPD patients who underwent lung resection for primary non small-cell lung cancer after previous physiotherapy (Group A) and 47 COPD patients (Group B) without physiotherapy before lung cancer surgery. In Group A, lung function and effort tolerance on admission were compared with the same parameters after preoperative physiotherapy. Both groups were compared in relation to lung function, effort tolerance and symptoms change after resection. In patients with tumors requiring a lobectomy, after preoperative physiotherapy, a highly significant increase in FEV1, VC, FEF50 and FEF25 of 20%, 17%, 18% and 16% respectively was registered with respect to baseline values. After physiotherapy, a significant improvement in 6-minute walking distance was achieved. After lung resection, the significant loss of FEV1 and VC occurred, together with significant worsening of the small airways function, effort tolerance and symptomatic status. After the surgery, a clear tendency existed towards smaller FEV1 loss in patients with moderate to severe, when compared to patients with mild baseline lung function impairment. A better FEV1 improvement was associated with more significant loss in FEV1. Physiotherapy represents an important part of preoperative and postoperative treatment in COPD patients undergoing a lung resection for primary lung cancer. PMID- 26618050 TI - Relationship between CYP17A1 Genetic Polymorphism and Essential Hypertension in a Chinese Population. AB - The relationship between CYP17A1 genetic polymorphisms and essential hypertension (EH) remains unclear. The aim of this study was to investigate the association of CYP17A1 genetic polymorphisms with EH in Han and Uighur populations in China. A Han population including 558 people (270 EH patients and 288 controls) and a Uighur population including 473 people (181 EH patients and 292 controls) were selected. Five single-nucleotide polymorphisms (SNPs) (rs4919686, rs1004467, rs4919687, rs10786712, and rs2486758) were genotyped using real-time PCR (TaqMan). In the Uighur population, for the total and the men, rs4919686, rs4919687 and rs10786712 were found to be associated with EH (rs4919686: P<=0.02, rs4919687: P<=0.002, rs10786712: P<=0.004, respectively). The difference remained statistically significant after the multivariate adjustment (all P<0.05). The overall distributions of the haplotypes established by SNP1-SNP3, SNP1-SNP4, SNP1 SNP3-SNP5 and SNP1-SNP4-SNP5 were significantly different between the EH patients and the control subjects (for the total: P=0.013, P=0.008, P=0.032, P=0.010, for men: P<0.001, P=0.001, P=0.010, P=0.00). In the Han population, for men, rs2486758 was found to be associated with EH in a recessive model (P=0.007); the significant difference was not retained after the adjustment for the covariates (date not shown). The A allele of rs4919686 could be a susceptible genetic marker, and the T allele of rs10786712 could be a protective genetic marker of EH. The AC genotype of rs4919686, the AG genotype of rs4919687 and the TT genotype of rs10786712 could be protective genetic markers of EH. PMID- 26618049 TI - Overexpression of miR-1260b in Non-small Cell Lung Cancer is Associated with Lymph Node Metastasis. AB - Lymph node (LN) metastasis is often an early event in the progression of malignant tumors and it contributes to the majority of cancer mortalities. MiRNAs play key roles in tumor metastasis. This study aimed to investigate the specific miRNAs as putative indicators of metastasis early diagnosis for non-small cell lung cancer (NSCLC). In this study, five NSCLC cases with LN metastasis and four cases without metastasis (NLN) were enrolled for Agilent Human miRNA array. The interested differentially expressed miRNA was validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in the LN metastasis (n = 46) and NLN (n = 39) groups. The microarray results revealed that three miRNAs (miR 1260b, miR-423-3p, miR-23a-5p) were differentially expressed in LN metastasis group compared with NLN group. The expression of miR-1260b was tested by qRT-PCR and the mean relative expression fold change (2(-DeltaDeltaCt)) in LN metastasis was significantly higher than that in the NLN group (3.942, 1.743 respectively, P = 1.179E-04). The patients with tumor-node-metastasis (TNM) stage III were identified more frequently in LN metastasis group (P = 1.772E-11) and with a higher expression level of miR-1260b (5.126, P = 1.147E-06). In addition, the LN metastasis cases were associated with a poorly differentiated degree (P = 0.007). The overexpression of miR-1260b in NSCLC with LN metastasis can be regarded as a specific signature for early progression and prognosis of NSCLC. PMID- 26618051 TI - Cell Therapy for Parkinson's Disease: New Hope from Reprogramming Technologies. AB - Parkinson's disease (PD) is a neurodegenerative disease with the major pathology being the progressive loss of dopaminergic (DA) midbrain neurons in the substantia nigra. As early as in the 1980s, open-label clinical trials employing fetal ventral mesencephalon (fVM) tissues have demonstrated significant efficacy for PD treatment, which led to two NIH-sponsored double-blind placebo-controlled clinical trials. However, both trials showed only mild outcome. Retrospective analysis revealed several possible reasons that include patient selection, heterogeneity of grafts, immune recognition of grafts, lack of standardization of transplantation procedure and uneven distribution of grafts. Recent years have seen advances in reprogramming technologies which may provide solutions to the problems associated with fVM tissues. Induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) hold promise for generating clinical grade DA neural cells that are safe, homogeneous, scalable and standardizable. These new technologies may bring back clinical trials using cell therapy for PD treatment in the future. PMID- 26618052 TI - Resolving Interparticle Heterogeneities in Composition and Hydrogenation Performance between Individual Supported Silver on Silica Catalysts. AB - Supported metal nanoparticle catalysts are commonly obtained through deposition of metal precursors onto the support using incipient wetness impregnation. Typically, empirical relations between metal nanoparticle structure and catalytic performance are inferred from ensemble averaged data in combination with high resolution electron microscopy. This approach clearly underestimates the importance of heterogeneities present in a supported metal catalyst batch. Here we show for the first time how incipient wetness impregnation leads to 10-fold variations in silver loading between individual submillimeter-sized silica support granules. This heterogeneity has a profound impact on the catalytic performance, with 100-fold variations in hydrogenation performance at the same level. In a straightforward fashion, optical microscopy interlinks single support particle level catalytic measurements to structural and compositional information. These detailed correlations reveal the optimal silver loading. A thorough consideration of catalyst heterogeneity and the impact thereof on the catalytic performance is indispensable in the development of catalysts. PMID- 26618053 TI - Reducing Viral Load Measurements to Once a Year in Patients on Stable, Virologically Suppressive Cart Regimen: Findings from the Australian HIV Observational Database. AB - Reducing viral-load measurements to annual testing in virologically suppressed patients increases the estimated mean time those patients remain on a failing regimen by 6 months. This translates to an increase in the proportion of patients with at least one Thymidine Analogue Mutation from 10% to 32% over one year. PMID- 26618054 TI - The Potential of Intralesional Rose Bengal to Stimulate T-Cell Mediated Anti Tumor Responses. AB - Rose Bengal (RB) is a red synthetic dye that was initially used in the garment industry and has been used safely for decades as a corneal stain by ophthalmologists. Antineoplastic properties of RB have also been observed, though the mechanism of action remained to be elucidated. Recently, interest in RB as a therapeutic cancer treatment has increased due to significant anti-tumor responses with direct tumor injection in human clinical trials for metastatic melanoma. In these patients, there has been the implication that RB may mount a T cell mediated anti-tumor response and impart antigen-specific responses in distant bystander lesions. This article serves to evaluate the potential of intralesional rose bengal to stimulate T-cell mediated anti-tumor responses in in vitro, pre-clinical, and clinical studies. PMID- 26618055 TI - Challenges and Needs Faced by Female Combat Veterans. AB - This article presents findings of a study conducted to identify stressors that may contribute to mental health issues of military female veterans. Female members in the U.S. Armed Forces currently occupy more non-traditional roles; therefore deployment to combat zones, commonly reserved for males, is being taken on by females. While at the present time females serving in the military are not allowed to serve in combat occupations, the reality is that many are being placed in combat roles or environments. Consequently, many are now confronted with stressors related to combat and multiple deployments. This study was based on a descriptive, non-probability, snowball design. In cases where participants displayed a reluctance to share some information in front of counterparts who may have been at a higher or lower rank level; subsequent semi-structured, one-to-one interviews were conducted. The latter approach proved more effective in gathering important information, such as issues of military sexual trauma (MST) and issues of intimacy upon re-entering the home environment. This study was conducted before January 2013, when Defense Secretary Leon Panetta announced the lift of the ban on women serving in combat. Therefore, future studies will need to be conducted to discern how these stressors will affect them in their new role as active combatants. PMID- 26618056 TI - CURRENT CONCEPTS IN PERIODIZATION OF STRENGTH AND CONDITIONING FOR THE SPORTS PHYSICAL THERAPIST. AB - The rehabilitation process is driven by the manipulation of training variables that elicit specific adaptations in order to meet established goals. Periodization is an overall concept of training that deals with the division of the training process into specific phases. Programming is the manipulation of the variables within these phases (sets, repetitions, load) that are needed to bring about the specific adaptations desired within that particular period. The current body of literature is very limited when it comes to how these variables are best combined in an injured population since most of the periodization research has been done in a healthy population. This manuscript explores what is currently understood about periodization, gives clinical guidelines for implementation, and provides the sports physical therapist with a framework to apply these principles in designing rehabilitation programs. LEVEL OF EVIDENCE: 5. PMID- 26618057 TI - CURRENT CONCEPTS OF MUSCLE AND TENDON ADAPTATION TO STRENGTH AND CONDITIONING. AB - Injuries to the muscle and/or associated tendon(s) are common clinical entities treated by sports physical therapists and other rehabilitation professionals. Therapeutic exercise is a primary treatment modality for muscle and/or tendon injuries; however, the therapeutic exercise strategies should not be applied in a "one-size-fits-all approach". To optimize an athlete's rehabilitation or performance, one must be able to construct resistance training programs accounting for the type of injury, the stage of healing, the functional and architectural requirements for the muscle and tendon, and the long-term goals for that patient. The purpose of this clinical commentary is to review the muscular and tendinous adaptations associated with strength training, link training adaptations and resistance training principles for the athlete recovering from an injury, and illustrate the application of evidence-based resistance training for patients with a tendinopathy. LEVEL OF EVIDENCE: 5. PMID- 26618059 TI - ROLLING REVISITED: USING ROLLING TO ASSESS AND TREAT NEUROMUSCULAR CONTROL AND COORDINATION OF THE CORE AND EXTREMITIES OF ATHLETES. AB - Rolling is a movement pattern seldom used by physical therapists for assessment and intervention with adult clientele with normal neurologic function. Rolling, as an adult motor skill, combines the use of the upper extremities, core, and lower extremities in a coordinated manner to move from one posture to another. Rolling is accomplished from prone to supine and supine to prone, although the method by which it is performed varies among adults. Assessment of rolling for both the ability to complete the task and bilateral symmetry may be beneficial for use with athletes who perform rotationally-biased sports such as golf, throwing, tennis, and twisting sports such as dance, gymnastics, and figure skating. When stability-based dysfunction exists, the rolling patterns can be used as intervention techniques, and have the ability to affect dysfunction of the upper quarter, core, and lower quarter. By applying proprioceptive neuromuscular facilitation (PNF) principles, the therapist may assist patients and clients who are unable to complete a rolling pattern. Examples given in the article include distraction/elongation, compression, and manual contacts to facilitate proper rolling. The authors assert that therapeutic use of the developmental pattern of rolling with techniques derived from PNF can be creatively and effectively utilized in musculoskeletal rehabilitation. Preliminary results from an exploration of the mechanism by which rolling may impact stability is presented, and available updated evidence is provided. The purpose of this clinical commentary is to describe techniques for testing, assessment, and treatment of dysfunction, using case examples that incorporate rolling. LEVEL OF EVIDENCE: 5. PMID- 26618058 TI - CURRENT CONCEPTS OF PLYOMETRIC EXERCISE. AB - As knowledge regarding rehabilitation science continues to increase, exercise programs following musculoskeletal athletic injury continue to evolve. Rehabilitation programs have drastically changed, especially in the terminal phases of rehabilitation, which include performance enhancement, development of power, and a safe return to activity. Plyometric exercise has become an integral component of late phase rehabilitation as the patient nears return to activity. Among the numerous types of available exercises, plyometrics assist in the development of power, a foundation from which the athlete can refine the skills of their sport. Therefore, the purpose of this clinical commentary is to provide an overview of plyometrics including: definition, phases, the physiological, mechanical and neurophysiological basis of plyometrics, and to describe clinical guidelines and contraindications for implementing plyometric programs. PMID- 26618060 TI - CORE MUSCLE ACTIVITY DURING THE CLEAN AND JERK LIFT WITH BARBELL VERSUS SANDBAGS AND WATER BAGS. AB - PURPOSE/BACKGROUND: While the traditional clean and jerk maneuver implies simultaneous participation of a large number of muscle groups, the use of this exercise with some variations to enhance core muscle activity remains uninvestigated. The purpose of this study was to compare the muscle activity during clean and jerk lift when performed with a barbell, sandbag and a water bag at same absolute load. STUDY DESIGN: Descriptive, repeated-measures study. METHODS: Twenty-one young fit male university students (age: 25 +/- 2.66 years; height: 180.71 +/- 5.42 cm; body mass: 80.32 +/- 9.8 kg; body fat percentage: 12.41 +/- 3.56 %) participated. Surface electromyographic (EMG) signals were recorded from the anterior deltoid (AD), external oblique (OBLIQ), lumbar erector spinae (LUMB), and gluteus medius (GM) and were expressed as a percentage of the maximum voluntary isometric contraction (MVIC). RESULTS: There were no significantly significant differences for AD muscle activity between conditions, whereas muscle activation values for OBLIQ (60%MVIC), GM (29%MVIC) and LUMB (85%MVIC) were significantly higher during the water bag power clean and jerk maneuver when compared with the other conditions. CONCLUSIONS: The clean and jerk is an exercise that may be used to enhance core muscle activity. Performing the maneuver with water bags resulted in higher core muscle activity compared with sandbag and standard barbell versions. LEVEL OF EVIDENCE: 3. PMID- 26618061 TI - EMG Analysis and Sagittal Plane Kinematics of the Two-Handed and Single-Handed Kettlebell Swing: A Descriptive Study. AB - INTRODUCTION: Kettlebell (KB) swing exercises have been proposed as a possible method to improve hip and spinal motor control as well as improve power, strength, and endurance. PURPOSE: To describe electromyographic (EMG) and sagittal plane kinematics during two KB exercises: the two-handed KB swing (THKS) and the single-handed KB swing (SHKS). In addition, the authors sought to investigate whether or not hip flexor length related to the muscular activity or the kinematics of the exercise. METHODS: Twenty-three healthy college age subjects participated in this study. Demographic information and passive hip flexor length were recorded for each subject. A maximum voluntary isometric contraction (MVIC) of bilateral gluteus maximus (GMAX), gluteus medius (GMED), and biceps femoris (BF) muscles was recorded. EMG activity and sagittal plane video was recorded during both the THKS and SHKS in a randomized order. Normalized muscular activation of the three studied muscles was calculated from EMG data. RESULTS: During both SHKS and THKS, the average percent of peak MVIC for GMAX was 75.02% +/- 55.38, GMED 55.47% +/- 26.33, and BF 78.95% +/- 53.29. Comparisons of the mean time to peak activation (TTP) for each muscle showed that the biceps femoris was the first muscle to activate during the swings. Statistically significant (p < .05), moderately positive correlations (r = .483 and .417) were found between passive hip flexor length and % MVIC for the GMax during the SHKS and THKS, respectively. CONCLUSIONS: The THKS and SHKS provide sufficient muscular recruitment for strengthening of all of the muscles explored. This is the first study to show significant correlations between passive hip flexor length and muscular activation of hip extensors, particularly the GMax. Finally, the BF consistently reached peak activity before the GMax and GMed during the SHKS. LEVEL OF EVIDENCE: Level 3. PMID- 26618062 TI - THE EFFECTS OF SELF-MYOFASCIAL RELEASE USING A FOAM ROLL OR ROLLER MASSAGER ON JOINT RANGE OF MOTION, MUSCLE RECOVERY, AND PERFORMANCE: A SYSTEMATIC REVIEW. AB - BACKGROUND: Self-myofascial release (SMR) is a popular intervention used to enhance a client's myofascial mobility. Common tools include the foam roll and roller massager. Often these tools are used as part of a comprehensive program and are often recommended to the client to purchase and use at home. Currently, there are no systematic reviews that have appraised the effects of these tools on joint range of motion, muscle recovery, and performance. PURPOSE: The purpose of this review was to critically appraise the current evidence and answer the following questions: (1) Does self-myofascial release with a foam roll or roller massager improve joint range of motion (ROM) without effecting muscle performance? (2) After an intense bout of exercise, does self-myofascial release with a foam roller or roller-massager enhance post exercise muscle recovery and reduce delayed onset of muscle soreness (DOMS)? (3) Does self-myofascial release with a foam roll or roller-massager prior to activity affect muscle performance? METHODS: A search strategy was conducted, prior to April 2015, which included electronic databases and known journals. Included studies met the following criteria: 1) Peer reviewed, english language publications 2) Investigations that measured the effects of SMR using a foam roll or roller massager on joint ROM, acute muscle soreness, DOMS, and muscle performance 3) Investigations that compared an intervention program using a foam roll or roller massager to a control group 4) Investigations that compared two intervention programs using a foam roll or roller massager. The quality of manuscripts was assessed using the PEDro scale. RESULTS: A total of 14 articles met the inclusion criteria. SMR with a foam roll or roller massager appears to have short-term effects on increasing joint ROM without negatively affecting muscle performance and may help attenuate decrements in muscle performance and DOMS after intense exercise. Short bouts of SMR prior to exercise do not appear to effect muscle performance. CONCLUSION: The current literature measuring the effects of SMR is still emerging. The results of this analysis suggests that foam rolling and roller massage may be effective interventions for enhancing joint ROM and pre and post exercise muscle performance. However, due to the heterogeneity of methods among studies, there currently is no consensus on the optimal SMR program. LEVEL OF EVIDENCE: 2c. PMID- 26618063 TI - ECCENTRIC AND CONCENTRIC JUMPING PERFORMANCE DURING AUGMENTED JUMPS WITH ELASTIC RESISTANCE: A META-ANALYSIS. AB - INTRODUCTION: The initial rapid eccentric contraction of a stretch-shortening cycle (SSC) activity is typically reported to accentuate the subsequent concentric jump performance. Some researchers have rationalized that adding elastic resistance (ER) to explosive type activities (e.g. countermovement jumps and drop jumps) would increase excitatory stretch reflex activity and mechanical recoil characteristics of the musculotendinous tissues. The purpose of this meta analysis was to examine the available literature on jumping movements augmented with ER and to provide a quantitative summary on the effectiveness of this technique for enhancing acute eccentric and concentric jumping performance. METHODS: In a random-effects model, the Hedges's g effect size (ES) was used to calculate the biased corrected standardized mean difference between the augmented and similar non-augmented jumps. RESULTS: The results demonstrated that augmented jumps provided a greater eccentric loading compared to free jumps (Hedges's g ES = 0.237, p = 0.028). However the concentric performance was significantly impaired, particularly if the downward elastic force was used during concentric phase as well (ES = -2.440, p < 0.001). Interestingly, no performance decrement was observed in those studies, which released the bands at the beginning of the concentric phase (ES = 0.397, p = 0.429). DISCUSSION: The authors postulated that the excessive eccentric loading might trigger reflex inhibition, alter the muscle stiffness, increase downward hip displacement and dissipate mechanical recoil properties. These results suggest that the release of elastic force at the beginning of the concentric phase seems to be a critical point to avoid impairment of acute concentric performance in augmented jumps. LEVEL OF EVIDENCE: 2a. PMID- 26618064 TI - STRENGTH & FUNCTIONAL ASSESSMENT OF HEALTHY HIGH SCHOOL FOOTBALL PLAYERS: ANALYSIS OF SKILLED AND NON-SKILLED POSITIONS. AB - BACKGROUND/PURPOSE: Identifying an athlete's functional capacity is an important consideration in determining when to allow an athlete to return to competition following injury. Establishing normative data for lower extremity functional assessment is valuable for comparison when making decisions regarding the high school athlete returning to play after injury. Therefore, the purpose of this study was to compare functional performance and strength between American high school football players of both skilled and non-skilled positions. METHODS: Forty nine high school football players (30 skilled; 19 non-skilled) completed a single session of testing consisting of a Figure of 8 test (F-8), single-leg vertical jump (SLVJ), single-leg broad jump (SLBJ), and isokinetic knee strength assessment. Pearson correlation coefficients were used to determine the relationships between the results of functional testing and isokinetic strength measures. Paired t-tests were used to determine the differences in functional performance and isokinetic muscle strength between skilled and non-skilled athletes. RESULTS: Knee extension peak torque/body weight (BW) was moderately correlated (p < .01) with SLBJ (r = .54-.61), SLVJ (r = .39-.48), and F-8 run times (r = -.50) for all athletes. Similar relationships were observed between knee flexion peak torque/BW and SLBJ (r = .48-.49), SLVJ (r = .28-.46), and the F 8 run times (r = .41-.52) for all subjects. No differences were observed between groups when examining raw peak torque values for knee flexion and extension (p > .05), however, skilled players did demonstrate greater peak torque/BW ratios (p < .05) for both knee extension and knee flexion at 60 and 240 degrees/sec. Skilled players also displayed faster F-8 times (9.4 sec +/- .3; p < .01) and greater SLBJ (p < .05) on both the dominant (81.0 in +/- 9.3) and non-dominant (83.0 in +/- 7.6) limbs (p < .01) when compared to non-skilled players. CONCLUSIONS: Overall, skilled football players displayed greater peak torque/BW ratios and functional performance when compared to non-skilled players. Furthermore, isokinetic peak torque/BW appears to be related to functional performance. This relationship is affected by position, with skilled players showing a stronger association. Limb dominance did not influence these functional and strength metrics. It is recommended that clinicians and coaches consider the positional differences in strength and functional performance when managing patients and athletes. LEVEL OF EVIDENCE: 4 - Cross-sectional Case Series. PMID- 26618065 TI - EFFECTS OF A DRY-LAND STRENGTHENING PROGRAM IN COMPETITIVE ADOLESCENT SWIMMERS. AB - BACKGROUND: Shoulder pain is common in competitive young swimmers. A relationship between shoulder strength and shoulder soreness in competitive young swimmers may indicate need for strengthening. PURPOSE: To determine if a shoulder exercise program will improve shoulder strength and decrease pain in competitive young swimmers. STUDY DESIGN: Randomized control. METHODS: Participants (10 control, 11 experimental), randomly assigned to a control or experiment group, completed the 12 week program. Strength was measured prior to the study for shoulder flexion, abduction, external rotation, internal rotation, and extension on the dominant arm using handheld dynamometry. The experimental group was then assigned exercises to be performed three times per week. The control group was instructed not to perform the exercises. All participants were re-tested at six and twelve weeks following initiation of the study. RESULTS: The changes in strength for each muscle group and pain were compared between groups using a mixed design two way ANOVA. The experimental group significantly increased external rotation strength compared to the control group. Shoulder soreness was not significantly different between groups. CONCLUSION: Adolescents who perform shoulder strengthening significantly increased their external rotation strength compared to adolescents who only participated in a regular swimming regimen. PMID- 26618066 TI - ASSOCIATION OF ISOMETRIC STRENGTH OF HIP AND KNEE MUSCLES WITH INJURY RISK IN HIGH SCHOOL CROSS COUNTRY RUNNERS. AB - BACKGROUND: High school cross country runners have a high incidence of overuse injuries, particularly to the knee and shin. As lower extremity strength is modifiable, identification of strength attributes that contribute to anterior knee pain (AKP) and shin injuries may influence prevention and management of these injuries. PURPOSE: To determine if a relationship existed between isometric hip abductor, knee extensor and flexor strength and the incidence of AKP and shin injury in high school cross country runners. MATERIALS/METHODS: Sixty-eight high school cross country runners (47 girls, 21 boys) participated in the study. Isometric strength tests of hip abductors, knee extensors and flexors were performed with a handheld dynamometer. Runners were prospectively followed during the 2014 interscholastic cross country season for occurrences of AKP and shin injury. Bivariate logistic regression was used to examine risk relationships between strength values and occurrence of AKP and shin injury. RESULTS: During the season, three (4.4%) runners experienced AKP and 13 (19.1%) runners incurred a shin injury. Runners in the tertiles indicating weakest hip abductor (chi square = 6.140; p=0.046), knee extensor (chi-square = 6.562; p=0.038), and knee flexor (chi-square = 6.140; p=0.046) muscle strength had a significantly higher incidence of AKP. Hip and knee muscle strength was not significantly associated with shin injury. CONCLUSIONS: High school cross country runners with weaker hip abductor, knee extensor and flexor muscle strength had a higher incidence of AKP. Increasing hip and knee muscle strength may reduce the likelihood of AKP in high school cross country runners. LEVEL OF EVIDENCE: 2b. PMID- 26618068 TI - TEST-RETEST RELIABILITY OF TETRAX(r) STATIC POSTUROGRAPHY SYSTEM IN YOUNG ADULTS WITH LOW PHYSICAL ACTIVITY LEVEL. AB - PURPOSE/BACKGROUND: Assessment of postural sway with force plates can be affected by type of measurement and various clinical parameters such as age and activity level of the individual person. For this reason, variability is detected in postural reactions of healthy subjects without balance impairment. Test-retest reliability of postural sway in adolescent athletes has been measured using a force plate and additional test-retest studies have been suggested for subjects of different age groups with different activity levels. Therefore, the purpose of this research was to assess test-retest reliability of Tetrax(r) Static Posturography in young adults with low physical activity level, and examine the relationship between posturography results and low activity level. METHODS: Young adults older than 18 years of age were included in the study. Demographic characteristics of the cases were recorded including age, weight, height, body mass index (BMI, kg/m2) and dominant extremity. Number of falls in the previous six months, lower body endurance (sit to stand test) and single-leg eyes closed stance test were recorded. Activity level of participants was determined according to the International Physical Activity Questionnaire (IPAQ). Posturographic evaluation of all volunteers was completed using the Tetrax(r) Interactive Postural Balance System (Sunlight Medical Ltd, Israel). Fall risk and general stability index (SI) calculated by the Tetrax(r) were recorded. Following the first test, measurements were repeated 24 to 48 hours later for reliability purposes. RESULTS: Sixty-five subjects (28 male, 37 female; mean age 22.2 +/- 1.1 years, mean BMI 22.6 +/- 3.3 kg/m(2)) were evaluated. All participants were classified as minimally active according to mean IPAQ score (1042.1 +/- 517.7 [231 - 2826] MET- minutes per week). ICC scores between the first and second tests for fall index and total stability index were excellent (ICC2,1=0.858, 0.850, respectively). Fall risk determined by using the Tetrax(r) device was negatively correlated with lower body endurance (p=0.001, r=-0.446), vigorous activity score (p=0.011, -0.312) and total activity score (p=0.029, r=-0.271), and positively correlated with single leg stance score (p=0.001, r=0.606). There was a weak correlation between fall risk history and the fall risk determined by using Tetrax(r) device (p=0.04, r=0.255). There were no correlations between fall risk and height, weight, and BMI (p>0.05). CONCLUSIONS: The results demonstrated the high test-retest reliability of Tetrax(r) interactive balance system in young healthy adults with low physical activity level. Future studies are needed to determine the effectiveness of increasing physical activity level on postural control. LEVEL OF EVIDENCE: III. PMID- 26618069 TI - EFFECTS OF NORMAL AGING ON LOWER EXTREMITY LOADING AND COORDINATION DURING RUNNING IN MALES AND FEMALES. AB - BACKGROUND: Runners sustain high injury rates. As greater numbers of individuals continue to run past the age of 60, normal physiological changes that occur with aging may further contribute to injuries. Male and female runners demonstrate different mechanics and injury rates. However, whether these mechanics further diverge as runners age and whether or not this potential divergence in mechanics may or may not be associated with a potential for increased injury risk is unknown. HYPOTHESIS/PURPOSE: The purpose of this study was to compare measures of loading and lower extremity coupling during running with respect to age and sex. It was hypothesized that males and females would demonstrate increasingly diverging mechanics with increased age. METHODS: Forty-one subjects were placed in four groups: younger males (n=13), younger females (n=6), older males (n=16), and older females (n=6). Ten running trials were collected and analyzed for each subject. Kinematic data were collected and reconstructed using a nine-camera motion analysis system and commercial software. Vertical loading rate (VLR), initial (GRF1) and peak vertical ground reaction force (GRF2) and lower leg joint coupling were calculated for each subject. Analysis was performed using a 2 factor ANOVA (sex X age) to determine differences between groups during the stance phase of running. RESULTS: Compared to younger subjects, older subjects demonstrated higher GRF1 per body weight (Y: 1.70 (0.19), O: 1.96 (0.23), p < 0.01), higher VLR in body weight/second (Y: 44.17 (6.73), O: 52.76 (8.39), p < 0.01) and lower GRF2 per body weight (Y: 2.47 (0.18), O: 2.35 (0.18), p=0.04). However, no differences existed between males and females or further diverged in the older subjects. There were no differences between or within groups in joint coupling. Finally, no significant differences were seen between sexes and no interactions were found between any variables in the current study. CONCLUSIONS: Older runners experience greater GRF1 and VLR and lower GRF2. These are factors previously associated with tibial loading and stress fractures. Males and females do not differ on these factors suggesting older female runners may be at no greater risk than younger runners or male runners for lower extremity bony injury based on normal mechanics. LEVEL OF EVIDENCE: 3. PMID- 26618067 TI - EFFECTIVENESS OF A MOTOR CONTROL THERAPEUTIC EXERCISE PROGRAM COMBINED WITH MOTOR IMAGERY ON THE SENSORIMOTOR FUNCTION OF THE CERVICAL SPINE: A RANDOMIZED CONTROLLED TRIAL. AB - BACKGROUND: Motor control therapeutic exercise (MCTE) for the neck is a motor relearning program that emphasizes the coordination and contraction of specific neck flexor, extensor, and shoulder girdle muscles. Because motor imagery (MI) improves sensorimotor function and it improves several motor aspects, such as motor learning, neuromotor control, and acquisition of motor skills, the authors hypothesized that a combination of MCTE and MI would improve the sensorimotor function of the cervical spine more effectively than a MCTE program alone. PURPOSE: The purpose of this study was to investigate the influence of MI combined with a MCTE program on sensorimotor function of the craniocervical region in asymptomatic subjects. STUDY DESIGN: This study was a single-blinded randomized controlled trial. METHODS: Forty asymptomatic subjects were assigned to a MCTE group or a MCTE+MI group. Both groups received the same MCTE program for the cervical region (60 minutes), but the MCTE+MI group received an additional intervention based on MI (15 minutes). The primary outcomes assessed were craniocervical neuromotor control (activation pressure value and highest pressure value), cervical kinesthetic sense (joint position error [JPE]), and the subjective perception of fatigue after effort. RESULTS: Intra-group significant differences were obtained between pre- and post interventions for all evaluated variables (p<0.01) in the MCTE+MI and MCTE groups, except for craniocervical neuromotor control and the subjective perception of fatigue after effort in the MCTE group. In the MCTE+MI group a large effect size was found for craniocervical neuromotor control (d between -0.94 and -1.41), cervical kinesthetic sense (d between 0.97 and 2.14), neck flexor muscle endurance test (d = -1.50), and subjective perception of fatigue after effort (d = 0.79). There were significant inter-group differences for the highest pressure value, joint position error (JPE) extension, JPE left rotation, and subjective perception of fatigue after effort. CONCLUSION: The combined MI and MCTE intervention produced statistically significant changes in sensorimotor function variables of the craniocervical region (highest pressure value, JPE extension and JPE left rotation) and the perception of subjective fatigue compared to MCTE alone. Both groups showed statistically significant changes in all variables measured, except for craniocervical neuromotor control and the subjective perception of fatigue after effort in the MCTE group. LEVEL OF EVIDENCE: 1b. PMID- 26618070 TI - ULTRASOUND IMAGING MEASUREMENT OF THE TRANSVERSUS ABDOMINIS IN SUPINE, STANDING, AND UNDER LOADING: A RELIABILITY STUDY OF NOVICE EXAMINERS. AB - BACKGROUND: Military personnel and first responders (police and firefighters) often carry large amounts of gear. This increased load can negatively affect posture and lead to back pain. The ability to quantitatively measure muscle thickness under loading would be valuable to clinicians to assess the effectiveness of core stabilization treatment programs and could aid in return to work decisions. Ultrasound imaging (USI) has the potential to provide such a measure, but to be useful it must be reliable. PURPOSE: To assess the intrarater and interrater reliability of measurements of transversus abdominis (TrA) and internal oblique (IO) muscle thickness conducted by novice examiners using USI in supine, standing, and with an axial load. STUDY DESIGN: Prospective, test-retest study. METHODS: Healthy, active duty military (N=33) personnel were examined by two physical therapy doctoral students (primary and secondary ultrasound technicians) without prior experience in USI. Thickness measurements of the TrA and IO muscles were performed at rest and during a contraction to preferentially activate the TrA in three positions (hook-lying, standing, and standing with body armor). Percent thickness changes and intraclass correlation coefficients (ICC) were calculated. RESULTS: Using the mean of three measurements for each of the three positions in resting and contracted muscle states, the intrarater ICC (3,3) values ranged from 0.90 to 0.98. The interrater ICC (2,1) values ranged from 0.39 to 0.79. The ICC values of percent thickness changes were lower than the individual ICC values for all positions and muscle states. CONCLUSION: There is excellent intrarater reliability of novice ultrasound technicians measuring abdominal muscle thickness using USI in three positions during the resting and contracted muscle states. However, interrater reliability of two novice technicians was poor to fair, so additional training and experience may be necessary to improve reliability. LEVEL OF EVIDENCE: 2b. PMID- 26618072 TI - Stress and Depression in Relation to Functional Health Behaviors in African American Patients with Systemic Lupus Erythematosus. AB - OBJECTIVE: While increased psychological distress in SLE has been clinically and empirically reported, the relationship between emotional distress, treatment adherence, and disease activity are complex and even more unclear in African American lupus patients. In an effort to elucidate this phenomenon in these patients, this exploratory study aimed to investigate relationships between stress, depression, and various health behaviors in this group. METHODS: Thirty patients invited to participate in this study were African American systemic lupus erythematosus (SLE) patients attending rheumatology clinics at the Medical University of South Carolina (MUSC). This study was part of a larger interventional pilot study, the Balancing Lupus Experiences with Stress Strategies (BLESS) study, that included a comprehensive battery of psychosocial, quality of life, and behavior change measures. RESULTS: When looking at the association between anxiety/stress and functionality, levels of reported stress had strong effects upon functionality, especially between health distress and functionality. When looking at the association between depressive symptoms and functionality, depressive symptoms had moderate effects upon social/role limitations and nights spent in the hospital. CONCLUSION: Not only did the larger pilot project demonstrate significant reductions in stress and depression as a result of workshop participation; this nested study also showed that those improvements were positively associated with improved health behaviors. These results could have implications for developing interventions to improve disease experience and quality of life in SLE patients with stress and depression. PMID- 26618071 TI - Role of Caveolin Proteins in Sepsis. AB - Despite the progress in medical treatment sepsis remains one of the major causes of death in pediatric and elderly patients. Understanding signaling pathways associated with sepsis may be of key significance for designing more efficient therapeutic approaches which could alleviate sepsis outcome. Earlier studies suggested that cholesteroland sphingolipid-rich lipid rafts and their morphologically distinct subset, caveolaecan be utilized by certain bacterial pathogens to enter and invade host cells. Moreover, there is also evidence that the expression levels of the major caveolar coat proteincaveolin-1 can be regulated by the major component of the outer membrane of Gram-negative bacteria,lipopolysaccharide (LPS) in various cell types involved in sepsis. In particular recent studies using caveolin-1 knockout mice and cells have revealed that caveolin-1 is directly involved in regulating numerous signalingpathways and functions in various cell types of the immune system and other cell types involved in sepsis. Moreover, the most recent report implies that in addition to extensively studied caveolin-1, caveolin-2 is also important in regulating LPS induced sepsis and might possibly play an opposite role to caveolin-1 in regulating certain pro-inflammatory signaling pathways. The purpose of this review is to discuss these new exciting discoveries relatedto the specific role of caveolin-1 and the less studiedcaveolin-2in regulating signaling and outcome associated with sepsis induced by LPS and pathogenic bacteria at molecular, cellular and systemic levels. PMID- 26618073 TI - A Retrospective Examination of Sleep Disturbance across the Course of Bipolar Disorder. AB - BACKGROUND: Sleep disturbance is a prevalent and clinically significant feature of bipolar disorder. However, there are aspects of sleep and bipolar disorder that have been minimally characterized. This study aims to fill several gaps in the literature by examining the prevalence, coexistence, and persistence of sleep disturbance retrospectively across a five-year period in bipolar disorder. METHODS: Fifty-one people with bipolar disorder I and comorbid insomnia who were currently inter-episode completed the NIMH Retrospective Life-Charting Methodology (the life chart). The life chart was used to document the prevalence, coexistence, and persistence of insomnia, hypersomnia, delayed sleep phase, reduced sleep need, and irregular sleep patterns across the course of five years. RESULTS: Across the five year period, manic months were primarily characterized by reduced sleep need (62.8%) and insomnia (38.1%), depressive months by hypersomnia (56.0%) and insomnia (51.9%), mixed months by all five types of sleep disturbance, and inter-episode months by insomnia (67.4%). There was coexistence in the types of sleep disturbance experienced. Further, each type of sleep disturbance demonstrated persistence across the five years, with persistence rates being the highest for insomnia (49.0-58.8%). CONCLUSIONS: Sleep disturbance is a prevalent and complex feature across mood episodes and inter-episode periods of bipolar disorder. Further, there is variation in the types of sleep disturbance experienced. PMID- 26618074 TI - Infectious Uveitis. AB - Infectious uveitis is one of the most common and visually devastating causes of uveitis in the US and worldwide. This review provides a summary of the identification, treatment, and complications associated with certain forms of viral, bacterial, fungal, helminthic, and parasitic uveitis. In particular, this article reviews the literature on identification and treatment of acute retinal necrosis due to herpes simplex virus, varicella virus, and cytomegalovirus. While no agreed-upon treatment has been identified, the characteristics of Ebola virus panuveitis is also reviewed. In addition, forms of parasitic infection such as Toxoplasmosis and Toxocariasis are summarized, as well as spirochetal uveitis. Syphilitic retinitis is reviewed given its increase in prevalence over the last decade. The importance of early identification and treatment of infectious uveitis is emphasized. Early identification can be achieved with a combination of maintaining a high suspicion, recognizing certain clinical features, utilizing multi-modal imaging, and obtaining specimens for molecular diagnostic testing. PMID- 26618075 TI - Current Concepts in the Management of Unique Post-keratoplasty Infections. AB - As corneal transplantation has evolved, the spectrum of post-surgical infection has changed and often presents a diagnostic and therapeutic challenge. Lamellar techniques hold the potential of improved outcomes and decreased post-operative complications, however, they create a lamellar interface, which is a potential space for sequestration of infectious organisms. In addition, while keratoprosthesis offers vision to patients who are poor candidates for traditional keratoplasty, infectious complications can be severe and sight threatening. Although antimicrobials remain the mainstay of treatment, definitive management often requires surgical intervention. PMID- 26618076 TI - Human Pluripotent Stem Cell-Derived Retinal Ganglion Cells: Applications for the Study and Treatment of Optic Neuropathies. PMID- 26618077 TI - Genetics of non-conventional lipoprotein fractions. AB - Lipoprotein subclass measures associate with cardiometabolic disease risk. Currently the information that lipoproteins convey on disease risk over that of traditional demographic and lipid measures is minimal, and so their use is clinics is limited. However, lipoprotein subclass perturbations represent some of the earliest manifestations of metabolic dysfunction, and their etiology is partially distinct from lipids, so information on the genetic etiology of lipoproteins offers promise for improved risk prediction, and unique mechanistic insights into IR and atherosclerosis. Here, I review the genetic variants validated as associating with lipoprotein measures to date, and show that the majority of identified variants have functionality that is best understood as related to lipid measures. Until we focus on the genes as they relate to lipoprotein subclass production, we are limiting our understanding of biological mechanisms underlying cardiometabolic disease. PMID- 26618078 TI - Analysis of structural relationship among the occupational dysfunction on the psychological problem in healthcare workers: a study using structural equation modeling. AB - Purpose. The purpose of this study is to demonstrate the hypothetical model based on structural relationship with the occupational dysfunction on psychological problems (stress response, burnout syndrome, and depression) in healthcare workers. Method. Three cross sectional studies were conducted to assess the following relations: (1) occupational dysfunction on stress response (n = 468), (2) occupational dysfunction on burnout syndrome (n = 1,142), and (3) occupational dysfunction on depression (n = 687). Personal characteristics were collected through a questionnaire (such as age, gender, and job category, opportunities for refreshment, time spent on leisure activities, and work relationships) as well as the Classification and Assessment of Occupational Dysfunction (CAOD). Furthermore, study 1 included the Stress Response Scale-18 (SRS-18), study 2 used the Japanese Burnout Scale (JBS), and study 3 employed the Center for Epidemiological Studies Depression Scale (CES-D). The Kolmogorov Smirnov test, confirmatory factor analysis (CFA), exploratory factor analysis (EFA), and path analysis of structural equation modeling (SEM) analysis were used in all of the studies. EFA and CFA were used to measure structural validity of four assessments; CAOD, SRS-18, JBS, and CES-D. For examination of a potential covariate, we assessed the correlation of the total and factor score of CAOD and personal factors in all studies. Moreover, direct and indirect effects of occupational dysfunction on stress response (Study 1), burnout syndrome (Study 2), and depression (Study 3) were also analyzed. Results. In study 1, CAOD had 16 items and 4 factors. In Study 2 and 3, CAOD had 16 items and 5 factors. SRS-18 had 18 items and 3 factors, JBS had 17 items and 3 factors, and CES-D had 20 items and 4 factors. All studies found that there were significant correlations between the CAOD total score and the personal factor that included opportunities for refreshment, time spent on leisure activities, and work relationships (p < 0.01). The hypothesis model results suggest that the classification of occupational dysfunction had good fit on the stress response (RMSEA = 0.061, CFI = 0.947, and TLI = 0.943), burnout syndrome (RMSEA = 0.076, CFI = 0.919, and TLI = 0.913), and depression (RMSEA = 0.060, CFI = 0.922, TLI = 0.917). Moreover, the detected covariates include opportunities for refreshment, time spent on leisure activities, and work relationships on occupational dysfunction. Conclusion. Our findings indicate that psychological problems are associated with occupational dysfunction in healthcare workers. Reduction of occupational dysfunction might be a strategy of better preventive occupational therapies for healthcare workers with psychological problems. However, longitudinal studies will be needed to determine a causal relationship. PMID- 26618079 TI - An evolving computational platform for biological mass spectrometry: workflows, statistics and data mining with MASSyPup64. AB - In biological mass spectrometry, crude instrumental data need to be converted into meaningful theoretical models. Several data processing and data evaluation steps are required to come to the final results. These operations are often difficult to reproduce, because of too specific computing platforms. This effect, known as 'workflow decay', can be diminished by using a standardized informatic infrastructure. Thus, we compiled an integrated platform, which contains ready-to use tools and workflows for mass spectrometry data analysis. Apart from general unit operations, such as peak picking and identification of proteins and metabolites, we put a strong emphasis on the statistical validation of results and Data Mining. MASSyPup64 includes e.g., the OpenMS/TOPPAS framework, the Trans Proteomic-Pipeline programs, the ProteoWizard tools, X!Tandem, Comet and SpiderMass. The statistical computing language R is installed with packages for MS data analyses, such as XCMS/metaXCMS and MetabR. The R package Rattle provides a user-friendly access to multiple Data Mining methods. Further, we added the non conventional spreadsheet program teapot for editing large data sets and a command line tool for transposing large matrices. Individual programs, console commands and modules can be integrated using the Workflow Management System (WMS) taverna. We explain the useful combination of the tools by practical examples: (1) A workflow for protein identification and validation, with subsequent Association Analysis of peptides, (2) Cluster analysis and Data Mining in targeted Metabolomics, and (3) Raw data processing, Data Mining and identification of metabolites in untargeted Metabolomics. Association Analyses reveal relationships between variables across different sample sets. We present its application for finding co-occurring peptides, which can be used for target proteomics, the discovery of alternative biomarkers and protein-protein interactions. Data Mining derived models displayed a higher robustness and accuracy for classifying sample groups in targeted Metabolomics than cluster analyses. Random Forest models do not only provide predictive models, which can be deployed for new data sets, but also the variable importance. We demonstrate that the later is especially useful for tracking down significant signals and affected pathways in untargeted Metabolomics. Thus, Random Forest modeling supports the unbiased search for relevant biological features in Metabolomics. Our results clearly manifest the importance of Data Mining methods to disclose non-obvious information in biological mass spectrometry . The application of a Workflow Management System and the integration of all required programs and data in a consistent platform makes the presented data analyses strategies reproducible for non-expert users. The simple remastering process and the Open Source licenses of MASSyPup64 (http://www.bioprocess.org/massypup/) enable the continuous improvement of the system. PMID- 26618080 TI - Phylogenetic analysis of higher-level relationships within Hydroidolina (Cnidaria: Hydrozoa) using mitochondrial genome data and insight into their mitochondrial transcription. AB - Hydrozoans display the most morphological diversity within the phylum Cnidaria. While recent molecular studies have provided some insights into their evolutionary history, sister group relationships remain mostly unresolved, particularly at mid-taxonomic levels. Specifically, within Hydroidolina, the most speciose hydrozoan subclass, the relationships and sometimes integrity of orders are highly unsettled. Here we obtained the near complete mitochondrial sequence of twenty-six hydroidolinan hydrozoan species from a range of sources (DNA and RNA-seq data, long-range PCR). Our analyses confirm previous inference of the evolution of mtDNA in Hydrozoa while introducing a novel genome organization. Using RNA-seq data, we propose a mechanism for the expression of mitochondrial mRNA in Hydroidolina that can be extrapolated to the other medusozoan taxa. Phylogenetic analyses using the full set of mitochondrial gene sequences provide some insights into the order-level relationships within Hydroidolina, including siphonophores as the first diverging clade, a well-supported clade comprised of Leptothecata-Filifera III-IV, and a second clade comprised of Aplanulata-Capitata s.s.-Filifera I-II. Finally, we describe our relatively inexpensive and accessible multiplexing strategy to sequence long-range PCR amplicons that can be adapted to most high-throughput sequencing platforms. PMID- 26618082 TI - Variation in partner benefits in a shrimp-sea anemone symbiosis. AB - Symbiotic interactions, where two species occur in close physical proximity for the majority of the participants' lifespans, may constrain the fitness of one or both of the participants. Host choice could result in lineage divergence in symbionts if fitness benefits vary across the interaction with hosts. Symbiotic interactions are common in the marine environment, particularly in the most diverse marine ecosystems: coral reefs. However, the variation in symbiotic interactions that may drive diversification is poorly understood in marine systems. We measured the fecundity of the symbiotic shrimp Periclimenes yucatanicus on two anemone hosts on coral reefs in Panama, and found that while fecundity varies among host species, this variation is explained largely by host size, not species. This suggests that shrimp on larger hosts may have higher fitness regardless of host species, which in turn could drive selection for host choice, a proposed driver of diversification in this group. PMID- 26618081 TI - The apparent permeabilities of Caco-2 cells to marketed drugs: magnitude, and independence from both biophysical properties and endogenite similarities. AB - We bring together fifteen, nonredundant, tabulated collections (amounting to 696 separate measurements) of the apparent permeability (P app) of Caco-2 cells to marketed drugs. While in some cases there are some significant interlaboratory disparities, most are quite minor. Most drugs are not especially permeable through Caco-2 cells, with the median P app value being some 16 ? 10(-6) cm s( 1). This value is considerably lower than those (1,310 and 230 ? 10(-6) cm s(-1)) recently used in some simulations that purported to show that P app values were too great to be transporter-mediated only. While these values are outliers, all values, and especially the comparatively low values normally observed, are entirely consistent with transporter-only mediated uptake, with no need to invoke phospholipid bilayer diffusion. The apparent permeability of Caco-2 cells to marketed drugs is poorly correlated with either simple biophysical properties, the extent of molecular similarity to endogenous metabolites (endogenites), or any specific substructural properties. In particular, the octanol:water partition coefficient, logP, shows negligible correlation with Caco-2 permeability. The data are best explained on the basis that most drugs enter (and exit) Caco-2 cells via a multiplicity of transporters of comparatively weak specificity. PMID- 26618083 TI - Trait correlates of distribution trends in the Odonata of Britain and Ireland. AB - A major challenge in ecology is understanding why certain species persist, while others decline, in response to environmental change. Trait-based comparative analyses are useful in this regard as they can help identify the key drivers of decline, and highlight traits that promote resistance to change. Despite their popularity trait-based comparative analyses tend to focus on explaining variation in range shift and extinction risk, seldom being applied to actual measures of species decline. Furthermore they have tended to be taxonomically restricted to birds, mammals, plants and butterflies. Here we utilise a novel approach to estimate occurrence trends for the Odonata in Britain and Ireland, and examine trait correlates of these trends using a recently available trait dataset. We found the dragonfly fauna in Britain and Ireland has undergone considerable change between 1980 and 2012, with 22 and 53% of species declining and increasing, respectively. Distribution region, habitat specialism and range size were the key traits associated with these trends, where habitat generalists that occupy southern Britain tend to have increased in comparison to the declining narrow-ranged specialist species. In combination with previous evidence, we conclude that the lower trend estimates for the narrow-ranged specialists could be a sign of biotic homogenization with ecological specialists being replaced by warm-adapted generalists. PMID- 26618084 TI - A new threat to bees? Entomopathogenic nematodes used in biological pest control cause rapid mortality in Bombus terrestris. AB - There is currently a great deal of concern about population declines in pollinating insects. Many potential threats have been identified which may adversely affect the behaviour and health of both honey bees and bumble bees: these include pesticide exposure, and parasites and pathogens. Whether biological pest control agents adversely affect bees has been much less well studied: it is generally assumed that biological agents are safer for wildlife than chemical pesticides. The aim of this study was to test whether entomopathogenic nematodes sold as biological pest control products could potentially have adverse effects on the bumble bee Bombus terrestris. One product was a broad spectrum pest control agent containing both Heterorhabditis sp. and Steinernema sp., the other product was specifically for weevil control and contained only Steinernema kraussei. Both nematode products caused >=80% mortality within the 96 h test period when bees were exposed to soil containing entomopathogenic nematodes at the recommended field concentration of 50 nematodes per cm(2) soil. Of particular concern is the fact that nematodes from the broad spectrum product could proliferate in the carcasses of dead bees, and therefore potentially infect a whole bee colony or spread to the wider environment. PMID- 26618085 TI - Testing the enemy release hypothesis in a native insect species with an expanding range. AB - The enemy release hypothesis (ERH) predicts that the spread of (invasive) species will be facilitated by release from their enemies as they occupy new areas. However, the ERH is rarely tested on native (non-invasive, long established) species with expanding or shifting ranges. I tested the ERH for a native damselfly (Enallagma clausum) whose range has recently expanded in western Canada, with respect to its water mite and gregarine parasites. Parasitism levels (prevalence and intensity) were also compared between E. clausum and a closely related species, Enallagma boreale, which has long been established in the study region and whose range is not shifting. A total of 1,150 damselflies were collected at three 'old' sites for E. clausum in Saskatchewan, and three 'new' sites in Alberta. A little more than a quarter of the damselflies collected were parasitized with, on average, 18 water mite individuals, and 20% were parasitized by, on average, 10 gregarine individuals. I assessed whether the differences between levels of infection (prevalence and intensity) were due to site type or host species. The ERH was not supported: Enallagma clausum has higher or the same levels of parasitism in new sites than old sites. However, E. boreale seems to be benefitting from the recent range expansion of a native, closely related species through ecological release from its parasites because the parasites may be choosing to infest the novel, potentially naive, host instead of the well established host. PMID- 26618086 TI - Tools for quantitative form description; an evaluation of different software packages for semi-landmark analysis. AB - The challenging complexity of biological structures has led to the development of several methods for quantitative analyses of form. Bones are shaped by the interaction of historical (phylogenetic), structural, and functional constrains. Consequently, bone shape has been investigated intensively in an evolutionary context. Geometric morphometric approaches allow the description of the shape of an object in all of its biological complexity. However, when biological objects present only few anatomical landmarks, sliding semi-landmarks may provide good descriptors of shape. The sliding procedure, mandatory for sliding semi landmarks, requires several steps that may be time-consuming. We here compare the time required by two different software packages ('Edgewarp' and 'Morpho') for the same sliding task, and investigate potential differences in the results and biological interpretation. 'Morpho' is much faster than 'Edgewarp,' notably as a result of the greater computational power of the 'Morpho' software routines and the complexity of the 'Edgewarp' workflow. Morphospaces obtained using both software packages are similar and provide a consistent description of the biological variability. The principal differences between the two software packages are observed in areas characterized by abrupt changes in the bone topography. In summary, both software packages perform equally well in terms of the description of biological structures, yet differ in the simplicity of the workflow and time needed to perform the analyses. PMID- 26618087 TI - Rapid drop in the reproduction number during the Ebola outbreak in the Democratic Republic of Congo. AB - The Democratic Republic of Congo (DRC) experienced a confined rural outbreak of Ebola virus disease (EVD) with 69 reported cases from July to October 2014. Understanding the transmission dynamics during the outbreak can provide important information for anticipating and controlling future EVD epidemics. I fitted an EVD transmission model to previously published data of this outbreak and estimated the basic reproduction number R 0 = 5.2 (95% CI [4.0-6.7]). The model suggests that the net reproduction number Rt fell below unity 28 days (95% CI [25 34] days) after the onset of symptoms in the index case. This study adds to previous epidemiological descriptions of the 2014 EVD outbreak in DRC, and is consistent with the notion that a rapid implementation of control interventions helped reduce further spread. PMID- 26618088 TI - Splicing Express: a software suite for alternative splicing analysis using next generation sequencing data. AB - Motivation. Alternative splicing events (ASEs) are prevalent in the transcriptome of eukaryotic species and are known to influence many biological phenomena. The identification and quantification of these events are crucial for a better understanding of biological processes. Next-generation DNA sequencing technologies have allowed deep characterization of transcriptomes and made it possible to address these issues. ASEs analysis, however, represents a challenging task especially when many different samples need to be compared. Some popular tools for the analysis of ASEs are known to report thousands of events without annotations and/or graphical representations. A new tool for the identification and visualization of ASEs is here described, which can be used by biologists without a solid bioinformatics background. Results. A software suite named Splicing Express was created to perform ASEs analysis from transcriptome sequencing data derived from next-generation DNA sequencing platforms. Its major goal is to serve the needs of biomedical researchers who do not have bioinformatics skills. Splicing Express performs automatic annotation of transcriptome data (GTF files) using gene coordinates available from the UCSC genome browser and allows the analysis of data from all available species. The identification of ASEs is done by a known algorithm previously implemented in another tool named Splooce. As a final result, Splicing Express creates a set of HTML files composed of graphics and tables designed to describe the expression profile of ASEs among all analyzed samples. By using RNA-Seq data from the Illumina Human Body Map and the Rat Body Map, we show that Splicing Express is able to perform all tasks in a straightforward way, identifying well-known specific events. Availability and Implementation. Splicing Express is written in Perl and is suitable to run only in UNIX-like systems. More details can be found at: http://www.bioinformatics-brazil.org/splicingexpress. PMID- 26618090 TI - The smell of success: the amount of prey consumed by predators determines the strength and range of cascading non-consumptive effects. AB - We examined whether chemically mediated risk perception by prey and the effects of changes in prey behavior on basal resources vary as a function of the amount of prey biomass consumed by the predator. We studied these issues using a tritrophic system composed of blue crabs, Callinectes sapidus (top predator), mud crabs Panopeus herbstii (intermediate prey), and oysters Crassostrea virginica (basal resource). Working in a well characterized field environment where experiments preserve natural patterns of water flow, we found that biomass consumed by a predator determines the range, intensity and nature of prey aversive responses. Predators that consume large amounts of prey flesh more strongly diminish consumption of basal resources by prey and exert effects over a larger range (in space and time) compared to predators that have eaten less. Less well-fed predators produce weaker effects, with the consequence that behaviorally mediated cascades preferentially occur in refuge habitats. Well-fed predators affected prey behavior and increased basal resources up to distances of 1-1.5 m, whereas predators fed restricted diet evoked changes in prey only when they were extremely close, typically 50 cm or less. Thus, consumptive and non-consumptive effects may be coupled; predators that have a greater degree of predatory success will affect prey traits more strongly and non-consumptive and consumptive effects may fluctuate in tandem, with some lag. Moreover, differences among predators in their degree of prey capture will create spatial and temporal variance in risk cue availability in the absence of underlying environmental effects. PMID- 26618089 TI - Spintharus flavidus in the Caribbean-a 30 million year biogeographical history and radiation of a 'widespread species'. AB - The Caribbean island biota is characterized by high levels of endemism, the result of an interplay between colonization opportunities on islands and effective oceanic barriers among them. A relatively small percentage of the biota is represented by 'widespread species,' presumably taxa for which oceanic barriers are ineffective. Few studies have explored in detail the genetic structure of widespread Caribbean taxa. The cobweb spider Spintharus flavidus Hentz, 1850 (Theridiidae) is one of two described Spintharus species and is unique in being widely distributed from northern N. America to Brazil and throughout the Caribbean. As a taxonomic hypothesis, Spintharus "flavidus" predicts maintenance of gene flow among Caribbean islands, a prediction that seems contradicted by known S. flavidus biology, which suggests limited dispersal ability. As part of an extensive survey of Caribbean arachnids (project CarBio), we conducted the first molecular phylogenetic analysis of S. flavidus with the primary goal of testing the 'widespread species' hypothesis. Our results, while limited to three molecular loci, reject the hypothesis of a single widespread species. Instead this lineage seems to represent a radiation with at least 16 species in the Caribbean region. Nearly all are short range endemics with several distinct mainland groups and others are single island endemics. While limited taxon sampling, with a single specimen from S. America, constrains what we can infer about the biogeographical history of the lineage, clear patterns still emerge. Consistent with limited overwater dispersal, we find evidence for a single colonization of the Caribbean about 30 million years ago, coinciding with the timing of the GAARLandia landbridge hypothesis. In sum, S. "flavidus" is not a single species capable of frequent overwater dispersal, but rather a 30 my old radiation of single island endemics that provides preliminary support for a complex and contested geological hypothesis. PMID- 26618091 TI - Lipopolysaccharide induces a downregulation of adiponectin receptors in-vitro and in-vivo. AB - Background. Adipose tissue contributes to the inflammatory response through production of cytokines, recruitment of macrophages and modulation of the adiponectin system. Previous studies have identified a down-regulation of adiponectin in pathologies characterised by acute (sepsis and endotoxaemia) and chronic inflammation (obesity and type-II diabetes mellitus). In this study, we investigated the hypothesis that LPS would reduce adiponectin receptor expression in a murine model of endotoxaemia and in adipoocyte and myocyte cell cultures. Methods. 25 mg/kg LPS was injected intra-peritoneally into C57BL/6J mice, equivalent volumes of normal saline were used in control animals. Mice were killed at 4 or 24 h post injection and tissues harvested. Murine adipocytes (3T3 L1) and myocytes (C2C12) were grown in standard culture, treated with LPS (0.1 ug/ml-10 ug/ml) and harvested at 4 and 24 h. RNA was extracted and qPCR was conducted according to standard protocols and relative expression was calculated. Results. After LPS treatment there was a significant reduction after 4 h in gene expression of adipo R1 in muscle and peri-renal fat and of adipo R2 in liver, peri-renal fat and abdominal wall subcutaneous fat. After 24 h, significant reductions were limited to muscle. Cell culture extracts showed varied changes with reduction in adiponectin and adipo R2 gene expression only in adipocytes. Conclusions. LPS reduced adiponectin receptor gene expression in several tissues including adipocytes. This reflects a down-regulation of this anti-inflammatory and insulin-sensitising pathway in response to LPS. The trend towards base line after 24 h in tissue depots may reflect counter-regulatory mechanisms. Adiponectin receptor regulation differs in the tissues investigated. PMID- 26618093 TI - When Seed and Soil Theory Meets Chicken or Egg Theory in Cancer Metastasis. PMID- 26618092 TI - Unbiased high-throughput characterization of mussel transcriptomic responses to sublethal concentrations of the biotoxin okadaic acid. AB - Background. Harmful Algal Blooms (HABs) responsible for Diarrhetic Shellfish Poisoning (DSP) represent a major threat for human consumers of shellfish. The biotoxin Okadaic Acid (OA), a well-known phosphatase inhibitor and tumor promoter, is the primary cause of acute DSP intoxications. Although several studies have described the molecular effects of high OA concentrations on sentinel organisms (e.g., bivalve molluscs), the effect of prolonged exposures to low (sublethal) OA concentrations is still unknown. In order to fill this gap, this work combines Next-Generation sequencing and custom-made microarray technologies to develop an unbiased characterization of the transcriptomic response of mussels during early stages of a DSP bloom. Methods. Mussel specimens were exposed to a HAB episode simulating an early stage DSP bloom (200 cells/L of the dinoflagellate Prorocentrum lima for 24 h). The unbiased characterization of the transcriptomic responses triggered by OA was carried out using two complementary methods of cDNA library preparation: normalized and Suppression Subtractive Hybridization (SSH). Libraries were sequenced and read datasets were mapped to Gene Ontology and KEGG databases. A custom-made oligonucleotide microarray was developed based on these data, completing the expression analysis of digestive gland and gill tissues. Results. Our findings show that exposure to sublethal concentrations of OA is enough to induce gene expression modifications in the mussel Mytilus. Transcriptomic analyses revealed an increase in proteasomal activity, molecular transport, cell cycle regulation, energy production and immune activity in mussels. Oppositely, a number of transcripts hypothesized to be responsive to OA (notably the Serine/Threonine phosphatases PP1 and PP2A) failed to show substantial modifications. Both digestive gland and gill tissues responded similarly to OA, although expression modifications were more dramatic in the former, supporting the choice of this tissue for future biomonitoring studies. Discussion. Exposure to OA concentrations within legal limits for safe consumption of shellfish is enough to disrupt important cellular processes in mussels, eliciting sharp transcriptional changes as a result. By combining the study of cDNA libraries and a custom-made OA-specific microarray, our work provides a comprehensive characterization of the OA-specific transcriptome, improving the accuracy of the analysis of expresion profiles compared to single-replicated RNA-seq methods. The combination of our data with related studies helps understanding the molecular mechanisms underlying molecular responses to DSP episodes in marine organisms, providing useful information to develop a new generation of tools for the monitoring of OA pollution. PMID- 26618094 TI - Comparative study between a single unit system and a two-unit cold standby system with varying demand. AB - The concerned paper illustrates the comparison of two stochastic models of a cable manufacturing plant with varying demand. Here, it shows the comparison between a single unit system (Model 1) and a two-unit cold standby system (Model 2). In Model 1, the system is either in working state on some demand or put to shut down mode on no demand. In Model 2, at initial stage, one of the units is operative while the other is kept as cold standby. At times when the operative unit stops working due to some breakdown/failure, the standby unit instantaneously becomes operative while the repairman repairs the failed unit. In this working model, only one unit remains operative at a time. However, there may be a state when both the units fail. The comparison of systems is done by means of MTSF (mean time to system failure), steady state availability and profit function using Laplace transforms and software package Code-Blocks 13.12. Different graphs have been plotted to discover which model is superior to the other model under the given conditions. The system is analysed by making use of semi-Markov processes and regenerative point technique. PMID- 26618095 TI - Anti-inflammatory properties of mutolide isolated from the fungus Lepidosphaeria species (PM0651419). AB - Mutolide an anti-inflammatory compound was isolated from the coprophilous fungus Lepidosphaeria sp. (PM0651419). The compound mitigated LPS-induced secretion of pro-inflammatory cytokines TNF-alpha and IL-6 from THP-1 cells as well as human peripheral blood mononuclear cells (hPBMCs). Mutolide also inhibited secretion of another pro-inflammatory cytokine IL-17 from anti-hCD3/anti-hCD28 stimulated hPBMCs. NF-kappaB is the major transcription factor involved in the secretion of pro-inflammatory cytokines including IL-17. Mechanistic evaluations revealed that mutolide inhibited induced NF-kappaB activation and translocation from cytoplasm into the nucleus. However, mutolide did not significantly affect activity of p38 MAPK enzyme, a serine/threonine kinase involved in cell cycle proliferation and cytokine secretion. These results indicate that mutolide may exert its anti inflammatory effect via NF-kappaB inhibition. Oral administration of mutolide at 100 mg/kg showed significant inhibition of LPS-induced release of TNF-alpha from Balb/c mice in an acute model of inflammation. Our results highlight the anti inflammatory properties of mutolide and suggest that further evaluation in a chronic model of inflammation is required to confirm the potential of mutolide as a druggable candidate for the treatment of inflammatory diseases. PMID- 26618097 TI - Binding studies of creatinine and urea on iron-nanoparticle. AB - Kidney diseases are complicated and can be fatal. Dialysis and transplantation are the only survival solutions to the patients suffering from kidney failures. Both hemodialysis and peritoneal dialysis are risky, due to the possibility of infection and these are expensive and time consuming. The development of simple and reliable technique for the clearance of creatinine and urea from the body is an important part of biotechnology. We have synthesized an iron nanoparticle (INP) and studied its binding with creatinine and urea. The DLS, TEM, AFM, FT-IR and Powder-XRD studies demonstrate strong binding of creatinine and urea to the nanoparticles. This finding may be helpful if it is used in the dialysis technologies. The proposed method may substantially decrease dialysis time and improve its quality in terms of urea and creatinine clearances. PMID- 26618096 TI - Limb volume measurements: comparison of accuracy and decisive parameters of the most used present methods. AB - Limb volume measurements are used for evaluating growth of muscle mass and effectivity of strength training. Beside sport sciences, it is used e.g. for detection of oedemas, lymphedemas or carcinomas or for examinations of muscle atrophy. There are several commonly used methods, but there is a lack of clear comparison, which shows their advantages and limits. The accuracy of each method is uncertainly estimated only. The aim of this paper is to determine and experimentally verify their accuracy and compare them among each other. Water Displacement Method (WD), three methods based on circumferential measures-Frustum Sign Model (FSM), Disc Model (DM), Partial Frustum Model (PFM) and two 3D scan based methods Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) were compared. Precise reference cylinders and limbs of two human subjects were measured 10 times by each method. Personal dependency of methods was also tested by measuring 10 times the same object by 3 different people. Accuracies: WD 0.3 %, FSM 2-8 % according person, DM, PFM 1-8 %, MRI 2 % (hand) or 8 % (finger), CT 0.5 % (hand) or 2 % (finger);times: FSM 1 min, CT 7 min, WD, DM, PFM 15 min, MRI 19 min; and more. WD was found as the best method for most of uses with best accuracy. The CT disposes with almost the same accuracy and allows measurements of specific regions (e.g. particular muscles), as same as MRI, which accuracy is worse though, but it is not harmful. Frustum Sign Model is usable for very fast estimation of limb volume, but with lower accuracy, Disc Model and Partial Frustum Model is useful in cases when Water Displacement cannot be used. PMID- 26618098 TI - Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol. AB - As of September 30, 2015, a total of 1589 laboratory-confirmed cases of infection with the Middle East respiratory syndrome coronavirus (MERS-CoV) have been reported to the World Health Organization (WHO). At present there is no effective specific therapy against MERS-CoV. The use of convalescent plasma (CP) has been suggested as a potential therapy based on existing evidence from other viral infections. We aim to study the feasibility of CP therapy as well as its safety and clinical and laboratory effects in critically ill patients with MERS-CoV infection. We will also examine the pharmacokinetics of the MERS-CoV antibody response and viral load over the course of MERS-CoV infection. This study will inform a future randomized controlled trial that will examine the efficacy of CP therapy for MERS-CoV infection. In the CP collection phase, potential donors will be tested by the enzyme linked immunosorbent assay (ELISA) and the indirect fluorescent antibody (IFA) techniques for the presence of anti-MERS-CoV antibodies. Subjects with anti-MERS-CoV IFA titer of >=1:160 and no clinical or laboratory evidence of MERS-CoV infection will be screened for eligibility for plasma donation according to standard donation criteria. In the CP therapy phase, 20 consecutive critically ill patients admitted to intensive care unit with laboratory-confirmed MERS-CoV infection will be enrolled and each will receive 2 units of CP. Post enrollment, patients will be followed for clinical and laboratory outcomes that include anti-MERS-CoV antibodies and viral load. This protocol was developed collaboratively by King Abdullah International Medical Research Center (KAIMRC), Gulf Cooperation Council (GCC) Infection Control Center Group and the World Health Organization-International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC-WHO) MERS-CoV Working Group. It was approved in June 2014 by the Ministry of the National Guard Health Affairs Institutional Review Board (IRB). A data safety monitoring board (DSMB) was formulated. The study is registered at http://www.clinicaltrials.gov (NCT02190799). PMID- 26618100 TI - Bioactive constituents of wood rot extract of tea, Camellia sinensis L.O. Kuntze against alates of low country live wood termite Glyptotermes dilatatus Bugnion and Popoff (Isoptera: Kalotermitidae). AB - Low country live wood termite (LCLWT), Glyptotermes dilatatus is attractive to rotted stumps of tea plant, Camellia sinensis. Rotted stumps are formed due to the attack of wood rot fungi in pruned stems. The objective of the present study was to investigate the response of LCLWT to extracts of rotted and healthy stems of susceptible tea cultivars, TRI 2023 and TRI 4042 and tolerant cultivars, TRI 2027 and TRI 4049 and isolate the LCLWT attractive fractions of tea stem extract. Since pieces of rotted stem of both susceptible and tolerant tea cultivars were more attractive to the alates than that of healthy stems, effects of EtOAc extracts of rotted and healthy stems of four tea cultivars were compared on behavior of the alates. The results revealed that the alates positively responded to extracts of rotted tea stems of four tea cultivars than that of healthy tea stems. Therefore hexane, chloroform and aqueous methanol fractions of the extracts of rotted stems were tested against alates using orientation bioassays. Results revealed that the hexane fraction of rotted stem of each cultivar was more attractive than that of the chloroform and methanol fractions. The results of bioassay guided fractionation of the hexane fraction using column chromatography revealed the presence of two bioactive sub-fractions suggesting non-polar compounds in rotted tea wood are more attractive to G. dilatatus than other sub-fractions. These two fractions can be used to develop a trapping mechanism to strengthen present IPM program of LCLWT. PMID- 26618099 TI - High incidence of triple negative breast cancers following pregnancy and an associated gene expression signature. AB - Breast cancer risk increases transiently in the period following pregnancy; pregnancy-associated breast cancers (PABC) are more aggressive than cases diagnosed in nulliparous women. We have previously reported that in the normal human breast pregnancy results in the upregulation of a number of inflammation related genes, suggesting a pro-tumorigenic environment as well as downregulation of ESR1 (ERalpha) and ERBB2 (HER2) and upregulation of ESR2 (ERbeta), suggesting a protective effect. In this study, we aimed to investigate the possibility of differential regulation of the same gene set modulated in the normal breast, in human breast tumors following pregnancy. Gene expression was measured by real time PCR on tumor regions isolated by laser capture microdissection from paraffin sections. Immunohistochemistry was performed on tissue microarrays (TMA) for protein expression. Hierarchical clustering was performed using the average linkage method to determine coordinate expression of sets of genes. We find that breast cancers detected within 10 years following pregnancy display a different gene expression pattern than those detected in nulliparous breast cancer patients. The gene expression difference is mainly attributable to a triple negative (TNBC) subgroup found to be more frequent in PABCs up to 10 years following a pregnancy. We also show that protein and mRNA expression levels correlate in half of the proteins tested by TMA. Despite the fact that this is a small study of 53 patients, we identified a gene expression signature that is differentially expressed in pregnancy-associated TNBC. PMID- 26618101 TI - Physico-chemical pretreatment and fungal biotreatment for park wastes and cattle dung for biogas production. AB - With the rising demand for renewable energy and environmental protection, anaerobic digestion of biogas technology has attracted considerable attention within the scientific community. The effect of physico-chemical pretreatment on cellulose degradation followed by fungal treatment by Aspergillus terreus and Trichoderma viride to treat cellulosic biomass for enhancing its digestibility was investigated. The tested substrate was digested with and without physical, chemical, and biological treatment. Fresh leaves, dry leaves and cattle dung were characterized by a total solids content 35, 84 and 17 %, volatile solids content 81.2, 59.49 and 64.5 % and C/N ratio 31, 45.4 and 13.6, respectively. Biogas total volume was determined using water replacement technique, while methane volume was determined using precipitation of CO2 in 20 % NaOH solution. Pretreatment steps were carried out by using mechanical and chemical pretreatments using 2.5 % NaOH mixed with 2.5 % NH4OH for 15 days, followed by biological treatment of A. terreus and T. viride. The potential of pretreatment of substrate was studied at regular intervals of 0, 7, 14, 21, 28, 35, 42, 49, 56, 63 and 70 days determining the change in chemical and physical compositions of used substrates. Biogas production was 102.6 and 125.9 L/KgVS from untreated and pretreated substrate, respectively. On the other hand, methane production was 61.4 and 79.8 L/KgVS from untreated and pretreated substrate, respectively. In conclusion, Physical (milling), chemical (NaOH and NH4OH) pretreatment in addition to fungal (A. terreus and T. viride) treatment for the tested substrate prior to AD was an efficient process for improvement of biogas and methane production. PMID- 26618102 TI - Approaches to Observe Anthropogenic Aerosol-Cloud Interactions. AB - Anthropogenic aerosol particles exert an-quantitatively very uncertain-effective radiative forcing due to aerosol-cloud interactions via an immediate altering of cloud albedo on the one hand and via rapid adjustments by alteration of cloud processes and by changes in thermodynamic profiles on the other hand. Large variability in cloud cover and properties and the therefore low signal-to-noise ratio for aerosol-induced perturbations hamper the identification of effects in observations. Six approaches are discussed as a means to isolate the impact of anthropogenic aerosol on clouds from natural cloud variability to estimate or constrain the effective forcing. These are (i) intentional cloud modification, (ii) ship tracks, (iii) differences between the hemispheres, (iv) trace gases, (v) weekly cycles and (vi) trends. Ship track analysis is recommendable for detailed process understanding, and the analysis of weekly cycles and long-term trends is most promising to derive estimates or constraints on the effective radiative forcing. PMID- 26618103 TI - Distinct functional states of astrocytes during sleep and wakefulness: Is norepinephrine the master regulator? AB - Astrocytes are the chief supportive cells in the central nervous system, but work over the past 20 years have documented that astrocytes also contribute to complex neural processes, such as working memory. Recent discoveries of norepinephrine mediated astrocytic Ca2+ responses have raised the possibility that astrocytic activity in the adult brain is driven by global responses to changes in behavioral state. Moreover, analysis of the interstitial space volume suggests that astrocytes may undergo changes in cell volume in response to activation of norepinephrine receptors. This review will focus on what is known about astrocytic functions within the nervous system, and how these functions interrelate with rapid changes in behavioral state mediated by norepinephrine signaling. PMID- 26618105 TI - Bone Tissue Engineering. AB - Medical advances have led to a welcome increase in life expectancy. However, accompanying longevity introduces new challenges: increases in age-related diseases and associated reductions in quality of life. The loss of skeletal tissue that can accompany trauma, injury, disease or advancing years can result in significant morbidity and significant socio-economic cost and emphasise the need for new, more reliable skeletal regeneration strategies. To address the unmet need for bone augmentation, tissue engineering and regenerative medicine have come to the fore in recent years with new approaches for de novo skeletal tissue formation. Typically, these approaches seek to harness stem cells, innovative scaffolds and biological factors that promise enhanced and more reliable bone formation strategies to improve the quality of life for many. This review provides an overview of recent developments in bone tissue engineering focusing on skeletal stem cells, vascular development, bone formation and the translation from preclinical in vivo models to clinical delivery. PMID- 26618104 TI - MicroRNAs: New players in cancer prevention targeting Nrf2, oxidative stress and inflammatory pathways. AB - miRNAs are endogenous small non-coding RNAs of 20-22 nucleotides that repress gene expression at the post-transcriptional level. There is growing interest in the role of miRNAs in cancer chemoprevention, and several naturally occurring chemopreventive agents have been found to be modulators of miRNA expression both in vitro and in vivo. Moreover, these chemopreventive phytochemicals commonly possess anti-oxidative and/or anti-inflammatory properties, and Nrf2 has been extensively studied as a molecular target in cancer prevention. The crosstalk between miRNAs and the traditional cellular signaling pathways of chemoprevention remain to be fully elucidated. This review summarizes the data regarding the potential interactions between miRNAs and anti-oxidative and anti-inflammatory pathways. Cellular redox homeostasis can affect the biogenesis and processing of miRNAs, which in turn regulate the Nrf2 pathway of detoxifying/anti-oxidative genes. We also discuss the miRNA regulatory mechanisms in relation to inflammation-related cancer signaling pathways. PMID- 26618106 TI - Polycystins and mechanotransduction: From physiology to disease. AB - Polycystins are key mechanosensor proteins able to respond to mechanical forces of external or internal origin. They are widely expressed in primary cilium and plasma membrane of several cell types including kidney, vascular endothelial and smooth muscle cells, osteoblasts and cardiac myocytes modulating their physiology. Interaction of polycystins with diverse ion channels, cell-cell and cell-extracellular matrix junctional proteins implicates them in the regulation of cell structure, mechanical force transmission and mechanotransduction. Their intracellular localization in endoplasmic reticulum further regulates subcellular trafficking and calcium homeostasis, finely-tuning overall cellular mechanosensitivity. Aberrant expression or genetic alterations of polycystins lead to severe structural and mechanosensing abnormalities including cyst formation, deregulated flow sensing, aneurysms, defective bone development and cancer progression, highlighting their vital role in human physiology. PMID- 26618108 TI - Enzymatic antioxidant system in vascular inflammation and coronary artery disease. AB - In biological systems there is a balance between the production and neutralization of reactive oxygen species (ROS). This balance is maintained by the presence of natural antioxidants and antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase. The enhancement of lipid peroxidation or the decrease of antioxidant protection present in metabolic diseases or bad lifestyle can induce endothelial dysfunction and atherosclerosis. Clinical studies have shown that oxidative stress can increase ROS reducing the formation of antioxidant defences, especially in subjects with coronary artery disease (CAD). Some observation indicated that in the early stages of the disease there is a homeostatic up-regulation of the antioxidant enzyme system in response to increased free radicals to prevent vascular damage. As soon as free radicals get to chronically elevated levels, this compensation ceases. Therefore, SOD and the other enzymes may represent a good therapeutic target against ROS, but they are not useful markers for the diagnosis of CAD. In conclusion antioxidant enzymes are reduced in presence of metabolic disease and CAD. However the existence of genes that promote their enzymatic activity could contribute to create new drugs for the treatment of damage caused by metabolic diseases or lifestyle that increases the plasma ROS levels. PMID- 26618109 TI - Disease control by regulation of P-glycoprotein on lymphocytes in patients with rheumatoid arthritis. AB - The main purpose of treatment of rheumatoid arthritis (RA) with disease modifying antirheumatic drugs (DMARDs) is to control activation of lymphocytes, although some patients do not respond adequately to such treatment. Among various mechanisms of multidrug resistance, P-glycoprotein (P-gp), a member of ATP binding cassette transporters, causes drug-resistance by efflux of intracellular drugs. Certain stimuli, such as tumor necrosis factor-alpha, activate lymphocytes and induce P-gp expression on lymphocytes, as evident in active RA. Studies from our laboratories showed spontaneous nuclear accumulation of human Y-box-binding protein-1, a multidrug resistance 1 transcription factor, in unstimulated lymphocytes, and surface overexpression of P-gp on peripheral lymphocytes of RA patients with high disease activity. The significant correlation between P-gp expression level and RA disease activity is associated with active efflux of drugs from the lymphocyte cytoplasm and in drug-resistance. However, the use of biological agents that reduce P-gp expression as well as P-gp antagonists (e.g., cyclosporine) can successfully reduce the efflux of corticosteroids from lymphocytes in vitro, suggesting that both types of drugs can be used to overcome drug-resistance and improve clinical outcome. We conclude that lymphocytes activated by various stimuli in RA patients with highly active disease acquire P gp-mediated multidrug resistance against corticosteroids and probably some DMARDs, which are substrates of P-gp. Inhibition/reduction of P-gp could overcome such drug resistance. Expression of P-gp on lymphocytes is a promising marker of drug resistance and a suitable therapeutic target to prevent drug resistance in patients with active RA. PMID- 26618107 TI - Endoplasmic reticulum stress-mediated pathways to both apoptosis and autophagy: Significance for melanoma treatment. AB - Melanoma is the most aggressive form of skin cancer. Disrupted intracellular signaling pathways are responsible for melanoma's extraordinary resistance to current chemotherapeutic modalities. The pathophysiologic basis for resistance to both chemo- and radiation therapy is rooted in altered genetic and epigenetic mechanisms that, in turn, result in the impairing of cell death machinery and/or excessive activation of cell growth and survival-dependent pathways. Although most current melanoma therapies target mitochondrial dysregulation, there is increasing evidence that endoplasmic reticulum (ER) stress-associated pathways play a role in the potentiation, initiation and maintenance of cell death machinery and autophagy. This review focuses on the reliability of ER-associated pathways as therapeutic targets for melanoma treatment. PMID- 26618110 TI - Association of insulin resistance with serum ferritin and aminotransferases-iron hypothesis. AB - AIM: To investigate the relationship of iron indices with diabetes mellitus (DM) in those without hemochromatosis. METHODS: This cross-sectional study examined data collected during the Third National Health and Nutrition Examination Survey (NHANES III). Only those who fasted properly and were not anemic with transferrin saturation < 45% were included (n = 6849). Insulin sensitivity and beta cell function were calculated from fasting glucose and insulin concentrations. Indices of iron metabolism were examined in the presence or absence of DM. We examined the relationship of insulin sensitivity and beta cell function with serum ferritin concentration. The influence of C-reactive protein and liver enzymes was also investigated. RESULTS: Serum ferritin concentration was significantly higher in diabetic subjects (P = 0.0001 to < 0.000001). The difference remained significant after adjustment for age, body mass index, alcohol consumption, and mineral/iron supplement (P = 0.03 to < 0.000001). In those who did not take insulin, serum ferritin concentration was negatively associated with insulin sensitivity (P = 0.05 to 0.00001), but not with beta cell function. The alanine aminotransferase was correlated with serum ferritin concentration (P = 0.02 to < 0.000001) but not with insulin sensitivity, suggesting the role of the liver in iron-associated insulin resistance. CONCLUSION: As most of diabetes is type 2 diabetes and insulin resistance is a cardinal feature of type 2 diabetes, disordered iron metabolism could play a role in the pathogenesis of insulin resistance and type 2 diabetes through its effect on liver function. PMID- 26618111 TI - How reliable is online diffusion of medical information targeting patients and families? AB - AIM: To determine whether online diffusion of the "Ten Warning Signs of Primary Immunodeficiency Diseases (PID)'' adheres to accepted scientific standards. METHODS: We analyzed how reproducible is online diffusion of a unique instrument, the "Ten Warning Signs of PID", created by the Jeffrey Modell Foundation (JMF), by Google-assisted searches among highly visited sites from professional, academic and scientific organizations; governmental agencies; and patient support/advocacy organizations. We examined the diffusion, consistency of use and adequate referencing of this instrument. Where applicable, variant versions of the instrument were examined for changes in factual content that would have practical impact on physicians or on patients and their families. RESULTS: Among the first 100 sites identified by Google search, 85 faithfully reproduced the JMF model, and correctly referenced to its source. By contrast, the other 15 also referenced the JMF source but presented one or more changes in content relative to their purported model and therefore represent uncontrolled variants, of unknown origin. Discrepancies identified in the latter included changes in factual content of the original JMF list (C), as well as removal (R) and introduction (I) of novel signs (Table 2), all made without reference to any scientific publications that might account for the drastic changes in factual content. Factual changes include changes in the number of infectious episodes considered necessary to raise suspicion of PID, as well as the inclusion of various medical conditions not mentioned in the original. Together, these changes will affect the way physicians use the instrument to consult or to inform patients, and the way patients and families think about the need for specialist consultation in view of a possible PID diagnosis. CONCLUSION: The retrieved adaptations and variants, which significantly depart from the original instrument, raise concerns about standards for scientific information provided online to physicians, patients and families. PMID- 26618112 TI - Looking Forward to the First Impact Factor of Archives of Plastic Surgery. PMID- 26618113 TI - The Relationship of a Combination of Human Adipose Tissue-Derived Stem Cells and Frozen Fat with the Survival Rate of Transplanted Fat. AB - BACKGROUND: The survival rate of grafted fat is difficult to predict, and repeated procedures are frequently required. In this study, the effects of the freezing period of harvested adipose tissue and the addition of human adipose tissue-derived stem cells (ASCs) on the process of fat absorption were studied. METHODS: Adipose tissue was obtained from patients who underwent a lipoaspirated fat graft. The fat tissue was cryopreserved at -20C in a domestic refrigerator. A total of 40 nude mice were used. The mice in the experimental group received three different subcutaneous injections in the back: an injection of fresh fat and ASCs, an injection of fat that had been frozen for one month and ASCs, and an injection of fat that had been frozen for two months and ASCs. The control mice received fat grafts without ASCs. The mice were sacrificed at four or eight weeks after the procedure, and the grafted fat tissues were harvested. The extracted fat was evaluated using photographic analysis, volume measurements, and histological examination. RESULTS: In the control group, the fat resorption rates four weeks after transplantation in the grafts of fresh fat, fat that had been frozen for one month, and fat that had been frozen for two months were 21.14%, 22.46%, and 42.56%, respectively. In the experimental group, the corresponding resorption rates were 6.68%, 13.0%, and 33.9%, respectively. CONCLUSIONS: ASCs can increase the fat graft survival rate. The use of ASCs in fat grafting can reduce the need for repeated fat grafts and provide good long term results. PMID- 26618114 TI - Wound Healing Effects of Rose Placenta in a Mouse Model of Full-Thickness Wounds. AB - BACKGROUND: Rosa damascena, a type of herb, has been used for wound healing in Eastern folk medicine. The goal of this study was to evaluate the effectiveness of rose placenta from R. damascena in a full-thickness wound model in mice. METHODS: Sixty six-week-old C57BL/6N mice were used. Full-thickness wounds were made with an 8-mm diameter punch. Two wounds were made on each side of the back, and wounds were assigned randomly to the control and experimental groups. Rose placenta (250 ug) was injected in the experimental group, and normal saline was injected in the control group. Wound sizes were measured with digital photography, and specimens were harvested. Immunohistochemical staining was performed to assess the expression of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGF-beta1), and CD31. Vessel density was measured. Quantitative analysis using an enzyme linked immunosorbent assay (ELISA) for EGF was performed. All evaluations were performed on postoperative days 0, 2, 4, 7, and 10. Statistical analyses were performed using the paired t-test. RESULTS: On days 4, 7, and 10, the wounds treated with rose placenta were significantly smaller. On day 2, VEGF and EGF expression increased in the experimental group. On days 7 and 10, TGF-beta1 expression decreased in the experimental group. On day 10, vessel density increased in the experimental group. The increase in EGF on day 2 was confirmed with ELISA. CONCLUSIONS: Rose placenta was found to be associated with improved wound healing in a mouse full-thickness wound model via increased EGF release. Rose placenta may potentially be a novel drug candidate for enhancing wound healing. PMID- 26618115 TI - The Vasodilator Effect of a Cream Containing 10% Menthol and 15% Methyl Salicylate on Random-Pattern Skin Flaps in Rats. AB - BACKGROUND: It is still difficult to prevent partial or full-thickness flap necrosis. In this study, the effects of a cream containing menthol and methyl salicylate on the viability of randompattern skin flaps were studied. METHODS: Forty female Sprague-Dawley rats were divided into two equal groups. Caudally based dorsal random-pattern skin flaps were elevated, including the panniculus carnosus. In the study group, 1.5 mL of a cream containing menthol and methyl salicylate was applied to the skin of the flap, and saline solution (0.9%) was used in the control group. Upon completion of the experiment, flap necrosis was analyzed with imaging software and radionuclide scintigraphy. Histopathological measurements were made of the percentage of viable flaps, the number of vessels, and the width of the panniculus carnosus muscle. RESULTS: According to the photographic analysis, the mean viable flap surface area in the study group was larger than that in the control group (P=0.004). According to the scintigrams, no change in radioactivity uptake was seen in the study group (P>0.05). However, a significant decrease was observed in the control group (P=0.006). No statistically significant differences were observed between the groups in terms of the percentage of viable flaps, the number of vessels, or the width of the panniculus carnosus muscle (P>0.05). CONCLUSIONS: Based on these results, it is certain that the cream did not reduce the viability of the flaps. Due to its vasodilatory effect, it can be used as a component of the dressing in reconstructive operations where skin perfusion is compromised. PMID- 26618116 TI - Columella Lengthening with a Full-Thickness Skin Graft for Secondary Bilateral Cleft Lip and Nose Repair. AB - BACKGROUND: Various techniques for lengthening short columellae have been used for bilateral cleft nose repair. However, previous methods have not yielded satisfactory results. We performed a full-thickness skin graft to lengthen short columellae during secondary cleft nose repair in adult patients. METHODS: Ten bilateral cleft lip and nose patients underwent secondary cheiloplasty with open rhinoplasty between July 2008 and August 2014. The patients underwent a full thickness skin graft on the medial crura to elongate the columella. The average age of the patients at the time of surgery was 22.2 years. Nasal profiles were evaluated before and after the operation using the photogrammetric method. RESULTS: The nasal profiles were improved in all patients, and all skin grafts were well taken, with the exception of one patient. Columellar height, nostril height, and columella-lip angle increased, and nasal width decreased significantly. The ratios of columellar height to nasal height, columellar height to nasal width, and nasal height to nasal width increased to a statistically significant extent. CONCLUSIONS: Columella lengthening with a full-thickness skin graft is a simple and effective method for the repair of severely short columellae in bilateral cleft nose patients. We had satisfactory outcomes, with good color matching and aesthetically pleasing contours. PMID- 26618117 TI - Clinical Approaches to Vascular Anomalies of the Lip. AB - BACKGROUND: The incidence of vascular anomalies in the head and neck is higher than in the extremities. It is especially common for vascular anomalies to involve the lip. The lips are a functionally and aesthetically important component of the head and neck area. A retrospective analysis of data from our vascular anomaly center was performed in order to understand the characteristics and treatment requirements of vascular anomalies of the lip and to establish which treatments are likely to lead to the best outcomes. METHODS: A retrospective review was performed of the medical records of patients diagnosed with vascular anomalies of the upper or lower lip from January 2001 to September 2013. Using clinical photographs, radiologic findings, and patient records, the diagnosis of each case and the location of the vascular anomaly were recorded, along with information about treatment and follow-up. RESULTS: A total of 1,606 patients were diagnosed with vascular anomalies over this time period, of whom 127 (7.9%) were found to have vascular anomalies in the lip only. Surgical treatment with or without embolization, sclerotherapy, laser therapy, medication only, and observation were the treatment strategies adopted in these cases. CONCLUSIONS: Vascular anomalies of the lip should be diagnosed accurately. Radiologic diagnosis played a crucial role in treatment planning, and several techniques were used to treat vascular anomalies of the lip. When surgical excision is indicated for the correction of vascular anomalies of the lip, the aesthetic and functional characteristics of the lip should be considered. PMID- 26618118 TI - Modified T-Plate Interpositional Arthroplasty for Temporomandibular Joint Ankylosis: A New and Versatile Option. AB - BACKGROUND: This study has been conducted with the aim of evaluating modified T plate interpositional arthroplasty. METHODS: A prospective comparative study in patients admitted with temporomandibular joint ankylosis. Ankylotic temporomandibular joint arthroplasty included condylectomy gap arthroplasty in 7, temporalis muscle flap interpositional arthroplasty in 8, and modified T-plate interpositional arthroplasty in 13 cases. The patients were followed for three years. Collected data were tabulated and subjected to Fisher's exact test, chi square test and probability estimation. RESULTS: A significant increase in interincisal distance of 32 mm was seen in 12 (92.31%) patients in the T-plate interposition group, in 2 (25%) cases of the temporalis muscle flap interposition group, and in 1 case (14.28%) of the condylectomy group at 12, 24, and 36 months. Re-ankylosis was observed in 1 case (9.69%) of the T-plate interposition group, while as it was observed in 4 (50%) cases in the temporalis muscle flap interposition group and 4 (57.14%) cases in the condylectomy group, and these differences were statistically significant. CONCLUSIONS: Our clinical experience with the use of the T-plate over the past 5 years has been encouraging, and our physiotherapy technique is quite simple. Even illiterate parents can assess it easily. Hence, we recommend this easy technique that does not damage the temporalis muscle for the management of temporomandibular joint ankylosis. PMID- 26618119 TI - A Phase III, Randomized, Multi-Center, Double-Masked, Matched-Pairs, Active Controlled Trial to Compare the Efficacy and Safety between Neuramis Deep and Restylane in the Correction of Nasolabial Folds. AB - BACKGROUND: We conducted this clinical study to compare the efficacy and safety between Neuramis Deep and Restylane in the correction of nasolabial folds. METHODS: In this phase III, randomized, multi-center, double-masked, matched pairs, active-controlled trial (ClinicalTrials.gov Identifier: NCT01585220), we evaluated a total of 67 subjects (n=67). All the subjects underwent Neuramis Deep treatment on one side and Restylane on the contralateral side of the bilateral nasolabial folds at a ratio of 1:1. To compare the efficacy of Neuramis Deep and Restylane, we evaluated the Wrinkle Severity Rating Scale scores and those of the Global Aesthetic Improvement Scale. In addition, we compared the safety of Neuramis Deep and Restylane based on adverse events, physical examination, and clinical laboratory tests. RESULTS: Neuramis Deep was not inferior in improving the nasolabial folds as compared with Restylane. In addition, there was no significant difference in the efficacy between Neuramis Deep and Restylane. There were no significant differences in safety parameters between Neuramis Deep and Restylane. CONCLUSIONS: In conclusion, our results indicate that Neuramis Deep may be a safe, effective material for improving the nasolabial folds. However, further studies are warranted to compare the tolerability of Neuramis Deep and Restylane based on histopathologic findings. PMID- 26618120 TI - Scar Revision Surgery: The Patient's Perspective. AB - BACKGROUND: Insufficient satisfaction outcome literature exists to assist consultations for scar revision surgery; such outcomes should reflect the patient's perspective. The aim of this study was to prospectively investigate scar revision patient satisfaction outcomes, according to specified patient selection criteria. METHODS: Patients (250) were randomly selected for telephone contacting regarding scar revisions undertaken between 2007-2011. Visual analogue scores were obtained for scars pre- and post-revision surgery. Surgery selection criteria were; 'presence' of sufficient time for scar maturation prior to revision, technical issues during or wound complications from the initial procedure that contributed to poor scarring, and 'absence' of site-specific or patient factors that negatively influence outcomes. Patient demographics, scar pathogenesis (elective vs. trauma), underlying issue (functional/symptomatic vs. cosmetic) and revision surgery details were also collected with the added use of a real-time, hospital database. RESULTS: Telephone contacting was achieved for 211 patients (214 scar revisions). Satisfaction outcomes were '2% worse, 16% no change, and 82% better'; a distribution maintained between body sites and despite whether surgery was functional/symptomatic vs. cosmetic. Better outcomes were reported by patients who sustained traumatic scars vs. those who sustained scars by elective procedures (91.80% vs. 77.78%, P=0.016) and by females vs. males (85.52% vs. 75.36%, P<0.05), particularly in the elective group where males (36.17%) were more likely to report no change or worse outcomes versus females (16.04%) (P<0.01). CONCLUSIONS: Successful scar revision outcomes may be achieved using careful patient selection. This study provides useful information for referring general practitioners, and patient-surgeon consultations, when planning scar revision. PMID- 26618121 TI - Botulinum Toxin Therapy versus Anterior Belly of Digastric Transfer in the Management of Marginal Mandibular Branch of the Facial Nerve Palsy: A Patient Satisfaction Survey. AB - BACKGROUND: Botulinum toxin (BT) chemodenervation and anterior belly of digastric muscle (ABD) transfer are both treatment options in the management of an isolated marginal mandibular branch of the facial nerve (MMB) palsy. We compare the patient satisfaction following either BT injections or ABD transfer in the management of their isolated MMB palsy. METHODS: Patients in the ABD-arm of the study were identified retrospectively from September 2007 to July 2014. The patients in the BT-arm of the study were identified prospectively from those attending the clinic. Both groups of patients completed a validated patient satisfaction survey. Statistical analysis was performed and a P-value <0.05 was considered statistically significant. RESULTS: Seven patients were in the ABD-arm and 11 patients in the BT-arm of the study. The patient satisfaction in both groups was high with 45% of ABD-arm patients and 40% of BT-arm patients rating their overall outcome as 'better' or 'much better', which was significantly more than the proportion rating their outcome as 'worse' or 'much worse' (P<0.001), although there was a significant trend towards those in the ABD-arm being more likely to be dissatisfied with their outcome (P=0.01). CONCLUSIONS: BT therapy is a good first-line intervention in the management of isolated MMB palsy. We have, however, shown that the overall satisfaction in both groups is high. Therefore, in patients who would prefer a more permanent solution to manage their facial asymmetry, ABD transfer remains a satisfactory treatment option with a good level of patient satisfaction. PMID- 26618122 TI - Outcomes of Take-Back Operations in Breast Reconstruction with Free Lower Abdominal Flaps. AB - BACKGROUND: Microvascular complications after free-flap breast reconstructions are potentially devastating problems that can increase patient morbidity and lead to flap loss. To date, no comprehensive study has examined the rates of salvage and the methods of microvascular revision in breast reconstruction. We reviewed the treatment of microvascular complications of free-flap breast reconstruction procedures over a seven-year period. METHODS: A retrospective review of all patients who underwent microvascular breast reconstruction at our institution between April 2006 and December 2013 was conducted. Based on their surgical records, all patients who required emergency re-exploration were identified, the rate of flap salvage was determined, the factors associated with flap salvage were evaluated, and the causes and methods of revision were reviewed. RESULTS: During the review period, 605 breast reconstruction procedures with a free lower abdominal flap were performed. Seventeen of these flaps were compromised by microvascular complications, and three flaps were lost. The overall salvage rate was 82.35%. No significant differences between the salvaged group and the failed group were observed with regard to age, BMI, axillary dissection, number of anastomotic arteries and veins, recipient vessel types, or use of the superficial inferior epigastric vein in the revision operation. Successful salvage of the flap was associated with a shorter time period between recognizing the signs of flap compromise and the take-back operation. CONCLUSIONS: The salvage rate of compromised lower abdominal flaps was high enough to warrant attempting re exploration. Immediate intervention after the onset of flap compromise signs is as important as vigilant postoperative monitoring. PMID- 26618123 TI - Analysis of the Clinical and Histopathological Patterns of 100 Consecutive Cases of Primary Cutaneous Melanoma and Correlation with Staging. AB - BACKGROUND: This study analyzed 100 consecutive patients with primary cutaneous melanoma over the course of 13 years to determine whether epidemiological differences correspond to different stages of the disease. We also investigated whether epidemiological characteristics affected the survival rate. Our results were compared with those of selected descriptive studies of melanoma in other East Asian populations, in order to determine whether cutaneous melanoma patterns are similar in East Asian populations. METHODS: The patients' medical records were reviewed retrospectively, and we analyzed the relationship of epidemiological characteristics to staging and survival rate. Additionally, papers from Hong Kong and Japan describing these phenomena in East Asian populations were subjected to a statistical comparison. RESULTS: The ratio of males to females was 1:1.8, and the foot was the most frequent tumor site (49%). Acral lentiginous melanoma occurred most frequently (55%). Nodular melanoma was associated with a higher stage. Stage III-IV tumors with Clark levels of IV-V were significantly associated with a low survival rate. A statistical analysis of comparable papers reported in Hong Kong and Japan showed similar results with regard to age, tumor location, and histopathological subtypes. CONCLUSIONS: This study provides the first full epidemiological description of 100 consecutive cases of primary cutaneous melanoma in Korea, with results similar to those observed in other East Asian populations. Corresponding to previous findings, nodular melanoma tended to occur at a higher stage than other types, and tumors with high Clark levels and high stages showed a lower survival rate. PMID- 26618124 TI - Fingernail Configuration. AB - BACKGROUND: A number of conditions can alter a person's fingernail configuration. The ratio between fingernail width and length (W/L) is an important aesthetic criterion, and some underlying diseases can alter the size of the fingernail. Fingernail curvature can be altered by systemic disorders or disorders of the fingernail itself. Although the shape and curvature of the fingernail can provide diagnostic clues for various diseases, few studies have precisely characterized normal fingernail configuration. METHODS: We measured the W/L ratio of the fingernail, transverse fingernail curvature, hand length, hand breadth, and distal interphalangeal joint width in 300 volunteers with healthy fingernails. We also investigated whether age, sex, height, and handedness influenced the fingernail W/L ratio and transverse fingernail curvature. RESULTS: In women, fingernail W/L ratios were similar across all five fingers, and were lower than those in men. The highest value of transverse fingernail curvature was found in the thumb, followed by the index, middle, ring, and little fingers. Handedness and aging influenced transverse fingernail curvature, but not the fingernail W/L ratio. Fingernails were flatter on the dominant hand than on the non-dominant hand. The radius of transverse fingernail curvature increased with age, indicating that fingernails tended to flatten with age. CONCLUSIONS: Our quantitative data on fingernail configuration can be used as a reference range for diagnosing various diseases and deformities of the fingernail, and for performing reconstructive or aesthetic fingernail surgery. PMID- 26618125 TI - Two-Step Incision for Periarterial Sympathectomy of the Hand. AB - BACKGROUND: Surgical scars on the palmar surface of the hand may lead to functional and also aesthetic and psychological consequences. The objective of this study was to introduce a new incision technique for periarterial sympathectomy of the hand and to compare the results of the new two-step incision technique with those of a Koman incision by using an objective questionnaire. METHODS: A total of 40 patients (17 men and 23 women) with intractable Raynaud's disease or syndrome underwent surgery in our hospital, conducted by a single surgeon, between January 2008 and January 2013. Patients who had undergone extended sympathectomy or vessel graft were excluded. Clinical evaluation of postoperative scars was performed in both groups one year after surgery using the patient and observer scar assessment scale (POSAS) and the Wake Forest University rating scale. RESULTS: The total patient score was 8.59 (range, 6-15) in the two step incision group and 9.62 (range, 7-18) in the Koman incision group. A significant difference was found between the groups in the total PS score (P value=0.034) but not in the total observer score. Our analysis found no significant difference in preoperative and postoperative Wake Forest University rating scale scores between the two-step and Koman incision groups. The time required for recovery prior to returning to work after surgery was shorter in the two-step incision group, with a mean of 29.48 days in the two-step incision group and 34.15 days in the Koman incision group (P=0.03). CONCLUSIONS: Compared to the Koman incision, the new two-step incision technique provides better aesthetic results, similar symptom improvement, and a reduction in the recovery time required before returning to work. Furthermore, this incision allows the surgeon to access a wide surgical field and a sufficient exposure of anatomical structures. PMID- 26618126 TI - Stabilizing Morbidity and Predicting the Aesthetic Results of Radial Forearm Free Flap Donor Sites. AB - BACKGROUND: The radial forearm flap is a versatile, widely used flap. However, the possibility of donor site complications has led to concern over its use. Some surgeons prefer using other flaps whose donor sites can be closed primarily with less morbidity, including avoiding unpleasant scarring. However, in our experience, donor site stability of the radial forearm flap can be reliably achieved by using well-implemented specific procedures. Here, we present a collection of donor site cases of the radial forearm flap and investigate factors that affect the aesthetic results as the basis for a reference for selecting a radial forearm flap. METHODS: In this retrospective study, we reviewed 171 cases in which a radial forearm flap was used for free tissue transfer after resecting head and neck cancer. We focused on donor site morbidity rates. Each operation involved a detailed procedure designed to minimize donor site morbidity. Moreover, statistical investigations were conducted for 22 cases to determine factors affecting the scar appearance. RESULTS: Only one case developed total skin graft necrosis as a major complication. Scar-related aesthetic results were acceptable, and the body-mass index, body weight, diabetes, and cardiac problems were significant factors related to the appearance of scars. CONCLUSIONS: Performing the radial forearm flap using a well-implemented detailed technique helps achieve acceptable donor site morbidity results. The aesthetic results were more promising for patients without excess body weight, diabetes, or cardiac problems. Therefore, anxiety about donor site morbidity should not be a reason to avoid selecting the radial forearm flap in suitable patients. PMID- 26618127 TI - Gender Reassignment Surgery in Human Immunodeficiency Virus-Positive Patients: A Report of Two Cases. AB - It is believed that surgery on human immunodeficiency virus (HIV)-positive patients is dangerous and should be avoided due to the possibility of postoperative infection of the patients or HIV occupational transmission to the medical staff. We discuss here the preparations and measures needed to conduct surgery safely on HIV-positive patients, based on our experience. We performed sex reassignment surgery on two HIV-positive patients from January 2013 to January 2015. Both of them were receiving highly active antiretroviral therapy and were asymptomatic, with a normal CD4 count (>500 cells/uL). The HIV-RNA was undetectable within the bloodstream. All the staff wore protective clothing, glasses, and three pairs of protective gloves in the operating room because of the possibility of transmission. Prophylactic antibiotics were administered to the patients, and antiviral therapy was performed during their perioperative course. Neither of the patients had postoperative complications, and none of the medical staff experienced accidental exposure. Both patients had satisfactory surgery outcomes without complications. HIV-positive patients can undergo surgery safely without increased risk of postoperative complications or HIV transmission to the staff through the proper use of antibiotics, active antiretroviral therapy, and supplemental protective measures with post-exposure prophylaxis for the staff in case of HIV exposure. PMID- 26618128 TI - "Mini-Flow-Through" Deep Inferior Epigastric Perforator Flap for Breast Reconstruction with Preservation of Both Internal Mammary and Deep Inferior Epigastric Vessels. AB - This procedure was developed for preservation of the rectus muscle components and deep inferior epigastric vessel after deep inferior epigastric perforator (DIEP) flap harvesting. A 53-year-old woman with granuloma caused by silicone injection underwent bilateral nipple-sparing mastectomies and immediate reconstruction with "mini-flow-through" DIEP flaps. The flaps were dissected based on the single largest perforator with a short segment of the lateral branch of the deep inferior epigastric vessel that was transected as a free flap for breast reconstruction. The short segments of the donor deep inferior epigastric vessel branch are primarily end-to-end anastomosed to each other. A short T-shaped pedicle mini-flow-through DIEP flap is interposed in the incised recipient's internal mammary vessels with two arterial and four concomitant venous anastomoses. Although it requires multiple vascular anastomoses and a short pedicle for the flap setting, the mini-flow-through DIEP flap provides a large pedicle caliber, enabling safer microsurgical anastomosis and well-vascularized tissue for creating a natural breast without consuming time or compromising the rectus muscle components and vascular flow of both the deep inferior epigastric and internal mammary vessels. PMID- 26618129 TI - Priority Claim to "Sentinel Lymph Node Transfer". PMID- 26618130 TI - Effects of NecroX-5 on the Survival of a Random Pattern Skin Flap in Mice. PMID- 26618131 TI - Traumatic Carotid-Cavernous Sinus Fistula in a Patient with Facial Bone Fractures. PMID- 26618132 TI - Giant Fibroadenoma in the Axilla: A Common Entity of Uncommon Size in a Rare Location. PMID- 26618134 TI - Peripheral Osteoma in the Mandibular Angle. PMID- 26618133 TI - Superficial Subcutaneous Leiomyosarcoma on the Face of a Pediatric Patient. PMID- 26618135 TI - Intercostal Nerve Schwannoma Encountered during a Rib-Latissimus Dorsi Osteomyocutaneous Flap Operation. PMID- 26618136 TI - Atypical Fibroxanthoma in a 115-Year-Old Patient. PMID- 26618137 TI - A Rare Case of Ecthyma Gangrenosum Caused by Proteus vulgaris and Candida albicans in a Patient with Castleman Disease. PMID- 26618138 TI - Basaloid Squamous Cell Carcinoma on the Skin of the Hand. PMID- 26618139 TI - Simultaneous Reconstruction of Forefoot and Hindfoot Defects with a Thoracodorsal Axis Chimeric Flap. PMID- 26618140 TI - Medial Sural Artery Perforator Flap: Using the Superficial Venous System to Minimize Flap Congestion. PMID- 26618141 TI - The Use of a Mechanical Stapler in Jejunal Free Flaps in Laryngopharyngectomy Defects. PMID- 26618142 TI - Mutant p53: Multiple Mechanisms Define Biologic Activity in Cancer. AB - The functional importance of p53 as a tumor suppressor gene is evident through its pervasiveness in cancer biology. The p53 gene is the most commonly altered gene in human cancer; however, not all genetic alterations are biologically equivalent. The majority of alterations involve p53 missense mutations that result in the production of mutant p53 proteins. Such mutant p53 proteins lack normal p53 function and may concomitantly gain novel functions, often with deleterious effects. Here, we review characterized mechanisms of mutant p53 gain of function in various model systems. In addition, we review mutant p53 addiction as emerging evidence suggests that tumors may depend on sustained mutant p53 activity for continued growth. We also discuss the role of p53 in stromal elements and their contribution to tumor initiation and progression. Lastly, current genetic mouse models of mutant p53 in various organ systems are reviewed and their limitations discussed. PMID- 26618143 TI - Impact of Charged Particle Exposure on Homologous DNA Double-Strand Break Repair in Human Blood-Derived Cells. AB - Ionizing radiation generates DNA double-strand breaks (DSB) which, unless faithfully repaired, can generate chromosomal rearrangements in hematopoietic stem and/or progenitor cells (HSPC), potentially priming the cells towards a leukemic phenotype. Using an enhanced green fluorescent protein (EGFP)-based reporter system, we recently identified differences in the removal of enzyme mediated DSB in human HSPC versus mature peripheral blood lymphocytes (PBL), particularly regarding homologous DSB repair (HR). Assessment of chromosomal breaks via premature chromosome condensation or gammaH2AX foci indicated similar efficiency and kinetics of radiation-induced DSB formation and rejoining in PBL and HSPC. Prolonged persistence of chromosomal breaks was observed for higher LET charged particles which are known to induce more complex DNA damage compared to X rays. Consistent with HR deficiency in HSPC observed in our previous study, we noticed here pronounced focal accumulation of 53BP1 after X-ray and carbon ion exposure (intermediate LET) in HSPC versus PBL. For higher LET, 53BP1 foci kinetics was similarly delayed in PBL and HSPC suggesting similar failure to repair complex DNA damage. Data obtained with plasmid reporter systems revealed a dose- and LET-dependent HR increase after X-ray, carbon ion and higher LET exposure, particularly in HR-proficient immortalized and primary lymphocytes, confirming preferential use of conservative HR in PBL for intermediate LET damage repair. HR measured adjacent to the leukemia-associated MLL breakpoint cluster sequence in reporter lines revealed dose dependency of potentially leukemogenic rearrangements underscoring the risk of leukemia-induction by radiation treatment. PMID- 26618144 TI - Targeting TREM-1 Signaling in the Presence of Antibiotics is Effective Against Streptococcal Toxic-Shock-Like Syndrome (STSLS) Caused by Streptococcus suis. AB - Streptococcus suis (S.suis), a major swine pathogen, is also a severe threat to human health. Infection with highly virulent strains of S. suis can cause human Streptococcal toxic-shock-like syndrome (STSLS), which is associated with high serum pro-inflammatory cytokine levels and a high mortality rate. Our previous study indicated that highly virulent S. suis infection could activate the TREM-1 signaling pathway, which promotes host clearance of S. suis during early infection. However, it remained to be elicited whether TREM-1 signaling could be a target against STSLS in the presence of antibiotic. In the present study, mice were infected with a highly virulent S. suis strain and then treated with rTREM-1 (the recombinant extracellular domain of TREM-1) to block TREM-1 signaling, antibiotics, both rTREM-1 and antibiotics, or PBS. The survival rates, clinical signs, serum IL-1beta and TNF-alpha levels, and serum bacterial loads were evaluated. Treatment with rTREM-1 could aggravate the outcome of infection as described previously. Although the conventional treatment with antibiotics contributed to effective S. suis clearance, it did not improve survival significantly. In comparison, due to the reduction of the exaggerated pro inflammatory response, treatment combined with rTREM-1 and antibiotics not only led to efficient bacterial clearance but also alleviated inflammation. In conclusion, TREM-1 signaling contributed to severe inflammatory response and benefited S. suis clearance. Therefore, blocking TREM-1 signaling could still be a target for the treatment of STSLS in the presence of antibiotics. PMID- 26618145 TI - Assessment of Age-Related Differences in Functional Capacity Using the Virtual Reality Functional Capacity Assessment Tool (VRFCAT). AB - Clinical trials for primary prevention and early intervention in preclinical AD require measures of functional capacity with improved sensitivity to deficits in healthier, non-demented individuals. To this end, the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) was developed as a direct performance-based assessment of functional capacity that is sensitive to changes in function across multiple populations. Using a realistic virtual reality environment, the VRFCAT assesses a subject's ability to complete instrumental activities associated with a shopping trip. The present investigation represents an initial evaluation of the VRFCAT as a potential co-primary measure of functional capacity in healthy aging and preclinical MCI/AD by examining test-retest reliability and associations with cognitive performance in healthy young and older adults. The VRFCAT was compared and contrasted with the UPSA-2-VIM, a traditional performance based assessment utilizing physical props. Results demonstrated strong age related differences in performance on each VRFCAT outcome measure, including total completion time, total errors, and total forced progressions. VRFCAT performance showed strong correlations with cognitive performance across both age groups. VRFCAT Total Time demonstrated good test-retest reliability (ICC=.80 in young adults; ICC=.64 in older adults) and insignificant practice effects, indicating the measure is suitable for repeated testing in healthy populations. Taken together, these results provide preliminary support for the VRFCAT as a potential measure of functionally relevant change in primary prevention and preclinical AD/MCI trials. PMID- 26618146 TI - Image-guided surgery and craniofacial applications: mastering the unseen. AB - Image-guided surgery potentially enhances intraoperative safety and outcomes in a variety of craniomaxillofacial procedures. We explore the efficiency of one intraoperative navigation system in a single complex craniofacial case, review the initial and recurring costs, and estimate the added cost (e.g., additional setup time, registration). We discuss the potential challenges and benefits of utilizing image-guided surgery in our specific case and its benefits in terms of educational and teaching purposes and compare this with traditional osteotomies that rely on a surgeon's thorough understanding of anatomy coupled with tactile feedback to blindly guide the osteotome during surgery. A 13-year-old presented with untreated syndromic multi-suture synostosis, brachycephaly, severe exorbitism, and midface hypoplasia. For now, initial costs are high, recurring costs are relatively low, and there are perceived benefits of imaged-guided surgery as an excellent teaching tool for visualizing difficult and often unseen anatomy through computerized software and multi-planar real-time images. PMID- 26618147 TI - Hyponatremia due to Severe Primary Hypothyroidism in an Infant. AB - Hyponatremia has been reported in the elderly with hypothyroidism and myxedema, but this has not been a universal finding in clinical studies and there have been only a few reports in children. We report a case of an infant who developed hyponatremia due to severe primary hypothyroidism. A 4-month-old ex-preterm male, who had been euthyroid on the newborn screen, developed unexplained hospital acquired hyponatremia (serum Na 124 mEq/L) while on full oral feeds. He was euvolemic, appeared well and was without myxedema. An evaluation of hyponatremia was negative with the exception of severe primary hypothyroidism (TSH 315.4 IU/mL, repeat 540 IU/mL). The hyponatremia resolved with thyroxine supplementation. This case demonstrates that severe hypothyroidism can result in hyponatremia in infants. It is critical to consider hypothyroidism in the evaluation of an infant with unexplained hyponatremia as untreated hypothyroidism can lead to profound developmental delays. PMID- 26618149 TI - Work-Life Balance: Hopeless Endeavor or Rather, a True Privilege? PMID- 26618150 TI - Seasonal Influenza Epidemics and El Ninos. AB - Seasonal influenza epidemics occur annually during the winter in the northern and southern hemispheres, but timing of peaks and severity vary seasonally. Low humidity, which enhances survival and transmission of influenza virus, is the major risk factor. Both El Nino and La Nina phases of El Nino-southern oscillation (ENSO), which determine inter-annual variation of precipitation, are putative risk factors. This study was done to determine if seasonality, timing of peak, and severity of influenza epidemics are coupled to phases of ENSO. Monthly time series of positive specimens for influenza viruses and of multivariate El Nino-Southern Oscillation Index from January 2000 to August 2015 were analyzed. Seasonality, wavelet spectra, and cross-wavelet spectra analyses were performed. Of 31 countries in the dataset, 21 were in the northern hemisphere and 10 in the southern hemisphere. The highest number of influenza cases occurred in January in the northern hemisphere, but in July in the southern hemisphere, p < 0.0001. Seasonal influenza epidemic was coupled to El Nino, while low occurrence was coupled to La Nina. The moderate La Nina of 2010-2011 was followed by weak seasonal influenza epidemic. The influenza pandemic of 2009-2010 followed the moderate El Nino of 2009-2010, which had three peaks. Spectrograms showed time varying periodicities of 6-48 months for ENSO, 6-24 months for influenza in the northern hemisphere, and 6-12 months for influenza in the southern hemisphere. Cross spectrograms showed time-varying periodicities at 6-36 months for ENSO and influenza in both hemispheres, p < 0.0001. Phase plots showed that influenza time series lagged ENSO in both hemispheres. Severity of seasonal influenza increases during El Nino, but decreases during La Nina. Coupling of seasonality, timing, and severity of influenza epidemics to the strength and waveform of ENSO indicate that forecast models of El Nino should be integrated into surveillance programs for influenza epidemics. PMID- 26618148 TI - Unraveling the Links Between the Initiation of Ventilation and Brain Injury in Preterm Infants. AB - The initiation of ventilation in the delivery room is one of the most important but least controlled interventions a preterm infant will face. Tidal volumes (V T) used in the neonatal intensive care unit are carefully measured and adjusted. However, the V Ts that an infant receives during resuscitation are usually unmonitored and highly variable. Inappropriate V Ts delivered to preterm infants during respiratory support substantially increase the risk of injury and inflammation to the lungs and brain. These may cause cerebral blood flow instability and initiate a cerebral inflammatory cascade. The two pathways increase the risk of brain injury and potential life-long adverse neurodevelopmental outcomes. The employment of new technologies, including respiratory function monitors, can improve and guide the optimal delivery of V Ts and reduce confounders, such as leak. Better respiratory support in the delivery room has the potential to improve both respiratory and neurological outcomes in this vulnerable population. PMID- 26618151 TI - Laboratory Diagnosis of Tick-Borne African Relapsing Fevers: Latest Developments. AB - In Africa, relapsing fevers caused by ectoparasite-borne Borrelia species are transmitted by ticks, with the exception of Borrelia recurrentis, which is a louse-borne spirochete. These tropical diseases are responsible for mild to deadly spirochetemia. Cultured Borrelia crocidurae, Borrelia duttonii, and Borrelia hispanica circulate alongside at least six species that have not yet been cultured in vectors. Direct diagnosis is hindered by the use of non-specific laboratory tools. Indeed, microscopic observation of Borrelia spirochaeta in smears of peripheral blood taken from febrile patients lacks sensitivity and specificity. Although best visualized using dark-field microscopy, the organisms can also be detected using Wright-Giemsa or acridine orange stains. PCR-based detection of specific sequences in total DNA extracted from a specimen can be used to discriminate different relapsing fever Borreliae. In our laboratory, we developed a multiplex real-time PCR assay for the specific detection of B. duttonii/recurrentis and B. crocidurae: multispacer sequence typing accurately identified cultured relapsing fever borreliae and revealed diversity among them. Other molecular typing techniques, such as multilocus sequence analysis of tick borne relapsing fever borreliae, showed the potential risk of human infection in Africa. Recent efforts to culture and sequence relapsing fever borreliae have provided new information for reassessment of the diversity of these bacteria. Recently, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry has been reported as a means of identifying cultured borreliae and of identifying both vectors and vectorized pathogens such as detecting relapsing fever borreliae directly in ticks. The lack of a rapid diagnosis test restricts the management of such diseases. We produced monoclonal antibodies against B. crocidurae in order to develop cheap assays for the rapid detection of relapsing fever borreliae. In this paper, we review point-of-care diagnosis and confirmatory methods. PMID- 26618152 TI - A Study of Stakeholder Views to Shape a Communication Strategy for GMO in Brazil. AB - This paper analyzes the view of stakeholders on genetically modified organisms (GMOs) and the implications of these views on communication strategies for agricultural biotechnology in Brazil. It identifies and describes common groups of attitudes toward GMOs using multivariate statistical analyses. The study then looks for patterns of association between the common attitude groups and the following variables: socioeconomic characteristics trust in institutions as information sources and familiarity with the Brazilian biosafety authority. The article contributes to the understanding of public awareness by highlighting how information sources, trust in institutions, and socioeconomic characteristics, such as age and occupational qualification, play important roles in defining patterns of attitudes toward GMOs. The paper also discusses the implications of this knowledge for the development of a communication strategy plan that would promote public awareness and stimulate a well-informed Brazilian public debate on biosafety. PMID- 26618153 TI - Phenotypic Changes in Transgenic Tobacco Plants Overexpressing Vacuole-Targeted Thermotoga maritima BglB Related to Elevated Levels of Liberated Hormones. AB - The hyperthermostable beta-glucosidase BglB of Thermotoga maritima was modified by adding a short C-terminal tetrapeptide (AFVY, which transports phaseolin to the vacuole, to its C-terminal sequence). The modified beta-glucosidase BglB was transformed into tobacco (Nicotiana tabacum L.) plants. We observed a range of significant phenotypic changes in the transgenic plants compared to the wild-type (WT) plants. The transgenic plants had faster stem growth, earlier flowering, enhanced root systems development, an increased biomass biosynthesis rate, and higher salt stress tolerance in young plants compared to WT. In addition, programed cell death was enhanced in mature plants. Furthermore, the C-terminal AFVY tetrapeptide efficiently sorted T. maritima BglB into the vacuole, which was maintained in an active form and could perform its glycoside hydrolysis function on hormone conjugates, leading to elevated hormone [abscisic acid (ABA), indole 3 acetic acid (IAA), and cytokinin] levels that likely contributed to the phenotypic changes in the transgenic plants. The elevation of cytokinin led to upregulation of the transcription factor WUSCHELL, a homeodomain factor that regulates the development, division, and reproduction of stem cells in the shoot apical meristems. Elevation of IAA led to enhanced root development, and the elevation of ABA contributed to enhanced tolerance to salt stress and programed cell death. These results suggest that overexpressing vacuole-targeted T. maritima BglB may have several advantages for molecular farming technology to improve multiple targets, including enhanced production of the beta-glucosidase BglB, increased biomass, and shortened developmental stages, that could play pivotal roles in bioenergy and biofuel production. PMID- 26618155 TI - Adenosine Signaling Mediates Osteogenic Differentiation of Human Embryonic Stem Cells on Mineralized Matrices. AB - Human embryonic stem cells (hESCs) are attractive cell sources for tissue engineering and regenerative medicine due to their self-renewal and differentiation ability. Design of biomaterials with an intrinsic ability that promotes hESC differentiation to the targeted cell type boasts significant advantages for tissue regeneration. We have previously developed biomineralized calcium phosphate (CaP) matrices that inherently direct osteogenic differentiation of hESCs without the need of osteogenic-inducing chemicals or growth factors. Here, we show that CaP matrix-driven osteogenic differentiation of hESCs occurs through A2b adenosine receptor (A2bR). The inhibition of the receptor with an A2bR-specific antagonist attenuated mineralized matrix-mediated osteogenic differentiation of hESCs. In addition, when cultured on matrices in an environment deficient of CaP minerals, exogenous adenosine promoted osteogenic differentiation of hESCs, but was attenuated by the inhibition of A2bR. Such synthetic matrices that intrinsically support osteogenic commitment of hESCs are not only beneficial for bone tissue engineering but can also be used as a platform to study the effect of the physical and chemical cues to the extracellular milieu on stem cell commitment. Insights into the cell signaling during matrix-induced differentiation of stem cells will also help define the key processes and enable discovery of new targets that promote differentiation of pluripotent stem cells for bone tissue engineering. PMID- 26618154 TI - Modifying Yeast Tolerance to Inhibitory Conditions of Ethanol Production Processes. AB - Saccharomyces cerevisiae strains having a broad range of substrate utilization, rapid substrate consumption, and conversion to ethanol, as well as good tolerance to inhibitory conditions are ideal for cost-competitive ethanol production from lignocellulose. A major drawback to directly design S. cerevisiae tolerance to inhibitory conditions of lignocellulosic ethanol production processes is the lack of knowledge about basic aspects of its cellular signaling network in response to stress. Here, we highlight the inhibitory conditions found in ethanol production processes, the targeted cellular functions, the key contributions of integrated omics analysis to reveal cellular stress responses according to these inhibitors, and current status on design-based engineering of tolerant and efficient S. cerevisiae strains for ethanol production from lignocellulose. PMID- 26618156 TI - Action Direction of Muscle Synergies in Three-Dimensional Force Space. AB - Redundancy in the musculoskeletal system was supposed to be simplified by muscle synergies, which modularly organize muscles. To clarify the underlying mechanisms of motor control using muscle synergies, it is important to examine the spatiotemporal contribution of muscle synergies in the task space. In this study, we quantified the mechanical contribution of muscle synergies as considering spatiotemporal correlation between the activation of muscle synergies and endpoint force fluctuations. Subjects performed isometric force generation in the three-dimensional force space. The muscle-weighting vectors of muscle synergies and their activation traces across different trials were extracted from electromyogram data using decomposing technique. We then estimated mechanical contribution of muscle synergies across each trial based on cross-correlation analysis. The contributing vectors were averaged for all trials, and the averaging was defined as action direction (AD) of muscle synergies. As a result, we extracted approximately five muscle synergies. The ADs of muscle synergies mainly depended on the anatomical functions of their weighting muscles. Furthermore, the AD of each muscle indicated the synchronous activation of muscles, which composed of the same muscle synergy. These results provide the spatiotemporal characteristics of muscle synergies as neural basis. PMID- 26618158 TI - Interfacing of Science, Medicine and Law: The Stem Cell Patent Controversy in the United States and the European Union. AB - The patent eligibility of stem cells-particularly those derived from human embryos-has long been under debate in both the scientific and legal communities. On the basis of moral grounds, the European Patent Office (EPO) has refrained from granting patents for stem cells obtained through the destruction of human embryos. On the contrary, the United States Patent and Trademark Office (USPTO) has historically granted patents regarding the isolation and use of human embryonic and other stem cells. To date, these US patents remain valid despite an increasing onslaught of challenges in court. However, recent precedents established in US courts significantly narrow the scope of patent eligibility within biotechnology. This article compares the implications of recent legal changes on stem cell patent eligibility between the EU and US. PMID- 26618157 TI - Assembling Kidney Tissues from Cells: The Long Road from Organoids to Organs. AB - The field of regenerative medicine has witnessed significant advances that can pave the way to creating de novo organs. Organoids of brain, heart, intestine, liver, lung and also kidney have been developed by directed differentiation of pluripotent stem cells. While the success in producing tissue-specific units and organoids has been remarkable, the maintenance of an aggregation of such units in vitro is still a major challenge. While cell cultures are maintained by diffusion of oxygen and nutrients, three- dimensional in vitro organoids are generally limited in lifespan, size, and maturation due to the lack of a vascular system. Several groups have attempted to improve vascularization of organoids. Upon transplantation into a host, ramification of blood supply of host origin was observed within these organoids. Moreover, sustained circulation allows cells of an in vitro established renal organoid to mature and gain functionality in terms of absorption, secretion and filtration. Thus, the coordination of tissue differentiation and vascularization within developing organoids is an impending necessity to ensure survival, maturation, and functionality in vitro and tissue integration in vivo. In this review, we inquire how the foundation of circulation is laid down during the course of organogenesis, with special focus on the kidney. We will discuss whether nature offers a clue to assist the generation of a nephro-vascular unit that can attain functionality even prior to receiving external blood supply from a host. We revisit the steps that have been taken to induce nephrons and provide vascularity in lab grown tissues. We also discuss the possibilities offered by advancements in the field of vascular biology and developmental nephrology in order to achieve the long-term goal of producing transplantable kidneys in vitro. PMID- 26618159 TI - Association of Chest Pain and Risk of Cardiovascular Disease with Coronary Atherosclerosis in Patients with Inflammatory Joint Diseases. AB - OBJECTIVES: The relation between chest pain and coronary atherosclerosis (CA) in patients with inflammatory joint diseases (IJD) has not been explored previously. Our aim was to evaluate the associations of the presence of chest pain and the predicted 10-year risk of cardiovascular disease (CVD) by use of several CVD risk algorithms, with CA verified by multidetector computed tomography (MDCT) coronary angiography. METHODS: Detailed information concerning chest pain and CVD risk factors was obtained in 335 patients with rheumatoid arthritis and ankylosing spondylitis. In addition, 119 of these patients underwent MDCT coronary angiography. RESULTS: Thirty-one percent of the patients (104/335) reported chest pain. Only six patients (1.8%) had atypical angina pectoris (pricking pain at rest). In 69 patients without chest pain, two thirds had CA, while in those who reported chest pain (n = 50), CA was present in 48.0%. In a logistic regression analysis, chest pain was not associated with CA (dependent variable) (p = 0.43). About 30% (Nagelkerke R (2)) of CA was explained by any of the CVD risk calculators: Systematic Coronary Risk Evaluation, Framingham Risk Score, or Reynolds Risk Score. CONCLUSION: The presence of chest pain was surprisingly infrequently reported in patients with IJD who were referred for a CVD risk evaluation. However, when present, chest pain was weakly associated with CA, in contrast to the predicted CVD risk by several risk calculators which was highly associated with the presence of CA. These findings suggest that clinicians treating patients with IJD should be alert of coronary atherosclerotic disease also in the absence of chest pain symptoms. PMID- 26618160 TI - The Elusive Antifibrotic Macrophage. AB - Fibrotic diseases, especially of the liver, the cardiovascular system, the kidneys, and the lungs, account for approximately 45% of deaths in Western societies. Fibrosis is a serious complication associated with aging and/or chronic inflammation or injury and cannot be treated effectively yet. It is characterized by excessive deposition of extracellular matrix (ECM) proteins by myofibroblasts and impaired degradation by macrophages. This ultimately destroys the normal structure of an organ, which leads to loss of function. Most efforts to develop drugs have focused on inhibiting ECM production by myofibroblasts and have not yielded many effective drugs yet. Another option is to stimulate the cells that are responsible for degradation and uptake of excess ECM, i.e., antifibrotic macrophages. However, macrophages are plastic cells that have many faces in fibrosis, including profibrotic behavior-stimulating ECM production. This can be dependent on their origin, as the different organs have tissue resident macrophages with different origins and a various influx of incoming monocytes in steady-state conditions and during fibrosis. To be able to pharmacologically stimulate the right kind of behavior in fibrosis, a thorough characterization of antifibrotic macrophages is necessary, as well as an understanding of the signals they need to degrade ECM. In this review, we will summarize the current state of the art regarding the antifibrotic macrophage phenotype and the signals that stimulate its behavior. PMID- 26618161 TI - A Retrospective, Unicentric Evaluation of Complicated Diverticulosis Jejuni: Symptoms, Treatment, and Postoperative Course. AB - BACKGROUND: In contrast to the diverticulosis of the colon, jejunal diverticulosis is a rare condition. The incidence is 0.06-5% in large autopsy series. Complicated diverticulosis jejuni (CDJ) often presents with unspecific symptoms. Therefore, diagnosis is often a challenging process and due to the clinical rarity generally valid recommendation of perioperative management does not exist. PATIENTS AND METHODS: We considered only patients who were operated in our center between April 2007 and August 2014. Patients were identified by data bank search via International Statistical Classification of Diseases and Related Health Problems diagnosis code K57.10. Data were manually screened, and patients with Meckel's and duodenal diverticula were excluded from this study. Eleven consecutive patients with CDJ were finally included in this study. We analyzed symptoms, diagnostic procedures, surgical treatment, and postoperative morbidity and mortality. RESULTS: The median age of our patients was 76 years (range: 34 87). CDJ presented most frequently as intestinal bleeding or as diverticulitis. Clinical symptoms were unspecific abdominal pain, hematemesis or melena, ileus, nausea, and emesis as well as patients with acute abdomen. Esophagogastroduodenoscopies confirmed CDJ in two of the three patients. An abdominal computed tomography scan only helped to diagnose CDJ in two of the 10 patients. Eight (72.7%) patients received an open segmental resection with primary anastomosis. In three (27.3%) cases, a reoperation was necessary. Overall morbidity rate was 45.5%, and perioperative mortality was 9.1%. CONCLUSION: Due to the acute character of the disease, patients with CDJ are seriously ill. To diagnose patients with CDJ remains challenging as diagnostic investigations are usually not helpful in confirming the diagnosis. Still, diagnosis of CDJ is most frequently confirmed intraoperatively. PMID- 26618162 TI - Neonatal Mitral Valve Repair in Biventricular Repair, Single Ventricle Palliation, and Secondary Left Ventricular Recruitment: Indications, Techniques, and Mid-Term Outcomes. AB - OBJECTIVES: Although mitral valve repair is rarely required in neonates, this population is considered to be at high risk for adverse outcomes. The aim of this study was to review the indications for surgery, mechanisms, repair techniques, and mid-term outcomes of neonatal mitral valve repair. METHODS: The demographic, procedural, and outcome data were obtained for all neonates who underwent mitral valve repair from 2005 to 2012. The primary endpoints included mortality, transplantation, and mitral valve reoperation. RESULTS: Twenty patients were included during the study period. Median age at operation was 11 days (range: 3 25). Eleven patients (55%) presented with mitral stenosis, three had regurgitation (15%), and six had mixed mitral disease (30%). Nineteen of 20 patients had mild or less regurgitation on immediate postoperative imaging. During a median follow-up of 5 months (1 month-4.8 years), six patients died at a median of 33 months (7-41 months) from repair and one patient required orthotopic heart transplantation. Six patients required mitral valve reoperation, five for mitral valve re-repair, and one for mitral valve replacement. Freedom from death, transplantation, or mitral valve replacement was 84.2 +/- 8.4% at 1 month, 71.3 +/- 11% at 6 months, 64.1 +/- 12% at 1 year, and 51.3 +/- 15% at 2 years and was worse for patients presenting with mitral regurgitation compared to stenosis or mixed mitral valve disease. CONCLUSION: Although mitral valve repair can be performed with acceptable immediate postoperative result, this procedure carries a high burden of late death and mitral valve reoperations. PMID- 26618163 TI - Quantitative Shotgun Proteomics Analysis of Rice Anther Proteins after Exposure to High Temperature. AB - In rice, the stage of development most sensitive to high temperature stress is flowering, and exposure at this stage can result in spikelet sterility, thereby leading to significant yield losses. In this study, protein expression patterns of rice anthers from Dianxi4, a high temperature tolerant Japonica rice variety, were compared between samples exposed to high temperature and those grown in natural field conditions in Korea. Shotgun proteomics analysis of three replicate control and high-temperature-treated samples identified 3,266 nonredundant rice anther proteins (false discovery rate < 0.01). We found that high levels of ATP synthase, cupin domain-containing proteins, and pollen allergen proteins were present in rice anthers. Comparative analyses of 1,944 reproducibly expressed proteins identified 139 differentially expressed proteins, with 95 increased and 44 decreased in response to high temperature conditions. Heat shock, DnaK family, and chaperone proteins showed highly increased expression, suggesting that the high temperature tolerance of Dianxi4 is achieved by stabilization of proteins in pollen cells. Trehalose synthase was also highly increased after heat treatment, suggesting a possible role for trehalose in preventing protein denaturation through desiccation. PMID- 26618164 TI - Regulated Control of the Assembly and Diversity of LPS by Noncoding sRNAs. AB - The outer membrane (OM) of Gram-negative bacteria is asymmetric due to the presence of lipopolysaccharide (LPS) facing the outer leaflet of the OM and phospholipids facing the periplasmic side. LPS is essential for bacterial viability, since it provides a permeability barrier and is a major virulence determinant in pathogenic bacteria. In Escherichia coli, several steps of LPS biosynthesis and assembly are regulated by the RpoE sigma factor and stress responsive two-component systems as well as dedicated small RNAs. LPS composition is highly heterogeneous and dynamically altered upon stress and other challenges in the environment because of the transcriptional activation of RpoE regulon members and posttranslational control by RpoE-regulated Hfq-dependent RybB and MicA sRNAs. The PhoP/Q two-component system further regulates Kdo2-lipid A modification via MgrR sRNA. Some of these structural alterations are critical for antibiotic resistance, OM integrity, virulence, survival in host, and adaptation to specific environmental niches. The heterogeneity arises following the incorporation of nonstoichiometric modifications in the lipid A part and alterations in the composition of inner and outer core of LPS. The biosynthesis of LPS and phospholipids is tightly coupled. This requires the availability of metabolic precursors, whose accumulation is controlled by sRNAs like SlrA, GlmZ, and GlmY. PMID- 26618165 TI - Prognostic Significance of Serum Alkaline Phosphatase Level in Osteosarcoma: A Meta-Analysis of Published Data. AB - BACKGROUND: Serum alkaline phosphatase (SALP) is commonly elevated in osteosarcoma patients. A number of studies have investigated the prognostic role of SALP level in patients with osteosarcoma but yielded inconsistent results. METHOD: Systematic computerized searches were performed in PubMed, Embase, and Web of Science databases for relevant original articles. The pooled hazard ratios (HRs) and relative risks (RRs) with corresponding confidence intervals (CIs) were calculated to assess the prognostic value of SALP level. RESULTS: Finally, 21 studies comprising 3228 patients were included. Overall, the pooled HRs of SALP suggested that elevated level had an unfavorable impact on osteosarcoma patients' overall survival (OS) (HR = 1.82; 95% CI: 1.61-2.06; p < 0.001) and event-free survival (EFS) (HR = 1.97; 95% CI: 1.61-2.42; p < 0.001). Combined RRs of SALP indicated that elevated level was associated with presence of metastasis at diagnosis (RR = 5.55; 95% CI: 1.61-9.49; p = 0.006). No significantly different results were obtained after stratified by variables of age range, cancer stage, sample size, and geographic region. CONCLUSION: This meta-analysis demonstrated that high SALP level is significantly associated with poor OS or EFS rate and presence of metastasis at diagnosis. SALP level is a convenient and effective biomarker of prognosis for osteosarcoma. PMID- 26618167 TI - Challenges for Diagnosis of Malaria and Neglected Tropical Diseases in Elimination Settings. PMID- 26618166 TI - Comparative Genome and Network Centrality Analysis to Identify Drug Targets of Mycobacterium tuberculosis H37Rv. AB - Potential drug targets of Mycobacterium tuberculosis H37Rv were identified through systematically integrated comparative genome and network centrality analysis. The comparative analysis of the complete genome of Mycobacterium tuberculosis H37Rv against Database of Essential Genes (DEG) yields a list of proteins which are essential for the growth and survival of the pathogen. Those proteins which are nonhomologous with human were selected. The resulting proteins were then prioritized by using the four network centrality measures: degree, closeness, betweenness, and eigenvector. Proteins whose centrality value is close to the centre of gravity of the interactome network were proposed as a final list of potential drug targets for the pathogen. The use of an integrated approach is believed to increase the success of the drug target identification process. For the purpose of validation, selective comparisons have been made among the proposed targets and previously identified drug targets by various other methods. About half of these proteins have been already reported as potential drug targets. We believe that the identified proteins will be an important input to experimental study which in the way could save considerable amount of time and cost of drug target discovery. PMID- 26618170 TI - Impact of Extracellular Matrix on Cellular Behavior: A Source of Molecular Targets in Disease. PMID- 26618169 TI - Vertebral Body Stapling versus Bracing for Patients with High-Risk Moderate Idiopathic Scoliosis. AB - PURPOSE: We report a comparison study of vertebral body stapling (VBS) versus a matched bracing cohort for immature patients with moderate (25 to 44 degrees ) idiopathic scoliosis (IS). METHODS: 42 of 49 consecutive patients (86%) with IS were treated with VBS and followed for a minimum of 2 years. They were compared to 121 braced patients meeting identical inclusion criteria. 52 patients (66 curves) were matched according to age at start of treatment (10.6 years versus 11.1 years, resp. [P = 0.07]) and gender. RESULTS: For thoracic curves 25-34 degrees , VBS had a success rate (defined as curve progression <10 degrees ) of 81% versus 61% for bracing (P = 0.16). In thoracic curves 35-44 degrees , VBS and bracing both had a poor success rate. For lumbar curves, success rates were similar in both groups for curves measuring 25-34 degrees . CONCLUSION: In this comparison of two cohorts of patients with high-risk (Risser 0-1) moderate IS (25 44 degrees ), in smaller thoracic curves (25-34 degrees ) VBS provided better results as a clinical trend as compared to bracing. VBS was found not to be effective for thoracic curves >=35 degrees . For lumbar curves measuring 25-34 degrees , results appear to be similar for both VBS and bracing, at 80% success. PMID- 26618168 TI - Enhanced Oxidative Stress and Other Potential Biomarkers for Retinopathy in Type 2 Diabetics: Beneficial Effects of the Nutraceutic Supplements. AB - We have studied the global risk of retinopathy in a Mediterranean population of type 2 diabetes mellitus (T2DM) patients, according to clinical, biochemical, and lifestyle biomarkers. The effects of the oral supplementation containing antioxidants/omega 3 fatty acids (A/omega3) were also evaluated. Suitable participants were distributed into two main groups: (1) T2DMG (with retinopathy (+DR) or without retinopathy (-DR)) and (2) controls (CG). Participants were randomly assigned (+A/omega3) or not (-A/omega3) to the oral supplementation with a daily pill of Nutrof Omega (R) for 18 months. Data collected including demographics, anthropometrics, characteristics/lifestyle, ophthalmic examination (best corrected visual acuity, ocular fundus photographs, and retinal thickness as assessed by optical coherence tomography), and blood parameters (glucose, glycosylated hemoglobin, triglycerides, malondialdehyde, and total antioxidant capacity) were registered, integrated, and statistically processed by the SPSS 15.0 program. Finally, 208 participants (130 diabetics (68 +DR/62 -DR) and 78 controls) completed the follow-up. Blood analyses confirmed that the T2DMG+DR patients had significantly higher oxidative stress (p < 0.05), inflammatory (p < 0.05), and vascular (p < 0.001) risk markers than the T2DMG-DR and the CG. Furthermore, the A/omega3 oral supplementation positively changed the baseline parameters, presumptively by inducing metabolic activation and ameliorating the ocular health after 18 months of supplementation. PMID- 26618171 TI - Macrocolonies (Granules) Formation as a Cause of False-Negative Results in the MGIT 960 System: Cause Analysis and Correlation with Mycobacterial Species. AB - BACKGROUND: The viable mycobacterial bacilli can sometimes form granules in the Mycobacterium Growth Indicator Tube (MGIT) to produce instrument-negative outcomes when BACTEC MGIT 960 culture is performed. The cause of this phenomenon has never been analyzed. METHODS: Thirty-one instrument-negative, granule presenting MGIT vials were collected for conducting acid-fast staining and also liquid and solid subculture. Species identification and drug susceptibility test were performed with the recovered strains. Cultivation test was done by inoculating small amount of bacilli into the MGIT vials. RESULTS: Twenty-four and twenty-nine of the tested MGIT vials were smear and culture positive, respectively. In total, 18, 4, and 7 of the cultivated strains were identified as Mycobacterium tuberculosis complex, M. intracellulare, and M. xenopi, respectively. When a limited amount of bacilli was inoculated, the granule formation was observed for M. xenopi strains in the MGIT system. CONCLUSIONS: The granules observed in the instrument-negative MGIT vials consisted of viable bacilli, which emphasized the need of visual inspection to increase recovery rate. Limited bacterial load and specific species might be the cause of granule forming. PMID- 26618173 TI - Fear of Falling in Women with Fibromyalgia and Its Relation with Number of Falls and Balance Performance. AB - OBJECTIVE: To evaluate fear of falling, number of falls, and balance performance in women with FM and to examine the relationship between these variables and others, such as balance performance, quality of life, age, pain, and impact of fibromyalgia. METHODS: A total of 240 women participated in this cross-sectional study. Of these, 125 had fibromyalgia. Several variables were assessed: age, fear of falling from 0 to 100, number of falls, body composition, balance performance, lower limb strength, health-related quality of life, and impact of fibromyalgia. RESULTS: Women with fibromyalgia reported more falls and more fear of falling. Fear of falling was associated with number of falls in the last year, stiffness, perceived balance problems, impact of FM, and HRQoL whereas the number of falls was related to fear of falling, balance performance with eyes closed, pain, tenderness to touch level, anxiety, self-reported balance problems, impact of FM, and HRQoL. CONCLUSION: FM has an impact on fear of falling, balance performance, and number of falls. Perceived balance problems seem to be more closely associated with fear of falling than objective balance performance. PMID- 26618172 TI - Variations in Antioxidant Genes and Male Infertility. AB - Oxidative stress and reactive oxygen species (ROS) are generated from both endogenous and environmental resources, which in turn may cause defective spermatogenesis and male infertility. Antioxidant genes, which include catalase (CAT), glutathione peroxidase (GPX), glutathione S-transferase (GST), nitric oxide synthase (NOS), nuclear factor erythroid 2-related factor 2 (NRF2), and superoxide dismutase (SOD), play important roles in spermatogenesis and normal sperm function. In this review, we discuss the association between variations in major antioxidant genes and male infertility. Numerous studies have suggested that genetic disruption or functional polymorphisms in these antioxidant genes are associated with a higher risk for male infertility, which include low sperm quality, oligoasthenoteratozoospermia, oligozoospermia, and subfertility. The synergistic effects of environmental ROS and functional polymorphisms on antioxidant genes that result in male infertility have also been reported. Therefore, variants in antioxidant genes, which independently or synergistically occur with environmental ROS, affect spermatogenesis and contribute to the occurrence of male infertility. Large cohort and multiple center-based population studies to identify new antioxidant genetic variants that increase susceptibility to male infertility as well as validate its potential as genetic markers for diagnosis and risk assessment for male infertility for precise clinical approaches are warranted. PMID- 26618174 TI - The Roles of miR-26, miR-29, and miR-203 in the Silencing of the Epigenetic Machinery during Melanocyte Transformation. AB - The epigenetic marks located throughout the genome exhibit great variation between normal and transformed cancer cells. While normal cells contain hypomethylated CpG islands near gene promoters and hypermethylated repetitive DNA, the opposite pattern is observed in cancer cells. Recently, it has been reported that alteration in the microenvironment of melanocyte cells, such as substrate adhesion blockade, results in the selection of anoikis-resistant cells, which have tumorigenic characteristics. Melanoma cells obtained through this model show an altered epigenetic pattern, which represents one of the first events during the melanocytes malignant transformation. Because microRNAs are involved in controlling components of the epigenetic machinery, the aim of this work was to evaluate the potential association between the expression of miR-203, miR-26, and miR-29 family members and the genes Dnmt3a, Dnmt3b, Mecp2, and Ezh2 during cells transformation. Our results show that microRNAs and their validated or predicted targets are inversely expressed, indicating that these molecules are involved in epigenetic reprogramming. We also show that miR-203 downregulates Dnmt3b in mouse melanocyte cells. In addition, treatment with 5-aza-CdR promotes the expression of miR-26 and miR-29 in a nonmetastatic melanoma cell line. Considering the occurrence of CpG islands near the miR-26 and miR-29 promoters, these data suggest that they might be epigenetically regulated in cancer. PMID- 26618175 TI - Doxorubicin Differentially Induces Apoptosis, Expression of Mitochondrial Apoptosis-Related Genes, and Mitochondrial Potential in BCR-ABL1-Expressing Cells Sensitive and Resistant to Imatinib. AB - Imatinib resistance is an emerging problem in the therapy of chronic myeloid leukemia (CML). Because imatinib induces apoptosis, which may be coupled with mitochondria and DNA damage is a prototype apoptosis-inducing factor, we hypothesized that imatinib-sensitive and -resistant CML cells might differentially express apoptosis-related mitochondrially encoded genes in response to genotoxic stress. We investigated the effect of doxorubicin (DOX), a DNA-damaging anticancer drug, on apoptosis and the expression of the mitochondrial NADH dehydrogenase 3 (MT-ND3) and cytochrome b (MT-CYB) in model CML cells showing imatinib resistance caused by Y253H mutation in the BCR-ABL1 gene (253) or culturing imatinib-sensitive (S) cells in increasing concentrations of imatinib (AR). The imatinib-resistant 253 cells displayed higher sensitivity to apoptosis induced by 1 MUM DOX and this was confirmed by an increased activity of executioner caspases 3 and 7 in those cells. Native mitochondrial potential was lower in imatinib-resistant cells than in their sensitive counterparts and DOX lowered it. MT-CYB mRNA expression in 253 cells was lower than that in S cells and 0.1 MUM DOX kept this relationship. In conclusion, imatinib resistance may be associated with altered mitochondrial response to genotoxic stress, which may be further exploited in CML therapy in patients with imatinib resistance. PMID- 26618176 TI - Heavy Metal Contents and Physical Parameters of Aegiceras corniculatum, Brassica juncea, and Litchi chinensis Honeys from Bangladesh. AB - The present study was undertaken to determine the heavy metal levels and the physicochemical parameters (pH, electrical conductivity (EC), and ash, moisture, and total sugar content) of honeys from Bangladesh. Three different floral honeys were investigated, namely, khalsi (Aegiceras corniculatum), mustard (Brassica juncea), and litchi (Litchi chinensis) honeys. The heavy metals in the honeys were determined by using a High Temperature Dry Oxidation method followed by Atomic Absorption Spectroscopy. The mean pH, EC, and ash, moisture, and total sugar contents of the investigated honeys were 3.6, 0.51 mS/cm, 0.18%, 18.83%, and 68.30%, respectively. Iron was the most abundant among all the investigated heavy metals, ranging from 13.51 to 15.44 mg/kg. The mean concentrations of Mn and Zn in the investigated honeys were 0.28 mg/kg and 2.99 mg/kg, respectively. Cd was below the detection limit, and lead was found in some honey samples, but their contents were below the recommended Maximum Acceptable Level. Cr was also found in all of the samples, but its concentration was within the limit. The physicochemical analysis of the honey samples yielded levels within the limits set by the international honey legislation, indicating that the honey samples were of good quality and had acceptable values for maturity, purity, and freshness. PMID- 26618177 TI - Comparison of Direct and Indirect Laryngoscopes in Vomitus and Hematemesis Settings: A Randomized Simulation Trial. AB - BACKGROUND: Videolaryngoscopes may not be useful in the presence of hematemesis or vomitus. We compared the utility of the Macintosh laryngoscope (McL), which is a direct laryngoscope, with that of the Pentax-AWS Airwayscope (AWS) and McGRATH MAC (McGRATH), which are videolaryngoscopes, in simulated hematemesis and vomitus settings. METHODS: Seventeen anesthesiologists with more than 1 year of experience performed tracheal intubation on an adult manikin using McL, AWS, and McGRATH under normal, hematemesis, and vomitus simulations. RESULTS: In the normal setting, the intubation success rate was 100% for all three laryngoscopes. In the hematemesis settings, the intubation success rate differed significantly among the three laryngoscopes (P = 0.021). In the vomitus settings, all participants succeeded in tracheal intubation with McL or McGRATH, while five failed in the AWS trial with significant difference (P = 0.003). The intubation time did not significantly differ in normal settings, while it was significantly longer in the AWS trial compared to McL or McGRATH trial in the hematemesis or vomitus settings (P < 0.001, compared to McL or McGRATH in both settings). CONCLUSION: The performance of McGRATH and McL can be superior to that of AWS for tracheal intubation in vomitus and hematemesis settings in adults. PMID- 26618178 TI - HPV Infection, but Not EBV or HHV-8 Infection, Is Associated with Salivary Gland Tumours. AB - Benign and malignant salivary gland tumours are clinically heterogeneous and show different histology. Little is known about the role of human herpes virus 8 (HHV 8), Epstein-Barr virus (EBV), and human papillomavirus (HPV) infection in salivary gland neoplasms. We investigated the presence of the three viruses in formalin-fixed, paraffin-embedded tissue samples in a cohort of 200 different salivary gland tumours. We performed EBV-LMP-1 and HHV-8 and p16 immunohistochemistry, a specific chip based hybridization assay for detection and typing of HPV and a chromogenic in situ hybridization for EBV analysis. Only one case, a polymorphic low-grade carcinoma, showed HHV-8 expression and one lymphoepithelial carcinoma was infected by EBV. In 17 cases (9%) moderate or strong nuclear and cytoplasmic p16 expression was detected. The HPV type was investigated in all of these cases and additionally in 8 Warthin's tumours. In 19 cases HPV type 16 was detected, mostly in Warthin's tumour, adenoid cystic carcinoma, and adenocarcinoma NOS. We concluded that HHV-8 infection and EBV infection are not associated with salivary gland cancer, but HPV infection may play a role in these tumour entities. PMID- 26618179 TI - Diagnostic, Prognostic, and Predictive Molecular Biomarkers and the Utility of Molecular Imaging in Common Gastrointestinal Tumors. PMID- 26618180 TI - Variations in the Intragene Methylation Profiles Hallmark Induced Pluripotency. AB - We demonstrate the potential of differentiating embryonic and induced pluripotent stem cells by the regularized linear and decision tree machine learning classification algorithms, based on a number of intragene methylation measures. The resulting average accuracy of classification has been proven to be above 95%, which overcomes the earlier achievements. We propose a constructive and transparent method of feature selection based on classifier accuracy. Enrichment analysis reveals statistically meaningful presence of stemness group and cancer discriminating genes among the selected best classifying features. These findings stimulate the further research on the functional consequences of these differences in methylation patterns. The presented approach can be broadly used to discriminate the cells of different phenotype or in different state by their methylation profiles, identify groups of genes constituting multifeature classifiers, and assess enrichment of these groups by the sets of genes with a functionality of interest. PMID- 26618182 TI - Innate-Adaptive Immune Crosstalk. PMID- 26618183 TI - From Mouth-level to Tooth-level DMFS: Conceptualizing a Theoretical Framework. AB - OBJECTIVE: There is no dearth of correlated count data in any biological or clinical settings, and the ability to accurately analyze and interpret such data remains an exciting area of research. In oral health epidemiology, the Decayed, Missing, Filled (DMF) index has been continuously used for over 70 years as the key measure to quantify caries experience. The DMF index projects a subject's caries status using either the DMF(T), the total number of DMF teeth, or the DMF(S), counting the total DMF teeth surfaces, for that subject. However, surfaces within a particular tooth or a subject constitute clustered data, and the DMFS mostly overlook this clustering effect to attain an over-simplified summary index, ignoring the true tooth-level caries status. Besides, the DMFT/DMFS might exhibit excess of some specific counts (say, zeroes representing the set of relatively disease-free carious state), or can exhibit overdispersion, and accounting for the excess responses or overdispersion remains a key component is selecting the appropriate modeling strategy. METHODS & RESULTS: This concept paper presents the rationale and the theoretical framework which a dental researcher might consider at the onset in order to choose a plausible statistical model for tooth-level DMFS. Various nuances related to model fitting, selection and parameter interpretation are also explained. CONCLUSION: The author recommends conceptualizing the correct stochastic framework should serve as the guiding force to the dental researcher's never-ending goal of assessing complex covariate-response relationships efficiently. PMID- 26618181 TI - Regulation of Murine Ovarian Epithelial Carcinoma by Vaccination against the Cytoplasmic Domain of Anti-Mullerian Hormone Receptor II. AB - Anti-Mullerian hormone receptor, type II (AMHR2), is a differentiation protein expressed in 90% of primary epithelial ovarian carcinomas (EOCs), the most deadly gynecologic malignancy. We propose that AMHR2 may serve as a useful target for vaccination against EOC. To this end, we generated the recombinant 399-amino acid cytoplasmic domain of mouse AMHR2 (AMHR2-CD) and tested its efficacy as a vaccine target in inhibiting growth of the ID8 transplantable EOC cell line in C57BL/6 mice and in preventing growth of autochthonous EOCs that occur spontaneously in transgenic mice. We found that AMHR2-CD immunization of C57BL/6 females induced a prominent antigen-specific proinflammatory CD4+ T cell response that resulted in a mild transient autoimmune oophoritis that resolved rapidly with no detectable lingering adverse effects on ovarian function. AMHR2-CD vaccination significantly inhibited ID8 tumor growth when administered either prophylactically or therapeutically, and protection against EOC growth was passively transferred into naive recipients with AMHR2-CD-primed CD4+ T cells but not with primed B cells. In addition, prophylactic AMHR2-CD vaccination of TgMISIIR-TAg transgenic mice significantly inhibited growth of autochthonous EOCs and provided a 41.7% increase in mean overall survival. We conclude that AMHR2-CD vaccination provides effective immunotherapy of EOC with relatively benign autoimmune complications. PMID- 26618184 TI - New Additions to the Toolkit for Forward/Inverse Problems in Electrocardiography within the SCIRun Problem Solving Environment. AB - Cardiac electrical imaging often requires the examination of different forward and inverse problem formulations based on mathematical and numerical approximations of the underlying source and the intervening volume conductor that can generate the associated voltages on the surface of the body. If the goal is to recover the source on the heart from body surface potentials, the solution strategy must include numerical techniques that can incorporate appropriate constraints and recover useful solutions, even though the problem is badly posed. Creating complete software solutions to such problems is a daunting undertaking. In order to make such tools more accessible to a broad array of researchers, the Center for Integrative Biomedical Computing (CIBC) has made an ECG forward/inverse toolkit available within the open source SCIRun system. Here we report on three new methods added to the inverse suite of the toolkit. These new algorithms, namely a Total Variation method, a non-decreasing TMP inverse and a spline-based inverse, consist of two inverse methods that take advantage of the temporal structure of the heart potentials and one that leverages the spatial characteristics of the transmembrane potentials. These three methods further expand the possibilities of researchers in cardiology to explore and compare solutions to their particular imaging problem. PMID- 26618185 TI - Comprehensive analysis of signal transduction in three-dimensional ECM-based tumor cell cultures. AB - Analysis of signal transduction and protein phosphorylation is fundamental to understanding physiological and pathological cell behavior and identifying novel therapeutic targets. Despite the fact that the use of physiological three dimensional cell culture assays is increasing, 3D proteomics and phosphoproteomics remain challenging due to difficulties with easy, robust and reproducible sample preparation. Here, we present an easy-to-perform, reliable and time-efficient method for the production of 3D cell lysates that does not compromise cell adhesion before cell lysis. The samples can be used for western blotting as well as phosphoproteome array technology. This technique will be of interest for researchers working in all fields of biology and drug development. PMID- 26618186 TI - Comprehending the impossible: what role do selectional restriction violations play? AB - To elucidate how different kinds of knowledge are used during comprehension, readers' eye movements were monitored as they read sentences that were: plausible, impossible because of a selectional restriction violation, or impossible because of a violation of general world knowledge. Eye movements on the pre-critical, critical, and post-critical words evidenced disruption in the selectional restriction violation condition compared to the other two conditions. These findings suggest that disruption associated with reading about impossible events is not directly determined by how impossible the event seems. Rather, the relationship between the verb and arguments in the sentence seems to matter. These findings are the strongest evidence to date that processing effects associated with selectional restrictions can dissociate from those associated with general world knowledge about events. PMID- 26618187 TI - Semi-automated Image Processing for Preclinical Bioluminescent Imaging. AB - OBJECTIVE: Bioluminescent imaging is a valuable noninvasive technique for investigating tumor dynamics and specific biological molecular events in living animals to better understand the effects of human disease in animal models. The purpose of this study was to develop and test a strategy behind automated methods for bioluminescence image processing from the data acquisition to obtaining 3D images. METHODS: In order to optimize this procedure a semi-automated image processing approach with multi-modality image handling environment was developed. To identify a bioluminescent source location and strength we used the light flux detected on the surface of the imaged object by CCD cameras. For phantom calibration tests and object surface reconstruction we used MLEM algorithm. For internal bioluminescent sources we used the diffusion approximation with balancing the internal and external intensities on the boundary of the media and then determined an initial order approximation for the photon fluence we subsequently applied a novel iterative deconvolution method to obtain the final reconstruction result. RESULTS: We find that the reconstruction techniques successfully used the depth-dependent light transport approach and semi-automated image processing to provide a realistic 3D model of the lung tumor. Our image processing software can optimize and decrease the time of the volumetric imaging and quantitative assessment. CONCLUSION: The data obtained from light phantom and lung mouse tumor images demonstrate the utility of the image reconstruction algorithms and semi-automated approach for bioluminescent image processing procedure. We suggest that the developed image processing approach can be applied to preclinical imaging studies: characteristics of tumor growth, identify metastases, and potentially determine the effectiveness of cancer treatment. PMID- 26618190 TI - A Model Chain Application to Estimate Mixing Layer Height Related to PM10 Dispersion Processes. AB - The mixing layer height (MLH) is a crucial parameter in order to investigate the near surface concentrations of air pollutants. The MLH can be estimated by measurements of some atmospheric variables, by indirect estimates based on trace gases concentration or aerosol, or by numerical models. Here, a modelling approach is proposed. The developed modelling system is based on the models WRF ARW and CALMET. This system is applied on Firenze-Prato-Pistoia area (Central Italy), during 2010, and it is compared with in situ measurements. The aim of this work is to evaluate the use of MLH model estimates to characterize the critical episodes for PM10 in a limited area. In order to find out the meteorological conditions predisposing accumulation of PM10 in the atmosphere's lower level, some indicators are used: daily mean wind speed, cumulated rainfall, and mean MLH estimates from CALMET model. This indicator is linked to orography, which has important consequences on local weather dynamics. However, during critical events the local emission sources are crucial to the determination of threshold exceeding of PM10. Results show that the modelled MLH, together with cumulative rainfall and wind speed, can identify the meteorological conditions predisposing accumulation of air pollutant at ground level. PMID- 26618189 TI - Early to Late Endosome Trafficking Controls Secretion and Zymogen Activation in Rodent and Human Pancreatic Acinar Cells. AB - BACKGROUND & AIMS: Pancreatic acinar cells have an expanded apical endosomal system, the physiological and pathophysiological significance of which is still emerging. Phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2) is an essential phospholipid generated by PIKfyve, which phosphorylates phosphatidylinositol-3 phosphate (PI(3)P). PI(3,5)P2 is necessary for maturation of early endosomes (EE) to late endosomes (LE). Inhibition of EE to LE trafficking enhances anterograde endosomal trafficking and secretion at the plasma membrane by default through a recycling endosome (RE) intermediate. We assessed the effects of modulating PIKfyve activity on apical trafficking and pancreatitis responses in pancreatic acinar cells. METHODS: Inhibition of EE to LE trafficking was achieved using pharmacological inhibitors of PIKfyve, expression of dominant negative PIKfyve K1877E, or constitutively active Rab5-GTP Q79L. Anterograde endosomal trafficking was manipulated by expression of constitutively active and dominant negative Rab11a mutants. The effects of these agents on secretion, endolysosomal exocytosis of lysosome associated membrane protein (LAMP1), and trypsinogen activation in response to high-dose CCK-8, bile acids and cigarette toxin was determined. RESULTS: PIKfyve inhibition increased basal and stimulated secretion. Adenoviral overexpression of PIKfyve decreased secretion leading to cellular death. Expression of Rab5-GTP Q79L or Rab11a-GTP Q70L enhanced secretion. Conversely, dominant-negative Rab11a-GDP S25N reduced secretion. High-dose CCK inhibited endolysosomal exocytosis that was reversed by PIKfyve inhibition. PIKfyve inhibition blocked intracellular trypsin accumulation and cellular damage responses to high CCK-8, tobacco toxin, and bile salts in both rodent and human acini. CONCLUSIONS: These data demonstrate that EE-LE trafficking acutely controls acinar secretion and the intracellular activation of zymogens leading to the pathogenicity of acute pancreatitis. PMID- 26618191 TI - Bioinformatics/Medical Informatics in Traditional Medicine and Integrative Medicine. PMID- 26618188 TI - Locus Coeruleus, norepinephrine and Abeta peptides in Alzheimer's disease. AB - Monoaminergic brainstem systems have widespread projections that participate in many central processes and, when dysregulated, contribute to a plethora of neuropsychiatric and neurodegenerative disorders. Synapses are the foundation of these neuronal circuits, and their local dysfunction results in global aberrations leading to pathophysiological disease states. This review focuses on the locus coeruleus (LC) norepinephrine (NE) brainstem system and its underappreciated role in Alzheimer's disease (AD). Amyloid beta (Abeta), a peptide that accumulates aberrantly in AD has recently been implicated as a modulator of neuronal excitability at the synapse. Evidence is presented showing that disruption of the LC-NE system at a synaptic and circuit level during early stages of AD, due to conditions such as chronic stress, can potentially lead to amyloid accumulation and contribute to the progression of this neurodegenerative disorder. Additional factors that impact neurodegeneration include neuroinflammation, and network de-synchronization. Consequently, targeting the LC NE system may have significant therapeutic potential for AD, as it may facilitate modulation of Abeta production, curtail neuroinflammation, and prevent sleep and behavioral disturbances that often lead to negative patient outcomes. PMID- 26618192 TI - Source Contributions of PM2.5 in the Severe Haze Episode in Hebei Cities. AB - Beijing-Tianjin-Hebei area is one of the most polluted areas in China. This paper used the Fifth-Generation Penn State/NCAR Mesoscale Model (MM5) and Model 3/Community Multiscale Air Quality (CMAQ) modeling system to quantify the source contribution to PM2.5 in Hebei cities in order to obtain an in-depth understanding haze process in January and February 2013, using the Multiresolution Emission Inventory for China (MEIC). The result showed that PM2.5 were mainly originated from the southern Hebei (SHB) with the fractions of 70.8% and 66.4% to Shijiazhuang, 70.6% and 63.9% to Xingtai, and 68.5% and 63.0% to Handan in January and February 2013, respectively. The northern Hebei (NHB) contributed 69.8% and 70.7% to Zhangjiakou, 68.7% and 66.2% to Chengde, and 57.7% and 59.6% to Qinhuangdao in January and February. In Cangzhou, Hengshui, and Langfang, regional joint policy making should be implemented due to the pollution of multiple sources. In Baoding and Tangshan, industrial emissions contributed 38.1% and 41.9% of PM2.5 to Baoding and 39.8% and 45.8% to Tangshan in January and February, respectively. Industrial and domestic emissions should be controlled in Tangshan and Baoding, especially for industrial emissions of NHB. PMID- 26618194 TI - Mussel Coating Protein-Derived Complex Coacervates Mitigate Frictional Surface Damage. AB - The role of friction in the functional performance of biomaterial interfaces is widely reckoned to be critical and complicated but poorly understood. To better understand friction forces, we investigated the natural adaptation of the holdfast or byssus of mussels that live in high-energy surf habitats. As the outermost covering of the byssus, the cuticle deserves particular attention for its adaptations to frictional wear under shear. In this study, we coacervated one of three variants of a key cuticular component, mussel foot protein 1, mfp-1 [(1) Mytilus californianus mcfp-1, (2) rmfp-1, and (3) rmfp-1-Dopa], with hyaluronic acid (HA) and investigated the wear protection capabilities of these coacervates to surfaces (mica) during shear. Native mcfp-1/HA coacervates had an intermediate coefficient of friction (MU ~0.3) but conferred excellent wear protection to mica with no damage from applied loads, F?, as high as 300 mN (pressure, P, > 2 MPa). Recombinant rmfp-1/HA coacervates exhibited a comparable coefficient of friction (MU ~0.3); however, wear protection was significantly inferior (damage at F? > 60 mN) compared with that of native protein coacervates. Wear protection of rmfp 1/HA coacervates increased 5-fold upon addition of the surface adhesive group 3,4 dihydroxyphenylalanine, (Dopa). We propose a Dopa-dependent wear protection mechanism to explain the differences in wear protection between coacervates. Our results reveal a significant untapped potential for coacervates in applications that require adhesion, lubrication, and wear protection. These applications include artificial joints, contact lenses, dental sealants, and hair and skin conditioners. PMID- 26618195 TI - Tunable in vivo circulation characteristics of PEGylated MPI tracers. PMID- 26618193 TI - Bardoxolone Methyl Prevents Mesenteric Fat Deposition and Inflammation in High Fat Diet Mice. AB - Mesenteric fat belongs to visceral fat. An increased deposition of mesenteric fat contributes to obesity associated complications such as type 2 diabetes and cardiovascular diseases. We have investigated the therapeutic effects of bardoxolone methyl (BARD) on mesenteric adipose tissue of mice fed a high-fat diet (HFD). Male C57BL/6J mice were administered oral BARD during HFD feeding (HFD/BARD), only fed a high-fat diet (HFD), or fed low-fat diet (LFD) for 21 weeks. Histology and immunohistochemistry were used to analyse mesenteric morphology and macrophages, while Western blot was used to assess the expression of inflammatory, oxidative stress, and energy expenditure proteins. Supplementation of drinking water with BARD prevented mesenteric fat deposition, as determined by a reduction in large adipocytes. BARD prevented inflammation as there were fewer inflammatory macrophages and reduced proinflammatory cytokines (interleukin-1 beta and tumour necrosis factor alpha). BARD reduced the activation of extracellular signal-regulated kinase (ERK) and Akt, suggesting an antioxidative stress effect. BARD upregulates energy expenditure proteins, judged by the increased activity of tyrosine hydroxylase (TH) and AMP-activated protein kinase (AMPK) and increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha), and uncoupling protein 2 (UCP2) proteins. Overall, BARD induces preventive effect in HFD mice through regulation of mesenteric adipose tissue. PMID- 26618196 TI - Caveolae-mediated Delivery of Therapeutic Nanoparticles across Blood-endothelial Barrier. PMID- 26618197 TI - Cortisol Responses to Psychosocial Stress: The Role of Childhood Maltreatment and Depression. AB - This study examined cortisol reactivity to repeated psychosocial stressors in 35 adolescents and young adults aged 12 to 26 years. Participants were divided into three study groups: controls with no history of major depressive disorder (MDD) or childhood maltreatment (n = 18); a diagnosis of MDD at Time 1 but no history of maltreatment (MDD-only; n = 10); and both MDD and maltreatment (MDD+MALTX; n = 7). Participants with MDD recovered from their depressive episode prior to the second psychosocial stress task. The MDD-only group had higher cortisol responses at Time 1 relative to other groups. No between-group differences were observed in cortisol responses at Time 2. Depressed individuals with maltreatment did not differ from controls in their cortisol responses at Time 1 or Time 2. Findings suggest that elevated cortisol stress reactivity is a state-dependent correlate of depression in youth with no history of maltreatment. PMID- 26618198 TI - Intentional Right Atrial Exit and Carbon Dioxide Insufflation to Facilitate Subxiphoid Needle Entry Into the Empty Pericardial Space: First Human Experience. AB - OBJECTIVES: The purpose of this study was to test whether a microcatheter can safely be advanced across the right atrial appendage to access the pericardium and then withdrawn despite subsequent high-intensity anticoagulation. We also tested whether transatrial pericardial insufflation of carbon dioxide (CO2) would enhance the safety of subxiphoid needle access to the empty pericardium by separating the heart from the anterior pericardium. BACKGROUND: Subxiphoid needle access to the empty pericardium, required for left atrial suture ligation and epicardial ablation for rhythm disorders, risks myocardial or coronary laceration. METHODS: A catheter from the femoral vein engaged the right atrial appendage for angiographic confirmation of position. Through that catheter, the back end of a 0.014- or 0.018-inch guidewire crossed the right atrial wall to enter the pericardium and delivered a 2.4-F microcatheter. CO2 1 to 2 ml/kg was insufflated into the pericardium immediately before subxiphoid needle access under lateral projection fluoroscopy. Thirteen patients undergoing subxiphoid suture ligation of the left atrial appendage consented to participate in this research protocol. RESULTS: Right atrial exit succeeded in 11 subjects (85%) and failed uneventfully in 2 subjects. CO2 insufflation of 96 +/- 22 ml achieved 12 +/- 4 mm separation of the anterior pericardium from the myocardial wall, allowed rapid and successful subxiphoid anterior needle and guidewire entry in all 11 subjects, and did not have any evident hemodynamic effects. The immediate pericardial aspirate was serous in all but 1 subject. CONCLUSIONS: We report the first human intentional transatrial exit procedure. Transatrial microcatheter access to the pericardium can be achieved safely. Pericardial insufflation with CO2 makes subxiphoid access to the empty pericardium rapid and safe. Although our clinical experience to date remains small, with further experience, this approach may prevent the life-threatening complications of "dry" subxiphoid pericardial access. PMID- 26618200 TI - Senile transthyretin cardiac amyloidosis in patients with plasma cell dyscrasias: importance of cardiac biopsy for making the correct diagnosis. AB - Amyloidosis refers to a group of widely diverse conditions characterized by the deposition of insoluble protein within the extracellular space, leading to disruption of normal organ function. AL primary amyloidosis is associated with plasma cell dyscrasias and is caused by the deposition of insoluble kappa or lambda light chains. Cardiac involvement by AL primary amyloidosis has a very poor prognosis, and patients are treated with systemic chemotherapy. Clinically, the presence of cardiac amyloidosis in patients with plasma cell disorders is usually presumed to represent AL primary amyloidosis, and they are often managed as such. We reported four cases of elderly patients with plasma cell disorders who were found to have biopsy-proven cardiac senile transthyretin amyloidosis. Our cases demonstrated that cardiac amyloidosis in patients with plasma cell disorders does not necessarily represent AL primary amyloidosis. Cardiac biopsy is important in making the correct diagnosis. Accurate subtyping of the amyloid has significant implications in the management of patients and discussion of prognosis. PMID- 26618201 TI - Objectively coding intervention fidelity during a phone-based obesity prevention study. AB - BACKGROUND: Childhood obesity prevention studies have yielded disappointing results. Understanding intervention fidelity is necessary in explaining why interventions are (or are not) successful and ultimately improving future intervention. In spite of this, intervention fidelity it is not consistently reported in the obesity prevention literature. The purpose of the current study was to develop and utilize a coding protocol to objectively assess intervention fidelity in a phone-based obesity prevention study for parents of preschool-aged children. FINDINGS: Both interventionists and independent coders completed session fidelity measures including time spent on target areas (media use, physical activity, etc.) and components of goal setting quality. Coders also rated participant engagement. Agreement between ratings by interventionists and coders, fidelity levels and changes in fidelity components over time are presented. Coders and interventionists showed high agreement when reporting time spent discussing different target areas. Interventionists consistently rated themselves higher than independent coders on measures of goal quality. Coder ratings of session quality were initially high, but some components declined slightly across the eight sessions. CONCLUSIONS: Future directions for intervention fidelity measurement and analysis are discussed, including utilizing changes in fidelity measures over time to predict study outcomes. Obtaining a more in-depth understanding of intervention fidelity has the potential to strengthen obesity interventions. PMID- 26618199 TI - Why does infection with some helminths cause cancer? AB - Infections with Opisthorchis viverrini, Clonorchis sinensis and Schistosoma haematobium are classified as Group 1 biological carcinogens: definitive causes of cancer. These worms are metazoan eukaryotes, unlike the other Group 1 carcinogens including human papilloma virus, hepatitis C virus, and Helicobacter pylori. By contrast, infections with phylogenetic relatives of these helminths, also trematodes of the phylum Platyhelminthes and major human pathogens, are not carcinogenic. These inconsistencies prompt several questions, including how might these infections cause cancer? And why is infection with only a few helminth species carcinogenic? Here we present an interpretation of mechanisms contributing to the carcinogenicity of these helminth infections, including roles for catechol estrogen- and oxysterol-metabolites of parasite origin as initiators of carcinogenesis. PMID- 26618204 TI - EFFECTS OF FATIGUE ON REAL-WORLD DRIVING IN DISEASED AND CONTROL PARTICIPANTS. AB - This study evaluated real world driver errors and sleepiness in 66 drivers with Obstructive Sleep Apnea (OSA) and 34 matched controls (24 younger and 22 older). Driving errors and driver state were derived from analyses of video data from "black-box" event recorders. Sleep fragmentation data in OSA was derived from actigraphy for 15 days prior to beginning standard treatment (positive airway pressure, PAP) and 15 days after beginning PAP treatment. Prior to starting PAP, OSAs appeared sleepier than controls in general and particularly at intersections, while making safety errors following nights with high levels of fragmented sleep compared to matched controls. Adverse effects of sleep fragmentation during the pre-PAP phase were reduced post-PAP. Greater hours of PAP-use were associated with lower sleepiness and errors on the road. PAP-use was associated with a decrease in high sleep fragmented nights. Findings suggest reduction in acute sleepiness is unlikely to be the only mediating factor that explains the driving safety benefits of PAP in OSA. PMID- 26618202 TI - Neural Response During a Mechanically Assisted Spinal Manipulation in an Animal Model: A Pilot Study. AB - INTRODUCTION: Mechanoreceptor stimulation is theorized to contribute to the therapeutic efficacy of spinal manipulation. Use of mechanically-assisted spinal manipulation (MA-SM) devices is increasing among manual therapy clinicians worldwide. The purpose of this pilot study is to determine the feasibility of recording in vivo muscle spindle responses during a MA-SM in an intervertebral fixated animal model. METHODS: Intervertebral fixation was created by inserting facet screws through the left L5-6 and L6-7 facet joints of a cat spine. Three L6muscle spindle afferents with receptive fields in back muscles were isolated. Recordings were made during MA-SM thrusts delivered to the L7 spinous process using an instrumented Activator IV clinical device. RESULTS: Nine MA-SM thrusts were delivered with peak forces ranging from 68-122N and with thrust durations of less than 5ms. High frequency muscle spindle discharge occurred during MA-SM. Following the MA-SM, muscle spindle responses included returning to pre manipulation levels, slightly decreasing for a short window of time, and greatly decreasing for more than 40s. CONCLUSION: This study demonstrates that recording in vivo muscle spindle response using clinical MA-SM devices in an animal model is feasible. Extremely short duration MA-SM thrusts (<5ms) can have an immediate and/or a prolonged (> 40s) effect on muscle spindle discharge. Greater peak forces during MA-SM thrusts may not necessarily yield greater muscle spindle responses. Determining peripheral response during and following spinal manipulation may be an important step in optimizing its' clinical efficacy. Future studies may investigate the effect of thrust dosage and magnitude. PMID- 26618203 TI - Towards a Hybrid Agent-based Model for Mosquito Borne Disease. AB - Agent-based models (ABM) are used to simulate the spread of infectious disease through a population. Detailed human movement, demography, realistic business location networks, and in-host disease progression are available in existing ABMs, such as the Epidemic Simulation System (EpiSimS). These capabilities make possible the exploration of pharmaceutical and non-pharmaceutical mitigation strategies used to inform the public health community. There is a similar need for the spread of mosquito borne pathogens due to the re-emergence of diseases such as chikungunya and dengue fever. A network-patch model for mosquito dynamics has been coupled with EpiSimS. Mosquitoes are represented as a "patch" or "cloud" associated with a location. Each patch has an ordinary differential equation (ODE) mosquito dynamics model and mosquito related parameters relevant to the location characteristics. Activities at each location can have different levels of potential exposure to mosquitoes based on whether they are inside, outside, or somewhere in-between. As a proof of concept, the hybrid network-patch model is used to simulate the spread of chikungunya through Washington, DC. Results are shown for a base case, followed by varying the probability of transmission, mosquito count, and activity exposure. We use visualization to understand the pattern of disease spread. PMID- 26618205 TI - Term Familiarity to indicate Perceived and Actual Difficulty of Text in Medical Digital Libraries. AB - With increasing text digitization, digital libraries can personalize materials for individuals with different education levels and language skills. To this end, documents need meta-information describing their difficulty level. Previous attempts at such labeling used readability formulas but the formulas have not been validated with modern texts and their outcome is seldom associated with actual difficulty. We focus on medical texts and are developing new, evidence based meta-tags that are associated with perceived and actual text difficulty. This work describes a first tag, term familiarity , which is based on term frequency in the Google corpus. We evaluated its feasibility to serve as a tag by looking at a document corpus (N=1,073) and found that terms in blogs or journal articles displayed unexpected but significantly different scores. Term familiarity was then applied to texts and results from a previous user study (N=86) and could better explain differences for perceived and actual difficulty. PMID- 26618206 TI - Residential Mobility and Lung Cancer Risk: Data-Driven Exploration Using Internet Sources. AB - Frequent relocation has been linked to health decline, particularly with respect to emotional and psychological wellbeing. In this paper we investigate whether there is an association between frequent relocation and lung cancer risk. For the initial investigation we used web crawling and tailored text mining to collect cancer and control subjects from online data sources. One data source includes online obituaries. The second data source includes augmented LinkedIn profiles. For each data source, the subjects' spatiotemporal history is reconstructed from the available information provided in the obituaries and from the education and work experience provided in the LinkedIn profiles. The study shows that lung cancer subjects have higher mobility frequency than the control group. This trend is consistent for both data sources. PMID- 26618207 TI - Comment on "Long-term durability of bioprosthetic aortic valves: implications from 12,569 implants". PMID- 26618208 TI - The Endocannabinoid System: A Look Back and Ahead. PMID- 26618209 TI - WHO CALLS FOR URGENT ACTION TO CURB HEPATITIS. PMID- 26618210 TI - WORLD HEPATITIS SUMMIT HARNESSES GLOBAL MOMENTUM TO ELIMINATE VIRAL HEPATITIS. PMID- 26618211 TI - Avertoxins A-D, Prenyl Asteltoxin Derivatives from Aspergillus versicolor Y10, an Endophytic Fungus of Huperzia serrata. AB - Aspergillus versicolor Y10 is an endophytic fungus isolated from Huperzia serrata, which showed inhibitory activity against acetylcholinesterase. An investigation of the chemical constituents of Y10 led to the isolation of four new prenylated asteltoxin derivatives, named avertoxins A-D (2-5), together with the known mycotoxin asteltoxin (1). In the present study, we report structure elucidation for 2-5 and the revised NMR assignments for asteltoxin and demonstrated that avertoxin B (3) is an active inhibitor against human acetylcholinesterase with the IC50 value of 14.9 MUM (huperzine A as the positive control had an IC50 of 0.6 MUM). In addition, the cytotoxicity of asteltoxin (1) and avertoxins A-D (2-5) against MDA-MB-231, HCT116, and HeLa cell lines was evaluated. PMID- 26618212 TI - Investigation of Lithium Insertion Mechanisms of a Thin-Film Si Electrode by Coupling Time-of-Flight Secondary-Ion Mass Spectrometry, X-ray Photoelectron Spectroscopy, and Focused-Ion-Beam/SEM. AB - Silicon is a serious candidate to replace graphite in electrodes because it offers a specific capacity almost 10 times higher than that of carbonaceous materials. However, cycling performances of Si electrodes remain very limited because of the huge volume changes upon alloying and dealloying with lithium. A fine understanding of the lithiation mechanism of silicon electrodes will help to design more robust architectures. In this work, an amorphous silicon thin film has been used as a model for a better understanding of lithiation mechanism. Lithium distribution in the Si layer has been thoroughly investigated by coupling powerful characterization tools: X-ray photoelectron spectroscopy (XPS) and secondary-ion mass spectrometry (ToF-SIMS). In particular, cross-analysis of different lithiation states has been carried out. A lithiation front moving forward over the state of charge has been highlighted. The quantification of the LixSi alloy indicates a lithium amount much higher than that of the Li/Si ratio estimated in previous studies. This anomaly leads to a description of the lithiation mechanism based on the presence of fast diffusion paths for Li throughout the Si layer. These paths would be a second driving force for silicon alloying and lithium segregation at the collector interface. SEM observations of a FIB cut corroborate this mechanism. PMID- 26618213 TI - Sleep, well-being, and psychological symptoms in adults with pediatric-onset spinal cord injury. AB - OBJECTIVE: To examine the prevalence of poor sleep quality in adults with pediatric-onset spinal cord injury (SCI) and to assess the clinical correlates. METHOD: Participants completed interviews that included demographic information and standardized measures of sleep (Pittsburgh Sleep Quality Index), physical (12 item Short-Form Health Survey, Version 2), mental (Beck Anxiety Inventory and Patient Health Questionnaire), and psychosocial well-being (Satisfaction With Life Scale). The study included 177 individuals between the ages of 19 and 50 years (M = 33.5 years, SD = 7.1) who sustained a, SCI prior to age 19 (M = 13.5 years, SD = 4.6) and had been injured for at least 1 year (M = 19.5 years, SD = 8. 2). Participants were recruited from 1 of 3 pediatric SCI programs in the United States and were predominantly male (62%) and White (84%). RESULTS: Sleep difficulties were fairly common, with half of participants self-reporting poor sleep quality within the last month (n = 91 [51.4%]). Both increased age (r = .20, p = .008) and tetraplegia, F(1, 175) = 6.62, p = .011, were significantly associated with poor sleep. Activity-interfering pain (r = .57, p < .001) and general health (r = .37, p < .001) were also strongly associated with poor sleep. Even after accounting for age, injury level, and pain as control variables, sleep quality explained a small, but significant, portion of the variance in depression (R2 = .06, p < .001) and anxiety (R2 = .04, p = .005), but not life satisfaction (R2 = .02, p = .075). CONCLUSION: These results suggest that adults with pediatric-onset SCI report more sleep difficulties than the standardization sample and that sleep is significantly associated with physical and psychological functioning. Consequently, better measures to detect and treat sleep problems among those with pediatric-onset SCI are recommended. PMID- 26618214 TI - Factors related to satisfaction with life in veterans with mild traumatic brain injury. AB - PURPOSE/OBJECTIVE: Satisfaction with life (SWL) is an important measure of outcome in rehabilitation. Previous research suggests that those with a history of traumatic brain injury (TBI), even mild TBI, report lower levels of life satisfaction when compared with the noninjured population. Although is it possible that TBI has a direct effect on SWL, various medical and psychosocial factors commonly affecting those recovering from TBI likely contribute to SWL. RESEARCH METHOD/DESIGN: The present study aimed to identify factors related to SWL in 95 veterans of Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) with a history of mild TBI. RESULTS: Regression analyses indicated that headache impact, pain interference, sleep quality, posttraumatic stress symptom severity, and social support were all significantly related to SWL. However, when secondary analyses were conducted including posttraumatic stress symptom severity as a covariate before the entry of other predictors, only sleep quality and social support remained significantly associated with SWL. CONCLUSIONS/IMPLICATIONS: These results indicate the importance of properly identifying and treating symptoms of posttraumatic stress in veterans with a history of mTBI, as posttraumatic stress symptoms appear to be strongly related to SWL in those with a history of mild TBI. Optimizing sleep quality and social support may also be important in improving SWL. PMID- 26618216 TI - Measurement characteristics and clinical utility of the Brief Pain Inventory Short Form for individuals with multiple sclerosis. AB - This Rehabilitation Measures Database summary provides a review of the psychometric properties of the BPI in individuals with MS. A full review of the BPI as well as reviews of over 330 other instruments can be found at www.rehabmeasures.org. PMID- 26618215 TI - Trajectories of life satisfaction after traumatic brain injury: Influence of life roles, age, cognitive disability, and depressive symptoms. AB - OBJECTIVES: (a) Identify life satisfaction trajectories after moderate to severe traumatic brain injury (TBI); (b) establish a predictive model for these trajectories across the first 5 years postinjury; and (c) describe differences in these life satisfaction trajectory groups, focusing on age, depressive symptoms, disability, and participation in specific life roles. RESEARCH METHOD: Analysis of the longitudinal TBI Model Systems National Database was performed on data collected prospectively at 1-, 2-, and 5-years post-TBI. Participants (n = 3,012) had a moderate to severe TBI and were 16 years old and older. RESULTS: Four life satisfaction trajectories were identified across the first 5 years postinjury, including: stable satisfaction, initial satisfaction declining, initial dissatisfaction improving, and stable dissatisfaction. Age, depressive symptoms, cognitive disability, and life role participation as a worker, leisure participant, and/ or religious participant at 1-year postinjury significantly predicted trajectory group membership. Life role participation and depressive symptoms were strong predictors of life satisfaction trajectories across the first 5 years post-TBI. CONCLUSIONS: The previously documented loss of life roles and prevalence of depression after a moderate to severe TBI make this a vulnerable population for whom low or declining life satisfaction is a particularly high risk. Examining individual life role participation may help to identify relevant foci for community-based rehabilitation interventions or supports. PMID- 26618217 TI - An investigation into the temporal scaling of community participation measurement. AB - PURPOSE: Community participation remains fundamental to contemporary models of disability. However, the effect of temporal scaling on the measurement of participation has not been explored. This study examined the similarities and differences between two different temporal scales (i.e., seven-day recall vs. in situ) on participation measurement. RESEARCH METHOD: We collected seven-day retrospective recall data using a self-report paper-and-pencil measure (i.e., the Brief Community Engagement Questionnaire) from a community-based sample (N = 525) of individuals who endorsed one or more items of the American Community Survey disability screening questions. A subset of these participants (n = 148) completed an ancillary ecological momentary assessment (EMA) study, which involved repeated, in situ, daily measurements of participation for two weeks. Corresponding participation items from each method were compared. RESULTS: Survey and EMA participation data were relatively consistent over repeated measurements, suggesting reliability across methods and temporal scaling. Consistency across activities was most evident for major activities that tend to require regular behavior (e.g., work and volunteering). Conversely, lower base rate behavior demonstrated less stability regardless of temporal resolution. CONCLUSION: Understanding the implications of temporal resolution for participation measures is valuable for advancing ecological participation models. Future research is needed to develop consensus on participation measurement and provide a solid basis for developing ecological models of participation. PMID- 26618218 TI - Applied ethics: Have we lost a crucial opportunity? AB - Comments on the article, "Guidelines for competency development and measurement in rehabilitation psychology postdoctoral training," by Stiers et al. (see record 2014-55195-001). A review of the recent publication of Stiers et al., a well organized distillation of the functional competencies required of practitioners of Rehabilitation Psychology that evolved from the Baltimore Consensus Conference (Stiers et al., 2012), revealed a potentially important omission in the section labeled Structured Observations of Competencies in Assessment and Intervention (Table 4, p. 117). Throughout the subsections regarding Knowledge, Skills/Abilities, and Attitudes/ Values, indirect reference to the American Psychological Association (APA) Ethical Principles of Psychologists and Code of Conduct (APA, 2010) is evident without formal citation of the Code. The concepts operationalized in the APA ethical principles suffuse the content of this section of the competencies, but without direct reference to those principles. The remainder of the tables (5-7, pp. 188 -120) include explicit inclusion of knowledge of ethics in the contexts of demonstrating competencies in consultation, research and evaluation, teaching and supervision, and management and administration. PMID- 26618219 TI - Continuous subcutaneous insulin infusion therapy and multiple daily insulin injections in type 1 diabetes mellitus: a comparative overview and future horizons. AB - INTRODUCTION: Continuous subcutaneous insulin infusion (CSII) therapy is currently accepted as a treatment strategy for type 1 diabetes. Transition from multiple daily injection therapy (MDI; including basal-bolus regimens) to CSII is based on expectations of better metabolic control and fewer hypoglycaemic events. Evidence to date has not been always conclusive. AREAS COVERED: Evidence for CSII and MDI in terms of glycaemic control, hypoglycaemia and psychosocial outcomes is reviewed in the adult and paediatric population with type 1 diabetes. Findings from studies on threshold-based insulin pump suspension and predictive low glucose management (PLGM) are outlined. Limitations of current CSII application and future technological developments are discussed. EXPERT OPINION: Glycaemic control and quality of life (QOL) may be improved by CSII compared to MDI depending on baseline HbA1c and hypoglycaemia rates. Future studies are expected to provide evidence on clinical and cost effectiveness in those who will benefit the most. Training, structured education and support are important to benefit from CSII. Novel technological approaches linking continuous glucose monitoring (CGM) and CSII may help mitigate against frequent hypoglycaemia in those at risk. Development of glucose-responsive automated closed-loop insulin delivery systems may reduce the burden of disease management and improve outcomes in type 1 diabetes. PMID- 26618220 TI - Clinical teaching as part of continuing professional development: Does teaching enhance clinical performance? AB - INTRODUCTION: Physicians identify teaching as a factor that enhances performance, although existing data to support this relationship is limited. PURPOSE: To determine whether there were differences in clinical performance scores as assessed through multisource feedback (MSF) data based on clinical teaching. METHODS: MSF data for 1831 family physicians, 1510 medical specialists, and 542 surgeons were collected from physicians' medical colleagues, co-workers (e.g., nurses and pharmacists), and patients and examined in relation to information about physician teaching activities including percentage of time spent teaching during patient care and academic appointment. Multivariate analysis of variance, partial eta squared effect sizes, and Tukey's HSD post hoc comparisons were used to determine between group differences in total MSF mean and subscale mean performance scores by teaching and academic appointment data. RESULTS: Higher clinical performance scores were associated with holding any academic appointment and generally with any time teaching versus no teaching during patient care. This was most evident for data from medical colleagues, where these differences existed across all specialty groups. CONCLUSION: More involvement in teaching was associated with higher clinical performance ratings from medical colleagues and co-workers. These results may support promoting teaching as a method to enhance and maintain high-quality clinical performance. PMID- 26618221 TI - Single Enzyme Experiments Reveal a Long-Lifetime Proton Leak State in a Heme Copper Oxidase. AB - Heme-copper oxidases (HCOs) are key enzymes in prokaryotes and eukaryotes for energy production during aerobic respiration. They catalyze the reduction of the terminal electron acceptor, oxygen, and utilize the Gibbs free energy to transport protons across a membrane to generate a proton (DeltapH) and electrochemical gradient termed proton motive force (PMF), which provides the driving force for the adenosine triphosphate (ATP) synthesis. Excessive PMF is known to limit the turnover of HCOs, but the molecular mechanism of this regulatory feedback remains relatively unexplored. Here we present a single enzyme study that reveals that cytochrome bo3 from Escherichia coli, an HCO closely homologous to Complex IV in human mitochondria, can enter a rare, long lifetime leak state during which proton flow is reversed. The probability of entering the leak state is increased at higher DeltapH. By rapidly dissipating the PMF, we propose that this leak state may enable cytochrome bo3, and possibly other HCOs, to maintain a suitable DeltapH under extreme redox conditions. PMID- 26618222 TI - Role of Static and Dynamic Obstacles in the Protein Search for Targets on DNA. AB - Protein search for specific sequences on DNA marks the beginning of major biological processes. Experiments indicate that proteins find and recognize their targets quickly and efficiently. Because of the large number of experimental and theoretical investigations, there is a reasonable understanding of the protein search processes in purified in vitro systems. However, the situation is much more complex in live cells where multiple biochemical and biophysical processes can interfere with the protein search dynamics. In this study, we develop a theoretical method that explores the effect of crowding on DNA chains during the protein search. More specifically, the role of static and dynamic obstacles is investigated. The method employs a discrete-state stochastic framework that accounts for most relevant physical and chemical processes in the system. Our approach also provides an analytical description for all dynamic properties. It is found that the presence of the obstacles can significantly modify the protein search dynamics. This effect depends on the size of the obstacles, on the spatial positions of the target and the obstacles, on the nature of the search regime, and on the dynamic nature of the obstacles. It is argued that the crowding on DNA can accelerate or slow down the protein search dynamics depending on these factors. A comparison with existing experimental and theoretical results is presented. Theoretical results are discussed using simple physical-chemical arguments, and they are also tested with extensive Monte Carlo computer simulations. PMID- 26618223 TI - An update of ALK inhibitors in human clinical trials. AB - The proto-oncogenic ALK is a druggable receptor tyrosine kinase for cancer treatment. Two small molecule inhibitors of ALK, crizotinib and ceritinib, have been recently approved for the treatment of metastatic non-small-cell lung cancer, with marked improvement of progression-free survival of patients. Independent case reports also indicate their potential therapeutic activity in other ALK-rearranged cancers. Numerous single-agent and combination therapy trials are ongoing in lung and many other cancers. Results of these trials are greatly anticipated. Here, we summarize our current understanding of ALK signaling, genomic aberrations in cancer and emerging mechanisms of drug resistance. We will also provide a timely review on all ALK inhibitors and their current status of development in clinical settings. PMID- 26618224 TI - Anosmia and olfactory outcomes following paediatric traumatic brain injury. AB - OBJECTIVE: Research into olfactory dysfunction (OD) following paediatric traumatic brain injury (TBI) is limited. The current study investigated the frequency of OD following paediatric TBI and the relationship between OD and injury characteristics including severity, site of impact and cause of injury. It was hypothesized that children with moderate/severe TBI would demonstrate greater OD than those with mild TBI. DESIGN/METHOD: Thirty-seven children aged 8-16 with TBI were recruited to a prospective longitudinal study at a metropolitan children's hospital. Olfactory assessment, using the University of Pennsylvania Smell Identification Test, was completed at 0-3 months post-injury. RESULTS: Nineteen per cent of participants demonstrated impaired olfaction, while a small number (5%) were anosmic. A significant relationship between OD and severity of injury was found. No other injury variables demonstrated a significant relationship with olfactory outcomes. CONCLUSIONS: OD was relatively common in this paediatric TBI cohort and the hypothesized relationship with severity of injury was supported. It is recommended that information about OD after TBI be routinely provided to children and families. Further research is needed in larger cohorts to support the implementation of routine clinical assessment, understand the relationship between OD and other injury characteristics, determine the functional implications of OD and document recovery trajectories. PMID- 26618225 TI - Addressing the primary care workforce crisis. AB - Our nation's primary care system is in crisis. As medical homes and accountable care organizations increasingly rely on a strong primary care workforce, the shortage of primary care physicians now calls for more policy attention and urgency. In the spirit of the 2014 Institute of Medicine recommendations on graduate medical education (GME) funding, we propose that CMS explicitly reward teaching hospitals if a certain share of their graduates (we propose 30%) remain in primary care 3 years after residency, either through additional payments or release of a withhold. Such a policy could allow hospitals to retain GME funding at a time when continued federal subsidization of GME is being called into question. Moreover, hospitals stand to benefit from producing primary care physicians, both under traditional fee-for-service contracts that reward volume through referrals and, especially, under risk contracts that reward for greater numbers of covered lives. PMID- 26618232 TI - High-Capacity Te Anode Confined in Microporous Carbon for Long-Life Na-Ion Batteries. AB - Sodium-ion batteries (SIBs) have attracted considerable attention as an alternative energy-storage technology in recent years. Developing advanced sodium storage anode materials with appropriate working potential, high capacity, and good cycling performance is very important. Herein, we demonstrate a nanostructured tellurium@carbon (nano-Te@C) composite by confining nano-Te molecules in the space of carbon micropores as an attractive anode material for SIBs. The nano-Te@C anode presents an appropriate redox potential in the range of 1.05-1.35 V (vs Na(+)/Na), which avoids the Na dendrite problem and achieves a high reversible capacity of 410 mA h g(-1) on the basis of a two-electron redox reaction mechanism. Notably, the nano-Te@C exhibits an admirable long-term cycling stability with a high capacity retention of 90% for 1000 cycles (i.e., ultralow capacity decay of 0.01% per cycle). The excellent electrochemical property of nano-Te@C benefits from the high electroactivity from the nanostructure design and the effective confinement of the microporous carbon host. In addition, a Na-ion full cell by using nano-Te@C as anode and Na2/3Ni1/3Mn2/3O2 as cathode is demonstrated for the first time and exhibits a remarkable capacity retention up to 95% after 150 cycles. The results put new insights for the development of advanced SIBs with long-cycle lifespan. PMID- 26618233 TI - Association of the -1031T>C polymorphism and soluble TNF-alpha levels with Acute Coronary Syndrome. AB - INTRODUCTION: Inflammation has gained a pivotal role in the pathophysiology of Acute Coronary Syndrome (ACS). TNF-alpha is a pro-inflammatory cytokine that could be a potential biomarker in ACS due to its multiple functions. The rs1799964 TNFA polymorphism (-1031T>C) has been associated with a decrease in gene transcription and cytokine levels. OBJECTIVE: To determine the association of rs1799964 TNFA polymorphism and TNF-alpha soluble levels in ACS. METHODS: A total of 251 patients diagnosed with ACS and 164 individuals without cardiovascular diseases classified as the reference group (RG), were included. The rs1799964 polymorphism was genotyped by PCR-RFLP. Soluble protein levels were determined by ELISA. Statistical analyses were performed using chi square and U Mann Whitney tests. RESULTS: The genotype and allele frequencies were different between ACS and RG (OR=0.317, p=0.01; OR=0.688, p=0.03 respectively). ACS patients had higher soluble TNF-alpha levels compared with the RG (31.08 vs 23.00pg/mL, p<0.001); according genotype significant differences were observed (T/T: 24.06 vs T/C: 34.95pg/mL, p=0.0001) in patients. In the RG, T/T carriers showed discrete lower levels than C/C genotype (22.14 vs 27.83pg/mL, p=0.04). CONCLUSIONS: The -1031C allele of the TNFA polymorphism confers protection for the development of ACS. The T/C genotype carriers had higher TNF-alpha serum levels compared to the T/T genotype in ACS. In addition, the -1031T>C TNFA polymorphism was associated with dyslipidemia in ACS in a Western Mexican population. PMID- 26618234 TI - Elevated plasma interleukin-17A in a subgroup of Myasthenia Gravis patients. AB - To better define the role of IL-17A in myasthenia gravis (MG), we assessed plasma concentrations in 69 adult patients with MG prior to initiation of immunosuppression and monitored their clinical course for the subsequent 2years with quantitative MG scores (QMGS) and Osserman classification. IL-17A was higher among patients than healthy control subjects. Early-onset women without thymoma had greater elevations of IL-17A. Logistic regression analysis indicated that the absence of thymoma rather than women gender or early-onset was the significant determinant associated with IL-17A elevation. Elevated IL-17A levels were associated with more severe MG. In summary, IL-17A has role in the pathogenesis of a subgroup of patients with early-onset women with MG with greater disease severity who are most likely to have thymic hyperplasia. This subgroup may be a target for IL-17 treatments, which are under development. PMID- 26618235 TI - Instability of Multiple Sex Chromosomes Systems in Fish: The Case of Erythrinus erythrinus (Bloch & Schneider, 1801) (Characiformes, Erythrinidae). AB - The fish species Erythrinus erythrinus belongs to the family Erythrinidae (order Characiformes, superorder Teleostei) and is considered a species complex because of the considerable differences between the karyotypes of analyzed populations. Whereas some populations present a sex chromosome system with male heterogamety, others do not show differentiated sex chromosomes. In this article, two novel karyotypes of E. erythrinus with the occurrence of male and female heterogamety are described, and a discussion of the stability of multiple sex chromosome systems is provided. A possible cause for sex chromosomes instability is that the Robertsonian rearrangements that originated the multiple systems did not prevent recombination with ancestral chromosomes, which also did not pass through a heterochromatinization process, the opposite of what usually happens with simple systems, especially of the ZZ/ZW or XX/XY type. It is suggested that multiple sex chromosome systems would not act as an effective postzygotic barrier, especially when there are hybridization zones between distinct karyomorphs that bear and that do not bear sex chromosome systems, allowing the generation of hybrids. This finding is important both for the comprehension of sex chromosomes evolution in fish and for conservation biology since the contact between populations with and without multiple sex chromosomes may compromise the regional biodiversity. PMID- 26618236 TI - Episodic Impacts from California Wildfires Identified in Las Vegas Near-Road Air Quality Monitoring. AB - Air pollutant concentrations near major highways are usually attributed to a combination of nearby traffic emissions and regional background, and generally presumed to be additive in nature. During a near-road measurement study conducted in Las Vegas, NV, the effects of distant wildfires on regional air quality were indicated over a several day period in the summer of 2009. Area-wide elevated particulate levoglucosan (maximum of 0.83 MUg/m(3)) and roadside measurements of ultraviolet light-absorbing particulate matter (UVPM) in comparison to black carbon (Delta-C) were apparent over the three-day period. Back-trajectory modeling and satellite images supported the measurement results and indicated the transport of air pollutants from wildfires burning in southern California. Separating roadside measurements under apparent biomass burning event (Delta-C > 1000 ng m(-3)) and nonevent (Delta-C < 1000 ng m(-3)) periods, and constraining to specific days of week, wind speed range, wind direction from the road and traffic volume range, roadside carbon monoxide, black carbon, total particle number count (20-200 nm), and accumulation mode particle number count (100-200 nm) increased by 65%, 146%, 58%, and 366%, respectively, when biomass smoke was indicated. Meanwhile, ultrafine particles (20-100 nm) decreased by 35%. This episode indicates that the presence of aged wildfire smoke may interact with freshly emitted ultrafine particles, resulting in a decrease of particles in the ultrafine mode. PMID- 26618237 TI - Increasing psychotherapists' adoption and implementation of the evidence-based practice of progress monitoring. AB - Evidence-based practices (EBPs) reach consumers slowly because practitioners are slow to adopt and implement them. We hypothesized that giving psychotherapists a tool + training intervention that was designed to help the therapist integrate the EBP of progress monitoring into his or her usual way of working would be associated with adoption and sustained implementation of the particular progress monitoring tool we trained them to use (the Depression Anxiety Stress Scales on our Online Progress Tracking tool) and would generalize to all types of progress monitoring measures. To test these hypotheses, we developed an online progress monitoring tool and a course that trained psychotherapists to use it, and we assessed progress monitoring behavior in 26 psychotherapists before, during, immediately after, and 12 months after they received the tool and training. Immediately after receiving the tool + training intervention, participants showed statistically significant increases in use of the online tool and of all types of progress monitoring measures. Twelve months later, participants showed sustained use of any type of progress monitoring measure but not the online tool. PMID- 26618238 TI - Exploring differences between the ICD-11 and DSM-5 models of PTSD: Does it matter which model is used? AB - Alternative symptom profiles for posttraumatic stress disorder (PTSD) are presented in the DSM-5 and ICD-11. This study compared DSM-5 PTSD symptom profiles with ICD-11 PTSD symptom profiles among a large group of trauma-exposed individuals from Denmark. Covariates, and rates of co-occurrence with other psychiatric disorders were also investigated. A sample of treatment-seeking adult survivors of childhood sexual abuse (n=434) were assessed using self-report measures of PTSD and other psychiatric disorders. A significantly larger proportion of individuals met caseness for DSM-5 PTSD (60.0%) compared to ICD-11 PTSD (49.1%). This difference was largely attributable to low endorsement of the ICD-11 re-experiencing criteria. Replacement of the 'recurrent nightmares' symptom with the 'recurrent thoughts/memories' symptom seemed to balance the proportion of individuals meeting caseness for both taxonomies. Levels of co occurrence with anxiety and thought disorder were higher for the DSM-5 model of PTSD compared to the ICD-11 model. Current results merit careful consideration in the selection of symptom indicators for the new ICD model of PTSD, particularly with respect to the re-experiencing symptom category. PMID- 26618240 TI - Strong reduction of spectral heterogeneity in gold bipyramids for single-particle and single-molecule plasmon sensing. AB - Single metal nanoparticles are attractive biomolecular sensors. Binding of analyte to a functional particle results in a plasmon shift that can be conveniently monitored in a far-field optical microscope. Heterogeneities in spectral properties of individual particles in an ensemble affect the reliability of a single-particle plasmon sensor, especially when plasmon shifts are monitored in real-time using a fixed irradiation wavelength. We compare the spectral heterogeneity of different plasmon sensor geometries (gold nanospheres, nanorods, and bipyramids) and correlate this to their size and aspect-ratio dispersion. We show that gold bipyramids exhibit a strongly reduced heterogeneity in aspect ratio and plasmon wavelength compared to commonly used gold nanorods. We show that this translates into a significantly improved homogeneity of the response to molecular binding without compromising single-molecule sensitivity. PMID- 26618239 TI - Body dissatisfaction and disordered eating in trans people: A systematic review of the literature. AB - Body dissatisfaction plays a prominent role in gender dysphoria. In some individuals body dissatisfaction appears to manifest disordered eating in order to suppress bodily features of natal gender and accentuate features of gender identity. To date, there has been no systematic review of the literature pertaining to body dissatisfaction and disordered eating in trans individuals. Such a review may highlight important implications for clinicians working with trans people. Therefore, the aim was to critically and systematically review the available literature examining body dissatisfaction or disordered eating in a trans population, and also the literature pertaining to how body dissatisfaction and disordered eating are related in trans people. This review found three studies that explored disordered eating in trans people, five studies that explored body image and disordered eating in trans people, and 18 studies that explored body image in trans people. The findings from this review suggest that body dissatisfaction is core to the distress trans people experience and that this dissatisfaction may also put some individuals at risk of developing disordered eating. Additionally, the findings appear to suggest that gender dysphoria treatment is successful at increasing body satisfaction and improving body image. The clinical implications are discussed. PMID- 26618241 TI - In silico study on beta-aminoketone derivatives as thyroid hormone receptor inhibitors: a combined 3D-QSAR and molecular docking study. AB - In order to explore the structure-activity correlation of a series of beta aminoketone analogs as inhibitors of thyroid hormone receptor (TR), a set of three-dimensional quantitative structure-activity relationship (3D-QSAR) models based on comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA), for the first time, were developed in the present work. The best CoMFA model with steric and electrostatic fields exhibited [Formula: see text], [Formula: see text] for TRbeta, and [Formula: see text], [Formula: see text] for TRalpha. 3D contour maps produced from the optimal models were further analyzed individually, which provide the areas in space where interactive fields would affect the inhibitory activity. In addition, the binding modes of inhibitors at the active site of TRs were examined using molecular docking, the results indicated that this series of inhibitors fit into the active site of TRs by forming hydrogen bonding and electrostatic interactions. The docking studies also revealed that Leu305, Val458 for TRbeta, and Asp407 for TRalpha are showing hydrogen bonds with the most active inhibitors. In any case, the 3D-QSAR models combined with the binding information will serve as a useful approach to explore the chemical space for improving the activity of TRbeta and TRalpha inhibitors. PMID- 26618244 TI - Ensuring excellence in immunization services. AB - In order to increase uptake of measles, mumps and rubella (MMR) vaccine, a domiciliary immunization service was established in Dudley primary care trust in England in 2010. Parents of unimmunized children were offered vaccines at home. Uptake of MMR vaccine among 2 year olds rose from 89% in 2007/08 to 96.9% in 2015. Children were also given any other outstanding immunizations. The domiciliary immunization service reached vulnerable unimmunized children who may otherwise have remained unprotected against life threatening childhood illnesses. Domiciliary immunization service was set up in 2010 to reduce inequalities in uptake of MMR vaccine among children aged between 2 and 5 years. PMID- 26618242 TI - Long non-coding RNA ANRIL regulates inflammatory responses as a novel component of NF-kappaB pathway. AB - Antisense Noncoding RNA in the INK4 Locus (ANRIL) is the prime candidate gene at Chr9p21, the well-defined genetic risk locus associated with multiple human diseases including coronary artery disease (CAD), while little is known regarding its role in the pathological processes. Endothelial dysfunction triggers atherosclerotic processes that are causatively linked to CAD. To evaluate the function of ANRIL in human endothelial cells (ECs), we examined ANRIL expression under pathological stimuli and found ANRIL was markedly induced by pro inflammatory factors. Loss-of-function and chromatin immunoprecipitation approaches revealed that NF-kappaB mediates TNF-alpha induced ANRIL expression. RNA sequencing revealed that ANRIL silencing dysregulated expression of inflammatory genes including IL6 and IL8 under TNF-alpha treatment. We explored the regulatory mechanism of ANRIL on IL6/8 and found that Yin Yang 1 (YY1), an ANRIL binding transcriptional factor revealed by RNA immunoprecipitation, was required for IL6/8 expression under TNF-alpha treatment. YY1 was enriched at promoter loci of IL6/8 and ANRIL silencing impaired the enrichment, indicating a cooperation between ANRIL and YY1 in the regulation of inflammatory genes. For the first time, we establish the connection between ANRIL and NF-kappaB pathway and show that ANRIL regulates inflammatory responses through binding with YY1. The newly identified TNF-alpha-NF-kappaB-ANRIL/YY1-IL6/8 pathway enhances understanding of the etiology of CAD and provides potential therapeutic target for treatment of CAD. PMID- 26618245 TI - Auditory lateralization of conspecific and heterospecific vocalizations in cats. AB - Auditory lateralization in response to both conspecific and heterospecific vocalizations (dog vocalizations) was observed in 16 tabby cats (Felis catus). Six different vocalizations were used: cat "purring," "meowing" and "growling" and dog typical vocalizations of "disturbance," "isolation" and "play." The head orienting paradigm showed that cats turned their head with the right ear leading (left hemisphere activation) in response to their typical-species vocalization ("meow" and "purring"); on the other hand, a clear bias in the use of the left ear (right hemisphere activation) was observed in response to vocalizations eliciting intense emotion (dogs' vocalizations of "disturbance" and "isolation"). Overall these findings suggest that auditory sensory domain seems to be lateralized also in cat species, stressing the role of the left hemisphere for intraspecific communication and of the right hemisphere in processing threatening and alarming stimuli. PMID- 26618243 TI - Reactogenicity, safety and immunogenicity of a protein-based pneumococcal vaccine in Gambian children aged 2-4 years: A phase II randomized study. AB - Pneumococcal conjugate vaccines (PCVs) have been successful in preventing invasive pneumococcal disease but effectiveness has been challenged by replacement of vaccine serotypes with non-vaccine serotypes. Vaccines targeting common pneumococcal protein(s) found in most/all pneumococci may overcome this limitation. This phase II study assessed safety and immunogenicity of a new protein-based pneumococcal vaccine containing polysaccharide conjugates of 10 pneumococcal serotypes combined with pneumolysin toxoid(dPly) and pneumococcal histidine triad protein D(PhtD) (PHiD-CV/dPly/PhtD-30) in African children. 120 Gambian children (2-4 years, not previously vaccinated against Streptococcus pneumoniae) randomized (1:1) received a single dose of PHiD-CV/dPly/PhtD-30 or PCV13. Adverse events occurring over 4 d post-vaccination were reported, and blood samples obtained pre- and 1-month post-vaccination. Serious adverse events were reported for 6 months post-vaccination. Solicited local and systemic adverse events were reported at similar frequency in each group. One child (PHiD CV/dPly/PhtD-30 group) reported a grade 3 local reaction to vaccination. Haematological and biochemical parameters seemed similar pre- and 1-month post vaccination in each group. High pre-vaccination Ply and PhtD antibody concentrations were observed in each group, but only increased in PHiD CV/dPly/PhtD-30 vaccinees one month post-vaccination. One month post-vaccination, for each vaccine serotype >=96.2% of PHiD-CV/dPly/PhtD-30 vaccinees had serotype specific polysaccharide antibody concentrations >=0.20ug/mL except serotypes 6B (80.8%) and 23F (65.4%), and >=94.1% had OPA titres of >=8 except serotypes 1 (51.9%), 5 (38.5%) and 6B (78.0%), within ranges seen in PCV13-vaccinated children. A single dose of PHiD-CV/dPly/PhtD-30 vaccine, administered to Gambian children aged 2-4 y not previously vaccinated with a pneumococcal vaccine, was well-tolerated and immunogenic. PMID- 26618246 TI - Secondary Structure Dependence and Hydration Effect of the Infrared Intensity of the Amide II Mode of Peptide Chains. AB - Every vibrational mode to be used as a marker of the structural, dynamical, and/or interaction properties demands our good understanding of the relations between those properties and the spectral features. The present study is devoted to elucidating the effects of secondary structure variations and hydration on the infrared (IR) intensity of the amide II mode of peptide chains. It is shown that the IR intensity is significantly enhanced for the C5 (fully extended planar beta strand) conformation because of the interpeptide charge flux through the H...O interaction of the C5 ring, and there is a small cooperative effect giving rise to a larger enhancement for a consecutive C5 conformation. In contrast, the IR intensity is reduced for the alpha-helix conformation because of the partially canceling polarization effect of the hydrogen-bond accepting O atom in the N H...O?C hydrogen bond and the absence of the interpeptide charge flux. With regard to the hydration effect, it is found that the IR intensity enhancement/reduction depends critically on the angular position of the hydrating water molecule, and is related to the presence/absence of the intermolecular charge flux and the polarization effect. It is suggested that, both for the secondary structure dependence and for the hydration effect, the geometrical relation between the vibrating N-H bond and the H...O interaction (of the C5 ring and/or the hydrogen bond) is an essential factor determining the enhancement/reduction of the IR intensity of the amide II mode. PMID- 26618247 TI - Correction to Nishiguchi, Takano, and Tanno (2015). AB - In the article "Explicitly Guided Attentional Bias Modification Promotes Attentional Disengagement From Negative Stimuli" by Yuki Nishiguchi, Keisuke Takano, and Yoshihiko Tanno (Emotion, 2015, Advance online publication. May 4, 2015. http://dx.doi.org/10.1037/a0039117), there was an error in the first paragraph of "Materials and Tasks" from the Methods section. The first paragraph should have read, "We selected 160 words (80 negative, 80 neutral) from Matsumoto's (2006) valence- and familiarity-controlled word list. Negative stimuli were selected according to the strength of negativity and did not correspond with specific emotional condition like depression or anxiety. These words were split into two word sets, each including 40 negative words and 40 neutral words." All versions of this article have been corrected. PMID- 26618248 TI - Transition-Metal-Free Self-Hydrogen-Transferring Allylic Isomerization. AB - Phenanthroline and tert-butoxide have been established as powerful radical initiators in reactions such as the SRN1-type coupling reactions due to the cooperation of large heteroarenes and a special feature of tert-butoxide. The first phenanthroline-tert-butoxide-catalyzed transition-metal-free allylic isomerization is described. The resulting ketones are key intermediates for indenes. The control experiments rule out the base-promoted allylic anion pathway. The radical pathway is supported by experimental evidence that includes kinetic study, kinetic isotope effect, isotope-labeling experiments, trapping experiments, and EPR experiments. PMID- 26618249 TI - Childhood Obesity Incidence in the United States: A Systematic Review. AB - BACKGROUND: This systematic review synthesizes the literature on incidence of obesity during childhood. METHODS: We searched PubMed, Excerpta Medica database (EMBASE), and Cumulative Index to Nursing and Allied Health Literature (CINAHL), and used the Web of Science tool in June 2015. Studies were included if they were published in English, presented results from primary or secondary analyses, used data about children in the US, provided obesity incidence data on children 0 to 18 years born after 1970, and did not pertain to clinically defined populations (disease, medication use, etc.). Author(s), study year, study design, location, sample size, age, and obesity incidence estimates were abstracted. RESULTS: Nineteen studies were included, three of which used nationally representative data. The median study-specific annual obesity incidences among studies using U.S. Centers for Disease Control and Prevention (CDC) growth charts were 4.0%, 3.2%, and 1.8% for preschool (2.0-4.9 years), school aged (5.0-12.9 years), and adolescence (13.0-18.0 years), respectively. This pattern of declining obesity incidence with age was consistent between and within studies. CONCLUSIONS: Studies of childhood obesity in the US indicate declining incidence with age. Childhood obesity prevention efforts should be targeted to ages before obesity onset. Longitudinal data and consistent obesity definitions that correlate with long-term morbidity are needed to better characterize the life history of obesity. PMID- 26618250 TI - Pixel classification based color image segmentation using quaternion exponent moments. AB - Image segmentation remains an important, but hard-to-solve, problem since it appears to be application dependent with usually no a priori information available regarding the image structure. In recent years, many image segmentation algorithms have been developed, but they are often very complex and some undesired results occur frequently. In this paper, we propose a pixel classification based color image segmentation using quaternion exponent moments. Firstly, the pixel-level image feature is extracted based on quaternion exponent moments (QEMs), which can capture effectively the image pixel content by considering the correlation between different color channels. Then, the pixel level image feature is used as input of twin support vector machines (TSVM) classifier, and the TSVM model is trained by selecting the training samples with Arimoto entropy thresholding. Finally, the color image is segmented with the trained TSVM model. The proposed scheme has the following advantages: (1) the effective QEMs is introduced to describe color image pixel content, which considers the correlation between different color channels, (2) the excellent TSVM classifier is utilized, which has lower computation time and higher classification accuracy. Experimental results show that our proposed method has very promising segmentation performance compared with the state-of-the-art segmentation approaches recently proposed in the literature. PMID- 26618251 TI - Safety and efficacy of uninterrupted periprocedural rivaroxaban in patients undergoing atrial fibrillation catheter ablation: A metaanalysis of 1,362 patients. PMID- 26618252 TI - Rationale and benefits of trimetazidine by acting on cardiac metabolism in heart failure. AB - Heart failure is a systemic and multiorgan syndrome with metabolic failure as a fundamental mechanism. As a consequence of its impaired metabolism, other processes are activated in the failing heart, further exacerbating the progression of heart failure. Recent evidence suggests that modulating cardiac energy metabolism by reducing fatty acid oxidation and/or increasing glucose oxidation represents a promising approach to the treatment of patients with heart failure. Clinical trials have demonstrated that the adjunct of trimetazidine to the conventional medical therapy improves symptoms, cardiac function and prognosis in patients with heart failure without exerting negative hemodynamic effects. This review focuses on the rationale and clinical benefits of trimetazidine by acting on cardiac metabolism in heart failure, and aims to draw attention to the readiness of this agent to be included in all the major guidelines dealing with heart failure. PMID- 26618253 TI - The abnormal status of uncarboxylated matrix Gla protein species represents an additional mortality risk in heart failure patients with vascular disease. AB - BACKGROUND: Matrix Gla protein (MGP) is a natural inhibitor of tissue calcification. In a previous study, we observed the positive association between abnormal concentrations of uncarboxylated MGP species and increased mortality risk in stable vascular patients. We explore whether co-incidence of abnormal status of uncarboxylated MPG and heart failure (HF) affects the mortality risk. METHODS: We examined 799 patients (mean age 65.1 years) with stable vascular disease and followed them in a prospective study. Both, desphospho-uncarboxylated and total uncarboxylated MGP (dp-ucMGP or t-ucMGP) were quantified by pre commercial ELISA assays. RESULTS: Elevated (>100 ng/L) circulating brain natriuretic peptide (BNP) and abnormal status of plasma uncarboxylated MGP species (i.e.: dp-ucMGP >= 977 pmol/L or t-ucMGP <= 2825 nmol/L) were all identified as robust predictors of all-cause 5-year mortality. However, their co incidence represented a substantial additional risk. We observed the highest mortality risk in patients with elevated BNP plus high dp-ucMGP compared to those with normal BNP plus low dp-ucMGP; fully adjusted HRR's were 4.86 (3.15-7.49). Likewise, the risk was increased when compared with patients with elevated BNP plus low dp-ucMGP; HRR 2.57 (1.60-4.10). Similar result we observed when co incidence of elevated BNP and low t-ucMGP was analyzed [corresponding HRR's were 4.16 (2.62-6.61) and 1.96 (1.24-3.12)]. CONCLUSIONS: The concomitant abnormality of uncarboxylated MGP and mild elevation of BNP leads in chronic patients with vascular disease to about two-fold increase of the relative mortality risk. We hypothesize that abnormal homeostasis of MGP is involved in the pathophysiology of HF. PMID- 26618254 TI - Regulatory T lymphocytes in myocardial infarction: A promising new therapeutic target. AB - Myocardial infarction (MI) is one of the leading causes of death especially in developed countries. Although the advent of early myocardial reperfusion therapy contributes to decreasing the mortality of patients with MI, cardiac ischemia reperfusion injury and adverse remodeling during the repair process still remain the major factors impairing cardiac function and resulting in unsatisfactory prognosis. Excessive inflammation and immune responses play a crucial role during the whole process of MI. Regulatory T lymphocytes, characterized by immunosuppressive capacity, are associated with many immune-related diseases. Recent studies have proven a protective role of regulatory T cells in MI, which is mainly achieved by modulating inflammation and immune responses. In this review, we will summarize current knowledge of regulatory T lymphocytes, and highlight their roles in the onset of MI, ischemia-reperfusion injury, as well as post-infarct cardiac healing and remodeling. PMID- 26618256 TI - A little innocent heart murmur in a child with accessory mitral valve tissue. PMID- 26618255 TI - Comparison of early versus delayed timing of left ventricular assist device implantation as a bridge-to-transplantation: An analysis of the UNOS dataset. AB - BACKGROUND: Placement of left ventricular assist devices (LVAD) as a bridge-to heart transplantation (HTx) has rapidly expanded due to organ donor shortage. However, the timing of LVAD implantation is variable and it remains unclear if earlier implantation improves survival. METHODS: We analyzed 14,187 adult candidates from the United Network of Organ Sharing database. Patients were classified by 3 treatment strategies including patients medically treated alone (MED, n=11,009), patients on LVAD support at listing (Early-LVAD, n=1588) and patients undergoing LVAD placement while awaiting HTx (Delayed-LVAD, n=1590). Likelihood of HTx and event-free survival were assessed in patients subcategorized by clinical strategies and UNOS status at listing. RESULTS: The device support strategy, despite the timing of placement, was not associated with increased likelihood of HTx compared to MED group. However, both LVAD implantation strategies showed better survival compared to MED group (Early-LVAD: HR 0.811 and 0.633, 95% CI 0.668-0.984 and 0.507-0.789, for 1A and 1B; p=0.034 and p<0.001, Delayed-LVAD: HR 0.553 and 0.696, 95% CI 0.415-0.736 and 0.571 0.847, for 1A and 1B; both p<0.001, respectively). Furthermore, there was no significant difference in survival between these LVAD implantation strategies in patients listed as 1B (p=0.500), although Early-LVAD implantation showed worse survival in patients listed as 1A (HR 1.467, 95% CI 1.076-2.000; p=0.015). CONCLUSION: LVAD support strategies offer a safe bridge-to-HTx. Those candidates who receive urgent upfront LVAD implantation for HTx, and improve to 1B status, would achieve competitive survival with those who receive elective LVAD implantation. PMID- 26618258 TI - Altered atrial conduction in postoperative atrial fibrillation. PMID- 26618257 TI - Management and outcomes in chronic thromboembolic pulmonary hypertension: From expert centers to a nationwide perspective. AB - BACKGROUND: The Spanish "Registry of Pulmonary Arterial Hypertension" (REHAP), started in 2007, includes chronic thromboembolic hypertension (CTEPH) patients. Based on data provided by this registry and retrospective data from patients diagnosed during 2006 (<= 12 months since the registry was created), clinical management and long-term outcomes of CTEPH patients are analyzed nationwide for the first time in a scenario of a decentralized organization model of CTEPH management. METHODS AND RESULTS: A total of 391 patients (median [Q1:Q3] age 63.7 [48.0;73.3] years, 58% females) with CTEPH included during the period January 1, 2006-December 31, 2013 in the REHAP registry were analyzed. Rate of pulmonary endarterectomy (PEA) was 31.2%, and highly asymmetric among centers: rate was 47.9% at two centers designated as CTEPH expert centers, while it was 4.6% in other centers. Among patients not undergoing PEA, 82% were treated with therapies licensed for pulmonary arterial hypertension (PAH). Five-year survival rate was 86.3% for PEA patients, and 64.9% for non-PEA patients. Among non-PEA patients, presenting proximal lesions (42% of non-referred patients) was associated with a 3-fold increase in mortality. PEA patients achieved significantly better hemodynamic and clinical outcomes at one-year follow-up compared to non-PEA patients. Patients not being referred for PEA assessment were older and had a worse functional capacity. Older age was the most deterrent factor for non operability. CONCLUSION: Despite the increase in diagnosis and expertise in PEA specialized centers, an important percentage of patients do not benefit of PEA in a decentralized organization model of CTEPH management. PMID- 26618259 TI - Intraoral Digital Impression Technique Compared to Conventional Impression Technique. A Randomized Clinical Trial. AB - PURPOSE: To compare digital and conventional impression techniques in a randomized clinical trial; specifically, procedure times, patient-centered outcomes, and clinical evaluation of the restorations. MATERIALS AND METHODS: Forty-two patients in need of tooth-supported single crowns and/or fixed partial prostheses up to six units were randomly allocated to one of the impression techniques. The procedure times, dentists' and patients' assessments using a visual analog scale (VAS), and clinical evaluation of the restorations were compared between the two groups. RESULTS: The mean total procedure times for digital and conventional impression technique were 14:33 +/- 5:27 and 20:42 +/- 5:42, respectively (p < 0.0001). Mean impression times were 7:33 +/- 3.37 and 11:33 +/- 1.56, respectively (p < 0.0001). Mean VAS scores for the dentist's assessment of difficulty (0 to 100; very difficult = 100) were 24.00 +/- 18.02 and 48.02 +/- 21.21, respectively (p < 0.0001). Mean VAS scores for the patients' assessment of discomfort (0 to 100; very discomforting = 100) was 6.50 +/- 5.87 and 44.86 +/- 27.13, respectively (p < 0.0001). Occlusal contacts showed a better result for the digital technique. CONCLUSION: The results of this study demonstrated that the digital technique was more efficient and convenient than the conventional impression technique. PMID- 26618261 TI - Occurrence, distribution and seasonal variation of organophosphate flame retardants and plasticizers in urban surface water in Beijing, China. AB - The occurrence, spatial distribution and seasonal variation of 14 organophosphate esters (OPEs) were investigated in urban surface water (river and lake water) from July 2013 to June 2014 in Beijing, China. Sewage influent and effluent samples, as well as rainwater and road runoff samples were also analyzed as the potential sources of OPEs in surface water. Tris(2-chloro-1-methylethyl) phosphate (TCPP) and tris(2-chloroethyl) phosphate (TCEP) were the most abundant OPEs with the average concentrations of 291 ng L(-1) and 219 ng L(-1), respectively. Relatively high concentrations of OPEs were detected in rivers located at southern and eastern urban of Beijing, which was probably attributed to the treated and untreated sewage discharge. Besides, higher levels of OPEs were observed in urban surface water in the summer, and the wet deposition (rainfall) was confirmed to be an important factor for this observation. Risk assessment showed low or medium risk of OPEs for the organisms (algae, crustacean and fish). PMID- 26618262 TI - Airborne fine particulate matter induces an upregulation of endothelin receptors on rat bronchi. AB - Airborne fine particulate matter (PM2.5) is a risk factor for respiratory diseases. However, little is known about the effects of PM2.5 on bronchi. The present study investigated the effect of airborne PM2.5 on rat bronchi and the underlying mechanisms. Isolated rat bronchial segments were cultured for 24 h. Endothelin (ET) receptor-mediated contractile responses were recorded using a wire myograph. The mRNA and protein expression levels of ET receptors were studied using quantitative real-time PCR, Western blotting, and immunohistochemistry. The results demonstrated that ETA and ETB receptor agonists induced remarkable contractile responses on fresh and cultured bronchial segments. PM2.5 (1.0 or 3.0 MUg/ml) significantly enhanced ETA and ETB receptor mediated contractile responses in bronchi with a markedly increased maximal contraction compared to the DMSO or fresh groups. PM2.5 increased the mRNA and protein expression levels of ETA and ETB receptors. U0126 (a MEK1/2 inhibitor) and SB203580 (a p38 inhibitor) significantly suppressed PM2.5-induced increases in ETB receptor-mediated contractile responses, mRNA and protein levels. SP600125 (a JNK inhibitor) and SB203580 significantly abrogated the PM2.5-induced enhancement of ETA receptor-mediated contraction and receptor expression. In conclusion, PM2.5 upregulates ET receptors in bronchi. ETB receptor upregulation is associated with MEK1/2 and p38 pathways, and the upregulation of ETA receptor is involved in JNK and p38 pathways. PMID- 26618263 TI - Simultaneous removal of acid green 25 and mercury ions from aqueous solutions using glutamine modified chitosan magnetic composite microspheres. AB - In this current work, the magnetic composite microsphere containing glutamine modified chitosan and silica coated Fe3O4 nanoparticles (CS-Gln-MCM) has been successfully prepared and extensively characterized, which is a kind of biodegradable materials. CS-Gln-MCM shows enhanced removal efficiency for both acid green 25 (AG25), an amphoteric dye, and mercury ions (Hg(2+)) from water in the respective while measured pH range compared with chitosan magnetic composite microsphere (CS-MCM) without modification. It is due to the fact that the grafted amino acid provides a variety of additional adsorption active sites and diverse adsorption mechanisms are involved. In AG25 and Hg(2+) aqueous mixture, the modified adsorbents bear preferential adsorption for AG25 over Hg(2+) in strong acidic solutions ascribed to multiple interactions between AG25 and CS-Gln-MCM, such as hydrogen bonding and electrostatic interactions. While, in weak acidic conditions, an efficient simultaneous removal is observed for different adsorption effects involved in aforementioned two pollutants. Besides, CS-Gln-MCM illuminates not only short equilibrium time for adsorption of each pollutant less than 20.0 min but also rapid magnetic separation from water and efficient regeneration after saturated adsorption. Therefore, CS-Gln-MCM bears great application potentials in water treatment. PMID- 26618264 TI - Ode to Healing Music in Health Care. AB - Music therapy has been around since the 1940s when physicians notice a positive effect that music had on the soldiers with "shell shock" (now more commonly known as posttraumatic stress disorder). For decades, veterans were the primary patients worked with by music therapists. In the 1970s, the hospice movement started to enter the health care continuum, largely due to Dr Elisabeth Kubler Ross, who advocated for home care and patient choice for the terminally ill. Two decades later, it became apparent that hospice patients could benefit from music. And currently, there are not enough people certified to work with music in hospice patients, veterans, or patients with dementia/Alzheimer's disease. No, music does not prolong life, but it does add life to the time left. PMID- 26618265 TI - Informing the Content and Composition of the CCM Certification Examination: A National Study From the Commission for Case Manager Certification: Part 2. AB - PURPOSE: The purpose of this national role and function study was to identify the essential activities and necessary knowledge areas of case management practice, meaning the work performed by case managers in various care settings and across diverse professional disciplines. PRIMARY PRACTICE SETTING(S): The national study covered case management practices and work settings across the full continuum of health care. METHODOLOGY AND SAMPLE: This cross-sectional descriptive study used the practice analysis method and online survey research design. The study employed a purposive sample of case managers, in which 52,370 individuals received an invitation to volunteer to participate. Data collection completed over a 4-week period resulted in 7,668 useable survey responses (nearly a 15% response rate). RESULTS: The study identified the common activities and knowledge areas necessary for competent and effective performance of case managers, as was highlighted in Part I of the two-part article series on the role and function study. The results of the study informed the needed update of the test specifications for the Certified Case Manager (CCM) certification examination. This work assures the CCM continues to be substantiated in current practice. Of special note are the emergence of specific activity and knowledge domains in the area of case management ethical, legal, and practice standards, and an increase in the number of employers requiring certified case managers to fill vacant positions and compensating them financially for such qualifications. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: The role and function study keeps the CCM credentialing examination evidence-based and maintains its validity for evaluating competency of case managers. Findings can be used to develop programs and curricula for the training and education of case managers. The study instrument also can be used for further research of case management practice. PMID- 26618266 TI - Individuals With Traumatic Brain Injury and Their Significant Others' Perceptions of Information Given About the Nature and Possible Consequences of Brain Injury: Analysis of a National Survey. AB - PURPOSE OF THE STUDY: An online survey was developed to assess how well individuals with brain injuries and family/friends of those with traumatic brain injury (TBI) (significant others) felt they were informed about the nature and consequences of brain injury. PARTICIPANTS: A total of 117 significant others completed the survey. They were primarily female (84.6%), white (94.9%), and well educated (81.2%). A total of 149 individuals with brain injuries completed the survey and again were primarily female (63.8%), white (88.2%), and well educated (82.9%). RESULTS: More than half of the significant other respondents indicated that they were not provided enough information about TBI (53.5%). Up to 53.8% of the respondents with TBI felt that they were not provided enough information, with 43% reporting dissatisfaction with services. Female survivors and those with mild brain injuries were significantly more likely to feel that they were not provided sufficient rehabilitation or information. Increased satisfaction with services was correlated with decreased time since injury (r = -0.165, p = .049). Qualitative analysis revealed key themes about prognostic information and the adequacy of discharge planning and resources. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Given that more than half of all surveyed indicated that they were not well-informed about brain injury and its possible effects, it is evident that case managers and their teams need to be aware of and invested in their efforts to educate both individuals with brain injuries and their significant others (family and friends) about both the nature and consequences of brain injury. Specific recommendations for practice are included. PMID- 26618267 TI - Evaluation of an Integrated Cluster Care and Supportive Housing Model for Unstably Housed Persons Using the Shelter System. AB - PURPOSE: To evaluate the feasibility of an integrated cluster care and supportive housing model. PRIMARY PRACTICE SETTING(S): Community shelters. METHODOLOGY AND SAMPLE: The Inner City Access Program (ICAP) is a new service delivery model employed by the Toronto Central Community Care Access Centre, which combines supportive housing services and health care for homeless, underhoused, and marginalized populations using the shelter system. We evaluated the effectiveness of the ICAP in facilitating access to health services, supporting goal-setting, and promoting interprofessional case management. Client interviews examined care goals, goal achievement, and satisfaction; staff interviews determined client centeredness of staff-identified care goals/planning; document reviews were conducted to obtain service utilization and process data. RESULTS: Twenty clients received service during a 15-month period before implementation. This increased to 147 clients during a 16-month period post-implementation at a 60% reduction in cost/client. Results indicated that regular interdisciplinary team meetings promoted greater service delivery efficiency; greater client satisfaction was associated with goal achievement (p < .01); and a trend toward greater perceived goal achievement (as reported separately by clients and staff) and client satisfaction when staff- and client-stated goals were more closely aligned. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: The ICAP proved an efficient and cost effective model in engaging marginalized populations. There was a trend toward greater client satisfaction when clients perceived success related to "education, employment, activities, and programs" goals. PMID- 26618269 TI - Transition to the ICD-10: The Time Has Come. PMID- 26618268 TI - Retirement--If You Fail to Plan, Then You Plan to Fail. PMID- 26618270 TI - Evaluating and Measuring Quality and Outcomes: A New "Essential Activity" of Case Management Practice. PMID- 26618271 TI - Patient Empowerment for Dual Eligibles: Teaching the Most Vulnerable Health Plan Members to Manage Their Health. PMID- 26618274 TI - Noncovalent Self-Assembled Monolayers on Graphene as a Highly Stable Platform for Molecular Tunnel Junctions. AB - Monolayer graphene is used as the bottom electrode to fabricate stable and high quality self-assembled monolayer (SAM)-based tunnel junctions. The SAMs are formed on graphene via noncovalent bonds without altering the structure of the graphene. This work paves the way to new types of molecular electronic junctions based on 2D materials. PMID- 26618276 TI - Contemporaneous international asthma guidelines present differing recommendations: An analysis. PMID- 26618275 TI - The effects of lung expansion therapy on lung function in patients with prolonged mechanical ventilation. PMID- 26618277 TI - Mini-Implants, Mega Solutions: A Case Series. AB - Dental implants have evolved as a standard of care for replacement of missing teeth. Though this treatment modality promises a high level of patient satisfaction and success, it cannot be performed in all cases. Apart from medically compromised patients, implant use is also restricted whenever there is limited available bone volume at the edentulous site. An example includes the mandibular incisor, the maxillary lateral incisor region, and other sites with reduced interdental spacing and atrophic edentulous maxillary and mandibular ridges. Bone volume at some of these sites can be increased by suitable augmentation procedure for placement of a regular diameter implant (3.75 to 4.2 mm). But many a times such procedure cannot be undertaken either due to financial constraint, risk of subjecting the patient to additional surgical procedure, added time factor, or guarded prognosis of the grafted site. In such cases, mini implants can be used. In this case series, mini-implants (2.5 to 3 mm) were used to replace teeth in all mouth quadrants and to retain a mandibular overdenture in a compromised case. The implants served well at all the sites with minimal bone loss and a high level of patient satisfaction. Mini-implants hold the potential to serve as an alternate to regular diameter implants in certain situations. Preferably they should be used in multiples to retain fixed dental prostheses and might serve as an efficient, low-cost solution for retaining overdentures in selected cases. PMID- 26618278 TI - Minilaparoscopy with Interchangeable, Full 5-mm End Effectors: First Human Use of a New Minimally Invasive Operating Platform. AB - BACKGROUND: The most common paradigm in minimally invasive surgery is entry of a single trocar through separate incisions in the abdomen. However, in an effort to decrease postoperative pain and minimize scarring, alternative techniques have been described. Needlescopic surgery uses instruments that are 3 mm or less in diameter. Prior uses of needlescopic instruments have been hindered somewhat by diminished shaft strength and small end-effector size. The PercuvanceTM (Teleflex, Wayne, PA) system uses a 2.9-mm shaft with interchangeable 5-mm end effectors in order to minimize abdominal wall trauma while maintaining the functionality of traditional laparoscopic instruments. MATERIALS AND METHODS: All patients evaluated for laparoscopic surgery by two surgeons with a foregut and general surgery practice at the Cleveland Clinic (Cleveland, OH) were included in the study. Fifteen consecutive patients were enrolled in the study. Patient demographics and operative results were reviewed. RESULTS: In March 2015, 15 patients underwent surgery using the Percuvance surgical system at the Cleveland Clinic. There was one conversion to open surgery due to extensive intraabdominal adhesions and unclear anatomy. There was one re-exploration for presumed anastomotic leak, which was negative. Operative time and length of hospital stay were similar to those of standard laparoscopic procedures. There were no deaths in this series. Subjective surgeon experience was overall positive, and functionality of the Percuvance system seemed equal to that of standard 5-mm laparoscopic instrumentation. CONCLUSIONS: This initial experience with the Percuvance system demonstrated effective exchange of 5-mm port sites for needlescopic instruments with similar handling to traditional laparoscopic instruments. This interchangeable system may allow performance similar to standard laparoscopic port instrument orientation and principles in the setting of decreased-caliber access. PMID- 26618279 TI - Mitochondria-Targeted Near-Infrared Fluorescent Off-On Probe for Selective Detection of Cysteine in Living Cells and in Vivo. AB - Cysteine (Cys) plays crucial roles in biological systems and in mitochondrial processes. Highly selective probes for specific detection of mitochondrial Cys over other biological thiols are rare. Herein, we designed and synthesized a mitochondria-targetable near-infrared (NIR) fluorescent off-on probe, NFL1, based on a fluorescein derivative for Cys detection. Probe NFL1 has a lipophilic cation unit as the mitochondria biomarker and an acrylate group as the Cys-recognition unit as well as a fluorescence quencher. The probe itself is nonfluorescent due to the photoinduced electron transfer process. Upon addition of Cys, marked enhancement in the NIR emission (735 nm) can be monitored due to cleavage of the acrylate moiety. This probe had great sensitivity and selectivity for the rapid detection of Cys over homocysteine (Hcy) and glutathione (GSH) with an ultralow detection limit of 14.5 nM. More importantly, the probe successfully targeted mitochondria, detected endogenous Cys, and assessed mitochondrial oxidative stress in living cells. Probe NFL1 was also capable of detecting and imaging Cys in living nude mice, indicating its significant potential in biological applications. PMID- 26618280 TI - Evaluating cognitive rehabilitation in multiple sclerosis: on the bumpy road to establishing evidence. PMID- 26618282 TI - Factors Affecting Visual Field Outcomes in the Idiopathic Intracranial Hypertension Treatment Trial. AB - BACKGROUND: To determine the prevalence of visual field (VF) performance failures (PF) and treatment failures (TFs), and identify factors associated with PFs in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). METHODS: A total of 165 participants from 38 sites with idiopathic intracranial hypertension (IIH) and mild visual loss were randomized to either acetazolamide-plus diet or placebo-plus diet. The IIHTT Visual Field Reading Center evaluated 2950 Swedish Interactive Threshold Algorithm Standard 24-2 VFs from the enrolled participants. A TF was defined when the participant's VF mean deviation (MD) worsened >=2 to 3 dB from the average baseline MD (range of -2 to -7 dB) with a second retest confirming the visual deterioration. A PF was determined when the participant's: 1) VF results met TF criteria but were not confirmed on retest, 2) deterioration was confirmed on retest but the IIHTT Adjudication Committee concluded a TF was clinically unlikely. RESULTS: TF was detected in 7/165 (4%) of the participants and PF was detected in 35/165 (21%) of the participants on at least 1 examination. Four of the 35 PFs were adjudicated for TF, however based on clinical review by the adjudication committee and a third retest, they were judged as PFs. Of the 2,950 total IIHTT VF examinations, 2.7% met PF criteria. CONCLUSIONS: PF was confirmed in 21% of subjects and in 2.7% of the total number of VF examinations and was reversible on repeat testing. We recommend retesting when perimetric worsening occurs in otherwise clinically stable or improving IIH patients. PMID- 26618287 TI - Celebrating the ACP Centennial: From the Annals Archives--Nurse Practitioners and Physicians. PMID- 26618281 TI - The role of NANOG transcriptional factor in the development of malignant phenotype of cancer cells. AB - NANOG is a transcription factor that is involved in the self-renewal of embryonic stem cells (ES) and is a critical factor for the maintenance of the undifferentiated state of pluripotent cells. Extensive data in the literature show that the NANOG gene is aberrantly expressed during the development of malignancy in cancer cells. ES and cancer stem cells (CSCs), a subpopulation of cancer cells within the tumor, are thought to share common phenotypic properties. This review describes the role of NANOG in cancer cell proliferation, epithelial mesenchymal transition (EMT), apoptosis and metastasis. In addition, this paper illustrates a correlation between NANOG and signal transducer and activator of transcription 3 (STAT3) in the maintenance of cancer stem cell properties and multidrug resistance. Together, the available data demonstrate that NANOG is strictly involved in the process of carcinogenesis and is a potential prognostic marker of malignant tumors. PMID- 26618283 TI - Size distribution and sources of humic-like substances in particulate matter at an urban site during winter. AB - This study investigates the size distribution and possible sources of humic-like substances (HULIS) in ambient aerosol particles collected at an urban site in Gwangju, Korea during the winter of 2015. A total of 10 sets of size-segregated aerosol samples were collected using a 10-stage Micro-Orifice Uniform Deposit Impactor (MOUDI), and the samples were analyzed to determine the mass as well as the presence of ionic species (Na(+), NH4(+), K(+), Ca(2+), Mg(2+), Cl(-), NO3( ), and SO4(2-)), water-soluble organic carbon (WSOC) and HULIS. The separation and quantification of the size-resolved HULIS components from the MOUDI samples was accomplished using a Hydrophilic-Lipophilic Balanced (HLB) solid phase extraction method and a total organic carbon analyzer, respectively. The entire sampling period was divided into two periods: non-Asian dust (NAD) and Asian dust (AD) periods. The contributions of water-soluble organic mass (WSOM = 1.9 * WSOC) and HULIS (=1.9 * HULIS-C) to fine particles (PM1.8) were approximately two times higher in the NAD samples (23.2 and 8.0%) than in the AD samples (12.8 and 4.2%). However, the HULIS-C/WSOC ratio in PM1.8 showed little difference between the NAD (0.35 +/- 0.07) and AD (0.35 +/- 0.05) samples. The HULIS exhibited a uni-modal size distribution (@0.55 MUm) during NAD and a bimodal distribution (@0.32 and 1.8 MUm) during AD, which was quite similar to the mass size distributions of particulate matter, WSOC, NO3(-), SO4(2-), and NH4(+) in both the NAD and AD samples. The size distribution characteristics and the results of the correlation analyses indicate that the sources of HULIS varied according to the particle size. In the fine mode (<=1.8 MUm), the HULIS composition during the NAD period was strongly associated with secondary organic aerosol (SOA) formation processes similar to those of secondary ionic species (cloud processing and/or heterogeneous reactions) and primary emissions during the biomass burning period, and during the AD period, it was only associated with SOA formation. In the coarse mode (3.1-10 MUm), it was difficult to identify the HULIS sources during the NAD period, and during the AD period, the HULIS was most likely associated with soil-related particles [Ca(NO3]2 and CaSO4) and/or sea-salt particles (NaNO3 and Na2SO4). PMID- 26618288 TI - Just One More Hug. PMID- 26618290 TI - Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PMID- 26618291 TI - Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PMID- 26618292 TI - Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PMID- 26618293 TI - Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PMID- 26618294 TI - Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PMID- 26618295 TI - Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PMID- 26618296 TI - Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PMID- 26618297 TI - In the Clinic. Prostate Cancer. PMID- 26618298 TI - Web Exclusives. Annals Graphic Medicine: The Last Ride of Mo Rosenzweig. PMID- 26618299 TI - Do sunbirds use taste to decide how much to drink? AB - Nectarivorous birds typically consume smaller meals of more concentrated than of less concentrated sugar solutions. It is not clear, however, whether they use taste to decide how much to consume or whether they base this decision on post ingestive feedback. Taste, a cue to nectar concentration, is available to nectarivores during ingestion whereas post-ingestive information about resource quality becomes available only after a meal. When conditions are variable, we would expect nectarivorous birds to base their decisions on how much to consume on taste, as post-ingestive feedback from previous meals would not be a reliable cue to current resource quality. Here, we tested whether white-bellied sunbirds (Cinnyris talatala), foraging from an array of artificial flowers, use taste to decide how much to consume per meal when nectar concentration is highly variable: they did not. Instead, how much they chose to consume per meal appeared to depend on the energy intake at the previous meal, that is how hungry they were. Our birds did, however, appear to use taste to decide how much to consume per flower visited within a meal. Unexpectedly, some individuals preferred to consume more from flowers with lower concentration rewards and some preferred to do the opposite. We draw attention to the fact that many studies perhaps misleadingly claim that birds use sweet taste to inform their foraging decisions, as they analyse mean data for multiple meals over which post-ingestive feedback will have become available rather than data for individual meals when only sensory information is available. We discuss how conflicting foraging rules could explain why sunbirds do not use sweet taste to inform their meal size decisions. PMID- 26618300 TI - Biofilms in churches built in grottoes. AB - We investigated microorganisms dwelling on rocks, walls and paintings in two votive chapels built in grottoes in the Region of Campania, Italy. One grotto was near the coast in an area with a Mediterranean climate, and the other grotto was inland on a mountain in an area with a cold continental climate. Color and distribution of biofilms in various areas of the grottoes were examined. Microbial components of biofilms were identified by light and electron microscopy and by molecular techniques (DNA analyses and Automatic rRNA Intergenic Spacer Analysis). Biofilms were also analyzed by X-ray diffraction to detect inorganic constituents deriving from rocks in the grottoes and walls of the churches and by X-ray fluorescence to detect the elements that made up the pigments of the mural paintings; optical cross sections were used to observe their relationships with substrata. Species of eubacteria, cyanobacteria and green algae were identified. Some of these species occurred in both grottoes, while others were exclusive to only one of the grottoes. The diversity of species, their common or exclusive occurrence in the grottoes, the relationships among microbial communities and the differences in color and distribution of biofilms were discussed on the basis of the different climatic factors affecting the two grottoes and the different inorganic components of substrata. PMID- 26618301 TI - ROS production and gene expression in alveolar macrophages exposed to PM(2.5) from Baghdad, Iraq: Seasonal trends and impact of chemical composition. AB - The objective of this study was to assess the impact of changes in atmospheric particulate matter (PM) composition on oxidative stress markers in an in-vitro alveolar macrophage (AM) model. Fifty-three PM2.5 samples were collected during a year-long PM sampling campaign in Baghdad, Iraq, a semi-arid region of the country. Monthly composites were analyzed for chemical composition and for biological activity using in-vitro measurements of ROS production and gene expression in the AM model. Twelve genes that were differentially expressed upon PM exposure were identified and their co-associations with the composition of PM2.5 were examined. Ten of those genes were up-regulated in January and April composites; samples which also exhibited high ROS activity and relatively high PM mass concentration. ROS production was statistically correlated with total PM2.5 mass, levoglucosan (a wood burning tracer) and several trace elements of the PM (especially V and Ni, which are associated with oil combustion). The expression of several cytokine genes was found to be moderately associated with PM mass, crustal materials (indication of dusty days or dust storms) and certain metals (e.g. V, Fe and Ni) in the PM. Thus, the ROS activity association with PM2.5, may, in part, be driven by redox-active metals. The antioxidant response genes (Nqo1 and Hmox1) were moderately associated with polyaromatic hydrocarbons (PAHs) and showed a good correlation (r-Pearson of >0.7) with metals linked to vehicle related emissions (i.e. Cu, Zn and Sb). Examining these associations in a larger sample pool (e.g. daily samples) would improve the power of the analysis and may strengthen the implication of these chemicals in the oxidative stress of biological systems, which could aid in the development of new metrics of PM toxicity. PMID- 26618302 TI - Fast and Efficient Fabrication of Intrinsically Stretchable Multilayer Circuit Boards by Wax Pattern Assisted Filtration. AB - Intrinsically stretchable multilayer circuit boards are fabricated with a fast and material efficient method based on filtration. Silver nanowire conductor patterns of outstanding performance are defined by filtration through wax printed membranes and the circuit board is assembled by subsequent transfers of the nanowires onto the elastomer substrate. The method is used to fabricate a bright stretchable light emitting diode matrix display. PMID- 26618303 TI - Local dynamic range compensation for scanning electron microscope imaging system by sub-blocking multiple peak HE with convolution. AB - This paper introduces new development technique to improve the Scanning Electron Microscope (SEM) image quality and we name it as sub-blocking multiple peak histogram equalization (SUB-B-MPHE) with convolution operator. By using this new proposed technique, it shows that the new modified MPHE performs better than original MPHE. In addition, the sub-blocking method consists of convolution operator which can help to remove the blocking effect for SEM images after applying this new developed technique. Hence, by using the convolution operator, it effectively removes the blocking effect by properly distributing the suitable pixel value for the whole image. Overall, the SUB-B-MPHE with convolution outperforms the rest of methods. SCANNING 38:492-501, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26618304 TI - Cytomorphological features of blastic plasmacytoid dendritic cell neoplasm on FNA and cerebrospinal fluid cytology: A review of 6 cases. AB - BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematopoietic tumor that was once believed to be derived from natural killer cells and is now recognized as originating from precursors of plasmacytoid dendritic cells. It generally involves the skin and has an aggressive clinical course. Due to its highly malignant behavior, a fast and accurate diagnosis of this condition is of the utmost importance. METHODS: Six cytology specimens from 5 patients diagnosed with BPDCN were reviewed as well as their clinical records. Findings were compared with 3 previously published cases. RESULTS: Two exfoliative cytology specimens (cerebrospinal fluid) and 4 fine-needle aspiration specimens (3 lymph node specimens and 1 cutaneous specimen) were reviewed. The cytomorphological aspects were similar in all cases. The smears were hypercellular with a monotonous population of intermediate-sized cells, dispersed singly or arranged in loose aggregates. The cells had round to oval nuclei, with fine chromatin and prominent nucleoli; the cytoplasm was generally scant, without visible granules. Intracytoplasmic microvacuoles were found in the majority of cases. Four cases were also characterized by flow cytometry, which revealed expression of CD 123, CD56 and/or CD4. Fine-needle aspiration was used in 1 case for primary diagnosis. Histological confirmation was available in all cases. CONCLUSIONS: BPDCN is a highly malignant neoplasm with a poor outcome. Cytology, in association with flow cytometry immunophenotyping and clinical history, is a reliable method with which to establish the diagnosis. PMID- 26618305 TI - Estimating malaria burden in Nigeria: a geostatistical modelling approach. AB - This study has produced a map of malaria prevalence in Nigeria based on available data from the Mapping Malaria Risk in Africa (MARA) database, including all malaria prevalence surveys in Nigeria that could be geolocated, as well as data collected during fieldwork in Nigeria between March and June 2007. Logistic regression was fitted to malaria prevalence to identify significant demographic (age) and environmental covariates in STATA. The following environmental covariates were included in the spatial model: the normalized difference vegetation index, the enhanced vegetation index, the leaf area index, the land surface temperature for day and night, land use/landcover (LULC), distance to water bodies, and rainfall. The spatial model created suggests that the two main environmental covariates correlating with malaria presence were land surface temperature for day and rainfall. It was also found that malaria prevalence increased with distance to water bodies up to 4 km. The malaria risk map estimated from the spatial model shows that malaria prevalence in Nigeria varies from 20% in certain areas to 70% in others. The highest prevalence rates were found in the Niger Delta states of Rivers and Bayelsa, the areas surrounding the confluence of the rivers Niger and Benue, and also isolated parts of the north eastern and north-western parts of the country. Isolated patches of low malaria prevalence were found to be scattered around the country with northern Nigeria having more such areas than the rest of the country. Nigeria's belt of middle regions generally has malaria prevalence of 40% and above. PMID- 26618306 TI - Spatial air pollution modelling for a West-African town. AB - Land use regression (LUR) modelling is a common approach used in European and Northern American epidemiological studies to assess urban and traffic related air pollution exposures. Studies applying LUR in Africa are lacking. A need exists to understand if this approach holds for an African setting, where urban features, pollutant exposures and data availability differ considerably from other continents. We developed a parsimonious regression model based on 48-hour nitrogen dioxide (NO2) concentrations measured at 40 sites in Kaedi, a medium sized West-African town, and variables generated in a geographic information system (GIS). Road variables and settlement land use characteristics were found to be important predictors of 48-hour NO2 concentration in the model. About 68% of concentration variability in the town was explained by the model. The model was internally validated by leave-one-out cross-validation and it was found to perform moderately well. Furthermore, its parameters were robust to sampling variation. We applied the model at 100 m pixels to create a map describing the broad spatial pattern of NO2 across Kaedi. In this research, we demonstrated the potential for LUR as a valid, cost-effective approach for air pollution modelling and mapping in an African town. If the methodology were to be adopted by environmental and public health authorities in these regions, it could provide a quick assessment of the local air pollution burden and potentially support air pollution policies and guidelines. PMID- 26618307 TI - Application of geo-spatial technology in schistosomiasis modelling in Africa: a review. AB - Schistosomiasis continues to impact socio-economic development negatively in sub Saharan Africa. The advent of spatial technologies, including geographic information systems (GIS), Earth observation (EO) and global positioning systems (GPS) assist modelling efforts. However, there is increasing concern regarding the accuracy and precision of the current spatial models. This paper reviews the literature regarding the progress and challenges in the development and utilization of spatial technology with special reference to predictive models for schistosomiasis in Africa. Peer-reviewed papers identified through a PubMed search using the following keywords: geo-spatial analysis OR remote sensing OR modelling OR earth observation OR geographic information systems OR prediction OR mapping AND schistosomiasis AND Africa were used. Statistical uncertainty, low spatial and temporal resolution satellite data and poor validation were identified as some of the factors that compromise the precision and accuracy of the existing predictive models. The need for high spatial resolution of remote sensing data in conjunction with ancillary data viz. ground-measured climatic and environmental information, local presence/absence intermediate host snail surveys as well as prevalence and intensity of human infection for model calibration and validation are discussed. The importance of a multidisciplinary approach in developing robust, spatial data capturing, modelling techniques and products applicable in epidemiology is highlighted. PMID- 26618308 TI - A review of spatial technologies with applications for malaria transmission modelling and control in Africa. AB - Spatial technologies, i.e. geographic information systems, remote sensing, and global positioning systems, offer an opportunity for rapid assessment of malaria endemic areas. These technologies coupled with prevalence/incidence data can provide reliable estimates of population at risk, predict disease distributions in areas that lack baseline data and provide guidance for intervention strategies, so that scarce resources can be allocated in a cost-effective manner. This review focuses on the spatial technology applications that have been used in epidemiology and control of malaria in Africa. Peer-reviewed papers identified through a PubMed search using the following keywords: geospatial technology OR Geographic Information Systems OR Remote Sensing OR Earth Observation OR Global Positioning Systems OR geospatial modelling OR malaria incidence OR malaria prevalence OR malaria risk prediction OR malaria mapping AND malaria AND Africa were used. These included mapping malaria incidence and prevalence, assessing the relationship between malaria and environmental variables as well as applications for malaria early warning systems. The potential of new spatial technology applications utilising emerging satellite information, as they hold promise to further enhance infectious risk mapping and disease prediction, are outlined. We stress current research needs to overcome some of the remaining challenges of spatial technology applications for malaria so that further and sustainable progress can be made to control and eliminate this disease. PMID- 26618309 TI - MALAREO: a user-driven project. AB - The aim of this study is to assess the capacity gaps and requirements of Earth observation (EO) and related technologies for malaria vector control and management in the Lubombo Spatial Development Initiative regions of South Africa, Swaziland and Mozambique. In order to achieve the core objective of this study, available EO data (including main characteristics and resources required to utilize them) and their potential applications for malaria epidemiology are reviewed. In addition, a survey was conducted to assess the availability of human and facility resources to operate EO and related technologies for control and management of the malaria control programs in these countries resulting in an analysis of capacity gaps, priorities and requirements. Earth observation in malaria vector control and management has two different applications: i) collection of relevant remotely sensed data for epidemiological use; and ii) direct support of ongoing malaria vector control activities. All malaria control programs and institutions recognize the significance of EO products to detect mosquito vector habitats, to monitor environmental parameters affecting mosquito vector populations as well as house mapping and distribution of information supporting residual spray planning and monitoring. It was found that only the malaria research unit (MRU) of the medical research council (MRC) in South Africa and the national malaria control program (MCP) in Swaziland currently have a fully functional geographic information systems (GIS), whereas the other surveyed MCPs in South Africa and Mozambique currently do not have this in place. Earth observation skills only exist in MRU of MRC, while spatial epidemiology is scarce in all institutions, which was identified as major gap. The survey has also confirmed that EO and GIS technologies have enormous potential as sources of spatial data and as analytical frameworks for malaria vector control. It is therefore evident that planning and management require capacity building with respect to GIS, EO and spatial epidemiology. PMID- 26618310 TI - Geostatistical modelling of the malaria risk in Mozambique: effect of the spatial resolution when using remotely-sensed imagery. AB - The study of malaria spatial epidemiology has benefited from recent advances in geographic information system and geostatistical modelling. Significant progress in earth observation technologies has led to the development of moderate, high and very high resolution imagery. Extensive literature exists on the relationship between malaria and environmental/climatic factors in different geographical areas, but few studies have linked human malaria parasitemia survey data with remote sensing-derived land cover/land use variables and very few have used Earth Observation products. Comparison among the different resolution products to model parasitemia has not yet been investigated. In this study, we probe a proximity measure to incorporate different land cover classes and assess the effect of the spatial resolution of remotely sensed land cover and elevation on malaria risk estimation in Mozambique after adjusting for other environmental factors at a fixed spatial resolution. We used data from the Demographic and Health survey carried out in 2011, which collected malaria parasitemia data on children from 0 to 5 years old, analysing them with a Bayesian geostatistical model. We compared the risk predicted using land cover and elevation at moderate resolution with the risk obtained employing the same variables at high resolution. We used elevation data at moderate and high resolution and the land cover layer from the Moderate Resolution Imaging Spectroradiometer as well as the one produced by MALAREO, a project covering part of Mozambique during 2010-2012 that was funded by the European Union's 7th Framework Program. Moreover, the number of infected children was predicted at different spatial resolutions using AFRIPOP population data and the enhanced population data generated by the MALAREO project for comparison of estimates. The Bayesian geostatistical model showed that the main determinants of malaria presence are precipitation and day temperature. However, the presence of wetlands and bare soil are also very important factors. The model validation performed on a subset of locations revealed that the use of high-resolution covariates (MALAREO land cover and elevation data) improved prediction performance. PMID- 26618311 TI - Improving AfriPop dataset with settlement extents extracted from RapidEye for the border region comprising South-Africa, Swaziland and Mozambique. AB - For modelling the spatial distribution of malaria incidence, accurate and detailed information on population size and distribution are of significant importance. Different, global, spatial, standard datasets of population distribution have been developed and are widely used. However, most of them are not up-to-date and the low spatial resolution of the input census data has limitations for contemporary, national- scale analyses. The AfriPop project, launched in July 2009, was initiated with the aim of producing detailed, contemporary and easily updatable population distribution datasets for the whole of Africa. High-resolution satellite sensors can help to further improve this dataset through the generation of high-resolution settlement layers at greater spatial details. In the present study, the settlement extents included in the MALAREO land use classification were used to generate an enhanced and updated version of the AfriPop dataset for the study area covering southern Mozambique, eastern Swaziland and the malarious part of KwaZulu-Natal in South Africa. Results show that it is possible to easily produce a detailed and updated population distribution dataset applying the AfriPop modelling approach with the use of high-resolution settlement layers and population growth rates. The 2007 and 2011 population datasets are freely available as a product of the MALAREO project and can be downloaded from the project website. PMID- 26618313 TI - Effects of weather and landscape on the equine West Nile virus infection risk in Mississippi, USA. AB - The West Nile virus (WNv) continues to be a public health concern in North America. Dry weather appears to increase human WNv infection risks, but it is uncertain whether dry weather conditions exert similar effects on the corresponding equine WNv infection. This study assessed the effects of precipitation of the previous year and land cover diversity on the equine WNv risk of Mississippi, USA, at the county level in the year 2002 using Bayesian hierarchical models. The risk estimated for 2002 was found to be inversely related to annual precipitation of the preceding year. Equine WNv risks were lower with greater land cover diversity probably due to the diluting effects of biodiversity. Correlation between the equine and human WNv risks was positive but relatively low. Dry weather conditions of the previous year might reduce mosquito competitors and predators and subsequently increase mosquito abundances and equine WNv risks in agricultural areas with low biodiversity. PMID- 26618312 TI - Monitoring techniques in the capture and adoption of dogs and cats. AB - The continuous improvement of the information systems of organizations that work toward the control of stray dog and cat populations facilitates the implementation of programs aimed at reducing the number of animals that roam free in public streets. This study aimed to present techniques to improve the understanding of the spatial distribution of stray dogs and cats and of people who adopt these animals and the fate of these animals in zoonosis control centers (ZCC). Ripley's K function was used with a Euclidean distance graph to detect the distribution pattern of dogs and cats captured and of the people who adopted these animals. An estimate of the kernel density was used to allow a better assessment of the spatial distribution of the phenomenon studied. The results showed that the distribution of captured animals and of the people who adopted these animals form a spatial cluster (p = 0.01). Most of the animals were captured near the premises of the ZCC and near the downtown area. Factors such as the abandonment of animals near animal control agencies and the availability of food sources are the main hypotheses associated to the distribution of the captures. The awareness of the people who live in places where there is a greater number of stray animals and the distribution of the urban population are the main hypotheses to explain the distribution of the adoptions. The results will help to implement control measures over these populations in the most problematic areas. PMID- 26618314 TI - Spatial access disparities to primary health care in rural and remote Australia. AB - Poor spatial access to health care remains a key issue for rural populations worldwide. Whilst geographic information systems (GIS) have enabled the development of more sophisticated access measures, they are yet to be adopted into health policy and workforce planning. This paper provides and tests a new national-level approach to measuring primary health care (PHC) access for rural Australia, suitable for use in macro-level health policy. The new index was constructed using a modified two-step floating catchment area method framework and the smallest available geographic unit. Primary health care spatial access was operationalised using three broad components: availability of PHC (general practitioner) services; proximity of populations to PHC services; and PHC needs of the population. Data used in its measurement were specifically chosen for accuracy, reliability and ongoing availability for small areas. The resultant index reveals spatial disparities of access to PHC across rural Australia. While generally more remote areas experienced poorer access than more populated rural areas, there were numerous exceptions to this generalisation, with some rural areas close to metropolitan areas having very poor access and some increasingly remote areas having relatively good access. This new index provides a geographically-sensitive measure of access, which is readily updateable and enables a fine granulation of access disparities. Such an index can underpin national rural health programmes and policies designed to improve rural workforce recruitment and retention, and, importantly, health service planning and resource allocation decisions designed to improve equity of PHC access. PMID- 26618315 TI - Spatiotemporal analysis of the relationship between socioeconomic factors and stroke in the Portuguese mainland population under 65 years old. AB - Stroke risk has been shown to display varying patterns of geographic distribution amongst countries but also between regions of the same country. Traditionally a disease of older persons, a global 25% increase in incidence instead was noticed between 1990 and 2010 in persons aged 20-<=64 years, particularly in low- and medium-income countries. Understanding spatial disparities in the association between socioeconomic factors and stroke is critical to target public health initiatives aiming to mitigate or prevent this disease, including in younger persons. We aimed to identify socioeconomic determinants of geographic disparities of stroke risk in people <65 years old, in municipalities of mainland Portugal, and the spatiotemporal variation of the association between these determinants and stroke risk during two study periods (1992-1996 and 2002-2006). Poisson and negative binomial global regression models were used to explore determinants of disease risk. Geographically weighted regression (GWR) represents a distinctive approach, allowing estimation of local regression coefficients. Models for both study periods were identified. Significant variables included education attainment, work hours per week and unemployment. Local Poisson GWR models achieved the best fit and evidenced spatially varying regression coefficients. Spatiotemporal inequalities were observed in significant variables, with dissimilarities between men and women. This study contributes to a better understanding of the relationship between stroke and socioeconomic factors in the population <65 years of age, one age group seldom analysed separately. It can thus help to improve the targeting of public health initiatives, even more in a context of economic crisis. PMID- 26618316 TI - Asthmatic symptoms and air pollution: a panel study on children living in the Italian Po Valley. AB - The Po Valley (Northern Italy) has elevated levels of air-pollution due to various sources of pollution and adverse weather conditions. This study evaluates the short-term effects of exposure to particulate matter with a diameter of 10 microns or less (PM10) on asthma symptoms in school-aged children. An initial cross-sectional survey was conducted in the area to estimate asthma prevalence in children. Out of a total of 250 asthmatic children identified by the study, 69 agreed to participate in a panel study. The PM10 exposure assessment was based on a combination of geographic and environmental measurements leading to a focus on three different areas, each characterised by its own daily PM10 level. Participants were monitored daily for respiratory symptoms for eight weeks (January-March 2006). We assessed the relationship between daily PM10 exposure and occurrence of asthma symptoms with a generalised linear model based on a total of 3864 person-days of observation. Exposure to PM10 per m3 was found to be particularly associated with cough (OR=1.03, CI 95% 0.99; 1.08) and phlegm (OR=1.05, CI 95% 1.00; 1.10). In the most polluted area, exposure to PM10 was also associated with wheezing (OR=1.18, CI 95% 1.02; 1.37). PMID- 26618317 TI - The food environment and adult obesity in US metropolitan areas. AB - This research examines the larger-scale associations between obesity and food environments in metropolitan areas in the United States (US). The US Census County Business Patterns dataset for 2011 was used to construct various indices of food environments for selected metropolitan areas. The numbers of employees engaged in supermarkets, convenience stores, full service restaurants, fast food restaurants, and snack/coffee shops were standardised using the location quotients, and factor analysis was used to produce two uncorrelated factors measuring food environments. Data on obesity were obtained from the 2011 Behavioral Risk Factor Surveillance System. Individual level obesity measures were linked to the metropolitan area level food environment factors. Models were fitted using generalised estimating equations to control for metropolitan area level intra-correlation and individual level sociodemographic characteristics. It was found that adults residing in cities with a large share of supermarket and full-service restaurant workers were less likely to be obese, while adults residing in cities with a large share of convenience store and fast food restaurant workers were more likely to be obese. Supermarkets and full-service restaurant workers are concentrated in the Northeast and West of the US, where obesity prevalence is relatively lower, while convenience stores and fast-food restaurant workers are concentrated in the South and Midwest, where obesity prevalence is relatively higher. The food environment landscapes measured at the metropolitan area level explain the continental-scale patterns of obesity prevalence. The types of food that are readily available and widely served may translate into obesity disparities across metropolitan areas. PMID- 26618318 TI - Associations between seasonal influenza and meteorological parameters in Costa Rica, Honduras and Nicaragua. AB - Seasonal influenza affects a considerable proportion of the global population each year. We assessed the association between subnational influenza activity and temperature, specific humidity and rainfall in three Central America countries, i.e. Costa Rica, Honduras and Nicaragua. Using virologic data from each country's national influenza centre, rainfall from the Tropical Rainfall Measuring Mission and air temperature and specific humidity data from the Global Land Data Assimilation System, we applied logistic regression methods for each of the five sub-national locations studied. Influenza activity was represented by the weekly proportion of respiratory specimens that tested positive for influenza. The models were adjusted for the potentially confounding co-circulating respiratory viruses, seasonality and previous weeks' influenza activity. We found that influenza activity was proportionally associated (P<0.05) with specific humidity in all locations [odds ratio (OR) 1.21-1.56 per g/kg], while associations with temperature (OR 0.69-0.81 per degrees C) and rainfall (OR 1.01-1.06 per mm/day) were location-dependent. Among the meteorological parameters, specific humidity had the highest contribution (~3-15%) to the model in all but one location. As model validation, we estimated influenza activity for periods, in which the data was not used in training the models. The correlation coefficients between the estimates and the observed were <=0.1 in 2 locations and between 0.6-0.86 in three others. In conclusion, our study revealed a proportional association between influenza activity and specific humidity in selected areas from the three Central America countries. PMID- 26618319 TI - Space-time scan statistics of 2007-2013 dengue incidence in Cimahi City, Indonesia. AB - Four dengue serotypes threatened more than 200 million people and has spread to over 400 districts in Indonesia. Furthermore, 26 districts in most densely populated province, West Java, have been declared as hyperendemic areas. Cimahi is an endemic city with the highest population (14,969 people per square kilometer). Evidence on distribution pattern of dengue cases is required to discover the spread of dengue cases in Cimahi. A study has been conducted to detect clusters of dengue incidence during 2007-2013. A temporal spatial analysis was performed using SaTScanTM software incorporated confirmed dengue monthly data from the Municipality Health Office and population data from a local Bureau of Statistics. A retrospective space-time analysis with a Poisson distribution model and monthly precision was performed. Our results revealed a significant most likely cluster (p<0.001) throughout period of study. The most likely cluster was detected in the centre of the city and moved to the northern region of Cimahi. Cimahi, Karangmekar, and Cibabat village were most likely cluster in 2007-2010 (p <0.001; RR = 2.16-2.98; pop at risk 12% total population); Citeureup were detected as the most likely cluster in 2011-2013 (p <0.001; RR 5.77), respectively. Temporaly, clusters were detected in the first quarter of each year each. In conclusion, a dynamic spread of dengue initiated from the centre to its surrounding areas during the period 2007-2013. Our study suggests the use of GIS to strengthen case detection and surveillance. An in-depth investigation to relevant risk factors in high-risk areas in Cimahi city is encouraged. PMID- 26618320 TI - Human infections and co-infections with helminths in a rural population in Guichi, Anhui Province, China. AB - Helminth infections are believed to be common in tropical and subtropical countries. A cross-sectional study was carried out in two villages located in Guichi District in Anhui Province, the People's Republic of China, where multiparasitism was investigated using parasitological tests. The data collected were fitted to Bayesian multi-level models to profile risk factors for helminth infections. The prevalence of Schistosoma (S.) japonicum, Ascaris (A.) lumbricoides and Trichuris (T.) trichiura were 0.43% (range: 0-0.87% at the village level), 2.28% (range: 1.69-2.88%), and 0.21% (range: 0-0.42%), respectively. No hookworm infection was found. With regard to multiparasitism, only a 33-year-old female was found to be co-infected with S. japonicum and A. lumbricoides. Multiparasitism was unexpectedly rare in the study area, which contrasts with results from other studies carried out elsewhere in the country. The long-term usage of albendazole for individuals serologically positive for schistosomiasis may be the main reason, but this needs to be confirmed by future studies. PMID- 26618321 TI - A topological multilayer model of the human body. AB - Geographical information systems deal with spatial databases in which topological models are described with alphanumeric information. Its graphical interfaces implement the multilayer concept and provide powerful interaction tools. In this study, we apply these concepts to the human body creating a representation that would allow an interactive, precise, and detailed anatomical study. A vector surface component of the human body is built using a three-dimensional (3-D) reconstruction methodology. This multilayer concept is implemented by associating raster components with the corresponding vector surfaces, which include neighbourhood topology enabling spatial analysis. A root mean square error of 0.18 mm validated the three-dimensional reconstruction technique of internal anatomical structures. The expansion of the identification and the development of a neighbourhood analysis function are the new tools provided in this model. PMID- 26618322 TI - Space-time clustering characteristics of dengue based on ecological, socio economic and demographic factors in northern Sri Lanka. AB - The aim of the present study was to identify geographical areas and time periods of potential clusters of dengue cases based on ecological, socio-economic and demographic factors in northern Sri Lanka from January 2010 to December 2013. Remote sensing (RS) was used to develop an index comprising rainfall, humidity and temperature data. Remote sensing data gathered by the AVNIR-2 instrument onboard the ALOS satellite were used to detect urbanisation, and a digital land cover map was used to extract land cover information. Other data on relevant factors and dengue outbreaks were collected through institutions and extant databases. The analysed RS data and databases were integrated into a geographical information system (GIS) enabling space-time clustering analysis. Our results indicate that increases in the number of combinations of ecological, socio economic and demographic factors that are present or above the average contribute to significantly high rates of space-time dengue clusters. The spatio-temporal association that consolidates the two kinds of associations into one can ensure a more stable model for forecasting. An integrated spatiotemporal prediction model at a smaller level using ecological, socioeconomic and demographic factors could lead to substantial improvements in dengue control and prevention by allocating the right resources to the appropriate places at the right time. PMID- 26618323 TI - Metropolitan urban hotspots of chronic sleep deprivation: evidence from a community health survey in Gyeongbuk Province, South Korea. AB - The geographic concentration of chronic sleep deprivation (CSD) remains largely unexplored. This paper examined the community-specific spatial pattern of the prevalence of CSD and the presence of clustered spatial hotspots among the Korean elderly population in Gyeongbuk Province, South Korea, revealing CSD hotspots and underscoring the importance of geography-focused prevention strategies. The study analysed cross-sectional data collected from 9847 elderly individuals aged 60 years and older who participated in a Korean Community Health Survey conducted in 2012. To assess the level of spatial dependence, an exploratory spatial data analysis was conducted using Global Moran's I statistic and the local indicator of spatial association. The results revealed marked geographic variations in CSD prevalence ranging from 33.4 to 73.4%, with higher values in the metropolitan urban areas and lower in the rural areas. Almost half of the community residents [both men (44.1%) and women (53.5%)] slept 6 h or less per 24 h. The average CSD prevalence (53.6% men and 65.1% women) in the hotspots was about 13.0% higher than that in other areas (42.6% for men and 51.1% for women). To our knowledge, this is the first study to generate a CSD hotspot map that includes data on sleep deprivation across metropolitan district levels. This study demonstrates that not only is sleep deprivation distributed differentially across communities but these differences may be explained by urbanisation. PMID- 26618324 TI - Assessing the spatial accessibility of hospital care in Sichuan Province, China. AB - Regional disparities in geographical access to hospital care are found throughout China. Understanding variations in the spatial accessibility of hospital care has the potential to provide decision support in healthcare planning. This study examines the hospital system in the Sichuan Province in China, which provides healthcare for more than 80 million people. We examine the impacts of accessibility characterisation via the conventional measurement approach by comparing the results to those derived using a floating catchment area approach. Employing a geographical information system based on population and hospital administrative data, we conducted a province-wide study of the spatial accessibility of hospital care in Sichuan Province, China. A shortest-path analysis and the enhanced two-step floating catchment area (E2SFCA) method were implemented. Substantial differences between these two approaches were found, including a roughly 15% difference in the total number of under-served areas. Generally, spatial accessibility was higher in the eastern regions of Sichuan. More than 5.5 million people were found to have limited access, with large variations across the province. These results indicate that the official method used by policy makers in China may not capture the true nature of spatial accessibility throughout the region. We recommend that the E2SFCA method be implemented for health services research in China, providing decision makers with more accurate information when setting healthcare policies. PMID- 26618325 TI - The dog and cat population on Maio Island, Cape Verde: characterisation and prediction based on household survey and remotely sensed imagery. AB - The objective was to estimate and characterise the dog and cat population on Maio Island, Cape Verde. Remotely sensed imagery was used to document the number of houses across the island and a household survey was carried out in six administrative areas recording the location of each animal using a global positioning system instrument. Linear statistical models were applied to predict the dog and cat populations based on the number of houses found and according to various levels of data aggregation. In the surveyed localities, a total of 457 dogs and 306 cats were found. The majority of animals had owners and only a few had free access to outdoor activities. The estimated population size was 531 dogs [95% confidence interval (CI): 453-609] and 354 cats (95% CI: 275-431). Stray animals were not a concern on the island in contrast to the rest of the country. PMID- 26618326 TI - Use of an ecologically relevant modelling approach to improve remote sensing based schistosomiasis risk profiling. AB - Schistosomiasis is a widespread water-based disease that puts close to 800 million people at risk of infection with more than 250 million infected, mainly in sub-Saharan Africa. Transmission is governed by the spatial distribution of specific freshwater snails that act as intermediate hosts and the frequency, duration and extent of human bodies exposed to infested water sources during human water contact. Remote sensing data have been utilized for spatially explicit risk profiling of schistosomiasis. Since schistosomiasis risk profiling based on remote sensing data inherits a conceptual drawback if school-based disease prevalence data are directly related to the remote sensing measurements extracted at the location of the school, because the disease transmission usually does not exactly occur at the school, we took the local environment around the schools into account by explicitly linking ecologically relevant environmental information of potential disease transmission sites to survey measurements of disease prevalence. Our models were validated at two sites with different landscapes in Cote d'Ivoire using high- and moderate-resolution remote sensing data based on random forest and partial least squares regression. We found that the ecologically relevant modelling approach explained up to 70% of the variation in Schistosoma infection prevalence and performed better compared to a purely pixel-based modelling approach. Furthermore, our study showed that model performance increased as a function of enlarging the school catchment area, confirming the hypothesis that suitable environments for schistosomiasis transmission rarely occur at the location of survey measurements. PMID- 26618327 TI - Initial hydration behavior of sodium iodide dimer: photoelectron spectroscopy and ab initio calculations. AB - We investigated (NaI)2(-)(H2O)n (n = 0-6) clusters to examine the initial solvation process of (NaI)2 in water, using negative ion photoelectron spectroscopy and theoretical calculations. The structures of these clusters and their neutrals were determined by comparing ab initio calculations with experimental results. It is found that bare (NaI)2(-) is a L-shaped structure and the corresponding neutral is a rhombus. In (NaI)2(-)(H2O), the water molecule prefers to interact with the middle Na atom of the L-shaped (NaI)2(-). For (NaI)2(-)(H2O)n clusters with n = 2-3, two types of structures are nearly degenerate in energy: one is L-shaped and the other is pyramid-shaped. As for (NaI)2(-)(H2O)n with n = 4-6, the dominant structures are pyramid-shaped. For the anionic clusters, one of the Na-I distances increases abruptly when n = 2; for the neutral clusters, rapid lengthening of the Na-I distances occurs when n = 4. Additionally, analyses of the reduced density gradient were carried out, and the results reveal that Na(+)-water interactions dominate in (NaI)2(-)(H2O)n for n<= 4, whereas I(-)-water and water-water interactions are significantly enhanced when n increases to 5. PMID- 26618328 TI - Implementing Family-Centered Cesarean Birth. AB - Cesarean birth is recognized as a physical and psychological stressor for many women. Maternity practices during cesarean birth should meet women's needs, while maintaining safety, to optimize the experience. Family-centered cesarean birth is a package of interventions that encourages a woman to participate in choosing interventions that would be helpful when undergoing a planned or unplanned cesarean birth. Included in family-centered cesarean birth is implementation of skin-to-skin care in the operating room for neonates who appear term and healthy. The process of attempting to implement family-centered cesarean birth at one academic center is presented, including steps for implementation, benefits, challenges, and areas for continued improvement and research. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health. PMID- 26618329 TI - Microscopic Dimensions Engineering: Stepwise Manipulation of the Surface Wettability on 3D Substrates for Oil/Water Separation. AB - Microscopic dimensions engineering is proposed to devise a series of 3D superhydrophobic substrates with microstructures of different dimensions. Combined theoretical modeling and experiments give the relationship of surface roughness and superhydrophobic properties, important for guiding the design of superior superwettable materials for water remediation and other uses. PMID- 26618330 TI - Joint Coordination and Muscle Activities of Ballet Dancers During Tiptoe Standing. AB - We aimed to investigate joint coordination of lower limbs in dancers during tiptoe standing and the relationship between joint coordination and muscle coactivation. Seven female ballet dancers performed tiptoe standing with six leg positions (fi e classical dance positions and one modern dance position) for 10 s. The kinematic data of the metatarsophalangeal (MP), ankle, knee, and hip joints was collected, and surface electromyography (EMG) of over 13 lower limb muscles was conducted. Principal component analysis was performed to determine joint coordination. MP-ankle and ankle-knee had in-phase coordination, whereas knee-hip showed anti-phase coordination in the sagittal plane. In addition, most EMG-EMG coherence around the MP and ankle joints was significant up to 50 Hz when these two joints swayed with in-phase. This suggests that different joint coordination patterns are associated with neural processing related to different muscle coactivation patterns. In conclusion, ballet dancers showed in-phase coordination from the MP to knee joints, which was associated with muscle coactivation to a higher frequency domain (up to 50 Hz) in comparison with anti phase coordination. PMID- 26618331 TI - Cocaine occupancy of sigma1 receptors and dopamine transporters in mice. AB - Activation of sigma1 (sigma1) receptors contributes to the behavioral and toxic effects of (-)-cocaine. We studied a key step, the ability of (-)-cocaine to occupy sigma1 receptors in vivo, using CD-1((r)) mice and the novel radioligand [(125) I]E-N-1-(3'-iodoallyl)-N'-4-(3",4"-dimethoxyphenethyl)-piperazine ([(125) I]E-IA-DM-PE-PIPZE). (-)-Cocaine displayed an ED50 of 68 MUmol/kg for inhibition of specific radioligand binding in whole brain, with values between 73 and 80 MUmol/kg for heart, lung, and spleen. For comparison, an ED50 of 26 MUmol/kg for (-)-cocaine occupancy of striatal dopamine transporters (DAT) was determined by inhibition of [(125) I]3beta-(4-iodophenyl)tropan-2beta-carboxylic acid isopropyl ester ([(125) I]RTI-121) binding. A chief finding is the relatively small potency difference between (-)-cocaine occupancy of sigma1 receptors and the DAT, although the DAT occupancy is likely underestimated. Interactions of (-)-cocaine with sigma1 receptors were assessed further using [(125) I]E-IA-DM-PE-PIPZE for regional cerebral biodistribution studies and quantitative ex vivo autoradiography of brain sections. (-)-Cocaine binding to cerebral sigma1 receptors proved directly proportional to the relative site densities known for the brain regions. Nonradioactive E-IA-DM-PE-PIPZE gave an ED50 of 0.23 MUmol/kg for occupancy of cerebral sigma1 receptors, and a 3.16 MUmol/kg (i.p.) dose attenuated (-)-cocaine-induced locomotor hyperactivity by 30%. This effect did not reach statistical significance, but suggests that E-IA-DM-PE-PIPZE is a probable sigma1 receptor antagonist. As groundwork for the in vivo studies, we used standard techniques in vitro to determine ligand affinities, site densities, and pharmacological profiles for the sigma1 and sigma2 receptors expressed in CD 1((r)) mouse brain. PMID- 26618333 TI - Facial flushing response to alcohol and the risk of esophageal squamous cell carcinoma: A comprehensive systematic review and meta-analysis. AB - OBJECTIVE: The alcohol flushing response is common among ethnic East Asian populations, and has been associated with an increased risk in developing esophageal cancer, especially squamous cell esophageal cancer (ESCC). We aimed to quantify the relationship between the facial flushing response to alcohol consumption and ESCC. METHODS: We conducted a meta-analysis of studies reporting on the association between the facial flushing response to alcohol consumption and ESCC. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using a random effects model for the risk of ESCC associated with the facial flushing response in general, as well for different levels of alcohol consumption. Four databases, Medline, PubMed, Embase, and Current Contents Connect, were searched to 31 August 2015. RESULTS: Seven studies, with 1014 ESCC cases, met the inclusion criteria. There was a positive relationship between the flushing response and ESCC (OR 1.97; 95% CI 1.25-3.13). Heterogeneity was observed (I(2)= 80%, P<0.001). Publication bias was not present. An increased risk of ESCC was present in the moderate and heavy drinkers who experienced flushing, compared with moderate and heavy drinkers who did not (OR 2.54; 95% CI 1.64-3.91, and OR 2.90; 95% CI 1.82-4.82, respectively). CONCLUSION: Individuals who experience a facial flushing response to alcohol intake may be at increased risk of developing ESCC, particularly if they are moderate to heavy drinkers. PMID- 26618334 TI - Global epidemiology of gastrointestinal stromal tumours (GIST): A systematic review of population-based cohort studies. AB - BACKGROUND: Gastrointestinal stromal tumours (GISTs) are rare, yet the most common mesenchymal tumour within the digestive tract. Lack of diagnostic criteria and no specific code in the ICD system has prevented epidemiological evaluation except from overt malignant cases in the past. A global estimate of incidence and disease patterns has thus not been available. METHODS: A systematic literature search of all available population-based studies on GIST published between January 2000 and December 2014 were reviewed. Descriptive epidemiological data are presented. RESULTS: The search found 29 studies of more than 13,550 patients from 19 countries that reported sufficient data for regional or national population-based statistics. Age at diagnosis ranged from 10 to 100 years, with median age being mid 60s across most studies. Gender distribution was equal across studies. On average, 18% of patients had an incidental diagnosis (range from 5% to 40%). Anatomical location of primary tumour in 9747 GISTs demonstrated gastric location as the most frequent (55.6%) followed by small bowel (31.8%), colorectal (6.0%), other/various location (5.5%) and oesophagus (0.7%). Most studies reported incidence at 10-15 per million per year. Notably, lowest incidence was in China (Shanxi province) with 4.3 per million per year. Highest incidence rates were reported also from China (Hong Kong and Shanghai areas), and in Taiwan and Norway (Northern part), with up to 19-22 per million per year. CONCLUSIONS: Epidemiology of GIST demonstrates some consistent features across geographical regions. Whether the reported extreme differences in incidence reflect real variation in population risk warrants further investigation. PMID- 26618332 TI - Optic nerve head and fibre layer imaging for diagnosing glaucoma. AB - BACKGROUND: The diagnosis of glaucoma is traditionally based on the finding of optic nerve head (ONH) damage assessed subjectively by ophthalmoscopy or photography or by corresponding damage to the visual field assessed by automated perimetry, or both. Diagnostic assessments are usually required when ophthalmologists or primary eye care professionals find elevated intraocular pressure (IOP) or a suspect appearance of the ONH. Imaging tests such as confocal scanning laser ophthalmoscopy (HRT), optical coherence tomography (OCT) and scanning laser polarimetry (SLP, as used by the GDx instrument), provide an objective measure of the structural changes of retinal nerve fibre layer (RNFL) thickness and ONH parameters occurring in glaucoma. OBJECTIVES: To determine the diagnostic accuracy of HRT, OCT and GDx for diagnosing manifest glaucoma by detecting ONH and RNFL damage. SEARCH METHODS: We searched several databases for this review. The most recent searches were on 19 February 2015. SELECTION CRITERIA: We included prospective and retrospective cohort studies and case control studies that evaluated the accuracy of OCT, HRT or the GDx for diagnosing glaucoma. We excluded population-based screening studies, since we planned to consider studies on self-referred people or participants in whom a risk factor for glaucoma had already been identified in primary care, such as elevated IOP or a family history of glaucoma. We only considered recent commercial versions of the tests: spectral domain OCT, HRT III and GDx VCC or ECC. DATA COLLECTION AND ANALYSIS: We adopted standard Cochrane methods. We fitted a hierarchical summary ROC (HSROC) model using the METADAS macro in SAS software. After studies were selected, we decided to use 2 x 2 data at 0.95 specificity or closer in meta analyses, since this was the most commonly-reported level. MAIN RESULTS: We included 106 studies in this review, which analysed 16,260 eyes (8353 cases, 7907 controls) in total. Forty studies (5574 participants) assessed GDx, 18 studies (3550 participants) HRT, and 63 (9390 participants) OCT, with 12 of these studies comparing two or three tests. Regarding study quality, a case-control design in 103 studies raised concerns as it can overestimate accuracy and reduce the applicability of the results to daily practice. Twenty-four studies were sponsored by the manufacturer, and in 15 the potential conflict of interest was unclear.Comparisons made within each test were more reliable than those between tests, as they were mostly based on direct comparisons within each study.The Nerve Fibre Indicator yielded the highest accuracy (estimate, 95% confidence interval (CI)) among GDx parameters (sensitivity: 0.67, 0.55 to 0.77; specificity: 0.94, 0.92 to 0.95). For HRT measures, the Vertical Cup/Disc (C/D) ratio (sensitivity: 0.72, 0.60 to 0.68; specificity: 0.94, 0.92 to 0.95) was no different from other parameters. With OCT, the accuracy of average RNFL retinal thickness was similar to the inferior sector (0.72, 0.65 to 0.77; specificity: 0.93, 0.92 to 0.95) and, in different studies, to the vertical C/D ratio.Comparing the parameters with the highest diagnostic odds ratio (DOR) for each device in a single HSROC model, the performance of GDx, HRT and OCT was remarkably similar. At a sensitivity of 0.70 and a high specificity close to 0.95 as in most of these studies, in 1000 people referred by primary eye care, of whom 200 have manifest glaucoma, such as in those who have already undergone some functional or anatomic testing by optometrists, the best measures of GDx, HRT and OCT would miss about 60 cases out of the 200 patients with glaucoma, and would incorrectly refer 50 out of 800 patients without glaucoma. If prevalence were 5%, e.g. such as in people referred only because of family history of glaucoma, the corresponding figures would be 15 patients missed out of 50 with manifest glaucoma, avoiding referral of about 890 out of 950 non-glaucomatous people.Heterogeneity investigations found that sensitivity estimate was higher for studies with more severe glaucoma, expressed as worse average mean deviation (MD): 0.79 (0.74 to 0.83) for MD < -6 db versus 0.64 (0.60 to 0.69) for MD >= -6 db, at a similar summary specificity (0.93, 95% CI 0.92 to 0.94 and, respectively, 0.94; 95% CI 0.93 to 0.95; P < 0.0001 for the difference in relative DOR). AUTHORS' CONCLUSIONS: The accuracy of imaging tests for detecting manifest glaucoma was variable across studies, but overall similar for different devices. Accuracy may have been overestimated due to the case-control design, which is a serious limitation of the current evidence base.We recommend that further diagnostic accuracy studies are carried out on patients selected consecutively at a defined step of the clinical pathway, providing a description of risk factors leading to referral and bearing in mind the consequences of false positives and false negatives in the setting in which the diagnostic question is made. Future research should report accuracy for each threshold of these continuous measures, or publish raw data. PMID- 26618335 TI - Vagal nerve activity predicts overall survival in metastatic pancreatic cancer, mediated by inflammation. AB - Recent research findings suggest neuro-modulation of tumors. Finding new modifiable prognostic factors paves the way for additional treatments, which is crucial in advanced cancer, particularly pancreatic cancer. This study examined the relationship between vagal nerve activity, indexed by heart rate variability (HRV), and overall survival (OS) in patients (N=272) with advanced pancreatic cancer. A "historical prospective" design was employed, where vagal activity and other confounders were retroactively obtained from medical charts at diagnosis, and subsequent OS was examined. HRV was obtained from 10 sec ECGs near diagnosis. Levels of C-reactive protein (CRP) were measured as an inflammatory marker. OS and survival date were obtained from medical charts and the Belgian national registry. Patients with high HRV (>20 msec) survived on average more than double the days (133.5) than those with low HRV (64.0). In a multivariate cox regression, higher initial HRV was significantly correlated with lower risk of death, independent of confounders including age and cancer treatments. This relationship was statistically mediated (accounted for) by CRP levels. Importantly, in patients who lived up to one month from diagnosis only, HRV was unrelated to CRP, while in patients surviving longer, HRV was significantly inversely related to CRP (r=-0.20, p<0.05). These results are in line with possible vagal nerve protection in a fatal cancer, and propose that the mechanism may involve neuroimmuno-modulation. Future studies must test whether vagal nerve activation may help patients with advanced cancers. PMID- 26618336 TI - Computer-aided Therapeutics in Treating Autoimmune Encephalitis--Reply. PMID- 26618339 TI - Why a Special Issue on Chronic Lymphocytic Leukemia? PMID- 26618338 TI - The high incidence of vascular thromboembolic events in patients with metastatic or unresectable urothelial cancer treated with platinum chemotherapy agents. AB - BACKGROUND: The current study compared the incidence of vascular thromboembolic events (VTEs) in patients with metastatic or unresectable urothelial carcinoma (UC) who were treated with gemcitabine and carboplatin (GCb); gemcitabine, carboplatin, and bevacizumab (GCbBev); or gemcitabine and cisplatin (GCis). METHODS: Patients with UC who were treated with GCbBev on protocol were analyzed prospectively and 2 contemporary control cohorts receiving GCb or GCis were evaluated retrospectively. VTE was defined as either venous or arterial (myocardial infarctions or cerebral vascular accidents) thrombosis. VTEs were considered to be related to treatment if they occurred during treatment or within 4 weeks of the completion of treatment. Associations with chemotherapy regimen were tested using either the Fisher exact test or Kruskal-Wallis test. Clinical factors associated with VTEs were analyzed using conditional logistic regression stratified by treatment regimen. RESULTS: Among 198 patients, VTEs occurred in 13 of 51 patients treated with GCbBev (26%), 22 of 92 patients treated with GCb (24%), and 8 of 55 patients treated with GCis (15%). Patient characteristics were significantly different between the treatment cohorts in terms of age, prior cystectomy, tumor location near pelvic vessels, Khorana risk group, and receipt of antiplatelet therapy. The incidence of VTE and type of VTE (arterial vs venous) did not differ by type of chemotherapy. Prior cystectomy was associated with an increased risk of VTE (odds ratio, 2.2; 95% confidence interval, 1.0-4.9 [P = .047]). CONCLUSIONS: The incidence of VTE in Cis-treated patients was similar to prior reports. However, the VTE rate in Cb-treated patients was > 20%, a figure not previously defined in patients with UC and higher than expected. This high incidence of both Cis-related and Cb-related VTEs warrants greater awareness by treating physicians and deserves further study. Cancer 2016;122:712 721. (c) 2015 American Cancer Society. PMID- 26618340 TI - Chronic Lymphocytic Leukemia in the Elderly: Epidemiology and Proposed Patient Related Approach. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) occurs primarily in the elderly, and the majority of deaths attributable to CLL occur in persons 65 years of age or older. The greater number of comorbidities and reduced functionality associated with aging have also made successful treatment of CLL in the elderly more difficult. METHODS: The authors reviewed current epidemiology and guidelines for treatment of CLL, as well as recently approved therapies and studies of physiological aging. RESULTS: Determination of physiological age and performance of a thorough geriatric assessment play critical roles in the selection of optimal therapeutic approaches for older patients diagnosed with CLL. CONCLUSION: Older age, expressed via a frailty index, is a prognostic factor for poorer outcome in patients with CLL. However, several novel treatment options may result in reduced mortality and lessened treatment-related toxicity in older CLL patients. PMID- 26618341 TI - Chronic Lymphocytic Leukemia in the Elderly, Which Investigations Are Necessary: A Map for the Practicing Oncologist. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL), the most prevalent leukemia in the Western world, is predominantly a disease of older individuals who also have other comorbidities as well as declining organ and bone marrow reserve. Although chemoimmunotherapy is the frontline therapy for fit CLL patients who can tolerate the therapy, many elderly patients cannot tolerate such intense therapy. METHODS: The authors first reviewed the most recent findings concerning CLL cytogenetics, molecular biology, and prognostic models. They then surveyed recent and ongoing trials of novel CLL agents and strategies, with a focus on those most relevant to elderly patients. RESULTS: Novel therapies, revised staging procedures, and careful assessment of individual patients' frailty and functional status will allow clinicians to provide optimal care management for older CLL patients. CONCLUSION: Therapy for the elderly CLL population must be tailored to each patient's fitness level and comorbid conditions, with special consideration for the potential quality-of-life impacts of various treatment recommendations. PMID- 26618342 TI - Management of Chronic Lymphocytic Leukemia in the Elderly. AB - BACKGROUND: Because chronic lymphocytic leukemia (CLL) typically follows an indolent course, many patients do not need to initiate therapy until they reach a relatively advanced age, when frailty and reduced organ function can make some of the standard treatments difficult to tolerate and less effective. However, recent advances in the understanding of CLL biology and the approval of agents in novel treatment classes have offered significant advances in the management of the disease. METHODS: The author reviewed current treatment goals in CLL management, including issues surrounding complete remission (CR) and minimal residual disease (MRD); the findings of trials of treatments from novel drug classes, primarily kinase inhibitors and monoclonal antibodies; and current strategies for use of standard and novel therapies for treatment of individuals diagnosed with CLL, particularly elderly patients. RESULTS: Several agents and regimens featuring improved clinical outcomes and tolerability are now available or in advanced development for the management of CLL patients, including the elderly and those with high-risk disease. These include ibrutinib, idelalisib plus rituximab, and obinutuzumab plus chlorambucil. CONCLUSION: The availability of Bruton's tyrosine kinase inhibitors and phosphatidylinositol 3-kinase inhibitors and other novel therapies will allow elderly CLL patients to receive more efficacious treatment with greater tolerability than available with traditional approaches for management of the disease. PMID- 26618345 TI - Temperature-Dependent Exciton and Trap-Related Photoluminescence of CdTe Quantum Dots Embedded in a NaCl Matrix: Implication in Thermometry. AB - Temperature-dependent optical studies of semiconductor quantum dots (QDs) are fundamentally important for a variety of sensing and imaging applications. The steady-state and time-resolved photoluminescence properties of CdTe QDs in the size range from 2.3 to 3.1 nm embedded into a protective matrix of NaCl are studied as a function of temperature from 80 to 360 K. The temperature coefficient is found to be strongly dependent on QD size, with the highest sensitivity obtained for the smallest size of QDs. The emission from solid-state CdTe QD-based powders is maintained with high color purity over a wide range of temperatures. Photoluminescence lifetime data suggest that temperature dependence of the intrinsic radiative lifetime in CdTe QDs is rather weak, and it is mostly the temperature-dependent nonradiative decay of CdTe QDs which is responsible for the thermal quenching of photoluminescence intensity. By virtue of the temperature-dependent photoluminescence behavior, high color purity, photostability, and high photoluminescence quantum yield (26%-37% in the solid state), CdTe QDs embedded in NaCl matrices are useful solid-state probes for thermal imaging and sensing over a wide range of temperatures within a number of detection schemes and outstanding sensitivity, such as luminescence thermochromic imaging, ratiometric luminescence, and luminescence lifetime thermal sensing. PMID- 26618344 TI - Regulators of genetic risk of breast cancer identified by integrative network analysis. AB - Genetic risk for breast cancer is conferred by a combination of multiple variants of small effect. To better understand how risk loci might combine, we examined whether risk-associated genes share regulatory mechanisms. We created a breast cancer gene regulatory network comprising transcription factors and groups of putative target genes (regulons) and asked whether specific regulons are enriched for genes associated with risk loci via expression quantitative trait loci (eQTLs). We identified 36 overlapping regulons that were enriched for risk loci and formed a distinct cluster within the network, suggesting shared biology. The risk transcription factors driving these regulons are frequently mutated in cancer and lie in two opposing subgroups, which relate to estrogen receptor (ER)(+) luminal A or luminal B and ER(-) basal-like cancers and to different luminal epithelial cell populations in the adult mammary gland. Our network approach provides a foundation for determining the regulatory circuits governing breast cancer, to identify targets for intervention, and is transferable to other disease settings. PMID- 26618343 TI - Integrated genomic characterization of IDH1-mutant glioma malignant progression. AB - Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach. PMID- 26618347 TI - Correction: Effects of the Staphylococcus aureus and Staphylococcus epidermidis Secretomes Isolated from the Skin Microbiota of Atopic Children on CD4+ T Cell Activation. PMID- 26618346 TI - Use of Pulmonary Artery Catheterization in US Patients With Heart Failure, 2001 2012. PMID- 26618348 TI - Organization and Chromosomal Distribution of Histone Genes and Transposable Rex Elements in the Genome of Astyanax bockmanni (Teleostei, Characiformes). AB - An important feature of eukaryotic organisms is the number of different repetitive DNA sequences in their genome, a feature not observed in prokaryotes. These sequences are considered to be important components for understanding evolutionary mechanisms and the karyotypic differentiation processes. Thus, we aimed to physically map the histone genes and transposable elements of the Rex family in 6 fish populations of Astyanax bockmanni. FISH results using a histone H1 gene probe showed fluorescent clusters in 2 chromosome pairs in all 6 samples analyzed. In contrast, FISH with a histone H3 probe showed conspicuous blocks in 4 chromosomes in 5 of the 6 populations analyzed. The sixth population revealed 7 chromosomes marked with this probe. Probes for the transposable elements Rex1 and Rex6 showed small sites dispersed on most chromosomes of the 6 populations, and the Rex3 element is located in a big block concentrated in only 1 acrocentric chromosome of 2 populations. As for the other populations, a Rex3 probe showed large blocks in more than 1 chromosome. Fish from Alambari and Campo Novo Stream have Rex3 elements dispersed along most of the chromosomes. Additionally, the conspicuous signals of Rex1, Rex3, and Rex6 were identified in the acrocentric B microchromosome of A. bockmanni found only in individuals of the Alambari River. Thus, we believe that different mechanisms drive the spread of repetitive sequences among the populations analyzed, which appear to be organized differently in the genome of A. bockmanni. The presence of transposable elements in the B chromosome also suggests that these sequences could play a role in the origin and maintenance of the supernumerary element in the genome of this species. PMID- 26618349 TI - Some Aspects of the Renin-Angiotensin-System in Hemodialysis Patients. AB - Understanding of the renin-angiotensin system (RAS) has changed remarkably over the past decade. Renin, angiotensin converting enzyme (ACE), angiotensin II (Ang II), and Ang II receptors are the main components of the RAS. Recent studies identified the ACE2/Ang 1-7/Mas receptor axis, which counter-regulates the classical RAS. Many studies have examined the effects of the RAS on the progression of cardiovascular disease and chronic kidney disease (CKD). In addition, many studies have documented increased levels of ACE in hemodialysis (HD) patients, raising concerns about the negative effects of RAS activation on the progression of renal disease. Elevated ACE increases the level of Ang II, leading to vasoconstriction and cell proliferation. Ang II stimulation of the sympathetic system leads to renal and cardiovascular complications that are secondary to uncontrolled hypertension. This review provides an overview of the RAS, evaluates new research on the role of ACE2 in dialysis, and reviews the evidence for potentially better treatments for patients undergoing HD. Further understanding of the role of ACE and ACE2 in HD patients may aid the development of targeted therapies that slow the progression of CKD and cardiovascular disease. PMID- 26618350 TI - Noncutaneous Melanomas: A Single-Center Analysis. AB - BACKGROUND: The optimal treatment algorithm for noncutaneous melanomas must yet be established. OBJECTIVE: To compare systemic treatment-relevant mutational status, metastatic pattern and response to systemic treatment in noncutaneous melanoma. METHODS: Retrospective single-center study analyzing 64 noncutaneous melanoma patients treated between January 2006 and September 2013. RESULTS: c-KIT mutations were found exclusively in vulvovaginal melanoma (4/7). Overall status for NRAS and BRAF mutations was low (1/7 and 0/21 detected mutations, respectively). Seven out of 7 vulvovaginal and 6/13 sinonasal melanomas first metastasized to lymph nodes, whereas 18/22 ocular melanomas first metastasized to the liver. Response to systemic treatment in vulvovaginal melanomas was best for imatinib with a disease control rate of 3/3 and overall for ipilimumab with a disease control rate of 3/10. Sorafenib was associated with adverse drug reactions (6/13) and poor results. CONCLUSION: Noncutaneous melanomas show few tumor-signaling pathway mutations and distinct metastasization patterns. Immunotherapy induces response rates in mucosal melanoma similar to those in cutaneous melanoma. PMID- 26618351 TI - Mapping Soluble Guanylyl Cyclase and Protein Disulfide Isomerase Regions of Interaction. AB - Soluble guanylyl cyclase (sGC) is a heterodimeric nitric oxide (NO) receptor that produces cyclic GMP. This signaling mechanism is a key component in the cardiovascular system. NO binds to heme in the beta subunit and stimulates the catalytic conversion of GTP to cGMP several hundred fold. Several endogenous factors have been identified that modulate sGC function in vitro and in vivo. In previous work, we determined that protein disulfide isomerase (PDI) interacts with sGC in a redox-dependent manner in vitro and that PDI inhibited NO stimulated activity in cells. To our knowledge, this was the first report of a physical interaction between sGC and a thiol-redox protein. To characterize this interaction between sGC and PDI, we first identified peptide linkages between sGC and PDI, using a lysine cross-linking reagent and recently developed mass spectrometry analysis. Together with Flag-immunoprecipitation using sGC domain deletions, wild-type (WT) and mutated PDI, regions of sGC involved in this interaction were identified. The observed data were further explored with computational modeling to gain insight into the interaction mechanism between sGC and oxidized PDI. Our results indicate that PDI interacts preferentially with the catalytic domain of sGC, thus providing a mechanism for PDI inhibition of sGC. A model in which PDI interacts with either the alpha or the beta catalytic domain is proposed. PMID- 26618352 TI - The Critical Periphery in the Growth of Social Protests. AB - Social media have provided instrumental means of communication in many recent political protests. The efficiency of online networks in disseminating timely information has been praised by many commentators; at the same time, users are often derided as "slacktivists" because of the shallow commitment involved in clicking a forwarding button. Here we consider the role of these peripheral online participants, the immense majority of users who surround the small epicenter of protests, representing layers of diminishing online activity around the committed minority. We analyze three datasets tracking protest communication in different languages and political contexts through the social media platform Twitter and employ a network decomposition technique to examine their hierarchical structure. We provide consistent evidence that peripheral participants are critical in increasing the reach of protest messages and generating online content at levels that are comparable to core participants. Although committed minorities may constitute the heart of protest movements, our results suggest that their success in maximizing the number of online citizens exposed to protest messages depends, at least in part, on activating the critical periphery. Peripheral users are less active on a per capita basis, but their power lies in their numbers: their aggregate contribution to the spread of protest messages is comparable in magnitude to that of core participants. An analysis of two other datasets unrelated to mass protests strengthens our interpretation that core-periphery dynamics are characteristically important in the context of collective action events. Theoretical models of diffusion in social networks would benefit from increased attention to the role of peripheral nodes in the propagation of information and behavior. PMID- 26618353 TI - The Development of a Strategic Prioritisation Method for Green Supply Chain Initiatives. AB - To maintain a competitive position, companies are increasingly required to integrate their proactive environmental strategies into their business strategies. The shift from reactive and compliance-based to proactive and strategic environmental management has driven companies to consider the strategic factors while identifying the areas in which they should focus their green initiatives. In previous studies little attention was given to providing the managers with a basis from which they could strategically prioritise these green initiatives across their companies' supply chains. Considering this lacuna in the literature, we present a decision-making method for prioritising green supply chain initiatives aligned with the preferred green strategies alternatives for the manufacturing companies. To develop this method, the study considered a position between determinism and the voluntarism orientation of environmental management involving both external pressures and internal competitive drivers and key resources as decision factors. This decision-making method was developed using the analytic network process (ANP) technique. The elements of the decision model were derived from the literature. The causal relationships among the multiple decision variables were validated based on the results of structural equation modelling (SEM) using a dataset collected from a survey of the ISO 14001 certified manufacturers in Malaysia. A portion of the relative weights required for computation in ANP was also calculated using the SEM results. A case study is presented to demonstrate the applicability of the method. PMID- 26618354 TI - Macrofaunal Patterns in and around du Couedic and Bonney Submarine Canyons, South Australia. AB - Two South Australian canyons, one shelf-incising (du Couedic) and one slope limited (Bonney) were compared for macrofaunal patterns on the shelf and slope that spanned three water masses. It was hypothesized that community structure would (H1) significantly differ by water mass, (H2) show significant regional differences and (H3) differ significantly between interior and exterior of each canyon. Five hundred and thirty-one species of macrofauna >= 1 mm were captured at 27 stations situated in depth stratified transects inside and outside the canyons from 100 to 1500 m depth. The macrofauna showed a positive relationship to depth in abundance, biomass, species richness and community composition while taxonomic distinctness and evenness remained high at all depths. Biotic variation on the shelf was best defined by variation in bottom water primary production while sediment characteristics and bottom water oxygen, temperature and nutrients defined biotic variation at greater depth. Community structure differed significantly (p<0.01) among the three water masses (shelf-flowing South Australian current, upper slope Flinders current and lower slope Antarctic Intermediate Water) (H1). Although community differences between the du Couedic and Bonney regions were marginally above significance at p = 0.05 (H2), over half of the species captured were unique to each region. This supports the evidence from fish and megafaunal distributions that the du Couedic and Bonney areas are in different bioregions. Overall, the canyon interiors were not significantly different in community composition from the exterior (H3). However, both canyons had higher abundance and/or biomass, increased species dominance, different species composition and coarser sediments near the canyon heads compared to outside the canyons at the same depth (500 m), suggestive of heightened currents within the canyons that influence community composition there. At 1000-1500 m, the canyon interiors were depauperate, typical of V-shaped canyons elsewhere. The large number of species captured, given the relatively low sampling effort and focus on the larger macrofauna, support previous studies that identify the South Australian coast as a high biodiversity area. PMID- 26618355 TI - The QTL within the H2 Complex Involved in the Control of Tuberculosis Infection in Mice Is the Classical Class II H2-Ab1 Gene. AB - The level of susceptibility to tuberculosis (TB) infection depends upon allelic variations in numerous interacting genes. In our mouse model system, the whole genome quantitative trait loci (QTLs) scan revealed three QTLs involved in TB control on chromosomes 3, 9, and in the vicinity of the H2 complex on chromosome 17. For the present study, we have established a panel of new congenic, MHC recombinant mouse strains bearing differential small segments of chromosome 17 transferred from the TB-susceptible I/St (H2j) strain onto the genetic background of TB-resistant C57BL/6 (B6) mice (H2b). This allowed narrowing the QTL interval to 17Ch: 33, 77-34, 34 Mb, containing 36 protein-encoding genes. Cloning and sequencing of the H2j allelic variants of these genes demonstrated profound polymorphic variations compare to the H2b haplotype. In two recombinant strains, B6.I-249.1.15.100 and B6.I-249.1.15.139, recombination breakpoints occurred in different sites of the H2-Abeta 1 gene (beta-chain of the Class II heterodimer H2 A), providing polymorphic variations in the domain beta1 of the Abeta-chain. These variations were sufficient to produce different TB-relevant phenotypes: the more susceptible B6.I-249.1.15.100 strain demonstrated shorter survival time, more rapid body weight loss, higher mycobacterial loads in the lungs and more severe lung histopathology compared to the more resistant B6.I-249.1.15.139 strain. CD4+ T cells recognized mycobacterial antigens exclusively in the context of the H2-A Class II molecule, and the level of IFN-gamma-producing CD4+ T cells in the lungs was significantly higher in the resistant strain. Thus, we directly demonstrated for the first time that the classical H2- Ab1 Class II gene is involved in TB control. Molecular modeling of the H2-Aj product predicts that amino acid (AA) substitutions in the Abeta-chain modify the motif of the peptide MHC binding groove. Moreover, unique AA substitutions in both alpha- and beta chains of the H2-Aj molecule might affect its interactions with the T-cell receptor (TCR). PMID- 26618356 TI - Substrate-Induced Dimerization of Engineered Monomeric Variants of Triosephosphate Isomerase from Trichomonas vaginalis. AB - The dimeric nature of triosephosphate isomerases (TIMs) is maintained by an extensive surface area interface of more than 1600 A2. TIMs from Trichomonas vaginalis (TvTIM) are held in their dimeric state by two mechanisms: a ball and socket interaction of residue 45 of one subunit that fits into the hydrophobic pocket of the complementary subunit and by swapping of loop 3 between subunits. TvTIMs differ from other TIMs in their unfolding energetics. In TvTIMs the energy necessary to unfold a monomer is greater than the energy necessary to dissociate the dimer. Herein we found that the character of residue I45 controls the dimer monomer equilibrium in TvTIMs. Unfolding experiments employing monomeric and dimeric mutants led us to conclude that dimeric TvTIMs unfold following a four state model denaturation process whereas monomeric TvTIMs follow a three state model. In contrast to other monomeric TIMs, monomeric variants of TvTIM1 are stable and unexpectedly one of them (I45A) is only 29-fold less active than wild type TvTIM1. The high enzymatic activity of monomeric TvTIMs contrast with the marginal catalytic activity of diverse monomeric TIMs variants. The stability of the monomeric variants of TvTIM1 and the use of cross-linking and analytical ultracentrifugation experiments permit us to understand the differences between the catalytic activities of TvTIMs and other marginally active monomeric TIMs. As TvTIMs do not unfold upon dimer dissociation, herein we found that the high enzymatic activity of monomeric TvTIM variants is explained by the formation of catalytic dimeric competent species assisted by substrate binding. PMID- 26618357 TI - Outcomes and Risk Factors for Mortality among Patients Treated with Carbapenems for Klebsiella spp. Bacteremia. AB - BACKGROUND: Extensive dissemination of carbapenemase-producing Enterobacteriaceae has led to increased resistance among Klebsiella species. Carbapenems are used as a last resort against resistant pathogens, but carbapenemase production can lead to therapy failure. Identification of risk factors for mortality and assessment of current susceptibility breakpoints are valuable for improving patient outcomes. AIM: The objective of this study was to evaluate outcomes and risk factors for mortality among patients treated with carbapenems for Klebsiella spp. bacteremia. METHODS: Patients hospitalized between 2006 and 2012 with blood cultures positive for Klebsiella spp. who received >= 48 hours of carbapenem treatment within 72 hours of positive culture were included in this retrospective study. Patient data were retrieved from electronic medical records. Multivariate logistic regression was used to identify risk factors for 30-day hospital mortality. RESULTS: One hundred seven patients were included. The mean patient age was 61.5 years and the median APACHE II score was 13 +/- 6.2. Overall, 30-day hospital mortality was 9.3%. After adjusting for confounding variables, 30-day mortality was associated with baseline APACHE II score (OR, 1.17; 95% CI, 1.01 1.35; P = 0.03), length of stay prior to index culture (OR, 1.03; 95% CI, 1.00 1.06; P = 0.04), and carbapenem non-susceptible (imipenem or meropenem MIC > 1 mg/L) infection (OR, 9.08; 95% CI, 1.17-70.51; P = 0.04). CONCLUSIONS: Baseline severity of illness and length of stay prior to culture were associated with 30 day mortality and should be considered when treating patients with Klebsiella bacteremia. These data support the change in carbapenem breakpoints for Klebsiella species. PMID- 26618358 TI - Uric Acid Levels Can Predict Metabolic Syndrome and Hypertension in Adolescents: A 10-Year Longitudinal Study. AB - The relationships between uric acid and chronic disease risk factors such as metabolic syndrome, type 2 diabetes mellitus, and hypertension have been studied in adults. However, whether these relationships exist in adolescents is unknown. We randomly selected 8,005 subjects who were between 10 to 15 years old at baseline. Measurements of uric acid were used to predict the future occurrence of metabolic syndrome, hypertension, and type 2 diabetes. In total, 5,748 adolescents were enrolled and followed for a median of 7.2 years. Using cutoff points of uric acid for males and females (7.3 and 6.2 mg/dl, respectively), a high level of uric acid was either the second or third best predictor for hypertension in both genders (hazard ratio: 2.920 for males, 5.222 for females; p<0.05). However, uric acid levels failed to predict type 2 diabetes mellitus, and only predicted metabolic syndrome in males (hazard ratio: 1.658; p<0.05). The same results were found in multivariate adjusted analysis. In conclusion, a high level of uric acid indicated a higher likelihood of developing hypertension in both genders and metabolic syndrome in males after 10 years of follow-up. However, uric acid levels did not affect the occurrence of type 2 diabetes in both genders. PMID- 26618360 TI - Heterogeneity of Regional Brain Atrophy Patterns Associated with Distinct Progression Rates in Alzheimer's Disease. AB - We aimed to identify and characterize subtypes of Alzheimer's disease (AD) exhibiting different patterns of regional brain atrophy on MRI using age- and gender-specific norms of regional brain volumes. AD subjects included in the Alzheimer's Disease Neuroimaging Initiative study were classified into subtypes based on standardized values (Z-scores) of hippocampal and regional cortical volumes on MRI with reference to age- and gender-specific norms obtained from 222 cognitively normal (CN) subjects. Baseline and longitudinal changes of clinical characteristics over 2 years were compared across subtypes. Whole-brain-level gray matter (GM) atrophy pattern using voxel-based morphometry (VBM) and cerebrospinal fluid (CSF) biomarkers of the subtypes were also investigated. Of 163 AD subjects, 58.9% were classified as the "both impaired" subtype with the typical hippocampal and cortical atrophy pattern, whereas 41.1% were classified as the subtypes with atypical atrophy patterns: "hippocampal atrophy only" (19.0%), "cortical atrophy only" (11.7%), and "both spared" (10.4%). Voxel-based morphometric analysis demonstrated whole-brain-level differences in overall GM atrophy across the subtypes. These subtypes showed different progression rates over 2 years; and all subtypes had significantly lower CSF amyloid-beta 1-42 levels compared to CN. In conclusion, we identified four AD subtypes exhibiting heterogeneous atrophy patterns on MRI with different progression rates after controlling the effects of aging and gender on atrophy with normative information. CSF biomarker analysis suggests the presence of Abeta neuropathology irrespective of subtypes. Such heterogeneity of MRI-based neuronal injury biomarker and related heterogeneous progression patterns should be considered in clinical trials and practice with AD patients. PMID- 26618361 TI - Seeing the Whole Elephant: Imaging Flow Cytometry Reveals Extensive Morphological Diversity within Blastocystis Isolates. AB - Blastocystis is a common protist isolated in humans and many animals. The parasite is a species complex composed of 19 subtypes, 9 of which have been found in humans. There are biological and molecular differences between Blastocystis subtypes although microscopy alone is unable to distinguish between these subtypes. Blastocystis isolates also display various morphological forms. Several of these forms, however, have not been properly evaluated on whether or not these play significant functions in the organism's biology. In this study, we used imaging flow cytometry to analyze morphological features of Blastocystis isolates representing 3 subtypes (ST1, ST4 and ST7). We also employed fluorescence dyes to discover new cellular features. The profiles from each of the subtypes exhibit considerable differences with the others in terms of shape, size and granularity. We confirmed that the classical vacuolar form comprises the majority in all three subtypes. We have also evaluated other morphotypes on whether these represent distinct life stages in the parasite. Irregularly-shaped cells were identified but all of them were found to be dying cells in one isolate. Granular forms were present as a continuum in both viable and non-viable populations, with non-viable forms displaying higher granularity. By analyzing the images, rare morphotypes such as multinucleated cells could be easily observed and quantified. These cells had low granularity and lower DNA content. Small structures containing nucleic acid were also identified. We discuss the possible biological implications of these unusual forms. PMID- 26618359 TI - Problematic Exercise in Anorexia Nervosa: Testing Potential Risk Factors against Different Definitions. AB - "Hyperactivity" has a wide prevalence range of 31% to 80% in the anorexia nervosa literature that could be partly due to the plethora of definitions provided by researchers in this field. The purpose of this study was two-fold: 1) To assess the variance across prevalence rates of problematic exercise encountered in patients with anorexia nervosa, in relation to seven different definitions found in the literature. 2) To examine how core eating disorder symptoms and the dimensions of emotional profile are associated with these different definitions and the impact of these definitions on the assessment of patients' quality of life. Exercise was evaluated in terms of duration, intensity, type and compulsion using a semi-structured questionnaire administered to 180 women suffering from severe anorexia nervosa. Seven different definitions of problematic exercise were identified in the literature: three entailing a single dimension of problematic exercise (duration, compulsion or intensity) and four combining these different dimensions. Emotional profile scores, obsessive-compulsive symptoms, eating disorder symptomatology, worries and concerns about body shape, self-esteem and quality of life were assessed using several established questionnaires. The prevalence of problematic exercise varied considerably from, 5% to 54%, depending on the number of criteria used for its definition. The type and level of eating disorder symptomatology was found to be associated with several definitions of problematic exercise. Surprisingly, a better self-reported quality of life was found among problematic exercisers compared to non-problematic exercisers in three of the definitions. The different definitions of problematic exercise explain the broad prevalence ranges and the conflicting associations generally reported in the literature between problematic exercise and eating disorder related psychological parameters. There is an urgent need for a valid consensus on the definition of problematic exercise in anorexia nervosa. This will support the development of further research on the etiology and treatment of problematic exercise. PMID- 26618362 TI - 3D Printing Bioceramic Porous Scaffolds with Good Mechanical Property and Cell Affinity. AB - Artificial bone grafting is widely used in current orthopedic surgery for bone defect problems. Unfortunately, surgeons remain unsatisfied with the current commercially available products. One of the major complaints is that these products cannot provide sufficient mechanical strength to support the human skeletal structure. In this study, we aimed to develop a bone scaffold with better mechanical property and good cell affinity by 3D printing (3DP) techniques. A self-developed 3D printer with laser-aided gelling (LAG) process was used to fabricate bioceramic scaffolds with inter-porous structures. To improve the mechanical property of the bioceramic parts after heating, CaCO3 was added to the silica ceramic slurry. CaCO3 was blended into a homogenous SiO2-sol dispersion at weight ratios varying from 0/100 to 5/95 to 9/91 (w/w). Bi component CaCO3/SiO2-sol was prepared as a biocomposite for the 3DP scaffold. The well-mixed biocomposite was used to fabricate the bioceramic green part using the LAG method. The varied scaffolds were sintered at different temperatures ranging from 900 to 1500 degrees C, and the mechanical property was subsequently analyzed. The scaffolds showed good property with the composite ratio of 5:95 CaCO3:SiO2 at a sintering temperature of 1300 degrees C. The compressive strength was 47 MPa, and the porosity was 34%. The topography of the sintered 3DP bioceramic scaffold was examined by SEM, EDS and XRD. The silica bioceramic presented no cytotoxicity and good MG-63 osteoblast-like cell affinity, demonstrating good biocompatibility. Therefore, the new silica biocomposite is viable for fabricating 3DP bone bioceramics with improved mechanical property and good cell affinity. PMID- 26618363 TI - Do patient or provider characteristics impact management of diabetes? AB - OBJECTIVES: Patients with diabetes often exceed desired glycated hemoglobin (A1C) levels for months prior to medication adjustments. To determine if provider and patient characteristics predict glycemic control and treatment intensification. STUDY DESIGN: Observational retrospective cohort study using electronic medical record data. METHODS: We studied 149 Kaiser Permanente Northwest primary care providers of 14,430 patients with diabetes, of whom 5823 (40.4%) were in optimal control (all A1Cs < 7%) and 2446 (17%) were in poor control (at least 1 A1C > 9%) in 2011. We also identified a subset of 107 primary care providers of 912 patients with diabetes who were initially in optimal control (A1C < 7%) but had a subsequent A1C > 7.5% from 2010 to 2011. We used hierarchical linear modeling to assess both patient and provider characteristics as predictors of glycemic control and treatment intensification after incident hyperglycemia. RESULTS: Patient characteristics associated with optimal control included older age, lower baseline A1C, shorter diabetes duration, and not using insulin (P < .001 for all). The inverse of these variables predicted poor control. No provider characteristics were associated with glycemic control or intensification. Older patients with a greater change in A1C were more likely to have therapy intensified after loss of glycemic control. CONCLUSIONS: Patient, but not provider characteristics, predicted glycemic control and therapy intensification. Improving systems of care such as disease management services may be a better use of resources than focusing on individual providers. PMID- 26618364 TI - The utility of cost discussions between patients with cancer and oncologists. AB - OBJECTIVES: Patients with cancer can experience substantial financial burden. Little is known about patients' preferences for incorporating cost discussions into treatment decision making or about the ramifications of those discussions. The objective of this study was to determine patient preferences for and benefits of discussing costs with doctors. STUDY DESIGN: Cross-sectional, survey study. METHODS: We enrolled insured adults with solid tumors on anticancer therapy who were treated at a referral cancer center or an affiliated rural cancer clinic. Patients were surveyed at enrollment and again 3 months later about cost discussions with doctors, decision making, and financial burden. Medical records were abstracted for disease and treatment data. Logistic regression investigated characteristics associated with greater desire to discuss costs. RESULTS: Of 300 patients (86% response rate), 52% expressed some desire to discuss treatment related out-of-pocket costs with doctors and 51% wanted their doctor to take costs into account to some degree when making treatment decisions. However, only 19% had talked to their doctor about costs. Of those, 57% reported lower out-of pocket costs as a result of cost discussions. In multivariable logistic regression, higher subjective financial distress was associated with greater likelihood to desire cost discussions (odds ratio [OR], 1.22; 95% CI, 1.10-1.36). Nonwhite race was associated with lower likelihood to desire cost discussions (OR, 0.53; 95% CI, 0.30-0.95). CONCLUSIONS: Patients with cancer varied in their desire to discuss costs with doctors, but most who discussed costs believed the conversations helped reduce their expenses. Patient-physician cost communication might reduce out-of-pocket costs even in oncology where treatment options are limited. PMID- 26618365 TI - Innovative approach to patient-centered care coordination in primary care practices. AB - OBJECTIVES: Although care coordination is an essential component of the patient centered medical home structure, current case manager models have limited usefulness to population health because they typically serve a small group of patients defined based on disease or utilization. Our objective was to support our health system's population health by implementing and evaluating a program that embedded nonlicensed coordinators within our primary care practices to support physicians in executing care plans and communicating with patients. STUDY DESIGN: Matched case-control differences-in-differences. METHODS: Comprehensive care coordinators (CCC) were introduced into 14 of the system's 28 practice sites in 2 waves. After a structured training program, CCCs identified, engaged, and intervened among patients within the practice in conjunction with practice primary care providers. We counted and broadly coded CCC activities that were documented in the intervention database. We examined the impact of CCC intervention on emergency department (ED) utilization at the practice level using a negative binomial multivariate regression model controlling for age, gender, and medical complexity. RESULTS: CCCs touched 10,500 unique patients over a 1 year period. CCC interventions included execution of care (38%), coordination of transitions (32%), self-management support/link to community resources (15%), monitor and follow-up (10%), and patient assessment (1%). The CCC intervention group had a 20% greater reduction in its prepost ED visit rate compared with the control group (P < .0001). CONCLUSIONS: Our CCC intervention demonstrated a significant reduction in ED visits by focusing on the centrality of the primary care provider and practice. Our model may serve as a cost-effective and scalable alternative for care coordination in primary care. PMID- 26618366 TI - Private sector risk-sharing agreements in the United States: trends, barriers, and prospects. AB - OBJECTIVES: Risk-sharing agreements (RSAs) between drug manufacturers and payers link coverage and reimbursement to real-world performance or utilization of medical products. These arrangements have garnered considerable attention in recent years. However, greater use outside the United States raises questions as to why their use has been limited in the US private sector, and whether their use might increase in the evolving US healthcare system. STUDY DESIGN: To understand current trends, success factors, and challenges in the use of RSAs, we conducted a review of RSAs, interviews, and a survey to understand key stakeholders' experiences and expectations for RSAs in the US private sector. METHODS: Trends in the numbers of RSAs were assessed using a database of RSAs. We also conducted in-depth interviews with stakeholders from pharmaceutical companies, payer organizations, and industry experts in the United States and European Union. In addition, we administered an online survey with a broader audience to identify perceptions of the future of RSAs in the United States. RESULTS: Most manufacturers and payers expressed interest in RSAs and see potential value in their use. Due to numerous barriers associated with outcomes-based agreements, stakeholders were more optimistic about financial-based RSAs. In the US private sector, however, there remains considerable interest--improved data systems and shifting incentives (via health reform and accountable care organizations) may generate more action. CONCLUSIONS: In the US commercial payer markets, there is continued interest among some manufacturers and payers in outcomes-based RSAs. Despite continued discussion and activity, the number of new agreements is still small. PMID- 26618367 TI - Improving partnerships between health plans and medical groups. PMID- 26618368 TI - Building upon the strong foundation of national healthcare quality. PMID- 26618369 TI - Categorical prototyping: incorporating molecular mechanisms into 3D printing. AB - We apply the mathematical framework of category theory to articulate the precise relation between the structure and mechanics of a nanoscale system in a macroscopic domain. We maintain the chosen molecular mechanical properties from the nanoscale to the continuum scale. Therein we demonstrate a procedure to 'protoype a model', as category theory enables us to maintain certain information across disparate fields of study, distinct scales, or physical realizations. This process fits naturally with prototyping, as a prototype is not a complete product but rather a reduction to test a subset of properties. To illustrate this point, we use large-scale multi-material printing to examine the scaling of the elastic modulus of 2D carbon allotropes at the macroscale and validate our printed model using experimental testing. The resulting hand-held materials can be examined more readily, and yield insights beyond those available in the original digital representations. We demonstrate this concept by twisting the material, a test beyond the scope of the original model. The method developed can be extended to other methods of additive manufacturing. PMID- 26618370 TI - Fluorescence turn-on detection of mercury ions based on the controlled adsorption of a perylene probe onto the gold nanoparticles. AB - A novel fluorescence turn-on strategy based on Au nanoparticles and a perylene probe for the sensing of Hg(2+) ions has been developed. It was observed that a perylene probe could be adsorbed onto the surface of Au NPs through strong electrostatic and hydrophobic interactions. Its fluorescence was efficiently quenched by the Au nanoparticles. However, in the presence of Hg(2+) and NaBH4, Hg(2+) was reduced and an Au/Hg amalgam was formed on the surface of the Au nanoparticles. The perylene probe could hardly be adsorbed and quenched by the Au/Hg amalgam. A turn on fluorescence signal was therefore detected. The assay is quite sensitive, and 5 nM Hg(2+) could be easily detected. It is also very selective, a number of metal ions were tested and no noticeable interference was observed. The assay was also successfully applied for the determination of Hg(2+) in lake water samples. A simple, fast, inexpensive, highly sensitive and selective Hg(2+) sensing strategy is therefore established. PMID- 26618371 TI - The e-patient and medical students. AB - The recent publicity around the tragic case of Bronte Doyne has highlighted a pressing need in healthcare delivery: the need for doctors to know that their patients, "e-patients," know medicine. In turn, this requires our medical students to be trained in how best to utilise the potential of e-patients in healthcare delivery. "I can't begin to tell you how it feels to have to tell an oncologist they are wrong, it's a young person's cancer. I had to, I'm fed up of trusting them." - Bronte Doyne (Vize 2015). PMID- 26618372 TI - Remyelination strategies in multiple sclerosis: a critical reflection. AB - Remyelination is the natural repair mechanism of demyelination and can be a highly efficient process in multiple sclerosis. However, in the majority of lesions, this regenerative approach is incomplete or fails. It is believed that remyelination protects against progressive axonal damage and thus long-term disability in patients with multiple sclerosis. For this reason, therapeutic promotion of remyelination represents an attractive option for preventing disease progression. In this editorial we casts a critical eye over the most frequently used experimental settings which aim to uncover potential remyelination promoting drugs. This article reflects upon the personal opinion of the author who currently used animal models allow to assess the potency of pharmacological interventions to accelerate, but not to induce myelin repair. Furthermore, it is discussed how remyelination and neuroprotection might well be two separate entities. Thus, induction of remyelination does not necessarily prevent disease progression in multiple sclerosis patients. PMID- 26618373 TI - Chemoselective Transformation of Diarylethanones to Arylmethanoic Acids and Diarylmethanones and Mechanistic Insights. AB - The chemoselective transformation of diarylethanones via either aerobic oxidative cleavage to give arylmethanoic acids or tandem aerobic oxidation/benzilic acid rearrangement/decarboxylation to give diarylmethanones has been developed. The transformation is controllable and applicable to a broad spectrum of substrates and affords the desired products in good to excellent yields. Mechanistic insights with control reactions, (1)H NMR tracking, and single-crystal X-ray diffraction reveal a complex mechanistic network in which two common intermediates, alpha-ketohydroperoxide and diarylethanedione, and three plausible pathways are proposed and verified. These pathways are interlinked and can be switched reasonably by changing the reaction conditions. This method enables scalable synthesis and access to a number of valuable compounds, including vitamin B3, diphenic acid, and the nonsteroidal anti-inflammatory drug ketoprofen. The present protocol represents a step forward in exploiting complex mechanistic networks to control reaction pathways, achieving divergent syntheses from the same class of starting materials. PMID- 26618375 TI - [Farewell open letter to SEFH members]. PMID- 26618374 TI - Sampling and analysis method for measuring airborne coal dust mass in mixtures with limestone (rock) dust. AB - Airborne coal dust mass measurements in underground bituminous coal mines can be challenged by the presence of airborne limestone dust, which is an incombustible dust applied to prevent the propagation of dust explosions. To accurately measure the coal portion of this mixed airborne dust, the National Institute for Occupational Safety and Health (NIOSH) developed a sampling and analysis protocol that used a stainless steel cassette adapted with an isokinetic inlet and the low temperature ashing (LTA) analytical method. The Mine Safety and Health Administration (MSHA) routinely utilizes this LTA method to quantify the incombustible content of bulk dust samples collected from the roof, floor, and ribs of mining entries. The use of the stainless steel cassette with isokinetic inlet allowed NIOSH to adopt the LTA method for the analysis of airborne dust samples. Mixtures of known coal and limestone dust masses were prepared in the laboratory, loaded into the stainless steel cassettes, and analyzed to assess the accuracy of this method. Coal dust mass measurements differed from predicted values by an average of 0.5%, 0.2%, and 0.1% for samples containing 20%, 91%, and 95% limestone dust, respectively. The ability of this method to accurately quantify the laboratory samples confirmed the validity of this method and allowed NIOSH to successfully measure the coal fraction of airborne dust samples collected in an underground coal mine. PMID- 26618376 TI - Linezolid-induced haematological toxicity. AB - OBJECTIVE: to determine the incidence of linezolid-induced haematological toxicity and study the influence of renal clearance on its appearance and the preventive effect of pyridoxine. METHODS: a retrospective observational study was conducted. Every patient treated with linezolid in a university hospital during 6 months was included. Haematological toxicity was defined as a decrease of 25% in hemoglobin, of 25% in platelets and/or 50% in neutrophils from baseline. The incidence of haematological toxicity and the percentage decrease in analytical variables were compared in patients with and without renal failure (creatinine clearance lower than 50 mL/min), using the 30 mL/min threshold, and with or without pyridoxine; using Chi -Square and U Mann-Whitney tests, respectively. RESULTS: thirty-eight patients were evaluated. Sixteen (42%) presented haematological toxicity (2 due to a decrease in haemoglobin, 9 in platelets and 8 in neutrophils). Two patients (5%) discontinued treatment due to thrombocytopenia. Toxicity incidence was similar in patients with and without renal failure, 42% vs 42%, p = 0.970, with more or less than 30 ml/min, 67% vs 40%, p = 0.369, or with or without pyridoxine, 47.8% vs 33%, p = 0.376. Patients with renal failure had a significantly greater reduction in platelet count, p = 0.0185. CONCLUSION: forty-two percent of patients had haematological toxicity, being more frequent platelets and neutrophils reduction. This was not significantly higher in patients with renal failure or in those without pyridoxine. Greater reduction in platelet count was observed in patients with renal failure. PMID- 26618377 TI - [Causes of the emergency department visits in cancer patients: postchemotherapy toxicity]. AB - PURPOSE: to assess the causes of the Emergency Department visits in cancer patients treated with antineoplastics. The secondary objective is to analyse the use of growth stimulating factors in febrile neutropenia. METHODS: a retrospective observational study was conducted during six months of 2012. The adult patients diagnosed with solid tumour that visited the Emergency Department and whose physician was an oncologist, were included. RESULTS: a total of 83 patients fulfilled the inclusion criteria. The causes of visits were: 63% due to the tumour, 31% due to the chemotherapy toxicity and 6% due to other causes. In patients with chemotherapy toxicity, 65% had fever or infection, 50% pain and 42% febrile neutropenia. The treatment and prophylaxis with filgrastim followed the recommendations. CONCLUSIONS: in cancer patients, most of emergencies are due to the tumour. The management of the pain, the fever and the neutropenia is important. PMID- 26618378 TI - Hospital medication errors in a pharmacovigilance system in Colombia. AB - OBJECTIVE: this study analyzes the medication errors reported to a pharmacovigilance system by 26 hospitals for patients in the healthcare system of Colombia. METHODS: this retrospective study analyzed the medication errors reported to a systematized database between 1 January 2008 and 12 September 2013. The medication is dispensed by the company Audifarma S.A. to hospitals and clinics around Colombia. Data were classified according to the taxonomy of the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP). The data analysis was performed using SPSS 22.0 for Windows, considering p values < 0.05 significant. RESULTS: there were 9 062 medication errors in 45 hospital pharmacies. Real errors accounted for 51.9% (n = 4 707), of which 12.0% (n = 567) reached the patient (Categories C to I) and caused harm (Categories E to I) to 17 subjects (0.36%). The main process involved in errors that occurred (categories B to I) was prescription (n = 1 758, 37.3%), followed by dispensation (n = 1 737, 36.9%), transcription (n = 970, 20.6%) and administration (n = 242, 5.1%). The errors in the administration process were 45.2 times more likely to reach the patient (CI 95%: 20.2-100.9). CONCLUSIONS: medication error reporting systems and prevention strategies should be widespread in hospital settings, prioritizing efforts to address the administration process. PMID- 26618380 TI - Development of the management for parenteral nutrition traceability in a standard hospital. AB - OBJECTIVE: to develop the traceability control and the hazard analysis in the processes of parenteral nutrients (PN). METHOD: a standardized graphical notation was generated, describing in detail each of the stages in the overall process. The presence of hazards was analysed by sequencing decisions. The existence of Control Points (CP) or Critical Control Points (CCP) was estimated by Criticality Index (CI) for each hazard taking into account the probability of occurrence and the severity of the damage. The threshold for the IC was set in 6. RESULTS: a specific flow chart for the management and traceability of PN was obtained, defining each of the stages in CPs (validation and transcription of the prescription and administration) or CCPs (preparation, storage and infusion pump flow and filter-). Stages regarding the delivery, the recovery and the recycle of the packing material of PNs are not considered CPs and, therefore, they were not included in the dashboard. CONCLUSIONS: PN must be dealt with in the frame of a standardized management system in order to improve patient safety, clinical relevance, maximize resource efficiency and minimize procedural issues. The proposed system provides a global management model whose steps are fully defined, allowing monitoring and verification of PN. It would be convenient to make use of a software application to support the monitoring of the traceability management and to store the historical records in order to evaluate the system. PMID- 26618379 TI - Efficacy and safety of alendronic acid in the treatment of osteoporosis in children. AB - OBJECTIVES: to describe the efficacy and safety of the off-label use of alendronate in the treatment of osteoporosis in children and adolescents. METHOD: a retrospective study (2008-2014) of all patients under 18 years who were dispensed alendronate for this indication. The criteria for initiating treatment were: bone mineral density with a Z-score <= -2.5 SD, a past history of bone fractures without a previous traumatism, and persistent pain. The variables collected were: demographic, treatment-related, clinical. and safety data. The treatment was considered to be effective when there was an increase in bone mineral density up to a Z-score > -2.5 SD. RESULTS: a total of 12 patients, 8 of them male, with a mean age of 11 years (?+/- 3 SD), were treated with alendronate. After a mean time of treatment of 2.15 years (?+/- 1.2 SD), there was an increase in bone mineral density in all patients, 9 of which achieved a Z score > -2.5 SD, so the drug was considered effective in 75% of cases. No patient had bone fractures or expressed adverse effects during treatment. CONCLUSIONS: alendronate increased bone mineral density and was well tolerated in all patients, therefore it could be considered as a therapeutic option in the treatment of osteoporosis in children. PMID- 26618381 TI - [Adherence to entecavir for chronic hepatitis B and correlation with effectiveness]. AB - PURPOSE: to evaluate adherence of patients with chronic hepatitis B initiated on entecavir as first-line treatment and to correlate adherence with effectiveness. METHODS: observational retrospective study performed between January 2007 and June 2013. Patients treated with entecavir for at least one year were included. A patient was considered to be adherent if median adherence was >= 95%. Virological response (HBV DNA < 20UI/ml by Polymerase Chain Reaction), biochemical response (normalized level of alanine amino transferase [AAT]) and serological response (loss of hepatitis B surface antigen [HBsAg]) was assessed at month 12. RESULTS: 85 patients were included. The median adherence rate was 94.2 (SD 12.8)%. 85.7% of the adherent patients achieved a virological response in contrast with 71.4% of the nonadherent patients (OR:2,40; IC95%:0,60-9,54;p = 0,19). 87.9% of the adherent patients and 85.7% of the nonadherent patients showed normalized level of AAT (OR:1,21; IC95%:0,22- 6,60;p = 0,56). Two adherent patients showed clearance of hepatitis B surface antigen. CONCLUSION: the median adherence is not high. Nonadherent patients have a trend towards a higher rate of virological failure so it is necessary to promote improved adherence to treatment. PMID- 26618382 TI - Physiopathology and treatment of critical bleeding: a literature review. AB - OBJECTIVES: to develop the different factors involved in the physiopathology of trauma-induced coagulopathy, through a review of publications on the matter; as well as to assess the evidence available on the treatment of critical bleeding and the recommendations by clinical practice guidelines. METHODS: a search has been conducted on the bibliography published about the physiopathology and treatment of critical bleeding in the PUBMED, BestPractice, UpToDate databases and the Cochrane Plus Library. The main key words used for this search were "early trauma induced coagulopathy", "mechanisms of early trauma-induced coagulopathy", "blood transfusion guidelines", "massive transfusion guidelines" and "fibrinogen replacement therapy". The most clinically relevant articles were selected for this review. CONCLUSIONS: the physiopathology of the trauma-induced coagulopathy is a more complex matter and involves more factors than was initially assumed. The early treatment of the coagulopathy is critical for the initial management of the critical bleeding. However, the use of blood derivatives should be rational and based on homogeneous and high-quality scientific evidence. The main cornerstones for the treatment of critical bleeding are: fluid therapy, fibrinogen concentrate, prothrombin complex concentrate, plasma, erythrocyte or platelet concentrates, tranexamic acid, and calcium. Their administration should be assessed depending on the clinical condition of each patient. PMID- 26618383 TI - [Vancomycin versus teicoplanin use as antibiotic prophylaxis in surgery]. PMID- 26618384 TI - [Treatment of Blue Rubber Bled Nevus syndrome with subcutaneous octreotide: a case report]. PMID- 26618385 TI - [Gastrointestinal perforation induced by bevacizumab treatment in cervix carcinoma]. PMID- 26618386 TI - [Acute oxalate nephropathy in a patient with malabsorption syndrome for chronic pancreatitis]. PMID- 26618388 TI - Transformation of Tetracycline Antibiotics and Fe(II) and Fe(III) Species Induced by Their Complexation. AB - Tetracycline antibiotics (TCs) are frequently detected micropollutants and are known to have a strong tendency to complex with metal ions such as Fe(II) and Fe(III) in aquatic environments. Experiments with Fe(II) and TCs showed that the complexation of Fe(II) with tetracycline (TTC), oxytetracycline (OTC), or chlorotetracycline (CTC) could lead to the accelerated oxidation of Fe(II) and the promoted degradation of TCs simultaneously. The reaction started with complexation of Fe(II) with TC followed by oxidation of the Fe(II)-TC complex by dissolved oxygen to generate a Fe(III)-TC complex and reactive oxygen species (ROS). The ROS (primarily .OH) then degraded TC. The oxidation rate constants of Fe(II) in the Fe(II)-H2L and Fe(II)-HL complexes were 0.269 and 1.511 min(-1), respectively, at ambient conditions (pH 7, 22 degrees C, and PO2 of 0.21 atm), which were about 60 and 350 times of the oxidation rate of uncomplexed Fe(II). Humic acids (HA) compete with TCs for Fe(II), but the effect was negligible at moderate HA concentrations (<=10 mg.L(-1)). Experiments with Fe(III) and TCs showed that the complexation of Fe(III) with TC could generate oxidized TC and Fe(II) without the need of oxygen at a relatively slower rate compared to the reaction involving Fe(II), O2, and TCs. These findings indicate the mutually influenced environmental transformation of TCs and Fe(II) and Fe(III) induced by their complexation. These newly identified reactions could play an important role in affecting the environmental fate of TCs and cycling of Fe(II) and Fe(III) in TCs-contaminated water and soil systems. PMID- 26618389 TI - Composition Dependence of the Na(+) Ion Conductivity in 0.5Na2S + 0.5[xGeS2 + (1 x)PS5/2] Mixed Glass Former Glasses: A Structural Interpretation of a Negative Mixed Glass Former Effect. AB - A negative mixed glass former effect (MGFE) in the Na(+) ion conductivity of glass has been found in 0.5Na2S + 0.5[xGeS2 + (1 - x)PS5/2] glasses where the Na(+) ion conductivity is significantly smaller for all of the ternary glasses than either of the binary end-member glasses. The minimum conductivity of ~0.4 * 10(-6) (Omega cm)(-1) at 25 degrees C occurs for the x = 0.7 glass. Prior to this observation, the alkali ion conductivity of sulfide glasses at constant alkali concentration, but variable ratio of one glass former for another (x) ternary mixed glass former (MGF) glasses, has always produced a positive MGFE in the alkali ion conductivity; that is, the ternary glasses have always had higher ion conductivities that either of the end-member binary glasses. While the Na(+) ion conductivity exhibits a single global minimum value, the conductivity activation energy exhibits a bimodal double maximum at x ~ 0.4 and x ~ 0.7. The modified Christensen-Martin-Anderson-Stuart (CMAS) model of the activation energies reveals the origin of the negative MGFE to be due to an increase in the dielectric stiffness (a decrease in relative dielectric permittivity) of these glasses. When coupled with an increase in the average Na(+) ion jump distance and a slight increase in the mechanical stiffness of the glass, this causes the activation energy to go through maximum values and thereby produce the negative MGFE. The double maximum in the conductivity activation energy is coincident with double maximums in CMAS calculated strain, DeltaES, and Coulombic, DeltaEC, activation energies. In these ternary glasses, the increase in the dielectric stiffness of the glass arises from a negative deviation of the limiting high frequency dielectric permittivity as compared to the binary end-member glasses. While the CMAS calculated total activation energies DeltaEact = DeltaES + DeltaEC are found to reproduce the overall shape of the composition dependence of the measured DeltaEact values, they are consistently smaller than the measured values for all compositions x. The new concept of an effective Madelung constant for the Na(+) ions in glass is introduced, MD(Na(+)), to account for the difference. Calculated MD(Na(+)) values necessary to bring the CMAS and experimental DeltaEact values into agreement are in excellent agreement with nominal values for typical oxide crystals containing Na(+). New MD simulations of oxide glasses were performed and were used to calculate MD(Na(+)) values for Na2O + SiO2 glasses for the first time and were found to agree quite well with the values for the sulfide glasses studied here. Insights from the current study have been used to predict and design new MGF systems that may lead to a positive MGFE in the ionic conductivity. PMID- 26618390 TI - Direct Evidence for Percolation of Immobilized Polymer Layer around Nanoparticles Accounting for Sol-Gel Transition in Fumed Silica Dispersions. AB - Immobilized polymer fractions have been claimed to be of vital importance for sol gel transitions generally observed in nanoparticle dispersions but remain a matter of debate regarding mechanism and difficulty for prediction. Here we investigate the immobilized layer structures of trifunctionality polyether polyol (PPG) near the surfaces of hydrophilic and hydrophobic fumed silica (FS) nanoparticles to reveal the role of surface chemistry on the molecular dynamics and sol-gel transitions of the dispersions. Using modulated differential scanning calorimetry, we measure the specific heat capacity during glass transition and the enthalpy during cold-crystallization. Comparing with hydrophobic FS that forms a fully immobilized (glassy) layer, we find that hydrophilic FS immobilizes more PPG, forming a partially immobilized outer layer being unable to crystallize next to the inner glassy layer. By correlating the thickness of the glassy layer with half of the minimum spacing between nanoparticles, we directly evidence the percolation of this layer along the nearest neighbor nanoparticles responsible for the sol-gel transition. Using effective volume fraction including the glassy layer, we successfully construct master curves of relative viscosity of both hydrophilic and hydrophobic FS dispersions, pointing to a common sol-gel transition mechanism mediated by the surface chemistry. PMID- 26618391 TI - Vanadium Dioxide Nanoparticle-based Thermochromic Smart Coating: High Luminous Transmittance, Excellent Solar Regulation Efficiency, and Near Room Temperature Phase Transition. AB - An annealing-assisted preparation method of well-crystallized VxW1-xO2(M)@SiO2 core-shell nanoparticles for VO2-based thermochromic smart coatings (VTSC) is presented. The additional annealing process reduces the defect density of the initial hydrothermally prepared VxW1-xO2(M) nanoparticles and enhances their crystallinity so that the thermochromic film based on VxW1-xO2(M)@SiO2 nanoparticles can exhibit outstanding thermochromic performance with balanced solar regulation efficiency (DeltaTsol) of 17.3%, luminous transmittance (Tlum) up to 52.2%, and critical phase transition temperature (Tc) around 40.4 degrees C, which is very promising for practical application. Furthermore, it makes great progress in reducing Tc of VTSC to near room temperature (25.2 degrees C) and simutaneously maintaining excellent optical properties (DeltaTsol = 14.7% and Tlum = 50.6%). Such thermochromic performance is good enough to make VTSC applicable to practical architecture. PMID- 26618394 TI - Superhydrophobic resistance to dynamic freshwater biofouling inception. AB - Superhydrophobic nanotextured surfaces have gained increased usage in various applications due to their non-wetting and self-cleaning abilities. The aim of this study was to investigate nanotextured surfaces with respect to their resistance to the inception of freshwater biofouling at transitional flow conditions. Several coatings were tested including industry standard polyurethane (PUR), polytetrafluoroethylene (PTFE), capstone mixed polyurethane (PUR + CAP) and nanocomposite infused polyurethane (PUR + NC). Each surface was exposed to freshwater conditions in a lake at 4 m s(-1) for a duration of 45 min. The polyurethane exhibited the greatest fouling elements, in terms of both height and number of elements, with the superhydrophobic nanocomposite based polyurethane (PUR + NC) showing very little to no fouling. A correlation between the surface characteristics and the degree of fouling inception was observed. PMID- 26618393 TI - Light-Activated Nuclear Translocation of Adeno-Associated Virus Nanoparticles Using Phytochrome B for Enhanced, Tunable, and Spatially Programmable Gene Delivery. AB - Gene delivery vectors that are activated by external stimuli may allow improved control over the location and the degree of gene expression in target populations of cells. Light is an attractive stimulus because it does not cross-react with cellular signaling networks, has negligible toxicity, is noninvasive, and can be applied in space and time with unparalleled precision. We used the previously engineered red (R)/far-red (FR) light-switchable protein phytochrome B (PhyB) and its R light dependent interaction partner phytochrome interacting factor 6 (PIF6) from Arabidopsis thaliana to engineer an adeno-associated virus (AAV) platform whose gene delivery efficiency is controlled by light. Upon exposure to R light, AAV engineered to display PIF6 motifs on the capsid bind to PhyB tagged with a nuclear localization sequence (NLS), resulting in significantly increased translocation of viruses into the host cell nucleus and overall gene delivery efficiency. By modulating the ratio of R to FR light, the gene delivery efficiency can be tuned to as little as 35% or over 600% of the unengineered AAV. We also demonstrate spatial control of gene delivery using projected patterns of codelivered R and FR light. Overall, our successful use of light-switchable proteins in virus capsid engineering extends these important optogenetic tools into the adjacent realm of nucleic acid delivery and enables enhanced, tunable, and spatially controllable regulation of viral gene delivery. Our current light triggered viral gene delivery prototype may be broadly useful for genetic manipulation of cells ex vivo or in vivo in transgenic model organisms, with the ultimate prospect of achieving dose- and site-specific gene expression profiles for either therapeutic (e.g., regenerative medicine) or fundamental discovery research efforts. PMID- 26618392 TI - Technology transfer of oil-in-water emulsion adjuvant manufacturing for pandemic influenza vaccine production in Romania: Preclinical evaluation of split virion inactivated H5N1 vaccine with adjuvant. AB - Millions of seasonal and pandemic influenza vaccine doses containing oil-in-water emulsion adjuvant have been administered in order to enhance and broaden immune responses and to facilitate antigen sparing. Despite the enactment of a Global Action Plan for Influenza Vaccines and a multi-fold increase in production capabilities over the past 10 years, worldwide capacity for pandemic influenza vaccine production is still limited. In developing countries, where routine influenza vaccination is not fully established, additional measures are needed to ensure adequate supply of pandemic influenza vaccines without dependence on the shipment of aid from other, potentially impacted first-world countries. Adaptation of influenza vaccine and adjuvant technologies by developing country influenza vaccine manufacturers may enable antigen sparing and corresponding increases in global influenza vaccine coverage capacity. Following on previously described work involving the technology transfer of oil-in-water emulsion adjuvant manufacturing to a Romanian vaccine manufacturing institute, we herein describe the preclinical evaluation of inactivated split virion H5N1 influenza vaccine with emulsion adjuvant, including immunogenicity, protection from virus challenge, antigen sparing capacity, and safety. In parallel with the evaluation of the bioactivity of the tech-transferred adjuvant, we also describe the impact of concurrent antigen manufacturing optimization activities. Depending on the vaccine antigen source and manufacturing process, inclusion of adjuvant was shown to enhance and broaden functional antibody titers in mouse and rabbit models, promote protection from homologous virus challenge in ferrets, and facilitate antigen sparing. Besides scientific findings, the operational lessons learned are delineated in order to facilitate adaptation of adjuvant technologies by other developing country institutes to enhance global pandemic influenza preparedness. PMID- 26618395 TI - Can textured insoles improve ankle proprioception and performance in dancers? AB - With the aim of determining both the acute and the chronic effects of textured insoles on the ankle discrimination and performance ability of dancers, 60 ballet dancers from the Australian Ballet School, aged 14-19 years, were divided into three groups (two intervention groups and a control group), age- and level matched. In the first 5 weeks (weeks 1 to 5), the first intervention group (GRP1) was asked to wear textured insoles in their ballet shoes and the second intervention group (GRP2) was not given textured insoles to wear. In the next 5 weeks (weeks 6 to 10), GRP2 was asked to wear the same type of textured insoles and GRP1 did not wear the textured insoles. The control group (CTRL) did not wear textured insoles during the whole 10 weeks. All participants were tested preintervention, after 5 weeks and after 10 weeks for ankle discrimination score (AUC scores). Dance performance was assessed by 5-7 dance teachers. Pre-to-post change in AUC scores was significantly greater for the groups wearing insoles than for the controls (P = .046) and the size of pre-to-post changes did not differ between the two intervention groups (P = .834). Significant correlation was found between ankle discrimination score and performance scores, using the textured insoles (r = .412; P = .024). In conclusion, the stimulation to the proprioceptive system arising from textured insoles worn for five weeks was sufficient to improve the proprioceptive ability and performance ability of ballet dancers. PMID- 26618397 TI - Glycosidic Bond Cleavage in DNA Nucleosides: Effect of Nucleobase Damage and Activation on the Mechanism and Barrier. AB - Although DNA damage can have a variety of deleterious effects on cells (e.g., senescence, death, and rapid growth), the base excision repair (BER) pathway combats the effects by removing several types of damaged DNA. Since the first BER step involves cleavage of the bond between the damaged nucleobase and the DNA sugar-phosphate backbone, we have used density functional theory to compare the intrinsic stability of the glycosidic bond in a number of common DNA oxidation, deamination, and alkylation products to the corresponding natural nucleosides. Our calculations predict that the dissociative (SN1) and associative (SN2) pathways are nearly isoenergetic, with the dissociative pathway only slightly favored on the Gibbs reaction surface for all canonical and damaged nucleosides, which suggests that DNA damage does not affect the inherently most favorable deglycosylation pathway. More importantly, with the exception of thymine glycol, all DNA lesions exhibit reduced glycosidic bond stability relative to the undamaged nucleosides. Furthermore, the trend in the magnitude of the deglycosylation barrier reduction directly correlates with the relative nucleobase acidity (at N9 for purines or N1 for pyrimidines), which thereby provides a computationally efficient, qualitative measure of the glycosidic bond stability in DNA damage. The effect of nucleobase activation (protonation) at different sites predicts that the positions leading to the largest reductions in the deglycosylation barrier are typically used by DNA glycosylases to facilitate base excision. Finally, deaza purine derivatives are found to have greater glycosidic bond stability than the canonical counterparts, which suggests that alterations to excision rates measured using these derivatives to probe DNA glycosylase function must be interpreted in reference to the inherent differences in the nucleoside reactivity. Combined with previous studies of the deglycosylation of DNA nucleosides, the current study provides a greater fundamental understanding about the reactivity of the glycosidic bond in damaged DNA, which has direct implications to the function of critical DNA repair enzymes. PMID- 26618396 TI - Immuno-potentiating pathway of HBsAg-HBIG immunogenic complex visualized. AB - Chronic viral hepatitis B (CHB) is a major global health problem. A therapeutic vaccine for CHB comprised of yeast-derived recombinant HBsAg-anti-HBs immunogenic complexes (YIC) has been devloped by us. A series of clinical trials has shown its therapeutic efficacy in decreasing HBV viral load and converting serum HBeAg positive to anti-HBe-positive status in a subpopulation of CHB patients. Herein, we present a study of the immuno-potentiating mechanisms of YIC revealed by live cell imaging technology. We studied internalization and dissociation of YIC in cells in vitro, and antigen presentation and T cell stimulation in mice. We found that after YIC was internalized via the Fcgamma receptors (FcgammaR) of antigen presenting cells, it was subsequently transferred through early and late endosomal into lysosomal compartments. The dissociation of YIC was mainly observed in the late endosome. Furthermore when YIC were injected into mice, the populations of IFN-gamma- and TNF-alpha-producing CD8+ and CD4+ T cells were higher in the YIC group than in controls receiving antigen or antibody alone. These observations supplement the known mechanisms of YIC action as a therapeutic vaccine for CHB. PMID- 26618398 TI - Early Chest Tube Removal After Thoracoscopic Esophagectomy with High Output. AB - BACKGROUND: The optimal volume threshold for removal of chest tubes after thoracic surgery has not been determined. The purpose of the study was to assess the new volume threshold for chest tube removal after thoracoscopic esophagectomy (TSE). MATERIALS AND METHODS: A retrospective study was conducted with a prospective database. All patients underwent TSE. Eligible patients were divided into two groups: Group A had their chest tubes removed at a drainage volume of 150 mL/day or less, whereas Group B had their chest tubes removed at a drainage volume of 300 mL/day or less. Chest drainage time, volume of drainage on postoperative day (POD) 1 and 2, postoperative hospital stay, postoperative complications, and the incidence of invasive re-intervention were evaluated. RESULTS: In total, 70 patients were included, with 32 patients in Group A and 38 patients in Group B. The mean chest drainage time in Group B was significantly shorter than that in Group A (2.6 +/- 0.8 versus 4.0 +/- 1.0 days, P < .001). There were no statistically significant differences in volume of drainage on POD 1 and 2, postoperative hospital stay, and postoperative complications between Group A and Group B (P > .05). A total of 4 patients in Group A and 3 patients in Group B developed postoperative pleural effusions requiring thoracentesis (P > .05). No patient was re-admitted because of pleural effusion during the 30-day follow-up period. CONCLUSIONS: This study showed that a 300 mL/day volume threshold for chest tube removal after TSE was capable of reducing the postoperative chest drainage time without compromising patient safety. PMID- 26618400 TI - Attenuation of oxidative stress, inflammation, and endothelial dysfunction in hypercholesterolemic rabbits by allicin. AB - Allicin, the active substance of garlic, exerts a broad spectrum of pharmacological activities and is considered to have potential therapeutic applications. The present study was designed to investigate the possible beneficial effects of allicin against oxidative stress, inflammation, and endothelial dysfunction in hypercholesterolemic rabbits. Male New Zealand white rabbits were used in this study. Rabbits randomly received 1 of the following treatments: normal chow diet for 4 weeks, 1% high cholesterol diet (HCD), HCD plus allicin (10 mg/kg/day), or HCD plus atorvastatin (10 mg/kg/day). Blood samples were collected at the end of experimental diets for measurement of serum total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD). In addition, the aorta was removed for measurement of vascular reactivity, histopathological changes, intima/media (I/M) ratio, and immunohistochemical staining of both tumor necrosis-alpha (TNF-alpha) and nuclear factor (NF)-kappaB. HCD induced significant increases in serum TC, TGs, low-density lipoprotein cholesterol (LDL-C), CRP, and MDA. Moreover, HCD caused significant decrease in serum GSH and SOD. In addition, aortic relaxation response to acetylcholine (ACh) was impaired. Immunohistochemical staining of aortic specimens from HCD-fed rabbits revealed high expression levels of both TNF alpha and the oxidant-induced transcription factor, NF-kappaB. Allicin supplementation significantly decreased serum MDA and CRP, increased serum HDL-C, GSH, and SOD levels while nonsignificantly affecting HCD-induced elevations in serum TC and LDL-C. Additionally, allicin significantly protected against HCD induced attenuation of rabbit aortic endothelium-dependent relaxation to ACh and elevation in I/M ratio. This effect was confirmed by histopathological examination of the aorta. Moreover, allicin has substantially beneficial effects on aortic expression of TNF-alpha and NF-kappaB compared with HCD-fed rabbits. In conclusion, these findings demonstrate that allicin may be useful in reducing oxidative stress, inflammation, vascular dysfunction, and the aortic pathology in hypercholesterolemic rabbits. PMID- 26618399 TI - The transcription initiation sites of eggplant latent viroid strands map within distinct motifs in their in vivo RNA conformations. AB - Eggplant latent viroid (ELVd), like other members of family Avsunviroidae, replicates in plastids through a symmetric rolling-circle mechanism in which elongation of RNA strands is most likely catalyzed by a nuclear-encoded polymerase (NEP) translocated to plastids. Here we have addressed where NEP initiates transcription of viroid strands. Because this step is presumably directed by sequence/structural motifs, we have previously determined the conformation of the monomeric linear (+) and (-) RNAs of ELVd resulting from hammerhead-mediated self-cleavage. In silico predictions with 3 softwares led to similar bifurcated conformations for both ELVd strands. In vitro examination by non-denaturing PAGE showed that they migrate as prominent single bands, with the ELVd (+) RNA displaying a more compact conformation as revealed by its faster electrophoretic mobility. In vitro SHAPE analysis corroborated the ELVd conformations derived from thermodynamics-based predictions in silico. Moreover, sequence analysis of 94 full-length natural ELVd variants disclosed co variations, and mutations converting canonical into wobble pairs or vice versa, which confirmed in vivo most of the stems predicted in silico and in vitro, and additionally helped to introduce minor structural refinements. Therefore, results from the 3 experimental approaches were essentially consistent among themselves. Application to RNA preparations from ELVd-infected tissue of RNA ligase-mediated rapid amplification of cDNA ends, combined with pretreatments to modify the 5' ends of viroid strands, mapped the transcription initiation sites of ELVd (+) and (-) strands in vivo at different sequence/structural motifs, in contrast with the situation previously observed in 2 other members of the family Avsunviroidae. PMID- 26618401 TI - Families in transition: A literature review. AB - Research on the transgender population is often limited to their medical care, and in particular to their mental well-being. The social and family environment in which a social gender role transition takes place is often overlooked. Although research is limited, this article reviews the existing literature on the family aspect of a gender transition. Articles regarding three different aspects were selected for this review: first, the issue of parenthood during transition and the experiences of children with a transgender parent, second, the experiences of partners and ex-partners of transgender individuals, and third, the experiences of parents with a gender variant child. Articles were restricted to those with a focus on family members and situations during transition. For all three contexts, several mediating factors, both individual and social, were distinguished. Various challenges for future research were identified. PMID- 26618402 TI - [In Process Citation]. AB - A novel model for the analysis of the rovibrational structure of a molecule based on anharmonic ladder operators associated with the vibrational degrees of freedom is presented. This is devised as an alternative method for the global spectral analysis of rovibrational data considering vibrational anharmonicities from the outset. The present method is thought up with an effective rovibrational Hamiltonian written in terms of angular momentum components and anharmonic Morse ladder operators, associated with rotational and vibrational degrees of freedom, respectively. The resulting Hamiltonian is diagonalized in a symmetry-adapted basis set expressed as a product of rotational states and individual 1D-Morse wave functions for each local vibrational degree of freedom. This approach has been successfully applied to the study of the vibrational structure (up to polyad 14) and the rovibrational structure (up to polyad 2 and J(max) = 20) of hydrogen sulfide. It was shown that this new global analysis formalism is able to reduce considerably the number of fitted parameters with respect to the spectral analysis carried out for separate polyads. PMID- 26618403 TI - Catalytic Arylsulfonyl Radical Triggered 1,7-Enyne Bicyclizations. AB - A new metal-free bicyclization reaction of 1,7-enynes anchored by alpha,beta conjugates with arylsulfonyl radicals generated in situ from sulfonyl hydrazides has been established using tert-butyl hydroperoxide and tetrabutylammonium iodide. The reactions occurred through sulfonylation/6-exo-dig/6-exo-trig bicyclization/in situ desulfonylation/5-exo-trig cyclization/alkyl or alkenyl migration cascade mechanism to give benzo[j]phenanthridines regioselectively. PMID- 26618404 TI - Could combined sleep and pain evaluation be useful in the diagnosis of disorders of consciousness (DOC)? Preliminary findings. AB - BACKGROUND: The diagnosis of Disorders of Consciousness (DOC) is still challenging. Indeed, ~ 40% of patients in vegetative state (VS) are misdiagnosed, suggesting the need of more appropriate diagnostic tools. Emerging data are showing that EEG, including sleep structure evaluation and multimodal evoked potential recording could be helpful in DOC diagnosis. Moreover, pain perception evaluation could further increase diagnosis accuracy in such individuals. METHODS: Fourteen individuals with DOC, due to severe brain injury, were enrolled and admitted to the Intensive Neurorehabilitation Unit of the Research Institute. All patients were evaluated by means of the Coma Recovery Scale-Revised, a 24(hh) polysomnography and a Laser Evoked Potential (LEP) paradigm. RESULTS: Clinically defined patients in Minimally Consciousness State showed a more preserved sleep structure, physiologic hypnic figures and preserved REM/NREM sleep distribution than subjects in VS. LEP showed increased latencies and reduced amplitudes and were also detectable in patients with more structured sleep. CONCLUSIONS: The data support previous findings concerning the importance of sleep study in DOC diagnosis, with more specific neurophysiological paradigms. Interestingly, the findings shed some light on the possible correlations among global brain connectivity, sleep structure and pain perception, which are related to the activity of the wide thalamo-cortical and cortico-cortical networks underlying consciousness. PMID- 26618406 TI - High Performance All-Solid-State Flexible Micro-Pseudocapacitor Based on Hierarchically Nanostructured Tungsten Trioxide Composite. AB - Microsupercapacitors (MSCs) are promising energy storage devices to power miniaturized portable electronics and microelectromechanical systems. With the increasing attention on all-solid-state flexible supercapacitors, new strategies for high-performance flexible MSCs are highly desired. Here, we demonstrate all solid-state, flexible micropseudocapacitors via direct laser patterning on crack free, flexible WO3/polyvinylidene fluoride (PVDF)/multiwalled carbon nanotubes (MWCNTs) composites containing high levels of porous hierarchically structured WO3 nanomaterials (up to 50 wt %) and limited binder (PVDF, <25 wt %). The work leads to an areal capacitance of 62.4 mF.cm(-2) and a volumetric capacitance of 10.4 F.cm(-3), exceeding that of graphene based flexible MSCs by a factor of 26 and 3, respectively. As a noncarbon based flexible MSC, hierarchically nanostructured WO3 in the narrow finger electrode is essential to such enhancement in energy density due to its pseudocapacitive property. The effects of WO3/PVDF/MWCNTs composite composition and the dimensions of interdigital structure on the performance of the flexible MSCs are investigated. PMID- 26618407 TI - Domestic cooking and food skills: A review. AB - Domestic cooking skills (CS) and food skills (FS) encompass multiple components, yet there is a lack of consensus on their constituent parts, inter-relatedness, or measurement, leading to limited empirical support for their role in influencing dietary quality. This review assessed the measurement of CS and FS in adults (>16 years); critically examining study designs, psychometric properties of measures, theoretical basis, and associations of CS/FS with diet. Electronic databases (PsychInfo), published reports, and systematic reviews on cooking and home food preparation interventions provided 834 articles of which 26 met the inclusion criteria. Multiple CS/FS measures were identified across three study designs-qualitative, cross-sectional, and dietary interventions-conducted from 1998 to 2013. Most measures were not theory-based, limited psychometric data were available, with little consistency of items or scales used for CS/FS measurements. Some positive associations between CS/FS and fruit and vegetables intake were reported, though lasting dietary changes were uncommon. The role of psycho-social (e.g., gender, attitudes) and external factors (e.g., food availability) on CS/FS is discussed. A conceptual framework of CS/FS components is presented for future measurement facilitation, which highlights the role for CS/FS on food-related behavior and dietary quality. This will aid future dietary intervention design. PMID- 26618405 TI - Upregulation of PP2Ac predicts poor prognosis and contributes to aggressiveness in hepatocellular carcinoma. AB - Protein phosphatase 2A (PP2A) is a heterotrimeric protein phosphatase consisting of a 36-kD catalytic C subunit (PP2Ac). This study aimed to explore the prognostic and biological significance of PP2Ac in human hepatocellular carcinoma (HCC). High PP2Ac expression was significantly (P < 0.01) associated with serum hepatitis B surface antigen positivity, serum hepatitis B e antigen positivity, liver cirrhosis, moderate to poor differentiation grade, advanced disease stage, intrahepatic metastasis, and early recurrence in HCC. Multivariate analysis revealed PP2Ac as an independent prognostic factor for overall survival. Enforced expression of hepatitis B virus X protein (HBx) and its carboxyl-terminal truncated isoform induced PP2Ac expression in HCC cells. Co-immunoprecipitation assay revealed a direct interaction between PP2Ac and HBx. Small interfering RNA mediated knockdown of PP2Ac significantly inhibited in vitro cell proliferation, colony formation, migration, and invasion and reduced tumor growth in an xenograft mouse model. In contrast, overexpression of PP2Ac promoted HCC cell proliferation, colony formation, and tumorigenesis. Additionally, silencing of PP2Ac impaired the growth-promoting effects on HepG2 HCC cells elicited by overexpression of carboxyl-terminal truncated HBx. Gene expression profiling analysis showed that PP2Ac downregulation modulated the expression of numerous genes involved in cell cycle and apoptosis regulation. Collectively, PP2Ac upregulation has a poor prognostic impact on the overall survival of HCC patients and contributes to the aggressiveness of HCC. PP2Ac may represent a potential therapeutic target for HCC. PMID- 26618410 TI - Reversible Electrochemical Trapping of Carbon Dioxide Using 4,4'-Bipyridine That Does Not Require Thermal Activation. AB - Sequestering carbon dioxide emissions by the trap and release of CO2 via thermally activated chemical reactions has proven problematic because of the energetic requirements of the release reactions. Here we demonstrate trap and release of carbon dioxide using electrochemical activation, where the reactions in both directions are exergonic and proceed rapidly with low activation barriers. One-electron reduction of 4,4'-bipyridine forms the radical anion, which undergoes rapid covalent bond formation with carbon dioxide to form an adduct. One-electron oxidation of this adduct releases the bipyridine and carbon dioxide. Reversible trap and release of carbon dioxide over multiple cycles is demonstrated in solution at room temperature, and without the requirement for thermal activation. PMID- 26618413 TI - An Inverted Appendix. PMID- 26618408 TI - Mapping the Free Energy Landscape of PKA Inhibition and Activation: A Double Conformational Selection Model for the Tandem cAMP-Binding Domains of PKA RIalpha. AB - Protein Kinase A (PKA) is the major receptor for the cyclic adenosine monophosphate (cAMP) secondary messenger in eukaryotes. cAMP binds to two tandem cAMP-binding domains (CBD-A and -B) within the regulatory subunit of PKA (R), unleashing the activity of the catalytic subunit (C). While CBD-A in RIalpha is required for PKA inhibition and activation, CBD-B functions as a "gatekeeper" domain that modulates the control exerted by CBD-A. Preliminary evidence suggests that CBD-B dynamics are critical for its gatekeeper function. To test this hypothesis, here we investigate by Nuclear Magnetic Resonance (NMR) the two domain construct RIalpha (91-379) in its apo, cAMP2, and C-bound forms. Our comparative NMR analyses lead to a double conformational selection model in which each apo CBD dynamically samples both active and inactive states independently of the adjacent CBD within a nearly degenerate free energy landscape. Such degeneracy is critical to explain the sensitivity of CBD-B to weak interactions with C and its high affinity for cAMP. Binding of cAMP eliminates this degeneracy, as it selectively stabilizes the active conformation within each CBD and inter-CBD contacts, which require both cAMP and W260. The latter is contributed by CBD-B and mediates capping of the cAMP bound to CBD-A. The inter CBD interface is dispensable for intra-CBD conformational selection, but is indispensable for full activation of PKA as it occludes C-subunit recognition sites within CBD-A. In addition, the two structurally homologous cAMP-bound CBDs exhibit marked differences in their residual dynamics profiles, supporting the notion that conservation of structure does not necessarily imply conservation of dynamics. PMID- 26618409 TI - Obesity, Asthma, and Exercise in Child and Adolescent Health. AB - Obesity increases the risk of asthma throughout life but the underlying mechanisms linking these all too common threats to child health are poorly understood. Acute bouts of exercise, aerobic fitness, and levels of physical activity clearly play a role in the pathogenesis and/or management of both childhood obesity and asthma. Moreover, both obesity and physical inactivity are associated with asthma symptomatology and response to therapy (a particularly challenging feature of obesity-related asthma). In this article, we review current understandings of the link between physical activity, aerobic fitness and the asthma-obesity link in children and adolescents (e.g., the impact of chronic low-grade inflammation, lung mechanics, and direct effects of metabolic health on the lung). Gaps in our knowledge regarding the physiological mechanisms linking asthma, obesity and exercise are often compounded by imprecise estimations of adiposity and challenges of assessing aerobic fitness in children. Addressing these gaps could lead to practical interventions and clinical approaches that could mitigate the profound health care crisis of the increasing comorbidity of asthma, physical inactivity, and obesity in children. PMID- 26618414 TI - A Self-Expanding Metal Colonic Stent Causing a Contained Splenic Perforation. PMID- 26618415 TI - Stomal Cytomegalovirus Infection Following Intestinal Transplant. PMID- 26618416 TI - A Rare Cause of Diarrhea and Weight Loss. PMID- 26618417 TI - Video of the Month: A Novel Endoscopic Full-Thickness Resection for Early Gastric Cancer. PMID- 26618422 TI - Data on Symptom Association Analysis in Patients Undergoing Endoscopic Therapy Is Useful to Better Define a Successful Therapeutic Approach. PMID- 26618423 TI - Randomized Controlled Trial of Transoral Incisionless Fundoplication Vs. Proton Pump Inhibitors for Treatment of Gastroesophageal Reflux Disease. PMID- 26618424 TI - Transient and Persistent Antibodies Against TNF-Inhibitors in IBD. PMID- 26618425 TI - Response to Steenholdt. PMID- 26618426 TI - Hepatocellular Carcinoma Surveillance: Moving Forward or Looking in the Rear-View Mirror? PMID- 26618427 TI - Response to Braillon. PMID- 26618428 TI - Endoscopy Training in Need of an Update. PMID- 26618429 TI - Reply to Sharma. PMID- 26618430 TI - Hepatocellular Carcinoma Occurs at an Earlier Age in Africans, Particularly in Association With Chronic Hepatitis B. PMID- 26618431 TI - Pseudomonas Meningitis During Vedolizumab Therapy for Crohn's Disease. PMID- 26618433 TI - Erratum: Colon-Like Megaesophagus. PMID- 26618434 TI - Erratum: Severe Mediastinitis and Pneumomediastinum Following Esophageal Perforation by a Fish Bone. PMID- 26618435 TI - Corrigendum: A Novel Case of an Unusual Esophageal Submucosal Tumor: An Esophageal Submucosal Gland Duct Hamartoma. PMID- 26618436 TI - Reply to "transforming oncology care": advancing value, accessing innovation. AB - Alternative payment models in oncology are already successfully standardizing care, curbing costs, and improving the patient experience. Yet, it is unclear whether decision makers are adequately considering patient access to innovation when creating these models, which could have severe consequences for a robust innovation ecosystem and the lives of afflicted patients. The suggested chart includes recommendations on: Allowing for the adoption of new, promising therapies; Promoting the measurement of patient-centered outcomes; and Providing support for personalized medicine. PMID- 26618437 TI - Payer source influence on effectiveness of lifestyle medicine programs. AB - OBJECTIVES: Many chronic diseases are responsive to interventions focused on diet and physical activity. The Complete Health Improvement Program (CHIP) is an intensive, community-based lifestyle intervention that effectively treats many chronic diseases and their risk factors. This is a pilot study examining the effect of payer source for CHIP tuition on participants' outcomes. STUDY DESIGN: Seventy-nine self-selected participants (73.4% female) attended 1 of 3 CHIP classes (classes 7-9) offered January through May 2013 in Athens, Ohio. Participants were categorized into 3 groups based on the source(s) of their tuition payment: self-pay, employer-pay, or scholarship. Chronic disease risk factors for each individual were assessed at the beginning and conclusion of the program. METHODS: Outcome variables included percent reduction between pre- and post CHIP measures in body mass index, systolic and diastolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and fasting blood glucose. Results were compared between type of payer source (out of pocket vs employer and/or scholarship) and between each individual CHIP class attended. RESULTS: There was no statistical difference in outcomes based on payer source. Those who received funding through their employer or a scholarship experienced similar effects from a lifestyle intervention program as those who paid out of pocket. CONCLUSIONS: This study demonstrates that the benefit of CHIP for reducing chronic disease risk factors exists independent of payment source, and thus suggests its benefit may cross socioeconomic lines. PMID- 26618438 TI - High-risk centers and the benefits for lower-risk transplants. AB - OBJECTIVES: Allogeneic hematopoietic cell transplantation (HCT) is the transplantation of stem cells from a donor and an effective treatment for many hematologic malignancies. We sought to compare allogeneic HCT survival outcomes and hazard of death among US centers that treat higher-risk patients versus those in centers that do not perform lower-risk HCT procedures. STUDY DESIGN: We utilized 2008 to 2010 Center for International Blood and Marrow Transplant Research data. We categorized patients into 4 risk categories that align with factors shown in the literature to be associated with HCT survival. We stratified centers into those that do and do not conduct high-risk pre-transplant HCT. METHODS: To further evaluate the association between pre-transplant mortality risk and HCT survival by transplant center, we examined the association between risk category score and hazard of death using Cox proportional hazard modeling. RESULTS: There were 12,436 HCT recipients at 147 transplant centers. Of the 147 centers, 74 performed HCT for patients ranging from the lowest risk category to the highest category, and 73 centers performed only lower-risk HCT. Adjusting for all other factors, lower-risk patients that underwent transplants in lower- or higher-risk centers had a similar relative hazard of death (P <= .05). CONCLUSIONS: Low-risk patients had similar survival outcomes irrespective of whether they underwent transplant at higher- or lower-risk centers. Patient and payer policy implications could include initiatives that reduce travel for low risk patients. Similarly, HCT center administrators and providers that manage higher-risk patients need not expect commensurate benefits in survival for lower risk patients. PMID- 26618439 TI - Targeting a high-risk group for fall prevention: strategies for health plans. AB - OBJECTIVES: Although Medicare has implemented incentives for health plans to reduce fall risk, the best way to identify older people at high risk of falling and to use screening results to target fall prevention services remains unknown. We evaluated 4 different strategies using a combination of administrative data and patient-reported information that health plans could easily obtain. STUDY DESIGN: Observational study. METHODS: We used data from 1776 patients 75 years or older in 4 community-based primary care practices who screened positive for a fear of falling and/or a history of falls. For these patients, we predicted fall related injuries in the 24 months after the date of screening using claims/encounter data. After controlling for age and gender, we predicted the number of fall-related injuries by adding Elixhauser comorbidity count, any claim for a fall-related injury during the 12 months prior to screening, and falls screening question responses in a sequential fashion using negative binomial regression models. RESULTS: Basic patient characteristics, including age and Elixhauser comorbidity count, were strong predictors of fall-related injury. Among falls screening questions, a positive response to, "Have you fallen 2 or more times in the past year?" was the most predictive of a fall-related injury (incidence rate ratio [IRR], 1.56; 95% CI, 1.25-1.94). Prior claim for a fall related injury also independently predicted this type of injury (IRR, 1.41; 95% CI, 1.05-1.89). The best model for predicting fall-related injuries combined all of these approaches. CONCLUSIONS: The combination of administrative data and a simple screening item can be used by health plans to target patients at high risk for future fall-related injuries. PMID- 26618440 TI - Socioeconomic disparities across ethnicities: an application to cervical cancer screening. AB - OBJECTIVES: Our aim is to investigate socioeconomic disparities in cervical cancer screening utilization among and between ethnic groups in the United States. STUDY DESIGN: Observational study. METHODS: Data on 26,338 women aged 21 to 64 years were obtained from the 2007 to 2011 years of the Medical Expenditure Panel Survey. Data on cervical cancer screening utilization in the preceding 12 months and 3 years, and a range of sociodemographic characteristics were included. Analyses were undertaken for all women and across racial/ethnic grouping (ie, white, black, Hispanic, and other). Concentration indices were used to measure the socioeconomic gradient across ethnic groups. Probit regression analyses were used to examine variations in utilization related to socioeconomic factors across ethnic groups controlling for a range of pertinent characteristics. RESULTS: Annual utilization rates are high in the United States (60.15%) and greatest among black women (66.25%). Disparities, as measured by concentration indices (CIs), are large in the United States, with the largest being for white women (CI, 0.179) relative to black (CI, 0.103) and Hispanic (CI, 0.081) women. Screening differences across income, education and insurance status are also greater amongst white women. CONCLUSIONS: Uptake of cervical cancer screening is common in the United States, with large socioeconomic disparities also evident. Those from lower socioeconomic or uninsured groups who are most likely to have, and to die from, cervical cancer, are least likely to use preventive screening. Disparities differ across ethnic groups and are greatest amongst white women. Incorporating organized screening may serve to improve both the systems efficiency and address disparities between and within groups. PMID- 26618441 TI - Predicting adherence trajectory using initial patterns of medication filling. AB - OBJECTIVES: To evaluate the ability of initial medication dispensings to predict long-term patterns of adherence. STUDY DESIGN: A retrospective cohort study of statin initiators enrolled in a Medicare Part D drug plan from CVS Caremark from 2005 to 2008. METHODS: We used group-based trajectory models to classify patients into 6 adherence trajectories based on patterns of statin filling over the year following therapy initiation. Baseline clinical characteristics and indicators of statin filling during the first 2 to 4 months following initiation were used to predict adherence trajectory in logistic regression models, separately within strata of the days' supply of the initial statin dispensing. Cross-validation was used to measure predictive accuracy of models in data not used for model estimation. RESULTS: Among 77,703 statin initiators, prediction using baseline variables only was poor (cross-validated C statistic <= 0.61). When using 3 months of initial adherence to predict trajectory, prediction was greatly improved among patients with an index supply <=30 days (0.62 <= C <= 0.91). With 4 months of initial adherence in the model, prediction was strong for all patients (C >= 0.72), especially for the best and worst trajectories (C = 0.90 and 0.94, respectively, in patients with an index supply <= 30 days; and C = 0.83 and 0.90, respectively, in patients with an index supply > 30 days). CONCLUSIONS: Initial filling behavior strongly predicted future adherence trajectory. Predicting adherence trajectories may facilitate better targeting of interventions to patients most likely to benefit. PMID- 26618442 TI - Developing evidence that is fit for purpose: a framework for payer and research dialogue. AB - OBJECTIVES: Matching the supply and demand of evidence requires an understanding of when more evidence is needed, as well as the type of evidence that will meet this need. This article describes efforts to develop and refine a decision-making framework that considers payers' perspectives on the utility of evidence generated by different types of research methods, including real-world evidence. STUDY DESIGN: Conceptual framework development with subsequent testing during a roundtable dialogue. METHODS: The framework development process included a literature scan to identify existing frameworks and relevant articles on payer decision making. The framework was refined during a stand-alone roundtable in December 2013 hosted by the research team, which included representatives from public and private payers, pharmacy benefit management, the life sciences industry, and researchers. The roundtable discussion also included an application of the framework to 3 case studies. RESULTS: Application of the framework to the clinical scenarios and the resulting discussion provided key insights into when new evidence is needed to inform payer decision making and what questions should be addressed. Payers are not necessarily seeking more evidence about treatment efficacy; rather, they are seeking more evidence for relevant end points that illustrate the differences between treatment alternatives that can justify the resources required to change practice. In addition, payers are interested in obtaining new evidence that goes beyond efficacy, with an emphasis on effectiveness, longer-term safety, and delivery system impact. CONCLUSIONS: We believe that our decision-making framework is a useful tool to increase dialogue between evidence generators and payers, while also allowing for greater efficiency in the research process. PMID- 26618443 TI - Interface effects on acceptor qubits in silicon and germanium. AB - Dopant-based quantum computing implementations often require the dopants to be situated close to an interface to facilitate qubit manipulation with local gates. Interfaces not only modify the energies of the bound states but also affect their symmetry. Making use of the successful effective mass theory we study the energy spectra of acceptors in Si or Ge taking into account the quantum confinement, the dielectric mismatch and the central cell effects. The presence of an interface puts constraints to the allowed symmetries and leads to the splitting of the ground state in two Kramers doublets (Mol et al 2015 Appl. Phys. Lett. 106 203110). Inversion symmetry breaking also implies parity mixing which affects the allowed optical transitions. Consequences for acceptor qubits are discussed. PMID- 26618444 TI - The coordinated movement of the spine and pelvis during running. AB - Previous research into running has demonstrated consistent patterns in pelvic, lumbar and thoracic motions between different human runners. However, to date, there has been limited attempt to explain why observed coordination patterns emerge and how they may relate to centre of mass (CoM) motion. In this study, kinematic data were collected from the thorax, lumbar spine, pelvis and lower limbs during over ground running in n=28 participants. These data was subsequently used to develop a theoretical understanding of the coordination of the spine and pelvis in all three body planes during the stance phase of running. In the sagittal plane, there appeared to be an antiphase coordinate pattern which may function to increase femoral inclination at toe off whilst minimising anterior-posterior accelerations of the CoM. In the medio-lateral direction, CoM motion appears to facilitate transition to the contralateral foot. However, an antiphase coordination pattern was also observed, most likely to minimise unnecessary accelerations of the CoM. In the transverse plane, motion of the pelvis was observed to lag slightly behind that of the thorax. However, it is possible that the close coupling between these two segments facilitates the thoracic rotation required to passively drive arm motion. This is the first study to provide a full biomechanical rationale for the coordination of the spine and pelvis during human running. This insight should help clinicians develop an improved understanding of how spinal and pelvic motions may contribute to, or result from, common running injuries. PMID- 26618445 TI - Aptamers: versatile molecular recognition probes for cancer detection. AB - In the past two decades, aptamers have emerged as a novel class of molecular recognition probes comprising uniquely-folded short RNA or single-stranded DNA oligonucleotides that bind to their cognate targets with high specificity and affinity. Aptamers, often referred to as "chemical antibodies", possess several highly desirable features for clinical use. They can be chemically synthesized and are easily conjugated to a wide range of reporters for different applications, and are able to rapidly penetrate tissues. These advantages significantly enhance their clinical applicability, and render them excellent alternatives to antibody-based probes in cancer diagnostics and therapeutics. Aptamer probes based on fluorescence, colorimetry, magnetism, electrochemistry, and in conjunction with nanomaterials (e.g., nanoparticles, quantum dots, single walled carbon nanotubes, and magnetic nanoparticles) have provided novel ultrasensitive cancer diagnostic strategies and assays. Furthermore, promising aptamer targeted-multimodal tumor imaging probes have been recently developed in conjunction with fluorescence, positron emission tomography (PET), single-photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI). The capabilities of the aptamer-based platforms described herein underscore the great potential they hold for the future of cancer detection. In this review, we highlight the most prominent recent developments in this rapidly advancing field. PMID- 26618446 TI - Cost of arthritis: a systematic review of methodologies used for direct costs. AB - A substantial amount of healthcare and costs are attributable to arthritis, which is a very common chronic disease. This paper presents the results of a systematic review of arthritis cost studies published from 2008 to 2013. MEDLINE, Embase, EconLit databases were searched, as well as governmental and nongovernmental organization websites. Seventy-one reports met the inclusion/exclusion criteria, and 24 studies were included in the review. Among these studies, common methods included the use of individual-level data, bottom-up costing approach, use of both an arthritis group and a control group to enable incremental cost computation of the disease, and use of regression methods such as generalized linear models and ordinary least squares regression to control for confounding variables. Estimates of the healthcare cost of arthritis varied considerably across the studies depending on the study methods, the form of arthritis and the population studied. In the USA, for example, the estimated healthcare cost of arthritis ranged from $1862 to $14,021 per person, per year. The reviewed study methods have strengths, weaknesses and potential improvements in relation to estimating the cost of disease, which are outlined in this paper. Caution must be exercised when these methods are applied to cost estimation and monitoring of the economic burden of arthritis. PMID- 26618447 TI - Metformin Decreases Thyroid Volume and Nodule Size in Subjects with Insulin Resistance: A Preliminary Study. AB - OBJECTIVE: The aim of this study was to investigate the effects of metformin on thyroid volume and nodule size. SUBJECTS AND METHODS: Prospective data were gathered on 100 newly diagnosed subjects with insulin resistance (68 female, 32 male) between August 2008 and May 2010. Each subject followed a standard diet and exercise program, and received 1,700 mg/day of metformin therapy for 6 months. The height, weight, waist circumference (WC) and thyroid hormone levels of each subject were measured. Additionally, the dimensions of the thyroid lobes and maximum diameter of each thyroid nodule were determined by ultrasonography. BMI and thyroid volumes were also calculated. Insulin resistance was estimated by homeostasis model assessment. All these parameters were measured at the beginning and at the end of the treatment period. RESULTS: BMI and WC decreased significantly after metformin therapy (34.5 +/- 5.1 vs. 32.7 +/- 4.8, p < 0.0001, and 106.3 +/- 11.8 vs. 101.8 +/- 19.0 cm, p = 0.008, respectively). Insulin resistance also decreased after metformin therapy (4.5 +/- 1.9 vs. 2.9 +/- 1.7, p < 0.0001). The mean thyroid volume (22.5 +/- 11.2 vs. 20.3 +/- 10.4 ml, p < 0.0001) and mean thyroid nodule size (12.9 +/- 7.6 vs. 11.7 +/- 7.2 mm, p < 0.0001) also decreased after treatment. CONCLUSION: In subjects with insulin resistance, metformin therapy significantly decreased thyroid volume and nodule size. PMID- 26618448 TI - New Staging System for Colorectal Cancer Patients with Synchronous Peritoneal Metastasis in Accordance with the Japanese Classification of Colorectal Carcinoma: A Multi-Institutional Study. AB - BACKGROUND: Peritoneal metastasis of colorectal cancer (CRC) is often discovered during initial surgery. The aim of this study is to propose a new staging system that could be used to help determine the management of CRC patients. METHODS: We evaluated a total of 766 Stage IV CRC patients with synchronous peritoneal metastasis. According to the Japanese classification, we divided the peritoneal metastasis into P1, P2, and P3. We distinguished distant metastasis from liver metastasis and peritoneal metastasis. According to the Cox proportional hazard model, we constructed a new staging group. RESULTS: According to a comparison of the R2 statistics, the combination of liver metastasis and peritoneal metastasis was selected as the final variables. Next, we defined P1H(-) as Grade A, P2H(-) as Grade B, and other groups as Grade C. Our proposed new stage (Akaike Information Criteria [AIC] 7,338.82; concordance index [c-index] 0.644; R2 0.123) could thus divide the patients into different prognostic groups more clearly than the current Japanese classification (AIC 7,373.89; c-index 0.619; R2 0.097). CONCLUSION: Our proposed new staging system is very simple and easy for general surgeons to follow. This system is useful for determining the appropriate operative strategy for CRC patients with peritoneal metastasis and for estimating the patients' prognosis. PMID- 26618449 TI - Comparison of Safety and Efficacy of Different Models of Target Vessel Regional Chemotherapy for Gastric Cancer with Liver Metastases. AB - BACKGROUND/AIMS: We previously demonstrated the safety and efficacy of low-dose, short-interval target vessel regional chemotherapy (TVRC(LDSI)) delivered through the hepatic artery with transarterial embolization (TAE) in patients with advanced gastric cancer (AGC). The present study aimed to compare the efficacy of TAE + TVRC(LDSI) with that of standard TAE + TVRC in AGC patients with liver metastases who failed to respond to first- or second-line systemic chemotherapy. METHODS: This study recruited a total of 58 GC patients with liver metastases after failure of first- or second-line systemic chemotherapy. Twenty-eight patients were assigned to the TAE + TVRC(LDSI) group and 30 patients to the TAE + TVRC group. The primary end point was overall survival (OS(TVRC)), which was defined as the time from the initiation of TVRC until the last follow-up or death. RESULTS: OS(TVRC), time to progression (TTP) until appearance of intra- and extrahepatic metastases, and overall TTP and treatment periods in the TAE + TVRC(LDSI) group were all significantly longer than in the TAE + TVRC group (all p < 0.001). CONCLUSION: TAE + TVRC(LDSI) had a higher efficacy and safety, which was reflected by OS rates, progression-free survival rates, longer duration of treatment and milder side effects compared to standard TAE + TVRC. PMID- 26618450 TI - Warming can enhance invasion success through asymmetries in energetic performance. AB - Both climate warming and biological invasions are prominent drivers of global environmental change and it is important to determine how they interact. However, beyond tolerance and reproductive thresholds, little is known about temperature dependence of invaders' performance, particularly in the light of competitive attributes of functionally similar native species. We used experimentally derived energy budgets and field temperature data to determine whether anticipated warming will asymmetrically affect the energy budgets of the globally invasive Ponto-Caspian mysid crustacean Hemimysis anomala and a functionally similar native competitor (Mysis salemaai) whose range is currently being invaded. In contrast to M. salemaai, which maintains a constant feeding rate with temperature leading to diminishing energy assimilation, we found that H. anomala increases its feeding rate with temperature in parallel with growing metabolic demand. This enabled the invader to maintain high energy assimilation rates, conferring substantially higher scope for growth compared to the native analogue at spring to-autumn temperatures. Anticipated warming will likely exacerbate this energetic asymmetry and remove the winter overlap, which, given the seasonal limitation of mutually preferred prey, appears to underpin coexistence of the two species. These results indicate that temperature-dependent asymmetries in scope for growth between invaders and native analogues comprise an important mechanism determining invasion success under warming climates. They also highlight the importance of considering relevant spectra of ecological contexts in predicting successful invaders and their impacts under warming scenarios. PMID- 26618451 TI - Fish collagen-based scaffold containing PLGA microspheres for controlled growth factor delivery in skin tissue engineering. AB - To design a scaffold controlled release system for skin tissue engineering, fish collagen/chitosan/chondroitin sulfate scaffolds were fabricated by freeze-drying and incorporated with bFGF-loaded PLGA microspheres (MPs). SEM showed that the scaffolds exhibited an interconnected porous structure, and the spherical MPs were uniformly distributed into the scaffolds. The higher swelling and degradation rate of scaffolds/MPs could lead to a higher diffusion rate of MPs from the scaffolds, causing an increase in the protein release. The release rate of proteins could be adjusted by the size of MPs and the ratio of collagen to chitosan of scaffolds. Circular dichroism spectroscopy and MTT of bFGF after release indicated that the released bFGF retained its structural integrity and bioactivity during preparation. Cell proliferation and in vivo evaluation results suggested that the scaffolds/MPs had a good biocompatibility and an ability to promote fibroblast cell proliferation and skin tissue regeneration. These results demonstrated that this scaffold/MP controlled release system has the potential for skin tissue engineering. PMID- 26618453 TI - Introduction for the Filler Special Issue. PMID- 26618452 TI - Origin of the Instability of Octadecylamine Langmuir Monolayer at Low pH. AB - It has been reported that an octadecylamine (ODA) Langmuir monolayer becomes unstable at low pH values with no measurable surface pressure at around pH 3.5, suggesting significant dissolution of the ODA molecule into the subphase solution (Albrecht, Colloids Surf. A 2006, 284-285, 166-174). However, by lowering the pH further, ODA molecules reoccupy the surface, and a full monolayer is recovered at pH 2.5. Using surface sum-frequency spectroscopy and pressure-area isotherms, it is found that the recovered monolayer at very low pH has a larger area per molecule with many gauche defects in the ODA molecules as compared to that at high pH values. This structural change suggests that the reappearance of the monolayer is due to the adsorbed Cl(-) counterions to the protonated amine groups, leading to partial charge neutralization. This proposition is confirmed by intentionally adding monovalent salts (i.e., NaCl, NaBr, or NaI) to the subphase to recover the monolayer at pH 3.5, in which the detailed structure of the monolayer is confirmed by sum frequency spectra and the adsorbed anions by X ray reflectivity. PMID- 26618454 TI - Anatomical Basis for Safe and Effective Volumization of the Temple. AB - BACKGROUND: One of the earliest but often unaddressed signs of facial aging is volume loss in the temple. Treatment of the area can produce satisfying results for both patient and practitioner. OBJECTIVE: Safe injection requires explicit knowledge of the anatomy to avoid complications related to the multitude of vessels that course throughout the region at various depths. The authors aim to detail the anatomy of the area and provide a safe and easy-to-follow method for injection. MATERIALS AND METHODS: The authors review the relevant anatomy of the temporal region and its application to cosmetic filler injections. RESULTS: The authors describe an easy-to-follow approach for a safe and effective injection window based on numerous anatomical studies. Injection in this area is not without risk, including potential blindness. The authors review the potential complications and their treatments. CONCLUSION: Hollowing of the temple is an early sign of aging that, when corrected, can lead to significant patient and practitioner satisfaction. Proper anatomically knowledge is required to avoid potentially severe complications. In this study, the authors present a reliable technique to safely and effectively augment this often undertreated area of the aging face. PMID- 26618455 TI - Volumizing Hyaluronic Acid Filler for Midface Volume Deficit: Results After Repeat Treatment. AB - BACKGROUND: Juvederm Voluma XC (VYC-20L; hyaluronic acid gel) is approved in the United States for correction of age-related midface volume deficit (MVD). OBJECTIVE: Assess safety and effectiveness of VYC-20L after repeat treatment. METHODS: Subjects with MVD underwent optional repeat treatment 12 to 24 months after initial treatment if correction was lost or at 24 months regardless of loss of correction (n = 167). Investigators rated outcomes on the Mid-Face Volume Deficit Scale (MFVDS) and the Global Aesthetic Improvement Scale (GAIS). Subject rated outcomes were the GAIS, overall satisfaction with facial appearance, achievement of treatment goal, and Self-Perception of Age questionnaire. Subjects recorded treatment-site responses in 30-day diaries. RESULTS: Mean injection volume for repeat treatment (3.13 mL) was approximately half the mean total injection volume for initial/touch-up treatment (6.8 mL). After repeat treatment, effectiveness was demonstrated on all investigator-rated and subject-rated measures, consistent with results observed after initial treatment. The percentage of subjects improving by >=1 point on the MFVDS was 82.8% and 91.1% at 6 and 12 months after repeat treatment, respectively. The incidence, severity, and duration of common treatment-site responses were lower after repeat versus initial treatment. CONCLUSION: Repeat treatment with VYC-20L was well tolerated and resulted in high levels of effectiveness and subject satisfaction. PMID- 26618456 TI - Safety and Effectiveness of the Hyaluronic Acid Filler, HYC-24L, for Lip and Perioral Augmentation. AB - BACKGROUND: Hyaluronic acid gels are increasingly used for augmentation of the lips. OBJECTIVE: To assess the safety and effectiveness of Juvederm Ultra XC, a 24 mg/mL hyaluronic acid gel containing 0.3% (wt/wt) lidocaine (HYC-24L), for augmentation of the lips. METHODS: This ongoing, multicenter, single-blind study randomized 213 subjects to the treatment group (n = 157) or concurrent no treatment control group that received delayed treatment (n = 56). The primary effectiveness endpoint was the responder rate (>=1 point improvement from baseline) based on the blinded evaluating investigator's assessment of the subject's overall lip fullness (or fullness of the eligible lip) using the validated Allergan 5-point Lip Fullness Scale. To meet this endpoint, the treatment group had to have a responder rate >=60% and significantly greater than the treatment control group at Month 3. RESULTS: The primary endpoint was met, with a 79.1% responder rate for the treatment group and 26.1% for the treatment control group (p < 0.0001). More than half of subjects (56.4%) maintained treatment response for 12 months. Common injection site responses were swelling, bruising, and firmness; most were of mild or moderate severity. CONCLUSION: HYC 24L is safe and effective for aesthetic lip augmentation, with results lasting up to 1 year. PMID- 26618457 TI - Five-Year Safety and Satisfaction Study of PMMA-Collagen in the Correction of Nasolabial Folds. AB - BACKGROUND: A polymethylmethacrylate-collagen filler is generally believed to give long-term benefits, but the risk of granuloma formation over time remains unclear. OBJECTIVE: To determine the incidence of granuloma formation and response to treatment and assess the degree of patient satisfaction over 5 years. MATERIALS AND METHODS: Adults seeking correction of nasolabial folds underwent up to 3 injection sessions over 2 months. Subjects were then queried regularly for the development of signs and symptoms of a granuloma. Any positive responses were evaluated, and lesions suspicious for granulomas were confirmed by biopsy. Granulomas were treated at the discretion of the investigator. Subjects also completed regular satisfaction questionnaires. RESULTS: A total of 1,008 subjects were enrolled and 871 completed the full 5 years of the study. A biopsy-confirmed granuloma developed in 1.7% of subjects. Almost all granulomas responded to treatment. At study exit, 0.9% of subjects had an unresolved granuloma. Patient satisfaction remained high throughout the duration of the study. CONCLUSION: The incidence of granuloma formation with a polymethylmethacrylate-collagen dermal filler is low, and almost all lesions are manageable with simple therapeutic measures. Patient satisfaction remains durable over 5 years. Polymethylmethacrylate-collagen offers a well-characterized and very favorable risk/benefit profile. PMID- 26618459 TI - Three-Dimensional Forehead Reflation. AB - BACKGROUND: The rising popularity of the three-dimensional reflation of the mid and lower face has prompted interest in upperfacial reflation. OBJECTIVE: We have been asked to share our technique for subgaleal three-dimensional forehead reflation. MATERIALS AND METHODS: We have described our anatomic approach, our modification of the hyaluronic acid (HA) filler to achieve reduced viscosity and our injection technique. RESULTS: Immediately after the forehead reflation there is mild brow ptosis due to the lidocaine within the HA filler. This reverses in 30 to 60 minutes post injection. There is a need for further enhancement about 2 3 weeks later in approximately 30 percent of subjects. The results last between 10-12 months. CONCLUSION: Three-dimensional subgaleal forehead reflation is an effective and safe procedure when performed with an HA filler and a knowledge of the periorbital vascular anatomy. PMID- 26618458 TI - Objective Analysis of Poly-L-Lactic Acid Injection Efficacy in Different Settings. AB - BACKGROUND: Poly-L-lactic acid (PLLA) filler is known to have continuous volume effect. OBJECTIVE: The objective of this study is to analyze objective volume effect of PLLA in different settings of injection schedule on the cheek. METHODS: A split-face, evaluator-blind randomized study in 24 volunteers was conducted. One side was injected 3 times with 4 cc dose and the other side was injected 2 times with 6 cc dose per visit. Facial volume loss scale (FVLS) and Vectra were evaluated. RESULTS: Measured average FVLS showed statistically significant improvement both in 3 and 2 times injection sides and maintained efficacy until 12 months. Vectra showed volume difference (cc) between before and after injection. In 3 times injection side, it was increased 2.12 (after 1 month) to 3.17 (after 12 months). In 2 times injection side, it was increased 2.26 (after 1 month) to 3.19 (after 12 months). Gradual volume improvement over 12 months was statistically significant in both sides. There was no statistically significant difference between 3 and 2 times injection in FVLS and Vectra. There was no severe adverse event. CONCLUSION: Poly-L-lactic acid has continuous volume effect and there was no significant difference by injection times at the same total injection volume. PMID- 26618460 TI - Patient Satisfaction and Efficacy of Full-Facial Rejuvenation Using a Combination of Botulinum Toxin Type A and Hyaluronic Acid Filler. AB - BACKGROUND: Combination treatments using hyaluronic acid (HA) fillers and botulinum toxin Type A (BoNT-A) are common in aesthetic medicine; however, this has been evaluated in only a few clinical studies. OBJECTIVE: To evaluate subject satisfaction, efficacy, and safety of BoNT-A (Speywood Unit; s.U) and a range of HA fillers for full-facial aesthetic rejuvenation. MATERIALS AND METHODS: A 6 month, multicenter, open-label clinical study, using BoNT-A (s.U) and 5 HA fillers to treat up to 13 facial zones. Subject satisfaction questionnaires were administered 3 weeks and 6 months after the last injection. Global aesthetic improvement and improvement on each treated zone as well as safety were evaluated. RESULTS: A high level of satisfaction was achieved throughout the study, with 96.5% of subjects at least satisfied with the full-facial aesthetic outcome at 3 weeks, and 92.9% at 6 months. More than 91% considered the treatment outcome to meet or surpass their expectations, and more than 94% would recommend the treatment to others. At Week 3, subject and investigator assessment showed aesthetic improvement for all subjects. The treatment was well tolerated. CONCLUSION: The combination of BoNT-A (s.U) and HA fillers results in high patient satisfaction and in an overall improvement of aesthetic outcomes and quality of life. PMID- 26618461 TI - The Facial Adipose System: Its Role in Facial Aging and Approaches to Volume Restoration. AB - BACKGROUND: Volume loss in facial adipose tissue plays a critical role in the aesthetics of facial aging. Furthermore, the facial adipose system is a complex network of distinct compartments, and a detailed understanding of these compartments is essential for optimal facial volume restoration. OBJECTIVE: To review the facial adipose system, age-related changes, and the role of volume restoration products for facial rejuvenation. METHODS: Publications including deceased donors' dissection studies and more recent studies using computed tomography were reviewed to provide an up-to-date understanding of the facial adipose system anatomy and age-related changes. Current volume restoration treatment options including hyaluronic acid, calcium hydroxylapatite, and poly-L lactic acid are discussed. RESULTS: Facial aging is associated with volume loss in superficial and deep adipose compartments, including those of the forehead, cheek, lip, chin, and jowl areas. Volume restoration products can be used to address the age-related changes of the facial adipose compartments. CONCLUSION: Understanding the complex network of facial adipose compartments and their age related changes allows for the optimal use of injectable volume restoration products for facial rejuvenation that can be customized to the anatomical needs of each patient. PMID- 26618462 TI - Retraction of the Plunger on a Syringe of Hyaluronic Acid Before Injection: Are We Safe? AB - BACKGROUND: Controversy exists concerning the need for aspiration before injection with hyaluronic acid (HA) fillers. OBJECTIVE: The authors undertook a study of HA products to determine if blood could be aspirated back into a syringe of HA when the needle has been primed or filled with HA. METHODS AND MATERIALS: Two studies were set up to determine if or when blood could be withdrawn from a heparinized fresh tube of blood into the HA syringe. Two different techniques were tested; one using a slow-pull retraction of the plunger and up to a 5-second waiting time before release versus a rapid pullback and quick release. RESULTS: Review of these data demonstrates that the usual clinical method, which involves quick withdrawal and instant release of the syringe plunger does not allow for sufficient removal of the filler found intraluminal in the needle and may give rise to false negative results in vitro and likely in vivo with the exception being the Galderma/Medicis products. CONCLUSION: In summary, withdrawal of the syringe plunger with no visible blood in the syringe does not eliminate the possibility of intravascular placement of the syringe needle. PMID- 26618463 TI - Hyaluronidase Caveats in Treating Filler Complications. AB - BACKGROUND: Most of the complications associated with hyaluronic acid (HA) fillers can be addressed by hyaluronidase. Extensive experience with this enzyme was accumulated in ophthalmology and anesthesia. In dermatologic use multiple aspects still remain controversial. OBJECTIVE: To elucidate questions with regard to hyaluronidase use in HA-induced complications, including appropriate dosage, timing, and technique of delivery, differences in the activity of hyaluronidases of different origins, interaction between the enzymes and different HA gels, and safety issues. MATERIALS AND METHODS: Extensive review of the relevant literature was conducted. The conclusions are based on this review and personal author's experience. RESULTS: FDA-approved hyaluronidases provide predictable results and can be used interchangeably. A physician has to be closely familiar with specific characteristics of other hyaluronidases. Different brands of HA fillers have different sensitivity to degradation by hyaluronidase. For filler overcorrection or misplacement, low dose of the enzyme has to be injected directly into the palpable HA mass. In case of vascular accident, flushing of the ischemic area with high doses of hyaluronidase is required. Hypersensitivity reactions to hyaluronidase are so far not reported in dermatologic literature. CONCLUSION: With increased popularity of HA fillers, hyaluronidase had become an indispensable tool in dermatology office. It is safe and reliable for treatment of HA-induced complications. PMID- 26618464 TI - Retro or PeriBulbar Injection Techniques to Reverse Visual Loss After Filler Injections. AB - BACKGROUND: With the increasing popularity of three dimensional filler treatments, the tip of the injecting needle or cannula is subdermal, often adjacent to the facial vasculature. Inadvertent canalization of these vessels can rarely result in vascular occlusion with consequent blindness or stroke. OBJECTIVE: The goal was to demonstrate a technique of retro or peribulbar injection of hyaluronidase should such an emergency arise if no ophthalmologist was immediately available. The treatment is needed urgently because the retina can only withstand up to 90 minutes of hypoxia. MATERIALS AND METHODS: We present verbal and diagrammatic instructions for this treatment and videos of both the retrobulbar technique (courtesy of Dr. D. Maberley) and peribulbar technique (courtesy of Dr. S. Fagien). RESULTS: None of us have yet used this technique to treat iatrogenic filler induced blindness but we present the information for the benefit of patient safety, given the limited time the retina can survive vascular occlusion. CONCLUSION: Inadvertent canalization of facial vessels can cause embolic occlusion of retinal vasculature because of the anastomotic nature of the facial vasculature and the end artery morphology of the retinal circulation. Embolism from 3-dimensional hyaluronic acid filler use is potentially reversible if hyaluronidase is injected into the adjacent tissue. PMID- 26618465 TI - The Myth of the "Biphasic" Hyaluronic Acid Filler. AB - BACKGROUND: The terms "biphasic" and "monophasic" have been used frequently as a means of differentiating hyaluronic acid (HA) fillers. This type of categorization is based on misinterpretations of the term "phase" and provides no help to the practitioner when selecting the most appropriate product for each indication, patient, and injection technique. OBJECTIVE: The purpose of this study was to analyze the properties of 2 HA filler families; Juvederm (JUV) (Allergan), often stated to be monophasic and Restylane (RES) (Galderma), often stated to be biphasic, and discuss what properties may have led to the use of the terms monophasic and biphasic. MATERIALS AND METHODS: Three different methods were used for JUV and RES: determination of extractable HA; determination of water uptake; and microscopy. RESULTS: The analyzed products were shown to contain both observable gel particles and extractable HA and have the ability to absorb added water. CONCLUSION: The categorization of HA fillers as biphasic or monophasic was shown to be scientifically incorrect and should therefore be avoided. Further analytical measurement of the properties leading to this misinterpretation can provide information to discriminate and categorize HA fillers on a sounder scientific basis. PMID- 26618466 TI - Is There a Method That Can Measure Cohesivity? Cohesion by Sensory Evaluation Compared With Other Test Methods. AB - BACKGROUND: Cohesion is described as the force between particles of the same substance that acts to unite them. Contrary to rheology, there are currently no ready-made instruments designed to measure cohesion, or methods which could be easily adapted to gels. To study and compare the possible clinical effects from the cohesive properties of a gel, it is necessary to standardize the definition and measurement of cohesion. OBJECTIVE: The purpose of this study was to develop and evaluate methods for measuring cohesion. METHODS AND MATERIALS: Three different methods were evaluated and compared with measures of perceived cohesion; compression force, dispersion in water and drop weight. Two different families of fillers (Emervel and Restylane) were used for evaluating the different methods. RESULTS: The compression force did not reflect the measures of perceived cohesion. The dispersion method showed variable results over time, had some practical issues, and is evaluated by subjective assessment. The best correlation to the perceived cohesion was found with the drop weight method. CONCLUSION: The drop weight method which closely resembles the definition of cohesion (IUPAC) was considered to be the best method for measuring cohesion. PMID- 26618467 TI - Rheological Properties and In Vivo Performance Characteristics of Soft Tissue Fillers. AB - BACKGROUND: Physicochemical properties and performance in nonclinical animal models can provide insights into soft tissue filler performance. OBJECTIVE: To evaluate the in vivo performance of fillers with different compositions and physicochemical properties. MATERIALS AND METHODS: Physicochemical properties were measured in vitro. Rat models were developed and used to compare lift capacity, resistance to deformation, and tissue integration. Four homogeneous hyaluronic acid (HA) fillers, 2 nonanimal stabilized HA (NASHA) fillers, and 1 calcium hydroxylapatite/carboxymethyl cellulose (CaHA/CMC) filler were evaluated. RESULTS: Filler lift capacity correlated better with filler composition/type (homogeneous > NASHA > CaHA/CMC) than with specific rheological properties. The CaHA/CMC filler had high initial resistance to deformation relative to other groups; all HA fillers exhibited lower initial resistance to deformation, which increased over time. Homogeneous HA fillers were integrated with surrounding tissue, whereas integration within particle-based fillers (NASHA and CaHA/CMC) was variable, with some areas void of tissue. CONCLUSION: The animal models provide a platform to make comparative evaluations among fillers. The results indicated that biological interaction plays an important role in how the filler performs. Rheology alone was not sufficient to understand filler performance but was most useful when comparing within fillers of similar composition. PMID- 26618468 TI - Soft Tissue Augmentation: It Is Not What You Use, It Is How You Use It. PMID- 26618469 TI - A Randomized, Blinded Study to Validate the Merz Hand Grading Scale for Use in Live Assessments. AB - BACKGROUND: The Merz Hand Grading Scale (MHGS) is a 5-point scale used to grade appearance of the dorsum of the hand. The MHGS has been previously validated for assessment of photographed hands but not for live assessment. OBJECTIVE: The purpose of this randomized, blinded study was to validate the MHGS for live assessment of the hands in the clinical setting. METHODS: Three physician raters completed a scale qualification program that included MHGS training, ratings of standardized hand photographs, and statistical analysis for reliability. Eighty four subjects (28 males, 30% Fitzpatrick skin Types IV-VI, mean age of 42 years), randomized to 2 live assessment sessions for independent and blinded observation of dorsa of their right hands, completed the study. RESULTS: Overall MHGS intrarater weighted Kappa value was 0.74 (0.68-0.79 [CI 95%]). First- and second time hand-rating agreement scores ranged from 64% to 75%. Interrater weighed Kappa values ranged from 0.59 to 0.71, representing between-rater paired results of each combination of raters. CONCLUSION: High-weighted Kappa values and agreements demonstrate that consistency at different time points can be achieved individually and by different raters for live assessments. The MHGS is a suitable instrument for live assessment in the clinical setting. PMID- 26618470 TI - Evaluation of the Merz Hand Grading Scale After Calcium Hydroxylapatite Hand Treatment. AB - BACKGROUND: Measurement scales that quickly and rigorously evaluate the effectiveness of filler treatment in hands are important tools in clinical practice. The Merz Hand Grading Scale (MHGS) is used to grade the appearance of the dorsal hand. The MHGS has been validated for photographic and live assessment of the hands. OBJECTIVE: To evaluate the sensitivity of the 5-point MHGS to detect clinically meaningful and aesthetically pleasing changes in hand appearance after treatment with a calcium hydroxylapatite (CaHA)-based dermal filler. METHODS: The controlled 4-week study randomized 30 subjects (60 hands) 2:1 to a Treatment group (treatment at enrollment) or a Control group (treatment at end of study). Effectiveness was evaluated with live MHGS ratings and photographic assessments with the Global Aesthetic Improvement Scale (GAIS). RESULTS: At Week 4, all Treatment group subjects (20/20) achieved a >=1-point improvement on the MHGS compared with 0/10 (0%) of the Control group (p < .0001). Subjects and treating physicians rated 92.5% (37/40) and 100% (40/40), respectively, of hands as at least "improved," using the GAIS. CONCLUSION: The MHGS is an appropriate and validated tool that clinicians can use to counsel patients and evaluate clinically meaningful and aesthetically pleasing changes after hand treatment with CaHA. PMID- 26618472 TI - Novel human hepatic organoid model enables testing of drug-induced liver fibrosis in vitro. AB - Current models for in vitro fibrosis consist of simple mono-layer cultures of rodent hepatic stellate cells (HSC), ignoring the role of hepatocyte injury. We aimed to develop a method allowing the detection of hepatocyte-mediated and drug induced liver fibrosis. We used HepaRG (Hep) and primary human HSCs cultured as 3D spheroids in 96-well plates. These resulting scaffold-free organoids were characterized for CYP induction, albumin secretion, and hepatocyte and HSC specific gene expression by qPCR. The metabolic competence of the organoid over 21 days allows activation of HSCs in the organoid in a drug- and hepatocyte dependent manner. After a single dose or repeated exposure for 14 days to the pro fibrotic compounds Allyl alcohol and Methotrexate, hepatic organoids display fibrotic features such as HSC activation, collagen secretion and deposition. Acetaminophen was identified by these organoids as an inducer of hepatotoxic mediated HSC activation which was confirmed in vivo in mice. This novel hepatic organoid culture model is the first that can detect hepatocyte-dependent and compound-induced HSC activation, thereby representing an important step forward towards in vitro compound testing for drug-induced liver fibrosis. PMID- 26618473 TI - Palladium-Catalyzed Markovnikov-Selective Hydroselenation of N-Vinyl Lactams with Selenols Affording N,Se-Acetals. AB - The highly regioselective hydroselenation of N-vinyl lactams has been revealed to successfully afford the corresponding N,Se-acetals as Markovnikov adducts. In the case of terminal N-vinyl lactams, Markovnikov-selective hydroselenation proceeds efficiently in the absence of any catalyst (or additive), owing to the acidity of the selenols. In contrast, the self-promoted hydroselenation is inefficient with internal N-vinyl lactams. In the presence of palladium diacetate (Pd(OAc)2), however, the desired hydroselenation of internal N-vinyl lactams proceeds efficiently to afford the corresponding N,Se-acetals. PMID- 26618471 TI - Association of Fitness in Young Adulthood With Survival and Cardiovascular Risk: The Coronary Artery Risk Development in Young Adults (CARDIA) Study. AB - IMPORTANCE: Although cardiorespiratory fitness (CRF) is prognostic in older adults, the effect of CRF during early adulthood on long-term cardiovascular structure, function, and prognosis is less clear. OBJECTIVE: To examine whether CRF in young adults is associated with long-term clinical outcome and subclinical cardiovascular disease (CVD). DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 4872 US adults aged 18 to 30 years who underwent treadmill exercise testing at a baseline study visit from March 25, 1985, to June 7, 1986, and 2472 individuals who underwent a second treadmill test 7 years later. Median follow-up was 26.9 years, with assessment of obesity, left ventricular mass and strain, coronary artery calcification (CAC), and vital status and incident CVD. Follow-up was complete on August 31, 2011, and data were analyzed from recruitment through the end of follow-up. MAIN OUTCOMES AND MEASURES: The presence of CAC was assessed by computed tomography at years 15 (2000-2001), 20 (2005-2006), and 25 (2010-2011), and left ventricular mass was assessed at years 5 (1990-1991) and 25 (with global longitudinal strain). Incident CVD and all-cause mortality were adjudicated. RESULTS: Of the 4872 individuals, 273 (5.6%) died and 193 (4.0%) experienced CVD events during follow-up. After comprehensive adjustment, each additional minute of baseline exercise test duration was associated with a 15% lower hazard of death (hazard ratio [HR], 0.85; 95% CI, 0.80-0.91; P < .001) and a 12% lower hazard of CVD (HR, 0.88; 95% CI, 0.81-0.96; P = .002). Higher levels of baseline CRF were associated with significantly lower left ventricular mass index (beta = -0.24; 95% CI, -0.45 to -0.03; P = .02) and significantly better lobal longitudinal strain (beta = -0.09; 95% CI, -0.14 to -0.05; P < .001) at year 25. Fitness was not associated with CAC. A 1-minute reduction in fitness by year 7 was associated with 21% and 20% increased hazards of death (HR, 1.21; 95% CI, 1.07-1.37; P = .002) and CVD (HR, 1.20; 95% CI, 1.06-1.37; P = .006), respectively, along with a more impaired strain (beta = 0.15; 95% CI, 0.08-0.23; P < .001). No association between change in fitness and CAC was found. CONCLUSIONS AND RELEVANCE: Higher levels of fitness at baseline and improvement in fitness early in adulthood are favorably associated with lower risks for CVD and mortality. Fitness and changes in fitness are associated with myocardial hypertrophy and dysfunction but not CAC. Regular efforts to ascertain and improve CRF in young adulthood may play a critical role in promoting cardiovascular health and interrupting early CVD pathogenesis. PMID- 26618474 TI - Metagenomic Classification Using an Abstraction Augmented Markov Model. AB - The abstraction augmented Markov model (AAMM) is an extension of a Markov model that can be used for the analysis of genetic sequences. It is developed using the frequencies of all possible consecutive words with same length (p-mers). This article will review the theory behind AAMM and apply the theory behind AAMM in metagenomic classification. PMID- 26618475 TI - Penicillin-Binding Protein 5 Sequence Alteration and Levels of plp5 mRNA Expression in Clinical Isolates of Enterococcus faecium with Different Levels of Ampicillin Resistance. AB - Eighty-two nonduplicated ampicillin-resistant Enterococcus faecium (AREF) isolates from clinical infections at the Charles Nicolle Hospital of Tunisia were investigated. They were collected from January 2001 to December 2009. Genetic relationship between them was studied using pulsed-field gel electrophoresis. The amino acid sequence difference variations of the C-terminal part of penicillin binding protein 5 (PBP5) versus levels of expressed mRNA were investigated by polymerase chain reaction (PCR), sequencing, and real-time PCR quantification of (PBP5), respectively. No beta-lactamase activity was detected and none of our strains showed resistance to glycopeptides, which retain their therapeutic efficiency against enterococcal infections in our hospital. Pattern analysis of the strains revealed six main clones disseminating in different wards. Sequence data revealed the existence of 19 different plp5 alleles with a difference in 16 amino acid positions spanning from residue 414 to 632. Each allele presented at least five amino acid substitutions (His-470->Gln, Asn-496->Lys, Ala-499->Thr, Glu-525->Asp, and Glu-629->Val). No correlation between amino acid sequence polymorphism of PBP5 and levels of ampicillin resistance was detected. The levels of plp5 mRNA expression varied between strains and did not always correlate with levels of ampicillin resistance in clinical AREF. PMID- 26618476 TI - Cytologic categorization of pancreatic neoplastic mucinous cysts with an assessment of the risk of malignancy: A retrospective study based on the Papanicolaou Society of Cytopathology guidelines. AB - BACKGROUND: Cytology plays a pivotal role in the preoperative diagnosis of pancreatic cysts. Here the Papanicolaou Society of Cytopathology (Pap Society) guidelines were used to reclassify and assess the malignancy risk of cytology diagnoses of histologically proven pancreatic neoplastic mucinous cysts. METHODS: A database search (January 2000 to June 2014) was performed for pancreatic neoplastic mucinous cyst resections with endoscopic ultrasound-guided fine-needle aspiration within the preceding year. Histologic diagnoses were reclassified according to the 2010 Word Health Organization criteria. For atypical/suspicious/positive cytology diagnoses, the cytology slides were reviewed, blinded to the histologic diagnoses. The cysts were reclassified according to the Pap Society guidelines, and the findings were correlated with the histology. RESULTS: One hundred thirty-eight cases of pancreatic neoplastic mucinous cysts were retrieved. Eleven cases with atypical/suspicious cytology diagnoses with unavailable slides were excluded. The remaining 127 cases included 81 intraductal papillary mucinous neoplasms and 46 mucinous cystic neoplasms. The sensitivity of cytology for the diagnosis of neoplastic mucinous cysts was 76.4%. The sensitivity, specificity, and accuracy of cytology for the diagnosis of malignancy (high-grade dysplasia or worse) were 48.3%, 94.9%, and 84.3%, respectively. The risk of malignancy was 17.4% for the nondiagnostic category, 0% for the negative category, 13% for the neoplastic category, 63.6% for the atypical category, 80% for the suspicious category, and 100% for a positive diagnosis. CONCLUSIONS: This study reveals that the Pap Society guidelines allow the accurate categorization of pancreatic neoplastic mucinous cysts with cytology. The diagnostic categories (from negative to positive) are associated with an increasing risk of malignancy, and this can further aid in patient management and risk stratification. PMID- 26618477 TI - Infaunal Benthic Communities from the Inner Shelf off Southwestern Africa Are Characterised by Generalist Species. AB - Infaunal communities of benthic macro-organisms (>= 1mm length) were studied from 81 samples collected across nine sites to the north and south of the Orange River in the Benguela upwelling ecosystem in 2003, with a view to describing communities and understanding the drivers of regional community structure, as well as to document diversity and to examine geographic affinities. Although the fauna was dominated by polychaetes and peracarid crustaceans, patterns in community structure could only weakly be explained by the measured environment (~35%). This is attributed to the generalist nature of the species recovered, which were widely distributed amongst different sediments, water-depths and latitudes. The fauna is dominated by species that enjoy a widespread regional and global distribution and is characterised by relatively low diversity, which is discussed. PMID- 26618480 TI - Stimuli-Responsive Free-Standing Layer-By-Layer Films. AB - Free-standing, stimuli-responsive polyelectrolyte multilayer films enabled by light-induced degradation of sacrificial compartments are introduced. Two examples are described: i) a triple responsive film that uses light, redox, and pH for different functions, and ii) different wavelengths of light for different functions. This approach to multiresponsive materials offers simple design and chemical synthesis while enabling different stimuli to perform separate functions in the same material. PMID- 26618478 TI - Do Lung Cancer Eligibility Criteria Align with Risk among Blacks and Hispanics? AB - BACKGROUND: Black patients have higher lung cancer risk despite lower pack years of smoking. We assessed lung cancer risk by race, ethnicity, and sex among a nationally representative population eligible for lung cancer screening based on Medicare criteria. METHODS: We used data from the National Health and Nutrition Examination Survey, 2007-2012 to assess lung cancer risk by sex, race and ethnicity among persons satisfying Medicare age and pack-year smoking eligibility criteria for lung cancer screening. We assessed Medicare eligibility based on age (55-77 years) and pack-years (>= 30). We assessed 6-year lung cancer risk using a risk prediction model from Prostate, Lung, Colorectal and Ovarian Cancer Screening trial that was modified in 2012 (PLCOm2012). We compared the proportions of eligible persons by sex, race and ethnicity using Medicare criteria with a risk cut-point that was adjusted to achieve comparable total number of persons eligible for screening. RESULTS: Among the 29.7 million persons aged 55-77 years who ever smoked, we found that 7.3 million (24.5%) were eligible for lung cancer screening under Medicare criteria. Among those eligible, Blacks had statistically significant higher (4.4%) and Hispanics lower lung cancer risk (1.2%) than non-Hispanic Whites (3.2%). At a cut-point of 2.12% risk for lung screening eligibility, the percentage of Blacks and Hispanics showed statistically significant changes. Blacks eligible rose by 48% and Hispanics eligible declined by 63%. Black men and Hispanic women were affected the most. There was little change in eligibility among Whites. CONCLUSION: Medicare eligibility criteria for lung cancer screening do not align with estimated risk for lung cancer among Blacks and Hispanics. Data are urgently needed to determine whether use of risk-based eligibility screening improves lung cancer outcomes among minority patients. PMID- 26618479 TI - Distinct Roles for CdtA and CdtC during Intoxication by Cytolethal Distending Toxins. AB - Cytolethal distending toxins (CDTs) are heterotrimeric protein exotoxins produced by a diverse array of Gram-negative pathogens. The enzymatic subunit, CdtB, possesses DNase and phosphatidylinositol 3-4-5 trisphosphate phosphatase activities that induce host cell cycle arrest, cellular distension and apoptosis. To exert cyclomodulatory and cytotoxic effects CDTs must be taken up from the host cell surface and transported intracellularly in a manner that ultimately results in localization of CdtB to the nucleus. However, the molecular details and mechanism by which CDTs bind to host cells and exploit existing uptake and transport pathways to gain access to the nucleus are poorly understood. Here, we report that CdtA and CdtC subunits of CDTs derived from Haemophilus ducreyi (Hd CDT) and enteropathogenic E. coli (Ec-CDT) are independently sufficient to support intoxication by their respective CdtB subunits. CdtA supported CdtB mediated killing of T-cells and epithelial cells that was nearly as efficient as that observed with holotoxin. In contrast, the efficiency by which CdtC supported intoxication was dependent on the source of the toxin as well as the target cell type. Further, CdtC was found to alter the subcellular trafficking of Ec-CDT as determined by sensitivity to EGA, an inhibitor of endosomal trafficking, colocalization with markers of early and late endosomes, and the kinetics of DNA damage response. Finally, host cellular cholesterol was found to influence sensitivity to intoxication mediated by Ec-CdtA, revealing a role for cholesterol or cholesterol-rich membrane domains in intoxication mediated by this subunit. In summary, data presented here support a model in which CdtA and CdtC each bind distinct receptors on host cell surfaces that direct alternate intracellular uptake and/or trafficking pathways. PMID- 26618481 TI - [The foundation of the German Society for Child Psychiatry and Therapeutic Education - Paul Schroeder's road to foundation chairman]. AB - The reconstruction of the evolutionary history of this professional association lays its focus on the developments which contributed to the society's formal foundation during the time of the patient killings in Germany after 1939. Methodologically the study follows strategies of historical network analysis including the main actors of the foundation process. The foundation of this society can be seen as the result of the interaction of a) the Reichs-Health Agency, its president Hans Reiter, and Fritz Rott as National Socialist health politicians, b) the scientific development geared to this policy of a young discipline that shared its knowledge base as well as its medical 'object' with established specialties like psychiatry and pediatrics, c) a postulated need for character studies, prognosis and selection, and d) personal as well as professional-political interests of the main protagonists Schroeder and Villinger. Once more it is obvious that medicine and politics were not only interwoven, but in certain areas in accordance with each other. Borders could rather be established between social regulatory "instances". The foundation of the DGKH (Deutsche Gesellschaft fur Kinderpsychiatrie und Heilpadagogik; German Society for Child Psychiatry and Therapeutic Education) is an example of a 'radical regulatory reasoning' according to Raphael, that by means of "institutional arrangements at medium level" (Raphael, 2001) was supposed to implement the 'new National-Socialist order'. PMID- 26618483 TI - Gentlemen, damn the sphenoid bone! PMID- 26618482 TI - Thymic Stromal Lymphopoietin Induction Is Mediated by the Major Whey Proteins alpha-Lactalbumin and beta-Lactoglobulin through the NF-kappaB Pathway in Immune Cells. AB - alpha-Lactalbumin and beta-lactoglobulin are two major whey proteins that specifically bind immunoglobulin E and are suspected as major allergens causing cow's milk allergy (CMA). Recent studies have shown that thymic stromal lymphopoietin is a critical factor linking at the interface of the body and environment to the T-helper 2 response. However, it is not known whether thymic stromal lymphopoietin expression is changed by alpha-lactalbumin and beta lactoglobulin in immune cells. Using RT-PCR and ELISA, the present study was conducted to examine if intravenous injection of alpha-lactalbumin and beta lactoglobulin increased pro-inflammatory cytokines, T-helper 2 cytokines, and thymic stromal lymphopoietin expression in several immune cells, including macrophages, mast cells, and keratinocytes. Results showed that alpha-lactalbumin and beta-lactoglobulin induced thymic stromal lymphopoietin, interleukin-6, and tumor necrosis factor-alpha expression. It was concluded that the allergenicity of alpha-lactalbumin and beta-lactoglobulin may be attributed to thymic stromal lymphopoietin induction, T-helper 2 cytokines, and pro-inflammatory cytokines. PMID- 26618486 TI - A comparison of haemolytic responses in fore-foot and rear-foot distance runners. AB - This study examined the haemolytic effects of an interval-based running task in fore-foot and rear-foot striking runners. Nineteen male distance runners (10 fore foot, 9 rear-foot) completed 8 * 3 min repeats at 90% vVO2peak on a motorised treadmill. Pre- and post-exercise venous blood samples were analysed for serum haptoglobin to quantify the haemolytic response to running. Vertical ground reaction forces were also captured via a force plate beneath the treadmill belt. Haptoglobin levels were significantly decreased following exercise (P = 0.001) in both groups (but not between groups), suggesting that the running task created a haemolytic stress. The ground reaction force data showed strong effect sizes for a greater peak force (d = 1.20) and impulse (d = 1.37) in fore-foot runners, and a greater rate of force development (d = 2.74) in rear-foot runners. The lack of difference in haptoglobin response between groups may be explained by the trend for fore-foot runners to experience greater peak force and impulse during the stance phase of their running gait, potentially negating any impact of the greater rate of force development occurring from the rear-foot runners' heel strike. Neither type of runner (fore-foot or rear-foot) appears more susceptible to technique-related foot-strike haemolysis. PMID- 26618487 TI - Cadmium sulfide nanoparticles trigger DNA alterations and modify the bioturbation activity of tubificidae worms exposed through the sediment. AB - To address the impact of cadmium sulfide nanoparticles (CdS NPs) in freshwater ecosystems, aquatic oligochaete Tubifex tubifex were exposed through the sediment to a low dose (0.52 mg of 8 nm in size of CdS NPs/kg) for 20 days using microcosms. Cadmium (Cd) was released from the CdS NPs-contaminated sediment to the water column, and during this period the average concentrations of Cd in the filtered water fraction were 0.026 +/- 0.006 ug/L in presence of oligochaetes. Similar experiments with microparticular CdS and cadmium chloride (CdCl2) were simultaneously performed for comparative purposes. CdS NPs exposure triggered various effects on Tubifex worms compared to control, microsized and ionic reference, including modification of genome composition as assessed using RAPD PCR genotoxicity tests. Bioaccumulation levels showed that CdS NPs were less bioavailable than CdCl2 to oligochaetes and reached 0.08 +/- 0.01 ug Cd/g for CdS NPs exposure versus 0.76 +/- 0.3 ug Cd/g for CdCl2 exposure (fresh weight). CdS NPs altered worm's behavior by decreasing significantly the bioturbation activity as assessed after the exposure period using conservative fluorescent particulate tracers. This study demonstrated the high potential harm of the CdS nanoparticular form despite its lower bioavailability for Tubifex worms. PMID- 26618488 TI - Distinct Upstream Role of Type I IFN Signaling in Hematopoietic Stem Cell-Derived and Epithelial Resident Cells for Concerted Recruitment of Ly-6Chi Monocytes and NK Cells via CCL2-CCL3 Cascade. AB - Type I interferon (IFN-I)-dependent orchestrated mobilization of innate cells in inflamed tissues is believed to play a critical role in controlling replication and CNS-invasion of herpes simplex virus (HSV). However, the crucial regulators and cell populations that are affected by IFN-I to establish the early environment of innate cells in HSV-infected mucosal tissues are largely unknown. Here, we found that IFN-I signaling promoted the differentiation of CCL2 producing Ly-6Chi monocytes and IFN-gamma/granzyme B-producing NK cells, whereas deficiency of IFN-I signaling induced Ly-6Clo monocytes producing CXCL1 and CXCL2. More interestingly, recruitment of Ly-6Chi monocytes preceded that of NK cells with the levels peaked at 24 h post-infection in IFN-I-dependent manner, which was kinetically associated with the CCL2-CCL3 cascade response. Early Ly 6Chi monocyte recruitment was governed by CCL2 produced from hematopoietic stem cell (HSC)-derived leukocytes, whereas NK cell recruitment predominantly depended on CC chemokines produced by resident epithelial cells. Also, IFN-I signaling in HSC-derived leukocytes appeared to suppress Ly-6Ghi neutrophil recruitment to ameliorate immunopathology. Finally, tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ dendritic cells appeared to produce initial CCL2 for migration based self-amplification of early infiltrated Ly-6Chi monocytes upon stimulation by IFN-I produced from infected epithelial cells. Ultimately, these results decipher a detailed IFN-I-dependent pathway that establishes orchestrated mobilization of Ly-6Chi monocytes and NK cells through CCL2-CCL3 cascade response of HSC-derived leukocytes and epithelium-resident cells. Therefore, this cascade response of resident-to-hematopoietic-to-resident cells that drives cytokine-to chemokine-to-cytokine production to recruit orchestrated innate cells is critical for attenuation of HSV replication in inflamed tissues. PMID- 26618490 TI - Forging the Future: Maintaining Midwifery Momentum in the Next Decade. PMID- 26618489 TI - Association of Habitual Patterns and Types of Physical Activity and Inactivity with MRI-Determined Total Volumes of Visceral and Subcutaneous Abdominal Adipose Tissue in a General White Population. AB - Population-based evidence for the role of habitual physical activity (PA) in the accumulation of visceral (VAT) and subcutaneous (SAAT) abdominal adipose tissue is limited. We investigated if usual patterns and types of self-reported PA and inactivity were associated with VAT and SAAT in a general white population. Total volumes of VAT and SAAT were quantified by magnetic resonance imaging in 583 men and women (61 +/- 11.9 y; BMI 27.2 +/- 4.4 kg/m2). Past-year PA and inactivity were self-reported by questionnaire. Exploratory activity patterns (APAT) were derived by principal components analysis. Cross-sectional associations between individual activities, total PA in terms of metabolic equivalents (PA MET), or overall APAT and either VAT or SAAT were analyzed by multivariable-adjusted robust or generalized linear regression models. Whereas vigorous-intensity PA (VPA) was negatively associated with both VAT and SAAT, associations between total PA MET, moderate-intensity PA (MPA), or inactivity and VAT and/or SAAT depended on sex. There was also evidence of a threshold effect in some of these relationships. Total PA MET was more strongly associated with VAT in men (B = 3.3 +/- 1.4; P = 0.02) than women (B = -2.1 +/- 1.1; P = 0.07), but was more strongly associated with SAAT in women (B = -5.7 +/- 2.5; P = 0.05) than men (B = -1.7 +/- 1.6; P = 0.3). Men (-1.52 dm3 or -1.89 dm3) and women (-1.15 dm3 or 2.61 dm3) in the highest (>6.8 h/wk VPA) or second (4.0-6.8 h/wk VPA) tertile of an APAT rich in VPA, had lower VAT and SAAT, respectively, than those in the lowest (<4.0 h/wk VPA) tertile (P <= 0.016; P trend <= 0.0005). They also had lower VAT and SAAT than those with APAT rich in MPA and/or inactivity only. In conclusion, our results suggest that in white populations, habitual APAT rich in MPA might be insufficient to impact on accumulation of VAT or SAAT. APAT including >= 4.0-6.8 h/wk VPA, by contrast, are more strongly associated with lower VAT and SAAT. PMID- 26618491 TI - Signal-to-noise ratio estimation using adaptive tuning on the piecewise cubic Hermite interpolation model for images. AB - An improvement to the existing technique of quantifying signal-to-noise ratio (SNR) of scanning electron microscope (SEM) images using piecewise cubic Hermite interpolation (PCHIP) technique is proposed. The new technique uses an adaptive tuning onto the PCHIP, and is thus named as ATPCHIP. To test its accuracy, 70 images are corrupted with noise and their autocorrelation functions are then plotted. The ATPCHIP technique is applied to estimate the uncorrupted noise-free zero offset point from a corrupted image. Three existing methods, the nearest neighborhood, first order interpolation and original PCHIP, are used to compare with the performance of the proposed ATPCHIP method, with respect to their calculated SNR values. Results show that ATPCHIP is an accurate and reliable method to estimate SNR values from SEM images. SCANNING 38:502-514, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26618493 TI - Research on the Top-Down Parsing Method for Context-Sensitive Graph Grammars. AB - The parsing problem is one of the key problems of graph grammars. The typical parsing algorithm uses the bottom-up method. The time-complexity of this method is high, and it is difficult to apply. In order to reduce the time-complexity, this paper uses the top-down method for parsing. This method avoids the subgraph isomorphism judgment and selects the productions specifically, so that the time complexity is greatly reduced. PMID- 26618492 TI - Brain Swelling and Loss of Gray and White Matter Differentiation in Human Postmortem Cases by Computed Tomography. AB - The purpose of this study was to evaluate the brain by postmortem computed tomography (PMCT) versus antemortem computed tomography (AMCT) using brains from the same patients. We studied 36 nontraumatic subjects who underwent AMCT, PMCT, and pathological autopsy in our hospital between April 2009 and December 2013. PMCT was performed within 20 h after death, followed by pathological autopsy including the brain. Autopsy confirmed the absence of intracranial disorders that might be related to the cause of death or might affect measurements in our study. Width of the third ventricle, width of the central sulcus, and attenuation in gray matter (GM) and white matter (WM) from the same area of the basal ganglia, centrum semiovale, and high convexity were statistically compared between AMCT and PMCT. Both the width of the third ventricle and the central sulcus were significantly shorter in PMCT than in AMCT (P < 0.0001). GM attenuation increased after death at the level of the centrum semiovale and high convexity, but the differences were not statistically significant considering the differences in attenuation among the different computed tomography scanners. WM attenuation significantly increased after death at all levels (P<0.0001). The differences were larger than the differences in scanners. GM/WM ratio of attenuation was significantly lower by PMCT than by AMCT at all levels (P<0.0001). PMCT showed an increase in WM attenuation, loss of GM-WM differentiation, and brain swelling, evidenced by a decrease in the size of ventricles and sulci. PMID- 26618494 TI - Intrahepatic Vascular Anatomy in Rats and Mice--Variations and Surgical Implications. AB - INTRODUCTION: The intra-hepatic vascular anatomy in rodents, its variations and corresponding supplying and draining territories in respect to the lobar structure of the liver have not been described. We performed a detailed anatomical imaging study in rats and mice to allow for further refinement of experimental surgical approaches. METHODS: LEWIS-Rats and C57Bl/6N-Mice were subjected to ex-vivo imaging using MUCT. The image data were used for semi automated segmentation to extract the hepatic vascular tree as prerequisite for 3D visualization. The underlying vascular anatomy was reconstructed, analysed and used for determining hepatic vascular territories. RESULTS: The four major liver lobes have their own lobar portal supply and hepatic drainage territories. In contrast, the paracaval liver is supplied by various small branches from right and caudate portal veins and drains directly into the vena cava. Variations in hepatic vascular anatomy were observed in terms of branching pattern and distance of branches to each other. The portal vein anatomy is more variable than the hepatic vein anatomy. Surgically relevant variations were primarily observed in portal venous supply. CONCLUSIONS: For the first time the key variations of intrahepatic vascular anatomy in mice and rats and their surgical implications were described. We showed that lobar borders of the liver do not always match vascular territorial borders. These findings are of importance for the design of new surgical procedures and for understanding eventual complications following hepatic surgery. PMID- 26618495 TI - Injury careers after blast exposure among combat veterans deployed to Iraq or Afghanistan. AB - During the Iraq and Afghanistan wars, blasts were the most common cause of combat injuries, including traumatic brain injury (TBI). Prior to 2007, service members were not systematically screened for TBI, and estimates suggest that tens of thousands of mild TBIs went undiagnosed. This study sought to understand post acute "injury careers," documenting the life- and health-related narratives of veterans who were at high risk of undocumented TBI due to being blast-exposed before 2007. Researchers conducted 38 in-depth interviews between May 2013 and August 2014 with Army veterans who served in combat-intense settings (n = 16) and their family members (n = 10). Respondents detailed a series of experiences in the months and years following blast exposure. We present this series as a model that draws upon the vernacular of participants who described veterans "downplaying" their injuries and later "detaching" themselves from friends, family, and communities, and "denying" or being "oblivious" to their circumstances until a "wake-up call" pushed them to "get help." Looking to the future, veterans grapple with uncertainties related to personal identity and professional or social expectations. This model is presented within a member checked metaphor of an individual being hurled into--and emerging from--a canyon. Policies and programs addressing veteran health, particularly among those exposed to multiple blasts prior to systematic TBI documentation, must consider the personal, social, and health system challenges faced by veterans and their families throughout their injury careers. PMID- 26618496 TI - Governing obesity policies from England, France, Germany and Scotland. AB - Defining a phenomenon as a political problem could be considered a crucial part of any political process. Body weight, when categorised as obesity, has been defined as a political problem since the beginning of the 21st century and has entered the political agenda in many countries. In this article, I present a study of four plans from four Western European countries: England, France, Germany and Scotland, identifying how obesity is defined as a political issue. The questions addressed are: How is the development in the obesity prevalence explained and who is considered responsible for the development? What are the suggested remedies and who is considered responsible for acting? All plans state that obesity is a political issue because it causes health problems; in fact, weight is almost equated to health. The English and Scottish plans present a bio political argument, characterising obesity as a serious threat to the countries' economies. So does the German plan, but not with the same emphasis. The plans portray people with obesity as being economically harmful to their fellow citizens. The French plan expresses another concern by focussing on the discrimination and stigmatization of obese people. All plans define the physical and food environment as a crucial factor in the obesity development, but only the Scottish Government is prepared to use statutory means towards industry and other actors to achieve change. The policies convey an unresolved dilemma: To govern or not to govern? The Governments want individuals to choose for themselves, yet they try to govern the populations to choose as the Governments find appropriate. The plans have a legitimising function, showing that the Governments take the issue seriously. Accordingly, in this case, the actual problematisations seem to be less crucial. PMID- 26618498 TI - High-Concentration Aqueous Dispersions of Nanoscale 2D Materials Using Nonionic, Biocompatible Block Copolymers. AB - Conditions for the dispersion of molybdenum disulfide (MoS2) in aqueous solution at concentrations up to 0.12 mg mL(-1) using a range of nonionic, biocompatible block copolymers (i.e., Pluronics and Tetronics) are identified. Furthermore, the optimal Pluronic dispersant for MoS2 is found to be effective for a range of other 2D materials such as molybdenum diselenide, tungsten diselenide, tungsten disulfide, tin selenide, and boron nitride. PMID- 26618499 TI - Self-Powered Photoelectrochemical Biosensor Based on CdS/RGO/ZnO Nanowire Array Heterostructure. AB - A CdS/reduced graphene oxide (RGO)/ZnO nanowire array (NWAs) heterostructure is designed, which exhibits enhanced photoelectrochemical (PEC) activity compared to pure ZnO, RGO/ZnO, and CdS/ZnO. The enhancement can be attributed to the synergistic effect of the high electron mobility of ordered 1D ZnO NWAs, extended visible-light absorption of CdS nanocrystals, and the formed type II band alignment between them. Moreover, the incorporation of RGO further promotes the charge carrier separation and transfer process due to its excellent charge collection and shuttling characteristics. Subsequently, the CdS/RGO/ZnO heterostructure is successfully utilized for the PEC bioanalysis of glutathione at 0 V (vs Ag/AgCl). The self-powered device demonstrates satisfactory sensing performance with rapid response, a wide detection range from 0.05 mm to 1 mm, an acceptable detection limit of 10 MUm, as well as certain selectivity, reproducibility, and stability. Therefore, the CdS/RGO/ZnO heterostructure has opened up a promising channel for the development of PEC biosensors. PMID- 26618500 TI - Rational Design of Ultralarge Pb1-x Snx Te Nanoplates for Exploring Crystalline Symmetry-Protected Topological Transport. AB - Ultralarge topological crystalline insulator Pb1-x Snx Te nanoplates are developed by controlling substrate surface chemical properties in a cost efficient chemical vapor deposition (CVD) process. Dominant topological surface transport is demonstrated by a gate-voltage-controlled weak (anti)localization effect, indicating the potential application of these nanoplates to low dissipation topological transistors. PMID- 26618501 TI - Cyanotryptophans as Novel Fluorescent Probes for Studying Protein Conformational Changes and DNA-Protein Interaction. AB - Described herein are the syntheses and photophysical characterization of three novel cyanotryptophans, and their efficient incorporation into proteins as fluorescent probes. Photophysical characteristics indicated that each was significantly brighter and red-shifted in fluorescence emission relative to tryptophan. Each analogue was used to activate a suppressor tRNA transcript and was incorporated with good efficiency into two different positions (Trp22 and Trp74) of Escherichia coli dihydrofolate reductase (ecDHFR). The Trp analogues could be monitored selectively in the presence of multiple native Trp residues in DHFR. 6-CNTrp (A) formed an efficient Forster resonance energy transfer (FRET) pair with l-(7-hydroxycoumarin-4-yl)ethylglycine (HCO, D) at position 17. Further, 6-CNTrp (A) was incorporated into two DNA binding proteins, including the Klenow fragment of DNA polymerase I and an RNA recognition motif (RRM2) of heterogeneous nuclear ribonucleoprotein L-like (hnRNP LL). Using these proteins, we demonstrated the use of FRET involving A as a fluorescence donor and benzo[g]quinazoline-2,4-(1H,3H)-dione 2'-deoxyriboside (Tf) or 4 aminobenzo[g]quinazoline-2-one 2'-deoxyriboside (Cf) as fluorescent acceptors to study the binding interaction of the Klenow fragment with duplex DNA oligomers (labeled with Tf), or the domain-specific association between hnRNP LL and the BCL2 i-motif DNA (labeled with Cf). Thus, the non-natural amino acid could be used as a FRET partner for studying protein-nucleic acid interactions. Together, these findings demonstrate the potential utility of 6-CNTrp (A) as a fluorescence donor for the study of protein conformational events. PMID- 26618503 TI - Irradiation of rainbow trout at early life stages results in trans-generational effects including the induction of a bystander effect in non-irradiated fish. AB - The bystander effect, a non-targeted effect (NTE) of radiation, which describes the response by non-irradiated organisms to signals emitted by irradiated organisms, has been documented in a number of fish species. However transgenerational effects of radiation (including NTE) have yet to be studied in fish. Therefore rainbow trout, which were irradiated as eggs at 48h after fertilisation, eyed eggs, yolk sac larvae or first feeders, were bred to generate a F1 generation and these F1 fish were bred to generate a F2 generation. F1 and F2 fish were swam with non-irradiated bystander fish. Media from explants of F1 eyed eggs, F1 one year old fish gill and F1 two year old fish gill and spleen samples, and F2 two year old gill and spleen samples, as well as from bystander eggs/fish, was used to treat a reporter cell line, which was then assayed for changes in cellular survival/growth. The results were complex and dependent on irradiation history, age (in the case of the F1 generation), and were tissue specific. For example, irradiation of one parent often resulted in effects not seen with irradiation of both parents. This suggests that, unlike mammals, in certain circumstances maternal and paternal irradiation may be equally important. This study also showed that trout can induce a bystander effect 2 generations after irradiation, which further emphasises the importance of the bystander effect in aquatic radiobiology. Given the complex community structure in aquatic ecosystems, these results may have significant implications for environmental radiological protection. PMID- 26618502 TI - Amyloid Precursor Protein Translation Is Regulated by a 3'UTR Guanine Quadruplex. AB - A central event in Alzheimer's disease is the accumulation of amyloid beta (Abeta) peptides generated by the proteolytic cleavage of the amyloid precursor protein (APP). APP overexpression leads to increased Abeta generation and Alzheimer's disease in humans and altered neuronal migration and increased long term depression in mice. Conversely, reduction of APP expression results in decreased Abeta levels in mice as well as impaired learning and memory and decreased numbers of dendritic spines. Together these findings indicate that therapeutic interventions that aim to restore APP and Abeta levels must do so within an ideal range. To better understand the effects of modulating APP levels, we explored the mechanisms regulating APP expression focusing on post transcriptional regulation. Such regulation can be mediated by RNA regulatory elements such as guanine quadruplexes (G-quadruplexes), non-canonical structured RNA motifs that affect RNA stability and translation. Via a bioinformatics approach, we identified a candidate G-quadruplex within the APP mRNA in its 3'UTR (untranslated region) at residues 3008-3027 (NM_201414.2). This sequence exhibited characteristics of a parallel G-quadruplex structure as revealed by circular dichroism spectrophotometry. Further, as with other G-quadruplexes, the formation of this structure was dependent on the presence of potassium ions. This G-quadruplex has no apparent role in regulating transcription or mRNA stability as wild type and mutant constructs exhibited equivalent mRNA levels as determined by real time PCR. Instead, we demonstrate that this G-quadruplex negatively regulates APP protein expression using dual luciferase reporter and Western blot analysis. Taken together, our studies reveal post-transcriptional regulation by a 3'UTR G-quadruplex as a novel mechanism regulating APP expression. PMID- 26618504 TI - Assessment of inhalation exposure to indoor air pollutants: Screening for health risks of multiple pollutants in Japanese dwellings. AB - Over the past few decades, multiple low level indoor pollutants have been found in domestic dwellings. The types and concentrations of these indoor pollutants have not been consistent over time and have changed with alterations in lifestyle, the development of novel products used in housing, and the development of new measurement technologies. To clarify the highest risk pollutants for which health risks should be reduced, we conducted a health risk assessment of 49 indoor air pollutants measured in 602 houses during winter and summer from 2012 to 2014. Inhalation reference concentrations were determined, and the margins of exposure were estimated for each indoor pollutant from measured indoor air concentrations. Health risks due to ammonia and acidic gases, including formic acid, acetic acid, and hydrogen chloride, were also assessed. Overall, during both winter and summer, the highest risk pollutants were acrolein, nitrogen dioxide, benzene, formic acid, and hydrogen chloride. The health risks of propanal, acetaldehyde, and 1,4-dichlorobenzene were also high. Principal component analysis (PCA) suggested an independent principal component for 1,4 dichlorobenzene. The primary source of exposure to 1,4-dichlorobenzene in Japan is an indoor household insect repellent. The improvement of individual lifestyle and housing may be appropriate targets for reducing the risk associated with this compound. The provision of further information on the risk to consumers and promotion of changes in consumer consciousness are needed. PCA suggested that the health risks of indoor air pollutants are amalgamated into similar chemical families, such as aldehydes, aliphatic hydrocarbons, aromatic hydrocarbons, or acetic esters. Our results suggest that health-based guidelines or source control measures, based on these chemical families and similar health endpoints, are appropriate for reducing total health risk due to multiple low level indoor pollutants. PMID- 26618505 TI - Effects of mobile phone exposure (GSM 900 and WCDMA/UMTS) on polysomnography based sleep quality: An intra- and inter-individual perspective. AB - BACKGROUND: Studies on effects of radio frequency-electromagnetic fields (RF-EMF) on the macrostructure of sleep so far yielded inconsistent results. This study investigated whether possible effects of RF-EMF exposure differ between individuals. OBJECTIVE: In a double-blind, randomized, sham-controlled cross-over study possible effects of electromagnetic fields emitted by pulsed Global System for Mobile Communications (GSM) 900 and Wideband Code-Division Multiple Access (WCDMA)/Universal Mobile Telecommunications System (WCDMA/UMTS) devices on sleep were analysed. METHODS: Thirty healthy young men (range 18-30 years) were exposed three times per exposure condition while their sleep was recorded. Sleep was evaluated according to the American Academy of Sleep Medicine standard and eight basic sleep variables were considered. RESULTS: Data analyses at the individual level indicate that RF-EMF effects are observed in 90% of the individuals and that all sleep variables are affected in at least four subjects. While sleep of participants was affected in various numbers, combinations of sleep variables and in different directions, showing improvements but also deteriorations, the only consistent finding was an increase of stage R sleep under GSM 900MHz exposure (9 of 30 subjects) as well as under WCDMA/UMTS exposure (10 of 30 subjects). CONCLUSIONS: The results underline that sleep of individuals can be affected differently. The observations found here may indicate an underlying thermal mechanism of RF-EMF on human REM sleep. Nevertheless, the effect of an increase in stage R sleep in one third of the individuals does not necessarily indicate a disturbance of sleep. PMID- 26618507 TI - Concurrent validity and classification accuracy of curriculum-based measurement for written expression. AB - The study presents a critical analysis of written expression curriculum-based measurement (WE-CBM) metrics derived from 3- and 10-min test lengths. Criterion validity and classification accuracy were examined for Total Words Written (TWW), Correct Writing Sequences (CWS), Percent Correct Writing Sequences (%CWS), and Correct Minus Incorrect Writing Sequences (CMIWS). Fourth grade students (n = 109) from 6 schools participated in the study. To assess criterion validity of each metric, total scores from writing tasks were correlated with the state achievement test's composition subtest. Each index investigated was moderately correlated with the subtest. Correlations increased with the longer sampling period, however they were not statistically significant. The accuracy at distinguishing between proficient and not proficient writers on the state assessment was analyzed for each index using discriminant function analysis and Receiver Operating Characteristic (ROC) curves. CWS and CMIWS, indices encompassing production and accuracy, were most accurate for predicting proficiency. Improvements were observed in classification accuracy with an increased sampling time. Utilizing cut scores to hold sensitivity above .90, specificity for each metric increased with longer probes. Sensitivity and specificity increased for all metrics with longer probes when using a 25th percentile cut. Visual analyses of ROC curves reveal where classification improvements were made. The 10-min sample for CWS more accurately identified at risk students in the center of the distribution. Without measurement guiding decisions, writers in the middle of the distribution are more difficult to classify than those who clearly write well or struggle. The findings have implications for screening using WE-CBM. (PsycINFO Database Record PMID- 26618508 TI - A zero dimensional model of lithium-sulfur batteries during charge and discharge. AB - Lithium-sulfur cells present an attractive alternative to Li-ion batteries due to their large energy density, safety, and possible low cost. Their successful commercialisation is dependent on improving their performance, but also on acquiring sufficient understanding of the underlying mechanisms to allow for the development of predictive models for operational cells. To address the latter, we present a zero dimensional model that predicts many of the features observed in the behaviour of a lithium-sulfur cell during charge and discharge. The model accounts for two electrochemical reactions via the Nernst formulation, power limitations through Butler-Volmer kinetics, and precipitation/dissolution of one species, including nucleation. It is shown that the flat shape of the low voltage plateau typical of the lithium-sulfur cell discharge is caused by precipitation. During charge, it is predicted that the dissolution can act as a bottleneck, because for large enough currents the amount that dissolves becomes limited. This results in reduced charge capacity and an earlier onset of the high plateau reaction, such that the two voltage plateaus merge. By including these effects, the model improves on the existing zero dimensional models, while requiring considerably fewer input parameters and computational resources than one dimensional models. The model also predicts that, due to precipitation, the customary way of experimentally obtaining the open circuit voltage from a low rate discharge might not be suitable for lithium-sulfur. This model can provide the basis for mechanistic studies, identification of dominant effects in a real cell, predictions of operational behaviour under realistic loads, and control algorithms for applications. PMID- 26618509 TI - A Genomic Approach to Resolving Relapse versus Reinfection among Four Cases of Buruli Ulcer. AB - BACKGROUND: Increased availability of Next Generation Sequencing (NGS) techniques allows, for the first time, to distinguish relapses from reinfections in patients with multiple Buruli ulcer (BU) episodes. METHODOLOGY: We compared the number and location of single nucleotide polymorphisms (SNPs) identified by genomic screening between four pairs of Mycobacterium ulcerans isolates collected at the time of first diagnosis and at recurrence, derived from a collection of almost 5000 well characterized clinical samples from one BU treatment center in Benin. PRINCIPAL FINDINGS: The findings suggest that after surgical treatment-without antibiotics-the second episodes were due to relapse rather than reinfection. Since specific antibiotics were introduced for the treatment of BU, the one patient with a culture available from both disease episodes had M. ulcerans isolates with a genomic distance of 20 SNPs, suggesting the patient was most likely reinfected rather than having a relapse. CONCLUSIONS: To our knowledge, this study is the first to study recurrences in M. ulcerans using NGS, and to identify exogenous reinfection as causing a recurrence of BU. The occurrence of reinfection highlights the contribution of ongoing exposure to M. ulcerans to disease recurrence, and has implications for vaccine development. PMID- 26618510 TI - Dimethyl Fumarate Ameliorates Lewis Rat Experimental Autoimmune Neuritis and Mediates Axonal Protection. AB - BACKGROUND: Dimethyl fumarate is an immunomodulatory and neuroprotective drug, approved recently for the treatment of relapsing-remitting multiple sclerosis. In view of the limited therapeutic options for human acute and chronic polyneuritis, we used the animal model of experimental autoimmune neuritis in the Lewis rat to study the effects of dimethyl fumarate on autoimmune inflammation and neuroprotection in the peripheral nervous system. METHODS AND FINDINGS: Experimental autoimmune neuritis was induced by immunization with the neuritogenic peptide (amino acids 53-78) of P2 myelin protein. Preventive treatment with dimethyl fumarate given at 45 mg/kg twice daily by oral gavage significantly ameliorated clinical neuritis by reducing demyelination and axonal degeneration in the nerve conduction studies. Histology revealed a significantly lower degree of inflammatory infiltrates in the sciatic nerves. In addition, we detected a reduction of early signs of axonal degeneration through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves. This reduction correlated with an increase of nuclear factor (erythroid derived 2) related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumarate. Furthermore, nuclear factor (erythroid derived 2)-related factor 2 expression in Schwann cells was only rarely detected and there was no increase of Schwann cells death during EAN. CONCLUSIONS: We conclude that immunomodulatory and neuroprotective dimethyl fumarate may represent an innovative therapeutic option in human autoimmune neuropathies. PMID- 26618511 TI - Differential Expression Levels of Integrin alpha6 Enable the Selective Identification and Isolation of Atrial and Ventricular Cardiomyocytes. AB - RATIONALE: Central questions such as cardiomyocyte subtype emergence during cardiogenesis or the availability of cardiomyocyte subtypes for cell replacement therapy require selective identification and purification of atrial and ventricular cardiomyocytes. However, current methodologies do not allow for a transgene-free selective isolation of atrial or ventricular cardiomyocytes due to the lack of subtype specific cell surface markers. METHODS AND RESULTS: In order to develop cell surface marker-based isolation procedures for cardiomyocyte subtypes, we performed an antibody-based screening on embryonic mouse hearts. Our data indicate that atrial and ventricular cardiomyocytes are characterized by differential expression of integrin alpha6 (ITGA6) throughout development and in the adult heart. We discovered that the expression level of this surface marker correlates with the intracellular subtype-specific expression of MLC-2a and MLC 2v on the single cell level and thereby enables the discrimination of cardiomyocyte subtypes by flow cytometry. Based on the differential expression of ITGA6 in atria and ventricles during cardiogenesis, we developed purification protocols for atrial and ventricular cardiomyocytes from mouse hearts. Atrial and ventricular identities of sorted cells were confirmed by expression profiling and patch clamp analysis. CONCLUSION: Here, we introduce a non-genetic, antibody based approach to specifically isolate highly pure and viable atrial and ventricular cardiomyocytes from mouse hearts of various developmental stages. This will facilitate in-depth characterization of the individual cellular subsets and support translational research applications. PMID- 26618512 TI - On-Going Frontal Alpha Rhythms Are Dominant in Passive State and Desynchronize in Active State in Adult Gray Mouse Lemurs. AB - The gray mouse lemur (Microcebus murinus) is considered a useful primate model for translational research. In the framework of IMI PharmaCog project (Grant Agreement n degrees 115009, www.pharmacog.org), we tested the hypothesis that spectral electroencephalographic (EEG) markers of motor and locomotor activity in gray mouse lemurs reflect typical movement-related desynchronization of alpha rhythms (about 8-12 Hz) in humans. To this aim, EEG (bipolar electrodes in frontal cortex) and electromyographic (EMG; bipolar electrodes sutured in neck muscles) data were recorded in 13 male adult (about 3 years) lemurs. Artifact free EEG segments during active state (gross movements, exploratory movements or locomotor activity) and awake passive state (no sleep) were selected on the basis of instrumental measures of animal behavior, and were used as an input for EEG power density analysis. Results showed a clear peak of EEG power density at alpha range (7-9 Hz) during passive state. During active state, there was a reduction in alpha power density (8-12 Hz) and an increase of power density at slow frequencies (1-4 Hz). Relative EMG activity was related to EEG power density at 2 4 Hz (positive correlation) and at 8-12 Hz (negative correlation). These results suggest for the first time that the primate gray mouse lemurs and humans may share basic neurophysiologic mechanisms of synchronization of frontal alpha rhythms in awake passive state and their desynchronization during motor and locomotor activity. These EEG markers may be an ideal experimental model for translational basic (motor science) and applied (pharmacological and non pharmacological interventions) research in Neurophysiology. PMID- 26618513 TI - Fracture Resistance of Molar Crowns Fabricated with Monolithic All-Ceramic CAD/CAM Materials Cemented on Titanium Abutments: An In Vitro Study. AB - PURPOSE: To assess the fracture resistance of single-tooth implant-supported crown restorations made with different CAD/CAM blocks. MATERIALS AND METHODS: Thirty-six titanium abutments were put on dental implant analogs (Mis Implant). For each of three test groups (n = 12/group), implant-supported, cement-retained mandibular molar single crowns were produced. Crowns were made of lithium disilicate glass (LD) IPS e.max CAD, feldspathic glass ceramic (FEL) Vita Mark II, and resin nano-ceramic (RNC) Lava Ultimate. The crowns were cemented with self-adhesive resin cement RelyX Unicem 2. After chewing cycling, crowns were tested to failure in a universal testing machine. Fracture values were calculated as initial (F-initial) and maximum fracture (F-max). RESULTS: The study groups were ranked, in order of having highest value, (LD > FEL) > RNC for F-initial load value and (LD > RNC) > FEL for F-max load value. This demonstrated that there was no parallel change in the F-initial and F-max values presenting the fracture resistance of specimens. CONCLUSIONS: There was no accordance between the F-initial and F-max values of the LD, RNC, and FEL after chewing simulation with thermocycling resembling 5 years of clinical functional use. LD had the highest fracture resistance during the fracture test. RNC had low fracture resistance; however, it had considerably high fracture resistance during the fracture test. FEL had considerably low fracture resistance values. PMID- 26618514 TI - Sialylation of anti-histone immunoglobulin G autoantibodies determines their capabilities to participate in the clearance of late apoptotic cells. AB - The Fc portion of immunoglobulin (Ig)G harbours a single glycosylation site. Glycan sialylation is critical for structure and for certain effector functions of IgG. Anti-histone IgG of patients with systemic lupus erythematosus is reportedly responsible for the recruitment of polymorphonuclear cells (PMN) to the clearance of apoptotic cells. Autoantibodies decorating secondary necrotic cells (SNEC) induce proinflammatory responses after activation of blood-borne phagocytes. Analysing the sialylation status of affinity-purified anti-histone IgG in patients with systemic lupus erythematosus (SLE), we demonstrated that the anti-histone IgG was contained preferentially in the non-sialylated fraction. In functional ex-vivo phagocytosis studies, non-sialylated anti-SNEC IgG directed SNEC preferentially into PMN but did not change their cytokine secretion profiles. In contrast, sialylated IgG reduced the phagocytosis by monocytes of SNEC. Moreover, the sialylated anti-SNEC IgG was not simply anti-inflammatory, but switched the cytokine secretion profiles from interleukin (IL)-6/IL-8 to tumour necrosis factor (TNF)-alpha/IL-1beta. Here we describe how different sialylation statuses of IgG autoantibodies contribute to the complex inflammatory network that regulates chronic inflammation. PMID- 26618516 TI - Impact of Home Hospice Care on Patients with Advanced Lung Cancer: A Longitudinal Population-Based Study in Taiwan. AB - BACKGROUND: The effectiveness of home hospice care was helping patients to die at home, and reducing symptom burden. OBJECTIVE: The study objective was to explore the impact of home hospice care on death at home, end-of-life (EOL) care, and health care costs among patients with advanced lung cancer in their last month of life. METHODS: Using Taiwan's National Health Insurance Claims Database, we analyzed factors associated with home hospice care using logistic regression analysis. RESULTS: We enrolled 568 patients with advanced lung cancer under hospice care who died during 1997-2011, of which 238 (41.9%) received home hospice care. Compared with the inpatient hospice (IH) group, the home hospice (HH) group had a larger portion die at home (55.5% versus 22.1%, p < 0.001), but a smaller portion stayed in hospital more than 14 days in their last month of life (67.3% versus 40.8%, p < 0.001). The mean health care cost was less in the HH group than in the IH group (US $1,385.00 +/- $1,370.00 and US $2,155.00 +/- $1,739.00 [p < 0.001], respectively). Female patients' (p = 0.001) decreased hospital stay in the last month of life (p < 0.001) and longer hospice care duration (p = 0.003) were predictors of receiving home hospice care in advanced lung patients. CONCLUSION: Home hospice care enables patients with advanced lung cancer to increase the 33.4% chance of dying at home, to spend an average of eight-days less in hospital stay, and to save 35.7% health care costs in the last month of life, compared with their counterparts with only inpatient hospice care. Female patients' decreased hospital stay and longer hospice care duration were the predictors of receiving home hospice care. PMID- 26618515 TI - In Vitro Effects of Plantago Major Extract, Aucubin, and Baicalein on Candida albicans Biofilm Formation, Metabolic Activity, and Cell Surface Hydrophobicity. AB - PURPOSE: To determine the in vitro effectiveness of Plantago major extract, along with two of its active components, aucubin and baicalein, on the inhibition of Candida albicans growth, biofilm formation, metabolic activity, and cell surface hydrophobicity. MATERIALS AND METHODS: Twofold dilutions of P. major, aucubin, and baicalein were used to determine the minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), and the minimum biofilm inhibitory concentration (MBIC) of each solution. Separately, twofold dilutions of P. major, aucubin, and baicalein were used to determine the metabolic activity of established C. albicans biofilm using a 2,3-bis (2- methoxy-4-nitro-5 sulfophenyl)-2H-tetrazolium-carboxanilide reduction assay. Twofold dilutions of P. major, aucubin, and baicalein were used to determine the cell surface hydrophobicity of treated C. albicans biofilm by a two-phase assay using hexadecane. The hydrophobicity percentage of the cell surface was then calculated. A mixed-model ANOVA test was used for intergroup comparisons. RESULTS: The MICs of P. major extract (diluted 1:2 to 1:8), aucubin (61 to 244 MUg/ml), and baicalein (0.0063 to 100 MUg/ml) on the total growth of C. albicans were noticeable at their highest concentrations, and the inhibition was dose dependent. The MFC was evaluated after 48 hours of incubation, and aucubin (244 MUg/ml) exhibited a strong fungicidal activity at its highest concentration against C. albicans growth. The MBIC indicated no growth or reduced growth of C. albicans biofilm at the highest concentrations of aucubin (61 to 244 MUg/ml) and baicalein (25 to 100 MUg/ml). Similarly, the effects of these reagents on C. albicans biofilm metabolic activity and hydrophobicity demonstrated high effectiveness at their highest concentrations. CONCLUSION: P. major extract, aucubin, and baicalein caused a dose-dependent reduction on the total growth, biofilm formation, metabolic activity, and cell surface hydrophobicity of C. albicans. This demonstrates their effectiveness as antifungals and suggests their promising potential use as solutions for C. albicans biofilm-related infections. PMID- 26618517 TI - Indentation Tests Reveal Geometry-Regulated Stiffening of Nanotube Junctions. AB - Here we report a unique method to locally determine the mechanical response of individual covalent junctions between carbon nanotubes (CNTs), in various configurations such as "X", "Y", and "Lambda"-like. The setup is based on in situ indentation using a picoindenter integrated within a scanning electron microscope. This allows for precise mapping between junction geometry and mechanical behavior and uncovers geometry-regulated junction stiffening. Molecular dynamics simulations reveal that the dominant contribution to the nanoindentation response is due to the CNT walls stretching at the junction. Targeted synthesis of desired junction geometries can therefore provide a "structural alphabet" for construction of macroscopic CNT networks with tunable mechanical response. PMID- 26618518 TI - Tandem Domains with Tuned Interactions Are a Powerful Biological Design Principle. AB - Allosteric effects of mutations, ligand binding, or post-translational modifications on protein function occur through changes to the protein's shape, or conformation. In a cell, there are many copies of the same protein, all experiencing these perturbations in a dynamic fashion and fluctuating through different conformations and activity states. According to the "conformational selection and population shift" theory, ligand binding selects a particular conformation. This perturbs the ensemble and induces a population shift. In a new PLOS Biology paper, Melacini and colleagues describe a novel model of protein regulation, the "Double-Conformational Selection Model", which demonstrates how two tandem ligand-binding domains interact to regulate protein function. Here we explain how tandem domains with tuned interactions-but not single domains-can provide a blueprint for sensitive activation sensors within a narrow window of ligand concentration, thereby promoting signaling control. PMID- 26618519 TI - PTSD symptoms and marital adjustment among ex-POWs' wives. AB - This study prospectively assessed the implications of war captivity and former prisoners of war's (ex-POWs) posttraumatic stress disorder (PTSD) and PTSD trajectory on their wives' marital adjustment, adjusting for their secondary traumatization (ST). Results show that marital adjustment of the wives of ex-POWs with PTSD (N = 66) was lower compared to wives of ex-POWs (N = 37) and combat veterans (N = 55) without PTSD symptoms. Investigating the possible mechanism underlying the lower marital adjustment, via a mediating model, indicated that husbands' PTSD symptoms mediated the association between captivity and the wives' marital adjustment. Moreover, husbands' PTSD trajectories assessed over 17 years were implicated in their wives' marital adjustment; wives of ex-POWs with chronic PTSD reported lower marital adjustment compared to wives of resilient ex-POWs. The substantial novelty was revealed in prospective deterioration found in dyadic adjustment among wives of ex-POWs with delayed PTSD, but not for wives of chronic or resilient ex-POWs. Implications for research and practice are discussed. PMID- 26618520 TI - Secondary traumatization of partners of war veterans: The role of boundary ambiguity. AB - The existing literature has shown that war veterans' posttraumatic stress disorder (PTSD) symptoms are associated with a higher level of distress in their female partners. However, less agreement exists regarding the sources of this distress and the mechanism by which this process occurs. The current study examined the consequences of Israeli war veterans' PTSD on their female partners, as manifested by the females' PTSD symptoms, mental health status, and functioning, while taking into account females' earlier traumatic events. Using the theory of ambiguous loss, it also suggested boundary ambiguity as a mediating variable by which the PTSD of the male veteran is transmitted to his female partner. Participants were 300 men who had served in the 2006 Israel-Lebanon War and their female partners. Results revealed direct associations between males' PTSD and their female partners' PTSD, functioning, and mental health. In addition, boundary ambiguity mediated the association between males' PTSD and females' adjustment. Finally, females' own earlier traumatic events were directly associated with their own PTSD symptoms. Implications of this model for intervention and research are further discussed. PMID- 26618522 TI - Optical reprogramming of human somatic cells using ultrashort Bessel-shaped near infrared femtosecond laser pulses. AB - We report a virus-free optical approach to human cell reprogramming into induced pluripotent stem cells with low-power nanoporation using ultrashort Bessel-shaped laser pulses. Picojoule near-infrared sub-20 fs laser pulses at a high 85 MHz repetition frequency are employed to generate transient nanopores in the membrane of dermal fibroblasts for the introduction of four transcription factors to induce the reprogramming process. In contrast to conventional approaches which utilize retro- or lentiviruses to deliver genes or transcription factors into the host genome, the laser method is virus-free; hence, the risk of virus-induced cancer generation limiting clinical application is avoided. PMID- 26618521 TI - Changes in parents' spanking and reading as mechanisms for Head Start impacts on children. AB - This study examined whether Head Start, the nation's main two-generation program for low-income families, benefits children in part through positive changes in parents' use of spanking and reading to children. Data were drawn from the 3-year old cohort of the national evaluation of the Head Start program known as the Head Start Impact Study (N = 2,063). Results indicated that Head Start had small, indirect effects on children's spelling ability at Age 4 and their aggression at Age 4 through an increase in parents' reading to their children. Taken together, the results suggest that parents play a role in sustaining positive benefits of the Head Start program for children's behavior and literacy skills, one that could be enhanced with a greater emphasis on parent involvement and education. (PsycINFO Database Record PMID- 26618523 TI - Imaginary part-based correlation mapping optical coherence tomography for imaging of blood vessels in vivo. AB - We present an imaginary part-based correlation mapping optical coherence tomography (IMcmOCT) technique for in vivo blood vessels imaging. In the conventional correlation mapping optical coherence tomography (cmOCT) method, two adjacent frames of intensity-based structural images are correlated to extract blood flow information and the size of correlation window has to be increased to improve the signal-to-noise ratio of microcirculation maps, which may cause image blur and miss the small blood vessels. In the IMcmOCT method, the imaginary part of a depth-resolved complex analytic signal in two adjacent B-scans is correlated to reconstruct microcirculation maps. Both phantom and in vivo experiments were implemented to demonstrate that the proposed method can provide improved sensitivity for extracting blood flow information in small vessels. PMID- 26618524 TI - Rapid and high-resolution imaging of human liver specimens by full-field optical coherence tomography. AB - We report rapid and high-resolution tomographic en face imaging of human liver specimens by full-field optical coherence tomography (FF-OCT). First, the arrangement of the FF-OCT system was described and the performance of the system was measured. The measured axial and lateral resolutions of the system are 0.8 and 0.9 MUm, respectively. The system has a sensitivity of ~60 dB and can achieve an imaging rate of 7 fps and a penetration depth of ~80 MUm. The histological structures of normal liver can be seen clearly in the en face tomographic images, including central veins, cords of hepatocytes separated by sinusoidal spaces, and portal area (portal vein, the hepatic arteriole, and the bile duct). A wide variety of histological subtypes of hepatocellular carcinoma was observed in en face tomographic images, revealing notable cancerous features, including the nuclear atypia (enlarged convoluted nuclei), the polygonal tumor cells with obvious resemblance to hepatocytes with enlarged nuclei. In addition, thicker fibrous bands, which make the cytoplasmic plump vesicular nuclei indistinct, were also seen in the images. Finally, comparison between the portal vein in a normal specimen versus that seen in the rare type of cholangiocarcinoma was made. The results show that the cholangiocarcinoma presents with a blurred pattern of portal vein in the lateral direction and an aggregated distribution in the axial direction; the surrounding sinusoidal spaces and nuclei of cholangiocarcinoma are absent. The findings in this work may be used as additional signs of liver cancer or cholangiocarcinoma, demonstrating capacity of FFOCT device for early cancer diagnosis and many other tumor-related studies in biopsy. PMID- 26618525 TI - Nickel(0)/N-Heterocyclic Carbene-Catalyzed Asymmetric [2 + 2 + 2] Cycloaddition of Two Enones and an Alkyne: Access to Cyclohexenes with Four Contiguous Stereogenic Centers. AB - A nickel(0)/chiral N-heterocyclic carbene (NHC)-catalyzed fully intermolecular, enantioselective [2 + 2 + 2] cycloaddition of two enones and an alkyne has been developed to access enantioenriched cyclohexenes. A single diastereomer was obtained with a successive generation of four contiguous stereogenic centers. The absolute configuration of cyclohexene derivative 3aa was determined by X-ray diffraction and circular dichroism (CD) spectral studies. PMID- 26618526 TI - Greater than the Sum of Its Parts: A Heterodinuclear Polymerization Catalyst. AB - Homodinuclear catalysts have good precedent for epoxide and carbon dioxide/anhydride copolymerizations; in contrast, so far pure heterodinuclear catalysts are unknown. The synthesis and properties of a heterodinuclear Zn(II)/Mg(II) complex coordinated by a symmetrical macrocyclic ligand are reported. It shows high polymerization selectivity, control, and significantly greater activity compared to either of the homodinuclear analogues or any combinations of them. Indeed, compared to a 50:50 mixture of the homodinuclear complexes, it shows 5 times (CO2/epoxide) or 40 times (anhydride/epoxide) greater activity. PMID- 26618527 TI - Untargeted Screening and Distribution of Organo-Bromine Compounds in Sediments of Lake Michigan. AB - Previously unreported natural and synthetic organo-bromine compounds (NSOBCs) have been found to contribute more than 99% of total organic bromine (TOB) in environmental matrices. We recently developed a novel untargeted method (data independent precursor isolation and characteristic fragment, DIPIC-Frag) and identified ~2000 NSOBCs in two sediments from Lake Michigan. In this study, this method was used to investigate the distributions of these NSOBCs in 23 surficial samples and 24 segments of a sediment core from Lake Michigan. NSOBCs were detected in all 23 surficial samples and exhibited 10- to 100-fold variations in peak abundance among locations. The pattern of distributions of NSOBCs was correlated with depth of the water column (r(2) = 0.61, p < 0.001). Hierarchical cluster analysis showed that sediments in close proximity exhibited similar profiles of NSOBCs. Distributions of NSOBCs in 24 segments of a sediment core dated from 1766 to 2008 were investigated, and samples from similar depths exhibited similar profiles of NSOBCs. NSOBCs were grouped into four clusters (soft-cluster analysis) with different temporal trends of abundances. 515 and 768 of the NSOBCs were grouped into cluster 1 and cluster 3 with increasing temporal trends, especially since 1950, indicating that abundances of these compounds might have been affected by human activities. PMID- 26618528 TI - Systemic listeriosis following vaccination with the attenuated Listeria monocytogenes therapeutic vaccine, ADXS11-001. PMID- 26618529 TI - What Is a Potential Source of Ozone in the Health Care Environment? PMID- 26618530 TI - Neuropathic Symptoms in World Trade Center Disaster Survivors and Responders. AB - OBJECTIVE: The objective of this research is to determine whether responders and survivors of the World Trade Center (WTC) disaster experience symptoms of neuropathy at a rate higher than those not exposed. METHODS: A survey of neuropathic symptoms in patients who were and were not exposed at the WTC based upon the Michigan Neuropathy Screening Instrument (MNSI). RESULTS: Even after correction for medical comorbidities, age, and depression, neuropathic symptoms are much more common in those exposed to WTC dust and increase with increasing exposure. CONCLUSIONS: This study provides evidence that exposure to WTC dust is associated with neuropathic symptoms. PMID- 26618531 TI - Levodopa-Carbidopa Intestinal Gel Infusion Therapy in Advanced Parkinson's Disease: Single Middle Eastern Center Experience. AB - BACKGROUND: Levodopa therapy in Parkinson's disease (PD) is often associated with disabling motor and non-motor complications in patients with advanced disease due to the variable absorption of levodopa because of an irregular or erratic emptying of the gastric content. METHODS: Prospective single movement disorder center study using pre-set selection criteria, unified PD scale (UPDRS III), non motor symptoms scale (NMSS), and PD questionnaire-8 (PDQ-8) to evaluate the efficacy, safety, and long-term treatment outcomes using levodopa-carbidopa intestinal gel (LCIG) infusion in patients with advanced PD, who were followed up every 6 months. RESULTS: Twenty patients were recruited over a period of 6 years. Disease duration prior to LCIG infusion ranged from 5 to 18 years (mean 11.4 +/- 4.2). The mean follow-up time on LCIG therapy was 48.5 +/- 23.2 months (range 11 83 months). Mean 'off' time, UPDRS III, NMSS, and PDQ-8 improvement were statistically significant. Two patients dropped out and 66.7% of patients required tube replacement. CONCLUSION: LCIG infusion monotherapy demonstrated significant improvement in reducing the 'off' time, reducing levodopa-induced dyskinesia, and improving non-motor symptoms and quality of life. This therapy is recommended for patients in whom motor fluctuations are inadequately treated with traditional oral PD therapy. PMID- 26618532 TI - Edelfosine Induced Suicidal Death of Human Erythrocytes. AB - BACKGROUND/AIMS: The anti-inflammatory, anti-autoimmune, antiparasitic, and anti viral ether phospholipid edelfosine (1-O-octadecyl-2-O-methylglycero-3 phosphocholine) stimulates apoptosis of tumor cells and is thus considered for the treatment of malignancy. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and phospholipid scrambling of the cell membrane with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include Ca2+ entry with increase of cytosolic Ca2+ activity ([Ca2+]i) and oxidative stress. The present study explored, whether and how edelfosine induces eryptosis. METHODS: Flow cytometry and photometry, respectively, were employed to estimate phosphatidylserine exposure at the cell surface from annexin V-binding, cell volume from forward scatter, hemolysis from hemoglobin release, [Ca2+]i from Fluo3-fluorescence, and abundance of reactive oxygen species (ROS) from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence. RESULTS: A 6 hours exposure of human erythrocytes to edelfosine (5 uM) significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter, and significantly increased Fluo3-fluorescence, but did not significantly modify DCFDA fluorescence. The effect of edelfosine on annexin-V binding was significantly blunted, but not abolished by removal of extracellular Ca2+. CONCLUSIONS: Edelfosine triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect in part due to stimulation of Ca2+ entry. PMID- 26618533 TI - Recent Advances in Development and Applications of the Mixed Quantum/Classical Theory for Inelastic Scattering. AB - A mixed quantum/classical approach to inelastic scattering (MQCT) is developed in which the relative motion of two collision partners is treated classically, and the rotational and vibrational motion of each molecule is treated quantum mechanically. The cases of molecule + atom and molecule + molecule are considered including diatomics, symmetric-top rotors, and asymmetric-top rotor molecules. Phase information is taken into consideration, permitting calculations of elastic and inelastic, total and differential cross sections for excitation and quenching. The method is numerically efficient and intrinsically parallel. The scaling law of MQCT is favorable, which enables calculations at high collision energies and for complicated molecules. Benchmark studies are carried out for several quite different molecular systems (N2 + Na, H2 + He, CO + He, CH3 + He, H2O + He, HCOOCH3 + He, and H2 + N2) in a broad range of collision energies, which demonstrates that MQCT is a viable approach to inelastic scattering. At higher collision energies it can confidently replace the computationally expensive full-quantum calculations. At low collision energies and for low-mass systems results of MQCT are less accurate but are still reasonable. A proposal is made for blending MQCT calculations at higher energies with full-quantum calculations at low energies. PMID- 26618535 TI - Tolerance, arsenic uptake, and oxidative stress in Acacia farnesiana under arsenate-stress. AB - Acacia farnesiana is a shrub widely distributed in soils heavily polluted with arsenic in Mexico. However, the mechanisms by which this species tolerates the phytotoxic effects of arsenic are unknown. This study aimed to investigate the tolerance and bioaccumulation of As by A. farnesiana seedlings exposed to high doses of arsenate (AsV) and the role of peroxidases (POX) and glutathione S transferases (GST) in alleviating As-stress. For that, long-period tests were performed in vitro under different AsV treatments. A. farnesiana showed a remarkable tolerance to AsV, achieving a half-inhibitory concentration (IC50) of about 2.8 mM. Bioaccumulation reached about 940 and 4380 mg As.kg(-1) of dry weight in shoots and roots, respectively, exposed for 60 days to 0.58 mM AsV. Seedlings exposed to such conditions registered a growth delay during the first 15 days, when the fastest As uptake rate (117 mg kg(-1) day(-1)) occurred, coinciding with both the highest rate of lipid peroxidation and the strongest up regulation of enzyme activities. GST activity showed a strong correlation with the As bioaccumulated, suggesting its role in imparting AsV tolerance. This study demonstrated that besides tolerance to AsV, A. farnesiana bioaccumulates considerable amounts of As, suggesting that it may be useful for phytostabilization purposes. PMID- 26618536 TI - Kennedy Disease Misdiagnosed as Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes (POEMS) Syndrome: A Case Report. AB - OBJECTIVE: The aim of this paper was to report the first case of Kennedy disease misdiagnosed as polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. CLINICAL PRESENTATION AND INTERVENTION: A 58-year-old Chinese man presented with limb numbness, progressive limb proximal weakness, lymph node and thyroid enlargement, edema, pigmentation in the lower limb, and obvious gynecomastia, which was initially diagnosed as POEMS syndrome and was treated with dexamethasone and small doses of cyclophosphamide without any improvement after 6 months. Finally, the patient diagnosis was confirmed as Kennedy disease (KD) by gene analysis. CONCLUSION: This case suggests that clinicians should pay more attention to the differential diagnosis between KD and POEMS syndrome. Gene analysis was helpful in detecting this rare confusing disease in this patient. PMID- 26618537 TI - Optimizing Adhesive Design by Understanding Compliance. AB - Adhesives have long been designed around a trade-off between adhesive strength and releasability. Geckos are of interest because they are the largest organisms which are able to climb utilizing adhesive toepads, yet can controllably release from surfaces and perform this action over and over again. Attempting to replicate the hierarchical, nanoscopic features which cover their toepads has been the primary focus of the adhesives field until recently. A new approach based on a scaling relation which states that reversible adhesive force capacity scales with (A/C)(1/2), where A is the area of contact and C is the compliance of the adhesive, has enabled the creation of high strength, reversible adhesives without requiring high aspect ratio, fibrillar features. Here we introduce an equation to calculate the compliance of adhesives, and utilize this equation to predict the shear adhesive force capacity of the adhesive based on the material components and geometric properties. Using this equation, we have investigated important geometric parameters which control force capacity and have shown that by controlling adhesive shape, adhesive force capacity can be increased by over 50% without varying pad size. Furthermore, we have demonstrated that compliance of the adhesive far from the interface still influences shear adhesive force capacity. Utilizing this equation will allow for the production of adhesives which are optimized for specific applications in commercial and industrial settings. PMID- 26618538 TI - Proton Pump Inhibitor Use and Magnesium Concentrations in Hemodialysis Patients: A Cross-Sectional Study. AB - Magnesium concentration is a proven predictor of mortality in hemodialysis patients. Recent reports have indicated that proton pump inhibitor (PPI) use affects serum magnesium levels, however few studies have investigated the relationship between PPI use and magnesium levels in hemodialysis patients. This study aimed to clarify the association between PPI use and serum magnesium levels in hemodialysis patients. We designed this cross sectional study and included 1189 hemodialysis patients in stable condition. Associations between PPI and magnesium-related factors, as well as other possible confounders, were evaluated using a multiple regression model. We defined hypomagnesemia as a value < 2.0 mg/dL, and created comparable logistic regression models to assess the association between PPI use and hypomagnesemia. PPI use is associated with a significantly lower mean serum magnesium level than histamine 2 (H2) receptor antagonists or no acid-suppressive medications (mean [SD] PPI: 2.52 [0.45] mg/dL; H2 receptor antagonist: 2.68 [0.41] mg/dL; no acid suppressive medications: 2.68 [0.46] mg/dL; P = 0.001). Hypomagnesemia remained significantly associated with PPI (adjusted OR, OR: 2.05; 95% CI: 1.14-3.69; P = 0.017). PPI use is associated with an increased risk of hypomagnesemia in hemodialysis patients. Future prospective studies are needed to explore magnesium replacement in PPI users on hemodialysis. PMID- 26618539 TI - Equality in Educational Policy and the Heritability of Educational Attainment. AB - Secular variation in the heritability of educational attainment are proposed to be due to the implementation of more egalitarian educational policies leading to increased equality in educational opportunities in the second part of the 20th century. The action of effect is hypothesized to be a decrease of shared environmental (e.g., family socioeconomic status or parents' education) influences on educational attainment, giving more room for genetic differences between individuals to impact on the variation of the trait. However, this hypothesis has not yet found consistent evidence. Support for this effect relies mainly on comparisons between countries adopting different educational systems or between different time periods within a country reflecting changes in general policy. Using a population-based sample of 1271 pairs of adult twins, we analyzed the effect of the introduction of a specific educational policy in Spain in 1970. The shared-environmental variance decreased, leading to an increase in heritability in the post-reform cohort (44 vs. 67%) for males. Unstandardized estimates of genetic variance were of a similar magnitude (.56 vs. .57) between cohorts, while shared environmental variance decreased from .56 to .04. Heritability remained in the same range for women (40 vs. 34%). Our results support the role of educational policy in affecting the relative weight of genetic and environmental factors on educational attainment, such that increasing equality in educational opportunities increases heritability estimates by reducing variation of non-genetic familial origin. PMID- 26618540 TI - Correction: Novel recA-Independent Horizontal Gene Transfer in Escherichia coli K 12. PMID- 26618541 TI - Development and validation of a weight-bearing finite element model for total knee replacement. AB - Total knee arthroplasty (TKA) is a successful procedure for osteoarthritis. However, some patients (19%) do have pain after surgery. A finite element model was developed based on boundary conditions of a knee rig. A 3D-model of an anatomical full leg was generated from magnetic resonance image data and a total knee prosthesis was implanted without patella resurfacing. In the finite element model, a restarting procedure was programmed in order to hold the ground reaction force constant with an adapted quadriceps muscle force during a squat from 20 degrees to 105 degrees of flexion. Knee rig experimental data were used to validate the numerical model in the patellofemoral and femorotibial joint. Furthermore, sensitivity analyses of Young's modulus of the patella cartilage, posterior cruciate ligament (PCL) stiffness, and patella tendon origin were performed. Pearson's correlations for retropatellar contact area, pressure, patella flexion, and femorotibial ap-movement were near to 1. Lowest root mean square error for retropatellar pressure, patella flexion, and femorotibial ap movement were found for the baseline model setup with Young's modulus of 5 MPa for patella cartilage, a downscaled PCL stiffness of 25% compared to the literature given value and an anatomical origin of the patella tendon. The results of the conducted finite element model are comparable with the experimental results. Therefore, the finite element model developed in this study can be used for further clinical investigations and will help to better understand the clinical aspects after TKA with an unresurfaced patella. PMID- 26618542 TI - Efficient hysteresis-less bilayer type CH3NH3PbI3 perovskite hybrid solar cells. AB - Bilayer type CH3NH3PbI3 (MAPbI3) perovskite hybrid solar cells were fabricated via a one-step spin-coating process by using solubility controlled MAPbI3 solutions of MAPbI3-DMSO (dimethyl sulfoxide) and MAPbI3-DMF (N, N dimethylformamide)-HI. The best DMSO-bilayer device showed 1.07 +/- 0.02 V V(oc) (open-circuit voltage), 20.2 +/- 0.1 mA cm(-2) J(sc) (short-circuit current density), 68 +/- 2% FF (fill factor), and 15.2 +/- 0.3% eta (overall power conversion efficiency) under the forward scan direction and 1.07 +/- 0.02 V V(oc), 20.4 +/- 0.1 mA cm(-2) J(sc), 70 +/- 3% FF, and 15.9 +/- 0.4% eta under the reverse scan direction. The best HI-bilayer device had 1.08 +/- 0.02 V V(oc), 20.6 +/- 0.1 mA cm(-2) J(sc), 75 +/- 1% FF, and 17.2 +/- 0.2% eta under the forward scan direction and 1.08 +/- 0.02 V V(oc), 20.6 +/- 0.1 mA cm(-2) J(sc), 76 +/- 2% FF, and 17.4 +/- 0.3% eta under the reverse scan direction. The deviation of average device efficiency (eta(avg)) of 20 DMSO samples and 20 HI samples was 14.2 +/- 0.95% and 16.2 +/- 0.85%, respectively. Therefore, the HI bilayer devices exhibited better device efficiency and smaller J-V (current density-voltage) hysteresis with respect to the scan direction than the DMSO bilayer devices due to the reduced recombination and traps by the formation of a purer and larger MAPbI3 perovskite crystalline film. PMID- 26618543 TI - Spontaneous resolution of visual loss due to optic pathway meningioma: A case report and a review of the literature. AB - BACKGROUND/AIM: Meningiomas of the anterior cranial fossa are often diagnosed after impaired visual function occurrence. Some epidemiologic studies suggest an association between exogenous or endogenous hormones and meningioma risk. The aim of this study is to briefly review the literature and relate a case report. PATIENT AND METHODS: This study presents a case of a 51-year-old woman with a moderate visual loss of 6/10 and markedly constricted visual field in the right eye. A normal visual acuity and peripheral reduction of visual field in the left eye was documented. During medical interview, she reported a prolonged assumption of oral contraceptive. Her visual deterioration had progressed over the previous 3 months and was associated with occasional headache. MRI scanning showed a small optic pathway meningioma. RESULTS: After various examinations, it was decided to 'wait and see' and no therapy was administered. The patient noticed a progressive improvement in the vision in her right eye, with corresponding improvement in the bilateral visual field. CONCLUSION: The case reports on the spontaneous resolution of visual loss due to the volume reduction of the anterior visual pathway compressive intracranial meningioma after interruption of prolonged assumption of oral contraceptive and focuses on the correlation between sexual hormone pathway and intracranial meningioma. PMID- 26618544 TI - Distortions of the Xanthophylls Caused by Interactions with Neighboring Pigments and the LHCII Protein Are Crucial for Studying Energy Transfer Pathways within the Complex. AB - It has been proposed that photoprotective non-photochemical quenching (NPQ) in higher plants arises from a conformational change in the antenna which alters pigment-pigment interactions. This brings about the formation of energy quenching "traps" that capture and dissipate excitation energy as heat. We have used the semiempirical AM1-CAS-CI method combined with the transition density cube (TDC) approach to model chlorophyll (Chl) to xanthophyll (Xanth) resonant Coulomb couplings in the crystal structure of LHCII. Due to its proposed role as the NPQ quenching site we have focused on lutein interactions and have explored how distortions to lutein conformation, as well as interpigment distances and relative orientations, affect this coupling. Our calculations indicate that distortions as well as Chl-lutein angle have a significant effect on coupling, whereas interpigment distances have a relatively minor effect. We therefore conclude that particular attention to the distortions of the Xanths should be given for calculation of energy transfer pathways and study of the NPQ mechanism. PMID- 26618545 TI - Increased Susceptibility of Humanized NSG Mice to Panton-Valentine Leukocidin and Staphylococcus aureus Skin Infection. AB - Staphylococcus aureus is a leading cause of skin and soft-tissue infections worldwide. Mice are the most commonly used animals for modeling human staphylococcal infections. However a supra-physiologic S. aureus inoculum is required to establish gross murine skin pathology. Moreover, many staphylococcal factors, including Panton-Valentine leukocidin (PVL) elaborated by community associated methicillin-resistant S. aureus (CA-MRSA), exhibit selective human tropism and cannot be adequately studied in mice. To overcome these deficiencies, we investigated S. aureus infection in non-obese diabetic (NOD)/severe combined immune deficiency (SCID)/IL2rgammanull (NSG) mice engrafted with human CD34+ umbilical cord blood cells. These "humanized" NSG mice require one to two log lower inoculum to induce consistent skin lesions compared with control mice, and exhibit larger cutaneous lesions upon infection with PVL+ versus isogenic PVL- S. aureus. Neutrophils appear important for PVL pathology as adoptive transfer of human neutrophils alone to NSG mice was sufficient to induce dermonecrosis following challenge with PVL+ S. aureus but not PVL- S. aureus. PMX53, a human C5aR inhibitor, blocked PVL-induced cellular cytotoxicity in vitro and reduced the size difference of lesions induced by the PVL+ and PVL- S. aureus, but PMX53 also reduced recruitment of neutrophils and exacerbated the infection. Overall, our findings establish humanized mice as an important translational tool for the study of S. aureus infection and provide strong evidence that PVL is a human virulence factor. PMID- 26618534 TI - Frequency, Risk Factors, and Outcome of Coexistent Small Vessel Disease and Intracranial Arterial Stenosis: Results From the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) Trial. AB - IMPORTANCE: Intracranial arterial stenosis (ICAS) and small vessel disease (SVD) may coexist. There are limited data on the frequency and risk factors for coexistent SVD and the effect of SVD on stroke recurrence in patients receiving medical treatment for ICAS. OBJECTIVE: To investigate the frequency and risk factors for SVD and the effect of SVD on stroke recurrence in patients with ICAS. DESIGN, SETTING, AND PARTICIPANTS: A post hoc analysis of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study, a prospective, multicenter clinical trial. Among 451 participants, 313 (69.4%) had baseline brain magnetic resonance imaging scans read centrally for SVD that was defined by any of the following: old lacunar infarction, grade 2 to 3 on the Fazekas scale (for high-grade white matter hyperintensities), or microbleeds. Patient enrollment in SAMMPRIS began November 25, 2008, and follow-up ended on April 30, 2013. Data analysis for the present study was performed from May 13, 2014, to July 29, 2015. MAIN OUTCOMES AND MEASURES: Risk factors in patients with vs without SVD and the association between SVD and other baseline risk factors with any ischemic stroke and ischemic stroke in the territory of the stenotic artery determined using proportional hazards regression. RESULTS: Of 313 patients, 155 individuals (49.5%) had SVD noted on baseline magnetic resonance imaging. Variables that were significantly higher in patients with SVD, reported as mean (SD), included age, 63.5 (10.5) years (P < .001), systolic blood pressure, 149 (22) mm Hg (P < .001), glucose level, 130 (50) mg/dL (P = .03), and lower Montreal Cognitive Assessment scores (median, >=24 [interquartile range, 20-26]; P = .02).Other significant variables were the number of patients with diabetes mellitus (88 of 155 [56.8%]; P = .003), coronary artery disease (46 [29.7%]; P = .004), stroke before the qualifying event (59 [38.1%]; P < .001), old infarct in the territory of the stenotic intracranial artery (88 [56.8%]; P < .001), and receiving antithrombotic therapy at the time of the qualifying event (109 [70.3%]; P = .005). The association between SVD and any ischemic stroke was nearly significant in the direction of a higher risk (18 [23.7%]); P = .07) for patients with SVD. On bivariate analysis, SVD was not associated with an increased risk on multivariable analyses (hazard ratio, 1.7 [95% CI, 0.8-3.8]; P = .20). In addition, SVD was not associated with an increased risk of stroke in the territory on either bivariate or multivariable analyses. CONCLUSIONS AND RELEVANCE: Although SVD is common in patients with ICAS, the presence of SVD on baseline magnetic resonance imaging is not independently associated with an increased risk of stroke in patients with ICAS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00576693. PMID- 26618546 TI - The Gondwana Breakup and the History of the Atlantic and Indian Oceans Unveils Two New Clades for Early Neobatrachian Diversification. AB - The largest anuran diversity belongs to the Neobatrachia, which harbor more than five thousand extant species. Here, we propose a new hypothesis for the historical aspects of the neobatrachian evolution with a formal biogeographical analysis. We selected 12 genes for 144 neobatrachian genera and four archaeobatrachian outgroups and performed a phylogenetic analysis using a maximum likelihood algorithm with the rapid bootstrap test. We also estimated divergence times for major lineages using a relaxed uncorrelated clock method. According to our time scale, the diversification of crown Neobatrachia began around the end of the Early Cretaceous. Our phylogenetic tree suggests that the first split of Neobatrachia is related to the geological events in the Atlantic and Indian Oceans. Hence, we propose names for these clades that indicate this connection, i.e., Atlanticanura and Indianura. The Atlanticanura is composed of three major neobatrachian lineages: Heleophrynidae, Australobatrachia and Nobleobatrachia. On the other hand, the Indianura consists of two major lineages: Sooglossoidea and Ranoides. The biogeographical analysis indicates that many neobatrachian splits occurred as a result of geological events such as the separation between South America and Africa, between India and the Seychelles, and between Australia and South America. PMID- 26618549 TI - Clinical outcome and adverse events associated with empiric and pre-emptive use of amphotericin B lipid complex in a single center in lebanon. PMID- 26618547 TI - The effect of antenatal dietary and lifestyle advice for women who are overweight or obese on emotional well-being: the LIMIT randomized trial. AB - INTRODUCTION: Our aim was to evaluate the effect of dietary and lifestyle advice given to women who were overweight or obese during pregnancy on maternal quality of life, anxiety and risk of depression, and satisfaction with care. MATERIAL AND METHODS: We conducted a randomized trial, involving pregnant women with body mass index >=25 kg/m(2) , recruited from maternity units in South Australia. Women were randomized to Lifestyle Advice or Standard Care, and completed questionnaires assessing risk of depression (Edinburgh Postnatal Depression Scale), anxiety (Spielberger State-Trait Anxiety Inventory), and quality of life (SF-36) at trial entry, 28 and 36 weeks' gestation, and 4 months postpartum. Secondary trial outcomes assessed for this analysis were risk of depression, anxiety, maternal quality of life, and satisfaction with care. RESULTS: One or more questionnaires were completed by 976 of 1108 (90.8%) women receiving Lifestyle Advice and 957 of 1104 (89.7%) women receiving Standard Care. The risk of depression [adjusted risk ratio 1.01; 95% confidence interval (CI) 0.82-1.24; p = 0.95], anxiety (adjusted risk ratio 1.09; 95% CI 0.93-1.27; p = 0.31), and health-related quality of life were similar between the two groups. Women receiving Lifestyle Advice reported improved healthy food choice [Lifestyle Advice 404 (68.9%) vs. Standard Care 323 (51.8%); p < 0.0001], and exercise knowledge [Lifestyle Advice 444 (75.8%) vs. Standard Care 367 (58.8%); p < 0.0001], and reassurance about their health [Lifestyle Advice 499 (85.3%) vs. Standard Care 485 (77.9%); p = 0.0112], and health of their baby [Lifestyle Advice 527 (90.2%) vs. Standard Care 545 (87.6%); p = 0.0143]. CONCLUSION: Lifestyle advice in pregnancy improved knowledge and provided reassurance without negatively impacting well-being. PMID- 26618551 TI - 20-hydroxyecdysone accumulation and regulation in Ajuga lobata D. Don suspension culture. AB - Suspension culture of Ajuga lobata D. Don cells provides a method of synthesis of the phytoecdysteroid 20-hydroxyecdysone (20E) which can regulate the molting process of larvae. We characterized the culture conditions to optimize 20E production. Growth of A. lobata D. Don cells fits the logistic equation curve with a growth cycle of 19 days. Medium conductivity was negatively correlated with dry cell weight and 20E accumulation, thus could be used to determine the optimal time for cell harvest. Continuous subculture reduced 20E synthesis, but supplementing medium with 20E precursors mevalonic (MVA), alpha-Pinene, and nitric oxide (NO) can significantly promote cell growth and influence 20E accumulation. Combination of alpha-Pinene, MVA, and SNP significantly elevated 20E accumulation, thus may synergistically enhance 20E synthesis in A. lobata D. Don. The optimal concentrations of alpha-Pinene, MVA, and NO donor SNP in suspension culture were 50 MUL L(-1), 10 mg L(-1), and 80 MUmol L(-1). PMID- 26618550 TI - Autologous stem cell transplantation for relapsed/refractory diffuse large B-cell lymphoma: efficacy in the rituximab era and comparison to first allogeneic transplants. A report from the EBMT Lymphoma Working Party. AB - In the era of chemoimmunotherapy, the optimal treatment paradigm for relapsed and refractory diffuse large B-cell lymphoma has been challenged. We reviewed the outcome of standard salvage therapy with an autologous stem cell transplant (autoSCT) over the last two decades and the outcome of allogeneic SCT (alloSCT) in the most recent decade. AutoSCT recipients diagnosed between 1992 and 2002 (n=2737) were compared with those diagnosed between 2002 and 2010 (n=3980). Patients diagnosed after 2002 had a significantly lower non-relapse mortality (NRM) and relapse incidence (RI) and a superior PFS and overall survival (OS). A total of 4210 patients diagnosed between 2002 and 2010 underwent either an autoSCT or an alloSCT as their first transplant procedure. Two-hundred and thirty patients received an alloSCT (myeloablative (MACalloSCT) n=132, reduced intensity (RICalloSCT) n=98). The 4-year NRM rates were 7%, 20% and 27% for autoSCT, RICalloSCT and MACalloSCT, respectively. The 4-year RI was 45%, 40% and 38% for autoSCT, RICalloSCT and MACalloSCT, respectively (NS). The 4-year PFS were 48%, 52% and 35% for autoSCT, RICalloSCT and MACalloSCT, respectively. The 4-year OS was 60%, 52% and 38% for autoSCT, RIC alloSCT and MACalloSCT, respectively. After adjustment for confounding factors NRM was significantly worse for patients undergoing alloSCT whilst there was no difference in the RI. PMID- 26618548 TI - Impact of conditioning with TBI in adult patients with T-cell ALL who receive a myeloablative allogeneic stem cell transplantation: a report from the acute leukemia working party of EBMT. AB - Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a therapeutic option for adult patients with T-cell ALL (T-ALL). Meanwhile, few allo-SCT data specific to adult T-ALL have been described thus far. Specifically, the optimal myeloablative conditioning regimen is unknown. In this retrospective study, 601 patients were included. Patients received allo-SCT in CR1, CR2, CR >2 or in advanced disease in 69%, 15%, 2% and 14% of cases, respectively. With an overall follow-up of 58 months, 523 patients received a TBI-based regimen, whereas 78 patients received a chemotherapy-based regimen including IV busulfan cyclophosphamide (IV Bu-Cy) (n=46). Unlike patients aged ?35 years, patients aged <35 years who received a TBI-based regimen displayed an improved outcome compared with patients who received a chemotherapy-based regimen (5-year leukemia-free survival (LFS) of 50% for TBI versus 18% for chemo-only regimen or IV Bu-Cy regimens, P=10(-5) and 10(-4), respectively). In multivariate analysis, use of TBI was associated with an improved LFS (hazard ratio (HR)=0.55 (0.34-0.86), P=0.01) and overall survival (HR=0.54 (0.34-0.87), P=0.01) in patients aged <35 years. In conclusion, younger adult patients with T-ALL entitled to receive a myeloablative allo-SCT may benefit from TBI-based regimens. PMID- 26618553 TI - Cardiovascular effects of Etanercept in patients with psoriatic arthritis: evidence from the cardiovascular risk in rheumatic diseases database. AB - INTRODUCTION: Many literature data support the possibility of an increased cardiovascular (CV) risk in psoriatic arthritis (PsA) patients compared with the general population. This cannot be entirely explained by the presence of traditional vascular risk factors. It has been suggested that inflammation may act synergistically with traditional vascular risk factors, thus contributing to the atherosclerotic process and to the increased CV risk. AREAS COVERED: In order to evaluate the CV effects of the control of systemic inflammation by Etanercept, in the present study we analyze data recorded in the Cardiovascular Risk in Rheumatic Diseases study group database to perform a further analysis on the effects of Etanercept on primary hemostasis, secondary hemostasis and carotid subclinical atherosclerosis. Platelet reactivity is increased in patients with poorly controlled PsA. Among patients receiving Etanercept, those achieving minimal disease activity show a platelet reactivity comparable to healthy controls. Similarly, the anti-inflammatory effect of Etanercept is associated with a significant improvement of hemostatic and fibrinolytic parameters in PsA subjects, maximal changes being documented in patients achieving minimal disease activity. In addition, the treatment with Etanercept seems to be associated with a carotid intima-media thickness significantly lower as compared with matched patients receiving traditional disease-modifying anti-rheumatic drugs. EXPERT OPINION: Our data can be suggestive of the reduction of the CV risk in patients with PsA treated with Etanercept. PMID- 26618552 TI - Effects of methylglyoxal and glyoxalase I inhibition on breast cancer cells proliferation, invasion, and apoptosis through modulation of MAPKs, MMP9, and Bcl 2. AB - Emerging evidence indicates that methylglyoxal (MG) can inhibit tumorigenesis. Glyoxalase I (GLOI), a MG degradation enzyme, is implicated in the progression of human malignancies. However, little is known about the roles of MG and GLOI in breast cancer. Our purpose was to investigate the anticancer effects of MG and inhibition of GLOI on breast cancer cells and the underlying mechanisms of these effects. Our findings demonstrate that cell viability, migration, invasion, colony formation, and tubule formation were significantly restrained by addition of MG or inhibition of GLOI, while apoptosis was significantly increased. Furthermore, the expression of p-JNK, p-ERK, and p-p38 was markedly upregulated by addition of MG or inhibition of GLOI, whereas MMP-9 and Bcl-2 expression levels were dramatically decreased. These effects were augmented by combined treatment with MG and inhibition of GLOI. Collectively, these data indicate that MG or inhibition of GLOI induces anticancer effects in breast cancer cells and that these effects are potentiated by combination of the 2. These effects were modulated by activation of the MAPK family and downregulation of Bcl-2 and MMP-9. These findings may provide a new approach for the treatment of breast cancer. PMID- 26618554 TI - Electron Confinement in Channel Spaces for One-Dimensional Electride. AB - Electrides are characteristic of anionic electrons trapped at the structural voids in the host lattice. Electrides are potentially useful in various technological applications; however, electrides, particularly their inorganic subgroup, have been discovered only in limited material systems, notably zero dimensional [Ca24Al28O64](4+):4e(-) and two-dimensional [Ca2N](+):e(-) and [Y2C](1.8+):1.8e(-). Here, on the basis of density functional theory calculations, we report the first one-dimensional (1D) electride with a [La8Sr2(SiO4)6](4+):4e(-) configuration, in which the four anionic electrons are confined in the channel spaces of the host material. According to this theoretical prediction, an insulator-semiconductor transition originating from electron confinement in the crystallographic channel sites was demonstrated experimentally, where 10.5% of the channel oxygen was removed by reacting an oxygen stoichiometric La8Sr2(SiO4)6O2 precursor with Ti metal at a high temperature. This study not only adds an unprecedented role to silicate apatite as a parent phase to a new 1D electride, but also, and more importantly, demonstrates an effective approach for developing new electrides with the assistance of computational design. PMID- 26618555 TI - Dietary supplementation with the polyphenol-rich acai pulps (Euterpe oleracea Mart. and Euterpe precatoria Mart.) improves cognition in aged rats and attenuates inflammatory signaling in BV-2 microglial cells. AB - OBJECTIVES: The present study was carried out to determine if lyophilized acai fruit pulp (genus, Euterpe), rich in polyphenols and other bioactive antioxidant and anti-inflammatory phytochemicals, is efficacious in reversing age-related cognitive deficits in aged rats. METHODS: The diets of 19-month-old Fischer 344 rats were supplemented for 8 weeks with 2% Euterpe oleracea (EO), Euterpe precatoria (EP), or a control diet. Rats were tested in the Morris water maze and then blood serum from the rats was used to assess inflammatory responses of BV-2 microglial cells. RESULTS: After 8 weeks of dietary supplementation with 2% EO or EP, rats demonstrated improved working memory in the Morris water maze, relative to controls; however, only the EO diet improved reference memory. BV-2 microglial cells treated with blood serum collected from EO-fed rats produced less nitric oxide (NO) than control-fed rats. Serum from both EO- and EP-fed rats reduced tumor necrosis factor-alpha (TNF-alpha). There is a relationship between performance in the water maze and the production of NO and TNF-alpha by serum treated BV-2 cells, such that serum from rats with better performance was more protective against inflammatory signaling. DISCUSSION: Protection of memory during aging by supplementation of lyophilized acai fruit pulp added to the diet may result from its ability to influence antioxidant and anti-inflammatory signaling. PMID- 26618556 TI - Electroemulsification in a Uniform Electric Field. AB - Emulsification using electric fields is an easy alternative to flow-induced drop breakup, and the former is reported to be more effective and economical than the latter, especially when the medium phase is poorly conducting and highly viscous. The emulsification of a coarse water-in-oil emulsion in a uniform electric field is studied. We perform a detailed experimental analysis of the effect of applied electric field strength and the duration of applied electric field on the drop size distribution. The average diameter as well as the time for emulsification decreases with an increase in the intensity of the electric field. Moreover, a narrow size distribution is observed. An average size of a few microns of the dispersed phase could be achieved. New breakup mechanisms at play in the emulsification process are discussed. Identified mechanisms involve charged lobe disintegration, charged drop breakup, chain formation in which several water droplets are interconnected by thin water bridges, electrospraying and charge transfer, and coalescence. The study shows that charged drop disintegration could be the key mechanism of fine emulsification of an initially electrically neutral coarse emulsion. PMID- 26618557 TI - Chitosan Coated Textiles May Improve Atopic Dermatitis Severity by Modulating Skin Staphylococcal Profile: A Randomized Controlled Trial. AB - BACKGROUND: Atopic dermatitis (AD) patients may benefit from using textiles coated with skin microbiome-modulating compounds. Chitosan, a natural biopolymer with immunomodulatory and antimicrobial properties, has been considered potentially useful. OBJECTIVE: This randomized controlled trial assessed the clinical utility of chitosan-coated garment use in AD. METHODS: Of the 102 patients screened, 78 adult and adolescents were randomly allocated to overnight use of chitosan-coated or uncoated cotton long-sleeved pyjama tops and pants for 8 weeks. The primary outcome was change in disease severity assessed by Scoring Atopic dermatitis index (SCORAD). Other outcomes were changes in quality of life, pruritus and sleep loss, days with need for rescue medication, number of flares and controlled weeks, and adverse events. Changes in total staphylococci and Staphylococcus aureus skin counts were also assessed. Comparisons were made using analysis of variance supplemented by repeated measures analysis for the primary outcome. Interaction term between time and intervention was used to compare time trends between groups. RESULTS: Chitosan group improved SCORAD from baseline in 43.8%, (95%CI: 30.9 to 55.9), P = 0.01, placebo group in 16.5% (-21.6 to 54.6); P = 0.02 with no significant differences between groups; Dermatology Quality of life Index Score significantly improved in chitosan group (P = 0.02) and a significant increase of skin Coagulase negative Staphylococci (P = 0.02) was seen. CONCLUSIONS: Chitosan coated textiles may impact on disease severity by modulating skin staphylococcal profile. Moreover, a potential effect in quality of life may be considered. TRIAL REGISTRATION: ClinicalTrials.gov NCT01597817. PMID- 26618558 TI - Glucose Regulated Protein 78 Phosphorylation in Sperm Undergoes Dynamic Changes during Maturation. AB - GRP78, a resident endoplasmic reticulum (ER) chaperone involved in protein transport, folding and assembly, has been reported in sperm. It is shown to be localized in the neck region of human sperm. We have previously reported GRP78 to be less phosphorylated in asthenozoosperm.The present study aimed to determine whether sperm GRP78 undergoes phosphorylation changes during epididymal maturation and whether there are any differences in GRP78 phosphoforms in asthenozoosperm vis-a-vis normozoosperm. Testicular- and cauda epididymal- sperm from adult male Holtzman rats, and semen ejaculates collected from normal and asthenozoospermic individuals were investigated. DIGE carried out to determine phosphorylation of GRP78 in asthenozoosperm and normal sperm reveals a shift in the location of GRP78 of asthenozoosperm towards the alkaline pH, indicative of reduced GRP78 phosphorylation. Immunoprecipitation studies using antibodies specific to GRP78, serine-, threonine-, and tyrosine phosphorylation and Pan phospho antibody demonstrates GRP78 to be phosphorylated at all three residues in rat spermatozoa. Phosphatase assays using Calf intestinal alkaline phosphatase and Lambda protein phosphatase followed by nanofluidic proteomic immunoassay (NIA) show that in rat, GP4.96, GP4.94 and GP4.85 are the three phosphoforms in mature (caudal) sperm as against two phosphoforms GP4.96and GP4.94in immature (testicular) sperm. In mature human sperm GP5.04, GP4.96, and GP4.94were the 3 phosphoforms observed. GP4.94[P = 0.014]andGP5.04 [P = 0.02] are significantly reduced in asthenozoosperm. Ours is the first report indicating GRP78 in sperm to be phosphorylated at serine, threonine and tyrosine residues contrary to published literature reporting GRP78 not to be tyrosine phosphorylated. We report the presence of GRP78 phosphoforms in rat- and human- sperm and our data suggest that GRP78 phosphorylation in sperm undergoes spatial reorganization during epididymal maturation. Significant differences observed in 2 out of 3 phosphoforms in asthenozoosperm suggest that GRP78 phosphorylation may have functional relevance in sperm with consequent clinical implications. PMID- 26618559 TI - Airway CD8(+) T Cells Are Associated with Lung Injury during Infant Viral Respiratory Tract Infection. AB - Infants and young children are disproportionately susceptible to severe complications from respiratory viruses, although the underlying mechanisms remain unknown. Recent studies show that the T cell response in the lung is important for protective responses to respiratory infections, although details on the infant/pediatric respiratory immune response remain sparse. The objectives of the present study were to characterize the local versus systemic immune response in infants and young children with respiratory failure from viral respiratory tract infections and its association to disease severity. Daily airway secretions were sampled from infants and children 4 years of age and younger receiving mechanical ventilation owing to respiratory failure from viral infection or noninfectious causes. Samples were examined for immune cell composition and markers of T cell activation. These parameters were then correlated with clinical disease severity. Innate immune cells and total CD3(+) T cells were present in similar proportions in airway aspirates derived from infected and uninfected groups; however, the CD8:CD4 T cell ratio was markedly increased in the airways of patients with viral infection compared with uninfected patients, and specifically in infected infants with acute lung injury. T cells in the airways were phenotypically and functionally distinct from those in blood with activated/memory phenotypes and increased cytotoxic capacity. We identified a significant increase in airway cytotoxic CD8(+) T cells in infants with lung injury from viral respiratory tract infection that was distinct from the T cell profile in circulation and associated with increasing disease severity. Airway sampling could therefore be diagnostically informative for assessing immune responses and lung damage. PMID- 26618560 TI - Organophosphorus insecticide poisoning. AB - INTRODUCTION: Acetylcholinesterase inhibition by organophosphorus insecticides can cause acute parasympathetic system dysfunction, muscle weakness, seizures, coma, and respiratory failure. Prognosis depends on the dose and relative toxicity of the specific compound, as well as pharmacokinetic factors. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of oxime treatment for acute organophosphorus insecticide poisoning? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 25 studies. After deduplication and removal of conference abstracts, 14 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of eight studies and the further review of six full publications. Of the six full articles evaluated, one update of a systematic review previously included in this review was added. We performed a GRADE evaluation for six PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for two comparisons based on information about the effectiveness and safety of oximes versus placebo or no oximes and oximes versus each other. PMID- 26618562 TI - Effects of Regioregularity and Molecular Weight on the Growth of Polythiophene Nanofibrils and Mixes of Short and Long Nanofibrils To Enhance the Hole Transport. AB - Morphological control over polythiophenes has been widely studied; however the impacts of regioregularity (RR) and molecular weight (MW) on their structural development have not been investigated systematically. This study examined a representative polythiophene, poly(3-hexylthiophene) (P3HT), to reveal that small differences in the RR can produce a large difference in the growth of nanofibrils. Low-RR P3HTs generated neat long nanofibrils (LNFs), whereas high-RR P3HTs formed short nanofibrils (SNFs). This study identified a critical RR (96 98%) depending on their MW, below which P3HT grew into LNFs and above which P3HT grew into SNFs. This study also found that the mixing ratio between high-RR P3HT and a low-RR P3HT in the solution phase is strongly correlated with the relative populations of SNF and LNF in the coated film. This study suggested that mixing high-RR and low-RR polymers may be a good strategy to optimize the electrical properties of polythiophenes for target applications. As an example, a mixture of high-RR (75%) P3HT and low-RR P3HT (25%) improved considerably the power conversion efficiency of bulk heterojunction polymer solar cells compared with the values obtained from the pure high-RR P3HT and the pure low-RR P3HT. PMID- 26618563 TI - Emerging targeted therapies in non-small cell lung cancer. AB - Lung cancer is the leading cause of cancer-related deaths in United States, accounting for more than one-fourth of the deaths annually. Although comparatively rare and relatively less studied, genetic abnormalities other than epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, and Kirsten rat sarcoma (KRAS) mutations account for significant proportion of the driver mutations identified thus far. The targeted agents against B-rapidly accelerated fibrosarcoma (BRAF) V600E mutation, MNNG-HOS transforming gene (MET) pathway, ROS1 rearrangement, rearranged during transfection (RET) rearrangement, and HER2 pathways offer promising therapeutic options. Recruiting patients with these rarer mutations to well-designed, large multicenter trials to further validate the use of targeted agents remains a challenge. The clinical data and ongoing trials with these agents are reviewed in this article. PMID- 26618561 TI - Direct High Affinity Interaction between Abeta42 and GSK3alpha Stimulates Hyperphosphorylation of Tau. A New Molecular Link in Alzheimer's Disease? AB - Amyloid beta peptide (Abeta42) assemblies are considered central to the development of Alzheimer's disease, but the mechanism of this toxicity remains unresolved. We screened protein microarrays with on-pathway oligomeric Abeta42 to identify candidate proteins interacting with toxic Abeta42 species. Samples prepared from Alexa546-Abeta42 and Abeta42 monomers at 1:5 molar ratio were incubated with the array during a time window of the amyloid fibril formation reaction during which the maximum number of transient oligomers exist in the reaction flux. A specific interaction was detected between Abeta42 and glycogen synthase kinase 3alpha (GSK3alpha), a kinase previously implicated in the disease pathology. This interaction was validated with anti-GSK3alpha immunoprecipitation assays in neuronal cell lysates. Confocal microscopy studies further identified colocalization of Abeta42 and GSK3alpha in neurites of mature primary mouse neurons. A high binding affinity (KD = 1 nM) was measured between Alexa488 Abeta42 and GSK3alpha in solution using thermophoresis. An even lower apparent KD was estimated between GSK3alpha and dextran-immobilized Abeta42 in surface plasmon resonance experiments. Parallel experiments with GSK3beta also identified colocalization and high affinity binding to this isoform. GSK3alpha-mediated hyperphosphorylation of the protein tau was found to be stimulated by Abeta42 in in vitro phosphorylation assays and identified a functional relationship between the proteins. We uncover a direct and functional molecular link between Abeta42 and GSK3alpha, which opens an important avenue toward understanding the mechanism of Abeta42-mediated neuronal toxicity in Alzheimer's disease. PMID- 26618564 TI - A rapid screening assay for identifying mycobacteria targeted nanoparticle antibiotics. AB - Antibiotic resistance is a serious problem. Nanotechnology offers enormous potential in medicine, yet there is limited knowledge regarding the toxicity of nanoparticles (NP) for mycobacterial species that cause serious human diseases (e.g. tuberculosis (TB) and leprosy). Mycobacterial diseases are a major global health problem; TB caused by Mycobacterium tuberculosis (Mtb) kills up to 2 million people annually and there are over 200 000 leprosy cases each year caused by Mycobacterium leprae (M. leprae). Few drugs are effective against these mycobacteria and increasing antibiotic resistance exacerbates the problem. As such, alternative therapies are urgently needed but most current assays used to assess the effectiveness of therapeutics against mycobacteria are slow and expensive. This study aimed to develop a rapid, low-cost assay which can be used for screening the antimicrobial properties of compounds against pathogenic mycobacteria and to assess the toxicity of three NP (silver [Ag], copper oxide [Cu(II)O], and zinc oxide [ZnO]) against a green fluorescent protein reporter strain of Mycobacterium avium subspecies paratuberculosis, a slow growing, pathogenic mycobacterial species causing paratuberculosis in ruminants. Fluorescence was used to monitor mycobacterial growth over time, with NP concentrations of 6.25-100 MUg/mL tested for up to 7 days, and a method of data analysis was designed to permit comparison between results. Mycobacterial sensitivity to the NP was found to be NP composition specific and toxicity could be ranked in the following order: Ag > Cu(II)O > ZnO. PMID- 26618565 TI - Halide coordinated homoleptic [Fe4S4X4](2-) and heteroleptic [Fe4S4X2Y2](2-) clusters (X, Y = Cl, Br, I)--alternative preparations, structural analogies and spectroscopic properties in solution and solid state. AB - New facile methods to prepare iron sulphur halide clusters [Fe4S4X4](2-) from [Fe(CO)5] and elemental sulphur were elaborated. Reactions of ferrous precursors like tetrahalidoferrates(ii) or simple ferrous halides with [Fe(CO)5] and sulphur turned out to be efficient methods to prepare homoleptic [Fe4S4X4](2-) (X = Cl, Br) and heteroleptic clusters [Fe4S4X4-nYn](2-) (X = Cl, Br; Y = Br, I). Solid materials were obtained as salts of BTMA(+) (= benzyltrimethylammonium); the new compounds containing [Fe4S4Br4](2-) and [Fe4S4X2Y2](2-) (X, Y = Cl, Br, I) were all isostructural to (BTMA)2[Fe4S4I4] (monoclinic, Cc) as inferred from synchrotron X-ray powder diffraction. While the solid materials contain defined heteroleptic clusters with a halide X : Y ratio of 2 : 2, dissolving these compounds leads to rapid scrambling of the halide ligands forming mixtures of all five possible [Fe4S4X4-nYn](2-) clusters as could be shown by UHR-ESI MS. The variation of X and Y allowed assignment of the absorption bands in the visible and NIR; the long-wavelength bands around 1100 nm were tentatively assigned to intervalence charge transfer (IVCT) transitions. PMID- 26618566 TI - Elevated serum alpha-fetoprotein levels in patients with chronic hepatitis C virus genotype 4: not the end of the story. AB - BACKGROUND AND AIM: Elevated serum alpha-fetoprotein (AFP) is not uncommonly seen among patients with chronic hepatitis C. This study aimed to identify clinical characteristics, histological characteristics, and biochemical markers associated with increased serum AFP levels in hepatitis C virus genotype 4-infected patients with no evidence of hepatocellular carcinoma and to determine the effect of lifestyle modification on these parameters. METHODS: The study included 447 chronic hepatitis C patients with no evidence of hepatocellular carcinoma and 100 healthy controls. They underwent liver biopsies, homeostasis model assessment insulin resistance (HOMA-IR), measurement of serum insulin, leptin, adiponectin, tumor necrosis factor-alpha, and interleukin-6 levels by an enzyme-linked immunosorbent assay, and assessment of AFP levels. Eighty patients with HOMA-IR greater than 3 received prospective longitudinal lifestyle intervention. RESULTS: In a multivariate analysis, platelet count less than 140*10/cm, a mean platelet volume of at least 9.5 fl, a neutrophil-lymphocyte ratio (NLR) of at least 2, an aspartate transaminase level of at least 55 IU/l, a gamma-glutamyl transpeptidase level of at least 40 IU/l, an albumin level of up to 3.8 g/dl, HOMA-IR greater than 3, a leptin level of at least 10 pg/ml, an iron level of at least 165 MUg/dl, a ferritin level of at level 175 ng/ml, and hepatic fibrosis F3-F4 were found to be independently associated with elevated AFP levels. The lifestyle intervention significantly improved BMI, platelet indices, NLR, gamma-glutamyl transpeptidase, leptin, leptin/adiponectin ratio, tumor necrosis factor-alpha, interleukin-6, HOMA-IR, and AFP levels. CONCLUSION: Elevated insulin resistance, leptin, serum iron, ferritin, mean platelet volume, NLR, and advanced fibrosis, as well as decreased platelet count and serum albumin, are independently associated with an elevated AFP level. Lifestyle modification can improve (reduce) insulin resistance, leptin, leptin/adiponectin ratio, platelet count and their indices, NLR, and AFP level. PMID- 26618567 TI - Clarithromycin Resistance Mutations in Helicobacter pylori in Association with Virulence Factors and Antibiotic Susceptibility of the Strains. AB - Antibiotic resistance is the major cause for Helicobacter pylori eradication failure. H. pylori clarithromycin resistance mutations were evaluated in 84 (82 phenotypically clarithromycin resistant and 2 intermediately susceptible) strains by allele-specific PCR and 3'-mismatched PCR. Many (57.1%) of these strains were metronidazole resistant. Prevalence of cagA(+), cagE(+), vacA s1a, m1, i1, and i2 strains was 76.2%, 58.0%, 82.1%, 35.7%, 50.0%, and 50.0%, respectively. A2143G, A2142G, A2142C, and A2143G+A2142G mutation rates were 64.3%, 23.8%, 1.2%, and 10.7%, respectively. Strains harboring the A2142G mutation showed 5.3-fold higher clarithromycin MIC50 than those harboring the A2143G mutation. The A2143G mutation alone was 1.7-fold more common in vacA i2 strains compared with vacA i1 strains, while the A2142G mutation alone was 3-fold more frequent in vacA i1 strains than vacA i2 strains and 3.1-fold more common in metronidazole susceptible compared with metronidazole-resistant strains. Briefly, clarithromycin resistance mutations were significantly linked to vacA i allele and metronidazole susceptibility. This is the first report about associations between the A2143G mutation and less virulent vacA i2 strains, and between the A2142G mutation and more virulent vacA i1 strains. As the 2143G mutation often predicts eradication failure by clarithromycin-based regimens, the results may be linked to the better eradication of more virulent strains compared with the less virulent strains. PMID- 26618568 TI - Evaluation and characterization of trypsin inhibitor from rice bean with inhibitory activity against gut proteases of Spodoptera litura. AB - Trypsin inhibitor (TI) in rice bean (Vigna umbellata) varied spatio-temporally in different parts of the plant, with the highest level (30.9 mg/g d.w.) noted in the maturing seeds of genotype BRS-2 at 160 days after planting (DAP). The TI from rice bean seeds was isolated and purified approximately 182-fold, with a final yield of 29% using ammonium sulfate precipitation, ion exchange chromatography through DEAE-Sepharose, gel permeation through Superdex-75, and finally by affinity chromatography using a trypsin-Sepharose column. The purified TI showed a single band on SDS-PAGE under reducing conditions with an apparent molecular mass of 24 kDa. The highest activity of purified inhibitor (about 90%) was recorded at pH 4.0 at 37 degrees C, suggesting the stability of the inhibitor under acidic conditions. The TI exhibited an inhibitory effect against Spodoptera litura larvae. A progressive decline in larval weight, growth, and survival rate of larval development was observed after feeding S. litura larvae on a diet supplemented with increasing concentrations of rice bean TI. The highest TI content in the seeds nearing maturity correlates to the role of TIs in protecting against insect pests. The study clarifies the role of rice bean protease inhibitors as a potential strategy against insectpests of economic importance. PMID- 26618569 TI - Two new polyacetylene derivatives from the Red Sea sponge Xestospongia sp. AB - Two new polyacetylenes (1 and 2), along with two known C-30 steroids (3 and 4) were identified from the Red Sea sponge, Xestospongia sp. The chemical structures were determined based on extensive spectroscopic measurements 1D (1H, 13C and DEPT) and 2D (COSY, HSQC and HMBC) NMR, UV, IR and MS. The new compounds 1 and 2 were evaluated for their antimicrobial and antitumor activities. 1 and 2 were active against multidrug- resistant bacteria with MICs ranged from 2.2 to 4.5 MUM. No toxicity was recorded for the two tested compounds up to 5 MUM using Artemia salina as a test organism. Compound 2 showed excellent antifungal activity against some pathogenic fungi such as Aspergillus niger and Candida albicans (MIC 2.2-2.5 MUM) and antitumor activity against both Ehrlich ascites carcinoma and lymphocytic leukemia (LD50 5.0 MUM). PMID- 26618570 TI - The extract, LXB-1, from the barks of Liriodendron * hybrid, induced apoptosis via Akt, JNK and ERK1/2 pathways in A549 lung cancer cells. AB - The effect of LXB-1, an extract from Liriodendron * hybrid, was determined on A549 human lung adenocarcinoma cell lines. Growth inhibition of LXB-1 was analyzed by MTT assay. Cancer cell cycle was measured by flow cytometry. To verify the apoptosis effect of LXB-1 on A549 cells, annexin V/PI double staining assay was performed. The expression levels of proapoptotic proteins were also measured by western blot. The potential mechanisms of LXB-1 inducing apoptosis - the expression and phosphorylation of ERK, p38, JNK and Akt - were investigated by western blot. The IC50 values of LXB-1 on A549 for 24, 48 and 72 h treatment were determined to be 12.97+/-1.53 MUg/mL, 9.55+/-1.42 MUg/mL, and 5.90+/-0.74 MUg/mL, respectively. LXB-1 induced an obvious G2/M cell cycle arrest in A549 cells and resulted in significant cell apoptosis. LXB-1 also increased the cleavage of both caspase-3 and caspase-9, and greatly decreased the protein levels of Bcl-2. Moreover, LXB-1 increased the expression of phosphorylated JNK but decreased the levels of phosphorylated ERK1/2 and Akt. These results suggest that that LXB-1 induced apoptosis through JNK, ERK1/2, and Akt pathways in A549 cells. PMID- 26618571 TI - Anti-biofilm activity of alpha-mangostin isolated from Garcinia mangostana L. AB - This study was carried out to further examine the anti-biofilm activity of alpha mangostin (alphaMG) isolated from Garcinia mangostana L. grown in Vietnam, against a strongly biofilm producing Streptococcus mutans, a major causative agent of dental caries. The obtained data indicated that topical applications (twice-daily, 60 s exposure each) of 150 MUM alphaMG during biofilm formation on the surfaces of hydroxyapatite disks (sHA) by S. mutans UA159 resulted in 30.7% reduction in biofilm accumulation after 68 h of growth. The treatment did not affect the viability of S. mutans cells in the biofilms. The surface activities of two key enzymes responsible for biofilm formation, i.e. the glycosyltransferases GtfB and GtfC, were reduced by 20 and 35%, respectively (vs. vehicle control, P < 0.05). Interestingly, alphaMG specifically targeted S. mutans in mixed biofilms, resulting in the decrease of the S. mutans population and total biofilm biomass. alphaMG was also found to accumulate within the biofilm of S. mutans up to 4.5 MUg/biofilm, equal to a concentration of >10 MUM/biofilm. In conclusion, this study confirmed anti-biofilm activity of alphaMG against S. mutans. A brief exposure to alphaMG may suppress biofilm formation by targeting key enzymes imvolved in biofilm formation. PMID- 26618572 TI - Purinergic signaling and the functioning of the nervous system cells. AB - Purinergic signaling in the nervous system has been the focus of a considerable number of studies since the 1970s. The P2X and P2Y receptors are involved in the initiation of purinergic signaling. They are very abundant in the central and peripheral nervous systems, where they are expressed on the surface of neurons and glial cells--microglia, astrocytes, oligodendrocytes and Schwann cells and the precursors of the latter two. Their ligands--extracellular nucleotides--are released in the physiological state by astrocytes and neurons forming synaptic connections, and are essential for the proper functioning of nervous system cells. Purinergic signaling plays a crucial role in neuromodulation, neurotransmission, myelination in the CNS and PNS, intercellular communication, the regulation of ramified microglia activity, the induction of the response to damaging agents, the modulation of synaptic activity and other glial cells by astrocytes, and the induction of astrogliosis. Understanding these mechanisms and the fact that P2 receptors and their ligands are involved in the pathogenesis of diseases of the nervous system may help in the design of drugs with different and more effective mechanisms of action. PMID- 26618573 TI - Proteasomes raise the microtubule dynamics in influenza A (H1N1) virus-infected LLC-MK2 cells. AB - The dynamics of microtubule networks are known to have an impact on replication of influenza A virus in some cellular models. Here we present evidence suggesting that at late stages of LLC-MK2 cell infection by influenza A (H1N1) virus the ubiquitin-proteasome protein degradation system participates in destabilization of microtubules, and favours virus replication. Chemical inhibition of proteasome activity partially suppresses influenza A virus replication, while stimulation of proteasome activity favours influenza A virus replication. Conversely, in another cellular model, A549 cells, inhibitors and activators of proteasomes have a small effect on influenza A virus replication. These data suggest that influenza A virus might take selective advantage of proteasome functions in order to set up a favourable cytoskeletal "environment" for its replication and spread. Furthermore, the relationship between influenza virus and the host cell is likely to depend on both the cellular model and the virus strain. PMID- 26618574 TI - Integrating a Career Planning and Development Program into the Baccalaureate Nursing Curriculum. Part II. Outcomes for New Graduate Nurses 12 Months Post Graduation. AB - New graduate nurses' (NGNs) transition into the nursing workforce is characterized as stressful and challenging. Consequently, a high percentage of them leave their first place of employment or the profession entirely within one year of graduation. Nursing literature describes this complicated shift from student to registered nurse, however, limited attention has focused on strategies that could be implemented during students' academic programs to prepare them for this difficult transition period. Therefore, a longitudinal intervention study was conducted to examine the influence of a career planning and development (CPD) program on the development of career resilience in baccalaureate nursing students and at 12 months post-graduation (NGN). The findings support including structured and progressive curriculum-based CPD opportunities in academic programs, not only for the positive outcomes that accrue to students, but also because of the benefits they extend to NGNs as they make the transition to their first professional nursing role. PMID- 26618575 TI - Integrating a Career Planning and Development Program into the Baccalaureate Nursing Curriculum: Part III. Impact on Faculty's Career Satisfaction and Confidence in Providing Student Career Coaching. AB - As career satisfaction has been identified as a predictor of retention of nurses across all sectors, it is important that career satisfaction of both new and experienced nursing faculty is recognized in academic settings. A study of a curriculum-based career planning and development (CPD) program was conducted to determine the program's effects on participating students, new graduate nurses, and faculty. This third in a series of three papers reports on how the CPD intervention affected faculty participants' sense of career satisfaction and confidence in their role as career educators and coaches. Faculty who participated in the intervention CPD intervention group reported an increase in confidence in their ability to provide career coaching and education to students. They further indicated that their own career development served to enhance career satisfaction; an outcome identified as a predictor of faculty career satisfaction. Study results suggest that interventions such as the one described in this paper can have a potentially positive impact in other settings as well. PMID- 26618576 TI - Integrating a Career Planning and Development Program into the Baccalaureate Nursing Curriculum: Part I. Impact on Students' Career Resilience. AB - Student nurses often embark on their professional careers with a lack of the knowledge and confidence necessary to navigate them successfully. An ongoing process of career planning and development (CPD) is integral to developing career resilience, one key attribute that may enable nurses to respond to and influence their ever-changing work environments with the potential outcome of increased job satisfaction and commitment to the profession. A longitudinal mixed methods study of a curriculum-based CPD program was conducted to determine the program's effects on participating students, new graduate nurses, and faculty. This first in a series of three papers about the overall study's components reports on undergraduate student outcomes. Findings demonstrate that the intervention group reported higher perceived career resilience than the control group, who received the standard nursing curriculum without CPD. The program offered students the tools and resources to become confident, self-directed, and active in shaping their engagement in their academic program to help achieve their career goals, whereas control group students continued to look uncertainly to others for answers and direction. The intervention group recognized the value of this particular CPD program and both groups, albeit differently, highlighted the key role that faculty played in students' career planning. PMID- 26618577 TI - Lactoferrin gene promoter variants and their association with clinical and subclinical mastitis in indigenous and crossbred cattle. AB - Lactoferrin (Lf) gene promoter was screened for the presence of single nucleotide polymphism in indigenous and crossbred cattle from North India and to evaluate its association with Mastitis. Study revealed the presence of genetic variation in regulatory region of bovine Lactoferrin gene using PCR-RFLP technique. Three genotypes namely GG, GH and HH were identified. A single nucleotide change, from guanine to adenine at 25th position was found to be significantly associated (p<0.05) with clinical mastitis in indigenous Sahiwal and crossbred Karan Fries cattle maintained at organised herd of National Dairy Research Institute, Karnal. A non-significant association was observed between subclinical mastitis, somatic cell score (SCS), and GG genotype in Karan Fries cattle, however, a lower SCS was observed in animals having GG genotype. Overall a lower incidence of clinical mastitis was recorded in those animals having GG genotype of Lf in Sahiwal and Karan Fries (KF) cattle. The SNP identified in the promoter region may effect expression lactoferrin protein, which may lead to different levels of antibacterial and anti-inflammatory activity of Lf gene. Results from this study indicated the probable role played by Lactoferrin promoter to serve as candidate gene for mastitis susceptibility among indigenous and crossbred milch cattle. PMID- 26618578 TI - Apoptotic-like changes of boar spermatozoa in freezing media supplemented with different antioxidants. AB - This study evaluated the effect of supplementing the freezing extender with exogenous anti-oxidants on apoptotic-like changes in post-thaw boar spermatozoa. A total of 36 ejaculates were resuspended in standard lactose-egg yolk-glycerol extender supplemented with antioxidant to final concentrations of 0 (as control), 2.5mM GSH (group I), 5.0 mM GSH (group II), 150 IU/mL SOD (group III), 300 IU/mL SOD (group IV), 200 IU/mL CAT (group V), 400 IU/mL CAT (group VI), 150 IU/mL SOD+200 IU/mL CAT (group VII), 300 IU/mL SOD+400 IU/mL CAT (group VIII). Sperm motility and apoptotic-like changes were determined before and after freeze thawing. The various markers of apoptotic-like changes were measured: plasma membrane permeability by YO-PRO-1/PI assay, phosphatidylserine (PS) translocation across the plasma membrane using fluorescein-labeled Annexin-V, mitochondrial transmembrane potential detected by JC-1, and DNA fragmentation evaluated by TUNEL assay. The highest percentage of progressive motile sperm was noticed in group II (PM% 64.2+/-15.4) compared with control (PM% 36.8+/-5.5). The supplementation of 400 IU/mL CAT (group VI) revealed significant (P<0.01) reduction of apoptotic-like changes (YO-PRO-1+/PI-: 13.1+/-7.5%, AnV+/PI-: 9.9+/ 4.1%) in frozen-thawed spermatozoa compared with extender supplemented with 200 IU/mL CAT (group V). Irrespective of the concentration used, SOD and CAT in combination (group VII and group VIII) significantly (P<0.01) improved post-thaw sperm survival compared with the control. Evaluation by TUNEL assay revealed that cryopreservation and thawing did not induce DNA fragmentation in boar spermatozoa. PMID- 26618579 TI - Cytomorphometry of serosal effusion in dogs. AB - Cytomorphometry made on cytological slides is the quantitative method of precise analysis of cellular structures, including both cytoplasm and nucleus. The aim of this study was to describe cytomorphometric parameters of mesothelial cells in the course of benign reactive and malignant proliferation and to compare them to carcinomas and adenocarcinomas located within serosal cavities in dogs. The second aim was to evaluate applicability of cytomorphometry to diagnostics of diseases causing accumulation of effusion in serosal cavities. Cytological samples of normal and non-malignant mesothelium, mesothelioma and various carcinomas were collected from dogs. Cytomorphometry was made on the smears stained with Giemsa solution. Mean nuclear and cellular perimeter, mean nuclear and cellular area, mean nuclear and cellular diameter, and mean nuclear and cellular roundness were determined. Moreover, nuclear to cytoplasmic ratio (N/C) was calculated. The data revealed statistically significant differences for all parameters, excluding mean nuclear perimeter, between compared groups. Normal mesothelium cells and their nuclei were significantly smaller and more elongated than cells and nuclei of both benign reactive and malignant neoplastic mesothelium. Only a few differences were observed between benign reactive mesothelium cells and mesothelioma cells - mean nuclear area and mean nuclear diameter of benign reactive mesothelium cells were significantly larger and N/C ratio was higher in comparison to mesothelioma cells. Even though some significant differences were observed, considerable overlap of these cytomorphometric parameters in animals with different diseases limited practical role of these observations. Cytomorphometric analysis of cellular samples collected from dogs with proliferative processes affecting serosal cavities can be only an auxiliary method increasing accuracy of preoperative diagnosis. PMID- 26618580 TI - The influence of experimental administration of low zearalenone doses on the expression of Th1 and Th2 cytokines and on selected subpopulations of lymphocytes in intestinal lymph nodes. AB - The aim of this study was to characterize the immune response taking place in ileocecal lymph nodes (ICLN) in control (n=15) and zearalenone (ZEN)-treated (n=15) pigs. The experiment was carried out over 42 days; a dose of 0.1 mg kg-1 feed day-1 of ZEN was administered to the animals. The dose used in the experiment was at a level where no adverse effects are observed (NOAEL) in the ovaries, uterus and vagina. ICLN samples for analysis were collected on the 14th, 28th and 42nd day of the experiment. The analysis of cytokine concentration in the tissues showed that pigs treated with ZEN had an increased level of cytokines produced by helper Th1 lymphocytes (IL-2, IL-12 and IFN-gamma) on the 28th day of the experiment. The level of cytokines produced by helper Th2 lymphocytes (IL-4 and IL-10) was characterized by a statistically non-significant upward trend, as compared with the control group. Flow cytometry showed a linear decrease in the percentage of CD21+ B, CD2+ T and CD4+CD8- T cells and an increase in the percentage of CD8+CD4- and TCRgammadelta + T cells in pigs treated with ZEN. Both ZEN and alpha-ZEL (alpha-zearalenone) concentrations increased over time in the liver, but only ZEN concentration increased in ICLN. The results obtained demonstrate that a NOAEL concentration of ZEN shifts the immune response in pig ICLN towards Th1/Th17, probably with a simultaneous activation of M1 macrophages. Moreover, we observed an increase in humoral cytokine secretion; this can be explained by a negative feedback loop and a phenotypic switch of macrophages from M1 to M2, as well as a switch of immune response from Th1 to Th2 type. ZEN can therefore influence the process of cytokine secretion and the percentage of lymphocytes in ileocecal lymph nodes. PMID- 26618581 TI - The influence of the feeding Flour Beetle Tribolium confusum-infested fodder on the selected indices of the health status of rats. AB - The present experiment was designed to demonstrate differences in the degree of fodder contamination with benzoquinones at various Tribolium confusum levels, the impact of infested feed on the beetle population and the impact of infested feed on the health status of rats. The feeding studies were done on female rats divided into 3 groups: a control group and two experimental groups. Experimental groups were fed with a fodder infested by 150 individuals of T. confusum per kg (group D1) and 300 individuals of T. confusum per kg (group D2). The insects were grown in the fodder for 5 months and the contaminated fodder was given to the laboratory animals for 8 weeks. After that period the rats were sacrificed, blood was drawn for morphological, biochemical and immunological analyses, as well as the samples of internal organs were taken for histopathology. Regardless of initial degree of infestation, after 5 months incubation period the content of benzoquinones in fodder reached the maximum level that reduced beetle population. The resulting concentration to benzoquinones had no effect upon feed intake nor growth of rate, whereas caused the presence of these substances in feces, urine and also in tissues which was indicated by pathological lesions observed in the study. The results obtained point to the possibility of the benzoquinones accumulation in the organisms of farm animals fed fodder containing pests. PMID- 26618582 TI - Characteristic and susceptibility to enterocins of enterococci in pheasants possessing virulence factor genes. AB - With an increasing number of pheasants as gamebirds being reared each year, these species are becoming a more prominent part of the workload of many veterinary practices. Only limited information can be found concerning the microflora of common pheasants. A significant part of the obligate microflora consists of lactic acid bacteria, including enterococci. In this study, faeces were sampled from 60 pheasants aged 16-17 weeks. Enterococcal counts reached 5.48+/-1.9 (log10) CFU/g. Strains (17) were taxonomically classified to the genus Enterococcus using the Maldi-Tof identification system; they were allotted to the species E. hirae (58.8%), E. faecium (23.5%) and E. faecalis (17.7%) by highly probable species identification or by secure genus identification/probable species identication. Species allocation was also confirmed using conventional biochemical tests. Most strains formed beta-hemolysis. Gelatinase active phenotype was found in three E. faecalis strains. Enterococci were beta glucuronidase negative, mostly trypsin negative with slight or moderate production of alpha-chymotrypsin. EH52b and EF42 strains possessed the highest potential for pathogenicity. Average value of lactic acid was 1.78+/-0.33 mmo/L. Most strains were tetracycline resistant (82.4%). Polyresistant E. faecalis strains with positive gelatinase phenotype and possessing virulence factor genes confirmed using PCR (gelE, efaAfs, ccf cob, cpd) were sensitive to enterocins (activity 1600-25,600 AU/mL). PMID- 26618583 TI - Distribution and chemical coding patterns of cocaine- and amphetamine-regulated transcript-like immunoreactive (CART-LI) neurons in the enteric nervous system of the porcine stomach cardia. AB - The aim of this study was to determine the presence of cocaine- and amphetamine regulated transcript-like immunoreactive (CART-LI) neurons and co-localisation of CART with vesicular acetylcholine transporter (VAChT), neuronal nitric oxide synthase (n-NOS), vasoactive intestinal polypeptide (VIP), substance P (SP) and leu-enkephalin (LENK) in the enteric nervous system of the porcine gastric cardia by using a double-labelling immunofluorescence technique. CART-LI neurons were observed in the myenteric plexus (18.2+/-2.6%). A dense network of CART-LI nerve fibers was mainly observed in the muscular layer. CART showed co-localization mainly with VAChT, n-NOS, VIP and to a lesser degree with LENK and SP. Distribution of CART and its co-localization with other neurotransmitters suggest that this peptide plays an important role in gastric motility in the pig. PMID- 26618584 TI - Effect of low-energy laser irradiation and antioxidant supplementation on cell apoptosis during skeletal muscle post-injury regeneration in pigs. AB - The aim of this study was to evaluate the effect of low-energy laser irradiation, coenzyme Q10 and vitamin E supplementation on the apoptosis of macrophages and muscle precursor cells during skeletal muscle regeneration after bupivacaine induced injury. The experiment was conducted on 75 gilts, divided into 5 experimental groups: I--control, II--low-energy laser irradiation, III--coenzyme Q10, IV--coenzyme Q10 and vitamin E, V--vitamin E. Muscle necrosis was induced by injection of 0.5% bupivacaine hydrochloride. The animals were euthanized on subsequent days after injury. Samples were formalin fixed and processed routinely for histopathology. Apoptosis was detected using the TUNEL method. The obtained results indicate that low-energy laser irradiation has a beneficial effect on macrophages and muscle precursor cell activity during muscle post-injury regeneration and protects these cells against apoptosis. Vitamin E has a slightly lower protective effect, limited mainly to the macrophages. Coenzyme Q10 co supplemented with vitamin E increases the activity of macrophages and muscle precursor cells, myotube and young muscle formation. Importantly, muscle precursor cells seem to be more sensitive to apoptosis than macrophages in the environment of regenerating damaged muscle. PMID- 26618585 TI - Tumor necrosis factor-alpha (TNFalpha) gene polymorphism and expression of membrane-bound TNFalpha protein on CD11b+ and IgM+ cells in cows naturally infected with bovine leukemia virus. AB - The aim of this study was to determine whether SNP at position -824 (promoter region) of the TNFalpha gene significantly differentiates the size of IgM+, CD5+ and CD11b+ cell subpopulations and affects the expression of membrane-bound TNFalpha protein (mTNFalpha) on these cells and their susceptibility to BLV infections. In this study, significant differences were determined for the first time between TNFalpha genotypes and the percentage of cells with the CD11b+TNFalpha+p24+ immunophenotype. Furthermore, greater expansion of lymphocytes with the IgM+TNFalpha+p24+ immunophenotype was reported in cows with the G/G genotype than in A/A homozygotes. Cells with the above immunophenotype were more frequently observed in cows with persistent leukocytosis than in aleukemic cattle. Our results suggest that polymorphism of the TNFalpha-824 A>G gene and mTNFalpha protein expression play an important role in the pathogenesis of enzootic bovine leukosis. PMID- 26618587 TI - Dynamic expression profile of DNA methyltransferases in rat testis development. AB - DNA methyltransferases (Dnmts) are unique and perform specific functions during male germ cell development. To further characterize the significance of Dnmts in the events leading to production of spermatozoa, we investigated whether the expression patterns in Dnmt1, Dnmt3a, Dnmt3b and Dnmt3l were apparent in rat testes at different time points during development. The qRT-PCR results showed that expression levels of Dnmt3a and Dnmt3l were abundant before birth and were present at the highest levels in testes tissue at 18.5 days postcoitus (dpc), and gradually decreased from day 0 postpartum (dpp) to 90 dpp. Expression of Dnmt1 and Dnmt3b reached a peak after birth (P <0.01), and then gradually reduced until adulthood. Western blotting and immunolocalization analysis of Dnmt3a and Dnmt3b further confirmed the differential expression and localization of the two proteins during rat testis development. The dynamic expression profile of Dnmts implies specific and potentially nonredundant roles for each of these enzymes in the developing rat testis. PMID- 26618586 TI - Differentially expressed proteins in the blood serum of piglets in response to a diet supplemented with inulin. AB - In the present study we introduced a two-dimensional electrophoresis and matrix assisted laser desorption/ionisation time of flight mass spectrometry-based proteomic workflow to identify proteins that show altered expression as a result of the addition of 2% of water extract of inulin-type fructans to the diet of growing piglets. This analysis allowed us to detect an average of 240 spots per gel with a mass range from 10 to 250 kDa and a pH ranging from 3 to 10. Twenty protein spots were found to show statistically significant differences in their expression. Of these, 7 protein spots were up-regulated, whereas 13 showed down regulation in response to the experimental diet. In total, 13 spots were identified, representing 8 distinct gene products. The experimental diet caused a significant change in proteins directly or indirectly involved in hemostasis and the innate immune response. Increased levels of fibrinogen along with decreased plasminogen expression may indicate that a fructan-rich diet favours the deposits of fibrin and promotes blood clotting. We also found increased expression of vitronectin and the alpha subunit of the complement component C8 which may protect the host organism against excessive cytolitic activity of the activated complement. The piglets from the experimental group had slightly increased values of IgG and IgA, whereas the IgM level tended to be decreased. The fructan-rich diet did not have any influence on plasma total cholesterol, HDL and LDL cholesterol and triglyceride levels. PMID- 26618588 TI - Effect of phytogenics on growth performance, fecal score, blood profiles, fecal noxious gas emission, digestibility, and intestinal morphology of weanling pigs challenged with Escherichia coli K88. AB - Phytogenic feed additives have become attractive alternatives for use in animal diets. The objective of the present study was to evaluate the effect of a phytogenic-based feed additive on growth performance, nutrient digestibility, blood profiles, fecal noxious gas emission, and intestinal morphology of weaning pigs after dietary challenge with E. coli K88. A total of 120 crossbred pigs [(Yorkshire*Landrace)*Duroc)] with an initial body weight (BW) of 6.09+/-0.96 kg (21 d of age) were assigned randomly to 1 of the 4 dietary treatments. Each pen housed 5 pigs, and there were 6 pens/treatment. Treatments included: T1, negative control (without antibiotics); T2, T1+antibiotic; T3, T1+0.05% phytogenics; and T4, T1+0.2% commercial mix of organic acids. Overall, the average daily gain (ADG) with the T3 treatment was higher (P<0.05). At wk 1, the apparent total tract digestibility (ATTD) of dry matter (DM) was increased (P<0.05) with T4 treatment. The ATTD of ash with T3 and T4 treatments was greater (P<0.05). At wk 3, pigs fed with the T4 diet had a significantly higher (P<0.05) ATTD of DM. The ATTD of ash and calcium (Ca) was significantly increased (P<0.05) with the T4 treatment. Pigs fed with the T3 diet had a higher (P<0.05) ATTD of phosphorus (P). At wk 6, the ATTD of ash was significantly increased (P<0.05) with the T1 and T3 treatments. The data indicate that phytogenics positively affect growth performance of weaning pigs, indicating that their use as an alternative in the diets of weaning pigs can significantly improve ADG, under challenge with E.coli K88. PMID- 26618589 TI - Morphological defects of epididymal spermatozoa in male roe deer (Capreolus capreolus) during the reproductive season. AB - The aim of this study was to analyse the morphology of the epididymal spermatozoa of male roe deer obtained postmortem at the beginning (May), peak (July/August) and the end (September) of the reproductive season. Spermatozoal abnormalities were divided into major (associated with impaired fertility) and minor (not associated with impaired fertility) defects. The highest percentage of abnormal spermatozoa was observed in May (17.78+/-1.88%), with a much higher proportion of major (12.35+/-1.11%) than minor defects (5.43+/-1.59%) being observed. The percentage of abnormal spermatozoa was lowest during the peak of the reproductive season (4.97+/-1.13%), with the proportion of major (2.68+/-0.78%) and minor defects (2.28+/-0.45%) being comparable during this period. The percentage of abnormal spermatozoa increased again in September (11.05+/-1.60%), with the major defects (6.15+/-1.04%) slightly surpassing the minor defects (4.90+/-0.77%); however, total abnormalities still remained lower than those found in May. These differences were statistically significant, with the exception of the difference in minor defects between the pre-rut and post-rut periods. These results indicate that the best period to collect epididymal spermatozoa from roe deer postmortem is the peak of the reproductive season (July/August); however, they can also be recovered at the end of the reproductive season (September), as the percentage of major defects is relatively low at this time. This study provides the basis for further research to determine optimal methods for the storage and cryopreservation of epididymal spermatozoa in this species. PMID- 26618590 TI - Identification of new 18S rRNA strains of Babesia canis isolated from dogs with subclinical babesiosis. AB - In this study, we used PCR to detect and characterize B. canis from naturally infected dogs in Poland with subclinical babesiosis by amplifying and sequencing a portion of the 18S ribosomal RNA (rRNA) gene. Venous blood samples were collected from ten dogs with subclinical babesiosis. A 559-bp fragment of the B. canis 18S rRNA gene was amplified by PCR. Sequencing of the PCR products led to the identification of a new variant of Babesia canis, differing from the previously detected protozoa genotypes (18S rRNA-A and 18S rRNA-B) with nucleotide substitutions in positions 150 and 151 of the tested gene fragment. The results indicate the emergence within the Polish territory of a new, previously unencountered Babesia canis genotype responsible for the development of subclinical babesiosis. PMID- 26618591 TI - Determination of the cytotoxic activity of Campylobacter strains isolated from bovine and swine carcasses in north-eastern Poland. AB - The study was carried out to determine the cytotoxin production by Campylobacter spp. isolated from slaughtered cattle and swine in north-eastern Poland. In total three commercial slaughterhouses were sampled during one year. Carcass swabs were taken to detect the level of Campylobacter spp. contamination. Campylobacter spp. was found in 50 (34%) out of 147 swine carcasses examined. PCR analysis revealed 4 (8%) isolates to be C. jejuni, and 46 (92%) to be C. coli. From a total of 373 bovine carcasses, Campylobacter spp. were isolated from 49 (13.1%) samples. The results regarding the occurrence of cdt genes associated with cytotoxicity indicated that 100% of C. jejuni and 67.4% C. coli obtained from pigs had all three cdtA, cdtB and cdtC genes. In case of C. jejuni strains isolated from cattle all cdt genes were confirmed in 93.9% isolates. The isolates possessesing all cdt genes had higher cytotoxic activity against cell lines used. The isolates both from cattle and swine were characterized by the highest cytotoxicity against HeLa cells. The values obtained reached 80.8% for C. jejuni isolates from cattle and 76.2% for C. jejuni and 69.0% for C. coli isolates from swine. High prevalence of cytotoxicity in Campylobacter spp. indicates a significant epidemiological role of this pathogen in human infections. PMID- 26618592 TI - Cytological evaluation of tracheal aspirate and broncho-alveolar lavage fluid in comparison to endoscopic assessment of lower airways in horses with recurrent airways obstruction or inflammatory airway disease. AB - The aim of the present study was to compare the grade of discharge accumulation in the tracheal lumen, area of tracheal bifurcation, main bronchi and the tracheal septum thickness with the cytology of the tracheal aspirate (TA) and broncho-alveolar lavage fluid (BALF) in horses with recurrent airways obstruction and inflammatory airway disease from those horses. This study was conducted on 96 horses with RAO, 139 horses with IAD and 10 control horses. In all the horses, both clinical and endoscopic examinations were performed. During endoscopy, a score of mucus accumulation was estimated in 3/4 lower of the trachea and in the tracheal bifurcation. In addition, thickening of the tracheal septum was also assessed; tracheal aspirates and broncho-alveolar lavage were performed. An estimate of cell percentage was done in TA and BALF samples. In horses suffering from RAO and IAD, there was a positive correlation between the percentage of neutrophils and the accumulation of discharge, and in the IAD group, there was a negative correlation between the percentage of eosinophils and the accumulation of discharge. There was no correlation between tracheal septum thickening and the percentage of neutrophils and/or eosinophils. PMID- 26618593 TI - Helmintofauna of turbot Scophthalmus maximus (Linnaeus, 1758) from the southern Baltic Sea including new data. AB - Turbot Scophthalmus maximus (Linnaeus, 1758) is a fish belonging to the Pleuronectiformes order. It is commonly observed in waters of the northern Atlantic, and also in the Baltic Sea. As an economically significant species, it is fished on an industrial scale, and also farmed in some European countries. Seventy-two turbots from the Gulf of Gdansk (26th ICES zone) were examined for parasite presence in the years 2010-2012. The study revealed the presence of the tapeworm Bothriocephalus scorpii (Muller, 1776) and acanthocephalan Corynosoma semerme (Forssell, 1904). The overall (both parasites) prevalence of turbot infection was 100% with a mean intensity of 18.7. C. semerme is a parasite which has not been noted so far in turbot from the southern Baltic. The presence of C. semerme in turbot was emphasized in the context of possible infection of terrestrial mammals, including humans. PMID- 26618594 TI - Outbreak of ranavirus infection in sheatfish, Silurus glanis (L.), in Poland. AB - Ranavirus was detected in adult sheatfish, with clinical signs, on a Polish fish farm in February. Farm isolates induced a strong cytopathic effect in vitro and were identified by electron microscopy and PCR amplification of the ranavirus specific gene fragment. Restriction analysis with the Acc I enzyme showed that isolated ranaviruses were different from the epizootic heamatopoietic necrosis virus (EHNV). We sequenced a fragment of the major capsid protein (MCP) gene and found that isolates were similar to other strains of ranaviruses, available in GenBank. PMID- 26618595 TI - Circannual changes in serum concentrations of thyroxine, calcitonin and parathormone in immature and mature red deer females (Cervus elaphus). AB - The aim of this study was to determine circannual changes in the serum concentrations of thyroxine, calcitonin and parathormone in mature and immature red deer females. Blood samples from 8 hinds were collected monthly for 26 months. Secretions of thyroxine and calcitonin showed circannual rhythms with significantly higher levels in the immature hinds compared to the mature animals (p<0.05). For thyroxine, the concentration was higher in the winter/spring period than in summer/autumn (p<0.05), while for calcitonin the concentration profile was the opposite (p<0.05). The concentration of parathormone was significantly higher in summer/autumn that in the other months of the experiment (p<0.01). These results may indicate that the hormones investigated may be involved in the regulation of seasonal reproductive activity and in processes contributing to entering puberty in red deer females. PMID- 26618596 TI - Leukocyte modifications during the first month after foaling in mares and their newborn foals. AB - During early post-partum period both neonatal foals and peripartum mares are most susceptible to diseases. The aim of this study was to establish physiologic modifications of leukogram during the first month after foaling in mares and their newborn foals. To this end blood samples were collected from nine mares and nine foals (T0-T10), every three days from the 1st day until the 30th day after foaling. Samples were analysed for white blood cell (WBC) count and differential leucocyte counts. Two-way repeated measure analysis of variance (ANOVA) showed, in postpartum mares WBC showed significant higher values at T0 (9.02+/-0.76) in respect to other time points, and at T2 (8.08+/-0.53) and T3 (7.92+/-0.59) compared to T1 (6.98+/-0.43), whereas in foals lower WBC values at T0 (6.11+/ 0.49) compared to other experimental periods except T1 (6.90+/-0.94), and at T1 compared to T8 (7.95+/-0.61) and T10 (7.90+/-0.36) were observed. The differential leucocyte counts showed significant modifications in the percentage of neutrophils (pi<0.001) and lymphocytes (p<0.001) both in postpartum mares and in foals during the experimental period. Furthermore ANOVA showed significant differences between postpartum mares and foals (P<0.01) in all studied parameters, and between postpartum mares and control mares in WBC and neutrophils values. The obtained results provide suitable information about the influence of foaling on leukogram of periparturient mares and reveal WBC dynamics in newborn foals during the first month post-partum. PMID- 26618597 TI - Genetic characterization of coagulase-positive staphylococci isolated from healthy pigeons. AB - Coagulase-positive staphylococci (CoPS) are opportunistic veterinary pathogens, of which Staphylococcus aureus, S. delphini and S. intermedius can be isolated from pigeons. The biochemical identification of S. delphini and S. intermedius isolates may be incorrect, because of their phenotypic similarity. The purpose of the present study was to isolate and identify CoPS from domestic and feral pigeons and to determine their genetic relatedness by PFGE. A total number of 31 isolates of CoPS were obtained, 15 were identified as S. delphini group B, six as S. aureus, four as S. delphini group A, three as S. intermedius and three as S. schleiferi subsp. coagulans. The results indicate that S. delphini group B is the predominant CoPS species among pigeons studied. PFGE restriction patterns of S. delphini group A and S. delphini group B form separate clusters, demonstrating their genetic heterogeneity. Indistinguishable or very similar PFGE patterns observed among S. delphini group B isolates from domestic and feral pigeons confirm the possibility of CoPS transmission between these birds. PMID- 26618598 TI - Regulation of melatonin secretion in the pineal organ of the domestic duck--an in vitro study. AB - The aim of study was to determine the mechanisms regulating melatonin secretion in the pineal organs of 1-day-old and 9-month-old domestic ducks. The pineals were cultured in a superfusion system under different light conditions. Additionally, some explants were treated with norepinephrine. The pineal glands of 1-day-old ducks released melatonin in a well-entrained, regular rhythm during incubation under a 12 hrs light:12 hrs dark cycle and adjusted their secretory activity to a reversed 12 hrs dark:12 hrs light cycle within 2 days. In contrast, the diurnal changes in melatonin secretion from the pineals of 9-month-old ducks were largely irregular and the adaptation to a reversed cycle lasted 3 days. The pineal organs of nestling and adult ducks incubated in a continuous light or darkness secreted melatonin in a circadian rhythm. The treatment with norepinephrine during photophases of a light-dark cycle resulted in: 1) a precise adjustment of melatonin secretion rhythm to the presence of this catecholamine in the culture medium, 2) a very high amplitude of the rhythm, 3) a rapid adaptation of the pineal secretory activity to a reversed light-dark cycle. The effects of norepinephrine were similar in the pineal organs of nestlings and adults. In conclusion, melatonin secretion in the duck pineal organ is controlled by three main mechanisms: the direct photoreception, the endogenous generator and the noradrenergic transmission. The efficiency of intra-pineal, photosensitivity based regulatory mechanism is markedly lower in adult than in nestling individuals. PMID- 26618599 TI - The experimental osteoporosis in sheep--clinical approach. AB - The implementation of new methods of oseoporotic therapy requires tests on an animal model. One of the best is the sheep, whose numerous advantages over other models are described in the literature. The aim of this study was induction of osteoporosis using steroids and ovariorectomy methods in sheep and description of the change in parameters with regard to healthy sheep. The study was performed on female "merino" breed sheep divided into three groups: Negative control (NC) healthy animals, positive control (PC) ovariorectomised animals and steroid group (SC) where methylprednisolone was implemented. Blood tests, diagnostic arthroscopy, quantitative computed tomography and X-Ray micro-tomography of bone were carried out. Blood tests revealed a decreased level of estrogens, progesterone and increased parathormone and cortisol levels in the SC group. A decrease in bone turnover markers and an increase in bone resorption markers in all groups were also noted. Diagnostic arthroscopy revealed osteoarthrosis in PC and SC groups. Radiological density tests showed a slight decrease in PC and NC groups whereas there was more than a triple decrease in SC. Results obtained from microCT showed quickly developing osteoporosis in the SC group, which is reflected in numerous parameters analysed in this study. The best effects for osteoporosis induction were obtained using ovariorectomised sheep with methylprednisolone injections. PMID- 26618600 TI - Expression of Cyclooxygenase-2 in naturally occurring bovine cutaneous fibropapillomas. AB - Bovine cutaneous fibropapillomas are benign skin tumours characterized by epithelial and dermal proliferation and induced by Bovine papillomaviruses (BPVs). Cyclooxygenase (COX) 1 and 2 are enzymes involved in pathological conditions, such as inflammation and epithelial carcinogenesis. Here we investigated biochemically and immunohistochemically COX-2 expression in bovine cutaneous fibropapillomas. Eight of twelve fibropapillomas (67%) showed COX-2 positive immunosignal mostly in the cytoplasm of the basal cell layer, while the normal skin did not stain. Biochemical analysis confirmed the expression of COX-2 in tumour samples. This study shows COX-2 expression in cutaneous fibropapillomas, suggesting a contribution in epithelial tumour development. PMID- 26618601 TI - Epidemiological situation of turkey coryza (bordetellosis) in Poland. AB - The present study investigated the prevalence of Bordetella avium (BA) infections in turkey flocks of different production type in Poland, based on serological examination of blood samples collected between 2012 and 2014. The results of our study indicate that BA infections are very common in turkey flocks, they are possible during the whole production cycle and that probability of the past infection increases with age. This situation is causing high level of specific anti-BA maternally derived antibody transfer to hatching poults. PMID- 26618602 TI - Zebrafish: an animal model for research in veterinary medicine. AB - The zebrafish (Danio rerio) has become known as an excellent model organism for studies of vertebrate biology, vertebrate genetics, embryonal development, diseases and drug screening. Nevertheless, there is still lack of detailed reports about usage of the zebrafish as a model in veterinary medicine. Comparing to other vertebrates, they can lay hundreds of eggs at weekly intervals, externally fertilized zebrafish embryos are accessible to observation and manipulation at all stages of their development, which makes possible to simplify the research techniques such as fate mapping, fluorescent tracer time-lapse lineage analysis and single cell transplantation. Although zebrafish are only 2.5 cm long, they are easy to maintain. Intraperitoneal and intracerebroventricular injections, blood sampling and measurement of food intake are possible to be carry out in adult zebrafish. Danio rerio is a useful animal model for neurobiology, developmental biology, drug research, virology, microbiology and genetics. A lot of diseases, for which the zebrafish is a perfect model organism, affect aquatic animals. For a part of them, like those caused by Mycobacterium marinum or Pseudoloma neutrophila, Danio rerio is a natural host, but the zebrafish is also susceptible to the most of fish diseases including Itch, Spring viraemia of carp and Infectious spleen and kidney necrosis. The zebrafish is commonly used in research of bacterial virulence. The zebrafish embryo allows for rapid, non-invasive and real time analysis of bacterial infections in a vertebrate host. Plenty of common pathogens can be examined using zebrafish model: Streptococcus iniae, Vibrio anguillarum or Listeria monocytogenes. The steps are taken to use the zebrafish also in fungal research, especially that dealing with Candida albicans and Cryptococcus neoformans. Although, the zebrafish is used commonly as an animal model to study diseases caused by external agents, it is also useful in studies of metabolic disorders including fatty liver disease and diabetes. The zebrafish is also a valuable tool as a model in behavioral studies connected with feeding, predator evasion, habituation and memory or lateralized control of behavior. The aim of the present article is to familiarize the reader with the possibilities of Danio rerio as an experimental model for veterinary medicine. PMID- 26618603 TI - Can we avoid primary sclerosing cholangitis recurrence? PMID- 26618604 TI - Direct Fluorescent Detection of a Polymethoxyflavone in Cell Culture and Mouse Tissue. AB - Convenient detection methods for bioactive food compounds and their metabolites in biological samples are needed to better understand their mechanism of actions. Herein, we developed a novel approach to directly monitor and visualize the distribution of 5,3',4'-tridemethylnobiletin (TDN), a unique polymethoxyflavone metabolite derived from citrus polymethoxyflavone, in biological samples such as cultured cells and mouse colonic tissues. Our results showed that a fluorescent conjugate could be formed between TDN and 2-aminoethyl diphenyl borate (DPBA) under simple reaction conditions, which was confirmed by both Raman spectroscopy and mass spectroscopy. We further demonstrated the application of DPBA-based conjugation reaction in the characterization of TDN in different biological samples including floating cells, adherent cells, and animal tissues. This is the first report demonstrating direct fluorescent detection of polymethoxyflavone in biological samples. PMID- 26618605 TI - Coarse Woody Debris Increases Microbial Community Functional Diversity but not Enzyme Activities in Reclaimed Oil Sands Soils. AB - Forest floor mineral soil mix (FMM) and peat mineral soil mix (PMM) are cover soils commonly used for upland reclamation post open-pit oil sands mining in northern Alberta, Canada. Coarse woody debris (CWD) can be used to regulate soil temperature and water content, to increase organic matter content, and to create microsites for the establishment of microorganisms and vegetation in upland reclamation. We studied the effects of CWD on soil microbial community level physiological profile (CLPP) and soil enzyme activities in FMM and PMM in a reclaimed landscape in the oil sands. This experiment was conducted with a 2 (FMM vs PMM) * 2 (near CWD vs away from CWD) factorial design with 6 replications. The study plots were established with Populus tremuloides (trembling aspen) CWD placed on each plot between November 2007 and February 2008. Soil samples were collected within 5 cm from CWD and more than 100 cm away from CWD in July, August and September 2013 and 2014. Microbial biomass was greater (p<0.05) in FMM than in PMM, in July, and August 2013 and July 2014, and greater (p<0.05) near CWD than away from CWD in FMM in July and August samplings. Soil microbial CLPP differed between FMM and PMM (p<0.01) according to a principal component analysis and CWD changed microbial CLPP in FMM (p<0.05) but not in PMM. Coarse woody debris increased microbial community functional diversity (average well color development in Biolog Ecoplates) in both cover soils (p<0.05) in August and September 2014. Carbon degrading soil enzyme activities were greater in FMM than in PMM (p<0.05) regardless of distance from CWD but were not affected by CWD. Greater microbial biomass and enzyme activities in FMM than in PMM will increase organic matter decomposition and nutrient cycling, improving plant growth. Enhanced microbial community functional diversity by CWD application in upland reclamation has implications for accelerating upland reclamation after oil sands mining. PMID- 26618606 TI - Cobalt(i)-catalysed CH-alkylation of terminal olefins, and beyond. AB - Cobalester, a natural nontoxic vitamin B12 derivative, was found to catalyse unusual olefinic sp(2) C-H alkylation with diazo reagents as a carbene source instead of the expected cyclopropanation. PMID- 26618607 TI - A Proximal Hamstring Injury--Getting Off a Slippery Slope. PMID- 26618608 TI - Beneficial Influence of Short-Term Germination on Decreasing Allergenicity of Peanut Proteins. AB - Most allergenic storage proteins in peanuts are degraded during seed germination. By altering this natural physiological process, it might be possible to reduce peanut protein allergenicity. However, little is known about the change in allergenic proteins and their corresponding immunocreactivity, and the effects of major environmental conditions on their allergenicity during germination. In this study, the influence of different germination conditions (temperature and light) on the degradation of Ara h1 and allergenicity changes of peanut seeds was evaluated by ELISA and Western blotting. The results showed that the 40- and 65 kDa proteins in peanut seeds degraded rapidly during the time course, beginning at 60 (at 25 degrees C) and 108 h (at 20 degrees C), and the corresponding immunocreactivity of Ara h1 decreased approximately one-third after 5 to 7 d of germination. Compared with the cotyledons, the embryonic axes had a higher proportion of Ara h1, which was then degraded relatively faster during germination, resulting in a significant reduction in its allergenicity. Although a higher temperature improved the seed germination rate, it affected sprout quality (as did light); therefore, 25 degrees C and dark surroundings were suitable conditions under which peanut sprouts were processed; neither factor significantly affected the allergenicity of Ara h1. These results provided a theoretical basis for studies using biological methods to reduce peanut allergenicity. PMID- 26618609 TI - Tissue inhibitor of metalloproteinases-4 (TIMP-4) regulates stemness in cervical cancer cells. AB - Tissue inhibitor of metalloproteinase-4 (TIMP-4) belongs to a family of extracellular matrix (ECM) metalloproteinases inhibitors that are overexpressed in several cancers. However, the role of TIMP-4 during carcinogenesis is poorly understood. To evaluate TIMP-4 functions in carcinogenesis, stably transfected cells overexpressing this tissue inhibitor were used. Xenograft tumor growth, stem cell enrichment, colony formation, and gene regulation were investigated. Microarrays and in silico analysis were carried out to elucidate TIMP-4 molecular mechanisms. In the present report, we show that in nude mice, cervical cancer cells that overexpress TIMP-4 formed tumors faster than control cell-derived tumors. Furthermore, in vivo limiting dilution assays showed that fewer TIMP-4 overexpressing cells are needed for tumor formation. In vitro analyses demonstrated that TIMP-4 overexpression or exposure to human recombinant TIMP-4 (hrTIMP4) caused an enrichment of the tumor progenitor cell (TPC) population. Accordingly, genome-wide expression and signaling pathway analyses showed that hrTIMP-4 modulated cell survival, cell proliferation, inflammation, and epithelial-mesenchymal transition (EMT) signaling networks. Notably, NFkappaB signaling pathway appeared to be globally activated upon hrTIMP-4 treatment. Overall, this report provides the first example that TIMP-4 regulates carcinogenesis through enriching the TPC population in cervical cancer cells. Understanding TIMP-4 effects on tumorigenesis may provide clues for future therapies design. (c) 2015 Wiley Periodicals, Inc. PMID- 26618610 TI - Synthesis of Terminal Allenes via a Copper-Catalyzed Decarboxylative Coupling Reaction of Alkynyl Carboxylic Acids. AB - Synthesis of terminal allenes via a copper-catalyzed decarboxylative coupling reaction was developed. Aryl alkynyl carboxylic acid, paraformaldehyde, and dicyclohexylamine were reacted with CuI (20 mol %) in diglyme at 100 degrees C for 2 h to produce the terminal allene in moderate to good yields. The method showed good functional group tolerance. PMID- 26618611 TI - Systematic review on first trimester three-dimensional placental volumetry predicting small for gestational age infants. AB - OBJECTIVE: A systematic review and pooled analysis was carried out to estimate (i) the reference values and (ii) the potential value of measuring the first trimester 3D-placental volume (PV) for predicting small for gestational age (SGA) infants. METHOD: A comprehensive literature search for relevant studies was conducted using the PubMed and Web of Knowledge databases. A simulation model was generated to calculate the detection rate (DR) of the PV for SGA infants. A random variable was generated having the same number of cases, and the same means and standard deviation as those reported in the articles considered for the analysis. RESULTS: For the evaluation of the normal values of PV, 12 studies met the inclusion criteria. Four also produced an equation for PV estimation at 11 to 14 weeks. The weighted mean PV [+/-standard error of mean (SEM)] of 7519 cases was 59.40 +/- 1.533 mL. For the estimation of PV performance in predicting SGA, five studies were included. The DR of the PV was 24.7% (19.3-30.1) at a 10% false positive rate. CONCLUSION: The mean PV estimation of the studies analyzed was burdened by a high degree of heterogeneity. Instead, discordant results were reported for the possible prediction of SGA infants using PV. Surprisingly, just two articles reported the DR for SGA infants and also had proper statistical power. The discriminatory ability of using PV alone for predicting SGA appears to be modest, but could successfully be integrated into a multivariable screening method for SGA infants. PMID- 26618612 TI - Photophysical properties of symmetrically substituted diarylacetylenes and diarylbuta-1,3-diynes. AB - A series of symmetrically substituted diarylacetylenes and diaryl-1,3-butadiynes were prepared and studied with an emphasis on their spectral and photophysical properties. The photophysical characteristics of these compounds were studied in relation to their structures and the influence of solvent or temperature. The observed spectral and photophysical properties are explained using potential energy maps of the ground and excited states obtained from density functional theory calculations. The structure-property relationships of all of the compounds are discussed and compared with the appropriate diphenylacetylene and diphenyl 1,3-butadiyne derivatives. PMID- 26618613 TI - Emerging tools, concepts and ideas to track the modulator genes underlying plant drought adaptive traits: An overview. AB - Crop vulnerability to multiple abiotic stresses is increasing at an alarming rate in the current global climate change scenario, especially drought. Crop improvement for adaptive adjustments to accomplish stress tolerance requires a comprehensive understanding of the key contributory processes. This requires the identification and careful analysis of the critical morpho-physiological plant attributes and their genetic control. In this review we try to discuss the crucial traits underlying drought tolerance and the various modes followed to understand their molecular level regulation. Plant stress biology is progressing into new dimensions and a conscious attempt has been made to traverse through the various approaches and checkpoints that would be relevant to tackle drought stress limitations for sustainable crop production. PMID- 26618614 TI - Triage of ASC-H: A meta-analysis of the accuracy of high-risk HPV testing and other markers to detect cervical precancer. AB - BACKGROUND: Women with a cytological diagnosis of atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) are usually immediately referred for colposcopy. However, triage may reduce the burden of the diagnostic workup and prevent overtreatment. METHODS: A meta-analysis was conducted to assess the accuracy of high-risk human papillomavirus (hrHPV) testing and testing for other molecular markers for the detection of grade 2 cervical intraepithelial neoplasia or worse (CIN2+) or grade 3 cervical intraepithelial neoplasia or worse (CIN3+) in women with ASC-H. An additional question that was assessed was whether triage would be useful in light of the relatively high pretriage probability of underlying precancer. RESULTS: The pooled absolute sensitivity and specificity of the Hybrid Capture 2 (HC2) assay for CIN2 + (derived from 19 studies) were 93% (95% confidence interval [CI], 89% 95%) and 45% (95% CI, 41%-50%), respectively. p16(INK4a) staining (only 3 studies) had similar sensitivity (93%; 95% CI, 75%-100%) but superior specificity (specificity ratio, 1.69) to HC2 for CIN2+. Testing for paired box 1 gene methylation (only 1 study) showed a superior specificity of 95% (specificity ratio, 2.08). The average pretest risk was 34% for CIN2 + and 20% for CIN3+. A negative HC2 result decreased this to 8% and 5%, respectively, whereas a positive result upgraded the risk to 47% and 28%, respectively. CONCLUSIONS: Because of the high probability of precancer with a diagnosis of ASC-H, the utility of triage is limited. The usual recommendation for referring women with ASC-H for colposcopy is not altered by a positive triage test, whatever test is used. A negative hrHPV DNA or p16(INK4a) test may allow repeat testing, but this recommendation will depend on local decision thresholds for referral. PMID- 26618616 TI - Wide-Range Tunable Fluorescence Lifetime and Ultrabright Luminescence of Eu Grafted Plasmonic Core-Shell Nanoparticles for Multiplexing. AB - Wide-range, well-separated, and tunable lifetime nanocomposites with ultrabright fluorescence are highly desirable for applications in optical multiplexing such as multiplexed biological detection, data storage, and security printing. Here, a synthesis of tunable fluorescence lifetime nanocomposites is reported featuring europium chelate grafted onto the surface of plasmonic core-shell nanoparticles, and systematically investigated their optical performance. In a single red color emission channel, more than 12 distinct fluorescence lifetime populations with high fluorescence efficiency (up to 73%) are reported. The fluorescence lifetime of Eu-grafted core-shell nanoparticles exhibits a wider tunable range, possesses larger lifetime interval and is more sensitive to separation distance than that of ordinary Eu-doping core-shell type. These superior performances are attributed to the unique nanostructure of Eu-grafed type. In addition, these as-prepared nanocomposites are used for security printing to demonstrate optical multiplexing applications. The optical multiplexing experiments show an interesting pseudo information "a rabbit in a well" and conceal the real message "NKU." PMID- 26618615 TI - A Stretchable Electronic Fabric Artificial Skin with Pressure-, Lateral Strain-, and Flexion-Sensitive Properties. AB - A stretchable and multiple-force-sensitive electronic fabric based on stretchable coaxial sensor electrodes is fabricated for artificial-skin application. This electronic fabric, with only one kind of sensor unit, can simultaneously map and quantify the mechanical stresses induced by normal pressure, lateral strain, and flexion. PMID- 26618617 TI - 3D Scaffolded Nickel-Tin Li-Ion Anodes with Enhanced Cyclability. AB - A 3D mechanically stable scaffold is shown to accommodate the volume change of a high-specific-capacity nickel-tin nanocomposite during operation as a Li-ion battery anode. The nickel-tin anode is supported by an electrochemically inactive conductive scaffold with an engineered free volume and controlled characteristic dimensions, which engender the electrode with significantly improved cyclability. PMID- 26618618 TI - Hollow Mesoporous Silica Nanocarriers with Multifunctional Capping Agents for In Vivo Cancer Imaging and Therapy. AB - Efficient drug loading and selectivity in drug delivery are two key features of a good drug-carrier design. Here we report on such a drug carrier formed by using hollow mesoporous silica nanoparticles (HMS NPs) as the core and specifically designed multifunctional amphiphilic agents as the encapsulating shell. These nanocarriers combine the advantages of the HMS NP core (favorable physical and structural properties) and the versatility of an organic-based shell (e.g., specificity in chemical properties and modifiability). Moreover, both the properties of the core and the shell can be independently varied. The varied core and shell could then be integrated into a single device (drug carrier) to provide efficient and specific drug delivery. In vitro and in vivo data suggests that these drug nanocarriers are biocompatible and are able to deliver hydrophobic drugs selectively to target tumor cells. After the break of the pH-labile linkages in the shell, the drug payload can be released and the tumor cells are killed. PMID- 26618620 TI - Structural Basis for Dimerization and DNA Binding of Transcription Factor FLI1. AB - FLI1 (Friend leukemia integration 1) is a metazoan transcription factor that is upregulated in a number of cancers. In addition, rearrangements of the fli1 gene cause sarcomas, leukemias, and lymphomas. These rearrangements encode oncogenic transcription factors, in which the DNA binding domain (DBD or ETS domain) of FLI1 on the C-terminal side is fused to a part of an another protein on the N terminal side. Such abnormal cancer cell-specific fusions retain the DNA binding properties of FLI1 and acquire non-native protein-protein or protein-nucleic acid interactions of the substituted region. As a result, these fusions trigger oncogenic transcriptional reprogramming of the host cell. Interactions of FLI1 fusions with other proteins and with itself play a critical role in the oncogenic regulatory functions, and they are currently under intense scrutiny, mechanistically and as potential novel anticancer drug targets. We report elusive crystal structures of the FLI1 DBD, alone and in complex with cognate DNA containing a GGAA recognition sequence. Both structures reveal a previously unrecognized dimer of this domain, consistent with its dimerization in solution. The homodimerization interface is helix-swapped and dominated by hydrophobic interactions, including those between two interlocking Phe362 residues. A mutation of Phe362 to an alanine disrupted the propensity of this domain to dimerize without perturbing its structure or the DNA binding function, consistent with the structural observations. We propose that FLI1 DBD dimerization plays a role in transcriptional activation and repression by FLI1 and its fusions at promoters containing multiple FLI1 binding sites. PMID- 26618619 TI - MicroRNA-200 Family Profile: A Promising Ancillary Tool for Accurate Cancer Diagnosis. AB - Cancer is one of the most threatening diseases in the world and great interests have been paid to discover accurate and noninvasive methods for cancer diagnosis. The value of microRNA-200 (miRNA-200, miR-200) family has been revealed in many studies. However, the results from various studies were inconsistent, and thus a meta-analysis was designed and performed to assess the overall value of miRNA200 in cancer diagnosis. Relevant studies were searched electronically from the following databases: PubMed, Embase, Web of Science, the Cochrane Library, and Chinese National Knowledge Infrastructure. Keyword combined with "miR-200," "cancer," and "diagnosis" in any fields was used for searching relevant studies. Then, the pooled sensitivity, specificity, area under the curve (AUC), and partial AUC were calculated using the random-effects model. Heterogeneity among individual studies was also explored by subgroup analyses. A total of 28 studies from 18 articles with an overall sample size of 3676 subjects (2097 patients and 1579 controls) were included in this meta-analysis. The overall sensitivity and specificity with 95% confidence intervals (95% CIs) are 0.709 (95% CI: 0.657 0.755) and 0.667 (95% CI: 0.617-0.713), respectively. Additionally, AUC and partial AUC for the pooled data is 0.735 and 0.627, respectively. Subgroup analyses revealed that using miRNA-200 family for cancer diagnosis is more effective in white than in Asian ethnic groups. In addition, cancer diagnosis by miRNA using circulating specimen is more effective than that using noncirculating specimen. Finally, miRNA is more accurate in diagnosing endometrial cancer than other types of cancer, and some miRNA family members (miR-200b and miR-429) have superior diagnostic accuracy than other miR-200 family members. In conclusion, the profiling of miRNA-200 family is likely to be a valuable tool in cancer detection and diagnosis. PMID- 26618621 TI - The smallest available estradiol transdermal patch: a new treatment option for the prevention of postmenopausal osteoporosis. AB - Minivelle((r)) (Noven Therapeutics, LLC, FL, USA) is an estradiol transdermal delivery system that has recently been approved in the USA for prevention of postmenopausal osteoporosis. The decline in estrogen during menopause leads to bone resorption, increasing the risk of fractures. Transdermal estradiol has been shown to increase bone mineral density. Safety studies of transdermal estradiol have shown a decreased risk in cardiovascular disease as compared with oral estrogen therapy. Minivelle is currently the smallest available transdermal estradiol patch, providing the lowest effective dose of estrogen. PMID- 26618622 TI - Inducing a concurrent motor load reduces categorization precision for facial expressions. AB - Motor theories of expression perception posit that observers simulate facial expressions within their own motor system, aiding perception and interpretation. Consistent with this view, reports have suggested that blocking facial mimicry induces expression labeling errors and alters patterns of ratings. Crucially, however, it is unclear whether changes in labeling and rating behavior reflect genuine perceptual phenomena (e.g., greater internal noise associated with expression perception or interpretation) or are products of response bias. In an effort to advance this literature, the present study introduces a new psychophysical paradigm for investigating motor contributions to expression perception that overcomes some of the limitations inherent in simple labeling and rating tasks. Observers were asked to judge whether smiles drawn from a morph continuum were sincere or insincere, in the presence or absence of a motor load induced by the concurrent production of vowel sounds. Having confirmed that smile sincerity judgments depend on cues from both eye and mouth regions (Experiment 1), we demonstrated that vowel production reduces the precision with which smiles are categorized (Experiment 2). In Experiment 3, we replicated this effect when observers were required to produce vowels, but not when they passively listened to the same vowel sounds. In Experiments 4 and 5, we found that gender categorizations, equated for difficulty, were unaffected by vowel production, irrespective of the presence of a smiling expression. These findings greatly advance our understanding of motor contributions to expression perception and represent a timely contribution in light of recent high-profile challenges to the existing evidence base. PMID- 26618623 TI - Object-scene relationships vary the magnitude of target prevalence effects in visual search. AB - Efficiency of visual search in real-world tasks is affected by several factors, including scene context and target prevalence. Observers are more efficient at detecting target objects in congruent locations, and less efficient at detecting rare targets. Although target prevalence and placement often covary, previous research has investigated context and prevalence effects independently. We conducted 2 experiments to explore the potential interaction between scene context and target prevalence effects. In Experiment 1, we varied target prevalence (high, low) and context (congruent, incongruent), and, for congruent contexts, target location (typical, atypical). Experiment 2 focused on the interaction between target prevalence (high, low) and location (typical, atypical) for congruent contexts, and recorded observers' eye movements to examine search strategies. Observers were poorer at detecting low versus high prevalence targets; however, prevalence effects were significantly reduced for targets in typical, congruent locations compared with atypical or incongruent locations. Eye movement analyses in Experiment 2 revealed this was related to observers dwelling disproportionately on the most typical target locations within a scene. This suggests that a byproduct of contextual guidance within scenes is that placing targets in unexpected or atypical locations will further increase miss rates for uncommon targets, which has implications for real-world situations in which rare targets appear in unexpected locations. Although prevalence effects are robust, our results suggest potential for mitigating the negative consequences of low prevalence through targeted training that teaches observers where to focus their search. (PsycINFO Database Record PMID- 26618624 TI - Similarity of actions depends on the functionality of previously observed actions. AB - People have a tendency to imitate the behavior of others, sometimes even automatically. And yet, evidence suggests that many of our actions are controlled, mediated by current goals and careful considerations. Here, we investigated whether the observation and evaluation of previous actions of another person modulates the similarity of actions between people in present trials. We manipulated the functionality of a confederate's actions and the interactive context in 2 behavioral tasks, which consisted of games that participants played against a confederate or a virtual computer opponent. To measure effects of working memory load on imitation rates, participants additionally performed an easy or difficult auditory n-back task in parallel to the tasks. We show that participants occasionally produced rather bizarre and dysfunctional behavior when the confederate had done so as well. Even more importantly, results from both tasks show that participants most likely copied dysfunctional behavior in the present trial when the confederate performed functional actions in the previous trial. Thus, the positive evaluation of action consequences in previous trials increases the probability of similarity between the participant's and confederate's actions in present trials despite a chance to copy improper actions. Furthermore, we found a trend of increased action similarities when participants were under high working memory load in Experiment 1 but not in Experiment 2. These results suggest that copying an observed action is an efficient and effortless behavioral and social strategy to achieve similar goals as others, though with an increased risk of maladaptive behavior. PMID- 26618625 TI - "Stress affects articulatory planning in reading aloud": Correction to Sulpizio, Spinelli, and Burani (2015). PMID- 26618626 TI - Extending models of visual-word recognition to semicursive scripts: Evidence from masked priming in Uyghur. AB - One basic feature of the Arabic script is its semicursive style: some letters are connected to the next, but others are not, as in the Uyghur word [see text]/ya x?i/ ("good"). None of the current orthographic coding schemes in models of visual-word recognition, which were created for the Roman script, assign a differential role to the coding of within letter "chunks" and between letter "chunks" in words in the Arabic script. To examine how letter identity/position is coded at the earliest stages of word processing in the Arabic script, we conducted 2 masked priming lexical decision experiments in Uyghur, an agglutinative Turkic language. The target word was preceded by an identical prime, by a transposed-letter nonword prime (that either kept the ligation pattern or did not), or by a 2-letter replacement nonword prime. Transposed letter primes were as effective as identity primes when the letter transposition in the prime kept the same ligation pattern as the target word (e.g., [see text]/inta_jin/-/itna_jin/), but not when the transposed-letter prime didn't keep the ligation pattern (e.g., [see text]/so_w_?a_t/-/so_?w_a_t/). Furthermore, replacement-letter primes were more effective when they kept the ligation pattern of the target word than when they did not (e.g., [see text]/so_d_?a_t/ /so_w_?a_t/ faster than [see text]/so_?d_a_t/-/so_w_?a_t/). We examined how input coding schemes could be extended to deal with the intricacies of semicursive scripts. PMID- 26618627 TI - "Sleep and native language interference affect non-native speech sound learning": Correction to Earle and Myers (2015). PMID- 26618629 TI - How strong are the metallocene-metallocene interactions? Cases of ferrocene, ruthenocene, and osmocene. AB - An exhaustive exploration of the potential energy surfaces of ferrocene, ruthenocene and osmocene dimers has been performed. Our computations involving dispersion show that only four different isomers are present in each metallocene dimer. The collective action of small interaction energies of dispersive nature leads to a dissociation energy of 7.5 kcal mol(-1) for the ferrocene dimer. Dispersion has strong effects on the geometrical parameters, reducing the M...M distances by almost 1 A. Our results also reveal that inclusion of entropic factors modifies the relative stability of the complexes. The nature of bonding is examined using the energy decomposition analysis and the non-covalent interaction index. Both analyses indicate that dispersion is the major contributing factor in stabilizing a metallocene dimer. PMID- 26618628 TI - Functional Characterization and Drug Response of Freshly Established Patient Derived Tumor Models with CpG Island Methylator Phenotype. AB - Patient-individual tumor models constitute a powerful platform for basic and translational analyses both in vitro and in vivo. However, due to the labor intensive and highly time-consuming process, only few well-characterized patient derived cell lines and/or corresponding xenografts exist. In this study, we describe successful generation and functional analysis of novel tumor models from patients with sporadic primary colorectal carcinomas (CRC) showing CpG island methylator phenotype (CIMP). Initial DNA fingerprint analysis confirmed identity with the patient in all four cases. These freshly established cells showed characteristic features associated with the CIMP-phenotype (HROC40: APCwt, TP53 mut, KRAS mut; 3/8 marker methylated; HROC43: APC mut, TP53 mut, KRAS mut; 4/8 marker methylated; HROC60: APCwt, TP53 mut, KRASwt; 4/8 marker methylated; HROC183: APC mut, TP53 mut, KRAS mut; 6/8 marker methylated). Cell lines were of epithelial origin (EpCAM+) with distinct morphology and growth kinetics. Response to chemotherapeutics was quite individual between cells, with stage I-derived cell line HROC60 being most susceptible towards standard clinically approved chemotherapeutics (e.g. 5-FU, Irinotecan). Of note, most cell lines were sensitive towards "non-classical" CRC standard drugs (sensitivity: Gemcitabin > Rapamycin > Nilotinib). This comprehensive analysis of tumor biology, genetic alterations and assessment of chemosensitivity towards a broad range of (chemo-) therapeutics helps bringing forward the concept of personalized tumor therapy. PMID- 26618630 TI - Treatment Outcomes Based on Patients' Self-Reported Measures after Receiving New Clasp or Precision Attachment-Retained Removable Partial Dentures. AB - PURPOSE: To evaluate effects of a treatment taking into consideration esthetics, chewing, and oral health-related quality of life (OHRQoL) of two tooth replacement strategies for maxillary partially edentulous patients with clasp (C RPD) and precision attachment (PA-RPD) retained removable partial dentures (RPD). MATERIALS AND METHODS: The study included 150 patients (72 men, 78 women) who received maxillary RPDs; 88 patients received clasp and 62 patients received precision attachment retained RPDs. Patients completed three questionnaires before treatment and again 3 months after treatment: the Orofacial Esthetic Scale (OES), the Oral Health Impact Profile (OHIP-14), and the Chewing Function Questionnaire (CFQ). Statistical analysis comprised descriptive statistics, paired t-test, and two-factor ANOVA. RESULTS: Both RPD treatments yielded better after-treatment summary scores when compared with the baseline scores (p < 0.01); however, better results were obtained in the PA-RPD group. Gender, as a single factor, did not yield significant effects; mutual interaction of retention type and gender yielded significant effects. The PA-RPD female group assessed esthetics, chewing function, and OHRQoL significantly better than males, and significantly worse than males in the C-RPD group. The covariate baseline scores yielded statistically significant effects; patients with worse pretreatment condition benefited more from both therapies. CONCLUSIONS: Treatment outcomes were better in the PA-RPD group than the C-RPDs. Women showed greater concern for the treatment outcomes; their rates were significantly better than in male patients in the PA-RPD group; however, when their satisfaction was lower, their rates were significantly worse than in male patients (in the C-RPD group). PMID- 26618632 TI - In Vitro Wear Resistance of Nano-Hybrid Composite Denture Teeth. AB - PURPOSE: To evaluate the wear resistance of nano-hybrid composite denture teeth as compared to two commonly used denture teeth: interpenetrating polymer network (IPN) and double crosslinking polymethylmethacrylate (PMMA) denture teeth. MATERIAL AND METHODS: 18 styli and 18 disk specimens were prepared from the three denture tooth materials: nano-hybrid composite, IPN, and double crosslinking PMMA. The specimens were mounted in a two-body wear testing machine to simulate chewing in the complete denture. The amount of wear from the styli specimens were measured before and after using a digital micrometer, and the depth of the wear track from the disk specimens was measured using a noncontact 3D optical profilometer. The total wear from each denture tooth group was compared using one way ANOVA with a 0.05 significance level. A Tukey post hoc test was used to determine differences between the three groups. RESULTS: The mean total wear in the nano-hybrid composite teeth group was 1.16 mm, SD = 0.5 mm, statistically significantly higher (p <= 0.0001) than the IPN (mean = 0.13 mm, SD = 0.05) and double crosslinking PMMA tooth groups (mean = 0.31 mm, SD = 0.19). There was no statistically significant difference between IPN denture teeth and double crosslinking PMMA denture teeth in the amount of wear. CONCLUSIONS: Nano-hybrid composite denture teeth exhibited statistically significantly more wear than the IPN and double crosslinking PMMA denture teeth. PMID- 26618631 TI - Novel therapeutic compound tuftsin-phosphorylcholine attenuates collagen-induced arthritis. AB - Treatment with helminthes and helminthes ova improved the clinical symptoms of several autoimmune diseases in patients and in animal models. Phosphorylcholine (PC) proved to be the immunomodulatory molecule. We aimed to decipher the tolerogenic potential of tuftsin-PC (TPC), a novel helminth-based compound in collagen-induced arthritis (CIA) a mouse model of rheumatoid arthritis (RA). CIA DBA/1 mice were treated with TPC subcutaneously (5 ug/0.1 ml) or orally (250 ug/0.1 ml), starting prior to disease induction. The control groups were treated with PBS. Collagen antibodies were tested by enzyme-linked immunosorbent assay (ELISA), cytokine protein levels by ELISA kits and regulatory T (Treg ) and regulatory B (Breg ) cell phenotypes by fluorescence-activated cell sorter (FACS). TPC-treated mice had a significantly lower arthritis score of 1.5 in comparison with control mice 11.8 (P < 0.0001) in both subcutaneous and orally treated groups at day 31. Moreover, histology analysis demonstrated highly inflamed joints in control mice, whereas TPC-treated mice maintained normal joint structure. Furthermore, TPC decreased the titres of circulating collagen II antibodies in mice sera (P < 0.0001), enhanced expression of IL-10 (P < 0.0001) and inhibited production of tumour necrosis factor (TNF)-alpha, interleukin (IL) 17 and IL-1beta (P < 0.0001). TPC significantly expanded the CD4(+) CD25(+) forkhead box protein 3 (FoxP3(+) ) Treg cells and CD19(+) IL-10(+) CD5(high) CD1d(high) T cell immunoglobulin mucin-1 (TIM-1(+) ) Breg cell phenotypes (P < 0.0001) in treated mice. Our data indicate that treatment with TPC attenuates CIA in mice demonstrated by low arthritic score and normal joints histology. TPC treatment reduced proinflammatory cytokines and increased anti-inflammatory cytokine expression, as well as expansion of Treg and Breg cells. Our results may lead to a new approach for a natural therapy for early rheumatoid arthritis onset. PMID- 26618633 TI - Exploring Consumer Perceptions and Economic Burden of Onchocerciasis on Households in Enugu State, South-East Nigeria. AB - INTRODUCTION: Onchocerciasis or river blindness constitutes a major burden to households especially in resource-poor settings, causing a significant reduction in household productivity. There has been renewed interest from policy makers to reduce the burden of Neglected Tropical Diseases (NTDs) such as onchocerciasis on individuals and households. This paper provides new information on the patient's perceptions of onchocerciasis and its economic burden on households in South eastern Nigeria. The information will be useful to health providers and policy makers for evidence-informed resource allocation decisions. METHODS: Information was generated from a cross-sectional household survey conducted in Achi community, Oji River Local Government Area (LGA) of Enugu State, Southeast Nigeria. A pre-tested interviewer-administered questionnaire was used to collect data. A total of 747 households were visited randomly and data were collected using pre-tested interviewer administered questionnaire from 370 respondents. The respondents' knowledge of the cause of symptoms of the disease, costs incurred for seeking treatment and productivity losses were elicited. Data were analyzed using tabulations and inferential statistics. A socio-economic status (SES) index was used to disaggregate some key variables by SES quintiles for equity analysis. RESULTS: Many people had more than one type of manifestation of onchocerciasis. However, more than half of the respondents (57%) had no knowledge of the cause of their symptoms. Male respondents had significantly more knowledge of the cause of symptoms than females (P = 0.04) but knowledge did not differ across SES (P = 0.82). The average monthly treatment cost per respondent was US$ 14.0. Drug cost (US$10) made up about 72% of total treatment cost. The per capita productivity loss among patients was US$16 and it was higher in the poorest (Q1) (US$20) and the third SES quintiles (Q3) (US$21). The average monthly productivity loss among caregivers was US$3.5. CONCLUSION: Onchocerciasis still constitutes considerable economic burden on patients due to the high cost of treatment and productivity loss. Prioritizing domestic resource allocation for the treatment of onchocerciasis is important for significant and sustained reduction in the burden of the disease. In addition, focused health promotion interventions such as health education campaigns should be scaled up in onchocerciasis-endemic communities. PMID- 26618634 TI - Oral Delivery of a Novel Recombinant Streptococcus mitis Vector Elicits Robust Vaccine Antigen-Specific Oral Mucosal and Systemic Antibody Responses and T Cell Tolerance. AB - The pioneer human oral commensal bacterium Streptococcus mitis has unique biologic features that make it an attractive mucosal vaccine or therapeutic delivery vector. S. mitis is safe as a natural persistent colonizer of the mouth, throat and nasopharynx and the oral commensal bacterium is capable of inducing mucosal antibody responses. A recombinant S. mitis (rS. mitis) that stably expresses HIV envelope protein was generated and tested in the germ-free mouse model to evaluate the potential usefulness of this vector as a mucosal vaccine against HIV. Oral vaccination led to the efficient and persistent bacterial colonization of the mouth and the induction of both salivary and systemic antibody responses. Interestingly, persistently colonized animals developed antigen-specific systemic T cell tolerance. Based on these findings we propose the use of rS. mitis vaccine vector for the induction of mucosal antibodies that will prevent the penetration of the mucosa by pathogens such as HIV. Moreover, the first demonstration of rS. mitis having the ability to elicit T cell tolerance suggest the potential use of rS. mitis as an immunotherapeutic vector to treat inflammatory, allergic and autoimmune diseases. PMID- 26618635 TI - Partial Dominance, Overdominance and Epistasis as the Genetic Basis of Heterosis in Upland Cotton (Gossypium hirsutum L.). AB - Determination of genetic basis of heterosis may promote hybrid production in Upland cotton (Gossypium hirsutum L.). This study was designed to explore the genetic mechanism of heterosis for yield and yield components in F2: 3 and F2: 4 populations derived from a hybrid 'Xinza No. 1'. Replicated yield field trials of the progenies were conducted in 2008 and 2009. Phenotypic data analyses indicated overdominance in F1 for yield and yield components. Additive and dominance effects at single-locus level and digenic epistatic interactions at two-locus level were analyzed by 421 marker loci spanning 3814 cM of the genome. A total of 38 and 49 QTLs controlling yield and yield components were identified in F2: 3 and F2: 4 populations, respectively. Analyses of these QTLs indicated that the effects of partial dominance and overdominance contributed to heterosis in Upland cotton simultaneously. Most of the QTLs showed partial dominance whereas 13 QTLs showing overdominance in F2:3 population, and 19 QTLs showed overdominance in F2:4. Among them, 21 QTLs were common in both F2: 3 and F2: 4 populations. A large number of two-locus interactions for yield and yield components were detected in both generations. AA (additive * additive) epistasis accounted for majority portion of epistatic effects. Thirty three complementary two-locus homozygotes (11/22 and 22/11) were the best genotypes for AA interactions in terms of bolls per plant. Genotypes of double homozygotes, 11/22, 22/11 and 22/22, performed best for AD/DA interactions, while genotype of 11/12 performed best for DD interactions. These results indicated that (1) partial dominance and overdominance effects at single-locus level and (2) epistasis at two-locus level elucidated the genetic basis of heterosis in Upland cotton. PMID- 26618636 TI - The Costs of Waiting: Implications of the Timing of Palliative Care Consultation among a Cohort of Decedents at a Comprehensive Cancer Center. AB - BACKGROUND: Palliative care is recommended along with oncologic care for patients with advanced cancer. However, there are limited data about how the timing of palliative care affects quality and costs. OBJECTIVE: Comparison of health care utilization and care quality for patients with cancer who died having received early versus late palliative care. DESIGN: Analysis of cancer registry, administrative, and billing databases. SETTING/SUBJECTS: Patients with cancer who died having received specialty palliative care consultation. MEASUREMENTS: Comparing early (more than 90 days prior to death) versus late (less than 90 days prior to death) palliative care, outcome measures included rates of health care utilization and health care costs. RESULTS: Among 922 decedents, 297 (32.2%) had palliative care referrals, with 93 (10.1%) receiving early referrals and 204 (22.1%) late referrals. Compared to patients receiving late palliative care, early palliative care patients had lower rates of inpatient (33% versus 66%, p < 0.01), ICU (5% versus 20%, p < 0.01), and ED utilization (34% versus 54%, p = 0.04) in the last month of life. Direct costs of inpatient care in the last 6 months of life for patients with early palliative care were lower compared to late palliative care ($19,067 versus $25,754, p < 0.01), while direct outpatient costs were similar ($13,040 versus $11,549, p = 0.85). Early palliative care was predominantly delivered in the outpatient setting (84%) while late palliative care was mostly delivered in the hospital (82%). CONCLUSIONS: Early palliative care is associated with less intensive medical care, improved quality outcomes, and cost savings at the end of life for patients with cancer. Despite recommendations that early palliative care be offered to all patients with metastatic cancer, palliative care services remain underutilized. PMID- 26618637 TI - Effect of Climate Change on Invasion Risk of Giant African Snail (Achatina fulica Ferussac, 1821: Achatinidae) in India. AB - The Giant African Snail (Achatina fulica) is considered to be one the world's 100 worst invasive alien species. The snail has an impact on native biodiversity, and on agricultural and horticultural crops. In India, it is known to feed on more than fifty species of native plants and agricultural crops and also outcompetes the native snails. It was introduced into India in 1847 and since then it has spread all across the country. In this paper, we use ecological niche modeling (ENM) to assess the distribution pattern of Giant African Snail (GAS) under different climate change scenarios. The niche modeling results indicate that under the current climate scenario, Eastern India, peninsular India and the Andaman and Nicobar Islands are at high risk of invasion. The three different future climate scenarios show that there is no significant change in the geographical distribution of invasion prone areas. However, certain currently invaded areas will be more prone to invasion in the future. These regions include parts of Bihar, Southern Karnataka, parts of Gujarat and Assam. The Andaman and Nicobar and Lakshadweep Islands are highly vulnerable to invasion under changed climate. The Central Indian region is at low risk due to high temperature and low rainfall. An understanding of the invasion pattern can help in better management of this invasive species and also in formulating policies for its control. PMID- 26618638 TI - Monolithically Integrated High-beta Nanowire Lasers on Silicon. AB - Reliable technologies for the monolithic integration of lasers onto silicon represent the holy grail for chip-level optical interconnects. In this context, nanowires (NWs) fabricated using III-V semiconductors are of strong interest since they can be grown site-selectively on silicon using conventional epitaxial approaches. Their unique one-dimensional structure and high refractive index naturally facilitate low loss optical waveguiding and optical recirculation in the active NW-core region. However, lasing from NWs on silicon has not been achieved to date, due to the poor modal reflectivity at the NW-silicon interface. We demonstrate how, by inserting a tailored dielectric interlayer at the NW-Si interface, low-threshold single mode lasing can be achieved in vertical-cavity GaAs-AlGaAs core-shell NW lasers on silicon as measured at low temperature. By exploring the output characteristics along a detection direction parallel to the NW-axis, we measure very high spontaneous emission factors comparable to nanocavity lasers (beta = 0.2) and achieve ultralow threshold pump energies <=11 pJ/pulse. Analysis of the input-output characteristics of the NW lasers and the power dependence of the lasing emission line width demonstrate the potential for high pulsation rates >=250 GHz. Such highly efficient nanolasers grown monolithically on silicon are highly promising for the realization of chip-level optical interconnects. PMID- 26618639 TI - Using complexity science to examine three dynamic patterns of intimate partner violence. AB - INTRODUCTION: The partner violence literature describes 3 dominant models of dynamics of partner aggression: cycle of violence, family systems theory, and Duluth model (power and control wheel). Complexity science describes 3 patterns of system dynamics: periodic, chaotic, and random. Are these parallel patterns? In this analysis, investigators calculated dynamic patterns (periodic, chaotic, and random) using 84 daily reports of male-to-female aggression and assessed the "fit" between time-series-derived patterns of male partners' violent behaviors and literature-based models of violence dynamics. METHOD: Participants were 200 women in moderately violent intimate relationships who completed a telephone survey about their relationships every day for 12 weeks. They also completed baseline and end-of-study surveys and maintained telephone contact with the study team weekly. Of 200 participants, 135 women provided enough data to be assigned to period, chaotic, or random groups. RESULTS: Group membership included 16 women in periodic, 40 in chaotic, and 79 in random groups. Consistent with the cycle of violence, periodic women found violence to be predictable and controllable. Consistent with the Duluth model, women in the random group found violence to be unpredictable and out of their control, occurring with high frequency. The chaotic group had the lowest frequency and severity of violence, lowest stress and arguments, and the highest marital satisfaction. DISCUSSION: The most common dynamic pattern in partner violence is random, which exhibits high frequency and unpredictability of aggression. Complexity science suggests interventions in random systems have unpredictable outcomes, posing great challenges for clinicians who work with victims of violence. PMID- 26618640 TI - Play it forward! A community-based participatory research approach to childhood obesity prevention. AB - BACKGROUND: To date there has been limited success with childhood obesity prevention interventions. This may be due in part, to the challenge of reaching and engaging parents in interventions. The current study used a community-based participatory research (CBPR) approach to engage parents in cocreating and pilot testing a childhood obesity prevention intervention. Because CBPR approaches to childhood obesity prevention are new, this study aims to detail the creation, including the formation of the citizen action group (CAG), and implementation of a childhood obesity prevention intervention using CBPR methods. METHOD: A CBPR approach was used to recruit community members to partner with university researchers in the CAG (n = 12) to create and implement the Play It Forward! childhood obesity intervention. The intervention creation and implementation took 2 years. During Year 1 (2011-2012), the CAG carried out a community needs and resources assessment and designed a community-based and family focused childhood obesity prevention intervention. During Year 2 (2012-2013), the CAG implemented the intervention and conducted an evaluation. Families (n = 50; 25 experimental/25 control group) with children ages 6-12 years participated in Play It Forward! RESULTS: Feasibility and process evaluation data suggested that the intervention was highly feasible and participants in both the CAG and intervention were highly satisfied. Specifically, over half of the families attended 75% of the Play It Forward! events and 33% of families attended all the events. CONCLUSION: Equal collaboration between parents and academic researchers to address childhood obesity may be a promising approach that merits further testing. PMID- 26618641 TI - Highly sensitive detection of urinary protein variations using tilted fiber grating sensors with plasmonic nanocoatings. AB - Surface plasmon resonance (SPR) optical fiber biosensors can be used as a cost effective and relatively simple-to-implement alternative to well established bulky prism configurations for high sensitivity biological sample measurements. The miniaturized size and remote operation ability offer them a multitude of opportunities for single-point sensing in hard-to-reach spaces, even possibly in vivo. The biosensor configuration reported in this work uses a tilted fiber Bragg grating (TFBG) in a commercial single mode fiber coated with a nanometer scale silver film. The key point is that by reducing the silver film thickness to around 20-30 nm (rather than 50 nm for optimal SPR excitation), different modes of the TFBG spectrum present very high but opposite sensitivities to refractive index (RI) changes around the TFBG. Experimental results obtained with the coated TFBG embedded inside a microfluidic channel show an amplitude sensitivity greater than 8000 dB/RIU (Refractive Index Unit) and a limit of detection of 10(-5)RIU. Using this device, the effect of different concentrations of protein in rat urine was clearly differentiated between healthy samples, nephropatic samples and samples from individuals under treatment, with a protein concentration sensitivity of 5.5 dB/(mg/ml) and a limit of detection of 1.5 * 10(-3)mg/ml. Those results show a clear relationship between protein outflow and variations in the RI of the urine samples between 1.3400 and 1.3408, pointing the way to the evaluation and development of new drugs for nephropathy treatments. The integration of TFBGs with microfluidic channels enables precise measurement control over samples with sub-microliter volumes and does not require accurate temperature control because of the elimination of the temperature cross sensitivity inherent in TFBG devices. Integration of the TFBG with a hypodermic needle on the other hand would allow similar measurements in vivo. The proposed optical fiber/microfluidic plasmonic biosensor represents an appealing solution for rapid, low consumption and highly sensitive detection of analytes at low concentrations in medicine as well as in chemical and environmental monitoring. PMID- 26618642 TI - Aptamer-functionalized nanoparticles for surface immobilization-free electrochemical detection of cortisol in a microfluidic device. AB - Monitoring the periodic diurnal variations in cortisol from small volume samples of serum or saliva is of great interest, due to the regulatory role of cortisol within various physiological functions and stress symptoms. Current detection assays are immunologically based and require cumbersome antibody immobilization chemistries, thereby limiting the assay versatility, kinetics, and reproducibility. We present a quantitative aptamer-based detection methodology for cortisol that does not require target labeling, capture probe immobilization on the detection surface or wash steps prior to readout. Using a recognition system of aptamer functionalized gold nanoparticles pre-bound with electro-active triamcinolone, the cortisol level is detected based on its competitive binding to the aptamer by following signal from the displaced triamcinolone using square wave voltammetry at patterned graphene-modified electrodes in a microfluidic or nanoslit device. Due to the 3D analyte diffusion profile at the aptamer interface and the ability to enhance the surface area for cortisol capture, this assay shows signal linearity over a five-log analyte concentration range (10 MUg/mL to 30 pg/mL) and exhibits rapid binding kinetics with cortisol versus other glucocorticoids, as apparent from the absence of interferences from estradiol, testosterone and progesterone. The assay is carried out within the biologically relevant range for glucocorticoids in serum and saliva matrices, and benchmarked versus ELISA and radioimmunoassays. Based on absence of cumbersome surface immobilization and wash steps for carrying out this assay, its quantitative signal characteristics and its ability to resist interferences from other glucocorticoids, we envision its application towards routine monitoring of cortisol within bio-fluids. PMID- 26618643 TI - Interactions of Prosthetic and Natural Vision in Animals With Local Retinal Degeneration. AB - PURPOSE: Prosthetic restoration of partial sensory loss leads to interactions between artificial and natural inputs. Ideally, the rehabilitation should allow perceptual fusion of the two modalities. Here we studied the interactions between normal and prosthetic vision in a rodent model of local retinal degeneration. METHODS: Implantation of a photovoltaic array in the subretinal space of normally sighted rats induced local degeneration of the photoreceptors above the chip, and the inner retinal neurons in this area were electrically stimulated by the photovoltaic implant powered by near-infrared (NIR) light. We studied prosthetic and natural visually evoked potentials (VEP) in response to simultaneous stimulation by NIR and visible light patterns. RESULTS: We demonstrate that electrical and natural VEPs summed linearly in the visual cortex, and both responses decreased under brighter ambient light. Responses to visible light flashes increased over 3 orders of magnitude of contrast (flash/background), while for electrical stimulation the contrast range was limited to 1 order of magnitude. The maximum amplitude of the prosthetic VEP was three times lower than the maximum response to a visible flash over the same area on the retina. CONCLUSIONS: Ambient light affects prosthetic responses, albeit much less than responses to visible stimuli. Prosthetic representation of contrast in the visual scene can be encoded, to a limited extent, by the appropriately calibrated stimulus intensity, which also depends on the ambient light conditions. Such calibration will be important for patients combining central prosthetic vision with natural peripheral sight, such as in age-related macular degeneration. PMID- 26618644 TI - Clinical Significance of the Location of Recurrent Optic Disc Hemorrhage in Glaucoma. AB - PURPOSE: To compare clinical characteristics and visual field (VF) progression between glaucomatous eyes with disc hemorrhage (DH) recurring at the same or different locations in relation to the initial DH location. METHODS: One hundred forty-seven open-angle glaucoma patients with DH who were observed for more than 4 years and had more than six VF tests were included. Disc hemorrhage that recurred at the same location as the initial DH was defined as a DH at the same location, and DH that recurred at a different location was defined as a DH at a different location. Overall rate of VF change using the mean deviation (MD) was compared between groups using a linear mixed model, and Kaplan-Meier survival analysis was performed. RESULTS: Seventy-seven (52.4%) eyes had nonrecurrent DH, and 70 (47.6%) eyes had recurrent DH detected during the follow-up period. Recurrent DH at the same location (-0.32 dB/y) was not significantly different from the nonrecurrent DH group in terms of the rate of VF change (P = 0.116). However, the recurrent DH group at different locations (-1.07 dB/y) had a significantly different rate of VF change compared to the recurrent DH group at the same location (P = 0.014). By Kaplan-Meier analysis, eyes with recurrent DH at different locations showed the fastest time to VF progression compared to other groups (log rank test, P < 0.001). CONCLUSIONS: Eyes with recurrent DH recurring at different locations from initial DH sites had more pronounced VF progression. PMID- 26618645 TI - N-Ethylmaleimide-Sensitive Factor b (nsfb) Is Required for Normal Pigmentation of the Zebrafish Retinal Pigment Epithelium. AB - PURPOSE: Despite the number of albinism-causing mutations identified in human patients and animal models, there remain a significant number of cases for which no mutation has been identified, suggesting that our understanding of melanogenesis is incomplete. Previously, we identified two oculocutaneous albinism mutations in zebrafish, au13 and au18. Here, we sought to identify the mutated loci and determine how the affected proteins contribute to normal pigmentation of the retinal pigment epithelium (RPE). METHODS: Complementation analyses revealed that au13 and au18 belonged to a single complementation group, suggesting that they affected the same locus. Whole-genome sequencing and single nucleotide polymorphism (SNP) analysis was performed to identify putative mutations, which were confirmed by cDNA sequencing and mRNA rescue. Transmission electron microscopy (TEM) and image quantification were used to identify the cellular basis of hypopigmentation. RESULTS: Whole-genome sequencing and SNP mapping identified a nonsense mutation in the N-ethylmaleimide-sensitive factor b (nsfb) gene in au18 mutants. Complementary DNA sequencing confirmed the presence of the mutation (C893T), which truncates the nsfb protein by roughly two-thirds (Y297X). No coding sequence mutations were identified in au13, but quantitative PCR revealed a significant decrease in nsfb expression, and nsfb mRNA injection rescued the hypopigmentation phenotype, suggesting a regulatory mutation. In situ hybridization revealed that nsfb is broadly expressed during embryonic development, including in the RPE. Transmission electron microscopy analyses indicated that average melanosome density and maturity were significantly decreased in nsfb mutants. CONCLUSIONS: au18 and au13 contain mutations in nsfb, which encodes a protein that is required for the maturation of melanosomes in zebrafish RPE. PMID- 26618647 TI - Role of Glial Cells in Regulating Retinal Blood Flow During Flicker-Induced Hyperemia in Cats. AB - PURPOSE: To investigate how glial cells participate in retinal circulation during flicker stimulation in cats. METHODS: Using laser Doppler velocimetry, we measured the vessel diameter and blood velocity simultaneously and calculated the retinal blood flow (RBF) in feline first-order retinal arterioles. Twenty-four hours after intravitreal injections of L-2-aminoadipic acid (LAA), a gliotoxic compound, and the solvent of 0.01 N hydrochloric acid as a control, we examined the changes in RBF in response to 16-Hz flicker stimulation for 3 minutes. We also measured the changes in RBF 2 hours after intravitreal injection of Nomega propyl-L-arginine (L-NPA), a selective neuronal nitric oxide synthase inhibitor, in LAA-treated eyes. To evaluate the effects of LAA on retinal neuronal function, ERGs were monitored. Immunohistochemical examinations were performed. RESULTS: In LAA-treated eyes, histologic changes selectively occurred in retinal glial cells. There were no significant reductions in amplitude or elongation of implicit time in ERG after LAA injections compared with controls. In control eyes, the RBF gradually increased and reached the maximal level (53.5% +/- 2.5% increase from baseline) after 2 to 3 minutes of flicker stimulation. In LAA-treated eyes, the increases in RBF during flicker stimulation were attenuated significantly compared with controls. In LAA-treated eyes 2 hours after injection of L-NPA, flicker-evoked increases in RBF decreased significantly compared with LAA-treated eyes. CONCLUSIONS: The current results suggested that increases in RBF in response to flicker stimulation were regulated partly by retinal glial cells. PMID- 26618646 TI - Aqueous Tear Deficiency Increases Conjunctival Interferon-gamma (IFN-gamma) Expression and Goblet Cell Loss. AB - PURPOSE: To investigate the hypothesis that increased interferon-gamma (IFN gamma) expression is associated with conjunctival goblet cell loss in subjects with tear dysfunction. METHODS: Goblet cell density (GCD) was measured in impression cytology from the temporal bulbar conjunctiva, and gene expression was measured in cytology samples from the nasal bulbar conjunctiva obtained from 68 subjects, including normal control, meibomian gland disease (MGD), non-Sjogren syndrome (non-SSATD)-, and Sjogren syndrome (SSATD)-associated aqueous tear deficiency. Gene expression was evaluated by real-time PCR. Tear meniscus height (TMH) was measured by optical coherence tomography. Fluorescein and lissamine green dye staining evaluated corneal and conjunctival disease, respectively. Between-group mean differences and correlation coefficients were calculated. RESULTS: Compared to control, IFN-gamma expression was significantly higher in both ATD groups, and its receptor was higher in SSATD. Expression of IL-13 and its receptor was similar in all groups. Goblet cell density was lower in the SSATD group; expression of MUC5AC mucin was lower and cornified envelope precursor small proline-rich region (SPRR)-2G higher in both ATD groups. Interferon-gamma transcript number was inversely correlated with GCD (r = -0.37, P < 0.04) and TMH (r = -0.37, P = 0.02), and directly correlated with lissamine green staining (r = 0.51, P < 0.001) and SPRR-2G expression (r = 0.32, P < 0.05). CONCLUSIONS: Interferon-gamma expression in the conjunctiva was higher in aqueous deficiency and correlated with goblet cell loss and severity of conjunctival disease. These results support findings of animal and culture studies showing that IFN-gamma reduces conjunctival goblet cell number and mucin production. PMID- 26618649 TI - Prehension of a Flanked Target in Individuals With Amblyopia. AB - PURPOSE: Reduced binocularity is a prominent feature of amblyopia and binocular cues are thought to be important for prehension. We examine prehension in individuals with amblyopia when the target-object was flanked, thus mimicking everyday prehension. METHODS: Amblyopes (n = 20, 36.4 +/- 11.7 years; 6 anisometropic, 3 strabismic, 11 mixed) and visually-healthy controls (n = 20, 27.5 +/- 6.3 years) reached forward, grasped, and lifted a cylindrical target object that was flanked with objects either (lateral) side of the target, or in front and behind it in depth. Only six amblyopes (30%) had measurable stereoacuity. Trials were completed in binocular and monocular viewing, using the better eye in amblyopic participants. RESULTS: Compared with visual normals, amblyopes displayed a longer overall movement time (P = 0.031), lower average reach velocity (P = 0.021), smaller maximum aperture (P = 0.007), and a longer duration between object contact and lift (P = 0.003). Differences between groups were more apparent when the flankers were in front and behind, compared with either side, as evidenced by significant group-by-flanker configuration interactions for reach duration (P < 0.001), size and timing of maximum aperture (P <= 0.009), end-of-reach to object-contact (P < 0.001), and object-contact to lift (P = 0.044), suggesting that amblyopic deficits are greatest when binocular cues are richest. Both groups demonstrated a significant binocular advantage, in that in both groups performance was worse for monocular compared with binocular viewing, but interestingly, amblyopic deficits in binocular viewing largely persisted during monocular viewing with the better eye. CONCLUSIONS: These results suggest that amblyopes either display considerable residual binocularity or that they have adapted to make good use of their abnormal binocularity. PMID- 26618648 TI - Rho-Associated Kinase Inhibitor Eye Drop (Ripasudil) Transiently Alters the Morphology of Corneal Endothelial Cells. AB - PURPOSE: Ripasudil (Glanatec), a selective Rho-associated coiled coil-containing protein kinase (ROCK) inhibitor, was approved in Japan in September 2014 for the treatment of glaucoma and ocular hypertension. The purpose of this study was to investigate the effect of ripasudil eye drops on corneal endothelial morphology, as ROCK signaling is known to modulate the actin cytoskeleton. METHODS: Morphological changes in the corneal endothelium were evaluated in human subjects by specular and slit-lamp microscopy, following topical administration of ripasudil. We also used a rabbit model to evaluate the effect of ripasudil on clinical parameters of the corneal endothelium. Twenty-four hours after ripasudil application, corneal specimens were evaluated by phalloidin staining, immunohistochemical analysis, and electron microscopy. RESULTS: Specular microscopy revealed morphological changes in human eyes, and slit-lamp microscopy showed guttae-like findings. The rabbit model showed morphological changes similar to those seen in human eyes after ripasudil administration. Electron microscopy demonstrated that these alterations are due to the formation of protrusions along the cell-cell borders, but this formation is transient. Expression of corneal endothelial function-related markers was not disrupted; corneal thickness and corneal volume were not changed; and no cell death was observed following ripasudil administration. CONCLUSIONS: Ripasudil induces transient guttae-like findings in humans, most likely due to protrusion formation along intracellular borders caused by the reduction in actomyosin contractility of the corneal endothelial cells. No severe adverse effects were observed. Physicians should be aware that ROCK inhibitors can cause these guttae-like findings, to avoid misdiagnosing patients as having Fuchs endothelial corneal dystrophy. (www.umin.ac.jp/ctr number, UMIN000018340.). PMID- 26618650 TI - The Time Course of Changes in Retinal Vessel Diameter in Response to Differing Durations of Flicker Light Provocation. AB - PURPOSE: To determine the response of retinal vessels to differing durations of flicker light (FL) stimulation. METHODS: We recorded retinal arterial and venous vessel dilation to 12.5 Hz FL provocation of varying duration (5, 7, 10, and 20 seconds) in 12 healthy young individuals (age range, 26-45 years). All participants underwent a full ocular examination including IOP and blood pressure measurements. RESULTS: Maximum dilation (MD) did not show a significant dependence on flicker duration in arteries, whereas maximum constriction (MC) did. In veins, however, MD significantly increased with flicker duration. Approximately 80% to 90% of MD in arteries is reached within 10 seconds of FL stimulation. CONCLUSIONS: The vast majority of arterial dilatory capacity is reached within 10 seconds of FL stimulation even though venous dilation continues strongly. Since MC of arteries shows a significant dependence on flicker duration, measurements at two different durations can provide more information about the retinal vascular system than at a single flicker duration alone. PMID- 26618651 TI - Optimal Combination of the Binocular Cues to 3D Motion. AB - PURPOSE: Perception necessarily entails combining separate sensory estimates into a single coherent whole. The perception of three-dimensional (3D) motion, for instance, can rely on two binocular cues: one related to the change in binocular disparity over time (CD) and the other related to interocular velocity differences (IOVD). Although previous work has shown that neither cue is strictly necessary for the perception of 3D motion, observers are able to judge 3D motion in displays in which one or the other cue has been eliminated, it is unclear whether or how the two cues are combined in situations in which both are present. METHODS: We tested the visual performance of a sample of 81 individuals (Mage = 20.34, 49 females) in four main conditions that measured, respectively, static stereoacuity, CD, IOVD, and combined CD+IOVD sensitivity. RESULTS: We show that the sensitivity to the two binocular cues to 3D motion varies substantially across observers (CD: Md' = 1.01, SDd' = 1.1; IOVD: Md' = 1.16, SDd' = 1.03). Furthermore, sensitivity to the two cues was independent across observers (r[48] = 0.12, P = 0.42). Importantly, however, observed CD+IOVD performance was well predicted based on the assumption that each observer combines the two cues in a statistically optimal fashion (r[79] = 0.75, P < 0.001). CONCLUSIONS: Our findings provide an explanation for the previously puzzling variability found in 3D perception across observers and laboratories, with some results suggesting that motion-in-depth percepts are largely determined by changes in binocular disparity, whereas others indicate that interocular velocity differences are key. Our results underline the existence of two complementary binocular mechanisms underlying 3D motion perception, with observers relying on these two mechanisms to different extents depending on their individual sensitivity. PMID- 26618653 TI - Control of Maintenance and Regeneration of Planarian Eyes by ovo. AB - PURPOSE: Following decapitation, the planarian Schmidtea mediterranea regenerates its head and eyes. The gene ovo is required for eye maintenance and regeneration in response to wounding. In this study, we investigated whether eye regeneration in S. mediterranea could occur absent a wound healing response. METHODS: One hundred twenty S. mediterranea were treated with ovo RNA interference (RNAi) or control (unc-22) RNAi by feeding double-stranded RNA (dsRNA). Following eye loss, ovo RNAi treatment was halted and replaced with control RNAi treatment. Quantitative real-time PCR (qPCR) was used to monitor ovo expression. Eye functionality was monitored via a phototaxis assay. Photoreceptor neurons were visualized via immunofluorescence staining of arrestin. RESULTS: Treatment with ovo RNAi caused eyes to gradually shrink until they were completely absent. One hundred percent of ovo RNAi-treated planarians lost both eyes within 137 days of treatment onset. ovo RNAi-treated planarians were unable to regenerate eyes in response to decapitation. Upon removal of ovo RNAi, eyes became visible as small pigmented spots in the head within 28 days. The eyes slowly developed, appearing to gain pigmented cells first and then nonpigmented photoreceptors. Phototaxis assays demonstrated functional eye loss and eye restoration. ovo mRNA was significantly decreased following treatment with ovo RNAi and significantly increased following removal of ovo RNAi. Arrestin staining was present in the eyes, optic nerves, and optic chiasm of worms with regenerated eyes but not in eyeless worms. CONCLUSIONS: S. mediterranea have the ability to generate functional eyes in the absence of a wound healing response. This ability requires the expression of ovo. PMID- 26618652 TI - Skewness of Fractional Anisotropy Detects Decreased White Matter Integrity Resulting From Acute Optic Neuritis. AB - PURPOSE: Diffusion tensor imaging (DTI) has demonstrated optic nerve damage associated with optic neuritis (ON); however, the usefulness of mean fractional anisotropy (FA) specifically is varied in the literature. We wished to determine whether histogram analysis of FA better detects ON damage than mean FA. METHODS: The ON patients (n = 24) underwent DTI within 1 month of symptoms and then 6 months later (n = 21). Twelve control subjects participated in one session. Mean FA and axial (AD), radial (RD), and mean (MD) diffusivities were compared between ON and fellow eyes, control eyes, and sessions. Values were sorted into bins, and coefficients of skewness of FA, AD, RD, and MD were compared between ON and fellow eyes, control eyes, and sessions. RESULTS: Mean AD, RD, and MD of ON eyes were significantly reduced compared with fellow eyes (P < 0.04) within 1 month of symptoms, but did not differ at 6 months. Mean AD and RD of ON eyes were significantly lower than control eyes (P < 0.05). No differences were observed for mean FA. The coefficient of skewness of FA was significantly different between ON eyes and fellow eyes (P = 0.03) and control eyes (P = 0.04) within 1 month of symptoms, but did not differ at 6 months. No differences were observed for AD, RD, and MD. CONCLUSIONS: Skewness of FA can detect white matter damage associated with ON and its recovery, which may further inform us of how DTI can measure white matter injury and repair. PMID- 26618655 TI - Cleckley's psychopaths: Revisited. AB - The most influential figure in the study of psychopathy is Hervey Cleckley, the author of the widely cited text, "The Mask of Sanity" (Cleckley, 1941, 1955). Researchers often refer to Cleckley when disputing what should belong within a conceptualization or assessment of psychopathy, at times disagreeing as to what Cleckley meant or intended. Cleckley though included within his text 15 detailed case studies of prototypic psychopaths. The current study was the first to provide systematic ratings of these 15 cases, including ratings with respect to (a) the 16 Cleckley criteria (e.g., anxiousness and inadequately motivated antisocial behavior), (b) 33 additional traits included within or considered for more recently developed measures and models of psychopathy (e.g., boldness, fearlessness, disobliged, cruelty, and aggression), and (c) 30 traits of the 5 factor model of general personality. The results are discussed with respect to implications for both historic and current models of psychopathy. PMID- 26618654 TI - Chronic anger as a precursor to adult antisocial personality features: The moderating influence of cognitive control. AB - Anger is among the earliest occurring symptoms of mental health, yet we know little about its developmental course. Further, no studies have examined whether youth with persistent anger are at an increased risk of exhibiting antisocial personality features in adulthood, or how cognitive control abilities may protect these individuals from developing such maladaptive outcomes. Trajectories of anger were delineated among 503 boys using annual assessments from childhood to middle adolescence (ages ~7-14). Associations between these trajectories and features of antisocial personality in young adulthood (age ~28) were examined, including whether cognitive control moderates this association. Five trajectories of anger were identified (i.e., childhood-onset, childhood-limited, adolescent onset, moderate, and low). Boys in the childhood-onset group exhibited the highest adulthood antisocial personality features (e.g., psychopathy, aggression, criminal charges). However, boys in this group were buffered from these problems if they had higher levels of cognitive control during adolescence. Findings were consistent across measures from multiple informants, replicated across distinct time periods, and remained when controlling for general intelligence and prior antisocial behavior. This is the first study to document the considerable heterogeneity in the developmental course of anger from childhood to adolescence. As hypothesized, good cognitive control abilities protected youth with persistent anger problems from developing antisocial personality features in adulthood. Clinical implications and future directions are discussed. PMID- 26618657 TI - Photochemical Aging of alpha-pinene and beta-pinene Secondary Organic Aerosol formed from Nitrate Radical Oxidation. AB - The nitrate radical (NO3) is the dominant nighttime oxidant in most urban and rural environments and reacts rapidly with biogenic volatile organic compounds to form secondary organic aerosol (SOA) and organic nitrates (ON). Here, we study the formation of SOA and ON from the NO3 oxidation of two monoterpenes (alpha pinene and beta-pinene) and investigate how they evolve during photochemical aging. High SOA mass loadings are produced in the NO3+beta-pinene reaction, during which we detected 41 highly oxygenated gas- and particle-phase ON possessing 4 to 9 oxygen atoms. The fraction of particle-phase ON in the beta pinene SOA remains fairly constant during photochemical aging. In contrast to the NO3+beta-pinene reaction, low SOA mass loadings are produced during the NO3+alpha pinene reaction, during which only 5 highly oxygenated gas- and particle-phase ON are detected. The majority of the particle-phase ON evaporates from the alpha pinene SOA during photochemical aging, thus exhibiting a drastically different behavior from that of beta-pinene SOA. Our results indicate that nighttime ON formed by NO3+monoterpene chemistry can serve as either permanent or temporary NOx sinks depending on the monoterpene precursor. PMID- 26618656 TI - Integrated Modeling of Gene Regulatory and Metabolic Networks in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (MTB) is the causative bacterium of tuberculosis, a disease responsible for over a million deaths worldwide annually with a growing number of strains resistant to antibiotics. The development of better therapeutics would greatly benefit from improved understanding of the mechanisms associated with MTB responses to different genetic and environmental perturbations. Therefore, we expanded a genome-scale regulatory-metabolic model for MTB using the Probabilistic Regulation of Metabolism (PROM) framework. Our model, MTBPROM2.0, represents a substantial knowledge base update and extension of simulation capability. We incorporated a recent ChIP-seq based binding network of 2555 interactions linking to 104 transcription factors (TFs) (representing a 3.5-fold expansion of TF coverage). We integrated this expanded regulatory network with a refined genome-scale metabolic model that can correctly predict growth viability over 69 source metabolite conditions and predict metabolic gene essentiality more accurately than the original model. We used MTBPROM2.0 to simulate the metabolic consequences of knocking out and overexpressing each of the 104 TFs in the model. MTBPROM2.0 improves performance of knockout growth defect predictions compared to the original PROM MTB model, and it can successfully predict growth defects associated with TF overexpression. Moreover, condition-specific models of MTBPROM2.0 successfully predicted synergistic growth consequences of overexpressing the TF whiB4 in the presence of two standard anti TB drugs. MTBPROM2.0 can screen in silico condition-specific transcription factor perturbations to generate putative targets of interest that can help prioritize future experiments for therapeutic development efforts. PMID- 26618658 TI - Lack of association of the CEP72 rs924607 TT genotype with vincristine-related peripheral neuropathy during the early phase of pediatric acute lymphoblastic leukemia treatment in a Spanish population. AB - Vincristine is a component of acute lymphoblastic leukemia (ALL) treatment with the potential to induce peripheral neuropathy. Recently, the CEP72 rs924607 TT genotype was found to be associated with vincristine-induced toxicity during the continuation phase in pediatric ALL patients treated on the Total XIIIB and COG AALL0433 protocols at St Jude Children's Research Hospital and Children's Oncology Group. This finding could provide a base for safer dosing of vincristine. Nevertheless, there are variations in vincristine regimens among ALL treatment protocols and phases in different populations. Therefore, the aim of this study was to determine whether the CEP72 rs924607 TT genotype is a useful marker of vincristine neuropathy during induction therapy among Spanish children with B-ALL treated on the LAL-SHOP protocols. No association was found between neurotoxicity during the induction phase and the rs924607 TT genotype. This lack of association could be because of population differences and/or differences in neurotoxicity etiology between induction and continuation phases of treatment. PMID- 26618659 TI - Mechanical properties derived from phase separation in co-polymer hydrogels. AB - Hydrogels can be synthesized with most of the properties needed for biomaterials applications. Soft, wettable, and highly permeable gels with a practically unlimited breadth of chemical functionalities are routinely made in the laboratory. However, the ability to make highly elastic and durable hydrogels remains limited. Here we describe an approach to generate stretchy, durable hydrogels, employing a high polymer-to-crosslink ratio for extensibility, combined with an aggregating copolymer phase to provide stability against swelling. We find that the addition of aggregating co-polymer can produce a highly extensible gel that fails at 1000% strain, recovers from large strains within a few minutes, maintains its elasticity over repeated cycles of large amplitude strain, and exhibits significantly reduced swelling. We find that the gel's enhanced mechanical performance comes from a kinetically arrested structure that arises from a competition between the disparate polymerization rates of the two components and the aggregation rate of the unstable phase. These results represent an alternative strategy to generating the type of stretchy elastomer like hydrogels needed for biomedical technologies. PMID- 26618660 TI - Introduction of a new Rotavirus vaccine: Initial results of uptake and impact on laboratory confirmed cases in Anglia and Essex, United Kingdom, July 2015. AB - Rotavirus gastroenteritis accounts for an estimated 130,000 GP consultations and 13,000 hospitalisations for children under 5 y old each year in England and Wales. In July 2013, an oral live attenuated rotavirus vaccine (Rotarix(r)) was introduced into the UK infant immunisation program as a 2 dose schedule at 2 and 3 months of age. We collected vaccination uptake from October 2013 to March 2015 and laboratory confirmed cases data on children under the age of 5 y from 1 January 2004 to 31 May 2015. The vaccine uptake rates and laboratory confirmed cases were compared to provide evidence of the impact of this vaccination program. Vaccine uptake rates were available from sentinel data with between 91 98% of GP practices in Anglia and Essex providing data every month. These data showed from February 2014 to March 2015 between 90-92% of infants received the recommended 2 doses of Rotarix(r) each month. The numbers of rotavirus cases reported by laboratories decreased on average by 82% in the post vaccination seasons. The mean number of cases reported in weeks 1-22 for 2004-2013 in Anglia and Essex was 1,318. For the same period in 2014, 256 cases were reported and initial data for 2015 report 226 cases. In the first 5 months 2014 the greatest reduction in cases (89%) was seen in those under 1 yr (who would have been directly affected by vaccination) with case numbers falling to 59 from a mean 537 cases in the equivalent period for 2004-2013. Initially data suggests a 92% reduction in 2015 compared to the same pre-vaccination periods. For those aged 1 to <5 y who would not have been vaccinated, a reduction of 75% was also evident in 2014 and 77% in 2015, suggesting indirect protection in this group. In conclusion, initial results following the introduction of the Rotavirus vaccine clearly indicates a very good uptake of the vaccine and a significant reduction in the numbers of laboratory confirmed cases. PMID- 26618661 TI - Treatment of Ipsilateral Distal Humerus and Diaphyseal Ulna Fractures by Using an Olecranon Osteotomy and Intramedullary Nail. AB - OBJECTIVE: To evaluate the results of treatment of an osteotomy of the olecranon and an ulnar diaphyseal fracture with a single nail, in cases with an ipsilateral ulnar diaphyseal fracture and a comminuted fracture of the distal humerus. DESIGN: Retrospective clinical study. SETTING: University-affiliated teaching hospital. PATIENTS: Eight patients with comminuted fractures of the distal humerus and ipsilateral ulnar diaphyseal fractures were included. INTERVENTION: Using a transolecranon approach, internal fixation of the distal humeral fracture with medial and lateral plates was performed. The ulnar diaphyseal fracture and additional osteotomy were fixed using a locked intramedullary nail. Subjective pain assessment was performed by using a visual analog scale (VAS). RESULTS: There were 6 (75%) male and 2 (25%) female patients, with a mean age of 40.9 (range, 32-56) years. The mean follow-up period was 24.6 (range, 12-36) months. All patients achieved union of the ulnar diaphyseal fracture and olecranon osteotomy. Union of the distal humeral fracture was observed in 7 (87.5%) patients. The mean time to union was 16.3 (range, 12-22) weeks, mean visual analog scale score was 1.8 (range, 0-3), median elbow performance score was 85 (range, 70-95), and median disabilities of the arm, shoulder, and hand score was 17.9 (range, 5-45.8). CONCLUSIONS: Osteotomy of the olecranon and ulnar diaphyseal fracture using an intramedullary nail was a cosmetically advantageous and safe technique that enabled rehabilitation during the early postoperative period. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26618664 TI - Does Insurance Status Affect the Management of Acute Clavicle Fractures? AB - OBJECTIVES: To evaluate whether insurance is an unrecognized factor that plays a role in determining whether a patient receives surgery. METHODS: A retrospective cross-sectional analysis was performed using the Healthcare Cost and Utilization Project data for Florida in the year 2010. Discharge level data from emergency departments and ambulatory surgery settings were used to identify clavicle fractures by International Classification of Diseases 9 codes 81,000, 81,002, and 81,003. Internal fixation was identified using the Current Procedural Terminology code 23,515. Clavicle fractures that did not result in a Current Procedural Terminology code of 23,515 were assumed to have been managed nonoperatively. Multivariate logistic regression, allowing for intragroup correlation among surgeons, was used to determine the influence of payer source on treatment modality adjusting for race, age, number of chronic conditions, and sex. RESULTS: In total, there were 7858 clavicle fractures that met criteria for inclusion. Observations were removed from the analysis if there was missing personal demographic data or if the ability to track patients from the emergency department to follow-up care was not possible. Therefore, the final sample consisted of 5185 clavicle fractures of which 233 received internal fixation (4.5%). The odds of a patient with private insurance receiving internal fixation was 7.58 times [95% confidence interval (CI) = (4.04 to -14.21), P < 0.001] greater than a self-pay patient, all else being held constant. Patients defined by "other" sources of coverage, a group that includes worker's compensation, CHAMPUS (military), CHAMPVA (veterans), or other government insurance other than Medicare and Medicaid were also associated with an increased likelihood of receiving internal fixation by a factor of 6.80 (95% CI = 3.15, 14.64, P < 0.001) relative to self-pay patients, all else being held constant. The likelihood of patients with Medicare or Medicaid receiving internal fixation did not differ statistically from self-pay patients. CONCLUSIONS: Patients with any form of insurance, when compared with the self-pay, Medicare, and Medicaid populations, had a higher likelihood of operative intervention in Florida in 2010. This may represent an unintended trend in treatment. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 26618662 TI - Reaming Does Not Affect Functional Outcomes After Open and Closed Tibial Shaft Fractures: The Results of a Randomized Controlled Trial. AB - OBJECTIVES: We sought to determine the effect of reaming on 1-year 36-item short form general health survey (SF-36) and short musculoskeletal function assessment (SMFA) scores from the Study to Prospectively Evaluate Reamed Intramedullary Nails in patients with Tibial Fractures. DESIGN: Prospective randomized controlled trial.1319 patients were randomized to reamed or unreamed nails. Fractures were categorized as open or closed. SETTING: Twenty-nine academic and community health centers across the US, Canada, and the Netherlands. PATIENTS/PARTICIPANTS: One thousand three hundred and nineteen skeletally mature patients with closed and open diaphyseal tibia fractures. INTERVENTION: Reamed versus unreamed tibial nails. MAIN OUTCOME MEASUREMENTS: SF-36 and the SMFA. Outcomes were obtained during the initial hospitalization to reflect preinjury status, and again at the 2-week, 3-month, 6-month, and 1-year follow-up. Repeated measures analyses were performed with P < 0.05 considered significant. RESULTS: There were no differences between the reamed and unreamed groups at 12 months for either the SF-36 physical component score [42.9 vs. 43.4, P = 0.54, 95% Confidence Interval for the difference (CI) -2.1 to 1.1] or the SMFA dysfunction index (18.0 vs. 17.6, P = 0.79. 95% CI, -2.2 to 2.9). At one year, functional outcomes were significantly below baseline for the SF-36 physical componentf score, SMFA dysfunction index, and SMFA bothersome index (P < 0.001). Time and fracture type were significantly associated with functional outcome. CONCLUSIONS: Reaming does not affect functional outcomes after intramedullary nailing for tibial shaft fractures. Patients with open fractures have worse functional outcomes than those with a closed injury. Patients do not reach their baseline function by 1 year after surgery. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 26618665 TI - The Acetabular Fracture Prognostic Nomogram: Does it Work for Fractures of the Posterior Wall? AB - OBJECTIVES: A recently proposed nomogram is an attempt to define the subset of acetabular fractures at risk for primary total hip arthroplasty (THA) within 2 years of open reduction and internal fixation (ORIF). Our objectives were to determine whether this nomogram provides information adequate to reliably (1) prognosticate outcome within 2 years after ORIF or (2) identify optimal initial treatment choice (THA vs. ORIF) for patients with a posterior wall fracture. DESIGN: Retrospective case series. SETTING: University level 1 Trauma Center. PATIENTS: From a database of consecutive posterior wall fractures treated by ORIF, 103 patients were identified for analysis: 6 with an unsatisfactory result at less than 2 years and 97 followed 2-14 years. INTERVENTION: Calculation of percent risk of requiring THA within 2 years using the nomogram. MAIN OUTCOME MEASUREMENTS: Comparison of this percent risk to the actual clinical outcome within 2 years after ORIF, measured in 2 ways: (1) THA performed (5 patients) and (2) overall unsatisfactory hip function determined by the modified Merle d'Aubigne score (9 patients total: the 5 with THA plus 4 additional without THA but having unsatisfactory hip function). RESULTS: The calculated percent risk ranged widely, with much overlap among patients having satisfactory or unsatisfactory results of ORIF. Statistical analysis did not yield a clinically useful positive predictive value: 0.25 [95% confidence interval (CI), 0.08-0.53] for THA and 0.44 (95% CI, 0.21-0.69) for an overall unsatisfactory clinical result. CONCLUSIONS: The acetabular fracture prognostic nomogram in its current form does not provide sufficient information to prognosticate outcome after ORIF or to determine appropriate surgical management for posterior wall fractures. LEVEL OF EVIDENCE: Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 26618666 TI - Reconstruction of Long Bone Infections Using the Induced Membrane Technique: Tips and Tricks. AB - The management of posttraumatic long bone osteomyelitis remains a challenging clinical problem. A systematic approach is necessary, beginning with eradication of the infected bone and soft tissue. There are a number of options for reconstruction of the remaining bone defect, including the induced membrane technique developed by Masquelet. We describe our technique for the 2-stage treatment of long bone osteomyelitis. The first stage involves a radical debridement, stabilization of the bone with either external fixation or an antibiotic-coated intramedullary nail, and placement of a polymethylmethacrylate spacer. The second stage includes excision of the spacer and placement of autologous bone graft. Various resection methods, fixation strategies, antibiotic additives, and types of bone grafts or substitutes can be used. The purpose of our technical article is to share our personal experience and describe several nuances that are critical for the success of this treatment strategy. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26618667 TI - Theoretical Study of Sodium Effect on the Gasification of Carbonaceous Materials with Carbon Dioxide. AB - The effect of sodium on the thermodynamics and kinetics of carbon gasification with carbon dioxide was studied by using quantum chemistry methods. Specifically, in the density functional context, two exchange-correlation functionals were used: B3LYP and M06. Some results obtained by these exchange-correlation functionals were contrasted with those obtained by the CCSD(T) method. It was found that density functional theory gives similar conclusions with respect to the coupled-cluster method. As one important conclusion we can mention that the thermodynamics of carbon monoxide desorption is not favored by the sodium presence. However, the presence of this metal induces: (a) an easier formation of one semiquinone group, (b) the dissociation of carbon dioxide, and PMID- 26618668 TI - Overpowering Images. PMID- 26618669 TI - Differential Progression of Dysphagia in Heredity and Sporadic Ataxias Involving Multiple Systems. AB - Sporadic ataxia affecting multiple systems, such as cerebellar, extrapyramidal, and autonomic systems, is known as multiple system atrophy cerebellar type (MSA C), while similar multisystem involvements are seen in certain types of hereditary ataxia, such as spinocerebellar ataxia type 3 (SCA3). Dysphagia is a common symptom that can predispose to aspiration pneumonia, a major cause of death in patients with these diseases. Although the progressions of dysphagia in patients with MSA-C have been reported sporadically, those in SCA3 have not been reported. We retrospectively compared the results of repetitive videofluoroscopic examinations in patients with SCA3 (n = 6) and in those with MSA-C (n = 7). The result showed that the gross progression of dysphagia was significantly slower in patients with SCA3 than in those with MSA-C, but the maximum progression speeds were not significantly different. The dysphagia severities were not associated with impaired activity of daily living evaluated by the Barthel index in MSA-C, but were associated in SCA3. Despite the small number of patients enrolled, these data suggest that physicians should monitor swallowing functions in patients with SCA3 after mild dysphagia develops because it may progress as rapidly as it does in MSA-C. PMID- 26618670 TI - Genome-Wide Microarray Analysis of Long Non-Coding RNAs in Eutopic Secretory Endometrium with Endometriosis. AB - BACKGROUND/AIMS: Dysregulated long non-coding RNAs (lncRNAs) can lead to the occurrence of various diseases; however, reports of the function of lncRNAs in endometriosis and related studies are scarce. The pathogenesis of endometriosis is still poorly understood. METHODS: Dysregulated lncRNAs and mRNAs between eutopic and normal endometrium (both are late secretory) were analyzed by lncRNA microarray. Eight lncRNAs and mRNA CDK6 were validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Bioinformatics prediction was used to investigate the potential function of these differentially expressed lncRNAs. RESULTS: Microarray expression profiling suggests 1277 lncRNAs (488 up- and 789 down-regulated) and 1216 mRNAs (578 up- and 638 down-regulated) were expressed differentially between eutopic and normal endometrium. Pathway analysis and gene ontology (GO) analysis found differently expressed lncRNAs associated with the cell cycle and immune regulation. The relative level of expression of CDK6 and AC002454.1 were obtained by qRT-PCR and the Pearson correlation coefficient was 0.747 (p<0.0001). A coding-noncoding gene co-expression (CNC) network was constructed for these validated lncRNAs. CONCLUSION: These dysregulated lncRNAs might provide information for new biomarkers or novel therapeutic targets of endometriosis. AC002454.1 might induce cell cycle disorder by regulating CDK6 to participate in the pathogenesis of endometriosis. PMID- 26618671 TI - Hampering of the Stability of Gold Electrodes by Ferri-/Ferrocyanide Redox Couple Electrolytes during Electrochemical Impedance Spectroscopy. AB - In the past decades, numerous measurements have applied electrochemical impedance spectroscopy (EIS) in an electrode-electrolyte system consisting of gold electrodes and the redox couple potassium ferrocyanide/potassium ferricyanide (HCF). Yet these measurements are often hampered by false positive and negative results. Electrochemical impedance signals often display a nonlinear drift in electrolyte systems containing the HCF redox couple, which can mask the accuracy of the analysis. Thus, this Article aims to elucidate the stability and reliability of this particular electrode-electrolyte system. Here, different gold electrode cleaning treatments were compared with respect to adsorption and roughness of the surface of gold electrodes. They show substantial nonlinear long term drifts of the charge-transfer resistance RD. In particular, the use of HCF containing electrolytes causes adsorption and corrosion on the gold electrode surface, resulting in a nonlinear impedance behavior that depends on the incubation period as well as on electrolyte composition. Consequently, it is strongly recommended not to use HCF containing electrolytes in combination with gold electrodes. PMID- 26618672 TI - U-turn on overseas nurses. PMID- 26618673 TI - Managing petechial rashes in children. PMID- 26618674 TI - Working together to manage common skin conditions. PMID- 26618675 TI - Old age and people on the autism spectrum: a focus group perspective. AB - Until recently, the focus of many within the 'autism service industry' has been on children and young adults who are on the autism spectrum where 'service transition' usually refers specifically to the transition from children to adult service provision. This article explores 'service transition' from the opposite end of the age scale, that of old age, and incorporates the views of older adults who are on the autism spectrum. In order to design and provide a service that is 'fit for purpose', training of health professionals and consulting with people on the autism spectrum is crucial. PMID- 26618676 TI - Implementing peer learning to prepare students for OSCEs. AB - First-year nursing students undertaking a first-year clinical skills module were given an opportunity to take part in a voluntary peer learning scheme, where they would learn from more senior students. It was envisaged this would help the students prepare for the module's summative assessment-an objective structured clinical examination (OSCE), which students can find stressful. The first-year students found peer learning helped them improve clinical skills, reduced anxiety and increased their self-confidence, and they appreciated the non-threatening learning environment and constructive feedback. The more senior students felt it helped prepare them for their mentoring role after registration. Incorporating peer learning more widely into the curriculum would allow it to be evaluated in more depth. PMID- 26618677 TI - Implementing an e-Assessment of Professional Practice. AB - The ability to accurately document undergraduate student nurses' development while in the clinical area is a requirement of the Nursing and Midwifery Council. Owing to a number of strategic and pragmatic drivers, the Faculty of Health Sciences at the University of Southampton has developed and implemented an e Assessment of Professional Practice (eAoPP). This platform enables the student, mentor and academic staff to access the portfolio from any internet enabled device and has been rolled out in phases over 2 years to more than 5000 students and mentors. The key factors underpinning the success of the project are presented along with an audit and preliminary analysis of support service activity provided during the roll out to 380 students in January 2015 across Hampshire and the Isle of Wight. Plans for future development, including employability and roll out to other student groups are discussed. PMID- 26618678 TI - Conducting a pilot study: case study of a novice researcher. AB - Pilot studies play a vital role in health research, but are often misused, mistreated and misrepresented. A well-conducted pilot study with clear aims and objectives within a formal framework ensures methodological rigour, can lead to higher-quality research and scientifically valid work that is publishable and can benefit patients and health service delivery. A pilot study contributes valuable information to assist researchers in the conduct of their study. Conducting a pilot study provides the researcher with the opportunity to develop and enhance the skills necessary before commencing the larger study. By conducting a pilot the researcher obtains preliminary data, can evaluate their data-analysis method and clarify the financial and human resources required. This article presents an overview of pilot studies, why they are conducted, what to consider when reporting pilot studies and the authors' experience of conducting a pilot study. To conduct a successful study, researchers need to develop their skills, choose the right methods and carefully plan for all aspects of the process. PMID- 26618679 TI - Communication and nursing: a study-abroad student's reflections. AB - Globalisation in the academic context provides the opportunity for sharing knowledge and innovations between institutions in different countries, through the creation of study abroad and academic mobility programmes. For nursing students, studying abroad facilitates the development of cultural sensitivity so that they may care appropriately for an increasingly multicultural patient population in their own countries. This article describes a Brazilian 'study abroad' student nurse's experience of studying a 'communication and therapeutic relationships' module in an Irish university. Johns' model of structured reflection was used to frame, describe and reflect on the experience. This reflection informs 'study abroad' students and their universities about the student experience through a personal account of one such student. PMID- 26618680 TI - Clinical holding with children who display behaviours that challenge. AB - Nurses hold children to administer treatment, prevent treatment interference and undertake clinical assessments, which can sometimes be invasive, as part of their regular duties. Clinical holding ensures this treatment or assessment is carried out safely, however, it has been reported that there is little training available in this area. This article explores the prevalent clinical holding techniques used by nursing staff when caring for children with behaviours that challenge. As an initial insight into what the researchers hope will become a more in-depth 2 year study, this investigation looks to explore current practice when holding children and the factors influencing this. It is hoped that this will inform the development of a training package offered to nurses when caring for these children. Thirteen semi-structured interviews took place with a small group of nurses, which were given thematic analysis. The overarching themes influencing holding practice were the nursing role itself along with intrinsic and external factors. PMID- 26618681 TI - Terrence Higgins Trust: governance and accountability. PMID- 26618682 TI - Writing for publication: Written communication: from staff nurse to nurse consultant. PMID- 26618683 TI - Nurturing a patient's dignity: small gestures can have a big impact. AB - In this monthly column, Aysha Mendes discusses the role of the nurse in facilitating the aspects of care that contribute to nurturing a patient's dignity and argues that the small things, as well as the big things, can have a valuable impact on a person's self-worth and quality of life. PMID- 26618684 TI - Staffing for neonatal units in jeopardy. AB - Emeritus professor Alan Glasper, from the University of Southampton, discusses the crisis in neonatal-unit staffing highlighted in a new report by the charity Bliss. PMID- 26618685 TI - The health and care of older people in England. AB - John Tingle discusses two reports that look at the care of older people in England. PMID- 26618686 TI - The duty of candour: what it means for practising nurses. AB - Nurses now have a statutory and professional duty to be open and candid with patients about any errors in their care and treatment. A professional duty of candour is a key requirement of the revised Code from the Nursing and Midwifery Council (NMC, 2015). Nurses are also subject to a statutory duty of candour imposed on their employer. In this article, the author considers the statutory and professional duties of candour and their impact on nurses. PMID- 26618687 TI - Evidence-based practice: the need for a collaborative approach. PMID- 26618689 TI - Welcome to Our New Journal: Journal of the Pediatric Infectious Diseases Society. PMID- 26618688 TI - Time to look again at our options for staffing. PMID- 26618690 TI - A Precis and Perspective of the Phylogeny of the Pediatric Infectious Diseases Society. PMID- 26618691 TI - A Comprehensive Intervention Associated With Reduced Surgical Site Infections Among Pediatric Cardiovascular Surgery Patients, Including Those With Delayed Closure. AB - BACKGROUND: Surgical site infections (SSIs) cause significant morbidity and mortality in patients undergoing cardiovascular (CV) surgery. Following an increase in SSIs in this population, driven by a high rate in those with delayed closure, we implemented an intervention to reduce these infections and assessed the intervention using both population- and patient-level analyses. METHODS: An intervention drawing from existing guidelines and targeting preoperative preparation of the patient, prophylactic antibiotics, and postoperative incision care was implemented. Special attention was paid to standardizing the care of the incision of patients with delayed closure. National Healthcare Safety Network criteria were used to prospectively identify SSIs. Population-level intervention effect was assessed using interrupted time series. To assess intervention adherence and effect in our patient population, retrospective chart review was performed on a cohort of patients undergoing cardiac procedures pre- and postintervention. Multivariate analysis was used to assess risk of SSI at the patient level. RESULTS: Timely preoperative prophylactic antibiotic dosing increased from 60% preintervention to 92% postintervention, and redosing during prolonged surgeries increased from 5% to 79% (both, P < .001). At the population level, a decrease of 6.7 infections per 100 surgeries per 6 months was observed directly following the intervention (P = .002). The SSI rate decreased from 40% to 0.8% (P < .001) in patients with delayed closure and from 4.3% to 1.8% (P = .02) in patients with immediate closure. In multivariate analyses, surgery prior to the intervention was the strongest predictor for SSI (incidence rate ratio, 3.98; 95% confidence interval, 1.59 to 9.97). CONCLUSIONS: Our intervention decreased SSIs in pediatric CV surgery patients, particularly those with delayed closures. PMID- 26618692 TI - Editorial Commentary: Healthcare-Associated Infections: One Size Does Not Fit All. PMID- 26618693 TI - The California Pertussis Epidemic 2010: A Review of 986 Pediatric Case Reports From San Diego County. AB - BACKGROUND: The California Department of Public Health (CDPH) declared a pertussis epidemic on 23 June 2010. More cases were reported in 2010 (9146) than in any year since 1947. We describe the characteristics of pertussis epidemiology and disease from 986 reported cases in children in San Diego County (population 3.2 million). METHODS: Descriptive statistics were abstracted from CDPH pertussis case report forms that were completed by public health nurses investigating reports of positive laboratory results for pertussis and reports of illnesses compatible with pertussis. RESULTS: Of 1144 reported adult and pediatric cases, 753 (66%) were confirmed and 391 were probable/suspect. Children aged <19 years comprised 86% of all reported cases in San Diego County; of these, 22% were aged 11-18 years, 29% were aged 6-10 years, 27% were aged 1-5 years, and 22% were aged <1 year (with 70% aged <6 months). Case rates were highest in infants aged <6 months (651 per 100 000 population). Of those aged >1 year, the highest attack rates were in preschool children aged 1-5 years (114 per 100 000) and elementary school children aged 6-10 years (141 per 100 000). Of 51 children hospitalized, 82% were aged <6 months; 2 deaths occurred in these young infants. Paroxysmal cough was noted in over 70% of children in all age groups; post-tussive vomiting occurred in 36% (aged 11-18 years) to 57% (aged <6 months) of children. CONCLUSIONS: Pertussis vaccine efficacy may decrease more rapidly than previously believed, facilitating spread of pertussis in elementary school-aged children. The highest case rates and the only mortality occurred in infants aged <6 months. PMID- 26618694 TI - Evaluation of an Interferon Gamma Release Assay to Detect Tuberculosis Infection in Children in San Diego, California. AB - QuantiFERON-TB Gold In-Tube (QFT-GIT) and tuberculin skin test (TST) results are reported in 23 children with active tuberculosis due to Mycobacterium tuberculosis and Mycobacterium bovis. Overall QFT-GIT (96%) was more sensitive than TST (74%) for detecting tuberculosis infection in these patients. PMID- 26618695 TI - Sixteen-Year-Old Boy From Nigeria With a Rash. AB - DATE: Thursday, October 20, 2011. SESSION TITLE: Pediatric Fellows' Day Workshop Hosting Organization: Infectious Diseases Society of America. HOSTING EVENT: 49th Annual Meeting of the Infectious Diseases Society of America. LOCATION: Boston, Massachusetts. PMID- 26618696 TI - An Adolescent With Hepatitis. AB - DATE: Thursday, October 20, 2011. SESSION TITLE: Pediatric Fellows' Day Workshop Hosting Organization: Infectious Diseases Society of America. HOSTING EVENT: 49th Annual Meeting of the Infectious Diseases Society of America. LOCATION: Boston, Massachusetts. PMID- 26618697 TI - Literature Review. PMID- 26618698 TI - Curbside Consultations in Pediatric Infectious Diseases. AB - The Pediatric ID Consultant section provides brief reviews of topics relevant to the day-to-day practice of pediatric infectious diseases. The reviews are placed in context by a short vignette, followed by one or more questions which are addressed. Pediatric infectious diseases physicians are often asked by medical colleagues to provide recommendations for management of a patient without the benefit of a formal consultation. This article relates a story exemplifying such a request and discusses the possible quality of care, medical liability, and financial implications of informal consultations. PMID- 26618703 TI - Ribosomal L22-like1 (RPL22L1) Promotes Ovarian Cancer Metastasis by Inducing Epithelial-to-Mesenchymal Transition. AB - Double minute chromosomes (DMs) have important implications for cancer progression because oncogenes frequently amplified on them. We previously detected a functionally undefined gene amplified on DMs, Ribosomal L22-like1 (RPL22L1). The relationship between RPL22L1 and cancer progression is unknown. Here, RPL22L1 was characterized for its role in ovarian cancer (OC) metastasis and its underlying mechanism was examined. DNA copy number and mRNA expression of RPL22L1 in OC cells was analyzed using data obtained from The Cancer Genome Atlas and the Gene Expression Omnibus database. An immunohistochemical analysis of clinical OC specimens was performed and the relationships between expression level and clinicopathological factors were evaluated. Additionally, in vivo and in vitro assays were performed to understand the role of RPL22L1 in OC. RPL22L1 expression was higher in OC specimens than in normal tissues, and its expression level was highly positively correlated with invasion and lymph node metastasis (P < 0.05). RPL22L1 over-expression significantly enhanced intraperitoneal xenograft tumor development in nude mice and promoted invasion and migration in vitro. Additionally, RPL22L1 knockdown remarkably inhibited UACC-1598 cells invasion and migration. Further, RPL22L1 over-expression up-regulated the mesenchymal markers vimentin, fibronectin, and alpha-SMA, reduced expression of the epithelial markers E-cadherin, alpha-catenin, and beta-catenin. RPL22L1 inhibition reduced expression of vimentin and N-cadherin. These results suggest that RPL22L1 induces epithelial-to-mesenchymal transition (EMT). Our data showed that the DMs amplified gene RPL22L1 is critical in maintaining the aggressive phenotype of OC and in triggering cell metastasis by inducing EMT. It could be employed as a novel prognostic marker and/or effective therapeutic target for OC. PMID- 26618705 TI - Correction: Genotyping of Enterocytozoon bieneusi in Farmed Blue Foxes (Alopex lagopus) and Raccoon Dogs (Nyctereutes procyonoides) in China. PMID- 26618704 TI - Exposure to Palladium Nanoparticles Affects Serum Levels of Cytokines in Female Wistar Rats. AB - BACKGROUND: Information currently available on the impact of palladium on the immune system mainly derives from studies assessing the biological effects of palladium salts. However, in the last years, there has been a notable increase in occupational and environmental levels of fine and ultrafine palladium particles released from automobile catalytic converters, which may play a role in palladium sensitization. In this context, the evaluation of the possible effects exerted by palladium nanoparticles (Pd-NPs) on the immune system is essential to comprehensively assess palladium immunotoxic potential. AIM: Therefore, the aim of this study was to investigate the effects of Pd-NPs on the immune system of female Wistar rats exposed to this xenobiotic for 14 days, by assessing possible quantitative changes in a number of cytokines: IL-1alpha, IL-2, IL-4, IL-6, IL 10, IL-12, GM-CSF, INF-gamma and TNF-alpha. METHODS: Twenty rats were randomly divided into four exposure groups and one of control. Animals were given a single tail vein injection of vehicle (control group) and different concentrations of Pd NPs (0.012, 0.12, 1.2 and 12 MUg/kg). A multiplex biometric enzyme linked immunosorbent assay was used to evaluate cytokine serum levels. RESULTS: The mean serum concentrations of all cytokines decreased after the administration of 0.012 MUg/kg of Pd-NPs, whereas exceeded the control levels at higher exposure doses. The highest concentration of Pd-NPs (12 MUg/kg) induced a significant increase of IL-1alpha, IL-4, IL-6, IL-10, IL-12, GM-CSF and INF-gamma compared to controls. DISCUSSION AND CONCLUSIONS: These results demonstrated that Pd-NP exposure can affect the immune response of rats inducing a stimulatory action that becomes significant at the highest administered dose. Our findings did not show an imbalance between cytokines produced by CD4+ T helper (Th) cells 1 and 2, thus suggesting a generalized stimulation of the immune system with a simultaneous activation and polarization of the naive T cells towards Th1 and Th2 phenotype. PMID- 26618707 TI - Laparoscopic Suture Rectopexy for Persistent Rectal Prolapse in Children: Is It a Safe and Effective First-Line Intervention? AB - BACKGROUND: Several techniques have been described for the surgical correction of rectal prolapse without any clear advantage for one technique over the other. We evaluated the use of laparoscopic suture rectopexy (LSRP) as a modality of treatment for rectal prolapse in children. MATERIALS AND METHODS: Prospective data were collected for all children who presented to our center between 2011 and 2014 and required surgery for rectal prolapse. All children underwent LSRP with fixation of the mobilized rectum to the sacral promontory with multiple nonabsorbable sutures. The median follow-up period was 14 months (range, 6-29 months). The operative time, operative complications, length of hospital stay, and postoperative complications were recorded and analyzed. RESULTS: Seventy-four patients presented with rectal prolapse during this period. Twenty patients (27%) required LSRP. Their median age at surgery was 4.4 years (range, 2-11 years), median operative time was 77.5 minutes (range, 30-150 minutes), and the median length of hospital stay was 1 day (range, 1-4 days). Only 1 patient had full thickness recurrence that required redo surgery, and another had mucosal prolapse, which spontaneously resolved. CONCLUSIONS: LSRP is a safe and effective technique for treating children with full-thickness rectal prolapse with the benefits of being minimally invasive, a short hospital stay, early recovery, and low recurrence rate. PMID- 26618706 TI - Do Beliefs about the Pathogenetic Role of Amyloid Affect the Interpretation of Amyloid PET in the Clinic. AB - BACKGROUND: Beliefs of dementia experts about the pathogenic role of amyloid in Alzheimer's disease (AD) may affect the use of amyloid positron emission tomography (PET). OBJECTIVE: To assess the role attributed to amyloid in AD pathogenesis by Italian dementia experts, and whether this modulates the impact of amyloid PET results in their diagnostic workup. METHODS: 22 dementia experts rated their beliefs about the pathogenic role of amyloid. Then, we asked them to rate the probability of change in diagnosis based on the result of amyloid PET for 7 case vignettes, depicting patients who initially received a diagnosis based on a comprehensive workup and later received amyloid PET results consistent or inconsistent with the clinical picture. RESULTS: 55% of the experts assigned a dominant role to amyloid, and 32% attributed a similar role to amyloid and tau in AD pathogenesis. The probability of change in diagnosis ranged from 17% (SD = 21.6) for cases with consistent to 51% (SD = 34) for cases with inconsistent PET versus clinical data. Diagnostic change was not biased by the clinicians' beliefs about AD pathogenesis. CONCLUSIONS: This work supports an unbiased interpretation of amyloid PET across different beliefs about the pathogenic role of amyloid, and a belief-independent reluctance to change diagnosis in cases where change is expected and recommended. PMID- 26618708 TI - Alagille Syndrome Mimicking Biliary Atresia in Early Infancy. AB - Alagille syndrome may mimic biliary atresia in early infancy. Since mutations in JAG1 typical for Alagille syndrome type 1 have also been found in biliary atresia, we aimed to identify JAG1 mutations in newborns with proven biliary atresia (n = 72). Five biliary atresia patients with cholestasis, one additional characteristic feature of Alagille syndrome and ambiguous liver histology were single heterozygotes for nonsense or frameshift mutations in JAG1. No mutations were found in the remaining 67 patients. All "biliary atresia" carriers of JAG1 null mutations developed typical Alagille syndrome at the age of three years. Our data do not support association of biliary atresia with JAG1 mutations, at least in Czech patients. Rapid testing for JAG1 mutations could prevent misdiagnosis of Alagille syndrome in early infancy and improve their outcome. PMID- 26618709 TI - Tunable Semicrystalline Thin Film Cellulose Substrate for High-Resolution, In Situ AFM Characterization of Enzymatic Cellulose Degradation. AB - In the field of enzymatic cellulose degradation, fundamental interactions between different enzymes and polymorphic cellulose materials are of essential importance but still not understood in full detail. One technology with the potential of direct visualization of such bioprocesses is atomic force microscopy (AFM) due to its capability of real-time in situ investigations with spatial resolutions down to the molecular scale. To exploit the full capabilities of this technology and unravel fundamental enzyme-cellulose bioprocesses, appropriate cellulose substrates are decisive. In this study, we introduce a semicrystalline-thin-film cellulose (SCFTC) substrate which fulfills the strong demands on such ideal cellulose substrates by means of (1) tunable polymorphism via variable contents of homogeneously sized cellulose nanocrystals embedded in an amorphous cellulose matrix; (2) nanoflat surface topology for high-resolution and high-speed AFM; and (3) fast, simple, and reproducible fabrication. The study starts with a detailed description of SCTFC preparation protocols including an in-depth material characterization. In the second part, we demonstrate the suitability of SCTFC substrates for enzymatic degradation studies by combined, individual, and sequential exposure to TrCel6A/TrCel7A cellulases (Trichoderma reesei) to visualize synergistic effects down to the nanoscale. PMID- 26618710 TI - A new flavone from Malaysia Borneo Marsdenia tinctoria. AB - Marsdenia tinctoria is an indigo producing plant commonly found in Borneo, Malaysia. In this present study, one new flavone kapitone (1) and three known compounds, that is 3,2'-dihydroxyflavone (2), 1-methylcyclobutene (3) and dimethyl isatoate (4) were isolated from the Malaysia Borneo M. tinctoria R. Br. (Apocynaceae). These compounds were isolated and characterised using extensive chromatographic and spectroscopic methods. PMID- 26618711 TI - Cultivar and Year Rather than Agricultural Practices Affect Primary and Secondary Metabolites in Apple Fruit. AB - Many biotic and abiotic parameters affect the metabolites involved in the organoleptic and health value of fruits. It is therefore important to understand how the growers' decisions for cultivar and orchard management can affect the fruit composition. Practices, cultivars and/or year all might participate to determine fruit composition. To hierarchize these factors, fruit weight, dry matter, soluble solids contents, titratable acidity, individual sugars and organics acids, and phenolics were measured in three apple cultivars ('Ariane', 'Melrose' and 'Smoothee') managed under organic, low-input and conventional management. Apples were harvested at commercial maturity in the orchards of the cropping system experiment BioREco at INRA Gotheron (Drome, 26) over the course of three years (2011, 2012 and 2013). The main factors affecting primary and secondary metabolites, in both apple skin and flesh, were by far the cultivar and the yearly conditions, while the management system had a very limited effect. When considering the three cultivars and the year 2011 to investigate the effect of the management system per se, only few compounds differed significantly between the three systems and in particular the total phenolic content did not differ significantly between systems. Finally, when considering orchards grown in the same pedoclimatic conditions and of the same age, instead of the usual organic vs. conventional comparison, the effect of the management system on the apple fruit quality (Fruit weight, dry matter, soluble solids content, titratable acidity, individual sugars, organic acids, and phenolics) was very limited to non significant. The main factors of variation were the cultivar and the year of cropping rather than the cropping system. More generally, as each management system (e.g. conventional, organic...) encompasses a great variability of practices, this highlights the importance of accurately documenting orchard practices and design beside the generic type of management in such studies. PMID- 26618712 TI - Preparation and evaluation of magnetic nanocomposite fibers containing alpha" Fe16N2 and alpha-Fe nanoparticles in polyvinylpyrrolidone via magneto electrospinning. AB - Two kinds of ferromagnetic nanocomposite fiber comprising alpha"-Fe16N2 and alpha Fe nanoparticles (NPs), which have the highest magnetic moments as hard and soft magnetic materials, respectively, embedded in polyvinylpyrrolidone (PVP) have been synthesized via the magneto-electrospinning method. Both alpha"-Fe16N2 and alpha-Fe were single-domain core-shell NPs with an average outer diameter of 50 nm and Al2O3 as the shell. Ferrofluid precursors used for the electrospinning were prepared by dispersing these NPs in a PVP-toluene-methanol solution. The results show that applying the magnetic field in the same direction as the electric field resulted in smaller and more uniform fiber diameters. Nanocomposite fibers containing alpha"-Fe16N2 had smaller diameters than those containing alpha-Fe NPs. These magnetic-field effects on the fiber formation were explained by referring to the kinetic energy of the moving jet in the electrospinning process. In addition, magnetic hysteresis curves showed an enhancement of the magnetic coercivity (H(c)) and remanence (M(r)) by 22.9% and 22.25%, respectively. These results imply a promising possibility of constructing bulk magnetic materials using alpha"-Fe16N2 NPs, which furthermore reveals attractive features for many other magnetic applications, such as magnetic sensors. PMID- 26618714 TI - Prediction of Surface and Bulk Partition of Nonionic Surfactants Using Free Energy Calculations. AB - The surface-bulk partition of nonionic surfactants was predicted by calculating chemical potential differences using two simulation boxes representing the surface and the bulk phases separately. A published coarse grained force field was modified and validated for this application. Thermodynamic integration (TI) was applied to compute excess chemical potentials. The high concentration surface was stabilized by applying an external harmonic potential, and the bulk was treated as ideal solution, which was confirmed by simulation using a lattice model at conditions near the critical micelle concentration (~10(-5) mol/L). Based on the calculated chemical potential differences with precision of ca. 1 kJ/mol, the equilibria of surface-bulk concentration was predicted well in comparison with the experimental data. PMID- 26618713 TI - Genome Sequence of African Swine Fever Virus BA71, the Virulent Parental Strain of the Nonpathogenic and Tissue-Culture Adapted BA71V. AB - The strain BA71V has played a key role in African swine fever virus (ASFV) research. It was the first genome sequenced, and remains the only genome completely determined. A large part of the studies on the function of ASFV genes, viral transcription, replication, DNA repair and morphogenesis, has been performed using this model. This avirulent strain was obtained by adaptation to grow in Vero cells of the highly virulent BA71 strain. We report here the analysis of the genome sequence of BA71 in comparison with that of BA71V. They possess the smallest genomes for a virulent or an attenuated ASFV, and are essentially identical except for a relatively small number of changes. We discuss the possible contribution of these changes to virulence. Analysis of the BA71 sequence allowed us to identify new similarities among ASFV proteins, and with database proteins including two ASFV proteins that could function as a two component signaling network. PMID- 26618715 TI - Acute effects of a wild green-oat (Avena sativa) extract on cognitive function in middle-aged adults: A double-blind, placebo-controlled, within-subjects trial. AB - OBJECTIVES: A wild green-oats extract (Neuravena(r)) containing a range of potentially bioactive components, including flavonoids and triterpene saponins, has previously been shown to enhance animal stress responses and memory, and improve cognitive performance in humans at a dose of 1600 mg. Methods This double blind, placebo-controlled, counterbalanced cross-over study assessed the effects of single doses of the green-oat extract (GOE) across a broad range of cognitive domains in healthy adults aged 40-65 years who self-reported that they felt that their memory had declined with age. Participants attended on six occasions, receiving a single dose of either placebo, 800, or 1600 mg GOE on each occasion, with the counterbalanced order of treatments repeated twice for each participant. Cognitive function was assessed with a range of computerized tasks measuring attention, spatial/working/episodic memory, and executive function pre-dose and at 1, 2.5, 4, and 6 hours post-dose. Results The results showed that 800mg GOE increased the speed of performance across post-dose assessments on a global measure including data from all of the timed tasks. It also improved performance of a delayed word recall task in terms of errors and an executive function task (Peg and Ball) in terms of decreased thinking time and overall completion time. Working memory span (Corsi blocks) was also increased, but only on the second occasion that this dose was taken. Discussion These results confirm the acute cognitive effects of GOE seen in previous research, and suggest that the optimal dose lies at or below 800 mg. PMID- 26618716 TI - Cognitive reserve and persistent post-concussion symptoms--A prospective mild traumatic brain injury (mTBI) cohort study. AB - PRIMARY OBJECTIVE: Having three or more persisting (i.e. > 3 months) post concussion symptoms (PCS) affects a significant number of patients after a mild traumatic brain injury (mTBI). A common complaint is cognitive deficits. However, several meta-analyses have found no evidence of long-term cognitive impairment in mTBI patients. The study sought to answer two questions: first, is there a difference in cognitive performance between PCS and recovered mTBI patients? Second, is lower cognitive reserve a risk factor for developing PCS? RESEARCH DESIGN: Prospective inception cohort study. METHODS AND PROCEDURE: One hundred and twenty-two adult patients were recruited from emergency departments within 24 hours of an mTBI. Three months post-injury, participants completed the Rivermead Post Concussion Symptoms Questionnaire and a neuropsychological assessment. A healthy control group (n = 35) were recruited. The estimate of cognitive reserve was based upon sub-test Information from Wechsler Adult Intelligence Scale and international classifications of educational level and occupational skill level. MAIN OUTCOME AND RESULTS: mTBI patients showed reduced memory performance. Patients with lower cognitive reserve were 4.14-times more likely to suffer from PCS. CONCLUSIONS: mTBI may be linked to subtle executive memory deficits. Lower cognitive reserve appears to be a risk factor for PCS and indicates individual vulnerabilities. PMID- 26618717 TI - Revealing the Nature of Molecule-Electrode Contact in Tunneling Junctions Using Raw Data Heat Maps. AB - Mechanistic understanding of charge transport through molecular tunnel junctions requires reproducible and statistically relevant data sets. This challenge has been overcome by development of large area junctions, especially those based on liquid-metal physi-sorbed top-electrodes, such as eutectic gallium-indium. A challenge with these junctions, however, is an inability to diagnose the quality of contact between the top-electrode and the SAMs. Since tunneling currents are dependent on the distance between the two electrodes, we demonstrate that by analyzing all raw unfitted data derived from a measurement using heat-maps, one can deduce the quality of contact and other minor bias-dependent fluctuations in the charge transport behavior. We demonstrate that the use of 3D plots would be challenging to interpret, but adoption of heat maps clearly captures details on junction quality irrespective of the total size of the data set or molecules used. We propose representation of raw data, rather than reliance on statistics, as proof of quality junctions. PMID- 26618718 TI - Dissolution of Danazol Amorphous Solid Dispersions: Supersaturation and Phase Behavior as a Function of Drug Loading and Polymer Type. AB - Amorphous solid dispersions (ASDs) are of great interest as enabling formulations because of their ability to increase the bioavailability of poorly soluble drugs. However, the dissolution of these formulations under nonsink dissolution conditions results in highly supersaturated drug solutions that can undergo different types of phase transitions. The purpose of this study was to characterize the phase behavior of solutions resulting from the dissolution of model ASDs as well as the degree of supersaturation attained. Danazol was chosen as a poorly water-soluble model drug, and three polymers were used to form the dispersions: polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), and hydroxypropylmethyl cellulose acetate succinate (HPMCAS). Dissolution studies were carried out under nonsink conditions, and solution phase behavior was characterized using several orthogonal techniques. It was found that liquid liquid phase separation (LLPS) occurred following dissolution and prior to crystallization for most of the dispersions. Using flux measurements, it was further observed that the maximum attainable supersaturation following dissolution was equivalent to the amorphous solubility. The dissolution of the ASDs led to sustained supersaturation, the duration of which varied depending on the drug loading and the type of polymer used in the formulation. The overall supersaturation profile observed thus depended on a complex interplay between dissolution rate, polymer type, drug loading, and the kinetics of crystallization. PMID- 26618719 TI - Insulin:Carbohydrate Ratio--Part of the Story. PMID- 26618720 TI - Use of Insulin Pump in Neonates and Toddlers. PMID- 26618722 TI - Parkinson's disease-associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes. AB - Mitochondrial dysfunction represents a critical step during the pathogenesis of Parkinson's disease (PD), and increasing evidence suggests abnormal mitochondrial dynamics and quality control as important underlying mechanisms. The VPS35 gene, which encodes a key component of the membrane protein-recycling retromer complex, is the third autosomal-dominant gene associated with PD. However, how VPS35 mutations lead to neurodegeneration remains unclear. Here we demonstrate that PD associated VPS35 mutations caused mitochondrial fragmentation and cell death in cultured neurons in vitro, in mouse substantia nigra neurons in vivo and in human fibroblasts from an individual with PD who has the VPS35(D620N) mutation. VPS35 induced mitochondrial deficits and neuronal dysfunction could be prevented by inhibition of mitochondrial fission. VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. Notably, oxidative stress increased the VPS35-DLP1 interaction, which we also found to be increased in the brains of sporadic PD cases. These results revealed a novel cellular mechanism for the involvement of VPS35 in mitochondrial fission, dysregulation of which is probably involved in the pathogenesis of familial, and possibly sporadic, PD. PMID- 26618725 TI - Analytic validation of a gas chromatography-mass spectrometry method for quantification of six amino acids in canine serum samples. AB - OBJECTIVE: To analytically validate a gas concentration of chromatography-mass spectrometry (GC-MS) method for measurement of 6 amino acids in canine serum samples and to assess the stability of each amino acid after sample storage. SAMPLES: Surplus serum from 80 canine samples submitted to the Gastrointestinal Laboratory at Texas A&M University and serum samples from 12 healthy dogs. PROCEDURES: GC-MS was validated to determine precision, reproducibility, limit of detection, and percentage recovery of known added concentrations of 6 amino acids in surplus serum samples. Amino acid concentrations in serum samples from healthy dogs were measured before (baseline) and after storage in various conditions. RESULTS: Intra- and interassay coefficients of variation (10 replicates involving 12 pooled serum samples) were 13.4% and 16.6% for glycine, 9.3% and 12.4% for glutamic acid, 5.1% and 6.3% for methionine, 14.0% and 15.1% for tryptophan, 6.2% and 11.0% for tyrosine, and 7.4% and 12.4% for lysine, respectively. Observed-to expected concentration ratios in dilutional parallelism tests (6 replicates involving 6 pooled serum samples) were 79.5% to 111.5% for glycine, 80.9% to 123.0% for glutamic acid, 77.8% to 111.0% for methionine, 85.2% to 98.0% for tryptophan, 79.4% to 115.0% for tyrosine, and 79.4% to 110.0% for lysine. No amino acid concentration changed significantly from baseline after serum sample storage at -80 degrees C for <= 7 days. CONCLUSIONS AND CLINICAL RELEVANCE: GC-MS measurement of concentration of 6 amino acids in canine serum samples yielded precise, accurate, and reproducible results. Sample storage at -80 degrees C for 1 week had no effect on GC-MS results. PMID- 26618723 TI - Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. AB - Intratumor heterogeneity (ITH) drives neoplastic progression and therapeutic resistance. We used the bioinformatics tools 'expanding ploidy and allele frequency on nested subpopulations' (EXPANDS) and PyClone to detect clones that are present at a >=10% frequency in 1,165 exome sequences from tumors in The Cancer Genome Atlas. 86% of tumors across 12 cancer types had at least two clones. ITH in the morphology of nuclei was associated with genetic ITH (Spearman's correlation coefficient, rho = 0.24-0.41; P < 0.001). Mutation of a driver gene that typically appears in smaller clones was a survival risk factor (hazard ratio (HR) = 2.15, 95% confidence interval (CI): 1.71-2.69). The risk of mortality also increased when >2 clones coexisted in the same tumor sample (HR = 1.49, 95% CI: 1.20-1.87). In two independent data sets, copy-number alterations affecting either <25% or >75% of a tumor's genome predicted reduced risk (HR = 0.15, 95% CI: 0.08-0.29). Mortality risk also declined when >4 clones coexisted in the sample, suggesting a trade-off between the costs and benefits of genomic instability. ITH and genomic instability thus have the potential to be useful measures that can universally be applied to all cancers. PMID- 26618726 TI - Effect of ketamine on the minimum infusion rate of propofol needed to prevent motor movement in dogs. AB - OBJECTIVE: To determine the minimum infusion rate (MIR) of propofol required to prevent movement in response to a noxious stimulus in dogs anesthetized with propofol alone or propofol in combination with a constant rate infusion (CRI) of ketamine. ANIMALS: 6 male Beagles. PROCEDURES: Dogs were anesthetized on 3 occasions, at weekly intervals, with propofol alone (loading dose, 6 mg/kg; initial CRI, 0.45 mg/kg/min), propofol (loading dose, 5 mg/kg; initial CRI, 0.35 mg/kg/min) and a low dose of ketamine (loading dose, 2 mg/kg; CRI, 0.025 mg/kg/min), or propofol (loading dose, 4 mg/kg; initial CRI, 0.3 mg/kg/min) and a high dose of ketamine (loading dose, 3 mg/kg; CRI, 0.05 mg/kg/min). After 60 minutes, the propofol MIR required to prevent movement in response to a noxious electrical stimulus was determined in duplicate. RESULTS: Least squares mean +/- SEM propofol MIRs required to prevent movement in response to the noxious stimulus were 0.76 +/- 0.1 mg/kg/min, 0.60 +/- 0.1 mg/kg/min, and 0.41 +/- 0.1 mg/kg/min when dogs were anesthetized with propofol alone, propofol and low-dose ketamine, and propofol and high-dose ketamine, respectively. There were significant decreases in the propofol MIR required to prevent movement in response to the noxious stimulus when dogs were anesthetized with propofol and low-dose ketamine (27 +/- 10%) or with propofol and high-dose ketamine (30 +/- 10%). CONCLUSIONS AND CLINICAL RELEVANCE: Ketamine, at the doses studied, significantly decreased the propofol MIR required to prevent movement in response to a noxious stimulus in dogs. PMID- 26618727 TI - Comparison of limb loading and movement of Icelandic horses while tolting and trotting at equal speeds. AB - OBJECTIVE: To compare gait mechanics and limb loading in Icelandic horses tolting and trotting at equal speeds and estimate their impact on orthopedic health. ANIMALS: 12 orthopedically normal Icelandic horses. PROCEDURES Kinetic and kinematic gait variables were simultaneously recorded as each horse was ridden at a tolt and trot on an instrumented treadmill at 3.4 m/s and 3.9 m/s. Differences between gaits were tested via 1-factor repeated-measures ANOVA. RESULTS: Horses had a higher stride rate and lower stride impulses at a tolt than at a trot. For forelimbs at a tolt, shorter relative stance duration resulted in higher peak vertical force (Fz(peak)). Conversely, for hind limbs, longer relative stance duration resulted in lower Fz(peak). The higher head-neck position at a tolt versus trot caused no weight shift to the hind limbs, but a higher forehoof flight arc and lower proretraction movement were identified. Stance durations for forelimbs were briefer than for hind limbs at a tolt, and the inverse was observed at a trot. Minimal height of the horse's trunk at the point of Fz(peak) of the respective limb suggested a spring-like mechanism for all limbs at a tolt. Hind limb measurements revealed no evidence of increased collection. Stride-to stride limb timing varied more at a tolt than at a trot. At a trot, horses had brief or no suspension phases and a slightly 4-beated footfall rhythm was common. Post hoc energetic estimations revealed that tolting at the measured speeds was less advantageous than trotting. CONCLUSIONS AND CLINICAL RELEVANCE: High forelimb action in Icelandic horses and higher head-neck position at a tolt were associated with more restricted limb proretraction, higher Fz(peak), and faster force onset than at a trot. The impact of these differences on orthopedic health needs to be investigated more in detail. PMID- 26618728 TI - Effects of high doses of enalapril and benazepril on the pharmacologically activated renin-angiotensin-aldosterone system in clinically normal dogs. AB - OBJECTIVE: To determine whether high doses of enalapril and benazepril would be more effective than standard doses of these drugs in suppressing the furosemide activated renin-angiotensin-aldosterone system (RAAS). ANIMALS: 6 healthy Beagles. PROCEDURES: 2 experiments were conducted; each lasted 10 days, separated by a 2-week washout period. In experiment 1, all dogs received furosemide (2 mg/kg, PO, q 12 h) and enalapril (1 mg/kg, PO, q 12 h) for 8 days (days 0 through 7). In experiment 2, dogs received furosemide (2 mg/kg, PO, q 12 h) and benazepril (1 mg/kg, PO, q 12 h) for 8 days. Effects on the RAAS were determined by assessing serum angiotensin-converting enzyme (ACE) activity on days -1, 3, and 7; serum aldosterone concentration on days -2, -1, 1, 3, and 7; and the urinary aldosterone-creatinine ratio (UAldo:C) in urine collected in the morning and evening of days -2, -1, 1, 3, and 7. RESULTS: High doses of enalapril and benazepril caused significant reductions in serum ACE activity on all days but were not more effective than standard doses used in other studies. Mean UAldo:C remained significantly higher on days 2 through 7, compared with baseline values. Serum aldosterone concentration also increased after drug administration, which mirrored changes in the UAldo:C. CONCLUSIONS AND CLINICAL RELEVANCE: In this study, administration of high doses of enalapril and benazepril significantly inhibited ACE activity, yet did not prevent increases in mean urine and serum aldosterone concentrations resulting from furosemide activation of RAAS. This suggested that aldosterone breakthrough from ACE inhibition was a dose independent effect of ACE inhibitors. PMID- 26618721 TI - The evolving roles of canonical WNT signaling in stem cells and tumorigenesis: implications in targeted cancer therapies. AB - The canonical WNT/beta-catenin signaling pathway governs a myriad of biological processes underlying the development and maintenance of adult tissue homeostasis, including regulation of stem cell self-renewal, cell proliferation, differentiation, and apoptosis. WNTs are secreted lipid-modified glycoproteins that act as short-range ligands to activate receptor-mediated signaling pathways. The hallmark of the canonical pathway is the activation of beta-catenin-mediated transcriptional activity. Canonical WNTs control the beta-catenin dynamics as the cytoplasmic level of beta-catenin is tightly regulated via phosphorylation by the 'destruction complex', consisting of glycogen synthase kinase 3beta (GSK3beta), casein kinase 1alpha (CK1alpha), the scaffold protein AXIN, and the tumor suppressor adenomatous polyposis coli (APC). Aberrant regulation of this signaling cascade is associated with varieties of human diseases, especially cancers. Over the past decade, significant progress has been made in understanding the mechanisms of canonical WNT signaling. In this review, we focus on the current understanding of WNT signaling at the extracellular, cytoplasmic membrane, and intracellular/nuclear levels, including the emerging knowledge of cross-talk with other pathways. Recent progresses in developing novel WNT pathway targeted therapies will also be reviewed. Thus, this review is intended to serve as a refresher of the current understanding about the physiologic and pathogenic roles of WNT/beta-catenin signaling pathway, and to outline potential therapeutic opportunities by targeting the canonical WNT pathway. PMID- 26618729 TI - Effect of firocoxib on cyclooxygenase 2, microsomal prostaglandin E2 synthase 1, and cytosolic phospholipase A2 gene expression in equine mononuclear cells. AB - OBJECTIVE: To validate primer sets for use in reverse transcription quantitative PCR assays to measure gene expression of cytosolic phospholipase A2 (cPLA2) and microsomal prostaglandin E2 synthase 1 (mPGES1) in equine mononuclear cells and determine the effects of firocoxib, a selective cyclooxygenase 2 (COX-2) inhibitor, on COX-2, cPLA2, and mPGES1 gene expression following incubation of mononuclear cells with lipopolysaccharide (LPS). ANIMALS: 8 healthy adult horses. PROCEDURES: Peripheral blood mononuclear cells were isolated by density gradient centrifugation and incubated at 37 degrees C with medium alone, firocoxib (100 ng/mL), LPS (1 ng/mL or 1 MUg/mL), or combinations of firocoxib and both LPS concentrations. After 4 hours, supernatants were collected and tested for prostaglandin E2 (PGE2) concentration with an enzyme inhibition assay, and gene expression in cell lysates was measured with PCR assays. RESULTS: Primer pairs for cPLA2 and mPGES1 yielded single products on dissociation curve analyses, with mean assay efficiencies of 102% and 100%, respectively. Incubation with firocoxib and LPS significantly decreased PGE2 supernatant concentrations and significantly reduced COX-2 and mPGES1 gene expression, compared with values following incubation with LPS alone. CONCLUSIONS AND CLINICAL RELEVANCE: Primer sets for mPGES1 and cPLA2 gene expression in equine mononuclear cells were successfully validated. Firocoxib significantly decreased LPS-induced COX-2 and mPGES1 expression, suggesting that it may be useful in the control of diseases in which expression of these genes is upregulated. PMID- 26618730 TI - Effects of training at a walk on conventional and underwater treadmills on fiber properties and metabolic responses of superficial digital flexor and gluteal muscles to high-speed exercise in horses. AB - OBJECTIVE: To compare effects of training on conventional and underwater treadmills on fiber properties and metabolic responses of the superficial digital flexor (SDF) and gluteal muscles to high-speed exercise in horses. SAMPLE: 6 unconditioned Quarter Horse-type horses. PROCEDURES: 6 horses were walked on underwater and conventional treadmills for 5 d/wk (maximum, 40 min/d) for 8 weeks in a randomized crossover design (60-day detraining period). Horses underwent a standardized exercise test (SET) at high speed before and after training. Analyte concentrations and fiber characteristics were measured in muscle biopsy specimens obtained from horses before and after each SET. RESULTS: Lactate concentration increased 2- to 3-fold in SDF and gluteal muscle after SETs. No training effect was identified on muscle fiber type composition, type II fiber diameter, muscle analyte concentrations, blood lactate concentration, or heart rate responses. Maximum diameters of type I fibers decreased significantly in gluteal muscle with conventional treadmill training and decreased in SDF muscle with both types of training, with maximum diameters greater for horses after underwater versus conventional treadmill training. No change was identified in minimum fiber diameters. CONCLUSIONS AND CLINICAL RELEVANCE: SETs involving near-maximal exertion resulted in an anaerobic response in SDF and gluteal muscles of horses. Eight weeks of conventional or underwater treadmill training resulted in minor changes in type I muscle fiber sizes, with no effect on muscle metabolic or heart rate responses to SETs. After rehabilitation involving underwater treadmills, training at progressing speeds is recommended for horses to develop the required fitness for speed work. PMID- 26618731 TI - Tear film osmolality and electrolyte composition in healthy horses. AB - OBJECTIVE: To evaluate the tear film osmolality and electrolyte composition in healthy horses. ANIMALS: 15 healthy adult horses. PROCEDURES: Each horse was manually restrained, and an ophthalmic examination, which included slit-lamp biomicroscopy, indirect ophthalmoscopy, and a Schirmer tear test, was performed. Tear samples were collected from both eyes with microcapillary tubes 3 times at 5 minute intervals. The tear samples for each horse were pooled, and the osmolality and electrolyte concentrations were measured. The mean (SD) was calculated for each variable to establish preliminary guidelines for tear film osmolality and electrolyte composition in healthy horses. RESULTS: The mean (SD) tear film osmolality was 283.51 (9.33) mmol/kg, and the mean (SD) sodium, potassium, magnesium, and calcium concentrations were 134.75 (10), 16.3 (5.77), 3.48 (1.97), and 1.06 (0.42) mmol/L, respectively. The sodium concentration in the tear film was similar to that in serum, whereas the potassium concentration in the tear film was approximately 4.75 times that of serum. CONCLUSIONS AND CLINICAL RELEVANCE: Results provided preliminary guidelines with which tear samples obtained from horses with keratopathies can be compared. Measurement of tear film osmolality in these horses was easy and noninvasive. The tear film concentration of divalent cations was greater than expected and was higher than the divalent cation concentrations in the tear films of rabbits and humans. These data may be clinically useful for the diagnosis and monitoring of hyperosmolar ocular surface disease in horses. PMID- 26618732 TI - Pharmacokinetics of butorphanol delivered with an osmotic pump during a seven-day period in common peafowl (Pavo cristatus). AB - OBJECTIVE: To determine pharmacokinetics of butorphanol delivered via osmotic pumps in common peafowl (Pavo cristatus) as a method for analgesic administration to avian species. ANIMALS: 14 healthy adult male common peafowl. PROCEDURES: A preliminary experiment was conducted with 2 birds to establish time point and concentration requirements. Then, the remaining 12 birds were anesthetized, and 2 osmotic pumps containing butorphanol (volume, 2 mL; mean dosage, 247 MUg/kg/h) were implanted subcutaneously in each bird for 7 days prior to removal. Blood samples were collected before pump implantation (time 0); 3, 6, 12, 24, 48, 72, 96, 120, 144, and 168 hours after pump implantation; and 3 and 6 hours after pump removal. Plasma butorphanol concentrations were measured via liquid chromatography-mass spectrometry. RESULTS: Plasma concentrations peaked (mean, 106.4 MUg/L; range, 61.8 to 133.0 MUg/L) at a mean of 39.0 hours, with no evidence of sedation in any bird. After pump removal, butorphanol was rapidly eliminated (half-life, 1.45 hours; range, 1.31 to 1.64 hours; n = 5). Mean clearance per fraction of dose absorbed was 2.89 L/kg/h (range, 2.00 to 5.55 L/kg/h). Mean amount of time the plasma butorphanol concentration was >= 60 MUg/L was 85.6 hours (range, 3.5 to 155.3 hours). CONCLUSIONS AND CLINICAL RELEVANCE: Plasma concentrations of butorphanol in common peafowl were maintained at or above reported efficacious analgesic concentrations. This study established a method for administering analgesics to avian patients without the need for frequent handling or injections. Use of these osmotic pumps may provide options for avian analgesia. PMID- 26618733 TI - Pharmacokinetics of a single intramuscular injection of ceftiofur crystalline free acid in red-tailed hawks (Buteo jamaicensis). AB - OBJECTIVE: To determine the pharmacokinetics and adverse effects at the injection site of ceftiofur crystalline-free acid (CCFA) following IM administration of 1 dose to red-tailed hawks (Buteo jamaicensis). ANIMALS: 7 adult nonreleasable healthy red-tailed hawks. PROCEDURES: In a randomized crossover study, CCFA (10 or 20 mg/kg) was administered IM to each hawk and blood samples were obtained. After a 2-month washout period, administration was repeated with the opposite dose. Muscle biopsy specimens were collected from the injection site 10 days after each sample collection period. Pharmacokinetic data were calculated. Minimum inhibitory concentrations of ceftiofur for various bacterial isolates were assessed. RESULTS: Mean peak plasma concentrations of ceftiofur-free acid equivalent were 6.8 and 15.1 MUg/mL for the 10 and 20 mg/kg doses, respectively. Mean times to maximum plasma concentration were 6.4 and 6.7 hours, and mean terminal half-lives were 29 and 50 hours, respectively. Little to no muscle inflammation was identified. On the basis of a target MIC of 1 MUg/mL and target plasma ceftiofur concentration of 4 MUg/mL, dose administration frequencies for infections with gram-negative and gram-positive organisms were estimated as every 36 and 45 hours for the 10 mg/kg dose and every 96 and 120 hours for the 20 mg/kg dose, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Study results suggested that CCFA could be administered IM to red-tailed hawks at 10 or 20 mg/kg to treat infections with ceftiofur-susceptible bacteria. Administration resulted in little to no inflammation at the injection site. Additional studies are needed to evaluate effects of repeated CCFA administration. PMID- 26618734 TI - Effect of castration on the urinary protein-to-creatinine ratio of male dogs. AB - OBJECTIVE: To assess the urinary protein-to-creatinine ratio (UPCR) of healthy sexually intact male dogs and to compare the UPCR of these dogs before and after castration. ANIMALS: 19 client- or shelter-owned healthy adult sexually intact male dogs. PROCEDURES: Physical, hematologic, and biochemical examinations and urinalysis (including calculation of the UPCR) were performed on each dog. Dogs were then castrated, and physical examination and urinalysis (including calculation of the UPCR) were performed again at least 15 days after castration. RESULTS: A dipstick test yielded positive results for protein in the urine of 10 sexually intact male dogs, but the UPCR was < 0.5 for all sexually intact male dogs. Mean UPCR for sexually intact male dogs was 0.12 (range, 0.10 to 0.32). The UPCR was < 0.2 for all castrated dogs, except for 1. Mean UPCR for all castrated dogs was 0.08 (range, 0.05 to 0.69). There was a significant difference between mean UPCR before and after castration. CONCLUSIONS AND CLINICAL RELEVANCE: In this study, pathological proteinuria was not detected in sexually intact male dogs. Positive results for a urine dipstick test should be interpreted with caution in sexually intact male dogs and should be confirmed by assessment of the UPCR. An increased UPCR in sexually intact male dogs may be considered abnormal. PMID- 26618735 TI - Mediation analysis for survival data using semiparametric probit models. AB - Causal mediation modeling has become a popular approach for studying the effect of an exposure on an outcome through mediators. Currently, the literature on mediation analyses with survival outcomes largely focused on settings with a single mediator and quantified the mediation effects on the hazard, log hazard and log survival time (Lange and Hansen 2011; VanderWeele 2011). In this article, we propose a multi-mediator model for survival data by employing a flexible semiparametric probit model. We characterize path-specific effects (PSEs) of the exposure on the outcome mediated through specific mediators. We derive closed form expressions for PSEs on a transformed survival time and the survival probabilities. Statistical inference on the PSEs is developed using a nonparametric maximum likelihood estimator under the semiparametric probit model and the functional Delta method. Results from simulation studies suggest that our proposed methods perform well in finite sample. We illustrate the utility of our method in a genomic study of glioblastoma multiforme survival. PMID- 26618736 TI - Characterization of a new Lactobacillus salivarius strain engineered to express IBV multi-epitope antigens by chromosomal integration. AB - To obtain adhesive and safe lactic acid bacteria (LAB) strains for expressing heterologous antigens, we screened LAB inhabitants in intestine of Tibetan chickens by analyzing their adhesion and safety properties and the selected LAB was engineered to express heterologous antigen (UTEpi C-A) based on chromosomal integration strategy. We demonstrated that a new Lactobacillu salivarius TCMM17 strain is strongly adhesive to chicken intestinal epithelial cells, contains no endogenous plasmids, is susceptible to tested antimicrobials, and shows no toxicities. In order to examine the potential of TCMM17 strain as heterogenous antigen delivering vehicle, we introduced a UTEpi C-A expression cassette in its chromosome by constructing a non-replicative plasmid (pORI280-UUTEpi C-AD). The recombinant TCMM17 strain (?TCMM17) stably was found to keep the gene cassette through 50 generations, and successfully displayed EpiC encoded by the cassette on its surface. This work provides a universal platform for development of novel oral vaccines and expression of further antigens of avian pathogens. PMID- 26618737 TI - Erratum. PMID- 26618738 TI - Congregational Participation of a National Sample of Adults With Intellectual and Developmental Disabilities. AB - Supporting people with intellectual and developmental disabilities (IDD) to thrive requires careful consideration of multiple avenues of community involvement. Yet little attention has focused on the place of faith community participation in the lives of adults with IDD. We examined attendance at religious services using National Core Indicator data for a sample of 12,706 adults with IDD residing in 24 states. Almost half of adults (48.3%) reported attending a religious service in the past month, and more than one third (34.6%) attended 3 or more times. Religious involvement varied considerably based on a variety of individual (e.g., race, disability type, behavioral support needs, communication mode) and contextual factors (e.g., geographic locale, residential type). Moreover, monthly involvement in religious activities was much less common than participation in other community activities (i.e., exercise, entertainment, eating out, shopping). We offer recommendations for supporting the spiritual lives of adults with IDD, as well as highlight areas for future research and practice. PMID- 26618739 TI - A Delphi Study on Staff Bereavement Training in the Intellectual and Developmental Disabilities Field. AB - The Delphi technique was used to obtain expert panel consensus to prioritize content areas and delivery methods for developing staff grief and bereavement curriculum training in the intellectual and developmental disabilities (IDD) field. The Delphi technique was conducted with a panel of 18 experts from formal and informal disability caregiving, nursing, and hospice and bereavement service provision. Results showed that training should help staff identify and support service users experiencing grief. Importantly, staff also needs help in managing their own grief. Organizational policies and resources should be instituted to support the grief processes of both service users and staff. Practice-based applications are discussed, and research implications are presented for training evaluation. PMID- 26618740 TI - Editor's Commentary: Looking Forward Glancing Back: Reflections on the National Goals Meeting. PMID- 26618741 TI - Honor the Past. Then Get Over It. AB - This speech was presented at a conference, the National Goals in Research, Policy, and Practice, held in Washington, DC, on August 6-7, 2015. The conference was a working meeting to summarize the current state of knowledge and identify a platform of national goals in research, practice, and policy in intellectual and developmental disabilities. The meeting was jointly organized by the Research and Training Center on Community Living, Institute on Community Integration, University of Minnesota; Rehabilitation Research and Training Center on Developmental Disabilities and Health, Institute on Disability and Human Development, University of Illinois Chicago; Rehabilitation Research and Training Center on Advancing Employment for Individuals with Intellectual and Developmental Disabilities, Institute for Community Inclusion, University of Massachusetts Boston; The Arc of the United States; Association of University Centers on Disabilities (AUCD); and American Association on Intellectual and Developmental Disabilities (AAIDD), with the support of National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR). PMID- 26618742 TI - The Learning of Difficult Visual Discriminations by the Moderately and Severely Retarded. AB - A procedure to effectively and efficiently train moderately and severely retarded individuals to make fine visual discriminations is described. Results suggest that expectancies for such individuals are in need of examination. Implications for sheltered workshops, work activity centers and classrooms are discussed. PMID- 26618743 TI - Poverty, Intelligence and Life in the Inner City. PMID- 26618744 TI - Issue at Point: The Dark Side of the Mirror. PMID- 26618745 TI - Presidential Address, 2015--Making a Difference Through Research, Practice, and Policy. PMID- 26618748 TI - On the Assessment of Paramedic Competence: A Narrative Review with Practice Implications. AB - INTRODUCTION: Paramedicine is experiencing significant growth in scope of practice, autonomy, and role in the health care system. Despite clinical governance models, the degree to which paramedicine ultimately can be safe and effective will be dependent on the individuals the profession deems suited to practice. This creates an imperative for those responsible for these decisions to ensure that assessments of paramedic competence are indeed accurate, trustworthy, and defensible. PURPOSE: The purpose of this study was to explore and synthesize relevant theoretical foundations and literature informing best practices in performance-based assessment (PBA) of competence, as it might be applied to paramedicine, for design or evaluation of assessment programs. METHODS: A narrative review methodology was applied to focus intentionally, but broadly, on purpose relevant, theoretically derived research that could inform assessment protocols in paramedicine. Primary and secondary studies from a number of health professions that contributed to and informed best practices related to the assessment of paramedic clinical competence were included and synthesized. RESULTS: Multiple conceptual frameworks, psychometric requirements, and emerging lines of research are forwarded. Seventeen practice implications are derived to promote understanding as well as best practices and evaluation criteria for educators, employers, and/or licensing/certifying bodies when considering the assessment of paramedic competence. CONCLUSIONS: The assessment of paramedic competence is a complex process requiring an understanding, appreciation for, and integration of conceptual and psychometric principles. The field of PBA is advancing rapidly with numerous opportunities for research. PMID- 26618749 TI - Ectopic hbox12 Expression Evoked by Histone Deacetylase Inhibition Disrupts Axial Specification of the Sea Urchin Embryo. AB - Dorsal/ventral patterning of the sea urchin embryo depends upon the establishment of a Nodal-expressing ventral organizer. Recently, we showed that spatial positioning of this organizer relies on the dorsal-specific transcription of the Hbox12 repressor. Building on these findings, we determined the influence of the epigenetic milieu on the expression of hbox12 and nodal genes. We find that Trichostatin-A, a potent and selective histone-deacetylases inhibitor, induces histone hyperacetylation in hbox12 chromatin, evoking broad ectopic expression of the gene. Transcription of nodal concomitantly drops, prejudicing dorsal/ventral polarity of the resulting larvae. Remarkably, impairing hbox12 function, either in a spatially-restricted sector or in the whole embryo, specifically rescues nodal transcription in Trichostatin-A-treated larvae. Beyond strengthen the notion that nodal expression is not allowed in the presence of functional Hbox12 in the same cells, these results highlight a critical role of histone deacetylases in regulating the spatial expression of hbox12. PMID- 26618751 TI - On the Control of the Fixed Charge Densities in Al2O3-Based Silicon Surface Passivation Schemes. AB - A controlled field-effect passivation by a well-defined density of fixed charges is crucial for modern solar cell surface passivation schemes. Al2O3 nanolayers grown by atomic layer deposition contain negative fixed charges. Electrical measurements on slant-etched layers reveal that these charges are located within a 1 nm distance to the interface with the Si substrate. When inserting additional interface layers, the fixed charge density can be continuously adjusted from 3.5 * 10(12) cm(-2) (negative polarity) to 0.0 and up to 4.0 * 10(12) cm(-2) (positive polarity). A HfO2 interface layer of one or more monolayers reduces the negative fixed charges in Al2O3 to zero. The role of HfO2 is described as an inert spacer controlling the distance between Al2O3 and the Si substrate. It is suggested that this spacer alters the nonstoichiometric initial Al2O3 growth regime, which is responsible for the charge formation. On the basis of this charge-free HfO2/Al2O3 stack, negative or positive fixed charges can be formed by introducing additional thin Al2O3 or SiO2 layers between the Si substrate and this HfO2/Al2O3 capping layer. All stacks provide very good passivation of the silicon surface. The measured effective carrier lifetimes are between 1 and 30 ms. This charge control in Al2O3 nanolayers allows the construction of zero-fixed charge passivation layers as well as layers with tailored fixed charge densities for future solar cell concepts and other field-effect based devices. PMID- 26618750 TI - Orthotopic transplantation of a tissue engineered diaphragm in rats. AB - The currently available surgical options to repair the diaphragm are associated with significant risks of defect recurrence, lack of growth potential and restored functionality. A tissue engineered diaphragm has the potential to improve surgical outcomes for patients with congenital or acquired disorders. Here we show that decellularized diaphragmatic tissue reseeded with bone marrow mesenchymal stromal cells (BM-MSCs) facilitates in situ regeneration of functional tissue. A novel bioreactor, using simultaneous perfusion and agitation, was used to rapidly decellularize rat diaphragms. The scaffolds retained architecture and mechanical properties and supported cell adhesion, proliferation and differentiation. Biocompatibility was further confirmed in vitro and in vivo. We replaced 80% of the left hemidiaphragm with reseeded diaphragmatic scaffolds. After three weeks, transplanted animals gained 32% weight, showed myography, spirometry parameters, and histological evaluations similar to native rats. In conclusion, our study suggested that reseeded decellularized diaphragmatic tissue appears to be a promising option for patients in need of diaphragmatic reconstruction. PMID- 26618752 TI - Sustainability Council of New Zealand Trust v. The Environmental Protection Authority: Gene editing technologies and the law. AB - In May 2014, a New Zealand court rendered the first judicial opinion in the world about the legal classification of gene-editing techniques. The court ruled that ZFN-1 and TALEs are techniques of genetic modification and thus within the New Zealand statute and regulations governing genetically modified organisms. This article explains the facts of this legal matter, the reasoning of the court, and provides commentary about the implications of this decision for New Zealand and other jurisdictions around the world. PMID- 26618754 TI - Mechanistic studies of the reactions of the reduced vitamin B12 derivatives with the HNO donor Piloty's acid: further evidence for oxidation of cob(I)alamin by (H)NO. AB - There is accumulating evidence for the existence of HNO in biological systems. Compared with NO (NO), much less is known about the chemical and biochemical reactivity of HNO. Kinetic and mechanistic studies have been carried out on the reaction between the vitamin B12-derived radical complex cob(II)alamin (Cbl(II), Cbl(II)) with the widely used HNO donor Piloty's acid (PA). A stoichiometry of 1 : 2 Cbl(II) : PA was obtained and PA decomposition to HNO and benzenesulfinate (C6H5SO2(-)) is the rate-determining step. No evidence was found for nitrite (Griess assay), ammonia (Nessler's test) or NH2OH (indooxine test) in the product solution, and it is likely that HNO is instead reduced to N2. A mechanism is proposed in which reduction of Cbl(II) by (H)NO results in formation of cob(I)alamin (Cbl(I)(-)) and NO. The Cbl(I)(-) intermediate is subsequently oxidized back to Cbl(II) by a second (H)NO molecule, and Cbl(II) reacts rapidly with NO to form nitroxylcobalamin (NOCbl). Separate studies on the reaction between Cbl(I)(-) and PA shows that this system involves an additional step in which Cbl(I)(-) is first oxidized by (H)NO to Cbl(II), which reacts further with (H)NO to form NOCbl, with an overall stoichiometry of 1 : 3 Cbl(I)(-) : PA. Experiments in the presence of nitrite for both systems support the involvement of a Cbl(I)(-) intermediate in the Cbl(II)/PA reaction. These systems provide the second example of oxidation of cob(I)alamin by (H)NO. PMID- 26618756 TI - The role of hyperthermia as a treatment for non-muscle invasive bladder cancer. AB - Non-muscle invasive bladder cancer (NMIBC) has a high tendency for recurrence and progression. Currently, all known intravesical agents are associated with adverse effects (AEs) and limited efficacy. The combination of hyperthermia (HT) with intravesical Mitomycin C (MMC) chemotherapy has been shown to improve outcomes. The added efficacy of HT to MMC was first shown in preclinical studies. The reports on patients with NMIBC have indicated that the treatment is safe and well tolerated. Several clinical studies reported the efficacy of radiofrequency induced chemotherapy effect (RITE) in the treatment of patients with NMIBC. This modality was shown to be superior to MMC alone. RITE was effective also in patients with high-risk NMIBC, including those who failed Bacillus Calmette Guerin (BCG). This study provides an updated review of literature regarding the use of RITE in patients with NMIBC. PMID- 26618755 TI - Modulation of Immune Response Using Engineered Nanoparticle Surfaces. AB - Nanoparticles (NPs) coated with a monolayer of ligands can be recognized by different components of the immune system, opening new doors for the modulation of immunological responses. By the use of different physical or chemical properties at the NP surface (such as charge, functional groups, and ligand density), NPs can be designed to have distinct cellular uptake, cytokine secretion, and immunogenicity, factors that influence the distribution and clearance of these particles. Understanding these immunological responses is critical for the development of new NP-based carriers for the delivery of therapeutic molecules, and as such several studies have been performed to understand the relationships between immune responses and NP surface functionality. In this review, we will discuss recent reports of these structure activity relationships, and explore how these motifs can be controlled to elicit therapeutically useful immune responses. PMID- 26618757 TI - Highlights for the cytology community from the 2015 American Thyroid Association clinical guidelines on the management of thyroid nodules and well-differentiated thyroid cancer. PMID- 26618758 TI - NAD-dependent dehydrogenase bioelectrocatalysis: the ability of a naphthoquinone redox polymer to regenerate NAD. AB - Electron mediation between NAD-dependent enzymes using quinone moieties typically requires the use of a diaphorase as an intermediary enzyme. The ability for a naphthoquinone redox polymer to independently oxidize enzymatically-generated NADH is demonstrated for application to glucose/O2 enzymatic fuel cells. PMID- 26618760 TI - [Anatomy of the Thalamus]. AB - The thalamus is a vital structure lying deep within the brain that has several important functions, such as sensory and motor function, attention, memory, speech, and emotion. Various thalamic nuclei with extensive nerve networks send signals all around the structures of the brain including the cerebral cortex. Thalamic lesions cause a wide variety of clinical symptoms; therefore, anatomical knowledge of the thalamus is important in clinical situations. In this paper, structure of the thalamus is outlined, sprinkled with examples of clinical cases. PMID- 26618759 TI - Pathology and Epidemiology of Ceruminous Gland Tumors among Endangered Santa Catalina Island Foxes (Urocyon littoralis catalinae) in the Channel Islands, USA. AB - In this study, we examined the prevalence, pathology, and epidemiology of tumors in free-ranging island foxes occurring on three islands in the California Channel Islands, USA. We found a remarkably high prevalence of ceruminous gland tumors in endangered foxes (Urocyon littoralis catalinae) occurring on Santa Catalina Island (SCA)--48.9% of the dead foxes examined from 2001-2008 had tumors in their ears, and tumors were found in 52.2% of randomly-selected mature (>= 4 years) foxes captured in 2007-2008, representing one of the highest prevalences of tumors ever documented in a wildlife population. In contrast, no tumors were detected in foxes from San Nicolas Island or San Clemente Island, although ear mites (Otodectes cynotis), a predisposing factor for ceruminous gland tumors in dogs and cats, were highly prevalent on all three islands. On SCA, otitis externa secondary to ear mite infection was highly correlated with ceruminous gland hyperplasia (CGH), and tumors were significantly associated with the severity of CGH, ceruminous gland dysplasia, and age group (older foxes). We propose a conceptual model for the formation of ceruminous gland tumors in foxes on SCA that is based on persistent, ubiquitous infection with ear mites, and an innate, over exuberant inflammatory and hyperplastic response of SCA foxes to these mites. Foxes on SCA are now opportunistically treated with acaricides in an attempt to reduce mite infections and the morbidity and mortality associated with this highly prevalent tumor. PMID- 26618761 TI - [Thalamus and Attention]. AB - Attention is the process by which information and selection occurs, the thalamus plays an important role in the selective attention of visual and auditory information. Selective attention is a conscious effort; however, it occurs subconsciously, as well. The lateral geniculate body (LGB) filters visual information before it reaches the cortex (bottom-up attention). The thalamic reticular nucleus (TRN) provides a strong inhibitory input to both the LGB and pulvinar. This regulation involves focusing a spotlight on important information, as well as inhibiting unnecessary background information. Behavioral contexts more strongly modulate activity of the TRN and pulvinar influencing feedforward and feedback information transmission between the frontal, temporal, parietal and occipital cortical areas (top-down attention). The medial geniculate body (MGB) filters auditory information the TRN inhibits the MGB. Attentional modulation occurring in the auditory pathway among the cochlea, cochlear nucleus, superior olivary complex, and inferior colliculus is more important than that of the MGB and TRN. We also discuss the attentional consequence of thalamic hemorrhage. PMID- 26618762 TI - [Neuroanatomical Networks Supporting Memory and Their Relation to Amnesia; a View from the Thalamus]. AB - The anterior and mediodorsal thalamic nuclei form neuroanatomical networks supporting memory along with the mammillary body, medial temporal structures, prefrontal cortices and posterior cingulate cortex. In this review article, we discuss human diencephalic amnesic syndromes, including Wernicke-Korsakoff syndrome and amnesia associated with thalamic infarcts, and animal neuropsychological studies from a neuroanatomical network perspective. In addition, we suggest future research directions for understanding the functional roles of the anterior and mediodorsal thalamic nuclei in memory function based on findings from recent animal studies. PMID- 26618763 TI - [Dominant Thalamus and Aphasia]. AB - Many studies have shown that lesions of the dominant thalamus precipitate language disorders in a similar manner to transcortical aphasias, in a phenomenon known as "thalamic aphasia." In some cases, however, aphasia may not occur or may appear transiently following thalamic lesions. Furthermore, dominant thalamic lesions can produce changes in character, as observed in patients with amnesic disorder. Previous work has explored the utility of thalamic aphasia as a discriminative feature for classification of aphasia. Although the thalamus may be involved in the function of the brainstem reticular activating system and play a role in attentional network and in memory of Papez circuit or Yakovlev circuit, the mechanism by which thalamic lesion leads to the emergence of aphasic disorders is unclear. In this review, we we survey historical and recent literature on thalamic aphasia in an attempt to understand the neural processes affected by thalamic lesions. PMID- 26618764 TI - [Thalamus and Emotion]. AB - The basolateral limbic circuit (mediodorsal thalamic nucleus, anterior cingulated and prefrontal orbital cortex, anterior temporal cortex, and amygdala), the mediodorsal thalamic nucleus circuit, and part of the frontal-subcortical circuits (anterior cingulate and prefrontal orbital cortex, caudate nucleus and nucleus accumbens, globus pallidus, and mediodorsal thalamic nucleus), and the anterior cingulate and prefrontal orbital cortex circuit are crucial systems for forming and expressing emotions. There are reciprocal projections between the hypothalamus, anterior cingulate cortex and prefrontal orbital cortex, and between the hypothalamus and the amygdale. Therefore, destruction of the mediodorsal thalamic nucleus and the hypothalamus can cause abnormal expression of emotions. Recently, converging evidence suggests that the pulvinar nucleus in the posterior thalamus mediates emotional visual information processing through the colliculo-pulvino-amygdalar pathway and/or through the colliculo-pulvino cortical pathways. These pathways seem to contribute to the unconscious and/or conscious fast processing of ecologically relevant stimuli. Therefore, destruction of the pulvinar can cause impaired reaction to visual threats, such as photographs of a cockroach and fearfull facial expressions, if the stimuli are exposed briefly. PMID- 26618765 TI - [Vitamin E and Alzheimer's Disease]. AB - It has been suggested that oxidative stress may contribute to the pathogenesis of Alzheimer's disease. Vitamin E is a potent antioxidant, and the results of some epidemiological studies have suggested that high intake of vitamin E through food is inversely associated with the incidence of Alzheimer's disease. Randomized controlled studies have shown that treatment with vitamin E could delay functional decline in patients with mild to moderate Alzheimer's disease. However, vitamin E had no cognitive benefits in patients with mild cognitive impairment or in generally healthy older women. Well-designed clinical trials or preventive interventions with vitamin E are necessary to establish its efficacy as therapeutic or preventive agents for Alzheimer's disease. PMID- 26618766 TI - [Sporadic Late-Onset Nemaline Myopathy Associated with MGUS]. AB - Sporadic late-onset nemaline myopathy is an uncommon disease. Clinically, it is characterized by progressive muscle weakness that can develop in limbs or axial muscles. Asymmetrical distal weakness, facial weakness, dropped head, and dysphagia can also occur. Since the serum creatine kinase level usually remains within the normal range, patients can be misdiagnosed with motor neuron disease. Recognition of nemaline rods on muscle biopsy is crucial for accurate diagnosis. If it is associated with monoclonal gammopathy of undetermined significance, the outcome is known to be unfavorable. In spite of various immunotherapies such as corticosteroids, immunosuppressants, and plasmapheresis, most patients die of respiratory failure within 5 years. Since the efficacy of autologous stem cell transplantation following high-dose melphalan was first reported in 2008, there have been accumulating reports that showed the positive effect of this therapy for the disease. PMID- 26618767 TI - [Role of Heat Shock Protein 70 in Retinitis Pigmentosa and a Novel Strategy for Treatment]. AB - Retinitis pigmentosa (RP) is a group of inherited disorders involving the photoreceptors of the retina and can lead to visual loss. There has been tremendous progress in the delineation of the biochemical and molecular basis of RP. Reactive oxygen species, calcium-calpain activation, and lipid peroxidation are known to be involved in the initiation of photoreceptor cell death, but the precise mechanisms of this process remain unknown. Heat shock protein 70 (HSP70) has been shown to function as a chaperone molecule that protects cells against environmental and physiological stresses. However, there are a few reports showing the role of HSP70 in photoreceptor cell death. Recently, we found that the production of 4-hydroxy-2-noneral caused the calpain-dependent cleavage of carbonylated HSP70 prior to photoreceptor cell death in RP model mice. Furthermore, HSP70 inducers, such as valproic acid and geranylgeranylacetone attenuated photoreceptor cell death. HSP70 inducers may be considered as candidate therapeutic agents for RP. PMID- 26618768 TI - [Skin Biopsy is a Useful Tool for the Diagnosis of Atypical CADASIL: A Case Report]. AB - A 57-year-old man developed migraine at the age of 25 years. Thereafter, he developed depression at the age of 50 years, and was admitted to a psychiatric hospital at the age of 54 years because of deteriorating depression. He returned to his work after receiving treatment for depression; however, he made mistakes several times in his work. He was referred to our hospital for further neurological evaluation. The results of the neurological examination performed on admission were unremarkable. His Mini Mental State Examination (MMSE) score was 24/30, and neuropsycological evaluations revealed executive dysfunction. There was no family history of dementia or cerebral infarction. Magnetic resonance fluid attenuated inversion recovery (MR FLAIR) image of the brain showed hyperintense lesions around the lateral ventricle without involvement in the temporal pole and external capsule. Despite a lack of family history of dementia and cerebral infarction and non-specific brain MRI findings, his history of headache and depression were suggestive of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Therefore, skin biopsy was performed; electron microscopy of the biopsied sample revealed granular osmiophilic material deposits. Genetic analysis of the NOTCH3 gene showed a missense mutation with substitution of R427C in exon 8, i.e., out of the hot-spot, exon 3, and 4. Thus, skin biopsy is a useful tool for diagnosing atypical CADASIL. PMID- 26618769 TI - The Untapped Potential of Pharmacy Leaflets for Informing Patients About Drug Benefits and Risks. PMID- 26618770 TI - Comparisons of prevalence and related factors of depression in middle-aged adults between urban and rural populations in Japan. AB - BACKGROUND: Findings of urban-rural differences in the prevalence of depression have been controversial, and few reports have directly compared the related factors of depression between urban and rural areas. The present study aimed to investigate differences between urban and rural areas in Japan with regards to the prevalence of and related factors of depression in middle-aged adults, in order to further understanding of the features of depression in this demographic. METHODS: We used a multistage, random sampling procedure and mailing method. In total, 5000 participants were recruited from urban and rural areas in Kumamoto Prefecture (2500 in each area). Participants were aged from 40 to 64 years. Depression was assessed using the Center for Epidemiologic Studies Depression scale (CES-D). RESULTS: The prevalence of middle-aged depression was not different between the urban and rural areas. Logistic regression analysis found that being female, living alone, and having a chronic illness were significantly associated with depression in urban-dwelling middle-aged adults. Younger age, sleep disturbance, and financial strain were significantly associated with depression in both urban and rural areas. LIMITATIONS: The definition of depression was based on CES-D scores, without corroborating clinical evaluation. CONCLUSIONS: We found no marked differences in the prevalence of middle-aged depression between the urban and rural areas. Some related factors of depression in middle-aged adults differed between urban and rural areas in Japan. Effective intervention programs for middle-aged adults with depression should consider regional differences. PMID- 26618772 TI - miR-143 suppresses epithelial-mesenchymal transition and inhibits tumor growth of breast cancer through down-regulation of ERK5. AB - Epithelial-mesenchymal transition (EMT) plays a pivotal role in the development of cancer invasion and metastasis. Many studies have significantly enhanced the knowledge on EMT through the characterization of microRNAs (miRNAs) influencing the signaling pathways and downstream events that define EMT on a molecular level. In this study, we found that miR-143 suppressed EMT. Up-regulating miR-143 enhanced E-cadherin-mediated cell-cell adhesion ability, reduced mesenchymal markers, and decreased cell proliferation, migration, and invasion in vitro. In vivo, the xenograft mouse model also unveiled the suppressive effects of miR-143 on tumor growth. Additionally, we demonstrated that up-regulating extracellular signal regulated kinase 5 (ERK5) was associated with poor prognosis of breast cancer patients. Moreover, we observed an inverse correlation between miR-143 and ERK5 in breast cancer tissues. miR-143 directly targeted seed sequences in the 3' untranslated regions of ERK5. Furthermore, we revealed that the downstream molecules of glycogen synthase kinase 3 beta (GSK-3beta)/Snail signaling were involved in EMT and modulated by ERK5. In summary, our findings demonstrated that miR-143 down-regulated its target ERK5, leading to the suppression of EMT induced by GSK-3beta/Snail signaling of breast cancer. (c) 2015 Wiley Periodicals, Inc. PMID- 26618771 TI - Air Pollution, Cardiovascular Outcomes, and Social Disadvantage: The Multi-ethnic Study of Atherosclerosis. AB - BACKGROUND: Social factors may enhance health effects of air pollution, yet empirical support is inconsistent. The interaction of social and environmental factors may only be evident with long-term exposures and outcomes that reflect long-term disease development. METHODS: We used cardiac magnetic resonance imaging data from the Multi-Ethnic Study of Atherosclerosis to assess left ventricular mass index (LVMI) and left-ventricular ejection fraction (LVEF). We assigned residential concentrations of fine particulate matter (PM2.5), oxides of nitrogen, and nitrogen dioxide in the year 2000 to each participant in 2000 using prediction models. We examined modifying roles of four measures of adversity: race/ethnicity, racial/ethnic residential segregation, and socioeconomic status and psychosocial adversity as composite indices on the association between air pollution and LVMI or LVEF. RESULTS: Compared with whites, blacks showed a stronger adjusted association between air pollution and LVMI. For example, for each 5 ug/m greater PM2.5 level, whites showed a 1.0 g/m greater LVMI (95% confidence interval = -1.3, 3.1), while blacks showed an additional 4.0 g/m greater LVMI (95% confidence interval = 0.3, 8.2). Results were similar for oxides of nitrogen and nitrogen dioxide with regard to black race and LVMI. However, we found no evidence of a modifying role of other social factors or ethnic groups. Furthermore, we found no evidence of a modifying role for any social factors or racial/ethnic groups on the association between air pollution and LVEF. CONCLUSIONS: Our results suggest that racial group membership may modify the association between air pollution and cardiovascular disease. PMID- 26618773 TI - Micromechanical measurements of the effect of surfactants on cyclopentane hydrate shell properties. AB - Investigating the effect of surfactants on clathrate hydrate growth and morphology, especially particle shell strength and cohesion force, is critical to advancing new strategies to mitigate hydrate plug formation. In this study, dodecylbenzenesulfonic acid and polysorbate 80 surfactants were included during the growth of cyclopentane hydrates at several concentrations above and below the critical micelle concentration. A novel micromechanical method was applied to determine the force required to puncture the hydrate shell using a glass cantilever (with and without surfactants), with annealing times ranging from immediately after the hydrate nucleated to 90 minutes after formation. It was shown that the puncture force was decreased by the addition of both surfactants up to a maximum of 79%. Over the entire range of annealing times (0-90 minutes), the thickness of the hydrate shell was also measured. However, there was no clear change in shell thickness with the addition of surfactants. The growth rate of the hydrate shell was found to vary less than 15% with the addition of surfactants. The cohesive force between two hydrate particles was measured for each surfactant and found to be reduced by 28% to 78%. Interfacial tension measurements were also performed. Based on these results, microscopic changes to the hydrate shell morphology (due to the presence of surfactants) were proposed to cause the decrease in the force required to break the hydrate shell, since no macroscopic morphology changes were observed. Understanding the hydrate shell strength can be critical to reducing the capillary bridge interaction between hydrate particles or controlling the release of unconverted water from the interior of the hydrate particle, which can cause rapid hydrate conversion. PMID- 26618774 TI - A Prospective Study of Fatty Liver Index and Incident Hypertension: The KoGES ARIRANG Study. AB - BACKGROUND: Although non-alcoholic fatty liver disease is the hepatic manifestation of metabolic syndrome, its influence on hypertension development is poorly understood. We investigated whether fatty liver disease, as assessed by the fatty liver index, could predict the development of hypertension independently of systemic insulin resistance, inflammatory status and adipokine levels. METHODS: Prospective cohort study of 1,521 adults (484 men and 1037 women) aged 40 to 70 years without baseline hypertension examined. An equation was used to calculate fatty liver index and classify patients as follows: fatty liver index <30, no non-alcoholic fatty liver disease; fatty liver index >= 60, non-alcoholic fatty liver disease; and 30 <= fatty liver index <60, intermediate fatty liver index. RESULTS: During an average of 2.6 years of follow-up, 153 subjects (10.06%) developed hypertension. Fatty liver index was positively associated with baseline blood pressure, homeostasis model assessment of insulin resistance, urinary albumin/creatinine excretion, and high sensitivity C-reactive protein. After adjustment for confounding factors, including markers of insulin resistance, systemic inflammation and adiponectin levels, the odds ratio [95% confidence interval] for the incident hypertension increased in a graded manner with fatty liver index (<30 vs. 30-59 vs. >= 60 = 1 vs. 1.83 [1.16~2.88] vs. 2.09 [1.08~4.055], respectively). CONCLUSIONS: Non-alcoholic fatty liver disease assessed by fatty liver index was an independent risk factor for hypertension. Our findings suggest that fatty liver index, a simple surrogate indicator of fatty liver disease, might be useful for identifying subjects at high risk for incident hypertension in clinical practice. PMID- 26618775 TI - The Complete Moss Mitochondrial Genome in the Angiosperm Amborella Is a Chimera Derived from Two Moss Whole-Genome Transfers. AB - Sequencing of the 4-Mb mitochondrial genome of the angiosperm Amborella trichopoda has shown that it contains unprecedented amounts of foreign mitochondrial DNA, including four blocks of sequences that together correspond almost perfectly to one entire moss mitochondrial genome. This implies whole genome transfer from a single moss donor but conflicts with phylogenetic results from an earlier, PCR-based study that suggested three different moss donors to Amborella. To resolve this conflict, we conducted an expanded set of phylogenetic analyses with respect to both moss lineages and mitochondrial loci. The moss DNA in Amborella was consistently placed in either of two positions, depending on the locus analyzed, as sister to the Ptychomniales or within the Hookeriales. This agrees with two of the three previously suggested donors, whereas the third is no longer supported. These results, combined with synteny analyses and other considerations, lead us to favor a model involving two successive moss-to Amborella whole-genome transfers, followed by recombination that produced a single intact and chimeric moss mitochondrial genome integrated in the Amborella mitochondrial genome. Eight subsequent recombination events account for the state of fragmentation, rearrangement, duplication, and deletion of this chimeric moss mitochondrial genome as it currently exists in Amborella. Five of these events are associated with short-to-intermediate sized repeats. Two of the five probably occurred by reciprocal homologous recombination, whereas the other three probably occurred in a non-reciprocal manner via microhomology-mediated break-induced replication (MMBIR). These findings reinforce and extend recent evidence for an important role of MMBIR in plant mitochondrial DNA evolution. PMID- 26618776 TI - Conditional Reduction of Predation Risk Associated with a Facultative Symbiont in an Insect. AB - Symbionts are widespread among eukaryotes and their impacts on the ecology and evolution of their hosts are meaningful. Most insects harbour obligate and facultative symbiotic bacteria that can influence their phenotype. In the pea aphid Acyrthosiphon pisum, an astounding symbiotic-mediated phenotype has been recently observed: when infected with the symbiotic bacteria Rickettsiella viridis, young red aphid larvae become greener at adulthood and even darker green when co-infected with Rickettsiella viridis and Hamiltonella defensa. As body colour affects the susceptibility towards natural enemies in aphids, the influence of the colour change due to these facultative symbionts on the host survival in presence of predators was tested. Our results suggested that the Rickettsiella viridis infection may impact positively host survival by reducing predation risk. Due to results from uninfected aphids (i.e., more green ones attacked), the main assumption is that this symbiotic infection would deter the predatory ladybird feeding by reducing the profitability of their hosts rather than decreasing host detection through body colour change. Aphids co-infected with Rickettsiella viridis and Hamiltonella defensa were, however, more exposed to predation suggesting an ecological cost associated with multiple infections. The underlying mechanisms and ecological consequences of these symbiotic effects are discussed. PMID- 26618777 TI - Functional Dissection of the Nascent Polypeptide-Associated Complex in Saccharomyces cerevisiae. AB - Both the yeast nascent polypeptide-associated complex (NAC) and the Hsp40/70 based chaperone system RAC-Ssb are systems tethered to the ribosome to assist cotranslational processes such as folding of nascent polypeptides. While loss of NAC does not cause phenotypic changes in yeast, the simultaneous deletion of genes coding for NAC and the chaperone Ssb (nacDeltassbDelta) leads to strongly aggravated defects compared to cells lacking only Ssb, including impaired growth on plates containing L-canavanine or hygromycin B, aggregation of newly synthesized proteins and a reduced translational activity due to ribosome biogenesis defects. In this study, we dissected the functional properties of the individual NAC-subunits (alpha-NAC, beta-NAC and beta'-NAC) and of different NAC heterodimers found in yeast (alphabeta-NAC and alphabeta'-NAC) by analyzing their capability to complement the pleiotropic phenotype of nacDeltassbDelta cells. We show that the abundant heterodimer alphabeta-NAC but not its paralogue alphabeta' NAC is able to suppress all phenotypic defects of nacDeltassbDelta cells including global protein aggregation as well as translation and growth deficiencies. This suggests that alphabeta-NAC and alphabeta'-NAC are functionally distinct from each other. The function of alphabeta-NAC strictly depends on its ribosome association and on its high level of expression. Expression of individual beta-NAC, beta'-NAC or alpha-NAC subunits as well as alphabeta'-NAC ameliorated protein aggregation in nacDeltassbDelta cells to different extents while only beta-NAC was able to restore growth defects suggesting chaperoning activities for beta-NAC sufficient to decrease the sensitivity of nacDeltassbDelta cells against L-canavanine or hygromycin B. Interestingly, deletion of the ubiquitin-associated (UBA)-domain of the alpha-NAC subunit strongly enhanced the aggregation preventing activity of alphabeta-NAC pointing to a negative regulatory role of this domain for the NAC chaperone activity in vivo. PMID- 26618778 TI - Multiscale Embedded Gene Co-expression Network Analysis. AB - Gene co-expression network analysis has been shown effective in identifying functional co-expressed gene modules associated with complex human diseases. However, existing techniques to construct co-expression networks require some critical prior information such as predefined number of clusters, numerical thresholds for defining co-expression/interaction, or do not naturally reproduce the hallmarks of complex systems such as the scale-free degree distribution of small-worldness. Previously, a graph filtering technique called Planar Maximally Filtered Graph (PMFG) has been applied to many real-world data sets such as financial stock prices and gene expression to extract meaningful and relevant interactions. However, PMFG is not suitable for large-scale genomic data due to several drawbacks, such as the high computation complexity O(|V|3), the presence of false-positives due to the maximal planarity constraint, and the inadequacy of the clustering framework. Here, we developed a new co-expression network analysis framework called Multiscale Embedded Gene Co-expression Network Analysis (MEGENA) by: i) introducing quality control of co-expression similarities, ii) parallelizing embedded network construction, and iii) developing a novel clustering technique to identify multi-scale clustering structures in Planar Filtered Networks (PFNs). We applied MEGENA to a series of simulated data and the gene expression data in breast carcinoma and lung adenocarcinoma from The Cancer Genome Atlas (TCGA). MEGENA showed improved performance over well-established clustering methods and co-expression network construction approaches. MEGENA revealed not only meaningful multi-scale organizations of co-expressed gene clusters but also novel targets in breast carcinoma and lung adenocarcinoma. PMID- 26618779 TI - Cryptic diversity, high host specificity and reproductive synchronization in army ant-associated Vatesus beetles. AB - Army ants and their arthropod symbionts represent one of the most species-rich animal associations on Earth, and constitute a fascinating example of diverse host-symbiont interaction networks. However, despite decades of research, our knowledge of army ant symbionts remains fragmentary due to taxonomic ambiguity and the inability to study army ants in the laboratory. Here, we present an integrative approach that allows us to reliably determine species boundaries, assess biodiversity, match different developmental stages and sexes, and to study the life cycles of army ant symbionts. This approach is based on a combination of community sampling, DNA barcoding, morphology and physiology. As a test case, we applied this approach to the staphylinid beetle genus Vatesus and its different Eciton army ant host species at La Selva Biological Station, Costa Rica. DNA barcoding led to the discovery of cryptic biodiversity and, in combination with extensive community sampling, revealed strict host partitioning with no overlap in host range. Using DNA barcoding, we were also able to match the larval stages of all focal Vatesus species. In combination with studies of female reproductive physiology, this allowed us to reconstruct almost the complete life cycles of the different beetle species. We show that Vatesus beetles are highly adapted to the symbiosis with army ants, in that their reproduction and larval development are synchronized with the stereotypical reproductive and behavioural cycles of their host colonies. Our approach can now be used to study army ant-symbiont communities more broadly, and to obtain novel insights into co-evolutionary and ecological dynamics in species-rich host-symbiont systems. PMID- 26618781 TI - Pd(OAc)2-Catalyzed, AgOAc-Promoted Z Selective Directed beta-Arylation of Acrylamide Systems and Stereoselective Construction of Z-Cinnamamide Scaffolds. AB - A Pd(OAc)2-catalyzed, AgOAc-promoted and bidentate ligand-directed Z selective C H activation, followed by the beta-arylation of the C(sp(2))-H bond of N (quinolin-8-yl)acrylamide systems with aryl- and heteroaryl iodides, and a contemporary method for the construction of various Z-cinnamamides and beta,beta diarylated acrylamides are reported. A plausible reaction mechanism comprising the bidentate ligand-aided, chelation-based C-H functionalization was proposed for the observed Z selective beta-arylation of N-(quinolin-8-yl)acrylamide systems. PMID- 26618780 TI - Possible pathways linking ploidy level to cell elongation and cuticular function in hypocotyls of dark-grown Arabidopsis seedlings. AB - The mechanisms underlying correlations between ploidy level and cell size in eukaryotes remain unclear. Recently, we showed that cell length was higher in tetraploid than in diploid dark-grown Arabidopsis hypocotyls. Cuticular function was aberrant, and expression of genes of cuticle formation was reduced. Here, the links between cell elongation, cuticular function, and ploidy level in the etiolated hypocotyl were examined. Seedlings defective in cuticle formation exhibited shorter hypocotyls. This was due to inhibition of cell elongation rather than cell proliferation, indicating that the reduced cuticular function was a consequence of tetraploidy-induced cell elongation rather than its cause. Inhibition of hypocotyl elongation by impaired cuticles was lower in tetraploid than diploid, indicating that tetraploid hypocotyls were less sensitive to cuticular damage. PMID- 26618782 TI - Intrauterine fetal demise after prenatal diagnosis of congenital heart disease: assessment of risk. AB - OBJECTIVES: Elective deliveries in fetal congenital heart disease (CHD) attempt to balance fetal and neonatal risk with the goal of optimizing overall outcome. However, the magnitude of the risk for intrauterine fetal demise (IUFD) is unclear. This study aimed to (1) determine the rate of IUFD and (2) identify fetal risk factors associated with IUFD. METHODS: Retrospective review of pregnancies complicated by CHD between 1998 and 2010. Data were collected regarding pregnancy outcome, extracardiac anomalies (ECA), genetic and cardiac diagnoses, severity of valve regurgitation, gestational age at birth and birth weight. Fisher's exact test and odds ratios were used to compare outcomes between groups. RESULTS: A total of 501 pregnancies analyzed resulted in 445 live births, 22 IUFD, 16 terminations and 18 unknown outcomes. Amongst IUFD, 27% had a genetic diagnosis, 50% had an ECA and 27% had severe valve regurgitation. IUFD odds increased threefold with ECA and sevenfold with severe valve regurgitation. IUFD occurred in 1.2% without risk factors. CONCLUSIONS: IUFD in fetuses with CHD is associated with ECA, genetic syndromes and severe valve regurgitation. In absence of these fetal characteristics, the occurrence of IUFD is low, although it remains higher than in fetuses without CHD. PMID- 26618783 TI - Selection during crop diversification involves correlated evolution of the circadian clock and ecophysiological traits in Brassica rapa. AB - Crop selection often leads to dramatic morphological diversification, in which allocation to the harvestable component increases. Shifts in allocation are predicted to impact (as well as rely on) physiological traits; yet, little is known about the evolution of gas exchange and related anatomical features during crop diversification. In Brassica rapa, we tested for physiological differentiation among three crop morphotypes (leaf, turnip, and oilseed) and for correlated evolution of circadian, gas exchange, and phenological traits. We also examined internal and surficial leaf anatomical features and biochemical limits to photosynthesis. Crop types differed in gas exchange; oilseed varieties had higher net carbon assimilation and stomatal conductance relative to vegetable types. Phylogenetically independent contrasts indicated correlated evolution between circadian traits and both gas exchange and biomass accumulation; shifts to shorter circadian period (closer to 24 h) between phylogenetic nodes are associated with higher stomatal conductance, lower photosynthetic rate (when CO2 supply is factored out), and lower biomass accumulation. Crop type differences in gas exchange are also associated with stomatal density, epidermal thickness, numbers of palisade layers, and biochemical limits to photosynthesis. Brassica crop diversification involves correlated evolution of circadian and physiological traits, which is potentially relevant to understanding mechanistic targets for crop improvement. PMID- 26618784 TI - Improved in situ saccharification of cellulose pretreated by dimethyl sulfoxide/ionic liquid using cellulase from a newly isolated Paenibacillus sp. LLZ1. AB - A cellulase producing strain was newly isolated from soil samples and identified as Paenibacillus sp. LLZ1. A novel aqueous-dimethyl sulfoxide (DMSO)/1-ethyl-3 methylimidazolium diethyl phosphate ([Emin]DEP)-cellulase system was designed and optimized. In the pretreatment, DMSO was found to be a low-cost substitute of up to 70% ionic liquid to enhance the cellulose dissolution. In the enzymatic saccharification, the optimum pH and temperature of the Paenibacillus sp. LLZ1 cellulase were identified as 6.0 and 40 degrees C, respectively. Under the optimized reaction condition, the conversion of microcrystalline cellulose and bagasse cellulose increased by 39.3% and 37.6%, compared with unpretreated cellulose. Compared to current methods of saccharification, this new approach has several advantages including lower operating temperature, milder pH, and less usage of ionic liquid, indicating a marked progress in environmental friendly hydrolysis of biomass-based materials. PMID- 26618785 TI - Evaluation of Different Polishing Systems and Speeds for Dental Zirconia. AB - PURPOSE: To evaluate two polishing systems and three polishing speeds on the gloss, roughness, and heat production of yttria stabilized tetragonal zirconia polycrystal (Y-TZP). MATERIALS AND METHODS: A Y-TZP block (Zenostar Zr Translucent) was sectioned into 4-mm-thick sections. Specimens (n = 30 per polishing system) were first wet ground with a fine diamond bur at 200,000 RPM for 15 seconds. The baseline gloss of all specimens was measured in a glossmeter (60 degrees angle) in a direction perpendicular to grinding. Initial surface roughness (Ra ) was determined on an optical profilometer in a direction perpendicular to grinding. The specimens were then polished with either a Dialite ZR Polishing Kit or a CeraMaster Polishing Kit. All grinding and polishing was performed by the same operator calibrated to apply approximately 2 N pressure. The medium grit polisher was used for 30 seconds, repeated for 30 seconds, and then the fine grit polisher was used. After each step, the gloss and roughness of each specimen was remeasured as described previously. Each polishing system was used at 5000, 15,000, and 40,000 RPM (n = 10 for each polish system/speed combination). A group of glazed specimens (n = 10) was evaluated for gloss and roughness as a control. The heat generated for each polishing step was measured with a thermocouple. The gloss and roughness of the specimens were analyzed using a linear mixed model and Tukey-Kramer post-hoc tests. Each step of polishing was compared to the glazed control group with an ANOVA and Dunnett's test. RESULTS: Polishing step, system, and speed were significant (p < 0.05) for gloss and roughness. Examination of system and step interaction was significant for gloss only. Post-hoc analysis revealed that 15,000 RPM produced higher gloss and lower roughness than other speeds. Each progressive step produced an improvement in gloss except for initial 30 seconds with the CeraMaster Coarse (medium polisher; p = 0.34). Roughness was also reduced at each progressive step. No polishing speed/system produced an increase in temperature above 41 degrees C. Both polishing systems were capable of achieving a similar or superior roughness and gloss as the glazed control specimens after the final polishing step at 15,000 RPM. CONCLUSIONS: Fifteen thousand RPM is an optimal polishing speed. Progressing through the polishing sequence significantly improves gloss and roughness and can create similar values as glazed zirconia. PMID- 26618786 TI - The Metabolic Effects of Traditional Chinese Medication Qiliqiangxin on H9C2 Cardiomyocytes. AB - BACKGROUND/AIMS: A traditional Chinese medicine, Qiliqiangxin (QLQX) has been identified to perform protective effects on myocardium energy metabolism in mice with acute myocardial infarction, though the effects of QLQX on myocardial mitochondrial biogenesis under physiological condition is still largely elusive. METHODS: H9C2 cells were treated with different concentrations of QLQX (0.25, 0.5, and 1.0 ug/mL) from 6 to 48 hours. Oxidative metabolism and glycolysis were measured by oxygen consumption and extracellular acidification with XF96 analyzer (SeaHorse). Mitochondrial content and ultrastructure were assessed by Mitotracker staining, confocal microscopy, flow cytometry, and transmission electron microscopy. Mitochondrial biogenesis-related genes were measured by qRT-PCR and Western blot. RESULTS: H9C2 cells treated with QLQX exhibited increased glycolysis at earlier time points (6, 12, and 24 hours), while QLQX could enhance oxidative metabolism and mitochondrial uncoupling in H9C2 cells with longer duration of treatment (48 hours). QLQX also increased mitochondrial content and mitochondrial biogenesis-related gene expression levels, including 16sRNA, SSBP1, TWINKLE, TOP1MT and PLOG, with an activation of peroxisome proliferator-activated receptor coactivator 1 alpha (PGC-1alpha) and its downstream effectors. Silencing PGC-1alpha could abolish the increased mitochondrial content in H9C2 cells treated with QLQX. CONCLUSION: Our study is the first to document enhanced metabolism in cardiomyocytes treated with QLQX, which is linked to increased mitochondrial content and mitochondrial biogenesis via activation of PGC-1alpha. PMID- 26618787 TI - Effect of Immobilized Thiolated Glycosaminoglycans on Fibronectin Adsorption and Behavior of Fibroblasts. AB - Glycosaminoglycans (GAGs) chondroitin sulfate, heparin, hyaluronan, and sulfated hyaluronan are lower and higher thiolated to enable a one-step covalent modification of gold or vinyl-terminated surfaces. Measurements of water contact angle and zeta potentials reveal that sulfated GAG-modified surfaces are more wettable and possess a negative surface potential. Additionally, higher thiolated GAGs (tGAGs) exhibit increased wettability and higher surface roughness. Fibronectin (FN) adsorption increases with sulfation degree of tGAGs. The tGAG functionalized surfaces with higher degree of sulfation promote fibroblast adhesion most under serum-free conditions. The preadsorption of FN allows for more cell adhesion on tGAG surfaces. Metabolic activity measurements show that cell growth is enhanced for tGAGs up to a certain thiolation degree. Overall, thiolation of GAGs does not hamper their bioactivity toward proteins and cells, which make them highly interesting for biomimetic surface modification of implants and tissue engineering scaffolds. PMID- 26618788 TI - Melting barriers to faunal exchange across ocean basins. AB - Accelerated loss of sea ice in the Arctic is opening routes connecting the Atlantic and Pacific Oceans for longer periods each year. These changes may increase the ease and frequency with which marine birds and mammals move between the Pacific and Atlantic Ocean basins. Indeed, recent observations of birds and mammals suggest these movements have intensified in recent decades. Reconnection of the Pacific and Atlantic Ocean basins will present both challenges to marine ecosystem conservation and an unprecedented opportunity to examine the ecological and evolutionary consequences of interoceanic faunal exchange in real time. To understand these changes and implement effective conservation of marine ecosystems, we need to further develop modeling efforts to predict the rate of dispersal and consequences of faunal exchange. These predictions can be tested by closely monitoring wildlife dispersal through the Arctic Ocean and using modern methods to explore the ecological and evolutionary consequences of these movements. PMID- 26618789 TI - Absenteeism and Presenteeism among Care Workers in Swiss Nursing Homes and Their Association with Psychosocial Work Environment: A Multi-Site Cross-Sectional Study. AB - BACKGROUND: Worker productivity is central to the success of organizations such as healthcare institutions. However, both absenteeism and presenteeism impair that productivity. While various hospital studies have examined the prevalence of presenteeism and absenteeism and its associated factors among care workers, evidence from nursing home settings is scarce. OBJECTIVE: To explore care workers' self-reported absenteeism and presenteeism in relation to nursing homes' psychosocial work environment factors. METHODS: We performed a cross-sectional study utilizing survey data of 3,176 professional care workers in 162 Swiss nursing homes collected between May 2012 and April 2013. A generalized estimating equation ordinal logistic regression model was used to explore associations between psychosocial work environment factors (leadership, staffing resources, work stressors, affective organizational commitment, collaboration with colleagues and supervisors, support from other personnel, job satisfaction, job autonomy) and self-reported absenteeism and presenteeism. RESULTS: Absenteeism and presenteeism were observed in 15.6 and 32.9% of care workers, respectively. While absenteeism showed no relationship with the work environment, low presenteeism correlated with high leadership ratings (odds ratio [OR] 1.22, 95% confidence interval [CI] 1.01-1.48) and adequate staffing resources (OR 1.18, 95% CI 1.02-1.38). CONCLUSION: Self-reported presenteeism is more common than absenteeism in Swiss nursing homes, and leadership and staffing resource adequacy are significantly associated with presenteeism, but not with absenteeism. PMID- 26618790 TI - Wearable Keyboard Using Conducting Polymer Electrodes on Textiles. AB - A wearable keyboard is demonstrated in which conducting polymer electrodes on a knitted textile sense tactile input as changes in capacitance. The use of a knitted textile as a substrate endows stretchability and compatibility to large area formats, paving the way for a new type of wearable human-machine interface. PMID- 26618791 TI - The current controversy regarding power morcellation in gynecologic surgery. PMID- 26618792 TI - Structural Insights into the Calcium-Mediated Allosteric Transition in the C Terminal Domain of Calmodulin from Nuclear Magnetic Resonance Measurements. AB - Calmodulin is a two-domain signaling protein that becomes activated upon binding cooperatively two pairs of calcium ions, leading to large-scale conformational changes that expose its binding site. Despite significant advances in understanding the structural biology of calmodulin functions, the mechanistic details of the conformational transition between closed and open states have remained unclear. To investigate this transition, we used a combination of molecular dynamics simulations and nuclear magnetic resonance (NMR) experiments on the Ca(2+)-saturated E140Q C-terminal domain variant. Using chemical shift restraints in replica-averaged metadynamics simulations, we obtained a high resolution structural ensemble consisting of two conformational states and validated such an ensemble against three independent experimental data sets, namely, interproton nuclear Overhauser enhancements, (15)N order parameters, and chemical shift differences between the exchanging states. Through a detailed analysis of this structural ensemble and of the corresponding statistical weights, we characterized a calcium-mediated conformational transition whereby the coordination of Ca(2+) by just one oxygen of the bidentate ligand E140 triggers a concerted movement of the two EF-hands that exposes the target binding site. This analysis provides atomistic insights into a possible Ca(2+)-mediated activation mechanism of calmodulin that cannot be achieved from static structures alone or from ensemble NMR measurements of the transition between conformations. PMID- 26618793 TI - Mediating the distal crime-drug relationship with proximal reactive criminal thinking. AB - This article describes the results of a study designed to test whether reactive criminal thinking (RCT) does a better job of mediating the crime -> drug relationship than it does mediating the drug -> crime relationship after the direct effects of crime on drug use/dependency and of drug use/dependency on crime have been rendered nonsignificant by control variables. All 1,170 male members of the Pathways to Desistance study (Mulvey, 2012) served as participants in the current investigation. As predicted, the total (unmediated) effects of crime on substance use/dependence and of substance use/dependence on crime were nonsignificant when key demographic and third variables were controlled, although the indirect (RCT-mediated) effect of crime on drug use was significant. Proactive criminal thinking (PCT), by comparison, failed to mediate either relationship. The RCT continued to mediate the crime -> drug relationship and the PCT continued to not mediate either relationship when more specific forms of offending (aggressive, income) and substance use/dependence (drug use, substance use dependency symptoms) were analyzed. This offers preliminary support for the notion that even when the total crime-drug effect is nonsignificant the indirect path from crime to reactive criminal thinking to drugs can still be significant. Based on these results, it is concluded that mediation by proximal reactive criminal thinking is a mechanism by which distal measures of crime and drug use/dependence are connected. PMID- 26618794 TI - Cannabis use disorder treatment barriers and facilitators among veterans with PTSD. AB - In light of recent data demonstrating large variability in the diagnosis of cannabis use disorders (CUDs) within the Veterans Affairs Health Care System (VA), it is important to elucidate VA-specific barriers and facilitators to CUD diagnosis and treatment engagement. This issue is particularly salient among veterans with posttraumatic stress disorder (PTSD), given that PTSD is the most common co-occurring psychiatric disorder among veterans with CUD and is associated with poorer treatment outcomes. The goal of the current study was to evaluate the potential role of system-, clinician-, and patient-level factors associated with both CUD diagnosis and treatment engagement. Key personnel were interviewed from PTSD programs with both low and high rates of CUD and substance use disorder (SUD) programs with both low and high rates of SUD treatment engagement. Common themes emerged across clinics that may represent barriers to CUD diagnosis and treatment engagement and included, for example, clinician's concerns about negative consequences associated with CUD diagnosis (e.g., service connection). Potential facilitators to CUD diagnosis and treatment also emerged and included the use of formal assessment approaches when evaluating veterans for SUDs. Together, findings suggest opportunities, such as CUD-specific education and training for clinicians, to improve VA care. PMID- 26618795 TI - Intraindividual covariation between e-cigarette and combustible cigarette use in Korean American emerging adults. AB - Critical gaps exist in understanding the patterns and correlates of dual use of electronic cigarettes (ECs) and combustible cigarettes (CCs), particularly in ethnic minority populations. In this study, we assessed CC and EC use in the naturalistic environment using ecological momentary assessment (EMA). We hypothesized that within-subject variation in EC use (yes/no each day) would be inversely associated with within-subject variation in number of CCs consumed and craving during that same day. We also examined gender and nicotine dependence as moderators of the EC-CC and EC-craving covariations. Korean American emerging adult (KAEA; 18-25 years old) smokers (N = 78) completed 7 days of EMA. Participants completed EMA surveys throughout the day, which assessed CC craving, and end-of-day surveys, which assessed EC use and the number of CCs smoked that day. Generalized linear mixed models were used to predict day-level EC use, with number of CCs smoked and craving during that same day, gender, and nicotine dependence as predictors (n = 501). We found that within-subject variation in CC use was not associated with same-day EC use; neither was within-subject variation in craving (ps > .27). Gender moderated the relationship between craving and EC use on a given day (p = .03); only for females, on the days with higher craving, the likelihood of their EC use that day was significantly heightened. This study does not suggest that EC use is linked with lower CC smoking quantity, at least at the day level and among KAEA smokers. CC craving may play a role in dual EC-CC use for KAEA female smokers. PMID- 26618796 TI - A mixed-methods evaluation of the feasibility, acceptability, and preliminary efficacy of a mobile intervention for methadone maintenance clients. AB - Despite the recent explosion of behavioral health interventions delivered on mobile devices, little is known about factors that make such applications practical, engaging and useful to their target audience. This study reports on the feasibility, acceptability and preliminary efficacy of a prototype of a novel, interactive mobile psychosocial intervention to reduce problematic drug use among clients in methadone maintenance treatment (MMT). A mixed-methods pilot study with new MMT clients (n = 25) indicated that the mobile intervention approach was feasible, and that participants found the intervention highly acceptable and useful. On 100-point visual analog scale (VAS) items, participants reported high levels of liking the program (M = 75.6), and endorsed it as useful (M = 77.5), easy to use (M = 80.7), and containing a significant amount of new information (M = 74.8). When compared with 25 study participants who received standard MMT alone, pilot participants rated their treatment significantly higher in interestingness and usefulness, and were significantly more satisfied with their treatment. In qualitative interviews, participants reported using the mobile intervention in a range of settings, including during times of heightened risk for substance use, and finding it helpful in managing drug cravings. Additionally, pilot participants showed evidence of increased treatment retention and abstinence from illicit opioids (in terms of effect size) over a 3-month period relative to those in standard MMT, suggesting the application's potential to enhance treatment outcomes. These promising findings suggest that an evidence based mobile therapeutic tool addressing substance use may appeal to drug treatment clients and have clinical utility as an adjunct to formal treatment. PMID- 26618797 TI - Exposure to electronic nicotine delivery systems (ENDS) visual imagery increases smoking urge and desire. AB - Use and awareness of electronic nicotine delivery systems (ENDS; also known as electronic cigarettes or e-cigarettes) has increased rapidly in recent years, particularly among young adults. As use of ENDS resembles traditional smoking in both hand-to-mouth movements and inhalation and exhalation behaviors, we determined whether exposure to e-cigarette use via video exposure would act as a cue to elicit urge and desire for a combustible cigarette. Young adult smokers (mean age of 26.3 +/- 4.1 years) were randomized to view a brief video montage of advertisements depicting either e-cigarette vaping (n = 38) or bottled water drinking (n = 40). Pre- and postcue exposure assessments were conducted in a controlled laboratory setting without other smoking or vaping cues present or behaviors allowed. Primary outcomes included change from pre-exposure baseline in smoking urge (Brief Questionnaire of Smoking Urges) and desire for a combustible and e-cigarette (visual analogue scales). Results showed that relative to exposure to the bottled water video, exposure to the ENDS video significantly increased smoking urge (p < .001) as well as desire for a regular cigarette (p < .05) and an e-cigarette (p < .001). These findings provide preliminary evidence that passive exposure to video imagery of ENDS use may generalize as a condition cue and evoke urges for a combustible cigarette in young adult smokers. It remains to be determined whether such increases in urge and desire correspond to increases in actual smoking behavior. PMID- 26618798 TI - The effect of a single HF-rTMS session over the left DLPFC on the physiological stress response as measured by heart rate variability. AB - OBJECTIVE: Previous research has demonstrated that prefrontal activity is related to control over stress responses. However, the causal mechanisms are not well understood. In this study we investigated the possible influence of brain stimulation on the physiological stress response system. Because an increased stress response is known to precipitate psychiatric disorders, further inquiry can have important clinical implications. METHOD: In 38 healthy, right-handed female participants, we examined the effects of a single sham-controlled high frequency (HF) repetitive Transcranial Magnetic Stimulation (rTMS) session over the left (n = 19) and right (n = 19) dorsolateral prefrontal cortex (DLPFC) on the autonomic nervous system stress response, as measured by heart rate variability (HRV). Stress was transiently induced through evaluative negative feedbacks. RESULTS: Although the induction procedure was efficient in increasing self-reported distress in all groups and conditions, only after real HF-rTMS over the left DLPFC the physiological stress response was diminished, as indicated by a significant increase in HRV. No effects were found in the sham or right side stimulation condition. CONCLUSIONS: These findings demonstrate that increasing brain activity by HF-rTMS over the left DLPFC can help attenuating physiological stress reactions. Results are indicative of the positive effects of rTMS on stress resilience and underscore the possible benefit of HF-rTMS as a transdiagnostic intervention. Finally, the results also show that effects only occur when stimulating the left DLPFC, which is in line with the therapeutic effects of HF-rTMS in affective disorders. (PsycINFO Database Record PMID- 26618799 TI - Coping mediates and moderates the relationship between executive functions and psychological adjustment in multiple sclerosis. AB - OBJECTIVE: To identify the moderating and mediating relationship of different coping strategies between executive function and stress, depression and anxiety in people with multiple sclerosis (PwMS). METHOD: Participants were 107 people with relapsing remitting or secondary progressive multiple sclerosis who were administered tasks of executive function and completed self-report measures of stress, depression, anxiety, and coping. RESULTS: An indirect relationship was found between executive function and psychosocial adjustment through maladaptive coping strategies: behavioral and mental disengagement, and substance abuse; adaptive coping strategies: acceptance, active, positive reinterpretation, and growth, as well as for an index of adaptive coping. In general, a relationship was found between better performance on tasks of executive function and psychosocial adjustment when adaptive coping strategies were low, as opposed to high, or maladaptive coping strategies were high, as opposed to low. Some unexpected findings are also discussed. CONCLUSION: Executive function and psychosocial adjustment is mediated and moderated by coping strategies used by PwMS. Well-preserved executive function provides relative protection from poorer adjustment in the presence of high maladaptive or low adaptive coping. PwMS who perform poorly on tasks of executive function benefit from using less cognitively demanding adaptive coping strategies to enhance adjustment outcomes and further research in this area would be advantageous to underpin effective intervention strategies. PMID- 26618800 TI - Inter- and Intramolecular Interactions in Crystalline 2-Nitrobenzoic Acid - An Experimental and Theoretical QTAIM Analysis. AB - We have quantified the inter- and intramolecular interactions in crystalline 2 nitrobenzoic acid from QTAIM analysis of the topology of the electron density distribution obtained from both a low temperature (20 K) X-ray diffraction experiment and from theoretical calculations. The covalent bonds have been characterized by the properties at their (3,-1) bond critical points; in particular the nature of the aromatic/nitro group C-N bond is discussed. All noncovalent bonds of the type O...H (both strong and weak), C...C, O...O, and O...C have also been characterized. Intermolecular interactions may be roughly divided into three types, the formation of a classical carboxylic acid hydrogen bonded dimer, an unusual ribbon of O...O interactions parallel to a, and a number of predominantly O...H interactions perpendicular to a. Integrated atomic charges (in particular for the acidic hydrogen, ~+0.6) and the derived molecular dipole moment are reported. PMID- 26618802 TI - Epitaxial Growth of Thin Ferroelectric Polymer Films on Graphene Layer for Fully Transparent and Flexible Nonvolatile Memory. AB - Enhancing the device performance of organic memory devices while providing high optical transparency and mechanical flexibility requires an optimized combination of functional materials and smart device architecture design. However, it remains a great challenge to realize fully functional transparent and mechanically durable nonvolatile memory because of the limitations of conventional rigid, opaque metal electrodes. Here, we demonstrate ferroelectric nonvolatile memory devices that use graphene electrodes as the epitaxial growth substrate for crystalline poly(vinylidene fluoride-trifluoroethylene) (PVDF-TrFE) polymer. The strong crystallographic interaction between PVDF-TrFE and graphene results in the orientation of the crystals with distinct symmetry, which is favorable for polarization switching upon the electric field. The epitaxial growth of PVDF-TrFE on a graphene layer thus provides excellent ferroelectric performance with high remnant polarization in metal/ferroelectric polymer/metal devices. Furthermore, a fully transparent and flexible array of ferroelectric field effect transistors was successfully realized by adopting transparent poly[bis(4-phenyl)(2,4,6 trimethylphenyl)amine] semiconducting polymer. PMID- 26618801 TI - gamma-H2AX Kinetic Profile in Mouse Lymphocytes Exposed to the Internal Emitters Cesium-137 and Strontium-90. AB - In the event of a dirty bomb scenario or an industrial nuclear accident, a significant dose of volatile radionuclides such as 137Cs and 90Sr may be dispersed into the atmosphere as a component of fallout and inhaled or ingested by hundreds and thousands of people. To study the effects of prolonged exposure to ingested radionuclides, we have performed long-term (30 day) internal-emitter mouse irradiations using soluble-injected 137CsCl and 90SrCl2 radioisotopes. The effect of ionizing radiation on the induction and repair of DNA double strand breaks (DSBs) in peripheral mouse lymphocytes in vivo was determined using the gamma-H2AX biodosimetry marker. Using a serial sacrifice experimental design, whole-body radiation absorbed doses for 137Cs (0 to 10 Gy) and 90Sr (0 to 49 Gy) were delivered over 30 days following exposure to each radionuclide. The committed absorbed doses of the two internal emitters as a function of time post exposure were calculated based on their retention parameters and their derived dose coefficients for each specific sacrifice time. In order to measure the kinetic profile for gamma-H2AX, peripheral blood samples were drawn at 5 specific timed dose points over the 30-day study period and the total gamma-H2AX nuclear fluorescence per lymphocyte was determined using image analysis software. A key finding was that a significant gamma-H2AX signal was observed in vivo several weeks after a single radionuclide exposure. A mechanistically-motivated model was used to analyze the temporal kinetics of gamma-H2AX fluorescence. Exposure to either radionuclide showed two peaks of gamma-H2AX: one within the first week, which may represent the death of mature, differentiated lymphocytes, and the second at approximately three weeks, which may represent the production of new lymphocytes from damaged progenitor cells. The complexity of the observed responses to internal irradiation is likely caused by the interplay between continual production and repair of DNA damage, cell cycle effects and apoptosis. PMID- 26618803 TI - RETINAL ASTROCYTIC HAMARTOMA: Optical Coherence Tomography Classification and Correlation With Tuberous Sclerosis Complex. AB - PURPOSE: To propose a classification of retinal astrocytic hamartoma based on spectral domain optical coherence tomography and correlate each class with systemic manifestations of tuberous sclerosis complex. METHODS: Retrospective chart review conducted at four international referral medical retina centers. There were 43 consecutive patients with an established diagnosis of tuberous sclerosis complex based on presence of at least 2 major or 1 major and 2 minor features of the diagnostic criteria. Clinical and spectral domain optical coherence tomography features regarding retinal astrocytic hamartoma were documented. RESULTS: The mean patient age at presentation was 16.2 years. The retinal astrocytic hamartoma was classified as Type I (n = 41), Type II (n = 25), Type III (n = 20), or Type IV (n = 12). Patients with Type II showed greater number of cutaneous fibrous plaques (odds ratio = 64.8; 92% confidence interval: 64.2-65; P < 0.001); those with Type III displayed higher incidence of subependymal giant-cell astrocytomas (odds ratio = 43.2; 95% confidence interval: 43.0-43.3; P < 0.001); and those with Type IV showed higher incidence of pulmonary lymphangiomyomatosis (odds ratio = 126; 95% confidence interval: 122 128; P < 0.001). CONCLUSION: Retinal astrocytic hamartoma can be classified into four morphologic groups, based on spectral domain optical coherence tomography. There are important systemic tuberous sclerosis complex correlations with each class. PMID- 26618804 TI - Chandelier-Assisted External Subretinal Fluid Drainage in Primary Scleral Buckling for Treatment of Rhegmatogenous Retinal Detachment. PMID- 26618805 TI - VERY EARLY DISEASE MANIFESTATIONS OF MACULAR TELANGIECTASIA TYPE 2. AB - BACKGROUND: To report very early morphologic and functional alterations in patients with macular telangiectasia type 2. METHODS: Patients with asymmetric disease manifestations, in whom retinal alterations characteristic for macular telangiectasia type 2 were present in one but not in the apparently unaffected fellow eye, underwent multimodal imaging and functional testing (microperimetry, visual acuity, reading ability, Amsler test). RESULTS: Fellow eyes not allowing the diagnosis of macular telangiectasia type 2 based on hitherto diagnostic standards consistently showed a severely reduced directional cone reflectance (Stiles-Crawford effect). Optical coherence tomography revealed an asymmetric configuration of the foveal pit with focal temporal thinning most pronounced at 1 degrees eccentricity. Topographically related, macular pigment optical density was reduced in a small wedge-shaped temporal paracentral sector, resulting in an increased signal on fundus autofluorescence and fluorescein angiography imaging. No functional deficits were detectable in fellow eyes. Haidinger brushes were perceived in the fellow eye but not in the affected index eye with pronounced loss of macular pigment. CONCLUSION: Specific morphologic alterations precede vascular alterations and functional deficits in macular telangiectasia type 2. The described alterations indicate a primarily degenerative process with a secondary retinal vascular phenotype, and may be helpful for early identification of patients and affected family members. PMID- 26618806 TI - Are sanitation interventions a threat to drinking water supplies in rural India? An application of tryptophan-like fluorescence. AB - Open defecation is practised by over 600 million people in India and there is a strong political drive to eliminate this through the provision of on-site sanitation in rural areas. However, there are concerns that the subsequent leaching of excreta from subsurface storage could be adversely impacting underlying groundwater resources upon which rural populations are almost completely dependent for domestic water supply. We investigated this link in four villages undergoing sanitary interventions in Bihar State, India. A total of 150 supplies were sampled for thermotolerant (faecal) coliforms (TTC) and tryptophan like fluorescence (TLF): an emerging real-time indicator of faecal contamination. Sanitary risk inspections were also performed at all sites, including whether a supply was located within 10 m of a toilet, the recommended minimum separation. Overall, 18% of water supplies contained TTCs, 91% of which were located within 10 m of a toilet, 58% had TLF above detection limit, and sanitary risk scores were high. Statistical analysis demonstrated TLF was an effective indicator of TTC presence-absence, with a possibility of TTCs only where TLF exceeded 0.4 MUg/L dissolved tryptophan. Analysis also indicated proximity to a toilet was the only significant sanitary risk factor predicting TTC presence-absence and the most significant predictor of TLF. Faecal contamination was considered a result of individual water supply vulnerability rather than indicative of widespread leaching into the aquifer. Therefore, increasing faecal contamination of groundwater-derived potable supplies is inevitable across the country as uptake of on-site sanitation intensifies. Communities need to be aware of this link and implement suitable decentralised low-cost treatment of water prior to consumption and improve the construction and protection of new supplies. PMID- 26618807 TI - Critical review on the stability of illicit drugs in sewers and wastewater samples. AB - Wastewater-based epidemiology (WBE) applies advanced analytical methods to quantify drug residues in wastewater with the aim to estimate illicit drug use at the population level. Transformation processes during transport in sewers (chemical and biological reactors) and storage of wastewater samples before analysis are expected to change concentrations of different drugs to varying degrees. Ignoring transformation for drugs with low to medium stability will lead to an unknown degree of systematic under- or overestimation of drug use, which should be avoided. This review aims to summarize the current knowledge related to the stability of commonly investigated drugs and, furthermore, suggest a more effective approach to future experiments. From over 100 WBE studies, around 50 mentioned the importance of stability and 24 included tests in wastewater. Most focused on in-sample stability (i.e., sample preparation, preservation and storage) and some extrapolated to in-sewer stability (i.e., during transport in real sewers). While consistent results were reported for rather stable compounds (e.g., MDMA and methamphetamine), a varying range of stability under different or similar conditions was observed for other compounds (e.g., cocaine, amphetamine and morphine). Wastewater composition can vary considerably over time, and different conditions prevail in different sewer systems. In summary, this indicates that more systematic studies are needed to: i) cover the range of possible conditions in sewers and ii) compare results more objectively. To facilitate the latter, we propose a set of parameters that should be reported for in-sewer stability experiments. Finally, a best practice of sample collection, preservation, and preparation before analysis is suggested in order to minimize transformation during these steps. PMID- 26618808 TI - A two pathway model for N2O emissions by ammonium oxidizing bacteria supported by the NO/N2O variation. AB - In this work, a new model for nitritation combining two N2O emission pathways was confronted with both NO and N2O measurements during nitrification. The model was calibrated with batch experiments and validated with long-term data collected in a sequencing batch reactor (SBR). A good prediction of the evolution of N2O emissions for a varying level of nitrite was demonstrated. The NO/N2O ratio was shown to vary during nitritation depending on the nitrite level. None of the models based on a single pathway could describe this variation of the NO/N2O ratio. In contrast, the 2 pathway model was capable of describing the trends observed for the NO/N2O ratio and gave better predictions of N2O emission factors. The model confirmed that the decrease of the NO/N2O ratio can be explained by an increase of the ND pathway to the detriment of the NN pathway. The ND pathway was systematically the predominant pathway during nitritation. The combined effect of nitrite (or free nitrous acid) and dissolved oxygen (DO) on the contribution of each pathway was in agreement with practical observations and the literature. PMID- 26618810 TI - The Legal Environment for Precision Medicine. PMID- 26618809 TI - Perceptions of the Pediatric Hospice Experience among English- and Spanish Speaking Families. AB - OBJECTIVE: Many children who die are eligible for hospice enrollment but little is known about parental perceptions of the hospice experience, the benefits, and disappointments. The objective of this study was to explore parental perspectives of the hospice experience in children with cancer, and to explore how race/ethnicity impacts this experience. STUDY DESIGN: We held 20 semistructured interviews with 34 caregivers of children who died of cancer and used hospice. Interviews were conducted in the caregivers' primary language: 12 in English and 8 in Spanish. Interviews were recorded, transcribed, and analyzed using accepted qualitative methods. RESULTS: Both English and Spanish speakers described the importance of honest, direct communication by medical providers, and anxieties surrounding the expectation of the moment of death. Five English-speaking families returned to the hospital because of unsatisfactory symptom management and the need for additional supportive services. Alternatively, Spanish speakers commonly stressed the importance of being at home and did not focus on symptom management. Both groups invoked themes of caregiver appraisal, but English speaking caregivers more commonly discussed themes of financial hardship and fear of insurance loss, while Spanish-speakers focused on difficulties of bedside caregiving and geographic separation from family. CONCLUSIONS: The intense grief associated with the loss of a child creates shared experiences, but Spanish- and English-speaking parents describe their hospice experiences in different ways. Additional studies in pediatric hospice care are warranted to improve the care we provide to children at the end of life. PMID- 26618811 TI - Fitness in Young Adults as an Independent Predictor of Risk for Cardiovascular Disease. PMID- 26618812 TI - Insights into White Matter Damage in Alzheimer's Disease: From Postmortem to in vivo Diffusion Tensor MRI Studies. AB - BACKGROUND: Alzheimer's disease (AD) has traditionally been considered a disease of the gray matter (GM). However, several pathological and neuroimaging studies provided evidence of white matter (WM) abnormalities in this disease. The advent of diffusion tensor (DT) MRI allowed researchers to study in vivo cerebral WM abnormalities in AD, including the earliest stage of the disease and its atypical variants. OBJECTIVE: To provide a concise overview of the main neuropathological and DT MRI studies that explored WM damage in AD providing new insights into the underlying pathophysiological mechanisms. RESULTS: Neuropathological studies revealed that GM and WM changes did not concur regionally in many areas, where well-preserved GM often lay over severely changed WM also in nondemented subjects with an underlying AD pathology. DT MRI studies confirmed in vivo a severe WM involvement in classical and atypical AD variants and in the prodromal stage of the disease. Microstructural WM damage was severer and more distributed than expected on the basis of cortical atrophy in all clinical AD phenotypes. CONCLUSIONS: AD is characterized by a relevant involvement of the WM as demonstrated by postmortem and in vivo evidence. WM microstructural damage in AD is not always secondary to neuronal loss, suggesting a role of other pathological mechanisms such as prion-like propagation of altered proteins or neuroinflammation. DT MRI offers new insight into AD pathophysiology and, more importantly, new possible targets for future experimental therapies. PMID- 26618814 TI - Correction. PMID- 26618813 TI - Drone-Based Telemedicine: A Brave but Necessary New World. PMID- 26618815 TI - A National Study of Primary Care Provided by Osteopathic Physicians. AB - CONTEXT: The establishment of a single accreditation system for graduate medical education in the United States suggests a convergence of osteopathic and allopathic medicine. OBJECTIVE: To compare the characteristics of medical care provided by osteopathic and allopathic physicians. METHODS: Five-year data from the National Ambulatory Medical Care Survey were used to study patient visits for primary care, including those for low back pain, neck pain, upper respiratory infection, hypertension, and diabetes mellitus. Patient status, primary reason for the visit, chronicity of the presenting problem, injury status, medication orders, physician referrals, source of payment, and time spent with the physician were used to compare osteopathic and allopathic patient visits. RESULTS: A total of 134,369 patient visits were surveyed, representing a population (SE) of 4.57 billion (220.2 million) patient visits. Osteopathic physicians provided 335.6 (29.9) million patient visits (7.3%), including 217.1 (20.9) million visits for primary care (9.7%). The 5 sentinel symptoms and medical diagnoses accounted for 233.0 (12.4) million primary care visits (10.4%). The mean age of patients seen during primary care visits provided by osteopathic physicians was 46.0 years (95% CI, 44.1-47.9 years) vs 39.9 years (95% CI, 38.8-41.0 years) during visits provided by allopathic physicians (P<.001). Osteopathic patient visits were less likely to involve preventive care (OR, 0.55; 95% CI, 0.44-0.68) and more likely to include care for injuries (OR, 1.60; 95% CI, 1.43-1.78). Osteopathic physicians spent slightly less time with patients during visits (mean, 16.4 minutes; 95% CI, 15.7-17.2 minutes) than allopathic physicians (mean, 18.2 minutes; 95% CI, 17.2-19.3 minutes). The most distinctive aspect of osteopathic medical care involved management of low back pain. Therein, osteopathic physicians were less likely to order medication (OR, 0.33; 95% CI, 0.15-0.75) or to refer patients to another physician (OR, 0.47; 95% CI, 0.23-0.94), despite having more visits paid through Worker's Compensation (OR, 3.63; 95% CI, 1.01 13.07). Osteopathic and allopathic medical care for upper respiratory infection, hypertension, and diabetes mellitus were comparable. CONCLUSION: Practice patterns of osteopathic physicians generally mirror those of allopathic physicians except that osteopathic physicians deliver more medical care for older patients and at later stages of disease. Osteopathic medicine should be promoted more vigorously among younger and healthier persons. New opportunities may arise for osteopathic physicians to demonstrate a distinctive approach to low back pain as changes emerge in graduate medical education. PMID- 26618816 TI - Femoral Nerve Block vs Periarticular Bupivacaine Liposome Injection After Primary Total Knee Arthroplasty: Effect on Patient Outcomes. AB - CONTEXT: Patients receiving femoral nerve blocks for total knee arthroplasty (TKA) have been shown to have a high incidence of postoperative falls, which has been attributed to weakening of the quadriceps muscles. Local injection of analgesic medication that allows for full motor function of the quadriceps and, therefore, better progress through inpatient physical therapy and decreased hospital stay, has been suggested as an option for postoperative pain relief. OBJECTIVE: To compare the number of inpatient physical therapy sessions and hospital days needed in patients receiving periarticular injection of extended release bupivacaine liposome vs femoral nerve block after TKA. METHODS: Data were retrospectively reviewed from the records of patients who underwent bilateral primary TKA, in which femoral nerve block was administered at the first operation and periarticular injection of an extended-release bupivacaine liposome mixture at the second operation. An average of 2.3 years had passed between the 2 procedures. The number of inpatient physical therapy sessions and hospital days needed were compared between both procedures for each patient. RESULTS: Sixteen patients (14 women) were included in the study, with a mean (SD) age of 63.8 (6.7) years. Compared with femoral nerve block, periarticular injection of analgesic medication resulted in fewer inpatient physical therapy sessions (femoral nerve block: mean [SD], 3.5 [1.3] sessions; periarticular injection: mean [SD], 2.3 [1.0] sessions; P=.002) and fewer hospital days (femoral nerve block: mean [SD], 1.9 [0.6] days; periarticular injection: mean [SD], 1.5 [0.6] days; P<.032). CONCLUSION: Compared with femoral nerve block, periarticular injection of analgesia was found to quicken postoperative recovery in patients hospitalized for TKA. The use of periarticular injections in patients undergoing TKA could yield substantial cost savings given the high frequency of this procedure. PMID- 26618817 TI - Utility of Colonoscopy to Exclude Underlying Malignant Polyps After Resolution of Uncomplicated Diverticulitis. PMID- 26618818 TI - Posterolateral Corner Knee Injuries: Review of Anatomy and Clinical Evaluation. AB - The structures in the posterolateral corner of the knee, which stabilize the joint, are often involved in injuries to the posterior cruciate ligament. Familiar structures include the anterior cruciate ligament, posterior cruciate ligament, tibial collateral ligament, and menisci. Less familiar are the structures of the posterolateral corner, the most important of which are the fibular collateral ligament, popliteus tendon, and popliteofibular ligament, which resist varus angulation, external rotation, or posterior translation of the tibia. Injury to the posterolateral corner can be assessed with the posterolateral drawer, dial, reverse pivot shift, external rotation recurvatum, and varus stress tests. The purpose of this review is to highlight the posterolateral corner of the knee and injuries to its structures so that physicians can more accurately diagnose these injuries and provide appropriate treatment. Management focuses on restoring the fibular collateral ligament, popliteofibular ligament, and, in certain cases, the popliteus tendon. PMID- 26618819 TI - Implementation of a Resident-Led Osteopathic Manipulative Treatment Clinic in an Allopathic Residency. AB - CONTEXT: With the growing number of osteopathic physicians practicing in the United States and the creation of a single graduate medical education system, a continued need exists for focused education in osteopathic principles, philosophy, and treatment modalities in primarily allopathic residency programs. OBJECTIVE: To create and integrate a resident-led osteopathic manipulative treatment (OMT) clinic in an allopathic residency program. METHODS: After an informal needs assessment on the basis of resident survey data, a resident-led OMT clinic was created within a military allopathic family medicine residency program. A standard operating procedure, resident survey, and scheduling system were created by the residents for approval by the departmental and hospital leadership. Resident survey data pertaining to the time available to perform OMT, education, and faculty supervision of OMT were obtained before the clinic implementation and 1 year after implementation. RESULTS: Nine osteopathic residents were surveyed before the OMT clinic implementation to illustrate a need for continued osteopathic medical education, faculty support, and skill maintenance. Sixteen osteopathic residents were surveyed after the OMT clinic implementation. More residents indicated that the establishment of an osteopathic curriculum was important (3 of 9 in the preclinic survey vs 9 of 16 in the postclinic survey) and that the program promoted the use of OMT (0 of 9 in the preclinic survey vs 13 of 16 in the postclinic survey). CONCLUSION: A resident led OMT clinic can be successfully implemented, maintained, and expanded in an allopathic residency program by implementing an OMT curriculum, offering elective rotations, and encouraging regular use of OMT. The current project can be used as a framework for implementing an OMT clinic. PMID- 26618820 TI - Progressively Worsening Cyclic Rash: Diagnosis and Approach to Care. AB - Autoimmune progesterone dermatitis (AIPD) is an uncommon condition in which allergic dermatitis to endogenous progesterone manifests in cyclic cutaneous eruptions. In this case series, we present 3 patients with AIPD, each with unique presentations and medical histories emblematic of the disease. Cyclic dermatitis related to menses in a premenopausal woman should raise high clinical suspicion for AIPD, especially in the primary care or emergency setting. Because of the rarity of this disorder, this case series seeks to describe AIPD to medical providers of young women, as well as present relevant literature related to the disease. We propose clinical considerations for women of reproductive age with AIPD. PMID- 26618821 TI - Hypertrophic Osteoarthropathy. PMID- 26618822 TI - Quality Improvement Measures for Increasing the Colorectal Cancer Screening Rates at a Community Health Center. AB - INTRODUCTION: Direct recommendation from health care professionals has been shown to generally increase colorectal cancer screening rates in the United States. However, data for rural, underserved communities are limited. OBJECTIVE: To increase colorectal cancer screening rates at a rural community health center (CHC) by increasing health care professionals' awareness of patients' screening eligibility. METHODS: Participants were health care professionals at a CHC treating patients eligible for colorectal cancer screening (defined as patients aged 50-74 years who visited the CHC between February 24, 2014, and March 15, 2014, and whose electronic medical records [EMRs] had no recording of colorectal cancer screening). For a 3-week period, these participants added electronic reminders to eligible patients' EMRs. Data reports for the screening rates of each participant, in addition to the overall CHC, were generated 4 weeks after the study period and compared with screening rates in 2013. RESULTS: Five health care professionals volunteered to participate. No statistically significant difference was found in screening rates of participants compared with overall clinic rates between the 2013 (P=.639) and 2014 (P=.583) sample dates. No statistically significant difference was found in the overall CHC screening rates (P=.052), which were 47.69% and 40.84% in 2013 and 2014, respectively. During the study period, 99 eligible patients were seen. An incidental finding revealed a substantial EMR flaw in uniform data system reporting measures: self-reported colorectal cancer screenings by patients, without official documentation provided, were documented in an EMR section that is not retrieved during uniform data system reporting. CONCLUSION: No associated change in colorectal cancer screening rates was found at the CHC after increasing participants' awareness of patients' screening eligibility using electronic flagging. However, colorectal cancer screening results cannot be reported with certainty given that incidental documentation and data collection discrepancies were found. PMID- 26618823 TI - Transaxillary Subcutaneouscopic Excision of Fibroadenoma of the Breast in Children: The Covert Scar Approach. AB - INTRODUCTION: Fibroadenoma is a common condition in adolescent girls. Most tumors are excised either through a periareolar approach or the inframammary approach. Both approaches produce visible scars in adolescent girls. We propose a new cosmetic approach to this lesion and report our experience with the transaxillary subcutaneouscopic approach for excision of the fibroadenoma of the breast. The purpose of this case report is to delineate an innovative surgical approach to resection of a breast fibroadenoma that yields an adequate resection without possible damage to the ductal system while optimizing cosmetic results by avoiding scars. MATERIALS AND METHODS: We retrospectively reviewed the medical records of four adolescent girls who underwent the above approach for excision of fibroadenoma of the breast. The age range was 14-16 years. RESULTS: There were no complications in all 4 patients. The final result at the 3-month follow-up revealed an esthetically pleasing skin incision that healed well and was hidden by the natural skin fold of the axilla. CONCLUSIONS: Transaxillary subcutaneouscopic excision of fibroadenoma of the breast in children is a safe and effective technique and should be considered for excision of benign breast lesions in children. PMID- 26618828 TI - Ten Questions With .... PMID- 26618825 TI - Frontlines: Wouldn't It Be Nice? PMID- 26618824 TI - Vaccine strategies against cystic fibrosis pathogens. AB - A great number of cystic fibrosis (CF) pathogens such as Pseudomonas aeruginosa, the Burkholderia cepacia and the Mycobacterium abscessus complex raised difficult therapeutic problems due to their intrinsic multi-resistance to numerous antibiotics. Vaccine strategies represent one of the key weapons against these multi-resistant bacteria in a number of clinical settings like CF. Different strategies are considered in order to develop such vaccines, linked either to priming the host response, or by exploiting genomic data derived from the bacterium. Interestingly, virulence factors synthesized by various pathogens might serve as targets for vaccine development and have been, for example, evaluated in the context of CF. PMID- 26618830 TI - Ask George. PMID- 26618831 TI - An HTM Perspective on Postmarket Surveillance Activities. PMID- 26618832 TI - Keeping an Eye On Medical Devices Postmarket Surveillance Enters New Age. PMID- 26618833 TI - Compensation Survey: HTM Professionals Express Overall Job Satisfaction. PMID- 26618834 TI - From the Trenches to the C-Suite: What it Takes to Move Upstairs. PMID- 26618835 TI - Special Series: A Clinical Engineer's Approach to CMS Compliance: Part Two. PMID- 26618836 TI - The Vital Role of Device Manufacturers As Cybercitizens. PMID- 26618837 TI - Decreasing False Alarms by Obtaining the Best Signal and Minimizing Artifact from Physiological Sensors. PMID- 26618838 TI - Risk Management Poised to Grow as Healthcare Evolves. PMID- 26618839 TI - Preventive Maintenance At VA Medical Center Gets a Boost. PMID- 26618841 TI - Retirement Poses A Challenge for HTM. PMID- 26618842 TI - Medical Device Risk Management For Performance Assurance Optimization and Prioritization. AB - Performance assurance (PA) is an integral component of clinical engineering medical device risk management. For that reason, the clinical engineering (CE) community has made concerted efforts to define appropriate risk factors and develop quantitative risk models for efficient data processing and improved PA program operational decision making. However, a common framework that relates the various processes of a quantitative risk system does not exist. This article provides a perspective that focuses on medical device quality and risk-based elements of the PA program, which include device inclusion/exclusion, schedule optimization, and inspection prioritization. A PA risk management framework is provided, and previous quantitative models that have contributed to the advancement of PA risk management are examined. A general model for quantitative risk systems is proposed, and further perspective on possible future directions in the area of PA technology is also provided. PMID- 26618843 TI - The Value of A Postmarket Knowledge Exchange. PMID- 26618844 TI - Back to Reality: The Postmarket Surveillance System Today. PMID- 26618846 TI - The transformation of ZnO submicron dumbbells into perfect hexagonal tubular structures using CBD: a post treatment route. AB - In this paper, we report the synthesis of dumbbell-shaped ZnO structures and their subsequent transformation into perfect hexagonal tubes by the extended chemical bath deposition (CBD) method, retaining all advantages such as reproducibility, simplicity, quickness and economical aspect. Well-dispersed sub micron-sized dumbbell-shaped ZnO structures were synthesized on a SiO2/Si substrate by the CBD method. As an extension of the CBD process the synthesized ZnO dumbbells were exposed to the evaporate coming out of the chemical bath for a few minutes (simply by adjusting the height of the deposit so that it remained just above the solution) to convert them into hexagonal tubes via the dissolution process. The possible dissolution mechanism responsible for the observed conversion is discussed. The optical properties (photo-luminescence) recorded at low temperature on both the structures showed an intense, sharp excitonic peak located at ~370 nm. The improved intensity and low FWHM of the UV peak observed in the hexagonal tubular structures assures high optical quality, and hence can be used for optoelectronic applications. PMID- 26618845 TI - A Ground-Nesting Galliform's Response to Thermal Heterogeneity: Implications for Ground-Dwelling Birds. AB - The habitat selection choices that individuals make in response to thermal environments influence both survival and reproduction. Importantly, the way that organisms behaviorally respond to thermal environments depends on the availability and juxtaposition of sites affording tolerable or preferred microclimates. Although, ground nesting birds are especially susceptible to heat extremes across many reproductive stages (i.e., breeding, nesting, brood rearing), the mechanistic drivers of nest site selection for these species are not well established from a thermal perspective. Our goal was to assess nest site selection relative to the configuration of the thermal landscape by quantifying thermal environments available to a ground-nesting bird species inhabiting a climatically stressful environment. Using northern bobwhite (Colinus virginanus) as a model species, we measured black bulb temperature (Tbb) and vegetation parameters at 87 nests, 87 paired sites and 205 random landscape sites in Western Oklahoma during spring and summer 2013 and 2014. We found that thermal space within the study area exhibited differences in Tbb of up to 40 degrees C during peak diurnal heating, resulting in a diverse thermal landscape available to ground-nesting birds. Within this thermally heterogeneous landscape, nest sites moderated Tbb by more than 12 degrees C compared to random landscape sites. Furthermore, successful nests remained on average 6 degrees C cooler than unsuccessful nests on days experiencing ambient temperatures >= 39 degrees C. Models of future Tbb associated with 2080 climate change projections indicate that nesting bobwhites will face substantially greater Tbb throughout the landscape for longer durations, placing an even greater importance on thermal choices for nest sites in the future. These results highlight the capacity of landscape features to act as moderators of thermal extremes and demonstrate how thermal complexity at organism-specific scales can dictate habitat selection. PMID- 26618847 TI - Update on Performance in Tobacco Control: A Longitudinal Analysis of the Impact of Tobacco Control Policy and the US Adult Smoking Rate, 2011-2013. AB - CONTEXT: Tobacco use remains the leading cause of preventable death in the United States. States and municipalities have instituted a variety of tobacco control measures (TCMs) to address the significant impact tobacco use has on population health. The American Lung Association annually grades state performance of tobacco control using the State of Tobacco Control grading framework. OBJECTIVE: To gain an updated understanding of how recent efforts in tobacco control have impacted tobacco use across the United States, using yearly State of Tobacco Control TCM assessments. DESIGN: The independent TCM variables of smoke-free air score, cessation score, excise tax, and percentage of recommended funding were selected from the American Lung Association State of Tobacco Control reports. Predictors of adult smoking rates were determined by a mixed-effects model. SETTING/PARTICIPANTS: The 50 US states and District of Columbia. MAIN OUTCOME MEASURE: Adult smoking rate in each state from 2011 to 2013. RESULTS: The average adult smoking rate decreased significantly from 2011 to 2013 (21.3% [SD: 3.5] to 19.3% [SD: 3.5], P = .016). All forms of TCMs varied widely in implementation levels across states. Excise taxes (beta = -.812, P = .006) and smoke-free air regulations (beta = -.057, P = .008) were significant, negative predictors of adult smoking. Cessation services (beta = .015, P = .46) did not have a measurable effect on adult smoking. CONCLUSION: Tobacco control measures with the strongest influence on adult smoking include the state excise tax and state smoke free air regulations. The lack of robust funding for tobacco cessation services across the majority of US states highlights an important shortfall in current tobacco control policy. PMID- 26618848 TI - Minigrants for Community Health: A Randomized Controlled Trial of Their Impact on Family Food Gardening. AB - OBJECTIVE: To evaluate the impact of minigrants on home food gardening and review 28 health-related minigrant programs reported in the literature for lessons relevant for using minigrant programs to promote community health. DESIGN: Randomized controlled trial of the impact of minigrants on square footage of food garden area and on garden initiation in 2010 versus 2011. Interviews with participants were also conducted and coded and the literature was reviewed for findings from other community health minigrant programs. SETTING: Laramie, Wyoming. PARTICIPANTS: Sixty adults living in 53 households who attended a gardening training workshop in April 2011. INTERVENTION: A $40 minigrant in the form of a voucher, valid at a local gardening store. RESULTS: Minigrant recipients were more likely to increase their gardening space than the control group. The average increase for the intervention group was 39.2 ft (3.62 m) while the control group average garden plot size decreased slightly, on average, by 1.4 ft (-0.13 m). However, the data were not normally distributed and, therefore, nonparametric statistical tests were used. For the subset of 20 households that did not garden at all in 2010, minigrants also provided motivation to start gardening (8 of 10 minigrant households started a garden vs 2 of 10 control households). Results reported from other health minigrant programs are also positive, though few had quantitative outcomes or control groups for comparison. CONCLUSIONS: Even with very small amounts of money, minigrants show promise as an ethical, inexpensive, empowering, and effective health promotion strategy to enable families and communities to improve their health. PMID- 26618849 TI - Urban Dissolved Silica: Quantifying the Role of Groundwater and Runoff in Wastewater Influent. AB - Human impacts on silicon (Si) cycling are just being explored. In particular, we know little about the role of urban environments in altering the flux of Si from land to sea. Here we describe the annual load of dissolved Si (DSi) in the influent of the second largest wastewater treatment plant (by volume) in the United States (Deer Island Wastewater Facility, Boston, MA). We partition the ~69 500 kmol DSi year(-1) influent load between three sources: runoff (12%), groundwater infiltration (39%), and sewage (49%). Based on these results, we hypothesized that instead of being delivered to local rivers, DSi in groundwater and runoff is redirected to the combined stormwater-sewage overflow system. To test this hypothesis we compared long-term (2007-2012) observations of DSi flux from the three urban rivers surrounding Boston to modeled DSi fluxes based on land use and land cover. As predicted, the modeled fluxes were higher than the measured fluxes indicating that the sewage infrastructure of Boston diverts watershed DSi to the treatment plant. This research increases our understanding of human changes to the Si cycle, demonstrates the potential usefulness of DSi as a groundwater infiltration tracer within sewage treatment systems, and highlights the underappreciated interannual variability of riverine DSi fluxes. PMID- 26618850 TI - High-Resolution Mapping of Thermal History in Polymer Nanocomposites: Gold Nanorods as Microscale Temperature Sensors. AB - A technique is reported for measuring and mapping the maximum internal temperature of a structural epoxy resin with high spatial resolution via the optically detected shape transformation of embedded gold nanorods (AuNRs). Spatially resolved absorption spectra of the nanocomposites are used to determine the frequencies of surface plasmon resonances. From these frequencies the AuNR aspect ratio is calculated using a new analytical approximation for the Mie-Gans scattering theory, which takes into account coincident changes in the local dielectric. Despite changes in the chemical environment, the calculated aspect ratio of the embedded nanorods is found to decrease over time to a steady-state value that depends linearly on the temperature over the range of 100-200 degrees C. Thus, the optical absorption can be used to determine the maximum temperature experienced at a particular location when exposure times exceed the temperature dependent relaxation time. The usefulness of this approach is demonstrated by mapping the temperature of an internally heated structural epoxy resin with 10 MUm lateral spatial resolution. PMID- 26618851 TI - Predation on the Invasive Copepod, Pseudodiaptomus forbesi, and Native Zooplankton in the Lower Columbia River: An Experimental Approach to Quantify Differences in Prey-Specific Feeding Rates. AB - Invasive planktonic crustaceans have become a prominent feature of aquatic communities worldwide, yet their effects on food webs are not well known. The Asian calanoid copepod, Pseudodiaptomus forbesi, introduced to the Columbia River Estuary approximately 15 years ago, now dominates the late-summer zooplankton community, but its use by native aquatic predators is unknown. We investigated whether three species of planktivorous fishes (chinook salmon, three-spined stickleback, and northern pikeminnow) and one species of mysid exhibited higher feeding rates on native copepods and cladocerans relative to P. forbesi by conducting 'single-prey' feeding experiments and, additionally, examined selectivity for prey types with 'two-prey' feeding experiments. In single-prey experiments individual predator species showed no difference in feeding rates on native cyclopoid copepods (Cyclopidae spp.) relative to invasive P. forbesi, though wild-collected predators exhibited higher feeding rates on cyclopoids when considered in aggregate. In two-prey experiments, chinook salmon and northern pikeminnow both strongly selected native cladocerans (Daphnia retrocurva) over P. forbesi, and moreover, northern pikeminnow selected native Cyclopidae spp. over P. forbesi. On the other hand, in two-prey experiments, chinook salmon, three spined stickleback and mysids were non- selective with respect to feeding on native cyclopoid copepods versus P. forbesi. Our results indicate that all four native predators in the Columbia River Estuary can consume the invasive copepod, P. forbesi, but that some predators select for native zooplankton over P. forbesi, most likely due to one (or both) of two possible underlying casual mechanisms: 1) differential taxon-specific prey motility and escape responses (calanoids > cyclopoids > daphnids) or 2) the invasive status of the zooplankton prey resulting in naivety, and thus lower feeding rates, of native predators feeding on invasive prey. PMID- 26618852 TI - Direct Analysis of Nonvolatile Chemical Compounds on Surfaces Using a Hand-Held Mass Spectrometer with Synchronized Discharge Ionization Function. AB - Synchronized discharge ionization (SDI) was previously developed for hand-held mass spectrometers with discontinuous atmospheric pressure interfaces. The function of SDI has been demonstrated for analysis of volatile organic compounds in air at high sensitivity, which is attributed to the fact that ions were produced next to the ion trap mass analyzer inside the vacuum manifold. In this study, a simple sampling device was designed and fitted to a hand-held mass spectrometer to characterize its potential in direct analysis of low-volatility chemicals on surfaces. Nine chemicals of vapor pressures ranging from 10(-4) to 10(-8) Torr (at room temperature), including pesticides, illicit drugs, and explosives, were selected to evaluate and demonstrate the analytical capability of the designed system. Compounds of vapor pressures below 10(-7) Torr, such as tetryl, cocaine, and tetrahydrocannabinol (THC), have been successfully detected. Direct analysis of pesticides from fruit and explosives from a large surface area has also been demonstrated. Tandem mass analysis was performed, which helped to confirm the analyte identity as well as to improve the signal-to-noise ratio (S/N). PMID- 26618853 TI - Adherence to iron chelation therapy and associated healthcare resource utilization and costs in Medicaid patients with sickle cell disease and thalassemia. AB - BACKGROUND: Sub-optimal patient adherence to iron chelation therapy (ICT) may impact patient outcomes and increase cost of care. This study evaluated the economic burden of ICT non-adherence in patients with sickle cell disease (SCD) or thalassemia. METHODS: Patients with SCD or thalassemia were identified from six state Medicaid programs (1997-2013). Adherence was estimated using the medication possession ratio (MPR) of >=0.80. All-cause and disease-specific resource utilization per-patient-per-month (PPPM) was assessed and compared between adherent and non-adherent patients using adjusted incidence rate ratios (aIRR). All-cause and disease-specific healthcare costs were computed using mean cost PPPM. Regression models adjusting for baseline characteristics were used to compare adherent and non-adherent patients. RESULTS: A total of 728 eligible patients treated with ICT in the SCD cohort, 461 (63%) adherent, and 218 in the thalassemia cohort, 137 (63%) adherent, were included in this study. In SCD patients, the adjusted rate of all-cause outpatient visits PPPM was higher in adherent patients vs non-adherent patients (aIRR [95% CI]: 1.05 [1.01-1.08], p < 0.0001). Conversely, adherent patients incurred fewer all-cause inpatients visits (0.87 [0.81-0.94], p < 0.001) and ER visits (0.86 [0.78-0.93], p < 0.001). Similar trends were observed in SCD-related resource utilization rates and in thalassemia patients. Total all-cause costs were similar between adherent and non adherent patients, but inpatient costs (adjusted cost difference = -$1530 PPPM, p = 0.0360) were lower in adherent patients. CONCLUSION: Patients adherent to ICT had less acute care need and lower inpatient costs than non-adherent patients, although they had more outpatient visits. Improved adherence may be linked to better disease monitoring and has the potential to avoid important downstream costs associated with acute care visits and reduce the financial burden on health programs and managed care plans treating SCD and thalassemia patients. PMID- 26618854 TI - Phrenic nerve conduction studies as a biomarker of respiratory insufficiency in amyotrophic lateral sclerosis. AB - Our objective was to examine the value of phrenic nerve conduction studies (PNCS) in quantifying diaphragm dysfunction in ALS, as no ideal test of respiratory insufficiency exists in ALS. We prospectively recorded bilateral PNCS, forced vital capacity (FVC), maximum inspiratory pressure (MIP), sniff nasal inspiratory pressure (SNIP), respiratory rate, ALSFRS-R, and respiratory symptoms in 100 ALS patients attending our clinic over a nine-month period. Survival data were collected for two years. Results showed that PNCS were reproducible and well tolerated. When the Pamp was abnormal (<0.3 mV), the relative risk of a respiratory rate >18 was 7.2 (95% CI 2.2-37.2, p <0.01) compared with a Pamp >=0.3 mV. Similarly, the relative risk of orthopnea was 3.5 (95% CI 1.6-8.7, p <0.01) and dyspnea 2.4 (95% CI 1.4-4.0, p <0.01). FVC had the strongest correlation with Pamp (R(2) = 0.48 (p <0.001)). Fourteen of 15 patients with a FVC <50% had a Pamp <0.3 mV. However, eight with a Pamp <0.3 had a FVC >80%. The median survival was 1.07 years when the Pamp was <0.3 mV and >2 years when the Pamp was >0.3 mV (p <0.001). In conclusion, the phrenic Pamp correlated closely with multiple symptoms, signs, and laboratory measures of respiratory insufficiency and may prove to be a useful biomarker of respiratory dysfunction in ALS. PMID- 26618856 TI - Effect of O-Linked Glycosylation on the Equilibrium Structural Ensemble of Intrinsically Disordered Polypeptides. AB - Glycosylation is one of the most common post-translational modifications (PTMs), which provides a large proteome diversity. Previous work on glycosylation of globular proteins has revealed remarkable effects of glycosylation on protein function, altering the folding stability and structure and/or altering the protein surface which affects their binding characteristics. Intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs) of large proteins are also frequently glycosylated, yet how glycosylation affects their function remains to be elucidated. An important open question is, does glycosylation affect IDP structure or binding characteristics or both? In this work, we particularly address the structural effects of O-linked glycosylation by investigating glycosylated and unglycosylated forms of two different IDPs, tau174 183 and human islet amyloid polypeptide (hIAPP), by all-atom explicit solvent simulations. We simulate these IDPs in aqueous solution for O-linked glycosylated and unglycosylated forms by employing two modern all-atom force fields for which glycan parameters are also available. We find that O-linked glycosylation only has a modest effect on equilibrium structural ensembles of IDPs, for the cases studied here, which suggests that the functional role of glycosylation may be primarily exerted by modulation of the protein binding characteristics rather than structure. PMID- 26618855 TI - The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Preserves Endothelial Function in Mesenteric Arteries from Type 1 Diabetic Rats without Decreasing Plasma Glucose. AB - The aim of the study was to investigate the effect of the DPP-4 inhibitor linagliptin on the mechanism(s) of endothelium-dependent relaxation in mesenteric arteries from STZ-induced diabetic rats. Both normal and diabetic animals received linagliptin (2 mg/kg) daily by oral gavage for a period of 4 weeks. To measure superoxide generation in mesenteric arteries, lucigenin-enhanced chemiluminescence was used. ACh-induced relaxation of mesenteric arteries was assessed using organ bath techniques and Western blotting was used to investigate protein expression. Pharmacological tools (1 MUM TRAM-34, 1 MUM apamin, 100 nM Ibtx, 100 MUM L-NNA, 10 MUM ODQ) were used to distinguish between NO and EDH mediated relaxation. Linagliptin did not affect plasma glucose, but did decrease vascular superoxide levels. Diabetes reduced responses to ACh but did not affect endothelium-independent responses to SNP. Linagliptin improved endothelial function indicated by a significant increase in responses to ACh. Diabetes impaired the contribution of both nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) to endothelium-dependent relaxation and linagliptin treatment significantly enhanced the contribution of both relaxing factors. Western blotting demonstrated that diabetes also increased expression of Nox2 and decreased expression and dimerization of endothelial NO synthase, effects that were reversed by linagliptin. These findings demonstrate treatment of type 1 diabetic rats with linagliptin significantly reduced vascular superoxide levels and preserved both NO and EDH-mediated relaxation indicating that linagliptin can improve endothelial function in diabetes independently of any glucose lowering activity. PMID- 26618857 TI - An Effective CUDA Parallelization of Projection in Iterative Tomography Reconstruction. AB - Projection and back-projection are the most computationally intensive parts in Computed Tomography (CT) reconstruction, and are essential to acceleration of CT reconstruction algorithms. Compared to back-projection, parallelization efficiency in projection is highly limited by racing condition and thread unsynchronization. In this paper, a strategy of Fixed Sampling Number Projection (FSNP) is proposed to ensure the operation synchronization in the ray-driven projection with Graphical Processing Unit (GPU). Texture fetching is also used utilized to further accelerate the interpolations in both projection and back projection. We validate the performance of this FSNP approach using both simulated and real cone-beam CT data. Experimental results show that compare to the conventional approach, the proposed FSNP method together with texture fetching is 10~16 times faster than the conventional approach based on global memory, and thus leads to more efficient iterative algorithm in CT reconstruction. PMID- 26618858 TI - The Genesis of Graphic Perseverations in Alzheimer's Disease and Vascular Dementia. AB - OBJECTIVE: Perseveration is the involuntary production of iterative responses. This study explored graphic perseverative errors in Alzheimer's disease and vascular dementia, to comprehend the neuropsychological correlates of this behavior. METHOD: We performed a retrospective analysis of graphic productions in 114 individuals with clinical diagnosis of Alzheimer's disease and in 63 individuals with clinical diagnosis of vascular dementia, who completed frontal executive, visuo-spatial, visuo-constructional, and verbal memory tests. For assessing perseverative behavior, we considered recurrent perseverations (inappropriate re-drawing of a figure drawn in a previous trial) and continuous perseverations (inappropriate replication of the same figure or of its element within one trial) produced in a standard copying task. RESULTS: Two or more graphic perseverative errors occurred in 66/114 individuals with Alzheimer's disease (57.9%) and in 31/63 individuals with vascular dementia (49.2%). Participants with moderate-to-severe dementia produced a significantly higher number of perseverations than individuals with mild dementia. Logistic regression revealed a significant relationship of graphic perseverations with frontal and visuo-constructive impairments, in both Alzheimer's disease and vascular dementia. CONCLUSIONS: Graphic perseverations are frequent in both Alzheimer's disease and vascular dementia. Frontal-executive defects can hamper inhibition of iterative graphic productions. Identification of graphic perseverations can be useful for detection and monitoring of frontal-executive impairments throughout the disease course in individuals with dementia. PMID- 26618859 TI - "Size-Independent" Single-Electron Tunneling. AB - Incorporating single-electron tunneling (SET) of metallic nanoparticles (NPs) into modern electronic devices offers great promise to enable new properties; however, it is technically very challenging due to the necessity to integrate ultrasmall (<10 nm) particles into the devices. The nanosize requirements are intrinsic for NPs to exhibit quantum or SET behaviors, for example, 10 nm or smaller, at room temperature. This work represents the first observation of SET that defies the well-known size restriction. Using polycrystalline Au NPs synthesized via our newly developed solid-state glycine matrices method, a Coulomb Blockade was observed for particles as large as tens of nanometers, and the blockade voltage exhibited little dependence on the size of the NPs. These observations are counterintuitive at first glance. Further investigations reveal that each observed SET arises from the ultrasmall single crystalline grain(s) within the polycrystal NP, which is (are) sufficiently isolated from the nearest neighbor grains. This work demonstrates the concept and feasibility to overcome orthodox spatial confinement requirements to achieve quantum effects. PMID- 26618860 TI - Mechanisms of Resilience in Children of Mothers Who Self-Report with Depressive Symptoms in the First Postnatal Year. AB - BACKGROUND: Symptoms of maternal postnatal depression are associated with an increased risk of adverse effects on child development. However, some children exposed to postnatal depression have outcomes similar to unexposed children, and can be referred to as resilient. This study aimed to determine the mechanisms of resilience in children exposed to depressive symptoms postnatally. METHOD: Data are from a prospective cohort study, the Avon Longitudinal Study of Parents and Children. Self-report questionnaire data were collected during pregnancy and the child's first 2 years regarding maternal views of parenting and her perception of the child. The Edinburgh Postnatal Depression Scale (EPDS) was completed postnatally at 8 months and the Strengths and Difficulties Questionnaire (SDQ) at age 11 years. Exposed children who scored above the median score of non-exposed children were defined as resilient. Structural equation modeling was used to investigate the development of resilience. RESULTS: From the core ALSPAC cohort, 1,009 children (6.9%) were exposed to maternal depression at 8 months postnatally. The SDQ total difficulties scores at 11 years of age indicated that 325 (32.2%) were resilient, 684 were non-resilient. Maternal positive feelings about parenting and child non-verbal communication at 15 months increased the likelihood of later resilience. CONCLUSIONS: In this study, resilience was associated with two factors: the child's nonverbal communication at 15 months and by maternal positive feelings about parenting. Early intervention to support mother-child interaction and foster child development in women identified with postnatal depressive symptoms may benefit later child resilience. PMID- 26618862 TI - Erratum. PMID- 26618861 TI - Neuronal Uptake and Neuroprotective Properties of Curcumin-Loaded Nanoparticles on SK-N-SH Cell Line: Role of Poly(lactide-co-glycolide) Polymeric Matrix Composition. AB - Curcumin, a neuroprotective agent with promising therapeutic approach has poor brain bioavailability. Herein, we demonstrate that curcumin-encapsulated poly(lactide-co-glycolide) (PLGA) 50:50 nanoparticles (NPs-Cur 50:50) are able to prevent the phosphorylation of Akt and Tau proteins in SK-N-SH cells induced by H2O2 and display higher anti-inflammatory and antioxidant activities than free curcumin. PLGA can display various physicochemical and degradation characteristics for controlled drug release applications according to the matrix used. We demonstrate that the release of curcumin entrapped into a PLGA 50:50 matrix (NPs-Cur 50:50) is faster than into PLGA 65:35. We have studied the effects of the PLGA matrix on the expression of some key antioxidant- and neuroprotective-related genes such as APOE, APOJ, TRX, GLRX, and REST. NPs-Cur induced the elevation of GLRX and TRX while decreasing APOJ mRNA levels and had no effect on APOE and REST expressions. In the presence of H2O2, both NPs-Cur matrices are more efficient than free curcumin to prevent the induction of these genes. Higher uptake was found with NPs-Cur 50:50 than NPs-Cur 65:35 or free curcumin. By using PLGA nanoparticles loaded with the fluorescent dye Lumogen Red, we demonstrated that PLGA nanoparticles are indeed taken up by neuronal cells. These data highlight the importance of polymer composition in the therapeutic properties of the nanodrug delivery systems. Our study demonstrated that NPs-Cur enhance the action of curcumin on several pathways implicated in the pathophysiology of Alzheimer's disease (AD). Overall, these results suggest that PLGA nanoparticles are a promising strategy for the brain delivery of drugs for the treatment of AD. PMID- 26618868 TI - A large-scale dynamo and magnetoturbulence in rapidly rotating core-collapse supernovae. AB - Magnetohydrodynamic turbulence is important in many high-energy astrophysical systems, where instabilities can amplify the local magnetic field over very short timescales. Specifically, the magnetorotational instability and dynamo action have been suggested as a mechanism for the growth of magnetar-strength magnetic fields (of 10(15) gauss and above) and for powering the explosion of a rotating massive star. Such stars are candidate progenitors of type Ic-bl hypernovae, which make up all supernovae that are connected to long gamma-ray bursts. The magnetorotational instability has been studied with local high-resolution shearing-box simulations in three dimensions, and with global two-dimensional simulations, but it is not known whether turbulence driven by this instability can result in the creation of a large-scale, ordered and dynamically relevant field. Here we report results from global, three-dimensional, general relativistic magnetohydrodynamic turbulence simulations. We show that hydromagnetic turbulence in rapidly rotating protoneutron stars produces an inverse cascade of energy. We find a large-scale, ordered toroidal field that is consistent with the formation of bipolar magnetorotationally driven outflows. Our results demonstrate that rapidly rotating massive stars are plausible progenitors for both type Ic-bl supernovae and long gamma-ray bursts, and provide a viable mechanism for the formation of magnetars. Moreover, our findings suggest that rapidly rotating massive stars might lie behind potentially magnetar-powered superluminous supernovae. PMID- 26618866 TI - ?F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. AB - Deletion of phenylalanine 508 of the cystic fibrosis transmembrane conductance regulator (?F508 CFTR) is the major cause of cystic fibrosis, one of the most common inherited childhood diseases. The mutated CFTR anion channel is not fully glycosylated and shows minimal activity in bronchial epithelial cells of patients with cystic fibrosis. Low temperature or inhibition of histone deacetylases can partly rescue ?F508 CFTR cellular processing defects and function. A favourable change of ?F508 CFTR protein-protein interactions was proposed as a mechanism of rescue; however, CFTR interactome dynamics during temperature shift and inhibition of histone deacetylases are unknown. Here we report the first comprehensive analysis of the CFTR and ?F508 CFTR interactome and its dynamics during temperature shift and inhibition of histone deacetylases. By using a novel deep proteomic analysis method, we identify 638 individual high-confidence CFTR interactors and discover a ?F508 deletion-specific interactome, which is extensively remodelled upon rescue. Detailed analysis of the interactome remodelling identifies key novel interactors, whose loss promote ?F508 CFTR channel function in primary cystic fibrosis epithelia or which are critical for CFTR biogenesis. Our results demonstrate that global remodelling of ?F508 CFTR interactions is crucial for rescue, and provide comprehensive insight into the molecular disease mechanisms of cystic fibrosis caused by deletion of F508. PMID- 26618882 TI - Design of active and stable Co-Mo-Sx chalcogels as pH-universal catalysts for the hydrogen evolution reaction. AB - Three of the fundamental catalytic limitations that have plagued the electrochemical production of hydrogen for decades still remain: low efficiency, short lifetime of catalysts and a lack of low-cost materials. Here, we address these three challenges by establishing and exploring an intimate functional link between the reactivity and stability of crystalline (CoS2 and MoS2) and amorphous (CoSx and MoSx) hydrogen evolution catalysts. We propose that Co(2+) and Mo(4+) centres promote the initial discharge of water (alkaline solutions) or hydronium ions (acid solutions). We establish that although CoSx materials are more active than MoSx they are also less stable, suggesting that the active sites are defects formed after dissolution of Co and Mo cations. By combining the higher activity of CoSx building blocks with the higher stability of MoSx units into a compact and robust CoMoSx chalcogel structure, we are able to design a low-cost alternative to noble metal catalysts for efficient electrocatalytic production of hydrogen in both alkaline and acidic environments. PMID- 26618871 TI - Growth and splitting of neural sequences in songbird vocal development. AB - Neural sequences are a fundamental feature of brain dynamics underlying diverse behaviours, but the mechanisms by which they develop during learning remain unknown. Songbirds learn vocalizations composed of syllables; in adult birds, each syllable is produced by a different sequence of action potential bursts in the premotor cortical area HVC. Here we carried out recordings of large populations of HVC neurons in singing juvenile birds throughout learning to examine the emergence of neural sequences. Early in vocal development, HVC neurons begin producing rhythmic bursts, temporally locked to a 'prototype' syllable. Different neurons are active at different latencies relative to syllable onset to form a continuous sequence. Through development, as new syllables emerge from the prototype syllable, initially highly overlapping burst sequences become increasingly distinct. We propose a mechanistic model in which multiple neural sequences can emerge from the growth and splitting of a common precursor sequence. PMID- 26618883 TI - Stress-stiffening-mediated stem-cell commitment switch in soft responsive hydrogels. AB - Bulk matrix stiffness has emerged as a key mechanical cue in stem cell differentiation. Here, we show that the commitment and differentiation of human mesenchymal stem cells encapsulated in physiologically soft (~0.2-0.4 kPa), fully synthetic polyisocyanopeptide-based three-dimensional (3D) matrices that mimic the stiffness of adult stem cell niches and show biopolymer-like stress stiffening, can be readily switched from adipogenesis to osteogenesis by changing only the onset of stress stiffening. This mechanical behaviour can be tuned by simply altering the material's polymer length whilst maintaining stiffness and ligand density. Our findings introduce stress stiffening as an important parameter that governs stem cell fate in a 3D microenvironment, and reveal a correlation between the onset of stiffening and the expression of the microtubule associated protein DCAMKL1, thus implicating DCAMKL1 in a stress-stiffening mediated, mechanotransduction pathway that involves microtubule dynamics in stem cell osteogenesis. PMID- 26618885 TI - Metal-insulator transition in films of doped semiconductor nanocrystals. AB - To fully deploy the potential of semiconductor nanocrystal films as low-cost electronic materials, a better understanding of the amount of dopants required to make their conductivity metallic is needed. In bulk semiconductors, the critical concentration of electrons at the metal-insulator transition is described by the Mott criterion. Here, we theoretically derive the critical concentration nc for films of heavily doped nanocrystals devoid of ligands at their surface and in direct contact with each other. In the accompanying experiments, we investigate the conduction mechanism in films of phosphorus-doped, ligand-free silicon nanocrystals. At the largest electron concentration achieved in our samples, which is half the predicted nc, we find that the localization length of hopping electrons is close to three times the nanocrystals diameter, indicating that the film approaches the metal-insulator transition. PMID- 26618886 TI - Solvent-free, supersoft and superelastic bottlebrush melts and networks. AB - Polymer gels are the only viable class of synthetic materials with a Young's modulus below 100 kPa conforming to biological applications, yet those gel properties require a solvent fraction. The presence of a solvent can lead to phase separation, evaporation and leakage on deformation, diminishing gel elasticity and eliciting inflammatory responses in any surrounding tissues. Here, we report solvent-free, supersoft and superelastic polymer melts and networks prepared from bottlebrush macromolecules. The brush-like architecture expands the diameter of the polymer chains, diluting their entanglements without markedly increasing stiffness. This adjustable interplay between chain diameter and stiffness makes it possible to tailor the network's elastic modulus and extensibility without the complications associated with a swollen gel. The bottlebrush melts and elastomers exhibit an unprecedented combination of low modulus (~100 Pa), high strain at break (~1,000%), and extraordinary elasticity, properties that are on par with those of designer gels. PMID- 26618884 TI - Hydrogels with tunable stress relaxation regulate stem cell fate and activity. AB - Natural extracellular matrices (ECMs) are viscoelastic and exhibit stress relaxation. However, hydrogels used as synthetic ECMs for three-dimensional (3D) culture are typically elastic. Here, we report a materials approach to tune the rate of stress relaxation of hydrogels for 3D culture, independently of the hydrogel's initial elastic modulus, degradation, and cell-adhesion-ligand density. We find that cell spreading, proliferation, and osteogenic differentiation of mesenchymal stem cells (MSCs) are all enhanced in cells cultured in gels with faster relaxation. Strikingly, MSCs form a mineralized, collagen-1-rich matrix similar to bone in rapidly relaxing hydrogels with an initial elastic modulus of 17 kPa. We also show that the effects of stress relaxation are mediated by adhesion-ligand binding, actomyosin contractility and mechanical clustering of adhesion ligands. Our findings highlight stress relaxation as a key characteristic of cell-ECM interactions and as an important design parameter of biomaterials for cell culture. PMID- 26618887 TI - Predictive factors of sagittal stability after treatment of Class II malocclusions. AB - OBJECTIVE: To determine the existence of factors permitting the prediction of sagittal stability after orthodontic treatment in patients with Angle Class II malocclusion. MATERIALS AND METHODS: PubMed, EMBASE, and the Cochrane Library were searched up to March 2015. Inclusion criteria were longitudinal studies with at least 10 subjects investigating associations between at least one factor and stability, with an average minimum follow-up period of 2 years; stability measured using posttreatment sagittal dental changes; and orthodontic treatment including removable and/or fixed appliances with or without extractions. Two reviewers independently selected and assessed the quality of the articles. RESULTS: The search strategy resulted in 1372 articles, of which 17 met the inclusion criteria. Large changes during treatment in molar and canine relationships were the only two factors found to be positively associated with relapse, but with limited evidence. Fourteen factors were found not to be predictive of relapse, also with limited evidence. These factors included treatment characteristics, patient pretreatment characteristics, and final posttreatment characteristics. CONCLUSIONS: There is currently limited evidence to support the influence of factors predictive of sagittal stability following Class II malocclusion treatment. More high-quality prospective studies are needed, and functional factors possibly affecting relapse also need to be further assessed. PMID- 26618888 TI - Glioblastoma care in the elderly. AB - Glioblastoma is common among elderly patients, a group in which comorbidities and a poor prognosis raise important considerations when designing neuro-oncologic care. Although the standard of care for nonelderly patients with glioblastoma includes maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide, the safety and efficacy of these modalities in elderly patients are less certain given the population's underrepresentation in many clinical trials. The authors reviewed the clinical trial literature for reports on the treatment of elderly patients with glioblastoma to provide evidence-based guidance for practitioners. In elderly patients with glioblastoma, there is a survival advantage for those who undergo maximal safe resection, which likely includes an incremental benefit with increasing completeness of resection. Radiotherapy extends survival in selected patients, and hypofractionation appears to be more tolerable than standard fractionation. In addition, temozolomide chemotherapy is safe and extends the survival of patients with tumors that harbor O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation. The combination of standard radiation with concurrent and adjuvant temozolomide has not been studied in this population. Although many questions remain unanswered regarding the treatment of glioblastoma in elderly patients, the available evidence provides a framework on which providers may base individual treatment decisions. The importance of tumor biomarkers is increasingly apparent in elderly patients, for whom the therapeutic efficacy of any treatment must be weighed against its potential toxicity. MGMT promoter methylation status has specifically demonstrated utility in predicting the efficacy of temozolomide and should be considered in treatment decisions when possible. Cancer 2016;122:189-197. (c) 2015 American Cancer Society. PMID- 26618889 TI - Double dissociation of a latent working memory process. AB - BACKGROUND: The study explored the construct validity of a computational model of working memory (WM) by determining whether model parameters manifested double dissociations of lesion laterality with type of material studied. The data set modeled involved psychometrically matched verbal and figural WM tasks on which a double dissociation between test version and lesion laterality failed to emerge when total test scores were used as the laterality marker. METHOD: This re analysis of a previously published study involved investigating the WM performance of 15 demographically matched controls with 15 adult patients with left-hemispheric (LH) lesions and 15 adult patients with right-hemispheric (RH) lesions. Each participant was given verbal and figural versions of a continuous paired associates test (CPAT). The two versions had previously been psychometrically matched in a larger sample of healthy individuals. A WM model composed of encoding, displacement, and episodic memory parameters was fit to each individual's performance profiles for both versions of the CPAT. RESULTS: Replicating the previous results for raw scores, rank transformed values of total score performance failed to reveal a double dissociation. Nonetheless an absolute double dissociation was observed for the model's displacement parameter: RH patients demonstrated deficits on the figural but not verbal WM displacement parameter, whereas LH patients demonstrated deficits on the verbal but not figural WM displacement parameter. Additionally, both LH and RH patients were impaired on the figural encode parameter, perhaps explaining the absence of a double dissociation in total score performance. CONCLUSIONS: By combining different patterns of profile and level data into theoretically motivated model parameters, computational models of neurocognition can enhance the construct validity of interpretations of neuropsychological performance. PMID- 26618890 TI - Dispersion in cognitive functioning: Age differences over the lifespan. AB - INTRODUCTION: A growing body of research suggests that intraindividual variability (IIV) may bring specific information on cognitive functioning, additional to that provided by the mean. The present paper focuses on dispersion, that is IIV across tasks, and its developmental trend across the lifespan. METHOD: A total of 557 participants (9-89 years) were administered a battery of response time (RT) tasks and of working memory (WM) tasks. Dispersion was analyzed separately for the two types of tasks. RESULTS: Dispersion across RT tasks showed a U-shaped age differences trend, young adults being less variable than both children and older adults. Dispersion across WM tasks (using accuracy scores) presented an opposite developmental trend. A cluster analysis revealed a group of individuals showing relatively little dispersion and good overall performance (faster in RTs and better in WM), contrasted with a group of individuals showing a large dispersion in the RT tasks as well as poorer overall performance. All young adults were grouped in the first cluster; children and older adults were distributed in both clusters. CONCLUSION: It is concluded that (a) across-task IIV is relatively large in the entire sample and should not be neglected, (b) children and older adults show a larger dispersion than young adults, but only as far as the RT tasks are concerned, PMID- 26618891 TI - Organic/Organic Cathode Bi-Interlayers Based on a Water-Soluble Nonconjugated Polymer and an Alcohol-Soluble Conjugated Polymer for High Efficiency Inverted Polymer Solar Cells. AB - In this work, organic/organic cathode bi-interlayers based on a water-soluble nonconjugated polymer PDMC and an alcohol-soluble conjugated polymer PFN were introduced to modifythe ITO cathode for inverted polymer solar cells (PSCs). PDMC with ultrahigh molecular weight would facilitate to form strong adsorption on the ITO substrate, while PFN could provide both compatibly interfacial contacts with the bottom PDMC interlayer and the upper organic active layer. The PDMC/PFN cathode bi-interlayers could decrease work function of the ITO cathode to 3.8 eV, supplying the most efficient ohmic interfacial contacts for electron collection at the ITO cathode. With a PTB7:PC71BM blend as the active layer, inverted PSCs based on the PDMC/PFN cathode bi-interlayers showed the highest efficiency of 9.01% and the best air stability within 60 days if compared with devices based on a separate PDMC or PFN cathode interlayer. The results suggest that the PDMC/PFN cathode bi-interlayers would play an important role to achieve high efficiency and stable inverted PSCs. PMID- 26618892 TI - Identification and Preliminary SAR Analysis of Novel Type-I Inhibitors of TIE-2 via Structure-Based Virtual Screening and Biological Evaluation in in vitro Models. AB - Angiopoietin (ANG) ligands and their downstream TIE receptors have been validated as the second vascular signaling system involving vessel remodeling and maturation. Among them, the ANG/TIE-2 signaling pathway is involved in numerous life-threatening diseases and has become an attractive potential therapeutic target. Several large-molecule inhibitors targeting the ANG/TIE-2 axis have recently entered clinical phase for the therapy of various solid tumors, but selective small-molecule inhibitors of TIE-2 are still quite limited. In the present work, structure-based virtual screening was performed to search for type I inhibitors of TIE-2. Of the only 41 compounds selected by our strategy, 8 molecules with the concentration of 25 MUg/mL exhibit over 50% inhibitory rate against TIE-2 in in vitro enzymatic activity assay, and the IC50 values of 2 hits are lower than 1 MUM. Further optimization and SAR analysis based on compound TP S1-30 and 31 were carried out by using substructure searching strategy, leading to the discovery of several sub-100 nM inhibitors. Among them, the most potent compound, TP-S1-68, showed an inhibitory IC50 of 0.149 MUM. These novel inhibitors of TIE-2 discovered in this study and the analogs of the active core scaffolds can serve as the starting points for further drug development. PMID- 26618893 TI - The 25th European Congress of clinical microbiology and infectious diseases (ECCMID) in Copenhagen, Denmark. PMID- 26618894 TI - p-Tolylimido rhenium(v) complexes with phenolate-based ligands: synthesis, X-ray studies and catalytic activity in oxidation with tert-butylhydroperoxide. AB - The reactions of mer-[Re(p-NTol)X3(PPh3)2] (X = Cl, Br) with chelating phenolate based ligands (2-(2-hydroxy-5-methylphenyl)benzotriazole (HL(1)), 2-(2 hydroxyphenyl)benzothiazole (HL(2)) or 2-(2-hydroxyphenyl)benzoxazole (HL(3))) afforded a series of p-tolylimido rhenium(v) complexes cis- or trans-(X,X)-[Re(p NTol)X2(L)(PPh3)].yMeCN (where X = Cl, Br; L = L(1), L(2), L(3) and y = 0-2) and [Re(p-NTol)X(L)(PPh3)2]Z.pPPh3 (where X = Cl, Br; Z = ReO4, PF6; L = L(1), L(2), L(3) and p = 0 or 1). The reported compounds were characterized by elemental analysis, FT-IR, NMR ((1)H, (13)C and (31)P) and X-ray crystallography. Interestingly, the halide ions of [Re(p-NTol)Cl2(L(1))(PPh3)].MeCN (1) and [Re(p NTol)Cl2(L(2))(PPh3)].2MeCN (3) are in cis relative dispositions, whereas the complexes [Re(p-NTol)Br2(L)(PPh3)] (L(1) for 2, L(2) for 4 and L(3) for 6) and [Re(p-NTol)Cl2(L(3))(PPh3)] (5) were found to be trans-(X,X) isomers. The compounds [Re(p-NTol)X(L)(PPh3)2](PF6) (X = Cl, Br; L = L(1) and L(2)) and [Re(p NTol)X(L(3))(PPh3)2](PF6).PPh3 (X = Cl, Br) have been tested in oxidative catalysis. A few compounds exhibited very good catalytic properties in oxidation of alcohols with tert-BuOOH (TBHP) in acetonitrile solution at moderate temperatures. Complex [Re(p-NTol)Cl(L(2))(PPh3)2]PF6 (13) is the catalyst of choice for oxidation of 1-phenylethanol to acetophenone (in 80% yield; turnover number attained 290 after 30 h) and cyclooctanol to cyclooctanone (in 88% yield). Notably lower activity has been found in the oxidation of alkanes with TBHP. Product distribution in the oxidation of methylcyclohexane indicates some steric hindrance around the reaction center. PMID- 26618896 TI - Postsynthesis of h-BN/Graphene Heterostructures Inside a STEM. AB - Combinations of 2D materials with different physical properties can form heterostructures with modified electrical, mechanical, magnetic, and optical properties. The direct observation of a lateral heterostructure synthesis is reported by epitaxial in-plane graphene growth from the step-edge of hexagonal BN (h-BN) within a scanning transmission electron microscope chamber. Residual hydrocarbon in the chamber is the carbon source. The growth interface between h BN and graphene is atomically identified as largely N-C bonds. This postgrowth method can form graphene nanoribbons connecting two h-BN domains with different twisting angles, as well as isolated carbon islands with arbitrary shapes embedded in the h-BN layer. The electronic properties of the vertically stacked h BN/graphene heterostructures are investigated by electron energy-loss spectroscopy (EELS). Low-loss EELS analysis of the dielectric response suggests a robust coupling effect between the graphene and h-BN layers. PMID- 26618898 TI - Ototoxicity (cochleotoxicity) classifications: A review. AB - OBJECTIVE: Drug-mediated ototoxicity, specifically cochleotoxicity, is a concern for patients receiving medications for the treatment of serious illness. A number of classification schemes exist, most of which are based on pure-tone audiometry, in order to assist non-audiological/non-otological specialists in the identification and monitoring of iatrogenic hearing loss. This review identifies the primary classification systems used in cochleototoxicity monitoring. By bringing together classifications published in discipline-specific literature, the paper aims to increase awareness of their relative strengths and limitations in the assessment and monitoring of ototoxic hearing loss and to indicate how future classification systems may improve upon the status-quo. DESIGN: Literature review. STUDY SAMPLE: PubMed identified 4878 articles containing the search term ototox*. RESULTS: A systematic search identified 13 key classification systems. Cochleotoxicity classification systems can be divided into those which focus on hearing change from a baseline audiogram and those that focus on the functional impact of the hearing loss. CONCLUSIONS: Common weaknesses of these grading scales included a lack of sensitivity to small adverse changes in hearing thresholds, a lack of high-frequency audiometry (>8 kHz), and lack of indication of which changes are likely to be clinically significant for communication and quality of life. PMID- 26618897 TI - Lithium Chloride Dependent Glycogen Synthase Kinase 3 Inactivation Links Oxidative DNA Damage, Hypertrophy and Senescence in Human Articular Chondrocytes and Reproduces Chondrocyte Phenotype of Obese Osteoarthritis Patients. AB - INTRODUCTION: Recent evidence suggests that GSK3 activity is chondroprotective in osteoarthritis (OA), but at the same time, its inactivation has been proposed as an anti-inflammatory therapeutic option. Here we evaluated the extent of GSK3beta inactivation in vivo in OA knee cartilage and the molecular events downstream GSK3beta inactivation in vitro to assess their contribution to cell senescence and hypertrophy. METHODS: In vivo level of phosphorylated GSK3beta was analyzed in cartilage and oxidative damage was assessed by 8-oxo-deoxyguanosine staining. The in vitro effects of GSK3beta inactivation (using either LiCl or SB216763) were evaluated on proliferating primary human chondrocytes by combined confocal microscopy analysis of Mitotracker staining and reactive oxygen species (ROS) production (2',7'-dichlorofluorescin diacetate staining). Downstream effects on DNA damage and senescence were investigated by western blot (gammaH2AX, GADD45beta and p21), flow cytometric analysis of cell cycle and light scattering properties, quantitative assessment of senescence associated beta galactosidase activity, and PAS staining. RESULTS: In vivo chondrocytes from obese OA patients showed higher levels of phosphorylated GSK3beta, oxidative damage and expression of GADD45beta and p21, in comparison with chondrocytes of nonobese OA patients. LiCl mediated GSK3beta inactivation in vitro resulted in increased mitochondrial ROS production, responsible for reduced cell proliferation, S phase transient arrest, and increase in cell senescence, size and granularity. Collectively, western blot data supported the occurrence of a DNA damage response leading to cellular senescence with increase in gammaH2AX, GADD45beta and p21. Moreover, LiCl boosted 8-oxo-dG staining, expression of IKKalpha and MMP-10. CONCLUSIONS: In articular chondrocytes, GSK3beta activity is required for the maintenance of proliferative potential and phenotype. Conversely, GSK3beta inactivation, although preserving chondrocyte survival, results in functional impairment via induction of hypertrophy and senescence. Indeed, GSK3beta inactivation is responsible for ROS production, triggering oxidative stress and DNA damage response. PMID- 26618899 TI - Environmental Risk Factors and Early-Life Exposures in Juvenile Idiopathic Arthritis: A Case-Control Study. AB - OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of disorders characterized by chronic arthritis in children with unknown etiology. Although research evaluating environmental or early-life exposures in JIA is scarce, there are data to suggest that infections, smoking exposure, and lack of breastfeeding play a role. This case-control study investigated the association of selected environmental and early-life risk factors with the development of JIA. METHODS: JIA cases were identified at a major pediatric rheumatology outpatient clinic. Each case was asked to identify up to 3 healthy playmates of similar age and same sex to serve as controls. Parents/caregivers of cases and controls completed a questionnaire on selected environmental and early-life exposures. Conditional logistic regression adjusted for age and socioeconomic status was used to determine the odds ratio (OR) for developing JIA with 95% confidence intervals (95% CIs) for the playmate-matched design. RESULTS: Included in the study were 225 JIA cases and 138 controls. Compared to playmate-matched controls, preterm delivery (OR 1.8 [95% CI 1.2-2.7]) was associated with JIA. There was no association between JIA and household smoking or maternal prenatal smoking, breastfeeding, hospitalization with infection in the first year of life, daycare attendance before 6 years of age, household pets, or residential area prior to the onset of JIA. CONCLUSION: There was no association between the previously reported risk factors of smoking, early-life infection, or breastfeeding and development of JIA in this study. The association of preterm delivery with JIA needs to be further studied. PMID- 26618900 TI - Improving Health Care Transition Services: Just Grow Up, Will You Please. PMID- 26618901 TI - Evaluation of uranium removal by Hydrilla verticillata (L.f.) Royle from low level nuclear waste under laboratory conditions. AB - The present study evaluated uranium (U) removal ability and tolerance to low level nuclear waste (LLNW) of an aquatic weed Hydrilla verticillata. Plants were screened for growth in 10%-50% waste treatments up to 3 d. Treatments of 20% and 50% waste imposed increasing toxicity with duration assessed in terms of change in fresh weight and in the levels of photosynthetic pigments and thiobarbituric acid-reactive substances. U concentration, however, did not show a progressive increase and was about 42 MUg g(-1) dw from 20% to 50% waste at 3 d. This suggested that a saturation stage was reached with respect to U removal due to increasing toxicity. However, in another experiment with 10% waste and 10% waste+10 ppm U treatments, plants showed an increase in U concentration with the maximum level approaching 426 MUg g(-1) dw at 3 d without showing any toxicity as compared to that at 20% and 50% waste treatments. Hence, plants possessed significant potential to take up U and toxicity of LLNW limited their U removal ability. This implies that the use of Hydrilla plants for U removal from LLNW is feasible at low concentrations and would require repeated harvesting at short intervals. PMID- 26618903 TI - Effects of Smoking on Central Corneal Thickness and the Corneal Endothelial Cell Layer in Otherwise Healthy Subjects. AB - OBJECTIVES: The effects of smoking on central corneal thickness (CCT), corneal endothelial cell density (ECD), and morphology were evaluated in otherwise healthy subjects. METHODS: The study included 103 current smokers and 106 healthy nonsmoking subjects without any eye disease apart from refractive errors. Endothelial cell density, percentage of hexagonality, and coefficient of variation (CV) in cell size were measured using noncontact specular microscopy. Central corneal thickness was measured by ultrasound pachymetry. RESULTS: The mean age of participants in the nonsmoker group was 31.4 +/- 5.1 years (18-60) and 33.0+/-9.1 years (18-58) in the current smoker group. The mean CCT value was 523.7+/-34 MUm in the nonsmoker group and 518.5+/-37 MUm in the smoker group. The mean ECD, CV, and percentage of hexagonality values were 2,881+/-293.7 cells per square millimeter, 32.5+/-6%, and 56.6+/-11% in the nonsmoker group, and 2,681+/ 323.9 cells per square millimeter, 33.4+/-5%, and 55.5+/-10% in the smoker group, respectively. Although there was no difference between the groups in terms of CCT, CV, and percentage of hexagonality values, a significant difference was determined in the case of ECD values[ZERO WIDTH SPACE][ZERO WIDTH SPACE] (P<0.001). The smoker group comprised 67 light smokers (65.0%) and 36 (35.0%) heavy smokers. Between these groups, there was no statistically significant difference in the mean values of CCT, ECD, CV, and the percentage of hexagonality. CONCLUSIONS: Although cigarette smoking has no effect on cell polymorphism and polymegethism, the results suggest that smoking reduces endothelial cell count. PMID- 26618904 TI - Seasonal Variation in the Presentation of Infectious Keratitis. AB - INTRODUCTION: Infectious keratitis is a common ophthalmic disease with the potential for severe ocular morbidity. Multiple studies have described various risk factors for the development of infectious keratitis. The purpose of this study was to analyze the seasonal variation in the presentation of infectious keratitis, and also seasonal changes in its etiologies and risk factors. METHODS: A retrospective chart review was performed on consecutive patients presenting to the emergency department at our tertiary care urban hospital center who were diagnosed with infectious keratitis from 2008 to 2013. A chi-square analysis was performed to determine whether a significant seasonal variation existed between the month, season, frequency of presentation of ulcers, and other risk factors. RESULTS: A total of 155 patients-53 men and 102 women-with a mean age of 40 (range, 3-97; median, 36) diagnosed with infectious keratitis were included in the analysis. Sixty-nine (44.5%) ulcers presented in the summer, 19 (12.3%) in the fall, 34 (21.9%) in the winter, and 33 (21.3%) in the spring (P<0.0001). Seventeen (11%) patients experienced diabetes mellitus, 60 (39%) were contact lens wearers, 12 (8%) ulcers occurred in the setting of trauma, and 19 (12%) patients underwent previous ocular surgery. A total of 92 ulcers were cultured, of which 53.8% were positive in the summer, 42.9% in the fall, 55.0% in the winter, and 42.1% in the spring. A significant seasonal variation in the frequency of 1 organism, Pseudomonas aeruginosa, was identified (P=<0.0001); up to 47.6% of culture-positive ulcers in the summer were P. aeruginosa positive, whereas cultures in the remaining seasons were 0, 9.1% and 12.5% positive for this organism. DISCUSSION: The summer months have a higher frequency of infectious keratitis and P. aeruginosa positivity in this study. Possible factors leading to this increased summer presentation include warmer temperatures, higher humidity, and greater ocular exposure to water. Clinicians should increase their vigilance and education to high-risk patients during these periods and potentially modify empiric treatment regimens. PMID- 26618902 TI - Ancestry of the Brazilian TP53 c.1010G>A (p.Arg337His, R337H) Founder Mutation: Clues from Haplotyping of Short Tandem Repeats on Chromosome 17p. AB - Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific spectrum of early cancers, defining the Li-Fraumeni Syndrome (LFS). A germline mutation at codon 337 (p.Arg337His, c1010G>A) is found in about 0.3% of the population of Southern Brazil. This mutation is associated with partially penetrant LFS traits and is found in the germline of patients with early cancers of the LFS spectrum unselected for familial history. To characterize the extended haplotypes carrying the mutation, we have genotyped 9 short tandem repeats on chromosome 17p in 12 trios of Brazilian p.Arg337His carriers. Results confirm that all share a common ancestor haplotype of Caucasian/Portuguese-Iberic origin, distant in about 72-84 generations (2000 years assuming a 25 years intergenerational distance) and thus pre-dating European migration to Brazil. So far, the founder p.Arg337His haplotype has not been detected outside Brazil, with the exception of two residents of Portugal, one of them of Brazilian origin. On the other hand, increased meiotic recombination in p.Arg337His carriers may account for higher than expected haplotype diversity. Further studies comparing haplotypes in populations of Brazil and of other areas of Portuguese migration are needed to understand the historical context of this mutation in Brazil. PMID- 26618905 TI - Temporospatial Control of Graphene Wettability. AB - The reversible migration of adatoms along a basal plane of graphene under electrical bias is experimentally demonstrated. Single-layer graphene oxide with partial oxygen adatom coverage is utilized for this demonstration. The intensity ratio of G and G' Raman modes is used to determine the oxygen adatoms migration. Finally, reversible wettability property of graphene due to oxygen adatom migration is demonstrated. PMID- 26618906 TI - Superior adsorption of pharmaceutical molecules by highly porous BN nanosheets. AB - Highly porous boron nitride nanosheets (BNNSs) were tested as a re-usable adsorbent for the removal of pharmaceuticals from aqueous solution. The BNNSs exhibit both unprecedentedly high adsorption capacities and excellent recyclability while maintaining their high adsorption capacity by a simple regeneration process. These advantages render BNNSs a promising material for water remediation applications. PMID- 26618908 TI - People mind wander more during massed than spaced inductive learning. AB - This article investigates the relation between mind wandering and the spacing effect in inductive learning. Participants studied works of art by different artists grouped in blocks, where works by a particular artist were either presented all together successively (the massed condition), or interleaved with the works of other artists (the spaced condition). The works of 24 artists were shown, with 12, 15, or 18 works by each artist being provided as exemplars. Later, different works by the same artists were presented for a test of the artists' identity. During the course of studying these works, participants were probed for mind wandering. It was found that people mind wandered more when the exemplars were presented in a massed rather than in a spaced manner, especially as the task progressed. There was little mind wandering and little difference between massed and spaced conditions toward the beginning of study. People were better able to correctly attribute the new works to the appropriate artist (inductive learning) when (a) they were in the spaced condition and (b) they had not been mind wandering. This research suggests that inductive learning may be influenced by mind wandering and that the impairment in learning with massed practice (compared to spaced practice) may be attributable, at least in part, to attentional factors-people are "on task" less fully when the stimuli are massed rather than spaced. (PsycINFO Database Record PMID- 26618907 TI - Nanoconnectomic upper bound on the variability of synaptic plasticity. AB - Information in a computer is quantified by the number of bits that can be stored and recovered. An important question about the brain is how much information can be stored at a synapse through synaptic plasticity, which depends on the history of probabilistic synaptic activity. The strong correlation between size and efficacy of a synapse allowed us to estimate the variability of synaptic plasticity. In an EM reconstruction of hippocampal neuropil we found single axons making two or more synaptic contacts onto the same dendrites, having shared histories of presynaptic and postsynaptic activity. The spine heads and neck diameters, but not neck lengths, of these pairs were nearly identical in size. We found that there is a minimum of 26 distinguishable synaptic strengths, corresponding to storing 4.7 bits of information at each synapse. Because of stochastic variability of synaptic activation the observed precision requires averaging activity over several minutes. PMID- 26618909 TI - Dissociating perception from action during conscious and unconscious conflict adaptation. AB - The detection of a conflict between relevant and irrelevant information on a given trial typically results in a smaller conflict effect on the next trial. This sequential effect has been interpreted as an expression of cognitive control implemented to resolve conflict. In this context, 2 different but related issues have received increasing attention in the literature. The first issue is whether the detection of motor conflict is necessary to induce cognitive control or, alternatively, whether the detection of perceptual conflict is sufficient. The second issue concerns whether awareness of the conflict is necessary to induce cognitive control. Here, we address both issues in a single design. Our reaction time (RT) results indicate that conflict-driven control is domain-specific. The detection of perceptual conflict on the previous trial selectively reduces perceptual conflict on the next trial. Similarly, the detection of motor conflict on the previous trial selectively reduces motor conflict on the next trial. For errors, adaptive control seemed to be more general: The detection of perceptual or motor conflict on the previous trial reduced the frequency of errors on response-conflict trials. Furthermore, unconsciously triggered conflict adaptation was observed, but not systematically. Results on errors provide some evidence that sensitivity to an unconscious conflict on the previous trial reduces the frequency of errors on the current trial. For RT analyses however, unconscious conflict appeared not to be sufficient to induce cognitive control. This pattern of results is in line with previous studies examining the role of consciousness in conflict adaptation. (PsycINFO Database Record PMID- 26618910 TI - Dissociating working memory updating and automatic updating: The reference-back paradigm. AB - Working memory (WM) updating is a controlled process through which relevant information in the environment is selected to enter the gate to WM and substitute its contents. We suggest that there is also an automatic form of updating, which influences performance in many tasks and is primarily manifested in reaction time sequential effects. The goal of the present study was to dissociate WM updating and automatic updating, characterize the nature of these operations and identify the memory system responsible for each. In addition, we investigated the relationship between WM updating and the P3 event-related potential component. In Experiment 1, we compared the sequential processes in 1-back and 2-alternative forced choice tasks. These results indicated differential sources of sequential processes in the 2 tasks. We proposed that automatic updating operates in long term memory on representations separate from WM representations. In addition, the event-related potential results of Experiment 1 are inconsistent with the idea that P3 is triggered through WM updating. Subsequently, in Experiments 2-3, we decomposed the 1-back task to major subprocesses. To this end, a new paradigm is introduced: the reference-back task. This paradigm facilitated the empirical distinction between automatic updating, comparison processes, gating and WM updating, within the same task. The results replicated the separate effects of WM updating and automatic updating on performance, and they provided behavioral evidence for a gating mechanism that separates WM from long-term memory. (PsycINFO Database Record PMID- 26618912 TI - The time course of familiar metonymy. AB - Metonymic words have multiple related meanings, such as college, as in the building ("John walked into the college") or the educational institution ("John was promoted by the college"). Most researchers have found support for direct access models of metonymy but one recent study, Lowder and Gordon (2013), found delayed reading times for metonymic sentences relative to literal controls, in support of an indirect access account. We conducted a speed-accuracy-tradeoff experiment to test whether their result was caused by lower retrieval probabilities, consistent with direct or indirect access models of metonymy, or slower retrieval dynamics, consistent only with indirect access accounts. We found lower retrieval probabilities for the metonymic sentences but no difference in the dynamics parameters. These results therefore suggest that literal senses do not have priority during processing and that established metonymic senses can be accessed directly. (PsycINFO Database Record PMID- 26618911 TI - The primacy of abstract syllables in Chinese word production. AB - Convergent evidence suggests that syllables play a primary and distinctive role in the phonological phase of Mandarin Chinese word production. Specifically, syllables are selected before other phonological components and guide subsyllabic encoding. The proximity of phonological syllables to word representations in Chinese languages ensures that they are also activated automatically by word perception. Therefore, in contrast to Indo-European languages, syllables but not necessarily subsyllabic components such as initial consonants can be perceptually primed in production. We tested this prediction in 2 masked-priming experiments. To isolate relevant phonological activation originating in primes, we used single character masked primes whose corresponding tones and lexical meanings always differed from those of the targets' first morphemes. Related primes potentially activated the atonal first syllables or the first consonants of target words. To strongly engage production-specific processes, we used pictures as prompts for disyllabic target words. Facilitation relative to unrelated controls was observed only in the syllable sharing condition. If anything, sharing of initial consonants had a negative valence, perhaps indicative of competition among similar coactivated words or syllables. These findings corroborate the view that abstract syllables are the first selected, proximate phonological units in Chinese word production, and that phonemic segments play a subordinate role. (PsycINFO Database Record PMID- 26618913 TI - Attention and the testing effect. AB - Memory retrieval often enhances still later memory as evidenced by the testing effect. Divided attention (DA) is known to produce different effects on encoding and retrieval, substantially disrupting the former and often producing little effect on the latter. The present experiments examine whether the mnemonic consequences of retrieval are similarly resilient in the face of distraction or if they have a similar sensitivity to DA as study-based encoding. In 2 experiments, participants initially studied a set of word pairs (Phase 1) then engaged in restudy of some pairs and retrieval practice of others (Phase 2), followed by either an immediate or (24-hr) delayed final cued-recall test (Phase 3). Phase 2 restudy and retrieval practice occurred under full attention (FA) or DA. Phase 2 performance replicated earlier research in finding little effect of DA on retrieval success, and greater disruption to the secondary task in the retrieval than restudy condition. More importantly, the testing effect on the final test (the difference between the retrieval and restudy conditions) was greater in the DA than FA condition. Final recall was substantially reduced by DA in the restudy condition but not in the retrieval condition. This pattern was found for related and unrelated word pairs, with feedback during retrieval practice and without, for immediate as well as delayed final tests, and for high as well as low performance on the secondary task. The encoding effects of retrieval appear to be more resilient in the face of distraction than the encoding effects of restudy. (PsycINFO Database Record PMID- 26618914 TI - Incidental biasing of attention from visual long-term memory. AB - Holding recently experienced information in mind can help us achieve our current goals. However, such immediate and direct forms of guidance from working memory are less helpful over extended delays or when other related information in long term memory is useful for reaching these goals. Here we show that information that was encoded in the past but is no longer present or relevant to the task also guides attention. We examined this by associating multiple unique features with novel shapes in visual long-term memory (VLTM), and subsequently testing how memories for these objects biased the deployment of attention. In Experiment 1, VLTM for associated features guided visual search for the shapes, even when these features had never been task-relevant. In Experiment 2, associated features captured attention when presented in isolation during a secondary task that was completely unrelated to the shapes. These findings suggest that long-term memory enables a durable and automatic type of memory-based attentional control. (PsycINFO Database Record PMID- 26618915 TI - Development of a Community-Based Rehabilitation Intervention for People with Schizophrenia in Ethiopia. AB - BACKGROUND: Community-based rehabilitation (CBR) is a multi-sectoral strategy to improve the functioning and quality of life of people with disabilities. The RISE (Rehabilitation Intervention for people with Schizophrenia in Ethiopia) trial will evaluate the effectiveness of CBR for people with schizophrenia in Ethiopia. Nevertheless, the components of CBR that are both feasible and likely to prove effective in low and middle-income countries such as Ethiopia are unclear. METHODS: In this study intervention development work was undertaken to design a CBR intervention that is acceptable and feasible in the local context. The development work consisted of five phases. 1: Identify potential components of CBR for schizophrenia, 2: Situational analysis, 3: Determine feasibility of CBR (Theory of Change workshops with experts and local stakeholders), 4: Determine acceptability of CBR (16 in-depth interviews and five focus group discussions with people with schizophrenia, caregivers, health workers and community leaders) and 5: Synthesise results to finalise intervention. A Theory of Change map was constructed showing the causal pathway for how we expect CBR to achieve its impact. RESULTS: People with schizophrenia in rural Ethiopia experience family conflict, difficulty participating in work and community life, and stigma. Stakeholders perceived CBR to be acceptable and useful to address these problems. The focus of CBR will be on the individual developing the skills and confidence to perform their previous or desired roles and activities. To ensure feasibility, non-health professionals will be trained to deliver CBR and provide supervision, rather than mental health specialists. Novel components of CBR for schizophrenia included family intervention and dealing with distressing symptoms. Microfinance was excluded due to concerns about stress and exploitation. Community mobilisation was viewed as essential to ensure the effectiveness and sustainability of CBR. CONCLUSION: Extensive formative research using a variety of methods has enabled the design of a culturally appropriate CBR intervention for people with schizophrenia that is acceptable and feasible. PMID- 26618916 TI - Anisotropic Lithium Ion Conductivity in Single-Ion Diblock Copolymer Electrolyte Thin Films. AB - Well-defined single-ion diblock copolymers consisting of a Li-ion conductive poly(styrenesulfonyllithium(trifluoromethylsulfonyl)imide) (PSLiTFSI) block associated with a glassy polystyrene (PS) block have been synthesized via reversible addition fragmentation chain transfer polymerization. Conductivity anisotropy ratio up to 1000 has been achieved from PS-b-PSLiTFSI thin films by comparing Li-ion conductivities of out-of-plane (aligned) and in-plane (antialigned) cylinder morphologies at 40 degrees C. Blending of PS-b-PSLiTFSI thin films with poly(ethylene oxide) homopolymer (hPEO) enables a substantial improvement of Li-ion transport within aligned cylindrical domains, since hPEO, preferentially located in PSLiTFSI domains, is an excellent lithium-solvating material. Results are also compared with unblended and blended PSLiTFSI homopolymer (hPSLiTFSI) homologues, which reveals that ionic conductivity is improved when thin films are nanostructured. PMID- 26618917 TI - Achieving Harmony among Different Social Identities within the Self-Concept: The Consequences of Internalising a Group-Based Philosophy of Life. AB - It can be hard for individuals to manage multiple group identities within their self-concept (e.g., being a Christian and a woman). We examine how the inter identity fit between potentially conflicting identities can become more harmonious through a self-defining group philosophy for life. Specifically, we test the hypothesis that holistic group identities (based in group philosophies for life that prescribe the behavior of their members in any situation, such as religion) become more strongly related to other identities in the self-concept (e.g., gender) when they are strongly self-defining (i.e., devotedly applied to daily life). In three studies we investigated the inter-identity fit between individuals' (highly holistic) religious identity and (less holistic) gender identity. Results provided converging support for our hypothesis across diverging methods (explicit questionnaires, more implicit associations, and a novel network analysis of group traits). We discuss the importance of understanding how some (i.e., holistic and self-defining) group identities may harmonize otherwise less harmonious group identities within one's self-concept. PMID- 26618918 TI - The essential role of coumarin secretion for Fe acquisition from alkaline soil. AB - Plant productivity is limited by the scarcity of the essential micronutrient iron particularly in alkaline soils. The root secretion of phenolics has long been recognized as a component of the acidification-reduction strategy to acquire iron (strategy I). However, very little molecular insight into this process was available until recently several research groups independently discovered the important role of coumarins for the growth of Arabidopsis thaliana under Fe limited conditions. Genome-wide analyses of iron deficiency responses, mutant screening and metabolomics experiments all converged on the finding that the synthesis and root exudation of scopoletin, esculetin and other coumarins is essential for iron uptake from substrates with low iron availability. Here we describe the evidence supporting this conclusion and discuss important questions that now have to be addressed in order to better understand the mechanistic basis of coumarin-dependent iron uptake and its significance within the plant kingdom. PMID- 26618919 TI - Synthesis of Oxazoles by Tandem Cycloisomerization/Allylic Alkylation of Propargyl Amides with Allylic Alcohols: Zn(OTf)2 as pi Acid and sigma Acid Catalyst. AB - A Zn(OTf)2-catalyzed tandem cycloisomerization/allylic alkylation of N (propargyl)arylamides and allylic alcohols to produce oxazole derivatives has been successfully developed. The zinc catalyst served as pi acid and also sigma acid in this reaction. The target allylic oxazoles have been transformed into multisubstituted diene structures, which are potential aggregation-induced emission active optical materials. PMID- 26618920 TI - Introduction: understanding mechanisms of the actions of rifaximin in selected gastrointestinal diseases. AB - BACKGROUND: Historically, the beneficial effects of the nonsystemic oral agent rifaximin on various gastrointestinal (GI) disorders have been attributed to direct antibiotic activity on gut microbiota. However, data are accumulating to suggest that other nonantibacterial effects may be involved in rifaximin efficacy. AIM: To explore the mechanisms of action of rifaximin that may underlie its clinical benefits in travellers' diarrhoea, hepatic encephalopathy and other cirrhosis complications, inflammatory bowel diseases, and irritable bowel syndrome with diarrhoea. METHODS: Gastroenterology experts convened a round-table discussion to address clinical and pre-clinical rifaximin data pertaining to select GI diseases and the potential mechanisms of action that underlie rifaximin efficacy profiles. As preparation, the literature was searched for publications related to rifaximin, its mechanisms of action, and its efficacy in travellers' diarrhoea, hepatic encephalopathy and other cirrhosis-related complications, inflammatory bowel diseases and irritable bowel syndrome. RESULTS: Gut microbiota dysbiosis and proinflammatory activities are thought to significantly contribute to disease pathophysiology of these conditions. Rifaximin may resolve gut microbiota dysbiosis by promoting GI colonisation of beneficial bacterial species without drastic alterations in overall diversity. Rifaximin-induced changes in the production and metabolism of bacteria-produced agents (e.g. deoxycholic acid, lipopolysaccharides) also may help preserve normal gut microbiota. Rifaximin may suppress local and systemic inflammatory processes by preserving epithelial function (e.g. limiting bacterial translocation), modulating bacterial virulence and reducing proinflammatory cytokine production. CONCLUSION: The commonality of pathological mechanisms underlying multiple GI diseases and the ability of rifaximin to modulate the gut microenvironment (i.e. gut microenvironment modulator) may explain its diverse efficacy profile. PMID- 26618921 TI - Review article: the antimicrobial effects of rifaximin on the gut microbiota. AB - BACKGROUND: Disruption of the gut microbiota through use of systemic antimicrobials or activation of the mucosal inflammatory response by pathogens can cause dysregulation of the intestinal mucosa. AIM: To explore the mechanisms of action of rifaximin that may underlie its clinical benefits in travellers' diarrhoea (TD). METHODS: A literature search was performed using the terms 'rifaximin' and 'L/105' in combination with the terms 'in vitro activity', 'diarrhea', 'microbiota' and 'gut flora'. RESULTS: Rifaximin has been traditionally identified as a nonsystemic, broad-spectrum, bactericidal antibiotic. Evidence shows that the activity of rifaximin against enteropathogens in this setting is likely enhanced by its increased solubility in the presence of bile acids in the small intestine. Results of clinical studies show that although rifaximin is efficacious in TD, a clinical cure often occurs without apparent bacterial eradication and with minimal effect on the gut microbiota, suggesting an effect of rifaximin other than direct antibiotic activity. CONCLUSIONS: Although definitive studies on the effect of rifaximin on the gut microbiota in large cohorts of healthy volunteers or patients have not been published, pre clinical studies provide some insight. These studies have shown that rifaximin may have effects on both the pathogen and host, including direct effects on pathogenic bacteria (such as reducing the expression of bacterial virulence factors) and indirect effects on the host (such as inhibiting bacterial attachment and internalisation at the intestinal mucosa and reducing mucosal inflammation). PMID- 26618922 TI - Review article: potential mechanisms of action of rifaximin in the management of hepatic encephalopathy and other complications of cirrhosis. AB - BACKGROUND: Progressive gut milieu (microbiota) changes occur in patients with cirrhosis and are associated with complications [e.g. hepatic encephalopathy (HE)]. AIM: To examine the role of rifaximin in the management of HE and other complications of cirrhosis, including potential mechanisms of action and the need for future studies. METHODS: A literature search was conducted using the keywords 'rifaximin', 'hepatic encephalopathy', 'ascites', 'variceal bleeding', 'peritonitis', 'portal hypertension', 'portopulmonary hypertension' and 'hepatorenal syndrome'. RESULTS: The nonsystemic agent rifaximin reduces the risk of HE recurrence and HE-related hospitalisations in cirrhosis. In patients with cirrhosis, rifaximin modulates the bacterial composition of the gut microbiota without a consistent effect on overall faecal microbiota composition. However, rifaximin can impact the function or activities of the gut microbiota. For example, rifaximin significantly increased serum levels of long-chain fatty acids and carbohydrate metabolism intermediates in patients with minimal HE. Rifaximin also favourably affects serum proinflammatory cytokine and faecal secondary bile acid levels. CONCLUSIONS: The gut microenvironment and associated microbiota play an important role in the pathogenesis of HE and other cirrhosis-related complications. Rifaximin's clinical activity may be attributed to effects on metabolic function of the gut microbiota, rather than a change in the relative bacterial abundance. PMID- 26618923 TI - Review article: the potential mechanisms of action of rifaximin in the management of inflammatory bowel diseases. AB - BACKGROUND: Gut microbiota dysbiosis contributes to the pathogenesis of inflammatory bowel diseases (IBD). Although the microbiota's role in IBD pathogenesis, specifically Crohn's disease (CD), provides a rationale for antibiotic treatment, antibiotic use in CD remains controversial. Rifaximin, traditionally identified as a nonsystemic bactericidal antibiotic, may be therapeutically beneficial for inducing CD remission. AIM: To examine the role of rifaximin in the management of IBD and its potential mechanisms of action. METHODS: A literature search using the following strategy: ('inflammatory bowel disease' OR 'Crohn's' OR 'ulcerative'), 'rifaximin' AND ('barrier' OR 'translocation' OR 'adhesion' OR 'internalization' OR 'pregnane X'), AND 'pregnane X' AND ('Crohn's' OR 'ulcerative colitis' OR 'inflammatory bowel disease'). RESULTS: In vitro data suggest rifaximin mediates changes in epithelial cell physiology and reduces bacterial attachment and internalisation. In experimental colitis models, rifaximin antagonised the effects of tumour necrosis factor-alpha on intestinal epithelial cells by activating pregnane X receptor, which inhibits nuclear factor-kappaB-mediated proinflammatory mediators and induces detoxification genes (e.g. multidrug resistance 1 and cytochrome P450 3A4). Rifaximin also inhibits bacterial translocation into the mesenteric lymph nodes. CONCLUSION: Accumulating evidence suggests that mechanisms of action of rifaximin in IBD may not be limited to direct bactericidal activity; therefore, rifaximin could potentially be redefined as a gut environment modulator. PMID- 26618924 TI - Review article: potential mechanisms of action of rifaximin in the management of irritable bowel syndrome with diarrhoea. AB - BACKGROUND: The role of gut microbiota in the pathophysiology of irritable bowel syndrome (IBS) is supported by various lines of evidence, including differences in mucosal and faecal microbiota between patients with IBS and healthy individuals, development of post-infectious IBS, and the efficacy of some probiotics and nonsystemic antibiotics (e.g. rifaximin). AIM: To review the literature regarding the role of rifaximin in IBS and its potential mechanism(s) of action. METHODS: A literature search was conducted using the terms 'rifaximin', 'irritable bowel syndrome' and 'mechanism of action'. RESULTS: Rifaximin was approved in 2015 for the treatment of IBS with diarrhoea. In contrast to other currently available IBS therapies that require daily administration to maintain efficacy, 2-week rifaximin treatment achieved symptom improvement that persisted >=12 weeks post-treatment. The mechanisms of action of rifaximin, therefore, may extend beyond direct bactericidal effects. Data suggest that rifaximin may decrease host proinflammatory responses to bacterial products in patients with IBS. In some cases, small intestinal bacterial overgrowth (SIBO) may play a role in the clinical symptoms of IBS. Because of the high level of solubility of rifaximin in the small intestine, rifaximin may reset microbial diversity in this environment. Consistent with this hypothesis, rifaximin has antibiotic efficacy against isolates derived from patients with SIBO. CONCLUSION: Resetting microbial diversity via rifaximin use may lead to a decrease in bacterial fermentation and a reduction in the clinical symptoms of IBS. PMID- 26618925 TI - Loss of Ifnar1 in Pancreatic Acinar Cells Ameliorates the Disease Course of Acute Pancreatitis. AB - Type I interferon constitutes an essential component of the combinational therapy against viral disease. Acute pancreatitis is one side effect of type I interferon based therapy, implying that activation of type I interferon signaling affects the homeostasis and integrity of pancreatic acinar cells. Here, we investigated the role of type I interferon signaling in pancreatic acinar cells using a caerulein-induced murine model of acute pancreatitis. Pancreas-specific ablation of interferon (alpha and beta) receptor 1 (Ifnar1) partially protected animals from caerulein-induced pancreatitis, as demonstrated by reduced tissue damage. Profiling of infiltrating immune cells revealed that this dampened tissue damage response correlated with the number of macrophages in the pancreas. Pharmacologic depletion of macrophages reversed the protective effect of Ifnar1 deficiency. Furthermore, expression of chemokine (C-C motif) ligand 2 (Ccl2), a potent factor for macrophage recruitment, was significantly increased in the Ifnar1-deficient pancreas. Thus, type I interferon signaling in pancreatic acinar cells controls pancreatic homeostasis by affecting the macrophage-mediated inflammatory response in the pancreas. PMID- 26618926 TI - Transcriptome sequencing reveals population differentiation in gene expression linked to functional traits and environmental gradients in the South African shrub Protea repens. AB - Understanding the environmental and genetic mechanisms underlying locally adaptive trait variation across the ranges of species is a major focus of evolutionary biology. Combining transcriptome sequencing with common garden experiments on populations spanning geographical and environmental gradients holds promise for identifying such mechanisms. The South African shrub Protea repens displays diverse phenotypes in the wild along drought and temperature gradients. We grew plants from seeds collected at 19 populations spanning this species' range, and sequenced the transcriptomes of these plants to reveal gene pathways associated with adaptive trait variation. We related expression in co expressed gene networks to trait phenotypes measured in the common garden and to source population climate. We found that expression in gene networks correlated with source-population environment and with plant traits. In particular, the activity of gene networks enriched for growth related pathways correlated strongly with source site minimum winter temperature and with leaf size, stem diameter and height in the garden. Other gene networks with enrichments for photosynthesis related genes showed associations with precipitation. Our results strongly suggest that this species displays population-level differences in gene expression that have been shaped by source population site climate, and that are reflected in trait variation along environmental gradients. PMID- 26618927 TI - Autoantibodies against Cytochrome P450 Side-Chain Cleavage Enzyme in Dogs (Canis lupus familiaris) Affected with Hypoadrenocorticism (Addison's Disease). AB - Canine hypoadrenocorticism likely arises from immune-mediated destruction of adrenocortical tissue, leading to glucocorticoid and mineralocorticoid deficiency. In humans with autoimmune Addison's disease (AAD) or autoimmune polyendocrine syndrome (APS), circulating autoantibodies have been demonstrated against enzymes associated with adrenal steroid synthesis. The current study investigates autoantibodies against steroid synthesis enzymes in dogs with spontaneous hypoadrenocorticism. Coding regions of canine CYP21A2 (21 hydroxylase; 21-OH), CYP17A1 (17-hydroxylase; 17-OH), CYP11A1 (P450 side-chain cleavage enzyme; P450scc) and HSD3B2 (3beta hydroxysteroid dehydrogenase; 3betaHSD) were amplified, cloned and expressed as 35S-methionine radiolabelled recombinant protein. In a pilot study, serum samples from 20 dogs with hypoadrenocorticism and four unaffected control dogs were screened by radio immunoprecipitation assay. There was no evidence of reactivity against 21-OH, 17 OH or 3betaHSD, but five dogs with hypoadrenocorticism showed immunoreactivity to P450scc compared with controls. Serum samples were subsequently obtained from 213 dogs diagnosed with hypoadrenocorticism and 110 dogs from a hospital control population. Thirty control dogs were randomly selected to establish a threshold for antibody positivity (mean + 3 * standard deviation). Dogs with hypoadrenocorticism were more likely to be P450scc autoantibody positive than hospital controls (24% vs. 1.2%, respectively; p = 0.0016). Sex was significantly associated with the presence of P450scc autoantibodies in the case population, with 30% of females testing positive compared with 17% of males (p = 0.037). Significant associations with breed (p = 0.015) and DLA-type (DQA1*006:01 allele; p = 0.017) were also found. This cross-sectional study indicates that P450scc autoantibodies are present in a proportion of dogs affected with hypoadrenocorticism. PMID- 26618928 TI - Parental concerns towards children and adolescents with epilepsy in Sri Lanka- Qualitative study. AB - PURPOSE: Social, cultural, psychological and many other factors significantly impact the lives of epileptic children and their families. Parental concerns towards their children are less known in south Asian children with epilepsy. We aimed to identify the parental concerns regarding their children and adolescents with epilepsy in Sri Lanka. METHODS: We carried out qualitative study in 3 districts of Sri Lanka, comprising 16 in-depth interviews with parents of children and adolescents with epilepsy and 3 focus group discussions with primary caregivers of epileptic children and key informants (schoolteachers, public health staffs). Content analysis of the interview data was performed. RESULTS: Parental concerns were spread among seven themes that emerged from the content analysis. These concerns were about the child's functioning in areas such as physical, behavioural, psychological and social, education, concerns related to anti-epileptic therapy and epilepsy as a disease. Parents were more concerned about their child's safety, educational achievements and future prospects in terms of employment and marriage. Unpredictability of seizures, fear of stigma and unawareness of epilepsy were the main reasons voiced by the parents for having such concerns. Increased concern and perception of vulnerability was seen among parents whose children had epilepsy and co-morbid illness. CONCLUSIONS: Parental concerns towards their children and adolescents show a multidimensional construct. Unpredictability of seizures, fear of stigma and unawareness of epilepsy were identified as key influential factors in moulding the parental concerns. PMID- 26618929 TI - Inferring the Forces Controlling Metaphase Kinetochore Oscillations by Reverse Engineering System Dynamics. AB - Kinetochores are multi-protein complexes that mediate the physical coupling of sister chromatids to spindle microtubule bundles (called kinetochore (K)-fibres) from respective poles. These kinetochore-attached K-fibres generate pushing and pulling forces, which combine with polar ejection forces (PEF) and elastic inter sister chromatin to govern chromosome movements. Classic experiments in meiotic cells using calibrated micro-needles measured an approximate stall force for a chromosome, but methods that allow the systematic determination of forces acting on a kinetochore in living cells are lacking. Here we report the development of mathematical models that can be fitted (reverse engineered) to high-resolution kinetochore tracking data, thereby estimating the model parameters and allowing us to indirectly compute the (relative) force components (K-fibre, spring force and PEF) acting on individual sister kinetochores in vivo. We applied our methodology to thousands of human kinetochore pair trajectories and report distinct signatures in temporal force profiles during directional switches. We found the K-fibre force to be the dominant force throughout oscillations, and the centromeric spring the smallest although it has the strongest directional switching signature. There is also structure throughout the metaphase plate, with a steeper PEF potential well towards the periphery and a concomitant reduction in plate thickness and oscillation amplitude. This data driven reverse engineering approach is sufficiently flexible to allow fitting of more complex mechanistic models; mathematical models of kinetochore dynamics can therefore be thoroughly tested on experimental data for the first time. Future work will now be able to map out how individual proteins contribute to kinetochore-based force generation and sensing. PMID- 26618930 TI - Heat Transfer and Thermal Stress Analysis of a Mandibular Molar Tooth Restored by Different Indirect Restorations Using a Three-Dimensional Finite Element Method. AB - PURPOSE: Daily consumption of food and drink creates rapid temperature changes in the oral cavity. Heat transfer and thermal stress caused by temperature changes in restored teeth may damage the hard and soft tissue components, resulting in restoration failure. This study evaluates the temperature distribution and related thermal stress on mandibular molar teeth restored via three indirect restorations using three-dimensional (3D) finite element analysis (FEA). MATERIALS AND METHODS: A 3D finite element model was constructed of a mandibular first molar and included enamel, dentin, pulp, surrounding bone, and indirect class 2 restorations of type 2 dental gold alloy, ceramic, and composite resin. A transient thermal FEA was performed to investigate the temperature distribution and the resulting thermal stress after simulated temperature changes from 36 degrees C to 4 or 60 degrees C for a 2-second time period. RESULTS: The restoration models had similar temperature distributions at 2 seconds in both the thermal conditions. Compared with 60 degrees C exposure, the 4 degrees C condition resulted in thermal stress values of higher magnitudes. At 4oC, the highest stress value observed was tensile stress (56 to 57 MPa), whereas at 60 degrees C, the highest stress value observed was compressive stress (42 to 43 MPa). These stresses appeared at the cervical region of the lingual enamel. The thermal stress at the restoration surface and resin cement showed decreasing order of magnitude as follows: composite > gold > ceramic, in both thermal conditions. CONCLUSIONS: The properties of the restorative materials do not affect temperature distribution at 2 seconds in restored teeth. The pulpal temperature is below the threshold for vital pulp tissue (42oC). Temperature changes generate maximum thermal stress at the cervical region of the enamel. With the highest thermal expansion coefficient, composite resin restorations exhibit higher stress patterns than ceramic and gold restorations. PMID- 26618931 TI - Surface Charge Convertible and Biodegradable Synthetic Zwitterionic Nanoparticles for Enhancing Cellular Drug Uptake. AB - To enhance drug cellular uptake, a biodegradable terpolymer is synthesized using taurine, N,N-Bis (acryloyl) cystamine, and dodecylamine as raw materials by Michael addition terpolymerization. The terpolymer is transformed to zwitterionic nanoparticles (NPs) through self-assembly. The surface charge of the NPs is convertible from negative at pH 7.4 to positive at pH 6.5, which endows the NPs' excellent nonfouling feature in bloodstream and effective uptake in tumor cells. The NPs display varied morphologies from solid micelles to polymersomes and nanorods depending on molar ratios of the structural units involved. The NPs can be biodegraded in l-glutathione (GSH) solution due to the split of disulfide bonds in main chains of the terpolymers. The NPs demonstrate good pH/reducing responsiveness in drug delivery and can be potentially used as anticancer drug vehicles for enhancement of cellular uptake of anticancer drug. PMID- 26618932 TI - Evaluation of the potential for virus dispersal during hand drying: a comparison of three methods. AB - AIMS: To use a MS2 bacteriophage model to compare three hand-drying methods, paper towels (PT), a warm air dryer (WAD) and a jet air dryer (JAD), for their potential to disperse viruses and contaminate the immediate environment during use. METHODS AND RESULTS: Participants washed their gloved hands with a suspension of MS2 bacteriophage and hands were dried with one of the three hand drying devices. The quantity of MS2 present in the areas around each device was determined using a plaque assay. Samples were collected from plates containing the indicator strain, placed at varying heights and distances and also from the air. Over a height range of 0.15-1.65 m, the JAD dispersed an average of >60 and >1300-fold more plaque-forming units (PFU) compared to the WAD and PT (P < 0.0001), respectively. The JAD dispersed an average of >20 and >190-fold more PFU in total compared to WAD and PT at all distances tested up to 3 m (P < 0.01) respectively. Air samples collected around each device 15 min after use indicated that the JAD dispersed an average of >50 and >100-fold more PFU compared to the WAD and PT (P < 0.001), respectively. CONCLUSIONS: Use of the JAD lead to significantly greater and further dispersal of MS2 bacteriophage from artificially contaminated hands when compared to the WAD and PT. SIGNIFICANCE AND IMPACT OF STUDY: The choice of hand-drying device should be considered carefully in areas where infection prevention concerns are paramount, such as healthcare settings and the food industry. PMID- 26618933 TI - Teaming Up for Women's Health: The 2015 American College of Obstetricians and Gynecologists Annual Clinical and Scientific Meeting. AB - 63rd Annual Clinical and Scientific Meeting of the American College of Obstetricians and Gynecologists, 2-6 May, 2015, San Francisco, CA, USA. In response to major practice changes in obstetrics and gynecology (OB/GYN), the 2015 Annual Clinical and Scientific Meeting of the American College of Obstetricians and Gynecologists responded with modification of the program organization, methods of presenting the information (debates, hands on, flip classrooms) and increased emphasis on current clinical research. The Presidential Program covered broad themes of changes in healthcare technology, teamwork in OB/GYN practice and the importance of advocating for patients. Over 400 abstracts representing a broad range of clinical and basic science research were presented. Changes in the Annual Clinical and Scientific Meeting should allow the membership to be more prepared and pro-active as the practice of OB/GYN evolves. PMID- 26618935 TI - Asymmetric Diketopyrrolopyrrole Conjugated Polymers for Field-Effect Transistors and Polymer Solar Cells Processed from a Nonchlorinated Solvent. AB - Newly designed asymmetric diketopyrrolopyrrole conjugated polymers with two different aromatic substituents possess a hole mobility of 12.5 cm(2) V(-1) s(-1) in field-effect transistors and a power conversion efficiency of 6.5% in polymer solar cells, when solution processed from a nonchlorinated toluene/diphenyl ether mixed solvent. PMID- 26618934 TI - Potential Utility of Multidetector Computed Tomography to Identify both Cardiac Embolic Sources and Coronary Artery Disease in Patients with Embolic Stroke. AB - OBJECTIVES: Our objective was to study the potential utility of multidetector computed tomography (MDCT) to identify both cardiac embolic sources and coronary artery disease (CAD) in embolic-stroke patients. METHODS: We performed MDCT for 184 patients with embolic stroke but without known CAD. Twenty-six patients had atrial fibrillation. We investigated the prevalence of the potential source of the embolism and the coronary characteristics. RESULTS: Overall, 64 potential embolic sources were detected in 59 patients (32.1%). Left atrial appendage thrombus, left ventricular thrombus and aortic atheroma were detected in 3.3, 0.5 and 15.8% of patients, respectively. Circulatory stasis and patent foramen ovale were detected in 8.7 and 6.5%, respectively. As for coronary calcium score, only 47 patients (25.5%) had a score of zero and 51 (27.7%) had a score of >= 400. Significant CAD was detected in 18 patients (9.8%). One hundred and thirty-seven (74.5%) had coronary plaques. The prevalence of positive remodeling, low attenuation plaque, spotty calcification and a napkin-ring sign was 7.1, 1.6, 5.4 and 2.7%, respectively. Importantly, only 34 patients (13.0%) had no abnormalities detected by MDCT. CONCLUSIONS: Our results suggest that MDCT has potential to identify both cardiac embolic sources and CAD in patients with embolic stroke but without known CAD. PMID- 26618936 TI - Coronary CT angiography for myocardial infarction: case studies of the Massachusetts General Hospital. PMID- 26618937 TI - Reliable dn/dc Values of Cellulose, Chitin, and Cellulose Triacetate Dissolved in LiCl/N,N-Dimethylacetamide for Molecular Mass Analysis. AB - Freeze-dried microfibrillated cellulose (MFC) was directly dissolved in 8.0% w/w lithium chloride/N,N-dimethylacetamide (LiCl/DMAc), and MFC/LiCl/DMAc solutions with accurate MFC concentrations were prepared. The different MFC solutions were diluted to 1.0% and 0.5% w/v LiCl/DMAc, and subjected to size-exclusion chromatography with multiangle laser-light scattering and refractive index analyses (SEC/MALLS/RI), and off-line RI analysis to determine their refractive index increments (dn/dc). Chitin, cellulose triacetate, a poly(styrene) standard, and cellobiose were used for comparison. Each of the two determination methods gave different dn/dc values for MFC and chitin but similar dn/dc values for cellulose triacetate and poly(styrene). The anomalously small dn/dc values of MFC and chitin were explainable in terms of stable cellulose-LiCl and chitin-LiCl structures (i.e., formation of apparent covalent bonds between hydroxyl groups and LiCl) in the solutions. Thus, the SEC/MALLS/RI method provides reliable molecular mass parameters for cellulose and chitin. PMID- 26618938 TI - Reflective functioning in parents of school-aged children. AB - Parental reflective functioning (RF) has garnered tremendous support as a predictor of secure attachment in infancy, though little work has examined RF among parents of older children. In this study, we used a high-risk community sample of parent-child dyads (N = 117) to explore whether parental RF comprises self- and child-focused factors, whether parental RF is associated with parent and child attachment security, and whether parental RF mediates the association between parent and child attachment security. Results suggested that parental RF can be characterized as having both self- and child-focused components, and that child-focused parental RF is associated with child but not parent attachment security. Further, child-focused parental RF indirectly mediates the association between parent attachment avoidance and child attachment security. These findings extend previous work on parental RF to parents of school-age children and, in so doing, inform developmental models of attachment relationships in middle childhood. Discussion focuses on the importance of these findings in informing theory, prevention, clinical practice, and policy. PMID- 26618939 TI - Relation of psychosocial factors to diverse behaviors and attitudes among Somali refugees. AB - Refugee studies have examined both resilience and adverse outcomes, but no research has examined how different outcomes co-occur or are distinct, and the social-contextual factors that give rise to these diverse outcomes. The current study begins to address this gap by using latent profile analysis to examine the ways in which delinquency, gang involvement, civic engagement, political engagement, and openness to violent extremism cluster among Somali refugees. We then use multivariable regression analyses to examine how adversity (e.g., discrimination, trauma, and marginalization) is associated with the identified latent classes. Data were collected from 374 Somali refugee young adults (Mage = 21.30 years, SD = 2.90, range 18-30, 38% female) from 4 different North American communities. Participants completed a structured survey assessing their experiences of adversity, delinquent and/or violent attitudes and behaviors (e.g., attitudes toward violent extremism, participation in delinquent behaviors, involvement in gangs), and positive outcomes (e.g., civic and political engagement). Our findings indicate that participants fall into 5 distinct groups, and that social-contextual and individual factors are uniquely related to those groups. Specifically, strong social bonds seem to be associated with positive outcomes. These findings point to the need to further examine both positive and negative outcomes, paying special attention to social-contextual factors. (PsycINFO Database Record PMID- 26618941 TI - Stanislas Dehaene: Award for Distinguished Scientific Contributions. AB - The APA Awards for Distinguished Scientific Contributions are presented to persons who, in the opinion of the Committee on Scientific Awards, have made distinguished theoretical or empirical contributions to basic research in psychology. One of the 2015 award winners is Stanislas Dehaene, who received this award for "outstanding empirical and theoretical contributions to not just one but three fields that are central to the enterprises of psychology and cognitive neuroscience." Dehaene's award citation, biography, and a selected bibliography are presented here. PMID- 26618942 TI - Edna B. Foa: Award for Distinguished Scientific Contributions. AB - The APA Awards for Distinguished Scientific Contributions are presented to persons who, in the opinion of the Committee on Scientific Awards, have made distinguished theoretical or empirical contributions to basic research in psychology. One of the 2015 award winners is Edna B. Foa, who received this award for "her outstanding and innovative research on the nature, measurement, and treatment of anxiety." Foa's award citation, biography, and a selected bibliography are presented here. PMID- 26618943 TI - Michael Tomasello: Award for Distinguished Scientific Contributions. AB - The APA Awards for Distinguished Scientific Contributions are presented to persons who, in the opinion of the Committee on Scientific Awards, have made distinguished theoretical or empirical contributions to basic research in psychology. One of the 2015 award winners is Michael Tomasello, who received this award for "outstanding empirical and theoretical contributions to understanding what makes the human mind unique. Michael Tomasello's pioneering research on the origins of social cognition has led to revolutionary insights in both developmental psychology and primate cognition." Tomasello's award citation, biography, and a selected bibliography are presented here. PMID- 26618945 TI - Michael E. Lamb: Award for Distinguished Scientific Applications of Psychology. AB - The APA Award for Distinguished Scientific Applications of Psychology is presented to a person who, in the opinion of the Committee on Scientific Awards, has made distinguished theoretical or empirical advances leading to the understanding or amelioration of important practical problems. The 2015 recipient is Michael E. Lamb, who "has significantly advanced understanding of the developmental and contextual factors affecting the delivery and impact of child care in the early years of life; the role of parent-child relationships in development; and the cognitive, emotional, and social factors affecting the quality of children's testimony, especially in cases of sexual and physical abuse." award citation, biography, and a selected bibliography are presented here. PMID- 26618946 TI - Toward developmentally aware practices in the legal system: Progress, challenge, and promise. AB - Much research in developmental psychology has implications for practice and policy. In this article, I first describe how initial attempts to understand early social development and embrace multidisciplinary perspectives helped inform more nuanced approaches to the development of parenting plans for children with separating and maltreating parents. Second, I trace the ways in which notorious child abuse cases fostered research on children's testimonial capacities, which, in turn, informed the development of more effective forensic interview techniques. Progress in these domains has, however, been offset by failures to apply similar developmentally sensitive principles when dealing with children classified as suspects rather than victims, with children who testify in court, and with children in the child welfare system. PMID- 26618948 TI - James MacKillop: Award for Distinguished Scientific Early Career Contributions to Psychology. AB - APA's Awards for Distinguished Scientific Early Career Contributions to Psychology recognize excellent young psychologists who have not held a doctoral degree for more than nine years. One of the 2015 award winners is James MacKillop for "distinguished contributions to the behavioral economic study of addiction." MacKillop's award citation, biography, and a selected bibliography are presented here. PMID- 26618949 TI - Iris B. Mauss: Award for Distinguished Scientific Early Career Contributions to Psychology. AB - APA's Awards for Distinguished Scientific Early Career Contributions to Psychology recognize excellent young psychologists who have not held a doctoral degree for more than nine years. One of the 2015 award winners is Iris B. Mauss for "contributions to the study of human emotion." Mauss's award citation, biography, and a selected bibliography are presented here. PMID- 26618950 TI - Bunmi O. Olatunji: Award for Distinguished Scientific Early Career Contributions to Psychology. AB - APA's Awards for Distinguished Scientific Early Career Contributions to Psychology recognize excellent young psychologists who have not held a doctoral degree for more than nine years. One of the 2015 award winners is Bunmi O. Olatunji for "his innovative and important research on the relevance of individual differences in disgust sensitivity in the development and maintenance of anxiety disorders." Olatunji's award citation, biography, and a selected bibliography are presented here. PMID- 26618951 TI - Nim Tottenham: Award for Distinguished Scientific Early Career Contributions to Psychology. AB - APA's Awards for Distinguished Scientific Early Career Contributions to Psychology recognize excellent young psychologists who have not held a doctoral degree for more than nine years. One of the 2015 award winners is Nim Tottenham for "her creative and insightful research on the development of the human limbic cortical interactions that undergird emotional reactivity and regulation." Tottenham's award citation, biography, and a selected bibliography are presented here. PMID- 26618952 TI - Nicholas B. Turk-Browne: Award for Distinguished Scientific Early Career Contributions to Psychology. AB - APA's Awards for Distinguished Scientific Early Career Contributions to Psychology recognize excellent young psychologists who have not held a doctoral degree for more than nine years. One of the 2015 award winners is Nicholas B. Turk-Browne for "precocious and impactful contributions to the study of statistical learning, attentional processing, predictive coding, and event representation in perception and memory." Turk-Browne's award citation, biography, and a selected bibliography are presented here. PMID- 26618953 TI - Simine Vazire: Award for Distinguished Scientific Early Career Contributions to Psychology. AB - APA's Awards for Distinguished Scientific Early Career Contributions to Psychology recognize excellent young psychologists who have not held a doctoral degree for more than nine years. One of the 2015 award winners is Simine Vazire for "original contributions to understanding the limits of self-knowledge and the constraints on our knowledge of others." Vazire's award citation, biography, and a selected bibliography are presented here. PMID- 26618955 TI - Michael E. Lamb: Award for Distinguished Senior Career Contributions to Psychology in the Public Interest. AB - The APA Awards for Distinguished Contributions to Psychology in the Public Interest recognize persons who have advanced psychology as a science and/or profession by a single extraordinary achievement or a lifetime of outstanding contributions in the public interest. The 2015 co-recipient of the Award for Distinguished Senior Career Contributions to Psychology in the Public Interest is Michael E. Lamb. Lamb was selected because his "work profoundly shaped the fields of developmental psychology, social welfare, child and family policy, and law." Lamb's award citation, biography, and a selected bibliography are presented here. PMID- 26618956 TI - Candice L. Odgers: Awards for Distinguished Early Career Contributions to Psychology in the Public Interest. AB - The APA Awards for Distinguished Contributions to Psychology in the Public Interest recognize persons who have advanced psychology as a science and/or profession by a single extraordinary achievement or a lifetime of outstanding contributions in the public interest. The 2015 co-recipient of the Award for Distinguished Senior Career Contributions to Psychology in the Public Interest is Candice L. Odgers. Odgers's work addressing the developmental course of externalizing and conduct disorders and substance use yielded key insights into genetic and environmental variations in risk, leading to policy recommendations regarding how best to target interventions." Odgers's award citation, biography, and a selected bibliography are presented here. PMID- 26618959 TI - Rodney K. Goodyear: Award for Distinguished Career Contributions to Education and Training in Psychology. AB - The Award for Distinguished Career Contributions to Education and Training in Psychology is given in recognition of the efforts of psychologists who have made distinguished contributions to education and training, who have produced imaginative innovations, or who have been involved in the developmental phases of programs in education and training in psychology. The Career designation is added to the award at the discretion of the Education and Training Awards Committee to recognize continuous significant contributions made over a lifelong career in psychology. The 2015 recipient of this award is Rodney K. Goodyear "for his substantive, sustained, and enduring contributions to research and practice in the training and supervision of students and educators in professional psychology, and for his leadership in helping to establish competency standards in the area of clinical supervision both in the United States and internationally. Goodyear's award citation, biography, and a selected bibliography are presented here. PMID- 26618957 TI - Income inequality and the developing child: Is it all relative? AB - Children from low-income families are at heightened risk for a number of poor outcomes, including depression, antisocial behavior, poor physical health, and educational failure. Growing up in poverty is generally seen as toxic for children. However, less is known about how the "economic distance" between children and their peers influences behavior and health. This article examines how both poverty and the growing divide between low-income children and their peers may be influencing low-income children's life chances. Among wealthy nations, children in countries with higher levels of income inequality consistently fare worse on multiple indices of health, educational attainment, and well-being. New research also suggests that low-income children may be experiencing worse outcomes, and a form of "double disadvantage," when they live and attend school alongside more affluent versus similarly positioned peers. The role of subjective social status in explaining why some low-income children appear to suffer when growing up alongside more affluent peers is explored, alongside a call for additional research focused on how children come to understand, and respond to, their perceived social status. (PsycINFO Database Record PMID- 26618960 TI - Using accountability mechanisms more intentionally: A framework and its implications for training professional psychologists. AB - Accountability plays an essential though underexplored role in ensuring quality psychology training. This article considers the accountability of not only training programs but also the people who are involved as faculty, supervisors, and trainees. It discusses the essential processes and purposes of accountability and then suggests a framework that might guide more intentional use of accountability mechanisms. The article then gives examples of how that knowledge might be used to improve psychology training. For example, it makes the distinction between process and outcome accountability and suggests ways in which the latter might be given more prominence. PMID- 26618962 TI - Robert L. Hatcher: Award for Distinguished Contributions of Applications of Psychology to Education and Training. AB - The Award for Distinguished Contributions of Applications of Psychology to Education and Training acknowledges psychologists who contribute to new teaching methods or solutions to learning problems through the use of research findings or evidence-based practices. Particular emphasis is placed on the use of psychological knowledge to improve learning in educational settings, including prekindergarten to Grade 12, or in communities. The 2014 recipient is Robert L. Hatcher. He is acknowledged "for his deep and abiding commitment to improving training for psychologists, for his leadership in developing practicum competencies, and for his vision for competency-based education in psychology." Hatcher's award citation, biography, and a selected bibliography are presented. PMID- 26618963 TI - Interpersonal competencies: Responsiveness, technique, and training in psychotherapy. AB - Professional practice in psychology is anchored in interpersonal or relational skills. These skills are essential to successful interactions with clients and their families, students, and colleagues. Expertise in these skills is desired and expected for the practicing psychologist. An important but little-studied aspect of interpersonal skills is what Stiles and colleagues (Stiles, Honos-Webb, & Surko, 1998; Stiles, 2009, 2013) have called appropriate responsiveness. In treatment relationships, appropriate responsiveness is the therapist's ability to achieve optimal benefit for the client by adjusting responses to the current state of the client and the interaction. This article was designed to clarify this aspect of responsiveness, showing its links to empathy, illustrating how responsiveness has been detected in controlled clinical trials, discussing how educators and supervisors have worked to enhance students' responsiveness, and considering how appropriate responsiveness has been assessed. The article also discusses the development of skills underlying appropriate responsiveness and the role of stable differences in talent in training of professional psychologists. Notwithstanding other pessimistic reports on psychologists' expertise, demonstrable expertise may exist in the effective, responsive use of these skills in treatment settings. Appropriate responsiveness may be a variety of executive functioning, organizing and guiding the use of many specific competencies. As such it may be a metacompetency, with implications for the design of competency schemes. Key to all of these considerations is the distinction between therapeutic techniques and their responsive use, which involves astute judgment as to when and how to utilize these responses to best effect in the treatment situation. PMID- 26618965 TI - Connor H. G. Patros: Psi Chi/APA Edwin B. Newman Graduate Research Award. AB - The Edwin B. Newman Graduate Research Award is given jointly by Psi Chi and APA. The award was established to recognize young researchers at the beginning of their professional lives and to commemorate both the 50th anniversary of Psi Chi and the 100th anniversary of psychology as a science (dating from the founding of Wundt's laboratory). The 2015 recipient is Connor H. G Patros. Patros was chosen for "an excellent research paper that examines the complex relationship between working memory, choice-impulsivity, and the attention-deficit/hyperactivity disorder (ADHD) phenotype." Patros's award citation, biography, and a selected bibliography are presented here. PMID- 26618967 TI - Leonard A. Jason: Award for Distinguished Professional Contributions to Applied Research. AB - The Award for Distinguished Professional Contributions to Applied Research is given to a psychologist whose research has led to important discoveries or developments in the field of applied psychology. To be eligible, this research should have led to innovative applications in an area of psychological practice, including but not limited to assessment, consultation, instruction, or intervention (either direct or indirect). The 2015 recipient is Leonard A. Jason. Jason "is among the most prolific community psychology researchers whose work has had measurable and significant real-world impact. His work is characterized by a continuing desire to apply knowledge to major social problems. His research is methodologically sound and creative, collaborative, and participatory, thereby increasing stakeholders' support for proposed changes." Jason's award citation, biography, and a selected bibliography are presented here. PMID- 26618968 TI - Ethical and diversity challenges in ecologically sensitive systems-oriented interventions. AB - This article discusses ethical and diversity challenges involved in implementing ecologically sensitive, systems-oriented research. These issues are considered with reference to a series of community-based interventions dealing with stigma and chronic illness, recovery from substance-use disorders, and prevention of tobacco use. Each of these ecological interventions incorporates a systems approach, which allows an understanding of how individuals affect and are influenced by their social environments. In addition, issues of diversity with respect to underrepresented and marginalized groups are considered, including overcoming obstacles to gaining access to resources and promoting increased opportunities and empowerment. Throughout, the central importance of developing relationships with key gatekeepers and stakeholders, as well as timely and effective communications with various coalition members, is highlighted. By bringing into the research and policy process diverse citizen/participant suggestions and input regarding the need for, or design and implementation of ecologically and systems-based interventions, researchers can build collaborative relationships that fuel trust and partnerships, leading to more ethically responsible research. (PsycINFO Database Record PMID- 26618970 TI - Glenn J. Larrabee: Award for Distinguished Professional Contributions to Independent Practice. AB - The Award for Distinguished Professional Contributions to Independent Practice is intended to recognize outstanding independent practitioners in psychology. Nominations are considered for psychologists working in any area of clinical specialization, health services provision, or consulting, and services provided to any patient population or professional clientele in an independent setting. The 2015 recipient is Glenn J. Larrabee, who "is internationally recognized for his publications on test validity, memory assessment, mild traumatic brain injury, malingering, and the scientific practice of forensic neuropsychology." Larrabee's award citation, biography, and a selected bibliography are presented here. PMID- 26618971 TI - The multiple validities of neuropsychological assessment. AB - This article discusses construct and criterion validity of neuropsychological tests, as well as assessment validity, which allows determination of whether an individual examinee is producing valid test results. Factor analyses identify 6 domains of abilities. Tests of learning and memory and processing speed are most sensitive to presence of brain dysfunction in both traumatic brain injury (TBI) and Alzheimer's disease (AD). Tests of processing speed, working memory, verbal symbolic functions, and visuoperceptual and visuospatial judgment and problem solving are sensitive to the severity of TBI and AD, as well as to the functional consequences of these disorders, including ability to work, financial and medical decision-making capacities, and driving ability. Unilateral hemisphere stroke allows study of impairment in sensorimotor skills and lateralized neuropsychological abilities, as well as the moderating effects of aphasia and neglect on test performance. Assessment validity is determined by performance validity tests, measuring whether an examinee is providing an accurate measure of their actual level of ability, and symptom validity tests, measuring whether an examinee is providing an accurate report of their actual symptom experience. A core neuropsychological battery is described that includes tests with established construct and criterion validity, and assessment validity, for comprehensive evidence-based evaluation. PMID- 26618973 TI - Rosie Phillips Bingham: Award for Distinguished Professional Contributions to Institutional Practice. AB - The APA Awards for Distinguished Professional Contributions to Institutional Practice are intended to recognize outstanding practitioners in psychology. One of the 2015 award winners is Rosie Phillips Bingham, who received this award for being "an extraordinary psychologist and dedicated, visionary leader who has made a tremendous difference in psychology and in the institutions in which she has worked." Rosie's award citation, biography, and a selected bibliography are presented here. PMID- 26618974 TI - The role of university and college counseling centers in advancing the professionalization of psychology. AB - Psychologists in university and college counseling centers (UCCCs) have helped to shape and advance the professionalization of psychology. Most definitions of a profession contain at least 5 components. A profession has (1) systematic theories and underlying principles; (2) authority to practice provided by the client; (3) a long educational process, including training and mentoring; (4) standards and a code of ethics; and (5) a culture of service and accountability to the public. UCCC professionals have evolved in a manner that demonstrates all 5 components of a profession. They advance the discipline of psychology as a profession through their counseling interventions because such interventions are based on scientific theories and principles. While their practice rests on scientific principles, their work helps to confirm and modify that science. Authority to practice is evidenced by the continuous growth of counseling centers since World War II. UCCCs aid the extended educational process for psychology graduate students as evidenced by their providing more internship training sites than any other category of training agencies. The majority of UCCC professionals are licensed and must abide by their state code of ethics. Such codes hold psychologists accountable to the public because they regularly deliver counseling service to at least 10% of the campus student population and offer outreach services to many more in their communities. PMID- 26618976 TI - Adam M. Reid: APA/APAGS Award for Distinguished Graduate Student in Professional Psychology. AB - The APA/APAGS Award for Distinguished Graduate Student in Professional Psychology is awarded on an annual basis by the APA Board of Professional Affairs (BPA) and the American Psychological Association of Graduate Students (APAGS) to a graduate student who has demonstrated outstanding practice and application of psychology. One of the 2015 award winners is Adam M. Reid, who received this award "for his community service, in which he has integrated the highest standards of professional psychological clinical practice and science." Adam's award citation, biography, and a selected bibliography are presented here. PMID- 26618978 TI - Walter J. Lonner: Award for Distinguished Contributions to the International Advancement of Psychology. AB - The Award for Distinguished Contributions to the International Advancement of Psychology is given to individuals who have made sustained and enduring contributions to international cooperation and the advancement of knowledge in psychology. One of the 2015 award winners is Walter J. Lonner, who received this award "for his distinguished career in contributing to the advancement of cross cultural psychology around the world." Walter's award citation, biography, and a selected bibliography are presented here. PMID- 26618979 TI - Half a century of cross-cultural psychology: A grateful coda. AB - This article provides brief commentaries on culture-oriented research in psychology and a synopsis of the author's 50-year involvement in cross-cultural psychology. Overviews of several areas with which he is more familiar are given. These include his career-long stewardship of the Journal of Cross-Cultural Psychology, of which he is founding and special issues editor, continuous involvement with the International Association for Cross-Cultural Psychology, ongoing interest in the search for psychological universals, studying the influence of cultures on personality, values, and other psychological dimensions, monitoring the inclusion of culture in introductory psychology texts, contributions to cross-cultural counseling, and sustained involvement with the Online Readings in Psychology and Culture since its inception. Also included are comments on both the ever-expanding research on culture's influence on behavior and thought by a growing network of scholars who have different, yet complementary, agendas and research methods. PMID- 26618981 TI - Sunil Bhatia: International Humanitarian Award. AB - The International Humanitarian Award recognizes extraordinary humanitarian services and activism by psychologists, including professional and volunteer work conducted primarily in the field with under served populations. One of the 2015 award winners is Sunil Bhatia, who received this award "using his knowledge of qualitative and ethnographic methods, which has formed alliances with over a dozen community partners and nongovernmental organizations (NGOs) in the United States and in his native city of Pune, India, to provide the urban poor with access to clean sanitation and private toilets." Sunil's award citation, biography, and a selected bibliography are presented here. PMID- 26618982 TI - Takotsubo Cardiomyopathy Following Acute Cerebral Events. AB - OBJECTIVE: Takotsubo cardiomyopathy (TCM) is characterized by transient apical ventricular dysfunction typically induced by acute stress. Acute cerebral events including ischemic stroke (IS) or epileptic events (EEs) may be associated with massive catecholamine release. We aimed to identify the characteristics and outcomes of patients who experienced the Takotsubo syndrome complicated by IS or EE. METHODS: Between 2008 and 2013, 87 patients were admitted to our intensive care unit for TCM. Of these, 6 had previously experienced acute cerebral symptoms within 2 days of experiencing either IS or EE. Takotsubo syndrome was diagnosed on cardiac MRI, echocardiography, electrocardiography (ECG), biology and coronary angiography data. RESULTS: Five women and 1 man were included in the study. The mean age was 63.7 +/- 20.1 years (range 44-84). Four of them (67%) initially presented an acute IS and 2 (33%) had EE. The suspected brain injury was found in the insular cortex for 4 patients and the posterior fossa for 2 patients. Hemiparesis, aphasia and cerebellar symptoms were the main neurological signs. Abnormal ECG findings including ST-segment elevation (33%) or T-wave inversion (50%) developed between a few hours and 48 h after the onset of the IS or EE. Peak troponin was 1.8 (0.79-14.11) ug/l. A transient reduction in the left ventricular ejection fraction (46 +/- 12%) with apical hypokinesis was found using echocardiography. Two (33%) patients went on to develop acute heart failure. Coronary angiography confirmed the lack of significant coronary stenosis for all 6 patients. CONCLUSION: TCM can develop within the first few days after an acute cerebral event. It occurs predominantly in women with insular or posterior fossa lesions and is possibly induced by vegetative reactions. PMID- 26618983 TI - Comments on 'Sleep Disordered Breathing and Periodic Limb Movements in Patients with Narcolepsy with Cataplexy'. PMID- 26618984 TI - Hydrogen Isotope Exchange of Chlorinated Ethylenes in Aqueous Solution: Possibly a Termolecular Liquid Phase Reaction. AB - This work reports an experimental study of the hydrogen/deuterium exchange in the basic aqueous solutions of trichloroethylene, trans-1,2-dichloroethylene, and cis 1,2-dichloroethylene using (1)H NMR as a monitoring method. 1,1-Dichlorethylene was also investigated but found not to exchange hydrogen isotopes with water. The kinetics of isotope exchange features two different pathways, the first is first order with respect to hydroxide ion, whereas the second is second order. The first pathway is interpreted as a straightforward bimolecular reaction between chloroethylene and hydroxide ion, which leads to the deprotonation of chloroethylene. The second pathway involves a transition state with the association of one molecule of the chloroethylene and two hydroxide ions. It is shown that the second pathway could involve the formation of a precursor complex composed of one chloroethylene molecule and one hydroxide ion, but a direct termolecular elementary reaction is also feasible, which is shown by deriving a theoretical highest limit for the rate constants of termolecular reactions in solution. PMID- 26618985 TI - Ultrafast Solvent-Assisted Sodium Ion Intercalation into Highly Crystalline Few Layered Graphene. AB - A maximum sodium capacity of ~35 mAh/g has hampered the use of crystalline carbon nanostructures for sodium ion battery anodes. We demonstrate that a diglyme solvent shell encapsulating a sodium ion acts as a "nonstick" coating to facilitate rapid ion insertion into crystalline few-layer graphene and bypass slow desolvation kinetics. This yields storage capacities above 150 mAh/g, cycling performance with negligible capacity fade over 8000 cycles, and ~100 mAh/g capacities maintained at currents of 30 A/g (~12 s charge). Raman spectroscopy elucidates the ordered, but nondestructive cointercalation mechanism that differs from desolvated ion intercalation processes. In situ Raman measurements identify the Na(+) staging sequence and isolates Fermi energies for the first and second stage ternary intercalation compounds at ~0.8 eV and ~1.2 eV. PMID- 26618986 TI - A PPARgamma AGONIST ENHANCES BACTERIAL CLEARANCE THROUGH NEUTROPHIL EXTRACELLULAR TRAP FORMATION AND IMPROVES SURVIVAL IN SEPSIS. AB - Dysregulation of the inflammatory response against infection contributes to mortality in sepsis. Inflammation provides critical host defense, but it can cause tissue damage, multiple organ failure, and death. Because the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) exhibits therapeutic potential, we characterized the role of PPARgamma in sepsis. We analyzed severity of clinical signs, survival rates, cytokine production, leukocyte influx, and bacterial clearance in a cecal ligation and puncture (CLP) model of sepsis in Swiss mice. The PPARgamma agonist rosiglitazone treatment improved clinical status and mortality, while increasing IL-10 production and decreasing TNF-alpha and IL-6 levels, and peritoneal neutrophil accumulation 24 h after CLP. We noted increased bacterial killing in rosiglitazone treated mice, correlated with increased generation of reactive oxygen species. Polymorphonuclear leukocytes (PMN) incubated with LPS or Escherichia coli and rosiglitazone increased peritoneal neutrophil extracellular trap (NET)-mediated bacterial killing, an effect reversed by the PPARgamma antagonist (GW 9662) treatment. Rosiglitazone also enhanced the release of histones by PMN, a surrogate marker of NET formation, effect abolished by GW 9662. Rosiglitazone modulated the inflammatory response and increased bacterial clearance through PPARgamma activation and NET formation, combining immunomodulatory and host dependent anti-bacterial effects and, therefore, warrants further study as a potential therapeutic agent in sepsis. PMID- 26618987 TI - EFFECT OF GTS-21, AN ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR AGONIST, ON CLP INDUCED INFLAMMATORY, GASTROINTESTINAL MOTILITY, AND COLONIC PERMEABILITY CHANGES IN MICE. AB - BACKGROUND: During abdominal sepsis, the inhibition of gastrointestinal (GI) motility together with mucosal barrier dysfunction will lead to increased bacterial translocation and maintenance of sepsis. The activation of the vagal anti-inflammatory pathway remains an appealing therapeutic strategy in sepsis. In this respect, selective alpha7 nicotinic acetylcholine receptor (alpha7nAChR) agonists have shown anti-inflammatory properties in several animal models of inflammation. METHODS: Sepsis was induced in OF-1 mice by cecal ligation and puncture (CLP). GI transit was quantified, and cytokine levels were determined in serum and colon. Colonic permeability was assessed by means of Evans blue injection. We studied the effect of GTS-21, an alpha7nAChR agonist, on the aforementioned parameters. Splenectomized animals as well as alpha7nAChR-knock out animals (Chrna7) were included to study the role of splenic macrophages and the alpha7nAChR during polymicrobial abdominal sepsis. RESULTS: In septic animals, GTS-21 significantly ameliorated GI motility, lowered systemic and colonic levels of IL-6, decreased colonic permeability, and decreased the number of positive cultures obtained from blood and mesenteric lymph nodes. Splenectomy prevented animals from developing sepsis-induced ileus. Chrna7 mice displayed a more severe septic phenotype, whereas GTS-21 remarkably was also beneficial in these animals. CONCLUSION: Our results show that peripheral targeting of the vagal anti-inflammatory pathway proves beneficial in an animal model of polymicrobial abdominal sepsis. A major role is allocated to splenic immune cells in the development of sepsis, as preventive splenectomy was protective for the development of sepsis. Data on the Chrna7 mice suggest that the beneficial effects mediated by GTS-21 on inflammation and motility might be related to activation of other receptors besides the alpha7nAChR. PMID- 26618988 TI - DIAGNOSTIC UTILITY OF DIFFERENT BLOOD COMPONENTS IN GENE EXPRESSION ANALYSIS OF SEPSIS. AB - RATIONALE: Most gene expression studies of sepsis have used either whole blood or specific leukocyte fractions as source tissues for RNA. Data regarding the relative utility of these different tissue sources are lacking. OBJECTIVES: To evaluate the utility of different source tissues in studying gene expression in sepsis. METHODS: We undertook a systematic analysis of sepsis gene expression studies, including both adult and pediatric cohorts. We used clustering methods to partition samples according to gene expression levels, and compared expression cluster labels to clinical diagnoses. We also quantified the strength of cluster formation based on expression data from different tissue sources using average silhouette widths as a measure of cluster cohesiveness. RESULTS: We included 22 separate expression datasets. Whole blood was used as the source tissue in 15 studies, while leukocyte isolates were used in seven studies. Whole blood samples yielded greater specificity for the diagnosis of sepsis than data from leukocyte isolates (94% vs 78%, P = 0.03). Whole blood-derived data also yielded more cohesive clusters (median silhouette widths 0.28 and 0.19 for whole blood and leukocyte isolates respectively, P < 0.01). CONCLUSION: Our results support the use of whole blood to derive gene expression data in sepsis studies investigating novel diagnostics and subtype discovery. This strategy has a number of practical advantages, and the resulting data also have potential utility in developing molecular classifications of sepsis syndromes. PMID- 26618990 TI - The capability set for work: development and validation of a new questionnaire. AB - OBJECTIVES: The aim of this study was to develop a questionnaire to measure work capabilities based on Amartya Sen's capability approach and evaluate its validity. METHODS: The development of the questionnaire was based on a combination of qualitative and quantitative methods: interviews, literature study, and an expert meeting. Additionally, in a survey, the validity was evaluated by means of hypotheses testing (using correlations and regression analyses). RESULTS: The questionnaire consists of a set of seven capability aspects for work. For each aspect, it is determined whether it is part of a worker's capability set, ie, when the aspect is considered valuable, is enabled in work, and is realized. The capability set was significantly correlated with work role functioning-flexibility demands (-0,187), work ability (-0.304), work performance (-0.282), worked hours (-0.073), sickness absence (yes/no) (0.098), and sickness absence days (0.105). The capability set and the overall capability item are significantly associated with all work outcomes (P<0.010). CONCLUSIONS: The new capability set for work questionnaire appears to be a valid instrument to measure work capabilities. The questionnaire is unique because the items include the valued aspects of work and incorporate whether a worker is able to achieve what (s)he values in his/her work. The questionnaire can be used to evaluate the capability set of workers in organizations to identify aspects that need to be addressed in interventions. PMID- 26618991 TI - 31(st) International Epilepsy Congress Istanbul, Turkey 5(th) -9(th) September, 2015. PMID- 26618992 TI - Technology and the Future of Palliative Care Education. PMID- 26618989 TI - Nmnat1-Rbp7 Is a Conserved Fusion-Protein That Combines NAD+ Catalysis of Nmnat1 with Subcellular Localization of Rbp7. AB - Retinol binding proteins (Rbps) are known as carriers for transport and targeting of retinoids to their metabolizing enzymes. Rbps are also reported to function in regulating the homeostatic balance of retinoid metabolism, as their level of retinoid occupancy impacts the activities of retinoid metabolizing enzymes. Here we used zebrafish as a model to study rbp7a function and regulation. We find that early embryonic rbp7a expression is negatively regulated by the Nodal/FoxH1 signaling pathway and we show that Nodal/FoxH1 activity has the opposite effect on aldh1a2, which encodes the major enzyme for early embryonic retinoic acid production. The data are consistent with a Nodal-dependent coordination of the allocation of retinoid precursors to processing enzymes with the catalysis of retinoic acid formation. Further, we describe a novel nmnat1-rbp7 transcript encoding a fusion of Rbp7 and the NAD+ (Nicotinamide adenine dinucleotide) synthesizing enzyme Nmnat1. We show that nmnat1-rbp7 is conserved in fish, mouse and chicken, and that in zebrafish regulation of nmnat1-rbp7a is distinct from that of rbp7a and nmnat1. Injection experiments in zebrafish further revealed that Nmnat1-Rbp7a and Nmnat1 have similar NAD+ catalyzing activities but a different subcellular localization. HPLC measurements and protein localization analysis highlight Nmnat1-Rbp7a as the only known cytoplasmic and presumably endoplasmic reticulum (ER) specific NAD+ catalyzing enzyme. These studies, taken together with previously documented NAD+ dependent interaction of RBPs with ER associated enzymes of retinal catalysis, implicate functions of this newly described NMNAT1-Rbp7 fusion protein in retinol oxidation. PMID- 26618993 TI - IPEG 2015 The 24(th) Annual Congress for Endosurgery in Children April 14-18, 2015, Nashville, Tennessee. PMID- 26618994 TI - Exclusion of Patients With Kidney Disease From Cardiovascular Trials. PMID- 26618995 TI - Persistence of Yellow Fever vaccine-induced antibodies after cord blood stem cell transplant. AB - We report the case of a cord blood haematopoietic stem cell transplant recipient who was vaccinated for Yellow Fever (YF) 7 days before initiating chemotherapy and had persistent YF antibodies more than 3 years after vaccination. Since the stem cell donor was never exposed to wild YF or to the YF vaccine, and our patient was not exposed to YF or revaccinated, this finding strongly suggests the persistence of recipient immunity. We briefly discuss potential consequences of incomplete elimination of recipient's leukocytes following existing haematopoietic cancer treatments. PMID- 26618996 TI - Prevalence of Multiple Sclerosis in Tuscany (Central Italy): A Study Based on Validated Administrative Data. AB - BACKGROUND: Multiple Sclerosis (MS) epidemiology in Italy is mainly based on population-based prevalence studies. Administrative data are an additional source of information, when available, in prevalence studies of chronic diseases such as MS. The aim of our study is to update the prevalence rate of MS in Tuscany (central Italy) as at 2011 using a validated case-finding algorithm based on administrative data. METHODS: The prevalence was calculated using an algorithm based on the following administrative data: hospital discharge records, drug dispensing records, disease-specific exemptions from copayment to health care, home and residential long-term care and inhabitant registry. To test algorithm sensitivity, we used a true-positive reference cohort of MS patients from the Tuscan MS register. To test algorithm specificity, we used another cohort of individuals who were presumably not affected by MS. RESULTS: As at December 31, 2011, we identified 6,890 cases (4,738 females and 2,152 males) with a prevalence of 187.9 per 100,000. The sensitivity of algorithm was 98% and the specificity was 99.99%. CONCLUSIONS: We found a prevalence higher than the rates present in literature. Our algorithm, based on administrative data, can accurately identify MS patients; moreover, the resulting cohort is suitable to monitor disease care pathways. PMID- 26618997 TI - Pressure-induced amorphization of YVO4:Eu3+ nanoboxes. AB - A structural transformation from the zircon-type structure to an amorphous phase has been found in YVO4:Eu(3+) nanoboxes at high pressures above 12.7 GPa by means of x-ray diffraction measurements. However, the pair distribution function of the high-pressure phase shows that the local structure of the amorphous phase is similar to the scheelite-type YVO4. These results are confirmed both by Raman spectroscopy and Eu(3+) photoluminescence which detect the phase transition to a scheelite-type structure at 10.1 and 9.1 GPa, respectively. The irreversibility of the phase transition is observed with the three techniques after a maximum pressure in the upstroke of around 20 GPa. The existence of two (5)D0-->(7)F0 photoluminescence peaks confirms the existence of two local environments for Eu(3+), at least for the low-pressure phase. One environment is the expected for substituting Y(3+) and the other is likely a disordered environment possibly found at the surface of the nanoboxes. PMID- 26619000 TI - Dense Nonaqueous-Phase Liquid Architecture in Fractured Bedrock: Implications for Treatment and Plume Longevity. AB - Partitioning tracer testing was performed in discrete intervals within a fractured bedrock tetrachloroethene (PCE) dense nonaqueous-phase liquid (DNAPL) source area to assess the fracture flow field and DNAPL architecture. Results confirmed that the partitioning tracer testing was able to identify and quantify low levels of residual DNAPL along flow paths in hydraulically conductive fractures. DNAPL fracture saturations (Sn) ranged from undetectable to 0.007 (DNAPL volume/fracture volume). A comparison of the fracture flow field to the DNAPL distribution indicated that the highest value of Sn was observed in the least transmissive fracture (or fracture zone). Application of a simple ambient dissolution model showed that the DNAPL present in this low transmissivity zone would persist longer than the DNAPL present in more transmissive fractures and would persist for 200 years (in the absence of any degradation reactions). Assessment of PCE mass distribution between the rock matrix and fractures showed that, due to the presence of DNAPL, the rock matrix accounted for less than 10% of the total PCE mass. The evaluation of PCE concentration profiles in the rock matrix and the estimated diffusional flux from the rock matrix suggest that the elevated PCE groundwater concentrations observed in the fractures likely are due to the presence of the residual DNAPL sources and that removal of the residual DNAPL sources within the fractures would result in a significant decrease in dissolved PCE concentrations in the source area. PMID- 26619002 TI - Fabrication of Slippery Lubricant-Infused Porous Surface for Inhibition of Microbially Influenced Corrosion. AB - Microbially influenced corrosion (MIC) accelerates the failure of metal in a marine environment. In this research, slippery lubricant-infused porous surface (SLIPS) was designed on aluminum, and its great potential for inhibiting MIC induced by sulfate-reducing bacteria (SRB) was demonstrated in a simulated marine environment. The inhibition mechanism of SLIPS to MIC was proposed based on its effective roles in the suppression of SRB settlement and isolation effect to corrosive metabolites. The liquid-like property is demonstrated to be the major contributor to the suppression effect of SLIPS to SRB settlement. The effects of environmental factors (static and dynamic conditions) and lubricant type to SRB settlement over SLIPS were also investigated. It was indicated that the as fabricated SLIPS can inhibit the SRB settlement in both static and dynamic marine conditions, and lubricant type presents a negligible effect on the SRB settlement. These results will provide a series of foundational data for the future practical application of SLIPS in the marine environment, and also a lubricant selecting instruction to construct SLIPS for MIC control. PMID- 26619001 TI - Longevity and GAPDH Stability in Bivalves and Mammals: A Convenient Marker for Comparative Gerontology and Proteostasis. AB - BACKGROUND: Comparative aging studies, particularly those that include species of exceptional resistance to aging processes, can potentially illuminate novel senescence-retarding mechanisms. In recent years, protein homeostasis (proteostasis) has been implicated in fundamental aging processes. Here we further evaluate the relationship between proteostasis and longevity in a selection of bivalve mollusks and mammals with maximum longevities ranging from 3 to 507 years. METHODS & RESULTS: We experimentally examined proteostasis using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a reporter, as it is ubiquitously expressed, highly conserved, and conveniently assayed. The ability to maintain this enzymatic function was tested with increasing concentrations of the chaotropic agent urea, revealing a robust relationship with longevity in bivalves and mice. While our shortest-lived mollusk and mouse lost all activity by 2.5 and 3.5 M urea respectively, the longest-lived mollusk species, Arctica islandica, still preserved 45% of its basal function even at 6 M urea. To confirm that GAPDH proteostasis has a broad association with longevity, we also investigated a selection of primate species ranging in maximum longevity from 22 to 122 years. They outperformed the mouse at all concentrations, but among the primates results were variable at low urea doses. Still, at 6 M urea baboon and human samples retained 10% of their activity while both mouse and marmoset samples had no activity. MECHANISM OF EXCEPTIONAL STRESS RESISTANCE: To explore possible mechanisms of the exceptional stress resistance of A. islandica GAPDH we enzymatically removed post-translational glycosylation, but observed no decrease in stability. We also removed molecules smaller than 30 kDa, which includes most small heat shock proteins, but again did not compromise the exceptional stress resistance of Arctica GAPDH. CONCLUSION: While the mechanism underlying A. islandica's exceptional stress resistance remains elusive, this research identifies an experimental system that may reveal hitherto unknown mechanisms of protein homeostasis. PMID- 26619003 TI - Mechanism of Polymer Collapse in Miscible Good Solvents. AB - We propose a physical mechanism for co-nonsolvency of a stimulus-responsive polymer in water/methanol mixed solution based on results obtained with molecular simulations. Even though the phenomenon is well known, the mechanism behind co nonsolvency is still under debate. Herein, we study co-nonsolvency of poly(N isopropylacrylamide) (PNiPAM) in methanol aqueous solutions, the most widely studied and experimentally well-characterized system. Our results show that at low alcohol content of the solution methanol preferentially binds to the PNiPAM globule and drives polymer collapse. The energetics of electrostatic, hydrogen bonding, or bridging-type interactions with the globule is found to play no role. Instead, preferential methanol binding results in a significant increase in the globule's configurational entropy, stabilizing methanol-enriched globular structures over wet globular structures in neat water. This mechanism drives the reduction of the lower critical solution temperature with increasing methanol content in the co-nonsolvency regime and eventually leads to polymer collapse. The globule-to-coil re-entrance at high methanol concentrations is instead driven by changes in solvent-excluded volume of the coil and globular states imparted by a decrease in solvent density with increasing methanol content of the solution: with increasing proportion of larger solvent particles (methanol), the entropic (cavity formation) cost of redistributing solvent molecules upon polymer re entrance becomes smaller. This effect provides a natural explanation for the experimentally observed dependence of the re-entrance transition on chain molecular weight. PMID- 26619004 TI - Correction: Identifying Areas of the Visual Field Important for Quality of Life in Patients with Glaucoma. PMID- 26619006 TI - Phonon-Electron Scattering Limits Free Charge Mobility in Methylammonium Lead Iodide Perovskites. AB - The nature of the photoconductivity in solution-processed films of methylammonium lead iodide perovskite is investigated by determining the variation of the photoconductive response with temperature. Ultrabroadband terahertz (THz) photoconductivity spectra in the 0.3-10 THz range can be reproduced well by a simple Drude-like response at room temperature, where free charge carrier motion is characterized by an average scattering time. The scattering time determined from Drude fits in the 0.3-2THz region increases from ~4 fs at 300 K (tetragonal phase; mobility of ~27 cm(2) V(-1) s(-1)) to almost ~25 fs at 77 K (orthorhombic phase, mobility of ~150 cm(2) V(-1) s(-1)). For the tetragonal phase (temperature range 150 < T < 300 K) the scattering time shows a ~T(-3/2) dependence, approaching the theoretical limit for pure acoustic phonon (deformation potential) scattering. Hence, electron-phonon, rather than impurity scattering, sets the upper limit on free charge transport for this perovskite. PMID- 26619005 TI - Leukocyte Telomere Length in Young Adults Born Preterm: Support for Accelerated Biological Ageing. AB - BACKGROUND: Subjects born preterm have an increased risk for age-associated diseases, such as cardiovascular disease in later life, but the underlying causes are largely unknown. Shorter leukocyte telomere length (LTL), a marker of biological age, is associated with increased risk of cardiovascular disease. OBJECTIVES: To compare LTL between subjects born preterm and at term and to assess if LTL is associated with other putative cardiovascular risk factors at young adult age. METHODS: We measured mean LTL in 470 young adults. LTL was measured using a quantitative PCR assay and expressed as T/S ratio. We analyzed the influence of gestational age on LTL and compared LTL between subjects born preterm (n = 186) and at term (n = 284). Additionally, we analyzed the correlation between LTL and potential risk factors of cardiovascular disease. RESULTS: Gestational age was positively associated with LTL (r = 0.11, p = 0.02). Subjects born preterm had shorter LTL (mean (SD) T/S ratio = 3.12 (0.44)) than subjects born at term (mean (SD) T/S ratio = 3.25 (0.46)), p = 0.003). The difference remained significant after adjustment for gender and size at birth (p = 0.001). There was no association of LTL with any one of the putative risk factors analyzed. CONCLUSIONS: Young adults born preterm have shorter LTL than young adults born at term. Although we found no correlation between LTL and risk for CVD at this young adult age, this biological ageing indicator may contribute to CVD and other adult onset diseases at a later age in those born preterm. PMID- 26619007 TI - Pompe disease: Shared and unshared features of lysosomal storage disorders. AB - Pompe disease, an inherited deficiency of lysosomal acid alpha-glucosidase (GAA), is a severe metabolic myopathy with a wide range of clinical manifestations. It is the first recognized lysosomal storage disorder and the first neuromuscular disorder for which a therapy (enzyme replacement) has been approved. As GAA is the only enzyme that hydrolyses glycogen to glucose in the acidic environment of the lysosome, its deficiency leads to glycogen accumulation within and concomitant enlargement of this organelle. Since the introduction of the therapy, the overall understanding of the disease has progressed significantly, but the pathophysiology of muscle damage is still not fully understood. The emerging complex picture of the pathological cascade involves disturbance of calcium homeostasis, mitochondrial abnormalities, dysfunctional autophagy, accumulation of toxic undegradable materials, and accelerated production of lipofuscin deposits that are unrelated to aging. The relationship of Pompe disease to other lysosomal storage disorders and potential therapeutic interventions for Pompe disease are discussed. PMID- 26619010 TI - Evaluating Multi-Level Models to Test Occupancy State Responses of Plethodontid Salamanders. AB - Plethodontid salamanders are diverse and widely distributed taxa and play critical roles in ecosystem processes. Due to salamander use of structurally complex habitats, and because only a portion of a population is available for sampling, evaluation of sampling designs and estimators is critical to provide strong inference about Plethodontid ecology and responses to conservation and management activities. We conducted a simulation study to evaluate the effectiveness of multi-scale and hierarchical single-scale occupancy models in the context of a Before-After Control-Impact (BACI) experimental design with multiple levels of sampling. Also, we fit the hierarchical single-scale model to empirical data collected for Oregon slender and Ensatina salamanders across two years on 66 forest stands in the Cascade Range, Oregon, USA. All models were fit within a Bayesian framework. Estimator precision in both models improved with increasing numbers of primary and secondary sampling units, underscoring the potential gains accrued when adding secondary sampling units. Both models showed evidence of estimator bias at low detection probabilities and low sample sizes; this problem was particularly acute for the multi-scale model. Our results suggested that sufficient sample sizes at both the primary and secondary sampling levels could ameliorate this issue. Empirical data indicated Oregon slender salamander occupancy was associated strongly with the amount of coarse woody debris (posterior mean = 0.74; SD = 0.24); Ensatina occupancy was not associated with amount of coarse woody debris (posterior mean = -0.01; SD = 0.29). Our simulation results indicate that either model is suitable for use in an experimental study of Plethodontid salamanders provided that sample sizes are sufficiently large. However, hierarchical single-scale and multi-scale models describe different processes and estimate different parameters. As a result, we recommend careful consideration of study questions and objectives prior to sampling data and fitting models. PMID- 26619008 TI - Thrombolytic-Related Asymptomatic Hemorrhagic Transformation Does Not Deteriorate Clinical Outcome: Data from TIMS in China. AB - OBJECTIVE: It has been unclear whether thrombolytic-related asymptomatic hemorrhagic transformation (AHT) affects the clinical outcome. To answer this question, we examined whether thrombolytic-related AHT affect short-term and long term clinical outcome. METHODS: All data were collected from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China) registry. The patients were diagnosed as having AHT group and non- hemorrhagic transformation (HT) group based on clinical and imaging data. The patients with symptomatic hemorrhagic transformation were excluded from this study. Thrombolytic-related AHT was defined according to European-Australasian Acute Stroke Study (ECASS) II criteria. 90-day functional outcome, 7-day National Institutes of Health Stroke Scale (NIHSS) score, 7-day and 90-day mortalities were compared between two groups. Logistic regression analysis was used to evaluate the effects of AHT on a short-term and long-term clinical outcome. RESULTS: 904 of all 1440 patients in TIMS-China registry were enrolled. 89 (9.6%) patients presented with AHT after thrombolysis within 24-36 h. These patients with AHT were more likely to be elder age, cardioembolic subtype, and to have higher National Institutes of Health Stroke Scale score before thrombolysis than patients without AHT. No significant difference was found on the odds of 7-day (95% CI:0.692 (0.218-2.195), (P = 0.532) or 90-day mortalities (95% CI:0.548 (0.237-1.268), P = 0.160) and modified Rankin Score(0-1) at 90-day (95% CI:0.798 (0.460-1.386), P = 0.423) or modified Rankin Score(0-2) at 90-day (95% CI:0.732 (0.429-1.253), P = 0.116) or modified Rankin Score(5-6) at 90-day (95% CI:0.375 (0.169-1.830), P = 0.116) between two groups. CONCLUSIONS: Thrombolytic-related AHT does not deteriorate short-term and long-term clinical outcome. PMID- 26619011 TI - Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. AB - Mutational hotspots indicate selective pressure across a population of tumor samples, but their prevalence within and across cancer types is incompletely characterized. An approach to detect significantly mutated residues, rather than methods that identify recurrently mutated genes, may uncover new biologically and therapeutically relevant driver mutations. Here, we developed a statistical algorithm to identify recurrently mutated residues in tumor samples. We applied the algorithm to 11,119 human tumors, spanning 41 cancer types, and identified 470 somatic substitution hotspots in 275 genes. We find that half of all human tumors possess one or more mutational hotspots with widespread lineage-, position and mutant allele-specific differences, many of which are likely functional. In total, 243 hotspots were novel and appeared to affect a broad spectrum of molecular function, including hotspots at paralogous residues of Ras-related small GTPases RAC1 and RRAS2. Redefining hotspots at mutant amino acid resolution will help elucidate the allele-specific differences in their function and could have important therapeutic implications. PMID- 26619012 TI - Mapping the effects of drugs on the immune system. AB - Understanding how drugs affect the immune system has consequences for treating disease and minimizing unwanted side effects. Here we present an integrative computational approach for predicting interactions between drugs and immune cells in a system-wide manner. The approach matches gene sets between transcriptional signatures to determine their similarity. We apply the method to model the interactions between 1,309 drugs and 221 immune cell types and predict 69,995 interactions. The resulting immune-cell pharmacology map is used to predict how five drugs influence four immune cell types in humans and mice. To validate the predictions, we analyzed patient records and examined cell population changes from in vivo experiments. Our method offers a tool for screening thousands of interactions to identify relationships between drugs and the immune system. PMID- 26619013 TI - Concentric-flow electrokinetic injector enables serial crystallography of ribosome and photosystem II. AB - We describe a concentric-flow electrokinetic injector for efficiently delivering microcrystals for serial femtosecond X-ray crystallography analysis that enables studies of challenging biological systems in their unadulterated mother liquor. We used the injector to analyze microcrystals of Geobacillus stearothermophilus thermolysin (2.2-A structure), Thermosynechococcus elongatus photosystem II (<3-A diffraction) and Thermus thermophilus small ribosomal subunit bound to the antibiotic paromomycin at ambient temperature (3.4-A structure). PMID- 26619014 TI - Cellular O-Glycome Reporter/Amplification to explore O-glycans of living cells. AB - Protein O-glycosylation has key roles in many biological processes, but the repertoire of O-glycans synthesized by cells is difficult to determine. Here we describe an approach termed Cellular O-Glycome Reporter/Amplification (CORA), a sensitive method used to amplify and profile mucin-type O-glycans synthesized by living cells. Cells convert added peracetylated benzyl-alpha-N acetylgalactosamine to a large variety of modified O-glycan derivatives that are secreted from cells, allowing for easy purification for analysis by HPLC and mass spectrometry (MS). Relative to conventional O-glycan analyses, CORA resulted in an ~100-1,000-fold increase in sensitivity and identified a more complex repertoire of O-glycans in more than a dozen cell types from Homo sapiens and Mus musculus. Furthermore, when coupled with computational modeling, CORA can be used for predictions about the diversity of the human O-glycome and offers new opportunities to identify novel glycan biomarkers for human diseases. PMID- 26619016 TI - Who Will Do My Autopsy? PMID- 26619015 TI - Challenges to Biomarker Testing for PD-1/PD-L1 Checkpoint Inhibitors for Lung Cancer. PMID- 26619017 TI - Edoxaban: Efficacy, Laboratory Monitoring, and Approach to Reversal. PMID- 26619018 TI - Pathology Education: Moving On. PMID- 26619019 TI - Updates on Surgical and Molecular Pathology Concerning Head and Neck Diseases. PMID- 26619020 TI - Value of Molecular Tests in Cytologically Indeterminate Lesions of Thyroid. AB - CONTEXT: Fine-needle aspiration has been the initial step in the workup of thyroid nodular lesions and has successfully reduced the number of unnecessary surgeries and improved preoperative malignancy detection. However, up to one third of cases fall in the diagnostically "indeterminate group," which poses a patient-management challenge. objective: To review the characteristics of molecular tests useful for stratifying the malignancy risk of indeterminate thyroid lesions, including their advantages and limitations. DATA SOURCES: PubMed. CONCLUSIONS: Molecular tests are useful for triage of indeterminate thyroid nodules initially diagnosed by using fine-needle aspiration. Immunocytochemistry is readily available with the shortest turnaround time among the molecular tests but suffers from poor reproducibility and low interpretation concordance. Gene mutation analysis is superior in detecting malignancies as a rule-in test, despite low specificity. Next-generation sequencing seems promising but needs more validations before widespread use. Gene expression profiling is more suitable for detecting benign lesions as a rule-out test to avoid unnecessary surgeries but is not reliable in excluding malignancies. MicroRNA profiling has great potential for both risk stratification and predicting prognosis but is limited by significant variations in sensitivity and specificity. Although many questions still need to be answered, taken together, molecular tests are a promising option for classifying cytologically indeterminate thyroid nodular lesions. PMID- 26619021 TI - Fine-Needle Aspiration Biopsy of Salivary Gland Lesions. AB - CONTEXT: Fine-needle aspiration (FNA) is a well-established diagnostic approach for salivary gland lesions; however, lack of a standard system of terminology for classification of salivary gland neoplasms collected by FNA and the relatively high frequency of uncertainty of diagnosis are likely partly responsible for current confusion in the interpretation of these FNA samples. OBJECTIVE: To propose a novel classification system for reporting salivary gland FNA samples and summarize recent progress in application of molecular and immunohistochemical markers in selected salivary gland neoplasms. DATA SOURCES: Literature review and authors' personal practice experience. CONCLUSIONS: The new classification system provides a more succinct, standardized interpretation of results and will ultimately assist in communication between clinicians, clinical decision making, and preoperative patient counseling. Impressive advances have been made in recent years in the understanding of molecular pathogenesis of salivary gland tumors. With the newly acquired diagnostic tools, significant improvement in diagnostic accuracy of salivary gland FNA can certainly be expected. PMID- 26619022 TI - The Differential Diagnosis of Sinonasal/Nasopharyngeal Neuroendocrine/Neuroectodermally Derived Tumors. AB - CONTEXT: The differential diagnosis of neuroendocrine neoplasms arising in the sinonasal tract is broad and includes lesions of epithelial, mesenchymal, and neuroectodermal origin. OBJECTIVE: To review the differential diagnosis of sinonasal neuroendocrine and neuroectodermally derived tumors. DATA SOURCES: The current literature was reviewed to provide updated information regarding the differential diagnosis and means for diagnosing neuroendocrine tumors including sinonasal neuroendocrine carcinoma, olfactory neuroblastoma, malignant melanoma, paraganglioma, pituitary adenoma, and Ewing family of tumors. CONCLUSIONS: The differential diagnosis of neoplasms with neuroendocrine differentiation in the sinonasal tract is broad, and diagnosis often includes not only histologic review but also immunohistochemical or molecular analysis. PMID- 26619023 TI - Differential Diagnosis of Necrotizing Sinonasal Lesions. AB - CONTEXT: A number of entities may result in necrosis in the sinonasal tract and lead to significant morbidity and mortality. These include infections, necrotizing vasculitis, neoplastic processes, and drug dependency. This review will concentrate on the differential diagnosis of sinonasal necrotizing lesions. OBJECTIVE: To review the differential diagnoses of necrotizing destructive lesions of the sinonasal tract. DATA SOURCES: The current literature was reviewed to provide updated information regarding the differential diagnosis of sinonasal necrotizing lesions, including infectious disease processes; antineutrophilic cytoplasmic antibody-associated vasculitides; neoplastic processes, particularly natural killer/T-cell lymphomas; and drug abuse. CONCLUSIONS: The differential diagnosis of necrotizing sinonasal lesions is broad, with often overlapping diagnostic features that lead to diagnostic challenges. Ancillary tests such as special stains and immunohistochemical studies can offer significant assistance. PMID- 26619024 TI - Performance Characteristics of Adenoid Cystic Carcinoma of the Salivary Glands in Fine-Needle Aspirates: Results From the College of American Pathologists Nongynecologic Cytology Program. AB - CONTEXT: Although the cytomorphology of adenoid cystic carcinoma (ACC) has been well described, the accuracy of this diagnosis in fine-needle aspirates (FNAs) of the salivary glands has not been extensively evaluated. OBJECTIVE: To assess participants' responses in the College of American Pathologists (CAP) Nongynecologic Cytology (NGC) Program to determine the accuracy and false negative rate of ACC cases in salivary gland FNAs. DESIGN: A retrospective review of the CAP NGC Program's cumulative data from 2000-2010 was performed for the general and the specific reference diagnosis categories for ACC in salivary gland FNAs according to preparation and participant types. RESULTS: Of 5156 responses, the overall concordance rates for both the general category of malignancy and the specific category of ACC were 63.6% (3279 of 5156) and 38.6% (1966 of 5088), respectively, with a false-negative rate of 36.4% (1877 of 5156). The most frequent false-negative responses were pleomorphic (1080) and monomorphic (526) adenoma (1614 of 5088, 31.5%), while lymphoma was the most frequent malignant misinterpretation. There was a significant statistical difference in concordance to the reference interpretation between the reader types: 39.9% (1006 of 2521) concordance rate for pathologists compared to 33.8% (503 of 1488) for cytotechnologists. However, there was no significant statistical difference for concordance to the general category or reference interpretation, based on preparation type (Papanicolaou versus modified Giemsa stained). CONCLUSIONS: In this interlaboratory comparison educational program, accurate identification of ACC has shown to be problematic, with ACC representing an important cause of false-negative responses. The most common diagnostic pitfall is distinguishing this entity from pleomorphic and monomorphic adenoma in the benign category and from lymphoma and adenocarcinoma in the malignant one. PMID- 26619025 TI - Expression of Angiogenic Factors in Invasive Retinoblastoma Tumors Is Associated With Increase in Tumor Cells Expressing Stem Cell Marker Sox2. AB - CONTEXT: Progression of retinoblastoma is associated with increased tumor angiogenesis. However, a clear relationship between the expression of angiogenic markers in specific regions of the tumor and tumor progression has not been established. This study investigates the association between angiogenic factors in retinoblastomas with choroidal and/or optic nerve invasion (high-risk/invasive retinoblastoma) and expression of Sox2, a stem cell marker. OBJECTIVE: To investigate the association between the expression of angiogenic factors and markers of tumor invasiveness, such as the stem cell marker Sox2, in retinoblastoma tissues. DESIGN: Immunohistochemistry was used to evaluate coexpression of the angiogenic growth factors vascular endothelial growth factor A (VEGF-A), VEGF receptor 2 (VEGFR-2), and endoglin (CD105); markers of glial differentiation (vimentin and glial fibrillary acidic protein); and a neural stem cell marker (Sox2). Expression was assessed in nonneoplastic and neoplastic ocular tissues collected from enucleated eyes of patients with retinoblastoma. During qualitative data interpretation, evaluating pathologists were masked to patient grouping. RESULTS: Expression of VEGF-A and VEGFR-2 in noninvasive (non high-risk feature) retinoblastoma tumors was lower than in the invasive, or high risk feature tumors. Moreover, our data indicate that the tumor cells, and not the surrounding stroma, secrete VEGF-A and that angiogenesis is mostly localized to the iris. Finally, our data showed that the expression of the neural stem cell marker Sox2 is associated with eyes with increased VEGF-A expression and tumor invasiveness. CONCLUSIONS: Increased expression of angiogenic factors, with a concomitant increase in expression of the stem cell marker Sox2 observed in retinoblastoma tissues, may partially explain the aggressiveness of these tumors. The complex interaction of angiogenic and stem cell-related pathways in these tumors, especially in high-risk feature retinoblastoma, suggests that targeting tumor cells capable of secreting vasculogenic factors, as well as proangiogenic genes and signaling pathways, may be necessary for development of effective antimetastatic retinoblastoma drugs. PMID- 26619026 TI - Diagnostic Discrepancies in Mandatory Slide Review of Extradepartmental Head and Neck Cases: Experience at a Large Academic Center. AB - CONTEXT: Medical error is a significant problem in the United States, and pathologic diagnoses are a significant source of errors. Prior studies have shown that second-opinion pathology review results in clinically major diagnosis changes in approximately 0.6% to 5.8% of patients. The few studies specifically on head and neck pathology have suggested rates of changed diagnoses that are even higher. Objectives .- To evaluate the diagnostic discrepancy rates in patients referred to our institution, where all such cases are reviewed by a head and neck subspecialty service, and to identify specific areas with more susceptibility to errors. DESIGN: Five hundred consecutive, scanned head and neck pathology reports from patients referred to our institution were compared for discrepancies between the outside and in-house diagnoses. Major discrepancies were defined as those resulting in a significant change in patient clinical management and/or prognosis. RESULTS: Major discrepancies occurred in 20 cases (4% overall). Informative follow-up material was available on 11 of the 20 patients (55.0%), among whom, the second opinion was supported in 11 of 11 cases (100%). Dysplasia versus invasive squamous cell carcinoma was the most common (7 of 20; 35%) area of discrepancy, and by anatomic subsite, the sinonasal tract (4 of 21; 19.0%) had the highest rate of discrepant diagnoses. Of the major discrepant diagnoses, 12 (12 of 20; 60%) involved a change from benign to malignant, one a change from malignant to benign (1 of 20; 5%), and 6 involved tumor classification (6 of 20; 30%). CONCLUSIONS: Head and neck pathology is a relatively high-risk area, prone to erroneous diagnoses in a small fraction of patients. This study supports the importance of second-opinion review by subspecialized pathologists for the best care of patients. PMID- 26619027 TI - Comparison of Oncotype DX Recurrence Score by Histologic Types of Breast Carcinoma. AB - CONTEXT: Oncotype DX (ODX) is a widely used commercial assay that estimates the risk of distant recurrence and may predict the benefit of chemotherapy in a subset of breast cancers. Some studies have shown the ability to predict Oncotype DX recurrence score (ODXRS), based on routinely reported pathologic features; however, there are limited data correlating specific histologic type of breast cancer to ODXRS. OBJECTIVE: To compare ODXRS to specific histologic types of breast cancer. DESIGN: One hundred eighty-four cases were sent for ODXRS testing and the results were compared with histologic type and grade. RESULTS: The highest average ODXRS was seen in invasive ductal carcinoma with micropapillary features (29) followed by invasive ductal carcinoma not otherwise specified (mean = 19.4, SD = 11.6), invasive mucinous carcinoma (mean = 17.2, SD = 5.9), invasive lobular carcinoma (mean = 15.7, SD = 7.2), mixed ductal and lobular carcinoma (mean = 14.1, SD = 7.7), tubular carcinoma (10.0), and mixed ductal and mucinous carcinoma (mean = 8.0, SD = 4.2). Most tumors that had a high ODXRS were grade 3 invasive ductal carcinoma, representing 13 of a total of 20 cases (65%). Interestingly, 3 of the 4 cases of pure invasive mucinous carcinoma had an intermediate ODXRS. CONCLUSIONS: Although the numbers are small, our findings raise further awareness of the significance between histologic type and grade, and RS in breast cancer. In some special histologic types of breast cancer, particularly those considered to follow either an excellent or poor clinical course by histology alone, it is unclear whether the ODXRS results are as meaningful as in carcinomas of no special type. Further investigation with higher numbers and outcome data is needed. PMID- 26619028 TI - Telepathology Impacts and Implementation Challenges: A Scoping Review. AB - CONTEXT: Telepathology is a particular form of telemedicine that fundamentally alters the way pathology services are delivered. Prior reviews in this area have mostly focused on 2 themes, namely technical feasibility issues and diagnosis accuracy. OBJECTIVES: To synthesize the literature on telepathology implementation challenges and broader organizational and societal impacts and to propose a research agenda to guide future efforts in this domain. DATA SOURCES: Two complementary databases were systematically searched: MEDLINE (PubMed) and ABI/INFORM (ProQuest). Peer-reviewed articles and conference proceedings were considered. The final sample consisted of 159 papers published between 1992 and 2013. CONCLUSIONS: This review highlights the diversity of telepathology networks and the importance of considering these distinctions when interpreting research findings. Various network structures are associated with different benefits. Although the dominant rationale in single-site projects is financial, larger centralized and decentralized telepathology networks are targeting a more diverse set of benefits, including extending access to pathology to a whole region, achieving substantial economies of scale in workforce and equipment, and improving quality by standardizing care. Importantly, our synthesis reveals that the nature and scale of encountered implementation challenges also varies depending on the network structure. In smaller telepathology networks, organizational concerns are less prominent, and implementers are more focused on usability issues. As the network scope widens, organizational and legal issues gain prominence. PMID- 26619029 TI - Mammary Hibernoma: A Rare Entity. AB - Hibernoma arising in the breast is rare and may present as an asymptomatic mass or may be detected by screening mammography. Four histologic types have been identified: typical, myxoid variant, spindle cell variant, and the lipoma-like variant. The most common "typical variant" is composed of pale to eosinophilic multivacuolated cells with interspersed univacuolar cells. Hibernomas are universally benign and are not known to recur or have an aggressive behavior, even in incompletely excised lesions. Hence, their clinical importance lies in distinguishing them from other benign and malignant breast neoplasms as well as inflammatory conditions that come into the histologic or radiologic differential. This review discusses the clinical features, radiologic and histopathologic characteristics, ancillary studies, suggested pathogenesis, differential diagnosis, and treatment of and prognosis for these uncommon lesions. PMID- 26619030 TI - Clinical Applications of 4-Factor Prothrombin Complex Concentrate: A Practical Pathologist's Perspective. AB - A 4-factor prothrombin complex concentrate (4F-PCC), containing therapeutic doses of vitamin K-dependent coagulation factors, was recently licensed in the United States for reversal of vitamin K antagonist therapy. However, given the emergence of several oral anticoagulants for which there are no specific reversal agents, and the existence of many other complex bleeding disorders, it is likely that clinicians will seek to use 4F-PCCs for any number of off-label indications. Thus, the goal of this review is to explore practical issues regarding 4F-PCC, with an emphasis on issues relevant to blood bankers and pathologists. Specifically, our aims are to (1) examine the role of 4F-PCC in vitamin K antagonist reversal, (2) review its potential use in the treatment of hemorrhage due to novel oral anticoagulants, and (3) explore potential uses in liver disease, trauma-associated bleeding, and rare coagulopathies. Safety and other practical considerations of 4F-PCCs will also be discussed. PMID- 26619031 TI - The rationale for patient-reported outcomes surveillance in cancer and a reproducible method for achieving it. AB - Patient-reported outcomes (PROs) measure quality of life, symptoms, patient functioning, and patient perceptions of care; they are essential for gaining a full understanding of cancer care and the impact of cancer on people's lives. Repeatedly captured facility-level and/or population-level PROs (PRO surveillance) could play an important role in quality monitoring and improvement, benchmarking, advocacy, policy making, and research. This article describes the rationale for PRO surveillance and the methods of the Patient Reported Outcomes Symptoms and Side Effects Study (PROSSES), which is the first PRO study to use the American College of Surgeons Commission on Cancer's Rapid Quality Reporting System to identify patients and manage study data flow. The American Cancer Society, the National Cancer Institute, the Commission on Cancer, and RTI International collaborated on PROSSES. PROSSES was conducted at 17 cancer programs that participated in the National Cancer Institute Community Cancer Centers Program among patients diagnosed with locoregional breast or colon cancer. The methods piloted in PROSSES were successful as demonstrated by high eligibility (93%) and response (61%) rates. Differences in clinical and demographic characteristics between respondents and nonrespondents were mostly negligible, with the exception that non-white individuals were somewhat less likely to respond. These methods were consistent across cancer centers and reproducible over time. If repeated and expanded, they could provide PRO surveillance data from patients with cancer on a national scale. PMID- 26619032 TI - General Practitioner Assessment of Cognition: use in primary care prior to memory clinic referral. AB - AIMS: To measure current and comparative frequencies of use of the General Practitioner Assessment of Cognition (GPCOG) scale in consecutive primary care referrals to a dedicated secondary care memory clinic. METHODS: Over 6 months (January-June 2015), referral letters from primary care (n = 121) were examined for mention of GPCOG use. RESULTS: The proportion of patients administered any cognitive screening instrument before referral was 41.3%, with 11.6% administered the GPCOG, a significant increase compared with prior cohorts. However, GPCOG was incorrectly used or documented in 29% of cases. CONCLUSION: GPCOG use is increasing in primary care settings, but training in its correct use and scoring may be required to ensure that its administration makes meaningful information available. PMID- 26619033 TI - Intraoperative dynamic pressure measurements in carpal tunnel syndrome: Correlations with clinical signs. AB - OBJECTIVE: This study was designed to evaluate the correlations between dynamic carpal tunnel pressure and clinical signs. METHODS: From December 2008 to May 2010, open carpal tunnel release (OCTR) was performed on a total of 90 hands (83 patients). All patients completed neurological and provocation tests (two-point discrimination, Tinel test, Phalen test, reverse-Phalen test and assessment of thenar muscle atrophy). Carpal tunnel pressure (CTP) was measured in two parts of carpal tunnel (proximal and distal carpal tunnel) and in three different postures (neutral, wrist flexion and wrist extension). RESULTS: There were 74 females and nine males aged 36 to 86 years (mean age 54). CTP values were more elevated in the wrist extension than wrist flexion in the proximal carpal tunnel but not at the distal carpal tunnel. There was no statistically significant correlation among CTP, provocation testing, and clinical signs. However, two-point discrimination (2-PD) showed a statistically significant correlation with CTP, especially in the proximal area in the wrist extension posture (P<0.01). Duration of symptoms (SD) statistically correlated with CTP in the distal carpal tunnel in the neutral posture (P<0.01). CONCLUSIONS: 2-PD and duration of symptoms are correlated with the CTP value in specific areas and with hand postures. This emphasizes the importance of releasing the entire carpal tunnel lesion since CTP values appear to vary within the carpal tunnel space and according to hand posture. PMID- 26619034 TI - Association between subthalamic nucleus deep brain stimulation and weight gain: Results of a case-control study. AB - OBJECTIVE: To evaluate whether weight change in patients with Parkinson's disease (PD) is different in those undergoing deep brain stimulation (DBS) of the subthalamic nucleus (STN) compared to those not undergoing DBS. PATIENTS AND METHODS: A retrospective case-control study was performed in PD patients who had undergone STN DBS (cases) compared to matched PD patients without DBS (controls). Demographic and clinical data including Unified Parkinson's Disease Rating Scale (UPDRS) motor scores were collected. Repeated measures mixed model regression was used to identify variables associated with weight gain. RESULTS: Thirty-five cases and 34 controls were identified. Baseline age, gender, diagnosis and weight were similar. Duration of diagnosis was longer in cases (6.3 vs 4.9 years, p=0.0015). At 21.3 months, cases gained 2.9 kg (+4.65%) while controls lost 1.8 kg (-3.05%, p<0.02). Postoperative UPDRS motor scores improved by 49% indicating surgical efficacy. Only younger age (p=0.0002) and DBS (p=0.008) were significantly associated with weight gain. CONCLUSION: In this case-control study, PD patients undergoing STN DBS experienced post-operative weight gain that was significantly different from the weight loss observed in non-DBS PD controls. Patients, especially overweight individuals, should be informed that STN DBS can result in weight gain. PMID- 26619035 TI - Prediction of pork color attributes using computer vision system. AB - Color image processing and regression methods were utilized to evaluate color score of pork center cut loin samples. One hundred loin samples of subjective color scores 1 to 5 (NPB, 2011; n=20 for each color score) were selected to determine correlation values between Minolta colorimeter measurements and image processing features. Eighteen image color features were extracted from three different RGB (red, green, blue) model, HSI (hue, saturation, intensity) and L*a*b* color spaces. When comparing Minolta colorimeter values with those obtained from image processing, correlations were significant (P<0.0001) for L* (0.91), a* (0.80), and b* (0.66). Two comparable regression models (linear and stepwise) were used to evaluate prediction results of pork color attributes. The proposed linear regression model had a coefficient of determination (R(2)) of 0.83 compared to the stepwise regression results (R(2)=0.70). These results indicate that computer vision methods have potential to be used as a tool in predicting pork color attributes. PMID- 26619036 TI - Controlled Formation of Metal@Al2O3 Yolk-Shell Nanostructures with Improved Thermal Stability. AB - Yolk-shell structured nanomaterials have shown interesting potential in different areas due to their unique structural configurations. A successful construction of such a hybrid structure relies not only on the preparation of the core materials, but also on the capability to manipulate the outside wall. Typically, for Al2O3, it has been a tough issue in preparing it into a uniform nanoshell, making the use of Al2O3-based yolk-shell structures a challenging but long-awaited task. Here, in benefit of our success in the controlled formation of Al2O3 nanoshell, we demonstrated that yolk-shell structures with metal confined inside a hollow Al2O3 nanosphere could be successfully achieved. Different metals including Au, Pt, Pd have been demonstrated, forming a typical core@void@shell structure. We showed that the key parameters of the yolk-shell structure such as the shell thickness and the cavity size could be readily tuned. Due to the protection of a surrounding Al2O3 shell, the thermal stability of the interior metal nanoparticles could be substantially improved, resulting in promising performance for the catalytic CO oxidation as revealed by our preliminary test on Au@Al2O3. PMID- 26619037 TI - Vaccines for the prevention of meningococcal capsular group B disease: What have we recently learned? AB - Meningococcal disease remains a feared and devastating cause of sepsis and meningitis. Disease incidence is highest among infants and children although a significant burden of disease is experienced by adolescents, young adults and those with specific risk-factors. Prevention of disease against capsular groups A, C, W and Y; 4 of the 5 most pathogenic groups is achievable using capsular polysaccharide vaccines. It has only recently been possible to provide protection against capsular group B (MenB) strains following the licensure of a 4 component group B vaccine (4CMenB) in Europe in 2013. Following licensure, 4CMenB has been used in specific at-risk groups and in response to outbreaks of MenB disease. The largest outbreak interventions have been in students at 2 universities in the United States and for all individuals aged 2 months to 20 years of age in Quebec, Canada. The vaccine was recommended in February 2014 for implementation into the UK infant schedule at 2, 4 and 12 months of age, although it has taken over 12 months to resolve procurement discussions to enable implementation. The UK recommendation incorporates prophylactic paracetamol with infant doses when 4CMenB is administered concomitantly with routine vaccines. This is based on recent data demonstrating the ability of paracetamol to reduce fever rates to background levels without impacting immunogenicity. Post-implementation surveillance will be important to provide vaccine efficacy data as this was not possible to determine in pre-licensure studies due to the relative infrequency of MenB cases. PMID- 26619038 TI - Controlling the molecular weights of polyethylene waxes using the highly active precatalysts of 2-(1-aryliminoethyl)-9-arylimino-5,6,7,8 tetrahydrocycloheptapyridylcobalt chlorides: synthesis, characterization, and catalytic behavior. AB - A series of 2-(1-aryliminoethyl)-9-arylimino-5,6,7,8 tetrahydrocycloheptapyridylcobalt chlorides were synthesized and characterized using FT-IR and elemental analysis, and the molecular structures of complexes , and were confirmed to present a pseudo-square-pyramidal or trigonal-bipyramidal geometry around the cobalt center using single-crystal X-ray diffraction. Upon activation with either methylaluminoxane (MAO) or modified methylaluminoxane (MMAO), all cobalt precatalysts gave high activities up to the level of 10(7) gPE mol(-1) (Co) h(-1) toward ethylene polymerization, being one of most active cobalt-based precatalysts. In comparison with cobalt analogues, the title precatalysts generally possessed longer lifetime along with good thermo stability; moreover, the resultant polyethylenes were highly linear and unimodal in most cases. PMID- 26619039 TI - Characterization, detection, and counting of metal nanoparticles using flow cytometry. AB - There is a need to accurately detect, characterize, and quantify nanoparticles in suspensions. This study helps to understand the complex interactions between similar types of nanoparticles. Before initiating a study of metal nanoparticles, five submicron PS beads with sizes between 200 nm and 1 um were used to derive a reference scale that was useful in evaluating the flow cytometer for functionality, sensitivity, resolution, and reproducibility. Side scatter intensity (SSC) from metal nanoparticles was obtained simultaneously from 405 nm and 488 nm lasers. The 405 nm laser generally yielded histogram distributions with smaller CVs, less side scatter intensity, better separation indices between beads and decreased scatter differences between different sized particles compared with the 488 nm laser. Submicron particles must be diluted to 10(6) and 10(7) particles/mL before flow cytometer analysis to avoid coincidence counting artifacts. When particles were too concentrated the following occurred: swarm, electronic overload, coincidence counting, activation of doublet discrimination and rejection circuitry, increase of mean SSC histogram distributions, alterations of SSC and pulse width histogram shape, decrease and fluctuations in counting rate and decrease or elimination of particulate water noise and 1 um reference bead. To insure that the concentrations were in the proper counting range, the nanoparticle samples were mixed with a known concentration of 1 um counting beads. Sequential dilutions of metal nanoparticles in a 1 um counting bead suspension helped determine the diluted concentration needed for flow cytometer analysis. It was found that the original concentrated nanoparticle samples had to be diluted, between 1:10,000 and 1:100,000, before characterization by flow cytometry. The concentration of silver or gold nanoparticles in the undiluted sample were determined by comparing them with a known concentration (1.9 * 10(6) beads/mL) of 1 um polystyrene reference beads. PMID- 26619040 TI - Silver nanoparticles of 70 nm and 20 nm affect differently the biology of human neutrophils. AB - The influence of size of nanoparticles (NP), especially in regard to pulmonary toxicity, has been widely investigated. In general, NP with smaller diameters are more pro-inflammatory in vivo, at least in terms of neutrophil influx. Nevertheless, the influence of size of NP on polymorphonuclear neutrophil (PMN) cell biology is poorly documented. In the study here, it was decided to determine if AgNP with a diameter of 70 nm (AgNP70) will alter the biology of human PMN similarly to AgNP20 previously reported to induce apoptosis and inhibit de novo protein synthesis. The results here indicated that, in contrast to AgNP20, AgNP70 delayed PMN apoptosis. However, both AgNP20 and AgNP70 inhibited de novo protein synthesis. Both forms of AgNP did not significantly increase reactive oxygen species (ROS) production, but AgNP20 significantly increased the cell production of the CXCL8 chemokine (IL-8). In addition, AgNP20, but not AgNP70, induced the release of albumin and matrix metalloproteinase-9 (MMP-9/gelatinase B) into culture supernatants. Consistent with this latter observation, gelatinase activity was increased by AgNP20, as assessed by zymography. From these outcomes, it is concluded that two NP with different initial diameters can possess similar as well as distinct - biological properties in modulating human PMN functions. These outcomes are testimony to the complexity of the modes of action of NP at the cellular level. PMID- 26619041 TI - Correction: Statistics of non-affine defect precursors: tailoring defect densities in colloidal crystals using external fields. PMID- 26619043 TI - Platforms Formed from a Three-Dimensional Cu-Based Zwitterionic Metal-Organic Framework and Probe ss-DNA: Selective Fluorescent Biosensors for Human Immunodeficiency Virus 1 ds-DNA and Sudan Virus RNA Sequences. AB - We herein report a water-stable three-dimensional Cu-based metal-organic framework (MOF) 1 supported by a tritopic quaternized carboxylate and 4,4' dipyridyl sulfide as an ancillary ligand. This MOF exhibits unique pore shapes with aromatic rings, positively charged pyridinium and unsaturated Cu(II) cation centers, free carboxylates, tessellating H2O, and coordinating SO4(2-) on the pore surface. Compound 1 can interact with two carboxyfluorescein (FAM)-labeled single-stranded DNA sequences (probe ss-DNA, delineated as P-DNA) through electrostatic, pi-stacking, and/or hydrogen-bonding interactions to form two P DNA@1 systems, and thus quench the fluorescence of FAM via a photoinduced electron-transfer process. These P-DNA@1 systems can be used as effective fluorescent sensors for human immunodeficiency virus 1 double-stranded DNA and Sudan virus RNA sequences, respectively, with detection limits of 196 and 73 pM, respectively. PMID- 26619042 TI - Validation of the Self-Efficacy for Managing Chronic Disease Scale: A Scleroderma Patient-Centered Intervention Network Cohort Study. AB - OBJECTIVE: Self-management programs for patients with chronic illnesses, including rheumatic diseases, seek to enhance self-efficacy for performing health management behaviors. No measure of self-efficacy has been validated for patients with systemic sclerosis (SSc; scleroderma). The objective of this study was to assess the validity and internal consistency reliability of the Self-Efficacy for Managing Chronic Disease (SEMCD) scale in SSc. METHODS: English-speaking SSc patients enrolled in the Scleroderma Patient-centered Intervention Network Cohort who completed the SEMCD scale at their baseline assessment between March 2014 and June 2015 were included. Patients were enrolled from 21 sites in Canada, the US, and the UK. Confirmatory factor analysis (CFA) was used to evaluate the factor structure of the SEMCD scale. Cronbach's alpha was calculated to assess internal consistency reliability. Hypotheses on the direction and magnitude of Pearson's correlations with psychological and physical outcome measures were formulated and tested to examine convergent validity. RESULTS: A total of 553 patients were included. CFA supported the single-factor structure of the SEMCD scale (Tucker Lewis Index = 0.99, comparative fit index = 0.99, root mean square error of approximation = 0.10). Internal consistency was high (alpha = 0.93), and correlations with measures of psychological and physical functioning were moderate to large (|r| = 0.48-0.67, P < 0.001), confirming study hypotheses. CONCLUSION: Scores from the SEMCD scale are valid for measuring self-efficacy in patients with SSc, and results support using the scale as an outcome measure to evaluate the effectiveness of self-management programs in SSc. PMID- 26619044 TI - Naringin Alleviates Diabetic Kidney Disease through Inhibiting Oxidative Stress and Inflammatory Reaction. AB - Naringin, a flavanone glycoside extracted from Citrus grandis Osbeck, has a wide range of pharmacological effects. In the present study we aimed at demonstrating the protective effect of naringin against diabetic kidney disease (DKD) and elucidating its possible molecular mechanism underlying. The beneficial effect of naringin was assessed in rats with streptozotocin (STZ)-induced diabetes and high glucose-induced HBZY-1 cells. According to our results, first we found that naringin relieved kidney injury, improved renal function and inhibited collagen formation and renal interstitial fibrosis. Second, we confirmed that naringin restrained oxidative stress by activating Nrf2 antioxidant pathway. Moreover, the results suggested that naringin significantly resisted inflammatory reaction by inhibiting NF- kappa B signaling pathway. Taken together, our results demonstrate that naringin effectively alleviates DKD, which provide theoretical basis for naringin clinically used to treatment of DKD. PMID- 26619045 TI - Association Between Atopic Disease and Anemia in US Children. AB - IMPORTANCE: Atopic disease is associated with chronic inflammation, food allergen avoidance, and use of systemic immunosuppressant medications. All these factors have been shown to be associated with anemia. OBJECTIVE: To investigate whether atopic disease is associated with increased risk of childhood anemia. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional survey and laboratory assessment were conducted using data from the 1997-2013 US National Health Interview Survey (NHIS) that included 207,007 children and adolescents and the 1999-2012 National Health and Nutrition Examination Survey (NHANES) that included 30,673 children and adolescents. Analysis of the data was conducted between August 1, 2014, and August 28, 2015. EXPOSURES: Caregiver-reported history of eczema, asthma, hay fever, and/or food allergy. MAIN OUTCOMES AND MEASURES: Anemia was defined by caregiver report in the NHIS and by hemoglobin levels for age and sex in the NHANES. RESULTS: Data were collected on 207,007 children and adolescents from NHIS, representing all pediatric age, sex, racial/ethnic, household educational level, and income groups. The US prevalence was 9.5% (95% CI, 9.4%-9.7%) from all years of the NHIS for health care-diagnosed eczema, 12.8% (95% CI, 12.6%-13.0%) for asthma, 17.1% (95% CI, 16.9%-17.3%) for hay fever, 4.2% (95% CI, 4.1%-4.3%) for food allergy, and 1.1% (95% CI, 1.1%-1.2%) for anemia. In multivariable logistic regression models controlling for age, sex, race/ethnicity, annual household income, highest educational level in the family, insurance coverage, number of persons in the household, birthplace in the United States, and history of asthma, hay fever, and food allergy, anemia was associated with eczema in 14 of 17 studies, asthma in 11, hay fever in 12, and food allergy in 12. In multivariable analysis across the NHIS (with results reported as adjusted odds ratios [95% CIs]), children with any eczema (1.83; 1.58-2.13), asthma (1.31; 1.14 1.51), hay fever (1.57; 1.36-1.81), and food allergy (2.08; 1.71-2.52) had higher odds of anemia (P < .001 for all). In the NHANES, current history of asthma (1.33; 1.04-1.70; P = .02) and eczema (1.93; 1.04-3.59; P = .04) were associated with higher odds of anemia, particularly microcytic anemia (asthma: 1.61; 1.09 2.38; P = .02; eczema: 2.03; 1.20-3.46; P = .009) while history of hay fever was not associated with anemia (0.85; 0.62-1.17; P = .33). CONCLUSIONS AND RELEVANCE: The association between atopic disease and anemia was reproducible in multiple cohorts. Future studies are needed to identify the determinants of association between atopic disease and anemia. PMID- 26619046 TI - A simple highly sensitive and selective aptamer-based colorimetric sensor for environmental toxins microcystin-LR in water samples. AB - A simple and highly sensitive aptamer-based colorimetric sensor was developed for selective detection of Microcystin-LR (MC-LR). The aptamer (ABA) was employed as recognition element which could bind MC-LR with high-affinity, while gold nanoparticles (AuNPs) worked as sensing materials whose plasma resonance absorption peaks red shifted upon binding of the targets at a high concentration of sodium chloride. With the addition of MC-LR, the random coil aptamer adsorbed on Au NPs altered into regulated structure to form MC-LR-aptamer complexes and broke away from the surface of Au NPs, leading to the aggregation of AuNPs, and the color converted from red to blue due to the interparticle plasmon coupling. Results showed that our aptamer-based colorimetric sensor exhibited rapid and sensitive detection performance for MC-LR with linear range from 0.5 nM to 7.5 MUM and the detection limit reached 0.37 nM. Meanwhile, the pollutants usually coexisting with MC-LR in pollutant water samples had not demonstrated disturbance for detecting of MC-LR. The mechanism was also proposed suggesting that high affinity interaction between aptamer and MC-LR significantly enhanced the sensitivity and selectivity for MC-LR detection. Besides, the established method was utilized in analyzing real water samples and splendid sensitivity and selectivity were obtained as well. PMID- 26619047 TI - Leachability of volatile fuel compounds from contaminated soils and the effect of plant exudates: A comparison of column and batch leaching tests. AB - Volatile fuel compounds such as fuel oxygenates (FO) (MTBE and ETBE) and BTEX (benzene, toluene, ethylbenzene and xylene) are some of the most soluble components of fuel. Characterizing the leaching potential of these compounds is essential for predicting their mobility through the soil profile and assessing the risk of groundwater contamination. Plant root exudates can play an important role in the modification of contaminant mobility in soil-plant systems, and such effects should also be considered in leaching studies. Artificially spiked samples of A and B horizons from an alumi-umbric Cambisol were leached in packed columns and batch experiments using Milli-Q water and plant root exudates as leaching agents. The leaching potential and rate were strongly influenced by soil contaminant interactions and by the presence of root exudates. Organic matter in A horizon preferably sorbed the most non-polar contaminants, lowering their leaching potential, and this effect was enhanced by the presence of root exudates. On the other hand, the inorganic components of the B horizon, showed a greater affinity for polar molecules, and the presence of root exudates enhanced the desorption of the contaminants. Column experiments resulted in a more realistic protocol than batch tests for predicting the leaching potential of volatile organic compounds in dissimilar soils. PMID- 26619048 TI - Aluminum electrocoagulation as pretreatment during microfiltration of surface water containing NOM: A review of fouling, NOM, DBP, and virus control. AB - Electrocoagulation (EC) is the intentional corrosion of sacrificial anodes (typically aluminum or iron) by passing electricity to release metal-ion coagulant species and destabilize a wide range of suspended, dissolved, and macromolecular contaminants. It can be integrated ahead of microfiltration (MF) to effectively control turbidity, microorganisms, and disinfection by-products (DBPs) and simultaneously maintain a high MF specific flux. This manuscript summarizes the current knowledge on MF pretreatment by aluminum EC particularly focusing on mechanisms of (i) electrocoagulant dosing, (ii) (bio)colloid destabilization, (iii) fouling reductions, and (iv) enhanced removal of viruses, natural organic matter (NOM), and DBP precursors. Electrolysis efficiently removes hydrophobic NOM, viruses, and siliceous foulants. Aluminum effectively electrocoagulates viruses by physically encapsulating them in flocs, neutralizing their surface charge and reducing electrostatic repulsion, and increasing hydrophobic interactions between any sorbed NOM and free viruses. New results included herein demonstrate that EC achieves DBP control by removing NOM, reducing chlorine-reactivity of remaining NOM, and inducing a slight shift toward more brominated trihalomethanes and haloacetic acids. EC reduces MF fouling by forming large flocs that tend to deposit on the membrane surface, i.e. decrease pore penetration and forming more permeable cakes and by reducing foulant mass in case of significant floc-flotation. PMID- 26619049 TI - A predictive multi-linear regression model for organic micropollutants, based on a laboratory-scale column study simulating the river bank filtration process. AB - This study investigated relationships between OMP biodegradation rates and the functional groups present in the chemical structure of a mixture of 31 OMPs. OMP biodegradation rates were determined from lab-scale columns filled with soil from RBF site Engelse Werk of the drinking water company Vitens in The Netherlands. A statistically significant relationship was found between OMP biodegradation rates and the functional groups of the molecular structures of OMPs in the mixture. The OMP biodegradation rate increased in the presence of carboxylic acids, hydroxyl groups, and carbonyl groups, but decreased in the presence of ethers, halogens, aliphatic ethers, methyl groups and ring structures in the chemical structure of the OMPs. The predictive model obtained from the lab-scale soil column experiment gave an accurate qualitative prediction of biodegradability for approximately 70% of the OMPs monitored in the field (80% excluding the glymes). The model was found to be less reliable for the more persistent OMPs (OMPs with predicted biodegradation rates lower or around the standard error=0.77d(-1)) and OMPs containing amide or amine groups. These OMPs should be carefully monitored in the field to determine their removal during RBF. PMID- 26619050 TI - Estimation of upper flammability limits of C-H compounds in air at standard atmospheric pressure and evaluation of temperature dependence. AB - This study focuses on estimating the upper flammability limits of C-H compounds. A method was developed to determine the upper flammability limits in air at standard atmospheric pressure for the following cases: (a) estimation of the UFLs of pure C-H compounds at standard ambient temperature (25 degrees C); (b) estimation of the UFLs of binary mixtures of C-H compounds at standard ambient temperature (25 degrees C); (c) estimation of the UFLs of C-H compounds at different initial temperatures. The method was accurate in all cases. In case (a), for a total set of 115 compounds, the absolute average relative error was 7.27% and a squared correlation coefficient of 0.9248 was obtained. In case (b), the average absolute relative error was 5.55%; in case (c) it was 2.19%. PMID- 26619051 TI - Sensitivity and uncertainty analysis for Abreu & Johnson numerical vapor intrusion model. AB - This study conducted one-at-a-time (OAT) sensitivity and uncertainty analysis for a numerical vapor intrusion model for nine input parameters, including soil porosity, soil moisture, soil air permeability, aerobic biodegradation rate, building depressurization, crack width, floor thickness, building volume, and indoor air exchange rate. Simulations were performed for three soil types (clay, silt, and sand), two source depths (3 and 8m), and two source concentrations (1 and 400 g/m(3)). Model sensitivity and uncertainty for shallow and high concentration vapor sources (3m and 400 g/m(3)) are much smaller than for deep and low-concentration sources (8m and 1g/m(3)). For high-concentration sources, soil air permeability, indoor air exchange rate, and building depressurization (for high permeable soil like sand) are key contributors to model output uncertainty. For low-concentration sources, soil porosity, soil moisture, aerobic biodegradation rate and soil gas permeability are key contributors to model output uncertainty. Another important finding is that impacts of aerobic biodegradation on vapor intrusion potential of petroleum hydrocarbons are negligible when vapor source concentration is high, because of insufficient oxygen supply that limits aerobic biodegradation activities. PMID- 26619052 TI - Trace amounts of Cu2+ ions influence ROS production and cytotoxicity of ZnO quantum dots. AB - 3-Aminopropyltrimethoxysilane (APTMS) was used as ligand to prepare ZnO@APTMS, Cu(2+)-doped ZnO (ZnO:Cu@APTMS) and ZnO quantum dots (QDs) with chemisorbed Cu(2+) ions at their surface (ZnO@APTMS/Cu). The dots have a diameter of ca. 5 nm and their crystalline and phase purities and composition were established by X ray diffraction, transmission electron microscopy, UV-visible and fluorescence spectroscopies and by X-ray photoelectron spectroscopy. The effect of Cu(2+) location on the ability of the QDs to generate reactive oxygen species (ROS) under light irradiation was investigated. Results obtained demonstrate that all dots are able to produce ROS (OH, O2(-), H2O2 and (1)O2) and that ZnO@APTMS/Cu QDs generate more OH and O2(-) radicals and H2O2 than ZnO@APTMS and ZnO:Cu@APTMS QDs probably via mechanisms associating photo-induced charge carriers and Fenton reactions. In cytotoxicity experiments conducted in the dark or under light exposure, ZnO@APTMS/Cu QDs appeared slightly more deleterious to Escherichia coli cells than the two other QDs, therefore pointing out the importance of the presence of Cu(2+) ions at the periphery of the nanocrystals. On the other hand, with the lack of photo-induced toxicity, it can be inferred that ROS production cannot explain the cytotoxicity associated to the QDs. Our study demonstrates that both the production of ROS from ZnO QDs and their toxicity may be enhanced by chemisorbed Cu(2+) ions, which could be useful for medical or photocatalytic applications. PMID- 26619053 TI - Extremely Low Contact Resistance on Graphene through n-Type Doping and Edge Contact Design. AB - The effects of graphene n-doping on a metal-graphene contact are studied in combination with 1D edge contacts, presenting a record contact resistance of 23 Omega MUm at room temperature (19 Omega MUm at 100 K). This contact scheme is applied to a graphene-perovskite hybrid photodetector, significantly improving its performance (0.6 -> 1.8 A W(-1) in photoresponsivity and 3.3 * 10(4) -> 5.4 * 10(4) Jones in detectivity). PMID- 26619054 TI - Inflammatory Bowel Disease Phenotype in Pediatric Primary Sclerosing Cholangitis. AB - BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that most often occurs in association with inflammatory bowel disease (IBD). We examined whether the activity or colonic distribution of IBD differed in pediatric patients with and without PSC. METHODS: We compared colonic disease distribution, physician global assessment scores, Mayo endoscopic severity scores, IBD-related hospital admissions, and colonic resection surgery rate in a retrospective cohort of pediatric patients with IBD with and without PSC. RESULTS: We identified 37 patients with PSC-IBD, and 137 non-PSC matched IBD controls. Pancolitis was seen in 89.7 versus 72.4% (P = 0.051) of patients with PSC-IBD and rectal sparing in 24.3 versus 21.6% (P = 0.721) of patients with IBD. Physician global assessment and Mayo scores at presentation and in follow-up were similar in PSC-IBD and IBD. Patients with PSC-IBD had 0.19 admissions per person year compared with 0.25 in patients with IBD. The incidence rate ratio for admission was 0.75 (95% confidence interval (CI), 0.51-1.08). The 5-year probability of colonic surgery was 16.4% (95% CI, 7.0-36.0) in patients with PSC IBD and 24.7% (95% CI, 17.7-33.8) in patients with IBD (P = 0.271). In a multivariate model, male sex (hazard ratio [HR] = 2.2 [95% CI, 1.1-4.3]) and the presence of a non-PSC immune-mediated comorbidity {HR = 3.9 (95% CI, 1.5-10.4), but not PSC (HR = 0.5 [95% CI, 0.2-1.3])} or Crohn's disease (HR = 0.5 [95% CI, 0.1-1.5]), were risk factors for colonic surgery in pediatric IBD. CONCLUSIONS: Patients with IBD and PSC were more likely to present with pancolitis, but had similar rates of rectal sparing. Patients with IBD showed similar disease activity across a wide range of measures, at presentation and in follow-up, regardless of the presence of PSC. PMID- 26619055 TI - Effects of biradical deuteration on the performance of DNP: towards better performing polarizing agents. AB - We study the effects of the deuteration of biradical polarizing agents on the efficiency of dynamic nuclear polarization (DNP) via the cross-effect. To this end, we synthesized a series of bTbK and TOTAPol biradicals with systematically increased deuterium substitution. The deuteration increases the radicals' relaxation time, thus contributing to a higher saturation factor and larger DNP enhancement, and reduces the pool of protons within the so-called spin diffusion barrier. Notably, we report that full or partial deuteration leads to improved DNP enhancement factors in standard samples, but also slows down the build-up of hyperpolarization. Improvements in DNP enhancements factors of up to 70% and time savings of up to 38% are obtained upon full deuteration. It is foreseen that this approach may be applied to other DNP polarizing agents thus enabling further sensitivity improvements. PMID- 26619056 TI - Are chronically ill patients high users of homecare services in Canada? AB - OBJECTIVES: Chronically ill patients often need healthcare and supportive services, with formal homecare services an important source of community-based assistance. Although people diagnosed with 1 or more chronic diseases are thought to be the most common homecare clients, and perhaps the highest users of homecare services, few studies have analyzed homecare services utilization by specific clients. A study was done to determine if a relationship exists between chronic illness and homecare services utilization. STUDY DESIGN: Descriptive-comparative, secondary analysis of population homecare data. METHODS: Three years (2003-2004, 2004-2005, and 2005-2006) of complete homecare client and services utilization data for 1 Canadian province were obtained and tested using 5 definitions of chronic illness to determine which clients among all 149,378 were high users in terms of annual homecare hours and service visits or episodes. RESULTS: Two definitions revealed clients with a disproportionately large share of homecare hours and service episodes: a) clients classified by homecare case managers as "long-term" and b) clients with service spans of >=90 days. Definitions involving medical diagnoses and International Classification of Diseases, Ninth Revision, Clinical Modification codes or chapters did not reveal high users. Age and gender also did not predict services utilization. CONCLUSIONS: The comprehensive pre service assessment completed by homecare case managers was the most successful at distinguishing people with substantial homecare service needs-people who could then be described as chronically ill. This assessment should be studied to develop a standardized minimum data tool for consistent and fair assessments. PMID- 26619057 TI - The impact of Kaua'i Care Transition Intervention on hospital readmission rates. AB - OBJECTIVES: To evaluate the effects of Kaua'i Care Transition Intervention (KCTI), a patient-centered intervention program, on reducing hospital readmission rates among patients 60 years or older. STUDY DESIGN: A prospective quasi experimental prepost design. METHODS: Hospital admissions data for the year 2010 (January 1 to December 31) served as the baseline data and were used to identify patients at risk of hospital readmission. KCTI was implemented over a 12-month period from April 1, 2012, to March 31, 2013, and 30-day, 60-day, and 1-year readmission rates were assessed for both the intervention and baseline periods. The impact of the intervention was examined by a logistic regression model, controlling for possible patient population differences. RESULTS: During the intervention period, a total of 269 patients 60 years or older were admitted to the hospital, of which, 58 were referred to the KCTI program. Logistic regression controlling for patients' primary health insurance, discharge sites, and certain admitting diagnoses (eg, arrhythmias, cellulitis, chronic obstructive pulmonary disease) found that the intervention reduced the 30-day readmission rate by two thirds (odds ratio [OR], 0.34; P = .003). Readmission rates within 60 days (OR, 0.42; P < .01) and within a year (OR, 0.48; P < .001) during the intervention period were less than half of the baseline rates. CONCLUSIONS: By selecting patients with identified risk factors, then empowering and educating them with the intervention program, this study was successful in reducing hospital readmission rates. This study also demonstrated the value of carefully selecting patients for intervention programs. PMID- 26619058 TI - Antibiotic use for viral acute respiratory tract infections remains common. AB - OBJECTIVES: To determine the type and number of antibiotic prescriptions filled in the 28 days following an index visit for acute respiratory tract infections (ARTIs) generally presumed to be viral. STUDY DESIGN: This was a secondary analysis of administrative data. METHODS: We linked administrative data for pharmacy, clinical encounters, and providers to identify all prescriptions for a relevant antibiotic filled within 28 days of an index visit for an ARTI. Data were analyzed descriptively. The primary outcome was whether or not the patient was prescribed an antibiotic or anti-influenza medication for an episode of presumed viral ARTI. RESULTS: There were 54,656 encounters for presumed viral ARTI. Most visits (84.4%) were to a primary care clinician, with 12% to an urgent care center and 3.6% to the emergency department. Within 28 days of an encounter for a presumed viral upper respiratory tract infection, 49.4% of patients filled an initial antibiotic prescription, 4.8% a prescription for an anti-influenza drug, and 1.2% received both. A second antibiotic prescription was filled after the initial prescription by 8.9% of patients, and a third by 0.7%. Antibiotic use was most common for acute bronchitis (67.8%) and in the urgent care setting (60.2%). Antibiotics were prescribed less often by pediatricians, whereas anti influenza medications were prescribed most often for patients aged 5 to 17 years by both pediatricians and family physicians. Antibiotic use has increased since 2007, when azithromycin became a generic drug. CONCLUSIONS: Prescribing antibiotics for ARTIs that are likely to be viral in origin remains common, despite extensive public health educational efforts. PMID- 26619059 TI - Clinician considerations when selecting high-risk patients for care management. AB - OBJECTIVES: Hybrid approaches to case finding show promise as a method to increase the success of care management programs (CMPs). A large healthcare system implemented a hybrid approach in which clinicians review algorithm generated lists of potential high-risk patients within their practice and select the patients most appropriate for the CMP. We sought to understand the criteria clinicians used when selecting patients. STUDY DESIGN: We conducted 20 semi structured interviews with a convenience sample of primary care clinicians and their care managers from a diverse set of practices. METHODS: Two independent reviewers thematically coded interview responses through an iterative process. RESULTS: In addition to clinical need (eg, disease severity or multiple comorbidities), interviewees considered a number of nonclinical patient characteristics that they felt placed patients at risk for suboptimal healthcare utilization and poor adherence. These include patients' predisposing (eg, health literacy or navigation challenges, physical vulnerabilities, insight regarding their health) and enabling characteristics (eg, social and home environment, coping skills, financial resources). Interviewees also considered patients' existing linkages with the health system and whether other clinicians were already meeting a patient's care needs. CONCLUSIONS: In selecting patients for a CMP, clinicians considered patient characteristics that are not easily captured in standard clinical and administrative data. A hybrid approach to case finding concentrates clinician review on patients who meet standard clinical and healthcare utilization criteria, and allows clinicians to incorporate knowledge of patients' predisposing and enabling characteristics that are not readily maintained in clinical data. PMID- 26619060 TI - "Meaningful" clinical quality measures for primary care physicians. AB - OBJECTIVES: To systematically solicit recommendations from Meaningful Use (MU) exemplars to inform Stage 3 MU clinical quality measure (CQM) requirements. STUDY DESIGN: The study combined an electronic health record (EHR)-based CQM performance assessment with focus groups among primary care practices with high performance (top tertile), or "exemplars." METHODS: This qualitative exploratory study was conducted in PPRNet, a national primary care practice-based research network. Focus groups among lead physicians from practices in the top tertile of performance on a CQM summary measure were held in early 2014 to learn their perspectives on questions posed by the Office of the National Coordinator related to Stage 3 MU CQMs. RESULTS: Twenty-three physicians attended the focus groups. There was consensus that CQMs should be evidence-based and focus on high-priority conditions relevant to primary care providers. Participants thought the emphasis of CQMs should largely be on outcomes and that reporting of CQMs should limit the burden on providers. Incorporating patient-generated data and accepting locally developed CQMs were viewed favorably. Participants unanimously concurred that platforms for population management were vital tools for improving health outcomes. CONCLUSIONS: Using a series of focus groups, we solicited Stage 3 MU CQM recommendations from a group of physicians who have already achieved "meaningful use" of their EHR, as demonstrated by their high performance on current MU CQMs. Adhering to the standards deemed to be important to high performing real-world physicians could ensure that the MU Incentive Programs achieve their ultimate goal to improve outcomes. PMID- 26619061 TI - Request of acute phase markers in primary care in Spain. AB - OBJECTIVES: To study the inter-practice variability in Spain--by institution, management, and regional characteristics--of the frequency and appropriateness of test requests made by primary care practitioners for acute phase markers. STUDY DESIGN: Observational cross-sectional study. METHODS: One hundred forty-one clinical laboratories were invited to participate by providing the number of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and complete blood count (CBC) tests requested by general practitioners. We calculated the ratio of test requests per 1000 inhabitants, ratios of related test requests, and variability index (90th percentile/10th percentile). We compared the results among the different areas according to their setting, location, and management. RESULTS: We recruited 64 laboratories (14,846,065 inhabitants). There were almost twice as many ESR requests as CRP requests; the variability index for ESR was almost double that of CRP. Furthermore, the latter was underrequested in rural urban areas compared with rural. The ESR/CBC and ESR/CRP ratios are lower in institutions with private management, and the number of ESR requested in institutions with private management are lower than that of public. The differences among Spanish regions were reported for ESR per 1000 inhabitants, ESR/CBC, and ESR/CRP. CONCLUSIONS: There was significant variability in the requests made by primary care practitioners for patients' acute phase markers. Rates were influenced by geographic location, hospital setting, and institution management. ESR was inappropriately overrequested; strong efforts should be made to adjust the requests of ESR and to standardize the use of CRP measurement. PMID- 26619062 TI - Protective Efficacy in Sheep of Adenovirus-Vectored Vaccines against Bluetongue Virus Is Associated with Specific T Cell Responses. AB - Bluetongue virus (BTV) is an economically important Orbivirus of the Reoviridae family that causes a hemorrhagic disease in ruminants. Its control has been achieved by inactivated-vaccines that have proven to protect against homologous BTV challenge although unable to induce long-term immunity. Therefore, a more efficient control strategy needs to be developed. Recombinant adenovirus vectors are lead vaccine candidates for protection of several diseases, mainly because of their potency to induce potent T cell immunity. Here we report the induction of humoral and T-cell mediated responses able to protect animals against BTV challenge by recombinant replication-defective human adenovirus serotype 5 (Ad5) expressing either VP7, VP2 or NS3 BTV proteins. First we used the IFNAR(-/-) mouse model system to establish a proof of principle, and afterwards we assayed the protective efficacy in sheep, the natural host of BTV. Mice were completely protected against BTV challenge, developing humoral and BTV-specific CD8+- and CD4+-T cell responses by vaccination with the different rAd5. Sheep vaccinated with Ad5-BTV-VP2 and Ad5-BTV-VP7 or only with Ad5-BTV-VP7 and challenged with BTV showed mild disease symptoms and reduced viremia. This partial protection was achieved in the absence of neutralizing antibodies but strong BTV-specific CD8+ T cell responses in those sheep vaccinated with Ad5-BTV-VP7. These data indicate that rAd5 is a suitable vaccine vector to induce T cell immunity during BTV vaccination and provide new data regarding the relevance of T cell responses in protection during BTV infection. PMID- 26619063 TI - Modification Pathways for Copoly(2-oxazoline)s Enabling Their Application as Antireflective Coatings in Photolithography. AB - Chromophore-functionalized copoly(2-oxazoline)s are successfully evaluated as bottom antireflective coatings (BARCs) in high-resolution photolithography. With respect to UV light sources used in photolithographic production routines, anthracene is chosen as a chromophore. For application as polymer in BARCs, the copolymer poly(2-ethyl-2-oxazolin)45 -stat-poly(2-dec-9'-enyl-2-oxazolin)20 -stat poly(2-(3'-(1"-(anthracen-9-ylmethyl)-1",2",3"-triazol-4-yl)propyl)-2-oxazolin)35 can be synthesized by the Huisgen cycloaddition click reaction of the copolymer poly(2-ethyl-2-oxazolin)45 -stat-poly(2-dec-9'-enyl-2-oxazolin)20 -stat-poly(2 pent-4'-inyl-2-oxazolin)35 and the corresponding azide-functionalized anthracenes. These copolymers can be crosslinked by the thermally induced thiol ene reaction involving the unsaturated C=C bonds of the poly(2-dec-9'-enyl-2 oxazoline) repetition units and a multifunctional thiol as crosslinker. Tests of this BARC in a clean room under production conditions reveal a significant decrease of the swing-curve of a chemically amplified positive photoresist by more than 50%, hence significantly increasing the resolution of the photoresist. PMID- 26619064 TI - Root developmental adaptation to Fe toxicity: Mechanisms and management. AB - Iron (Fe) is an essential microelement but is highly toxic when in excess. To cope with Fe excess, plants have evolved complex adaptive responses that include morphological and physiological modifications. The highly dynamic adjustments in overall root system architecture (RSA) determine root plasticity and allow plants to efficiently adapt to environmental constraints. However, the effects of Fe excess on RSA are poorly understood. Recently, we showed that excess Fe treatment in Arabidopsis not only directly impairs primary root (PR) growth but also arrests lateral root (LR) formation by acting at the tip of the growing primary root. Such a change is believed to help RSA adjust and restrict excessive Fe absorption in the part of the rhizosphere subject to acute toxicity while maintaining the absorption of other nutrients in the less stressed components of the root system. We further showed that the suppression of PR growth and LR formation under excess Fe is alleviated by K(+) addition, providing useful insight into the effectiveness of nutrient management to improve RSA and alleviate Fe toxicity symptoms in the field. PMID- 26619065 TI - Bioinspired Synthesis of a Sedaxane Metabolite Using Catalytic Vanadyl Acetylacetonate and Molecular Oxygen. AB - A bioinspired synthesis of the sedaxane metabolite 2 from intermediate 3 using catalytic VO(acac)2 and O2 is described. Intermediate 3 was synthesized starting from 2-bromostyrene in four steps. The inner cyclopropyl ring of 3 was assembled with trans geometry using a highly diastereoselective Nishiyama cyclopropanation, and the outer hydroxycyclopropyl ring was installed using the Kulinkovich cyclopropanation. Additionally, conversion of 3 into 2 was demonstrated in in vitro microbial culture experiments consisting of bacteria and fungi. PMID- 26619066 TI - Constraints on Negative Prefixation in Polish Sign Language. AB - The aim of this article is to describe a negative prefix, NEG-, in Polish Sign Language (PJM) which appears to be indigenous to the language. This is of interest given the relative rarity of prefixes in sign languages. Prefixed PJM signs were analyzed on the basis of both a corpus of texts signed by 15 deaf PJM users who are either native or near-native signers, and material including a specified range of prefixed signs as demonstrated by native signers in dictionary form (i.e. signs produced in isolation, not as part of phrases or sentences). In order to define the morphological rules behind prefixation on both the phonological and morphological levels, native PJM users were consulted for their expertise. The research results can enrich models for describing processes of grammaticalization in the context of the visual-gestural modality that forms the basis for sign language structure. PMID- 26619067 TI - Impact of intra- and extrauterine growth on bone mineral density and content in the neonatal period of very-low-birth-weight infants. AB - BACKGROUND: Very-low-birthweight infants (VLBWIs) are at high risk for suboptimal bone mineral density (BMD) and bone mineral content (BMC). Small-for-gestational age (SGA) status also causes reduced bone mineralization in full-term infants. However, the impact of intrauterine and postnatal extrauterine growth on BMD and BMC in VLBWIs is inconclusive. METHODS: We retrospectively investigated n=68 VLBWIs, comprising 45 appropriate-for-gestational-age (AGA) and 23 SGA infants who underwent lumbar spine dual-energy X-ray absorptiometry at term-equivalent age. RESULTS: BMD and BMC did not differ between AGA and SGA VLBWIs. Subgroup analyses of infants with birthweight<1000 g vs 1000-1500 g, and GA<27 weeks vs >= 27 weeks also showed no differences in BMD and BMC between AGA and SGA infants. In contrast, infants with extrauterine growth restriction (EUGR) showed significantly lower values than those without (BMD: 0.124 +/- 0.023 vs 0.141 +/- 0.032 g/cm(2), P=0.02; BMC: 0.80 +/- 0.26 vs 0.94 +/- 0.23 g, P=0.04). There were no differences between AGA and SGA infants with EUGR. However, in the AGA cohort, infants with EUGR showed significantly lower values than those without (BMD: 0.121 +/- 0.022; 0.141 +/- 0.03 g/cm(2), P=0.02; BMC: 0.73 +/- 0.23 vs 0.94 +/- 0.23 g, P=0.005). Multiple regression analyses showed GA, weight and head circumference at birth, and weight percentile at term correlated with term BMD. Conversely, only weight percentile at term significantly correlated with term BMC. CONCLUSION: EUGR, rather than IUGR, is a risk factor for reduced BMD and BMC in the neonatal period in VLBWIs. PMID- 26619068 TI - Relationship quality for mothers of very preterm infants. AB - There is a paucity of information on couple relationship quality in mothers of preterm infants during the first year of life. AIM: To determine couple relationship quality in mothers of very preterm infants in comparison to mothers of term infants and to examine maternal and infant factors associated with impaired couple relationship for the preterm mothers. METHODS: At 4 and 12 months (corrected for prematurity for the preterm cohort), the mothers completed the Dyadic Adjustment Scale, the Edinburgh Postnatal Depression Scale, the Parenting Stress Index and the Short Temperament Scale. At 12 months, the infants had a neurodevelopmental assessment. RESULTS: 86 mothers of preterm infants and 97 term mothers participated at 4 months, with 101 mothers of the preterm infants and 98 term mothers participating at 12 months. Comparisons of the two groups revealed no differences in Dyadic Adjustment or for any of the subscales. For the preterm mothers at 4 months, the independent variables associated with poor dyadic adjustment were ethnicity and higher levels of parenting stress. At 12 months, parenting stress was also an independent variable associated with impaired couple relationship. CONCLUSIONS: No differences in the incidence of poor quality couple relationship was found between mothers of very preterm and term infants. For preterm mothers, impaired couple relationship was associated with parenting stress. PMID- 26619069 TI - Clinical utility of right ventricular fractional area change in preterm infants. AB - INTRODUCTION: Right ventricular fractional area change (RV FAC) is a novel non invasive quantitative measure of RV function. Reference values of RV FAC and RV end systolic and diastolic areas (RVEDA, RVESA) have recently been established in preterm infants, but their role as marker to assess the efficacy of patient management strategies in the first week of life is largely unknown. The aims of this study were to assess the relationship between RV FAC and gestational age/birthweight, assess the RV FAC on day one of age to predict the later evolution of peri/intraventricular haemorrhage (P/IVH), and assess the influence of a persistent patent ductus arteriosus (PDA) on RV FAC during the first week of age. METHODS: Preterm infants <29 weeks gestation underwent echocardiography assessments on days 1, 2 and 5-7. RVEDA and RVESA were traced in the RV-focused apical four-chamber view, and RV FAC was calculated using the formula [(RVEDA RVESA)/(RVEDA)] * 100. PDA treatment was not carried out during the study period. A cranial ultrasound was carried out on all infants on Days 5-7 of age. P/IVH was defined as IVH grades II to IV. RESULTS: One hundred and one infants with a mean gestation of 26.5 (1.4) weeks and a birthweight of 983 (240) grams were enrolled in the study. There was no relationship between RV FAC and birthweight (r=-0.02, p=0.86) but there was a negative correlation between RV FAC and echo-measured SVR (r=-0.57, p<0.001). On Day 1, RV FAC was lower in infants who developed P/IVH (24% [18-34] vs. 31% [25-40], p=0.04). On Days 5-7 infants with a PDA had a lower RV FAC compared with those without [42 (7) vs. 49 (9) %, p<0.001]. CONCLUSION: RV FAC may be a useful addition to the haemodynamic assessment of preterm infants during the first week of age. PMID- 26619070 TI - Multilevel Correlates of Non-Adherence in Kidney Transplant Patients Benefitting from Full Cost Coverage for Immunosuppressives: A Cross-Sectional Study. AB - BACKGROUND: Adherence is the result of the interaction of the macro, meso, micro, and patient level factors. The macro level includes full coverage of immunosuppressive medications as is the case in Brazil. We studied the correlates of immunosuppressive non-adherence in post kidney transplant patients in the Brazilian health care system. METHODS: Using a cross-sectional design, adherence to immunosuppressives was assessed in a sample of 100 kidney transplant patients using a composite non-adherence score consisting of three methods (self-report [i.e., The Basel Adherence Scale for Assessment of Immunossupressives-BAASIS], collateral report, and immunosuppressive blood levels). Multilevel correlations of non-adherence were assessed (macro, meso, micro and patient level). Univariate and multivariate logistic regression was applied to assess the correlates of non adherence. RESULTS: Our sample consisted primarily of male (65%), Caucasians (72%) with a mean age of 45.0 +/- 13.5 years old, who received grafts from a living donor (89%), with a mean time after transplantation of 72.3 +/- 44.4 months. Prevalence of non-adherence was 51%. Family income higher than five reference wages (21.6 vs. 4%; OR 6.46 [1.35-30.89], p = 0.009; patient level), and having access to private health insurance (35.3% vs. 18.4%; OR 2.42 [0.96 6.10], p = 0.04; meso level) were associated with non-adherence in univariate analysis. Only the higher family income variable was retained in the multiple logistic regression model (OR 5.0; IC: 1.01-25.14; p = 0.04). CONCLUSIONS: Higher family income was the only factor that was associated with immunosuppressive non adherence. In Brazil, lower income recipients benefit from better access to care and coverage of health care costs after transplantation. This is supposed to result in a better immunosuppressive adherence compared to high-income patients who have experienced these benefits continuously. PMID- 26619071 TI - Prognostic significance of forkhead box M1 (FoxM1) expression and antitumour effect of FoxM1 inhibition in melanoma. AB - AIMS: Forkhead box M1 (FoxM1) is a transcription factor that regulates cell-cycle progression and tumour progression, but limited information is available regarding its clinical significance in melanoma. The aim of this study was to investigate the potency of FoxM1 as a therapeutic target in melanoma. METHODS AND RESULTS: We investigated 60 melanoma clinical samples and a melanoma WM266-4 cell line using immunohistochemical staining and molecular biological approaches. Patients with a FoxM1-overexpressing melanoma had significantly shorter survival [both for melanoma-specific survival (MSS) and disease-free survival (DFS)] than the other patients (P < 0.001, respectively). The FoxM1 overexpression was also an adverse prognostic factor for both MSS and DFS on the Cox multivariate analyses [hazard ratio (HR): 3.96, 95% confidence interval (CI): 1.12-14.27, P = 0.032; HR: 3.21, 95% CI: 1.08-9.67, P = 0.037, respectively). FoxM1 inhibition using siRNA and an inhibitor (thiostrepton) each suppressed the cell proliferation of the melanoma cell line. Furthermore, FoxM1 inhibition improved chemosensitivity to dacarbazine, whereas it reduced cell migration and invasion. These results suggest that FoxM1 plays important roles in tumour progression and the chemoresistance of melanoma. CONCLUSION: We have shown the prognostic impact of FoxM1 on melanoma patients. FoxM1 inhibition may be a potential therapeutic option for advanced melanoma. PMID- 26619072 TI - Genetic architecture of wood properties based on association analysis and co expression networks in white spruce. AB - Association studies are widely utilized to analyze complex traits but their ability to disclose genetic architectures is often limited by statistical constraints, and functional insights are usually minimal in nonmodel organisms like forest trees. We developed an approach to integrate association mapping results with co-expression networks. We tested single nucleotide polymorphisms (SNPs) in 2652 candidate genes for statistical associations with wood density, stiffness, microfibril angle and ring width in a population of 1694 white spruce trees (Picea glauca). Associations mapping identified 229-292 genes per wood trait using a statistical significance level of P < 0.05 to maximize discovery. Over-representation of genes associated for nearly all traits was found in a xylem preferential co-expression group developed in independent experiments. A xylem co-expression network was reconstructed with 180 wood associated genes and several known MYB and NAC regulators were identified as network hubs. The network revealed a link between the gene PgNAC8, wood stiffness and microfibril angle, as well as considerable within-season variation for both genetic control of wood traits and gene expression. Trait associations were distributed throughout the network suggesting complex interactions and pleiotropic effects. Our findings indicate that integration of association mapping and co-expression networks enhances our understanding of complex wood traits. PMID- 26619073 TI - Joint design of kT-points trajectories and RF pulses under explicit SAR and power constraints in the large flip angle regime. AB - In Magnetic Resonance Imaging at ultra-high field, kT-points radiofrequency pulses combined with parallel transmission are a promising technique to mitigate the B1 field inhomogeneity in 3D imaging applications. The optimization of the corresponding k-space trajectory for its slice-selective counterpart, i.e. the spokes method, has been shown in various studies to be very valuable but also dependent on the hardware and specific absorption rate constraints. Due to the larger number of degrees of freedom than for spokes excitations, joint design techniques based on the fine discretization (gridding) of the parameter space become hardly tractable for kT-points pulses. In this article, we thus investigate the simultaneous optimization of the 3D blipped k-space trajectory and of the kT-points RF pulses, using a magnitude least squares cost-function, with explicit constraints and in the large flip angle regime. A second-order active-set algorithm is employed due to its demonstrated success and robustness in similar problems. An analysis of global optimality and of the structure of the returned trajectories is proposed. The improvement provided by the k-space trajectory optimization is validated experimentally by measuring the flip angle on a spherical water phantom at 7T and via Quantum Process Tomography. PMID- 26619074 TI - Using magnetic coupling to implement (1)H, (19)F, (13)C experiments in routine high resolution NMR probes. AB - We report in this paper the design of (1)H, (19)F, (13)C circuitry using magnetic coupling which can do on demand experiments where one of the three nuclei is observed and the other two are decoupled. The implementation of this circuitry in routine NMR probes is compared with capacitive coupling methods where it was found that by using magnetic coupling the performance of the routine NMR probe was not impacted by the addition of this circuitry. It is surmised that using this type of circuitry would be highly desirable for those chemists doing routine (19)F NMR. PMID- 26619075 TI - Prediction of binding modes and affinities of 4-substituted-2,3,5,6 tetrafluorobenzenesulfonamide inhibitors to the carbonic anhydrase receptor by docking and ONIOM calculations. AB - Inhibition activities of a series of 4-substituted-2,3,5,6 tetrafluorobenzenesulfonamides against the human carbonic anhydrase II (HCAII) enzyme have been explored by employing molecular docking and hybrid QM/MM methods. The docking protocol has been employed to assess the best pose of each ligand in the active site cavity of the enzyme, and probe the interactions with the amino acid residues. The docking calculations reveal that the inhibitor binds to the catalytic Zn(2+) site through the deprotonated sulfonamide nitrogen atom by making several hydrophobic and hydrogen bond interactions with the side chain residues depending on the substituted moiety. A cross-docking approach has been adopted prior to the hybrid QM/MM calculation to validate the docked poses. A correlation between the experimental dissociation constants and the docked free energies for the enzyme-inhibitor complexes has been established. Two-layered ONIOM calculations based on QM/MM approach have been performed to evaluate the binding efficacy of the inhibitors. The inhibitor potency has been predicted from the computed binding energies after taking into account of the electronic phenomena associated with enzyme-inhibitor interactions. Both the hybrid (B3LYP) and meta-hybrid (M06-2X) functionals are used for the description of the QM region. To improve the correlation between the experimental biological activity and the theoretical results, a three-layered ONIOM calculation has been carried out and verified for some of the selected inhibitors. The charge transfer stabilization energies are calculated via natural bond orbital analysis to recognize the donor-acceptor interaction in the binding pocket of the enzyme. The nature of binding between the inhibitors and HCAII active site is further analyzed from the electron density distribution maps. PMID- 26619077 TI - Snoring and Obstructive Sleep Apnea: Objective Efficacy and Impact of a Chairside Fabricated Mandibular Advancement Device. AB - PURPOSE: Obstructive sleep apnea (OSA) has been described as a common sleep respiratory disorder. Its prevalence in the adult population has been reported to be high, varying from 3% to 28%. Dental practitioners play a key role in the treatment of this disease, using tailor-made mandibular advancement devices (MADs). This pilot study assessed the efficacy and compliance of a custom-fitted thermoplastic MAD for the treatment of moderate to severe OSA syndrome. MATERIALS AND METHODS: In this open study without a control group, OSA syndrome sufferers were enrolled by four centers. One specific MAD was custom fitted to the patients. Polysomnography, Epworth, and snoring scales were administered from inclusion to 45 days postinclusion. RESULTS: The study population consisted of 33 men and 8 women; 35 patients completed the study. Patient response was high with 69% of them considered as responders, and 60% showing a complete response. Also, 77.3% of patients with moderate OSA syndrome presented a complete response. An improvement was observed in the apnea hypopnea index, which decreased from 34.1 +/- 18.9 to 12.8 +/- 14.1. The Epworth Sleepiness Scale score, snoring, and quality of sleep scores decreased with the device (p < 0.0001). Compliance rates were high, with patients wearing the device 6.5 nights a week. Side effects and patient complaints were minor and transient. CONCLUSION: This custom-fitted MAD improved respiratory and somnolence parameters, with response rates similar to those published in the literature with other devices. PMID- 26619076 TI - Chromosome Architecture and Genome Organization. AB - How the same DNA sequences can function in the three-dimensional architecture of interphase nucleus, fold in the very compact structure of metaphase chromosomes and go precisely back to the original interphase architecture in the following cell cycle remains an unresolved question to this day. The strategy used to address this issue was to analyze the correlations between chromosome architecture and the compositional patterns of DNA sequences spanning a size range from a few hundreds to a few thousands Kilobases. This is a critical range that encompasses isochores, interphase chromatin domains and boundaries, and chromosomal bands. The solution rests on the following key points: 1) the transition from the looped domains and sub-domains of interphase chromatin to the 30-nm fiber loops of early prophase chromosomes goes through the unfolding into an extended chromatin structure (probably a 10-nm "beads-on-a-string" structure); 2) the architectural proteins of interphase chromatin, such as CTCF and cohesin sub-units, are retained in mitosis and are part of the discontinuous protein scaffold of mitotic chromosomes; 3) the conservation of the link between architectural proteins and their binding sites on DNA through the cell cycle explains the "mitotic memory" of interphase architecture and the reversibility of the interphase to mitosis process. The results presented here also lead to a general conclusion which concerns the existence of correlations between the isochore organization of the genome and the architecture of chromosomes from interphase to metaphase. PMID- 26619078 TI - Mu insertion in feuD triggers the increase in nisin immunity in Lactococcus lactis subsp. lactis N8. AB - AIMS: This study aims to explore how feuD mutation triggered the increase in nisin immunity of Lactococcus lactis L58, which was proven to be a feuD::Em-Mu mutant of Lc. lactis N8. METHODS AND RESULTS: The significant difference genes of Lc. lactis L58 and Lc. lactis N8 were compared at transcription and protein levels. Analysis revealed that the feuD mutation induced decrease in histidine containing phosphocarrier protein PtsH (HPr) and increase in thioredoxin reductase TrxB (TR). Determination of iron concentration and cytoplasmic membrane potential (MP) showed the iron concentration decreased around 10% and the MP decreased approx. 14% in Lc. lactis L58. CONCLUSIONS: The increase in nisin immunity was dominated by TR up-expression by two main mechanisms in Lc. lactis L58. First, the TR-TRX (thioredoxin reductase) system changed the composition of cytoplasmic membrane by regulating the lipid metabolism to enhance the cells' resistance to nisin. Second, iron starvation stress induced decrease in MP; hence, the binding affinity of nisin to lipid II of Lc. lactis L58 decreased, which, in turn, increased the nisin immunity. SIGNIFICANCE AND IMPACT OF THE STUDY: The knowledge on regulation mechanism of nisin immunity was enriched, and the theoretical basis for improving nisin production in engineering strain could be provided. PMID- 26619080 TI - Correction: The Force at the Tip - Modelling Tension and Proliferation in Sprouting Angiogenesis. PMID- 26619079 TI - What's in a Friendship? Partner Visibility Supports Cognitive Collaboration between Friends. AB - Not all cognitive collaborations are equally effective. We tested whether friendship and communication influenced collaborative efficiency by randomly assigning participants to complete a cognitive task with a friend or non-friend, while visible to their partner or separated by a partition. Collaborative efficiency was indexed by comparing each pair's performance to an optimal individual performance model of the same two people. The outcome was a strong interaction between friendship and partner visibility. Friends collaborated more efficiently than non-friends when visible to one another, but a partition that prevented pair members from seeing one another reduced the collaborative efficiency of friends and non-friends to a similar lower level. Secondary measures suggested that verbal communication differences, but not psychophysiological arousal, contributed to these effects. Analysis of covariance indicated that females contributed more than males to overall levels of collaboration, but that the interaction of friendship and visibility was independent of that effect. These findings highlight the critical role of partner visibility in the collaborative success of friends. PMID- 26619081 TI - Interaction Forces between Supported Lipid Bilayers in the Presence of PEGylated Polymers. AB - Using the surface forces apparatus (SFA), interaction forces between supported lipid bilayers were measured in the presence of polyethylene glycol and two other commercially available pegylated triblock polymers, Pluronic F68 and F127. Pluronic F68 has a smaller central hydrophobic block compared to F127 and therefore is more hydrophilic. The study aimed to unravel the effects of polymer architecture and composition on the interactions between the bilayers. Our keys findings show that below the critical aggregation concentration (CAC) of the polymers, a soft, weakly anchored, polymer layer is formed on the surface of the bilayers. The anchoring strength of this physisorbed layer was found to increase significantly with the size of the hydrophobic block of the polymer, and was strongest for the more hydrophobic polymer, F127. Above the CAC, a dense polymer layer, exhibiting gel-like properties, was found to rapidly grow on the bilayers even after mechanical disruption. The cohesive interaction maintaining the gel layer structure was found to be stronger for F127, and was also found to promote the formation of highly structured aggregates on the bilayers. PMID- 26619082 TI - Post abortion contraception. AB - A safe induced abortion has no impact on future fertility. Ovulation may resume as early as 8 days after the abortion. There is no difference in return to fertility after medical or surgical abortion. Most women resume sexual activity soon after an abortion. Contraceptive counseling and provision should therefore be an integrated part of the abortion services to help women avoid another unintended pregnancy and risk, in many cases an unsafe, abortion. Long-acting reversible contraceptive methods that includes implants and intrauterine contraception have been shown to be the most effective contraceptive methods to help women prevent unintended pregnancy following an abortion. However, starting any method is better than starting no method at all. This Special Report will give a short guide to available methods and when they can be started after an induced abortion. PMID- 26619083 TI - High- or Standard-Dose Influenza Vaccine for Middle-Aged Adults with Cardiovascular Disease: What's a Doctor to Do. PMID- 26619084 TI - Effects of the M1 muscarinic antagonist dicyclomine on emotional memory retrieval. AB - Extensive research has shown the involvement of the central cholinergic system in the acquisition and consolidation of tasks involving conditioned fear responses, such as those observed in contextual fear conditioning (CFC), tone fear conditioning (TFC) and inhibitory avoidance (IA). However, there are few data concerning the role of this system in the memory retrieval process. Therefore, the present study aimed to compare the effects of the administration of an M1 antagonist on retrieval during these tasks. For each behavioral procedure, groups of male Wistar rats were trained. Twenty-four hr later, they were treated with different doses of dicyclomine (16, 32, or 64 mg/kg, i.p.) or with saline 30 min before the test session. The results showed that dicyclomine at doses of 16 and 32 mg/kg impaired CFC without interfering with IA performance. Moreover, only 64 mg/kg impaired TFC. These data suggest that M1 muscarinic receptors contribute to memory retrieval in CFC and TFC but are not essential for retrieval in IA. PMID- 26619085 TI - Medibots: Dual-Action Biogenic Microdaggers for Single-Cell Surgery and Drug Release. AB - An innovative concept for the fabrication of dual-action microrobots capable of performing single-cell microsurgery along with a site-directed drug-delivery feature is presented. These multi-action plant-derived biocompatible "medibots" can play a pivotal role in understanding micromotor interactions at the cellular level, aiming toward the destruction of harmful cells (like cancer) among others in living systems. PMID- 26619087 TI - Correction to Few et al. (2015). PMID- 26619089 TI - Internalizing and externalizing personality subtypes predict differences in functioning and outcomes among veterans in residential substance use disorder treatment. AB - There is a long history of using personality to subtype patients in treatment for substance use disorders (SUD). However, no one has validated a typology of SUD patients using a structural model of normal-range personality, particularly indicating whether subtypes differ on treatment processes and outcomes. We developed a personality-based typology among 196 military veterans enrolled in residential SUD treatment at a Veterans Affairs medical center. Patients were assessed at treatment entry, 1 month into treatment, and at discharge from treatment. Personality was assessed using the Multidimensional Personality Questionnaire-Brief Form at treatment entry. Latent profile analyses identified a 3-group solution consisting of low pathology, internalizing, and externalizing groups. The internalizing group scored lowest on measures of functioning at treatment entry, whereas the externalizing group scored more poorly on treatment processes and outcomes over the course of their residential stay (e.g., more stressful relationships with other residents, lower program alliance). These findings support a clinically meaningful typology of SUD patients based on a 3 factor model of personality and can serve as a guide for future efforts aimed at developing targeted interventions that can address the individual differences of patients in this population. (PsycINFO Database Record PMID- 26619088 TI - Is boldness relevant to psychopathic personality? Meta-analytic relations with non-Psychopathy Checklist-based measures of psychopathy. AB - Two recent meta-analyses have suggested that boldness, as assessed by the Psychopathic Personality Inventory (PPI) Fearless Dominance dimension, is largely unrelated to total or factor scores on the Psychopathy Checklist-Revised (PCL-R), raising questions concerning the relevance of largely adaptive features to psychopathy. Nevertheless, given that the PCL was developed and validated among prisoners, it may place less emphasis than do other psychopathy measures on adaptive traits, such as fearlessness, social poise, and emotional resilience. We conducted a meta-analysis (N = 10,693) of the relations between (a) boldness, as assessed by the PPI and its derivatives or measures of the triarchic model of psychopathy, and (b) non-PCL-based psychopathy measures across 32 samples. The average weighted correlation between boldness and psychopathy was medium to large (r = .39) and considerably higher than reported in prior meta-analyses; when analyses were restricted to well-validated psychopathy measures, the correlation rose to r = .44. We did not find support for the position that boldness is significantly less related to psychopathy than are the other 2 dimensions of the triarchic model. Our findings strongly suggest that boldness is relevant to at least some well-validated measures of psychopathy, and raise further questions regarding the boundaries of this condition. (PsycINFO Database Record PMID- 26619090 TI - A Catalan adaptation and validation of the Pain Catastrophizing Scale for Children. AB - Pain catastrophizing is a key factor in modern conceptualizations of pain. The development of the Pain Catastrophizing Scale for Children (PCS-C) has greatly contributed to the interest shown by pediatric pain specialists. The purpose of this work was to study the factor structure of the Pain Catastrophizing Scale and analyze its reliability and convergent, discriminant, and criteria related validity. Three hundred sixteen adolescents (12-19 years) completed the Catalan version of the PCS-C and provided information about pain intensity. A subgroup of 136 participants also completed measures of disability, anxiety sensitivity and pain coping strategies. The results confirmed the 3-factor model solution for the PCS-C, and demonstrated good internal consistency for the total Catastrophizing Scale (0.89) and for the Rumination (0.80) and Helplessness (0.82) PCS-C subscales. Internal consistency for the Magnification subscale, however, was not quite as good (0.63). This 3-factor model could be improved by removing Item 8 and developing additional items for the Rumination PCS-C subscale. The results also provide evidence of the convergent, discriminant and criterion-related validity of the PCS-C scores when used with Catalan-speaking adolescents. Our data demonstrate that the Catalan version of the PCS-C is a psychometrically sound questionnaire that provides valid and reliable scores when used to assess pain catastrophizing in adolescents. (PsycINFO Database Record PMID- 26619091 TI - Cross-cultural validation of the Depression Anxiety Stress Scale-21 in China. AB - The gap between the demand and delivery of mental health services in mainland China can be reduced by validating freely available and psychometrically sound psychological instruments. The present research examined the Chinese version of the 21-item Depression Anxiety Stress Scales (DASS-21). Study 1 administered the DASS-21 to 1,815 Chinese college students and found internal consistency indices (Cronbach's alpha) of .83, .80, and .82 for the Depression, Anxiety, and Stress subscales, respectively, and .92 for the total DASS total. Test-retest reliability over a 6-month interval was .39 to .46 for each of the 3 subscales and .46 for the total DASS. Moderate convergent validity of the Depression and Anxiety subscales was demonstrated via significant correlations with the Chinese Beck Depression Inventory (r = .51 at Time 1 and r = .64 at Time 2) and the Chinese State-Trait Anxiety Inventory (r = .41), respectively. Confirmatory factor analyses supported the original 3-factor model with 1 minor change (nonnormed fit index [NNFI] = .964, comparative fit index [CFI] = .968, and root mean square error of approximation [RMSEA] = .079). Study 2 examined the clinical utility of the Chinese DASS-21 in 166 patients with schizophrenia and 90 matched healthy controls. Patients had higher Depression and Anxiety but not Stress subscale scores than healthy controls. A discriminant function composed of the linear combination of 3 subscale scores correctly discriminated 69.92% of participants, which again supported the potential clinical utility of the DASS in mainland China. Taken together, findings in these studies support the cross cultural validity of the DASS-21 in China. (PsycINFO Database Record PMID- 26619092 TI - Evaluating the applied use of a mental health screener: Structural validity of the Social, Academic, and Emotional Behavior Risk Screener. AB - Universal screening for mental health has gained prominence in schools with the adoption of multitiered systems of support. However, there is a general lack of brief, psychometrically defensible instruments that assess emotional and behavioral risk. This study employed a multilevel, confirmatory bifactor analysis to evaluate the factor structure of a novel screening instrument-the Social, Academic, and Emotional Behavioral Risk Screener (SAEBRS; Kilgus & von der Embse, 2014)-examining the structure at the student (within) and teacher or rater (between) levels. Item response theory (IRT) analyses were then used to examine the functioning of 2 existing factors, social risk and academic risk, in addition to a newly introduced third factor, emotional risk, within a sample of 834 elementary and middle school students. Results indicated good fit of a bifactor model including the addition of the new Emotional Behavior subscale. IRT analyses suggested strong item-level discriminative properties (a > 1.0) for 17 of the 19 SAEBRS items and indicated that scale precision was greatest within the low to moderate range of each respective dimension (social, academic, and behavioral risk). Overall, the findings provide support for the use of the SAEBRS as a screener for mental health-related concerns. Implications for model interpretation and model use are discussed. (PsycINFO Database Record PMID- 26619086 TI - Epidemiology of RBC Transfusions in Patients With Severe Acute Kidney Injury: Analysis From the Randomized Evaluation of Normal Versus Augmented Level Study. AB - OBJECTIVE: To assess the epidemiology and outcomes associated with RBC transfusion in patients with severe acute kidney injury requiring continuous renal replacement therapy. DESIGN: Post hoc analysis of data from a multicenter, randomized, controlled trial. SETTING: Thirty-five ICUs in Australia and New Zealand. PATIENTS: Cohort of 1,465 patients enrolled in the Randomized Evaluation of Normal versus Augmented Level replacement therapy study. INTERVENTIONS: Daily information on morning hemoglobin level and amount of RBC transfused were prospectively collected in the Randomized Evaluation of Normal versus Augmented Level study. We analyzed the epidemiology of such transfusions and their association with clinical outcomes. MEASUREMENTS AND MAIN RESULTS: Overall, 977 patients(66.7%) received a total of 1,192 RBC units. By day 5, 785 of 977 transfused patients (80.4%) had received at least one RBC transfusion. Hemoglobin at randomization was lower in transfused than in nontransfused patients (94 vs 111 g/L; p < 0.001). Mean daily hemoglobin was 88 +/- 7 and 99 +/- 12 g/L in transfused and nontransfused patients. Among transfused patients, 228 (46.7%) had died by day 90 when compared with 426 (43.6%) of nontransfused patients (p = 0.27). Survivors received on average 316 +/- 261 mL of RBC, whereas nonsurvivors received 302 +/- 362 mL (p = 0.42). On multivariate Cox regression analysis, RBC transfusion was independently associated with lower 90-day mortality (hazard ratio, 0.55; 95% CI, 0.38-0.79). However, we found no independent association between RBC transfusions and mortality when the analyses were restricted to patients surviving at least 5 days (hazard ratio, 1.29; 95% CI, 0.90-1.85). We found no independent association between RBC transfusion and renal replacement therapy-free days, mechanical ventilator-free days, or length of stay in ICU or hospital. CONCLUSIONS: In patients with severe acute kidney injury treated with continuous renal replacement therapy, we found no association of RBC transfusion with 90-day mortality or other patient-centered outcomes. The optimal hemoglobin threshold for RBC transfusion in such patients needs to be determined in future randomized controlled trials. PMID- 26619094 TI - Who are we missing? Nondisclosure in online suicide risk screening questionnaires. AB - The use of self-report surveys for suicide risk screening is a key first step in identifying currently suicidal individuals and connecting them with appropriate follow-up assessment and care. Online methods for suicide risk screening are becoming more common, yet they present a number of complexities compared with traditional methods. This study aimed to assess whether forcing item responses may unintentionally hide or misrepresent otherwise useful missing suicide risk data. We investigated in secondary analyses of 3 independent samples of undergraduates (ns = 1,306; 694; 172) whether participants who chose not to respond specifically to current suicide risk screening items (i.e., Nondisclosers) scored significantly different from other risk response groups (i.e., Deniers, Lower-Risk Endorsers, and Higher-Risk Endorsers) on auxiliary measures related to suicidality. Multivariate Analysis of Variance (MANOVA) tests for each sample revealed that Nondisclosers were rare (ns = 7, 6, 7) and scored significantly higher than Deniers and similarly to Endorsers on suicide risk related measures. In 1 sample, Nondisclosers tended to score higher than all groups on suicide risk related measures. These findings suggest that nondisclosure for suicide risk screening questions is a preferred option for a distinct group of respondents who are likely at elevated suicide risk. Allowing for and flagging Nondisclosers for follow-up suicide risk assessment may be an ethical and feasible way to enhance the sensitivity of online suicide risk screenings for weary respondents, who if forced, may choose to underreport their suicide risk and misrepresent data. (PsycINFO Database Record PMID- 26619093 TI - Brief self-efficacy scales for use in weight-loss trials: Preliminary evidence of validity. AB - Self-efficacy is a commonly included cognitive variable in weight-loss trials, but there is little uniformity in its measurement. Weight-loss trials frequently focus on physical activity (PA) and eating behavior, as well as weight loss, but no survey is available that offers reliable measurement of self-efficacy as it relates to each of these targeted outcomes. The purpose of this study was to test the psychometric properties of brief, pragmatic self-efficacy scales specific to PA, healthful eating and weight-loss (4 items each). An adult sample (n = 1,790) from 28 worksites enrolled in a worksite weight-loss program completed the self efficacy scales, as well as measures of PA, dietary fat intake, and weight, at baseline, 6-, and 12-months. Confirmatory factor analysis supported the hypothesized factor structure indicating, 3 latent self-efficacy factors, specific to PA, healthful eating, and weight-loss. Measurement equivalence/invariance between relevant demographic groups, and over time was also supported. Parallel growth processes in self-efficacy factors and outcomes (PA, fat intake, and weight) support the predictive validity of score interpretations. Overall, this initial series of psychometric analyses supports the interpretation that scores on these scales reflect self-efficacy for PA, healthful eating, and weight-loss. The use of this instrument in large-scale weight-loss trials is encouraged. (PsycINFO Database Record PMID- 26619095 TI - The psychometric properties of the Kessler Psychological Distress Scale (K6) in a general population sample of adolescents. AB - The 6-item Kessler Psychological Distress Scale (K6; Kessler et al., 2002) is a screener for psychological distress that has robust psychometric properties among adults. Given that a significant proportion of adolescents experience mental illness, there is a need for measures that accurately and reliably screen for mental disorders in this age group. This study examined the psychometric properties of the K6 in a large general population sample of adolescents (N = 4,434; mean age = 13.5 years; 44.6% male). Factor analyses were conducted to examine the dimensionality of the K6 in adolescents and to investigate sex-based measurement invariance. This study also evaluated the K6 as a predictor of scores on the Strengths and Difficulties Questionnaire (SDQ; Goodman, 1997). The K6 demonstrated high levels of internal consistency, with the 6 items loading primarily on 1 factor. Consistent with previous research, females reported higher mean levels of psychological distress when compared with males. The identification of sex-based measurement noninvariance in the item thresholds indicated that these mean differences most likely represented reporting bias in the K6 items rather than true differences in the underlying psychological distress construct. The K6 was a fair to good predictor of abnormal scores on the SDQ, but predictive utility was relatively low among males. Future research needs to focus on refining and augmenting the K6 scale to maximize its utility in adolescents. (PsycINFO Database Record PMID- 26619096 TI - Promotion of Oxygen Reduction by Exsolved Silver Nanoparticles on a Perovskite Scaffold for Low-Temperature Solid Oxide Fuel Cells. AB - Solid oxide fuel cells (SOFCs) have potential to be the cleanest and most efficient electrochemical energy conversion devices with excellent fuel flexibility. To make SOFC systems more durable and economically competitive, however, the operation temperature must be significantly reduced, which depends sensitively on the development of highly active electrocatalysts for oxygen reduction reaction (ORR) at low temperatures. Here we report a novel silver nanoparticle-decorated perovskite oxide, prepared via a facile exsolution process from a Sr0.95Ag0.05Nb0.1Co0.9O3-delta (SANC) perovskite precursor, as a highly active and robust ORR electrocatalyst for low-temperature SOFCs. The exsolved Sr0.95Ag0.05Nb0.1Co0.9O3-delta (denoted as e-SANC) electrode is very active for ORR, achieving a very low area specific resistance (~0.214 Omega cm(2) at 500 degrees C). An anode-supported cell with the new heterostructured cathode demonstrates very high peak power density (1116 mW cm(-2) at 500 degrees C) and stable operation for 140 h at a current density of 625 mA cm(-2). The superior ORR activity and stability are attributed to the fast oxygen surface exchange kinetics and the firm adhesion of the Ag nanoparticles to the Sr0.95Nb0.1Co0.9O3 delta (SNC0.95) support. Moreover, the e-SANC cathode displays improved tolerance to CO2. These unique features make the new heterostructured material a highly promising cathode for low-temperature SOFCs. PMID- 26619098 TI - Microsatellite instability in colorectal cancer: clinicopathological significance. AB - Although often viewed as a single disease, colorectal cancer more accurately represents a constellation of heterogeneous subtypes that result from different combinations of genetic events and epigenetic alterations. Chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) have been identified as the three major molecular characteristics, which interact with other significant mutations, such as mutations in the KRAS and BRAF genes. High-level MSI (MSI-H) is of eminent clinical importance. It is the seminal molecular feature for the identification of individuals with Lynch syndrome, but it may also occur in sporadic cancers with CIMP phenotype, which arise from serrated precursor lesions. MSI-H status is a marker of favorable prognosis and may be used for outcome prediction, that is, molecular grading. Among others, mucinous and medullary histology, signet-ring cell differentiation, and a marked anti-tumoral immune response are histological features suggesting MSI. Universal tumor testing is recommended and may be performed using immunohistochemistry (mismatch repair protein expression) or molecular analysis, as has recently been recommended by an international task force. In this review, we consider in detail the molecular pathogenesis of colorectal cancer, focusing on the diagnosis of MSI in both hereditary and sporadic tumors. PMID- 26619097 TI - Antimicrobial evaluation of new metallic complexes with xylitol active against P. aeruginosa and C. albicans: MIC determination, post-agent effect and Zn-uptake. AB - Xylitol (xylH5) is metabolized via the pentose pathway in humans, but it is unsuitable as an energy source for many microorganisms where it produces a xylitol-induced growth inhibition and disturbance in protein synthesis. For this reason, xylitol is used in the prophylaxis of several infections. In the search of better antimicrobial agents, new copper and zinc complexes with xylitol were synthesized and characterized by analytical and spectrosco pic methods: Na2[Cu3(xylH-4)2].NaCl.4.5H2O (Cu-xyl) and [Zn4(xylH-4)2(H2O)2].NaCl.3H2O (Zn xyl). Both copper and zinc complexes presented higher MIC against Pseudomona aeruginosa than the free xylitol while two different behaviors were found against Candida albicans depending on the complex. The growth curves showed that Cu-xyl presented lower activity than the free ligand during all the studied period. In the case of Znxyl the growth curves showed that the inhibition of the microorganism growth in the first stage was equivalent to that of xylitol but in the second stage (after 18 h) Zn-xyl inhibited more. Besides, the PAE (post agent effect)obtained for Zn-xyl and xyl showed that the recovery from the damage of microbial cells had a delay of 14 and 13 h respectively. This behavior could be useful in prophylaxis treatments for infectious diseases where it is important that the antimicrobial effect lasts longer. With the aim to understand the microbiological activities the analysis of the particle size, lipophilicity and Zn uptake was performed. PMID- 26619099 TI - Fibroadenomas of anogenital mammary-like glands: from embryogenesis anomaly to apocrine origin. AB - Mammary-like anogenital fibroadenomas are rare entities within the wide spectrum of female genital pathology. Our paper provides an up-to-date review, by systematization of the concepts and controversies, from the origin to the development and the diagnosis of the lesion. The theories pertaining to its histogenesis incorporate its debated origin of ectopic mammary-derived lesions, of cutaneous apocrine, eccrine, sebaceous, and mammary-like anogenital glands. Although rare, both clinicians and pathologists should consider this lesion type within the differential diagnosis of anogenital pathology, regardless of the woman's age, and pathological confirmation is mandatory to exclude the possibility of other tumours, including malignancy. Immunohistochemistry may represent a useful tool in tumor characterisation and in differential diagnosis. PMID- 26619100 TI - Immunoreactive hepatic stellate cells in biopsy material in children with chronic hepatitis B. The first report in pediatric patients. AB - The research objective was to identify and quantify the immunohistochemically (IHC) stained hepatic stellate cells (HSCs) in children with chronic hepatitis B (CHB), including staging (S), location in the hepatic lobule, and correlation with hepatocyte count. Retrospective morphological analysis was based on liver biopsies obtained from 70 CHB children before antiviral treatment. To determine fibrosis stage, the Batts and Ludwig scoring system was applied. Immunohistochemical examinations used monoclonal antibodies against - SMA. IHC observations in CHB children revealed a significant positive correlation between the mean number of SMA immunopositive HSCs within the hepatic lobule (r = 0.518; p < 0.001) and fibrosis stage. In biopsy specimens with intensive fibrosis, most HSCs had an elongated shape and demonstrated evidently strong immunoexpression of cytoskeletal protein - SMA. The mean counts of HSCs/100 hepatocytes (in high power field) in 4 study groups, i.e. with S-0, S-1, S-2, S-3, were 5.00; 5.98; 9.80; 12.19, respectively. Interestingly, in most groups the highest count of immunoreactive HSCs/100 hepatocytes was in the intermediate zone, indicating its high metabolic activity in liver fibrogenesis. Immunohistochemical and statistical investigations of HSCs in children with CHB showed a close positive correlation of cell count with fibrosis intensity, which may have prognostic implications in this pathology. PMID- 26619101 TI - Omentin serum concentration and hepatic expression in chronic hepatitis C patients - together or apart? AB - Chronic hepatitis C (CHC) is accompanied by numerous metabolic disorders, partially associated with altered adipokine system regulation. Omentin (intelectin-1) is a novel adipokine known to play a pivotal role in metabolic regulation in CHC. In a group of 63 CHC patients (29 men/34 women) infected with genotype 1b, aged 6.6 +/- 14.6 years, serum omentin levels and its gene expression in liver tissue were examined and their association with metabolic and histopathological features was assessed. Serum omentin levels were significantly higher in CHC patients compared to controls (p < 0.001), regardless of sex, body mass index (BMI), insulin sensitivity and lipid concentrations. There was no correlation between serum omentin and omentin hepatic expression. Neither parameter was associated with any histological features. Serum omentin in non obese CHC patients seems not to be related to metabolic disorders or liver pathology. Omentin hepatic expression shows no relationship with either serum omentin levels or histopathological features. This suggests different mechanisms regulating circulating omentin concentration and omentin hepatic expression in CHC. PMID- 26619102 TI - PARP-1 expression in CD34+ leukemic cells in childhood acute lymphoblastic leukemia: relation to response to initial therapy and other prognostic factors. AB - Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear protein that impacts DNA repair and apoptosis. Both experimental and ongoing clinical studies indicate that PARP-1 inhibitors are potent and promising anticancer agents. However, the outcome of treatment with PARP-1 inhibitors depends on the expression of PARP-1 protein in the tumor cells. This study aimed to assess PARP-1 expression in peripheral blood CD34+ leukemic cells before and after 12 hours of prednisone administration as well as the relation between PARP-1 expression and early treatment response to initial therapy and other prognostic factors (immunophenotype, age, initial peripheral blood white blood count [WBC], and risk factor group). The study comprised 43 children with de novo ALL. Cytospins of peripheral blood were stained with mouse anti-CD34-FITC and anti-PARP-1 antibody followed by goat anti-mouse APC-conjugated antibody. DNA was counterstained with PI (propidium iodide). Cellular fluorescence was measured by a laser scanning cytometer. Statistically significant differences in baseline PARP-1 expression with respect to early treatment response (good vs. poor), ALL immunophenotype (ALL B vs. ALL T), age (children < 1 years and > 6 years vs. children 1-6 years), initial WBC (< 20 000/ul vs. >= 20 000/ul), and risk factor group (SR vs. IR vs. HR) were not found. PARP-1 expression was increased 12 hours after treatment in poor early treatment responders, whereas it remained statistically unchanged with respect to ALL immunophenotype, age, initial WBC, risk factor group and early treatment response. The overexpression of PARP-1 in poor early treatment responders suggests that it may contribute to treatment failure in this group of children with ALL. Our observation - if confirmed by other studies - may form the rationale for administration of PARP inhibitors in selected subsets of ALL children. PMID- 26619103 TI - Relationship among mismatch repair deficiency, CDX2 loss, p53 and E-cadherin in colon carcinoma and suitability of using a double panel of mismatch repair proteins by immunohistochemistry. AB - Biomarkers such as mismatch repair proteins, CDX2, p53, and E-cadherin are blamed for colon cancers, but the relationships of these biomarkers with each other and with pathological risk factors in colon carcinoma are still not clear. The aim of this study was to evaluate the association of these biomarkers with each other by using immunohistochemical staining and to compare their expression with pathological risk factors for colonic adenocarcinoma. We also aimed to study the usability of a double panel of mismatch repair proteins. One hundred and eleven cases with colonic adenocarcinoma were examined. There was a statistically significant relationship between tumor histological differentiation and perineural invasion, vascular invasion, mismatch repair deficiency, p53, CDX2, and E-cadherin (p < 0.05). PMS2 and MSH6 loss covered 100% of cases with mismatch repair deficiency. Mismatch repair deficiency was correlated with CDX2 loss and E cadherin expression (p < 0.05). It was also observed that cases with PMS2 loss covered all the cases with CDX2 loss. In conclusion, this double panel may be used instead of a quadruple panel for detecting mismatch repair deficiency. Association of CDX2 and PMS2 in the present study is necessary to conduct further genetic and pathological studies focusing on these two markers together. PMID- 26619104 TI - Geographic particularities in incidence and etiopathogenesis of sporadic gastric cancer. AB - It is known that geographical differences in the prevalence and etiopathogenesis of gastric cancer exist across the world. Eastern Europe and East Asia are two of the largest endemic areas of gastric cancer in the world, yet there are few studies comparing its features in these two regions. Based on our experience and literature data, we performed a review that is mainly focused on the etiology and pathogenesis of sporadic gastric cancer and its geographic particularities. Geographic prevalence of specific Helicobacter pylori strains is also synthesized. The pathogenesis of gastric cancer in patients from countries of the authors, respectively Japan, Romania, Hungary and Poland, is particularly examined. PMID- 26619105 TI - Histopathological factors influencing results of combined treatment in patients with laryngeal cancer. AB - The aim of the study was to assess the prognostic value of postoperative histopathological factors as well as the clinical usefulness of the modified risk score for recurrence. In a group of 197 patients with laryngeal cancer who underwent surgery followed by radiation therapy, partial resection was performed in 21.5% of patients and total resection in 78.5%. The majority of patients had T3 or T4 (74%) and N0 (63%) cancer. Macroscopically positive margins were reported in 10% of patients after partial resection and in 7% of patients after total resection, whereas microscopically positive margins were observed in 31% and 20% of cases, respectively. Extracapsular extension was observed in 22% of patients. In order to estimate local and nodal recurrence risk rates, criteria developed by Peters were used. Five-year local control (LC) was achieved in 88% of patients, disease-free survival (DFS) in 68% of patients and overall survival (OS) in 73% of patients. In the case of macroscopically positive margins, the 5 year DFS was 33% lower compared to radical surgery and 25% lower in the case of microscopically positive margins. The 5-year DFS was reduced by 29% due to extracapsular extension. Cox model analysis indicated that the degree of recurrence risk was the most potent independent prognostic factor for postoperative radiation therapy in laryngeal cancer. Negative histopathological factors influencing results of combined treatment of laryngeal cancer include macro- and microscopically positive margins, neck lymph node involvement and extracapsular extension. PMID- 26619106 TI - CD99 correlates with low cyclin D1, high topoisomerase 2? status and triple negative molecular phenotype but is prognostically irrelevant in breast carcinoma. AB - CD99 is a protein initially described in the Ewing sarcoma family of tumors, but growing evidence has shown its expression in other tumors of mesenchymal, hematopoietic and even epithelial origin. Some articles report CD99 in metaplastic carcinoma of the breast, a subtype of breast carcinoma (BC) with pronounced epithelial to mesenchymal (EMT) phenotype. Our aim was to analyse the potential relationship between CD99 and selected EMT (vimentin, E-cadherin, Twist) and proliferation markers (Ki-67, c-myc, cyclin D1, topoisomerase 2?), molecular subtypes of BC, as well as overall survival (OS) and progression-free survival (PFS). In a group of 122 cases CD99 membrane expression was seen in 14 (11.5%) cases: strong in 11 (9%) and moderate in 3 (2.5%). Expression of CD99 correlated with low cyclin D1 index, high level of topoisomerase 2? expression and lack of progesterone receptor (PR) but not with EMT characteristics. Additionally, strong expression of CD99 correlated with triple negative molecular BC phenotype. CD99 was prognostically irrelevant for OS and PFS. CD99 correlates with selected proliferative markers and low ER/PR receptor status but not with patients' outcome in BC. Further studies are required to explain precisely its role in molecular pathogenesis of BC. PMID- 26619107 TI - Modifier loci in non-mutant, female Wistar Kyoto rats influence cellular pathogenesis of nephronophthisis in Lewis polycystic kidney rats. AB - Genetic modifier loci influence the inheritance of diseases and lead to variability in phenotype progression. We report the influence of modifier loci in female Wistar Kyoto (WKY) rats on cellular pathogenesis of nephronophthisis inherited from Lewis polycystic kidney (LPK) rats. The loci modified cellular expression and progression of nephronophthisis in the backcross 1 (BC1) progeny. Mating experiments to produce BC1 progeny were carried out between three male LPK and seven female WKY rats. Fifteen female rats from the F1 generation were mated with the male LPK rats to produce the BC1 progeny. The rats with cystic kidney disease were identified and histology of the kidneys was carried out. Mapping studies and linkage analysis were carried out to identify the modifier loci. The BC1 progeny were less affected than the LPK strain with respect to disease severity and progression of the kidneys to end stage renal disease. It was found that the mean values of all the disease phenotypes of the mutant BC1 progeny were significantly different from those of the LPK rats, and these segregated with the genotypes of the markers located on chromosomes 5q34-q36 and 7q11-q34, giving maximum LOD scores greater than 3 (p < 0.001). PMID- 26619108 TI - The first protocol of stable isotope ratio assessment in tumor tissues based on original research. AB - Thanks to proteomics and metabolomics, for the past several years there has been a real explosion of information on the biology of cancer, which has been achieved by spectroscopic methods, including mass spectrometry. These modern techniques can provide answers to key questions about tissue structure and mechanisms of its pathological changes. However, despite the thousands of spectroscopic studies in medicine, there is no consensus on issues ranging from the choice of research tools, acquisition and preparation of test material to the interpretation and validation of the results, which greatly reduces the possibility of transforming the achieved knowledge to progress in the treatment of individual patients. The aim of this study was to verify the utility of isotope ratio mass spectrometry in the evaluation of tumor tissues. Based on experimentation on animal tissues and human neoplasms, the first protocol of stable isotope ratio assessment of carbon and nitrogen isotopes in tumor tissues was established. PMID- 26619109 TI - Age- and degeneration-related variations in cell density and glycosaminoglycan content in the human cervical intervertebral disc and its endplates. AB - The first aim of this study was to quantify cell density in cervical intervertebral discs (IVDs) and endplates of varying age and degeneration grade. The second aim was to analyze glycosaminoglycan (GAG) content in cervical IVDs and their endplates. Sixty cervical IVDs were excised from 30 human cadavers, not later than 24 hours post-mortem. Each sample underwent sectioning. Half of each sample underwent GAG content analysis using the dimethylmethylene blue binding assay. The other half underwent histological processing, histological degeneration grading, and cell density assessment using the Abercrombie method. The nucleus pulposus (NP) (4218 +/- 417 cells/mm3) had significantly higher cell density than the anterior annulus fibrosus (AF) (3283 +/- 438 cells/mm3; p < 0.0001), and similar cell density (4464 +/- 551 cells/mm3; p = 0.36) to the posterior AF. Cell density was similar throughout the different regions of the endplate. The NP (619 +/- 178 ug/mg dry weight) had a significantly higher GAG content than both the anterior (428 +/- 199 ug/mg dry weight; p < 0.0001) and posterior AF (524 +/- 218 ug/mg dry weight; p < 0.0001). In conclusion, this study introduces detailed 3D maps of cervical IVD and endplate cell density and GAG content. Furthermore, it shows that cervical IVDs and their endplates only slightly differ, in terms of cell density and GAG content, from lumbar IVDs. PMID- 26619111 TI - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - literature review apropos an autopsy case. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a non-atherosclerotic, non-amyloid cerebral angiopathy involving small arteries and arterioles. This entity presents vascular changes in the form of smooth muscle degeneration with swollen myocytes and PAS positive granular deposits, together with vascular fibrosis and hyalinization. In parallel, diffuse white matter destruction with infarcts, tissue rarefaction, spongiosis, lacunes and demyelination are characteristic. Ultrastructurally, vascular granular osmiophilic material (GOM) is pathognomonic for this hereditary disease caused by NOTCH3 mutation. We diagnosed CADASIL in the autopsy examination of a 53-year-old woman with a 9-year history of a progressive neurological disease with complex motor and cognitive deficits, accompanied by non-specific diffuse white matter changes on neuroimaging. Despite several multicentre hospitalizations, the precise diagnosis was not established until the post-mortem examination of the brain was made. CADASIL is a rare entity, but it should be considered by a pathologist in a differential diagnosis of vascular diseases of the brain, especially in cases with atypical clinical presentation and familial history. The prompt diagnosis depends on the quality of the brain autopsy and proper sampling. The post mortem examination, where "Morituri vivos docent", is still significant. PMID- 26619110 TI - Correlation between blood and lymphatic vessel density and results of contrast enhanced spectral mammography. AB - Contrast-enhanced spectral mammography (CESM) is a novel technique used for detection of tumour vascularity by imaging the moment in which contrast, delivered to the lesion by blood vessels, leaks out of them, and flows out through lymphatic vessels. In our study, we included 174 women for whom spectral mammography was performed for diagnostic purposes. The relationship between enhancement in CESM and blood vessel density (BVD), lymphatic vessel density (LVD) or the percentage of fields with at least one lymphatic vessel (distribution of podoplanin-positive vessels - DPV) and other related parameters was assessed in 55 cases. BVD, LVD and DPV were assessed immunohistochemically, applying podoplanin and CD31/CD34 as markers of lymphatic and blood vessels, respectively. The sensitivity (in detection of malignant lesions) of CESM was 100%, while its specificity - 39%. We found a significant positive correlation between the intensity of enhancement in CESM and BVD (p = 0.007, r = 0.357) and a negative correlation between the intensity of enhancement in CESM and DPV (p = 0.003, r = -0.390). Lesions with the highest enhancement in CESM showed a high number of blood vessels and a low number of lymphatics. CONCLUSIONS: 1) CESM is a method characterized by high sensitivity and acceptable specificity; 2) the correlation between CESM results and blood/lymphatic vessel density confirms its utility in detection of tissue angiogenesis and/or lymphangiogenesis. PMID- 26619112 TI - Peritoneal "melanosis". AB - A case of a23 year old female with peritoneal melanosis associated with adenocarcinoma of the rectum is reported. During laparoscopic anterior resection of the rectum, diffuse black pigmentations on the parietal peritoneum, greater omentum, mesenteric lymph nodes and ovaries were discovered. The histopathological findings revealed the presence of macrophages packed with black pigment. These results together with clinical data excluded metastatic melanoma and confirmed the diagnosis of the race condition called peritoneal melanosis. Due to the begin character of the lesions the laparoscopic treatment was continued. There were no remissions or progression of the reported in English literature and this is the second case of peritoneal melanosis that has been associated with adenocarcinoma of the large intestine. PMID- 26619113 TI - Role of the Lakes in Groundwater Recharge and Discharge in the Young Glacial Area, Northern Poland. AB - The aim of this research was to delineate characteristic hydrogeological lake types in the Young Glacial Area (YGA). The YGA is in the central and east part of the Kashubian Lake District (KLD) in Northern Poland, an area covered by deposits of Quaternary glaciation. All the bigger lakes were investigated in the area of about 1500 km(2) (39 lakes). The role of lakes in groundwater recharge and discharge was determined from total dissolved solids (TDS) in lake waters and also from groundwater flow simulation. The general trend was that gaining lakes, as determined by flow modeling, had higher values of TDS than losing lakes. In addition to typical gaining lakes (with TDS > 250 mg/l), there were losing lakes perched on glacial till deposits with very low TDS (<100 mg/l). Two groups of losing lakes were delineated: ones with very low TDS and another group with slightly higher TDS (due to local contact with groundwater). Flow-through lakes with TDS of 170-200 mg/l were also delineated. PMID- 26619116 TI - The Role of Energy Regulation in the Tubular Epithelial Cell Response to Sepsis. AB - Sepsis is considered today a major public health problem. Despite that mortality has been consistently associated with organ compromise, the mechanisms by which sepsis causes multiple organ dysfunction are not well understood, and hence, therapy remains reactive and non-specific. Recent studies have challenged previous paradigms by demonstrating that acute kidney injury can occur in the setting of a normal or an even increased renal blood flow, and that it is characterized by tubular injury and not by necrosis or apoptosis. This finding suggests that mechanisms other than hypoperfusion may be at play, and that adaptive responses of the tubular epithelial cell may be key to understanding the origin of organ dysfunction in the setting of sepsis. In this review, we discuss evidence suggesting that the activation of energy regulatory processes and mitochondrial quality control processes may not only be drivers of this response, but also be factors that may alter the course of organ dysfunction during sepsis in clinically relevant ways. PMID- 26619114 TI - A Venue-Based Survey of Malaria, Anemia and Mobility Patterns among Migrant Farm Workers in Amhara Region, Ethiopia. AB - BACKGROUND: Mobile populations present unique challenges to malaria control and elimination efforts. Each year, a large number of individuals travel to northwest Amhara Region, Ethiopia to seek seasonal employment on large-scale farms. Agricultural areas typically report the heaviest malaria burden within Amhara thereby placing migrants at high risk of infection. Yet little is known about these seasonal migrants and their malaria-related risk factors. METHODS AND FINDINGS: In July 2013, a venue-based survey of 605 migrant laborers 18 years or older was conducted in two districts of North Gondar zone, Amhara. The study population was predominantly male (97.7%) and young (mean age 22.8 years). Plasmodium prevalence by rapid diagnostic test (RDT) was 12.0%; One quarter (28.3%) of individuals were anemic (hemoglobin <13 g/dl). Nearly all participants (95.6%) originated from within Amhara Region, with half (51.6%) coming from within North Gondar zone. Around half (51.2%) slept in temporary shelters, while 20.5% regularly slept outside. Only 11.9% of participants had access to a long lasting insecticidal net (LLIN). Reported net use the previous night was 8.8% overall but 74.6% among those with LLIN access. Nearly one-third (30.1%) reported having fever within the past two weeks, of whom 31.3% sought care. Cost and distance were the main reported barriers to seeking care. LLIN access (odds ratio [OR] = 0.30, P = 0.04) and malaria knowledge (OR = 0.50, P = 0.02) were significantly associated with reduced Plasmodium infection among migrants, with a similar but non-significant trend observed for reported net use the previous night (OR = 0.16, P = 0.14). CONCLUSIONS: High prevalence of malaria and anemia were observed among a young population that originated from relatively proximate areas. Low access to care and low IRS and LLIN coverage likely place migrant workers at significant risk of malaria in this area and their return home may facilitate parasite transport to other areas. Strategies specifically tailored to migrant farm workers are needed to support malaria control and elimination activities in Ethiopia. PMID- 26619117 TI - E2F1 mediates sustained lipogenesis and contributes to hepatic steatosis. AB - E2F transcription factors are known regulators of the cell cycle, proliferation, apoptosis, and differentiation. Here, we reveal that E2F1 plays an essential role in liver physiopathology through the regulation of glycolysis and lipogenesis. We demonstrate that E2F1 deficiency leads to a decrease in glycolysis and de novo synthesis of fatty acids in hepatocytes. We further demonstrate that E2F1 directly binds to the promoters of key lipogenic genes, including Fasn, but does not bind directly to genes encoding glycolysis pathway components, suggesting an indirect effect. In murine models, E2F1 expression and activity increased in response to feeding and upon insulin stimulation through canonical activation of the CDK4/pRB pathway. Moreover, E2F1 expression was increased in liver biopsies from obese, glucose-intolerant humans compared with biopsies from lean subjects. Finally, E2f1 deletion completely abrogated hepatic steatosis in different murine models of nonalcoholic fatty liver disease (NAFLD). In conclusion, our data demonstrate that E2F1 regulates lipid synthesis and glycolysis and thus contributes to the development of liver pathology. PMID- 26619118 TI - Endothelial LRP1 transports amyloid-beta(1-42) across the blood-brain barrier. AB - According to the neurovascular hypothesis, impairment of low-density lipoprotein receptor-related protein-1 (LRP1) in brain capillaries of the blood-brain barrier (BBB) contributes to neurotoxic amyloid-beta (Abeta) brain accumulation and drives Alzheimer's disease (AD) pathology. However, due to conflicting reports on the involvement of LRP1 in Abeta transport and the expression of LRP1 in brain endothelium, the role of LRP1 at the BBB is uncertain. As global Lrp1 deletion in mice is lethal, appropriate models to study the function of LRP1 are lacking. Moreover, the relevance of systemic Abeta clearance to AD pathology remains unclear, as no BBB-specific knockout models have been available. Here, we developed transgenic mouse strains that allow for tamoxifen-inducible deletion of Lrp1 specifically within brain endothelial cells (Slco1c1-CreER(T2) Lrp1(fl/fl) mice) and used these mice to accurately evaluate LRP1-mediated Abeta BBB clearance in vivo. Selective deletion of Lrp1 in the brain endothelium of C57BL/6 mice strongly reduced brain efflux of injected [125I] Abeta(1-42). Additionally, in the 5xFAD mouse model of AD, brain endothelial-specific Lrp1 deletion reduced plasma Abeta levels and elevated soluble brain Abeta, leading to aggravated spatial learning and memory deficits, thus emphasizing the importance of systemic Abeta elimination via the BBB. Together, our results suggest that receptor mediated Abeta BBB clearance may be a potential target for treatment and prevention of Abeta brain accumulation in AD. PMID- 26619119 TI - SLAMF1 regulation of chemotaxis and autophagy determines CLL patient response. AB - Chronic lymphocytic leukemia (CLL) is a variable disease; therefore, markers to identify aggressive forms are essential for patient management. Here, we have shown that expression of the costimulatory molecule and microbial sensor SLAMF1 (also known as CD150) is lost in a subset of patients with an aggressive CLL that associates with a shorter time to first treatment and reduced overall survival. SLAMF1 silencing in CLL-like Mec-1 cells, which constitutively express SLAMF1, modulated pathways related to cell migration, cytoskeletal organization, and intracellular vesicle formation and recirculation. SLAMF1 deficiency associated with increased expression of CXCR4, CD38, and CD44, thereby positively affecting chemotactic responses to CXCL12. SLAMF1 ligation with an agonistic monoclonal antibody increased ROS accumulation and induced phosphorylation of p38, JNK1/2, and BCL2, thereby promoting the autophagic flux. Beclin1 dissociated from BCL2 in response to SLAMF1 ligation, resulting in formation of the autophagy macrocomplex, which contains SLAMF1, beclin1, and the enzyme VPS34. Accordingly, SLAMF1-silenced cells or SLAMF1(lo) primary CLL cells were resistant to autophagy activating therapeutic agents, such as fludarabine and the BCL2 homology domain 3 mimetic ABT-737. Together, these results indicate that loss of SLAMF1 expression in CLL modulates genetic pathways that regulate chemotaxis and autophagy and that potentially affect drug responses, and suggest that these effects underlie unfavorable clinical outcome experienced by SLAMF1(lo) patients. PMID- 26619120 TI - RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure. AB - RNA splicing is a major contributor to total transcriptome complexity; however, the functional role and regulation of splicing in heart failure remain poorly understood. Here, we used a total transcriptome profiling and bioinformatic analysis approach and identified a muscle-specific isoform of an RNA splicing regulator, RBFox1 (also known as A2BP1), as a prominent regulator of alternative RNA splicing during heart failure. Evaluation of developing murine and zebrafish hearts revealed that RBFox1 is induced during postnatal cardiac maturation. However, we found that RBFox1 is markedly diminished in failing human and mouse hearts. In a mouse model, RBFox1 deficiency in the heart promoted pressure overload-induced heart failure. We determined that RBFox1 is a potent regulator of RNA splicing and is required for a conserved splicing process of transcription factor MEF2 family members that yields different MEF2 isoforms with differential effects on cardiac hypertrophic gene expression. Finally, induction of RBFox1 expression in murine pressure overload models substantially attenuated cardiac hypertrophy and pathological manifestations. Together, this study identifies regulation of RNA splicing by RBFox1 as an important player in transcriptome reprogramming during heart failure that influence pathogenesis of the disease. PMID- 26619121 TI - TRAF6 regulates satellite stem cell self-renewal and function during regenerative myogenesis. AB - Satellite cells are a stem cell population within adult muscle and are responsible for myofiber regeneration upon injury. Satellite cell dysfunction has been shown to underlie the loss of skeletal muscle mass in many acquired and genetic muscle disorders. The transcription factor paired box-protein-7 (PAX7) is indispensable for supplementing the reservoir of satellite cells and driving regeneration in normal and diseased muscle. TNF receptor-associated factor 6 (TRAF6) is an adaptor protein and an E3 ubiquitin ligase that mediates the activation of multiple cell signaling pathways in a context-dependent manner. Here, we demonstrated that TRAF6-mediated signaling is critical for homeostasis of satellite cells and their function during regenerative myogenesis. Selective deletion of Traf6 in satellite cells of adult mice led to profound muscle regeneration defects and dramatically reduced levels of PAX7 and late myogenesis markers. TRAF6 was required for the activation of MAPKs ERK1/2 and JNK1/2, which in turn activated the transcription factor c-JUN, which binds the Pax7 promoter and augments Pax7 expression. Moreover, TRAF6/c-JUN signaling repressed the levels of the microRNAs miR-1 and miR-206, which promote differentiation, to maintain PAX7 levels in satellite cells. We also determined that satellite cell specific deletion of Traf6 exaggerates the dystrophic phenotype in the mdx (a mouse model of Duchenne muscular dystrophy) mouse by blunting the regeneration of injured myofibers. Collectively, our study reveals an essential role for TRAF6 in satellite stem cell function. PMID- 26619123 TI - Ongoing Use of Pulmonary Artery Catheters Despite Negative Trial Findings. PMID- 26619122 TI - Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma. AB - BACKGROUND: Recurrence and/or metastasis occurs in more than half of patients with head and neck squamous cell carcinoma (HNSCC), and these events pose the greatest threats to long-term survival. We set out to identify genetic alterations that underlie recurrent/metastatic HNSCC. METHODS: Whole-exome sequencing (WES) was performed on genomic DNA extracted from fresh-frozen whole blood and patient-matched tumor pairs from 13 HNSCC patients with synchronous lymph node metastases and 10 patients with metachronous recurrent tumors. Mutational concordance within and between tumor pairs was used to analyze the spatiotemporal evolution of HNSCC in individual patients and to identify potential therapeutic targets for functional evaluation. RESULTS: Approximately 86% and 60% of single somatic nucleotide variants (SSNVs) identified in synchronous nodal metastases and metachronous recurrent tumors, respectively, were transmitted from the primary index tumor. Genes that were mutated in more than one metastatic or recurrent tumor, but not in the respective primary tumors, include C17orf104, inositol 1,4,5-trisphosphate receptor, type 3 (ITPR3), and discoidin domain receptor tyrosine kinase 2 (DDR2). Select DDR2 mutations have been shown to confer enhanced sensitivity to SRC-family kinase (SFK) inhibitors in other malignancies. Similarly, HNSCC cell lines harboring endogenous and engineered DDR2 mutations were more sensitive to the SFK inhibitor dasatinib than those with WT DDR2. CONCLUSION: In this WES study of patient-matched tumor pairs in HNSCC, we found synchronous lymph node metastases to be genetically more similar to their paired index primary tumors than metachronous recurrent tumors. This study outlines a compendium of somatic mutations in primary, metastatic, and/or recurrent HNSCC cancers, with potential implications for precision medicine approaches. FUNDING: National Cancer Institute, American Cancer Society, Agency for Science, Technology and Research of Singapore, and Gilead Sciences Inc. PMID- 26619124 TI - Tyrosinase Depletion Prevents the Maturation of Melanosomes in the Mouse Hair Follicle. AB - The mechanisms that lead to variation in human skin and hair color are not fully understood. To better understand the molecular control of skin and hair color variation, we modulated the expression of Tyrosinase (Tyr), which controls the rate-limiting step of melanogenesis, by expressing a single-copy, tetracycline inducible shRNA against Tyr in mice. Moderate depletion of TYR was sufficient to alter the appearance of the mouse coat in black, agouti, and yellow coat color backgrounds, even though TYR depletion did not significantly inhibit accumulation of melanin within the mouse hair. Ultra-structural studies revealed that the reduction of Tyr inhibited the accumulation of terminal melanosomes, and inhibited the expression of genes that regulate melanogenesis. These results indicate that color in skin and hair is determined not only by the total amount of melanin within the hair, but also by the relative accumulation of mature melanosomes. PMID- 26619126 TI - Root Uptake of Pharmaceuticals and Personal Care Product Ingredients. AB - Crops irrigated with reclaimed wastewater or grown in biosolids-amended soils may take up pharmaceuticals and personal care product ingredients (PPCPs) through their roots. The uptake pathways followed by PPCPs and the propensity for these compounds to bioaccumulate in food crops are still not well understood. In this critical review, we discuss processes expected to influence root uptake of PPCPs, evaluate current literature on uptake of PPCPs, assess models for predicting plant uptake of these compounds, and provide recommendations for future research, highlighting processes warranting study that hold promise for improving mechanistic understanding of plant uptake of PPCPs. We find that many processes that are expected to influence PPCP uptake and accumulation have received little study, particularly rhizosphere interactions, in planta transformations, and physicochemical properties beyond lipophilicity (as measured by Kow). Data gaps and discrepancies in methodology and reporting have so far hindered development of models that accurately predict plant uptake of PPCPs. Topics warranting investigation in future research include the influence of rhizosphere processes on uptake, determining mechanisms of uptake and accumulation, in planta transformations, the effects of PPCPs on plants, and the development of predictive models. PMID- 26619125 TI - Interventions to increase seasonal influenza vaccine coverage in healthcare workers: A systematic review and meta-regression analysis. AB - Influenza vaccination is recommended for healthcare workers (HCWs), but coverage is often low. We reviewed studies evaluating interventions to increase seasonal influenza vaccination coverage in HCWs, including a meta-regression analysis to quantify the effect of each component. Fourty-six eligible studies were identified. Domains conferring a high risk of bias were identified in most studies. Mandatory vaccination was the most effective intervention component (Risk Ratio of being unvaccinated [RRunvacc] = 0.18, 95% CI: 0.08-0.45), followed by "soft" mandates such as declination statements (RRunvacc = 0.64, 95% CI: 0.45 0.92), increased awareness (RRunvacc = 0.83, 95% CI: 0.71-0.97) and increased access (RRunvacc = 0.88, 95% CI: 0.78-1.00). For incentives the difference was not significant, while for education no effect was observed. Heterogeneity was substantial (tau(2) = 0.083). These results indicate that effective alternatives to mandatory HCWs influenza vaccination do exist, and need to be further explored in future studies. PMID- 26619127 TI - Surface adsorption and self-assembly of Cu(II) ions on TEMPO-oxidized cellulose nanofibers in aqueous media. AB - TEMPO-mediated oxidized cellulose nanofibers (TOCNFs) have shown potential in the bioremediation of metal ions from contaminated water due to their interaction with positively charged metal ions via electrostatic interactions involving surface carboxyl groups. Copper is one of the most common pollutants in industrial effluents and is thus the target metal in the current study. The specific surface adsorption of Cu(II) was similar for TOCNFs with different degrees of functionalization and directly impacted the zeta potential. SEM imaging of the TOCNF after Cu(II) adsorption revealed interesting nanostructured clusters that were attributable to Cu(II) ions first being adsorbed by carboxylate groups on the TOCNF and subsequently being reduced and self-assembled to Cu(0) nanoparticles (NPs) or copper oxide NPs by microprecipitation. TOCNF turned superhydrophilic and resulted in faster water filtration after copper adsorption due to the stronger polarity of the copper ions or the self-assembled Cu(0) NPs creating voids or highly water-permeable channels at the interface between the interconnected TEMPO-oxidized nanofibers. Thus, the adsorption of Cu(II) ions and self-assembly into the Cu NPs on TOCNF favors a faster water purification process and provides a viable route to reuse/recycle TOCNFs studded with Cu nanoparticles as biocidal materials. PMID- 26619128 TI - Influence of surface modification on structure formation and micromechanical properties of spray-dried silica aggregates. AB - Spray drying processes were utilized for the production of hierarchical materials with defined structures. The structure formation during the spray drying process and the micromechanical properties of the obtained aggregates depend on the particle-particle interactions, the primary particle size and morphology as well as the process parameters of the spray drying process. Hence, the effect of different primary particle systems prepared as stable dispersions with various surface modifications were investigated on the colloidal structure formation and the micromechanical properties of silica particles as model aggregates and compared to theoretical considerations. The obtained results show that the structure formation of aggregates during the spray drying process for stable suspensions is almost independent on the functional groups present at the particle surface. Further, the mechanical properties of these aggregates differ considerably with the content of the bound ligand. This allows the defined adjustment of the aggregate properties, such as the strength and surface properties, as well as the formation of defined hierarchical aggregate structures. PMID- 26619129 TI - Morphological synthesis of Prussian blue analogue Zn3[Fe(CN)6]2?xH2O micro /nanocrystals and their excellent adsorption performance toward methylene blue. AB - Prussian blue analogue Zn3[Fe(CN)6]2?xH2O (Zn-PBA) micro-/nanocrystals with well defined spherical, cubic and polyhedral morphologies have been successfully synthesized by a simple room-temperature solution method. The morphologies and sizes of the micro-/nanocrystals can be easily tuned by HCl dosage and polymer additive. The as-prepared products are characterized by X-ray powder diffraction, scanning electron microscopy, transmission electron microscopy, thermogravimetric analysis and Brunauer Emmet Teller adsorption-desorption analysis. The possible formation mechanism for these Zn-PBA micro-/nanocrystals is then proposed. In addtion, adsorption performances of these micro-/nanocrystals toward organic dyes are systematically investigated. It is demonstrated that they exhibit strong adsorption selectivity to methylene blue (MB) with an extraordinary adsorption capacity as high as 1.016gg(-1) due to the proper pore size and large specific surface area (643.2m(2)g(-1)) of the product as well as the strong electrostatic interaction between MB molecules and Zn-PBA particles. It is found that the morphology and size of the micro-/nanocrystals have an important effect on their adsorption performance. Moreover, the adsorbed MB dye can be well released in some organic solvents such as ethanol and trichloromethane. The facile morphology controlled synthesis and excellent adsorption property afford the materials promising application in adsorption related fields. PMID- 26619130 TI - A quantitative method to discriminate between non-specific and specific lectin glycan interactions on silicon-modified surfaces. AB - Essential to the success of any surface-based carbohydrate biochip technology is that interactions of the particular interface with the target protein be reliable and reproducible and not susceptible to unwanted nonspecific adsorption events. This condition is particularly important when the technology is intended for the evaluation of low-affinity interactions such as those typically encountered between lectins and their monomeric glycan ligands. In this paper, we describe the fabrication of glycan (mannoside and lactoside) monolayers immobilized on hydrogenated crystalline silicon (111) surfaces. An efficient conjugation protocol featuring a key "click"-based coupling step has been developed which ensures the obtention of interfaces with controlled glycan density. The adsorption behavior of these newly developed interfaces with the lectins, Lens culinaris and Peanut agglutinin, has been probed using quantitative IR-ATR and the data interpreted using various isothermal models. The analysis reveals that protein physisorption to the interface is more prevalent than specific chemisorption for the majority of washing protocols investigated. Physisorption can be greatly suppressed through application of a strong surfactinated rinse. The coexistence of chemisorption and physisorption processes is further demonstrated by quantification of the amounts of adsorbed proteins distributed on the surface, in correlation with the results obtained by atomic force microscopy (AFM). Taken together, the data demonstrates that the nonspecific adsorption of proteins to these glycan-terminated surfaces can be effectively eliminated through the proper control of the chemical structure of the surface monolayer combined with the implementation of an appropriate surface-rinse protocol. PMID- 26619131 TI - Effective fingerprint recognition technique using doped yttrium aluminate nano phosphor material. AB - First time the yttrium aluminate nanoparticles are used to improve the fingerprint quality. Eco-friendly green combustion process is used to synthesize YAlO3:Sm(3+) (0.5-11mol%) nanophosphor using green tea leaf extract as non-toxic and eco-friendly fuel. Powder X-ray diffraction study confirms the orthorhombic phase. The average sizes of the crystallites were found to be in the range 20 35nm. The emission peaks centered at 564, 601 and 647nm is attributed to 4f-4f (4)G5/2->(6)HJ=5/2,7/2,9/2 forbidden transitions of Sm(3+) ions. Judd-Ofelt theory is applied to experimental data for providing qualitative support by determining J-O intensity parameters. The Commission International De I-Eclairage chromaticity co-ordinates are very close to National Television System Committee standard value of white emission (x=0.296, y=0.237). Further, correlated color temperature is found to be ~11,900K. A simple, fast, highly sensitive and low cost method for the detection and enhancement of fingermarks in a broad range of surfaces is developed and constitutes an alternative to traditional luminescent powders. PMID- 26619132 TI - Different nanostructures caused by competition of intra- and inter-beta-sheet interactions in hierarchical self-assembly of short peptides. AB - To understand how molecular interactions lead to the self-assembly of twisted, helical and flat nanoribbons, we have compared the hierarchical self-assembly processes of three selected octapeptides with the same amino acid composition but different sequences by both experiments and molecular dynamics (MD) simulations. KE-F8 (NH2-KEFFFFKE-CONH2) and EK-F8 (NH2-KEFFFFEK-CONH2) have the same distribution of hydrophobic residues and only differ by swapping the positive and negative charged residues at their C-terminals, while KFE-8 (NH2-KFEFKFEF-CONH2) differs from KE-F8 and EK-F8 by having all hydrophobic and charged residues evenly distributed. MD simulations indicated that the competition between electrostatic and hydrophobic interactions at the molecular level results in different initial packing modes: KE-F8 monomers form completely matched anti parallel beta-sheets, EK-F8 monomers align with one residue shifting, and KFE-8 monomers pack beta-sheets with two heterogeneous surfaces, consistent with previously suggested models. Driven by inter-strand and inter-sheet interactions, further growth of these molecular templates leads to larger oligomers with different twisting and stacking degrees, which are structurally consistent with the experimentally observed self-assembled morphologies. Further MD simulations showed that the competition between intra-beta-sheet and inter-beta-sheet interactions is responsible for the different twisting and stacking degrees of beta-sheets and the subsequent formation of different nanostructures (twisted ribbons for KE-F8, helical ribbons/tubes for EK-F8 and flat ribbons for KFE-8). This study thus provided an important mechanistic insight into the fine tuning of molecular packing and interactions via peptide sequence variation leading to controllable self-assembly of twisted, helical and flat nanostructures. PMID- 26619133 TI - Shear-induced emulsion droplet diffusion studies using NMR. AB - HYPOTHESIS: Shear-induced droplet diffusion of flowing hard spheres is relatively well understood and has been extensively studied both experimentally and via simulations. The same however is not true of soft spheres, specifically emulsions, despite their broad and extensive industrial relevance. Here we seek to demonstrate that appropriate NMR techniques can be used to quantitatively measure shear-induced droplet diffusion. Limited literature indicates that dilute dispersions of soft spheres experience significantly larger shear-induced droplet diffusion relative to otherwise equivalent hard sphere suspensions. Here we explore whether this effect persists to high concentrations. EXPERIMENTS: Nuclear Magnetic Resonance (NMR) pulsed field gradient (PFG) techniques were used to measure shear-induced droplet diffusion for capillary flow of various water-in oil (w/o) emulsions in a direction transverse to flow. Two adaptations were necessary - the acquired signal was analyzed so as to quantitatively distinguish restricted molecular diffusion within the emulsion droplets from shear-induced diffusion of the droplets, whilst flow-compensated PFG pulse sequences were shown to be necessary to account for any erroneous effects due to flow. A range of w/o emulsions were considered to enable measurement of shear-induced droplet diffusion as a function of both water content and mean shear rate. The surfactant content of these emulsions was adjusted such that they presented similar (stationary) emulsion droplet size distributions (DSD) which were also measured using NMR PFG techniques. FINDINGS: The droplet shear-induced diffusion data for the emulsion systems were compared against relevant results from the literature. Consistent with predictions for dilute systems, significantly greater droplet diffusion was measured relative to hard sphere suspensions at all concentrations, and a quadratic dependence was found between droplet diffusion and mean droplet size. For more concentrated emulsions, a peak in the droplet diffusion concentration relationship was observed for the first time in emulsions, prior to the onset of emulsion inversion. PMID- 26619134 TI - Male mice are susceptible to high fat diet-induced hyperglycaemia and display increased circulatory retinol binding protein 4 (RBP4) levels and its expression in visceral adipose depots. AB - Vitamin A and its metabolites are known to modulate adipose tissue development and its associated complications. Here, we assessed the vitamin A status and its metabolic pathway gene expression in relation to sexual dimorphism by employing 35 days old C57BL/6J male and female mice, which were fed either stock or high fat (HF) diet for 26 weeks. HF diet feeding increased body weight/weight gain and white adipose tissue (WAT) of visceral and subcutaneous regions, however, increase in vitamin A levels observed only in subcutaneous WAT. Further, the expression of most of the vitamin A metabolic pathway genes showed no sexual dimorphism. The observed HF diet-induced hyperglycaemia in male corroborates with increased retinol binding protein 4 (RBP4) levels in plasma and its expression in visceral adipose depots. In conclusion, the male mice are susceptible to high fat diet-induced hyperglycaemia and display higher plasma RBP4 levels, possibly due to its over-expression in visceral adipose depots. PMID- 26619135 TI - Fate of Organic Functionalities Conjugated to Theranostic Nanoparticles upon Their Activation. AB - Neutron activation is widely applied for the preparation of radioactive isotopes to be used in imaging and/or therapy. The type of diagnostic/therapeutic agents varies from small chelates coordinating radioactive metal ions to complex nanoparticulate systems. Design of these agents often relies on conjugation of certain organic functionalities that determine their pharmacokinetics, biodistribution, targeting, and cell-penetrating abilities, or simply on tagging them with an optical label. The conjugation chemistry at the surface of nanoparticles and their final purification often require laborious procedures that become even more troublesome when radioactive materials are involved. This study represents a thorough investigation on the effects of neutron activation on the organic moieties of functionalized nanoparticles, with special focus on (166)Ho2O3 particles conjugated with PEG-fluorescein and PEG-polyarginine motives. Spectroscopic and thermogravimetric analyses demonstrate only a limited degradation of PEG-fluorescein upon irradiation of the particles up to 10 h using a thermal neutron flux of 5 * 10(16) m(-2) s(-1). Cell experiments show that the polyarginine-based mechanisms of membrane penetration remain unaltered after exposure of the functionalized particles to the mixed field of neutrons and gammas present during activation. This confirms that radiation damage on the PEG polyarginines is minimal. Intrinsic radiations from (166)Ho do not seem to affect the integrity of conjugated organic material. These findings open up a new perspective to simplify the procedures for the preparation of functionalized metal-based nanosystems that need to be activated by neutron irradiation in order to be applied for diagnostic and/or therapeutic purposes. PMID- 26619136 TI - The Value of Nutrigenomics Science. PMID- 26619137 TI - Correction: Therapeutic Non-Toxic Doses of TNF Induce Significant Regression in TNFR2-p75 Knockdown Lewis Lung Carcinoma Tumor Implants. PMID- 26619139 TI - Facile Fabrication of a Silver Nanoparticle Immersed, Surface-Enhanced Raman Scattering Imposed Paper Platform through Successive Ionic Layer Absorption and Reaction for On-Site Bioassays. AB - We introduce a novel, facile, rapid, low-cost, highly reproducible, and power free synthesizable fabrication method of paper-based silver nanoparticle (AgNP) immersed surface-enhanced Raman scattering (SERS) platform, known as the successive ionic layer absorption and reaction (SILAR) method. The rough and porous properties of the paper led to direct synthesis of AgNPs on the surface as well as in the paper due to capillary effects, resulting in improved plasmon coupling with interparticles and interlayers. The proposed SERS platform showed an enhancement factor of 1.1 * 10(9), high reproducibility (relative standard deviation of 4.2%), and 10(-12) M rhodamine B highly sensitive detection limit by optimizing the SILAR conditions including the concentration of the reactive solution (20/20 mM/mM AgNO3/NaBH4) and the number of SILAR cycles (six). The applicability of the SERS platform was evaluated using two samples including human cervical fluid for clinical diagnosis of human papillomavirus (HPV) infection, associated with cervical cancer, and a malachite green (MG) solution for fungicide and parasiticide in aquaculture, associated with human carcinogenesis. The AgNP-immersed SERS-functionalized platform using the SILAR technique allowed for high chemical structure sensitivity without additional tagging or chemical modification, making it a good alternative for early clinical diagnosis of HPV infection and detection of MG-activated human carcinogenesis. PMID- 26619138 TI - Effects of Drought, Pest Pressure and Light Availability on Seedling Establishment and Growth: Their Role for Distribution of Tree Species across a Tropical Rainfall Gradient. AB - Tree species distributions associated with rainfall are among the most prominent patterns in tropical forests. Understanding the mechanisms shaping these patterns is important to project impacts of global climate change on tree distributions and diversity in the tropics. Beside direct effects of water availability, additional factors co-varying with rainfall have been hypothesized to play an important role, including pest pressure and light availability. While low water availability is expected to exclude drought-intolerant wet forest species from drier forests (physiological tolerance hypothesis), high pest pressure or low light availability are hypothesized to exclude dry forest species from wetter forests (pest pressure gradient and light availability hypothesis, respectively). To test these hypotheses at the seed-to-seedling transition, the potentially most critical stage for species discrimination, we conducted a reciprocal transplant experiment combined with a pest exclosure treatment at a wet and a dry forest site in Panama with seeds of 26 species with contrasting origin. Establishment success after one year did not reflect species distribution patterns. However, in the wet forest, wet origin species had a home advantage over dry forest species through higher growth rates. At the same time, drought limited survival of wet origin species in the dry forest, supporting the physiological tolerance hypothesis. Together these processes sort species over longer time frames, and exclude species outside their respective home range. Although we found pronounced effects of pests and some effects of light availability on the seedlings, they did not corroborate the pest pressure nor light availability hypotheses at the seed-to-seedling transition. Our results underline that changes in water availability due to climate change will have direct consequences on tree regeneration and distributions along tropical rainfall gradients, while indirect effects of light and pests are less important. PMID- 26619140 TI - Can we design drugs for HIV/AIDS that are less susceptible to resistance? PMID- 26619142 TI - Preferential Solvation in Binary and Ternary Mixtures. AB - Preferential solvation has become a useful tool to help characterize and understand the properties of liquid mixtures. Here, we provide a new quantitative measure of preferential solvation in binary and ternary mixtures that uses Kirkwood-Buff integrals as input, but differs from traditional measures. The advantages of the new measure are highlighted and compared with established literature approaches. Molecular dynamics simulations are performed to further investigate the nature of binary mixtures, as described by the new and existing measures of preferential solvation. It is shown that the new measure of preferential solvation is rigorous, has a simple physical interpretation, can be easily related to the underlying thermodynamic properties of the mixture, and naturally leads to zero values for ideal mixtures. PMID- 26619141 TI - What the Erythrocytic Nuclear Alteration Frequencies Could Tell Us about Genotoxicity and Macrophage Iron Storage? AB - Erythrocytic nuclear alterations have been considered as an indicative of organism's exposure to genotoxic agents. Due to their close relationship among their frequencies and DNA damages, they are considered excellent markers of exposure in eukaryotes. However, poor data has been found in literature concerning their genesis, differential occurrence and their life span. In this study, we use markers of cell viability; genotoxicity and cellular turn over in order to shed light to these events. Tilapia and their blood were exposed to cadmium in acute exposure and in vitro assays. They were analyzed using flow cytometry for oxidative stress and membrane disruption, optical microscopy for erythrocytic nuclear alteration, graphite furnace atomic absorption spectrometry for cadmium content in aquaria water, blood and cytochemical and analytical electron microscopy techniques for the hemocateretic aspects. The results showed a close relationship among the total nuclear alterations and cadmium content in the total blood and melanomacrophage centres area, mismatching reactive oxygen species and membrane damages. Moreover, nuclear alterations frequencies (vacuolated, condensed and blebbed) showed to be associated to cadmium exposure whereas others (lobed and bud) were associated to depuration period. Decrease on nuclear alterations frequencies was also associated with hemosiderin increase inside spleen and head kidney macrophages mainly during depurative processes. These data disclosure in temporal fashion the main processes that drive the nuclear alterations frequencies and their relationship with some cellular and systemic biomarkers. PMID- 26619143 TI - Effect of Community Engagement Interventions on Patient Safety and Risk Reduction Efforts in Primary Health Facilities: Evidence from Ghana. AB - BACKGROUND: Patient safety and quality care remain major challenges to Ghana's healthcare system. Like many health systems in Africa, this is largely because demand for healthcare is outstripping available human and material resource capacity of healthcare facilities and new investment is insufficient. In the light of these demand and supply constraints, systematic community engagement (SCE) in healthcare quality assessment can be a feasible and cost effective option to augment existing quality improvement interventions. SCE entails structured use of existing community groups to assess healthcare quality in health facilities. Identified quality gaps are discussed with healthcare providers, improvements identified and rewards provided if the quality gaps are closed. PURPOSE: This paper evaluates whether or not SCE, through the assessment of health service quality, improves patient safety and risk reduction efforts by staff in healthcare facilities. METHODS: A randomized control trail was conducted in 64 primary healthcare facilities in the Greater Accra and Western regions of Ghana. Patient risk assessments were conducted in 32 randomly assigned intervention and control facilities. Multivariate multiple regression test was used to determine effect of the SCE interventions on staff efforts towards reducing patient risk. Spearman correlation test was used to ascertain associations between types of community groups engaged and risk assessment scores of healthcare facilities. FINDINGS: Clinic staff efforts towards increasing patient safety and reducing risk improved significantly in intervention facilities especially in the areas of leadership/accountability (Coef. = 10.4, p<0.05) and staff competencies (Coef. = 7.1, p<0.05). Improvement in service utilization and health resources could not be attributed to the interventions because these were outside the control of the study and might have been influenced by institutional or national level developments between the baseline and follow-up period. Community groups that were gender balanced, religious/faith based, and had structured leadership appeared to be better options for effective SCE in healthcare quality assessment. CONCLUSION: Community engagement in healthcare quality assessment is a feasible client-centered quality improvement option that should be discussed for possible scale-up in Ghana and other resource poor countries in Africa. PMID- 26619145 TI - Lower Extremity Radicular Pain Caused by Entrapped Sigmoid Colon Between L5 and S1 Vertebrae. AB - Intestinal entrapment between two vertebral bodies is very rare. In all previous cases, it occurred by major trauma. However, the bowel entrapment between two vertebral bodies without trauma has never been reported, not to mention as the cause of lower extremity radicular pain. We describe the case of an 82-year-old female patient with right lower extremity radicular pain without recent trauma history. The patient was diagnosed sigmoid colon entrapment between the L5 and S1 vertebrae by lumbar spinal computerized tomography and magnetic resonance imaging, and showed improvement in radicular pain after manual reduction of interpositioned colon during surgery. Intestinal entrapment between two vertebrae without trauma is caused by degenerative and vacuum changes of the intervertebral disc combined with the anterior longitudinal ligament injury. PMID- 26619144 TI - Pharmacoeconomic and clinical implications of sequential therapy for metastatic renal cell carcinoma patients in Central and Eastern Europe. AB - INTRODUCTION: The incidence and mortality rates of kidney cancer in the Central and Eastern European (CEE) region are among the highest in the world. Access to second and subsequent lines of metastatic renal cell carcinoma (mRCC) therapies is highly varied in the region. Despite the increasing body of evidence supporting the clinical benefit of multiple lines of treatment, access to treatment beyond first line is restricted in many of these countries. AREAS COVERED: The adoption of targeted therapies for the first-line treatment of mRCC in the region was slow and faced many obstacles. In order to evaluate the current status of treatment beyond the first-line setting in the CEE region, this review examines the availability and reimbursement of mRCC drugs and clinical practice in institutions that treat patients with mRCC. EXPERT OPINION: This review highlights the need to raise awareness among physicians, payers and regulators on clinical trial and cost-effectiveness data regarding the treatment of mRCC beyond the first line. The obstacles to mRCC drug access highlighted in this review need to be overcome to ensure that patients are receiving the best treatment available. PMID- 26619146 TI - Elongated Silicon-Carbon Bonds at Graphene Edges. AB - We study the bond lengths of silicon (Si) atoms attached to both armchair and zigzag edges using aberration corrected transmission electron microscopy with monochromation of the electron beam. An in situ heating holder is used to perform imaging of samples at 800 degrees C in order to reduce chemical etching effects that cause rapid structure changes of graphene edges at room temperature under the electron beam. We provide detailed bond length measurements for Si atoms both attached to edges and also as near edge substitutional dopants. Edge reconstruction is also involved with the addition of Si dopants. Si atoms bonded to the edge of graphene are compared to substitutional dopants in the bulk lattice and reveal reduced out-of-plane distortion and bond elongation. An extended linear array of Si atoms at the edge is found to be energy-favorable due to inter-Si interactions. These results provide detailed structural information about the Si-C bonds in graphene, which may have importance in future catalytic and electronic applications. PMID- 26619147 TI - GFI1 proteins orchestrate the emergence of haematopoietic stem cells through recruitment of LSD1. AB - In vertebrates, the first haematopoietic stem cells (HSCs) with multi-lineage and long-term repopulating potential arise in the AGM (aorta-gonad-mesonephros) region. These HSCs are generated from a rare and transient subset of endothelial cells, called haemogenic endothelium (HE), through an endothelial-to haematopoietic transition (EHT). Here, we establish the absolute requirement of the transcriptional repressors GFI1 and GFI1B (growth factor independence 1 and 1B) in this unique trans-differentiation process. We first demonstrate that Gfi1 expression specifically defines the rare population of HE that generates emerging HSCs. We further establish that in the absence of GFI1 proteins, HSCs and haematopoietic progenitor cells are not produced in the AGM, revealing the critical requirement for GFI1 proteins in intra-embryonic EHT. Finally, we demonstrate that GFI1 proteins recruit the chromatin-modifying protein LSD1, a member of the CoREST repressive complex, to epigenetically silence the endothelial program in HE and allow the emergence of blood cells. PMID- 26619150 TI - Inhibitory dysfunction in amyotrophic lateral sclerosis: future therapeutic opportunities. AB - In amyotrophic lateral sclerosis, motor neuron hyperexcitability and inhibitory dysfunction is emerging as a potential causative link in the dysfunction and degeneration of the motoneuronal circuitry that characterizes the disease. Interneurons, as key regulators of excitability, may mediate much of this imbalance, yet we know little about the way in which inhibitory deficits perturb excitability. In this review, we explore inhibitory control of excitability and the potential contribution of altered inhibition to amyotrophic lateral sclerosis disease processes and vulnerabilities, identifying important windows of therapeutic opportunity and potential interventions, specifically targeting inhibitory control at key disease stages. PMID- 26619148 TI - Tropomyosin controls sarcomere-like contractions for rigidity sensing and suppressing growth on soft matrices. AB - Cells test the rigidity of the extracellular matrix by applying forces to it through integrin adhesions. Recent measurements show that these forces are applied by local micrometre-scale contractions, but how contraction force is regulated by rigidity is unknown. Here we performed high temporal- and spatial resolution tracking of contractile forces by plating cells on sub-micrometre elastomeric pillars. We found that actomyosin-based sarcomere-like contractile units (CUs) simultaneously moved opposing pillars in net steps of ~2.5 nm, independent of rigidity. What correlated with rigidity was the number of steps taken to reach a force level that activated recruitment of alpha-actinin to the CUs. When we removed actomyosin restriction by depleting tropomyosin 2.1, we observed larger steps and higher forces that resulted in aberrant rigidity sensing and growth of non-transformed cells on soft matrices. Thus, we conclude that tropomyosin 2.1 acts as a suppressor of growth on soft matrices by supporting proper rigidity sensing. PMID- 26619149 TI - Strand-specific in vivo screen of cancer-associated miRNAs unveils a role for miR 21(*) in SCC progression. AB - MicroRNAs play diverse roles in both normal and malignant stem cells. Focusing on miRs and/or miR(*)s abundant in squamous cell carcinoma (SCC) stem cells, we engineer an efficient, strand-specific expression library, and apply functional genomics screening in mice to identify which of 169 cancer-associated miRs are key drivers in malignant progression. Not previously linked functionally to cancer, miR-21(*) was the second top hit, surfacing in >12% of tumours. miR-21(*) also correlates with poor prognosis in human SCCs and enhances tumour progression in xenografts. On deleting the miR-21 gene and rescuing each strand separately, we document the dual, but independent, oncogenicity of miR-21 and miR-21(*). A cohort of predicted miR-21(*) targets inversely correlate with miR-21(*) in SCCs. Of particular interest is Phactr4, which we show is a miR-21(*) target in SCCs, acting through the Rb/E2F cell cycle axis. Through in vivo physiological miR screens, our findings add an interesting twist to an increasingly important oncomiR locus. PMID- 26619151 TI - An ultrabright and monochromatic electron point source made of a LaB6 nanowire. AB - Electron sources in the form of one-dimensional nanotubes and nanowires are an essential tool for investigations in a variety of fields, such as X-ray computed tomography, flexible displays, chemical sensors and electron optics applications. However, field emission instability and the need to work under high-vacuum or high-temperature conditions have imposed stringent requirements that are currently limiting the range of application of electron sources. Here we report the fabrication of a LaB6 nanowire with only a few La atoms bonded on the tip that emits collimated electrons from a single point with high monochromaticity. The nanostructured tip has a low work function of 2.07 eV (lower than that of Cs) while remaining chemically inert, two properties usually regarded as mutually exclusive. Installed in a scanning electron microscope (SEM) field emission gun, our tip shows a current density gain that is about 1,000 times greater than that achievable with W(310) tips, and no emission decay for tens of hours of operation. Using this new SEM, we acquired very low-noise, high-resolution images together with rapid chemical compositional mapping using a tip operated at room temperature and at 10-times higher residual gas pressure than that required for W tips. PMID- 26619152 TI - High-speed DNA-based rolling motors powered by RNase H. AB - DNA-based machines that walk by converting chemical energy into controlled motion could be of use in applications such as next-generation sensors, drug-delivery platforms and biological computing. Despite their exquisite programmability, DNA based walkers are challenging to work with because of their low fidelity and slow rates (~1 nm min(-1)). Here we report DNA-based machines that roll rather than walk, and consequently have a maximum speed and processivity that is three orders of magnitude greater than the maximum for conventional DNA motors. The motors are made from DNA-coated spherical particles that hybridize to a surface modified with complementary RNA; the motion is achieved through the addition of RNase H, which selectively hydrolyses the hybridized RNA. The spherical motors can move in a self-avoiding manner, and anisotropic particles, such as dimerized or rod shaped particles, can travel linearly without a track or external force. We also show that the motors can be used to detect single nucleotide polymorphism by measuring particle displacement using a smartphone camera. PMID- 26619153 TI - Using patient-reported outcome measures as quality indicators in routine cancer care. PMID- 26619154 TI - Inkjet Printed Circuits on Flexible and Rigid Substrates Based on Ambipolar Carbon Nanotubes with High Operational Stability. AB - Inkjet printed ambipolar transistors and circuits with high operational stability are demonstrated on flexible and rigid substrates employing semiconducting single walled carbon nanotubes (SWCNTs). All patterns, which include electrodes, semiconductors, and vias, are realized by inkjet printing without the use of rigid physical masks and photolithography. An Al2O3 layer deposited on devices by atomic layer deposition (ALD) transforms p-type SWCNT thin-film transistors (TFTs) into ambipolar SWCNT TFTs and encapsulates them effectively. The ambipolar SWCNT TFTs have balanced electron and hole mobilities, which facilitates their use in multicomponent circuits. For example, a variety of logic gates and ring oscillators are demonstrated based on the ambipolar TFTs. The three-stage ring oscillator operates continuously for longer than 80 h under ambient conditions with only slight deviations in oscillation frequency. The successful demonstration of ambipolar devices by inkjet printing will enable a new class of circuits that utilize n-channel, p-channel, and ambipolar circuit components. PMID- 26619156 TI - Exploring the reducing role of boron: added insights from theory. AB - Carbon-carbon coupling in CO molecules is a challenging proposition, and very few main group complexes have been shown to effect this process. A recently reported triply bonded diboryne system (1) is notable for coupling four CO molecules to produce a (bis)boralactone species. The current full quantum chemical computational investigation with density functional theory (DFT) provides important insights into the nature of the CO coupling process by triply bonded diboryne systems. The complete reaction pathway leading to the formation of the (bis)boralactone has been determined. Factors that make this system so successful in coupling CO groups have been elucidated, and pertinent issues, such as why the coupling process stops after four CO additions, have been explored. Also, importantly, insights have been gained through the natural bond orbital (NBO) analysis into how the back-donation from diboryne activates CO. PMID- 26619155 TI - Vaccination during pregnancy: Today's need in India. AB - Immunization during pregnancy is a simple and effective way to protect the mother and child from certain infections. The immunological changes occur during pregnancy which may be responsible for the susceptibility of certain infectious diseases that increases the risk of more serious outcomes. Vaccination of pregnant women can protect to mother against vaccine-preventable infections, and in so doing potentially protect the fetus. Immunization during pregnancy can also directly protect the fetus and infant via transferred of antibodies from the mother to the fetus. This is why vaccinations during pregnancy are so important. Vaccination during pregnancy is a cost-effective strategy to improve pregnancy outcomes in India. Globally, no scientific study exist which shows the risk of fetus after vaccination of pregnant women with inactivated vaccines or bacterial vaccines or toxoids. Even live vaccines causing risk to fetus is theoretical. Vaccination with inactivated virus, bacterial or toxoid in pregnancy is risk to a developing fetus during pregnancy is theoretical. But definitely the live vaccine poses a theoretical risk to a developing fetus. Therefore, all live vaccines should be avoided during pregnancy. The developing country like India where the people can't afford these vaccines, the government should be included these vaccines in routine immunization program. PMID- 26619157 TI - Wettability by Ionic Liquids. AB - Ionic liquids (ILs) have become particularly attractive recently because they have demonstrated themselves to be important construction units in the broad fields of chemistry and materials science, from catalysis and synthesis to analysis and electrochemistry, from functional fluids to clean energy, from nanotechnology to functional materials. One of the greatest issues that determines the performance of ILs is the wettability of correlated surfaces. In this concept article, the key developments and issues in IL wettability are surveyed, including the electrowetting of ILs in gas-liquid-solid systems and liquid-liquid-solid systems, ILs as useful probe fluids, the superwettability of Ils, and future directions in IL wettability. This should generate extensive interest in the field and encourage more scientists to engage in this area to tackle its scientific challenges. PMID- 26619159 TI - The Effect of Small Artery Disease on the Occurrence and Management of Large Artery Disease. PMID- 26619158 TI - L-DOPA-Coated Manganese Oxide Nanoparticles as Dual MRI Contrast Agents and Drug Delivery Vehicles. AB - Manganese oxide nanoparticles (MONPs) are capable of time-dependent magnetic resonance imaging contrast switching as well as releasing a surface-bound drug. MONPs give T2/T2* contrast, but dissolve and release T1-active Mn(2+) and L-3,4 dihydroxyphenylalanine. Complementary images are acquired with a single contrast agent, and applications toward Parkinson's disease are suggested. PMID- 26619160 TI - Increasing proliferation of murine adipose tissue-derived mesenchymal stem cells by TNF-alpha plus IFN-gamma. AB - The objective of the current study was to assess the effects of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) along with their simultaneous application on proliferation and pluripotency genes of murine adipose tissue-derived mesenchymal stem cells (AT-MSCs). The proliferation, doubling time (DT), colony-forming unit-fibroblast (CFU-F), pluripotency genes expression, and proliferation-related immunomodulatory markers of MSCs were analyzed upon activation with TNF-alpha (10 ng/ml), IFN-gamma (10 ng/ml) and both TNF-alpha and IFN-gamma (5 ng/ml + 5 ng/ml). Pluripotency genes including Oct-4, Sox-2, and Nanog as well as proliferation-associated immunomodulatory cytokines such as insulin-like growth factor 1 (IGF-1) and transforming growth factor-beta (TGF-beta) expression were evaluated using real-time PCR. Surface expression of Qa2 (HLA-G) was analyzed by flow cytometry. Pretreatment of MSCs with TNF-alpha plus IFN-gamma led to significantly increased proliferation, DT and CFU-F as well as expression of pluripotency genes in AT-MSCs (p < 0.01). MSCs expressed more IGF-1, TGF-beta, and Qa2 upon activation with TNF-alpha plus IFN-gamma and IFN gamma. MSCs expressed significantly decreased amounts of TGF-beta and Qa2 in presence of TNF-alpha. TNF-alpha combined with IFN-gamma may be improved the proliferation of AT-MSCs. Conversely, expanded MSCs pointed out low levels of the immunomodulatory marker, s especially Qa2 in the presence of TNF-alpha. In conclusion, we showed that TNF-alpha together with IFN-gamma increased the proliferation of MSCs and slightly enhanced the expression of pluripotency genes. PMID- 26619161 TI - Multiplexed Dosing Assays by Digitally Definable Hydrogel Volumes. AB - Stable and low-cost multiplexed drug sensitivity assays using small volumes of cells or tissue are in demand for personalized medicine, including patient specific combination chemotherapy. Spatially defined projected light photopolymerization of hydrogels with embedded active compounds is introduced as a flexible and cost-efficient method for producing multiplexed dosing assays. The high spatial resolution of light projector technology defines multiple compound doses by the volume of individual compound-embedded hydrogel segments. Quantitative dosing of multiple proteins with a dynamic range of 1-2 orders of magnitude is demonstrated using fluorescently labeled albumins. The hydrogel matrix results from photopolymerization of low-cost poly(ethylene glycol) diacrylates (PEGDA), and tuning of the PEGDA composition enables fast complete dosing of all tested species. Dosing of hydrophilic and hydrophobic compounds is demonstrated using two first-line chemotherapy regimens combining oxaliplatin, SN 38, 5-fluorouracil, and folinic acid, with each compound being dosed from a separate light-defined hydrogel segment. Cytotoxicity studies using a colorectal cancer cell line show equivalent effects of dissolved and released compounds. Further control of the dosing process is demonstrated by liposomal encapsulation of oxaliplatin, stable embedding of the liposomes in hydrogels for more than 3 months, and heat-triggered complete release of the loaded oxaliplatin. PMID- 26619163 TI - Editor's Note. PMID- 26619162 TI - Requirements of first-principles calculations of X-ray absorption spectra of liquid water. AB - A computational benchmark study on X-ray absorption spectra of water has been performed by means of transition-potential density functional theory (TP-DFT), damped time-dependent density functional theory (TDDFT), and damped coupled cluster (CC) linear response theory. For liquid water, using TDDFT with a tailored CAM-B3LYP functional and a polarizable embedding, we find that an embedding with over 2000 water molecules is required to fully converge spectral features for individual molecules, but a substantially smaller embedding can be used within averaging schemes. TP-DFT and TDDFT calculations on 100 MD structures demonstrate that TDDFT produces a spectrum with spectral features in good agreement with experiment, while it is more difficult to fully resolve the spectral features in the TP-DFT spectrum. Similar trends were also observed for calculations of bulk ice. In order to further establish the performance of these methods, small water clusters have been considered also at the CC2 and CCSD levels of theory. Issues regarding the basis set requirements for spectrum simulations of liquid water and the determination of gas-phase ionization potentials are also discussed. PMID- 26619164 TI - Editorial Commentary: Galactomannan Antigen Testing for Diagnosis of Invasive Aspergillosis in Pediatric Hematology Patients. PMID- 26619165 TI - Invasive Mold Infections in Pediatric Cancer Patients Reflect Heterogeneity in Etiology, Presentation, and Outcome: A 10-Year, Single-Institution, Retrospective Study. AB - BACKGROUND: There is scarcity of data regarding invasive mold infections (IMIs) in children with cancer. METHODS: We retrospectively identified patients (18 years old or younger) with malignant disease who developed proven or probable IMIs (European Organization for Research on the Treatment of Cancer/Mycoses Study Group criteria) during a 10-year period (1998-2008). We reviewed their risk factors and clinical characteristics and assessed their crude mortality rates and treatment outcomes 12 weeks after IMI diagnosis. RESULTS: Forty-eight patients (30 males) were identified, 30 (63%) of whom had a proven IMI. The most prevalent mold were Aspergillus species (40%), followed by Mucorales (20%) and Fusarium species (11%). Acute leukemia was the most common underlying malignancy (39 patients, [81%]). Twenty-three (59%) of them had refractory leukemia. Neutropenia was present at the day of IMI diagnosis in 67% of the patients. Sixty-two percent of the patients received prior corticosteroids. The dominant site of infection was the lungs (79%), followed by skin (29%) and sinuses (10%). Seventy-one percent of patients had radiological findings suggestive of fungal pneumonia (either nodules or masses). The mainstay of antifungal therapy was a lipid formulation of amphotericin B. Antifungal therapy resulted in 54% response rate (33% complete) at 12 weeks. The crude 12-week mortality rate was 31%. Logistic regression analysis demonstrated that monocytopenia (P = .013), malnutrition (P = .012), and intensive care admission in the month prior to IMI diagnosis (P = .027) were risk factors for death within 12 weeks. CONCLUSIONS: Although Aspergillus spp. was the most common mold in our pediatric cancer population, the epidemiology of the IMIs was diverse. Adults and children share similar risk factors for and epidemiology of IMIs. PMID- 26619166 TI - Human Parechovirus and Other Enteric Viruses in Childcare Attendees in the Era of Rotavirus Vaccines. AB - OBJECTIVE: We studied the prevalence of enteric viruses, including rotavirus, enterovirus, norovirus, adenovirus, and human parechovirus (HPeV), in stool samples of childcare attendees. The prevalence of enteric viruses was described in children with and those without gastroenteritis. METHODS: Children aged 1-19 months were recruited from 2 childcare centers in Tacoma, Washington, from October 2008 through June 2009. Stool samples were obtained at enrollment and during diarrheal illnesses for enteric virus testing. A symptom diary was completed by parents. RESULTS: One hundred six children (mean age, 10 months) were followed for an average of 170 days. At enrollment, 78 asymptomatic children had stool samples available. Forty-eight illnesses with acute diarrhea (stool samples were available for 24 illnesses) occurred in 37 children. Rotavirus was not detected in samples from symptomatic or asymptomatic children. HPeV was present in 21% and adenovirus in 46% of symptomatic children. At least 1 virus was detected in 78% of samples from asymptomatic children, including HPeV in 27% and adenovirus in 55%. No differences were found in symptom prevalence between HPeV-positive and HPeV-negative diarrheal illnesses. Molecular analysis revealed a diversity of HPeV types. CONCLUSIONS: Our study highlights the high level of HPeV circulation in childcare. The lack of rotavirus detected in this study supports the impact of rotavirus vaccine and emphasizes the need for a greater focus on the epidemiology of non-rotavirus etiologies of gastroenteritis. PMID- 26619167 TI - Infections in Pediatric Solid Organ Transplant Recipients. AB - Infectious complications are an important cause of morbidity and mortality in children undergoing solid organ transplantation. Knowledge gained over the last 30 years provides a growing understanding of these infections. This review identifies risk factors for and timing of infections describes the common infectious syndromes and pathogens seen in children undergoing solid organ transplantation, and reviews preventive strategies. PMID- 26619168 TI - Influence of Culture Results on Management and Outcome of Pediatric Osteomyelitis and/or Septic Arthritis. AB - Children with uncomplicated osteomyelitis and/or septic arthritis were more likely (P < .01) to have positive focus than blood cultures. Those who grew a pathogen and/or started on a single antibiotic were more likely to be discharged on a single antibiotic, and those sent home on oral therapy had fewer adverse events. PMID- 26619169 TI - Intrauterine Herpes Simplex Virus Infection in a Monochorionic Twin Gestation. PMID- 26619170 TI - A Unique Presentation of Chronic Primary Sternal Osteomyelitis With Mediastinal Abscess. PMID- 26619171 TI - Literature Review. PMID- 26619172 TI - Rationale for the 2010 Revised Susceptibility Breakpoints for Cephalosporins, Aztreonam, and Carbapenems for Enterobacteriaceae. PMID- 26619173 TI - Putting the New CLSI Cephalosporin and Carbapenem Breakpoint Changes Into Practice in Clinical Microbiology Laboratories. PMID- 26619179 TI - Is dosimetry still a necessity in current dental practice? AB - Today, dentists have a wide range of imaging modalities to choose from, the film based techniques, digital techniques, and the recent introduction of 3D volumetric or cone beam computed tomography (CBCT). The inherent design features of the new generation dental x-ray equipment has significantly improved over the years with no evidence of substandard x-ray units in operation. In dental facilities radiological workload is comparatively low, newer radiation equipments and accessories follow safety guidelines and employ better radiation protection measures for the patient and the operator. Dentists' knowledge and expertise in radiation protection measures is good, enabling them to carry out riskfree radiation procedures in their practice. Therefore, the present study is aimed at assessing the need for dosimeters in current dental scenario. 'Is there currently a significant risk from dental radiography to merit the use of personal dosimetery in dental practice. 'Dental health professionals (Oral radiologists) and radiographic assistants of fourteen dental colleges in Karnataka state participated in this questionnaire study. The questionnaire consisted of the following questions--the make, type, year of manufacture of radiographic machines used in their setup, number of radiographs made per day in the institution, type of receptors used, number of personnel at risk for radiation exposure, radiation protection measures used, regular monitoring by personal dosimeters, equivalent dosage readings for the past 12 months and whether the reading of thermoluminescent dosimeters (TLD) for any personnel had exceeded the recommended exposure value in the last 3 years. Dosimetry records of the radiology staff in the last three years shows doses no more than 1.50 mSv per year. The various institutions' dose (person mSv) was in the range of 3.70 mSv-3.90 mSv. Personal monitoring for Dentists can be omitted in the dental colleges since the estimated dose of oral radiologists contributed less than 0.01 mSv to the total average annual effective dose equivalent. Hence personal monitoring services (TLD Badges) for dentists employed in dental colleges should not be made mandatory. PMID- 26619180 TI - Highly Efficient Organic Hole Transporting Materials for Perovskite and Organic Solar Cells with Long-Term Stability. AB - Small molecules based on N-atom-linked phenylcarbazole-fluorene as the main scaffold, end-capped with spirobifluorene derivatives, are developed as organic hole-transporting materials for highly efficient perovskite solar cells (PSCs) and bulk heterojunction (BHJ) inverted organic solar cells (IOSCs). The CzPAF-SBF based devices show remarkable device performance with excellent long-term stability in PSCs and BHJ IOSCs with a maximum PCE of 17.21% and 7.93%, respectively. PMID- 26619182 TI - Comparative cost-effectiveness of 11 oral antipsychotics for relapse prevention in schizophrenia within Singapore using effectiveness estimates from a network meta-analysis. AB - This study modelled the cost-effectiveness of 11 oral antipsychotics for relapse prevention among patients with remitted schizophrenia in Singapore. A network meta-analysis determined the relative efficacy and tolerability of 11 oral antipsychotics (amisulpride, aripiprazole, chlorpromazine, haloperidol, olanzapine, paliperidone, quetiapine, risperidone, sulpiride, trifluoperazine and ziprasidone). The clinical estimates were applied in a Markov model to estimate lifetime costs and quality-adjusted life-years gained. Quality-of-life data were obtained from published literature. Resource utilization and cost data were retrieved from local hospital databases. The annual direct cost of healthcare services for a patient experiencing a relapse episode was three-fold that of a patient not in relapse of schizophrenia. The most favourable pharmacological treatment for relapse prevention was olanzapine with an annual probability of relapse of 0.24 (0.13-0.38) with placebo as a reference of 0.75 (0.73-0.78). Olanzapine emerged as the dominant treatment with the highest quality-adjusted life-years gained and lowest lifetime costs. Ziprasidone, aripiprazole and paliperidone incurred higher lifetime costs compared with no treatment. Probability and cost of relapse were key drivers of cost-effectiveness in sensitivity analyses. The data can help prescribers in choosing appropriate treatment and payers in allocating resources for the clinical management of this serious psychiatric disorder. PMID- 26619183 TI - Evaluation of the treatment gap between clinical guidelines and the utilization of renin-angiotensin-aldosterone system inhibitors. AB - OBJECTIVES: This study examined renin-angiotensin-aldosterone system (RAAS) inhibitor dose levels in a US patient population and investigated the impact of hyperkalemia on RAAS inhibitor dose and the association between dose levels and clinical outcomes. STUDY DESIGN: De-identified medical records from a large database of electronic health records (Humedica) for patients 5 years of age or older with at least 2 serum potassium readings were analyzed (N = 205,108 patients; 1.7 million records). METHODS: Inclusion criteria required 1 RAAS inhibitor prescription and 12 months' data prior to July 1, 2009 (index date). Patients were classified by comorbidities (chronic kidney disease, heart failure, or diabetes) and RAAS inhibitor dose level at index date, as determined by prescription information. Additional analyses examined RAAS inhibitor dose changes following hyperkalemia and the frequency of cardiorenal adverse outcome/mortality or mortality alone by post index dose level. RESULTS: Dose level was similarly distributed irrespective of patient comorbidity status, with RAAS inhibitors prescribed at maximum dose in 19% to 26% of patients and submaximum dose in 58% to 65% of patients; RAAS inhibitors were discontinued in 14% to 16% of patients. RAAS inhibitor dose was down-titrated after 16% to 21% of hyperkalemia events and discontinued after 22% to 27% of hyperkalemia events. Cardiorenal adverse event/mortality and mortality occurred in 34.3% and 11.0% of patients who discontinued RAAS inhibitors, 24.9% and 8.2% of patients on submaximum doses, and 24.9% and 4.1% of patients on maximum doses, respectively. CONCLUSIONS: Relatively few patients were prescribed maximum doses of RAAS inhibitors, and dose and usage declined following hyperkalemia. Patients on submaximum doses or who discontinued RAAS inhibitors had worse outcomes than patients on maximum doses. PMID- 26619181 TI - A Novel bHLH Transcription Factor Involved in Regulating Anthocyanin Biosynthesis in Chrysanthemums (Chrysanthemum morifolium Ramat.). AB - Chrysanthemums (Chrysanthemum morifolium Ramat.) exhibit a variety of flower colors due to their differing abilities to accumulate anthocyanins. One MYB member, CmMYB6, has been verified as a transcription regulator of chrysanthemum genes involved in anthocyanin biosynthesis; however, the co-regulators for CmMYB6 remain unclear in chrysanthemum. Here, the expression pattern of CmbHLH2, which is clustered in the IIIf bHLH subgroup, was shown to be positively correlated with the anthocyanin content of cultivars with red, pink and yellow flower colors, respectively. CmbHLH2 significantly upregulated the CmDFR promoter and triggered anthocyanin accumulation when co-expressed with CmMYB6. Yeast one hybrid analyses indicated that CmbHLH2 was able to bind directly to the CmDFR promoter. Moreover, yeast two-hybrid assays indicated protein-protein interaction between CmbHLH2 and CmMYB6. These results suggest that CmbHLH2 is the essential partner for CmMYB6 in regulating anthocyanin biosynthesis in chrysanthemum. PMID- 26619184 TI - Tonoplast Sugar Transporters (SbTSTs) putatively control sucrose accumulation in sweet sorghum stems. AB - Carbohydrates are differentially partitioned in sweet versus grain sorghums. While the latter preferentially accumulate starch in the grain, the former primarily store large amounts of sucrose in the stem. Previous work determined that neither sucrose metabolizing enzymes nor changes in Sucrose transporter (SUT) gene expression accounted for the carbohydrate partitioning differences. Recently, 2 additional classes of sucrose transport proteins, Tonoplast Sugar Transporters (TSTs) and SWEETs, were identified; thus, we examined whether their expression tracked sucrose accumulation in sweet sorghum stems. We determined 2 TSTs were differentially expressed in sweet vs. grain sorghum stems, likely underlying the massive difference in sucrose accumulation. A model illustrating potential roles for different classes of sugar transport proteins in sorghum sugar partitioning is discussed. PMID- 26619185 TI - Bronsted Acid-Catalyzed Three-Component Reaction of Anilines, alpha-Oxoaldehydes, and alpha-Angelicalactone for the Synthesis of Complex Pyrrolidones. AB - A green and efficient three-component reaction of easily available anilines, alpha-oxoaldehydes, and alpha-angelicalactone was developed for the synthesis of highly functionalized pyrrolidones using dilute sulfuric acid as the catalyst. Products were obtained in good to high yields at room temperature and under solvent-free conditions. The reaction could also be performed on a multigram scale with the same efficiency. PMID- 26619186 TI - Ecological Niche Modelling Predicts Southward Expansion of Lutzomyia (Nyssomyia) flaviscutellata (Diptera: Psychodidae: Phlebotominae), Vector of Leishmania (Leishmania) amazonensis in South America, under Climate Change. AB - Vector borne diseases are susceptible to climate change because distributions and densities of many vectors are climate driven. The Amazon region is endemic for cutaneous leishmaniasis and is predicted to be severely impacted by climate change. Recent records suggest that the distributions of Lutzomyia (Nyssomyia) flaviscutellata and the parasite it transmits, Leishmania (Leishmania) amazonensis, are expanding southward, possibly due to climate change, and sometimes associated with new human infection cases. We define the vector's climatic niche and explore future projections under climate change scenarios. Vector occurrence records were compiled from the literature, museum collections and Brazilian Health Departments. Six bioclimatic variables were used as predictors in six ecological niche model algorithms (BIOCLIM, DOMAIN, MaxEnt, GARP, logistic regression and Random Forest). Projections for 2050 used 17 general circulation models in two greenhouse gas representative concentration pathways: "stabilization" and "high increase". Ensemble models and consensus maps were produced by overlapping binary predictions. Final model outputs showed good performance and significance. The use of species absence data substantially improved model performance. Currently, L. flaviscutellata is widely distributed in the Amazon region, with records in the Atlantic Forest and savannah regions of Central Brazil. Future projections indicate expansion of the climatically suitable area for the vector in both scenarios, towards higher latitudes and elevations. L. flaviscutellata is likely to find increasingly suitable conditions for its expansion into areas where human population size and density are much larger than they are in its current locations. If environmental conditions change as predicted, the range of the vector is likely to expand to southeastern and central-southern Brazil, eastern Paraguay and further into the Amazonian areas of Bolivia, Peru, Ecuador, Colombia and Venezuela. These areas will only become endemic for L. amazonensis, however, if they have competent reservoir hosts and transmission dynamics matching those in the Amazon region. PMID- 26619178 TI - International and Interdisciplinary Identification of Health Care Transition Outcomes. AB - IMPORTANCE: There is a lack of agreement on what constitutes successful outcomes for the process of health care transition (HCT) among adolescent and young adults with special health care needs. OBJECTIVE: To present HCT outcomes identified by a Delphi process with an interdisciplinary group of participants. DESIGN, SETTING, AND PARTICIPANTS: A Delphi method involving 3 stages was deployed to refine a list of HCT outcomes. This 18-month study (from January 5, 2013, of stage 1 to July 3, 2014, of stage 3) included an initial literature search, expert interviews, and then 2 waves of a web-based survey. On this survey, 93 participants from outpatient, community-based, and primary care clinics rated the importance of the top HCT outcomes identified by the Delphi process. Analyses were performed from July 5, 2014, to December 5, 2014. EXPOSURES: Health care transition outcomes of adolescents and young adults with special health care needs. MAIN OUTCOMES AND MEASURES: Importance ratings of identified HCT outcomes rated on a Likert scale from 1 (not important) to 9 (very important). RESULTS: The 2 waves of surveys included 117 and 93 participants as the list of outcomes was refined. Transition outcomes were refined by the 3 waves of the Delphi process, with quality of life being the highest-rated outcome with broad agreement. The 10 final outcomes identified included individual outcomes (quality of life, understanding the characteristics of conditions and complications, knowledge of medication, self-management, adherence to medication, and understanding health insurance), health services outcomes (attending medical appointments, having a medical home, and avoidance of unnecessary hospitalization), and a social outcome (having a social network). Participants indicated that different outcomes were likely needed for individuals with cognitive disabilities. CONCLUSIONS AND RELEVANCE: Quality of life is an important construct relevant to HCT. Future research should identify valid measures associated with each outcome and further explore the role that quality of life plays in the HCT process. Achieving consensus is a critical step toward the development of reliable and objective comparisons of HCT outcomes across clinical conditions and care delivery locations. PMID- 26619187 TI - Prevalence of Chlamydial Infections in Fattening Pigs and Their Influencing Factors. AB - Chlamydial infections in pigs are associated with respiratory disease, diarrhea, conjunctivitis and other pathologies. The aim of this study was to define the prevalence of Chlamydiaceae in Swiss fattening pigs by applying sensitive and specific detection methods and to correlate prior antibiotic treatment and farm related factors with differences in prevalence. Conjunctival and fecal swabs were collected from 636 pigs in 29 Swiss fattening pig farms with and without antibiotic treatment, at the beginning and the end of the fattening period. The swabs were screened by real-time PCR for Chlamydiaceae. For the chlamydial detection and species-identification, a DNA-microarray analysis was performed. All farms were positive for Chlamydiaceae with 94.3 and 92.0% prevalence in fecal swabs as well as 45.9 and 32.6% in conjunctival swabs at the first and second time points, respectively. Antibiotic treatment could not clear the infection on herd level. Potential contact with wild boars was a significant risk factor, while hygiene criteria did not influence chlamydial prevalence. A correlation of chlamydial positivity to diarrhea, but not to conjunctivitis was evident. Chlamydia suis was the predominant species. Mixed infections with C. suis and C. pecorum were common, with a substantial increase in C. pecorum positivity at the end of the fattening period, and this finding was associated with ruminant contact. C. abortus was detected in one conjunctival swab. In this study, C. suis inhabited the intestinal tract of nearly all examined pigs, implying a long-term infection. C. pecorum was also common and might be transmitted to pigs by ruminants. PMID- 26619189 TI - Registration of dynamic multiview 2D ultrasound and late gadolinium enhanced images of the heart: Application to hypertrophic cardiomyopathy characterization. AB - Describing and analyzing heart multiphysics requires the acquisition and fusion of multisensor cardiac images. Multisensor image fusion enables a combined analysis of these heterogeneous modalities. We propose to register intra-patient multiview 2D+t ultrasound (US) images with multiview late gadolinium-enhanced (LGE) images acquired during cardiac magnetic resonance imaging (MRI), in order to fuse mechanical and tissue state information. The proposed procedure registers both US and LGE to cine MRI. The correction of slice misalignment and the rigid registration of multiview LGE and cine MRI are studied, to select the most appropriate similarity measure. It showed that mutual information performs the best for LGE slice misalignment correction and for LGE and cine registration. Concerning US registration, dynamic endocardial contours resulting from speckle tracking echocardiography were exploited in a geometry-based dynamic registration. We propose the use of an adapted dynamic time warping procedure to synchronize cardiac dynamics in multiview US and cine MRI. The registration of US and LGE MRI was evaluated on a dataset of patients with hypertrophic cardiomyopathy. A visual assessment of 330 left ventricular regions from US images of 28 patients resulted in 92.7% of regions successfully aligned with cardiac structures in LGE. Successfully-aligned regions were then used to evaluate the abilities of strain indicators to predict the presence of fibrosis. Longitudinal peak-strain and peak-delay of aligned left ventricular regions were computed from corresponding regional strain curves from US. The Mann-Withney test proved that the expected values of these indicators change between the populations of regions with and without fibrosis (p < 0.01). ROC curves otherwise proved that the presence of fibrosis is one factor amongst others which modifies longitudinal peak-strain and peak-delay. PMID- 26619188 TI - Predicting infant cortical surface development using a 4D varifold-based learning framework and local topography-based shape morphing. AB - Longitudinal neuroimaging analysis methods have remarkably advanced our understanding of early postnatal brain development. However, learning predictive models to trace forth the evolution trajectories of both normal and abnormal cortical shapes remains broadly absent. To fill this critical gap, we pioneered the first prediction model for longitudinal developing cortical surfaces in infants using a spatiotemporal current-based learning framework solely from the baseline cortical surface. In this paper, we detail this prediction model and even further improve its performance by introducing two key variants. First, we use the varifold metric to overcome the limitations of the current metric for surface registration that was used in our preliminary study. We also extend the conventional varifold-based surface registration model for pairwise registration to a spatiotemporal surface regression model. Second, we propose a morphing process of the baseline surface using its topographic attributes such as normal direction and principal curvature sign. Specifically, our method learns from longitudinal data both the geometric (vertices positions) and dynamic (temporal evolution trajectories) features of the infant cortical surface, comprising a training stage and a prediction stage. In the training stage, we use the proposed varifold-based shape regression model to estimate geodesic cortical shape evolution trajectories for each training subject. We then build an empirical mean spatiotemporal surface atlas. In the prediction stage, given an infant, we select the best learnt features from training subjects to simultaneously predict the cortical surface shapes at all later timepoints, based on similarity metrics between this baseline surface and the learnt baseline population average surface atlas. We used a leave-one-out cross validation method to predict the inner cortical surface shape at 3, 6, 9 and 12 months of age from the baseline cortical surface shape at birth. Our method attained a higher prediction accuracy and better captured the spatiotemporal dynamic change of the highly folded cortical surface than the previous proposed prediction method. PMID- 26619190 TI - MRSA Carriage in Community Outpatients: A Cross-Sectional Prevalence Study in a High-Density Livestock Farming Area along the Dutch-German Border. AB - OBJECTIVES: MRSA poses a considerable public health threat to the community. The objectives of this study were to assess the prevalence of MRSA carriage and determine factors that were associated with MRSA carriage among outpatients who had used antibiotics in the previous three months and who lived in a high-density livestock farming area along the Dutch-German border. METHODS: Cross-sectional prevalence study carried out between November 2011 and June 2012. Nasal swabs and questionnaires were collected in patients (>4 years) who had used antibiotics in the previous three months from twelve Dutch General Practitioners (GPs), seven German GPs and two German outpatient urologists. To assess nasal carriage, swabs were analyzed using selective MRSA agars after broth enrichment. MRSA positive samples were spa typed. RESULTS: Data were collected from 513 GP outpatients in the Netherlands, 261 GP outpatients in Germany and 200 urologist outpatients in Germany. The overall prevalence of MRSA carriage was 0.8%, 1.1% and 2.0%, respectively. In the GP outpatient populations, the prevalence was similar in both countries (0.8% and 1.1%, respectively, p = 0.879), all spa types were indicative for livestock-associated MRSA (4xt011 in the Netherlands; 2xt034 and t011 in Germany) and being a farmer, living on or near (<5km) to a farm were associated with MRSA carriage. In the urologist outpatient population, the prevalence was higher (2.0%), all spa types were indicative for healthcare associated MRSA (t068, t032, t003, t10231) and being a farmer, living on or near to a farm were factors not associated with MRSA carriage. CONCLUSIONS: The prevalence of MRSA carriage in these community outpatient populations along the Dutch-German border was low. There were striking similarities in livestock associated MRSA carriage and clonal spread in the outpatient populations seeing their GP in both countries. In contrast, urologist outpatients in Germany were colonized with spa types indicative of healthcare-associated MRSA. PMID- 26619191 TI - Challenges in transition to adulthood for young adult patients with hemophilia: Quantifying the psychosocial issues and developing solutions. PMID- 26619192 TI - Young adults with hemophilia in the U.S.: demographics, comorbidities, and health status. AB - Improvements in hemophilia care over the last several decades might lead to expectations of a near-normal quality of life for young adults with hemophilia. However, few published reports specifically examine health status indicators in this population. To remedy this knowledge gap, we examined the impact of hemophilia on physical and social functioning and quality of life among a national US cohort of 141 young men with hemophilia aged 18-34 years of age who received care at 10 geographically diverse, federally funded hemophilia treatment centers in 11 states between 2005 and 2013 and enrolled in the Hemophilia Utilization Group Studies. Indicators studied included educational achievement, employment status, insurance, health-related quality of life, and prevalence of the following comorbidities: pain, range of motion limitation, overweight/obesity, and viral status. The cohort was analyzed to compare those aged 18-24 to those aged 25-34 years. When compared to the general US adult population, this nationally representative cohort of young US adults with hemophilia experienced significant health and social burdens: more liver disease, joint damage, joint pain, and unemployment as well as lower high-school graduation rates. Nearly half were overweight or obese. Conversely, this cohort had higher levels of health insurance and equivalent mental health scores. While attention has typically focused on newborns, children, adolescents, and increasingly, on older persons with hemophilia, our findings suggest that a specific focus on young adults is warranted to determine the most effective interventions to improve health and functioning for this apparently vulnerable age group. PMID- 26619193 TI - Unmet needs in the transition to adulthood: 18- to 30-year-old people with hemophilia. AB - Young adults with hemophilia face unique challenges during the transition to adulthood, including issues associated with switching from pediatric to adult hematology care, building mature interpersonal relationships, and establishing an independent career with an assurance of medical insurance coverage. A greater understanding of these challenges is essential for developing effective strategies to address the specific needs of this population. These challenges may be differentiated from those of older adults with hemophilia in large part because of more extensive childhood prophylaxis and safer factor products, resulting in fewer joint problems and lower rates of HIV and HCV infections. This analysis of the changing nature and unmet needs of today's young adults entering into adult hemophilia treatment centers, as well as potential strategies for optimally addressing these needs, was developed following roundtable discussions between patients, caregivers, hematologists, and other health care professionals participating in comprehensive care. Challenges identified among young adults with hemophilia include psychosocial issues related to maturity, personal responsibility, and increased independence, as well as concerns regarding when and with whom to share information about one's hemophilia, limited awareness of educational and financial resources, and a low perceived value of regular hematology care. The initiatives proposed herein highlight important opportunities for health care professionals at pediatric and adult hemophilia treatment centers, as well as national organizations, community groups, and career counselors, to address key unmet needs of this patient population. PMID- 26619194 TI - Treatment outcomes, quality of life, and impact of hemophilia on young adults (aged 18-30 years) with hemophilia. AB - The Hemophilia Experiences, Results and Opportunities (HERO) initiative assessed psychosocial issues reported by people with moderate to severe hemophilia and was led by a multidisciplinary international advisory board. This analysis reports data from young adult respondents (aged 18-30 years), including both US and overall global (including US respondents) results, and investigates treatment outcomes, quality of life, and impacts of hemophilia on relationships. More young adults in HERO received prophylaxis than on-demand treatment, although a majority reported not using factor products exactly as prescribed, and 50% of global respondents and 26% of US respondents reported issues with access to factor replacement therapy in the previous 5 years. Many young adults with hemophilia reported comorbidities, including bone/skeletal arthritis, chronic pain, and viral infections, and nearly half of young adults reported anxiety/depression. Most reported pain interference with daily activities in the past 4 weeks, although a majority reported participating in lower-risk activities and approximately half in intermediate-risk activities. Most young adults were very or quite satisfied with the support of partners/spouses, family, and friends, although roughly one-third reported that hemophilia affected their ability to develop close relationships with a partner. A majority of young adults reported that hemophilia has had a negative impact on employment, and 62% of global respondents and 78% of US respondents were employed at least part-time. Together these data highlight the psychosocial issues experienced by young adults with hemophilia and suggest that increased focus on these issues may improve comprehensive care during the transition to adulthood. PMID- 26619196 TI - In vitro anticancer activities of Schiff base and its lanthanum complex. AB - Schiff base metal complexes are well-known to intercalate DNA. The La(III) complexes have been synthesized such that they hinder with the role of the topoisomerases, which control the topology of DNA during the cell-division cycle. Although several promising chemotherapeutics have been developed, on the basis of Schiff base metal complex DNA intercalating system they did not proceed past clinical trials due to their dose-limiting toxicity. Herein, we discuss an alternative compound, the La(III) complex, [La(L(1))2Cl3].7H2O based on a Schiff base ligand 2,3-dihydro-1H-indolo-[2,3-b]-phenazin-4(5H)-ylidene)benzothiazole-2 amine (L(1)), and report in vitro cell studies. Results of antitumor activity using cell viability assay, reactive oxygen species (ROS) generation and nuclear condensation in PC-3 (Human, prostate carcinoma) cells show that the metal complex is more potent than ligand. La(III) complexes have been synthesized by reaction of lanthanum(III) salt in 1:2M ratio with ligands L(1) and 3 (ethoxymethylene)-2,3-dihydro-1H-indolo[2,3-b]-phenazin-4(5H) ylidene)benzathiazole-2-amine (L(2)) in methanol. The ligands and their La(III) complexes were characterized by molar conductance, magnetic susceptibility, elemental analyses, FT-IR, UV-Vis, (1)H/(13)C NMR, thermogravimetric, XRD, and SEM analysis. PMID- 26619195 TI - The Polyunsaturated Fatty Acids Arachidonic Acid and Docosahexaenoic Acid Induce Mouse Dendritic Cells Maturation but Reduce T-Cell Responses In Vitro. AB - Long-chain polyunsaturated fatty acids (PUFAs) might regulate T-cell activation and lineage commitment. Here, we measured the effects of omega-3 (n-3), n-6 and n 9 fatty acids on the interaction between dendritic cells (DCs) and naive T cells. Spleen DCs from BALB/c mice were cultured in vitro with ovalbumin (OVA) with 50 MUM fatty acids; alpha-linolenic acid, arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), linoleic acid or oleic acid and thereafter OVA-specific DO11.10 T cells were added to the cultures. Fatty acids were taken up by the DCs, as shown by gas chromatography analysis. After culture with arachidonic acid or DHA CD11c+ CD11b+ and CD11c+ CD11bneg DCs expressed more CD40, CD80, CD83, CD86 and PDL-1, while IAd remained unchanged. However, fewer T cells co-cultured with these DCs proliferated (CellTrace Violet low) and expressed CD69 or CD25, while more were necrotic (7AAD+). We noted an increased proportion of T cells with a regulatory T cell (Treg) phenotype, i.e., when gating on CD4+ FoxP3+ CTLA-4+, CD4+ FoxP3+ Helios+ or CD4+ FoxP3+ PD-1+, in co cultures with arachidonic acid- or DHA-primed DCs relative to control cultures. The proportion of putative Tregs was inversely correlated to T-cell proliferation, indicating a suppressive function of these cells. With arachidonic acid DCs produced higher levels of prostaglandin E2 while T cells produced lower amounts of IL-10 and IFNgamma. In conclusion arachidonic acid and DHA induced up regulation of activation markers on DCs. However arachidonic acid- and DHA-primed DCs reduced T-cell proliferation and increased the proportion of T cells expressing FoxP3, indicating that these fatty acids can promote induction of regulatory T cells. PMID- 26619197 TI - Wood phenology, not carbon input, controls the interannual variability of wood growth in a temperate oak forest. AB - Although the analysis of flux data has increased our understanding of the interannual variability of carbon inputs into forest ecosystems, we still know little about the determinants of wood growth. Here, we aimed to identify which drivers control the interannual variability of wood growth in a mesic temperate deciduous forest. We analysed a 9-yr time series of carbon fluxes and aboveground wood growth (AWG), reconstructed at a weekly time-scale through the combination of dendrometer and wood density data. Carbon inputs and AWG anomalies appeared to be uncorrelated from the seasonal to interannual scales. More than 90% of the interannual variability of AWG was explained by a combination of the growth intensity during a first 'critical period' of the wood growing season, occurring close to the seasonal maximum, and the timing of the first summer growth halt. Both atmospheric and soil water stress exerted a strong control on the interannual variability of AWG at the study site, despite its mesic conditions, whilst not affecting carbon inputs. Carbon sink activity, not carbon inputs, determined the interannual variations in wood growth at the study site. Our results provide a functional understanding of the dependence of radial growth on precipitation observed in dendrological studies. PMID- 26619198 TI - Identifying Heat Waves in Florida: Considerations of Missing Weather Data. AB - BACKGROUND: Using current climate models, regional-scale changes for Florida over the next 100 years are predicted to include warming over terrestrial areas and very likely increases in the number of high temperature extremes. No uniform definition of a heat wave exists. Most past research on heat waves has focused on evaluating the aftermath of known heat waves, with minimal consideration of missing exposure information. OBJECTIVES: To identify and discuss methods of handling and imputing missing weather data and how those methods can affect identified periods of extreme heat in Florida. METHODS: In addition to ignoring missing data, temporal, spatial, and spatio-temporal models are described and utilized to impute missing historical weather data from 1973 to 2012 from 43 Florida weather monitors. Calculated thresholds are used to define periods of extreme heat across Florida. RESULTS: Modeling of missing data and imputing missing values can affect the identified periods of extreme heat, through the missing data itself or through the computed thresholds. The differences observed are related to the amount of missingness during June, July, and August, the warmest months of the warm season (April through September). CONCLUSIONS: Missing data considerations are important when defining periods of extreme heat. Spatio temporal methods are recommended for data imputation. A heat wave definition that incorporates information from all monitors is advised. PMID- 26619200 TI - Dyrk1A-ASF-CaMKIIdelta Signaling Is Involved in Valsartan Inhibition of Cardiac Hypertrophy in Renovascular Hypertensive Rats. AB - OBJECTIVES: It is known that the expression, activity and alternative splicing of Ca2+/calmodulin-dependent protein kinase IIdelta (CaMKIIdelta) are dysregulated in the cardiac remodeling process. Recently, we found a further signaling pathway, by which dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) regulates the alternative splicing of CaMKIIdelta via the alternative splicing factor (ASF), i.e., Dyrk1A-ASF-CaMKIIdelta. In this study, we aimed to investigate whether Dyrk1A-ASF-CaMKIIdelta signaling was involved in valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats. METHODS: Rats were subjected to two kidney-one clip (2K1C) surgery and then treated with valsartan (30 mg/kg/day) for 8 weeks. Hypertrophic parameter analysis was then performed. Western blot analysis was used to determine the protein expression of Dyrk1A and ASF and RT-PCR was used to analyze the alternative splicing of CaMKIIdelta in the left ventricular (LV) sample. RESULTS: Valsartan attenuated cardiac hypertrophy in 2K1C rats but without impairment of cardiac systolic function. Increased protein expression of Dyrk1A and decreased protein expression of ASF were observed in the LV sample of 2K1C rats. Treatment of 2K1C rats with valsartan reversed the changes in Dyrk1A and ASF expression in the LV sample. Valsartan adjusted the 2K1C-induced imbalance in alternative splicing of CaMKIIdelta by upregulating the mRNA expression of CaMKIIdeltaC and downregulating the mRNA expression of CaMKIIdeltaA and CaMKIIdeltaB. CONCLUSIONS: Valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats was mediated, at least partly, by Dyrk1A-ASF-CaMKIIdelta signaling. PMID- 26619199 TI - Variation in Rural African Gut Microbiota Is Strongly Correlated with Colonization by Entamoeba and Subsistence. AB - The human gut microbiota is impacted by host nutrition and health status and therefore represents a potentially adaptive phenotype influenced by metabolic and immune constraints. Previous studies contrasting rural populations in developing countries to urban industrialized ones have shown that industrialization is strongly correlated with patterns in human gut microbiota; however, we know little about the relative contribution of factors such as climate, diet, medicine, hygiene practices, host genetics, and parasitism. Here, we focus on fine-scale comparisons of African rural populations in order to (i) contrast the gut microbiota of populations inhabiting similar environments but having different traditional subsistence modes and either shared or distinct genetic ancestry, and (ii) examine the relationship between gut parasites and bacterial communities. Characterizing the fecal microbiota of Pygmy hunter-gatherers as well as Bantu individuals from both farming and fishing populations in Southwest Cameroon, we found that the gut parasite Entamoeba is significantly correlated with microbiome composition and diversity. We show that across populations, colonization by this protozoa can be predicted with 79% accuracy based on the composition of an individual's gut microbiota, and that several of the taxa most important for distinguishing Entamoeba absence or presence are signature taxa for autoimmune disorders. We also found gut communities to vary significantly with subsistence mode, notably with some taxa previously shown to be enriched in other hunter-gatherers groups (in Tanzania and Peru) also discriminating hunter gatherers from neighboring farming or fishing populations in Cameroon. PMID- 26619201 TI - Association of intra-tumoral tumour-infiltrating lymphocytes and neutrophil-to lymphocyte ratio is an independent prognostic factor in non-small cell lung cancer. AB - BACKGROUND: Studies suggest that tumour-infiltrating lymphocytes (TILs) and inflammation markers have independent roles in non-small cell lung cancer (NSCLC), but the relationship between the two pronostic factors remains unclear. In this study, we investigated TILs and inflammation markers in with patients advanced stage NSCLC and assessed the association of their levels with prognosis. MATERIALS AND METHODS: TILs were evaluated by immunohistochemical staining for cluster of differentiation 3 (CD3) and cluster of differentiation 5 (CD5) and by hematoxylin and eosin staining for non-specific lymphocyte. We investigated the localisation pattern of TILs in advanced stage NSCLC. We divided all cases into two groups: TILs-high and TILs-low groups, by 75th percentile of the population of. In our study, inflammation markers were assessed by C-reactive protein (CRP) and the neutrophil-to-lymphocyte ratio (NLR). RESULTS: The results showed that the presence of intra-tumoral high CD3+ and low CD5+ were an independent prognostic factor for overall survival (respectively, P = 0.022 and P = 0.025). Moreover, the high NLR and serum high CRP levels were associated with poor survival (respectively, P = 0.008; P = 0.027). In multi-variate survival analysis, the high CD3+ , low CD5+ , high NLR, tumour node metastasis (TNM) stage, depth of tumour invasion and lymph node metastasis remained independent prognostic factors (respectively, P = 0.018, P = 0.020, P = 0.024, P = 0.038, P = 0.020 and P = 0.047).The high NLR was detected negative correlation with intra tumoral CD3+ and positive correlation with intra-tumoral CD5+ (respectively, r = 0.623, P = 0.012; r = 0.628, P = 0.028). CONCLUSIONS: This study is first report demonstrating the prognostic value of intra-tumoral low CD5+ with NSCLC. Increased CD3+ and low CD5+ was observed in patients with poor prognosis; the two molecules were correlated with NLR, suggesting that inflammation might be used as improve therapeutic efficacy to immunotherapy for advanced NSCLC. PMID- 26619202 TI - The Impact of Exercising During Haemodialysis on Blood Pressure, Markers of Cardiac Injury and Systemic Inflammation--Preliminary Results of a Pilot Study. AB - BACKGROUND/AIMS: Patients requiring haemodialysis have cardiovascular and immune dysfunction. Little is known about the acute effects of exercise during haemodialysis. Exercise has numerous health benefits but in other populations has a profound impact upon blood pressure, inflammation and immune function; therefore having the potential to exacerbate cardiovascular and immune dysfunction in this vulnerable population. METHODS: Fifteen patients took part in a randomised-crossover study investigating the effect of a 30-min bout of exercise during haemodialysis compared to resting haemodialysis. We assessed blood pressure, plasma markers of cardiac injury and systemic inflammation and neutrophil degranulation. RESULTS: Exercise increased blood pressure immediately post-exercise; however, 1 hour after exercise blood pressure was lower than resting levels (106+/-22 vs. 117+/-25 mm Hg). No differences in h-FABP, cTnI, myoglobin or CKMB were observed between trial arms. Exercise did not alter circulating concentrations of IL-6, TNF-alpha or IL-1ra nor clearly suppress neutrophil function. CONCLUSIONS: This study demonstrates fluctuations in blood pressure during haemodialysis in response to exercise. However, since the fall in blood pressure occurred without evidence of cardiac injury, we regard it as a normal response to exercise superimposed onto the haemodynamic response to haemodialysis. Importantly, exercise did not exacerbate systemic inflammation or immune dysfunction; intradialytic exercise was well tolerated. PMID- 26619204 TI - Does the Prevalence of Periodontal Pathogens Change in Elderly Edentulous Patients after Complete Denture Treatment? AB - PURPOSE: To determine if wearing complete dentures can cause changes in prevalence of some of the most common periodontal pathogens in elderly edentulous patients. The need for understanding the composition of oral microflora in edentulous patients has been recognized by some authors, but no studies have dealt with the changes that occur in periodontal pathogens' prevalence as a result of complete dentures. MATERIALS AND METHODS: A total of 30 edentulous elderly (average age 71) patients participated in the study. Complete dentures were fabricated for each patient, and the residual alveolar ridges were swabbed before denture insertion. After a period of 6 months swabs were taken again. Identification of P. intermedia, A. actinomycetemcomitans, P. gingivalis, T. forsythia, T. denticola, and F. nucleatum was done by the polymerase chain reaction (PCR) method and primers specific for each microorganism. RESULTS: A noticeable increase in the presence of periodontal pathogens was observed after 6 months of denture wearing; targeted bacteria were identified in 17 pre-insertion samples compared to 28 post-insertion samples. The McNemar test was used to compare the prevalence of periodontal pathogenic bacteria before and after dental treatment. p<0.05 indicated statistical significance. Three microorganisms showed a statistically significant difference between the first and second swabbing-A. actinomycetemcomitans (6.7% vs. 40.0%, p = 0.006), P. intermedia (30.0% vs. 73.3%, p = 0.004), and T. forsythia (6.7% vs. 30.0%, p = 0.004). There was also an increase in bacteria co-associations 6 months post-insertion of complete dentures. CONCLUSIONS: The results of the present study suggested that wearing complete dentures caused a considerable increase of periodontopathic bacteria prevalence in elderly patients. Better understanding of oral microflora and the impact dental treatment has on bacterial colonies is important in modern dentistry. PMID- 26619203 TI - Competition and Cooperation among Relational Memory Representations. AB - Mnemonic processing engages multiple systems that cooperate and compete to support task performance. Exploring these systems' interaction requires memory tasks that produce rich data with multiple patterns of performance sensitive to different processing sub-components. Here we present a novel context-dependent relational memory paradigm designed to engage multiple learning and memory systems. In this task, participants learned unique face-room associations in two distinct contexts (i.e., different colored buildings). Faces occupied rooms as determined by an implicit gender-by-side rule structure (e.g., male faces on the left and female faces on the right) and all faces were seen in both contexts. In two experiments, we use behavioral and eye-tracking measures to investigate interactions among different memory representations in both younger and older adult populations; furthermore we link these representations to volumetric variations in hippocampus and ventromedial PFC among older adults. Overall, performance was very accurate. Successful face placement into a studied room systematically varied with hippocampal volume. Selecting the studied room in the wrong context was the most typical error. The proportion of these errors to correct responses positively correlated with ventromedial prefrontal volume. This novel task provides a powerful tool for investigating both the unique and interacting contributions of these systems in support of relational memory. PMID- 26619205 TI - Giant Nonlinearity of an Optically Reconfigurable Plasmonic Metamaterial. AB - Metamaterial nanostructures actuated by light give rise to a large optical nonlinearity. Plasmonic metamolecules on a flexible support structure cut from a dielectric membrane of nanoscale thickness are rearranged by optical illumination. This changes the optical properties of the strongly coupled plasmonic structure and therefore results in modulation of light with light. PMID- 26619206 TI - A highly conserved metalloprotease effector enhances virulence in the maize anthracnose fungus Colletotrichum graminicola. AB - Colletotrichum graminicola causes maize anthracnose, an agronomically important disease with a worldwide distribution. We have identified a fungalysin metalloprotease (Cgfl) with a role in virulence. Transcriptional profiling experiments and live cell imaging show that Cgfl is specifically expressed during the biotrophic stage of infection. To determine whether Cgfl has a role in virulence, we obtained null mutants lacking Cgfl and performed pathogenicity and live microscopy assays. The appressorium morphology of the null mutants is normal, but they exhibit delayed development during the infection process on maize leaves and roots, showing that Cgfl has a role in virulence. In vitro chitinase activity assays of leaves infected with wild-type and null mutant strains show that, in the absence of Cgfl, maize leaves exhibit increased chitinase activity. Phylogenetic analyses show that Cgfl is highly conserved in fungi. Similarity searches, phylogenetic analysis and transcriptional profiling show that C. graminicola encodes two LysM domain-containing homologues of Ecp6, suggesting that this fungus employs both Cgfl-mediated and LysM protein-mediated strategies to control chitin signalling. PMID- 26619208 TI - Expression of SOX10 in Salivary Gland Oncocytic Neoplasms: A Review and a Comparative Analysis with Other Immunohistochemical Markers. AB - OBJECTIVES: We evaluated SOX10 (SRY-related HMG-box 10) in differentiating acinic cell carcinoma (AciCC) from other salivary gland neoplasms with oncocytic features on fine-needle aspiration cell blocks (FNA CB) and compared its performance to DOG1 (discovered on gastrointestinal stromal tumor 1). MATERIAL AND METHODS: 35 FNA CB of oncocytic salivary gland neoplasms, i.e. 13 cases of AciCC, 16 of Warthin tumor (WT), 3 of mucoepidermoid carcinoma (MEC) and 3 of oncocytoma (ONC), and 75 salivary gland resections, i.e. 26 AciCC, 7 WT, 36 MEC, 3 ONC, 2 mammary analog secretory carcinomas (MASC) and 1 papillary cystadenoma were stained for SOX10 and DOG1. RESULTS: None of the benign oncocytic neoplasms were immunoreactive for SOX10 on CB or resection, similar to DOG1. On CB, 61.5 and 77% of AciCC were positive for SOX10 and DOG1, respectively. All surgically resected AciCC cases were positive for SOX10 and DOG1; other malignant oncocytic lesions such as MEC and MASC demonstrated variable SOX10 and DOG1 staining. CONCLUSION: The use of SOX10 may increase the diagnostic accuracy of oncocytic lesions on FNA. In this context, SOX10 is equivalent to DOG1 in ruling out benign lesions such as WT and ONC; however, negative results for SOX10 as well as DOG1 do not favor a benign diagnosis since MEC is often negative for both markers. PMID- 26619207 TI - Abrogation of Autophagy by Chloroquine Alone or in Combination with mTOR Inhibitors Induces Apoptosis in Neuroendocrine Tumor Cells. AB - BACKGROUND: Everolimus (RAD001), an mTORC1 inhibitor, demonstrated promising, but limited, anticancer effects in neuroendocrine tumors (NETs). Torin1 (a global mTOR inhibitor) and NVP-BEZ235 (a PI3K/mTOR inhibitor) seem to be more effective than RAD001. Autophagy, a degradation pathway that may promote tumor growth, is regulated by mTOR; mTOR inhibition results in stimulation of autophagy. Chloroquine (CQ) inhibits autophagy. AIM: To explore the effect of CQ alone or in combination with RAD001, Torin1 or NVP-BEZ235 on autophagy and on NET cell viability, proliferation and apoptosis. METHODS: The NET cell line BON1 was treated with CQ with or without different mTOR inhibitors. siRNA against ATG5/7 was used to genetically inhibit autophagy. Cellular viability was examined by XTT, proliferation by Ki-67 staining and cell cycles by flow cytometry. Apoptosis was analyzed by Western blotting for cleaved caspase 3 and staining for annexin V; autophagy was evaluated by Western blotting and immunostaining for LC3. RESULTS: RAD001, Torin1, NVP-BEZ235 and CQ all decreased BON1 cell viability. The effect of RAD001 was smaller than that of the other mTOR inhibitors or CQ. Torin1 and NVP-BEZ235 markedly inhibited cell proliferation, without inducing apoptosis. CQ similarly decreased cell proliferation, while robustly increasing apoptosis. Treatment with Torin1 or NVP-BEZ235 together with CQ was additive on viability, without increasing CQ-induced apoptosis. Inhibition of autophagy by ATG5/7 knockdown increased apoptosis in the presence or absence of mTOR inhibitors, mimicking the CQ effects. CONCLUSION: CQ inhibits NET growth by inducing apoptosis and by inhibiting cell proliferation, probably via inhibition of autophagy. CQ may potentiate the antitumor effect of mTOR inhibitors. PMID- 26619209 TI - Plasma Catalysis: Synergistic Effects at the Nanoscale. AB - Thermal-catalytic gas processing is integral to many current industrial processes. Ever-increasing demands on conversion and energy efficiencies are a strong driving force for the development of alternative approaches. Similarly, synthesis of several functional materials (such as nanowires and nanotubes) demands special processing conditions. Plasma catalysis provides such an alternative, where the catalytic process is complemented by the use of plasmas that activate the source gas. This combination is often observed to result in a synergy between plasma and catalyst. This Review introduces the current state-of the-art in plasma catalysis, including numerous examples where plasma catalysis has demonstrated its benefits or shows future potential, including CO2 conversion, hydrocarbon reforming, synthesis of nanomaterials, ammonia production, and abatement of toxic waste gases. The underlying mechanisms governing these applications, as resulting from the interaction between the plasma and the catalyst, render the process highly complex, and little is known about the factors leading to the often-observed synergy. This Review critically examines the catalytic mechanisms relevant to each specific application. PMID- 26619210 TI - Relative Pigment Composition and Remote Sensing Reflectance of Caribbean Shallow Water Corals. AB - Reef corals typically contain a number of pigments, mostly due to their symbiotic relationship with photosynthetic dinoflagellates. These pigments usually vary in presence and concentration and influence the spectral characteristics of corals. We studied the variations in pigment composition among seven Caribbean shallow water Scleractinian corals by means of High Performance Liquid Chromatography (HPLC) analysis to further resolve the discrimination of corals. We found a total of 27 different pigments among the coral species, including some alteration products of the main pigments. Additionally, pigments typically found in endolithic algae were also identified. A Principal Components Analysis and a Hierarchical Cluster Analysis showed the separation of coral species based on pigment composition. All the corals were collected under the same physical environmental conditions. This suggests that pigment in the coral's symbionts might be more genetically-determined than influenced by prevailing physical conditions of the reef. We further investigated the use of remote sensing reflectance (Rrs) as a tool for estimating the total pigment concentration of reef corals. Depending on the coral species, the Rrs and the total symbiont pigment concentration per coral tissue area correlation showed 79.5-98.5% confidence levels demonstrating its use as a non-invasive robust technique to estimate pigment concentration in studies of coral reef biodiversity and health. PMID- 26619212 TI - Representational and questionnaire measures of attachment: A meta-analysis of relations to child internalizing and externalizing problems. AB - Although the quality of the attachment relationship is often cited as an important determinant of development, the extent of impact of this environmental influence in shaping behavioral outcomes has been a matter of considerable debate. This may, in part, be because of the variability in methodologies used for assessing attachment across infancy, childhood, and adolescence, including behavioral, representational, and questionnaire measures of attachment. Previous meta-analyses of the relations between attachment and internalizing and externalizing problems have focused on the behavioral measures of attachment used primarily in infancy. The current meta-analysis is a comprehensive examination of the literature on attachment and behavioral problems in children aged 3-18 years, focusing on the representational and questionnaire measures most commonly used in this age range. When secure attachment was compared with insecure attachment, modest associations with internalizing behavior (165 studies; 48,224 families; d = .58; 95% confidence interval [CI] [.52-.64]) were found. Multivariate moderator analyses were used to disentangle the unique influence of each significant univariate moderator more precisely, and results revealed that effect sizes decreased as the child aged, and were larger in studies in which the participants were ethnically White, where the child was the problem informant, and when the internalizing measure was depressive symptoms. Attachment and externalizing behavior were also associated (116 studies; 24,689 families; d = .49; 95% CI [42 .56]), and effect sizes were larger in ethnically White samples, and in those where the child was the problem informant. Avoidant, ambivalent, and disorganized attachment classifications were associated with internalizing behavior, but only disorganized attachment was associated with externalizing behavior. PMID- 26619213 TI - Remotely Controlled Isomer Selective Molecular Switching. AB - Nonlocal addressing-the "remote control"-of molecular switches promises more efficient processing for information technology, where fast speed of switching is essential. The surface state of the (111) facets of noble metals, a confined two dimensional electron gas, provides a medium that enables transport of signals over large distances and hence can be used to address an entire ensemble of molecules simultaneously with a single stimulus. In this study we employ this characteristic to trigger a conformational switch in anthradithiophene (ADT) molecules by injection of hot carriers from a scanning tunneling microscope (STM) tip into the surface state of Cu(111). The carriers propagate laterally and trigger the switch in molecules at distances as far as 100 nm from the tip location. The switching process is shown to be long-ranged, fully reversible, and isomer selective, discriminating between cis and trans diastereomers, enabling maximum control. PMID- 26619211 TI - Reward devaluation: Dot-probe meta-analytic evidence of avoidance of positive information in depressed persons. AB - Cognitive theories of depression and anxiety have traditionally emphasized the role of attentional biases in the processing of negative information. The dot probe task has been widely used to study this phenomenon. Recent findings suggest that biased processing of positive information might also be an important aspect of developing psychopathological symptoms. However, despite some evidence suggesting persons with symptoms of depression and anxiety may avoid positive information, many dot-probe studies have produced null findings. The present review used conventional and novel meta-analytic methods to evaluate dot-probe attentional biases away from positive information and, for comparison, toward negative information, in depressed and anxious individuals. Results indicated that avoidance of positive information is a real effect exhibiting substantial evidential value among persons experiencing psychopathology, with individuals evidencing primary symptoms of depression clearly demonstrating this effect. Different theoretical explanations for these findings are evaluated, including those positing threat-processing structures, even-handedness, self-regulation, and reward devaluation, with the novel theory of reward devaluation emphasized and expanded. These novel findings and theory suggest that avoidance of prospective reward helps to explain the cause and sustainability of depressed states. Suggestions for future research and methodological advances are discussed. PMID- 26619214 TI - The balance sheet of benefits and harms of breast cancer population-based screening in Europe: outcome research, practice and future challenges. AB - Breast cancer screening programs are still object of harsh debate. In 2012, the Independent UK Panel reviewed the benefits and harms of mammography screening based on randomized trials and the EUROSCREEN Working Group reviewed European observational outcome studies. The conclusion was that screening programs should continue, while acknowledging that harms, such as the occurrence of false positive results and overdiagnosis, can have a negative impact on a woman's life. Information on the balance sheet of the benefits and harms of breast cancer screening should help women and their physicians to make an informed choice. The future challenge for breast screening programs is to assess the feasibility, acceptability, effectiveness and impact of risk-based screening in order to maximize benefit-to-harm ratios. PMID- 26619215 TI - Early life exposure to a rodent carcinogen propiconazole fungicide induces oxidative stress and hepatocarcinogenesis in medaka fish. AB - Conazole pollution is an emerging concern to human health and environmental safety because of the broad use of conazole fungicides in agriculture and medicine and their frequent occurrence in aquifers. The agricultural pesticide propiconazole has received much regulatory interest because it is a known rodent carcinogen with evidence of multiple adverse effects in mammals and non-targeted organisms. However, the carcinogenic effect and associated mechanism of propiconazole in fish under microgram-per-liter levels of environmental-relevant exposure remains unclear. To explore whether early life of propiconzaole exposure would induce oxidative stress and latent carcinogenic effects in fish, we continuously exposed larvae of wild type or p53(-/-) mutant of medaka fish (Oryzias latipes) to propiconazole (2.5-250MUg/L) for 3, 7, 14 or 28 days and assessed liver histopathology and/or the oxidative stress response and gene expression during exposure and throughout adulthood. Propiconazole dose dependently induced reactive oxygen species (ROS) level, altered homeostasis of antioxidant superoxide dismutase, catalase and glutathione S-transferase and caused lipid and protein peroxidation during early life exposure in wild type medaka. Such exposure also significantly upregulated gene expression of the cytochrome P450 CYP1A, but marginally suppressed that of tumor suppressor p53 in adults. Furthermore, histopathology revealed that p53(-/-) mutant medaka with early life exposure to propiconazole showed increased incidence of hepatocarcionogensis, as compared to the p53(-/-) control group and wild type strain. We demonstrated that propiconazole can initiate ROS-mediated oxidative stress and induce hepatic tumorigenesis associated with CYP1A- and/or p53 mediated pathways with the use of wild type and p53(-/-) mutant of medaka fish. The toxic response of medaka to propiconazole is compatible with that observed in rodents. PMID- 26619216 TI - The Dutch Long-Term Care System in Transition: Implications for Municipalities. AB - INTRODUCTION: The aim of this study is to examine the preparedness of Dutch municipalities (in terms of system readiness for innovation) for the challenges resulting from their new responsibilities under the long-term care reform of January 1, 2015. METHODS: A qualitative research approach was used by conducting semi-structured interviews with representatives of nine Dutch municipalities responsible for the long-term care of older people in their respective municipalities. RESULTS: Municipalities consider themselves to be largely prepared for their new responsibilities resulting from the long-term care reform. However, this perception mainly applies to practical changes (related to municipalities' organizational preparation for their new responsibilities) occurring in the short-term transition phase, not to the more long-term transformation phase. CONCLUSION: We argue that municipalities highly underestimate the long-term challenges that lie ahead of them (such as the development of a dedicated 'participation society') and, in fact, seem to fear the uncertainty of the consequences of these challenges. PMID- 26619217 TI - [Differences in the Provision of Lifestyle Counseling for Cardiovascular Disease Prevention Between Urban and Rural Regions in Germany. Findings from a National Survey of Primary Care Physicians]. AB - AIMS: In Germany, shortages in primary care physicians (PCPs) were reported in some rural regions. In this paper, we explored if regional differences in the distribution of PCPs are associated with the provision of lifestyle counseling in primary care. METHODS: In a nationwide study, a total of 4,074 randomly selected PCPs were asked about provision of lifestyle counseling to their patients, their attitudes, and perceived barriers. RESULTS: PCPs from rural regions provided less frequently lifestyle advice for cardiovascular disease prevention. Compared to their colleagues in urban areas, more PCPs from rural regions believed that were inadequately qualified for the lifestyle counseling and that they had been less successful in helping patients to modify their lifestyles. Physicians from rural practices named more often than PCPs from urban practices a lack of adherence by the patients (65 vs. 57%), insufficient opportunities to collaborate with providers of preventive services (62 vs. 55%), and lack of time (66 vs. 52%; all p<0.001) as barriers in providing patients with lifestyle counseling. CONCLUSION: Taking into account the expected increased shortages in PCPs in rural regions, the results show the need for targeted interventions for improving lifestyle counseling in rural practices. PMID- 26619218 TI - [The Willingness to Consent to the Linkage of Primary and Secondary Data: An Analysis Based on a Survey of Patients with Primary Breast Cancer in Northrhine Westfalia]. AB - Introduction: By linking data it is possible to merge, for example, survey data with routine data from statutory health insurance (GKV), to gain benefit from the advantages of both. As personal data is involved, it is necessary to obtain consent. Previous studies show that willingness to release this kind of data for scientific research is limited. This fact restricts the number of participants and can cause selection bias. The aim of our study was to analyze willingness to consent to the linkage of survey data with statutory health insurance data in patients with primary breast cancer. Associations between approval and socio demographic characteristics were explored. Method: In the annual survey of patients with primary breast cancer in certified breast centers in North Rhine Westphalia, all included patients were questioned concerning their willingness to consent to data linkage. We distinguished between patients insured by AOK Rhineland/Hamburg and all other patients: based on cooperation with AOK Rhineland/Hamburg, we obtained consent to actually link the data for all patients insured there. All other patients were questioned in terms of their insurance and their willingness to consent in general. Results: A total of 2,387 questionnaires were returned, giving a return rate of 49.3%. For the AOK Rhineland/Hamburg insured patients, the consent rate was at 89.6%. At 75.7%, positive attitudes towards data linkage turned out to be a bit lower for patients with other insurers. Under the assumption that all non-responders disapprove data linkage, still 38.1% of patients showed a positive attitude towards data linkage. As a result of the multivariable model, insurance status (private vs. statutory) and first language turned out to be the only significant factors influencing the response. The consent of patients insured by AOK Rhineland/Hamburg is not significantly influenced by any of the measured socio-demographic factors. Conclusion: Currently, there is not much knowledge on the acceptance of data linkage in patients suffering from an acute illness. Although our results are restricted to breast cancer patients, they are able to uncover problems and chances concerning data linkage. PMID- 26619219 TI - [Association of Health Insurance and Socio-economic Factors with Health Care for Malignant Melanoma]. AB - Objective: To analyze the relationship between socio-demographic and regional factors, health insurance status and clinical features of malignant melanoma (MM). Methods: Primary data from a nationwide dermato-histopathologic laboratory on all consecutive excisions with proven diagnosis of MM over the 5-year period 2009-2013 were analyzed regarding tumor-specific and socioeconomic characteristics. The tumor depth (Breslow index) being a predictor of invasive MM progression and mortality was defined as a major indicator for early detection and intervention, thus reflecting quality of health care. Results: N=4 840 histologically verified MM samples from 4 583 patients were analyzed; of these, 2 537 (52.4%) were invasive MM. The tumor depth, which was 1.09 mm on average, increased with age from 1.00 mm in the lowest to 1.56 mm in the highest age group, p<0.001). Controlled for age and sex, the members of agricultural health insurances (LKK) and of German local public health insurances (AOK) showed significantly increased tumor depths (1.67 resp. 1.20 mm). The lowest average levels were found in members of the substitute health funds (e. g. Barmer GEK 0.93 mm) and in privately insured persons (0.99 mm). Based on a regional 4-step classification, there was a gradient in MM depth from more populated to more rural areas, ranging from 1.05 mm in nucleated cities to 1.22 in small rural communities. Distribution of MM locations varied significantly by health insurance: The highest proportion of MM in the head/neck area was seen in members of the agricultural (52.3%) and of the local public health insurances (30.2%) vs. 18.5% in patients from the substitute health funds. In contrast, MM located on the trunk and lower extremities was more prevalent in private, substitute and company health insurance funds. Conclusion: Age, gender and health insurance status are relevant determinants of MM health care and progression risk in Germany. Prevention and early detection programs by health insurances should take this into account. PMID- 26619220 TI - [Identification of Systemic Contaminations with Legionella Spec. in Drinking Water Plumbing Systems: Sampling Strategies and Corresponding Parameters]. AB - After the amendment of the Drinking Water Ordinance in 2011, the requirements for the hygienic-microbiological monitoring of drinking water installations have increased significantly. In the BMBF-funded project "Biofilm Management" (2010 2014), we examined the extent to which established sampling strategies in practice can uncover drinking water plumbing systems systemically colonized with Legionella. Moreover, we investigated additional parameters that might be suitable for detecting systemic contaminations. We subjected the drinking water plumbing systems of 8 buildings with known microbial contamination (Legionella) to an intensive hygienic-microbiological sampling with high spatial and temporal resolution. A total of 626 drinking hot water samples were analyzed with classical culture-based methods. In addition, comprehensive hygienic observations were conducted in each building and qualitative interviews with operators and users were applied. Collected tap-specific parameters were quantitatively analyzed by means of sensitivity and accuracy calculations. The systemic presence of Legionella in drinking water plumbing systems has a high spatial and temporal variability. Established sampling strategies were only partially suitable to detect long-term Legionella contaminations in practice. In particular, the sampling of hot water at the calorifier and circulation re-entrance showed little significance in terms of contamination events. To detect the systemic presence of Legionella,the parameters stagnation (qualitatively assessed) and temperature (compliance with the 5K-rule) showed better results. PMID- 26619221 TI - Darcy Velocity Is Not a Velocity. PMID- 26619223 TI - Correction: Chemosensory Gene Families in Adult Antennae of Anomala corpulenta Motschulsky (Coleoptera: Scarabaeidae: Rutelinae). PMID- 26619222 TI - First-line treatment with hepatic arterial infusion plus capecitabine vs capecitabine alone for elderly patients with unresectable colorectal liver metastases. AB - This study aimed to compare the efficacy and safety of HAI fluoropyrimidine (FUDR)/capecitabine or single capecitabine as first-line treatment for elderly patients with unresectable colorectal liver metastases (CLMs). Fifty-one elderly patients with liver-only CLMs were eligible for enrollment. Patients were divided into HAI FUDR /capecitabine group and single capecitabine group randomly. The primary endpoint was median survival time (MST), defined as the time from the date of catheter implantation to the date of death or the date of the last follow up. The secondary endpoint was objective antitumor response and adverse events. The HAI pump was implanted before chemotherapy. All patients received a 3-week cycle of oral capecitabin. In Group A, the RR and DCR were both 95.8%. In Group B, the RR and DCR were 48.1% and 81.5%, respectively. There was significant difference between the RRs of the 2 groups (P < 0.001). But there was no significant difference between the DCRs of the 2 groups (P = 0.053). There was a statistical difference between the MSTs of the 2 groups (18.5 vs.13 months, P = 0.0312). HAI FUDR combined with oral capecitabine as the first-line treatment for elderly patients with CLMs has promising efficacy and safety. PMID- 26619224 TI - Newly Developed Sarcopenia as a Prognostic Factor for Survival in Patients who Underwent Liver Transplantation. AB - INTRODUCTION: The relationship between a perioperative change in sarcopenic status and clinical outcome of liver transplantation (LT) is unknown. We investigated whether post-LT sarcopenia and changes in sarcopenic status were associated with the survival of patients. METHOD: This retrospective study was based on a cohort of 145 patients from a single transplant center who during a mean of 1 year after LT underwent computed tomography imaging evaluation. The cross-sectional area of the psoas muscle of LT patients was compared with that of age- and sex-matched healthy individuals. The Cox proportional hazards regression model was used to determine whether post-LT sarcopenia and changes in sarcopenic status affect post-LT survival. RESULTS: The mean age at LT of the 116 male and 29 female patients was 50.2 +/- 7.9 years; the mean follow-up duration was 51.6 +/- 32.9 months. All pre-LT patients with sarcopenia still had sarcopenia 1 year after LT; 14 (15%) patients had newly developed sarcopenia. The mean survival duration was 91.8 +/- 4.2 months for non-sarcopenic patients and 80.0 +/- 5.2 months for sarcopenic patients (log-rank test, p = 0.069). In subgroup analysis, newly developed sarcopenia was an independent negative predictor for post-LT survival (hazard ratio: 10.53, 95% confidence interval: 1.37-80.93, p = 0.024). CONCLUSION: Sarcopenia in LT recipients did not improve in any of the previously sarcopenic patients and newly developed within 1 year in others. Newly developed sarcopenia was associated with increased mortality. Newly developed sarcopenia can be used to stratify patients with regard to the risk of post-LT mortality. PMID- 26619225 TI - Effect of Temperature and Pressure on the Stability of Protein Microbubbles. AB - Protein microbubbles are air bubbles with a network of interacting proteins at the air-water interface. Protein microbubbles are commonly used in medical diagnostic and therapeutic research. They have also recently gained interest in the research area of food as they can be used as structural elements to control texture, allowing for the manufacture of healthier foods with increased consumer perception. For the application of microbubbles in the food industry, it is important to gain insights into their stability under food processing conditions. In this study, we tested the stability of protein microbubbles against heating and pressurization. Microbubbles could be heated to 50 degrees C for 2 min or pressurized to 100 kPa overpressure for 15 s without significantly affecting their stability. At higher pressures and temperatures, the microbubbles became unstable and buckled. Buckling was observed above a critical pressure and was influenced by the shell modulus. The addition of cross-linkers like glutaraldehyde and tannic acid resulted in microbubbles that were stable against all tested temperatures and overpressures, more specifically, up to 120 degrees C and 470 kPa, respectively. We found a relation between the storage temperatures of microbubble dispersions (4, 10, 15, and 21 degrees C) and a decrease in the number of microbubbles with the highest decrease at the highest storage temperature. The average rupture time of microbubbles stored at different storage temperatures followed an Arrhenius relation with an activation energy for rupture of the shell of approximately 27 kT. This strength ensures applicability of microbubbles in food processes only at moderate temperatures and storage for a moderate period of time. After the proteins in the shell are cross-linked, the microbubbles can withstand pressures and temperatures that are representative of food processes. PMID- 26619227 TI - Long-Term Exposure to Primary Traffic Pollutants and Lung Function in Children: Cross-Sectional Study and Meta-Analysis. AB - BACKGROUND: There is widespread concern about the possible health effects of traffic-related air pollution. Nitrogen dioxide (NO2) is a convenient marker of primary pollution. We investigated the associations between lung function and current residential exposure to a range of air pollutants (particularly NO2, NO, NOx and particulate matter) in London children. Moreover, we placed the results for NO2 in context with a meta-analysis of published estimates of the association. METHODS AND FINDINGS: Associations between primary traffic pollutants and lung function were investigated in 4884 children aged 9-10 years who participated in the Child Heart and Health Study in England (CHASE). A systematic literature search identified 13 studies eligible for inclusion in a meta-analysis. We combined results from the meta-analysis with the distribution of the values of FEV1 in CHASE to estimate the prevalence of children with abnormal lung function (FEV1<80% of predicted value) expected under different scenarios of NO2 exposure. In CHASE, there were non-significant inverse associations between all pollutants except ozone and both FEV1 and FVC. In the meta-analysis, a 10 MUg/m3 increase in NO2 was associated with an 8 ml lower FEV1 (95% CI: -14 to -1 ml; p: 0.016). The observed effect was not modified by a reported asthma diagnosis. On the basis of these results, a 10 MUg/m3 increase in NO2 level would translate into a 7% (95% CI: 4% to 12%) increase of the prevalence of children with abnormal lung function. CONCLUSIONS: Exposure to traffic pollution may cause a small overall reduction in lung function and increase the prevalence of children with clinically relevant declines in lung function. PMID- 26619228 TI - Computers in the Examination Room. PMID- 26619226 TI - Triple reuptake inhibitors as potential next-generation antidepressants: a new hope? AB - The current therapy for depression is less than ideal with remission rates of only 25-35% and a slow onset of action with other associated side effects. The persistence of anhedonia originating from depressed dopaminergic activity is one of the most treatment-resistant symptoms of depression. Therefore, it has been hypothesized that triple reuptake inhibitors (TRIs) with potency to block dopamine reuptake in addition to serotonin and norepinephrine transporters should produce higher efficacy. The current review comprehensively describes the development of TRIs and discusses the importance of evaluation of in vivo transporter occupancy of TRIs, which should correlate with efficacy in humans. PMID- 26619229 TI - Double Stent Insertion for Combined Malignant Airway and Esophageal Stenoses: Feasibility, Safety, and Long-Term Outcome. AB - PURPOSE: We determined the feasibility, safety, and long-term outcome of double stent insertion in management of combined malignant airway and esophageal stenoses (CAES). PATIENTS AND METHODS: Between March 2005 and May 2014, 11 consecutive patients (9 males and 2 females), 56-78 years of age (mean, 63.4 +/- 6.1 years), with CAES who underwent double stent insertion (airway and esophageal stents) were enrolled in this retrospective study. Data regarding the technical success, clinical success, and long-term outcome were collected and analyzed. RESULTS: Airway and esophageal stents were successfully inserted in all patients. The interval between insertion of the two stents was 0-42 days (mean, 13.2 +/- 14.2 days). No procedure-related complication occurred. Relief of dyspnea and dysphagia was achieved in all patients. The mean Hugh-Jones grade improved from 4.5 +/- 0.7 before airway stent insertion to 1.5 +/- 0.5 after airway stent insertion (P < .001). The mean dysphagia grade improved from 3.5 +/- 0.5 before esophageal stent insertion to 1.3 +/- 0.5 after esophageal stent insertion (P < .001). Stent-related complications included restenosis of the airway stent (n = 2) and mild migration of the esophageal stent (n = 2). There was no occurrence of airway-esophageal fistula after treatment. The mean survival of the 11 patients after double stent insertion was 105.5 +/- 18.5 days. The cumulative 3- and 6 month survival rates after double stent insertion were 54.5% and 9.1%, respectively. CONCLUSIONS: Double stent insertion is an easy, safe, and effective method in palliative treatment for patients with CAES. PMID- 26619230 TI - The time course of lexical competition during spoken word recognition in Mandarin Chinese: an event-related potential study. AB - The present study investigated the effect of lexical competition on the time course of spoken word recognition in Mandarin Chinese using a unimodal auditory priming paradigm. Two kinds of competitive environments were designed. In one session (session 1), only the unrelated and the identical primes were presented before the target words. In the other session (session 2), besides the two conditions in session 1, the target words were also preceded by the cohort primes that have the same initial syllables as the targets. Behavioral results showed an inhibitory effect of the cohort competitors (primes) on target word recognition. The event-related potential results showed that the spoken word recognition processing in the middle and late latency windows is modulated by whether the phonologically related competitors are presented or not. Specifically, preceding activation of the competitors can induce direct competitions between multiple candidate words and lead to increased processing difficulties, primarily at the word disambiguation and selection stage during Mandarin Chinese spoken word recognition. The current study provided both behavioral and electrophysiological evidences for the lexical competition effect among the candidate words during spoken word recognition. PMID- 26619231 TI - Glutamate metabolism of astrocytes during hyperbaric oxygen exposure and its effects on central nervous system oxygen toxicity. AB - Hyperbaric oxygen (HBO) has been used widely in many underwater missions and clinical work. However, exposure to extremely high oxygen pressure may cause central nervous system oxygen toxicity (CNS-OT). The regulation of astrocyte glutamate metabolism is closely related to epilepsy. This study aimed to observe the effects of HBO exposure on glutamate metabolism in astrocytes and confirm the role of glutamate metabolism in CNS-OT. Anesthetized rats were exposed to 5 atmosphere absolute HBO for 80 min and microdialysis samples of brain interstitial fluid were continuously collected. Extracellular glutamate and glutamine concentrations were also detected. Freely moving rats were exposed to HBO of the same pressure for 20 min and glutamine synthetase (GS) activity in brain tissues was measured. Finally, we observed the effects of different doses of drugs related to glutamate metabolism on the latency of CNS-OT. Results showed that HBO exposure significantly increased glutamate content, whereas glutamine content was significantly reduced. Moreover, HBO exposure significantly reduced GS activity. Glutamate transporter-1 (GLT-1) selective antagonist ceftriaxone prolonged CNS-OT latency, whereas GLT-1 selective inhibitor dihydrokainate shortened CNS-OT latency. In summary, HBO exposure improved glutamate concentration and reduced glutamine concentration by inhibition of GS activity. GLT-1 activation also participated in the prevention of HBO-induced CNS-OT. Our research will provide a potential new target to terminate or attenuate CNS-OT. PMID- 26619232 TI - How do musical tonality and experience affect visual working memory? AB - The influence of music on the human brain has continued to attract increasing attention from neuroscientists and musicologists. Currently, tonal music is widely present in people's daily lives; however, atonal music has gradually become an important part of modern music. In this study, we conducted two experiments: the first one tested for differences in perception of distractibility between tonal music and atonal music. The second experiment tested how tonal music and atonal music affect visual working memory by comparing musicians and nonmusicians who were placed in contexts with background tonal music, atonal music, and silence. They were instructed to complete a delay matching memory task. The results show that musicians and nonmusicians have different evaluations of the distractibility of tonal music and atonal music, possibly indicating that long-term training may lead to a higher auditory perception threshold among musicians. For the working memory task, musicians reacted faster than nonmusicians in all background music cases, and musicians took more time to respond in the tonal background music condition than in the other conditions. Therefore, our results suggest that for a visual memory task, background tonal music may occupy more cognitive resources than atonal music or silence for musicians, leaving few resources left for the memory task. Moreover, the musicians outperformed the nonmusicians because of the higher sensitivity to background music, which also needs a further longitudinal study to be confirmed. PMID- 26619233 TI - The neural basis of desire reasoning for self and others: an event-related potential study. AB - Theory of mind refers to the ability to attribute mental states to self and others, and predict actions in terms of mental states. It is still unclear how certain kinds of processing occur in theory of mind operation. The present study compared neural activities elicited by desire reasoning for self and for others under consistent or inconsistent conditions using the event-related potential method. The results showed that the late positive component (LPC) associated with desire reasoning was larger during the 450-550 ms time period in the condition of reasoning for self than that for others when desires were inconsistent. A left hemisphere effect on the scalp distribution was observed for the LPC component. The present study showed that a left frontal LPC component might reflect the subjective categorization process in desire reasoning. PMID- 26619234 TI - Rediscovering holism. PMID- 26619235 TI - Using social media to create discussion. PMID- 26619236 TI - The characteristics and experiences of anticipatory mourning in caregivers of teenagers and young adults. AB - This article reports a systematic review of literature undertaken to identify characteristics and experiences of anticipatory mourning in caregivers of teenagers and young adults with life-limiting or life-threatening conditions. A comprehensive literature search was conducted using the key words 'anticipatory', 'mourning', 'grief', and synonyms. This review focused on six studies that met inclusion criteria and reported characteristics of anticipatory mourning in caregivers of teenagers and young adults. Characteristics and experiences were sorted into four main themes: symptoms; a sense of loss; caregiver behaviour; and the unique experience of caring for, or losing, a teenager or young adult. The review suggests that there are characteristics and experiences of anticipatory mourning that are unique to caregivers of this age group. The review also suggests that consideration of anticipatory mourning is important in offering holistic care to young adults and their caregivers, and points to the need for further research in this area. PMID- 26619237 TI - Palliative and end-of-life decision-making in dementia care. AB - This paper will highlight some of the pertinent issues associated with palliative and end-of-life decision-making in relation to dementia. To achieve this, the author will consider why there is disparity in relation to shared decision-making practices across non-malignant disease through exploration of models of disease trajectories. The author will then go on to highlight how people living with dementia, a non-malignant disease, have a human right to receive palliative care and be an active agent in the shared decision-making process about their future and care preferences. The challenges of shared decision-making in dementia care will be discussed along with some implications for nursing practice. The aim of this paper is to provide nurses, practising across all settings, with an overview of the fundamental importance of timely palliative and end-of-life shared decision-making in dementia care. PMID- 26619238 TI - 'Fighting for care': parents' perspectives of children's palliative care in South Tyrol, Italy. AB - BACKGROUND: Children's palliative care in Italy develops comparatively slowly. Recent legislation is enabling, but foundational research exploring parental experiences and perceptions is lacking. AIM: To investigate the experiences and perceptions of parents in South Tyrol, Italy regarding caring for a child with a life-threatening or life-limiting illness. DESIGN: A mixed qualitative design incorporated both an online survey and parent interviews. Using purposive sampling, 13 parents undertook 9 interviews and 7 parents completed the survey. RESULTS: The authors highlight a major parental theme describing difficult relationships with health services requiring them to 'fight the system' for services. DISCUSSION: The authors raise a disturbing possibility that such 'fighting the system' is now so widely recognised worldwide that it cannot be considered to be accidental. CONCLUSION: The authors recommend the establishment of a specialist, dedicated paediatric palliative care service in South Tyrol with the international recognised values and operating standards that would render such parental 'fighting' unnecessary. PMID- 26619239 TI - Can a community of practice enhance a palliative approach for people drawing close to death with dementia? AB - This action research study was conducted to trial a strategy intended to support a consistent, high-quality, palliative approach for people with dementia drawing close to death-the implementation of a community of practice. Professionals from community/residential care and hospitals formed this community of practice, which took on the role of an action research group. The group was supported to identify and address practice problems. Four action plans were implemented; outcomes from two are reported. When actioning the plan 'providing education and information for the staff', the staff's ratings of sessions and resources were positive but impacts upon knowledge, views, or confidence were small. When actioning 'supporting families', families providing care in non-hospital settings received information about severe dementia from suitably prepared staff, plus contact details to access support. Family feedback was primarily positive. Reference to additional practice change frameworks and inclusion of specialist palliative care professionals are recommendations for future initiatives; also focusing on targeted, achievable goals over longer timeframes. PMID- 26619240 TI - Communication differences when patients and caregivers are seen separately or together. AB - BACKGROUND: Southern Adelaide Palliative Care Services introduced a nurse-led early introduction to a palliative care clinic in 2011. The clinic offers a thorough psychosocial assessment and the provision of information and an introduction to future care planning. The patients and their caregivers are seen together by the nurse practitioner initially for a physical assessment. They are then seen by a social worker to focus on advanced care planning and assessment of social and emotional factors. After the social work visit, the patient and caregiver are separated, and the patient sees the psychosocial nurse for coping and adjustment to illness and the carer sees the caregiver network facilitator to assess their informal supports to assist in the role of community-based caregiving. The pilot study looks at the nature of communication in the clinic where patient and carer are together and compares that to when they are separated. METHODS: A total of 33 patients and their caregivers agreed for their coversations to be tape recorded between May and November of 2013. All tape recordings were transcribed verbatim. Ten patient transcripts (n=40) have been coded for quantitative analysis. The codes identify content and function of speech, cues for information and emotion and whether they are responded to by clinicians. RESULTS: Pilot results reveal that caregivers contribute little in the combined clinics and dominate the conversation in the private clinic. Patients, when seen alone, predominantly express emotion related cues, opposed to cues for information. The clinicians focus on their area of specialty, which results in little duplication in this clinic setting. CONCLUSION: An earlier evaluation of this clinic found that patients and their caregivers appreciate being separated in the clinic setting to have time and privacy to reveal fears and feelings related to end-of-life care. This current study quantifies the patient and caregiver experience and confirms those earlier findings. PMID- 26619242 TI - Politics and palliative care: Guadeloupe. AB - Dion Smyth's review of the internet for palliative nursing. PMID- 26619244 TI - Plastic Transition to Switch Nonlinear Optical Properties Showing the Record High Contrast in a Single-Component Molecular Crystal. AB - To switch bulk nonlinear optical (NLO) effects represents an exciting new branch of NLO material science, whereas it remains a great challenge to achieve high contrast for "on/off" of quadratic NLO effects in crystalline materials. Here, we report the supereminent NLO-switching behaviors of a single-component plastic crystal, 2-(hydroxymethyl)-2-nitro-1,3-propanediol (1), which shows a record high contrast of at least ~150, exceeding all the known crystalline switches. Such a breakthrough is clearly elucidated from the slowing down of highly isotropic molecular motions during plastic-to-rigid transition. The deep understanding of its intrinsic plasticity and superior NLO property allows the construction of a feasible switching mechanism. As a unique class of substances with short-range disorder embedded in long-range ordered crystalline lattice, plastic crystals enable response to external stimuli and fulfill specific photoelectric functions, which open a newly conceptual avenue for the designing of new functional materials. PMID- 26619243 TI - Gene-Gene Associations with the Susceptibility of Kawasaki Disease and Coronary Artery Lesions. AB - Kawasaki disease (KD) is a systemic vasculitis primarily affecting children < 5 years old. Genes significantly associated with KD mostly involve cardiovascular, immune, and inflammatory responses. Recent studies have observed stronger associations for KD risk with multiple genes compared to individual genes. Therefore, we investigated whether gene combinations influenced KD susceptibility or coronary artery lesion (CAL) formation. We examined 384 single-nucleotide polymorphisms (SNPs) for 159 immune-related candidate genes in DNA samples from KD patients with CAL (n = 73), KD patients without CAL (n = 153), and cohort controls (n = 575). Individual SNPs were first assessed by univariate analysis (UVA) and multivariate analysis (MVA). We used multifactor dimensionality reduction (MDR) to examine individual SNPs in one-, two-, and three-locus best fit models. UVA identified 53 individual SNPs that were significantly associated with KD risk or CAL formation (p < 0.10), while 35 individual SNPs were significantly associated using MVA (p <= 0.05). Significant associations in MDR analysis were only observed for the two-locus models after permutation testing (p <= 0.05). In logistic regression, combined possession of PDE2A (rs341058) and CYFIP2 (rs767007) significantly increased KD susceptibility (OR = 3.54; p = 4.14 x 10(-7)), while combinations of LOC100133214 (rs2517892) and IL2RA (rs3118470) significantly increased the risk of CAL in KD patients (OR = 5.35; p = 7.46 x 10( 5)). Our results suggest varying gene-gene associations respectively predispose individuals to KD risk or its complications of CAL. PMID- 26619246 TI - Low-dose levetiracetam for seizure prophylaxis after traumatic brain injury. AB - OBJECTIVE: The primary objective of this study was to determine the effectiveness of a lower dose of levetiracetam (500 mg every 12 hours) to prevent early seizures after traumatic brain injury (TBI). It was hypothesized that the seizure rate would be low and comparable to previous studies using phenytoin. METHODS: This was a retrospective cohort study conducted in a tertiary care, academic institution that is designated as a level 1 trauma centre in the US. Consecutive patients with TBI were evaluated. Patients who were given a levetiracetam dose of 500 mg every 12 hours were included. The primary outcome was the occurrence of a seizure within 7 days of TBI. RESULTS: There were a total of 169 patients included in the study, who were treated with levetiracetam 500 mg every 12 hours. The median time to first dose of levetiracetam was 3.5 hours after injury (interquartile range = 1-13 hours). After initiation of levetiracetam, there were four (2.4%) patients who had a seizure within 7 days. This was not significantly different than the hypothesized population value of 3.6% (p = 0.390). CONCLUSIONS: A lower dose of levetiracetam 500 mg every 12 hours after TBI may be effective for early seizure prevention after TBI. PMID- 26619245 TI - Pancreatic cancer: Update on immunotherapies and algenpantucel-L. AB - Pancreatic adenocarcinoma is notoriously lethal, and despite improvements in systemic chemotherapy approaches bringing survival rates for metastatic disease to almost 1 year, by 2030 it is expected to become the second leading cause of cancer death. Pancreatic cancer (PC) prognosis has been associated with both the presence of intratumoral helper and cytotoxic T lymphocytes, as well as humoral immune responses to tumor associated antigens like mesothelin. It is well described that the PC microenvironment is characterized by a fibroinflammatory and immunosuppressive stroma. On these premises several immune-targeted strategies have been developed to harness the adaptable immune system with a goal of improving survival with little toxicity. Cancer vaccines involve the administration of tumor-associated antigens with the goal of inducing an endogenous anti-tumor response. Among several strategies discussed, we will focus on the algenpantucel-L (HyperAcuteTM Pancreas) immunotherapy. Algenpantucel-L is a whole cell immunotherapy consisting of irradiated allogeneic PC cells genetically engineered to express the murine enzyme alpha(1,3) galactosyltransferase (alphaGT), which ultimately leads to hyperacute rejection with complement- and antibody-dependent cytotoxicity. While phase III data in the adjuvant treatment of pancreatic cancer are pending, phase II results have been encouraging, particularly for patients who demonstrated humoral immunologic responses. Novel strategies using immune checkpoint inhibitors, costimulatory antibodies, and combinations with cancer vaccines may overcome immunotolerance and improve treatment success. PMID- 26619247 TI - Passive Sampling in Regulatory Chemical Monitoring of Nonpolar Organic Compounds in the Aquatic Environment. AB - We reviewed compliance monitoring requirements in the European Union, the United States, and the Oslo-Paris Convention for the protection of the marine environment of the North-East Atlantic, and evaluated if these are met by passive sampling methods for nonpolar compounds. The strengths and shortcomings of passive sampling are assessed for water, sediments, and biota. Passive water sampling is a suitable technique for measuring concentrations of freely dissolved compounds. This method yields results that are incompatible with the EU's quality standard definition in terms of total concentrations in water, but this definition has little scientific basis. Insufficient quality control is a present weakness of passive sampling in water. Laboratory performance studies and the development of standardized methods are needed to improve data quality and to encourage the use of passive sampling by commercial laboratories and monitoring agencies. Successful prediction of bioaccumulation based on passive sampling is well documented for organisms at the lower trophic levels, but requires more research for higher levels. Despite the existence of several knowledge gaps, passive sampling presently is the best available technology for chemical monitoring of nonpolar organic compounds. Key issues to be addressed by scientists and environmental managers are outlined. PMID- 26619248 TI - Filling the Green Gap of a Megadalton Photosystem I Complex by Conjugation of Organic Dyes. AB - Photosynthesis is Nature's major process for converting solar into chemical energy. One of the key players in this process is the multiprotein complex photosystem I (PSI) that through absorption of incident photons enables electron transfer, which makes this protein attractive for applications in bioinspired photoactive hybrid materials. However, the efficiency of PSI is still limited by its poor absorption in the green part of the solar spectrum. Inspired by the existence of natural phycobilisome light-harvesting antennae, we have widened the absorption spectrum of PSI by covalent attachment of synthetic dyes to the protein backbone. Steady-state and time-resolved photoluminescence reveal that energy transfer occurs from these dyes to PSI. It is shown by oxygen-consumption measurements that subsequent charge generation is substantially enhanced under broad and narrow band excitation. Ultimately, surface photovoltage (SPV) experiments prove the enhanced activity of dye-modified PSI even in the solid state. PMID- 26619251 TI - Skin biomarkers for neurodegenerative disease: a future perspective. PMID- 26619250 TI - Mechanism of hydrogen activation by [NiFe] hydrogenases. AB - The active site of [NiFe] hydrogenases contains a strictly conserved arginine that suspends a guanidine nitrogen atom <4.5 A above the nickel and iron atoms. The guanidine headgroup interacts with the side chains of two conserved aspartic acid residues to complete an outer-shell canopy that has thus far proved intractable to investigation by site-directed mutagenesis. Using hydrogenase-1 from Escherichia coli, the strictly conserved residues R509 and D574 have been replaced by lysine (R509K) and asparagine (D574N) and the highly conserved D118 has been replaced by alanine (D118A) or asparagine (D118N/D574N). Each enzyme variant is stable, and their [(RS)2NiMU(SR)2Fe(CO)(CN)2] inner coordination shells are virtually unchanged. The R509K variant had >100-fold lower activity than native enzyme. Conversely, the variants D574N, D118A and D118N/D574N, in which the position of the guanidine headgroup is retained, showed 83%, 26% and 20% activity, respectively. The special kinetic requirement for R509 implicates the suspended guanidine group as the general base in H2 activation by [NiFe] hydrogenases. PMID- 26619252 TI - Opportunistic Gram-negative rods' capability of creating biofilm structures on polivynyl chloride and styrene-acronitrile copolymer surfaces. AB - Biofilms are highly organized microbial communities displaying high resistance to disinfectants and other external environmental factors. Medical equipment, such as stents and catheters, can be colonized by a variety of bacteria including opportunistic pathogens circulating in the environment and dangerous to immunocompromised patients. Application of materials resistant to biofilm formation will minimize the risk of patients' infection. Hence, the aim of this research was to determine the biofilm growth of environmental bacteria isolates on polyvinyl chloride and styrene-acronitrile copolymer surfaces. Nine strains (Pseudomonas aeruginosa, Burkholderia cepacia and Serratia liquefacies) isolated from cosmetics, and a reference P. aeruginosa strain ATCC 15442, were tested. The ability and dynamics of biofilm formation on intubation catheters (30 degrees C, up to 24 h) in bacterial growth cultures (10(7)-10(8) CFU/ml) was investigated, with subsequent sonication and quantification by agar plate count method. The results indicated that all the tested bacteria expressed a strong ability for the polymer surface adhesion, reaching 4.6 to 6.7 log CFU/cm(2) after 30 minutes. Moreover, for the majority of strains, the level of 24-hour biofilm production was from 6.67-7.61 log CFU/cm(2). This research indicates that the environmental strains circulating between the cosmetics and patients may pose a threat of biofilm formation on medical equipment surfaces, and presumably in the clinical surroundings as well. PMID- 26619249 TI - A synthetic lethal approach for compound and target identification in Staphylococcus aureus. AB - The majority of bacterial proteins are dispensable for growth in the laboratory but nevertheless have important physiological roles. There are no systematic approaches to identify cell-permeable small-molecule inhibitors of these proteins. We demonstrate a strategy to identify such inhibitors that exploits synthetic lethal relationships both for small-molecule discovery and for target identification. Applying this strategy in Staphylococcus aureus, we have identified a compound that inhibits DltB, a component of the teichoic acid D alanylation machinery that has been implicated in virulence. This D-alanylation inhibitor sensitizes S. aureus to aminoglycosides and cationic peptides and is lethal in combination with a wall teichoic acid inhibitor. We conclude that DltB is a druggable target in the D-alanylation pathway. More broadly, the work described demonstrates a systematic method to identify biologically active inhibitors of major bacterial processes that can be adapted to numerous organisms. PMID- 26619253 TI - Helicobacter pylori antigens, acetylsalicylic acid, LDL and 7-ketocholesterol - their potential role in destabilizing the gastric epithelial cell barrier. An in vitro model of Kato III cells. AB - Colonization of gastric tissue in humans by H. pylori Gram-negative bacteria initiates gastric and duodenal ulcers and even gastric cancers. Infections promote inflammation and damage to gastric epithelium which might be followed by the impairment of its barrier function. The role of H. pylori components in these processes has not been specified. H. pylori cytotoxicity may potentially increase in the milieu of anti-inflammatory drugs including acetylsalicylic acid (ASA). The lipid transport-associated molecule such as low density lipoprotein (LDL), which is a classic risk factor of coronary heart disease (CHD) and 7 ketocholesterol (7-kCh) a product of cholesterol oxidation, which may occur during the oxidative stress in LDL could also be considered as pro-inflammatory. The aim of this study was to evaluate the cytotoxicity of H. pylori antigens, ASA, LDL and 7-kCh towards Kato III gastric epithelial cells, on the basis of the cell ability to reduce tetrazolium salt (MTT) and morphology of cell nuclei assessed by 4',6-diamidino-2-phenylindole (DAPI) staining. Kato III cells were stimulated for 24 h, at 37 degrees C and 5% CO2, with H. pylori antigens: cytotoxin associated gene A (CagA) protein, the urease A subunit (UreA), lipopolysaccharide (LPS) and ASA, LDL or 7-kCh. H. pylori LPS, ASA, LDL and 7 kCh, but not H. pylori glycine acid extract (GE), demonstrated cytotoxicity against Kato III cells, which was related to a diminished percentage of MTT reducing cells and to an increased cell population with the signs of DNA damage. The results suggest that damage to gastric epithelial cells can be induced independently by H. pylori antigens, ASA and endogenous lipid transport associated molecules. During H. pylori infection in vivo, especially in CHD patients, synergistic or antagonistic interactions between these factors might possibly influence the disease course. Further study is necessary to explain these potential effects. PMID- 26619254 TI - The impact of polyphenols on Bifidobacterium growth. AB - Polyphenols are a common group of plant based bioactive compounds, that can affect human health because of their antioxidant and antimicrobial properties as well as free-radical scavenging activity. An increasing interest is observed in the interaction between polyphenols and microbiota occurring in food and the human gut. The aim of the work presented here, was to evaluate the effect of some polyphenolic compounds on the growth of two strains of Bifidobacterium: B. adolescentis and B. bifidum. The influence of some flavonoids: naringinin, hesperidin, rutin, quercetin as well as phenolic acids: gallic, caffeic, p coumaric, ferulic, chlorogenic, vanillic and sinapic was determined by a 96-well microtiter plate assay. In the experiments the effect of three different concentrations of polyphenols: 2, 20 and 100 ug/ml on the growth of Bifidobacterium strains was investigated. All tested compounds influenced the growth of the examined bacteria. Both stimulatory and inhibitory effects were observed in comparison to the positive control. The strongest impact on the growth of bifidobacteria was observed during the first hours of incubation. The constant inhibitory effect was observed for hesperidin and quercetin addition and was dose-dependent. B. bifidum showed a stronger dependence on phenolic acids content in the medium than B. adolescentis during the first hours of incubation. PMID- 26619255 TI - New approaches for improving the production of the 1st and 2nd generation ethanol by yeast. AB - Increase in the production of 1st generation ethanol from glucose is possible by the reduction in the production of ethanol co-products, especially biomass. We have developed a method to reduce biomass accumulation of Saccharomyces cerevisiae by the manipulation of the intracellular ATP level due to overexpression of genes of alkaline phosphatase, apyrase or enzymes involved in futile cycles. The strains constructed accumulated up to 10% more ethanol on a cornmeal hydrolysate medium. Similar increase in ethanol accumulation was observed in the mutants resistant to the toxic inhibitors of glycolysis like 3 bromopyruvate and others. Substantial increase in fuel ethanol production will be obtained by the development of new strains of yeasts that ferment sugars of the abundant lignocellulosic feedstocks, especially xylose, a pentose sugar. We have found that xylose can be fermented under elevated temperatures by the thermotolerant yeast, Hansenula polymorpha. We combined protein engineering of the gene coding for xylose reductase (XYL1) along with overexpression of the other two genes responsible for xylose metabolism in yeast (XYL2, XYL3) and the deletion of the global transcriptional activator CAT8, with the selection of mutants defective in utilizing ethanol as a carbon source using the anticancer drug, 3-bromopyruvate. Resulted strains accumulated 20-25 times more ethanol from xylose at the elevated temperature of 45 degrees C with up to 12.5 g L(-1) produced. Increase in ethanol yield and productivity from xylose was also achieved by overexpression of genes coding for the peroxisomal enzymes: transketolase (DAS1) and transaldolase (TAL2), and deletion of the ATG13 gene. PMID- 26619256 TI - Characterization of two aminotransferases from Candida albicans. AB - Aminoadipate aminotransferase (AmAA) is an enzyme of alpha-aminoadipate pathway (AAP) for L-lysine biosynthesis. AmAA may also participated in biosynthesis or degradation of aromatic amino acids and in D-tryptophan based pigment production. The AAP is unique for fungal microorganisms. Enzymes involved in this pathway have specific structures and properties. These features can be used as potential molecular markers. Enzymes catalyzing reactions of L-lysine biosynthesis in Candida albicans may also become new targets for antifungal chemotherapy. Search of the NCBI database resulted in identification of two putative aminoadipate aminotransferase genes from Candida albicans: ARO8 (ORFs 19.2098 and 19.9645) and YER152C (ORFs 19.1180 and 19.8771). ARO8 from C. albicans exhibits 53% identity to ARO8 from S. cerevisiae, while YER152C exhibits 30% identity to ARO8 and 45% to YER152C from S. cerevisiae. We amplified two genes from the C. albicans genome: ARO8 and YER152C. Both were cloned and expressed as His-tagged fusion proteins in E. coli. The purified Aro8CHp gene product revealed aromatic and alpha-aminoadipate aminotransferase activity. Basic molecular properties of the purified protein were determined. We obtained catalytic parameters of Aro8CHp with aromatic amino acids and aminoadipate (AA) (Km(L-Phe) 0.05+/-0.003 mM, Km(L Tyr) 0.1+/-0.008 mM, Km(L-AA) 0.02+/-0.006 mM) and confirmed the enzyme broad substrate spectrum. The assays also demonstrated that this enzyme may use 2 oxoadipate and 2-oxoglutarate (2-OG) as amino acceptors. Aro8-CHp exhibited pH optima range of 8, which is similar to AmAA from S. cerevisiae. Our results also indicate that CaYer152Cp has a possible role only in aromatic amino acids degradation, in contrast to CaAro8CHp. PMID- 26619257 TI - Theoretical Characterization of the Minimum-Energy Structure of (SF6)2. AB - MP2 and symmetry-adapted perturbation theory calculations are used in conjunction with the aug-cc-pVQZ basis set to characterize the SF6 dimer. Both theoretical methods predict the global minimum structure to be of C2 symmetry, lying 0.07 0.16 kJ/mol below a C2h saddle point structure, which, in turn, is predicted to lie energetically 0.4-0.5 kJ/mol below the lowest-energy D2d structure. This is in contrast with IR spectroscopic studies that infer an equilibrium D2d structure. It is proposed that the inclusion of vibrational zero-point motion gives an averaged structure of D2d symmetry. PMID- 26619260 TI - Bicomponent electrospun scaffolds to design extracellular matrix tissue analogs. AB - In the last decade, bicomponent fibers have been proposed to fabricate bio inspired systems for tissue repair, regenerative medicine, medical healthcare and clinical applications. In comparison with monocomponent fibers, key advantage concerns their ability of self-adapting to the physiological conditions through an extended pattern of signals--morphological, chemical and physical ones- confined at the single fiber level. Hydrophobic/hydrophilic phases may be variously organized by tuneable processing modes (i.e., blending, core/shell, interweaving) thus offering different benefits in terms of biological activity, fluid sorption and molecular transport properties (first generation). The possibility to efficiently graft cell-adhesive proteins and peptide sequences onto the fiber surface mediated by spacers or impregnating hydrogels allows to trigger cell late activities by a controlled and sustained release in vitro of specific biomolecules (i.e., morphogens, growth factors). Here, we introduce an overview of current approaches based on bicomponent fiber use as extra cellular matrix analogs with cell-instructive functions and hierarchal organization of living tissues. PMID- 26619261 TI - La2O2CO3 Encapsulated La2O3 Nanoparticles Supported on Carbon as Superior Electrocatalysts for Oxygen Reduction Reaction. AB - Constructing nanoscale hybrid materials with unique interfacial structures by using various metal oxides and carbon supports as building blocks are of great importance to develop highly active, economical hybrid catalysts for oxygen reduction reaction (ORR). In this work, La2O2CO3 encapsulated La2O3 nanoparticles on a carbon black (La2O2CO3@La2O3/C) were fabricated via chemical precipitation in an aqueous solution containing different concentrations of cetyltrimethyl ammonium bromide (CTAB), followed by calcination at 750 degrees C. At a given CTAB concentration 24.8 mmol/L, the obtained lanthanum compound nanoparticles reach the smallest particle size (7.1 nm) and are well-dispersed on the carbon surface. X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) results demonstrate the formation of La2O2CO3 located on the surface of La2O3 nanoparticles in the hybrid. The synthesized La2O2CO3@La2O3/C hybrid exhibits a significantly enhanced electrocatalytic activity in electrocatalysis experiments relative to pure La2O3, La2O2CO3, and carbon in an alkaline environment, by using the R(R)DE technique. Moreover, its long-term stability also outperforms that obtained by commercial Pt/C catalysts (E-TEK). The exact origin of the fast ORR kinetics is mainly ascribed to the La2O2CO3 layer sandwiched at the interface of carbon and La2O3, which contributes favorable surface-adsorbed hydroxide (-OH( )(ad)) substitution and promotes active oxygen adsorption at the interfaces. The unique covalent -C-O-C(?O)-O-La-O- bonds, formed at the interfaces between La2O2CO3 and carbon, can act as active sites for the improved ORR kinetics over this hybrid catalyst. Therefore, the fabrication of lanthanum compound-based hybrid material with an unique interfacial structure maybe open a new way to develop carbon-supported metal oxides as next-generation of ORR catalysts. PMID- 26619259 TI - Using computer-extracted image phenotypes from tumors on breast magnetic resonance imaging to predict breast cancer pathologic stage. AB - BACKGROUND: The objective of this study was to demonstrate that computer extracted image phenotypes (CEIPs) of biopsy-proven breast cancer on magnetic resonance imaging (MRI) can accurately predict pathologic stage. METHODS: The authors used a data set of deidentified breast MRIs organized by the National Cancer Institute in The Cancer Imaging Archive. In total, 91 biopsy-proven breast cancers were analyzed from patients who had information available on pathologic stage (stage I, n = 22; stage II, n = 58; stage III, n = 11) and surgically verified lymph node status (negative lymph nodes, n = 46; >= 1 positive lymph node, n = 44; no lymph nodes examined, n = 1). Tumors were characterized according to 1) radiologist-measured size and 2) CEIP. Then, models were built that combined 2 CEIPs to predict tumor pathologic stage and lymph node involvement, and the models were evaluated in a leave-1-out, cross-validation analysis with the area under the receiver operating characteristic curve (AUC) as the value of interest. RESULTS: Tumor size was the most powerful predictor of pathologic stage, but CEIPs that captured biologic behavior also emerged as predictive (eg, stage I and II vs stage III demonstrated an AUC of 0.83). No size measure was successful in the prediction of positive lymph nodes, but adding a CEIP that described tumor "homogeneity" significantly improved discrimination (AUC = 0.62; P = .003) compared with chance. CONCLUSIONS: The current results indicate that MRI phenotypes have promise for predicting breast cancer pathologic stage and lymph node status. Cancer 2016;122:748-757. (c) 2015 American Cancer Society. PMID- 26619262 TI - Molecular dynamics of zinc-finger ubiquitin binding domains: a comparative study of histone deacetylase 6 and ubiquitin-specific protease 5. AB - HDAC6 is a unique cytoplasmic histone deacetylase characterized by two deacetylase domains, and by a zinc-finger ubiquitin binding domain (ZnF-UBP) able to recognize ubiquitin (Ub). The latter has recently been demonstrated to be involved in the progression of neurodegenerative diseases and in mediating infection by the influenza A virus. Nowadays, understanding the dynamic and energetic features of HDAC6 ZnF-UBP-Ub recognition is considered as a crucial step for the conception of HDAC6 potential modulators. In this study, the atomic, solvent-related, and thermodynamic features behind HDAC6 ZnF-UBP-Ub recognition have been analyzed through molecular dynamics simulations. The behavior was then compared to the prototypical ZnF-UBP from ubiquitin-specific protease 5 (USP5) in order to spot relevant differences useful for selective drug design. Principal component analysis highlighted flapping motions of the L2A loop which were lowered down upon Ub binding in both systems. While polar and nonpolar interactions involving Ub G75 and G76 residues were also common features stabilizing both complexes, salt bridges showed a different pattern, more significant in HDAC6 ZnF-UBP-Ub, whose energetic contribution in USP5 ZnF-UBP-Ub was compensated by the presence of a more stable bridging water molecule. Whereas molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) free energies of binding were comparable for both systems, in agreement with experiments, computational alanine scanning and free energy decomposition data revealed that HDAC6 E1141 and D1178 are potential hotspots for the design of selective HDAC6 modulators. PMID- 26619263 TI - Automatic tracking of vessel-like structures from a single starting point. AB - The identification of vascular networks is an important topic in the medical image analysis community. While most methods focus on single vessel tracking, the few solutions that exist for tracking complete vascular networks are usually computationally intensive and require a lot of user interaction. In this paper we present a method to track full vascular networks iteratively using a single starting point. Our approach is based on a cloud of sampling points distributed over concentric spherical layers. We also proposed a vessel model and a metric of how well a sample point fits this model. Then, we implement the network tracking as a min-cost flow problem, and propose a novel optimization scheme to iteratively track the vessel structure by inherently handling bifurcations and paths. The method was tested using both synthetic and real images. On the 9 different data-sets of synthetic blood vessels, we achieved maximum accuracies of more than 98%. We further use the synthetic data-set to analyze the sensibility of our method to parameter setting, showing the robustness of the proposed algorithm. For real images, we used coronary, carotid and pulmonary data to segment vascular structures and present the visual results. Still for real images, we present numerical and visual results for networks of nerve fibers in the olfactory system. Further visual results also show the potential of our approach for identifying vascular networks topologies. The presented method delivers good results for the several different datasets tested and have potential for segmenting vessel-like structures. Also, the topology information, inherently extracted, can be used for further analysis to computed aided diagnosis and surgical planning. Finally, the method's modular aspect holds potential for problem-oriented adjustments and improvements. PMID- 26619266 TI - Iodine-Mediated Etching of Gold Nanorods for Plasmonic ELISA Based on Colorimetric Detection of Alkaline Phosphatase. AB - Here, we propose a plasmonic enzyme-linked immunosorbent assay (ELISA) based on highly sensitive colorimetric detection of alkaline phosphatase (ALP), which is achieved by iodine-mediated etching of gold nanorods (AuNRs). Once the sandwich type immunocomplex is formed, the ALP bound on the polystyrene microwells will hydrolyze ascorbic acid 2-phosphate into ascorbic acid. Subsequently, iodate is reduced to iodine, a moderate oxidant, which etches AuNRs from rod to sphere in shape. The shape change of AuNRs leads to a blue-shift of longitudinal localized surface plasmon resonance. As a result, the solution of AuNRs changes from blue to red. Benefiting from the highly sensitive detection of ALP, the proposed plasmonic ELISA has achieved an ultralow detection limit (100 pg/mL) for human immunoglobulin G (IgG). Importantly, the visual detection limit (3.0 ng/mL) allows the rapid differential diagnosis with the naked eye. The further detection of human IgG in fetal bovine serum indicates its applicability to the determination of low abundance protein in complex biological samples. PMID- 26619265 TI - Substrate protein folds while it is bound to the ATP-independent chaperone Spy. AB - Chaperones assist in the folding of many proteins in the cell. Although the most well-studied chaperones use cycles of ATP binding and hydrolysis to assist in protein folding, a number of chaperones have been identified that promote folding in the absence of high-energy cofactors. Precisely how ATP-independent chaperones accomplish this feat is unclear. Here we characterized the kinetic mechanism of substrate folding by the small ATP-independent chaperone Spy from Escherichia coli. Spy rapidly associates with its substrate, immunity protein 7 (Im7), thereby eliminating Im7's potential for aggregation. Remarkably, Spy then allows Im7 to fully fold into its native state while it remains bound to the surface of the chaperone. These results establish a potentially widespread mechanism whereby ATP-independent chaperones assist in protein refolding. They also provide compelling evidence that substrate proteins can fold while being continuously bound to a chaperone. PMID- 26619264 TI - Architecture of the Rix1-Rea1 checkpoint machinery during pre-60S-ribosome remodeling. AB - Ribosome synthesis is catalyzed by ~200 assembly factors, which facilitate efficient production of mature ribosomes. Here, we determined the cryo-EM structure of a Saccharomyces cerevisiae nucleoplasmic pre-60S particle containing the dynein-related 550-kDa Rea1 AAA(+) ATPase and the Rix1 subcomplex. This particle differs from its preceding state, the early Arx1 particle, by two massive structural rearrangements: an ~180 degrees rotation of the 5S ribonucleoprotein complex and the central protuberance (CP) rRNA helices, and the removal of the 'foot' structure from the 3' end of the 5.8S rRNA. Progression from the Arx1 to the Rix1 particle was blocked by mutational perturbation of the Rix1-Rea1 interaction but not by a dominant-lethal Rea1 AAA(+) ATPase-ring mutant. After remodeling, the Rix1 subcomplex and Rea1 become suitably positioned to sense correct structural maturation of the CP, which allows unidirectional progression toward mature ribosomes. PMID- 26619267 TI - 3-Oxo-hexahydro-1H-isoindole-4-carboxylic Acid as a Drug Chiral Bicyclic Scaffold: Structure-Based Design and Preparation of Conformationally Constrained Covalent and Noncovalent Prolyl Oligopeptidase Inhibitors. AB - Bicyclic chiral scaffolds are privileged motifs in medicinal chemistry. Over the years, we have reported covalent bicyclic prolyl oligopeptidase inhibitors that were highly selective for POP over a number of homologous proteins. Herein, we wish to report the structure-based design and synthesis of a novel class of POP inhibitors based on hexahydroisoindoles. A docking study guided the selection of structures for synthesis. The stereochemistry, decoration, and position within the molecule of the bicyclic scaffolds were assessed virtually. Following the synthesis of the best candidates, in vitro assays revealed that one member of this chemical series was more active than any of our previous inhibitors with a Ki of 1.0 nM. Additional assays also showed that the scaffold of this potent inhibitor, in contrast to one of our previously reported chemical series, is highly metabolically stable, despite the foreseen potential sites of metabolism. Interestingly, computer docking calculations accurately predicted the optimal features of the inhibitors. PMID- 26619268 TI - Obtaining consent for the immunization of adults. AB - Effective immunization in adults is a desired health outcome, however it is not mandatory. Immunization of adults must be undertaken in accordance with a patient's real and informed consent. This paper discusses requirements for the lawful administration of an immunization to both capable and incapable adults. PMID- 26619269 TI - Chirality at metal and helical ligand folding in optical isomers of chiral bis(naphthaldiminato)nickel(II) complexes. AB - Enantiopure bis[{(R or S)-N-1-(Ar)ethyl-2-oxo-1-naphthaldiminato kappa(2)N,O}]nickel(ii) complexes {Ar = C6H5 ( or ), p-OMeC6H4 ( or ), and p BrC6H4 ( or )} are synthesized from the reactions between (R or S)-N-1-(Ar)ethyl 2-oxo-1-naphthaldimine and nickel(ii) acetate. Circular-dichroism spectra and their density-functional theoretical simulation reveal the expected mirror image relationship between the enantiomeric pairs / and / in solution. CD spectra are dominated by the metal-centered Lambda- or Delta-chirality of non-planar four coordinated nickel, this latter being in turn dictated by the ligand chirality. Single crystal structure determination for and shows that there are two symmetry independent molecules (A and B) in each asymmetric unit that give a Z' = 2 structure. Two asymmetric and chiral bidentate N^O-chelate Schiff base ligands coordinate to the nickel atom in a distorted square planar N2O2-coordination sphere. The conformational difference between the symmetry-independent molecules arises from the "up-or-down" folding of the naphthaldiminato ligand with respect to the coordination plane, which creates right- (P) or left-handed (M) helical conformations. Overall, the combination of ligand chirality, chirality at the metal and ligand folding gives rise to discrete metal helicates of preferred helicity in a selective way. Cyclic voltammograms (CV) show an oxidation wave at ca. 1.30 V for the [Ni(L)2]/[Ni(L)2](+) couple, and a reduction wave at ca. -0.35 V for the [Ni(L)2]/[Ni(L)2](-) couple in acetonitrile. PMID- 26619270 TI - Free-Standing Graphene Thermophone on a Polymer-Mesh Substrate. AB - A graphene thermoacoustic loudspeaker with a thin polymer mesh is fabricated using screen-printing. An experiment with substrates of various free-standing areas shows that a higher sound pressure level can be achieved as compared to previously reported graphene thermoacoustic loudspeakers. Moreover, a modified equation to predict the sound pressure level of the thermoacoustic loudspeaker with a thin and patterned substrate is proposed and verified by experimental results. PMID- 26619271 TI - Single-Step Fluorocarbon Plasma Treatment-Induced Wrinkle Structure for High Performance Triboelectric Nanogenerator. AB - A triboelectric nanogenerator (TENG) has been thought to be a promising method to harvest energy from environment. To date, the utilization of surface structure and material modification has been considered the most effective way to increase its performance. In this work, a wrinkle structure based high-performance TENG is presented. Using the fluorocarbon plasma treatment method, material modification and surface structure are introduced in one step. The output ability of TENG is dramatically enhanced. After the optimization of plasma treatment, the maximum current and surface charge density are 182 MUA about 165 MUC m(-2). Compared with untreated TENG, the wrinkle structure makes the current and surface charge density increase by 810% and 528%, separately. X-ray photoelectron spectroscopy is employed to analyze the chemical modification mechanism of this fluorocarbon plasma treatment. Facilitated by its high output performance, this device could directly light 76 blue light emitting diodes under finger typing. The output electric energy could be stored then utilized to power a commercial calculator. As a result of the simple fabrication process and high output ability, devices fabricated using this method could bring forward practical applications using TENGs as power sources. PMID- 26619272 TI - Dancing Jaw and Dancing Eyes. PMID- 26619273 TI - Home-based clinical video teleconferencing care: Clinical considerations and future directions. AB - Clinical video teleconferencing (CVT) is a treatment delivery modality that can be used to provide services to clinical populations that experience barriers to accessing mental health care. Recently, home-based CVT (HBCVT) has been developed in order to deliver treatment via CVT to patients in their homes. A number of clinical considerations, including the appropriate clinical population and individual patient factors, need to be taken into account when delivering CVT. Particular challenges can exist when setting up the home environment for HBCVT. Concerns about maintaining patient privacy while living in shared spaces, ensuring adequate CVT technology in the patient's home, and conducting risk management remotely are important to consider when delivering treatment via CVT. Since treatments delivered via CVT are often conducted across state lines, novel ethical and legal issues such as privacy laws, licensing of providers, prescribing practices, and insurance reimbursements need to be addressed when conducting services via these modalities. Future research on HBCVT will provide researchers and clinicians with information regarding which patients are most appropriate for treatment delivered via this modality and help further develop evidence for the cost-effectiveness of CVT and HBCVT clinical practice guidelines. PMID- 26619274 TI - Vibrational anharmonicity of small gold and silver clusters using the VSCF method. AB - We study the vibrational spectra of small neutral gold (Au2-Au10) and silver (Ag2 Au5) clusters using the vibrational self-consistent field method (VSCF) in order to account for anharmonicity. We report harmonic, VSCF, and correlation-corrected VSCF calculations obtained using a vibrational configuration interaction approach (VSCF/VCI). Our implementation of the method is based on an efficient calculation of the potential energy surfaces (PES), using periodic density functional theory (DFT) with a plane-wave pseudopotential basis. In some cases, we use an efficient technique (fast-VSCF) assisted by the Voter-Chen potential in order to get an efficient reduction of the number of pair-couplings between modes. This allows us to efficiently reduce the computing time of 2D-PES without degrading the accuracy. We found that anharmonicity of the gold clusters is very small with maximum rms deviations of about 1 cm(-1), although for some particular modes anharmonicity reaches values slightly larger than 2 cm(-1). Silver clusters show slightly larger anharmonicity. In both cases, large differences between calculated and experimental vibrational frequencies (when available) stem more likely from the quality of the electronic structure method used than from vibrational anharmonicity. We show that noble gas embedding often affects the vibrational properties of these clusters more than anharmonicity, and discuss our results in the context of experimental studies. PMID- 26619276 TI - Pediatric Global Health Education: Past, Present, and Future. AB - Recent outbreaks of diseases erroneously thought by many to be contained by borders or eliminated by vaccines have highlighted the need for proper training of all residents in global health. Beyond infectious diseases, all pediatricians should know how to care for other conditions in global child health, ranging from malnutrition to the nuances of care for immigrant and refugee children. The call for broader education for pediatric residents in global health has been increasing over the last decade, with all major pediatric organizations underscoring its importance in statement and action. Herein, the current status of global child health education in pediatric residency training in the United States is summarized, highlighting where it has been, where it is now, and where it should go next. PMID- 26619275 TI - Dopamine D3 Receptor Mediates Preadolescent Stress-Induced Adult Psychiatric Disorders. AB - Several studies have shown that repeated stressful experiences during childhood increases the likelihood of developing depression- and anxiety-related disorders in adulthood; however, the underlying mechanisms are not well understood. We subjected drd3-EGFP and drd3-null mice to daily, two hour restraint stress episodes over a five day period during preadolescence (postnatal day 35 to 39), followed by social isolation. When these mice reached adulthood (post-natal day > 90), we assessed locomotor behavior in a novel environment, and assessed depression-related behavior in the Porsolt Forced Swim test. We also measured the expression and function of dopamine D3 receptor in limbic brain areas such as hippocampus, nucleus accumbens and amygdala in control and stressed drd3-EGFP mice in adulthood. Adult male mice subjected to restraint stress during preadolescence exhibited both anxiety- and depression-related behaviors; however, adult female mice subjected to preadolescent restraint stress exhibited only depression-related behaviors. The development of preadolescent stress-derived psychiatric disorders was blocked by D3 receptor selective antagonist, SB 277011 A, and absent in D3 receptor null mice. Adult male mice that experienced stress during preadolescence exhibited a loss of D3 receptor expression and function in the amygdala but not in hippocampus or nucleus accumbens. In contrast, adult female mice that experienced preadolescent stress exhibited increased D3 receptor expression in the nucleus accumbens but not in amygdala or hippocampus. Our results suggest that the dopamine D3 receptor is centrally involved in the etiology of adult anxiety- and depression-related behaviors that arise from repeated stressful experiences during childhood. PMID- 26619277 TI - Polymicrobial Oral Infection with Four Periodontal Bacteria Orchestrates a Distinct Inflammatory Response and Atherosclerosis in ApoE null Mice. AB - Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoE null mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression. Polybacterial infections have established gingival colonization in ApoE null hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta. Polybacterial infection induced significantly higher levels of serum risk factors oxidized LDL (p < 0.05), nitric oxide (p < 0.01), altered lipid profiles (cholesterol, triglycerides, Chylomicrons, VLDL) (p < 0.05) as well as accelerated aortic plaque formation in ApoE null mice (p < 0.05). Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis. Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNgamma, IL-1beta, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules. This study demonstrates unique differences in the host immune response to a polybacterial periodontal infection with atherosclerotic lesion progression in a mouse model. PMID- 26619278 TI - Changing Names with Changed Address: Integrated Taxonomy and Species Delimitation in the Holarctic Colymbetes paykulli Group (Coleoptera: Dytiscidae). AB - Species delimitation of geographically isolated forms is a long-standing problem in less studied insect groups. Often taxonomic decisions are based directly on morphologic variation, and lack a discussion regarding sample size and the efficiency of migration barriers or dispersal/migration capacity of the studied species. These problems are here exemplified in a water beetle complex from the Bering Sea region that separates North America from Eurasia. Only a few sampled specimens occur from this particular area and they are mostly found in museum and private collections. Here we utilize the theory of integrated taxonomy to discuss the speciation of the Holarctic Colymbetes paykulli water beetle complex, which historically has included up to five species of which today only two are recognized. Three delimitation methods are used; landmark based morphometry of body shape, variation in reticulation patterns of the pronotum exo-skeleton and sequence variation of the partial mitochondrial gene Cyt b. Our conclusion is that the Palearctic and Nearctic populations of C. paykulli are given the status of separate species, based on the fact that all methods showed significant separation between populations. As a consequence the name of the Palearctic species is C. paykulli Erichson and the Nearctic species should be known as C. longulus LeConte. There is no clear support for delineation between Palearctic and Nearctic populations of C. dahuricus based on mtDNA. However, significant difference in size and reticulation patterns from the two regions is shown. The combined conclusion is that the C. dahuricus complex needs a more thorough investigation to fully disentangle its taxonomic status. Therefore it is here still regarded as a Holarctic species. This study highlights the importance to study several diagnosable characters that has the potential to discriminate evolutionary lineage during speciation. PMID- 26619279 TI - Protocol Improvements for Low Concentration DNA-Based Bioaerosol Sampling and Analysis. AB - INTRODUCTION: As bioaerosol research attracts increasing attention, there is a need for additional efforts that focus on method development to deal with different environmental samples. Bioaerosol environmental samples typically have very low biomass concentrations in the air, which often leaves researchers with limited options in choosing the downstream analysis steps, especially when culture-independent methods are intended. OBJECTIVES: This study investigates the impacts of three important factors that can influence the performance of culture independent DNA-based analysis in dealing with bioaerosol environmental samples engaged in this study. The factors are: 1) enhanced high temperature sonication during DNA extraction; 2) effect of sampling duration on DNA recoverability; and 3) an alternative method for concentrating composite samples. In this study, DNA extracted from samples was analysed using the Qubit fluorometer (for direct total DNA measurement) and quantitative polymerase chain reaction (qPCR). RESULTS AND FINDINGS: The findings suggest that additional lysis from high temperature sonication is crucial: DNA yields from both high and low biomass samples increased up to 600% when the protocol included 30-min sonication at 65 degrees C. Long air sampling duration on a filter media was shown to have a negative impact on DNA recoverability with up to 98% of DNA lost over a 20-h sampling period. Pooling DNA from separate samples during extraction was proven to be feasible with margins of error below 30%. PMID- 26619281 TI - The advantages of creating a positive radiation safety culture in the higher education and research sectors. AB - The safety culture of any organisation plays a critical role in setting the tone for both effective delivery of service and high standards of performance. By embedding safety at a cultural level, organisations are able to influence the attitudes and behaviours of stakeholders. To achieve this requires the ongoing commitment of heads of organisations and also individuals to prioritise safety no less than other competing goals (e.g. in universities, recruitment and retention are key) to ensure the protection of both people and the environment. The concept of culture is the same whatever the sector, e.g. medical, nuclear, industry, education, and research, but the higher education and research sectors within the UK are a unique challenge in developing a strong safety culture. This report provides an overview of the challenges presented by the sector, the current status of radiation protection culture, case studies to demonstrate good and bad practice in the sector and the practical methods to influence change. PMID- 26619282 TI - Effect of Temporal Resolution on Diagnostic Performance of Dynamic Contrast Enhanced Magnetic Resonance Imaging of the Prostate. AB - OBJECTIVE: The aim of this study was to assess the effect of temporal resolution on semiquantitative and pharmacokinetic parameters from dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and their diagnostic accuracy regarding the detection of potentially malignant prostate lesions. MATERIALS AND METHODS: Sixty consecutive male patients (age, 64.5 +/- 7.0 years) with clinically suspected prostate cancer were included. All patients underwent multiparametric MRI of the prostate (T2-weighted, diffusion-weighted imaging, and DCE-MRI) on a 3 T MRI scanner. Patients were divided into 2 groups depending on Prostate Imaging Reporting and Data System (PI-RADS) score of the detected lesions (group A: PI RADS score <=3, n = 30; group B: PI-RADS score >3, n = 30). In all patients, DCE MRI was performed using a CAIPIRINHA-Dixon-TWIST Volume-Interpolated Breath-Hold Examination sequence (spatial resolution, 3 * 1.2 * 1.2 mm; temporal resolution, 5 seconds; total sampling duration, 4:10 minutes [250 seconds]) with body weight adapted administration of contrast agent (gadobutrol, Gadovist; Bayer Healthcare, Berlin, Germany). Six DCE-MRI series with different temporal resolutions ranging from 5 to 30 seconds per time point were retrospectively generated from the original data sets. Semiquantitative parameters (ie, wash-in, wash-out, and time to-peak [TTP]) as well as pharmacokinetic parameters (ie, Ktrans, Kep, and ve) were calculated for the different temporal resolutions. Both lesion groups and all 6 DCE-MRI series were compared regarding semiquantitative and pharmacokinetic parameters. Diagnostic accuracy for the detection of potentially malignant lesions was calculated for all 6 series using ROC analysis. RESULTS: A significant effect of temporal resolution was found on wash-in (P < 0.001). Series with temporal resolution lower than 10 s/time point showed significantly lower wash-in values with more pronounced effects in group B compared with group A. For 30-second series, the differences between both groups diminished reaching insignificant levels (P = 0.052), resulting in a significant decrease of the diagnostic accuracy of wash-in (area under the curve, 0.609; 95% confidence interval, 0.451-0.766; P < 0.015). No significant effects were detected on wash out. For TTP, a significant effect of temporal resolution was detected (P < 0.001) with significantly increasing TTP levels for all down-sampled series compared with the original 5-second series. These effects did not impact the diagnostic accuracy of TTP. No significant effects of temporal resolution were detected on pharmacokinetic parameters (P < 0.112). CONCLUSIONS: In DCE-MRI of the prostate, temporal resolution affects the diagnostic performance of semiquantitative parameters. For a sufficient detection of malignant prostate lesions on DCE-MRI, a temporal resolution of at least 10 s/time point or higher is recommended. PMID- 26619283 TI - Hepatocellular Carcinoma Screening With Computed Tomography Using the Arterial Enhancement Fraction With Radiologic-Pathologic Correlation. AB - OBJECTIVE: The aim of this study was to investigate the performance of the arterial enhancement fraction (AEF) in multiphasic computed tomography (CT) acquisitions to detect hepatocellular carcinoma (HCC) in liver transplant recipients in correlation with the pathologic analysis of the corresponding liver explants. MATERIALS AND METHODS: Fifty-five transplant recipients were analyzed: 35 patients with 108 histologically proven HCC lesions and 20 patients with end stage liver disease without HCC. Six radiologists looked at the triphasic CT acquisitions with the AEF maps in a first readout. For the second readout without the AEF maps, 3 radiologists analyzed triphasic CT acquisitions (group 1), whereas the other 3 readers had 4 contrast acquisitions available (group 2). A jackknife free-response reader receiver operating characteristic analysis was used to compare the readout performance of the readers. Receiver operating characteristic analysis was used to determine the optimal cutoff value of the AEF. RESULTS: The figure of merit (theta = 0.6935) for the conventional triphasic readout was significantly inferior compared with the triphasic readout with additional use of the AEF (theta = 0.7478, P < 0.0001) in group 1. There was no significant difference between the fourphasic conventional readout (theta = 0.7569) and the triphasic readout (theta = 0.7615, P = 0.7541) with the AEF in group 2. Without the AEF, HCC lesions were detected with a sensitivity of 30.7% (95% confidence interval [CI], 25.5%-36.4%) and a specificity of 97.1% (96.0% 98.0%) by group 1 looking at 3 CT acquisition phases and with a sensitivity of 42.1% (36.2%-48.1%) and a specificity of 97.5% (96.4%-98.3%) in group 2 looking at 4 CT acquisition phases. Using the AEF maps, both groups looking at the same 3 acquisition phases, the sensitivity was 47.7% (95% CI, 41.9%-53.5%) with a specificity of 97.4% (96.4%-98.3%) in group 1 and 49.8% (95% CI, 43.9% 55.8%)/97.6% (96.6%-98.4%) in group 2. The optimal cutoff for the AEF was 50%. CONCLUSION: The AEF is a helpful tool to screen for HCC with CT. The use of the AEF maps may significantly improve HCC detection, which allows omitting the fourth CT acquisition phase and thus making a 25% reduction of radiation dose possible. PMID- 26619280 TI - Dancing through Life: Molecular Dynamics Simulations and Network-Centric Modeling of Allosteric Mechanisms in Hsp70 and Hsp110 Chaperone Proteins. AB - Hsp70 and Hsp110 chaperones play an important role in regulating cellular processes that involve protein folding and stabilization, which are essential for the integrity of signaling networks. Although many aspects of allosteric regulatory mechanisms in Hsp70 and Hsp110 chaperones have been extensively studied and significantly advanced in recent experimental studies, the atomistic picture of signal propagation and energetics of dynamics-based communication still remain unresolved. In this work, we have combined molecular dynamics simulations and protein stability analysis of the chaperone structures with the network modeling of residue interaction networks to characterize molecular determinants of allosteric mechanisms. We have shown that allosteric mechanisms of Hsp70 and Hsp110 chaperones may be primarily determined by nucleotide-induced redistribution of local conformational ensembles in the inter-domain regions and the substrate binding domain. Conformational dynamics and energetics of the peptide substrate binding with the Hsp70 structures has been analyzed using free energy calculations, revealing allosteric hotspots that control negative cooperativity between regulatory sites. The results have indicated that cooperative interactions may promote a population-shift mechanism in Hsp70, in which functional residues are organized in a broad and robust allosteric network that can link the nucleotide-binding site and the substrate-binding regions. A smaller allosteric network in Hsp110 structures may elicit an entropy-driven allostery that occurs in the absence of global structural changes. We have found that global mediating residues with high network centrality may be organized in stable local communities that are indispensable for structural stability and efficient allosteric communications. The network-centric analysis of allosteric interactions has also established that centrality of functional residues could correlate with their sensitivity to mutations across diverse chaperone functions. This study reconciles a wide spectrum of structural and functional experiments by demonstrating how integration of molecular simulations and network-centric modeling may explain thermodynamic and mechanistic aspects of allosteric regulation in chaperones. PMID- 26619285 TI - Factors contributing to young moped rider accidents in Denmark. AB - Young road users still constitute a high-risk group with regard to road traffic accidents. The crash rate of a moped is four times greater than that of a motorcycle, and the likelihood of being injured in a road traffic accident is 10 20 times higher among moped riders compared to car drivers. Nevertheless, research on the behaviour and accident involvement of young moped riders remains sparse. Based on analysis of 128 accident protocols, the purpose of this study was to increase knowledge about moped accidents. The study was performed in Denmark involving riders aged 16 or 17. A distinction was made between accident factors related to (1) the road and its surroundings, (2) the vehicle, and (3) the reported behaviour and condition of the road user. Thirteen accident factors were identified with the majority concerning the reported behaviour and condition of the road user. The average number of accident factors assigned per accident was 2.7. Riding speed was assigned in 45% of the accidents which made it the most frequently assigned factor on the part of the moped rider followed by attention errors (42%), a tuned up moped (29%) and position on the road (14%). For the other parties involved, attention error (52%) was the most frequently assigned accident factor. The majority (78%) of the accidents involved road rule breaching on the part of the moped rider. The results indicate that preventive measures should aim to eliminate violations and increase anticipatory skills among moped riders and awareness of mopeds among other road users. Due to their young age the effect of such measures could be enhanced by infrastructural measures facilitating safe interaction between mopeds and other road users. PMID- 26619284 TI - Identifying Loci Contributing to Natural Variation in Xenobiotic Resistance in Drosophila. AB - Natural populations exhibit a great deal of interindividual genetic variation in the response to toxins, exemplified by the variable clinical efficacy of pharmaceutical drugs in humans, and the evolution of pesticide resistant insects. Such variation can result from several phenomena, including variable metabolic detoxification of the xenobiotic, and differential sensitivity of the molecular target of the toxin. Our goal is to genetically dissect variation in the response to xenobiotics, and characterize naturally-segregating polymorphisms that modulate toxicity. Here, we use the Drosophila Synthetic Population Resource (DSPR), a multiparent advanced intercross panel of recombinant inbred lines, to identify QTL (Quantitative Trait Loci) underlying xenobiotic resistance, and employ caffeine as a model toxic compound. Phenotyping over 1,700 genotypes led to the identification of ten QTL, each explaining 4.5-14.4% of the broad-sense heritability for caffeine resistance. Four QTL harbor members of the cytochrome P450 family of detoxification enzymes, which represent strong a priori candidate genes. The case is especially strong for Cyp12d1, with multiple lines of evidence indicating the gene causally impacts caffeine resistance. Cyp12d1 is implicated by QTL mapped in both panels of DSPR RILs, is significantly upregulated in the presence of caffeine, and RNAi knockdown robustly decreases caffeine tolerance. Furthermore, copy number variation at Cyp12d1 is strongly associated with phenotype in the DSPR, with a trend in the same direction observed in the DGRP (Drosophila Genetic Reference Panel). No additional plausible causative polymorphisms were observed in a full genomewide association study in the DGRP, or in analyses restricted to QTL regions mapped in the DSPR. Just as in human populations, replicating modest-effect, naturally-segregating causative variants in an association study framework in flies will likely require very large sample sizes. PMID- 26619286 TI - Powerful Tests for Multi-Marker Association Analysis Using Ensemble Learning. AB - Multi-marker approaches have received a lot of attention recently in genome wide association studies and can enhance power to detect new associations under certain conditions. Gene-, gene-set- and pathway-based association tests are increasingly being viewed as useful supplements to the more widely used single marker association analysis which have successfully uncovered numerous disease variants. A major drawback of single-marker based methods is that they do not look at the joint effects of multiple genetic variants which individually may have weak or moderate signals. Here, we describe novel tests for multi-marker association analyses that are based on phenotype predictions obtained from machine learning algorithms. Instead of assuming a linear or logistic regression model, we propose the use of ensembles of diverse machine learning algorithms for prediction. We show that phenotype predictions obtained from ensemble learning algorithms provide a new framework for multi-marker association analysis. They can be used for constructing tests for the joint association of multiple variants, adjusting for covariates and testing for the presence of interactions. To demonstrate the power and utility of this new approach, we first apply our method to simulated SNP datasets. We show that the proposed method has the correct Type-1 error rates and can be considerably more powerful than alternative approaches in some situations. Then, we apply our method to previously studied asthma-related genes in 2 independent asthma cohorts to conduct association tests. PMID- 26619287 TI - Ultraviolet Exposure and Protection Behavior in the General Population: A Structured Interview Survey. AB - BACKGROUND: Exposure to solar ultraviolet (UV) radiation is a known and controllable risk factor for skin cancer. OBJECTIVE: To study the UV exposure and protection behavior of the general population. METHODS: Structured interview survey. RESULTS: A random sample of 865 volunteers from the EDEN (European Dermato-Epidemiology Network) Fragrance Study cohort was recruited. The individual skin type did not influence the occupation or leisure. The proportion of people who regularly used sunscreens was lower in the oldest age groups, where the risk of skin cancer is highest. Women used sunscreens significantly more frequently than men did and were more likely to have their moles checked by a specialist. CONCLUSIONS: A demand for public information on the risk factors for skin cancer and the role of protection was demonstrated by our study. The subpopulation of aged men represents a relevant target group for educational public campaigns on skin cancer risk avoidance. PMID- 26619289 TI - Effects of Renin-Angiotensin System Inhibitors on Renal Expression of Renalase in Sprague-Dawley Rats Fed With High Salt Diet. AB - BACKGROUND/AIMS: The aim of our study was to investigate the effect of high-salt diet on the renal expression of renalase and the potential role of the local renin-angiotensin system in this process. METHODS: Sprague-Dawley (SD) rats were divided into groups according to salt content in diet and drug treatment as follows: normal-salt diet (NS), high-salt diet (HS), high-salt intake with hydralazine (HS+H), high-salt diet with enalapril (HS+E), and high-salt diet with valsartan (HS+V). The dietary intervention and drugs were given for four weeks. Renin activity and angiotensin II type 1 receptor (AT1R) levels were detected by real-time PCR. Renalase mRNA and protein were also measured. RESULTS: After four weeks, systolic blood pressure and proteinuria were significantly increased in the HS group with respect to the NS group. Dietary salt intake caused a dramatic decrease in renalase expression in the rat kidneys. Renal cortex renin and AT1R increased significantly in the HS and HS+H groups. Urinary protein was positively correlated with renal renin and AT1R levels. However, in the HS+E and HS+V groups, enalapril and valsartan failed to influence renal renalase expression but abolished the increase in proteinuria, renal cortex renin, and AT1R levels with respect to the HS group. CONCLUSION: This study indicates that high salt intake reduces renal expression, and renal RAS may be not involved in the regulation of renalase in SD rats fed with high-salt diet. PMID- 26619288 TI - AtHESPERIN: a novel regulator of circadian rhythms with poly(A)-degrading activity in plants. AB - We report the identification and characterization of a novel gene, AtHesperin (AtHESP) that codes for a deadenylase in Arabidopsis thaliana. The gene is under circadian clock-gene regulation and has similarity to the mammalian Nocturnin. AtHESP can efficiently degrade poly(A) substrates exhibiting allosteric kinetics. Size exclusion chromatography and native electrophoresis coupled with kinetic analysis support that the native enzyme is oligomeric with at least 3 binding sites. Knockdown and overexpression of AtHESP in plant lines affects the expression and rhythmicity of the clock core oscillator genes TOC1 and CCA1. This study demonstrates an evolutionary conserved poly(A)-degrading activity in plants and suggests deadenylation as a mechanism involved in the regulation of the circadian clock. A role of AtHESP in stress response in plants is also depicted. PMID- 26619291 TI - Tamoxifen impairs prepubertal mammary development and alters expression of estrogen receptor alpha (ESR1) and progesterone receptors (PGR). AB - Research has shown that prepubertal heifers experience allometric mammary growth that is influenced by the ovaries. Our purpose was to determine the role of estrogen in prepubertal mammary gland development. Sixteen Holstein calves were randomly assigned to 1 of 2 treatment groups: tamoxifen-injected (TAM) or control (CON). Calves were administered the antiestrogen tamoxifen (0.3 mg kg(1) d(1)) or placebo from 28 to 120 d of age. At 120 d, calves were euthanized and udders removed. Weight and DNA content of trimmed parenchymal tissue were halved (P <= 0.0001) in TAM compared with CON calves. Parenchymal samples from 3 zones of the left rear mammary gland (lower, middle, and outer regions) were processed for immunohistochemical staining for estrogen receptor alpha (ESR1) and progesterone receptor (PGR), Ki67-positive cells, and 5-bromo-2'-deoxyuridine label retaining cells (LRCs). Overall, neither the percentage nor location within the epithelial tissue layer of either ESR1- or PGR-positive cells was impacted by TAM treatment. However, image analysis indicated a 6.2-fold lower (P = 0.0001) level of ESR1 protein expression in TAM calves. Similarly, messenger RNA expression of ESR1 was also reduced (P = 0.0001) in TAM heifers. In contrast, expression of PGR protein was greater by 43% (P = 0.03) in TAM calves, but messenger RNA expression did not differ between treatments. Overall, TAM calves had a higher (P <= 0.03) percentage and density (cells per tissue area) of Ki67-positive cells. Irrespective of treatment, there were also more Ki67-labeled cells in the outer zones of the mammary gland (P <= 0.001). We were able to effectively use multispectral imaging to identify positive cells and quantify the expression of ESR1 and PGR protein. We also identified and counted the proportion of label retaining cells (LCR) (putative epithelial stem cells). We noted an overall 2.9 fold greater number of LRCs in TAM heifers and more LRCs in the outer sampling zones. This suggests that a cohort of LCR cells in TAM remained inactivated in comparison with CON heifers, which exhibited markedly increased growth of the mammary parenchymal tissue over the treatment period. These results suggest that the impacts of ovariectomy are partially explained by loss of ESR1 expression and/or estrogen receptor signaling in the prepubertal bovine mammary gland. The significance of mammary expression of PGR in control of prepubertal bovine mammary development remains unresolved. PMID- 26619290 TI - The association of mood disorders with breast cancer survival: an investigation of linked cancer registration and hospital admission data for South East England. AB - BACKGROUND: Data linkage studies find that depression before or after a breast cancer diagnosis predicts reduced survival. This study aimed to determine whether depression or bipolar recorded in routine hospital admission data independently predicts survival in English breast cancer patients and whether onset in relation to cancer diagnosis is significant. METHODS: Data on 77,173 women diagnosed with breast cancer (ICD-10 C50) in South East England, 2000-2009, were included. Of these, 131 women had a diagnosis of bipolar affective disorder (ICD-10 F31) and 955 of depression (either depressive episodes (ICD-10 F32) or depressive disorder (ICD-10 F33)) recorded in Hospital Episode Statistics between 3 years before and a year following cancer diagnosis. Kaplan-Meier plots were used to examine overall survival. Cox regression analyses were carried out overall and separately for mood disorder diagnoses before and after the cancer diagnosis and adjusted for confounding variables. RESULTS: A record of depression was a predictor of worse overall survival in breast cancer patients (adjusted HR = 1.33, 95% CI: 1.20-1.48, p < 0.001), while the effect of bipolar was not statistically significant (adjusted HR = 1.33, 95% CI: 0.97-1.82, p = 0.079). New recordings of depression and bipolar diagnoses following a cancer diagnosis appeared better predictors of overall survival than a prior history of either. CONCLUSIONS: There is evidence that English breast cancer patients with depression and bipolar recorded in routine hospital data have worse overall survival than those without these mood disorders. Further work exploring the concordance of records within administrative health data with clinical diagnosis and cause-specific death within these patient groups is needed. PMID- 26619293 TI - Central Serous Chorioretinopathy Treatments: A Mini Review. AB - Central serous chorioretinopathy (CSC) is a retinal disorder that primarily affects young (20- to 50-year-old) white men, although it is seen occasionally in older patients and females. CSC is characterized by avascular focal leakage through the retinal pigment epithelium (RPE), resulting in serous detachment of the neurosensory retina. The course is usually self-limiting and in most cases resolves spontaneously within a 3-month period, with visual acuity usually recovering to 20/30 or better. However, chronic CSC may develop as a consequence of recurrences or persistent neurosensory detachment, and can result in progressive RPE atrophy and permanent visual loss. A primary involvement of the RPE and choroidal vascularization play a significant role in the pathogenesis of CSC and the current treatment options attempt to restore the functions of the RPE and the normal choroidal vasculature. The aim of the current review is to provide an overview of the current therapeutical approaches to CSC, including observation, laser treatment, photodynamic therapy with verteporfin, intravitreal anti-vascular endothelial growth factor therapy and the mineralocorticoid receptor antagonists. PMID- 26619292 TI - IgG Suppresses Antibody Responses in Mice Lacking C1q, C3, Complement Receptors 1 and 2, or IgG Fc-Receptors. AB - Antigen-specific IgG antibodies, passively administered to mice or humans together with large particulate antigens like erythrocytes, can completely suppress the antibody response against the antigen. This is used clinically in Rhesus prophylaxis, where administration of IgG anti-RhD prevents RhD-negative women from becoming immunized against RhD-positive fetal erythrocytes aquired transplacentally. The mechanisms by which IgG suppresses antibody responses are poorly understood. We have here addressed whether complement or Fc-receptors for IgG (FcgammaRs) are required for IgG-mediated suppression. IgG, specific for sheep red blood cells (SRBC), was administered to mice together with SRBC and the antibody responses analyzed. IgG was able to suppress early IgM- as well as longterm IgG-responses in wildtype mice equally well as in mice lacking FcgammaRIIB (FcgammaRIIB knockout mice) or FcgammaRI, III, and IV (FcRgamma knockout mice). Moreover, IgG was able to suppress early IgM responses equally well in mice lacking C1q (C1qA knockout mice), C3 (C3 knockout mice), or complement receptors 1 and 2 (Cr2 knockout mice) as in wildtype mice. Owing to the previously described severely impaired IgG responses in the complement deficient mice, it was difficult to assess whether passively administered IgG further decreased their IgG response. In conclusion, Fc-receptor binding or complement-activation by IgG does not seem to be required for its ability to suppress antibody responses to xenogeneic erythrocytes. PMID- 26619294 TI - Formal Synthesis of (+)-Kopsihainanine A and Synthetic Study toward (+) Limaspermidine. AB - The formal synthesis of (+)-kopsihainanine A has been achieved via stereoselective reduction of tetracyclic iminium ion intermediates (24). However, attempts to synthesize (+)-limaspermidine by reduction of the same tetracyclic iminium ion intermediates have failed. The synthesis features a Suzuki cross coupling reaction, a cyclization reaction mediated by trifluoromethanesulfonic anhydride, and stereoselective reduction of an iminium ion. PMID- 26619295 TI - Interdisciplinary Education from a College of Nursing and School of Medicine. AB - We examine a newly designed, interdisciplinary education program and clinical rotation for the first-year obstetrics and gynecology resident, implemented at the University of Colorado, Denver, Colorado, between the College of Nursing midwifery faculty and the School of Medicine Department of Obstetrics and Gynecology. The barriers to program development, along with the advantages and disadvantages of collaboration between nursing and medical schools, are reviewed. The clinical experience, consisting of 5 clinical shifts, was designed using the conceptual model of collaborative intelligence. A formal rotation with the midwife was constructed for the first-year resident on the labor and delivery unit, providing care to intrapartum and postpartum women and families. The program included didactic and clinical teaching, with an emphasis on the normal physiologic process of birth and introduction to the midwifery scope of practice and philosophy of care. Formative evaluation of the clinical rotation demonstrated strong interest for continuation of the program and an ability to appreciate midwifery components of care in a limited exposure. Moreover, program development was successful without requiring large curricular changes for the resident. Future planning includes expansion of the program with increased emphasis on the postpartum and breastfeeding woman and continued program evaluation. The long-term success of such collaborations will depend on the continued support of the American College of Nurse-Midwives and the American Congress of Obstetricians and Gynecologists in developing and improving interdisciplinary educational teams. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health. PMID- 26619296 TI - Melanoma: understanding relevant molecular pathways as well as available and emerging therapies. AB - Since 2011, 6 therapies, including cell signaling kinase inhibitors and immune checkpoint targeting antibodies, have been approved by the FDA for the treatment of melanoma. Due to advancements in research and a greater understanding of the role of the immune system in cancer as well as the molecular biology of melanoma tumors, novel therapies are emerging to combat and effectively manage melanoma tumors. Advances in research are resulting in prolonging rates of survival of patients with metastatic melanoma. Research is ongoing to gain deeper insight to discover (1) which patients are most likely to respond to and benefit from immunotherapy, (2) how to treat patients who have disease progression after treatment with targeted agents, and (3) how best to combine these approved immunologic therapies, targeted drugs, and emerging therapies, as well as their safety and efficacy. PMID- 26619297 TI - Strategies for individualizing management of patients with metastatic melanoma: a managed care perspective. AB - The management of metastatic melanoma has been revolutionized in recent years with the development of both targeted therapy and immunotherapy. Although potentially extending the life expectancy for patients, these therapies also significantly increase the healthcare expenditure. In this paper, we review the monthly costs for drugs approved by the FDA since 2011. Additionally, factors that affect the cost, such as dosing strategies, biomarkers, combination therapies, and political/legislative issues, will be discussed. PMID- 26619300 TI - Cryptic eco-evolutionary dynamics. AB - Natural systems harbor complex interactions that are fundamental parts of ecology and evolution. These interactions challenge our inclinations and training to seek the simplest explanations of patterns in nature. Not least is the likelihood that some complex processes might be missed when their patterns look similar to predictions for simpler mechanisms. Along these lines, theory and empirical evidence increasingly suggest that environmental, ecological, phenotypic, and genetic processes can be tightly intertwined, resulting in complex and sometimes surprising eco-evolutionary dynamics. The goal of this review is to temper inclinations to unquestioningly seek the simplest explanations in ecology and evolution, by recognizing that some eco-evolutionary outcomes may appear very similar to purely ecological, purely evolutionary, or even null expectations, and thus be cryptic. We provide theoretical and empirical evidence for observational biases and mechanisms that might operate among the various links in eco evolutionary feedbacks to produce cryptic patterns. Recognition that cryptic dynamics can be associated with outcomes like stability, resilience, recovery, or coexistence in a dynamically changing world provides added impetus for finding ways to study them. PMID- 26619298 TI - Investigating Tissue Optical Properties and Texture Descriptors of the Retina in Patients with Multiple Sclerosis. AB - PURPOSE: To assess the differences in texture descriptors and optical properties of retinal tissue layers in patients with multiple sclerosis (MS) and to evaluate their usefulness in the detection of neurodegenerative changes using optical coherence tomography (OCT) image segmentation. PATIENTS AND METHODS: 38 patients with MS were examined using Stratus OCT. The raw macular OCT data were exported and processed using OCTRIMA software. The enrolled eyes were divided into two groups, based on the presence of optic neuritis (ON) in the history (MSON+ group, n = 36 and MSON- group, n = 31). Data of 29 eyes of 24 healthy subjects (H) were used as controls. A total of seven intraretinal layers were segmented and thickness as well as optical parameters such as contrast, fractal dimension, layer index and total reflectance were measured. Mixed-model ANOVA analysis was used for statistical comparisons. RESULTS: Significant thinning of the retinal nerve fiber layer (RNFL), ganglion cell/inner plexiform layer complex (GCL+IPL) and ganglion cell complex (GCC, RNFL+GCL+IPL) was observed between study groups in all comparisons. Significant difference was found in contrast in the RNFL, GCL+IPL, GCC, inner nuclear layer (INL) and outer plexiform layer when comparing MSON+ to the other groups. Higher fractal dimension values were observed in GCL+IPL and INL layers when comparing H vs. MSON+ groups. A significant difference was found in layer index in the RNFL, GCL+IPL and GCC layers in all comparisons. A significant difference was observed in total reflectance in the RNFL, GCL+IPL and GCC layers between the three examination groups. CONCLUSION: Texture and optical properties of the retinal tissue undergo pronounced changes in MS even without optic neuritis. Our results may help to further improve the diagnostic efficacy of OCT in MS and neurodegeneration. PMID- 26619301 TI - A novel benzofuran, 4-methoxybenzofuran-5-carboxamide, from Tephrosia purpurea suppressed histamine H1 receptor gene expression through a protein kinase C-delta dependent signaling pathway. AB - Histamine H1 receptor (H1R) gene is upregulated in patients with allergic rhinitis (AR), and its expression level is strongly correlated with the severity of allergic symptoms. We previously reported isolation of the putative anti allergic compound, 4-methoxybenzofuran-5-carboxamide (MBCA) from Tephrosia purpurea and its chemical synthesis (Shill et al., Bioorg Med Chem 2015;23:6869 6874). However, the mechanism underlying its anti-allergic activity remains to be elucidated. Here, we report the mechanism of MBCA on phorbol 12-myristate-13 acetate (PMA)- or histamine-induced upregulation of H1R gene expression in HeLa cells, and in vivo effects of MBCA were also determined in toluene-2,4 diisocyanate (TDI)-sensitized rats. MBCA suppressed PMA- and histamine-induced upregulation of H1R expression at both mRNA and protein levels and inhibited PMA induced phosphorylation of PKCdelta at Tyr(311) and subsequent translocation to the Golgi. Furthermore, MBCA ameliorated allergic symptoms and suppressed the elevation of H1R and helper T cell type 2 (Th2) cytokine mRNAs in TDI-sensitized rats. Data suggest that MBCA alleviates nasal symptoms in TDI-sensitized rats through the inhibition of H1R and Th2 cytokine gene expression. The mechanism of its H1R gene suppression underlies the inhibition of PKCdelta activation. PMID- 26619302 TI - Three-Component Integrated Ultrathin Organic Photosensors for Plastic Optoelectronics. AB - By three-component integration, an integrated organic photosensor is presented using common organic dyes as building blocks. Gray-scale photosensing and signal amplification are achieved in the device within a wide range of light intensities. Moreover, with ultrathin film techniques, 470 nm thick devices are realized and continue to work when harshly bent. PMID- 26619303 TI - A closer look at the hedonics of everyday meaning and satisfaction. AB - Contrasts between eudaimonic well-being and hedonic well-being often compare meaning and happiness. Less work has examined the extent to which meaning and satisfaction can be distinguished. Across 5 diary studies (N = 923) and a large cross-sectional survey (N = 1,471), we examined the affective profile of meaning and satisfaction in everyday life. Using response surface methodology, both judgments were modeled as a joint function of positive (PA) and negative (NA) affect. Affective discrepancy (preponderance of PA over NA) was more strongly associated with satisfaction than meaning. In general, meaning correlated less with affect than satisfaction, but the 2 judgments differ more in their correlation with NA than PA. This implies that people are sometimes able to derive meaning (but not necessarily satisfaction) from negative experiences. We content-coded the events reported by participants for goal directedness, social interactions, and their potential future impact. Interpersonal conflicts and impactful negative events were associated with less satisfaction and meaning at zero-order. However, after controlling for affect and satisfaction, these negative experiences were associated with greater meaning. This effect may reflect additional cognitive processes that enhance meaning but not satisfaction. In all studies, we also observed a positivity dominance effect: At subjectively equivalent levels, PA is weighted more than NA in judgments of meaning and satisfaction. There was no evidence of negativity bias. Results were replicated across different measures and cultural groups (Singapore and the United States). (PsycINFO Database Record PMID- 26619304 TI - Stability and change of personality traits, self-esteem, and well-being: Introducing the meta-analytic stability and change model of retest correlations. AB - The stability of individual differences is a fundamental issue in personality psychology. Although accumulating evidence suggests that many psychological attributes are both stable and change over time, existing research rarely takes advantage of theoretical models that capture both stability and change. In this article, we present the Meta-Analytic Stability and Change model (MASC), a novel meta-analytic model for synthesizing data from longitudinal studies. MASC is based on trait-state models that can separate influences of stable and changing factors from unreliable variance (Kenny & Zautra, 1995). We used MASC to evaluate the extent to which personality traits, life satisfaction, affect, and self esteem are influenced by these different factors. The results showed that the majority of reliable variance in personality traits is attributable to stable influences (83%). Changing factors had a greater influence on reliable variance in life satisfaction, self-esteem, and affect than in personality (42%-56% vs. 17%). In addition, changing influences on well-being were more stable than changing influences on personality traits, suggesting that different changing factors contribute to personality and well-being. Measures of affect were less reliable than measures of the other 3 constructs, reflecting influences of transient factors, such as mood on affective judgments. After accounting for differences in reliability, stability of affect did not differ from other well being variables. Consistent with previous research, we found that stability of individual differences increases with age. (PsycINFO Database Record PMID- 26619305 TI - Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: 10-Color flow cytometry diagnosis and HyperCVAD therapy. AB - Few studies describe the comprehensive immunophenotypic pattern of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in the bone marrow and its treatment. This retrospective analysis evaluates the diagnostic flow cytometry (FCM) pattern and outcome of nine patients diagnosed with BPDCN. A four-tube 10 color FCM panel used for diagnosis of acute leukemia (AL), showed cells in the blast gate (CD45dim/low SSC) and were positive for CD4(bright), CD33(dim), CD56(heterogenous), CD123(bright), CD36, CD38, HLA-DR, CD71. Seven patients received front-line induction therapy with HyperCVAD with an overall response rate of 86%. Five of six responders underwent planned allogeneic hematopoietic cell transplantation (allo-HCT). For a median follow up of 13.3 months, the 1 year disease free survival and overall survival were 56 and 67%, respectively. An accurate diagnosis of BPDCN can be made by 10-color FCM using a four-tube AL panel demonstrating a characteristic pattern of antigen expression. Front-line induction chemotherapy with HyperCVAD can yield high remission rates, but allo HCT is required for long-term durable remissions. PMID- 26619306 TI - A Retrospective 2-Year Clinical Study of Immediate Prosthetic Rehabilitation of Edentulous Jaws with Four Implants and Prefabricated Bars. AB - PURPOSE: The purpose of this retrospective investigation was to evaluate the use of a prefabricated bar system for immediately loaded implants placed and restored according to the All-on-Four concept with up to 24-month follow-up. MATERIALS AND METHODS: A total of 51 patients (31 males and 20 females; mean age 63.4 years) presented with edentulous or partially edentulous jaws with severe atrophy of the posterior regions. All patients were treated with full-arch fixed prostheses (28 maxillary, 34 mandibular) each supported by four implants (two vertical, two distally tilted). The implants were immediately loaded with screw-retained full arch restorations. Each prosthesis was supported by a prefabricated metal bar combined with high-density acrylic resin. Follow-up visits were scheduled at 6, 12, and 24 months after initial prosthetic loading. Intraoral radiographs were obtained immediately after surgery and at each follow-up visit by using a custom radiograph holder and parallel technique. Marginal bone levels were assessed using digital image analysis. Implant and prosthetic survival and success rates were evaluated. Patient satisfaction was further assessed using a 100-mm visual analog scale (VAS). Data were compared by means of the Mantel-Haenszel test. RESULTS: No drop-outs occurred. The overall implant survival rates were 100% and 98.38% for the vertical and tilted implants respectively. Two of the 62 definitive fixed prostheses were lost during the observation period due to implant failure. Since restoration replacement due to implant failure was not judged a prosthodontic failure according to the survival criteria provided in this study, the overall prosthetic survival rate was 100%. No statistically significant differences in marginal bone levels between vertical and tilted implants were detected at 24-month follow-up evaluation in either jaw. All participants were functionally and esthetically satisfied with their definitive restorations after 2 years functioning, as confirmed by the average VAS scores (masticatory function: 99.7; phonetic function: 99.5, esthetics: 99.2). CONCLUSIONS: The preliminary 24-month results indicate that immediate loading of vertical and tilted implants using the evaluated prefabricated bar system may be a viable solution for edentulous jaw rehabilitation; however, more long-term prospective clinical trials are needed to affirm the effectiveness of this surgical-prosthetic protocol. PMID- 26619307 TI - Resident experiences with and post-training plans for cystoscopy at the time of hysterectomy. AB - AIMS: To determine OB/GYN residents' experience with and opinions toward cystoscopy at the time of hysterectomy. STUDY DESIGN: An internet survey of OB/GYN residents assessed utilization of cystoscopy at the time of hysterectomy, familiarity with literature regarding universal versus selective cystoscopy, and plans post residency. RESULTS: Cystoscopy was performed universally in the minority of cases of vaginal hysterectomy (12%), laparoscopically assisted vaginal hysterectomy (14%), supracervical hysterectomy (0%), total abdominal hysterectomy (2%), laparoscopic supracervical hysterectomy (9%), total laparoscopic hysterectomy (27%), and hysterectomy with adnexa removal (5%). Residents planned universal cystoscopy post-training more frequently for all hysterectomy types. CONCLUSION: Cystoscopy at the time of hysterectomy was performed universally in the minority for all hysterectomy categories. For all hysterectomy types, residents planned post-graduation to utilize universal cystoscopy at the time of hysterectomy more often than occurred in training. PMID- 26619308 TI - Differential modulation of claudin 4 expression and myosin light chain phosphorylation by thyroid function in lung injury. AB - BACKGROUND: Trauma and ventilator-induced lung injury is often associated with endothelial-epithelial barriers breakdown, which may lead to multiple system organ failure (MSOF) and death in critically ill patients. Although molecular mechanism involved in MSOF is not known, junctional opening is believed to happen. In vitro, thyroid hormones inhibit myosin light chain (MLC) phosphorylation and may, thus, inhibit cellular contraction and junctional opening. Trauma is also associated with tissue hypo-thyroid state. Therefore, we examined the effects of thyroid function on expression of phospho-MLC (pp-MLC) and claudin 4 (Clud4), key proteins involved in regulation of junctional tightness, in lung injury. METHODS: Rats were rendered hypo-thyroid (Hypo) or hyperthyroid (Hyper) by adding methimazole or levo-thyroxine, respectively, to their drinking water. Untreated euthyroid (Eue) animals were used as control. Lung pp-MLC and Clud4 proteins were assessed by western blotting and in situ immunodetection, respectively. Lung injury was induced by high tidal volume mechanical ventilation. RESULTS: Lung injury was significantly enhanced in Hypo animals and attenuated in Hyper animals. Parallel changes in expression of lung pp-MLC were detected. Alterations in lung histomorphology correlated with the level of pp-MLC. Expression of alveolar and bronchiolar Clud4 protein was differentially affected by the state of thyroid gland. CONCLUSIONS: Our data suggest that thyroid function plays significant role in lung injury perhaps by modulating expression of the proteins involved in junctional tightness. Besides, they strongly support the idea that the tissue hypo-thyroid state may contribute to endothelial-epithelial barriers breakdown associated with trauma. PMID- 26619309 TI - Highly Efficient, Simplified, Solution-Processed Thermally Activated Delayed Fluorescence Organic Light-Emitting Diodes. AB - Highly efficient, simplified, solution-processed thermally activated delayed fluorescence organic light-emitting diodes can be realized by using pure-organic thermally activated delayed fluorescence emitters and a multifunctional buffer hole-injection layer, in which high EQE (~24%) and current efficiency (~73 cd A( 1) ) are demonstrated. High-efficiency fluorescence red-emitting and blue emitting devices can also be fabricated in this manner. PMID- 26619310 TI - Application of novel catalytic-ceramic-filler in a coupled system for long-chain dicarboxylic acids manufacturing wastewater treatment. AB - To gain systematic technology for long-chain dicarboxylic acids (LDCA) manufacturing wastewater treatment, catalytic micro-electrolysis (CME) coupling with adsorption-biodegradation sludge (AB) process was studied. Firstly, novel catalytic-ceramic-filler was prepared from scrap iron, clay and copper sulfate solution and packed in the CME reactor. To remove residual n-alkane and LDCA, the CME reactor was utilized for LDCA wastewater pretreatment. The results revealed that about 94% of n-alkane, 98% of LDCA and 84% of chemical oxygen demand (COD) were removed by the aerated CME reactor at the optimum hydraulic retention time (HRT) of 3.0 h. In this process, catalysis from Cu and montmorillonites played an important role in improving the contaminants removal. Secondly, to remove residual COD in the wastewater, AB process was designed for the secondary biological treatment, about 90% of the influent COD could be removed by biosorption, bio-flocculation and biodegradation effects. Finally, the effluent COD (about 150 mg L(-1)) discharged from the coupled CME-AB system met the requirement of the national discharged standard (COD <= 300 mg L(-1)). All of these results suggest that the coupled CME-AB system is a promising technology due to its high-efficient performance, and has the potential to be applied for the real LDCA wastewater treatment. PMID- 26619311 TI - Anodic fabrication of advanced titania nanotubes photocatalysts for photoelectrocatalysis decolorization of Orange G dye. AB - Titania nanotubes (TNTs) were fabricated on Ti mesh substrates by the anodizing technique. The effects of preparation variables, such as anodizing voltage, time and calcination temperature on the textural characteristics and photocatalytic activity of TNTs were investigated. The surface morphology, crystalline phase, and chemical composition were analyzed using field emission-scanning electron microscopy and X-ray diffraction. The photo-electrochemical properties of TNTs were examined by voltammetry. The TNTs were tested as a photoanode for advanced oxidation processes, such as photocatalytic, electrocatalytic, and photoelectrocatalytic decolorization of Orange G dye. The well-arranged TNTs electrode prepared in this work showed a high photocurrent density of 101 uA cm( 2) at an optimum length-to-diameter aspect ratio of 31.2. In dye decolorization tests, the electrochemical photocatalytic system using TNTs as the photoanode achieved total decolorization and 64% mineralization under extended reaction time. These results show that TNTs prepared by this method is greatly stable in prolonged use and suitable as a photoanode in the photocatalytic/photoelectrocatalytic treatments of dye wastewater. PMID- 26619312 TI - Dietary intake polycyclic aromatic hydrocarbons (PAHs) and associated cancer risk in a cohort of Chinese urban adults: Inter- and intra-individual variability. AB - Dietary intake is one of the major exposure pathways of polycyclic aromatic hydrocarbons (PAHs), especially in Chinese people because foods are often prepared with grilling and/or frying that would produce high levels of PAHs. In this paper, we assessed daily dietary intakes (DDI) of PAHs, using a "duplicate plate method", among 100 Chinese urban residents. The DDI of benzo(a)pyrene ranged from 0.06 ug per day to 13.5 ug per day with a median of 0.69 ug per day, varying largely across subjects. The median Incremental Lifetime Cancer Risk (ILCR) attributable to PAH dietary intake was 6.65 * 10(-5) (4.41 * 10(-5) to 1.02 * 10(-4) as inter-quartile range). The contribution of several high-PAH containing foods like barbecued, smoked or deep-fried meats to the overall DDIs was about 13%. The use of raw foods may underestimate dietary intake of PAHs and associated exposure risk considerably. Results from foods sampled in different seasons suggested that seasonal variability within an individual may contribute notably to overall variability measured in a population and more future studies with longer-term investigation on food ingestion and pollutant exposure are needed. The study indicates that measuring actually consumed foods is more appropriate for dietary intake exposure assessment, and intra-individual variance should be taken into account during study design and data analysis. PMID- 26619313 TI - Ecotoxicological effects of earthworm following long-term Dechlorane Plus exposure. AB - Dechlorane Plus (DP), similar to persistent organic pollutants, has been widely detected in environmental matrices, especially in sediment and soil. In this study, earthworms Eisenia fetida were exposed to 0.1, 0.5, 6.25 and 12.5 mg kg( 1) DP for 28 d. Lethality, oxidative stress, neurotoxicity and cellulase of E. fetida were assessed to investigate ecotoxicological effects of DP after long term exposure. Results showed that the direct toxicity of DP was very low. However, death rate, as well as SOD activity, together with changes in activities of CAT, GSH-Px, and GSH levels, indicating that oxidative stress may play a significant role in DP exposure. In addition, DP also changes the AChE and cellulase activity of earthworms even under low DP concentration after long-term exposure. Moreover, comet assay results showed that DP exposure increased the levels of tDNA significantly (p < 0.05) even in the lowest treatment (0.1 mg kg( 1) DP). Combined with the results of enzyme activity, oxidative damage and comet assay, it can be suggested that earthworms experience more stress of DP during long-time exposure. This study provides insight into the toxicological effects of DP on earthworm model, and may be useful for risk assessment of DP on soil ecosystems. PMID- 26619314 TI - A study on the toxigenesis by Clostridium botulinum in nitrate and nitrite reduced dry fermented sausages. AB - Nitrite has been traditionally used to control Clostridium botulinum in cured meat products. However, in the case of dry fermented sausages, environmental factors such as pH, aw and the competitive microbiota may exert a more relevant role than nitrite in the inhibition of the growth and toxin production by C. botulinum. In this challenge test study, two varieties of Mediterranean dry sausages (salchichon and fuet) were inoculated with spores of C. botulinum Group I (proteolytic) and C. botulinum Group II (nonproteolytic). Sausages were prepared with 150 mg/kg of NaNO3 and 150 mg/kg of NaNO2 (maximum ingoing amounts allowed by the European Union regulation), with a 25% and 50% reduction, and without nitrate/nitrite. The initial pH in both products was 5.6, and decreased to values below 5.0 in salchichon and to 5.2 in fuet. Lactic acid bacteria counts reached 8-9 log cfu/g after fermentation. The aw decreased from initial values of 0.96 to about 0.88-0.90 at the end of ripening. Botulinum neurotoxin was not detected in any of the sausages, including those manufactured without nitrate and nitrite. Despite the environmental conditions were within the range for germination and growth of C. botulinum Group I during the first 8 days of the ripening process in fuet and 10-12 days in salchichon, acidity, aw and incubation temperature combined to inhibit the production of toxin, independently of the concentration of curing agents. Although decreasing or even removing nitrate/nitrite from the formula did not compromise safety regarding C. botulinum in the conditions tested in this study, their antimicrobial role should not be underestimated in the case that other hurdles could fail or other ripening conditions were used, and also considering the effect of nitrite on other pathogens. PMID- 26619315 TI - Rapid prediction of ochratoxin A-producing strains of Penicillium on dry-cured meat by MOS-based electronic nose. AB - The availability of rapid diagnostic methods for monitoring ochratoxigenic species during the seasoning processes for dry-cured meats is crucial and constitutes a key stage in order to prevent the risk of ochratoxin A (OTA) contamination. A rapid, easy-to-perform and non-invasive method using an electronic nose (e-nose) based on metal oxide semiconductors (MOS) was developed to discriminate dry-cured meat samples in two classes based on the fungal contamination: class P (samples contaminated by OTA-producing Penicillium strains) and class NP (samples contaminated by OTA non-producing Penicillium strains). Two OTA-producing strains of Penicillium nordicum and two OTA non producing strains of Penicillium nalgiovense and Penicillium salamii, were tested. The feasibility of this approach was initially evaluated by e-nose analysis of 480 samples of both Yeast extract sucrose (YES) and meat-based agar media inoculated with the tested Penicillium strains and incubated up to 14 days. The high recognition percentages (higher than 82%) obtained by Discriminant Function Analysis (DFA), either in calibration and cross-validation (leave-more out approach), for both YES and meat-based samples demonstrated the validity of the used approach. The e-nose method was subsequently developed and validated for the analysis of dry-cured meat samples. A total of 240 e-nose analyses were carried out using inoculated sausages, seasoned by a laboratory-scale process and sampled at 5, 7, 10 and 14 days. DFA provided calibration models that permitted discrimination of dry-cured meat samples after only 5 days of seasoning with mean recognition percentages in calibration and cross-validation of 98 and 88%, respectively. A further validation of the developed e-nose method was performed using 60 dry-cured meat samples produced by an industrial-scale seasoning process showing a total recognition percentage of 73%. The pattern of volatile compounds of dry-cured meat samples was identified and characterized by a developed HS SPME/GC-MS method. Seven volatile compounds (2-methyl-1-butanol, octane, 1R-alpha pinene, d-limonene, undecane, tetradecanal, 9-(Z)-octadecenoic acid methyl ester) allowed discrimination between dry-cured meat samples of classes P and NP. These results demonstrate that MOS-based electronic nose can be a useful tool for a rapid screening in preventing OTA contamination in the cured meat supply chain. PMID- 26619317 TI - Small GTPases and their guanine-nucleotide exchange factors and GTPase-activating proteins in neutrophil recruitment. AB - PURPOSE OF REVIEW: The review describes the roles of Rho- and Rap-guanosine triphosphatases (GTPases) and of their activators, guanine-nucleotide exchange factors (GEFs), and inhibitors, GTPase activating proteins (GAPs), in neutrophil recruitment from the blood stream into inflamed tissues, with a focus on recently identified roles in neutrophils, endothelial cells, and platelets. RECENT FINDINGS: Recent studies have identified important roles of Rho- and Rap-GTPases, and of their GEFs and GAPs, in the neutrophil recruitment cascade. These proteins control the upregulation and/or activation of adhesion molecules on the surface of neutrophils, endothelial cells, and platelets, and they alter cell/cell adhesion in the vascular endothelium. This enables the capture of neutrophils from the blood stream, their migration along and through the vessel wall, and their passage into the inflamed tissue. In particular, it has recently become clear that P-Rex and Vav family Rac-GEFs in platelets are crucial for neutrophil recruitment. SUMMARY: These recent findings have contributed greatly to our understanding of the signalling pathways that control neutrophil recruitment to sites of inflammation and have opened up new avenues of research in this field. PMID- 26619316 TI - Streptomyces strains producing mitochondriotoxic antimycin A found in cereal grains. AB - Reasons for mammalian cell toxicity observed in barley and spring wheat grains were sought. Streptomyces sp. isolates from wheat and barley produced heat-stable methanol-soluble substances which inhibited the motility of exposed porcine spermatozoa used as a toxicity indicator. Several barley isolates produced antimycin A (2 to 5 ng/mg wet wt of biomass), a macrolide antibiotic known to block oxygen utilization in mitochondria. The antimycin-producing isolates were members of the Streptomyces albidoflavus group. In in vitro assays with porcine kidney tubular epithelial cells, the specific toxicity of antimycin A towards mitochondria was higher than that of the mycotoxin enniatin B but lower than that of the mitochondriotoxins cereulide and paenilide, produced by food-related Bacillus cereus and Paenibacillus tundrae, respectively. The toxic wheat isolates, related to Streptomyces sedi, did not produce antimycin A and or any other known toxin. Our results suggest that the presence of toxin-producing streptomycetes in stored cereal grains may pose a thus far unrecognized threat for food and feed safety. PMID- 26619318 TI - Cyclo[6]aramide-Tropylium Charge Transfer Complex as a Colorimetric Chemosensor for Differentiation of Intimate and Loose Ion Pairs. AB - Shape-persistent iso-C16-cyclo[6]aramide (1) was found to form a charge-transfer (CT) complex with aromatic carbonium tropylium (Tr(+)). The resulting CT complex was evidenced by both experimental results and theoretical calculations. Particularly, dibutylammonium salt with PF6(-) as the counterion can extrude Tr(+) from the CT complex, but it cannot do so with Cl(-), thereby offering a visual approach to identify organic intimate ion pairs and loose ion pairs. PMID- 26619319 TI - Expressions of Senescence-Associated beta-Galactosidase and Senescence Marker Protein-30 are Associated with Lens Epithelial Cell Apoptosis. AB - BACKGROUND To investigate associations of senescence marker protein-30 and senescence-associated beta-galactosidase expression with lens epithelial cells apoptosis among Chinese age-related cataract patients. MATERIAL AND METHODS A total of 145 age-related cataract patients (69 cases with nuclear cataract in 91 eyes and 76 cases of cortical cataract with 102 eyes) were enrolled in our study. An annular tear of the central part of anterior lens capsules was performed for each patient. Immunohistochemical staining and real-time PCR were used to detect the protein and mRNA expression levels, and TUNEL was used to assess lens epithelial cells apoptosis. Comparisons of protein expression levels and lens epithelial cells apoptosis were made between the 2 groups. RESULTS The results showed a higher protein expression level of senescence marker protein-30 in surrounding parts of the anterior lens capsule compared with the central part of the anterior lens capsule; however, the positive rate of senescence-associated beta-galactosidase was remarkably higher in the central part than in the surrounding part. Compared with cortical cataract patients, nuclear cataract patients had elevated senescence marker protein-30 protein and mRNA expression levels, but had a decreased positive rate of senescence-associated beta galactosidase. TUNEL results showed that the lens epithelial cell apoptosis rate was higher in the central part of the anterior lens capsule than in the surrounding part in both groups. Within either central or surrounding area of anterior lens capsule, cortical cataract patients exhibited a significantly higher lens epithelial cell apoptosis rate in contrast with nuclear cataract patients. CONCLUSIONS Our study results suggest that senescence marker protein-30 and senescence-associated beta-galactosidase expressions in both nuclear cataract and cortical cataract patients were associated with lens epithelial cells apoptosis. PMID- 26619320 TI - Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human. AB - The importance of tumor associated neutrophils (TANs) in cancer development is in the meantime well established. Numerous of clinical data document the adverse prognostic effects of neutrophil infiltration in solid tumors. However, certain tumor therapies need functional neutrophils to be effective, suggesting altered neutrophil polarization associated with different outcomes for cancer patients. Therefore, modulation of neutrophilic phenotypes represents a potent therapeutic option, but factors mediating neutrophil polarization are still poorly defined. In this manuscript we provide evidence that type I IFNs alter neutrophilic phenotype into anti-tumor, both in mice and human. In the absence of IFN-beta, pro-tumor properties, such as reduced tumor cytotoxicity with low neutrophil extracellular traps (NETs) expression, low ICAM1 and TNF-alpha expression, dominated neutrophil phenotypes in primary lesion and premetastatic lung. Interestingly, such neutrophils have significantly prolonged life-span. Notably, interferon therapy in mice altered TAN polarization towards anti-tumor N1. Similar changes in neutrophil activation could be observed in melanoma patients undergoing type I IFN therapy. Altogether, these data highlight the therapeutic potential of interferons, suggesting optimization of its clinical use as potent anti-tumor agent. PMID- 26619321 TI - Prosocial behavior and childhood trajectories of internalizing and externalizing problems: The role of neighborhood and school contexts. AB - This study investigated the role of the interaction between prosocial behavior and contextual (school and neighborhood) risk in children's trajectories of externalizing and internalizing problems at ages 3, 5, and 7. The sample was 9,850 Millennium Cohort Study families who lived in England when the cohort children were aged 3. Neighborhood context was captured by the proportion of subsidized (social rented) housing in the neighborhood and school context by school-level achievement. Even after adjustment for child- and family-level covariates, prosocial behavior was related both to lower levels of problem behavior at school entry and to its trajectory before and after. Neighborhood social housing was related to the trajectory of problem behavior, and school level achievement to lower levels of problem behavior at school entry. The negative association between prosocial and problem behavior was stronger for children attending low-performing schools or living in disadvantaged neighborhoods. The adverse "effect" of low prosocial behavior, associated with low empathy and guilt and with constricted emotionality, on internalizing and externalizing problems appears to be exacerbated in high-risk contexts. PMID- 26619322 TI - Developmental change in social responsibility during adolescence: An ecological perspective. AB - Social responsibility can be defined as a set of prosocial values representing personal commitments to contribute to community and society. Little is known about developmental change-and predictors of that change-in social responsibility during adolescence. The present study used an accelerated longitudinal research design to investigate the developmental trajectory of social responsibility values and ecological assets across family, school, community, and peer settings that predict these values. Data come from a 3-year study of 3,683 U.S. adolescents enrolled in upper-level elementary, middle, and high schools in rural, semiurban, and urban communities. Social responsibility values significantly decreased from age 9 to 16 before leveling off in later adolescence. Family compassion messages and democratic climate, school solidarity, community connectedness, and trusted friendship, positively predicted within-person change in adolescents' social responsibility values. These findings held after accounting for other individual-level and demographic factors and provide support for the role of ecological assets in adolescents' social responsibility development. In addition, fair society beliefs and volunteer experience had positive between- and within-person associations with social responsibility values. The manuscript discusses theoretical and practical implications of the conclusion that declines in ecological assets may partly explain age-related declines in social responsibility values. (PsycINFO Database Record PMID- 26619323 TI - Stability and change in executive function abilities from late adolescence to early adulthood: A longitudinal twin study. AB - Executive functions (EFs)-the higher level cognitive abilities that enable us to control our own thoughts and actions-continue to develop into early adulthood, yet no longitudinal study has examined their stability during the important life transition from late adolescence to young adulthood. In this twin study (total N = 840 individuals from 424 families), we examined the stability of individual differences in 3 EF components across a 6-year period, from approximately age 17 years (Wave 1) to 23 years (Wave 2). Specifically, we address the following questions: (a) How stable are individual differences in multiple EFs across this time period? and (b) What (genetic and/or environmental) influences affect stability and change in EFs? Results indicated that individual differences in EFs are quite stable across this 6-year period (phenotypic latent variable correlations ranged from 0.86 to 1.0). However, there was evidence for change, particularly in the factor common to multiple EFs (Common EF). Multivariate twin models suggested that stability was due almost entirely to high genetic correlations across time; there was no new genetic variance at Wave 2. Change in Common EF was due to small but significant nonshared environmental influences at Wave 2 (15%). The results suggest that individual differences in EFs are quite heritable and stable by late adolescence, yet are still sensitive to environmental influences. PMID- 26619324 TI - Absent Thalami Caused by a Homozygous EARS2 Mutation: Expanding Disease Spectrum of LTBL. AB - Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) is caused by autosomal recessive EARS2 mutations. Onset is most often in infancy, but in severe cases in the neonatal period. Patients typically have magnetic resonance imaging (MRI) signal abnormalities involving the thalamus, brainstem, and deep cerebral white matter. Most signal abnormalities resolve, but in severe cases at the expense of tissue loss. Here, we report a patient with an encephalopathy of antenatal onset. His early MRI at 8 months of age showed signal abnormalities in the deep cerebral white matter that improved over time. The thalami were absent with the configuration of a developmental anomaly, without evidence of a lesion. We hypothesized that this was a case of LTBL in which the thalamic damage occurred antenatally and was incorporated in the normal brain development. The diagnosis was confirmed by a novel homozygous EARS2 mutation. Our case adds to the phenotypic and genetic spectrum of LTBL. PMID- 26619326 TI - Electron States of Uniaxially Strained Graphene. AB - We report an experimental study of electron states and the resulting electronic transport properties of uniaxially strained graphene. For this study we developed a novel strain application method that is compatible with the planar device technology. We identify the value of the strain induced in graphene by Raman spectroscopy and show with atomic force microscopy that its topography consists of wrinkles up to 4 nm height aligned along the direction of the applied strain. Transport experiments reveal a broadening of the charge neutrality region and the convergence of Landau levels to multiple Dirac points in Landau-fan diagrams. These observations are consistent with large fluctuations of the scalar potential via the strain-induced wrinkles, which is experimentally observed for the first time. PMID- 26619325 TI - Identification of fungal pathogens in a patient with acute myelogenic leukemia using a pathogen detection array technology. AB - Invasive zygomycosis in immunocompromised patients results in a high mortality rate, and early identification is crucial to optimize therapy and to reduce morbidity. However, diagnosing specific species of zygomycetes fungi possess challenge in the clinical laboratories. A need for a rapid and sensitive diagnostic tool for early recognition of a zygomycetes fungus in clinical samples to the species level will lead to prompt and accurate therapy and the PathoChip provides one such platform. We utilized a pathogen array technology referred to as PathoChip, comprised of oligonucleotide probes that can detect all the sequenced viruses as well as known pathogenic bacteria, fungi and parasites and family-specific conserved probes, thus providing a means for detecting previously uncharacterized members of a family. We rapidly identified a zygomycetous fungus, Rhizomucor pusillus, an otherwise challenge for the clinical laboratories, predominantly in a patient with acute myelogenous leukemia. This report highlights the value of PathoChip as a diagnostic tool to identify micro organisms to the species level, especially for those difficult to identify in most clinical laboratories. It will also help clinicians to obtain a critical snapshot of the infection profile of a patient to plan treatment strategies. PMID- 26619327 TI - Threat captures attention but does not affect learning of contextual regularities. AB - Some of the stimulus features that guide visual attention are abstract properties of objects such as potential threat to one's survival, whereas others are complex configurations such as visual contexts that are learned through past experiences. The present study investigated the two functions that guide visual attention, threat detection and learning of contextual regularities, in visual search. Search arrays contained images of threat and non-threat objects, and their locations were fixed on some trials but random on other trials. Although they were irrelevant to the visual search task, threat objects facilitated attention capture and impaired attention disengagement. Search time improved for fixed configurations more than for random configurations, reflecting learning of visual contexts. Nevertheless, threat detection had little influence on learning of the contextual regularities. The results suggest that factors guiding visual attention are different from factors that influence learning to guide visual attention. PMID- 26619328 TI - Correction: Large-Scale Range Collapse of Hawaiian Forest Birds under Climate Change and the Need 21st Century Conservation Options. PMID- 26619329 TI - Multi-targeting Peptide-Functionalized Nanoparticles Recognized Vasculogenic Mimicry, Tumor Neovasculature, and Glioma Cells for Enhanced Anti-glioma Therapy. AB - Chemotherapy failure of glioma, the most aggressive and devastating cancer, might be ascribed to the physiologic barriers of the tumor mainly including heterogeneous tumor perfusion and vascular permeability, which result in a limited penetration of chemotherapeutics. Besides, the vasculogenic mimicry (VM) channels, which are highly resistant to anti-angiogenic therapy and serve as a complement of angiogenesis, were abound in glioma and always associated with tumor recurrence. In order to enhance the therapy effect of anti-glioma, we developed a PEG-PLA-based nanodrug delivery system (nanoparticles, NP) in this study and modified its surface with CK peptide, which was composed of a human sonic hedgehog (SHH) targeting peptide (CVNHPAFAC) and a KDR targeting peptide (K237) through a GYG linker, for facilitating efficient VM channels, tumor neovasculature, and glioma cells multi-targeting delivery of paclitaxel. In vitro cellular assay showed that CK-NP-PTX not only exhibited the strongest antiproliferation effect on U87MG cells and HUVEC cells but also resulted in the most efficient destruction of VM channels when compared with CVNHPAFAC-NP, K237 NP, and the unmodified ones. Besides, CK-NP accumulated more selectively at the glioma site as demonstrated by in vivo and ex vivo imaging. As expected, the glioma-bearing mice treated with CK-NP-PTX achieved the longest median survival time compared to those treated with CVNHPAFAC-NP-PTX and K237-NP-PTX. These findings indicated that the multi-targeting therapy mediated by CK peptide might provide a promising way for glioblastoma therapy. PMID- 26619331 TI - Training Models in Pediatric Minimally Invasive Surgery: Rabbit Model Versus Porcine Model: A Comparative Study. AB - AIM: The porcine model is the most widely used animal model for laparoscopic training. However, in pediatric surgery, an experimental setting with smaller animals could improve the training conditions. We compared the efficiency of a rabbit model versus the porcine model for training in pediatric minimally invasive surgery (MIS). MATERIALS AND METHODS: At the training center of Cardarelli Hospital in Naples, Italy, 10 young pediatric surgeons underwent training sessions on rabbit and porcine models under the supervision of five experienced tutors. The results of four laparoscopic techniques (inguinal hernia repair, varicocelectomy [basic procedures], nephrectomy, and fundoplication [advanced procedures]) were evaluated in regard to mean operative time, intraoperative complications, and surgical performances. Results were analyzed using Fisher's exact test and Student's t test. RESULTS: Practitioners were significantly more confident in the rabbit model compared with the pig model, especially for advanced procedures (P = .03). The overall surgical performance score (ranging from 0 [unacceptable] to 10 [excellent]) was significantly higher in the rabbit model compared with the pig model (8.1 versus 6.0; P = .01). The most significant scoring differences between the surgical performances of the trainees in the two models were reported in regard to dissection, suturing and knot-tying, tissue handling, and handling of instruments. In addition, the length of surgery for advanced procedures was statistically shorter in the rabbit model compared with the pig model (P = .01). We found that only the performances of those who started on the pig had a significantly higher improvement when transitioning to the rabbit compared with those who started on the rabbit (P = .01). Of the trainees, 90% preferred the rabbit model to the pig model. CONCLUSIONS: On the basis of our preliminary results, rabbits are preferred over pigs as the training model in pediatric MIS. In the rabbit model it is possible to perform more procedures and perform them more easily compared with the porcine model. The rabbit model provides a comfortable approach to technical training in basic and advanced laparoscopic procedures. PMID- 26619330 TI - Responders to Wide-Pulse, High-Frequency Neuromuscular Electrical Stimulation Show Reduced Metabolic Demand: A 31P-MRS Study in Humans. AB - Conventional (CONV) neuromuscular electrical stimulation (NMES) (i.e., short pulse duration, low frequencies) induces a higher energetic response as compared to voluntary contractions (VOL). In contrast, wide-pulse, high-frequency (WPHF) NMES might elicit--at least in some subjects (i.e., responders)--a different motor unit recruitment compared to CONV that resembles the physiological muscle activation pattern of VOL. We therefore hypothesized that for these responder subjects, the metabolic demand of WPHF would be lower than CONV and comparable to VOL. 18 healthy subjects performed isometric plantar flexions at 10% of their maximal voluntary contraction force for CONV (25 Hz, 0.05 ms), WPHF (100 Hz, 1 ms) and VOL protocols. For each protocol, force time integral (FTI) was quantified and subjects were classified as responders and non-responders to WPHF based on k-means clustering analysis. Furthermore, a fatigue index based on FTI loss at the end of each protocol compared with the beginning of the protocol was calculated. Phosphocreatine depletion (DeltaPCr) was assessed using 31P magnetic resonance spectroscopy. Responders developed four times higher FTI's during WPHF (99 +/- 37 * 10(3) N.s) than non-responders (26 +/- 12 * 10(3) N.s). For both responders and non-responders, CONV was metabolically more demanding than VOL when DeltaPCr was expressed relative to the FTI. Only for the responder group, the ?PCr/FTI ratio of WPHF (0.74 +/- 0.19 M/N.s) was significantly lower compared to CONV (1.48 +/- 0.46 M/N.s) but similar to VOL (0.65 +/- 0.21 M/N.s). Moreover, the fatigue index was not different between WPHF (-16%) and CONV (-25%) for the responders. WPHF could therefore be considered as the less demanding NMES modality--at least in this subgroup of subjects--by possibly exhibiting a muscle activation pattern similar to VOL contractions. PMID- 26619332 TI - Representation of Patients With Kidney Disease in Trials of Cardiovascular Interventions: An Updated Systematic Review. PMID- 26619333 TI - Clinical and Surgical Predictors of Complications Following Surgery for the Treatment of Cervical Spondylotic Myelopathy: Results From the Multicenter, Prospective AOSpine International Study of 479 Patients. AB - BACKGROUND: Surgery for cervical spondylotic myelopathy (CSM) is generally safe and effective. Nonetheless, complications occur in 11% to 38% of patients. Knowledge of important predictors of complications will help clinicians identify high-risk patients and institute prevention and management strategies. OBJECTIVE: To identify clinical and surgical predictors of perioperative complications in CSM patients. METHODS: Four hundred seventy-nine surgical CSM patients were enrolled in the prospective CSM-International study at 16 sites. A panel of physicians reviewed all adverse events and classified each as related or unrelated to surgery. Univariate analyses were performed to determine differences between patients who experienced a perioperative complication and those who did not. A complication prediction rule was developed using multiple logistic regression. RESULTS: Seventy-eight patients experienced 89 perioperative complications (16.25%). On univariate analysis, the major clinical risk factors were ossification of the posterior longitudinal ligament (OPLL) (P = .055), number of comorbidities (P = .002), comorbidity score (P = .006), diabetes mellitus (P = .001), and coexisting gastrointestinal (P = .039) and cardiovascular (P = .046) disorders. Patients undergoing a 2-stage surgery (P = .002) and those with a longer operative duration (P = .001) were at greater risk of perioperative complications. A final prediction model consisted of diabetes mellitus (odds ratio [OR] = 1.96, P = .060), number of comorbidities (OR = 1.20, P = .069), operative duration (OR = 1.07, P = .002), and OPLL (OR = 1.75, P = .040). CONCLUSION: Surgical CSM patients have a higher risk of perioperative complications if they have a greater number of comorbidities, coexisting diabetes mellitus, OPLL, and a longer operative duration. Surgeons can use this information to discuss the risks and benefits of surgery with patients, to plan case-specific preventive strategies, and to ensure appropriate management in the perioperative period. ABBREVIATIONS: BMI, body mass indexCSM, cervical spondylotic myelopathymJOA, modified Japanese Orthopaedic AssociationOPLL, ossification of the posterior longitudinal ligament. PMID- 26619334 TI - Intracerebral Hematoma Due to Aneurysm Rupture: Are There Risk Factors Beyond Aneurysm Location? AB - BACKGROUND: Along with subarachnoid hemorrhage (SAH), a ruptured aneurysm may also cause an intracerebral hematoma (ICH), which negatively impacts the functional outcome of SAH. OBJECTIVE: To identify independent risk factors of aneurysmal ICH. METHODS: Six hundred thirty-two consecutive patients with aneurysmal SAH treated at our institution from January 2005 to December 2012 were eligible for this study. Demographic parameters and preexisting comorbidities of patients, as well as various clinical and radiographic characteristics of SAH were correlated with the incidence and volume of aneurysmal ICH. RESULTS: One hundred fifty-five patients (25%) had ICH on initial computed tomography with a mean volume of 26.7 mL (+/-26.8 mL). Occurrence and volume of ICH were associated with the location (distal anterior or middle cerebral artery >proximal anterior cerebral or internal carotid artery >posterior circulation, P < .001/P < .001) and size (>12 mm, P = .026/P < .001) of the ruptured aneurysm. Vascular risk factors independently increased the risk of ICH as well (arterial hypertension: odds ratio [OR] = 1.62, P = .032; diabetes mellitus: OR = 3.06, P = .009), while the use of aspirin (P = .037) correlated with the volume of ICH. The predictors of ICH were included into a risk score (0-9 points) that strongly predicted the occurrence of ICH (P = .01). Poor functional outcome after SAH was independently associated with the occurrence of ICH (P = .003, OR = 2.77) and its volume (P = .001, OR = 1.07 per-mL-increase). CONCLUSION: Aneurysmal ICH is strongly associated with poorer functional outcome and seems to be predictable even before the bleeding event. The proposed risk factors for aneurysmal ICH require further validation and may be considered for treatment decisions regarding unruptured intracranial aneurysms. ABBREVIATIONS: ACA, anterior cerebral arteryDHC, decompressive hemicraniectomyEVD, external ventricular drainageICA, internal carotid arteryICH, intracerebral hematomaMCA, middle cerebral arterymRS, modified Rankin scalePC, posterior circulationSAH, subarachnoid hemorrhageSIRS, systemic inflammatory response syndromeTCD, transcranial Doppler sonography. PMID- 26619335 TI - Assessment of Impact of Long-Cassette Standing X-Rays on Surgical Planning for Cervical Pathology: An International Survey of Spine Surgeons. AB - BACKGROUND: Understanding the role of regional segments of the spine in maintaining global balance has garnered significant attention recently. Long cassette radiographs (LCR) are necessary to evaluate global spinopelvic alignment. However, it is unclear how LCRs impact operative decision-making for cervical spine pathology. OBJECTIVE: To evaluate whether the addition of LCRs results in changes to respondents' operative plans compared to standard imaging of the involved cervical spine in an international survey of spine surgeons. METHODS: Fifteen cases (5 control cases with normal and 10 test cases with abnormal global alignment) of cervical pathology were presented online with a vignette and cervical imaging. Surgeons were asked to select a surgical plan from 6 options, ranging from the least (1 point) to most (6 points) extensive. Cases were then reordered and presented again with LCRs and the same surgical plan question. RESULTS: One hundred fifty-seven surgeons completed the survey, of which 79% were spine fellowship trained. The mean response scores for surgical plan increased from 3.28 to 4.0 (P = .003) for test cases with the addition of LCRs. However, no significant changes (P = .10) were identified for the control cases. In 4 of the test cases with significant mid thoracic kyphosis, 29% of participants opted for the more extensive surgical options of extension to the mid and lower thoracic spine when they were provided with cervical imaging only, which significantly increased to 58.3% upon addition of LCRs. CONCLUSION: In planning for cervical spine surgery, surgeons should maintain a low threshold for obtaining LCRs to assess global spinopelvic alignment. PMID- 26619336 TI - In Reply: Petroclival Synchondrosis and Its Relevance to Operative Feel. PMID- 26619337 TI - Letter: Petroclival Synchondrosis and Its Relevance to Operative Feel. PMID- 26619339 TI - Longitudinal assessment of medical student attitudes toward older people. AB - Delivering adequate care to older people requires an increasing number of physicians competent in the treatment of this expanding subpopulation. Attitudes toward older adults are important as predictors of the quality of care of older people and of medical trainee likelihood to enter the geriatrics field. This study assessed the attitudes of 404 US medical students (MS) from the start of medical school to graduation using the University of California, Los Angeles (UCLA) Geriatrics Attitude Scale. It is the first study to utilize a longitudinal design to assess attitudes among students in a medical school with a longitudinal geriatrics clinical experience in the first two years and a required geriatrics clerkship in the third year. Participants' attitude scores toward older people were found to significantly decrease from 3.9 during the first two years to 3.7 during the final two. Significant differences existed between MS1 and MS3, MS1 and MS4, MS2 and MS3, and MS2 and MS4. Women and older students held significantly more positive attitudes than men and younger students. These results show that planned clinical exposures to older adults may not be sufficient to halt the decline in attitudes in medical school. A comprehensive empathy-building intervention embedded in the curriculum may better prevent this decline. PMID- 26619340 TI - Diabetes Prevalence in Sweden at Present and Projections for Year 2050. AB - BACKGROUND: Data on the future diabetes burden in Scandinavia is limited. Our aim was to project the future burden of diabetes in Sweden by modelling data on incidence, prevalence, mortality, and demographic factors. METHOD: To project the future burden of diabetes we used information on the prevalence of diabetes from the national drug prescription registry (adults >= 20 years), previously published data on relative mortality in people with diabetes, and population demographics and projections from Statistics Sweden. Alternative scenarios were created based on different assumptions regarding the future incidence of diabetes. RESULTS: Between 2007 and 2013 the prevalence of diabetes rose from 5.8 to 6.8% in Sweden but incidence remained constant at 4.4 per 1000 (2013). With constant incidence and continued improvement in relative survival, prevalence will increase to 10.4% by year 2050 and the number of afflicted individuals will increase to 940 000. Of this rise, 30% is accounted for by changes in the age structure of the population and 14% by improved relative survival in people with diabetes. A hypothesized 1% annual rise in incidence will result in a prevalence of 12.6% and 1 136 000 cases. Even with decreasing incidence at 1% per year, prevalence of diabetes will continue to increase. CONCLUSION: We can expect diabetes prevalence to rise substantially in Sweden over the next 35 years as a result of demographic changes and improved survival among people with diabetes. A dramatic reduction in incidence is required to prevent this development. PMID- 26619341 TI - Protic Ruthenium Tris(pyrazol-3-ylmethyl)amine Complexes Featuring a Hydrogen Bonding Network in the Second Coordination Sphere. AB - We synthesized ruthenium complexes bearing a tris(pyrazol-3-ylmethyl)amine ligand LH3 and revealed that this tripodal ligand allows predictable accumulation of three proton-delivering NH groups around a coordination site. The Bronsted acidity of the NH groups in LH3 led to the formation of multiple hydrogen bonds with the substrate ligand and deprotonation. The chlorido complex ligated by LH3 catalyzed disproportionation of 1,2-diphenylhydrazine. PMID- 26619343 TI - Somatosensory Rehabilitation for Neuropathic Pain in Burn Survivors: A Case Series. AB - Neuropathic pain is an enormous rehabilitation challenge that has a substantial negative effect on patient function and quality of life. Somatosensory rehabilitation is a novel, nonpharmacological intervention described by Spicher based on the neuroplasticity of the somatosensory system. The rationale for somatosensory rehabilitation is that treating hypoesthesia will decrease neuropathic pain. Particularly for those with established neuropathic pain, the hypoesthesia may be masked by mechanical allodynia, which must be treated before treating the underlying hyposensitive zone. This case series describes the outcome of 17 burn survivors treated with somatosensory rehabilitation for their neuropathic pain. Before initiating treatment a modified version of the McGill Pain Questionnaire-short form (Questionnaire de la douleur St. Antoine, QDSA) was completed with the patients. The total score (*/64) was converted to percentage. The mechanical allodynia was assessed with the Rainbow Pain Scale that uses touch with the 15-g Semmes Weinstein Monofilaments (SWMs) and that was rated as painful on the visual analog scale (3/10 or resting pain + 1/10), as the criteria for mechanical allodynia. The severity level was assessed using seven predetermined SWMs to identify the smallest that elicited pain. The treatment consisted of avoiding all touch in the allodynic zone while concurrently providing proximal sensory and vibratory counter stimulation. Once the mechanical allodynia was eliminated, the underlying hypoesthesia was treated. Hypoesthesia was evaluated with the SWMs, and the percent improvement from baseline was calculated. The sensory reeducation treatment for hypoesthesia consisted of touch discrimination, texture perception, and vibratory stimulation. Seventeen patients (71/29% male/female, 21 +/- 25% TBSA burned, 486 +/- 596 days postburn) were evaluated and treated. Of these 15 initially presented with mechanical allodynia. The SWM scores had improved by 27 +/- 21% (n = 14) and 29 +/- 26% (n = 12) at 2 and 3 months posttreatment, respectively. The QDSA scores had improved by 9 +/- 14% (n = 8) and 23 +/- 23% (n = 6) at 2 and 3 months posttreatment, respectively. There were two patients who initially presented with hypoesthesia and six who had their zone of hypoesthesia treated after the mechanical allodynia had resolved. For these eight patients, their ability to perceive light touch improved by 27 +/- 17% (n = 8) and 35 +/- 25% (n = 6) at 2 and 3 months postsensory reeducation treatment initiation, respectively. The QDSA improved by 9 and 50% for the two patients who initially presented with hypoesthesia. In this case series, the majority of patients (13/17 or 76%) showed substantial improvements after somatosensory rehabilitation suggesting this is a treatment approach that should be considered with burn survivors experiencing neuropathic pain. There is a need, however, for future controlled studies to further investigate this approach and to determine if there is a subpopulation of burn survivors that are more likely than others to benefit from this approach. PMID- 26619338 TI - Cost-Effectiveness of Peer Counselling for the Promotion of Exclusive Breastfeeding in Uganda. AB - BACKGROUND: Community based breastfeeding promotion programmes have been shown to be effective in increasing breastfeeding prevalence. However, there is limited data on the cost-effectiveness of these programmes in sub-Saharan Africa. This paper evaluates the cost-effectiveness of a breastfeeding promotion intervention targeting mothers and their 0 to 6 month old children. METHODS: Data were obtained from a community randomized trial conducted in Uganda between 2006-2008, and supplemented with evidence from several studies in sub-Saharan Africa. In the trial, peer counselling was offered to women in intervention clusters. In the control and intervention clusters, women could access standard health facility breastfeeding promotion services (HFP). Thus, two methods of breastfeeding promotion were compared: community based peer counselling (in addition to HFP) and standard HFP alone. A Markov model was used to calculate incremental cost effectiveness ratios between the two strategies. The model estimated changes in breastfeeding prevalence and disability adjusted life years. Costs were estimated from a provider perspective. Uncertainty around the results was characterized using one-way sensitivity analyses and a probabilistic sensitivity analysis. FINDINGS: Peer counselling more than doubled the breastfeeding prevalence as reported by mothers, but there was no observable impact on diarrhoea prevalence. Estimated incremental cost-effectiveness ratios were US$68 per month of exclusive or predominant breastfeeding and U$11,353 per disability adjusted life year (DALY) averted. The findings were robust to parameter variations in the sensitivity analyses. CONCLUSIONS: Our strategy to promote community based peer counselling is unlikely to be cost-effective in reducing diarrhoea prevalence and mortality in Uganda, because its cost per DALY averted far exceeds the commonly assumed willingness-to-pay threshold of three times Uganda's GDP per capita (US$1653). However, since the intervention significantly increases prevalence of exclusive or predominant breastfeeding, it could be adopted in Uganda if benefits other than reducing the occurrence of diarrhoea are believed to be important. PMID- 26619344 TI - Variations in Environmental Signals in Tree-Ring Indices in Trees with Different Growth Potential. AB - We analysed two groups of Quercus robur trees, growing at nearby plots with different micro-location condition (W-wet and D-dry) in the floodplain Krakovo forest, Slovenia. In the study we compared the growth response of two different tree groups to environmental variables, the potential signal stored in earlywood (EW) structure and the potential difference of the information stored in carbon isotope discrimination of EW and latewood (LW). For that purpose EW and LW widths and carbon isotope discrimination for the period 1970-2008 AD were measured. EW and LW widths were measured on stained microscopic slides and chronologies were standardised using the ARSTAN program. alpha-cellulose was extracted from pooled EW and LW samples and homogenized samples were further analysed using an elemental analyser and IRMS. We discovered that W oaks grew significantly better over the whole analysed period. The difference between D and W oaks was significant in all analysed variables with the exception of stable carbon isotope discrimination in latewood. In W oaks, latewood widths correlated with summer (June to August) climatic variables, while carbon isotope discrimination was more connected to River Krka flow during the summer. EW discrimination correlated with summer and autumn River Krka flow of the previous year, while latewood discrimination correlated with flow during the current year. In the case of D oaks, the environmental signal appears to be vague, probably due to less favourable growth conditions resulting in markedly reduced increments. Our study revealed important differences in responses to environmental factors between the two oak groups of different physiological conditions that are preconditioned by environmental stress. Environmental information stored in tree-ring features may vary, even within the same forest stand, and largely depends on the micro environment. Our analysis confirmed our assumptions that separate EW and LW analysis of widths and carbon isotope discrimination provides complementary information in Q. robur dendroecology. PMID- 26619345 TI - Upregulation of Nicotinic Acetylcholine Receptor alph4+beta2 through a Ligand Independent PI3Kbeta Mechanism That Is Enhanced by TNFalpha and the Jak2/p38Mapk Pathways. AB - High affinity nicotine-binding sites in the mammalian brain are neuronal nicotinic acetylcholine receptors (nAChR) assembled from at least alpha4 and beta2 subunits into pentameric ion channels. When exposed to ligands such as nicotine, these receptors respond by undergoing upregulation, a correlate of nicotine addiction. Upregulation can be measured using HEK293 (293) cells that stably express alpha4 and beta2 subunits using quantification of [3H]epibatidine ([3H]Eb) binding to measure mature receptors. Treatment of these cells with choline also produces upregulation through a hemicholinium3 (HC3)-sensitive (choline kinase) and an HC3-insensitive pathway which are both independent of the mechanism used by nicotine for upregulation. In both cases, upregulation is significantly enhanced by the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha) which signals through its receptor Tnfr1 to activate p38Mapk. Here we report that the inhibition of class1 phosphoinositide 3-kinases isoform PI3Kbeta using the selective antagonist PI828 is alone sufficient to produce upregulation and enhance both nicotine and choline HC3-sensitive mediated upregulation. Further, these processes are impacted upon by an AG-490 sensitive Jak2-associated pathway. Both PI3Kbeta (negative) and Jak2 (positive) modulation of upregulation converge through p38Mapk and both overlap with TNFalpha enhancement of this process. Upregulation through the PI3Kbeta pathway did not require Akt. Collectively these findings support upregulation of endogenous alpha4beta2 as a balance among cellular signaling networks that are highly responsive to multiple environmental, inflammatory and metabolic agents. The findings also suggest how illness and metabolic stress could alter the expression of this important nicotinic receptor and novel avenues to intercede in modifying its expression. PMID- 26619346 TI - Predicting the Role of IL-10 in the Regulation of the Adaptive Immune Responses in Mycobacterium avium Subsp. paratuberculosis Infections Using Mathematical Models. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is an intracellular bacterial pathogen that causes Johne's disease (JD) in cattle and other animals. The hallmark of MAP infection in the early stages is a strong protective cell mediated immune response (Th1-type), characterized by antigen-specific gamma interferon (IFN-gamma). The Th1 response wanes with disease progression and is supplanted by a non-protective humoral immune response (Th2-type). Interleukin-10 (IL-10) is believed to play a critical role in the regulation of host immune responses to MAP infection and potentially orchestrate the reversal of Th1/Th2 immune dominance during disease progression. However, how its role correlates with MAP infection remains to be completely deciphered. We developed mathematical models to explain probable mechanisms for IL-10 involvement in MAP infection. We tested our models with IL-4, IL-10, IFN-gamma, and MAP fecal shedding data collected from calves that were experimentally infected and followed over a period of 360 days in the study of Stabel and Robbe-Austerman (2011). Our models predicted that IL-10 can have different roles during MAP infection, (i) it can suppress the Th1 expression, (ii) can enhance Th2 (IL-4) expression, and (iii) can suppress the Th1 expression in synergy with IL-4. In these predicted roles, suppression of Th1 responses was correlated with increased number of MAP. We also predicted that Th1-mediated responses (IFN-gamma) can lead to high expression of IL-10 and that infection burden regulates Th2 suppression by the Th1 response. Our models highlight areas where more experimental data is required to refine our model assumptions, and further test and investigate the role of IL-10 in MAP infection. PMID- 26619348 TI - Obituary: Monty Winston Charles (1944-2015). PMID- 26619347 TI - Virulence Attributes and Host Response Assays for Determining Pathogenic Potential of Pseudomonas Strains Used in Biotechnology. AB - Pseudomonas species are opportunistically pathogenic to humans, yet closely related species are used in biotechnology applications. In order to screen for the pathogenic potential of strains considered for biotechnology applications, several Pseudomonas strains (P.aeruginosa (Pa), P.fluorescens (Pf), P.putida (Pp), P.stutzeri (Ps)) were compared using functional virulence and toxicity assays. Most Pa strains and Ps grew at temperatures between 28 degrees C and 42 degrees C. However, Pf and Pp strains were the most antibiotic resistant, with ciprofloxacin and colistin being the most effective of those tested. No strain was haemolytic on sheep blood agar. Almost all Pa, but not other test strains, produced a pyocyanin-like chromophore, and caused cytotoxicity towards cultured human HT29 cells. Murine endotracheal exposures indicated that the laboratory reference strain, PAO1, was most persistent in the lungs. Only Pa strains induced pro-inflammatory and inflammatory responses, as measured by elevated cytokines and pulmonary Gr-1 -positive cells. Serum amyloid A was elevated at >= 48 h post exposure by only some Pa strains. No relationship was observed between strains and levels of peripheral leukocytes. The species designation or isolation source may not accurately reflect pathogenic potential, since the clinical strain Pa10752 was relatively nonvirulent, but the industrial strain Pa31480 showed comparable virulence to PAO1. Functional assays involving microbial growth, cytotoxicity and murine immunological responses may be most useful for identifying problematic Pseudomonas strains being considered for biotechnology applications. PMID- 26619349 TI - Correlation Analysis of Trp-Cage Dynamics in Folded and Unfolded States. AB - A fundamental and still debated problem is how folded structures of proteins are related to their unfolded state. Besides the classical view, in which a large number of conformations characterize the unfolded state while the folded one is dominated by a single structure, recently a reassessment of the denatured state has been suggested. A growing amount of evidence indicates that not only the folded but also the unfolded state is at least partially organized. Here, we try to answer the question of how different protein dynamics is in folded and unfolded states by performing all-atom molecular dynamics simulations on the model protein Trp-cage. Random matrix theory inspired analysis of the correlation matrices has been carried out. The spectra of these correlation matrices show that the low rank modes of Trp-cage dynamics are outside of the limit expected for a random system both in folded and in unfolded conditions. These findings shed light on the nature of the unfolded state of the proteins, suggesting that it is much less random than previously thought. PMID- 26619350 TI - Evaluation of antiviral therapy performed after curative therapy in patients with hepatitis B virus-related hepatocellular carcinoma: An updated meta-analysis. PMID- 26619351 TI - Fine-Tuning of Crystal Packing and Charge Transport Properties of BDOPV Derivatives through Fluorine Substitution. AB - Molecular packing in organic single crystals greatly influences their charge transport properties but can hardly be predicted and designed because of the complex intermolecular interactions. In this work, we have realized systematic fine-tuning of the single-crystal molecular packing of five benzodifurandione based oligo(p-phenylenevinylene) (BDOPV)-based small molecules through incorporation of electronegative fluorine atoms on the BDOPV backbone. While these molecules all exhibit similar column stacking configurations in their single crystals, the intermolecular displacements and distances can be substantially modified by tuning of the amounts and/or the positions of the substituent fluorine atoms. Density functional theory calculations showed that the subtle differences in charge distribution or electrostatic potential induced by different fluorine substitutions play an important role in regulating the molecular packing of the BDOPV compounds. Consequently, the electronic couplings for electron transfer can vary from 71 meV in a slipped stack to 201 meV in a nearly cofacial antiparallel stack, leading to an increase in the electron mobility of the BDOPV derivatives from 2.6 to 12.6 cm(2) V(-1) s(-1). The electron mobility of the five molecules did not show a good correlation with the LUMO levels, indicating that the distinct difference in charge transport properties is a result of the molecular packing. Our work not only provides a series of high-electron-mobility organic semiconductors but also demonstrates that fluorination is an effective approach for fine-tuning of single-crystal packing modes beyond simply lowering the molecular energy levels. PMID- 26619352 TI - Aging, Spatial Disparity, and the Sound-Induced Flash Illusion. AB - The present study examined age-related differences in multisensory integration and the effect of spatial disparity on the sound-induced flash illusion--an illusion used in previous research to assess age-related differences in multisensory integration. Prior to participation in the study, both younger and older participants demonstrated their ability to detect 1-2 visual flashes and 1 2 auditory beep presented unimodally. After passing the pre-test, participants were then presented 1-2 flashes paired with 0-2 beeps that originated from one of five speakers positioned equidistantly 100 cm from the participant. One speaker was positioned directly below the screen, two speakers were positioned 50 cm to the left and right from the center of the screen, and two more speakers positioned to the left and right 100 cm from the center of the screen. Participants were told to report the number of flashes presented and to ignore the beeps. Both age groups showed a significant effect of the beeps on the perceived number of flashes. However, neither younger nor older individuals showed any significant effect of spatial disparity on the sound-induced flash illusion. The presence of a congruent number of beeps increased accuracy for both older and younger individuals. Reaction time data was also analyzed. As expected, older individuals showed significantly longer reaction times when compared to younger individuals. In addition, both older and younger individuals showed a significant increase in reaction time for fusion trials, where two flashes and one beep are perceived as a single flash, as compared to congruent single flash trials. This increase in reaction time was not found for fission trials, where one flash and two beeps were perceived as two flashes. This suggests that processing may differ for the two forms for fission as compared to fusion illusions. PMID- 26619353 TI - Interactions of conjugate vaccines and co-administered vaccines. AB - Conjugate vaccines play an important role in the prevention of infectious diseases such as those caused by the bacteria Haemophilus influenzae (Hi) type b (Hib), Neisseria meningitidis, and Streptococcus pneumoniae. Vaccines developed against these 3 pathogens utilize 3 main carrier proteins, non-toxic mutant of diphtheria toxin (CRM197), diphtheria toxoid (DT) and tetanus toxoid (TT). Current pediatric immunisation schedules include the administration of several vaccines simultaneously, therefore increasing the potential for immune interference (both positively and negatively) to the antigens administered. Knowledge of vaccine interactions is principally derived from clinical trials, these are reviewed here to explore immune interference which may result of from carrier-specific T-cell helper interactions, bystander interference and carrier induced epitopic suppression. PMID- 26619354 TI - Payer and Policy Maker Steps to Support Value-Based Pricing for Drugs. PMID- 26619355 TI - A randomized, double-blind trial on the use of 1% hydrocortisone cream for the prevention of acute radiation dermatitis. AB - BACKGROUND: To determine whether the application of 1% hydrocortisone cream during radiation therapy can prevent the occurrence of moist desquamation. METHODS: Fifty adult female breast carcinoma patients were randomized after modified radical mastectomy and chemotherapy to receive prophylactic placebo cream (n = 27) or 1% hydrocortisone cream (n = 23) during radiation therapy. The patients, caregiver and assessor were all blinded to the treatment received. Occurrence of moist desquamation, severity of acute radiation dermatitis (ARD) and hyperpigmentation were evaluated weekly until the end of radiotherapy. RESULTS & CONCLUSION: Five patients in each group developed moist desquamation; however, its extent and severity were milder in the steroid group. Mean ARD scores were also lower in the steroid group (0.713 vs. 0.874, p = 0.024). A lower incidence of Grades 1 and 2 radiation dermatitis was also noted in the steroid group at weeks 2 and 4, respectively, indicating prophylactic use of steroids delayed the onset of radiodermatitis. PMID- 26619356 TI - The Structure of Co-Occurring Bullying Experiences and Associations with Suicidal Behaviors in Korean Adolescents. AB - OBJECTIVE: This study had two main goals: to examine the structure of co occurring peer bullying experiences among adolescents in South Korea from the perspective of victims and to determine the effects of bullying on suicidal behavior, including suicidal ideation and suicide attempts, among adolescents. METHOD: This study used data gathered from 4,410 treatment-seeking adolescents at their initial visits to 31 local mental health centers in Gyeonggi Province, South Korea. The structure of peer bullying was examined using latent class analysis (LCA) to classify participants' relevant experiences. Then, a binomial logistic regression adjusted by propensity scores was conducted to identify relationships between experiences of being bullied and suicidal behaviors. RESULTS: The LCA of experiences with bullying revealed two distinct classes of bullying: physical and non-physical. Adolescents who experienced physical bullying were 3.05 times more likely to attempt suicide than those who were not bullied. Victims of (non-physical) cyber bullying were 2.94 times more likely to attempt suicide than were those who were not bullied. CONCLUSIONS: Both physical and non-physical bullying were associated with suicide attempts, with similar effect sizes. Schools and mental health professionals should be more attentive than they currently are to non-physical bullying. PMID- 26619357 TI - Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci. AB - We characterized DNA methylation quantitative trait loci (mQTLs) in a large collection (n = 166) of human fetal brain samples spanning 56-166 d post conception, identifying >16,000 fetal brain mQTLs. Fetal brain mQTLs were primarily cis-acting, enriched in regulatory chromatin domains and transcription factor binding sites, and showed substantial overlap with genetic variants that were also associated with gene expression in the brain. Using tissue from three distinct regions of the adult brain (prefrontal cortex, striatum and cerebellum), we found that most fetal brain mQTLs were developmentally stable, although a subset was characterized by fetal-specific effects. Fetal brain mQTLs were enriched amongst risk loci identified in a recent large-scale genome-wide association study (GWAS) of schizophrenia, a severe psychiatric disorder with a hypothesized neurodevelopmental component. Finally, we found that mQTLs can be used to refine GWAS loci through the identification of discrete sites of variable fetal brain methylation associated with schizophrenia risk variants. PMID- 26619359 TI - Pertuzumab in gastrointestinal cancer. AB - INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) and HER3 are altered in multiple tumor types, including gastrointestinal cancer. The HER2/HER3 dimer is crucial for HER2-mediated signaling in HER2-positive tumors. HER2 targeting agents, including trastuzumab, lapatinib, trastuzumab emtansine, and pertuzumab, have been approved for the treatment of HER2-positive breast cancer, with trastuzumab also approved for the treatment of HER2-positive gastric cancer. Pertuzumab, a recombinant humanized immunoglobulin (Ig) G1 monoclonal antibody targeting HER-2, binds to the dimerization domain (extracellular domain II) of HER2, which leads to blocking of ligand-induced HER2 heterodimerization. It is under investigation in gastrointestinal cancers, including HER2-positive gastric cancer. AREA COVERED: In this review, the authors summarize the biology of HER2/HER3 and its alterations in gastrointestinal cancers. The authors focus specifically on the current status of development of pertuzumab in gastrointestinal cancers. EXPERT OPINION: The HER2/HER3 alteration in gastrointestinal cancers is quite interesting. In HER2-positive gastric cancer, the dual blockade of HER2 and HER3 using trastuzumab and pertuzumab is being tested in an international phase III trial, the JACOB study. This strategy may benefit HER2-positive gastric cancer patients more as in the case of HER2 positive breast cancer. In other gastrointestinal cancers, including biliary tract cancer, esophageal cancer, pancreatic cancer, and colorectal cancer, there is huge room for the development of pertuzumab. PMID- 26619358 TI - Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex. AB - DNA methylation (DNAm) is important in brain development and is potentially important in schizophrenia. We characterized DNAm in prefrontal cortex from 335 non-psychiatric controls across the lifespan and 191 patients with schizophrenia and identified widespread changes in the transition from prenatal to postnatal life. These DNAm changes manifest in the transcriptome, correlate strongly with a shifting cellular landscape and overlap regions of genetic risk for schizophrenia. A quarter of published genome-wide association studies (GWAS) suggestive loci (4,208 of 15,930, P < 10(-100)) manifest as significant methylation quantitative trait loci (meQTLs), including 59.6% of GWAS-positive schizophrenia loci. We identified 2,104 CpGs that differ between schizophrenia patients and controls that were enriched for genes related to development and neurodifferentiation. The schizophrenia-associated CpGs strongly correlate with changes related to the prenatal-postnatal transition and show slight enrichment for GWAS risk loci while not corresponding to CpGs differentiating adolescence from later adult life. These data implicate an epigenetic component to the developmental origins of this disorder. PMID- 26619360 TI - Inhibiting Interfacial Recombination Events in Dye-Sensitized Solar Cells using Self-Assembled Bilayers. AB - The rate and efficiency of electron transfer events at the semiconductor-dye electrolyte interface is of critical importance to the overall performance of dye sensitized solar cells (DSSCs) and dye-sensitized photoelectrosynthesis cells. In this work, we introduce self-assembled bilayers composed of a metal oxide electrode, bridging molecules, linking ions, and dye as an effective strategy to manipulate interfacial electron transfer events at the photoanode of DSSCs. Spectroelectrochemical measurements including current-voltage, incident photon-to current efficiency, and electrochemical impedance spectroscopy are used to quantify interfacial electron transfer and transport events with respect to the length of the bridging molecules. The general trend in increased lifetime and diffusion length in TiO2 as well as an increase in open circuit voltage with bridge length indicate that the bilayer is an effective strategy in inhibiting the TiO2(e(-)) to redox mediator recombination events. However, the increased separation between the dye and the semiconductor also reduces the electron injection rate resulting in a decrease in photocurrent as the bridge length increases. The observed enhancement in open circuit voltages are far outweighed by the significant decrease in photocurrent and thus overall device performance decreases with increasing bridge length. PMID- 26619361 TI - Computer-aided Therapeutics in Treating Autoimmune Encephalitis. PMID- 26619363 TI - Ligand noninnocence in FeNO corroles: insights from beta-octabromocorrole complexes. AB - The first FeNO octabromocorroles have been synthesized including four beta octabromo-meso-tris(p-X-phenyl)corrole derivatives Fe[Br8TpXPC](NO) (X = CF3, H, CH3, OCH3) and the beta-octabromo-meso-tris(pentafluorophenyl)corrole complex, Fe[Br8TPFPC](NO). The last complex, which proved amenable to single-crystal X-ray structure determination, exhibits the geometry parameters: Fe-N(O) 1.643(8) A, N O 1.158(9) A, and a FeNO angle of 176.4(6) degrees . The more electron-deficient complexes exhibit increased instability with respect to NO loss and also higher infrared NO stretching frequencies (nuNO). Interestingly, DFT calculations and IR marker bands indicate a noninnocent {FeNO}(7)-(corrole(2-)) formulation for all FeNO corroles, both beta-H8 and beta-Br8, with essentially the same degree of corrole radical character. Instead, an electron-deficient corrole appears to exert a field effect resulting in reduced Fe-to-NO backdonation, which accounts for both the increased instability with respect to NO loss and the higher nuNO's. PMID- 26619362 TI - Dose-Dependent Therapeutic Distinction between Active and Passive Targeting Revealed Using Transferrin-Coated PGMA Nanoparticles. AB - The paradigm of using nanoparticle-based formulations for drug delivery relies on their enhanced passive accumulation in the tumor interstitium. Nanoparticles with active targeting capabilities attempt to further enhance specific delivery of drugs to the tumors via interaction with overexpressed cellular receptors. Consequently, it is widely accepted that drug delivery using actively targeted nanoparticles maximizes the therapeutic benefit and minimizes the off-target effects. However, the process of nanoparticle mediated active targeting initially relies on their passive accumulation in tumors. In this article, it is demonstrated that these two tumor-targeted drug delivery mechanisms are interrelated and dosage dependent. It is reported that at lower doses, actively targeted nanoparticles have distinctly higher efficacy in tumor inhibition than their passively targeted counterparts. However, the enhanced permeability and retention effect of the tumor tissue becomes the dominant factor influencing the efficacy of both passively and actively targeted nanoparticles when they are administered at higher doses. Importantly, it is demonstrated that dosage is a pivotal parameter that needs to be taken into account in the assessment of nanoparticle mediated targeted drug delivery. PMID- 26619364 TI - Role of the thalamus in natural recovery of cognitive impairment in patients with mild traumatic brain injury. AB - INTRODUCTION: Patients with mild traumatic brain injury (mTBI) may have normal neuroimaging but manifest with a broad-spectrum of cognitive-deficits, which may resolve eventually. The function of the thalamus in the process of natural recovery remains elusive. The current study investigates the role of the thalamus in natural-recovery of cognitive-deficits in patients with mTBI. METHODS: Twenty one patients with mTBI were evaluated with an initial MRI scan, within 36 hours of injury and assessed with neuropsychological tests(NPT) at 3-4 weeks after injury. First and second follow-up MRI and NPT were performed at 3-4 months and 6 7 months, respectively. The volume and tensor measures of the thalamus and cognitive-scores were analysed at each assessment using repeated-measures of variance. The association of cognitive-scores with corresponding period imaging measures was analysed using bivariate-correlation. RESULTS: Serial evaluation showed that all the cognitive-domains improved significantly. During this period there was a significant increase in mean thalamic volume (p = 0.049, effect-size = 0.18). After 3-4 months there was emergence of anisotropic thalamo-cortical connections. At 2-3 weeks and 6-7 months after injury, the alterations in diffusivity values were positively associated with improvement in memory-scores. Improvement in attention-scores correlated significantly with changes in tensor values at the 6-7 months after-injury. CONCLUSION: The correlation between improvement in cognitive-scores and changes in thalamic tensor and volume measures reflect the role of the thalamus in natural-recovery after mTBI. PMID- 26619366 TI - What is Gillick competence? AB - This article considers the requirements for Gillick competence, it highlights the factors that must be considered when determining whether a child is competent to give consent to treatment. PMID- 26619365 TI - Simultaneous or Sequential Orthogonal Gradient Formation in a 3D Cell Culture Microfluidic Platform. AB - Biochemical gradients are ubiquitous in biology. At the tissue level, they dictate differentiation patterning or cell migration. Recapitulating in vitro the complexity of such concentration profiles with great spatial and dynamic control is crucial in order to understand the underlying mechanisms of biological phenomena. Here, a microfluidic design capable of generating diffusion-driven, simultaneous or sequential, orthogonal linear concentration gradients in a 3D cell-embedded scaffold is described. Formation and stability of the orthogonal gradients are demonstrated by computational and fluorescent dextran-based characterizations. Then, system utility is explored in two biological systems. First, stem cells are subjected to orthogonal gradients of morphogens in order to mimic the localized differentiation of motor neurons in the neural tube. Similarly to in vivo, motor neurons preferentially differentiate in regions of high concentration of retinoic acid and smoothened agonist (acting as sonic hedgehog), in a concentration-dependent fashion. Then, a rotating gradient is applied to HT1080 cancer cells and the change in migration direction is investigated as the cells adapt to a new chemical environment. The response time of ~4 h is reported. These two examples demonstrate the versatility of this new design that can also prove useful in many applications including tissue engineering and drug screening. PMID- 26619367 TI - Resveratrol inhibits ovarian tumor growth in an in vivo mouse model. AB - BACKGROUND: Resveratrol inhibits the growth of ovarian carcinoma cells in vitro through the inhibition of glucose metabolism and the induction of both autophagy and apoptosis. In the current study, we investigated the metabolic and therapeutic effects of resveratrol in vivo. METHODS: A fluorescent xenograft mouse model of ovarian cancer was used. Mice were treated with cisplatin, resveratrol, or vehicle alone. Tumor burden was assessed using whole-body imaging. The effect of resveratrol on glucose uptake in vivo was determined using micro-positron emission tomography scanning. To determine whether resveratrol could inhibit tumor regrowth, tumor-bearing mice were treated with cisplatin followed by either daily resveratrol or vehicle. Autophagic response in resected tumors taken from mice treated with resveratrol was examined by transmission electron microscopy. Glycolysis and mitochondrial respiration in ovarian tumor cells after treatment with resveratrol was assessed. RESULTS: Mice treated with resveratrol and cisplatin were found to have a significantly reduced tumor burden compared with control animals (P<.001). Resveratrol-treated mice demonstrated a marked decrease in tumor uptake of glucose compared with controls. After treatment with cisplatin, "maintenance" resveratrol resulted in the suppression of tumor regrowth compared with mice receiving vehicle alone (P<.01). Tumors resected from mice treated with resveratrol exhibited autophagosomes consistent with the induction of autophagy. Treatment with resveratrol inhibited glycolytic response in ovarian tumor cells with high baseline glycolytic rates. CONCLUSIONS: Treatment with resveratrol inhibits glucose uptake and has a significant antineoplastic effect in a preclinical mouse model of ovarian cancer. Resveratrol treatment suppresses tumor regrowth after therapy with cisplatin, suggesting that this agent has the potential to prolong disease-free survival. Cancer 2016;122:722-729. (c) 2015 American Cancer Society. PMID- 26619368 TI - Fasting and postprandial regulation of the intracellular localization of adiponectin and of adipokines secretion by dietary fat in rats. AB - BACKGROUND/OBJECTIVE: Dietary fat sources modulate fasting serum concentration of adipokines, particularly adiponectin. However, previous studies utilized obese animals in which adipose tissue function is severely altered. Thus, the present study aimed to assess the postprandial regulation of adipokine secretion in nonobese rats that consumed high-fat diet (HFD) composed of different types of fat for a short time. METHODS: The rats were fed a control diet or a HFD containing coconut, safflower or soybean oil (rich in saturated fatty acid, monounsaturated fatty acid or polyunsaturated fatty acid, respectively) for 21 days. The serum concentrations of adiponectin, leptin, retinol, retinol-binding protein-4 (RBP-4), visfatin and resistin were determined at fasting and after refeeding. Adiponectin multimerization and intracellular localization, as well as the expression of endoplasmic reticulum (ER) chaperones and transcriptional regulators, were evaluated in epididymal white adipose tissue. RESULTS: In HFD fed rats, serum adiponectin was significantly decreased 30 min after refeeding. With coconut oil, all three multimeric forms were reduced; with safflower oil, only the high-molecular-weight (HMW) and medium-molecular-weight (MMW) forms were decreased; and with soybean oil, only the HMW form was diminished. These reductions were due not to modifications in mRNA abundance or adiponectin multimerization but rather to an increment in intracellular localization at the ER and plasma membrane. Thus, when rats consumed a HFD, the type of dietary fat differentially affected the abundance of endoplasmic reticulum resident protein 44 kDa (ERp44), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor gamma (PPARgamma) mRNAs, all of which are involved in the post-translational processing of adiponectin required for its secretion.Leptin, RBP-4, resistin and visfatin serum concentrations did not change during fasting, whereas modest alterations were observed after refeeding. CONCLUSIONS: The short-term consumption of a HFD affected adiponectin localization in adipose tissue, thereby decreasing its secretion to a different magnitude depending on the dietary fat source. Evaluating the fasting serum concentration of adipokines was not sufficient to identify alterations in their secretion, whereas postprandial values provided additional information as dynamic indicators. PMID- 26619370 TI - The need to redefine age- and gender-specific overweight and obese body mass index cutoff points. AB - For convenience, health practitioners and clinicians are inclined to classify people/patients as overweight or obese based on body mass index (BMI) cutoff points of 25 and 30 kg m(-2) respectively, irrespective of age and gender. The purpose of the current study was to identity whether, for the same levels of adiposity, BMI is the same across different age groups and gender. A two-way ANCOVA revealed significant differences in BMI between different age groups and gender (plus an interaction), using body fat (%) as the covariate, data taken from a random sample of the English population (n=2993). Younger people had greater BMI than older people for the same levels of adiposity (differences ranged by 4 BMI units for males, and 3 BMI units for females). In conclusion, if BMI thresholds for overweight (BMI=25 kg m(-2)) and obese (BMI=30 kg m(-2)) are to reflect the same levels of adiposity across all gender and age groups within a population, then age- and gender-specific BMI adjustments outlined here are necessary to more accurately/fairly reflect the same critical levels of adiposity. PMID- 26619369 TI - The application of omics technologies in the functional evaluation of inulin and inulin-containing prebiotics dietary supplementation. AB - Inulin, a natural renewable polysaccharide resource produced by various plants in nature, has been reported to possess a significant number of diverse pharmaceutical and food applications. Recently, there has been rapid progress in high-throughput technologies and platforms to assay global mRNA, proteins, metabolites and gut microbiota. In this review, we will describe the current status of utilizing omics technologies of elucidating the impact of inulin and inulin-containing prebiotics at the transcriptome, proteome, metabolome and gut microbiome levels. Although many studies in this review have addressed the impact of inulin comprehensively, these omics technologies only enable us to understand physiological information at each different stage of mRNA, protein, metabolite and gut microbe. We believe that a synergistic approach is vital in order to fully illustrate the intricate beauty behind the relatively modest influence of food factors like inulin on host health. PMID- 26619371 TI - Part-Digitizing System of Impression and Interocclusal Record for Complete Denture Fabrication. AB - Few studies have reported the application of digital technology to removable dentures, particularly for the process of impression and interocclusal recording for complete denture fabrication. This article describes a part-digitizing system of impression and interocclusal records for complete denture fabrication. The denture foundation area in an edentulous mouth, including the border areas and residual ridge, is outlined by tracing the surfaces with a 3-D pen-type digitizer. Specialized trays for final impressions and interocclusal records were generated using computer-aided design and manufactured using the digital data. Final impression and interocclusal records were carried out using these specialized trays. The computer-aided method using preliminary digital impressions and specialized trays would be feasible for clinical use for complete denture fabrication. PMID- 26619372 TI - Intellectual disability in Autism Spectrum Disorder: Investigation of prevalence in an Italian sample of children and adolescents. PMID- 26619373 TI - Obstacle crossing in 7-9-year-old children with Down syndrome. AB - This study aimed to investigate obstacle crossing in 7-9-year-old children with Down syndrome (DS). Fifteen children with DS, age- and gender-matched with 15 typically developing (TD) children, were recruited to walk and cross obstacles with heights of 10%, 20% and 30% of their leg lengths. End-point and kinematic variables of obstacle crossing were obtained using a three-dimensional motion analysis system. The results showed that children with DS tend to adopt a lower speed and larger step width when they perceive instability. Moreover, unlike TD children, children with DS adopt a pelvic strategy (i.e., greater pelvic leading side listing and forward rotation) to achieve a higher leading toe clearance with a longer step length, presumably for safety reasons. This pelvic strategy increased the frontal plane motion of the whole leg and trunk, and thus possibly stability, during obstacle crossing. However, this strategy may be inefficient. Trailing toe clearance did not differ significantly between two groups. The results of this study suggest that children with DS tend to use inefficient and conservative strategies for obstacle crossing. Knowledge of both end-point and kinematic control of obstacle crossing in children with DS is useful for understanding the mechanisms of obstacle-related falls. Moreover, obstacle crossing can be used as a task-oriented rehabilitation program for children with DS. PMID- 26619374 TI - The Evolving Role of Midwives as Laborists. AB - This article examines the history and present state of the midwife as laborist. The role of the midwife and obstetrician laborist/hospitalist is rapidly evolving due to the need to improve patient safety and provide direct care due to reduced resident work hours, as well as practice demands experienced by community providers and other factors. Models under development are customized to meet the needs of different communities and hospitals. Midwives are playing a prominent role in many laborist/hospitalist practices as the first-line hospital provider or as part of a team with physicians. Some models incorporate certified nurse midwives/certified midwives as faculty to residents and medical students. The midwifery laborist/hospitalist practices at Baystate Medical Center in Springfield, Massachusetts, are presented as an example of how midwives are functioning as laborists. Essential components of a successful midwife laborist program include interdisciplinary planning, delineation of problems the model should solve, establishment of program metrics, clear practice guidelines and role definitions, and a plan for sustained funding. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health. PMID- 26619376 TI - Treatment with anti-cytokine monoclonal antibodies can potentiate the target cytokine rather than neutralize its activity. PMID- 26619377 TI - Genetic polymorphisms and mutation rates of 27 Y-chromosomal STRs in a Han population from Guangdong Province, Southern China. AB - In this study, we collected blood samples from 1033 father-son pairs of a Han population from Guangdong Province, Southern China, of which 1007 fathers were unrelated male individuals. All together, 2040 male individuals were analyzed at 27 Y-chromosomal short tandem repeats (Y-STRs) with Yfiler((r)) Plus system. A total of 1003 different haplotypes were observed among 1007 unrelated fathers, with the overall haplotype diversity (HD) 0.999992 and discrimination capacity (DC) 0.996. The gene diversity (GD) values for the 27 Y-STR loci ranged from 0.4400 at DYS438 to 0.9597 at DYS385a/b. 11 off-ladder alleles and 25 copy number variants were detected in 1007 males. Population relationships were analyzed by comparison with 19 other worldwide populations. With 27,920 allele transfers in 1033 father-son pairs, 124 mutation events occurred, of which 118 were one-step mutations and 6 were two-step mutations. Eleven father-son pairs were found to have mutations at two loci, while one pair at three loci. The estimated locus specific mutation rates varied from 0 to 1.74*10(-2), with an average estimated mutation rate 4.4*10(-3) (95%CI: 3.7*10(-3) to 5.3*10(-3)). Mutations were most frequently observed at three rapidly mutating Y-STRs (RM Y-STRs), DYS576, DYS518 and DYS627. However, at DYS570, DYS449 and DYF387S1 loci, which were also described as RM Y-STRs, the mutation rates in Guangdong Han population were not as high as estimated in other populations. PMID- 26619378 TI - NIR-Remote Selected Activation Gene Expression in Living Cells by Upconverting Microrods. AB - An NIR-controlled gene expression system based on upconverting rods (UCRs) is demonstrated. The UCRs can harvest the "biocompatible" NIR light and convert it into local UV light, resulting in cleavage of the photosensitive molecule (4 (hydroxymethyl)-3-nitrobenzoic acid, ONA) and on-demand release of gene carriers, thus realizing target gene expression at high spatial and temporal resolutions. PMID- 26619379 TI - Generalized onset seizures with focal evolution (GOFE) - A unique seizure type in the setting of generalized epilepsy. AB - PURPOSE: We report clinical and electrographic features of generalized onset seizures with focal evolution (GOFE) and present arguments for the inclusion of this seizure type in the seizure classification. METHODS: The adult and pediatric Epilepsy Monitoring Unit databases at Vanderbilt Medical Center and Children's Hospital were screened to identify generalized onset seizures with focal evolution. We reviewed medical records for epilepsy characteristics, epilepsy risk factors, MRI abnormalities, neurologic examination, antiepileptic medications before and after diagnosis, and response to medications. We also reviewed ictal and interictal EEG tracings, as well as video-recorded semiology. RESULTS: Ten patients were identified, 7 males and 3 females. All of the patients developed generalized epilepsy in childhood or adolescence (ages 3-15years). Generalized onset seizures with focal evolution developed years after onset in 9 patients, with a semiology concerning for focal seizures or nonepileptic events. Ictal discharges had a generalized onset on EEG, described as either generalized spike-and-wave and/or polyspike-and-wave discharges, or generalized fast activity. This electrographic activity then evolved to focal rhythmic activity most commonly localized to one temporal or frontal region; five patients had multiple seizures evolving to focal activity in different regions of both hemispheres. The predominant interictal epileptiform activity included generalized spike-and-wave and/or polyspike-and-wave discharges in all patients. Taking into consideration all clinical and EEG data, six patients were classified with genetic (idiopathic) generalized epilepsy, and four were classified with structural/metabolic (symptomatic) generalized epilepsy. All of the patients had modifications to their medications following discharge, with three becoming seizure-free and five responding with >50% reduction in seizure frequency. CONCLUSION: Generalized onset seizures may occasionally have focal evolution with semiology suggestive of focal seizures, leading to a misdiagnosis of focal onset. This unique seizure type may occur with genetic as well as structural/metabolic forms of epilepsy. The identification of this seizure type may help clinicians choose appropriate medications, avoiding narrow spectrum agents known to aggravate generalized onset seizures. PMID- 26619380 TI - Impact of Surgical Template on the Accuracy of Implant Placement. AB - PURPOSE: To achieve functional and esthetic results, implants must be placed accurately; however, little information is available regarding the effect of surgical templates on the accuracy of implant placement. Thus, the aim of this study was to measure the deviation between actual and planned implant positions, and determine the deviation caused by the surgical template. MATERIALS AND METHODS: Jaws from 16 patients were scanned using cone beam computed tomography (CBCT). For our study, 53 implants were planned in a virtual 3D environment, of which 35 were inserted in the mandible and 18 in the maxilla. A stereolithographic (SLA) surgical template was created. A CBCT scan of the surgical template fitted on a plaster model was performed, and the images obtained were matched to virtual implant plan images that contained the planned implant position. The actual implant position was acquired from the registration position of the surgical template. Deviation between actual and planned implant positions was analyzed. RESULTS: Mean central deviation at the hex and apex was 0.456 mm and 0.515 mm, respectively. Mean value of horizontal deviation at the hex was 0.193 mm, horizontal deviation at the apex was 0.277 mm, vertical deviation at the hex was 0.388 mm, vertical deviation at the apex was 0.390 mm, and angular deviation was 0.621 degrees . CONCLUSION: Our study results revealed a significant deviation between actual and planned implant positions caused by the surgical template. PMID- 26619381 TI - Cervical cancer prevention in Australia: Planning for the future. AB - The high rate of coverage that has been achieved to date by the Australian government's Human Papillomavirus (HPV) Vaccination Program has already led to profound reductions in the prevalence of biopsy-confirmed, high-grade abnormalities and of vaccine-preventable HPV types in Australia. Declines in the prevalence of vaccine preventable HPV have occurred not only in vaccinated women but also in unvaccinated women, suggesting a herd-immunity affect. These declines were anticipated on the basis of modelling and were the major drivers for the changes proposed to the Australian National Cervical Screening Program. The federal and state-based Australian governments established a "Renewal Steering Committee," which conducted a literature search and a review of the available evidence to assess its applicability and quality. Together with this information the committee also used modeling to determine the optimal screening pathway for cervical cancer screening and constructed a plan for implementing the changes that will be required to transition from the currently successful screening program to the renewed program. The committee recommended that Australia move to a screening program based on testing every 5 years using an HPV test with partial genotyping with reflex liquid-based cytology (LBC) triage for HPV-vaccinated and unvaccinated women ages 25 to 69 years, and an additional exit test for women up to age 74 years. Primary HPV testing and reflex LBC will be funded by government. Symptomatic women outside the screening program will also be able to access government funded testing. The new screening program, to be rolled out in 2017, will also provide a cost-effective framework for an evaluation of the national HPV vaccination program, enabling ongoing monitoring of HPV genotypes and cervical lesions in screened women. PMID- 26619382 TI - Thermochromic Infrared Metamaterials. AB - An infrared artificial thermochromic material composed of a metamaterial emitter and a bimaterial micro-electro-mechanical system is investigated. A differential emissivity of over 30% is achieved between 623 K and room temperature. The passive metamaterial device demonstrates the ability to independently control the peak wavelength and temperature dependence of the emissivity, and achieves thermal emission following a super Stefan-Boltzmann power curve. PMID- 26619384 TI - Chemical Burn-Induced Stromal Demarcation Line. AB - PURPOSE: A stromal demarcation line is a well-known sign after collagen cross linking. It has been proposed that this line is the transition zone between cellular and acellular stroma, and thus it might reveal the depth of photochemical changes in the corneal stroma. We report 2 cases of a similar demarcation line after chemical alkali burns. To the best of our knowledge, this is the first report of a stromal demarcation line after a chemical burn. OBSERVATION: Two patients presented to the emergency department after an ocular alkali burn. At presentation, both had total corneal erosion, corneal edema, and limbal ischemia. After 12 to 15 days, a stromal line was apparent by both slit lamp examination and anterior segment optical coherence tomography. The stromal demarcation lines disappeared approximately 3 months after the injury. CONCLUSIONS: A stromal demarcation line may appear not only after collagen cross linking but also after a chemical burn. The line depth may be associated with the severity of the injury, and therefore, may have prognostic significance. Patients with chemical burns should be examined for evidence of a stromal line in the cornea. PMID- 26619383 TI - Congenital Corneal Endothelial Dystrophies Resulting From Novel De Novo Mutations. AB - PURPOSE: To describe 2 cases of congenital corneal endothelial edema resulting from novel de novo mutations. METHODS: Case A patient was a 15-month-old white child and case B patient was a 3-year-old Hispanic child presenting with bilateral cloudy corneas since birth. Clinicopathologic findings are presented. DNA samples were screened for mutations in candidate genes by Sanger sequencing. RESULTS: Slit-lamp examination of case A patient revealed stromal edema and haze. Histology of the keratoplasty button showed stromal thickening with loss of endothelium and thin Descemet membrane. Sanger sequencing established the diagnosis of congenital hereditary endothelial dystrophy by detection of a compound heterozygous mutation in SLC4A11. The proband displayed a novel de novo frameshift mutation in one SLC4A11 allele, p.(Pro817Argfs*32), in conjunction with a maternally inherited missense mutation in SLC4A11, p.(Arg869His). Case B patient similarly presented with stromal edema and stromal haze. Histopathologic analysis revealed a spongy epithelium, focal discontinuities in Bowman layer, stromal thickening with areas of compacted posterior stroma, variable thickness of Descemet membrane, and regional multilayered endothelium. Sanger sequencing found a novel de novo nonsense mutation in the first exon of ZEB1, p.(Cys7*). CONCLUSIONS: To the authors' knowledge, we report the earliest clinical presentation of posterior polymorphous corneal dystrophy resulting from a de novo mutation in ZEB1. Additionally, we present a congenital hereditary endothelial dystrophy case with a thin Descemet membrane with a novel compound heterozygous SLC4A11 mutation. In the absence of a family history or consanguinity, de novo mutations may result in congenital corneal endothelial dystrophies. PMID- 26619385 TI - Comparison of the Efficacy of Fluorometholone With and Without Benzalkonium Chloride in Ocular Surface Disease. AB - PURPOSE: The purpose of this study was to compare the cytotoxicity and antiinflammatory effect of preserved and unpreserved 0.1% fluorometholone (FML). METHODS: Drug-induced morphological changes and cytotoxicity were examined in human corneal epithelial cells. Dry eye was induced in mice by treatment with 0.2% benzalkonium chloride (BAC) for the first 2 weeks, and then, the eyes (4 groups; Normal saline, BAC, preserved FML, and unpreserved FML) were treated thrice daily with each formulation for the next 2 weeks. Corneal tissues were embedded in paraffin and stained with hematoxylin and eosin for histopathological examination. Immunofluorescence staining was performed for tumor necrosis factor alpha, interleukin-6, and human leukocyte antigen-DR. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay was performed to evaluate drug-induced cytotoxicity. RESULTS: BAC and preserved FML caused cell shrinkage and detachment from the plate in a dose-dependent manner, and cell viability decreased significantly. However, cytotoxicity was reduced on treatment with unpreserved FML. Hematoxylin-eosin staining revealed surface desquamation, irregular surface, loss of cell borders, and stromal shrinkage in the group treated with BAC. On BAC exposure, tumor necrosis factor-alpha, interleukin-6, and human leukocyte antigen DR were strongly detected, and cytotoxicity was markedly increased, as evidenced by a positive result in the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Ocular surface damage and inflammation were slightly reduced on treatment with preserved FML. In comparison, unpreserved FML did not induce morphological changes; moreover, decreased cell cytotoxicity and ocular surface inflammation were observed. CONCLUSIONS: The cytotoxicity of antiinflammatory eye drops evaluated in this study was induced by the preservative BAC. Accordingly, unpreserved FML is more effective than preserved eye drops in decreasing ocular inflammation. PMID- 26619386 TI - Differences in Corneal Parameters Between Affected and Normal Contralateral Eyes in Patients With Hemifacial Spasm Treated With Botulinum Toxin-A: Outcomes During One Complete Treatment Cycle. AB - PURPOSE: To investigate possible temporary differences in corneal topographic parameters between affected and normal eyes in patients with hemifacial spasm (HFS) treated with botulinum toxin-A (BTX-A), over the course of 1 treatment cycle. METHODS: This prospective study evaluated corneal topographic differences between affected and normal contralateral eyes during a 4-month period in patients with HFS treated with BTX-A (the duration of action of BTX-A for HFS ranges from 2 to 4 months). Corneal topographic analysis was performed using a conventional topographer (Atlas; Carl Zeiss Meditec, Dublin, CA). Steep K and astigmatism measurements were evaluated before BTX-A application and after 15 days and 2, 3, and 4 months. RESULTS: Twenty-four patients (16 women and 8 men) were evaluated. Steep K [46.9 +/- 3.6 diopters (D)] and astigmatism values (2.6 +/- 2.5 D) were significantly higher in affected eyes of HFS patients than in nonaffected eyes (45.0 +/- 1.4 D and 0.9 +/- 0.6 D) before treatment (P = 0.001 for steep K and P = 0.0003 for astigmatism). Astigmatism values also showed significant differences between the affected eye (1.4 +/- 0.8 D) and nonaffected eye (0.9 +/- 0.6 D) at 4 months (P = 0.006), whereas steep K showed significant differences between both eyes at 15 days (affected eye: 45.6 +/- 1.5 D, nonaffected eye: 45.0 +/- 1.4 D, P = 0.008), 3 months (affected eye: 45.6 +/- 1.8 D, nonaffected eye: 45.1 +/- 1.3 D, P = 0.03) and 4 months (affected eye: 45.8 +/ 1.2 D, nonaffected eye: 45.1 +/- 1.4 D, P = 0.003) after treatment. CONCLUSIONS: The differences in steep K, and especially in astigmatism values, between eyes tended to reduce during the period of action of BTX-A. At 4 months, when the BTX A effect is considered to be over or very reduced, a significant difference between eyes for both parameters was noted again. PMID- 26619387 TI - Suggested Guidelines for Reporting Keratoprosthesis Results: Consensus Opinion of the Cornea Society, Asia Cornea Society, EuCornea, PanCornea, and the KPRO Study Group. AB - PURPOSE: To propose a series of standardized guidelines for reporting keratoprosthesis (KPRO) results. METHODS: At the most recent KPRO Study Group Meeting (Barcelona, 2015), representatives of the 4 multinational corneal societies (Cornea Society, Asia Cornea Society, EuCornea, and PanCornea) and the KPRO Study Group agreed to propose consistent terminology for reporting KPRO results, especially in describing the length of follow-up and in the description of the KPRO itself. Consensus was reached for minimal reporting guidelines. RESULTS: The 4 multinational corneal societies and the KPRO Study Group agreed to standardized terminology for reporting the length of follow-up, preoperative diagnosis grouping, and data stratification based on the KPRO type used. CONCLUSIONS: Guidelines suggesting minimal reporting standards will assist in both data collection and reporting and will allow for better comparative analysis and pooling of the available data. PMID- 26619388 TI - Preparation of 4-([2,2':6',2"-terpyridin]-4'-yl)-N,N-diethylaniline Ni(II) and Pt(II) complexes and exploration of their in vitro cytotoxic activities. AB - Two metal complexes of NiLCl2 (1) and [PtLCl]Cl (2) with 4-([2,2':6',2" terpyridin]-4'-yl)-N,N-diethylaniline (L) were synthesized and characterized. 1 and 2 exhibited selective cytotoxicity to T-24 cells more than L, compared with the normal liver cell line (HL-7702). Various experiments showed that L, 1 and 2 caused T-24 cell cycle arrest at S phase, as shown by the down-regulation of cdc25 A, cyclin A, cyclin B and CDK2 and the up-regulation of p21, p27 and p53. Furthermore, complexes 1 and 2, especially complex 2, acted as telomerase inhibitors targeting c-myc G-quadruplex DNA and triggered cell apoptosis. In addition, 1 and 2 also caused mitochondrial dysfunction. Taken together, we found that 1 and 2 exerted their cytotoxic activity mainly via inhibiting telomerase by interaction with c-myc quadruplex and disruption of mitochondrial function. PMID- 26619389 TI - 4-Arylamino-6-nitroquinazolines: Synthesis and their activities against neglected disease leishmaniasis. AB - 4-Arylamino-6-nitroquinazolines (2-25) were synthesized and evaluated for their leishmanicidal activities against Leishmania major promastigotes in vitro with IC50 values = 1.87-61.48 MUM. Among the twenty four synthetic derivatives, 4-[4' (methylsulfanyl)phenyl]amino-6-nitroquinazoline (21), and 4-(2' methoxyphenyl)amino-6-nitroquinazoline (8) showed excellent antileishmanial activities with IC50 values 1.87 +/- 0.31 and 4.37 +/- 0.02 MUM, respectively, more active than the standard drug, pentamidine (IC50 = 5.09 +/- 0.09 MUM). Compound 16 (IC50 = 6.53 +/- 0.21 MUM) displayed an activity comparable to the standard. Compounds 15 (IC50 = 9.04 +/- 0.03 MUM), 18 (IC50 = 12.28 +/- 0.18 MUM), 14 (IC50 = 19.87 +/- 0.22 MUM), and 5 (IC50 = 24.03 +/- 2.71 MUM) also showed good activities. PMID- 26619390 TI - Abortion Surveillance - United States, 2012. AB - PROBLEM/CONDITION: Since 1969, CDC has conducted abortion surveillance to document the number and characteristics of women obtaining legal induced abortions in the United States. REPORTING PERIOD COVERED: 2012. DESCRIPTION OF SYSTEM: Each year, CDC requests abortion data from the central health agencies of 52 reporting areas (the 50 states, the District of Columbia, and New York City). The reporting areas provide this information voluntarily. For 2012, data were received from 49 reporting areas. For trend analysis, abortion data were evaluated from 47 areas that reported data every year during 2003-2012. Census and natality data, respectively, were used to calculate abortion rates (number of abortions per 1,000 women) and ratios (number of abortions per 1,000 live births). RESULTS: A total of 699,202 abortions were reported to CDC for 2012. Of these abortions, 98.4% were from the 47 reporting areas that provided data every year during 2003-2012. Among these same 47 reporting areas, the abortion rate for 2012 was 13.2 abortions per 1,000 women aged 15-44 years, and the abortion ratio was 210 abortions per 1,000 live births. From 2011 to 2012, the total number and ratio of reported abortions decreased 4% and the abortion rate decreased 5%. From 2003 to 2012, the total number, rate, and ratio of reported abortions decreased 17%, 18%, and 14%, respectively, and reached their lowest level in 2012 for the entire period of analysis (2003-2012). In 2012 and throughout the period of analysis, women in their 20s accounted for the majority of abortions and had the highest abortion rates; women in their 30s and older accounted for a much smaller percentage of abortions and had lower abortion rates. In 2012, women aged 20-24 and 25-29 years accounted for 32.8% and 25.4% of all abortions, respectively, and had abortion rates of 23.3 and 18.9 abortions per 1,000 women aged 20-24 and 25 29 years, respectively. In contrast, women aged 30-34, 35-39, and >=40 years accounted for 16.4%, 9.1%, and 3.7% of all abortions, respectively, and had abortion rates of 12.4, 7.3, and 2.8 abortions per 1,000 women aged 30-34 years, 35-39 years, and >=40 years, respectively. Throughout the period of analysis, abortion rates decreased among women aged 20-24, 25-29, and 30-34 years by 24%, 18%, and 10%, respectively, whereas they increased among women aged >=40 years by 8%. In 2012, adolescents aged <15 and 15-19 years accounted for 0.4% and 12.2% of all abortions, respectively, and had abortion rates of 0.8 and 9.2 abortions per 1,000 adolescents aged <15 and 15-19 years, respectively. From 2003 to 2012, the percentage of abortions accounted for by adolescents aged 15-19 years decreased 27% and their abortion rate decreased 40%. These decreases were greater than the decreases for women in any older age group. In contrast to the percentage distribution of abortions and abortion rates by age, abortion ratios in 2012 and throughout the entire period of analysis were highest among adolescents aged <=19 years and lowest among women aged 30-39 years. Abortion ratios decreased from 2003 to 2012 for women in all age groups. In 2012, the majority (65.8%) of abortions were performed by <=8 weeks' gestation, and nearly all (91.4%) were performed by <=13 weeks' gestation. Few abortions (7.2%) were performed between 14-20 weeks' gestation or at >=21 weeks' gestation (1.3%). From 2003 to 2012, the percentage of all abortions performed at <=8 weeks' gestation increased 7%; the percentage performed at >13 weeks remained consistently low (<=9.0%). In 2012, among the 40 reporting areas that included medical (nonsurgical) abortion on their reporting form, a total of 69.4% of abortions were performed by curettage at <=13 weeks' gestation, 20.8% were performed by early medical abortion (a nonsurgical abortion at <=8 weeks' gestation), and 8.7% were performed by curettage at >13 weeks' gestation; all other methods were uncommon. Among abortions performed at <=8 weeks' gestation that were eligible on the basis of gestational age for early medical abortion, 30.8% were completed by this method. The percentage of abortions reported as early medical abortions increased 10% from 2011 to 2012. Deaths of women associated with complications from abortions for 2012 are being investigated as part of CDC's Pregnancy Mortality Surveillance System. In 2011, the most recent year for which data were available, two women were identified to have died as a result of complications from known legal induced abortions. No reported deaths were associated with known illegal induced abortions. INTERPRETATION: Among the 47 areas that reported data every year during 2003-2012, the notable decreases that occurred during 2008-2011 in the total number, rate, and ratio of reported abortions continued from 2011 to 2012 and resulted in historic lows for all three measures of abortion. PUBLIC HEALTH ACTIONS: The data in this report can help to identify groups of women at greatest risk for abortion and can be used to guide and evaluate prevention efforts. Because unintended pregnancy is the major contributor to abortion, and unintended pregnancies are rare among women who use the most effective methods of contraception, increasing access to and use of these methods can help further reduce the number of unintended pregnancies, and therefore abortions, performed in the United States. PMID- 26619391 TI - Pulmonary metastasectomy for metastasized hepatocellular carcinoma after liver resection and liver transplantation: a single center experience. AB - BACKGROUND: The role of surgery in the treatment of metastasized hepatocellular carcinoma (HCC) remains uncertain. We here report our single centre experience with pulmonary metastasectomy (PM) for metachronous HCC metastases to the lung following curative liver resection (LR) and liver transplantation (LT), respectively. METHODS: Of 270 patients with HCC being treated by LR or LT at the University Hospital of Leipzig between January 1996 and July 2014, PM was performed in the follow up of 10 patients because of metachronous pulmonary HCC metastases. We retrospectively analyzed demographic and clinicopathological factors as well as the outcome after primary and secondary tumor treatment in these patients. RESULTS: Following LR/LT and metastasectomy, respectively, mean overall survival was 4.58 +/- 0.84 years and 2.4 +/- 0.69 years. Postoperative morbidity after primary and secondary tumor treatment was 30 % and 20 %, respectively. Perioperative 30-day mortality was 0 %. Univariate analysis suggest tumor grading (p < 0.05), and a disease free-intervall > 1 year (p = 0.02) as significant prognostic parameters for survival in our collective. CONCLUSION: PM can be performed safely with a reasonable morbidity even in immunosuppressed patients after LT. Further studies are needed to evaluate whether PM can increase long-term survival in selected patients with resectable metastases and represents an alternative or additive treatment modality to the protein kinase inhibitor sorafenib. PMID- 26619392 TI - Selective extinction drives taxonomic and functional alpha and beta diversities in island bird assemblages. AB - Taxonomic diversity considers all species being equally different from each other and thus disregards species' different ecological functions. Exploring taxonomic and functional aspects of biodiversity simultaneously can better understand the processes of community assembly. We analysed taxonomic and functional alpha and beta diversities of breeding bird assemblages on land-bridge islands in the Thousand Island Lake, China. Given the high dispersal ability of most birds at this spatial scale (several kilometres), we predicted (i) selective extinction driving alpha and beta diversities after the creation of land-bridge islands of varying area and (ii) low taxonomic and functional beta diversities that were not correlated to spatial distance. Breeding birds were surveyed on 37 islands annually from 2007 to 2014. We decomposed beta diversity of breeding birds into spatial turnover and nestedness-resultant components, and related taxonomic and functional diversities to island area and isolation using power regression models (for alpha diversity) and multiple regression models on distance matrices (for beta diversity). We then ran simulations to assess the strength of the correlations between taxonomic and functional diversities. Results revealed that both taxonomic and functional alpha diversities increased with island area. The taxonomic nestedness-resultant and turnover components increased and decreased with difference in area, respectively, but functional counterparts did not. Isolation played a minor role in explaining alpha- and beta-diversity patterns. By partitioning beta diversity, we found low levels of overall taxonomic and functional beta diversities. The functional nestedness-resultant component dominated overall functional beta diversity, whereas taxonomic turnover was the dominant component for taxonomic beta diversity. The simulation showed that functional alpha and beta diversities were significantly correlated with taxonomic diversities, and the observed values of correlations were significantly different from null expectations of random extinction. Our assessment of island bird assemblages validated the predictions of no distance effects and low beta diversity due to pervasive dispersal events among islands and also suggested that selective extinction drives taxonomic and functional alpha and beta diversities. The contrasting turnover and nestedness-resultant components of taxonomic and functional beta diversities demonstrate the importance of considering the multifaceted nature of biodiversity when examining community assembly. PMID- 26619393 TI - Association Between Clinician Computer Use and Communication With Patients in Safety-Net Clinics. PMID- 26619394 TI - Effects of hemodialysis on iodine-131 biokinetics in thyroid carcinoma patients with end-stage chronic renal failure. AB - OBJECTIVES: Radioiodine therapy could be challenging in chronic renal failure patients requiring hemodialysis. The aim of this study was to establish the effects of hemodialysis on elimination of radioiodine from the body in thyroid carcinoma patients with end-stage chronic renal failure and to determine its effects on environmental radiation dose. MATERIALS AND METHODS: Three end-stage chronic renal failure patients (four cases) diagnosed with differentiated thyroid carcinoma requiring radioiodine therapy were included in our study. Each patient was given 50-75 mCi (1850-2775 MBq) iodine-131 with 50% dose reduction. Dose rate measurement was performed at the 2nd, 24th, and 48th hour (immediately before and after hemodialysis) after radioiodine administration. The Geiger-Muller probe was held at 1 m distance at the level of the midpoint of the thorax for the dose rate measurement. RESULTS AND CONCLUSION: The effective half-life of iodine-131 for three patients was found to be 44 h. In conclusion, the amount of radioiodine excreted per hemodialysis session was calculated to be 51.25%. PMID- 26619395 TI - Is the bullhead sign on bone scintigraphy really common in the patient with SAPHO syndrome? A single-center study of a 16-year experience. AB - OBJECTIVE: The aim of this study was to assess the bone lesion distribution and analyze the frequency of the bullhead sign in patients with SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome using whole-body bone scintigraphy (WBBS) in a relatively populous study population. METHODS: In this study, the Nuclear Medicine Department's records of one center were retrospectively reviewed and the patients who fulfilled the diagnostic criteria for SAPHO syndrome and underwent Tc-99m-methylene diphosphonate WBBS were identified over a 16-year period. The following data were collected from patients, including age, sex, surgically proved pathology of the bone lesions, WBBS surveillance interval, and SAPHO syndrome components. The bone lesion distribution and the frequency of bullhead sign involving the manubrium and bilateral sternoclavicular junctions were analyzed. RESULTS: Forty-eight patients were enrolled in this study. The initial WBBS indicated bone involvement in all of the 48 (100%) patients, in whom the most commonly affected region was the anterior chest wall (ACW) (100%, 48/48). The frequency of the upper costosternal junction involvement was the highest (38/48, 79.2%), and 28.9% (11/38) patients were found to show isolated involvement of the first rib in ACW. The frequency of the bullhead sign was only 22.9% (11/48, 95% CI: 12.0-37.3). In the eight (16.7%, 8/48) patients who were followed up using WBBS with an interval that ranged from 1 to 10 years, one patient with an initially single sternoclavicular junction lesion developed a typical bullhead sign over 10 years; other patients with or without the initial typical bullhead sign showed stable appearance over 1-4 years. CONCLUSION: This retrospective study shows that in patients with proposed SAPHO syndrome, the bone lesions are most likely located in ACW, and the configuration of the bullhead sign is characteristic, but not entirely sensitive. The value of upper costosternal junction involvement, especially the first rib, may be underevaluated. PMID- 26619396 TI - Temporary changes in neutrophil-to-lymphocyte, platelet-to-lymphocyte ratios, and mean platelet volume reflecting the inflammatory process after radioiodine therapy. AB - OBJECTIVE: Data on the effects of radioiodine (RAI) therapy on systemic inflammation are very limited. The aim of this study is to explore alterations of subclinical systemic inflammatory markers, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and mean platelet volume (MPV), after RAI therapy in patients with differentiated thyroid carcinoma (DTC). MATERIALS AND METHODS: We evaluated 57 DTC patients treated with RAI (RAI group), 37 DTC patients not treated with RAI (non-RAI control group), and 37 age-matched healthy individuals (healthy control group). NLR, PLR, and MPV levels were compared among the study groups; these were also examined after RAI in the RAI group. RESULTS: Initially, NLR was significantly higher in the RAI group than in the healthy controls. NLR and PLR increased significantly and MPV decreased significantly 2 months after RAI therapy (P=0.021, 0.001, and 0.008, respectively). Although NLR and PLR levels decreased, they were still high compared with the preoperative values. MPV returned to normal levels at 6 months. These parameters did not change significantly in the non-RAI control group. CONCLUSION: This is the first study to evaluate changes in NLR, PLR, and MPV after RAI therapy. Our findings suggest that NLR, PLR, and MPV changes indicate systemic inflammation that occurs after RAI therapy because of thyroid remnant tissue ablation. PMID- 26619397 TI - Technetium-99m-labeled doxorubicin as an imaging probe for murine breast tumor (4T1 cell line) identification. AB - OBJECTIVE: Early diagnosis of malignant tumors is essential to successfully plan a radical and curative approach. In this study we describe the direct radiolabeling of doxorubicin (DOX) at physiological pH to identify murine breast tumor (4T1 cells)-bearing BALB/c mice. MATERIALS AND METHODS: Technetium-99m (99mTc) DOX was prepared by adding 99mTc-pertechnetate to a PBS (pH 7.4) solution containing DOX in the presence of stannous chloride. Radiochemical purity and in vitro stability were determined. The circulation time of 99mTc-DOX was determined by measuring blood radioactivity in healthy animals. Scintigraphic images and biodistribution studies were carried out in tumor-bearing mice at 1, 4, and 8 h after injection. RESULTS: The 99mTc-DOX complex showed high radiochemical purity (99.27 +/- 0.34%) and in-vitro stability until 8 h. Tc-DOX levels in blood declined in a biphasic manner, with an alpha half-life of 4.5 min and a beta half life of 277.2 min. High uptake was achieved in kidneys, liver, and spleen, because of the drug elimination routes. Moreover, tumor uptake was higher than that of control tissue, resulting in high tumor-to-muscle ratios. CONCLUSION: DOX was successfully labeled with 99mTc-pertechnetate and showed high stability. Biodistribution and scintigraphic studies indicated high tumor-to-muscle ratios in breast tumor-bearing BALB/c mice. These results suggested the feasibility of 99mTc-DOX as a functional agent in tumor diagnosis. PMID- 26619398 TI - Evaluating simultaneous chromate and nitrate reduction during microbial denitrification processes. AB - Sulfur-based autotrophic denitrification and heterotrophic denitrification have been demonstrated to be promising technological processes for simultaneous removal of nitrate NO3(-) and chromate (Cr (VI)), two common contaminants in surface and ground waters. In this work, a mathematical model was developed to describe and evaluate the microbial and substrate interactions among sulfur oxidizing denitrifying organism, methanol-based heterotrophic denitrifiers and chromate reducing bacteria in the biofilm systems for simultaneous nitrate and chromate removal. The concomitant multiple chromate reduction pathways by these microbes were taken into account in this model. The validity of the model was tested using experimental data from three independent biofilm reactors under autotrophic, heterotrophic and mixotrophic conditions. The model sufficiently described the nitrate, chromate, methanol, and sulfate dynamics under varying conditions. The modeling results demonstrated the coexistence of sulfur-oxidizing denitrifying bacteria and heterotrophic denitrifying bacteria in the biofilm under mixotrophic conditions, with chromate reducing bacteria being outcompeted. The sulfur-oxidizing denitrifying bacteria substantially contributed to both nitrate and chromate reductions although heterotrophic denitrifying bacteria dominated in the biofilm. The mixotrophic denitrification could improve the tolerance of autotrophic denitrifying bacteria to Cr (VI) toxicity. Furthermore, HRT would play an important role in affecting the microbial distribution and system performance, with HRT of higher than 0.15 day being critical for a high level removal of nitrate and chromate (over 90%). PMID- 26619399 TI - Life cycle assessment of water supply alternatives in water-receiving areas of the South-to-North Water Diversion Project in China. AB - To alleviate the water shortage in northern China, the Chinese government launched the world's largest water diversion project, the South-to-North Water Diversion Project (SNWDP), which delivers water from water-sufficient southern China to water-deficient northern China. However, an up-to-date study has not been conducted to determine whether the project is a favorable option to augment the water supply from an environmental perspective. The life cycle assessment (LCA) methodology integrated with a freshwater withdrawal category (FWI) was adopted to compare water supply alternatives in the water-receiving areas of the SNWDP, i.e., water diversion, wastewater reclamation and seawater desalination. Beijing, Tianjin, Jinan and Qingdao were studied as representative cities because they are the primary water-receiving areas of the SNWDP. The results revealed that the operation phase played the dominant role in all but one of the life cycle impact categories considered and contributed to more than 70% of their scores. For Beijing and Tianjin, receiving water through the SNWDP is the most sustainable option to augment the water supply. The result can be drawn in all of the water-receiving areas of the middle route of the SNWDP. For Jinan and Qingdao, the most sustainable option is the wastewater reclamation system. The seawater desalination system obtains the highest score of the standard impact indicators in all of the study areas, whereas it is the most favorable water supply option when considering the freshwater withdrawal impact. Although the most sustainable water supply alternative was recommended through an LCA analysis, multi-water resources should be integrated into the region's water supply from the perspective of water sustainability. The results of this study provide a useful recommendation on the management of water resources for China. PMID- 26619400 TI - Multiple region whole-exome sequencing reveals dramatically evolving intratumor genomic heterogeneity in esophageal squamous cell carcinoma. AB - Cancer is a disease of genome instability and genomic alterations; now, genomic heterogeneity is rapidly emerging as a defining feature of cancer, both within and between tumors. Motivation for our pilot study of tumor heterogeneity in esophageal squamous cell carcinoma (ESCC) is that it is not well studied, but the highest incidences of esophageal cancers are found in China and ESCC is the most common type. We profiled the mutations and changes in copy number that were identified by whole-exome sequencing and array-based comparative genomic hybridization in multiple regions within an ESCC from two patients. The average mutational heterogeneity rate was 90% in all regions of the individual tumors in each patient; most somatic point mutations were nonsynonymous substitutions, small Indels occurred in untranslated regions of genes, and copy number alterations varied among multiple regions of a tumor. Independent Sanger sequencing technology confirmed selected gene mutations with more than 88% concordance. Phylogenetic analysis of the somatic mutation frequency demonstrated that multiple, genomically heterogeneous divergent clones evolve and co-exist within a primary ESCC and metastatic subclones result from the dispersal and adaptation of an initially non-metastatic parental clone. Therefore, a single region sampling will not reflect the evolving architecture of a genomically heterogeneous landscape of mutations in ESCC tumors and the divergent complexity of this genomic heterogeneity among patients will complicate any promise of a simple genetic or epigenetic diagnostic signature in ESCC. We conclude that any potential for informative biomarker discovery in ESCC and targeted personalized therapies will require a deeper understanding of the functional biology of the ontogeny and phylogeny of the tumor heterogeneity. PMID- 26619401 TI - A positive feedback loop between Gli1 and tyrosine kinase Hck amplifies shh signaling activities in medulloblastoma. AB - Sonic hedgehog (Shh) signaling is critical during normal development, and the abnormal activation of the Shh pathway is involved in many human cancers. As a target gene of the Shh pathway and as a transcription activator downstream of Shh signaling, Gli1 autoregulates and increases Shh signaling output. Gli1 is one of the key oncogenic factors in Shh-induced tumors such as medulloblastoma. Gli1 is posttranslationally modified, but the nature of the active form of Gli1 was unclear. Here we identified a Src family kinase Hck as a novel activator of Gli1. In Shh-responsive NIH3T3 cells, Hck interacts with Gli1 and phosphorylates multiple tyrosine residues in Gli1. Gli1-mediated target gene activation was significantly enhanced by Hck with both kinase activity-dependent and independent mechanisms. We provide evidence showing that Hck disrupts the interaction between Gli1 and its inhibitor Sufu. In both NIH3T3 cells and cerebellum granule neuron precursors, the Hck gene is also a direct target of Gli1. Therefore, Gli1 and Hck form a positive feedback loop that amplifies Shh signaling transcription outcomes. In Shh-induced medulloblastoma, Hck is highly expressed and Gli1 is tyrosine phosphorylated, which may enhance the tumorigenic effects of the Gli1 oncogene. RNAi-mediated inhibition of Hck expression significantly repressed medulloblastoma cell growth. In summary, a novel positive feedback loop contributes to maximal Gli1 oncogenic activities in Shh-induced tumors such as medulloblastoma. PMID- 26619404 TI - The Pediatric Infectious Diseases Society Annual Awards, 2012. PMID- 26619405 TI - Impact of a Prospective-Audit-With-Feedback Antimicrobial Stewardship Program at a Children's Hospital. AB - BACKGROUND: The emergence of antibiotic-resistant organisms and the lack of development of new antimicrobials have made it imperative that additional strategies be developed to maintain the effectiveness of these existing antibiotics. The objective of this study was to describe the impact of a prospective-audit-with-feedback antimicrobial stewardship program (ASP) on antibiotic use in a children's hospital. METHOD: A quasi-experimental study design with a control group was performed to assess the impact of a prospective audit-with-feedback ASP. The control group was the combined antibiotic use at 25 similar children's hospitals that are members of the Child Health Corporation of America. RESULTS: The ASP reviewed 10 460 broad-spectrum or select antibiotics in 8765 patients in the 30 months following the intervention. The most common select antibiotics reviewed were ceftriaxone/cefotaxime (43%), vancomycin (18%), ceftazidime (12%), and meropenem (7%). A total of 2378 recommendations were made in 1703 (19%) patients; the most common recommendation was to stop antibiotics (41%). Clinicians were compliant with agreed-upon ASP recommendations in 92% of patients. When comparing our antibiotic use with that of the control group, a monthly decline in all antibiotics of 7% (P = .045) and 8% (P = .045) was observed for days of therapy (DoT) and length of therapy (LoT) per 1000 patient days, respectively. An even greater effect was observed in the select antibiotics as the monthly DoT per 1000 patient-days declined 17% (P < .001) and the monthly LoT per 1000 patient-days declined 18% (P < .001). CONCLUSIONS: A prospective audit-with-feedback ASP can have a significant impact on decreasing antibiotic use at a children's hospital. PMID- 26619402 TI - Targeting self-renewal pathways in cancer stem cells: clinical implications for cancer therapy. AB - Extensive cancer research in the past few decades has identified the existence of a rare subpopulation of stem cells in the grove of cancer cells. These cells are known as the cancer stem cells marked by the presence of surface biomarkers, multi-drug resistance pumps and deregulated self-renewal pathways (SRPs). They have a crucial role in provoking cancer cells leading to tumorigenesis and its progressive metastasis. Cancer stem cells (CSCs) are much alike to normal stem cells in their self-renewal mechanisms. However, deregulations in the SRPs are seen in CSCs, making them resistant to conventional chemotherapeutic agents resulting in the tumor recurrence. Current treatment strategies in cancer fail to detect and differentiate the CSCs from their non-tumorigenic progenies owing to absence of specific biomarkers. Now, it has become imperative to understand complex functional biology of CSCs, especially the signaling pathways to design improved treatment strategies to target them. It is hopeful that the SRPs in CSCs offer a promising target to alter their survival strategies and impede their tumorigenic potential. However, there are many perils associated with the direct targeting method by conventional therapeutic agents such as off targets, poor bioavailability and poor cellular distribution. Recent evidences have shown an increased use of small molecule antagonists directly to target these SRPs may lead to severe side-effects. An alternative to solve these issues could be an appropriate nanoformulation. Nanoformulations of these molecules could provide an added advantage for the selective targeting of the pathways especially Hedgehog, Wnt, Notch and B-cell-specific moloney murine leukemia virus integration site 1 in the CSCs while sparing the normal stem cells. Hence, to achieve this goal a complete understanding of the molecular pathways corroborate with the use of holistic nanosystem (nanomaterial inhibition molecule) could possibly be an encouraging direction for future cancer therapy. PMID- 26619403 TI - Prognostic significance of Versican expression in gastric adenocarcinoma. AB - Gastric cancer (GC) is the leading malignancy in the digestive system. Versican is a ubiquitous component of the extracellular matrix and has a role in tumor progression. We aim to examine the expression of Versican in GC and the relationship between Versican levels and patient survival. We detected the mRNA expression of Versican in tumorous pairs and adjacent normal tissues (ANTs) of 78 GC patients by quantitative real-time polymerase chain reaction. The protein expression of Versican in 101 cases of matched GC and ANT, as well as in 27 intraepithelial neoplastic (IN) samples, was evaluated by immunohistochemistry. We analyzed the correlation between Versican levels and clinical outcomes. Finally, we performed CCK-8 cell counting assay and transwell assay in GC cell lines. Versican mRNA expression was significantly greater in tumor tissues (P<0.001) than in ANT. Versican was majorly expressed in the stroma surrounding tumor epithelium and minorly some areas of tumor epithelium. The Versican expression level was higher in GC than in ANT (P=0.004), but no significant difference was observed between ANT and IN (P=0.517). The Versican mRNA and protein levels were consistent in GC. High Versican mRNA and protein expression correlated with greater tumor invasion depth (P=0.030, P=0.027). Univariate and multivariate analysis revealed that patients with high Versican mRNA expression exhibited poor disease-specific survival (P<0.001). In vitro experiments showed that Versican overexpression promoted cell proliferation and invasion. Our data indicate that Versican may be a novel prognostic indicator in GC and may be a potential target for clinical diagnosis. PMID- 26619406 TI - Editorial Commentary: Quasi-Experimental and Interrupted Time-Series Design. PMID- 26619407 TI - Clinicians' Attitudes Towards an Antimicrobial Stewardship Program at a Children's Hospital. AB - BACKGROUND: In pediatrics, limited data are available on how to develop and implement an antimicrobial stewardship program (ASP). In addition, no data exist on clinicians' impression of such programs. The objectives of this study were to describe the development and implementation of an ASP in a children's hospital and to describe the thoughts and attitudes of the clinicians interacting with the ASP. METHODS: A qualitative description of the development and implementation of an ASP is provided. In addition, 2 years after the implementation of a prospective-audit-with-feedback ASP, an electronic survey was administered to clinicians to assess their attitudes toward the ASP. RESULTS: A 5-step process for developing this ASP included the following: team development; selecting the stewardship strategy(ies) and antimicrobials to monitor; establishing a method to identify patients; program evaluation; and implementation. Of 365 participants surveyed, 205 (56%) responded, and 80% (160 of 199) had never worked with an ASP before its implementation. Clinicians agreed that the ASP decreased inappropriate use of antibiotics (84%, 162 of 194), improved the quality of patient care (82%, 159 of 194), and provided knowledge and education about appropriate antibiotic use (91%, 177 of 194). Negative feelings regarding the ASP included the following: 11% (22 of 194) felt a loss of autonomy; 6% (12 of 194) felt that it interfered with clinical decision-making; and 5% (9 of 194) felt threatened. Clinicians thought that to further decrease inappropriate antibiotic use, guidelines of empiric antibiotic choices (80%, 152 of 189) should be developed, and better training in medical school and residency should be provided (80%, 152 of 189). Finally, our clinicians felt that the problem of antibiotic resistance and inappropriate antibiotic use was worse nationally than at our institution. CONCLUSIONS: A prospective-audit-with-feedback ASP was successfully developed and implemented at a children's hospital. The ASP was perceived by clinicians to reduce inappropriate antibiotic use and to improve the quality of care of hospitalized children, with minimal loss of physician autonomy or interference in clinical decision-making. PMID- 26619408 TI - Editorial Commentary: Improving Antimicrobial Use in Children by Interacting With Prescribing Clinicians. PMID- 26619409 TI - Prevalence and Characteristics of Human Metapneumovirus Infection Among Hospitalized Children at High Risk for Severe Lower Respiratory Tract Infection. AB - BACKGROUND: Human metapneumovirus (HMPV) is a significant cause of respiratory tract infections. Little is known about HMPV in children who are at high risk for lower respiratory tract infection (LRTI). METHODS: To determine the prevalence of HMPV in high-risk children and to identify HMPV risk factors, children <=24 months with prematurity, chronic lung disease, and/or congenital cardiac disease who were hospitalized with LRTI were prospectively enrolled. Nasopharyngeal aspirates were tested for HMPV, respiratory syncytial virus (RSV), influenza A and B, and parainfluenza types 1-3. Demographics, medical history, and outcomes for those with HMPV and RSV were compared. A multivariate analysis was performed to determine HMPV risk factors. RESULTS: Over 4 years, 1126 eligible children were enrolled. Pathogens were identified in 61% of subjects. HMPV was identified in 9.0%, second to RSV (45%). Coinfection with HMPV and RSV occurred in <1% of subjects. Subjects infected with HMPV were older (8.2 vs 4.0 months, P < .001), were born more prematurely (27 vs 33 weeks, P < .001), and more commonly had chronic lung disease (59.3% vs 21.8%, P < .001) compared with subjects infected with RSV. In a multivariate analysis that compared children infected with HMPV to all others, increasing age and household exposure to children ages 6-12 were associated with an increased risk, whereas birth at older gestational age and exposure to children age >12 were associated with a decreased risk. CONCLUSIONS: HMPV was detected in 9% of high-risk children who were hospitalized with lower respiratory tract disease, representing the second most common virus in this population. Compared with all other subjects (including RSV-infected), subjects infected with HMPV were older but were born more prematurely. PMID- 26619410 TI - Neonatal Cryptococcosis: Beware of False-positive Results. AB - Although cryptococcal meningitis is uncommon in children and rare in neonates, it does occur. We highlight circumstances in which the diagnosis should be considered and methods required to confirm the diagnosis in young patients. PMID- 26619411 TI - Unexplained Fever After a Camping Trip in the American Southwest. PMID- 26619412 TI - Literature Review. PMID- 26619413 TI - Drug Safety Resources for Healthcare Professionals and Consumers. PMID- 26619414 TI - Erratum. PMID- 26619419 TI - Pediatric Infectious Diseases Society 2012 IDWeek Award Recipients. PMID- 26619421 TI - Exploring the Epidemiology of Hospital-Acquired Bloodstream Infections in Children in England (January 2009-March 2010) by Linkage of National Hospital Admissions and Microbiological Databases. AB - BACKGROUND: Hospital-acquired bloodstream infection (HA-BSI) requires immediate effective antibiotic treatment. However, there are no published national data for England that describe the pathogen profile and antibiotic resistance rates of HA BSI in children. METHODS: Probabilistic matching methods were used to link national data on microbiologically confirmed BSI to hospital in-patient admissions data for the period of January 2009-March 2010. HA-BSI was defined as a positive blood culture drawn from a child aged 1 month-18 years 2 or more days after admission (and before discharge). RESULTS: A total of 8718 episodes of BSI was reported during the study period. Linkage allowed 82% of records to be matched, of which 23% (1734) were HA-BSI, giving a rate of 4.74 per 1000 admissions. The median age of infection was 1 year, and 54% of infections were in males. Methicillin resistance was seen in 83% and 17% of coagulase-negative staphylococci and Staphylococcus aureus, respectively. Penicillin resistance was rare in pyogenic streptococci but more common in viridans streptococci (39%). Among Gram-positive organisms, only 3% were vancomycin-resistant. The overall proportion of Gram-negative bacteria resistant to recommended empirical antibiotics (meropenem or piperacillin/tazobactam) was 5% and 16%, respectively, but <4% of isolates were resistant when either of these drugs were combined with gentamicin. CONCLUSIONS: This study provides the first national estimates of the proportion of pediatric BSI that is hospital-acquired and describes the antimicrobial resistance of organisms causing infection. Pediatric HA-BSI remains unacceptably high; interventions must focus on identifying effective means of preventing HA-BSI, fostering antibiotic stewardship, and improving surveillance. PMID- 26619420 TI - Assessment of Cytomegalovirus Hybrid Preventative Strategy in Pediatric Heart Transplant Patients. AB - BACKGROUND: Prevention strategies for cytomegalovirus (CMV) in pediatric transplant recipients are sparsely reported. A hybrid strategy that combines prophylaxis with preemptive therapy using serial CMV viral load monitoring is an emerging option. We report our clinical outcomes with a hybrid strategy in pediatric heart transplant recipients. METHODS: A retrospective chart review was performed for pediatric heart transplant recipients who received a hybrid strategy of 2-4 weeks intravenous ganciclovir followed by serial whole blood CMV monitoring from 2002 to 2010. Subject demographics, medications, drug levels, serial CMV viral loads, intravascular ultrasound and angiography reports, and histopathology were collected. Descriptive statistics and patient groups were compared using chi(2), Fisher's exact, and Wilcoxon rank-sum tests. RESULTS: Twelve females and 13 males, ranging from 4 months to 19 years of age, underwent 26 heart transplants. Mean follow-up was 39 months (range, 5-94 months). Fourteen (54%) subjects were CMV donor (D) + /recipient (R) - , 8 (31%) were D + /R + , and 4 (15%) were D - /R + . Six subjects (23%) died of complications unrelated to CMV. Median prophylaxis duration was 25 days (range, 7-70 days). Ten (38%) subjects developed CMV infection: 1 subject had 2 episodes of CMV syndrome, and 1 subject had 2 episodes CMV. Although 6 of 14 patients with coronary artery vasculopathy had prior CMV, no association was found (P = .81). Median time to first CMV DNAemia was 2.3 months (range, 9 days to 24.8 months). Median time to viral load clearance was 29 days (range, 4-233 days). In addition, 25 D - /R- patients were transplanted and received no prophylaxis; 2 (8%) patients developed CMV infection. CONCLUSIONS: Pediatric heart transplant recipients who were at risk for CMV and treated with a novel preventative hybrid strategy developed CMV infection, syndrome, and disease at rates similar to those reported in literature for prophylactic strategies. PMID- 26619422 TI - Electrocardiograph Abnormalities in Children With Lyme Meningitis. AB - OBJECTIVE: The objective of the study was to estimate the prevalence of and identify risk factors for electrocardiographic (ECG) changes in children presenting with Lyme meningitis. DESIGN: This was a cross-sectional study. SETTING: The study was set in three large urban pediatric tertiary care centers. PARTICIPANTS: Children who were diagnosed with Lyme meningitis and underwent ECG testing were included. OUTCOME MEASURE: The presence of an ECG abnormality associated with early-disseminated Lyme infection was the outcome measure. RESULTS: Multivariable logistic regression was used to identify factors independently associated with ECG abnormalities. ECG testing was performed in 103 (66%) of 157 children with Lyme meningitis. The median age of these children was 10.8 years; 68% were male. ECG abnormalities, identified in 34 (33%) subjects, included one or more of the following: atrioventricular block (n = 16; 16%), ST-T wave changes (n = 14; 14%), and prolongation of the corrected QT interval (n = 11; 11%). In multivariate analysis, age >=13 years and fever for >=5 days were independently associated with ECG abnormalities. The probability of ECG abnormalities was greater than 50% in those with fever for >=5 days or age >=13 years, and if a subject fulfilled both criteria, the probability of ECG abnormalities was 83% (95% confidence interval: 50%-96%). CONCLUSIONS: Electrocardiographic abnormalities occur commonly in children with Lyme meningitis. While older children with prolonged fever were most likely to have such abnormalities, the clinical consequences of asymptomatic ECG abnormalities in children with Lyme meningitis are not known. PMID- 26619424 TI - Community-Acquired Pneumonia in the Conjugate Vaccine Era. AB - Community-acquired pneumonia (CAP) remains one of the most common serious infections encountered among children worldwide. In this review, we highlight important literature and recent scientific discoveries that have contributed to our current understanding of pediatric CAP. We review the current epidemiology of childhood CAP in the developed world, appraise the state of diagnostic testing for etiology and prognosis, and discuss disease management and areas for future research in the context of recent national guidelines. PMID- 26619423 TI - Primary Maternal Herpes Simplex Virus-1 Gingivostomatitis During Pregnancy and Neonatal Herpes: Case Series and Literature Review. AB - BACKGROUND: Neonatal herpes simplex virus (HSV) is a serious, life-threatening infection that is usually acquired during birth from contact with infected maternal genital secretions. Primary maternal HSV gingivostomatitis is a rare occurrence during pregnancy, and HSV type 1 (HSV-1) neonatal disease after primary maternal HSV gingivostomatitis during pregnancy has not been reported in detail. METHODS: We reviewed the medical records of neonates (<=28 days of age) with a confirmed diagnosis of neonatal HSV-1 at a single pediatric center from January 1981 to January 2010 to identify cases in which the mother had primary gingivostomatitis during pregnancy or at term. RESULTS: Seven neonates whose mothers had primary HSV-1 gingivostomatitis during pregnancy were identified from a review of 48 neonates with laboratory-proven HSV-1 neonatal disease. Of the 7 women, 2 presented with symptoms of primary HSV-1 gingivostomatitis during the first trimester and 5 in the third trimester. Three of the neonates developed skin, eye, and mucous membrane disease, 2 developed central nervous system disease, and 2 developed disseminated disease. One of the neonates with disseminated HSV-1 disease died. CONCLUSIONS: Primary maternal HSV gingivostomatitis during pregnancy may lead to HSV-1 transmission to the neonate. Physicians caring for pregnant women should communicate the diagnosis of HSV gingivostomatitis to the neonate's primary provider to ensure proper surveillance, early evaluation, and prompt treatment. PMID- 26619425 TI - Duration of Shedding and Secondary Household Transmission of Shiga Toxin Producing Escherichia coli O26 During an Outbreak in a Childcare Center, Oregon, October-December 2010. AB - We assessed shedding duration and secondary household transmission of Shiga toxin 1-positive Escherichia coli O26 during a childcare-associated outbreak. No severe illness was noted. Shedding duration was 15-46 days (median, 29). No secondary transmission to household members was identified. Value of isolating asymptomatic infected children with this low-virulence infection remains uncertain. PMID- 26619426 TI - Ustilago as a Cause of Fungal Peritonitis: Case Report and Review of the Literature. AB - Fungal peritonitis is an uncommon complication of ambulatory peritoneal dialysis in children and often necessitates catheter removal, prolonged hospitalization and conversion to hemodialysis. The majority of these infections are due to Candida albicans and related species. We present an uncommon case of peritonitis due to the unusual plant pathogen Ustilago. PMID- 26619427 TI - Escherichia coli Bacteremia, Epididymo-Orchitis, and Scrotal Abscess in a Neonate. AB - Epididymo-orchitis (EO) is a rare but important cause of scrotal swelling in pediatric patients. EO is caused by bacteremia leading to hematogenous seeding or ascending infection of the urinary tract. EO can be associated with abscess, bacteremia, and other serious infections, and must be distinguished from other causes of scrotal swelling such as testicular torsion. We present a case of a 16 day-old male with EO, scrotal abscess, and bacteremia from Escherichia coli. PMID- 26619428 TI - Biomarkers in Infectious Diseases. AB - Biomarkers are becoming increasingly important tools within all areas of medicine. Potential applications of biomarkers in infectious diseases include distinguishing bacterial from nonbacterial infection, monitoring response to therapy, and predicting outcomes. Continued research into a number of noninvasive urinary, serologic, and genetic biomarkers will help clinicians with diagnosis, prognosis, and treatment. The following is a brief synopsis of several recent publications exploring the potential roles of biomarkers in infectious diseases. PMID- 26619429 TI - A Pink Milk Bottle Mystery. PMID- 26619431 TI - Letter to the Editor. PMID- 26619437 TI - Characteristics of Severe Bordetella pertussis Infection Among Infants <=90 Days of Age Admitted to Pediatric Intensive Care Units - Southern California, September 2009-June 2011. AB - BACKGROUND: Bordetella pertussis infection can cause severe illness and death among young infants. METHODS: We collected demographic and clinical information from the medical records of infants who were <=90 days of age and hospitalized for pertussis in 5 Southern California pediatric intensive care units (PICUs) from September 1, 2009 to June 30, 2011. Infants who died or were diagnosed with pulmonary hypertension were considered to have more severe pertussis. RESULTS: Thirty-one infants were admitted to a participating PICU. Eight infants had more severe infections, 6 infants had pulmonary hypertension, and 4 infants died. The 8 infants with more severe infections had white blood cell counts that exceeded 30 000, heart rates that exceeded 170, and respiratory rates that exceeded 70 more rapidly after cough onset than the 23 infants with less severe illness. CONCLUSIONS: Identifying higher-risk infants earlier might allow for more rapid implementation of interventions. PMID- 26619438 TI - Risk Factors Associated With Rotavirus Gastroenteritis During a Community Outbreak in Chiapas, Mexico During the Postvaccination Era. AB - BACKGROUND: In January 2010, surveillance detected a rotavirus gastroenteritis outbreak in Chiapas, Mexico. We aimed to identify risk and protective factors for developing rotavirus gastroenteritis of any severity among children in the epidemic setting. METHODS: A case-control study was conducted, comparing case patients (defined as children <36 months of age with acute gastroenteritis of any severity whose stool tested positive for rotavirus by enzyme immunoassay) with age- and municipality-matched controls. Information was obtained through face-to face interviews on clinical outcome, demographics, breastfeeding history, rotavirus immunization status, and indicators of socioeconomic status. RESULTS: Eighty-five case patients and 170 controls were enrolled. Factors associated with lower risk of rotavirus gastroenteritis included current breastfeeding, owning a refrigerator, and being immunized with 1 or 2 doses of a live-attenuated monovalent rotavirus vaccine. History of previous diarrheal episodes and living with 7 or more people in the same household were associated with higher risk of developing rotavirus gastroenteritis. CONCLUSION: During this outbreak, dietary, socioeconomic, and environmental factors were independently associated with risk of developing rotavirus disease. Rotavirus vaccine also offered significant protection against rotavirus disease of any severity, emphasizing the value of vaccination as a simple and highly effective public health strategy for prevention of rotavirus illness. PMID- 26619439 TI - Clinical Predictors of Influenza in Young Children: The Limitations of "Influenza Like Illness". AB - BACKGROUND: Influenza-like illness (ILI) definitions have been infrequently studied in young children. Despite this, clinical definitions of ILI play an important role in influenza surveillance. This study aims to identify clinical predictors of influenza infection in children <=5 years old from which age specific ILI definitions are then constructed. METHODS: Children aged 6-59 months with a history of fever and acute respiratory symptoms were recruited in the Western Australia Influenza Vaccine Effectiveness (WAIVE) Study. Clinical data and per-nasal specimens were obtained from all children. Logistic regression identified significant predictors of influenza infection. Different ILI definitions were compared for diagnostic accuracy. RESULTS: Children were recruited from 2 winter influenza seasons (2008-2009; n = 944). Of 919 eligible children, 179 (19.5%) had laboratory-confirmed influenza infection. Predictors of infection included increasing age, lack of influenza vaccination, lower birth weight, fever, cough, and absence of wheeze. An ILI definition comprising fever >=38 degrees C, cough, and no wheeze had 58% sensitivity (95% confidence interval [CI], 50-66), 60% specificity (95% CI, 56-64), 26% positive predictive value (95% CI, 21-31), and 86% negative predictive value (95% CI, 82-89). The addition of other symptoms or higher fever thresholds to ILI definition had little impact. The Centers for Disease Control and Prevention definition of ILI (presence of fever [>=37.8 degrees C] and cough and/or sore throat) was sensitive (92%; 95% CI, 86-95), yet lacked specificity (10%; 95% CI, 8-13) in this population. CONCLUSIONS: Influenza-like illness is a poor predictor of laboratory-confirmed influenza infection in young children but can be improved using age-specific data. Incorporating age-specific ILI definitions and/or diagnostic testing into influenza surveillance systems will improve the accuracy of epidemiological data. PMID- 26619440 TI - Molecular Characterization of Invasive Staphylococcus aureus Infection in Central New York Children: Importance of Two Clonal Groups and Inconsistent Presence of Selected Virulence Determinants. AB - BACKGROUND: The genetic makeup of circulating Staphylococcus aureus (SA) populations varies by region. The extent to which SA virulence determinants contribute to the severity of pediatric infections is poorly understood. The study objective was to describe the genetic population of invasive SA (ISA) isolates from children in the Central New York (CNY) area and the prevalence of selected virulence genes. METHODS: Clinical and demographic information for hospitalized children <19 years of age with community-onset or community associated ISA infections, determined from clinical microbiology records, was extracted from medical records from Upstate Golisano Children's Hospital in CNY. Antibiotic susceptibility was assessed, and available isolates were genotyped and tested for the presence of selected virulence determinants. Associations between clinical and laboratory findings were evaluated using standard statistical techniques. RESULTS: Ninety patients with ISA disease diagnosed between 2007 and 2010 were included in the study; 74% were due to methicillin-susceptible SA (MSSA). The most common clinical diagnosis was bacteremia. Fifty-seven of 90 isolates were available for further testing. The SA pulsed-field gel electrophoresis type, agr type, and clonal complexes most commonly isolated were USA300 (n = 25, 44%), agr1 (n = 30, 52%), and CC8 (n = 25, 44%), respectively. USA300 strains were more likely to be associated with deep abscesses (P = .007), whereas non-USA300 strains were associated with medical device infections (P = .018). Isolates from patients with deep abscesses and pneumonia were more likely to carry luk-PV genes (P = .023 and P = .051, respectively). CONCLUSIONS: MSSA remains an important problem of pediatric ISA infection in our region and results from genetically diverse SA populations. PMID- 26619441 TI - Washington State Licensed Child Care Facility Directors' Perspectives on Childhood Immunization. AB - BACKGROUND: The study objective was to determine Washington State childcare facility directors' compliance with state immunization education and monitoring requirements and the role of directors' immunization attitudes and beliefs on compliance. METHODS: We mailed a self-administered survey to 2000 randomly selected childcare facility directors in Washington State. The primary outcome measures were reported compliance with state requirements to educate parents about the importance of immunizations and monitor the immunization status of enrolled children. RESULTS: Our response rate was 28%. The majority of respondents worked at facilities with a licensed capacity of <25 children, had >=11 years of experience, and were parents themselves. Overall, 68% agreed that they educated enrolled parents about the importance of immunizations and 90% agreed that they monitored the immunization status of enrolled children. However, 60% were concerned that children might have a serious side effect from an immunization, 51% were concerned that any one of the childhood immunizations might not be safe, and 11% were distrustful of the immunization information they received. These beliefs were associated with a statistically significant decreased likelihood of educating parents about immunization (adjusted odds ratios [aORs]: 0.57, 0.46, 0.19, respectively) and monitoring immunization status of children (aORs: 0.32, 0.32, 0.19, respectively). CONCLUSIONS: Most Washington State child care facility directors who responded to our survey are compliant with state requirements for immunization education and monitoring. A substantial number of directors are concerned about vaccine safety, however, and these concerns may decrease the likelihood of these requirements being followed. PMID- 26619442 TI - Central Nervous System Vasculopathy in HIV-Infected Children Enrolled in the Pediatric AIDS Clinical Trials Group 219/219C Study. AB - BACKGROUND: Central nervous system (CNS) vasculopathy has been reported in human immunodeficiency virus-infected (HIV+) adults and children. In children, it often presents with HIV encephalopathy, stroke, or intracerebral aneurysms. The etiology, incidence, and risk factors of HIV-associated CNS vasculopathy in children are unknown. METHODS: We identified HIV+ children with a diagnosis of vasculopathy or other cerebrovascular events among children enrolled between 1993 and 2004 in 2 prospective, multicenter cohort studies. Demographic and laboratory data, history of antiretroviral use, and signs, symptoms, and diagnostic studies pertaining to the CNS event were reviewed. RESULTS: Among the 3338 HIV+ children, 51 had diagnoses that suggested CNS vasculopathy. Of these, 12 (24%) were included in this analysis, after excluding those with alternative diagnoses and those from closed sites. Among these 12, 4 (33%) were female, 4 (33%) were white, and 10 (83%) had perinatal HIV. Their average age at the event was 10.8 years with a median CD4 count of 22 cells/mm(3) and median HIV-1 viral load of 94 304 copies/mL. Fifty-eight percent of subjects had a history of opportunistic infections before the CNS event. Fifty percent had cerebral aneurysms on imaging. The overall incidence among HIV+ subjects was 3.4 cases per 10 000 person-years (95% confidence interval, 1.8-6.0). CONCLUSIONS: CNS vasculopathy in HIV+ children is uncommon but more common than in the general pediatric population. Cerebral aneurysms are the most common manifestation. Although the pathogenesis remains unclear, older children and those with low CD4 counts and high HIV viral loads are at the highest risk. PMID- 26619443 TI - Editorial Commentary: Challenges to Estimating Norovirus Disease Burden. PMID- 26619444 TI - Use of Administrative Data for the Identificationof Laboratory-Confirmed Influenza Infection: The Validity ofInfluenza-Specific ICD-9 Codes. AB - We used Pediatric Health Information System data and laboratory records from 3 children's hospitals to determine whether administrative data accurately identify children with laboratory-confirmed influenza. Among 23 282 inpatients, diagnosis codes for influenza detected 73% of laboratory-confirmed influenza cases, whereas <1% of patients without a diagnosis code had laboratory-confirmed influenza. PMID- 26619445 TI - A Randomized, Controlled Trial of Catheter-Related Infectious Event Rates Using Antibiotic-Impregnated Catheters Versus Conventional Catheters in Pediatric Cardiovascular Surgery Patients. AB - : We conducted a randomized, controlled clinical trial to determine whether a difference in catheter-associated blood stream infection (CABSI) incidence existed between children who underwent cardiac surgery and had a central venous catheter impregnated with minocycline and rifampin versus those who had a conventional, nonimpregnated catheter after cardiac surgery. Due to a lower number of infections than expected, the study was terminated early. Among 288 evaluable patients, the rates of CABSI and line-related complications were similar between the 2 groups. PMID- 26619446 TI - Cytomegalovirus Enterocolitis Mimicking Necrotizing Enterocolitis: Case Reports and Review of the Literature. AB - A case of necrotizing enterocolitis (NEC) with pathologic evidence of cytomegalovirus (CMV) infection is presented. This preterm infant developed abdominal distention and tachycardia, and a clinical diagnosis of NEC was made. Acute bowel obstruction occurred 20 days later. Biopsy specimens of the ileum obtained during laparotomy showed extensive CMV inclusion bodies and positive immunoperoxidase staining for CMV. Urine culture and polymerase chain reaction from the blood were also positive for CMV. The patient was treated with ganciclovir and recovered. Thirty-two similar cases of CMV enterocolitis and intestinal obstruction in premature and full term babies are reviewed here. PMID- 26619447 TI - Broncholithiasis From Histoplasmosis in a Pediatric Patient: Case Reports and Review of Literature. AB - Broncholithiasis is a calcification in the airway. Though broncholiths are not common, it is even more unusual in a pediatric patient. We present a 15-year-old immunocompetent pediatric patient who had a broncholith that was found and removed by bronchoscopy. PMID- 26619448 TI - Acute Amoebic Appendicitis: Case Reports and Review of Parasitic Appendicitis. AB - Amoebic appendicitis is very rare, occurring in about 0.5% to 2% of acute appendicitis, and usually not reported in children. We report a case of confirmed acute amoebic appendicitis complicating amoebic colitis in a 7-year-old Pakistani boy living in southern Jeddah, Saudi Arabia, and briefly review the literature on parasitic appendicitis. PMID- 26619450 TI - False-Positive Results for Immunoglobulin M Serologic Results: Explanations and Examples. PMID- 26619449 TI - Clostridium difficile Infection. AB - The incidence and severity of Clostridium difficile infections have increased over the past few decades. New challenges have developed in the treatment and prevention of both hospital- and community-acquired disease. As mentioned by Tamma and Sandora [ 1] in their recent review, many questions about C difficile management in children remain unanswered, forcing pediatricians to rely on adult studies for guidance. The following is a brief synopsis of a few recent publications that focused on C difficile infections, including comments regarding the implications within pediatric infectious diseases. PMID- 26619451 TI - Jerry Shenep, MD. PMID- 26619456 TI - Tribute to Caren Hall. PMID- 26619457 TI - Update From the Advisory Committee on Immunization Practices. PMID- 26619458 TI - Measles Outbreak Associated With International Travel, Indiana, 2011. AB - BACKGROUND: Endemic measles was declared eliminated in the United States in 2000, but imported measles cases continue to cause outbreaks. On June 20, 2011, 5 epidemiologically linked measles cases were reported to the Indiana State Department of Health. We investigated to identify additional cases and to prevent further spread. METHODS: Case findings and contact investigations during the June 3, 2011-August 13, 2011 outbreak identified measles cases, exposed persons, and exposure settings. Laboratory confirmation included measles serology and reverse transcription polymerase chain reaction. Control measures included evaluating measles immune status and providing post-exposure prophylaxis, isolation, and quarantine. RESULTS: Fourteen confirmed measles illnesses were identified (10 [71%] females; median age, 11.5 years [range, 15 months-27 years]). The source patient was an unvaccinated US resident who recently traveled from Indonesia. Twelve patients were unvaccinated members of the source patient's extended family. Two hospitalizations and no deaths were reported. Among 868 exposed persons identified through contact investigation, 644 (74%) had documented measles immunity, 153 (18%) were lost to follow-up, and 71 (8%) lacked evidence of immunity. CONCLUSIONS: Misdiagnosis of measles in an unvaccinated patient with recent travel history to a measles-endemic region resulted in the second largest measles outbreak in the United States during 2011. Clinicians should consider measles among patients presenting with febrile rash illness and history of recent travel, and clinicians should promptly report suspected illnesses. Early identification of infectious patients, rapid public health investigation, and maintenance of high vaccine coverage are critical for the prevention and control of measles outbreaks. PMID- 26619459 TI - Significance of Negative Cultures in the Treatment of Acute Hematogenous Bone and Joint Infections in Children. AB - BACKGROUND: Synovial fluid and blood cultures often remain negative in acute bone and joint infections of childhood even when characteristic symptoms, signs, and/or radiologic proof are present. METHODS: We analyzed 345 prospectively documented osteoarticular infections in children at age 3 months to 15 years. In 23% of the cases (N = 80), synovial, bone, and/or blood cultures remained negative. The characteristics of these cases were compared with patients with culture-positive bone and joint infections. RESULTS: The 2 groups did not differ in age or gender distribution, surgical procedures performed, or outcome. In the culture-negative cases, the initial serum C-reactive protein level was lower (58 vs 87 mg/L, P < .0001) and the hospital stay was shorter (8 vs 11 days, P < .0001). CONCLUSIONS: Bone and joint infections in which cultures fail to identify the causative agent can be treated similarly as culture-positive cases. PMID- 26619460 TI - The Prevalence of Disclosure of HIV Status to HIV-Infected Children in Western Kenya. AB - BACKGROUND: As antiretroviral therapy (ART) allows the world's 2.3 million human immunodeficiency virus (HIV)-infected children to grow and thrive, these children need to be informed of their HIV status. Neither the prevalence of disclosure to children nor its impact has been evaluated in most resource-limited settings. METHODS: We conducted a prospective assessment of a random sample of HIV-infected children ages 6-14 years enrolled in HIV care at a large referral clinic in Eldoret, Kenya. Clinicians administered questionnaires to children and caregivers independently at routine clinic visits to assess disclosure status, ART adherence, stigma, and depression. Children's demographic and clinical characteristics were extracted from chart review. We calculated descriptive statistics and performed logistic regression to assess the association between disclosure and other characteristics. RESULTS: Two hundred seventy children caregiver dyads completed questionnaires. The mean child age was 9.3 years (standard deviation 2.6); 49% were male, and 42% were orphans. 11.1% of children had been informed of their HIV status (N = 30). Of those under 10 years, 3.3% knew their status, whereas 9.2% of 10- to 12-year-olds and 39.5% of 13- to 14 year-olds knew they had HIV. Only age was significantly associated with disclosure status in both bivariate analyses (P < .0001) and multiple logistic regression (odds ratio 1.67, 95% confidence interval 1.36-2.05) when considering social demographics, disease stage variables, adherence, stigma measures, and depression. CONCLUSIONS: Rates of informing children in western Kenya of their HIV status are low, even among older children. Guiding families through developmentally appropriate disclosure processes should be a key facet of long term pediatric HIV management. PMID- 26619461 TI - Editorial Commentary: Disclosure of HIV Status to HIV-Infected Children in Areas With High HIV Prevalence. PMID- 26619462 TI - Serum Concentrations of Mannan-Binding Lectin (MBL) and MBL-Associated Serine Protease-2 and the Risk of Adverse Events in Pediatric Patients With Cancer and Fever in Neutropenia. AB - BACKGROUND: It is unknown whether serum concentrations of mannan-binding lectin (MBL) and MBL-associated serine protease-2 (MASP-2) influence the risk of adverse events (AEs) in children with cancer presenting with fever in neutropenia (FN). METHODS: Pediatric patients with cancer presenting with FN after non myeloablative chemotherapy were observed in a prospective multicenter study. Mannan-binding lectin and MASP-2 were measured using commercially available enzyme-linked immunosorbent assay in serum taken at cancer diagnosis. Multiple FN episodes per patient were allowed. Associations of MBL and MASP-2 with AE in general, with bacteremia, and with serious medical complications (SMC) during FN were analyzed using mixed logistic regression. RESULTS: Of 278 FN episodes, AE was reported in 84 (30%), bacteremia was reported in 42 (15%), and SMC was reported in 16 (5.8%). Median MBL was 2152 ng/mL (range, 7-10 060). It was very low (<100) in 11 (9%) patients, low (100-999) in 36 (29%) patients, and normal (>=1000) in 79 (63%) patients. Median MASP-2 was 410 ng/mL (range, 68-2771). It was low (<200) in 18 (14%) patients and normal in the remaining 108 (86%) patients. Mannan-binding lectin and MASP-2 were not significantly associated with AE or bacteremia. Normal versus low MBL was independently associated with a significantly higher risk of SMC (multivariate odds ratio, 12.8; 95% confidence interval, 1.01-163; P = .050). CONCLUSIONS: Mannan-binding lectin and MASP-2 serum concentrations were not found to predict the risk to develop AEs or bacteremia during FN. Normal MBL was associated with an increased risk of SMC during FN. This finding, in line with earlier studies, does not support the concept of MBL supplementation in MBL-deficient children with cancer presenting with FN. PMID- 26619464 TI - Gastric Aspirate Yield For Children With Suspected Pulmonary Tuberculosis. AB - The optimal number of gastric aspirates to diagnose tuberculosis is unclear. Thirty-two of 280 (11%) children in whom gastric aspirates were obtained grew Mycobacterium tuberculosis. First, second, and third specimens yielded initial culture positivity in 24 of 32, 6 of 32, and 2 of 24 cases, respectively. Intermittent positivity and paucibacillary disease necessitate obtaining multiple specimens. PMID- 26619463 TI - Implications of Age-Dependent Immune Responses to Enterovirus 71 Infection for Disease Pathogenesis and Vaccine Design. AB - Epidemics of enterovirus serotype 71 (EV71) infection in Asia appear to be increasing in size and severity, and there is increasing concern for pandemic spread. Efforts are underway to develop an effective EV71 vaccine. However, the immunologic correlates of protection against EV71 infection are not fully understood, and studies suggest that severe complications may result from a combination of pathological immune responses and direct viral effects. Severe disease and death typically occur only in young children, which is likely due in part to a lack of EV71-specific adaptive immunity but possibly also due to age dependent hyperactive innate immune responses. Infants are the primary targets of EV71 vaccination strategies. Therefore, studies are needed to understand the interplay between age, immunopathology, and severity of EV71 infection to distinguish protective from harmful immune responses and to guide the development of effective EV71 vaccines. This review summarizes our current understanding and outlines the next steps forward. PMID- 26619465 TI - Bacillary Angiomatosis in Patients With Cancer: A Pediatric Case Report and a Review of the Literature. PMID- 26619466 TI - Acyclovir Dosing in the Neonatal Period and Beyond. PMID- 26619468 TI - About the Cover (March 2013). PMID- 26619467 TI - It Takes an Epidemic to Move a Village: Severe Pertussis Disease in Infants in the 21st Century. PMID- 26619469 TI - Murray et al (J Pediatric Infect Dis Soc 2013; 2:1-6). PMID- 26619474 TI - 35th Annual Pediatric Infectious Diseases Society Awards. AB - The following is a compilation of the 2013 Pediatric Infectious Diseases Society Awards presented on Monday, May 6, 2013 during the Pediatric Academic Societies meeting in Washington, DC. Award summaries were adapted from submissions provided by the nominating physician. PMID- 26619475 TI - Changes in Advanced Immunosuppression and Detectable HIV Viremia Among Perinatally HIV-Infected Youth in the Multisite United States HIV Research Network. AB - BACKGROUND: Due to successful antiretroviral therapy (ART), perinatally human immunodeficiency virus (PHIV)-infected children are reaching adolescence and young adulthood. Adolescence is characterized by factors (eg, increased risk taking) that may hamper management. We examined PHIV-infected youth in a multisite US cohort, assessing factors associated with changes in advanced immunosuppression and detectable viremia over time. METHODS: We conducted a retrospective study of 521 PHIV-infected youth, 12 years and older, followed at 16 HIV clinics in the HIV Research Network between 2002 and 2010. We assessed demographic and clinical factors associated with CD4 <200 cells/mm(3) and viral load >=2.60 log10 HIV-1 RNA copies/mL using multivariable logistic regression. RESULTS: Between 2002 and 2010, the median age of PHIV-infected youth in care increased from 14 to 18 years. The proportion prescribed ART increased from 67.4% to 84%, with virologic suppression increasing from 35.5% to 63.0% (P trend < .01). Older age, Black and Hispanic race/ethnicity, and increasing viremia were independently associated with CD4 <200 cells/mm(3). Older age, Black race and Hispanic ethnicity were independently associated with higher likelihood of detectable viremia, whereas more recent year of evaluation and being prescribed ART were associated with a lower likelihood. CONCLUSIONS: The proportion of PHIV infected youth on ART has increased. Rates of viremia and advanced immunosuppression have decreased in recent years, but both rates are higher for older PHIV-infected youth. Factors associated with advanced immunosuppression and viremia offer the chance to define strategies to optimize outcomes. PMID- 26619476 TI - Spectrum of Disease in Children Treated for Tuberculosis at a Tertiary Children's Hospital in Australia. AB - BACKGROUND: Tuberculosis (TB) notification rates in Australia have plateaued at a low level, but the pediatric disease burden remains poorly described. Child cases provide a marker of recent transmission and present unique diagnostic challenges. METHODS: We performed an audit of all children (<18 years of age) treated for TB at the Children's Hospital at Westmead, Sydney, Australia from January 2008 to December 2011. Demographics, clinical presentation, diagnostics, disease profile, treatment, and outcome were reviewed. RESULTS: A total of 25 children were treated for TB: 15 had microbiologically confirmed TB; 7 were diagnosed on clinical grounds; and in 3, an alternate diagnosis was established (2 bacille Calmette-Guerin disease and 1 atypical mycobacterial infection). Of the 22 TB cases, 21 had a history of immigration or travel to a TB-endemic country and 4 reported recent contact with a TB source case within Australia. Isolated intrathoracic TB was documented in 16 (72%) cases. Symptoms on presentation included the following: lethargy, weakness, or malaise (75%); fever (73%); and cough (64%). Among the 15 children with microbiologically confirmed TB, 11 (73%) were positive by culture and 11 of 13 (85%) by polymerase chain reaction test. Tuberculin skin test was positive (>=10 mm) in 80% (16 of 20) of cases, and interferon-gamma release assay was positive in 87% (13 of 15) of cases. All children received directly observed therapy and recovered. CONCLUSIONS: This series demonstrates the broad spectrum of disease with which pediatric TB cases present and the need for ongoing vigilance. A more comprehensive review of pediatric TB cases throughout Australia would be informative. PMID- 26619477 TI - Epidemiology of Infant Salmonellosis in the United States, 1996-2008: A Foodborne Diseases Active Surveillance Network Study. AB - BACKGROUND: Infants have increased risk for salmonellosis; but epidemiologic information is limited. METHODS: We reviewed Foodborne Diseases Active Surveillance Network reports of laboratory-confirmed non-Typhi Salmonella infections in infants from 1996-2008. We calculated incidence, estimated relative risks, and assessed trends over the duration of the study period, using the first 3 years as reference. RESULTS: Average annual incidence of salmonellosis per 100 000 infants was 177.8 (95% confidence interval [CI], 152.7-202.8) in blacks, 129.7 (95% CI, 94.8-164.7) in Asians, and 81.1 (95% CI, 70.2-92.0) in whites. Our analysis of ethnicity independent of race showed salmonellosis incidence of 86.7 (95% CI, 74.6-98.9) in Hispanics and 69.4 (95% CI, 54.8-84.1) in non-Hispanics. Salmonellosis was invasive more often in blacks (9.4%) and Asians (6.4%) than whites (3.6%, P <.001 and P = .01, respectively). Asian infants with salmonellosis were older (median, 31 weeks [range, 0-52]) than black (24 weeks [range, 0-52], P < .001) or white infants (23 weeks [range, 0-52], P < .001). Incidence of all salmonellosis remained stable for whites from 1996-1998 through 2008, but blacks had a sustained decrease, with relative risk of 0.48 (95% CI, .37-.63) in 2008 compared with 1996-1998. However, 2008 incidence remained highest among blacks (141.0 of 100 000 vs 113.5 of 100 000 among whites and 109.9 of 100 000 among Asians). CONCLUSION: Black infants had a greater risk of salmonellosis and invasive disease than other racial groups, and despite the greatest decrease in incidence over the study period, they continued to have the highest incidence of salmonellosis. The decrease in salmonellosis in black infants suggests that future improvements may be possible for other population subgroups. PMID- 26619478 TI - Effects of Rhinovirus Infection on Nasopharyngeal Bacterial Colonization in Infants With Wild or Variant Types of Mannose-Binding Lectin and Toll-Like Receptors 3 and 4. AB - BACKGROUND: Development of respiratory tract infections is determined by interactions between viruses, bacteria, and the host innate immune response. We investigated the impact of natural rhinovirus infection on nasopharyngeal bacterial colonization in infants with or without gene polymorphisms of mannose binding lectin (MBL) and Toll-like receptors (TLRs) 3 and 4. METHODS: Rhinoviruses were detected by reverse transcription-polymerase chain reaction and bacteria by culture of nasopharyngeal specimens from 2- to 3-month-old infants. Gene polymorphisms in MBL at codons 52, 54, and 57, TLR3 Leu412Phe, and TLR4 Asp299Gly were detected by pyrosequencing. RESULTS: Of 337 infants, 61 were positive for rhinovirus and 187 were colonized by Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenzae, or Staphylococcus aureus. Gene polymorphisms of MBL were detected in 32%, TLR3 in 51%, and TLR4 in 18% of subjects. Presence of rhinovirus was associated with increased colonization by S pneumoniae in children with MBL polymorphisms (8 of 20 [40%] with rhinovirus, vs 9 of 87 [10%] without rhinovirus; P = .003), but not in those with wild-type MBL. In logistic regression analyses, S pneumoniae colonization associated with MBL variant (P = .035) and with the interaction between rhinovirus and MBL variant (P = .004), and M catarrhalis colonization associated with the detection of rhinovirus (P = .033). CONCLUSIONS: The association between rhinovirus infection and nasopharyngeal pneumococcal colonization in early infancy is linked to genetic variations of MBL. PMID- 26619479 TI - Treatment of Latent Tuberculosis Infection in Children. AB - Treatment of latent tuberculosis infection (LTBI) is an effective way of preventing future cases of tuberculosis disease. We review pediatric and adult studies of LTBI treatment (isoniazid and rifampin monotherapy, isoniazid plus rifampin, isoniazid plus rifapentine, and rifampin plus pyrazinamide). Based upon this review and our pediatric experience, we can offer recommendations for routine (isoniazid) and alternative courses of therapy. PMID- 26619480 TI - Vancomycin Dosing Practices, Trough Concentrations, and Predicted Area Under the Curve in Children With Suspected Invasive Staphylococcal Infections. AB - Recent guidelines recommend empiric vancomycin dosing of 60 mg/kg per day and consideration of higher trough concentrations (15-20 mcg/mL) in children with invasive infections. In this study, we report a retrospective review evaluating the dose/trough relationship and predicted area under the curve in pediatric patients receiving vancomycin for invasive staphylococcal infections. PMID- 26619481 TI - Variability in the Diagnosis of Encephalitis by Pediatric Subspecialists: The Need For a Uniform Definition. AB - Research definitions of encephalitis vary widely. When surveyed on the criteria used in clinical diagnosis, 88 pediatric specialists demonstrated diverse responses, with pediatric neurologists and pediatric infectious disease specialists differing significantly in their consideration of cerebrospinal fluid pleocytosis and abnormal neuroimaging. Results emphasize the need for a uniform definition. PMID- 26619482 TI - Allograft-Transmitted Histoplasma capsulatum Infection in a Solid Organ Transplant Recipient. PMID- 26619483 TI - Endocarditis Due to Cardiobacterium hominis in a 4-Year-Old Boy, Complicated by Right Lower Lobe Pulmonary Artery Mycotic Aneurysm. PMID- 26619484 TI - Guidelines for Management of Children With Fever and Neutropenia. AB - Children presenting with fever and neutropenia (FN) pose unique diagnostic and management challenges. The absence of pediatric-specific guidelines has led physicians to rely on local expertise, interpretation of available data without benefit of national consensus, and extrapolation of adult guidelines for direction. However, the causes, treatment, and outcomes of children with FN differ in important ways from those of adults. Although individual studies have focused on different aspects of the management of FN in children, a universal approach has not been adopted. The literature review below provides a synopsis of a recently published international guideline on management of children with FN. The guideline reviewed represents the first evidence-based, consensus-driven approach to address management of FN in children. PMID- 26619485 TI - Ganciclovir, Foscarnet, and Cidofovir: Antiviral Drugs Not Just for Cytomegalovirus. PMID- 26619486 TI - Vancomycin Dosing Practices, Trough Concentrations, and Predicted Area Under the Curve in Children With Suspected Invasive Staphylococcal Infections. PMID- 26619487 TI - Vancomycin Dosing Practices, Trough Concentrations, and Predicted Area Under the Curve in Children With Suspected Invasive Staphylococcal Infections. PMID- 26619492 TI - Executive Summary: Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children: Recommendations From the National Institutes of Health, the Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. AB - The Guidelines for the Prevention and Treatment of Opportunistic Infections (OIs) in HIV-Exposed and HIV-Infected Children in the United States were developed by a panel of specialists in pediatric HIV infection and infectious diseases from the U.S. government and academic institutions, intended for use by clinicians and health care workers providing medical care for HIV-exposed and HIV-infected children in the United States. For each OI, pediatric specialists with subject matter expertise reviewed the literature for new information since the last guidelines were published (2009) and then proposed revised recommendations that were reviewed and approved by the full Panel and endorsing governmental agencies and professional organizations. This executive summary highlights the most important, rated recommendations for each OI from the full Guidelines document. PMID- 26619493 TI - Update From the Advisory Committee on Immunization Practices. PMID- 26619494 TI - Completion of Latent Tuberculosis Therapy in Children: Impact of Country of Origin and Neighborhood Clinics. AB - BACKGROUND: Successful treatment of latent tuberculosis infection (LTBI) is an important objective in the United States' strategy for tuberculosis (TB) control. We review the impact of demographic variables and community treatment upon completion of medical therapy of LTBI in a large pediatric cohort. METHODS: We performed a retrospective analysis of prospectively collected data from children referred for evaluation and treatment of LTBI. Children were followed in the main hospital TB clinic or in 1 of 2 hospital-run neighborhood clinics. Those completing and not completing medical treatment were compared based on demographic and history variables, clinic location, and distance to clinic. Propensity score techniques were used to match children treated at the main hospital and neighborhood clinics on collected demographic and history variables. RESULTS: Of 1516 children evaluated, 1184 (78.1%) initiated medical therapy and returned for at least 1 visit. Of these, treatment was completed by 89.2% (166 of 186) of children in the neighborhood clinics versus 83.2% (830 of 998) of children in the main hospital TB clinic (P < .037). Neighborhood and main hospital clinic children did not differ in rates of completion when propensity score-matched groups were compared. Country of origin was the most important factor in determining both initiation and completion of therapy. CONCLUSIONS: Obstacles remain for successful initiation and treatment of children from identified geographic regions. Most of the dropout occurs early in treatment, and use of neighborhood clinics does not provide an obvious advantage when similar patient groups are compared. Emphasis upon initial education and early non-clinic follow-up may be useful in enhancing therapy completion. PMID- 26619495 TI - Pre-Travel Health Preparation of Pediatric International Travelers: Analysis From the Global TravEpiNet Consortium. AB - BACKGROUND: Children frequently travel internationally. Health-related data on such children are limited. We sought to investigate the demographics, health characteristics, and preventive interventions of outbound US international pediatric travelers. METHODS: We analyzed data from 32 099 travelers presenting for pre-travel healthcare at the Global TravEpiNet (GTEN), a national consortium of 19 travel clinics, from January 1, 2009 to June 6, 2012. RESULTS: A total of 3332 (10%) of all GTEN travelers were children (<18 years of age). These children traveled mostly for leisure (36%) or to visit friends or relatives (VFR) (36%). Most popular destination regions were Africa (41%), Southeast Asia (16%), Central America (16%), and the Caribbean (16%). Compared with children traveling for leisure, VFR children were more likely to present <14 days before departure for pre-travel consultation (44% vs 28%), intended to travel for 28 days or longer (70% vs 22%), and to travel to Africa (62% vs 32%). Nearly half of the pediatric travelers (46%) received at least 1 routine vaccine, and most (83%) received at least 1 travel-related vaccine. Parents or guardians of one third of the children (30%) refused at least 1 recommended travel-related vaccine. Most pediatric travelers visiting a malaria-endemic country (72%) received a prescription for malaria chemoprophylaxis. CONCLUSIONS: Ten percent of travelers seeking pre travel healthcare at GTEN sites are children. VFR-travel, pre-travel consultation close to time of departure, and refusal of recommended vaccines may place children at risk for travel-associated illness. Strategies to engage pediatric travelers in timely, pre-travel care and improve acceptance of pre-travel healthcare interventions are needed. PMID- 26619496 TI - Editorial Commentary: Vaccine Refusal Among Pediatric Travelers. PMID- 26619497 TI - Staphylococcus aureus Infections in Children With Congenital Heart Disease. AB - BACKGROUND: Congenital heart disease (CHD) is the most common risk factor for infective endocarditis (IE) in children. Staphylococcus aureus is among the most common organisms to cause IE, yet there are little data describing the risk factors for invasive S aureus disease in children with CHD. We examined the epidemiology of S aureus infections in children with CHD. METHODS: Patients with a history of CHD and S aureus infection were identified from a surveillance study of S aureus infections at Texas Children's Hospital. Clinical and laboratory data from medical records were reviewed. All isolates were screened for the presence of the antiseptic tolerance gene qacA/B. Dichotomous variables were compared with Fisher's exact test and continuous variables with Mann-Whitney U tests, and two tailed P values of <.05 were considered significant. RESULTS: Two hundred forty eight S aureus infections developed in 216 patients with CHD. Methicillin resistance was seen in 53.6% of isolates. Surgical site infections accounted for 28.2% of cases and bacteremia accounted for 20.4% of cases. Bacteremia was associated with IE in 29.5% of the episodes. Infective endocarditis was more often associated with prolonged bacteremia, thrombocytopenia, and a higher C reactive protein (CRP) compared with uncomplicated bacteremia. The qacA/B gene was found in 16.9% of isolates and was associated with bacteremia and prolonged hospitalization. CONCLUSIONS: Staphylococcus aureus is an important cause of morbidity among children with CHD. Infective endocarditis was common with S aureus bacteremia in this population; in addition, prolonged bacteremia, thrombocytopenia, and CRP >10 mg/dL may serve as diagnostic adjuncts for IE. qacA/B-positive isolates are associated with adverse clinical outcomes. PMID- 26619498 TI - Initial Antibiotic Choice in the Treatment of Group A Streptococcal Pharyngitis and Return Visit Rates. AB - BACKGROUND: Our objectives were to describe the incidence of return visits for children with Group A Streptococcal (GAS) pharyngitis (ie, clinical treatment failure) and to assess whether initial treatment with amoxicillin or penicillin was associated with the rate of retreatment for GAS pharyngitis. METHODS: This analysis was a retrospective cohort study of 5533 children 0-17 years from a multisite practice. Eligible visits (n = 6585) were associated with a positive test for GAS, receipt of antibiotics within 7 days, no allergies to penicillins or cephalosporins, and no codiagnoses requiring antibiotic treatment. Retreatment for GAS pharyngitis was defined as an index visit followed by another visit within 1-4 weeks. Five hundred episodes (250 treatment failures and 250 controls) were randomly selected for chart review to validate cases. RESULTS: Amoxicillin or penicillin was the initial antibiotic treatment at 76.1% of visits, and retreatment for GAS pharyngitis occurred after 5.8% of initial visits. Children initially prescribed amoxicillin or penicillin had higher odds of retreatment of GAS pharyngitis even after adjusting for age, sex, symptoms, and community-level covariates such as race, income, and education (odds ratio, 1.51; 95% confidence interval, 1.07-2.13). CONCLUSIONS: Retreatment for GAS pharyngitis was uncommon and associated with receipt of amoxicillin or penicillin, although the impact of GAS carriage is unknown. Recommendations for initial treatment of GAS pharyngitis should reflect both individual and societal considerations, including the potential impact on antibiotic resistance in the community. PMID- 26619499 TI - Overview of Influenza Vaccines in Children. AB - Prevention of influenza infection through vaccination is the best strategy to reduce its disease burden; however, annual revaccination is required to provide protection from circulating virus strains. Currently available influenza vaccines are trivalent inactivated influenza vaccines (IIV) or live-attenuated influenza vaccines (LAIV); however, quadrivalent formulations of IIV and LAIV are expected to be available for the 2013-2014 influenza season. Among children 6 months through 8 years of age receiving their first influenza vaccination, 2 doses of vaccines are required to provide adequate protection. Because of the wide range of circulating influenza viruses and host immune responses, estimates of vaccine effectiveness vary widely by year, age group, and vaccine studied. We summarize the evidence base for pediatric influenza vaccination, and we describe the challenges and limitations of protecting this population with currently available vaccines. PMID- 26619500 TI - Antibiotic Management of Animal Bites in Children During the Methicillin Resistant Staphylococcus aureus Era. AB - Children presenting to an emergency department following an animal bite were found to be at risk for infection if they had puncture wounds, crush wounds, or were bitten by a cat. Of the infected wounds that were cultured, methicillin resistant Staphylococcus aureus was not isolated as a pathogen. PMID- 26619501 TI - The Young and the Resistant: HIV-Infected Adolescents at the Time of Transfer to Adult Care. AB - Combined antiretroviral therapy allows children with human immunodeficiency virus (HIV) to reach adulthood. We studied 45 adolescents at the time of transfer to adult care. Despite universal healthcare access, over two-thirds of the adolescents were failing treatment, which was manifested by detectable HIV-1 viral load, CD4 counts <200 cells/ mm(3), and/or triple-class drug resistance. PMID- 26619502 TI - Blastomycosis in Children: A Study of 14 Cases. AB - We retrospectively reviewed 14 children with active blastomycosis. Pulmonary disease occurred in 86% of the cohort and extrapulmonary dissemination was noted in 46%. Urine blastomycosis or histoplasmosis antigens were positive in all tested patients. Acute kidney injury was common in patients who were treated with amphotericin. Mortality tended to be associated with a delay in diagnosis. PMID- 26619503 TI - A Newborn With Hydrops, Hydrocephalus, and Ophthalmologic Abnormalities. PMID- 26619504 TI - Mycobacterium simiae Infection of the Parotid Gland in an Immunocompetent Child. PMID- 26619505 TI - Acute Demyelinating Lesion of the Upper Thoracic Spine Complicating Kawasaki Disease. AB - We present the first reported case of a child with Kawasaki disease (KD) complicated by meningoencephalitis and an acute focal demyelinating lesion. Neurologic outcome in this patient was excellent without any persistent neurologic deficits. We also review the neurologic complications associated with KD. PMID- 26619506 TI - Literature Review. PMID- 26619507 TI - Local Health Department Influenza Surveillance Estimates and Projections of Peak Pediatric Intensive Care Unit Occupancy During the 2009 Influenza A Pandemic. PMID- 26619508 TI - A Case of Cronobacter (Enterobacter sakazakii) Bacteremia in a Breastfed Infant. AB - Cronobacter multispecies complex (Cronobacter) is a member of the Enterobacteriaceae family that was described as a new genus in 2007 [ 1]. Consumption of contaminated powdered infant formula (PIF) has been associated with invasive Cronobacter infection in infants [ 1, 2]. The Food and Agricultural Organization and World Health Organization expert consultations in 2004 and 2006 concluded that Cronobacter contamination of PIF did cause infection and disease in infants [ 2]. Although the presence of Cronobacter in PIF is well documented, the nature of this organism may lead to exposure through other sources [ 1, 3]. Our case illustrates a rare example of Cronobacter bacteremia in an exclusively breastfed infant of a healthcare worker. PMID- 26619513 TI - Reacting With or Without Detecting. AB - We begin our response by clarifying the concept of detection, and explaining why this is needed for initiating, but not for adjusting a movement. We present a simulation to illustrate this difference. Several commentators referred to studies with results that might seem in conflict with our proposal that movement adjustments have short latencies because there is no need to detect anything. In the last part of our response, we discuss how we interpret these studies as being in line with our proposal. PMID- 26619514 TI - [Epidemic characteristics of student pulmonary tuberculosis analysis in Yuman province, 2013]. PMID- 26619515 TI - [Analysis on common virus pathogens in 6089 hospitalized children with respiratory tract infection]. PMID- 26619516 TI - A variational approach for dissipative quantum transport in a wide parameter space. AB - Recent development of theoretical method for dissipative quantum transport has achieved notable progresses in the weak or strong electron-phonon coupling regime. However, a generalized theory for dissipative quantum transport in a wide parameter space had not been established. In this work, a variational polaron theory for dissipative quantum transport in a wide range of electron-phonon coupling is developed. The optimal polaron transformation is determined by the optimization of the Feynman-Bogoliubov upper bound of free energy. The free energy minimization ends up with an optimal mean-field Hamiltonian and a minimal interaction Hamiltonian. Hence, second-order perturbation can be applied to the transformed system, resulting in an accurate and efficient method for the treatment of dissipative quantum transport with different electron-phonon coupling strength. Numerical benchmark calculation on a single site model coupled to one phonon mode is presented. PMID- 26619518 TI - Notice of Retraction. PMID- 26619517 TI - [Was vascular ring the cause of dyspnea?]. PMID- 26619519 TI - Review of the 2015 influenza season in the southern hemisphere. PMID- 26619520 TI - 'Cadillac' tax repeal gains momentum. PMID- 26619522 TI - Mental health advocates dare to believe Congress will pass reforms. PMID- 26619521 TI - A suitor turned grudging merger target. PMID- 26619523 TI - THIRDQUARTER CEO POWER PANEL SURVEY. Closer provider-insurer ties bring new challenges. PMID- 26619524 TI - Hospitals slow to adopt patient apology policies. PMID- 26619525 TI - Competing for kids. Children's hospitals face challenge from emerging megasystems. PMID- 26619527 TI - Providers need to embrace a new normal in the movement to pay for quality. PMID- 26619526 TI - Off-label drug marketing: another nail in the cost-control coffin. PMID- 26619528 TI - Teaching docs how to have end-of-life talks. PMID- 26619529 TI - Pressure from purchasers will be 'painful' but 'beneficial'. PMID- 26619530 TI - By the numbers. Highest-paid chief financial officers at not-for-profit healthcare organizations. Ranked by total compensation for 2013 as reported in available IRS Form 990 filings. PMID- 26619531 TI - [Segment Cloning and Expression of Human VIGILIN Gene]. AB - OBJECTIVE: To investigate the mechanisms of interaction between high-density lipoprotein binding protein (HDLBP)-VIGILIN with other proteins, we cloned VIGILIN cDNA N, KH1-7, KH8-12, KH13-14, and C fragments separately into expression vector, and identify the expressed proteins. METHODS: The recombinant plasmid pDsred2-N1/VIGILIN was used as template to amplify VIGILIN full length, VIGILIN N terminal, KH1- 7, KH8-12, KH13-14, C terminal and recombinated them with pGEX 5X 3. After transformed into E. coli BL21 cells, the recombinants were confirmed by enzyme digestion and sequence analysis. After optimizing the IPTG inducing condition, we induced GST-VIGILIN fusion proteins on the appropriate conditions. RESULT: The recombinant plasmids of pGEX 5X 3/VIGILIN FL, pGEX 5X 3/VIGILIN N terminal, pGEX 5X 3/VIGILIN KH1-7, pGEX 5X 3/VIGILIN KH8-12, pGEX 5X 3/VIGILIN KH13-14, pGEX 5X 3/VIGILIN C terminal were constructed successfully, and induced the GST-VIGILIN fusion proteins. CONCLUSION: pGEX 5X 3/VIGILIN FL, pGEX 5X 3/VIGILIN N terminal, pGEX 5X 3/VIGILIN KH1-7, pGEX SX 3/VIGILIN KH8-12, pGEX 5X 3/ VIGILIN KH13-14, pGEX 5X 3/VIGILIN C terminal recombinant plasmids were constructed successfully, and their corresponding fusion proteins were successfully expressed. PMID- 26619532 TI - [Isolation and Identification of Rat Kidney Stem Cells]. AB - OBJECTIVE: To isolate and steadily culture kidney stem cells (KSCs) from rat renal papilla, and to identify the biological characteristics of KSCs. METHODS: KSCs were isolated from the tips of renal papilla in 4 weeks-old Sprague-Dawley rats. The morphology of KSCs was observed under inversion microscope, and the phenotye characteristics of kSCs were identified through flow cytometry and immunofluorescence. The abilities of KSCs in adipogenic and osteogenic differentiation were evaluated. The differences of gene expression between KSCs and rat renal tubular epithelial cells (RTECs)were compared using quantitative real time polymerase chain reaction (qRT-PCR). RESULTS: KSCs showed a spindle shaped and arborization-like growth pattern. Immunofluorescence indicated that KSCs staining with alpha-sooth muscle actin (alpha-SMA), Vimentin, N-Cadherin, Nestin, CD133 marker, and without E-cadherin, cytokeratin-18 (CK-18), zona occludens protein-1 (ZO-1). The positive staining of CD29, CD90, CD73 were 99. 0%, 95. 8%, 99. 9% respectively, the positive staining of CD45 was 3. 4%. The positive stainings of stem cell marker CD133 and Nestin were 33. 2% and 70. 2% respectively, while the double staining rate was 31. 4%., KSCs showed positive staining by oil red 0 after adipogenic differentiation, and orange calcium deposition by alizarin red staining after osteogenic differentiation. qRT-PCR showed that the expressions of embryonic stem cell marker Nanog, Oct4/pou5f1,Sox2/sry-box-2 in KSCs were higher than those in RTECs (P< 0.01), and the expressions of mesenchymal marker c-SMA, Vimentin were also higher in KSCs (P<0. 01). Compared with RTECs, the expressions of mature epithelium marker E Cadherin, CK18 in KSCs were lower (P< 0. 01). CONCLUSION: KSCs were isolated successfully and steadily cultured from the rat renal papilla, which were identified with featured biological characteristics. PMID- 26619533 TI - [The Role of Cancer-associated Fibroblasts in Invasive Behavior of Pituitary Adenoma]. AB - OBJECTIVE: To determine the role of cancer associated fibroblasts (CAFs) in the invasive behavior of pituitary adenoma. METHODS: Pituitary adenoma tissues were divided into invasive group (IPA) and non-invasive group (nIPA) according to pre operative MRI and observations during surgery. Those tissues were cultured and CAFs were identified through a smooth muscle actin (alpha-SMA). The migratory and invasive ability of CAFs was tested with transwell migration and invasion assay. The expressions of alpha-SMA and matrix metalloproteinase (MMP)-9 from CAFs were determined by immunocytochemistry and Western blot. RESULTS: All cultured CAFs expressed alpha-SMA. No significant difference in migratory ability of CAFs was found between the IPA and nIPA tissues; however, CAFs from the IPA tissues had stronger invasive ability than those from the nIPA tissues (P= 0. 010). Higher levels of MMP-9 expression were found in group IPA as compared with nIPA (P=0. 025). No significant difference in the expression of alpha-SMA was found between the two groups. CONCLUSION: CAFs may promote invasive behavior by secreting more MMP-9, which may play a part in the invasive behavior of pituitary adenomas. PMID- 26619534 TI - [The Study of Altered Immune Status of UCMSC upon the Activation of TLR1/2 Pathway]. AB - OBJECTIVE: To study whether the activation of Toll like receptor 1/2 (TLR1/2) has influence on the immune status of umbilical cord mesenchymal stem cell (UCMSC). METHODS: TLR1/2 agonist Pam3CSK4 was conducted in UCMSC-peripheral blood mononuclear cell (PBMC) co-culture system. Flow cytometry and lactate dehydrogenase (LDH) detection were used to measure the proliferation of PBMC and immune attack of PBMC to UCMSC, respectively. The detection of expressions of co stimulator and stem cell markers of UCMSC upon TLR1/2 activation was completed by flow cytometry. Real-time PCR was introduced to assay the expression of many immune-related molecules in UCMSC. Cell differentiation staining was conducted to study the change of differentiation ability of UCMSC. RESULTS: Activation of TLR1/2 pathway in UCMSC increased the proliferation of PBMC and attack of PBMC to UCMSC, but without influenced the expressions of co-stimulator and stem cell markers. The results of real-time PCR showed that many immune-related molecules were dramatically induced in UCMSC upon TLR1/2 activation, such as Cinterleukin (IL)-2, IL-6, IL-10, IL-12, interferon-gamma (IFN-gamma), nuclear factor-kappaB (NF-kappaB), tumor necrosis factor-alpha (TNF-alpha)]. However, the activation of TLR1/2 had no influence on the differentiation ability of UCMSC. CONCLUSION: Activation of TLR1/2 altered the immune status of UCMSC, including increase the immune attack to UCMSC. PMID- 26619535 TI - [Isolation and Study on the Aflatoxin Genes of Aflatoxin-producing Fungi in Paprika Samples in Chengdu]. AB - OBJECTIVE: To isolate aflatoxin-producing strains from paprika samples and to do a preliminarily study on the relationship between aflatoxin-producing ability and the genes aflR, omt-1 and ver-1. METHODS: Fungi were isolated by traditional culture method. Potential aflatoxin-producing strains were screened by phenotypic traits and multiplex PCR. After these potential aflatoxin-producing strains cultured in the toxigenic culture medium, the levels of aflatoxin B, (AFB1) of the cultures were tested with ELISA method. The phylogenetic tree of aflR, omt-1 and ver-1 was constructed to explore the relationship between these genes and the AFB1-producing capacity. RESULTS: 17 potential aflatoxin-producing fungi were isolated. The ratio of positive toxigenic strains is 64. 71%. 11 isolates were positive in AFB1 detection while existing high sequence homology with AS 3. 4408, 6 isolates were negative in AFB1 detection while existing high sequence homology with Aspergillus oryzae. CONCLUSION: Aspergillus flavus are potential candidates for aflatoxin control. Not all Aspergillus flavus have AFB1-producing capacity, aflR gene had a direct relation to AFB1-producing capacity, while ver-1 and omt-1 were related to the level of AFB1 producing. PMID- 26619536 TI - [The Pharmacokinetics and Pharmacodynamics of Intravenous Uricase Multivesicular Liposomes]. AB - OBJECTIVE: To determine and compare the pharmacokinetics and pharmacodynamics of uricase-multivesicular liposomes (UOMVLs) with free uricase (UOX) in rats. METHODS: UOMVLs were prepared by the double emulsion method and confirmed with its entrapment efficiency, size and Zeta potential. Twelve healthy rats were randomly divided into two groups: one with i. v. injection of UOMVLs, and the other with i. v. injection of UOX. Their serum activity of uricase was assayed. The pharmacokinetic parameters were calculated using software DAS 2. 1. 1. Another 24 male SD rats were enrolled, the rat model of hyperuricemia was established with hypoxanthine and potassium oxonate, while normal group (n=6) was set as control. Injection of UOMVLs (1 mL, 0. 47 U/mL), UOX (1 mL, 0. 47 U/mL) and nothiy were given 1 h later in UOMVLs group (n=6), UOX group (n=6) and model group (n=6), and their serum uric acid levels were determined 1, 2, 3, 5, 7, 9, 12, 24, 36, 48 h after the establishment of hyperuricemia model. RESULTS: The entrapment efficiency of UOMVLs was (63. 75 +/- 3. 65) %, with an average particle size of (22. 56 +/- 1. 70) um and Zeta potential of (-41. 81+/-6. 59) mV. The pharmacokinetic parameters of UOMVLs and UOX were as follows, respectively: area under time-concentration curve from 0 to infinity time (AUC0 infinity) (498. 83 +/- 58. 85) U/L . h and (28. 49 +/- 9. 95) U/L . h; time to peak concentration (Tmax) (1. 00+/-0. 00) h and (0. 00+/-0. 00) h; peak concentration (Cmax) (73. 04+/-6. 35) U/L and (31. 00+/-6. 03) U/L; elimination half-life (t1/2) (3. 49+/-0. 80) h and (1. 17+/-0. 33) h. The relative bioavailability of UOMVLs was (1 750. 90+/-206. 56) %. UOMVLs decreased serum uric to normal in 9 h; whereas it took 48 h for the UOX group and the model group to return to normal. CONCLUSION: UOMVLs can prolong tmax and t1/2 and improve the relative bioavailability. UOMVLs decrease serum uric acid levels in rats with hyperuricemia more effectively than UOX. PMID- 26619537 TI - [Epidemiology and Resistance Mechanisms of Group B Streptococci in Late-pregnant Maternal Birth Canal]. AB - OBJECTIVE: To study the antibiotic-resistant rate of group B streptococci (GBS) in obstetric canal of late-pregnant women, evaluate the antibiotic-resistant status and finally to support the GBS prevention and curing by proper antibiotics. METHODS: 31 pregnant women between 35 to 37 gestational weeks were included, for whom the antibiotic sensitivity as well as the drug (erythromycin and clindamycin) resistance genes of GBS in obstetric canal was analyzed. RESULTS: 12 (38. 7%) strains of GBS were resistant to clindamycin, while 21 (67. 7%) to erythromycin, within which 12 strains were intrinsic phenotype - cMLS type clindamycin resistance, other 9 were active efflux phenotype - MS type clindamycin sensitive and all of which were confirmed by Double disk diffusion method. Eleven strains were mef (A) positive, and 12 strains were erm (B) positive, in which 3 with erm (C). CONCLUSIONS: In our research the GBS strains show a high erythromycin and clindamycin resistance rate. The resistance of our GBS strains are mainly caused by the ribosomal target changes induced by erm (B) and the increased efflux of clindamycin induced by mef (A). PMID- 26619538 TI - [The Mechanisms by which Bax Induces the Apoptosis of Human Ovarian Cancer Cells]. AB - OBJECTIVE: The purpose of this study was to observe the apoptosis of A2780 cells transfected with the recombinant plasmid of pcDNA-Bax and to observe the release of cytochrome C from the mitochondria. METHODS: The recombinant plasmid of pcDNA Bax was constructed and transfected into A2784 cells. The Hoechst 33258 stain method was applied to evaluate the apoptosis of the transfected cells and MTT mothod was used to test the cell viability. Western blot analysis was performed to determine the overexpression of Bax and the release of cytochrome C from the mitochondria. RESULTS: The recombinant plasmid of pcDNA-Bax was successfully constructed by using endonuclease digestion and the sequence analysis. The apoptosis of A2780 cells was induced after transfected with pcDNA3. 1-Bax as demonstrated with Hoechst staining. The cell viability were decreased in the pcDNA3. 1-Bax transfected group by MTT assay. The release of cytochrome C from the mitochondria was observed when using Western blotting analysis. And the caspase-9 and the caspase-3 were activated. CONCLUSION: Our data suggestted that Bax exhibited potent pro-apoptotic activity against the ovarian cancer cells. This study is a foundation for the further research in the pro-apoptotic activity of Bax. PMID- 26619539 TI - [The Effect of Chronic Intermittent Hypoxia on Cognitive Function and Prefrontal Cortex Neurons in Rats]. AB - OBJECTIVE: To determine the effect of chronic intermittent hypoxia on cognitive function and prefrontal cortex neurons in rats. METHODS: 48 adult male Wistar rats were randomly divided into two groups: control group and 50 mL/L intermittent hypoxia group (50 mL/L CIH). Rats in the CIH group were placed in the low oxygen tank, simulating intermittent hypoxia environment. At 7 d, 14 d, 21 d, and 28 d, the learning and memory ability of the rats was assessed with the Morris water maze (MWM) test; the expressions of cysteinyl aspartate specific protease (caspase)-8 protein in their prefrontal cortex were determined using Western blot method; the apoptosis of neurons was detected by the TdT mediated UTP nick end labeling (TUNEL) method. RESULTS: Compared with the controls, the CIH rats had significantly prolonged escape latency at 14 d, 21 d, and 28 d (P<0. 05) and decreased target quadrant time (P<0. 05). The prolonged escape latency increased and target quadrant time shortened with length of exposure to hypoxia (P<0. 05). Compared with controls, the CIH rats had gradually increased caspase-8 in their frontal cortex neurons, peaked at 28 d (P<0. 05). The CIH rats showed obvious structural damage and reduced neuron density in their frontal cortex neurons. They had higher levels of nerve cell apoptosis (P<0. 05), with apoptosis index increasing with length of exposure to hypoxia (P<0. 05). CONCLUSION: Severe chronic intermittent hypoxia can lead to pathological changes of frontal,cortex of rats, possibly PMID- 26619540 TI - [Effect of Dermal Multipotent Cells Transplantation on Skin Elasticity in Aged Murine]. AB - OBJECTIVE: To investigate the elasticity changes in aged dermis after injection of dermal multipotent cells (DMCs). METHODS: Dermal multipotent cells were isolated and cultured from 3-day-old BALB/c mice and then transplanted into the dermis of aged (12-week-old) BALB/c mice. Adult fibroblasts (FBs) were employed as control. At 2 and 4 weeks after the transplantation, we examined dermal elasticity by MPA580 skin test machine. RESULTS: The skin elasticity were improve at 2 weeks after the transplantion in both DMCs group and FBs group (P=0. 000) but have no statistical difference between these two groups (P=0. 216). The different effect between these two groups appeared in 4 weeks after the transplantation (P=0. 031). CONCLUSION: Dermal multipotent cells appear more effective than fibroblasts in increasing skin elasticity. PMID- 26619541 TI - [The Expressions of Somatostatin and Cycloxygenase-2 in Chronic Hepatitis, Hepatic Cirrhosis, Precancerous Lesion and Hepatocellular Carcinoma]. AB - OBJECTIVE: To investigate the expression difference of somatostatin (SST) , SST receptors (SSTR) and COX-2 in chronic hepatitis, hepatic cirrhosis, precancerous lesion and hepatocellular Carcinoma, and explore the relationship between portal hypertension and SST/SSTR expressions. METHODS: A series of human liver tissues were obtained from surgery, including normal liver 4 cases, chronic hepatitis 14 cases, hepatic cirrhosis 40 cases, precancerous lesion 40 cases and HCC tissues 40 cases. Peripheral bloods were collected from 20 patients before and after the operation of transjugular intrahepatic portosystemic shunt (TIPS). SSTR 1-5 subtypes in hepatic tissues were detected by immunohistochemical study and RT PCR. Levels of SST and COX-2 were quantified by radioimmunoassay and Western blot. RESULTS: 90% of precancerosis expressed high levels of SSTR 2, 5 subtypes, and SSTR mainly distributed surrounding portal vein. At lest 60%o of HCC expressed SSTR 2, 5 subtypes, and there were positive correlations between levels of SSTR 1-5 and SST. Levels of SST in peripheral blood of cirrhotic patients significantly increased after TIPS(P<0. 05). Levels of COX-2 were highest in cirrhosis (about 90%), and decreased in precancerosis (about 80%) and HCC tissues. CONCLUSIONS: Precancerosis or early stage of HCC may be the optimum time for synergetic medication of SST analogue and COX-2 inhibitor. PMID- 26619543 TI - [Research on the Combined Detection of Urine UmAlb and Urinary Nephrin, Podocalyxin in Podocyte of MKR Mice with Diabetic Nephropathy]. AB - OBJECTIVE: To explore the combined detection of urine UmAlb and urinary nephrin (Unephrin), podocalyxin (UPCX) in podocyte of MKR mice with diabetic nephropathy. METHODS: Thirty 8 weeks old MKR mice were randomly divided into two groups as follows: negative control group, DN model group, and another 15 wild C57 mice were used as normal control. Mice in DN model group were received unilateral nephrectomy and high-fat diet feed for 2 months. The morphological structure changes of the podocytes were observed by transmission electron microscopes. The levels of FBG were detected by electrochemical detection method, The nephrin and PCX protein expression were measured by western blotting. The levels of UmAlb, Unephrin and UPCX were detected by ELISA. RESULTS: The podocyte damage in the mice of DN model group increased significantly when compared with normal control. As compared with normal control, FBG in the model group increased significantly (P<0. 01), the expression level of nephrin and PCX in Renal Tissue and Unephrin, UPCX, and urine UmAlb were also increased significantly (P<0. 01). CONCLUSION: The level of Unephrin and UPCX were positive correlated with the level of urine UmAlb, the loss of podocyte strcture protein might be one of the mechanism in leading proteinuria in diabetic nephropathy. PMID- 26619542 TI - [The Effects of the Hemopexin on Generation of Free Radicals and Brain Edema after Intracerebral Hemorrhage]. AB - OBJECTIVE: To explore the effects of the Hemopexin (Hx) on the generation of free radicals and brain edema after intracerebral hemorrhage (ICH). METHODS: One hundred SD rats were randomly and evenly divided into four groups (25 rats in each group) which named Sham group, ICH control group, Hx removal group and Hx intervention group respectively. There were five observation points (1 d, 3 d, 7 d, 14 d, 21 d) and which contain five rats for each. The stereotactic injection technique was used to make the ICH model, which adopted rat autologous Whole blood that was removed or mixed with Hx and then injected to the right caudate nucleus of the brain. Sham group were only injected with 50 uL saline to the right caudate nucleus and ICH control group were injected with 50 pL autologous whole blood; Hx removal group were injected 50 uL autologous whole blood of removal Hx and Hx intervention group were injected 50 uL autologous whole blood which contain 0. 25 mg (5 ug/ uL) Hx. Bederson's method was applied to evaluate whether the model was established successfully or not. Garcia' s method was used to estimate the neurological dysfunction scores by. Water contents of brain tissue around the hematoma was detected by dry-wet weigh method . The superoxide dismutase (SOD) activity were measured with the xanthine oxidase method. The content of the malonyldialdehyde (MDA) was measured by the thiobarbituric acid method. Pathological changes of brain tissue around the hematoma were detected by immunohistochemical method at each observation time points; and the immunohistochemical scores result was judged by the double semiquantitative evaluation method. RESULTS: Compared with Sham group, at 3-21 d, there were statistically significant differences (P<0. 05) in the neurological disorders and water content of the brain tissue and immunohistochemistry scores within ICH control group, Hx intervention group and Hx removal group. Compared with Sham group, at 1-21 d, there were statistically significant differences (P<0. 05) in SOD activity and the content of the MDA within ICH control group, Hx intervention group and Hx removal group. All the indexes above were superior in Hx intervention group to ICH control group (P<0. 05), and inferior in Hx removal group to ICH control group (P< 0. 05). CONCLUSION: The Hemopexin may attenuate the generation of the free radicals and encephalaedema in the brain tissue around the hematoma after intracerebral hemorrhage. PMID- 26619544 TI - [Consumptions of Meat and Dairy Products, Zinc Intake and Pubertal Development in Adolescents in Chengdu]. AB - OBJECTIVE: To determine the associations between meat, dairy and zinc intake and pubertal development in adolescents in Chengdu. METHODS: A total of 1320 children and adolescents aged 9-15 years in Chengdu were recruited using a stratified cluster sampling strategy. Dietary intake was assessed by the food frequency questionnaire (FFQ) and 3-day 24-hour dietary recall. Pubertal development was evaluated through physical examinations. Consumptions of meat and dairy, and zinc intake were compared between groups with different levels of pubertal development according to the Tanner criteria. RESULTS: The median age of spermarche was 13. 00 years. The boys who had had spermarche consumed more meat (including red meat) and dairy products than those who had not yet (P<0. 05). Daily consumption of total meat was positively correlated with the level of pubertal development (P<0. 05). The median age of menarche was 12. 11 years. The girls who had had menarche consumed more meat and less diiry products than those who had not yet (P<0. 05). Daily consumption of dairy products was negatively associated with breast development and the level of pubertal development (P < 0. 05). CONCLUSION: Consumptions of meat, red meat and dairy products are associated with pubertal development in adolescents in Chengdu. However, the differences between boys and girls warrant further studies. PMID- 26619545 TI - [Validity of Caprini Risk Assessment Scale for Assessing Risk of Venous Thromboembolism in Hospitalized Critically Ill Patients]. AB - OBJECTIVE: To test the validity of Caprini risk assessment scale in identifying hospitalized critically ill patients with high venous thromboepbolism (VTE) risks. METHODS: A case-control study was conducted, with 78 VTE patients who were admitted to the ICU of Sichuan Provincial People's Hospital from February 2008 to June 2014 in the case group, and a randomly selected group of 156 non-VTE patients who were-admitted during the same period serving as controls. The medical history, laboratory tests and other related clinical data of the participants. were retrieved. Their VTE risks were assessed using the Caprini risk assessment scale. Multivariate logistic regression analysis was performed to establish the association between Caprini VTE risk classification and the presence of VTE. RESULTS: VTE patients had a Caprini score of 8. 7+/-3. 5, higher than that of the controls (4. 2 +/- 2. 6). More than 88. 4% of VTE ill patients were rated as having "high or very high" risk of VTE by Caprini rating scale, significantly higher than the percentage in the controls (P<0. 001). The logistic regression model identified eight risk factors in the Caprini scale as predictors of VTE: bed-bound in internal medicine wards, severe lung disease (<1 month), sepsis (<1 month), large operation (<1 month), malignant tumor (past or prevalence), deep venous thrombosis (DVT)/pulmonary thromboembolism (PTE) history, family history, and thrombosis'of multiple trauma (<1 month). The odds ratio of VTE in patients with a high and very high risk as identified by Caprini scale was 2. 042 and 11. 681, respectively, compared with those with a low risk. Conclusion Caprini risk assessment scale can predict the risk of VTE in hospitalized critically ill patients. PMID- 26619546 TI - [Determination of the Association Between Smoking and Recurrence of Ischemic Stroke using a Competing Risks Model]. AB - OBJECTIVE: To determine the association between smoking and ischemic stroke recurrence. METHODS: We conducted a prospective follow-up study of patients with first incidence of stroke. A competing risks model was used to establish the association between smoking and stroke recurrence. RESULTS: A total of 594 stroke patients were recruited. Among the 361 male patients, 59 recurrent events and 13 competing events occurred. Among the 233 female patients (all were non-smokers), 49 recurrent events and 11 competing events occurred. Adjusted for confounding factors, male nonsmokers exposed to passive smoking had a SHR of 3. 040 in comparison with those without exposure to smoking and the P value was borderline significant. Those who smoked 100-200 cigarettes a year had a SHR of 0. 947. The other groups with exposure to smoking had a greater than 1 SHR, but without statistical significance. Moreover, no significant associations between recurrence of ischemic stroke and smoking index/cumulative smoking were found. The female nonsmokers who had exposure to passive smoking only at follow-ups had a SHR of 1. 4 (and all other groups had less than 1 SHR). But no statistical significances were found in the comparisons. CONCLUSION: Further research with a larger sample size is needed to establish the association between smoking and recurrence of ischemic stroke. PMID- 26619547 TI - [Validity of Self-reported Hypertension in Chinese Elderly Populations]. AB - OBJECTIVE: To determine the validity of self-reported hypertension and its associated factors in Chinese elderly populations. METHODS: Self-reported data of 13 610 elderly participants of the China Health and Retirement Longitudinal Study were compared with their actual blood pressure measurements. The sensitivity and specificity of self-reported hypertension were calculated corrected for current medication use. Multivariate logistic regression analysis was performed to identify individual characteristics that independently predicted the accuracy of self-reports. RESULTS: Overall, self-reported hypertension had low sensitivity (56. 3%) and high specificity (96.9%). Agreement between self-reported data and medical records was moderate (Kappa= 0. 57). The multivariate analysis identified age, sex, education, financial situation, health service utilization, history of diabetes and types of medical insurance as significant factors that determined the validity of self-reported data. CONCLUSION: Self-reporting leads to underestimation of the prevalence of hypertension. The accuracy of self-reporting differs among subpopulations. PMID- 26619548 TI - [Association Between Serum Uric Acid and Acute Cerebral Infarction: a Case Control Study]. AB - OBJECTIVE: To determine the association between serum uric acid levels and acute cerebral infarction. METHODS: 700 patients with acute cerebral infarction were recruited in the study, with 700 healthy individuals serving as controls. Blood samples of the participants were collected to measure uric acid, triglyceride, cholesteral, blood glucose, urea and creatinine. Logistic regression model was established to examine the association between serum uric acid and acute cerebral infarction. RESULTS: The patients with acute cerebral infarction had lower levels of serum uric acid than the healthy controls (P <0. 05). The logistic regression model showed that decreased levels of serum uric acid were barely associated with acute cerebral infarction (odds ratio: 0. 998, 95% confidence interval: 0. 996-1. 000, P<0. 05), after controlling for other confounding factors. CONCLUSION: Association between serum uric acid and acute cerebral infarction is not confirmed. PMID- 26619549 TI - [The Association Between Serum Uric Acid and Creatinine in Patients with Hypothyroidism]. AB - OBJECTIVE: To determine the relationship between serum uric acid (SUA) and creatinine (SCr) in patients with hypothyroidism. METHODS: A total of 2 078 people who took physical examinations in the West China Hospital, Sichuan University in May 2014 participated in this study. Serum thyrotropin (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) were detected by electrochemiluminescence. SUA was measured using uricase UV method. The participants were divided into three groups according to their thyroid function: hypothyroidism, subclinical hypothyroidism (SCH) and control. The prevalence of hyperuricemia in each group was Estimated. Correlation analyses were performed for the serum indicators. RESULTS: There were 1 685 participants in the control group, 38 in the hypothyroidism group, and 355 in the subclinical hypothyroidism group. Hypothyroidism patients had significantly higher levels of TSH than those in the control and SCH groups. Significant differences in serum levels of FT3 and FT4 were found between the three groups. Higher levels of SCr (P=0. 005) and SUA (P=0. 008) were also found in hypothyroidism patients compared with those in the control and SCH groups. In those younger than 60 years, men were more likely to catch hyperuricemia than women, with 50-59 year old men having the highest prevalence of hyperuricemia. Higher prevalence of hyperuricemia in men (compared to women) was also found in those older than 60 years, but without statistical significance (P=0. 09). After correcting for gender, TSH showed no correlations with SUA (r=-0. 01, P=0. 648) and SCr (r=-0. 02, P=0. 284); FT4 showed negative correlations with SUA (r= -0. 978, P=0. 001) and SCr (r= -0. 599, P= 5. 012); FT3 showed negative correlations with SUA (r= -0. 745, P=0. 007) and SCr (r -0. 457, P=0. 034). CONCLUSION: Reduced thyroid hormone levels may lead to elevated SCr levels. And elevated SCr levels may be issociated with elevated levels of SUA in patients with hypothyroidism. PMID- 26619550 TI - [Association of Serum Uric Acid with 2-hour Postload Glucose in Predibetic Patients]. AB - OBJECTIVE: To investigate whether serum uric acid (SUA) is associated with 2-hour postload glucose (2-h PG) in predibetic patients. METHODS: There were 3 588 subjects enrolled in this study from May 2014 to March 2015 in the department of physical examination center and outpatient clinic of West China Hospital of Sichuan University. All the subjects received a 75-g oral glucose tolerance test (OGTT) and measurements of serum uric acid (SUA), Creatinine, Cystatin (Cys-C), serum lipid and glycosylated hemoglobin (HbAlc). According to the results of glucose and HbAlc, the subjects were divided into three groups, including normal glucose regulation (NGT), impaired glucose regulation (IGR) and Type 2 Diabetes Mellitus (T2DM) group. The correlation between 2-h PG and serum uric acid in each group was analyzed. RESULTS: Based on the exam results, there were 556 cases of NGT, 1 019 cases of IGR, 2 013 cases of T2DM. There were statistically significant differences of glucose, serum insulin, triglycerides, high density lipoprotein, HbAlc, SUA, Creatinine, Cys-C levels among the three groups (P<0. 05). Multiple linear regression analysis showed that SUA level was positively correlated to 2-h PG level (P<0. 05) in NGT and IGR groups, but there was no correlation in T2DM group (P=0. 156). In the entire study population, levels of HbAlc and FPG were positive to 2-h PG correlated (P<0. 05). Positive correlation existed between FPG and 2-h PG in NGT group (P=0. 031). In IGR and T2DM group, HbAlc and 2-h PG were positively correlated (P<0. 05). HbAlc, FPG and SUA levels were independent risk factors for 2-h PG. CONCLUSION: In prediabetes, 2-h PG is associated with SUA and independent of FPG, HbAlc and other known risk factors. SUA may play a key role in the prediabetic condition as a risk indicator of T2DM. PMID- 26619551 TI - [Effect of Serum Uric Acid on Renal Function of Patients with Abnormal Glucose Metabolism]. AB - OBJECTIVE: To determine the effect of serum uric acid on renal function of patients with abnormal glucose metabolism. METHODS: A total of 1 495 people who took physical examinations in West China Hospital of Sichuan University in May 2014 were recruited in this study. Serum nitrogen (BUN), creatinine (SCr), triglycerides (TG), cholesterol (TC), high-density lipoprotein (HDL-C), low density lipoprotein (LDL-C) and uric acid (SUA) of the participants were detected by an automatic biochemical analyzer. The glomerular filtration rate, (eGFR) was calculated with CKD-EPI. According to hyperuriceima (HUA), the participants were divided into groups with impaired fasting glucose (IFG), diabetes (DM), IFG with hyperuicimia, and DM with hyperuricemia. The participants with normal fasting plasma glucose served as controls. Renal dysfunction was detected using eGFR<=50 mL/(min . 1. 73 m2) and SCr<=1. 7 ug/mL. RESULTS: About 13. 18% (197/1 495) participants were identified as IFG with HUA: male (158)/female (39) ratio =4.05; 4.41% (66/1 495) as DM with HUA: male (58)/female (8) ratio = 7. 25. Participants with HUA in the control, IFG and DM groups had higher levels of BUN and SCr and lower levels of eGFR than those without HUA (P<0. 05). HUA was more likely to be associated with serum. lipid in the control and IFG groups (most P<0. 05) than in the DM group (P>0. 05). DM patients without HUA had better renal function and serum lipid levels than those who had HUA in their early stage of abnormal glucose metabolism (IFG with HUA) (P<0. 05). The prevalence of renal dysfunction of IFG patients with HUA was significantly higher than those without HUA, similar to the prevalence of renal dysfunction of DM patients with HIUA (P0. 05) among the participants of the five groups. The phantoms were used to measure spatial resolution and contrast resolution of the scan images. Dose length product (DLP) was recorded during CT scanning for calculating effective dose (ED) of exposure. The quality of images was evaluated using a list of quality scoring criteria. RESULTS: (1) Under 330, 140, 80, 80 and 50 mAs, the images had a spatial resolution of 1.0 mm, with contrast resolution of 2. 0, 3. 0, 4. 5, 4. 5 and 6. 0 mm, respectively. (2) Significant differences in ED values were found among the five groups (F=1 064. 119, P=0. 000) and between every two of those groups (P<0. 05). Group E had the lowest ED (0. 19 mSv), 86. 52%, 67. 24%, 45. 71%, and 38. 71% lower than that in Group A, B, C and D, respectively (P<0. 05). (3) All of the five groups obtained an image quality score above 3, and no statistical differences appeared among the 5 groupl (F=1. 978, P>0. 05). The diagnostic results of the spiral CT were consistent with those of orthodontic surgery. CONCLUSION: Low dose spiral CT scanning can meet the image quality requirements for diagnosing impacted teeth, minimizing radiation exposure effectively. PMID- 26619557 TI - [Determination of Desloratadine and Its Metabolite 3-OH Desloratadine in Human Plasma by LC-MS/MS]. AB - OBJECTIVE: To develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of desloratadine and its metabolite 3 OH desloratadine in human plasma. METHODS: 24 healthy male volunteers received a single oral dose of 5 mg desloratadine tablets in a randomized crossover bioequivalence study with two preparations of tablets. Serial plasma samples were taken and analyzed by the LC-MS/MS method. The pharmacokinetic parameters of the two preparations were calculated and compared statistically to evaluate their bioequivalence using Winnonlin 6. 3. RESULTS: The calibration curves of desloratadine and 3-OH desloratadine were both linear over the concentration range of 0. 050-6. 0 ng/mL, with intra-batch and inter-batch relative standard deviations less than 15%. The 90% confidence intervals (CIs) of peak concentration (Cmax) area under the curve (AUC)0t and AUC0-infinity of desloratadine and 3-OH desloratadine all resided within the bioequivalence limit 80%-125%. No significant difference in peak time (Tmax) was demonstrated between the two preparations. CONCLUSION: The LC-MS/MS method can be used for simultaneous determination of desloratadine and 3-OH desloratadine in human plasma, which has been successfully applied-to a bioequivalence study. PMID- 26619559 TI - ON NHS PRODUCTIVITY. Productivity growth is no cause for celebration. PMID- 26619560 TI - TARGET SUCCESS WILL ONLY BE SHORT LIVED. PMID- 26619558 TI - [Pathogen Characteristics of Catheter-related Bloodstream Infection]. AB - OBJECTIVE: To determine thepathogen characteristics of catheter-related bloodstream infection (CRBSI). METHODS: The clinical data of patients with CRBSI who were admitted in West China Hospital, Sichuan University during January 1, 2011 and October 15, 2014 were retrieved, along with findings of pathogen culture and drug susceptibility tests. RESULTS: Eighty-four strains of pathogens were isolated from 77 patients, which included 41 strains (48. 8%) of Gram-negative bacteria, 23 strains (27. 4%) of Gram-positive bacteria, and 20 strains of fungus (23. 8%). Enterobacteriaceae was predominant (29/41, 70.7%) in the Gram-negative bacteria,followed by non-fermenting bacteria (12/41, 29. 3%). Staphylococcus spp. was the main (16/23, 69. 6%) species of Gram- positive bacteria. Candida albicans led to 35. 0% (7/20) fungi infection. Resistance of Enterobacteriaceae to ceftriaxone was high (65. 5%, the highest), compared with its resistance to imipenem (3. 4%, the lowest). The non-fermentative bacterial had complete (100%) resistance to nitrofurantoin, and 16. 7% resistance (the lowest)to levofloxacin. Staphylococcus spp. had 81. 3% resistance (highest) to clindamycin, and zero resistance to vancomycin andlinezolid. Resistance to amphotericin and 5 flucytosine was not found in Candida spp. isolates. CONCLUSION: Prevention and control of CRBSI caused by Gram negative bacilli should be strengthened in the hospital. Clinical treatments should be guided by the in vitro drug susceptibility of pathogens. PMID- 26619561 TI - THE NHS COMPETITION DEBATE RAGES ON. PMID- 26619562 TI - INNOVATION. Look further afield to integrate care locally. PMID- 26619563 TI - PERFORMANCE. HOW TO HIT THE A&E TARGET. PMID- 26619565 TI - MANCHESTER'S 'HEALTHOPOLIS' CAN RESCUE THE NHS. PMID- 26619564 TI - ON ELECTION MANIFESTOS. Certainty is lacking in post-election prospects. PMID- 26619566 TI - HEALTH SERVICES MUST BE COORDINATED. PMID- 26619567 TI - A LEADING QUESTION. PMID- 26619568 TI - SURVEY. WHAT NOT TO DO AFTER THE ELECTION. PMID- 26619569 TI - ON RESPECT FOR MANAGERS. Stamping down on pay belittles NHS top jobs. PMID- 26619570 TI - WE NEED A COMMON LANGUAGE TO MAKE PREVENTION REAL. PMID- 26619571 TI - DELVE DEEPER THAN DELAYED DISCHANGES. PMID- 26619572 TI - MENTAL HEALTH. Put a lid on patient overspill to private care. PMID- 26619573 TI - LEADERSHIP. TAKE CREATIVE FLIGHT. PMID- 26619574 TI - ON ONLINE THERAPIES. Virtual therapies can stop the clock on suicide. PMID- 26619576 TI - PERSUADE THE PUBLIC TO TRUST DATA SHARING. PMID- 26619575 TI - THE CURRENT A&E APPROACH IS NOT FIT FOR PURPOSE. PMID- 26619577 TI - MENTAL HEALTH. Mental health hangs in the balance without parity. PMID- 26619578 TI - SURVEY. WE NEED QUALITY TIME. PMID- 26619579 TI - LEADERSHIP. Listen and learn under one roof. PMID- 26619580 TI - ON BUDGET DEVOLUTION. As risks rise, be careful what you wish for. PMID- 26619581 TI - INTERACTIONS MATTER MOST IN PATIENT EXPERIENCE. PMID- 26619582 TI - TARGETS ARE NO MEASURE OF GOVERNANCE. PMID- 26619583 TI - HOSPITAL TRANSFORMATION. The race is on to tackle A&E winter pressures. PMID- 26619584 TI - HSJ serco COMMISSION on HOSPITAL CARE for FRAIL OLDER PEOPLE. PMID- 26619585 TI - RECONFIGURATION. PLAY THE LONG GAME. PMID- 26619586 TI - CANCER CARE IS NOT BLACK AND WHITE. PMID- 26619587 TI - ON THE FUTURE CARE OF OLDER PEOPLE. Everybody's going to need good neighbours. PMID- 26619588 TI - PLAN FOR YOUR END OF LIFE CARE BEFORE IT IS TOO LATE. PMID- 26619589 TI - DEFUSE THE CANCER TIME BOMB. PMID- 26619590 TI - INNOVATION. Using social media in the NHS gets the thumbs up. PMID- 26619591 TI - WORKFORCE. See the light of bright ideas from the front line. PMID- 26619593 TI - FEARMONGERING HEADLINES HARM END OF LIFE CARE. PMID- 26619592 TI - ON THE GENERAL ELECTION 2015. The health secretary will face an uphill battle. PMID- 26619594 TI - SELF-REFERRAL BENEFITS MUST BE REALISED. PMID- 26619595 TI - WORKFORCE. Support doctors under scrutiny. PMID- 26619596 TI - A PROGRAMME WE WILL ALL BE WATCHING. PMID- 26619597 TI - ON THE ELECTION AFTERMATH. The future is tough, whoever's in power. PMID- 26619598 TI - THE NHS NEEDS A CONSISTENT INQUIRY PROCESS. PMID- 26619599 TI - THE NHS NEEDS SYSTEM LEADERSHIP. PMID- 26619600 TI - Patient data: Look at the bigger picture. PMID- 26619601 TI - ON NHS EXPORTS. There's a world of opportunities. PMID- 26619602 TI - LEADING BY COACHING. NOT DIRECTING. PMID- 26619603 TI - LEADERSHIP Q&A. Leading with military precision. PMID- 26619604 TI - COMMISSIONING. The art and science of creative therapies. PMID- 26619605 TI - FOOD FOR THOUGHT. PMID- 26619607 TI - THE NHS CANNOT AVOID LAW CHANGES FOR EVER. PMID- 26619606 TI - ON AGENCY PAY. Are staffing agencies ripping off the NHS? PMID- 26619608 TI - SERVICE IMPROVEMENT. 'THE UK IS OUT OF SYNC'. PMID- 26619609 TI - PATIENT CARE: CASE STUDIES. THE WAYS AND MEANS. PMID- 26619610 TI - PARTNERSHIPS. RAPID RESPONSE. PMID- 26619611 TI - HEALTH SECRETARY'S ATTITUDE IS EVERYTHING. PMID- 26619612 TI - INFORMATICS. Bring order to your data. PMID- 26619613 TI - INTEGRATION. TAKE A WHOLE SYSTEM APPROACH. PMID- 26619614 TI - Prescription-price sticker shock: Will federal lawmakers intervene? PMID- 26619615 TI - In battle over reproductive healthcare, the ACLU hunts for best challenge to Catholic hospitals' ethical rules. PMID- 26619617 TI - Healthcare struggling to recruit top cybersecurity professionals. PMID- 26619616 TI - Latest mammogram guidelines stress need for doctor/patient dialogue. PMID- 26619618 TI - Surmounting shortages. GPOs work creatively with manufacturers to avert drug shortfalls. PMID- 26619619 TI - Got enough NURSES? Nurse groups cite Kentucky case to support push for staffing ratio laws. PMID- 26619620 TI - A bungled bundle. PMID- 26619621 TI - Use financial incentives to reduce racial and ethnic disparities in healthcare. PMID- 26619622 TI - Modifying the EHR to ease research. PMID- 26619623 TI - 'There is tremendous profit-taking going on in healthcare'. PMID- 26619624 TI - By the numbers. Medicaid budgets by state. Ranked by average spending per enrollee, 2014. PMID- 26619625 TI - Small practices lead the way on EHRs. PMID- 26619626 TI - Financing technology the right way. PMID- 26619627 TI - Medical Economics Best EHRS Physician reviewed. PMID- 26619628 TI - Why you must avoid EHR note cloning. PMID- 26619629 TI - Increasing patient portal use: Lessons from my practice. PMID- 26619630 TI - Find the right EHR for your practice. PMID- 26619631 TI - Interoperability: How close are we? PMID- 26619632 TI - Avoiding an EHR-related malpractice suit. PMID- 26619633 TI - Top apps for medical practices. A list of physician-recommended apps you can download today. PMID- 26619634 TI - The FLEX-IT 2 Act: More posturing than promise. PMID- 26619635 TI - [The 24-hour-daycare]. PMID- 26619636 TI - [Medical care and unlimited laughter - pediatric clinics in Kabul]. PMID- 26619638 TI - [NaturalWave nipple by Lansinoh and natural sucking of a breastfed baby]. PMID- 26619637 TI - [The skin in the diaper area - prevention and therapy of diaper dermatitis]. PMID- 26619639 TI - [Adult learning]. PMID- 26619640 TI - [Deadline 13 December 2014: European Union consumer information about foods]. PMID- 26619641 TI - [Is "baby-led weaning" the new form of supplemental food?]. PMID- 26619642 TI - [The Chamber of Nursing in Lower Saxony is a step ahead]. PMID- 26619644 TI - ON DIGITAL INNOVATION. A digital NHS is a moral imperative. PMID- 26619643 TI - [Local alliances for reconciling work and family]. PMID- 26619645 TI - THE NHS CAN LEARN FROM AMERICA'S RISK MANAGEMENT. PMID- 26619646 TI - NHS LEADERSHIP MUST BE OPENED UP TO PATIENTS AND CARERS. PMID- 26619647 TI - FOWARD MOMENTUM. PMID- 26619648 TI - Setting up shop in the high street. PMID- 26619649 TI - [The mechanism of blood pressure regulation by the central nervous system]. PMID- 26619650 TI - [Epidemiological characteristic of hypertension in Japan]. AB - Sixty percent and 45% of Japanese men and women, aged over 30 years have hypertension, respectively. The number of hypertensive patients in Japan was estimated to be about 43 million. The treatment rate and the control rate have also increased during the past 30 years. The control rate has reached about 30 and 40% in men and women, respectively. The annual number of deaths due to hypertension in Japan is estimated to be about 100,000. Approximately 50% of deaths from cardiovascular diseases and 50% or more of deaths from stroke are estimated to be attributed to high blood pressure levels beyond optimal values. Among blood pressure parameters, systolic blood pressure more strongly predicts the cardiovascular disease risk. PMID- 26619651 TI - [Pathogenic mechanism of primary hypertension]. AB - Blood pressure is controlled by baroreceptor reflex and pressure natriuresis which consists of renal blood flow autoregulation and tubuloglomerular feedback loop. The tissue renin-angiotensin system in the kidneys contributes to the sensitivity of pressure natriuresis, and the sympathetic nervous activity further affects the tissue renin-angiotensin system in the kidneys and baroreceptor reflex. Moreover, the brain renin-angiotensin system enhances the sympathetic nervous activity. It is therefore likely that the brain renin-angiotensin system plays a pivotal role in the pathogenesis of primary hypertension. Recent studies showed that the expression levels of (pro) renin receptor increase in the brain of hypertensive rats, and that knocking down (pro) renin receptor expression leads to normalization of blood pressure. Because the (pro)renin receptor is known to regulate the tissue renin-angiotensin system, brain (pro) renin receptor may be a novel therapeutic target for primary hypertension. PMID- 26619652 TI - [Treatment of hypertension in Japan--the present condition and future prospects]. AB - In Japan, hypertension (HT) is the second greatest cause of death from non communicable diseases next to tobacco. The 2007 National Health and Nutrition Survey showed that only half of HT patient currently receiving drugs for the control of high blood pressure. And the proportion of undiagnosed and untreated patients in Japan was greater than estimated numbers reported from the 2007 US Survey. Calcium channel blocker is the most commonly used antihypertensive drug class following angiotensin receptor blocker which is very different from US. In order to ameliorating hypertension, life style modification, "Project of Health Japan 21", "Tailor-made medicine using candidate gene of essential hypertension", and "Quality of blood pressure control", such as control of night time blood pressure, control of central blood pressure, and blood pressure variability are required more in future. PMID- 26619653 TI - [Clinic blood pressure, home blood pressure, and ambulatory blood pressure monitoring]. AB - Hypertension is closely associated with cardiovascular events, so it is important to strictly control blood pressure (BP) throughout 24 hours. Home BP (HBP), which is also a better predictor of organ damage and cardiovascular disease, is treated with priority in JSH2014. We can detect white coat hypertension(WCH) and masked hypertension (MH) used by either HBP monitoring(HBPM) or ambulatory blood pressure monitoring (ABPM). Especially masked nocturnal hypertension, which is reported to be present of one fourth of well controlled morning hypertension, is associated with advanced organ damage. HBPM is available to detect masked nocturnal hypertension. Therefore, self-measured sleep BP at home would be spread in the future. It is important to properly recognize hypertensive's condition and treat that using various BP monitoring. PMID- 26619654 TI - [Biomarker for evaluation and management of hypertensives]. AB - Biomarkers for hypertension should be widely applied to diagnosis, evaluation for risks and therapeutic efficiency. The guidelines from Japan and ESH/ESC list markers to evaluate cardiovascular risks and organ damages which should be applied after careful physical examination and sensitivity, specificity and likelihood of markers must be taken into account. Proteome, metabolome analysis, microRNAs or new markers in blood and urine is promising for future diagnosis of salt-sensitivity, tubular damages and other organ damages. Accumulation of evidence for established markers such as CAVI, AI, FMD or other markers are expected. PMID- 26619655 TI - [Endothelial function test]. AB - Endothelial dysfunction is thought to have pivotal roles for the development of hypertension, initiation/progression of hypertensive organ damages, and prognosis. In clinical setting, flow-mediated vasodilatation (FMD) of brachial artery is used as a marker of endothelial function. However, well-trained sonographer is needed to conduct FMD measurement, and therefore, FMD has not been fully standardized (i.e., the reference value of FMD has not been established). Even so, FMD predicts future cardiovascular events. Lifestyle modifications (i.e., smoking cessation, exercise, or weight loss) and antihypertensive medication provide beneficial effects on endothelial function. Thus, FMD have a potential as a useful surrogate marker for the management of hypertension. PMID- 26619656 TI - [The criteria for the selection of antihypertensive drugs by JSH2014 guidelines]. AB - The preventive effects of antihypertensive drugs on cardiovascular disease are determined by the degree to which blood pressure decreases rather than its class. Appropriate antihypertensive drugs should be selected considering compelling indications, contraindications and conditions that require the careful use of drugs and the presence or absence of complications. In hypertensive patients without compelling indications, the antihypertensive drug to be first administered should be selected from Ca channel blockers, angiotensin-receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors and diuretics. The use of two or three drugs in combination is often necessary to achieve the target of blood pressure control. Combination therapy with different classes of antihypertensive drugs exhibits potent hypotensive effects, and is useful for achieving the target of blood pressure control. PMID- 26619657 TI - [Chronotherapy of hypertension]. AB - Blunted blood pressure (BP) decline during night-time leads to the higher risk of cardiovascular events in hypertensive patients. Therefore, to improve the prognosis of the patients, it is essential for properly controlling BP during night-time sleep as well as day-time activity. In addition, the dosing-time dependent changes are observed in the pharmacokinetics and pharmacodynamics of some antihypertensive drugs. Thus, the efficacy and toxicity of drugs might be affected by their dosing-time. Chronotherapy is the therapeutic application of chronopharmacology and chronotoxicology to enhance the effectiveness and tolerance of drugs by determining optical dosing-time of drugs from a circadian perspective. In this article, chronotherapy of angiotensin-converting enzyme inhibitor, Ca channel blocker, alpha1 blocker, diuretics and angiotensin II receptor blocker will be discussed. PMID- 26619658 TI - [Lifestyle modifications]. AB - Lifestyle modifications are important in the prevention and treatment of hypertension. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH2014) recommend salt reduction (< 6 g/day), increased intake of vegetables/fruit and fish (fish oil), reduced intake of cholesterol and saturated fatty acids, weight loss (body mass index < 25kg/m2), exercise (>= 30 min/day), reduction of alcohol intake (<= 20-30 mL/day in men, <= 10-20 mL/day in women as ethanol), and quitting smoking. These lifestyle modifications are capable of reducing blood pressure and ameliorating other cardiovascular risk factors. However, the reduction in blood pressure is mild to moderate and the adherence to lifestyle modifications has been still suboptimal. PMID- 26619659 TI - [Device treatment approaches targeting the sympathetic nervous system in patients with resistant hypertension]. AB - A large percentage of patients with hypertension do not meet guideline blood pressure goal, which increases cardiovascular morbidity and mortality. Involvement of sympathetic nervous system has been recognized but our intervention for the system was limited to pharmacological therapy. The new interventions, such as intra-renal artery ablation and baroreflex activation therapies, directed toward the sympathetic nervous system, were intensely examined in various areas of cardiovascular disease. These interventions are promising with some conflicting results. PMID- 26619660 TI - [Hypertension associated with cerebrovascular disease]. AB - In hypertensive patients with cerebrovascular disease, subjects to be treated with antihypertensive drugs and the target level of blood pressure control are determined on the basis of clinical disease type, interval after onset, severity, age, and the use of antithrombotic drugs. According to the guideline of the Japanese Society of Hypertension 2014 (JSH2014), in the hyperacute and acute phases of cerebral infarction, for which thrombolytic therapy is not indicated, the target of blood pressure control should be 85-90% of the pretreatment value when systolic and diastolic blood pressures exceed 220 and 120 mmHg, respectively. In the hyperacute and acute phases of cerebral hemorrhage antihypertensive therapy should be indicated for patients with a systolic blood pressure of > 180 mmHg or a mean blood pressure of > 130 mmHg. The target blood pressure should be < 140/90 mmHg. In the chronic phase of cerebral infarction, cerebral hemorrhage and subarachnoid hemorrhage, the target blood pressure should be < 140/90 mmHg. In patients with lacunar infarction, those taking antithrombotic drugs, cerebral hemorrhage and subarachnoid hemorrhage, a lower level, < 130/80 mmHg should be targeted if possible. Oral antihypertensive drugs such as Ca channel blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and diuretics are recommended for patients with cerebrovascular disease. PMID- 26619661 TI - [Anti-hypertensive therapies in patients with heart disease]. AB - Abstract Hypertension is the major cause of cardiovascular disease. Persistent hypertension leads to cardiovascular remodeling and resulted in heart diseases such as coronary artery disease, heart failure, and arrhythmia. The presence of hypertension could also be a precipitating factor of heart diseases and form vicious cycle. Therefore, perfect blood pressure control is essential for the prevention of cardiovascular events. Additionally, it is ideal to choose anti hypertensive agents, which have cardiovascular-protective effects as well as strong blood pressure-lowering effects. We herein describe anti-hypertensive therapies in patients with heart disease in accordance with JSH2014 and JCS guidelines. PMID- 26619662 TI - [Hypertension with chronic kidney disease: anti-hypertensive therapy recommended for the management of hypertension with CKD in JSN-CKD GL 2013 and JSH2014]. AB - For clinical practice guidelines for the management of hypertension with CKD, the Japanese Society of Nephrology (JSN) and the Japanese Society of Hypertension (JSH) evaluated recently published evidence in corporation with each other. After considerable and careful discussion, both JSN and JSH revised their respective guidelines [the Evidence-based Clinical Practice Guideline for CKD 2013 (JSN-CKD GL 2013) and JSH2014]. This section will mainly introduce anti-hypertensive therapy recommended for the management of hypertension with CKD in both guidelines. Recommendation statements for the Management of Hypertension with CKD are as follows: 1) Anti-hypertensive therapy in CKD is strongly recommended to inhibit or prevent the progression of renal dysfunction and to prevent the occurrence or recurrence of CVD by reducing blood pressure (BP) (Grade A). 2) In all diabetic CKD, the target level of clinic BP is recommended as < 130/80 mmHg, irrespective of the presence or absence of albuminuria/proteinuria (Grade B). 3) In all non-diabetic CKD, the target level of clinic BP is strongly recommended as consistently < 140/90 mmHg, irrespective of the presence or absence of albuminuria/proteinuria (Grade A). 4) In non-diabetic CKD with A2 and A3 categories, the target level of clinic BP can be set as < 130/80 mmHg (Grade C1). 5) In diabetic CKD with A1 category, ARBs and ACE inhibitors are suggested as first-line anti-hypertensive drugs(Grade C1). 6) In diabetic CKD with A2 and A3 categories, ARBs and ACE inhibitors are recommended as first-line anti hypertensive drugs (Grade A). 7) In non-diabetic CKD with A1 category, ARBs, ACE inhibitors, calcium channel blockers (CCBs) and diuretics are recommended as first-line anti-hypertensive drugs (Grade B). 8) In non-diabetic CKD with A2 and A3 categories, ARBs and ACE inhibitors are recommended as first-line anti hypertensive drugs (Grade B). PMID- 26619663 TI - [Hypertension and diabetes mellitus]. AB - The goal of diabetes treatment is to maintain a quality of life. Hypertension is a common diabetes comorbidity and is a risk factor for mortality. Epidemiological studies show that blood pressure (BP) lowering is associated with improving prognosis in this population. However, recent clinical trials and meta-analyses report no benefit of an intensive BP lowering of < 130/80 mmHg on mortality and cardiovascular complications, except stroke. Furthermore, the excess BP lowering should be avoided not to increase the risk of adverse effects such as hypotension, especially in elderly patients or those with adverse vascular complications. In Japanese diabetes guidelines, a BP target of < 130/80 mmHg is still recommended in diabetic patients with hypertension because of the high incidence of stroke in Japanese. PMID- 26619664 TI - [Childhood hypertension]. AB - For accurate diagnosis of childhood hypertension, selection of appropriate manchette size according to the child age and the circumstantial size of upper limb is essentially important. In addition, except for the emergency case of hypertension, repeated measurement of blood pressure would be desirable in several weeks interval. Recently, childhood hypertension might be closely related to the abnormality of maternal gestational period caused by the strict diet and the maternal smoking. Developmental Origins of Health and Disease(DOHaD) theory is now highlighted in the pathogenesis of adulthood hypertension. To prevent hypertension of small-for-date baby in later phase of life, maternal education for child nursing should be conducted. In children, secondary hypertension caused by renal, endocrinologic, or malignant disease is predominant rather than idiopathic hypertension. PMID- 26619665 TI - [Management of pregnancy induced hypertension]. AB - Pregnancy induced hypertension (PIH) is classified according to the severity of hypertension. The Japan Society of Hypertension made practice guidelines in 2014, and the Japan Society for the Study of Hypertension in Pregnancy made guidelines subsequently in 2015, too. Both guidelines state that the basic treatment for PIH is the interruption of pregnancy, and antihypertensive therapy should be given for protection in mother complicated by severe hypertension. The fetal heart rates should be monitored enough due to worsening fetal circulation. It recommends that methyldopa, hydralazine, labetalol, and long-acting nifedipine (only after 20 weeks of gestation) should be used as the first-choice antihypertensive oral drugs. Intravenous administration should be selected when a hypertensive emergency occurs. PMID- 26619666 TI - [Hypertension in people with dementia]. AB - The importance of dementia as a comorbidity of hypertension has enlarged with recent increase in the prevalence of dementia among elderly population. However, several questions about the link between hypertension and dementia remain unsolved. In this report, four clinical questions about hypertension and dementia are discussed. (1) Is hypertension a risk factor of dementia? (2) Does anti hypertensive therapy improve dementia? (3) Is the management of blood pressure for hypertensive patients with dementia different from those with normal cognitive function? (4) What kind of attentions should be paid for the treatment for hypertensive patients with dementia? PMID- 26619667 TI - [Hypertension of old people in frailty]. AB - In older people, the therapeutic importance for hypertension is different from young people because of wide interindividual variability in organ failure or dysfunction. The association with the severity and mortality of hypertension is known to be attenuated by aging Here, we describe the therapeutic strategy for hypertension of old people in frailty. PMID- 26619668 TI - [Drug resistant hypertension]. AB - Abstract Resistant hypertension is defined as the condition unable to attain target clinic blood pressure (BP) level below 140/90 mmHg despite at least 3 classes of antihypertensive drugs including diuretics. It is frequently seen in clinical practice and sometimes difficult to manage. In principle, it is important to uncover the factors which could make the subjects as drug resistant: white-coat resistant hypertension, substances which elevate BP level, insufficient drug regimen, and secondary hypertension including sleep apnea. After confirming truly drug resistance, clinicians should refer them to hypertension specialists to consider device-based antihypertensive therapy. In this article, up-to-date findings of resistant hypertension will be reviewed. PMID- 26619669 TI - [Treatment of hypertension crises]. AB - A hypertensive emergency is medical condition with severe hypertension involves acute and rapidly progressed target cardiovascular organ damage. This situation requires immediate blood pressure reduction to prevent lethal target-organ damage. A patient must be treated under intensive-care monitoring and with intravenous antihypertensive medicines. To avoid organ ischemia which is caused by rapid reduction in blood pressure, the recommended aims are reduction of mean arterial pressure by no more than 25% during the first one hour, followed by 160/100-110 mmHg within the next 2-6 hours. While a hypertensive urgency which does not accompany any evidence of target-organ damages can be treated with oral antihypertensives agents. PMID- 26619670 TI - [Secondary hypertension]. AB - Hypertension is a common disease and a crucial predisposing factor of cardiovascular diseases. Approximately 10% of hypertensive patients are secondary hypertension, a pathogenetic factor of which can be identified. Secondary hypertension consists of endocrine, renal, and other diseases. Primary aldosteronism, Cushing's syndrome, pheochromocytoma, hyperthyroidism, and hypothyroidism result in endocrine hypertension. Renal parenchymal hypertension and renovascular hypertension result in renal hypertension. Other diseases such as obstructive sleep apnea syndrome are also very prevalent in secondary hypertension. It is very crucial to find and treat secondary hypertension at earlier stages since most secondary hypertension is curable or can be dramatically improved by specific treatment. One should keep in mind that screening of secondary hypertension should be done at least once in a daily clinical practice. PMID- 26619671 TI - [Therapeutic effect of RAS inhibitors on epigenetic changes in life-style related diseases]. AB - Recently emerging evidence has shown that epigenetic mechanisms are involved in initiation and progression of life-style related diseases, including hypertension. In this article, we reviewed therapeutic effect of renin angiotensin system (RAS) inhibitors on epigenetic changes in the disease states. We have recently reported that transcription factor Kruppel-like factor 4(KLF4) is expressed in kidney podocytes and modulates podocyte phenotype by gene selective epigenetic control, and that the effect of RAS inhibitors is mediated by epigenetic modulation through KLF4 in part. It is suggested that the 'memory' or 'legacy' effect of RAS inhibitors previously reported in human studies may be partly due to the epigenetic modulation by these agents, and further studies are necessary for investigation of new therapeutic target. PMID- 26619672 TI - [Blood pressure variability-induced aggravation of hypertensive organ damages]. AB - There is increasing evidence that not only the elevation of systolic and diastolic blood pressure(BP) but also the increase in BP variability (or fluctuation) are associated with hypertensive organ damages and the morbidity and mortality of cerebrovascular and cardiovascular events, as well as cognitive dysfunction. However, the molecular mechanism whereby the increase in BP variability aggravates hypertensive organ damages remains unknown. Thus, we created a rat chronic model of a combination of hypertension and large BP variability by performing bilateral sino-aortic denervation in spontaneously hypertensive rat. A series of our studies using this model revealed that large BP variability induces chronic myocardial inflammation by activating local angiotensin II and mineralocorticoid receptor systems and thereby aggravates cardiac hypertrophy and myocardial fibrosis, leading to systolic dysfunction, in hypertensive hearts. In addition, large BP variability induces the aggravation of arteriolosclerotic changes and ischemic cortical fibrosis in hypertensive kidney via local angiotensin II system. It is interesting that the initial target sites of the large BP variability are the intramyocardial arterioles in the heart and pre-glomerular arterioles in the juxtamedullary renal cortex, so called "strain vessels". Accordingly, we advocate new concept that the large BP-induced aggravation of hypertensive organ damage is attributable to "strain vessel vasculopathy". PMID- 26619673 TI - [Usefulness for detection of inappropriate blood pressure variability using 'wearable blood pressure sensor']. AB - In the clinical settings, it has frequently seen that the elderly have rapid blood pressure (BP) elevation and decline, leading to such as orthostatic disorders and post-urination syncope. Excessive blood pressure variability (BPV) according to aging leads to aggravation of hypertensive target organ damage due to both disturbed baroreflex function and arterial stiffening. We developed continuous BP monitoring sensor using newly developing device 'wearable BP sensor', as our advantageous approach of without a cuff-stress. The new mobile device could reflect continuous beat-to-beat systolic BP, heart rate(HR), these very close changes and double product(sBPX HR) as a major indicator of cardiac lead, in consistent with cuff-based BP value. Our new challenge using this device might approach to the potential to achieve the quality-up of treatment strategy with consideration for very short-term BPV. PMID- 26619674 TI - [Development trends for antihypertensive drug]. AB - Hypertension is recognized as a significant risk factor for cardiovascular complications and associated with mortality. Many antihypertensive drugs have been developed in last decades and several placebo-controlled trials have demonstrated that lowering blood pressure with drug treatment reduces the incidence of cardiovascular diseases including stroke, coronary disease and renal injury. However, blood pressure control remains insufficient in many hypertensive patients who are treated with antihypertensive drugs. In addition, several clinical trials failed to demonstrate that different classes of antihypertensive agents vary in their capacity to decrease cardiovascular and renal disease, independent of their ability to lower blood pressure. Thus, further efforts will be needed to develop the new antihypertensive agent in order to prevent cardiovascular disease outcomes or death. This article provides an overview of currently available data on development trends for antihypertensive drug. In particular, we will focus on the new drugs related to the renin-angiotensin aldosterone system. We will not discuss novel interventional approaches such as renal denervation, carotid body ablation and arteriovenous fistula placement. PMID- 26619676 TI - Family Bibles and chicken dinners. PMID- 26619675 TI - [Kenny-Caffey syndrome and its related syndromes]. AB - Kenny-Caffey syndrome (KCS) is a very rare dysmorphologic syndrome characterized by proportionate short stature, cortical thickening and medullary stenosis of tubular bones, delayed closure of anterior fontanelle, eye abnormalities, and hypoparathyroidism. Two types of KCS were known: the autosomal recessive form (KCS type 1), which is caused by mutations of the TBCE gene, and the autosomal dominant form (KCS type 2), which is caused by mutations of the FAM111A gene. TBCE mutation also causes hypoparathyroidism-retardation-dysmorphism syndrome, and FAM111A mutation also causes gracile bone dysplasia. These two diseases can be called as KCS-related syndromes. In this article, we review the clinical manifestations of KCS and discuss its related syndromes. PMID- 26619677 TI - PCMH playbook. 7 steps to plan today for a value-based payment future. PMID- 26619678 TI - VOLUNTEERING. The benefits and risks for physicians. PMID- 26619679 TI - 5 FINANCIAL METRICS. EVERY PRACTICE SHOULD TRACK EACH MONTH. PMID- 26619680 TI - Fulfilling the promise of remote patient monitoring. PMID- 26619681 TI - MINIMIZING YOUR RISK. WHEN PRACTICING TELEMEDICINE. PMID- 26619682 TI - Understanding physician compensation caps. Physicians working in a productivity model need to understand how compensation caps can affect their income. PMID- 26619684 TI - 10 reasons to outsource medical billing. PMID- 26619683 TI - LEVELS OF CARE. CLEARING UP CODING CONFUSION. PMID- 26619685 TI - THE RISE AND FALL OF THE PATIENT-CENTERED MEDICAL HOME. Why a PCMH pioneer may abandon the model in his practice. PMID- 26619686 TI - Experts divided on threat from latest ACA legal challenge. PMID- 26619687 TI - Feisty House hearing portends more battles over consolidation. PMID- 26619688 TI - Cuts to Planned Parenthood have troubling impact on states. PMID- 26619689 TI - Investors hope to profit from sharing the bundled payment load. PMID- 26619690 TI - Defective rewards. How design flaws have hobbled Medicare's incentive programs. PMID- 26619692 TI - Who needs beds? New ambulatory centers offer everything except inpatient care. PMID- 26619691 TI - Flipping the code switch. Healthcare industry nervous about readiness for big ICD 10 conversion. PMID- 26619693 TI - A special Data Points for lawmakers debating Planned Parenthood. PMID- 26619694 TI - Telehealth expansion requires advances in payment and coverage policies. PMID- 26619695 TI - Residency trains new nurses in advanced skills. PMID- 26619696 TI - Aiming to provide concierge care 'for the masses'. PMID- 26619697 TI - Hospital utilization by state. Ranked by total acute-care discharges per 1,000 people, based on fiscal 2014 data. PMID- 26619698 TI - [Twenty years of the Cochlear Implant Center of Swiss University]. PMID- 26619699 TI - [Vestibular function: the 6th sense... ignored]. AB - Dizzy patients are often misunderstood by doctors. Those with a complete vestibular deficit and whose function is restored by a vestibular implant use all kinds of words to describe what they feel when the neuroprosthesis is turned on. Their feeling varied from a strong emotion to a feeling of heat. The notion of dizziness or motion was rare. How to describe the sensations provided by an ignored and unconscious sense? With the eyes, one sees; with the ears one hears; no term exists that describes what we do with the vestibular system! Should we say we vestibulise? The notion traditionally taught that patients suffering from a vestibular disorder should describe an imbalance or a rotatory vertigo, be able specify the direction of rotation, etc. is inadequate, unrealistic. PMID- 26619700 TI - [Concomitant anosmia and ageusia: a case report]. AB - Olfactory loss due to head trauma is a frequent finding. It is attributed to the tearing or severing of the olfactory fibers at the cribriform plate. In contrast, posttraumatic gustatory loss is observed and reported rarely and the underlying mechanism is less understood. Here we present a case of a concomitant post traumatic anosmia and ageusia. Imaging showed a considerable frontobasal brain damage and it is speculated that the gustatory impairment is due to a central injury of the secondary taste cortex. Based on this observation, we believe that this clinical presentation might be much more frequent than previously reported. PMID- 26619701 TI - [Therapeutic perspectives in the treatment of chronic subjective tinnitus]. AB - There are no effective therapies for the treatment of chronic subjective tinnitus. The present study aims to compare two therapeutic approaches: Tinnitus Retraining Therapy (TRT) and a Biopsychosocial Approach (BPS). Results show no difference in evolution of tinnitus' perception between the beginning of the study and after 12 months of treatment in both treatment groups. Important anxiety could be a factor contributed towards the abandonment or ineffectiveness of treatments. Patients with more biopsychosocial comorbidities are more receptive to therapies. The practicioners therefore must assess specific needs, comorbidities and biopsychosocial profiles of patients suffering from tinnitus. PMID- 26619702 TI - [Laryngeal amyloidosis: a clinical case and review of literature]. AB - Amyloidosis consists of different forms of systemic or isolated organ lesions characterised by fibrillary protein deposits in extra-cellular tissue. The isolated involvement of the larynx is the most frequent form in the ENT sphere. We present a clinical case of a 67 year-old woman addressed for a sub-acute laryngitis resistant to conservative treatment, and finally diagnosed with laryngeal amyloidosis. We reviewed its physiopathology, the scientific literature as well as the different possibilities of management. Laryngeal amyloidosis is rare. A thorough additional work-up for the research of multifocal or systemic forms is highly recommended. The treatment aims at a minimal invasive endoscopic surgery with functional organ preservation. PMID- 26619703 TI - [Head and neck cancer treatment in the elderly]. AB - We compared the treatment modalities as well as the oncologic outcome between young elderly (65-79 years old), elderly (>80 years old) and the reference population (<65 years old.) We reviewed 1047 patients treated between 2002 and 2012. Tumor sites, TNM stages, type of treatment, and the oncologic results are compared with survival statistics. The elderly group was associated with an increase in palliative treatment, more women and advanced T stages. For the 947 patients treated with curative intent, 5 year recurrence free survival was comparable. The overall-survival decreases with the age because of intercurrent deaths. Nevertheless, the treatment efficacy is similar. In conclusion, an advanced age is associated with worse survival, without a decrease in loco regional control. The chronological age should not be used as a predictive factor for treatment response. PMID- 26619704 TI - [Acute respiratory failure in neuromuscular disease]. AB - Neuromuscular diseases can affect all respiratory muscles, leading to acute respiratory failure, which is the most common cause of morbidity and mortality in those patients. Two situations must be distinguished. 1) Acute respiratory failure as part of a neuromuscular disorder of acute onset and possibly reversible (Guillain-Barre syndrome, myasthenic crisis...). 2) Acute respiratory failure occurring in a patient with an already advanced neuromuscular disease (amyotrophic lateral sclerosis, Duchenne muscular dystrophy...). This article describes the neuromuscular acute respiratory failure in these different aspects, discusses its initial management in the emergency department and identifies the parameters that have to be monitored. PMID- 26619705 TI - [Attitudes and adaptations of women and gynecologists to menopause]. AB - From a socio-anthropological perspective, this article, based on observations and interviews with French-speaking women and gynecologists at a teaching hospital in western Switzerland, shows that women self-represent and live with menopause in different ways that influence their management practices and guide exchanges with gynecologists. Regarding gynecologists, beyond scientific knowledge, they also have representations of menopause and its treatments as well as personal convictions and professional trajectories underlying their practices. As a consequence, the relationship between women and gynecologists may vary according to the protagonists and can take several forms from consensus to conflict. PMID- 26619706 TI - [The fight against malaria: progress and resistance]. PMID- 26619707 TI - [Medical education and the intuition of students]. PMID- 26619708 TI - [Breast feeding treated as a statistical and political subject]. PMID- 26619710 TI - [Miscellaneous. Drug costs and sexual fantasies]. PMID- 26619709 TI - [Purpose of perioperative anticoagulation in atrial fibrillation]. PMID- 26619711 TI - [Worry over rising Assura premiums]. PMID- 26619712 TI - [The Socialist party wants to limit premiums to 10% of revenue]. PMID- 26619713 TI - [Volkswagen, study 329, the same]. PMID- 26619714 TI - ON THE ECONOMICS OF PHARMA CARE. Market abuse is not picked up fast enough. PMID- 26619715 TI - UNLEASH THE POTENTIAL OF COMMUNITY HEALTH. PMID- 26619717 TI - LEADERSHIP. WATCH THIS SPACE. PMID- 26619716 TI - 'COMMAND AND CONTROL' WONT WORK FOR FTs. PMID- 26619718 TI - [A new Revue du Praticien]. PMID- 26619719 TI - [Paracetamol: do we have to reconsider the benefit/risk ratio?]. PMID- 26619720 TI - [Oral anticoagulants: managing the hemorrhagic risk after 75 years]. PMID- 26619721 TI - [Health to the help of negotiations on climate]. PMID- 26619722 TI - [Is hypoglycemia dangerous in type 2 diabetes?]. PMID- 26619723 TI - [HEALTH ECONOMIC ANALYSIS AND FAIR DECISION MAKING]. AB - Health technology assessment consists in evaluating the incremental cost-benefit ratio of a medicine, a medical device, a vaccine, a health strategy, in comparison to alternative health technologies. This form of socio-eoonomic evaluation aims at optimizing resource allocation within the health system. By setting the terms of valid alternatives, it is useful to highlight public choices, but it cannot in itself make the decision as regards the public funding of patient's access to the considered technology. The decision to include such technology in the basket of health goods and sercices covered, the levels and conditions of the coverage, also result from budget constraints, from economic situation and from a political vision about health policy, social protection and public expenditure. Accordingly, health economic analysis must be implemented on specific and targeted topics. The decision making process, with its health, economic and ethical stakes, calls for a public procedure and debate, based on shared information and argument. Otherwise, health system regulation, confronted with radical and costly innovations in the coming years, will become harder to handle. This requires the development of health economic research teams able to contribute to this assessment exercise. PMID- 26619724 TI - [EPIDEMIOLOGY OF SUDDEN CARDIAC DEATH: DATA FROM THE PARIS SUDDEN DEATH EXPERTISE CENTER REGISTRY]. AB - Sudden cardiac death is an unexpected cardiac arrest without obvious extra cardiac cause. Epidemiology of sudden cardiac death has been poorly documented in France, mainly because of challenging requirement in order to capture all cases in a specific area. The Parisian registry (Sudden Death Expertise Center, European Georges Pompidou Hospital, Paris) was initiated in May 2011 and analyzed data of all sudden death in Paris and suburbs (6.6 millions inhabitants). Over 3 years, the annual incidence estimated to 50-70 per 100,000. Those occurred mainly in men (69%), with a mean age of 65 year, and at home (75%). The event was witnessed in 80% of cases, but bystander cardiopulmonary resuscitation was initiated in only half of cases. Initial cardiac rhythm was ventricular fibrillation in 25%. Survival to hospital discharge remains low (8%). PMID- 26619725 TI - [SPORTS-RELATED SUDDEN DEATH: LESSONS FROM THE FRENCH REGISTRY]. AB - So far, sports-related sudden death has been mainly studied through young competitive athletes. The national sports-related sudden death French registry (2005-2010) is the first study evaluating sudden death during sports activities in the general population, estimating that approximately 1000 cases occur each year in France. The vast majority occurs among middle age men practicing recreational activities, with women presenting a very low risk (up to 30-fold lower) compared to men. Outcomes dramatically vary across districts with survival to hospital discharge from 0 to 50%. Those differences are mainly the result of major disparities between districts regarding cardiopulmonary resuscitation initiated by bystanders. Coronary artery disease remains the most frequent cardiovascular disease associated with such events. PMID- 26619726 TI - [RESUSCITATION MEASURES IN CASE OF CARDIAC ARREST]. AB - Improving the survival rate of sudden cardiac death victims mainly relies in the prompt activation of the "chain of survival", resulting in efficient performance at basic life support maneuvers by bystanders. Among these maneuvers, cardiac compressions and use of automated external defibrillation are the most important components. Since basic life support is easy to learn, spreading its practice throughout the general population should be a priority for public health policy. Following initial resuscitation, the last step of the "chain of survival" is ensured by expert pre-hospital and ICU teams, which are able to provide appropriate care. Organization and sequence of these different steps are the object of regularly updated guidelines, summarized in the form of algorithms that facilitate their application. PMID- 26619727 TI - [Isolated spontaneous dissection of the celiac artery]. PMID- 26619728 TI - [Good's syndrome]. PMID- 26619729 TI - [A painful acute lumbar syndrome with haematuria]. PMID- 26619730 TI - [Kidney failure]. PMID- 26619731 TI - [What's new in ... hematology]. PMID- 26619732 TI - [MANAGEMENT OF LUNG CANCER IN ELDERLY]. AB - In France, more than 50% of patients diagnosed with lung cancer are elderly but recommendations about their management are scant. Several patient characteristics, as comorbidities, age-related physiological variations of the main body functions, or eventual long-term treatments, are predictive of survival and must consider for therapeutic decision. The Comprehensive Geriatric Assessment (CGA) is the best tool to evaluate elderly with lung cancer and to identify fit patients who are more likely to benefit from standard treatment from frail ones who are candidates for supportive care. PMID- 26619733 TI - [SMOKING CESSATION IN PREGNANCY]. AB - Smoking during pregnancy is the leading preventable cause of perinatal morbidity. Half of smokers are weaned during pregnancy resulting in 15% of female smokers at time of delivery. Most often, women spontaneously withdraw at the announcement of pregnancy. Thus, the action of professionals has a modest effect. But this effect is real and should encourage us to take care for patients who smoke. They should feel free with guilty. The spouse must be included in this support to create an enabling environment. Every action has its effectiveness. Nicotine prescription should be reserved for cases where it reduces consumption and keep the medicalized link. It is possible to smoke with a nicotine patch in place; the substitution then reduces the cosumption of each cigarette. PMID- 26619734 TI - [VACCINATION AGAINST HEPATITIS B: WHAT'S UP?]. AB - The vaccination against hepatitis B has been shown to be effective and safe. 15 years after a scare suggesting a relationship between the HBV vaccine and the development of demyelinating diseases, studies have not confirmed this suspected link. The french HBV vaccination strategy in effect since the 1990's (vaccination of newborns, a catch-up campaign in children and adolescents and vaccination of high risk populations) is well adapted to the existing epidemiological situation. Vaccination coverage in newborns has increased significantly since 2008. Catch-up of children and adolescents is insufficient. The very limited data on vaccination coverage in populations at high risk of HBV suggests that coverage is largely insufficient. The mandatory vaccination of healthcare workers since 1991 has nearly completely eradicated worksite HBV. Nevertheless: persistent circulation of the virus and the risk of healthcare worker-patient transmission, and insufficient coverage justifies continued vaccination and mandatory proof of immunization. Specific vaccination protocols are needed because certain co morbidities can reduce the probability and strength of the response to the vaccine. The physician should evaluate this risk case-by-case and adapt the vaccination protocol accordingly. Between 2007 and 2012, more than 200 patients have undergone liver transplantation associated with HBV (cirrhosis, hepatocellular carcinoma, fulminant hepatitis). Many of these transplantations could have been avoided thanks to vaccination, and these grafts could have been proposed to other patients. PMID- 26619735 TI - [RESTLESS LEGS SYNDROME--WILLIS-EKBOM DISEASE]. AB - Restless legs syndrome (RLS) is a sensorimotor disorder with a high prevalence (10% in Caucasian populations). It is a purely clinical diagnosis characterized by an urge to move the lower limbs usually accompanied or caused by unpleasant sensations in the legs with an improvement in symptoms with movement. These sensations occur during inactivity or at rest and worsen in the evening or at night. RLS may not only impact the quality of life for an individual, but may also increase mortality. Disease markers such as genetic predispositions have been identified, as well as reduced iron stores with altered intracerebral iron homeostasis and dopaminergic dysfunction. Medication is often necessary in severe forms, with low doses of dopaminergic agonists being the first-line of treatment. The use of alpha2delta ligands is an alternative. Finally benzodiazepines and opioid medications can be effective in refractory cases. In less severe forms of RLS, a non-pharmacological approach is usually sufficient with avoidance of stimulants and correction of contributing factors. PMID- 26619736 TI - [Drug hypersensitivity]. PMID- 26619737 TI - [Drug hypersensitivity: definitions and mechanisms]. PMID- 26619738 TI - [DRUGS-INDUCED URTICARIA AND ANGIOEDEMA]. AB - Drug-induced urticaria and/or angioedema is a frequent issue encountered in family medicine. A specific collection of the anamnesis and of the general context is very important to appreciate the involved mechanism, allergic or not, and potential cofactors. If in doubt about an allergic mechanism, tests will be conducted, mostly under a hospital setting. Bradykinin-mediated angioedema, so much rare than histamine-mediated one, has to be known, because it is potentially lethal. It is often iatrogenic (ACE inhibitors especially). At the end of the allergology work-up, a course of action is proposed to the patient and his family practitioner as far as the rechallenge of the drug is concerned, In case of non allergic urticaria, much more frequent than allergy, taking the drug is possible with a premedication with antihistamines. PMID- 26619739 TI - [DRUG RELATED SYSTEMIC ANAPHYLAXES AND ANAPHYLACTIC SHOCK]. AB - Anaphylactic shock is a systemic immediate hypersensitivity reaction involving 2 or more organs. Symptoms occur in the minutes after the administration of a drug, a food or after hymenoptera sting and are the consequence of the activation of tissue mast cells and blood basophils which release histamine and other inflammatory mediatars. This chapter, written by allergo-anesthesists, concerns mostly, but not exclusively, per-anesthetic anaphylaxis, its diagnosis, prevention and treatment. PMID- 26619740 TI - [DRUG INDUCED EXANTHEMA AND SEVERE CUTANEOUS DRUG REACTIONS]. AB - Cutaneous adverse drug reactions (CADR) are delayed hypersensivities. Their clinical presentation and severity are very diverse ranging from the frequent and benign exanthemas to the rare but severe CADR involving deep organs in the case of drug reaction with eosinophilia and systemic symptoms (DRESS) or leading to skin bulla and epidermal detachment in toxic epidermal necrolysis. The main differential diagnoses are infections, especially viral ones, which could give clinical symptoms identical to those occurring in CADR. PMID- 26619741 TI - [DRUGS DESENSITIZATION]. AB - We now have the means to give a patient the drug he absolutely needs even if these have been responsible for immediate or delayed hypersensitivity reactions. We use so-called "desensitization protocols" which rely on strong experimental pathophysiological bases. We take as examples immediate hypersensitivity to aspirin/NSAID and chemotherapy and non-severe delayed hypersensitivity to antibiotic for which tolerance induction gives excellent results. PMID- 26619742 TI - Historic commitment paves way for ratios. PMID- 26619743 TI - Power lies in local brancches. PMID- 26619744 TI - Blood sampling in critical care - every drop counts! PMID- 26619745 TI - Can--and should--what you do on social media cost you your career? PMID- 26619746 TI - INCAPACITATED by bureaucracy. A mental health nurse's perspective on the Australian mental health care crisis. PMID- 26619747 TI - Nanoscale Polysulfides Reactors Achieved by Chemical Au-S Interaction: Improving the Performance of Li-S Batteries on the Electrode Level. AB - In this work, the chemical interaction of cathode and lithium polysulfides (LiPSs), which is a more targeted approach for completely preventing the shuttle of LiPSs in lithium-sulfur (Li-S) batteries, has been established on the electrode level. Through simply posttreating the ordinary sulfur cathode in atmospheric environment just for several minutes, the Au nanoparticles (Au NPs) were well-decorated on/in the surface and pores of the electrode composed of commercial acetylene black (CB) and sulfur powder. The Au NPs can covalently stabilize the sulfur/LiPSs, which is advantageous for restricting the shuttle effect. Moreover, the LiPSs reservoirs of Au NPs with high conductivity can significantly control the deposition of the trapped LiPSs, contributing to the uniform distribution of sulfur species upon charging/discharging. The slight modification of the cathode with <3 wt % Au NPs has favorably prospered the cycle capacity and stability of Li-S batteries. Moreover, this cathode exhibited an excellent anti-self-discharge ability. The slight decoration for the ordinary electrode, which can be easily accessed in the industrial process, provides a facile strategy for improving the performance of commercial carbon-based Li-S batteries toward practical application. PMID- 26619748 TI - Telephone versus in-person intake assessment for bereavement intervention: Does efficiency come at a cost? AB - Standardized, evidence-based risk assessment is an important component in providing effective bereavement care. E-health intake assessments have been offered alongside or instead of in-person assessments, although evidence concerning the equivalence of assessment results is lacking. This article examines differences between a semistructured intake assessment for grief intervention conducted over the telephone (n = 330) and in-person (n = 115). Differences in scores and clinical implications were evaluated. Although composite assessment scores were lower in the telephone condition, further examination revealed this occurred in the semistructured assessment of risk of complications, not the structured grief symptom assessment. Implications for care provision are discussed. PMID- 26619749 TI - Biomechanics of the incudo-malleolar-joint - Experimental investigations for quasi-static loads. AB - Under large quasi-static loads, the incudo-malleolar joint (IMJ), connecting the malleus and the incus, is highly mobile. It can be classified as a mechanical filter decoupling large quasi-static motions while transferring small dynamic excitations. This is presumed to be due to the complex geometry of the joint inducing a spatial decoupling between the malleus and incus under large quasi static loads. Spatial Laser Doppler Vibrometer (LDV) displacement measurements on isolated malleus-incus-complexes (MICs) were performed. With the malleus firmly attached to a probe holder, the incus was excited by applying quasi-static forces at different points. For each force application point the resulting displacement was measured subsequently at different points on the incus. The location of the force application point and the LDV measurement points were calculated in a post processing step combining the position of the LDV points with geometric data of the MIC. The rigid body motion of the incus was then calculated from the multiple displacement measurements for each force application point. The contact regions of the articular surfaces for different load configurations were calculated by applying the reconstructed motion to the geometry model of the MIC and calculate the minimal distance of the articular surfaces. The reconstructed motion has a complex spatial characteristic and varies for different force application points. The motion changed with increasing load caused by the kinematic guidance of the articular surfaces of the joint. The IMJ permits a relative large rotation around the anterior-posterior axis through the joint when a force is applied at the lenticularis in lateral direction before impeding the motion. This is part of the decoupling of the malleus motion from the incus motion in case of large quasi static loads. PMID- 26619750 TI - Corticofugal Modulation of DPOAEs in Gerbils. AB - Efferent auditory feedback on cochlear hair cells is well studied regarding olivocochlear brainstem mechanisms. Less is known about how the descending corticofugal system may shape efferent feedback and modulate cochlear mechanics. Distortion-product otoacoustic emissions (DPOAEs) are a suitable tool to assess outer hair cell function, as they are by-products of the nonlinear cochlear amplification process. The present project investigates the effects of cortical activity on cubic and quadratic DPOAEs in mongolian gerbils, Meriones unguiculatus, through cortical deactivation using the sodium-channel blocker lidocaine. Contralateral cortical microinjections of lidocaine can lead to either an increase or decrease of median DPOAE levels of up to 10.95 dB. The effects are reversible and comparable at all tested frequencies (0.5-40 kHz). They are not restricted to the preferred frequency of the cortical site of injection. Recovery times are between 20 and 120 min depending on stimulation levels and emission type. When the injection is performed in the ipsilateral hemisphere, DPOAE level shifts are lower in amplitude compared to those after injection in the contralateral hemisphere. No significant changes in DPOAE levels are obtained after saline microinjections. Results indicate that deactivation of auditory cortex activity through lidocaine has a considerable impact on peripheral auditory responses in form of DPOAEs, probably through cortico-olivocochlear pathways. PMID- 26619751 TI - Evaluation of galectin-3 levels in acute coronary syndrome. AB - Galectin-3 is a new biomarker that is assumed to reflect fibrogenesis and inflammation. In this study, we aimed to evaluate the levels of galectin-3 in patients with acute coronary syndrome (ACS) and the relation of galectin-3 to the burden of atherosclerosis. Nineteen patients with ACS who underwent coronary angiography and 17 age-matched healthy controls were enrolled. The burden of atherosclerosis was assessed with Gensini score and with the number of involved vessels. Galectin-3 levels were measured on admission by using ELISA. The mean age of the cohort was 62.8+/-10.6 and 56% of the patients were male. Compared to control group, median galectin-3 levels were significantly higher in ACS patients (0.77ng/mL [0.50-1.19] vs. 0.51ng/mL [0.41-0.78], P=0.01). Patients were classified into three groups according to the number of involved vessels. Median galectin-3 levels did not differ significantly among groups (one vessel: 0.68ng/mL [0.55-0.74], two vessels: 0.67ng/mL [0.46-1.84], three vessels 0.90ng/mL [0.53-1.38], P=0.62). There was a strong correlation between galectin-3 levels and Gensini score (r=0.625, P=0.004). In conclusion, galectin-3 levels were elevated in patients with ACS and there was a strong correlation between galectin-3 levels and Gensini score. PMID- 26619752 TI - Hello Sunday Morning: Alcohol, (non)consumption and selfhood. AB - BACKGROUND: Hello Sunday Morning (HSM) is an online program that encourages people to commit to a period of non-drinking and blog about their experiences. The purpose of this paper is to explore how HSM members negotiated their periods of abstention, with a focus on how not drinking influenced their narratives of selfhood. METHODS: Thematic analysis was undertaken of 2844 blog posts from 154 Victorians who signed up to HSM in 2013 or 2014. RESULTS: Analysis revealed three key narratives of selfhood offered by participants: (1) abstinence resulting in a disrupted sense of self, (2) non-consumption facilitating the development of a new healthy self, and (3) anti-consumption facilitating the development of a resistant self. CONCLUSION: Individuals construct and maintain their sense of self through consumption (or non-consumption) activities, and this occurs within the broader context of the relationship between selfhood, consumption and culture. HSM members developed narratives of self by drawing on a range of wider discursive structures concerning pleasure, healthism and resistance. The typologies of non-drinking selves identified in this paper could be disseminated through platforms such as HSM to support people who are new to non-drinking in choosing how they might construct and enact alternative selfhoods in contexts where alcohol consumption is deeply embedded. PMID- 26619754 TI - An overview of early drug development for endometriosis. AB - INTRODUCTION: Endometriosis is an estrogen-dependent chronic disease of women of fertile age requiring chronic therapy. Although available drugs have good efficacy and safety profiles, some patients experience partial or no improvement of pain with conventional treatment and recurrence of symptoms after discontinuation of the therapies. For these reasons, many new compounds are currently under investigation for the treatment of endometriosis. AREAS COVERED: This review offers the reader a complete and updated overview on emerging therapies for the treatment of endometriosis. The authors describe, in detail, the laboratory and clinical studies on these therapies and highlight the potential advantages and limitations associated with the administration of these new agents. EXPERT OPINION: Gonadotropin-releasing hormone antagonists are the most intriguing emerging agents for the treatment of patients with endometriosis. It should be noted that while there are a number of drugs under investigation, a large majority of these new compounds have only been investigated in laboratory studies with more extensive research required to better elucidate their efficacy and safety profiles. PMID- 26619755 TI - Axonal degeneration in multiple sclerosis: defining therapeutic targets by identifying the causes of pathology. AB - Current therapeutics in multiple sclerosis (MS) target the putative inflammation and immune attack on CNS myelin. Despite their effectiveness in blunting the relapse rate in MS patients, such therapeutics do not prevent MS disease progression. Importantly, specific clinical dilemma arises through inability to predict MS progression and thereby therapeutically target axonal injury during MS, limiting permanent disability. The current review identifies immune and neurobiological principles that govern the sequelae of axonal degeneration during MS disease progression. Defining the specific disease arbiters, inflammatory and autoimmune, oligodendrocyte dystrophy and degenerative myelin, we discuss a basis for a molecular mechanism in axons that may be targeted therapeutically, in spatial and temporal manner to limit axonal degeneration and thereby halt progression of MS. PMID- 26619753 TI - Intracellular trafficking of the pyridoxal cofactor. Implications for health and metabolic disease. AB - The importance of the vitamin B6-derived pyridoxal cofactor for human health has been established through more than 70 years of intensive biochemical research, revealing its fundamental roles in metabolism. B6 deficiency, resulting from nutritional limitation or impaired uptake from dietary sources, is associated with epilepsy, neuromuscular disease and neurodegeneration. Hereditary disorders of B6 processing are also known, and genetic defects in pathways involved in transport of B6 into the cell and its transformation to the pyridoxal-5' phosphate enzyme cofactor can contribute to cardiovascular disease by interfering with homocysteine metabolism and the biosynthesis of vasomodulatory polyamines. Compared to the processes involved in cellular uptake and processing of the B6 vitamers, trafficking of the PLP cofactor across intracellular membranes is very poorly understood, even though the availability of PLP within subcellular compartments (particularly the mitochondrion) may have important health implications. The aim of this review is to concisely summarize the state of current knowledge of intracellular trafficking of PLP and to identify key directions for future research. PMID- 26619756 TI - Observation Units as Substitutes for Hospitalization or Home Discharge. AB - STUDY OBJECTIVE: Observation unit admissions have been increasing, a trend that will likely continue because of recent changes in reimbursement policies. The purpose of this study is to determine the effect of the availability of observation units on hospitalizations and discharges to home for emergency department (ED) patients. METHODS: We studied ED visits with a final diagnosis of chest pain in the National Hospital Ambulatory Medical Care Survey from 2007 to 2010. ED visits that resulted in an observation unit admission were propensity score matched to visits at hospitals without an observation unit. We used logistic regression to develop a prediction model for hospitalization versus discharge home for matched patients treated at nonobservation hospitals. The model was applied to matched observation unit patients to determine the likely alternative disposition had the observation unit not been available. RESULTS: There were 1,325 eligible visits that represented 5,079,154 visits in the United States. Two hundred twenty-seven visits resulted in an observation unit admission. The predictive model for hospitalization had a c statistic of 0.91; variables significantly associated with subsequent hospitalization included age, history of coronary atherosclerosis, systolic blood pressure less than 115 beats/min, and administration of antianginal medications. When the model was applied to matched observation unit patients, 49.9% of them were categorized as discharge home likely. CONCLUSION: In this study, we estimated that half of ED visits for chest pain that resulted in an observation unit admission were made by patients who may have been discharged home had the observation unit not been available. Increased availability of observation units may result in both decreased hospitalizations and decreased discharges to home. PMID- 26619757 TI - Best Practices for Prescription Drug Monitoring Programs in the Emergency Department Setting: Results of an Expert Panel. AB - Prescription drug monitoring programs are generally underused in emergency departments (ED) and nationwide enrollment is low among emergency physicians. We aimed to develop consensus recommendations for prescription drug monitoring program policy and design to optimize their functionality and use in the ED. We assembled a technical expert panel with key stakeholders in emergency medicine, public health, and public policy. The panel included academic and community-based emergency physicians, a pediatric fellowship-trained emergency physician, a medical toxicologist, a public health expert, a patient advocate, a legal expert, and two state prescription drug monitoring program administrators. We compiled prescription drug monitoring program policies and characteristics and organized them into domains based on user-prescription drug monitoring program interaction. The panel convened for 3 rounds in which the policies and characteristics were introduced, discussed, and modified in an iterative fashion to achieve consensus. The process yielded policy recommendations and design features, with majority agreement. The panel made 18 policy recommendations within these main themes: enrollment should be mandatory, with an automatic process to mitigate the workload; registration should be open to all prescribers; delegates should have access to prescription drug monitoring program to alleviate work flow burdens; prescription drug monitoring program data should be pushed into hospital electronic health records; prescription drug monitoring program review should be mandatory for patients receiving opioid prescriptions and based on objective criteria; the prescription drug monitoring program content should be standardized and updated in a timely manner; and states should encourage interstate data sharing. An expert panel identified 18 recommendations that can be used by states and policymakers to improve prescription drug monitoring program design to increase use in the ED setting. PMID- 26619758 TI - Who Am I to Decide Whether This Person Is to Die Today? Physicians' Life-or-Death Decisions for Elderly Critically Ill Patients at the Emergency Department-ICU Interface: A Qualitative Study. AB - STUDY OBJECTIVE: We explored physicians' perceptions of and attitudes toward triage and end-of-life decisions for elderly critically ill patients at the emergency department (ED)-ICU interface. METHODS: This was a qualitative study with thematic analysis of data collected through semistructured interviews (15 emergency physicians and 9 ICU physicians) and nonparticipant observations (324 hours, 8 units, in 2 hospitals in France). RESULTS: Six themes emerged: (1) Physicians revealed a representation of elderly patients that comprised both negative and positive stereotypes, and expressed the concept of physiologic age. (2) These age-related factors influenced physicians' decisionmaking in resuscitate/not resuscitate situations. (3) Three main communication patterns framed the decisions: interdisciplinary decisions, decisions by 2 physicians on their own, and unilateral decisions by 1 physician; however, some physicians avoided decisions, facing uncertainty and conflicts. (4) Conflicts and communication gaps occurred at the ED-ICU interface and upstream of the ED-ICU interface. (5) End-of-life decisions were perceived as more complex in the ED, in the absence of family or of information about elderly patients' end-of-life preferences, and when there was conflict with relatives, time pressure, and a lack of training in end-of-life decisionmaking. (6) During decisionmaking, patients' safety and quality of care were potentially compromised by delayed or denied intensive care and lack of palliative care. CONCLUSION: These qualitative findings highlight the cognitive heuristics and biases, interphysician conflicts, and communication gaps influencing physicians' triage and end-of-life decisions for elderly critically ill patients at the ED-ICU interface and suggest strategies to improve these decisions. PMID- 26619759 TI - Gingival pustules and sterile diffuse sclerosing osteomyelitis as a feature of synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome. AB - Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome represents the rare co-occurrence of sterile inflammatory osteoarticular disease in association with a variety of cutaneous manifestations. Oral involvement is uncommon. The etiology of SAPHO is complex and is likely the combined result of infectious, genetic, and immunologic factors. Due to diverse clinical presentations, SAPHO is difficult to diagnose. Here, we describe the case of a 74 year-old man, who had a history of SAPHO syndrome and presented with gingival pustules and sterile diffuse sclerosing osteomyelitis of the mandible. This is the first case report describing neutrophilic mucositis as a feature of SAPHO. PMID- 26619760 TI - A Developmental Cascade Model of Behavioral Sleep Problems and Emotional and Attentional Self-Regulation Across Early Childhood. AB - This article documents the longitudinal and reciprocal relations among behavioral sleep problems and emotional and attentional self-regulation in a population sample of 4,109 children participating in Growing Up in Australia: The Longitudinal Study of Australian Children (LSAC)-Infant Cohort. Maternal reports of children's sleep problems and self-regulation were collected at five time points from infancy to 8-9 years of age. Longitudinal structural equation modeling supported a developmental cascade model in which sleep problems have a persistent negative effect on emotional regulation, which in turn contributes to ongoing sleep problems and poorer attentional regulation in children over time. Findings suggest that sleep behaviors are a key target for interventions that aim to improve children's self-regulatory capacities. PMID- 26619761 TI - Donohue syndrome. Extreme insulin resistance in the neonatal period. PMID- 26619762 TI - Cerebral blood flow and oximetry response to blood transfusion in relation to chronological age in preterm infants. AB - OBJECTIVE: Preterm infants frequently receive blood transfusion (BT) and the aim of this study was to measure the effect of BT on cerebral blood flow and oxygenation in preterm infants in relation to chronological age. PATIENTS: Preterm infants undergoing intensive care recruited to three chronological age groups: 1 to 7 (Group 1; n=20), 8 to 28 (Group 2; n=21) & >=29days of life (Group 3; n=18). METHODS: Pre and post-BT anterior cerebral artery (ACA) time averaged mean velocity (TAMV) and superior vena cava (SVC) flow were measured. Cerebral Tissue Haemoglobin Index (cTHI) and Oxygenation Index (cTOI) were measured from 15-20min before to 15-20min post-BT using NIRS. Vital parameters and blood pressure were measured continuously. RESULTS: Mean BP increased significantly, and there was no significant change in vital parameters following BT. Pre-BT ACA TAMV was higher in Group 2 and 3 compared to Group 1 (p<0.001). Pre-BT ACA TAMV decreased significantly (p<=0.04) in all 3 groups; pre-BT SVC flow decreased significantly in Group 1 (p=0.03) and Group 3 (p<0.001) following BT. Pre-BT cTOI was significantly lower in Group 3 compared to Group 1 (p=0.02). cTHI (p<0.001) and cTOI (p<0.05) increased significantly post-BT in all three groups. PDA had no effect on these measurements. CONCLUSION: Baseline cTOI decreases and ACA TAMV increases with increasing chronological age. Blood transfusion increased cTOI and cTHI and decreased ACA TAMV in all groups. PDA had no impact on the baseline cerebral oximetry and blood flow as well as changes following blood transfusion. PMID- 26619763 TI - Variable reproducibility in genome-scale public data: A case study using ENCODE ChIP sequencing resource. AB - Genome-wide data is accumulating in an unprecedented way in the public domain. Re mining this data shows great potential to generate novel hypotheses. However this approach is dependent on the quality (technical and biological) of the underlying data. Here we performed a systematic analysis of chromatin immunoprecipitation (ChIP) sequencing data of transcription and epigenetic factors from the encyclopaedia of DNA elements (ENCODE) resource to demonstrate that about one third of conditions with replicates show low concordance between replicate peak lists. This serves as a case study to demonstrate a caveat concerning genome-wide analyses and highlights a need to validate the quality of each sample before performing further associative analyses. PMID- 26619765 TI - Exposure to genocide and the risk of schizophrenia: a population-based study. AB - BACKGROUND: No evidence exists on the association between genocide and the incidence of schizophrenia. This study aims to identify critical periods of exposure to genocide on the risk of schizophrenia. METHOD: This population-based study comprised of all subjects born in European nations where the Holocaust occurred from 1928 to 1945, who immigrated to Israel by 1965 and were indexed in the Population Register (N = 113 932). Subjects were followed for schizophrenia disorder in the National Psychiatric Case Registry from 1950 to 2014. The population was disaggregated to compare groups that immigrated before (indirect exposure: n = 8886, 7.8%) or after (direct exposure: n = 105 046, 92.2%) the Nazi or fascist era of persecutions began. The latter group was further disaggregated to examine likely initial prenatal or postnatal genocide exposures. Cox regression modelling was computed to compare the risk of schizophrenia between the groups, adjusting for confounders. RESULTS: The likely direct group was at a statistically (p < 0.05) greater risk of schizophrenia (hazard ratio = 1.27, 95% confidence interval 1.06-1.51) than the indirect group. Also, the likely combined in utero and postnatal, and late postnatal (over age 2 years) exposure subgroups were statistically at greater risk of schizophrenia than the indirect group (p < 0.05). The likely in utero only and early postnatal (up to age 2 years) exposure subgroups compared with the indirect exposure group did not significantly differ. These results were replicated across three sensitivity analyses. CONCLUSIONS: This study showed that genocide exposure elevated the risk of schizophrenia, and identified in utero and postnatal (combined) and late postnatal (age over 2 years) exposures as critical periods of risk. PMID- 26619767 TI - Professor Andrew E. Czeizel, Hungary (April 3, 1935-August 10, 2015). PMID- 26619764 TI - Crystal structure of the Z-ring associated cell division protein ZapC from Escherichia coli. AB - Bacterial cell division involves a contractile ring that organises downstream proteins at the division site and which contains the tubulin homologue FtsZ. ZapC has been discovered as a non-essential regulator of FtsZ. It localises to the septal ring and deletion of zapC leads to a mild phenotype, while overexpression inhibits cell division. Interference with cell division is facilitated by an interaction with FtsZ. Here, we present the 2.9 A crystal structure of ZapC from Escherichia coli. ZapC forms a dimer and comprises two domains that belong to the Royal superfamily of which many members bind methylated arginines or lysines. ZapC contains an N-terminal chromo-like domain and a Tudor-like C-terminal domain. We show by ITC that ZapC binds the C-terminal tail of FtsZ. PMID- 26619766 TI - Dextran sulfate triggers platelet aggregation via direct activation of PEAR1. AB - Dextran sulfate (DxS; Mr 500 kD) induces fibrinogen receptor (alphaIIbbeta3) activation via CLEC-2/Syk signaling and via a Syk-independent SFK/PI3K/Akt dependent tyrosine kinase pathway in human and murine platelets. The platelet surface receptor, responsible for the DxS-induced Syk-independent Akt-activation, has hitherto not been identified. We found that DxS elicited a concentration dependent aggregation of human platelets resulting from direct PEAR1 activation by DxS. Blocking the PEAR1 receptor, in combination with a selective Syk inhibitor, completely abrogated the DxS-driven platelet aggregation. The DxS induced Syk-phosphorylation was not affected in Pear1(-/-) platelets, but Akt phosphorylation was largely abolished. As a result, the aggregation of Pear1(-/-) platelets was reduced and reversible, i.e. aggregates were less stable compared to wild-type platelet aggregates. Moreover, DxS-induced Pear1(-/-) platelet aggregation was fully abrogated by Syk inhibition, indicating that the remaining platelet aggregation of Pear1(-/-) platelets was Syk dependent. Hence, the Pear1/c-Src/PI3K/Akt- and CLEC-2/Syk-signaling pathways are independently and additively activated during platelet aggregation by DxS. CONCLUSION: The DxS induced aggregation of human and murine platelets is the result of activation of PI3K/Akt through direct PEAR1 phosphorylation and parallel Syk-signaling through CLEC-2. PMID- 26619768 TI - Pediatric Psychopharmacology Trials: Beyond Efficacy. PMID- 26619769 TI - Finding the Balance Between Safety and Threat May Hold the Key to Success When Treating PTSD. PMID- 26619770 TI - Adjunctive Ziprasidone in Major Depression and the Current Status of Adjunctive Atypical Antipsychotics. PMID- 26619771 TI - 2015 in Review. PMID- 26619772 TI - Management of Alcohol Use Disorder in Patients Requiring Liver Transplant. PMID- 26619773 TI - Cognition and Plasma Ratio of Clozapine to N-desmethylclozapine in Patients With Clozapine-Resistant Schizophrenia. PMID- 26619774 TI - Response to Thornton et al. PMID- 26619775 TI - Treatment of Compulsive Pornography Use With Naltrexone: A Case Report. PMID- 26619781 TI - Skin sensitization quantitative risk assessment: A review of underlying assumptions. AB - Toxicological risk assessment informs exposure limits, so the potential for adverse effects to human health are minimised or avoided. For skin sensitisers, the situation is complicated by asymptomatic induction of contact allergy, a necessary prerequisite for expression of the disease allergic contact dermatitis (ACD). For fragrance skin sensitisers, the development of quantitative risk assessment (QRA) arose from the need to improve the extent to which contact allergy occurred. However, the perceived impact has been less than anticipated. Accordingly, the science and assumptions upon which QRA was founded have been scrutinised and proposals for refinement have been made. In addition, areas of uncertainty have been made explicit, e.g. inter-individual variability and the impact of concomitant disease, clarifying where numerical safety assessment factors are based on expert judgement. Also, the relatively small contribution of factors eg. age, gender, ethnic origin, vehicle matrix and skin permeability are highlighted by reference to the (now controversial) human experiments carried out in the second half of the last century. Adoption and widespread implementation of the current recommendations for QRA, taken in concert with improved assessment of aggregate exposure from multiple sources, should ensure that the frequency of contact allergy will decrease over the coming years. PMID- 26619782 TI - Embryo-fetal development toxicity of honokiol microemulsion intravenously administered to pregnant rats. AB - The aim of this study was to evaluate the embryo-fetal development toxicity of honokiol microemulsion. The drug was intravenously injected to pregnant SD rats at dose levels of 0, 200, 600 and 2000 MUg/kg/day from day 6-15 of gestation. All the pregnant animals were observed for body weights and any abnormal changes and subjected to caesarean-section on gestation day (GD) 20; all fetuses obtained from caesarean-section were assessed by external inspection, visceral and skeletal examinations. No treatment-related external alterations as well as visceral and skeletal malformations were observed in honokiol microemulsion groups. There was no significant difference in the body weight gain of the pregnant rats, average number of corpora lutea, and the gravid uterus weight in the honokiol microemulsion groups compared with the vehicle control group. However, at a dose level of 2000 MUg/kg/day, there was embryo-fetal developmental toxicity observed, including a decrease in the body length and tail length of fetuses. In conclusion, the no-observed-adverse-effect level (NOAEL) of honokiol microemulsion is 600 MUg/kg/day, 75 times above the therapeutic dosage and it has embryo-fetal toxicity at a dose level of 2000 MUg/kg/day, which is approximately 250 times above the therapeutic dosage. PMID- 26619783 TI - A review of toxicity studies of single-walled carbon nanotubes in laboratory animals. AB - We summarized the findings of in vivo toxicity studies of single-walled carbon nanotubes (SWCNTs) in laboratory animals. The large majority addressed the pulmonary toxicity of SWCNTs in rodents. Inhalation, pharyngeal aspiration, and intratracheal instillation studies revealed that SWCNTs caused acute and chronic inflammation, granuloma formation, collagen deposition, fibrosis, and genotoxic effects in the lungs. Pulmonary toxicity of well-dispersed SWCNTs was more potent than less dispersed ones. Airway exposure to SWCNTs also induced cardiovascular diseases in mice. Oxidative stress was caused by the administration of SWCNTs. Injected SWCNTs were distributed throughout most of the organs including the brain, mainly retained in the lungs, liver, and spleen, and eliminated through the kidney and bile duct. Orally administered SWCNTs are suggested to be absorbed from the gastrointestinal tract to the blood circulation in mice and rats. Although no definitive study on the carcinogenicity of SWCNTs is available at present, evidence of carcinogenicity has not been reported in toxicity studies cited in this review. Overall, the available data provides initial information on SWCNT toxicity. To further clarify their toxicity and risk assessment, studies should be conducted using well-characterized SWCNTs, standard protocols, and the relevant route and doses of human exposure. PMID- 26619784 TI - Transdermal nicotine absorption handling e-cigarette refill liquids. AB - The concentrated nicotine in e-cigarette refill liquids can be toxic if inadvertently ingested or absorbed through the skin. Reports of poisonings due to accidental ingestion of nicotine on refill liquids are rapidly increasing, while the evaluation of nicotine dermally absorbed still lacks. For that reason we studied transdermal nicotine absorption after the skin contamination with e liquid. Donor chambers of eight Franz diffusion cells were filled with 1 mL of 0.8 mg/mL nicotine e-liquid for 24 h. The concentration of nicotine in the receiving phase was determined by high-performance liquid chromatography (LOD:0.1 MUg/mL). Nicotine was detectable in receiving solution 2 h after the start of exposure and increased progressively. The medium flux calculated was 4.82 +/- 1.05 MUg/cm(2)/h with a lag time of 3.9 +/- 0.1 h. After 24 h, the nicotine concentration in the receiving compartment was 101.02 +/- 22.35 MUg/cm(2) corresponding to 3.04 mg of absorbed nicotine after contamination of a skin surface of 100 cm(2). Skin contamination with e-liquid can cause nicotine skin absorption: caution must be paid when handling refill e-liquids. PMID- 26619785 TI - Using patient-specific hemodynamic response function in epileptic spike analysis of human epilepsy: a study based on EEG-fNIRS. AB - Functional near-infrared spectroscopy (fNIRS) can be combined with electroencephalography (EEG) to continuously monitor the hemodynamic signal evoked by epileptic events such as seizures or interictal epileptiform discharges (IEDs, aka spikes). As estimation methods assuming a canonical shape of the hemodynamic response function (HRF) might not be optimal, we sought to model patient-specific HRF (sHRF) with a simple deconvolution approach for IED-related analysis with EEG-fNIRS data. Furthermore, a quadratic term was added to the model to account for the nonlinearity in the response when IEDs are frequent. Prior to analyzing clinical data, simulations were carried out to show that the HRF was estimable by the proposed deconvolution methods under proper conditions. EEG-fNIRS data of five patients with refractory focal epilepsy were selected due to the presence of frequent clear IEDs and their unambiguous focus localization. For each patient, both the linear sHRF and the nonlinear sHRF were estimated at each channel. Variability of the estimated sHRFs was seen across brain regions and different patients. Compared with the SPM8 canonical HRF (cHRF), including these sHRFs in the general linear model (GLM) analysis led to hemoglobin activations with higher statistical scores as well as larger spatial extents on all five patients. In particular, for patients with frequent IEDs, nonlinear sHRFs were seen to provide higher sensitivity in activation detection than linear sHRFs. These observations support using sHRFs in the analysis of IEDs with EEG fNIRS data. PMID- 26619786 TI - Spatial properties of objects predict patterns of neural response in the ventral visual pathway. AB - Neuroimaging studies have revealed topographically organised patterns of response to different objects in the ventral visual pathway. These patterns are thought to be based on the form of the object. However, it is not clear what dimensions of object form are important. Here, we determined the extent to which spatial properties (energy across the image) could explain patterns of response in these regions. We compared patterns of fMRI response to images from different object categories presented at different retinal sizes. Although distinct neural patterns were evident to different object categories, changing the size (and thus the spatial properties) of the images had a significant effect on these patterns. Next, we used a computational approach to determine whether more fine-grained differences in the spatial properties can explain the patterns of neural response to different objects. We found that the spatial properties of the image were able to predict patterns of neural response, even when categorical factors were removed from the analysis. We also found that the effect of spatial properties on the patterns of response varies across the ventral visual pathway. These results show how spatial properties can be an important organising principle in the topography of the ventral visual pathway. PMID- 26619787 TI - The right inferior frontal cortex in response inhibition: A tDCS-ERP co registration study. AB - In any given common situation, when an individual controls him/herself or obeys and stops a current action when asked to do, it is because the brain executes an inhibitory process. This ability is essential for adaptive behaviour, and it is also a requirement for accurate performance in daily life. It has been suggested that there are two main inhibitory functions related to behaviour, as inhibition is observed to affect behaviour at different time intervals. Proactive inhibition permits the subject to control his behavioural response over time by creating a response tendency, while reactive inhibition is considered to be a process that usually inhibits an already initiated response. In this context, it has been established that inhibitory function is implemented by specific fronto-basal ganglia circuits. In the present study, we investigated the role of the right inferior frontal cortex (rIFC) in response inhibition by combining into a single task the Go-NoGo task and the Stop-Signal task. Concurrently, we applied transcranial direct current stimulation (tDCS) over the IFC and recorded electroencephalography (EEG). Thus, we obtained online EEG measurements of the tDCS-induced modifications in the IFC together with the participant's performance in a response inhibition task. We found that applying bilateral tDCS on the IFC (right anodal/left cathodal) significantly increased proactive inhibition, although the behavioural parameters indicative of reactive inhibition were unaffected by the stimulation. Finally, the inhibitory-P3 component reflected a similar modulation under both inhibitory conditions induced by the stimulation. Our data indicates that an online tDCS-ERP approach is achievable, but that a tDCS bilateral montage may not be the most efficient one for modulating the rIFC. PMID- 26619788 TI - Quantitative beta mapping for calibrated fMRI. AB - The metabolic and hemodynamic dependencies of the blood oxygenation level dependent (BOLD) signal form the basis for calibrated fMRI, where the focus is on oxidative energy demanded by neural activity. An important part of calibrated fMRI is the power-law relationship between the BOLD signal and the deoxyhemoglobin concentration, which in turn is related to the ratio between oxidative demand (CMRO2) and blood flow (CBF). The power-law dependence between BOLD signal and deoxyhemoglobin concentration is signified by a scaling exponent beta. Until recently most studies assumed a beta value of 1.5, which is based on numerical simulations of the extravascular BOLD component. Since the basal value of CMRO2 and CBF can vary from subject-to-subject and/or region-to-region, a method to independently measure beta in vivo should improve the accuracy of calibrated fMRI results. We describe a new method for beta mapping through characterizing R2' - the most sensitive relaxation component of BOLD signal (i.e., the reversible magnetic susceptibility component that is predominantly of extravascular origin at high magnetic field) - as a function of intravascular magnetic susceptibility induced by an FDA-approved superparamagnetic contrast agent. In alpha-chloralose anesthetized rat brain, at 9.4 T, we measured beta values of ~0.8 uniformly across large neocortical swathes, with lower magnitude and more heterogeneity in subcortical areas. Comparison of beta maps in rats anesthetized with medetomidine and alpha-chloralose revealed that beta is independent of neural activity levels at these resting states. We anticipate that this method for beta mapping can help facilitate calibrated fMRI for clinical studies. PMID- 26619790 TI - Eight-day consumption of inulin added to a yogurt breakfast lowers postprandial appetite ratings but not energy intakes in young healthy females: a randomised controlled trial. AB - Increasing feelings of satiety may reduce appetite and energy intake. The role of inulin consumption in impacting satiety is unclear. A randomised double-blind controlled crossover trial aimed to determine the effects of inulin+yogurt on satiety after 1 and 8-d consumption. The preload breakfast included 100 g vanilla yogurt with (yogurt-inulin (YI)) and without (yogurt-control (YC)) 6 g inulin. A total of nineteen healthy females (22.8 (sd 2.7) years) with non-restrained eating behaviour and taking hormonal contraceptives participated in the study. Day 1 and 8 visual analogue scale (VAS) ratings of Hunger, Fullness, Desire to Eat and Prospective Food Consumption (PFC) were collected at fasting and every 30 min for 180 min. Energy intake was calculated from a weighed ad libitum lunch and remainder of day food records. Total AUC was calculated for each VAS. Day 1 (VAS only) and 8 (VAS and energy intakes) data were compared between YI and YC using ANCOVA, and ANOVA was used to compare energy intakes on Day 1. There were no significant differences between Day 1 YI and YC AUC appetite ratings or energy intakes. However, 8-d consumption of YI v. YC was associated with lower Desire to Eat and PFC ratings but similar lunch and total day energy intakes. Therefore, the addition of 6 g inulin to a commercially available yogurt affected feelings of appetite, but not energy intake, after repeated consumption. These results suggest that inulin may be a suitable ingredient to increase dietary fibre consumption, with potential to impact appetite. PMID- 26619789 TI - RBFOX3/NeuN is Required for Hippocampal Circuit Balance and Function. AB - RBFOX3 mutations are linked to epilepsy and cognitive impairments, but the underlying pathophysiology of these disorders is poorly understood. Here we report replication of human symptoms in a mouse model with disrupted Rbfox3. Rbfox3 knockout mice displayed increased seizure susceptibility and decreased anxiety-related behaviors. Focusing on hippocampal phenotypes, we found Rbfox3 knockout mice showed increased expression of plasticity genes Egr4 and Arc, and the synaptic transmission and plasticity were defective in the mutant perforant pathway. The mutant dentate granules cells exhibited an increased frequency, but normal amplitude, of excitatory synaptic events, and this change was associated with an increase in the neurotransmitter release probability and dendritic spine density. Together, our results demonstrate anatomical and functional abnormality in Rbfox3 knockout mice, and may provide mechanistic insights for RBFOX3-related human brain disorders. PMID- 26619792 TI - Sex determination from fingerprint ridge density and white line counts in Filipinos. AB - Fingerprints are distinct physical characteristics that remain unchanged throughout an individual's lifetime. This study derived Filipino-specific probability formulae from fingerprints to be used for sex discrimination in human identification cases. Ridge density from three different areas - distal radial area, distal ulnar area, and proximal area - as well as white line counts from fingerprints of 200 male and 200 female Filipinos were collected and analyzed statistically. Ridge densities of radial and ulnar areas emerged as displaying significant differences between the sexes, with 16ridges/25mm(2) or more in radial area and 15ridges/25mm(2) or more in ulnar area being more likely to be female, whereas 13ridges/25mm(2) or less in radial area and 12ridges/25mm(2) or less in ulnar area were more likely to be male. A white line count of 0 was more likely to be male while a white line count of 2 or more was more likely to be female. The results of this study show sex differences in Filipino fingerprints and support the observation of previous studies that females have finer ridges than males. PMID- 26619791 TI - Ecosensitivity and genetic polymorphism of somatic traits in the perinatal development of twins. AB - In view of criticism regarding the usefulness of heritability coefficients, the aim of this study was to analyze separately the information on genetic and environmental variability. Such an approach, based on the normalization of trait's variability for its value, is determined by the coefficients of genetic polymorphism (Pg) and ecosensitivity (De). The studied material included 1263 twin pairs of both sexes (among them 424 pairs of monozygotic twins and 839 pairs of dizygotic twins) born between the 22nd and 41st week of gestation. Variability of six somatic traits was analyzed. The zygosity of same-sex twins was determined based on the polymorphism of DNA from lymphocytes of the umbilical cord blood, obtained at birth. The coefficients of genetic polymorphism and ecosensitivity for analyzed traits of male and female twins born at various months of gestation were calculated. Our study revealed that a contribution of the genetic component predominated over that of the environmental component in determining the phenotypic variability of somatic traits of newborns from twin pregnancies. The genetically determined phenotypic variability in male twins was greater than in the females. The genetic polymorphism and ecosensitivity of somatic traits were relatively stable during the period of fetal ontogeny analyzed in this study. Only in the case of body weight, a slight increase in the genetic contribution of polygenes to the phenotypic variance could be observed with gestational age, along with a slight decrease in the influence of environmental factors. PMID- 26619793 TI - Highly selective fluorescence sensors for the fluoride anion based on carboxylate bridged diiron complexes. AB - A new ligand bearing anthracene and its Fe(III) and Ru(III) derivatives have been synthesized and characterized exactly. The studies show that these dinuclear metal complexes serve as candidates of fluorescence chemosensors for anions. The interactions between these complexes and anions have been investigated by means of UV-Vis absorption spectra, fluorescence spectra, titration studies and (1)H NMR. The results illustrated that two diiron complexes, [Cp*Fe(MU-SR)2(MU-eta(2) L)FeCp*][PF6] (, R = Me; , R = Et; L = 4-(3-(anthracen-9 ylmethyl)ureido)benzoate), showed rapid and selective recognition for the fluoride ion over other anions with strong enhancement of emission intensities. The sensing mechanisms indicate that the hydrogen bonding interaction has been observed between chemosensors and F(-). PMID- 26619794 TI - Tracking of radiation exposure in pediatric stone patients: The time is now. AB - BACKGROUND: Despite the increasing incidence of pediatric nephrolithiasis, there is little data quantifying the radiation exposure associated with treatment of this disease. In this study, pediatric patients with nephrolithiasis who were managed at a single institution were identified, and the average fluoroscopy time and estimated radiation exposure associated with their procedures were reported. METHODS: Stone procedures performed on pediatric patients between 2005 and 2012 were retrospectively identified. Procedures were classified as primary ureteroscopy (URS), stent placement prior to ureteroscopy (SURS), percutaneous nephrolithotomy (PCNL), and bilateral ureteroscopy (BLURS). Patient demographic information, stone size, stone location, number of radiographic images, and fluoroscopy times were analyzed. RESULTS: A total of 152 stone procedures were included in the final analysis (92 URS, 38 SURS, eight BLURS and 14 PCNL). Mean patient age at time of stone treatment was 15.94 +/- 4.1 years. Median fluoroscopy times were 1.6 (IQR 0.8-2.4), 2.1 (IQR 1.6-3.0), 2.5 (IQR 2.0-2.9), and 11.7 (IQR 5.0-18.5) minutes for URS, SURS, BLURS and PCNL, respectively. There was a moderate correlation between stone size and fluoroscopy time (r = 0.33). When compared with ureteroscopic procedures, PCNL was associated with a significantly higher fluoroscopy time (11.7 vs 2.1 min, P < 0.001). The estimated median effective dose was 3 mSv for ureteroscopic procedures and 16.8 mSv for PCNL. In addition to radiation exposure during treatment, patients in this cohort were exposed to an average of one (IQR1-3) CT scan and three (IQR 1-8) abdominal X-rays. No new malignancies were identified during the limited follow-up period. CONCLUSIONS: Radiation exposure during treatment of pediatric stone disease is not trivial, and is significantly greater when PCNL is performed. Given the recommended maximum effective dose of 50 mSv in any one year, urologists should closely monitor the amount of fluoroscopy used, and consider the potential for radiation exposure when choosing the operative approach. Prospective studies are currently underway to elucidate precise dose measurements and localize sites of radiation exposure in children during stone treatment. PMID- 26619795 TI - Preservation of mullerian structures with laparoscopic management of intra abdominal testes in persistent mullerian duct syndrome. AB - BACKGROUND: Laparoscopic management of remnant uterine structures for patients with persistent mullerian duct syndrome (PMDS) and bilateral intra-abdominal testes include supracervical hysterectomy or splitting of the uterine structure to facilitate orchiopexy. A laparoscopic uterine-sparing approach, however, has not been described in the literature. METHODS: We present a case of a 10-year-old male with PMDS who underwent laparoscopic two-step Fowler-Stephens orchiopexy (FSO) with uterine preservation. Diagnostic laparoscopy revealed bilateral intra abdominal testes, a robust right vas deferens but diminutive left vas deferens, and a rudimentary uterine structure posterior to the bladder. At the time of the second-stage FSO, the decision was made to preserve the uterine structure to keep all future fertility options viable. A more extensive dissection was undertaken on the left side to gain adequate length for both testes to reach the scrotum and give the best chance for survival to the right testis with its accompanying robust vas deferens. CONCLUSION: Our case highlights a laparoscopic approach to a challenging problem in pediatric urology. If uterine preservation is preferred, a laparoscopic two-step FSO with uterine preservation is technically feasible and should be a consideration for patients with PMDS and intra-abdominal testes. PMID- 26619796 TI - Association between the serum level of vitamin D and systemic sclerosis in a Chinese population: a case control study. AB - AIM: Several autoimmune diseases have been associated with reduced vitamin D levels. However, the serum level of vitamin D in Chinese systemic sclerosis (SSc) patients have not been reported. The aim of this study was to evaluate the serum levels of vitamin D in Chinese SSc patients and analyze the association between vitamin D and SSc. METHODS: 25-hydroxy vitamin D 125 I RIA kit was applied to evaluate the serum levels of vitamin D in 60 SSc patients and 60 healthy controls from Anhui Provincial Hospital, China. The data of epidemiological and clinical characteristics of SSc patients were also collected. RESULTS: The serum levels of vitamin D were significantly lower in SSc patients than that in healthy controls (26.51 +/- 6.27 vs. 36.29 +/- 14.24 ng/mL, P < 0.001). The ratio of pulmonary involvement in vitamin D insufficiency patients was higher than that in normal vitamin D patients, but the difference missed statistical significance. The differences in other aspects were not statistically significant in the two groups. CONCLUSION: Serum levels of vitamin D in patients with SSc were lower than that in healthy controls. Further studies are needed to determine whether vitamin D supplement could provide some positive effects. PMID- 26619797 TI - Dysphagia Following Putaminal Hemorrhage at a Rehabilitation Hospital. AB - BACKGROUND: Dysphagia occurs frequently during the acute phase of cerebral hemorrhage; however, there are few reports of dysphagia associated with cerebral hemorrhage in the subacute and chronic phase. We focused on putaminal hemorrhage at a rehabilitation hospital and evaluated the relationships between the frequencies of dysphagia, focus, and hematoma volume and type. METHODS: A hundred patients with putaminal hemorrhage referred to our rehabilitation hospital were evaluated. Bedside swallowing assessments (BSAs) were conducted and results were evaluated relative to the information obtained on computed tomography imaging, including hematoma type and volume, and oral intake at the time of admission/discharge from the hospital. RESULTS: A regular diet was provided to 48 patients, dysphagia diet to 44 patients, and enteral feeding to 8 patients. There were significant feeding group differences in age, hematoma volume and type, existence of ventricle rupture, neurological manifestation, cognitive function, existence of unilateral neglect and aphasia, initial BSA, activities of daily living (ADL) score using the Functional Independence Measure at the time of admission/discharge from the hospital, and length of stay. At discharge, we provided a regular diet to 81 patients and dysphagia diet to 19 patients. Age and ADL score had the greatest influence on oral intake at the time of discharge from the hospital. CONCLUSION: The prognosis of dysphagia caused by putaminal hemorrhage is good, with no patient requiring enteral feeding, although putaminal hemorrhage often causes dysphagia. Patient age and ADL score on admission are used to predict the residual factors of dysphagia. PMID- 26619798 TI - Quantitative Structure-Property Relationship Modeling of Electronic Properties of Graphene Using Atomic Radial Distribution Function Scores. AB - The intrinsic relationships between nanoscale features and electronic properties of nanomaterials remain poorly investigated. In this work, electronic properties of 622 computationally optimized graphene structures were mapped to their structures using partial-least-squares regression and radial distributions function (RDF) scores. Quantitative structure-property relationship (QSPR) models were calibrated with 70% of a virtual data set of 622 passivated and nonpassivated graphenes, and we predicted the properties of the remaining 30% of the structures. The analysis of the optimum QSPR models revealed that the most relevant RDF scores appear at interatomic distances in the range of 2.0 to 10.0 A for the energy of the Fermi level and the electron affinity, while the electronic band gap and the ionization potential correlate to RDF scores in a wider range from 3.0 to 30.0 A. The predictions were more accurate for the energy of the Fermi level and the ionization potential, with more than 83% of explained data variance, while the electron affinity exhibits a value of ~80% and the energy of the band gap a lower 70%. QSPR models have tremendous potential to rapidly identify hypothetical nanomaterials with desired electronic properties that could be experimentally prepared in the near future. PMID- 26619799 TI - Protein profiling reveals consequences of lifestyle choices on predicted biological aging. AB - Ageing is linked to a number of changes in how the body and its organs function. On a molecular level, ageing is associated with a reduction of telomere length, changes in metabolic and gene-transcription profiles and an altered DNA methylation pattern. Lifestyle factors such as smoking or stress can impact some of these molecular processes and thereby affect the ageing of an individual. Here we demonstrate by analysis of 77 plasma proteins in 976 individuals, that the abundance of circulating proteins accurately predicts chronological age, as well as anthropometrical measurements such as weight, height and hip circumference. The plasma protein profile can also be used to identify lifestyle factors that accelerate and decelerate ageing. We found smoking, high BMI and consumption of sugar-sweetened beverages to increase the predicted chronological age by 2-6 years, while consumption of fatty fish, drinking moderate amounts of coffee and exercising reduced the predicted age by approximately the same amount. This method can be applied to dried blood spots and may thus be useful in forensic medicine to provide basic anthropometrical measures for an individual based on a biological evidence sample. PMID- 26619800 TI - HDAC4 mediates IFN-gamma induced disruption of energy expenditure-related gene expression by repressing SIRT1 transcription in skeletal muscle cells. AB - Metabolic homeostasis is achieved through balanced energy storage and output. Impairment of energy expenditure is a hallmark event in patients with obesity and type 2 diabetes. Previously we have shown that the pro-inflammatory cytokine interferon gamma (IFN-gamma) disrupts energy expenditure in skeletal muscle cells via hypermethylated in cancer 1 (HIC1)-class II transactivator (CIITA) dependent repression of SIRT1 transcription. Here we report that repression of SIRT1 transcription by IFN-gamma paralleled loss of histone acetylation on the SIRT1 promoter region with simultaneous recruitment of histone deacetylase 4 (HDAC4). IFN-gamma activated HDAC4 in vitro and in vivo by up-regulating its expression and stimulating its nuclear accumulation. HIC1 and CIITA recruited HDAC4 to the SIRT1 promoter and cooperated with HDAC4 to repress SIRT1 transcription. HDAC4 depletion by small interfering RNA or pharmaceutical inhibition normalized histone acetylation on the SIRT1 promoter and restored SIRT1 expression in the presence of IFN-gamma. Over-expression of HDAC4 suppressed the transcription of genes involved in energy expenditure in a SIRT1-dependent manner. In contrast, HDAC4 knockdown/inhibition neutralized the effect of IFN-gamma on cellular metabolism by normalizing SIRT1 expression. Therefore, our data reveal a role for HDAC4 in regulating cellular energy output and as such provide insights into rationalized design of novel anti-diabetic therapeutics. PMID- 26619801 TI - Hydrogen peroxide-mediated induction of SOD1 gene transcription is independent from Nrf2 in a cellular model of neurodegeneration. AB - BACKGROUND: It is still unclear whether oxidative stress (OS) is a disease consequence or is directly involved in the etiology of neurodegenerative disorders (NDs) onset and/or progression; however, many of these conditions are associated with increased levels of oxidation markers and damaged cell components. Previously we demonstrated the accumulation of reactive oxygen species (ROS) and increased SOD1 gene expression in H2O2-treated SH-SY5Y cells, recapitulating pathological features of Amyotrophic Lateral Sclerosis (ALS). Since we observed a post-transcriptional regulation of SOD1 gene in this cellular model, we investigated the transcriptional regulation of SOD1 mRNA under oxidative stress (OS). RESULTS: In response to H2O2 treatment, PolII increased its association to SOD1 promoter. Electrophoretic mobility shift assays and mass spectrometry analyses on SOD1 promoter highlighted the formation of a transcriptional complex bound to the ARE sequences. Western Blotting experiments showed that in our in vitro model, H2O2 exposure increases Nrf2 expression in the nuclear fraction while immunoprecipitation confirmed its phosphorylation and release from Keap1 inhibition. However, H2O2 treatment did not modify Nrf2 binding on SOD1 promoter, which seems to be regulated by different transcription factors (TFs). CONCLUSIONS: Although our data suggest that SOD1 is transcriptionally regulated in response to OS, Nrf2 does not appear to associate with SOD1 promoter in this cellular model of neurodegeneration. Our results open new perspectives in the comprehension of two key antioxidant pathways involved in neurodegenerative disorders. PMID- 26619802 TI - Knockdown of long non-coding RNA MALAT1 increases the blood-tumor barrier permeability by up-regulating miR-140. AB - The blood-tumor barrier (BTB) forms a major obstacle in brain tumor therapy by preventing the delivery of sufficient quantities of therapeutic drugs. Long non coding RNAs (lncRNAs) play important roles in both normal development and diseases including cancer. Here, we elucidated the expression of lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) and defined its functional role in the regulation of BTB function as well as its possible molecular mechanisms. Our results proved that MALAT1 expression was up-regulated in brain microvessels of human glioma and glioma endothelial cells (GECs) which were obtained by co-culturing endothelial cells with glioma cells. Functionally, knockdown of MALAT1 resulted in an impairment and increased the permeability of BTB as well as decreased the expression of ZO-1, occludin and claudin-5 in GECs. Further, there was reciprocal repression between MALAT1 and miR-140, and miR-140 mediated the effects that MALAT1 knockdown exerted. Mechanistic investigations defined that nuclear factor YA (NFYA), a CCAAT box-binding transcription factor, was a direct and functional downstream target of miR-140, which was involved in the MALAT1 knockdown induced regulation of BTB function. Furthermore, NFYA could up-regulate the promoter activities and bind to the promoters of ZO-1, occludin and claudin-5 in GECs. Taken together, we have demonstrated the fact that knockdown of MALAT1 resulted in the increased permeability of BTB, which might contribute to establishing potential therapeutic strategies for human gliomas. PMID- 26619804 TI - Cerebral oxygen saturation and tissue hemoglobin concentration as predictive markers of early postoperative outcomes after pediatric cardiac surgery. AB - BACKGROUND: Near-infrared spectroscopy (NIRS) provides an assessment of cerebral oxygenation and tissue hemoglobin concentration. AIM: The aim of this study was to investigate whether the cerebral oxygenation and hemoglobin concentration measured with NIRS could predict outcomes after pediatric cardiac surgery. METHOD: We conducted a retrospective observational study in 399 patients who underwent pediatric cardiac surgery. Associations were determined between postoperative outcome and preoperative and postoperative cerebral tissue oxygenation index (TOI), postoperative normalized tissue hemoglobin index (nTHI), concentration changes in oxygenated hemoglobin (Delta[HbO2 ]) and deoxygenated hemoglobin (Delta[HHb]). RESULTS: Thirty-nine children had major postoperative morbidity and 12 died. Using Spearman's correlation analysis, postoperative lower TOI and higher Delta[HHb] were associated with longer stays in the Intensive Care Unit (ICU) (r = -0.48, P < 0.001, r = 0.31, P < 0.001, respectively) and longer duration of intubation (r = -0.48, P < 0.001, r = 0.31, P < 0.001, respectively) and higher probability of death determined by the Risk Adjusted Classification for Congenital Heart Surgery (RACHS-1) (r = -0.39, P < 0.001, r = 0.23, P < 0.001, respectively). In multivariate regression analysis, postoperative TOI was independently associated with major morbidity and mortality and Delta[HHb] was independently associated with major morbidity. In receiver operating characteristic analysis, postoperative TOI and Delta[HHb] predicted major morbidity (Area under the curve [AUC] = 0.72, 0.68, respectively) and mortality (AUC = 0.81, 0.69, respectively). CONCLUSION: Lower TOI or higher [HHb] at the end of surgery and higher RACHS-1 category predicted worse outcomes. PMID- 26619803 TI - Pilot study of the pharmacokinetics of betel nut and betel quid biomarkers in saliva, urine, and hair of betel consumers. AB - Approximately 600 million people worldwide practise the carcinogenic habit of betel nut/quid chewing. Carcinogenic N-nitroso compounds have been identified in saliva or urine of betel chewers and the betel alkaloid arecoline in hair from habitual betel quid chewers. However, the pharmacokinetic parameters of these compounds have been little explored. Assessment of betel use by biomarkers is urgently needed to evaluate the effectiveness of cessation programmes aimed at reducing betel consumption to decrease the burden of cancers in regions of high betel consumption. In the search for biomarkers of betel consumption, we measured by liquid chromatography-mass spectrometry (LC-MS) the appearance and disappearance of betel alkaloids (characteristic for betel nuts), N-nitroso compounds, and chavibetol (characteristic for Piper Betle leaves) in saliva (n=4), hair (n=2), and urine (n=1) of occasional betel nut/quid chewers. The betel alkaloids arecoline, guvacoline, guvacine, and arecaidine were detected in saliva of all four participants and peaked within the first 2 h post-chewing before returning to baseline levels after 8 h. Salivary chavibetol was detected in participants consuming Piper Betle leaves in their quid and peaked ~1 h post chewing. Urinary arecoline, guvacoline, and arecaidine excretion paralleled saliva almost exactly while chavibetol glucuronide excretion paralleled salivary chavibetol. No betel nut related compounds were detected in the tested hair samples using various extraction methods. From these preliminary results, we conclude that betel exposure can only be followed on a short-term basis (<=8 h post-chewing) using the applied biomarkers from urine and saliva while the feasibility of using hair has yet to be validated. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26619805 TI - Where does brain neural activation in aesthetic responses to visual art occur? Meta-analytic evidence from neuroimaging studies. AB - Here we aimed at finding the neural correlates of the general aspect of visual aesthetic experience (VAE) and those more strictly correlated with the content of the artworks. We applied a general activation likelihood estimation (ALE) meta analysis to 47 fMRI experiments described in 14 published studies. We also performed four separate ALE analyses in order to identify the neural substrates of reactions to specific categories of artworks, namely portraits, representation of real-world-visual-scenes, abstract paintings, and body sculptures. The general ALE revealed that VAE relies on a bilateral network of areas, and the individual ALE analyses revealed different maximal activation for the artworks' categories as function of their content. Specifically, different content-dependent areas of the ventral visual stream are involved in VAE, but a few additional brain areas are involved as well. Thus, aesthetic-related neural responses to art recruit widely distributed networks in both hemispheres including content-dependent brain areas of the ventral visual stream. Together, the results suggest that aesthetic responses are not independent of sensory, perceptual, and cognitive processes. PMID- 26619806 TI - Statistical methods for studying disease subtype heterogeneity. AB - A fundamental goal of epidemiologic research is to investigate the relationship between exposures and disease risk. Cases of the disease are often considered a single outcome and assumed to share a common etiology. However, evidence indicates that many human diseases arise and evolve through a range of heterogeneous molecular pathologic processes, influenced by diverse exposures. Pathogenic heterogeneity has been considered in various neoplasms such as colorectal, lung, prostate, and breast cancers, leukemia and lymphoma, and non neoplastic diseases, including obesity, type II diabetes, glaucoma, stroke, cardiovascular disease, autism, and autoimmune disease. In this article, we discuss analytic options for studying disease subtype heterogeneity, emphasizing methods for evaluating whether the association of a potential risk factor with disease varies by disease subtype. Methods are described for scenarios where disease subtypes are categorical and ordinal and for cohort studies, matched and unmatched case-control studies, and case-case study designs. For illustration, we apply the methods to a molecular pathological epidemiology study of alcohol intake and colon cancer risk by tumor LINE-1 methylation subtypes. User-friendly software to implement the methods is publicly available. PMID- 26619807 TI - Dysfunctional tubular endoplasmic reticulum constitutes a pathological feature of Alzheimer's disease. AB - Pathological features in Alzheimer's brains include mitochondrial dysfunction and dystrophic neurites (DNs) in areas surrounding amyloid plaques. Using a mouse model that overexpresses reticulon 3 (RTN3) and spontaneously develops age dependent hippocampal DNs, here we report that DNs contain both RTN3 and REEPs, topologically similar proteins that can shape tubular endoplasmic reticulum (ER). Importantly, ultrastructural examinations of such DNs revealed gradual accumulation of tubular ER in axonal termini, and such abnormal tubular ER inclusion is found in areas surrounding amyloid plaques in biopsy samples from Alzheimer's disease (AD) brains. Functionally, abnormally clustered tubular ER induces enhanced mitochondrial fission in the early stages of DN formation and eventual mitochondrial degeneration at later stages. Furthermore, such DNs are abrogated when RTN3 is ablated in aging and AD mouse models. Hence, abnormally clustered tubular ER can be pathogenic in brain regions: disrupting mitochondrial integrity, inducing DNs formation and impairing cognitive function in AD and aging brains. PMID- 26619808 TI - APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease. AB - Alzheimer's disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed ~50 000 common and rare functional genomic variants from 71 individuals of the 'Paisa' pedigree, the world's largest pedigree segregating a severe form of early-onset AD, who were affected carriers of the fully penetrant E280A mutation in the presenilin-1 (PSEN1) gene. Affected carriers with ages at the extremes of the ADAOO distribution (30s-70s age range), and linear mixed-effects models were used to build single-locus regression models outlining the ADAOO. We identified the rs7412 (APOE*E2 allele) as a whole exome wide ADAOO modifier that delays ADAOO by ~12 years (beta=11.74, 95% confidence interval (CI): 8.07-15.41, P=6.31 * 10(-8), PFDR=2.48 * 10(-3)). Subsequently, to evaluate comprehensively the APOE (apolipoprotein E) haplotype variants (E1/E2/E3/E4), the markers rs7412 and rs429358 were genotyped in 93 AD affected carriers of the E280A mutation. We found that the APOE*E2 allele, and not APOE*E4, modifies ADAOO in carriers of the E280A mutation (beta=8.24, 95% CI: 4.45-12.01, P=3.84 * 10(-5)). Exploratory linear mixed-effects multilocus analysis suggested that other functional variants harbored in genes involved in cell proliferation, protein degradation, apoptotic and immune dysregulation processes (i.e., GPR20, TRIM22, FCRL5, AOAH, PINLYP, IFI16, RC3H1 and DFNA5) might interact with the APOE*E2 allele. Interestingly, suggestive evidence as an ADAOO modifier was found for one of these variants (GPR20) in a set of patients with sporadic AD from the Paisa genetic isolate. This is the first study demonstrating that the APOE*E2 allele modifies the natural history of AD typified by the age of onset in E280A mutation carriers. To the best of our knowledge, this is the largest analyzed sample of patients with a unique mutation sharing uniform environment. Formal replication of our results in other populations and in other forms of AD will be crucial for prediction, follow-up and presumably developing new therapeutic strategies for patients either at risk or affected by AD. PMID- 26619809 TI - Overlapping expression of serotonin transporters and neurokinin-1 receptors in posttraumatic stress disorder: a multi-tracer PET study. AB - The brain serotonergic system is colocalized and interacts with the neuropeptidergic substance P/neurokinin-1 (SP/NK1) system. Both these neurochemical systems have independently been implicated in stress and anxiety, but interactions between them might be crucial for human anxiety conditions. Here, we examined the serotonin and substance P/neurokinin-1 (SP/NK1) systems individually as well as their overlapping expression in 16 patients with posttraumatic stress disorder (PTSD) and 16 healthy controls. Participants were imaged with the highly selective radiotracers [(11)C]-3-amino-4-(2 dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) and [(11)C]GR205171 assessing serotonin transporter (SERT) and NK1 receptor availability, respectively. Voxel-wise analyses in the amygdala, our a priori-defined region of interest, revealed increased number of NK1 receptors, but not SERT in the PTSD group. Symptom severity, as indexed by the Clinician-administered PTSD Scale, was negatively related to SERT availability in the amygdala, and NK1 receptor levels moderated this relationship. Exploratory, voxel-wise whole-brain analyses revealed increased SERT availability in the precentral gyrus and posterior cingulate cortex of PTSD patients. Patients, relative to controls, displayed lower degree of overlapping expression between SERT and NK1 receptors in the putamen, thalamus, insula and lateral orbitofrontal gyrus, lower overlap being associated with higher PTSD symptom severity. Expression overlap also explained more of the symptomatology than did either system individually, underscoring the importance of taking interactions between the neurochemical systems into account. Thus, our results suggest that aberrant serotonergic-SP/NK1 couplings contribute to the pathophysiology of PTSD and, consequently, that normalization of these couplings may be therapeutically important. PMID- 26619812 TI - Citalopram and sertraline exposure compromises embryonic bone development. PMID- 26619810 TI - Erasure of fear memories is prevented by Nogo Receptor 1 in adulthood. AB - Critical periods are temporary windows of heightened neural plasticity early in development. For example, fear memories in juvenile rodents are subject to erasure following extinction training, while after closure of this critical period, extinction training only temporarily and weakly suppresses fear memories. Persistence of fear memories is important for survival, but the inability to effectively adapt to the trauma is a characteristic of post-traumatic stress disorder (PTSD). We examined whether Nogo Receptor 1 (NgR1) regulates the plasticity associated with fear extinction. The loss of NgR1 function in adulthood eliminates spontaneous fear recovery and fear renewal, with a restoration of fear reacquisition rate equal to that of naive mice; thus, mimicking the phenotype observed in juvenile rodents. Regional gene disruption demonstrates that NgR1 expression is required in both the basolateral amygdala (BLA) and infralimbic (IL) cortex to prevent fear erasure. NgR1 expression by parvalbumin expressing interneurons is essential for limiting extinction dependent plasticity. NgR1 gene deletion enhances anatomical changes of inhibitory synapse markers after extinction training. Thus, NgR1 robustly inhibits elimination of fear expression in the adult brain and could serve as a therapeutic target for anxiety disorders, such as PTSD. PMID- 26619811 TI - Activation of a ventral hippocampus-medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine. AB - A single sub-anesthetic dose of ketamine exerts rapid and sustained antidepressant effects. Here, we examined the role of the ventral hippocampus (vHipp)-medial prefrontal cortex (mPFC) pathway in ketamine's antidepressant response. Inactivation of the vHipp with lidocaine prevented the sustained, but not acute, antidepressant-like effect of ketamine as measured by the forced swim test (FST). Moreover, optogenetic as well as pharmacogenetic specific activation of the vHipp-mPFC pathway using DREADDs (designer receptors exclusively activated by designer drugs) mimicked the antidepressant-like response to ketamine; importantly, this was pathway specific, in that activation of a vHipp to nucleus accumbens circuit did not do this. Furthermore, optogenetic inactivation of the vHipp/mPFC pathway at the time of FST completely reversed ketamine's antidepressant response. In addition, we found that a transient increase in TrkB receptor phosphorylation in the vHipp contributes to ketamine's sustained antidepressant response. These data demonstrate that activity in the vHipp-mPFC pathway is both necessary and sufficient for the antidepressant-like effect of ketamine. PMID- 26619813 TI - Renal Denervation vs Pharmacotherapy for Resistant Hypertension: A Meta-Analysis. AB - The effect of renal denervation (RD) for resistant hypertension remains controversial because of the conflicting results of finished and ongoing studies. The authors performed a meta-analysis of case-control studies to identify whether renal sympathetic denervation or pharmacotherapy (PHAR) was more effective for resistant hypertension. A systematic Internet database search of relevant papers written in English was performed. A total of nine studies met the inclusion criteria, with a total of 1096 patients. When comparing the RD group with the PHAR group, there was a significant decrease in systolic blood pressure (SBP) (weighted mean difference, -12.81 mm Hg; 95% confidence interval [CI], -22.77 mm Hg to -2.85 mm Hg; P=.01) and diastolic blood pressure (DBP) (weighted mean difference, -5.56; 95% CI, -8.15 mm Hg to -2.97 mm Hg; P<.0001). This pooled analysis shows that for patients with resistant hypertension, RD is more effective in reducing SBP and DBP than PHAR. RD may be more effective in special subgroups of patients, which needs to be identified in future investigations. PMID- 26619814 TI - Magnetically Controllable Polymer Nanotubes from a Cyclized Crosslinker for Site Specific Delivery of Doxorubicin. AB - Externally controlled site specific drug delivery could potentially provide a means of reducing drug related side effects whilst maintaining, or perhaps increasing therapeutic efficiency. The aim of this work was to develop a nanoscale drug carrier, which could be loaded with an anti-cancer drug and be directed by an external magnetic field. Using a single, commercially available monomer and a simple one-pot reaction process, a polymer was synthesized and crosslinked within the pores of an anodized aluminum oxide template. These polymer nanotubes (PNT) could be functionalized with iron oxide nanoparticles for magnetic manipulation, without affecting the large internal pore, or inherent low toxicity. Using an external magnetic field the nanotubes could be regionally concentrated, leaving areas devoid of nanotubes. Lastly, doxorubicin could be loaded to the PNTs, causing increased toxicity towards neuroblastoma cells, rendering a platform technology now ready for adaptation with different nanoparticles, degradable pre-polymers, and various therapeutics. PMID- 26619815 TI - Vascular and ductal elastotic changes in pancreatic cancer. AB - This study aims to identify and define the type and frequency of elastotic alterations of vessels and ducts in pancreatic ductal carcinoma (PDAC) and evaluate its diagnostic significance. Representative tissue from 36 Whipple specimens, stained with Verhoeff's Van-Gieson, was studied focusing on the density and distribution of elastic fibers in walls of vessels and ducts, in perivascular and periductal tissue and in tumor stroma. Vessels and ducts within the carcinoma, at tumor periphery and in non-tumoral pancreas were grouped and examined separately. Vimentin and alpha-SMA immunostains were used for the depiction of fibroblasts and myofibroblasts. Histochemistry revealed mild to severe elastotic changes of vessels and ducts in all examined cases. Vascular and ductal elastosis was more prominent within the tumor and diminished at tumor periphery. In tumor stroma and non-tumoral pancreatic tissue mild or no elastosis was identified. alpha-SMA+ cells were observed in large numbers in tumor stroma and as a ring around carcinomatous structures. There were scant alpha-SMA+ cells around elastotic and non-elastotic vessels. Conclusively, vascular and ductal elastosis is a tumor-associated phenomenon in PDAC. Its presence is indicative of benignity acquiring a possible diagnostic role. PMID- 26619817 TI - Efficacy and Safety of Tranexamic Acid in Bilateral Total Knee Replacement: A Meta-Analysis and Systematic Review. AB - BACKGROUND Tranexamic acid (TXA) has been well documented to reduce blood loss and transfusion requirements in patients undergoing unilateral total knee arthroplasty (TKA). However, the efficacy and safety of TXA in simultaneous bilateral TKA have not been clearly defined. The aim of our study was to systematically review the existing evidence regarding the role of TXA in patients undergoing simultaneous bilateral TKA. MATERIAL AND METHODS A systematic search of all studies published through June 2014 was performed using Medline, EMBASE, OVID, and other databases. All studies that compared the efficacy and safety of TXA administration in simultaneous bilateral TKA patients were identified. The data from the included trials were extracted and analyzed regarding blood loss and transfusion rates. The evidence quality levels of the selected articles were evaluated using a grading system. RESULTS Six studies were included, in which a total of 245 patients received TXA and 271 patients were controls. Overall, the results demonstrated that the use of TXA significantly reduced total blood loss by a mean of 371.1 ml (95% confidence interval (CI)=-412.12 to -330.09; p<0.001) and reduced the number of patients requiring blood transfusion (risk ratio (RR)=0.16; 95% CI=0.10 to 0.28; p<0.001). No significant differences in adverse effects such as deep vein thrombosis (DVT) or pulmonary embolism (PE) were noted in any group. CONCLUSIONS The intravenous use of TXA in patients undergoing simultaneous bilateral TKA is effective and safe and results in significantly reduced estimated blood loss and transfusion rates. No significant difference was observed in the incidence of side effects. Due to the limitations in the evidence quality of current meta-analyses, well-conducted, larger, high-quality randomized controlled trials (RCTs) are required. PMID- 26619818 TI - Long-distance nitrate signaling displays cytokinin dependent and independent branches. AB - The long-distance signaling network allowing a plant to properly develop its root system is crucial to optimize root foraging in areas where nutrients are available. Cytokinin is an essential element of the systemic signaling network leading to the enhancement of lateral root proliferation in areas where nitrate is available. Here, we explore more precisely: (i) which particular traits of lateral root growth (density and length of emerged lateral roots) are the targets of systemic signaling in a context of heterogeneous nitrate supply; and (ii) if the systemic signaling depends only on cytokinin or on a combination of several signalings. PMID- 26619819 TI - Transcriptomes reveal the genetic mechanisms underlying ionic regulatory adaptations to salt in the crab-eating frog. AB - The crab-eating frog, Fejervarya cancrivora, is the only frog that lives near seas. It tolerates increased environmental concentrations of sodium, chloride and potassium partly by raising ion and urea levels in its blood plasma. The molecular mechanism of the adaptation remains rarely documented. Herein, we analyze transcriptomes of the crab-eating frog and its closely related saline intolerant species, F. limnocharis, to explore the molecular basis of adaptations to such extreme environmental conditions. Analyses reveal the potential genetic mechanism underlying the adaptation to salinity for the crab-eating frog. Genes in categories associated with ion transport appear to have evolved rapidly in F. cancrivora. Both positively selected and differentially expressed genes exhibit enrichment in the GO category regulation of renal sodium excretion. In this category, the positively selected sites of ANPEP and AVPR2 encode CD13 and V2 receptors, respectively; they fall precisely on conserved domains. More differentially expressed rapidly evolved genes occur in the kidney of F. cancrivora than in F. limnocharis. Four genes involved in the regulation of body fluid levels show signs of positive selection and increased expression. Significant up-regulation occurs in several genes of F. cancrivora associated with renin-angiotensin system and aldosterone-regulated sodium reabsorption pathways, which relate to osmotic regulation. PMID- 26619820 TI - Intensity correction for multichannel hyperpolarized 13C imaging of the heart. AB - PURPOSE: Develop and test an analytic correction method to correct the signal intensity variation caused by the inhomogeneous reception profile of an eight channel phased array for hyperpolarized (13) C imaging. THEORY AND METHODS: Fiducial markers visible in anatomical images were attached to the individual coils to provide three dimensional localization of the receive hardware with respect to the image frame of reference. The coil locations and dimensions were used to numerically model the reception profile using the Biot-Savart Law. The accuracy of the coil sensitivity estimation was validated with images derived from a homogenous (13) C phantom. Numerical coil sensitivity estimates were used to perform intensity correction of in vivo hyperpolarized (13) C cardiac images in pigs. RESULTS: In comparison to the conventional sum-of-squares reconstruction, improved signal uniformity was observed in the corrected images. CONCLUSION: The analytical intensity correction scheme was shown to improve the uniformity of multichannel image reconstruction in hyperpolarized [1-(13) C]pyruvate and (13) C-bicarbonate cardiac MRI. The method is independent of the pulse sequence used for (13) C data acquisition, simple to implement and does not require additional scan time, making it an attractive technique for multichannel hyperpolarized (13) C MRI. PMID- 26619821 TI - Efficacy of transcutaneous electrical nerve stimulation for rotator cuff tendinopathy: a systematic review. AB - OBJECTIVE: To perform a systematic review on the efficacy of transcutaneous electrical nerve stimulation (TENS) for the treatment of rotator cuff tendinopathy in adults. METHODS: A literature search was conducted in four databases (CINAHL, Embase, PubMed and PeDRO) for randomised controlled trials published from date of inception until April 2015, comparing the efficacy of TENS for the treatment of rotator cuff tendinopathy with placebo or any other intervention. Risk of bias was evaluated using the Cochrane risk of bias tool. Results were summarised qualitatively. RESULTS: Six studies were included in this review. The mean methodological score was 49% (standard deviation 16%), indicating an overall high risk of bias. One placebo-controlled trial reported that a single TENS session provided immediate pain reduction for patients with rotator cuff tendinopathy, but did not follow the participants in the short, medium or long term. Two trials that compared ultrasound therapy with TENS reported discrepancy and contradictory results in terms of pain reduction and shoulder range of motion. Corticosteroid injections were found to be superior to TENS for pain reduction in the short term, but the differences were not clinically important. Other studies included in this review concluded that TENS was not superior to heat or pulsed radiofrequency. CONCLUSION: Due to the limited number of studies and the overall high risk of bias of the studies included in this review, no conclusions can be drawn on the efficacy of TENS for the treatment of rotator cuff tendinopathy. More methodologically sound studies are needed to document the efficacy of TENS. Until then, clinicians should prefer other evidence-based rehabilitation interventions proven to be efficacious to treat patients with rotator cuff tendinopathy. PMID- 26619822 TI - Effect of whole body vibration training on quadriceps muscle strength in individuals with knee osteoarthritis: a systematic review and meta-analysis. AB - BACKGROUND: Several studies have reported the effects of whole body vibration (WBV) training on muscle strength. This systematic review investigates the current evidence regarding the effects of WBV training on quadriceps muscle strength in individuals with knee osteoarthritis (OA). DATA SOURCES: We searched PubMed, CINAHL, Embase, Scopus, PEDro, and Science citation index for research articles published prior to March 2015 using the keywords whole body vibration, vibration training, strength and vibratory exercise in combination with the Medical Subject Heading 'Osteoarthritis knee'. STUDY SELECTION: This meta analysis was limited to randomized controlled trials published in the English language. DATA EXTRACTION: The quality of the selected studies was assessed by two independent evaluators using the PEDro scale and criteria given by the International Society of Musculoskeletal and Neuronal Interactions (ISMNI) for reporting WBV intervention studies. The risk of bias was assessed using the Cochrane collaboration's tool for domain-based evaluation. Isokinetic quadriceps muscle strength was calculated for each intervention. RESULTS: Eighteen studies were identified in the search. Of these, four studies met the inclusion criteria. Three of these four studies reached high methodological quality on the PEDro scale. Out of the four studies, only one study found significantly greater quadriceps muscle strength gains following WBV compared to the control group. CONCLUSIONS: In three of the four studies that compared a control group performing the same exercise as the WBV groups, no additional effect of WBV on quadriceps muscle strength in individuals with knee OA was indicated. PMID- 26619823 TI - Absence of Elovl6 attenuates steatohepatitis but promotes gallstone formation in a lithogenic diet-fed Ldlr(-/-) mouse model. AB - Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that can develop into liver cirrhosis and cancer. Elongation of very long chain fatty acids (ELOVL) family member 6 (Elovl6) is a microsomal enzyme that regulates the elongation of C12-16 saturated and monounsaturated fatty acids (FAs). We have previously shown that Elovl6 plays an important role in the development of hepatic insulin resistance and NASH by modifying FA composition. Recent studies have linked altered hepatic cholesterol homeostasis and cholesterol accumulation to the pathogenesis of NASH. In the present study, we further investigated the role of Elovl6 in the progression of lithogenic diet (LD)-induced steatohepatitis. We showed that the absence of Elovl6 suppresses hepatic lipid accumulation, plasma total cholesterol and total bile acid (BA) levels in LDL receptor-deficient (Ldlr(-/-)) mice challenged with a LD. The absence of Elovl6 also decreases hepatic inflammation, oxidative stress and liver injury, but increases the formation of cholesterol crystals in the less dilated gallbladder. These findings suggest that Elovl6-mediated changes in hepatic FA composition, especially oleic acid (C18:1n-9), control handling of hepatic cholesterol and BA, which protects against hepatotoxicity and steatohepatitis, but promotes gallstone formation in LD-fed Ldlr(-/-) mice. PMID- 26619824 TI - Medical Complexity among Children with Special Health Care Needs: A Two Dimensional View. AB - OBJECTIVE: To identify subgroups of U.S. children with special health care needs (CSHCN) and characterize key outcomes. DATA SOURCE: Secondary analysis of 2009 2010 National Survey of CSHCN. STUDY DESIGN: Latent class analysis grouped individuals into substantively meaningful classes empirically derived from measures of pediatric medical complexity. Outcomes were compared among latent classes with weighted logistic or negative binomial regression. PRINCIPAL FINDINGS: LCA identified four unique CSHCN subgroups: broad functional impairment (physical, cognitive, and mental health) with extensive health care (Class 1), broad functional impairment alone (Class 2), predominant physical impairment requiring family-delivered care (Class 3), and physical impairment alone (Class 4). CSHCN from Class 1 had the highest ED visit rates (IRR 3.3, p < .001) and hospitalization odds (AOR: 12.0, p < .001) and lowest odds of a medical home (AOR: 0.17, p < .001). CSHCN in Class 3, despite experiencing more shared decision making and medical home attributes, had more ED visits and missed school than CSHCN in Class 2 (p < .001); the latter, however, experienced more cost related difficulties, care delays, and parents having to stop work (p < .001). CONCLUSIONS: Recognizing distinct impacts of cognitive and mental health impairments and health care delivery needs on CSHCN outcomes may better direct future intervention efforts. PMID- 26619825 TI - Pharmacokinetic Herb-Drug Interaction between Essential Oil of Aniseed (Pimpinella anisum L., Apiaceae) and Acetaminophen and Caffeine: A Potential Risk for Clinical Practice. AB - Aniseed (Pimpinella anisum L., Apiaceae) and its essential oil (EO) have been widely used. Because there are some data about the impact of aniseed EO on drug effects, this survey aimed to assess the potential of pharmacokinetic herb-drug interaction between aniseed EO and acetaminophen and caffeine in mice. The chemical analysis (gas chromatography-mass spectrometry) of aniseed EO has confirmed trans-anethole (87.96%) as the main component. The pharmacokinetic studies of intraperitoneally (i.p.) and orally applied acetaminophen (200 mg/kg) and caffeine (20 mg/kg) were performed in mice after 5 days of oral treatment with human equivalent dose of aniseed EO (0.3 mg/kg/day). The analysis of pharmacokinetic data showed that in the group treated by aniseed EO, the significant decrease in the peak plasma concentration of acetaminophen after oral application (p = 0.024) was revealed when compared with control group and the reduction of systemic exposure to the drug after oral application (74 +/- 32% vs. 85 +/- 35% in the control) was noted. The bioavailability of orally applied caffeine was also significantly decreased (p = 0.022) after the EO treatment in comparison with the control (57 +/- 24% vs. 101 +/- 29%). Therefore, the compromised therapeutic efficacy of acetaminophen and caffeine during the usage of aniseed EO preparations should be considered. PMID- 26619827 TI - The relation between physical activity, fitness, and fatness in adolescents: A mediation analysis. AB - OBJECTIVES: To investigate the total, direct and mediated (by fatness) association of physical activity (PA) with fitness. METHODS: Body fat percentage (%Fat), maximal oxygen uptake (VO2max ) and PA were measured directly in 18-year olds (n=202) and their association analyzed with a linear regression-based mediation analysis after controlling for sex. RESULTS: The total association between PA and VO2max was significant (c=0.66, P<0.001) and was significantly mediated by %Fat (ab=0.25, 95% CI: 0.04-0.49). The direct association was also significant (c=0.41, P<0.001). CONCLUSION: Physical activity is associated with VO2max in 18-year-old adolescents but a little over a third of that association is mediated by %Fat. Regardless of fatness, PA is important for fitness in this age group. Am. J. Hum. Biol. 28:584-586, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26619826 TI - Lactic acid is a sperm motility inactivation factor in the sperm storage tubules. AB - Although successful fertilization depends on timely encounters between sperm and egg, the decoupling of mating and fertilization often confers reproductive advantages to internally fertilizing animals. In several vertebrate groups, postcopulatory sperm viability is prolonged by storage in specialized organs within the female reproductive tract. In birds, ejaculated sperm can be stored in a quiescent state within oviductal sperm storage tubules (SSTs), thereby retaining fertilizability for up to 15 weeks at body temperature (41 degrees C); however, the mechanism by which motile sperm become quiescent within SSTs is unknown. Here, we show that low oxygen and high lactic acid concentrations are established in quail SSTs. Flagellar quiescence was induced by lactic acid in the concentration range found in SSTs through flagellar dynein ATPase inactivation following cytoplasmic acidification (34 degrees C in adult patients after cardiac arrest were retrieved. Two investigators independently selected RCTs and completed an assessment of the quality of the studies. Data were analysed by the methods recommended by the Cochrane Collaboration. Random errors were evaluated with trial sequential analysis. RESULTS: Six RCTs, including one abstract, were included. The meta analysis of included trials revealed that MIH did not significantly decrease the mortality at hospital discharge (risk ratio (RR) = 0.92; 95 % confidence interval (CI), 0.82-1.04; p = 0.17) or at 6 months or 180 days (RR = 0.94; 95 % CI, 0.73 1.21; p = 0.64), but it did reduce the mortality of patients with shockable rhythms at hospital discharge (RR = 0.74; 95 % CI, 0.59-0.92; p = 0.008) and at 6 months or 180 days. However, MIH can improve the outcome of neurological function at hospital discharge (RR = 0.80; 95 % CI, 0.64-0.98; p = 0.04) especially in those patients with shockable rhythm but not at 6 months or 180 days. Moreover, the incidence of complications in the MIH group was significantly higher than that in the control group. Finally, trial sequential analysis indicated lack of firm evidence for a beneficial effect. CONCLUSION: The available RCTs suggest that MIH does not appear to improve the mortality of patients with cardiac arrest while it may have a beneficial effect for patients with shockable rhythms. Although MIH may result in some adverse events, it helped lead to better outcomes regarding neurological function at hospital discharge. Large-scale ongoing trials may provide data better applicable to clinical practice. PMID- 26619836 TI - Aberrant association of misfolded SOD1 with Na(+)/K(+)ATPase-alpha3 impairs its activity and contributes to motor neuron vulnerability in ALS. AB - Amyotrophic lateral sclerosis (ALS) is an adult onset progressive motor neuron disease with no cure. Transgenic mice overexpressing familial ALS associated human mutant SOD1 are a commonly used model for examining disease mechanisms. Presently, it is well accepted that alterations in motor neuron excitability and spinal circuits are pathological hallmarks of ALS, but the underlying molecular mechanisms remain unresolved. Here, we sought to understand whether the expression of mutant SOD1 protein could contribute to altering processes governing motor neuron excitability. We used the conformation specific antibody B8H10 which recognizes a misfolded state of SOD1 (misfSOD1) to longitudinally identify its interactome during early disease stage in SOD1G93A mice. This strategy identified a direct isozyme-specific association of misfSOD1 with Na(+)/K(+)ATPase-alpha3 leading to the premature impairment of its ATPase activity. Pharmacological inhibition of Na(+)/K(+)ATPase-alpha3 altered glutamate receptor 2 expression, modified cholinergic inputs and accelerated disease pathology. After mapping the site of direct association of misfSOD1 with Na(+)/K(+)ATPase-alpha3 onto a 10 amino acid stretch that is unique to Na(+)/K(+)ATPase-alpha3 but not found in the closely related Na(+)/K(+)ATPase alpha1 isozyme, we generated a misfSOD1 binding deficient, but fully functional Na(+)/K(+)ATPase-alpha3 pump. Adeno associated virus (AAV)-mediated expression of this chimeric Na(+)/K(+)ATPase-alpha3 restored Na(+)/K(+)ATPase-alpha3 activity in the spinal cord, delayed pathological alterations and prolonged survival of SOD1G93A mice. Additionally, altered Na(+)/K(+)ATPase-alpha3 expression was observed in the spinal cord of individuals with sporadic and familial ALS. A fraction of sporadic ALS cases also presented B8H10 positive misfSOD1 immunoreactivity, suggesting that similar mechanism might contribute to the pathology. PMID- 26619837 TI - Diffusion-weighted magnetic resonance imaging for the initial characterization of non-fatty soft tissue tumors: correlation between T2 signal intensity and ADC values. AB - OBJECTIVE: To evaluate the performance of quantitative diffusion-weighted imaging (DWI) correlated with T2 signal in differentiating non-fatty benign from malignant tumors. MATERIAL AND METHODS: A total of 76 patients with a histologically confirmed non-fatty soft tissue tumors (46 benign and 30 malignant) were prospectively included in this ethics committee approved study. All patients signed an informed consent and underwent MRI with DWI with two b values (0 and 600). ADC values from the solid components of these tumors were obtained and were correlated with the lesion's signal intensity on T2-weighted fat-saturated sequences. ADC values were obtained from adjacent normal muscle to allow calculation of tumor/muscle ADC ratios. RESULTS: There were 58 hyperintense and 18 iso or hypointense lesions. All hypointense lesions were benign. The mean ADC values for benign and malignant tumors were 1.47 +/- 0.54 * 10(-3) and 1.17 +/- 0.38 * 10(-3) mm(2)/s respectively (p < 0.005). The mean ADC ratio in benign iso or hypointense tumors was significantly lower than that of hyperintense ones (0.76 +/- 0.21 versus 1.58 +/- 0.82 - p < 0.0001). An ADC ratio lower than 0.915 was highly specific for malignancy (96.4 %), whereas an ADC ratio higher than 1.32 was highly sensitive for benign lesions (90 %). CONCLUSION: ADC analysis can be useful in the initial characterization of T2 hyperintense non-fatty soft tissue masses, although this technique alone is not likely to change patient management. PMID- 26619838 TI - Osteoarthritis prevalence and modifiable factors: a population study. AB - BACKGROUND: This study's objectives were to investigate the prevalence of self reported knee and hip osteoarthritis (OA) stratified by age and sex and to examine the association of modifiable factors with knee and hip OA prevalence. The study was conducted using randomly sampled data gathered from four communities in the province of Alberta, Canada. METHODS: A large adult population sample (N = 4733) of individuals >=18 years were selected. Health-related information was collected through telephone interviews and community measurement clinics for which a sub-sample (N = 1808) attended. Participants self-reported OA during telephone interviews. Clinic interviews further assessed if the diagnosis was made by a health care professional. Statistical analyses compared prevalence of OA between sexes and across age categories. Associations between modifiable factors for OA and the prevalence of knee and hip OA were assessed using binary logistic regression modelling. RESULTS: Overall prevalence of self-reported OA in the total sample was 14.8 %, where 10.5 % of individuals reported having knee OA and 8.5 % reported having hip OA. Differences in prevalence were found for males and females across age categories for both knee and hip OA. In terms of modifiable factors, being obese (BMI >30 kg/m2) was significantly associated with the prevalence of knee (OR: 4.37; 95 % CI: 2.08,9.20) and hip (OR: 2.52; 95 % CI: 1.17,5.43) OA. Individuals who stand or walk a lot, but do not carry or lift things during their occupational activities were 2.0 times less likely to have hip OA (OR: 0.50; 95 % CI: 0.26,0.96). Individuals who usually lift or carry light loads or have to climb stairs or hills were 2.2 times less likely to have hip OA (OR: 0.45; 95 % CI: 0.21,0.95). The odds of having hip OA were 1.9 times lower in individuals consuming recommended or higher vitamin C intake (OR: 0.52; 95 % CI: 0.29,0.96). Significant differences in prevalence were found for both males and females across age categories. CONCLUSION: The prevalence of knee and hip OA obtained in this study is comparable to other studies. Females have greater knee OA prevalence and a greater proportion of women have mobility limitations as well as hip and knee pain; it is important to target this sub group. PMID- 26619839 TI - The Impact of Endocrine Therapy on Cognitive Functions of Breast Cancer Patients: A Systematic Review. AB - BACKGROUND AND OBJECTIVE: The purpose of the present review was to study the impact of endocrine therapy (ET) on the cognitive outcomes of breast cancer patients. MATERIALS AND METHODS: We systematically searched the literature using the MEDLINE (1966-2015), Scopus (2004-2015), ClinicalTrials.gov (2008-2015) and Cochrane Central Register (CENTRAL) databases, as well as the references of the electronically retrieved articles. RESULTS: Twelve studies were included in the present systematic review, which assessed the cognitive function of 2756 patients. Among these patients, 2381 received ET, whereas the remaining 375 served as controls (placebo or no therapy). The majority of patients were postmenopausal, and the minimum follow-up period was 3 months and the maximum 2 years. Treatment with ET seems to be accompanied by altered cognitive abilities, including verbal memory, verbal fluency, motor speed, attention and working memory. Tamoxifen seems to be related to decreased cognitive performances compared with treatment with an aromatase inhibitor. CONCLUSIONS: ET among breast cancer patients seems to negatively alter the cognitive outcomes of breast cancer patients. However, the methodological heterogeneity of the included studies, as well as the relatively small follow-up period, render imperative the conduct of further studies in the field. PMID- 26619841 TI - Validation of the Postgraduate Hospital Educational Environment Measure (PHEEM) in a sample of 731 Greek residents. AB - BACKGROUND: The Greek version of the Postgraduate Hospital Educational Environment Measure (PHEEM) was evaluated to determine its psychometric properties, i.e., validity, internal consistency, sensitivity and responsiveness to be used for measuring the learning environment in Greek hospitals. METHODS: The PHEEM was administered to Greek hospital residents. Internal consistency was measured using Cronbach's alpha. Root Mean Square Error of Approximation (RMSEA) was used to evaluate the fit of Structural Equation Models. Content validity was addressed by the original study. Construct validity was tested using confirmatory (to test the set of underlying dimensions suggested by the original study) and exploratory (to explore the dimensions needed to explain the variability of the given answers) factor analysis using Varimax rotation. Convergent validity was calculated by Pearson's correlation coefficient regarding the participant's PHEEM score and participant's overall satisfaction score of the added item "Overall, I am very satisfied with my specialization in this post". Sensitivity was checked by comparing good versus poor aspects of the educational environment and by satisfied versus unsatisfied participants. RESULTS: A total of 731 residents from 83 hospitals and 41 prefectures responded to the PHEEM. The original three-factor model didn't fit better compared to one factor model that is accounting for 32% of the variance. Cronbach's alpha was 0.933 when assuming one-factor model. Using a three-factor model (autonomy, teaching, social support), Cronbach's alpha were 0.815 (expected 0.830), 0.908 (0.839), 0.734 (0.793), respectively. The three factor model gave an RMSEA value of 0.074 (90% confidence interval 0.071, 0.076), suggesting a fair fit. Pearson's correlation coefficient between total PHEEM and global satisfaction was 0.765. Mean question scores ranged from 19.0 (very poor) to 73.7 (very good), and mean participant scores from 5.5 (very unsatisfied) to 96.5 (very satisfied). CONCLUSIONS: The Greek version of PHEEM is a valid, reliable, and sensitive instrument measuring the educational environment among junior doctors in Greek hospitals and it can be used for evidence-based SWOT analysis and policy. PMID- 26619842 TI - Adenylyl Cyclase 9 Polymorphisms Reveal Potential Link to HDL Function and Cardiovascular Events in Multiple Pathologies: Potential Implications in Sickle Cell Disease. AB - Adenylyl cyclase 9 (ADCY9) mediates beta2-adrenoceptor (beta2-AR) signalling. Both proteins are associated with caveolae, specialized cholesterol-rich membrane substructures. Apolipoprotein A1 (ApoA1), the major protein component of high density lipoprotein (HDL), removes cholesterol from cell membrane and caveolae and may thereby influence beta2-AR signalling, shown in vitro to be modulated by cholesterol. Patients with Sickle Cell Disease (SCD) typically have low HDL and ApoA1 levels. In patients, mainly of African origin, with SCD, beta2-AR activation may trigger adhesion of red blood cells to endothelial cells, leading to vascular occlusive events. Moreover, ADCY9 polymorphism is associated with risk of stroke in SCD. In recent clinical trials, ADCY9 polymorphism was found to be a discriminant factor associated with the risk of cardiovascular (CV) events in Caucasian patients treated with the HDL-raising compound dalcetrapib. We hypothesize that these seemingly disparate observations share a common mechanism related to interaction of HDL/ApoA1 and ADCY9 on beta2-AR signalling. This review also raises the importance of characterizing polymorphisms that determine the response to HDL-raising and -mimicking agents in the non-Caucasian population at high risk of CV diseases and suffering from SCD. This may facilitate personalized CV treatments. PMID- 26619843 TI - Expression and prognostic value of the aldehyde dehydrogenase 1 (ALDH1) and N-myc downstream regulated gene 2 (NDRG2) as potential markers in human astrocytomas. AB - In this study, immunohistochemical analysis was used to evaluate the expression of ALDH1 and NDRG2 in astrocytoma tissue samples and normal brain tissues. ALDH1 protein staining displayed that AlDH1 expression was not detectable in eight astrocytoma tissues (8/36) and in all of normal brain tissues. There was a significant difference between ALDH1 expression and WHO grades (P = 0.03). Furthermore, no correlation was determined between expression levels of ALDH1 and other clinicopathological characteristics including age, sex, and tumor size. Immunohistochemistry showed that a high level of NDRG2 protein expression was markedly detected in normal brain tissues and expression of NDRG2 protein was significantly decreased in astrocytoma tissues. There was a significant association between pathological grading and NDRG2 expression level (P < 0.001, Table 1), but no correlation was determined between expression levels of NDRG2 and other clinicopathological characteristics including age, sex, and tumor size. We also obtained detailed follow-up data and evaluated the association of ALDH1/NDRG2 expressions with overall survival. Kaplan-Meier survival and log-rank analysis indicated that the patients with high proportion of ALDH1-positive cells and low proportion of NDRG2-positive had shorter overall survival (P < 0.001; P = 0.001). Univariate analysis indicated that the high proportion of ALDH1-positive cells (P < 0.001), the low proportion of NDRG2-positive cells (P = 0.009), and the advanced grade (P < 0.005) were markedly linked to the prognosis in patients. Furthermore, in the multivariate analysis, ALDH1 cells' expression (P = 0.012), low proportion of NDRG2-positive cells (P = 0.025), and advanced grade (P < 0.03) were linked to poor overall survival. Our results suggest that NDRG2 expression is related to decreased survival rates and NDRG2 may be a potential marker in the astrocytoma prognosis. NDRG2 may be a potential marker in the astrocytoma prognosis. ALDH1 expression was related to advanced pathological grade and survival rate in astrocytoma patients. PMID- 26619844 TI - Combined analysis of pri-miR-34b/c rs4938723 and TP53 Arg72Pro with cervical cancer risk. AB - miR-34 family members can form a p53-miR-34 positive feedback loop and induce apoptosis, DNA repair, angiogenesis, and cell cycle arrest. We conducted a case control study to examine whether two polymorphisms (i.e., rs4938723 in the promoter of pri-miR-34b/c and TP53 Arg72Pro) were linked to the carcinogenesis of cervical cancer among Chinese Han women. Genotypes of the two polymorphisms in 328 cervical cancer patients and 568 control subjects were determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. We found a significantly increased cervical cancer risk in the pri-miR-34b/c rs4938723 under dominant and overdominant model (CT/CC vs. TT: adjusted OR = 1.34, 95 % CI = 1.01-1.77; CT vs. TT/CC: adjusted OR = 1.37, 95 % CI = 1.05-1.80, respectively). Increased cervical cancer risks were also found in the TP53 Arg72Pro under a heterozygous comparison and overdominant model (CG vs. GG: adjusted OR = 1.44, 95 % CI = 1.06-1.95; CG vs. GG/CC: adjusted OR = 1.47, 95 % CI = 1.12-1.94, respectively). Stratification analysis showed that patients carrying the pri-miR-34b/c rs4938723 CT genotype had a significantly increased risk for developing poorly differential status and clinical stage I. Moreover, increased cancer risks were observed for the TP53 Arg72Pro polymorphism in patients with poorly differential status, clinical stage II, and without lymph node metastasis. Combined analysis revealed that the genotypes of rs4938723 CT/CC and TP53 Arg72Pro CG/CC had an increased cervical cancer risk (OR = 2.21, 95 % CI = 1.38-3.53). These findings suggest that the pri-miR-34b/c rs4938723 and TP53 Arg72Pro polymorphisms may contribute to the genesis of cervical cancer. PMID- 26619845 TI - The small conductance calcium-activated potassium channel 3 (SK3) is a molecular target for Edelfosine to reduce the invasive potential of urothelial carcinoma cells. AB - Metastasis is the survival-determining factor in urothelial carcinoma (UC) of the urinary bladder. The small conductance calcium-activated potassium channel 3 (SK3) enhances tumor cell invasion in breast cancer and malignant melanoma. Since Edelfosine, a glycerophospholipid with antitumoral properties, effectively inhibits SK3 channel activity, our goal was to evaluate SK3 as a potential molecular target to inhibit the gain of an invasive phenotype in UC. SK3 protein expression was analyzed in 208 tissue samples and UC cell lines. Effects of Edelfosine on SK3 expression and intracellular calcium levels as well as on cell morphology, cell survival and proliferation were assessed using immunoblotting, potentiometric fluorescence microscopy, and clonogenic/cell survival assay; furthermore, we analyzed the effect of Edelfosine and SK3 RNAi knockdown on tumor cell migration and invasion in vitro and in vivo. We found that SK3 is strongly expressed in muscle-invasive UC and in the RT112 cellular tumor model. Higher concentrations of Edelfosine have a strong antitumoral effect on UC cells, while 1 MUM effectively inhibits migration/invasion of UC cells in vitro and in vivo comparable to the SK3 knockdown phenotype. Taken together, our results show strong expression of SK3 in muscle-invasive UC, consistent with the postulated role of the protein in tumor cell invasion. Edelfosine is able to effectively inhibit migration and invasion of UC cells in vitro and in vivo in an SK3 dependent way, pointing towards a possible role for Edelfosine as an antiinvasive drug to effectively inhibit UC cell invasion and metastasis. PMID- 26619848 TI - A lump on the nose. PMID- 26619846 TI - The potential effect of patulin on mice bearing melanoma cells: an anti-tumour or carcinogenic effect? AB - Mycotoxins are bioactive compounds that are noxious to human. Their effects on oncogenesis have been satisfactorily elucidated, and some of mycotoxins have been classified as carcinogenic to humans. Nevertheless, patulin (PAT) is considered by the International Agency of Research on Cancer as 'not carcinogenic to humans'. The present study was designed to understand the effect of this mycotoxin on melanoma cells (B16F10) by measuring cell proliferation and assessing the anti-tumour effect in vivo in Balb/c mice. Our results revealed that intraperitoneally administration of PAT for 20 days significantly induces tumour regression in B16F10 cell-implanted mice. This effect was evidenced by the activation of apoptosis which is supported by the increase in p53 and Bax expressions, the downregulation of the protein levels of Bcl2, and the increase in caspase-3 activity. Moreover, systemic toxicity analysis demonstrated that there is no potential toxicity following PAT treatment unlike untreated melanoma mice which suffer from anaemia, inflammation and liver dysfunction. Remarkably, this is the first published report demonstrating the therapeutic efficacy of PAT in vivo models. PMID- 26619847 TI - Does the addition of drugs targeting the vascular endothelial growth factor pathway to first-line chemotherapy increase complete response? A meta-analysis of randomized clinical trials. AB - Drugs targeting the vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling (anti-VEGF/VEGFR drugs) are the most validated anti-angiogenic strategies for cancer treatment. Complete response (CR) is a rare event in cancer patients receiving chemotherapy. A meta-analysis was conducted to determine whether adding anti-VEGF/VEGFR drugs to chemotherapy can further increase the chance of CR in the first-line therapy. Relevant databases were systematically searched for the period 2000-2015. Eligible studies were selected according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The incidence, relative risk (RR), and 95 % confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies. A total of 12,453 patients from 28 randomized controlled trials were included. The overall incidence of CR in patients treated with anti-VEGF/VEGFR drugs plus chemotherapy was 1.5 % (95 % CI, 1.0-2.0 %) compared to 1.1 % (95 % CI, 0.7-1.4 %) in the chemotherapy-alone arm. Adding anti VEGF/VEGFR drugs was associated with significant improvement of CR (RR, 1.52, 95 % CI, 1.18-1.95, P = 0.001). When stratified by drug type, adding VEGFR tyrosin kinase inhibitors (TKIs) did not increase the chance of CR (RR, 0.87, 95 % CI, 0.51-1.49; P = 0.614). The addition of bevacizumab with 7.5 mg/kg every 3 weeks, but not 15 mg/kg every 3 weeks, significantly improves the CR (7.5 mg, RR, 2.43, 95 % CI, 1.64-3.60, P = 0.000; 15 mg, RR, 1.07, 95 % CI, 0.63-1.81, P = 0.799). In subgroup analysis, a significant improvement of CR by the addition of anti VEGF/VEGFR drugs was observed in patients with colorectal cancer (RR, 2.10, 95 % CI 1.21-3.63, P = 0.008), ovarian cancer (RR, 3.07; 95 % CI, 1.68-5.62, P = 0.000), and patients who are treated with platinum-based regimens (RR, 1.78, 95 % CI, 1.23-2.59, P = 0.002). Low-dose bevacizumab, rather than VEGFR TKIs or high dose bevacizumab, can increase the chance of CR in patients receiving chemotherapy. PMID- 26619849 TI - Psychiatric disorder and work life: A longitudinal study of intra-generational social mobility. AB - BACKGROUND: Intra-generational social mobility, which describes the mobility within an individual's own working life, is seldom studied among employees with psychiatric disorders (EPD). There is need of knowledge of the intra-generational mobility patterns, in a broader perspective, among EPD. AIMS: To investigate intra-generational social mobility in employed individuals diagnosed with affective disorder, personality disorder, schizophrenia and drug dependence in a national Swedish cohort. METHOD: We identified a national sample of employed Swedish adults born in 1939-1949 (N = 876, 738), and among them individuals with a first-time hospital admission for affective psychosis, neurosis and personality disorder, alcoholism, drug dependence or schizophrenia in 1964-1980 (N = 18, 998). Employed individuals without hospital admission for such diagnoses were utilised as a comparison group (N = 866, 442). Intra-individual social class changes between 1980 and 1990 among EPD and the comparison group were described through summary statistics and graphs. RESULTS: EPD more often held Low manual occupations at baseline in 1980 than the comparison group (44% vs. 28%), although parental social class was similar. In 1990, 19% of EPD and 4% of the comparison group had lost contact with the labour market. Social stability was less common among EPD (49 %) than in the comparison group (67%). Mobility out of the labour force increased and social stability decreased by number of inpatient admissions. Employees diagnosed with affective psychosis or neurosis and personality disorder fared better in the labour market than employees with schizophrenia. CONCLUSION: Employees suffering from psychiatric disorder do not maintain their social class or remain in the labour force to the same extent as individuals without those problems, irrespective of their parental class. Our results support the social drift hypothesis that individuals with poor psychiatric health move downward in the social hierarchy. PMID- 26619850 TI - Does Sexual Orientation Precede Childhood Sexual Abuse? Childhood Gender Nonconformity as a Risk Factor and Instrumental Variable Analysis. AB - Research suggests that there is a relation between childhood sexual abuse (CSA) and adulthood nonheterosexual orientation. To explore whether nonheterosexual orientation increases the risk of CSA, we recruited a large sample, added the variable of childhood gender nonconformity (CGNC), and applied the instrumental variable method. We found that heterosexual and nonheterosexual men who were more gender nonconforming in childhood were significantly more likely to report having a history of CSA than their gender-conforming counterparts. There was no relation between CSA and CGNC for heterosexual and nonheterosexual women. The instrumental variable analysis revealed that the increased prevalence of CSA experienced by nonheterosexuals compared with heterosexuals may be due to the influence of sexual orientation on CSA. In sum, the results suggest that nonheterosexuality may increase the risk of childhood sexual abuse. PMID- 26619851 TI - Hand-hygiene practices and observed barriers in pediatric long-term care facilities in the New York metropolitan area. AB - OBJECTIVE: To describe hand-hygiene practices in pediatric long-term care (pLTC) facilities and to identify observed barriers to, and potential solutions for, improved infection prevention. DESIGN: Observational study using (i) the World Health Organization's '5 Moments for Hand Hygiene' validated observation tool to record indications for hand hygiene and adherence; and (ii) individual logs of subjective impressions of behavioral and/or systemic barriers witnessed during direct observation. SETTING: Staff in three pLTC facilities (284 beds total) were observed by two trained nurses 1 day a week for 3 weeks in February and March 2015. PARTICIPANTS: Direct providers of health, therapeutic and rehabilitative care, and other staff responsible for social and academic activities for children with complex, chronic medical conditions. MAIN OUTCOME MEASURES: Hand-hygiene indications, adherence and barriers. RESULTS: Hand hygiene was performed for 40% of the 847 indications observed and recorded. Adherence increased at one site and decreased in the other two sites during the study period. Adherence appeared to be influenced by individuals' knowledge, attitudes, beliefs and work setting. CONCLUSIONS: Poor hand-hygiene adherence was observed overall. Specific barriers were identified, which suggest a contextual approach to the interpretation of results indicated in this uniquely challenging setting. We offer some practical suggestions for overcoming those barriers or mitigating their effect. Ultimately, an adaptation of the '5 Moments for Hand Hygiene' may be necessary to improve infection prevention in pLTC. PMID- 26619852 TI - Sexual dysfunction of male, after pelvic fracture. AB - PURPOSE: Pelvic fractures are usually the result of high-energy trauma, and sexual dysfunction after a pelvic fracture is an often complication. Though organic pathologies can be the reason for sexual disorders, psychological factors following a trauma may also be linked to sexual problems. We aimed to evaluate the frequency of sexual dysfunction after pelvic fractures, and help these patients with their usually undisclosed sexual problems, and offer them support. MATERIALS AND METHODS: During a 4-year period, between June 2008 and May 2012, 40 male patients (out of 57) with a mean age of 42.6 years (range 18-65 years) were evaluated retrospectively. Patients having organic pathologies (vascular, neural, and urogenital system pathologies) were excluded from the study. Patients were requested to complete the Arizona Sexual Experience Scale (ASEX), which is a 5 item self-evaluation scale. According to the results of the questionnaire, patients needing supportive treatment were referred to the psychiatry department. RESULTS: Twenty-two patients (55 %) scored 10 points or less in the ASEX questionnaire (normal). Eighteen patients (45 %) had 11 points or more (can be problematic). Four of these 18 patients had a score of 19 points or more (needing psychiatric evaluation). Patients with a score of >=19 points, for any one item with a score of 5 or 6 points, or any three or more items with a score of 4 points were considered to have a high probability of sexual dysfunction after psychiatric evaluation. CONCLUSION: The frequency of sexual dysfunction in pelvic fractured patients was tested, and the need for investigating sexual disorders is stressed. This study attracts attention to sexual dysfunction after pelvic fractures and the necessity of referring these patients to the related clinics, for treatment. LEVEL OF EVIDENCE: Retrospective case series. PMID- 26619853 TI - Practice management of acute trauma haemorrhage and haemostatic disorders across German trauma centres. AB - PURPOSE: Early detection and management of trauma haemorrhage and coagulopathy have been associated with improved outcomes. We assessed infrastructure, logistics and management practice of trauma-associated haemorrhage and coagulopathy across German trauma centres. METHODS: A web-based survey of 20 questions was developed using the open source survey application LimeSurvey(r). It was disseminated among surgeons and anaesthetists in Germany. RESULTS: 145 Questionnaires were returned of which 106 were completed and analysed. Two-thirds of the respondents declared they worked in level I trauma centres. Only 61 % followed a treatment algorithm. Over 90 % used standard laboratory and coagulation tests for decision-making. 56.6 % declared they additionally used extended coagulation assays (TEG/ROTEM). Packed red blood cells, fresh frozen plasma, platelet concentrates, prothrombin complex concentrates, tranexamic acid, calcium, fibrinogen and vitamin K were used by more than 85 % of the respondents for the initial treatment. In all hospitals, irrespective of care level, the first blood product was administered in less than 30 min upon patient arrival (49 % <15 min, 48.1 % <30 min). New oral anticoagulants (NOACs) were identified as an increasing problem in today's trauma care (>95 %) and 65 % of the respondents necessitated reliable tests for early risk stratification. 57.6 % necessitated interdisciplinary training programs to improve clinical skills. CONCLUSIONS: There is variation in the local infrastructure, logistics and management of trauma haemorrhage and coagulopathy across German trauma centres. More than one third of the respondents declare they do not consistently follow a treatment algorithm. NOACs are considered as an increasing problem in acute trauma care. PMID- 26619855 TI - NHS phone triage system sends too many to emergency departments, study finds. PMID- 26619854 TI - Predictors of retained hemothorax after trauma and impact on patient outcomes. AB - PURPOSE: Hemo/pneumothoraces are a common result of thoracic injury. Some of these injuries will be complicated by retained hemothorax (RH), which has previously been shown to be associated with longer hospitalizations. It has been proposed that early versus delayed intervention with video-assisted thoracoscopic surgery can reduce the duration of mechanical ventilation, hospital and ICU LOS, and costs in patients with RH. However, little is known regarding the effect of RH on these outcomes relative to patients with uncomplicated hemo/pneumothoraces. The aim of our study was to characterize factors present on admission that may be associated with RH and assess the impact of RH on outcomes. METHODS: A retrospective chart review was conducted and included all patients who underwent tube thoracostomy (TT) for traumatic hemo/pneumothorax admitted to a single urban adult and pediatric level I trauma center from January 2008 to September 2013. RESULTS: The study cohort included 398 patients, 17.6 % developed RH. RH was associated with significantly longer total duration of TT drainage (p < 0.001), hospital LOS (p < 0.001), and total hospital charges (p < 0.001). These associations remained significant in a subgroup analysis excluding patients with traumatic brain injury. Patients with bilateral injuries (OR 4.25, p < 0.001) and patients intubated on the day of admission (OR 2.30, p = 0.002) were significantly more likely to develop RH. There was also a small, but highly significant, association between increasing ISS and the development of RH (OR 1.07, p < 0.001). CONCLUSIONS: Our study suggests patients requiring ventilator support on admission and those with bilateral injuries are at increased risk of developing RH. Early identification of patients at risk for RH may allow for earlier intervention and potential benefits to the patient. PMID- 26619856 TI - A Comparison of In Vitro and In Vivo Asexual Embryogenesis. AB - In plants, embryogenesis generally occurs through the sexual process of double fertilization, which involves a haploid sperm cell fusing with a haploid egg cell to ultimately give rise to a diploid embryo. Embryogenesis can also occur asexually in the absence of fertilization, both in vitro and in vivo. Somatic or gametic cells are able to differentiate into embryos in vitro following the application of plant growth regulators or stress treatments. Asexual embryogenesis also occurs naturally in some plant species in vivo, from either ovule cells as part of a process defined as apomixis, or from somatic leaf tissue in other species. In both in vitro and in vivo asexual embryogenesis, the embryo precursor cells must attain an embryogenic fate without the act of fertilization. This review compares the processes of in vitro and in vivo asexual embryogenesis including what is known regarding the genetic and epigenetic regulation of each process, and considers how the precursor cells are able to change fate and adopt an embryogenic pathway. PMID- 26619857 TI - Somatic Versus Zygotic Embryogenesis: Learning from Seeds. AB - Plant embryogenesis is a fascinating developmental program that is very successfully established in nature in seeds. In case of in vitro somatic embryogenesis this process is subjected to several limitations such as asynchronous differentiation and further development of somatic embryos, malformations and disturbed polarity, precocious germination, lack of maturity, early loss of embryogenic potential, and strong genotypic differences in the regeneration efficiency. Several studies have shown the similarity of somatic and zygotic embryos in terms of morphological, histological, biochemical, and physiological aspects. However, pronounced differences have also been reported and refer to much higher stress levels, less accumulation of storage compounds and a missing distinction of differentiation and germination by a quiescent phase in somatic embryos. Here, an overview on recent literature describing both embryogenesis pathways, comparing somatic and zygotic embryos and analyzing the role of the endosperm is presented. By taking zygotic embryos as the reference and learning from the situation in seeds, somatic embryogenesis can be improved and optimized in order to make use of the enormous potential this regeneration pathway offers for plant propagation and breeding. PMID- 26619858 TI - Recent Advances on Genetic and Physiological Bases of In Vitro Somatic Embryo Formation. AB - Somatic embryogenesis involves a broad repertoire of genes, and complex expression patterns controlled by a concerted gene regulatory network. The present work describes this regulatory network focusing on the main aspects involved, with the aim of providing a deeper insight into understanding the total reprogramming of cells into a new organism through a somatic way. To the aim, the chromatin remodeling necessary to totipotent stem cell establishment is described, as the activity of numerous transcription factors necessary to cellular totipotency reprogramming. The eliciting effects of various plant growth regulators on the induction of somatic embryogenesis is also described and put in relation with the activity of specific transcription factors. The role of programmed cell death in the process, and the related function of specific hemoglobins as anti-stress and anti-death compounds is also described. The tools for biotechnology coming from this information is highlighted in the concluding remarks. PMID- 26619859 TI - Do Mitochondria Play a Central Role in Stress-Induced Somatic Embryogenesis? AB - This review highlights a four-step rational for the hypothesis that mitochondria play an upstream central role for stress-induced somatic embryogenesis (SE): (1) Initiation of SE is linked to programmed cell death (PCD) (2) Mitochondria are crucially connected to cell death (3) SE is challenged by stress per se (4) Mitochondria are centrally linked to plant stress response and its management. Additionally the review provides a rough perspective for the use of mitochondrial derived functional marker (FM) candidates to improve SE efficiency. It is proposed to apply SE systems as phenotyping tool for identifying superior genotypes with high general plasticity under severe plant stress conditions. PMID- 26619860 TI - Dying with Style: Death Decision in Plant Embryogenesis. AB - Embryogenesis is a fascinating event during the plant life cycle encompassing several steps whereby the zygote develops into a fully developed embryo which, in angiosperms, is composed of an axis separating the apical meristems, and two cotyledons. Recapitulation of embryogenesis can also occur in vitro through somatic embryogenesis, where somatic cells are induced to form embryos, and androgenesis, in which embryos originate from immature male gametophytes. Besides cell division and differentiation, embryo patterning in vivo and in vitro requires the dismantling and selective elimination of cells and tissues via programmed cell death (PCD). While the manifestation of the death program has long been acknowledged in vivo, especially in relation to the elimination of the suspensor during the late phases of embryo development, PCD during in vitro embryogenesis has only been described in more recent years. Independent studies using the gymnosperm Norway spruce and the angiosperm maize have shown that the death program is crucial for the proper formation and further development of immature somatic embryos. This chapter summarizes the recent advances in the field of PCD during embryogenesis and proposes novel regulatory mechanisms activating the death program in plants. PMID- 26619861 TI - Somatic Embryogenesis in Broad-Leaf Woody Plants: What We Can Learn from Proteomics. AB - Proteomic approaches have been used to understand several regulatory aspects of plant development. Somatic embryogenesis is one of those developmental pathways that have beneficiated from the integration of proteomics data to the understanding of the molecular mechanisms that control embryogenic competence acquisition, somatic embryo development and conversion into viable plants. Nevertheless, most of the results obtained are based on the traditional model systems, very often not easily compared with the somatic embryogenesis systems of economical relevant woody species. The aim of this work is to summarize some of the applications of proteomics in the understanding of particular aspects of the somatic embryogenesis process in broad-leaf woody plants (model and non-model systems). PMID- 26619862 TI - Advances in Conifer Somatic Embryogenesis Since Year 2000. AB - This review compiles research results published over the last 14 years on conifer somatic embryogenesis (SE). Emphasis is placed on the newest findings that affect the response of seed embryos (typical explants) and shoot primordia (rare explants) to the induction of SE and long-term culture of early somatic embryos. Much research in recent years has focused on maturation of somatic embryos, with respect to both yield and quality, as an important stage for the production of a large number of vigorous somatic seedlings. Attempts to scale up somatic embryo production numbers and handling have resulted in a few bioreactor designs, the utility of which may prove beneficial for an industrial application. A few simplified cryopreservation methods for embryonal masses (EM) were developed as a means to ensure cost-efficient long-term storage of genotypes during clonal field testing. Finally, recent long-term studies on the growth of somatic trees in the field, including seed production yield and comparison of seed parameters produced by somatic versus seed-derived trees, are described. PMID- 26619863 TI - Molecular Aspects of Conifer Zygotic and Somatic Embryo Development: A Review of Genome-Wide Approaches and Recent Insights. AB - Genome-wide profiling (transcriptomics, proteomics, metabolomics) is providing unprecedented opportunities to unravel the complexity of coordinated gene expression during embryo development in trees, especially conifer species harboring "giga-genome." This knowledge should be critical for the efficient delivery of improved varieties through seeds and/or somatic embryos in fluctuating markets and to cope with climate change. We reviewed "omics" as well as targeted gene expression studies during both somatic and zygotic embryo development in conifers and tentatively puzzled over the critical processes and genes involved at the specific developmental and transition stages. Current limitations to the interpretation of these large datasets are going to be lifted through the ongoing development of comprehensive genome resources in conifers. Nevertheless omics already confirmed that master regulators (e.g., transcription and epigenetic factors) play central roles. As in model angiosperms, the molecular regulation from early to late embryogenesis may mainly arise from spatiotemporal modulation of auxin-, gibberellin-, and abscisic acid-mediated responses. Omics also showed the potential for the development of tools to assess the progress of embryo development or to build genotype-independent, predictive models of embryogenesis-specific characteristics. PMID- 26619864 TI - Androgenesis in Solanaceae. AB - The Solanaceae is one of the most important families for global agriculture. Among the different solanaceous species, tobacco (Nicotiana tabacum), potato (Solanum tuberosum), tomato (Solanum lycopersicum), eggplant (Solanum melongena), and pepper (Capsicum annuum) are five crops of outstanding importance worldwide. In these crops, maximum yields are produced by hybrid plants created by crossing pure (homozygous) lines with the desired traits. Pure lines may be produced by conventional breeding methods, which is time consuming and costly. Alternatively, it is possible to accelerate the production of pure lines by creating doubled haploid (DH) plants derived from (haploid) male gametophytes or their precursors (androgenesis). In this way, the different steps for the production of pure lines can be reduced to only one generation, which implies important time and cost savings. This and other advantages make androgenic DHs the choice in a number of important crops where any of the different experimental in vitro techniques (anther culture or isolated microspore culture) is well set up. The Solanaceae family is an excellent example of heterogeneity in terms of response to these techniques, including highly responding species such as tobacco, considered a model system, and tomato, one of the most recalcitrant species, where no reliable and reproducible methods are yet available. Interestingly, the first evidence of androgenesis, particularly through in vitro anther culture, was demonstrated in a solanaceous species, Datura innoxia. In this chapter, we report the state of the art of the research about androgenic DHs in Solanaceae, paying special attention to datura, tobacco, potato, tomato, eggplant, and pepper. PMID- 26619865 TI - Bioreactors for Plant Embryogenesis and Beyond. AB - A variety of different bioreactors have been developed for use in initiating and cultivating somatic embryos. The various designs for embryogenesis and culture are critically evaluated here. Bioreactor optimization and operation methods are also described along with recommendations for use based on desired outcome. PMID- 26619866 TI - Somatic Embryogenesis and Genetic Modification of Vitis. AB - Grapevine embryogenic cultures are ideal target tissues for inserting desired traits of interest and improving existing cultivars via precision breeding (PB). PB is a new approach that, like conventional breeding, utilizes only DNA fragments obtained from sexually compatible grapevine plants. Embryogenic culture induction occurs by placing leaves or stamens and pistils on induction medium with a dark/light photoperiod cycle for 12-16 weeks. Resulting cultures produce sectors of embryogenic and non-embryogenic callus, which can be identified on the basis of callus morphology and color. Somatic embryo development occurs following transfer of embryogenic callus to development medium and cultures can be maintained for extended periods of time by transfer of the proliferating proembryonic masses to fresh medium at 4-6-week intervals. To demonstrate plant recovery via PB, somatic embryos at the mid-cotyledonary stage are cocultivated with Agrobacterium containing the desired gene of interest along with a, non-PB, enhanced green fluorescent protein/neomycin phosphotransferase II (egfp/nptII) fusion gene. Modified cultures are grown on proliferation and development medium to produce uniformly modified somatic embryos via secondary embryogenesis. Modified embryos identified on the basis of green fluorescence and kanamycin resistance are transferred to germination medium for plant development. The resulting plants are considered to prototype examples of the PB approach, since they contain egfp/nptII, a non-grapevine-derived fusion gene. Uniform green fluorescent protein (GFP) fluorescence can be observed in all tissues of regenerated plants. PMID- 26619867 TI - Somatic Embryogenesis in Peach-Palm (Bactris gasipaes) Using Different Explant Sources. AB - Peach palm (Bactris gasipaes Kunth) is a member of the family Arecaceae and is a multipurpose but underutilized species. Nowadays, fruit production for subsistence and local markets, and heart-of-palm production for local, national, and international markets are the most important uses of this plant. Conventional breeding programs in peach palm are long-term efforts due to the prolonged generation time, large plant size, difficulties with controlled pollination and other factors. Although it is a caespitose palm, its propagation is currently based on seeds, as off-shoots are difficult to root. Hence, tissue culture techniques are considered to be the most likely strategy for efficient clonal plantlet regeneration of this species. Among various techniques, somatic embryogenesis offers the advantages of potential automated large-scale production and putative genetic stability of the regenerated plantlets. The induction of somatic embryogenesis in peach palm can be achieved by using different explant sources including zygotic embryos, immature inflorescences and thin cell layers from the young leaves and shoot meristems. The choice of a particular explant depends on whether clonal propagation is desired or not, as well as on the plant conditions and availability of explants. Protocols to induce and express somatic embryogenesis from different peach palm explants, up to acclimatization of plantlets, are described in this chapter. PMID- 26619868 TI - Somatic Embryogenesis: Still a Relevant Technique in Citrus Improvement. AB - The genus Citrus contains numerous fresh and processed fruit cultivars that are economically important worldwide. New cultivars are needed to battle industry threatening diseases and to create new marketing opportunities. Citrus improvement by conventional methods alone has many limitations that can be overcome by applications of emerging biotechnologies, generally requiring cell to plant regeneration. Many citrus genotypes are amenable to somatic embryogenesis, which became a key regeneration pathway in many experimental approaches to cultivar improvement. This chapter provides a brief history of plant somatic embryogenesis with focus on citrus, followed by a discussion of proven applications in biotechnology-facilitated citrus improvement techniques, such as somatic hybridization, somatic cybridization, genetic transformation, and the exploitation of somaclonal variation. Finally, two important new protocols that feature plant regeneration via somatic embryogenesis are provided: protoplast transformation and Agrobacterium-mediated transformation of embryogenic cell suspension cultures. PMID- 26619869 TI - Somatic Embryogenesis Induction and Plant Regeneration in Strawberry Tree (Arbutus unedo L.). AB - Somatic embryogenesis is a powerful tool both for cloning and studies of genetic transformation and embryo development. Most protocols for somatic embryogenesis induction start from zygotic embryos or embryonic-derived tissues which do not allow the propagation of elite trees. In the present study, a reliable protocol for somatic embryogenesis induction from adult trees of strawberry tree is described. Leaves from in vitro proliferating shoots were used to induce somatic embryo formation on a medium containing an auxin and a cytokinin. Somatic embryos germinated in a plant growth regulator-free medium. PMID- 26619871 TI - Somatic Embryogenesis in Crocus sativus L. AB - Saffron (Crocus sativus L.) is one of the most important species in Crocus genus because of its effective usage. It is not only a very expensive spice, but it has also a big ornamental plant potential. Crocus species are propagated by corm and seed, and male sterility is the most important problem of this species. Hence, somatic embryogenesis can be regarded as a strategic tool for the multiplication of saffron plants. In this chapter, the production of saffron corms via somatic embryogenesis is described. PMID- 26619870 TI - Somatic Embryogenesis in Olive (Olea europaea L. subsp. europaea var. sativa and var. sylvestris). AB - Protocols for olive somatic embryogenesis from zygotic embryos and mature tissues have been described for both Olea europaea sub. europaea var. sativa and var. sylvestris. Immature zygotic embryos (no more than 75 days old), used after fruit collection or stored at 12-14 degrees C for 2-3 months, are the best responsive explants and very slightly genotype dependent, and one single protocol can be effective for a wide range of genotypes. On the contrary, protocols for mature zygotic embryos and for mature tissue of cultivars are often genotype specific, so that they may require many adjustments according to genotypes. The use of thidiazuron and cefotaxime seems to be an important trigger for induction phase particularly for tissues derived from cultivars. Up to now, however, the application of this technique for large-scale propagation is hampered also by the low rate of embryo germination; it proves nonetheless very useful for genetic improvement. PMID- 26619872 TI - Somatic Embryogenesis in Lisianthus (Eustoma russellianum Griseb.). AB - Somatic embryogenesis is, for the main floricultural crops, a promising system for commercial scale-up, providing cloned material to be traded as seedlings. Somatic embryos, having the contemporary presence of root apical meristem and shoot apical meristem, can be readily acclimatized. For Lisianthus it is possible to induce embryogenic callus from leaf fragments of selected genotypes and to obtain embryos either in agarized substrate or in liquid suspension culture. The production of somatic embryos in liquid medium is high and can be modulated in order to synchronize the cycle and the size of the neoformed structures. The possibility to use the liquid substrate with high propagation rates reduces labor costs and could support the costs of eventual automation. In this paper we report a stepwise protocol for somatic embryogenesis in the species Eustoma russellianum. PMID- 26619873 TI - Somatic Embryogenesis in Two Orchid Genera (Cymbidium, Dendrobium). AB - The protocorm-like body (PLB) is the de facto somatic embryo in orchids. Here we describe detailed protocols for two orchid genera (hybrid Cymbidium Twilight Moon 'Day Light' and Dendrobium 'Jayakarta', D. 'Gradita 31', and D. 'Zahra FR 62') for generating PLBs. These protocols will most likely have to be tweaked for different cultivars as the response of orchids in vitro tends to be dependent on genotype. In addition to primary somatic embryogenesis, secondary (or repetitive) somatic embryogenesis is also described for both genera. The use of thin cell layers as a sensitive tissue assay is outlined for hybrid Cymbidium while the protocol outlined is suitable for bioreactor culture of D. 'Zahra FR 62'. PMID- 26619874 TI - Somatic Embryogenesis of Lilium from Microbulb Transverse Thin Cell Layers. AB - A reliable somatic embryogenesis protocol is a prerequisite for application of other plant biotechniques. Several protocols were reported for genus Lilium, with variable success. Between them, transverse Thin Cell Layers (tTCL) were used efficiently to induce indirect somatic embryogenesis of Lilium. Somatic embryogenesis potential is dependent on the genotype, explant, and culture medium composition, especially as for plant growth regulators and environmental conditions. Usually, the process comprises three phases: embryogenic callus induction, embryogenic callus proliferation and somatic embryo germination. Somatic embryo germination can be achieved in light or dark. In the first case, complete plantlets are formed, with green leaves and pseudobulb in the base. In darkness, microbulbs are formed from single somatic embryos or clusters. A last phase of microbulb enlargement allows plantlets or microbulbs to increase their biomass. These enlarged microbulbs do not need special acclimatization conditions when transferred to soil and quickly produce sturdy plants. This chapter describes a protocol for somatic embryogenesis of Lilium using tTCL from microbulbs. PMID- 26619876 TI - Somatic Embryogenesis in Pinus spp. AB - Somatic embryogenesis (SE) has been the most important development for plant tissue culture, not only for mass propagation but also for enabling the implementation of biotechnological tools that can be used to increase the productivity and wood quality of plantation forestry. Development of SE in forest trees started in 1985 and nowadays many studies are focused on the optimization of conifer SE system. However, these advances for many Pinus spp. are not sufficiently refined to be implemented commercially. In this chapter, a summary of the main systems used to achieve SE in Pinus spp. is reported. PMID- 26619875 TI - Somatic Embryogenesis and Plant Regeneration of Brachiaria brizantha. AB - The genus Brachiaria (Trin.) Griseb. belongs to the family Poaceae, order Poales, class Monocotyledonae. In Brachiaria brizantha (Hochst. ex A. Rich.) Stapf., embryogenic callus can be induced from seeds from apomictic plants, which results in high frequency somatic embryo development and plant regeneration. We report here a detailed protocol for callus induction from apomictic seed; followed by in vitro morphogenesis (somatic embryo and bud differentiation), plant regeneration, and acclimatization in the greenhouse. Important details regarding the positioning of seeds for callus induction and precautions to avoid endophytic contamination and the occurrence of albino plants are presented. PMID- 26619877 TI - Somatic Embryogenesis of Abies cephalonica Loud. AB - Greek fir (Abies cephalonica Loudon) belongs to the Mediterranean fir species and is widely distributed in the mountains of Central and Southern Greece. Considering a climatic scenario, infestation by pathogens or insects and fire episodes, it has been proposed that Mediterranean firs could be in danger in some parts of their present range but, on the other hand, could also replace other species in more northern zones with temperate humid climates (e.g., silver fir, Abies alba Mill.). As fir species are generally highly productive and therefore important for commercial forestry, they have traditionally been involved in conventional tree improvement programs. A lot of effort has been put into the development of vegetative propagation methods for firs, in order to rapidly gain the benefits of traditional breeding to be utilized in reforestation. The present paper provides up to date information on protocols for somatic embryogenesis (i.e., the most promising in vitro method for vegetative propagation) of Greek fir. Moreover, the protocols for cryopreservation and long-term storage of embryogenic material are described as well. PMID- 26619878 TI - Somatic Embryogenesis in Horse Chestnut (Aesculus hippocastanum L.). AB - Embryogenic cultures of horse chestnut (Aesculus hippocastanum L.) can be obtained from different organs and tissues. We describe here the induction from stamen filaments and the procedures applied for the successive phases of somatic embryo development and maturation. Embryogenic tissues are obtained on Murashige and Skoog medium containing 9.0 MUM 2,4-dichlorophenoxyacetic acid. Somatic embryos develop after transfer to hormone-free medium enriched with glutamine. Maturation and germination of isolated embryos are achieved by transfer to medium containing polyethylene glycol 4000 and activated charcoal, successive desiccation treatment, and cold storage at 4 degrees C for 8 weeks. PMID- 26619879 TI - Somatic Embryogenesis in Araucaria angustifolia (Bertol.) Kuntze (Araucariaceae). AB - This chapter deals with the features of somatic embryogenesis (SE) in Araucaria angustifolia, an endangered and native conifer from south Brazil. In this species SE includes the induction and proliferation of embryogenic cultures composed of pro-embryogenic masses (PEMs), which precede somatic embryos development. A. angustifolia SE model encompasses induction, proliferation, pre-maturation, and maturation steps. Double-staining with acetocarmine and Evan's blue is useful to evaluate the embryonic somatic structures. In this chapter we describe A. angustifolia SE protocols and analyzes morphological features in the different SE developmental stages. PMID- 26619880 TI - Anther Culture in Eggplant (Solanum melongena L.). AB - The technique of in vitro anther culture is the most favorite to incite the production of plants from microspore through direct embryogenesis or regeneration from callus. Anther culture has been employed since 1980s in eggplant to obtain double-haploid plants from microspore derived embryos. From that time it has been refined and widely applied both at commercial level for a fast generation double haploid parental lines of F1 hybrids, as well as for experimental studies as the complete homozygosis of the microspore-derived plants make more simply the genetic analysis. In this chapter, a step-by-step procedure is reported, taking into consideration all the aspects of the technique, including the growth condition of the anther donor plant, the in vitro regeneration of the androgenetic plantlets, their ploidy analysis, and the colchicine treatment to double the chromosome number of the haploids. PMID- 26619881 TI - Anther Culture in Pepper (Capsicum annuum L.). AB - Anther culture is the most popular of the techniques used to induce microspore embryogenesis. This technique is well set up in a wide range of crops, including pepper. In this chapter, a protocol for anther culture in pepper is described. The protocol presented hereby includes the steps from the selection of buds from donor plants to the regeneration and acclimatization of doubled haploid plants derived from the embryos, as well as a description of how to analyze the ploidy level of the regenerated plants. PMID- 26619882 TI - Microspore Embryogenesis Through Anther Culture in Citrus clementina Hort. ex Tan. AB - Anther culture is a biotechnological method that allows to obtain, in one step, homozygous plants, very important to plant breeding, due to their numerous applications in mutation research, selection, genome sequencing, genetic analysis, and transformation. To induce the microspores, i.e., the immature male gametes, to switch from the normal gametophytic pathway to the sporophytic one, it is necessary to submit them to a type of stress, such as high or low temperature, starvation, or magnetic field. Stress can be applied to the donor plants and/or the floral buds or the anthers or the isolated microspores, before or during the culture. In this chapter, the protocol to induce gametic embryogenesis from anther culture of several cultivars of Citrus clementina Hort. ex Tan. is reported. PMID- 26619883 TI - Detection of Epigenetic Modifications During Microspore Embryogenesis: Analysis of DNA Methylation Patterns Dynamics. AB - Methylation of 5-deoxy-cytidines of DNA constitutes a prominent epigenetic modification of the chromatin fiber which is locked in a transcriptionally inactive conformation. Changes in global DNA methylation are involved in many plant developmental processes during proliferation and differentiation events. The analysis of the changes of global DNA methylation distribution patterns during microspore embryogenesis induction and progression will inform on the regulatory mechanisms of the process, helping in the design of protocols to improve its efficiency in different species. To investigate the DNA methylation dynamics during microspore embryogenesis in the different cell types present in the cultures, the analysis of spatial and temporal pattern of nuclear distribution of 5-methyl-deoxy-cytidine (5mdC) constitutes a potent approach. The immunolocalization of 5mdC on sections and subsequent confocal laser microscopy analysis have been developed for in situ cellular analysis of a variety of plant samples, including embryogenic microspore and anther cultures. Quantification of 5mdC immunofluorescence intensity by image analysis software also permits to estimate differences in global DNA methylation levels among different cell types during development. PMID- 26619884 TI - Embryogenesis and Plant Regeneration from Isolated Wheat Zygotes. AB - Wheat zygotes can be mechanically isolated and cultivated to continue their development in vitro. Since each zygote needs to be individually isolated, only relatively few of these cells are available per experiment. To facilitate embryonic growth despite of this limitation, the zygotes are kept within a culture insert placed in a larger dish which itself contains embryogenic pollen cocultivated for continuous medium conditioning. This setup ensures that the two cultures, while being physically separated from one another, can exchange essential intercellular signal molecules passing through the bottom of the insert which is made of a permeable membrane. Thanks to the natural fate of zygotes, which is to form an embryo followed by the generation of a plant, embryogenesis and plant regeneration are achieved at much higher efficiency as compared to other single-cell systems. While the method is largely independent of the genotype, it allows for the nondestructive observation, manipulation, and individual analysis of zygotes and very young embryos. PMID- 26619885 TI - From Somatic Embryo to Synthetic Seed in Citrus spp. Through the Encapsulation Technology. AB - In vitro propagation by somatic embryogenesis represents an efficient alternative method to produce high-quality and healthy plants in Citrus species. The regenerated somatic embryos need protection from mechanical damages during manipulation and transport, as well as nutritive support for their evolution in plantlets after sowing. The encapsulation technology allows to obtain synthetic seeds by covering somatic embryos with a gel of calcium alginate enriched by nutrients. This chapter describes the procedure for producing synthetic seeds containing somatic embryos from different Citrus genotypes. PMID- 26619886 TI - From Stress to Embryos: Some of the Problems for Induction and Maturation of Somatic Embryos. AB - Although somatic embryogenesis has been successfully achieved in numerous plant species, little is known about the mechanism(s) underlying this process. Changes in the balance of growth regulators of the culture medium, osmolarity, or amino acids as well as the genotype and developmental stage of the tissue used as initial explant may have a pivotal influence on the induction of somatic embryogenic cultures. Moreover, different stress agents (ethylene, activated charcoal, cold or heat or electrical shocks), as well as abscisic acid, can also foster the induction or further development of somatic embryos. In the process, cells first return to a stem cell-like status and then either enter their new program or dye when the stress level exceeds cell tolerance. Recalcitrance to differentiation of somatic cells into embryos is frequently observed, and problems such as secondary or recurrent embryogenesis, embryo growth arrest (at the globular stage or during the transition from torpedo to cotyledonary stage), and development of only the aerial part of somatic embryos can appear, interfering with normal germination and conversion of embryos to plants. Some solutions to solve these problems associated to embryogenesis are proposed and two very efficient somatic embryogenesis protocols for two model plant species are detailed. PMID- 26619887 TI - Cryotechniques for the Long-Term Conservation of Embryogenic Cultures from Woody Plants. AB - Since its development in the 1960s, plant cryopreservation is considered an extraordinary method of safe long-term conservation of biological material, as it does not induce genetic alterations and preserve the regeneration potential of the stored material. It is based on the storage of explants at cryogenic temperatures, such as the one of liquid nitrogen (-196 degrees C), where the metabolism within the cells is suspended; thus, the time for these cells is theoretically "stopped". Cryopreservation is particularly important for embryogenic cultures, as they require periodic subculturing for their maintenance, and this, in turn, increases the risk of losing the material, as well as its embryogenic potential. Periodic re-initiation of embryogenic cultures is possible; however, it is labor intensive, expensive, and particularly difficult when working with species for which embryogenic explants are available only during a limited period of the year. Among various methods of cryopreservation available for embryogenic cultures, slow cooling is still the most common approach, especially in callus cultures from softwood species. This chapter briefly reviews the cryopreservation of embryogenic cultures in conifers and broadleaf trees, and describes as well a complete protocol of embryogenic callus cryopreservation from common ash tree (Fraxinus excelsior L.) by slow cooling. PMID- 26619888 TI - Direct Probing of Dispersion Quality of ZrO2 Nanoparticles Coated by Polyelectrolyte at Different Concentrated Suspensions. AB - This study reports useful application of the electrokinetic sonic amplitude (ESA) technique in combination with rheometry and electron microscopy techniques for direct probing the stability of low and high-concentrated zirconia (ZrO2) nanosuspensions in the presence of an alkali-free anionic polyelectrolyte dispersant Dolapix CE64. A comparative study of the electrokinetic characteristics and the rheological behavior of concentrated ZrO2 nanosuspensions has been done. Good agreement was obtained from relationship between the electrokinetic characteristics (zeta potential, ESA signal), viscosity, and its pH dependence for each concentrated ZrO2 nanosuspension with different dispersant concentration in the range of 0.9-1.5 mass%. A nanoscale colloidal hypothesis is proposed to illustrate that the addition of different amounts of dispersant influences on both the stability and the electrokinetic and rheological properties of concentrated ZrO2 nanosuspensions. It is found that an optimum amount of 1.4 mass% dispersant at the inherent pH (>9.2) can be attached fully onto the nanoparticles with sufficient electrosteric dispersion effects, suitable for casting applications. Supplementary scanning electron microscopy (SEM) and high-resolution transmission electron microscopy (HR-TEM) analyses followed by colorization effect were taken to verify the visible interaction between dispersant and nanoparticles surfaces. SEM and HR-TEM images proved the existence of visible coverage of dispersant on the surface of individual nanoparticles and showed that thin polyelectrolyte layers were physically bound onto the particles' surfaces. This study will be of interest to materials scientists and engineers who are dealing with dispersion technology, nanoparticle surface treatments, functionalization, characterization, and application of bio/nanoparticle suspensions at various concentrations using different types of polymers. PMID- 26619889 TI - The Polymerization Effect on Synthesis and Visible-Light Photocatalytic Properties of Low-Temperature beta-BiNbO4 Using Nb-Citrate Precursor. AB - Low-temperature beta-BiNbO4 powders (denoted as Low-beta) were prepared by citrate and Pechini methods using homemade water-soluble niobium precursors. The addition of ethylene glycol and the resultant polymerization effect on the synthesis and visible-light photocatalytic performance of beta-BiNbO4 powders were fully investigated. The polymerization effect is beneficial to lower the phase formation temperature and obtain smaller particle catalysts. Both methods can synthesize catalysts with excellent performance of visible-light degradation of methyl violet (MV). The Low-beta BiNbO4 powder prepared by citrate method shows better degradation rate of about 1 h to decompose 80 % of MV and also displays good photocatalytic stability. The photodegradation of MV under the visible-light irradiation followed the pseudo-first-order kinetics according to the Langmuir-Hinshelwood model, and the obtained first-order rate constant and half-time are 2.85 * 10(-2) min(-1) and 24.3 min, respectively. The better photocatalytic performance of BiNbO4 powders prepared by citrate method can be attributed to its smaller band gap and better crystallinity. PMID- 26619891 TI - Electroacupuncture attenuates hepatic lipid accumulation via AMP-activated protein kinase (AMPK) activation in obese rats. AB - BACKGROUND: Electroacupuncture (EA) may offer an effective alternative approach for the treatment of obesity. EA mobilizes energy stores, but its effect on hepatic lipid metabolism is unknown, and the underlying mechanisms remain unclear. OBJECTIVE: To examine the effect of EA on hepatic lipid accumulation in diet-induced obese (DIO) rats, and to explore potential underlying mechanisms. METHODS: Male Sprague-Dawley rats were fed a normal diet (control group, n=10) or a high-fat diet (HFD) for 12 weeks to induce obesity. Those exhibiting diet induced obesity were subdivided into two groups, one receiving EA (DIO+EA group, n=10) and one left untreated (DIO group, n=10) and observed for a further 4 weeks. Body, liver and fat pad weight were measured, and liver injury was assessed histologically as well as by measuring serum values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Hepatic triglyceride (TG) and total cholesterol were quantified by enzymatic colorimetric methods. Expression of liver AMP-activated protein kinase (AMPK), acetyl-coenzyme A carboxylase (ACC), and carnitine palmitoyltransferase (CPT-1) was measured by Western blotting. RESULTS: EA treatment led to a reduction in body, liver and fat pad weight in DIO rats. This was accompanied by decreases in hepatic TG and total cholesterol values, fatty droplet accumulation, and serum concentrations of ALT and AST. Furthermore, EA treatment restored phosphorylation levels of AMPK (Thr(172)) and ACC (Ser(79)) inhibited by HFD, and increased CPT-1 expression. CONCLUSIONS: EA reduces HFD-induced hepatic lipid accumulation, an effect that appears to be mediated through AMPK signalling pathways. Our results shed new light on the mechanisms by which EA may reduce obesity. PMID- 26619890 TI - Structural and Functional Hierarchy in Photosynthetic Energy Conversion-from Molecules to Nanostructures. AB - Basic principles of structural and functional requirements of photosynthetic energy conversion in hierarchically organized machineries are reviewed. Blueprints of photosynthesis, the energetic basis of virtually all life on Earth, can serve the basis for constructing artificial light energy-converting molecular devices. In photosynthetic organisms, the conversion of light energy into chemical energy takes places in highly organized fine-tunable systems with structural and functional hierarchy. The incident photons are absorbed by light harvesting complexes, which funnel the excitation energy into reaction centre (RC) protein complexes containing redox-active chlorophyll molecules; the primary charge separations in the RCs are followed by vectorial transport of charges (electrons and protons) in the photosynthetic membrane. RCs possess properties that make their use in solar energy-converting and integrated optoelectronic systems feasible. Therefore, there is a large interest in many laboratories and in the industry toward their use in molecular devices. RCs have been bound to different carrier matrices, with their photophysical and photochemical activities largely retained in the nano-systems and with electronic connection to conducting surfaces. We show examples of RCs bound to carbon-based materials (functionalized and non-functionalized single- and multiwalled carbon nanotubes), transitional metal oxides (ITO) and conducting polymers and porous silicon and characterize their photochemical activities. Recently, we adapted several physical and chemical methods for binding RCs to different nanomaterials. It is generally found that the P(+)(QAQB)(-) charge pair, which is formed after single saturating light excitation is stabilized after the attachment of the RCs to the nanostructures, which is followed by slow reorganization of the protein structure. Measuring the electric conductivity in a direct contact mode or in electrochemical cell indicates that there is an electronic interaction between the protein and the inorganic carrier matrices. This can be a basis of sensing element of bio-hybrid device for biosensor and/or optoelectronic applications. PMID- 26619892 TI - Anorectal Dysfunction in Distal Ulcerative Colitis: Challenges and Opportunities for Topical Therapy. PMID- 26619894 TI - Three-Dimensional Nanoporous Graphene-Carbon Nanotube Hybrid Frameworks for Confinement of SnS2 Nanosheets: Flexible and Binder-Free Papers with Highly Reversible Lithium Storage. AB - The practical applications of transition-metal dichalcogenides for lithium-ion batteries are severely inhibited by their inferior structural stability and electrical conductivity, which can be solved by optimizing these materials to nanostructures and confining them within conductive frameworks. Thus, we report a facile approach to prepare flexible papers with SnS2 nanosheets (SnS2 NSs) homogeneously dispersed and confined within the conductive graphene-carbon nanotube (CNT) hybrid frameworks. The confinement of SnS2 NSs in graphene-CNT matrixes not only can effectively prevent their aggregation during the discharge charge procedure, but also can assist facilitating ion transfer across the interfaces. As a result, the optimized SGC papers give an improved capacity of 1118.2 mA h g(-1) at 0.1 A g(-1) along with outstanding stability. This report demonstrates the significance of employing graphene-CNT matrixes for confinement of various active materials to fabricate flexible electrode materials. PMID- 26619893 TI - Clinical Features and HLA Association of 5-Aminosalicylate (5-ASA)-induced Nephrotoxicity in Inflammatory Bowel Disease. AB - BACKGROUND AND AIMS: Nephrotoxicity is a rare idiosyncratic reaction to 5 aminosalicylate (5-ASA) therapies. The aims of this study were to describe the clinical features of this complication and identify clinically useful genetic markers so that these drugs can be avoided or so that monitoring can be intensified in high-risk patients. METHODS: Inflammatory bowel disease patients were recruited from 89 sites around the world. Inclusion criteria included normal renal function prior to commencing 5-ASA, >=50% rise in creatinine any time after starting 5-ASA, and physician opinion implicating 5-ASA strong enough to justify drug withdrawal. An adjudication panel identified definite and probable cases from structured case report forms. A genome-wide association study was then undertaken with these cases and 4109 disease controls. RESULTS: After adjudication, 151 cases of 5-ASA-induced nephrotoxicity were identified. Sixty eight percent of cases were males, with nephrotoxicity occurring at a median age of 39.4 years (range 6-79 years). The median time for development of renal injury after commencing 5-ASA was 3.0 years (95% confidence interval [CI] 2.3-3.7). Only 30% of cases recovered completely after drug withdrawal, with 15 patients requiring permanent renal replacement therapy. A genome-wide association study identified a suggestive association in the HLA region (p = 1*10(-7)) with 5-ASA induced nephrotoxicity. A sub-group analysis of patients who had a renal biopsy demonstrating interstitial nephritis (n = 55) significantly strengthened this association (p = 4*10(-9), odds ratio 3.1). CONCLUSIONS: This is the largest and most detailed study of 5-ASA-induced nephrotoxicity to date. It highlights the morbidity associated with this condition and identifies for the first time a significant genetic predisposition to drug-induced renal injury. PMID- 26619896 TI - Psychiatry HeAL thyself! PMID- 26619895 TI - Self-harm: Prevalence estimates from the second Australian Child and Adolescent Survey of Mental Health and Wellbeing. AB - OBJECTIVE: To (1) estimate the lifetime and 12-month prevalence of self-harm without suicide intent in young people aged 12-17 years, (2) describe the co morbidity of these behaviours with mental illness and (3) describe their co variation with key social and demographic variables. METHOD: A nationally representative random sample of households with children aged 4-17 years recruited in 2013-2014. The survey response rate was 55% with 6310 parents and carers of eligible households participating. In addition, 2967 (89%) of young people aged 11-17 completed a self-report questionnaire with 2653 of the 12- to 17-year-olds completing questions about self-harm behaviour. RESULTS: In any 12 month period, about 8% of all 12- to 17-year-olds (an estimated 137,000 12- to 17 year-olds) report engaging in self-harming behaviour without suicide intent. This prevalence increases with age to 11.6% in 16- to 17-year-olds. Eighteen percent (18.8%; 95% confidence interval [CI] = [14.5, 23.0]) of all 12- to 17-year-old young people with any mental health disorder measured by parent or carer report said that they had engaged in self-harm in the past 12 months. Among young people who were measured by self-report and met criteria for the Diagnostic and Statistical Manual of Mental Disorders' major depressive disorder almost half (46.6%; 95% CI = [40.0, 53.1]) also reported that they had engaged in self-harm in the past 12 months. Suicide risk among those who self-harm is significantly elevated relative to the general population. CONCLUSION: The demonstrated higher risks in these young people for continued harm or possible death support the need for ongoing initiatives to reduce self-harm through mental health promotion, improved mental health literacy and continuing mental health reform to ensure services are accessible to, and meet the needs of families and young persons. PMID- 26619897 TI - Treatment of comorbid bipolar disorder and anxiety disorders: A great challenge to modern psychiatry. PMID- 26619898 TI - How many carbonic anhydrase inhibition mechanisms exist? AB - Six genetic families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) were described to date. Inhibition of CAs has pharmacologic applications in the field of antiglaucoma, anticonvulsant, anticancer, and anti-infective agents. New classes of CA inhibitors (CAIs) were described in the last decade with enzyme inhibition mechanisms differing considerably from the classical inhibitors of the sulfonamide or anion type. Five different CA inhibition mechanisms are known: (i) the zinc binders coordinate to the catalytically crucial Zn(II) ion from the enzyme active site, with the metal in tetrahedral or trigonal bipyramidal geometries. Sulfonamides and their isosters, most anions, dithiocarbamates and their isosters, carboxylates, and hydroxamates bind in this way; (ii) inhibitors that anchor to the zinc-coordinated water molecule/hydroxide ion (phenols, carboxylates, polyamines, 2-thioxocoumarins, sulfocoumarins); (iii) inhibitors which occlude the entrance to the active site cavity (coumarins and their isosters), this binding site coinciding with that where CA activators bind; (iv) compounds which bind out of the active site cavity (a carboxylic acid derivative was seen to inhibit CA in this manner), and (v) compounds for which the inhibition mechanism is not known, among which the secondary/tertiary sulfonamides as well as imatinib/nilotinib are the most investigated examples. As CAIs are used clinically in many pathologies, with a sulfonamide inhibitor (SLC 0111) in Phase I clinical trials for the management of metastatic solid tumors, this review updates the recent findings in the field which may be useful for a structure-based drug design approach of more selective/potent modulators of the activity of these enzymes. PMID- 26619899 TI - Sleep in Children With Autism Spectrum Disorders: How Are Measures of Parent Report and Actigraphy Related and Affected by Sleep Education? AB - Sleep disturbance is common in children with autism, resulting in a great need for effective treatments. To evaluate treatments for sleep disturbance in this population, it is critical to understand the relationship between measures of sleep captured by parent report and objective measures. The Children's Sleep Habits Questionnaire (CSHQ) and actigraphy-measured data from 80 children with autism and sleep-onset delay were evaluated. Reported problems with sleep-onset delay were concurrent with sleep duration problems in 66% of children, night wakings in 72% of children, and bedtime resistance in 66% of children; 38% of children were reported to have problems with all CSHQ insomnia domains. Actigraphy-measured sleep duration was correlated with estimates using CSHQ reported bed and wake times. PMID- 26619900 TI - Improved Chemical Structure-Activity Modeling Through Data Augmentation. AB - Extending the original training data with simulated unobserved data points has proven powerful to increase both the generalization ability of predictive models and their robustness against changes in the structure of data (e.g., systematic drifts in the response variable) in diverse areas such as the analysis of spectroscopic data or the detection of conserved domains in protein sequences. In this contribution, we explore the effect of data augmentation in the predictive power of QSAR models, quantified by the RMSE values on the test set. We collected 8 diverse data sets from the literature and ChEMBL version 19 reporting compound activity as pIC50 values. The original training data were replicated (i.e., augmented) N times (N ? 0, 1, 2, 4, 6, 8, 10), and these replications were perturbed with Gaussian noise (MU = 0, sigma = sigmanoise) on either (i) the pIC50 values, (ii) the compound descriptors, (iii) both the compound descriptors and the pIC50 values, or (iv) none of them. The effect of data augmentation was evaluated across three different algorithms (RF, GBM, and SVM radial) and two descriptor types (Morgan fingerprints and physicochemical-property-based descriptors). The influence of all factor levels was analyzed with a balanced fixed-effect full-factorial experiment. Overall, data augmentation constantly led to increased predictive power on the test set by 10-15%. Injecting noise on (i) compound descriptors or on (ii) both compound descriptors and pIC50 values led to the highest drop of RMSEtest values (from 0.67-0.72 to 0.60-0.63 pIC50 units). The maximum increase in predictive power provided by data augmentation is reached when the training data is replicated one time. Therefore, extending the original training data with one perturbed repetition thereof represents a reasonable trade off between the increased performance of the models and the computational cost of data augmentation, namely increase of (i) model complexity due to the need for optimizing sigmanoise and (ii) the number of training examples. PMID- 26619901 TI - Neurological disorders and celiac disease. AB - Celiac disease (CD) determines neurologic manifestations in 10% of all CD patients. We describe the most common clinical manifestations as cerebellar ataxia, gluten encephalopathy, multiple sclerosis, peripheral neuropathies, sensorineural hearing loss, epilepsy, headache, depression, cognitive deficiencies and other less described clinical conditions. Our aim is to perform, as more as possible, a review about the most recent update on the topics in international literature. It is important to consider clinical neurological manifestations in celiac patients and to research these conditions also in the follow-up because they may start also one year after the start of gluten free diet (GFD) as peripheral neuropathy. The association with autism is analysed and possible new association with non-celiac gluten sensitivity (NCGS) are considered. PMID- 26619902 TI - Personality diatheses and Hurricane Sandy: effects on post-disaster depression. AB - BACKGROUND: According to diathesis-stress models, personality traits, such as negative emotionality (NE) and positive emotionality (PE), may moderate the effects of stressors on the development of depression. However, relatively little empirical research has directly examined whether NE and PE act as diatheses in the presence of stressful life events, and no research has examined whether they moderate the effect of disaster exposure on depressive symptoms. Hurricane Sandy, the second costliest hurricane in US history, offers a unique opportunity to address these gaps. METHOD: A total of 318 women completed measures of NE and PE 5 years prior to Hurricane Sandy. They were also assessed for lifetime depressive disorders on two occasions, the latter occurring an average of 1 year before the hurricane. Approximately 8 weeks after the disaster (mean = 8.40, s.d. = 1.48 weeks), participants completed a hurricane stress exposure questionnaire and a measure of current depressive symptoms. RESULTS: Adjusting for lifetime history of depressive disorders, higher levels of stress from Hurricane Sandy predicted elevated levels of depressive symptoms, but only in participants with high levels of NE or low levels of PE. CONCLUSIONS: These findings support the role of personality in the development of depression and suggest that personality traits can be useful in identifying those most vulnerable to major stressors, including natural disasters. PMID- 26619904 TI - Arginine behaviour after arginine or citrulline administration in older subjects. AB - Arginine (ARG) and its precursor citrulline (CIT) are popular dietary supplements, especially for the elderly. However, age-related reductions in lean body mass and alterations in organ functions could change their bioavailability. Pharmacokinetics and tolerance to amino acid (AA) loads are poorly documented in elderly subjects. The objective here was to characterise the plasma kinetics of CIT and ARG in a single-dosing study design. Eight fasting elderly men underwent two separate isomolar oral loading tests (10 g of CIT or 9.94 g of ARG). Blood was withdrawn over an 8-h period to measure plasma AA concentrations. Only CIT, ornithine and ARG plasma concentrations were changed. Volume of distribution was not dependent on AA administered. Conversely, parameters related to ARG kinetics were strongly dependent on AA administered: after ARG load, elimination was higher (ARG>CIT; P=0.041) and admission period+time at peak concentration was lower (ARG= 18 years old who had undergone >= 1 level of lumbar fusion with available preoperative magnetic resonance imaging scans and at least 1 year of follow-up were included. Axial psoas muscle thickness was measured at each lumbar intervertebral space. Psoas muscle thickness at each vertebral level was compared between patients with and without the occurrence of specific clinical outcomes. RESULTS: There were 257 patients included. The average age was 58.15 years; about 45% of patients were men. Most of the patients underwent a transforaminal interbody fusion surgery (58.4%). The average psoas muscle thickness ranged from 11.49 mm at L1-2 to 36.51 mm at L4-5. Patients with postoperative hip flexor weakness and increased time to ambulation had significantly smaller psoas muscle thickness. Also, patients with >50% improvement in visual analog scale pain score had significantly greater psoas muscle thickness. CONCLUSIONS: This study shows that the psoas muscle can be beneficial in overall postoperative rehabilitation with early ambulation and greater improvement in functional outcomes. Given the role of the psoas muscle in spinal stabilization, the effect of psoas muscle thickness on postoperative functional outcomes warrants further investigation. PMID- 26619921 TI - Erythrodysestesia-like skin eruption due to docetaxel with a nonimmediate positive intradermal skin test result. PMID- 26619922 TI - Cholinergic Urticaria with Anaphylaxis: An Underrecognized Clinical Entity. AB - BACKGROUND: Cholinergic urticaria is a form of physical urticaria triggered by high ambient temperature, strenuous physical activity, and strong emotion. These same triggers may cause multisystem reactions that can be life-threatening. A study of patients with cholinergic urticaria with anaphylaxis was undertaken to describe the demographic and clinical features of this form of anaphylaxis. OBJECTIVE: To describe a cohort of patients with anaphylaxis triggered by high ambient temperature, exertion, and stress. METHODS: Patients from an academic allergy practice in a university teaching hospital were identified by retrospective chart review. RESULTS: A total of 19 patients with recurrent episodes of anaphylaxis due to cholinergic triggers were identified. The female:male ratio was 15:4 (79% females). The mean age of onset was 27.5 years. Patients experienced a mean of 9.41 episodes per year. All 19 patients (100%) reported anaphylaxis triggered by high ambient temperature, 89.5% reported anaphylaxis triggered by strenuous exertion, and 78.9% reported anaphylaxis triggered by stress. Cutaneous involvement was present in 94.7%; 78.9% had upper airway obstructive symptoms, 78.9% had lower airway involvement, 57.9% had gastrointestinal involvement, and 78.9% had cardiovascular manifestations. Anaphylaxis severity scores were grade 1 (mild) in 11.1%, grade 2 (moderate) in 44.4%, and grade 3 (severe) in 44.4%. Baseline tryptase levels were normal in all but 1 patient. CONCLUSIONS: Anaphylaxis due to cholinergic triggers is underreported, with only several case reports in the literature. Reactions are multisystem with cutaneous, upper and lower airway, and cardiovascular involvement in most patients. Manifestations may be life-threatening, and reactions are often severe. PMID- 26619923 TI - Characteristics and Outcomes of HEDIS-Defined Asthma Patients with COPD Diagnostic Coding. AB - BACKGROUND: Little is known of the disease burden of patients with persistent asthma (PA) who also have a chronic obstructive pulmonary disease (COPD) diagnosis code (AS-COPD). OBJECTIVE: The objective of this study was to characterize and compare patients with AS-COPD with those with PA without COPD diagnosis, and determine in AS-COPD the relationship between blood eosinophil count and future asthma exacerbations. METHODS: This retrospective cohort study used administrative pharmacy and health care utilization data to identify, characterize, and compare the burden and asthma exacerbations in adults with AS COPD (N = 901) with those with PA (N = 2392). Negative binomial regression and Poisson regression models were used to evaluate the relationships between baseline blood eosinophil counts (high vs low) based on various cutoff points and asthma exacerbations in the follow-up year, adjusting for demographics, comorbidities, and asthma burden. RESULTS: Compared with patients with PA, those with AS-COPD were significantly (all P < .001) older, more frequently female, less well educated, more likely to be or have been a smoker, had more comorbidities, received more asthma controller medications, and had greater rates and frequencies of asthma exacerbations, but had similar blood eosinophil counts. The rate of asthma exacerbations/person-year in AS-COPD during follow-up was 1.61 (95% CI, 1.18-2.20). Patients with AS-COPD with a blood eosinophil count >=400 cells/mm(3) had an increased rate of future asthma exacerbations compared with those whose blood eosinophil count was <400 cells/mm(3) (adjusted rate ratio, 1.44, 95% CI, 1.09-1.90). CONCLUSIONS: Compared with patients with PA, those with AS-COPD had more disease burden, but a similar relationship of high blood eosinophil count to more future asthma exacerbations. These findings suggest a common inflammatory component between AS-COPD and PA. PMID- 26619925 TI - Deep molecular divergence and exceptional morphological stasis in dwarf cannibal snails Nata sensu lato Watson, 1934 (Rhytididae) of southern Africa. AB - The genus Nata Watson, 1934 is a southern African endemic belonging to the Gondwanan family of carnivorous snails, Rhytididae. We present a molecular phylogeny of the genus based on two mitochondrial (16S and COI) and two nuclear genes (ITS2 and 28S RNA), and complement this with an appraisal of morphological characters relating to both the shell and soft parts. We identify four reciprocally monophyletic lineages for which valid names are already available, plus two undescribed species restricted to the Albany Thicket Biome. We show that Nata sensu lato may not be monophyletic. Rather there exist two deep lineages within Nata s.l., one lineage potentially sister to a clade dominated by the Australian and New Zealand radiation, and the other occupying a basal position within Rhytididae. Accordingly we recommend a revision recognising two genera, namely Nata s.s. and Natella respectively. Despite deep molecular divergences within Nata s.s., phenotypic evolution has been remarkably conserved, and contrasts greatly with that exhibited across other major lineages within the Rhytididae. PMID- 26619924 TI - Distribution and dynamics of electron transport complexes in cyanobacterial thylakoid membranes. AB - The cyanobacterial thylakoid membrane represents a system that can carry out both oxygenic photosynthesis and respiration simultaneously. The organization, interactions and mobility of components of these two electron transport pathways are indispensable to the biosynthesis of thylakoid membrane modules and the optimization of bioenergetic electron flow in response to environmental changes. These are of fundamental importance to the metabolic robustness and plasticity of cyanobacteria. This review summarizes our current knowledge about the distribution and dynamics of electron transport components in cyanobacterial thylakoid membranes. Global understanding of the principles that govern the dynamic regulation of electron transport pathways in nature will provide a framework for the design and synthetic engineering of new bioenergetic machinery to improve photosynthesis and biofuel production. This article is part of a Special Issue entitled: Organization and dynamics of bioenergetic systems in bacteria, edited by Conrad Mullineaux. PMID- 26619926 TI - [Anti-pneumococcal vaccine coverage for hospitalized risk patients: Assessment and suggestions for improvements]. AB - Streptococcus pneumoniae can cause invasive infections. Incidence and severity are linked to patients' risk factors. Due to the resistance to leading antibiotics, the anti-pneumococcal vaccination has become a major public health issue. The purpose of this survey was to evaluate the anti-pneumococcal vaccine coverage in a population of adults with risk factors. This was a prospective study that included patients with at least one recommendation for pneumococcal vaccination as indicated by the Weekly Epidemiological Bulletin (BEH), to which three further US recommendations were added (diabetes, obesity and age>65years). One hundred and thirty-four patients with an average age of 70 years were included. The physician could only confirm 68 % of the patients' vaccination status. Vaccination coverage as recommended by the BEH board was 30 % (n=54). All HIV patients were vaccinated (n=2) and the vaccination coverage was 75 % (n=8) for patients treated for autoimmune diseases and only 10 % (n=20) for patients treated with chemotherapy. Patients with no vaccination didn't know the existence of the vaccine or didn't know that vaccination was recommended to them. This study has highlighted a deficit in pneumococcal vaccination coverage and a high level of ignorance of the existence of recommended vaccination. In addition to awareness campaign for patients and caregiver training, the expansion of the vaccine e-book utilization could improve the vaccination status. PMID- 26619927 TI - Prognostic value of Ki-67 in solid pseudopapillary tumor of the pancreas: Huashan experience and systematic review of the literature. AB - BACKGROUND: Solid pseudopapillary tumor of the pancreas (SPTP) is considered to have a low Ki-67 proliferation index, which may explain the generally good clinical outcome. The aim of our study was to evaluate whether Ki-67 has prognostic value in SPTP. METHODS: A case series study of patients with SPTP treated in our institution from June 2002 to April 2014 was conducted. Prognostic factors for clinical outcomes were analyzed by the use of clinical decision and survival analysis. In addition, we performed a systematic review and pooled analysis to evaluate our results. RESULTS: The institutional data included 71 patients (13 male and 58 female) ranging in age from 12 to 64 years (median, 31 years). Three patients developed local recurrence and/or liver metastasis after initial surgery. The 5-year recurrence-free survival rate was 93.6%. One patient died of disease, with the 5-year disease-specific survival rate of 98.5%. Ki-67 index >= 4% was found significantly associated with the survival of SPTP. Twenty six studies comprising 163 patients were included in the pooled analysis based on our inclusion criteria. A total of 15 cases showed a Ki-67 index >= 4%. Kaplan Meier survival analysis confirmed that Ki-67 index >= 4% was significantly associated with poorer recurrence-free survival and disease-specific survival (both P < .001). CONCLUSION: This study highlighted a potential role of Ki-67 in predicting adverse outcome of patients with SPTP and should be considered as part of routine histological reporting of SPTP. PMID- 26619928 TI - Donor gluconate rescues livers from uncontrolled donation after cardiac death. AB - BACKGROUND: Ischemia from organ preservation or donation causes cells and tissues to swell owing to loss of energy-dependent mechanisms of control of cell volume. These volume changes cause substantial preservation injury, because preventing these changes by adding cell impermeants to preservation solutions decreases preservation injury. The objective of this study was to assess if this effect could be realized early in uncontrolled donation after cardiac death (DCD) livers by systemically loading donors with gluconate immediately after death to prevent accelerated swelling injury during the warm ischemia period before liver retrieval. METHODS: Uncontrolled DCD rat livers were cold-stored in University of Wisconsin solution for 24 hours and reperfused on an isolated perfused liver (IPL) device for 2 hours or transplanted into a rat as an allograft for 7 days. Donors were pretreated with a solution of the impermeant gluconate or a saline control immediately after cardiac death. Livers were retrieved after 30 minutes. RESULTS: In vivo, gluconate infusion in donors immediately before or after cardiac death prevented DCD-induced increases in total tissue water, decreased vascular resistance, increased oxygen consumption and synthesis of adenosine triphosphate, increased bile production, decreased lactate dehydrogenase release, and decreased histology injury scores after reperfusion on the IPL relative to saline-treated DCD controls. In the transplant model, donor gluconate pretreatment significantly decreased both alanine aminotransferase the first day after transplantation and total bilirubin the seventh day after transplantation. CONCLUSION: Cell and tissue swelling plays a key role in preservation injury of uncontrolled DCD livers, which can be mitigated by early administration of gluconate solutions to the donor immediately after death. PMID- 26619929 TI - The accuracy of MRI, endorectal ultrasonography, and computed tomography in predicting the response of locally advanced rectal cancer after preoperative therapy: A metaanalysis. AB - BACKGROUND: To perform a metaanalysis to determine and compare the diagnostic performance of MRI, endorectal ultrasonography (ERUS), and computed tomography (CT) in predicting the response of locally advanced rectal cancer after preoperative therapy. METHODS: All previously published articles on the role of MRI, CT, and/or ERUS in predicting the response of rectal cancer to preoperative therapy were collected. We divided the objective in 3 parts: the accuracy to assess (i) complete response, (ii) to detect T4 tumors with invasion to the circumferential resection margin (CRM), and (iii) to predict the presence of lymph node metastasis. The pooled estimates of, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated using a bivariate mixed effect analysis. RESULTS: Forty-six studies comprising 2,224 patients were included. (i) The pooled accuracy to assess complete tumor response were (a) 75% for MRI, (b) 82% for ERUS, (c) and 83% for CT. (ii) Pooled accuracy to detect T4 tumors with invasion to the CRM were (a) 88% and (b) 94% for ERUS. (iii) Pooled accuracy to predict the presence of lymph node metastasis was (a) 72% for MRI, (b) 72% for ERUS, (c) and 65% for CT. CONCLUSION: MRI, CT, and ERUS cannot be used to predict complete response of locally advanced rectal cancer after CRT. In addition, the positive predictive value for these imaging techniques is low for the assessment of tumor invasion in the CRM. The accuracy of the modalities to predict the presence of metastatic lymph node disease is also low. PMID- 26619931 TI - [Critically ill pediatric hemato-oncology patient: What we do is what we should do?]. AB - OBJECTIVE: Primary objective, to describe the management and monitorization of critically ill pediatric hemato-oncology patient (CIPHO) in the Spanish pediatric intensive care units (PICU). Secondary objective, through a literature review, to identify possible areas of improvement. MATERIAL AND METHODS: Observational transversal descriptive study. An anonymous web-based survey was sent to 324 Spanish pediatric intensivists from April 2011 to May 2011. None of them were pediatric residents. RESULTS: The survey was answered by 105 intensivists, 59/105 always agreed their treatment with the oncologist. In case of hemodynamic instability, non-invasive blood pressure monitoring is always done by 85/105 and almost always optimized by intra-arterial measuring (85/105) and central venous pressure (70/105). If respiratory failure the use of non-invasive ventilation (NIPPV) is always (36/105) or frequently (60/105) established prior to conventional mechanical ventilation. To replace or withdraw non-invasive ventilation only 44/96 of the respondents to this question use a clinical protocol. Before the instauration of conventional mechanical ventilation the oncological prognosis is considered by 72/105. In case of acute oliguric renal failure the renal replacement techniques are widely used (74/105). The withdrawal of sustaining life support is frequently discussed (75/103) and agreed with the oncologist (91/103) and caregivers (81/103). CONCLUSIONS: In our study, despite there is not a defined standard-of-care, the respondents showed similar therapeutics and monitorization choices. The use of NIPPV as first respiratory assistance is extended. Prospective, observational and multicenter studies should be developed to establish the results of this management in this population. PMID- 26619932 TI - Girls' physical activity and sedentary behaviors: Does sexual maturation matter? A cross-sectional study with HBSC 2010 Portuguese survey. AB - OBJECTIVES: The purpose of this study was to examine the relationship between girls' sexual maturation (age of menarche) and physical activity and sedentary behaviors. METHODS: Data were collected from a national representative sample of girls in 2010 (pre-menarcheal girls n = 583, post-menarcheal girls n = 741). Physical activity (times/week and hours/week) and screen-based sedentary time (minutes/day) including television/video/DVD watching, playing videogames, and computer use were self-reported. RESULTS: Pre-menarcheal girls engaged significantly more times in physical activity in the last 7 days than post menarcheal girls (3.5 +/- 1.9 times/week vs. 3.0 +/- 1.7 times/week, P < 0.001). There was no significant difference between pre-menarcheal and post-menarcheal girls in time (hours/week) spent in physical activity. Post-menarcheal girls spent significantly more minutes per day than pre-menarcheal girls watching TV, playing videogames, and using computers on weekdays (TV: 165.2 +/- 105.8 vs. 136.0 +/- 106.3, P < 0.001; videogames 72.0 +/- 84.8 vs. 60.3 +/- 78.9, P = 0.015; computer: 123.3 +/- 103.9 vs. 82.8 +/- 95.8, P < 0.001) and on weekends (TV: 249.0 +/- 116.2 vs. 209.3 +/- 124.8, P < 0.001; videogames: 123.0 +/- 114.0 vs. 104.7 +/- 103.5, P = 0.020; computer: 177.0 +/- 122.2 vs. 119.7 +/- 112.7, P < 0.001). After adjusting analyses for age, BMI, and socioeconomic status, differences were still significant for physical activity and for computer use. CONCLUSION: Specific interventions should be designed for girls to increase their physical activity participation and decrease time spent on the computer, for post menarcheal girls in particular. Am. J. Hum. Biol. 28:471-475, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26619933 TI - A global, comprehensive review of literature related to paper recycling: A pressing need for a uniform system of terms and definitions. AB - A global, comprehensive review of terms and definitions related to paper recycling was conducted in this article. Terms and definitions related to paper recycling have varied in the course of time. Different terms and different definitions for the same thing are being used in different geographical regions and by different organizations. Definitions are different based on varying conceptions of waste paper as a raw material. Definitions of how to make various calculations related to paper recycling activity are inconsistent. Even such fundamental basic definitions like how to calculate recycling rate and paper consumption are not uniform. It could be concluded that there is no uniform system of terms and definitions related to paper recycling and the implications of this deficiency are profound. For example, it is difficult to reliably compare with each other statistics from different times and from different geographical regions. It is not possible to measure if targets for recycling activities are met if the terms describing the targets are not uniformly defined. In cases of reporting data for recycling targets, the lack of uniform terminology can, for example, impede the necessary transparency between different stakeholders and may allow for deception. The authors conclude there is a pressing need to develop a uniform system of terms and definition for terms related to paper recycling. PMID- 26619934 TI - Windrow composting as horticultural waste management strategy - A case study in Ecuador. AB - In Ecuador, enormous quantities of vegetable wastes are produced annually from the horticultural industries. Composting can be a feasible treatment to stabilise horticultural wastes and, thus, to improve their properties for use as organic fertilisers. In this study, two different piles were prepared, using laying hen manure and sawdust mixed with broccoli or tomato waste, respectively, and composted by the turned windrow composting system. Throughout the composting process, the temperature of the mixtures was monitored and physico-chemical and chemical properties and the degree of maturity were determined. Also, principal component analysis was used to interpret the data set of compost characteristics. In both piles, the temperature exceeded 55 degrees C for more than 2weeks, which ensured maximum pathogen reduction. Organic matter (OM) losses followed a first order kinetic equation in both piles. The final composts showed a suitable degree of stability and maturity and an absence of phytotoxins, as observed in the evolution and final values of the total organic carbon/total nitrogen ratio (Corg/NT<20), water-soluble organic carbon (Cw<1.7%), germination index (GI>50%) and cation exchange capacity (CEC>67meq (100g OM)(-1)). As well, the evolution of different humification indexes during composting was a good indicator of the OM humification process. The type of vegetable waste used influenced OM and NT mineralisation and the final properties of the composts, showing the mixture with tomato waste a higher fertilising capacity and less environmental problems. PMID- 26619935 TI - A sweet spot for highly efficient growth of vertically aligned single-walled carbon nanotube forests enabling their unique structures and properties. AB - We investigated the correlation between growth efficiency and structural parameters of single-walled carbon nanotube (SWCNT) forests and report the existence of a SWCNT "sweet spot" in the CNT diameter and spacing domain for highly efficient synthesis. Only within this region could SWCNTs be grown efficiently. Through the investigation of the growth rates for ~340 CNT forests spanning diameters from 1.3 to 8.0 nm and average spacing from 5 to 80 nm, this "sweet spot" was found to exist because highly efficient growth was constrained by several mechanistic boundaries that either hindered the formation or reduced the growth rate of SWCNT forests. Specifically, with increased diameter SWCNTs transitioned to multiwalled CNTs (multiwall border), small diameter SWCNTs could only be grown at low growth rates (low efficiency border), sparse SWCNTs lacked the requirements to vertically align (lateral growth border), and high density catalysts could not be prepared (high catalyst density border). As a result, the SWCNTs synthesized within this "sweet spot" possessed a unique set of characteristics vital for the development applications, such as large diameter, long, aligned, defective, and high specific surface area. PMID- 26619936 TI - Synthesis, crystal structure and magnetic properties of a new copper oxo-antimony sulphate CuSb6O8(SO4)2. AB - The new copper oxo-antimony sulphate CuSb6O8(SO4)2 crystallizes in the triclinic space group P1[combining macron] with the unit cell parameters a = 5.5342(4) A, b = 7.6706(6) A, c = 9.2374(7) A, alpha = 96.505(5) degrees , beta = 93.818(4) degrees , gamma = 109.733(4) degrees and Z = 1. The crystal structure is made up of layers stacking along [001]. The layers are charge neutral and are connected to each other by only weak interactions. The copper atoms adopt a square planar [CuO4] coordination and such units are well separated from each other by corner and edge sharing to [SbO4] building blocks. The latter polymerize to form sheets with the formula [Sb3O8]infinity. Sulphate groups connect to the antimony oxide sheets by corner sharing and are located at the interface of the layers. Above ~10 K the magnetic susceptibility follows very well a Curie-Weiss law whereas below 10 K increasing deviations indicate the onset of antiferromagnetic correlations. Fitting the data in the range 10-50 K yields a Curie-Weiss temperature theta of -2.25(5) K. A sharp anomaly centered at TC = 0.67 K in the heat capacity data indicates long-range magnetic ordering. Short range antiferromagnetic correlations well above TC are seen in the magnetic contribution to the heat capacity and the magnetic susceptibility. These can be well described by the magnetism of a spin S = 1/2 Heisenberg chain with the nearest neighbor antiferromagnetic spin exchange interaction of Jintra = ~2.8 K. PMID- 26619938 TI - Finite-time stability for discrete-time system with time-varying delay and nonlinear perturbations. AB - In this paper, the problem of finite-time stability for discrete-time system with time-varying delay and nonlinear perturbations is investigated. By constructing a novel Lyapunov-Krasovskii functional and employing a new summation inequality named discrete Wirtinger-based inequality, reciprocally convex approach and zero equality, the improved finite-time stability criteria are derived to guarantee that the state of the system with time-varying delay does not exceed a given threshold when fixed time interval. Furthermore, the obtained conditions are formulated in forms of linear matrix inequalities which can be solved by using some standard numerical packages. Finally, three numerical examples are given to show the effectiveness and less conservatism of the proposed method. PMID- 26619939 TI - Multivariable control of the bifurcation and harmonic perturbations to improve the performance of air-handling units. AB - In this research, nonlinear dynamics of an air-ehandling unit (AHU) is studied for tracking objectives, in the presence of harmonic perturbations. Three arbitrary realistic set-paths are considered for the indoor temperature and relative humidity. Two controllers based on feedback linearization (FBL) and pole placement approaches are designed to preserve the dynamic system around the desired tracking paths. It is shown that FBL controller works efficiently in bifurcation control and transforms the quasi-periodic limit cycles into the periodic ones (and consequently comfortable indoor conditions). In addition, FBL controller guarantees suppression of larger periodic limit cycles into the smaller ones, while it requires the lower air and cold water flow rates with less oscillatory behavior (in comparison with the pole-placement controller). However, it is observed that FBL controller fails in bifurcation control when the disturbance frequency increases. Re-tuning the dynamic gains of FBL controller is essential under such conditions. PMID- 26619937 TI - Glucocorticoid receptor and nuclear factor kappa-b affect three-dimensional chromatin organization. AB - BACKGROUND: The impact of signal-dependent transcription factors, such as glucocorticoid receptor and nuclear factor kappa-b, on the three-dimensional organization of chromatin remains a topic of discussion. The possible scenarios range from remodeling of higher order chromatin architecture by activated transcription factors to recruitment of activated transcription factors to pre established long-range interactions. RESULTS: Using circular chromosome conformation capture coupled with next generation sequencing and high-resolution chromatin interaction analysis by paired-end tag sequencing of P300, we observed agonist-induced changes in long-range chromatin interactions, and uncovered interconnected enhancer-enhancer hubs spanning up to one megabase. The vast majority of activated glucocorticoid receptor and nuclear factor kappa-b appeared to join pre-existing P300 enhancer hubs without affecting the chromatin conformation. In contrast, binding of the activated transcription factors to loci with their consensus response elements led to the increased formation of an active epigenetic state of enhancers and a significant increase in long-range interactions within pre-existing enhancer networks. De novo enhancers or ligand responsive enhancer hubs preferentially interacted with ligand-induced genes. CONCLUSIONS: We demonstrate that, at a subset of genomic loci, ligand-mediated induction leads to active enhancer formation and an increase in long-range interactions, facilitating efficient regulation of target genes. Therefore, our data suggest an active role of signal-dependent transcription factors in chromatin and long-range interaction remodeling. PMID- 26619940 TI - The higher order auditory cortex is involved in the assignment of affective value to sensory stimuli. AB - The sensory cortex participates in emotional memory but its role is poorly understood. Here we show that inactivation of the higher order auditory cortex Te2 in rats during early memory consolidation impairs remote first- and second order fear memories but not the association between two neutral cues. Furthermore, Te2 inactivation prevents changes in the valence of such information. Following the presentation of two auditory cues previously paired with either pleasant or painful stimuli, a large percentage of cells responds to both experiences but also a small fraction of neurons responds exclusively to one of them. The latter type of neurons signals the valence rather than the salience or the motor responses associated with the stimuli, and reflects selective associative processes. Pharmacogenetic silencing of memory-activated neurons causes amnesia. Thus, Te2 represents a crucial node for the assignment of the affective value to sensory stimuli and for the storage of such information. PMID- 26619941 TI - Role of NO-cGMP pathway in ovine cervical relaxation induced by Erythroxylum caatingae Plowman. AB - Erythroxylum caatingae Plowman has a myorelaxing effect on smooth muscle tissue. We investigated the effect of the crude ethanolic extract of E. caatingae Plowman (Ec-EtOH) on the contractility of the ovine cervix. In an isometric system, circular strips were subjected to 90mM potassium (K(+)) or 30MUM carbamylcholine (CCh)-induced contraction. We then exposed the tissue to cumulative concentrations of Ec-EtOH (1-729 MUg/ml). In other bath solutions, the tissues were exposed to l-NG-nitroarginine methyl ester (l-NAME; 100MUM), l-NAME (100MUM)+l-arginine (300MUM), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ; 5MUM), 4-aminopyridine (4-AP; 3mM), tetraethylammonium (TEA; 0.3mM), glybenclamide (1MUM), atosiban (10MUM) or verapamil (3MUM), followed by the addition of Ec-EtOH (1-729 MUg/ml). We also evaluated the effect of cervical Ec EtOH infusion (2mg) on cervical contractility in vivo. Ec-EtOH decreased cervical contractility induced by K(+) or CCh, and 729 MUg/ml Ec-EtOH decreased 85.4+/ 5.1% the amplitude of basal contractility in vitro, with an EC50 of 17.9+/-3.7 MUg/ml. This effect of Ec-EtOH was prevented by l-NAME or ODQ. l-arginine impaired the blunting effect of l-NAME on cervical relaxation caused by Ec-EtOH. However, the potassium channel blockers 4-AP, TEA, and glybenclamide did not modify this myorelaxation triggered by Ec-EtOH. Ec-EtOH also decreased acetylcholine-induced contractions in tissue preincubated with verapamil. In addition, Ec-EtOH decreased ovine cervical contractions in vivo. Thus, Ec-EtOH had a relaxant effect on ovine cervical contractions. This may involve the nitric oxide signal, mediated by cGMP cellular transduction, and be related to intracellular calcium sequestration. PMID- 26619942 TI - Enriching membrane cholesterol improves stability and cryosurvival of buffalo spermatozoa. AB - Buffalo spermatozoa are comparatively more susceptible to freezing hazards than cattle spermatozoa. In recent times incubation of spermatozoa with cholesterol loaded-cyclodextrins (CLC) has shown improvements in semen quality in several species. Therefore, this study was undertaken to evaluate the incubation level of CLC at which maximum benefit is derived for the buffalo spermatozoa. For the study, 120 million spermatozoa were incubated in 2, 3 and 4 mg/mL of CLC (Gr II, III and IV, respectively) and cholesterol and phospholipids content, their ratio, flow cytometric evaluation of plasma membrane integrity (PMI), plasma membrane fluidity and extent of cryoinjury (Chlortetracycline, CTC assay) were compared with an untreated control (Gr I). Additionally the ability of cholesterol-loaded spermatozoa to undergo induced acrosome reaction (IAR) using ionophore calcium (A23187) was evaluated in frozen-thaw samples. Data show a significant and linear increase (CV=0.88) in cholesterol content of spermatozoa in Gr II, III and IV and a significant decrease in phospholipids content at frozen-thaw stage in Gr IV than Gr III spermatozoa. The study revealed a significant improvement in PMI and significant reduction in plasma membrane fluidity and cryoinjury of CLC treated spermatozoa at progressive stages in three groups compared to control. Nevertheless, spermatozoa of Gr II, III and IV were significantly less responsive to ionophore calcium (A23187) than Gr I. This study shows for the first time that incubation of buffalo bull spermatozoa with CLC (3mg/120*10(6)) prior to processing permits greater numbers of sperm to survive cryopreservation while allowing spermatozoa to capacitate and the acrosome to react to AR inducer ionophore calcium (A23187). PMID- 26619943 TI - Analysing the nutrition-disease nexus: the case of malaria. AB - BACKGROUND: Motivated by the observation that children suffering from undernutrition are more likely to experience disease and are more likely to die if they do contract a disease, mathematical modelling is used to explore the ramifications of targeting preventive disease measures to undernutritioned children. METHODS: A malaria model is constructed with superinfection and heterogeneous susceptibility, where a portion of this susceptibility is due to undernutrition (as measured by weight-for-age z scores); so as to isolate the impact of supplementary food on malaria from the influence of confounding factors, the portion of the total susceptibility that is due to undernutrition is estimated from a large randomized trial of supplementary feeding. Logistic regression is used to estimate mortality given malaria infection as a function of weight-for-age z scores. The clinical malaria morbidity and malaria mortality are analytically computed for a variety of policies involving supplementary food and insecticide-treated bed nets. RESULTS: The portion of heterogeneity in susceptibility that is due to undernutrition is estimated to be 90.3 %. Targeting insecticide-treated bed nets to undernutritioned children leads to fewer malaria deaths than the random distribution of bed nets in the hypoendemic and mesoendemic settings. When baseline bed net coverage for children is 20 %, supplementary food given to underweight children is estimated to reduce malaria mortality by 7.2-22.9 % as the entomological inoculation rate ranges from 500 to 1.0. In the hyperendemic setting, supplementary food has a bigger impact than bed nets, particularly when baseline bed net coverage is high. CONCLUSIONS: Although the results are speculative (e.g., they are based on parameter estimates that do not possess the traditional statistical significance level), the biological plausibility of the modelling assumptions and the high price-sensitivity of demand for bed nets suggest that free bed net distribution targeted to undernutritioned children in areas suffering from both undernutrition and malaria (e.g., sub-Saharan Africa) should be the subject of a randomized trial in a hypoendemic or mesoendemic setting. PMID- 26619944 TI - Reclassification of Eubacterium rectale (Hauduroy et al. 1937) Prevot 1938 in a new genus Agathobacter gen. nov. as Agathobacter rectalis comb. nov., and description of Agathobacter ruminis sp. nov., isolated from the rumen contents of sheep and cows. AB - Three strains of a butyrate-producing bacterium were isolated from the rumen contents of grazing sheep and cows. The strains were anaerobic, with Gram positive cell walls, straight-to-slightly-curved, rod-shaped, non-spore-forming and single flagellate. C14 : 1, C14 : 0, C16 : 0 and C16 : 1 were the predominant fatty acids. The cell-wall peptidoglycan type was A1gamma. The DNA G+C content varied from 41.4 to 42.2 mol%. 16S rRNA gene sequence similarities between the isolates and Eubacterium rectale, Roseburia hominis and Roseburia intestinalis were found to be 96, 95 and 95 %, respectively. The phylogenetic tree showed that the strains constituted a different taxon, separate from other taxa with validly published names and forming a cluster with strains of Eubacterium rectale. On the basis of phenotypic, chemotaxonomic and phylogenetic results (16S RNA, dnaK, groEL, atpA genes), the isolates are considered to represent a novel species of a new genus of the family Lachnospiraceae, for which the name Agathobacter ruminis gen. nov., sp. nov. is proposed (type strain JK623T = DSM 29029T = LMG 28559T). We also propose the transfer of Eubacterium rectale to the new genus as Agathobacter rectalis gen. nov., comb nov. This new genus represents saccharoclastic, chemo-organotrophic and obligatory anaerobic, non-spore-forming rods with Gram-positive membrane. The main fermentation products on peptone yeast glucose (PYG) medium were butyrate, acetate, hydrogen and lactate. The type species of the genus is Agathobacter rectalis gen. nov., comb nov. (Prevot, 1938) with type strain ATCC 33656T ( = JCM 17463T). PMID- 26619945 TI - Complexity of Heart Rate Variability Can Predict Stroke-In-Evolution in Acute Ischemic Stroke Patients. AB - About one-third of acute stroke patients may experience stroke-in-evolution, which is often associated with a worse outcome. Recently, we showed that multiscale entropy (MSE), a non-linear method for analysis of heart rate variability (HRV), is an early outcome predictor in non-atrial fibrillation (non AF) stroke patients. We aimed to further investigate MSE as a predictor of SIE. We included 90 non-AF ischemic stroke patients admitted to the intensive care unit (ICU). Nineteen (21.1%) patients met the criteria of SIE, which was defined as an increase in the National Institutes of Health Stroke Scale score of >=2 points within 3 days of admission. The MSE of HRV was analyzed from 1-hour continuous ECG signals during the first 24 hours of admission. The complexity index was defined as the area under the MSE curve. Compared with patients without SIE, those with SIE had a significantly lower complexity index value (21.3 +/- 8.5 vs 26.5 +/- 7.7, P = 0.012). After adjustment for clinical variables, patients with higher complexity index values were significantly less likely to have SIE (odds ratio = 0.897, 95% confidence interval 0.818-0.983, P = 0.020). In summary, early assessment of HRV by MSE can be a potential predictor of SIE in ICU-admitted non-AF ischemic stroke patients. PMID- 26619947 TI - Risk factors and acute in-hospital costs for infected pressure ulcers among gunshot-spinal cord injury victims in southeastern Michigan. AB - BACKGROUND: Management of pressure ulcers (PrUs) in patients with gunshot-spinal cord injuries (SCIs) presents unique medical and economic challenges for practitioners. METHODS: A retrospective chart review was conducted at 3 acute care hospitals in metropolitan Detroit for patients admitted with PrUs due to gunshot-SCIs between January 2004 and December 2008. Multivariate analysis using logistic regression was conducted to choose for the independent predictors of infected PrUs. Mean adjusted in-hospital costs per patient and per hospitalization were calculated and compared between infected and noninfected PrUs. RESULTS: The study cohort included 201 gunshot-SCI patients with PrUs contributing to 395 admissions, including readmissions, between 2004 and 2008. Seventy-six patients (38%) had infected PrUs at time of the index admission. Independent predictors of infected PrUs on index admission included Charlson Comorbidity Index >=2 (odds ratio, 2.18, P = .026) and stage III/IV PrU (odds ratio, 4.82; P <.0001). During the study period, the cumulative median duration of hospitalization per patient was 12 days (interquartile range, 6-24 days), resulting in a mean adjusted cost of $19,969 +/- $6639 per patient. The mean adjusted cost per hospitalization for patients with infected PrUs was significantly higher than that for patients with noninfected PrUs ($16,735 +/- $8310 vs $12,356 +/- $7007; P <.001). CONCLUSIONS: A multidisciplinary approach including home-based rehabilitation programs and SCI wound clinics might help prevent PrUs and their complications and reduce associated costs. PMID- 26619948 TI - Novel highly specific anti-periostin antibodies uncover the functional importance of the fascilin 1-1 domain and highlight preferential expression of periostin in aggressive breast cancer. AB - Periostin (POSTN), a secreted homodimeric protein that binds integrins alphavbeta3, alphavbeta5, and alpha6beta4, was originally found to be expressed in fetal tissues and in the adult upon injury particularly bone fractures due to its role in remodelling and repair. Recently it was found to be over-expressed in human breast cancer and a variety of other tumour types including head and neck squamous cell carcinoma, where its overexpression correlates with increased tumour invasion. Progress in studying its functional role in tumour pathogenesis has been hampered by the paucity of antibodies for its specific and sensitive detection. It has proven very difficult to obtain monoclonal antibodies (mAbs) against this highly conserved protein but we report here that combining infection of mice with lactate dehydrogenase elevating virus (LDV), a B cell activating arterivirus, with conjugation of human POSTN to ovalbumin as an immunogenic carrier, enabled us to develop six mAbs recognizing both human and mouse POSTN and inhibiting its binding to alphavbeta3 integrin. Two of the mAbs, MPB4B1 and MPC5B4, were tested and found to inhibit POSTN-induced migration of human endothelial colony forming cells. All six mAbs recognized amino acids 136-51 (APSNEAWDNLDSDIRR) within the POSTN fascilin (FAS) 1-1 domain revealing the functional importance of this motif; this was further highlighted by the ability of aa 136-151 peptide to inhibit integrin-mediated cell migration. Immunohistochemistry using MPC5B4, indicated that breast tumour cell POSTN expression was a strong prognostic indicator, along with tumour size, lymph node, and human epidermal growth factor receptor 2 (HER2) status. PMID- 26619949 TI - The quality of denominator data in surgical site infection surveillance versus administrative data in Norway 2005-2010. AB - BACKGROUND: High quality of surveillance systems for surgical site infections (SSIs) is the key to their usefulness. The Norwegian Surveillance System for Antibiotic Consumption and Healthcare-Associated Infections (NOIS) was introduced by regulation in 2005, and is based largely on automated extraction of data from underlying systems in the hospitals. METHODS: This study investigates the quality of NOIS-SSI's denominator data by evaluating completeness, representativeness and accuracy compared with de-identified administrative data for 2005-2010. Comparisons were made by region, hospital type and size, age and sex for 4 surgical procedures. RESULTS: The completeness of NOIS improved from 29.2 % in 2005 to 79.8 % in 2010. NOIS-SSI became representative over time for most procedures by hospital size and type, but not by region. It was representative by age and sex for all years and procedures. Accuracy was good for all years and procedures by all explanatory variables. CONCLUSIONS: A flexible and incremental implementation strategy has encouraged the development of computer-based surveillance systems in the hospitals which gives good accuracy, but the same strategy has adversely affected the completeness and representativeness of the denominator data. For the purpose of evaluating risk factors and implementing prevention and precautionary measures in the individual hospitals, representativeness seems sufficient, but for benchmarking and/or public reporting it is not good enough. PMID- 26619946 TI - Future perspectives in melanoma research: meeting report from the "Melanoma Bridge": Napoli, December 3rd-6th 2014. AB - The fourth "Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma. PMID- 26619951 TI - Pro: Antifibrinolytics Should Be Used in Routine Cardiac Cases Using Cardiopulmonary Bypass (Unless Contraindicated). PMID- 26619950 TI - Development of Alendronate-conjugated Poly (lactic-co-glycolic acid)-Dextran Nanoparticles for Active Targeting of Cisplatin in Osteosarcoma. AB - In this study, we developed a novel poly (lactic-co-glycolic acid)-dextran (PLD) based nanodelivery system to enhance the anticancer potential of cisplatin (CDDP) in osteosarcoma cells. A nanosized CDDP-loaded PLGA-DX nanoparticle (PLD/CDDP) controlled the release rate of CDDP up to 48 h. In vitro cytotoxicity assay showed a superior anticancer effect for PLD/CDDP and with an appreciable cellular uptake via endocytosis-mediated pathways. PLD/CDDP exhibited significant apoptosis of MG63 cancer cells compared to that of free CDDP. Approximately ~25% of cells were in early apoptosis phase after PLD/CDDP treatment comparing to ~15% for free CDDP after 48h incubation. Similarly, PLD/CDDP exhibited ~30% of late apoptosis cells comparing to only ~8% for free drug treatment. PLD/CDDP exhibited significantly higher G2/M phase arrest in MG63 cells than compared to free CDDP with a nearly 2-fold higher arrest in case of PLD/CDDP treated group (~60%). Importantly, PLD/CDDP exhibited a most significant anti-tumor activity with maximum tumor growth inhibition. The superior inhibitory effect was further confirmed by a marked reduction in the number of CD31 stained tumor blood vessels and decrease in the Ki67 staining intensity for PLD/CDDP treated animal group. Overall, CDDP formulations could provide a promising and most effective platform in the treatment of osteosarcoma. PMID- 26619952 TI - Acute, Severe Chest Pain in the Presence of Known Coronary Artery Disease: New Myocardial Ischemia, Aortic Dissection, or Some Other Evolving Cardiovascular Catastrophe? PMID- 26619953 TI - Chemotherapy Agents With Known Pulmonary Side Effects and Their Anesthetic and Critical Care Implications. PMID- 26619954 TI - A Rare Cause of Cyanosis in a Neonate. PMID- 26619955 TI - The Hypoglycemic and Synergistic Effect of Loganin, Morroniside, and Ursolic Acid Isolated from the Fruits of Cornus officinalis. AB - Hypoglycemic activity-guided separation of ethanol extracts from the fruits of Cornus officinalis Sieb. et Zucc (CO) led to the isolation of loganin, morroniside, and ursolic acid. The antidiabetic capacity of CO extracts and related compounds was further investigated in diabetes mellitus mice. The results suggested that both CO extracts and pure compounds could ameliorate diabetes associated damages and complications. Oral administration of loganin and morroniside decreased fasting blood glucose levels in diabetes mellitus mice. Ursolic acid exhibited the highest reactive oxygen species scavenging activity and alpha-glucosidase inhibitory activity. Notably, we noticed an interesting synergistic effect between loganin and ursolic acid. Given these favorable hypoglycemic properties, C. officinalis, a food and medicinal plant in China, may be used as a valuable food supplement for the treatment of diabetes mellitus. PMID- 26619956 TI - Planting seeds for the future of food. AB - The health and wellbeing of future generations will depend on humankind's ability to deliver sufficient nutritious food to a world population in excess of 9 billion. Feeding this many people by 2050 will require science-based solutions that address sustainable agricultural productivity and enable healthful dietary patterns in a more globally equitable way. This topic was the focus of a multi disciplinary international conference hosted by Nestle in June 2015, and provides the inspiration for the present article. The conference brought together a diverse range of expertise and organisations from the developing and industrialised world, all with a common interest in safeguarding the future of food. This article provides a snapshot of three of the recurring topics that were discussed during this conference: soil health, plant science and the future of farming practice. Crop plants and their cultivation are the fundamental building blocks for a food secure world. Whether these are grown for food or feed for livestock, they are the foundation of food and nutrient security. Many of the challenges for the future of food will be faced where the crops are grown: on the farm. Farmers need to plant the right crops and create the right conditions to maximise productivity (yield) and quality (e.g. nutritional content), whilst maintaining the environment, and earning a living. New advances in science and technology can provide the tools and know-how that will, together with a more entrepreneurial approach, help farmers to meet the inexorable demand for the sustainable production of nutritious foods for future generations. PMID- 26619957 TI - Fisetin and luteolin protect human retinal pigment epithelial cells from oxidative stress-induced cell death and regulate inflammation. AB - Degeneration of retinal pigment epithelial (RPE) cells is a clinical hallmark of age-related macular degeneration (AMD), the leading cause of blindness among aged people in the Western world. Both inflammation and oxidative stress are known to play vital roles in the development of this disease. Here, we assess the ability of fisetin and luteolin, to protect ARPE-19 cells from oxidative stress-induced cell death and to decrease intracellular inflammation. We also compare the growth and reactivity of human ARPE-19 cells in serum-free and serum-containing conditions. The absence of serum in the culture medium did not prevent ARPE-19 cells from reaching full confluency but caused an increased sensitivity to oxidative stress-induced cell death. Both fisetin and luteolin protected ARPE-19 cells from oxidative stress-induced cell death. They also significantly decreased the release of pro-inflammatory cytokines into the culture medium. The decrease in inflammation was associated with reduced activation of MAPKs and CREB, but was not linked to NF- kappaB or SIRT1. The ability of fisetin and luteolin to protect and repair stressed RPE cells even after the oxidative insult make them attractive in the search for treatments for AMD. PMID- 26619958 TI - Improved In vivo Assessment of Pulmonary Fibrosis in Mice using X-Ray Dark-Field Radiography. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease with a median life expectancy of 4-5 years after initial diagnosis. Early diagnosis and accurate monitoring of IPF are limited by a lack of sensitive imaging techniques that are able to visualize early fibrotic changes at the epithelial-mesenchymal interface. Here, we report a new x-ray imaging approach that directly visualizes the air-tissue interfaces in mice in vivo. This imaging method is based on the detection of small-angle x-ray scattering that occurs at the air-tissue interfaces in the lung. Small-angle scattering is detected with a Talbot-Lau interferometer, which provides the so-called x-ray dark-field signal. Using this imaging modality, we demonstrate-for the first time-the quantification of early pathogenic changes and their correlation with histological changes, as assessed by stereological morphometry. The presented radiography method is significantly more sensitive in detecting morphological changes compared with conventional x-ray imaging, and exhibits a significantly lower radiation dose than conventional x-ray CT. As a result of the improved imaging sensitivity, this new imaging modality could be used in future to reduce the number of animals required for pulmonary research studies. PMID- 26619959 TI - The apportionment of human diversity revisited. AB - OBJECTIVES: Studies of the apportionment of human genetic diversity have found that local populations harbor nearly as much diversity as the species as a whole. These studies have been a valuable cornerstone in rejecting race as a biological framework in anthropology. The current study presents new analyses that use updated statistical methods based on bifurcating trees to assess the structure of human genetic diversity and its implications for the existence of canonical biological races. MATERIALS AND METHODS: We examine patterns of both goodness-of fit and lack-of-fit of two bifurcating trees to patterns of diversity determined from autosomal short tandem repeat genotypes in 1,037 people representing 52 populations with worldwide distribution. RESULTS: From goodness-of-fit, we infer a root for the tree within Africa, and we recapitulate a pattern of decreasing genetic diversity with increasing geographic distance from Africa. From lack-of fit, we present tentative evidence for admixture events with archaic hominins. We do not find evidence that long-range migration or local gene flow have contributed appreciably to the lack of fit at a global scale. CONCLUSION: This is the first study to find a root for a tree of human populations without comparison to a nonhuman out-group, and it is one of the first studies to identify a signature of admixture with archaic hominins without reference to ancient DNA. Our findings complement previous studies of the apportionment of human diversity and provide a more solid evolutionary foundation for the rejection of biological race. Am J Phys Anthropol 160:561-569, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26619960 TI - Slice-selective adiabatic magnetization T2 -preparation (SAMPA) for efficient T2 weighted imaging at ultrahigh field strengths. AB - PURPOSE: At high field, T2 -weighted (T2 w) imaging is limited by transmit field inhomogeneity and increased radiofrequency power deposition. In this work, we introduce SAMPA (Slice-selective Adiabatic Magnetization T2 PrepAration) and demonstrate its use for efficient brain T2 w imaging at 7 Tesla (T). METHODS: SAMPA was designed by subsampling an optimized B1 insensitive rotation (BIR4) waveform with small tip angle linear subpulses. To perform T2 w imaging, SAMPA was inserted before a fast gradient echo acquisition. The off-resonance behavior, B1 robustness, and slice selectivity of the novel T2 preparation module were analyzed using Bloch simulations. The performance of SAMPA for T2 w imaging was demonstrated in phantom experiments as well as in the brains of healthy volunteers at 7T. RESULTS: Based on simulations, the proposed design operates at peak B1 of 15 MUT and higher, within a 400 Hz bandwidth. T2 values were in strong agreement with spin echo-based T2 mapping in phantom experiments. Whole brain, interleaved multislab three-dimensional imaging could be acquired with 0.8 mm3 isotropic resolution in 5:36 min per T2 weighting. CONCLUSION: Compared with previous adiabatic T2 preparation techniques, SAMPA allows for slice-selectivity, which can lead to efficient and robust acquisitions for T2 w imaging at high field. Magn Reson Med 76:1741-1749, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26619961 TI - Face likeability mediates the memory-enhancing effect of face attractiveness in young but not older adults. AB - Evidence of effects of face attractiveness on memory is mixed and little is known about the underlying mechanisms of this relationship. Previous work suggests a possible mediating role of affective responding to faces (i.e., face likeability) on the relationship between face attractiveness and memory. Age-related change in social motivation may reduce the relevance of face attractiveness in older adults, with downstream effects on memory. In the present study, 50 young and 51 older participants were presented with face-trait pairs. Faces varied in attractiveness. Participants then completed a face-trait associative recognition memory task and provided likeability ratings for each face. There was a memory enhancing effect of face attractiveness in young (but not older) participants, which was partially mediated by face likeability. In addition, more attractive and less attractive (compared to moderately attractive) faces were more likely remembered by both young and older participants. This quadratic effect of face attractiveness on memory was not mediated by face likeability. Findings are discussed in the context of motivational influences on memory that vary with age. PMID- 26619964 TI - Evaluation of local treatment effect by borrowing information from similar countries in multi-regional clinical trials. AB - One key objective of a multi-regional clinical trial (MRCT) is to quantify country-specific treatment effects to support local registration. Naive estimate of the treatment effects based on country-specific subsets of data are inefficient because of relatively sparse country-specific sample sizes, even in large MRCTs, and subject to many limitations. The recently developed shrinkage estimate approach improves efficiency by incorporating data from other countries but treating all other countries equally, thus ignoring similarity to the country of interest. Ideally, for the estimation of treatment effect in a country of interest, it is more efficient to use all relevant data such as that from countries that are similar to the one of interest. We propose a tree-based approach to incorporate similarity, with branches or forks used to represent the relationship of treatment effects between countries. Similarity in certain characteristics among countries in either continuous scale or categorical scale is used to build the tree. By allowing local treatment effects for countries to be random effects and follow a Gaussian process along the tree, we demonstrate that countries sharing the same internal parent nodes are more correlated and a country borrows more information from the neighbors sharing the same parent node. We illustrated this statistical framework using a MRCT with a continuous endpoint. PMID- 26619963 TI - OVOL2, an Inhibitor of WNT Signaling, Reduces Invasive Activities of Human and Mouse Cancer Cells and Is Down-regulated in Human Colorectal Tumors. AB - BACKGROUND & AIMS: Activation of WNT signaling promotes the invasive activities of several types of cancer cells, but it is not clear if it regulates the same processes in colorectal cancer (CRC) cells, or what mechanisms are involved. We studied the expression and function of OVOL2, a member of the Ovo family of conserved zinc-finger transcription factors regulated by the WNT signaling pathway, in intestinal tumors of mice and human beings. METHODS: We analyzed the expression of OVOL2 protein and messenger RNA in CRC cell lines and tissue arrays, as well as CRC samples from patients who underwent surgery at Xiamen University in China from 2009 to 2012; clinical information also was collected. CRC cell lines (SW620) were infected with lentivirus expressing OVOL2, analyzed in migration and invasion assays, and injected into nude mice to assess tumor growth and metastasis. Tandem affinity purification was used to purify the OVOL2 containing complex from CRC cells; the complex was analyzed by liquid chromatography, tandem mass spectrometry, and immunoprecipitation experiments. Gene promoter activities were measured in luciferase reporter assays. We analyzed mice with an intestine-specific disruption of Ovol2 (Ovol2(flox/+) transgenic mice), as well as Apc(min/+) mice; these mice were crossed and analyzed. RESULTS: Analysis of data from patients indicated that the levels of OVOL2 messenger RNA were significantly lower in colon carcinomas than adenomas, and decreased significantly as carcinomas progressed from grades 2 to 4. Immunohistochemical analysis of a tissue array of 275 CRC samples showed a negative association between tumor stage and OVOL2 level. Overexpression of OVOL2 in SW620 cells decreased their migration and invasion, reduced markers of the epithelial-to mesenchymal transition, and suppressed their metastasis as xenograft tumors in nude mice; knockdown of OVOL2 caused LS174T cells to transition from epithelial to mesenchymal phenotypes. OVOL2 bound T-cell factor (TCF)4 and beta-catenin, facilitating recruitment of histone deacetylase 1 to the TCF4-beta-catenin complex; this inhibited expression of epithelial-to-mesenchymal transition related genes regulated by WNT, such as SLUG, in CRC cell lines. OVOL2 was a downstream target of WNT signaling in LS174T and SW480 cells. The OVOL2 promoter was hypermethylated in late-stage CRC specimens from patients and in SW620 cells; hypermethylation resulted in OVOL2 down-regulation and an inability to inhibit WNT signaling. Disruption of Ovol2 in Apc(min/+) mice increased WNT activity in intestinal tissues and the formation of invasive intestinal tumors. CONCLUSIONS: OVOL2 is a colorectal tumor suppressor that blocks WNT signaling by facilitating the recruitment of histone deacetylase 1 to the TCF4-beta-catenin complex. Strategies to increase levels of OVOL2 might be developed to reduce colorectal tumor progression and metastasis. PMID- 26619962 TI - Magnitude of Missed Esophageal Adenocarcinoma After Barrett's Esophagus Diagnosis: A Systematic Review and Meta-analysis. AB - BACKGROUND & AIMS: A proportion of patients with Barrett's esophagus (BE) are diagnosed with esophageal adenocarcinoma (EAC) within 1 year of an endoscopic examination that produced negative findings. These cases of missed cancers have not been well studied, despite current surveillance strategies for BE. We performed a systematic review and meta-analysis to determine the magnitude of missed EAC in cohorts of patients with BE. METHODS: We searched MEDLINE, EMBASE, and Web of Science from their inception to May 31, 2015 to identify cohort studies of adults with BE (baseline nondysplastic BE +/- BE with low-grade dysplasia) and at least a 3-year follow-up period, providing data on missed and incident EACs (diagnosed within 1 year and diagnosed more than 1 year after the initial endoscopy in which BE was diagnosed, respectively). The main outcome measure was pooled proportion of missed and incident EACs (of all EACs detected after initial endoscopy) among BE cohorts, using a random effects model. RESULTS: In a meta-analysis of 24 studies reporting on 820 missed and incident EACs, 25.3% were classified as missed (95% confidence interval: 16.4%-36.8%) and 74.7% as incident EACs (95% CI: 63.2%-83.6%), although there was substantial heterogeneity among studies (I2 = 74%). When the analysis was restricted to nondysplastic BE cohorts (15 studies), 23.9% of EACs were classified as missed (95% confidence interval: 15.3%-35.4%; I2 = 0%). In a meta-analysis of 10 studies with follow-up periods of >=5 years (a total of 239 EACs), 22.0% were classified as missed (95% confidence interval: 8.7%-45.5%), with substantial heterogeneity (I2 = 68%). CONCLUSIONS: Among adults with nondysplastic BE (or BE with low-grade dysplasia) at their index endoscopy and at least a 3-year follow-up period, 25% of EACs are diagnosed within 1 year after the index endoscopy. Additional resources should be allocated to detect missed EAC. PMID- 26619965 TI - Disruption of effective connectivity from the dorsolateral prefrontal cortex to the orbitofrontal cortex by negative emotional distraction in obsessive compulsive disorder. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) has been associated with abnormal cognitive and emotional functions and these dysfunctions may be dependent on the disruption of dynamic interactions within neuronal circuits associated with emotion regulation. Although several studies have shown the aberrant cognitive affective processing in OCD patients, little is known about how to characterize effective connectivity of the disrupted neural interactions. In the present study, we applied effective connectivity analysis using dynamic causal modeling to explore the disturbed neural interactions in OCD patients. METHOD: A total of 20 patients and 21 matched healthy controls performed a delayed-response working memory task under emotional or non-emotional distraction while undergoing functional magnetic resonance imaging. RESULTS: During the delay interval under negative emotional distraction, both groups showed similar patterns of activations in the amygdala. However, under negative emotional distraction, the dorsolateral prefrontal cortex (DLPFC) and the orbitofrontal cortex (OFC) exhibited significant differences between groups. Bayesian model averaging indicated that the connection from the DLPFC to the OFC was negatively modulated by negative emotional distraction in patients, when compared with healthy controls (p < 0.05, Bonferroni-corrected). CONCLUSIONS: Exaggerated recruitment of the DLPFC may induce the reduction of top-down prefrontal control input over the OFC, leading to abnormal cortico-cortical interaction. This disrupted cortico cortical interaction under negative emotional distraction may be responsible for dysfunctions of cognitive and emotional processing in OCD patients and may be a component of the pathophysiology associated with OCD. PMID- 26619966 TI - Controlling Solid-Electrolyte-Interphase Layer by Coating P-Type Semiconductor NiOx on Li4Ti5O12 for High-Energy-Density Lithium-Ion Batteries. AB - Li4Ti5O12 is a promising anode material for rechargeable lithium batteries due to its well-known zero strain and superb kinetic properties. However, Li4Ti5O12 shows low energy density above 1 V vs Li(+)/Li. In order to improve the energy density of Li4Ti5O12, its low-voltage intercalation behavior beyond Li7Ti5O12 has been demonstrated. In this approach, the extended voltage window is accompanied by the decomposition of liquid electrolyte below 1 V, which would lead to an excessive formation of solid electrolyte interphase (SEI) films. We demonstrate an effective method to improve electrochemical performance of Li4Ti5O12 in a wide working voltage range by coating Li4Ti5O12 powder with p-type semiconductor NiOx. Ex situ XRD, XPS, and FTIR results show that the NiOx coating suppresses electrochemical reduction reactions of the organic SEI components to Li2CO3, thereby promoting reversibility of the charge/discharge process. The NiOx coating layer offers a stable SEI film for enhanced rate capability and cyclability. PMID- 26619968 TI - A Psychometric Review of the Personality Inventory for DSM-5 (PID-5): Current Status and Future Directions. AB - The paradigm of personality psychopathology is shifting from one that is purely categorical in nature to one grounded in dimensional individual differences. Section III (Emerging Measures and Models) of the Diagnostic and Statistical Manual of Mental Disorders (5th ed. [DSM-5]; American Psychiatric Association, 2013), for example, includes a hybrid categorical/dimensional model of personality disorder classification. To inform the hybrid model, the DSM-5 Personality and Personality Disorders Work Group developed a self-report instrument to assess pathological personality traits-the Personality Inventory for the DSM-5 (PID-5). Since its recent introduction, 30 papers (39 samples) have been published examining various aspects of its psychometric properties. In this article, we review the psychometric characteristics of the PID-5 using the Standards for Educational and Psychological Testing as our framework. The PID-5 demonstrates adequate psychometric properties, including a replicable factor structure, convergence with existing personality instruments, and expected associations with broadly conceptualized clinical constructs. More research is needed with specific consideration to clinical utility, additional forms of reliability and validity, relations with psychopathological personality traits using clinical samples, alternative methods of criterion validation, effective employment of cut scores, and the inclusion of validity scales to propel this movement forward. PMID- 26619967 TI - PRKAR1A-negative familial Cushing's syndrome: two case reports. AB - INTRODUCTION: Determining the etiology of Cushing's syndrome is very challenging to endocrinologists, with most of the difficulty arising from subtype differentiation of adrenocorticotropic hormone-dependent Cushing's syndrome. We present the pitfalls of evaluating a rare cause of adrenocorticotropic hormone independent Cushing's syndrome in the transition period between adolescence and adulthood. CASE PRESENTATION: A sibling pair with familial isolated primary pigmented nodular adrenocortical disease is described. The index case, a 20-year old Chinese woman, presented with premenopausal osteoporosis with T12 compression fracture and young hypertension. Biochemical analysis confirmed adrenocorticotropic hormone-independent Cushing's syndrome (elevated 0800 h plasma cortisol 808 nmol/L with suppressed adrenocorticotropic hormone level <5 pg/ml). Computed tomography of her adrenal glands revealed a 0.7-cm left adrenal hypodense nodule. After a left adrenalectomy, she had residual hypercortisolism (progressive weight gain, new T10 compression fracture, and not glucocorticoid dependent postoperatively). Completion of contralateral adrenalectomy was performed upon recognition of typical histologic characteristics of primary pigmented nodular adrenocortical disease found in an initial left adrenalectomy specimen. Similarly, her younger brother developed adrenocorticotropic hormone independent Cushing's syndrome at age 18 years, with typical cushingoid habitus, but no osteoporosis or hypertension. His adrenal computed tomographic scans showed micronodularities over bilateral adrenal glands. He was successfully treated with bilateral adrenalectomy. Screening for Carney's complex and PRKAR1A gene mutation was negative. Signs and symptoms of Cushing's syndrome resolved after bilateral adrenalectomy for both patients. They were placed on lifelong glucocorticoid and mineralocorticoid replacement therapy and long-term surveillance for Carney's complex. CONCLUSIONS: The cases of these two patients illustrate the difficulties involved in diagnosing primary pigmented nodular adrenocortical disease, a variant of adrenocorticotropic hormone-independent Cushing's syndrome that is managed with bilateral adrenalectomy. A high index of suspicion for this disease is needed, especially in adolescents with adrenocorticotropic hormone-independent Cushing's syndrome who have a significant family history, features of Carney's complex, and no resolution of Cushing's syndrome after unilateral adrenalectomy. Patients with primary pigmented nodular adrenocortical disease can either have bilateral/multiple adrenal nodules or normal adrenal glands visualized by computed tomography. Long-term surveillance is imperative in patients with confirmed Carney's complex and in those who have not undergone complete genetic testing to exclude this hereditary disorder. PMID- 26619970 TI - Direct oral provocation tests in non-immediate mild cutaneous reactions related to beta-lactam antibiotics. AB - BACKGROUND: Skin testing has a limited role in the diagnosis of non-immediate beta-lactam hypersensitivity in children. The aim of this study was to report the results of oral provocation tests performed without skin tests in children with non-immediate mild cutaneous reactions without systemic symptoms caused by beta lactam antibiotics. METHODS: Oral provocation tests with suspected antibiotics were performed to patients with non-immediate mild cutaneous reactions without systemic symptoms caused by beta-lactam antibiotics. Skin tests were not performed before provocation tests. A total of five doses were administered with half-an-hour intervals in increasing doses. Provocation was continued for 5 days. RESULTS: A total of 119 patients with a median age of 4.3 (IQR: 2-7.5) years, of whom 58% were males, were included in the study. Amoxicillin-clavulanic acid was the most frequently responsible agent in 87 (73.1%) patients, and most common type of rash was maculopapular in 74 (62.2%) patients. Four patients (3.4%) had an urticarial reaction during the provocation test. CONCLUSION: We did not experience any severe reactions during oral provocation test without previous skin tests performed to children with non-immediate mild cutaneous reactions without systemic symptoms. Omitting skin tests before oral provocation test in this group of children can help decreasing the burden of allergy clinics and alleviating the discomfort of children. PMID- 26619971 TI - Injury-induced rapid activation of MAPK signaling in dechorionated eggs and larvae of the silkworm Bombyx mori. AB - Previous study showed that diapause in Bombyx mori eggs can be terminated by dechorionation and that activation in the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) in dechorionated cultured eggs is involved in diapause termination. In the present study, the possible mechanism underlying activation of ERK upon dechorionation was further investigated. Results showed that mechanical injury of diapause eggs without medium incubation also resulted in rapid increase in the phospho-ERK levels and that injury increased the phospho-ERK levels at different stages of both diapause eggs and eggs in which diapause initiation was prevented by HCl. Effects of anaerobiosis on dechorionation-stimulated phospho-ERK levels showed that the mechanical injury itself but not the dramatic increase in oxygen uptake upon injury is involved in a rapid activation of ERK. Chemical anaerobiosis on dechorionation-stimulated phospho-ERK levels and the in vivo effect of anaerobiosis showed that the supply of oxygen also plays a role in ERK signaling. In addition, injury induced the phosphorylation of c-jun N-terminal kinases (JNKs) and p38 kinase, components of two parallel MAPK pathways. A kinase assay showed a dramatic increase in JNK kinase activity in egg lysates upon injury. When newly hatched first instar larvae were injured, an increase in the phospho-ERK levels similar to that in dechorionated eggs was observed. From the results, we hypothesize that the injury induced rapid activation of MAPK signaling, which serves as a natural signal for embryonic development, is related to diapause termination in dechorionated eggs. PMID- 26619969 TI - Deterministic Tractography of the Nigrostriatal-Nigropallidal Pathway in Parkinson's Disease. AB - We hypothesized that deterministic tractography is practical and sensitive to changes in the complex nigrostriatal and nigropallidal pathway (NSP) in Parkinson's disease (PD). Using diffusion tensor imaging (DTI) tractography, we investigated the NSP to evaluate differences between PD patients and controls, and examined their clinico-radiologic correlation. Structural and DTI brain scans were obtained in 40 subjects (21 PD patients and 19 healthy controls). We isolated the NSP using a user-friendly DTI toolkit based on deterministic brute force tractography. DTI parameters of fractional anisotropy (FA), mean, axial, and radial diffusivity, and streamline count of the NSP were measured. Average FA (p < 0.01) and streamline count (p < 0.001) were significantly lower in the PD compared to control group. Mean diffusivity and radial diffusivity were significantly higher in the PD group (p < 0.05). Average streamline count correlated with the United Parkinson's Disease Rating Scale motor score (p < 0.05). Point-to-point FA profiles of the tract demonstrated peak divergence between PD and control towards the tract midpoint rather than the distal grey matter. Our findings demonstrated a clinically and radiologically practical application of DTI tractography to the NSP in PD, without requiring complex imaging sequences for anatomical localization or segmentation software. PMID- 26619972 TI - Helicobacter pylori screening: options and challenges. AB - Helicobacter pylori gastritis is the most frequent infectious disease in the gastrointestinal tract. Clinical sequelae of the infection including peptic ulcer disease, sporadic gastric cancer (GC) and primary B-cell gastric lymphoma (MALT lymphoma) may develop in up to 20% of the infected individuals. The H. pylori screen-and-treat strategy is addressed to members of communities with high GC incidence, and first-degree relatives of GC patients. For primary GC prevention, H. pylori screen-and-treat is most effective in patients without precancerous conditions. In populations at moderate risk, strategies for GC prevention need to be explored. A special clinical scenario for primary and secondary prevention of H. pylori related benign complications are patients on non-steroidal anti inflammatory drugs and low-dose aspirin. Vaccination represents another option for eliminating H. pylori infection in the population and a new H. pylori vaccine has shown promising results. However, long-term effects with the use of vaccine are not available. PMID- 26619974 TI - Electrostatically Embedded Many-Body Expansion for Simulations. AB - We have applied the electrostatically embedded many-body (EE-MB) method truncated at the two-body level (also called the pairwise additive EE-MB method or the EE PA approximation) and the three-body level (called EE-3B) to calculate the gradient of the potential energy for a simulation box containing 64 water molecules. We employed the B3LYP density functional with the 6-31+G(d,p) basis set for this test case. We found that the EE-PA method is able to reproduce the magnitude of the gradient from a B3LYP/6-31+G(d,p) calculation on the entire system to within 1.0% with a 1.3% error for the maximum component of the gradient. Furthermore, the EE-3B method is able to reproduce the magnitude of the gradient to within 0.1% with a 0.2% error for the maximum component of the gradient. The good performance of the EE-MB methods for calculating forces and the highly parallel nature of these methods make them well suited for use in molecular dynamics simulations. Furthermore, since the methods can be used for efficient and accurate calculations of forces with any level of electronic structure theory that has analytic gradients and with any electronic structure package that allows for the presence of a field of point charges, these methods can readily be used with a wide variety of density functional theory and wave function theory methods. PMID- 26619973 TI - Effect of X-ray beam quality on determination of exposure index. AB - We investigated the effect of X-ray beam qualities RQA3, 5, 7, and 9 on the exposure index (EI) as defined by International Electrotechnical Commission guideline 62494-1. Half-value layers (HVLs) of RQA5 X-rays passing through anti scatter grids (grid ratios 6:1, 8:1, 10:1, and 12:1) were also evaluated because grids are frequently used in clinical situations. The maximum percent differences in the EIs for RQA3, 7, and 9 with respect to RQA5 were 35.0, 11.6, and 38.7 %, respectively. The range of HVLs for RQA5-7 beams was 7.10-9.10 mm of aluminum (mm Al). This was wider than the range of HVLs when grids were used (6.94-7.29 mm Al). The effect of variations in X-ray beam qualities in the RQA series on the EI was significantly greater than the effect of grids. This study indicated that, in clinical settings, the EI should be used carefully in X-ray examinations with different X-ray beam qualities. PMID- 26619975 TI - Accurate Induction Energies for Small Organic Molecules: 1. Theory. AB - The induction energy often plays a very important role in determining the structure and properties of clusters of organic molecules, but only in recent years has an effort been made to include this energy in such calculations, notably in the field of organic crystal structure prediction. In this paper and the following one in this issue we provide ab initio methods suitable for the accurate inclusion of the induction energy for molecules containing as many as 30 atoms or so. These techniques are based on Symmetry-Adapted Perturbation Theory using Density Functional Theory [SAPT(DFT)] and use distributed polarizabilities computed using the recently developed density-fitting algorithm with constrained refinement. With this approach we are able to obtain induction models of varying complexity and study the effects of overlap and related numerical issues. Basis set effects on the exact and asymptotic induction energies are investigated, and the roles of higher-order induction energies and many-body effects are explored. PMID- 26619976 TI - Accurate Induction Energies for Small Organic Molecules. 2. Development and Testing of Distributed Polarizability Models against SAPT(DFT) Energies. AB - In part 1 of this two-part investigation we set out the theoretical basis for constructing accurate models of the induction energy of clusters of moderately sized organic molecules. In this paper we use these techniques to develop a variety of accurate distributed polarizability models for a set of representative molecules that include formamide, N-methyl propanamide, benzene, and 3 azabicyclo[3.3.1]nonane-2,4-dione. We have also explored damping, penetration, and basis set effects. In particular, we have provided a way to treat the damping of the induction expansion. Different approximations to the induction energy are evaluated against accurate SAPT(DFT) energies, and we demonstrate the accuracy of our induction models on the formamide-water dimer. PMID- 26619977 TI - Evaluation of the Electrostatically Embedded Many-Body Expansion and the Electrostatically Embedded Many-Body Expansion of the Correlation Energy by Application to Low-Lying Water Hexamers. AB - We have applied a many-body (MB) expansion, the electrostatically embedded many body (EE-MB) approximation, and the electrostatically embedded many-body expansion of the correlation energy (EE-MB-CE), each at the two-body (MB = PA, where PA denotes pairwise additive) and three-body (MB = 3B) levels, to calculate total energies for a series of low-lying water hexamers using eight correlated levels of theory including second-order and fourth-order Moller-Plesset perturbation theory (MP2 and MP4) and coupled cluster theory with single, double, and quasipertubative triple excitations (CCSD(T)). Comparison of the expansion methods to energies obtained from full (i.e., unexpanded) calculations shows that the EE-3B-CE method is able to reproduce the full cluster energies to within 0.03 kcal/mol, on average. We have also found that the deviations of the results predicted by the expansion methods from those obtained with full calculations are nearly independent of the correlated level of theory used; this observation will allow validation of the many-body methods on large clusters at less expensive levels of theory (such as MP2) to be extrapolated to the CCSD(T) level of theory. Furthermore, we have been able to rationalize the accuracies of the MB, EE-MB, and EE-MB-CE methods for the six hexamers in terms of the specific many-body effects present in each cluster. PMID- 26619978 TI - Revisiting the S1/S0 Degeneracy Space along the Exocyclic Methylene Twist Motion of Fulvene through a Two-Step Procedure. AB - We have characterized the degeneracy space (DS) between the ground (S0) state and the first excited (S1) state along the exocyclic methylene twist motion of fulvene, using our calculation strategy, i.e., a two-step procedure with CASSCF. The origin of the "cancellation error" on locating degeneracy points under geometrical constraints is analyzed, leading to a method to assess adequacy of the strategy. According to our estimation, these S1/S0 DPs are optimized for energy within 2.0 * 10(-)(3) Eh A(-)(1) (the value of root-mean-square). From the obtained S1/S0 DS, we provide some information about the exocyclic methylene rotation by 180(?). PMID- 26619979 TI - Inductive and External Electric Field Effects in Pentacoordinated Phosphorus Compounds. AB - Pentacoordination at phosphorus is associated with a nucleophilic displacement reaction at tetracoordinated phosphorus compounds and shows a great variability in what respects their geometrical and energetic features. By means of a systematic theoretical study on a series of elementary model compounds, we have analyzed the bonding features. The pentacoordinated phosphorus compounds are held together by dative bonds, and the geometry and stability depends on the inductive effects originated by different substitutes at phosphorus. We show also that an external electric field can modify the geometrical features and the reactivity of the nucleophilic substitution reactions. This issue may have great interest in biological reactions involving pentacoordinated phosphorus where the electric field originated by the folded protein could influence the catalytic process. We report also additional calculations on the geometry and NMR spectra on three triphenyl phosphonium ylide derivatives, and our results compare well with the experimental data. PMID- 26619980 TI - Parallel Calculation of CCSD and CCSD(T) Analytic First and Second Derivatives. AB - In this paper we present a parallel adaptation of a highly efficient coupled cluster algorithm for calculating coupled-cluster singles and doubles (CCSD) and coupled-cluster singles and doubles augmented by a perturbative treatment of triple excitations (CCSD(T)) energies, gradients, and, for the first time, analytic second derivatives. A minimal-effort strategy is outlined that leads to an amplitude-replicated, communication-minimized implementation by parallelizing the time-determining steps for CCSD and CCSD(T). The resulting algorithm is aimed at affordable cluster architectures consisting of compute nodes with sufficient memory and local disk space and that are connected by standard communication networks like Gigabit Ethernet. While this scheme has disadvantages in the limit of very large numbers of compute nodes, it proves to be an efficient way of reducing the overall computational time for large-scale coupled-cluster calculations. In this way, CCSD(T) calculations of molecular properties such as vibrational frequencies or NMR-chemical shifts for systems with more than 1000 basis functions are feasible. A thorough analysis of the time-determining steps for CCSD and CCSD(T) energies, gradients, and second derivatives is carried out. Benchmark calculations are presented, proving that the parallelization of these steps is sufficient to obtain an efficient parallel scheme. This also includes the calculation of parallel CCSD energies and gradients using unrestricted (UHF) and restricted open-shell (ROHF) Hartree-Fock references, parallel UHF-CCSD(T) energies and gradients, parallel ROHF-CCSD(T) energies as well as parallel equation-of-motion CCSD energies and gradients for closed- and open-shell references. First applications to the calculation of the NMR chemical shifts of benzene using large basis sets and to the calculation of the equilibrium geometry of ferrocene as well as energy calculations with more than 1300 basis functions demonstrate the efficiency of the implementation. PMID- 26619981 TI - Zn Coordination Chemistry: Development of Benchmark Suites for Geometries, Dipole Moments, and Bond Dissociation Energies and Their Use To Test and Validate Density Functionals and Molecular Orbital Theory. AB - We present nonrelativistic and relativistic benchmark databases (obtained by coupled cluster calculations) of 10 Zn-ligand bond distances, 8 dipole moments, and 12 bond dissociation energies in Zn coordination compounds with O, S, NH3, H2O, OH, SCH3, and H ligands. These are used to test the predictions of 39 density functionals, Hartree-Fock theory, and seven more approximate molecular orbital theories. In the nonrelativisitic case, the M05-2X, B97-2, and mPW1PW functionals emerge as the most accurate ones for this test data, with unitless balanced mean unsigned errors (BMUEs) of 0.33, 0.38, and 0.43, respectively. The best local functionals (i.e., functionals with no Hartree-Fock exchange) are M06 L and tau-HCTH with BMUEs of 0.54 and 0.60, respectively. The popular B3LYP functional has a BMUE of 0.51, only slightly better than the value of 0.54 for the best local functional, which is less expensive. Hartree-Fock theory itself has a BMUE of 1.22. The M05-2X functional has a mean unsigned error of 0.008 A for bond lengths, 0.19 D for dipole moments, and 4.30 kcal/mol for bond energies. The X3LYP functional has a smaller mean unsigned error (0.007 A) for bond lengths but has mean unsigned errors of 0.43 D for dipole moments and 5.6 kcal/mol for bond energies. The M06-2X functional has a smaller mean unsigned error (3.3 kcal/mol) for bond energies but has mean unsigned errors of 0.017 A for bond lengths and 0.37 D for dipole moments. The best of the semiempirical molecular orbital theories are PM3 and PM6, with BMUEs of 1.96 and 2.02, respectively. The ten most accurate functionals from the nonrelativistic benchmark analysis are then tested in relativistic calculations against new benchmarks obtained with coupled-cluster calculations and a relativistic effective core potential, resulting in M05-2X (BMUE = 0.895), PW6B95 (BMUE = 0.90), and B97-2 (BMUE = 0.93) as the top three functionals. We find significant relativistic effects (~0.01 A in bond lengths, ~0.2 D in dipole moments, and ~4 kcal/mol in Zn-ligand bond energies) that cannot be neglected for accurate modeling, but the same density functionals that do well in all-electron nonrelativistic calculations do well with relativistic effective core potentials. Although most tests are carried out with augmented polarized triple-zeta basis sets, we also carried out some tests with an augmented polarized double-zeta basis set, and we found, on average, that with the smaller basis set DFT has no loss in accuracy for dipole moments and only ~10% less accurate bond lengths. PMID- 26619982 TI - Comparison of the Standard 6-31G and Binning-Curtiss Basis Sets for Third Row Elements. AB - Ab initio calculations were carried out for isogyric reactions involving the third row elements, Ga, Ge, As, Se, and Br. Geometries of all the reactants and products were optimized at the HF, MP2, and B3LYP levels of theory using the 6 31G(d) and 6-31G(d,p) basis sets. For molecules containing third row elements geometries, frequencies and thermodynamic properties were calculated using both the standard 6-31G and the Binning-Curtiss (BC6-31G) basis sets. In order to determine the performance of these basis sets, the calculated thermodynamic properties were compared to G3MP2 values and where possible to experimental values. Geometries and frequencies calculated with the standard 6-31G and the BC6 31G basis sets were found to differ significantly. Frequencies calculated with the standard 6-31G basis set were generally in better agreement with the experimental values (MAD=40.1 cm(-1) at B3LYP/6-31G(d,p) and 94.2 cm(-1) at MP2/6 31G(d,p) for unscaled frequencies and 29.6 cm(-1) and 24.4 cm(-1), respectively, for scaled frequencies). For all the reactions investigated, the thermodynamic properties calculated with the standard 6-31G basis set were found to consistently be in better agreement with the G3MP2 and the available experimental results. However, the BC6-31G basis set performs poorly for the reactions involving both second and third row elements. Since, in general, the standard 6 31G basis set performs well for all the reactions, we recommend that the standard 6-31G basis set be used for calculations involving third row elements. Using G3MP2 enthalpies of reaction and available experimental heats of formation (DeltaHf), previously unknown DeltaHf for CH3SeH, SiH3SeH, CH3AsH2, SiH3AsH2, CH3GeH3, and SiH3GeH3 were found to be 18.3, 18.0, 38.4, 82.4, 41.9, and 117.4 kJ mol(-1), respectively. PMID- 26619983 TI - Mechanism of Air Oxidation of the Fragrance Terpene Geraniol. AB - The fragrance terpene geraniol autoxidizes upon air exposure and forms a mixture of oxidation products, some of which are skin sensitizers. Reactions of geraniol with O2 have been studied with DFT (B3LYP) and the computational results compared to experimentally observed product ratios. The oxidation is initiated by hydrogen abstraction, forming an allylic radical which combines with an O2 molecule to yield an intermediate peroxyl radical. In the subsequent step, geraniol differs from previously studied cases, in which the radical chain reaction is propagated through intermolecular hydrogen abstraction. The hydroxy-substituted allylic peroxyl radical prefers an intramolecular rearrangement, producing observable aldehydes and the hydroperoxyl radical, which in turn can propagate the radical reaction. Secondary oxidation products like epoxides and formates were also considered, and plausible reaction pathways for formation are proposed. PMID- 26619984 TI - CHARMM Force Field Parameters for Nitroalkanes and Nitroarenes. AB - New CHARMM force field (FF) parameters are developed for nitro compounds, referred to here as C27rn, for subsequent use in molecular dynamics (MD) simulations. The nonbonded terms are adjusted to best fit densities and hydration energies of nitropropane and nitrobenzene. High-level quantum mechanical calculations are used to obtain accurate conformational energies of nitroalkanes and nitrobenzene and to adjust the torsional potential of the CHARMM FF. For nitroalkanes, the calculated gauche (g) conformer of the C-C-C-N torsion is more stable than trans (t). Consequently, nitropropane MD simulations with C27rn result in 74% population of this g conformer. The C27rn FF is in excellent agreement with experiment for various bulk (density, isothermal compressibility, and heat of vaporization) and interfacial (surface tension) properties of nitropropane, nitrobutane, and nitrobenzene. MD simulations with the OPLS-AA FF for nitropropane and nitrobenzene result in similar property predictions as C27rn, except a reduced stability of the C-C-C-N g conformer. PMID- 26619985 TI - P-LINCS: A Parallel Linear Constraint Solver for Molecular Simulation. AB - By removing the fastest degrees of freedom, constraints allow for an increase of the time step in molecular simulations. In the last decade parallel simulations have become commonplace. However, up till now efficient parallel constraint algorithms have not been used with domain decomposition. In this paper the parallel linear constraint solver (P-LINCS) is presented, which allows the constraining of all bonds in macromolecules. Additionally the energy conservation properties of (P-)LINCS are assessed in view of improvements in the accuracy of uncoupled angle constraints and integration in single precision. PMID- 26619986 TI - TD-DFT Performance for the Visible Absorption Spectra of Organic Dyes: Conventional versus Long-Range Hybrids. AB - The pi -> pi* transitions of more than 100 organic dyes from the major classes of chromophores (quinones, diazo, ...) have been investigated using a Time-Dependent Density Functional Theory (TD-DFT) procedure relying on large atomic basis sets and the systematic modeling of solvent effects. These calculations have been performed with pure (PBE) as well as conventional (PBE0) and long-range (LR) corrected hybrid functionals (LC-PBE, LC-omegaPBE, and CAM-B3LYP). The computed wavelengths are systematically guided by the percentage of exact exchange included at intermediate interelectronic distance, i.e., the lambdamax value always follows the PBE > PBE0 > CAM-B3LYP > LC-PBE > LC-omegaPBE > HF sequence. The functional giving the best estimates of the experimental transition energies may vary, but PBE0 and CAM-B3LYP tend to outperform all other approaches. The latter functional is shown to be especially adequate to treat molecules with delocalized excited states. The mean absolute error provided by PBE0 is 22 nm (0.14 eV) with no deviation exceeding 100 nm (0.50 eV): PBE0 is able to deliver reasonable estimates of the color of most organic dyes of practical or industrial interest. By using a calibration curve, we found that the LR functionals systematically allow an even more consistent description of the low-lying excited state energies than the conventional hybrids. Indeed, linearly corrected LR approaches yield an average error of 10 nm for each dye family. Therefore, when such statistical treatments can be designed for given sets of dyes, a simple and rapid theoretical procedure allows both a chemically sound and a numerically accurate description of the absorption wavelengths. PMID- 26619987 TI - Application of the TraPPE Force Field for Predicting the Hildebrand Solubility Parameters of Organic Solvents and Monomer Units. AB - Configurational-bias Monte Carlo simulations in the isothermal-isobaric and Gibbs ensembles using the transferable potentials for phase equilibria (TraPPE) force field were carried out to compute the liquid densities, the Hildebrand solubility parameters, and the heats of vaporization for a set of 32 organic molecules with different functional groups at a temperature of 298.15 K. In addition, the heats of vaporization were determined at the normal boiling points of these compounds. Comparison to experimental data demonstrates that the TraPPE force field is significantly more accurate than predictions obtained from molecular dynamics simulations with the Dreiding force field [Belmares et al. J. Comput. Chem. 2004, 25, 1814] and an equation of state approach [Stefanis et al. Fluid Phase Equil. 2006, 240, 144]. For the TraPPE force field, the mean unsigned percent errors for liquid density, the Hildebrand solubility parameter, and the heat of vaporization at 298.15 K are 1.3, 3.3, and 4.5%, respectively. PMID- 26619988 TI - Computational Study of the Small Zr(IV) Polynuclear Species. AB - Despite widespread zirconium use ranging from nuclear technology to antiperspirants, important aspects of its solvation chemistry, such as the nature of small zirconium(IV) hydroxy cluster ions in aqueous solution, are not known due to the complexity of the zirconium aqueous chemistry. Using a combination of Car-Parrinello molecular dynamics simulations and conventional quantum mechanical calculations, we have determined the structural characteristics and analyzed the aqueous solution dynamics of the two smallest zirconium(IV) cluster species possible, i.e., the dimer and trimer. Our study points to and provides detailed geometrical information for a stable structural motif for building zirconium polymers, the Zr(OH)2Zr bridging unit with 7-8 coordinated Zr ions, which, however, cannot be used to construct a stable structure for the trimer. We find that a stacked trimer, not featuring this motif, is a possible structure, though not a very stable one, shedding new light on this species, and its possible importance in the aqueous chemistry of Zr(4+) ion. PMID- 26619989 TI - Ab Initio Molecular Dynamics Study of Mg(2+) and Ca(2+) Ions in Liquid Methanol. AB - Ab initio Car-Parrinello molecular dynamics simulations have been performed in order to investigate the solvation properties of Mg(2+) and Ca(2+) in fully deuterated methanol solution to better understand polarization effects induced by the ions. Charge transfer and dipole moment calculations have been performed to give more detailed insight on the role of the electronic reorganization and its effect on the first solvation shell stability. The perturbation of the methanol H bond network has been investigated. PMID- 26619990 TI - 'Dynamic Distance' Reaction Coordinate for Competing Bonds: Applications in Classical and Ab Initio Simulations. AB - A versatile reaction coordinate, the "dynamic distance", is introduced for the study of reactions involving the rupture and formation of a series of chemical bonds or contacts. The dynamic distance is a mass-weighted mean of selected distances. When implemented as a generalized constraint, the dynamic distance is particularly suited for driving activated processes by controlled increase during a simulation. As a single constraint acting upon multiple degrees of freedom, the sequence of events along the resulting reaction pathway is determined unambiguously by the underlying energy landscape. Free energy profiles can be readily obtained from the mean constraint force. In this paper both theoretical aspects and numerical implementation are discussed, and the unique and diverse properties of this reaction coordinate are demonstrated using three examples: In the framework of Car-Parrinello molecular dynamics, we present results for the prototypical double proton-transfer reaction in formic acid dimer and the photocycle of the guanine-cytosine DNA base pair. As a classical mechanical example, the opening of the binding pocket of the enzyme rubisco is analyzed. PMID- 26619991 TI - Biased Molecular Simulations for Free-Energy Mapping: A Comparison on the KcsA Channel as a Test Case. AB - The calculation of free-energy landscapes in proteins is a challenge for modern numerical simulations. As to the case of potassium ion channels is concerned, it is particularly interesting because of the nanometric dimensions of the selectivity filter, where the complex electrostatics is highly relevant. The present study aims at comparing three different techniques used to bias molecular dynamics simulations, namely Umbrella Sampling, Steered Molecular Dynamics, and Metadynamics, never applied all together in the past to the same channel protein. Our test case is represented by potassium ions permeating the selectivity filter of the KcsA channel. PMID- 26619992 TI - Stability of the Free and Bound Microstates of a Mobile Loop of alpha-Amylase Obtained from the Absolute Entropy and Free Energy. AB - The hypothetical scanning molecular dynamics (HSMD) method is a relatively new technique for calculating the absolute entropy, S, and free energy, F, from a given sample generated by any simulation procedure. Thus, each sample conformation, i, is reconstructed by calculating transition probabilities that their product leads to the probability of i, hence to the entropy. HSMD is an exact method where all interactions are considered, and the only approximation is due to insufficient sampling. In previous studies HSMD (and HS Monte Carlo - HSMC) has been applied very successfully to liquid argon, TIP3P water, self avoiding walks, and peptides in a alpha-helix, extended, and hairpin microstates. In this paper HSMD is developed further as applied to the flexible 7-residue surface loop, 304-310 (Gly-His-Gly-Ala-Gly-Gly-Ser) of the enzyme porcine pancreatic alpha-amylase. We are mainly interested in entropy and free energy differences DeltaS = Sfree - Sbound (and DeltaF=Ffree-Fbound) between the free and bound microstates of the loop, which are obtained from two separate MD samples of these microstates without the need to carry out thermodynamic integration. As for peptides, we find that relatively large systematic errors in Sfree and Sbound (and Ffree and Fbound) are cancelled in DeltaS (DeltaF) which is thus obtained efficiently with high accuracy, i.e., with a statistical error of 0.1-0.2 kcal/mol (T=300 K) using the AMBER force field and AMBER with the implicit solvation GB/SA. We provide theoretical arguments in support of this cancellation, discuss in detail the problems involved in the computational definition of a microstate in conformational space, suggest potential ways for enhancing efficiency further, and describe the next development where explicit water will replace implicit solvation. PMID- 26619993 TI - Beyond the Wade-Mingos Rules in Bare 10- and 12-Vertex Germanium Clusters: Transition States for Symmetry Breaking Processes. AB - The lowest energy structures of bare Gen(z) clusters (n = 10, 12; z = -6, 0, +2, +4) obtained using density functional theory (DFT) at the hybrid B3LYP level often are relatively low-symmetry polyhedra not readily recognizable by the Wade Mingos rules. However, such optimized structures may arise from higher symmetry transition states through symmetry breaking processes. Thus the lowest energy structures for the Ge10(6)(-) and Ge12(6)(-) clusters with hyperelectronic arachno 2n + 6 skeletal electron counts are derived from pentagonal and hexagonal prism transition states, respectively, and retain the pentagonal and hexagonal faces of the prisms upon symmetry-breaking optimization. In addition, a variety of capped cube, prism, and antiprism transition states are found for the hypoelectronic Ge10(4+), Ge12, and Ge12(4+) clusters, which go to low-energy low symmetry optimized structures, typically Cs or Ci, upon following the normal modes of the imaginary vibrational frequencies. PMID- 26619994 TI - Minimalist Explicit Solvation Models for Surface Loops in Proteins [J. Chem. Theory Comput. 2, 1135-1151 (2006)]. PMID- 26619995 TI - Post-treatment weight change in oral cavity and oropharyngeal squamous cell carcinoma. AB - PURPOSE: Incidence of head and neck cancer (HNC) due to human papillomavirus (HPV) infection has been increasing. Treatment regimens have evolved. These changes might result in alterations of assumed treatment-related weight changes for HNC patients. We aimed to compare the trajectory of pre- to post-treatment weight changes of oropharyngeal squamous cell carcinoma (OPSCC) versus oral cavity squamous cell carcinoma (OCSCC) patients and to compare weight changes between patients with primary surgery +/- adjuvant therapy to patients with primary radiation and/or chemotherapy. METHODS: This retrospective cohort study examined adult OPSCC and OCSCC patients with initial definitive treatment at the University of Pennsylvania from January 1, 2009 to December 31, 2010. Patient demographics, medical history, treatments, and pre- and post-treatment body weight data were collected from electronic medical records. Mixed-effects modeling was performed. RESULTS: Among 354 patients who met the inclusion criteria, 290 (82 %) survivors were available for inclusion by 24-month follow up. More than 70 % OPSCC and OCSCC patients were overweight or obese at all pre- and post-treatment time points. The average weight among OPSCC patients was 6.63 kg higher than OCSCC patients at all time points (mean = 6.63, 95 % confidence interval (CI), 2.46-10.79, p = 0.002). After adjusting for potential confounders, patients with primary surgery had significantly more weight gain from pre treatment to 12-18 month post-treatment follow-up as compared to patients with primary radiation and/or chemotherapy (adjusted mean = 4.01, 95 % CI, 0.16-7.87, p = 0.041). CONCLUSION: Overweight and obesity may be a new challenge in OPSCC and OCSCC patient care. Further study is needed to evaluate whether exercise and nutritional interventions can improve their survivorship. PMID- 26619996 TI - Effectiveness and implementation of interventions to increase commuter cycling to school: a quasi-experimental study. AB - BACKGROUND: Active transportation to school has been positively associated with various health parameters whereas only sparse evidence exists on risk of injury while commuting to school. This study investigated the overall effectiveness of cycling promotion combined with structural changes on cycling to school. METHODS: Interventions at public schools in three different regions in Denmark were based on planned infrastructural changes near schools (e.g. road surface and traffic regulation) and school-motivation for promoting commuter cycling. Participants were pupils from control schools (n = 12) or intervention schools (n = 13). All children (n = 2415) from the 4(th) and 5(th) grade were measured at baseline during spring 2010 and at follow-up one year later. RESULTS: No significant differences in commuter cycling were detected in the adjusted analyses comparing the intervention with the control group neither when assessed as changes in short term (beta: 0.15 trips/week, p = 0.463) nor when assessed as changes in long term school cycling (beta: -0.02 units, p = 0.485). No differences were observed neither in the incidence of traffic injuries nor in the characteristics of injuries when comparing the control group and the intervention group. Approximately 50 % of all traffic injuries occurred during school transport with most injuries categorized as solo injuries. The only significant predictor of future traffic injuries was previous school transport injuries. CONCLUSION: This multifaceted school cycling promotion programme did not affect school cycling behaviour or the health parameters assessed. Implementation issues relevant in the planning of future school cycling interventions are discussed in the article. The one year incidence of being involved in a traffic injury was approximately 25 % with almost 50 % of all traffic injuries occurred during school transport. Previous school transport injury predicted future school traffic injuries. PMID- 26619997 TI - Salvage stereotactic radiosurgery with adjuvant use of bevacizumab for heavily treated recurrent brain metastases: a preliminary report. AB - It is not uncommon for brain metastasis (BM) treated with stereotactic radiosurgery (SRS) to demonstrate radiographic enlargement, with the patient developing neurological deficits attributable to a lesion at the site of SRS. The management of both local recurrence and radiation-induced necrosis (RN) poses a significant therapeutic dilemma, if surgical resection is not feasible, and effective therapies have yet to be established. This preliminary study introduces our initial experience with salvage SRS using adjuvant bevacizumab for this refractory entity. We retrospectively reviewed five patients who had received salvage SRS using adjuvant bevacizumab for recurrent BM complicated by RN. The diagnosis was based on clinical features, serial imaging studies and/or histopathological findings. Patients underwent salvage SRS followed by the first cycle of bevacizumab (7.5-10 mg/kg intravenous). Bevacizumab was repeated every 3 4 weeks until tumor progression or significant toxic events. The number of bevacizumab doses ranged from 2 to 16 (median 4). Follow-up MR imaging demonstrated a clear radiographic response in all lesions. Neurological symptoms improved in three patients and stabilized in two. In two patients, bevacizumab treatment was discontinued due to anemia and gastrointestinal bleeding, respectively. At the time of data analysis, four patients had died and the other was still alive. The causes of death were neurological decline and systemic disease progression in two patients each. Salvage SRS with adjuvant bevacizumab use appeared to provide an adequate radiographic response as well as neurological palliation for selected patients with heavily treated recurrent BM complicated by RN. PMID- 26619999 TI - Serum Calcium Status among Pregnancies Complicated By Pre-Eclampsia in Bangladesh. AB - This case control cross sectional study was carried out in the department of biochemistry, Mymensingh medical college in collaboration with the outpatient department, family planning model clinic and antenatal obstetric ward of Mymensingh medical college hospital, Mymensingh during the period of July 2003 to June 2004. The aim of the study was to explore the status of serum calcium among pregnancies complicated by pre-eclampsia in Bangladesh as a means to monitor the possibility of management of these patients. A total of 82 subjects were selected and were grouped as Group I (32 healthy women with uncomplicated pregnancy as control subjects) and Group II (50 pregnant women with pre-eclampsia as cases). Serum calcium was estimated by colorimetric method from each sample. Statistical analysis was done by using SPSS windows package. Among the groups, mean+/-SD (Standard Deviation) of Group I and Group II serum calcium were 8.71+/-1.00 and 10.78+/-1.44 mg/dl respectively. By comparing Group I with Group II highly significant difference were found in case of serum calcium (P<0.001). It is evident from the study that serum calcium level significantly increases among pregnancies complicated by pre-eclampsia in Bangladesh. PMID- 26619998 TI - One-year outcome of postoperative swallowing impairment in pediatric patients with posterior fossa brain tumor. AB - Impaired swallowing in children who underwent posterior fossa brain tumor (PFBT) resection disrupts development and quality of life, yet its downstream consequences remain unclear. This study explored the risk factors and functional prognosis of postoperative swallowing impairment in pediatric patients (<19 years old) with PFBT. Among 183 patients with PFBT who underwent surgical resection, 39 patients with postoperative swallowing difficulty were analyzed using the videofluoroscopic swallowing study (VFSS). The association between clinical features, swallowing characteristics, and swallowing impairment was explored during the early postoperative phase and 1-year following surgical resection. Duration of tube feeding was investigated using Kaplan-Meier analysis. Twenty seven (14.8 %) patients needed tube feeding in the early postoperative phase and 11 (6.01 %) at 1-year after surgical resection. Mean duration of tube feeding was 240.2 days and differed by tumor pathologies (P = 0.001), delayed triggering of pharyngeal swallow (DTP) (P = 0.002) and pharyngeal wall coating (P = 0.033). Tumor pathology was associated significantly with the referral for swallowing evaluation (P < 0.001) and 1-year tube feeding (P = 0.019). Tube feeding at 1 year was significantly associated with the tumor's brainstem involvement (P = 0.039), and swallowing abnormalities at early phase including DTP (P = 0.030) and pharyngeal wall coating (P = 0.004). Our results suggest that tumor pathology, brainstem involvement, and specific swallowing abnormalities at early phase are important risk factors for sustained 1-year swallowing impairment following surgical resection. These results can be applied to determine the plan of evaluation, nutrition, and intervention in clinical practice. PMID- 26620000 TI - Re-DCR with Silicone Tube Intubation: An Effective Method of Management of Failed DCR. AB - This prospective observational study was performed with twenty nine eyes of Twenty eight patients who were operated upon for chronic dacryocystitis eight months to two years six months before, presented with history of persistent watering and discharge. Number of male was 6(21%) and female was 22(79%). Re-DCR with silicone tube intubation was performed in all the patients. Post operative follow up for a period of 12-24 months revealed absence of symptoms in 28 eyes (97%) while 1(3%) eye persisted with watering and discharge despite uncomplicated surgical procedure. There are so many options for management of Failed DCR, among them Re-DCR with Silicone Tube Intubation is the most safe and less cost effective method. PMID- 26620001 TI - Rotavirus is Predominent Enteropathogen in Acute Childhood Diarrhea in Mymensingh. AB - The study was carried out from July 2011 to June 2012 in the Department of Microbiology, Mymensingh Medical College. A total of 200 clinically diagnosed diarrheal paediatrics patients were included in this study. Stool specimens were examined by standard laboratory methods for identification of enteropathogens. Diarrheagenic Escherichia coli strains were detected by Multiplex PCR following standard methods and Rotavirus genome was detected by Polyacrylamide Gel Electrophoresis (PAGE). Rotavirus was the most common enteropathogen detected in 69(34.5%) cases, followed by Diarrheagenic Escherichia coli (DEC) and Campylobacter species in 34(17.0%) and 23(11.5%) cases respectively. Rotavirus detection rate was high in upto 1 year age group which was 51(25.5%). PMID- 26620002 TI - Clinical Profile of Peripheral Neuropathy in Leprosy. AB - The objectives of the study were to see the association of peripheral neuropathy in leprosy and to find out the clinical profile of peripheral neuropathy and disability status in leprosy. It was descriptive type of cross sectional study was conducted among the cases of leprosy attended in the out-patient departments of neurology, Mymensingh Medical College Hospital (MMCH) and Mymensingh tuberculosis and leprosy hospital that fulfilled the inclusion criteria were included in this study, during the study period of January 2010 to December 2011.In this study of 62 cases revealed that leprosy is more common in male (71%) people and 21% leprosy patient had contact with known case of leprosy. Leprosy causes peripheral neuropathy (61.3%). Duration of occurrence of peripheral neuropathy was prolonged (>6 month) in most of the patients (47.4%) and the disease progression was also slow (63.2%). Numbness was complained by 89.4% patients and 65.8% subjects complained of weakness of limbs. Deformities and ulcers were present in 26.3% and 50% of patients respectively. Ulnar nerve (43.6%), Lateral popliteal nerve (41.9%), Posterior tibial nerve (41.9%) and Great auricular nerve (17.7%) were the most commonly involved thickened peripheral nerves. The rate of visible physical impairment (WHO Grade 2 disability) among people affected by leprosy in feet was 27.4% and in hands was 16.1%. The position and vibration sense was found to normal all patients of peripheral neuropathy. PMID- 26620003 TI - Histological Spectrum of Chronic Hepatitis in HBeAg Positive and HBeAg Negative Hepatitis B Virus Infection. AB - Hepatitis B virus (HBV) is a major cause of chronic liver disease and an important public health issue. This study was conducted with the objective of evaluating the histological features in patients infected with precore and wild type HBV infection; compare the histological activity and fibrosis stage and early treatment of HBeAg negative hepatitis. Total thirty six (36) patients were selected. Eighteen (18) were HBe(+ve) and another 18 were HBe(-ve). All had persistent or intermittent elevation of SGPT. Histological examination of liver biopsy specimen was done by Haematoxyn and Eosin (H & E) Stain. Histological activity index (Necroinflaminatory score) was calculated in both groups and compared. Among the patients with wild type of HBV the average HAI was 4.5. While patients with pre-core mutant chronic HBV infection the average HAI was 6.3. The difference between the two groups was not statistically significant. Average periportal necrosis among the patients with wild type was 1.88. While patients with precore mutant chronic HBV infection the average was 2.72. The difference between the two groups was statistically significant (P value<0.01). Average intralobular degeneration and local necrosis of the study group among the patients with wild type was 0.88, while patients with precore mutant chronic infection, the average were 7.7. The difference between the two groups was statistically significant (P value<0.5). Average portal inflammation among the patient with wild type was 1.66. While patients with precore mutant HBV infection the average was 2.11. The difference between the two groups was not statistically significant (P value>0.05). We also found that the progression of disease in terms of liver fibrosis rather than disease activity was more significant in PCM infection than in wild-type HBV infection. PMID- 26620004 TI - Pattern of Dermatophytes in Patients Attend in Mymensingh Medical College Hospital. AB - Dermatophytosis is a common fungal disease which involves the keratinized tissue. This is an attempt to observe the spectrum of dermatophytes among the clinically suspected cases of dermatophytosis attending the outpatient department of Dermatology and Venereology, Mymensingh Medical College Hospital, Mymensingh during the period of July 2013 to December 2014. Two hundred thirty (230) clinically suspected cases of dermatophytosis were subjected in this study. Sixty three cases (27.39%) were positive for fungus in direct microscopy while 53(23.04%) were culture positive. Among the clinical types tinea unguium was the most common followed by tinea corporis. Dermatophytosis was more common in the age group of 21-30 years. The male to female ratio was 1.53:1. Trichophyton rubrum 44(83.04%) was found common etiological dermatophyte species followed by Trichophyton mentagrophytes 5(9.43%) and Epidermophyton floccosum 4(7.55%). PMID- 26620005 TI - Study on Neurological Manifestations of Eclampsia & Findings of CT scan of Brain. AB - This cross sectional study was carried out in the Department of Obstetrics & Gynaecology in Mymensingh Medical College Hospital during the period of January 2011 to December 2012 to evaluate neurological manifestations in eclampsia by CT scan of brain. A total 35 patients with eclampsia were studied, who underwent CT scan of brain in Radiology & Imaging Department of Mymensingh Medical College Hospital. The study patients were divided into two groups, those who had changes in brain on CT scan (Group A) & those who had no changes in brain on CT scan (Group B). Finally the study variables were compared between these two groups. Each selected patient fulfilling the criteria was sent to the department of Radiology & Imaging for CT scanning of brain. In antepartum cases of eclampsia CT scan of brain were done after delivery/ termination of pregnancy. In all cases, CT scan of brain was done within 72 hours of admission. Out of 35 patients total 85.72% had changes in brain on CT scan & 14.28% had no changes in brain on CT scan. Among them 45.72% patients had cerebral oedema, 37.14% had cerebral infarct & 2.86% patients had intracerebral haemorrhage. Comparison of neurological parameters were done & showed that there were statistically significant difference between the two groups regarding headache, visual disturbance, hypereflexia & depression of consciousness. There was no statistically significant difference regarding aphasia & hemiplegia between the two groups. So the CT scan of brain has been useful in demonstrating the lesion of brain in patients with eclampsia & also helpful to evaluate the neurological manifestations in eclampsia. PMID- 26620006 TI - Lipid Profile in Post-Acute Coronary Syndrome Setting: Lipidic Risk Assessment in Young People beyond LDL-C. AB - This case-control study was carried out in Department of Cardiology, Mymensingh Medical College Hospital, Bangladesh, within the period from June 2009 to May 2010. A total 50 case of 18-45 years of age with first attack of acute coronary syndrome admitted in coronary care unit and 50 healthy controls of same age and sex distribution were studied. Among the lipid parameters, TC, HDL-C, LDL-C and non-HDL-C were significantly lower in cases than in controls. Apo B was significantly higher in the cases (98.7+/-25.1 mg/dl vs. 77.5+/-35.2 mg/dl in control). Importantly, among the cases with hyper Apo B condition, 25 (50.0%) had LDL-C level within normal limit, thus conventional lipid profile underestimated the ACS risk. In multivariate analysis Apo B was an independent determinant of ACS. Among the controls 23(46.0%) with high LDL-C had hyper Apo condition. Hyper Apo B in these controls may cause acute coronary syndrome in future. The present study shows estimation of Apo B can predict basal or residual risk of acute coronary syndrome in young people, what from calculated LDL-C level cannot be inferred. PMID- 26620007 TI - Psychosocial Consequences of Infertility on Infertile Women. AB - This study explores to find out the qualitative and quantitative psychosocial consequences of infertility in women coming for infertility treatment in tertiary infertility center. A total of 400 infertile couples who agreed to participate in the study were asked to fill up the questionnaires and later interviewed to access the psychosocial consequences of infertility on their personal life in a tertiary infertility clinic in Dhaka at Center for Assisted Reproduction (CARe Hospital), Dhaka from June 2011 to December 2011 and agreed to participate in the study were included in the study. The data was analyzed and the quantitative and qualitative psychosocial factors were evaluated. Four hundred infertile couple who filled the questionnaires was included in the study. Sixty three percent of the women belonged to age group >20 30 years at the time of interview. Regarding age at marriage 43.8% of the women were married by 20 years, 51.3% were married between 20 30 years. Mean+/-SD duration of present married life was 7.20+/-4.45 (range 1 to 28) years and 74.4% of the women were living with their husbands. Of them 75.5% women were housewife. When asked whether they knew what was the reason of infertility in the couple, 32.5% knew the cause was in the female partner, 14.5%, knew the cause was in the male partner, 10.3% knew the cause was in both partners, 21.5% knew cause of infertility was not in any of the partners, and 21.3% had no idea about the cause of infertility. The male partner's response about the issue of prognosis and outcome of couple's infertility revealed 37.3% believed their wives will conceive someday, 31.3% had no intention for a second marriage, 13% were indifferent, 11.3% blamed their wives for infertility and 4.8% threatened for a second marriage. Only 2.5% of the male partners were suggested on consulting and continuing treatment by specialist. The family pressure by in laws and relatives towards their infertility was that 57.3% insisted on consulting a good gynaecologist, 29.8% had no family pressure, 11.3% insisted the male partners to remarry, and 1.8% insisted the husbands to divorce their wives. In evaluating the social response it showed that 55.8% was suggested to consult a good gynaecologist, 31% asks embarrassing questions, 13% taunted and 0.3% insisted the husband to divorce the wife. In developing countries, despite overpopulation, unwanted childlessness is also an important psychosocial burden that needs attention. The consequences of infertility have greater impact on woman's life and can be a life time crisis. There is no direct intervention regarding infertility from government or NGO's. National services is lacking because policy makers and donor NGOs are not interested to invest on it and also women want to hide their infertility as long as they can. PMID- 26620008 TI - Gender Variation in the Risk Factors with Ischemic Stroke: Bangladesh Perspective. AB - It is suggested in different studies that gender has a great impact on the distribution of risk factors of stroke. This study aims at determining the gender differences in risk factors of acute ischemic stroke among male and female patients. Data extracted for this study were taken from a case control study which was carried out in the departments of Neurology and Medicine of Dhaka Medical College Hospital (DMCH) and Shaheed Suhrawardy Medical College Hospital (ShSMCH) Dhaka from July 2009 to June 2011. We collected data of 125 patients with ischemic stroke and 129 healthy controls from the primary source. All secondary data were divided on the basis of gender. Among all male respondents 70 stroke patients were considered as case and 72 healthy respondents were considered as control and in female group 55 were stroke patients (case) and 57 were healthy control. Risk factors of stroke for male and female were evaluated separately. After multivariate analysis ever smoking (both present and ex smoker) (adj. OR 3.799, 95% CI 1.416, 10.19), diabetes mellitus (adj. OR 5.687, 95% CI 1.99, 16.26), hypertension (adj. OR 18.53, 95% CI 6.43, 53.4) and total cholesterol (adj. OR 1.017, 95% CI 1.01, 1.03) were found significant predictors for stroke in male whereas diabetes mellitus (adj. OR 6.989, 95% CI 1.54, 31.64), hypertension (adj. OR 17.85, 95% CI 5.1, 62.38), serum low density lipoprotein (LDL) (adj. OR 1.04, 95% CI 1.013, 1.07) and serum triglyceride (TG) (adj. OR 1.012, 95% CI 1.004, 1.02) were found significant in female. Besides taking the controlling measure for hypertension and diabetes mellitus, life style modification is an important factor to prevent stroke in both sexes. PMID- 26620009 TI - Chronic Gastritis and its Association with H. Pylori Infection. AB - This cross sectional study was designed to see association of chronic gastritis including its type with H. pylori infection. Consecutive patients undergoing endoscopic examination having histopathological evidence of chronic gastritis were enrolled in the study and was done in Sylhet MAG Osmani Medical College from July 2011 to June 2012. Biopsies were taken from antrum, body and fundus in all patients. Histopathological examinations were done using H-E stain and for detection of H. pylori, rapid urease test, anti-H.pylori antibody test and histopathological test with modified Giemsa stain were done. Patients having results positive in at least two methods were considered infected by H. pylori. Total 80 dyspeptic patients having chronic gastritis were evaluated. Out of them 67(83.8%) had H. pylori infection and 13(16.2%) were H. pylori negative. Among all patients 57(71.2%) had pangastritis and 23(28.8%) had antral gastritis with female and male predominance respectively. H. pylori infection was present in 49(86.0%) cases of pangastritis and 18(78.3%) cases of antral gastritis. H. pylori infection was a little higher among males (34, 50.7%) females (33, 49.3%). H. pylori infection is the predominant cause of chronic gastritis and pangastritis is the major type. PMID- 26620010 TI - Patterns of Coronary Artery Anomalous Origin Reviewed by Coronary Angiogram in a Cardiac Center of Bangladesh. AB - Coronary Angiogarm (CAG) has been used to detect coronary artery anomalies. This cross sectional observational study aimed to assess the prevalence of anomalous origin of the coronary artery in the Bangladeshi patients. The researchers summarized responses of the target patients who underwent coronary angiography (CAG) from August 2010 to March 2011 in United Hospital Ltd., Gulshan, Dhaka, Bangladesh and data of anomalous origin of the coronary artery in Bangladeshi patients were recorded. Eighteen hundred (1800) patients underwent CAG during that period; 66 patients with an anomalous origin of the coronary artery were detected, giving a prevalence of 3.6%. The prevalence of anomalous origin of the coronary artery in Bangladeshi people in this study is 3.6%. CAG can visualize the anomalous origin of the coronary artery and is a useful screening modality. PMID- 26620011 TI - Morphometric Study of Fully Ossified Dry Head and Shaft of Left Human Humerus. AB - Humerus is the largest bone of upper limb. Upper limb is the most movable part and main working tools of human body. This is a cross sectional, analytic type of study carried out in the department of Anatomy, Sir Salimullah Medical College (SSMC), Dhaka from July 2011 to Dec 2012. The present study was performed on two hundred (n=200; male=117 & female=83) left sided fully ossified dry humerus bones collected from Department of Anatomy and the medical students of 1st and 2nd year MBBS course of Sir Salimullah Medical College (SSMC), Dhaka and Dhaka National Medical College (DNMC), Dhaka. Morphometric study was carried out on all samples by direct physical method. There was statistically significant difference (p=0.001) between male and female bone in the diameter of the head and shaft of the left humerus. The present study was attempted to provide a morphometric base line data of fully ossified human left humerus. PMID- 26620012 TI - Prediction of Risk Factors of Frequent Relapse Idiopathic Nephrotic Syndrome. AB - This case control study was aimed to identify the predictive risk factors for frequent relapse idiopathic nephrotic syndrome (INS) and conducted in Sir Salimullah Medical College & Mitford Hospital, Dhaka and at Renal and Dialysis Unit of Dhaka Shishu Hospital and Bangladesh Institute of Child Health (BICH), Dhaka, from January 2006 to December 2006. We examined retrospectively the clinical course of fifty cases of frequent relapse nephrotic syndrome (FRNS) as cases and fifty cases of infrequent relapse nephrotic syndrome (IRNS) as control who met the predefined enrollment criteria, followed for at least one year after initial onset of disease. After enrollment following parameters were studied as predictors of frequent relapse: i) Socio-demographic variables: age, sex, socio economic condition, number of living room ii) Disease related variables i.e. age of onset, duration of illness, frequency of relapse within the 1st year, regimen of initial steroid therapy, total cumulative dose of steroid for remission, day of remission after starting steroid, association with atopy and infection, concomitant upper respiratory illness iii) Biochemical and pathological variables (at the time of initial attack) i.e. Serum albumin, serum cholesterol, blood urea, 24 hours urinary protein, serum creatinine, complete blood count, urine RBC, urine pus cell, urine culture. The test statistics used to analyses the data were descriptive statistics, Chi-square probability test, Student's t-test and Binary logistic regression analysis for Odds ratio. Both univariate and multivariate logistic regression analysis revealed that age of onset (P<0.001, OR=0.9, 95% CI=0.85-0.95), poor socioeconomic status (P<0.034, OR=0.5.8, 95% CI=1.14-29.5) and low serum albumin level at the time of initial presentation (P<0.022, OR=0.8, 95% CI=0.65-0.97) were independent predictors of frequent relapse nephrotic syndrome. In conclusion, we demonstrated that age at onset, poor socioeconomic condition and low serum albumin level at the time of initial attack is independent risk factors for frequent relapse idiopathic nephrotic children. This information can be used as a predictor of FRNS. PMID- 26620013 TI - Comparison of Consanguinity between Parents of Hearing Impaired and Public School Children with Estimation of Risk. AB - Deafness is the hidden disability and the most common human sensory defects which lead to poor educational and employment prospects of childhood. Is there any association of consanguinity and hearing loss or are there any difference of association of consanguinity and hearing loss in specialized and public school children and how much risk is associated?--were the research questions of this study. Total 428 participants have been selected randomly. Hearing impaired were 186 participants and 242 participants were normal hearing school boy. This was a case control, analytical, hypotheses testing study. In normal public school children group, consanguinity was present in 2.5% parents. The rest were married with non relatives. In parents of hearing impaired children group, consanguinity was very high (17.2%). Pearson chi-square test and Odds ratio analysis was done. The value was less than 0.05 and ratio was 8.173. The 'p' value of Pearson chi square test was less than 0.05. So, the test was highly significant at 95% confidence interval. Odds ratio showed that the risk of profound sensorineural hearing loss in the baby of parents of consanguineous marriages 8.173 times higher than that of non consanguineous marriages. PMID- 26620014 TI - Postnatal Support Strategies for Improving Rates of Exclusive Breastfeeding in Case of Caesarean Baby. AB - Despite awarness of the many advantages of breast feeding exclusive breastfeeding (EBF) rate is still lower than recommended practice and the rate is less in case of caesarean baby. In an effort towards achieving better breast feeding practices, UNICEF and WHO launched the baby friendly hospital initiative in 1991 to ensure that all maternity facilities support mothers in making the best choice about feeding. The implementation of effective programs improves rates of short and long term exclusive breast feeding even in case of caesarean baby. The objective of present study was to investigate whether postnatal support improves the rate of exclusive breast feeding in case of caesarean baby compared with usual hospital care. This was a longitudinal study over one and half year period, from April 2009 to October 2011 done in Combined Military Hospital in Mymensingh. A total of 565 pregnant women were included this study. Primary outcome was early establishment of breast feeding after caesarean section. Secondary outcome was exclusive breast feeding at discharge from hospital, two weeks and six weeks after caesarean section delivery. Early establishment of breast feeding within one hour after caesarean section was higher in postnatal support group than usual care group (70.29% vs. 57.14%). Rates of exclusive breastfeeding in the postnatal support strategies group were significantly higher when compared with those who received usual hospital care at discharge (89.13% vs. 75.94%, p=0.004), at 2 weeks (85.51% vs. 53.38%, p<0.001) and at 6 weeks (74.64% vs. 38.35%, p<0.001). Postnatal lactation support, as single intervention based in hospital significantly improves rates of exclusive breast feeding. PMID- 26620015 TI - Serum C-reactive Protein (CRP) Level in Tuberculous Patients. AB - The present prospective case control study was carried out to assess the role of C-reactive protein (CRP) level as a diagnostic and prognostic tool of tuberculous patients. The study was conducted in the Department of Paediatrics over a period of one year. Total 60 persons were included. Case was 30 and control was 30. Out of 30 tuberculosis patients 18(60%) had pulmonary tuberculosis, 6(20%) had abdominal TB, 3(10%) had pleural effusion and 3(10%) had tubercular lymphadenopathy. CRP was positive>6 mg/L in 25(83.3%) cases. CRP level was negative after 4 weeks of treatment. There is significant difference at p<0.001 in serum CRP level in between tuberculosis and healthy children. The study concluded that CRP level is a useful indication for diagnosis and prognosis of tuberculous patients. PMID- 26620016 TI - Thrombotic Thrombocytopenic Purpura: Issues in Diagnosis and Treatment. AB - Thrombotic thrombocytopenic purpura (TTP) is a hematologic emergency fatal without prompt treatment. Plasma exchange (PEX), the treatment of choice for TTP, is not readily available and has major complications. We report seven cases of TTP, both acquired immune and secondary. Two patients had TTP secondary to malignancy and one secondary to SLE. Male to female ratio was 1:3 and median age at presentation 38 years. Six patients had moderate to very high level of LDH while one primary TTP had only mild elevation. Median haemoglobin and platelet at presentation were 6.3 gm/dL and 38 k/UL respectively. Median LDH value was 4595 u/L. All patients were treated with plasma exchange (PEX) except the two cases secondary to malignancy. One patient died of cardiac arrest during plasma exchange. None of the patients treated with PEX had relapsed over a median follow up of 18 months. PMID- 26620017 TI - Hypothyroidism and its Effect on Menstrual Pattern and Fertility. AB - Hypothyroidism is one of the most common endocrine disorders encountered in clinical practice. Thyroid disorder is very common among the female. The aim of this study was to evaluate the effects of hypothyroidism on menstrual pattern and sub-fertility. This cross-sectional comparative study was carried out in the Department of Obstetrics and Gynecology with collaboration of endocrine department of Bangabandhu Sheikh Mujib Medical University (BSMMU) from July 2006 to June 2008, cases were collected from the thyroid clinic of this hospital. Total study subject were 139, among them hypothyroid cases were 79 and euthyroid were 60. Among the hypothyroidism group 62.0% (n=49) had normal menstrual cycle, 21.5% (n=16) had oligomenorrhoea, 10.1% (n=8) had polymenorrhoea and 6.3% (n=6) had amenorrhoea. On the contrary in euthyroid group 86.7% (n=52) had normal menstrual cycle, 6.7% (n=4) had oligomenorrhoea, 5.0% (n=3) had polymenorrhoea and 1.7% (n=1) had amenorrhoea. Proportion of abnormal menstrual history was found to high among hypothyroid group almost 34% (n=27) compared to euthyroid group 13.4% (n=8) and the difference was statistically significant (p<0.001). The proportion of primary subfertility in hypothyroid 11.4% (n=9) whereas in euthyroid cases 1.7% (n=1) and secondary subfertility in hypothyroid 7.6% (n=6) where as in euthyroid cases 5.0% (n=3). So, sub-fertility was higher among hypothyroid group compared to euthyroid group but the difference was not statistically significant (p>0.05). Overall sub-fertility was 13.7% (n=10) and it was 6.7% (n=4) among the euthyroid group. Among total hypothyroid group 60.7% (n=48) are the overt hypothyroid and 39.20% (n=31) are the sub-clinical hypothyroid group. The effect of hypothyroidism is significant on menstrual pattern and on fertility. Hypothyroid women had more menstrual disorders and also suffering from sub-fertility. PMID- 26620018 TI - Pigtail Catheter in the Management of Liver Abscess. AB - Amoebic liver abscess is a common condition in Bangladesh. Though conservative treatment plays a major role, refractory patients can be successfully treated with minimally invasive approach. This prospective study was carried out to evaluate the prospect of sono-guided percutaneous catheter drainage for liver abscess patients not responding to conservative treatment. This study was done at Dhaka Medical College Hospital from January 2005 to June 2006 among patients with liver abscess that were treated conservatively outside and got admitted in different surgery and medicine units. Included 35 patients were evaluated clinically and through relevant investigations. Sono-guided percutaneous pigtail catheter was introduced for drainage and patients were followed up for two weeks on average at hospital indoor by amount of drainage, clinical improvement and serial follow up USG. After discharge from the hospital, all patients were followed up monthly and assessed clinically and ultrasonographically up to two months on outdoor basis. Thirty five patients underwent pigtail catheter drainage that was refractory to conservative treatment or needle aspiration. Following insertion of catheter patients who were pyrexic, fever subsided in two to three days and never back during the postoperative period and follow up. Antimicrobials were changed according to the report of the culture and sensitivity of the aspirate that was done routinely. Maximum total (4300 ml) amount of pus was drained in a patient. Average duration of catheter drainage in this study was 8 days. With a very low morbidity and zero mortality rates, minimum treatment costs and early return to regular life style proved this minimally invasive procedure to be a rational treatment option for amoebic liver abscess in selective cases. PMID- 26620019 TI - Markers of Hepatitis Viruses by ELISA among Healthy Blood Donors. AB - This cross sectional study was done to have a comprehensive idea about prevalence and distribution of HBsAg and anti-HCV. The present serosurveilance study was done on healthy selected blood donors and conducted in the Department of Transfusion Medicine, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh for their relatives and friends and also voluntarily from January 2001 to July 2003. Samples were collected from blood donors (Voluntary and Party) who came for donation of blood. Blood samples taken from 10,200 apparently healthy blood donors with or without the previous history of jaundice in the Transfusion Medicine department of BSMMU was tested for HBsAg and Anti-HCV by standard commercial ELISA method during the period from 1st January 2001 to 30th June 2003. Reactive samples were retested. Samples positive in duplicate tests were taken as positive. Within 10,200 samples 550(5.39%) were found positive for HBsAg and 84(0.823%) positive for anti-HCV. Among 8670(8%) male donors 470(5.42%) was positive for HBaAg and 70(0.91%) positive for anti-HCV. Among 1530(15%) female donors 80(5.29%) found positive for HBsAg and 14(0.807%) positive for anti-HCV. Prevalence of both is more in male than female, young donors below 30 years (80%) are of least prevalence 4.43% for HBsAg and 0.73% for anti-HCV. Markers are raised in prevalence with age, highest among aged donors above 40 years 14.5% and 2.62 respectively. Markers are of least prevalence among students (4.47% and 0.47%), highest among working people (7.90 and 0.91%). Within 10,200 donors no one was found concomitantly positive for HBsAg and anti-HCV, study may help to have a comprehensive idea about prevalence and distribution of HBV and HCV among healthy blood donors/party donors 9,996(98%) and voluntary donors 204(2%). PMID- 26620020 TI - Copper and Zinc Status in Patients with Preeclampsia in Bangladesh. AB - This study assessed maternal serum copper and zinc levels in preeclampsia to find out the role of trace element disorder in the aetiology of preeclampsia. This cross sectional study was conducted in the dept of Physiology of BSMMU during 2009. Sixty patients of Preeclampsia (BP--140/90 aged 18-39 years, with >20th weeks of pregnancy with proteinuria and edema) participated. Thirty normotensive gravida was control. All subjects were collected from in and out patient department of Obstetric and Gynecology of BSMMU and Dhaka medical college hospital. Serum copper and zinc levels were measured by auto analyzer and atomic absorption sprectrophotometric method respectively. Data were compared between preeclampsia and normotensive pregnant women. Data were expressed as mean and SD and independent sample 't' test and two proportion 'z' test was used for statistical analysis. Mean value of maternal serum zinc (p<0.001) and copper (<0.01) levels were significantly decreased in preeclampsia. In addition Cu/Zn ratio was significantly higher (<0.01) in preeclampsia. Hypozincemia was found in 13% and hypocupremia was found in 38% of preeclampsia. The result of this study concludes that trace element disorders may be involved in the etiology of preeclampsia. PMID- 26620021 TI - Carcinoma Tongue--Clinicopathological Presentation. AB - This prospective study was done to observe the diversity of clinical presentation of carcinoma of tongue and to study the pathological variety of carcinoma of tongue and was conducted in the Department of General Surgery and Otolaryngology and Head Neck Surgery in Bangabandhu Sheikh Mujib Medical University, Dhaka Medical College Hospital on 50 patients from January 2011 to July 2013. In this series highest number of patients were middle aged (36%). Male female ratio was 2:1. Average socioeconomic conditions of the patient were poor (68%). Betel nut and leaves chewing (88%) and smoking (56%) habits were commonly practiced for more than 10 years among the patients. Depending on site of involvement, variation in presenting symptoms has been observed. Oral tongue carcinoma mostly was presented with tongue lesion, pain and dysphagia where as the carcinoma of base of tongue commonly was presented with dysphagia, lump in neck. Lateral border of tongue (60%) was seen commonly involved. Ulcerative lesion (56%) predominantly was found in tongue lesion. Eighty percent (80%) of cases had no palpable Lymph node. Only few patients were found with Lymph node metastasis and most of them had carcinoma in base of the tongue (75%). Most of the carcinoma was well differentiated Squamous cell carcinoma. Carcinoma of tongue in our study commonly found in middle aged male patients. Variation of symptoms has depended on anatomical site involved. Most of the carcinoma was well differentiated Squamous cell carcinoma. Carcinoma other than squamous cell was not found. PMID- 26620022 TI - Views of Medical Teachers Regarding the Need of Training or Course on Medical Education. AB - Medical education in Bangladesh is poorly assessed and there is a general lack of documented knowledge about the challenges facing this field and the needs for its development. It was Cross-sectional descriptive type of study carried out among the teachers of two public (Sir Salimullah Medical College, Dhaka and Sher-E Bangla Medical College, Barisal) and two non-government Medical Colleges (Northern Medical College, Dhaka and IBN Sina Medical College, Dhaka) during the period of July 1, 2011 to June 30, 2012 to explore their views regarding the training or course in medical education. The sample size was 204 who were selected purposively. The data were collected by a semi-structured and self administered questionnaire. From the study it was revealed that majority 201(98.5%) of respondents showed their interest for training or course on medical education. Among them 123(61.2%) preferred a regular course, 58(28.8%) desired for training program and 20(9.9%) for refresher training on medical education. Most 83(67.4%) of the respondents agreed that there are barriers to participate in a training or course on medical education. Thirty four (43.6%) expressed their opinion that the duration of the training should be at least three months. PMID- 26620023 TI - Isolation and Characterization of Enteropathogenic Escherichia coli (EPEC) in Paediatric Diarrhoeal Patients by Detection of bfpA gene by PCR and HeLa cell Adherence Assay. AB - This study has been undertaken to investigate the isolation and identification of EPEC strains from paediatric diarrhoeal patients. The study was carried out in the department of Microbiology, Sir Salimullah Medical College & Mitford Hospital, Bangladesh during January to December, 2011. Total 272 samples were studied. Samples from patients with diarrhoea were collected from two tertiary care hospital. At first Esch. coli were isolated from these specimens using standard microbiological techniques and then EPEC strains were identified on the basis of presence of bundle forming pilus (bfpA) gene. Virulence of EPEC strains were determined by detection of bfpA gene and observing localized adherence (LA) in HeLa cell adherence assay. Esch. coli was isolated and identified from all the 272 samples from patients using standard microbiological techniques. Among 272 samples 20(7.35%) isolates were identified as EPEC on the basis of presence of bfpA gene detected by polymerase chain reaction. EPEC strains were identified from those 240 samples, from which Esch. coli had been isolated only. Out of twenty EPEC strains, 17 strains (85%) showed a pattern of localized adherence in Hela cell adherence assay. EPEC strains can be identified by bfpA gene detection and by adherence assays. HeLa cell adherence assay is the most specific method for detection of EPEC strains which has bfpA gene, responsible for localized adherence (LA) in HeLa cell line. Rapid and reliable detection of EPEC is required for successful microbiological surveillance and for treatment of EPEC mediated diarrhoeal disease. PMID- 26620024 TI - Characteristics and Management of Children with Continuous Spikes and Waves during Slow Sleep. AB - This study was done to describe the clinical spectrum, EEG characteristics and treatment modalities in children with continuous spike and slow wave in sleep (CSWS). Ten patients with CSWS had been treated between 2012 and 2013. Mean age of the patients was 6.9 years; male female ratio was 3:2. The main etiologic group in this study was epilepsy (10), cerebral palsy (3) and brain lesion (arachnoid cyst). All the patients had prior seizure. Presenting features were abnormal behavior (4), agitation (4), aggression (4), eye blinking (2) and involuntary movement (2). Three patients had speech regression and 1 had motor regression. Regarding EEG finding, 7 out 10 cases had SWI>85% whereas, rest of them had SWI 50 to 80%. Most of the patients were resistant to two or more oral AED. The AED found to be efficacious were Midazolam drip, pulse methyl prednisolone and valproate. Eighty percent (80%) patient responded to midazolam drip. Methyl prednisolone caused 50% improvement in one patient but failed in 2 cases. In contrast to the previous studies where high dose valproic acid, levetiracetam, Injection ACTH was more efficacious, this study demonstrates significant positive result with midazolam drip. PMID- 26620025 TI - Hepatitis-B Infections among the Injection Drug Abusers: An Emerging Risk in Public Health, Bangladesh. AB - The objective of the study was to determine the incidence of Hepatitis-B (HBV) infection among the injection drugs abusers (IDUs). The research work was a cross sectional study. A total of 400 IDUs were selected from July 2012 to June 2013 at the Outpatient Department of the Central Drug Addiction Treatment Center, Tejgaon, Dhaka, Bangladesh. They were selected consecutively following the purposive sampling method on the basis of defined selection criteria. Research instruments were a pre-tested interviewer questionnaire and blood specimen. Results showed that 79.70%(315) of the IDUs were found literate and 20.3%(85) illiterate. In present occupation, majority of them 60.5%(242) had no work and 39.5%(158) specific occupation. The mean age of them was 27.9+/-6.4 years. In marital status, 46.5%(186) were unmarried, 20.7%(83) married after addiction and 30.3%(121) married before addiction. Majority of the IDUs 75.2%(289) started their addiction with cannabis. In addition to injection drugs use, all of them were multiple drug abusers. In response to the sharing of needle, 35.7%(143) of the IDUs shared needle uncommonly and 64.3%(257) did not shared it at all. Ninety three percent (372) of them were heterosexual and polygamous having extramarital sex with multiple partners. The quality of sex-partners was wife, friends, brothel & hotel based sex sellers and street sex sellers. Majority of IDUs {82.0%(328)} did not use condom at all and 15.5(62) sold blood several times in their lifetime. Seven percent {7.0%(28)} injection drug abusers had been suffering from hepatitis-B virus (HBV) infection. HBV infection was found to be significantly (p>=0.05) associated with the quality of sex partners and number of sex partners, and age and marital status. There is no significant association with sharing of needle particularly occasional sharing of needle. Altering the behaviors of IDUs, especially their sexual lifestyles, drug habit, using of disposable syringe without sharing of needle, and also alternative preventive measures against injection drugs are still the applicable way to control spread of the HBV among the IDUs in Bangladesh. PMID- 26620026 TI - Outcome of Induction of Labour in Prolonged Pregnancy. AB - This was a hospital based prospective clinical study conducted among women having prolonged pregnancy to assess the outcome of induction of labour in prolonged pregnancy cases. One hundred and thirty nine women having uncomplicated prolonged pregnancy were studied. The study was carried out in Sir Salimullah Medical College & Mitford Hospital, Dhaka from 01 July 2010 to 30 March 2011. In this study 66% of the respondents had vaginal delivery on routine induction of labour and in 34% cases induction failed. Ninety three percent (93%) of the multigravida had vaginal delivery and in primigravida their vaginal delivery rate was 47.5%. Regarding cervical condition for delivery, 75% of the respondents having favourable cervix had vaginal delivery and in case of unfavourable cervix respondents, they had 55% cases of vaginal delivery. About the foetal outcome it was evidenced from this study that the perinatal adverse outcome increases with the increasing age of gestation beyond 40 completed weeks of gestation. This study showed that the use of prostaglandins for cervical ripening and by confirming the diagnosis of prolonged pregnancy, the delivery outcome in prolonged pregnancy can be improved. The study also showed that induction of labour is not associated with any major complications and the routine induction of labour in prolonged pregnancy is beneficial for both mother and the baby. PMID- 26620027 TI - Study of Commonest Variety of Sinonasal Malignancy and Its Sex Wise Distribution. AB - This study was done to find the commonest variety of sinonasal malignancy and its association with sex.This cross-sectional study was conducted in the Department of Otolaryngology - Head & Neck Surgery Department, Dhaka Medical College & Hospital and in the Department of Otolaryngology - Head & Neck Surgery Department, Bangabandhu Sheikh Mujib Medical University between January 2009 and December 2009. A total of 146 cases of sinonasal malignancy were consecutively included in the study. The diagnosis was confirmed by histopathology. The mean age was 47.8 years (range: 22-75 years). Over three-quarters (77%) of the patients were male with male to female ratio being 3:1. Nearly one-third (30.8%) of the patients was farmer and over one-third (36.3%) was illiterate. The right sinonasal region was involved in 48.6% cases, left sinonasal region in 39% and both sinonasal region in 12.4% cases. Histopathological diagnosis of sinonasal malignancy revealed that squamous cell carcinoma accounted for 82.9% of sinonasal malignancies, 9.6% adenocarcinoma and the rest were olfactory neuroblastoma, adenoid cystic carcinoma and mucoepidermoid carcinoma. About 96.6% of the tumours involved nasal cavity, 97.9% maxillary sinuses, 17.8% frontal sinuses, 48.6% ethmoidal sinuses and 13% sphenoid sinuses. Over 80% of patients were smoker. Exposure to wood dust was found in 26% of cases. Lather tanning in 4.8% of cases and welding in 4.1% of cases. T staging shows that nearly half (48.6%) of the patients lesion was T2, 29.5% T3, 19.9% T4 and 2.1% T1. None of the patients exhibited lymph node involvement or distant metastasis. Males tend to develop squamous cell carcinoma significantly more than the females with risk of acquiring squamous cell carcinoma being nearly 3(1.1-7.1) times higher in male than that in female (p=0.022). The study concludes that the most common histopathological variety of sinonasal malignancy is squamous cell carcinoma and males are prone to develop this malignancy more frequently than the females. PMID- 26620028 TI - Use of Iron Chelating Agents in Transfusion Dependent Thalassaemia Major Patients. AB - This cross-sectional study was done to find and investigate the utilization pattern of iron chelating agents among 73 transfusion-dependent thalassaemia major patients with continuous enrolment for at least 1 year in a day care treatment centre run by The Thalassaemia Society of India, Kolkata from November 2014 to January 2015. Transfusion dependent thalassaemia major patients above the age of 2 years managed by various haematologists and Thalassaemia specialists were studied. The administration of iron chelators namely Desferrioxamine (DFO), Deferiprone (DFP) and Deferasirox (DFX) were evaluated. Forty seven (64%) of the thalassaemics had serum ferritin level below 2500 ng/dl, of whom 20(27%) patients have ferritin level below 1000ng/dl. A number of 55(75%) of 73 patients who were treated with a single chelating agent consisted 50 patients only on DFX. Exact 8(67%) patients were on DFO+DFP and 4(33%) are treated with DFX+DFP. The mean age was 19 and mean serum ferritin level was 2280 ng/dl among the thalassaemia major patients. DFX was used 68% of patients as monotherapy and 5% patients in combination therapy with DFP. DFX in the dose of 30-40 mg/kg/day was prescribed in 52% of patients. Mean dose of 15 mg/kg/day of DFX was been administered in combination with DFP (75 mg/kg/day) in 5% patients. DFO+DFP were preferred by 8 patients, out of which 6 were aged above 25. Cost of monotherapy is twice that of combination therapy. These data demonstrates the ferritin status and present scenario of utilization of chelating agents among thalassaemia major patients on repeated transfusions. The dosing of new drug, Deferasirox and the cost analysis of various chelating regimen has also been dealt. Individualization rather than rationalization of chelation therapy should be focussed upon in managing iron overload in thalassaemia. PMID- 26620029 TI - Orthodontic Management of A Young Girl with Class II Div1 Malocclusion. AB - We describe the treatment of a young girl age, 25 years, with Class II Div1 malocclusion. She presented with an over jet of 12 mm, and the overbite was 10 mm and incomplete. Teeth on upper anterior segment of jaw were proclined and spaced. Teeth on lower jaw were crowded with buccaly placed 1st premolar on right side. Molar relationship was Class II on both sides. Incisior relation was class II div1. Her oral hygiene was good. Treatment consisted mainly of premolars extractions, canine retraction, labeling and alignment with Edgewise fixed appliances by multi loops technique. Once the canine retraction was complete, arch contraction was accomplished with 0.016*0.022 inch closing-loop arch wires followed by finishing with 0.014 inch round wires. The treatment resulted in Class I molar occlusion with proper alignment of both upper and lower anterior segment, an ideal over jet, overbite and incisor angulation. PMID- 26620030 TI - Longitudinal Stent-Shortening during Percutaneous Transluminal Angioplasty with Stenting of Right Superficial Femoral Artery: A Case Report. AB - Longitudinal stent deformation (LSD) involving coronary arteries during PCI have been reported in several literatures. But, LSD occurring during PTA (Percutaneous Transluminal Angioplasty) involving peripheral arteries is rare. We had such a case who presented with coronary and peripheral artery disease. Longitudinal stent deformation occurred during PTA with stenting of right superficial femoral artery (SFA). For CAD, PCI to RCA and LAD was done beforehand and the peripheral procedure was done 4 days later to avoid increased contrast load. Due to LSD occurring during PTA to Rt. SFA, we had to deploy another stent to cover the lesion over that artery. There was no technical fault or difficulty during negotiating the stent and positioning it covering the lesion. So, we did not find any obvious reason for this complication. Since longitudinal stent deformation is uncommon during PCI of coronary arteries and probably rare during PTA of peripheral arteries and we did not find any literature regarding this, we decided to report this case. PMID- 26620031 TI - Mesoblastic Nephroma in a 22 Years Old Woman. AB - Mesoblastic nephroma is an uncommon renal tumor of infancy and rarely occurs in adults. We report a case of mesoblastic nephroma in adult. A 22-year-old woman, who presented with left flank pain, was found to have a left renal mass by abdominal ultrasonography. Computed tomography revealed a heterogeneous tumor. Left radical nephrectomy was performed. The tumor was a creamy white solid mass. Microscopically, the tumor was composed of spindle cell proliferation. Atypia and mitoses were not identified. Among the tumor cells, there were tubular arranged epithelial elements. The patient was free of recurrence 18 months postoperatively. Mesoblastic nephroma is classified as a benign tumor but recurrence and malignant transformation of this tumor have been reported, so regular postoperative follow up is required. PMID- 26620032 TI - Ambras Syndrome: First Reported Case in Bangladesh and its Oral Rehabilitation. AB - People with rare hypertrichosis syndromes became crowd-drawing money-making phenomena in many 19th century sideshow acts. These individuals have been referred to as dog-men, hair-men, and werewolves. In 1993, Baumister et al. described congenital hypertrichosis lanuginose or Ambras syndrome: a distinct form of congenital hypertrichosis characterized by excessive hair growth over the body and face associated with facial and occasional dental anomalies. Much is not known about this syndrome since fewer than 50 cases have been documented worldwide. In this case report, a nine year old girl presented with excessive hair growth throughout her body that was denser along her midline. Furthermore, her face displayed the typical dysmorphic features characteristic of Ambras syndrome: a round tip nose, thickened nasal cartilage, antiverted nares, prominent philtrum with deep groove, and a trapezoid mouth. Oral examination revealed normal oral mucosa with completely missing and unerupted decidious and permanent teeth. Panoramic radiographs confirmed unerupted deciduous teeth. Previous case reports have mentioned the presence of occasional dental anomalies such as retarded first and second dentition and absence of some teeth. However, this is the first reported case of Ambras syndrome presenting with complete anodontia. Prior cytogenetic studies performed on persons with Ambras syndrome have implicated a balanced pericentric inversion of chromosome 8. However, it is likely that dental anomalies are likely a result of a different genetic rearrangement. Further studies are needed to explore the cause of this rare phenotype of Ambras syndrome with complete unerupted dentition. PMID- 26620033 TI - A Rare Case of Metachromatic Leukodystrophy Confirmed by Arylsulfatase A. AB - Metachromatic leukodystrophy (MLD) is the rare neurometabolic disease caused by the deficiency of a lysosomal enzyme arylsulfatase A (ARSA) activity. The absence or deficiency of arylsulfatase a leads to accumulation of cerebroside sulfate within the myelinseath of the central nervous system (CNS) and the peripheral nervous system (PNS). This in turn causes the CNS and PNS to progressively deteriorate leading to both features of upper and lower motor neuron dysfunctions. Metachromatic leukodystrophy gets its name from the way cells with an accumulation of salfatides appear when viewed under a microscope. The salfatides form granules that are described as metachromatic which means they pick up colour differently than surrounding cellular material when stained for examination. The clinical features of brain dysfunction like gait disturbance, speech, hearing and visual problems appear gradually, become progressive and fatal over time. Our patient a 5 years and 6 months old developmentally normal boy presenting walking difficulty since his 2 years and 6 months which was gradually increasing. During this period he also developed speech difficulty, seizure followed by unconsciousness and severe respiratory distress for ten days. His investigations were suggestive of metachromatic leukodystrophy. There is no specific treatment to cure the disease. So proper counseling was done regarding the bad prognosis of the disease with symptomatic treatment. PMID- 26620034 TI - Late lead Perforation Following Permanent Pace Maker Implantation--A Case report. AB - Ventricular lead perforation is an infrequent but it's a critical complication of pacemaker implantation. Perforation was usually associated with the use of small caliber active fixation leads, and can occur beyond the first few days (sub acute) or even more than a month after implantation (late). We report the case of right ventricular perforation by a ventricular fixation lead in 61 years old man detected more than two months after implantation. Radiology and echocardiography can confirm the perforation by revealing progression of the lead beyond the cardiac silhouette or indirectly visualizing the presence of pericardial effusion. However, its pathophysiology and optimal management are currently unclear. PMID- 26620035 TI - Non-alcoholic Fatty Liver Disease (NAFLD)--A Review. AB - Non-alcoholic fatty liver disease (NAFLD) is an emerging problem in Hepatology clinics. It is closely related to the increased frequency of overweight or obesity. It has recognised association with metabolic syndrome. Central obesity, diabetes mellitus, dyslipidemia are commonest risk factors. Association with hepatitis C genotype 3 is also recognised. NAFLD is an important cause of cyptogenic cirrhosis of liver. It affects all populations and all age groups. Most patients with NAFLD are asymptomatic or vague upper abdominal pain. Liver function tests are mostly normal or mild elevation of aminotranferases. Histological features almost identical to those of alcohol-induced liver damage and can range from mild steatosis to cirrhosis. Two hit hypothesis is prevailing theory for the development of NAFLD. Diagnosis is usually made by imaging tools like ultrasonogram which reveal a bright liver while liver biopsy is gold standard for diagnosis as well as differentiating simple fatty liver and non alcoholic steatohepatitis (NASH). Prognosis is variable. Simple hepatic steatosis generally has a benign long-term prognosis. However, one to two third of NASH progress to fibrosis or cirrhosis and may have a similar prognosis as cirrhosis from other liver diseases. Treatment is mostly control of underlying disorders and dietary advice, exercise, insulin sensitizers, antioxidants, or cytoprotective agents. The prevalence of NAFLD is increasing. So it needs more research to address this problem. PMID- 26620036 TI - Chronic Pain in Irish Prison Officers: Profile and Predictors of Pain-Related Disability and Depression. AB - OBJECTIVE: International research has consistently found increased risk for physical health and psychological difficulties among prison officers including elevated risk of assault resulting in acute pain. This study represented an exploratory examination of the experience of chronic pain conditions among Irish prison officers with particular reference to the psychosocial predictors of pain severity, pain interference, and depression. DESIGN: A questionnaire battery was completed by 152 Irish prison officers. The questionnaires measured pain severity and interference, anxiety, depression, social support, coping strategies, and resilience. RESULTS: Results showed that 48% of participants reported chronic pain based on the International Association for the Study of Pain definition. Psychological distress was high among respondents reporting chronic pain, with 38% of participants meeting the criteria for "probable depression" while 51% met the criteria for "probable anxiety disorder." In regression analyses, depression emerged as a significant predictor of both pain severity and pain interference while anxiety and pain interference emerged as significant predictors of depression. CONCLUSION: Chronic pain appears to be prevalent in prison officers and is associated with both physical and psychological impairment. Health care staff in correctional facilities should be aware that these health difficulties are prevalent in the prison work environment. PMID- 26620037 TI - Inhibition of Osteoclastogenesis and Bone Resorption in vitro and in vivo by a prenylflavonoid xanthohumol from hops. AB - Excessive RANKL signaling leads to superfluous osteoclast formation and bone resorption, is widespread in the pathologic bone loss and destruction. Therefore, targeting RANKL or its signaling pathway has been a promising and successful strategy for this osteoclast-related diseases. In this study, we examined the effects of xanthohumol (XN), an abundant prenylflavonoid from hops plant, on osteoclastogenesis, osteoclast resorption, and RANKL-induced signaling pathway using both in vitro and in vivo assay systems. In mouse and human, XN inhibited osteoclast differentiation and osteoclast formation at the early stage. Furthermore, XN inhibited osteoclast actin-ring formation and bone resorption in a dose-dependent manner. In ovariectomized-induced bone loss mouse model and RANKL-injection-induced bone resorption model, we found that administration of XN markedly inhibited bone loss and resorption by suppressing osteoclast activity. At the molecular level, XN disrupted the association of RANK and TRAF6, resulted in the inhibition of NF-kappaB and Ca(2+)/NFATc1 signaling pathway during osteoclastogenesis. As a results, XN suppressed the expression of osteoclastogenesis-related marker genes, including CtsK, Nfatc1, Trap, Ctr. Therefore, our data demonstrated that XN inhibits osteoclastogenesis and bone resorption through RANK/TRAF6 signaling pathways. XN could be a promising drug candidate in the treatment of osteoclast-related diseases such as postmenopausal osteoporosis. PMID- 26620039 TI - Vitamin D is associated with cardiopulmonary exercise capacity: results of two independent cohorts of healthy adults. AB - Vitamin D has an important role in calcium homeostasis and is known to have various health-promoting effects. Moreover, potential interactions between vitamin D and physical activity have been suggested. This study aims to investigate the relationship between 25-hydroxyvitamin D (25(OH)D) and exercise capacity quantified by cardiopulmonary exercise testing (CPET). For this, 1377 participants from the Study of Health in Pomerania (SHIP-1) and 750 participants from the independent SHIP-TREND cohort were investigated. Standardised incremental exercise tests on a cycle ergometer were performed to assess exercise capacity by VO2 at anaerobic threshold, peakVO2, O2 pulse and peak power output. Serum 25(OH)D levels were measured by an automated chemiluminescence immunoassay. In SHIP-1, 25(OH)D levels were positively associated with all considered parameters of cardiopulmonary exercise capacity. Subjects with high 25(OH)D levels (4th quartile) showed an up to 25% higher exercise capacity compared with subjects with low 25(OH)D levels (1st quartile). All associations were replicated in the independent SHIP-TREND cohort and were independent of age, sex, season and other interfering factors. In conclusion, significant positive associations between 25(OH)D and parameters of CPET were detected in two large cohorts of healthy adults. PMID- 26620040 TI - Stochastic modeling for dynamics of HIV-1 infection using cellular automata: A review. AB - Recently, the description of immune response by discrete models has emerged to play an important role to study the problems in the area of human immunodeficiency virus type 1 (HIV-1) infection, leading to AIDS. As infection of target immune cells by HIV-1 mainly takes place in the lymphoid tissue, cellular automata (CA) models thus represent a significant step in understanding when the infected population is dispersed. Motivated by these, the studies of the dynamics of HIV-1 infection using CA in memory have been presented to recognize how CA have been developed for HIV-1 dynamics, which issues have been studied already and which issues still are objectives in future studies. PMID- 26620038 TI - Secondary cancers after a childhood cancer diagnosis: a nationwide hospital-based retrospective cohort study in Japan. AB - BACKGROUND: The epidemiology of secondary cancers in childhood cancer survivors has been unknown in Asian countries. Our aim is to assess the incidence and risk factors for secondary cancers through a nationwide survey in Japan. METHODS: A retrospective cohort study comprising 10,069 children who were diagnosed with cancer between 1980 and 2009 was conducted in 15 Japanese hospitals. The cumulative incidence rate was calculated using death as the competing risk and compared by the Gray method. The standardized incidence ratio (SIR) was defined as the ratio of the number of observed cancers divided by the number of expected cancers. The risk factors were analyzed using Cox regression analysis. RESULTS: One hundred and twenty-eight patients (1.3 %) developed secondary cancers within a median follow-up of 8.4 years. The cumulative incidence rate was 1.1 % (95 % confidence interval [CI] 0.9-1.4) at 10 years and 2.6 % (95 % CI 2.1-3.3) at 20 years after primary cancer diagnosis. Sensitivity analysis, limited to 5-year survivors (n = 5,387), confirmed these low incidence rates. The SIR of secondary cancers was 12.1 (95 % CI 10.1-14.4). In the Cox analysis, the hazard ratios for secondary cancers were 3.81 (95 % CI 1.53-9.47) for retinoblastoma, 2.78 (95 % CI 1.44-5.38) for bone/soft tissue sarcomas, and 1.81 (95 % CI 1.16-2.83) for allogeneic stem cell transplantation. CONCLUSIONS: The cumulative incidence of secondary cancers in children in Japan was not high; however, the SIR was relatively high. Retinoblastoma or sarcoma in addition to allogeneic stem cell transplantation were significant risk factors for secondary cancers. PMID- 26620041 TI - Discovery of synergistic genetic network: A minimum spanning tree-based approach. AB - Identification of gene interactions is one of the very well-known and important problems in the field of genetics. However, discovering synergistic gene interactions is a relatively new problem which has been proven to be as significant as the former in genetics. Several approaches have been proposed in this regard and most of them depend upon information theoretic measures. These approaches quantize the gene expression levels, explicitly or implicitly and therefore, may lose information. Here, we have proposed a novel approach for identifying synergistic gene interactions directly from the continuous expression levels, using a minimum spanning tree (MST)-based algorithm. We have used this approach to find pairs of synergistically interacting genes in prostate cancer. The advantages of our method are that it does not need any discretization and it can be extended straightway to find synergistically interacting sets of genes having three or more elements as per the requirement of the situation. We have demonstrated the relevance of the synergistic genes in cancer biology using KEGG pathway analysis and otherwise. PMID- 26620042 TI - Effects of infant flow Bi-NCPAP on apnea of prematurity. AB - BACKGROUND: Infant flow biphasic nasal continuous positive airway pressure (Bi NCPAP) and regular NCPAP (Re-NCPAP) are equally useful with respect to the rate of successful weaning from mechanical ventilation. It remains unclear, however, whether Bi-NCPAP or Re-NCPAP is more effective for reducing apnea of prematurity (AOP). METHODS: A multicenter randomized controlled study was conducted of 66 infants assigned to receive Bi-NCPAP and 66 assigned to receive Re-NCPAP for respiratory support after extubation. Primary outcome was the number of AOP events during the 48 h observation period after successful extubation, defined as no reintubation and no adverse events associated with the use of NCPAP during the observation period. The secondary outcome was successful extubation. Reintubation was at the discretion of the attending physician. RESULTS: Baseline characteristics were similar between the two groups. The number of AOP events during the 48 h observation period was significantly lower in infants with Bi NCPAP than in those with Re-NCPAP (5.2 +/- 6.5 vs 10.3 +/- 10.9 per infant, respectively; P = 0.002). The rate of successful extubation tended to be greater in those with Bi-NCPAP than in those with Re-NCPAP (92.4%, 61/66 vs 80.3%, 53/66, respectively; P = 0.074). Adverse events occurred in only one of 132 infants: erosive dermatitis developed on the nose after application of Re-NCPAP. The risk of reintubation did not differ significantly between the two groups (7.6%, 5/66 for Bi-NCPAP vs 18.2%, 12/66 for Re-NCPAP; P = 0.117). CONCLUSIONS: Bi-NCPAP was superior to Re-NCPAP for reduction of AOP following extubation. PMID- 26620043 TI - Continual Low-Dose Infusion of Sulfamidase Is Superior to Intermittent High-Dose Delivery in Ameliorating Neuropathology in the MPS IIIA Mouse Brain. AB - Mucopolysaccharidosis IIIA (MPS IIIA) is a neurodegenerative lysosomal storage disorder characterised by progressive loss of learned skills, sleep disturbance and behavioural problems. Reduced activity of lysosomal sulfamidase results in accumulation of heparan sulfate and secondary storage of glycolipids in the brain. Intra-cisternal sulfamidase infusions reduce disease-related neuropathology; however, repeated injections may subject patients to the risk of infection and tissue damage so alternative approaches are required. We undertook a proof-of-principle study comparing the ability of slow/continual or repeat/bolus infusion to ameliorate neuropathology in MPS IIIA mouse brain. Six week-old MPS IIIA mice were implanted with subcutaneously located mini-osmotic pumps filled with recombinant human sulfamidase (rhSGSH) or vehicle, connected to lateral ventricle-directed cannulae. Pumps were replaced at 8 weeks of age. Additional MPS IIIA mice received intra-cisternal bolus infusions of the same amount of rhSGSH (or vehicle), at 6 and 8 weeks of age. Unaffected mice received vehicle via each strategy. All mice were euthanised at 10 weeks of age and the brain was harvested to assess the effect of treatment on neuropathology. Mice receiving pump-delivered rhSGSH exhibited highly significant reductions in lysosomal storage markers (lysosomal integral membrane protein-2, GM3 ganglioside and filipin-positive lipids) and neuroinflammation (isolectin B4-positive microglia, glial fibrillary acidic protein-positive astroglia). MPS IIIA mice receiving rhSGSH via bolus infusion displayed reductions in these markers, but the effectiveness of the strategy was inferior to that seen with slow/pump-based delivery. Continual low-dose infusion may therefore be a more effective strategy for enzyme delivery in MPS IIIA. PMID- 26620044 TI - 1-Year outcome of concomitant intracarpal lesions in patients with dislocated distal radial fractures: a systematic assessment of 78 distal radial fractures. AB - INTRODUCTION: Ligamentous lesions are concomitant to dislocated distal radius fractures in a high percentage. The purpose of this study was to evaluate the relevance of intracarpal lesions. METHODS: Seventy eight of an original cohort of 104 distal radius fractures (74%) were studied over a follow-up period of one year after surgery with complete data (X-rays, CT, MRI, follow-up X-rays and questionnaire). RESULTS: Most of our radius fractures (AO 23 type: A 39, B 9, C 30) present additional lesions: 97%. One-year evaluation showed an average Castaing score of 4.5 +/- 2.5 points, means a "good" result of a scale of 0-27. Fifty five of seventy eight had an "excellent" or "good" result (<6 points). No patient had more than 12 points ("fair"). CONCLUSIONS: The dislocated distal radial fracture implies severe and complex injury to the whole wrist, mostly concerning intracarpal concomitant lesions (MRI). Surgical therapy of dislocated radius fractures followed by 6 weeks relief through thermoplastic splint seems to be sufficient to achieve good 1-year results. MRI-detectable carpal lesions at the time of the radial fracture are common, but only a few of them seem to decompensate later, give symptoms and became of therapeutic relevance. PMID- 26620045 TI - Clonal analysis of Aerococcus urinae isolates by using the repetitive extragenic palindromic PCR (rep-PCR). PMID- 26620046 TI - [Levosimendan for septic shock with takotsubo cardiomyopathy]. AB - As a stress-induced disease, takotsubo cardiomyopathy can also occur in septic syndromes; however, the hemodynamic management is fundamentally different from the treatment approaches for classical septic cardiomyopathy, as beta mimetics can increase the heart failure symptoms in takotsubo cardiomyopathy. This article reports the case of an 82-year-old female patient who presented with acute abdomen due to adhesion ileus and takotsubo cardiomyopathy, developed severe septic shock with peritonitis and could be successfully hemodynamically stabilized with levosimendan. PMID- 26620048 TI - Pharmacokinetics and Pharmacodynamics of Edoxaban, a Non-Vitamin K Antagonist Oral Anticoagulant that Inhibits Clotting Factor Xa. AB - Edoxaban, a once daily non-vitamin K antagonist oral anticoagulant, is a direct, selective, reversible inhibitor of factor Xa (FXa). In healthy subjects, single oral doses of edoxaban result in peak plasma concentrations within 1.0-2.0 h of administration, followed by a biphasic decline. Exposure is approximately dose proportional for once daily doses of 15-150 mg. Edoxaban is predominantly absorbed from the upper gastrointestinal tract, and oral bioavailability is approximately 62 %. Food does not affect total exposure to edoxaban. The terminal elimination half-life in healthy subjects ranges from 10 to 14 h, with minimal accumulation upon repeat once daily dosing up to doses of 120 mg. The steady state volume of distribution is approximately 107 L, and total clearance is approximately 22 L/h; renal clearance accounts for approximately 50 % of total clearance, while metabolism and biliary secretion account for the remaining 50 %. Intrinsic factors, such as age, sex and race, do not affect edoxaban pharmacokinetics after renal function is taken into account. Oral administration of edoxaban results in rapid changes in anticoagulatory biomarkers, with peak effects on anticoagulation markers (such as anti-FXa), the prothrombin time and the activated partial thromboplastin time occurring within 1-2 h of dosing. PMID- 26620049 TI - Efficacy and Safety of Vildagliptin as an Add-on to Insulin with or without Metformin in Japanese Patients with Type 2 Diabetes Mellitus: A 12-week, Double Blind, Randomized Study. AB - INTRODUCTION: To assess the efficacy and safety of vildagliptin as add-on therapy in Japanese patients with type 2 diabetes mellitus (T2DM), inadequately controlled on stable long-acting, intermediate-acting, or pre-mixed insulin, with or without concomitant metformin. METHODS: In this 12-week placebo-controlled study, patients were randomized to receive either vildagliptin 50 mg twice daily (bid) or placebo treatment in a 1:1 ratio. The primary endpoint was change in glycated hemoglobin A1c (HbA1c) from baseline to 12-week endpoint. Secondary endpoints included proportion of patients achieving pre-defined HbA1c targets of <=6.5%, <7.0%, and HbA1c <7.0% in patients with baseline HbA1c <=8.0% and change in fasting plasma glucose (FPG) after 12 weeks of treatment. Regular monitoring was performed to record any treatment-emergent adverse events (AEs) and serious adverse events or hypoglycemic episodes. RESULTS: Of the 156 patients randomized, 96.8% completed the study (vildagliptin, n = 76; placebo, n = 75). Patient demographics and clinical characteristics were comparable between the groups at baseline. Addition of vildagliptin resulted in statistically significant reductions in HbA1c after 12 weeks (-1.01 +/- 0.06%), with a between-treatment difference of -0.91 +/- 0.09% (p < 0.001). FPG levels reduced from baseline to 12 weeks in the vildagliptin group (-1.2 +/- 0.2 mmol/L), with a between-treatment difference of -1.2 +/- 0.3 mmol/L which was significant (p < 0.001). The proportion of patients achieving HbA1c targets was higher with vildagliptin treatment for all pre-defined responder rate categories. The overall incidence of AEs was comparable between groups (vildagliptin, 46.2% vs. placebo, 43.6%). The overall incidence of hypoglycemic events was low and all events were self treatable without using drug therapy. No severe hypoglycemic events were reported. CONCLUSION: Treatment with vildagliptin 50 mg bid as add-on to insulin with or without metformin resulted in statistically significant reductions in HbA1c in Japanese patients with T2DM. Overall, vildagliptin was well tolerated with a safety profile similar to that of placebo in this patient population. ClinicalTrials.gov Identifier, NCT02002221 FUNDING: Novartis Pharma K.K. PMID- 26620050 TI - Global Histone H4 Acetylation in the Olfactory Bulb of Lactating Rats with Different Patterns of Maternal Behavior. AB - In rats, variations in the levels of neuromodulatory molecules and in the expression of their receptors are observed during pregnancy and postpartum. These changes may contribute to the development and management of maternal behavior. The frequency of licking the pups is used to evaluate maternal care, having mothers with low licking (LL) and high licking (HL) frequencies. Previously, we found that HL had increased levels of transcriptional expression of the receptors for serotonin (HTR1a, HTR1b), estrogen (Eralpha), dopamine (D1a), and prolactin (Prlr) than LL in the olfactory bulb (OB); however, the molecular mechanisms behind this phenomenon are unknown. Since evidences pointed out that epigenetic marks, which may alter gene expression, are modulated by environmental factors such as exercise, diet, maternal care, and xenobiotic exposure, our objective was to verify the acetylation levels of histone-H4 in the OB of LL and HL rats. Maternal behavior was studied for the first 7 postpartum days. LL (n = 4) and HL (n = 5) mothers were selected according to the behavior of licking their pups. Acetylation levels of histone-H4 were determined using the Global Histone-H4 Acetylation Assay Kit and expressed as ng/mg protein (mean +/- SD). Analysis revealed that HL (278.36 +/- 68.95) had increased H4 acetylation levels than LL (183.24 +/- 73.05; p = 0.045). The enhanced expression of the previously studied receptors in the OB could be related, at least in part, to the hyperacetylation status of histone-H4 here observed. Afterward, the modulation of histone acetylation levels could exert a pivotal role through molecular mechanisms involved in the different patterns of maternal behavior. PMID- 26620047 TI - Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II. AB - Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article (Part II), we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. Several studies demonstrate that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared with MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include '-omics'-based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics as well as proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses. PMID- 26620051 TI - Knockdown of IRF6 Attenuates Hydrogen Dioxide-Induced Oxidative Stress via Inhibiting Mitochondrial Dysfunction in HT22 Cells. AB - Oxidative stress-induced cell damage is involved in many neurological diseases. Interferon regulatory factor 6 (IRF6), a member of the IRF family of transcription factors, is required for the differentiation of skin, breast epithelium, and oral epithelium. However, the regulation and function of IRF6 in central nervous system remain unknown. This study aimed to investigate the role of IRF6 in hydrogen peroxide (H2O2)-induced oxidative neuronal injury in HT22 mouse hippocampal cells. Treatment with H2O2 significantly increased the expression of IRF6 at both mRNA and protein levels, and knockdown of IRF6 using specific small interfering RNA reduced H2O2-induced cytotoxicity, as evidenced by increased cell viability and decreased apoptosis. Knockdown of IRF6 attenuated intracellular reactive oxygen species (ROS) generation and lipid peroxidation, and also preserved endogenous antioxidant enzyme activities. The inhibitory effect of IRF6 knockdown on mitochondrial dysfunction was demonstrated by reduced mitochondrial oxidative level, preserved mitochondrial membrane potential (MMP) and ATP generation, as well as attenuated mitochondrial swelling. In addition, down-regulation of IRF6 inhibited the activation of mitochondrial apoptotic factors, whereas IRF6 knockdown together with caspase inhibitors had no extra effect on cell viability and LDH release. These results suggest that knockdown of IRF6 has protective effects against H2O2-induced oxidative stress by reducing ROS accumulation and apoptosis, and these protective effects are dependent on preservation of mitochondrial function. PMID- 26620052 TI - Effects of the Methanolic Extract of Vitellaria paradoxa Stem Bark Against Scopolamine-Induced Cognitive Dysfunction and Oxidative Stress in the Rat Hippocampus. AB - Vitellaria paradoxa C.F. Gaertn (Sapotaceae) is a perennial three which naturally grows in the northern part of Cameroon. It has been traditionally used in the Cameroonian folk medicine for treating inflammation and pain. In the present study, we evaluate the possible anti-amnesic and antioxidative effects of the methanolic extract of V. paradoxa stem bark in an Alzheimer's disease (AD) rat model of scopolamine. Rats received a single injection of scopolamine (1.5 mg/kg) before behavioral testing and were treated with the methanolic extract (25 and 50 mg/kg), daily, for eight continuous days. Also, the antioxidant activity in the hippocampus was assessed using the total content of reduced glutathione and malondialdehyde levels. The scopolamine-treated rats exhibited the following: decrease of exploratory time and discrimination index within the novel object recognition test, decrease of spontaneous alternations percentage within Y-maze task, and increase of working memory errors, reference memory errors, and time taken to consume all five baits within radial arm-maze task. Administration of the methanolic extract significantly improved these parameters, suggesting positive effects on memory formation processes and antioxidant potential. Our results suggest that the methanolic extract ameliorates scopolamine-induced memory impairment by attenuation of the oxidative stress in the rat hippocampus. PMID- 26620053 TI - Anti-beta2 glycoprotein I antibodies in complex with beta2 glycoprotein I induce platelet activation via two receptors: apolipoprotein E receptor 2' and glycoprotein I balpha. AB - Anti-beta2 glycoprotein I (anti-beta2GPI ) antibodies are important contributors to thrombosis, especially in patients with antiphospholipid syndrome (APS). However, the mechanism by which anti-beta2GPI antibodies are involved in the pathogenesis of thrombosis is not fully understood. In this report, we investigated the role of anti- beta2GPI antibodies in complexes with beta2GPI as mediators of platelet activation, which can serve as a potential source contributing to thrombosis. We examined the involvement of the apolipoprotein E receptor 2' (apoER2') and glycoprotein I ba (GP I ba) in platelet activation induced by the anti-beta2GPI /beta2GPI complex. The interaction between the anti beta2GPI /beta2GPI complex and platelets was examined using in vitro methods, in which the Fc portion of the antibody was immobilized using protein A coated onto a microtiter plate. Platelet activation was assessed by measuring GPII b/III a activation and P-selectin expression and thromboxane B2 production as well as p38 mitogen-activated protein kinase phosphorylation. Our results revealed that the anti-beta2GPI /beta2GPI complex was able to activate platelets, and this activation was inhibited by either the anti-GP I balpha antibody or the apoER2' inhibitor. Results showed that the anti-beta2GPI /beta2GPI complex induced platelet activation via GPI ba and apoER2', which may then contribute to the prothrombotic tendency in APS patients. PMID- 26620054 TI - The Potential for Long-Term Sustainability in Seminatural Forestry: A Broad Perspective Based on Woodpecker Populations. AB - We assessed ecological sustainability of seminatural forestry by analyzing 80 year dynamics and the current distribution of all woodpecker species in Estonia. We found that, despite the clear-cutting-based forestry system, woodpeckers inhabited commercial seminatural forests in substantial numbers, including the species generally considered vulnerable to timber harvesting. The only negative trend, a drastic decline in the Green Woodpecker, paralleled the loss of seminatural, wooded grasslands and is mostly an issue for landscape planning and agricultural land use. Major silvicultural factors supporting other species in commercial forests include natural regeneration with multiple native tree species and deadwood abundance. In such context, the main role of protected areas is to provide ecological resilience; however, we estimated that the current strict reserves could further double their carrying capacities for woodpeckers through successional recovery and, perhaps, active restoration. The long time series used were instrumental in detecting unexpected dynamics and the impacts of climatically extreme years. We conclude that (1) seminatural forestry can serve as a basis for reconciling timber harvesting and biodiversity protection at the landscape scale, given appropriate attention to key structures and landscape zoning and (2) woodpeckers represent a biological indicator system for the sustainability of forest landscapes in Europe. PMID- 26620055 TI - D14 repeat polymorphism of the asporin gene is associated with primary osteoarthritis of the knee in a Mexican Mestizo population. AB - BACKGROUND: Asporin is a novel extracellular matrix protein (ECM) with an important role in the development of osteoarthritis (OA), because it has been reported that functional polymorphisms in the aspartic acid repeat (D) of the asporin gene (ASPN) are associated with susceptibility to OA. AIM: This study was planned to investigate the association of the ASPN polymorphism with primary OA of the knee in a Mexican population, including several countryside regions. METHODS: We conducted a case-control study in which 93 cases with primary OA of the knee and 118 controls were included. Cases included patients > 40 years of age, with a body mass index (BMI) <= 27 and a radiologic score for OA of the knee of >= 2. Controls were subjects > 40 years of age with a radiologic score of < 2. The D repeat polymorphism was genotyped and logistic regression was developed to evaluate risk magnitude. RESULTS: The D14 allele was more common in our cases and was associated with an increased risk for developing OA, while the frequencies of the remaining alleles did not exhibit differences. CONCLUSION: Our data suggest that the D14 allele of the ASPN polymorphism could exert an influence on primary OA of the knee etiology in a Mexican Mestizo population. PMID- 26620056 TI - Stridor: a rare presentation of oesophageal malignancy. AB - A middle-aged ex-smoker, with a history of curative surgery for oesophageal squamous cell carcinoma 7 years earlier, presented to the casualty department at Mater Dei Hospital with stridor and a 2-week history of progressively worsening dyspnoea. A thoracic CT scan showed the presence of a posterior mediastinal mass involving the upper half of the stomach and posterior wall of the trachea. Histology of an exophytic ulcerating lesion at 25 cm of the oesophagus was that of squamous cell carcinoma. Bronchoscopy performed to ascertain the cause of the stridor showed the trachea to be 70% occluded. The patient showed symptomatic improvement with radiotherapy and intravenous dexamethasone; however, he passed away a few weeks later due to respiratory failure secondary to tracheal occlusion. PMID- 26620057 TI - Examining Clinical Predictors of Change in Recreational Preference Congruence Among Nursing Home Residents Over Time. AB - OBJECTIVE: There remains a significant gap in the field regarding the measurement of preference-based care over time in nursing homes (NHs). This study discusses the use of a quality indicator that tracks recreational preference congruence (PC; that is, the match between NH residents' important preferences in recreational activities and their weekly attendance in these preferred activities). METHOD: Using a sample of 199 older adults, we examine the change in PC over 52 weeks using multilevel-mixed effects regression analyses. RESULTS: PC over time is highly variable and residents with greater functional limitations (vision, language comprehension, incontinence) and no diagnoses of mental health or neurological disorders have lower PC over time. DISCUSSION: Certain clinical characteristics have greater impact on resident PC over time. Particular attention needs to be given to the recreational attendance of residents with incontinence, and visual and language comprehension difficulties. PMID- 26620058 TI - Ultrasensitive detection of protease activity of anthrax and botulinum toxins by a new PCR-based assay. AB - Anthrax and botulism are dangerous infectious diseases that can be fatal unless detected and treated quickly. Fatalities from these diseases are primarily due to endopeptidase toxins secreted by the pathogens. Rapid and sensitive detection of the presence of active toxins is the key element for protection from natural outbreaks of anthrax and botulism, as well as from the threat of bioterrorism. We describe an ultrasensitive polymerase chain reaction (PCR)-based assay for detecting proteolytic activity of anthrax and botulinum toxins using composite probes consisting of covalent peptide-DNA conjugate for the detection of anthrax, and noncovalent protein-aptamer assembly to assay botulinum toxin activity. Probes immobilized on the solid-phase support are cleaved by toxins to release DNA, which is detected by real-time PCR. Both assays can detect subpicogram quantities of active toxins isolated from composite matrices. Special procedures were developed to isolate intact toxins from the matrices under mild conditions. The assay is rapid, uses proven technologies, and can be modified to detect other proteolytic and biopolymer-degrading enzymes. PMID- 26620059 TI - Trichodysplasia Spinulosa in a 20-Month-Old Girl With a Good Response to Topical Cidofovir 1%. AB - Trichodysplasia spinulosa (TS) is a rare entity, characterized by a follicular digitate keratosis predominantly affecting the face and variable degrees of hair loss, most severely facial hair, that occurs in immunosuppressed individuals, and is considered to be a viral infection caused by a human polyomavirus, the "TS associated polyomavirus." Histologically it is characterized by hair follicles with excessive inner root-sheath differentiation and intraepithelial viral inclusions. Correlation of these findings with clinical features is required for diagnosis. Treatment with antiviral agents appears to be the most effective. We report the occurrence of TS in a 20-month-old girl with multivisceral transplantation due to short-bowel syndrome secondary to intestinal atresia and gastroschisis. The patient was treated with cidofovir 1% cream, with significant improvement and without any adverse effects. We describe the youngest patient, to our knowledge, with TS. PMID- 26620060 TI - The Family Perspective on Hospital to Home Transitions: A Qualitative Study. AB - BACKGROUND AND OBJECTIVE: Transitions from the hospital to home can be difficult for patients and families. Family-informed characterization of this vulnerable period may facilitate the identification of interventions to improve transitions home. Our objective was to develop a comprehensive understanding of hospital-to home transitions from the family perspective. METHODS: Using qualitative methods, focus groups and individual interviews were held with caregivers of children discharged from the hospital in the preceding 30 days. Focus groups were stratified based upon socioeconomic status. The open-ended, semistructured question guide included questions about communication and understanding of care plans, transition home, and postdischarge events. Using inductive thematic analysis, investigators coded the transcripts, resolving differences through consensus. RESULTS: Sixty-one caregivers participated across 11 focus groups and 4 individual interviews. Participants were 87% female and 46% nonwhite; 38% were the only adult in their household, and 56% resided in census tracts with >=15% of residents living in poverty. Responses from participants yielded a conceptual model depicting key elements of families' experiences with hospital-to-home transitions. Four main concepts resulted: (1) "In a fog" (barriers to processing and acting on information), (2) "What I wish I had" (desired information and suggestions for improvement), (3) "Am I ready to go home?" (discharge readiness), and (4) "I'm home, now what?" (confidence and postdischarge care). CONCLUSIONS: Transitions from hospital to home affect the lives of families in ways that may affect patient outcomes postdischarge. The caregiver is key to successful transitions, and the family perspective can inform interventions that support families and facilitate an easier re-entry to the home. PMID- 26620061 TI - The Individuals With Disabilities Education Act (IDEA) for Children With Special Educational Needs. AB - The pediatric health care provider has a critical role in supporting the health and well-being of children and adolescents in all settings, including early intervention (EI), preschool, and school environments. It is estimated that 15% of children in the United States have a disability. The Individuals with Disabilities Education Act entitles every affected child in the United States from infancy to young adulthood to a free appropriate public education through EI and special education services. These services bolster development and learning of children with various disabilities. This clinical report provides the pediatric health care provider with a summary of key components of the most recent version of this law. Guidance is also provided to ensure that every child in need receives the EI and special education services to which he or she is entitled. PMID- 26620063 TI - Maltreatment of Children Under Age 2 With Specific Birth Defects: A Population Based Study. AB - BACKGROUND AND OBJECTIVES: Children with disabilities are at an increased risk for maltreatment. However, the risk of maltreatment is unknown for children with specific types of birth defects. This study was conducted to determine whether the risk and predictors of maltreatment differ between children with and without 3 birth defects: Down syndrome, cleft lip with/without cleft palate, and spina bifida. METHODS: This population-based study of substantiated childhood maltreatment was conducted in Texas from 2002 to 2011. Linked data were used to describe the risk and types of maltreatment that occurred before age 2 years in children with and without specific birth defects. Poisson regression was used to identify predictors of maltreatment and assess differences in those predictors between children with and without these specific birth defects. RESULTS: The risk of maltreatment (any type) in children with cleft lip with/without cleft palate and spina bifida was increased by 40% and 58%, respectively, compared with children with no birth defects. The risk of any maltreatment was similar between children with Down syndrome and unaffected children. Across birth defect groups, the risk of medical neglect was 3 to 6 times higher than in the unaffected group. Child-, family-, and neighborhood-level factors predicted maltreatment in children with and without birth defects. CONCLUSIONS: The overall risk of substantiated maltreatment was significantly higher for some but not all birth defect groups. The factors associated with increased risk were similar across groups. Enhancement of existing maltreatment prevention and early intervention programs may be effective mechanisms to provide at-risk families additional support. PMID- 26620064 TI - Critical Elements for the Pediatric Perioperative Anesthesia Environment. AB - The American Academy of Pediatrics proposes guidance for the pediatric perioperative anesthesia environment. Essential components are identified to optimize the perioperative environment for the anesthetic care of infants and children. Such an environment promotes the safety and well-being of infants and children by reducing the risk of adverse events. PMID- 26620065 TI - Newborn Screening for Biliary Atresia. AB - Biliary atresia is the most common cause of pediatric end-stage liver disease and the leading indication for pediatric liver transplantation. Affected infants exhibit evidence of biliary obstruction within the first few weeks after birth. Early diagnosis and successful surgical drainage of bile are associated with greater survival with the child's native liver. Unfortunately, because noncholestatic jaundice is extremely common in early infancy, it is difficult to identify the rare infant with cholestatic jaundice who has biliary atresia. Hence, the need for timely diagnosis of this disease warrants a discussion of the feasibility of screening for biliary atresia to improve outcomes. Herein, newborn screening for biliary atresia in the United States is assessed by using criteria established by the Discretionary Advisory Committee on Heritable Disorders in Newborns and Children. Published analyses indicate that newborn screening for biliary atresia by using serum bilirubin concentrations or stool color cards is potentially life-saving and cost-effective. Further studies are necessary to evaluate the feasibility, effectiveness, and costs of potential screening strategies for early identification of biliary atresia in the United States. PMID- 26620067 TI - Parental Monitoring and Its Associations With Adolescent Sexual Risk Behavior: A Meta-analysis. AB - CONTEXT: Increasingly, health care providers are using approaches targeting parents in an effort to improve adolescent sexual and reproductive health. Research is needed to elucidate areas in which providers can target adolescents and parents effectively. Parental monitoring offers one such opportunity, given consistent protective associations with adolescent sexual risk behavior. However, less is known about which components of monitoring are most effective and most suitable for provider-initiated family-based interventions. OBJECTIVE: We performed a meta-analysis to assess the magnitude of association between parental monitoring and adolescent sexual intercourse, condom use, and contraceptive use. DATA SOURCES: We conducted searches of Medline, the Cumulative Index to Nursing and Allied Health Literature, PsycInfo, Cochrane, the Education Resources Information Center, Social Services Abstracts, Sociological Abstracts, Proquest, and Google Scholar. STUDY SELECTION: We selected studies published from 1984 to 2014 that were written in English, included adolescents, and examined relationships between parental monitoring and sexual behavior. DATA EXTRACTION: We extracted effect size data to calculate pooled odds ratios (ORs) by using a mixed-effects model. RESULTS: Higher overall monitoring (pooled OR, 0.74; 95% confidence interval [CI], 0.69-0.80), monitoring knowledge (pooled OR, 0.81; 95% CI, 0.73-0.90), and rule enforcement (pooled OR, 0.67; 95% CI, 0.59-0.75) were associated with delayed sexual intercourse. Higher overall monitoring (pooled OR, 1.12; 95% CI, 1.01-1.24) and monitoring knowledge (pooled OR, 1.14; 95% CI, 1.01 1.31) were associated with greater condom use. Finally, higher overall monitoring was associated with increased contraceptive use (pooled OR, 1.42; 95% CI, 1.09 1.86), as was monitoring knowledge (pooled OR, 2.27; 95% CI, 1.42-3.63). LIMITATIONS: Effect sizes were not uniform across studies, and most studies were cross-sectional. CONCLUSIONS: Provider-initiated family-based interventions focused on parental monitoring represent a novel mechanism for enhancing adolescent sexual and reproductive health. PMID- 26620068 TI - IgE Immunoadsorption Knocks Down the Risk of Food-Related Anaphylaxis. AB - The effects of an immunoadsorption procedure, specifically designed to remove immunoglobulin E (IgE), on food-induced anaphylaxis have never been evaluated. We evaluate the effects of IgE removal on the allergic thresholds to foods. A 6-year old boy with anaphylaxis to multiple foods and steroid-resistant unstable allergic asthma displayed serum IgE levels of 2800 to 3500 kU/L. To lower IgE serum concentrations, which could be overridden by a high dose of omalizumab, 1.5 plasma volumes were exchanged in 8 apheresis sessions. During the procedure, serum IgE levels fell to 309 kU/L. After the procedure, the threshold of reactivity to baked milk increased from 0.125 to 5 g of milk protein (full tolerance) after the first session, and the threshold of reactivity to hazelnut increased from 0.037 to 0.142 g of protein after the first session, 0.377 g after the eighth, and 1.067 g (full tolerance) after the first administration of omalizumab. Immediately after the sixth IgE immunoadsorption, we started omalizumab therapy. In the next 40 days, the threshold of reactivity to hazelnut increased to 7.730 (full tolerance). Asthma control was obtained, treatment with montelukast was stopped, and fluticasone was tapered from 500 to 175 MUg/day. The boy became partially or fully tolerant to all the tested foods, and quality of life was improved. IgE immunoadsorption, used to establish the starting basis for omalizumab administration, is able to increase the tolerance threshold to foods. PMID- 26620069 TI - Central obesity in India is no longer confined to wealthier people, survey finds. PMID- 26620070 TI - Relationship Between Comorbidities in Patients With Cognitive Complaint and Caregiver Burden: A Cross-Sectional Study. AB - BACKGROUND/OBJECTIVES: Informal caregivers of patients with a cognitive impairment may face exhaustion while taking care of their relatives, and are themselves at higher risk of disease. The objective was to assess the relationship between patients' comorbidities evaluated with the Charlson index, and the caregiver burden, independently of health disorders related to cognitive impairment. DESIGN: Cross-sectional observational study. SETTING: Memory clinic at the University Hospital of Lyon. PARTICIPANTS: Outpatients with cognitive complaint and consulting a Clinical and Research Memory Centre of Lyon (n = 1300). MEASUREMENTS: Comorbidity was measured using the Charlson Comorbidity Index related to age (CCI). The caregiver burden was measured with the short version of the Zarit Burden Interview (ZBI). The relationship was assessed between the CCI and the mini-Zarit and other patients' characteristics: behavior, cognition, autonomy as assessed respectively by the Neuropsychiatric Inventory (NPI), Mini Mental State Examination (MMSE), Instrumental Activities of Daily Living (IADL), etiology, and stage of the cognitive impairment. RESULTS: The study included 1300 outpatients: mean age: 80.8 +/- 7 years. The mean CCI was 4.8 +/- 1.7. The mini-Zarit score: 3.1 +/- 2.0. The caregiver burden increased by 0.22 per unit of CCI (95% confidence interval 0.15-0.28, P < .001) in unadjusted analysis. The caregiver burden remained significantly associated with CCI, after adjustment for the MMSE, IADL, and NPI. CONCLUSION: The caregiver burden is higher when patients' comorbidities increase, independently of behavioral and psychological symptoms, level of functional autonomy, and the stage of the cognitive disease. However, dementia may be the comorbidity that contributes the most to caregiver burden. PMID- 26620071 TI - Comprehensive Geriatric Care: Effectiveness as Well as Efficacy. PMID- 26620072 TI - Telemedicine: Coming to Nursing Homes in the Near Future. PMID- 26620073 TI - Trajectories of Disability Among Older Persons Before and After a Hospitalization Leading to a Skilled Nursing Facility Admission. AB - OBJECTIVES: To identify distinct sets of disability trajectories in the year before and after a Medicare qualifying skilled nursing facility (Q-SNF) admission, evaluate the associations between the pre-and post-Q-SNF disability trajectories, and determine short-term outcomes (readmission, mortality). DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study including 754 community dwelling older persons, 70+ years, and initially nondisabled in their basic activities of daily living. The analytic sample included 394 persons, with a first hospitalization followed by a Q-SNF admission between 1998 and 2012. MAIN OUTCOMES AND MEASURES: Disability in the year before and after a Q-SNF admission using 13 basic, instrumental, and mobility activities. Secondary outcomes included 30-day readmission and 12-month mortality. RESULTS: The mean (SD) age of the sample was 84.9 (5.5) years. We identified 3 disability trajectories in the year before a Q-SNF admission: minimal disability (37.3% of participants), mild disability (44.6%), and moderate disability (18.2%). In the year after a Q-SNF admission, all participants started with moderate to severe disability scores. Three disability trajectories were identified: substantial improvement (26.0% of participants), minimal improvement (36.5%), and no improvement (37.5%). Among participants with minimal disability pre-Q-SNF, 52% demonstrated substantial improvement; the other 48% demonstrated minimal improvement (32%) or no improvement (16%) and remained moderately to severely disabled in the year post-Q SNF. Among participants with mild disability pre-Q-SNF, 5% showed substantial improvement, whereas 95% showed little to no improvement. Of participants with moderate disability pre-Q-SNF, 15% remained moderately disabled showing little improvement, whereas 85% showed no improvement. Participants who transitioned from minimal disability pre-Q-SNF to no improvement post-Q-SNF had the highest rates of 30-day readmission and 12-month mortality (rate/100 person-days 1.3 [95% CI 0.6-2.8] and 0.3 [95% CI 0.15-0.45], respectively). CONCLUSIONS: Among older persons, distinct disability trajectories were observed in the year before and after a Q-SNF admission. The likelihood of improvement in disability was greatly constrained by the pre-Q-SNF disability trajectory. Most older persons remained moderately to severely disabled in the year following a Q-SNF admission. PMID- 26620074 TI - Two different centered monoclinic crystals of the E. coli outer-membrane protein OmpF originate from the same building block. AB - Macromolecule crystal formation can be divided in two major steps: 1. the formation of a nucleus and 2. the growth of this nucleus into a full mature crystal. The latter is well described and understood, while the former remains elusive due to the difficulty to study it and is described by nucleation theories. Here we report the structure of the Escherichia coli outer membrane porin OmpF in two centered monoclinic space groups. Strikingly, the two crystals originate from the same building block, made of two trimers of OmpF interacting via their rough side. The different crystallization conditions trigger the formation of distinct arrangement of these building blocks, leading to the formation of translational non-crystallographic symmetry (tNCS) in one case, made possible by the loose lateral packing mediated by detergents. In light of nucleation theories, these results allow us to speculate that these two crystals originate from nuclei made of either clusters of building blocks, or already forming columns that later associate laterally using detergents as glue. PMID- 26620075 TI - Mineralocorticoid receptor mediated liposomal delivery system for targeted induction of apoptosis in cancer cells. AB - Mineralocorticoid receptors (MRs) are nuclear hormone receptors that are ubiquitously present in all cell types and are known to mediate distinct physiological functions like regulating Na(+) and K(+) balance and water excretion. MRs are linked to cell proliferation and can be exploited for the targeted control of cell mass in cancer. The present study is aimed towards extending the concept of using MR ligand spironolactone for selective delivery of genes in cancer cells. The lipoplex (SP) has shown MR mediated targeted transfections as indicated by receptor down-regulation studies using MR antagonists and siRNA. SP-targeted delivery of genes resulted in apoptosis in cell-specific manner while free drug was found to be cytotoxic irrespective of the cancerous or non-cancerous nature. In conclusion, this study presents MR as a target for efficiently delivering anticancer genes and thereby treating cancer through MR-mediated pathway. PMID- 26620076 TI - Meta-audit of laboratory ISO accreditation inspections: measuring the old emperor's clothes. AB - Accreditation to ISO/IEC 17025 is required for EC official food control and veterinary laboratories by Regulation (EC) No. 882/2004. Measurements in hospital laboratories and clinics are increasingly accredited to ISO/IEC 15189. Both of these management standards arose from command and control military standards for factory inspection during World War II. They rely on auditing of compliance and have not been validated internally as assessment bodies require of those they accredit. Neither have they been validated to criteria outside their own ideology such as the Cochrane principles of evidence-based medicine which might establish whether any benefit exceeds their cost. We undertook a retrospective meta-audit over 14 years of internal and external laboratory audits that checked compliance with ISO 17025 in a public health laboratory. Most noncompliances arose solely from clauses in the standard and would not affect users. No effect was likely from 91% of these. Fewer than 1% of noncompliances were likely to have consequences for the validity of results or quality of service. The ISO system of compliance auditing has the performance characteristics of a poor screening test. It adds substantially to costs and generates more noise (false positives) than informative signal. Ethical use of resources indicates that management standards should not be used unless proven to deliver the efficacy, effectiveness, and value required of modern healthcare interventions. PMID- 26620077 TI - SOLiD SAGE sequencing shows differential gene expression in jejunal lymph node samples of resistant and susceptible red deer (Cervus elaphus) challenged with Mycobacterium avium subsp. paratuberculosis. AB - This study compared in vivo lymph node gene expression levels between six young red deer that were either relatively resistant (R) or susceptible (S) to paratuberculosis following experimental challenge with Mycobacterium avium subsp. paratuberculosis. Intestinal lymph nodes were biopsied at 4, 12 and 50 weeks post challenge (pc) and parallel changes in histopathology, immunology and bacterial load monitored. SOLiD SAGE (serial analysis of gene expression) next generation sequencing of biopsied lymph node samples generated a total of 373 million transcript tags 26-28bp in length after filtering. A total of 36,632 unique transcripts were identified and 14,325 of these were able to be annotated. The copy number of each transcript was counted, averaged and compared for R and S animals (R-S). P values and False Discovery Rates (FDR) were calculated for each transcript. Genes differentially upregulated >=2 fold (FDR<0.5) totalled 9, 40 and 32 in R animals (+ values) and 23, 164 and 47 in S animals (- values) at weeks 4, 12, and 50pc, respectively. Transcripts displaying greatest differential expression between R and S animals at each time point were IFIT2 (189 fold) and S100A8 (-32.7 fold) at week 4, LRR1 (52.7 fold), SERPINF2 (-214.6 fold) at week 12 and CEACAM8 (84.6 fold), and STK31 (-129.5 fold) at week 50, respectively. All 9 genes significantly upregulated at week 4 in R animals relate specifically to host defence and all involve Type I interferon stimulated genes. By contrast genes upregulated in S animals at week 4, relate predominantly to inflammation, but also involve adaptive immune responses, mitochondrial function and apoptosis regulation. At week 12, the genes differentially upregulated in R animals are linked predominantly to regulation of adaptive immunity and mucosal immunity, while many of the genes in S animals are associated with pro-inflammatory interleukins involved with innate and adaptive immunity. These correlated with greater lesion severity and higher MAP numbers in lymph nodes of S animals. By week 50 the number of upregulated genes declined in both groups. A number of genes upregulated in R animals appear to be associated with host resistance and regulation of adaptive immunity, especially CEACAM8. Genes upregulated in S animals involve antigen presentation (ENDOD1) and gut associated immune pathology (HSH2D). In conclusion, gene expression in jejunal lymph nodes of resistant and susceptible deer infer that the resistant phenotype is associated with pathways of adaptive immunity, while susceptibility is linked with upregulated non protective pro-inflammatory responses, following experimental MAP infection. PMID- 26620078 TI - Transcriptome analysis of the endangered Chinese giant salamander (Andrias davidianus): Immune modulation in response to Aeromonas hydrophila infection. AB - The endangered Chinese giant salamander (Andrias davidianus) is the largest extant amphibian species. Disease outbreaks represent one of the major factors threatening A. davidianus populations in the wild and the viability of artificial breeding programmes. Development of future immune therapies to eliminate infectious disease in A. davidianus is dependent on a thorough understanding of the immune mechanisms elicited by pathogen encounters. To this end we have undertaken, for the first time in amphibians, differential transcriptome analysis of the giant salamander response to Aeromonas hydrophila, one of the most devastating pathogens affecting amphibian populations. Out of 87,204 non redundant consensus unigenes 19,216 were annotated, 6834 of which were upregulated and 906 down-regulated following bacterial infection. 2058 unigenes were involved with immune system processes, including 287 differentially expressed unigenes indicative of the impact of bacterial infection on several innate and adaptive immune pathways in the giant salamander. Other pathways not directly associated with immune-related activity were differentially expressed, including developmental, structural, molecular and growth processes. Overall, this work provides valuable insights into the underlying immune mechanisms elicited during bacterial infection in amphibians that may aid in the future development of disease control measures in protecting the Chinese giant salamander. With the unique position of amphibians in the transition of tetrapods from aquatic to terrestrial habitats, our study will also be invaluable towards the further understanding of the evolution of tetrapod immunity. PMID- 26620079 TI - Virulence factors, antimicrobial resistance pattern and molecular analysis of Enterococcal strains isolated from burn patients. AB - The enterococci are emerging as a significant cause of hospital acquired infections. The pathogenesis of enterococci is attributed to the production of virulence factors and resistance to antibiotics. The purpose of the study was to assess the prevalence of genes encoding virulence factor, antimicrobial resistance determinant and molecular characteristic of enterococci isolated from burn patients. A total of 57 enterococci isolated from wound specimens of patients with burn injury were characterized by phenotypic and genotypic methods. The efaA was the most frequently detected gene (100%), followed by ace (89.1%), asa1 (54.3%), gelE (50%), cylA (30.4%), esp (23.9%) and hyl (8.7%) among Enterococcus faecalis isolates. The Enterococcus faecium strains carried asa1 and ace genes. All isolates were susceptible to tigecycline and vancomycin. Inducible resistance to clindamycin was not observed and 64% of isolates had resistance to erythromycin. High-level gentamicin resistance (HLGR) was seen in 65.2% of E. faecalis strains. The aac(6')-Ie-aph(2")-Ia gene was found in 47.8% of E. faecalis isolates. Our data indicated that the efaA, ace and asa1 were most frequent genes encoding virulence factors among Enterococci isolated from burn wound infection and the incidence of virulence factor genes was higher in E. faecalis rather than other isolates. The molecular analysis demonstrated high genetic diversity among Enterococcus populations from burn patients. PMID- 26620080 TI - Antioxidant defense response induced by Trichoderma viride against Aspergillus niger Van Tieghem causing collar rot in groundnut (Arachis hypogaea L.). AB - The study was conducted to examine the antioxidant enzymes induced by Trichoderma viride JAU60 as initial defense response during invasion of rot pathogen Aspergillus niger Van Tieghem in five groundnut varieties under pot culture. Seed treatment of T. viride JAU60 reduced 51-58% collar rot disease incidence in different groundnut varieties under pathogen infected soil culture. The activities of the antioxidant enzymes, viz., superoxide dismutase (SOD, EC 1.15.1.1), guaiacol peroxidase (GPX, EC 1.11.1.7) and ascorbate peroxidase (APX, EC 1.11.1.11), elevated in response to pathogen infection, in higher rate by tolerant varieties (J-11 and GG-2) compared with susceptible (GAUG-10, GG-13, GG 20) and further induced by T. viride treatment. Trichoderma treatment remarkably increased the 2.3 fold SOD, 5 fold GPX and 2.5 fold APX activities during disease development in tolerant varieties and the same was found about 1.2, 1.5 and 2.0 folds, respectively, in susceptible varieties. Overall, T. viride JAU60 treated seedlings (T3) witnessed higher activities of SOD (1.5 fold), GPX (3.25 fold) and APX (1.25 fold) than pathogen treatment (T2) possibly suggest the induction of antioxidant defense response by Trichoderma bio-controller to combat oxidative burst produced by invading pathogen. PMID- 26620081 TI - Adjuvant effect of cranberry proanthocyanidin active fraction on antivirulent property of ciprofloxacin against Pseudomonas aeruginosa. AB - Quorum sensing inhibitors (QSIs) act as antivirulent agents since quorum sensing (QS) plays a vital role in regulating pathogenesis of Pseudomonas aeruginosa. However, application of single QSI may not be effective as pathogen is vulnerable to successful mutations. In such conditions, combination of QSIs can be exploited as there can be synergistic or adjuvant action. In the present study, we evaluated the antivirulence efficacy of combination of Vaccinium macrocarpon proanthocyanidin active fraction (PAF) and ciprofloxacin (CIP) at their sub-MICs using standard methods followed by analysis of their mode of action on QS using TLC and molecular docking. There was significant improvement in action of CIP when it was combined with PAF in reducing the QS controlled virulence factors (p < 0.05), motilities and biofilm of P. aeruginosa. TLC profiles of QS signals [(Acyl homoserine lactone (AHL) and Pseudomonas quinolone signal (PQS)] indicated that CIP in combination with PAF, besides showing inhibitory action on production of AHLs, also modulated production and inactivation of PQS. Docking scores also supported the observation. We therefore hypothesize that PAF-CIP combination, having improved anti-virulence property; can be exploited as a potent drug pairing against P. aeruginosa. PMID- 26620082 TI - High potential of adhesion to biotic and abiotic surfaces by opportunistic Staphylococcus aureus strains isolated from orthodontic appliances. AB - Orthodontic and other oral appliances act as reservoir of opportunistic pathogens that can easily become resistant to antibiotics and cause systemic infections. The aim of this study was to investigate the ability of Staphylococcus aureus strains isolated from healthy patients with orthodontic appliances, to adhere to biotic (HeLa cells) and abiotic surfaces (polystyrene and dental alloy). Adhesive ability to polystyrene was tested by crystal violet staining and quantitative biofilm production on dental alloy surfaces was evaluated by MTT reduction assay. In addition, the presence of icaA and icaD genes was achieved by polymerase chain reaction (PCR). Qualitative biofilm production revealed that 70.6% of strains were slime producers. The metabolic activity of S. aureus biofilms on dental alloy surfaces was high and did not differ between tested strains. Moreover, all the isolates were adhesive to HeLa cells and 94% of them harbor icaA and icaD genes. Considerable adhesion and internalization capacity to the epithelial HeLa cells and strong biofilm production abilities together, with a high genotypic expression of icaA/icaD genes are an important equipment of S. aureus to colonize orthodontic appliances and eventually to disseminate towards other body areas. PMID- 26620083 TI - Involvement of oxidative stress in bactericidal activity of 2-(2-nitrovinyl) furan against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. AB - The involvement of reactive oxygen species and oxidative stress in 2-(2 nitrovinyl) furan mediated bacterial cell death was investigated in Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. Time kill assay resulted in significant decrease in the optical density and colony-forming unit (CFU) of E. coli, P. aeruginosa and S. aureus. The level of superoxide anion radical and nitric oxide increased significantly in concentration dependent when compared with dimethyl sulfoxide (DMSO) treated bacteria. Similar concentration dependent increase in the activity of superoxide dismutase and catalase were recorded. The non-enzymatic antioxidant glutathione decreased significantly with a concomitant increase in glutathione disulfide. The level of malondialdehyde and fragmented DNA increased significantly in the bacterial cells treated with 2-(2-nitrovinyl) furan when compared with DMSO treated cells. The CFU of E. coli, P. aeruginosa and S. aureus following exposure to 2-(2-nitrovinyl) furan increased significantly (p < 0.05) in the presence of 2,2' bipyridyl, an Fe chelator, significantly when compared with only 2-(2-nitrovinyl) furan suggesting the involvement of hydroxyl radical in the cell death. The available data from this study showed that 2-(2-nitrovinyl) furan induced oxidative stress in E. coli, P. aeruginosa and S. aureus as evident from elevated levels of superoxide anion radical nitric oxides and antioxidant enzymes. PMID- 26620085 TI - FGF23-S129F mutant bypasses ER/Golgi to the circulation of hyperphosphatemic familial tumoral calcinosis patients. AB - FGF23 is essential for the homeostasis of phosphate, and vitamin D. Loss-of function mutations in this hormone cause hyperphosphatemic familial tumoral calcinosis (HFTC). Earlier reports suggested that intact FGF23 from loss of function mutants such as FGF23/S129F (iFGF23/S129F) is retained intracellularly while the carboxy-terminal fragment is secreted. We sought to investigate the fate of iFGF23/S129F mutant hormone in vivo and in vitro. Five patients clinically diagnosed with HFTC and confirmed by DNA sequencing to carry the c.386 C>T; p.S129F mutation in the homozygous state were studied. Healthy and heterozygous individuals were used as controls in the study. Using ELISA assays, we showed that iFGF23/S129F was 2-5 folds higher in patients' plasma, compared to heterozygous or healthy controls. Importantly, the mutant hormone could not be detected in the patients' sera. However, using proteinase inhibition profiling, we found that a serum metalloproteinase degraded the iFGF23/S129F explaining our failure to detect it in sera. The serum metalloproteinase degrades the WT and the mutant at different rates. Also, confocal microscopy imaging using wild-type (WT) FGF23 or FGF23/S129F mutant in transiently transfected HEK293 and HeLa cells showed weak staining of the Golgi complex with some vesicular staining resembling the ER. Additionally, FGF23 variants (FGF23/WT, FGF23/S129F, FGF23/S71G, and FGF23/R176Q) from stably transfected HEK293 cells secreted high levels into a serum-free medium that can be detected by ELISA and Western blot. Our results suggest that iFGF23/S129F mutant bypasses the ER/Golgi quality control system to the circulation of HFTC patients by an unknown pathway. Finally, we hypothesize that either the mutant hormone is unable to bind alpha-Klotho-FGFR1c, or it binds the dyad receptor with low affinity and, therefore, incapable of initiating maximal intracellular signaling. Our findings raise the potential use of the WT hormone in therapies of some HFTC patients. PMID- 26620084 TI - Physical activity, sedentary behavior, and vitamin D metabolites. AB - Physical activity is associated with circulating 25-hydroxyvitamin D (25(OH)D). However, the influence of activity and/or sedentary behavior on the biologically active, seco-steroid hormone 1alpha,25-dihydroxyvitamin D (1,25(OH)2D) is unknown. We conducted a cross-sectional analysis among ursodeoxycholic acid (UDCA) randomized trial participants (n=876) to evaluate associations between physical activity, sedentary behavior, and circulating vitamin D metabolite concentrations. Continuous vitamin D metabolite measurements and clinical thresholds were evaluated using multiple linear and logistic regression models, mutually adjusted for either 1,25(OH)2D or 25(OH)D and additional confounding factors. A statistically significant linear association between 1,25(OH)2D and moderate-vigorous physical activity per week was strongest among women (beta (95% CI): 3.10 (1.51-6.35)) versus men (beta (95% CI): 1.35 (0.79-2.29)) in the highest tertile of activity compared to the lowest (p-interaction=0.003). Furthermore, 25(OH)D was 1.54ng/ml (95% CI 1.09-1.98) higher per hour increase in moderate-vigorous activity (p=0.001) and odds of sufficient 25(OH)D status was higher among physically active participants (p=0.001). Sedentary behavior was not significantly associated with either metabolite in linear regression models, nor was a statistically significant interaction by sex identified. The current study identified novel associations between physical activity and serum 1,25(OH)2D levels, adjusted for 25(OH)D concentrations. These results identify the biologically active form of vitamin D as a potential physiologic mechanism related to observed population-level associations between moderate-vigorous physical activity with bone health and chronic disease risk. However, future longitudinal studies are needed to further evaluate the role of physical activity and vitamin D metabolites in chronic disease prevention. PMID- 26620086 TI - Periodontal disease exacerbates systemic ovariectomy-induced bone loss in mice. AB - Periodontal pathogens and/or inflammatory products from periodontitis participate in the development or progression of systemic diseases. In this context, periodontitis acts as a modifying factor to systemic health, including diabetes and cardiovascular diseases. Osteoporosis is an increasingly prevalent condition in our aging population and considered a risk factor for periodontal disease, but the effect of periodontitis on systemic bone homeostasis is unknown. We thus evaluated the effects of experimental periodontitis (EP) on systemic bone loss and the influence of estrogen deficiency in this context, using a mouse model of combined periodontitis and osteoporosis. Experimental periodontitis (EP) was induced by a ligature insertion around the mandibular first molars and Porphyromonas gingivalis infection. Three-dimensional microcomputed tomographic analyses performed 48days following infection revealed that EP and ovariectomy (OVX) induced a significantly higher femoral and mandibular bone loss compared to EP or OVX alone. EP alone did not induce systemic bone loss. In addition, the EP+OVX and EP groups showed significantly higher levels of tumor necrosis factor (TNF)-alpha than OVX and control groups at end point. These results suggest that periodontitis could be a risk factor for systemic bone loss, especially in post menopausal women, and warrant further clinical investigations to confirm this association and propose adapted prophylactic and curative therapies. PMID- 26620087 TI - Ihh and PTH1R signaling in limb mesenchyme is required for proper segmentation and subsequent formation and growth of digit bones. AB - Digit formation is a process, which requires the proper segmentation, formation and growth of phalangeal bones and is precisely regulated by several important factors. One such factor is Ihh, a gene linked to BDA1 and distal symphalangism in humans. In existing mouse models, mutations in Ihh have been shown to cause multiple synostosis in the digits but lead to perinatal lethality. To better study the exact biological and pathological events which occur in these fused digits, we used a more viable Prx1-Cre;Ihh(fl/fl) model in which Cre recombinase is expressed during mesenchymal condensation in the earliest limb buds at E9.5 dpc and found that mutant digits continuously fuse postnatally until phalanges are finally replaced by an unsegmented "one-stick bone". Mutant mice displayed osteocalcin-positive mature osteoblasts, but had reduced proliferation and abnormal osteogenesis. Because of the close interaction between Ihh and PTHrP during endochondral ossification, we also examined the digits of Prx1 Cre;PTH1R(fl/fl) mice, where the receptor for PTHrP was conditionally deleted. Surprisingly, we found PTH1R deletion caused symphalangism, demonstrating another novel function of PTH1R signaling in digit formation. We characterized the symphalangism process whereby initial cartilaginous fusion prevented epiphyseal growth plate formation, resulting in resorption and replacement of the remaining cartilage by bony tissue. Chondrocyte differentiation displayed abnormal directionality in both mutants. Lastly, Prx1-Cre;Ihh(fl/fl);Jansen Tg mice, in which a constitutively active PTH1R allele was introduced into Ihh mutants, were established to address the possible involvement of PTH1R signaling in Ihh mutant digits. These rescue mice failed to show significantly improved phenotype, suggesting that PTH1R signaling in chondrocytes is not sufficient to restore digit formation. Our results demonstrate that Ihh and PTH1R signaling in limb mesenchyme are both essential to regulate proper development of digit structures, although they appear to use different mechanisms. PMID- 26620088 TI - Synovitis and radiographic progression in non-erosive and erosive hand osteoarthritis: is erosive hand osteoarthritis a separate inflammatory phenotype? AB - OBJECTIVE: To compare the prevalence of synovitis, pain and radiographic progression in non-erosive and erosive hand osteoarthritis (HOA), and to explore whether the different rate of disease progression is explained by different levels of synovitis and structural damage. DESIGN: We included 31 and 34 participants with non-erosive and erosive HOA at baseline, respectively. Using Generalized Estimating Equations, we explored whether participants with erosive HOA had more synovitis (by MRI, ultrasound and clinical examination) independent of the degree of structural damage. Similarly, we explored whether pain at baseline and radiographic progression after 5 years were higher in erosive HOA, independent of the levels of synovitis and structural damage. All analyses were adjusted for age and sex. RESULTS: Power Doppler activity was found mainly in erosive HOA. Participants with erosive HOA demonstrated more moderate-to-severe synovitis, assessed by MRI (OR = 1.73, 95% CI 1.11-2.70), grey-scale ultrasound (OR = 2.02, 95% CI 1.25-3.26) and clinical examination (OR = 1.80, 95% CI 1.44 2.25). The associations became non-significant when adjusting for more structural damage. The higher frequency of joint tenderness in erosive HOA was at least partly explained more structural damage and inflammation. Radiographic progression (OR = 2.53, 95% CI 1.73-3.69) was more common in erosive HOA independent of radiographic HOA severity and synovitis (here: adjusted for grey scale synovitis by ultrasound). CONCLUSION: Erosive HOA is characterized by higher frequency and more severe synovitis, pain and radiographic progression compared to non-erosive HOA. The higher rate of disease progression was independent of baseline synovitis and structural damage. PMID- 26620089 TI - Novel statistical methodology reveals that hip shape is associated with incident radiographic hip osteoarthritis among African American women. AB - INTRODUCTION: Hip shape is a risk factor for the development of hip osteoarthritis (OA), and current methods to assess hip shape from radiographs are limited; therefore this study explored current and novel methods to assess hip shape. METHODS: Data from a prior case-control study nested in the Johnston County OA Project were used, including 382 hips (from 342 individuals). Hips were classified by radiographic hip OA (RHOA) status as RHOA cases (baseline Kellgren Lawrence grade [KLG] 0 or 1, follow-up [mean 6 years] KLG >= 2) or controls (KLG = 0 or 1 at both baseline and follow-up). Proximal femur shape was assessed using a 60-point model as previously described. The current analysis explored commonly used principal component analysis (PCA), as well as novel statistical methodologies suited to high dimension low sample size settings (Distance Weighted Discrimination [DWD] and Distance Projection Permutation [DiProPerm] hypothesis testing) to assess differences between cases and controls. RESULTS: Using these novel methodologies, we were able to better characterize morphologic differences by sex and race. In particular, the proximal femurs of African American women demonstrated significantly different shapes between cases and controls, implying an important role for sex and race in the development of RHOA. Notably, discrimination was improved with the use of DWD and DiProPerm compared to PCA. CONCLUSIONS: DWD with DiProPerm significance testing provides improved discrimination of variation in hip morphology between groups, and enables subgroup analyses even under small sample sizes. PMID- 26620090 TI - Subchondral and epiphyseal bone remodeling following surgical transection and noninvasive rupture of the anterior cruciate ligament as models of post-traumatic osteoarthritis. AB - OBJECTIVE: Animal models are frequently used to study post-traumatic osteoarthritis (PTOA). A common anterior cruciate ligament (ACL) injury model is surgical transection, which may introduce confounding factors from surgery. Noninvasive models could model human injury more closely. The purpose of this study was to compare subchondral and epiphyseal trabecular bone remodeling after surgical transection and noninvasive rupture of the ACL. METHODS: Thirty-six rats were randomized to an uninjured control, surgical transection (Transection), or noninvasive rupture (Rupture). Animals were randomized to 4 or 10 week time points (n = 6 per group). Micro computed tomography (MUCT) imaging was performed with an isotropic voxel size of 12 MUm. Subchondral and epiphyseal bone was segmented semi-automatically, and morphometric analysis was performed. RESULTS: Transection caused a greater decrease in subchondral bone volume fraction (BV/TV) than Rupture in the femur and tibia. Rupture had greater subchondral bone tissue mineral density (TMD) at 4 and 10 weeks in the femur and tibia. Subchondral bone thickness (SCB.Th) was decreased in the femur in Transection only. Epiphyseal BV/TV was decreased in Transection only, and Rupture exhibited increased femoral epiphyseal TMD compared to both Control and Transection. Rupture exhibited greater femoral epiphyseal trabecular thickness (Tb.Th.) compared to Control and Transection at 4 weeks, and both Rupture and Transection had increased femoral epiphyseal Tb.Th. at 10 weeks. Epiphyseal trabecular number (Tb.N) was decreased in both injury groups at both time points. Femoral and tibial epiphyseal structure model index (SMI) increased in both groups. CONCLUSIONS: The two injury models cause differences in post-injury bone morphometry, and surgical transection may be introducing confounding factors that affect downstream bony remodeling. PMID- 26620092 TI - Cost-utility of exercise therapy in patients with hip osteoarthritis in primary care. AB - OBJECTIVE: To determine the cost-effectiveness (CE) of exercise therapy (intervention group) compared to 'general practitioner (GP) care' (control group) in patients with hip osteoarthritis (OA) in primary care. METHOD: This cost utility analysis was conducted with 120 GPs in the Netherlands from the societal and healthcare perspective. Data on direct medical costs, productivity costs and quality of life (QoL) was collected using standardised questionnaires which were sent to the patients at baseline and at 6, 13, 26, 39 and 52 weeks follow-up. All costs were based on Euro 2011 cost data. RESULTS: A total of 203 patients were included. The annual direct medical costs per patient were significantly lower for the intervention group (? 1233) compared to the control group (? 1331). The average annual societal costs per patient were lower in the intervention group (? 2634 vs ? 3241). Productivity costs were higher than direct medical costs. There was a very small adjusted difference in QoL of 0.006 in favour of the control group (95% CI: -0.04 to +0.02). CONCLUSION: Our study revealed that exercise therapy is probably cost saving, without the risk of noteworthy negative health effects. TRIAL REGISTRATION NUMBER: NTR1462. PMID- 26620091 TI - MR T1rho and T2 of meniscus after acute anterior cruciate ligament injuries. AB - OBJECTIVE: To evaluate differences in meniscal T1rho and T2 quantification in patients with acute anterior cruciate ligament (ACL) injuries and to determine correlations of these differences with MR morphological grading and patient reported outcomes. DESIGN: Bilateral knees of 52 patients with acute ACL injury and 20 healthy controls were scanned using 3 T magnetic resonance imaging (MRI) T1rho and T2 mapping in this prospective study. Quantitative analysis of the meniscus was performed in anterior and posterior horns of the lateral and medial menisci. Morphological meniscal damage was assessed using modified whole-organ MRI scores (WORMS). Measurements were compared between injured, uninjured contralateral, and control knees using a mixed-effects regression model. Correlations between meniscal T1rho/T2, WORMS and Knee Injury and Osteoarthritis Outcome Scores (KOOS) were examined using partial correlation analysis. RESULTS: Mean meniscal T1rho and T2 values were significantly higher in ACL-injured knees compared to control and contralateral knees. Menisci of ACL-injured knees without tears, including those limited to modified meniscal WORMS grade 0, also had significantly higher T1rho and T2 values compared to menisci of uninjured knees. Within ACL-injured knees, T1rho and T2 values showed significant positive associations with meniscal WORMS and significant negative associations with KOOS. CONCLUSION: Acute ACL injuries are associated with significantly increased meniscal T1rho and T2 values in both patients with and without meniscal lesions or tears, suggesting quantitative MRI provides more sensitive measures of meniscal differences compared to traditional morphological MRI sequences. Correlation between meniscal T1rho/T2 and KOOS suggest that quantitative MRI is reflective of the extent of patients' clinical symptoms. PMID- 26620093 TI - [A rare cause of oral pain: The pterygoid hamulus syndrome]. AB - INTRODUCTION: Pterygoid hamulus syndrome (PHS) is a rare cause of orofacial and oropharyngeal pain. PHS can be associated with a hamulus hypertrophy or with a bursitis of the palatosalpingeus but it has not always an anatomic cause. OBSERVATION: A 36-year-old woman was seen for a constant posterior palatal pain spreading towards oropharynx, increasing during swallowing and lasting for more than 6 months. Physical examination showed an erythema of the soft palate, medially to the hamulus. Hamulus palpation was painful and revealed hamulus hypertrophia on both sides. A bilateral PHS was evocated. DISCUSSION: This observation is typical of a PHS. We propose a review of the literature of this little-known syndrome. Treatment is initially conservative (corticosteroids) but surgery can be proposed in case of morphological anomalies of the hamulus. PMID- 26620094 TI - Busy Bs. PMID- 26620096 TI - Effects of habitat degradation, microsite, and seed density on the persistence of two native herbs in a subtropical shrubland. AB - PREMISE OF THE STUDY: Species in degraded ecosystems may interact differently with their surroundings from those under historic conditions. Understanding factors affecting variation in early life history stages of plants is fundamental to assessing their persistence in intact and degraded habitats, and the value of degraded lands. We evaluated the effect of seed density on the seed dynamics of two herbaceous species (annual, biennial), and considered how seed availability may influence population dynamics in different habitats (degraded, intact Florida scrub) and microsites (bare sand, leaf litter, shrub). METHODS: We used data on responses to experimental treatments (seed removal, seedling emergence, establishment) and models to evaluate how effects of these factors may change over time since the last disturbance. KEY RESULTS: Probability of any seed removal, emergence, and establishment per unit increased with seed density, although proportion removal for Chamaecrista fasciculata, proportion emergence for Balduina angustifolia, and proportion establishment for both species decreased with density. When animals were given selective access to seeds, invertebrates were primarily responsible for seed removal of both study species. Models with dynamics changing with time-since-disturbance for both species predicted that population growth may decrease slightly if local available seed density increases. CONCLUSIONS: Detailed demographic comparisons of populations in intact and degraded conditions can be used to understand the way that environmental conditions (habitat, microsite) combine with seed density effects to influence population dynamics of herb species. Degraded habitat may act as a transitional state in a trajectory toward intact conditions for some species, or as refugia for other native species. PMID- 26620097 TI - Plant evolution in the urban jungle. PMID- 26620095 TI - Suitability of Patients with Autosomal Dominant Polycystic Kidney Disease for Renal Transcatheter Arterial Embolization. AB - In patients with autosomal dominant polycystic kidney disease (ADPKD), massive renal enlargement is a serious problem. Renal transcatheter arterial embolization (TAE) can reduce renal volume (RV), but effectiveness varies widely, and the reasons remain unclear. We investigated factors affecting renal volume reduction rate (RVRR) after renal TAE in all 449 patients with ADPKD who received renal TAE at Toranomon Hospital from January of 2006 to July of 2013, including 228 men and 221 women (mean age =57.0+/-9.1 years old). One year after renal TAE, the RVRR ranged from 3.9% to 84.8%, and the least squares mean RVRR calculated using a linear mixed model was 45.5% (95% confidence interval [95% CI], 44.2% to 46.8%). Multivariate analysis using the linear mixed model revealed that RVRR was affected by the presence of large cysts with wall thickening (regression coefficient [RC], -6.10; 95% CI, -9.04 to -3.16; P<0.001), age (RC, -0.82; 95% CI, -1.03 to -0.60; P<0.001), dialysis duration (RC, -0.10; 95% CI, -0.18 to 0.03; P<0.01), systolic BP (RC, 0.39; 95% CI, 0.19 to 0.59; P<0.001), and the number of microcoils used for renal TAE (RC, 1.35; 95% CI, 0.83 to 1.86; P<0.001). Significantly more microcoils were needed to achieve renal TAE in patients with younger age and shorter dialysis duration. In conclusion, cyst wall thickening had an important effect on cyst volume reduction. Renal TAE was more effective in patients who were younger, had shorter dialysis duration, or had hypertension, parameters that might associate with cyst wall stiffness and renal artery blood flow. PMID- 26620098 TI - Immunosensing procedures for carcinoembryonic antigen using graphene and nanocomposites. AB - Two-dimensional (2D) graphene, sp2-hybridized carbon, and its two major derivatives, graphene oxide (GO) and reduced graphene oxide (rGO) have played an important role in immunoassays (IAs) and immunosensing (IMS) platforms for the detection of carcinoembryonic antigen (CEA), an implicated tumor biomarker found in several types of cancer. The graphene family with high surface area is functionalized to form stable nanocomposites with gold nanoparticles (AuNPs) and electron mediators. The capture anti-CEA antibody (Ab) with high density can be anchored on AuNPs of such composites to provide remarkable detection sensitivity, significantly below the level found in normal subjects and cancer patients. Electrochemical and fluorescence/chemiluminescence-quenching properties of graphene-based nanocomposites are exploited in various detection schemes. Future endeavors are envisioned for the development of an array platform with high throughput for CEA together with other tumor biomarkers and C-reactive protein, a universal biomarker for infection and inflammation. The ongoing efforts dedicated to the replacement of a lab-based detector by a cellphone with smart applications will further enable cost-effective and frequent monitoring of CEA in order to establish its clinical relevance and provide tools for real-time monitoring of patients during chemotherapy. PMID- 26620099 TI - Histological evaluation of direct pulp capping of rat pulp with experimentally developed low-viscosity adhesives containing reparative dentin-promoting agents. AB - OBJECTIVES: This study examines the wound healing process in exposed rat pulp when capped with experimental adhesive resin systems. METHODS: Experimental adhesive resin system for direct pulp capping was composed of primer-I (PI), -II (PII), and -III (PIII) and an experimental bonding agent (EBA). PI was Clearfil((r)) SE Bond((r))/Primer (CSP) containing 5.0 wt% CaCl2, PII was PI containing 10 wt% nanofiller (Aerosil((r)) 380), and PIII was CSP containing 5.0 wt% of compounds of equal moles of synthetic peptides (pA and pB) derived from dentin matrix protein 1. EBA was Clearfil((r)) SE Bond((r))/Bond (CSB) containing 10 wt% hydroxyapatite powders. Three experimental groups were designed. PI was assigned to experimental Groups 1 and 3. PII was assigned to experimental Groups 2 and 3. PIII and EBA were assigned to all experimental adhesive groups. Control teeth were capped with calcium hydroxide preparation (Dycal((r))), and CSP and CSB were applied to the cavity. The rats were sacrificed after each observation period (14, 28, 56, and 112 days). The following parameters were evaluated: pulp tissue disorganization, inflammatory cell infiltration, reparative dentin formation (RDF), and bacterial penetration. RESULTS: There were no significant differences among all the groups for all parameters and all observation periods (p>0.05, Kruskal-Wallis test). All groups showed initial RDF at 14 days postoperatively and extensive RDF until 112 days postoperatively. Groups 2 and 3 demonstrated higher quantity of mineralized dentin bridge formation compared with Group 1. CONCLUSIONS: Addition of nanofillers to the primer was effective in promoting high-density RDF. CLINICAL SIGNIFICANCE: Experimentally developed adhesive resin systems induce the exposed pulp to produce almost the same quantity of reparative dentin as calcium hydroxide. However, we need further studies to elucidate whether the same results could be obtained in humans. PMID- 26620100 TI - Effect of placing intentionally high restorations: Randomized clinical trial. AB - OBJECTIVE: The aim of this study was to examine the behavior of posterior teeth restored with single-tooth restorations with intentionally high occlusal contacts. METHODS: Consent was obtained from 17 patients who were seen a total of 5 times over 3.5 years. The restorations placed were all full occlusal coverage gold restorations. Tooth mobility was recorded using the Periotest device and tooth movement was determined from impressions and 3D imaging. Patients were randomly assigned into two groups, the control group which received restorations with no intentional increase of the occlusal vertical dimension; or the treatment group where they received intentionally high restorations in 0.5mm supraocclusion. RESULTS: Statistical analysis showed no significant difference in mobility between visits for both the control and the treatment groups while a significant dependency and difference in tooth movement was observed between the subjects of the two groups. Most patients from the treatment group reported discomfort but no pain for the first 7-10 days after the restoration was fitted, which subsided over a period of couple of weeks. At review, 3 years later, no mobility or additional movement was observed. CONCLUSIONS: Cementation of an intentionally high single-tooth restoration causes no increase in tooth mobility while occlusal adaptation re-establishes and restores the occlusal plane. PMID- 26620101 TI - A Phase 1b/2a study of the safety, pharmacokinetics and antiviral activity of BIT225 in patients with HIV-1 infection. AB - OBJECTIVES: BIT225 (N-carbamimidoyl-5-(1-methyl-1H-pyrazol-4-yl)-2-naphthamide), a novel acyl-guanidine, is a novel antiviral drug that blocks Vpu ion channel activity and has anti-HIV-1 activity in vitro. The antiviral effect of BIT225 is most pronounced in cells of the myeloid lineage. With infected circulating monocytes and tissue-resident macrophages representing a key cellular reservoir of HIV-1, BIT225 has a potential role in the eradication of the virus from the host. PATIENTS AND METHODS: BIT225-004 is a Phase 1b/2a, placebo-controlled, randomized study of the safety, pharmacokinetics and antiviral activity of BIT225 in 21 HIV-1-infected, ART-naive subjects. Twenty-one subjects were enrolled and received BIT225 (400 mg twice daily) or placebo treatment for 10 days (randomized 2:1). The anti-HIV-1 effect of BIT225 in the monocyte reservoir was measured in CD14+ monocytes isolated from the peripheral blood on days 1 (pre-dose), 5, 10 and 20; isolated monocytes were co-cultured ex vivo with MT4 T cells. De novo HIV 1 replication was measured by p24 activity of released virus into the culture supernatant to day 25 of co-culture. In addition, monocyte samples were collected for analysis by RT-PCR total HIV-1 DNA single-copy assay. RESULTS: Measurement of HIV-1 directly within the patient's monocyte population indicated that BIT225 treatment significantly reduced the viral burden in myeloid lineage cells, which was more evident in those individuals with the highest viral loads. In addition, BIT225-treated subjects demonstrated a significantly reduced level of monocyte activation (sCD163) compared with the placebo controls. CONCLUSIONS: This study's unique design demonstrates that BIT225 can significantly reduce the dissemination of HIV-1 from infected monocytes. This has important ramifications for diminishing the seeding/re-seeding of the viral reservoir. PMID- 26620102 TI - The novel arylamidine T-2307 demonstrates in vitro and in vivo activity against echinocandin-resistant Candida glabrata. AB - OBJECTIVES: Candida species are major causes of invasive mycoses in immunocompetent and immunocompromised hosts. Treatment options are limited in the setting of antifungal resistance and increased rates of echinocandin-resistant Candida glabrata have been reported. The novel arylamidine T-2307 demonstrates potent in vitro antifungal activity against Candida species. Our objective was to evaluate the in vitro and in vivo activity of T-2307 against resistant C. glabrata. METHODS: In vitro activity was determined against 42 clinical C. glabrata isolates, including 17 echinocandin-resistant strains. Neutropenic ICR mice were inoculated intravenously with an echinocandin-resistant C. glabrata isolate (T-2307; caspofungin MICs <=0.008 and 0.5 mg/L, respectively). Therapy with vehicle control, T-2307 (0.75, 1.5, 3 or 6 mg/kg subcutaneously once daily) or caspofungin (1 or 10 mg/kg intraperitoneally once daily) began 1 day post challenge. Kidneys were collected on day 8 and fungal burden was assessed by counting cfu. RESULTS: T-2307 demonstrated potent in vitro activity against C. glabrata (geometric mean MIC 0.0135 mg/L), which was maintained against echinocandin-resistant isolates (geometric mean MIC 0.0083 mg/L). T-2307 also demonstrated in vivo efficacy in mice infected with echinocandin-resistant C. glabrata. Significant reductions in fungal burden were observed at each dosage level of T-2307 compared with control. Reductions in fungal burden were also observed with high-dose caspofungin. CONCLUSIONS: T-2307 demonstrated potent in vitro activity against C. glabrata, including echinocandin-resistant isolates, which translated into in vivo efficacy against invasive candidiasis caused by an echinocandin-resistant C. glabrata strain. These results demonstrate the potential for T-2307 as therapy against echinocandin-resistant Candida. PMID- 26620104 TI - Preparation of hollow microsphere@onion-like solid nanosphere MoS2 coated by a carbon shell as a stable anode for optimized lithium storage. AB - A one-step hydrothermal method was successfully used to fabricate hollow microsphere@onion-like solid nanosphere MoS2. Then the as-prepared sS-MoS2 was decorated with a carbon shell using dopamine as a carbon source by a facile route, resulting in hollow microsphere@onion-like solid nanosphere MoS2 decorated with carbon shell (sS-MoS2@C). A synergistic effect was observed for the two component material, leading to new electrochemical processes for lithium storage, with improved electroconductivity and structural soundness, triggering an ascending capacity upon cycling. The as-prepared sS-MoS2@C exhibits optimized electrochemical behaviour with high specific capacity (1107 mA h g(-1) at 100 mA g(-1)), superior high-rate capability (805 mA h g(-1) at 5000 mA g(-1)) and good cycling stability (91.5% of capacity retained after 100 cycles), suggesting its potential application in high-energy lithium-ion batteries. PMID- 26620103 TI - Critical Analysis of Interventional Research Designs to Promote Coping in Pediatric Patients. AB - PURPOSE: The purpose of this article is to analyze the strengths and limitations of research designs of studies implementing coping based training interventions in adolescents. METHODS: Quantitative and mixed methods studies were selected and reviewed for critical analysis of strengths, limitations, and validity concerns. RESULTS: Methodological strengths and weaknesses were assessed. The major limitation to the studies reviewed is selection bias in both quasi-experimental studies and randomized controlled trials. PRACTICE IMPLICATIONS: Improved coping strategies and skills were found in participants of coping skill training intervention programs. Decreased depressive symptoms and less impact of individual disease burden was found in the treatment intervention groups. PMID- 26620105 TI - Magnetic resonance diffusion tensor imaging of cervical spinal cord and lumbosacral enlargement in patients with cervical spondylotic myelopathy. AB - PURPOSE: To identify the correlations of diffusion tensor imaging (DTI) indices between the cervical spinal cord and lumbosacral enlargement in healthy volunteers and patients with cervical spondylotic myelopathy (CSM). MATERIALS AND METHODS: DTI was performed at the cervical spinal cord and lumbosacral enlargement in 10 CSM patients and 10 volunteers at 1.5T. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values of were measured and compared between CSM patients and volunteers. DTI indices of different cervical segments in volunteers were compared. DTI indices of the cervical spinal cord were correlated with those of the lumbosacral enlargement. RESULTS: In healthy subjects, DTI indices of different cervical cord sections showed no significant difference (ADC: F = 0.62; P = 0.65; FA: F = 1.228; P = 0.312); there was no correlation between the DTI indices of the cervical spinal cord and those of the lumbosacral enlargement (ADC: r = 0.442, P = 0.201; FA: r = -0.054, P = 0.881). In the CSM patients, the ADC value significantly increased, while the FA value significantly decreased in the cervical spinal cord (ADC: P = 0.002; FA: P < 0.001) and lumbosacral enlargement (ADC: P = 0.003; FA: P < 0.001) compared with the healthy group. Both DTI indices showed no correlation between the cervical spinal cord and those of the lumbosacral enlargement in the CSM group (ADC: r = 0.052, P = 0.887; FA: r = 0.129, P = 0.722). CONCLUSION: The ADC value of the cervical spinal cord and lumbosacral enlargement in CSM patients showed significant increase compared with healthy volunteers, while the FA value significantly decreased. Both DTI indices of the cervical spinal cord had no linear correlation with those of the lumbosacral enlargement. J. Magn. Reson. Imaging 2016;43:1484-1491. PMID- 26620106 TI - Adult autoinflammatory disease frequency and our diagnostic experience in an adult autoinflammatory clinic. AB - OBJECTIVE: Systemic autoinflammatory diseases (SAIDs) mainly include monogenic hereditary periodic fever syndromes, and NOD2-associated AID (NAID) is a polygenic SAID. Our aim was to study the disease frequency and report our diagnostic experience. METHODS: A total of 266 adult patients with clinical phenotypes suspicious for SAIDs were studied at the Cleveland Clinic between November 2009 and February 2015. All patients were genotyped for NOD2 mutations or periodic fever syndrome panel. The definite diagnosis of each disease was deemed to be present if both clinical phenotypes and genetic confirmation were met. RESULTS: Of the 266 patients, 79 (29.7%) were diagnostic of SAIDs, including 54 cases of NAID, 13 familial Mediterranean fever (FMF), 6 tumor necrosis factor receptor-associated periodic syndrome (TRAPS), 5 cryopyrin-associated periodic disease (CAPS), and 1 hyper IgD periodic syndrome (HIDS). NOD2 genotyping had a higher concordance rate with the clinical phenotype for the diagnosis of NAID. Of 29 patients, 13 (44.8%) were clinically suspicious for FMF and had positive genetic testing. Of 66 patients, 6 (9%) were tested positive for TRAPS. Out of 23 patients, 5 (21.7%) were tested positive for CAPS. Only 1 patient tested positive for HIDS. The concordance between the working clinical diagnosis and positive genetic testing varied among the SAIDs. CONCLUSIONS: Our study demonstrates that NAID and FMF are relatively common in adults. TRAPS and HIDS are extremely rare, and the concordance between the working clinical diagnosis and positive genetic testing is considerably disproportional for TRAPS. Ordering of genetic testing for SAIDs should highly consider both the disease frequency and stringent phenotypes. PMID- 26620107 TI - Key mendelian variants. AB - Genetic comparison of the effects of mutant and wild-type alleles is a powerful way to define gene function. But those few disease-causing variants that provide qualitatively different insights into the disease mechanisms of more common sporadic diseases have the greatest translational value. PMID- 26620108 TI - William Martin Gelbart 1945-2015. PMID- 26620109 TI - Diabetes in the post-GWAS era. AB - Large sample sizes, high-resolution arrays and comprehensive imputation are pushing genetic fine-mapping of complex trait loci to its limits without, in most cases, pinpointing a unique variant-gene combination. Superimposing these results on sophisticated maps of functional chromatin elements promises to break this logjam, as a new study of type 2 diabetes compellingly demonstrates. PMID- 26620110 TI - A taste of pineapple evolution through genome sequencing. AB - The genome sequence assembly of the highly heterozygous Ananas comosus and its varieties is an impressive technical achievement. The sequence opens the door to a greater understanding of pineapple morphology and evolution. PMID- 26620111 TI - Deciphering durable resistance one R gene at a time. AB - Characterizations of durable resistance genes in crop plants are coming to the fore. A new study characterizing the wheat gene Lr67 shows that how a plant manages sugar transport affects the ability of a broad group of fungal pathogens to colonize their host. PMID- 26620112 TI - Multisystem Lewy body disease and the other parkinsonian disorders. AB - Here we prioritize as multisystem Lewy body disease (MLBD) those genetic forms of Parkinson's disease that point the way toward a mechanistic understanding of the majority of sporadic disease. Pathological diagnosis of genetic subtypes offers the prospect of distinguishing different mechanistic trajectories with a common mutational etiology, differing outcomes from varying allelic bases, and those disease-associated variants that can be used in gene-environment analysis. Clearly delineating parkinsonian disorders into subclasses on the basis of molecular mechanisms with well-characterized outcome expectations is the basis for refining these forms of neurodegeneration as research substrate through the use of cell models derived from affected individuals while ensuring that clinically collected data can be used for therapeutic decisions and research without increasing the noise and confusion engendered by the collection of data against a range of historically defined criteria. PMID- 26620113 TI - The MAOA, COMT, MTHFR and ESR1 gene polymorphisms are associated with the risk of depression in menopausal women. AB - OBJECTIVE: The aim of the study was assessment of a possible relationship between the polymorphisms of the candidate genes participating in the etiology of some neurological and psychiatric disorders and the risk of depression in perimenopausal and postmenopausal women. METHODS: A total of 167 (54 perimenopausal and 113 postmenopausal) Caucasian women from western Poland, aged 42-67, were recruited as the patient group in the study because of depressive symptoms, and another 321 healthy women (102 perimenopausal and 219 postmenopausal) served as the controls. All study participants were evaluated for climacteric and depressive disorders according to the Kupperman index and Hamilton rating scale for depression (HRSD), respectively. The following candidate genes were selected for the study: 5HTR2A, 5HTR1B, 5HTR2C, TPH1, TPH2, MAOA, COMT, NET, GABRB1, ESR1, MTHFR, MTR and MTHFD1. In each group the frequencies of the polymorphisms were determined using PCR-RFLP analysis. RESULTS: After correcting for Bonferroni multiple tests, we found associations between the MAOA c.1460C>T (SNP 1137070), COMT c.472G>A (SNP 4680), MTHFR c.677C>T (SNP 1801133) and ESR1 454(-351) A>G (SNP 9340799) polymorphisms to mild and moderate depressive symptoms in menopausal women. In the perimenopausal and postmenopausal women, genotype association of the MAOA c.1460 CT and c.1460 CT+TT (OR=1.83; pcorr=0.009 and OR=1.85; pcorr=0.003, resp.), and of the MTHFR c.677 TT and c.677 CT+TT (OR=3.52; pcorr=0.00009 and OR=2.06; pcorr=0.0006, resp.), as well as of the COMT c.472 GA and COMT c.472 GA+AA genotypes (OR=2.23; pcorr=0.03 and OR=2.17; pcorr=0.027, resp.) in the postmenopausal women revealed significantly higher frequencies of these variants in depressed female patients than in controls, whereas the ESR1 454(-351) AG and 454(-351) AG+GG genotypes were associated with lower risk of depression in postmenopausal women (OR=0.48; pcorr=0.012, and OR=0.52; pcorr=0.015, resp.). CONCLUSIONS: Our study substantiates the involvement of the MAOA and MTHFR polymorphisms in climacteric depression and offers evidence that the COMT and ESR1 genes may also play a role in the susceptibility to depressive mood in postmenopausal women. PMID- 26620115 TI - Oxidation catalysis via visible-light water activation of a [Ru(bpy)3](2+) chromophore BSA-metallocorrole couple. AB - Light induced enantioselective oxidation of an organic molecule with water as the oxygen atom source is demonstrated in a system where chirality is induced by a protein, oxygen atom transfer by a manganese corrole, and photocatalysis by ruthenium complexes. PMID- 26620116 TI - Influence of cerclages on primary stability of tumor megaprostheses subjected to distal femur defects. AB - BACKROUND: Purpose of this experimental study was to investigate the influence of cerclages on the primary stability of the MUTARS system using distally fractured synthetic femora. METHODS: 4 MUTARS prostheses were implanted in synthetic femora respectively. Groups consisted of 4 intact bones, 4 fractured with cerclages and 4 fractured bones without cerclages. Spatial micromovements were measured with a high-precision rotational setup. FINDINGS: The order from the weakest to the strongest torque transmission of the intact bones was rm1-rm4-rm2-rm3 (p=0.011) and of the fractured bones with cerclages rm4-rm1-rm3-rm2 (p=0.013). The MUTARS stems broke out of the fractured femoral shaft by removing cerclages (p<0.001) and by the influence of bone defect A (p<0.001). Overall micromovements of the intact bones were lower than those of the fractured bones without cerclages (p<0.001) and overall micromovements of the fractured bones with cerclages were lower than those of bones without cerclages (p<0.001). INTERPRETATION: Due to high press-fit at the proximal and distal isthmus region fissural fractures of the femur may occur. This should always be taken into account. It is advisable to secure them and provide a prophylaxis for these fissural fractures by means of cerclages. PMID- 26620117 TI - Evaluation of stability of osteosynthesis with K-wires on an artificial model of tibial malleolus fracture. AB - BACKGROUND: Paediatric ankle fractures comprise approximately 4% of all paediatric fractures and 30% of all epiphyseal fractures. Integrity of the ankle "mortise", which consists of tibial and fibular malleoli, is significant for stability and function of the ankle joint. Tibial malleolar fractures are classified as SH III or SH IV intra-articular fractures and, in cases where the fragments are displaced, anatomic reposition and fixation is mandatory. METHODS: Type SH III-IV fractures of the tibial malleolus are usually treated with open reduction and fixation with cannulated screws that are parallel to the physis. Two K-wires are used for temporary stabilisation of fragments during reduction. A third "guide wire" for the screw is then placed parallel with the physis. Considering the rules of mechanics, it is assumed that the two temporary pins with the additional third pin placed parallel to the physis create a strong triangle and thus provide strong fracture fixation. To prove this hypothesis, an experiment was conducted on the artificial models of the lower end of the tibia from the company "Sawbones". Each model had been sawn in a way that imitates the fracture of medial malleoli and then reattached with 1.8mm pins in various combinations. Prepared models were then tested for tensile and pressure forces. RESULTS: The least stable model was that in which the fractured pieces were attached with only two parallel pins. The most stable model comprised three pins, where two crossed pins were inserted in the opposite compact bone and the third pin was inserted through the epiphysis parallel with and below the growth plate. CONCLUSION: A potential method of choice for fixation of tibial malleolar fractures comprises three K-wires, where two crossed pins are placed in the opposite compact bone and one is parallel with the growth plate. The benefits associated with this method include shorter operating times and avoidance of a second operation for screw removal. PMID- 26620118 TI - Secondary stroke in patients with polytrauma and traumatic brain injury treated in an Intensive Care Unit, Karlovac General Hospital, Croatia. AB - Traumatic brain injury (TBI) is divided into primary and secondary brain injury. Primary brain injury occurs at the time of injury and is the direct consequence of kinetic energy acting on the brain tissue. Secondary brain injury occurs several hours or days after primary brain injury and is the result of factors including shock, systemic hypotension, hypoxia, hypothermia or hyperthermia, intracranial hypertension, cerebral oedema, intracranial bleeding or inflammation. The aim of this retrospective analysis of a prospective database was to determine the prevalence of secondary stroke and stroke-related mortality, causes of secondary stroke, treatment and length of stay in the ICU and hospital. This study included patients with TBI with or without other injuries who were hospitalised in a general ICU over a five-year period. The following parameters were assessed: demographics (age, sex), scores (Glasgow Coma Score, APACHE II, SOFA), secondary stroke (prevalence, time of occurrence after primary brain injury, causes of stroke and associated mortality), length of stay in the ICU and hospital, vital parameters (state of consciousness, cardiac function, respiration, circulation, thermoregulation, diuresis) and laboratory values (leukocytes, C-reactive protein [CRP], blood glucose, blood gas analysis, urea, creatinine). Medical data were analysed for 306 patients with TBI (median age 56 years, range 18-93 years) who were treated in the general ICU. Secondary stroke occurred in 23 patients (7.5%), 10 of whom died, which gives a mortality rate of 43.4%. Three patients were excluded as the cause of the injury was missile trauma. The study data indicate that inflammation is the most important cause of secondary insults. Levels of CRP were elevated in 65% of patients with secondary brain injury; leukocytosis was present in 87% of these patients, and blood glucose was elevated in 73%. The lungs and urinary tract were the most common sites of infection. In conclusion, elevated inflammatory markers (white blood cell count and CRP) and hyperglycaemia are associated with secondary brain injury. The lack of routine use of intracranial pressure (ICP) monitoring may explain the high mortality rate and the occurrence of secondary stroke in patients with TBI. PMID- 26620119 TI - High reliability in classification of tibia fractures in the Swedish Fracture Register. AB - INTRODUCTION: The Swedish Fracture Register (SFR) was started in 2011 and registers fractures of all types, treated either surgically or non-surgically. Twenty-six orthopaedic departments in Sweden are affiliated and a total of 84,000 fractures have been registered. The physician who establishes the diagnosis of the fracture registers and classifies it according to the AO/OTA classification. The accuracy of the classification of fractures is important for the reliability of the data in the SFR. This study aimed to evaluate how accurate the classification of tibia fractures in the register is. METHODS: Three experienced trauma surgeons (raters) were presented with the radiographs of 114 patients with tibia fractures randomly allocated from the SFR. The raters classified the fractures independently and blinded to clinical patient information in two classification sessions with a time interval of one month. The AO/OTA classification coded by the three expert raters (our predefined gold standard) was compared with the classifications in the SFR. Inter- and intra-observer agreement was evaluated. The degree of agreement was reported using the approach of Landis and Koch. RESULTS: The accuracy of the SFR, defined as agreement between the SFR and the gold standard classification, was kappa=0.75 for the AO/OTA type and 0.56 for the AO/OTA group, corresponding to substantial and moderate agreement, respectively. Inter-observer agreement across the three expert raters was kappa=0.74 for the AO/OTA type and 0.53 for the AO/OTA group. Intra-observer agreement was kappa=0.74-0.79 for the AO/OTA type and 0.62-0.64 for the AO/OTA group. CONCLUSION: This study shows that the accuracy of classification of tibia fractures in the SFR was substantial for the AO/OTA type (kappa=0.75) and moderate for the AO/OTA group (kappa=0.56) as defined by Landis and Koch. This degree of accuracy is similar to that in previous studies. We interpret this as meaning that the results of this study demonstrate the high reliability of the data in the SFR and enable the SFR to be used for further scientific analysis. PMID- 26620120 TI - Bounding the per-protocol effect in randomized trials: an application to colorectal cancer screening. AB - BACKGROUND: The per-protocol effect is the effect that would have been observed in a randomized trial had everybody followed the protocol. Though obtaining a valid point estimate for the per-protocol effect requires assumptions that are unverifiable and often implausible, lower and upper bounds for the per-protocol effect may be estimated under more plausible assumptions. Strategies for obtaining bounds, known as "partial identification" methods, are especially promising in randomized trials. RESULTS: We estimated bounds for the per-protocol effect of colorectal cancer screening in the Norwegian Colorectal Cancer Prevention trial, a randomized trial of one-time sigmoidoscopy screening in 98,792 men and women aged 50-64 years. The screening was not available to the control arm, while approximately two thirds of individuals in the treatment arm attended the screening. Study outcomes included colorectal cancer incidence and mortality over 10 years of follow-up. Without any assumptions, the data alone provide little information about the size of the effect. Under the assumption that randomization had no effect on the outcome except through screening, a point estimate for the risk under no screening and bounds for the risk under screening are achievable. Thus, the 10-year risk difference for colorectal cancer was estimated to be at least -0.6 % but less than 37.0 %. Bounds for the risk difference for colorectal cancer mortality (-0.2 to 37.4 %) and all-cause mortality (-5.1 to 32.6 %) had similar widths. These bounds appear helpful in quantifying the maximum possible effectiveness, but cannot rule out harm. By making further assumptions about the effect in the subpopulation who would not attend screening regardless of their randomization arm, narrower bounds can be achieved. CONCLUSIONS: Bounding the per-protocol effect under several sets of assumptions illuminates our reliance on unverifiable assumptions, highlights the range of effect sizes we are most confident in, and can sometimes demonstrate whether to expect certain subpopulations to receive more benefit or harm than others. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00119912 (registered 6 July 2005). PMID- 26620121 TI - Non-traditional stable isotope behaviors in immiscible silica-melts in a mafic magma chamber. AB - Non-traditional stable isotopes have increasingly been applied to studies of igneous processes including planetary differentiation. Equilibrium isotope fractionation of these elements in silicates is expected to be negligible at magmatic temperatures (delta(57)Fe difference often less than 0.2 per mil). However, an increasing number of data has revealed a puzzling observation, e.g., the delta(57)Fe for silicic magmas ranges from 00/00 up to 0.60/00, with the most positive delta(57)Fe almost exclusively found in A-type granitoids. Several interpretations have been proposed by different research groups, but these have so far failed to explain some aspects of the observations. Here we propose a dynamic, diffusion-induced isotope fractionation model that assumes Si-melts are growing and ascending immiscibly in a Fe-rich bulk magma chamber. Our model offers predictions on the behavior of non-traditional stable isotope such as Fe, Mg, Si, and Li that are consistent with observations from many A-type granitoids, especially those associated with layered intrusions. Diffusion-induced isotope fractionation may be more commonly preserved in magmatic rocks than was originally predicted. PMID- 26620122 TI - Repeated Plasmodium vivax malaria relapses in a Peruvian sailor. AB - Two Plasmodium vivax recurrences in a Peruvian sailor with weight above the 60 kg (cap for primaquine dosage) highlight the importance of adequate radical cure weight dosage for patient treatment and control efforts, particularly within the military. PMID- 26620123 TI - Long-term prostate-specific antigen contamination in the Spanish arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC). AB - OBJECTIVES: Recently, the European Randomized Study of Screening for Prostate Cancer achieved a reduction in prostate cancer mortality by measuring serum prostate-specific antigen (PSA) levels. These results were not reproduced in the Spanish arm of European Randomized Study of Screening for Prostate Cancer. PSA contamination (opportunistic measurements outside the study) could decrease the study's contrasting power if performed in the control arm. We have calculated the long-term rate of PSA contamination and its effect on performing prostate biopsy and detecting cancer. MATERIAL AND METHODS: A total of 4,276 men were randomised (2,415 to the screening arm, 1,861 to the control arm) in the Spanish section of the European Randomized Study of Screening for Prostate Cancer. PSA measurements were not scheduled in the control arm. Sextant prostate biopsy was indicated if PSA levels were >=3 ng/mL. All PSA readings performed outside the study were labelled as "PSA contamination". We calculated the rates of PSA contamination, biopsy implementation and cancer detection. RESULTS: The median age and follow-up time were 57 and 15.1 years, respectively. A total of 2,511 men underwent at least one PSA reading outside the study. PSA contamination at 5, 10 and 15 years was 22.0%, 47.1% and 66.3% in the screening arm, respectively, and 20.8%, 43.2% and 58.6% in the control arm, respectively (P<.0001). The biopsy rate at 5, 10 and 15 years was 19.3%, 22.6% and 24.1% (screening), respectively, and 1.0%, 3.6% and 7.1% (control), respectively (P<.0001). The PC detection rate was 6.7% (screening) and 4.3% (control; P=.0006). CONCLUSIONS: Although the cumulative PSA contamination was pronounced in the 2 study arms, the rate of prostate biopsies was low in the control arm. We therefore believe that the effect of PSA contamination on the study's statistical power should be limited. PMID- 26620124 TI - Use of individual containers for prostate biopsy samples: Do we gain diagnostic performance? AB - OBJECTIVE: Prostate cores from transrectal biopsies are usually sent in separate vials for pathological processing. Although this is a common practice, there are controversial studies on its usefulness. We wanted to compare the rate of prostate cancer diagnosis between processing samples in 2 containers and processing them in individual containers to see if there are differences. Our secondary objective was to check the rate of diagnosis of various tumour subtypes in each of the 2 groups. MATERIAL AND METHODS: A retrospective observational study was conducted of 2,601 cases of prostate biopsies. Ten cores were extracted in each biopsy. We divided the sample into 2 groups: biopsies sent in 2 containers to the department of pathology (left and right lobes) or sent in 10 (one for each cylinder), according to the different criteria used in our centre in the past. We then classified the cases according to the absence of neoplasia, insignificant tumour (involvement of just 1 cylinder, <5%, Gleason score<7), Gleason 6 or Gleason>=7. A bivariate statistical analysis was performed using the chi-squared test. RESULTS: A total of 1,777 participants were included in the 2 container group, and 824 were included in the 10-container group. We diagnosed a rate of 32.4% of cancers in the 2-container group and 40% in the 10-container group, a difference that was statistically significant (P<.001). The insignificant carcinomas were diagnosed more often in the 2-container group than in the 10-container group (6.4% vs. 4.3%, respectively; P=.03). Samples with a Gleason score of 6 were diagnosed more often in the 10-container group than in the 2-container group (11.9% vs. 8.1%, respectively; P=.002). The same occurred with the Gleason score>=7 (23.8% in the 10-container group vs. 17.9% in the 2 container group; P<.001). CONCLUSIONS: We diagnosed more prostate cancers when sending biopsied cores in individual containers. Once the procedure was conducted, we also observed in our series a reduction in the diagnoses of insignificant carcinoma to the detriment of an increased diagnosis of not insignificant carcinomas. PMID- 26620125 TI - A unique species in Phytophthora clade 10, Phytophthora intercalaris sp. nov., recovered from stream and irrigation water in the eastern USA. AB - A novel species of the genus Phytophthora was recovered during surveys of stream and nursery irrigation water in Maryland, Massachusetts, North Carolina, Virginia and West Virginia in the USA. The novel species is heterothallic, and all examined isolates were A1 mating type. It produced rare ornamented oogonia and amphigynous antheridia when paired with A2 mating type testers of Phytophthora cinnamomi and Phytophthora cryptogea. Sporangia of this novel species were non papillate and non-caducous. Thin-walled intercalary chlamydospores were abundant in hemp seed agar and carrot agar, while they were produced only rarely in aged cultures grown in clarified V8 juice agar. Phylogenetic analyses based on sequences of the internal transcribed spacer region and the beta-tubulin and mitochondrial cytochrome-c oxidase 1 (cox1) genes indicated that the novel species is phylogenetically close to Phytophthora gallica in Phytophthora clade 10. The novel species has morphological and molecular features that are distinct from those of other species in Phytophthora clade 10. It is formally described here as Phytophthora intercalaris sp. nov. Description of this unique clade-10 species is important for understanding the phylogeny and evolution of Phytophthora clade 10. PMID- 26620126 TI - (1)H NMR metabolomics analysis of renal cell carcinoma cells: Effect of VHL inactivation on metabolism. AB - Von Hippel-Lindau (VHL) is an onco-suppressor involved in oxygen and energy dependent promotion of protein ubiquitination and proteosomal degradation. Loss of function mutations of VHL (VHL-cells) result in organ specific cancers with the best studied example in renal cell carcinomas. VHL has a well-established role in deactivation of hypoxia-inducible factor (HIF-1) and in regulation of PI3K/AKT/mTOR activity. Cell culture metabolomics analysis was utilized to determined effect of VHL and HIF-1alpha or HIF-2alpha on metabolism of renal cell carcinomas (RCC). RCC cells were stably transfected with VHL or shRNA designed to silence HIF-1alpha or HIF-2alpha genes. Obtained metabolic data was analysed qualitatively, searching for overall effects on metabolism as well as quantitatively, using methods developed in our group in order to determine specific metabolic changes. Analysis of the effect of VHL and HIF silencing on cellular metabolic footprints and fingerprints provided information about the metabolic pathways affected by VHL through HIF function as well as independently of HIF. Through correlation network analysis as well as statistical analysis of significant metabolic changes we have determined effects of VHL and HIF on energy production, amino acid metabolism, choline metabolism as well as cell regulation and signaling. VHL was shown to influence cellular metabolism through its effect on HIF proteins as well as by affecting activity of other factors. PMID- 26620128 TI - Comparison of hemostatic dressings for superficial wounds using a new spectrophotometric coagulation assay. AB - BACKGROUND: Due to demographical changes the number of elderly patients depending on oral anticoagulation is expected to rise. Prolonged bleeding times in case of traumatic injuries represent the drawback of these medications, not only in major trauma, but also in superficial wounds. Therefore, dressings capable of accelerating coagulation onset and shortening bleeding times are desirable for these patients. METHODS: The hemostatic potential and physical properties of different types of superficial wound dressings (standard wound pad, two alginates, chitosan, collagen (Lyostypt((r))), oxidized cellulose, and QuikClot((r))) were assessed in vitro. For this purpose the clotting times of blood under the influence of the named hemostatics from healthy volunteers were compared with Marcumar((r)) or ASS((r)) treated patients. For that, a newly developed coagulation assay based on spectrophotometric extinction measurements of thrombin activity was used. RESULTS: The fastest coagulation onset was observed for oxidized cellulose (O 2.47 min), Lantor alginate-L (O 2.50 min) and QuikClot((r)) (O 3.01 min). Chitosan (O 5.32 min) and the collagen Lyostypt((r)) (O 7.59 min) induced clotting comparatively late. Regarding physical parameters, QuikClot((r)) showed the lowest absorption capacity and speed while chitosan and both alginates achieved the highest. While oxidized cellulose displayed the best clotting times, unfortunately it also revealed low absorption capacity. CONCLUSIONS: All tested specimens seem to induce clotting independently from the administered type of oral anticoagulant, providing the possibility to neglect the disadvantage in clotting times arising from anticoagulation on a local basis. QuikClot((r)), oxidized cellulose and unexpectedly alginate-L were superior to chitosan and Lyostypt((r)). Due to its additional well-known positive effect on wound healing alginate-L should be considered for further investigations. PMID- 26620127 TI - Discovery and characterization of novel inhibitors of the sodium-coupled citrate transporter (NaCT or SLC13A5). AB - Citrate is a key regulatory metabolic intermediate as it facilitates the integration of the glycolysis and lipid synthesis pathways. Inhibition of hepatic extracellular citrate uptake, by blocking the sodium-coupled citrate transporter (NaCT or SLC13A5), has been suggested as a potential therapeutic approach to treat metabolic disorders. NaCT transports citrate from the blood into the cell coupled to the transport of sodium ions. The studies herein report the identification and characterization of a novel small dicarboxylate molecule (compound 2) capable of selectively and potently inhibiting citrate transport through NaCT, both in vitro and in vivo. Binding and transport experiments indicate that 2 specifically binds NaCT in a competitive and stereosensitive manner, and is recognized as a substrate for transport by NaCT. The favorable pharmacokinetic properties of 2 permitted in vivo experiments to evaluate the effect of inhibiting hepatic citrate uptake on metabolic endpoints. PMID- 26620129 TI - Comparison between two methods of bioelectrical impedance analyses for accuracy in measuring abdominal visceral fat area. AB - OBJECTIVES: To compare the accuracy of abdominal visceral fat area (VFA) measurements between abdominal dual bioelectrical impedance analysis (BIA) and whole-body BIA referenced to computed tomography (CT) measures. METHODS: Abdominal VFAs were measured in 102 individuals: 59 men and 43 women with a mean age of 44.2 +/- 16.3 years (range 21 - 76), body mass index 23.9 +/- 7.8 kg/m(2) (range 18 - 35) using a DUALSCAN HDS-2000 machine (dual abdominal BIA) and an InBody720 machine (whole-body BIA). The VFA values from each machine were compared with those from CT under various conditions. RESULTS: Mean abdominal VFAs were 116 +/- 69 cm(2) by CT, 89 +/- 47 cm(2) by dual abdominal BIA, and 84 +/- 33 cm(2) by whole-body BIA. The former measure showed a higher correlation with the CT measure than the latter (r=0.89 vs. r=0.64, P<0.001). Both BIA methods tended to underestimate abdominal VFAs compared with CT scans when CT VFA was not small. The dual abdominal BIA had less bias than the whole-body BIA in the assessment of VFAs. The whole-body BIA was affected by subcutaneous fat area. CONCLUSIONS: Dual BIA was more accurate in assessing abdominal VFA than whole body BIA. PMID- 26620130 TI - Scutellaria radix Extract as a Natural UV Protectant for Human Skin. AB - Ultraviolet (UV) radiation induces oxidative injury and inflammation in human skin. Scutellaria radix (SR, the root of Scutellaria baicalensis Georgi) contains flavonoids with high UV absorptivity and antioxidant properties. The purpose of this study was to examine the potential use of SR extract as an additive in cosmetic products for UV protection. SR extract and its butanol (BuOH) fraction strongly absorbed UV radiation and displayed free radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl radials and 2,2'-azinobis-(3 ethylbenzothiazoline-6-sulfonic acid) radicals. They also attenuated the UV induced death of HaCaT cells. Sunscreen creams, with or without supplementation of SR extract BuOH fraction, were tested in vivo in human trials to evaluate potential skin irritation and determine the sun protection factor (SPF). Both sunscreen creams induced no skin irritation. A sunscreen cream containing 24% ZnO showed an SPF value of 17.8, and it increased to 22.7 when supplemented with 5% SR extract BuOH fraction. This study suggests that SR-derived materials are useful as safe cosmetic additives that provide UV protection. PMID- 26620131 TI - The burden of comorbidity in people with chronic kidney disease stage 3: a cohort study. AB - BACKGROUND: Multimorbidity is a growing concern for healthcare systems, with many countries experiencing demographic transition to older population profiles. Chronic kidney disease (CKD) is common but often considered in isolation. The extent and prognostic significance of its comorbidities is not well understood. This study aimed to assess the extent and prognostic significance of 11 comorbidities in people with CKD stage 3. METHODS: A prospective cohort of 1741 people with CKD stage 3 was recruited from primary care between August 2008 and March 2010. Participants underwent medical history, clinical assessment, blood and urine sampling. Comorbidity was defined by self-reported doctor-diagnosed condition, disease-specific medication or blood results (hemoglobin), and treatment burden as number of ongoing medications. Logistic regression was used to identify associations with greater treatment burden (taking >5 medications) and greater multimorbidity (3 or more comorbidities). Kaplan Meier plots and multivariate Cox proportional hazards models were used to investigate associations between multimorbidity and all-cause mortality. RESULTS: One thousand seven hundred forty-one people were recruited, mean age 72.9 +/-9 years. Mean baseline eGFR was 52 ml/min/1.73 m(2). Only 78/1741 (4 %) had no comorbidities, 453/1741 (26 %) had one, 508/1741 (29 %) had two and 702/1741 (40 %) had >2. Hypertension was common (88 %), 30 % had 'painful condition', 24 % anemia, 23 %, ischaemic heart disease, 17 % diabetes and 12 % thyroid disorders. Median medication use was 5 medications (interquartile range 3-8) and increased with degree of comorbidity. Greater treatment burden and multimorbidity were independently associated with age, smoking, increasing body mass index and decreasing eGFR. Treatment burden was also independently associated with lower education status. After median 3.6 years follow-up, 175/1741 (10 %) died. Greater multimorbidity was independently associated with mortality (hazard ratio 2.81 (95 % confidence intervals 1.72-4.58), p < 0.001) for 3 or more comorbidities vs 0 or 1). CONCLUSIONS: Isolated CKD was rare and multimorbidity the norm in this cohort of people with moderate CKD. Increasing multimorbidity was associated with greater medication burden and poorer survival. CKD management should include consideration of comorbidities. PMID- 26620132 TI - Prediction and Characterisation of the System Effects of Aristolochic Acid: A Novel Joint Network Analysis towards Therapeutic and Toxicological Mechanisms. AB - Aristolochic acid (AA) is the major active component of medicinal plants from the Aristolochiaceae family of flowering plants widely utilized for medicinal purposes. However, the molecular mechanisms of AA systems effects remain poorly understood. Here, we employed a joint network analysis that combines network pharmacology, a protein-protein interaction (PPI) database, biological processes analysis and functional annotation analysis to explore system effects. Firstly, we selected 15 protein targets (14 genes) in the PubChem database as the potential target genes and used PPI knowledge to incorporate these genes into an AA-specific gene network that contains 129 genes. Secondly, we performed biological processes analysis for these AA-related targets using ClueGO, some of new targeted genes were randomly selected and experimentally verified by employing the Quantitative Real-Time PCR assay for targeting the systems effects of AA in HK-2 cells with observed dependency of concentration. Thirdly, the pathway-based functional enrichment analysis was manipulated using WebGestalt to identify the mostly significant pathways associated with AA. At last, we built an AA target pathway network of significant pathways to predict the system effects. Taken together, this joint network analysis revealed that the systematic regulatory effects of AA on multidimensional pathways involving both therapeutic action and toxicity. PMID- 26620133 TI - The impact of Anastrazole and Letrozole on the metabolic profile in an experimental animal model. AB - Anastrazole and Letrozole are used as endocrine therapy for breast cancer patients. Previous studies suggested a possible association with metabolic and liver adverse effects. Their results are conflicting. Fifty-five 4-week-old female Wistar rats were allocated in 4 groups 1) ovariectomy control (OC), 2) ovariectomy-Anastrazole (OA) 3) ovariectomy -Letrozole (OL), 4) control. Serum glucose, cholesterol, triglycerides, HDL-c and LDL-c were measured at baseline, 2 and 4 months. At the end, the animals' liver were dissected for pathology. At 4 months, total cholesterol differed among the OC and OL groups (p = 0.15) and the control and OL groups (p = 0.12). LDL-C differed between the control and OC groups (p = 0.015) as well as between the control and OA (p =0 .015) and OL groups (p = 0.002). OC group triglycerides, differed from those of the OL group (p =0 .002) and the control group (p = 0.007). The OA also significantly differed from the OL (p = 0.50). Liver pathology analysis revealed differences among groups with favored mild steatosis and ballooning. Anastrazole and Letrozole seem to negatively influence the lipid profile in our experimental model. This information should be taken in caution by medical oncologists when addressing patients with altered lipid metabolism. PMID- 26620135 TI - Virtual reality treatment and assessments for post-stroke unilateral spatial neglect: A systematic literature review. AB - Unilateral spatial neglect (USN) is a highly prevalent post-stroke deficit. Currently, there is no gold standard USN assessment which encompasses the heterogeneity of this disorder and that is sensitive to detect mild deficits. Similarly, there is a limited number of high quality studies suggesting that conventional USN treatments are effective in improving functional outcomes and reducing disability. Virtual reality (VR) provides enhanced methods for USN assessment and treatment. To establish best-practice recommendations with respect to its use, it is necessary to appraise the existing evidence. This systematic review aimed to identify and appraise existing VR-based USN assessments; and to determine whether VR is more effective than conventional therapy. Assessment tools were critically appraised using standard criteria. The methodological quality of the treatment trials was rated by two authors. The level of evidence according to stage of recovery was determined. Findings were compiled into a VR based USN Assessment and Treatment Toolkit (VR-ATT). Twenty-three studies were identified. The proposed VR tools augmented the conventional assessment strategies. However, most studies lacked analysis of psychometric properties. There is limited evidence that VR is more effective than conventional therapy in improving USN symptoms in patients with stroke. It was concluded that VR-ATT could facilitate identification and decision-making as to the appropriateness of VR-based USN assessments and treatments across the continuum of stroke care, but more evidence is required on treatment effectiveness. PMID- 26620134 TI - The Incremental Value of Magnetic Resonance Imaging for Identification of Apical Pouch in Patients with Apical Variant of Hypertrophic Cardiomyopathy. AB - BACKGROUND: The development of a left ventricular (LV) apical pouch in patients with apical hypertrophic cardiomyopathy (aHCM) has been thought to be the transition point that can become an apical aneurysm, which is linked to higher risk of adverse events. In our study, we sought to compare the ability of transthoracic echocardiography (echo) and cardiac magnetic resonance imaging (cMRI) to accurately identify the presence of an apical pouch or aneurysm in patients with aHCM. METHODS: We retrospectively reviewed the charts of all consecutive patients that had features of aHCM on imaging. Data from cMRI and echo examinations were abstracted, and the ability of these diagnostic modalities to identify the presence of a LV apical pouch and aneurysm was analyzed. RESULTS: Of 31 patients with aHCM, 17 (54.8%) had an apical pouch and 2 were found to have apical aneurysm (6.5%) on cMRI. Echo with and without perflutren contrast was able to accurately identify both aneurysms, but only 47.1% (8/17) of apical pouches seen by cMRI. Two patients had apical thrombus that was identified by cMRI, but not by echo. CONCLUSION: Our findings indicate that cMRI is superior to echo in identifying apical pouches in patients with aHCM. Our results also suggest that in patients undergoing echo, the use of perflutren contrast for LV opacification increases the diagnostic yield. Further study is necessary to delineate whether earlier identification of an apical pouch will be of clinical benefit for patients with aHCM by altering clinical management and avoiding adverse cardiovascular events. PMID- 26620136 TI - Combined Aortic Valve Replacement and Renal Cell Carcinoma Thrombectomy. AB - Although nephrectomy for renal cell carcinoma with inferior vena cava invasion is a common procedure, it is rare to have level IV invasion necessitating cardiopulmonary bypass (CPB). Furthermore, it is exceptionally rare to perform cardiac surgery concomitantly with this resection. We report a case in which an aortic valve replacement was done in the same surgical setting as a level IV thrombectomy. We have demonstrated that although it can be difficult to manage the coagulopathy post-CPB, this can be successfully accomplished with adequate prior preparation and a coordinated team effort. PMID- 26620137 TI - Preoperative Physiology, Imaging, and Management of Ebstein's Anomaly of the Tricuspid Valve. AB - Ebstein's anomaly of the tricuspid valve (TV) refers to an embryological derangement of TV formation causing tethering of the septal and posterior leaflets of the valve to the underlying myocardium and apical displacement of the effective valve annulus, resulting in significant TV insufficiency and dilation of the right heart structures. The pathological abnormalities of the valve can vary significantly, resulting in a wide range of clinical presentations. Fetal diagnosis and neonatal presentations of the disease are typically the most severe and are associated with the highest mortality rates. Patients with less-severe disease will present later in life with symptoms of right heart failure and tachyarrhythmias. Medical and surgical management strategies are driven by the age at presentation, severity of disease, and any associated cardiac abnormalities. There are an increasing number of surgical options focused on valve repair. PMID- 26620138 TI - Ten Years Experiences With Preoperative Evaluation Clinic for Day Admission Cardiac and Major Vascular Surgical Patients: Model for "Perioperative Anesthesia and Surgical Home". AB - Admission on the day of surgery for elective cardiac and noncardiac surgery is the prevalent practice in North America and Canada. This approach realizes medical, psychological and logistical benefits, and its success is predicated on an effective outpatient preoperative evaluation. The establishment of a highly functional preoperative clinic with a comprehensive set up and efficient logistical pathways is invaluable. This notion in recent years has included the entire perioperative period, and the concept of a perioperative anesthesia/surgical home (PASH) is gaining popularity. The anesthesiologists as perioperative physicians can organize and lead the entire process from the preoperative evaluation, through the hosptial discharge. The functions of the PASH include preoperative optimization of medical conditions and psychological preparation of the patients and their support system; the care in the operating room and intensive care unit; pain management; respiratory therapy; cardiac rehabilitation; and specialized nutrition. Along with oversight of the medical issues, the preoperative visit is an opportune time for counseling, clarification of expectations and discussion of research, as well as for utilization of various informatics systems to consolidate the pertinent information and distribute it to relevant health care providers. We review the scientific foundation and practical applications of a preoperative visit and share our experience with the development of the preoperative evaluation clinic, designed specifically for cardiac and major vascular patients scheduled for day admission surgery. The ultimate goal of preoperative evaluation clinic is to ensure a safe, efficient, and cost-effective perioperative care for patients undergoing a complex type of surgery. PMID- 26620139 TI - Transfemoral Transcatheter Aortic Valve Replacement for Mixed Aortic Valve Disease in Child's Class C Liver Disease Prior to Orthotopic Liver Transplantation: A Case Report. AB - The American Association for the Study of Liver Diseases practice guidelines list severe cardiac disease as a contraindication to liver transplantation. Transcatheter aortic valve replacement has been shown to decrease all-cause mortality in patients with severe aortic stenosis who are not considered candidates for surgical aortic valve replacement. We report our experience of liver transplantation in a patient with severe aortic stenosis and moderate aortic insufficiency who underwent transcatheter aortic valve replacement with Child-Pugh Class C disease at a Model For End-Stage Liver Disease score of 29. The patient had a difficult post procedure course that was successfully medically managed. After liver transplantation the patient was discharged to home on postoperative day 11. The combination of cardiac disease and end stage liver disease is challenging but these patients can have a successful outcome despite very severe illness. PMID- 26620140 TI - The anaesthetist and peri-operative medicine: migration and evolution. PMID- 26620141 TI - Specialist pre-operative assessment clinics. AB - While specialist pre-operative assessment is not new, its focus has evolved in response to more operations and changes in the surgical population. Patients are older and have more long-term medical comorbidities. At the same time, there has been a move from paternalistic medical decision-making to shared decision-making, based on an individual patient's choice or preference. Specialist pre-operative consultations have had to adapt to these changes by broadening their scope. Pre operative clinics have a central role in shared decision-making, coordinating and planning care before, during and after surgery, including rehabilitation and discharge planning. Multiple specialties need to work together to deliver quality patient-centred care. PMID- 26620142 TI - Peri-operative nutrition. AB - Patients are frequently malnourished or are at risk of malnutrition before surgery. Peri-operative nutritional support can improve their outcomes. This review focuses on new developments in peri-operative nutrition, including: patient preparation and pre-operative fasting; the role of nutritional supplementation; the optimal route and timing of nutrient delivery; and the nutritional management of specific groups including critically ill, obese and elderly patients. PMID- 26620143 TI - Pre-operative haematological assessment in patients scheduled for major surgery. AB - Peri-operative anaemia, blood loss and allogeneic blood transfusion are associated with increased postoperative morbidity and mortality, and prolonged hospital stay. A multidisciplinary, multimodal, individualised strategy, collectively termed 'patient blood management', may reduce or eliminate allogeneic blood transfusion and improve outcomes. This approach has three objectives: the detection and treatment of peri-operative anaemia; the reduction of peri-operative bleeding and coagulopathy; and harnessing and optimising the physiological tolerance of anaemia. This review focuses on the pre-operative evaluation of erythropoiesis, coagulation status and platelet function. Where possible, evidence is graded systematically and recommended therapies follow recently published consensus guidance. PMID- 26620144 TI - Peri-operative cardiac protection for non-cardiac surgery. AB - Cardiovascular complications are an important cause of morbidity and mortality after non-cardiac surgery. Pre-operative identification of high-risk individuals and appropriate peri-operative management can reduce cardiovascular risk. It is important to continue chronic beta-blocker and statin therapy. Statins are relatively safe and peri-operative initiation may be beneficial in high-risk patients and those scheduled for vascular surgery. The pre-operative introduction of beta-blockers reduces myocardial injury but increases rates of stroke and mortality, possibly due to hypotension. They should only be considered in high risk patients and the dose should be titrated to heart rate. Alpha-2 agonists may also contribute to hypotension. Aspirin continuation can increase the risk of major bleeding and offset the benefit of reduced myocardial risk. Contrary to the initial ENIGMA study, nitrous oxide does not seem to increase the risk of myocardial injury. Volatile anaesthetic agents and opioids have been shown to be cardioprotective in animal laboratory studies but these effects have, so far, not been conclusively reproduced clinically. PMID- 26620145 TI - Peri-operative fluid management to enhance recovery. AB - 'Enhanced recovery after surgery' protocols implement a series of peri-operative interventions intended to improve recovery after major operations, one aspect of which is fluid management. The pre-operative goal is to prepare a hydrated, euvolaemic patient by avoiding routine mechanical bowel preparation and by encouraging patients to drink clear liquids up to two hours before induction of anaesthesia. The intra-operative goal is to achieve a 'zero' fluid balance at the end of uncomplicated surgery: goal-directed fluid therapy is recommended for poorly prepared or sick patients or those undergoing more complex surgery. The postoperative goal is eating and drinking without intravenous fluid infusions. Postoperative oliguria should be expected and accepted, as urine output does not indicate overall fluid status. PMID- 26620146 TI - Peri-operative pulmonary dysfunction and protection. AB - Pulmonary complications are a major cause of peri-operative morbidity and mortality, but have been researched less thoroughly than cardiac complications. It is important to try and predict which patients are at risk of peri-operative pulmonary complications and to intervene to reduce this risk. Anaesthetists are in a unique position to do this during the whole peri-operative period. Pre operative training, smoking cessation and lung ventilation with tidal volumes of 6-8 ml.kg(-1) and low positive end-expiratory pressure probably reduce postoperative pulmonary complications. PMID- 26620147 TI - Peri-operative renal dysfunction: prevention and management. AB - Postoperative increases in serum creatinine concentration, by amounts historically viewed as trivial, are associated with increased morbidity and mortality. Acute kidney injury is common, affecting one in five patients admitted with acute medical disease and up to four in five patients admitted to intensive care, of whom one in two have had operations. This review is focused principally on the identification of patients at risk of acute kidney injury and the prevention of injury. In the main, there are no interventions that directly treat the damaged kidney. The management of acute kidney injury is based on correction of dehydration, hypotension, and urinary tract obstruction, stopping nephrotoxic drugs, giving antibiotics for bacterial infection, and commencing renal replacement therapy if necessary. PMID- 26620148 TI - Peri-operative cognitive dysfunction and protection. AB - Cognition may decline after surgery. Postoperative delirium, especially when hyperactive, may be easily recognised, whereas cognitive dysfunction is subtle and can only be detected using neuropsychological tests. The causes for these two conditions are largely unknown, although they share risk factors, the predominant one being age. Ignorance of the causes for postoperative cognitive dysfunction contributes to the difficulty of conducting interventional studies. Postoperative cognitive disorders are associated with increased mortality and permanent disability. Peri-operative interventions can reduce the rate of delirium in the elderly, but in spite of promising findings in animal experiments, no intervention reduces postoperative cognitive dysfunction in humans. PMID- 26620149 TI - Preventing chronic postoperative pain. AB - Chronic postoperative pain is common. Nerve injury and inflammation promote chronic pain, the risk of which is influenced by patient factors, including psychological characteristics. Interventional trials to prevent chronic postoperative pain have been underpowered with inadequate patient follow-up. Ketamine may reduce chronic postoperative pain, although the optimum treatment duration and dose for different operations have yet to be identified. The evidence for gabapentin and pregabalin is encouraging but weak; further work is needed before these drugs can be recommended for the prevention of chronic pain. Regional techniques reduce the rates of chronic pain after thoracotomy and breast cancer surgery. Nerve-sparing surgical techniques may be of benefit, although nerve injury is not necessary or sufficient for chronic pain to develop. PMID- 26620150 TI - Postoperative recovery and outcomes--what are we measuring and for whom? AB - Recovery is an abstract quantity the definition of which varies according to the pre-dilection of individual institutions, clinicians or patients. While traditionally focused on immediate postoperative restitution of function and readiness for discharge, recovery assessment has progressively expanded its focus to include other clinically relevant time periods, each of which is influenced by specific factors. Assessment tools have progressed from assessing one dimension of recovery, such as physiological variables, to multidimensional assessment of physical, nociceptive, emotive, functional and cognitive performance. They should be validated ideally for repeat measures and should provide real-time recovery data, as recovery can be viewed as a continuous process. PMID- 26620152 TI - Manipulation of host plant cells and tissues by gall-inducing insects and adaptive strategies used by different feeding guilds. AB - Biologists who study insect-induced plant galls are faced with the overwhelming diversity of plant forms and insect species. A challenge is to find common themes amidst this diversity. We discuss common themes that have emerged from our cytological and histochemical studies of diverse neotropical insect-induced galls. Gall initiation begins with recognition of reactive plant tissues by gall inducers, with subsequent feeding and/or oviposition triggering a cascade of events. Besides, to induce the gall structure insects have to synchronize their life cycle with plant host phenology. We predict that reactive oxygen species (ROS) play a role in gall induction, development and histochemical gradient formation. Controlled levels of ROS mediate the accumulation of (poly)phenols, and phytohormones (such as auxin) at gall sites, which contributes to the new cell developmental pathways and biochemical alterations that lead to gall formation. The classical idea of an insect-induced gall is a chamber lined with a nutritive tissue that is occupied by an insect that directly harvests nutrients from nutritive cells via its mouthparts, which function mechanically and/or as a delivery system for salivary secretions. By studying diverse gall-inducing insects we have discovered that insects with needle-like sucking mouthparts may also induce a nutritive tissue, whose nutrients are indirectly harvested as the gall-inducing insects feeds on adjacent vascular tissues. Activity of carbohydrate-related enzymes across diverse galls corroborates this hypothesis. Our research points to the importance of cytological and histochemical studies for elucidating mechanisms of induced susceptibility and induced resistance. PMID- 26620153 TI - Cellular Analysis Using Microfluidics. PMID- 26620151 TI - Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a novel soluble epoxide hydrolase inhibitor. AB - AIMS: Endothelial-derived epoxyeicosatrienoic acids may regulate vascular tone and are metabolized by soluble epoxide hydrolase enzymes (sEH). GSK2256294 is a potent and selective sEH inhibitor that was tested in two phase I studies. METHODS: Single escalating doses of GSK2256294 2-20 mg or placebo were administered in a randomized crossover design to healthy male subjects or obese smokers. Once daily doses of 6 or 18 mg or placebo were administered for 14 days to obese smokers. Data were collected on safety, pharmacokinetics, sEH enzyme inhibition and blood biomarkers. Single doses of GSK2256294 10 mg were also administered to healthy younger males or healthy elderly males and females with and without food. Data on safety, pharmacokinetics and biliary metabolites were collected. RESULTS: GSK2256294 was well-tolerated with no serious adverse events (AEs) attributable to the drug. The most frequent AEs were headache and contact dermatitis. Plasma concentrations of GSK2256294 increased with single doses, with a half-life averaging 25-43 h. There was no significant effect of age, food or gender on pharmacokinetic parameters. Inhibition of sEH enzyme activity was dose dependent, from an average of 41.9% on 2 mg (95% confidence interval [CI] -51.8, 77.7) to 99.8% on 20 mg (95% CI 99.3, 100.0) and sustained for up to 24 h. There were no significant changes in serum VEGF or plasma fibrinogen. CONCLUSIONS: GSK2256294 was well-tolerated and demonstrated sustained inhibition of sEH enzyme activity. These data support further investigation in patients with endothelial dysfunction or abnormal tissue repair, such as diabetes, wound healing or COPD. PMID- 26620154 TI - Cooperative reaction chemistry derived from a borata-diene framework. AB - The bifunctional frustrated BH(-)/B hydridoborate nucleophile/borane Lewis acid pair 6 is prepared starting from the borata-diene 3 by a sequence of sequential protonation/hydride attachment, followed by hydroboration with Piers' borane [HB(C6F5)2]. The trans-1,2-bifunctional system 6 reduced carbon monoxide eventually to the aldehyde product 10. PMID- 26620155 TI - A robust potency assay highlights significant donor variation of human mesenchymal stem/progenitor cell immune modulatory capacity and extended radio resistance. AB - The inherent immunomodulatory capacity of mesenchymal stem/progenitor cells (MSPCs) encouraged initiation of multiple clinical trials. Release criteria for therapeutic MSPCs cover identity, purity and safety but appropriate potency assessment is often missing. Reports on functional heterogeneity of MSPCs created additional uncertainty regarding donor and organ/source selection. We established a robust immunomodulation potency assay based on pooling responder leukocytes to minimize individual immune response variability. Comparing various MSPCs revealed significant potency inconsistency and generally diminished allo-immunosuppression compared to dose-dependent inhibition of mitogenesis. Gamma-irradiation to block unintended MSPC proliferation did not prohibit chondrogenesis and osteogenesis in vivo, indicating the need for alternative safety strategies. PMID- 26620156 TI - Convergent Validity of the Early Memory Index in Two Primary Care Samples. AB - Karliner, Westrich, Shedler, and Mayman (1996) developed the Early Memory Index (EMI) to assess mental health, narrative coherence, and traumatic experiences in reports of early memories. We assessed the convergent validity of EMI scales with data from 103 women from an urban primary care clinic (Study 1) and data from 48 women and 24 men from a suburban primary care clinic (Study 2). Patients provided early memory narratives and completed self-report measures of psychopathology, trauma, and health care utilization. In both studies, lower scores on the Mental Health scale and higher scores on the Traumatic Experiences scale were related to higher scores on measures of psychopathology and childhood trauma. Less consistent associations were found between the Mental Health and Traumatic Experiences scores and measures of health care utilization. The Narrative Coherence scale showed inconsistent relationships across measures in both samples. In analyses assessing the overall fit between hypothesized and actual correlations between EMI scores and measures of psychopathology, severity of trauma symptoms, and health care utilization, the Mental Health scale of the EMI demonstrated stronger convergent validity than the EMI Traumatic Experiences scale. The results provide support for the convergent validity of the Mental Health scale of the EMI. PMID- 26620157 TI - Workplace interventions for common mental disorders: a systematic meta-review. AB - Depression and anxiety disorders are the leading cause of sickness absence and long-term work incapacity in most developed countries. The present study aimed to carry out a systematic meta-review examining the effectiveness of workplace mental health interventions, defined as any intervention that a workplace may either initiate or facilitate that aims to prevent, treat or rehabilitate a worker with a diagnosis of depression, anxiety or both. Relevant reviews were identified via a detailed systematic search of academic and grey literature databases. All articles were subjected to a rigorous quality appraisal using the AMSTAR assessment. Of the 5179 articles identified, 140 studies met the inclusion criteria, of which 20 were deemed to be of moderate or high quality. Together, these reviews analysed 481 primary research studies. Moderate evidence was identified for two primary prevention interventions; enhancing employee control and promoting physical activity. Stronger evidence was found for CBT-based stress management although less evidence was found for other secondary prevention interventions, such as counselling. Strong evidence was also found against the routine use of debriefing following trauma. Tertiary interventions with a specific focus on work, such as exposure therapy and CBT-based and problem focused return-to-work programmes, had a strong evidence base for improving symptomology and a moderate evidence base for improving occupational outcomes. Overall, these findings demonstrate there are empirically supported interventions that workplaces can utilize to aid in the prevention of common mental illness as well as facilitating the recovery of employees diagnosed with depression and/or anxiety. PMID- 26620158 TI - The reconstruction of complex networks with community structure. AB - Link prediction is a fundamental problem with applications in many fields ranging from biology to computer science. In the literature, most effort has been devoted to estimate the likelihood of the existence of a link between two nodes, based on observed links and nodes' attributes in a network. In this paper, we apply several representative link prediction methods to reconstruct the network, namely to add the missing links with high likelihood of existence back to the network. We find that all these existing methods fail to identify the links connecting different communities, resulting in a poor reproduction of the topological and dynamical properties of the true network. To solve this problem, we propose a community-based link prediction method. We find that our method has high prediction accuracy and is very effective in reconstructing the inter-community links. PMID- 26620160 TI - Diagnosis and therapy of acute disseminated encephalomyelitis and its variants. AB - Acute disseminated encephalomyelitis (ADEM) is traditionally regarded as a monophasic demyelinating disorder of the central nervous system occurring in children after infection or vaccination. ADEM in children has a polysymptomatic presentation that includes encephalopathy, fever and meningeal signs. In adults, encephalopathy is less frequent and the clinical presentation is usually dominated by long tract involvement. Despite the initial clinical severity, the functional outcome is favorable in most cases. ADEM is a subgroup within the broader spectrum of postinfectious neurological syndromes (PINSs), which includes variants characterized by additional peripheral nervous system involvement, and variants characterized by a relapsing or chronic progressive course. The literature on the matter is scarce, mostly consisting of retrospective studies. The aims of this paper are to review the clinical and paraclinical profile of ADEM and its variants, to identify potential predictors of outcome, to summarize current treatment strategies and to outline research perspectives. PMID- 26620159 TI - Communicating hunger and satiation in the first 2 years of life: a systematic review. AB - Responsive feeding has been identified as important in preventing overconsumption by infants. However, this is predicated on an assumption that parents recognise and respond to infant feeding cues. Despite this, relatively little is understood about how infants engage parental feeding responses. Therefore, the aim of this systematic review was to identify what is known about infant communication of hunger and satiation and what issues impact on the expression and perception of these states. A search of Medline, CINAHL, Web of Science, PsycINFO, Science Direct and Maternal and Infant care produced 27 papers. Eligibility criteria included peer reviewed qualitative and/or quantitative publications on feeding behaviours, hunger, and satiation/satiety cues of typically developing children in the first 2 years of life. Papers published between 1966 and 2013 were included in the review. The review revealed that feeding cues and behaviours are shaped by numerous issues, such as infants' physical attributes, individual psychological factors and environmental factors. Meanwhile, infant characteristics, external cues and mothers' own characteristics affect how feeding cues are perceived. The existing literature provides insights into many aspects of hunger and satiation in infancy; however, there are significant gaps in our knowledge. There is a lack of validated tools for measuring hunger and satiation, a need to understand how different infant characteristics impact on feeding behaviour and a need to extricate the respective contributions of infant and maternal characteristics to perceptions of hunger and satiation. Further research is also recommended to differentiate between feeding driven by liking and that driven by hunger. PMID- 26620162 TI - Toward Large Scale Parallelization for Molecular Dynamics of Small Chemical Systems: A Combined Parallel Tempering and Domain Decomposition Approach. AB - A combined parallel tempering (replica exchange) and domain decomposition approach is presented, which allows for the effective use of large numbers of processor cores (>256) on modest sized simulations of chemical systems (~5000 sites). The approach is implemented in the gbmoldd molecular dynamics program for the simulation of coarse-grained molecular systems composed of combinations of isotropic and/or anisotropic particles. Benchmark results are presented for two test systems: a C24 united atom chain and a coarse-grained system of spherocylinders. PMID- 26620161 TI - Recombinant human bone morphogenetic protein 2 outcomes for maxillary sinus floor augmentation: a systematic review and meta-analysis. AB - AIMS: To study the effect of the recombinant human bone morphogenetic protein 2 (rhBMP-2) on sinus volumetric and histometric changes after sinus floor augmentation compared to a conventional approach of non-biologic bone grafting materials. MATERIALS AND METHODS: An electronic search of 4 databases (January 1990-February 2015), including PubMed/MEDLINE, EMBASE, Web of Science and Cochrane Central, and a hand search of peer-reviewed journals for relevant articles were performed. Human clinical trials with data on comparison of sinus volumetric and/or histometric outcomes with and without the use of rhBMP-2 in sinus grafting procedures, with >=10 augmentation sites in each study group, and with a follow-up period of at least 6 months, were included. Random-effects meta analyses were performed to analyze weighted mean difference (WMD) and confidence interval (CI) for the recorded variables according to PRISMA guidelines. RESULTS: Six randomized controlled trials (RCTs) were included. The results of the meta analyses showed that the WMD of vertical bone height gain was -0.14 mm (95% CI = 1.91 to 1.62 mm, P = 0.87), the WMD of bone density was -142.42 mg/cm3 (95% CI = 310.62-25.78 mg/cm3 , P = 0.10), the WMD of the percentage of vital bone was 4.59% (95% CI = -11.73-2.56%, P = 0.21), and the WMD of the percentage of residual bone grafting materials was -9.90% (95% CI = -26.38-6.58%, P = 0.21). The comparison of implant survival rate presented an overall risk ratio of 1.00 (95% CI = 0.94-1.07). The two approaches (conventional bone grafting compared to BMPs) demonstrated comparable effectiveness for both clinical and histomorphometric measures. CONCLUSIONS: This systematic review revealed that the use of rhBMP-2 in maxillary sinus floor augmentation achieved similar clinical and histometric outcomes when compared to conventional sinus grafting procedures after a healing period of 6-9 months. However, previous studies showed the morbidity and other patient-reported outcomes were improved in rhBMP-2 approaches as compared to bone autograft procedures (both intraoral and extraoral bone harvesting because no donor site is required). Long-term studies are required to determine the cost-benefit of sinus floor augmentation procedures for patients requiring implant reconstruction. PMID- 26620163 TI - Bonding in Low-Coordinate Environments: Electronic Structure of Distorted Square Planar Iron-Imido Complexes With Pincer-Type Ligands. AB - Low-coordinate architectures sustain unusual chemistry for middle and late transition metals, of which imido complexes are an excellent example. Recent DFT studies have uncovered a number of unusual features in the bonding in trigonal planar and pseudotetrahedral imido complexes. Herein, we have extended these studies to a unique, distorted square-planar iron-imido complex with a pincer type pyridine-2,6-diimine (PDI) supporting ligand. DFT calculations indicate that the iron center in the formally Fe(II) complex Fe(PDI)(NPh) is better described as intermediate-spin Fe(III), antiferromagnetically coupled to a b2-symmetry PDI pi-anion radical. A comparative analysis of the major classes of low-coordinate imido complexes has uncovered a certain similarity between Fe(PDI)(NPh) and a trigonal-planar Fe(III)-nacnac-imido complex. Both ligand architectures afford a total of four energetically accessible d orbitals, resulting in intermediate-spin Fe(III) centers. PMID- 26620164 TI - Efficient Parallel Implementation of the CCSD External Exchange Operator and the Perturbative Triples (T) Energy Calculation. AB - A new, efficient parallel algorithm is presented for the most expensive step in coupled cluster singles and doubles (CCSD) energy calculations, the external exchange operator (EEO). The new implementation requires much less input/output than our previous algorithm and takes better advantage of integral screening. It is formulated as a series of matrix multiplications. Both the atomic orbital integrals and the corresponding CC coefficients are broken up into smaller blocks to diminish the memory requirement. Integrals are presorted to make their sparsity pattern more regular. This allows the simultaneous use of two normally conflicting techniques for speeding up the CCSD procedure: the use of highly efficient dense matrix multiplication routines and the efficient utilization of sparsity. We also describe an efficient parallel implementation of the perturbative triples correction to CCSD and related methods. Using the Array Files tool for distributed filesystems, parallelization is straightforward and does not compromise efficiency. Representative timings are shown for calculations with 282-1528 atomic orbitals, 68-228 correlated electrons, and various symmetries, C1 to C2h. PMID- 26620165 TI - On the Bonding of Selenocyanates and Isoselenocyanates and Their Protonated Derivatives. AB - The structure, bonding, and protonation of NCSeX and XNCSe (X = Me, F, Cl, Br) derivatives has been investigated at the B3LYP/6-311++G(3df,2p)//B3LYP/6 31+G(d,p) level of theory. Three different approaches, namely, ELF, AIM, and NBO indicate that three main factors are responsible for the enhanced stability of the selenocyanates with respect to the isoselenocyanates when the substituents are halogens, whereas for alkyl substituents, it is the other way around: (a) the Se-X (X = F, Cl, Br) bonds are much stronger than the Se-X (X = Me); (b) the N-X (X = F, Cl, Br) bonds are much weaker than the N-X (X = Me) ones; (c) on going from the selenocyanates to the isoselenocyanates, when the substituents are halogen atoms, there is a significant weakening of the CN bond, which becomes essentially a double bond, whereas upon methyl substitution the CN bond retains its triple bond character. The same stability trends are observed for the corresponding N-protonated species. More importantly, the calculated stability differences are rather similar to those obtained for the neutral compounds, so that selenocyanates and isoselenocyanates exhibit rather similar basicities in the gas phase. Both types of isomers behave as gas-phase nitrogen bases. PMID- 26620166 TI - Efficiency and Accuracy of the Generalized Solvent Boundary Potential for Hybrid QM/MM Simulations: Implementation for Semiempirical Hamiltonians. AB - We report the implementation of the generalized solvent boundary potential (GSBP) [ Im , W. , Berneche , S. , and Roux , B. J. Chem. Phys. 2001, 114, 2924 ] in the framework of semiempirical hybrid quantum mechanical/molecular mechanical (QM/MM) methods. Application of the GSBP is connected with a significant overhead that is dominated by numerical solutions of the Poisson-Boltzmann equation for continuous charge distributions. Three approaches are presented that accelerate computation of the values at the boundary of the simulation box and in the interior of the macromolecule and solvent. It is shown that these methods reduce the computational overhead of the GSBP significantly with only minimal loss of accuracy. The accuracy of the GSBP to represent long-range electrostatic interactions is assessed for an extensive set of its inherent parameters, and a set of optimal parameters is defined. On this basis, the overhead and the savings of the GSBP are quantified for model systems of different sizes in the range of 7000 to 40 000 atoms. We find that the savings compensate for the overhead in systems larger than 12 500 atoms. Beyond this system size, the GSBP reduces the computational cost significantly, by 70% and more for large systems (>25 000 atoms). PMID- 26620167 TI - Assessment of Density Functionals for Intramolecular Dispersion-Rich Interactions. AB - A range of density functional theory methods, including conventional hybrid and meta-hybrid functionals, a double-hybrid functional, and DFT-D (DFT augmented with an empirical dispersion term) were assessed for their ability to describe the three minima along the phiGly rotational profile of one particular Tyr-Gly conformer. Previous work had shown that these minima are sensitive to intramolecular dispersion and basis set superposition error, the latter rendering MP2 calculations with small to medium-sized basis sets unsuitable for describing this molecule. Energy profiles for variation of the phiGly torsion angle were compared to an estimated CCSD(T)/CBS reference profile. The hybrid functionals and the meta-hybrid PWB6K failed to predict all three minima; the meta-hybrid functionals M05-2X and M06-2X and the nonhybrid meta functional M06-L as well as the double-hybrid mPW2-PLYP and the B3LYP-D method did find all three minima but underestimated the relative stability of the two with rotated C-terminus. The best performance was delivered by the most elaborate density functional theory model employed: mPW2-PLYP-D. Only M06-2X and mPW2-PLYP-D predicted the correct order of stability of the three minima. PMID- 26620168 TI - Massively Multicore Parallelization of Kohn-Sham Theory. AB - A multicore parallelization of Kohn-Sham density functional theory is described, using an accelerator technology made by ClearSpeed Technology. Efficiently scaling parallelization over 2304 cores is achieved. To deliver this degree of parallelism, the Coulomb problem is reformulated to use Poisson density fitting with numerical quadrature of the required three-index integrals; extensive testing reveals negligible errors from the additional approximations. PMID- 26620169 TI - On the Balance of Simplification and Reality in Molecular Modeling of the Electron Density. AB - Fused-sphere (van der Waals) surfaces and their variants such as solvent accessible surfaces and molecular surfaces are simple molecular models that are commonly used for many diverse purposes across a broad range of scientific disciplines due to their low computational resource demands. Fused-sphere models require atomic radii to be defined. Many different atomic radii have been proposed, with each set of radii being applicable to a relatively limited scope of molecular types or situations. The large number of differing radii sets actually serves to emphasize the simplicity of the model and its inability to accurately represent the reality of the molecule: its electron density. By measuring the similarity of fused-sphere, fuzzy fused-sphere, and calculated electron density representations of a set of small molecules via symmetric volume differences and the shape group method, it can be seen that fused-sphere models are very poor at representing the real electronic charge distribution of small molecules, especially where pi bond systems, lone pair electrons, and aromatic rings are involved. Larger molecules, conceivably, will be even more poorly represented. With advances in computational power and modeling techniques to arrive at high-quality calculated electron density representations for large molecules already in existence, abandoning the use of fused-sphere models should be considered for many applications. PMID- 26620170 TI - A Simple Definition of Ionic Bond Order. PMID- 26620171 TI - DFT Study and Monte Carlo Simulation on the Aminolysis of XC(O)OCH3 (X = NH2, H, and CF3) with Monomeric and Dimeric Ammonias. AB - The aminolysis of substituted methylformates (XC(O)OCH3, X = NH2, H, and CF3) in the gas phase and acetonitrile are investigated by the density functional theory B3LYP/6-311+G(d,p) method and Monte Carlo (MC) simulation with free energy perturbation (FEP) techniques. The direct and the ammonia-assisted aminolysis processes are considered, involving the monomeric and dimeric ammonia molecules, respectively. In each case, two different pathways, the concerted and stepwise, are explored. The calculated results show that, for the direct aminolysis, the activation barrier of the concerted path is lower than that of the rate controlling step of the stepwise process for all three reaction systems. In contrast, for the ammonia-assisted mechanism, the stepwise process is more favorable than the concerted pathway. The substituent effects at the carboxyl C atom of methylformate are discussed. This aminolysis of substituted methylformates is more favored for X = CF3 than for X = H and NH2 in the gas phase for both the direct and the ammonia-assisted processes. Solvent effects of CH3CN on the reaction of HC(O)OCH3 + nNH3 (n = 1, 2) are determined by Monte Carlo simulation. The potential energy profiles along the minimum energy paths in the gas phase and in acetonitrile are obtained. It is shown that CH3CN lowers the energy barriers of all reactions. PMID- 26620172 TI - Mechanism for the Substitution of an Aqua Ligand of UO2(OH2)5(2+) by Chloride. AB - Geometry and energy of the reactant (UO2(OH2)5.Cl(+)), the transition state (UO2(OH2)5...Cl(+) (?)), and the product (UO2Cl(OH2)4.OH2(+)) of the title reaction have been computed with complete active space SCF (geometries and vibrational frequencies) and multiconfiguration quasi-degenerate second-order perturbation theory (total energies). Hydration was treated using the polarizable continuum model. The two investigated active spaces, (12/11) and (12/12), produce the same results. In contrast to the water exchange reaction on UO2(OH2)5(2+), which proceeds via the associative (A) mechanism (which is a two step reaction involving an intermediate with an increased coordination number, UO2(OH2)6(2+)), water substitution by chloride follows the associative interchange (Ia) mechanism (which does not proceed via any intermediate). In this case, structure and imaginary mode of the transition state are not straightforward criteria for the attribution of the substitution mechanism, since they are both typical for the A pathway. The Ia mechanism was derived from the computed intrinsic reaction coordinate, which showed that no intermediate (for example UO2Cl(OH2)5(+)) exists as a local minimum on the potential energy surface. The activation free enthalpy is 31 kJ mol(-1). As for the water exchange reaction, the dissociative mechanism is unlikely to operate because of its higher free activation enthalpy (by ~25 kJ mol(-1)). PMID- 26620173 TI - Energy Analysis of Zn Polycoordination in a Metalloprotein Environment and of the Role of a Neighboring Aromatic Residue. What Is the Impact of Polarization? AB - We analyze the intermolecular interaction energies stabilizing the complex of ethanol in the binding site of alcohol dehydrogenase Zn-metalloenzyme (ADH). In this site Zn(II) is ligated by two cysteine and one imidazole residue and by the ethanol substrate. Ethanol is stacked over a phenylalanine residue. The system has been studied by means of SIBFA (Sum of Interactions Between Fragments Ab initio computed) polarizable molecular mechanics (PMM) supplemented by quantum chemical (QC) computations at various levels of theory. The nonadditivities of the QC interaction energies can be traced back by energy-decomposition analyses and are essentially due to polarization, charge-transfer, and electron correlation energies. These contributions can be reproduced by PMM computations. Interestingly, the polarization energy associated with the presence of the benzene ring in the ADH complex is canceled due to many-body/nonadditivity effects. Therefore this ring does not contribute to stabilization prior to including electron correlation/dispersion effects in the QC calculations or in the absence of the PMM dispersion energy contribution. When these effects are taken into account, the stabilization it contributes is in the 3-9 kcal/mol range, reflecting the need for an accurate reproduction of all components of the interaction energy by PMM. PMID- 26620174 TI - Donor-Acceptor Dissociation Energies of Group 13-15 Donor-Acceptor Complexes Containing Fluorinated Substituents: Approximate Lewis Acidities of (F3C)3M vs (F5C6)3M and the Effects of Phosphine Steric Bulk. AB - To study donor-acceptor complexes containing fluoroalkyl and -aryl substituents on the acceptors, ONIOM methods for optimizing large complexes and determining single point energies were tested. A two-layer ONIOM optimization procedure utilizing the MPW1K model followed by single point calculations using the composite three-layer ONIOM G2R3 method proved acceptable. The optimization model predicts M-X bond distances well when compared to experiment and shows that the distances increase discontinuously with the bulk of the phosphine. Unexpectedly, (RF)3B-XR3 and (RF)3Al-XR3 bond dissociation energies (DeltaEDA) are comparable for several R substituents. For RF = CF3, both are predicted to exhibit M-X DeltaEDA values in the range 55-80 kcal mol(-1), exceptionally strong for dative bond energies. For RF = C6F5, the DeltaEDA values are predicted to lie in the range 30-45 kcal mol(-1). (F5C6)3BP(t-Bu)3, which does not contain a B-P bond, is predicted to display DeltaEDA = 19 kcal mol(-1). The DeltaEDA energies do not change smoothly as the steric bulk of the phosphine increases. However, intrinsic DeltaEDA energies DeltaEint show a regular increase as the donor ability of the phosphine increases, confirming that the reorganization energy of the individual moieties contributes sizably to the overall DeltaEDA. The data indicate that PPh3 is approximately equivalent to PMe3 as a donor in terms of DeltaEint. PMID- 26620175 TI - First Principles Study of NO and NNO Chemisorption on Silicon Carbide Nanotubes and Other Nanotubes. AB - Using methods based on first principles, we find that NO and NNO molecules can be chemisorbed on silicon carbide nanotubes (SiCNTs) with an appreciable binding energy and that this is not the case for either carbon nanotubes (CNTs) or boron nitride nanotubes (BNNTs). A detailed analysis of the energetics, geometry, and electronic structure of various isomers of the complexes was performed. The adsorption energy (~-0.7 eV) is larger for the SiCNT-NO complex. The complex exhibits magnetism, and a ferromagnetic coupling of spins is observed when more than one NO molecule is adsorbed. This observation suggests that magnetic properties can be used to sense the amount of NO molecules adsorbed. The SiCNT NNO complex is a nonmagnetic system in which five-membered rings form at the binding site. PMID- 26620176 TI - A Systematic Comparison of Pairwise and Many-Body Silica Potentials. AB - The role of many-body effects in modeling silica was investigated using self consistent force matching. Both pairwise and polarizable classical force fields were developed systematically from ab initio density functional theory force calculations, allowing for a direct comparison of the role of polarization in silica. It was observed that the pairwise potential performed remarkably well at reproducing the basic silica tetrahedral structure. However, the Si-O-Si angle that links the silica tetrahedra showed small but distinct differences with the polarizable potential, a result of the inability of the pairwise potential to properly account for variations in the polarization of the oxygens. Furthermore, the transferability of the polarizable potential was investigated and suggests that additional forces may be necessary to more completely describe silica annealing. PMID- 26620177 TI - Role of Electrostatic Interactions on Engineering Reaction Barriers: The Case of CO Dissociation on Supported Cobalt Particles. AB - We demonstrate a systematic optimization of the activation barrier of CO dissociation on cobalt surfaces on the basis of a chemical bonding picture of the corresponding transition structures. In particular, Co clusters adsorbed on MgO(100), graphene, and carbon nanotubes have been investigated. We discovered that the C-O moiety has a polar covalent character at the transition state which is feasibly stabilized by electrostatic interactions. This can be realized by replacing the beta-Co atom with a less electronegative transition metal atom. The effect of 13 different substituting elements on CO dissociation has been investigated. PMID- 26620178 TI - Anthrax Lethal Factor Investigated by Molecular Simulations. AB - The anthrax disease is caused by the lethal toxin secreted by the bacterium Bacillus anthracis. The toxin is a protein aggregate which contains a Zn-based hydrolase called anthrax Lethal Factor (LF). In this work, we investigate the structure of its Michaelis complex with an optimized MAPKK-like substrate using several computational methods including density functional theory, molecular dynamics, and coarse grained techniques. Our calculations suggest that (i) the presence of second-shell ligands is crucial for tuning the structure, energetics, and protonation state of the metal binding site, as found in other Zn-based enzymes; (ii) the nucleophilic agent is a Zn-bound water molecule; (iii) substrate binding to the active site groove is mainly stabilized by van der Waals interactions; (iv) the bonds most likely involved in the substrate hydrolysis are only mildly polarized by the protein scaffold; and (v) part of helix alpha19, which is present in one solid state structure of LF (PDB: 1JKY ), assumes a coiled conformation. PMID- 26620179 TI - Remarkably Strong T-Shaped Interactions between Aromatic Amino Acids and Adenine: Their Increase upon Nucleobase Methylation and a Comparison to Stacking. AB - T-shaped geometries and interaction energies between select DNA nucleobases (adenine or 3-methyladenine) and all aromatic amino acids (histidine, phenylalanine, tyrosine, or tryptophan) were examined using BSSE-corrected MP2/6 31G*(0.25) potential energy surface scans, which determined the preferred nucleobase (face)-amino acid (edge) and nucleobase (edge)-amino acid (face) interactions. The energies of dimers with the strongest interactions were further studied at the CCSD(T)/CBS level of theory, which suggests that the T-shaped interactions in adenine dimers are very strong (up to -35 kJ mol(-1)). Nucleobase methylation to form a cationic damaged base (3-methyladenine) plays a large role in the relative monomer orientations and magnitude of the interactions, which increase by 17-125%. Most importantly, this study is the first to compare the stacking and T-shaped interactions between all aromatic amino acids and select (natural and damaged) DNA nucleobases where the differences between stacking and T-shaped interactions at the CCSD(T)/CBS level are small. Therefore, our results indicate that T-shaped interactions cannot be ignored when studying biological processes, and this manuscript discusses the importance of these interactions in the context of DNA repair. PMID- 26620180 TI - Influence of Nitroxide Spin Labels on RNA Structure: A Molecular Dynamics Simulation Study. AB - Pulsed electron double resonance (PELDOR) experiments on oligonucleotides provide a distance ruler that allows the measurement of nanometer distances accurately. The technique requires attachment of nitroxide spin labels to the nucleotides, which may possibly perturb its conformation. To study to what extent nitroxide spin labels may affect RNA structure, all-atom molecular dynamics simulations in explicit solvent are performed for six double-labeled RNA duplexes. A new parametrization of the force field for the nitroxide spin label is developed, which leads to intramolecular distances that are in good agreement with experimental results. Comparison of the results for spin-labeled and unlabeled RNA reveals that the conformational effect of the spin label depends significantly on whether the spin label is attached to the major or the minor groove of RNA. While major-groove spin labeling may to some extent affect the conformation of nearby base pairs, minor-groove spin labeling has the advantage of mostly preserving the RNA conformation. PMID- 26620181 TI - Nature of Glycine and Its alpha-Carbon Radical in Aqueous Solution: A Theoretical Investigation. AB - Quantum chemistry calculations and classical molecular dynamics simulations have been used to examine the equilibria in solution between the neutral and zwitterionic forms of glycine and also of the glycyl radical. The established preference (by 30 kJ mol(-1)) for the zwitterion of glycine was confirmed by both the quantum chemical calculations and the classical molecular dynamics simulations. The best agreement with experiment was derived from thermodynamic integration calculations of explicitly solvated systems, which gives a free energy difference of 36.6 +/- 0.6 kJ mol(-1). In contrast, for the glycyl radical in solution, the neutral form is preferred, with a calculated free energy difference of 54.8 +/- 0.6 kJ mol(-1). A detailed analysis of the microsolvation environments of each species was carried out by evaluating radial distribution functions and hydrogen bonding patterns. This analysis provides evidence that the change in preference between glycine and glycyl radical is due to the inherent gas-phase stability of the neutral alpha-carbon radical rather than to any significant difference in the solvation behavior of the constituent species. PMID- 26620182 TI - Molecular Polarization Effects on the Relative Energies of the Real and Putative Crystal Structures of Valine. AB - The computer-generation of the crystal structures of the alpha-amino acid valine is used as a challenging test of lattice energy modeling methods for crystal structure prediction of flexible polar organic molecules and, specifically, to examine the importance of molecular polarization on calculated relative energies. Total calculated crystal energies, which combine atom-atom model potential calculations of intermolecular interactions with density functional theory intramolecular energies, do not effectively distinguish the real (known) crystal structures from the rest of the low energy computer-generated alternatives when the molecular electrostatic models are derived from isolated molecule calculations. However, we find that introducing a simple model for the bulk crystalline environment when calculating the molecular energy and electron density distribution leads to important changes in relative total crystal energies and correctly distinguishes the observed crystal structures from the set of computer-generated possibilities. This study highlights the importance of polarization of the molecular charge distribution in crystal structure prediction calculations, especially for polar flexible molecules, and suggests a computationally inexpensive approach to include its effect in lattice energy calculations. PMID- 26620184 TI - Burkholderia pseudomallei is frequently detected in groundwater that discharges to major watercourses in northern Australia. AB - Burkholderia pseudomallei is the environmental bacterium that causes the serious disease melioidosis. Recently, a high prevalence of viable B. pseudomallei was reported from natural groundwater seeps around Castle Hill, a clinical focus of melioidosis in Townsville, Australia. This study sought to expand previous findings to determine the extent of B. pseudomallei in more diverse natural groundwater seeps in northern Queensland to ascertain if the presence of the organism in groundwater on Castle Hill was an isolated occurrence. Analysis of water samples (n = 26) obtained from natural groundwater seeps following an intensive rainfall event in the Townsville region determined the presence of B. pseudomallei DNA in duplicates of 18 samples (69.2 % [95 % CI, 51.5 to 87.0]). From 26 water samples, a single isolate of B. pseudomallei was recovered despite plating of both pre-enriched samples and original water samples onto selective media, indicating that the sensitivity of these molecular techniques far exceeds culture-based methods. Furthermore, the identification of new environments endemic for melioidosis may be more effectively determined by analysing surface groundwater seeps than by the analysis of random soil samples. This study suggests that a higher incidence of melioidosis following monsoonal rains may be partially the result of exposure to groundwater sources carrying B. pseudomallei, and that modifications to public health messages in endemic regions may be warranted. Moreover, these findings have implications for predictive models of melioidosis, effective models requiring consideration of topographical and surface hydrological data. PMID- 26620183 TI - A molecular ruler regulates cytoskeletal remodelling by the Rho kinases. AB - The Rho-associated coiled-coil kinases (ROCK) are essential regulators of the actin cytoskeleton; however, the structure of a full-length ROCK is unknown and the mechanisms by which its kinase activity is controlled are not well understood. Here we determine the low-resolution structure of human ROCK2 using electron microscopy, revealing it to be a constitutive dimer, 120 nm in length, with a long coiled-coil tether linking the kinase and membrane-binding domains. We find, in contrast to previous reports, that ROCK2 activity does not appear to be directly regulated by binding to membranes, RhoA, or by phosphorylation. Instead, we show that changing the length of the tether modulates ROCK2 function in cells, suggesting that it acts as a molecular ruler. We present a model in which ROCK activity is restricted to a discrete region of the actin cytoskeleton, governed by the length of its coiled-coil. This represents a new type of spatial control, and hence a new paradigm for kinase regulation. PMID- 26620185 TI - Cuff depth and continuous chest auscultation method for determination of tracheal tube insertion depth in nasal intubation: observational study. AB - BACKGROUND: Incorrect endobronchial placement of the tracheal tube can lead to serious complications. Hence, it is necessary to determine the accuracy of tracheal tube positioning. Markers are included on tracheal tubes, in the process of their manufacture, as indicators of approximate intubation depth. In addition, continuous chest auscultation has been used for determining the proper position of the tube. We examined insertion depth using the cuff depth and continuous chest auscultation method (CC method), compared with insertion depth determined by the marker method, to assess the accuracy of these methods. METHODS: After induction of anesthesia, tracheal intubation was performed in each patient. In the CC method, the depth of tube insertion was measured when the cuff had passed through the glottis, and again when breath sounds changed in quality; the depth of tube insertion was determined from these values. In the marker method, the depth of tube insertion was measured and determined when the marker of the tube had reached the glottis, using insertion depth according to the marker as an index. RESULTS: Insertion depth by the marker method was 26.6 +/- 1.2 cm and by the CC method was 28.0 +/- 1.2 cm (P < 0.0001). The CC method indicated a significantly greater depth than the marker method. CONCLUSION: This study determined the safe range of tracheal tube placement. Tube positions determined by the CC method were about 1 cm deeper than those determined by the marker. This information is important to prevent accidental one-lung ventilation and accidental extubation. CLINICAL TRIAL REGISTRATION: UMIN No. UMIN000011375. PMID- 26620187 TI - Efficacy of entomopathogenic nematodes against larvae of Tuta absoluta in the laboratory. AB - BACKGROUND: Previous studies have indicated the control potential of entomopathogenic nematodes (EPNs) against Tuta absoluta. Here, the potential of Steinernema feltiae, S. carpocapsae and Heterorhabditis bacteriophora is studied when applied against larvae of T. absoluta inside leaf mines in tomato leaf discs by means of an automated spray boom. RESULTS: The studied EPN species were effective against all four larval instars of T. absoluta but caused higher mortality in the later instars (e.g. fourth instar: 77.1-97.4% mortality) than in the first instars (36.8-60.0% mortality). Overall, S. feltiae and S. carpocapsae yielded better results than H. bacteriophora. Steinernema carpocapsae and H. bacteriophora performed better at 25 degrees C (causing 55.3 and 97.4% mortality respectively) than at 18 degrees C (causing 12.5 and 34.2% mortality respectively), whereas S. feltiae caused 100% mortality at both temperatures. Under optimal spraying conditions and with the use of Addit and Silwet L-77 adjuvants, a reduced dosage of 6.8 infective juveniles (IJs) cm(-2) yielded equally good control as a recommended dosage of 27.3 IJs cm(-2) . CONCLUSION: Under laboratory conditions, S. feltiae and S. carpocapsae showed good potential against the larvae of T. absoluta inside tomato leaf mines. Results need to be confirmed in greenhouse experiments. (c) 2015 Society of Chemical Industry. PMID- 26620188 TI - Validity of the Stages of Change in Steps instrument (SoC-Step) for achieving the physical activity goal of 10,000 steps per day. AB - BACKGROUND: Physical activity (PA) offers numerous benefits to health and well being, but most adults are not sufficiently physically active to afford such benefits. The 10,000 steps campaign has been a popular and effective approach to promote PA. The Transtheoretical Model posits that individuals have varying levels of readiness for health behavior change, known as Stages of Change (Precontemplation, Contemplation, Preparation, Action, and Maintenance). Few validated assessment instruments are available for determining Stages of Change in relation to the PA goal of 10,000 steps per day. The purpose of this study was to assess the criterion-related validity of the SoC-Step, a brief 10,000 steps per day Stages of Change instrument. METHODS: Participants were 504 Australian adults (176 males, 328 females, mean age = 50.8 +/- 13.0 years) from the baseline sample of the Walk 2.0 randomized controlled trial. Measures included 7-day accelerometry (Actigraph GT3X), height, weight, and self-reported intention, self efficacy, and SoC-Step: Stages of Change relative to achieving 10,000 steps per day. Kruskal-Wallis H tests with pairwise comparisons were used to determine whether participants differed by stage, according to steps per day, general health, body mass index, intention, and self-efficacy to achieve 10,000 steps per day. Binary logistic regression was used to test the hypothesis that participants in Maintenance or Action stages would have greater likelihood of meeting the 10,000 steps goal, in comparison to participants in the other three stages. RESULTS: Consistent with study hypotheses, participants in Precontemplation had significantly lower intention scores than those in Contemplation (p = 0.003) or Preparation (p < 0.001). Participants in Action or Maintenance stages were more likely to achieve >=10,000 steps per day (OR = 3.11; 95 % CI = 1.66,5.83) compared to those in Precontemplation, Contemplation, or Preparation. Intention (p < 0.001) and self-efficacy (p < 0.001) to achieve 10,000 steps daily differed by stage, and participants in the Maintenance stage had higher general health status and lower body mass index than those in Precontemplation, Contemplation and Preparation stages (p < 0.05). CONCLUSIONS: This brief SoC-Step instrument appears to have good criterion-related validity for determining Stages of Change related to the public health goal of 10,000 steps per day. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry reference: ACTRN12611000157976 World Health Organization Universal Trial Number: U111-1119-1755. PMID- 26620189 TI - Patterns of relative magnitudes of soil energy channels and their relationships with environmental factors in different ecosystems in Romania. AB - The percentage compositions of soil herbivorous, bacterivorous and fungivorous nematodes in forests, grasslands and scrubs in Romania was analysed. Percentages of nematode abundance, biomass and metabolic footprint methods were used to evaluate the patterns and relative size of herbivory, bacterial- and fungal mediated channels in organic and mineral soil horizons. Patterns and magnitudes of herbivore, bacterivore and fungivore energy pathways differed for a given ecosystem type and soil depth according to the method used. The relevance of herbivore energy channel increased with soil depth due to higher contribution of root-feeders. Ectoparasites, sedentary parasites and epidermal cell and root hair feeders were the most important contributors to the total biomass and metabolic footprints of herbivores. Metabolic footprint method revealed the general dominance of bacterial-based energy channel in all five types of ecosystems. The influence of altitude and climatic factors on percentages of abundance, biomass and metabolic footprints of herbivores, bacterivores and fungivores decreased with soil depth, whereas the influence of humus content, cation-exchange capacity and base saturation increased. Vegetation, altitude, climate and soil physico chemical characteristics are important factors that influenced the abundance, biomass and metabolic footprints of herbivores, bacterivores and fungivores. PMID- 26620190 TI - Loss of SDHB Elevates Catecholamine Synthesis and Secretion Depending on ROS Production and HIF Stabilization. AB - Germline mutations in genes encoding succinate dehydrogenase subunits are associated with the development of familial pheochromocytomas and paragangliomas [hereditary paraganglioma/pheochromocytoma syndrome (HPPS)]. In particular, a mutation in succinate dehydrogenase subunit B (SDHB) is highly associated with abdominal paraganglioma and subsequent distant metastasis (malignant paraganglioma), indicating the importance of SDHB genetic testing. The discovery of HPPS suggests an association among genetic mitochondrial defects, tumor development, and catecholamine oversecretion. To investigate this association, we transfected pheochromocytoma cells (PC12) with SDHB-specific siRNA. SDHB silencing virtually abolished complex II activity, demonstrating the utility of this in vitro model for investigating the pseudo-hypoxic drive hypothesis. Lack of complex II activity resulting from RNA interference of SDHB increased tyrosine hydroxylase (TH; the rate-limiting enzyme in catecholamine biosynthesis) activity and catecholamine secretion. Reduced apoptosis was observed accompanied by Bcl-2 accumulation in PC12 cells, consistent with the phenotypes of paragangliomas with SDHB mutations. In addition, SDHB silencing increased reactive oxygen species (ROS) production and nuclear HIF1alpha stabilization under normoxic conditions. Furthermore, phenotypes induced by complex II activity knockdown were abolished by pretreatment with N-acetyl cysteine (an ROS scavenger) and by prior HIF1alpha knockdown, indicating an ROS- and HIF1alpha-dependent mechanism. Our results indicate that increased ROS may act as signal transduction messengers that induce HIF1alpha stabilization and may be necessary for the pseudo-hypoxic states observed in our experimental model. To our knowledge, this is the first study demonstrating that pseudo-hypoxic states resulting from SDHB knockdown are associated with increased TH activity and catecholamine oversecretion. PMID- 26620192 TI - Random forest Granger causality for detection of effective brain connectivity using high-dimensional data. AB - Studies have shown that the brain functions are not localized to isolated areas and connections but rather depend on the intricate network of connections and regions inside the brain. These networks are commonly analyzed using Granger causality (GC) that utilizes the ordinary least squares (OLS) method for its standard implementation. In the past, several approaches have shown to solve the limitations of OLS by using diverse regularization systems. However, there are still some shortcomings in terms of accuracy, precision, and false discovery rate (FDR). In this paper, we are proposing a new strategy to use Random Forest as a regularization technique for computing GC that will improve these shortcomings. We have demonstrated the effectiveness of our proposed methodology by comparing the results with existing Least absolute shrinkage and selection operator (LASSO), and Elastic-Net regularized implementations of GC using simulated dataset. Later, we have used our proposed approach to map the network involved during deductive reasoning using real StarPlus dataset. PMID- 26620191 TI - Fat mass- and obesity-associated genotype, dietary intakes and anthropometric measures in European adults: the Food4Me study. AB - The interplay between the fat mass- and obesity-associated (FTO) gene variants and diet has been implicated in the development of obesity. The aim of the present analysis was to investigate associations between FTO genotype, dietary intakes and anthropometrics among European adults. Participants in the Food4Me randomised controlled trial were genotyped for FTO genotype (rs9939609) and their dietary intakes, and diet quality scores (Healthy Eating Index and PREDIMED-based Mediterranean diet score) were estimated from FFQ. Relationships between FTO genotype, diet and anthropometrics (weight, waist circumference (WC) and BMI) were evaluated at baseline. European adults with the FTO risk genotype had greater WC (AA v. TT: +1.4 cm; P=0.003) and BMI (+0.9 kg/m2; P=0.001) than individuals with no risk alleles. Subjects with the lowest fried food consumption and two copies of the FTO risk variant had on average 1.4 kg/m2 greater BMI (Ptrend=0.028) and 3.1 cm greater WC (Ptrend=0.045) compared with individuals with no copies of the risk allele and with the lowest fried food consumption. However, there was no evidence of interactions between FTO genotype and dietary intakes on BMI and WC, and thus further research is required to confirm or refute these findings. PMID- 26620193 TI - Neonatal handling causes impulsive behavior and decreased pharmacological response to methylphenidate in male adult wistar rats. AB - Neonatal handling has an impact on adult behavior of experimental animals and is associated with rapid and increased palatable food ingestion, impaired behavioral flexibility, and fearless behavior to novel environments. These symptoms are characteristic features of impulsive trait, being controlled by the medial prefrontal cortex (mPFC). Impulsive behavior is a key component of many psychiatric disorders such as attention deficit hyperactivity disorder (ADHD), manic behavior, and schizophrenia. Others have reported a methylphenidate (MPH) induced enhancement of mPFC functioning and improvements in behavioral core symptoms of ADHD patients. The aims of the present study were: (i) to find in vivo evidence for an association between neonatal handling and the development of impulsive behavior in adult Wistar rats and (ii) to test whether neonatal handling could have an impact on monoamine levels in the mPFC and the pharmacological response to MPH in vivo. Therefore, experimental animals (litters) were classified as: "non-handled" and "handled" (10[Formula: see text]min/day, postnatal days 1-10). After puberty, they were exposed to either a larger and delayed or smaller and immediate reward (tolerance to delay of reward task). Acute MPH (3[Formula: see text]mg/Kg. i.p.) was used to suppress and/or regulate impulsive behavior. Our results show that only neonatally handled male adult Wistar rats exhibit impulsive behavior with no significant differences in monoamine levels in the medial prefrontal cortex, together with a decreased response to MPH. On this basis, we postulate that early life interventions may have long-term effects on inhibitory control mechanisms and affect the later response to pharmacological agents during adulthood. PMID- 26620199 TI - Stakeholders' Perceptions Regarding the Use of Patient Photographs Integrated with Medical Imaging Studies. AB - Integrating digital facial photographs of pediatric patients as identifiers (ID) with medical imaging (integrated photographic IDs) may increase the detection of mislabeled studies. The purpose of this study was to determine how different stakeholders would receive this novel technology. Parents or guardians of patients in a children's hospital outpatient radiology department, radiology faculty and residents, and radiology technologists and nurses were asked to complete a survey. The perception about the anticipated use of integrated photographic ID in different clinical scenarios was investigated, and its predictors were determined using logistic regression analysis. Four hundred ninety-eight parents responded (response rate 83 %); 96 and 97 % supported the use of integrated photographic ID, if it improves the radiologist's imaging interpretation or decreases the rate of mislabeled errors, respectively. Thirty eight percent were worried that photographic IDs would impact patients' privacy. Ninety-four percent believed that they should be asked for their consent prior to obtaining their child's photograph. Seventy-eight radiologists responded (response rate 39 %); 63 and 59 % believed that the use of integrated photographic ID would result in improvement in accurate interpretation of images and identification of mislabeled patient errors, respectively. Forty-nine percent of radiologists had concern that integrated photographic ID would increase interpretation time. Fifty technologists and nurses responded (response rate 59 %); 71 and 73 % supported the technology if it resulted in more acute interpretation of images and identification of mislabeled patients, respectively. A majority of stakeholders support integrated photographic ID in order to improve safety. A majority of parents believe that consent should be obtained. PMID- 26620200 TI - A Feasibility Study of Smartphone-Based Telesonography for Evaluating Cardiac Dynamic Function and Diagnosing Acute Appendicitis with Control of the Image Quality of the Transmitted Videos. AB - Our aim was to prove the feasibility of the remote interpretation of real-time transmitted ultrasound videos of dynamic and static organs using a smartphone with control of the image quality given a limited internet connection speed. For this study, 100 cases of echocardiography videos (dynamic organ)-50 with an ejection fraction (EF) of >=50 s and 50 with EF <50 %-and 100 cases of suspected pediatric appendicitis (static organ)-50 with signs of acute appendicitis and 50 with no findings of appendicitis-were consecutively selected. Twelve reviewers reviewed the original videos using the liquid crystal display (LCD) monitor of an ultrasound machine and using a smartphone, to which the images were transmitted from the ultrasound machine. The resolution of the transmitted echocardiography videos was reduced by approximately 20 % to increase the frame rate of transmission given the limited internet speed. The differences in diagnostic performance between the two devices when evaluating left ventricular (LV) systolic function by measuring the EF and when evaluating the presence of acute appendicitis were investigated using a five-point Likert scale. The average areas under the receiver operating characteristic curves for each reviewer's interpretations using the LCD monitor and smartphone were respectively 0.968 (0.949-0.986) and 0.963 (0.945-0.982) (P = 0.548) for echocardiography and 0.972 (0.954-0.989) and 0.966 (0.947-0.984) (P = 0.175) for abdominal ultrasonography. We confirmed the feasibility of remotely interpreting ultrasound images using smartphones, specifically for evaluating LV function and diagnosing pediatric acute appendicitis; the images were transferred from the ultrasound machine using image quality-controlled telesonography. PMID- 26620201 TI - A simple histological technique to improve immunostaining when using DNA denaturation for BrdU labelling. AB - The typical immunohistochemistry technique used to reveal 5-bromo-2'-deoxyuridine (BrdU) incorporation requires denaturation of the DNA by heat and acid to permeabilize the cell nucleus. This treatment can damage tissue and reduce the antigenicity of several proteins, which then leads to weak immunostaining and/or false negatives. We show that an overnight post-fixation step following immunohistochemistry for antigens of interest protects immunostaining during the acid/heat denaturation treatment for subsequent BrdU staining. We used this technique to study the differentiation of recently divided oligodendrocyte progenitor cells in NG2CreER:EYFP reporter mice. We used a GFP anti-EYFP antibody to maximize visualization of the EYFP-containing oligodendrocyte progenitor cells, Olig1, and GST-pi to confirm the cell phenotype. Immunostaining for GFP, Olig1, and GST-pi is reduced by DNA denaturation. We found that incorporating a post-fixation step after double immunostaining for GFP/Olig1 and GFP/GST-pi prior to DNA denaturation prevented the fading and false negatives associated with this treatment. This simple addition to BrdU immunohistochemistry protocols extends the range of proteins that can be detected in combination with BrdU, along with the number of antibodies that can be used successfully in the study of cell proliferation. PMID- 26620202 TI - High-content analysis of alpha-synuclein aggregation and cell death in a cellular model of Parkinson's disease. AB - BACKGROUND: Alpha-synuclein (alpha-SYN) aggregates represent a key feature of Parkinson's disease, but the exact relationship between alpha-SYN aggregation and neurodegeneration remains incompletely understood. Therefore, the availability of a cellular assay that allows medium-throughput analysis of alpha-SYN-linked pathology will be of great value for studying the aggregation process and for advancing alpha-SYN-based therapies. NEW METHOD: Here we describe a high-content neuronal cell assay that simultaneously measures oxidative stress-induced alpha SYN aggregation and apoptosis. RESULTS: We optimized an automated and reproducible assay to quantify both alpha-SYN aggregation and cell death in human SH-SY5Y neuroblastoma cells. COMPARISON WITH EXISTING METHODS: Quantification of alpha-SYN aggregates in cells has typically relied on manual imaging and counting or cell-free assays, which are time consuming and do not allow a concurrent analysis of cell viability. Our high-content analysis method for quantification of alpha-SYN aggregation allows simultaneous measurements of multiple cell parameters at a single-cell level in a fast, objective and automated manner. CONCLUSIONS: The presented analysis approach offers a rapid, objective and multiparametric approach for the screening of compounds and genes that might alter alpha-SYN aggregation and/or toxicity. PMID- 26620203 TI - Systematic review of survival time in experimental mouse stroke with impact on reliability of infarct estimation. AB - BACKGROUND: Stroke is the second most common cause of death worldwide. Only one treatment for acute ischemic stroke is currently available, thrombolysis with rt PA, but it is limited in its use. Many efforts have been invested in order to find additive treatments, without success. A multitude of reasons for the translational problems from mouse experimental stroke to clinical trials probably exists, including infarct size estimations around the peak time of edema formation. Furthermore, edema is a more prominent feature of stroke in mice than in humans, because of the tendency to produce larger infarcts with more substantial edema. PURPOSE: This paper will give an overview of previous studies of experimental mouse stroke, and correlate survival time to peak time of edema formation. Furthermore, investigations of whether the included studies corrected the infarct measurements for edema and a comparison of correction methods will be discussed. METHOD: Relevant terms were searched in the National Library of Medicine PubMed database. A method for classification of infarct measurement methods was made using a naming convention. CONCLUSION: Our study shows that infarct size estimations are often performed around the peak time of edema, with a median of 24h. Most studies do consider edema formation, however, there is no consensus on what method to use to correct for edema. Furthermore, investigations into neuroprotective drugs should use longer survival times to ensure completion of the investigated process. Our findings indicate a need for more research in this area, and establishment of common correction methodology. PMID- 26620204 TI - New osseous soft markers for trisomy 13, 18 and 21. AB - INTRODUCTION: For ultrasonographic diagnosis of a fetal trisomy so-called "soft markers" (=ultrasonographically detectable morphological variants) are used. Detection of a certain number of them increases the diagnostic certainty of a fetal trisomy. Up to now there are very few diagnostically accepted osseous soft markers for trisomy. Hence potential osseous soft markers applicable for first and second trimester ultrasound screening for trisomy 21, 18 or 13 were studied. METHODS: Postmortal fetal X-rays (ap, lateral) of 358 fetuses (trisomy 21: n = 109, trisomy 18: n = 46; trisomy 13: n = 38, control group: n = 165). RESULTS: Not yet described but with trisomy 21 statistically associated soft markers were un-timely os sternale ossification, delayed os sacrum ossification, shortened os maxillare, reduced os maxillare-jaw-corner distance, augmented orbita height, premature os calcaneus ossification, bell-shaped thorax, coronal clefts, trend to wider binocular as well as wider intraocular distances; for trisomy 18: elevated clavicula slope, reduced number of ribs, bell-shaped thorax, coronal clefts, reduced os maxillare-jaw-corner distance, shortened ramus mandibulare, shortened os metacarpale IV and V, augmented ratio between biparietal diameter and (osseus and soft-tissue) shoulder width; for trisomy 13: longer os nasale, elevated clavicula slope, premature sternum, delayed os sacrum ossification, delayed/premature cranium ossification, reduced number of ribs, coronal clefts, reduced os maxillare-jaw-corner distance, shortened ramus mandibulare, augmented orbita height, shortened os metacarpale V and a tendency for a shortened os metacarpale IV. CONCLUSION: We found several not yet published osseous soft markers statistically associated with trisomy 21, 18 and 13, which can help to ensure sonographically these aneuploidy diagnoses. PMID- 26620205 TI - [Socioeconomic differences in physical activity in the middle-aged working population: The role of education, occupation, and income]. AB - BACKGROUND: Regular physical activity has positive effects on health at all ages. This study aims to investigate how far physical activity and regular sports engagement, as a more specific type of physical activity, are associated with socioeconomic factors in the middle-aged working population. METHODS: Data were obtained from 21,699 working men and women aged between 30 and 64 years who participated in the 2009 and 2010 population-based national German Health Update (GEDA) surveys conducted by the Robert Koch Institute. Besides a multi dimensional index of socioeconomic status (SES), three single dimensions of SES (education, occupation, and income) were used to analyse socioeconomic differences in total physical activity and regular sports engagement. RESULTS: While the prevalence of total physical activity increased with lower SES, the proportion of people with regular sports engagement decreased with lower SES. These associations remained after adjusting for age in men and women. After mutual adjustment of the three single socioeconomic dimensions, physical activity was independently associated with lower education and lower occupational status. Regular sports engagement was observed to be independently associated with higher education, higher occupational status, as well as higher income after mutual adjustment. CONCLUSIONS: This study demonstrates significant socioeconomic differences in physical and sports activity in the middle-aged working population. Education, occupation, and income show varying independent associations with physical activity behaviour. Such differences need to be considered when identifying target groups for health-enhancing physical activity interventions. PMID- 26620206 TI - Psychiatric Disorders and Montelukast in Children: A Disproportionality Analysis of the VigiBase((r)). AB - INTRODUCTION: In 2008, the US FDA issued an alert about an increased risk of psychiatric events associated with montelukast. Recent national pharmacovigilance analyses in Sweden, France and Spain detected a potential increase in reporting risk of the association. AIM: Our objective was to analyse spontaneous reports of psychiatric events in children and adolescents worldwide treated with montelukast. METHODS: We conducted a retrospective analysis of Individual Case Safety Reports (ICSRs) recorded up to 1 January 2015 in the World Health Organization (WHO) database (VigiBase((r))), in which montelukast was associated with 'psychiatric disorders'. We used the Bayesian Confidence Propagation Neural Network (BCPNN) approach for signal generation. RESULTS: A total of 14,670 ICSRs for montelukast were recorded, of which 2630 corresponded to psychiatric disorders in people aged <18 years. The main symptoms reported for infants (aged <2 years) were sleep disorders, for children (aged 2-11 years) the main symptoms were depression/anxiety, and for adolescents (aged 12-17 years) they were suicidal behaviour and depression/anxiety. Suicidal behaviour was over represented in all age groups with information component (IC) values that reached 5.01 in children and 3.85 in adolescents. Unexpectedly, completed suicides were reported more frequently for children (IC: 3.15; IC025: 1.98) than for adolescents (IC: 3.11; IC025: 2.61) or the total population (IC 1.95; IC025: 1.73). CONCLUSIONS: Neuropsychiatric disorders as side effects of montelukast were more frequently reported for children than for adults. Infants and children seem to be more prone to sleep disturbances, whereas adolescents present symptoms of depression/anxiety and psychotic reactions more often. Suicidal behaviour and completed suicide appear to be more frequently reported than previously thought in practice. Risk management plans and epidemiological studies are needed to quantify the risk. Practitioners should be aware of the risk of neuropsychiatric events associated with montelukast use, and should advise the patient and report new cases. PMID- 26620207 TI - Simultaneously increased expression of microRNA-155 and suppressor of cytokine signaling 1 (SOCS1) gene in the peripheral blood mononuclear cells of patients with primary Sjogren's syndrome. AB - AIM: The microRNA-155 (miR-155) is regarded as a central modulator of T-cell responses and could be a potential therapeutic target for certain inflammatory diseases. In our present study we analyzed the expression rate of miR-155 and its functionally linked gene, the suppressor gene of cytokine signaling 1 (SOCS1) in primary Sjogren's syndrome (pSS). METHOD: We enrolled 23 pSS patients and 10 healthy individuals in the study. The expression of miR-155 and SOCS1 gene were measured by real-time polymerase chain reaction. RESULTS: We observed the over expression of miR-155 in the peripheral mononuclear cells of patients with pSS. Surprisingly, SOCS1 gene was also over-expressed in pSS patients. CONCLUSION: This unanticipated phenomenon might be a laboratory characteristic of Sjogren's syndrome, and presumably a consequence of the noteworthy difference in the pSS immune system reacting with Epstein-Barr virus. PMID- 26620209 TI - Brain metastases in malignant pleural mesothelioma. AB - The brain is a rare site of metastasis in malignant pleural mesothelioma (MPM), and its clinical features and prognosis remain unclear. The aim of this study was to investigate the incidence, prognosis, and risk factors for brain metastases (BM) in MPM patients. Between July 1993 and October 2014, 150 patients with histologically proven MPM were included in this retrospective study. The cumulative incidence of BM was estimated with the Kaplan-Meier method, and differences between groups were analyzed by the log-rank test. Multivariate logistic regression analysis was applied to assess risk factors for BM. The median follow-up time was 11 months (range 0-154.0 months). A total of eight patients (5.3 %) developed BM during the course of their illness. Multivariate analysis identified age <65 years (odds ratio [OR] = 5.83, p = 0.038) and International Mesothelioma Interest Group stage IV (OR = 1.69, p = 0.040) as independent factors related to increased risk of developing BM. The 1-and 2-year cumulative rates of BM were 4.0 % (95 % confidence intervals [CI] 1.4-8.5 %) and 5.3 % (95 % CI 2.3-10.2 %), respectively. Our study showed that the overall survival (OS) of patients with BM was worse than that of patients without BM (median OS 6.5 vs. 11.0 months, p = 0.037). The prognosis for BM in MPM patients is poor. Clinicians should perform careful screening for BM, especially in patients with risk factors. PMID- 26620208 TI - Anti-angiogenic alternatives to VEGF blockade. AB - Angiogenesis is a major requirement for tumour formation and development. Anti angiogenic treatments aim to starve the tumour of nutrients and oxygen and also guard against metastasis. The main anti-angiogenic agents to date have focused on blocking the pro-angiogenic vascular endothelial growth factors (VEGFs). While this approach has seen some success and has provided a proof of principle that such anti-angiogenic agents can be used as treatment, the overall outcome of VEGF blockade has been somewhat disappointing. There is a current need for new strategies in inhibiting tumour angiogenesis; this article will review current and historical examples in blocking various membrane receptors and components of the extracellular matrix important in angiogenesis. Targeting these newly discovered pro-angiogenic proteins could provide novel strategies for cancer therapy. PMID- 26620210 TI - Long-term outcome after treatment of pulmonary atresia with ventricular septal defect: nationwide study of 109 patients born in 1970-2007. AB - OBJECTIVES: Treatment of pulmonary atresia with ventricular septal defect (PA + VSD) has evolved during recent decades, but it still remains challenging. This study evaluated 41-year experience of outcome, survival and treatment of PA + VSD patients. METHODS: Patient records and angiograms of 109 patients with PA + VSD born in Finland between 1970 and 2007, and treated at the Children's Hospital, Helsinki University Central Hospital, were retrospectively analysed in this nationwide study. RESULTS: Of the 109 patients, 66 (61%) had simple PA + VSD without major aortopulmonary collateral arteries (MAPCAs). Although we observed no difference in overall survival between those with or without MAPCAs, the patients without MAPCAs had better probability to achieve repair (64 vs 28%, P < 0.0003). Only 3 patients were treated by compassionate care. Overall survival was affected by the size of true central pulmonary arteries on the first angiogram (P = 0.001) and whether repair was achieved (P < 0.0001). After successful repair, the survival rate was 93% at 1 year, 91% from the second year, and functional capacity as assessed by New York Heart Association (NYHA) I-II remained in 85% of patients alive at the end of follow-up. Palliated patients at 1, 5, 10 and 20 years of age had Kaplan-Meier estimated survival rates of 55, 42, 34 and 20%, respectively. Patients who underwent repair attempts but were left palliated with right ventricle (RV)-pulmonary artery connection and septal fenestration had better survival than the rest of the palliated patients (P = 0.001). Further, the McGoon index improved after implementation of a systemic-pulmonary artery shunt in the overall PA + VSD population (P < 0.0001). CONCLUSIONS: These findings show that achievement of repair and initial size of true central pulmonary arteries affect survival of patients with PA + VSD. Although the overall survival of patients with MAPCAs showed no difference compared with simple PA + VSD patients, they had a higher risk of remaining palliated. However, palliative surgery may have a role in treatment of PA + VSD because the size of pulmonary arteries increased after placement of systemic-pulmonary artery shunt. In addition, subtotal repair by a RV-pulmonary artery connection and septal fenestration improved survival over extracardiac palliation. PMID- 26620212 TI - Natural Orifice Translumenal Endoscopic Surgery: Review of Its Applications in Bariatric Procedures. AB - This review aims to summarise clinical applications of natural orifice translumenal endoscopic surgery (NOTES) in bariatric surgery. A review of data, until December 2014, was carried out regarding techniques and outcomes of bariatric NOTES procedures. Nine publications were included in the final analysis, with another six papers describing endolumenal procedures included for comparison. All NOTES studies adopted a hybrid procedure. Hybrid NOTES sleeve gastrectomy (hNSG) was described in four humans and two porcine studies. In humans, six subjects (23.1%) were converted to conventional laparoscopic methods, and one postoperative complication (3.8%) was reported. Mean excess weight loss was 46.6% (range 35.2-58.9). Transvaginal-assisted sleeve gastrectomy appears feasible and safe when performed by appropriately trained professionals. However, improvements must be made to overcome current technical limitations. PMID- 26620211 TI - Improved Treatment Efficacy of Antiangiogenic Therapy when Combined with Picornavirus Vaccination in the GL261 Glioma Model. AB - The addition of antiangiogenic therapy to the standard-of-care treatment regimen for recurring glioblastoma has provided some clinical benefits while also delineating numerous caveats, prompting evaluation of the elicited alterations to the tumor microenvironment. Of critical importance, given the steadily increasing incorporation of immunotherapeutic approaches clinically, is an enhanced understanding of the interplay between angiogenic and immune response pathways within tumors. In the present study, the GL261 glioma mouse model was used to determine the effects of antiangiogenic treatment in an immune-competent host. Following weekly systemic administration of aflibercept, an inhibitor of vascular endothelial growth factor, tumor volume was assessed by magnetic resonance imaging and changes to the tumor microenvironment were determined. Treatment with aflibercept resulted in reduced tumor burden and increased survival compared with controls. Additionally, decreased vascular permeability and preservation of the integrity of tight junction proteins were observed. Treated tumors also displayed hallmarks of anti-angiogenic evasion, including marked upregulation of vascular endothelial growth factor expression and increased tumor invasiveness. Aflibercept was then administered in combination with a picornavirus-based antitumor vaccine and tumor progression was evaluated. This combination therapy significantly delayed tumor progression and extended survival beyond that observed for either therapy alone. As such, this work demonstrates the efficacy of combined antiangiogenic and immunotherapy approaches for treating established gliomas and provides a foundation for further evaluation of the effects of antiangiogenic therapy in the context of endogenous or vaccine-induced inflammatory responses. PMID- 26620213 TI - Fully Ambulatory Laparoscopic Sleeve Gastrectomy: 328 Consecutive Patients in a Single Tertiary Bariatric Center. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is becoming one of the most popular bariatric procedures because of its short operative time, good resolution of comorbidities, excellent weight loss, and low complications rate. However, the safety of LSG as a day-surgery procedure has not yet been widely documented. METHODS: A retrospective analysis of a prospectively collected bariatric database, in a single institution, between August 2012 and February 2015, yielded 980 patients who underwent LSG; 328 patients (33.5 %) responded to established criteria and were operated on a 1-day surgery basis (length of stay < 12 h). RESULTS: There were 258 (78 %) primary LSG and 70 revisional LSG (22 %) performed on 284 females and 44 males, with a mean age (+/-SD) of 38 +/- 9 years. Mean (+/ SD) preoperative body mass index (BMI) was 45 +/- 6 kg/m(2). Operative time was 68 +/- 17 min (mean +/- SD). There were no deaths. A total of 322 patients (98.2 %) were discharged home the day of surgery. There were 6 (1.8 %) unplanned overnight hospitalization, and 28 patients (8.5 %) were readmitted between days 1 and 30. Most patients (25/34, 73 %) were hospitalized for minor problems, such as pain, nausea, and/or vomiting. There were two cases of (0.6 %) gastric staple line leaks, three (0.9 %) of intra-abdominal hematomas, two (0.6 %) of pneumonia, one (0.3 %) of acute pancreatitis, and one (0.3 %) of urinary tract infection. All patients recovered well. CONCLUSIONS: LSG can be performed as an outpatient procedure in selected patients, with acceptable results in terms of retention, readmission, and complication rates. PMID- 26620214 TI - Response to the Comment on: Occipital C1-C2 Neuromodulation Decreases Body Mass and Fat Stores and Modifies Activity of the Autonomic Nervous System in Morbidly Obese Patients--a Pilot Study. PMID- 26620215 TI - The %EBMIL/%EWL Double Booby-Trap. A Comment on Studies that Compare the Effect of Bariatric Surgery Between Heavier and Lighter Patients. PMID- 26620216 TI - Reply to the Letter to Editor Entitled "The %EBMIL/%EWL Double-Booby Trap. A Comment on Studies that Compare the Effect of Bariatric Surgery Between Heavier and Lighter Patients". PMID- 26620217 TI - Laparoscopic Conversion of Vertical Banded Gastroplasty into Roux-en-Y Gastric Bypass. AB - Laparoscopic conversion of vertical banded gastroplasty (VBG) into Roux-en-Y gastric bypass is a technically demanding procedure. This article demonstrates the feasibility of conversion of failed VBG to Roux-en-Y gastric bypass (RYGBP).We have a series of 15 patients who underwent conversion from VBG to RYGBP, and the results were satisfactory regarding the percent excess weight loss and the resolution of the comorbidities, without a significant increase in the complications. In patients with a difficult anatomy below the cardia, dividing the esophagus just above the esophagogastric junction and performing an esophagojejunostomy may be a safe alternative to converting to a Scopinaro-BPD. Laparoscopic conversion of failed VBG to RYGBP is safe and feasible. PMID- 26620218 TI - The Effect of Bariatric Surgery on Urinary Incontinence in Women. AB - BACKGROUND: Little is known regarding the effect of bariatric surgery on urinary incontinence. METHODS: Between September 2008 and November 2014, 240 female patients underwent bariatric surgery. RESULTS: The prevalence of urinary incontinence preoperatively was 45 % (108). Eighty-two (76 %) completed urinary function questionnaires pre-operatively and post-operatively. Fifty-seven (70 %) underwent laparoscopic gastric bypass, twenty-four (29 %) underwent sleeve gastrectomy and one underwent a banding procedure. Thirty-one (38 %) reported leaking on sneezing or coughing-stress urinary incontinence (SUI). Thirteen (16 %) complained of leaking before reaching the toilet-overactive bladder syndrome (OAB). The remaining thirty-eight (46 %) reported mixed symptoms. The mean pre operative weight and BMI were 133 (18) kg and 50 (SD = 6.2) kg/m(2) respectively. The mean post-operative BMI drop was 16 (SD = 5.2) kg/m(2). Preoperatively, 61 (75 %) reported moderate to very severe urinary incontinence compared to 30 (37 %) post-operatively (chi (2) = 3.24.67, p = 0.050). Twenty-seven (33 %) patients reported complete resolution of their urinary incontinence. Fifty-one (62 %) patients required incontinence pads on a daily basis pre-operatively, compared to 35 (43 %) post-operatively (chi (2) = 22.211.6, p = 0.00). The mean International Consultation on Incontinence Questionnaire- Urinary Incontinence short form (ICIQ UI SF) score was 9.3 (SD = 4.4) pre-operatively compared to 4.9 (SD = 5.3) post operatively (t = 7.2, p = 0.000). The improvement score post-operatively was 8 (SD = 3). A significant difference in the ICIQ-UI SF was identified between OAB and SUI groups when adjusting for age, number of children, type of delivery and pre-op BMI (t = 1.98, p = 0.05). CONCLUSION: Bariatric surgery results in a clinically significant improvement in urinary incontinence. However, this is not proportional to pre-operative BMI, weight loss, age, parity and mode of delivery. PMID- 26620219 TI - Pathological findings in patients with low anterior inferior iliac spine impingement. AB - PURPOSE: Femoroacetabular impingement (FAI) has been well described in recent years as one of the major causes of hip pain potentially leading to acetabular labral tears and cartilage damage, which may in turn lead to the development of early degenerative changes. More recently, extra-articular patterns of impingement such as the anterior inferior iliac spine (AIIS)/subspine hip impingement have gained focus as a cause of hip pain and limitation in terminal hip flexion and internal rotation. The purpose of this study was to evaluate the prevalence of low AIIS in patients undergoing hip arthroscopy and to characterize the concomitant intra-articular lesions. METHODS: Between November 2011 and April 2013, 100 consecutive patients underwent hip arthroscopy for various diagnoses by a single surgeon. After intra-operative diagnosis of low AIIS was made, a comprehensive review of the patients' records, preoperative radiographs, and intra-operative findings was conducted to document the existence and location of labral and chondral lesions. RESULTS: Twenty-one (21 %) patients had low AIIS. There were 13 males (mean age 38.4 years) and eight females (mean age 35.5 years). Eight patients had pre-operative radiographic evidence of low AIIS. All patients had a labral tear anteriorly, at the level of the AIIS; 17 had chondrolabral disruption and 17 had chondral lesions in zone two (antero superior); and four patients had lesion in zones two and three. CONCLUSIONS: Low AIIS is a common intra-operative finding in hip arthroscopy patients. Characteristic labral and chondral lesions are routinely found in a predictable location that effaces the low AIIS. Level of Evidence-Level IV, Case Series. PMID- 26620221 TI - Vital Capacity Impairment due to Neuromuscular Disease and its Correlation with Diaphragmatic Ultrasound: A Preliminary Study. AB - The purpose of this pilot study was to evaluate the correlation between diaphragmatic excursion measured by a right sub-costal ultrasound approach and forced vital capacity in patients with amyotrophic lateral sclerosis (ALS) or myotonic dystrophy (MD). All patients referred for pulmonary function testing underwent ultrasonic measurement of diaphragmatic excursion during quiet breathing, voluntary sniffing (Esniff) and forced breathing (EDEmax). Forty-five patients were included, mainly for amyotrophic lateral sclerosis or myotonic dystrophy. There was a significant correlation between EDEmax values and forced vital capacity (FVC) values (r = 0.68 [0.46-0.90], p < 0.0001) and between EDEmax values and percentage of predicted FVC values (r = 0.75 [0.55-0.95], p < 0.0001). At a threshold of EDEmax < 5.5 cm, the sensitivity and specificity of ultrasonic diaphragmatic excursion in predicting FVC <= 50% of theoretical values were 100% [66%-100%] and 69% [52%-84%] respectively, without any significant difference between males and females. There was no statistical correlation between maximal inspiratory pressure and Esniff. PMID- 26620220 TI - Genomic Profile of Fatigued Men Receiving Localized Radiation Therapy. AB - PURPOSE: The purpose of this study was to explore gene expression changes in fatigued men with nonmetastatic prostate cancer receiving localized external beam radiation therapy (EBRT). METHODS: Fatigue was measured in 40 men with prostate cancer (20 receiving EBRT and 20 controls on active surveillance) using the Functional Assessment of Cancer Therapy-Fatigue (FACT-F). EBRT subjects were followed from baseline to midpoint and end point of EBRT, while controls were seen at one time point. EBRT subjects were categorized into high- and low-fatigue groups based on change in FACT-F scores from baseline to EBRT completion. Full genome microarray was performed from peripheral leukocyte RNA to determine gene expression changes related to fatigue phenotypes. Real-time polymerase chain reaction and enzyme-linked immunosorbent assay confirmed the most differentially expressed gene in the microarray experiment. RESULTS: At baseline, mean FACT-F scores were not different between EBRT subjects (44.3 +/- 7.16) and controls (46.7 +/- 4.32, p = .24). Fatigue scores of EBRT subjects decreased at treatment midpoint (38.6 +/- 9.17, p = .01) and completion (37.6 +/- 9.9, p = .06), indicating worsening fatigue. Differential expression of 42 genes was observed between fatigue groups when EBRT time points were controlled. Membrane-spanning four domains, subfamily A, member (MS4A1) was the most differentially expressed gene and was associated with fatigue at treatment end point (r = -.46, p = .04). CONCLUSION: Fatigue intensification was associated with MS4A1 downregulation, suggesting that fatigue during EBRT may be related to impairment in B-cell immune response. The 42 differentially expressed fatigue-related genes are associated with glutathione biosynthesis, gamma-glutamyl cycle, and antigen presentation pathways. PMID- 26620222 TI - Diagnostic Efficacy of Ultrasonographic Characteristics of Thyroid Carcinoma in Predicting Cervical Lymph Node Metastasis. AB - The goals of this study were to determine the ultrasonographic characteristics of thyroid carcinoma (TC) and to explore the diagnostic efficacy of these ultrasonographic characteristics in predicting cervical lymph node metastasis (LNM). From June 2012 to June 2014, a total of 186 TC patients were recruited from the Central Hospital of Chengde City, Hebei, China. We divided them into two groups: the metastatic group comprised 129 nodules (n = 86), and the non metastatic group 117 nodules (n = 100). Univariate and multivariate analyses were used to evaluate the relationship between ultrasonographic characteristics and cervical LNM. Spectral Doppler ultrasound was employed to estimate peak systolic velocity, pulsatility index and resistive index. Receiver operating characteristic curves were drawn to evaluate the efficacy of ultrasonographic characteristics in predicting cervical LNM. The sensitivity, specificity, positive predictive value and negative predictive value of ultrasonographic diagnosis were 81.40% (105/129), 92.32% (108/117), 92.11% (105/114) and 81.82% (108/132), respectively. Cervical LNM in TC frequently occurred at the cervical level VI (37.98%) and was located mainly in the middle pole (46.51%) or lower pole (41.09%). Peak systolic velocity and resistive index values were significantly higher in the metastatic group than in the non-metastatic group (both p < 0.001). Multivariate analysis revealed that nodular diameter, capsular invasion, microcalcification and flow grade were risk factors for TC patients with cervical LNMs (all p < 0.05). Furthermore, receiver operating characteristic curve analysis revealed that nodular diameter, capsular invasion, microcalcification and flow grade had excellent accuracy in predicting cervical LNM. We conclude that ultrasonographic characteristics of TC, including maximum nodular diameter, capsular invasion, microcalcification and flow grade, may predict cervical LNM. PMID- 26620223 TI - Comparison of drug release from poly(lactide-co-glycolide) microspheres and novel fibre formulations. AB - Intraperitoneal cisplatin delivery has recently been shown to benefit ovarian cancer patients. Cisplatin-containing poly(lactide-co-glycolide) (PLGA) microspheres have been proposed for cisplatin delivery. The drug loading of cisplatin containing microspheres produced elsewhere is 3-10%w. Similar microspheres are reported here with a mean diameter of 38.8 um, and a drug loading of 11.7%w, but using ethyl acetate as a safer solvent. In addition, novel formulations of cisplatin-containing solid and hollow PLGA 65:35 (lactide:glycolide) fibres were prepared and are reported here for the first time. PLGA hollow fibres were produced by phase inversion with a high drug loading of 27%w. Mechanistic mathematical models were applied to the cisplatin release profiles to allow quantitative comparison of microsphere, solid fibre and hollow fibre formulations. The diffusion coefficient of cisplatin eluting from a typical batch of PLGA microspheres was 4.8 * 10(-13) cm(2) s(-1); this low diffusivity of cisplatin in microspheres was caused by the low porosity of the polymer matrix. The diffusion coefficients of cisplatin eluting from a batch of PLGA solid fibres and hollow fibres were 6.1 * 10(-10) and 3.3 * 10(-10) cm(2) s( 1), respectively. These fibres allowed the controlled release of high doses of cisplatin over four days and may represent an improvement in slow release technology for treatment of ovarian cancer. PMID- 26620224 TI - Mini-symposium: Upper Airway Anomalies. PMID- 26620225 TI - MiR-631/ZAP70: A novel axis in the migration and invasion of prostate cancer cells. AB - MicroRNAs (miRNAs) are short, endogenous non-coding RNA molecules involved in cancer initiation and progression. Using transwell migration and invasion assays, we found that miR-631 inhibited the migration and invasion of prostate cancer (PCa) cells. Bioinformatic algorithms indicated the 3'-untranslated region (3' UTR) of zeta-associated protein 70 (ZAP70) has a putative binding site for miR 631. We found that miR-631 can bind to the 3'-UTR of ZAP70 and decrease its expression. Further studies confirmed that ZAP70 facilitates PCa cell migration and invasion. Interestingly, using gain- and loss-of function experiments, we found that ZAP70 is a major target of miR-631 and largely mediates its activity. In addition, we further discovered that miR-631 was downregulated and ZAP70 was overexpressed in PCa cell lines and PCa tissues. A concordant inverse correlation between miR-631 and ZAP70 was also found in PCa tissues. In all, our study demonstrates that miR-631 decreases PCa cell migration and invasion by dampening ZAP70 expression. PMID- 26620226 TI - Expression of hypoxia-inducible factor-1 by trophectoderm cells in response to hypoxia and epidermal growth factor. AB - The low oxygen environment in the uterine environment requires pre-implantation embryos to adapt to oxygen deficiency. Hypoxia-inducible factor (HIF)-1 is a master regulator whereby cells adapt to changes in oxygen concentrations. In addition to hypoxic conditions, non-hypoxic stimuli such as growth factors also activate expression of HIF-1. In this study, the mechanisms underlying low oxygen dependent and epidermal growth factor (EGF)-dependent expression of HIF-1alpha were explored using porcine trophectoderm (pTr) cells. The results indicated that expression of HIF-1alpha and HIF-1beta mRNAs was not affected by low concentrations of oxygen; however, hypoxic conditions markedly increased the abundance of HIF-1alpha protein, especially in nuclei of pTr cells. Even under normoxic conditions, the abundance of HIF-1alpha protein increased in response to EGF. This EGF-mediated increase in HIF-1alpha protein was blocked through inhibition of translation by cycloheximide. The inhibitors LY294002 (PI3K-AKT inhibitor), U0126 (inhibitor of ERK1/2) and rapamycin (mTOR inhibitor) also blocked the ability of EGF to increase HIF-1alpha protein and to phosphorylate AKT, ERK1/2 and mTOR proteins. Both hypoxia and EGF induced proliferation of pTr cells. This ability of EGF to stimulate proliferation of pTr cells was suppressed by EGFR siRNA, but not HIF-1alpha siRNA, but a significant decrease in EGF induced HIF-1alpha protein occurred when pTr cells were transfected with HIF 1alpha siRNA. The results of the present study suggest that pTr cells adapt to oxygen deficiency and proliferate in response to an oxygen-dependent HIF-1 system, and that EGF at maternal-conceptus interface can increase the abundance of HIF-1alpha protein via translational regulation through AKT, ERK1/2 and mTOR signaling cascades. PMID- 26620228 TI - LYATK1 potently inhibits LPS-mediated pro-inflammatory response. AB - Lipopolysaccharide (LPS)-primed monocytes/macrophages produce pro-inflammatory cytokines, which could lead to endotoxin shock. TGF-beta-activated kinase1 (TAK1) activation is involved in the process. In the current study, we studied the potential effect of a selective TAK1 inhibitor, LYTAK1, on LPS-stimulated response both in vitro and in vivo. We demonstrated that LYTAK1 inhibited LPS induced mRNA expression and production of several pro-inflammatory cytokines [interleukin 1beta (IL-1beta), tumor necrosis factor-alpha (TNFalpha) and interleukin-6 (IL-6)] in RAW 264.7 macrophages. LYTAK1's activity was almost nullified with TAK1 shRNA-knockdown. Meanwhile, in both primary mouse bone marrow derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs), LPS-induced pro-inflammatory cytokine production was again attenuated with LYTAK1 co-treatment. Molecularly, LYTAK1 dramatically inhibited LPS-induced TAK1-nuclear factor kappa B (NFkappaB) and mitogen-activated protein kinase (Erk, Jnk and p38) activation in RAW 264.7 cells, mouse BMDMs and human PBMCs. In vivo, oral administration of LYTAK1 inhibited LPS-induced activation of TAK1-NFkappaB-p38 in ex-vivo cultured PBMCs, and cytokine production and endotoxin shock in mice. Together, these results demonstrate that LYTAK1 inhibits LPS-induced production of several pro-inflammatory cytokines and endotoxin shock probably through blocking TAK1-regulated signalings. PMID- 26620227 TI - Differential susceptibility of transgenic mice expressing human surfactant protein B genetic variants to Pseudomonas aeruginosa induced pneumonia. AB - Surfactant protein B (SP-B) is essential for lung function. Previous studies have indicated that a SP-B 1580C/T polymorphism (SNP rs1130866) was associated with lung diseases including pneumonia. The SNP causes an altered N-linked glycosylation modification at Asn129 of proSP-B, e.g. the C allele with this glycosylation site but not in the T allele. This study aimed to generate humanized SP-B transgenic mice carrying either SP-B C or T allele without a mouse SP-B background and then examine functional susceptibility to bacterial pneumonia in vivo. A total of 18 transgenic mouse founders were generated by the DNA microinjection method. These founders were back-crossed with SP-B KO mice to eliminate mouse SP-B background. Four founder lines expressing similar SP-B levels to human lung were chosen for further investigation. After intratracheal infection with 50 MUl of Pseudomonas aeruginosa solution (1 * 10(6) CFU/mouse) or saline in SP-B-C, SP-B-T mice the mice were sacrificed 24 h post-infection and tissues were harvested. Analysis of surfactant activity revealed differential susceptibility between SP-B-C and SP-B-T mice to bacterial infection, e.g. higher minimum surface tension in infected SP-B-C versus infected SP-B-T mice. These results demonstrate for the first time that human SP-B C allele is more susceptible to bacterial pneumonia than SP-B T allele in vivo. PMID- 26620230 TI - CQC's inspection of private hospitals is inadequate, report says. PMID- 26620229 TI - Duration criterion of respiratory events for children with obstructive sleep apnea. AB - OBJECTIVE: To investigate the duration criterion of respiratory events in children with obstructive sleep apnea syndrome (OSAS) by analyzing standard nocturnal polysomnograms (PSG). To provide reference values for pediatric PSG. METHODS: 107 OSAS children diagnosed by PSG from January 2004 to May 2006 were randomly selected. The decrease in arterial oxygen saturation (DeltaSaO2) and the corresponding event duration of each respiratory event were observed. RESULTS: (1) There was significant positive correlation between oxygen desaturation values (DeltaSaO2=0-17%) and the corresponding durations of respiratory events (P<0.001). (2) There was no significant difference in durations of respiratory events in rapid eye movement (REM) sleep and NREM sleep, the demographics between male and female children. (3) Significant positive correlation between age and duration of respiratory events (apnea/hypopnea) when oxygen desaturation values equal to 4% (DeltaSaO2=4%) was observed. (4) The lower limit of 95% confidence intervals of which duration of oxygen desaturation value equals to 4% was 5.4s. CONCLUSION: (1) PSG studies may allow the establishment of the duration criterion of significant respiratory events; (2) 5.4s can be defined as duration criteria of respiratory events; (3) the present study provides reference values for Pediatric PSG. PMID- 26620231 TI - [A new title and a new cover for our journal]. PMID- 26620232 TI - The Trajectory of Dyspnea in Hospitalized Patients. AB - CONTEXT: The trajectory of dyspnea for patients hospitalized with acute cardiopulmonary disease, who are not terminally ill, is poorly characterized. OBJECTIVES: To investigate the natural history of dyspnea during hospitalization and examine the role that admission diagnosis, and patient factors play in altering symptom resolution. METHODS: Prospective cohort study of patients hospitalized for an acute cardiopulmonary condition at a large tertiary care center. Dyspnea levels and change in dyspnea score were the main outcomes of interest and were assessed at admission, 24 and 48 hours, and at discharge using the verbal 0-10 numeric scale. RESULTS: Among 295 patients enrolled, the median age was 68 years, and the most common admitting diagnoses were heart failure (32%), chronic obstructive pulmonary disease (COPD) (39%), and pneumonia (13%). The median dyspnea score at admission was 9 (interquartile range [IQR] 7-10); decreased to 4 (IQR 2-7) within the first 24 hours; and subsequently plateaued at 48 hours. At discharge, the median score had decreased to 2.75 (IQR 1-4). Compared to patients with heart failure, patients with COPD had higher median dyspnea score at baseline and admission and experienced a slower resolution of dyspnea symptoms. After adjusting for patient characteristics, the change in dyspnea score from admission to discharge was not significantly different between patients hospitalized with congestive heart failure, COPD, or pneumonia. CONCLUSION: Most patients admitted with acute cardiopulmonary conditions have severe dyspnea on presentation, and their symptoms improve rapidly after admission. The trajectory of dyspnea is associated with the underlying disease process. These findings may help set expectations for the resolution of dyspnea symptoms in hospitalized patients with acute cardiopulmonary diseases. PMID- 26620233 TI - Does Mode of Survey Administration Matter? Using Measurement Invariance to Validate the Mail and Telephone Versions of the Bereaved Family Survey. AB - CONTEXT: The Veterans Health Administration evaluates outcomes of end-of-life (EOL) care using the Bereaved Family Survey (BFS). Originally, the BFS was administered as a telephone survey but was transitioned to a mail survey beginning October 2012. The transition necessitated an evaluation of the tool's validity using this new mode of administration. OBJECTIVES: The objective of this study was to validate the mail version and to test for measurement invariance (MI) across the two administration modes. METHODS: Telephone and mail versions of the BFS were validated separately between October 2009 and September 2013. MI was evaluated using a series of confirmatory factor analyses (CFAs). Construct validity was evaluated by calculating Cronbach alpha coefficients and examining differences between BFS factor scores for groups with and without quality care indicators (e.g., receipt of a palliative care consult). RESULTS: Our sample consisted of 35,682 decedent BFS scores (27,109 telephone surveys; 8573 mail surveys). BFS item scores were slightly skewed, with a predominance of higher scores for both the telephone and mail version. The average missing rate for each BFS item was minimal, just 2% for each version. The CFA models demonstrated dimensional, configural, metric, and factor mean invariance across administration modes. BFS factor scores were consistently higher when a patient received EOL quality care indicators regardless of mode of administration. CONCLUSION: These findings demonstrate the MI and robust psychometric properties for the BFS across administration modes. PMID- 26620235 TI - Loss of Dignity in Severe Chronic Obstructive Pulmonary Disease. AB - CONTEXT: The maintenance of dignity is an important concept in palliative care, and the loss of dignity is a significant concern among patients with advanced cancer. OBJECTIVES: The goals of this study were to examine whether loss of dignity is also a concern for patients receiving interdisciplinary rehabilitation for Stage III or IV chronic obstructive pulmonary disease. We examined the prevalence and correlates of loss of dignity and determined whether it improves with treatment. METHODS: Inpatients underwent a structured interview inquiry around their sense of dignity and completed measures of pulmonary, physical, and psychological function at admission (n = 195) and discharge (n = 162). RESULTS: Loss of dignity was identified as a prominent ongoing concern for 13% of patients. It was correlated with measures of depression and anxiety sensitivity, but not with pulmonary capacity or functional performance. A robust improvement in loss of dignity was demonstrated, with 88% of those who reported a significant problem at admission no longer reporting one at discharge. CONCLUSION: The prevalence of a problematic loss of dignity among patients with severe chronic obstructive pulmonary disease is at least as high as among those receiving palliative cancer care. Loss of dignity may represent a concern among people with medical illnesses more broadly, and not just in the context of "death with dignity" at the end of life. Furthermore, interdisciplinary care may help to restore a sense of dignity to those individuals who are able to participate in rehabilitation. PMID- 26620234 TI - Prevalence and Predictors of Burnout Among Hospice and Palliative Care Clinicians in the U.S. AB - CONTEXT: Many clinical disciplines report high rates of burnout, which lead to low quality of care. Palliative care clinicians routinely manage patients with significant suffering, aiming to improve quality of life. As a major role of palliative care clinicians involves educating patients and caregivers regarding identifying priorities and balancing stress, we wondered how clinician self management of burnout matches against the emotionally exhaustive nature of the work. OBJECTIVES: We sought to understand the prevalence and predictors of burnout using a discipline-wide survey. METHODS: We asked American Academy of Hospice and Palliative Medicine clinician members to complete an electronic survey querying demographic factors, job responsibilities, and the Maslach Burnout Inventory. We performed univariate and multivariate regression analyses to identify predictors of high rates of burnout. RESULTS: We received 1357 responses (response rate 30%). Overall, we observed a burnout rate of 62%, with higher rates reported by nonphysician clinicians. Most burnout stemmed from emotional exhaustion, with depersonalization comprising a minor portion. Factors associated with higher rates of burnout include working in smaller organizations, working longer hours, being younger than 50 years, and working weekends. We did not observe different rates between palliative care clinicians and hospice clinicians. Higher rated self-management activities to mitigate burnout include participating in interpersonal relationships and taking vacations. CONCLUSIONS: Burnout is a major issue facing the palliative care clinician workforce. Strategies at the discipline-wide and individual levels are needed to sustain the delivery of responsive, available, high-quality palliative care for all patients with serious illness. PMID- 26620236 TI - [(R)evolution in laboratory medicine]. PMID- 26620237 TI - [Euromedlab'15 (Paris): Conference notes]. PMID- 26620238 TI - [Circulating endothelial cells: new biomarker of the endothelial dysfunction in hematological malignancies]. PMID- 26620239 TI - [Monoclonal B-cell lymphocytosis: asymptomatic condition or pretumoral stage]. PMID- 26620240 TI - [Chronic lymphocytic leukemia: a paradigm shift What is the role of the biologist in this new world?]. PMID- 26620241 TI - [Interest of Droplet digital PCR in non-invasive prenatal testing]. PMID- 26620242 TI - [Hepcidin: a new biomarker of the iron deficiency anemia in elderly patients?]. PMID- 26620243 TI - [Direct oral anticoagulants: what is the exact assessment of coagulation tests and plasma levels by laboratory tests in clinical practice?]. PMID- 26620244 TI - [Early biological detection of prostate cancer: which test to use?]. PMID- 26620245 TI - [Urinary iodine: an update]. PMID- 26620246 TI - Psychometric Evaluation of the D-Catch, an Instrument to Measure the Accuracy of Nursing Documentation. AB - PURPOSE: To evaluate the psychometric properties of the D-Catch instrument. METHODS: A cross-sectional methodological study. Validity and reliability were estimated with confirmatory factor analysis (CFA) and internal consistency and inter-rater reliability, respectively. FINDINGS: A sample of 250 nursing documentations was selected. CFA showed the adequacy of a 1-factor model (chronologically descriptive accuracy) with an outlier item (nursing diagnosis accuracy). Internal consistency and inter-rater reliability were adequate. CONCLUSIONS: The D-Catch is a valid and reliable instrument for measuring the accuracy of nursing documentation. Caution is needed when measuring diagnostic accuracy since only one item measures this dimension. IMPLICATIONS FOR NURSING PRACTICE: The D-Catch can be used as an indicator of the accuracy of nursing documentation and the quality of nursing care. PMID- 26620247 TI - Robust and effective methodologies for cryopreservation and DNA extraction from anaerobic gut fungi. AB - Cell storage and DNA isolation are essential to developing an expanded suite of microorganisms for biotechnology. However, many features of non-model microbes, such as an anaerobic lifestyle and rigid cell wall, present formidable challenges to creating strain repositories and extracting high quality genomic DNA. Here, we establish accessible, high efficiency, and robust techniques to store lignocellulolytic anaerobic gut fungi long term without specialized equipment. Using glycerol as a cryoprotectant, gut fungal isolates were preserved for a minimum of 23 months at -80 degrees C. Unlike previously reported approaches, this improved protocol is non-toxic and rapid, with samples surviving twice as long with negligible growth impact. Genomic DNA extraction for these isolates was optimized to yield samples compatible with next generation sequencing platforms (e.g. Illumina, PacBio). Popular DNA isolation kits and precipitation protocols yielded preps that were unsuitable for sequencing due to carbohydrate contaminants from the chitin-rich cell wall and extensive energy reserves of gut fungi. To address this, we identified a proprietary method optimized for hardy plant samples that rapidly yielded DNA fragments in excess of 10 kb with minimal RNA, protein or carbohydrate contamination. Collectively, these techniques serve as fundamental tools to manipulate powerful biomass-degrading gut fungi and improve their accessibility among researchers. PMID- 26620248 TI - Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. AB - BACKGROUND: Hypertension is a common comorbidity in patients with type 2 diabetes mellitus and a major risk factor for microvascular and macrovascular disease. Although the blood pressure-lowering effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors are already established, guidance is needed on how to use these drugs in patients already receiving antihypertensive therapy. We aimed to compare blood pressure and glycaemic effects of the SGLT2 inhibitor dapagliflozin with placebo in patients with inadequately controlled type 2 diabetes mellitus and hypertension. METHODS: In this double-blind, placebo-controlled, phase 3 study we enrolled patients from 311 centres in 16 countries across five continents. Patients had uncontrolled type 2 diabetes (HbA1c 7.0%-10.5%; 53-91 mmol/mol) and hypertension (systolic 140-165 mm Hg and diastolic 85-105 mm Hg at both enrolment and randomisation, and a mean 24 h blood pressure of >=130/80 mm Hg by ambulatory monitoring within 1 week of randomisation) and were receiving oral antihyperglycaemic drugs, insulin, or both, plus a renin-angiotensin system blocker and an additional antihypertensive drug. Using an interactive voice response system, we randomly assigned (1:1) patients to dapagliflozin 10 mg once a day or to placebo, with randomisation stratified by additional antihypertensive drug use and insulin use at baseline, in a block size of two. The co-primary endpoints were changes in seated systolic blood pressure and HbA1c measured in the full analysis set, which included all patients who received at least one dose of study drug and had both a baseline and at least one post-baseline measurement of efficacy. This trial is registered with ClinicalTrials.gov, number NCT01195662. FINDINGS: Between Oct 29, 2010, and Oct 4, 2012, we randomly assigned 225 patients to dapagliflozin and 224 to placebo. Seated systolic blood pressure was significantly reduced in the group assigned to dapagliflozin (adjusted mean change from baseline -11.90 mm Hg [95% CI -13.97 to -9.82]) compared with those assigned to placebo (-7.62 mm Hg [-9.72 to -5.51]; placebo adjusted difference for dapagliflozin -4.28 mm Hg [-6.54 to -2.02]; p=0.0002). Reductions in HbA1c concentrations were also significantly greater in patients assigned to dapagliflozin (adjusted mean change from baseline -0.63% [95% CI 0.76 to -0.50]) than in those assigned to placebo (-0.02% [-0.15 to 0.12]; placebo-adjusted difference -0.61% [-0.76 to -0.46,]; p<0.0001). In a post-hoc analysis, we found difference in blood pressure versus placebo was greater in patients receiving a beta blocker (-5.76 mm Hg [95% CI -10.28 to -1.23]) or a calcium-channel blocker (-5.13 mm Hg, [-9.47 to -0.79]) as their additional antihypertensive drug than in those receiving a thiazide diuretic (-2.38 mm Hg [ 6.16 to 1.40]). Adverse events were similar in the dapagliflozin and placebo groups (98 [44%] patients vs 93 [42%], respectively, had at least one adverse event), with few adverse events related to renal function (1% vs <1%) or volume depletion (<1% vs 0%). INTERPRETATION: Dapagliflozin 10 mg significantly improved blood pressure and HbA1c and was tolerated similarly to placebo. Its blood pressure-lowering properties were particularly favourable in patients already receiving a beta blocker or calcium-channel blocker. Dapagliflozin could benefit patients with type 2 diabetes who need a diuretic-like effect to optimise control of blood pressure, adding meaningful efficacy to antihypertensive drug regimens. FUNDING: Bristol-Myers Squibb, AstraZeneca. PMID- 26620249 TI - Diabetes and tuberculosis co-epidemic: the Bali Declaration. PMID- 26620250 TI - Antihypertensive effects of SGLT2 inhibitors in type 2 diabetes. PMID- 26620252 TI - Autologous dermal fat graft modification for skate flap nipple reconstruction. PMID- 26620251 TI - Sex-Specific Effects of Stress on Oxytocin Neurons Correspond With Responses to Intranasal Oxytocin. AB - BACKGROUND: Oxytocin (OT) is considered to be a stress-buffering hormone, dampening the physiologic effects of stress. However, OT can also be anxiogenic. We examined acute and long-lasting effects of social defeat on OT neurons in male and female California mice. METHODS: We used immunohistochemistry for OT and c fos cells to examine OT neuron activity immediately after defeat (n = 6-9) and 2 weeks (n = 6-9) and 10 weeks (n = 4-5) later. We quantified Oxt messenger RNA with quantitative polymerase chain reaction (n = 5-9). Intranasal OT was administered to naive and stressed mice tested in social interaction and resident intruder tests (n = 8-14). RESULTS: Acute exposure to a third episode of defeat increased OT/c-fos colocalizations in the paraventricular nucleus of both sexes. In the medioventral bed nucleus of the stria terminalis, defeat increased Oxt messenger RNA, total OT neurons, and OT/c-fos colocalizations in female mice but not male mice. Intranasal OT failed to reverse stress-induced social withdrawal in female mice and reduced social interaction behavior in female mice naive to defeat. In contrast, intranasal OT increased social interaction in stressed male mice and reduced freezing in the resident-intruder test. CONCLUSIONS: Social defeat induces long-lasting increases in OT production and OT/c-fos cells in the medioventral bed nucleus of the stria terminalis of female mice but not male mice. Intranasal OT largely reversed the effects of stress on behavior in male mice, but effects were mixed in female mice. These results suggest that changes in OT-sensitive networks contribute to sex differences in behavioral responses to stress. PMID- 26620253 TI - Displaying inguinal lymph nodes before transplantation in a deep inferior epigastric perforator flap breast reconstruction using an innovative projection method. AB - INTRODUCTION: Lymphedema of the arm is a common postoperative complication as a result of breast cancer surgery. One of the surgical treatments comprises modification of a deep inferior epigastric perforator (DIEP) flap breast reconstruction to facilitate additional lymph node transplantation from the inguinal area. Using computed tomography angiography (CTA), the distribution of these lymph nodes can be assessed. A virtual planning based on this CTA created for the DIEP flap is presented, with the inguinal lymph nodes included, followed by preoperatively projecting this information on the patient's abdomen. METHODS: A total of 10 patients underwent the standard imaging protocol: A preoperative CTA to assess the vascular anatomy of the lower abdomen. A three-dimensional (3D) model of the blood vessels was produced, and the inguinal lymph nodes in this reconstruction were included. Preoperative projection of the 3D model onto the patients' abdomen and inguinal area was performed, followed by tracing of this image. Intraoperatively found lymph nodes were identified by touch and compared with the markings on the skin. RESULTS: In all 10 patients, all lymph nodes located preoperatively were found intraoperatively within a 1-cm radius of the marking on the skin; and these were more easily located by two operating surgeons. CONCLUSION: Virtual planning of lymph node transplantations in a deep inferior epigastric artery perforator flap breast reconstruction seems feasible and can be performed quickly. This additional visual support aids the surgeon in locating the lymph nodes in the inguinal area. PMID- 26620254 TI - Calycosin inhibits oxidative stress-induced cardiomyocyte apoptosis via activating estrogen receptor-alpha/beta. AB - Oxidative stress-induced myocardial apoptosis is a key step in the pathogenesis of ischemic heart disease. Calycosin is a phytoestrogen extracted from Radix astragali. In this study, we examined the effects and mechanisms of calycosin on oxidative stress-induced myocardial apoptosis. Molecular docking showed that calycosin can couple into binding site of ERalpha and beta. Pretreatment with calycosin increased the expression levels of ERalpha and beta. In H9C2 cells, H2O2 reduced cell viability and induced apoptosis, however, calycosin diminished the effects of H2O2 in a dose-dependent manner. Pretreatment with ICI 182,780, an estrogen receptor inhibitor, negated the protective effect of calycosin against H2O2-induced apoptosis. In addition, Akt phosphorylation was upregulated by calycosin mono treatment and downregulated by co-treatment with calycosin and ICI 182,780. These data demonstrated that calycosin exhibits anti-apoptotic effects by activating ERalpha/beta and enhancing Akt phosphorylation in cardiomyocytes. PMID- 26620255 TI - Discovery of the imidazole-derived GPR40 agonist AM-3189. AB - As a follow-up to the GPR40 agonist AMG 837, which was evaluated in clinical trials for the treatment of type II diabetes, further optimization led to the discovery of AM-3189 (13k). AM-3189 is representative of a new class of compounds with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837. PMID- 26620256 TI - Vasopressin regulates renal calcium excretion in humans. AB - Antidiuretic hormone or arginine vasopressin (AVP) increases water reabsorption in the collecting ducts of the kidney. Three decades ago, experimental models have shown that AVP may increase calcium reabsorption in rat kidney. The objective of this study was to assess whether AVP modulates renal calcium excretion in humans. We analyzed calcium, potassium, and sodium fractional excretion in eight patients affected by insipidus diabetes (nephrogenic or central) under acute vasopressin receptor agonist action and in 10 patients undergoing oral water load test affected or not by inappropriate antidiuretic hormone secretion (SIADH). Synthetic V2 receptor agonist (dDAVP) reduced significantly calcium fractional excretion from 1.71% to 0.58% (P < 0.05) in patients with central diabetes insipidus. In patients with nephrogenic diabetes insipidus (resistant to AVP), calcium fractional excretion did not change significantly after injection (0.48-0.68%, P = NS). In normal subjects undergoing oral water load test, calcium fractional excretion increased significantly from 1.02% to 2.54% (P < 0.05). Patients affected by SIADH had a high calcium fractional excretion at baseline that remained stable during test from 3.30% to 3.33% (P = NS), possibly resulting from a reduced calcium absorption in renal proximal tubule. In both groups, there was a significant correlation between urine output and calcium renal excretion. In humans, dDAVP decreases calcium fractional excretion in the short term. Conversely, water intake, which lowers AVP concentration, increases calcium fractional excretion. The correlation between urine output and calcium excretion suggests that AVP-related antidiuresis increases calcium reabsorption in collecting ducts. PMID- 26620257 TI - The tyrosine kinase inhibitor imatinib prevents lung injury and death after intravenous LPS in mice. AB - Severe sepsis and septic shock are frequent causes of the acute respiratory distress syndrome, and important sources of human mortality. Lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls, plays a major role in the pathogenesis of severe sepsis and septic shock. LPS exposure induces the production of harmful reactive oxygen species, and the resultant oxidant injury has been implicated in the pathogenesis of both severe sepsis and ARDS. We previously showed that the tyrosine kinase inhibitor imatinib increases lung endothelial antioxidant enzymes and protects against pulmonary endothelial antioxidant injury. In the present study, we tested the hypothesis that imatinib would protect against lung injury and systemic inflammation caused by intravenous LPS in an intact mouse model of endotoxemia mimicking early sepsis. We found that intravenous LPS induced a significant increase in the activity of lung xanthine oxidoreductase (XOR), an enzyme which is a major source of reactive oxygen species and implicated in the pathogenesis of acute lung injury. Imatinib had no effect of LPS-induced XOR activity. However, pretreatment of mice with imatinib increased lung catalase activity and decreased intravenous LPS-induced lung oxidant injury as measured by gamma-H2AX, a marker of oxidant-induced DNA damage, lung apoptosis, and pulmonary edema. Imatinib also attenuated systemic cytokine expression after intravenous LPS exposure. Finally, imatinib completely prevented mortality in an in vivo, intravenous LPS mouse model of endotoxemia and lung injury. These results support the testing of imatinib as a novel pharmacologic agent in the treatment of Gram-negative sepsis and sepsis-induced ARDS. PMID- 26620258 TI - Involvement of acetylcholinesterase and protein kinase C in the protective effect of caffeine against beta-amyloid-induced alterations in red blood cells. AB - It is well known the role of oxidative stress in the pathophysiology of Alzheimer's disease (AD) and of other neurodegenerative pathologies. We have previously documented that Amyloid beta peptide (1-42) (Abeta) dependent oxidative modifications affect red blood cell (RBC) morphology and function. Experimental studies show that caffeine (CF) consumption is inversely correlated with AD. In this study, we investigated the role played by RBC in the protective mechanism elicited by CF against Abeta mediated toxicity. PS exposure levels by FACS analysis, as well as protein band 3 functionality analysis, indicated that CF at 100 MUM protected against Abeta-mediated membrane alterations, which are known to occur in AD. Moreover, CF counteracts inhibition of ATP release from RBC by Abeta, restoring its ability to modulate vasodilation. Concurrently, analysis of protein kinase C (PKC) and caspase 3 activities, responsible for cytoskeleton alterations, revealed that unlike to caspase 3, PKCalpha activation induced by Abeta was fully abolished by CF through a mechanism involving Acetylcholinesterase (AChE), located on external face of RBC plasma membrane. These results provide support for the hypothesis concerning the protective role of CF in AD patients could include also a peripheral mechanism involving RBC. PMID- 26620260 TI - The Risk of Vocal Fold Atrophy after Serial Corticosteroid Injections of the Vocal Fold. AB - OBJECTIVE: The aim of this study was to illustrate the risk of vocal fold atrophy in patients who receive serial subepithelial steroid injections for vocal fold scar. METHODS: This study is a retrospective case report of two patients who underwent a series of weekly subepithelial infusions of 10 mg/mL dexamethasone for benign vocal fold lesion. Shortly after the procedures, both patients developed a weak and breathy voice. The first patient was a 53-year-old man with radiation-induced vocal fold stiffness. Six injections were performed unilaterally, and 1 week later, he developed unilateral vocal fold atrophy with new glottal insufficiency. The second patient was a 67-year-old woman with severe vocal fold inflammation related to laryngitis and calcinosis, Raynaud's phenomenon, esophagean dysmotility, sclerodactyly, and telangiectasia (CREST) syndrome. Five injections were performed bilaterally, and 1 week later, she developed bilateral vocal fold atrophy with a large midline glottal gap during phonation. In both cases, the steroid-induced vocal atrophy resolved spontaneously after 4 months. OUTCOMES & IMPORTANCE: Serial subepithelial steroid infusions of the vocal folds, although safe in the majority of patients, carry the risk of causing temporary vocal fold atrophy when given at short intervals. PMID- 26620259 TI - Markerless Analysis of Articulatory Movements in Patients With Parkinson's Disease. AB - OBJECTIVES: A large percentage of patients with Parkinson's disease have hypokinetic dysarthria, exhibiting reduced peak velocities of jaw and lips during speech. This limitation implies a reduction of speech intelligibility for such patients. This work aims at testing a cost-effective markerless approach for assessing kinematic parameters of hypokinetic dysarthria. STUDY DESIGN: Kinematic parameters of the lips are calculated during a syllable repetition task from 14 Parkinsonian patients and 14 age-matched control subjects. METHODS: Combining color and depth frames provided by a depth sensor (Microsoft Kinect), we computed the three-dimensional coordinates of main facial points. The peak velocities and accelerations of the lower lip during a syllable repetition task are considered to compare the two groups. RESULTS: Results show that Parkinsonian patients exhibit reduced peak velocities of the lower lip, both during the opening and the closing phase of the mouth. In addition, peak values of acceleration are reduced in Parkinsonian patients, although with significant differences only in the opening phase with respect to healthy control subjects. CONCLUSIONS: The novel contribution of this work is the implementation of an entirely markerless technique capable to detect signs of hypokinetic dysarthria for the analysis of articulatory movements during speech. Although a large number of Parkinsonian patients have hypokinetic dysarthria, only a small percentage of them undergoes speech therapy to increase their articulatory movements. The system proposed here could be easily implemented in a home environment, thus, increasing the percentage of patients who can perform speech rehabilitation at home. PMID- 26620261 TI - Heterogeneity in Smokers' Responses to Tobacco Control Policies. AB - This paper uses unconditional quantile regression to estimate whether smokers' responses to tobacco control policies change across the distribution of smoking levels. I measure smoking behavior with the number of cigarettes smoked per day and also with serum cotinine levels, a continuous biomarker of nicotine exposure, using individual-level repeated cross-section data from the National Health and Nutrition Examination Surveys. I find that the cigarette taxes lead to reductions in both the number of cigarettes smoked per day and in smokers' cotinine levels. These reductions are most pronounced in the middle quantiles of both distributions in terms of marginal effects, but most pronounced in the lower quantiles in terms of tax elasticities. I do not find that higher cigarette taxes lead to statistically significant changes in the amount of nicotine smokers ingest from each cigarette. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26620263 TI - Direct synthesis of large-scale hierarchical MoS2 films nanostructured with orthogonally oriented vertically and horizontally aligned layers. AB - Hierarchical MoS2 thin films nanostructured with orthogonally oriented vertically and horizontally aligned layers were designed and excellent passive Q-switching behavior in a fiber laser was demonstrated. A special solvothermal system containing a small amount of water was applied to synthesize such hierarchical MoS2 nanofilms, in which the reaction rate is carefully controlled by the diffusion rate of the sulfur precursor. Wafer-scale MoS2 thin films with hierarchical structures are formed on various substrates. Moreover, the hierarchical MoS2 thin films consisting of both vertical and horizontal layers can be tuned to possess only horizontally aligned layers by controlling the solvothermal time. To show the potential application proof-of-concept, the nonlinear optical performance of the hierarchical MoS2 was investigated. Superior passive Q-switching behavior in a fiber laser with a minimum pulse width of 2.2 MUs was observed. PMID- 26620262 TI - sigma Factor and Anti-sigma Factor That Control Swarming Motility and Biofilm Formation in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is capable of causing a variety of acute and chronic infections. Here, we provide evidence that sbrR (PA2895), a gene previously identified as required during chronic P. aeruginosa respiratory infection, encodes an anti-sigma factor that inhibits the activity of its cognate extracytoplasmic-function sigma factor, SbrI (PA2896). Bacterial two-hybrid analysis identified an N-terminal region of SbrR that interacts directly with SbrI and that was sufficient for inhibition of SbrI-dependent gene expression. We show that SbrI associates with RNA polymerase in vivo and identify the SbrIR regulon. In cells lacking SbrR, the SbrI-dependent expression of muiA was found to inhibit swarming motility and promote biofilm formation. Our findings reveal SbrR and SbrI as a novel set of regulators of swarming motility and biofilm formation in P. aeruginosa that mediate their effects through muiA, a gene not previously known to influence surface-associated behaviors in this organism. IMPORTANCE: This study characterizes a sigma factor/anti-sigma factor system that reciprocally regulates the surface-associated behaviors of swarming motility and biofilm formation in the opportunistic pathogen Pseudomonas aeruginosa. We present evidence that SbrR is an anti-sigma factor specific for its cognate sigma factor, SbrI, and identify the SbrIR regulon in P. aeruginosa. We find that cells lacking SbrR are severely defective in swarming motility and exhibit enhanced biofilm formation. Moreover, we identify muiA (PA1494) as the SbrI-dependent gene responsible for mediating these effects. SbrIR have been implicated in virulence and in responding to antimicrobial and cell envelope stress. SbrIR may therefore represent a stress response system that influences the surface behaviors of P. aeruginosa during infection. PMID- 26620264 TI - Harmonisation of D-dimer - A call for action. PMID- 26620265 TI - Optogenetic Destabilization of the Memory Trace in CA1: Insights into Reconsolidation and Retrieval Processes. AB - Reactivation of memory can cause instability necessitating the reconsolidation of the trace. This process can be blocked by amnestic treatments administered after memory reactivation resulting in subsequent memory deficits. While the basolateral amygdala (BLA) is known to be crucial for reconsolidation, evidence for a contribution of the hippocampal CA1 region has only started to accumulate. Moreover, the effect of a reconsolidation blockade in CA1 has only been evaluated behaviorally, and it is unknown whether this manipulation has a long-term effect on neuronal activity. We combined optogenetic and high-resolution molecular imaging techniques to inhibit cell firing in CA1 following the reactivation of a fear memory in mice, evaluated memory performance and imaged neuronal activity the next day upon reexposure to the conditioning context. Blocking memory reconsolidation led to severe memory impairments that were associated with reduced neuronal activity not only in CA1 but also in CA3 and the BLA. Thus, our results indicate that CA1 is necessary for reconsolidation and suggest the involvement of a CA3-CA1-BLA network in the retrieval of contextual fear memory. Further investigations of this network might contribute to the validation of new brain targets for the treatment of pathologies such as posttraumatic stress disorders. PMID- 26620266 TI - Intrinsic Connections of the Core Auditory Cortical Regions and Rostral Supratemporal Plane in the Macaque Monkey. AB - In the ventral stream of the primate auditory cortex, cortico-cortical projections emanate from the primary auditory cortex (AI) along 2 principal axes: one mediolateral, the other caudorostral. Connections in the mediolateral direction from core, to belt, to parabelt, have been well described, but less is known about the flow of information along the supratemporal plane (STP) in the caudorostral dimension. Neuroanatomical tracers were injected throughout the caudorostral extent of the auditory core and rostral STP by direct visualization of the cortical surface. Auditory cortical areas were distinguished by SMI-32 immunostaining for neurofilament, in addition to established cytoarchitectonic criteria. The results describe a pathway comprising step-wise projections from AI through the rostral and rostrotemporal fields of the core (R and RT), continuing to the recently identified rostrotemporal polar field (RTp) and the dorsal temporal pole. Each area was strongly and reciprocally connected with the areas immediately caudal and rostral to it, though deviations from strictly serial connectivity were observed. In RTp, inputs converged from core, belt, parabelt, and the auditory thalamus, as well as higher order cortical regions. The results support a rostrally directed flow of auditory information with complex and recurrent connections, similar to the ventral stream of macaque visual cortex. PMID- 26620267 TI - Impaired Interneuron Development after Foxg1 Disruption. AB - Interneurons play pivotal roles in the modulation of cortical function; however, the mechanisms that control interneuron development remain unclear. This study aimed to explore a new role for Foxg1 in interneuron development. By crossing Foxg1fl/fl mice with a Dlx5/6-Cre line, we determined that conditional disruption of Foxg1 in the subpallium results in defects in interneuron development. In developing interneurons, the expression levels of several receptors, including roundabout-1, Eph receptor A4, and C-X-C motif receptor 4/7, were strongly downregulated, which led to migration defects after Foxg1 ablation. The transcription factors Dlx1/2 and Mash1, which have been reported to be involved in interneuron development, were significantly upregulated at the mRNA levels. Foxg1 mutant cells developed shorter neurites and fewer branches and displayed severe migration defects in vitro. Notably, Prox1, which is a transcription factor that functions as a key regulator in the development of excitatory neurons, was also dramatically upregulated at both the mRNA and protein levels, suggesting that Prox1 is also important for interneuron development. Our work demonstrates that Foxg1 may act as a critical upstream regulator of Dlx1/2, Mash1, and Prox1 to control interneuron development. These findings will further our understanding of the molecular mechanisms of interneuron development. PMID- 26620268 TI - Acetylcholine Facilitates a Depolarization-Induced Enhancement of Inhibition in Rat CA1 Pyramidal Neurons. AB - Cholinergic mechanisms in the hippocampus regulate forms of synaptic plasticity linked with cognition and spatial navigation, but the underlying mechanisms remain largely unknown. Here, in rat hippocampal CA1 pyramidal cells under blockade of ionotropic glutamate receptors, we report that a single acetylcholine pulse and repeated depolarization activated a robust and enduring postsynaptic depolarization-induced enhancement of inhibition (DEI) that masked a presynaptic depolarization-induced suppression of inhibition (DSI). Increased cytosolic Ca2+ and M1-muscarinic receptor activation caused the rise in voltage-sensitive alpha5betagamma2-containing gamma-aminobutyric acid type-A receptors that generated DEI. In summary, this muscarinic-mediated activity-dependent plasticity rapidly transfers depolarization effects on inhibition from presynaptic suppression or DSI to postsynaptic enhancement or DEI, a change potentially relevant in behavior. PMID- 26620270 TI - Enabling High Efficiency Nanoplasmonics with Novel Nanoantenna Architectures. AB - Surface plasmon polaritons (SPPs) are propagating excitations that arise from coupling of light with collective electron oscillations. Characterized by high field intensity and nanometric dimensions, SPPs fashion rapid expansion of interest from fundamental and applicative perspectives. However, high metallic losses at optical frequencies still make nanoplasmonics impractical when high absolute efficiency is paramount, with major challenge is efficient plasmon generation in deep nanoscale. Here we introduce the Plantenna, the first reported nanodevice with the potential of addressing these limitations utilizing novel plasmonic architecture. The Plantenna has simple 2D structure, ultracompact dimensions and is fabricated on Silicon chip for future CMOS integration. We design the Plantenna to feed channel (20 nm * 20 nm) nanoplasmonic waveguides, achieving 52% coupling efficiency with Plantenna dimensions of lambda(3)/17,000. We theoretically and experimentally show that the Plantenna enormously outperforms dipole couplers, achieving 28 dB higher efficiency with broad polarization diversity and huge local field enhancement. Our findings confirm the Plantenna as enabling device for high efficiency plasmonic technologies such as quantum nanoplasmonics, molecular strong coupling and plasmon nanolasers. PMID- 26620269 TI - Detection of G119S ace-1 (R) mutation in field-collected Anopheles gambiae mosquitoes using allele-specific loop-mediated isothermal amplification (AS-LAMP) method. AB - BACKGROUND: Malaria vectors have developed resistance to the four families of insecticides available for public health purposes. For example, the kdr mutation is associated with organochlorines and pyrethroids resistance. It is of particular concern that organophosphate and carbamate resistance associated with the G119S ace-1 (R) mutation has recently increased in West Africa in extent and frequency, and is now spreading through the Anopheles gambiae malaria vector population. There is an urgent need to improve resistance management using existing insecticides and new tools to quickly assess resistance level for rapid decision-making. METHODS: DNA extracted from field-collected mosquitoes was used to develop the method. Specific primers were designed manually to match the mutation region and an additional mismatched nucleotide in the penultimate position to increase specificity. Other primers used are common to both wild and mutant types. The allele specific (AS)-LAMP method was compared to the PCR restriction fragment length polymorphism (PCR-RFLP) and real-time PCR (RT-PCR) methods using the genomic DNA of 104 field-collected mosquitoes. RESULTS: The primers designed for LAMP were able to distinguish between the wild type (ace-1 (S) ) and mutated type allele (ace-1 (R) ). Detection time was 50 min for the wild type homozygous and 64 min for the heterozygous. No amplification of the resistant allele took place within the 75-min test period when using the wild type primers. For the ace-1 (R) resistant type, detection time was 51 min for the resistant homozygous and 55 min for the heterozygous. No amplification of the wild type allele took place within the 75-min test period when using the resistant type primers. Gel electrophoresis of LAMP products confirmed that amplification was primer-DNA specific, i.e., primers could only amplify their target specific DNA. AS-LAMP, PCR-RFLP, and RT-PCR showed no significant difference in the sensitivity and specificity of their ace-1 (R) detection ability. CONCLUSIONS: The AS-LAMP method could detect the ace-1 (R) mutation within 60 min, which is faster than conventional PCR-RFLP. This method may be used to quickly detect the ace-1 (R) mutation for rapid decision-making, even in less well-equipped laboratories. PMID- 26620271 TI - Pulmonary wedge resection plus parietal pleurectomy (WRPP) versus parietal pleurectomy (PP) for the treatment of recurrent primary pneumothorax (WOPP trial): study protocol for a randomized controlled trial. AB - BACKGROUND: For the surgical treatment of recurrent primary spontaneous pneumothoraces (rPSP) different operative therapies are applied to achieve permanent freedom from recurrence. METHODS/DESIGN: This multicenter clinical trial evaluates the long-term results of two commonly applied surgical techniques for the treatment of rPSP. Based on the inclusion and exclusion criteria, and after obtaining the patients' informed consent, participants are randomized into the two surgical treatment arms: pulmonary wedge resection plus parietal pleurectomy (WRPP) or parietal pleurectomy alone (PP). Consecutively, all study participants will be followed up for two years to evaluate the surgical long-term effect. The primary efficacy endpoint is the recurrence rate of pneumothorax within 24 months after surgery. The calculated sample size is 360 patients (n = 180 per treatment arm) to prove superiority of one of the two treatments. So far, 22 surgical sites have submitted their declaration of commitment, giving the estimated number of participating patients. DISCUSSION: A prospective randomized clinical trial has been started to compare two established surgical therapies to evaluate the long-term results regarding recurrence rates. Furthermore, cost of treatment, and influence on the perioperative morbidity and mortality as well as on quality of life are analyzed. If the study reveals equivalence for both surgical techniques, unnecessary pulmonary resections could be avoided. TRIAL REGISTRATION: ClinicalTrials gov: NCT01855464 , 06.05 2013. PMID- 26620273 TI - An amphoteric reactivity of a mixed-valent bis(MU-oxo)dimanganese(III,IV) complex acting as an electrophile and a nucleophile. AB - A mixed-valent bis(MU-oxo)dimanganese(III,IV) complex, [(dpaq)Mn(III)(O)2Mn(IV)(dpaq)](+) (1), was prepared by reacting a hydroxomanganese(III) complex, [(dpaq)Mn(III)(OH)](+), with hydrogen peroxide in the presence of triethylamine. The mixed-valent bis(MU-oxo)dimanganese(III,IV) complex (1) was well characterised by UV-vis, EPR and CSI-MS techniques. The electrophilic reactivity of 1 was investigated in the oxidation of 2,6-di-tert butylphenol derivatives by 1, in which the relative rate afforded a good Hammett correlation with a rho value of -1.0. The nucleophilic character of 1 was then investigated in aldehyde deformylation reactions, using 2-phenylpropionaldehyde (2-PPA) and benzaldehyde derivatives as substrates. In contrast to the case of the reaction of 1 with 2,6-di-tert-butylphenol derivatives, a positive rho value of 0.89 was obtained in the Hammett plot, demonstrating that the bis(MU-oxo) dimanganese(III,IV) complex is an active nucleophilic oxidant. Thus, 1 exhibited an amphoteric reactivity in both electrophilic and nucleophilic oxidative reactions. PMID- 26620274 TI - A new ultrasound-guided pubic approach for proximal obturator nerve block: clinical study and cadaver evaluation. AB - We evaluated an alternative technique for ultrasound-guided proximal level obturator nerve block that might facilitate needle visualisation using in-plane ultrasound guidance. Twenty patients undergoing transurethral bladder tumour resection requiring an obturator nerve block were enrolled into a prospective observational study. With the patient in the lithotomy position, the transducer was placed on the medial thigh along the extended line of the inguinal crease, and aimed cephalad to view a thick fascia between the pectineus and obturator externus muscles that contains the obturator nerve. A stimulating nerve block needle was inserted at the pubic region and advanced in-plane with the transducer in an anterior-to-posterior direction. Eight ml levobupivacaine 0.75% was injected within the fascia. The median (IQR [range]) duration for ultrasound identification of the target and injection were 8.5 (7-12 [5-24]) s and 62 (44.5 78.25 [39-383]) s, respectively. All blocks were successful. A cadaver evaluation demonstrated that the dye injected into the target fascia using our technique travelled retrogradely through the obturator canal, and surrounded the anterior and posterior branches of the obturator nerve both proximally and distally to the obturator canal. We believe that this is a promising new technique for ultrasound guided proximal level obturator nerve block. PMID- 26620272 TI - Molecular therapy for acute myeloid leukaemia. AB - Acute myeloid leukaemia (AML) is a heterogeneous disease that is, in general, associated with a very poor prognosis. Multiple cytogenetic and molecular abnormalities that characterize different forms of AML have been used to better prognosticate patients and inform treatment decisions. Indeed, risk status in patients with this disease has classically been based on cytogenetic findings; however, additional molecular characteristics have been shown to inform risk assessment, including FLT3, NPM1, KIT, and CEBPA mutation status. Advances in sequencing technology have led to the discovery of novel somatic mutations in tissue samples from patients with AML, providing deeper insight into the mutational landscape of the disease. The majority of patients with AML (>97%) are found to have a clonal somatic abnormality on mutational profiling. Nevertheless, our understanding of the utility of mutation profiling in clinical practice remains incomplete and is continually evolving, and evidence-based approaches to application of these data are needed. In this Review, we discuss the evidence base for integrating mutational data into treatment decisions for patients with AML, and propose novel therapeutic algorithms in the era of molecular medicine. PMID- 26620275 TI - Exploring factors related to physical activity in cervical dystonia. AB - BACKGROUND: People with disabilities have reported worse health status than people without disabilities and receiving fewer preventive health services such as counseling around exercise habits. This is noteworthy considering the negative consequences associated with physical inactivity. No research has been conducted on physical activity in cervical dystonia (CD), despite its possible major impact on self-perceived health and disability. Considering the favorable consequences associated with physical activity it is important to know how to promote physical activity behavior in CD. Knowledge of variables important for such behavior in CD is therefore crucial. The aim of this study was to explore factors related to physical activity in individuals with cervical dystonia. METHODS: Subjects included in this cross-sectional study were individuals diagnosed with CD and enrolled at neurology clinics (n = 369). Data was collected using one surface mailed self-reported questionnaire. Physical activity was the primary outcome variable, measured with the Physical Activity Disability Survey. Secondary outcome variables were: impact of dystonia measured with the Cervical Dystonia Impact Scale; fatigue measured with the Fatigue Severity Scale; confidence when carrying out physical activity measured with the Exercise Self-Efficacy Scale; confidence in performing daily activities without falling measured with the Falls Efficacy Scale; enjoyment of activity measured with Enjoyment of Physical Activity Scale, and social influences on physical activity measured with Social Influences on Physical Activity in addition to demographic characteristics such as age, education level and employment status. RESULTS: The questionnaire was completed by 173 individuals (47% response rate). The multivariate association between related variables and physical activity showed that employment, self efficacy for physical activity, education level and consequences for daily activities explained 51% of the variance in physical activity (Adj R 0.51, F (5, 162) = 35.611, p = 0.000). Employment and self-efficacy for physical activity contributed most strongly to the association with physical activity. CONCLUSIONS: Considering the favorable consequences associated with physical activity it could be important to support the individuals with CD to remain in work and self efficacy to physical activity as employment and self-efficacy had significant influence on physical activity level. Future research is needed to evaluate causal effects of physical activity on consequences related to CD. PMID- 26620276 TI - Ahrensia marina sp. nov., a dimethylsulfoniopropionate-cleaving bacterium isolated from seawater, and emended descriptions of the genus Ahrensia and Ahrensia kielensis. AB - A Gram-stain-negative, strictly aerobic, light-beige, rod-shaped, motile bacterium with peritrichous flagella that cleaves dimethylsulfoniopropionate (DMSP), designated strain LZD062T, was isolated from bottom seawater of the East China Sea. The isolate required sea salts for growth and grew optimally at pH 8.0 and 28 degrees C and in the presence of 2 % (w/v) NaCl. The major fatty acid (>10 %) was summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) and the major polar lipids were phosphatidylglycerol, diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylmonomethylethanolamine, one unidentified aminolipid and one unidentified glycolipid. Ubiquinone Q-10 was the only quinone detected. Phylogenetic analyses based on 16S rRNA and atpD gene sequences placed LZD062T within the genus Ahrensia of the family Phyllobacteriaceae in the class Alphaproteobacteria. The most closely related type strain was, in both cases, Ahrensia kielensis JCM 20689T ( = IAM 12618T = DSM 5890T), which gave sequence similarities of 97.7 % in the 16S rRNA gene and 90.4 % in the atpD gene. Genome relatedness between strain LZD062T and A. kielensis JCM 20689T was computed using both genome-to-genome distance analysis and average nucleotide identity, giving values of 22.10 +/- 2.35 and 79.55 %, respectively. The genomic DNA G+C content calculated from the genome sequence was 50.1 mol%. On the basis of our polyphasic analyses, strain LZD062T is considered to represent a novel species of the genus Ahrensia, for which the name Ahrensia marina sp. nov. is proposed. The type strain is LZD062T ( = MCCC 1K00254T = JCM 30117T = DSM 28886T). Emended descriptions of the genus Ahrensia and Ahrensia kielensis are also proposed. PMID- 26620278 TI - Outcome after a dose "de-intensification" strategy with anti-TNF drugs in patients with Crohn's disease. AB - BACKGROUND: Dose "intensification" is a recommended strategy to recover therapeutic benefit in Crohn's disease (CD) patients who have lost initial response to anti-TNF therapy. Once patients have achieved remission, dose "de intensification" can be used for cost and safety reasons. OBJECTIVES: The primary aim of this study was to evaluate the long-term durability of remission after stepping down anti-TNF therapy. The secondary aim was to identify predictive factors associated with loss of response after "de-intensification" and to evaluate the effectiveness of a second "re-intensification" in patients who lost response after the treatment was stepped down. METHODS: We evaluated CD patients who received at least one standard anti-TNF dosage after achieving remission with "intensified" anti-TNF therapy. RESULTS: Twenty-four patients were included. The treatment was "intensified" because of partial response in 11 patients, loss of response in 10, and primary lack of response in 3. Eight of the 24 patients had lost response after a median follow-up of only 7 months after "de intensification" of the anti-TNF therapy. The anti-TNF drug was "intensified" again in all 8 patients. Three patients did not respond to the new "intensification", two had partial response and three achieved remission. On univariate analysis, no predictive factors were identified for loss of response after treatment "de-intensification". CONCLUSIONS: After only 7 months of follow up, one-third of the CD patients who received "de-intensification" therapy lost response; of these, two-thirds did not achieve response after subsequent "re intensification". PMID- 26620277 TI - Distal coronary embolization following acute myocardial infarction increases early infarct size and late left ventricular wall thinning in a porcine model. AB - BACKGROUND: Distal coronary embolization (DCE) of thrombotic material occurs frequently during percutaneous interventions for acute myocardial infarction and can alter coronary flow grades. The significance of DCE on infarct size and myocardial function remains unsettled. The aims of this study were to evaluate the effects of DCE sufficient to cause no-reflow on infarct size, cardiac function and ventricular remodeling in a porcine acute myocardial infarction model. METHODS AND RESULTS: Female Yorkshire pigs underwent 60 min balloon occlusion of the left anterior descending coronary artery followed by reperfusion and injection of either microthrombi (prepared from autologous porcine blood) sufficient to cause no-reflow (DCE), or saline (control). Animals were sacrificed at 3 h (n = 5), 3 days (n = 20) or 6 weeks (n = 20) post-AMI. Cardiovascular magnetic resonance (CMR), serum troponin-I, and cardiac gelatinase (MMP) and survival kinase (Akt) activities were assessed. At 3d, DCE increased infarct size (CMR: 18.8% vs. 14.5%, p = 0.04; serum troponin-I: 13.3 vs. 6.9 ng/uL, p < 0.05) and MMP-2 activity levels (0.81 vs. 0.49, p = 0.002), with reduced activation of Akt (0.06 versus 0.26, p = 0.02). At 6 weeks, there were no differences in infarct size, ventricular volume or ejection fraction between the two groups, although infarct transmurality (70% vs. 57%, p< 0.04) and ventricular thinning (percent change in mid anteroseptal wall thickness:-25.6% vs. 0.7%, p = 0.03) were significantly increased in the DCE group. CONCLUSIONS: DCE increased early infarct size, but without affecting later infarct size, cardiac function or ventricular volumes. The significance of the later remodelling changes (ventricular thinning and transmurality) following DCE, possibly due to changes in MMP-2 activity and Akt activation, merits further study. PMID- 26620279 TI - Vascular anatomy relevant to distal biceps tendon repair. AB - BACKGROUND: Avoiding bleeding and vascular complications in open repair of distal biceps tendon rupture requires knowledge of the local vascular anatomy. This study examined the vascular anatomy relevant to distal biceps tendon repair. METHODS: The antecubital regions of 17 cadaveric upper extremities were dissected using *2.5 loupe magnification to identify the brachial artery, the radial artery and its recurrent branches, and venous branches crossing the distal biceps tendon. With the elbow in full extension and supination, the position of each vascular structure was measured relative to the most proximal aspect of the bicipital tuberosity. RESULTS: The most common pattern (13 of 17 specimens) was a single radial recurrent artery (RRA) crossing volar to the tendon at a mean of 4 mm proximal to the tuberosity and positioned 15.4 mm volar to the tuberosity. The RRA bifurcated 2 to 9 mm from its origin in 6 arms and demonstrated a single bifurcation. In 8 of 17 specimens, an additional recurrent branch off the brachial artery traveled dorsal to the intact biceps tendon 16 mm proximal to the RRA. Two arms demonstrated a high brachial artery bifurcation. The crossing veins were venae comitantes of the RRAs and radial and ulnar arteries. They connected to the superficial veins by way of a perforating branch. Most often, 3 transverse veins positioned on average 0.2 mm proximal and 16 mm volar to the tuberosity were seen. CONCLUSIONS: The vascular anatomy encountered during distal biceps repair is variable, and RRAs occasionally travel dorsal to the biceps tendon. Most often, a single RRA on average 4 mm proximal to the tuberosity will branch once. PMID- 26620280 TI - Effects of exercise therapy for the treatment of symptomatic full-thickness supraspinatus tears on in vivo glenohumeral kinematics. AB - BACKGROUND: The high incidence of rotator cuff disease combined with high failure rates for nonoperative treatment of full-thickness rotator cuff tears underlines the importance of improving nonoperative management of rotator cuff tears. The study objective was to assess changes in in vivo glenohumeral kinematics of patients with a symptomatic full-thickness supraspinatus tear before and after a 12-week exercise therapy program. It was hypothesized that successful exercise therapy would result in improved kinematics (smaller translations and increased subacromial space). MATERIALS AND METHODS: Five patients were recruited for the study and underwent dynamic stereoradiography analysis before and after a 12-week exercise therapy protocol to measure changes in glenohumeral joint translations and subacromial space during coronal plane abduction. Strength and patient reported outcomes (American Shoulder and Elbow Surgeons; Disabilities of the Arm, Shoulder and Hand; Western Ontario Rotator Cuff Index) were also evaluated. RESULTS: After therapy, no subject went on to receive surgery. It was found that the contact path length of the humerus translating on the surface of the glenoid was reduced by 29% from 67.2% +/- 36.9% glenoid height to 43.1% +/- 26.9% glenoid height (P = .036) after therapy. Minimum acromiohumeral distance showed a small increase from 0.9 +/- 0.6 mm to 1.3 +/- 0.8 mm (P = .079). Significant improvements in strength and patient-reported outcomes were also observed (P < .05). CONCLUSIONS: Successful exercise therapy for treatment of small full thickness supraspinatus tears results in improvements in glenohumeral joint kinematics and patient-reported outcomes through increases in rotator cuff muscle strength and joint stability. This study may enable identification of prognostic factors that predict the response of a patient with a rotator cuff tear to exercise therapy. PMID- 26620282 TI - Tetra-cationic imidazoliumyl-substituted phosphorus-sulfur heterocycles from a cationic organophosphorus sulfide. AB - The reaction of imidazoliumyl-substituted P((III)) cations of type [L((R,Me))PCl2](+) (3a,b(+); L(R,Me) = imidazolium-2-yl a: R = Me; b: R = iPr) with (Me3Si)2S leads to the formation of tetra-cationic, eight-membered phosphorus sulfur heterocycles [L((R,Me))PS]4(4+) (9a,b(4+)), which can be explained by the tetramerization of the intermediately formed cationic phosphorus monosulfide [L((R,Me))PS](+) (8a,b(+)). The P4S4 ring adopts a crown conformation as observed for cyclo-S8. The Lewis base DMAP (4-dimethylaminopyridine) initiates a deoligomerization- and dismutation reaction of 9a,b(4+) to give P((I)) centered cation [L((R,Me))2P](+) (12a,b(+)) and phosphorus disulfide [(DMAP)2PS2](+) (14(+)). PMID- 26620281 TI - Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity. AB - Glucokinase (GK), mainly expressed in the liver and pancreatic beta-cells, is critical for maintaining glucose homeostasis. GK expression and kinase activity, respectively, are both modulated at the transcriptional and post-translational levels. Post-translationally, GK is regulated by binding the glucokinase regulatory protein (GKRP), resulting in GK retention in the nucleus and its inability to participate in cytosolic glycolysis. Although hepatic GKRP is known to be regulated by allosteric mechanisms, the precise details of modulation of GKRP activity, by post-translational modification, are not well known. Here, we demonstrate that GKRP is acetylated at Lys5 by the acetyltransferase p300. Acetylated GKRP is resistant to degradation by the ubiquitin-dependent proteasome pathway, suggesting that acetylation increases GKRP stability and binding to GK, further inhibiting GK nuclear export. Deacetylation of GKRP is effected by the NAD(+)-dependent, class III histone deacetylase SIRT2, which is inhibited by nicotinamide. Moreover, the livers of db/db obese, diabetic mice also show elevated GKRP acetylation, suggesting a broader, critical role in regulating blood glucose. Given that acetylated GKRP may affiliate with type-2 diabetes mellitus (T2DM), understanding the mechanism of GKRP acetylation in the liver could reveal novel targets within the GK-GKRP pathway, for treating T2DM and other metabolic pathologies. PMID- 26620283 TI - Native extracellular matrix preserves mesenchymal stem cell "stemness" and differentiation potential under serum-free culture conditions. AB - INTRODUCTION: Bone marrow-derived mesenchymal stem cells (BM-MSCs) for clinical use should not be grown in media containing fetal bovine serum (FBS), because of serum-related concerns over biosafety and batch-to-batch variability. Previously, we described the preparation and use of a cell-free native extracellular matrix (ECM) made by bone marrow cells (BM-ECM) which preserves stem cell properties and enhances proliferation. Here, we compare colony-forming ability and differentiation of MSCs cultured on BM-ECM with a commercially available matrix (CELLstartTM) and tissue culture plastic (TCP) under serum-free conditions. METHODS: Primary MSCs from freshly isolated bone marrow-derived mononuclear cells or passaged MSCs (P1) were grown in serum-containing (SCM) or serum-free (SFM) media on BM-ECM, CELLstartTM, or TCP substrates. Proliferation, cell composition (phenotype), colony-forming unit replication, and bone morphogenetic protein-2 (BMP-2) responsiveness were compared among cells maintained on the three substrates. RESULTS: Proliferation of primary BM-MSCs was significantly higher in SCM than SFM, irrespectively of culture substrate, suggesting that the expansion of these cells requires SCM. In contrast, passaged cells cultured on BM-ECM or CELLstartTM in SFM proliferated to nearly the same extent as cells in SCM. However, morphologically, those on BM-ECM were smaller and more aligned, slender, and long. Cells grown for 7 days on BM-ECM in SFM were 20-40 % more positive for MSC surface markers than cells cultured on CELLstartTM. Cells cultured on TCP contained the smallest number of cells positive for MSC markers. MSC colony forming ability in SFM, as measured by CFU-fibroblasts, was increased 10-, 9-, and 2-fold when P1 cells were cultured on BM-ECM, CELLstartTM, and TCP, respectively. Significantly, CFU-adipocyte and -osteoblast replication of cells grown on BM-ECM was dramatically increased over those on CELLstartTM (2X) and TCP (4-7X). BM-MSCs, cultured in SFM and treated with BMP-2, retained their differentiation capacity better on BM-ECM than on either of the other two substrates. CONCLUSIONS: Our findings indicate that BM-ECM provides a unique microenvironment that supports the colony-forming ability of MSCs in SFM and preserves their stem cell properties. The establishment of a robust culture system, combining native tissue-specific ECM and SFM, provides an avenue for preparing significant numbers of potent MSCs for cell-based therapies in patients. PMID- 26620284 TI - Proteomic Biomarker Discovery in 1000 Human Plasma Samples with Mass Spectrometry. AB - The overall impact of proteomics on clinical research and its translation has lagged behind expectations. One recognized caveat is the limited size (subject numbers) of (pre)clinical studies performed at the discovery stage, the findings of which fail to be replicated in larger verification/validation trials. Compromised study designs and insufficient statistical power are consequences of the to-date still limited capacity of mass spectrometry (MS)-based workflows to handle large numbers of samples in a realistic time frame, while delivering comprehensive proteome coverages. We developed a highly automated proteomic biomarker discovery workflow. Herein, we have applied this approach to analyze 1000 plasma samples from the multicentered human dietary intervention study "DiOGenes". Study design, sample randomization, tracking, and logistics were the foundations of our large-scale study. We checked the quality of the MS data and provided descriptive statistics. The data set was interrogated for proteins with most stable expression levels in that set of plasma samples. We evaluated standard clinical variables that typically impact forthcoming results and assessed body mass index-associated and gender-specific proteins at two time points. We demonstrate that analyzing a large number of human plasma samples for biomarker discovery with MS using isobaric tagging is feasible, providing robust and consistent biological results. PMID- 26620285 TI - Factors Associated With Suicide Outcomes 12 Months After Screening Positive for Suicide Risk in the Emergency Department. AB - OBJECTIVE: The main objective was to identify which patient characteristics have the strongest association with suicide outcomes in the 12 months after an index emergency department (ED) visit. METHODS: Data were analyzed from the first two phases of the Emergency Department Safety Assessment and Follow-up Evaluation (ED SAFE). The ED-SAFE study, a quasi-experimental, interrupted time-series design, involved participation from eight general medical EDs across the United States. Participants included adults presenting to the ED with active suicidal ideation or an attempt in the past week. Data collection included baseline interview; six- and 12-month chart reviews; and six-, 12-, 24-, 36-, and 52-week telephone follow up assessments. Regression analyses were conducted. RESULTS: Among 874 participants, the median age was 37 years (interquartile range 27-47), with 56% of the sample being female (N=488), 74% white (N=649), and 13% Hispanic (N=113). At baseline, 577 (66%) participants had suicidal ideation only, whereas 297 (34%) had a suicide attempt in the past week. Data sufficient to determine outcomes were available for 782 (90%). In the 12 months after the index ED visit, 195 (25%) had documentation of at least one suicide attempt or suicide. High school education or less, an ED visit in the preceding six months, prior nonsuicidal self-injury, current alcohol misuse, and suicidal intent or plan were predictive of future suicidal behavior. CONCLUSIONS: Continuing to build an understanding of the factors associated with future suicidal behaviors for this population will help guide design and implementation of improved suicide screening and interventions in the ED and better allocation of scarce resources. PMID- 26620286 TI - Implementing Computer-Based Psychotherapy Among Veterans in Outpatient Treatment for Substance Use Disorders. AB - OBJECTIVE: Computer-based psychotherapy interventions (CBPIs) are increasingly offered as first-level access to evidence-based mental health treatment. However, their implementation has not been evaluated in public-sector outpatient settings. METHODS: An evidence-based CBPI for insomnia was implemented with provider and patient education sessions, on-site Internet access, and clinician telephone support. Persons receiving care at a Veterans Health Administration substance abuse treatment clinic were screened for chronic insomnia and offered CBPI access. The feasibility of this strategy was evaluated in a pre-post design, which assessed engagement and completion rates, participant-reported acceptability, and clinical outcomes. RESULTS: Of 100 veterans referred, 51 enrolled in the program, of whom 22 (43%) completed all sessions, 13 (26%) partially completed the program, and 16 (31%) did not engage. There were no statistically significant differences between these three groups in baseline characteristics. In the total sample, Insomnia Severity Index (ISI) scores decreased (improved) by 32% (mean+/-SD of 6.3+/-6.2 points, t=6.82, df=44, p<.001). Veterans who completed all six sessions displayed clinically and statistically significant improvements on the ISI compared with those who did not engage, as shown in a regression analysis that controlled for baseline insomnia severity, time between assessments, and sedative-hypnotic medication use (F=3.87, df=4 and 40, p<=.004). Among all participants, 67% agreed that they would engage in another CBPI in the future. When questioned about potential barriers, 36% of the full sample endorsed a preference for face-to-face therapy. CONCLUSIONS: A strategy of brief provider and patient education, on-site Internet access, and telephone support was feasible and effective for implementing CBPIs in outpatient substance abuse treatment settings for veterans. PMID- 26620287 TI - Increasing Access to State Psychiatric Hospital Beds: Exploring Supply-Side Solutions. AB - OBJECTIVE: The objective of this study was to identify supply-side interventions to reduce state psychiatric hospital admission delays. METHODS: Healthcare Enterprise Accounts Receivable Tracking System (HEARTS) data were collected for all patients admitted between July 1, 2010, and July 31, 2012, to one of North Carolina's three state-operated psychiatric hospitals (N=3,156). Additional information on hospital use was collected at nine meetings with hospital administrators and other local stakeholders. A discrete-event simulation model was built to simulate the flow of adult nonforensic patients through the hospital. Hypothetical scenarios were used to evaluate the effects of varying levels of increased capacity on annual number of admissions and average patient wait time prior to admission. RESULTS: In the base case, the model closely approximated actual state hospital utilization, with an average of 1,251+/-65 annual admissions and a preadmission wait time of 3.3+/-.1 days across 50 simulations. Results from simulated expansion scenarios highlighted substantial capacity shortfalls in the current system. For example, opening an additional 24 bed unit was projected to decrease average wait time by only 6%. Capacity would need to be increased by 165% (356 beds) to reduce average wait time below 24 hours. CONCLUSIONS: Without more robust community-based hospital and residential capacity, major increases in state psychiatric hospital inpatient capacity are necessary to ensure timely admission of people in crisis. PMID- 26620288 TI - Effects of Mental Health Parity on High Utilizers of Services: Pre-Post Evidence From a Large, Self-Insured Employer. AB - OBJECTIVE: This study evaluated utilization of mental health and substance use services among enrollees at a large employee health plan following changes to benefit limits after passage in 2008 of federal mental health parity legislation. METHODS: This study used a pre-post design. Benefits and claims data for 43,855 enrollees in the health plan in 2009 and 2010 were analyzed for utilization and costs after removal of a 30-visit cap on the number of covered mental health visits. RESULTS: There was a large increase in the proportion of health plan enrollees with more than 30 outpatient visits after the cap's removal, an increase of 255% among subscribers and 176% among dependents (p<.001). The number of people near the 30-visit limit for substance use disorders was too few to observe an effect. CONCLUSIONS: Federal mental health parity legislation is likely to increase utilization of mental health services by individuals who had previously met their benefit limit. PMID- 26620289 TI - A Multiple-City RCT of Housing First With Assertive Community Treatment for Homeless Canadians With Serious Mental Illness. AB - OBJECTIVE: Housing First with assertive community treatment (ACT) is a promising approach to assist people with serious mental illness to exit homelessness. The article presents two-year findings from a multisite trial on the effectiveness of Housing First with ACT. METHODS: The study design was a randomized controlled trial conducted in five Canadian cities. A sample of 950 participants with serious mental illness who were absolutely homeless or precariously housed were randomly assigned to receive either Housing First with ACT (N=469) or treatment as usual (N=481). RESULTS: Housing First participants spent more time in stable housing than participants in treatment as usual (71% versus 29%, adjusted absolute difference [AAD]=42%, p<.01). Compared with treatment-as-usual participants, Housing First participants who entered housing did so more quickly (73 versus 220 days, AAD=146.4, p<.001), had longer housing tenures at the study end-point (281 versus 115 days, AAD=161.8, p<.01), and rated the quality of their housing more positively (adjusted standardized mean difference [ASMD]=.17, p<.01). Housing First participants reported higher quality of life (ASMD=.15, p<.01) and were assessed as having better community functioning (ASMD=.18, p<.01) over the two-year period. Housing First participants showed significantly greater gains in community functioning and quality of life in the first year; however, differences between the two groups were attenuated by the end of the second year. CONCLUSIONS: Housing First with ACT is an effective approach in various contexts for assisting individuals with serious mental illness to rapidly exit homelessness. PMID- 26620290 TI - Criminal Activity or Treatable Health Condition? News Media Framing of Opioid Analgesic Abuse in the United States, 1998-2012. AB - OBJECTIVE: Opioid analgesic abuse is a complex and relatively new public health problem, and to date little is known about how the news media frame the issue. METHODS: To better understand how this issue has been framed in public discourse, an analysis was conducted of the volume and content of news media coverage of opioid analgesic abuse over a 15-year period from 1998 to 2012 (N=673 news stories). A 70-item structured coding instrument was used to measure items in four domains that prior research suggests can influence public attitudes about health and social issues: causes, solutions, and consequences of the problem and individual depictions of persons who abuse opioid analgesics. RESULTS: Although experts have deemed opioid analgesic abuse a public health crisis, results of our study suggest that the news media more often frame the problem as a criminal justice issue. The most frequently mentioned cause of the problem was illegal drug dealing, and the most frequently mentioned solutions were law enforcement solutions designed to arrest and prosecute the individuals responsible for diverting opioid analgesics onto the illegal market. Prevention-oriented approaches, such as prescription drug-monitoring programs, were mentioned more frequently in the latter years of the study period, but less than 5% of news stories overall mentioned expanding substance abuse treatment, and even fewer mentioned expanding access to evidence-based medication-assisted treatments, such as buprenorphine. CONCLUSIONS: Findings underscore the need for a concerted effort to reframe opioid analgesic abuse as a treatable condition addressable via well-established public and behavioral health approaches. PMID- 26620291 TI - Sustaining Screening of Key Health Risk Factors in New York State Mental Health Clinics After Implementation of the Health Indicator Initiative. AB - OBJECTIVE: Screening data on obesity and smoking among adult outpatients in state operated clinics were collected and analyzed by the New York State Office of Mental Health to determine relationships between demographic and clinical risk factors and obesity and smoking. Predictors of weight loss and smoking cessation were examined. METHODS: Individuals enrolled in 2010-2012 with two or more valid body mass index measures and two or more valid smoking measures (N=22,574) were selected. Chi square tests examined associations between demographic and clinical risk factors and obesity and smoking. Multivariable logistic regression identified predictors of weight loss and smoking cessation. RESULTS: The prevalence of obesity and smoking was 45% and 50%, respectively. The odds of losing weight or remaining at a stable weight were higher among males (versus females), individuals ages <=49 (versus >=50), smokers (versus nonsmokers) at baseline, and individuals with diabetes (versus without diabetes). The odds of gaining weight were higher among individuals prescribed psychotropic medications compared with those who were not prescribed psychotropic medications. Individuals ages <=49 and those with a pulmonary condition or psychotic or substance use disorders (versus without these conditions) were less likely to quit smoking. Individuals who were obese (versus not obese) at baseline and those with an endocrine condition (versus without this condition) were more likely to quit smoking. CONCLUSIONS: Significant associations were found between demographic and clinical risk factors and obesity, smoking, and improvements in smoking and obesity outcomes. Continued work is needed to identify critical points of intervention to prevent weight gain and promote weight loss and smoking cessation in this population. PMID- 26620292 TI - Increased Mortality Among Older Veterans Admitted to VA Homelessness Programs. AB - OBJECTIVE: National Death Index data were examined to describe mortality patterns among older veterans who are homeless. METHODS: Homelessness and health care records from the U.S. Department of Veterans Affairs were used to identify old (ages 55-59) and older (ages >=60) veterans who were (N=4,475) or were not (N=20,071) homeless. Survival functions and causes of death of the two samples over an 11-year follow-up period were compared. RESULTS: Substantially more veterans who were homeless (34.9%) died compared with the control sample (18.2%). Veterans who were homeless were approximately 2.5 years younger at time of death compared with the control sample. Older veterans who were homeless had the lowest survival rate (58%). No disease category appeared to be critical in reducing survival time. Suicide was twice as frequent in the homeless (.4%) versus the control (.2%) sample. CONCLUSIONS: Older veterans who were homeless experienced excess mortality and increased suicide risk. PMID- 26620293 TI - Factors Associated With Timely Follow-Up Care After Psychiatric Hospitalization for Youths With Mood Disorders. AB - OBJECTIVES: This study identified patient-, hospital-, and community-level factors associated with timely follow-up care following psychiatric hospitalization for children and adolescents with mood disorders. METHODS: The patients were 7,826 youths (ages six to 17) admitted to psychiatric hospitals with a primary diagnosis of mood disorder (July 2009-November 2010). Outcome variables were defined as one or more mental health visits within seven days and 30 days of psychiatric hospitalization. Predictor variables included patient-, hospital-, and community-level factors obtained from Medicaid claim files from four states (California, Florida, Maryland, and Ohio), the American Hospital Association annual survey, and the Area Resource File. Multilevel modeling was used to assess the association between patient-, hospital-, and community-level factors and receipt of follow-up care. RESULTS: Following discharge, an outpatient mental health visit was obtained by 48.9% of children and adolescents within seven days and by 69.2% of children and adolescents within 30 days. Positive predictors of follow-up at both seven and 30 days included prior outpatient mental health care, foster care, psychiatric comorbidity, care in teaching hospitals and psychiatric hospitals, and residence in counties with more child and adolescent psychiatrists. Negative predictors included older age, black race, care in hospitals with higher levels of Medicaid penetration, and substance use disorders. CONCLUSIONS: One in three youths did not receive mental health follow-up in the 30 days after psychiatric hospitalization. Linkage to follow-up care appears to be complex and multidetermined. Study findings underscored the need for quality improvement interventions targeting vulnerable populations and promoting successful transitions from inpatient to outpatient care. PMID- 26620294 TI - From Alienism to ACOs: Integrating Psychiatry, Again. AB - This column describes the gradual integration of psychiatrists into mainstream general medical care, from their exile as "alienists" in isolated asylums to their current roles in accountable care organizations. The authors note that a contemporary form of alienism persists and argue that conceptual parity-the idea that mental illnesses exist within the same ontological realm as other illnesses must first be achieved before full integration can be realized. Some steps toward achieving conceptual parity, such as the development of quality measures for behavioral health care and improved training programs, are described. PMID- 26620295 TI - Saggy skin as a presenting sign of angioimmunoblastic T-cell lymphoma. AB - Angioimmunoblastic T-cell lymphoma (AITL) is a rare, aggressive form of peripheral T-cell lymphoma that has a variety of cutaneous manifestations. To our knowledge, saggy skin has not been documented as one of these manifestations. We report a case of a patient with angioimmunoblastic T-cell lymphoma presenting initially with pruritus and saggy skin, which later progressed into erythroderma despite chemotherapy; the disease eventually resolved with autologous stem cell transplant. Appreciating the cutaneous manifestations of AITL may allow for earlier diagnosis and treatment. PMID- 26620297 TI - Is Subchondral Acetabular Edema or Cystic Change on MRI a Contraindication for Hip Arthroscopy in Patients With Femoroacetabular Impingement? AB - BACKGROUND: The outcome for arthroscopic treatment of femoroacetabular impingement (FAI) can worsen with increasing arthritis. However, there remains a subset of hips with relatively maintained joint space but with acetabular subchondral edema and cystic change with unknown outcome on magnetic resonance imaging (MRI). PURPOSE: (1) To correlate MRI findings of subchondral acetabular edema/cystic change with arthroscopy grading of articular cartilage and (2) to determine whether postoperative outcome was worse for patients with subchondral edema/cystic change compared with a matched control group. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: The records of all patients who underwent arthroscopic hip surgery for FAI at a single institution between 2007 and 2013 were reviewed for subchondral edema/cyst on preoperative MRI. Lesions were characterized by grade using an established classification system and were correlated with arthroscopic articular cartilage changes. A matched cohort of patients without evidence of subchondral edema or cyst was identified. Minimum 2 year outcomes were compared using prospectively collected Hip Outcome Score (HOS) activities of daily living and sport subscales as well as the modified Harris Hip Score (mHHS). RESULTS: Overall, 104 patients were included. Thirty-six patients (18 men, 18 women) with a mean age of 41 years (range, 19-67 years) had subchondral edema, with or without the presence of cystic acetabular changes, at minimum 2-year follow-up (range, 24-60 months). Two patients who underwent total hip replacement were excluded in the outcome score comparison. Thirty-one of 34 patients (91%) had a grade 4 full-thickness cartilage lesion at the time of diagnostic arthroscopy. The mean mHHS was inferior for all patients with subchondral edema/cystic change (79.9 +/- 18.7 vs 86.6 +/- 12.5; P = .03), and the HOS was also lower (69.1 +/- 27.0 vs 79.5 +/- 21.4; P = .02). The overall success rate was 67% for all patients with subchondral edema/cystic change compared with 85% in the control group (P = .04). CONCLUSION: The presence of a subchondral edema with an acetabular cyst on MRI is indicative of a full thickness cartilage lesion at the time of arthroscopy. These patients have inferior outcomes for arthroscopic treatment of FAI compared with patients with similar age and activity level without MRI subchondral cystic changes. PMID- 26620296 TI - Is Knee Separation During a Drop Jump Associated With Lower Extremity Injury in Adolescent Female Soccer Players? AB - BACKGROUND: Knee injuries are common in older adolescent and adult female soccer players, and abnormal valgus knee appearance characterized by low normalized knee separation (NKS) is a proposed injury risk factor. What constitutes normal NKS in younger adolescents and whether low NKS is an injury risk factor are unknown. PURPOSE: To determine the normal range of NKS using a drop-jump test in female perimenarchal youth soccer players and whether low NKS contributes to lower extremity injuries or knee injuries. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: From 2008 to 2012, a total of 351 female elite youth soccer players (age range, 11-14 years) were followed for 1 season, with complete follow up on 92.3% of players. Baseline drop-jump testing was performed preseason. Lower extremity injuries during the season were identified using a validated, Internet based injury surveillance system with weekly email reporting. Normalized knee separation at prelanding, landing, and takeoff was categorized 2 ways: as <=10th percentile (most extreme valgus appearance) compared with >10th percentile and as a continuous measure of 1 SD. Poisson regression modeling with adjustment for clustering by team estimated the relative risk (RR) and 95% confidence interval (CI) of the association between the NKS and the risk of lower extremity and knee injury, stratified by menarche. RESULTS: Of the study participants, 134 players experienced 173 lower extremity injuries, with 43 (24.9%) knee injuries. For postmenarchal players (n = 210), those with NKS <=10th percentile were at 92% increased risk of lower extremity injury (RR, 1.92; 95% CI, 1.17-3.15) and a 3.62 fold increased risk of knee injury (RR, 3.62; 95% CI, 1.18-11.09) compared with NKS >10th percentile at prelanding and landing, respectively. Among postmenarchal players, there was an 80% increased risk of knee injury (RR, 1.80; 95% CI, 1.01 3.23) with a decrease of 1 SD in landing NKS and a 66% increased risk of knee injury (RR, 1.66; 95% CI, 1.04-2.64) with a decrease of 1 SD in takeoff NKS. Among premenarchal players (n = 141), there was no statistically significant association between the NKS at prelanding, landing, and takeoff and the risk of lower extremity or knee injury. CONCLUSION: Low NKS was associated with increased risk of lower extremity and knee injury only among postmenarchal players. PMID- 26620298 TI - Risk Factors Associated With Grade 3 Pivot Shift After Acute Anterior Cruciate Ligament Injuries. AB - BACKGROUND: Recent literature has demonstrated that involvement in pivoting sports at the time of injury, increased posterior-inferior tibial slope (PITS), anterolateral capsular ligament (ALCL) disruptions, and combined lateral meniscal lesions all contribute to a higher grade of pivot shift after acute anterior cruciate ligament (ACL) injuries. PURPOSE: To identify risk factors associated with grade 3 pivot shift after acute ACL injuries. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A database of patients undergoing primary ACL reconstruction from 2009 to 2015 after acute ACL injuries was retrospectively reviewed. A total of 30 patients (30 knees) with grade 3 pivot shift were identified as the study group. Moreover, 30 patients (30 knees) with grade 1 and 30 patients (30 knees) with grade 2 pivot shift were randomly chosen as the 2 control groups. All pivot-shift tests were performed with the patients under anesthesia. Predictors of grade 3 pivot shift that were explored included patient age, sex, time from injury to surgery, pivoting sports involvement at the time of injury, lateral PITS, medial PITS, ALCL disruptions, preoperative KT-1000 arthrometer side-to-side difference, and combined lateral or medial meniscal lesions. Comparisons were performed between the study group and the 2 control groups. Univariable and multivariable logistic regressions were used to identify independent risk factors that were associated with grade 3 pivot shift. RESULTS: Univariable and multivariable logistic regressions between the study group and the 2 control groups showed that pivoting sports involvement at the time of injury (odds ratio1 [OR1; grade 3 vs grade 1 pivot shift with grade 1 = reference], 11.88; 95% CI, 1.94-149.91; OR2 [grade 3 vs grade 2 pivot shift with grade 2 = reference], 3.41; 95% CI, 1.92-22.60), abnormal degree of lateral PITS (OR1, 14.41; 95% CI, 1.69-174.78; OR2, 6.41; 95% CI, 1.48-47.70), ALCL disruptions (OR1, 8.28; 95% CI, 1.71-117.14; OR2, 4.96; 95% CI, 1.07-28.75), and combined lateral meniscal lesions (OR1, 27.56; 95% CI, 5.48-240.52; OR2, 5.83; 95% CI, 1.21-38.56) were independent risk factors of grade 3 pivot shift after acute ACL injuries. CONCLUSION: For acute ACL injuries, the best set of predictors of grade 3 pivot shift were pivoting sports involvement at the time of injury, abnormal lateral PITS, ALCL disruptions, and combined lateral meniscal lesions. These results may provide additional information for counseling patients on residual laxity and risks for graft rerupture after ACL reconstruction. PMID- 26620299 TI - Arthroscopic Management of Dysplastic Hip Deformities: Predictors of Success and Failures With Comparison to an Arthroscopic FAI Cohort. AB - BACKGROUND: Reports regarding arthroscopy for mild hip dysplasia have conflicting results. HYPOTHESIS: Arthroscopy for borderline/mild hip dysplasia would lead to improved outcomes but be inferior to arthroscopy for femoroacetabular impingement (FAI). STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 88 hips (77 patients, 71% female; mean age, 33.9 years) with dysplastic radiographic findings were retrospectively reviewed at a mean follow-up of 26.0 months after hip arthroscopy. Specific procedures included labral repair (76%), labral debridement (23%), capsular repair/plication (82%), and femoral osteochondroplasty (72%). Radiographic parameters included lateral center-edge angle, neck-shaft angle, Tonnis angle, extrusion index, femoral head lateralization, and break in the Shenton line. Pre- and postoperative function were evaluated prospectively with the modified Harris Hip Score (mHHS), 12-Item Short Form Health Survey, and visual analog scale for pain. The results of the dysplastic cohort were compared with an age-matched cohort of 231 hips without radiographic dysplasia that underwent arthroscopic FAI correction during the study period (mean follow-up, 22.7 months). RESULTS: The mean lateral center-edge angle was 20.8 degrees (range, 8.7 degrees -24.5 degrees ), and the mean Tonnis angle was 11.0 degrees (range, 0 degrees -22.2 degrees ). At the time of final follow-up, the dysplastic cohort demonstrated a mean mHHS of 81.3 with a mean 15.6-point improvement in mHHS, compared with 88.4 and 24.4 points, respectively, in the FAI cohort (P = .00044). The dysplastic cohort had 60.9% good/excellent results and 32.2% failures, compared with 81.2% good/excellent results and 10.5% failures for the FAI cohort (P < .01). Failure was defined as an mHHS <=70 or eventual pelvic/femoral osteotomy or total hip arthroplasty. Dysplastic hips that underwent capsular plication and labral repair had greater good/excellent results (73%) and mean latest mHHS (85), as well as lower failure rates (18%) compared with the remainder of the dysplastic cohort (P < .05). Grade 4 chondral defects were predictive of lower scores (P = .02). There were no other statistically significant differences for outcomes regarding sex, age, or radiographic parameters (P > .05). There were no iatrogenic subluxations/dislocations. CONCLUSION: Arthroscopic management of mild to moderate acetabular dysplasia had inferior good/excellent results and higher failure rates when compared with an FAI cohort; therefore, isolated arthroscopic procedures in this population should be cautiously considered. These results were independent of patient sex. Labral repair and capsular plication resulted in better clinical outcomes in this mildly dysplastic cohort. PMID- 26620300 TI - The clinical relevance of an interpersonal-psychotherapy-oriented postnatal program for a non-clinical sample of Chinese first-time mothers: A comment on Gao and colleagues (2015) and authors' response. PMID- 26620301 TI - Contribution of rare germline copy number variations and common susceptibility loci in Lynch syndrome patients negative for mutations in the mismatch repair genes. AB - In colorectal carcinoma (CRC), 35% of cases are known to have a hereditary component, while a lower proportion (~ 5%) can be explained by known genetic factors. In this study, copy number variations (CNVs) were evaluated in 45 unrelated patients with clinical hypothesis of Lynch syndrome (Amsterdam or Bethesda criteria); negative for MLH1, MSH2, MSH6, PMS2, CHEK2*1100delC and TP53 pathogenic mutations; aiming to reveal new predisposing genes. Analyses with two different microarray platforms (Agilent 180K and Affymetrix CytoScan HD) revealed 35 rare CNVs covering 67 known genes in 22 patients. Gains (GALNT6 and GALNT11) and losses (SEMA3C) involving the same gene families related to CRC susceptibility were found among the rare CNVs. Segregation analysis performed on four relatives from one family suggested the involvement of GALNT11 and KMT2C in those at risk of developing CRC. Notably, in silico molecular analysis revealed that 61% (41/67) of the genes covered by rare CNVs were associated with cancer, mainly colorectal (17 genes). Ten common SNPs, previously associated with CRC, were genotyped in 39 index patients and 100 sporadic CRC cases. Although no significant, an increased number of risk alleles was detected in the index cases compared with the sporadic CRC patients. None of the SNPs were covered by CNVs, suggesting an independent effect of each alteration in cancer susceptibility. In conclusion, rare germline CNVs and common SNPs may contribute to an increased risk for hereditary CRC in patients with mismatch repair proficiency. PMID- 26620303 TI - Improving phosphorus uptake and wheat productivity by phosphoric acid application in alkaline calcareous soils. AB - BACKGROUND: Low phosphorus (P) efficiency from existing granular fertilisers necessitates searching for efficient alternatives to improve wheat productivity in calcareous soil. RESULTS: Multi-location trials have shown that phosphoric acid (PA) produced 16% higher wheat grain over commercial P fertilisers, i.e. diammonium phosphate (DAP) and triple superphosphate (TSP). Methods of P application significantly influenced grain yield and the efficiency of methods was observed in the order: PA placement below seed > PA, DAP or TSP fertigation > DAP or TSP broadcast. The sub-surface application of PA produced highest grain yields (mean of all rates), i.e. 4669, 4158 and 3910 kg ha(-1) in Bagh, Bhalwal and Shahpur soil series, respectively. Phosphoric acid at 66 kg P2 O5 ha(-1) was found more effective in increasing gain yield over that of control. Trend in grain P uptake was found similar to that observed for grain yield. Maximum P uptake by grain was recorded at the highest P rate and the lowest at zero P. The significant increase in P uptake with P rates was generally related to the increase in yield rather than its concentration in grain. Phosphorus agronomic efficiency (PAE) and phosphorus recovery efficiency (PRE) were found higher at lower P rate (44 kg P2 O5 ha(-1) ) and decreased with P application. However, PA applied by the either method resulted in higher PAE and PRE compared to DAP and TSP. CONCLUSION: Phosphoric acid is suggested as an efficient alternative to commercial granular P fertilisers for wheat production in alkaline calcareous soils. (c) 2015 Society of Chemical Industry. PMID- 26620302 TI - Evidence for transcriptional interference in a dual-luciferase reporter system. AB - The dual-luciferase reporter assay is widely used for microRNA target identification and the functional validation of predicted targets. To determine whether curcumin regulates expression of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) by targeting its 3'untranslated region (3'UTR), two luciferase reporter systems containing exactly the same sequence of the EZH2 3'UTR were used to perform dual-luciferase reporter assays. Surprisingly, there were certain discrepancies between the luciferase activities derived from these two reporter constructs. We normalized luciferase activity to an internal control to determine the amount of the reporter construct successfully transfected into cells, induced a transcriptional block with flavopiridol, quantified renilla luciferase mRNA levels, and compared the absolute luciferase activity among the different groups. The results suggested that curcumin promoted the transcription of the luciferase genes located downstream of the simian vacuolating virus 40 (SV40) early enhancer/promoter, but not those located downstream of the human cytomegalovirus (CMV) immediate-early or the herpes simplex virus thymidine kinase (HSV-TK) promoters. These results explain the discrepancies between the two luciferase reporter systems. The current study underscores the importance of taking caution when interpreting the results of dual-luciferase reporter assays and provides strategies to overcome the potential pitfall accompanying dual luciferase reporter systems. PMID- 26620304 TI - Honey bee microRNAs respond to infection by the microsporidian parasite Nosema ceranae. AB - In order to study the effects of Nosema ceranae infection on honey bee microRNA (miRNA) expression, we deep-sequenced honey bee miRNAs daily across a full 6-day parasite reproduction cycle. Seventeen miRNAs were differentially expressed in honey bees infected by N. ceranae that potentially target over 400 genes predicted to primarily involve ion binding, signaling, the nucleus, transmembrane transport, and DNA binding. Based on Enzyme Code analysis, nine biological pathways were identified by screening target genes against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, seven of which involved metabolism. Our results suggest that differentially expressed miRNAs regulate metabolism related genes of host honey bees in response to N. ceranae infection. PMID- 26620306 TI - Exercise-induced pneumomediastinum. AB - BACKGROUND: A sudden onset of chest pain, which often reflects a life-threatening disease, requires prompt diagnosis in the emergency department. FINDINGS: A 12 year-old boy presented with sustained chest pain and dyspnea after diving into a swimming pool and was transferred to our emergency department. A chest examination noted a crunching and rasping sound at the precordium, synchronous with the heartbeat. Chest radiography showed lucent streaks and the mediastinal pleura at the left cardiac outline. Additionally, computed tomography showed massive pneumomediastinum surrounding the heart. Thus, he was diagnosed with spontaneous pneumomediastinum. CONCLUSIONS: Spontaneous pneumomediastinum should be considered in the differential diagnosis of chest pain. In addition to medical history-taking, careful physical examination, which can identify the characteristic finding of a friction sound synchronous with the heartbeat (Hamman's sound), will help in the immediate diagnosis of spontaneous pneumomediastinum. PMID- 26620305 TI - Camellia sinensis Ameliorates the Efficacy of Last Line Antibiotics Against Carbapenem Resistant Escherichia coli. AB - Aquo-ethanolic extract of Camellia sinensis (PTRC-31911-A), standardized using Fourier transform infrared analysis, was found to have seven common functional groups in comparison with pre-identified marker compound 'quercetin'. Phyto chemical quantitation analysis revealed the presence of 10.65 ug/mg of flavonoids. The bioactivity fingerprint profile of PTRC-31911-A includes IC50 (Hydroxyl radical site specific scavenging) = 11.36 +/- 0.5 ug/mL, IC80 (Hydroxyl radical non-site specific scavenging) = 26.44 +/- 0.5 ug/mL and IC50 (Superoxide ion scavenging) = 10.141 +/- 0.5 ug/mL. The drug combination analysis of PTRC-31911-A with five third-line antibiotics was carried out against carbapenem-resistant Escherichia coli. The analysis of combination of PTRC-31911 A (6.25-1000 ug/mL) and antibiotics (6.25-1000 ug/mL) revealed synergistic behaviour (fractional inhibitory concentration indices < 1) with tigecycline, ertapenem, meropenem, colistin and augmentin. The lead combination of PTRC-31911 A + ertapenem or meropenem showed maximum augmentative potential at 50 and 100 ug/mL, respectively, with nearly five-fold decrease in minimum inhibitory concentrations as compared with respective antibiotics alone. The synergistic effects implied that the antibacterial combinations of PTRC-31911-A and ertapenem, meropenem, colistin, tigecycline or augmentin would be more effective than a single monotherapy with either of the antibacterial agent. PMID- 26620307 TI - Transuncovertebral joint screw placement: technical note. AB - PURPOSE: Although a C2 pedicle screw and a C1-2 transarticular screw are the most rigid anchors, these screws cannot be used in cases with bilateral high-riding vertebral arteries. The authors describe their recent experience using a novel method of C2-3 transuncovertebral joint screw placement for occipitocervical fixation. METHODS: A 67-year-old patient suffered myelopathy due to instability at C1-2. The patient had bilateral high-riding vertebral arteries that precluded the use of a C2 pedicle screw or a C1-2 transarticular screw. RESULTS: A C2-3 transuncovertebral joint screw was applied bilaterally under 3D navigation guidance. The patient's postoperative course was uneventful, and his neurological status improved after the surgery. Bony fusion was achieved after the surgery. CONCLUSIONS: This is the first report to describe the technique of transuncovertebral joint screw. Using a C2-3 transuncovertebral joint screw, a long screw could be used, and it provided an anchor at C3 and C2 from a posterior approach. PMID- 26620308 TI - Lumbar sequestrectomy via a translaminar approach. PMID- 26620309 TI - Depressive symptoms and glycated hemoglobin A1c: a reciprocal relationship in a prospective cohort study. AB - BACKGROUND: The aim of this study was to evaluate the dynamic association between depressive symptoms and glycated hemoglobin A1c (HbA1c) levels using data from the English Longitudinal Study of Ageing (ELSA). METHOD: The sample was comprised of 2886 participants aged ?50 years who participated in three clinical assessments over an 8-year period (21% with prediabetes and 7% with diabetes at baseline). Structural equation models were used to address reciprocal associations between depressive symptoms and HbA1c levels and to evaluate the mediating effects of lifestyle-related behaviors and cardiometabolic factors. RESULTS: We found a reciprocal association between depressive symptoms and HbA1c levels: depressive symptoms at one assessment point predicted HbA1c levels at the next assessment point (standardized beta = 0.052) which in turn predicted depressive symptoms at the following assessment point (standardized beta = 0.051). Mediation analysis suggested that both lifestyle-related behaviors and cardiometabolic factors might mediate the association between depressive symptoms and HbA1c levels: depressive symptoms at baseline predicted lifestyle-related behaviors and cardiometabolic factors at the next assessment, which in turn predicted HbA1c levels 4 years later. A similar association was observed for the other direction: HbA1c levels at baseline predicted lifestyle-related behaviors and cardiometabolic factors at the next assessment, which in turn predicted depressive symptoms 4 years later. CONCLUSIONS: Our results suggest a dynamic relationship between depressive symptoms and HbA1c which might be mediated by both lifestyle and cardiometabolic factors. This has important implications for investigating the pathways which could link depressive symptoms and increased risk of diabetes. PMID- 26620310 TI - Expression of YKL-40 and MIP-1a proteins in exudates and transudates: biomarkers for differential diagnosis of pleural effusions? A pilot study. AB - BACKGROUND: YKL-40 is an extracellular matrix glycoprotein with a significant role in tissue inflammation and remodeling. MIP-1a has chemotactic and pro inflammatory properties, and is induced by YKL-40 in several lung disorders. The aim of this study was to determine the levels of YKL-40 and MIP-1a in blood serum and pleural fluids of various pulmonary diseases, and to evaluate their potential role as differential diagnosis biomarkers. METHODS: We recruited 60 patients (age: 62.5 +/- 20.6 years) with pleural effusions: 49 exudates and 11 transudates (T). Exudates were further classified based on the underlying disease: ten with tuberculosis (TB), 13 with lung cancer (LCa), 15 with metastatic cancer (MCa) of non-lung origin and 11 with parapneumonic (PN) effusions. YKL-40 and MIP-1a levels were measured by ELISA. RESULTS: Pleural YKL-40 levels (ng/ml) were similar among all patient groups (TB: 399 +/- 36, LCa: 401 +/- 112, MCa: 416 +/- 34, PN: 401 +/- 50, T: 399 +/- 42, p = 0.92). On the contrary, YKL-40 was significantly lower in the serum of TB patients (TB: 58 +/- 22, LCa: 212 +/- 106, MCa: 254 +/- 140, PN: 265 +/- 140, T: 229 +/- 123, p < 0.001). Pleural MIP-1a protein levels (ng/ml) were statistically lower only in patients with LCa (TB: 25.0 +/- 20.2, LCa: 7.3 +/- 6.0, MCa: 16.1 +/- 14.9, PN: 25.4 +/- 27.9, T: 18.5 +/- 7.9, p = 0.012), a finding also observed in serum MIP-1a levels (TB: 17.1 +/- 7.6, LCa: 9.4 +/- 7.0, MCa: 28.7 +/- 28.7, PN: 33.3 +/- 24.0, T: 22.9 +/- 8.7, p = 0.003). CONCLUSIONS: Our data suggest that both YKL-40 and MIP-1a, particularly in serum, could prove useful for the differentiation of pleural effusions in clinical practice, especially of TB or LCa origin. However, large-scale studies are needed to validate these findings. PMID- 26620311 TI - Prolonged Release of Bioactive Model Proteins from Anionic Microgels Fabricated with a New Microemulsion Approach. AB - PURPOSE: Therapeutic proteins have become an integral part of health care. However, their controlled delivery remains a challenge. Protein function depends on a delicate three dimensional structure, which can be damaged during the fabrication of controlled release systems. This study presents a microgel-based controlled release system capable of high loading efficiencies, prolonged release and retention of protein function. METHODS: A new DMSO/Pluronic microemulsion served as a reaction template for the crosslinking of poly(acrylic acid) and oligo (ethylene glycol) to form microgels. Poly(acylic acid) molecular weights and microgel crosslinking densities were altered to make a series of microgels. Microgel capacity to capture and retain proteins of different sizes and isoelectric points, to control their release rate (over ~30 days) and to maintain the biofunctionality of the released proteins were evaluated. RESULTS: Microgels of different sizes and morphologies were synthesized. Loading efficiencies of 100% were achieved with lysozyme in all formulations. The loading efficiency of all other proteins was formulation dependent. Release of lysozyme was achieved for up to 30 days and the released lysozyme retained over 90% of its activity. CONCLUSIONS: High loading efficiencies and prolonged release of different proteins was achieved. Furthermore, lysozyme's functionality remained uncompromised after encapsulation and release. This work begins to lay the foundation for a broad platform for the delivery of therapeutic proteins. PMID- 26620312 TI - Nanocarriers to Enhance the Accumulation of Vitamin K1 into the Skin. AB - PURPOSE: Vitamin K1 (VK1) is a molecule abundant in some species of leaf vegetables with beneficial effects in humans following administration on the skin. This work investigates the possibility to use formulations based on lipid vesicles, namely liposomes, transfersomes and ethosomes, suitable to be administered on the skin by nebulization and alternative to fat semisolid preparations present on the market. METHODS: Lipid vesicles encapsulating VK1 were prepared and characterized. Ex-vivo experiments on Franz cells were carried out to study the VK1 accumulation/permeation in/through the skin. Vesicles interaction with the skin was investigated by confocal laser scanning microscopy (CLSM) and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy. RESULTS: All developed carriers were stable following long-term storage and were not altered following nebulization. In ex-vivo experiments, vesicles with the highest deformability index, namely transfersomes and ethosomes, led to an enhanced VK1 accumulation/permeation into/through the skin. Interestingly, the nebulization of the vesicles led to a further increase of VK1 accumulation into the skin. CONCLUSIONS: In conclusion, to achieve a local effect of VK1 on the skin, the topical nebulization of VK1-containing transfersomes could offer a good compromise between a high VK1 penetration into the skin and a limited permeation through it. PMID- 26620314 TI - Forearm muscle activity is modified bilaterally in unilateral lateral epicondylalgia: A case-control study. AB - Lateral epicondylalgia (LE) is associated with a reduced wrist extensor muscle activity and altered biomechanics. This study compared the coordination between forearm muscles during gripping in individuals with LE and pain-free controls. Intramuscular electrodes recorded myoelectric activity from extensor carpi radialis brevis/longus (ECRB/ECRL), extensor digitorum communis (EDC), flexor digitorum superficialis/profundus (FDS/FDP), and flexor carpi radialis (FCR), bilaterally, in 15 participants with unilateral LE and 15 pain-free controls. Participants performed a gripping task at 20% maximum force in four arm positions. The contribution of each muscle was expressed as a proportion of the summed electromyography of all muscles. In individuals with LE, ECRB contributed less to total electromyography in the symptomatic arm but not the asymptomatic arm than pain-free controls. The contribution of EDC and FDP to total electromyography was greater in both the symptomatic and asymptomatic arm of the LE group, than pain-free controls. No other differences were observed between groups. Subtle differences in muscle activation were present with differing arm positions. These findings indicate forearm muscle activity is modified in LE. It is unknown whether this is cause or effect. Changes in the asymptomatic side may imply involvement of central mechanisms. PMID- 26620313 TI - Enhanced Stability of Inactivated Influenza Vaccine Encapsulated in Dissolving Microneedle Patches. AB - PURPOSE: This study tested the hypothesis that encapsulation of influenza vaccine in microneedle patches increases vaccine stability during storage at elevated temperature. METHODS: Whole inactivated influenza virus vaccine (A/Puerto Rico/8/34) was formulated into dissolving microneedle patches and vaccine stability was evaluated by in vitro and in vivo assays of antigenicity and immunogenicity after storage for up to 3 months at 4, 25, 37 and 45 degrees C. RESULTS: While liquid vaccine completely lost potency as determined by hemagglutination (HA) activity within 1-2 weeks outside of refrigeration, vaccine in microneedle patches lost 40-50% HA activity during or shortly after fabrication, but then had no significant additional loss of activity over 3 months of storage, independent of temperature. This level of stability required reduced humidity by packaging with desiccant, but was not affected by presence of oxygen. This finding was consistent with additional stability assays, including antigenicity of the vaccine measured by ELISA, virus particle morphological structure captured by transmission electron microscopy and protective immune responses by immunization of mice in vivo. CONCLUSIONS: These data show that inactivated influenza vaccine encapsulated in dissolving microneedle patches has enhanced stability during extended storage at elevated temperatures. PMID- 26620315 TI - Genome-scale detection of hypermethylated CpG islands in circulating cell-free DNA of hepatocellular carcinoma patients. PMID- 26620316 TI - Synergistic antitumor activity of pro-apoptotic agent PAC-1 with cisplatinum by the activation of CASP3 in pulmonary adenocarcinoma cell line H1299. AB - AIM: Evasion of apoptosis is a hallmark of human cancer cells. We sought to explore the potential synergistic antitumor activity and underlying mechanisms of the pro-apoptotic agent PAC-1 plus cisplatinum (Cis) in non-small cell lung cancer (NSCLC) cell lines. METHODS: The adenocarcinoma cell lines H1299, A549, PC9, H1650 and H1975 were used as in vitro models. Colorimetric MTT assays, Western blotting and flow cytometry were used to evaluate the anti-growth effects of PAC-1 and/or Cis and apoptosis status. The activated form of CASP3 (C-CASP3) was assessed by immunofluorescent staining. RESULTS: Single-agent Cis and PAC-1 were able to inhibit the cancer cell growth in certain dose ranges, with IC50 values of 1.9-11.7 and 5.6-14.8 MUM, respectively. Sequential Cis->PAC-1 or concurrent Cis + PAC-1, but not PAC-1->Cis combinations showed synergistic effects on cell growth inhibition in H1299 cells (combination index, CI <= 0.6). In contrast, other combination modes mostly showed seemingly antagonistic effects (CI > 1.0). Flow cytometric analysis showed that Cis->PAC-1 sequential combination showed strong pro-apoptotic effects in H1299 cells. Western blots showed that in H1299, PC9 and H1975 cells, PAC-1 promoted the C-CASP3, but only in H1299 cells was there a synergistic effect with Cis on the CASP3 activation. CONCLUSIONS: PAC-1 showed anti-tumor activity in NSCLCs in vitro and a synergistic effect with cisplatin in EGFR(wt)KRAS(wt) H1299 cells. Our data suggest a potential treatment approach using cisplatin plus a pro-apoptotic agent acting via CASP3 activation for this subgroup of pulmonary adenocarcinomas. PMID- 26620317 TI - Selective targeting of nuclear receptor FXR by avermectin analogues with therapeutic effects on nonalcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) has become a predictive factor of death from many diseases. Farnesoid X receptor (FXR) is an ideal target for NAFLD drug development due to its crucial roles in lipid metabolism. The aim of this work is to examine the molecular mechanisms and functional roles of FXR modulation by avermectin analogues in regulating metabolic syndromes like NAFLD. We found that among avermectin analogues studied, the analogues that can bind and activate FXR are effective in regulating metabolic parameters tested, including reducing hepatic lipid accumulation, lowering serum cholesterol and glucose levels, and improving insulin sensitivity, in a FXR dependent manner. Mechanistically, the avermectin analogues that interact with FXR exhibited features as partial agonists, with distinctive properties in modulating coregulator recruitment. Structural features critical for avermectin analogues to selectively bind to FXR were also revealed. This study indicated that in addition to antiparasitic activity, avermectin analogues are promising drug candidates to treat metabolism syndrome including NAFLD by directly targeting FXR. Additionally, the structural features that discriminate the selective binding of FXR by avermectin analogues may provide a unique safe approach to design drugs targeting FXR signaling. PMID- 26620318 TI - Efficient production of gamma-aminobutyric acid using Escherichia coli by co localization of glutamate synthase, glutamate decarboxylase, and GABA transporter. AB - Gamma-aminobutyric acid (GABA) is an important bio-product, which is used in pharmaceutical formulations, nutritional supplements, and biopolymer monomer. The traditional GABA process involves the decarboxylation of glutamate. However, the direct production of GABA from glucose is a more efficient process. To construct the recombinant strains of Escherichia coli, a novel synthetic scaffold was introduced. By carrying out the co-localization of glutamate synthase, glutamate decarboxylase, and GABA transporter, we redirected the TCA cycle flux to GABA pathway. The genetically engineered E. coli strain produced 1.08 g/L of GABA from 10 g/L of initial glucose. Thus, with the introduction of a synthetic scaffold, we increased GABA production by 2.2-fold. The final GABA concentration was increased by 21.8% by inactivating competing pathways. PMID- 26620319 TI - Sidney Blatt's Contributions to Personality Assessment. AB - Over a long, distinguished career, Sidney Blatt contributed to theory and research in personality development, personality assessment, and psychotherapy. Best known for his 2-configurations model of personality and author or co-author of more than 250 articles and 18 books and monographs, Blatt was also a master clinician, a psychoanalyst who was awarded the 1989 Bruno J. Klopfer Award by the Society for Personality Assessment (SPA) for his contributions to both self report and performance-based assessment. He was also the president of SPA from 1984 to 1986. This special series contains papers by writers who participated in all aspects of Blatt's contributions to personality assessment, both self-report and performance-based. Topics covered include Blatt's 2-configurations model of personality, development, and psychopathology; boundary disturbance and psychosis in performance-based assessment; the interaction of gender and personality on narrative assessments; and the Object Relations Inventory and differentiation relatedness, especially as these relate to therapeutic outcome. PMID- 26620320 TI - Prognostic and predictive biomarkers in melanoma: an update. AB - Malignant melanoma is one of the most aggressive cancers. Several new therapeutic strategies that focus on immuno- and/or targeted therapy have been developed, which have entered clinical trials or already been approved. This review provides an update on prognostic and predictive biomarkers in melanoma that may be used to improve the clinical management of patients. Prognostic markers include conventional histopathological characteristics, chromosomal aberrations, gene expression patterns and miRNA profiles. There is a trend towards multi-marker assays and whole-genome molecular screening methods to determine the prognosis of individual patients. Predictive biomarkers, including targeted components of signal transduction, developmental or transcriptional pathways, can be used to determine patient response towards a particular treatment or combination thereof. The rapid evolution of sequencing technologies and multi-marker screening will change the spectrum of patients who become candidates for therapeutic agents, and in addition create new ethical and regulatory challenges. PMID- 26620321 TI - Lack of negative effects of the biological control agent Duddingtonia flagrans on soil nematodes and other nematophagous fungi. AB - The possible environmental effects of the massive use of Duddingtonia flagrans for controlling sheep nematodes were evaluated in two regions. Non-supplemented faeces and faeces from sheep supplemented with D. flagrans were deposited three times on pasture plots and samples were collected 7 and 14 days post-deposition. Samples were cultured in agar-water (2%) with Panagrellus spp. to recover D. flagrans and other nematophagous fungi, and soil nematodes were extracted using Baermann funnels and counted. No significant differences in the populations of soil nematodes and fungi colonizing sheep faeces (P > 0.05) were observed between supplemented and non-supplemented groups, except in one sample. The topsoil in contact with the faeces was sampled 1-4 months post-deposition, revealing that, with one exception, D. flagrans did not persist in soil beyond 2 months post deposition. Duddingtonia flagrans does not affect faecal colonization by other fungi and soil nematodes and, once deployed on pasture, does not survive for long periods in the environment. PMID- 26620322 TI - The 2015 AANS Presidential Address: Neurosurgery's founding principles. AB - These are turbulent times for American neurosurgery. It is important to look ahead and prepare for the future but it is also important to look back-for it is memory and tradition that prevent the tyranny of the present. It is impossible to know where we are going if we don't remember where we were. In this paper I want to discuss the founding principles of neurosurgery-the principles that have allowed neurosurgery to prosper in its first century-and to stress the importance of adhering to these principles in times of change. I also want to talk to you about how the American Association of Neurological Surgeons (AANS) is helping neurosurgeons honor our founding principles, while preparing neurosurgery for its second century. PMID- 26620323 TI - High mobility emissive organic semiconductor. AB - The integration of high charge carrier mobility and high luminescence in an organic semiconductor is challenging. However, there is need of such materials for organic light-emitting transistors and organic electrically pumped lasers. Here we show a novel organic semiconductor, 2,6-diphenylanthracene (DPA), which exhibits not only high emission with single crystal absolute florescence quantum yield of 41.2% but also high charge carrier mobility with single crystal mobility of 34 cm(2) V(-1) s(-1). Organic light-emitting diodes (OLEDs) based on DPA give pure blue emission with brightness up to 6,627 cd m(-2) and turn-on voltage of 2.8 V. 2,6-Diphenylanthracene OLED arrays are successfully driven by DPA field effect transistor arrays, demonstrating that DPA is a high mobility emissive organic semiconductor with potential in organic optoelectronics. PMID- 26620324 TI - Folding Peptides into Lipid Bilayer Membranes. AB - The adsorption, insertion, and folding of a synthetic 16-residue WALP peptide was studied at physiological time scales (>MUs) by atomic detail molecular dynamics simulation using a fully explicit DPPC/DMPC lipid bilayer setup. The temperature was elevated to 80 degrees C/44 degrees C respectively to increase sampling. After spontaneous adsorption the peptide crosses the polar interfaces to locate at the hydrophobic bilayer core. Remarkably, insertion occurs before folding, and the dominant configurations are inserted beta-hairpins. For the DPPC simulation a trans-membrane helix formed but was not stable. Unfolded membrane insertion of WALP was first observed by Nymeyer and co-workers using a replica exchange method. However, both results are in stark contrast to current theory and simulations with implicit membrane models, which rule out unfolded insertion into the hydrophobic core. At present the exact reasons for this unexpected behavior cannot be unambiguously determined, due to the lack suitable experimental and simulation data to compare to. Nevertheless, the results demonstrate that simulation studies can now in principle provide atomic detail insights into complex biophysical phenomena at physiologically relevant time scales. Future effort must now concentrate on suitable ways to verify current force fields and methodologies for such simulations. PMID- 26620325 TI - Degenerate Perturbation Theory for Electronic g Tensors: Leading-Order Relativistic Effects. AB - A new approach for the evaluation of the leading-order relativistic corrections to the electronic g tensors of molecules with a doublet ground state is presented. The methodology is based on degenerate perturbation theory and includes all relevant contributions to the g tensor shift up to order O(alpha(4)) originating from the one-electron part of the Breit-Pauli Hamiltonian-that is, it allows for the treatment of scalar relativistic, spin-orbit, and mixed corrections to the spin and orbital Zeeman effects. This approach has been implemented in the framework of spin-restricted density functional theory and is in the present paper, as a first illustration of the theory, applied to study relativistic effects on electronic g tensors of dihalogen anion radicals X2(-) (X = F, Cl, Br, I). The results indicate that the spin-orbit interaction is responsible for the large parallel component of the g tensor shift of Br2(-) and I2(-), and furthermore that both the leading-order scalar relativistic and spin orbit corrections are of minor importance for the perpendicular component of the g tensor in these molecules since they effectively cancel each other. In addition to investigating the g tensors of dihalogen anion radicals, we also critically examine the importance of various relativistic corrections to the electronic g tensor of linear molecules with Sigma-type ground states and present a two-state model suitable for an approximate estimation of the g tensor in such molecules. PMID- 26620326 TI - Benzene Dimer: High-Level Wave Function and Density Functional Theory Calculations. AB - High-level OVOS (optimized virtual orbital space) CCSD(T) interaction energy calculations (up to the aug-cc-pVQZ basis set) and various extrapolations toward the complete basis set (CBS) limit are presented for the most important structures on the benzene dimer potential energy surface. The geometries of these structures were obtained via an all-coordinate gradient geometry optimization using the DFT-D/BLYP method, covering the empirical dispersion correction fitted exclusively for this system. The fit was carried out against two estimated CCSD(T)/CBS potential energy curves corresponding to the distance variation between two benzene rings for the parallel-displaced (PD) and T-shaped (T) structures. The effect of the connected quadruple excitations on the interaction energy was estimated using the CCSD(TQf) method in a 6-31G*(0.25) basis set, destabilizing the T and T-shaped tilted (TT) structures by ~0.02 kcal/mol and the PD structure by ~0.04 kcal/mol. Our best CCSD(T)/CBS results show, within the error bars of the applied methodology, that the energetically lowest-lying structure is the TT structure, which is nearly 0.1 kcal/mol more stable than the almost isoenergetic PD and T structures. The specifically parametrized DFT-D/BLYP method leads to a correct energy ordering of the structures, with the errors being smaller by 0.2 kcal/mol with respect to the most accurate CCSD(T) values. PMID- 26620327 TI - Benzene Dimer: Dynamic Structure and Thermodynamics Derived from On-the-Fly ab initio DFT-D Molecular Dynamic Simulations. AB - The dynamic nature of the benzene dimer was explored by on-the-fly molecular dynamics simulations based on the DFT-D method covering the dispersion energy. An all-electron DFT was performed at the BLYP/TZVP level. The parameters in the dispersion correction term were fitted to mimic the benchmark CCSD(T)/complete basis set limit potential energy curves for both the parallel-displaced (PD) and T-shaped (TS) structures of the dimer exactly. A dynamic description is important at temperatures above 10 K, where interconversion between the TS and PD structures is possible and a mixture of these two species exists. The higher the temperature, the more dominant the TS structure because of a favorable entropic contribution to the free energy. An analysis of the TS structures revealed that the symmetric c2v structure, a low-lying transition state, is practically not populated and that the tilted cs TS structure is prevalent. This finding is in perfect agreement with infrared spectroscopy. PMID- 26620328 TI - Chiral Aromaticities. A Topological Exploration of Mobius Homoaromaticity. AB - A series of C2-symmetric homoderivatives of the cyclo C9H9(+) cation first identified by Schleyer as Mobius aromatic are shown to themselves sustain Mobius 4n-pi-electron homoaromaticity. Analogous double-twist Mobius bis-homoaromatics follow a 4n+2 electron rule. AIM (atoms-in-molecules) and ELF (electron localization function) analysis of the electron topology in the region of the homobond of these systems reveals that the presence of a AIM bond-critical point in this region is not mandatory, it being unstable to subtle variations in the local electron density induced by local or remote substituents, and which can in turn induce self-annihilation or creation of a pair of bond and ring critical points. The same substituent-induced annihilation/creation of such a BCP/RCP pair can also be observed in the nonclassical norbornyl cation. We suggest that the ELF and ELFpi thresholds for any basin found in the homoregion are better indicators of the delocalized nature of the homoaromatic interaction and the aromaticity of the system. PMID- 26620329 TI - Exploring the Limit of Accuracy of the Global Hybrid Meta Density Functional for Main-Group Thermochemistry, Kinetics, and Noncovalent Interactions. AB - The hybrid meta density functionals M05-2X and M06-2X have been shown to provide broad accuracy for main group chemistry. In the present article we make the functional form more flexible and improve the self-interaction term in the correlation functional to improve its self-consistent-field convergence. We also explore the constraint of enforcing the exact forms of the exchange and correlation functionals through second order (SO) in the reduced density gradient. This yields two new functionals called M08-HX and M08-SO, with different exact constraints. The new functionals are optimized against 267 diverse main-group energetic data consisting of atomization energies, ionization potentials, electron affinities, proton affinities, dissociation energies, isomerization energies, barrier heights, noncovalent complexation energies, and atomic energies. Then the M08-HX, M08-SO, M05-2X, and M06-2X functionals and the popular B3LYP functional are tested against 250 data that were not part of the original training data for any of the functionals, in particular 164 main-group energetic data in 7 databases, 39 bond lengths, 38 vibrational frequencies, and 9 multiplicity-changing electronic transition energies. These tests include a variety of new challenges for complex systems, including large-molecule atomization energies, organic isomerization energies, interaction energies in uracil trimers, and bond distances in crowded molecules (in particular, cyclophanes). The M08-HX functional performs slightly better than M08-SO and M06 2X on average, significantly better than M05-2X, and much better than B3LYP for a combination of main-group thermochemistry, kinetics, noncovalent interactions, and electronic spectroscopy. More important than the slight improvement in accuracy afforded by M08-HX is the conformation that the optimization procedure works well for data outside the training set. Problems for which the accuracy is especially improved by the new M08-HX functional include large-molecule atomization energies, noncovalent interaction energies, conformational energies in aromatic peptides, barrier heights, multiplicity-changing excitation energies, and bond lengths in crowded molecules. PMID- 26620330 TI - Structures, Bonding, and One-Bond B-N and B-H Spin-Spin Coupling Constants for a Series of Neutral and Anionic Five-Membered Rings Containing BN Bonds. AB - The structures and bonding of a series of five-membered rings with BN bonds CxNyBzH5 (x + y + z = 5) and their most stable deprotonated anions CxNyBzH4(-) as well as anionic rings CxNyBzH5(-) have been investigated at the MP2/6-311++G(d,p) level of theory. The great majority of these rings present BN bond orders close to that found in borazine, suggesting that there is substantial electron delocalization in these rings. This observation is also supported by both NBO and ELF analyses. Ab initio equation-of-motion coupled-cluster singles and doubles (EOM-CCSD) calculations have also been performed to obtain the (15)N-(11)B and (1)H-(11)B spin-spin coupling constants. For neutral systems, the former range from -10 to -35 Hz, thereby bracketing the value of (1)J(B-N) for borazine, which is -29 Hz. (1)J(B-N) spans an even greater range in the anions, from -3 to -36 Hz. The absolute value of (1)J(B-N) decreases upon deprotonation if coupling involves the deprotonated nitrogen or a boron atom bonded to the deprotonated N. (1)J(B-H) always decreases upon nitrogen deprotonation. PMID- 26620331 TI - Thermochemistry of Hydrocarbons. Back to Extended Huckel Theory. AB - A modified Extended Huckel method that provides accurate values of heats of formation and structural parameters of hydrocarbons is described. The results are reported for an extensive set of molecules and radicals belonging to different classes. The calculated heats of formation for 120 molecules and 26 radicals are close to the experimental data with the mean absolute error of 1.90 kcal/mol. The internal consistency of the calculated data allows reliable prediction of the reaction enthalpy for various hydrocarbon transformations. The proposed scheme is computationally very efficient, and the calculation of a large system requires only a few seconds on a PC. A computer program for the calculation is provided in the Supporting Information . PMID- 26620332 TI - On the Pt(+) and Rh(+) Catalytic Activity in the Nitrous Oxide Reduction by Carbon Monoxide. AB - Nitrous oxide activation by CO in the presence of platinum and rhodium monocations was elucidated by density functional methods for ground and first excited states. Platinum and rhodium cations fulfill the thermodynamic request for the oxygen-atom transport that allows the catalytic cycle to be completed, but actually, just the first one meaningfully improves the kinetics of the process. For both catalysts, the reaction pathways show the only activation barrier in correspondence of nitrogen release and monoxide cation formation. The kinetic analysis of the potential energy profile, in agreement with ICP/SIFT MS experimental data, indicates that platinum performs more in the reduction, while the whole process is not sufficiently fast in the case of rhodium ionic catalyst. PMID- 26620333 TI - Toward a Coarse-Grained Protein Model Coupled with a Coarse-Grained Solvent Model: Solvation Free Energies of Amino Acid Side Chains. AB - Recently, we reported that molecular dynamics (MD) simulations using a coarse grained (CG) peptide model coupled with a CG water model are able to reproduce many of the structural and thermodynamic features of short peptides with nonpolar side chains at 10(3) times the normal speed (JCTC, 2007, 3, 2146-2161). To further develop a CG protein model for MD simulations, we systematically parametrized the side chains of all 20 naturally occurring amino acids. We developed the parameters by fitting the dihedral potentials of 13 small molecules, the densities and self-solvation free energies of liquids of eight organic molecules, and the hydration free energies of 35 small organic molecules. In a set of 11 classes of compounds (105 in total) including alkanes, alcohols, ethers, ketones/aldehydes, amines, amides, aromatics, carboxylic acids, sulfides/thiols, alkyl ammoniums, and carboxylate ions, the average error in the calculated hydration free energies compared with experimental results is about 1.4 kJ/mol. The average error in the calculated transfer free energies of the 19 side-chain analogues of amino acids from cyclohexane to water is about 2.2 kJ/mol. These results are comparable to the results of all-atom models. PMID- 26620334 TI - Ab Initio and Density Functional Theory Modeling of the Chiroptical Response of Glycine and Alanine in Solution Using Explicit Solvation and Molecular Dynamics. AB - We investigate ways in which simple point charge (SPC) water models can be used in place of more expensive quantum mechanical water molecules to efficiently model the solvent effect on a solute molecule's chiroptical responses. The effect that SPC waters have on the computed circular dichroism of a solvated glycine molecule are comparable to, albeit somewhat weaker than, that of quantum mechanical waters at the coupled cluster CC2 level of theory. The effects of SPC waters in fact correlate better with QM-CC2 waters than quantum mechanical waters computed with density functional theory (DFT) methods, since they do not promote spurious charge transfer excitations that are a known deficiency with most popular density functionals. Furthermore, the near zero order scaling of point charge waters allows multiple layers of explicit solvation to be modeled with negligible computational cost, which is not practical with CC2 or DFT levels. As a practical example, we model the molar rotations of glycine and alanine, and track their convergence. PMID- 26620335 TI - Multiscale Modeling of the Atomic Layer Deposition of HfO2 Thin Film Grown on Silicon: How to Deal with a Kinetic Monte Carlo Procedure. AB - An original integrated approach developed within a multiscale strategy, which combines first-principles quantum simulations and kinetic Monte Carlo (KMC), is presented to investigate the atomic layer deposition (ALD) of HfO2 on Si(100) surface. Density functional theory within the hybrid functional is used to determine the detailed physicochemical mechanisms and associated energetics of the two half cycles taking place during the initial stage of film growth. A kinetic Monte Carlo model is then proposed that deals with the stochastic nature of the calculated DFT mechanisms and barriers. Beyond the chemical information emanating from DFT calculations, the lattice-based KMC approach requires preliminary physical considerations issued from the crystal structures that the system is intended to adopt. This is especially critical in the case of heterogeneous systems like oxides deposited on silicon. We also describe (i) how atomistic configuration changes are performed as a result of local events consisting in elementary reaction mechanisms occurring on specific lattice sites, (ii) the temporal dynamics, governed by transition probabilities, calculated for every event from DFT activation barriers, and (iii) the relation of KMC with the ALD experimental procedure. Some preliminary validation results of the whole multiscale strategy are given for illustration and pertinence with regard of the technological main issues. PMID- 26620336 TI - Protein Folding Pathways Revealed by Essential Dynamics Sampling. AB - The characterization of the protein folding process represents one of the major challenges in molecular biology. Here, a method to simulate the folding process of a protein to its native state is reported, the essential dynamics sampling (EDS) method, and is successfully applied to detecting the correct folding pathways of two small proteins, the all-beta SH3 domain of Src tyrosine kinase transforming protein (SH3) and the alpha/beta B1 domain of streptococcal protein G (GB1). The main idea of the method is that a subset of the natural modes of fluctuation in the native state is key in directing the folding process. A biased molecular dynamics simulation is performed, in which the restrained degrees of freedom are chosen among those obtained by a principal component, or essential dynamics, analysis of the positional fluctuations of the Calpha atoms in the native state. Successful folding is obtained if the restraints are applied only to the eigenvectors with lowest eigenvalues, representing the most rigid quasi constraint motions. If the essential eigenvectors, the ones accounting for most of the variance, are used, folding is not successful. These results clearly show that the eigenvectors with lowest eigenvalues contain the main mechanical information necessary to drive the folding process, while the essential eigenvectors represent the large concerted motions which can occur without folding/unfolding the protein. PMID- 26620337 TI - Direct Comparison of Experimental and Calculated NMR Scalar Coupling Constants for Force Field Validation and Adaptation. AB - The ability to measure scalar coupling constants across hydrogen bonds ((3h)JNC') from high-resolution NMR experiments allows the characterization of detailed structural properties of biomolecules. To analyze those, a parametrized model based on the linear combination of atomic orbitals relates H-bond geometries with the measured (3h)JNC' coupling magnitude. In the present study the dependence of calculated (3h)JNC' coupling constants on force field parameters is assessed. It is shown that increased polarity of the hydrogen bond improves the calculated (3h)JNC' coupling constants and shifts the conformational ensemble sampled from the molecular dynamics (MD) simulations toward the experimentally measured one. Increased charges lead to more narrow distance and angle distributions and improve the agreement between calculated and measured (3h)JNC' couplings. However, different secondary structures are better represented by different magnitudes of electrostatic interactions-different atomic partial charges in the present work-as indicated by root-mean square deviations (rsmds) between observed and calculated coupling constants (3h)JNC'. The parametrization of the empirical formula is found to be meaningful and robust, but the parameter values are not universal across different proteins and different secondary structural elements (alpha-helices, beta-sheets and loops). Using standard and slightly increased CHARMM charges, predictions for the as-yet unknown scalar coupling constants for the V54A and I6A mutants of protein G are made. PMID- 26620338 TI - Geometrical Preferences of the Hydrogen Bonds on Protein-Ligand Binding Interface Derived from Statistical Surveys and Quantum Mechanics Calculations. AB - We have conducted potential of mean force (PMF) analyses to derive the geometrical parameters of various types of hydrogen bonds on protein-ligand binding interface. Our PMF analyses are based on a set of 4535 high-quality protein-ligand complex structures, which are compiled through a systematic mining of the entire Protein Data Bank. Hydrogen bond donor and acceptor atoms are classified into several basic types. Both distance- and angle-dependent statistical potentials are derived for each donor-acceptor pair, from which distance and angle cutoffs are obtained in an objective, unambiguous manner. These donor-acceptor pairs are also studied by quantum mechanics (QM) calculations at the MP2/6-311++G** level on model molecules. Comparison of the outcomes of PMF analyses and QM calculations suggests that QM calculation may serve as an alternative approach for characterizing hydrogen bond geometry. Both of our PMF analyses and QM calculations indicate that C-H...O hydrogen bonds are relatively weak as compared to common hydrogen bonds formed between nitrogen and oxygen atoms. A survey on the protein-ligand complex structures in our data set has revealed that Calpha-H...O hydrogen bonds observed in protein-ligand binding are frequently accompanied by bifurcate N-H...O hydrogen bonds. Thus, the Calpha H...O hydrogen bonds in such cases would better be interpreted as secondary interactions. PMID- 26620339 TI - Theoretical and Crystallographic Study of the Dual sigma/pi Anion Binding Affinity of Quinolizinylium Cation. AB - Benzoquinolizinylium salts are important compounds in the regulation of transmembrane conductance regulator channels. In this manuscript, the geometrical position (sigma/pi) of the counteranion in quinolizinylium salts has been studied by means of ab initio calculations at the RI-MP2(full)/6-31++G** level of theory. A search in the Cambridge Structural Database determines that the position of the anion depends upon its nature. Halogen anions prefer anion-sigma interactions, and BF4(-) and PF6(-) anions prefer anion-pi interactions. The dual sigma/pi binding affinity of title compound has been studied by means of ab initio and molecular interaction potential with polarization (MIPp) calculations and the Bader's theory of "atoms-in-molecules". PMID- 26620340 TI - CHARMM Additive All-Atom Force Field for Acyclic Carbohydrates and Inositol. PMID- 26620341 TI - Association between the V Leiden G1691A mutation and sudden sensorineural hearing loss in Italian population: a meta-analysis. AB - Epidemiological studies have reported inconsistent findings on the association between the V Leiden G1691A mutation and sudden sensorineural hearing loss (SSNHL) in Italian population. The aim of this meta-analysis was to clarify this association. PubMed, Embase, and the China National Knowledge Infrastructure (CNKI) were searched up to April 1, 2015. We used STATA12.0 to calculate summary odds ratios (ORs) with 95 % confidence intervals (CIs). Four studies including 958 patients were identified. Pooled data showed no significant association between V Leiden G1691A mutation and risk of SSNHL in Italian population: A vs. G (OR = 1.660, 95 % CI 0.428-6.446, P OR = 0.464) and AG vs. GG (OR = 1.680, 95 % CI 0.422-6.688, P OR = 0.462). The present meta-analysis suggests that V Leiden G1691A mutation is not significantly associated with increased risk of SSNHL disease in Italian population. Further large and well-designed studies are needed to confirm this association. PMID- 26620342 TI - Mitochondrial DNA deletions in patients with chronic suppurative otitis media. AB - The aim of this study was to investigate the 4977 and 7400 bp deletions of mitochondrial DNA in patients with chronic suppurative otitis media and to indicate the possible association of mitochondrial DNA deletions with chronic suppurative otitis media. Thirty-six patients with chronic suppurative otitis media were randomly selected to assess the mitochondrial DNA deletions. Tympanomastoidectomy was applied for the treatment of chronic suppurative otitis media, and the curettage materials including middle ear tissues were collected. The 4977 and 7400 bp deletion regions and two control regions of mitochondrial DNA were assessed by using the four pair primers. DNA was extracted from middle ear tissues and peripheral blood samples of the patients, and then polymerase chain reactions (PCRs) were performed. PCR products were separated in 2 % agarose gel. Seventeen of 36 patients had the heterozygote 4977 bp deletion in the middle ear tissue but not in peripheral blood. There wasn't any patient who had the 7400 bp deletion in mtDNA of their middle ear tissue or peripheral blood tissue. The patients with the 4977 bp deletion had a longer duration of chronic suppurative otitis media and a higher level of hearing loss than the others (p < 0.01). Long time chronic suppurative otitis media and the reactive oxygen species can cause the mitochondrial DNA deletions and this may be a predisposing factor to sensorineural hearing loss in chronic suppurative otitis media. An antioxidant drug as a scavenger agent may be used in long-term chronic suppurative otitis media. PMID- 26620344 TI - Medically-attended respiratory illnesses amongst pregnant women in Brisbane, Australia. AB - There are limited community-based data on the burden of influenza and influenza like illnesses during pregnancy to inform disease surveillance and control. We aimed to determine the incidence of medically-attended respiratory illnesses (MARI) in pregnant women and the proportion of women who are tested for respiratory pathogens at these visits. We conducted a nested retrospective cohort study of a non-random sample of women aged 18 years or over who had a live birth in maternity units in Brisbane, Queensland, from March 2012 to October 2014. The primary outcomes were self-reported doctor visits for MARI and laboratory investigations for respiratory pathogens. Descriptive analyses were performed. Among 1,202 participants, 222 (18.5%, 95%CI 16.3%-20.7%) self-reported MARI during their pregnancy. Of those with an MARI, 20.3% (45/222) self-reported a laboratory test was performed. We were able to confirm with health service providers that 46.7% (21/45) of tests were undertaken, responses from providers were not received for the remainder. Whilst one in 5 women in this population reported a MARI in pregnancy, only 3.7% (45/1,202) reported a clinical specimen had been arranged at the consultation and the ability to validate that self report was problematic. As the focus on maternal immunisation increases, ascertainment of the aetiological agent causing MARI in this population will be required and efficient and reliable methods for obtaining these data at the community level need to be established. PMID- 26620343 TI - Effect of Age and Refractive Error on the Melanopsin Mediated Post-Illumination Pupil Response (PIPR). AB - Melanopsin containing intrinsically photosensitive Retinal Ganglion cells (ipRGCs) mediate the pupil light reflex (PLR) during light onset and at light offset (the post-illumination pupil response, PIPR). Recent evidence shows that the PLR and PIPR can provide non-invasive, objective markers of age-related retinal and optic nerve disease; however there is no consensus on the effects of healthy ageing or refractive error on the ipRGC mediated pupil function. Here we isolated melanopsin contributions to the pupil control pathway in 59 human participants with no ocular pathology across a range of ages and refractive errors. We show that there is no effect of age or refractive error on ipRGC inputs to the human pupil control pathway. The stability of the ipRGC mediated pupil response across the human lifespan provides a functional correlate of their robustness observed during ageing in rodent models. PMID- 26620345 TI - Notification and management of congenital syphilis in the Northern Territory 2009 to 2014. AB - OBJECTIVE: To determine whether cases of congenital syphilis in the Northern Territory between 2009 and 2014 were correctly notified based on probable or confirmed case criteria stipulated by the Communicable Diseases Network Australia (CDNA). METHODS: Pregnant women with positive syphilis serology defined as reactive treponemal test and rapid plasma reagin titre >=1:8 were identified from the Northern Territory Syphilis Register Information System. Risk classification was performed based on local guidelines, and CDNA criteria for probable/confirmed cases of congenital syphilis were applied to determine whether cases were appropriately notified. RESULTS: Thirty-four cases of positive maternal syphilis serology in pregnancy were identified from 31 women; all were Indigenous. Twenty one cases fulfilled criteria for probable congenital syphilis; 1 case was formally notified to the Centre for Disease Control. Twenty cases (95%) fulfilling CDNA criteria for probable congenital syphilis were not notified over the study period. CONCLUSIONS: Application of standard case definitions significantly increases the rate of congenital syphilis cases in the Northern Territory. Improved education regarding CDNA criteria for notification of congenital syphilis is necessary for clinicians and public health staff. Emerging evidence has supported the recent simplification of CDNA criteria for notification of congenital syphilis, effective 1 July 2015. PMID- 26620346 TI - Pertussis immunisation in pregnancy: a summary of funded Australian state and territory programs. AB - The Australian Immunisation Handbook, 10th edition now recommends pertussis vaccination during pregnancy as the preferred option for protecting vulnerable young infants. Jurisdictionally funded pertussis immunisation programs for pregnant women have been progressively introduced in all Australian states and territories between August 2014 and June 2015. A meeting convened by the National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases was held on 31 May 2015 to share information regarding jurisdictional policies and program implementation. This report of that meeting provides the first published comparison of these jurisdictional programs, which are of a broadly similar nature but with important differences. Monitoring and evaluation of the uptake, safety and impact of the current programs in Australia will be important to inform future policy decisions. PMID- 26620347 TI - Australian Rotavirus Surveillance Program annual report, 2014. AB - The Australian Rotavirus Surveillance Program, together with collaborating laboratories Australia-wide, reports the rotavirus genotypes responsible for the hospitalisation of children with acute gastroenteritis. During the survey period of 1 January to 31 December 2014, 1,022 faecal samples were referred for rotavirus G and P genotype analysis, and of these 733 were confirmed as rotavirus positive. A total of 480 specimens were collected from children under 5 years of age, while 253 were from older children and adults. Genotype analysis of the 733 rotavirus samples collected from both children and adults revealed that G12P[8] was the dominant genotype in this reporting period, identified in 29.6% of strains nationally. Genotype G1P[8] was the 2nd most common strain nationally, representing 22.9% of samples, followed by genotype G3P[8] (14.9%). This report highlights the continued significance of G12P[8] strains as the major cause of disease in this population. The genotype distribution was slightly altered when the analysis was restricted to samples collected from children under 5 years of age, with G1P[8] being the dominant genotype (29%) followed by G12P[8] as the 2nd most common genotype (26%). Fluctuations in genotype distribution were also observed based on the vaccine type in use. Genotype G12P[8] was more common in states and territories using RotaTeq, while G1P[8] was more common in the locations using Rotarix. This survey highlights the yearly fluctuations in rotavirus genotypes observed since vaccine introduction. The continuation of G12P[8] as the dominant genotype further illustrates the dynamic and diversity present in the wild-type rotavirus population evident in the Australian population since vaccine introduction. PMID- 26620348 TI - Australian Gonococcal Surveillance Programme annual report, 2014. AB - The Australian Gonococcal Surveillance Programme (AGSP) has continuously monitored antimicrobial resistance in clinical isolates of Neisseria gonorrhoeae from all states and territories since 1981. In 2014, 4,804 clinical isolates of gonococci from public and private sector sources were tested for in vitro antimicrobial susceptibility by standardised methods. Decreased susceptibility to ceftriaxone (MIC value 0.06-0.125 mg/L) was found nationally in 5.4% of isolates, a lower proportion than that reported in the AGSP 2013 annual report (8.8%). The highest proportions were reported from New South Wales and Victoria (7.1% and 6.6% respectively). The proportion of strains resistant to penicillin in urban and rural Australia ranged from 11% in South Australia to 43% in New South Wales. In rural and remote Northern Territory penicillin resistance rates remained low (1.5%). In remote Western Australia relatively low numbers of strains are available for testing, however there is now widespread molecular testing for penicillin resistance in Western Australia to monitor resistance and inform guidelines and, for first time, these data are included in the AGSP annual report. Quinolone resistance ranged from 27% in the urban and rural areas of the Northern Territory, to 44% in the Australian Capital Territory, and quinolone resistance rates remain comparatively low in remote areas of the Northern Territory (3.1%) and remote areas of Western Australia (5.6%). Azithromycin resistance ranged from 0.5% in South Australia to 5.3% in rural and urban Western Australia. High rates were also reported from the Australian Capital Territory but relatively low numbers were tested. High level resistance to azithromycin (MIC value >=256 mg/L) was again reported in 2014, in 2 strains from New South Wales. No resistance was reported from the Northern Territory, or remote Western Australia. PMID- 26620349 TI - Influenza epidemiology in adults admitted to sentinel Australian hospitals in 2014: the Influenza Complications Alert Network (FluCAN). AB - The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance program that operates at sites in all states and territories in Australia. This report summarises the epidemiology of hospitalisations with laboratory-confirmed influenza during the 2014 influenza season. In this observational study, cases were defined as patients admitted to one of the sentinel hospitals with an acute respiratory illness with influenza confirmed by nucleic acid detection. During the period 3 April to 31 October 2014 (the 2014 influenza season), 1,692 adult patients (>16 years) were admitted with confirmed influenza to one of 15 of 17 FluCAN sentinel hospitals (excluding 2 paediatric hospitals). Of these, 47% were over 65 years of age, 10% were Indigenous Australians, 3.3% were pregnant and 85% had chronic co-morbidities. The majority of cases were due to influenza A. Influenza B was detected in 7% of patients. There were a large number of hospital admissions detected with confirmed influenza in this national observational surveillance system in 2014. These are estimated to represent a national annual burden of around 15,000 admissions and almost 100,000 bed-days nationally. PMID- 26620350 TI - Flutracking weekly online community survey of influenza-like illness: 2013 and 2014. AB - Flutracking is a national online community influenza-like illness (ILI) surveillance system that monitors weekly ILI activity and field vaccine effectiveness. This article reports on the 2013 and 2014 findings from Flutracking. From 2013 to 2014 there was a 14.0% increase in participants who completed at least 1 survey to 21,021 participants. By the end of the 2013 and 2014 seasons, respectively 59.7% and 59.1% of all participants had received the seasonal influenza vaccine. The 2013 Flutracking national ILI weekly incidence peaked in late August at 4.3% in the unvaccinated group, 1 week earlier than national counts of laboratory confirmed influenza. The 2014 Flutracking national ILI weekly incidence also peaked in late August at 4.7% in the unvaccinated group, in the same week as national counts of laboratory confirmed influenza. A lower percentage of Flutracking participants took two or more days off from work or normal duties in 2013 (peak level 1.6%) compared with 2014 (peak level 2.5%) and sought health advice in 2013 (peak level of 1.1%) compared with 2014 (peak of 1.6%). Flutracking ILI surveillance suggests that 2014 was a moderately more intense season than 2013 and similar to 2012. PMID- 26620351 TI - Surveillance of adverse events following immunisation in Australia annual report, 2013. AB - This report summarises Australian passive surveillance data for adverse events following immunisation (AEFI) for 2013 reported to the Therapeutic Goods Administration (TGA) for 2013 and describes reporting trends over the 14-year period 1 January 2000 to 31 December 2013. There were 3,161 AEFI records for vaccines administered in 2013. This is an annual AEFI reporting rate of 13.9 per 100,000 population, the 2nd highest since 2000 and an increase of 59% compared with 2012 (1,994 AEFI records; 8.8 per 100,000 population). The increase was partly due to implementation of enhancements to vaccine safety reporting. This included stimulated reporting of AEFI as part of the extension of national human papillomavirus (HPV) vaccination under the National Immunisation Program to males aged 12-13 years, along with a catch-up program for males aged 14 and 15 years in February 2013 (n=785; includes males and females), in which certain events, such as syncope, were closely monitored. Eighty-two per cent (n=341/414) of the syncope reports were following HPV vaccination and of these 57% (n=195) were males and 43% (n=146) were females. In addition, reporting rates for most other the vaccines were higher in 2013 compared with 2012. The majority of AEFI reports described non-serious events while 5% (n=158) were classified as serious. There were 4 reports of death; however, all deaths were investigated by the TGA and no clear causal relationship with vaccination was found. The most commonly reported reactions were injection site reaction (13%), rash (10%), pyrexia (8%), and syncope (7%). PMID- 26620352 TI - Australia's notifiable disease status, 2013: Annual report of the National Notifiable Diseases Surveillance System. AB - In 2013, 65 diseases and conditions were nationally notifiable in Australia. States and territories reported a total of 224,434 notifications of communicable diseases to the National Notifiable Diseases Surveillance System, a decrease of 8% on the number of notifications in 2012. In 2013, the most frequently notified diseases were sexually transmissible infections (100,949 notifications, 45% of total notifications), vaccine preventable diseases (59,630 notifications, 26.6% of total notifications), and gastrointestinal diseases (32,536 notifications, 14.5% of total notifications). There were 17,919 notifications of bloodborne diseases; 10,831 notifications of vectorborne diseases; 1,932 notifications of other bacterial infections; 634 notifications of zoonoses and 3 notifications of quarantinable diseases. PMID- 26620353 TI - OzFoodNet quarterly report, 1 October to 31 December 2013. PMID- 26620354 TI - National Notifiable Diseases Surveillance System, 1 April to 30 June 2015. PMID- 26620355 TI - Australian childhood immunisation coverage, assessed as at 31 March 2015. PMID- 26620356 TI - Australian Meningococcal Surveillance Programme quarterly report, 1 April to 30 June 2015. PMID- 26620357 TI - Australian Sentinel Practices Research Network, 1 April to 30 June 2015. PMID- 26620358 TI - Invasive pneumococcal disease surveillance Australia, 1 April to 30 June 2015. PMID- 26620359 TI - Psychometric Properties of the Catastrophic Cognitions Questionnaire-Modified (CCQ-Modified) Among Community Samples in Malaysia. AB - The Catastrophic Cognitions Questionnaire-Modified (CCQ-M) is a common instrument for measuring catastrophic thoughts. In some countries, however, CCQ-M still poses concerns following the lack of appropriate validation among their populations. The current study aimed to examine the factor structure of the CCQ M, the reliability, and the validity in community samples in Malaysia. The Malay version of CCQ-M and additional measures assessing the symptoms and cognitions relevant to anxiety disorders were completed by 682 university students and general community. Exploratory factor analysis revealed a two-factor structure accounting for 62.2% of the total variance. Confirmatory factor analysis confirmed the two-factor model by deleting four items. The Cronbach's alpha coefficients for the total and the two subscales were .94, .90, and .92, respectively. Test-retest reliability analysis was conducted on 82 university students in the interval period of 14 days, and the result was r = .58. Evidence supported the concurrent, convergent, and discriminant validity. In conclusion, the 17-item CCQ-M-Malaysia is a valid and reliable instrument for assessing catastrophic cognitions among Malaysian populations. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26620360 TI - Disparity of basal and therapeutically activated interferon signalling in constraining hepatitis E virus infection. AB - Hepatitis E virus (HEV) represents one of the foremost causes of acute hepatitis globally. Although there is no proven medication for hepatitis E, pegylated interferon-alpha (IFN-alpha) has been used as off-label drug for treating HEV. However, the efficacy and molecular mechanisms of how IFN signalling interacts with HEV remain undefined. As IFN-alpha has been approved for treating chronic hepatitis C (HCV) for decades and the role of interferon signalling has been well studied in HCV infection, this study aimed to comprehensively investigate virus host interactions in HEV infection with focusing on the IFN signalling, in comparison with HCV infection. A comprehensive screen of human cytokines and chemokines revealed that IFN-alpha was the sole humoral factor inhibiting HEV replication. IFN-alpha treatment exerted a rapid and potent antiviral activity against HCV, whereas it had moderate and delayed anti-HEV effects in vitro and in patients. Surprisingly, blocking the basal IFN pathway by inhibiting JAK1 to phosphorylate STAT1 has resulted in drastic facilitation of HEV, but not HCV infection. Gene silencing of the key components of JAK-STAT cascade of the IFN signalling, including JAK1, STAT1 and interferon regulatory factor 9 (IRF9), stimulated HEV infection. In conclusion, compared to HCV, HEV is less sensitive to IFN treatment. In contrast, the basal IFN cascade could effectively restrict HEV infection. This bears significant implications in management of HEV patients and future therapeutic development. PMID- 26620361 TI - Efficient induction of cross-presentating human B cell by transduction with human adenovirus type 7 vector. AB - Although human autologous B cells represent a promising alternative to dendritic cells (DCs) for easy large-scale preparation, the naive human B cells are always poor at antigen presentation. The safe and effective usage record of human adenovirus type 7 (HAdV7) live vaccines makes it attractive as a promising vaccine vector candidate. To investigate whether HAdV7 vector could be used to induce the human B cells cross-presentation, in the present study, we constructed the E3-defective recombinant HAdV7 vector encoding green fluorescent protein (GFP) and carcinoembryonic antigen (CEA). We demonstrated that naive human B cells can efficiently be transduced, and that the MAPKs/NF-kappaB pathway can be activated by recombinant HAdV7. We proved that cytokine TNF-alpha, IL-6 and IL 10, surface molecule MHC class I and the CD86, antigen-processing machinery (APM) compounds ERp57, TAP-1, and TAP-2. were upregulated in HAdV7 transduced human B cells. We also found that CEA-specific IFNgamma expression, degranulation, and in vitro and ex vivo cytotoxicities are induced in autologous CD8(+) T cells presensitized by HAd7CEA modified human B cells. Meanwhile, our evidences clearly show that Toll-like receptors 9 (TLR9) antagonist IRS 869 significantly eliminated most of the HAdV7 initiated B cell activation and CD8(+) T cells response, supporting the role and contribution of TLR9 signaling in HAdV7 induced human B cell cross-presentation. Besides a better understanding of the interactions between recombinant HAdV7 and human naive B cells, to our knowledge, the present study provides the first evidence to support the use of HAdV7 modified B cells as a vehicle for vaccines and immunotherapy. PMID- 26620362 TI - Overlooked hematological markers of disease activity in rheumatoid arthritis. AB - AIM: The aim of this study was to investigate the relationship between hematological markers and disease activity in patients with rheumatoid arthritis (RA). METHOD: The study was designed and performed in the Department of Rheumatology of the Sakarya University Faculty of Medicine. In total, 102 patients with RA were retrospectively enrolled. We used the Disease Activity Score of 28 joints (DAS28) instrument to evaluate disease activity. Laboratory assessments included complete blood cell counts, measurement of erythrocyte sedimentation rate (ESR) and assessment of C-reactive protein (CRP) level. Exclusion criteria included active infection and/or the presence of any hematological, cardiovascular or metabolic disorder. RESULTS: We found that the neutrophil lymphocyte ratio (NLR) and mean platelet volume (MPV) varied by disease activity status. NLR values correlated positively with the DAS28 scores of RA patients. Especially, higher NLR values (3.92 +/- 0.31) were evident in the group exhibiting high-level disease activity, whereas the MPV values were lowest (7.11 +/- 0.91 fL) in this group. Additionally, no significant difference was evident between DAS28 scores and platelet distribution width (PDW) values in patients with RA (r = -0.055, P = 0.124). CONCLUSIONS: We found that the MPV value may serve as a marker of the absence of acute-phase disease, and the NLR level as a marker of the presence of such disease, in patients with RA. More detailed analysis of disease activity is required to further explain the associations of the markers described above with disease activity. PMID- 26620363 TI - Investigating the factorial structure and availability of work time control in a representative sample of the Swedish working population. AB - AIMS: Past research has often neglected the sub-dimensions of work time control (WTC). Moreover, differences in levels of WTC with respect to work and demographic characteristics have not yet been examined in a representative sample. We investigated these matters in a recent sample of the Swedish working population. METHODS: The study was based on the 2014 data collection of the Swedish Longitudinal Occupational Survey of Health. We assessed the structure of the WTC measure using exploratory and confirmatory factor analysis. Differences in WTC by work and demographic characteristics were examined with independent samplet-tests, one-way ANOVAs and gender-stratified logistic regressions. RESULTS: Best model fit was found for a two-factor structure that distinguished between control over daily hours and control over time off (root mean square error of approximation = 0.06; 95% CI 0.04 to 0.09; Comparative Fit Index (CFI) = 0.99). Women, shift and public-sector workers reported lower control in relation to both factors. Age showed small associations with WTC, while a stronger link was suggested for civil status and family situation. Night, roster and rotating shift work seemed to be the most influential factors on reporting low control over daily hours and time off. CONCLUSIONS: Our data confirm the two-dimensional structure underlying WTC, namely the components 'control over daily hours' and 'control over time off'. Women, public-sector and shift workers reported lower levels of control. Future research should examine the public health implications of WTC, in particular whether increased control over daily hours and time off can reduce health problems associated with difficult working-time arrangements. PMID- 26620364 TI - Co-occurrence of substance use related and mental health problems in the Finnish social and health care system. AB - AIM: Many studies have noted that substance abuse and mental health problems often occur simultaneously. The aim of the work reported here was to study the co occurrence of mental health problems and problems related to substance use in a sample of clients visiting the Finnish social and health care services for issues related to substance use. We collected background information on the clients and considered the parts of the treatment system in which these clients were treated. DATA AND METHODS: Survey data on intoxicant-related cases in the Finnish health care and social services were gathered on a single day in 2011. During the 24 hours of data collection, all intoxicant-related cases were reported and data were obtained for 11,738 intoxicant-related cases. In this analysis we took into account the clients' background variables, mental health variables, information on the treatment type and the main reasons for the client being in treatment. The chi(2) test, Fisher's exact test and binary logistic regression analysis were used. RESULTS: Half of the visiting clients had both substance use related and mental health problems. The strongest factors associated with the co-occurrence of substance use related and mental health problems were female sex, younger age and single marital status. Clients with co-occurring problems were more often treated in the health care services, whereas clients with only substance use related problems were primarily treated in specialized services for the treatment of substance abuse. CONCLUSIONS: It is important to identify clients with co occurring substance use related and mental health problems. In this study, half of the clients presenting to the Finnish social and health care treatment system had both these problems. PMID- 26620365 TI - [Anaplastic large-cell lymphoma CD30(+) ALK(+)]. AB - We present a case of primary systemic anaplastic large-cell lymphoma, which manifested itself through skin involvement in a 32-year-old man. Only the third histological investigation with immunophenotyping resulted in the correct diagnosis of CD30(+) ALK(+) anaplastic large cell lymphoma. After combined chemotherapy and adjuvant radiotherapy, complete remission of the disease was achieved and one year after completion of therapy no relapse occurred. The diagnostic pitfalls and therapeutic options are discussed. PMID- 26620366 TI - Talimogene Laherparepvec: First Global Approval. AB - Talimogene laherparepvec (ImlygicTM) is an oncolytic viral therapy that is being developed by BioVex (a subsidiary of Amgen) for the intralesional treatment of various cancers, including malignant melanoma. Talimogene laherparepvec is a genetically modified, live, attenuated, herpes simplex virus type 1 that is designed to promote an antitumour response through selective viral replication in tumour cells and stimulation of systemic antitumour immunity. In October 2015, talimogene laherparepvec was the first genetically modified, oncolytic viral therapy to be approved in the USA for the local treatment of unresectable cutaneous, subcutaneous and nodal lesions in patients with melanoma recurrent after initial surgery, although it has not been shown to improve overall survival or have an effect on visceral metastases. Talimogene laherparepvec has been recommended for approval in adults with unresectable metastatic melanoma in the EU, and is being evaluated in several countries for use as neoadjuvant or combination therapy in malignant melanoma; it is also in development for soft tissue sarcoma and liver cancer in the USA. This article summarizes the milestones in the development of talimogene laherparepvec leading to this first approval in malignant melanoma. PMID- 26620368 TI - Quality-of-Life Analysis of the German Prospective Multicentre Trial of Single cycle Adjuvant BEP Versus Retroperitoneal Lymph Node Dissection in Clinical Stage I Nonseminomatous Germ Cell Tumours. AB - BACKGROUND: The superiority of one course of bleomycin, etoposide, and cisplatin (BEP) over retroperitoneal lymph node dissection (RPLND) as adjuvant treatment in patients with clinical stage I nonseminomatous germ cell tumours (CSI-NSGCT) in terms of recurrence has been shown. However, studies providing validated prospective quality-of-life (QoL) data in patients with CSI-NSGCT treated with only one cycle of BEP are lacking. OBJECTIVE: To examine and compare QoL issues in patients with CSI-NSGCT after adjuvant treatment. DESIGN, SETTING, AND PARTICIPANTS: Between 1996 and 2005, we randomly assigned a total of 382 patients with CSI-NSGCT to receive either one course of BEP or RPLND after orchiectomy. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) plus additional scales questionnaire (QLQ-C30+) was completed prospectively according to an a priori schedule, with a final assessment in 2011. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used the Mann-Whitney U test to detect a difference >=17% on the global QoL item "overall strain." RESULTS AND LIMITATIONS: Of 382 patients randomised to receive either one course of BEP (n=191, arm A) or RPLND (n=191, arm B), completed QLQ-C30+ and data on treatment response were available in 162 and 164 patients, respectively. All participants were included for intention-to-treat analysis. We evaluated treatment-related changes in QoL for the follow-up period up to 3 yr after treatment. We observed no significant differences between the treatment groups in any QoL domain except alopecia. Compared to QoL assessments in the general population, both arms had already recovered to normal values in all items by 6 mo. CONCLUSIONS: The QoL assessment of this large randomised trial was not able to detect significant differences in QoL scores between patients undergoing RPLND and BEP in a community-based setting. PATIENT SUMMARY: Retroperitoneal lymph node dissection and bleomycin, etoposide, and cisplatin are two adjuvant treatment options for patients with CSI-NSGCT after orchiectomy. Quality of life had already recovered to normal levels in both groups by 6 mo after treatment. No clinically relevant differences were detected. PMID- 26620369 TI - Peer Support Providers' Role Experiences on Interprofessional Mental Health Care Teams: A Qualitative Study. AB - This study explores how peer support providers' roles are defined and integrated in inter-professional mental health care teams, and how these providers relate to other practitioners and clients. Interviews were conducted with peer support providers in two different formal models of peer support employment. Qualitative data analysis was undertaken. The findings indicate that: peer support providers experience ambiguity and that some ambiguity may offer benefits; peer support providers enhance team acceptance of their role through several means and strategies; setting boundaries with clients is a delicate issue that requires several considerations that we discuss. PMID- 26620367 TI - Targeted Therapies for Advanced Oesophagogastric Cancer: Recent Progress and Future Directions. AB - The genomic landscape of oesophagogastric (OG) cancer is highly complex. The recent elucidation of some of the pathways involved has suggested a number of novel targets for therapy. This therapy is urgently required as with conventional chemotherapy regimens patients with advanced OG cancer still have a median overall survival of under a year. This review outlines the rationale for the current treatment of OG cancer with chemotherapy and describes both previously conducted and ongoing clinical trials of novel agents in this area. The targets and associated treatments discussed include HER-2, EGFR, VEGF, c-Met, FGFR-2, PI3K, mTOR andIGF-1. To date only two targeted treatments, trastuzumab and ramucirumab, have become part of the treatment paradigm for OG cancer, partly due to difficulties in defining predictive biomarkers in this disease. However, there are a number of promising drugs in the pipeline and this article seeks to describe these and other potential novel approaches including targeting DNA repair deficiencies and the immune system. PMID- 26620370 TI - Enhancement of Dissolution Rate and Intestinal Stability of Clopidogrel Hydrogen Sulfate. AB - BACKGROUND AND OBJECTIVES: Clopidogrel is an antiplatelet and antithrombotic prodrug. It has poor oral bioavailability due to poor dissolution and possible premature degradation in the intestine. Accordingly, the objective of this study was to enhance clopidogrel dissolution rate and to reduce its premature degradation in rabbit intestine. METHODS: Solid dispersion (SD) systems of clopidogrel with gelucire 50/13 and/or cremophor RH40 were prepared using fusion technique. The SD systems were characterized with respect to drug dissolution. The characterization included thermal analysis and infrared investigations. The stability of clopidogrel in the fluid extracted from small intestinal and colonic mucosal surfaces was monitored both in absence and presence of cremophor or gelucire. RESULTS: SD formation enhanced drug dissolution with the enhancement increasing at higher concentrations of either cremophor or gelucire. The ternary SD of clopidogrel with cremophor and gelucire reflected synergism between them. This synergism was manifested by enhanced dissolution efficiency of drug to reach 85 % at pH 6.8 and 89 % at pH 7.4 compared to unprocessed drug which liberated 16.2 and 15.2 % at the same pH values, respectively. Enhanced dissolution from SD was mainly due to micellar solubilization for cremophor and was due to change in the crystalline nature of drug with a contribution to self-emulsification in case of gelucire. Clopidogrel showed premature degradation in the intestinal fluid. Cremophor RH 40 reduced this degradation but gelucire failed in this respect. CONCLUSION: The study introduced SD system for enhanced dissolution rate of clopidogrel with a potential of reduced premature degradation in the intestine. PMID- 26620371 TI - A crucial role for ATR in the regulation of deoxycytidine kinase activity. AB - Deoxycytidine kinase (dCK) (EC 2.7.1.74) is a key enzyme for salvage of deoxynucleosides and activation of numerous anticancer and antiviral nucleoside analogs. dCK activity is enhanced in response to several genotoxic treatments, which has been correlated with an increase of dCK phosphorylation at Ser-74. ATM was recently identified as the kinase responsible for Ser-74 phosphorylation and dCK activation after ionizing radiation (IR). Here, we investigated the role of ATM and the related kinase ATR in dCK activation induced by other types of DNA damage. Using ATM-deficient cells or the ATM inhibitor KU-60019, we found that ATM was not required for dCK activation caused by UV light, aphidicolin, cladribine, and unexpectedly also IR. On the other hand, the selective ATR inhibitor VE-821 significantly reduced up-regulation of dCK activity induced by these genotoxic agents, though not IR, and also down-regulated basal dCK activity. A role for ATR in the control of dCK activity was confirmed by using ATR siRNA and ATR-Seckel cells. ATR was also found to directly phosphorylate dCK at Ser-74 in vitro. Further studies revealed that ATR, which is also activated in response to IR, although later than ATM, was responsible for IR-induced dCK activation in ATM-deficient cells or in the presence of KU-60019. Overall, our results demonstrate that ATR controls basal dCK activity and dCK activation in response to replication stress and indicate that ATR can activate dCK after IR if ATM is lacking or inhibited. PMID- 26620372 TI - Neutrophilic dermatoses and autoinflammatory diseases with skin involvement- innate immune disorders. AB - Neutrophilic dermatoses (NDs) such as Sweet's syndrome and pyoderma gangrenosum were first described more than 50 years ago and grouped based on their clinical features combined with the typical, neutrophil-rich cutaneous inflammation. In contrast, the recently identified autoinflammatory diseases (ADs) that are also associated with neutrophil granulocyte infiltration of the skin were first characterized based on their genetic architecture. Though both the older ND and the newer AD encompass distinct conditions, they can be seen as parts of a spectrum of innate inflammation. Both groups of diseases show so many overlapping clinical, pathogenetic, histologic, and genetic features that together they should likely be considered as innate immune disorders. PMID- 26620373 TI - Docosahexaenoic Acid Attenuates Cardiovascular Risk Factors via a Decline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Plasma Levels. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that regulates cholesterol metabolism by promoting LDL receptor degradation in the liver and has recently been proposed as a therapeutic target in the management of hyperlipidaemia. We investigated the impact of dietary fat on the metabolism of sterols and on plasma PCSK9 concentrations to explore likely clinical usefulness. In a post hoc analysis of a double-blind randomised crossover controlled feeding trial, the Canola Oil Multicenter Intervention Trial (COMIT), volunteers (n = 54) with at least one condition related to metabolic syndrome consumed diets with one of the following treatment oils in beverages: (1) conventional canola oil (Canola); (2) canola oil rich in docosahexanoic acid (DHA) (CanolaDHA); and (3) high-oleic acid canola oil (CanolaOleic). The enrichment in oleic acid resulted in lower plasma cholesterol concentration compared with diets enriched in DHA. Contrarily, DHA-enriched oil significantly decreased plasma PCSK9 and triacylglycerols levels, but increased circulating levels of sterols. The variations in lathosterol, sitosterol, and campesterol indicate that plasma PCSK9 levels are sensitive to changes in cholesterol synthesis and/or absorption. There was a significant correlation between plasma PCSK9 levels and plasma triacylglicerol and apolipoprotein B levels, which was not affected by dietary fat. Therefore, our results suggest that the impact of dietary fats should not be discarded as complementary treatment in the management of patients with hyperlipidaemia. These findings should be considered in the analysis of ongoing studies and may represent a cautionary note in the treatment of patients with cardiovascular risk. PMID- 26620374 TI - Rapid Quantitative Determination of Squalene in Shark Liver Oils by Raman and IR Spectroscopy. AB - Squalene is sourced predominantly from shark liver oils and to a lesser extent from plants such as olives. It is used for the production of surfactants, dyes, sunscreen, and cosmetics. The economic value of shark liver oil is directly related to the squalene content, which in turn is highly variable and species dependent. Presented here is a validated gas chromatography-mass spectrometry analysis method for the quantitation of squalene in shark liver oils, with an accuracy of 99.0 %, precision of 0.23 % (standard deviation), and linearity of >0.999. The method has been used to measure the squalene concentration of 16 commercial shark liver oils. These reference squalene concentrations were related to infrared (IR) and Raman spectra of the same oils using partial least squares regression. The resultant models were suitable for the rapid quantitation of squalene in shark liver oils, with cross-validation r (2) values of >0.98 and root mean square errors of validation of <=4.3 % w/w. Independent test set validation of these models found mean absolute deviations of the 4.9 and 1.0 % w/w for the IR and Raman models, respectively. Both techniques were more accurate than results obtained by an industrial refractive index analysis method, which is used for rapid, cheap quantitation of squalene in shark liver oils. In particular, the Raman partial least squares regression was suited to quantitative squalene analysis. The intense and highly characteristic Raman bands of squalene made quantitative analysis possible irrespective of the lipid matrix. PMID- 26620376 TI - Spectrum and treatment of anaerobic infections. AB - Anaerobes are the most predominant components of the normal human skin and mucous membranes bacterial flora, and are a frequent cause of endogenous bacterial infections. Anaerobic infections can occur in all body locations: the central nervous system, oral cavity, head and neck, chest, abdomen, pelvis, skin, and soft tissues. Treatment of anaerobic infection is complicated by their slow growth in culture, by their polymicrobial nature and by their growing resistance to antimicrobials. Antimicrobial therapy is frequently the only form of therapy needed, whereas in others it is an important adjunct to drainage and surgery. Because anaerobes generally are isolated mixed with aerobes, the antimicrobial chosen should provide for adequate coverage of both. The most effective antimicrobials against anaerobes are: metronidazole, the carbapenems (imipenem, meropenem, doripenem, ertapenem), chloramphenicol, the combinations of a penicillin and a beta-lactamase inhibitors (ampicillin or ticarcillin plus clavulanate, amoxicillin plus sulbactam, piperacillin plus tazobactam), tigecycline, cefoxitin and clindamycin. PMID- 26620378 TI - Association between Aortic Remodeling and Stent Graft-Induced New Entry in Extensive Residual Type A Dissecting Aortic Aneurysm after Hybrid Arch Repair. AB - BACKGROUND: This study evaluated sequential aortic morphologic remodeling and influencing factors between distal stent graft-induced new entry (SINE) in chronic residual type A dissecting aortic aneurysm after extensive hybrid arch repair. METHODS: We retrospectively analyzed operative and follow-up data of 30 consecutive patients with chronic residual type A aortic dissection aneurysm treated by hybrid type III arch repair (ascending aortic and arch replacement combined with elephant trunk technique before stent-graft deployment) between November 2006 and October 2011. RESULTS: In 3 years, follow-up of 24 patients with successful 1-stage hybrid arch repair and stent grafting. The ratio of true lumen area increased at pulmonary artery level, but minimal change was seen in the thoracic segment distal to stent graft and abdominal aorta. Late distal SINE occurred in 14 patients (SINE group). Cross-sectional area showed significant differences in distal end of pre-stenting graft oversizing ratio (SINE group 4.32 vs. non-SINE group 2.23, P = 0.021(*)). The thoracic segment thrombosis rate was 90% in SINE and 57% in non-SINE (P = 0.089) groups. CONCLUSIONS: In homogenous population of chronic residual type A dissection, noticeable false lumen thrombosis with true lumen progressive dilatation was only found at the proximal descending aortic segment extending to the middle of stent grafts in both groups. A smaller size selection of the distal stent graft by area measurement would be accompanied with poor aortic remodeling but might be beneficial for SINE prevention. On the other hand, a larger size selection of the distal stent graft area might be favorable for aortic remodeling but could potentially induce SINE. PMID- 26620379 TI - Metastatic Angiosarcoma Presenting as Ischemic Anterior Circulation Stroke. AB - BACKGROUND: Angiosarcoma is a rare malignant neoplasm that can arise from vascular endothelium. We report a case of angiosarcoma that presented as thromboembolic stroke, review the current literature, and discuss the management challenges. CASE REPORT: A 77-year-old man presented with a right anterior circulation stroke with a history of multiple, recent transient ischemic attacks. The diagnosis was confirmed on computed tomography and subsequent investigation revealed thrombus within the distal common carotid artery, with an atherosclerotic plaque causing a significant stenosis of the origin of the internal carotid artery above this. In the context of the presentation with recurrent events, carotid endarterectomy was recommended and subsequently performed. At the time of surgery, the common, internal, and external carotid arteries had macroscopic evidence of atherosclerotic disease but appeared otherwise normal. Intraoperatively friable thrombus adherent to the common carotid endothelium was retrieved and sent for histologic assessment. Subsequent immunohistochemistry evaluation revealed changes pathognomic with angiosarcoma. RESULTS: It is unclear in this case whether the pathology originated in the carotid artery or was the result of embolization from a proximal source. There was no extraluminal carotid pathology identified at the time of surgery, and no abnormalities identified on cross-sectional imaging. Similarly, there was no evidence of a proximal source that may have resulted in tumor embolization. As such, it has proved impossible to define an optimal therapeutic pathway for this patient. PMID- 26620375 TI - Revisiting Human Cholesterol Synthesis and Absorption: The Reciprocity Paradigm and its Key Regulators. AB - Hypercholesterolemia is a major risk factor for cardiovascular disease. Cholesterol homeostasis in the body is governed by the interplay between absorption, synthesis, and excretion or conversion of cholesterol into bile acids. A reciprocal relationship between cholesterol synthesis and absorption is known to regulate circulating cholesterol in response to dietary or therapeutic interventions. However, the degree to which these factors affect synthesis and absorption and the extent to which one vector shifts in response to the other are not thoroughly understood. Also, huge inter-individual variability exists in the manner in which the two systems act in response to any cholesterol-lowering treatment. Various factors are known to account for this variability and in light of recent experimental advances new players such as gene-gene interactions, gene environmental effects, and gut microbiome hold immense potential in offering an explanation to the complex traits of inter-individual variability in human cholesterol metabolism. In this context, the objective of the present review is to provide an overview on cholesterol metabolism and discuss the role of potential factors such as genetics, epigenetics, epistasis, and gut microbiome, as well as other regulators in modulating cholesterol metabolism, especially emphasizing the reciprocal relationship between cholesterol synthesis and absorption. Furthermore, an evaluation of the implications of this push-pull mechanism on cholesterol-lowering strategies is presented. PMID- 26620380 TI - Listeria Infected Pseudoaneurysm of the Superficial Femoral Artery. AB - We present a unique case of listeria-infected pseudoaneurysm of the superficial femoral artery. Listeria monocytogenes, a gram positive, intracellular bacterium, is widespread in the environment. The manifestation of infection in humans ranges from mild gastroenteritis to life-threatening listeriosis. The incidence in the healthy population is low (0.7 per 100,000) but rises sharply in pregnancy, the immunocompromised and patients with malignancy. Listeria rarely causes mycotic aneurysm formation, with fewer than 40 cases reported in the literature. Further investigation revealed the patient to be diagnosed with a hepatocellular carcinoma. It is likely that the two pathologies were linked. Hence, we would advocate investigation for underlying malignancy in patients presenting with a mycotic aneurysm, particularly those resulting from Listeria infection. PMID- 26620381 TI - Drop-Attacks Revealing a Cervical Cystic Lymphangioma. AB - We report the case of a 28-year-old man who presented in emergency for recurrent drop-attacks. Ultrasound imaging and angio computed tomography revealed a left cervical tumor, and the patient underwent surgery. The diagnosis of cystic lymphangioma was done on the anatomic characteristics of the surgical specimen and the results of the histological study. This is the first reported case of late diagnosis of a cervical cystic lymphangioma revealed by recurrent drops attack. PMID- 26620383 TI - A Concept Analysis of Self-Care Based on Islamic Sources. AB - PURPOSE: This article describes the concept of self-care from Islamic texts. METHOD: Rodgers' evolutionary model of concept analysis was used in this study. FINDINGS: Self-care is a series of responsible activities to God for health promotion, preventive disease and remedy. It encompasses physical, mental, spiritual, and social dimensions. CONCLUSION: A comprehensive definition of the concept of self-care ensued from a review of Islamic literature. IMPLICATIONS FOR NURSING PRACTICE: Since the nurses instruct and assist individuals as they engage in self-care, using a comprehensive definition of self-care based on Islamic sources would provide an anchor linking for them as they interact with Muslim patients. PMID- 26620382 TI - Interictal high-frequency oscillations (HFOs) as predictors of high frequency and conventional seizure onset zones. AB - We investigated the relationship between the interictal high-frequency oscillations (HFOs) and the seizure onset zones (SOZs) defined by the ictal HFOs or conventional frequency activity (CFA), and evaluated the usefulness of the interictal HFOs as spatial markers of the SOZs. We analysed seizures showing discrete HFOs at onset on intracranial EEGs acquired at >=1000-Hz sampling rate in a training cohort of 10 patients with temporal and extratemporal epilepsy. We classified each ictal channel as: HFO+ (HFOs at onset with subsequent evolution), HFO- (HFOs at onset without evolution), CFA (1.6-70-Hz activity at onset with evolution), or non-ictal. We defined the SOZs as: hSOZ (HFO+ channels only), hfo+&-SOZ (HFO+ and HFO- channels), and cSOZ (CFA channels). Using automated methods, we detected the interictal HFOs and extracted five features: density, connectivity, peak frequency, log power, and amplitude. We created logistic regression models using these features, and tested their performance in a separate replication cohort of three patients. The models containing the five interictal HFO features reliably differentiated the channels located inside the SOZ from those outside in the training cohort (p<0.001), reaching the highest accuracy for the classification of hSOZ. Log power and connectivity had the highest odds ratios, both being higher for the channels inside the SOZ compared with those outside the SOZ. In the replication cohort of novel patients, the same models differentiated the HFO+ from HFO- channels, and predicted the extents of the hSOZ and hfo+&-SOZ (F1 measure >0.5) but not the cSOZ. Our study shows that the interictal HFOs are useful in defining the spatial extent of the SOZ, and predicting whether or not a given channel in a novel patient would be involved in the seizure. The findings support the existence of an abnormal network of tightly linked ictal and interictal HFOs in patients with intractable epilepsy. PMID- 26620385 TI - Positive Youth Development, Part 3. Youth Suicide Prevention Is Everybody's Business. PMID- 26620384 TI - Maternal and Perinatal Outcomes Among Adolescents and Mature Women: A Hospital Based Study in the North of Mexico. AB - STUDY OBJECTIVE: To compare maternal and newborn pregnancy outcomes from adolescents and mature women. DESIGN, SETTING, AND PARTICIPANTS: A cross sectional study was carried out in a public hospital, including women with singleton pregnancies, who were classified according to their age, as follows: group 1: younger than 16 years old (n = 37), group 2: 16-19 years old (n = 288), and group 3: 20-34 years old (n = 632). INTERVENTIONS AND MAIN OUTCOME MEASURES: Information on clinical characteristics, gynecological and obstetric history, pregnancy complications, and perinatal outcomes was obtained through interviews and from clinical records. RESULTS: Thirty-four percent of deliveries were from adolescents. Mature women were more likely to have prepregnancy overweight or obesity than adolescents (odds ratio [OR] = 2.4, 95% confidence interval [CI], 1.7-3.4). The frequency of maternal complications during pregnancy or delivery was not different between groups. Birth asphyxia was more frequent in group 2 (P = .02). Women with inadequate prenatal care had an increased risk of preterm deliveries (OR = 1.64; 95% CI, 1.06-2.54) and of having newborns with low birth weight (OR = 2.02; 95% CI, 1.22-3.35). Weight of newborns from noncomplicated pregnancies was lower in group 1 (P = .02), after adjustment for prepregnancy body mass index, gestational weight gain, preterm delivery, and newborn sex. CONCLUSION: The frequency of maternal and perinatal complications was similar in adolescents and mature women. Birth weight was decreased in noncomplicated pregnancies of adolescents younger than 16 years of age. Adequate prenatal care might be helpful in prevention of some adverse perinatal outcomes. PMID- 26620386 TI - Partial Cervical Agenesis and Complete Vaginal Atresia. AB - BACKGROUND: The objective of this study was to report 2 cases of the combined congenital anomalies of complete vaginal atresia and partial cervical agenesis, and highlight the limitations of magnetic resonance imaging for definitive initial diagnosis, and consequently the importance of early definitive management, to avoid life-threatening sepsis. Herein we provide a retrospective case audit of two patients with congenital abnormalities between 2005 and 2013 who were treated in a quaternary statewide pediatric and adolescent gynecology center. CASES: Two patients with the combined congenital anomalies of complete vaginal agenesis and partial cervical agenesis highlight the difficulties encountered with the limitations of magnetic resonance imaging in accuracy of diagnosis, as well as development of life-threatening sepsis that requires hysterectomy. Both patients were initially imaged as having distended endometrial cavities and cervical canals with what was thought to be an obstructive upper vaginal septum and absent lower vagina. Both required initial neovagina creation, however the cervices were never clinically or surgically visualized. SUMMARY AND CONCLUSION: Partial cervical agenesis is a relatively rare form of Mullerian abnormality which, if not diagnosed and definitively treated early, can have significant morbidity and mortality. Although magnetic resonance imaging is the diagnostic imaging gold standard for Mullerian abnormalities, it is important to recognize the limitations of this modality, the potential sequelae of these limitations, and to appreciate the importance of early accurate diagnosis and treatment of this condition. Importantly, if the imaging diagnosis does not completely correlate with the clinical and surgical findings, then a high suspicion of complete or partial cervical agenesis is prudent, because the consequences of nondefinitive early treatment can be life-threatening and potentially fatal. PMID- 26620387 TI - New alliance of 19 health bodies adds voice to call for sugar tax. PMID- 26620389 TI - Diabetes self-management education improves medication utilization and retinopathy screening in the elderly. AB - AIMS: To evaluate the effect of diabetes education program attendance, which provides patients with diabetes self-management education, on prescriptions for cardiovascular risk reduction, prescriptions for diabetes treatments, and visits for retinopathy screening. METHODS: A population based cohort study of residents of Ontario, Canada with diagnosed diabetes aged >=65 years was performed using administrative databases. Diabetes education program attendance was identified using a registry of visits to all diabetes education programs in the province in 2006. Using propensity score methods, 22,606 diabetes education program attendees were matched to an equal number of non-attendees. The proportions of patients with prescriptions filled and with ophthalmology/optometry visits were compared. RESULTS: Patients attending diabetes education programs had greater utilization of statins (70.6%) than non-attendees (69.4%, p<0.0001). Diabetes education program attendance was also associated with greater utilization of glucose lowering medications (83.7% vs. 82.0%, p<0.0001), antihypertensive medications (90.2% vs. 89.7%, p<0.0001), angiotensin converting enzyme inhibitors/angiotensin receptor blockers (79.8% vs. 78.9% p<0.0001), and glucose monitoring strips (82.2% vs. 65.6%, p<0.0001); and visits to ophthalmology/optometry (78.7% vs. 72.7%, p<0.0001). CONCLUSIONS: Diabetes self-management education at diabetes education programs is associated with better quality of care in the elderly in Ontario. PMID- 26620388 TI - Prevalence of HIV, hepatitis B, and hepatitis C in people with severe mental illness: a systematic review and meta-analysis. AB - BACKGROUND: Although people with serious mental illnesses have a high risk of contracting blood-borne viral infections, sexual health has largely been neglected by researchers and policy makers involved in mental health. Failure to address this shortcoming could increase morbidity and mortality as a result of undetected and untreated infection. We did a systematic review and meta-analysis to estimate the prevalence of blood-borne viral infection in people with serious mental illness. METHOD: We searched the Cochrane Library, Medline, Embase, PsycInfo, CINAHL, and DARE for studies of the prevalence of HIV, hepatitis B virus, and hepatitis C virus in people with serious mental illness, published between Jan 1, 1980, and Jan 1, 2015. We group prevalence data by region and by virus and estimated pooled prevalence. We did a sensitivity analysis of the effect of study quality on prevalence. FINDINGS: After removal of duplicates, we found 373 abstracts, 91 of which met our eligibility criteria. The prevalences of blood-borne viral infections in people with serious mental illness were higher than in the general population in places with low prevalence of blood-borne viruses, such as the USA and Europe, and on par with the general population in regions with high prevalence of blood-borne viruses (Africa for HIV and southeast Asia for hepatitis B virus and hepatitis C virus). Pooled prevalence of HIV in people with serious mental illness in the USA was 6.0% (95% CI 4.3-8.3). Sensitivity analysis showed that quality scores did not significantly affect prevalence. INTERPRETATION: People with serious mental illness are at risk of blood-borne viral infections. However, because of methodological limitations of the studies the prevalence might be overestimated. Serious mental illness is unlikely to be a sole risk factor and risk of blood-borne viral infection is probably multifactorial and associated with low socioeconomic status, drug and alcohol misuse, ethnic origin, and sex. Health providers should routinely discuss sexual health and risks for blood-borne viruses (including risks related to drug misuse) with people who have serious mental illness, as well as offering testing and treatment for those at risk. FUNDING: Wellcome Trust. PMID- 26620390 TI - Minichromosome maintenance protein 7 as prognostic marker of tumor aggressiveness in pituitary adenoma patients. AB - BACKGROUND: Ki-67 labeling index (LI) is currently regarded as a useful prognostic marker of pituitary adenoma (PA) clinical behavior, although its relevance as a reliable clinical indicator is far from being universally accepted, since both validations and criticisms are found in the literature. Minichromosome maintenance 7 (MCM7), a cell-cycle regulator protein, has been recently proposed as a marker of tumor aggressiveness in tumors from many sites, including the CNS. Therefore, we evaluated MCM7, in comparison to Ki-67, as a potential marker of clinical outcome in PA. DESIGN AND METHODS: In this single institution retrospective study, 97 patients with PA (23 ACTH, 12 GH, 29 PRL, 10 FSH/LH, and 23 non-secreting adenomas) were recruited and the prognostic value of both MCM7 and Ki-67 was evaluated by immunohistochemical techniques. In addition, p53 nuclear expression and mitotic index were also evaluated. RESULTS: Twenty-six of the 97 PA patients recurred during the follow-up period. Cox's regression analysis showed that high nuclear expression of MCM7 LI, unlike Ki-67 LI, was directly associated with a higher (7.7-fold) risk of recurrence/progression. Kaplan-Meier analysis of recurrence/progression-free survival curves revealed that patients with high MCM7 LI (>=15%) had a shorter recurrence/progression-free survival than those with low MCM7 LI (<15%). Moreover, among patients with invasive tumors, high MCM7 LI identified those with the highest risk of recurrence/progression. CONCLUSIONS: Data from this study suggest that MCM7 is a prognostic marker of clinical outcome in PA patients, more reliable and informative than Ki-67. PMID- 26620391 TI - Reduced beta-cell function in early preclinical type 1 diabetes. AB - OBJECTIVE: We aimed to characterize insulin responses to i.v. glucose during the preclinical period of type 1 diabetes starting from the emergence of islet autoimmunity. DESIGN AND METHODS: A large population-based cohort of children with HLA-conferred susceptibility to type 1 diabetes was observed from birth. During regular follow-up visits islet autoantibodies were analysed. We compared markers of glucose metabolism in sequential intravenous glucose tolerance tests between 210 children who were positive for multiple (>=2) islet autoantibodies and progressed to type 1 diabetes (progressors) and 192 children testing positive for classical islet-cell antibodies only and remained healthy (non-progressors). RESULTS: In the progressors, the first phase insulin response (FPIR) was decreased as early as 4-6 years before the diagnosis when compared to the non progressors (P=0.001). The difference in FPIR between the progressors and non progressors was significant (P<0.001) in all age groups, increasing with age (at 2 years: difference 50% (95% CI 28-75%) and at 10 years: difference 172% (95% CI 128-224%)). The area under the 10-min insulin curve showed a similar difference between the groups (P<0.001; at 2 years: difference 36% (95% CI 17-58%) and at 10 years: difference 186% (95% CI 143-237%)). Insulin sensitivity did not differ between the groups. CONCLUSIONS: FPIR is decreased several years before the diagnosis of type 1 diabetes, implying an intrinsic defect in beta-cell mass and/or function. PMID- 26620392 TI - Trends in traumatic out-of-hospital cardiac arrest in Perth, Western Australia from 1997 to 2014. AB - AIM: This study aims to describe and compare traumatic and medical out-of hospital cardiac arrest (OHCA) occurring in Perth, Western Australia, between 1997 and 2014. METHODS: The St John Ambulance Western Australia (SJA-WA) OHCA Database was used to identify all adult (>= 16 years) cases. We calculated annual crude and age-sex standardised incidence rates (ASIRs) for traumatic and medical OHCA and investigated trends over time. RESULTS: Over the study period, SJA-WA attended 1,354 traumatic OHCA and 16,076 medical OHCA cases. The mean annual crude incidence rate of traumatic OHCA in adults attended by SJA-WA was 6.0 per 100,000 (73.9 per 100,000 for medical cases), with the majority resulting from motor vehicle collisions (56.7%). We noted no change to either incidence or mechanism of injury over the study period (p>0.05). Compared to medical OHCA, traumatic OHCA cases were less likely to receive bystander cardiopulmonary resuscitation (CPR) (20.4% vs. 24.5%, p=0.001) or have resuscitation commenced by paramedics (38.9% vs. 44.8%, p<0.001). However, rates of bystander CPR and resuscitation commenced by paramedics increased significantly over time in traumatic OHCA (p<0.001). In cases where resuscitation was commenced by paramedics there was no difference in the proportion who died at the scene (37.2% traumatic vs. 34.3% medical, p=0.17), however, fewer traumatic OHCAs survived to hospital discharge (1.7% vs. 8.7%, p<0.001). CONCLUSIONS: Despite temporal increases in rates of bystander CPR and paramedic resuscitation, traumatic OHCA survival remains poor with only nine patients surviving from traumatic OHCA over the 18-year period. PMID- 26620393 TI - Survival is surfing on the guidelines wave. PMID- 26620394 TI - Effects of Price, Information, and Transactions Cost Interventions to Raise Voluntary Enrollment in a Social Health Insurance Scheme: A Randomized Experiment in the Philippines. AB - A cluster randomized experiment was undertaken testing two sets of interventions encouraging enrollment in the Individually Paying Program (IPP), the voluntary component of the Philippines' social health insurance program. In early 2011, 1037 unenrolled IPP-eligible families in 179 randomly selected intervention municipalities were given an information kit and offered a 50% premium subsidy valid until the end of 2011; 383 IPP-eligible families in 64 control municipalities were not. In February 2012, the 787 families in the intervention sites who were still IPP-eligible but had not enrolled had their vouchers extended, were resent the enrollment kits and received SMS reminders. Half the group also received a 'handholding' intervention: in the endline interview, the enumerator offered to help complete the enrollment form, deliver it to the insurer's office in the provincial capital, and mail the membership cards. The main intervention raised the enrollment rate by 3 percentage points (ppts) (p = 0.11), with an 8 ppt larger effect (p < 0.01) among city-dwellers, consistent with travel time to the insurance office affecting enrollment. The handholding intervention raised enrollment by 29 ppts (p < 0.01), with a smaller effect (p < 0.01) among city-dwellers, likely because of shorter travel times, and higher education levels facilitating unaided completion of the enrollment form. Copyright (c) The World Bank Health Economics (c) 2015 John Wiley & Sons, Ltd. PMID- 26620395 TI - Predicting a new phase (T'') of two-dimensional transition metal di-chalcogenides and strain-controlled topological phase transition. AB - Single layered transition metal dichalcogenides have attracted tremendous research interest due to their structural phase diversities. By using a global optimization approach, we have discovered a new phase of transition metal dichalcogenides (labelled as T''), which is confirmed to be energetically, dynamically and kinetically stable by our first-principles calculations. The new T'' MoS2 phase exhibits an intrinsic quantum spin Hall (QSH) effect with a nontrivial gap as large as 0.42 eV, suggesting that a two-dimensional (2D) topological insulator can be achieved at room temperature. Most interestingly, there is a topological phase transition simply driven by a small tensile strain of up to 2%. Furthermore, all the known MX2 (M = Mo or W; X = S, Se or Te) monolayers in the new T'' phase unambiguously display similar band topologies and strain controlled topological phase transitions. Our findings greatly enrich the 2D families of transition metal dichalcogenides and offer a feasible way to control the electronic states of 2D topological insulators for the fabrication of high-speed spintronics devices. PMID- 26620396 TI - Short-term changes in tinnitus pitch related to audiometric shape in sudden sensorineural hearing loss. AB - OBJECTIVE: Sudden sensorineural hearing loss (SSNHL) is frequently accompanied by tinnitus. This study investigated the relationships between new-onset tinnitus and audiometric parameters in SSNHL patients. METHODS: Sixty-one patients with SSNHL with new-onset tinnitus were enrolled. Changes of tinnitus pitch, and their correlations with the maximum hearing loss frequency (Fmax) and the edge frequency (Fedge) at initial and 1-month follow-up (FU) were analyzed. RESULTS: At 1-month FU, tinnitus disappeared in 16 (26%) patients and they also showed hearing normalization. In 36 patients who still showed tonal tinnitus, the mean tinnitus pitch (2.9 kHz) at initial examination, which was close to Fedge (2.7 kHz), increased to a significantly higher frequency (4.6 kHz) at 1-month examination, which was close to Fmax (5.6 kHz). The tinnitus pitch had a more significant correlation with Fedge (r=0.46) than with Fmax (r=0.33) at initial examination and the tinnitus pitch showed a significant correlation only with Fmax (r=0.52) at 1-month examination. CONCLUSIONS: Hearing normalization was crucial for the disappearance of tinnitus at 1-month FU. Patients who still had tonal tinnitus at 1-month FU showed the tinnitus pitch closer to the edge frequency (Fedge) at initial examination, and this tinnitus pitch increased to the maximum hearing loss frequency (Fmax) at 1-month FU. This change in tinnitus pitch may give insight about tinnitus generation. PMID- 26620397 TI - Meta-Analysis of Studies Evaluating the Effect of Cilostazol on Major Outcomes After Carotid Stenting. AB - PURPOSE: To evaluate the effect of cilostazol on major outcomes after carotid artery stenting (CAS). METHODS: A systematic literature review was conducted conforming to established criteria in order to identify articles published prior to May 2015 evaluating major post-CAS outcomes in patients treated with cilostazol vs patients not treated with cilostazol. Major outcomes included in stent restenosis (ISR) within the observation period, the revascularization rate, major/minor bleeding, and the myocardial infarction/stroke/death rate (MI/stroke/death) at 30 days and within the observation period. Data were pooled for all studies containing adequate data for each outcome investigated; effect estimates are presented as the odds ratios (ORs) and 95 confidence intervals (CI). RESULTS: Overall, 7 studies pertaining to 1297 patients were eligible. Heterogeneity was low among studies so a fixed-effect analysis was conducted. Six studies (n=1233) were compared for the ISR endpoint, showing a significantly lower ISR rate with cilostazol treatment after a mean follow-up of 20 months (OR 0.158, 95% CI 0.072 to 0.349, p<0.001). Five studies (n=649) were compared regarding 30-day MI/stroke/death (OR 0.724, 95% CI 0.293 to 1.789, p=0.484) and 3 studies (n=1076) were analyzed regarding MI/stroke/death within the entire follow up period (OR 0.768, 95% CI 0.477 to 1.236, p=0.276); no significant difference was found between the groups. Data on bleeding rates and revascularization rates post ISR were inadequate to conduct further analysis. CONCLUSION: Cilostazol seems to decrease total ISR rates in patients undergoing CAS without affecting MI/stroke/death events, both in the early and late settings. PMID- 26620398 TI - Global Experience With the Nellix Endosystem for Ruptured and Symptomatic Abdominal Aortic Aneurysms. AB - PURPOSE: To assess the feasibility and safety of the endovascular aneurysm sealing (EVAS) technique in the treatment of acute abdominal aortic aneurysm (AAA). METHODS: A retrospective, multicenter, observational study was conducted at 8 centers (7 European and 1 in New Zealand) experienced with EVAS in the elective setting. From February 2013 to April 2015, 58 patients (mean age 74+/-9 years; 46 men) with an acute AAA were treated (28 ruptured and 30 symptomatic). The primary endpoint of the study was 30-day mortality; secondary endpoints included endoleak, reinterventions, and 30-day morbidity. RESULTS: The overall intensive care unit and hospital stays were 2.2+/-6.6 days and 9.7+/-11.4 days, respectively. Thirty-day mortality rates were 32% (9/28) for the ruptured group and 7% (2/30) for the symptomatic group, with morbidity rates of 57% and 17%, respectively. Early endoleak was present in only 2 (3%) patients, one in each group; both leaks were type Ia. Reinterventions within 30 days were performed in 8 patients in the ruptured group; in the symptomatic patients, the only perioperative reintervention was embolization a type Ia endoleak. The mean follow up was 9.3+/-3.1 months in the ruptured group and 12.4+/-5.4 months in the symptomatic group. The mean aneurysm diameter at 30-day follow-up was 71.8+/-16.0 mm compared with 74.7+/-15.7 mm preoperatively in the ruptured group and 66.1+/ 13.5 mm compared with 65.8+/-13.0 mm in the symptomatic group. CONCLUSION: EVAS in the acute setting appears safe and feasible and concordant with the literature for endovascular aneurysm repair. More robust prospective and comparative data are required to establish the position of the technique in the treatment algorithm of acute AAA. PMID- 26620399 TI - Evaluation of the Biodegradable Igaki-Tamai Scaffold After Drug-Eluting Balloon Treatment of De Novo Superficial Femoral Artery Lesions: The GAIA-DEB Study. AB - PURPOSE: To evaluate the safety and efficacy of the Igaki-Tamai biodegradable scaffold after drug-eluting balloon (DEB) angioplasty in patients with occlusive superficial femoral artery (SFA) disease. METHODS: A prospective, single-center, nonrandomized study enrolled 20 patients (mean age 66.7+/-11.6 years; 14 men) with symptomatic de novo SFA lesions undergoing angioplasty with the In.Pact Admiral paclitaxel-coated balloon and subsequent implantation of the Igaki-Tamai bioresorbable scaffold. All patients were claudicants. The average diameter stenosis was 89.7%, and the mean length was 43.6 mm. Clinical examinations with duplex sonography were performed after 1, 6, 9, and 12 months. The main study outcomes were technical success, restenosis, target lesion revascularization (TLR), ankle-brachial index (ABI) improvement, and changes in quality of life evaluated with the walking impairment questionnaire. Safety was assessed by monitoring the occurrence of adverse events. RESULTS: Angioplasty with a paclitaxel-coated balloon was performed in all patients, resulting in an average diameter stenosis of 24%. Subsequent implantation of the Igaki-Tamai scaffold reduced the average diameter stenosis to 3.5%. In the first 6 months, 2 cases of restenosis were reported, with no TLRs within that period. However, by the 12 month follow-up in 19 patients, 11 patients had lost in-stent patency. Among these patients, 8 had TLRs, which were the only adverse events recorded that were referable to the procedure. Quality-of-life assessments showed improvement in the majority of patients. CONCLUSION: The GAIA-DEB study shows that DEB treatment of the femoral artery prior to the implantation of the biodegradable Igaki-Tamai scaffold is safe. However, the antiproliferative actions of paclitaxel in the vessel wall were not effective in preventing restenosis. In-stent restenosis occurred predominantly after 6 months. PMID- 26620400 TI - Inhibition of Lysyl Oxidases Improves Drug Diffusion and Increases Efficacy of Cytotoxic Treatment in 3D Tumor Models. AB - Tumors are characterized by a rigid, highly cross-linked extracellular matrix (ECM), which impedes homogeneous drug distribution and potentially protects malignant cells from exposure to therapeutics. Lysyl oxidases are major contributors to tissue stiffness and the elevated expression of these enzymes observed in most cancers might influence drug distribution and efficacy. We examined the effect of lysyl oxidases on drug distribution and efficacy in 3D in vitro assay systems. In our experiments elevated lysyl oxidase activity was responsible for reduced drug diffusion under hypoxic conditions and consequently impaired cytotoxicity of various chemotherapeutics. This effect was only observed in 3D settings but not in 2D-cell culture, confirming that lysyl oxidases affect drug efficacy by modification of the ECM and do not confer a direct desensitizing effect. Both drug diffusion and efficacy were strongly enhanced by inhibition of lysyl oxidases. The results from the in vitro experiments correlated with tumor drug distribution in vivo, and predicted response to therapeutics in murine tumor models. Our results demonstrate that lysyl oxidase activity modulates the physical barrier function of ECM for small molecule drugs influencing their therapeutic efficacy. Targeting this process has the potential to significantly enhance therapeutic efficacy in the treatment of malignant diseases. PMID- 26620401 TI - Larval habitat characteristics of the main malaria vectors in the most endemic regions of Colombia: potential implications for larval control. AB - BACKGROUND: Malaria incidence has recently decreased globally and, as malaria elimination is envisioned as a possibility by the health authorities, guidance is needed to strengthen malaria control strategies. Larval source treatment, which could complement routine vector control strategies, requires knowledge regarding the Anopheles larval habitats. METHODS: A cross-sectional study was conducted in three of the most malaria-endemic regions in Colombia. A total of 1116 potential larval habitats in 70 villages were sampled in three states located in western Colombia: Cordoba, Valle del Cauca and Narino. RESULTS: Overall, 17.5 % (195) of the potential larval habitats were found positive for different Anopheles species. A total of 1683 larvae were identified belonging to seven species: Anopheles albimanus, Anopheles calderoni, Anopheles darlingi, Anopheles neomaculipalpus, Anopheles nuneztovari s.l., Anopheles pseudopunctipennis, and Anopheles triannulatus. The most widely distributed species was An. nuneztovari s.l., which was found mainly in human-made fishponds in Cordoba and temporary puddles in Valle del Cauca. Anopheles albimanus and An. calderoni were associated with human-made wells or excavation sites in Narino. Cordoba displayed the greatest Anopheles species diversity with a total of six species (Shannon diversity index H': 1.063). Although Valle del Cauca had four species, one more than Narino, the diversity was lower because only one species predominated, An. nuneztovari s.l. The larval habitats with the highest Shannon diversity index were lagoons (H': 1.079) and fishponds (H': 1.009) in Cordoba, excavation sites in Narino (H': 0.620) and puddles in Valle del Cauca (H': 0.764). CONCLUSIONS: This study provides important information regarding the larval habitats of the main malaria vectors in the most malaria-endemic regions of Colombia, which will be useful in guiding larval control operations. PMID- 26620403 TI - The phenotypic screening pendulum swings. PMID- 26620404 TI - Pioneering biased ligand offers efficacy with reduced on-target toxicity. PMID- 26620408 TI - Karen Midthun. PMID- 26620402 TI - Improving the organisation of maternal health service delivery and optimising childbirth by increasing vaginal birth after caesarean section through enhanced women-centred care (OptiBIRTH trial): study protocol for a randomised controlled trial (ISRCTN10612254). AB - BACKGROUND: The proportion of pregnant women who have a caesarean section shows a wide variation across Europe, and concern exists that these proportions are increasing. Much of the increase in caesarean sections in recent years is due to a cascade effect in which a woman who has had one caesarean section is much more likely to have one again if she has another baby. In some places, it has become common practice for a woman who has had a caesarean section to have this procedure again as a matter of routine. The alternative, vaginal birth after caesarean (VBAC), which has been widely recommended, results in fewer undesired results or complications and is the preferred option for most women. However, VBAC rates in some countries are much lower than in other countries. METHODS/DESIGN: The OptiBIRTH trial uses a cluster randomised design to test a specially developed approach to try to improve the VBAC rate. It will attempt to increase VBAC rates from 25 % to 40 % through increased women-centred care and women's involvement in their care. Sixteen hospitals in Germany, Ireland and Italy agreed to join the study, and each hospital was randomly allocated to be either an intervention or a control site. DISCUSSION: If the OptiBIRTH intervention succeeds in increasing VBAC rates, its application across Europe might avoid the 160,000 unnecessary caesarean sections that occur every year at an extra direct annual cost of more than ?150 million. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10612254 , registered 3 April 2013. PMID- 26620410 TI - Immunotherapy: Remote control CARs. PMID- 26620409 TI - Pain: TLR5 opens the door to neuropathic-pain treatment. PMID- 26620413 TI - Acinetobacter equi sp. nov., isolated from horse faeces. AB - The taxonomic position of five strains isolated from horse faeces, and which shared identical 16S rRNA gene sequences, were studied. Cells of all isolates are Gram-stain-negative, obligately aerobic and have a rod-shaped appearance. The strains show highest 16S rRNA gene sequence similarities to Acinetobacter lwoffii (98.3 %), Acinetobacter haemolyticus (98.0 %), Acienetobacter johnsonii (97.9 %) and Acinetobacter brisouii (97.9 %). Whole-genome sequencing of strain 114T and phylogeny reconstruction based on a core set of 1061 Acinetobacter genes indicated that A. bouvetii CIP 107468T was the closest relative among species of the genus Acinetobacter for which whole genome sequences are available. The genomic DNA G+C content of strain 114T is 34.9 mol%, which is lower than any other value reported for the genus Acinetobacter. The predominant polyamine is 1,3-diaminopropane, which is typical for the genus Acinetobacter. The most abundant fatty acids are C16 : 1omega7c and/or iso-C15 : 0 2-OH (36 %) and C16 : 0 (28 %). The proportion of C18 : 1omega9c (7 %) is distinctively low compared to most species of the genus. The major ubiquinone of strain 114T is Q-9. Microscopic studies revealed the presence of pili and the absence of flagella. The capability of all five strains to utilize l-arabinose and gentisate as well as their lack of growth at temperatures of 41 degrees C and above provide sufficient criteria to distinguish the isolates from all species of the genus Acinetobacter with validly published names. Based on these combined data, the five isolates represent a novel species of the genus Acinetobacter, for which the name Acinetobacter equi sp. nov. is proposed. The type strain is 114T ( = DSM 27228T = CCUG 65204T). PMID- 26620415 TI - Functional Analysis of a Novel Connexin30 Mutation in a Large Family with Hearing Loss, Pesplanus, Ichthyosis, Cutaneous Nodules, and Keratoderma. AB - Mutations in the gap-junction gene Cx30 (Connexin30, GJB6) are a known cause of hearing loss. Here, we report our findings on a large multigeneration family in which severe to profound sensorineural hearing impairment is associated with a variety of skin-related anomalies. Genome-wide analysis of the family showed that the locus maps to chromosome region 13ptel-q12.1 and that a novel mutation, p.N54K, in Cx30, cosegregates with the phenotype. Unlike wild-type Cx30, p.N54K Cx30 is predominantly localized in the cytoplasm and does not permit transfer of neurobiotin, suggesting improper cellular localization and abolishment of gap junction activity. PMID- 26620414 TI - KPT-330, a potent and selective exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and survivin [corrected] in prostate cancer models. AB - BACKGROUND AND AIMS: Increased expression of Chromosome Region Maintenance (CRM 1)/exportin-1 (XPO-1) has been correlated with poor prognosis in several aggressive tumors, making it an interesting therapeutic target. Selective Inhibitor of Nuclear Export (SINE) compounds bind to XPO-1 and block its ability to export cargo proteins. Here, we investigated the effects of a new class of SINE compounds in models of prostate cancer. MATERIAL AND METHODS: We evaluated the expression of XPO-1 in human prostate cancer tissues and cell lines. Next, six SINE (KPT-127, KPT-185, KPT-205, KPT-225, KPT-251 and KPT-330) compounds having different potency with broad-spectrum, tumor-selective cytotoxicity, tolerability and pharmacokinetic profiles were tested in a panel of prostate cancer cells representing distinct differentiation/progression states of disease and genotypes. Two SINE candidates for clinical trials (KPT-251 and KPT-330) were also tested in vivo in three cell models of aggressive prostate cancer engrafted in male nude mice. RESULTS AND CONCLUSIONS: XPO-1 is overexpressed in prostate cancer compared to normal or hyperplastic tissues. Increased XPO-1 expression, mainly in the nuclear compartment, was associated with increased Gleason score and bone metastatic potential supporting the use of SINEs in advanced prostate cancer. SINE compounds inhibited proliferation and promoted apoptosis of tumor cells, but did not affect immortalized non-transformed prostate epithelial cells. Nuclei from SINE treated cells showed increased protein localization of XPO-1, survivin and cyclin D1 followed by degradation of these proteins leading to cell cycle arrest and apoptosis. Oral administration of KPT-251 and KPT-330 in PC3, DU145 and 22rv1 tumor-bearing nude mice reduced tumor cell proliferation, angiogenesis and induced apoptosis. Our results provide supportive evidence for the therapeutic use of SINE compounds in advanced/castration resistant prostate cancers and warrants further clinical investigation. PMID- 26620416 TI - Decreased Frequency of IL-17F rs763780 Site Allele G is Associated With Genetic Susceptibility to Immune Thrombocytopenia in a Chinese Population. AB - Interleukin 17F (IL-17F) is an inflammatory cytokine that plays an important role in autoimmune disease by inducing the expression of multiple chemokines, cytokines, and adhesion molecules. In vitro functional analysis revealed that IL 17F rs763780 polymorphism is associated with IL-17 expression and activity. Thus, considering the abnormal percentage of T helper 17 cells in patients with primary immune thrombocytopenia (ITP), we speculated there was a possible association between the IL-17F rs763780 polymorphisms and genetic susceptibility to ITP in a Chinese Han population. A total of 165 patients with ITP and 149 healthy controls were included in this study, and IL-17F rs763780 polymorphisms were analyzed by a polymerase chain reaction-restriction fragment length polymorphism system. The results showed that the frequency of the IL-17F rs763780 G allele in total patients with ITP or patients with chronic ITP was significantly lower than in normal controls (total ITP 3.6% vs controls 7.7%, P = .026; chronic ITP 3.5% vs controls 7.7%, P = .031). However, no significant difference in genotype frequencies was found among total patients with ITP, patients with chronic ITP, and normal controls. We further analyzed the association of IL-17F polymorphisms with clinical parameters of patients with ITP, and no association revealed between gene distribution and first onset age, clinical therapy response to glucocorticoids, or disease course. What's more, an evident discrepancy with allelic frequencies was observed between female patients with ITP and gender matched controls. In conclusion, IL-17F rs763780 polymorphisms may be associated with the development of ITP in a Chinese Han population. PMID- 26620417 TI - Direct Oral Anticoagulants for Very Elderly People With Atrial Fibrillation: Efficacy and Safe Enough? AB - BACKGROUND: Four direct oral anticoagulants (DOACs) have been licensed for the treatment of atrial fibrillation (AF); efficacy and safety have been shown in clinical trials, but its real use in elderly and very elderly people is still unclear. AIM: To evaluate the impact of DOACs in our patients (pts) aged >=75 years and switched from other treatments. METHODS: From September 2013 to May 2015, all consecutive pts aged >=75 years, males and females, in treatment for AF and switched to DOACs are considered in this study. Follow-up (FU) was scheduled after 3 and 6 months by phone and after 12 months by visit. RESULTS: Two hundred thirty-two pts in treatment for AF were switched to DOACs, among these 143 (61.6%) pts aged >=75 years (mean age, 81 years). The medium FU was 9.6 months, during which 4 minor bleedings in 4 different pts and 1 clinically relevant nonmajor bleeding were reported, all treated with temporary cessation or reduction in DOACs. Two strokes occurred in pts in treatment with dabigatran 110 mg, both resolved without serious sequelae; 2.8% of pts had nausea, itching, vomiting, or discomfort, half of these returned to acenocumarol, and the remaining switched to other DOAC. Four pts died, but the deaths were not related to anticoagulation. CONCLUSION: As reported for general people, also in our elderly population, DOACs resulted in a good alternative to old antithrombotic therapies. Efficacy and safety associated with a higher compliance by pts bring these drugs to be the first choice for long-term anticoagulation. PMID- 26620418 TI - Thrombophilia in 67 Patients With Thrombotic Events After Starting Testosterone Therapy. AB - We compared thrombophilia in 67 cases (59 men and 8 women) with thrombotic events after starting testosterone therapy (TT) versus 111 patient controls having unprovoked venous thrombotic events without TT. In the 67 patients, thrombosis (47 deep venous thrombosis-pulmonary embolism, 16 osteonecrosis, and 4 ocular thrombosis) occurred 6 months (median) after starting TT. Cases differed from controls for factor V Leiden heterozygosity (16 of the 67 [24%] vs 13 [12%] of the 111, P = .038) and for lupus anticoagulant (9 [14%] of the 64 vs 4 [4%] of the 106, P = .019). After a first thrombotic event and continuing TT, 11 cases had a second thrombotic event, despite adequate anticoagulation, 6 of whom, still anticoagulated, had a third thrombosis. Screening for thrombophilia before starting TT should identify men and women at high risk for thrombotic events with an adverse risk-benefit ratio for TT. When TT is given to patients with familial and acquired thrombophilia, thrombosis may occur and recur in thrombophilic men despite anticoagulation. PMID- 26620419 TI - Necrotising glomerulonephritis in levamisole-contaminated cocaine use. PMID- 26620420 TI - Segmented nitinol guidewires with stiffness-matched connectors for cardiovascular magnetic resonance catheterization: preserved mechanical performance and freedom from heating. AB - BACKGROUND: Conventional guidewires are not suitable for use during cardiovascular magnetic resonance (CMR) catheterization. They employ metallic shafts for mechanical performance, but which are conductors subject to radiofrequency (RF) induced heating. To date, non-metallic CMR guidewire designs have provided inadequate mechanical support, trackability, and torquability. We propose a metallic guidewire for CMR that is by design intrinsically safe and that retains mechanical performance of commercial guidewires. METHODS: The NHLBI passive guidewire is a 0.035" CMR-safe, segmented-core nitinol device constructed using short nitinol rod segments. The electrical length of each segment is less than one-quarter wavelength at 1.5 Tesla, which eliminates standing wave formation, and which therefore eliminates RF heating along the shaft. Each of the electrically insulated segments is connected with nitinol tubes for stiffness matching to assure uniform flexion. Iron oxide markers on the distal shaft impart conspicuity. Mechanical integrity was tested according to International Organization for Standardization (ISO) standards. CMR RF heating safety was tested in vitro in a phantom according to American Society for Testing and Materials (ASTM) F-2182 standard, and in vivo in seven swine. Results were compared with a high-performance commercial nitinol guidewire. RESULTS: The NHLBI passive guidewire exhibited similar mechanical behavior to the commercial comparator. RF heating was reduced from 13 degrees C in the commercial guidewire to 1.2 degrees C in the NHLBI passive guidewire in vitro, using a flip angle of 75 degrees . The maximum temperature increase was 1.1 +/- 0.3 degrees C in vivo, using a flip angle of 45 degrees . The guidewire was conspicuous during left heart catheterization in swine. CONCLUSIONS: We describe a simple and intrinsically safe design of a metallic guidewire for CMR cardiovascular catheterization. The guidewire exhibits negligible heating at high flip angles in conformance with regulatory guidelines, yet mechanically resembles a high performance commercial guidewire. Iron oxide markers along the length of the guidewire impart passive visibility during real-time CMR. Clinical translation is imminent. PMID- 26620421 TI - Outcomes of Chopart Amputation in a Tertiary Referral Diabetic Foot Clinic: Data From a Consecutive Series of 83 Hospitalized Patients. AB - The purpose of the present retrospective study was to evaluate the outcomes (ie, ulcer recurrence, major amputation, death) in diabetic patients undergoing Chopart amputation because of deep infection or gangrene extending to the midfoot. From 2009 to 2011, 83 patients, aged 71.4 +/- 9.3 years, underwent a midtarsal amputation and were followed up until December 31, 2012 (mean follow-up 2.8 +/- 0.8 years). Of the 83 patients, 26 were female, 61 required insulin, 47 had renal insufficiency, 19 underwent hemodialysis, 65 had hypertension, 34 had a history of cardiac disease, and 4 had a history of stroke. Chopart amputation was performed in 38 patients (45.8%) with gangrene, 31 (37.4%) with abscess, and 14 (16.9%) with osteomyelitis. Urgent surgery was performed in 56 patients (67.5%). Effective revascularization was performed in 64 patients (77.1%) patients. Of the 83 patients, 47 had healed at a mean period of 164.7 (range 11 to 698) days. Ulcer recurrence developed in 15 patients (31.9%). A major amputation was necessary in 23 patients (27.7%), with an annual incidence of 13.0%. None of the included variables on logistic regression analysis was significantly associated with proximal amputation. Of the 83 patients, 38 (45.8%) died, with an annual incidence of 25.8%. On logistic regression analysis, age (odds ratio [OR] 1.11, 95% confidence interval [CI] 1.01 to 1.16), history of stroke (OR 9.94, 95% CI 3.16 to 31.24), and urgent surgery (OR 2.60, 95% CI 1.14 to 5.93) were associated with mortality. Chopart amputation represents the last chance to avoid major amputation for diabetic patients with serious foot complications. Our success rate was great enough to consider Chopart amputation a viable option for limb salvage in this high-risk population. PMID- 26620422 TI - Mechanical control of cardiac myofibroblasts. AB - Fibroblasts produce and turn over collagenous extracellular matrix as part of the normal adaptive response to increased mechanical load in the heart, e.g. during prolonged exercise. However, chronic overload as a consequence of hypertension or myocardial injury trigger a repair program that culminates in the formation of myofibroblasts. Myofibroblasts are opportunistically activated from various precursor cells that all acquire a phenotype promoting excessive collagen secretion and contraction of the neo-matrix into stiff scar tissue. Stiff fibrotic tissue reduces heart distensibility, impedes pumping and valve function, contributes to diastolic and systolic dysfunction, and affects myocardial electrical transmission, potentially leading to arrhythmia and heart failure. Here, we discuss how mechanical factors, such as matrix stiffness and strain, are feeding back and cooperate with cytokine signals to drive myofibroblast activation. We elaborate on the importance of considering the mechanical boundary conditions in the heart to generate better cell culture models for mechanistic studies of cardiac fibroblast function. Elements of the force transmission and mechanoperception apparatus acting in myofibroblasts are presented as potential therapeutic targets to treat fibrosis. PMID- 26620423 TI - Interfacial Engineering of Semiconductor-Superconductor Junctions for High Performance Micro-Coolers. AB - The control of electronic and thermal transport through material interfaces is crucial for numerous micro and nanoelectronics applications and quantum devices. Here we report on the engineering of the electro-thermal properties of semiconductor-superconductor (Sm-S) electronic cooler junctions by a nanoscale insulating tunnel barrier introduced between the Sm and S electrodes. Unexpectedly, such an interface barrier does not increase the junction resistance but strongly reduces the detrimental sub-gap leakage current. These features are key to achieving high cooling power tunnel junction refrigerators, and we demonstrate unparalleled performance in silicon-based Sm-S electron cooler devices with orders of magnitudes improvement in the cooling power in comparison to previous works. By adapting the junctions in strain-engineered silicon coolers we also demonstrate efficient electron temperature reduction from 300 mK to below 100 mK. Investigations on junctions with different interface quality indicate that the previously unexplained sub-gap leakage current is strongly influenced by the Sm-S interface states. These states often dictate the junction electrical resistance through the well-known Fermi level pinning effect and, therefore, superconductivity could be generally used to probe and optimize metal semiconductor contact behaviour. PMID- 26620424 TI - Leucas aspera (Willd.) Link Essential Oil from India: beta-Caryophyllene and 1 Octen-3-ol Chemotypes. AB - Leucas aspera (Willd.) Link (Lamiaceae) is an annual, branched herb used in traditional medicine as an antipyretic and insecticide. The hydro-distilled essential oil was obtained from the aerial parts of L. aspera growing wild in North West Karnataka region of India and analyzed by gas chromatography equipped with flame ionization detector and gas chromatography coupled with mass spectrometry. Forty-three compounds were identified, representing 98.1% of the total oil. The main constituents were identified as beta-caryophyllene (34.2%), 1 octen-3-ol (14.8%), alpha-humulene (6.3%), alpha-pinene (5.8%), epi-alpha bisabolol (4.6%) and limonene (4.5%). The oil was found to be rich in sesquiterpene hydrocarbons (47.7%), followed by others (long chain hydrocarbons (LCH), oxygenated LCH and phenyl derivative constituents) (20.2%), monoterpene hydrocarbons (14.8%), oxygenated sesquiterpenes (14.8%) and oxygenated monoterpenes (0.6%) type compounds. PMID- 26620425 TI - Simultaneous Determination of Five Components in Aster tataricus by Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry. AB - A novel quantitative method using high-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry was developed for simultaneous determination of the important active constituents including shionone, luteolin, quercetin, kaempferol and ferulic acid in Aster tataricus from different habitats. The separation was performed on a C18 column with acidified aqueous acetonitrile gradients. Quantification of the analytes was achieved by the use of a hybrid quadrupole spectrometer. Multiple reaction monitoring scanning was employed with positive and negative modes at the same time in a single run. The validated results of the method indicated that the method was simple, rapid, specific and reliable. The results demonstrated that the quantitative difference in content of five active compounds was useful not only for chemotaxonomy of numerous samples from different sources but also for the standardization and differentiation of several similar samples. It was the first time to report a UPLC-ESI-MS-MS method for determination of five components in A. tataricus extract. Simultaneous quantification of bioactive components by UPLC-ESI-MS could be a well-acceptable strategy to control the quality of A. tataricus extract comprehensively. PMID- 26620427 TI - Money and Mental Health. PMID- 26620426 TI - The challenges and promises of allogeneic mesenchymal stem cells for use as a cell-based therapy. AB - Mesenchymal stem cells (MSCs) are ideal for cell-based therapy in various inflammatory diseases because of their immunosuppressive and tissue repair properties. Moreover, their immunosuppressive properties and low immunogenicity contribute to a reduced or weakened immune response elicited by the implantation of allogeneic MSCs compared with other cell types. Therefore, implantation of allogeneic MSCs may be a promising cell-based therapy. In this review, we first summarize the unique advantages of allogeneic MSCs for therapeutic applications. Second, we critically analyze the factors influencing their therapeutic effects, including administration routes, detection time-points, disease models, differentiation of MSCs in vivo, and timing and dosage of MSC administration. Finally, current approaches to allogeneic MSC application are discussed. In conclusion, allogeneic MSCs are a promising option because of their low immunogenicity and immunosuppressive and tissue repair capabilities. Further investigations are needed to enhance the consistency and efficacy of MSCs when used as a cell-based therapy in inflammatory diseases as well as for tissue repair. PMID- 26620439 TI - A plasma cytokine and angiogenic factor (CAF) analysis for selection of bevacizumab therapy in patients with metastatic colorectal cancer. AB - This study intends to identify biomarkers that could refine the selection of patients with metastatic colorectal cancer (mCRC) for bevacizumab treatment. Pretreatment 36 plasma cytokines and angiogenic factors (CAFs) were first measured by protein microarray analysis in patients who received first-line bevacizumab-containing therapies (discovery cohort, n = 64), and further evaluated by enzyme-linked immunosorbent assay in patients treated on regimens with or without bevacizumab (validation cohort, n = 186). Factor levels were correlated with clinical outcomes, predictive values were assessed using a treatment by marker interaction term in the Cox model. Patients with lower pretreatment levels of hepatocyte growth factor (HGF) or VEGF-A(121) gain much more benefit from bevacizumab treatment as measured by progression-free survival (PFS) and overall survival (OS), while angiopoietin-like 4 (ANGPTL4) levels negatively correlated with PFS and response rate following bevacizumab (all adjusted interaction P < 0.05). A baseline CAF signature combining these three markers has greater predictive ability than individual markers. Signature negative patients showed impaired survival following bevacizumab treatment (PFS, 7.3 vs 7.0 months; hazard ratio [HR] 1.03; OS, 29.9 vs 21.1 months, HR 1.33) compared with signature-positive patients (PFS, 6.5 vs 11.9 months, HR 0.52; OS, 28.0 vs 55.3 months, HR 0.67). These promising results warrant further prospective studies. PMID- 26620440 TI - Opportunities and challenges of Integral Projection Models for modelling host parasite dynamics. AB - Epidemiological dynamics are shaped by and may in turn shape host demography. These feedbacks can result in hard to predict patterns of disease incidence. Mathematical models that integrate infection and demography are consequently a key tool for informing expectations for disease burden and identifying effective measures for control. A major challenge is capturing the details of infection within individuals and quantifying their downstream impacts to understand population-scale outcomes. For example, parasite loads and antibody titres may vary over the course of an infection and contribute to differences in transmission at the scale of the population. To date, to capture these subtleties, models have mostly relied on complex mechanistic frameworks, discrete categorization and/or agent-based approaches. Integral Projection Models (IPMs) allow variance in individual trajectories of quantitative traits and their population-level outcomes to be captured in ways that directly reflect statistical models of trait-fate relationships. Given increasing data availability, and advances in modelling, there is considerable potential for extending this framework to traits of relevance for infectious disease dynamics. Here, we provide an overview of host and parasite natural history contexts where IPMs could strengthen inference of population dynamics, with examples of host species ranging from mice to sheep to humans, and parasites ranging from viruses to worms. We discuss models of both parasite and host traits, provide two case studies and conclude by reviewing potential for both ecological and evolutionary research. PMID- 26620441 TI - Isotretinoin treatment of autosomal recessive congenital ichthyosis complicated by coexisting dysferlinopathy. AB - Consanguinity is known to be associated with an increase in the prevalence of autosomal recessive disorders such as autosomal recessive congenital ichthyosis (ARCI). ARCI often responds well to retinoid treatment. We describe a patient with ARCI who improved under isotretinoin treatment. The patient subsequently developed elevated levels of serum creatinine phosphokinase (CPK), which led to the diagnosis of a second autosomal recessive disorder, dysferlinopathy, a rare myopathy characterized by muscle weakness, decreased tendon reflexes and marked elevation of CPK levels. This report demonstrates the need for physicians to remain alert to the possible coexistence of rare and mutually relevant disorders in populations with a high rate of consanguinity. PMID- 26620442 TI - Intracranial pressure changes during mouse development. AB - During early stages of postnatal development, pressure from the growing brain as well as cerebrospinal fluid, i.e. intracranial pressure (ICP), load the calvarial bones. It is likely that such loading contributes to the peripheral bone formation at the sutural edges of calvarial bones, especially shortly after birth when the brain is growing rapidly. The aim of this study was to quantify ICP during mouse development. A custom pressure monitoring system was developed and calibrated. It was then used to measure ICP in a total of seventy three wild type mice at postnatal (P) day 3, 10, 20, 31 and 70. Retrospectively, the sample in each age group with the closest ICP to the average value was scanned using micro computed tomography to estimate cranial growth. ICP increased from 1.33+/ 0.87mmHg at P3 to 1.92+/-0.78mmHg at P10 and 3.60+/-1.08mmHg at P20. In older animals, ICP plateaued at about 4mmHg. There were statistically significant differences between the ICP at the P3 vs. P20, and P10 vs. P20. In the samples that were scanned, intracranial volume and skull length followed a similar pattern of increase up to P20 and then plateaued at older ages. These data are consistent with the possibility of ICP being a contributing factor to bone formation at the sutures during early stages of development. The data can be further used for development and validation of computational models of skull growth. PMID- 26620443 TI - Letter to the editor regarding "In vitro flow investigations in the aortic arch during cardiopulmonary bypass with stereo-PIV". PMID- 26620444 TI - Active Site Structure and Peroxidase Activity of Oxidatively Modified Cytochrome c Species in Complexes with Cardiolipin. AB - We report a resonance Raman and UV-vis characterization of the active site structure of oxidatively modified forms of cytochrome c (Cyt-c) free in solution and in complexes with cardiolipin (CL). The studied post-translational modifications of Cyt-c include methionine sulfoxidation and tyrosine nitration, which lead to altered heme axial ligation and increased peroxidase activity with respect to those of the wild-type protein. In spite of the structural and activity differences between the protein variants free in solution, binding to CL liposomes induces in all cases the formation of a spectroscopically identical bis His axial coordination conformer that more efficiently promotes lipid peroxidation. The spectroscopic results indicate that the bis-His form is in equilibrium with small amounts of high-spin species, thus suggesting a labile distal His ligand as the basis for the CL-induced increase in enzymatic activity observed for all protein variants. For Cyt-c nitrated at Tyr74 and sulfoxidized at Met80, the measured apparent binding affinities for CL are ~4 times larger than for wild-type Cyt-c. On the basis of these results, we propose that these post-translational modifications may amplify the pro-apoptotic signal of Cyt-c under oxidative stress conditions at CL concentrations lower than for the unmodified protein. PMID- 26620445 TI - Suppurative peritonitis by Klebsiella pneumoniae in captive gold-handed tamarin (Saguinus midas midas). AB - This report describes an outbreak of suppurative peritonitis caused by Klebsiella pneumoniae in an adult female of captive golden-handed tamarin (Saguinus midas midas). Two virulent and multidrug-resistant strains were isolated and classified through MLST as ST60 and ST1263. The microbiological diagnosis works as a support tool for preventive measures. PMID- 26620447 TI - Reliability and agreement of adipose tissue fat fraction measurements with water fat MRI in patients with manifest cardiovascular disease. AB - The supraclavicular fat depot is known for brown adipose tissue presence. To unravel adipose tissue physiology and metabolism, high quality and reproducible imaging is required. In this study we quantified the reliability and agreement of MRI fat fraction measurements in supraclavicular and subcutaneous adipose tissue of 25 adult patients with clinically manifest cardiovascular disease. MRI fat fraction measurements were made under ambient temperature conditions using a vendor supplied mDixon chemical-shift water-fat multi-echo pulse sequence at 1.5 T field strength. Supraclavicular fat fraction reliability (intraclass correlation coefficientagreement , ICCagreement ) was 0.97 for test-retest, 0.95 for intra-observer and 0.56 for inter-observer measurements, which increased to 0.88 when ICCconsistency was estimated. Supraclavicular fat fraction agreement displayed mean differences of 0.5% (limit of agreement (LoA) -1.7 to 2.6) for test-retest, -0.5% (LoA -2.9 to 2.0) for intra-observer and 5.6% (LoA 0.4 to 10.8) for inter-observer measurements. Median fat fraction in supraclavicular adipose tissue was 82.5% (interquartile range (IQR) 78.6-84.0) and 89.7% (IQR 87.2-91.5) in subcutaneous adipose tissue (p < 0.0001). In conclusion, water-fat MRI has good reliability and agreement to measure adipose tissue fat fraction in patients with manifest cardiovascular disease. These findings enable research on determinants of fat fraction and enable longitudinal monitoring of fat fraction within adipose tissue depots. Interestingly, even in adult patients with manifest cardiovascular disease, supraclavicular adipose tissue has a lower fat fraction compared with subcutaneous adipose tissue, suggestive of distinct morphologic characteristics, such as brown adipose tissue. PMID- 26620446 TI - Within patient microevolution of Mycobacterium tuberculosis correlates with heterogeneous responses to treatment. AB - Genetic heterogeneity of Mycobacterium tuberculosis (MTB) within a patient has caused great concern as it might complicate antibiotic treatment and cause treatment failure. But the extent of genetic heterogeneity has not been described in detail nor has its association with heterogeneous treatment response. During treatment of a subject with MDR-TB, serial computed tomography (CT) scans showed this subject had six anatomically discrete lesions and they responded to treatment with disparate kinetics, suggesting heterogeneous MTB population may exist. To investigate this heterogeneity, we applied deep whole genome sequencing of serial sputum isolates and discovered that the MTB population within this patient contained three dominant sub-clones differing by 10 ~ 14 single nucleotide polymorphisms (SNPs). Differential mutation patterns in known resistance alleles indicated these sub-clones had different drug-resistance patterns, which may explain the heterogeneous treatment responses between lesions. Our results showed clear evidence of branched microevolution of MTB in vivo, which led to a diverse bacterial community. These findings indicated that complex sub-populations of MTB might coexist within patient and contribute to lesions' disparate responses to antibiotic treatment. PMID- 26620448 TI - Clinical and radiological outcome after anterior cervical discectomy and fusion with stand-alone empty polyetheretherketone (PEEK) cages. AB - OBJECTIVE: To evaluate long-term results after one-, two-, and three-level anterior cervical discectomy and fusion (ACDF) with stand-alone empty polyetheretherketone (PEEK) cages. METHODS: We performed a retrospective review of a consecutive patient cohort that underwent ACDF with stand-alone empty PEEK cages between 2007 and 2010 with a minimum follow-up of 12 months. Radiographic follow-up included static and flexion/extension radiographs. Changes in the operated segments were measured and compared to radiographs directly after surgery. Clinical outcome was evaluated by a physical examination, pain visual analog scale (VAS), and health-related quality of life (HRQL) using the EuroQOL questionnaire (EQ-5D). Analysis of associations between fusion, subsidence, cervical alignment, and clinical outcome parameters were performed. RESULTS: Of 407 consecutive cases, 318 met all inclusion criteria. Follow-up data were obtained from 265 (83 %) cases. The mean age at presentation was 55 years and 139 patients were male (52 %). In the sample, 127, 125, and 13 patients had one-, two , and three-level surgeries, respectively; 132 (49 %) presented with spondylotic cervical myelopathy and 133 (50 %) with cervical radiculopathy. Fusion was achieved in 85, 95, and 94 % of segments in one-, two-, and three-level surgeries, respectively. Non-fusion was associated with higher VAS pain levels. Radiographic adjacent segment disease (ASD) was observed in 20, 29, and 15 % in one-, two-, and three-level surgeries, respectively. ASD was associated with lower HRQL. Subsidence was observed in 25, 27, and 15 % of segments in one-, two , and three-level surgeries, respectively. However, this had no influence on clinical outcome. Follow-up operations for symptomatic adjacent disc disease and implant failure at index level were needed in 16 (6 %) and four (1.5 %) cases, respectively. Younger age was associated with better clinical outcome. Multilevel surgery favored better myelopathy outcomes and fusion reduced overall pain. ASD worsened EuroQOL-Index values. Worsening of the cervical alignment induced arm pain. CONCLUSIONS: One- and two-level ACDF with stand-alone empty PEEK cages achieved very high fusion rates and a low rate of follow-up operations. The rate of good clinical outcome is highly satisfactory. Younger age was the single most influential factor associated with better clinical outcome. PMID- 26620450 TI - Exploring factors underlying the attitude of community pharmacists to generic substitution: a nationwide study from Poland. AB - BACKGROUND: Generic uptake will increasingly be promoted by governments in the face of increasing healthcare costs and global economic uncertainties. OBJECTIVE: The purpose of this study was to investigate attitudes towards generic substitution among community pharmacists, with a focus on the perception of the efficacy, knowledge of the generics characteristics, as well as the willingness to recommend generic substitution. SETTING: Community pharmacies in Poland. METHOD: The survey was conducted in 2013 by telephone interviews with 802 holders of an MSc degree in pharmacy working as community pharmacists. Stratified sampling was implemented to make the study representative in geographic terms. MAIN OUTCOME MEASURE: Pharmacists' attitudes towards generics drugs. RESULTS: The study showed that only 40 % of pharmacists always inform patients about their right to choose a generic substitute. It was also shown that the less time a pharmacist has been practising, the less likely they are to invite consumers to choose between generic and innovator products. The likelihood of informing was not affected by pharmacist's sex or age, or by pharmacy location or status (chain vs. independent pharmacy) (p > 0.05). Pharmacists varied in their approach to their statutory obligation to inform about a generic; a more or less equal share of respondents were either in favour or against it. Approximately 60 % pharmacists were shown to be familiar with the definition of a generic medicine. Pharmacists with shorter time of practice proved to know more about generics. However, more than 30 % respondents failed to choose the correct statement on generic versus reference medicine dosage. The majority of respondents (67 %) believed there are no differences in efficacy between generics and innovator drugs, whereas 31 % claimed that original brands could be more effective. A significant correlation was demonstrated between the views of pharmacists on the therapeutic efficacy and their willingness to substitute for generics whenever permitted by a physician. CONCLUSION: It is important to address all concerns pharmacists may have over generics, for example by implementing comprehensive awareness-raising campaigns. Also, pharmacotherapy monitoring systems (i.e. provided in a framework of pharmaceutical care) could be considered to identify any safety or quality concerns that may arise. PMID- 26620452 TI - Learning in Cardiology Fellowship: Opportunities for Optimization. AB - Cardiology fellowship is filled with opportunities for learning; however, numerous obstacles must be successfully navigated to complete training with the knowledge, skills, and attitudes necessary for a successful career. To assist Cardiology fellows in prioritizing their time and energy in order to fully gain from their training, a list of recommendations with rationales has been provided. PMID- 26620451 TI - The association between childhood relocations and subsequent risk of suicide attempt, psychiatric problems, and low academic achievement. AB - BACKGROUND: Given the frequency with which families change residences, the effects of childhood relocations have gained increasing research attention. Many researchers have demonstrated that childhood relocations are associated with a variety of adverse outcomes. However, drawing strong causal claims remains problematic due to uncontrolled confounding factors. METHOD: We utilized longitudinal, population-based Swedish registers to generate a nationally representative sample of offspring born 1983-1997 (n = 1 510 463). Using Cox regression and logistic regression, we examined the risk for numerous adverse outcomes after childhood relocation while controlling for measured covariates. To account for unmeasured genetic and environmental confounds, we also compared differentially exposed cousins and siblings. RESULTS: In the cohort baseline model, each annual relocation was associated with risk for the adverse outcomes, including suicide attempt [hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.19-1.20]. However, when accounting for offspring and parental covariates (HR 1.08, 95% CI 1.07-1.09), as well as genetic and environmental confounds shared by cousins (HR 1.07, 95% CI 1.05-1.09) and siblings (HR 1.00, 95% CI 0.97-1.04), the risk for suicide attempt attenuated. We found a commensurate pattern of results for severe mental illness, substance abuse, criminal convictions, and low academic achievement. CONCLUSIONS: Previous research may have overemphasized the independent association between relocations and later adverse outcomes. The results suggest that the association between childhood relocations and suicide attempt, psychiatric problems, and low academic achievement is partially explained by genetic and environmental confounds correlated with relocations. This study demonstrates the importance of using family-based, quasi-experimental designs to test plausible alternate hypotheses when examining causality. PMID- 26620453 TI - Longitudinal influence of musculo-skeletal injuries and extra physical education on physical fitness in schoolchildren. AB - The aims of this study were to investigate if (A) injuries and (B) increased physical education (PE) influenced the development of physical fitness in schoolchildren. Simultaneously, to investigate if a possible PE effect was modified by sport participation outside school hours. This was a longitudinal controlled school-based study. Six schools with 270 min of PE (extra PE) and four schools with 90 min of PE were followed up for 2.5 years. In total, 1054 children were included for analysis (normal PE = 443, extra PE = 611). Development in fitness was analyzed using composite z-scores from six fitness tests measured four times. Information of injury and sport was derived from weekly automated mobile phone text messages surveying the presence of musculo-skeletal pain and organized sport participation. Injury and extra PE both influenced the development of physical fitness. Injury decreased development of physical fitness with -1.01 composite z-score units (95% CI: -1.57; -0.45). Extra PE increased physical fitness development with 0.80 (95% CI: 0.49; 1.10) composite z-score units. The influence of injury was not dependent on extra PE. No modifying effect was found by mean weekly sport participation outside school hours. In conclusion, extra PE had a positive effect, whereas injuries had a negative effect on physical fitness development in schoolchildren. PMID- 26620454 TI - Refining the American Urological Association and American Society for Radiation Oncology guideline for adjuvant radiotherapy after radical prostatectomy using the pathologic Gleason score. AB - Recently, it has been suggested that the guideline for adjuvant radiotherapy (ART) following radical prostatectomy (RP) sponsored by the American Urological Association and American Society for Radiation Oncology (AUA/ASTRO) may result in a significant overtreatment. Thus, the objective of the present study was to refine the AUA/ASTRO guideline for ART in patients at risk for biochemical recurrence (BCR) after RP. To this end, we reviewed our prospectively maintained database and selected 193 patients who met the AUA/ASTRO ART criteria. With a median follow-up of 24.0 months, BCR rate was 17.6% (34/193). When stratified by the Gleason score, BCR rate in men with Gleason score 6 was 6.8%. There was no significant association between BCR-free survival and surgical margin (P = 0.690) and pathologic stage (P = 0.353) in patients with the Gleason score 6. However, in patients with positive surgical margins (PSMs)/pathologic stage >=T3, there was a significant difference in BCR-free survival according to Gleason score (<= 7 vs 8-10, P = 0.047). Multivariate Cox regression analysis demonstrated that pathologic stage >=T3 (HR = 2.106; P= 0.018), PSMs (HR = 2.411; P= 0.003), and pathologic Gleason score 8-10 (HR = 4.715; P< 0.001) were independent predictors of BCR after RP. Therefore, in addition to pathologic stage >=T3 and PSMs, Gleason score 8-10 predicts BCR after RP. In patients with Gleason score 6, observation rather than ART may be more appropriate regardless of stage and surgical margin status. PMID- 26620449 TI - The effect of journal impact factor, reporting conflicts, and reporting funding sources, on standardized effect sizes in back pain trials: a systematic review and meta-regression. AB - BACKGROUND: Low back pain is a common and costly health complaint for which there are several moderately effective treatments. In some fields there is evidence that funder and financial conflicts are associated with trial outcomes. It is not clear whether effect sizes in back pain trials relate to journal impact factor, reporting conflicts of interest, or reporting funding. METHODS: We performed a systematic review of English-language papers reporting randomised controlled trials of treatments for non-specific low back pain, published between 2006-2012. We modelled the relationship using 5-year journal impact factor, and categories of reported of conflicts of interest, and categories of reported funding (reported none and reported some, compared to not reporting these) using meta regression, adjusting for sample size, and publication year. We also considered whether impact factor could be predicted by the direction of outcome, or trial sample size. RESULTS: We could abstract data to calculate effect size in 99 of 146 trials that met our inclusion criteria. Effect size is not associated with impact factor, reporting of funding source, or reporting of conflicts of interest. However, explicitly reporting 'no trial funding' is strongly associated with larger absolute values of effect size (adjusted beta=1.02 (95 % CI 0.44 to 1.59), P=0.001). Impact factor increases by 0.008 (0.004 to 0.012) per unit increase in trial sample size (P<0.001), but does not differ by reported direction of the LBP trial outcome (P=0.270). CONCLUSIONS: The absence of associations between effect size and impact factor, reporting sources of funding, and conflicts of interest reflects positively on research and publisher conduct in the field. Strong evidence of a large association between absolute magnitude of effect size and explicit reporting of 'no funding' suggests authors of unfunded trials are likely to report larger effect sizes, notwithstanding direction. This could relate in part to quality, resources, and/or how pragmatic a trial is. PMID- 26620455 TI - Augmented reality assisted surgery: a urologic training tool. AB - Augmented reality is widely used in aeronautics and is a developing concept within surgery. In this pilot study, we developed an application for use on Google Glass (r) optical head-mounted display to train urology residents in how to place an inflatable penile prosthesis. We use the phrase Augmented Reality Assisted Surgery to describe this novel application of augmented reality in the setting of surgery. The application demonstrates the steps of the surgical procedure of inflatable penile prosthesis placement. It also contains software that allows for detection of interest points using a camera feed from the optical head-mounted display to enable faculty to interact with residents during placement of the penile prosthesis. Urology trainees and faculty who volunteered to take part in the study were given time to experience the technology in the operative or perioperative setting and asked to complete a feedback survey. From 30 total participants using a 10-point scale, educational usefulness was rated 8.6, ease of navigation was rated 7.6, likelihood to use was rated 7.4, and distraction in operating room was rated 4.9. When stratified between trainees and faculty, trainees found the technology more educationally useful, and less distracting. Overall, 81% of the participants want this technology in their residency program, and 93% see this technology in the operating room in the future. Further development of this technology is warranted before full release, and further studies are necessary to better characterize the effectiveness of Augmented Reality Assisted Surgery in urologic surgical training. PMID- 26620456 TI - The performance characteristics of prostate-specific antigen and prostate specific antigen density in Chinese men. AB - We investigated the performance characteristics of prostate-specific antigen (PSA) and PSA density (PSAD) in Chinese men. All Chinese men who underwent transrectal ultrasound-guided prostate biopsy (TRUS-PB) from year 2000 to 2013 were included. The receiver operating characteristic (ROC) curves for both PSA and PSAD were analyzed. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) at different cut-off levels were calculated. A total of 2606 Chinese men were included. For the ROC, the area under curve was 0.770 for PSA (P < 0.001) and 0.823 for PSAD (P < 0.001). PSA of 4.5 ng ml-1 had sensitivity of 94.4%, specificity of 14.1%, PPV of 29.5%, and NPV of 86.9%; PSAD of 0.12 ng ml-1 cc-1 had sensitivity of 94.5%, specificity of 26.6%, PPV of 32.8%, and NPV of 92.7%. On multivariate logistic regression analyses, PSA cut-off at 4.5 ng ml-1 (OR 1.61, 95% CI 1.05-2.45, P= 0.029) and PSAD cut-off at 0.12 ng ml-1 cc-1 (OR 6.22, 95% CI 4.20-9.22, P< 0.001) were significant predictors for prostate cancer detection on TRUS-PB. In conclusion, the performances of PSA and PSAD at different cut-off levels in Chinese men were very different from those in Caucasians. PSA of 4.5 ng ml-1 and PSAD of 0.12 ng ml-1 cc-1 had near 95% sensitivity and were significant predictors of prostate cancer detection in Chinese men. PMID- 26620457 TI - Comparison of quercetin and resveratrol in the prevention of injury due to testicular torsion/detorsion in rats. AB - Quercetin (QE) and resveratrol (RSV) are powerful antioxidants with the potential to protect the testes against ischemia/reperfusion (I/R) injury. We compared their effects in testicular torsion/detorsion (T/D) in adult rats. Twenty-four male Wistar rats were divided into four groups: sham (group A), T/D (group B), T/D treated with QE (group C), and T/D treated with RSV (group D). QE (20 mg kg-1 ) and RSV (20 mg kg-1 ) were injected intra-peritoneally at 60 min of torsion. After 90 min of surgically induced torsion, the testicular cord was restored to its anatomical position. Twenty-four hour after torsion, blood and tissue samples were obtained for further examination. Testicular tissue malondialdehyde (MDA) and nitric oxide (NO) levels and serum total oxidant status (TOS) were higher in group B than in group A (P < 0.05). Group A had higher serum total antioxidant status (TAS) than group B. (P < 0.05) QE and RSV significantly lowered MDA, NO, and TOS levels and TAS consumption (P < 0.05). QE reduced the MDA and TOS levels more than RSV (P < 0.05), but their effects on NO reduction and TAS consumption were similar (P > 0.05). Group A had normal testicular architecture (grade 1). Groups C (mean grade 2.60) and D (mean grade 3.00) had lower testicular injury grades than group B (mean grade 3.45) (P < 0.05). Group C had lower testicular injury grade than group D (P < 0.05). Treatment with QE and RSV protects against I/R injury after testicular T/D. QE may exhibit better function than RSV at the doses tested in this study. PMID- 26620459 TI - Intracytoplasmic sperm injection outcomes in Chinese men with multiple morphological abnormalities of sperm flagella. PMID- 26620460 TI - Critical appraisal of conventional semen analysis in the context of varicocele. AB - Varicocele is present in approximately 15% of men, and, although it is the most commonly diagnosed cause of male infertility, nearly two-thirds of men with varicoceles remain fertile. It was decided to make use of the current evidence obtained from the previous meta-analyses between 2004 and 2015 as well as available articles covering this field, preferably randomized controlled articles dealing with the topic of semen analysis before and after repair. Two important meta-analyses were discussed as well as other articles dealing with the topic of semen analysis before and after varicocelectomy. The evidence suggests that all semen parameters improve after varicocele repair. Based on the available evidence, it is clear that there is a benefit in treating men with a palpable varicocele. One can expect that all semen parameters will improve within 3 months after repair. PMID- 26620458 TI - Clinical and preclinical treatment of urologic diseases with phosphodiesterase isoenzymes 5 inhibitors: an update. AB - Phosphodiesterase isoenzymes 5 inhibitors (PDE5-Is) are the first-line therapy for erectile dysfunction (ED). The constant discoveries of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) cell-signaling pathway for smooth muscle (SM) control in other urogenital tracts (UGTs) make PDE5-Is promising pharmacologic agents against other benign urological diseases. This article reviews the literature and contains some previously unpublished data about characterizations and activities of PDE5 and its inhibitors in treating urological disorders. Scientific discoveries have improved our understanding of cell-signaling pathway in NO/cGMP-mediated SM relaxation in UGTs. Moreover, the clinical applications of PDE5-Is have been widely recognized. On-demand PDE5-Is are efficacious for most cases of ED, while daily-dosing and combination with testosterone are recommended for refractory cases. Soluble guanylate cyclase (sGC) stimulators also have promising role in the management of severe ED conditions. PDE5-Is are also the first rehabilitation strategy for postoperation or postradiotherapy ED for prostate cancer patients. PDE5-Is, especially combined with alpha-adrenoceptor antagonists, are very effective for benign prostatic hyperplasia (BPH) except on maximum urinary flow rate (Q max ) with tadalafil recently proved for BPH with/without ED. Furthermore, PDE5-Is are currently under various phases of clinical or preclinical researches with promising potential for other urinary and genital illnesses, such as priapism, premature ejaculation, urinary tract calculi, overactive bladder, Peyronie's disease, and female sexual dysfunction. Inhibition of PDE5 is expected to be an effective strategy in treating benign urological diseases. However, further clinical studies and basic researches investigating mechanisms of PDE5-Is in disorders of UGTs are required. PMID- 26620462 TI - The nervous systems of Tylodelphys metacercariae (Digenea: Diplostomidae) from the catfish Clarias gariepinus (Clariidae) in freshwater habitats of Tanzania. AB - The nervous systems of three Tylodelphys metacercariae (T. mashonense, Tylodelphys spp. 1 and 2) co-occurring in the cranial cavity of the catfish, Clarias gariepinus, were examined by the activity of acetylthiocholine iodide (AcThI), with the aim of better understanding the arrangement of sensillae on the body surface and the nerve trunks and commissures, for taxonomic purposes. Enzyme cytochemistry demonstrated a comparable orthogonal arrangement in the three metacercariae: the central nervous system (CNS) consisting of a pair of cerebral ganglia, from which anterior and posterior neuronal pathways arise and inter-link by cross-connectives and commissures. However, the number of transverse nerves was significantly different in the three diplostomid metacercariae: Tylodelphys sp. 1 (30), Tylodelphys sp. 2 (21) and T. mashonense (15). The observed difference in the nervous system of the three metacercariae clearly separates them into three species. These findings suggest that consistent differences in the transverse nerves of digenean metacercariae could enable the differentiation of metacercariae to the species level in the absence of molecular techniques. This, however, might require further testing on a larger number of species of digenean metacercariae. PMID- 26620461 TI - iTRAQ proteomic analysis of extracellular matrix remodeling in aortic valve disease. AB - Degenerative aortic stenosis (AS) is the most common worldwide cause of valve replacement. The aortic valve is a thin, complex, layered connective tissue with compartmentalized extracellular matrix (ECM) produced by specialized cell types, which directs blood flow in one direction through the heart. There is evidence suggesting remodeling of such ECM during aortic stenosis development. Thus, a better characterization of the role of ECM proteins in this disease would increase our understanding of the underlying molecular mechanisms. Aortic valve samples were collected from 18 patients which underwent aortic valve replacement (50% males, mean age of 74 years) and 18 normal control valves were obtained from necropsies (40% males, mean age of 69 years). The proteome of the samples was analyzed by 2D-LC MS/MS iTRAQ methodology. The results showed an altered expression of 13 ECM proteins of which 3 (biglycan, periostin, prolargin) were validated by Western blotting and/or SRM analyses. These findings are substantiated by our previous results demonstrating differential ECM protein expression. The present study has demonstrated a differential ECM protein pattern in individuals with AS, therefore supporting previous evidence of a dynamic ECM remodeling in human aortic valves during AS development. PMID- 26620463 TI - Construct Validity of the Relationship Profile Test: Links With Measures of Psychopathology and Adult Attachment. AB - This study assessed the construct validity of the Relationship Profile Test (RPT; Bornstein & Languirand, 2003 ) with a substance abuse sample. One hundred-eight substance abuse patients completed the RPT, Experiences in Close Relationships Scale-Short Form (Wei, Russell, Mallinckrodt, & Vogel, 2007 ), Personality Assessment Inventory (Morey, 1991 ), and Symptom Checklist-90-Revised (Derogatis, 1983 ). Results suggest that the RPT has good construct validity when compared against theoretically related broadband measures of personality, psychopathology, and adult attachment. Overall, health dependency was negatively related to measures of psychopathology and insecure attachment, and overdependence was positively related to measures of psychopathology and attachment anxiety. Many of the predictions regarding RPT detachment and the criterion measures were not supported. Implications of these findings are discussed. PMID- 26620464 TI - Applications of molecular diagnostics for personalized treatment of head and neck cancer: state of the art. AB - Squamous cell carcinomas of the head and neck are the sixth most frequent tumors worldwide. Risk factors are carcinogenic exposure, infection with the human papillomavirus (HPV) and genetic predisposition. Lymph node metastasis in the neck and HPV status are major prognostic factors. There are several important clinical challenges that determine the research agenda in head and neck cancer. The first is more accurate staging, particularly of occult metastatic lymph nodes in the neck. A second challenge is the lack of biomarkers for personalized therapy. There are a number of treatment modalities that can be employed both single and in combination, but at present only site and stage of the tumor are used for treatment planning. Provided here is an overview of the successes and failures of molecular diagnostic approaches that have been and are being evaluated to address these clinical challenges. PMID- 26620465 TI - Erratum to: Giant extragenital Bowen's disease. PMID- 26620466 TI - [Are artificial disorders common in palliative care? A Case report]. AB - The main task of palliative care specialists is to focus on symptom control such as pain, nausea or fatigue. Thorough anamnesis, physical examination, laboratory examination, and differential diagnosis can ensure appropriate treatment. In an increasing number of cases psychiatric conditions like depression or anxiety increase also occur so palliative care physicians need to be more prepared to handle them. The question of this case report is, how a palliative care specialist can distinguish between a malignant disease or neurological disease progression and a presentation primarily psychiatric in etiology, as is the case in factitious disorders. We are also interested in the incidence rate of such factitious disorders. Our case study demonstrates that it is rare but not impossible that a doctor will encounter factitious symptoms in the palliative setting. This suggest being aware of evidence of psychiatric origins even in discharge letters and referrals that indicate palliative care needs, to ensure that palliative care really is the best treatment option for the patient. We do believe such cases to be rare in a palliative setting, however. PMID- 26620467 TI - [Risc factors for assisted suicide for cancer patients - mental burden of bereaved]. AB - Chronic and progressive disease represents a significant risk factor for suicidal behavior. Cancer patients have almost twice the rate of suicides compared to the general population. Based on a case report, the suicidal risk factors for cancer patients are presented. It is further investigated to what extent professional support by a mobile palliative care team can affect the wish for assisted suicide or the suicidal behavior generally among patients receiving palliative care. In addition, the mental impact on individuals, who were witnesses of assisted suicide of relatives or close friends are presented. The occurrence of posttraumatic stress disorder (PTSD), depressions, anxiety disorders and complicated grief (CG) in close family members is shown. However, further research will be necessary to develop adequate support for patients (and their relatives), who plan an assisted suicide. PMID- 26620468 TI - When is an invasive palliative intervention in an acute internal medical patient worth it? A structured palliative approach. AB - A 67-year-old patient with coronary artery disease (CAD), diabetes, and chronic obstructive pulmonary disease (COPD) was scheduled for coronary artery bypass graft (CABG) surgery after a recent myocardial infarction despite a high perioperative risk of death. While waiting, acute renal failure developed, and the patient was admitted to the intensive care unit (ICU). After the patient and his wife were informed that CABG surgery was no longer possible, he declined further intensive care treatment and subsequently died peacefully.We show that a structured palliative approach which has been proposed for cancer patients may also be feasible in palliative situations concerning nononcologic patients. PMID- 26620469 TI - Top 25 cited articles on Gamma Knife surgery published since 2005 in journals of the American Association of Neurological Surgeons. PMID- 26620471 TI - Kinetic Model of Surface Segregation in Pt-Based Alloys. AB - A new vacancy model describes the kinetic process of surface segregation on clean surfaces via atomic movement through vacancies. The detailed segregation mechanism of two impurity metals (Au and Co) in Pt(111) is examined using periodic density functional theory, carefully evaluating energy barriers for each step in the segregation process. Au shows a strong surface segregation trend to the clean Pt(111) surface, while Co segregating to the surface is neither thermodynamically nor kinetically favorable. PMID- 26620470 TI - Stable kinetochore-microtubule attachment is sufficient to silence the spindle assembly checkpoint in human cells. AB - During mitosis, duplicated sister chromatids attach to microtubules emanating from opposing sides of the bipolar spindle through large protein complexes called kinetochores. In the absence of stable kinetochore-microtubule attachments, a cell surveillance mechanism known as the spindle assembly checkpoint (SAC) produces an inhibitory signal that prevents anaphase onset. Precisely how the inhibitory SAC signal is extinguished in response to microtubule attachment remains unresolved. To address this, we induced formation of hyper-stable kinetochore-microtubule attachments in human cells using a non-phosphorylatable version of the protein Hec1, a core component of the attachment machinery. We find that stable attachments are sufficient to silence the SAC in the absence of sister kinetochore bi-orientation and strikingly in the absence of detectable microtubule pulling forces or tension. Furthermore, we find that SAC satisfaction occurs despite the absence of large changes in intra-kinetochore distance, suggesting that substantial kinetochore stretching is not required for quenching the SAC signal. PMID- 26620472 TI - Assessment of the Performance of the M05-2X and M06-2X Exchange-Correlation Functionals for Noncovalent Interactions in Biomolecules. AB - The highly parametrized, empirical exchange-correlation functionals, M05-2X and M06-2X, developed by Zhao and Truhlar have been shown to describe noncovalent interactions better than density functionals which are currently in common use. However, these methods have yet to be fully benchmarked for the types of interactions important in biomolecules. M05-2X and M06-2X are claimed to capture "medium-range" electron correlation; however, the "long-range" electron correlation neglected by these functionals can also be important in the binding of noncovalent complexes. Here we test M05-2X and M06-2X for the nucleic acid base pairs in the JSCH-2005 database. Using the CCSD(T) binding energies as a benchmark, the performance of these functionals is compared to that of a nonempirical density functional, PBE, and also to that of PBE plus Grimme's empirical dispersion correction, PBE-D. Due to the importance of "long-range" electron correlation in hydrogen-bonded and interstrand base pairs, PBE-D provides more accurate interaction energies on average for the JSCH-2005 database when compared to M05-2X or M06-2X. M06-2X does, however, perform somewhat better than PBE-D for interactions between stacked base pairs. PMID- 26620473 TI - United-Atom Discrete Molecular Dynamics of Proteins Using Physics-Based Potentials. AB - We present a method for the efficient simulation of the equilibrium dynamics of proteins based on the well established discrete molecular dynamics algorithm, which avoids integration of Newton equations of motion at short time steps, allowing then the derivation of very large trajectories for proteins with a reduced computational cost. In the presented implementation we used an all heavy atoms description of proteins, with simple potentials describing the conformational region around the experimental structure based on local physical interactions (covalent structure, hydrogen bonds, hydrophobic contacts, solvation, steric hindrance, and bulk dispersion interactions). The method shows a good ability to describe the flexibility of 33 diverse proteins in water as determined by atomistic molecular dynamics simulation and can be useful for massive simulation of proteins in crowded environments or for refinement of protein structure in large complexes. PMID- 26620474 TI - Al5O4: A Superatom with Potential for New Materials Design. AB - The Al5O4(-) cluster displays a highly symmetric (D4h) planar ring structure and magic cluster stability. The enhanced stability of this nonstoichiometric cluster is the result of an unconventional electronic distribution within the cluster, which is different from that found in stoichiometric Al2O3. The corresponding neutral Al5O4 cluster exhibits a strong electron affinity (3.5 eV) that is very close to that of a chlorine atom (3.6 eV). When interacting with the electropositive metals (M = Li, Na, K, etc.), the neutral cluster captures one electron and forms a "binary salt" composed of Al5O4(-) anion and M(+) cation. Interestingly, the geometric and electronic structure of bare Al5O4(-) is completely retained in the salt structure. This suggests that Al5O4 behaves as a superatom and Al5O4M is reminiscent of a diatomic ionic molecule such as NaCl or KCl. We have also demonstrated that Al5O4M can be used as a building block to construct new solid state materials. A detailed structural analysis of the monomer, dimer, and trimer of Al5O4M reveals that while M tends to coordinate with the cluster oxygen in monomeric Al5O4M, the binding preference is significantly changed in the presence of multiple metal and cluster ions. In this case, M favors coordinating to the terminal Al atoms in the cluster where the four highest occupied molecular orbitals are distributed. Based on these observations, we have designed new 1-D, 2-D, and 3-D extended networks using Al5O4M as the building block. The 3-D periodic lattice displays a structure similar to that in zeolites and, therefore, may exhibit behavior useful for applications as molecular sieves. PMID- 26620475 TI - Fragment-Localized Kohn-Sham Orbitals via a Singles Configuration-Interaction Procedure and Application to Local Properties and Intermolecular Energy Decomposition Analysis. AB - As for generating localized Hartree-Fock orbitals, we propose a potentially linear-scaling singles-CI scheme to construct fragment-localized density functional theory (DFT) orbitals for molecular systems as water clusters. Due to the use of a deformation step instead of a localization step, the influence of the environment on each separate molecule can be studied in detail. The generated orbital set for the whole molecular system is strictly equivalent to a set of canonical orbitals and is a subsequent energy decomposition of intermolecular interactions into electrostatic, exchange repulsion, and orbital interaction, well beyond dimer systems. Beyond this, the correspondence of the individual orbitals to the initial monomer orbitals permits to assess how an interaction deforms an electron density. We show this for dipole moments, which may be decomposed into monomer contributions, polarization, and charge-transfer contribution. Applications to a water and an ammonia dimer and chains of water molecules show possible further developments toward multipolar expansions and other orbital-based schemes for parametrizing force fields. PMID- 26620476 TI - Implementation and Performance of DFT-D with Respect to Basis Set and Functional for Study of Dispersion Interactions in Nanoscale Aromatic Hydrocarbons. AB - The implementation, optimization, and performance of various DFT-D schemes have been tested on models for polar-pi interactions between arenes spaced at van der Waals distances and on a series of functionalized corannulene derivatives and complexes. For DFT-D schemes involving a semiempirical correction, optimized parameters are proposed for several basis sets. Performance of the different DFT D strategies is compared, where functionals include some of the most recently proposed, B97D, B2PLYP, BMK, and M06-2X functionals, together with several other well-known functionals. Semiempircally corrected dispersion functionals hold some promise as useful and affordable methods for studies involving large polynuclear aromatic molecules and molecules on metal surfaces. PMID- 26620477 TI - Local Hybrid Divide-and-Conquer Method for the Computation of Medium and Large Molecules. AB - A local hybrid divide-and-conquer method (LHDC) which combines the high accuracy of sophisticated wave function theory (WFT) methods and the low cost of density functional theory (DFT) has been proposed for computational studies of medium and large molecules. In the method, a large system is divided into small subsystems for which the coefficients of the exchange functional in a hybrid functional are first optimized according to the energy calculated by an accurate WFT method. The hybrid coefficients are then used to evaluate the energy of the whole system. The method not only can reproduce the total energies of the chosen WFT method in good accuracy but also provides electronic structure information for the entire system. PMID- 26620478 TI - Accurate Spin-State Energies for Iron Complexes. AB - A critical assessment of the OPBE functional is made for its performance for the geometries and spin-states of iron complexes. In particular, we have examined its performance for the geometry of first-row transition-metal (di)halides (MnX2, FeX2, CoX2, NiX2, CuX, X=[F, Cl]), whose results were previously [J. Chem. Theory Comput. 2006, 2, 1282] found to be representative for a much larger and more diverse set of 32 metal complexes. For investigating the performance for spin ground-states of iron complexes, we examined a number of small iron complexes (Fe(II)Cl4(2-), Fe(III)Cl4(1-), Fe(II)Cl6(4-), Fe(III)Cl6(3-), Fe(II)CN6(4-), Fe(III)CN6(3-), Fe(VI)O4(2-), Fe(III)(NH3)6(3+)), benchmark systems (Fe(II)(H2O)6(2+), Fe(II)(NH3)6(2+), Fe(II)(bpy)3(2+)), and several challenging iron complexes such as the Fe(II)(phen)2(NCS)2 spin-crossover compound, the monopyridylmethylamine Fe(II)(amp)2Cl2 and dipyridylmethylamine Fe(II)(dpa)2(2+), and the bis complex of Fe(III)-1,4,7-triazacyclononane (Fe(III)((9)aneN3)2(3+). In all these cases OPBE gives excellent results. PMID- 26620479 TI - Gas-Phase Reaction of NH2(+) with Acetic Acid: Implications in Astrochemistry. AB - A theoretical study of the ion-molecule reaction, NH2(+) with acetic acid that could lead to precursors of glycine in the interstellar medium, has been carried out on the triplet and singlet potential energy surfaces. All stationary points and transition states on the (NO2C2H6)(+) triplet and singlet surfaces have been determined at the MP2(full) level with the cc-pVTZ basis set. Energetic data have been obtained at the CCSD(T) level employing the aug-cc-pVTZ basis set. The global minimum of the (NO2C2H6)(+) system is predicted to be protonated glycine in its singlet state, (1)A', and in general singlet states are more stable than the corresponding triplet ones. Formation of ionized glycine from this reaction is shown to be a feasible process under interstellar conditions, but the proton transfer channel and the formation of the compound CH2COOH(+) seem to be more favorable processes on the triplet and singlet potential surfaces, respectively. PMID- 26620480 TI - Prediction of Vibronic Coupling and Absorption Spectra of Dimers from Time Dependent Density Functional Theory: The Case of a Stacked Streptocyanine. AB - Methods based on density functional theory calculations have been used to simulate the absorption spectra of a streptocyanine and of its covalently bonded dimer. Two approaches, based on multimode Franck-Condon overlap integrals, have been employed. In the first approach the monomer and the dimer are treated as single molecules, and the Franck-Condon factors are determined for both systems. The second approach is based on the diagonalization of the dimer Hamiltonian which is constructed from the monomer Franck-Condon overlap integrals and quantities describing the intermonomer electronic coupling. Both approaches succeed in reproducing the hypsochromic shift of the maximum of absorption occurring upon dimerization with an accuracy of 0.05 eV. The vibronic structure of the monomer is also in good agreement with experiment and depends little on the inclusion of Duschinsky rotation effects. The shape and relative intensity of the dimer spectrum is qualitatively reproduced by the two methods, each of them being able to describe most of the vibronic features. Moreover, accounting for the solvent effects in the calculation of the intermonomer electronic coupling improves the agreement with experiment by reducing the intensity of the maximum and by enlarging the spectrum at longer wavelengths. PMID- 26620481 TI - Covalent Excited States of Polyenes C2nH2n+2 (n = 2-8) and Polyenyl Radicals C2n 1H2n+1 (n = 2-8): An Ab Initio Valence Bond Study. AB - The ab initio valence bond (VB) methods, VBSCF and VBCI, are applied to the ground states and the covalent excited states of polyenes C2nH2n+2 (n = 2-8) and polyenyl radicals C2n-1H2n+1 (n = 2-8). The excitation energy gap was computed at the ab initio VB level, which is in good agreement with the semiempirical VB method, VBDFT(s), and the experimental values as well as with the molecular orbital theory based methods, CASPT3 and MRCI. The ab initio VB wave functions of systems are also in very good agreement with those of the VBDFT(s) method, even though the former is based on the ab initio VB scheme while the latter is a semiempirical Huckel type method, in which no orbital optimization procedure is performed. The computational results show that the ab initio VB method is capable now of providing numerical accuracy not only for bond forming and breaking processes, as shown in the past, but also for excitation energies, as shown here. In addition, the computational results validate the efficiency of the VBDFT(s) method, which is a simple VB model with less computational effort but which provides intuitive insights into the excited states of conjugated molecules. PMID- 26620482 TI - Explaining Asymmetric Solvation of Pt(II) versus Pd(II) in Aqueous Solution Revealed by Ab Initio Molecular Dynamics Simulations. AB - The solvation behavior of Pt(II) versus Pd(II) has been studied in ambient water using ab initio molecular dynamics. Beyond the well-defined square-planar first solvation shell encompassing four tightly bonded water molecules as predicted by ligand field theory, a second coordination shell containing about 10 H2O is found in the equatorial region. Additional solvation in the axial regions is observed for both metals which is demonstrated to be induced by the condensed phase. For the Pt(II) aqua complex, however, this water molecule is bonded with one of its hydrogen atoms toward the cation, thus establishing a typical anionic solvation pattern, which is traced back to the electronic structure of Pt(2+) versus Pd(2+) cations, in particular to the anisotropic polarizability of their tetrahydrates. Systematic model calculations based on suitable aqua complex fragments embedded in a polarizable continuum solvent support the idea that anionic hydration is facilitated by the liquid. Furthermore, transient protolysis of water molecules in the first shell is observed for both divalent transition metal cations, being more pronounced for Pt(II) versus Pd(II). The relevance of these solvation features is discussed with respect to the different acidity of Pt(2+) versus Pd(2+) aqua ions in water, their different water ligand exchange rates, and force field modeling approaches. PMID- 26620483 TI - Influence of Structure on the Polarizability of Hydrated Methane Sulfonic Acid Clusters. AB - The relationship between polarizability and structure is investigated in methane sulfonic acid (MSA) and in 36 hydrated MSA clusters. The polarizabilities are calculated at B3LYP and MP2 level and further partitioned into molecular contributions using classic and iterative Hirshfeld methods. The differences in the two approaches for partitioning of polarizabilities are thoroughly analyzed. The polarizabilities of the molecules are found to be influenced in a systematic way by the hydrogen bond network in the clusters, proton transfer between MSA and water molecules, and weak interactions between water molecules and the methyl group of MSA. PMID- 26620484 TI - Accurate First-Principle Prediction of (29)Si and (17)O NMR Parameters in SiO2 Polymorphs: The Cases of Zeolites Sigma-2 and Ferrierite. AB - The magnetic shielding tensors of silica polymorphs have been investigated by means of quantum chemical calculations. Several levels of theory, from Hartree Fock to the last generation of Density Functional Theory based approaches, have been tested on predicting (29)Si and (17)O isotropic and principal components of the chemical shift tensors together with (17)O quadrupolar coupling constants. The NMR parameters have been computed on all known silica systems, namely, alpha quartz, alpha-cristobalite, coesite, Sigma-2, and ferrierite zeolites. Besides, cluster based approaches have been compared to a hybrid Quantum Mechanics/Molecular-Mechanics (QM/MM) method, within the ONIOM scheme. The convergence of computed (17)O NMR parameters with respect to cluster size is found to be system-dependent. Excellent agreement between computed and experimental data has been found for (29)Si NMR parameters of the different Si sites of silica polymorphs and of Sigma-2 and ferrierite zeolites. PMID- 26620485 TI - Characterization of Chitin and Chitosan Molecular Structure in Aqueous Solution. AB - Molecular dynamics simulations have been used to characterize the structure of single chitin and chitosan chains in aqueous solutions. Chitin chains, whether isolated or in the form of a beta-chitin nanoparticle, adopt the 2-fold helix with phi and phi values similar to its crystalline state. In solution, the intramolecular hydrogen bond HO3(n)...O5(n+1) responsible for the 2-fold helical motif in these polysaccharides is stabilized by hydrogen bonds with water molecules in a well-defined orientation. On the other hand, chitosan can adopt five distinct helical motifs, and its conformational equilibrium is highly dependent on pH. The hydrogen bond pattern and solvation around the O3 atom of insoluble chitosan (basic pH) are nearly identical to these quantities in chitin. Our findings suggest that the solubility and conformation of these polysaccharides are related to the stability of the intrachain HO3(n)...O5(n+1) hydrogen bond, which is affected by the water exchange around the O3-HO3 hydroxyl group. PMID- 26620486 TI - Milestones in the Activation of a G Protein-Coupled Receptor. Insights from Molecular-Dynamics Simulations into the Human Cholecystokinin Receptor-1. AB - Activation of G protein-coupled receptors (GPCRs) obeys an allosteric mechanism triggered by ligand binding. To understand how the signal is transduced in the cell, identification of the milestones paving the pathway between the active and the inactive states of the receptor is necessary. A model of the human cholecystokinin receptor-1 (CCK1R) has been proposed recently. The complex formed by CCK1R and an agonist ligand will serve as a paradigm of an active conformation to capture milestones in GPCR activation. To reach this goal, assuming microreversibility, the initial step toward the inactivation of CCK1R was modeled using free energy calculations, whereby the ligand is removed from the binding pocket. However accurate the reproduction of the experimental affinity constant, this simulation only represents an embryonic stage of the inactivation process. Starting from the apo receptor, an unprecedented 0.1-MUs molecular dynamics trajectory was generated, bereft of experimental biases, bringing into the light key events in the inactivation of CCK1R, chief among which the hydration of its internal cavity, concomitant with the spatial rearrangement of the transmembrane helical segments. Hydration is intimately related to the isomerization of the highly conserved residue W326 of helix VI, acting as a two-state toggle switch, and of residue M121 of helix III. In the active state, the former residue obstructs the crevice, thereby preventing water leakage, which would otherwise trigger the disruption of an ionic lock between helices II and III involving the signature E/DRY motif ubiquitous to GPCRs. PMID- 26620487 TI - Flat-Bottom Strategy for Improved Accuracy in Protein Side-Chain Placements. AB - We present a new strategy for protein side-chain placement that uses flat-bottom potentials for rotamer scoring. The extent of the flat bottom depends on the coarseness of the rotamer library and is optimized for libraries ranging from diversities of 0.2 A to 5.0 A. The parameters reported here were optimized for forcefields using Lennard-Jones 12-6 van der Waals potential with DREIDING parameters but are expected to be similar for AMBER, CHARMM, and other forcefields. This Side-Chain Rotamer Excitation Analysis Method is implemented in the SCREAM software package. Similar scoring function strategies should be useful for ligand docking, virtual ligand screening, and protein folding applications. PMID- 26620488 TI - Three-dimensional collimated self-accelerating beam through acoustic metascreen. AB - We report the generation of three-dimensional acoustic collimated self accelerating beam in non-paraxial region with sourceless metascreen. Acoustic metascreen with deep subwavelength spatial resolution, composed of hybrid structures combining four Helmholtz resonators and a straight pipe, transmitting sound efficiently and shifting fully the local phase is evidenced. With an extra phase profile provided by the metascreen, the transmitted sound can be tuned to propagate along arbitrary caustic curvatures to form a focused spot. Due to the caustic nature, the formed beam possesses the capacities of bypassing obstacles and holding the self-healing feature, paving then a new way for wave manipulations and indicating various potential applications, especially in the fields of ultrasonic imaging, diagnosis and treatment. PMID- 26620489 TI - Erratum to: FDG-PET scans in patients with Kraepelinian and non-Kraepelinian schizophrenia. PMID- 26620490 TI - Burning Out Faculty at Doctoral Research Universities. AB - The present study examined the importance of time allocation, pressure and support variables together as determinants of faculty burnout. Using a large sample of university faculty (N = 1439), we were able to show that time allocation variables and perceived pressure contribute to faculty burnout. As expected, decreased social support, family, sleep and leisure time were related to higher levels of burnout. Grantsmanship and service activities appeared as the most critical factors associated with faculty burnout. Faculty burnout is an important topic, and the insights provided here help offer some directions for future research as well as the development of effective institutional policies. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26620491 TI - A simple strategy for managing many recessive disorders in a dairy cattle breeding program. AB - BACKGROUND: High-density single nucleotide polymorphism genotypes have recently been used to identify a number of novel recessive mutations that adversely affect fertility in dairy cattle, as well as to track other conditions such as red coat color and polled. Most current methods for mate allocation fail to consider this information, and it will become increasingly difficult to manage matings as the number of recessive mutations to be accounted for increases. METHODS: A modified version of a mating strategy that constrains inbreeding based on genomics (the Pryce method) was developed that also accounts for the economic effects of Mendelian disorders on overall economic merit (modified Pryce method) and compared with random mating, truncation selection, and the Pryce scheme. Several scenarios were considered, including scenarios with six hypothetical recessive alleles and 12 recessive alleles that are currently segregating in the US Holstein population. RESULTS: The Pryce method and the modified Pryce method showed similar ability to reduce frequencies of recessive alleles, particularly for loci with frequencies greater than 0.30. The modified Pryce method outperformed the Pryce method for low-frequency alleles with small economic value. Cumulative genetic gain for the selection objective was slightly greater when using the Pryce method, but rates of inbreeding were similar across methods. CONCLUSIONS: The proposed method reduces allele frequencies faster than other methods, and also can be used to maintain or increase the frequency of desirable recessives. It can be easily implemented in software for mate allocation, and the code used in this study is freely available as a reference implementation. PMID- 26620492 TI - Weight change and healthcare resource use in English patients with type 2 diabetes mellitus initiating a new diabetes medication class. AB - AIMS: The aim of this study was to investigate the association between weight change and healthcare resource use (HCRU) and costs in English primary care patients with type 2 diabetes mellitus (T2DM) initiating treatment with a new diabetes medication class. METHODS: Patients diagnosed with T2DM initiating a new diabetes medication class (first-line, switch or add-on treatment) were selected from Clinical Practice Research Datalink. Weight change (index date) was measured 6 months after initiating new treatment. HCRU was derived up to 1 year after index. Adjusted analyses evaluated the association between weight change and HCRU and costs (GBP, 2013 prices). RESULTS: Of 9031 patients, about half (n = 4901) experienced < 3% weight change (weight neutral); the proportions gaining or losing weight were similar. Compared with the weight neutral group, weight gain was associated with significantly increased total costs within a year (3.0-5.4% weight gain: L58.9; p = 0.01, >= 5.5% weight gain: L52.9; p = 0.04) and diabetes primary care costs (3.0-5.4% weight gain: L29.2; p < 0.001, >= 5.5% weight gain: L34.2; p < 0.001). This included increased rates of prescribing drugs for diabetes and, in >= 5.5% weight gain, increased primary care contacts. A >= 5.5% weight loss was associated with increased hospital admissions (odds ratio = 1.4; p < 0.0001) and total costs (L126.3; p < 0.001). CONCLUSION: Weight gain after initiating a new glucose-lowering medication is associated with increased prescribing and contact with primary care clinicians, with increased costs in primary care and total spending. This study supports that weight gain in diabetes is associated with increased healthcare costs. PMID- 26620494 TI - Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring. AB - Numerous basic and epidemiological studies have connected prenatal maternal immune activation with the occurrence of schizophrenia and/or autism. Depending on subtle differences in protocols of the used animal model, a variety of behavioral abnormalities has been reported. This study investigated behavioral differences in Wistar rat offspring of both genders, exposed to the 100 MUg/kg per day dose of lipopolysaccharide (LPS) in late embryogenesis (embryonic days 15 and 16), while tested at their adolescent and young adult age (postnatal days 40 and 60, respectively). Immune activation was confirmed by detecting high levels of TNF-alpha and IL-6 in dam blood withdrawn 2h after the first dose of LPS. The animals were assessed in three consecutive trials of locomotor activity (novelty exploration, response to i.p. saline injection and challenge with 0.5mg/kg amphetamine), Morris water maze and social interaction tests. Overt behavioral dysfunction was perceived in adult rats only, and these changes were gender distinctive. When compared with control rats, LPS females displayed baseline hypolocomotion and a decreased reactivity to amphetamine, while LPS males exhibited spatial learning (acquisition trials) and memory (probe trial) impairments. Prenatal treatment did not affect the time spent in social interaction. As maternal exposure to LPS in late gestation resulted in behavioral changes in offspring in early adulthood, it may model schizophrenia-like, but not autism-like endophenotypes. However, lack of a potentiated response to amphetamine testified that this model could not mimic positive symptoms, but rather certain traits of cognitive dysfunction and deficit symptoms, in males and females, respectively. PMID- 26620495 TI - How does environmental enrichment reduce repetitive motor behaviors? Neuronal activation and dendritic morphology in the indirect basal ganglia pathway of a mouse model. AB - Repetitive motor behaviors are observed in many neurodevelopmental and neurological disorders (e.g., autism spectrum disorders, Tourette syndrome, fronto-temporal dementia). Despite their clinical importance, the neurobiology underlying these highly stereotyped, apparently functionless behaviors is poorly understood. Identification of mechanisms that mediate the development of repetitive behaviors will aid in the discovery of new therapeutic targets and treatment development. Using a deer mouse model, we have shown that decreased indirect basal ganglia pathway activity is associated with high levels of repetitive behavior. Environmental enrichment (EE) markedly attenuates the development of such aberrant behaviors in mice, although mechanisms driving this effect are unknown. We hypothesized that EE would reduce repetitive motor behaviors by increasing indirect basal ganglia pathway function. We assessed neuronal activation and dendritic spine density in basal ganglia of adult deer mice reared in EE and standard housing. Significant increases in neuronal activation and dendritic spine densities were observed only in the subthalamic nucleus (STN) and globus pallidus (GP), and only for those mice that exhibited an EE-induced decrease in repetitive motor behavior. As the STN and GP lie within the indirect pathway, these data suggest that EE-induced attenuation of repetitive motor behaviors is associated with increased functional activation of the indirect basal ganglia pathway. These results are consistent with our other findings highlighting the importance of the indirect pathway in mediating repetitive motor behaviors. PMID- 26620498 TI - Immunophilin ligands in peripheral nerve regeneration. AB - Immunophilins are a family of receptors for immunosuppressive drugs like cyclo sporin A, FK506, rapamycin and their non-immunosuppressive analogues, which are collectively referred to as immunophilin ligands. The present study aimed to review neuroprotective and neuroregenerative actions of immunophilin ligands on peripheral nerve injuries. The special emphasis was given to well-known immunosuppressive drug FK506. Its historical background, administration routes, dosages, neuroregenerative, neuroprotective actions, therapeutic time window in administration, action mechanism and side effects of FK506 were reviewed. PMID- 26620496 TI - A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors. AB - BACKGROUND: MK-5108 is a potent/highly selective Aurora A kinase inhibitor. METHODS: A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1-2 in 14-21 day cycles either alone (MT; Panel1/n = 18; 200 to 1800 mg) or in combination (CT; Panel2/n = 17; 100 to 225 mg) with IV docetaxel 60 mg/m(2), determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK 5108 doses below the anticipated PK exposure target. RESULTS: 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; three patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6 to 13.5 h across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day). CONCLUSIONS: MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 MUM*hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated. PMID- 26620499 TI - Sex differences of human corpus callosum revealed by polar coordinate system: magnetic resonance imaging study. AB - BACKGROUND: Evaluation of morphological and size changes related to various pathological conditions of the corpus callosum (CC) requires the data about sex dimorphism of the CC. The purpose of our study is to define potential morphological sex differences of the CC by the use of polar coordinate system as a system of measurements. MATERIALS AND METHODS: After division of the CC into three equal segments by the use of polar coordinate system, we investigated the length of the hemisphere (A-A'), the CC size as its midsagittal section area (CCA), the size of its segments (C1, C2, C3), thickness of the thinnest part of the CC (TCC) and the angular coordinate (a angle) of dorsal point of the TCC in a sample of 30 human brains magnetic resonance images (15 males and 15 females, age 20-50 years). RESULTS: We found significantly larger CCA, C3 segment and the TCC in males. Statistically significant correlation in both, males and females, was found between parameters of the CCA and of all of its segments (C1, C2, C3), the C1 and C2, the C2 and C3 segments, as well as like as between the C2 and TCC. Sex differences were also in findings of significant correlation between the C1 and C3 segments, between CCA and TCC, and of significant negative correlation between the a angle and A-A' only in females. CONCLUSIONS: We concluded that the use of polar coordinate system appropriately reflects the anatomical and encephalometric characteristics of human CC. PMID- 26620497 TI - Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches. AB - Precision oncology is now the evidence-based standard of care for the management of many advanced non-small cell lung cancers (NSCLCs). Expert consensus has defined minimum requirements for routine testing and identification of epidermal growth factor (EGFR) mutations (15% of tumors harbor EGFR exon 19 deletions or exon 21 L858R substitutions) and anaplastic lymphoma kinase (ALK) rearrangements (5% of tumors) in advanced lung adenocarcinomas (ACs). Application of palliative targeted therapies with oral tyrosine kinase inhibitors (TKIs) in advanced/metastatic lung ACs harboring abnormalities in EGFR (gefitinib, erlotinib, afatinib) and ALK/ROS1/MET (crizotinib) has consistently led to more favorable outcomes compared with traditional cytotoxic agents. In addition, mutations leading to resistance to first-line EGFR and ALK TKIs can now be successfully inhibited by soon to be approved third-generation EGFR TKIs (osimertinib, rociletinib) and second-generation ALK TKIs (ceritinib, alectinib). Notably, increasing feasibility, accessibility, and application of molecular profiling technologies has permitted dynamic growth in the identification of actionable driver oncogenes. Emerging genomic aberrations for which TKIs have shown impressive results in clinical trials and expansion of drug labels for approved agents are awaited include ROS1 rearrangements (1-2% of tumors, drug: crizotinib) and BRAF-V600E mutations (1-3% of tumors, drugs: vemurafenib, dafrafenib + trametinib). Evolving genomic events in which TKI responses have been reported in smaller series include MET exon 14 skipping mutations (2-4% of tumors, drug: crizotinib); high-level MET amplification (1-2% of tumors, drug: crizotinib); RET rearrangements (1% of tumors, drug: cabozantinib); and ERBB2 mutations (2-3% of tumors, drug: afatinib), among others. Unfortunately, the most common genomic event in NSCLC, KRAS mutations (25-30% of tumors), is not targetable with approved or in development small molecule inhibitors. Here, we review currently approved, emerging, and evolving systemic precision therapies matched with their driver oncogenes for the management of advanced NSCLC. PMID- 26620500 TI - A 3 tesla magnetic resonance imaging volumetric analysis of the hippocampal formation: dependence on handedness and age. AB - BACKGROUND: The hippocampal formation (HF) is one of the most important parts of the brain in the magnetic resonance imaging (MRI) volumetric analysis in various domains, but not completely from all aspects, including the handedness. The aim of our study was to evaluate the possible differences in the volume of the right and left HF among the healthy right-handed and left-handed subjects, and to determine whether the volume differences are age related. MATERIALS AND METHODS: The MRI of this prospective study was performed using T1 fast field echo (FFE) sequence. The 124 subsequent coronal slices (thickness 1.5 mm) were performed in each participant. The obtained HF volumes were normalised and statistically compared. Volunteers comprised 30 persons aged 22.0 years, 12 of whom were the left-handed, and 30 persons aged 75.2 years on average, 9 of whom were the left handed. RESULTS: The right and left HF volumes averaged 2.986 cm3 and 2.858 cm3 in the right-handed, and 2.879 cm3 and 3.020 cm3 in the left-handed young volunteers, as well as 2.728 cm3 and 2.650 cm3 in the right-handed, and 2.617 cm3 and 2.780 cm3 in the left-handed elderly persons. The HF volume ratios in the young left-handed participants showed a significant left-greater-than-right asymmetry. A significant difference was also noticed within the right-to-left volume ratios of the right- and left-handed young and elderly participants. The latter reduction in the HF volume within the aged group can be interpreted as a slight atrophy of the HF. CONCLUSIONS: There is a significant difference in the volumes of the left and right HF of the left-handed young participants. The age related HF volume differences were proven between the groups of the young and elderly volunteers. The obtained data should be included into the future MRI studies of the HF volumes in various clinical domains. PMID- 26620501 TI - Reduced level of synapsin I protein in the rat striatum after intraventricular administration of proteasome inhibitors: preliminary studies. AB - BACKGROUND: We have recently described changes present in nigrostriatal terminals after intraperitoneal administration of MG-132 and changes that occur in the walls of the rat lateral ventricle after intraventricular administration of MG 132, lactacystin and epoxomicin - different classes of proteasome inhibitors. Substances that inhibit ubiquitin-proteasome system (UPS) activity, are intensively studied due to their potential role as novel therapeutic strategies in the treatment of cancer and ischaemia-reperfusion injury in the brain. The aim of this study is to determine the influence of intraventricular administration of MG-132, lactacystin and epoxomicin on the level in the rat striatum synapsin I - one of the most prominent neuron-specific phosphoproteins in the brain. MATERIALS AND METHODS AND RESULTS: Two weeks after administration of studied proteasome inhibitors, substantial reduction (up to 80%) of synapsin I was ob-served in the rat striatum. Because neurons, and especially dopaminergic ones, are sensitive to the depletion of proteasome function, we assume that observed synapsin I decrease may reflect changes in population of striatal neurons and/or nigrostriatal terminals. CONCLUSIONS: Understanding of cellular mechanisms standing behind our findings needs further studies, and could provide valuable contribution to the discussion on the mechanisms linking UPS inhibition and survival of neurons. PMID- 26620502 TI - Separate muscle bundles of the flexor digitorum superficialis overlying the ulnar nerve. AB - BACKGROUND: The aim of this study was to elucidate the morphological charac teristics of the muscle bundles of the flexor digitorum superficialis (FDS) attached to the intermuscular aponeurosis (IMA) and any related structure that could potentially compress the ulnar nerve. MATERIALS AND METHODS: Fifty embalmed limbs of 34 adult cadavers were studied. RESULTS: The FDS arose as multiple separate bundles from the IMA of the lateral surface of the flexor carpi ulnaris in 76% of specimens. Below their origin, these separate bundles became attached continuously as a single mass to form the muscle belly. There were 1, 2, 3, 4 and 5 arising FDS muscle bundles in 28%, 30%, 4%, 10% and 4% of specimens, respectively. The muscle bundles were attached either only superficially (24% of cases) or across the entire width (20% of cases) of the IMA. In 32% of the specimens, bundles arose from the IMA in a combined fashion, being attached to the IMA superficially, deep and across the entire structure. The muscle bundles that arose from the deep part or entire width of the IMA were in contact with the ulnar nerve in 52% of specimens. In 11 (22%) specimens, the deep borders of the lowest muscle bundles close to the ulnar nerve were composed of tendinous fibres that divided from the IMA of the lateral surface of the flexor carpi ulnaris. The distance from the medial epicondyle to the lowest point of the FDS arising from the IMA was 62.0 +/- 19.7 mm. CONCLUSIONS: The thick tendinous deep border of the lowest muscle bundle of the FDS where it attaches to the IMA is a potential cause of ulnar nerve compression. PMID- 26620503 TI - Macro/micro observational studies of fibres maintaining the biceps brachii tendon in the bicipital groove: application to surgery, pathology and kinesiology. AB - BACKGROUND: There is controversy over the nature of tissues covering the bicipital groove protecting the biceps brachii tendon from dislocation/subluxation causing shoulder pain. Recent researches on cadaveric dissection and histological studies have changed the old concept of the transverse humeral ligament covering the bicipital groove to tendinous fibres of the subscapularis or interdigitating fibres of the subscapularis and supraspinatus. The change has not been incorporated into standard text books of anatomy. Therefore, the aim of the study is to support the new or old concept. MATERIALS AND METHODS: Eighteen embalmed shoulders were dissected to determine the nature of the tissues over the bicipital groove. Tissues from 4 shoulders were processed and 16 histological slides were examined for fibre types. Theoretical analysis of ligament and tendon has also been carried out. RESULTS: The dissection study revealed that the tissues over the bicipital groove were tendinous fibres of subscapularis/interdigitating fibres of the subscapularis and supraspinatus and fibrous expansions from the posterior lamina of the pectoralis major. This was supported by the histological slides which showed the signatures of collagen fibres with the characteristics of tendinous fibres. CONCLUSIONS: No separate anatomical entity such as the transverse humeral ligament was detected in this study. Thus present study supports the view that the tissues covering the bicipital groove were formed by tendinous rather than ligamentous fibres. PMID- 26620504 TI - The ameliorative potential of Hyphaene thebaica on streptozotocin-induced diabetic nephropathy. AB - BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. The aim of the current study is to investigate the possible beneficial effects of Hyphaene thebaica in DN. MATERIALS AND METHODS: For this, 50 male albino rats were divided into five groups: group I - represented the control group; group II - received Hyp-haene thebaica extracts of 150 mg/kg BW by oral gavage for 6 weeks; group III - received single intraperitoneal injections of streptozotocin (50 mg/kg BW) to induce type-2 diabetes mellitus; group IV (protective) - diabetic rats recei-ved Hyphaene thebaica extract (150 mg/kg BW) orally for 6 weeks; group V (curative) - received Hyphaene thebaica extract (150 mg/kg BW) orally after the diagnosis of DN. RESULTS: In the DN protected group, blood glucose, urea, and creatinine decreased significantly, while insulin and C peptide increased significantly. Moreover, cystatin C and neutrophil gelatinase associated lipocalin decreased. Collagen fibre deposition is increased with an apparent thickening of the parietal layer of Bowman's capsules and the basal lamina of convoluted tubules, as well as increase of the immune-reaction of caspase-3 and desmin. The introduction of Hyphaene thebaica led to greater amelioration in the biochemical markers, apoptotic alterations, and podocyte injuries of the protected group than in the curative group. CONCLUSIONS: Hyphaene thebaica may be advised as a good choice that can delay diabetic renal complications. PMID- 26620505 TI - Clinical implications of cephalic vein morphometry in routine cardiac implantable electronic device insertion. AB - BACKGROUND: Morphometric parameters of the venous vasculature constitute an important aspect in successful cardiac implantable electronic device (CIED) insertion. The purpose of this study was to present morpho-anatomical variations of the cephalic vein (CV) and their effect on the course of CIED implantation procedures, based on the patients from our centre. MATERIALS AND METHODS: We analysed contrast venography results obtained during first-time lead placement. Venography was indicated in the cases of problematic lead introduction with either the CV cutdown or axillary/subclavian vein puncture techniques. The 214 cases of venography (15%) performed out of 1425 first-time lead placement in the period 2011-2013 were divided into 9 subgroups according to the most commonly observed CV variations of similar morpho-anatomical features that limited the use of the CV cutdown technique for lead insertion. RESULTS: The following CV morphometric parameters were found to be unfavo-urable in terms of lead placement: CV diameter of <= 1 mm (18%), sharp curva-ture of the terminal CV segment as it joined the axillary vein (14%), terminal CV bifurcation (9%), additional CV branches (7%) or tributaries (7%), stenoses (5%), sharply winding course (5%), single CV with a supraclavicular course (4%). CONCLUSIONS: The radiographic records obtained during the procedures allowed us to assess the prevalence of those atypical CV variations in our study group, with graphic presentation of characteristic types and sporadically reported CV variations. PMID- 26620506 TI - Morphological study of the tuberculum sphenoidalis in macerated skulls of adult individuals. AB - The tuberculum sphenoidalis (TS) is an anatomical structure of variable form located at the anterior extremity of the infratemporal crest of the greater wing of the sphenoid. The object of this study was to analyse the morphology and frequency of the TS in macerated skulls. We examined 304 macerated skulls belonging to individuals of both sexes, Amerindian and Caucasian. The TS were classified morphologically into spiniform, pyramidal and laminar. TS was present in 96.3% of the skulls; the spiniform type was most frequent (40.3%), followed by pyramidal (37%) and laminar (19%). The most frequent type in females and Amerindian individuals was spiniform; in males and Caucasian individuals, the most frequent types were spiniform and pyramidal. The TS is a frequent anatomical structure on the sphenoid bone. The spiniform and pyramidal types are both very frequent. We suggest that it should be incorporated into international anatomical terminology. The term 'sphenoidal tuberculum' may be the most appropriate. PMID- 26620507 TI - Change of the agenesis rate of palmaris longus muscle in an isolated village in Ukraine. AB - BACKGROUND: The palmaris longus muscle (PLM) is a slender, fusiform muscle which lies on the flexor surface of the forearm. Its agenesis is considered the most frequent anatomic variation in the human body. Agenesis of PLM shows strong racial and ethnic variability. The aim of this study was to examine the prevalence of agenesis of PLM in Dercen, an isolated Hungarian village in Ukraine. MATERIALS AND METHODS: Five hundred forty-eight persons were examined by Thompson's, Shaffer's, Pushpakumar's, Mishra's 1, and Mishra's 2 tests to confirm or refute the presence of a PLM. All the examined subjects were of Hungarian ethnic origin. RESULTS: The overall prevalence of absence of the palmaris longus was 52.92%. During the examination, unusual results appeared regarding the agenesis of PLM in the elder population of village. Further tests among elder population shoved that in people born before 1945 the agenesis rate of PLM was higher than 70%, and in villagers born after 1945 the agenesis rate drops by 23%. CONCLUSIONS: In the light of historical events of the country, we can say that the unexpected change of the PLM agenesis rate in 1945 was caused by invasion of soviet army and deportation of local men from their homeland. PMID- 26620508 TI - A case of elongated styloid process in a modern-age skull from Puerto Cabello, Venezuela. AB - BACKGROUND: The styloid process (SP) arises from cartilage of the second branchial arch and tends to calcify during later life. If the length of the SP is more than 30 mm, it can be considered abnormally elongated. Clinical symptoms associated with elongation of this type are defined as Eagle's syndrome. The paper presents a case of an elongated SP in a modern skull from Puerto Cabello, Venezuela, obtained from a series of skulls of African slaves kept at the Department of Anthropology, Polish Academy of Sciences in Wroclaw. MATERIALS AND METHODS: The skull belonged to a male individual, aged ca. 55 years at death (maturus). In terms of basic anthropometric features it had slightly greater facial width parameters in comparison to the cerebral part, and a shorter length of neurocranium when compared to average values of morphological features in African skulls from Uganda. RESULTS: Further macroscopic analysis revealed the presence of an elongated SP (ca. 70.1 mm) with secondary lesions remaining after a healed fracture. Imaging of the bone structure of the elongated SP was carried out using a computed to-mography scan, with multilevel image analysis without contrast. The elongation and calcification of the left ligament in anterior orientation could have caused irritation to the structure of cranial nerves, running within the parapharyngeal space, and to sympathetic fibres running in the wall of cervical arteries. CONCLUSIONS: Analyses of craniological materials recovered during excavations or as part of old osteological collections are rare due to the fragility of this bone structure, and for that reason they may be a valuable source of information on the health status of historic human populations. PMID- 26620509 TI - Long term effects of maternal protein restriction on postnatal lung alveoli development of rat offspring. AB - Poor nutrition of women during pregnancy causes reduction in foetal growth and can adversely affect the development of the foetal lungs. The purpose of the present study was to assess the effects of maternal protein restriction on the postnatal lung development in neonatal period, and on lung structure in adult rat offspring. Female virgin Sprague-Dawley albino rats (more than 200 g) were used. One male rat was introduced into a cage with one female for matting. Once the pregnancy was confirmed, pregnant rats were divided into two main groups; each consists of 6 female as follow: 1 - normally nourished group; 2 - protein deficient group. After delivery, offspring were subdivided into three groups: 1 day after delivery, 2 weeks and 2 months postnatal. Rat body and lung weight were recorded and ratio of lung weight to body weight was assessed. Total plasma protein and serum albumin were assessed for all groups. Lung tissue stained with H&E for histological and morphometric analysis. Immunohistochemistry was performed to evaluate the number of cells positive for pulmonary surfactant protein A. Our results showed that protein restriction interfere with neonatal and postnatal lung development resulting in morphological and morphometric changes of normal lung development. We concluded that protein deficiency lead to developmental retardation of lung. PMID- 26620510 TI - Evidence of increased axillary blood flow velocity without increased handgrip strength and endurance in persons with a fibromuscular axillary arch. AB - BACKGROUND: The purpose of this in vivo study was to compare axillary artery blood flow velocity, and maximal handgrip strength and endurance performance in young subjects with and without an axillary arch (AA). MATERIALS AND METHODS: One hundred and fifty-six young adults were screened for the presence of an AA on their dominant arm side. After physical examination subjects were checked using diagnostic echography for the presence of an AA. Sixteen subjects with an AA and 15 without an AA had their axillary artery peak systolic velocity quantified in 3 different arm positions using Doppler ultrasound. Maximal handgrip strength and endurance performance was quantified in the same positions using a functional rehabilitation system. RESULTS: Mean peak systolic velocity was significantly higher in the AA group compared to controls in abduction/external rotation of the arm during muscle relaxation (p = 0.003) and contraction (p = 0.01). No significant differences between groups were found for maximal handgrip strength and endurance performance. CONCLUSIONS: This study provides evidence for a transient axillary artery compression by the AA in a throwing position. This is not reinforced by additional contraction of the shoulder muscles along with the AA. Axillary artery compression does not influence maximal handgrip strength and endurance performance in symptom-free young adults. PMID- 26620511 TI - The size of anterior teeth in patients with gaps in the upper dental arch. AB - BACKGROUND: The aim of this study was to assess the size of upper incisors and canines in patients with gaps in the upper dental arch, especially medium gap between upper central incisors. MATERIALS AND METHODS: Diagnostic orthodontic models of 30 adult patients with full permanent dentition with diastema in the upper arch were studied. Patients with severe malocclusion, missing teeth and periodontal disease were excluded. Width-to-length (W/L) ratio of the clinical crown of the central, lateral incisors and canines for both sides was measured. Together 180 teeth were tested. The results were compared with the values indicated by Sterrett et al. RESULTS: In all patients, the clinical crowns of central incisors were symmetrical. In most cases, a higher W/L ratio was found, which indicates that the clinical crowns of medial incisors were too broad in relation to the length. Lateral incisors: In most cases, the ratio was the same for the right and the left side; however, a few patients had asymmetry of lateral incisors. Most of the lateral incisors had higher W/L ratios, which means that the teeth were wider than they were long; some had reduced ratios and only in one case the ratio was proper. Canines were also asymmetrical, and none of the canine exhibited perfect proportions. The vast majority showed increased W/L ratio of the clinical crown. In several cases, the W/L ratio was decreased. CONCLUSIONS: Patients with gaps between the teeth have abnormal W/L ratio of the clinical crowns of the upper front teeth. The values were increased in the majority of cases, which indicates that the front teeth were wider than they were long in patients with gaps. Moreover, despite the disturbed W/L proportions, central incisors remained symmetrical. In contrast, lateral incisors and canines more often exhibited asymmetries. PMID- 26620512 TI - Morphological evaluation of the mandibular lingula using cone-beam computed tomography. AB - BACKGROUND: Lingula is a tongue-like flap of bone that overlaps the mandibular foramen antero-medially and location is clinically significant in oral and maxillofacial surgeries. The aim of this study was to assess the shape and precise location of lingula using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: In this study, 3-dimensional images provided by CBCT of 63 patients (28 females, 35 males, age range 25-70 years) were retrospectively evaluated. All CBCT images were performed due to implant planning. From both sides of 63 mandibles were classified in the following shapes: triangular, truncated, nodular and assimilated. The location was determined by 5 distances from the lingula: the anterior and the posterior borders of the mandibular ramus, man-dibular notch and lover border of mandible. Height of the lingula was measured from the lingular tip to the mandibular foramen. RESULTS: Nodular shape of lingula was the most commonly found (32.5%). The mean distance of lingula from anterior and posterior borders of mandibular ramus was 18.5 +/- 2.3 and 16.9 +/- 3.5 mm, respectively. The lingula was located at 18.1 +/- 3.6 mm from the mandibular notch and 38.3 mm from the lover border of mandible. The mean height of lingula was 7.8 +/- 2.4 mm. CONCLUSIONS: The present study provides the morphological variation and localization of the lingula. The lingula is an important clinical landmark for mandibular osteotomy, and for determining the distance to mandibular foramen entrance. PMID- 26620513 TI - Acceptance of the bodypainting as supportive method to learn the surface locomotor apparatus anatomy of the horse. AB - Although bodypainting has been reported as a great resource for teaching surface anatomy of humans, its use in veterinary anatomy has not been scientifically reported. In the present study, bodypainting was performed on 4 horses for anatomy teaching purposes of the equine locomotor apparatus. We aimed to use the bodypainting method as an additional tool to classic teaching and to test the relevance of our purpose. Twenty one Brazilian veterinary students were given a 90-min session, which included a presentation of painted horses, with opportunities for the students to ask questions and to palpate anatomic locations on the horses. Based on a questionnaire, there was unanimous student satisfaction with this technique. Furthermore, student scores on practical tests to evaluate the attention retain given immediately before and 1 h after the session were 33.9 +/- 19.8% and 69.0 +/- 18.4%, respectively (p < 0.001). We concluded that bodypainting has great potential for support the classic lectures of the equine locomotor apparatus. PMID- 26620514 TI - The relationship between facial skeleton morphology and bite force in people with a normal relation of the bases of jaws and skull. AB - BACKGROUND: Better knowledge on the relationship between craniofacial structure and bite force may serve as a reference point for prophylactic and therapeutic activities targeted at developmental age patients. The aim of the study was to assess the correlation between facial skeletal morphology and bite force. MATERIALS AND METHODS: The study included 54 subjects aged 7-16 years with a normal relation of the bases of jaws and skull, according to Segner's and Hasund's analysis standards (ML-NL and ML-NSL angles values were 20.0 +/- 7.0 degrees and 28.0 +/- 5.0 degrees , respectively). The study group included patients who volunteered to diagnosis and possible orthodontic treatment. Bite force was tested with a digital dynamometer calibrated in Newtons. The measurement was performed at the level of the first permanent molars. Cephalometric analysis was based on lateral cephalometric radiographs. The vertical relations were assessed using the following measurements: ML-NSL, ML-NL, NL-NSL, N-Me, Sp-Me, SpMe:NMe, ms-NL, SGo:NMe. RESULTS: Bite force does not depend on the following factors: lower anterior face height (Sp-Me), lower anterior face height to total anterior face height ratio (SpMe:NMe), posterior to anterior face height ratio (SG0:NMe), and the value of ML-NL, ML-NSL and NL-NSL angles. CONCLUSIONS: The posterior height of the maxilla alveolar process (ms-NL) exerts the greatest influence on bite force in people with a normal relation of the bases of jaws and skull: with an increase in ms-NL value bite force is reduced. PMID- 26620515 TI - Bite force and its correlation with long face in children and youth. AB - BACKGROUND: Bite force is one of the indicators of proper functioning of the stomatognathic system, and its value may have diagnostic significance in disorders of the musculoskeletal system of facial bones. The aim of the study was to evaluate the relationship between gender and age, and bite force in patients with high--angle vertical relationship of jaws and cranial bases. MATERIALS AND METHODS: The study group comprised 66 subjects aged 7-17 years, in whom the mandibular jaw base line and maxillary jaw-base line (ML-NL) angles were greater than 27 degrees and the mandibular jaw-baseline and the anterior cranial base line (ML-NSL) above 33 degrees , and a control group (n = 54) aged 7-16 years, in which the ML-NL angles were 20.0 +/- 7.0 degrees and ML-NSL 28.0 +/- 5.0 degrees . For measuring the bite force, a Japanese digital dynamometer Imada type ZPS-LM- 2000N was used. RESULTS: In the study group no statistically significant correlation between the bite force and gender was shown, and in the control group the average bite force on the right side was significantly different for boys and girls, whereas for boys it was higher. In the study group the relationship between the age and average and maximum bite force on the right and left side was significant. In the group of people with a high-angle relationship of bases of jaws and skull no statistically significant correlation between the bite force and gender was shown. CONCLUSIONS: The was no effect of gender on the bite force in all subjects up to 18 years of age, both in patients with a high-angle and normal relationship of bases of jaws and skull. In people with a high-angle relationship of bases of jaws and cranium masticatory forces increase with age. PMID- 26620516 TI - A patient with abnormalities of the coronary arteries and non-compaction of the left ventricular myocardium resulting in ischaemic heart disease symptoms. AB - Left ventricular non-compaction (LVNC) is a rare cardiomyopathy that results from unsettled embryogenesis of myocardium. It is morphologically characterised by the presence of non-compacted, this is hypertrabeculated, myocardium of the left ventricle with deep endocardial recesses. The clinical spectrum of symptoms is very wide - from asymptomatic patients through the cases of heart failure to the patients requiring heart transplantation. The diagnosis is most frequently based on the echocardiography. LVNC is often coexisted with other heart defects and coronary artery abnormalities. We described a case of a 58-year-old man with LVNC and coronary artery anomalies. PMID- 26620517 TI - Craniovertebral anomalies associated with pituitary gland duplication. AB - BACKGROUND: An extremely rare occurrence of the pituitary gland duplication inspired us to examine in detail the accompanying craniovertebral congenital anomalies in a patient involved. MATERIALS AND METHODS: T1-wighted magnetic resonance imaging (MRI) was performed, as well as the multislice computerised tomography (MSCT) and MSCT angiography in our patient, as well as in a control group of 10 healthy subjects. RESULTS: In a 20-year-old male a double pituitary gland was identified, as well as hypothalamic enlargement, tuberomamillary fusion and hamartoma. In addition, the patient also showed a duplicated hypophyseal fossa and posterior clinoid processes, notch of the upper sphenoid, prominent inner relief of the skull, inverse shape of the foramen magnum, third occipital condyle, partial aplasia of the anterior and posterior arches of the atlas with a left arcuate foramen, duplication of the odontoid process and the C2 body, and fusion of the C2-C4 and T12-L1 vertebrae. The MSCT angiography presented a segmental dilatation of both vertebral arteries and the A2 segment of the anterior cerebral artery, as well as a duplication of the basilar artery. CONCLUSIONS: This patient is unique due to complex craniovertebral congenital anomalies associated with a duplication of the pituitary gland. PMID- 26620518 TI - Accessory spleen mimicking pancreatic tumour: evaluation by 99mTc-labelled colloid SPECT/CT study. Report of two cases and a review of nuclear medicine methods utility. AB - The accessory spleen is a common congenital anomaly, typically asymptomatic and harmless to the patient. However, in some clinical cases, this anomaly beco-mes significant as it can be mistaken for a tumour or lymph node and be missed during a therapeutic splenectomy. There are nuclear medicine modalities which can be applied in the identification and localisation of an accessory spleen. They include scintigraphy with radiolabelled colloids or heat damaged red blood cells, which are trapped in the splenic tissue. Modern techniques, including hybrid imaging, enable simultaneous structure and tracer distribution evaluations. Additionally, radiation-guided surgery can be used in cases where the accessory spleen, which is usually small (not exceeding 1 cm) and difficult to find among other tissues, has to be removed. In the study, we would like to present 2 cases of patients in which the malignancy had to be excluded for the reason that the multiple accessory spleens were very closely related to the pancreas. There was a lack of certainty in the multi-phase computed tomography (CT) evaluation; however, this situation was clearly resolved by using the 99mTc-stannous colloid single photon emission computed tomography/ CT study. We would also like to briefly analyse the clinical applications of nuclear medicine in case of an accessory spleen. PMID- 26620519 TI - Ring-shaped variation of the coeliac trunk branches. AB - Aberrant arterial variations in the branching pattern of the coeliac trunk are of great interest to surgeons and radiologists. We report on a rare arterial variation found in a 79-year-old cadaver during educational dissection. Specifically, the coeliac axis formed a unique incomplete trunk termed the hepato hepatic trunk. The splenic artery arose separately from the anterior aspect of the abdominal aorta. On the right side, there was a right hepatic artery giving rise to a gastroduodenal but an absence of the left hepatic. On the left side, there was a branch coursing towards the porta hepatis; the left hepatic artery, dividing into the left gastric, an accessory left gastric, and a branch to the distal oesophagus. The hepato-hepatic trunk formed a ring-shaped vascular structure around the caudate lobe of the liver. Precise mapping and observation of the extrahepatic arteries and bile duct branches is essential in a variety of hepato-biliary laparoscopic procedures of the liver and gallbladder. Other operative procedures requiring, a comprehensive kno-wledge of the varied coeliac trunk patterns are liver transplantation and arterial embolism for hepatic tumour therapy. PMID- 26620520 TI - Anomalous connection of the left posterior renal vein with the left ascending lumbar vein in a Japanese cadaver. AB - A rare variation was found in one of the two left renal veins in a 94-year-old male cadaver undergoing routine dissection. The characteristic findings in the cadaver included, in addition to the primary left renal vein, the presence of a posterior left renal vein draining to the left ascending lumbar vein without communicating with the inferior vena cava and other renal veins. Variations in the number and arrangement of the vessels terminating in the renal veins are common, but to our knowledge, variation similar to our findings has not been previously reported. This variation may represent an immature form of the complicated development of the renal vessels. PMID- 26620521 TI - Bilateral lingual-facial trunk: anatomic and clinical implications. AB - Common origin of lingual and facial artery is a relatively frequent anatomic varia-tion. Instead, bilateral lingual-facial trunk has been described only sparsely in the literature. In this report authors describe and analyse a case of bilateral common lingual-facial trunk in the context of its anatomical, clinical and embryological implications. We also describe possible consequences in performance of elective and emergent surgical operations and modification in surgical techniques that should be considered. We believe that surgeons should be suspicious for this variation's existence and keep alternative solutions in their armentarium. PMID- 26620522 TI - PPIM: A Protein-Protein Interaction Database for Maize. AB - Maize (Zea mays) is one of the most important crops worldwide. To understand the biological processes underlying various traits of the crop (e.g. yield and response to stress), a detailed protein-protein interaction (PPI) network is highly demanded. Unfortunately, there are very few such PPIs available in the literature. Therefore, in this work, we present the Protein-Protein Interaction Database for Maize (PPIM), which covers 2,762,560 interactions among 14,000 proteins. The PPIM contains not only accurately predicted PPIs but also those molecular interactions collected from the literature. The database is freely available at http://comp-sysbio.org/ppim with a user-friendly powerful interface. We believe that the PPIM resource can help biologists better understand the maize crop. PMID- 26620523 TI - Seed Dormancy in Arabidopsis Is Controlled by Alternative Polyadenylation of DOG1. AB - DOG1 (Delay of Germination 1) is a key regulator of seed dormancy in Arabidopsis (Arabidopsis thaliana) and other plants. Interestingly, the C terminus of DOG1 is either absent or not conserved in many plant species. Here, we show that in Arabidopsis, DOG1 transcript is subject to alternative polyadenylation. In line with this, mutants in RNA 3' processing complex display weakened seed dormancy in parallel with defects in DOG1 proximal polyadenylation site selection, suggesting that the short DOG1 transcript is functional. This is corroborated by the finding that the proximally polyadenylated short DOG1 mRNA is translated in vivo and complements the dog1 mutant. In summary, our findings indicate that the short DOG1 protein isoform produced from the proximally polyadenylated DOG1 mRNA is a key player in the establishment of seed dormancy in Arabidopsis and characterizes a set of mutants in RNA 3' processing complex required for production of proximally polyadenylated functional DOG1 transcript. PMID- 26620525 TI - Last-Century Increases in Intrinsic Water-Use Efficiency of Grassland Communities Have Occurred over a Wide Range of Vegetation Composition, Nutrient Inputs, and Soil pH. AB - Last-century climate change has led to variable increases of the intrinsic water use efficiency (Wi; the ratio of net CO2 assimilation to stomatal conductance for water vapor) of trees and C3 grassland ecosystems, but the causes of the variability are not well understood. Here, we address putative drivers underlying variable Wi responses in a wide range of grassland communities. Wi was estimated from carbon isotope discrimination in archived herbage samples from 16 contrasting fertilizer treatments in the Park Grass Experiment, Rothamsted, England, for the 1915 to 1929 and 1995 to 2009 periods. Changes in Wi were analyzed in relation to nitrogen input, soil pH, species richness, and functional group composition. Treatments included liming as well as phosphorus and potassium additions with or without ammonium or nitrate fertilizer applications at three levels. Wi increased between 11% and 25% (P < 0.001) in the different treatments between the two periods. None of the fertilizers had a direct effect on the change of Wi (DeltaWi). However, soil pH (P < 0.05), species richness (P < 0.01), and percentage grass content (P < 0.01) were significantly related to DeltaWi. Grass-dominated, species-poor plots on acidic soils showed the largest DeltaWi (+14.7 MUmol mol(-1)). The DeltaWi response of these acidic plots was probably related to drought effects resulting from aluminum toxicity on root growth. Our results from the Park Grass Experiment show that Wi in grassland communities consistently increased over a wide range of nutrient inputs, soil pH, and plant community compositions during the last century. PMID- 26620524 TI - CCoAOMT Down-Regulation Activates Anthocyanin Biosynthesis in Petunia. AB - Anthocyanins and volatile phenylpropenes (isoeugenol and eugenol) in petunia (Petunia hybrida) flowers have the precursor 4-coumaryl coenzyme A (CoA) in common. These phenolics are produced at different stages during flower development. Anthocyanins are synthesized during early stages of flower development and sequestered in vacuoles during the lifespan of the flowers. The production of isoeugenol and eugenol starts when flowers open and peaks after anthesis. To elucidate additional biochemical steps toward (iso)eugenol production, we cloned and characterized a caffeoyl-coenzyme A O-methyltransferase (PhCCoAOMT1) from the petals of the fragrant petunia 'Mitchell'. Recombinant PhCCoAOMT1 indeed catalyzed the methylation of caffeoyl-CoA to produce feruloyl CoA. Silencing of PhCCoAOMT1 resulted in a reduction of eugenol production but not of isoeugenol. Unexpectedly, the transgenic plants had purple-colored leaves and pink flowers, despite the fact that cv Mitchell lacks the functional R2R3-MYB master regulator ANTHOCYANIN2 and has normally white flowers. Our results indicate that down-regulation of PhCCoAOMT1 activated the anthocyanin pathway through the R2R3-MYBs PURPLE HAZE (PHZ) and DEEP PURPLE, with predominantly petunidin accumulating. Feeding cv Mitchell flowers with caffeic acid induced PHZ expression, suggesting that the metabolic perturbation of the phenylpropanoid pathway underlies the activation of the anthocyanin pathway. Our results demonstrate a role for PhCCoAOMT1 in phenylpropene production and reveal a link between PhCCoAOMT1 and anthocyanin production. PMID- 26620526 TI - Structural Basis of Reversible Phosphorylation by Maize Pyruvate Orthophosphate Dikinase Regulatory Protein. AB - Pyruvate orthophosphate dikinase (PPDK) is one of the most important enzymes in C4 photosynthesis. PPDK regulatory protein (PDRP) regulates the inorganic phosphate-dependent activation and ADP-dependent inactivation of PPDK by reversible phosphorylation. PDRP shares no significant sequence similarity with other protein kinases or phosphatases. To investigate the molecular mechanism by which PDRP carries out its dual and competing activities, we determined the crystal structure of PDRP from maize (Zea mays). PDRP forms a compact homo-dimer in which each protomer contains two separate N-terminal (NTD) and C-terminal (CTD) domains. The CTD includes several key elements for performing both phosphorylation and dephosphorylation activities: the phosphate binding loop (P loop) for binding the ADP and inorganic phosphate substrates, residues Lys-274 and Lys-299 for neutralizing the negative charge, and residue Asp-277 for protonating and deprotonating the target Thr residue of PPDK to promote nucleophilic attack. Surprisingly, the NTD shares the same protein fold as the CTD and also includes a putative P-loop with AMP bound but lacking enzymatic activities. Structural analysis indicated that this loop may participate in the interaction with and regulation of PPDK. The NTD has conserved intramolecular and intermolecular disulfide bonds for PDRP dimerization. Moreover, PDRP is the first structure of the domain of unknown function 299 enzyme family reported. This study provides a structural basis for understanding the catalytic mechanism of PDRP and offers a foundation for the development of selective activators or inhibitors that may regulate photosynthesis. PMID- 26620527 TI - A Tandem Array of ent-Kaurene Synthases in Maize with Roles in Gibberellin and More Specialized Metabolism. AB - While most commonly associated with its role in gibberellin phytohormone biosynthesis, ent-kaurene also serves as an intermediate in more specialized diterpenoid metabolism, as exemplified by the more than 800 known derived natural products. Among these are the maize kauralexins. However, no ent-kaurene synthases (KSs) have been identified from maize. The maize gibberellin-deficient dwarf-5 (d5) mutant has been associated with a loss of KS activity. The relevant genetic lesion has been previously mapped, and was found here to correlate with the location of the KS-like gene ZmKSL3. Intriguingly, this forms part of a tandem array with two other terpene synthases (TPSs). Although one of these, ZmTPS1, has been previously reported to encode a sesquiterpene synthase, and both ZmTPS1 and that encoded by the third gene, ZmKSL5, have lost the N-terminal gamma domain prototypically associated with KS(L)s, all three genes fall within the KS(L) or TPS-e subfamily. Here it is reported that all three genes encode enzymes that are targeted to the plastid in planta, where diterpenoid biosynthesis is initiated, and which all readily catalyze the production of ent-kaurene. Consistent with the closer phylogenetic relationship of ZmKSL3 with previously identified KSs from cereals, only transcription of this gene is affected in d5 plants. On the other hand, the expression of all three of these genes is inducible, suggesting a role in more specialized metabolism, such as that of the kauralexins. Thus, these results clarify not only gibberellin phytohormone, but also diterpenoid phytoalexin biosynthesis in this important cereal crop plant. PMID- 26620529 TI - Conventional Matrices Loaded Onto a Graphene Layer Enhances MALDI-TOF/TOF Signal: Its Application to Improve Detection of Phosphorylated Peptides. AB - This is the first study where graphene is used as a MALDI adjuvant in combination with the traditional matrix alpha-cyano-4-hydroxycinnamic acid (CHCA) to improve the signal intensity of peptide samples. Use of this amended matrix not only leads to increased signals but also to a higher number of peaks detected in complex samples. Additionally, the use of graphene has a stabilizing effect that can also be exploited to improve the detection of easily cleavable molecules. Graphical Abstract ?. PMID- 26620528 TI - ALA10, a Phospholipid Flippase, Controls FAD2/FAD3 Desaturation of Phosphatidylcholine in the ER and Affects Chloroplast Lipid Composition in Arabidopsis thaliana. AB - The biogenesis of photosynthetic membranes relies on galactoglycerolipids, which are synthesized via pathways that are dispatched over several cell compartments. This membrane biogenesis requires both trafficking of lipid intermediates and a tight homeostatic regulation. In this work, we address the role of ALA10 (for aminophospholipid ATPase), a P4-type ATPase, in a process counteracting the monogalactosyldiacylglycerol (MGDG) shortage in Arabidopsis (Arabidopsis thaliana) leaves. ALA10 can interact with protein partners, ALIS1 (for ALA interacting subunit1) or ALIS5, leading to differential endomembrane localizations of the interacting proteins, close to the plasma membrane with ALIS1 or to chloroplasts with ALIS5. ALA10 interacts also with FATTY ACID DESATURASE2 (FAD2), and modification of ALA10 expression affects phosphatidylcholine (PC) fatty acyl desaturation by disturbing the balance between FAD2 and FAD3 activities. Modulation of ALA10 expression downstream impacts the fatty acyl composition of chloroplast PC. ALA10 expression also enhances leaf growth and improves the MGDG-PC ratio, possibly through MGDG SYNTHASE1 (MGD1) activation by phosphatidic acid. The positive effect of ALA10 on leaf development is significant in conditions such as upon treatment of plants with Galvestine-1, an inhibitor of MGDG synthases, or when plants are grown at chilling temperature. PMID- 26620530 TI - Can Nonpolar Polyisobutylenes be Measured by Electrospray Ionization Mass Spectrometry? Anion-Attachment Proved to be an Appropriate Method. AB - Polyisobutylenes (PIBs) with different end-groups including chlorine, exo-olefin, hydroxyl, and methyl prepared from aliphatic and aromatic initiators were studied by electrospray ionization mass spectrometry (ESI-MS). Independently of the end groups, presence or absence of aromatic initiator moiety, these PIB derivatives were capable of forming adduct ions with NO3 (-) and Cl(-) ions, thus allowing the direct characterization of these compounds in the negative ion mode of ESI MS. To obtain [PIB + NO3](-) and [PIB + Cl](-) adduct ions with appreciable intensities, addition of polar solvents such as acetone, 2-propanol, or ethanol to the dichloromethane solution of PIBs was necessary. Furthermore, increasing both the polarity (by increasing the acetone content) and the ion-source temperature give rise to enhanced intensities for both [PIB + NO3](-) and [PIB + Cl](-) ions. Energy-dependent collision induced dissociation studies (CID) revealed that increasing the collision voltages resulted in the shift of the apparent molecular masses to higher ones. CID studies also showed that dissociation of the [PIB + Cl](-) ions requires higher collision energy than that of [PIB + NO3](-). In addition, Density Functional Theory calculations were performed to gain insights into the nature of the interactions between the highly non-polar PIB chains and anions NO3 (-) and Cl(-) as well as to determine the zero-point corrected electronic energies for the formation of [PIB + NO3](-) and [PIB + Cl](-) adduct ions. PMID- 26620531 TI - Ion Mobility Spectrometry-Hydrogen Deuterium Exchange Mass Spectrometry of Anions: Part 3. Estimating Surface Area Exposure by Deuterium Uptake. AB - Gas-phase hydrogen deuterium exchange (HDX), collision cross section (CCS) measurement, and molecular dynamics simulation (MDS) techniques were utilized to develop and compare three methods for estimating the relative surface area exposure of separate peptide chains within bovine insulin ions. Electrosprayed [M - 3H](3-) and [M - 5H](5-) insulin ions produced a single conformer type with respective collision cross sections of 528 +/- 5 A(2) and 808 +/- 2 A(2). [M - 4H](4-) ions were comprised of more compact (Omega = 676 +/- 3 A(2)) and diffuse (i.e., more elongated, Omega = 779 +/- 3 A(2)) ion conformer types. Ions were subjected to HDX in the drift tube using D2O as the reagent gas. Collision induced dissociation was used to fragment mobility-selected, isotopically labeled [M - 4H](4-) and [M - 5H](5-) ions into the protein subchains. Deuterium uptake levels of each chain can be explained by limited inter-chain isotopic scrambling upon collisional activation. Using nominal ion structures from MDS and a hydrogen accessibility model, the deuterium uptake for each chain was correlated to its exposed surface area. In separate experiments, the per-residue deuterium content for the protonated and deprotonated ions of the synthetic peptide KKDDDDDIIKIIK were compared. The differences in deuterium content indicated the regional HDX accessibility for cations versus anions. Using ions of similar conformational type, this comparison highlights the complementary nature of HDX data obtained from positive- and negative-ion analysis. PMID- 26620533 TI - Genetic programming of catalytic Pseudomonas putida biofilms for boosting biodegradation of haloalkanes. AB - Bacterial biofilms outperform planktonic counterparts in whole-cell biocatalysis. The transition between planktonic and biofilm lifestyles of the platform strain Pseudomonas putida KT2440 is ruled by a regulatory network controlling the levels of the trigger signal cyclic di-GMP (c-di-GMP). This circumstance was exploited for designing a genetic device that over-runs the synthesis or degradation of c di-GMP--thus making P. putida to form biofilms at user's will. For this purpose, the transcription of either yedQ (diguanylate cyclase) or yhjH (c-di-GMP phoshodiesterase) from Escherichia coli was artificially placed under the tight control of a cyclohexanone-responsive expression system. The resulting strain was subsequently endowed with a synthetic operon and tested for 1-chlorobutane biodegradation. Upon addition of cyclohexanone to the culture medium, the thereby designed P. putida cells formed biofilms displaying high dehalogenase activity. These results show that the morphologies and physical forms of whole-cell biocatalysts can be genetically programmed while purposely designing their biochemical activity. PMID- 26620532 TI - Biosynthetic engineering and fermentation media development leads to gram-scale production of spliceostatin natural products in Burkholderia sp. AB - A key challenge in natural products drug discovery is compound supply. Hundreds of grams of purified material are needed to advance a natural product lead through preclinical development. Spliceostatins are polyketide-nonribosomal peptide natural products that bind to the spliceosome, an emerging target in cancer therapy. The wild-type bacterium Burkholderia sp. FERM BP-3421 produces a suite of spliceostatin congeners with varying biological activities and physiological stabilities. Hemiketal compounds such as FR901464 were the first to be described. Due to its improved properties, we were particularly interested in a carboxylic acid precursor analog that was first reported from Burkholderia sp. MSMB 43 and termed thailanstatin A. Inactivation of the iron/alpha-ketoglutarate dependent dioxygenase gene fr9P had been shown to block hemiketal biosynthesis. However, a 4-deoxy congener of thailanstatin A was the main product seen in the dioxygenase mutant. We show here that expression of the cytochrome P450 gene fr9R is a metabolic bottle neck, as use of an l-arabinose inducible system led to nearly complete conversion of the 4-deoxy analog to the target molecule. By integrating fermentation media development approaches with biosynthetic engineering, we were able to improve production titers of the target compound >40 fold, going from the starting ~60 mg/L to 2.5 g/L, and to achieve what is predominantly a single component production profile. These improvements were instrumental in enabling preclinical development of spliceostatin analogs as chemotherapy. PMID- 26620534 TI - Pulmonary IgG4-related disease and colon adenocarcinoma: possible paraneoplastic syndrome. AB - Malignancy has a complicated association with immunoglobulin G4-related disease (IgG4-RD) both being an item in the differential diagnosis as well as malignancy occurring in the background of IgG4-RD in the same organ. However, recently there is evidence of higher rates of distant malignancy in patients with IgG4-RD. Here we report a case of pulmonary IgG4-RD potentially consistent with a paraneoplastic phenomenon which improved with treatment of the underlying colon adenocarcinoma. PMID- 26620535 TI - Detection of Quorum Sensing Molecules and Biofilm Formation in Ralstonia solanacearum. AB - Many bacteria use small diffusible signaling molecules to communicate each other termed as quorum sensing (QS). Most Gram-negative bacteria use acyl homoserine lactone (AHL) as QS signal molecules. Using these signaling molecules, bacteria are able to express specific genes in response to population density. This work aimed to detect the production of QS signal molecules and biofilm formation in Ralstonia solanacearum isolated from various diseased tomato plants with symptoms of bacterial wilt. A total of 30 R. solanacearum strains were investigated for the production of QS signal molecules using Chromobacterium violaceum CV026 and Agrobacterium tumefaciens NT1 (pZLR4) biosensor systems. All 30 bacterial isolates from various bacterial wilt-affected tomato plants produced AHL molecules that induced the biosensor. The microtiter plate assay demonstrated that of the 30 bacterial isolates, 60 % formed biofilm, among which four isolates exhibited a higher degree of biofilm formation. The biofilm-inducing factor was purified from these four culture supernatants. The structure of the responsible molecule was solved using nuclear magnetic resonance and mass spectroscopy and was determined to be 2-hydroxy-4-((methylamino)(phenyl)methyl) cyclopentanone (HMCP), which was confirmed by chemical synthesis and NMR. The Confocal laser scanning microscopic analysis showed well-developed biofilm architecture of bacteria when treated with HMCP. The knowledge we obtained from this study will be useful for further researcher on the role of HMCP molecule in biofilm formation. PMID- 26620536 TI - Changing the Codon Usage of hfq Gene has Profound Effect on Phenotype and Pathogenicity of Salmonella Typhimurium. AB - Genome recoding with bias codons (synonymous rare codons) or codon pair bias is being used as a method to attenuate virulence mostly in viruses. The target gene chosen for attenuation in general in bacteria is mostly toxin or virulence gene. We have used RNA chaperone hfq, a global post-transcriptional regulator of bacterial gene expression that regulates about 20 % genes in Salmonella, as the target of recoding. The hfq gene was recoded by replacing the codons of hfq gene with synonymous rare codons. Recoding decreased the expression of Hfq protein about two-fold in the mutant as compared to the parent strain. Recoding did not affect growth kinetics, but in growth competition the mutant strain was outcompeted by the parent strain. There was significant decrease in survivability of mutant strain in macrophage as compared to the parent strain. The biofilm formation was significantly impaired in case of recoded mutant. The mutants were also less motile as compared to the parent strain. Intraperitoneal infection of mice with the mutant strain had shown better survival as compared to parent strain. The results show that recoding is an effective method of reducing virulence. PMID- 26620537 TI - Fecal Bacterial Composition of the Endangered Yangtze Finless Porpoises Living Under Captive and Semi-natural Conditions. AB - Intestinal microbiota is essential to the health and physiology of host animals. We undertook the first microbiological study of the fecal bacterial composition from critically endangered (CR) Yangtze finless porpoises (Neophocaena asiaeorientalis asiaeorientalis; YFPs) living under captive and semi-natural conditions using both high-throughput sequencing method and 16S rRNA gene clone library method. As determined by high-throughput sequencing of V3-V4 regions of the 16S rRNA gene, semi-natural samples harbored 30 and 36 operational taxonomic units (OTUs), which was more than the 22 and 27 OTUs detected from YFPs living in captivity. In captive YFPs Firmicutes was the predominant phylum, whereas this was Proteobacteria for YFPs living in semi-nature conditions. This suggests habitat-specific fecal bacterial composition of YFPs. Plesiomonas spp. and Aeromonas spp., which are potentially pathogenic, were identified in all the feces. Bacterial diversity from one porpoise living in captivity was also determined by constructing a 16S rRNA gene clone library and only 1 phylum was identified. High-throughput sequencing was more effective at determining the bacterial diversity compared to the 16S rRNA gene clone library. This study provides important information for the management and conservation of the CR YFPs. PMID- 26620538 TI - Significance of single lung transplantation in the current situation of severe donor shortage in Japan. AB - OBJECTIVE: Although bilateral lung transplantation is the procedure of choice internationally, single lung transplantation is preferred in Japan because of the severe donor shortage except in cases of contraindications to single lung transplantation. This study aimed to evaluate the clinical characteristics of single lung transplant recipients and outcomes of this procedure at one of the largest lung transplant centers in Japan. METHODS: Between April 2002 and May 2015, 57 cadaveric lung transplantations (33 single and 24 bilateral) were performed in Kyoto University Hospital. The clinical characteristics of the lung transplant recipients and outcomes of these procedures, including overall survival and postoperative complications, were investigated. RESULTS: Overall, the 1-, 3-, and 5-year survival rates were 86, 77, and 72 %, respectively, with a median follow-up period of 1.9 years. There was no significant difference in survival between patients who underwent single lung transplantations and those who underwent bilateral lung transplantations (p = 0.92). The median waiting time was significantly shorter for single lung transplant patients than for bilateral lung transplant patients (p = 0.02). Native lung complications were seen in 14 out of 33 patients (42 %) who underwent single lung transplantation. There was no significant difference in survival between patients with and without postoperative native lung complications. CONCLUSIONS: Single lung transplantation has been performed with acceptable outcomes in our institution. In the current situation of severe donor shortage in Japan, single lung transplantation can remain the first choice of treatment except in cases of contraindications to single lung transplantation. PMID- 26620539 TI - Current status of brain protection during surgery for congenital cardiac defect. AB - The long-term neurodevelopmental outcome has been a great concern for cardiac surgeons although it is still unclear. There are some risks regarding the neurological and neuropsychological deficits before, during and after cardiovascular surgery. Current status of brain protection during congenital heart surgery could be reported. The incidence of neurologic outcome and the appropriate CPB strategy for brain protection are stated, and the latest data of neurodevelopmental outcome after pediatric cardiac surgery are clarified. PMID- 26620540 TI - Unusual late presentation of metastatic extrathoracic thymoma to gastrohepatic lymph node treated by surgical resection. AB - In advanced stages, thymic tumors tend to spread locally. Distant metastatic disease is rare. We present the first report of single metastatic abdominal lymph node in a 37-year-old female patient and 5 years after an extrapleural pneumonectomy for stage IV thymoma followed by radiotherapy with no other evidence of abdominal disease successfully treated by robotic surgical resection. PMID- 26620541 TI - Dorsal raphe nucleus acetylcholine-mediated neurotransmission modulates post ictal antinociception: The role of muscarinic and nicotinic cholinergic receptors. AB - The dorsal raphe nucleus (DRN) is a key structure of the endogenous pain inhibitory system. Although the DRN is rich in serotoninergic neurons, cholinergic neurons are also found in that nucleus. Both ictal and inter-ictal states are followed by post-ictal analgesia. The present study investigated the role of cholinergic mechanisms in postictal antinociceptive processes using microinjections of atropine and mecamylamine, muscarinic and nicotinic cholinergic receptor antagonists, respectively, in the DRN of rats. Intraperitoneal injection of pentylenetetrazole (PTZ) (at 64mg/kg) caused tonic and tonic-clonic seizures. The convulsive motor reactions were followed by an increase in pain thresholds, a phenomenon known as post-ictal analgesia. Pre treatment of the DRN with atropine or mecamylamine at 1ug, 3ug and 5ug/0.2uL decreased the post-ictal antinociceptive phenomenon. The present results showed that the post-ictal analgesia was mediated by muscarinic and nicotinic cholinergic receptors in the DRN, a structure crucially involved in the neural network that organises post-ictal hypoalgesia. PMID- 26620542 TI - Psychotropic effects of Lactobacillus plantarum PS128 in early life-stressed and naive adult mice. AB - Ingestion of specific probiotics, namely "psychobiotics", produces psychotropic effects on behavior and affects the hypothalamic-pituitary-adrenal axis and neurochemicals in the brain. We examined the psychotropic effects of a potential psychobiotic bacterium, Lactobacillus plantarum strain PS128 (PS128), on mice subjected to early life stress (ELS) and on naive adult mice. Behavioral tests revealed that chronic ingestion of PS128 increased the locomotor activities in both ELS and naive adult mice in the open field test. In the elevated plus maze, PS128 significantly reduced the anxiety-like behaviors in naive adult mice but not in the ELS mice; whereas the depression-like behaviors were reduced in ELS mice but not in naive mice in forced swimming test and sucrose preference test. PS128 administration also reduced ELS-induced elevation of serum corticosterone under both basal and stressed states but had no effect on naive mice. In addition, PS128 reduced inflammatory cytokine levels and increased anti inflammatory cytokine level in the serum of ELS mice. Furthermore, the dopamine level in the prefrontal cortex (PFC) was significantly increased in PS128 treated ELS and naive adult mice whereas serotonin (5-HT) level was increased only in the naive adult mice. These results suggest that chronic ingestion of PS128 could ameliorate anxiety- and depression-like behaviors and modulate neurochemicals related to affective disorders. Thus PS128 shows psychotropic properties and has great potential for improving stress-related symptoms. PMID- 26620543 TI - A human neural stem cell line provides neuroprotection and improves neurological performance by early intervention of neuroinflammatory system. AB - A human neural stem cell line, HB1.F3, demonstrated neuroprotective properties in cerebral ischemia animal models. In this study, we have investigated about the mechanisms of such neuroprotection, mainly focusing on the neuroinflammatory system at an earlier time point of the pathology. Cerebral ischemia model was generated by middle cerebral artery occlusion (MCAO) in adult male Wister rats. HB1.F3 cells were transplanted through jugular vein 6h after MCAO. Forty eight hours after MCAO, transplanted rats showed better neurological performance and decreased TUNEL positive apoptotic cell number in the penumbra. However, haematoxylin and eosin staining and immunostaining showed that, HB1.F3 cells did not affect the necrotic cell death. Twenty four hours after MCAO (18h after HB1.F3 transplantation), infiltrated granulocytes and macrophage/microglia number in the core regions were decreased compared to PBS-treated controls. Immunohistochemical analysis further demonstrated that the transplantation decreased inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expressing cell number in the core and penumbra, respectively. Double immunofluorescence results revealed that iNOS was mainly expressed in granulocytes and macrophage/microglia in the core region, and COX-2 mainly expressed in neurons, endothelial cells and granulocytes in penumbra. Further analysis showed that although the percentage of iNOS expressing granulocytes and macrophage/microglia was not decreased, COX-2 expressing neurons and vessel number was decreased by the transplantation. In vitro mRNA analysis showed that brain-derived neurotrophic factor (BDNF), basic fibroblast growth factor (betaFGF) and bone morphogenic protein (BMP)-4 expression was high in cultured HB1.F3 cells. Thus, our results demonstrated that HB1.F3 cell transplantation provide neuroprotection possibly through the regulation of early inflammatory events in the cerebral ischemia condition. PMID- 26620544 TI - Margaret McCartney: Early cancer diagnosis: how low should we go? PMID- 26620545 TI - Preparation of an intensive care unit in France for the reception of a confirmed case of Ebola virus infection. AB - The current Ebola Virus Disease (EVD) outbreak in West Africa is a major challenge for the worldwide medical community. On April 29th 2015, the World Health Organization (WHO) declared 26,277 infected cases; among them, 10,884 have deceased. The epidemic is still ongoing, particularly in Sierra Leone. It is now clear that northern countries will be implicated in the care of EVD patients, both in the field and back at home. Because of the severity of EVD, a fair amount of patients may require intensive care. It is highly probable that intensive care would be able to significantly reduce the mortality linked with EVD. The preparation of a modern Intensive Care Unit (ICU) to treat an EVD patient in good conditions requires time and specific equipment. The cornerstone of this preparation includes two main goals: treating the patient and protecting healthcare providers. Staff training is time consuming and must be performed far in advance of patient arrival. To be efficient, preparation should be planned at a national level with help from public authorities, as was the case in France during the summer of 2014. Due to the severity of the disease, the high risk of transmission and scarce knowledge on EVD treatment, our propositions are necessarily original and innovative. Our review includes four topics: a brief report on the actual outbreak, where to receive and hospitalize the patients, the specific organization of the ICU and finally ethical aspects. PMID- 26620546 TI - Characterization of ictal slow waves in epileptic spasms. AB - We characterized the clinico-neurophysiological features of epileptic spasms, particularly focusing on high-voltage slow waves during ictal EEG. We studied 22 patients with epileptic spasms recorded during digital video-scalp EEG, including five individuals who still had persistent spasms after callosotomy. We analysed the duration, amplitude, latency to onset of electromyographic bursts, and distribution of the highest positive and negative peaks of slow waves in 352 spasms. High-voltage positive slow waves preceded the identifiable muscle contractions of spasms. The mean duration of these positive waves was 569+/-228 m, and the mean latency to electromyographic onset was 182+/-127 m. These parameters varied markedly even within a patient. The highest peak of the positive component was distributed in variable regions, which was not consistent with the location of lesions on MRI. The peak of the negative component following the positivity was distributed in the neighbouring or opposite areas of the positive peak distribution. No changes were evident in the pre- or post-surgical distributions of the positive peak, or in the interhemispheric delay between both hemispheres, in individuals with callosotomy. Our data imply that ictal positive slow waves are the most common EEG changes during spasms associated with a massive motor component. Plausible explanations for these widespread positive slow waves include the notion that EEG changes possibly reflect involvement of both cortical and subcortical structures. PMID- 26620547 TI - Interprofessional education increases knowledge, promotes team building, and changes practice in the care of Parkinson's disease. AB - OBJECTIVE: Examine outcomes for the National Parkinson Foundation (NPF) Allied Team Training for Parkinson (ATTP), an interprofessional education (IPE) program in Parkinson's disease (PD) and team-based care for medicine, nursing, occupational, physical and music therapies, physician assistant, social work and speech-language pathology disciplines. BACKGROUND: Healthcare professionals need education in evidence-based PD practices and working effectively in teams. Few evidence-based models of IPE in PD exist. METHODS: Knowledge about PD, team-based care, the role of other disciplines and attitudes towards healthcare teams were measured before and after a protocol-driven training program. Knowledge, attitudes and practice changes were again measured at 6-month post-training. Trainee results were compared to results of controls. RESULTS: Twenty-six NPF ATTP trainings were held across the U.S. (2003-2013). Compared to control participants (n = 100), trainees (n = 1468) showed statistically significant posttest improvement in all major outcomes, including self-perceived (p < 0.001) and objective knowledge (p < 0.001), Understanding Role of Other Disciplines (p < 0.001), Attitudes Toward Health Care Teams Scale (p < 0.001), and the Attitudes Toward Value of Teams (p < 0.001) subscale. Despite some decline, significant improvements were largely sustained at six-month post-training. Qualitative analyses confirmed post-training practice changes. CONCLUSIONS: The NPF-ATTP model IPE program showed sustained positive gains in knowledge of PD, team strategies and role of other disciplines, team attitudes, and important practice improvements. Further research should examine longer-term outcomes, objectively measure practice changes and mediators, and determine impact on patient outcomes. PMID- 26620549 TI - Nitro-oleic acid modulates classical and regulatory activation of macrophages and their involvement in pro-fibrotic responses. AB - Inflammation is an immune response triggered by microbial invasion and/or tissue injury. While acute inflammation is directed toward invading pathogens and injured cells, thus enabling tissue regeneration, chronic inflammation can lead to severe pathologies and tissue dysfunction. These processes are linked with macrophage polarization into specific inflammatory "M1-like" or regulatory "M2 like" subsets. Nitro-fatty acids (NO2-FAs), produced endogenously as byproducts of metabolism and oxidative inflammatory conditions, may be useful for treating diseases associated with dysregulated immune homeostasis. The goal of this study was to characterize the role of nitro-oleic acid (OA-NO2) in regulating the functional specialization of macrophages induced by bacterial lipopolysaccharide or interleukin-4, and to reveal specific signaling mechanisms which can account for OA-NO2-dependent modulation of inflammation and fibrotic responses. Our results show that OA-NO2 inhibits lipopolysaccharide-stimulated production of both pro-inflammatory and immunoregulatory cytokines (including transforming growth factor-beta) and inhibits nitric oxide and superoxide anion production. OA NO2 also decreases interleukin-4-induced macrophage responses by inhibiting arginase-I expression and transforming growth factor-beta production. These effects are mediated via downregulation of signal transducers and activators of transcription, mitogen-activated protein kinase and nuclear factor-kB signaling responses. Finally, OA-NO2 inhibits fibrotic processes in an in vivo model of angiotensin II-induced myocardial fibrosis by attenuating expression of alpha smooth muscle actin, systemic transforming growth factor-beta levels and infiltration of both "M1-" and "M2-like" macrophage subsets into afflicted tissue. Overall, the electrophilic fatty acid derivative OA-NO2 modulates a broad range of "M1-" and "M2-like" macrophage functions and represents a potential therapeutic approach to target diseases associated with dysregulated macrophage subsets. PMID- 26620550 TI - PTPRN2 and PLCbeta1 promote metastatic breast cancer cell migration through PI(4,5)P2-dependent actin remodeling. AB - Altered abundance of phosphatidyl inositides (PIs) is a feature of cancer. Various PIs mark the identity of diverse membranes in normal and malignant cells. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) resides predominantly in the plasma membrane, where it regulates cellular processes by recruiting, activating, or inhibiting proteins at the plasma membrane. We find that PTPRN2 and PLCbeta1 enzymatically reduce plasma membrane PI(4,5)P2 levels in metastatic breast cancer cells through two independent mechanisms. These genes are upregulated in highly metastatic breast cancer cells, and their increased expression associates with human metastatic relapse. Reduction in plasma membrane PI(4,5)P2 abundance by these enzymes releases the PI(4,5)P2-binding protein cofilin from its inactive membrane-associated state into the cytoplasm where it mediates actin turnover dynamics, thereby enhancing cellular migration and metastatic capacity. Our findings reveal an enzymatic network that regulates metastatic cell migration through lipid-dependent sequestration of an actin-remodeling factor. PMID- 26620552 TI - Malaria case in Madagascar, probable implication of a new vector, Anopheles coustani. AB - BACKGROUND: Indoor spraying of insecticides and the use of insecticide-treated bed nets are key strategies for national malaria vector control in the central highlands of Madagascar. During the year 2013, malaria outbreaks were reported by the National Malaria Control Programme in the highlands, including the district of Ankazobe. METHODS: Entomological trapping was carried out in April and May 2013 and in March 2014, using human landing catches, collection of mosquitoes resting in stables and in houses by oral aspirators, and Centers for Disease Control and Prevention light traps. Detection of Plasmodium in mosquitoes was carried out on head and thorax of anopheline females by ELISA, CSP and PCR (Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, or Plasmodium ovale). Human biting rate (HBR), sporozoite index and entomological infection rate (EIR) were calculated for Anopheles funestus, Anopheles arabiensis, Anopheles mascarensis, and Anopheles coustani. RESULTS: In Ankazobe district, the presence of malaria vectors such as An. funestus, An. arabiensis and An. mascarensis was confirmed, and a new and abundant potential vector, An. coustani was detected. Indeed, one individual of An. funestus and two An. coustani were detected positive with P. falciparum while one An. mascarensis and four An. coustani were positive with P. vivax. For An. coustani, in March 2014, the EIR varied from 0.01 infectious bites/person/month (ipm) outdoors to 0.11 ipm indoors. For An. funestus, in April 2013, the EIR was 0.13 ipm. The highest HBR value was observed for An. coustani, 86.13 ipm outdoors. The highest sporozoite rate was also for An. coustani, 9.5 % of An. coustani caught in stable was sporozoite positive. CONCLUSION: The implication of An. coustani in malaria transmission was not previously mentioned in Madagascar. Its very high abundance and the detection of Plasmodium coupled with an opportunistic feeding behaviour in villages with malaria cases supports its role in malaria transmission in Madagascar. PMID- 26620551 TI - BRPF3-HBO1 regulates replication origin activation and histone H3K14 acetylation. AB - During DNA replication, thousands of replication origins are activated across the genome. Chromatin architecture contributes to origin specification and usage, yet it remains unclear which chromatin features impact on DNA replication. Here, we perform a RNAi screen for chromatin regulators implicated in replication control by measuring RPA accumulation upon replication stress. We identify six factors required for normal rates of DNA replication and characterize a function of the bromodomain and PHD finger-containing protein 3 (BRPF3) in replication initiation. BRPF3 forms a complex with HBO1 that specifically acetylates histone H3K14, and genomewide analysis shows high enrichment of BRPF3, HBO1 and H3K14ac at ORC1-binding sites and replication origins found in the vicinity of TSSs. Consistent with this, BRPF3 is necessary for H3K14ac at selected origins and efficient origin activation. CDC45 recruitment, but not MCM2-7 loading, is impaired in BRPF3-depleted cells, identifying a BRPF3-dependent function of HBO1 in origin activation that is complementary to its role in licencing. We thus propose that BRPF3-HBO1 acetylation of histone H3K14 around TSS facilitates efficient activation of nearby replication origins. PMID- 26620554 TI - Paenibacillus nasutitermitis sp. nov., isolated from a termite gut. AB - A Gram-stain-positive, non-motile, aerobic and terminal-endospore-forming rod shaped bacterium, strain P5-1T, was isolated from the hindgut of a wood-feeding higher termite, Nasutitermes sp. Phylogenetic analysis of 16S rRNA gene sequences showed that the strain was closely related to Paenibacillus sepulcri CCM 7311T (97.5 % similarity). Growth was observed at 10-40 degrees C (optimum, 30 degrees C) and at pH 5.5-9.0 (optimum, pH 7.5). The DNA G+C content of strain P5 1T was 48.9 mol%. Cells contained menaquinone 7 (MK-7) as the sole respiratory quinone and the major fatty acids were anteiso-C15 : 0 and iso-C15 : 0. The cellular polar lipids comprised phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, one unidentified phospholipid, one unidentified glycolipid and one unidentified aminophospholipid. The diamino acid of the cell wall peptidoglycan was meso-diaminopimelic acid. Based on the phylogenetic, chemotaxonomic and phenotypic data obtained within this study, strain P5-1T represents a novel species of the genus Paenibacillus, for which the name Paenibacillus nasutitermitis sp. nov. is proposed. The type strain is P5-1T ( = CGMCC 1.15178T = NBRC 111536T). PMID- 26620553 TI - Impact of incontinence on the quality of life of caregivers of older persons with incontinence: A qualitative study in four European countries. AB - The aim of this study was to assess the impact of incontinence management on informal caregivers of older persons with incontinence. In order to investigate this phenomenon in different welfare systems via qualitative interviews and a content analysis methodology, the study was carried out in four European countries (Italy, the Netherlands, Slovak Republic and Sweden). To this purpose, 50 semi-structured interviews were conducted with spouses and children of older people receiving their help to manage the consequences of involuntary urinary and/or faecal leakage. Findings show that incontinence has a remarkably strong effect on caregivers' quality of life, because it results in progressive social isolation, causing them financial problems as well as psychological and physical exhaustion. The lack of appropriate support and the general silence regarding the problem, which is still considered a taboo by many, aggravate the caregivers' situation. It is therefore crucial that caregivers can count on a strong public and private support network, appropriate information and suitable incontinent products, in order to better handle incontinence and care tasks in general. PMID- 26620555 TI - A safety study of transumbilical single incision versus conventional laparoscopic surgery for colorectal cancer: study protocol for a randomized controlled trial. AB - BACKGROUND: Single-incision laparoscopic surgery (SILS) is an emerging minimally invasive surgery to reduce abdominal incisions. However, despite the increasing clinical application of SILS, no evidence from large-scale, randomized controlled trials is available for assessing the feasibility, short-term safety, oncological safety, and potential benefits of SILS compared with conventional laparoscopic surgery (CLS) for colorectal cancer. METHODS/DESIGN: This is a single-center, open-label, noninferiority, randomized controlled trial. A total of 198 eligible patients will be randomly assigned to transumbilical single incision plus one port laparoscopic surgery (SILS plus one) group or to a CLS group at a 1:1 ratio. Patients ranging in age from 18 to 80 years with rectosigmoid cancer diagnosed as cT1-4aN0-2 M0 and a tumor size no larger than 5 cm are considered eligible. The primary endpoint is early morbidity, as evaluated by an independent investigator. Secondary outcomes include operative outcomes (operative time, estimated blood loss, and incision length), pathologic outcomes (tumor size, length of proximal and distal resection margins, and number of harvested lymph nodes), postoperative inflammatory and immune responses (white blood cells [WBC], neutrophil percentage [NE %], C-reactive protein [CRP], interleukin-6 [IL-6], and tumor necrosis factor alpha [TNF-alpha]), postoperative recovery (time to first ambulation, flatus, liquid diet, soft diet, and duration of hospital stay), pain intensity, body image and cosmetic assessment, 3-year disease free survival (DFS), and 5-year overall survival (OS). Follow-up visits are scheduled for 1 and 3 months after surgery, then every 3 months for the first 2 years and every 6 months for the next 3 years. DISCUSSION: This trial will provide valuable clinical evidence for the objective assessment of the feasibility, safety, and potential benefits of SILS plus one compared with CLS for the radical resection of rectosigmoid cancer. The hypothesis is that SILS plus one is feasible for the radical resection of rectosigmoid cancer and offers short-term safety and long-term oncological safety comparable to that of CLS, and that SILS plus one offers better cosmetic results and faster convalescence compared to CLS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02117557 (registered on 16 April 2014). PMID- 26620556 TI - Reactive Center Loop (RCL) Peptides Derived from Serpins Display Independent Coagulation and Immune Modulating Activities. AB - Serpins regulate coagulation and inflammation, binding serine proteases in suicide-inhibitory complexes. Target proteases cleave the serpin reactive center loop scissile P1-P1' bond, resulting in serpin-protease suicide-inhibitory complexes. This inhibition requires a near full-length serpin sequence. Myxomavirus Serp-1 inhibits thrombolytic and thrombotic proteases, whereas mammalian neuroserpin (NSP) inhibits only thrombolytic proteases. Both serpins markedly reduce arterial inflammation and plaque in rodent models after single dose infusion. In contrast, Serp-1 but not NSP improves survival in a lethal murine gammaherpesvirus68 (MHV68) infection in interferon gamma-receptor deficient mice (IFNgammaR(-/-)). Serp-1 has also been successfully tested in a Phase 2a clinical trial. We postulated that proteolytic cleavage of the reactive center loop produces active peptide derivatives with expanded function. Eight peptides encompassing predicted protease cleavage sites for Serp-1 and NSP were synthesized and tested for inhibitory function in vitro and in vivo. In engrafted aorta, selected peptides containing Arg or Arg-Asn, not Arg-Met, with a 0 or +1 charge, significantly reduced plaque. Conversely, S-6 a hydrophobic peptide of NSP, lacking Arg or Arg-Asn with -4 charge, induced early thrombosis and mortality. S-1 and S-6 also significantly reduced CD11b(+) monocyte counts in mouse splenocytes. S-1 peptide had increased efficacy in plasminogen activator inhibitor-1 serpin-deficient transplants. Plaque reduction correlated with mononuclear cell activation. In a separate study, Serp-1 peptide S-7 improved survival in the MHV68 vasculitis model, whereas an inverse S-7 peptide was inactive. Reactive center peptides derived from Serp-1 and NSP with suitable charge and hydrophobicity have the potential to extend immunomodulatory functions of serpins. PMID- 26620557 TI - The Orphan G Protein-coupled Receptor GPR17 Negatively Regulates Oligodendrocyte Differentiation via Galphai/o and Its Downstream Effector Molecules. AB - Recent studies have recognized G protein-coupled receptors as important regulators of oligodendrocyte development. GPR17, in particular, is an orphan G protein-coupled receptor that has been identified as oligodendroglial maturation inhibitor because its stimulation arrests primary mouse oligodendrocytes at a less differentiated stage. However, the intracellular signaling effectors transducing its activation remain poorly understood. Here, we use Oli-neu cells, an immortalized cell line derived from primary murine oligodendrocytes, and primary rat oligodendrocyte cultures as model systems to identify molecular targets that link cell surface GPR17 to oligodendrocyte maturation blockade. We demonstrate that stimulation of GPR17 by the small molecule agonist MDL29,951 (2 carboxy-4,6-dichloro-1H-indole-3-propionic acid) decreases myelin basic protein expression levels mainly by triggering the Galphai/o signaling pathway, which in turn leads to reduced activity of the downstream cascade adenylyl cyclase-cAMP PKA-cAMP response element-binding protein (CREB). In addition, we show that GPR17 activation also diminishes myelin basic protein abundance by lessening stimulation of the exchange protein directly activated by cAMP (EPAC), thus uncovering a previously unrecognized role for EPAC to regulate oligodendrocyte differentiation. Together, our data establish PKA and EPAC as key downstream effectors of GPR17 that inhibit oligodendrocyte maturation. We envisage that treatments augmenting PKA and/or EPAC activity represent a beneficial approach for therapeutic enhancement of remyelination in those demyelinating diseases where GPR17 is highly expressed, such as multiple sclerosis. PMID- 26620558 TI - Systemic Central Nervous System (CNS)-targeted Delivery of Neuropeptide Y (NPY) Reduces Neurodegeneration and Increases Neural Precursor Cell Proliferation in a Mouse Model of Alzheimer Disease. AB - Neuropeptide Y (NPY) is one of the most abundant protein transmitters in the central nervous system with roles in a variety of biological functions including: food intake, cardiovascular regulation, cognition, seizure activity, circadian rhythms, and neurogenesis. Reduced NPY and NPY receptor expression is associated with numerous neurodegenerative disorders including Alzheimer disease (AD). To determine whether replacement of NPY could ameliorate some of the neurodegenerative and behavioral pathology associated with AD, we generated a lentiviral vector expressing NPY fused to a brain transport peptide (apoB) for widespread CNS delivery in an APP-transgenic (tg) mouse model of AD. The recombinant NPY-apoB effectively reversed neurodegenerative pathology and behavioral deficits although it had no effect on accumulation of Abeta. The subgranular zone of the hippocampus showed a significant increase in proliferation of neural precursor cells without further differentiation into neurons. The neuroprotective and neurogenic effects of NPY-apoB appeared to involve signaling via ERK and Akt through the NPY R1 and NPY R2 receptors. Thus, widespread CNS-targeted delivery of NPY appears to be effective at reversing the neuronal and glial pathology associated with Abeta accumulation while also increasing NPC proliferation. Overall, increased delivery of NPY to the CNS for AD might be an effective therapy especially if combined with an anti-Abeta therapeutic. PMID- 26620559 TI - Uracil-DNA Glycosylase UNG Promotes Tet-mediated DNA Demethylation. AB - In mammals, active DNA demethylation involves oxidation of 5-methylcytosine (5mC) into 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) by Tet dioxygenases and excision of these two oxidized bases by thymine DNA glycosylase (TDG). Although TDG is essential for active demethylation in embryonic stem cells and induced pluripotent stem cells, it is hardly expressed in mouse zygotes and dispensable in pronuclear DNA demethylation. To search for other factors that might contribute to demethylation in mammalian cells, we performed a functional genomics screen based on a methylated luciferase reporter assay. UNG2, one of the glycosylases known to excise uracil residues from DNA, was found to reduce DNA methylation, thus activating transcription of a methylation-silenced reporter gene when co-transfected with Tet2 into HEK293T cells. Interestingly, UNG2 could decrease 5caC from the genomic DNA and a reporter plasmid in transfected cells, like TDG. Furthermore, deficiency in Ung partially impaired DNA demethylation in mouse zygotes. Our results suggest that UNG might be involved in Tet-mediated DNA demethylation. PMID- 26620560 TI - RUTBC1 Functions as a GTPase-activating Protein for Rab32/38 and Regulates Melanogenic Enzyme Trafficking in Melanocytes. AB - Two cell type-specific Rab proteins, Rab32 and Rab38 (Rab32/38), have been proposed as regulating the trafficking of melanogenic enzymes, including tyrosinase and tyrosinase-related protein 1 (Tyrp1), to melanosomes in melanocytes. Like other GTPases, Rab32/38 function as switch molecules that cycle between a GDP-bound inactive form and a GTP-bound active form; the cycle is thought to be regulated by an activating enzyme, guanine nucleotide exchange factor (GEF), and an inactivating enzyme, GTPase-activating protein (GAP), which stimulates the GTPase activity of Rab32/38. Although BLOC-3 has already been identified as a Rab32/38-specific GEF that regulates the trafficking of tyrosinase and Tyrp1, no physiological GAP for Rab32/38 in melanocytes has ever been identified, and it has remained unclear whether Rab32/38 is involved in the trafficking of dopachrome tautomerase, another melanogenic enzyme, in mouse melanocytes. In this study we investigated RUTBC1, which was originally characterized as a Rab9-binding protein and GAP for Rab32 and Rab33B in vitro, and the results demonstrated that RUTBC1 functions as a physiological GAP for Rab32/38 in the trafficking of all three melanogenic enzymes in mouse melanocytes. The results of this study also demonstrated the involvement of Rab9A in the regulation of the RUTBC1 localization and in the trafficking of all three melanogenic enzymes. We discovered that either excess activation or inactivation of Rab32/38 achieved by manipulating RUTBC1 inhibits the trafficking of all three melanogenic enzymes. These results collectively indicate that proper spatiotemporal regulation of Rab32/38 is essential for the trafficking of all three melanogenic enzymes in mouse melanocytes. PMID- 26620561 TI - Binding Affinities among DNA Helicase-Primase, DNA Polymerase, and Replication Intermediates in the Replisome of Bacteriophage T7. AB - The formation of a replication loop on the lagging strand facilitates coordinated synthesis of the leading- and lagging-DNA strands and provides a mechanism for recycling of the lagging-strand DNA polymerase. As an Okazaki fragment is completed, the loop is released, and a new loop is formed as the synthesis of a new Okazaki fragment is initiated. Loop release requires the dissociation of the complex formed by the interactions among helicase, DNA polymerase, and DNA. The completion of the Okazaki fragment may result in either a nick or a single stranded DNA region. In the replication system of bacteriophage T7, the dissociation of the polymerase from either DNA region is faster than that observed for the dissociation of the helicase from DNA polymerase, implying that the replication loop is released more likely through the dissociation of the lagging-strand DNA from polymerase, retaining the polymerase at replication fork. Both dissociation of DNA polymerase from DNA and that of helicase from a DNA polymerase . DNA complex are much faster at a nick DNA region than the release from a ssDNA region. These results suggest that the replication loop is released as a result of the nick formed when the lagging-strand DNA polymerase encounters the previously synthesized Okazaki fragment, releasing lagging-strand DNA and retaining DNA polymerase at the replication fork for the synthesis of next Okazaki fragment. PMID- 26620562 TI - The Transcription Factor Bach2 Is Phosphorylated at Multiple Sites in Murine B Cells but a Single Site Prevents Its Nuclear Localization. AB - The transcription factor Bach2 regulates the immune system at multiple points, including class switch recombination (CSR) in activated B cells and the function of T cells in part by restricting their terminal differentiation. However, the regulation of Bach2 expression and its activity in the immune cells are still unclear. Here, we demonstrated that Bach2 mRNA expression decreased in Pten deficient primary B cells. Bach2 was phosphorylated in primary B cells, which was increased upon the activation of the B cell receptor by an anti-immunoglobulin M (IgM) antibody or CD40 ligand. Using specific inhibitors of kinases, the phosphorylation of Bach2 in activated B cells was shown to depend on the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway. The complex of mTOR and Raptor phosphorylated Bach2 in vitro. We identified multiple new phosphorylation sites of Bach2 by mass spectrometry analysis of epitope-tagged Bach2 expressed in the mature B cell line BAL17. Among the sites identified, serine 535 (Ser-535) was critical for the regulation of Bach2 because a single mutation of Ser-535 abolished cytoplasmic accumulation of Bach2, promoting its nuclear accumulation in pre-B cells, whereas Ser-509 played an auxiliary role. Bach2 repressor activity was enhanced by the Ser-535 mutation in B cells. These results suggest that the PI3K-Akt-mTOR pathway inhibits Bach2 by both repressing its expression and inducing its phosphorylation in B cells. PMID- 26620563 TI - SIRT3 Deacetylates Ceramide Synthases: IMPLICATIONS FOR MITOCHONDRIAL DYSFUNCTION AND BRAIN INJURY. AB - Experimental evidence supports the role of mitochondrial ceramide accumulation as a cause of mitochondrial dysfunction and brain injury after stroke. Herein, we report that SIRT3 regulates mitochondrial ceramide biosynthesis via deacetylation of ceramide synthase (CerS) 1, 2, and 6. Reciprocal immunoprecipitation experiments revealed that CerS1, CerS2, and CerS6, but not CerS4, are associated with SIRT3 in cerebral mitochondria. Furthermore, CerS1, -2, and -6 are hyperacetylated in the mitochondria of SIRT3-null mice, and SIRT3 directly deacetylates the ceramide synthases in a NAD(+)-dependent manner that increases enzyme activity. Investigation of the SIRT3 role in mitochondrial response to brain ischemia/reperfusion (IR) showed that SIRT3-mediated deacetylation of ceramide synthases increased enzyme activity and ceramide accumulation after IR. Functional studies demonstrated that absence of SIRT3 rescued the IR-induced blockade of the electron transport chain at the level of complex III, attenuated mitochondrial outer membrane permeabilization, and decreased reactive oxygen species generation and protein carbonyls in mitochondria. Importantly, Sirt3 gene ablation reduced the brain injury after IR. These data support the hypothesis that IR triggers SIRT3-dependent deacetylation of ceramide synthases and the elevation of ceramide, which could inhibit complex III, leading to increased reactive oxygen species generation and brain injury. The results of these studies highlight a novel mechanism of SIRT3 involvement in modulating mitochondrial ceramide biosynthesis and suggest an important role of SIRT3 in mitochondrial dysfunction and brain injury after experimental stroke. PMID- 26620564 TI - Lipid Requirements for the Enzymatic Activity of MraY Translocases and in Vitro Reconstitution of the Lipid II Synthesis Pathway. AB - Screening of new compounds directed against key protein targets must continually keep pace with emerging antibiotic resistances. Although periplasmic enzymes of bacterial cell wall biosynthesis have been among the first drug targets, compounds directed against the membrane-integrated catalysts are hardly available. A promising future target is the integral membrane protein MraY catalyzing the first membrane associated step within the cytoplasmic pathway of bacterial peptidoglycan biosynthesis. However, the expression of most MraY homologues in cellular expression systems is challenging and limits biochemical analysis. We report the efficient production of MraY homologues from various human pathogens by synthetic cell-free expression approaches and their subsequent characterization. MraY homologues originating from Bordetella pertussis, Helicobacter pylori, Chlamydia pneumoniae, Borrelia burgdorferi, and Escherichia coli as well as Bacillus subtilis were co-translationally solubilized using either detergent micelles or preformed nanodiscs assembled with defined membranes. All MraY enzymes originating from Gram-negative bacteria were sensitive to detergents and required nanodiscs containing negatively charged lipids for obtaining a stable and functionally folded conformation. In contrast, the Gram-positive B. subtilis MraY not only tolerates detergent but is also less specific for its lipid environment. The MraY.nanodisc complexes were able to reconstitute a complete in vitro lipid I and lipid II forming pipeline in combination with the cell-free expressed soluble enzymes MurA-F and with the membrane-associated protein MurG. As a proof of principle for future screening platforms, we demonstrate the inhibition of the in vitro lipid II biosynthesis with the specific inhibitors fosfomycin, feglymycin, and tunicamycin. PMID- 26620565 TI - Transcriptional Regulation of Cystathionine-gamma-Lyase in Endothelial Cells by NADPH Oxidase 4-Dependent Signaling. AB - The gasotransmitter, hydrogen sulfide (H2S) is recognized as an important mediator of endothelial cell homeostasis and function that impacts upon vascular tone and blood pressure. Cystathionine-gamma-lyase (CSE) is the predominant endothelial generator of H2S, and recent evidence suggests that its transcriptional expression is regulated by the reactive oxygen species, H2O2. However, the cellular source of H2O2 and the redox-dependent molecular signaling pathway that modulates this is not known. We aimed to investigate the role of Nox4, an endothelial generator of H2O2, in the regulation of CSE in endothelial cells. Both gain- and loss-of-function experiments in human endothelial cells in vitro demonstrated Nox4 to be a positive regulator of CSE transcription and protein expression. We demonstrate that this is dependent upon a heme-regulated inhibitor kinase/eIF2alpha/activating transcription factor 4 (ATF4) signaling module. ATF4 was further demonstrated to bind directly to cis-regulatory sequences within the first intron of CSE to activate transcription. Furthermore, CSE expression was also increased in cardiac microvascular endothelial cells, isolated from endothelial-specific Nox4 transgenic mice, compared with wild-type littermate controls. Using wire myography we demonstrate that endothelial specific Nox4 transgenic mice exhibit a hypo-contractile phenotype in response to phenylephrine that was abolished when vessels were incubated with a CSE inhibitor, propargylglycine. We, therefore, conclude that Nox4 is a positive transcriptional regulator of CSE in endothelial cells and propose that it may in turn contribute to the regulation of vascular tone via the modulation of H2S production. PMID- 26620566 TI - Sorafenib suppresses the epithelial-mesenchymal transition of hepatocellular carcinoma cells after insufficient radiofrequency ablation. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) played an important role in the progression of hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA). However, whether sorafenib could be used to suppress the EMT of HCC after insufficient RFA and further prevent the progression of residual HCC remains poorly unknown. METHODS: Insufficient RFA was simulated using a water bath (47 degrees C 5, 10, 15, 20 and 25 min gradually). MTT assay and transwell assay were used to evaluate the effects of sorafenib on viability, migration and invasion of HepG2 and SMMC7721 cells after insufficient RFA in vitro. After insufficient RFA, the molecular changes in HCC cells with the treatment of sorafeinb were evaluated using western blot and ELISAs. An ectopic nude mice model was used to evaluate the effect of sorafenib on the growth of HepG2 cells in vivo after insufficient RFA. RESULTS: HepG2 and SMMC7721 cells after insufficient RFA (named as HepG2-H and SMMC7721-H) exhibited enhanced viability, migration and invasion in vitro. Sorafenib inhibited the enhanced viability, migration and invasion of HepG2 and SMMC7721 cells after insufficient RFA. Molecular changes of EMT were observed in HepG2-H and SMMC7721-H cells. Sorafenib inhibited the EMT of HepG2-H and SMMC7721-H cells. HepG2-H cells also exhibited larger tumor size in vivo. Higher expression of PCNA, Ki67, N-cadherin, MMP-2 and MMP-9, was also observed in HepG2-H tumors. Sorafenib blocked the enhanced growth of HepG2 cells in vivo after insufficient RFA. CONCLUSIONS: Sorafenib inhibited the EMT of HCC cells after insufficient RFA, and may be used to prevent the progression of HCC after RFA. PMID- 26620567 TI - Validation of a model of intensive training in digestive laparoscopic surgery. AB - INTRODUCTION: Our objective was to assess a laparoscopic training model for general surgery residents. METHODS: Twelve general surgery residents carried out a training program, consisting of a theoretical session (one hour) and a hands-on session on simulator (7 h) and on animal model (13 h). For the first and last repetitions of simulator tasks and the Nissen fundoplication technique, time and scores from the global rating scale objective structured assessment of technical skills (OSATS) were registered. Before and after the course, participants performed 4 tasks on the virtual reality simulator LAPMentorTM: 1) hand-eye coordination, 2) hand-hand coordination, 3) transference of objects and 4) cholecystectomy task, registering time and movement metrics. Moreover, the residents completed a questionnaire related to the training components on a 5 point rating scale. RESULTS: The last repetition of the tasks and the Nissen fundoplication technique were performed faster and with a higher OSATS score. After the course, the participants performed all LAPMentorTM tasks faster, increasing the speed of movements in all tasks. Number of movements decreased in tasks 2, 3 and 4; as well as path length in tasks 2 and 4. Training components were positively rated by residents, being the suture task the aspect best rated (4.90 +/- 0.32). CONCLUSIONS: This training model in digestive laparoscopic surgery has demonstrated to be valid for the improvement of basic and advanced skills of general surgery residents. Intracorporeal suturing and the animal model were the best rated training elements. PMID- 26620568 TI - Bioengineering thermodynamics of biological cells. AB - BACKGROUND: Cells are open complex thermodynamic systems. They can be also regarded as complex engines that execute a series of chemical reactions. Energy transformations, thermo-electro-chemical processes and transports phenomena can occur across the cells membranes. Moreover, cells can also actively modify their behaviours in relation to changes in their environment. METHODS: Different thermo electro-biochemical behaviours occur between health and disease states. But, all the living systems waste heat, which is no more than the result of their internal irreversibility. This heat is dissipated into the environment. But, this wasted heat represent also a sort of information, which outflows from the cell toward its environment, completely accessible to any observer. RESULTS: The analysis of irreversibility related to this wasted heat can represent a new approach to study the behaviour of the cells themselves and to control their behaviours. So, this approach allows us to consider the living systems as black boxes and analyze only the inflows and outflows and their changes in relation to the modification of the environment. Therefore, information on the systems can be obtained by analyzing the changes in the cell heat wasted in relation to external perturbations. CONCLUSIONS: The bioengineering thermodynamics bases are summarized and used to analyse possible controls of the calls behaviours based on the control of the ions fluxes across the cells membranes. PMID- 26620569 TI - Tactile asymbolia. AB - Agraphesthesia has been attributed to impairment of the ability to detect more rudimentary directionality of lines written on the skin (directional cutaneous kinesthesia). We examined a patient who had a dissociation between preserved perception of line directionality and the loss of graphesthesia for letters and numbers. A man with a metastatic right parietal lesion was tested for the ability to determine the directionality of lines drawn on the palms and forehead and then evaluated for recognition of letters and numbers in these regions. Our patient could identify the directions of lines, letters and numbers drawn on paper. The ability to detect the direction and shape of lines drawn on the skin of the palms and on the forehead was preserved but he had agraphesthesia for numbers and letters in these same locations. The finding of isolated agraphesthesia for letters and numbers may be assigned to damage in the right parietal lobe. It represents a deficit of somatosensory processing that is of a higher order than detection of line directionality. The term "tactile asymbolia" may capture the dissociation. These clinical findings suggest that tactile cortex in humans, like visual cortex, may be hierarchically organized, as has been demonstrated in primates. PMID- 26620570 TI - Fat on sale: role of adipose-derived stem cells as anti-fibrosis agent in regenerative medicine. AB - The potential use of stem cells for cell-based tissue repair and regeneration offers alternative therapeutic strategies for various diseases. Adipose-derived stem cells (ADSCs) have emerged as a promising source of stem cells suitable for transplantation in regenerative medicine and wound repair. A recent publication in Stem Cell Research & Therapy by Zhang and colleagues reports a new finding about the anti-fibrosis role of ADSCs and conditioned media derived from them on hypertrophic scar formation in vivo. PMID- 26620571 TI - Epidermal growth factor: Porcine uterine luminal epithelial cell migratory signal during the peri-implantation period of pregnancy. AB - The majority of early conceptus mortality in pregnancy occurs during the peri implantation period, suggesting that this period is important for conceptus viability and the establishment of pregnancy. Successful establishment of pregnancy in all mammalian species depends on the orchestrated molecular events that transpire at the conceptus-uterine interface during the peri-implantation period of pregnancy. This maternal-conceptus interaction is especially crucial in pigs because they have a non-invasive epitheliochorial placentation during a protracted peri-implantation period. During the pre-implantation period of pregnancy, conceptus survival and the establishment of pregnancy depend on the developing conceptus receiving an adequate supply of histotroph which contains a wide range of nutrients and growth factors. Evidence links epidermal growth factor (EGF) to embryogenesis or implantation in various mammalian species. EGF exhibits potential growth-promoting activities on the conceptus and endometrium; however, in the case of pigs, little is known its functions, especially their regulatory mechanisms at the maternal-conceptus interface. EGF receptor (EGFR) mRNA and protein are abundant in endometrial luminal (LE) and glandular (GE) epithelia and conceptus trophectoderm on Days 13-14 of pregnancy, suggesting that EGF provides an autocrine signal to uterine LE and GE just prior to implantation. Therefore, the objectives of this study were to determine: 1) the potential intracellular signaling pathways responsible for the activities of EGF in porcine uterine LE (pLE) cells; and 2) the changes in cellular activities induced by EGF. EGF treatment of pLE cells increased the abundance of phosphorylated (p)-ERK1/2, p-P70RSK and p-RPS6 compared to that for control cells. Furthermore, EGF stimulated phosphorylation of ERK1/2 MAPK was inhibited in pLE cells transfected with an EGFR siRNA compared with control siRNA-transfected pLE cells. Moreover, EGF stimulated migration of pLE cells, but this stimulatory effect was blocked by U0126, a pharmacological inhibitor or ERK1/2 MAPK. Collectively, these results provide new insights into mechanisms whereby EGF regulates development of the peri-implantation uterine LE at the fetal-maternal interface. These results indicate that endometrial- and/or conceptus derived EGF effects migration of uterine LE and that those stimulatory effects are regulated via the ERK1/2 MAPK pathway during early pregnancy in pigs. PMID- 26620573 TI - A Member of Complementary Medicinal Food: Anatolian Royal Jellies, Their Chemical Compositions, and Antioxidant Properties. AB - This study investigated various chemical and antioxidant properties of Anatolian royal jelly samples. Moisture, pH, total protein, 10-hydroxy-2-decenoic acid (10 HDA) and sugars were analyzed from 18 samples. Total phenolic contents, ferric reducing antioxidant capacity and 2,2-diphenyl-1-picryhydrazyl (DPPH) free radical scavenging activity were measured as antioxidant determinants. 10-HDA contents and total protein content of fresh weight ranged between 1.0% and 3.9%, and 11.4% and 15.8%, respectively. The main sugars detected were glucose and fructose. Maltose, trehalose, and melibiose were detected at less than 1.0% in all samples. Lactose, a milk sugar, was detected in only 3 samples, at values between 0.8% and 1.4%. Total henolic content ranged from 91.0 to 301.0 mg gallic acid equivalents/kg fresh weight. Antioxidant activity is due to both to the total phenolic content, proteins and fatty acids of royal jelly. Anatolian royal jelly samples were not different from other royal jelly samples from across the world. PMID- 26620574 TI - Protective Effect of Ocimum basilicum Essential Oil Against Acetic Acid-Induced Colitis in Rats. AB - Ocimum basilicum L has been traditionally used for the treatment of inflammatory bowel disease in Iran. This study investigates the ameliorative effect of Ocimum basilicum essential oil on an acetic acid-induced colitis model in rats. Ocimum basilicum essential oil with 2 doses (200 and 400 MUL/kg) significantly ameliorated wet weight/length ratio of colonic tissue compared to the control group. Higher doses of essential oil (200 and 400 MUL/kg) significantly reduced ulcer severity, ulcer area, and ulcer index. On the other hand, histological examination revealed the diminution of total colitis index as a marker for inflammatory cell infiltration in the colonic segments of rats treated with Ocimum basilicum essential oil (200 and 400 MUL/kg). The increased level of myeloperoxidase was significantly decreased after the treatment with the essential oil (200 and 400 MUL/kg). These results suggest that Ocimum basilicum exhibits protective effect against acetic acid-induced colitis. PMID- 26620572 TI - Two-hit exposure to polychlorinated biphenyls at gestational and juvenile life stages: 2. Sex-specific neuromolecular effects in the brain. AB - Exposures to polychlorinated biphenyls (PCBs) during early development have long lasting, sexually dimorphic consequences on adult brain and behavior. However, few studies have investigated their effects during juvenile development, a time when increases in pubertal hormones influence brain maturation. Here, male and female Sprague Dawley rats were exposed to PCBs (Aroclor 1221, 1 mg/kg/day) or vehicle prenatally, during juvenile development, or both, and their effects on serum hormone concentrations, gene expression, and DNA methylation were assessed in adulthood. Gene expression in male but not female brains was affected by 2 hits of PCBs, a result that paralleled behavioral effects of PCBs. Furthermore, the second hit often changed the effects of a first hit in complex ways. Thus, PCB exposures during critical fetal and juvenile developmental periods result in unique neuromolecular phenotypes, with males most vulnerable to the treatments. PMID- 26620575 TI - Permeability of plumbagin across human intestinal cell in vitro. AB - Plumbagin is the active compound isolated from plants used in traditional medicine for treatment of various diseases such as activities malaria, leishmaniasis, viral infections and cancers. The aim of the study was to investigate the permeability of plumbagin across Caco-2 (human epithelial colorectal adenocarcinoma) cell monolayer and its effects on the expression and function of P-glycoprotein. The integrity of Caco-2 cell monolayer was evaluated by measuring trans-epithelial electrical resistance and permeation (Papp) of Lucifer yellow across the cell monolayer. The effect of plumbagin on P glycoprotein was detected by measuring its interference with the transport of the P-glycoprotein substrate (R123) and the effect on MDR-1 mRNA expression was detected by RT-PCR. The Papp of plumbagin (2-8 uM) for the apical to basolateral and basolateral to apical directions were 10.29-15.96 * 10(-6) and 7.40-9.02 * 10(-6) cm/s, respectively, with the efflux ratios of 0.57-0.73. Plumbagin is not either a substrate or inhibitor of P-glycoprotein. It did not interfere with the P-glycoprotein-mediated R123 transport across Caco-2 cell monolayer, as well as the function of P-glycoprotein and the expression of MDR-1 mRNA. Results suggest moderate permeability of plumbagin across the Caco-2 cell monolayer in both directions. The transport mechanism is likely to be a passive transport. PMID- 26620576 TI - A novel protocol for the one-pot borylation/Suzuki reaction provides easy access to hinge-binding groups for kinase inhibitors. AB - The one-pot borylation/Suzuki reaction is a very efficient means of accessing cross-coupling products of two aryl-halide partners that generally requires the use of specific catalysts or ligands and/or relatively long reaction times. This new microwave-assisted method provides a quick one-pot borylation/Suzuki reaction protocol that we applied to the synthesis of various bi- or poly-aryl scaffolds, including a variety of aryl and heteroaryl ring systems and the core frameworks of kinase inhibitors vemurafenib and GDC-0879. PMID- 26620577 TI - The effect of body weight on distal airway function and airway inflammation. AB - BACKGROUND/OBJECTIVES: Obesity is a global health problem that adversely influences the respiratory system. We assessed the effects of body mass index (BMI) on distal airway function and airway inflammation. SUBJECTS/METHODS: Impulse oscillometry (IOS) as a measure of distal airway function, together with spirometry, were assessed in adults with a range of different BMIs. Airway inflammation was assessed with the fraction of exhaled nitric oxide (FeNO) and participants exhaled at various exhalation flows to determine alveolar and bronchial NO. RESULTS: In total 34 subjects were enrolled in the study; 19 subjects had a normal BMI (18.50-24.99), whilst 15 subjects were overweight (BMI 25.00-29.99), or obese (BMI >=30). All subjects had normal spirometry. However, IOS measures of airway resistance (R) at 5Hz, 20Hz and frequency dependence (R5 20) were elevated in overweight/obese individuals, compared to subjects with a normal BMI (median (interquartile range)); 5Hz: 0.41 (0.37, 0.45) vs. 0.32 (0.30, 0.37)kPa/l/s; 20Hz: 0.34 (0.30, 0.37) vs. 0.30 (0.26, 0.33)kPa/l/s; R5-20: 0.06 (0.04, 0.11) vs. 0.03 (0.01, 0.05)kPa/l/s; p<0.05), whereas airway reactance at 20Hz was decreased in overweight/obese individuals (20Hz: 0.07 (0.03, 0.09) vs. 0.10 (0.07, 0.13)kPa/l/s, p=0.009; 5Hz: -0.12 (-0.15, -0.10) vs. -0.10 (-0.13, 0.09)kPa/l/s, p=0.07). In contrast, within-breath IOS measures (a sign of expiratory flow limitation) and FeNO inflammatory measures, did not differ between groups (p>0.05). CONCLUSIONS: Being overweight has significant effects on distal and central airway function as determined by IOS, which is not detected by spirometry. Obesity does not influence airway inflammation as measured by FeNO. IOS is a reliable technique to identify airway abnormalities in the presence of normal spirometry in overweight people. PMID- 26620578 TI - Effect of restricted protein diet supplemented with keto analogues in chronic kidney disease: a systematic review and meta-analysis. AB - BACKGROUND: To evaluate the efficacy and safety of the restricted protein diet (low or very low protein diet) supplemented with keto analogues in the treatment of chronic kidney disease (CKD). METHODS: The Cochrane library, PubMed, Embase, CBM and CENTRAL databases were searched and reviewed up to April 2015. Clinical trials were analyzed using RevMan 5.3 software. RESULTS: Seven random control trials, one cross-over trial and one non-randomized concurrent control trial were selected and included in this study according to our inclusion and exclusion criteria. The changes of eGFR, BUN, Scr, albumin, PTH, triglyceride, cholesterol, calcium, phosphorus and nutrition indexes (BMI, lean body mass and mid-arm muscular circumference) before and after treatment were analyzed. The meta analysis results indicated that, comparing with normal protein diet, low protein diet (LPD) or very low protein diet (vLPD) supplemented with keto analogues (s(v)LPD) could significantly prevent the deterioration of eGFR (P < 0.001), hyperparathyroidism (P = 0.04), hypertension (P < 0.01) and hyperphosphatemia (P < 0.001). No differences in BUN, Scr, Albumin, triglyceride, cholesterol, hemoglobin, calcium and nutrition indexes were observed between different protein intake groups. CONCLUSION: Restricted protein diet supplemented with keto analogues (s(v)LPD) could delay the progression of CKD effectively without causing malnutrition. PMID- 26620579 TI - Operationalizing reflexivity to improve the rigor of palliative care research. AB - Reflective practice involves deliberate consideration of actions, attitudes and behaviors. Reflexivity in research is considered important for ensuring that research is ethically and rigorously conducted. This paper details the challenges of conducting research involving patients with palliative care needs within the acute hospital environment. It discusses the contribution of reflexivity to a pilot study using the Patient Dignity Question (PDQ) "What do I need to know about you as a person to take the best care of you that I can?" as a brief intervention to foster a more person-centered climate. Challenges that emerged are discussed from the perspectives of the researchers, the participants, and the setting; they relate to: timing and recruitment, the nature of palliative care illness, attitudes to research, and the research environment. Awareness of such issues can prompt researchers to devise appropriate strategies and approaches that may inform and assist the rigor and conduct of future research. PMID- 26620580 TI - Ultrasound Color histogram assessment allows better view of echotexture damage. AB - INTRODUCTION: The colored ultrasound images can better highlight the joint echotexture damage. OBJECTIVE: To detect echotexture changes in joints of patients with rheumatic diseases, through a color histogram, and to correlate the area measurements with the gray scale (GS). METHODS: Four patients with chondrocalcinosis, 5 patients with osteoarthritis and 1 patient with psoriatic arthritis were evalutated. A total of 104 synovitis (SYN) and calcifications (calcif) measurements in cm2 were performed in the dorsal radiocarpal joint (DRR); triangular fibrocartilage complex (TFC); dorsal metacarpophalangeal joints (MCP) and lateral and medial knee suprapatellar recesses. For each GS measure, one was performed for each standard color image. Spearman was used for correlation analysis. RESULTS: Mean+/-SD of image patterns: RGB (Red, Green and Blue) SYN 16.96+/-0.25cm2; indigo SYN 6.43+/-0.07cm2, RGB Calcif 0.03+/-0.00cm2; indigo Calcif 0.06+/-0.03cm2; GS SYN 16.13+/-0.35cm2 and GS Calcif 0.56+/ 0.01cm2. Correlations of color images patterns RGB DRR SYN and indigo DRR SYN: r=1, p<0.001; indigo DRR SYN and RGB suprapattelar SYN: r=1, p<0.001; RGB MCP SYN and indigo MCP SYN: r=1, p<0.001; indigo DRR calcif and RGB TFC calcif: r=1 p<0.001; the RGB and indigo measurement standards when correlated with GS for SYN and calcifs were not statistically significant (p=0.333 to 0.667). CONCLUSION: The RGB and indigo patterns seem to better define these echotexture damage. PMID- 26620582 TI - The structure of adolescent psychopathology: a symptom-level analysis. AB - BACKGROUND: Most empirical studies into the covariance structure of psychopathology have been confined to adults. This work is not developmentally informed as the meaning, age-of-onset, persistence and expression of disorders differ across the lifespan. This study investigates the underlying structure of adolescent psychopathology and associations between the psychopathological dimensions and sex and personality risk profiles for substance misuse and mental health problems. METHOD: This study analyzed data from 2175 adolescents aged 13.3 years. Five dimensional models were tested using confirmatory factor analysis and the external validity was examined using a multiple-indicators multiple-causes model. RESULTS: A modified bifactor model, with three correlated specific factors (internalizing, externalizing, thought disorder) and one general psychopathology factor, provided the best fit to the data. Females reported higher mean levels of internalizing, and males reported higher mean levels of externalizing. No significant sex differences emerged in liability to thought disorder or general psychopathology. Liability to internalizing, externalizing, thought disorder and general psychopathology was characterized by a number of differences in personality profiles. CONCLUSIONS: This study is the first to identify a bifactor model including a specific thought disorder factor. The findings highlight the utility of transdiagnostic treatment approaches and the importance of restructuring psychopathology in an empirically based manner. PMID- 26620584 TI - Remediation and course repetition: the domino effect on academics and economics. AB - The international nursing shortage has increased recruitment of students, who may be under or unprepared, into higher education institutions (college or university). BACKGROUND: The global economic downturn and the movement toward standardizing nursing education and practice regulations has encouraged higher education to recruit and retain aspiring nursing students. However, deficiencies in mathematics and English have been linked to disappointing results with economic consequences. PURPOSE: The objective of this study was to describe the incidence and monetary costs associated with remediation, course repetitions, delay to graduation, and first time passage on the American licensing exam National Council Licensure Examination for Registered Nurses. METHODOLOGY: A convenience sample of 103 sophomore nursing students from a college in the northeast United States was followed to graduation. The sample was predominately female, single, age 18-25 years, and White. FINDINGS: Mathematics and English remediation courses taken were 123. There were 148 course repetitions with 104 in the biological sciences and 44 in nursing. Direct relationships were found between the number of overall remedial courses and course repeats (r = .40, p = <.001, CI = 95%) with a strong negative correlation with the number of course repetitions (r = -.60, p = <.001, CI = 95%) and on-time graduation. Sixty-two students (60%) of the original cohort graduated and took the registered nurse licensing examination with 56 passing. In this American study, the direct and indirect cost of remediation, course repetition and lost income opportunity was greater than $1.6 million. CONCLUSION: Interdisciplinary collaboration, including nursing faculty, is critical in the recruitment and retention of nursing students. Without structured pre-admission evaluation the short and long term financial and academic effects of under or unprepared students is disquieting. PMID- 26620583 TI - Idiographic quality of life assessment before radical cystectomy. AB - BACKGROUND: We sought to determine if idiographic, or self-defined, measures added to our understanding of patients with bladder cancer's quality of life (QOL) prior to radical cystectomy (RC). We tested whether idiographic measures increased prediction of global QOL beyond standard (nomothetic) measures of QOL components. METHODS: We administered the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (QLQ)-C30 and QLQ-BLM30, and our own idiographic Quality of Life Appraisal Profile prior to RC. Idiographic measures included number of goal statements, distance from goal attainment, and ability to complete goal attainment activities. Multivariate linear regression was used to predict measures of global QOL and related constructs of life satisfaction and mental health. RESULTS: Two hundred fiftheen patients reported a median of 8 (interquartile range [IQR] 6, 11) goals and half had an average goal attainment rating above 6.9 out of 10 (IQR 5.5, 8.2). On multivariable analysis, QLQ-C30 role functioning and QLQ-BLM30 future perspective explained 15.7% of the variability in preoperative global QOL. Including goal attainment and activity difficulty explained an additional 12% of global QOL variance. Smaller gains were seen on measures of global health, life satisfaction, mental health, and activity, suggesting that idiographic measures capture aspects of QOL distinct from health and functional status defined by nomothetic scales. CONCLUSIONS: Idiographic assessment of QOL added to prediction of global QOL above and beyond health-related components measured using nomothetic instruments. This self defined information may be valuable in communicating with cancer patients about their QOL. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26620581 TI - Molecular Imaging of Pancreatic Cancer with Antibodies. AB - Development of novel imaging probes for cancer diagnostics remains critical for early detection of disease, yet most imaging agents are hindered by suboptimal tumor accumulation. To overcome these limitations, researchers have adapted antibodies for imaging purposes. As cancerous malignancies express atypical patterns of cell surface proteins in comparison to noncancerous tissues, novel antibody-based imaging agents can be constructed to target individual cancer cells or surrounding vasculature. Using molecular imaging techniques, these agents may be utilized for detection of malignancies and monitoring of therapeutic response. Currently, there are several imaging modalities commonly employed for molecular imaging. These imaging modalities include positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance (MR) imaging, optical imaging (fluorescence and bioluminescence), and photoacoustic (PA) imaging. While antibody-based imaging agents may be employed for a broad range of diseases, this review focuses on the molecular imaging of pancreatic cancer, as there are limited resources for imaging and treatment of pancreatic malignancies. Additionally, pancreatic cancer remains the most lethal cancer with an overall 5-year survival rate of approximately 7%, despite significant advances in the imaging and treatment of many other cancers. In this review, we discuss recent advances in molecular imaging of pancreatic cancer using antibody-based imaging agents. This task is accomplished by summarizing the current progress in each type of molecular imaging modality described above. Also, several considerations for designing and synthesizing novel antibody-based imaging agents are discussed. Lastly, the future directions of antibody-based imaging agents are discussed, emphasizing the potential applications for personalized medicine. PMID- 26620585 TI - Replication of a chronic hepatitis B virus genotype F1b construct. AB - Genotype F is one of the less-studied genotypes of human hepatitis B virus, although it is widely distributed in regions of Central and South American. Our previous studies have shown that HBV genotype F is prevalent in Chile, and phylogenetic analysis of its full-length sequence amplified from the sera of chronically infected patients identified it as HBV subgenotype F1b. We have previously reported the full-length sequence of a HBV molecular clone obtained from a patient chronically infected with genotype F1b. In this report, we established a system to study HBV replication based on hepatoma cell lines transfected with full-length monomers of the HBV genome. Culture supernatants were analyzed after transfection and found to contain both HBsAg and HBeAg viral antigens. Consistently, fractionated cell extracts revealed the presence of viral replication, with both cytoplasmic and nuclear DNA intermediates. Analysis of HBV transfected cells by indirect immunofluorescence or immunoelectron microscopy revealed the expression of viral antigens and cytoplasmic viral particles, respectively. To test the functionality of the ongoing viral replication further at the level of chromatinized cccDNA, transfected cells were treated with a histone deacetylase inhibitor, and this resulted in increased viral replication. This correlated with changes posttranslational modifications of histones at viral promoters. Thus, the development of this viral replication system for HBV genotype F will facilitate studies on the regulation of viral replication and the identification of new antiviral drugs. PMID- 26620587 TI - Suppression of lytic replication of Kaposi's sarcoma-associated herpesvirus by autophagy during initial infection in NIH 3T3 fibroblasts. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of the angioproliferative neoplasm Kaposi's sarcoma (KS). We first confirmed the susceptibility of NIH 3T3 fibroblasts to KSHV by infecting them with BCP-1 derived KSHV. Lytic replication of KSHV was confirmed by PCR amplification of viral DNA isolated from culture supernatants of KSHV-infected cells. The template from KSHV-infected NIH 3T3 cells resulted in an intense viral DNA PCR product. A time course experiment revealed the disappearance of KSHV-specific DNA in culture supernatant of NIH 3T3 cells during a period between 48 h and 72 h postinfection. Furthermore, 3 days postinfection, infected NIH 3T3 cells showed no evidence of latent or lytic transcripts, including LANA, vFLIP, vCyclin, and vIL-6. These results imply that KSHV infection in NIH 3T3 cells is unstable and is rapidly lost on subsequent culturing. Additionally, we detected an enhancement of autophagy early in infection with KSHV. More interestingly, inhibition of autophagy by Beclin 1 siRNA or 3-methyladenine significantly increased the amount of KSHV-specific DNA in the culture supernatant of NIH 3T3 cells when compared to the group treated with KSHV infection alone, implying that autophagy prevents lytic replication of KSHV. Taken together, our data suggest that autophagy could be one of the cellular mechanisms utilized by host cells to promote viral clearance. PMID- 26620586 TI - Complete genome sequence of a Chinese isolate of pepper vein yellows virus and evolutionary analysis based on the CP, MP and RdRp coding regions. AB - The genome sequence of pepper vein yellows virus (PeVYV) (PeVYV-HN, accession number KP326573), isolated from pepper plants (Capsicum annuum L.) grown at the Hunan Vegetables Institute (Changsha, Hunan, China), was determined by deep sequencing of small RNAs. The PeVYV-HN genome consists of 6244 nucleotides, contains six open reading frames (ORFs), and is similar to that of an isolate (AB594828) from Japan. Its genomic organization is similar to that of members of the genus Polerovirus. Sequence analysis revealed that PeVYV-HN shared 92% sequence identity with the Japanese PeVYV genome at both the nucleotide and amino acid levels. Evolutionary analysis based on the coat protein (CP), movement protein (MP), and RNA-dependent RNA polymerase (RdRP) showed that PeVYV could be divided into two major lineages corresponding to their geographical origins. The Asian isolates have a higher population expansion frequency than the African isolates. Negative selection and genetic drift (founder effect) were found to be the potential drivers of the molecular evolution of PeVYV. Moreover, recombination was not the distinct cause of PeVYV evolution. This is the first report of a complete genomic sequence of PeVYV in China. PMID- 26620588 TI - Health-related quality of life in Iranian women with polycystic ovary syndrome: a qualitative study. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with a range of challenging symptoms which impact patient's lives. Iranian women with PCOS are likely to face a number of unique difficulties given particular societal and cultural norms for women. Understanding health-related quality of life (HRQoL) from a patients'perspective is critical to developing the appropriate support interventions. The present study aimed to generate an in-depthunderstanding of HRQoL Iranian women with PCOS. METHODS: Twenty Iranian women were interviewed and data was subjected to thematic analysis. RESULTS: Women reported substantial effects of PCOS on their quality of life, Themes generated from the data related to sexual - physical problems (An unsexualised self: loss, change and pain; and Being pained and painful); exposure and nvasion: the rejecting and invading social world (Concealing and Avoiding and Public property: public scrutiny), diminished self and diminished life (Infertile as inferior and Exhausted mind andbody) respectively. CONCLUSION: PCOS is a physical - sexual, psychological and social syndrome; therefore, it is necessary to taking a more holistic approach to patient care beyond treating physical symptoms. PMID- 26620590 TI - How much is too much . . . And in what setting? PMID- 26620589 TI - Monoclonal antibodies: the new magic bullets for allergy: IUPHAR Review 17. AB - Allergic diseases and conditions are widespread and their incidence is on the increase. They are characterized by the activation of mast cells resident in tissues and the consequent infiltration and stimulation of several inflammatory cells, predominantly eosinophils. Cell-cell cross-talk and the release of mediators are responsible for the symptoms and for the modulation of the response. The gold standard of therapeutic intervention is still glucocorticosteroids, although they are not effective in all patients and may cause numerous side effects. Symptomatic medications are also widespread. As research has led to deeper insights into the mechanisms governing the diseases, new avenues have been opened resulting in recent years in the development of monoclonal antibodies (mAbs) such as anti-IgE mAbs (omalizumab) and others still undergoing clinical trials aimed to specifically target molecules involved in the migration and stimulation of inflammatory cells. In this review, we summarize new developments in the field of anti-allergic mAbs with special emphasis on the treatment of asthma, particularly severe forms of this condition, and atopic dermatitis, which are two unmet clinical needs. PMID- 26620591 TI - Genome-wide association study in Spanish identifies ADAM metallopeptidase with thrombospondin type 1 motif, 9 (ADAMTS9), as a novel asthma susceptibility gene. PMID- 26620592 TI - Reply. PMID- 26620593 TI - How well can body size represent effects of the environment on demographic rates? Disentangling correlated explanatory variables. AB - Demographic rates are shaped by the interaction of past and current environments that individuals in a population experience. Past environments shape individual states via selection and plasticity, and fitness-related traits (e.g. individual size) are commonly used in demographic analyses to represent the effect of past environments on demographic rates. We quantified how well the size of individuals captures the effects of a population's past and current environments on demographic rates in a well-studied experimental system of soil mites. We decomposed these interrelated sources of variation with a novel method of multiple regression that is useful for understanding nonlinear relationships between responses and multicollinear explanatory variables. We graphically present the results using area-proportional Venn diagrams. Our novel method was developed by combining existing methods and expanding upon them. We showed that the strength of size as a proxy for the past environment varied widely among vital rates. For instance, in this organism with an income breeding life history, the environment had more effect on reproduction than individual size, but with substantial overlap indicating that size encompassed some of the effects of the past environment on fecundity. This demonstrates that the strength of size as a proxy for the past environment can vary widely among life-history processes within a species, and this variation should be taken into consideration in trait based demographic or individual-based approaches that focus on phenotypic traits as state variables. Furthermore, the strength of a proxy will depend on what state variable(s) and what demographic rate is being examined; that is, different measures of body size (e.g. length, volume, mass, fat stores) will be better or worse proxies for various life-history processes. PMID- 26620594 TI - Delivery of miR-34a by chitosan/PLGA nanoplexes for the anticancer treatment of multiple myeloma. AB - The encapsulation of miR-34a into chitosan/PLGA nanoparticles in order to obtain nanoplexes useful for the modulation of the biopharmaceutical features of the active compound was studied. The nanoplexes were obtained through nanoprecipitation and were characterized by a mean diameter of ~160 nm, a good size distribution and a positive surface charge. The structure of the nanoparticles allowed a high level of entrapment efficiency of the miR-34a and provided protection of the genetic material from the effects of RNase. A high degree of transfection efficiency of the nanoplexes and a significant in vitro antitumor effect against multiple myeloma cells was demonstrated. The therapeutic properties of the nanoplexes were evaluated in vivo against human multiple myeloma xenografts in NOD-SCID mice. The systemic injection of miR-34a mimic loaded nanoparticles significantly inhibited tumor growth and translated into improved survival of the laboratory mice. RT-PCR analysis carried out on retrieved tumors demonstrated the presence of a high concentration of miR-34a mimics. The integrity of the nanoplexes remained intact and no organ toxicity was observed in treated animals. PMID- 26620595 TI - Simulated moving bed chromatography for the separation of ethyl esters of eicosapentaenoic acid and docosahexaenoic acid under nonlinear conditions. AB - In this study, ethyl esters of eicosapentaenoic acid and docosahexaenoic acid were separated with simulated moving bed (SMB) chromatography, where the stationary phase was C18 silica gel with particle size of 10MUm packed in eight columns, and the mobile phase was pure methanol. The Henry constants, transport parameters and total porosity were measured from pulse response chromatographic experiments using a single column. The Henry constants were obtained from the first moment analysis. The transport parameters including axial dispersion coefficients and effective mass transfer coefficients were obtained from the second moment analysis. Nonlinear adsorption equilibrium isotherms for the pure components and their mixture were determined from adsorption-desorption method. The Langmuir model was used to fit the experimental data, and the corresponding parameters were further used to predict the competitive adsorption equilibria of the mixture. The validity of mathematical model parameters was checked by a frontal chromatography experiment. The simulated results of the SMB process using these parameters agreed well with the experimental results. At the feed concentration of 100g/L, the SMB separation was able to produce both solutes with relative purity above 99%, productivity of 13.11g/L adsorbent/h, and solvent consumption of 0.46L/g. PMID- 26620596 TI - Application of ultra-high performance supercritical fluid chromatography for the determination of carotenoids in dietary supplements. AB - A quick and simple ultra-high performance supercritical fluid chromatography photodiode array detector method was developed and validated for the simultaneous determination of 9 carotenoids in dietary supplements. The influences of stationary phase, co-solvent, pressure, temperature and flow rate on the separation of carotenoids were evaluated. The separation of the carotenoids was carried out using an Acquity UPC(2) HSS C18 SB column (150mm*3.0mm, 1.8MUm) by gradient elution with carbon dioxide and a 1:2 (v:v) methanol/ethanol mixture. The column temperature was set to 35 degrees C and the backpressure was 15.2MPa. Under these conditions, 9 carotenoids and the internal standard, beta-apo-8' carotenal, were successfully separated within 10min. The correlation coefficients (R(2)) of the calibration curves were all above 0.997, the limits of detection for the 9 carotenoids were in the range of 0.33-1.08MUg/mL, and the limits of quantification were in the range of 1.09-3.58MUg/mL. The mean recoveries were from 93.4% to 109.5% at different spiking levels, and the relative standard deviations were between 0.8% and 6.0%. This method was successfully applied to the determination of 9 carotenoids in commercial dietary supplements. PMID- 26620597 TI - Optimization of reversed-phase chromatography methods for peptide analytics. AB - The analytical description and quantification of peptide solutions is an essential part in the quality control of peptide production processes and in peptide mapping techniques. Traditionally, an important tool is analytical reversed phase liquid chromatography. In this work, we develop a model-based tool to find optimal analytical conditions in a clear, efficient and robust manner. The model, based on the Van't Hoff equation, the linear solvent strength correlation, and an analytical solution of the mass balance on a chromatographic column describing peptide retention in gradient conditions is used to optimize the analytical scale separation between components in a peptide mixture. The proposed tool is then applied in the design of analytical reversed phase liquid chromatography methods of five different peptide mixtures. PMID- 26620598 TI - Office spirometry correlates with laboratory spirometry in patients with symptomatic asthma and COPD. AB - OBJECTIVES: Spirometry remains underutilized in the evaluation of obstructive lung disease. While office spirometry (OS) has been compared to formal laboratory based spirometry (LS) in healthy subjects, the correlation has never been formally assessed in patients with symptomatic obstructive lung disease. The aim of this study was to investigate the correlation in this population. METHODS: We used a retrospective study design to analyze spirometry data from patients that underwent both OS and LS. Two flow sensing office (portable) spirometers were used and compared with laboratory-based (body plethymosgraph) spirometer. Accuracy and reliability were assessed using Bland Altman analysis. RESULTS: Among 185 patients with symptomatic obstructive lung disease, 129 had undergone both OS and LS. Of these, 107 patients had both tests performed less than 90 days apart and were included in final analyses. Mean age was 54 years with mean FEV1 of 1.97 L (65% predicted). Ninety-two patients had airflow obstruction, as determined by a FEV1/FVC ratio of <70%. We found significant correlation in the values between OS and LS for both FEV1 and FVC (r = 0.937 and 0.90, respectively, P < 0.001). Eighty-seven percent of patients had a concordant spirometry in terms of airflow obstruction. Correlation was independent of the office spirometer (and hence the Flow-sensing mechanism) used. CONCLUSIONS: In patients with known asthma and chronic obstructive pulmonary disease (COPD), OS is accurate and reliable when compared to formal laboratory-based spirometry. Routine use of OS should be encouraged to improve spirometry utilization and healthcare outcomes in patients with Asthma and COPD. PMID- 26620599 TI - Cooperative dimerization of a stably folded protein directed by a flexible RNA in the assembly of the HIV Rev dimer-RRE stem II complex. AB - The binding of the HIV-1 Rev protein as an oligomer to a viral RNA element, the Rev-response element (RRE), mediates nuclear export of genomic RNA. Assembly of the Rev-RRE ribonucleoprotein (RNP) complex is nucleated by the binding of the first Rev molecule to stem IIB of the RRE. This is followed by stepwise addition of a total of ~six Rev molecules along the RRE through a combination of RNA protein and protein-protein interactions. RRE stem II, which forms a three-way junction consisting of stems IIA, IIB and IIC, has been shown to bind to two Rev molecules in a cooperative manner, with the second Rev molecule binding to the junction region of stem II. The results of base substitutions at the stem II junction, and characterization of stem II junction variants selected from a randomized library showed that an "open" flexible structure is preferred for binding of the second Rev molecule, and that binding of the second Rev molecule to the junction region is not sequence-specific. Alanine substitutions of a number of Rev amino acid residues implicated to be important for Rev folding in previous structural studies were found to result in a dramatic decrease in the binding of the second Rev molecule. These results support the model that proper folding of Rev is critical in ensuring that the flexible RRE is able to correctly position Rev molecules for specific RNP assembly, and suggests that targeting Rev folding may be effective in the inhibition of Rev function. PMID- 26620601 TI - [The importance of structured care in the infected patient in Emergency Department]. PMID- 26620600 TI - [Spontaneous bacterial peritonitis due to Sphingomonas paucimobilis in a cirrhotic patient]. PMID- 26620602 TI - [Recurrent disease due to ribotype 027 Clostridium difficile]. PMID- 26620603 TI - [Diagnostic value of procalcitonin and renal failure]. PMID- 26620604 TI - [Assessment of 2 automated microdilution techniques compared to an agar dilution method in determining sensitivity to fosfomycin in strains of carbapenem resistant Pseudomonas aeruginosa]. AB - Carbapenems-resistance in Pseudomonas aeruginosa isolates has been widely reported. Fosfomycin has been shown to act synergistically with other antimicrobials. The agar dilution method was approved for susceptibility testing for fosfomycin and Pseudomonas aeruginosa. However, broth microdilution methods are the basis of systems currently used in clinical microbiology laboratories. The results of this study indicate that these methods are acceptable as susceptibility testing methods for fosfomycin against these organisms. PMID- 26620606 TI - Ophthalmomyiasis and nasal myiasis by Oestrus ovis in a patient from the Canary Islands with uncommon epidemiological characteristics. PMID- 26620605 TI - Analytical performance of the AlereTM i Influenza A&B assay for the rapid detection of influenza viruses. AB - The analytical performance of the new AlereTM i Influenza A&B kit (AL-Flu) assay, based on isothermal nucleic acids amplification, was evaluated and compared with an antigen detection method, SD Bioline Influenza Virus Antigen Test (SDB), and an automated real-time RT-PCR, SimplexaTM Flu A/B & VRS Direct assay (SPX), for detection of influenza viruses. An "in-house" RT-PCR was used as the reference method. Sensitivity of AL-Flu, SDB, and SPX was 71.7%, 34.8%, and 100%, respectively. Specificity was 100% for all techniques. The turnaround time was 13min for AL-Flu, 15min for SDB, and 75min for SPX. The AlereTM i Influenza A&B assay is an optimal point-of-care assay for influenza diagnosis in clinical emergency settings, and is more sensitive and specific than antigen detection methods. PMID- 26620607 TI - Laser treatment for female facial hirsutism: are quality-of-life benefits sustainable? AB - BACKGROUND: Facial hirsutism in women impairs quality of life (QoL). Laser hair removal (LHR) has been shown to confer significant improvements in QoL for up to 6 months after treatment, but the longer-term benefits have not been investigated. AIM: To assess the sustainability of LHR benefits to the QoL of hirsute women up to 30 months after treatment. METHODS: Hirsute women about to undergo National Health Service (NHS)-funded LHR in 2010-2012 (n = 142) completed proforma questionnaires quantifying the burden of hirsutism on their QoL. These included: the Dermatology Life Quality Index (DLQI) (assessing functional impact on QoL), the number of days spent removing hair per week and a 10-point scale assessing how much their condition bothered them (emotional burden on QoL). Postal questionnaires recorded QoL changes up to 30 months after LHR. Improvements in QoL scores for each woman were compared. Responses were then grouped into periods of 0-6, 6-12 and 12-30 months post-treatment, and the magnitude of change between these time groups was compared for each QoL measure. RESULTS: In total, 63 women responded to the post-LHR questionnaire. QoL was severely affected, but improved with LHR. The number of days spent removing hair reverted to baseline at 12-30 months post-LHR, and a significant decline was seen in the magnitude of improvement in emotional burden on QoL over time (P = 0.04). However, no significant difference existed between improvements in DLQI scores (P = 0.12). CONCLUSION: LHR supplies some functional QoL benefits up to 30 months post-treatment. Emotional benefits are less sustainable. Further LHR treatment is required to maintain QoL benefits. PMID- 26620608 TI - An update on the diagnosis and management of ejaculatory duct obstruction. AB - Ejaculatory duct obstruction (EDO) remains a rare but surgically correctable cause of male sexual dysfunction and male infertility due to obstructive azoospermia, diagnosed in up to 5% of infertile men. EDO should, therefore, be considered within the list of differential diagnoses for men undergoing infertility investigations, with work up including clinical examination, transurethral ultrasonography, semen analysis, chromotubation, seminal vesiculography and seminal vesicle aspiration. Obstruction can be limited to the distal ends of the ducts or it can extend proximally to include the terminal portions of the vasa deferentia, with the site and length of the obstruction having implications for surgical intervention. Early endoscopic treatment can reverse symptoms and prevent the progression of partial obstruction to bilateral, complete obstruction, and transurethral resection of the ejaculatory duct remains the main treatment option for EDO. Alternative treatment options include endoscopic laser-assisted resection of the ducts, antegrade seminal-vesicle lavage to relieve EDO secondary to inspissated material or calculi, or dilatation of the ejaculatory ducts using 9F seminal vesicoscopy or balloon. PMID- 26620611 TI - Prostate cancer: PD-L1 expression is common and indicates poor prognosis. PMID- 26620610 TI - Neural control of micturition in humans: a working model. AB - Results from functional brain scanning have shown that neural control of the bladder involves many different regions. Yet, many aspects of this complex system can be simplified to a working model in which a few forebrain circuits, acting mainly on the midbrain periaqueductal grey (PAG), advance or delay the triggering of the voiding reflex and generate bladder sensations according to the volume of urine in the bladder, the safety of voiding and the emotional and social propriety of doing so. Understanding these circuits seems to offer a route to treatment of conditions, such as urgency incontinence or overactive bladder, in patients without overt neurological disease. Two of these circuits include, respectively, the medial prefrontal cortex and the parahippocampal complex, as well as the PAG. These circuits belong to a well-known network that is active at rest and deactivated when attention is required. Another circuit, comprising the insula and the midcingulate or dorsal anterior cingulate cortex, is activated by bladder filling and belongs to a salience network that generates sensations such as the desire to void. Behavioural treatments of urgency incontinence lead to changes in brain function that support the working model and suggest the mechanism of this type of treatment. PMID- 26620609 TI - A practical overview of considerations for penile prosthesis placement. AB - Penile prostheses have remained the gold-standard therapy for medically refractory erectile dysfunction (ED) since their popularization. Advances in device design and surgical techniques have yielded improved rates of infection, satisfaction, and mechanical survival of devices. Operative techniques in penile prosthesis surgery include the use of adjunctive procedures (such as ventral phalloplasty and release of the suspensory ligament), management of penile fibrosis, and manoeuvres to correct Peyronie's-disease-related curvature. Complications include urethral and corporal perforation, crossover, infection, impending erosion, and/or supersonic transporter deformity. Long-term data regarding mechanical, overall, and infection-free survival demonstrate excellent results, and, given the consistently high satisfaction rates and limited alternatives for medically refractory ED, penile prostheses are likely to remain a relevant and important treatment strategy for the foreseeable future. PMID- 26620612 TI - Infection in 2015: HIV protection with PrEP - implications for controlling other STIs. AB - HIV and bacterial sexually transmitted infection incidence remains persistently high for men who have sex with men. Results of new studies show that clinicians might be able to address this challenge by providing oral HIV pre-exposure prophylaxis and by intensifying efforts to diagnose and treat other sexually transmitted infections. PMID- 26620613 TI - Basic research: Just keep swimming - sperm exhibit a 2D slither motion. PMID- 26620615 TI - Infection: The path of least resistance. PMID- 26620616 TI - Religion politics and ethics: Moral and ethical dilemmas facing faith-based organizations and Africa in the 21(st) century-implications for Nigeria in a season of anomie. PMID- 26620617 TI - Ethics of palliative care in late-stage cancer management and end-of-life issues in a depressed economy. AB - The Hippocratic Oath has often been referred to as the ethical foundation of medical practice with the key restriction "cause no harm" which is also the principle of benevolence in bioethics. In medical profession, the Oath still exemplifies the key virtues of a doctor in its emphasis on the obligations toward the well-being of the individual patient. In management of end-stage cancer in a depressed economy such as Nigeria, we frequently encounter a wide range of ethical issues that arise in the provision of palliative care mostly due to the prevailing economic situation and cultural setting. Since most of these patients came from a lower economic class of the society, with little or no formal education and lived at a subsistence level, they often find it difficult to provide the medications needed. In a poor setting where health inequity is rife, and ignorance and poverty are commonplace, a good understanding of medical ethics with a good model of health care system will contribute to the health professional's decision-making that will be in the best interest of the patients. Physicians must protect the lives of their patients and should never hasten their death. In end-stage cancer management, we have to relieve suffering and pains, promote palliative care, and give psychological support but never abandoning the patient or initiate terminating their life. This presentation is a clinical analysis of the ethical issues regarding the management of end-stage cancer patients in a poor economy with a critical overview of end-of-life issues in African perspective. PMID- 26620614 TI - Kisspeptin signalling in the physiology and pathophysiology of the urogenital system. AB - Kisspeptin is a peptide hormone, which signals via the G-protein-coupled kisspeptin receptor (KISS1R). Kisspeptin-KISS1R signalling has been implicated in various physiological and pathophysiological processes in the urogenital system, including critical roles in ovarian function as a key player in the regulation of oocyte development. Kisspeptin also has roles in several different functions of the male reproductive tract, such as spermatogenesis and sperm capacitation, and is also thought to be involved in kidney physiology - studies in preclinical animal models have reported that expression of kisspeptin and/or KISS1R is altered in chronically impaired kidneys. The wider importance of kisspeptin action in the urogenital tract has been highlighted by the finding that it suppresses metastasis of urogenital carcinomas; besides the possible therapeutic potential of this finding, tissue and tumour-stage-specific alterations in kisspeptin and KISS1/KISS1R expression could potentially be used as biomarkers for the diagnosis and prognosis of urogenital carcinomas. PMID- 26620618 TI - Medical incidents in developing countries: A few case studies from Nigeria. AB - The moral worth of a clinician's, action in patients' management depends exclusively on the moral acceptability of the rule of obligation to duty on which the clinician acts. Since every rational being thinks of him or herself as an end, all people must act in such a way that they treat humanity, whether in their own person or in the person of another, always as an end and never simply as a means. A duty of care is, therefore, paramount in the relationship between clinician and patient. While litigation in healthcare system is rapidly increasing globally, which affords individual explanation and compensation for perceived wrong diagnosis and treatment; it is still rudimentary in Nigeria. This default position has made most health care providers indifferent in the presence of gross clinical negligence and medical errors. Though most Nigerians may be aware of their rights to institute legal action in situations such as, negligence with serious harm or death, but, the socioeconomic factors, cultural, and religious notions among other reasons within the society often makes litigation impossible for an individual. Attributing every medical adverse event in the course of treatment as "God's Will" and the saying "It's God's Time" for every death among most African people has also become a great impediment to curbing clinical negligence in our environment. This paper presents a few case studies from author's experience and complaints from patients during clinical practice. PMID- 26620619 TI - Challenges in regulation of biomedical research: The case of Kenya. AB - Unregulated biomedical research has previously caused untold suffering to humankind. History is full of examples of abuse of animal and human subjects for research. Several codes and instruments have been formulated to regulate biomedical research. In Kenya, the Science, Technology and Innovation Act, 2014, together with the Constitution of Kenya, 2010, provide a fairly robust legal framework. Possible challenges include capacity building, overlap of functions of institutions, monitoring and evaluation, scientific/technological advances, intellectual property rights, funding for research, and dispute resolution. It is hoped that the new legislation will adequately address these challenges. PMID- 26620620 TI - Ethical and legal dilemmas around termination of pregnancy for severe fetal anomalies: A review of two African neonates presenting with ventriculomegaly and holoprosencephaly. AB - Termination of pregnancy (TOP) or feticide for severe fetal anomalies is ethically and morally challenging and maybe considered illegal in countries with restrictive abortion laws. While diagnostic modalities such as fetal ultrasound, magnetic resonance imaging, and genetic screening have improved prenatal diagnosis, these technologies remain scarce in many African countries making diagnosis and counseling regarding TOP difficult. Ethical dilemmas such as women's autonomy rights may conflict with fetus' right to personhood, and doctor's moral obligations to society. In liberal jurisdictions, previable fetuses may not have legal rights of personhood; therefore, appropriate action would be to respect pregnant women's decisions regarding TOP. However, in countries with restrictive abortion laws the fetus maybe imbued with the right of personhood at conception, making TOP illegal and exposing doctors and patients to potential criminal prosecution. Birth of a severely disabled baby with independent legal rights creates further conflicts between parents and clinicians complicating healthcare decision-making. Irrespective of the maternal decision to accept or refuse TOP, the psychological and emotional impact of an impaired fetus or neonate, often lead to moral distress and posttraumatic stress reactions in parents. Doctors have legal and ethical obligations to provide an accurate antenatal diagnosis with full disclosure to enable informed decision making. Failure to provide timely or accurate diagnosis may lead to allegations of negligence with potential liability for "wrongful birth" or "wrongful life" following birth of severely disabled babies. Mismanagement of such cases also causes misuse of scarce healthcare resources in resource-poor countries. This paper describes ethical challenges in clinical management of two neonates born following declined and failed feticide for severe central nervous system anomalies with a critical appraisal of the relevant literature. PMID- 26620621 TI - Ethics of physiotherapy practice in terminally ill patients in a developing country, Nigeria. AB - Physiotherapy has been widely defined as a healthcare profession that assesses, diagnoses, treats, and works to prevent disease and disability through physical means. The World Confederation for Physical Therapy describes physiotherapy as providing services to people and populations to develop, maintain, and restore maximum movement and functional ability throughout the lifespan. Physiotherapists working with terminally ill patients face a myriad of ethical issues which have not been substantially discussed in bioethics especially in the African perspective. In the face of resource limitation in developing countries, physiotherapy seems to be a cost-effective means of alleviating pain and distressing symptoms at the end-of-life, ensuring a more dignified passage from life to death, yet referrals to physiotherapy are not timely. Following extensive literature search using appropriate keywords, six core ethical themes related to physiotherapy in terminally ill patients were identified and using the four principles of bioethics (patient's autonomy, beneficence, nonmaleficence, and justice), an ethical analysis of these themes was done to highlight the ethical challenges of physiotherapists working in a typical African setting such as Nigeria. PMID- 26620622 TI - "Because I want to be informed, to be part of the decision-making": Patients' insights on informed consent practices by healthcare professionals in South Africa. AB - BACKGROUND: Informed consent (IC) is a legally enforceable right in South Africa based on constitutionally protected rights to bodily integrity and well-being. In terms of the law, patients cannot be involved in medical treatment or research without IC. Healthcare providers must inform patients about diagnosis, risks, benefits, treatment options, and right of refusal in a language patients understand based their literacy level. This study reports an empirical study on patients' perceptions of IC as practiced by doctors and nurses in South Africa. MATERIALS AND METHODS: A cross-sectional study, using a bilingual semi-structured questionnaire was conducted among patients attending randomly selected public hospitals in eThekwini Metropolitan Municipality (Durban), KwaZulu-Natal province. Competent patients or legal surrogates were eligible for inclusion. IC was obtained from all participants. RESULTS: Four hundred and four participants completed questionnaires of which 68% were female. The median age of participants was 35 years (range 11-91 years). Most respondents spoke IsiZulu (55%), were single (56%), unemployed (66%), and with secondary school education (69%). Patients were generally informed about the diagnosis (81%), risks (57%), and benefits of treatment (61%). Few were informed about treatment options (41%), recommended treatment (28%), and right of refusal (25%). IC was obtained verbally in 73% of cases. Patients favored disclosure of all material risks (78%) and few consulted surrogates before decision-making (76%). There was an association between participant's age and knowledge of the age of consent (P = 0.005). Most patients were satisfied with information disclosed (91%) and did not feel coerced. Some were afraid to ask questions for fear of losing free treatment (8%). CONCLUSION: This study reveals that South African patients are aware of the right to IC, but many were vulnerable due to indigence. Barriers to IC include poverty, language, and low educational level. South African patients prefer disclosure of all material risks, better communication skills by healthcare workers, and a shift toward informed or shared healthcare decision-making. PMID- 26620623 TI - Ethical issues in newer assisted reproductive technologies: A view from Nigeria. AB - BACKGROUND: Infertility is a prevalent condition in many developing countries with significant physical and psychosocial implications. The aim of this study is to discuss briefly the ethics of newer assisted reproductive technology (ART) with special emphasis on the peculiarities in Nigeria. METHODS: MEDLINE and Google Scholar were searched for English-language articles from January 1990 to July 2014 using the search terms "ethics of ART AND Nigeria," "ethical issues in in vitro fertilization AND Nigeria." Using the above search phrases, a total of 43 articles were retrieved out of which only 5 dealt specifically with the subject matter. RESULTS: The core ethical issues found in the reviewed literature are listed in [Table 1]. Inequitable access to ART due to its high cost, lack of regulatory body, safety of the procedure, and fate of the embryos were the main themes identified from the papers. Surrogacy, sex selection, and gamete donation were additional relevant ethical issues. CONCLUSION: There is an urgent need for stakeholders in developing countries to formulate cultural and context-specific guidelines to help address some of these ethical dilemmas. PMID- 26620624 TI - Impact of a short biostatistics course on knowledge and performance of postgraduate scholars: Implications for training of African doctors and biomedical researchers. AB - BACKGROUND AND OBJECTIVES: This study was designed to evaluate the impact of a short biostatistics course on knowledge and performance of statistical analysis by biomedical researchers in Africa. It is recognized that knowledge of biostatistics is essential for understanding and interpretation of modern scientific literature and active participation in the global research enterprise. Unfortunately, it has been observed that basic education of African scholars may be deficient in applied mathematics including biostatistics. MATERIALS AND METHODS: Forty university affiliated biomedical researchers from South Africa volunteered for a 4-day short-course where participants were exposed to lectures on descriptive and inferential biostatistics and practical training on using a statistical software package for data analysis. A quantitative questionnaire was used to evaluate participants' statistical knowledge and performance pre- and post-course. Changes in knowledge and performance were measured using objective and subjective criteria. Data from completed questionnaires were captured and analyzed using Statistical Package for Social Sciences. Participants' pre- and post-course data were compared using nonparametric Wilcoxon signed ranks tests for nonnormally distributed variables. A P < 0.05 was considered statistically significant. RESULTS: Baseline testing of statistical knowledge showed a median score of 0, with 75th percentile at 28.6%, and a maximum score of 71.4%. Postcourse evaluation revealed improvement in participants' core knowledge with the median score increasing to 28.5%; and the 75th percentile score to 85.7%; signifying improved understanding of statistical concepts and ability to carry out data analyses. CONCLUSIONS: This study just showed poor baseline knowledge of biostatistics among postgraduate scholars and health science researchers in this cohort and highlights the potential benefits of short-courses in biostatistics to improve the knowledge and skills of biomedical researchers and scholars in Africa. PMID- 26620625 TI - A pilot study of women's experiences after being offered late termination of pregnancy for severe fetal anomaly. AB - OBJECTIVE: We investigated the attitudes and experiences of women pregnant with an anomalous fetus after being offered late termination of pregnancy (LTOP) before and after delivery or TOP. METHODS: This was a pre- and post-intervention structured interview questionnaire-based study. Pregnant women with severe fetal abnormalities (lethal and nonlethal) diagnosed after 24 weeks gestation were recruited. All were managed according to standard protocol. Interviews were conducted by the researcher over a 3 months period (August-October 2010). Experiences, demographic profile, and sociocultural characteristics were compared between the groups that accepted and declined LTOP. RESULTS: Fifteen pregnant women with severe fetal anomalies were enrolled. Around 5 (33.3%) requested termination, and 10 (66.6%) continued the pregnancy. Those who continued their pregnancies were significantly younger (mean age 25 years, range 20-32 years) than those who requested termination (mean age 31 years, range 22-35 years) (P < 0.05). Mean parity was one (range 0-3) in the patients who continued the pregnancy, and 2 (1-3) in those who terminated it. Partners and immediate family members influenced decision making. All women reported a positive experience of the treatment protocol. CONCLUSION: The decision to continue or terminate a pregnancy for severe fetal abnormalities diagnosed after viability is complex and variable. Younger primigravidas were more likely to continue with the pregnancy in the hope that the baby would be born normal. Good support from partners and family, after delivery, was associated with less regret about the decision that had been made. PMID- 26620626 TI - A legal "right" to mental health care? Impediments to a global vision of mental health care access. AB - Mental health law across many jurisdictions provides a legal framework for the compulsory detention and, where appropriate, treatment in hospital of people with mental health problems. Latent within many of these "systems" of mental health provision is the concern that the quality of care people receive does not always meet legal and ethical norms. For many, there remains the very serious recognition that access to mental health care in its entirety remains elusive. International human rights discourse has influenced the shaping of modern mental health laws in many developed countries. In 2008, the Convention on the Rights of Persons with Disabilities (CRPD) entered into force. For many countries, such as South Africa, the CRPD provides a human rights instrument with the scope to establish a worldwide means of bolstering human rights. This paper examines both the UK and the broader African position with regard to the extent redress can be sought if and when an individual does not receive the care and treatment needed. Within this, consideration will be given to one of the paradoxes of mental health care which bedevil mental health systems: How do legal frameworks for detaining and treating people without their consent work when there is no corresponding enforceable right that appropriate treatment or suitable conditions of detention must be provided. The focus of this paper is the question of whether there is indeed a legal "right" to mental health care. PMID- 26620627 TI - Regional Arterial Infusion Chemotherapy improves the Pathological Response rate for advanced gastric cancer with Short-term Neoadjuvant Chemotherapy. AB - To identify clinicopathologic and treatment variables that could predict pathologic tumor response to short-term neoadjuvant chemotherapy (NAC) for patients with locally advanced gastric cancer. A retrospective analysis was conducted of 178 patients who underwent short-term NAC with EOX regimen followed by surgery from January 2008 to December 2010. Neoadjuvant treatment response was evaluated using tumor regression grade. Relationships between pathologic tumor response and clinicopathological factors were evaluated using logistic regression analysis. The benefits of regional arterial infusion chemotherapy were investigated separately. The postoperative pathological response rate was 46.1% (82/178) and 4 patients (2.2%) had complete pathological remission. Pathological response was significantly associated with tumor differentiation (P = 0.008), abnormal a-fetoprotein levels (P = 0.01) and administration approach to chemotherapy (intravenous versus regional arterial infusion chemotherapy) (P = 0.018). Most bone marrow toxicities, vomiting, nausea, alopecia, and fatigue were acceptable. Grade 3/4 toxicities were not commonly observed. The 3-year overall survival (OS) and recurrence free survival (RFS) were 67.0% and 53.0%, respectively. Regional arterial infusion NAC group had significantly better median RFS (48.0 versus 34.0 months) than the intravenous NAC group (P = 0.049). In conclusion, regional arterial infusion NAC can improve the pathological response rate of advanced gastric cancer treated with EOX regimen. PMID- 26620628 TI - Does prenatal restraint stress change the craniofacial growth pattern of rat offspring? AB - A major and frequently encountered condition underlying the long-term programming effects of the intrauterine environment is exposure to stress. Gestational stress is an environmental factor that induces physical and behavioral alterations in offspring. Seventy female virgin Wistar rats were mated with one male rat for a maximum of four times, after which 52 pregnant rats were divided into two groups. In the experimental group the rats were exposed to restraint stress during pregnancy, whereas the control group did not receive the stress protocol. One male litter was randomly chosen from the offspring of each rat with 8-13 pups. A total of 40 male rat offspring were available for analysis. Thirty-one linear and angular measurements were analyzed in both study groups to investigate whether prenatal restraint stress changes the craniofacial growth pattern of rat offspring. In the prenatally stressed group, anterior cranial base length and viscerocranium measures were significantly increased compared with the control group, whereas cranial width, mandibular dimensions, and posterior cranial height and length remained unchanged. Furthermore, the prenatally stressed group showed backward rotation of the midface and decreased flattening of the cranial vault. It was concluded that prenatal chronic stress can induce alterations in the craniofacial growth pattern by promoting endochondral growth in the cranial base and nasal septum. PMID- 26620629 TI - The niche in single-cell technologies. AB - The niche is the microenvironment in which each cell exists and is able to keep its own peculiar characteristics. The importance of the niche has been intensively studied especially in the context of stem cells, as it is responsible for both the maintenance of stemness and activation of differentiation. In the past few years, a variety of single-cell technologies have shed light on the extraordinary variability that characterizes different stem cell populations both in vitro and in vivo, but in most cases positional information is lost. Recent developments of new technologies aim to integrate both the transcriptomic profiling of cells and their spatial location. In this review I will discuss the state of the art of these technologies and the integration with others approaches that will be important in the study of stem cell populations. PMID- 26620631 TI - Self-organization of laterally asymmetrical movements as a consequence of space time optimization. AB - Laterally asymmetrical movements are ubiquitous among organisms. A bilaterally symmetrical organism cannot maneuver through a two- or three-dimensional space unless and until one side of its body leads, because the forces that cause the movements of the body are generated within the body. One question follows: are there any costs or benefits of laterally asymmetrical movements? We test whether directionally consistent laterally asymmetrical movements at different levels of organization of movements (at the individual, and not the population level) can work synergistically. We show-by means of a hypothetical system resembling a humanoid robot-that a laterally asymmetrical movement at a lower level of organization of movements can stimulate laterally asymmetrical movements that are directionally consistent at consecutive higher levels. We show-by comparing two hypothetical systems, incorporating laterally symmetrical and asymmetrical movements, respectively-that the asymmetrical system outperforms the symmetrical system by optimizing space and time and that this space-time advantage increases with the increasing complexity of the task. Together, these results suggest that laterally asymmetrical movements can self-organize as a consequence of space-time optimization. PMID- 26620630 TI - Single-cell technologies are revolutionizing the approach to rare cells. AB - In the last lustrum single-cell techniques such as single-cell quantitative PCR, RNA and DNA sequencing, and the state-of-the-art cytometry by time of flight (CyTOF) mass cytometer have allowed a detailed analysis of the sub-composition of different organs from the bone marrow hematopoietic compartment to the brain. These fine-grained analyses have highlighted the great heterogeneity within each cell compartment revealing previously unknown subpopulations of cells. In this review, we analyze how this fast technological evolution has improved our understanding of the biological processes with a particular focus on rare cells of the immune system. PMID- 26620632 TI - Cooperative nutrient accumulation sustains growth of mammalian cells. AB - The coordination of metabolic processes to allow increased nutrient uptake and utilization for macromolecular synthesis is central for cell growth. Although studies of bulk cell populations have revealed important metabolic and signaling requirements that impact cell growth on long time scales, whether the same regulation influences short-term cell growth remains an open question. Here we investigate cell growth by monitoring mass accumulation of mammalian cells while rapidly depleting particular nutrients. Within minutes following the depletion of glucose or glutamine, we observe a growth reduction that is larger than the mass accumulation rate of the nutrient. This indicates that if one particular nutrient is depleted, the cell rapidly adjusts the amount that other nutrients are accumulated, which is consistent with cooperative nutrient accumulation. Population measurements of nutrient sensing pathways involving mTOR, AKT, ERK, PKA, MST1, or AMPK, or pro-survival pathways involving autophagy suggest that they do not mediate this growth reduction. Furthermore, the protein synthesis rate does not change proportionally to the mass accumulation rate over these time scales, suggesting that intracellular metabolic pools buffer the growth response. Our findings demonstrate that cell growth can be regulated over much shorter time scales than previously appreciated. PMID- 26620633 TI - Immune imbalance of regulatory T/type 2 helper cells in the pathogenesis of allergic rhinitis in children. AB - OBJECTIVES: To determine the role of regulatory T/type 2 helper cell-mediated immune imbalance in the pathogenesis of allergic rhinitis and examine the association between clinical severity and regulatory T/type 2 helper cell mediated immune imbalance. METHODS: Levels of interleukins 4 and 5 and transforming growth factor beta1, and expression of FOXP3 and GATA3 (which are functionally related to regulatory T and type 2 helper cells, respectively), were evaluated in 46 allergic rhinitis patients and 42 healthy subjects. RESULTS: Compared to controls, allergic rhinitis patients showed significantly higher interleukin 4 and 5 levels, but lower transforming growth factor beta1 levels. Furthermore, FOXP3 messenger RNA expression was lower in allergic rhinitis patients, while GATA3 messenger RNA and protein expression was significantly higher. Regulatory T/type 2 helper cell ratio was inversely correlated with clinical symptom scores. CONCLUSION: Regulatory T/type 2 helper cell immune imbalance may contribute to allergic rhinitis development. These findings provide a new insight into disease pathogenesis and potential therapeutic approaches. PMID- 26620634 TI - Systolic aortic pressure-time area is a useful index describing arterial wave properties in rats with diabetes. AB - The accurate measurement of arterial wave properties in terms of arterial wave transit time (tauw) and wave reflection factor (Rf) requires simultaneous records of aortic pressure and flow signals. However, in clinical practice, it will be helpful to describe the pulsatile ventricular afterload using less-invasive parameters if possible. We investigated the possibility of systolic aortic pressure-time area (PTAs), calculated from the measured aortic pressure alone, acting as systolic workload imposed on the rat diabetic heart. Arterial wave reflections were derived using the impulse response function of the filtered aortic input impedance spectra. The cardiovascular condition in the rats with either type 1 or type 2 diabetes was characterized by (1) an elevation in PTAs; and (2) an increase in Rf and decrease in tauw. We found that an inverse linear correlation between PTAs and arterial tauw reached significance (tauw = 38.5462 - 0.0022 * PTAs; r = 0.7708, P < 0.0001). By contrast, as the PTAs increased, the reflection intensity increased: Rf = -0.5439 + 0.0002 * PTAs; r = 0.8701; P <0 .0001. All these findings suggested that as diabetes stiffened aortas, the augmented aortic PTAs might act as a useful index describing the diabetes-related deterioration in systolic ventricular workload. PMID- 26620637 TI - Use of adjuvants in the treatment of Acinetobacter baumannii. AB - The current antibiotic crisis to treat infections by Acinetobacter baumannii is linked with the increase of antimicrobial resistance and the lack of development of new antimicrobial drugs. For this reason, new alternatives for the treatment and control of infections by A. baumannii are necessary. Several studies have reported the effect of adjuvants to restore the efficacy of existing antimicrobial agents. Herein, we analyzed the main results on the development of adjuvant drugs, as monotherapy or in combination therapy with existing antimicrobial agents, which have shown promising results in vitro and in vivo. However, caution is needed and further extensive in vivo studies have to be performed to confirm the potential use of these adjuvants as true therapeutic alternatives. PMID- 26620639 TI - Rewarding Work, Priceless Collaborations, Much Gratitude. AB - In this editorial of his final issue as Editor-in-Chief, Dr Guy G. Simoneau shares his thoughts on how changes in the areas of physical therapy research design, professional collaboration, publishing and communication technology, and publication standards played out in the world of JOSPT and recognize the many people who supported and implemented the changes. PMID- 26620640 TI - JOSPT Experiences Tremendous Growth, Change in 14 Years With Editor-in-Chief Simoneau in Charge. AB - As Editor-in-Chief, Dr Guy G. Simoneau and his editorial board have taken JOSPT from an acceptable US-based journal to a highly influential worldwide force behind contemporary orthopaedic and sports physical therapy research and practice. Today, the bridge Dr Simoneau constructed spans the orthopaedic and sports physical therapy globe for the betterment of clinical practice and research. His work fully supports JOSPT's latest strategic plan to provide value added knowledge translation, develop a broader authorship and readership, increase global marketing of the JOSPT brand, and expand current relationships to new partners and stakeholders. The bridge places JOSPT on very firm footing, tying its rich history to the promise of an exciting and successful future. PMID- 26620641 TI - A Special Thanks to 2015 JOSPT Contributors. AB - Editor-in-Chief Dr Guy G. Simoneau recognizes the authors, associate editors, International Editorial Review Board members, and manuscript and musculoskeletal imaging reviewers who contributed to the various aspects of the Journal over the past 12 months. PMID- 26620638 TI - Branched-chain amino acid catabolism is a conserved regulator of physiological ageing. AB - Ageing has been defined as a global decline in physiological function depending on both environmental and genetic factors. Here we identify gene transcripts that are similarly regulated during physiological ageing in nematodes, zebrafish and mice. We observe the strongest extension of lifespan when impairing expression of the branched-chain amino acid transferase-1 (bcat-1) gene in C. elegans, which leads to excessive levels of branched-chain amino acids (BCAAs). We further show that BCAAs reduce a LET-363/mTOR-dependent neuro-endocrine signal, which we identify as DAF-7/TGFbeta, and that impacts lifespan depending on its related receptors, DAF-1 and DAF-4, as well as ultimately on DAF-16/FoxO and HSF-1 in a cell-non-autonomous manner. The transcription factor HLH-15 controls and epistatically synergizes with BCAT-1 to modulate physiological ageing. Lastly and consistent with previous findings in rodents, nutritional supplementation of BCAAs extends nematodal lifespan. Taken together, BCAAs act as periphery-derived metabokines that induce a central neuro-endocrine response, culminating in extended healthspan. PMID- 26620642 TI - Comminuted C2 Articular Pillar Fracture in a Patient With Multiple Sclerosis and Recurrent Falls. AB - The patient was a 60-year-old woman, with long-standing balance deficits due to multiple sclerosis, referred to physical therapy by her primary care physician secondary to increasing fall frequency. Following evaluation, the physical therapist escorted the patient to her primary care physician's office, where a computed tomography scan was immediately performed, revealing a comminuted C2 articular pillar fracture. PMID- 26620644 TI - Special Online Issue: Author Disclosure Summary. PMID- 26620645 TI - Prognostic Significance of Carcinoembryonic Antigen Staining in Cancer Tissues of Gastric Cancer Patients. AB - PURPOSE: The aim of this study was to assess the significance of the correlation among tissue carcinoembryonic antigen (CEA) expression with serum CEA (sCEA) levels and long-term survival to highlight the clinical prognostic significance of tissue CEA expression in gastric cancer patients. METHODS: Immunohistological method and radioimmunoassay were used to assess tissue and sCEA expression, respectively. Univariate and multivariate analyses were performed to determine correlations, and the Kaplan-Meier method was used to investigate the prognostic significance. RESULTS: Our results demonstrate that tissue CEA in gastric cancer is significantly correlated with preoperative sCEA levels (p = 0.031), depth of invasion (p = 0.001), lymph node metastasis (p < 0.001), distant metastasis (p = 0.001), and TNM staging (p < 0.001). The 5-year survival rates were 67.6, 53.9, and 40.1 % for negatively, moderately, and intensely positively stained tissues (p < 0.001), and 57.0 and 37.9 % for serum with normal and elevated CEA expression (p = 0.031). Multivariate analysis revealed that tissue CEA can be considered an independent prognostic factor. Further analysis illustrated that patients with negative expression in both tissue and serum had better prognosis compared with those positively expressing CEA in both tissue and serum and/or those positively expressing CEA in either tissue or serum (p < 0.001). Our results also demonstrated that patients with negative tissue CEA staining and elevated sCEA expression had a better 5-year survival. CONCLUSION: Tissue CEA expression in gastric cancer is directly correlated with sCEA levels and long term prognosis. Thus, tissue CEA expression can be considered as a useful biomarker to improve the interpretation of sCEA levels in predicting long-term survival. PMID- 26620646 TI - Is All Advanced Gastric Cancer Suitable for Laparoscopy-Assisted Gastrectomy With Extended Lymphadenectomy? A Case-Control Study Using a Propensity Score Method. AB - BACKGROUND: The oncologic outcomes of laparoscopy-assisted gastrectomy (LAG) for the treatment of patients with local advanced gastric cancer (AGC) have not been evaluated. This study aimed to validate the oncologic efficacy of LAG for AGC. METHODS: The data from 539 patients who underwent LAG and 539 patients treated with open gastrectomy (OG) were selected using the propensity score-matching method from a database prospectively constructed between 2005 and 2011. The therapeutic value of lymph node (LN) dissection and the long-term surgical outcomes of these matched groups were compared. RESULTS: The groups were well balanced after the propensity score matched. The LAG and OG groups did not differ significantly in terms of clinicopathologic characteristics. The number of dissected LNs at stations 11 and 12a were significantly higher in the LAG group. However, the therapeutic index at each LN station did not differ significantly between the two groups. Although the overall survival curve at each stage did not differ significantly (P > 0.05), the survival rate increased overall for patients with pT4aN3bM0 in the OG group (P < 0.05). The stratified analysis showed that overall survival was inferior for LAG surgeons with fewer than 40 completed cases. The survival results for surgeons who had performed more than 40 cases were similar to the results from open surgery. CONCLUSIONS: Although LAG yields comparable oncologic outcomes for local AGC, patients with pT4aN3bM0 gastric cancer may not be suitable for laparoscopic surgery, especially for surgeons with limited experience. PMID- 26620647 TI - Dirofilaria immitis exposure status in client-owned cats with or without lower airway/lung-associated signs: case-control study in a canine heartworm-endemic area. AB - Objectives Heartworm-associated respiratory disease (HARD) is a recently recognised pathological manifestation in cats caused by Dirofilaria immitis exposure. This study aimed to estimate the percentage of cats at risk of developing HARD in a heartworm-endemic area (Taipei, Taiwan), and to test the correlation of heartworm exposure and the presence of lower airway/lung clinical signs (LA/L signs). Methods This was a prospective case-control study. The study design called for the enrolment of at least 80 cats with LA/L signs and at least 80 cats without such clinical signs in a 1 year period. The D immitis antibody seroprevalence of the two cohorts was compared. Results From February 2014 to January 2015, 187 client-owned cats were prospectively enrolled: 83 clinical cases with LA/L signs and 104 cats without such signs. Antibody seropositivity was approximately twice as frequent in cats with LA/L signs (13.3%) than in cats without signs (7.8%) (odds ratio [OR] 1.814); nevertheless, no statistically significant difference between the two cohorts ( P = 0.22) was found. We used 41 frozen samples from free-roaming cats to examine the possibility of different exposure rates to mosquito bites between client-owned cats and stray cats, finding the seroprevalence to be 7.5% in free-roaming cats - a result not statistically different to that in client-owned cats ( P = 0.60). Outdoor access was a significant risk factor for heartworm exposure in client-owned cats (OR 3.748; P = 0.03); however, living entirely indoors did not provide complete protection from exposure/infection. Conclusions and relevance Our results did not show statistically significant differences in antibody seroprevalence between cats with and without LA/L signs. LA/L signs were not always present under conditions of natural exposure. However, exposure to D immitis is not rare among client-owned cats, suggesting that heartworm prophylactics should be a part of routine care in all cats living in areas endemic for canine heartworm. PMID- 26620648 TI - Ambulatory electrocardiogram recordings in cats with primary asymptomatic hypertrophic cardiomyopathy. AB - Objectives The aims of the study were to determine the heart rate, rhythm, number of ventricular premature complexes (VPCs) and atrial premature complexes (APCs) in unsedated cats with asymptomatic hypertrophic cardiomyopathy (HCM), using 24 h ambulatory electrocardiogram (ECG) (Holter) in the home environment and to compare the results with those from healthy control cats. Methods Fifteen privately owned cats with asymptomatic HCM entered the study. Data from 23 healthy cats, previously published by our group, were used as the control. Clinical examination, measurement of blood pressure, echocardiographic examination, Holter recordings and biochemical analyses were performed in all cats. Holter recordings were obtained in the home environment. Results Three-lead ECGs of good quality were obtained from 15 cats with HCM. The median heart rate was 145 (interquartile range [IQR] 137-184) beats per minute for the cats with HCM. All cats with HCM presented with normal sinus rhythm; 60% of cats had intermittent sinus arrhythmia. Median number of VPCs was 3 (IQR 1-17). Three cats had APCs and three cats had both escape beats and intermittent sinus arrhythmia. Conclusions and relevance Asymptomatic cats with HCM had few VPCs and APCs on 24 h ambulatory ECG in the home environment. Intermittent sinus arrhythmia was observed in 60% of cats with HCM. The present study shows that the heart rate and the number of VPCs and APCs in cats with asymptomatic HCM are similar to that found in healthy control cats. PMID- 26620649 TI - Evaluation of an ultrasound-guided technique for axillary brachial plexus blockade in cats. AB - Objectives The aim of this study was to evaluate and refine an ultrasound (US) guided technique to block the brachial plexus (BP) at the level of the axillary space in live cats. Methods Eight adult experimental cats were enrolled into the study. The animals were sedated and positioned in dorsal recumbency with the limb to be blocked abducted 90o. The US transducer was placed in the axillary region and a non-traumatic peripheral nerve block needle was inserted in-plane with respect to the transducer, medial to the BP up to the level of the axillary artery. Lidocaine 1% (0.4 ml/kg) was injected as the needle was being progressively withdrawn in a caudal-to-cranial direction. The efficacy of the block was confirmed by evaluation of the motor and sensory functions of the blocked forelimb. Motor blockade was assessed observing the position of the blocked leg on standing and walking patterns. Sensory blockade was evaluated by the stimulation of mechanical nociceptors in the dermatomes supplied by the four major sensory nerves of the distal thoracic limb. Results The BP was successfully located by US in all cases. The achieved BP block was complete in six cats (75%) and partial in the remaining two cats (25%). All animals recovered uneventfully from the sedation and the BP blocks. Conclusions and relevance The US-guided block at the axillary space evaluated in this study is a feasible, reproducible and safe technique to block the BP plexus in experimental live cats. PMID- 26620650 TI - Ultrasonographic anatomy of the healthy southern tigrina ( Leopardus guttulus) abdomen: comparison with domestic cat references. AB - Objectives The aim of the study was to describe the normal abdominal echoanatomy of the tigrina and to compare it with the abdominal echoanatomy of the domestic cat. Reference intervals for the normal abdominal ultrasonographic anatomy of individual species are important for accurate diagnoses and interpretation of routine health examinations. The hypothesis was that the echoanatomy of the tigrina was similar to that of the domestic cat. Methods Eighteen clinically healthy tigrina were selected for abdominal ultrasound examination, in order to obtain normal parameters of the bladder, spleen, adrenal gland, kidney, gastrointestinal tract, liver and gall bladder, and Doppler parameters of liver and kidney vessels. Results The splenic parenchyma was consistently hyperechoic to the kidneys and liver. The liver, kidneys and spleen had similar echotexture, shape and dimensions when compared with the domestic cat. The gall bladder was lobulated and surrounded by a clearly visualized thin, smooth, regular echogenic wall. The adrenal glands had a bilobulated shape. The urinary bladder had a thin echogenic wall. The Doppler parameters of the portal vein and renal artery were similar to the domestic cat. Conclusions and relevance The results support the hypothesis that the ultrasonographic parameters of the abdominal viscera of the southern tigrina are similar to those of the domestic cat. PMID- 26620653 TI - Conservative Algorithm for an Adaptive Change of Resolution in Mixed Atomistic/Coarse-Grained Multiscale Simulations. AB - We derive a Hamiltonian and present a simulation protocol for mixed-resolution systems that allows for a change in resolution of selected groups of atoms during a molecular dynamics simulation. The Hamiltonian uses a low-resolution force field for the part of the system distant from an active site (for efficiency) and an atomistic force field for the active site and its direct environment (for accuracy). A microcanonical simulation protocol conserves energy and angular and linear momentum. The method is also applicable to simulations in other ensembles. PMID- 26620651 TI - Football training in men with prostate cancer undergoing androgen deprivation therapy: activity profile and short-term skeletal and postural balance adaptations. AB - PURPOSE: To investigate the activity profile of football training and its short term effects on bone mass, bone turnover markers (BTMs) and postural balance in men with prostate cancer (PCa) undergoing androgen deprivation therapy (ADT). METHODS: This was a randomised 12-week study in which men with PCa undergoing ADT were assigned to a football intervention group [FTG, n = 29, 67 +/- 7 (+/-SD) years] training 2-3 times per week for 45-60 min or to a control group (n = 28, 66 +/- 5 years). The activity profile was measured using a 5-Hz GPS. The outcomes were total body and leg bone mineral content (BMC) and density, BTMs and postural balance. RESULTS: In the last part of the 12 weeks, FTG performed 194 +/- 41 accelerations and 296 +/- 65 decelerations at >0.6 m/s/s and covered a distance of 905 +/- 297 m at speeds >6 km/h and 2646 +/- 705 m per training session. Analysis of baseline-to-12-week change scores showed between-group differences in favour of FTG in total body BMC [26.4 g, 95 % confidence interval (CI): 5.8-46.9 g, p = 0.013], leg BMC (13.8 g, 95 % CI: 7.0-20.5 g, p < 0.001) and markers of bone formation: P1NP (36.6 ug/L, 95 % CI: 10.4-62.8 ug/L, p = 0.008) and osteocalcin (8.6 ug/L, 95 % CI: 3.3-13.8 ug/L, p < 0.01). The number of decelerations correlated to the increase in leg BMC (r = 0.65, p = 0.012). No between-group differences were observed for the remaining outcomes. CONCLUSION: Football training involves numerous runs, accelerations and decelerations, which may be linked to marked increases in bone formation markers and preserved bone mass in middle-aged and elderly men with PCa undergoing ADT. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01711892. PMID- 26620654 TI - Quantum Chemistry on Graphical Processing Units. 1. Strategies for Two-Electron Integral Evaluation. AB - Modern videogames place increasing demands on the computational and graphical hardware, leading to novel architectures that have great potential in the context of high performance computing and molecular simulation. We demonstrate that Graphical Processing Units (GPUs) can be used very efficiently to calculate two electron repulsion integrals over Gaussian basis functions [Formula: see text] the first step in most quantum chemistry calculations. A benchmark test performed for the evaluation of approximately 10(6) (ss|ss) integrals over contracted s orbitals showed that a naive algorithm implemented on the GPU achieves up to 130 fold speedup over a traditional CPU implementation on an AMD Opteron. Subsequent calculations of the Coulomb operator for a 256-atom DNA strand show that the GPU advantage is maintained for basis sets including higher angular momentum functions. PMID- 26620655 TI - Investigations into the Nature of Halogen Bonding Including Symmetry Adapted Perturbation Theory Analyses. AB - In recent years it has been recognized that, because of their unique properties, halogen bonds have tremendous potential in the development of new pharmaceutical compounds and materials. In this study we investigate the phenomenon of halogen bonding by carrying out ab initio calculations on the halomethane-formaldehyde complexes as well as the fluorine substituted FnH3-nCX...OCH2 dimers, where the halogen bonding halogens (X) are chlorine, bromine, and iodine. Coupled cluster (CCSD(T)/aug-cc-pVTZ) calculations indicate that the binding energies for these type of interactions lie in the range between -1.05 kcal/mol (H3CCl...OCH2) and 3.72 kcal/mol (F3CI...OCH2). One of the most important findings in this study is that, according to symmetry adapted perturbation theory (SAPT) analyses, halogen bonds are largely dependent on both electrostatic and dispersion type interactions. As the halogen atom involved in halogen bonding becomes larger the interaction strength for this type of interaction also gets larger and, interestingly, more electrostatic (and less dispersive) in character. Halogen bonding interactions also become stronger and more electrostatic upon substitution of (the very electronegative) fluorines onto the halomethane molecule. PMID- 26620656 TI - Monoligand Zn(II) Complexes: Ab Initio Benchmark Calculations and Comparison with Density Functional Theory Methodologies. AB - A systematic theoretical study on several models of Zn(II) complexes has been carried out employing both ab initio correlated wave function and density functional methods. The performance of five different functionals namely PW91, PBE, B3LYP, MPWLYP1M, and TPSS in the prediction of metal-ligand bond distances, binding energies, and proton affinities has been assessed comparing the results to those obtained with the MP2 and CCSD(T) wave function methodologies. Several basis sets ranging from double-zeta up to quintuple-zeta quality have been used, including the recently developed all-electron correlation consistent basis sets for zinc. It is shown that all the tested functionals overestimate both the metal ligand bond distances and the binding energies, being that the B3LYP and TPSS functionals are the ones that perform the best. An analysis of the metal-ligand interaction energy shows that induction and charge-transfer effects play a prominent role in the bonding of these systems, even for those complexes with the less polarizable ligands. This finding highlights the importance of a correct description of the polarization of the monomers' charge densities by any theoretical method which aims to be applied to the study of Zn(II) complexes. PMID- 26620657 TI - New Algorithms for Optimizing and Linking Conical Intersection Points. AB - In this paper we present two new algorithms to study the extended nature of the crossing seam between electronic potential energy surfaces. The first algorithm is designed to optimize conical intersection geometries: both minima and saddle points. In addition, this method will optimize conical intersection geometries using arbitrary geometrical constraints. We demonstrate its potential on different crossing seams of benzene, z-penta-3,5-dieniminium, and 1,3-butadiene. The second algorithm is designed to explicitly compute the intersection-space minimum energy coordinate. Our computations show how an intersection seam and the energy along it can be unambiguously defined. A finite region of the S0/S1 1,3 butadiene crossing seam has been mapped out, and a new saddle point linked with two lower-lying geometries on the seam. PMID- 26620658 TI - On the Accuracy of Density Functional Theory to Predict Shifts in Nuclear Magnetic Resonance Shielding Constants due to Hydrogen Bonding. AB - We present the first systematic investigation of shifts in the nuclear magnetic resonance (NMR) shielding constant due to hydrogen bonding using either the series of wave function based methods, Hartree-Fock (HF), second-order Moller Plesset perturbation theory (MP2), Coupled Cluster Singles and Doubles (CCSD) and CCSD extended with an approximate description of triples (CCSD(T)), or Density Functional Theory (DFT) employing either the B3LYP, PBE0, or KT3 exchange correlation (xc) functionals. The molecular systems considered are (i) the water dimer and (ii) formaldehyde in complex with two water molecules. Specially for the (17)O in formaldehyde we observe significant differences between the DFT and CCSD(T) predictions. However, the extent of these deviations depends crucially on the applied xc functional. Compared to CCSD(T) we find the KT3 functional to provide accurate results, whereas both B3LYP and PBE0 are in significant error. Potential consequences of this observation are discussed in the context of general predictions of NMR shielding constants in condensed phase. PMID- 26620659 TI - DFT Approach to the Calculation of Mossbauer Isomer Shifts. AB - With the help of a recently suggested computational scheme [J. Chem. Phys. 2007, 127, 084101], Mossbauer isomer shifts are calculated within the context of density functional theory, for a series of iron containing compounds. The influence of the choice of a density functional and of the truncation of a basis set on the results of calculations is analyzed. It has been observed that the hybrid density functionals, especially BH&HLYP, provide better correlation with experimental results than pure density functionals. The analysis of basis set truncation reveals that the addition (or removal) of the tightmost primitive functions to a large uncontracted basis set has only a minor influence on the calculated isomer shift values. It is observed that, with the use of a small contracted basis set, a reasonable accuracy for the calculated isomer shifts can be achieved. PMID- 26620660 TI - The Shell Structure of Atoms. AB - The total electron density distribution of an isolated atom or an atom in a molecule does not reveal an atomic shell structure. Many localization functions, such as the radial averaged electron density, the Laplacian of the electron density, or the electron localization function have been proposed to visualize and analyze the shell structure of atoms. It was found that for light main group elements the correct number of shells is revealed by such functions. Later it was recognized that for heavy main group elements and for transition metals many of these diagnostic tools fail to reveal the full set of electronic shells as expected from the periodic table. In this work we focus on the radial structure of isolated atoms as revealed by the Laplacian of the electron density. We will demonstrate that it is the nodal structure of the orbitals of the inner shells which is responsible for the diminishing of at least one valence shell of third row transition metal atoms. Particular attention is paid to the effect of different electronic configurations on the shell structure of atoms and the question if the changes observed in the Laplacian of the radial density are sufficiently large for experimental studies on the topology of the electron density. Our presentation is as general as possible and, hence, employs a fully relativistic, i.e., four-component picture and a multiconfigurational ansatz for the wave function, which is thus valid for the whole periodic table of elements. PMID- 26620661 TI - Performance of B3LYP Density Functional Methods for a Large Set of Organic Molecules. AB - Testing of the commonly used hybrid density functional B3LYP with the 6-31G(d), 6 31G(d,p), and 6-31+G(d,p) basis sets has been carried out for 622 neutral, closed shell organic compounds containing the elements C, H, N, and O. The focus is comparison of computed and experimental heats of formation and isomerization energies. In addition, the effect of an empirical dispersion correction term has been evaluated and found to improve agreement with the experimental data. For the 622 compounds, the mean absolute errors (MAE) in the heats of formation are 3.1, 2.6, 2.7, and 2.4 kcal/mol for B3LYP/6-31G(d), B3LYP/6-31G(d,p), B3LYP/6 31+G(d,p), and B3LYP/6-31+G(d,p) with the dispersion correction. A diverse set of 34 isomerizations highlights specific issues of general interest, such as performance on differences in steric effects, conjugation, and bonding. The corresponding MAEs for the isomerizations are 2.7, 2.4, 2.2, and 1.9 kcal/mol. Improvement is obtained for isomerizations of amines and alcohols when both polarization and diffuse functions are used, but the overstabilization of linear alkanes compared to branched isomers can be relieved only with the dispersion correction. Besides the insights on DFT methods, the study also aimed to quantify the gains in accuracy that can be achieved by replacing energetics from NDO-based semiempirical methods with DFT results. Since the MAEs obtained with the PDDG/PM3 method for the 622 heats of formation and 34 isomerizations are 2.8 and 2.3 kcal/mol, negligible advantage in accuracy for the B3LYP-based methods emerged in the absence of the dispersion corrections. PMID- 26620662 TI - Density Functional Theory in Transition-Metal Chemistry: Relative Energies of Low-Lying States of Iron Compounds and the Effect of Spatial Symmetry Breaking. AB - The ground and lower excited states of Fe2, Fe2(-), and FeO(+) were studied using a number of density functional theory (DFT) methods. Specific attention was paid to the relative state energies, the internuclear distances (re), and the harmonic vibrational frequencies (omegae). A number of factors influencing the calculated values of these properties were examined. These include basis sets, the nature of the density functional chosen, the percentage of Hartree-Fock exchange in the density functional, and constraints on orbital symmetry. A number of different types of generalized gradient approximation (GGA) density functionals (straight GGA, hybrid GGA, meta-GGA, and hybrid meta-GGA) were examined, and it was found that the best results were obtained with hybrid GGA or hybrid meta-GGA functionals that contain nonzero fractions of HF exchange; specifically, the best overall results were obtained with B3LYP, M05, and M06, closely followed by B1LYP. One significant observation was the effect of enforcing symmetry on the orbitals. When a degenerate orbital (pi or delta) is partially occupied in the (4)Phi excited state of FeO(+), reducing the enforced symmetry (from C6v to C4v to C2v) results in a lower energy since these degenerate orbitals are split in the lower symmetries. The results obtained were compared to higher level ab initio results from the literature and to recent PBE+U plane wave results by Kulik et al. (Phys. Rev. Lett. 2006, 97, 103001). It was found that some of the improvements that were afforded by the semiempirical +U correction can also be accomplished by improving the form of the DFT functional and, in one case, by not enforcing high symmetry on the orbitals. PMID- 26620663 TI - On the Catalytic Role of Ge(+) and Se(+) in the Oxygen Transport Activation of N2O by CO. AB - The different reactivity of two first row cations selenium and germanium, in activating the reduction of nitrous oxide by carbon monoxide, was theoretically investigated at the density functional level using large basis sets and pseudopotential for metal atoms. In the two examined cases, the reaction mechanisms appeared to be quite different. Germanium shows a very good performance as far as thermodynamic and kinetic aspects are concerned. Selenium, experimentally recognized as an inactive catalyst, was instead found potentially able to catalyze the process through a mechanism of spin orbit coupling involving species with doublet multiplicity. PMID- 26620652 TI - Transmission of HIV Drug Resistance and the Predicted Effect on Current First line Regimens in Europe. AB - BACKGROUND: Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. METHODS: Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. RESULTS: The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008 2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. CONCLUSIONS: Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected. PMID- 26620664 TI - Branching Ratios of Aliphatic Amines + OH Gas-Phase Reactions: A Variational Transition-State Theory Study. AB - A theoretical study on the mechanism of the OH + aliphatic amines reactions is presented. Geometry optimization and frequencies calculations have been performed at the BHandHLYP/6-311++G(2d,2p) level of theory for all stationary points. Energy values have been improved by single-point calculations at the above geometries using CCSD(T) and the same basis set. All the possible hydrogen abstraction channels have been modeled, involving the rupture of C-H and N-H bonds. It was found that as the temperature decreases the contributions of the channels involving NH sites to the overall reaction also decrease, suggesting that for upper layers in the troposphere these channels become less important. Their percentage contributions to the overall reaction, at 298 K, were found to be about 20%, 2%, and 48% for methylamine, ethlylamine, and dimethylamine, respectively. PMID- 26620665 TI - Application of the Correlation Consistent Composite Approach (ccCA) to Third-Row (Ga-Kr) Molecules. AB - The correlation consistent composite approach (ccCA) has been applied to the G3/05 training set of 51 energetic properties for the atoms and molecules that contain the 4p elements, Ga-Kr. When atomic and molecular first-order spin orbit coupling corrections are added to open shell atoms and molecules, the ccCA has a mean absolute deviation from experiment (MAD) of 0.95 kcal mol(-1), an improvement of 0.10 kcal mol(-1) over G3 and G3X model chemistries. The performance of the ccCA on third-row-containing atoms and molecules is, therefore, commensurate in accuracy with previous studies on lighter main group elements H-Ar. While the typical methods used to compute theoretical molecular spin orbit corrections may go against the spirit of "black box" model chemistries, such corrections may be necessary for molecules containing heavy elements such as Ga-Kr. For example, when second-order spin orbit corrections are added to the atomic and molecular energies, the ccCA MAD is reduced to 0.88 kcal mol(-1). PMID- 26620666 TI - Molecular Dynamics Simulation Study of the Influence of Cluster Geometry on Formation of C60 Fullerene Clusters in Aqueous Solution. AB - We have performed atomistic molecular dynamics simulations of linear (1 dimensional), planar (2-dimensional), and icosahedral (3-dimensional) clusters of C60 fullerenes in aqueous solution in order to investigate the influence of cluster geometry on their free energy of formation. As was found in our previous study of the potential of mean force (PMF) as a function of separation for a single pair of fullerenes in aqueous solution, the interaction between fullerenes for all cluster geometries was dominated by direct fullerene-fullerene interactions and not by water-induced hydrophobic interactions. A coarse-grained implicit solvent (CGIS) potential, given by the PMF for the fullerene pair in water obtained from atomistic simulations, was found to describe well the free energy of formation of the linear cluster, indicating that many-body effects, i.e., the influence of neighboring fullerenes on the water-induced interaction between a fullerene pair, are negligible for the 1-dimensional geometry. For the 2-dimensional and particularly the 3-dimensional geometry, however, many-body effects were found to strongly influence hydration, leading to complete dehydration of the central fullerene at close fullerene-fullerene separations for the icosahedral cluster. This strong influence of geometry on hydration translates into water-induced interactions that, while remaining repulsive, as is found for the fullerene pair, are not well described by the two-body CGIS potential obtained from the isolated fullerene pair, particularly for the 3 dimensional geometry. PMID- 26620667 TI - Structural and Electronic Properties of Selected Rutile and Anatase TiO2 Surfaces: An ab Initio Investigation. AB - Five low-index stoichiometric TiO2 rutile and anatase surfaces, i.e., rutile (110), (100), and (001) as well as anatase (101) and (100), have been investigated using different Hamiltonians with all-electron Gaussian basis sets, within a periodic approach. Full-relaxations of the aforementioned surfaces have been essentially carried out at the Hartree-Fock (HF) level, but selected surfaces were treated also using pure and hybrid Density Functional Theory (DFT) models. Mulliken charges, band structures, and total and projected-densities of states have been computed both at the HF and the hybrid DFT (B3LYP and PBE0) levels. As regards DFT, the local density (LDA) and generalized gradient approximations (GGA) have been used. No matter which Hamiltonian is considered, as long as sufficiently thick slabs are taken into account, computed atomic relaxations show an overall excellent agreement with the most recent experimental reports. This is especially true when using hybrid functionals which enable the clarification of some conflicting results. Moreover, both at the LDA and HF levels, we were able to classify the surface relative energies in the following sequence: anatase (101) < rutile (110) < anatase (100) < rutile (100) ? rutile (001). Instead, when using PBE, B3LYP, or PBE0, the two most stable surfaces are reversed. PMID- 26620668 TI - Properties and 3D Structure of Liquid Water: A Perspective from a High-Rank Multipolar Electrostatic Potential. AB - We propose a new rigid, nonpolarizable high-rank multipolar potential for the simulation of liquid water. The electrostatic interaction is represented by spherical tensor multipole moments on oxygen and hydrogen, up to hexadecupole. The Quantum Chemical Topology (QCT) method yields the atomic multipole moments from a MP2/aug-cc-p-VTZ electron density of a single water molecule in the gas phase. These moments reproduce the experimental molecular dipole and quadrupole moment within less than 1%. Given its high-rank multipole moments, used in conjunction with a consistent high-rank multipolar Ewald summation, the QCT potential is ideal to assess the performance of exhaustive "gas phase" electrostatics in molecular dynamics simulations of liquids. The current article explores the performance of this potential at 17 temperatures between -35 degrees C (238 K) and 90 degrees C (363 K) and at 7 pressures between 1 and 10 000 atm. The well-known maximum in the liquid's density at 4 degrees C is reproduced at 6 degrees C. Six bulk properties are calculated and found to deviate from experiment in a homogeneous manner, that is, without serious outliers, compared to several other potentials. Spatial distribution functions (i.e., gOO(r,Omega)) and the (more common) radial distribution functions are used to analyze the local water structure. At the lone pair side of a central water, neighboring waters form a continuous horseshoe-like distribution, with substantial narrowing in the central part. The latter feature is unique to the QCT potential. Under high pressure, the local structure undergoes dramatic rearrangement and results in the collapse of second shell neighbors into the interstitial region of the first shell, which is in close agreement with experiment. Our results also corroborate the suggestion that the local hydrogen bonded network remains largely intact even under such conditions. PMID- 26620669 TI - Theoretical Analysis of the Reaction Mechanism of Biotin Carboxylase. AB - A computational approach is taken to clarify the reaction mechanism of biotin carboxylase (BC) by using the B3LYP density functional method. The overall reaction of BC is supposed to consist of two steps: in the first step, carboxyphosphate (CP) is generated from bicarbonate and ATP, and it is subject to nucleophilic attack on its carboxyl group by biotin to form carboxybiotin in the second step. The activation energies for the transition states of the first and second steps are computed to be 46.6 and 7.9 kcal/mol, respectively, demonstrating that the first step limits the overall reaction of BC. In the second step, the ureido moiety of biotin undergoes enolization with the aid of general acid-base catalysis by CP, followed by collapse of CP into CO2 and phosphate. The resulting bent CO2 is highly labile and condenses quickly with enolic biotin to give carboxybiotin. Implicit in this scheme as they are, ingenious proton movements between the two substrates, CP and biotin, dictate all of the succeeding chemical events. PMID- 26620670 TI - Quantum Zeno and Zeno-like effects in nitrogen vacancy centers. AB - We present a proposal to realize the quantum Zeno effect (QZE) and quantum Zeno like effect (QZLE) in a proximal (13)C nuclear spin by controlling a proximal electron spin of a nitrogen vacancy (NV) center. The measurement is performed by applying a microwave pulse to induce the transition between different electronic spin states. Under the practical experimental conditions, our calculations show that there exist both QZE and QZLE in a (13)C nuclear spin in the vicinity of an NV center. PMID- 26620672 TI - Determinants of sexual dysfunction and interventions for patients with obstructive sleep apnoea: a systematic review. AB - AIMS: Obstructive sleep apnoea (OSA) may negatively affect a couple's sexual relationship. This systematic review evaluated what characteristics are determinants of sexual function and dysfunction in women and men with OSA, and what interventions are shown to be effective. METHODS: A systematic literature review was conducted using PubMed, CINAHL, Cochrane and TRIP, and articles published between January 2004 and December 2014 in English; original research; adults >= 18 years; and both experimental and non-experimental designs. The Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies was used to assess study quality. Of 21 studies, six studies (no randomised control trials, RCTs) included women and 15 (with six RCTs) studies included men. Extracted data were scrutinised and adjusted until consensus was reached; suitable quantitative data were pooled in statistical meta-analysis. RESULTS: Sexual function was affected similarly in both genders, but effective interventions were reported only for men. In some studies, OSA severity and medications contributed to greater sexual dysfunction. In women, menopausal status, hormone levels and SaO2 < 90% were determinants of sexual dysfunction, while for men factors included BMI, hormonal status and inflammatory markers. Continuous positive airway pressure (CPAP) not only improved clinical measures such as excessive daytime sleepiness but also the erectile and orgasmic function. Nevertheless, sildenafil was superior CPAP with regard to erectile dysfunction. CONCLUSIONS: The findings illustrate important contributors to sexual dysfunction; however, firm generalisations cannot be made. There were limited RCTs and none for women, indicating further RCTs are needed to determine how OSA affects sexual function. PMID- 26620671 TI - Variation in NAT2 acetylation phenotypes is associated with differences in food producing subsistence modes and ecoregions in Africa. AB - BACKGROUND: Dietary changes associated to shifts in subsistence strategies during human evolution may have induced new selective pressures on phenotypes, as currently held for lactase persistence. Similar hypotheses exist for arylamine N acetyltransferase 2 (NAT2) mediated acetylation capacity, a well-known pharmacogenetic trait with wide inter-individual variation explained by polymorphisms in the NAT2 gene. The environmental causative factor (if any) driving its evolution is as yet unknown, but significant differences in prevalence of acetylation phenotypes are found between hunter-gatherer and food producing populations, both in sub-Saharan Africa and worldwide, and between agriculturalists and pastoralists in Central Asia. These two subsistence strategies also prevail among sympatric populations of the African Sahel, but knowledge on NAT2 variation among African pastoral nomads was up to now very scarce. Here we addressed the hypothesis of different selective pressures associated to the agriculturalist or pastoralist lifestyles having acted on the evolution of NAT2 by sequencing the gene in 287 individuals from five pastoralist and one agriculturalist Sahelian populations. RESULTS: We show that the significant NAT2 genetic structure of African populations is mainly due to frequency differences of three major haplotypes, two of which are categorized as decreased function alleles (NAT2*5B and NAT2*6A), particularly common in populations living in arid environments, and one fast allele (NAT2*12A), more frequently detected in populations living in tropical humid environments. This genetic structure does associate more strongly with a classification of populations according to ecoregions than to subsistence strategies, mainly because most Sahelian and East African populations display little to no genetic differentiation between them, although both regions hold nomadic or semi-nomadic pastoralist and sedentary agriculturalist communities. Furthermore, we found significantly higher predicted proportions of slow acetylators in pastoralists than in agriculturalists, but also among food-producing populations living in the Sahelian and dry savanna zones than in those living in humid environments, irrespective of their mode of subsistence. CONCLUSION: Our results suggest a possible independent influence of both the dietary habits associated with subsistence modes and the chemical environment associated with climatic zones and biomes on the evolution of NAT2 diversity in sub-Saharan African populations. PMID- 26620673 TI - Destination memory for self-generated actions. AB - BACKGROUND AND AIMS: There is a substantial body of literature showing memory enhancement for self-generated information in normal aging. The present paper investigated this outcome for destination memory or memory for outputted information. METHODS: In Experiment 1, younger adults and older adults had to place (self-generated actions) and observe an experimenter placing (experiment generated actions) items into two different destinations (i.e., a black circular box and a white square box). On a subsequent recognition task, the participants had to decide into which box each item had originally been placed. These procedures showed better destination memory for self- than experimenter-generated actions. In Experiment 2, destination and source memory were assessed for self generated actions. Younger adults and older adults had to place items into the two boxes (self-generated actions), take items out of the boxes (self-generated actions), and observe an experimenter taking items out of the boxes (experiment generated actions). On a subsequent recognition task, they had to decide into which box (destination memory)/from which box (source memory) each item had originally been placed/taken. RESULTS: For both populations, source memory was better than destination memory for self-generated actions, and both were better than source memory for experimenter-generated actions. DISCUSSIONS AND CONCLUSIONS: Taken together, these findings highlight the beneficial effect of self-generation on destination memory in older adults. PMID- 26620674 TI - The role of continuous versus fractionated physical training on muscle oxidative stress parameters and calcium-handling proteins in aged rats. AB - Age-associated decline in skeletal muscle mass and strength is associated with oxidative stress and Ca(2+) homeostasis disturbance. Exercise should be considered a viable modality to combat aging of skeletal muscle. This study aimed to investigate whether continuous and fractionated training could be useful tools to attenuate oxidative damage and retain calcium-handling proteins. We conducted the study using 24-month-old male Wistar rats, divided into control, continuous, and fractionated groups. Animals ran at 13 m min(-1) for five consecutive days (except weekends) for 6 weeks, for a total period of 42 days. Each session comprised 45 min of exercise, either continuous or divided into three daily sessions of 15 min each. Metabolic and oxidative stress markers, protein levels of mitochondrial transcription factors, and calcium-handling proteins were analyzed. Continuous exercise resulted in reduced ROS production as well as showed a decrease in TBARS levels and carbonyl content. On the other hand, fractionated training increased the antioxidant enzyme activities. The ryanodine receptor and phospholamban protein were regulated by continuous training while sodium calcium exchange protein was increased by the fractionated training. These data suggest that intracellular Ca(2+) can be modulated by various training stimuli. In addition, the modulation of oxidative stress by continuous and fractionated training may play an important regulatory role in the muscular contraction mechanism of aged rats, due to changes in calcium metabolism. PMID- 26620675 TI - Kaempferol inhibits Entamoeba histolytica growth by altering cytoskeletal functions. AB - The flavonoid kaempferol obtained from Helianthemum glomeratum, an endemic Mexican medicinal herb used to treat gastrointestinal disorders, has been shown to inhibit growth of Entamoeba histolytica trophozoites in vitro; however, the mechanisms associated with this activity have not been documented. Several works reported that kaempferol affects cytoskeleton in mammalian cells. In order to gain insights into the action mechanisms involved in the anti-amoebic effect of kaempferol, here we evaluated the effect of this compound on the pathogenic events driven by the cytoskeleton during E. histolytica infection. We also carried out a two dimensional gel-based proteomic analysis to evidence modulated proteins that could explain the phenotypical changes observed in trophozoites. Our results showed that kaempferol produces a dose-dependent effect on trophozoites growth and viability with optimal concentration being 27.7 MUM. Kaempferol also decreased adhesion, it increased migration and phagocytic activity, but it did not affect erythrocyte binding nor cytolytic capacity of E. histolytica. Congruently, proteomic analysis revealed that the cytoskeleton proteins actin, myosin II heavy chain and cortexillin II were up-regulated in response to kaempferol treatment. In conclusion, kaempferol anti-amoebic effects were associated with deregulation of proteins related with cytoskeleton, which altered invasion mechanisms. PMID- 26620676 TI - CD4 T cell knockout does not protect against kidney injury and worsens cancer. AB - Most previous studies of cisplatin-induced acute kidney injury (AKI) have been in models of acute, high-dose cisplatin administration that leads to mortality in non-tumor-bearing mice. The aim of the study was to determine whether CD4 T cell knockout protects against AKI and cancer in a clinically relevant model of low dose cisplatin-induced AKI in mice with cancer. Kidney function, serum neutrophil gelatinase-associated lipocalin (NGAL), acute tubular necrosis (ATN), and tubular apoptosis score were the same in wild-type and CD4 -/- mice with AKI. The lack of protection against AKI in CD4 -/- mice was associated with an increase in extracellular signal-regulated kinase (ERK), p38, CXCL1, and TNF-alpha, mediators of AKI and fibrosis, in both cisplatin-treated CD4 -/- mice and wild-type mice. The lack of protection was independent of the presence of cancer or not. Tumor size was double, and cisplatin had an impaired therapeutic effect on the tumors in CD4 -/- vs. wild-type mice. Mice depleted of CD4 T cells using the GK1.5 antibody were not protected against AKI and had larger tumors and lesser response to cisplatin. In summary, in a clinically relevant model of cisplatin-induced AKI in mice with cancer, (1) CD4 -/- mice were not protected against AKI; (2) ERK, p38, CXCL1, and TNF-alpha, known mediators of AKI, and interstitial fibrosis were increased in CD4 -/- kidneys; and (3) CD4 -/- mice had faster tumor growth and an impaired therapeutic effect of cisplatin on the tumors. The data warns against the use of CD4 T cell inhibition to attenuate cisplatin-induced AKI in patients with cancer. KEY MESSAGE: A clinically relevant low-dose cisplatin model of AKI in mice with cancer was used. CD4 -/- mice were not functionally or histologically protected against AKI. CD4 -/- mice had faster tumor growth. CD4 /- mice had an impaired therapeutic effect of cisplatin on the tumors. Mice depleted of CD4 T cells were not protected against AKI and had larger tumors. PMID- 26620677 TI - A flow cytometry-based reporter assay identifies macrolide antibiotics as nonsense mutation read-through agents. AB - A large number of human diseases are caused by nonsense mutations. These mutations result in premature protein termination and the expression of truncated, usually nonfunctional products. A promising therapeutic strategy for patients suffering from premature termination codon (PTC)-mediated disorders is to suppress the nonsense mutation and restore the expression of the affected protein. Such a suppression approach using specific antibiotics and other read through promoting agents has been shown to suppress PTCs and restore the production of several important proteins. Here, we report the establishment of a novel, rapid, and very efficient method for screening stop-codon read-through agents. We also show that, in both mammalian cells and in a transgenic mouse model, distinct members of the macrolide antibiotic family can induce read through of disease-causing stop codons leading to re-expression of several key proteins and to reduced disease phenotypes. Taken together, our results may help in the identification and characterization of well-needed customized pharmaceutical PTC suppression agents. KEY MESSAGES: Establishment of a flow cytometry-based reporter assay to identify nonsense mutation read-through agents. Macrolide antibiotics can induce read-through of disease-causing stop codons. Macrolide-induced protein restoration can alleviate disease-like phenotypes. PMID- 26620678 TI - Downregulation of microRNA-193a-3p is involved in invertebral disc degeneration by targeting MMP14. AB - Accumulating evidence suggests that microRNAs (miRNAs) play an important role in intervertebral disc degeneration (IDD), but the precise role of specific miRNAs involved in this disease remains elusive. The purpose of this study was to identify IDD-specific miRNAs, followed by functional validation of results. MiRNA expression profile was determined in nucleus pulposus (NP) tissues from patients with IDD and controls, employing Solexa sequencing and quantitative real-time PCR (qRT-PCR). Biological functions of differential expression miRNAs were further investigated in vitro and in vivo. Luciferase reporter assays and Western blotting were performed to determine miRNA targets. We identified 28 miRNAs that were differentially expressed in patients compared with controls. Following qRT PCR confirmation, miR-193a-3p was significantly down-regulated in degenerative NP tissues. Moreover, its level was correlated with grade of disc degeneration. Through gain- and loss-of-function studies, miR-193a-3p was demonstrated to significantly promote type II collagen expression in NP cells. Knockdown of MMP14 induced effects on NP cells similar to those induced by miR-193a-3p. Bioinformatics target prediction identified MMP14 as a putative target of miR 193a-3p. Furthermore, luciferase reporter assays and Western blotting demonstrated that miR-193a-3p directly targets MMP14. MiR-193a-3p inhibited IDD in vitro and in vivo. The downregulation of miR-193a-3p induces the expression of MMP14, which promotes loss of type II collagen and thereby contributes to the development of human IDD. Our findings extend the role of miR-193a-3p in the pathogenesis of IDD and provide a potential novel therapeutic target for degenerative disc disease. KEY MESSAGES: Intervertebral disc degeneration (ICC) specific miRNA profile generated by next generation sequencing. Downregulation of miR-193a-3p promoted loss of type II collagen by directly targeting MMP14 in IDD. miR-193a-3p inhibited IDD in vitro and in vivo. miR-193a-3p may be a promising candidate for prevention of degenerative disc disease. PMID- 26620679 TI - Geoenvironmental factors related to high incidence of human urinary calculi (kidney stones) in Central Highlands of Sri Lanka. AB - An area with extremely high incidence of urinary calculi was investigated in the view of identifying the relationship between the disease prevalence and the drinking water geochemistry. The prevalence of the kidney stone disease in the selected Padiyapelella-Hanguranketa area in Central Highlands of Sri Lanka is significantly higher compared with neighboring regions. Drinking water samples were collected from water sources that used by clinically identified kidney stone patients and healthy people. A total of 83 samples were collected and analyzed for major anions and cations. The anions in the area varied in the order HCO3 (-) > Cl(-) > SO4 (2-) > NO3 (-) and cations varied in the order Ca(2+) > Mg(2+) > Na(+) > K(+) > Fe(2+). The dissolved silica that occurs as silicic acid (H4SiO4) in natural waters varied from 8.8 to 84 mg/L in prevalence samples, while it was between 9.7 and 65 mg/L for samples from non-prevalence locations. Hydrogeochemical data obtained from the two groups were compared using the Wilcoxon rank-sum test. It showed that pH, total hardness, Na(+), Ca(2+) and Fe(2+) had significant difference (p < 0.005) between water sources used by patients and non-patients. Elemental ratio plots, Gibbs' plot and factor analysis indicated that the chemical composition of water sources in this area is strongly influenced by rock-water interactions, particularly the weathering of carbonate and silicate minerals. This study reveals a kind of association between stone formation and drinking water geochemistry as evident by the high hardness/calcium contents in spring water used by patients. PMID- 26620680 TI - Multi-centre National Population Health Examination Survey (WOBASZ II study): assumptions, methods, and implementation. AB - BACKGROUND: Cardiovascular diseases (CVDs) are the main cause of morbidity and mortality in developed countries. Despite the progress in diagnostics and treatment, it is expected that CVD will still be the main cause of death worldwide until at least 2030. From 1991 CVD mortality in Poland systematically decreased, but it is still higher than the average in Western Europe. In 2013 CVDs were the cause of 46% of all deaths in Poland (40.9% in men and 51.1% in women) and 26.9% of deaths among persons under 65 years of age. The epidemiologic assessment of prevalence, control and treatment of CVD risk factors, and monitoring of healthy behaviour and morbidity due to diseases like coronary artery disease, hypertension and diabetes is very important for health policy planning. The WOBASZ II is the newest Polish population based survey, performed in 2013-2014 to evaluate prevalence, control, treatment, and morbidity. The study was the continuation of WOBASZ (2003-2005). AIM: To describe the goals and methods of the WOBASZ II study and to present the results of the recruitment. METHODS: The WOBASZ II study was planned as a cross-sectional survey of a random sample of Polish residents aged over 20 years. The selection, using the National Identity Card Registry of the Ministry of Internal Affairs, was made as a three stage sampling, stratified according to administrative units (voivodeships), type of urbanisation (commune), and gender. The study protocol consisted of a questionnaire used in face-to-face interviews, physical examination, and blood samples. WOBASZ II was coordinated by the Department of Epidemiology, Cardiovascular Diseases Prevention and Health Promotion of the Institute of Cardiology in Warsaw in cooperation with medical universities in Gdansk, Katowice, Krakow, Lodz, and Poznan. RESULTS: Out of 15,120 persons, 1557 persons were not eligible. Out of eligible persons, 6170 (2760 men and 3410 women) were examined (the response rate 45.5%). The highest response rates were observed in Warminsko-Mazurskie (64.2%), Zachodniopomorskie (58.1%), and Kujawsko-Pomorskie (53.1%). CONCLUSIONS: The importance of the WOBASZ study for the monitoring of the health state of Polish society, and for the as-sessment of prophylaxis efficiency and treatment of CVD and metabolic diseases, as well as for the evaluation of the actions in the field of health promotion, is difficult to overstate. PMID- 26620681 TI - Forced expiratory volume in one second can predict SYNTAX score in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: The SYNTAX score is an angiographic score that predicts coronary artery disease (CAD) complexity. It has been shown to be useful for decision making about percutaneous coronary intervention or coronary artery bypass grafting among patients with CAD. Higher SYNTAX scores are indicative of more complex disease. Chronic obstructive pulmonary disease (COPD) is characterised by limitation of airflow. Measurement of forced expiratory volume in one second (FEV1) in spirometry is used for diagnosis and to determine the severity of the disease. AIM: To evaluate the relationship between FEV1 and SYNTAX score in patients with COPD. METHODS: Seventy-eight patients with a previous diagnosis of COPD and 48 patients without COPD were enrolled. Spirometry and coronary angiography were performed in all patients. SYNTAX score was calculated and compared between the two groups. The correlation between FEV1 and SYNTAX score was analysed. RESULTS: SYNTAX score was higher in patients with COPD than in patients without COPD (23.22 +/- 12.10 vs. 17.92 +/- 11.21, respectively; p = 0.013). Multivariate analysis demonstrated that COPD was independently predictive for intermediate and high SYNTAX score (odds ratio 4.833; 95% confidence interval 2.228-10.485; p < 0.001). Mean FEV1 (% predicted) was 64.7 +/- 11.4 and negatively correlated with SYNTAX score in COPD group (r = -0.266 and p = 0.018). The receiver operating characteristic analysis yielded a cutoff value of 65.5 for the FEV1 to predict SYNTAX score >= 23, with sensitivity and specificity being 78.6% and 70%, respectively. CONCLUSIONS: COPD is a predictor of higher SYNTAX scores. FEV1 is associated with more severe and complex CAD. PMID- 26620682 TI - The effect of sedation during transoesophageal echocardiography on heart rate variability: a comparison of hypnotic sedation with medical sedation. AB - BACKGROUND: There is no ideal sedation technique that can be used during transoesophageal echocardiography (TEE), and the data concerning the effects of available sedation techniques on heart rate variability (HRV) are limited. AIM: To compare the effects of sedation through hypnotherapy with medical sedation achieved by midazolam on HRV. METHODS: We recruited 76 patients with an indication of TEE; the age range was 18-83 years. In Group T there were 26 patients who had the procedure under topical pharyngeal anaesthesia, in Group D there were 23 patients who received midazolam, and in Group H there were 27 patients receiving hypnosis. All patients had an IV access; throughout the procedure heart rate, rhythm electrocardiography, and peripheric O2 saturation were monitored with a non-invasive monitor, and blood pressure measurements were taken every 3 min. Rhythm Holter recordings were obtained from all patients and TEE was performed. RESULTS: When time domain parameters for HRV were compared in all three groups, the hypnosis group had significant increases in pNN50 and RMSSD compared to Groups D and T (p < 0.05). As concerns frequency domain parameters, there were no significant differences between groups where low frequency (LF) was decreased in hypnosis group and high frequency (HF) was increased (p > 0.05). However, LF/HF was decreased statistically significantly (p < 0.05) when compared with the midazolam group. CONCLUSIONS: Contrary to standard sedation in TEE patients, when hypnosis is used autonomic cardiac tone is modified to a significant extent. Hypnotic sedation achieves this by increasing the parasympathetic activity, decreasing the sympathetic activity, and changing the sympathovagal interaction balance. PMID- 26620683 TI - Is plasma-soluble CD36 associated with density of atheromatous plaque and ankle brachial index in early-onset coronary artery disease patients? AB - BACKGROUND: CD36 is a major macrophage scavenger receptor for oxidised low density lipoprotein particles. Soluble CD36 (sCD36) is circulating as a ligand bound complex and may be present in microparticles shed from cells such as platelets, monocytes/macrophages, or adipocytes. Positive association of plasma sCD36 with insulin resistance has been reported, and it has been proposed that sCD36 might represent a marker of macrophage activation and inflammation leading to atherosclerosis. Recently we have identified an association between CD36 polymorphism and low thickness of atheromatous plaque, suggesting its protective effect against atherosclerosis development. AIM: To obtain insight into the relationship between plasma concentration of sCD36 and radiological parameters of atherosclerosis in patients with early-onset coronary artery disease (CAD). METHODS: The study group comprised 70 clinically stable patients (18 women and 52 men) with early CAD (aged no more than 50 years for men and 55 years for women). Fasting blood sample was taken for serum glucose, lipid profile, ApoA1, ApoB, Lp(a), and plasma sCD36 protein measurements. Each subject's weight, height, waist and hip circumference, and systolic and diastolic blood pressure were measured, and the body mass index, waist-to-hip ratio, and mean arterial pressure were calculated. Doppler ultrasound examinations of carotid and peripheral arteries were performed in all patients. Thickness of intima-media complex (IMC) of common carotid (CCA) and brachial arteries, as well as density and thickness of atheromatous plaque at CCA bifurcation, were measured with M'Ath programme. Plasma concentrations of CD36 antigen were measured by ELISA. Correlations between quantitative variables and sCD36 plasma concentration were assessed with the Spearman rank correlation coefficient (Rs). Associations between qualitative variables and sCD36 plasma concentration were tested with the Mann-Whitney U test. RESULTS: We observed no significant correlations between sCD36 concentration and radiological parameters of atherosclerosis. We found only borderline significant negative correlation of sCD36 concentration with thickness of IMC of left brachial artery. We also observed a significantly negative correlation with CCA plaque density, but only in the female subgroup and on the right side. Borderline higher sCD36 plasma concentrations were observed in patients with lower ankle-brachial index value (< 0.9). CONCLUSIONS: The results of the study show no strong associations and do not prove either detrimental or beneficial influence of sCD36 on radiological parameters of atherosclerosis. Further research is necessary to assess the association of high plasma sCD36 concentrations with the risk of plaque instability in patients with early-onset CAD. PMID- 26620684 TI - Polish adaptation and reliability testing of the nine-item European Heart Failure Self-care Behaviour Scale (9-EHFScBS). AB - BACKGROUND: According to the guidelines of the European Society of Cardiology, education in heart failure (HF) should focus on preparing the patient for self control and self-care. Only systematic assessment of the level of self-care in HF enables the optimisation and adaptation of education to meet the patient's needs. The research tool commonly used to assess self-care in HF patients is the nine item European Heart Failure Self-care Behaviour Scale (9-EHFScBS). AIM: To test the reliability of the Polish version of the 9-EHFScBS. METHODS: A standard guideline was used for the translation and cultural adaptation of the English version of the 9-EHFScBS into Polish. The study included 110 Polish patients (mean age 66.0 +/- 11.4 years); 51 men and 59 women. Cronbach's alpha was used for the analysis of the internal consistency of the 9-EHFScBS. RESULTS: The mean overall level of self-care in the study group was 27.65 points (SD 7.13 points). Good or satisfactory levels of self-care were found in three out of nine analysed variables. The reliability of the self-care scale was alpha = 0.787. The value of Cronbach's alpha after the exclusion of individual statements ranged from 0.75 to 0.81. CONCLUSIONS: The 9-EHFScBS questionnaire is a reliable research tool in assessing the level of self-care among patients with HF in the Polish population. PMID- 26620685 TI - Utilisation of bivalirudin and vascular closure devices for same-day discharge after percutaneous coronary and peripheral interventions. AB - BACKGROUND: Currently the majority of coronary and peripheral interventions are performed with an overnight stay. This increases the cost and does not reduce logistic constraints on hospital resources. We hypothesised that by combining bivalirudin with vascular closure devices we can safely discharge patients on the same day after percutaneous coronary intervention (PCI) and percutaneous transluminal angioplasty (PTA) without increasing their risk of bleeding. AIM: To evaluate the safety and the feasibility of same-day discharge after PCI and PTA using bivalirudin and vascular closure devices. METHODS: This is a retrospective analysis of 833 consecutive patients who underwent percutaneous procedures in our centre between January 2007 and February 2010. The population was divided into interventional and diagnostic arms. All interventions were done with use of bivalirudin for anticoagulation and vascular closure devices for achieving haemostasis. Haemostasis in the diagnostic cohort was achieved with standard manual compression. The mean time of observation was 30 days. The mean age of patients was 64.3 years. The primary endpoint was any bleeding event meeting GUSTO criteria. The secondary endpoints included local vascular complications, major adverse cardiac and cerebrovascular events, time to ambulation and discharge, as well as need for overnight hospitalisation. RESULTS: In 30-day observation the primary endpoint occurred in 4.0% of patients in the interventional group and in 2.6% of patients in the diagnostic group (p = 0.31). The frequency of local vascular complications was higher in the interventional group although it was not statistically significant (3.1% vs. 2.9%; p = 0.33). Patients from the interventional group were ambulated sooner compared to the diagnostic group (117.5 vs. 131 min; p = 0.003). Time to discharge was 316.4 +/- 38.7 min and 214.2 +/- 23.4 min for interventional and diagnostic procedures, respectively (p < 0.001). CONCLUSIONS: PCI and PTA in the selected group of patients, with use of bivalirudin and vascular closure devices, do not appear to have increased risk of post-procedural events when compared to diagnostic procedures, and can be done safely without the need for an overnight stay. PMID- 26620686 TI - Diagnosing pelvic osteomyelitis beneath pressure ulcers in spinal cord injured patients: a prospective study. AB - There is no consensus on a diagnostic strategy for osteomyelitis underlying pressure ulcers. We conducted a prospective study to assess the accuracy of multiple bone biopsies and imaging to diagnose pelvic osteomyelitis. Patients with clinically suspected osteomyelitis beneath pelvic pressure ulcers were enrolled. Bone magnetic resonance imaging (MRI) and surgical bone biopsies (three or more for microbiology and one for histology per ulcer) were performed. Bacterial osteomyelitis diagnosis relied upon the association of positive histology and microbiology (at least one positive culture for non-commensal microorganisms or three or more for commensal microorganisms of the skin). From 2011 to 2014, 34 patients with 44 pressure ulcers were included. Bacterial osteomyelitis was diagnosed for 28 (82.3%) patients and 35 (79.5%) ulcers according to the composite criterion. Discrepancy was observed between histology and microbiology for 5 (11.4%) ulcers. Most common isolates were Staphylococcus aureus (77.1%), Peptostreptococcus (48.6%) and Bacteroides (40%), cultured in three or more samples in 42.9% of ulcers for S. aureus and >=20% for anaerobes. Only 2.8% of ulcers had three or more positive specimens with coagulase-negative staphylococci, group B Streptococcus, and nil with enterococci and Pseudomonas aeruginosa. Staphylococcus aureus, Proteus and group milleri Streptococcus were recovered from one sample in 22.8%, 11.4% and 11.4% of ulcers, respectively. Agreement was poor between biopsies and MRI (kappa 0.2). Sensitivity of MRI was 94.3% and specificity was 22.2%. The diagnosis of pelvic osteomyelitis relies on multiple surgical bone biopsies with microbiological and histological analyses. At least three bone samples allows the detection of pathogens and exclusion of contaminants. MRI is not routinely useful for diagnosis. PMID- 26620687 TI - Epidemiology of rheumatic diseases in Iran from analysis of four COPCORD studies. AB - AIM: To calculate the epidemiology of Rheumatic Diseases in Iran. MATERIALS AND METHODS: The data of Tehran, Zahedan, Sanandaj (urban) and Tuyserkan (rural) stage Community Oriented Program for the Control of Rheumatic Diseases (COPCORD) studies were gathered. The data were adjusted to the population number of the studied areas to represent Iran. RESULTS: The population of Iran is 75 149 669 (71.5% urban areas, males 50.4%) and of the mentioned area were respectively 10 000 000, 580 071, 311 444 and 109 262. The interviewed subjects were 10 291, 1565, 2100 and 5830. Male/female ratio was 0.9/1, 0.8/1, 08/1 and 0.8/1. Musculoskeletal complaints during the past 7 days (people aged >= 15 years) were detected in 44.7% of subjects. They were: shoulder 15.6%, wrist 10.4%, hands and fingers 10.2%, hip 8.3%, knee 27.4%, ankle 12.3%, toes 6.2%, cervical spine 14.2% and dorsolumbar spine 23.7%. Osteoarthritis (OA) was detected in 16.9%: knee 15.5%, hands 2.9% and hip 0.32%. Low back pain was found in 15.7%, sciatica in 0.94%, and soft tissue rheumatism in 4.6% (shoulder tenosynovitis 2.5%, frozen shoulder 0.56%, tennis elbow 1.2%, golf elbow 0.48%, de Quervain tenosynovitis 0.24%, trigger finger 0.2%, carpal tunnel syndrome 1.3%). Rheumatoid arthritis was detected in 0.37%, seronegative spondyloarthropathy in 0.24%, ankylosing spondylitis in 0.12%, systemic lupus erythematosus in 0.06%, Behcet's disease in 0.08%, fibromyalgia in 0.79% and gout in 0.13%. CONCLUSION: Compared to other COPCORD reports (17 countries), Iran gets the following rank: musculoskeletal complaints second, low back pain fourth, osteoarthritis second, knee osteoarthritis third, soft tissue rheumatism sixth, rheumatoid arthritis tenth, seronegative spondyloarthropathies fifth, gout eleventh and fibromyalgia fifth. PMID- 26620688 TI - Electrophysiological evidence of sublexical phonological access in character processing by L2 Chinese learners of L1 alphabetic scripts. AB - While Chinese character reading relies more on addressed phonology relative to alphabetic scripts, skilled Chinese readers also access sublexical phonological units during recognition of phonograms. However, sublexical orthography-to phonology mapping has not been found among beginning second language (L2) Chinese learners. This study investigated character reading in more advanced Chinese learners whose native writing system is alphabetic. Phonological regularity and consistency were examined in behavioral responses and event-related potentials (ERPs) in lexical decision and delayed naming tasks. Participants were 18 native English speakers who acquired written Chinese after age 5 years and reached grade 4 Chinese reading level. Behaviorally, regular characters were named more accurately than irregular characters, but consistency had no effect. Similar to native Chinese readers, regularity effects emerged early with regular characters eliciting a greater N170 than irregular characters. Regular characters also elicited greater frontal P200 and smaller N400 than irregular characters in phonograms of low consistency. Additionally, regular-consistent characters and irregular-inconsistent characters had more negative amplitudes than irregular consistent characters in the N400 and LPC time windows. The overall pattern of brain activities revealed distinct regularity and consistency effects in both tasks. Although orthographic neighbors are activated in character processing of L2 Chinese readers, the timing of their impact seems delayed compared with native Chinese readers. The time courses of regularity and consistency effects across ERP components suggest both assimilation and accommodation of the reading network in learning to read a typologically distinct second orthographic system. PMID- 26620689 TI - Kaposi sarcoma in HIV-seronegative children presenting to the paediatric oncology ward in The Queen Elizabeth Central Hospital, Blantyre, Malawi during 2002-2014. AB - One of the most common malignancies in HIV-endemic, resource-poor countries is Kaposi sarcoma (KS). It is an AIDS-defining disease and as Malawi's incidence and prevalence of HIV is high, KS is now the most common cancer in adult male Malawians and the second most common in women and children. Most attention has focused on HIV-seropositive adults as their number far outweighs those of children. This audit concerns the presentation and outcome of HIV-seronegative children with KS who presented in a 12-year period (2002-2014) to The Queen Elizabeth Central Hospital. Twenty (10.5%) of the 191 children with KS presenting to the paediatric oncology ward during 2002-2014 were HIV-seronegative. They were usually younger than seropositive children and 62% had severe anaemia. The main presenting complaints in the HIV-seronegative group were woody oedema, commonly of a limb, and lymphadenopathy. Woody oedema was common in children with or without HIV infection. Seronegative children with KS were less likely to have oral KS than HIV infected children. Of 11 children who completed courses of chemotherapy, seven (63%) had complete cure sustained over a 1-year follow-up period. KS is potentially curable in this group of children. Chemotherapy regimens are equally effective in HIV-seropositive and HIV-seronegative children. The presentation of HIV-seronegative children with KS differs from adults and HIV seropositive children. Further research is necessary to determine possible triggers for developing KS in HIV-seronegative children. PMID- 26620691 TI - Company reneges on promise to cut price of toxoplasmosis drug. PMID- 26620690 TI - Cartilage collagen type II seromarker patterns in axial spondyloarthritis and psoriatic arthritis: associations with disease activity, smoking and HLA-B27. AB - The aim of the study was to assess the possible association between type II collagen turnover seromarkers and disease profile in patients with axial spondyloarthritis (SpA) and psoriatic arthritis (PsA). Outpatients with axial SpA (n = 110) or PsA (n = 101) underwent clinical examination including disease activity measures and HLA-B27 typing. The procollagen IIA N-terminal peptide (PIIANP) and a matrix metalloproteinase-generated type II collagen fragment (C2M) were quantified in serum by ELISA. C2M was higher in SpA than in controls, 0.41 versus 0.36 ng/ml (p = 0.004), while PIIANP did not differ between patients and healthy subjects, 2252 versus 2142 ng/ml (p = 0.13). However, DMARD-naive SpA patients had higher PIIANP, 2461 ng/ml (p = 0.01) and C2M, 0.44 ng/ml (p = 0.0007) levels than controls, and PIIANP correlated with CRP (rho = 0.34). C2M was lower in SpA smokers, 0.36 ng/ml versus non-smokers, 0.43 ng/ml (p = 0.02), while PIIANP was higher in HLA-B27 positive, 2312 ng/ml versus negative patients, 2021 ng/ml (p = 0.03). In PsA, PIIANP and C2M did not differ between patients and controls, but PIIANP was elevated in patients not receiving DMARDs, 2726 ng/ml. In PsA, PIIANP and C2M did not differ according to smoking and HLA-B27. Cartilage degradation assessed by C2M is increased in SpA irrespective of treatment but not in PsA. Cartilage synthesis reflected by PIIANP is increased in untreated SpA and PsA. PIIANP correlates with CRP in SpA while not in PsA. In DMARD-naive SpA but not in PsA, HLA-B27 positivity and smoking are associated with a chondro proliferative metabolic pattern. PMID- 26620692 TI - Inhibitory effects of alternaramide on inflammatory mediator expression through TLR4-MyD88-mediated inhibition of NF-kB and MAPK pathway signaling in lipopolysaccharide-stimulated RAW264.7 and BV2 cells. AB - Alternaramide (1), a novel lipophilic depsipeptide, has been isolated from the extract of the marine-derived fungus Alternaria sp. SF-5016. In the course of extensive biological evaluation of 1, its anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW264.7 and BV2 cells were observed. In our initial study of the anti-inflammatory effects of 1, the compound suppressed production of nitric oxide (NO) and prostaglandin E2 (PGE2) in LPS-stimulated RAW264.7 and BV2 cells. Suppression of NO and PGE2 production was correlated with the inhibitory effect of 1 on expression of LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein level in RAW264.7 and BV2 cells. In addition, 1 reduced production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, and IL-12 in LPS-stimulated RAW264.7 and BV2 cells. In the evaluation of the molecular mechanisms underlying the anti-inflammatory effects of 1, the compound was found to suppress the nuclear factor-kappa B (NF-kappaB) signaling pathway in RAW264.7 and BV2 cells stimulated with LPS. This suppression was mediated by disruption of phosphorylation and degradation of IkappaBalpha, an inhibitor of NF-kappaB, in the cytoplasm, and blocking of nuclear translocation of the NF-kappaB p50-p65 heterodimer. Furthermore, 1 inhibited phosphorylation of c-Jun N-terminal kinases (JNKs) and p38 mitogen-activated protein kinase (MAPK), demonstrating its capacity to inhibit MAPK signaling. Finally, 1 markedly reduced expression of Toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88) at the mRNA and protein levels in LPS-stimulated RAW264.7 and BV2 cells. Taken together, the results of the present study suggest that 1 modulates several TLR4-mediated inflammatory pathways, demonstrating its potential in the treatment of inflammatory and neuroinflammatory conditions. PMID- 26620693 TI - The augmented anticancer potential of AP9-cd loaded solid lipid nanoparticles in human leukemia Molt-4 cells and experimental tumor. AB - AP9-cd, a novel lignan composition from Cedrus deodara has significant anticancer potential, and to further enhance its activity, it was lucratively encumbered into solid lipid nanoparticles (SLNs). These nanoparticles were formulated by micro-emulsion technique with 70% drug trap competence. AP9-cd-SLNs were regular, solid, globular particles in the range of 100-200 nm, which were confirmed by electron microscopic studies. Moreover, AP9-cd-SLNs were found to be stable for up to six months in terms of color, particle size, zeta potential, drug content and entrapment. AP9-cd-SLNs have 30-50% higher cytotoxic and apoptotic potential than the AP9-cd alone. The augmented anticancer potential of AP9-cd-SLNs was observed in cytotoxic IC50 value, apoptosis signaling cascade and in Ehrlich ascites tumor (EAT) model. AP9-cd-SLNs induce apoptosis in Molt-4 cells via both intrinsic and extrinsic pathway. Moreover, the dummy nanoparticles (SLNs without AP9-cd) did not have any cytotoxic effect in cancer as well as in normal cells. Consequently, SLNs of AP9-cd significantly augment the apoptotic and antitumor potential of AP9-cd. The present study provides a podium for ornamental the remedial latent via novel delivery systems like solid lipid nanoparticles. PMID- 26620694 TI - Molecular diagnosis of infectious diseases using cytological specimens. AB - Pathologists have an important role in the diagnosis of infectious disease (ID). In many cases, a definitive diagnosis can be made using cytopathology alone. However, several ancillary techniques can be used on cytological material to reach a specific diagnosis by identifying the causative agent and consequently defining the management of the patient. This review aims to present the effectiveness of the application of molecular studies on cytological material to diagnose IDs and discuss the advantages and disadvantages of the various molecular techniques according to the type of cytological specimen and the infectious agents. PMID- 26620695 TI - Case-control or cross-sectional design? Discussing the epidemiological aspects of a recent self-immolation study. PMID- 26620696 TI - The risk for end-stage renal disease is increased after burn. AB - OBJECTIVE: Acute kidney injury (AKI) commonly complicates burn. Recently, AKI has been suggested to be causally related to chronic end-stage renal disease (ESRD), but controversial data also exist. Our aim was to study the risk of ESRD after burn in a nationwide analysis. METHODS: All burn patients undergoing hospitalization between 1998 and 2011 were identified from the National Hospital Discharge Register, and the data were linked with the Finnish Registry for Kidney Diseases, which includes all individuals receiving chronic renal replacement therapy (RRT) in Finland. RESULTS: Altogether 41,179 adults were treated at hospitals for burns in Finland between 1998 and 2011. Of these, 86 had a diagnosis of AKI related to the burn. Forty-three burn survivors had ESRD and RRT initiated related to or after the burn. The overall risk for ESRD after burn was increased (standardized incidence ratio, SIR, 2.40, 95% CI 1.73-3.23) compared with the Finnish population. Standardized incidence ratio was 3.11 (95% CI 1.66 5.32) in women and 1.89 (95% CI 1.27-2.69) in men. Of these 43 patients, 38 had a specific non-burn-related diagnosis of ESRD identified in the registry, and ESRD was deemed unlikely to be directly related to the burn. In five patients, the diagnosis of ESRD was unknown cause of renal failure, and causality of the burn with ESRD was evaluated as plausible. CONCLUSION: In conclusion, a significantly increased risk of ESRD was recorded after a severe burn. Our results do not support increased incidence of ESRD solely as a consequence of AKI due to burn, but burn may increase the risk of ESRD in patients with pre-existing chronic kidney disease. PMID- 26620698 TI - An assessment of data quality in a multi-site electronic medical record system in Haiti. AB - OBJECTIVES: Strong data quality (DQ) is a precursor to strong data use. In resource limited settings, routine DQ assessment (DQA) within electronic medical record (EMR) systems can be resource-intensive using manual methods such as audit and chart review; automated queries offer an efficient alternative. This DQA focused on Haiti's national EMR - iSante - and included longitudinal data for over 100,000 persons living with HIV (PLHIV) enrolled in HIV care and treatment services at 95 health care facilities (HCF). METHODS: This mixed-methods evaluation used a qualitative Delphi process to identify DQ priorities among local stakeholders, followed by a quantitative DQA on these priority areas. The quantitative DQA examined 13 indicators of completeness, accuracy, and timeliness of retrospective data collected from 2005 to 2013. We described levels of DQ for each indicator over time, and examined the consistency of within-HCF performance and associations between DQ and HCF and EMR system characteristics. RESULTS: Over all iSante data, age was incomplete in <1% of cases, while height, pregnancy status, TB status, and ART eligibility were more incomplete (approximately 20 40%). Suspicious data flags were present for <3% of cases of male sex, ART dispenses, CD4 values, and visit dates, but for 26% of cases of age. Discontinuation forms were available for about half of all patients without visits for 180 or more days, and >60% of encounter forms were entered late. For most indicators, DQ tended to improve over time. DQ was highly variable across HCF, and within HCFs DQ was variable across indicators. In adjusted analyses, HCF and system factors with generally favorable and statistically significant associations with DQ were University hospital category, private sector governance, presence of local iSante server, greater HCF experience with the EMR, greater maturity of the EMR itself, and having more system users but fewer new users. In qualitative feedback, local stakeholders emphasized lack of stable power supply as a key challenge to data quality and use of the iSante EMR. CONCLUSIONS: Variable performance on key DQ indicators across HCF suggests that excellent DQ is achievable in Haiti, but further effort is needed to systematize and routinize DQ approaches within HCFs. A dynamic, interactive "DQ dashboard" within iSante could bring transparency and motivate improvement. While the results of the study are specific to Haiti's iSante data system, the study's methods and thematic lessons learned holdgeneralized relevance for other large scale EMR systems in resource-limited countries. PMID- 26620700 TI - Nevirapine modulation of paraoxonase-1 in the liver: An in vitro three-model approach. AB - INTRODUCTION: Nevirapine is associated with severe hepatotoxicity, through the formation of reactive metabolites. Paraoxonase-1 (PON-1) is a promiscuous enzyme involved in the metabolism of xeno- and endobiotics and proposed as a biomarker of hepatotoxicity. The aim of this work was to explore the effects of nevirapine and its phase I metabolites, 2-hydroxy-nevirapine and 12-hydroxy-nevirapine, on PON-1 activities. MATERIAL AND METHODS: 2D and 3D primary cultures of rat hepatocytes, and also HepG2 2D cell cultures, were exposed to nevirapine, 2 hydroxy-nevirapine, and 12-hydroxy-nevirapine. The paraoxonase (POase), arylesterase (AREase) and lactonase (LACase) activities of PON-1 were quantified. RESULTS: Effects of nevirapine and its metabolites were only observed in the 3D cell model. Both nevirapine and 12-hydroxy-nevirapine increased POase (p<0.05, p<0.01) and LACase activities (p<0.05, p<0.001). The AREase activity was increased only upon 12-hydroxy-nevirapine exposure (p<0.01). These modulatory effects were observed at 300MUM concentrations of nevirapine and 12-hydroxy nevirapine. CONCLUSIONS: The formation of 12-hydroxy-nevirapine seems to be the main factor responsible for the increase of PON-1 activities induced by nevirapine exposure. This effect was only observed in the 3D model, suggesting that an in vivo-like system is necessary for this modulation to occur. The present data suggest that the 3D model is a more suitable in vitro model than the conventional ones to explore drug effects on PON-1. PMID- 26620702 TI - Micromonospora ovatispora sp. nov. isolated from mangrove soil. AB - An oval spore-forming actinomycete, designated 2701SIM06T, was isolated from mangrove soil in Sanya, Hainan province, China. The 16S rRNA gene sequence of strain 2701SIM06T showed highest similarity to Micromonospora pattaloongensis TJ2 2T (98.6 %), Micromonospora polyrhachis NEAU-ycm2T (98.6 %) and Micromonospora sonneratiae 274745T (98.5 %). Phylogenetic analysis based on both the 16S rRNA gene and the gyrB gene supported this relationship. The chemotaxonomic results confirmed the isolate as a member of the genus Micromonospora, but morphological, physiological and biochemical properties differentiated it from its closest relatives. Based on these observations, strain 2701SIM06T represents a novel species, for which the name Micromonospora ovatispora sp. nov. is proposed. The type strain is 2701SIM06T ( = CCTCC AA 2012009T = DSM 45759T). PMID- 26620701 TI - Haplotypes of the endothelial protein C receptor (EPCR) gene are not associated with severe malaria in Tanzania. AB - BACKGROUND: Endothelial protein C receptor (EPCR) was recently identified as a key receptor for Plasmodium falciparum erythrocyte membrane protein 1 mediating sequestration of P. falciparum-infected erythrocytes in patients suffering from severe malaria. Soluble EPCR (sEPCR) inhibits binding of P. falciparum to EPCR in vitro and increased levels of sEPCR have been associated with the H3 haplotype of the EPCR encoding PROCR gene. It has been hypothesized that elevated sEPCR levels, possibly linked to the PROCR H3 genetic variant, may confer protection against severe forms of malaria. This study determined the frequencies of PROCR haplotypes H1-4 and plasma levels of sEPCR in a Tanzanian study population to investigate a possible association with severe malaria. METHODS: Study participants were children under 5 years of age admitted at the Korogwe District Hospital (N = 143), and diagnosed as having severe malaria (N = 52; including cerebral malaria N = 17), uncomplicated malaria (N = 24), or an infection other than malaria (N = 67). In addition, blood samples from 71 children living in nearby villages were included. The SNPs defining the haplotypes of PROCR gene were determined by post-PCR ligation detection reaction-fluorescent microsphere assay. RESULTS: Individuals carrying at least one H3 allele had significantly higher levels of sEPCR than individuals with no H3 alleles (P < 0.001). No difference in the frequency of H3 was found between the non-malaria patients, malaria patients or the village population (P > 0.1). Plasma levels of sEPCR differed between these three groups, with higher sEPCR levels in the village population compared to the hospitalized patients (P < 0.001) and higher levels in malaria patients compared to non-malaria patients (P = 0.001). However, no differences were found in the distribution of H3 (P = 0.2) or levels of sEPCR (P = 0.8) between patients diagnosed with severe and uncomplicated malaria. CONCLUSION: Frequencies of SNPs determining PROCR haplotypes were in concordance with other African studies. The PROCR H3 allele was associated with higher levels of sEPCR, confirming earlier findings, however, in this Tanzanian population; neither PROCR haplotype nor level of sEPCR was associated with severe malaria, however, larger studies are needed to confirm these findings. PMID- 26620703 TI - Nebulized bronchodilators and left ventricular outflow obstruction. PMID- 26620704 TI - Clinical metagenomic identification of Balamuthia mandrillaris encephalitis and assembly of the draft genome: the continuing case for reference genome sequencing. AB - BACKGROUND: Primary amoebic meningoencephalitis (PAM) is a rare, often lethal, cause of encephalitis, for which early diagnosis and prompt initiation of combination antimicrobials may improve clinical outcomes. METHODS: In this study, we sequenced a full draft assembly of the Balamuthia mandrillaris genome (44.2 Mb in size) from a rare survivor of PAM, and recovered the mitochondrial genome from six additional Balamuthia strains. We also used unbiased metagenomic next generation sequencing (NGS) and SURPI bioinformatics analysis to diagnose an ultimately fatal case of Balamuthia mandrillaris encephalitis in a 15-year-old girl. RESULTS AND DISCUSSION: Comparative analysis of the mitochondrial genome and high-copy number genes from six additional Balamuthia mandrillaris strains demonstrated remarkable sequence variation, and the closest Balamuthia homologs corresponded to other amoebae, hydroids, algae, slime molds, and peat moss. Real time NGS testing of hospital day 6 CSF and brain biopsy samples detected Balamuthia on the basis of high-quality hits to 16S and 18S ribosomal RNA sequences present in the National Center for Biotechnology Information (NCBI) nt reference database. The presumptive diagnosis of PAM by visualization of amoebae on brain biopsy histopathology and NGS analysis was subsequently confirmed at the US Centers for Disease Control and Prevention (CDC) using a Balamuthia-specific PCR assay. Retrospective analysis of a day 1 CSF sample revealed that more timely identification of Balamuthia by metagenomic NGS, potentially resulting in a better clinical outcome, would have required availability of the complete genome sequence. CONCLUSIONS: These results underscore the diverse evolutionary origins of Balamuthia mandrillaris, provide new targets for diagnostic assay development, and will facilitate further investigations of the biology and pathogenesis of this eukaryotic pathogen. The failure to identify PAM from a day 1 sample without a fully sequenced Balamuthia genome in the database highlights the critical importance of whole-genome reference sequences for microbial detection by metagenomic NGS. PMID- 26620705 TI - The C-terminal Region and SUMOylation of Cockayne Syndrome Group B Protein Play Critical Roles in Transcription-coupled Nucleotide Excision Repair. AB - Cockayne syndrome (CS) is a recessive disorder that results in deficiencies in transcription-coupled nucleotide excision repair (TC-NER), a subpathway of nucleotide excision repair, and cells from CS patients exhibit hypersensitivity to UV light. CS group B protein (CSB), which is the gene product of one of the genes responsible for CS, belongs to the SWI2/SNF2 DNA-dependent ATPase family and has an ATPase domain and an ubiquitin-binding domain (UBD) in the central region and the C-terminal region, respectively. The C-terminal region containing the UBD is essential for the functions of CSB. In this study, we generated several CSB deletion mutants and analyzed the functions of the C-terminal region of CSB in TC-NER. Not only the UBD but also the C-terminal 30-amino acid residues were required for UV light resistance and TC-NER. This region was needed for the interaction of CSB with RNA polymerase II, the translocation of CS group A protein to the nuclear matrix, and the association of CSB with chromatin after UV irradiation. CSB was modified by small ubiquitin-like modifier 2/3 in a UV light dependent manner. This modification was abolished in a CSB mutant lacking the C terminal 30 amino acid residues. However, the substitution of lysine residues in this region with arginine did not affect SUMOylation or TC-NER. By contrast, substitution of a lysine residue in the N-terminal region with arginine decreased SUMOylation and resulted in cells with defects in TC-NER. These results indicate that both the most C-terminal region and SUMOylation are important for the functions of CSB in TC-NER. PMID- 26620706 TI - Intra-tumor heterogeneity in TP53 null High Grade Serous Ovarian Carcinoma progression. AB - BACKGROUND: High grade serous ovarian cancer is characterised by high initial response to chemotherapy but poor outcome in the long term due to acquired resistance. One of the main genetic features of this disease is TP53 mutation. The majority of TP53 mutated tumors harbor missense mutations in this gene, correlated with p53 accumulation. TP53 null tumors constitute a specific subgroup characterised by nonsense, frameshift or splice-site mutations associated to complete absence of p53 expression. Different studies show that this kind of tumors may have a worse prognosis than other TP53 mutated HGSC. METHODS: In this study, we sought to characterise the intra-tumor heterogeneity of a TP53 null HGSC consisting of six primary tumor samples, two intra-pelvic and four extra pelvic recurrences using exome sequencing and comparative genome hybridisation. RESULTS: Significant heterogeneity was found among the different tumor samples, both at the mutational and copy number levels. Exome sequencing identified 102 variants, of which only 42 were common to all three samples; whereas 7 of the 18 copy number changes found by CGH analysis were presented in all samples. Sanger validation of 20 variants found by exome sequencing in additional regions of the primary tumor and the recurrence allowed us to establish a sequence of the tumor clonal evolution, identifying those populations that most likely gave rise to recurrences and genes potentially involved in this process, like GPNMB and TFDP1. Using functional annotation and network analysis, we identified those biological functions most significantly altered in this tumor. Remarkably, unexpected functions such as microtubule-based movement and lipid metabolism emerged as important for tumor development and progression, suggesting its potential interest as therapeutic targets. CONCLUSIONS: Altogether, our results shed light on the clonal evolution of the distinct tumor regions identifying the most aggressive subpopulations and at least some of the genes that may be implicated in its progression and recurrence, and highlights the importance of considering intra-tumor heterogeneity when carrying out genetic and genomic studies, especially when these are aimed to diagnostic procedures or to uncover possible therapeutic strategies. PMID- 26620707 TI - Bromodomain containing protein represses the Ras/Raf/MEK/ERK pathway to attenuate human hepatoma cell proliferation during HCV infection. AB - Hepatitis C virus (HCV) infection facilitates the development of hepatocellular carcinoma (HCC). Activation of Ras/Raf/MEK/ERK pathway is found in more than 30% human cancers. Here, we revealed a novel mechanism underlying the regulation of hepatoma cell proliferation mediated by HCV. On one hand, hepatoma cell proliferation is facilitated by HCV infection through a positive feedback regulatory cycle. HCV promotes hepatoma cell proliferation by activating the Ras/Raf/MEK/ERK pathway, which in turn facilitates HCV replication to further enhance hepatoma cell proliferation. On the other hand, hepatoma cell proliferation is attenuated by the bromodomain containing 7 (BRD7), a tumor suppressor, through a negative feedback regulatory mechanism. After activation, the Ras/Raf/MEK/ERK pathway stimulates BRD7 production, which in turn represses the Ras/Raf/MEK/ERK pathway, leading to the attenuation of hepatoma cell proliferation. However, HCV persistent infection attenuates BRD7 gene expression and facilitates the protein degradation to release the Ras/Raf/MEK/ERK signaling, which results in the facilitation of hepatoma cell proliferation. Therefore, we proposed that the balance between BRD7 function and Ras/Raf/MEK/ERK activity is important for determining the outcomes of HCV infection and HCC development. PMID- 26620708 TI - Loss of labelling efficiency caused by carotid stent in pseudocontinuous arterial spin labelling perfusion study. AB - AIM: To elucidate the cause of cerebral hypoperfusion on the stent placement side after carotid artery stent placement (CAS) measured by pseudocontinuous arterial spin labelling (PCASL) perfusion imaging. MATERIALS AND METHODS: Consecutive patients with symptomatic internal carotid artery stenosis receiving CAS were included in the study. Cerebral blood flow (CBF) was measured by PCASL perfusion imaging at 3 T magnetic resonance imaging (MRI) the day before and 3 days after the procedure. Changes in cerebral haemodynamics after CAS were assessed. RESULTS: Twenty-two patients were included; 17 patients had increased or stationary CBF after CAS and five patients had significantly reduced CBF on the stenting side after CAS whereas CBF increased on the contralateral side. High stent position was noticed in the five patients. After labelling plane adjustment to avoid labelling on the stent, no more cerebral hypoperfusion was noticed. CONCLUSION: When using PCASL perfusion imaging to monitor post-stenting CBF, the stent may cause an artefact that leads to a low CBF in the territory of the stented vessel. Routinely adding a fast T2 star gradient-echo echo-planar-imaging covering the upper neck region before PCASL perfusion imaging to identify the stent position and avoid the stent-related artefact is recommended. PMID- 26620709 TI - Systems thinking and complexity: considerations for health promoting schools. AB - The health promoting schools concept reflects a comprehensive and integrated philosophy to improving student and personnel health and well-being. Conceptualized as a configuration of interacting, interdependent parts connected through a web of relationships that form a whole greater than the sum of its parts, school health promotion initiatives often target several levels (e.g. individual, professional, procedural and policy) simultaneously. Health promoting initiatives, such as those operationalized under the whole school approach, include several interconnected components that are coordinated to improve health outcomes in complex settings. These complex systems interventions are embedded in intricate arrangements of physical, biological, ecological, social, political and organizational relationships. Systems thinking and characteristics of complex adaptive systems are introduced in this article to provide a perspective that emphasizes the patterns of inter-relationships associated with the nonlinear, dynamic and adaptive nature of complex hierarchical systems. Four systems thinking areas: knowledge, networks, models and organizing are explored as a means to further manage the complex nature of the development and sustainability of health promoting schools. Applying systems thinking and insights about complex adaptive systems can illuminate how to address challenges found in settings with both complicated (i.e. multi-level and multisite) and complex aspects (i.e. synergistic processes and emergent outcomes). PMID- 26620710 TI - ZnO modified ZSM-5 and Y zeolites fabricated by atomic layer deposition for propane conversion. AB - ZnO modified ZSM-5 and Y zeolites are synthesized by performing atomic layer deposition (ALD) of ZnO to HZSM-5 and HY using diethyl zinc and water as the precursors. The surface area and pore volume of ZSM-5 and Y zeolites are progressively reduced with the increasing number of ZnO ALD cycles. XRD and SEM characterization methods show that highly dispersed ZnO species are deposited on the internal and external surfaces of both zeolites. The ZnO species deposited on ZSM-5 are in an amorphous form while nano-crystallites of ZnO are present on Y zeolites after performing >=2 cycles of ZnO ALD. XPS and TPR characterization methods reveal that isolated Zn(OH)(+) species are predominantly formed on both zeolites after the first cycle of ZnO ALD and the ZnO clusters gradually grow larger with the increasing number of ALD cycles. The type and strength of acid sites on the parent and the ALD ZnO modified zeolites are studied by FTIR spectra of adsorbed pyridine. Incorporation of ZnO into Y zeolite by ALD completely eliminates the Bronsted acid sites and increases the number of strong Lewis acid sites. Similar effects are obtained on ALD ZnO modified ZSM-5 except that the Bronsted acid sites are only partially removed. Catalytic properties of the ALD ZnO modified zeolites are evaluated in propane conversion. Introduction of ZnO species significantly improves the activities of both zeolites. Propylene is the major reaction product on ALD ZnO modified Y zeolite while high selectivities to aromatics are achieved on ALD ZnO modified ZSM-5. These results suggest that ZnO species merely promote the dehydrogenation reaction while the subsequent oligomerization and cyclization reactions require Bronsted acid sites. For both zeolites the catalyst fabricated by only 1 or 2 cycles of ZnO ALD performs better than those fabricated by multiple cycles of ALD, indicating that isolated Zn(OH)(+) species are more effective for the conversion of propane to propylene and aromatics. PMID- 26620711 TI - Development of a resilience scale for Thai substance-dependent women: A mixed methods approach. AB - The purpose of this study was to develop a resilience scale based on the experiences of substance-dependent women in Thailand and evaluate its validity and reliability. A sequential exploratory mixed methods design was employed as the main methodology to develop the resilience scale according to the results from qualitative data by analyzing focus group discussions of 13 participants. Then, the scale was administered to 252 substance-dependent women from four substance-treatment centers. The psychometric properties were explored with an index of item objective congruence (IOC), Pearson correlation, second-order confirmatory factor analysis and Cronbach's alpha coefficient to estimate the quantitative data. The qualitative results showed that resilience is defined by three themes: individual, family and community factors, consisted of 13 different categories. The quantitative results also revealed that all 71 items in the resilience scale passed the IOC criteria, convergence and construct validity. The goodness-of-fit indices demonstrated that the resilience model was consistent with the empirical data. (Chi-square=74.28, df=59, p-value=0.08, RMSEA=0.03, SRMR=0.04, NNFI=0.99, CFI=0.99, GFI=0.96). The internal consistency, assessed by a Cronbach's alpha score of 0.92, can be interpreted as demonstrating high reliability. Furthermore, the structure of the resilience scale was confirmed by the available resilience literature. This study can help clinicians gain a more comprehensive understanding regarding the complex process of resilience among substance-dependent women and aid them in providing these women with the appropriate interventions. PMID- 26620712 TI - The first microbial environment of infants born by C-section: the operating room microbes. AB - BACKGROUND: Newborns delivered by C-section acquire human skin microbes just after birth, but the sources remain unknown. We hypothesized that the operating room (OR) environment contains human skin bacteria that could be seeding C section born infants. RESULTS: To test this hypothesis, we sampled 11 sites in four operating rooms from three hospitals in two cities. Following a C-section procedure, we swabbed OR floors, walls, ventilation grids, armrests, and lamps. We sequenced the V4 region of the 16S rRNA gene of 44 samples using Illumina MiSeq platform. Sequences were analyzed using the QIIME pipeline. Only 68 % of the samples (30/44, >1000 sequences per site) yielded sufficient DNA reads to be analyzed. The bacterial content of OR dust corresponded to human skin bacteria, with dominance of Staphylococcus and Corynebacterium. Diversity of bacteria was the highest in the ventilation grids and walls but was also present on top of the surgery lamps. Beta diversity analyses showed OR dust bacterial content clustering first by city and then by hospital (t test using unweighted UniFrac distances, p < 0.05). CONCLUSIONS: We conclude that the dust from ORs, collected right after a C-section procedure, contains deposits of human skin bacteria. The OR microbiota is the first environment for C-section newborns, and OR microbes might be seeding the microbiome in these babies. Further studies are required to identify how this OR microbiome exposure contributes to the seeding of the neonatal microbiome. The results might be relevant to infant health, if the current increase in risk of immune and metabolic diseases in industrialized societies is related to lack of natural exposure to the vaginal microbiome during labor and birth. PMID- 26620713 TI - High-fat-diet-induced obesity is associated with decreased antiinflammatory Lactobacillus reuteri sensitive to oxidative stress in mouse Peyer's patches. AB - OBJECTIVE: Diet-induced inflammation in the small intestine may represent an early event that precedes and predisposes to obesity and insulin resistance. This is related to decrease of lactobacilli in Peyer's patches (PP) revealed in our previous study. The present study aimed to clarify specific changes of PP Lactobacillus on the strain level and related biological activity. METHODS: C57 BL/6 J male mice were fed with either low-fat diet (control [CT]; 10% calories from fat) or high-fat diet (HFD; 50% calories from fat) for 25 wk, and the HFD fed mice were classified into obesity prone (OP) or obesity resistant (OR) on the basis of their body weight gain. Lactobacillus was isolated from PP using a selective medium. Oxidative resistance and cytokine-inducing effect were analyzed in vitro. RESULTS: We obtained 52, 18, and 22 isolates from CT, OP, and OR mice, respectively. They belonged to 13 different types according to enterobacterial repetitive intergenic consensus sequence-PCR analysis. Lactobacillus reuteri was the most abundant strain, but its abundance in OP mice was much lower than that in CT and OR mice. This strain includes eight subgroups according to genotyping. L. reuteri L3 and L. reuteri L8 were the specific strains found in CT and OP mice, respectively. Oxidative-resistant L. reuteri was much higher in HFD-fed mice. When co-cultured with PP cells, L8 induced higher production of proinflammatory cytokines such as interleukin (IL)-6, IL-12, and tumor necrosis factor-alpha, whereas L3 induced higher production of an anti-inflammatory cytokine (IL-10). CONCLUSION: HFD may induce oxidative stress that drives strain selection of Lactobacillus strains, resulting in decreased anti-inflammatory response in PP. PMID- 26620714 TI - Exploratory analysis of diffusion tensor imaging in children with attention deficit hyperactivity disorder: evidence of abnormal white matter structure. AB - Abnormalities in the white matter microstructure of the attentional system have been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Diffusion tensor imaging (DTI) is a promising magnetic resonance imaging (MRI) technology that has increasingly been used in studies of white matter microstructure in the brain. The main objective of this work was to perform an exploratory analysis of white matter tracts in a sample of children with ADHD versus typically developing children (TDC). For this purpose, 13 drug-naive children with ADHD of both genders underwent MRI using DTI acquisition methodology and tract-based spatial statistics. The results were compared to those of a sample of 14 age- and gender-matched TDC. Lower fractional anisotropy was observed in the splenium of the corpus callosum, right superior longitudinal fasciculus, bilateral retrolenticular part of the internal capsule, bilateral inferior fronto-occipital fasciculus, left external capsule and posterior thalamic radiation (including right optic radiation). We conclude that white matter tracts in attentional and motor control systems exhibited signs of abnormal microstructure in this sample of drug-naive children with ADHD. PMID- 26620715 TI - Impact of alterations in target vessel curvature on branch durability after endovascular repair of thoracoabdominal aortic aneurysms. AB - OBJECTIVE: The aim of this study was to evaluate curvature and its effect on the durability of visceral and renal branches in patients undergoing endovascular repair of thoracoabdominal aortic aneurysms (TAAAs) with fenestrated/branched endovascular aneurysm repair (F/B-EVAR). METHODS: Quantitative branch vessel curvature assessment on branches arising from reinforced fenestrations was performed for 168 patients undergoing F/B-EVAR for type II and type III TAAAs. Preoperative and postoperative centerline coordinates were obtained using iNtuition (TeraRecon, Foster City, Calif) and exported into MATLAB (The MathWorks, Inc, Natick, Mass) based on thin-slice computed tomography imaging. Spline interpolation was applied to the centerline coordinates and resampled at 100 equally spaced points, and curvature calculations (kappa, mm(-1)) were applied. Global and maximal curvatures for each of the target vessels were measured and categorized by severity. Categories for curvature were 0 to 0.05 mm( 1) (low), 0.05 to 0.1 mm(-1) (medium), 0.1 to 0.15 mm(-1) (high), and >0.15 mm( 1) (extreme) for global curvature and 0 to 0.2 mm(-1), 0.2 to 0.4 mm(-1), 0.4 to 0.6 mm(-1), and >0.6 mm(-1), respectively, for maximum curvature. Curvature variances were assessed for an association with vessel patency and need for reintervention. RESULTS: There were 558 vessels that underwent analysis based on repairs involving 650 vessels, whereby 92 vessels were excluded as they were treated with an external helical branch (58 celiac arteries and 34 superior mesenteric arteries). There was a significant difference found before and after F/B-EVAR for the global celiac artery curvature (median difference, -0.01; P < .001), global left renal artery curvature (median, -0.01; P = .014), maximum left renal artery curvature (median, 0.05; P < .001), and maximum right renal artery curvature (median, 0.03; P = .009). Maximum artery curvature was found to have shifted distally in all vessels postoperatively; 37 adverse events (AEs) were observed in 30 patients (6 branched occlusions and 31 reinterventions [24 type III endoleaks, 5 vessel stenoses, and 2 vessel occlusions]). The majority of AEs (>70%) occurred within the range of low to medium curvature. Univariate analysis found gender to be a dependent variable associated with high (maximum) preoperative curvature (odds ratio, 0.395; P = .02). The use of self-expanding stents (vs balloon-expandable stents alone) in vessels with high preoperative curvature (>0.6 mm(-1)) was significant in the right renal artery (P = .044). CONCLUSIONS: This study did not show a significant relationship between the severity of artery curvature or changes in curvature and AEs found for visceral or renal branches after F/B-EVAR for extensive TAAA. Surprisingly, the majority of AEs occurred in low- and medium-curved vessels. This study is limited in that it does not take into account other factors that may affect AEs, like motion, which would be valuable in future studies. PMID- 26620717 TI - Pd(II)-catalyzed intramolecular oxidative Heck dearomative reaction: approach to thiazole-fused pyrrolidinones with a C2-azaquarternary center. AB - A Pd(II)-catalyzed intramolecular oxidative Heck dearomative reaction for the construction of thiazole-fused pyrrolidinones with a C2-azaquarternary center and C3-exo-double bond has been achieved for the first time. The reaction exhibited good functional group tolerance and gram-scale capacity. PMID- 26620716 TI - Characterization of tibial velocities by duplex ultrasound in severe peripheral arterial disease and controls. AB - BACKGROUND: The relationship between tibiopopliteal velocities and peripheral arterial disease (PAD) severity is not well understood. We sought to characterize tibiopopliteal velocities in severe PAD and non-PAD control patients. METHODS: Patients with an arterial duplex ultrasound (DUS) examination with PAD evaluated during a 5-year period were retrospectively compared with non-PAD controls. Control DUS examinations were collected sequentially during a 6-month period, retrospectively. PAD patients included those with lifestyle-limiting intermittent claudication warranting revascularization and patients with critical limb ischemia, defined as ischemic rest pain, gangrene, or a nonhealing ischemic ulcer. For each, tibial and popliteal artery peak systolic velocity (PSV) was measured at the proximal, mid, and distal segment of each artery, and a mean PSV for each artery was calculated. Mean PSV, ankle-brachial indices, peak ankle velocity (PAV), average ankle velocity (AAV), mean tibial velocity (MTV), and ankle-profunda index (API) were compared between the two groups using independent t-tests. PAV is the maximum PSV of the distal peroneal, posterior tibial (PT), or anterior tibial (AT) artery; AAV is the average PSV of the distal peroneal, PT, and AT arteries; MTV is calculated by first averaging the proximal, mid, and distal PSV for each tibial artery and then averaging the three means together; API is the AAV divided by proximal PSV of the profunda. RESULTS: DUS was available in 103 patients with PAD (68 patients with critical limb ischemia and 35 patients with intermittent claudication) and 68 controls. Mean ankle-brachial index in the PAD group was 0.64 +/- 0.25 compared with 1.08 +/- 0.09 in controls (P = .006). Mean PSVs were significantly lower in PAD patients than in controls at the popliteal (64.6 +/- 42.2 vs 76.2 +/- 29.6; P = .037), peroneal (34.3 +/- 26.4 vs 53.8 +/- 23.3; P < .001), AT (43.7 +/- 31.4 vs 65.4 +/- 25.0; P < .001), and PT (43.4 +/- 42.3 vs 74.1 +/- 30.6; P < .001) and higher at the profunda (131.5 +/- 88.0 vs 96.2 +/- 44.8; P = .001). Tibial parameters including PAV (52.6 +/- 45.0 vs 86.9 +/- 35.7; P < .001), AAV (37.4 +/- 26.4 vs 64.5 +/- 21.7; P < .001), MTV (41.7 +/- 30.4 vs 65.4 +/- 21.7; P < .001), and API (0.43 +/- 0.45 vs 0.75 +/- 0.30; P < .001) were significantly lower in the PAD group than in controls. Nonoverlapping 95% confidence interval reference ranges were established for severe PAD and non-PAD controls. CONCLUSIONS: This study aims to characterize lower extremity arterial PSVs and ankle parameters in severe PAD and non-PAD controls. These early criteria establish reference ranges to guide vascular laboratory interpretation and clinical decision-making. PMID- 26620718 TI - Design, synthesis and preliminary biological studies of pyrrolidine derivatives as Mcl-1 inhibitors. AB - Anti-apoptotic proteins, such as B-cell lymphoma (Bcl-2) protein, myeloid cell leukemia sequence 1 (Mcl-1) protein, are potential targets for cancer treatment. In the studies, a series of pyrrolidine derivatives were developed as potent Mcl 1 inhibitors. The preliminary biological studies suggested that most of target compounds exhibit good abilities for targeting Mcl-1 protein. Among them, compound 21 (Ki=0.53MUM) exhibited equal inhibitory activities towards Mcl-1 protein compared to positive control gossypol (Ki=0.39MUM). This compound also possessed good antiproliferative activities against MDA-MB-231 and PC-3 cancer cells. PMID- 26620719 TI - Language Problems Among Abused and Neglected Children: A Meta-Analytic Review. AB - Research data show that exposure to abuse and neglect has detrimental effects on a child's language development. In this meta-analysis, we analyze studies (k = 23), to compare the language skills (receptive language, expressive language, pragmatics) of children who have experienced abuse and/or neglect with the language skills of children who have not experienced abuse and/or neglect and to examine whether age or type of maltreatment moderate the relationship between maltreatment and language skills. Results confirm that the language skills of children who have experienced abuse and/or neglect are delayed when compared to children who have not experienced abuse and/or neglect. Compared to older children, young children seem particularly vulnerable to abuse and neglect. No significant differences were demonstrated concerning the type of maltreatment suffered by the child. These findings support the necessity of early detection of language problems in abused and neglected children as well as early intervention in order to implement interventions that will positively stimulate their development. PMID- 26620721 TI - Facile Synthesis of Folic Acid-Modified Iron Oxide Nanoparticles for Targeted MR Imaging in Pulmonary Tumor Xenografts. AB - PURPOSE: The purpose of this study was to develop folic acid (FA)-modified iron oxide (Fe3O4) nanoparticles (NPs) for targeted magnetic resonance imaging (MRI) of H460 lung carcinoma cells. PROCEDURES: Water-dispersible Fe3O4 NPs synthesized via a mild reduction method were conjugated with FA to generate FA-targeted Fe3O4 NPs. The specificity of FA-targeted Fe3O4 NPs to bind FA receptor was investigated in vitro by cellular uptake and cell MRI and in vivo by MRI of H460 tumors. RESULTS: The formed NPs displayed good biocompatibility and ultrahigh r 2 relaxivity (440.01/mM/s). The targeting effect of the NPs to H460 cells was confirmed by in vitro cellular uptake and cell MRI. H460 tumors showed a significant reduction in T2 signal intensity at 0.85 h, which then recovered and returned to control at 2.35 h. CONCLUSIONS: The results indicate that the prepared FA-targeted Fe3O4 NPs have potential to be used as T2 negative contrast agents in targeted MRI. PMID- 26620720 TI - Which adolescents develop persistent substance dependence in adulthood? Using population-representative longitudinal data to inform universal risk assessment. AB - BACKGROUND: To our knowledge, there are no universal screening tools for substance dependence that (1) were developed using a population-based sample, (2) estimate total risk briefly and inexpensively by incorporating a relatively small number of well-established risk factors, and (3) aggregate risk factors using a simple algorithm. We created a universal screening tool that incorporates these features to identify adolescents at risk for persistent substance dependence in adulthood. METHOD: Participants were members of a representative cohort of 1037 individuals born in Dunedin, New Zealand in 1972-1973 and followed prospectively to age 38 years, with 95% retention. We assessed a small set of childhood and adolescent risk factors: family history of substance dependence, childhood psychopathology (conduct disorder, depression), early exposure to substances, frequent substance use in adolescence, sex, and childhood socioeconomic status. We defined the outcome (persistent substance dependence in adulthood) as dependence on one or more of alcohol, tobacco, cannabis, or hard drugs at ?3 assessment ages: 21, 26, 32, and 38 years. RESULTS: A cumulative risk index, a simple sum of nine childhood and adolescent risk factors, predicted persistent substance dependence in adulthood with considerable accuracy (AUC = 0.80). CONCLUSIONS: A cumulative risk score can accurately predict which adolescents in the general population will develop persistent substance dependence in adulthood. PMID- 26620722 TI - Validity, specificity, feasibility and acceptability of a brief pediatric distress thermometer in outpatient clinics. AB - OBJECTIVE: Psychosocial distress is under-recognized in children with cancer and other serious medical illnesses because of a focus on pressing medical concerns. AIMS: This study assessed the validity, inter-rater reliability, sensitivity/specificity, acceptability, and feasibility of administration of a pediatric distress thermometer (DT) designed to screen for the presence of psychosocial distress in youth with serious medical illnesses. MATERIALS & METHODS: Two hundred eighty-one patient-caregiver-provider triads were enrolled from two hospital outpatient clinics. Patients diagnosed with cancer and other life-threatening diseases, caregivers, and providers completed the DT and a DT acceptability rating. Patients and caregivers completed standardized measures of anxiety, depression, pain, and fatigue. Providers completed a measure of disease severity. Data collectors completed a feasibility rating. RESULTS: The DT was significantly correlated with both caregiver and patient reports of depression, anxiety, pain, and fatigue, exhibiting concurrent validity. Parent, child, and caregiver report demonstrated significant, moderate inter-rater reliability, with lower concordance between raters in the youngest age group. The DT is a sensitive instrument for screening of psychosocial distress when compared with the selected gold standard (Brief Symptom Inventory 18 depression subscale and the Children's Depression Inventory). The DT is not highly specific but quickly identifies those in need of further psychosocial assessment. DISCUSSION: Screening, using an adapted pediatric DT, is valid, feasible, and acceptable to patients, caregivers, and medical providers across chronic medical illnesses. CONCLUSION: As patient and caregiver reports are not always concordant, both patient and caregiver report of distress are important for the provider to obtain clinically meaningful information to guide interventions. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. PMID- 26620723 TI - A Chemokine Receptor, CXCR4, Which Is Regulated by Hypoxia-Inducible Factor 2alpha, Is Crucial for Functional Endothelial Progenitor Cells Migration to Ischemic Tissue and Wound Repair. AB - Endothelial progenitor cells (EPCs) have the ability to form new blood vessels and protect ischemic tissues from damage. We previously reported that EPCs with low activity of aldehyde dehydrogenase (Alde-Low EPCs) possess the greater ability to treat ischemic tissues compared with Alde-High EPCs. The expression level of the hypoxia-inducible factors (HIFs), HIF-1alpha and HIF-2alpha, was found to be greater in Alde-Low EPCs than in Alde-High EPCs. However, the precise role of the HIF factors in the regulation of EPC activity remains obscure. In this study, we demonstrate a critical role of HIF-2alpha and its target gene CXCR4 for controlling the migratory activity of EPC to ischemic tissue. We found that coculture of Alde-High EPCs with microvesicles derived from Alde-Low EPCs improved their ability to repair an ischemic skin flap, and the expression of CXCR4 and its ligand SDF1 was significantly increased following the coculture. In Alde-Low EPCs, the expression of CXCR4 was suppressed by short hairpin RNA (shRNA)-mediated HIF-2alpha, but not HIF-1alpha downregulation. Chromatin immunoprecipitation assays showed that HIF-2alpha, but not HIF-1alpha, binds to the promoter region of CXCR4 gene. The CXCR4 shRNA treatment in Alde-Low EPCs almost completely abrogated their migratory activity to ischemic tissues, whereas the reduction of vascular endothelial growth factor (VEGF) showed much less effect. The CXCR4 overexpression in Alde-High EPCs resulted in a partial, but significant improvement in their repairing ability in an ischemic skin flap. Collectively, these findings indicate that the CXCR4/SDF-1 axis, which is specifically regulated by HIF-2alpha, plays a crucial role in the regulation of EPC migration to ischemic tissues. PMID- 26620724 TI - Emergency general surgery in the geriatric patient. AB - BACKGROUND: Emergency general surgery in the elderly is a particular challenge to the surgeon in charge of their care. The aim was to review contemporary aspects of managing elderly patients needing emergency general surgery and possible alterations to their pathways of care. METHODS: This was a narrative review based on a PubMed/MEDLINE literature search up until 15 September 2015 for publications relevant to emergency general surgery in the geriatric patient. RESULTS: The number of patients presenting as an emergency with a general surgical condition increases with age. Up to one-quarter of all emergency admissions to hospital may be for general surgical conditions. Elderly patients are a particular challenge owing to added co-morbidity, use of drugs and risk of poor outcome. Frailty is an important potential risk factor, but difficult to monitor or manage in the emergency setting. Risk scores are not available universally. Outcomes are usually severalfold worse than after elective surgery, in terms of both higher morbidity and increased mortality. A care bundle including early diagnosis, resuscitation and organ system monitoring may benefit the elderly in particular. Communication with the patient and relatives throughout the care pathway is essential, as indications for surgery, level of care and likely outcomes may evolve. Ethical issues should also be addressed at every step on the pathway of care. CONCLUSION: Emergency general surgery in the geriatric patient needs a tailored approach to improve outcomes and avoid futile care. Although some high quality studies exist in related fields, the overall evidence base informing perioperative acute care for the elderly remains limited. PMID- 26620725 TI - GnRH-agonist implantation of prepubertal male cats affects their reproductive performance and testicular LH receptor and FSH receptor expression. AB - This study was conducted to investigate the effect of GnRH-agonist implantation in prepubertal tomcats on sexual behavior, reproductive performance, and expression of testicular LH receptor (LHR) and FSH receptor (FSHR) and also to compare the testicular characteristics, LHR and FSHR expression between prepubertal and adult tomcats. In experiment 1, 3-month-old tomcats (n = 6/group) were either treated with or left without 4.7 mg deslorelin implants. Semen collection and evaluation were performed just before castration at 48 weeks after treatment; removed testes were analyzed for mRNA and protein expression of LHR and FSHR. We were able to collect semen from six non-treated cats, whereas in treated cats, semen was uncollectable. The results revealed that sexual behavior was absent in the implanted cats throughout the study period. Testicular volume was found to decrease from 30 weeks after treatment onward in the implanted cats compared to the controls (P < 0.05). Semen production was found only in non implanted cats. Testicular tissue score, seminiferous tubule diameter, and LHR protein expression were found lower in the implanted cats (P < 0.05), but no differences were observed in mRNA expression of LHR and protein expression of FSHR between groups. The mRNA expression of FSHR was higher in the implanted (P < 0.05) compared to control cats. In experiment 2, testes from prepubertal (n = 6) and adult (n = 6) male cats were collected after castration and analyzed for mRNA and protein expression of LHR and FSHR. No differences were observed in the protein expression of LHR and FSHR between the two groups, whereas mRNA expression of FSHR was higher in prepubertal cats (P < 0.05). Testicular and epididymal weight, diameter of seminiferous tubules, and the testicular grade were higher in the adult compared to prepubertal cats (P < 0.05). In conclusion, deslorelin implants suppressed protein expression of LHR and enhanced mRNA expression of FSHR along with suppression of reproductive function without any adverse effects for at least 48 weeks in male cats. PMID- 26620726 TI - MicroRNAs: Modulators of the Ras Oncogenes in Oral Cancer. AB - Oral squamous cell carcinoma (OSCC) of the head and neck is one of the six most common cancers in the world. OSCC remains the most common cause of cancer deaths in Asian countries. Conventional treatments for OSCC have not improved the overall 5 years survival and therefore alternative therapeutic targets are often sought. Ras is one of the most frequently deregulated oncogenes in oral cancer. Direct targeting the ras has proven unrealistic and hence, exploring and understanding alternative pathways and/or molecules which regulate ras and its signaling that could pave the way for novel molecular targets and therapy for oral cancer. Recently, microRNAs (miRNAs) have been reported to regulate ras oncogenes in human cancers. In this article, we address the microRNA-mediated regulation of the ras oncogenes in oral cancer. We describe extensively the tumor suppressive and oncogenic roles of miRNAs in regulation of ras oncogenes in OSCC. We also discuss the role of miRNA-mediated ras regulation in therapeutic determination of oral cancer. Complete understanding of the miRNA regulation of ras oncogenes in oral cancer may facilitate to plan better strategies for diagnosis, molecular therapeutic targeting and the overall prognosis of this common and deadly cancer. PMID- 26620727 TI - Astronomical and Hydrological Perspective of Mountain Impacts on the Asian Summer Monsoon. AB - The Asian summer monsoon has great socioeconomic impacts. Understanding how the huge Tibetan and Iranian Plateaus affect the Asian summer monsoon is of great scientific value and has far-reaching significance for sustainable global development. One hypothesis considers the plateaus to be a shield for monsoon development in India by blocking cold-dry northerly intrusion into the tropics. Based on astronomical radiation analysis and numerical modeling, here we show that in winter the plateaus cannot block such a northerly intrusion; while in summer the daily solar radiation at the top of the atmosphere and at the surface, and the surface potential temperature to the north of the Tibetan Plateau, are higher than their counterparts to its south, and such plateau shielding is not needed. By virtue of hydrological analysis, we show that the high energy near the surface required for continental monsoon development is maintained mainly by high water vapor content. Results based on potential vorticity-potential temperature diagnosis further demonstrate that it is the pumping of water vapor from sea to land due to the thermal effects of the plateaus that breeds the Asian continental monsoon. PMID- 26620728 TI - Eyewitness to history: Landmarks in the development of computerized electrocardiography. AB - The use of digital computers for ECG processing was pioneered in the early 1960s by two immigrants to the US, Hubert Pipberger, who initiated a collaborative VA project to collect an ECG-independent Frank lead data base, and Cesar Caceres at NIH who selected for his ECAN program standard 12-lead ECGs processed as single leads. Ray Bonner in the early 1970s placed his IBM 5880 program in a cart to print ECGs with interpretation, and computer-ECG programs were developed by Telemed, Marquette, HP-Philips and Mortara. The "Common Standards for quantitative Electrocardiography (CSE)" directed by Jos Willems evaluated nine ECG programs and eight cardiologists in clinically-defined categories. The total accuracy by a representative "average" cardiologist (75.5%) was 5.8% higher than that of the average program (69.7, p<0.001). Future comparisons of computer-based and expert reader performance are likely to show evolving results with continuing improvement of computer-ECG algorithms and changing expertise of ECG interpreters. PMID- 26620729 TI - Coronary microvascular dysfunction is associated with baseline QTc prolongation amongst patients with chest pain and non-obstructive coronary artery disease. AB - BACKGROUND: Coronary microvascular dysfunction (CMD) causes ischemia and is linked to adverse cardiovascular events. Acute transmural ischemia is associated with QT prolongation, but whether CMD affects repolarization is unknown. The aim of this study was to determine if CMD is associated with prolongation of resting heart rate corrected QT interval (QTc). METHODS: In patients presenting to the catheterization laboratory with chest pain and non-obstructive coronary artery disease (CAD) at angiography, coronary flow reserve (CFR) in response to intracoronary adenosine was measured and compared to baseline to give a CFR ratio. The Bazett's-derived QTc was manually derived from patients' 12-lead ECG obtained prior to the procedure. QTc was compared between patients with normal and abnormal (CFR ratio<=2.5) coronary microvascular function. RESULTS: Of the 926 patients included in this study, 281 patients (30%) had CMD (mean age 53.2 years [SD 12.7], 25% male). QTc was significantly longer in those with an abnormal CFR response to adenosine (median [Q1, Q3] ms: 420 [409, 438] vs. 416 [405, 432]; p value<0.001) and patients in the lowest quartile of CFR had a significantly longer QTc compared to those in the highest quartile (median [Q1, Q3] ms: 420 [409, 439] vs. 413 [402, 426]; p<0.001). In a linear regression model adjusting for age and sex, CMD was associated with an increase in QTc of 3.09 ms (p=0.055). CONCLUSION: Our data suggest that CMD may be associated with an increase in baseline QTc, however the precise clinical relevance of this finding needs to be better investigated in larger clinical studies. PMID- 26620730 TI - Regulation of p53 under hypoxic and inflammatory conditions in periodontium. AB - OBJECTIVES: Different studies suggest that inflammation as well as hypoxia leads to an increase of p53 protein levels. However, the implication of p53 during oral inflammatory processes is still unknown. The aim of this study was therefore to investigate the effect of hypoxia and inflammation on p53 regulation in human periodontium in vitro and in vivo. MATERIALS AND METHODS: Under hypoxic and normoxic conditions, human primary periodontal ligament (PDL) fibroblasts (n = 9) were stimulated with lipopolysaccharides (LPS) from Porphyromonas gingivalis (P.g.), a periodontal pathogenic bacterium. After different time points, cell viability was tested; p53 gene expression, protein synthesis, and activation were measured using quantitative RT-PCR, immunoblotting, and immunofluorescence. Moreover, healthy and inflamed periodontal tissues were obtained from 12 donors to analyze p53 protein in oral inflammatory diseases by immunohistochemistry. RESULTS: LPS-P.g. and hypoxia initially induced a significant upregulation of p53 mRNA expression and p53 protein levels. Nuclear translocation of p53 after inflammatory stimulation supported these findings. Hypoxia first enhanced p53 levels, but after 24 h of incubation, protein levels decreased, which was accompanied by an improvement of PDL cell viability. Immunohistochemistry revealed an elevation of p53 immunoreactivity in accordance to the progression of periodontal inflammation. CONCLUSIONS: Our data indicate that p53 plays a pivotal role in PDL cell homeostasis and seems to be upregulated in oral inflammatory diseases. CLINICAL RELEVANCE: Upregulation of p53 may promote the destruction of periodontal integrity. A possible relationship with carcinogenesis may be discussed. PMID- 26620731 TI - Influence of metabolic-linked early life factors on the eruption timing of the first primary tooth. AB - AIM: Early eruption of permanent teeth has been associated with childhood obesity and diabetes mellitus, suggesting links between tooth eruption and metabolic conditions. This longitudinal study aimed to identify pre-, peri- and postnatal factors with metabolic consequences during infancy that may affect the eruption timing of the first primary tooth (ETFT) in children from an ethnically heterogeneous population residing within the same community. MATERIAL AND METHODS: Participants were recruited (n = 1033) through the GUSTO (Growing Up in Singapore Towards healthy Outcomes) birth cohort (n = 1237). Oral examinations were performed at 3-month intervals from 6 to 18 months of age. Crude and adjusted analyses, with generalized linear modelling, were conducted to link ETFT to potential determinants occurring during pregnancy, delivery/birth and early infancy. RESULTS: Overall mean eruption age of the first primary tooth was 8.5 (SD 2.6) months. Earlier tooth eruption was significantly associated with infant's rate of weight gain during the first 3 months of life and increased maternal childbearing age. Compared to their Chinese counterparts, Malay and Indian children experienced significantly delayed tooth eruption by 1.2 and 1.7 months, respectively. CONCLUSIONS: Infant weight gain from birth to 3 months, ethnicity and maternal childbearing age were significant determinants of first tooth eruption timing. Early life influences can affect primary tooth development, possibly via metabolic pathways. CLINICAL RELEVANCE: Timing of tooth eruption is linked to general growth and metabolic function. Therefore, it has potential in forecasting oral and systemic conditions such as caries and obesity. PMID- 26620732 TI - Does periodontal treatment have an effect on clinical and immunological parameters of periodontal disease in obese subjects? A systematic review and meta analysis. AB - AIM: The aim of this study was to systematically review the literature to answer the questions: (i) "Is periodontal treatment effective to improve clinical and immunological conditions in obese subjects?"; (ii) "Do obese subjects present different clinical and immunological response after periodontal therapy when compared to non-obese subjects?" METHODS: Searches were performed in six databases up to August 2014. Interventional studies were included if the following data were described: (1) Obesity/overweight assessment; (2) definition of periodontal disease; (3) periodontal therapy; (4) inflammatory marker in serum/plasma, and/or clinical parameters of periodontal disease. Assessment of quality was performed with the Downs and Black scale. Meta-analyses were conducted with the available data. RESULTS: Of 489 articles, 5 were included, and only 3 proceeded to meta-analysis of clinical outcomes. Included studies presented fair methodological quality. Statistical analysis demonstrated that periodontal therapy in obese subjects was effective to improve clinical outcomes. No clinical differences between post-therapy results of obese and non-obese were observed. Effects of periodontal therapy on inflammatory markers remain unclear. CONCLUSIONS: Periodontal treatment seems to be effective to improve healing in obese individuals. No differences on periodontal healing between obese and non obese subjects were observed; however, only limited and fragile base of evidence was available for analysis. CLINICAL RELEVANCE: Periodontal treatment is effective to improve clinical and immunological periodontal parameters in adults. Also, obesity seems to not modify the periodontal healing after treatment. PMID- 26620734 TI - Gene expression signatures, pathways and networks in carotid atherosclerosis. AB - BACKGROUND: Embolism from unstable atheromas in the carotid bifurcation is a major cause of stroke. Here, we analysed gene expression in endarterectomies from patients with symptomatic (S) and asymptomatic (AS) carotid stenosis to identify pathways linked to plaque instability. METHODS: Microarrays were prepared from plaques (n = 127) and peripheral blood samples (n = 96) of S and AS patients. Gene set enrichment, pathway mapping and network analyses of differentially expressed genes were performed. RESULTS: These studies revealed upregulation of haemoglobin metabolism (P = 2.20E-05) and bone resorption (P = 9.63E-04) in S patients. Analysis of subgroups of patients indicated enrichment of calcification and osteoblast differentiation in S patients on statins, as well as inflammation and apoptosis in plaques removed >1 month compared to <2 weeks after symptom. By prediction profiling, a panel of 30 genes, mostly transcription factors, discriminated between plaques from S versus AS patients with 78% accuracy. By meta-analysis, common gene networks associated with atherosclerosis mapped to hypoxia, chemokines, calcification, actin cytoskeleton and extracellular matrix. A set of dysregulated genes (LMOD1, SYNPO2, PLIN2 and PPBP) previously not described in atherosclerosis were identified from microarrays and validated by quantitative PCR and immunohistochemistry. CONCLUSIONS: Our findings confirmed a central role for inflammation and proteases in plaque instability, and highlighted haemoglobin metabolism and bone resorption as important pathways. Subgroup analysis suggested prolonged inflammation following the symptoms of plaque instability and calcification as a possible stabilizing mechanism by statins. In addition, transcriptional regulation may play an important role in the determination of plaque phenotype. The results from this study will serve as a basis for further exploration of molecular signatures in carotid atherosclerosis. PMID- 26620733 TI - Analysis of the dentoalveolar effects of slow and rapid maxillary expansion in complete bilateral cleft lip and palate patients: a randomized clinical trial. AB - OBJECTIVES: The purpose of this study was to compare the dentoalveolar effects of slow (SME) and rapid (RME) maxillary expansions in patients with complete bilateral cleft lip and palate (BCLP). MATERIAL AND METHODS: A sample of 50 patients with BCLP and maxillary arch constriction was randomly and equally allocated into two groups. Group SME comprised patients (mean age of 8.8 years) treated with quad-helix appliance. Group RME comprised individuals (mean age of 8.9 years) treated with Hyrax expander. Digital dental models obtained immediately pre-expansion (T1) and 6 months after the active expansion period (T2) were used for measuring maxillary dental arch widths, arch perimeter, arch length, palatal depth, buccolingual inclination of posterior teeth and differential amount of expansion accomplished at the canine and molar regions. Inter-phase and intergroup comparisons were performed using paired t tests and t tests, respectively (p < 0.05). RESULTS: SME and RME caused significant increase of arch widths and arch perimeter. Arch length and palatal depth decreased nonsignificantly with SME but significantly with RME. Buccal tooth inclination was significant only for maxillary deciduous canines in both groups. The quad helix appliance showed a significant differential expansion between anterior and posterior regions. No differences were observed between SME and RME for all variables. CONCLUSIONS: Differences were not found between the dentoalveolar effects of SME and RME in patients with BCLP. SME demanded a greater therapy time compared to RME. CLINICAL RELEVANCE: Both expansion procedures can be similarly indicated to correct maxillary arch constriction in patients with BCLP in the mixed dentition. PMID- 26620735 TI - Effect of 6-minute walk test on neuromuscular properties of patients with chronic obstructive pulmonary disease. AB - OBJECTIVE: The objective of this study was to evaluate the neuromechanical properties of the knee extensor muscles before and after the 6-minute walk test (6MWT) in chronic obstructive pulmonary disease (COPD) patients and control subjects. MATERIALS AND METHODS: COPD patients from the Department of Pulmonology of the Hospital de Clinicas de Porto Alegre and age- and sex-matched control volunteers without COPD were included in this study. Body composition and lower limb strength assessed by maximal voluntary isometric contraction (MVIC) of the knee extensors) were assessed before and after the 6MWT. The total reaction time (TRT), premotor time (PMT) and motor time (MT) were assessed using surface electromyography of the rectus femoris and vastus lateralis knee extensor muscles. RESULTS: Eighteen patients COPD patients (10 men, FEV1 36 +/- 12% of predicted) and 8 control subjects (5 men, FEV1 82 +/- 7% of predicted) were included. COPD patients had lower muscle strength before (21.77 +/- 7.86 kg) and after the 6MWT (11.16 +/- 4.70 kg) compared with control subjects (33.50 +/- 14.01 kg before; 29.25 +/- 16.66 kg after). After the 6MWT, COPD patients showed a significant reduction in the MVIC and a significant increase in the TRT and PMT, which did not occur in control subjects. The reaction time parameters were higher in COPD patients after the 6MWT compared with control subjects. The TRT (r = -0.535, P < 0.005) and PMT (r = -0.549, P < 0.005) were inversely correlated with the MVIC after the 6MWT. CONCLUSIONS: Neuromuscular changes associated with upper motor neuron activation contribute to MVIC impairment in COPD patients after performing a functional test. PMID- 26620736 TI - [Optimization of information on the medication of polypharmacy patients in primary care]. AB - As part of the protocol of the Health Service of the Principality of Asturias (Spain), primary care physicians periodically receive listings of the treatments of patients of any age taking 10 or more drugs/day for 6 months. Currently, the Health Service of the Principality of Asturias is developing a project that aims to assess the medications of polypharmacy patients. The aim is to identify: 1) the consumption of medicines of low therapeutic usefulness, 2) the consumption of potentially nephrotoxic drugs in patients with a low glomerular filtration rate, and 3) potentially inappropriate prescribing in patients aged 65 years or older. The project was started in Health Area II and the aim is to extend it to the remaining health areas. In our opinion, its automation and general implementation could be useful to optimize drug prescription. PMID- 26620737 TI - Retrospective review of diphencyprone in the treatment of alopecia areata. AB - BACKGROUND: Contact immunotherapy with diphencyprone (DCP) is used to treat alopecia areata (AA). Its reported efficacy is variable, and individual response cannot be predicted. AIM: To identify patient and treatment course variables that may affect treatment outcome, and to review DCP service to identify potential areas for development and improvement. METHODS: This was a retrospective review of a DCP service over a 20-year period (1991-2010). RESULTS: Complete data was available for 205 treatment courses, and 162 (79%) treatment courses were completed for 133 patients. Overall, 72.2% (96/133) of patients had some hair regrowth (any grade). In 15.8% of cases (21/133), response was > 90% regrowth. However, 27.1% (36/133) had no response. We found that extent of alopecia at baseline and duration of disease were statistically significant when comparing patients with an optimal outcome to those without (P < 0.05). In contrast to other reports, atopy, age at onset and nail dystrophy were not statistically significant. For patients receiving more than one course, response to DCP treatment was broadly consistent. CONCLUSIONS: Extent of alopecia at baseline and duration of disease are important factors in predicting response. Our results suggest that atopy should not be considered a predictor of poor outcome with respect to DCP treatment. A need for improved data collection, particularly regarding longer-term outcomes, was identified. The role of maintenance therapy requires objective assessment. Opportunities for DCP self-administration by patients should be explored. Limitations of this study include the retrospective nature of the review and lack of long-term follow-up data. PMID- 26620739 TI - Early Outcome of Liver Resections in Octogenarians. AB - BACKGROUND: Reports on safety and feasibility of liver resection in patients 80 years and older are very limited. OBJECTIVE: Here, we intend to analyze the perioperative outcomes of liver resections in octogenarians performed at a single tertiary level teaching hospital over a ten years period. METHOD: Retrospective review of the medical records (between 2004 to 2014) of patients of the defined age group was performed. Clinicopathological features, indications, extent of resections, intraoperative parameters, postoperative complications and final outcome were analyzed. Findings were compared with similar studies published in literature. RESULT: Total 19 (11 male, 8 female, maximum age 85 years) patients of the study group underwent liver resection during the defined period. Commonest indication was colorectal liver metastasis (9 patients). One patient had pancreaticodudenectomy for periampullary malignancy four years prior to present with liver metastasis and subsequently had liver resection for recurrence of disease. Except one, all had open surgery. Types of resection ranged from sub segmental to major right (8 patients) and left (1 patient) hepatectomy. Total 3 (27%) out of 11 patients on whom drain was not placed required radiological drainage of abdominal collection. One patient developed liver abscess postoperatively and was also successfully drained under radiological guidance. Only 2 (10.5%) had prolonged Intensive Care Unit (ICU) stay and remaining patients were discharged to ward after 24 hrs of observation in high dependency/Intensive care unit. Median hospital stay was 11 days. Postoperative complications were 3 of grade II, 4 of grade IIIa, 1 of IIIb and 2 of IVa. Total 9 patients were discharged to rehabilitation centers and remaining 10 could be discharged home. There was 0% mortality. CONCLUSION: In appropriately selected cases, when performed in specialized tertiary centers excellent perioperative outcomes of liver resections can be achieved even in patients of 80 years of age and above. PMID- 26620738 TI - Racial differences in the relationship between clinical prostatitis, presence of inflammation in benign prostate and subsequent risk of prostate cancer. AB - BACKGROUND: Epidemiologic studies, primarily done in white men, suggest that a history of clinically-diagnosed prostatitis increases prostate cancer risk, but that histological prostate inflammation decreases risk. The relationship between a clinical history of prostatitis and histologic inflammation in terms of how these two manifestations of prostatic inflammation jointly contribute to prostate cancer risk and whether racial differences exist in this relationship is uncertain. METHODS: Using a nested design within a cohort of men with benign prostate tissue specimens, we analyzed the data on both clinically-diagnosed prostatitis (NIH categories I-III) and histological inflammation in 574 prostate cancer case-control pairs (345 white, 229 African American). RESULTS: Clinical prostatitis was not associated with increased prostate cancer risk in the full sample, but showed a suggestive inverse association with prostate cancer in African Americans (odds ratio (OR)=0.47; 95% confidence interval (CI)=0.27-0.81). In whites, clinical prostatitis increased risk by 40%, but was only associated with a significant increased prostate cancer risk in the absence of evidence of histological inflammation (OR=3.56; 95% CI=1.15-10.99). Moreover, PSA velocity (P=0.008) and frequency of PSA testing (P=0.003) were significant modifiers of risk. Clinical prostatitis increased risk of prostate cancer almost three-fold (OR=2.97; 95% CI=1.40-6.30) in white men with low PSA velocity and about twofold in white men with more frequent PSA testing (OR=1.91; 95% CI=1.09-3.35). CONCLUSIONS: In our cohort of men with benign prostate specimens, race, and histological inflammation were important cofactors in the relationship between clinical prostatitis and prostate cancer. Clinical prostatitis was associated with a slightly decreased risk for prostate cancer in African American men. In white men, the relationship between clinical prostatitis and prostate cancer risk was modified by histological prostatic inflammation, PSA velocity, and frequency of PSA testing-suggesting a complex interplay between these indications of prostatic inflammation and prostate cancer detection. PMID- 26620740 TI - The World is Changing and Along with it the World of Dermatology. PMID- 26620741 TI - Undertreated Hypertension and its Implications for Public Health in Nepal: Nationwide Population-Based Survey. AB - BACKGROUND: Hypertension (HTN), a major risk factor for cardiovascular diseases (CVDs), is a substantial global public health problem. Occasional studies indicate a high prevalence of HTN in the Nepalese population, but no nationwide population-based data exist so far. We opportunistically used a survey of major disorders of the brain in Nepal to measure blood pressure (BP) in participants selected randomly from the adult general population. OBJECTIVE: To establish the prevalence of elevated BP (eBP), and factors associated with it, regardless of any antihypertensive therapy being taken. We took this to be indicative of unmet health-care need. METHOD: This was a cross-sectional study, conducted by unannounced household visits, employing multistage random cluster sampling. To achieve representativeness, 15 districts out of 75 in the country were investigated: one district from each of the three physiographic divisions in each of the five development regions of Nepal. One adult aged 18-65 years was selected from each household and interviewed by structured questionnaire. BP was recorded in a standardised manner by digital device (Microlife 3BM1-3(r)). RESULT: From 2,109 eligible households, 2,100 adults (99.6%) participated. The prevalence of eBP (>140/90 mmHg on >=2 readings) was found to be 15.1%. Multivariate logistic regression showed significant and independent associations with demographic variables (higher age, male gender), with life-style factors (daily alcohol consumption, BMI >=25), and with living at high altitude (>=2000 m). CONCLUSION: In the context of the survey we could not collect data on antihypertensive therapy being taken but, clearly, whatever this might have been, it was failing to meet treatment needs. Almost one in six adults met criteria for hypertension, carrying risk implications for CVDs and their substantial public-health consequences. Two remediable associated factors were identified, although in a cross-sectional survey we could not prove causation. PMID- 26620742 TI - Dentigerous Cysts of Maxillofacial Region- Clinical, Radiographic and Biochemical Analysis. AB - BACKGROUND: Dentigerous cyst is the second most common type of odontogenic cysts that encloses the crown of an unerupted tooth by expansion of its follicle due to the collection of cystic fluid. In view of the capability of these lesions attaining a marked size if not diagnosed early and treated properly, the present study was done based on the clinical and radiographic presentation of the dentigerous cyst in addition to the analysis of the cystic contents. OBJECTIVE: The present study reported 14 cases of dentigerous cysts (DC) with their incidence and relative distribution of the maxillofacial region along with the clinical and radiographic features and biochemical analysis of cystic fluid. METHOD: The study was conducted at Sri Govind Tricentenary Dental College, Hospital and Research Institute, Gurgaon, Haryana for a period of one year and six months. A detailed case history and thorough clinical examination was done for the patients who were provisionally found to have odontogenic cysts. Necessary radiographs, aspiration of the cystic fluid and incisional biopsy were performed to the 14 patients who were provisionally diagnosed with dentigerous cysts (DC) after obtaining the informed consent and the cystic fluid was subjected to biochemical analysis. RESULTS: Majority of the affected patients with DC were in their second decade and showed more predilection for mandible with a male predominance. The area of predilection was third molar region in the mandible and it is the canine region in maxilla. All the cases were associated with impacted teeth and majority showed expansion of the buccal/labial cortical plate. The various biochemical variables (total protein content, albumin, globulin and albumin: globulin ratio) were also assessed in the present study. CONCLUSION: The awareness of protean features of DC evident through this study is essential for the general as well as specialty practitioners for the accurate diagnosis and proper treatment planning of these non cancerous but potentially destructive lesions and also opens new avenues for further research. PMID- 26620743 TI - Academic Staff Perspectives Towards Adoption of E-learning at Melaka Manipal Medical College: Has E-learning Redefined our Teaching Model? AB - BACKGROUND: E-learning is the use of Information and Communication Technology (ICT) to provide online education and learning. E- Learning has now been integrated into the traditional teaching as the concept of 'blended learning' that combines digital learning with the existing traditional teaching methods to address the various challenges in the field of medical education. Structured e learning activities were started in Melaka Manipal Medical College in 2009 via e learning platform (MOODLE-Modular Object-Oriented Dynamic Learning Environment). OBJECTIVES: The objective of the present study is to investigate the faculty opinions toward the existing e-learning activities, and to analyse the extent of adopting and integration of e-learning into their traditional teaching methods. METHODS: A cross sectional study was conducted among faculties of Medicine and Dentistry using pre-tested questionnaires. The data was analyzed by using the statistical package for social science, SPSS, version 16.0. RESULTS: The result of our survey indicates that majority of our faculty (65.4%) held positive opinion towards e-learning. Among the few, who demonstrated reservations, it is attributed to their average level of skills and aptitude in the use of computers that was statistically significant (p<0.05). CONCLUSION: Our study brings to light the need for formal training as perquisite to support e-learning that enables smooth transition of the faculty from their traditional teaching methods into blended approach. Our results are anticipated to strengthen the existing e learning activities of our college and other universities and convincingly adopt e-learning as a viable teaching and learning strategy. PMID- 26620744 TI - Association of Ambient Air Quality with Male's Pulmonary Function in Kolkata City, India. AB - BACKGROUND: Kolkata is one of the polluted metropolitan cities in India where health effects of air pollution are raising serious concern. OBJECTIVES: Purpose of the present study was to analyze association between levels of air pollutants and pulmonary function of adult males living in two different air pollutant zones of Kolkata. METHODS: Air pollution data of two ambient air quality monitoring stations located at Rabindrabharati and Victoria Memorial was collected from West Bengal Pollution Control Board, Kolkata for the period from January to March 2012. Study was conducted on 200 males (17-22 yrs), subdivided into two groups from living within 3 km radius of that two monitoring stations. They were investigated for their spirometric lung functions following method and technique recommended by American Thoracic Society. Results were expressed as mean +/- SD and independent samples T test was conducted to compare between groups. RESULTS: PM10, SO2 concentrations were significantly higher in Rabindrabharati zone, whereas no significant differences were noted in NO2 and CO concentrations though values were higher at Rabindrabharati than Victoria Memorial. FVC, FEV1, FEF25 75%, MVV were significantly lower in males of Rabindrabharati zone. CONCLUSION: Exposure to high air pollutant concentration might be associated with reduced pulmonary function in adult males. PMID- 26620745 TI - Relation of Sociodemographics and Personal Hygiene on Different Childhood Dermatoses. AB - BACKGROUND: Skin diseases in children contribute to significant morbidity and psychological distress. Infective dermatoses are one of the major dermatoses in children. Low socioeconomic status, overcrowding and poor personal hygiene has been linked to skin diseases. OBJECTIVE: To find out the prevalence of infectious skin disease in children, rate of transmissible skin disease and association of sociodemographic factors and personal hygiene on infective childhood dermatoses. METHOD: This was a cross-sectional study conducted in the Pediatric and Dermatology Department, Manipal Teaching Hospital, Pokhara, Nepal. A total of 226 patients were examined over a period of one year. Relation of sociodemographics, crowding and personal hygiene on skin disease were assessed. RESULT: The most common category was Infections and Infestations (51.3%) followed by Dermatitis (27.9%). Transmissible skin disease was seen in 49.6%. Low socioeconomic status and overcrowding were associated with increased risk for infective dermatoses. CONCLUSION: Skin disease in children constitutes a public health problem. Improving the socioeconomic status and personal hygiene can help to reduce the incidence of skin disease in children. PMID- 26620746 TI - Surgical Outcomes in Cases of Marcus-Gunn Jaw-Winking Phenomenon. AB - BACKGROUND: Markus-Gunn Jaw-winking Phenomenon (MGJW) is a congenital ptosis associated with synkinetic movement of upper lid on masticating movements of jaw. It results from aberrant connection between motor division of trigeminal nerve and oculomotor nerve. OBJECTIVE: To investigate the clinical characteristics of MGJW phenomenon and evaluate its surgical outcomes of unilateral levator excision and frontalis suspension. METHOD: It is a retrospective analysis of nine cases of MGJW phenomenon seen from 2007 to 2013 AD. The clinical features were recorded and analysed. Unilateral levator excision and frontalis suspension for the correction of synkinesis and ptosis was done for all the patients. The result of surgery was analysed. RESULT: MGJW phenomenon was seen more in males. All the cases had unilateral ptosis with jaw winking phenomenon. Ipsilateral hypotropia and refractive errors were seen in 44%. One week post operative margin reflex distance was good in 67% of cases. Persistent jaw-winking was seen in 3 cases, two underwent repeat surgery to abolish the synkinesis. At one year follow up, 33% had good margin reflex distance of more than 4mm and 22% had fairly good margin reflex distance of 3mm. CONCLUSION: Patients with Marcus Gunn jaw winking synkinesis can present at a wide age range. There may be an associated vertical muscle imbalance, which should be managed before ptosis surgery to avoid ptosis under correction. Unilateral frontalis flap suspension combined levator excision can correct ptosis very well for patients with Marcus-Gunn syndrome. PMID- 26620747 TI - Assessment of Knowledge Regarding Oral Hygiene among Parents of Pre-School Children Attending Pediatric Out Patient Department in Dhulikhel Hospital. AB - BACKGROUND: Level of knowledge regarding oral hygiene among the parents of pre school children plays an important role on maintaining the good oral hygiene of their children. In Nepal, sufficient research has not been carried out on this area. OBJECTIVE: Objective of this study is to assess the level of knowledge on oral hygiene of preschool children's parents attending pediatric outpatient department in Dhulikhel Hospital. METHOD: A descriptive study was conducted from November 2012 to January 2013 among one hundred parents of preschool children visiting pediatrics outpatient department of Dhulikhel Hospital. Paper and pencil based semi structured questionnaire was used for collecting data. Questions related to demographic information and knowledge were asked. Thirty questions were used for assessing knowledge level. Knowledge score was calculated by allocating one point for each correct answer and zero point for each wrong answer. Analyzed data were presented in terms of numbers and percentages. Total knowledge scores were categorized based on percentage. Knowledge score was categorized on four group - exclusive intervals - namely-poor (0-40%), moderate (40-60%), good (60-80%) and excellent (80-100%). Mann-Whitney U test and Kruskal Wallis test were applied to check significance difference and chisquare test was used to check association among different background characteristic. RESULT: It was found that 81% had moderate knowledge, 15% had poor knowledge and 4% had good knowledge about oral hygiene. Median knowledge score was found to be 15 with range 10 to 21. Following variables were found to be significant difference on knowledge category: Education status (p<0.001), education level (p= 0.041), past experience about oral health problem (p = 0.008), Further significant association was found between knowledge category and educational status (p<0.001) and between knowledge category and past experience (p< 0.001). CONCLUSION: Knowledge regarding oral hygiene was found satisfactory among the parents of preschool children visiting pediatric OPD of Dhulikhel Hospital. PMID- 26620748 TI - Screening for Postpartum Depression and Associated Factors among Women who Deliver at a University Hospital, Nepal. AB - BACKGROUND: Postpartum depression (PPD) is a neglected area of maternal health care in developing countries like Nepal; not only in the treatment aspect, but also, in the areas of research. However, it is important to identify and treat postpartum depression because it can have grave consequences for both the mother and her children. OBJECTIVE: To determine the screening prevalence and risk factors of postpartum depression, among women who deliver at university hospital Nepal. METHOD: This is a cross-sectional study investigating the relationship between postpartum depression and various factors. A total of 100 postpartum women who presented to a Dhulikhel hospital for delivery were interviewed on days 2-3 after delivery. The mothers were administered Edinburgh Postnatal Depression Scale (EPDS) as well as a proforma that included questions about the known risk factors (sociodemographic and sociocultural factors, and mother-related, pregnancy-related, and child related factors). RESULT: The overall screening prevalence of depressive symptoms in the postnatal period (defined as EPDS=>13) was 29 %( 95% CI 20.1%-37.8%). On univariate analysis (chi square test), postpartum depression was significantly associated with pregnancy complications (p<0.01), infant's health problems (p< .001) and vaginal delivery (p <0.05). CONCLUSION: Postpartum depression is common among Nepalese women and can be detected early in the postpartum periods; and many psychosocial factors like pregnancy complications, infant's health problems and vaginal delivery are associated with it. It is recommended that mothers with high risk should be routinely screened for postpartum depression. PMID- 26620749 TI - Evaluation of Etiology of Epistaxis and its Management in Dhulikhel Hospital. AB - BACKGROUND: Epistaxis is one of the most common and most difficult emergencies presenting in 7-14% of the general population each year. Although its lifetime incidence is about 60%, only 6% require formal medical intervention but they can be serious and even life threatening. OBJECTIVE: The main objectives are to study different etiology, types, modality of treatment of epistaxis. Specific objective is also to find out if the modality of treatment is associated with age, site, amount of bleeding and etiology. METHOD: It is a prospective, cross sectional, longitudinal, analytical study done in Department of ENT, Dhulikhel hospital, Kathmandu University School of Medical Sciences (KUSMS) from Aug. 2010 to Aug. 2013. Data was collected. This study was cleared through institutional review committee of hospital. Statistical analysis was done using SPSS 16.0. RESULT: 487 patients were studied during the period. There was significant association between age group with type of treatment (p value 0.002); and with admission (p value < 0.001). Significance in the study was also shown in the correlation between site of bleeding and the type of treatment and also with alcohol intake with site of bleeding (p value < 0.001).However there was no significance between hypertension and the type of treatment methods chosen (p value > 0.01). CONCLUSION: Management of epistaxis is challenging. Most are managed by non surgical means whereas some by surgical treatment. Non surgical treatment is still useful, safe and cost effective. Type of treatment and need for hospital stay is related to age and site of bleeding. PMID- 26620750 TI - Percutaneous Ilio-Sacral Screw Fixation in Supine Position under Fluoroscopy Guidance. AB - BACKGROUND: Pelvic ring disruption when treated conservatively can be associated with prolonged hospital stay and immobilization, mal-union, chronic pain, limb length discrepancy if they are treated conservatively. Open reduction and fixation in an already compromised soft tissue and hemodynamically unstable patient causes more soft tissue injury, heamatoma, infection and neurovascular injury. Percutaneous iliosacral joint fixation can be an alternative technique for sacro-iliac joint injury and sacral fracture. OBJECTIVE: To evaluate technique and safety of percutaneous ilio-sacral screw fixation in supine position under single fluoroscopy guidance for sacral fracture and sacro-iliac joint disruption. METHOD: Twenty one patients either with sacral fracture or sacro-iliac joint disruption with percutaneous ilio-sacral screw fixation with cannulated cancellous screw fixation in between 2008 to 2014 were retrospectively evaluated including AP, inlet and outlet views of pelvis X rays and CT scan. Tile's classification and Dennis classification were used for pelvis and sacral injury. RESULT: Thirty five percutaneous ilio-sacral screws were placed (Male: 6, Female: 15; range: 15 to 54) for sacral fracture involving zone 2 (8 with sacral fracture only and 5 with pelvis injury; Tile's type B in four and type C in one) and sacro-iliac joint injury (Tile's type B in three and type C in five). Commonest mode of injury was motor vehicle accidents (10) followed by fall related injury (6). Injury hospital interval and injury surgery interval was five hours to 13 days and 2 to 20 days respectively. Follow period was 3 months to 6 years. One patient developed post-operative deep vein thrombosis and another patient had post-operative haematoma. Two screws were juxtra-foramial. Good to excellent outcome were in 16 patients, fair in four and poor in one patient (Majeed Scoring). CONCLUSION: Percutaneous ilio-sacral screw fixation for sacro iliac joint injury and sacral fracture with C arm guidance is safe and minimally invasive technique. Clear images and accurate interpretation of X-rays, CT scans and per operative C arm images are important to avoid malpositioning of screws and iatrogenic neurovascular injuries. PMID- 26620752 TI - A Cross-Sectional Study of Medication Adherence Pattern and Factors Affecting the Adherence in Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is considered as a major health problem, associated with mortality and morbidities. Various disease management strategies have been established to optimize patient's longevity and functional status where patient adherence to the prescribed treatment plays a key role. Poor adherence to medication is common among COPD patients and is affected by number of factors like number of medicines, delivery devices and patient related factors. OBJECTIVE: This study aims to investigate the adherence pattern in the management of COPD and factors affecting patient adherence to the prescribed treatment. METHOD: This study is a cross-sectional study which was conducted in a tertiary care hospital. Those patients suffering from COPD of all age were enrolled in this study and prior informed consent was obtained from patients. The structured questionnaire was used to interview those patients. RESULT: Total 100 patients were enrolled in this study, among which most patients (45%) were of age groups 60-70 years. Unintentional non-adherence to medication attributed for 65% of patients and the major reason was forgetfulness (52.3%). Most patients had discontinued the medication due to experience of side effects (63.3%). The result showed significant association between adherence and polypharmacy (p=0.00). However, there was no significant association between adherence and age, sex, mode of administration of drugs, technics to use delivery devices etc. CONCLUSION: Majority of COPD patients were elderly (mean age= 68.4 years). Forgetfulness was associated with medication non-adherence. Most of the patients had discontinued medication because of side effects. Polypharmacy is one of the major factors associated with non-adherence to medication in COPD. PMID- 26620751 TI - Radiation Exposure to the Patient During Diagnostic Coronary Angiogram at Dhulikhel Hospital. AB - BACKGROUND: Radiation is a necessary evil in Coronary Angiogram. The Interventional Cardiology procedure provides huge benefit to the patient but at the cost of radiation. There is evidence of cumulative effect of radiation. Therefore it is essential to keep the radiation dose as minimum as possible. OBJECTIVE: The aim of this study is to find out radiation exposed to the patient undergoing diagnostic coronary angiogram. METHOD: A retrospective study was done. Those patients who underwent diagnostic coronary angiogram were selected for the study. There were total of 166 patients. Radiation exposure in terms of fluoroscopy time in minute and dose area product (DAP) in Gy.cm2 was recorded. RESULT: Out 166 patients 92 were male and 74 female. Age range was from 39 to 79 years with mean age 58.13+/-9.14. Amount of contrast used was in range of 30 to 100 ml with mean of 45.54+/-14.06. Range of fluoroscopy time was 2.60 to 37.00 minutes with mean 11.38+/-6.80. Mean fluoroscopy time in male was 10.92+/-5.82 minutes and in females it was 11.92+/-7.68 minutes, with p 0.331. The range of DAP was 11.00 Gy.cm2 to 106.00 Gy.cm2 with mean 40.73+/-23.58 Gy.cm2. The mean DAP in male and female was 38.77+/-23.26 Gy.cm2 and 43.16+/-23.90 Gy.cm2 respectively with p 0.234. CONCLUSION: From this study we can conclude that the radiation exposure to our patient undergoing coronary angiogram is similar to the international values in terms DAP but more in terms of fluoroscopy time. When males and females compared there is no difference. PMID- 26620753 TI - Vitamin D and Other Risk Factors among Stroke Patients. AB - BACKGROUND: Stroke is common neurological problems in Nepal. The common risk factors for stroke are age, hypertension, diabetes, dyslipidemia and atrial fibrillation. Vitamin D is an emerging risk factors for cardio-cerebrovascular disease. OBJECTIVE: This study is to find out Vitamin D and risk factors in stroke patient in Nepalese population. METHOD: We reviewed the record of 281 stroke patients, admitted to Neurology ward of College of Medical Sciences, Bharatpur, Nepal from 1st January to 31st December 2013. The records were analyzed on the basis of age, sex, hypertension (HTN), body mass index (BMI), smoking habits, hemoglobin(Hb), diabetes mellitus(DM), Lipid profile, Atrial fibrillation(AF) and vascular territory with clinical and radiological evidences. The vitamin D analysis was done all stroke patients. RESULT: Total patient were 281, with male 161 and age range from 18 - 87. Ischemic stroke was noted in 86.8% and hemorrhagic stroke was noted in 13.2% of patients. Middle cerebral artery (MCA) ischemia was noted in 51.5% of patients and anterior cerebral artery (ACA) ischemia was noted in 3% of patients. Multiple infarcts were noted in 12.90% of patients. About half of them were smoker, hypertension 47.40%, Diabetes mellitus 24.20% and 14.1% had atrial fibrillation. 174 (61.92%) of the stroke had less than sufficient Vitamin D. CONCLUSION: The common risk factors for stroke patients like smoking, hypertension, diabetes mellitus and atrial fibrillations are present in Nepalese population. The level of vitamin D was also low in stroke patients. PMID- 26620754 TI - Anomalous Facial Nerve: An Unusual Cause of Obstruction of Middle Ear Ventilation. AB - Numerous anomalies and variations of facial nerve anatomy leading to iatrogenic injury are described. However, there are no reports of facial nerve dehiscence near its second genu causing a hump and obstructing middle ear ventilation pathway, as found in our case. This particular anomaly of facial nerve is being reported to highlight its uniqueness and that a dehiscent facial nerve may be a rare but dangerous cause of obstruction of the attic ventilation. One has to be aware of this unusual anomaly to prevent inadvertent damage to the facial nerve while clearing aditus block in persistent otitis media. PMID- 26620755 TI - Community-Acquired Methicillin Resistant Staphylococcus aureus Bacteremia: Case Series. AB - Community-acquired methicillin resistant Staphylococcus aureus (MRSA) usually causes skin and soft tissue infections. However, community-acquired methicillin resistant S.aureus has been identified as a causative agent of many invasive infections like necrotizing fasciitis, pneumonia and bacteremia. Risk factors such as immunodeficiency and skin and soft tissue infections have been identified for acquiring bacteremia. We present four cases of bacteremia caused by community acquired methicillin resistant S.aureus, risk factors and outcome. PMID- 26620756 TI - Anesthetic Management of a Patient with Myasthenia Gravis for Meningioma Surgery A Case Report. AB - Myasthenia gravis is a disease of great challenge to the anesthesiologist, because it affects the neuromuscular junction. Anesthetic management involves either muscle relaxant or non-muscle relaxant techniques. This case report documents the safe use of fentanyl, propofol and sevoflurane combination guided by bispectral index, without the use of muscle relaxants in a patient with myasthenia gravis who presented for meningioma surgery. PMID- 26620757 TI - Point-of-care Ultrasonography in Critically Ill Patients. AB - Point-of-care ultrasonography has been used frequently by the physicians involved in managing critically ill patients. It allows direct visualization of pathology or abnormal physiological state at the bed side. The examination may be safely and effectively repeated as needed to follow the evolution of illness and the response to therapy. It is helpful to guide the therapy in patients with undifferentiated shock and for bedside diagnosis of common pathological conditions in acute care setting. It can facilitate common bedside procedures and interventions. PMID- 26620758 TI - HIV/AIDS: A Persistent Health Issue for Women and Children in Mid and Far Western Nepal. AB - This article reviews the effect of male migration on the spread of HIV infections in mid and far-western Nepal. It explains the link between male mobility and HIV in women and children. Materials were collected by a systematic search of the databases and the websites of national and international agencies. HIV infection amongst male migrants was found to be high. Their risk behaviors such as unprotected sex with multiple partners and sex workers increase the risk of HIV infection. Substance abuse, loneliness, separation from families, peer pressure, long working hours and poor living conditions are factors that promote unsafe sex. Literacy and awareness about HIV is a key measure to decrease the prevalence of the disease and reduce social stigma among people affected. HIV is a major public health issue especially in Nepal with migration playing a major role in its spread. Negligence to sexual health and lack of comprehensive knowledge on the disease among male migrants are the major obstacles that have exacerbated the disease. There is a need for further research on the existing HIV cases affecting women and children of these two regions to get a clear picture of the gravity of the disease. PMID- 26620759 TI - The FOXO1 Transcription Factor Instructs the Germinal Center Dark Zone Program. AB - The pathways regulating formation of the germinal center (GC) dark zone (DZ) and light zone (LZ) are unknown. In this study we show that FOXO1 transcription factor expression was restricted to the GC DZ and was required for DZ formation, since its absence in mice led to the loss of DZ gene programs and the formation of LZ-only GCs. FOXO1-negative GC B cells displayed normal somatic hypermutation but defective affinity maturation and class switch recombination. The function of FOXO1 in sustaining the DZ program involved the trans-activation of the chemokine receptor CXCR4, and cooperation with the BCL6 transcription factor in the trans repression of genes involved in immune activation, DNA repair, and plasma cell differentiation. These results also have implications for the role of FOXO1 in lymphomagenesis because they suggest that constitutive FOXO1 activity might be required for the oncogenic activity of deregulated BCL6 expression. PMID- 26620760 TI - PI3 Kinase and FOXO1 Transcription Factor Activity Differentially Control B Cells in the Germinal Center Light and Dark Zones. AB - Phosphatidylinositol 3' OH kinase (PI3K) signaling and FOXO transcription factors play opposing roles at several B cell developmental stages. We show here abundant nuclear FOXO1 expression in the proliferative compartment of the germinal center (GC), its dark zone (DZ), and PI3K activity, downregulating FOXO1, in the light zone (LZ), where cells are selected for further differentiation. In the LZ, however, FOXO1 was expressed in a fraction of cells destined for DZ reentry. Upon FOXO1 ablation or induction of PI3K activity, GCs lost their DZ, owing at least partly to downregulation of the chemokine receptor CXCR4. Although this prevented proper cyclic selection of cells in GCs, somatic hypermutation and proliferation were maintained. Class switch recombination was partly lost due to a failure of switch region targeting by activation-induced deaminase (AID). PMID- 26620761 TI - Large genomic fragment deletion and functional gene cassette knock-in via Cas9 protein mediated genome editing in one-cell rodent embryos. AB - The CRISPR-Cas RNA-guided system has versatile uses in many organisms and allows modification of multiple target sites simultaneously. Generating novel genetically modified mouse and rat models is one valuable application of this system. Through the injection of Cas9 protein instead of mRNA into embryos, we observed fewer off-target effects of Cas9 and increased point mutation knock-in efficiency. Large genomic DNA fragment (up to 95 kb) deletion mice were generated for in vivo study of lncRNAs and gene clusters. Site-specific insertion of a 2.7 kb CreERT2 cassette into the mouse Nfatc1 locus allowed labeling and tracing of hair follicle stem cells. In addition, we combined the Cre-Loxp system with a gene-trap strategy to insert a GFP reporter in the reverse orientation into the rat Lgr5 locus, which was later inverted by Cre-mediated recombination, yielding a conditional knockout/reporter strategy suitable for mosaic mutation analysis. PMID- 26620762 TI - Effect of a functional monomer (MDP) on the enamel bond durability of single-step self-etch adhesives. AB - The present study aimed to determine the effect of the functional monomer, 10 methacryloxydecyl dihydrogen phosphate (MDP), on the enamel bond durability of single-step self-etch adhesives through integrating fatigue testing and long-term water storage. An MDP-containing self-etch adhesive, Clearfil Bond SE ONE (SE), and an experimental adhesive, MDP-free (MF), which comprised the same ingredients as SE apart from MDP, were used. Shear bond strength (SBS) and shear fatigue strength (SFS) were measured with or without phosphoric acid pre-etching. The specimens were stored in distilled water for 24 h, 6 months, or 1 yr. Although similar SBS and SFS values were obtained for SE with pre-etching and for MF after 24 h of storage in distilled water, SE with pre-etching showed higher SBS and SFS values than MF after storage in water for 6 months or 1 yr. Regardless of the pre etching procedure, SE showed higher SBS and SFS values after 6 months of storage in distilled water than after 24 h or 1 yr. To conclude, MDP might play an important role in enhancing not only bond strength but also bond durability with respect to repeated subcritical loading after long-term water storage. PMID- 26620763 TI - The Benzyl Ester Group of Amino Acid Monomers Enhances Substrate Affinity and Broadens the Substrate Specificity of the Enzyme Catalyst in Chemoenzymatic Copolymerization. AB - The chemoenzymatic polymerization of amino acid monomers by proteases involves a two-step reaction: the formation of a covalent acyl-intermediate complex between the protease and the carboxyl ester group of the monomer and the subsequent deacylation of the complex by aminolysis to form a peptide bond. Although the initiation with the ester group of the monomer is an important step, the influence of the ester group on the polymerization has not been studied in detail. Herein, we studied the effect of the ester groups (methyl, ethyl, benzyl, and tert-butyl esters) of alanine and glycine on the synthesis of peptides using papain as the catalyst. Alanine and glycine were selected as monomers because of their substantially different affinities toward papain. The efficiency of the polymerization of alanine and glycine benzyl esters was much greater than that of the other esters. The benzyl ester group therefore allowed papain to equally polymerize alanine and glycine, even though the affinity of alanine toward papain is substantially higher. The characterization of the copolymers of alanine and glycine in terms of the secondary structure and thermal properties revealed that the thermal stability of the peptides depends on the amino acid composition and resultant secondary structure. The current results indicate that the nature of the ester group drastically affects the polymerization efficiency and broadens the substrate specificity of the protease. PMID- 26620764 TI - Benzenediamine analog FC-99 inhibits TLR2 and TLR4 signaling in peritoneal macrophage in vitro. AB - AIM: Inflammatory bowel disease (IBD) is an inflammatory disorder, characterized by abnormally increased expression of Toll-like receptors TLR2 and TLR4 in the colon and increased pro-inflammatory cytokine production by macrophages. MAIN METHODS: In the present study, we explored the effect of FC-99, a novel benzenediamine analog, on dextran sulfate sodium (DSS)-induced mouse colitis and investigated its potential mechanism. KEY FINDINGS: The results revealed that FC 99 improved the colon morphology and the clinical parameters in DSS-induced mouse colitis. FC-99 inhibited the increase of DSS-induced T helper cells (Th) 1 and Th17 and enhanced the number of regulatory T cells (Treg) in mesenteric lymph nodes (MLN), but had no effect on Th2 cells. FC-99 also suppressed the DSS induced secretion of interleukin (IL)-1beta, IL-6, and the tumor necrosis factor (TNF)-alpha in the colon and hindered the infiltration of macrophages into colon lamina propria. Flow cytometric analysis also confirmed that FC-99 reduced CD11b(+)F4/80(+) colon macrophages, and down-regulated TNF-alpha level in situ. Moreover, FC-99 inhibited concentration-dependently the expression of TNF-alpha and IL-6 in vitro from mouse peritoneal macrophages, which were induced by TLR ligands: PamCSK4 and peptidoglycan (PGN, TLR2 ligand) as well as LPS (TLR4 ligand). Of note, FC-99 also suppressed the activation of TLR2 and TLR4 signaling pathways and the downstream nuclear factor-kappaB (NF-kappaB) in the DSS-induced mouse colitis. SIGNIFICANCE: FC-99 improved the condition of DSS-induced mouse colitis by inhibiting the activation of TLR2 and TLR4 signaling pathways in macrophage. These results suggest that FC-99 may be developed as a new therapeutic drug for IBD. PMID- 26620765 TI - Essential roles of mGluR1 and inhibitory synaptic transmission in NMDA independent long-term potentiation in the spinal trigeminal interpolaris. AB - AIMS: Patterns of synaptic activity determine synaptic strengthening or weakening that is typically represented as long-term potentiation (LTP) and long-term depression (LTD), respectively. In the present study, we aim to test whether a conditioning stimulation of the spinal trigeminal subnucleus caudalis (Vc) induces LTP at excitatory synapses in the subnucleus interpolaris (Vi) and to characterize the LTP. MAIN METHODS: Generally, a presynaptic high-frequency stimulation (HFS) protocol can induce LTP at excitatory synapses in the brain, including the spinal cord. Therefore, LTP in the Vi was induced by the HFS (3 tetani at 100 Hz) of Vc in the horizontal brainstem slices. By pretreating slices with antagonists for NMDA receptors, metabotropic glutamate receptor subtype 1 or 5 (mGluR1 or 5), GABAA receptors, glycine receptors and Ca(2+) chelator, the LTP was characterized. KEY FINDINGS: The HFS reliably but slowly induced LTP of excitatory synaptic transmission in the Vi. This LTP was not dependent on NMDA receptor activation; however, it did require the activation of mGluR1, but not mGluR5, and an intracellular Ca(2+) rise. Interestingly, this LTP induction required inhibitory synaptic transmission mediated by GABAA and glycine receptors, and coincided with the slow development of LTD at GABAergic synapses. The GABAergic LTD was mediated by mGluR1 and the intracellular Ca(2+) rise. SIGNIFICANCE: These data suggest that the modulation of GABAergic synaptic transmission by conditioning synaptic activity contributes to the induction and expression of LTP at excitatory synapses in the Vi. PMID- 26620766 TI - The central nervous norepinephrine network links a diminished sense of emotional well-being to an increased body weight. AB - OBJECTIVES: The neurobiological mechanisms linking obesity to emotional distress remain largely undiscovered. METHODS: In this pilot study, we combined positron emission tomography, using the norepinephrine transporter (NET) tracer [(11)C]-O methylreboxetine, with functional connectivity magnetic resonance imaging, the Beck depression inventory (BDI), and the impact of weight on quality of life-Lite questionnaire (IWQOL-Lite), to investigate the role of norepinephrine in the severity of depression (BDI), as well as in the loss of emotional well-being with body weight (IWQOL-Lite). RESULTS: In a small group of lean-to-morbidly obese individuals (n=20), we show that an increased body mass index (BMI) is related to a lowered NET availability within the hypothalamus, known as the brain's homeostatic control site. The hypothalamus displayed a strengthened connectivity in relation to the individual hypothalamic NET availability to the anterior insula/frontal operculum, as well as the medial orbitofrontal cortex, assumed to host the primary and secondary gustatory cortex, respectively (n=19). The resting state activity in these two regions was correlated positively to the BMI and IWQOL-Lite scores, but not to the BDI, suggesting that the higher the resting state activity in these regions, and hence the higher the BMI, the stronger the negative impact of the body weight on the individual's emotional well-being was. CONCLUSIONS: This pilot study suggests that the loss in emotional well-being with weight is embedded within the central norepinephrine network. PMID- 26620768 TI - Local anaesthesia and conscious sedation for cochlear implantation: experience with 20 patients. AB - OBJECTIVE: Cochlear implantation is mostly performed under general anaesthesia. This study aimed to evaluate cochlear implantation performed under local anaesthesia and sedation. METHOD: Twenty patients had a cochlear implant fitted under combined local anaesthesia (local anaesthesia group) and 41 patients had one fitted under general anaesthesia (general anaesthesia group) for bilateral profound hearing loss, from 2011 to 2014. Surgical duration, period of post operative hospitalisation and early post-operative symptoms were compared. In the local anaesthesia group, operative symptoms reported during the surgery and by questionnaire were analysed. RESULTS: Mean surgical duration was significantly shorter in the local anaesthesia group: 87 versus 122 minutes (p < 0.001). No significant difference was observed between the local anaesthesia and general anaesthesia groups regarding mean post-operative hospitalisation and early post operative symptoms. Under local anaesthesia, patients had no particular symptoms in 60 per cent of cases. The remaining patients in this group experienced vertigo (10 per cent), pain (20 per cent) and pain-related movement (10 per cent) during the intervention. These symptoms can be controlled with symptomatic treatment. CONCLUSION: Combined local anaesthesia for cochlear implantation is a good alternative to general anaesthesia for co-operating patients. PMID- 26620767 TI - Hydrodynamic Gene Delivery of CC Chemokine Binding Fc Fusion Proteins to Target Acute Vascular Inflammation In Vivo. AB - Blockade of CC chemokines is an attractive yet under utilized therapeutic strategy. We report the in vivo pharmacokinetics of a broad-spectrum vaccinia virus CC chemokine binding protein (35 K) fused to human IgG1 Fc. We demonstrate that the in vivo efficacy of the protein can be interrogated using hydrodynamic gene delivery of a standard mammalian expression plasmid. High plasma levels of the 35 K-Fc protein are maintained for at least 14 days post gene transfer, with the protein still detectable at 5 weeks. We confirm that the protein has biological activity in acute inflammation, causing a significant reduction in monocyte recruitment during zymosan induced peritonitis. The ability of 35 K-Fc to block more complex pathologies is demonstrated using aortic digests to assess angiotensin II mediated leukocyte recruitment to the aorta. Angiotensin II causes upregulation of mCCL2 in the aorta causing the accumulation of CCR2+ cells. Peak monocyte recruitment to the aorta occurs within 3 days and this process is CC chemokine dependent, being significantly reduced by hydrodynamic delivery of 35 K Fc. PMID- 26620770 TI - The synthesis of sterically hindered amines by a direct reductive amination of ketones. AB - An atom-economical methodology for the synthesis of sterically hindered tertiary amines was developed, which is based on complementary Rh- and Ru-catalyzed direct reductive amination of ketones with primary and secondary amines using carbon monoxide as a deoxygenating agent. PMID- 26620771 TI - Comparison of different models for genetic evaluation of egg weight in Mazandaran fowl. AB - 1. The aim of the present study was to compare different models to estimate variance components for egg weight (EW) in laying hens. 2. The data set included 67 542 EW records of 18 245 Mazandaran hens at 24, 28, 30, 32 and 84 weeks of age, during 19 consecutive generations. Variance components were estimated using multi-trait, repeatability, fixed regression and random regression models (MTM, RM, FRM and RRM, respectively) by Average Information-Restricted Maximum Likelihood algorithm (AI-REML). The models were compared based on Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC). 3. The MTM was the best model followed by the Legendre RRMs. A RRM with 2nd degree of fit for fixed regression and 3(rd) and 2(nd) degrees of fit for random regressions of direct additive genetic and permanent environmental effects, respectively, was the best RRM. The FRM and RM were not proper models to fit the data. However, nesting curves within contemporary groups improved the fit of FRM. 4. Heritability estimates for EW by MTM (0.06-0.41) were close to the estimates obtained by the best RRM (0.09-0.45). In both MTM and RRM, positive genetic correlations were estimated for EW records at different ages, with higher correlations for adjacent records. 5. The results suggest that MTM is the best model for EW data, at least when the records are taken at relatively few age points. Though selection based on EW at higher ages might be more precise, 30 or 32 weeks of age could be considered as the most appropriate time points for selection on EW to maximise genetic improvement per time unit. PMID- 26620772 TI - Comparative proteomic analysis of compartmentalised Ras signalling. AB - Ras proteins are membrane bound signalling hubs that operate from both the cell surface and endomembrane compartments. However, the extent to which intracellular pools of Ras can contribute to cell signalling is debated. To address this, we have performed a global screen of compartmentalised Ras signalling. We find that whilst ER/Golgi- and endosomal-Ras only generate weak outputs, Ras localised to the mitochondria or Golgi significantly and distinctly influence both the abundance and phosphorylation of a wide range of proteins analysed. Our data reveal that ~80% of phosphosites exhibiting large (>=1.5-fold) changes compared to control can be modulated by organellar Ras signalling. The majority of compartmentalised Ras-specific responses are predicted to influence gene expression, RNA splicing and cell proliferation. Our analysis reinforces the concept that compartmentalisation influences Ras signalling and provides detailed insight into the widespread modulation of responses downstream of endomembranous Ras signalling. PMID- 26620773 TI - Distribution of genetic variants of oxidative stress metabolism genes: Paraoxonase 1 (PON1) and Glutathione S-transferase (GSTM1/GSTT1) in a population from Southeastern Mexico. AB - BACKGROUND: Paraoxonase 1 (PON1) and glutathione S-transferases (GSTs) are involved in the biotransformation of xenobiotics. Variation in the enzyme concentration and activity suggests individual differences for the degree of protection against oxidative stress. AIM: This study analysed the distribution of SNPs Q192R, L55M (PON1) and variants in GSTM1 and GSTT1 genes in a population from Southeastern Mexico. SUBJECTS AND METHODS: One hundred and fifty-one Mexican Mestizo healthy volunteers were included. PON1 polymorphisms were determined by Taqman allele discrimination real time-PCR, whereas GSTM1 and GSTT1 genes were determined with a multiplex PCR-based method. RESULTS: All genotypes were in Hardy-Weinberg equilibrium, except for GSTM1. The genotypic distributions of Q192R and L55M were 22% QQ, 48% QR, 30% RR, 62% LL, 34% LM and 4% MM, respectively, whereas the allele frequencies were 0.46 (Q), 0.54 (R), 0.79 (L) and 0.21 (M). The most frequent haplotype was R/L (46.7%). It was found that 31% and 9% of the individuals had the GSTM1 and GSTT1 null genotype, respectively. The frequency of the combined null genotype GSTM1*0/GSTT1*0 was 4.64%. CONCLUSION: The results showed that the frequencies of polymorphisms of PON1, GSTM1 and GSTT1 in the Yucatan population differ to those observed in other ethnic groups and provide useful data for epidemiological studies. PMID- 26620776 TI - Computational Biomechanics for Patient-Specific Applications. PMID- 26620775 TI - Recalibration of the earthworm tier 1 risk assessment of plant protection products. AB - In the first step of earthworm risk assessment for plant protection products (PPPs), the risk is assessed by comparing the no-observed effect levels (NOELs) from laboratory reproduction tests with the predicted exposure of the PPP in soil, while applying a trigger value (assessment factor [AF]) to cover uncertainties. If this step indicates a potential risk, field studies are conducted. However, the predicted environmental concentration in soil, which can be calculated, for example, for different soil layers (ranging from 0-1 cm to 0 20 cm), and the AF determine the conservatism that is applied in this first step. In this review paper, the tier 1 earthworm risk assessment for PPPs is calibrated by comparing the NOEL in earthworm reproduction tests with effect levels on earthworm populations under realistic field conditions. A data set of 54 pairs of studies conducted in the laboratory and in the field with the same PPP was compiled, allowing a direct comparison of relevant endpoints. The results indicate that a tier 1 AF of 5 combined with a regulatory relevant soil layer of 0 to 5 cm provides a conservative tier 1 risk assessment. A risk was identified by the tier 1 risk assessment in the majority of the cases at application rates that were of low risk for natural earthworm populations under field conditions. Increasing the conservatism in the tier 1 risk assessment by reducing the depth of the regulatory relevant soil layer or by increasing the tier 1 AF would increase the number of false positives and trigger a large number of additional field studies. This increased conservatism, however, would not increase the margin of safety for earthworm populations. The analysis revealed that the risk assessment is conservative if an AF of 5 and a regulatory relevant soil layer of 0 to 5 cm is used. Integr Environ Assess Manag 2016;12:643-650. (c) 2015 SETAC. PMID- 26620774 TI - MicroRNA miR124 is required for the expression of homeostatic synaptic plasticity. AB - Homeostatic synaptic plasticity is a compensatory response to alterations in neuronal activity. Chronic deprivation of neuronal activity results in an increase in synaptic AMPA receptors (AMPARs) and postsynaptic currents. The biogenesis of GluA2-lacking, calcium-permeable AMPARs (CP-AMPARs) plays a crucial role in the homeostatic response; however, the mechanisms leading to CP-AMPAR formation remain unclear. Here we show that the microRNA, miR124, is required for the generation of CP-AMPARs and homeostatic plasticity. miR124 suppresses GluA2 expression via targeting its 3'-UTR, leading to the formation of CP-AMPARs. Blockade of miR124 function abolishes the homeostatic response, whereas miR124 overexpression leads to earlier induction of homeostatic plasticity. miR124 transcription is controlled by an inhibitory transcription factor EVI1, acting by association with the deacetylase HDAC1. Our data support a cellular cascade in which inactivity relieves EVI1/HDAC-mediated inhibition of miR124 gene transcription, resulting in enhanced miR124 expression, formation of CP-AMPARs and subsequent induction of homeostatic synaptic plasticity. PMID- 26620777 TI - A Finite Element Method to Predict Adverse Events in Intracranial Stenting Using Microstents: In Vitro Verification and Patient Specific Case Study. AB - Clinical studies have demonstrated the efficacy of stent supported coiling for intra-cranial aneurysm treatment. Despite encouraging outcomes, some matters are yet to be addressed. In particular closed stent designs are influenced by the delivery technique and may suffer from under-expansion, with the typical effect of "hugging" the inner curvature of the vessel which seems related to adverse events. In this study we propose a novel finite element (FE) environment to study potential failure able to reproduce the microcatheter "pull-back" delivery technique. We first verified our procedure with published in vitro data and then replicated the intervention on one patient treated with a 4.5 * 22 mm Enterprise microstent (Codman Neurovascular; Raynham MA, USA). Results showed good agreement with the in vitro test, catching both size and location of the malapposed area. A simulation of a 28 mm stent in the same geometry highlighted the impact of the delivery technique, which leads to larger area of malapposition. The patient specific simulation matched the global stent configuration and zones prone to malapposition shown on the clinical images with difference in tortuosity between actual and virtual treatment around 2.3%. We conclude that the presented FE strategy provides an accurate description of the stent mechanics and, after further in vivo validation and optimization, will be a tool to aid clinicians to anticipate the acute procedural outcome avoiding poor initial results. PMID- 26620778 TI - Biaxial Mechanical Evaluation of Absorbable and Nonabsorbable Synthetic Surgical Meshes Used for Hernia Repair: Physiological Loads Modify Anisotropy Response. AB - The aim of this study was to obtain information about the mechanical properties of six meshes commonly used for hernia repair (Surgipro((r)), Optilene((r)), Infinit((r)), DynaMesh((r)), UltraproTM and TIGR((r))) by planar biaxial tests. Stress-stretch behavior and equibiaxial stiffness were evaluated, and the anisotropy was determined by testing. In particular, equibiaxial test (equal simultaneous loading in both directions) and biaxial test (half of the load in one direction following the Laplace law) were selected as a representation of physiologically relevant loads. The majority of the meshes displayed values in the range of 8 and 18 (N/mm) in each direction for equibiaxial stiffness (tangent modulus under equibiaxial load state in both directions), while a few achieved 28 and 50 (N/mm) (Infinit ((r)) and TIGR ((r))). Only the Surgipro ((r)) mesh exhibited planar isotropy, with similar mechanical properties regardless of the direction of loading, and an anisotropy ratio of 1.18. Optilene ((r)), DynaMesh ((r)), Ultrapro ((r)) and TIGR ((r)) exhibited moderate anisotropy with ratios of 1.82, 1.84, 2.17 and 1.47, respectively. The Infinit ((r)) scaffold exhibited very high anisotropy with a ratio of 3.37. These trends in material anisotropic response changed during the physiological state in the human abdominal wall, i.e. T:0.5T test, which the meshes were loaded in one direction with half the load used in the other direction. The Surgipro ((r)) mesh increased its anisotropic response (Anis[Formula: see text] = 0.478) and the materials that demonstrated moderate and high anisotropic responses during multiaxial testing presented a quasi-isotropic response, especially the Infinit((r)) mesh that decreased its anisotropic response from 3.369 to 1.292. PMID- 26620779 TI - First-Principle Molecular Dynamics Study of Selected Schiff and Mannich Bases: Application of Two-Dimensional Potential of Mean Force to Systems with Strong Intramolecular Hydrogen Bonds. AB - Car-Parrinello Molecular Dynamics simulations were performed for selected anharmonic systems, i.e., Schiff and Mannich base-type compounds, to investigate the vibrational properties associated with O-H stretching. All calculations were performed in the gas phase to compare them with available experimental data. First the vibrational properties of the two compounds were analyzed on the basis of well-established approaches: Fourier transformation of the autocorrelation function of both the atomic velocities and dipole moments. Then path integral molecular dynamics simulations were performed to demonstrate the influence of quantum effects on the proton's position in the hydrogen bridge. In addition, quantum effects were incorporated a posteriori into calculations of O-H stretching envelopes for the Schiff and Mannich bases. Proton potential snapshots were extracted from the ab initio molecular dynamics trajectory. Vibrational Schrodinger equations (one- and two-dimensional) were solved numerically for the snapshots, and the O-H stretching envelopes were calculated as a superposition of the 0->1 transitions. Subsequently, one- and two-dimensional potentials of mean force (1D and 2D pmf) were calculated for the proton stretching mode from the proton vibrational eigenfunctions and eigenvalues incorporating statistical sampling and nuclear quantum effects. The results show that the applied methodologies are in good agreement with experimental infrared spectra. Additionally, it is demonstrated that the 2D pmf method could be applied in systems with strong anharmonicity to describe the properties of the O-H stretching mode more accurately. Future applications of the 2D pmf technique include, in principle, large biomolecular systems treated within the QM/MM framework. PMID- 26620780 TI - On the Nature of the CP Bond in Phosphaalkynes. AB - In this work, we report results of calculations based on the density functional theory (B3LYP/6-311+G(2d,2p)) of different species containing a terminal cyaphide bond. The chosen species range from small molecules and anions (C?P(-), HC?P, tBuC?P, [(CF3)3BC?P)](-)) to large transition-metal containing complexes ([(dppe)2Ru(H)(C?P)], trans-[Pt(PMe3)2(Cl)(C?P)], trans [Pt(PMe3)2(Cl)(CP)Pt(PMe3)2]). A comparative analysis of the description of the C?P bond obtained by different methodologies is presented. Topological analyses of the electron density in the framework of the theory of atoms in molecules (AIM) and of the electron localization function (ELF) are complemented with the results obtained by natural bond orbital analysis (NBO). PMID- 26620781 TI - Full Configuration-Interaction Study on the Tetrahedral Li4 Cluster. AB - The Li4 cluster low lying electronic states were studied. In particular we investigated the tetrahedral geometry at full CI and coupled cluster level, with basis sets of increasing quality. The (5)A2 electronic state, characterized by having all the valence electrons unpaired, forming a quite stable no-pair bonding state, was studied in greater detail. In order to compare the energies we also studied the Li4 rhombus singlet ground state. The ability of coupled cluster with perturbative triples to correctly reproduce energy levels in a quasi-degenerate system was validated with respect to the full CI. PMID- 26620782 TI - Flexible-Boundary Quantum-Mechanical/Molecular-Mechanical Calculations: Partial Charge Transfer between the Quantum-Mechanical and Molecular-Mechanical Subsystems. AB - Based on the principle of electronic chemical potential equalization, we propose a flexible-boundary scheme to account for partial charge transfers between the quantum-mechanical (QM) and molecular-mechanical (MM) subsystems in combined QM/MM calculations. The QM subsystem is viewed as an open system with a fluctuating number of electrons and is described by a statistical mixture of ensemble that consists of states of integer number of electrons. The MM subsystem serves as a reservoir that exchanges electrons with the QM subsystem. The electronic chemical potential of the MM subsystem varies whenever charges flow in or out, until equilibrium is established for the electronic chemical potentials between the QM and MM subsystems. Our scheme is demonstrated by calculations of the partial atomic charges for 7 small model systems, each consisting of a singly charged ion and a water molecule, as well as for the Eigen cation, a model system for the solvated structure of hydronium ion in water. Encouraging results are obtained for the partial atomic charges, which are in reasonable agreement with full-QM calculations on those model systems. The averaged mean unsigned deviations between the QM/MM and full-QM calculations are 0.16 e for the partial atomic charges of the entire systems and 0.13 e for the amount of charge transferred between the QM and MM subsystems. PMID- 26620783 TI - Effect of Structural Parameters on the Polarizabilities of Methanol Clusters: A Hirshfeld Study. AB - The polarizabilities of fifty methanol clusters (CH3OH)n, n = 1 to 12, were calculated at the B3LYP/6-311++G** level of theory and partitioned into molecular contributions using the Hirshfeld-I method. The resulting molecular polarizabilities were found to be determined by the polarizabilities of the two parts of the molecule, the hydrophilic hydroxyl group and the hydrophobic methyl group, each exhibiting a different dependency upon the local environment. The polarizability of the hydroxyl group was found to be dependent on the number, type, and strength of the hydrogen bonds a methanol molecule makes, whereas the polarizability of the methyl groups is mostly influenced by sterical hindrance. The findings were compared with the results obtained in a previous study on water clusters. The influence of the BSSE correction was investigated and found to increase polarizability values by up to 8.5%. PMID- 26620784 TI - GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. AB - Molecular simulation is an extremely useful, but computationally very expensive tool for studies of chemical and biomolecular systems. Here, we present a new implementation of our molecular simulation toolkit GROMACS which now both achieves extremely high performance on single processors from algorithmic optimizations and hand-coded routines and simultaneously scales very well on parallel machines. The code encompasses a minimal-communication domain decomposition algorithm, full dynamic load balancing, a state-of-the-art parallel constraint solver, and efficient virtual site algorithms that allow removal of hydrogen atom degrees of freedom to enable integration time steps up to 5 fs for atomistic simulations also in parallel. To improve the scaling properties of the common particle mesh Ewald electrostatics algorithms, we have in addition used a Multiple-Program, Multiple-Data approach, with separate node domains responsible for direct and reciprocal space interactions. Not only does this combination of algorithms enable extremely long simulations of large systems but also it provides that simulation performance on quite modest numbers of standard cluster nodes. PMID- 26620785 TI - Influence of Density Functionals and Basis Sets on One-Bond Carbon-Carbon NMR Spin-Spin Coupling Constants. AB - The basis set and the functional dependence of one-bond carbon-carbon NMR spin spin coupling constants (SSCC) have been analyzed using density functional theory. Four basis sets (6-311G**, TZVP, EPR-III, and aug-cc-pVTZ-J) and four functionals (PBE, PW91, B3LYP, and B3P86) are tested by comparison with 70 experimental values corresponding to 49 molecules that represent multiple types of hybridization of the carbon atoms. The two hybrid functionals B3P86 and B3LYP combined either EPR-III or aug-cc-pVTZ-J basis sets lead to the best accuracy of calculated SSCC. However, a simple linear regression allows for the obtaining of scaled coupling constants that fit much better with the experimental data and where the differences between the different basis sets and/or functional results are significantly reduced. For large molecules the TZVP basis set can be an appropriate election presenting a good compromise between quality of results and computational cost. PMID- 26620786 TI - Strong Two-Photon Circular Dichroism in Helicenes: A Theoretical Investigation. AB - Using a recently derived origin-invariant quadratic response approach combined with time-dependent density functional theory, four representative helicenes are shown to present a very strong two-photon circular dichroism (TPCD) response, which makes them candidates for the first experimental observation of a TPCD effect. The large response is attributed to the unique combination of chirality and electron delocalization. Comparison with electronic circular dichroism and two-photon absorption (TPA) shows that the three effects exhibit complementary features for unravelling the molecular structures. In particular, for the four (M)-helicenes studied here, the first, i.e., low-energy, dominant Cotton band is always negative, whereas for TPCD it is positive. From an analysis of the frontier orbitals describing most of the one-electron excitation vectors, the largest TPCD response of tetramethoxy-bisquinone-dithia-[7]-helicene has been attributed to the charge-transfer character of the excited state, like for the parent TPA effect. Moreover, the TPCD intensities are found to be mostly governed by the electric and magnetic dipole contributions, while the electric quadrupole terms are, on a relative basis, less important. PMID- 26620787 TI - Molecular Graphics of Convex Body Fluids. AB - Coarse-grained modeling of molecular fluids is often based on nonspherical convex rigid bodies like ellipsoids or spherocylinders representing rodlike or platelike molecules or groups of atoms, with site-site interaction potentials depending both on the distance among the particles and the relative orientation. In this category of potentials, the Gay-Berne family has been studied most extensively. However, conventional molecular graphics programs are not designed to visualize such objects. Usually the basic units are atoms displayed as spheres or as vertices in a graph. Atomic aggregates can be highlighted through an increasing amount of stylized representations, e.g., Richardson ribbon diagrams for the secondary structure of proteins, Connolly molecular surfaces, density maps, etc., but ellipsoids and spherocylinders are generally missing, especially as elementary simulation units. We fill this gap providing and discussing a customized OpenGL-based program for the interactive, rendered representation of large ensembles of convex bodies, useful especially in liquid crystal research. We pay particular attention to the performance issues for typical system sizes in this field. The code is distributed as open source. PMID- 26620788 TI - Combining Elastic Network Analysis and Molecular Dynamics Simulations by Hamiltonian Replica Exchange. AB - Coarse-grained elastic network models (ENM) of proteins can be used efficiently to explore the global mobility of a protein around a reference structure. A new Hamiltonian-replica exchange molecular dynamics (H-RexMD) method has been designed that effectively combines information extracted from an ENM analysis with atomic-resolution MD simulations. The ENM analysis is used to construct a distance-dependent penalty (flooding or biasing) potential that can drive the structure away from its current conformation in directions compatible with the ENM model. Various levels of the penalty or biasing potential are added to the force field description of the MD simulation along the replica coordinate. One replica runs at the original force field. By focusing the penalty potential on the relevant soft degrees of freedom the method avoids the rapid increase of the replica number with increasing system size to cover a desired temperature range in conventional (temperature) RexMD simulations. The application to domain motions in lysozyme of bacteriophage T4 and to peptide folding indicates significantly improved conformational sampling compared to conventional MD simulations. PMID- 26620789 TI - Evaluation of Salt Bridge Structure and Energetics in Peptides Using Explicit, Implicit, and Hybrid Solvation Models. AB - Replica exchange or parallel tempering molecular dynamics (REMD) is widely used to enhance the exploration of free energy landscapes for complex molecular systems. However its application to large systems is hampered by the scaling of the number of required replicas with an increasing system size. We recently proposed an improved REMD method where the exchange probabilities were calculated using a hybrid explicit/implicit solvent model. We previously tested this hybrid solvent REMD approach on alanine polypeptides of 1, 3, and 10 residues and obtained very good agreement with fully solvated REMD simulations while significantly reducing the number of replicas required. In this study we continue evaluating the applicability of the hybrid solvent REMD method through comparing the free energy of formation of ion pairs using model peptides. In accord with other studies, pure GB simulations resulted in overstabilized salt bridges, whereas the hybrid models produced free energy profiles in close agreement with fully solvated simulations, including solvent separated minima. Furthermore, the structure of the salt bridge in explicit solvent is reproduced by the hybrid solvent REMD method, while the GB simulations favor a different geometry. PMID- 26620790 TI - Computational Electrochemistry of Ruthenium Anticancer Agents. Unprecedented Benchmarking of Implicit Solvation Methods. AB - Two ruthenium(III) complexes {(HIm)[trans-RuCl4(DMSO)(Im)] (NAMI-A) and (HInd)[trans-RuCl4(Ind)2] (KP1019), DMSO = dimethyl sulfoxide, Im = imidazole, Ind = indazole} have been tested in phase I clinical trials as potential anticancer drugs. Ru(III) anticancer agents are likely activated in vivo upon reduction to their Ru(II) analogs. Aiming at benchmarking implicit solvation methods in DFT studies of ruthenium pharmaceuticals at the B3LYP level, we have calculated the standard redox potentials (SRPs) of Ru(III/II) pairs that were electrochemically characterized in the literature. 80 SRP values in four solvents were calculated using three implicit solvation methods and five solute cavities of molecular shape. Comparison with experimental data revealed substantial errors in some of the combinations of solvation method and solute cavity. For example, the overall mean unsigned error (MUE) with the PCM/UA0 combination, which is the popular default in Gaussian 03, amounts to 0.23 V (5.4 kcal/mol). The MUE with the CPCM/UAKS combination, which was employed by others for recent computational studies on the hydrolysis of NAMI-A and trans-[RuCl4(Im)2](-), amounts to 0.30 V (7.0 kcal/mol) for all compounds and to 0.60 V (13.9 kcal/mol) for a subset of compounds of the medicinally relevant type, trans-[RuCl4(L)(L')](-). The SRPs calculated with the PCM or CPCM methods in Gaussian 03 can be significantly improved by a more compact solute cavity constructed with Bondi's set of atomic radii. Earlier findings that CPCM performs better than PCM cannot be confirmed, as the overall MUE amounts to 0.19 V (4.3-4.4 kcal/mol) for both methods in combination with Bondi's set of radii. The Poisson-Boltzmann finite element method (PBF) implemented in Jaguar 7 together with the default cavity performs slightly better, with the overall MUE being 0.16 V (3.7 kcal/mol). Because the redox pairs considered in this study bear molecular charges from +3/+2 to -1/-2 and the prediction of solvation free energies is most challenging for highly charged species, the present work can serve as a general benchmarking of the implicit solvation methods. PMID- 26620791 TI - Improved Energy Selection of Nativelike Protein Loops from Loop Decoys. AB - We demonstrate the performance of a new implicit solvent model on native protein loop prediction from a large set of loop decoys of 4- to 12-residue in length. The physics-based energy function combines a hydrophobic potential of mean force (HPMF) description with a Generalized Born model for polarization of protein charge by the high dielectric solvent, which we combine with AMBER force field for the protein chain. The novelty of our energy function is the stabilizing effect of hydrophobic exposure to aqueous solvent that defines the HPMF hydration physics, which in principle should be an important stabilizing factor for loop conformations of a protein that typically are more solvent exposed. While our results for short loop decoy sets are comparably good to existing energy functions, we find demonstrable superiority for loop lengths of 8-residue and greater, and the quality of our predictions is largely insensitive to the length of the target loop on a filtered set of decoys. Given that the current weakness in loop modeling is the ability to select the most nativelike loop conformers from loop ensembles, this energy function provides a means for greater prediction accuracy in structure prediction of homologous and distantly related proteins, thereby aiding large-scale genomics efforts in comparative modeling. PMID- 26620792 TI - Is the Induction Energy Important for Modeling Organic Crystals? AB - We compare two methods for estimating the induction energy in organic molecular crystals by approximating the charge density polarization in the crystalline state. The first is a distributed atomic polarizability model combined with distributed multipole moments, derived from ab initio monomer properties. The second uses an ab initio calculation of the molecular charge density in a point charge field. Various parameters of the models, such as the rank of polarizability model, effect of self-consistent iterations, and damping, are investigated. The methods are applied to a range of observed and predicted crystal structures of three particularly challenging molecules, namely oxalyl dihydrazide, 3-azabicyclo[3,3,1]nonane-2,4-dione, and carbamazepine, as well as demonstrating the importance of induction in the naphthalene crystal. The two models agree well considering the different approximations made, and it is shown that the induction energy can be an important discriminator in the relative lattice energies of structures with substantially different hydrogen-bonding motifs. PMID- 26620793 TI - Structure, Binding Energies, and IR-Spectral Fingerprinting of Formic Acid Dimers. AB - We describe equilibrium structures for a variety of species likely to be formed as intermediate species in the dimerization of formic acid to produce the stable C2h-symmetric doubly H-bonded dimer and perhaps produced as the vapor is irradiated. For several low-lying species the rearrangement pathways to the stable form are characterized at the MP2/6-311+G(d,p) level of theory, with optimized structures and vibrations computed with full counterpoise corrections for basis set superposition error. Estimates of vibrational frequencies with corrections for anharmonicity suggest that infrared transitions (CO stretches and OH out-of-plane motions) could signal the presence of species less stable than the C2h dimer, observable in irradiation studies of formic acid vapor. PMID- 26620794 TI - Computational Study on Cesium Azide Trapped in a Cyclopeptidic Tubular Structure. AB - The structures and the electronic properties of host-guest complexes formed by a cyclopeptidic tubular aggregate and the species CsN3, Cs2(N3)2, and Cs2N6 have been investigated by means of density functional theory. Taking advantage of the azide property to act as a bridge ligand between two or more metal cations, it may be possible to trapions inside a confined space. This could be important for the preparation of polynitrogen molecules Nn. Results show that there are significant attractive interactions between the azide ion and the cavity walls, which make the ion stay inside the inner empty space of the cyclopeptidic aggregate. The confinement of the species Cs2(N3)2 forces the azide moieties to get closer together. Further, the Cs2N6 molecule shows a remarkable interaction with the tubular host, which may indicate a stabilization of N6. PMID- 26620795 TI - An integrated network of Arabidopsis growth regulators and its use for gene prioritization. AB - Elucidating the molecular mechanisms that govern plant growth has been an important topic in plant research, and current advances in large-scale data generation call for computational tools that efficiently combine these different data sources to generate novel hypotheses. In this work, we present a novel, integrated network that combines multiple large-scale data sources to characterize growth regulatory genes in Arabidopsis, one of the main plant model organisms. The contributions of this work are twofold: first, we characterized a set of carefully selected growth regulators with respect to their connectivity patterns in the integrated network, and, subsequently, we explored to which extent these connectivity patterns can be used to suggest new growth regulators. Using a large-scale comparative study, we designed new supervised machine learning methods to prioritize growth regulators. Our results show that these methods significantly improve current state-of-the-art prioritization techniques, and are able to suggest meaningful new growth regulators. In addition, the integrated network is made available to the scientific community, providing a rich data source that will be useful for many biological processes, not necessarily restricted to plant growth. PMID- 26620796 TI - Public involvement in research within care homes: benefits and challenges in the APPROACH study. AB - BACKGROUND: Public involvement in research (PIR) can improve research design and recruitment. Less is known about how PIR enhances the experience of participation and enriches the data collection process. In a study to evaluate how UK care homes and primary health-care services achieve integrated working to promote older people's health, PIR was integrated throughout the research processes. OBJECTIVES: This paper aims to present one way in which PIR has been integrated into the design and delivery of a multisite research study based in care homes. DESIGN: A prospective case study design, with an embedded qualitative evaluation of PIR activity. SETTING AND PARTICIPANTS: Data collection was undertaken in six care homes in three sites in England. Six PIR members participated: all had prior personal or work experience in care homes. DATA COLLECTION: Qualitative data collection involved discussion groups, and site-specific meetings to review experiences of participation, benefits and challenges, and completion of structured fieldwork notes after each care home visit. RESULTS: PIR members supported recruitment, resident and staff interviews and participated in data interpretation. Benefits of PIR work were resident engagement that minimized distress and made best use of limited research resources. Challenges concerned communication and scheduling. Researcher support for PIR involvement was resource intensive. DISCUSSION AND CONCLUSIONS: Clearly defined roles with identified training and support facilitated involvement in different aspects of the data collection process. This can also ensure that vulnerable older people who participate in research have a positive experience that reinforces the value of their views. PMID- 26620798 TI - Super-enhancer lncs to cardiovascular development and disease. AB - Cardiac development, function and pathological remodelling in response to stress depend on the dynamic control of tissue specific gene expression by distant acting transcriptional enhancers. Recently, super-enhancers (SEs), also known as stretch or large enhancer clusters, are emerging as sentinel regulators within the gene regulatory networks that underpin cellular functions. It is becoming increasingly evident that long noncoding RNAs (lncRNAs) associated with these sequences play fundamental roles for enhancer activity and the regulation of the gene programs hardwired by them. Here, we review this emerging landscape, focusing on the roles of SEs and their derived lncRNAs in cardiovascular development and disease. We propose that exploration of this genomic landscape could provide novel therapeutic targets and approaches for the amelioration of cardiovascular disease. Ultimately we envisage a future of ncRNA therapeutics targeting the SE landscape to alleviate cardiovascular disease. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID- 26620799 TI - Sharing with your children: Mechanisms of peroxisome inheritance. AB - Organelle inheritance is the process by which eukaryotic cells actively replicate and equitably partition their organelles between mother cell and daughter cell at cytokinesis to maintain the benefits of subcellular compartmentalization. The budding yeast Saccharomyces cerevisiae has proven invaluable in helping to define the factors involved in the inheritance of different organelles and in understanding how these factors act and interact to maintain balance in the organelle populations of actively dividing cells. Inheritance factors can be classified as motors that transport organelles, tethers that retain organelles, and connectors (receptors) that mediate the attachment of organelles to motors and anchors. This article will review how peroxisomes are inherited by cells, with a focus on budding yeast, and will discuss common themes and mechanisms of action that underlie the inheritance of all membrane-enclosed organelles. PMID- 26620800 TI - The molecular and functional identities of atrial cardiomyocytes in health and disease. AB - Atrial cardiomyocytes are essential for fluid homeostasis, ventricular filling, and survival, yet their cell biology and physiology are incompletely understood. It has become clear that the cell fate of atrial cardiomyocytes depends significantly on transcription programs that might control thousands of differentially expressed genes. Atrial muscle membranes propagate action potentials and activate myofilament force generation, producing overall faster contractions than ventricular muscles. While atria-specific excitation and contractility depend critically on intracellular Ca(2+) signalling, voltage dependent L-type Ca(2+) channels and ryanodine receptor Ca(2+) release channels are each expressed at high levels similar to ventricles. However, intracellular Ca(2+) transients in atrial cardiomyocytes are markedly heterogeneous and fundamentally different from ventricular cardiomyocytes. In addition, differential atria-specific K(+) channel expression and trafficking confer unique electrophysiological and metabolic properties. Because diseased atria have the propensity to perpetuate fast arrhythmias, we discuss our understanding about the cell-specific mechanisms that lead to metabolic and/or mitochondrial dysfunction in atrial fibrillation. Interestingly, recent work identified potential atria specific mechanisms that lead to early contractile dysfunction and metabolic remodelling, suggesting highly interdependent metabolic, electrical, and contractile pathomechanisms. Hence, the objective of this review is to provide an integrated model of atrial cardiomyocytes, from tissue-specific cell properties, intracellular metabolism, and excitation-contraction (EC) coupling to early pathological changes, in particular metabolic dysfunction and tissue remodelling due to atrial fibrillation and aging. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID- 26620797 TI - Volume-regulated anion channel--a frenemy within the brain. AB - The volume-regulated anion channel (VRAC) is a ubiquitously expressed yet highly enigmatic member of the superfamily of chloride/anion channels. It is activated by cellular swelling and mediates regulatory cell volume decrease in a majority of vertebrate cells, including those in the central nervous system (CNS). In the brain, besides its crucial role in cellular volume regulation, VRAC is thought to play a part in cell proliferation, apoptosis, migration, and release of physiologically active molecules. Although these roles are not exclusive to the CNS, the relative significance of VRAC in the brain is amplified by several unique aspects of its physiology. One important example is the contribution of VRAC to the release of the excitatory amino acid neurotransmitters glutamate and aspartate. This latter process is thought to have impact on both normal brain functioning (such as astrocyte-neuron signaling) and neuropathology (via promoting the excitotoxic death of neuronal cells in stroke and traumatic brain injury). In spite of much work in the field, the molecular nature of VRAC remained unknown until less than 2 years ago. Two pioneer publications identified VRAC as the heterohexamer formed by the leucine-rich repeat-containing 8 (LRRC8) proteins. These findings galvanized the field and are likely to result in dramatic revisions to our understanding of the place and role of VRAC in the brain, as well as other organs and tissues. The present review briefly recapitulates critical findings in the CNS and focuses on anticipated impact on the LRRC8 discovery on further progress in neuroscience research. PMID- 26620801 TI - Phosphorylation negatively regulates exosome mediated secretion of cryAB in glioma cells. AB - Exosomes mediate secretion of crystallin alphaB (cryAB), a well characterized molecular chaperone with anti-apoptotic activity. However, the mechanisms governing its packaging and secretion remained unexplored. In glioma cells, notwithstanding extensive phosphorylation of cryAB at Ser59 followed by Ser45 (Ser19 is largely unphosphorylated), we discovered that the majority of secreted exosomal cryAB is nonphosphorylated. Transient ectopic expression of a yellow fluorescent protein (YFP) tagged triple phosphomimic (3-SD) cryAB construct in cryAB absent glioma cells led to the formation of large cytosolic inclusions. Our findings demonstrate that mimicking phosphorylation significantly reduces cryAB secretion via exosomes. Moreover, decreased colocalization of 3-SD YFP-cryAB with multivesicular endosome (MVE) and exosome marker, CD63 or Rab27, a small GTPase regulating exocytosis of MVEs, suggests that phosphorylation deters packaging of cryAB in vesicles bound for secretion as exosomes. Additionally, we found that preventing O-GlcNAcylation on cryAB also curtailed its colocalization with CD63 and Rab27 resulting in reduced exosomal secretion. Thus, our study points to O GlcNAcylation and lack of phosphorylation as being the selective processes involved in the packaging and secretion of cryAB via exosomes. PMID- 26620803 TI - A systematic review and meta-analysis of the use of antifibrinolytic agents in total hip arthroplasty. AB - BACKGROUND: Antifibrinolytic agents such as tranexamic acid (TXA), epsilon aminocaproic acid (EACA), and aprotinin are widely used to reduce bleeding and the need for transfusion in cardiac, orthopaedic, and hepatic surgery. We aimed to assess the efficacy and safety of antifibrinolytic agents in total hip arthroplasty (THA). METHODS: A systematic literature search was performed using MEDLINE, PubMed, EMBASE, and Cochrane databases, as well as the reference lists of relevant articles. Only randomised controlled trials were eligible for this study. The weighted mean difference in blood loss, number of transfusions per patient, and the summary risk ratio of transfusion requirements and deep-vein thrombosis (DVT) were calculated in the antifibrinolytic agents-treated and control groups. RESULTS: A total of 28 randomised controlled trials involving 2,131 patients were included. Patients receiving antifibrinolytic agents had a reduced total blood loss by a mean of 389.14 ml (95% CI, -483.05 to -295.23), and the number of blood transfusions per patient by 0.65 units (95% CI, -1.19 to 0.12). Antifibrinolytic agents led to a significant reduction in transfusion requirements (RR 0.55; 95% CI, 0.43 to 0.70) and no increase in the risk of DVT (RR 0.85; 95% CI, 0.51 to 1.42). CONCLUSIONS: Our meta-analysis demonstrated that antifibrinolytic agents significantly reduce blood loss and blood transfusion requirements while not increasing the risk of DVT in patients undergoing total hip arthroplasty. PMID- 26620804 TI - Hyperimmunoglobulin D syndrome in an Indian family undiagnosed for 11 years. PMID- 26620805 TI - Distribution and molecular phylogeny of biliary trematodes (Opisthorchiidae) infecting native Lutra lutra and alien Neovison vison across Europe. AB - The recent identification of Pseudamphistomum truncatum, (Rudolphi, 1819) (Trematoda: Opisthorchiidae) and Metorchis bilis (Braun, 1790) Odening, 1962 (synonymous with Metorchis albidus (Braun, 1893) Loos, 1899 and Metorchis crassiusculus (Rudolphi, 1809) Looss, 1899 (Trematoda: Opisthorchiidae)) in otters from Britain caused concern because of associated biliary damage, coupled with speculation over their alien status. Here, we investigate the presence, intensity and phylogeny of these trematodes in mustelids (principally otters) across Europe (Czech Republic, Denmark, France, Germany, Norway, Poland and Sweden and Britain). The trematodes were identified to species using the internal transcribed spacer II (ITS2) locus. Both parasites were found across Europe but at unequal frequency. In the German state of Saxony, eight out of eleven (73%) otters examined were infected with P. truncatum whilst this parasite was not found in either mink from Scotland (n=40) or otters from Norway (n=21). Differences in the phylogenies between the two species suggest divergent demographic histories possibly reflecting contrasting host diet or competitive exclusion, with M. bilis exhibiting greater mitochondrial diversity than P. truncatum. Shared haplotypes within the ranges of both parasite species probably reflect relatively unrestricted movements (both natural and anthropogenic) of intermediate and definitive hosts across Europe. PMID- 26620807 TI - Response to: Case-control studies require appropriate population controls: an example of error in the SSRI birth defect literature. PMID- 26620806 TI - The Use of a Small Private Online Course to Allow Educators to Share Teaching Resources Across Diverse Sites: The Future of Psychiatric Case Conferences? AB - OBJECTIVE: The authors sought to demonstrate the feasibility of integrating small private online course (SPOC) technology with flipped classroom techniques in order to improve neuroscience education across diverse training sites. METHODS: Post-graduate medical educators used SPOC web conferencing software and video technology to implement an integrated case conference and in-depth neuroscience discussion. RESULTS: Ten psychiatry training programs from across the USA and from two international sites took part in the conference. Feedback from participants was largely positive. CONCLUSION: This pilot demonstrated the feasibility of such a program and provided a diverse audience with the opportunity to engage in an interactive learning experience with expert faculty discussants. This may be a useful model for programs with limited local expertise to expand their teaching efforts in a wide range of topics. PMID- 26620802 TI - Chloroplast phylogenomic analysis of chlorophyte green algae identifies a novel lineage sister to the Sphaeropleales (Chlorophyceae). AB - BACKGROUND: The class Chlorophyceae (Chlorophyta) includes morphologically and ecologically diverse green algae. Most of the documented species belong to the clade formed by the Chlamydomonadales (also called Volvocales) and Sphaeropleales. Although studies based on the nuclear 18S rRNA gene or a few combined genes have shed light on the diversity and phylogenetic structure of the Chlamydomonadales, the positions of many of the monophyletic groups identified remain uncertain. Here, we used a chloroplast phylogenomic approach to delineate the relationships among these lineages. RESULTS: To generate the analyzed amino acid and nucleotide data sets, we sequenced the chloroplast DNAs (cpDNAs) of 24 chlorophycean taxa; these included representatives from 16 of the 21 primary clades previously recognized in the Chlamydomonadales, two taxa from a coccoid lineage (Jenufa) that was suspected to be sister to the Golenkiniaceae, and two sphaeroplealeans. Using Bayesian and/or maximum likelihood inference methods, we analyzed an amino acid data set that was assembled from 69 cpDNA-encoded proteins of 73 core chlorophyte (including 33 chlorophyceans), as well as two nucleotide data sets that were generated from the 69 genes coding for these proteins and 29 RNA-coding genes. The protein and gene phylogenies were congruent and robustly resolved the branching order of most of the investigated lineages. Within the Chlamydomonadales, 22 taxa formed an assemblage of five major clades/lineages. The earliest-diverging clade displayed Hafniomonas laevis and the Crucicarteria, and was followed by the Radicarteria and then by the Chloromonadinia. The latter lineage was sister to two superclades, one consisting of the Oogamochlamydinia and Reinhardtinia and the other of the Caudivolvoxa and Xenovolvoxa. To our surprise, the Jenufa species and the two spine-bearing green algae belonging to the Golenkinia and Treubaria genera were recovered in a highly supported monophyletic group that also included three taxa representing distinct families of the Sphaeropleales (Bracteacoccaceae, Mychonastaceae, and Scenedesmaceae). CONCLUSIONS: Our phylogenomic study advances our knowledge regarding the circumscription and internal structure of the Chlamydomonadales, suggesting that a previously unrecognized lineage is sister to the Sphaeropleales. In addition, it offers new insights into the flagellar structures of the founding members of both the Chlamydomonadales and Sphaeropleales. PMID- 26620808 TI - What is the role of modifiable environmental and lifestyle risk factors in young onset dementia? AB - Young onset dementia (YOD) is associated with significant costs and burden, but its cause is poorly understood. The aim of this review was to determine whether environmental and lifestyle factors are associated with risk for non-autosomal dominant degenerative and vascular YOD. Academic databases were searched to March 2015 for studies assessing the impact of modifiable factors (e.g. education, cardiovascular illness, psychiatric illness, alcohol use) in participants under 65 years at symptom onset. Cardiovascular illness, traumatic brain injury, psychiatric illness, heavy alcohol use and estrogen-related factors were identified as potential risk factors for YOD. Evidence for education, childhood development, smoking and heavy metal exposure was inconsistent or of poor quality. A dose-response relationship was found between cumulative and/or increasing severity of exposure and risk for YOD. Environmental and lifestyle risk factors may be relevant to YOD, particularly with severe or cumulative exposure. More high quality research is required to confirm which factors confer risk and when. PMID- 26620809 TI - Generic versus brand-name drugs used in cardiovascular diseases. AB - This meta-analysis aimed to compare the efficacy and adverse events, either serious or mild/moderate, of all generic versus brand-name cardiovascular medicines. We searched randomized trials in MEDLINE, Scopus, EMBASE, Cochrane Controlled Clinical Trial Register, and ClinicalTrials.gov (last update December 1, 2014). Attempts were made to contact the investigators of all potentially eligible trials. Two investigators independently extracted and analyzed soft (including systolic blood pressure, LDL cholesterol, and others) and hard efficacy outcomes (including major cardiovascular adverse events and death), minor/moderate and serious adverse events. We included 74 randomized trials; 53 reported >=1 efficacy outcome (overall sample 3051), 32 measured mild/moderate adverse events (n = 2407), and 51 evaluated serious adverse events (n = 2892). We included trials assessing ACE inhibitors (n = 12), anticoagulants (n = 5), antiplatelet agents (n = 17), beta-blockers (n = 11), calcium channel blockers (n = 7); diuretics (n = 13); statins (n = 6); and others (n = 3). For both soft and hard efficacy outcomes, 100 % of the trials showed non-significant differences between generic and brand-name drugs. The aggregate effect size was 0.01 (95 % CI -0.05; 0.08) for soft outcomes; -0.06 (-0.71; 0.59) for hard outcomes. All but two trials showed non-significant differences in mild/moderate adverse events, and aggregate effect size was 0.07 (-0.06; 0.20). Comparable results were observed for each drug class and in each stratified meta-analysis. Overall, 8 serious possibly drug-related adverse events were reported: 5/2074 subjects on generics; 3/2076 subjects on brand-name drugs (OR 1.69; 95 % CI 0.40-7.20). This meta-analysis strengthens the evidence for clinical equivalence between brand name and generic cardiovascular drugs. Physicians could be reassured about prescribing generic cardiovascular drugs, and health care organization about endorsing their wider use. PMID- 26620810 TI - Semantic congruency but not temporal synchrony enhances long-term memory performance for audio-visual scenes. AB - Human long-term memory for visual objects and scenes is tremendous. Here, we test how auditory information contributes to long-term memory performance for realistic scenes. In a total of six experiments, we manipulated the presentation modality (auditory, visual, audio-visual) as well as semantic congruency and temporal synchrony between auditory and visual information of brief filmic clips. Our results show that audio-visual clips generally elicit more accurate memory performance than unimodal clips. This advantage even increases with congruent visual and auditory information. However, violations of audio-visual synchrony hardly have any influence on memory performance. Memory performance remained intact even with a sequential presentation of auditory and visual information, but finally declined when the matching tracks of one scene were presented separately with intervening tracks during learning. With respect to memory performance, our results therefore show that audio-visual integration is sensitive to semantic congruency but remarkably robust against asymmetries between different modalities. PMID- 26620811 TI - Transitive reasoning distorts induction in causal chains. AB - A probabilistic causal chain A->B->C may intuitively appear to be transitive: If A probabilistically causes B, and B probabilistically causes C, A probabilistically causes C. However, probabilistic causal relations can only guaranteed to be transitive if the so-called Markov condition holds. In two experiments, we examined how people make probabilistic judgments about indirect relationships A->C in causal chains A->B->C that violate the Markov condition. We hypothesized that participants would make transitive inferences in accordance with the Markov condition although they were presented with counterevidence showing intransitive data. For instance, participants were successively presented with data entailing positive dependencies A->B and B->C. At the same time, the data entailed that A and C were statistically independent. The results of two experiments show that transitive reasoning via a mediating event B influenced and distorted the induction of the indirect relation between A and C. Participants' judgments were affected by an interaction of transitive, causal-model-based inferences and the observed data. Our findings support the idea that people tend to chain individual causal relations into mental causal chains that obey the Markov condition and thus allow for transitive reasoning, even if the observed data entail that such inferences are not warranted. PMID- 26620812 TI - Factors Related to the Intention of Israelis to Use Complementary and Alternative Medicine. AB - PURPOSE: Despite the significant rise in the use of complementary and alternative medicine (CAM) in Israel, the factors affecting the decision to do so remain unclear. Thus, the purpose of the study was to explore factors that affect Israelis' intention to use CAM, using the theory of planned behavior (TPB). DESIGN: A quantitative correlational study. METHOD: A convenience sample of 200 Hebrew-speaking Israelis aged 21+ completed a questionnaire based on the TPB. FINDINGS: Respondents expressed moderate intention to use CAM. The TPB predictability of this intention was 57% (R2 = .57), with behavioral beliefs being the most influential factor. The family was identified as another significant factor. Previous experience with CAM was also found to raise the intention to use it in the future. CONCLUSIONS: When referring a patient for services of CAM, it is important to provide in-depth explanations emphasizing positive anticipated outcomes of these services in order to effect a change in the patient's behavioral beliefs. Patient's family should be considered as a possible resource to promote usage of CAM. PMID- 26620813 TI - The Role of Spirituality and Religiosity in Persons Living With Sickle Cell Disease: A Review of the Literature. AB - PURPOSE: Sickle cell disease (SCD) is a serious debilitating chronic illness, affecting approximately 90,000 Americans and millions globally. Spirituality and religiosity (S/R) may ease the burden faced by persons living with SCD. The purpose of this study was to examine the role of S/R in adolescents and adults living with SCD in the research literature. METHOD: The electronic databases Cumulative Index to Nursing and Allied Health Literature, Health Source Nursing/Academic, ProQuest Health Module, PsycINFO, Medline, PubMed, and the American Theological Library Association were searched from January 1995 to December 2014. FINDINGS: Of the 89 studies retrieved, 11 articles between 2001 and 2013 met the inclusion criteria and were reviewed. Four themes emerged. The themes included (a) S/R as sources of coping, (b) S/R enhance pain management, (c) S/R influence health care utilization, and (d) S/R improve quality of life. DISCUSSION: Use of S/R may be significant in coping with SCD, managing pain, affecting hospitalizations, and affecting quality of life. This review can direct researchers exploring S/R in adolescents and adults living with SCD. PMID- 26620814 TI - A comparative differential scanning calorimetry study of the effects of cholesterol and various oxysterols on the thermotropic phase behavior of dipalmitoylphosphatidylcholine bilayer membranes. AB - We have carried out a comparative differential scanning calorimetric (DSC) study of the effects of cholesterol (C) and the eight most physiologically relevant oxysterols on the thermotropic phase behavior of dipalmitoylphosphatidylcholine (DPPC) bilayer membranes. The structures of these oxysterols differ from that of C by the presence of additional hydroxyl, keto or epoxy groups on the steroid ring system or by the presence of a hydroxyl group in the alkyl side chain. In general, the progressive incorporation of these oxysterols reduces the temperature, cooperativity and enthalpy of the pretransition of DPPC to a greater extent than C, indicating that their presence thermally destabilizes and disorders the gel states of DPPC bilayers to a greater extent than C. Similarly, the incorporation of these oxysterols either increases the temperature of the broad component of the main phase transition to a smaller extent than C or actually decreases it. Again, this indicates that the presence of these compounds is less effective at thermally stabilizing and ordering the sterol-rich domains of DPPC bilayers than is C itself. Moreover, the incorporation of these oxysterols decrease the cooperativity and enthalpy of the main phase transition of DPPC to a smaller extent than C, indicating that they are somewhat less miscible in fluid DPPC bilayers than is C. Particularly notable in this regard is 25-hydroxycholesterol, which exhibits a markedly reduced miscibility in both gel and fluid DPPC bilayers compared to C itself. In general, the effectiveness of these oxysterols in stabilizing and ordering DPPC bilayers decreases as their rate of interbilayer exchange and the polarity of the oxysterol increases. We close by providing a tentative molecular explanation for the results of our DSC studies and of those of previous biophysical studies of the effects of various oxysterol on lipid bilayer model membranes. PMID- 26620815 TI - A systematic approach to expound the variations in taxane production under different dissolved oxygen conditions in Taxus chinensis cells. AB - KEY MESSAGE: Our results provide an evidence that the changes in taxane production caused by dissolved oxygen shifts could be associated with the global variations in the cell central carbon metabolism. Taxol is an important taxane synthesized by the Taxus plant. A two-stage culture of Taxus in vitro has been considered as an attractive alternative approach to produce Taxol and its precursors. To investigate the consequences of dissolved oxygen (DO) shifts for cell primary and secondary metabolism, we conducted metabolomic and transcriptomic profiling analyses under low dissolved oxygen (LDO), medium dissolved oxygen (MDO), and high dissolved oxygen (HDO) conditions in a suspension culture of Taxus chinensis cells. Under LDO, the results indicate a significant increase in the production of Taxol and its main precursors by 3.4- to 1.4-fold compared with those under MDO and HDO on 9th day. Multiple acyl taxanes (MAT) are abundant taxanes in the cells, and exhibited only a slight increase under the same conditions. Metabolomic analysis based on 209 primary metabolites indicated that several pathways in central carbon metabolism were involved, including the enhancement of the glycolysis pathway of glucose-6 phosphate to fructose-6-phosphate and pyruvate and the mevalonate pathway of terpene biosynthesis, and decline in the tricarboxylic acid pathway under LDO. These results indicate the mechanism by which related taxanes accumulate through enhancing the supplies of substrates and expression levels of hydroxylases. Excess acetyl-CoA supply induced by high oxygen stress was found to be correlated with high productivity of MAT. Our results provide an evidence that the changes in taxane production caused by DO shifts could be associated with the global variations in the cell central carbon metabolism. PMID- 26620816 TI - Racial and ethnic disparities in cost-related medication non-adherence among cancer survivors. AB - PURPOSE: Cancer survivors are delaying or avoiding necessary care due to costs, and medication non-adherence is an important aspect of deferred treatment. This study estimates the prevalence of cost-related medication non-adherence (CRN) by race and ethnicity and examines factors associated with CRN among cancer survivors. METHODS: Using the 2006-2013 National Health Interview Survey, we examine self-reported CRN among cancer survivors compared with cancer-free controls. Descriptive statistics and multiple logistic regression models were used to identify factors associated with CRN among cancer survivors. RESULTS: In a nationally representative sample of 472,542 adults, 10,998 participants reported a history of cancer and 461,544 did not. Among 10,998 cancer survivors, 1397 (12.70 %) reported CRN. Among older cancer survivors, African-Americans were 2.64 times more likely (95 % confidence interval (CI), 1.73 to 4.01) and Hispanics 2.07 times more likely (95 % CI, 1.32 to 3.24) than whites to report CRN. Among younger cancer survivors, Hispanics were 1.61 times more likely (95 % CI, 1.23 to 2.10) than whites to report CRN. CONCLUSIONS: Significant racial and ethnic disparities in CRN were evident among cancer survivors. Older African American and Hispanic overall survivors were more likely to report CRN in the past year compared with non-Hispanic whites. IMPLICATIONS FOR CANCER SURVIVORS: Given increasing prescription drug expenditure, it is important to closely monitor CRN in high-risk subgroups. Racial and ethnic minority groups at high risk for CRN should be counseled on the importance of medication adherence and offered support services to promote medication adherence. Further studies are warranted to establish effective policies and interventions in vulnerable populations. PMID- 26620817 TI - The Cognitive Symptom Checklist-Work in cancer patients is related with work functioning, fatigue and depressive symptoms: a validation study. AB - PURPOSE: The study objectives are to translate the 21-item Cognitive Symptom Checklist-Work (CSC-W21) to Dutch (CSC-W DV) and to validate the CSC-W DV in working cancer patients. METHODS: The CSC-W21 was cross-culturally translated and adapted to a Dutch version. In this 19-item version, the dichotomous response option was changed to an ordinal five-point scale. A validation study of the CSC W DV was conducted among cancer patients who had returned to work during or following cancer treatment. Internal consistency (Cronbach's alpha), structural validity (exploratory factor analysis) and construct validity (hypothesis testing) were evaluated. RESULTS: In a cohort of 364 cancer patients, 341 (94 %) completed the CSC-W DV (aged 50.6 +/- 8.6 years, 60 % women). Exploratory factor analysis revealed two subscales 'working memory' and 'executive function'. The internal consistency of the total scale and subscales was high (Cronbach's alpha = 0.93-0.95). Hypothesis testing showed that self-reported cognitive limitations at work were related to work functioning (P < 0.001), fatigue (P = 0.001) and depressive symptoms (P < 0.001), but not to self-rated health (P = 0.14). CONCLUSIONS: The CSC-W DV showed high internal consistency and reasonable construct validity for measuring work-specific cognitive symptoms in cancer patients. The CSC-W DV was associated in expected ways with work functioning, fatigue and depressive symptoms. IMPLICATIONS FOR CANCER SURVIVORS: It is important to enhance knowledge about cognitive symptoms at work in cancer patients, to guide and support cancer patients as good as possible when they are back at work and to improve their work functioning over time. PMID- 26620818 TI - Vaginal brachytherapy for postoperative endometrial cancer: 2014 Survey of the American Brachytherapy Society. AB - PURPOSE: Report current practice patterns for postoperative endometrial cancer emphasizing vaginal brachytherapy (VBT). METHODS AND MATERIALS: A 38-item survey was e-mailed to 1,598 American Brachytherapy Society (ABS) members and 4,329 US radiation oncologists in 2014 totaling 5,710 recipients. Responses of practitioners who had delivered VBT in the previous 12 months were included in the analysis. Responses were tabulated to determine relative frequency distributions. chi(2) analysis was used to compare current results with those from the 2003 ABS survey. RESULTS: A total of 331 respondents initiated the VBT survey, of whom 289 (87.3%) administered VBT in the prior 12 months. Lymph node dissection and number of nodes removed influenced treatment decisions for 90.5% and 69.8%, respectively. High-dose-rate was used by 96.2%. The most common vaginal length treated was 4 cm (31.0%). Three-dimensional planning was used by 83.2% with 73.4% of those for the first fraction only. Doses to normal tissues were reported by 79.8%. About half optimized to the location of dose specification and/or normal tissues. As monotherapy, the most common prescriptions were 7 Gy for three fractions to 0.5-cm depth and 6 Gy for five fractions to the surface. As a boost, the most common prescriptions were 5 Gy for three fractions to 0.5-cm depth and 6 Gy for three fractions to the vaginal surface. Optimization points were placed at the apex and lateral vagina by 73.1%. Secondary quality assurance checks were performed by 98.9%. CONCLUSIONS: VBT is a common adjuvant therapy for endometrial cancer patients, most commonly with HDR. Fractionation and planning processes are variable but generally align with ABS recommendations. PMID- 26620820 TI - Low dose cyclophosphamide: Mechanisms of T cell modulation. AB - Cyclophosphamide is considered one of the most successful chemotherapy drugs and is listed on the World Health Organisations List of Essential Medicines. Since its initial synthesis in 1958, it has been widely used to treat a range of cancers but its use has been declining due to the advent of platinum based and other chemotherapy agents. However, cyclophosphamide is still used either as a single agent or as adjuvant therapy to treat lymphomas, and breast and ovarian cancers at much lower doses. The efficacy of low dose cyclophosphamide is primarily due to its ability to promote anti-tumour immunity, by selectively depleting regulatory T cells and enhancing effector T cell function. Compared to effecter T cells, regulatory T cells have metabolic adaptations that make them more susceptible to cyclophosphamide-mediated cytotoxicity. In this review, we highlight the potential for improving the efficacy of low dose cyclophosphamide by combining insights on the mechanisms of cyclophosphamide-mediated cytotoxicity, and how these cytotoxic effects of cyclophosphamide influence T cell function, thereby contributing to anti-tumour immunity. PMID- 26620819 TI - Adjuvant therapy for pancreas cancer in an era of value based cancer care. AB - In resected pancreas cancer, adjuvant therapy improves outcomes and is considered the standard of care for patients who recover sufficiently post operatively. Chemotherapy or combined chemotherapy and radiation therapy (chemoradiation; CRT) are strategies used in the adjuvant setting. However, there is a lack of evidence to suggest whether the addition of RT to chemotherapy translates to an improvement in clinical outcomes. This is true even when accounting for the subset of patients with a higher risk for recurrence, such as those with R1 and lymph node positive disease. When considering the direct and indirect costs, impact on quality of life and questionable added clinical benefit, the true "net health benefit" from added RT to chemotherapy becomes more uncertain. Future directions, including the utilization of modern RT, integration of novel therapies, and intensifying chemotherapy regimens may improve outcomes in resected pancreas cancer. PMID- 26620821 TI - Diaphragm myoclonus followed by generalised atonia in a patient with trisomy 4p: unusual semiology in an unusual condition. AB - In this report, we describe a female patient with trisomy 4p, a rare genetic condition, with unusual seizure semiology. The patient is one of the oldest reported survivors with this condition. This semiology was noted while she was being monitored by inpatient video telemetry. We observed a series of myoclonic shoulder jerks, followed by hiccup-like episodes, and finally an atonic head drop. Corresponding ictal EEG showed semi-rhythmic high-amplitude slow waves with spikes superimposed over the frontotemporal areas. This semiology was confirmed as habitual by her parents. Subsequent hiccup-like episodes had no EEG correlate, and the head drop was again associated with semi-rhythmic high-amplitude slow waves and superimposed spikes, more prominent over the right hemisphere. In addition, we review the several cases in which hiccups have been associated with seizures and how this may relate to the neural pathways involved in the pathophysiology of hiccups. We believe the ictal hiccup-like episodes followed by atonia to be a seizure semiology that has not previously been documented. [Published with video sequence]. PMID- 26620823 TI - Treatment strategies for coronary in-stent restenosis: systematic review and hierarchical Bayesian network meta-analysis of 24 randomised trials and 4880 patients. PMID- 26620822 TI - The effects of working memory on brain-computer interface performance. AB - OBJECTIVE: The purpose of the present study is to evaluate the relationship between working memory and BCI performance. METHODS: Participants took part in two separate sessions. The first session consisted of three computerized tasks. The List Sorting Working Memory Task was used to measure working memory, the Picture Vocabulary Test was used to measure general intelligence, and the Dimensional Change Card Sort Test was used to measure executive function, specifically cognitive flexibility. The second session consisted of a P300-based BCI copy-spelling task. RESULTS: The results indicate that both working memory and general intelligence are significant predictors of BCI performance. CONCLUSIONS: This suggests that working memory training could be used to improve performance on a BCI task. SIGNIFICANCE: Working memory training may help to reduce a portion of the individual differences that exist in BCI performance allowing for a wider range of users to successfully operate the BCI system as well as increase the BCI performance of current users. PMID- 26620824 TI - Plasmonics, Tracking and Manipulating, and Living Cells: general discussion. PMID- 26620825 TI - Stability of lyophilized teriparatide, PTH(1-34), after reconstitution. AB - The peptide teriparatide, also known as parathyroid hormone (1-34), PTH(1-34), was developed for intranasal delivery, requiring extended stability of the reconstituted product for up to four weeks at room temperature. Lyophilized formulations of PTH(1-34), containing glycine and trehalose and using lactate as the buffer, are stable for months upon storage. However, the physical stability of the peptide after reconstitution unexpectedly varied considerably, depending on peptide concentration and storage temperature, with precipitation seen within two to four weeks in some samples. By comparison, equivalent samples that did not undergo lyophilization did not display any precipitation upon storage in the liquid state for as long as twelve weeks. PTH(1-34) appears to adopt a higher order structure that is perturbed by the combined stresses of freezing and drying, leading to greater propensity to aggregate, which is accentuated at higher peptide concentrations and at higher temperatures. The precipitation seems to be correlated with increased amounts of subvisible particles. This study shows the importance of peptide conformation in long-term stability and illustrates the ability of lyophilization to cause increased propensity to aggregate, even in a peptide. PMID- 26620826 TI - A Qualitative Examination of Situational Risk Recognition Among Female Victims of Physical Intimate Partner Violence. AB - Little is known about intimate partner violence (IPV) victims' situational risk recognition, defined as the ability to identify situational factors that signal imminent risk of victimization. Using semi-structured interviews, qualitative data were collected from a community sample of 31 female victims of IPV episodes involving substance use. Thirteen themes were identified, the most prevalent being related to the partner's verbal behavior, tone of voice, motor behavior, alcohol or drug use, and facial expression. Participants reporting at least some anticipation of physical aggression (61.3% of the sample) tended to identify multiple factors (M = 3.47), suggesting numerous situational features often contribute to situational risk recognition. PMID- 26620828 TI - Erratum to: Lactosaminated mesoporous silica nanoparticles for asialoglycoprotein receptor targeted anticancer drug delivery. PMID- 26620829 TI - Nonomuraea thermotolerans sp. nov., a thermotolerant actinomycete isolated from mushroom compost. AB - A novel thermotolerant actinomycete, designated strain 3-33-9BT, was isolated from mushroom compost in Nanning, Guangxi province, China. The strain grew at 25 60 degrees C, pH 7.0-11.0 and with 0-2.0 % (w/v) NaCl. Strain 3-33-9BT formed extensively branched aerial mycelia and substrate mycelia. Spiral spore chains with one to three turns were composed of about 3-15 non-motile spores with a wrinkled surface. The organism contained meso-diaminopimelic acid as the diagnostic diamino acid in the cell-wall peptidoglycan. Whole-cell hydrolysates contained madurose, galactose, glucose and ribose. The cellular fatty acid profile mainly consisted of iso-C16 : 0 and C17 : 0. The quinone system was predominantly composed of MK-9(H4). The DNA G+C content of strain 3-33-9BT was 72.5 mol%. The organism showed a combination of morphological and chemotaxonomic properties typical of members of the genus Nonomuraea. Moreover, 16S rRNA gene sequence analysis also showed that the organism belonged to the genus Nonomuraea; in the 16S rRNA gene tree of the genus Nonomuraea, strain 3-33-9BT formed a distinct phyletic line and was most closely related to Nonomuraea fastidiosa NBRC 14680T (97.3 % 16S rRNA gene sequence similarity). However, phenotypic characteristics of strain 3-33-9BT were significantly different from N. fastidiosa NBRC 14680T, and DNA-DNA hybridization showed little relatedness (31.6 35.2 %) between the two strains. Based on the phenotypic and phylogenetic data, strain 3-33-9BT represents a novel species of the genus Nonomuraea, for which the name Nonomuraea thermotolerans sp. nov. is proposed. The type strain is 3-33-9BT ( = ATCC BAA-2629T = CGMCC 4.7161T). PMID- 26620827 TI - Traumatic Events Associated With Posttraumatic Stress Disorder: The Role of Race/Ethnicity and Depression. AB - This study sought to examine specific types of potentially traumatic experiences as predictors of posttraumatic stress disorder (PTSD) and the moderating effect of race/ethnicity and major depressive disorder (MDD) among non-Hispanic White, non-Hispanic Black, and Hispanic U.S. women. The study sample was drawn from two waves of the National Epidemiologic Surveys of Alcohol and Related Conditions. Sexual assault, intimate partner violence, and childhood trauma were the strongest predictors of PTSD compared with the reference group (indirect/witnessed trauma). Similar patterns were revealed across racial/ethnic groups, although the estimates were most robust among White women. Findings also suggest that MDD moderates the effect of traumatic experiences on PTSD. PMID- 26620830 TI - Trans fat and cardiovascular disease mortality: Evidence from bans in restaurants in New York. AB - This paper analyzes the impact of trans fat bans on cardiovascular disease (CVD) mortality rates. Several New York State jurisdictions have restricted the use of ingredients containing artificial trans fat in food service establishments. The resulting within-county variation over time and the differential timing of the policy's rollout is used in estimation. The results indicate that the policy caused a 4.5% reduction in CVD mortality rates, or 13 fewer CVD deaths per 100,000 persons per year. The averted deaths can be valued at about $3.9 million per 100,000 persons annually. PMID- 26620831 TI - Soft-tissue changes in Class II malocclusion patients treated with extractions: a systematic review. AB - BACKGROUND: Concerns about the effects caused by premolar extractions on the soft tissue profile have motivated many investigations in different malocclusions. OBJECTIVES: To evaluate the cephalometric facial soft-tissue changes after orthodontic treatment with premolar extractions of Class II division 1 malocclusion subjects. SEARCH METHODS: Electronic databases PubMed, Web of Science, Embase, and Scopus were searched. SELECTION CRITERIA: Abstracts that appeared to fulfil the initial criteria (premolar extraction; cephalometric soft tissue analyses/changes) were selected. The full-text original articles were then retrieved. Their references were also hand-searched. DATA COLLECTION AND ANALYSIS: By consensus of two researchers, the articles that fulfilled the selection criteria and quantified facial soft-tissue changes were individually analysed. Some methodological flaws were identified and some articles were excluded. The studies were rated according to the type of study, sample description and homogeneity, malocclusion severity, consideration of confounding factors, validity of the method, and statistical analyses. RESULTS: Heterogeneous information about malocclusion severity before treatment was found in most articles. Statistically significant soft-tissue changes reported included nasolabial angle (NLA) increasing from 2.4 to 5.40degrees in 2-premolar extraction protocol and from 1 to 6.84degrees in 4-premolar extraction protocol. Retrusion of the upper and lower lips were also verified, with less retraction of the lower lip in 2-premolar extraction groups. CONCLUSIONS: When Class II division 1 malocclusion is treated with premolar extractions, the NLA increases and the lips are retracted. However, there is less retraction of the lower lip in the 2-maxillary premolar extraction protocol. PMID- 26620832 TI - Profiling tissue-resident T cell repertoires by RNA sequencing. AB - Deep sequencing of recombined T cell receptor (TCR) genes and transcripts has provided a view of T cell repertoire diversity at an unprecedented resolution. Beyond profiling peripheral blood, analysis of tissue-resident T cells provides further insight into immune-related diseases. We describe the extraction of TCR sequence information directly from RNA-sequencing data from 6738 tumor and 604 control tissues, with a typical yield of 1 TCR per 10 million reads. This method circumvents the need for PCR amplification of the TCR template and provides TCR information in the context of global gene expression, allowing integrated analysis of extensive RNA-sequencing data resources. PMID- 26620834 TI - Erratum to: Lack of a significant impact of Gag-Protease-mediated HIV-1 replication capacity on clinical parameters in treatment-naive Japanese individuals. PMID- 26620833 TI - Subanesthetic ketamine infusions for the treatment of children and adolescents with chronic pain: a longitudinal study. AB - BACKGROUND: Chronic pain is common in children and adolescents and is often associated with severe functional disability and mood disorders. The pharmacological treatment of chronic pain in children and adolescents can be challenging, ineffective, and is mostly based on expert opinions and consensus. Ketamine, an N-methyl-D-aspartate receptor antagonist, has been used as an adjuvant for treatment of adult chronic pain and has been shown, in some instances, to improve pain and decrease opioid-requirement. We examined the effects of subanesthetic ketamine infusions on pain intensity and opioid use in children and adolescents with chronic pain syndromes treated in an outpatient setting. METHODS: Longitudinal cohort study of consecutive pediatric patients treated with subanesthetic ketamine infusions in a tertiary outpatient center. Outcome measurements included self-reported pain scores (numeric rating scale) and morphine-equivalent intake. RESULTS: Over a 15-month period, 63 children and adolescents (median age 15, interquartile range 12-17 years) with chronic pain received 277 ketamine infusions. Intravenous administration of subanesthetic doses of ketamine to children and adolescents on an outpatient basis was safe and not associated with psychotropic effects or hemodynamic perturbations. Overall, ketamine significantly reduced pain intensity (p < 0.001) and yielded greater pain reduction in patients with complex regional pain syndrome (CRPS) than in patients with other chronic pain syndromes (p = 0.029). Ketamine-associated reductions in pain scores were the largest in postural orthostatic tachycardia syndrome (POTS) and trauma patients and the smallest in patients with chronic headache (p = 0.007). In 37% of infusions, patients had a greater than 20 % reduction in pain score. Conversely, ketamine infusions did not change overall morphine-equivalent intake (p = 0.3). CONCLUSIONS: These data suggest that subanesthetic ketamine infusion is feasible in an outpatient setting and may benefit children and adolescents with chronic pain. Further, patients with CRPS, POTS, and a history of trauma-related chronic pain are more likely to benefit from this therapeutic modality. PMID- 26620835 TI - Expression pattern of the Hedgehog signaling pathway in pituitary adenomas. AB - Several studies have demonstrated the role of Wnt and Notch signaling in the pathogenesis of pituitary adenomas, but data are scarce regarding the role of Hedgehog signaling. In this study we investigated the differential expression of gene targets of the Hedgehog signaling pathway. Formalin-fixed, paraffin-embedded specimens from adult patients who underwent transphenoidal resection and normal human pituitary tissues that were obtained from autopsies were used. Clinical information and data from pre-operative MRI scan (extracellular tumor extension, tumor size, displacement of the optic chiasm) were retrieved from the Hospital's database. We used a customized RT(2) Profiler PCR Array, to investigate the expression of genes related to Notch and Hedgehog signaling pathways (PTCH1, PTCH2, GLI1, GLI3, NOTCH3, JAG1, HES1, and HIP). A total of 52 pituitary adenomas (32 non-functioning adenomas, 15 somatotropinomas and 5 prolactinomas) were used in the final analysis. In non-functioning pituitary adenomas there was a significant decrease (approximately 75%) in expression of all Hedgehog related genes that were tested, while Notch3 and Jagged-1 expression was found significantly increased, compared with normal pituitary tissue controls. In contrast, somatotropinomas demonstrated a significant increase in expression of all Hedgehog related genes and a decrease in the expression of Notch3 and Jagged 1. There was no significant difference in the expression of Hedgehog and Notch related genes between prolactinomas and healthy pituitary tissues. Hedgehog signalling appears to be activated in somatotropinomas but not in non-functioning pituitary adenomas in contrast to the expression pattern of Notch signalling pathway. PMID- 26620837 TI - Fe3O4 and Au nanoparticles dispersed on the graphene support as a highly active catalyst toward the reduction of 4-nitrophenol. AB - We report a highly efficient and reusable bifunctional nanostructured composite catalyst synthesized by a scalable facile hydrothermal method which enables the precise control of size and morphology of nanoparticles, wherein Au nanoparticles (NPs) and Fe3O4 particles exhibit excellent dispersing ability on the rGO (reduced graphene oxide) sheet surface (designated as rGO/Fe3O4/Au) to avoid adverse agglomeration between the nano particles and overlapping of the rGO sheets concurrently. The resultant bifunctional composite shows a high performance in the catalytic reduction of 4-nitrophenol (4-NP) with a conversion of 97% in 5 min and presents good reusability through highly efficient recovery by using external magnetic fields. In particular, there was no significant loss in catalytic activity of the reused catalysts even after being recycled for 8 cycles, displaying attractive potential in industrial applications where separation and recycling are imperative. The rational design provides an approach to synthesize a graphene-based composite with an interesting structure and multi functional properties as well. PMID- 26620836 TI - Lipopolysaccharide induced anxiety- and depressive-like behaviour in mice are prevented by chronic pre-treatment of esculetin. AB - Inflammation and oxidative stress are involved in the pathophysiology of anxiety and depression. Esculetin (ESC), a coumarin derived potent antioxidant, also possessing anti-inflammatory and neuroprotective activity. This study investigated the effect of ESC in lipopolysaccharide (LPS)-induced anxiety- and depressive-like behaviour in mice. ESC (25 and 50mg/kg, p.o.) was administered daily for 14 days, and challenged with saline or LPS (0.83mg/kg; i.p.) on the 15th day. Behavioural paradigms such as elevated plus maze (EPM), open field test (OFT), forced swim test (FST) and tail suspension test (TST) were employed to assess anxiety- and depressive-like behaviour in mice post-LPS injection. Hippocampal cytokines, MDA and GSH level, and plasma corticosterone (CORT) were measured. ESC pre-treatment significantly (P<0.05) attenuated LPS-induced anxiety like behaviour by modulating EPM and OFT parameters. Moreover, LPS-induced increase in immobility time in FST and TST were also prevented significantly (P<0.05) by ESC (50mg/kg). ESC pre-treatment ameliorated LPS-induced neuroinflammation by attenuating brain IL-1beta, IL-6, TNF-alpha level, and oxidative stress as well as plasma CORT level. In conclusion, the results suggest that ESC prevented LPS-induced anxiety- and depressive-like behaviour which may be governed by inhibition of cytokine production, oxidative stress and plasma CORT level. The results support the potential usefulness of ESC in the treatment of psychiatric disorders associated with inflammation and oxidative stress. PMID- 26620840 TI - DNA vaccination of poultry: The current status in 2015. AB - DNA vaccination is a promising alternative strategy for developing new human and animal vaccines. The massive efforts made these past 25 years to increase the immunizing potential of this kind of vaccine are still ongoing. A relatively small number of studies concerning poultry have been published. Even though there is a need for new poultry vaccines, five parameters must nevertheless be taken into account for their development: the vaccine has to be very effective, safe, inexpensive, suitable for mass vaccination and able to induce immune responses in the presence of maternal antibodies (when appropriate). DNA vaccination should meet these requirements. This review describes studies in this field performed exclusively on birds (chickens, ducks and turkeys). No evaluations of avian DNA vaccine efficacy performed on mice as preliminary tests have been taken into consideration. The review first describes the state of the art for DNA vaccination in poultry: pathogens targeted, plasmids used and different routes of vaccine administration. Second, it presents strategies designed to improve DNA vaccine efficacy: influence of the route of administration, plasmid dose and age of birds on their first inoculation; increasing plasmid uptake by host cells; addition of immunomodulators; optimization of plasmid backbones and codon usage; association of vaccine antigens and finally, heterologous prime-boost regimens. The final part will indicate additional properties of DNA vaccines in poultry: fate of the plasmids upon inoculation, immunological considerations and the use of DNA vaccines for purposes other than preventing infectious diseases. PMID- 26620839 TI - Assessment of the hepatitis B birth dose vaccination program, Papua New Guinea, 2014. AB - INTRODUCTION: Papua New Guinea (PNG) implemented hepatitis B birth dose (BD) vaccination in 2005 yet since that time coverage has remained low, allowing mother-to-child transmission to occur. We conducted a field assessment of the BD vaccination program to develop strategies for improving the BD coverage. METHODS: We selected five provinces with higher hepatitis B prevalence and five with lower prevalence based on the results of a 2013 hepatitis B serological survey. Within each province, we interviewed district and provincial health officers, health workers, village volunteers, and caregivers from ten randomly selected health facilities. Data were collected on knowledge, practice, vaccine management and data recording/reporting. To identify enabling factors and barriers, we compared health facilities with higher BD coverage with those with lower coverage, and compared caregivers whose children received BD with those whose children did not. RESULTS: Overall timely BD coverage was 31% and BD vaccination was taking place in 81% of sampled health facilities. Lack of cold chain and vaccine were the major reasons for not providing the BD. Insufficiencies in supervision, vaccine management, community outreach, and data management were identified as obstacles to achieving high timely hepatitis B BD coverage. Good supervision, knowledge of hepatitis B and hepatitis B vaccination, antenatal care including information about the hepatitis B BD, provision of vaccine refrigerators in maternity wards, and outreach vaccination for home deliveries were associated with higher timely BD coverage. DISCUSSION: Several steps will likely be effective in improving BD coverage: strengthening training and supervision among health workers and officers, educating caregivers on the benefits of the BD and delivery in health facilities, improving vaccine management, and improving data quality. Considerable effort and leadership will be needed to achieve these steps. PMID- 26620838 TI - Generation of a reassortant avian influenza virus H5N2 vaccine strain capable of protecting chickens against infection with Egyptian H5N1 and H9N2 viruses. AB - BACKGROUND: Avian influenza H5N1 viruses have been enzootic in Egyptian poultry since 2006. Avian influenza H9N2 viruses which have been circulating in Egyptian poultry since 2011 showed high replication rates in embryonated chicken eggs and mammalian cells. METHODS: To investigate which gene segment was responsible for increasing replication, we constructed reassortant influenza viruses using the low pathogenic H1N1 PR8 virus as backbone and included individual genes from A/chicken/Egypt/S4456B/2011(H9N2) virus. Then, we invested this finding to improve a PR8-derived H5N1 influenza vaccine strain by incorporation of the NA segment of H9N2 virus instead of the NA of H5N1. The growth properties of this virus and several other forms of reassortant H5 viruses were compared. Finally, we tested the efficacy of this reassortant vaccine strain in chickens. RESULTS: We observed an increase in replication for a reassortant virus expressing the neuraminidase gene (N2) of H9N2 virus relative to that of either parental viruses or reassortant PR8 viruses expressing other genes. Then, we generated an H5N2 vaccine strain based on the H5 from an Egyptian H5N1 virus and the N2 from an Egyptian H9N2 virus on a PR8 backbone. This strain had better replication rates than an H5N2 reassortant strain on an H9N2 backbone and an H5N1 reassortant on a PR8 backbone. This virus was then used to develop a killed, oil-emulsion vaccine and tested for efficacy against H5N1 and H9N2 viruses in chickens. Results showed that this vaccine was immunogenic and reduced mortality and shedding. DISCUSSION: Our findings suggest that an inactivated PR8-derived H5N2 influenza vaccine is efficacious in poultry against H5N1 and H9N2 viruses and the vaccine seed replicates at a high rate thus improving vaccine production. PMID- 26620841 TI - Prediction and identification of novel IBV S1 protein derived CTL epitopes in chicken. AB - Infectious bronchitis virus (IBV) is a major pathogen common in the poultry industry. Broad cytotoxic T lymphocyte (CTL) response against IBV is one of the crucial factors that help to control viral replication. Spike glycoproteins on the surface of the IBV virion harbor major T cell epitopes. In this study, based on the peptide-binding motifs of chicken MHC I molecules for the BF2*4, BF2*12, BF2*15, and BF2*19 haplotypes, potential CTL epitopes were predicted using S1 proteins from different IBV strains. Twenty-one peptides were predicted to be potential CTL epitopes; they were manually synthesized and the CTL responses to them tested in vitro. Spleen lymphocytes were collected from specific-pathogen free (SPF) chicken that had been immunized with the S1 protein expression plasmid, pV-S1, and were stimulated by the synthesized peptides. IFN-gamma secretion and CD8(+) T cell proliferation in chickens were tested by ELISpot array and flow cytometry, respectively. Four epitopes (P8SRIQTATDP, P9SRNATGSQP, P18GAYAVVNV, and P19SRIQTATQP) were identified to stimulate CD8(+) T cell proliferation and IFN-gamma secretion, indicating their efficacy as CTL epitopes in chicken. Poly-CTL-epitope DNA vaccine (pV-S1T) was constructed by inserting nucleotide sequences encoding the P8, P9, P18, and P19 CTL epitopes into the pVAX1 vector. Chickens were vaccinated with either pV-S1, pV-S1T, or pVAX1 and the protection efficacy was analyzed, revealing that ninety percent of chickens immunized with pV-S1T were protected after challenge with 10(6) ELD50 of IBV, demonstrating that these novel CTL epitopes were effective against IBV challenge. This study provides a new method to screen virus CTL epitopes in chicken and to develop poly-CTL-epitope DNA vaccines. PMID- 26620843 TI - Impact of microemulsion inspired approaches on the formation and destabilisation mechanisms of triglyceride nanoemulsions. AB - Even after 30+ years of research, there are still few examples of physically stable transparent nanoemulsions despite their high potential to revolutionise pharmaceutical, personal care, and food products. In this study, we examine how low-energy "microemulsion inspired" (co-solvent/co-surfactant) approaches impact the formation and destabilisation mechanisms of homogenised triglyceride nanoemulsions. The addition of n-alcohol co-solvents and Span 80 co-surfactants had two effects on nanoemulsion droplet diameter; a beneficial one that reduced droplet diameter from 120 to 50 nm and a deleterious one that caused destabilisation. The decrease in nanoemulsion droplet diameter facilitated by n alcohols is thought to arise from changes in: (i) solvent quality near the interface and (ii) interface spontaneous curvature which dramatically reduce interfacial tension. The strength of this effect was magnified by n-alcohol partitioning behaviour and their tendency to associate with the headgroup of POE surfactants. Addition of an excess of n-alcohol led to nanoemulsion destabilisation, unusually for nanoemulsions, destabilisation was not via Ostwald ripening, instead coalescence was found to be the primary destabilisation mechanism. A rapid increase in nanoemulsion droplet growth rate with increasing n alcohol content was observed for each n-alcohol. Such rapid changes in nanoemulsion instability with composition are reminiscent of PIC/PIT emulsions in the Winsor III region, whose instability has been described to be a function of the activation energy barrier to coalescence. The microemulsion inspired approaches developed in this work highlight a new general approach to the creation of transparent nanoemulsions, and are particularly advantageous for triglyceride oils which are inherently stable against Ostwald ripening. PMID- 26620842 TI - Active immunizations with peptide-DC vaccines and passive transfer with antibodies protect neutropenic mice against disseminated candidiasis. AB - We previously report that peptide-pulsed dendritic cell (DC) vaccination, which targeting two peptides (Fba and Met6) expressed on the cell surface of Candida albicans, can induce high degree of protection against disseminated candidiasis in immunocompetent mice. Passive transfer of immune sera from the peptide immunized mice or peptide-related monoclonal antibodies demonstrated that protection was medicated by peptide-specific antibodies. In this study the efficacy of active and passive immunization against disseminated candidiasis was tested in mice with cyclophosphamide-induced neutropenia. Peptide-DC vaccines were given to mice prior to induction of neutropenia. We show active immunization with either Fba or Met6 peptide-DC vaccine significantly improved the survival and reduced the fungal burden of disseminated candidiasis in those immunocompromised mice. Importantly, we show that administration of two protective monoclonal antibodies also protect neutropenic mice against the disease, implying possibility of developing a successful passive immunotherapy strategy to treat the disease and protect against disseminated candidiasis. The results of this study are crucial as they address the fundamental questions as to whether the synthetic peptide vaccine induced immunity protects the host during a neutropenic episode. We anticipate that this peptide-vaccine study will serve as the foundation of future investigations into new peptide vaccines comprised of cell surface peptides from other medically important Candida species, as well as other fungi. PMID- 26620844 TI - Systematic review and meta-analysis of non RCT's on health related quality of life after radical cystectomy using validated questionnaires: Better results with orthotopic neobladder versus ileal conduit. AB - PURPOSE: The current literature on the impact of different urinary diversions on patients' health related quality of life (HR-QoL) showed a marginally better quality of life scores of orthotopic neobladder (ONB) compared to ileal conduit (IC). The aim of this study was to update the review of all relevant published studies on the comparison between ONB and IC. MATERIALS AND METHODS: Studies were identified by searching multiple literature databases, including MEDLINE, CINAHL, the Cochrane Library, PubMed Data were synthesized using meta-analytic methods conformed to the PRISMA statement. RESULTS: The current meta-analysis was based on 18 papers that reported a HR-QoL comparison between IC and ONB using at least a validate questionnaire. Pooled effect sizes of combined QoL outcomes for IC versus ONB showed a slight, but not significant, better QoL in patients with ONB (Hedges' g = 0.150; p = 0.066). Patients with ileal ONB showed a significant better QoL than those with IC (Hedges' g = 0.278; p = 0.000); in case series with more than 65% males, ONB group showed a slight significant better QoL than IC (Hedges' g = 0.190; p = 0.024). Pooled effects sizes of all EORTC-QLQ-C30 aspects showed a significant better QoL in patients with ONB (Hedges' g = 0.400; p = 0.0000). CONCLUSIONS: This meta-analysis of not-randomized comparative studies on the impact of different types of urinary diversions on HR-QoL showed demonstrated a significant advantage of ileal ONB compared to IC in terms of HR-QoL. PMID- 26620845 TI - LMNA cardiomyopathy detected in Japanese arrhythmogenic right ventricular cardiomyopathy cohort. AB - BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease. While desmosomal gene mutations are considered major causes of ARVC, LMNA mutations have been reported to be possible causes of ARVC. In this study, we performed extensive genetic screening for LMNA mutations in our Japanese ARVC cohort to assess the prevalence and characteristics of LMNA mutation-positive ARVC cases. METHODS: Our study cohort consisted of 57 ARVC probands. Genetic analyses were performed by using direct sequencing and targeted sequencing of LMNA and four desmosomal genes. We compared clinical features of probands with desmosomal gene mutations to those of probands with LMNA mutations. RESULTS: Among 57 clinically diagnosed ARVC probands, we identified desmosomal gene mutations in 26 probands (45.6%) and two LMNA mutations in two probands. The first LMNA mutation p.M1K was detected in a 62-year-old male proband, while the second mutation p.W514X was found in a 70-year-old male proband. Compared to the 26 probands with desmosomal gene mutations, in the two probands with LMNA mutations, the mean age at diagnosis was significantly higher, and their heart rate at the diagnosis was significantly slower. While both probands with LMNA mutations underwent pacemaker implantation, only one proband with desmosomal mutations received this treatment (2/2 vs. 1/26). CONCLUSION: Genetic screening for LMNA gene is important for ARVC patients, particularly in patients with bradycardia. PMID- 26620846 TI - Comprehensive assessment of impaired peripheral and coronary artery endothelial functions in smokers using brachial artery ultrasound and oxygen-15-labeled water PET. AB - BACKGROUND: Comprehensive evaluation of endothelium-dependent and endothelium independent vascular functions in peripheral arteries and coronary arteries in smokers has never been performed previously. Through the use of brachial artery ultrasound and oxygen-15-labeled water positron emission tomography (PET), we sought to investigate peripheral and coronary vascular dysfunctions in smokers. METHODS AND RESULTS: Eight smokers and 10 healthy individuals underwent brachial artery ultrasound at rest, during reactive hyperemia [250mmHg cuff occlusion (flow-mediated dilatation (FMD)], and following sublingual nitroglycerin (NTG) administration. Myocardial blood flow (MBF) was assessed through O-15-labeled water PET at rest, during adenosine triphosphate (ATP) administration, and during a cold pressor test (CPT). Through ultrasound, smokers were shown to have significantly reduced %FMD compared to controls (6.62+/-2.28% vs. 11.29+/-2.75%, p=0.0014). As assessed by O-15-labeled water PET, smokers were shown to have a significantly lower CPT response than were controls (21.1+/-9.5% vs. 50.9+/ 16.9%, p=0.0004). There was no relationship between %FMD and CPT response (r=0.40, p=0.097). Endothelium-independent vascular dilatation was similar for both groups in terms of coronary flow reserve with PET (p=0.19). Smokers tended to have lower %NTG in the brachial artery (p=0.055). CONCLUSIONS: Smokers exhibited impaired coronary endothelial function as well as peripheral brachial artery endothelial function. In addition, there was no correlation between PET and ultrasound measurements, possibly implying that while smokers may have systemic vascular endothelial dysfunction, the characteristics of that dysfunction may be different in peripheral arteries and coronary arteries. PMID- 26620847 TI - On the iteration of coincidence summing correction for determination of gamma-ray intensities. AB - In order to determine the gamma-ray emission intensities of nuclei far from the beta-stability line with HPGe detectors under large solid-angle geometry, coincidence summing corrections should be performed, even if full energy peak efficiencies of detectors are accurately measured with standard sources. Because the summing effects depend on decay schemes and emission intensities, the correction needs to be iterated several times starting from the initial values of intensities obtained directly from the measured peak counts of gamma-rays. Considering (134)Cs, (154)Eu and (56)Co as typical examples, we discuss the number of iterations of summing correction required for self-consistency with respect to the total efficiencies of the detectors. PMID- 26620848 TI - Microbial biogeography of a university campus. AB - BACKGROUND: Microorganisms are distributed on surfaces within homes, workplaces, and schools, with the potential to impact human health and disease. University campuses represent a unique opportunity to explore the distribution of microorganisms within built environments because of high human population densities, throughput, and variable building usage. For example, the main campus of the University of Waterloo spans four square kilometres, hosts over 40,000 individuals daily, and is comprised of a variety of buildings, including lecture halls, gyms, restaurants, residences, and a daycare. RESULTS: Representative left and right entrance door handles from each of the 65 buildings at the University of Waterloo were swabbed at three time points during an academic term in order to determine if microbial community assemblages coincided with building usage and whether these communities are stable temporally. Across all door handles, the dominant phyla were Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes, which comprised 89.0 % of all reads. A total of 713 genera were observed, 16 of which constituted a minimum of 1 % of the 2,458,094 classified and rarefied reads. Archaea were found in low abundance (~0.03 %) but were present on 42.8 % of the door handles on 96 % of buildings across all time points, indicating that they are ubiquitous at very low levels on door handle surfaces. Although inter-handle variability was high, several individual building entrances harbored distinct microbial communities that were consistent over time. The presence of visible environmental debris on a subset of handles was associated with distinct microbial communities (beta diversity), increased richness (alpha diversity), and higher biomass (adenosine 5'-triphosphate; ATP). CONCLUSIONS: This study demonstrates highly variable microbial communities associated with frequently contacted door handles on a university campus. Nonetheless, the data also revealed several building-specific and temporally stable bacterial and archaeal community patterns, with a potential impact of accumulated debris, a possible result of low human throughput, on detected microbial communities. PMID- 26620850 TI - A subtest analysis of the Montreal cognitive assessment (MoCA): which subtests can best discriminate between healthy controls, mild cognitive impairment and Alzheimer's disease? AB - BACKGROUND: It is necessary to continue to explore the psychometric characteristics of key cognitive screening tests such as the Montreal Cognitive Assessment (MoCA) to diagnose cognitive decline as early as possible and to attend to the growing need of clinical trials involving mild cognitive impairment (MCI) participants. The main aim of this study was to assess which MoCA subtests could best discriminate between healthy controls (HC), participants with MCI, and Alzheimer's disease (AD). METHODS: Cross-sectional analysis of 136 elderly with more than four years of education. All participants were submitted to detailed clinical, laboratory, and neuroimaging evaluation. The MoCA, Mini-Mental State Examination (MMSE), the Cambridge Cognitive Examination (CAMCOG), Geriatric Depression Scale (GDS), and Functional Activities Questionnaire (FAQ) were applied to all participants. The MoCA test was not used in the diagnostic procedure. RESULTS: Median MoCA total scores were 27, 23 and 18 for HC, MCI, and AD, respectively (p < 0.001). Word repetition, inverse digits, serial 7, phrases, verbal fluency, abstraction, and word recall discriminated between MCI and HC participants (p < 0.001). The clock drawing, the rhino naming, delayed recall of five words and orientation discriminated between patients with MCI and AD (p < 0.001). A reduced version of the MoCA with only these items did not improve accuracy between MCI and HC (p = 0.076) or MCI and AD (p = 0.119). CONCLUSIONS: Not all MoCA subtests might be fundamental to clinical diagnosis of MCI. The reduced versions of MoCA did not add diagnostic accuracy. PMID- 26620849 TI - Rest and exercise echocardiography for early detection of pulmonary hypertension. AB - Early detection of pulmonary hypertension (PH) is essential to ensure that patients receive timely and appropriate treatment for this progressive disease. Rest and exercise echocardiography has been used to screen patients in an attempt to identify early stage PH. However, current PH guidelines recommend against exercise tests because of the lack of evidence. We reviewed previous studies to discuss the current standpoint concerning rest and exercise echocardiography in PH. Around 20 exercise echocardiography studies were included to assess the cutoff value for exercise-induced pulmonary hypertension (EIPH). Approximately 40 exercise echocardiography studies were also included to evaluate the pulmonary artery pressure-flow relationship as assessed by the slope of the mean pulmonary artery pressure and cardiac output (DeltamPAP/DeltaQ). There were several EIPH and DeltamPAP/DeltaQ reference values in individuals with pulmonary vascular disease. We believed that assessing the DeltamPAP/DeltaQ makes sense from a physiological standpoint, and the clinical value should be confirmed in future studies. Exercise echocardiography is an appealing alternative in PH. Further studies are needed to assess the prognostic value of the pulmonary artery pressure-flow relationship in high-risk subjects. PMID- 26620851 TI - Feasibility and Effectiveness of Memory Specificity Training in Depressed Outpatients: A Pilot Study. AB - BACKGROUND: Research has shown that depressed patients suffer from reduced autobiographical memory specificity (rAMS). This cognitive phenomenon is associated with the maintenance and recurrence of depressive symptoms. OBJECTIVES: This pilot study aims to investigate the feasibility and effectiveness of a relatively new group-based intervention (Memory Specificity Training; MeST) that aims to reduce rAMS in an outpatient setting. METHODS: Twenty-six depressed outpatients received MeST during the waiting period prior to psychotherapy. The Client Satisfaction Questionnaire (CSQ-8) was used to measure client satisfaction after the training. The Autobiographical Memory Test (AMT) was used to measure memory specificity before and after the training. Depressive symptoms were measured using the Beck Depression Inventory (BDI-II) and the Montgomery Asberg Depression Rating Scale (MADRS), before and after the training, and at a 3-month follow-up. RESULTS: Participants as well as trainers were positive about the use of MeST. Participants also showed an increase in memory specificity and a decrease in depressive symptoms. CONCLUSIONS: This study suggests that MeST is feasible in an outpatient setting, that it increases autobiographical memory specificity and that it may decrease depressive symptoms. A randomized controlled trial is recommended to examine MeST and its effects on autobiographical memory specificity, depressive symptoms and depressive relapse more extensively. Copyright (c) 2015 John Wiley & Sons, Ltd. Key Practitioner Message: Research suggests that modification of rAMS can advance recovery and reduce the chance of developing a depression relapse. However, most existing psychotherapies for depression do not include these specific interventions. This is the first study to show that MeST in an outpatient setting is feasible and can lead to an increase in autobiographical memory specificity and that it may decrease depressive symptoms. A larger scale randomized controlled trial is required to examine whether the addition of MeST to care as usual decreases depressive symptoms more effectively than care as usual without MeST, and to examine whether subgroups of patients benefit specifically from this intervention (e.g. patients with more severely decreased memory specificity). PMID- 26620852 TI - Impact of size, secondary structure, and counterions on the binding of small ribonucleic acids to layered double hydroxide nanoparticles. AB - Use of ribonucleic acid (RNA) interference to regulate protein expression has become an important research topic and gene therapy tool, and therefore, finding suitable vehicles for delivery of small RNAs into cells is of crucial importance. Layered double metal hydroxides such as hydrotalcite (HT) have shown great promise as nonviral vectors for transport of deoxyribose nucleic acid (DNA), proteins, and drugs into cells, but the adsorption of RNAs to these materials has been little explored. In this study, the binding of small RNAs with different lengths and levels of secondary structure to HT nanoparticles has been analyzed and compared to results obtained with small DNAs in concurrent experiments. Initial experiments established the spectrophotometric properties of HT in aqueous solutions and determined that HT particles could be readily sedimented with near 100% efficiencies. Use of RNA+HT cosedimentation experiments as well as electrophoretic mobility shift assays demonstrated strong adsorption of RNA 25mers to HT, with twofold greater binding of single-stranded RNAs relative to double-stranded molecules. Strong affinities were also observed with ssRNA and dsRNA 54mers and with more complex transfer RNA molecules. Competition binding and RNA displacement experiments indicated that RNA-HT associations were strong and were only modestly affected by the presence of high concentrations of inorganic anions. PMID- 26620853 TI - A Comparison of Coronal Tooth Discoloration Elicited by Various Endodontic Reparative Materials. AB - INTRODUCTION: The purpose of this study was to evaluate coronal tooth discoloration of ProRoot MTA (Dentsply Tulsa Dental, Johnson City, TN), white ProRoot MTA, EndoSequence Root Repair Material (Brasseler USA, Savannah, GA), MTA Angelus (Angelus Solucoes Odontologicas, Londrina, Brazil), and Biodentine (Septodont, Saint Maur des Fosses, France) when used in an ex vivo pulpotomy model. METHODS: Freshly extracted mandibular third molars were collected and stored in 1% chloramine-T solution. Teeth were randomly assigned into 6 groups (n = 15) and stored individually in phosphate buffered saline at 37 degrees C in 100% humidity. A standardized endodontic access was made in 5 groups. A 3-mm thick increment of reparative material was placed on the pulpal floor, covered by glass ionomer, and the access opening restored with composite. Color (Commission Internationale de l'eclairage L*a*b*) was recorded with the Vita Easy Shade spectrophotometer (VITA Zahnfabrik, Bad Sackingen, Germany) on the midbuccal surface at baseline; after access preparation; after material placement; and then after 1, 7, 30, and 60 days. Changes in Commission Internationale de l'eclairage L*a*b* were measured for each experimental group and compared with ProRoot MTA (positive control) and no treatment (negative control) using the following equation: DeltaE = ([Li - L0*]2 + [ai - a0*]2 + [bi - b0*]2)(1/2). The mean results were analyzed within each group and between groups using the Friedman 2 way analysis post hoc test (P < .05). RESULTS: There were no significant differences between white ProRoot MTA, MTA Angelus, and the positive control group. EndoSequence Root Repair Material and Biodentine produced significantly less discoloration than white ProRoot MTA, MTA Angelus, and ProRoot MTA. CONCLUSIONS: Under the conditions of this study, EndoSequence and Biodentine had significantly less discoloration compared with white ProRoot MTA, MTA Angelus, and ProRoot MTA. The potential for discoloration may or may not correlate when materials are used clinically. PMID- 26620854 TI - Comparison of long-term mortality after ruptured abdominal aortic aneurysm in England and Sweden. AB - BACKGROUND: Concern has been raised regarding international discrepancies in perioperative mortality after repair of ruptured abdominal aortic aneurysm (rAAA). The variation in in-hospital mortality is difficult to interpret, owing to international differences in discharge strategies. This study compared 90-day and 5-year mortality in patients who had a rAAA in England and Sweden. METHODS: Patients undergoing rAAA repair were identified from English Hospital Episode Statistics and the Swedish Vascular Registry (Swedvasc) between 2003 and 2012. Ninety-day and 5-year mortality were compared after matching for age and sex. Within-country analyses examined the impact of co-morbidity, teaching hospital status or hospital annual caseload, adjusted with causal inference techniques. RESULTS: Some 12 467 patients underwent rAAA repair in England, of whom 83.2 per cent were men; the median (i.q.r.) age was 75 (70-80) years. A total of 2829 Swedish patients underwent rAAA repair, of whom 81.3 per cent were men; their median (i.q.r.) age was 75 (69-80) years. The 90-day mortality rate was worse in England (44.0 per cent versus 33.4 per cent in Sweden; P < 0.001), as was 5-year mortality (freedom from mortality 38.6 versus 46.3 per cent respectively; P < 0.001). In England, lower mortality was seen in teaching hospitals with larger bed capacity, higher annual caseloads and greater use of endovascular aneurysm repair (EVAR). In Sweden, lower mortality was associated with EVAR, high annual caseload, or surgery on weekdays compared with weekends. CONCLUSION: Short- and long-term mortality after rAAA repair was higher in England. In both countries, mortality was lowest in centres performing greater numbers of AAA repairs per annum, and more EVAR procedures. PMID- 26620856 TI - PCBs: exposures, effects, remediation, and regulation with special emphasis on PCBs in schools. PMID- 26620855 TI - Valproic Acid Enhances iPSC Induction From Human Bone Marrow-Derived Cells Through the Suppression of Reprogramming-Induced Senescence. AB - Reprogramming of human somatic cells into pluripotent cells (iPSCs) by defined transcription factors is an extremely inefficient process. Treatment with the histone deacetylase inhibitor valproic acid (VPA) during reprogramming can improve the induction of iPSCs. To examine the specific mechanism underlying the role of VPA in reprogramming, we transfected human bone marrow-derived cells (HSC J2 and HSC-L1) with lentiviruses carrying defined factors (OCT4, SOX2, KLF4, and c-MYC, OSKM) in the presence of VPA. We found that, OSKM lentiviruses caused significant senescence in transfected cells. Administration of VPA, however, significantly suppressed this reprogramming-induced stress. Notably, VPA treatment improved cell proliferation in the early stages of reprogramming, and this was related to the down-regulation of the activated p16/p21 pathway. In addition, VPA also released the G2/M phase blockade in lentivirus-transfected cells. This study demonstrates a new mechanistic role of the histone deacetylase inhibitor in enhancing the induction of pluripotency. J. Cell. Physiol. 231: 1719 1727, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26620857 TI - A comparative study of removal of fluoride from contaminated water using shale collected from different coal mines in India. AB - Low-cost water defluoridation technique is one of the most important issues throughout the world. In the present study, shale, a coal mine waste, is employed as novel and low-cost adsorbent to abate fluoride from simulated solution. Shale samples were collected from Mahabir colliery (MBS) and Sonepur Bazari colliery (SBS) of Raniganj coalfield in West Bengal, India, and used to remove fluoride. To increase the adsorption efficiency, shale samples were heat activated at a higher temperature and samples obtained at 550 degrees C are denoted as heat activated Mahabir colliery shale (HAMBS550) and heat-activated Sonepur Bazari colliery shale (HASBS550), respectively. To prove the fluoride adsorption onto different shale samples and ascertain its mechanism, natural shale samples, heat activated shale samples, and their fluoride-loaded forms were characterized using scanning electron microscopy, energy dispersive X-ray analysis, X-ray diffraction study, and Fourier transform infrared spectroscopy. The effect of different parameters such as pH, adsorbent dose, size of particles, and initial concentration of fluoride was investigated during fluoride removal in a batch contactor. Lower pH shows better adsorption in batch study, but it is acidic in nature and not suitable for direct consumption. However, increase of pH of the solution from 3.2 to 6.8 and 7.2 during fluoride removal process with HAMBS550 and HASBS550, respectively, confirms the applicability of the treated water for domestic purposes. HAMBS550 and HASBS550 show maximum removal of 88.3 and 88.5 %, respectively, at initial fluoride concentration of 10 mg/L, pH 3, and adsorbent dose of 70 g/L. PMID- 26620858 TI - Effects of dicyandiamide and dolomite application on N2O emission from an acidic soil. AB - Soil acidification is a major problem for sustainable agriculture since it limits productivity of several crops. Liming is usually adopted to ameliorate soil acidity that can trigger soil processes such as nitrification, denitrification, and loss of nitrogen (N) as nitrous oxide (N2O) emissions. The loss of N following liming of acidic soils can be controlled by nitrification inhibitors (such as dicyandiamide). However, effects of nitrification inhibitors following liming of acidic soils are not well understood so far. Here, we conducted a laboratory study using an acidic soil to examine the effects of dolomite and dicyandiamide (DCD) application on N2O emissions. Three levels of DCD (0, 10, and 20 mg kg(-1); DCD0, DCD10, and DCD20, respectively) were applied to the acidic soil under two levels of dolomite (0 and 1 g kg(-1)) which were further treated with two levels of N fertilizer (0 and 200 mg N kg(-1)). Results showed that N2O emissions were highest at low soil pH levels in fertilizer-treated soil without application of DCD and dolomite. Application of DCD and dolomite significantly (P <= 0.001) reduced N2O emissions through decreasing rates of NH4 (+)-N oxidation and increasing soil pH, respectively. Total N2O emissions were reduced by 44 and 13% in DCD20 and dolomite alone treatments, respectively, while DCD20 + dolomite reduced N2O emissions by 54% when compared with DCD0 treatment. The present study suggests that application of DCD and dolomite to acidic soils can mitigate N2O emissions. PMID- 26620859 TI - Relationships of physiologically equivalent temperature and hospital admissions due to I30-I51 other forms of heart disease in Germany in 2009-2011. AB - We aimed to understand relationships of the weather as biometeorological and hospital admissions due to other forms of heart disease by subtypes, which have been paid less attention, in a national setting in recent years. This is an ecological study. Ten percent of daily hospital admissions of the included hospitals (n = 1618) across Germany that were available between 1 January 2009 and 31 December 2011 (n = 5,235,600) were extracted from Statistisches Bundesamt, Germany. We identified I30-I51 other forms of heart disease by the International Classification of Diseases version 10 as the study outcomes. Daily weather data from 64 weather stations that have covered 13 German states, including air temperature, humidity, wind speed, cloud cover, radiation flux and vapour pressure, were obtained and generated into physiologically equivalent temperature (PET). Admissions due to other diseases of pericardium, nonrheumatic mitral valve disorders, nonrheumatic aortic valve disorders, cardiomyopathy, atrioventricular and left bundle-branch block, other conduction disorders, atrial fibrillation and flutter, and other cardiac arrhythmias peaked when PET was between 0 and 10 degrees C. Complications and ill-defined descriptions of heart disease admissions peaked at PET 0 degrees C. Cardiac arrest and heart failure admissions peaked when PET was between 0 and -10 degrees C while the rest did not vary significantly. A common drop of admissions was found when PET was above 10 degrees C. More medical resources could have been needed for heart health on days when PETs were <10 degrees C than on other days. Adaptation to such weather change for medical professionals and the general public would seem to be imperative. PMID- 26620860 TI - Induced metal redistribution and bioavailability enhancement in contaminated river sediment during in situ biogeochemical remediation. AB - In situ sediment remediation using Ca(NO3)2 or CaO2 for odor mitigation and acid volatile sulfide (AVS) and organic pollutant (such as TPH and PAHs) removal was reported in many studies and fieldwork. Yet, the associated effects on metal mobilization and potential distortion in bioavailability were not well documented. In this study, contaminated river sediment was treated by Ca(NO3)2 and CaO2 in bench studies. Through the investigation of AVS removal, organic matter removal, the changes in sediment oxidation-reduction potential (ORP), microbial activity, and other indigenous parameters, the effects on metal bioavailability, bioaccessibility, and fraction redistribution in sediment were evaluated. The major mechanisms for sediment treated by Ca(NO3)2 and CaO2 are biostimulation with indigenous denitrifying bacteria and chemical oxidation, respectively. After applying Ca(NO3)2 and CaO2, the decreases of metal concentrations in the treated sediment were insignificant within a 35-day incubation period. However, the [SEMtot-AVS]/f OC increased near to the effective boundary of toxicity (100 MUmol g(-1) organic carbon (OC)), indicating that both bioavailability and bioaccessibility of metals (Cu, Zn, and Ni) to benthic organisms are enhanced after remediation. Metals were found redistributed from relatively stable fractions (oxidizable and residual fractions) to weakly bound fractions (exchangeable and reducible fractions), and the results are in line with the enhanced metal bioavailability. Compared with Ca(NO3)2, CaO2 led to higher enhancement in metal bioavailability and bioaccessibility, and more significant metal redistribution, probably due to its stronger chemical reactive capacity to AVS and sediment organic matter. The reactions in CaO2-treated sediment would probably shift from physicochemical to biochemical heterotrophic oxidation for sediment organic matter degradation. Therefore, further investigation on the long-term metal redistribution and associated mobility as well as bioavailability is recommended. PMID- 26620861 TI - The composition, seasonal variation, and potential sources of the atmospheric wet sulfur (S) and nitrogen (N) deposition in the southwest of China. AB - The composition, seasonal variation, and potential sources of sulfate (S) and nitrogen (N) deposition in precipitation in the southwest of China from 2003 to 2013 were investigated. The results showed that the concentration of SO4 (2-), NO3 (-), and NH4 (+) in rainwater were 10.57-1360, 7.16-523.71, and 7.54-1020 MUeq l(-1), with an annual volume-weighted mean (VWM) concentration of 103.99, 46.73, and 97.30 MUeq l(-1), respectively. The annual wet deposition of SO4 (2-), NO3 (-), and NH4 (+) was 21.66, 8.16, and 17.49 kg S (N) ha(-1), respectively. The temporal variations of the ions showed that the abrupt decreasing breakpoints were in 2008 for SO4 (2-) and in 2009 for NO3 (-) and NH4 (+), and increasing trends were observed after 2010 for the three ions. These trends reflected the effect of economy recession and the policy of controlling SO2 and NOx emissions. The acid rain type of precipitation was shifted from sulfur to a mixed one. The ions of SO4 (2-), NO3 (-), and NH4 (+) presented high values in winter and spring and low values in autumn and summer. A highly positive linear correlation between SO4 (2-) and NO3 (-) (R(2) = 0.71), SO4 (2-) and NH4 (+) (R(2) = 0.74), and NO3 ( ) and NH4 (+) (R(2) = 0.84) existed while a strong negative correlation was found between the three main ionic concentrations and precipitation. The SO4 (2-) was mainly from fossil fuel combustion (60.53%), aged sea salt (19.03%), agriculture (11.38%), crust (6.66%), and biomass burning (2.40%); the NO3 (-) was mainly from fossil fuel combustion (75.41%), biomass burning (9.67%), aged sea salt (7.97%), and agriculture (6.96%); and the NH4 (+) was mainly from agriculture (86.38%), fossil fuel combustion (10.52%), and aged sea salt (3.09%). PMID- 26620862 TI - The impact of CO2 emissions on economic growth: evidence from selected higher CO2 emissions economies. AB - The main purpose of this work is to analyze the impact of environmental degradation proxied by CO2 emissions per capita along with some other explanatory variables namely energy use, trade, and human capital on economic growth in selected higher CO2 emissions economies namely China, the USA, India, and Japan. For empirical analysis, annual data over the period spanning between 1971 and 2013 are used. After using relevant and suitable tests for checking data properties, the panel fully modified ordinary least squares (FMOLS) method is employed as an analytical technique for parameter estimation. The panel group FMOLS results reveal that almost all variables are statistically significant, whereby test rejects the null hypotheses of non cointegration, demonstrating that all variables play an important role in affecting the economic growth role across countries. Where two regressors namely CO2 emissions and energy use show significantly negative impacts on economic growth, for trade and human capital, they tend to show the significantly positive impact on economic growth. However, for the individual analysis across countries, the panel estimate suggests that CO2 emissions have a significant positive relationship with economic growth for China, Japan, and the USA, while it is found significantly negative in case of India. The empirical findings of the study suggest that appropriate and prudent policies are required in order to control pollution emerging from areas other than liquefied fuel consumption. The ultimate impact of shrinking pollution will help in supporting sustainable economic growth and maturation as well as largely improve society welfare. PMID- 26620863 TI - Resonance Raman imaging as a tool to assess the atmospheric pollution level: carotenoids in Lecanoraceae lichens as bioindicators. AB - Raman spectroscopy differentiation of carotenoids has traditionally been based on the nu 1 position (C = C stretching vibrations in the polyene chain) in the 1500 1600 cm(-1) range, using a 785 nm excitation laser. However, when the number of conjugated double bonds is similar, as in the cases of zeaxanthin and beta carotene, this distinction is still ambiguous due to the closeness of the Raman bands. This work shows the Raman results, obtained in resonance conditions using a 514 mm laser, on Lecanora campestris and Lecanora atra species, which can be used to differentiate and consequently characterize carotenoids. The presence of the carotenoid found in Lecanoraceae lichens has been demonstrated to depend on the atmospheric pollution level of the environment they inhabit. Astaxanthin, a superb antioxidant, appears as the principal xanthophyll in highly polluted sites, usually together with the UV screening pigment scytonemin; zeaxanthin is the major carotenoid in medium polluted environments, while beta-carotene is the major carotenoid in cleaner environments. Based on these observations, an indirect classification of the stress suffered in a given environment can be assessed by simply analysing the carotenoid content in the Lecanoraceae lichens by using resonance Raman imaging. PMID- 26620864 TI - Analyses of combined effects of cytostatic drugs on micronucleus formation in the Tradescantia. AB - Recent experiments showed that 5-fluorouracil (5FU), cisplatin (CDDP), etoposide (ET), and imatinib mesylate (IM), which are currently among the most widely used anticancer drugs, cause damage of the genetic material in higher plants. The aim of the present study was to determine whether mixtures of these drugs cause synergistic or antagonistic effects which may have an impact on their environmental safety. Therefore, the effects of binary mixtures of these anticancer drugs on the induction of micronuclei (MN) which reflect structural and numerical chromosomal aberrations were assessed in Tradescantia tetrads. Synergistic/antagonistic effects were determined by comparison with single exposures that would be equally effective in a reference model of independent action. This comparison was performed at two distinct effect sizes. We found clear evidence for synergisms in combination experiments with IM and antagonism in a high-dose experiment with ET and 5FU. Our findings indicate that IM increases the genotoxic effects of other anticancer drugs. The maximal effects which we found were in the range between 19 and 38 % in the excess of effect sizes predicted under independent action. These effects may have an impact on the overall genotoxic activities of untreated hospital waste waters but not on the environment in general as the predicted environmental concentrations of the studied drugs are several orders of magnitude lower as the levels which are required to cause induction of MN in higher plants. PMID- 26620865 TI - Atmospheric pollutants in peri-urban forests of Quercus ilex: evidence of pollution abatement and threats for vegetation. AB - Peri-urban vegetation is generally accepted as a significant remover of atmospheric pollutants, but it could also be threatened by these compounds, with origin in both urban and non-urban areas. To characterize the seasonal and geographical variation of pollutant concentrations and to improve the empirical understanding of the influence of Mediterranean broadleaf evergreen forests on air quality, four forests of Quercus ilex (three peri-urban and one remote) were monitored in different areas in Spain. Concentrations of nitrogen dioxide (NO2), ammonia (NH3), nitric acid (HNO3) and ozone (O3) were measured during 2 years in open areas and inside the forests and aerosols (PM10) were monitored in open areas during 1 year. Ozone was the only air pollutant expected to have direct phytotoxic effects on vegetation according to current thresholds for the protection of vegetation. The concentrations of N compounds were not high enough to directly affect vegetation but could be contributing through atmospheric N deposition to the eutrophization of these ecosystems. Peri-urban forests of Q. ilex showed a significant below-canopy reduction of gaseous concentrations (particularly NH3, with a mean reduction of 29-38%), which indicated the feasibility of these forests to provide an ecosystem service of air quality improvement. Well-designed monitoring programs are needed to further investigate air quality improvement by peri-urban ecosystems while assessing the threat that air pollution can pose to vegetation. PMID- 26620866 TI - Impacts of several pollutants on the distribution of recent benthic foraminifera: the southern coast of Gulf of Gabes, Tunisia. AB - In addition to physicochemical methods, benthic foraminifera have become an essential tool for the assessment of polluted environments. The main objectives of the present work were to study the distribution of benthic foraminifera along the coastline of Skhira and Gabes (southern coast of Gulf of Gabes) and to predict the impact of pollution on these organisms. Thirty-one samples were studied and a polluted area was delimited by chemical analysis, where heavy metal, fluoride, phosphorus, nitrogen, and COT contents are very high. Thirty four species of benthic foraminifera were identified and their response to pollution is very remarkable, in which their distribution shows barren area, corresponding to the highly polluted area. Away from the contaminated area, the density and the diversity of these organisms increase. Statistical analyses (principal component analysis (PCA)/FA and matrix correlation) show a possible control of these pollutants on biotic indices (with negative correlation), in addition to the presence of tolerant and sensitive species to pollution. A variety of test malformations were noticed especially in Ammonia beccarii, Peneroplis planatus, Sorites variabilis, and Adelosina pulchella. Unpolluted stations were dominated by species characteristic of shallow water environments with sandy sediment such Ammonia parkinsoniana, Triloculina trigonula, Quinqueloculina agglutinans, and P. planatus. PMID- 26620867 TI - A hybrid study of multiple contributors to per capita household CO2 emissions (HCEs) in China. AB - Given the large expenditures by households on goods and services that contribute a large proportion of global CO2 emissions, increasing attention has been paid to household CO2 emissions (HCEs). However, compared with industrial CO2 emissions, efforts devoted to mitigating HCEs are relatively small. A good understanding of the effects of some driving factors (i.e., urbanization rate, per capita GDP, per capita income/disposable income, Engel coefficient, new energy ratio, carbon intensity, and household size) is urgently needed prior to considering policies for reducing HCEs. Given this, in the study, the direct and indirect per capita HCEs were quantified in rural and urban areas of China over the period 2000-2012. Correlation analysis and gray correlation analysis were initially used to identify the prime drivers of per capita HCEs. Our results showed that per capita income/disposable income, per capita GDP, urbanization rate, and household size were the most significantly correlated with per capita HCEs in rural areas. Moreover, the conjoint effects of the potential driving factors on per capita HCEs were determined by performing principal component regression analysis for all cases. Based on the combined analysis strategies, alternative polices were also examined for controlling and mitigating HCEs growth in China. PMID- 26620868 TI - Removal of mercury by adsorption: a review. AB - Due to natural and production activities, mercury contamination has become one of the major environmental problems over the world. Mercury contamination is a serious threat to human health. Among the existing technologies available for mercury pollution control, the adsorption process can get excellent separation effects and has been further studied. This review is attempted to cover a wide range of adsorbents that were developed for the removal of mercury from the year 2011. Various adsorbents, including the latest adsorbents, are presented along with highlighting and discussing the key advancements on their preparation, modification technologies, and strategies. By comparing their adsorption capacities, it is evident from the literature survey that some adsorbents have shown excellent potential for the removal of mercury. However, there is still a need to develop novel, efficient adsorbents with low cost, high stability, and easy production and manufacture for practical utility. PMID- 26620870 TI - A Comparison of Parenting Dimensions Between Deaf and Hearing Children. AB - Effective parenting is vital for intellectual, physical, social, and emotional development of a child. This study examined the differences between the parenting dimensions of deaf children and healthy ones. The sample of the study consisted of 292 children and their parents (146 of them deaf children and 146 of them healthy ones). Dimensions of parenting (warmth, rejection, structure, chaos, autonomy, and coercion) were measured using the Parent as Social Context Questionnaire. The mean scores of the positive parenting dimensions of warmth and autonomy of deaf children were significantly lower; however, the mean scores of the negative dimensions of chaos and coercion of deaf children were significantly higher than those of healthy ones. Deaf children can become successful adults with the help of their parents. Our results regarding parenting dimensions will be a guide for future nursing interventions planned to develop the relationships between deaf children and their parents. PMID- 26620871 TI - Spontaneous bilateral haemothorax as presentation of primary pleural epithelioid haemangioendothelioma. AB - Pleural epithelioid haemangioendothelioma (EHE) is a rare tumour that originates in the vascular endothelium with an intermediate degree of malignancy between haemangioma and angiosarcoma. Smoking and asbestos exposure are unproven risk factors and diagnosis is usually confirmed by thoracoscopy, since pleural fluid (PF) cytology is often not conclusive. Immunohistochemistry can also help to confirm the diagnosis. We report an 85-year-old patient with bilateral pleural EHE diagnosed by thoracoscopy, who debuted with a spontaneous bilateral haemothorax, the second described so far, and we conducted a thorough review of the literature to describe the clinical, radiological and prognostic features, as well as the PF, of this rare tumour. PMID- 26620872 TI - [Pathogenesis of large vessel vasculitis]. AB - Giant cell arteritis (GCA) and Takayasu's arteritis (TA) are two granulomatous vasculitis affecting large arteries that present specific epidemiological and clinical features. Their pathogenesis is not fully understood but major advances have been obtained during the last years, thus allowing the emergence of new therapeutic strategies. GCA and TA develop on a specific genetic background but share some similarities regarding the immunological pathways involved in their pathogenesis. The trigger of these diseases is not clearly identified but it is thought that an infectious agent could activate and lead to the maturation of dendritic cells that are localized in the adventitia of arteries. Then, the cells of the adaptative immune response are recruited and activated: CD4 T cells that polarize into Th1 and Th17 cells, cytotoxic CD8 T cells and Natural Killer cells. Furthermore, the T regulatory cells (Treg) are decreased both in GCA and TA. Humoral immune response seems also to be involved, especially in TA. Then, the cytokines produced by T lymphocytes (especially IL-17 and IFN-gamma) trigger the recruitment and activation of monocytes and their differentiation into macrophages and multinuclear giant cells that produce IL-1beta and IL-6 that are responsible for general symptoms of GCA and TA, and cytotoxic mediators and growth factors that trigger the remodeling of the arterial wall leading to aneurysms and ischemic manifestations of GCA an TA. PMID- 26620869 TI - A Linear Dose-Response Relationship between Fasting Plasma Glucose and Colorectal Cancer Risk: Systematic Review and Meta-analysis. AB - For many years, the question of whether hyperglycaemia, a manifestation of prediabetes, diabetes mellitus and metabolic syndrome, is a risk factor for colorectal cancer has been intensely studied. In fact, even after the conclusion of several prospective studies, the topic is still controversial. We conducted a systematic review and meta-analysis to investigate the dose-response relationship between blood glucose concentration and the incidence of colorectal cancer. A linear (P = 0.303 for non-linearity) dose-response relationship was observed between fasting plasma glucose (FPG) and colorectal cancer risk without significant heterogeneity. The relative risk (RR) for colorectal cancer per 20 mg/dL increase in FPG was 1.015 (95% CI: 1.012-1.019, P = 0.000). In subgroup analyses, the pooled RRs for colon cancer (CC) and rectal cancer (RC) studies were 1.035 (95% CI 1.008-1.062, P = 0.011) and 1.031 (95% CI: 0.189-5.628, P = 0.972), respectively; in the analysis comparing men and women, the pooled RRs were 1.016 (95% CI: 1.012-1.020, P = 0.000) and 1.011 (95% CI: 0.995-1.027, P = 0.164), respectively. Sensitivity analyses using two methods showed similar results. In conclusion, there is a significant linear dose-response relationship between FPG and the incidence risk of colorectal cancer. For people with diabetes or prediabetes, controlling blood glucose might be useful to prevent colorectal cancer. PMID- 26620873 TI - The clinical utility of the continuous performance test and objective measures of activity for diagnosing and monitoring ADHD in children: a systematic review. AB - Attention-deficit hyperactivity disorder (ADHD) is typically diagnosed using clinical observation and subjective informant reports. Once children commence ADHD medication, robust monitoring is required to detect partial or non responses. The extent to which neuropsychological continuous performance tests (CPTs) and objective measures of activity can clinically aid the assessment and titration process in ADHD is not fully understood. This review describes the current evidence base for the use of CPTs and objectively measured activity to support the diagnostic procedure and medication management for children with ADHD. Four databases (PsycINFO, Medline, Allied and Complementary Medicine (AMED), and PsycARTICLES) were systematically searched to understand the current evidence base for (1) the use of CPTs to aid clinical assessment of ADHD; (2) the use of CPTs to aid medication management; and (3) the clinical utility of objective measures of activity in ADHD. Sixty relevant articles were identified. The search revealed six commercially available CPTs that had been reported on for their clinical use. There were mixed findings with regard to the use of CPTs to assess and manage medication, with contrasting evidence on their ability to support clinical decision-making. There was a strong evidence base for the use of objective measures of activity to aid ADHD/non-ADHD group differentiation, which appears sensitive to medication effects and would also benefit from further research on their clinical utility. The findings suggest that combining CPTs and an objective measure of activity may be particularly useful as a clinical tool and worthy of further pursuit. PMID- 26620874 TI - Ex Vivo Assessment of an Ultrasound-Guided Injection Technique of the Navicular Bursa in the Horse. AB - Synovitis of the navicular bursa is common in performance horses. The objective of this study was to describe an ultrasound-guided technique to inject a distended navicular bursa and to evaluate its feasibility for use by a clinician not trained in the technique. Twenty distal limbs of horses of various breeds and sizes were used. To produce synovial distension, the navicular bursa of each limb was injected with contrast medium using a lateral approach and radiography was performed to confirm that the contrast medium was distending the bursa. The digit was positioned with the distal interphalangeal joint in hyperextension. A microconvex ultrasound probe was placed in the hollow of the pastern, palmar to the middle phalanx and the region was assessed in a transverse plane slightly oblique to the horizontal plane. The ultrasound probe was rotated to visualize both the lateral and medial recesses and to select which side was more distended to inject. A 21G 0.8 * 50 mm needle was inserted abaxially to the probe in the plane of the ultrasound beam into the proximal recess of this navicular bursa and a methylene blue solution was injected. Following injection, dissection was performed to assess whether the navicular bursa had been successfully injected. This ultrasound-guided technique was reliably performed with a success rate of 68%. The success of injection is influenced by hyperextension of the foot, quality of ultrasound images and degree of distension of the bursa. PMID- 26620875 TI - Do spinal cord-injured individuals with stronger sense of coherence use different psychological defense styles? AB - OBJECTIVES: Although the importance of sense of coherence (SOC) and psychological defense mechanisms (PDMs) in the process of coping has been demonstrated, it has not yet been clarified whether individuals with stronger SOC use specific PDMs. STUDY DESIGN: Cross-sectional. SETTING: Iran. METHODS: Demographic and injury related variables including injury level, time since injury, American Spinal Cord Association (ASIA) Scale and Spinal cord independence measure-III were collected among individuals with spinal cord injury (SCI). SOC was assessed by the Short form Sense of Coherence Scale. PDMs were identified using 40-version of the Defense Style Questionnaire. RESULTS: Neurotic defense style was the most commonly used style especially. The overall most commonly used PDM was 'rationalization', which was used by 95%. Individuals with stronger SOC used more mature style (P=0.001, r=0.52), particularly 'humor' and 'suppression' mechanisms (P<0.0001 and 0.024, respectively). There was a negative correlation between stronger SOC and the use of immature defenses including passive aggression (P=0.001, r=-0.51), acting out (P=0.001, r=-0.48), isolation (P=0.009, r=-0.50), autistic fantasy (P=0.010, r=-0.30) and somatization (P<0.0001, r=-0.62). Married individuals had significantly stronger SOC (P=0.01). Age, gender, age at the time of injury incidence, time since injury, ASIA score and cause of injury were not determinants of SOC. CONCLUSION: In this study, PDMs, which are more probable to be used by individuals with stronger SOC, have been identified. Mature defenses including 'humor' and 'suppression' are used by stronger SOC more often, whereas immature mechanisms are less likely to be used. PMID- 26620876 TI - Medical complications during pregnancy and childbirth in women with SCI in Switzerland. AB - STUDY DESIGN: A retrospective interview study of mothers with spinal cord injuries (SCIs) who gave birth over the last 15 years. OBJECTIVES: To identify the medical complications of women with SCIs during pregnancy and childbirth in Switzerland and to describe how they dealt with these complications. SETTINGS: Swiss Paraplegic Research in Nottwil, the University of Lausanne and participants' homes. METHODS: Data were collected by self-reported questionnaires and descriptive analysis was conducted. RESULTS: Seventeen women with SCIs who gave birth to 23 children were included. Thirteen of the women were paraplegics and four were tetraplegics. All of them practiced an independent bladder management. Three women changed their bladder management techniques during pregnancy. Five women reported an increased bladder evacuation frequency during pregnancy, and six women reported a new onset or increase in incontinence. We observed no significant increase in bowel dysfunction or skin breakdown due to their pregnancies. Ten women were hospitalised during the course of their pregnancies. Aside from urinary tract infections/pyelonephritis, women were hospitalised for falls, hypertension, pneumonia, preeclampsia, pre-term labour or tachycardia. CONCLUSION: The results of our study clearly demonstrated that, although medical complications are not infrequent during pregnancy in women with SCIs, pregnancy and delivery in this group of women are possible without posing intolerable risks to the mothers or the children. Urological problems seemed to be the most frequent complication during pregnancy. PMID- 26620877 TI - Characteristics of neuropathic pain and its relationship with quality of life in 72 patients with spinal cord injury. AB - STUDY DESIGN: A cross-sectional study. OBJECTIVES: Neuropathic pain (NP) after spinal cord injury (SCI) tends to be hard to treat, and its heterogeneous properties make it difficult to identify and characterize. This study was conducted to assess the characteristics of SCI-related NP in detail. SETTING: A single hospital for SCI rehabilitation. METHODS: This study included 72 patients who were seen at our hospital in 2012 and 2013 and who had sustained SCI at least 3 months before enrollment. The patients completed the Neuropathic Pain Symptom Inventory (NPSI) and the Short Form (SF)-36 Health Inventory. The NPSI score was analyzed for correlations with clinical presentations of SCI and SF-36 subitems. RESULTS: Paresthesia/dysesthesia was the most common subtype of NP after SCI. With regard to location, below-level superficial NP was significantly more intense than at-level pain. Patients who underwent surgery showed significantly less evoked pain compared with patients with non-surgery. Patients reported significantly more severe pain if >1 year had elapsed after the SCI. Patients with an American Spinal Injury Association Impairment Scale grade of B for completeness of injury reported more intense NP than those with other grades. Among the SF-36 subitems, NP correlated significantly with bodily pain, general health and mental health. CONCLUSION: NP in SCI patients was significantly associated with the location of pain, the time period since the injury, surgery and quality-of-life factors. A more detailed understanding of the characteristics of NP may contribute to better strategies for relieving the pain associated with SCI. PMID- 26620878 TI - Risk factors for symptomatic urinary tract infections in individuals with chronic neurogenic lower urinary tract dysfunction. AB - STUDY DESIGN: Retrospective investigation. OBJECTIVES: To investigate the association of patient and injury characteristics, as well as bladder management, with the occurrence of patient-reported, symptomatic urinary tract infection(s) UTI(s) in patients with chronic neurogenic lower urinary tract dysfunction (NLUTD). SETTING: Tertiary urologic referral center. METHODS: The patient database was screened for patients with chronic (>12 months) NLUTD who had presented between 2008 and 2012. Patient characteristics, bladder evacuation management, the annual number of patient-reported, symptomatic UTIs and the type of prophylactic treatment to prevent UTIs were collected. Binary logistic regression analysis was used to investigate the effects of the investigated risk factors on the occurrence of symptomatic UTI(s) and recurrent symptomatic UTIs (?3 annual UTIs). RESULTS: The data of 1104 patients with a mean NLTUD duration of 20.3+/-11.6 years were investigated. The evacuation method was a significant (P?0.004) predictor for the occurrence of symptomatic UTI and recurrent symptomatic UTIs. The greatest annual number of symptomatic UTIs was observed in patients using transurethral indwelling catheters, and the odds of experiencing a UTI and recurrent UTIs were increased more than 10- and 4-fold, respectively. The odds of a UTI or recurrent UTIs were also increased significantly (P?0.014) in patients using intermittent catheterization (IC). Botulinum toxin injections into the detrusor increased the odds of a UTI ~10-fold (P=0.03). CONCLUSIONS: The bladder evacuation method is the main predictor for symptomatic UTIs in individuals with NLUTD. Transurethral catheters showed the highest odds of symptomatic UTI and should be avoided whenever possible. PMID- 26620879 TI - The effect of melatonin on spinal cord after ischemia in rats. AB - STUDY DESIGN: Experimental animal model to assess ischemic spinal cord injury (SCI) following occlusion of the thoraco-abdominal aorta. OBJECTIVES: In the present study, we aimed to investigate the role of melatonin on SCI induced by ischemia and following reperfusion. SETTING: Animal Research Laboratory, Inonu University, Malatya, Turkey. METHODS: We evaluated oxidative damage and caspase-3 activity. In total, 32 adult Wistar albino rats were divided into four groups: Group 1, control (n=8); Group 2 (n=8), those subjected to ischemia/reperfusion (IR) by clamping the thoraco-abdominal aorta; Group 3 (n=8), melatonin (50 mg kg( 1)) treated; and Group 4 (n=8), melatonin (50 mg kg(-1)) followed by ischemia. All animals were kept alive for 48 h, and then spinal cord samples were removed. We assayed oxidative damage by measuring malondialdehyde (MDA), apoptosis by measuring activated caspase-3 (using immunoblots) and intrinsic antioxidative capacity by measuring reduced glutathione (GSH) levels in the spinal cord. RESULTS: The results indicated a significant decrease in activity of caspase-3 in SCI animals after treatment with melatonin, as it significantly decreased the formation of MDA and decelerated the loss of GSH. CONCLUSION: This study suggested that melatonin could be an effective neuroprotective agent for treatment of SCI. PMID- 26620880 TI - The characteristics of posttraumatic syringomyelia. AB - STUDY DESIGN: Retrospective cross-sectional study. OBJECTIVES: To investigate the characteristics of posttraumatic symptomatic syringomyelia after spinal cord injury (SCI). SETTING: Swiss Paraplegic Centre, Nottwil, Switzerland. METHODS: The patient database was screened for patients diagnosed with posttraumatic syringomyelia. Syrinx characteristics were determined on T2-weighted magnetic resonance images. Binary logistic regression analysis was used to investigate the effects of age, injury level, injury severity and syrinx location on early syrinx formation, syrinx length and syrinx extending cranial to the lesion. RESULTS: The data of 138 patients were analyzed. The majority of the patients (78.3%) suffered from motor and sensory complete SCI (American Spinal Injury Association Impairment Scale (AIS) A). Syringomyelia was diagnosed a median 15.0 years after SCI at a median age of 42 years. The cervical spine was involved in >57% of the patients, and syringomyelia extended over a median seven vertebral levels. Complete SCI (P=0.035) and age (P=0.001) were significant predictors of early syrinx formation. Syringomyelia occurred significantly earlier in older (>30 years) patients (P?0.002) and those with complete SCI (P=0.027) compared with younger patients (?30 years) and those with incomplete SCI (AIS B-D), respectively. Age, injury level, injury severity (AIS A) and syrinx location did not have any significant (P>0.9) effect on syrinx extending cranially or syrinx length. CONCLUSIONS: Posttraumatic syringomyelia mainly occurs in patients with complete SCI (AIS A) and involves the cervical spine in 6 of the 10 patients. Patients with complete SCI and those age >30 years have an increased risk of syrinx formation within 5 years after injury. PMID- 26620881 TI - Understanding complex clinical reasoning in infectious diseases for improving clinical decision support design. AB - BACKGROUND: Clinical experts' cognitive mechanisms for managing complexity have implications for the design of future innovative healthcare systems. The purpose of the study is to examine the constituents of decision complexity and explore the cognitive strategies clinicians use to control and adapt to their information environment. METHODS: We used Cognitive Task Analysis (CTA) methods to interview 10 Infectious Disease (ID) experts at the University of Utah and Salt Lake City Veterans Administration Medical Center. Participants were asked to recall a complex, critical and vivid antibiotic-prescribing incident using the Critical Decision Method (CDM), a type of Cognitive Task Analysis (CTA). Using the four iterations of the Critical Decision Method, questions were posed to fully explore the incident, focusing in depth on the clinical components underlying the complexity. Probes were included to assess cognitive and decision strategies used by participants. RESULTS: The following three themes emerged as the constituents of decision complexity experienced by the Infectious Diseases experts: 1) the overall clinical picture does not match the pattern, 2) a lack of comprehension of the situation and 3) dealing with social and emotional pressures such as fear and anxiety. All these factors contribute to decision complexity. These factors almost always occurred together, creating unexpected events and uncertainty in clinical reasoning. Five themes emerged in the analyses of how experts deal with the complexity. Expert clinicians frequently used 1) watchful waiting instead of over- prescribing antibiotics, engaged in 2) theory of mind to project and simulate other practitioners' perspectives, reduced very complex cases into simple 3) heuristics, employed 4) anticipatory thinking to plan and re-plan events and consulted with peers to share knowledge, solicit opinions and 5) seek help on patient cases. CONCLUSION: The cognitive strategies to deal with decision complexity found in this study have important implications for design future decision support systems for the management of complex patients. PMID- 26620882 TI - Gender Bias in Diagnostic Radiology Resident Selection, Does it Exist? AB - RATIONALE AND OBJECTIVES: To investigate whether there is a bias in the residency selection process that influences the proportion of females entering diagnostic radiology residencies. MATERIALS AND METHODS: A total of 4117 applications to one diagnostic radiology residency program from 2008 to 2014 were analyzed. Invitations to interview were evaluated by each year, specifically looking at gender. Ranking of applicants, especially those placed in top 25% of the rank, was also assessed. Additional data analyzed included United States Medical Licensing Examination Step 1 board examination score (a proxy for academic performance), interview scores, and final position on rank list. RESULTS: Female applicants averaged 24% of the total applicant pool during the years studied, yet made up a disproportionately high percentage of applicants invited to interview (30%) and those ranked in top 25% (38%). It was found that female applicants had slightly higher mean interview scores and lower Step 1 scores than male applicants. CONCLUSIONS: Our findings suggest that program directors in one program want to increase gender diversity by making strides to keep the female candidate pool and the proportion of female residents in the program at least stable. The pipeline of female medical students pursuing a career in radiology appears to be a limiting factor rather than a bias against women in the resident selection process. Identifying such trends is important as it provides a better understanding of the etiology for an overall lack of gender diversity within the field. Furthermore, it may lead to closing the gender gap in radiology. PMID- 26620883 TI - Aldioxa improves delayed gastric emptying and impaired gastric compliance, pathophysiologic mechanisms of functional dyspepsia. AB - Delayed gastric emptying and impaired gastric accommodation (decreased gastric compliance) play important roles in functional dyspepsia (FD). Here we screen for a clinically used drug with an ability to improve delayed gastric emptying in rats. Oral administration of aldioxa (dihydroxyaluminum allantoinate) partially improved clonidine- or restraint stress-induced delayed gastric emptying. Administration of allantoin, but not aluminium hydroxide, restored the gastric emptying. Both aldioxa and allantoin inhibited clonidine binding to the alpha-2 adrenergic receptor, suggesting that antagonistic activity of the allantoin moiety of aldioxa on this receptor is involved in the restoration of gastric emptying activity. Aldioxa or aluminium hydroxide but not allantoin restored gastric compliance with restraint stress, suggesting that aluminium hydroxide moiety is involved in this restoration. We propose that aldioxa is a candidate drug for FD, because its safety in humans has already been confirmed and its ameliorating effect on both of delayed gastric emptying and impaired gastric compliance are confirmed here. PMID- 26620884 TI - Central calcification in a rectal neuroendocrine tumor. PMID- 26620885 TI - Additive Manufacturing of a Photo-Cross-Linkable Polymer via Direct Melt Electrospinning Writing for Producing High Strength Structures. AB - Melt electrospinning writing (MEW) is an emerging additive manufacturing technique that enables the design and fabrication of micrometer-thin fibrous scaffolds made of biocompatible and biodegradable polymers. By using a computer aided deposition process, a unique control over pore size and interconnectivity of the resulting scaffolds is achieved, features highly interesting for tissue engineering applications. However, MEW has been mainly used to process low melting point thermoplastics such as poly(epsilon-caprolactone). Since this polymer exhibits creep and a reduction in modulus upon hydration, we manufactured scaffolds of poly(L-lactide-co-epsilon-caprolactone-co-acryloyl carbonate) (poly(LLA-epsilon-CL-AC)), a photo-cross-linkable and biodegradable polymer, for the first time. We show that the stiffness of the scaffolds increases significantly (up to ~10-fold) after cross-linking by UV irradiation at room temperature, compared with un-cross-linked microfiber scaffolds. The preservation of stiffness and high average fiber modulus (370 +/- 166 MPa) within the cross linked hydrated scaffolds upon repetitive loading (10% strain at 1 Hz up to 200,000 cycles) suggests that the prepared scaffolds may be of potential interest for soft connective tissue engineering applications. Moreover, the approach can be readily adapted through manipulation of polymer properties and scaffold geometry to prepare structures with mechanical properties suitable for other tissue engineering applications. PMID- 26620886 TI - Three-dimensional simulations of the cell growth and cytokinesis using the immersed boundary method. AB - In this paper, we present a three-dimensional immersed boundary method to simulate the eukaryotic cell growth and cytokinesis. The proposed model and numerical method are a non-trivial three-dimensional extension of the previous work (Li et al., 2012). Unstructured triangular meshes are employed to discretize the cell membrane. The nodes of the surface mesh constitute a set of Lagrangian control points used to track the motion of the cell. A surface remeshing algorithm is applied to prevent mesh distortion during evolution. We also use a volume-conserving algorithm to maintain the mass of cells in cytokinesis. The ability of the proposed method to simulate cell growth and division processes is numerically demonstrated. PMID- 26620887 TI - Diagnostic accuracy of body mass index to identify obesity in older adults: NHANES 1999-2004. AB - BACKGROUND: Body composition changes with aging lead to increased adiposity and decreased muscle mass, making the diagnosis of obesity challenging. Conventional anthropometry, including body mass index (BMI), while easy to use clinically may misrepresent adiposity. We determined the diagnostic accuracy of BMI using dual energy X-ray absorptiometry (DEXA) in assessing the degree of obesity in older adults. METHODS: The National Health and Nutrition Examination Surveys 1999-2004 were used to identify adults aged ?60 years with DEXA measures. They were categorized (yes/no) as having elevated body fat by gender (men: ?25%; women ?35%) and by BMI ?25 and ?30 kg m(-)(2). The diagnostic performance of BMI was assessed. Metabolic characteristics were compared in discordant cases of BMI/body fat. Weighting and analyses were performed per NHANES (National Health and Nutrition Examination Survey) guidelines. RESULTS: We identified 4984 subjects (men: 2453; women: 2531). Mean BMI and % body fat was 28.0 kg m(-2) and 30.8% in men, and 28.5 kg m(-)(2) and 42.1% in women. A BMI ?30 kg m(-)(2) had a low sensitivity and moderately high specificity (men: 32.9 and 80.8%, concordance index 0.66; women: 38.5 and 78.5%, concordance 0.69) correctly classifying 41.0 and 45.1% of obese subjects. A BMI ?25 kg m(-2) had a moderately high sensitivity and specificity (men: 80.7 and 99.6%, concordance 0.81; women: 76.9 and 98.8%, concordance 0.84) correctly classifying 80.8 and 78.5% of obese subjects. In subjects with BMI <30 kg m(-)(2), body fat was considered elevated in 67.1% and 61.5% of men and women, respectively. For a BMI ?30 kg m(-)(2), sensitivity drops from 40.3% to 14.5% and 44.5% to 23.4%, whereas specificity remains elevated (>98%), in men and women, respectively, in those 60-69.9 years to subjects aged ?80 years. Correct classification of obesity using a cutoff of 30 kg m(-)(2) drops from 48.1 to 23.9% and 49.0 to 19.6%, in men and women in these two age groups. CONCLUSIONS: Traditional measures poorly identify obesity in the elderly. In older adults, BMI may be a suboptimal marker for adiposity. PMID- 26620889 TI - Decrease in microvesicle-associated tissue factor activity in morbidly obese patients after bariatric surgery. AB - BACKGROUND: Tissue factor (TF) is the main in vivo initiator of the blood coagulation cascade. Active circulating TF was detected on small, negatively charged membrane vesicles, the so-called microvesicles (MVs), which are released upon cell activation and apoptosis from a variety of cells. Increased coagulation activation was found in morbidly obese patients, and elevated levels of TF bearing MVs may contribute to the prothrombotic state in these patients. AIM: To determine MV-associated TF activity levels in morbidly obese patients before and after weight loss due to bariatric surgery. METHODS: MV-TF activity was measured with a factor Xa generation assay in morbidly obese patients before and 2 years after bariatric surgery. In addition, clinical parameters were determined. RESULTS: Seventy-four morbidly obese patients (mean age: 42 (+/-11) years; 61 females) were included in this study. After bariatric surgery, the body mass index decreased from (median, 25-75th percentile) 45.5 (42.3-50.2) to 30.5 (28.0 34.4 kg m(-2); P<0.001), and a significant improvement in metabolic parameters was observed. Preoperative MV-TF activity correlated with C-reactive protein levels (r=0.3; P=0.02). Postoperatively, the mean MV-TF activity decreased significantly from 0.20 pg ml(-1) (0.18-0.47) to 0.02 (0.00-0.28; P<0.01). CONCLUSION: We could demonstrate a significant decrease in MV-TF activity after weight loss in morbidly obese patients. Decreased MV-TF activity might contribute to an improved coagulation profile in these patients after weight loss. PMID- 26620888 TI - Anorexia-cachexia and obesity treatment may be two sides of the same coin: role of the TGF-b superfamily cytokine MIC-1/GDF15. AB - Anorexia-cachexia associated with cancer and other diseases is a common and often fatal condition representing a large area of unmet medical need. It occurs most commonly in advanced cancer and is probably a consequence of molecules released by tumour cells, or tumour-associated interstitial or immune cells. These may then act directly on muscle to cause atrophy and/or may cause anorexia, which then leads to loss of both fat and lean mass. Although the aetiological triggers for this syndrome are not well characterized, recent data suggest that MIC 1/GDF15, a transforming growth factor-beta superfamily cytokine produced in large amounts by cancer cells and as a part of other disease processes, may be an important trigger. This cytokine acts on feeding centres in the hypothalamus and brainstem to cause anorexia leading to loss of lean and fat mass and eventually cachexia. In animal studies, the circulating concentrations of MIC-1/GDF15 required to cause this syndrome are similar to those seen in patients with advanced cancer, and at least some epidemiological studies support an association between MIC-1/GDF15 serum levels and measures of nutrition. This article will discuss its mechanisms of central appetite regulation, and the available data linking this action to anorexia-cachexia syndromes that suggest it is a potential target for therapy of cancer anorexia-cachexia and conversely may also be useful for the treatment of severe obesity. PMID- 26620892 TI - Implantable Bladder Sensors for Long-term Monitoring of Bladder Volume. PMID- 26620890 TI - Role of MCP-1 on inflammatory processes and metabolic dysfunction following high fat feedings in the FVB/N strain. AB - BACKGROUND: Monocyte chemoattractant protein 1 (MCP-1) is known to be an important chemokine for macrophage recruitment. Thus, targeting MCP-1 may prevent the perturbations associated with macrophage-induced inflammation in adipose tissue. However, inconsistencies in the available animal literature have questioned the role of this chemokine in this process. The purpose of this study was to examine the role of MCP-1 on obesity-related pathologies. METHODS: Wild type and MCP-1-deficient mice on an friend virus B NIH (FVB/N) background were assigned to either low-fat diet or high-fat diet (HFD) treatment for a period of 16 weeks. Body weight and body composition were measured weekly and monthly, respectively. Fasting blood glucose and insulin, and glucose tolerance were measured at 16 weeks. Macrophages, T-cell markers, inflammatory mediators and markers of fibrosis were examined in the adipose tissue at the time of killing the mice. RESULTS: As expected, HFD increased adiposity (body weight, fat mass, fat percent and adipocyte size), metabolic dysfunction (impaired glucose metabolism and insulin resistance) macrophage number (CD11b(+)F480(+) cells, and gene expression of EMR1 and CD11c), T-cell markers (gene expression of CD4 and CD8), inflammatory mediators (pNFkappaB and pJNK, and mRNA expression of MCP-1, CCL5, C-X-C motif chemokine-14, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6)) and fibrosis (expression of IL-10, IL-13, TGF-beta and matrix metalloproteinase-2 (MMP2); P<0.05). However, contrary to our hypothesis, MCP-1 deficiency exacerbated many of these responses resulting in a further increase in adiposity (body weight, fat mass, fat percent and adipocyte size), metabolic dysregulation, macrophage markers (EMR1), inflammatory cell infiltration and fibrosis (formation of type I and III collagens, mRNA expression of IL-10 and MMP2; P<0.05). CONCLUSIONS: These data suggest that MCP-1 may be a necessary component of the inflammatory response required for adipose tissue protection, remodeling and healthy expansion in the FVB/N strain in response to HFD feedings. PMID- 26620893 TI - Interleukin-33 as a Potential Therapeutic Target for Interstitial Cystitis: New Perspectives on Mast Cell Regulation. PMID- 26620891 TI - 16p11.2 Locus modulates response to satiety before the onset of obesity. AB - BACKGROUND: The 600 kb BP4-BP5 copy number variants (CNVs) at the 16p11.2 locus have been associated with a range of neurodevelopmental conditions including autism spectrum disorders and schizophrenia. The number of genomic copies in this region is inversely correlated with body mass index (BMI): the deletion is associated with a highly penetrant form of obesity (present in 50% of carriers by the age of 7 years and in 70% of adults), and the duplication with being underweight. Mechanisms underlying this energy imbalance remain unknown. OBJECTIVE: This study aims to investigate eating behavior, cognitive traits and their relationships with BMI in carriers of 16p11.2 CNVs. METHODS: We assessed individuals carrying a 16p11.2 deletion or duplication and their intrafamilial controls using food-related behavior questionnaires and cognitive measures. We also compared these carriers with cohorts of individuals presenting with obesity, binge eating disorder or bulimia. RESULTS: Response to satiety is gene dosage dependent in pediatric CNV carriers. Altered satiety response is present in young deletion carriers before the onset of obesity. It remains altered in adolescent carriers and correlates with obesity. Adult deletion carriers exhibit eating behavior similar to that seen in a cohort of obesity without eating disorders such as bulimia or binge eating. None of the cognitive measures are associated with eating behavior or BMI. CONCLUSIONS: These findings suggest that abnormal satiety response is a strong contributor to the energy imbalance in 16p11.2 CNV carriers, and, akin to other genetic forms of obesity, altered satiety responsiveness in children precedes the increase in BMI observed later in adolescence. PMID- 26620894 TI - Implantable Bladder Sensors: A Methodological Review. AB - The loss of urinary bladder control/sensation, also known as urinary incontinence (UI), is a common clinical problem in autistic children, diabetics, and the elderly. UI not only causes discomfort for patients but may also lead to kidney failure, infections, and even death. The increase of bladder urine volume/pressure above normal ranges without sensation of UI patients necessitates the need for bladder sensors. Currently, a catheter-based sensor is introduced directly through the urethra into the bladder to measure pressure variations. Unfortunately, this method is inaccurate because measurement is affected by disturbances in catheter lines as well as delays in response time owing to the inertia of urine inside the bladder. Moreover, this technique can cause infection during prolonged use; hence, it is only suitable for short-term measurement. Development of discrete wireless implantable sensors to measure bladder volume/pressure would allow for long-term monitoring within the bladder, while maintaining the patient's quality of life. With the recent advances in microfabrication, the size of implantable bladder sensors has been significantly reduced. However, microfabricated sensors face hostility from the bladder environment and require surgical intervention for implantation inside the bladder. Here, we explore the various types of implantable bladder sensors and current efforts to solve issues like hermeticity, biocompatibility, drift, telemetry, power, and compatibility issues with popular imaging tools such as computed tomography and magnetic resonance imaging. We also discuss some possible improvements/emerging trends in the design of an implantable bladder sensor. PMID- 26620896 TI - Inhibitory Effect and Possible Mechanism of Intraurethral Stimulation on Overactive Bladder in Female Rats. AB - PURPOSE: To investigate the inhibitory effect and possible mechanism of intraurethral stimulation on overactive bladder (OAB) induced by acetic acid irritation. METHODS: Cystometry was performed in 13 urethane-anesthetized female rats. Intravesical infusion of 0.5% acetic acid was used to irritate the bladder and induce OAB. Multiple cystometrograms were performed with mirabegron, continuous stimulation, mirabegron plus continuous stimulation, and beta3 adrenoceptor antagonist plus continuous stimulation to determine the mechanism underlying the inhibitory effect by intraurethral stimulation. RESULTS: Infusion of acetic acid significantly decreased bladder capacity. Intraurethral stimulation at 2.5 Hz plus mirabegron significantly increased bladder capacity and decreased the nonvoiding contraction count. The changes were strongly inhibited after the beta3-adrenoceptor antagonist was administered. CONCLUSIONS: Activation of urethral afferent nerves can reverse OAB, which activates C-fiber afferent nerves. This animal study indicates that intraurethral stimulation may interfere with OAB through hypogastric nerve activation and pudendal nerve neuromodulation. PMID- 26620895 TI - Interleukin-33 and Mast Cells Bridge Innate and Adaptive Immunity: From the Allergologist's Perspective. AB - Interleukin (IL) 33, a member of the IL-1 superfamily, is an "alarmin" protein and is secreted in its active form from damaged cells undergoing necrotic cell death. Mast cells are one of the main effector cell types in allergic disorders. They secrete a variety of mediators, including T helper 2 cytokines. As mast cells have high-affinity IgE receptors (FcepsilonRI) on their surface, they can capture circulating IgE. IgE-bound mast cells degranulate large amounts of histamine, heparin, and proteases when they encounter antigens. As IL-33 is an important mediator of innate immunity and mast cells play an important role in adaptive immune responses, interactions between the two could link innate and adaptive immunity. IL-33 promotes the adhesion of mast cells to laminin, fibronectin, and vitronectin. IL-33 increases the expression of adhesion molecules, such as intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, in endothelial cells, thus enhancing mast cell adhesion to blood vessel walls. IL-33 stimulates mast cell proliferation by activating the ST2/Myd88 pathway; increases mast cell survival by the activation of survival proteins such as Bcl-XL; and promotes the growth, development, and maturation of mast cell progenitors. IL-33 is also involved in the activation of mature mast cells and production of different proinflammatory cytokines. The interaction of IL-33 and mast cells could have important clinical implications in the field of clinical urology. Epithelial dysfunction and mast cells could play an important role in the pathogenesis of interstitial cystitis. Urinary levels of IL-33 significantly increase in patients with interstitial cystitis. In addition, the number of mast cells significantly increase in the urinary bladders of patients with interstitial cystitis. Therefore, inhibition of mast cell activation and degranulation in response to increase in IL-33 is a potential therapeutic target in the treatment of interstitial cystitis. PMID- 26620897 TI - Increased Expression of Neuregulin 1 and erbB2 Tyrosine Kinase in the Bladder of Rats With Cyclophosphamide-Induced Interstitial Cystitis. AB - PURPOSE: The aim of this study was to evaluate changes in expressions of neuregulin (NRG)1 and erbB2 tyrosine kinase (ErbB2) in bladders of rats with cyclophosphamide (CYP)-induced interstitial cystitis (IC). METHODS: Twenty-four Sprague-Dawley rats were divided into the IC group (n=16) and the control group (n=8). After inducing IC with intraperitoneal CYP injection, expressions of NRG1 and ErbB2 were analyzed using western blotting and reverse transcriptase polymerase chain reaction. RESULTS: In Western blotting, relative intensities and distributions of both NRG1 and ErbB2 were approximately 1.5- and 3.2-fold higher, respectively, in the IC group than in the control group (mean+/-standard deviation: 1.42+/-0.09 vs. 0.93+/-0.15 and 0.93+/-0.16 vs. 0.29+/-0.08, P<0.05). In the rat bladder samples, mRNA expression levels of NRG1 and ErbB2 were higher in the IC group than in the control group (P<0.05). CONCLUSIONS: Our study has demonstrated significant changes in mRNA expression and immunoreactivity of NRG1 and ErbB2 receptors in the urinary bladder after CYP-induced IC. These results suggest that the up-regulated NRG1 may play a role in inducing an overactive bladder and promoting regeneration in the inflammatory bladder with CYP-induced IC. PMID- 26620898 TI - Is There a Relationship Between Pelvic Organ Prolapse and Tissue Fibrillin-1 Levels? AB - PURPOSE: Pelvic organ prolapse is a multifactorial disorder in which extracellular matrix defects are implicated. Fibrillin-1 level is reduced in stress urinary incontinence. In Marfan syndrome, which is associated with mutations in Fibrillin-1, pelvic floor disorders are commonly observed. We hypothesize that Fibrillin-1 gene expression is altered in pelvic organ prolapse. METHODS: Thirty women undergoing colporrhaphy or hysterectomy because of cystocele, rectocele, cystorectocele, or uterine prolapse were assigned to a pelvic prolapse study group, and thirty women undergone hysterectomy for nonpelvic prolapse conditions were assigned to a control group. Real-time polymerase chain reaction was conducted on vaginal tissue samples to measure the expression of Fibrillin-1. Expression levels were compared between study and control groups by Mann-Whitney U test with Bonferroni revision. RESULTS: Fibrillin-1 gene expression was not significantly lower in the study group than in the control group. Similarly, no significant correlation between Fibrillin-1 levels and grade of pelvic prolapse was found. Age over 40 years (P=0.018) and menopause (P=0.027) were both associated with reduced Fibrillin-1 levels in the pelvic prolapse group, whereas the delivery of babies weighing over 3,500 g at birth was associated with increased Fibrillin-1 expression (P=0.006). CONCLUSIONS: The results did not indicate a significant reduction in Fibrillin-1 gene expression in pelvic prolapse disorders; however, reduced Fibrillin-1 may contribute to increased pelvic organ prolapse risk with age and menopause. Increased Fibrillin-1 gene expression may be a compensatory mechanism in cases of delivery of babies with high birth weight. Further studies are needed for a better understanding of these observations. PMID- 26620899 TI - Duration of Antimuscarinic Administration for Treatment of Overactive Bladder Before Which One Can Assess Efficacy: An Analysis of Predictive Factors. AB - PURPOSE: To determine the duration of antimuscarinic therapy for overactive bladder syndrome (OAB) appropriate for assessment of the efficacy of treatment, and to evaluate the possible predictive factors for response to therapy. METHODS: All OAB patients who visited a urology outpatient clinic of a tertiary referral center and who were prescribed 5 mg of solifenacin or 4 mg of tolterodine extended release capsules daily were enrolled in the study. Patients were asked to continue therapy for 6 months. All enrolled patients completed the patient perception of bladder condition, overactive bladder symptom score (OABSS), and the modified Indevus Urgency Severity Scale questionnaires. All patients underwent uroflowmetry. RESULTS: A total of 164 patients were enrolled and 125 patients (76%) had at least one follow-up visit. The mean follow-up interval was 1 month (range, 0.5-6 months). Sixty-two patients (49.6%; 95% confidence interval [CI], 40.7-58.5) responded to antimuscarinic treatment. The median time for the onset of response was 3 months (95% CI, 1-6). Multivariate Cox proportional hazards model revealed that elevated baseline OABSS was an independent predictor of responsiveness to therapy. Receiver operating characteristic (ROC) curve analysis revealed an optimal OABSS cutoff value of >=7, with an area under the ROC curve of 0.79 (95% CI, 0.70-0.88; sensitivity, 91.9%; specificity, 60.7%). CONCLUSIONS: The median time for a therapeutic response was 3 months, and OABSS was the only predictor for responsiveness. These findings may serve as a guideline when prescribing antimuscarinic treatment for OAB patients. PMID- 26620900 TI - The Efficacy of Continuous Positive Airway Pressure Therapy on Nocturia in Patients With Obstructive Sleep Apnea: A Systematic Review and Meta-Analysis. AB - PURPOSE: To assess the efficacy of the continuous positive airway pressure (CPAP) on nocturia in patients with obstructive sleep apnea (OSA). METHODS: A literature review was performed to identify all published clinical trials of CPAP for the treatment of nocturia. The search included the following databases: MEDLINE, Embase, and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. RESULTS: Five publications involving a total of 307 patients were used in the analysis, which compared the number of incidents of nocturia before and after CPAP treatment. We found that patients with OSA and nocturia who were treated with CPAP had a significant decrease in the frequency of nocturia and the volume of urine associated with it. The mean number of nocturia incidents (standardized mean difference [SMD], -2.28; 95% confidence interval [CI], -2.42 to -2.15; P<0.00001) and the associated urine volume (SMD, -183.12; 95% CI, -248.27 to -117.98; P<0.00001) indicated that CPAP was effective. Besides, the Epworth Sleepiness Scale (SMD, -5.88; 95% CI, -6.56 to -5.21; P<0.00001) and the CPAP apnea-hypopnea index (SMD, -31.57; 95% CI, 33.87 to -29.28; P<0.00001) indicated that CPAP significantly improved the quality of sleep. CONCLUSIONS: This meta-analysis indicates that CPAP maybe an effective treatment for reducing nocturia associated with OSA and improving the quality of life of such patients. PMID- 26620901 TI - Underactive Bladder: Clinical Features, Urodynamic Parameters, and Treatment. AB - PURPOSE: Underactive bladder is a complex clinical condition that remains poorly understood due to limited literature. This study aimed to determine its prevalence among patients with voiding dysfunction, presenting symptoms, risk factors, urodynamic findings, and ongoing treatment. METHODS: A retrospective chart review of consecutive urodynamic studies performed on voiding dysfunction between 2012 and 2014 was conducted to identify patients with detrusor underactivity. Detrusor underactivity was defined by a bladder contractility index of less than 100. Charts and urodynamic tracings were examined for patient demographics, suspected risk factors, presenting symptoms, urodynamic parameters, and treatment undertaken. Descriptive statistics were utilized to analyze the data. RESULTS: The prevalence of detrusor underactivity in this study was 23% (79 of 343). Average age of the patients was 59.2 years (range, 19-90 years). Women represented 68.4% (54 of 79) of the patients. The most common reported symptoms were urinary urgency (63.3%), weak stream (61.0%), straining (57.0%), nocturia (48.1%), and urinary frequency (46.8%). Prior pelvic surgery and prior back surgery were noted in 40.5% and 19.0% of the patients, respectively. The most common management was intermittent self-catheterization in 54.4%, followed by observation/conservative treatment in 25.3% and sacral neuromodulation in 12.7%. CONCLUSIONS: Although underactive bladder is a common condition, its precise diagnosis and treatment remain a challenge. Its symptoms significantly overlap with those of other bladder disorders, and hence, urodynamic evaluation is particularly useful in identifying patients with impaired detrusor contractility. This will help prevent mismanagement of patients with surgery or medical therapy, as that may worsen their condition. Much work needs to be done to better understand this condition and establish optimal management of patients. PMID- 26620902 TI - The Effectiveness of Silodosin for Nocturnal Polyuria in Elderly Men With Benign Prostatic Hyperplasia: A Multicenter Study. AB - PURPOSE: To investigate improvement in nocturia and nocturnal polyuria in nocturnal polyuria patients after silodosin administration by using a 3-day frequency volume chart. METHODS: This was a prospective multicenter study. We enrolled nocturnal polyuria patients (nocturnal polyuria index [NPi]>0.33), aged >=60 years, diagnosed with the 3-day frequency volume charts of patients with benign prostatic hyperplasia taking alpha-blockers. Of the 54 patients, 30 (55.6%) completed the study according to the study protocol (per-protocol group), and 24 dropped out (dropout group). RESULTS: Of the 24 patients in the dropout group, 5 withdrew consent due to side effects or lack of efficacy, 7 were lost to follow-up at 4 weeks, 8 were lost to follow-up at 12 weeks, and 4 dropped out due to failure to complete 3-day frequency volume charts at 12 weeks. In the per protocol group, there was significant improvement in the International Prostate Symptom Score (IPSS), especially question numbers 1, 3, 4, 5, 6, 7, and the quality of life question (P=0.001, P=0.007, P<0.001, P=0.003, P=0.049, P<0.001, and P<0.001, respectively). The Leeds sleep evaluation questionnaire (LSEQ) score for the sleep question improved from 64.36 to 70.43 (P=0.039). The NPi reduced from 0.4005 to 0.3573 (P=0.027); however, in many cases, there was no improvement in nocturnal polyuria itself. In intention-to-treat analysis, there were significant improvements in IPSS and LSEQ in 45 patients. CONCLUSIONS: In elderly nocturnal polyuria patients, silodosin monotherapy exhibits good efficacy in improving nocturia and nocturnal polyuria; however, the mean NPi was still >0.33. Considering the high dropout rate of our study due to no implementation of 3-day frequency volume charts, prospective and large-scale studies are needed to confirm our results. PMID- 26620903 TI - Alcohol, Smoking, Physical Activity, Protein, and Lower Urinary Tract Symptoms: Prospective Longitudinal Cohort. AB - PURPOSE: To evaluate risk factors for deterioration of lower urinary tract symptoms (LUTS) in elderly men in a community-based, prospective longitudinal cohort study. METHODS: In a suburban area in Korea, 1,514 subjects aged >=45 years were randomly selected by systematic sampling. A total of 918 elderly subjects were enrolled in this in-depth clinical study in 2004. Of these, 547 participants were followed up for 3 years and the data was analyzed in 2014. Standard questionnaires were administered face-to-face by trained interviewers. After excluding women, 224 male participants with complete data including transrectal ultrasonography were included in the final analysis. LUTS were diagnosed using the International Prostate Symptom Score (IPSS) questionnaire. Symptom deterioration was defined as a score of >=8 points during the 3-year follow-up period. RESULTS: LUTS prevalence increased to 13.1% and the mean IPSS increased by 2.6 points during the 3-year period. After adjusting for confounders, a smoking history of >=50 pack-years was an independent risk factor for deterioration of LUTS and storage subsymptoms compared with no history of smoking (3.1 and 5.1 odds, respectively). Physical activity had a protective effect on voiding subsymptoms. However, high protein diet and alcohol intake were not associated with LUTS deterioration. CONCLUSIONS: The LUTS prevalence among elderly men living in a suburban area increased to 13.1% and the IPSS increased by 2.6 points during the 3-year period. A history of heavy smoking, low physical activity, and high protein intake were associated with LUTS deterioration. However, there was no significant association between alcohol intake and LUTS deterioration. PMID- 26620904 TI - Meningitis-Retention Syndrome. AB - Meningitis-retention syndrome (MRS) is a clinical entity that has recently appeared in the literature. We present the case of a 22-year-old man with fever and headache who, in the course of his hospitalization with a diagnosis of aseptic meningitis, developed acute urinary retention. Fewer than 30 such cases have been described and in several of them, no clear associations with other disorders have been made. In some cases, direct association with viral infection has been proved, and in others, there are indications of an underlying demyelinating condition. To further complicate the issue, various conditions such as Elsberg syndrome and acute disseminated encephalomyelitis, which not only have some similarities but also have some distinct differences, have been placed under the umbrella definition of MRS. In our review, we attempt to address these conditions and better define MRS by establishing diagnostic criteria based on what has thus far been described in the literature. PMID- 26620905 TI - Textbook of Voiding Dysfunction and Female Urology. 3rd ed. PMID- 26620906 TI - Enhanced adaptive focusing through semi-transparent media. AB - Adaptive optics can focus light through opaque media by compensating the random phase delay acquired while crossing a scattering curtain. The technique is commonly exploited in many fields, including astrophysics, microscopy, biomedicine and biology. A turbid lens has the capability of producing foci with a resolution higher than conventional optics, however it has a fundamental limit: to obtain a sharp focus one has to introduce a strongly scattering medium in the optical path. Indeed a tight focusing needs strong scattering and, as a consequence, high resolution focusing is obtained only for weakly transmitting samples. Here we describe a novel method allowing to obtain highly concentrated optical spots even by introducing a minimum amount of scattering in the beam path with semi-transparent materials. By filtering the pseudo-ballistic components of the transmitted beam we are able to experimentally overcome the limits of the adaptive focus resolution, gathering light on a spot with a diameter which is one third of the original speckle correlation function. PMID- 26620908 TI - A feedforward loop of NLRC5 (de)ubiquitination keeps IKK-NF-kappaB in check. AB - Many receptors signal via adaptors to the IKK-NF-kappaB axis, transducing extracellular cues to transcriptional regulation. In this issue, Meng et al. (2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201505091) reveal that the IKK regulator NLRC5 shapes NF-kappaB activity through a feedforward loop of NLRC5 ubiquitination and deubiquitination, highlighting a new pathway modulating IKK-NF kappaB activity. PMID- 26620907 TI - An Asp-CaM complex is required for centrosome-pole cohesion and centrosome inheritance in neural stem cells. AB - The interaction between centrosomes and mitotic spindle poles is important for efficient spindle formation, orientation, and cell polarity. However, our understanding of the dynamics of this relationship and implications for tissue homeostasis remains poorly understood. Here we report that Drosophila melanogaster calmodulin (CaM) regulates the ability of the microcephaly associated protein, abnormal spindle (Asp), to cross-link spindle microtubules. Both proteins colocalize on spindles and move toward spindle poles, suggesting that they form a complex. Our binding and structure-function analysis support this hypothesis. Disruption of the Asp-CaM interaction alone leads to unfocused spindle poles and centrosome detachment. This behavior leads to randomly inherited centrosomes after neuroblast division. We further show that spindle polarity is maintained in neuroblasts despite centrosome detachment, with the poles remaining stably associated with the cell cortex. Finally, we provide evidence that CaM is required for Asp's spindle function; however, it is completely dispensable for Asp's role in microcephaly suppression. PMID- 26620909 TI - Reversible ubiquitination shapes NLRC5 function and modulates NF-kappaB activation switch. AB - NLRC5 is an important regulator in innate immune responses. However, the ability of NLRC5 to inhibit NF-kappaB activation is controversial in different cell types. How dynamic modification of NLRC5 shapes NF-kappaB signaling remains unknown. We demonstrated that NLRC5 undergoes robust ubiquitination by TRAF2/6 after lipopolysaccharide treatment, which leads to dissociation of the NLRC5 IkappaB kinase complex. Experimental and mathematical analyses revealed that the K63-linked ubiquitination of NLRC5 at lysine 1,178 generates a coherent feedforward loop to further sensitize NF-kappaB activation. Meanwhile, we found USP14 specifically removes the polyubiquitin chains from NLRC5 to enhance NLRC5 mediated inhibition of NF-kappaB signaling. Furthermore, we found that different cell types may exhibit different sensitivities to NF-kappaB activation in response to NLRC5 ablation, possibly as a result of the various intrinsic levels of deubiquitinases and NLRC5. This might partially reconcile controversial studies and explain why NLRC5 exhibits diverse inhibitory efficiencies. Collectively, our results provide the regulatory mechanisms of reversible NLRC5 ubiquitination and its role in the dynamic control of innate immunity. PMID- 26620910 TI - Peroxisomes, lipid droplets, and endoplasmic reticulum "hitchhike" on motile early endosomes. AB - Intracellular transport is mediated by molecular motors that bind cargo to be transported along the cytoskeleton. Here, we report, for the first time, that peroxisomes (POs), lipid droplets (LDs), and the endoplasmic reticulum (ER) rely on early endosomes (EEs) for intracellular movement in a fungal model system. We show that POs undergo kinesin-3- and dynein-dependent transport along microtubules. Surprisingly, kinesin-3 does not colocalize with POs. Instead, the motor moves EEs that drag the POs through the cell. PO motility is abolished when EE motility is blocked in various mutants. Most LD and ER motility also depends on EE motility, whereas mitochondria move independently of EEs. Covisualization studies show that EE-mediated ER motility is not required for PO or LD movement, suggesting that the organelles interact with EEs independently. In the absence of EE motility, POs and LDs cluster at the growing tip, whereas ER is partially retracted to subapical regions. Collectively, our results show that moving EEs interact transiently with other organelles, thereby mediating their directed transport and distribution in the cell. PMID- 26620911 TI - Nutrition and physical activity for the prevention and treatment of age-related sarcopenia. AB - Sarcopenia, defined as loss of skeletal muscle mass and function, is associated with adverse outcomes such as physical disability, impaired quality of life and increased mortality. Several mechanisms are involved in the development of sarcopenia. Potentially modifiable factors include nutrition and physical activity. Protein metabolism is central to the nutritional issues, along with other potentially modifying nutritional factors as energy balance and vitamin D status. An increasing but still incomplete knowledge base has generated recent recommendations on an increased protein intake in the elderly. Several factors beyond the total amount of protein consumed emerge as potentially important in this context. A recent summit examined three hypotheses: (1) A meal threshold; habitually consuming 25-30 g protein at breakfast, lunch and dinner provides sufficient protein to effectively stimulate muscle protein anabolism; (2) Protein quality; including high-quality protein at each meal improves postprandial muscle protein synthesis; and (3) performing physical activity in close temporal proximity to a high-quality protein meal enhances muscle anabolism. Optimising the potential for muscle protein anabolism by consuming an adequate amount of high-quality protein at each meal, in combination with physical activity, appears as a promising strategy to prevent or delay the onset of sarcopenia. However, results of interventions are inconsistent, and well-designed, standardised studies evaluating exercise or nutrition interventions are needed before guidelines can be developed for the prevention and treatment of age-related sarcopenia. PMID- 26620912 TI - Evaluating the autoinduction expression system and one-step purification for high level expression and purification of gallbladder-derived rhIL-1Ra. AB - Recent advancement in fermentation technologies resulted in the increased yields of recombinant proteins of biopharmaceutical and medicinal importance. Consequently, there is an important task to develop simple and easily scalable methods that can facilitate the production of high-quality recombinant protein. Most of the recent reports described the expression of recombinant human IL-1 receptor antagonist (rhIL-1Ra) in Escherichia coli using isopropyl-beta-d thiogalacto pyranoside (IPTG), a nonmetabolizable and expensive compound, as an expression inducer. In this study, we describe the expression and one-step purification of gallbladder-derived rhIL-1Ra by autoinduction in E. coli. This method includes special media that automatically induce the target protein expression from T7 promoter and allow the production of the target protein in high yield than the conventional IPTG induction method. In addition to fermentation process improvements, one-step purification strategy is essential to make the process economical. We developed a single-step cation exchange chromatography and obtained 300 mg/L of rhIL-1Ra with 98% purity. Purified protein was characterized by SDS-PAGE and Ion exchange HPLC (IEX-HPLC). The described method can be used to scale up the production of rhIL-1Ra and other recombinant proteins. PMID- 26620913 TI - Mechanistic interrogation of the asymmetric lithiation-trapping of N-thiopivaloyl azetidine and pyrrolidine. AB - A fundamental mechanistic study of the s-BuLi/chiral diamine-mediated lithiation trapping of N-thiopivaloyl azetidine and pyrrolidine is reported. We show that lithiated thiopivalamides are configurationally unstable at -78 degrees C. Reaction then proceeds via a dynamic resolution of diastereomeric lithiated intermediates and this accounts for the variable sense and degree of asymmetric induction observed compared to N-Boc heterocycles. PMID- 26620914 TI - Trends and Most Frequent Methods of Suicide in Chile Between 2001 and 2010. AB - BACKGROUND: Despite the many studies trying to evaluate the magnitude of suicide in Chile, none of them include the new valid data, recently published by the DEIS of the Chilean Health Ministry. AIM: This paper sought to describe how suicide rates changed among Chileans who were at least 15 years of age during the period of 2001-2010; these rates were stratified by sex, age, urban/rural status, and region of the country. METHOD: An exploratory and temporal study was conducted. Suicide mortality rates were calculated by collecting information from the Chilean Ministry of Health's death registry between 2001 and 2010 among subjects who were at least 15 years of age. Crude and age-adjusted mortality rates were computed. RESULTS: The standardized suicide rate in Chile during 2001-2010 was 14.7 deaths per 100,000, the highest in South America. The minimum age-adjusted suicide rate observed during the examined period was 13.49 per 100,000 in 2005, and the maximum, 16.67 per 100,000 in 2008. Suicide rates among men were up to 4.8 times the suicide rates among women. In addition, rates in rural areas were double compared with urban areas. Hanging was the most common suicide method, followed by use of firearms and explosives in men and poisoning in women. Finally, there was a progressive increase in suicide rates in the southernmost regions of the country. CONCLUSION: Suicide rates in Chile are relatively high among male subjects in rural areas. There is a disturbing increase in suicide rates among younger individuals and women, although these rates remain lower among younger individuals and women than among adults in general. PMID- 26620915 TI - Does Social Belonging to Primary Groups Protect Young People From the Effects of Pro-Suicide Sites? AB - BACKGROUND: The Internet has facilitated the existence of extreme and pathological communities that share information about ways to complete suicide or to deliberately harm or hurt oneself. This material is user-generated and easily accessible. AIMS: The present study analyzed the buffering effect of social belonging to a primary group in the situation of pro-suicide site exposure. METHOD: Cross-national data were collected from the US, UK, Germany, and Finland in spring 2013 and 2014 from respondents aged 15-30 years (N = 3,567). Data were analyzed by using linear regression separately for women and men for each country. RESULTS: A higher level of belonging to a primary group buffered the negative association of pro-suicide site exposure with mental health, measured as happiness, although the results were not consistent in the subgroups. US male subjects showed a significant buffering effect of the sense of belonging to family while the belonging to friends had a buffering effect among four other subgroups: British female and male subjects and Finnish female and male subjects. CONCLUSION: The results underline the positive potential of primary groups to shield young people's mental health in the situation of pro-suicide site exposure. PMID- 26620916 TI - Too Much to Bear: Psychometric Evidence Supporting the Perceived Burdensomeness Scale. AB - BACKGROUND: People who feel they have become a burden on others may become susceptible to suicidal ideation. When people no longer feel capable or productive, they may assume that friends and family members would be better off without them. AIM: The present study was designed to assess preliminary psychometric properties of a new measure, the Perceived Burdensomeness (PBS) Scale. METHOD: Depressed psychiatric patients (N = 173) were recruited from a veterans affairs medical center. Patients were assessed with a structured diagnostic interview and self-report measures assessing perceived burdensomeness, depression severity, hopelessness, and suicidal ideation. RESULTS: The present study supported preliminary evidence of reliability and concurrent validity of the PBS. Additionally, perceived burdensomeness was significantly associated with higher levels of hopelessness and suicidal ideation. CONCLUSION: It is hoped that with the aid of the PBS clinicians may be able to intervene more specifically in the treatment of suicidality. PMID- 26620917 TI - Emergency Department Visits Prior to Suicide and Homicide: Linking Statewide Surveillance Systems. AB - BACKGROUND: Emergency departments (EDs) serve a wide range of patients who present at risk of impending suicide and homicide. AIMS: Two statewide surveillance systems were probabilistically linked to understand who utilizes EDs and then dies violently within 6 weeks. METHOD: Each identified case was matched with four randomly selected controls on sex, race, date of birth, resident zip code, and date of ED visit vs. date of death. Matched-pair odds ratios were estimated by conditional logistic regression to assess differences between cases and controls on reported diagnoses and expected payment sources. RESULTS: Of 1,599 suicides and 569 homicides in the 3-year study period, 10.7% of decedents who died by suicide (mean = 13.6 days) and 8.3% who died by homicide (mean = 16.3 days) were seen in a state ED within 6 weeks prior to death. ED attendees who died by suicide were more likely to have a diagnosis of injury/ poisoning diagnosis or mental disorder and more likely to have Medicare. Those who died by homicide were more likely to have a diagnosis of injury/poisoning and less likely to have commercial insurance. CONCLUSION: It is essential for research to further explore risk factors for imminent suicide and homicide in ED patients who present for psychiatric conditions and general injuries. PMID- 26620918 TI - Dating Violence Victimization, Interpersonal Needs, and Suicidal Ideation Among College Students. AB - BACKGROUND: Victims of dating violence experience suicidal ideation at a higher rate than the general population. However, very few studies have examined the relationship between dating violence and suicidal ideation within an empirically supported theory of suicide. The interpersonal-psychological theory of suicide posits that thwarted interpersonal needs (i.e., thwarted belongingness and perceived burdensomeness) are proximal antecedents to suicidal ideation. The experience of dating violence may thwart such interpersonal needs, thus increasing risk for suicidal ideation. AIMS: We aimed to examine the relationships among dating violence, thwarted interpersonal needs, and suicidal ideation and test the interpersonal-psychological theory of suicide. METHOD: We conducted two cross-sectional studies on college students in dating relationships to examine these research questions. RESULTS: Study 1 indicated positive correlations among dating violence (i.e., physical and psychological), thwarted belongingness, and perceived burdensomeness. Study 2 generally replicated the bivariate relationships of Study 1 and demonstrated that, at high levels of thwarted belongingness, perceived burdensomeness was correlated with suicidal ideation, while accounting for the effects of depressive symptoms and drug use. CONCLUSION: These results highlight the importance of using theory-guided research to understand the relationship between dating violence and suicidal ideation. PMID- 26620919 TI - A Pilot Study of Antithrombin Replacement Prior to Cardiopulmonary Bypass in Neonates. AB - Neonates have low levels of antithrombin. Inadequate anticoagulation during cardiopulmonary bypass (CPB) due to low antithrombin activity may result in a poor preservation of the coagulation system during bypass. We hypothesize that antithrombin replacement to neonates prior to CPB will preserve the hemostatic system and result in less postoperative bleeding. A randomized, double-blinded, placebo-controlled pilot study of antithrombin replacement to neonates prior to CPB was conducted. Preoperative antithrombin levels determined the dose of recombinant antithrombin or placebo to be given. Antithrombin levels were measured following the dosing of the antithrombin/placebo, after initiation of bypass, near the completion of bypass, and upon intensive care unit admission. Eight subjects were enrolled. No subject had safety concerns. Mediastinal exploration occurred in two antithrombin subjects and one placebo subject. Antithrombin activity levels were significantly higher in the treated group following drug administration; levels continued to be higher than preoperatively but not different from the placebo group at all other time points. Total heparin administration was less in the antithrombin group; measurements of blood loss were similar in both groups. A single dose of recombinant antithrombin did not maintain 100% activity levels throughout the entire operation. Although no safety concerns were identified in this pilot study, a larger trial is necessary to determine clinical efficacy. PMID- 26620920 TI - Production of butyrate from lysine and the Amadori product fructoselysine by a human gut commensal. AB - Human intestinal bacteria produce butyrate, which has signalling properties and can be used as energy source by enterocytes thus influencing colonic health. However, the pathways and the identity of bacteria involved in this process remain unclear. Here we describe the isolation from the human intestine of Intestinimonas strain AF211, a bacterium that can convert lysine stoichiometrically into butyrate and acetate when grown in a synthetic medium. Intestinimonas AF211 also converts the Amadori product fructoselysine, which is abundantly formed in heated foods via the Maillard reaction, into butyrate. The butyrogenic pathway includes a specific CoA transferase that is overproduced during growth on lysine. Bacteria related to Intestinimonas AF211 as well as the genetic coding capacity for fructoselysine conversion are abundantly present in colonic samples from some healthy human subjects. Our results indicate that protein can serve as a source of butyrate in the human colon, and its conversion by Intestinimonas AF211 and related butyrogens may protect the host from the undesired side effects of Amadori reaction products. PMID- 26620922 TI - Different expression of miR-29b and VEGFA in glioma. AB - Glioma is one of the most common carcinomas in terms of both incidence and mortality worldwide. This is a case-control study with 240 cases and age- and gender-matched controls in the rate of 1:1. The results of this present word indicated that the expressions of both miR-29b and VEGFA in blood were significantly different compared with the control group, and thus may help to differentiate glioma cases from the controls. In addition, the diagnostic role of miR-29b and VEGFA was important for the clinical application. In conclusion, circulating miR-29b and VEGFA could be used as diagnosis biomarkers. PMID- 26620921 TI - Neurodegenerative disease-associated mutants of a human mitochondrial aminoacyl tRNA synthetase present individual molecular signatures. AB - Mutations in human mitochondrial aminoacyl-tRNA synthetases are associated with a variety of neurodegenerative disorders. The effects of these mutations on the structure and function of the enzymes remain to be established. Here, we investigate six mutants of the aspartyl-tRNA synthetase correlated with leukoencephalopathies. Our integrated strategy, combining an ensemble of biochemical and biophysical approaches, reveals that mutants are diversely affected with respect to their solubility in cellular extracts and stability in solution, but not in architecture. Mutations with mild effects on solubility occur in patients as allelic combinations whereas those with strong effects on solubility or on aminoacylation are necessarily associated with a partially functional allele. The fact that all mutations show individual molecular and cellular signatures and affect amino acids only conserved in mammals, points towards an alternative function besides aminoacylation. PMID- 26620923 TI - Expectations, observations, and the cognitive processes that bind them: expert assessment of examinee performance. AB - Performance-based assessment (PBA) is a valued assessment approach in medical education, be it in a clerkship, residency, or practice context. Raters are intrinsic to PBA and the increased use of PBA has lead to an increased interest in rater cognition. Although several researchers have tackled factors that may influence the variability in rater judgment, the critical examination of rater observation of performance and the translation of that data into judgements are being investigated. The purpose of this study was to qualitatively investigate the cognitive processes of raters, and to create a framework that conceptualizes those processes when raters assess a complex performance. We conducted semi structured interviews with 11 faculty members (nominated as excellent assessors) from a Department of Medicine to investigate how raters observe, interpret, and translate performance into judgments. The transcribed verbal protocols were analyzed using Constructivist Grounded Theory in order to develop a theoretical model of raters' assessment processes. Several themes emerged from the data and were grouped according to three macro-level themes describing how the raters balance two sources of data [(1) external sources of information and (2) internal/personal sources of information] by relying on specific cognitive processes to assess an examinee performance. The results from our study demonstrate that assessment is a difficult cognitive task that involves nuance using specific cognitive processes to weigh external and internal data against each other. Our data clearly draws attention to the constant struggle between objectivity and subjectivity that is observed in assessment as illustrated by the importance given to nuancing the examinee's observed performance. PMID- 26620924 TI - Do hepatic flares really promote rapid decline of serum hepatitis B surface antigen (HBsAg) in patients with HBsAg seroclearance? PMID- 26620925 TI - Supplementation of nitrocompounds in broiler diets: Effects on bird performance, ammonia volatilization and nitrogen retention in broiler manure. AB - A study was conducted to evaluate the effects of dietary nitrocompounds on bird performance, ammonia volatilization, and changes in manure nitrogen (N). A total of 200 one-day-old male chicks (Cobb 500) were used for this study. The chicks were raised in electrically heated battery brooders for 18 days. On day 1, birds were allocated into five treatment groups with four replicated pens: (T1) control, a corn and soybean meal diet (3,100 kcal kg-1 metabolizable energy (ME) and 21% Crude Protein (CP)); (T2) 16.7 mg kg-1 nitroethanol (NEL); (T3) 33.3 mg kg-1 NEL; (T4) 16.7 mg kg-1 nitropropanol (NPL); and (T5) 33.3 mg kg-1 NPL. The body weight gain, feed intake and feed efficiency were measured on days 7, 14 and 18. Volatized ammonia (VA) and other N forms were measured at collection and following 2 weeks of incubation at 30 degrees C. Broiler growth was not adversely affected by the nitrocompounds at concentrations up to 33.3 mg kg-1. The results show that initial manure pH was reduced by adding nitroethanol (NEL) and nitropropanol (NPL) to the diet by 0.2 and 0.5 pH units, respectively. Total VA after 2 weeks was unaffected by dietary treatment. The amounts of uric acid decomposed and ammonia produced were closely balanced in the control sample. However, this balance was significantly different among the manures produced by birds receiving nitrocompound treatments. The inclusion of NEL and NPL resulted in the presence of measurable amounts of Xanthine not found in the control group. This study indicates that supplementation of nitroethanol or nitropropanol into broiler diets up to 33.3 mg kg-1 influences uric acid degradation and ammonia production in broiler manure while maintaining optimal growth performance. PMID- 26620926 TI - MiR-181b regulates cisplatin chemosensitivity and metastasis by targeting TGFbetaR1/Smad signaling pathway in NSCLC. AB - MicroRNAs (miRNAs) have been identified as important post-transcriptional regulators involved in various biological and pathological processes of cells, but their underlying mechanisms in chemosensitivity and metastasis have not been fully elucidated. The objective of this study was to identify miR-181b and its mechanism in the chemosensitivity and metastasis of NSCLC. We found that miR-181b expression levels were lower in A549/DDP cells compared with A549 cells. Functional assays showed that the overexpression of miR-181b inhibited proliferation, enhanced chemosensitivity to DDP, attenuated migration and metastatic ability in NSCLC cell lines in vitro and in vivo. TGFbetaR1 was subsequently identified as a novel functional target of miR-181b. TGFbetaR1 knockdown revealed similar effects as that of ectopic miR-181b expression, whereas overexpression of TGFbetaR1 rescued the function of miR-181b-mediated growth, chemosensitivity and metastasis in NSCLC cells. In addition, miR-181b could inactivate the TGFbetaR1/Smad signaling pathway. We also observed that decreased miR-181b expression and increased TGFbetaR1 expression were significantly associated with chemosensitivity to DDP and tumor metastasis in NSCLC patients. Consequently, miR-181b functions as a tumor suppressor and has an important role in proliferation, chemosensitivity to DDP and metastasis of NSCLC by targeting TGFbetaR1/Smad signaling pathway. PMID- 26620928 TI - Cardio-visual integration modulates the subjective perception of affectively neutral stimuli. AB - Interoception, which refers to the perception of internal body signals, has been consistently associated with emotional processing and with the sense of self. However, its influence on the subjective appraisal of affectively neutral and body-unrelated stimuli is still largely unknown. Across two experiments we sought to investigate this issue by asking participants to detect changes in the flashing rhythm of a simple stimulus (a circle) that could either be pulsing synchronously with their own heartbeats or following the pattern of another person's heart. While overall task performance did not vary as a function of cardio-visual synchrony, participants were better at identifying trials in which no change occurred when the flashes were synchronous with their own heartbeats. This study adds to the growing body of research indicating that we use our body as a reference point when perceiving the world; and extends this view by focusing on the role that signals coming from inside the body, such as heartbeats, may play in this referencing process. Specifically we show that private interoceptive sensations can be combined with affectively neutral information unrelated to the self to influence the processing of a multisensory percept. Results are discussed in terms of both standard multisensory integration processes and predictive coding theories. PMID- 26620927 TI - A novel 3q29 deletion associated with autism, intellectual disability, psychiatric disorders, and obesity. AB - Copy number variation (CNV) has been associated with a variety of neuropsychiatric disorders, including intellectual disability/developmental delay (ID/DD), autism spectrum disorder (ASD), and schizophrenia (SCZ). Often, individuals carrying the same pathogenic CNV display high clinical variability. By array-CGH analysis, we identified a novel familial 3q29 deletion (1.36 Mb), centromeric to the 3q29 deletion region, which manifests with variable expressivity. The deletion was identified in a 3-year-old girl diagnosed with ID/DD and autism and segregated in six family members, all affected by severe psychiatric disorders including schizophrenia, major depression, anxiety disorder, and personality disorder. All individuals carrying the deletion were overweight or obese, and anomalies compatible with optic atrophy were observed in three out of four cases examined. Amongst the 10 genes encompassed by the deletion, the haploinsufficiency of Optic Atrophy 1 (OPA1), associated with autosomal dominant optic atrophy, is likely responsible for the ophthalmological anomalies. We hypothesize that the haploinsufficiency of ATPase type 13A4 (ATP13A4) and/or Hairy/Enhancer of Split Drosophila homolog 1 (HES1) contribute to the neuropsychiatric phenotype, while HES1 deletion might underlie the overweight/obesity. In conclusion, we propose a novel contiguous gene syndrome due to a proximal 3q29 deletion variably associated with autism, ID/DD, psychiatric traits and overweight/obesity. PMID- 26620929 TI - Individual differences in dopamine level modulate the ego depletion effect. AB - Initial exertion of self-control impairs subsequent self-regulatory performance, which is referred to as the ego depletion effect. The current study examined how individual differences in dopamine level, as indexed by eye blink rate (EBR), would moderate ego depletion. An inverted-U-shaped relationship between EBR and subsequent self-regulatory performance was found when participants initially engaged in self-control but such relationship was absent in the control condition where there was no initial exertion, suggesting individuals with a medium dopamine level may be protected from the typical ego depletion effect. These findings are consistent with a cognitive explanation which considers ego depletion as a phenomenon similar to "switch costs" that would be neutralized by factors promoting flexible switching. PMID- 26620930 TI - Accelerated Superposition State Molecular Dynamics for Condensed Phase Systems. AB - An extension of superposition state molecular dynamics (SSMD) [Venkatnathan and Voth J. Chem. Theory Comput. 2005, 1, 36] is presented with the goal to accelerate timescales and enable the study of "long-time" phenomena for condensed phase systems. It does not require any a priori knowledge about final and transition state configurations, or specific topologies. The system is induced to explore new configurations by virtue of a fictitious (free-particle-like) accelerating potential. The acceleration method can be applied to all degrees of freedom in the system and can be applied to condensed phases and fluids. PMID- 26620931 TI - An Investigation of the Accuracy of Different DFT Functionals on the Water Exchange Reaction in Hydrated Uranyl(VI) in the Ground State and the First Excited State. AB - We discuss the accuracy of density functional theory (DFT) in the gas phase for the water-exchange reactions in the uranyl(VI) aqua ion taking place both in the electronic ground state and in the first excited state (the luminescent (3)Deltag state). The geometries of the reactant and intermediates have been optimized using DFT and the B3LYP functional, with a restricted closed-shell formalism for the electronic ground state and either an unrestricted open-shell formalism or the time-dependent DFT method for the (3)Deltag state. The relative energies have been computed with wave-function-based methods such as Moller-Plesset second order perturbation theory, or a minimal multireference perturbative calculation (minimal CASPT2); coupled-cluster method (CCSD(T)); DFT with B3LYP, BLYP, and BHLYP correlation and exchange functionals; and the hybrid DFT-multireference configuration interaction method. The results obtained with second-order perturbative methods are in excellent agreement with those obtained with the CCSD(T) method. However, DFT methods overestimate the energies of low coordination numbers, yielding to too high and too low reaction energies for the associative and dissociative reactions, respectively. Part of the errors appears to be associated with the amount of Hartree-Fock exchange used in the functional; for the dissociative intermediate in the ground state, the pure DFT functionals underestimate the reaction energy by 20 kJ/mol relative to wave-function-based methods, and when the amount of HF exchange is increased to 20% (B3LYP) and to 50% (BHLYP), the error is decreased to 13 and 4 kJ/mol, respectively. PMID- 26620932 TI - Response of Scalar Fields and Hydrogen Bonding to Excited-State Molecular Solvation of Carbonyl Compounds. AB - An attempt has been made to understand the mechanism of excited-state molecular solvation and its effect on hydrogen bonding in carbonyl compounds in aqueous solution. The correlation between solvation and electronic transitions has been investigated by comparing results obtained either with a supermolecular description in terms of hydrogen-bonded clusters or with a combined method embedding such clusters with a polarizable continuum dielectric mimicking the bulk water. Popular scalar fields such as molecular electrostatic potential and molecular electron density have been used as useful tools to probe the changes in the hydrogen bonding passing from ground to excited states in the gas as well as solvent phase. PMID- 26620933 TI - Embedding Fragment ab Initio Model Potentials in CASSCF/CASPT2 Calculations of Doped Solids: Implementation and Applications. AB - In this article, we present a fragment model potential approach for the description of the crystalline environment as an extension of the use of embedding ab initio model potentials (AIMPs). The biggest limitation of the embedding AIMP method is the spherical nature of its model potentials. This poses problems as soon as the method is applied to crystals containing strongly covalently bonded structures with highly nonspherical electron densities. The newly proposed method addresses this problem by keeping the full electron density as its model potential, thus allowing one to group sets of covalently bonded atoms into fragments. The implementation in the MOLCAS 7.0 quantum chemistry package of the new method, which we call the embedding fragment ab inito model potential method (embedding FAIMP), is reported here, together with results of CASSCF/CASPT2 calculations. The developed methodology is applied for two test problems: (i) the investigation of the lowest ligand field states (2)A1 and (2)B1 of the Cr(V) defect in the YVO4 crystal and (ii) the investigation of the lowest ligand field and ligand-metal charge transfer (LMCT) states at the Mn(II) substitutional impurity doped into CaCO3. Comparison with similar calculations involving AIMPs for all environmental atoms, including those from covalently bounded units, shows that the FAIMP treatment of the YVO4 units surrounding the CrO4(3-) cluster increases the excitation energy (2)B1 -> (2)A1 by ca. 1000 cm( 1) at the CASSCF level of calculation. In the case of the Mn(CO3)6(10-) cluster, the FAIMP treatment of the CO3(2-) units of the environment give smaller corrections, of ca. 100 cm(-1), for the ligand-field excitation energies, which is explained by the larger ligands of this cluster. However, the correction for the energy of the lowest LMCT transition is found to be ca. 600 cm(-1) for the CASSCF and ca. 1300 cm(-1) for the CASPT2 calculation. PMID- 26620934 TI - Initial Hardness Response and Hardness Profiles in the Study of Woodward-Hoffmann Rules for Electrocyclizations. AB - The fundamental principles of pericyclic reactions are governed by the Woodward Hoffmann rules, which state that these reactions can only take place if the symmetries of the reactants' molecular orbitals and the products' molecular orbitals are the same. As such, these rules rely on the nodal structure of either the wave function or the frontier molecular orbitals, so it is unclear how these rules can be recovered in the density functional reactivity theory (or "conceptual DFT"), where the basic quantity is the strictly positive electron density. A third, nonsymmetry based approach to predict the outcome of pericyclic reactions is due to Zimmerman which uses the concept of the aromatic transition states: allowed reactions possess aromatic transition states, while forbidden reactions possess antiaromatic transition states. Based on our recent work on cycloadditions, we investigate the initial response of the chemical hardness, a central DFT based reactivity index, along the reaction profiles of a series of electrocyclizations. For a number of cases, we also compute complete initial reaction coordinate (IRC) paths and hardness profiles. We find that the hardness response is always higher for the allowed modes than for the forbidden modes. This suggests that the initial hardness response along the IRC is the key for casting the Woodward-Hoffmann rules into conceptual DFT. PMID- 26620935 TI - Theory of High-Spin d(4) Complexes: An Angular-Overlap Model Parametrization of the Ligand Field in Vibronic-Coupling Calculations. AB - A new theoretical approach for the calculation of the electronic and molecular structures of octahedrally-coordinated high-spin d(4) complexes is described. A prescription for the construction of an effective (3)T1 + (5)E (O) Hamiltonian from the ligand-field matrices of a complex with general trigonal symmetry is given, where the ligand field is parametrized in terms of the angular-overlap model (AOM). The Jahn-Teller matrices for the (3)T1 + ((5)E?e) vibronic Hamiltonian are constructed and the lowest eigenvalues are calculated by a numerical method. The model obviates the need to assume a temperature dependence of bonding parameters, inherent to the conventional ligand-field-theory approach and is applicable over the whole range of vibronic-coupling strengths, as demonstrated by example calculations on the [Mn(OD2)6](3+) cation and MgO:Cr(2+). PMID- 26620936 TI - Calculating Reaction Rates with Partial Hessians: Validation of the Mobile Block Hessian Approach. AB - In an earlier paper, the authors have developed a new method, the mobile block Hessian (MBH), to accurately calculate vibrational modes for partially optimized molecular structures [J. Chem. Phys. 2007, 126 (22), 224102]. The proposed procedure remedies the artifact of imaginary frequencies, occurring in standard frequency calculations, when parts of the molecular system are optimized at different levels of theory. Frequencies are an essential ingredient in predicting reaction rate coefficients due to their input in the vibrational partition functions. The question arises whether the MBH method is able to describe the chemical reaction kinetics in an accurate way in large molecular systems where a full quantum chemical treatment at a reasonably high level of theory is unfeasible due to computational constraints. In this work, such a validation is tested in depth. The MBH method opens a lot of perspectives in predicting accurate kinetic parameters in chemical reactions where the standard full Hessian procedure fails. PMID- 26620937 TI - How Efficient Is Replica Exchange Molecular Dynamics? An Analytic Approach. AB - Replica exchange molecular dynamics (REMD) has become a standard technique for accelerating relaxation in biosimulations. Despite its widespread use, questions remain about its efficiency compared with conventional, constant temperature molecular dynamics (MD). An analytic approach is taken to describe the relative efficiency of REMD with respect to MD. This is applied to several simple two state models and to several real proteins-protein L and the B domain of protein A to predict the relative efficiency of REMD with respect to MD in actual applications. In agreement with others, we find the following: as long as there is a positive activation energy for folding, REMD is more efficient than MD; the effectiveness of REMD is strongly dependent on the activation enthalpy; and the efficiency of REMD for actual proteins is a strong function of the maximum temperature. Choosing the maximum temperature too high can result in REMD becoming significantly less efficient than conventional MD. A good rule of thumb appears to be to choose the maximum temperature of the REMD simulation slightly above the temperature at which the enthalpy for folding vanishes. Additionally, we find that the number of replicas in REMD, while important for simulations shorter than one or two relaxation times, has a minimal effect on the asymptotic efficiency of the method. PMID- 26620938 TI - Theoretical Investigation of the Geometries and UV-vis Spectra of Poly(l-glutamic acid) Featuring a Photochromic Azobenzene Side Chain. AB - The geometries and UV-vis spectra of azobenzene dyes grafted as a side chain on poly(l-glutamic acid) have been investigated using a combination of quantum mechanics/molecular mechanics (QM/MM) and time-dependent density functional theory (TD-DFT) methods at the TD-PBE0/6-311+G(d,p)//B3LYP/6-311G(d,p):Amber ff99 level of theory. The influence of the secondary structure of the polypeptide on the electronic properties of both the trans and cis conformations of azobenzene dyes has been studied. It turns out that the grafted dyes exhibit a red-shift of the pi -> pi* absorption energies mainly due to the auxochromic shift induced by the peptidic group used to link the chromophoric unit to the polypeptide and that specific interactions between the glutamic side chain and the azobenzene moiety lead to a large blue-shift of the n -> pi* transition. PMID- 26620939 TI - Mechanism of the Ethylene Polymerization at Very High Pressure. AB - The reaction of ethylene in condensed phases under high pressure has been investigated by ab initio molecular dynamics. Both disordered and crystalline samples have been simulated, and some insights on the reaction mechanism have been obtained. System size effects have been investigated for the disordered samples. A polymerization reaction occurs by an ionic mechanism. In both the disordered and the crystal phases, the reaction products obtained (linear chains in the disordered systems and branched chains in the crystal) are in qualitative agreement with the experiments. PMID- 26620940 TI - Molecular Dynamics of Surface-Moving Thermally Driven Nanocars. AB - We developed molecular models describing the thermally initiated motion of nanocars, nanosized vehicles composed of two to four spherical fullerene wheels chemically coupled to a planar chassis, on a metal surface. The simulations were aimed at reproducing qualitative features of the experimentally observed migration of nanocars over gold crystals as determined by scanning tunneling microscopy. Coarse-grained-type molecular dynamics simulations were carried out for the species "Trimer" and "Nanotruck", the simplified versions of the experimentally studied nanomachines. Toward this goal, we developed a version of the rigid body molecular dynamics based on the symplectic quaternion scheme in conjunction with the Nose-Poincare thermostat approach. Interactions between rigid fragments were described by using the corrected CHARMM force field parameters, while several empirical models were introduced for interactions of nanocars with gold crystals. With the single adjusted potential parameter, the computed trajectories are consistent with the qualitative features of the thermally activated migration of the nanocars: the primary pivoting motion of Trimer and the two-dimensional combination of translations and pivoting of Nanotruck. This work presents a first attempt at a theoretical analysis of nanocars' dynamics on a surface by providing a computationally minimalist approach. PMID- 26620941 TI - Implicit Solvent Models and the Energy Landscape for Aggregation of the Amyloidogenic KFFE Peptide. AB - This study compares the performance of four implicit solvent models in describing peptide aggregation. The solvent models are the effective energy function-1 (EEF1) and three generalized Born (GB) models: one following the original implementation of Still (GB1), the analytical continuum electrostatics (ACE) potential, and GB with "simple switching" (GBSW). For each solvent model the first step of aggregation, namely dimerization, is investigated for the KFFE peptide, which is one of the shortest peptides known to form amyloid fibrils in vitro. Using basin-hopping for global optimization and replica exchange molecular dynamics simulations, we conclude that of the four solvent models considered, the EEF1 potential provides the most reliable description for the formation of KFFE amyloid precursors. It produces results that are closest to the experimental findings of a partial beta-strand conformation for the KFFE peptide in solution along with the formation of fibrils exhibiting antiparallel beta-strand structure. The ACE and GB1 potentials also show a significant beta-propensity for the KFFE peptide but fail to produce stable KFFE dimers. The GBSW potential, on the other hand, supports a very stable antiparallel dimer structure, but in a turn rather than a beta conformation. PMID- 26620942 TI - Transition-State Docking of Flunitrazepam and Progesterone in Cytochrome P450. AB - We have developed a method to dock a transition-state structure into the active site of an enzyme. Such an approach is more discriminative than standard docking when looking for substrates of an enzyme, because a transition state has more sterical restrictions than a nonreactive state. We use an accurate and tailored force field for the transition-state for the hydroxylation reaction in cytochrome P450, obtained with the Q2MM method. We apply this method to the docking of two drugs, progesterone and flunitrazepam, to the active sites of two human cytochromes P450, 2C9 and 3A4. We obtain a qualitative agreement compared to experiments, both for hydrogen atoms bound to the same carbon atom (for which the force-field energies are directly comparable) and for general sites on the drug molecules, if the method is combined with an estimate of the intrinsic reactivity of the various sites. However, the method does not rank all the sites correctly. It is not significantly improved if the proteins are allowed to relax locally or if it is combined with the MM/PBSA approach, which fully accounts for the protein flexibility and explicitly treats solvation and entropy effects. On the other hand our method performs better than standard docking with the GOLD software or predictions of metabolic sites with the MetaSite software. PMID- 26620943 TI - Genetic markers and clinical relevance in rheumatoid arthritis. PMID- 26620944 TI - Kinematic and fatigue biomechanics of an interpositional facet arthroplasty device. AB - BACKGROUND CONTEXT: Although approximately 30% of chronic lumbar pain can be attributed to the facets, limited surgical options exist for patients. Interpositional facet arthroplasty (IFA) is a novel treatment for lumbar facetogenic pain designed to provide patients who gain insufficient relief from medical interventional treatment options with long-term relief, filling a void in the facet pain treatment continuum. PURPOSE: This study aimed to quantify the effect of IFA on segmental range of motion (ROM) compared with the intact state, and to observe device position and condition after 10,000 cycles of worst-case loading. STUDY DESIGN/SETTING: In situ biomechanical analysis of the lumbar spine following implantation of a novel IFA device was carried out. METHODS: Twelve cadaveric functional spinal units (L2-L3 and L5-S1) were tested in 7.5 Nm flexion extension, lateral bending, and torsion while intact and following device implantation. Additionally, specimens underwent 10,000 cycles of worst-case complex loading and were testing in ROM again. Load-displacement and fluoroscopic data were analyzed to determine ROM and to evaluate device position during cyclic testing. Devices and facets were evaluated post testing. Institutional support for implant evaluation was received by Zyga Technology. RESULTS: Range of motion post implantation decreased versus intact, and then was restored post cyclic testing. Of the tested devices, 6.5% displayed slight movement (0.5-2 mm), all from tight L2-L3 facet joints with misplaced devices or insufficient cartilage. No damage was observed on the devices, and wear patterns were primarily linear. CONCLUSIONS: The results from this in situ cadaveric biomechanics and cyclic fatigue study demonstrate that a low-profile, conformable IFA device can maintain position and facet functionality post implantation and through 10,000 complex loading cycles. In vivo conditions were not accounted for in this model, which may affect implant behavior not predictable via a biomechanical study. However, these data along with published 1-year clinical results suggest that IFA may be a valid treatment option in patients with chronic lumbar zygapophysial pain who have exhausted medical interventional options. PMID- 26620945 TI - A rare location: isolated multiple psammomatous meningiomas. PMID- 26620946 TI - Pharmacokinetics of single-dose cefuroxime in porcine intervertebral disc and vertebral cancellous bone determined by microdialysis. AB - BACKGROUND: Pyogenic spondylodiscitis is associated with prolonged antimicrobial therapy and high relapse rates. Nevertheless, tissue pharmacokinetic studies of relevant antimicrobials in both prophylactic and therapeutic situations are still sparse. Previous approaches based on bone biopsy and discectomy exhibit important methodological limitations. PURPOSE: The objective of this study was to assess the C3-C4 intervertebral disc (IVD), C3 vertebral body cancellous bone, and subcutaneous adipose tissue (SCT) pharmacokinetics of cefuroxime by use of microdialysis in a large animal model. STUDY DESIGN: This was a single-dose, dense sampling large animal study of cefuroxime spine penetration. METHODS: Ten female pigs were assigned to receive 1,500 mg of cefuroxime intravenously over 15 minutes. Measurements of cefuroxime were obtained from plasma, SCT, vertebral cancellous bone, and IVD for 8 hours thereafter. Microdialysis was applied for sampling in solid tissues. RESULTS: For both IVD and vertebral cancellous bone, the area under the concentration curve from zero to the last measured value (AUC(0-last)) was significantly lower than that of free plasma. As estimated by the ratio of tissue AUC(0-last) to plasma AUC(0-last), tissue penetration (95% confidence interval) of cefuroxime was significantly incomplete for the IVD 0.78 (0.57; 0.99), whereas for vertebral cancellous bone 0.78 (0.51; 1.04) and SCT 0.94 (0.73; 1.15) it was not. The penetration of cefuroxime from plasma to the IVD was delayed, and the maximal concentration and the elimination of cefuroxime were also reduced compared with both SCT and vertebral cancellous bone. Because of this delay in elimination of cefuroxime, the time with concentrations above the minimal inhibitory concentration (T(>MIC)) was significantly longer in the IVD compared with the remaining compartments up to MICs of 6 ug/mL. CONCLUSIONS: Microdialysis was successfully applied for serial assessment of the concentration of cefuroxime in the IVD and the vertebral cancellous bone. Penetration of cefuroxime from plasma to IVD was found to be incomplete and delayed, but because of a prolonged elimination, superior T(>MIC) was found in the IVD up to MICs of 6 ug/mL. PMID- 26620947 TI - Triose phosphate use limitation of photosynthesis: short-term and long-term effects. AB - MAIN CONCLUSION: The triose phosphate use limitation was studied using long-term and short term changes in capacity. The TPU limitation caused increased proton motive force; long-term TPU limitation additionally reduced other photosynthetic components. Photosynthetic responses to CO2 can be interpreted primarily as being limited by the amount or activity of Rubisco or the capacity for ribulose bisphosphate regeneration, but at high rates of photosynthesis a third response is often seen. Photosynthesis becomes insensitive to CO2 or even declines with increasing CO2, and this behavior has been associated with a limitation of export of carbon from the Calvin-Benson cycle. It is often called the triose phosphate use (TPU) limitation. We studied the long-term consequences of this limitation using plants engineered to have reduced capacity for starch or sucrose synthesis. We studied short-term consequences using temperature as a method for changing the balance of carbon fixation capacity and TPU. A long-term and short-term TPU limitation resulted in an increase in proton motive force (PMF) in the thylakoids. Once a TPU limitation was reached, any further increases in CO2 was met with a further increase in the PMF but no increase or little increase in net assimilation of CO2. A long-term TPU limitation resulted in reduced Rubisco and RuBP regeneration capacity. We hypothesize that TPU, Rubisco activity, and RuBP regeneration are regulated so that TPU is normally in slight excess of what is required, and that this results in more effective regulation than if TPU were in large excess. PMID- 26620948 TI - Clostridium difficile outbreak caused by NAP1/BI/027 strain and non-027 strains in a Mexican hospital. AB - BACKGROUND: Clostridium difficile infections caused by the NAP1/B1/027 strain are more severe, difficult to treat, and frequently associated with relapses. METHODS: A case-control study was designed to examine a C. difficile infection (CDI) outbreak over a 12-month period in a Mexican hospital. The diagnosis of toxigenic CDI was confirmed by real-time polymerase chain reaction, PCR (Cepheid Xpert C. difficile/Epi). RESULTS: During the study period, 288 adult patients were evaluated and 79 (27.4%) patients had confirmed CDI (PCR positive). C. difficile strain NAP1/B1/027 was identified in 31 (39%) of the patients with confirmed CDI (240 controls were included). Significant risk factors for CDI included any underlying disease (p<0.001), prior hospitalization (p<0.001), and antibiotic (p<0.050) or steroid (p<0.001) use. Laboratory abnormalities included leukocytosis (p<0.001) and low serum albumin levels (p<0.002). Attributable mortality was 5%. Relapses occurred in 10% of patients. Risk factors for C. difficile NAP1/B1/027 strain infections included prior use of quinolones (p<0.03). Risk factors for CDI caused by non-027 strains included chronic cardiac disease (p<0.05), chronic renal disease (p<0.009), and elevated serum creatinine levels (p<0.003). Deaths and relapses were most frequent in the 027 group (10% and 19%, respectively). CONCLUSIONS: C. difficile NAP1/BI/027 strain and non-027 strains are established pathogens in our hospital. Accordingly, surveillance of C. difficile infections is now part of our nosocomial prevention program. PMID- 26620949 TI - Mild primary hyperparathyroidism as defined in the Italian Society of Endocrinology's Consensus Statement: prevalence and clinical features. AB - BACKGROUND: Mild primary hyperparathyroidism (PHPT) was recently clearly defined for the first time. Our study was thus aimed to pinpoint proportion and clinical characteristics of this kind of patients. DESIGN AND PATIENTS: We retrospectively evaluated our series of 360 consecutive patients with PHPT, selecting those with all features allowing a correct classification (serum total and ionized calcium, phosphate, creatinine, PTH, 25OHD, urinary calcium, renal and neck ultrasound, MIBI scintiscan, and DEXA at lumbar spine, femoral neck, and distal third of radius). Patients were defined asymptomatic (aPHPT) when bone or kidney was not involved and no hypercalcemic symptom occurred; mild PHPT was defined as aPHPT not meeting updated surgical criteria. RESULTS: Seventy-five patients among 172 classified as aPHPT had all available data required for surgical evaluation and could be evaluated. Sixty/75 met surgical criteria and the remaining 15 were classified as mild. Mild PHPT patients had lower total and ionized calcium, urinary calcium, and PTH levels than aPHPT meeting surgical criteria, while vitamin D levels and BMD were similar. CONCLUSIONS: Mild PHPT strictly defined according to the last consensus represents a small subgroup with a less active form of the disease. PMID- 26620950 TI - Surgical management of secondary hyperparathyroidism: how to effectively reduce recurrence at the time of primary surgery. AB - BACKGROUND: Successful parathyroidectomy (PTX) often results in a dramatic drop in the parathyroid hormone (PTH) levels, relieves the patient from clinical symptoms, and reduces mortality. Although PTX is generally a successful treatment for progressive secondary hyperparathyroidism (SHPT) patients subjected to surgery, a significant proportion develops recurrent SHPT following PTX. KEY MESSAGE: SHPT requiring PTX occurs more commonly in progressive chronic kidney disease and in long-term lithium therapy. Operative approaches include subtotal PTX, total PTX with or without autotransplantation, and possible thymectomy. Each approach has its proponents, advantages, and disadvantages. Although PTX offers the highest percentage cure for SHPT, compared to all other medical and surgical treatment, recurrent hyperparathyroidism can be observed in some patients dependent on follow-up time. A literature review and analysis of recent data regarding how to reduce recurrence of SHPT at the time of primary surgery was performed. The current literature and our own experience in the field have confirmed that pre-operative imaging, thymectomy, stereo magnifier, and surgical procedure may effectively reduce recurrence of SHPT at the time of primary surgery. PMID- 26620951 TI - Linking the soil moisture distribution pattern to dynamic processes along slope transects in the Loess Plateau, China. AB - Soil moisture pulses are a prerequisite for other land surface pulses at various spatiotemporal scales in arid and semi-arid areas. The temporal dynamics and profile variability of soil moisture in relation to land cover combinations were studied along five slopes transect on the Loess Plateau during the rainy season of 2011. Within the 3 months of the growing season coupled with the rainy season, all of the soil moisture was replenished in the area, proving that a type stability exists between different land cover soil moisture levels. Land cover combinations disturbed the trend determined by topography and increased soil moisture variability in space and time. The stability of soil moisture resulting from the dynamic processes could produce stable patterns on the slopes. The relationships between the mean soil moisture and vertical standard deviation (SD) and coefficient of variation (CV) were more complex, largely due to the fact that different land cover types had distinctive vertical patterns of soil moisture. The spatial SD of each layer had a positive correlation and the spatial CV exhibited a negative correlation with the increase in mean soil moisture. The soil moisture stability implies that sampling comparisons in this area can be conducted at different times to accurately compare different land use types. PMID- 26620952 TI - Assessment of ecological passages along road networks within the Mediterranean forest using GIS-based multi criteria evaluation approach. AB - Major roads cause barrier effect and fragmentation on wildlife habitats that are suitable places for feeding, mating, socializing, and hiding. Due to wildlife collisions (Wc), human-wildlife conflicts result in lost lives and loss of biodiversity. Geographical information system (GIS)-based multi criteria evaluation (MCE) methods have been successfully used in short-term planning of road networks considering wild animals. Recently, wildlife passages have been effectively utilized as road engineering structures provide quick and certain solutions for traffic safety and wildlife conservation problems. GIS-based MCE methods provide decision makers with optimum location for ecological passages based on habitat suitability models (HSMs) that classify the areas based on ecological requirements of target species. In this study, ecological passages along Motorway 52 within forested areas in Mediterranean city of Osmaniye in Turkey were evaluated. Firstly, HSM coupled with nine eco-geographic decision variables were developed based on ecological requirements of roe deer (Capreolus capreolus) that were chosen as target species. Then specified decision variables were evaluated using GIS-based weighted linear combination (WLC) method to estimate movement corridors and mitigation points along the motorway. In the solution process, two linkage nodes were evaluated for eco-passages which were determined based on the least-cost movement corridor intersecting with the motorway. One of the passages was identified as a natural wildlife overpass while the other was suggested as underpass construction. The results indicated that computer-based models provide accurate and quick solutions for positioning ecological passages to reduce environmental effects of road networks on wild animals. PMID- 26620953 TI - [Undescended testis: current treatment guidelines]. AB - BACKGROUND: Cryptorchidism is the most common genital malformation in male newborns. In recent years, guidelines concerning diagnosis and therapy have undergone considerable evolution with the implementation of recent knowledge in pathophysiology, diagnosis, and therapy. OBJECTIVES: The aim of this publication is to provide an overview of the current national and international guideline recommendations concerning diagnosis and treatment of cryptorchidism. Critical points are discussed in light of current scientific literature. MATERIALS AND METHODS: The current guidelines of the European Association of Urology (EAU)/European Society for Pediatric Urology (ESPU), the American Association of Urology (AUA), the pediatric urologic task force of the Austrian Society of Urology (OGU), the international consultation on urological disease (ICUD) and the German Society of Urology (DGU)/German Association of Pediatric Surgery (DGKCh) have been analyzed concerning the most important aspects of treatment and diagnosis. RESULTS: There is broad consensus concerning most steps and decisions for the treatment of cryptorchidism. However, some aspects of diagnostic imaging, the use of hormonal therapy, and surgical access in nonpalpable testis warrant further discussion and are the fields of considerable changes. PMID- 26620955 TI - Continued misinterpretation of confidence intervals: response to Miller and Ulrich. AB - Miller and Ulrich (2015) critique our claim (Hoekstra et al., Psychonomic Bulletin & Review, 21(5), 1157-1164, 2014), based on a survey given to researchers and students, of widespread misunderstanding of confidence intervals (CIs). They suggest that survey respondents may have interpreted the statements in the survey that we deemed incorrect in an idiosyncratic, but correct, way, thus calling into question the conclusion that the results indicate that respondents could not properly interpret CIs. Their alternative interpretations, while correct, cannot be deemed acceptable renderings of the questions in the survey due to the well-known reference class problem. Moreover, there is no support in the data for their contention that participants may have had their alternative interpretations in mind. Finally, their alternative interpretations are merely trivial restatements of the definition of a confidence interval, and have no implications for the location of a parameter. PMID- 26620954 TI - Measuring propionyl-CoA carboxylase activity in phytohemagglutinin stimulated lymphocytes using high performance liquid chromatography. AB - BACKGROUND: Propionyl-CoA carboxylase (PCC) is a mitochondrial enzyme involved in the catabolism of several essential amino acids and odd chain fatty acids. Previous PCC assays have involved either a radiometric assay or have required mitochondria isolation and/or enzyme purification. METHODS: We developed an enzymatic method to analyze PCC activity in phytohemagglutinin (PHA) stimulated lymphocytes that involves high performance liquid chromatography. RESULTS: The method shows good linearity and sensitivity. PCC activity was unaffected even when lymphocytes were isolated and PHA stimulated after a whole blood sample had been stored at 4 degrees C for 5days. This indicates that this method is suitable for analyzing samples from distant medical centers. The PCC activity of patients with propionic acidemia was found to be much lower than that of normal individuals and carriers. However, this PCC assay is significantly affected by the red blood cell contamination. In conclusion, this is a reliable method for performing PCC assays and only requires 0.5 to 1.0ml of whole blood from newborns. CONCLUSIONS: The PCC assay established in this study is useful for the confirmation of PA in individuals, and prenatal diagnosis and genetic counseling for the affected families. PMID- 26620957 TI - The domain specificity of intertemporal choice in pinyon jays. AB - When choosing between a piece of cake now versus a slimmer waistline in the future, many of us have difficulty with self-control. Food-caching species, however, regularly hide food for later recovery, sometimes waiting months before retrieving their caches. It remains unclear whether these long-term choices generalize outside of the caching domain. We hypothesized that the ability to save for the future is a general tendency that cuts across different situations. To test this hypothesis, we measured and experimentally manipulated caching to evaluate its relationship with operant measures of self-control in pinyon jays (Gymnorhinus cyanocephalus). We found no correlation between caching and self control at the individual level, and experimentally increasing caching did not influence self-control. The self-control required for caching food, therefore, does not carry over to other foraging tasks, suggesting that it is domain specific in pinyon jays. PMID- 26620956 TI - Contributions of parvocellular and magnocellular pathways to visual perception near the hands are not fixed, but can be dynamically altered. AB - Visual perception is altered near the hands, and several mechanisms have been proposed to account for this, including differences in attention and a bias toward magnocellular-preferential processing. Here we directly pitted these theories against one another in a visual search task consisting of either magnocellular- or parvocellular-preferred stimuli. Surprisingly, we found that when a large number of items are in the display, there is a parvocellular processing bias in near-hand space. Considered in the context of existing results, this indicates that hand proximity does not entail an inflexible bias toward magnocellular processing, but instead that the attentional demands of the task can dynamically alter the balance between magnocellular and parvocellular processing that accompanies hand proximity. PMID- 26620958 TI - The Yield of Pre-operative Breast MRI in Patients According to Breast Tissue Density. AB - OBJECTIVE: To determine the yield of pre-operative breast MRI according to breast tissue density. METHODS: We performed a retrospective review of 665 consecutive patients who underwent breast MRI in 2012 for pre-operative staging of biopsy proven breast cancer, 582 of whom had digital mammograms available within 6 months of the MRI were evaluated for breast tissue density and additional lesions seen on breast MRI not identified on mammography. Lesions that could change surgical management if positive were confirmed by percutaneous biopsy. RESULTS: MRI identified additional lesions changing surgical management in 19 of 61 patients (31%) with fat density, 94/269 (35%) with scattered fibroglandular parenchyma, 89/210 (42%) with heterogeneously dense breasts, and 26/42 (62%) with dense breasts. There was a significant difference between breast density and number of additional findings on MRI (p<0.0001). Patients with dense breasts were 5.1x more likely to have additional findings on MRI in comparison to patients with fat density breasts (95% CI 2.2-12.1, p=0.0001). CONCLUSION: Patients with dense breasts are more likely to have additional findings on pre-operative breast MRI in comparison to patients with fat tissue density breasts; if selective use of pre-operative MRI is necessary, patients with dense breast tissue density seem to show the maximal benefit. HIGHLIGHTS: * Preoperative MRI detects many additional lesions not seen on mammography. * Increased breast density correlates with more findings on preoperative breast MRI (p<0.0001). * Extremely dense breasts are more likely to have additional findings on MRI. * Increased breast density is associated with more MRI findings that changed management. PMID- 26620959 TI - Choledochal cysts in children: Intrahepatic ductal dilatation does not indicate true intrahepatic biliary duct disease. AB - BACKGROUND/AIMS: Choledochal cysts (CCs) are rare abnormalities of the biliary tract. Presenting our clinical experience with CCs herein, we aimed to identify if intrahepatic ductal dilatation indicates true intrahepatic biliary duct disease. MATERIALS AND METHODS: We retrospectively reviewed all cases of CCs in children diagnosed at a single center (Baskent University Fac-ulty of Medicine, Department of Pediatric Surgery) institution from 2005 to 2015. RESULTS: Of 18 patients with CCs, 7 were males (39%). The age range was 3 months to 17 years (mean age, 6.2+/-3.8 years). Intrahepatic bile duct dilatation was detected in 13 (72%) patients by preoperative scanning. Type I, II, III, and IVA cysts were diagnosed in 13, 1, 1, and 3 patients, respectively. In all patients, total cyst excision and Roux-en-Y hepaticoenterostomy were performed. CONCLUSION: In this study, most intrahepatic ductal dilatations seen on preoperative imaging were thought to be caused by a distal obstruction, not true intrahepatic biliary duct disease. This study supports the hypothesis that preoperatively distinguishing between type I and type IVA CCs is not necessary; it does not affect the initial treatment. We consider that complete cyst excision with Roux-en-Y hepaticojejunostomy is safe and should be performed soon after diagnosis, irrespective of symptom severity to avoid future complications. PMID- 26620960 TI - Cirrhotic Ascites management via procalcitonin level and a new approach B-mode gray-scale histogram. AB - BACKGROUND/AIMS: To determine the role of serum procalcitonin levels and ascites/subcutaneous echogenicity ratio (ASER) in predicting ascites infection in hospitalized cirrhotic patients. MATERIALS AND METHODS: A total of 50 patients hospitalized because of cirrhosis-related ascites were included in this study. In these patients, 44% of ascites were infected (peritonitis), whereas 56% of ascites were sterile. These two groups were compared in terms of procalcitonin levels and ASER for predicting ascites infection. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of ASER, and the predicting outcome of ASER was compared with procalcitonin levels. RESULTS: The ASER values of the patients with the diagnosis of infected ascites were significantly higher than in those with the diagnosis of sterile ascites (p<0.001). ROC analysis was performed to determine the diagnostic ASER value for infected ascites. An ASER greater than 0.0019 determined peritonitis with 95.5% sensitivity and 100% specificity. A procalcitonin level greater than 0.05 determined peritonitis with 86.4% sensitivity and 75% specificity. Using ROC analysis, an ASER greater than 0.0019 [area under curve (AUC): 0.974, 95% confidence interval (CI) (0.884-0.999, p<0.001)] was a significantly better diagnostic marker than a procalcitonin level >0.5 mg/dL [AUC: 0.860, 95% CI (0.884-0.999, p<0.001) (p<0.045)]. CONCLUSION: According to our findings, the determination of ASER and serum procalcitonin levels seems to provide satisfactory diagnostic accuracy in differentiating ascites infections in hospitalized cirrhotic patients. ASER values significantly differentiate ascites infections better than procalcitonin levels. PMID- 26620961 TI - Two cases with Plummer-Vinson syndrome in the 21st century. AB - Plummer-Vinson syndrome (PVS) is characterized by the presence of postcricoid dysphagia, iron deficiency anemia, and upper esophageal web. This syndrome is now a rare condition because of the improvement in nutritional status and increased awareness regarding iron deficiency anemia and the early diagnosis and easy treatment of this anemia or underlying causes. In this presentation, we report two middle-aged female patients with PVS and briefly review the literature. PMID- 26620962 TI - Evaluation of antiviral treatment response on liver histopathology in chronic hepatitis B infection patients. PMID- 26620963 TI - Conservative therapy for superior mesenteric artery syndrome. PMID- 26620964 TI - Comment on "The relationship of recurrent aphthous stomatitis and Helicobacter pylori, cytokine gene polymorphism and cobalamin". PMID- 26620967 TI - Self-concentrating buoyant glass microbubbles for high sensitivity immunoassays. AB - Here, we report the novel application of a material with self-concentrating properties for enhancing the sensitivity of immunoassays. Termed as glass microbubbles, they are antibody functionalized buoyant hollow glass microspheres that simultaneously float and concentrate into a dense monolayer when dispensed in a liquid droplet. This self-concentrating charactaristic of the microbubbles allow for autonomous signal localization, which translates to a higher sensitivity compared to other microparticle-based immunoassays. We then demonstrated a "microbubble array" platform consisting of the glass microbubbles floating in a microfluidic liquid hemisphere array for performing multiplex immunoassays. PMID- 26620966 TI - Does Surgical Approach Affect Patient-reported Function After Primary THA? AB - BACKGROUND: Total hip arthroplasty (THA) relieves pain and improves physical function in patients with hip osteoarthritis, but requires a year or more for full postoperative recovery. Proponents of intermuscular surgical approaches believe that the direct-anterior approach may restore physical function more quickly than transgluteal approaches, perhaps because of diminished muscle trauma. To evaluate this, we compared patient-reported physical function and other outcome metrics during the first year after surgery between groups of patients who underwent primary THA either through the direct-anterior approach or posterior approach. QUESTIONS/PURPOSES: We asked: (1) Is a primary THA using a direct-anterior approach associated with better patient-reported physical function at early postoperative times (1 and 3 months) compared with a THA performed through the posterior approach? (2) Is the direct-anterior approach THA associated with shorter operative times and higher rates of noninstitutional discharge than a posterior approach THA? METHODS: Between October 2008 and February 2010, an arthroplasty fellowship-trained surgeon performed 135 THAs. All 135 were performed using the posterior approach. During that period, we used this approach when patients had any moderate to severe degenerative joint disease of the hip attributable to any type of arthritis refractory to nonoperative treatment measures. Of the patients who were treated with this approach, 21 (17%; 23 hips) were lost to followup, whereas 109 (83%; 112 hips) were available for followup at 1 year. Between February and September 2011, the same surgeon performed 86 THAs. All 86 were performed using the direct-anterior approach. During that period, we used this approach when patients with all types of moderate to severe degenerative joint disease had nonoperative treatment measures fail. Of the patients who were treated with this approach, 35 (41%; 35 hips) were lost to followup, whereas 51 (59%; 51 hips) were available for followup at 1 year. THAs during the surgeon's direct-anterior approach learning period (February 2010 through January 2011) were excluded because both approaches were being used selectively depending on patient characteristics. Clinical outcomes included operative blood loss; allogeneic transfusion; adverse events; patient reported Veterans RAND-12 Physical (PCS) and Mental Component Summary (MCS) scores, and University of California Los Angeles (UCLA) activity scores at 1 month, 3 months, and 1 year after surgery. Resource utilization outcomes included operative time, length of stay, and discharge disposition (home versus institution). Outcomes were compared using logistic and linear regression techniques. RESULTS: After controlling for relevant confounding variables including age, sex, and BMI, the direct-anterior approach was associated with worse adjusted MCS changes 1 and 3 months after surgery (1-month score change, 9; 95% CI, -13 to -5; standard error, 2), compared with the posterior approach (3 month score change, -9; 95% CI, -14 to -3; standard error, 3) (both p < 0.001), while the direct-anterior approach was associated with greater PCS improvement at 3 months compared with the posterior approach (score change, 6; 95% CI, 2-10; standard error, 2; p = 0.008). There were no differences in adjusted PCS at either 1 month or 12 months, and no clinically important differences in UCLA scores. Although the PCS score differences are greater than the minimum clinically important difference of 5 points for this endpoint, the clinical importance of such a small effect is questionable. At 1 year after THA, there were no intergroup differences in self-reported physical function, although both groups had significant loss-to-followup at that time. Operative time (skin incision to skin closure) between the two groups did not differ (81 versus 79 minutes; p = 0.411). Mean surgical blood loss (403 versus 293 mL; p < 0.001; adjusted, 119 more mL; 95% CI, 79-160; p < 0.001) and in-hospital transfusion rates (direct-anterior approach, 20% [17/86] versus posterior approach, 10% [14/135], p = 0.050; adjusted odds ratio, 3.6; 95% CI, 1.3-10.1; p = 0.016) were higher in the direct-anterior approach group. With the numbers available, there was no difference in the frequency of adverse events between groups when comparing intraoperative complications, perioperative Technical Expert Panel complications, and other non-Technical Expert Panel complications within 1 year of surgery, although this study was not adequately powered to detect differences in rare adverse events. CONCLUSIONS: With suitable experience, the direct anterior approach can be performed with expected results similar to those of the posterior approach. There may be transient and small benefits to the direct anterior approach, including improved physical function at 3 months after surgery. However, the greater operative blood loss and greater likelihood of blood transfusions, even when the surgeon is experienced, may be a disadvantage. Given some of the kinds of bias present that we found, including loss to followup, the conclusions we present should be considered preliminary, but it appears that any benefits that accrue to the patients who had the direct-anterior approach would be transient and modest. Prospective randomized studies on the topic are needed to address the differences between surgical approaches more definitively. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26620969 TI - Patients organise and train doctors to provide better care. PMID- 26620965 TI - Mechanism, assessment and management of pain in chronic pancreatitis: Recommendations of a multidisciplinary study group. AB - DESCRIPTION: Pain in patients with chronic pancreatitis (CP) remains the primary clinical complaint and source of poor quality of life. However, clear guidance on evaluation and treatment is lacking. METHODS: Pancreatic Pain working groups reviewed information on pain mechanisms, clinical pain assessment and pain treatment in CP. Levels of evidence were assigned using the Oxford system, and consensus was based on GRADE. A consensus meeting was held during PancreasFest 2012 with substantial post-meeting discussion, debate, and manuscript refinement. RESULTS: Twelve discussion questions and proposed guidance statements were presented. Conference participates concluded: Disease Mechanism: Pain etiology is multifactorial, but data are lacking to effectively link symptoms with pathologic feature and molecular subtypes. Assessment of Pain: Pain should be assessed at each clinical visit, but evidence to support an optimal approach to assessing pain character, frequency and severity is lacking. MANAGEMENT: There was general agreement on the roles for endoscopic and surgical therapies, but less agreement on optimal patient selection for medical, psychological, endoscopic, surgical and other therapies. CONCLUSIONS: Progress is occurring in pain biology and treatment options, but pain in patients with CP remains a major problem that is inadequately understood, measured and managed. The growing body of information needs to be translated into more effective clinical care. PMID- 26620968 TI - Maturation stage enamel malformations in Amtn and Klk4 null mice. AB - Amelotin (AMTN) and kallikrein-4 (KLK4) are secreted proteins specialized for enamel biomineralization. We characterized enamel from wild-type, Amtn(-/-), Klk4(-/-), Amtn(+/-)Klk4(+/-) and Amtn(-/-)Klk4(-/-) mice to gain insights into AMTN and KLK4 functions during amelogenesis. All of the null mice were healthy and fertile. The mandibular incisors in Amtn(-/-), Klk4(-/-) and Amtn(-/-)Klk4(-/ ) mice were chalky-white and chipped. No abnormalities except in enamel were observed, and no significant differences were detected in enamel thickness or volume, or in rod decussation. Micro-computed tomography (MUCT) maximum intensity projections localized the onset of enamel maturation in wild-type incisors distal to the first molar, but mesial to this position in Amtn(-/-), Klk4(-/-) and Amtn( /-)Klk4(-/-) mice, demonstrating a delay in enamel maturation in Amtn(-/-) incisors. Micro-CT detected significantly reduced enamel mineral density (2.5 and 2.4gHA/cm(3)) in the Klk4(-/-) and Amtn(-/-)Klk4(-/-) mice respectively, compared with wild-type enamel (3.1gHA/cm(3)). Backscatter scanning electron microscopy showed that mineral density progressively diminished with enamel depth in the Klk4(-/-) and Amtn(-/-)Klk4(-/-) mice. The Knoop hardness of the Amtn(-/-) outer enamel was significantly reduced relative to the wild-type and was not as hard as the middle or inner enamel. Klk4(-/-) enamel hardness was significantly reduced at all levels, but the outer enamel was significantly harder than the inner and middle enamel. Thus the hardness patterns of the Amtn(-/-) and Klk4(-/-) mice were distinctly different, while the Amtn(-/-)Klk4(-/-) outer enamel was not as hard as in the Amtn(-/-) and Klk4(-/-) mice. We conclude that AMTN and KLK4 function independently, but are both necessary for proper enamel maturation. PMID- 26620970 TI - The Tortoise and the Hare: Evolving Regulatory Landscapes for Biosimilars. AB - Challenges in demonstrating interchangeability and safety, as well as the ongoing evolution of regulations governing biosimilars, have meant that the development of the biosimilars industry has not been, and will not be, a carbon copy of the generics industry. Complexity in the development process reduces the cost advantages for biosimilars that generics offer over originators. There has been a marked difference in the number of biosimilars approved by the European Medicines Agency (EMA) and US FDA due to a lack of consensus and the different rates of progress in establishing both law and stable evidence-based regulatory guidelines for biosimilars. In this review, we provide a precis of the history and status of the regulatory regimes in the USA and Europe. Included is an assessment of market and nonmarket factors that may continue to influence the development of the biosimilars industry. PMID- 26620971 TI - New Technologies for Insect-Resistant and Herbicide-Tolerant Plants. AB - The advent of modern molecular biology and recombinant DNA technology has resulted in a dramatic increase in the number of insect-resistant (IR) and herbicide-tolerant (HT) plant varieties, with great economic benefits for farmers. Nevertheless, the high selection pressure generated by control strategies for weed and insect populations has led to the evolution of herbicide and pesticide resistance. In the short term, the development of new techniques or the improvement of existing ones will provide further instruments to counter the appearance of resistant weeds and insects and to reduce the use of agrochemicals. In this review, we examine some of the most promising new technologies for developing IR and HT plants, such as genome editing and antisense technologies. PMID- 26620972 TI - Impact of the Usher syndrome on olfaction. AB - Usher syndrome is a genetically and clinically heterogeneous disease in humans, characterized by sensorineural hearing loss, retinitis pigmentosa and vestibular dysfunction. This disease is caused by mutations in genes encoding proteins that form complex networks in different cellular compartments. Currently, it remains unclear whether the Usher proteins also form networks within the olfactory epithelium (OE). Here, we describe Usher gene expression at the mRNA and protein level in the OE of mice and showed interactions between these proteins and olfactory signaling proteins. Additionally, we analyzed the odor sensitivity of different Usher syndrome mouse models using electro-olfactogram recordings and monitored significant changes in the odor detection capabilities in mice expressing mutant Usher proteins. Furthermore, we observed changes in the expression of signaling proteins that might compensate for the Usher protein deficiency. In summary, this study provides novel insights into the presence and purpose of the Usher proteins in olfactory signal transduction. PMID- 26620973 TI - Current Management of Hyperlipidemia in Patients Discharged With a Diagnosis of Acute Coronary Syndrome. PMID- 26620974 TI - Interventricular Septum Dissection: A Rare Complication. PMID- 26620975 TI - The rs361525 polymorphism does not increase production of tumor necrosis factor alpha by monocytes from alpha-1 antitrypsin deficient subjects with chronic obstructive pulmonary disease - a pilot study. AB - BACKGROUND: Polymorphisms in the TNF-A gene have been associated with chronic obstructive pulmonary disease (COPD) in some case-control studies. Previous work has shown that COPD/chronic bronchitis subjects with alpha-1 antitrypsin deficiency with the rs361525 TNF-alpha single nucleotide polymorphism have 100 times more TNF-in spontaneous sputum than disease matched controls. Our objective was to determine if the presence of this polymorphism increased TNF-alpha production by blood monocytes from COPD subjects. FINDINGS: Monocytes from 18 COPD/alpha-1 antitrypsin deficient subjects, with and without the rs361525 polymorphism, were cultured in the presence or absence of lipopolysaccharide. Cell-free supernatants were analyzed by ELISA and real-time PCR performed using cDNA from extracted RNA. Baseline expression of TNF-alpha messenger RNA was no different between the groups. No difference in messenger RNA or secreted protein was observed over time in un-stimulated cells. TNF-alpha messenger RNA expression and protein was not higher in lipopolysaccharide-stimulated monocytes from subjects with the polymorphism compared to cells from patients with the wild-type allele. CONCLUSIONS: This small pilot study did not provide an explanation for the findings of earlier observations of the association of the rs361525 polymorphism with TNF-alpha in airways secretions. Possible reasons for the lack of concordance include the study of blood rather than tissue cells, the use of a single stimulant rather than biological secretions and the need for far greater subject numbers to overcome intra-subject variation in monocyte TNF-alpha production. PMID- 26620976 TI - Imipramine administration induces changes in the phosphorylation of FAK and PYK2 and modulates signaling pathways related to their activity. AB - BACKGROUND: Antidepressants can modify neuronal functioning by affecting many levels of signal transduction pathways that are involved in neuroplasticity. We investigated whether the phosphorylation status of focal adhesion kinase (FAK/PTK2) and its homolog, PYK2/PTK2B, and their complex with the downstream effectors (Src kinase, p130Cas, and paxillin) are affected by administration of the antidepressant drug, imipramine. The treatment influence on the levels of ERK1/2 kinases and their phosphorylated forms (pERK1/2) or the Galphaq, Galpha11 and Galpha12 proteins were also assessed. METHODS: Rats were injected with imipramine (10 mg/kg, twice daily) for 21 days. The levels of proteins investigated in their prefrontal cortices were measured by Western blotting. RESULTS: Imipramine induced contrasting changes in the phosphorylation of FAK and PYK2 at Tyr397 and Tyr402, respectively. The decreased FAK phosphorylation and increased PYK2 phosphorylation were reflected by changes in the levels of their complex with Src and p130Cas, which was observed predominantly after chronic imipramine treatment. Similarly only chronic imipramine decreased the Galphaq expression while Galpha11 and Galpha12 proteins were untouched. Acute and chronic treatment with imipramine elevated ERK1 and ERK2 total protein levels, whereas only the pERK1 was significantly affected by the drug. CONCLUSION: The enhanced activation of PYK2 observed here could function as compensation for FAK inhibition. GENERAL SIGNIFICANCE: These data demonstrate that treatment with imipramine, which is a routine in counteracting depressive disorders, enhances the phosphorylation of PYK2, a non-receptor kinase instrumental in promoting synaptic plasticity. This effect documents as yet not considered target in the mechanism of imipramine action. PMID- 26620977 TI - Advenella alkanexedens sp. nov., an alkane-degrading bacterium isolated from biogas slurry samples. AB - A novel aerobic bacterium, designated strain LAM0050T, was isolated from a biogas slurry sample, which had been enriched with diesel oil for 30 days. Cells of strain LAM0050T were gram-stain-negative, non-motile, non-spore-forming and coccoid-shaped. The optimal temperature and pH for growth were 30-35 degrees C and 8.5, respectively. The strain did not require NaCl for growth, but tolerated up to 5.3 % (w/v) NaCl. Phylogenetic analysis of 16S rRNA gene sequences revealed that strain LAM0050T was a member of the genus Advenella, and was most closely related to Advenella faeciporci KCTC 23732T, Advenella incenata CCUG 45225T, Advenella kashmirensis DSM 17095T and Advenella mimigardefordensis DSM 17166T, with 98.1, 96.6, 96.6 and 96.3 % sequence similarity, respectively. The DNA-DNA hybridization relatedness between strain LAM0050T and A. faeciporci KCTC 23732T was 41.7 +/- 2.4 %. The genomic DNA G+C content was 51.2 mol%, as determined by the Tm method. The major fatty acids of strain LAM0050T were C16 : 0, C17 : 0 cyclo, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c). The predominant ubiquinone was Q-8. The main polar lipids were diphosphatidyglycerol, phosphatidylethanolamine, phosphatidylmethylethanolamine and four unidentified phospholipids. Based on the phenotypic and genotypic properties, strain LAM0050T is suggested to represent a novel species of the genus Advenella, for which the name Advenella alkanexedens sp. nov., is proposed, the type strain is LAM0050T ( = ACCC 06485T = JCM 30465T). PMID- 26620978 TI - Assessing the pollution risk of a groundwater source field at western Laizhou Bay under seawater intrusion. AB - Coastal areas have great significance for human living, economy and society development in the world. With the rapid increase of pressures from human activities and climate change, the safety of groundwater resource is under the threat of seawater intrusion in coastal areas. The area of Laizhou Bay is one of the most serious seawater intruded areas in China, since seawater intrusion phenomenon was firstly recognized in the middle of 1970s. This study assessed the pollution risk of a groundwater source filed of western Laizhou Bay area by inferring the probability distribution of groundwater Cl(-) concentration. The numerical model of seawater intrusion process is built by using SEAWAT4. The parameter uncertainty of this model is evaluated by Markov Chain Monte Carlo (MCMC) simulation, and DREAM(ZS) is used as sampling algorithm. Then, the predictive distribution of Cl(-) concentration at groundwater source field is inferred by using the samples of model parameters obtained from MCMC. After that, the pollution risk of groundwater source filed is assessed by the predictive quantiles of Cl(-) concentration. The results of model calibration and verification demonstrate that the DREAM(ZS) based MCMC is efficient and reliable to estimate model parameters under current observation. Under the condition of 95% confidence level, the groundwater source point will not be polluted by seawater intrusion in future five years (2015-2019). In addition, the 2.5% and 97.5% predictive quantiles show that the Cl(-) concentration of groundwater source field always vary between 175mg/l and 200mg/l. PMID- 26620979 TI - Parental views on acute otitis media (AOM) and its therapy in children--results of an exploratory survey in German childcare facilities. AB - BACKGROUND: Acute otitis media (AOM) is one of the main reasons for medical consultation and antibiotic use during childhood. Although 80% of AOM cases are self-limiting, antibiotic prescription is still high, either for physician- or for parent-related factors. This study aims to identify parental knowledge about, beliefs and attitudes towards, and experiences with AOM and its therapy and thus to gain insights into parents' perspectives within the German health care system. METHODS: An exploratory survey was conducted among German-speaking parents of children aged 2 to 7 years who sent their children to a childcare facility. Childcare facilities were recruited by convenience sampling in different urban and rural sites in Germany, and all parents with children at those facilities were invited to participate. Data were evaluated using descriptive statistical analyses. RESULTS: One-hundred-thirty-eight parents participated. Of those, 75.4% (n = 104) were AOM-experienced and 75.4% (n = 104) had two or more children. Sixty-six percent generally agree that bacteria cause AOM. 20.2% generally agree that viruses cause AOM. 30.5% do not generally agree that viruses cause AOM. Eight percent generally agree that AOM resolves spontaneously, whereas 53.6% do not generally agree. 92.5% generally (45.7%) and partly (42.8%) agree that AOM needs antibiotic treatment. With respect to antibiotic effects, 56.6% generally agree that antibiotics rapidly relieve earache. 60.1% generally agree that antibiotics affect the gastrointestinal tract and 77.5% generally agree that antibiotics possibly become ineffective after frequent use. About 40% generally support and about 40% generally reject a "wait-and-see" strategy for AOM treatment. Parental-reported experiences reveal that antibiotics are by far more often prescribed (70.2%) than actively requested by parents (26.9%). CONCLUSIONS: Parental views on AOM, its therapy, and antibiotic effects reveal uncertainties especially with respect to causes, the natural course of the disease and antibiotic effects on AOM. These results indicate that more evidence-based information is needed if parents' health literacy in the treatment of children with AOM is to be enhanced. The discrepancy between reported parental requests for antibiotics and reported actual prescriptions contradicts the hypothesis of high parental influence on antibiotic use in AOM. PMID- 26620980 TI - Dental pulp stem cells. Biology and use for periodontal tissue engineering. AB - Inflammatory periodontal disease is a major cause of loss of tooth-supporting structures. Novel approaches for regeneration of periodontal apparatus is an area of intensive research. Periodontal tissue engineering implies the use of appropriate regenerative cells, delivered through a suitable scaffold, and guided through signaling molecules. Dental pulp stem cells have been used in an increasing number of studies in dental tissue engineering. Those cells show mesenchymal (stromal) stem cell-like properties including self-renewal and multilineage differentiation potentials, aside from their relative accessibility and pleasant handling properties. The purpose of this article is to review the biological principles of periodontal tissue engineering, along with the challenges facing the development of a consistent and clinically relevant tissue regeneration platform. This article includes an updated review on dental pulp stem cells and their applications in periodontal regeneration, in combination with different scaffolds and growth factors. PMID- 26620981 TI - The association between the CC chemokine ligand 5 -28C>G gene polymorphism and tuberculosis susceptibility. AB - OBJECTIVES: To assess the association between chemotactic chemokine (C-C motif) ligand 5 (CCL5) -28C>G polymorphism and tuberculosis (TB) risk. METHODS: PubMed, Web of Science, and WanFang were searched up to April 2015 for eligible studies on CCL5 -28C>G polymorphism. Data was extracted, and pooled odd ratios (ORs) as well as 95% confidence intervals (95% CI) were calculated. RESULTS: Eight case-control studies were extracted from 8 articles on the polymorphism involving 1852 TB cases and 2068 controls. The results of meta-analysis showed that significant reduced risks were found for the polymorphism with the risk of TB in Asians and Arabs as follows: OR=0.12, 95% CI=0.06-0.26, p=0.000 for mutant homozygous (GG) versus wild-type homozygous (CC) for Asian descent, OR=0.14, 95% CI=0.07-0.28, p=0.000 for GG versus CC in the Arab descent. CONCLUSION: Our findings demonstrated that CCL5 gene -28C>G polymorphism might be a protective factor for the development of TB. PMID- 26620982 TI - Recognition of oxidized albumin and thyroid antigens by psoriasis autoantibodies. A possible role of reactive-oxygen-species induced epitopes in chronic plaque psoriasis. AB - OBJECTIVES: To investigate the role of reactive-oxygen-species (ROS) induced epitopes on human-serum-albumin (HSA) and thyroid antigens in psoriasis autoimmunity. METHODS: This study was performed in the College of Medicine, Qassim University, Buraidah, Saudi Arabia between May 2014 and February 2015. The study was designed to explore the role of ROS-induced epitopes in psoriasis autoimmunity. Singlet-oxygen (or ROS)-induced epitopes on protein (ROS-epitopes albumin) was characterized by in-vitro and in-vivo. Thyroid antigens were prepared from rabbit thyroid, and thyroglobulin was isolated from thyroid extract. Immunocross-reactions of protein-A purified anti-ROS-epitopes-HSA immunoglobulin G (IgGs) with thyroid antigen, thyroglobulin, and their oxidized forms were determined. Binding characteristics of autoantibodies in chronic plaque psoriasis patients (n=26) against ROS-epitopes-HSA and also with native and oxidized thyroid antigens were screened, and the results were compared with age-matched controls (n=22). RESULTS: The anti-ROS-epitopes-HSA-IgGs showed cross-reactions with thyroid antigen, thyroglobulin and with their oxidized forms. High degree of specific binding by psoriasis IgGs to ROS-epitopes-HSA, ROS thyroid antigen and ROS-thyroglobulin was observed. Immunoglobulin G from normal human-controls showed negligible binding with all tested antigens. Moreover, sera from psoriasis patients had higher levels of carbonyl contents compared with control sera. CONCLUSION: Structural alterations in albumin, thyroid antigens by ROS, generate unique neo-epitopes that might be one of the factors for the induction of autoantibodies in psoriasis. PMID- 26620983 TI - Lack of association between the insulin receptor substrates-1 Gly972Arg polymorphism and type-2 diabetes mellitus among Saudis from Eastern Saudi Arabia. AB - OBJECTIVES: To investigate the association between the insulin receptor substrate-1 (IRS1) Gly972Arg polymorphism and type-2 diabetes mellitus (T2DM) among Saudis from Eastern Saudi Arabia. METHODS: This study was conducted between May and December 2014 at King Fahad Hospital of the University, Al Khobar, Kingdom of Saudi Arabia. In a case-control study design, a total of 143 subjects (age range: 35-73 years) comprising 74 healthy controls and 69 patients with T2DM were examined. Blood samples were collected from subjects and subjected to genomic DNA extraction and chemical analysis. The IRS1 Gly972Arg polymorphism was then genotyped using the standard polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: Eight out of 74 (10.8%) of the control group carried at least one copy of the mutated allele. The frequency (8.7%) of the IRS1 variant was also found in the diabetic group. Logistic regression analysis showed an adjusted odds ratio of 1.04, 95% confidence interval 0.28 - 3.95, and a p-value of 0.94. CONCLUSION: We failed to find any association between the IRS1 Gly972Arg polymorphism and T2DM. PMID- 26620984 TI - Does social support affect development of cognitive dysfunction in individuals with diabetes mellitus? AB - OBJECTIVES: To determine cognitive functions and perceived social support (SS) among individuals with diabetes mellitus (DM), and the effects of SS on the development of cognitive dysfunction (CD). METHODS: This cross-sectional study was conducted in 121 patients with DM presenting at the Endocrinology Clinic of Cumhuriyet University Health Services Application and Research Hospital, Sivas, Turkey between April and June 2014. Data were collected utilizing the "Patient Assessment Form", "Standardized Mini Mental State Examination (SMMSE)" and "Multidimensional Scale of Perceived Social Support (MSPSS)". RESULTS: The mean score obtained for DM patients from the SMMSE was 21.55+/-5.7, with 65.3% found to have cognitive impairment. The total mean score of the participants for MSPSS was considered moderate (66.61+/-14.42). There was a significant positive correlation between cognitive function and SS (r=0.273, p=0.002). It was determined that individuals with CD had low levels of perceived SS, and that insufficient support from families and significant others contributed to the development of CD (p=0.008). CONCLUSION: In this study, it was determined that the cognitive function of individuals with DM was impaired and would improve as the perception of SS increased, and that perceived SS would affect the development of CD. Therefore, health professionals can contribute to the improvement of cognitive function of individuals with DM by facilitating the use of SS sources. PMID- 26620985 TI - Effects of 12-month, 2000IU/day vitamin D supplementation on treatment naive and vitamin D deficient Saudi type 2 diabetic patients. AB - OBJECTIVES: To determine whether 12-month, 2000IU/day vitamin D supplementation cardiometabolically improves treatment naive type 2 diabetes mellitus (T2DM) Saudi patients with vitamin D deficiency. METHODS: This 12-month interventional study was conducted at primary health centers in 5 different residential areas in Riyadh, Saudi Arabia between January 2013 and January 2014. Forty-five Saudi T2DM patients were enrolled. Baseline anthropometrics, glycemic, and lipid profiles were measured and repeated after 6 and 12 months. All subjects were provided with 2000IU vitamin D supplements for one year. RESULTS: Vitamin D deficiency at baseline was 46.7%, 31.8% after 6 months, and 35.6% after 12 months, indicating an overall improvement in the vitamin D status in the entire cohort. Insulin and homeostatic model assessment-insulin resistance (HOMA-IR) after 12 months were significantly lower than a 6 months (p less than 0.05), but comparable to baseline values. Mean levels of triglycerides increased overtime from baseline (1.9+/-0.01 mmol/l) to 12 months (2.1+/-0.2 mmol). This modest increase in serum triglycerides was parallel to the insignificant decrease in circulating high-density lipoprotein -cholesterol levels. CONCLUSION: Twelve month vitamin D supplementation of 2000IU per day in a cohort of treatment naive Saudi patients with T2DM resulted in improvement of several cardiometabolic parameters including systolic blood pressure, insulin, and HOMA-IR. Further studies that include a placebo group are suggested to reinforce findings. PMID- 26620986 TI - Preoperative duplex ultrasound parameters predicting male fertility after successful varicocelectomy. AB - OBJECTIVES: To assess duplex ultrasound (DUS) parameters, and predicti the outcome of varicocele ligation in male infertility. METHODS: This retrospective and follow up study was conducted at Dr. Sulaiman Al Habib Hospital, AlQassim, Saudi Arabia between January 2011 and December 2012. Eighty-two patients were selected, who presented with clinical/subclinical varicocele and male infertility. All these patients had DUS of the scrotum and underwent for low ligation varicocelectomy. These patients were followed for a period of 12-24 months after surgery for the occurrence of paternity. We reviewed pre-operative scrotal DUS of these 82 patients for the testicular size and volume, pampiniform veins caliber and duration of reflux in the dilated veins at rest, and after valsalva maneuver. These DUS parameters were correlated with the postoperative paternity rate. RESULTS: Postoperative paternity was achieved in 18 patients (31.6%) with normal-sized testes, and in 3 patients (12%) with small size testes. The positive paternity rate was higher (38.5%) in patients with clinically detected varicocele, compared with only 16.7% of patients with subclinical varicocele (detected by ultrasound only). In addition, postoperative paternity was significantly higher in patients with bilateral varicocele (70.6%), with shunt-type varicocele (71.4%), and patients with a permanent grade of venous reflux (62.5%). CONCLUSION: Selection of patients for the successful paternity after varicocele repair depends mainly on DUS parameters, which includes normal size testicles with shunt type of bilateral varicocele and continuous reflux. PMID- 26620987 TI - Parker Flex-It stylet is as effective as GlideRite Rigid stylet for orotracheal intubation by Glidescope. AB - OBJECTIVES: To evaluate Parker Flex-It stylet as an alternative to GlideRite Rigid stylet to aid tracheal intubation with the Glidescope. METHODS: This prospective randomized trial was conducted at King Abdulaziz University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia between May and December 2014. Sixty American Society of Anesthesiologists I-II patients were randomly assigned to one of 2 equal groups receiving intubation by Glidescope using either GlideRite Rigid stylet (Group GS) or Parker Flex-It stylet (Group PS). The total intubation time, ease of intubation, incidences of successful intubation at first attempt, number of intubation attempts, use of optimization maneuvers, and possible complications were recorded. RESULTS: No significant differences between both groups regarding the total intubation time (p=0.08) was observed. Intubation was significantly easier in group PS compared with group GS as measured by visual analogue scale (p=0.001) with no significant differences between the groups regarding the rate of successful tracheal intubation from first attempt (p=0.524). However, the number of attempts at intubation and usage of external laryngeal manipulation were similar in both groups (p greater than 0.05). The incidence of sore throat, dysphagia, hoarseness, and trauma were significantly higher in group GS (p less than 0.05). CONCLUSION: Parker Flex-It stylet is as effective as GlideRite Rigid stylet when used by experienced operators in patients with normal airways using Glidescope; however, it is easier and less traumatic. PMID- 26620988 TI - Treatment of ventilator-associated pneumonia and ventilator-associated tracheobronchitis in the intensive care unit. A national survey of clinicians and pharmacists in Saudi Arabia. AB - OBJECTIVES: To assess current practices of different healthcare providers for treating extensively drug-resistant (XDR) Acinetobacter baumannii (AB) infections in tertiary-care centers in Saudi Arabia. METHODS: This cross sectional study was performed in tertiary-care centers of Saudi Arabia between March and June 2014. A questionnaire consisting of 3 parts (respondent characteristics; case scenarios on ventilator-associated pneumonia [VAP] and tracheobronchitis [VAT], and antibiotic choices in each scenario) was developed and sent electronically to participants in 34 centers across Saudi Arabia. RESULTS: One-hundred and eighty-three respondents completed the survey. Most of the respondents (54.6%) preferred to use colistin-based combination therapy to treat VAP caused by XDR AB, and 62.8% chose to continue treatment for 2 weeks. Most of the participants (80%) chose to treat VAT caused by XDR AB with intravenous antibiotics. A significant percentage of intensive care unit (ICU) fellows (41.3%) and clinical pharmacists (35%) opted for 2 million units (mu) of colistin every 8 hours without a loading dose, whereas 60% of infectious disease consultants, 45.8% of ICU consultants, and 44.4% of infectious disease fellows preferred a 9 mu loading dose followed by 9 mu daily in divided doses. The responses for the scenarios were different among healthcare providers (p less than 0.0001). CONCLUSION: Most of the respondents in our survey preferred to use colistin-based combination therapy and intravenous antibiotics to treat VAP and VAT caused by XDR AB. However, colistin dose and duration varied among the healthcare providers. PMID- 26620989 TI - Characteristics and treatment outcomes of patients with multi-drug resistant tuberculosis at a tertiary care hospital in Peshawar, Pakistan. AB - OBJECTIVES: To determine characteristics and treatment outcomes of multidrugs resistant tuberculosis (MDR-TB) patients and risk factors for poor outcomes in MDR-TB patients in a tertiary care hospital in Peshawar, Pakistan. METHODS: This retrospective study was conducted at the Programmatic Management of Drug Resistant TB Unit, Lady Reading Hospital Peshawar, Pakistan and included all MDR TB patients registered between January 2012 and December 2012. A special proforma was used for data collection. Analysis was performed using SPSS version 16, after exporting data from the proforma. Differences in proportions were assessed using Pearson's Chi square test whereas for predictors of poor outcomes, multivariate logistic regression analysis with Wald Statistical criteria using backward elimination method was performed. RESULTS: The treatment success rate was 74.3%. In univariate analysis, poor outcomes were associated in patients with age >=44 years (odds ratio [OR]=0.250; 95% confidence interval [CI]: 0.114-0.519, p=0.001), rural residence (OR=0.417; 95% CI: 0.18-0.937, p=0.03), lung cavitation (OR=0.22; 95% CI, 0.007-0.067, p=0.001), resistance to second line drugs (SLD) (OR=3.441; 95% CI: 1.579-7.497, p=0.001), and resistance to ofloxacin (OR=2.944; 95% CI: 1.361-6.365, p=0.005); whereas multivariate logistic regression analysis, poor outcomes were associated in patients with age >=44 years (OR=0.249, 95% CI: 0.075-0.828, p=0.023), rural residence (OR=0.143, 95% CI: 0.052-0.774, p=0.032), and cavitatory lungs (OR=0.022, 95% CI: 0.007-0.072, p=0.000). CONCLUSION: The MDR-TB patient needs special attention for better treatment outcomes. The presence of older age, rural area residence, resistance to ofloxacin, SLD resistance, and cavitary disease are independent prognostic factors for poor outcome in patients with MDR-TB. PMID- 26620990 TI - Shared clinical decision making. A Saudi Arabian perspective. AB - OBJECTIVES: To determine preferences of patients regarding their involvement in the clinical decision making process and the related factors in Saudi Arabia. METHODS: This cross-sectional study was conducted in a major family practice center in King Abdulaziz Medical City, Riyadh, Saudi Arabia, between March and May 2012. Multivariate multinomial regression models were fitted to identify factors associated with patients preferences. RESULTS: The study included 236 participants. The most preferred decision-making style was shared decision-making (57%), followed by paternalistic (28%), and informed consumerism (14%). The preference for shared clinical decision making was significantly higher among male patients and those with higher level of education, whereas paternalism was significantly higher among older patients and those with chronic health conditions, and consumerism was significantly higher in younger age groups. In multivariate multinomial regression analysis, compared with the shared group, the consumerism group were more likely to be female [adjusted odds ratio (AOR) =2.87, 95% confidence interval [CI] 1.31-6.27, p=0.008] and non-dyslipidemic (AOR=2.90, 95% CI: 1.03-8.09, p=0.04), and the paternalism group were more likely to be older (AOR=1.03, 95% CI: 1.01-1.05, p=0.04), and female (AOR=2.47, 95% CI: 1.32-4.06, p=0.008). CONCLUSION: Preferences of patients for involvement in the clinical decision-making varied considerably. In our setting, underlying factors that influence these preferences identified in this study should be considered and tailored individually to achieve optimal treatment outcomes. PMID- 26620991 TI - Dental knowledge of educators and healthcare providers working with children with autism spectrum disorders. AB - OBJECTIVES: To evaluate dental knowledge and attitudes toward oral health care among healthcare providers and educators working with children with autism spectrum disorders (ASD) in central Saudi Arabia. METHODS: There were 305 questionnaires distributed to 7 special-needs centers between September and November 2014. A total of 217 questionnaires were collected with a response rate of 71.1%. The study took place in the College of Dentistry, King Saud University, Riyadh, Kingdom of Saudi Arabia. RESULTS: Approximately 50.2% of the participants did not offer any toothbrushing advice, and 73.3% never recommended dental checkup visits to parents, and 75.6% never performed dental examinations to children under their care. Ten percent thought that children should have their first dental visit after 6 years of age. Almost all participants agreed that children should practice oral hygiene, and 60.4% think they should brush twice per day. In general, the participants choose toothbrushes and toothpaste as the main tools to perform oral hygiene. There were 35% of participants who believed that parents should be responsible for the children's oral hygiene, and a few participants mentioned teachers and therapists to be responsible. Most of the participants (71.4%) did not receive any dental information from dental professional resources, only 14.3% of participants believed bacteria to be the cause of dental cavities. CONCLUSION: There is a clear lack of dental knowledge and attitudes, and its practical application among the participating group of healthcare providers working with children with ASD in Riyadh. PMID- 26620992 TI - Spontaneous Achilles tendon rupture in alkaptonuria. AB - Alkaptonuria (AKU) is a rare inborn metabolic disease characterized by accumulation of homogentisic acid (HGA). Excretion of HGA in urine causes darkening of urine and its deposition in connective tissues causes dark pigmentation (ochronosis), early degeneration of articular cartilage, weakening of the tendons, and subsequent rupture. In this case report, we present a rare case of a patient presented with unilateral spontaneous rupture of Achilles tendon due to AKU. The patient developed most of the orthopedic manifestations of the disease earlier than typical presentations. Alkaptonuria patients should avoid strenuous exercises and foot straining especially in patients developing early orthopedic manifestations. PMID- 26620993 TI - Torsion of a wandering spleen. A rare cause of acute abdomen. AB - Wandering spleen is a rare condition that accounts for less than 0.25% of all indications for splenectomy. It is characterized by ectopic localization of the spleen owing to the lack or weakening of its ligaments. Torsion is the most common complication due to its long pedicle and high mobility, which may result in acute abdomen. We report a case of torsion in a wandering spleen in a 28-year old male presenting with an acute abdomen that was treated by splenectomy. PMID- 26620994 TI - Wernicke's encephalopathy following Roux en Y gastric bypass surgery. AB - Wernicke's encephalopathy (WE) is a serious neurological disorder characterized by a classical triad of acute mental confusion, ataxia, and opthalmoplegia due to thiamine deficiency. It was initially described in chronic alcoholics; however, any condition resulting in poor nutritional status places the patient at risk of WE. Bariatric surgery is now considered as an emergent cause of WE. The number of bariatric surgery is increasing for morbid obesity. We present a case of a 40 year-old male who presented with confusion and difficulty in maintaining the balance while walking 3 months after Roux en Y gastric bypass surgery. Diagnosis of WE was made on clinical ground and confirmed by magnetic resonance imaging of the brain, which showed bilateral hyperintense signals in paramedian thalami. Parenteral thiamine replacement was started, and patient showed complete recovery. PMID- 26620995 TI - Aligning the SaudiMED framework with the National Commission for Academic Accreditation and Assessment domains. PMID- 26620996 TI - Contra-lateral shoulder dislocation caused by seat belts in drivers and front seat passengers. PMID- 26620997 TI - Out-of-hospital adult cardiac arrests in a university hospital in Central Saudi Arabia. PMID- 26620998 TI - Platelet changes in healthy male smokers.Scientific views. PMID- 26620999 TI - Aesthetic discomfort in hand osteoarthritis: results from the LIege Hand Osteoarthritis Cohort (LIHOC). AB - INTRODUCTION: The primary complaint of patients with hand osteoarthritis (OA) is frequently the inelegant appearance of their hands. Only one study has been conducted to assess the magnitude of and identify the determinants of aesthetic discomfort in hand OA. METHODS: The LIege Hand Osteoarthritis Cohort is a prospective cohort of 203 patients diagnosed with hand OA. At baseline, these patients rated their aesthetic discomfort on a 100-mm visual analogue scale (VAS) and used a Likert scale (range 0-7) to quantify the magnitude of their aesthetic damage. RESULTS: The median value of the aesthetic discomfort VAS was 35.0 [interquartile range (Q1-Q3) 6.0-59.0]. The median damage was rated 3.0 (Q1-Q3 1.0-4.0), corresponding to a moderate level. Both were significantly (p < 0.02) associated with the female gender, the duration of hand OA, the radiological severity of OA (Verbruggen-Veys and Kellgren-Lawrence scales) and pain, disability, or stiffness [Australian Canadian Osteoarthritis Hand Index (AUSCAN) and Functional Index for Hand Osteoarthritis ]. After a stepwise analysis, the parameters correlated to the aesthetic discomfort were the presence of erosive joints (p = 0.0048), the AUSCAN score (p < 0.0001), the number of joints with severe radiological damage (p = 0.023), and gender (p = 0.0009). For aesthetic damage, the parameters associated were AUSCAN score (p < 0.0001), duration of hand OA >10 years (p = 0.001), and presence of erosive joints (p < 0.0001). Compared with patients with low aesthetic discomfort (VAS <=33 mm), those with the highest discomfort (VAS >=66 mm) had more erosive OA (p = 0.014), a higher Verbruggen and Veys score (p = 0.0039), and a higher AUSCAN score (p < 0.001). CONCLUSIONS: Aesthetic discomfort and damage are significant complaints in patients with hand OA. The determinants of the magnitude of these are gender, radiological severity, duration of hand OA, presence of erosive joints, and impact on pain, function, and stiffness as assessed with the AUSCAN. PMID- 26621000 TI - [Relationship between primary lung cancer and tobacco consumption. Results of the KBP-2010-CPHG study by the French College of General Hospital Respiratory Physicians]. AB - INTRODUCTION: The College des Pneumologues des Hopitaux Generaux has performed a prospective multicentre epidemiological study which aims to describe the baseline characteristics of all new cases of primary lung cancer histologically or cytologically diagnosed in 2010 and followed-up in the respiratory department of general hospitals. The present publication compares the characteristics of these presentations according to their smoking history. METHODS: Seven thousand and fifty-one adult patients were included from 104 respiratory departments. A standardized form was completed at diagnosis and a steering committee checked the completeness of inclusion. RESULTS: Only 10.9% of patients were never-smokers and 89.1% ever-smokers (i.e., current or former smokers). Respectively, 3.7%, 10.7% and 85.6% of ever-smokers consumed/had consumed 1-10, 11-20, and >20 pack-years. Mean smoking duration was 37.5 years. Former smokers had stopped smoking on average 14.8 years previously. Only 20.7% of never-smokers reported that they had been exposed to tobacco smoke passively. At diagnosis, statistically significant differences were found between never- and ever-smokers (P<0.0001) for sex (women: 60.8% vs 18.8%), age (mean: 70.7 years vs 64.9 years), stage (IV: 70.8% vs 58.7%), histology (adenocarcinoma: 68.5% vs 42.6%), EGFR mutation exploration (51.4% vs 28.0%) and positivity (37.0% vs 4.6%). Differences between never- and ever-smokers rose with increasing tobacco consumption. CONCLUSIONS: This study confirms that differences exist between never- and ever-smoker patients presenting with primary lung cancer and shows the impact of the level of tobacco consumption, in particular on histology. PMID- 26621002 TI - A systematic review of genetic variants associated with metabolic syndrome in patients with schizophrenia. AB - Metabolic syndrome (MetS) is a cluster of factors that increases the risk of cardiovascular disease (CVD), one of the leading causes of mortality in patients with schizophrenia. Incidence rates of MetS are significantly higher in patients with schizophrenia compared to the general population. Several factors contribute to this high comorbidity. This systematic review focuses on genetic factors and interrogates data from association studies of genes implicated in the development of MetS in patients with schizophrenia. We aimed to identify variants that potentially contribute to the high comorbidity between these disorders. PubMed, Web of Science and Scopus databases were accessed and a systematic review of published studies was conducted. Several genes showed strong evidence for an association with MetS in patients with schizophrenia, including the fat mass and obesity associated gene (FTO), leptin and leptin receptor genes (LEP, LEPR), methylenetetrahydrofolate reductase (MTHFR) gene and the serotonin receptor 2C gene (HTR2C). Genetic association studies in complex disorders are convoluted by the multifactorial nature of these disorders, further complicating investigations of comorbidity. Recommendations for future studies include assessment of larger samples, inclusion of healthy controls, longitudinal rather than cross-sectional study designs, detailed capturing of data on confounding variables for both disorders and verification of significant findings in other populations. In future, big genomic datasets may allow for the calculation of polygenic risk scores in risk prediction of MetS in patients with schizophrenia. This could ultimately facilitate early, precise, and patient-specific pharmacological and non-pharmacological interventions to minimise CVD associated morbidity and mortality. PMID- 26621001 TI - Alterations of lateral temporal cortical gray matter and facial memory as vulnerability indicators for schizophrenia: An MRI study in youth at familial high-risk for schizophrenia. AB - BACKGROUND: Structural alterations of the lateral temporal cortex (LTC) in association with memory impairments have been reported in schizophrenia. This study investigated whether alterations of LTC structure were linked with impaired facial and/or verbal memory in young first-degree relatives of people with schizophrenia and, thus, may be indicators of vulnerability to the illness. METHODS: Subjects included 27 non-psychotic, first-degree relatives of schizophrenia patients, and 48 healthy controls, between the ages of 13 and 28. Participants underwent high-resolution magnetic resonance imaging (MRI) at 1.5Tesla. The LTC was parcellated into superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus, and temporal pole. Total cerebral and LTC volumes were measured using semi-automated morphometry. The Wechsler Memory Scale - Third Edition and the Children's Memory Scale - Third Edition assessed facial and verbal memory. General linear models tested for associations among LTC subregion volumes, familial risk and memory. RESULTS: Compared with controls, relatives had significantly smaller bilateral middle temporal gyri. Moreover, right middle temporal gyral volume showed a significant positive association with delayed facial memory in relatives. CONCLUSION: These results support the hypothesis that smaller middle temporal gyri are related to the genetic liability to schizophrenia and may be linked with reduced facial memory in persons at genetic risk for the illness. The findings add to the growing evidence that children at risk for schizophrenia on the basis of positive family history have cortical and subcortical structural brain abnormalities well before psychotic illness occurs. PMID- 26621003 TI - Obstructive sleep apnea and schizophrenia: A systematic review to inform clinical practice. AB - BACKGROUND: Risk factors for obstructive sleep apnea (OSA) are common in people with schizophrenia. Identification and treatment of OSA may improve physical health in this population; however there are no guidelines to inform screening and management. OBJECTIVES: Systematic review to determine, in people with schizophrenia and related disorders: the prevalence of OSA; the prevalence of OSA compared to general population controls; the physical and psychiatric correlates of OSA, associations between antipsychotic medications and OSA; the impact of treatment of OSA on psychiatric and physical health; and the diagnostic validity of OSA screening tools. DATA SOURCES: Medline, EMBASE, ISI Web of Science and PsycINFO electronic databases. Cohort, case-control and cross-sectional studies and RCTs reporting on prevalence of OSA in subjects with schizophrenia and related disorders were reviewed. RESULTS: The prevalence of OSA varied between 1.6% and 52%. The prevalence of OSA was similar between people with schizophrenia and population controls in two studies. Diagnosis of OSA was associated with larger neck circumference, BMI>25, male sex and age>50years. There were no data on physical or psychiatric outcomes following treatment of OSA. The diagnostic utility of OSA screening tools had not been investigated. CONCLUSION: OSA may be prevalent and potentially under-recognized in people with schizophrenia. Further research is required to determine utility of OSA screening tools, the relationships between antipsychotic medications and OSA and any benefits of treating OSA. We propose a strategy for the identification of OSA in people with schizophrenia and related disorders. PMID- 26621004 TI - A comparison of surgical outcome of fasciocutaneous V-Y advancement flap and Limberg transposition flap for recurrent sacrococcygeal pilonidal sinus disease. AB - OBJECTIVE: The aim of this study was to compare the surgical outcome of fasciocutaneous V-Y advancement flap and limberg transposition flap used to treat recurrent sacrococcygeal PSD. METHODS: A total of 58 patients with recurrent pilonidal sinus who underwent surgery were evaluated retrospectively between January 2008 to December 2013. Fasciocutaneous V-Y advancement flap was performed in 25 patients (Group VYF), and limberg transposition flap repair was performed in 33 patients (Group LTF). Patient demographics, operative and postoperative outcomes were recorded then retrospectively analyzed. RESULTS: The mean age (p = 0.69), sex ratio (p = 0.48), and concomitant diseases (p = 0.98) were not statistically different when compared the VYF with LTF groups. Mean operative time was 55 +/- 19 min for the LTF group and 75 +/- 25 min for the VYF group (p = 0.01). When length of hospital stay were compared, there was a significant difference between the groups (p = 0.01). Return to work was carryed out after a mean of 23 +/- 1.1 days in VYF group and 16.7 +/- 1.2 days in LTF group, which is significantly different (p < 0.0004). Between the groups, there was no significantly different regarding surgical complication and recurrent rate. Only one recurrence (4%) was found in VYF group. CONCLUSION: Limberg transposition flap may be use in recurrent cases of PSD, because of the lower recurrence rate and less hospital stay time, early return to work. Most important advantage of fasciocutaneous V-Y advancement flap is the ability to close larger defects in recurrent cases. PMID- 26621005 TI - Primary prevention of cardiovascular disease in a primary care setting. AB - AIM: This study was designed to investigate primary prevention of cardiovascular disease in a primary care setting in Jordan. METHODS: Adult patients without clinical cardiovascular disease who attended a primary care setting were interviewed and their medical files were reviewed. Data collected to assess primary prevention of cardiovascular disease included lifestyle/risk factor screening, weight assessment, blood pressure measurement and control, and blood lipid measurement and control. RESULTS: A total of 224 patients were interviewed. The proportions of patients' files with risk factors documentation were 37.9% for smoking status, 30.4% for physical activity assessment and 72.8% for blood pressure assessment. The majority of hypertensive patients (95.9%) had a blood pressure reading at their most recent visit of ? 140/90 or was prescribed ? 2 antihypertensive medications. CONCLUSION: Documentation of cardiovascular disease risk factors was suboptimal. Healthcare providers should be encouraged to document and assess cardiovascular risk factors to improve primary prevention. PMID- 26621007 TI - Presidential Address of the American Orthopaedic Society for Sports Medicine: Embracing Our Craft, the Only Solution to the Challenges of Today and Tomorrow. PMID- 26621009 TI - Corrigendum. PMID- 26621011 TI - Effects of Ramadan Fasting on Glucose Homeostasis, Lipid Profiles, Inflammation and Oxidative Stress in Women with Polycystic Ovary Syndrome in Kashan, Iran. AB - BACKGROUND: To our knowledge, no reports are available indicating the effects of Ramadan fasting on metabolic parameters, inflammatory factors and oxidative stress in polycystic ovary syndrome (PCOS). The current study was designed to evaluate the effects of Ramadan fasting on metabolic status among women with PCOS. METHODS: This cross-sectional study was conducted on twenty seven PCOS patients who had fasted for a mean period of 16.5 hours a day during the 29 days of the month of Ramadan in Kashan, Iran. Fasting blood samples were collected at the beginning of the study and after 29 days of the study to quantify related variables. To identify within-group differences (before and after Ramadan), paired-samples t-tests were used. RESULTS: Plasma nitric oxide (NO) levels in PCOS women after Ramadan fasting were significantly higher compared to the baseline values (70.63 +/- 15.78 vs. 59.94 +/- 13.87 MUmol/L, P = 0.003). Post Ramadan levels of plasma glutathione (GSH) increased significantly in comparison with pre-Ramadan (974.95 +/- 414.20 vs. 746.96 +/- 205.93 MUmol/L, P = 0.011). In addition, a trend toward a significant effect of Ramadan fasting on reducing serum high sensitivity C-reactive protein (hs-CRP) concentrations (2001.07 +/- 1686.08 vs. 2962.72 +/- 2845.21 ng/mL, P = 0.072) was seen. We did not observe any significant effect of Ramadan fasting on glucose hemostasis parameters, lipid profiles or total antioxidant capacity (TAC). CONCLUSION: In conclusion, Ramadan fasting in women with PCOS for 4 weeks had beneficial effects on NO and GSH levels, but did not affect glucose hemostasis parameters, lipid profiles or TAC. PMID- 26621012 TI - The Incidence, Nature and Consequences of Adverse Events in Iranian Hospitals. AB - INTRODUCTION: Adverse events are relatively common in healthcare, leading to extensive harm to patients and a significant drain on healthcare resources. Identifying the extent, nature and consequences of adverse events is an important step in preventing adverse events and their consequences which is the subject of this study. METHODS: This is a retrospective review of medical records randomly selected from patients admitted to 4 general hospitals, staying more than 24 hours and discharged between April and September 2012. We randomly selected 1200 records and completed the record review for 1162 of these records. Standard forms (RF1 and RF2) were used to review medical records in two stages by nurses and medical doctors. RESULTS: Eighty-five (7.3%) of the 1162 records had an adverse event during the admission; and in 43 (3.7%) of the 1162 records, the patient was admitted to the hospital due to an adverse event that occurred before the admission. Therefore, a total of 128 (11.0%) adverse events occurred in 126 (10.9) records as two patients had more than one adverse event. Forty-four (34.3%) of these 128 adverse events were considered preventable. CONCLUSIONS: This study confirms that adverse events, particularly adverse drug reactions, post-operative infections, bedsore and hospital acquired infections are common and potentially preventable sources of harm to patients in Iranian hospitals. PMID- 26621010 TI - Does stroke location predict walk speed response to gait rehabilitation? AB - OBJECTIVES: Recovery of independent ambulation after stroke is a major goal. However, which rehabilitation regimen best benefits each individual is unknown and decisions are currently made on a subjective basis. Predictors of response to specific therapies would guide the type of therapy most appropriate for each patient. Although lesion topography is a strong predictor of upper limb response, walking involves more distributed functions. Earlier studies that assessed the cortico-spinal tract (CST) were negative, suggesting other structures may be important. EXPERIMENTAL DESIGN: The relationship between lesion topography and response of walking speed to standard rehabilitation was assessed in 50 adult onset patients using both volumetric measurement of CST lesion load and voxel based lesion-symptom mapping (VLSM) to assess non-CST structures. Two functional mobility scales, the functional ambulation category (FAC) and the modified rivermead mobility index (MRMI) were also administered. Performance measures were obtained both at entry into the study (3-42 days post-stroke) and at the end of a 6-week course of therapy. Baseline score, age, time since stroke onset and white matter hyperintensities score were included as nuisance covariates in regression models. PRINCIPAL OBSERVATIONS: CST damage independently predicted response to therapy for FAC and MRMI, but not for walk speed. However, using VLSM the latter was predicted by damage to the putamen, insula, external capsule and neighbouring white matter. CONCLUSIONS: Walk speed response to rehabilitation was affected by damage involving the putamen and neighbouring structures but not the CST, while the latter had modest but significant impact on everyday functions of general mobility and gait. Hum Brain Mapp 37:689-703, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26621013 TI - Quality of Diabetes Management in Saudi Arabia: A Review of Existing Barriers. AB - BACKGROUND: Diabetes mellitus is a complex disorder that requires continuous management and medical care. The purpose of this review is to identify and summarize the barriers that affect diabetes management in Saudi Arabia. METHODS: Studies that have examined the quality of diabetes management in Saudi Arabia were identified through online and manual literature searches. Two researchers independently searched and assessed for inclusion/exclusion criteria. All studies were screened by a specialist for the significance of the review. Studies that were included were evaluated for relevance, methodological rigor, and credibility by giving a quality score based on Russell and Gregory's criteria. RESULTS: This review presents an overview of the quality of diabetes management and issues and barriers concerning the improvement of diabetes care in Saudi Arabia. The online literature search yielded 11 studies which met the inclusion criteria. Factors affecting the quality of diabetes care can be categorized into patient factors (such as adherence, compliance, attitudes, beliefs, knowledge, financial resources and co-morbidities) and healthcare providers' factors (including beliefs, attitudes and knowledge, patient - provider interaction and communication). CONCLUSION: The identified barriers, both from patients and healthcare providers, will help healthcare authorities to improve diabetes management in Saudi Arabia. Improvement of health awareness about disease and disease management should be tailored through continuous patient education. Continuous training and seminars will also expand providers' knowledge that will ensure quality and effective diabetes management. PMID- 26621014 TI - Animal Bite and Deficiencies in Rabies Post-Exposure Prophylaxis in Tehran, Iran. AB - BACKGROUND: Rabies post-exposure prophylaxis (PEP) is an effective measure if administered immediately. We evaluated the primary health care provided after animal bite and determined the deviations from rabies PEP protocol. METHODS: This 6-year population-based cross-sectional study was conducted in Tehran, the capital of Iran, from April 2006 to March 2012. The study population included people who referred to health centers of Tehran, seeking PEP. The data were extracted from rabies registry databases using a checklist of items according to the context of the health records. All statistical analyses were performed at a significance level of 0.05 using Stata software, version 11. RESULTS: Of 22,766 cases of animal bite, 84.5% were men, 31.9% were aged 21-30 years, and 66.3% lived in urban areas. Most cases were the result of a dog bite (81.7%), mostly at midday (29.9%), and more frequently in spring (27.9%) and summer (27.7). Legs (45.6%) and hands (43.4%) were the most common sites of animal bite. The PEP was associated with a variety of shortcomings as follows. A majority of cases who had indication of receiving a 5-dose vaccination schedule had received only three doses. Most of the cases with a wound in the head and neck and many of cases with deep wounds had not received immunoglobulin. A number of cases needed to receive one-mL dose of vaccine while they had received 0.5-mL doses. CONCLUSIONS: According to our results, rabies PEP is not well monitored and the preventive measures are associated with some insufficiencies and deviations from the national PEP protocol which must be taken into consideration by public health authorities to ensure that rabies surveillance is efficient. PMID- 26621015 TI - Analysis of Early Kidney Injury-Related Factors in Patients with Hypertension and Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS). AB - OBJECTIVE: The aim of this study was to analyze the related factors of obstructive sleep apnea hypopnea syndrome (OSAHS) that would affect early kidney injury in patients with hypertension (Hyp). METHODS: A total of 457 Hyp patients with nocturnal snoring were selected for polysomnography (PSG). The patients were divided into four groups according to the apnea hypopnea index (AHI), and the related factors that would impact blood urea, creatinine, 24 hr urinary protein (24 hr UTP), 24 h urinary microalbuminuria and serum cystatin C (Cyst C) were analyzed in the groups. RESULTS: Severe OSAHS (OR = 4.880, 95% CI = 1.577~15.099) was the influencing factor for 24 hr UTP; blood pressure control (OR = 2.335, 95% CI = 1.326~4.112) and Obesity (OR = 2.072, 95% CI = 1.236~3.474) were the influencing factors for 24 hr urinary microalbuminuria; age (OR = 1.996, 95% CI = 1.366~2.917), blood pressure control (OR = 2.895, 95% CI = 1.267~6.615) and severe OSAHS (OR = 6.093, 95% CI = 1.267~29.303) were the influencing factors for Cyst C. As for the Hyp patients associated with OSAHS, severe OSAHS were the influencing factors for 24 hr UTP; blood pressure control and Obesity were the influencing factors for 24 hr urinary microalbuminuria; age, blood pressure control and severe OSAHS were the influencing factors for Cyst C. CONCLUSIONS: OSAHS is a risk factor of early kidney injury. PMID- 26621016 TI - Evaluation of Naturally Acquired Antibody Responses to Two Variant Forms of Plasmodium vivax Apical Membrane Antigen-1 in Individuals Living in Areas of Low and Unstable Malaria Transmission of Iran. AB - BACKGROUND: Acquired antibody responses following natural infection provide valuable information for selection of candidate antigens for malaria vaccines. Apical membrane antigen-1 of Plasmodium vivax (PvAMA-1) has potential as a component of a subunit vaccine for vivax malaria. In addition, genetic diversity in this antigen is responsible for challenges in the development of an effective PvAMA-1 based vaccine. Therefore, the main aim of this study was to determine whether allelic polymorphisms in pvama-1 influence the recognition of naturally occurring antibodies. Also, the profile of IgG isotypes to two sequence types of PvAMA-1 antigen was evaluated among subjects exposed to P. vivax in areas of low and unstable transmission. METHODS: For this purpose, the two variant forms of PvAMA-1 (PvAMA-1A and B) were expressed in Escherichia coli M15-pQE30 system using genomic DNA from Iranian individuals with patent P. vivax infection. Anti AMA-1 response and isotype composition to two variant forms were measured in target P. vivax-infected individuals (n = 110, 2 to 65 years old) using Enzyme linked immunosorbent assay. RESULTS: The results showed that 65.5% of the studied individuals had positive IgG responses to two PvAMA-1 variants, and the prevalence of responders did not differ significantly (P = 0.32). Also, a marked isotype switching to cytophilic (IgG1 /IgG3) antibodies was evident with increasing age, and adults responded more frequently to these antigens than did younger children. CONCLUSION: The presence of mature, protective isotype antibodies and equal immune responses to two genetically distinct variant forms of antigens in individuals from low transmission areas implicates that one of these forms could be used in a universal blood-stage vaccine based on PvAMA-1 antigen. PMID- 26621017 TI - Prevalence of Endometriosis in Malignant Epithelial Ovarian Tumor. AB - BACKGROUND: The present study aims to assess the prevalence and histological characteristics of endometriosis in different types of ovarian surface epithelial tumors. METHODS: Microscopic slides of 110 ovarian tumors (89 malignant and 21 borderlines) were reviewed from 2008 to 2013 in two major gynecological centers affiliated with the Shiraz University of Medical Sciences, Shiraz, Iran. The presence or absence of endometriosis and transitions from atypical endometriosis to carcinoma were also histologically evaluated. Chi-square and t-test were used to compare the study groups. RESULTS: The mean age of the patients was 49.93 +/- 9.36 years in the Endometriosis-Associated Ovarian Carcinomas (EAOC) group and 50.18 +/- 12.8 years in the non-EAOC group. Among the 110 patients, 28 (25.4%) had endometriosis. According to ovarian cancer subtype 67% (4/6) of clear cell adenocarcinoma, 65% (11/17) of endometrioid adenocarcinoma, 28% (7/25) of low grade serous adenocarcinoma, 4% (1/25) of high grade serous adenocarcinoma, 30% (4/13) of borderline serous tumor, and 25% (1/4) of mixed carcinoma had endometriosis. None of the mucinous borderline tumors and mucinous adenocarcinoma cases had endometriosis. Moreover, 23 cases had typical endometriosis, while 14 had atypical endometriosis. On the other hand, 19 cases had both typical and atypical endometriosis. Furthermore, transition from atypical endometriosis to carcinoma was seen in 11 cases. CONCLUSION: Clear cell and endometrioid carcinoma are the most common types of EACO. Atypical endometriosis was more commonly seen in endometrioid and clear cell carcinomas which are included in type I ovarian cancer. Thus, it can be concluded that atypical endometriosis is a precursor for type I ovarian cancer. PMID- 26621018 TI - Key Policy Makers' Awareness of Tobacco Taxation Effectiveness through a Sensitization Program. AB - The implementation of 5 of the 6 WHO MPOWER program in Iran is satisfactory; the only notable shortcoming is the lack of tobacco taxation increases. This study was designed to increase key policy makers' awareness of tobacco taxation effectiveness through a sensitization program in Iran. This analytical and semi experimental study in 2014 included 110 tobacco control key policy makers, who were trained and received educational materials on the importance of tobacco taxation. A valid and reliable questionnaire was completed before and three months after intervention. Data were analyzed using mean (SD), t-Test and analysis of variance. The mean (SD) scores at pre- and post-test were 2.7 +/- 3 and 8.8 +/- 1 out of 10, respectively. Paired t-tests demonstrated a significant difference in the pre- post-test knowledge scores. Increasing knowledge and promoting favorable attitudes of policy makers can lead to greater attention which could in turn change tobacco taxation policies. PMID- 26621019 TI - Kefir and Cancer: A Systematic Review of Literatures. AB - Some studies have suggested chemopreventive effects of kefir, a fermented milk product, on carcinogenesis. The aim of this review study was to evaluate the scientific evidence for effects of kefir on cancer prevention and treatment. We systematically searched for all relevant studies published before June 2015, using PubMed, Google scholar, Cochrane and Science Direct, SID, MedLib and Srlst databases. Relevant studies were reviewed based on systematic review (PRISMA) guidelines. From a total of 2208 papers obtained at the initial database search, 11 publications including 7 in vitro and 4 experimental studies were eligible. In vitro studies on breast, colon, skin and gastric cancers and leukemia cell lines and experimental studies on different sarcomas consistently showed beneficial effects of kefir on cancer prevention and treatment. The results of this systematic review suggest that kefir may be associated with cancer prevention and it also has beneficial effects in cancer treatment. This protection may be associated with kefir bioactive components including peptides, polysaccharides and sphingolipids. PMID- 26621020 TI - Peripheral Primitive Neuroectodermal Tumor (pPNET) of the Parotid: Report of a Rare Case. AB - Primitive neuroectodermal tumors (PNETs) are a family of highly malignant soft tissue neoplasms mostly occurring in children and young adults. PNETs usually develop in the thoracopulmonary region, abdomen, pelvis, and rarely in the head and neck region. Here, a case of PNET located in the parotid gland is reported. PMID- 26621021 TI - Congenital Posterior Spinal Agenesis Leads to L2-L3 Instability: a Case Report and Review of the Literature. AB - Congenital absence of posterior elements of the lumbar column is an extremely uncommon anomaly and we found no any reported cases of incomplete congenital absence of the posterior elements of lumbar vertebra in the literature. Here, we present a case with congenital absence of posterior elements of lumbar vertebra. The patient was a 51-year-old man with a history of 20 years of back pain. Imaging of the lumbar spine revealed instability in L2 and L3 and there was evidence of retrolisthesis, agenesis of pars interarticularis, spinous processes, lamina, transverse processes and facets at L2 and L3. The patient underwent lumbar discectomy and posterior spinal fixation and instrumentation was then done using pedicle screw fixation. Four pedicle screws, two rods, and one cross link were employed to bilaterally fix the L2 and L3 and then we used autograft and allograft bone for interbody fusion, substitutes from iliac crest for posterior fusion. There were no postoperative complications, and at 6, 12 and 24 months of follow-up, his leg and back pain had improved, and the patient did not need any analgesic for pain relief. Complete congenital absence of the lumbar posterior element has been rarely reported in the literature. Patients whose congenital anomalies lead to segmental instability are surgical fusion candidates, but if these anomalies occur in pars interarticularis such as spondylolysis isthmus, fixation and inter segmental fusion techniques are useful. PMID- 26621022 TI - Professor M. Gholi Chams "Father of Modern Ophthalmology in Iran". PMID- 26621023 TI - History of the School of Public Health and Institute of Public Health Research of Tehran University. PMID- 26621024 TI - Gigantism Remains a Clinical Challenge. PMID- 26621025 TI - Randomized controlled expressive writing pilot in individuals with Parkinson's disease and their caregivers. AB - BACKGROUND: Individuals with Parkinson's disease (PD) and their caregivers are at risk for emotional distress and hypercortisolism. Expressive writing is an effective complementary intervention to ameliorate the psychological and physiological effects of chronic illness. This pilot study aimed to evaluate feasibility and preliminary effectiveness of an expressive writing intervention for individuals with PD and their caregivers. METHODS: Individuals with PD (N = 27) and their caregivers (N = 14) were randomly assigned to expressive (N = 15 patients, eight caregivers) or neutral (N = 12 patients, six caregivers) writing conditions. Cortisol awakening response (CAR), non-motor functioning, quality of life, and performance on tests of cognitive functioning were assessed at baseline, immediate post, 4-month, and 10-month post intervention. RESULTS: Attrition was a challenge as eight patients (29.62 %) and four caregivers (28.57 %) chose to discontinue before beginning the intervention or were lost to follow up prior to completing the intervention or the first follow up visit. Significant reduction in anxiety, marginally significant improvement in depression and caregiver burden, and significant improvements in performance on tests of learning and memory were observed, but these changes did not differ by writing condition. CAR significantly differed over time between patients and caregivers and writing conditions. CONCLUSIONS: Some evidence for the feasibility and effectiveness of writing to alleviate hypercortisolism was demonstrated in a small sample of PD patients; however, relatively high attrition rates and the lack of difference between expressive and neutral writing conditions on emotional and neurocognitive outcomes suggests expressive writing procedure modifications may be needed to obtain optimal results for this population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02217735 , Study Start Date: August 30, 2011. PMID- 26621026 TI - Proposal for research and education: joint lectures and practicals on central nervous system anatomy and physiology. AB - We coordinated anatomy and physiology lectures and practicals to facilitate an integrated understanding of morphology and function in a basic medical science program for dental students and to reduce the time spent on basic science education. This method is a means to provide the essential information and skills in less time. The overall impression was that the practice of joint central nervous system lectures and practicals was an efficient method for students, which suggests that joint lectures might also be useful for clinical subjects. About two-thirds of students felt that the joint anatomy and physiology lecture on the central nervous system was useful and necessary in understanding the relationship between morphology and function, at least for this subject. One third of students were neutral on the effectiveness of this method. However, the survey results suggest that improvements are needed in the method and timing of joint lectures and practicals. The present teaching approach can be further improved by conducting combined lectures in which the form and function of anatomic structures are presented by the relevant departments during the same lecture. Finally, joint lecturers and practicals offer an opportunity to increase student understanding of the importance of new research findings by the present authors and other researchers. PMID- 26621027 TI - Evaluation of alumina toughened zirconia implants with a sintered, moderately rough surface: An experiment in the rat. AB - OBJECTIVE: Alumina toughened zirconia (ATZ) is more fracture resistant than unmodified zirconia and has been shown to be a viable substrate for the growth of osteoblasts. In this study, we examined the histological and biomechanical behavior of moderately roughened ATZ implants in rat femoral bone. METHODS: Miniature implants made of ATZ with pore-building polymers sintered onto the surface and electrochemically anodized titanium (TiUnite(r)) were placed into the femurs of Sprague-Dawley rats. Implant surface topography was analyzed by 3D laserscan measurements and scanning electron microscopy (SEM). After a healing period of 14 and 28 days, respectively, histologic and biomechanical testing was performed. RESULTS: Under the SEM, the TiUnite(r) surface could be clearly distinguished from the ATZ surface, but 3D laserscan measurements indicated a moderately rough surface topography for both, TiUnite(r) (Sa=1.31MUm) and ATZ (Sa=1.51MUm). The mean mineralized bone-to-implant contact showed the highest values after 14 and 28 days for TiUnite(r) (58%/75%) as compared to ATZ (24%/41%). The push-in values after a healing period of 14 and 28 days, respectively, increased from 20N to 39N for TiUnite(r) and from 10N to 25N for ATZ. SIGNIFICANCE: Our findings suggest that the moderately roughened ATZ implant surface is well accepted by rat bone tissue. However, compared to titanium, the osseointegration-process of ATZ seems to proceed more slowly in that early phase of implant integration. PMID- 26621029 TI - Multicentre observational study of the Gatekeeper for faecal incontinence. AB - BACKGROUND: A variety of therapeutic approaches are available for faecal incontinence. Implantation of Gatekeeper prostheses is a new promising option. The primary endpoint of this prospective observational multicentre study was to assess the clinical efficacy of Gatekeeper implantation in patients with faecal incontinence. Secondary endpoints included the assessment of patients' quality of life, and the feasibility and safety of implantation. METHODS: Patients with faecal incontinence, with either intact sphincters or internal anal sphincter lesions extending for less than 60 degrees of the anal circumference, were selected. Intersphincteric implantation of six prostheses was performed. At baseline, and 1, 3 and 12 months after implantation, the number of faecal incontinence episodes, Cleveland Clinic Faecal Incontinence, Vaizey and American Medical Systems, Faecal Incontinence Quality of Life Scale and Short Form 36 Health Survey scores were recorded. Endoanal ultrasonography was performed at baseline and follow-up. RESULTS: Fifty-four patients were implanted. After Gatekeeper implantation, incontinence to gas, liquid and solid stool improved significantly, soiling was reduced, and ability to defer defaecation enhanced. All faecal incontinence severity scores were significantly reduced, and patients' quality of life improved. At 12 months, 30 patients (56 per cent) showed at least 75 per cent improvement in all faecal incontinence parameters, and seven (13 per cent) became fully continent. In three patients a single prosthesis was extruded during surgery, but was replaced immediately. After implantation, prosthesis dislodgement occurred in three patients; no replacement was required. CONCLUSION: Anal implantation of the Gatekeeper in patients with faecal incontinence was effective and safe. Clinical benefits were sustained at 1-year follow-up. PMID- 26621030 TI - Fibronectin Fiber Extension Decreases Cell Spreading and Migration. AB - The extracellular matrix (ECM) is present in a range of molecular conformations and intermolecular arrangements. Fibronectin (Fn) molecules that constitute fibers within the ECM can exist in a variety of conformations that result from both mechanical stress and chemical factors such as allosteric binding partners. The long-standing hypothesis that conformational changes regulate the binding of cells to Fn fibers has only been tested for mutated molecules of Fn and has yet to be fully evaluated with Fn fibers. Using time-lapse microscopy we examined how mechanical extension of single fibers of Fn affects the adhesion and migration of endothelial cells. Using this single fiber adhesion technique, we show that high levels of mechanical strain applied to Fn fibers decreases the rates of both cell spreading and cell migration. These data indicate a fundamental cellular response to mechanical strain in the ECM that might have important implications for understanding how cells are recruited during tissue development and repair. J. Cell. Physiol. 231: 1728-1736, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26621028 TI - Bioactive glass fillers reduce bacterial penetration into marginal gaps for composite restorations. AB - OBJECTIVE: Bioactive glass (BAG) is known to possess antimicrobial and remineralizing properties; however, the use of BAG as a filler for resin based composite restorations to slow recurrent caries has not been studied. Accordingly, the objective of this study was to investigate the effect of adding 15wt% BAG to a resin composite on bacterial biofilms penetrating into marginal gaps of simulated tooth fillings in vitro during cyclic mechanical loading. METHODS: Human molars were machined into approximately 3mm thick disks of dentin and 1.5-2mm deep composite restorations were placed. A narrow 15-20 micrometer wide dentin-composite gap was allowed to form along half of the margin by not applying dental adhesive to that region. Two different 72wt% filled composites were used, one with 15wt% BAG filler (15BAG) and the balance silanated strontium glass and one filled with aerosol silica and silanated strontium glass without BAG (0BAG-control). Samples of both groups had Streptococcus mutans biofilms grown on the surface and were tested inside a bioreactor for two weeks while subjected to periods of cyclic mechanical loading. After post-test biofilm viability was confirmed, each specimen was fixed in glutaraldehyde, gram positive stained, mounted in resin and cross-sectioned to reveal the gap profile. Depth of biofilm penetration for 0BAG and 15BAG was quantified as the fraction of gap depth. The data were compared using a Student's t-test. RESULTS: The average depth of bacterial penetration into the marginal gap for the 15BAG samples was significantly smaller (~61%) in comparison to 0BAG, where 100% penetration was observed for all samples with the biofilm penetrating underneath of the restoration in some cases. SIGNIFICANCE: BAG containing resin dental composites reduce biofilm penetration into marginal gaps of simulated tooth restorations. This suggests BAG containing composites may have the potential to slow the development and propagation of secondary tooth decay at restoration margins. PMID- 26621031 TI - Role of epithelial Na+ channels in endothelial function. AB - An increasing number of mechano-sensitive ion channels in endothelial cells have been identified in response to blood flow and hydrostatic pressure. However, how these channels respond to flow under different physiological and pathological conditions remains unknown. Our results show that epithelial Na(+) channels (ENaCs) colocalize with hemeoxygenase-1 (HO-1) and hemeoxygenase-2 (HO-2) within the caveolae on the apical membrane of endothelial cells and are sensitive to stretch pressure and shear stress. ENaCs exhibited low levels of activity until their physiological environment was changed; in this case, the upregulation of HO 1, which in turn facilitated heme degradation and hence increased the carbon monoxide (CO) generation. CO potently increased the bioactivity of ENaCs, releasing the channel from inhibition. Endothelial cells responded to shear stress by increasing the Na(+) influx rate. Elevation of intracellular Na(+) concentration hampered the transportation of l-arginine, resulting in impaired nitric oxide (NO) generation. Our data suggest that ENaCs that are endogenous to human endothelial cells are mechano-sensitive. Persistent activation of ENaCs could inevitably lead to endothelium dysfunction and even vascular diseases such as atherosclerosis. PMID- 26621033 TI - The formins FHOD1 and INF2 regulate inter- and intra-structural contractility of podosomes. AB - Podosomes are actin-rich adhesion structures that depend on Arp2/3-complex-based actin nucleation. We now report the identification of the formins FHOD1 and INF2 as novel components and additional actin-based regulators of podosomes in primary human macrophages. FHOD1 surrounds the podosome core and is also present at podosome-connecting cables, whereas INF2 localizes at the podosome cap structure. Using a variety of microscopy-based methods; including a semiautomated podosome reformation assay, measurement of podosome oscillations, FRAP analysis of single podosomes, and structured illumination microscopy, both formins were found to regulate different aspects of podosome-associated contractility, with FHOD1 mediating actomyosin contractility between podosomes, and INF2 regulating contractile events at individual podosomes. Moreover, INF2 was found to be a crucial regulator of podosome de novo formation and size. Collectively, we identify FHOD1 and INF2 as novel regulators of inter- and intra-structural contractility of podosomes. Podosomes thus present as one of the few currently identified structures which depend on the concerted activity of both Arp2/3 complex and specific formins and might serve as a model system for the analysis of complex actin architectures in cells. PMID- 26621034 TI - Emotionally Abusive Behavior in Italian Middle School Teachers as Identified by Students. AB - The aim of this article was to estimate the prevalence of psychological maltreatment in Italian middle school students by their teachers, and to test the applicability of surveying instruments for this phenomenon in Italian educational settings. The sample consisted of 105 teachers and 128 middle school students, who were asked about their experiences with emotionally abusive behaviors (i.e., demeaning, discriminating, dominating, destabilizing, distancing, and diverse) in the Italian school system. Teachers did not tend to perceive their behavior as abusive, while the students showed a very high perception of abuse (98%). Males were more likely to be victims of abuse, and they also reported lower scores in the Achievement scale. Emotional child abuse is highly present in Italian educational settings, and there is a strong need for interventions aimed at supporting teacher education, in the hopes of increasing the general well-being in schools. PMID- 26621032 TI - Activation of apoptosis in NAF-1-deficient human epithelial breast cancer cells. AB - Maintaining iron (Fe) ion and reactive oxygen species homeostasis is essential for cellular function, mitochondrial integrity and the regulation of cell death pathways, and is recognized as a key process underlying the molecular basis of aging and various diseases, such as diabetes, neurodegenerative diseases and cancer. Nutrient-deprivation autophagy factor 1 (NAF-1; also known as CISD2) belongs to a newly discovered class of Fe-sulfur proteins that are localized to the outer mitochondrial membrane and the endoplasmic reticulum. It has been implicated in regulating homeostasis of Fe ions, as well as the activation of autophagy through interaction with BCL-2. Here we show that small hairpin (sh)RNA mediated suppression of NAF-1 results in the activation of apoptosis in epithelial breast cancer cells and xenograft tumors. Suppression of NAF-1 resulted in increased uptake of Fe ions into cells, a metabolic shift that rendered cells more susceptible to a glycolysis inhibitor, and the activation of cellular stress pathways that are associated with HIF1alpha. Our studies suggest that NAF-1 is a major player in the metabolic regulation of breast cancer cells through its effects on cellular Fe ion distribution, mitochondrial metabolism and the induction of apoptosis. PMID- 26621035 TI - Who Is the Rotten Apple? Mock Jurors' Views of Teacher-Student Sexual Contact. AB - The present study investigated mock jurors' ( N = 541) perceptions of a hypothetical case of teacher-student sexual contact. Mock jurors read a brief vignette describing an alleged sexual encounter where the gender and age of both the teacher and student were manipulated. Participants rendered legal decisions (i.e., verdict, degree of guilt, and sentence length), as well as culpability judgments pertaining to both the teacher and the student (i.e., blame, cause, and desire for the sexual contact). In addition, the effects of mock juror gender and attitudes regarding both rape myth acceptance and homophobia were investigated. Teacher gender and both teacher and student age predicted mock jurors' recommended sentences, with male teachers, older teachers, and younger students leading to greater sentences. Overall, student age was most consistently related to multiple culpability judgments, and the culpability judgments regarding the victim were the most consistently predicted by the independent variables. We did not find any evidence of homosexist attitudes, meaning that same-gender teacher student contact was not judged any differently than opposite-gender contact. Worth noting, we found an interaction such that male students victimized by female teachers were judged to have wanted the contact more than any other gender combination, especially by male participants. The authors discuss these findings in the context of the child sexual abuse (CSA) literature concluding that many of the findings of more prototypical CSA cases extend to the teacher-student context. We also discuss the implications of these findings in terms of gendered judgments of adolescents who are victimized by teachers, possibly decided by legal professionals, school administrators, and jurors themselves. In particular, the three-way gender interaction can be interpreted in the context of stereotypes regarding sexual development marking sexual contact between adolescent males and older females as a "rite of passage" into adulthood. PMID- 26621036 TI - Mental Health Pathways Linking Childhood Maltreatment to Interpersonal Revictimization During Adolescence for Girls in the Child Welfare System. AB - This study compares the association of histories of childhood emotional, physical, and sexual abuse, and physical neglect with revictimization among adolescent girls, and investigates the role of posttraumatic stress and symptoms of depression as mediators. Participants were 234 girls aged 12 to 19 years, who have been involved with the child welfare system in a Midwestern urban area. Data were collected from baseline surveys of a trauma-focused group program to which the participants were referred. The majority of participants were youths of color (75%) who were primarily African American (70%), and the remaining participants were White, non-Hispanic (25%). Data were collected through surveys that assessed histories of child abuse and neglect, symptoms of posttraumatic stress and depression, and experiences of physical, verbal, and relational revictimization in the last 3 months. All types of abuse and neglect were significantly associated with higher frequencies of revictimization and higher levels of posttraumatic stress and depressive symptoms. Parallel mediation analyses demonstrated that both posttraumatic stress and depression fully mediated the relationships between emotional abuse and revictimization, and sexual abuse and revictimization. Physical abuse was fully mediated by posttraumatic stress, but not by depression. Results also indicated that neither posttraumatic stress nor depression were mediators for the relationship between neglect and revictimization. There were similar pathways to revictimization in adolescents from emotional and sexual abuse through posttraumatic stress and depression. Evidence is mounting for the deleterious effects of emotional abuse. There is evidence that treatment of both posttraumatic stress and depression in emotionally and sexually abused adolescents involved in child welfare is warranted to prevent future revictimization. PMID- 26621037 TI - Effects of Violence Prevention Behavior on Exposure to Workplace Violence and Threats: A Follow-Up Study. AB - This longitudinal study investigates the relationship between prevention behaviors, that is, enacted violence prevention policies, and exposure to workplace violence and threats across four different high risk work sectors: psychiatry, special schools, eldercare, and the prison and probation services. Logistic regression analysis of a 1-year follow-up sample of 3.016 employees from these four sectors shows that prevention behaviors are significantly and negatively associated with self-reported exposure to workplace violence and threats-in the prison and probation services, eldercare, and in psychiatry, while no significant associations are found for special schools. The results therefore show clear sector differences with regard to the preventive effect of violence prevention behaviors. Furthermore, this multisector comparison suggests that prevention behaviors are more effective in relation to a moderate frequency of violence and threats, and that only top management prevention behavior can prevent very frequent incidents (odds ratio [ OR] = 0.58). This study contributes to the literature by use of a longitudinal design and acceptable response rates, while also simultaneously investigating several high risk sectors. The results imply that when managing workplace violence in high risk areas of human service work, there should be emphasis on the use of violence prevention behaviors from top management, supervisor, and among coworkers. However, type of sector and the frequency of workplace violence should be analyzed to evaluate the potential impact of prevention behaviors. PMID- 26621038 TI - The Old Model of Addiction Treatment Must Change. AB - Thanks to the Affordable Care Act and Mental Health Parity and Addiction Equity Act, more people have access to addiction treatment, and investors are taking notice. But as new players enter this field, we must ensure that they invest in evidence-based treatment. PMID- 26621039 TI - The European Medicines Agency Review of Brentuximab Vedotin (Adcetris) for the Treatment of Adult Patients With Relapsed or Refractory CD30+ Hodgkin Lymphoma or Systemic Anaplastic Large Cell Lymphoma: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use. AB - BACKGROUND: On October 25, 2012, a conditional marketing authorization valid throughout the European Union (EU) was issued for brentuximab vedotin for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL) and for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). For HL, the indication is restricted to treatment after autologous stem cell transplantation (ASCT) or after at least two previous therapies when ASCT or multiagent chemotherapy is not a treatment option. MATERIALS AND METHODS: Brentuximab vedotin is an antibody-drug conjugate (ADC) composed of a CD30-directed monoclonal antibody (recombinant chimeric IgG1) that is covalently linked to the antimicrotubule agent monomethyl auristatin E (MMAE). Binding of the ADC to CD30 on the cell surface initiates internalization of the MMAE-CD30 complex, followed by proteolytic cleavage that releases MMAE. The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. RESULTS: Brentuximab vedotin as a single agent was evaluated in two single-arm studies. Study SG035-003 included 102 patients with relapsed or refractory HL. An objective response was observed in 76 patients (75%), with complete remission in 34 (33%). Study SG035-004 included 58 patients with relapsed or refractory sALCL. An objective response was observed in 50 patients (86%), with complete remission in 34 (59%). The most frequently observed toxicities were peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, vomiting, pyrexia, and upper respiratory tract infection. CONCLUSION: The present report summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of the product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu). IMPLICATIONS FOR PRACTICE: Brentuximab vedotin was approved in the European Union for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma or systemic anaplastic large cell lymphoma. For Hodgkin lymphoma, brentuximab vedotin should only be used after autologous stem cell transplantation or following at least two prior therapies when transplantation or multiagent chemotherapy is not a treatment option. In two studies involving 160 patients, partial or complete responses were observed in the majority of patients. Although there was no information on the survival of patients treated in the studies at the time of approval, the responses were considered a clinically relevant benefit. PMID- 26621040 TI - Delayed Efficacy After Treatment With Lenalidomide or Thalidomide in Patients With Mucosa-Associated Lymphoid Tissue Lymphoma. AB - BACKGROUND: The immunomodulatory drugs (IMiDs) thalidomide and lenalidomide have both been tested for treatment of mucosa-associated lymphoid tissue (MALT) lymphoma, with lenalidomide, in particular, showing promising activity. However, long-term results are missing. Because of the late-onset remissions registered in individual patients, we have systemically analyzed the patients treated with IMiDs at our institution for long-term results. METHODS: Within the present retrospective analysis, we identified 25 patients who had been treated with lenalidomide (n = 18) or thalidomide (n = 7) and were available for long-term assessments of outcome. All patients were followed up according to a standardized follow-up protocol. RESULTS: Of the 25 patients, 7 (28%) experienced delayed onset responses without further treatment (thalidomide, n = 2; lenalidomide, n = 5). In 4 patients (16%), the initial outcome switched to a better result (partial remission [PR] to complete remission [CR], n = 1; stable disease [SD] to PR, n = 1; SD to CR, n = 1; and PD to CR, n = 1) after a median time of 19.5 months (range, 10.9-32.0). Furthermore, 2 patients showed ongoing shrinkage of the target lesion for 47.4+ and 43.5+ months, respectively, and 1 patient had durable disease stabilization for 16.2+ months. The median time to the best response for all responding patients (13 of 25; 53%) was 7.3 months (interquartile range [IQR], 5.6-22.5). After a median follow-up of 46 months (IQR, 32.0-58.5), 23 of 25 patients (92%) were alive. CONCLUSION: Our findings suggest that late-onset remissions might be a common phenomenon in the use of IMiDs for the treatment of MALT lymphoma. Thus, sufficient follow-up time after treatment before the initiation of further therapy appears crucial to assess the full effect of therapy and avoid unnecessary overtreatment. IMPLICATIONS FOR PRACTICE: The immunomodulatory drugs (IMiDs) thalidomide and lenalidomide have been tested for the treatment of mucosa-associated lymphoid tissue (MALT) lymphoma, with lenalidomide showing promising activity. However, long-term results are missing. The present findings suggest that late-onset remissions and delayed responses could be a common phenomenon with IMiD use for MALT lymphoma. Using a standardized restaging protocol to ensure concise follow-up data, these findings suggest it is of major importance to ensure a sufficient follow-up time after treatment with these compounds and before initiation of further treatment lines, because nearly one third of treated patients showed further improvement during prolonged follow-up. PMID- 26621042 TI - Intermittent hypercapnia-induced phrenic long-term depression is revealed after serotonin receptor blockade with methysergide in anaesthetized rats. AB - NEW FINDINGS: What is the central question of this study? Intermittent hypercapnia is a concomitant feature of breathing disorders. Hypercapnic stimuli evoke a form of respiratory plasticity known as phrenic long-term depression in experimental animals. This study was performed to investigate the putative role of serotonin receptors in the initiation of phrenic long-term depression in anaesthetized rats. What is the main finding and its importance? Phrenic nerve long-term depression was revealed in animals pretreated with the serotonin broad spectrum antagonist, methysergide. This study highlights that serotonin receptors modulate respiratory plasticity evoked by acute intermittent hypercapnia in anaesthetized rats. This study was performed to test the hypothesis that intermittent hypercapnia can evoke a form of respiratory plasticity known as long term depression of the phrenic nerve (pLTD) and that 5-HT receptors play a role in the initiation of pLTD. Adult male urethane-anaesthetized, vagotomized, paralysed, mechanically ventilated Sprague-Dawley rats were exposed to an acute intermittent hypercapnia protocol. One group received i.v. injection of the non selective 5-HT receptor antagonist methysergide and another group received i.v. injection of the selective 5-HT1A receptor antagonist WAY-100635 20 min before exposure to intermittent hypercapnia. A control group received i.v. injection of saline. Peak phrenic nerve activity and respiratory rhythm parameters were analysed at baseline (T0), during each of five hypercapnic episodes, and 15, 30 and 60 min (T60) after the last hypercapnia. Intravenous injection of methysergide before exposure to acute intermittent hypercapnia induced development of amplitude pLTD at T60 (decreased by 46.1 +/- 6.9%, P = 0.003). Conversely, in control and WAY-100635-pretreated animals, exposure to acute intermittent hypercapnia did not evoke amplitude pLTD. However, a long-term decrease in phrenic nerve frequency was evoked both in control (42 +/- 4 breaths min(-1) at T0 versus 32 +/- 5 breaths min(-1) at T60; P = 0.036) and in methysergide-pretreated animals (42 +/- 2 breaths min(-1) at T0 versus 32 +/- 3 breaths min(-1) at T60; P = 0.028). In WAY-100635 pretreated animals, frequency pLTD was prevented. These results suggest that 5-HT receptors modulate respiratory plasticity induced by acute intermittent hypercapnia in anaesthetized rats. PMID- 26621041 TI - Age and Gender Moderate the Impact of Early Palliative Care in Metastatic Non Small Cell Lung Cancer. AB - BACKGROUND: Studies demonstrate that early palliative care (EPC) improves advanced cancer patients' quality of life (QOL) and mood. However, it remains unclear whether the role of palliative care differs based upon patients' demographic characteristics. We explored whether age and gender moderate the improvements in QOL and mood seen with EPC. METHODS: We performed a secondary analysis of data from a randomized controlled trial of patients with metastatic non-small cell lung cancer. Patients received either EPC integrated with oncology care or oncology care alone. We assessed the degree to which QOL (Trial Outcome Index [TOI]) and mood (Hospital Anxiety and Depression Scale [HADS] and Patient Health Questionnaire 9 [PHQ-9]) outcomes at week 12 varied by patient age (<65) and gender. The week 12 data of 107 patients are included in this analysis. RESULTS: At 12 weeks, younger patients receiving EPC reported better QOL (TOI mean = 62.04 vs. 49.43, p = .001) and lower rates of depression (HADS-Depression = 4.0% vs. 52.4%, p < .001; PHQ-9 = 0.0% vs. 28.6%, p = .006) than younger patients receiving oncology care alone. Males receiving EPC reported better QOL (TOI mean = 58.81 vs. 48.30, p = .001) and lower rates of depression (HADS Depression = 18.5% vs. 60.9%, p = .002; PHQ-9 = 3.8% vs. 34.8%, p = .008) than males receiving oncology care alone. At 12 weeks, QOL and mood did not differ between study groups for females and older patients. CONCLUSION: Males and younger patients who received EPC had better QOL and mood than those who received oncology care alone. However, these outcomes did not differ significantly between treatment groups for females or older patients. IMPLICATIONS FOR PRACTICE: This study found that early palliative care improves patients' quality of life and mood differentially based on their age and gender. Specifically, males and younger patients receiving early palliative care experienced better quality of life and mood than those receiving oncology care alone. Conversely, females and older patients did not experience this treatment effect. Thus, palliative care interventions may need to be tailored to patients' age- and gender-specific care needs. Studying how patients' demographic characteristics affect their experience with palliative care will enable the development of interventions targeted to the distinct supportive care needs of patients with cancer. PMID- 26621043 TI - Pulse Oximetry Waveform: Important Bedside Tool to Assess Cardiac Tamponade. PMID- 26621044 TI - Crib Bumpers Continue to Cause Infant Deaths: A Need for a New Preventive Approach. AB - OBJECTIVES: To assess whether clutter (comforters, blankets, pillows, toys) caused bumper deaths and provide an analysis of bumper-related incidents/injuries and their causal mechanisms. STUDY DESIGN: Bumper-related deaths (January 1, 1985, to October 31, 2012) and incidents/injuries (January 1, 1990, to October 31, 2012) were identified from the US Consumer Product Safety Commission (CPSC) databases and classified by mechanism. Statistical analyses include mean age, 95% CIs, chi(2) test for trend, and ANOVA with a paired-comparisons information criterion post hoc test for age differences among injury mechanisms. RESULTS: There were 3 times more bumper deaths reported in the last 7 years than the 3 previous time periods (chi(2)(3) = 13.5, P <= .01). This could be attributable to increased reporting by the states, diagnostic shift, or both, or possibly a true increase in deaths. Bumpers caused 48 suffocations, 67% by a bumper alone, not clutter, and 33% by wedgings between a bumper and another object. The number of CPSC-reported deaths was compared with those from the National Center for the Review and Prevention of Child Deaths, 2008-2011; the latter reported substantially more deaths than CPSC, increasing the total to 77 deaths. Injury mechanisms showed significant differences by age (F4,120 = 3.2, P < .001) and were caused by design, construction, and quality control problems. Eleven injuries were apparent life-threatening events. CONCLUSION: The effectiveness of public health recommendations, industry voluntary standard requirements, and the benefits of crib bumper use were not supported by the data. Study limitations include an undercount of CPSC-reported deaths, lack of denominator information, and voluntary incident reports. PMID- 26621045 TI - Professional Responsibility and Early Childhood Vaccination. PMID- 26621046 TI - Pseudo Darier Sign: A Distinctive Finding for Congenital Smooth Muscle Hamartoma. PMID- 26621047 TI - Early Anesthesia Exposure and the Effect on Visual Acuity, Refractive Error, and Retinal Nerve Fiber Layer Thickness of Young Adults. AB - OBJECTIVE: To investigate whether being anesthesia administered at least once in early life influenced 3 main proxies of visual function: visual acuity, refractive error, and optic nerve health in young adulthood. STUDY DESIGN: At age 20 years, participants of the Western Australian Pregnancy Cohort Study had comprehensive ocular examinations including visual acuity, postcycloplegic refraction, and multiple scans of the optic disc. We identified individuals who had at least 1 procedure requiring anesthesia during the first 3 years of life (between 1990 and 1994) and compared their visual outcomes with nonexposed individuals. We excluded 40 participants with strabismus or other ophthalmic disease or surgery and 136 with non-European background. RESULTS: Of 834 participants, 15.2% (n = 127) were exposed to anesthesia at least once before age 3 years. In both exposed and nonexposed groups, median visual acuity (measured using the logarithm of the minimum angle of resolution [LogMAR] chart) was -0.06 LogMAR in the right eye and -0.08 LogMAR in the left eye (P > .05). Median spherical equivalent refractive error was +0.44 diopters (IQR -0.25, +0.63) and +0.31 diopters (IQR -0.38, +0.63) in the exposed and nonexposed group, respectively (P = .126). No difference was detected in mean global retinal nerve fiber layer thickness of the 2 groups (100.7 vs 100.1 MUm, P = .830). CONCLUSIONS: We were unable to demonstrate an association of exposure to anesthesia as a child with reduced visual acuity or increased myopia or thinning of retinal nerve fiber layer. These findings support the view that anesthesia is unlikely to impair visual development, but further work is needed to establish whether more subtle defects are present and repeated exposures have any effects. PMID- 26621049 TI - Effects of Long-term Conservation Tillage on Soil Nutrients in Sloping Fields in Regions Characterized by Water and Wind Erosion. AB - Conservation tillage is commonly used in regions affected by water and wind erosion. To understand the effects of conservation tillage on soil nutrients and yield, a long-term experiment was set up in a region affected by water and wind erosion on the Loess Plateau. The treatments used were traditional tillage (CK), no tillage (NT), straw mulching (SM), plastic-film mulching (PM), ridging and plastic-film mulching (RPM) and intercropping (In). Our results demonstrate that the available nutrients in soils subjected to non-traditional tillage treatments decreased during the first several years and then remained stable over the last several years of the experiment. The soil organic matter and total nitrogen content increased gradually over 6 years in all treatments except CK. The nutrient content of soils subjected to conservative tillage methods, such as NT and SM, were significantly higher than those in soils under the CK treatment. Straw mulching and film mulching effectively reduced an observed decrease in soybean yield. Over the final 6 years of the experiment, soybean yields followed the trend RPM > PM > SM > NT > CK > In. This trend has implications for controlling soil erosion and preventing non-point source pollution in sloping fields by sacrificing some food production. PMID- 26621048 TI - Does Breastmilk Influence the Development of Bronchopulmonary Dysplasia? AB - OBJECTIVE: To assess whether breastmilk feeding is associated with a reduced risk of bronchopulmonary dysplasia (BPD). Secondary outcome measures analyzed were retinopathy of prematurity (ROP) and necrotizing enterocolitis (NEC). STUDY DESIGN: In an ongoing multicenter cohort study, the data of 1433 very low birth weight infants born before 32 weeks of gestation and discharged in 2013 were analyzed. We compared growth and neonatal complications of infants who received breastmilk exclusively (N = 223) with those who received formula feedings exclusively (N = 239). Logistic regression models were estimated for BPD, ROP, and NEC using nutrition as an independent variable. The Firth logistic regression model and Lasso were used for sensitivity analyses. RESULTS: Exclusively breastmilk-fed infants gained less weight compared with formula-fed infants. SDS for weight decreased between birth and discharge (median (Q1-Q3): formula -0.9 ( 1.4 to [-0.5]) vs breastmilk -1.1 (-1.7 to [-0.6])). Exclusive formula feeding of very low birth weight infants was associated with increased risks of BPD (OR 2.6) as well as NEC (OR 12.6) and ROP (OR 1.80) after controlling for known risk factors. CONCLUSIONS: Exclusive breastmilk feeding was associated with lower growth rates and a reduced risk of BPD as well as NEC and ROP. PMID- 26621050 TI - Arm strength training improves activities of daily living and occupational performance in patients with COPD. AB - OBJECTIVES: Arm strength training may improve functional performance for patients with chronic obstructive pulmonary disease (COPD). This trial investigated the effects of arm strength training on arm exercise capacity, activities of daily living (ADL) and occupational performance in patients with COPD. METHODS: These was a randomized controlled trial in an outpatient clinic. Forty-two stable patients with COPD were randomly assigned into treatment and control groups. The treatment group underwent an 8-week (23 sessions) arm strength training programme. Both groups completed daily breathing exercises at home. Tests included hand grip strength, arm ergometer test, the Glittre-ADL and ADL Simulation tests and measures included the Milliken ADL Scale (MAS) and the Canadian Occupational Performance Measure (COPM). RESULTS: Statistically significant increases were detected in hand grip strength and %hand grip strength values, peak arm ergometer workload and the number of ADL simulation test cycles for the treatment group (P < 0.05). Significant decreases were also found in dyspnea and arm fatigue perception during arm ergometer test, and heart rate and dyspnea perception during Glittre-ADL test in the treatment group (P < 0.05). The treatment group also showed significant increases in MAS-house cleaning and laundry and MAS-other activities integrated scores and COPM-performance and satisfaction scores (P < 0.05). CONCLUSIONS: Arm strength training increases peripheral muscle strength, arm exercise capacity, ADL performance and patients' ADL performance satisfaction. Training decreases dyspnea and arm fatigue perception during supported arm exercises, and dyspnea perception during ADL. Arm strength training is a reliable and feasible treatment for COPD patients. PMID- 26621051 TI - Advances in Patient Self-Monitoring of Blood Glucose. AB - In 2 articles of the present issue, Bendini et al report about performance results obtained with 2 blood glucose monitoring systems of the Contour Next platform. Using several analysis methods, the authors demonstrate a very high accuracy, which meets all actual regulatory performance criteria. With consistent MARD results < 5% under daily routine conditions, this meter platform is finally fulfilling the accuracy request as set forth by the American Diabetes Association already in the late 1980s. This meter platform is representative for the successful effort of the device manufacturers who were consequently improving the analytical performance of blood glucose meters during the Past 2 decades, starting with an MARD of 12-15% at the end of the past century and reaching an excellent accuracy < 5% today. PMID- 26621052 TI - Ion exchanger in the brain: Quantitative analysis of perineuronally fixed anionic binding sites suggests diffusion barriers with ion sorting properties. AB - Perineuronal nets (PNs) are a specialized form of brain extracellular matrix, consisting of negatively charged glycosaminoglycans, glycoproteins and proteoglycans in the direct microenvironment of neurons. Still, locally immobilized charges in the tissue have not been accessible so far to direct observations and quantifications. Here, we present a new approach to visualize and quantify fixed charge-densities on brain slices using a focused proton-beam microprobe in combination with ionic metallic probes. For the first time, we can provide quantitative data on the distribution and net amount of pericellularly fixed charge-densities, which, determined at 0.4-0.5 M, is much higher than previously assumed. PNs, thus, represent an immobilized ion exchanger with ion sorting properties high enough to partition mobile ions in accord with Donnan equilibrium. We propose that fixed charge-densities in the brain are involved in regulating ion mobility, the volume fraction of extracellular space and the viscosity of matrix components. PMID- 26621055 TI - The Journey of Ronald A. Hites. PMID- 26621053 TI - Adaptation to sustained nitrogen starvation by Escherichia coli requires the eukaryote-like serine/threonine kinase YeaG. AB - The Escherichia coli eukaryote-like serine/threonine kinase, encoded by yeaG, is expressed in response to diverse stresses, including nitrogen (N) starvation. A role for yeaG in bacterial stress response is unknown. Here we reveal for the first time that wild-type E. coli displays metabolic heterogeneity following sustained periods of N starvation, with the metabolically active population displaying compromised viability. In contrast, such heterogeneity in metabolic activity is not observed in an E. coli ?yeaG mutant, which continues to exist as a single and metabolically active population and thus displays an overall compromised ability to survive sustained periods of N starvation. The mechanism by which yeaG acts, involves the transcriptional repression of two toxin/antitoxin modules, mqsR/mqsA and dinJ/yafQ. This, consequently, has a positive effect on the expression of rpoS, the master regulator of the general bacterial stress response. Overall, results indicate that yeaG is required to fully execute the rpoS-dependent gene expression program to allow E. coli to adapt to sustained N starvation and unravels a novel facet to the regulatory basis that underpins adaptive response to N stress. PMID- 26621056 TI - BIS/BAS sensitivity and emotional modulation in a prepulse-inhibition paradigm: A brain potential study. AB - We investigated whether prepulse inhibition (PPI) is sensitive to emotion modulation vis-a-vis individual differences in the sensitivity of the behavioral inhibition system (BIS) and behavioral activation system (BAS). Participants (n=50) performed a PPI task while recording the eyeblink reflex and auditory evoked potentials (i.e., N100 and P200). The results showed an increase in PPI from positive to negative stimuli at parietal sites, for both the N100 and P200. The N100 wave of the auditory evoked potential was sensitive to emotional valence high in arousal, whereas the P200 wave was sensitive to emotional valence low in arousal. Importantly, individual differences in BAS sensitivity, but not BIS sensitivity, influenced the emotional modulation of the startle response and PPI. This influence was most evident for the N100. Our findings are consistent with previous reports showing that PPI is sensitive to emotion modulation. The current results extent previous findings by highlighting the importance of the combined influence of valence and arousal. The findings indicate that state and trait emotions bias selective encoding of affective stimuli thereby priming behavioral output. PMID- 26621054 TI - Active surveillance for prostate cancer. AB - It is worth distinguishing between the two strategies of expectant management for prostate cancer. Watchful waiting entails administering non-curative androgen deprivation therapy to patients on development of symptomatic progression, whereas active surveillance entails delivering curative treatment on signs of disease progression. The objectives of the two management strategies and the patients enrolled in either are different: (i) to review the role of active surveillance as a management strategy for patients with low-risk prostate cancer; and (ii) review the benefits and pitfalls of active surveillance. We carried out a systematic review of active surveillance for prostate cancer in the literature using the National Center for Biotechnology Information's electronic database, PubMed. We carried out a search in English using the terms: active surveillance, prostate cancer, watchful waiting and conservative management. Selected studies were required to have a comprehensive description of the demographic and disease characteristics of the patients at the time of diagnosis, inclusion criteria for surveillance, and a protocol for the patients' follow up. Review articles were included, but not multiple papers from the same datasets. Active surveillance appears to reduce overtreatment in patients with low-risk prostate cancer without compromising cancer-specific survival at 10 years. Therefore, active surveillance is an option for select patients who want to avoid the side-effects inherent to the different types of immediate treatment. However, inclusion criteria for active surveillance and the most appropriate method of monitoring patients on active surveillance have not yet been standardized. PMID- 26621057 TI - Nocifensive behavior-related laser heat-evoked component in the rostral agranular insular cortex revealed using morphine analgesia. AB - The rostral agranular insular cortex (RAIC), an opioid-responsive site, is essential for modulating nociception in rats. Our previous studies have shown that morphine suppressed long latency laser heat-evoked nociceptive responses in the primary somatosensory cortex (SmI). By contrast, morphine significantly attenuated both short and long latency responses in the anterior cingulate cortex (ACC). The present study assessed the effect of morphine on laser heat-evoked responses in the RAIC. Laser heat irradiation applied to the rat forepaws at graded levels was used as a specific noxious stimulus. In the RAIC, the first part of the long latency component (140-250ms) of the laser heat-evoked response was enhanced by intraperitoneal morphine (5mg/kg). When the laser heat-evoked cortical responses were examined for trials showing strong nocifensive movement (paw licking), moderate nocifensive movement (paw lifting), and no nocifensive movement, a 140-250ms period enhancement was observed in the RAIC only for the paw lifting movement. This enhancement was absent in the SmI. Thus, our data suggest that the RAIC has a pain-related behavior-dependent neuronal component. Furthermore, the RAIC, ACC, and SmI are differentially modulated by morphine analgesia. PMID- 26621058 TI - Organoiodine(III) Reagents as Active Participants and Ligands in Transition Metal Catalyzed Reactions: Iodosylarenes and (Imino)iodoarenes. AB - This chapter overviews the roles of transition metal complexes having the organoiodine(III) reagents iodosylarenes (ArIO) and (imino)iodoarenes (ArINR) as ligands in catalysis. Mechanistic implications are discussed. PMID- 26621060 TI - Intracranial pressure elevation after ischemic stroke in rats: cerebral edema is not the only cause, and short-duration mild hypothermia is a highly effective preventive therapy. AB - Correction to: Journal of Cerebral Blood Flow & Metabolism (2015) 35, 592-600; doi:10.1038/jcbfm.2014.230; published online 17 December 2014. Following the publication of this article, the authors noticed the following error: The Results section of the article contains a typographical error under subheading 'Study III Effect of Mild Hypothermia, Hematoxylin and Eosin Edema'. . The edema volumes of '3.1+/-0.65 mm3 versus 27.9+/-6.5 mm3' should read '0.7+/-1.2 mm3 versus 6.5 +/- 9.2 mm3.' PMID- 26621059 TI - A generic solution for web-based management of pseudonymized data. AB - BACKGROUND: Collaborative collection and sharing of data have become a core element of biomedical research. Typical applications are multi-site registries which collect sensitive person-related data prospectively, often together with biospecimens. To secure these sensitive data, national and international data protection laws and regulations demand the separation of identifying data from biomedical data and to introduce pseudonyms. Neither the formulation in laws and regulations nor existing pseudonymization concepts, however, are precise enough to directly provide an implementation guideline. We therefore describe core requirements as well as implementation options for registries and study databases with sensitive biomedical data. METHODS: We first analyze existing concepts and compile a set of fundamental requirements for pseudonymized data management. Then we derive a system architecture that fulfills these requirements. Next, we provide a comprehensive overview and a comparison of different technical options for an implementation. Finally, we develop a generic software solution for managing pseudonymized data and show its feasibility by describing how we have used it to realize two research networks. RESULTS: We have found that pseudonymization models are highly heterogeneous, already on a conceptual level. We have compiled a set of requirements from different pseudonymization schemes. We propose an architecture and present an overview of technical options. Based on a selection of technical elements, we suggest a generic solution. It supports the multi-site collection and management of biomedical data. Security measures are multi-tier pseudonymity and physical separation of data over independent backend servers. Integrated views are provided by a web-based user interface. Our approach has been successfully used to implement a national and an international rare disease network. CONCLUSIONS: We were able to identify a set of core requirements out of several pseudonymization models. Considering various implementation options, we realized a generic solution which was implemented and deployed in research networks. Still, further conceptual work on pseudonymity is needed. Specifically, it remains unclear how exactly data is to be separated into distributed subsets. Moreover, a thorough risk and threat analysis is needed. PMID- 26621061 TI - Violence and unsafety in a major Italian hospital: experience and perceptions of health care workers. AB - Workers' experience of violence and perceived unsafety can have a profound impact on job satisfaction, job performance, and workers' decision to leave. OBJECTIVES: The aim of the study was to assess the prevalence of physical and non-physical violence among hospital workers, explore the complaints and reactions of victims, assess the relationship between violence and psychosocial/work factors and analyze the levels of perceived unsafety. METHODS: A cross-sectional study was conducted, via a structured self-administered questionnaire given to all the employees of a major hospital in Italy. Cronbach's alpha coefficient was used to assess the internal consistency of the questionnaire. A logistic regression model was used for data analysis. RESULTS: 903 questionnaires out of 1853 (48.7%) were correctly returned; 11.5% had experience of physical violence and 40.2% had been victims of verbal violence in the previous 12 months. The most common consequences were fear, anger, frustration, and anxiety. Verbal violence was influenced by age, role, department, night/holiday shift work and experience in the current ward. Experiences of physical violence were related to gender, role, and department; 469 responders (51.9%) reported feelings of unsafety, which were related to their professional role, department, shift work, experience of physical or psychological violence, having seen episodes of violence and having received specific training. CONCLUSIONS: Our findings suggest that several factors are associated with workplace violence in health care settings and some of these also influenced the levels of perceived unsafety. PMID- 26621062 TI - Occupational health physicians and the impact of the Great Recession on the health of workers: a qualitative study. AB - BACKGROUND: Italy is one of the Eurozone members where the 2008 "Great Recession" struck worst, with a 9% drop in national GDP between 2008 and 2013. The negative effects of the recession on the health of the Italian population were documented on a nation-wide level. However, few local or regional studies are currently available in the scientific literature. OBJECTIVES: To assess the impact on workers' health of the economic recession in the industrial area of Sassuolo (Modena, Northern Italy), and to provide recommendations for targeted interventions. METHODS: Two focus groups were conducted, involving 8 occupational health physicians (OHPs) active in the area. Rough descriptions were analyzed using MAXQDA 11, according to the principles of grounded theory. RESULTS: 261 segments were coded, divided into four areas. The first, "changes in contemporary world", pointed out that the recession may have just made pre-existing problems worse, accelerating reductions in staff and workers' benefits. The second, "social area", highlighted a decrease in vertical social capital and the beginning of new trends in emigration. The third, "work area", covered workers' fear of losing their jobs if they were ill and a reduction in horizontal social capital, namely difficult relations between co-workers. The fourth, "medical area", indicated a general worsening of workers' health in the Sassuolo ceramic district compared to previous years. The OHPs reported an increase in muscular skeletal complaints, gastritis, tension-type headache, irritable bowel syndrome symptoms, back pain, panic attacks, insomnia, tachycardia, and other medically unexplained symptoms. Anxiety problems seemed to prevail over depressive manifestations. An increase was reported for antidepressants and benzodiazepines consumption. CONCLUSIONS: The local impact of the economic crisis on health was mainly negative, consistent with available national data. Mental health professionals could work together with OHPs, e.g., through Balint Group-like meetings, to develop targeted psychosocial and clinical interventions addressing the medical, psychological and social needs of workers, also involving advocacy and fostering workers' empowerment. PMID- 26621063 TI - [Asbestos at the time of the First World War]. AB - Between the end of the 19th century and the beginning of the 20th numerous asbestos industries began operations in various parts of the world. At the time of the First World War there is ample evidence of the use of this mineral in shipbuilding, the aircraft industry and in the construction industry. In the years 1912-17 the writer Franz Kafka was co-proprietor of a small asbestos factory in Prague. Some of the writer's novels and journal pages were inspired by this experience. In this way asbestos entered into the history of 20th century European literature. In 1917 asbestos extraction was started at the quarry in Balangero, near Turin, Italy. Risks related to the use of asbestos were known at the beginning of the 20th century and legislation aimed at preventing the harmful effects of the mineral were approved in Italy. PMID- 26621064 TI - [Mesothelioma and acceleration]. AB - INTRODUCTION: Taking a publication by Berry in 2007 (3) as a cue, this paper presents in didactic form the topic of acceleration of events as a consequence of a harmful exposure and extends the proposed approach to the case of the asbestos mesothelioma relationship. METHODS: Berry's approach was applied to lung cancer and mesothelioma data. RESULTS: The effects of the acceleration of events are presented as a function of age at onset in exposed subjects, relative risk, scale factor, in addition to age and geographical variability of the relationship between age and mesothelioma rates. DISCUSSION: The discussion regards the general characteristics of the method of acceleration, its meaning and interpretation, and the difficulties associated with its application in the context of diseases with low occurrence; the conditions, applicability constraints, and specific results in the case of mesothelioma; the epidemiologic meaning of acceleration and the difficulties of its extension to individual subjects. PMID- 26621065 TI - Griffin and Neal's safety model: Determinants and components of individual safety performance in the Italian context. AB - INTRODUCTION: Griffin and Neal's model is a useful model to understand workers' different safety behaviour (compliance and participation) starting from their mastery of safety procedures (safety knowledge) and the motivation to put them in place (safety motivation). Although the theoretical model has proven to be adequate and is widely used in research, two problems arise: 1) there is no Italian validation of the four scales measuring the key constructs of the model; 2) the hypothesis regarding the differential impact of the determinants on the components of safety performance produced mixed evidence. OBJECTIVES: The study had a twofold objective: 1) validate an Italian version of the four scales, primarily assessing their construct validity; 2) verify the relationships between the constructs according to the assumptions made within the theoretical model. METHODS: The psychometric properties of the scales as well as the relationships between the constructs were investigated in a sample of 277 workers in the construction and logistics sectors, using questionnaires. The analyses were based on the use of structural equation modelling technique. RESULTS: Results confirmed the validity and reliability of the Italian scales, showing indices that were both satisfactory and aligned with those from previous studies. The relationships between the constructs were substantially consistent with the safety model. CONCLUSIONS: The study provided a valid version of the scales measuring determinants and components of individual safe performance. Such scales can be appropriately used in the Italian context for the development of theoretical as well as practical contributions on work safety. The results suggest that interventions to increase overall safe performance should address both knowledge and motivation for safety. PMID- 26621066 TI - [Nurses and Organizational Citizenship Behavior: contribution to the Italian validation of the Podsakoff et al. scale]. AB - BACKGROUND: Workers engaging in Organizational Citizenship Behaviour (OCB) can benefit colleagues, organization and stakeholders. Such behavior is vital to the efficacy of health care organizations as they can have a positive effect on the quality of care and users' satisfaction. Therefore, it is important to assess such behaviour with a valid and reliable instrument. OBJECTIVES: The purpose of this study was to test, from a confirmatory perspective, the dimensionality of the Italian version of the Podsakoff et al. OCB scale in a large sample of nurses, and at the same time to evaluate the differences in nurses' OCB considering socio-demographic and job characteristics. METHODS: The study included 886 nurses from different health organizations in Italy. The psychometric characteristics of the Italian OCB scale were tested through confirmatory factor analysis (CFA). The differences in nurses' OCB, according to several socio-demographic and job characteristics, were evaluated through a series of correlations and analysis of variance. RESULTS: The CFA of the Italian OCB scale confirmed the hypothesized factor structure, consisting of three dimensions: altruism, civic virtue and conscientiousness. Nurses' gender and professional training were positively correlated with OCB, while the amount of extra work was negatively correlated. In regard to clinical work settings, palliative care nurses engaged in OCB more than nurses working in other areas. CONCLUSIONS: The Italian OCB scale is a valid and reliable instrument. Its use can support all individuals involved in the promotion of workers' organizational well-being in implementing processes aimed at fostering nurses' OCB. PMID- 26621067 TI - [What's new about the thermal comfort in the Italian law? A comparison of the Dpr n.74/2013 and the technical standards Uni En Iso]. PMID- 26621069 TI - Processed meat: the real villain? AB - Meat is a food rich in protein, minerals such as iron and zinc as well as a variety of vitamins, in particular B vitamins. However, the content of cholesterol and saturated fat is higher than in some other food groups. Processed meat is defined as products usually made of red meat that are cured, salted or smoked (e.g. ham or bacon) in order to improve the durability of the food and/or to improve colour and taste, and often contain a high amount of minced fatty tissue (e.g. sausages). Hence, high consumption of processed foods may lead to an increased intake of saturated fats, cholesterol, salt, nitrite, haem iron, polycyclic aromatic hydrocarbons, and, depending upon the chosen food preparation method, also heterocyclic amines. Several large cohort studies have shown that a high consumption of processed (red) meat is related to increased overall and cause-specific mortality. A meta-analysis of nine cohort studies observed a higher mortality among high consumers of processed red meat (relative risk (RR) = 1.23; 95 % CI 1.17, 1.28, top v. bottom consumption category), but not unprocessed red meat (RR = 1.10; 95 % CI 0.98, 1.22). Similar associations were reported in a second meta-analysis. All studies argue that plausible mechanisms are available linking processed meat consumption and risk of chronic diseases such as CVD, diabetes mellitus or some types of cancer. However, the results of meta-analyses do show some degree of heterogeneity between studies, and it has to be taken into account that individuals with low red or processed meat consumption tend to have a healthier lifestyle in general. Hence, substantial residual confounding cannot be excluded. Information from other types of studies in man is needed to support a causal role of processed meat in the aetiology of chronic diseases, e.g. studies using the Mendelian randomisation approach. PMID- 26621070 TI - Immobilization of Acidithiobacillus ferrooxidans on cotton gauze for biological oxidation of ferrous ions in a batch bioreactor. AB - The ability of Acidithiobacillus ferrooxidans to oxidize ferrous iron has been extensively studied in bioleaching to recover metal resources. Although immobilization of A. ferrooxidans is of great importance to achieve high bioleaching performance in practical application, the reported approaches of immobilization of A. ferrooxidans are still limited. This paper is attempting to develop a novel method to immobilize A. ferrooxidans by a less-costly effective carrier from zeolite, activated carbon, and cotton gauze. The results showed that cotton gauze was the most suitable carrier to immobilize A. ferrooxidans cells in comparison with zeolite and activated carbon. Acidithiobacillus ferrooxidans immobilized on the cotton gauze by gravity dehydration could achieve an average ferrous iron oxidation rate of 0.73 g/(L.h). Furthermore, the ferrous iron oxidation ratio attained in the bioreactor under batch operation was maintained above 97.83%. All results indicated that cotton gauze could be an efficient carrier for immobilizing A. ferrooxidans cells for the biooxidation of ferrous ions. PMID- 26621068 TI - Spliced leader RNA trans-splicing discovered in copepods. AB - Copepods are one of the most abundant metazoans in the marine ecosystem, constituting a critical link in aquatic food webs and contributing significantly to the global carbon budget, yet molecular mechanisms of their gene expression are not well understood. Here we report the detection of spliced leader (SL) trans-splicing in calanoid copepods. We have examined nine species of wild-caught copepods from Jiaozhou Bay, China that represent the major families of the calanoids. All these species contained a common 46-nt SL (CopepodSL). We further determined the size of CopepodSL precursor RNA (slRNA; 108-158 nt) through genomic analysis and 3'-RACE technique, which was confirmed by RNA blot analysis. Structure modeling showed that the copepod slRNA folded into typical slRNA secondary structures. Using a CopepodSL-based primer set, we selectively enriched and sequenced copepod full-length cDNAs, which led to the characterization of copepod transcripts and the cataloging of the complete set of 79 eukaryotic cytoplasmic ribosomal proteins (cRPs) for a single copepod species. We uncovered the SL trans-splicing in copepod natural populations, and demonstrated that CopepodSL was a sensitive and specific tool for copepod transcriptomic studies at both the individual and population levels and that it would be useful for metatranscriptomic analysis of copepods. PMID- 26621071 TI - Fluorescent probes for the selective detection of chemical species inside mitochondria. AB - During the last few years, the preparation of novel fluorescent probes for the selective detection of chemical species inside mitochondria has attracted considerable attention because of their wide applications in chemistry, biology, and medical science. This feature article focuses on the recent advances in the design principles and recognition mechanisms of these kinds of fluorescent probes. In addition, their applications for the detection of reactive oxygen species (ROS), nitric oxide, reactive sulfur species (RSS), thioredoxin (Trx), metal ions, anions, etc. in the mitochondrion is discussed as well. PMID- 26621072 TI - Twenty-Year Outcome After Right Ventricular Outflow Tract Repair Using Heterotopic Pulmonary Conduits in Infants and Children. AB - Durability of pulmonary conduits (PCs) used for reconstruction of the right ventricular outflow tract (RVOT) may be affected by a variety of factors. Among these, the technique used for PC implantation, whether in orthotopic or heterotopic position, strictly dependent upon the underlying anatomy, has been suggested to influence long-term outcome after RVOT repair. To determine the outcome of heterotopic implantation in infants and children treated at our institution, late results of heterotopic PC in non-Ross patients were analyzed and compared with data of orthotopic PC in age-matched pediatric Ross patients operated during the same time period. Between November 1991 and January 2015, 58 infants and children, 32 male and 26 female, with a median age of 9.4 years (range 1 day-18 years) underwent implantation of heterotopic PC (31 homografts [HG] and 27 xenografts [XG]) for reconstruction of RVOT. Median age in the XG group was significantly lower than in the HG group (0.9 vs. 13.4 years, P = 0.01), while male/female ratio was similar. Fifty (86%) patients had undergone one or more prior cardiac operations, while 32 (55%) required associated procedures during PC implantation. Comparison with data in 305 children and with a median age of 9.4 years, receiving orthotopic PC between 1990 and 2012 (Italian Pediatric Ross Registry), was undertaken. Descriptive, univariate, and Kaplan Meier analysis defined outcome. There were three (5.2%) early and five (9.0%) late deaths, during a median follow-up of 7.6 years (range 2 months-23 years). Patients having XG had trend toward higher hospital mortality (2/27 vs. 1/31, P = 0.2), but similar late mortality (2/24 vs. 3/30, P = 0.3). Overall survival was 88 and 62%, while freedom from PC replacement was 49 and 21%, at 10 and 20 years, respectively. The latter proved significantly worse than freedom from orthotopic PC replacement, which was 94 +/- 2 and 70 +/- 9% at 10 and 20 years (P = 0.02). When stratified for type of heterotopic PC, late survival proved comparable (81 and 81% for XG vs. 92 and 60% for HG, at 10 and 20 years, respectively, P = 0.7). However, freedom from PC replacement was significantly higher in patients with heterotopic HG (21 and 5% for XG vs. 63 and 48% for HG, at 10 and 20 years, respectively, P = 0.001). RVOT repair using either XG or HG in heterotopic position is a safe procedure associated with low hospital mortality and satisfactory late survival. Freedom from reoperation is significantly lower than that observed in age-matched children having orthotopic HG. Freedom from reoperation in heterotopic XG is poorer than in HG, although different baseline demography may have influenced this finding. PMID- 26621073 TI - High yield and ultrafast sources of electrically triggered entangled-photon pairs based on strain-tunable quantum dots. AB - Triggered sources of entangled photon pairs are key components in most quantum communication protocols. For practical quantum applications, electrical triggering would allow the realization of compact and deterministic sources of entangled photons. Entangled-light-emitting-diodes based on semiconductor quantum dots are among the most promising sources that can potentially address this task. However, entangled-light-emitting-diodes are plagued by a source of randomness, which results in a very low probability of finding quantum dots with sufficiently small fine structure splitting for entangled-photon generation (~10(-2)). Here we introduce strain-tunable entangled-light-emitting-diodes that exploit piezoelectric-induced strains to tune quantum dots for entangled-photon generation. We demonstrate that up to 30% of the quantum dots in strain-tunable entangled-light-emitting-diodes emit polarization-entangled photons. An entanglement fidelity as high as 0.83 is achieved with fast temporal post selection. Driven at high speed, that is 400 MHz, strain-tunable entangled-light emitting-diodes emerge as promising devices for high data-rate quantum applications. PMID- 26621074 TI - Assessing the dermal compatibility of a new female incontinence product line. AB - CONTEXT: We have developed a line of products designed to better meet the overall needs of women suffering from urinary incontinence. The products are more discrete and contain a unique odor neutralizing technology (ONT). OBJECTIVE: This paper describes the overall skin compatibility program for this product line in which the new products were compared to negative controls and/or commercially marketed reference products with an established history of safe use. MATERIALS AND METHODS: Test products consisted of several product forms (light pads/pantiliners, moderate pads, briefs and taped diapers) with ONT and having various degrees of protection. Studies were conducted using standard protocols for 4-day and 21-day cumulative irritation, the Human Repeat Insult Patch Test (HRIPT), and the Behind-the-Knee (BTK) test for mechanical and chemical irritation. In one 4-day irritation study and one HRIPT, test subjects consisted of individuals with self-assessed sensitive skin. In addition, one 4-day study was conducted using normal skin sites, and sites compromised by tape stripping. Nonirritant controls were physiologic saline and/or current, commercially marketed incontinence products. All responses were evaluated by visual scoring of erythema. In addition, in the BTK, transepidermal water loss (TEWL) and adverse sensory effects collected from panelists' daily diaries were also evaluated. RESULTS AND DISCUSSION: Two 4-day cumulative irritation studies and one 21-day study demonstrated that a wide range of product forms (liners, light and moderate pads, briefs and adult diapers) produced skin reactions similar to the nonirritant controls. The 4-day study conducted using sensitive skin subjects showed good skin compatibility, and the test products were comparable to the nonirritant controls. In the 4-day study with both normal and compromised skin sites, test products produced mean erythema scores similar to the nonirritant controls. Three HRIPT separate studies confirm that the products do not induce contact sensitization, including one study conducted on individuals with self assessed sensitive skin. In the BTK, test and control products produced similar irritation, as assessed by erythema, TEWL and sensory effects. CONCLUSION: The results from the patch tests and mechanical irritation test demonstrate good skin compatibility of the new line of products with the unique ONT. In addition, the forms of the product (i.e. liner, pad or brief), were equally compatible with skin. PMID- 26621076 TI - Predictors of long-term work disability among patients with type I and II bipolar disorder: a prospective 18-month follow-up study. AB - OBJECTIVES: Bipolar disorder (BD) is one of the leading causes of disability worldwide. However, vocational ability and predictors of long-term work disability have rarely been studied among patients with BD. We investigated clinical predictors of work disability among patients with BD in psychiatric care. METHODS: The Jorvi Bipolar Study (JoBS) is a naturalistic prospective cohort study (N = 191) representing adult (18-59 years) psychiatric inpatients and outpatients with DSM-IV bipolar I disorder (BD-I) and bipolar II disorder (BD II) in three Finnish cities. Within the JoBS, we investigated the prevalence of disability pensions at baseline, and predictors for being granted a disability pension during an 18-month follow-up of the 151 patients in the labor force at baseline. Cox models were used to determine predictors for onset of disability pension. RESULTS: At baseline, 21% (40/191) of the patients already had a disability pension. During the follow-up, a further 38 patients (25% of the 151 followed) were granted a new disability pension. The predictors included older age, male gender, depressive index episode, higher number of psychiatric hospitalizations, generalized anxiety disorder, avoidant personality disorder, and depressive burden during follow-up. However, the predictors differed depending on bipolar subtype, age, and gender. CONCLUSIONS: BD-I and BD-II are associated with a major risk of long-term work disability, the proportion of patients with a disability pension rising to 41% in the medium-term follow-up of the Finnish cohort investigated in the present study. Severe clinical course, depression, comorbidities, age, and gender are likely to be the main predictors but predictors may vary depending on the subgroup. PMID- 26621075 TI - Exploring molecular variation in Schistosoma japonicum in China. AB - Schistosomiasis is a neglected tropical disease that affects more than 200 million people worldwide. The main disease-causing agents, Schistosoma japonicum, S. mansoni and S. haematobium, are blood flukes that have complex life cycles involving a snail intermediate host. In Asia, S. japonicum causes hepatointestinal disease (schistosomiasis japonica) and is challenging to control due to a broad distribution of its snail hosts and range of animal reservoir hosts. In China, extensive efforts have been underway to control this parasite, but genetic variability in S. japonicum populations could represent an obstacle to eliminating schistosomiasis japonica. Although a draft genome sequence is available for S. japonicum, there has been no previous study of molecular variation in this parasite on a genome-wide scale. In this study, we conducted the first deep genomic exploration of seven S. japonicum populations from mainland China, constructed phylogenies using mitochondrial and nuclear genomic data sets, and established considerable variation between some of the populations in genes inferred to be linked to key cellular processes and/or pathogen-host interactions. Based on the findings from this study, we propose that verifying intraspecific conservation in vaccine or drug target candidates is an important first step toward developing effective vaccines and chemotherapies against schistosomiasis. PMID- 26621078 TI - Development of a sensitive, competitive, indirect ELISA for the detection of fumonisin B1 in corn originating from Anhui province, China. AB - Fumonisin B1 (FB1) is a secondary metabolite produced by Fusarium verticillioides or Fusarium proliferatum, which present in food and feed. It causes hazardous effects on human and animal health. A monoclonal antibody (mAb) against FB1 was produced and a simple, reliable and sensitive, competitive, indirect enzyme linked immunosorbent assay (ci-ELISA) for detection of FB1 was developed and the experiment conditions were optimized. The coating concentration of FB1-ovalbumin (FB1-OVA) was 500 ng mL-1, the action concentrations of anti-FB1 mAb and goat anti-mouse IgG were 1.28 * 104 and 1:5000, respectively. The 50% inhibitory concentration (IC50) was 11 ng mL-1, with a detectable range of 1.25-250 ng mL-1, and a limit of determination (LOD) of 1.15 ng mL-1. The cross-reactivity (CR) of the antibody against fumonisin B2 (FB2) was 60.4, and <1% against deoxynivalenol (DON), aflatoxin B1 (AFB1), ochratoxin A (OTA) or zearalenone (ZEN). In spiked samples (250 ng g-1, 500 ng g-1, 1000 ng g-1), the mean recoveries ranged from 86.7 +/- 5% to 102 +/- 4%, and the coefficient of variation (CV) ranged from 3% to 10%. A survey of 96 corn samples from Bozhou, Fuyang, Bengbu, and Hefei, in Anhui province, China, was performed. Frequencies of FB1 contamination were 83.3%, 95.8%, 20.8% and 91.7%, and the mean concentrations of positive samples were 0.702 MUg kg-1, 0.883 MUg kg-1, 0.074 MUg kg-1, and 0.276 MUg kg-1, respectively. The results of this study suggest that the ci-ELISA developed in this study can be used to identify FB1 in corn, furthermore, further study is needed to investigate FB1 contamination in food and feed to prevent its harmful health effects. PMID- 26621077 TI - Synchrotron FTIR micro-spectroscopy for structural analysis of Lewy bodies in the brain of Parkinson's disease patients. AB - Lewy bodies (LBs), which mainly consist of alpha-synuclein (alpha-syn), are neuropathological hallmarks of patients with Parkinson's disease (PD). The fine structure of LBs is unknown, and LBs cannot be made artificially. Nevertheless, many studies have described fibrillisation using recombinant alpha-syn purified from E. coli. An extremely fundamental problem is whether the structure of LBs is the same as that of recombinant amyloid fibrils. Thus, we used synchrotron Fourier transform infrared micro-spectroscopy (FTIRM) to analyse the fine structure of LBs in the brain of PD patients. Our results showed a shift in the infrared spectrum that indicates abundance of a beta-sheet-rich structure in LBs. Also, 2D infrared mapping of LBs revealed that the content of the beta-sheet structure is higher in the halo than in the core, and the core contains a large amount of proteins and lipids. PMID- 26621079 TI - Hyaluronic acid/carboxymethyl cellulose directly applied to transected nerve decreases axonal outgrowth. AB - Neuroma management is an unresolved problem. Biomaterials to limit unwanted axonal growth could be a tool to manage neuroma. Hyaluronic acid/carboxymethyl cellulose (HA/CMC) is an antiadhesive, biodegradable material that is nontoxic to nerve. The purpose of this study was to evaluate the efficacy of this biomaterial to limit axonal growth. Rats received a sciatic nerve transection and repair with a short conduit (5 mm) containing HA/CMC, fibrin, or nothing (empty conduit). In another study, nerve was transected and either left undisturbed or wrapped with HA/CMC around the proximal and distal ends. In a final study, nerve was transected and repaired with an HA/CMC wrap. Four weeks following the procedures, nerves were harvested and assessed using histomorphometry to measure axonal regeneration. Axonal regeneration following transection was significantly inhibited by direct axonal contact with HA/CMC, whether within a conduit or wrapped around the transected proximal nerve end. Axonal regeneration following epineurial repair was not affected by HA/CMC wrapped around nerve, demonstrating axonal growth inhibition due to direct contact of regenerating axons with HA/CMC. These studies demonstrate the efficacy of HA/CMC to limit axonal outgrowth by contact with regenerating axons. HA/CMC barriers may prove to be a tool to prevent neuroma formation by inhibiting axonal growth. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 568-574, 2017. PMID- 26621080 TI - Complete genome sequence of Hymenobacter sp. DG25B, a novel bacterium with gamma radiation resistance isolated from soil in South Korea. AB - A Gram-negative, rod-shaped, non-motile, gamma and UV radiation resistant bacterium Hymenobacter radioresistens DG25B was isolated from a soil sample collected in South Korea. The complete genome sequence of H. radioresistens DG25B consists of one circular chromosome (3,874,646 bp). The bacterium was isolated from gamma ray irradiated soil and contains the genomic features of enzymes involved in the nucleotide excision repair (NER) pathway that protect the damaged DNA. The genome also contains other genes involved in the efficient removal of double-strand breaks (DSB) caused by the ionizing radiations. PMID- 26621082 TI - Application of the Electrostatically Embedded Many-Body Expansion to Microsolvation of Ammonia in Water Clusters. AB - The electrostatically embedded many-body expansion (EE-MB), at both the second and third order, that is, the electrostatically embedded pairwise additive (EE PA) approximation and the electrostatically embedded three-body (EE-3B) approximation, are tested for mixed ammonia-water clusters. We examine tetramers, pentamers, and hexamers for three different density functionals and two levels of wave function theory, We compare the many-body results to the results of full calculations performed without many-body expansions. Because of the differing charge distributions in the two kinds of monomers, this provides a different kind of test of the usefulness of the EE-MB method than was provided by previous tests on pure water clusters. We find only small errors due to the truncation of the many-body expansion for the mixed clusters. In particular, for tests on tetramers and pentamers, the mean absolute deviations for truncation at second order are 0.36-0.98 kcal/mol (average: 0.66 kcal/mol), and the mean absolute deviations for truncation at third order are 0.04-0.28 (average: 0.16 kcal/mol). These may be compared to a spread of energies as large as 4.24 kcal/mol in the relative energies of various structures of pentamers and to deviations of up to 8.57 kcal/mol of the full calculations of relative energies from the best estimates of the relative energies. When the methods are tested on hexamers, the mean unsigned deviation per monomer remains below 0.10 kcal/mol for EE-PA and below 0.03 kcal/mol for EE-3B. Thus the additional error due to the truncation of the expansion is small compared to the accuracy needed or the other approximations involved in practical calculations. This means that the EE-MB expansion in combination with density functional theory or wave function theory for the oligomers provides a useful practical model chemistry for making electronic structure calculations and simulations more affordable by improving the scaling with respect to system size. PMID- 26621081 TI - Comparative transcriptomic analysis of Clostridium acetobutylicum biofilm and planktonic cells. AB - Biofilm-based immobilization of solventogenic Clostridia has been extensively exploited to overcome traditional bottlenecks in biobutanol production like solvent toxicity and low productivities. However, the molecular basis of solventogenic Clostridia biofilm is rarely explored. Here, for the first time, we report DNA array-based study of Clostridium acetobutylicum biofilm cells to elucidate the transcriptional modulation. Results showed that 16.2% of the C. acetobutylicum genome genes within the biofilm cells were differentially expressed, with most genes being up-regulated. The most dramatic changes occurred with amino acid biosynthesis, with sulfur uptake and cysteine biosynthesis being the most up-regulated and histidine biosynthesis being the most down-regulated in the biofilm cells. It was demonstrated that C. acetobutylicum biofilm cells increased metabolic activities probably by up-regulating iron and sulfur uptake and Fe-S cluster biosynthesis genes as well as glycolysis genes. Furthermore, genes involved in sporulation, granulose formation, extracellular polymer degradation, pentose catabolisms, and various other processes were also notably regulated, indicating that the biofilm mode of growth rendered the cells a distinct phenotype. This study provides valuable insights into the transcriptional regulation in C. acetobutylicum biofilm cells and should be highly useful for understanding and developing the biofilm-based processes. PMID- 26621083 TI - Visualization of Molecular Orbitals and the Related Electron Densities. AB - When plotting different orbitals with consistent contour values, one can create illusions about the relative extension of charge distributions. We suggest that the comparison is not biased when plots reproduce the same fraction of the total charge. We have developed an algorithm and software that facilitate this type of visualization. We propose superimposing molecules and associated orbitals, and creating cross-sections by selecting a particular part of the orbital limited by pre-defined planes. PMID- 26621084 TI - Cholesky Decomposition-Based Multiconfiguration Second-Order Perturbation Theory (CD-CASPT2): Application to the Spin-State Energetics of Co(III)(diiminato)(NPh). AB - The electronic structure and low-lying electronic states of a Co(III)(diiminato)(NPh) complex have been studied using multiconfigurational wave function theory (CASSCF/CASPT2). The results have been compared to those obtained with density functional theory. The best agreement with ab initio results is obtained with a modified B3LYP functional containing a reduced amount (15%) of Hartree-Fock exchange. A relativistic basis set with 869 functions has been employed in the most extensive ab initio calculations, where a Cholesky decomposition technique was used to overcome problems arising from the large size of the two-electron integral matrix. It is shown that this approximation reproduces results obtained with the full integral set to a high accuracy, thus opening the possibility to use this approach to perform multiconfigurational wave function-based quantum chemistry on much larger systems relative to what has been possible until now. PMID- 26621085 TI - Electronic Structures of AlGaN2 Nanotubes and AlN-GaN Nanotube Superlattice. AB - The electronic properties of single-wall AlGaN2 nanotubes were investigated using first-principles calculations and generalized gradient approximation. All AlGaN2 nanotubes considered are semiconductors, but their band structures depend on their chirality and size due to curvature effect and symmetry. The zigzag AlGaN2 nanotubes are direct band gap semiconductors, while armchair AlGaN2 nanotubes are indirect band gap semiconductors. The calculations on the electronic properties of AlN-GaN nanotubes superlattice show that the band gap engineering can be realized by changing the composition of the AlN-GaN nanotubes superlattice. PMID- 26621086 TI - Density Functional and Basis Set Dependence of Hydrated Ln(III) Properties. AB - Benchmark studies of Ln(H2O)1,8-9(3+) (Ln = La, Lu) have been performed to assess the calculated properties obtained with local density approximation, generalized gradient approximation (GGA), meta-GGA, and hybrid functionals, when used with small- and large-core relativistic effective core potentials and their associated bases. Basis set dependence and the importance of specific functions to adequately describe the Ln atomic orbitals have been determined. The lanthanide contraction has been found to be an insufficient metric for characterizing the quality of a method/basis set combination due to cancellation of the errors. The electrostatic description obtained by natural population analysis has been examined, and an alternative partitioning of the valence space, which includes the 6s6p5d4f natural atomic orbitals, has been proposed. PMID- 26621087 TI - Basis Set Convergence of Nuclear Magnetic Shielding Constants Calculated by Density Functional Methods. AB - The previously proposed polarization consistent basis sets, optimized for density functional calculations, are evaluated for calculating nuclear magnetic shielding constants. It is shown that the basis set convergence can be improved by adding a single p-type function with a large exponent and allowing for a slight decontraction of the p functions. The resulting pcS-n basis sets should be suitable for calculating nuclear magnetic shielding constants with density functional methods and are shown to perform significantly better than existing alternatives for a comparable computational cost. PMID- 26621088 TI - Ab Initio Highly Correlated Conformational Analysis of 1,2-Difluorethane and 1,2 Dichloroethane. AB - Temperature-dependent conformational population calculations for anti and gauche forms of 1,2-dichloroethane and 1,2-difluorethane were carried out at a highly correlated level of theory (MP4(SDTQ) and CCSD(T)) employing good quality basis sets (6-311++G(3df,3pd) and aug-cc-pVQZ) for the determination of gas relative conformational energies, making use of the statistical thermodynamics formalism for the evaluation of the thermal energy correction at the MP2/6-311++G(3df,3pd) and MP2/aug-cc-pVTZ levels. In addition to the standard calculation of thermodynamic partition functions, a treatment of the lowest-frequency vibrational mode as hindered rotation and anharmonic correction to vibrational frequencies was also included. We found a good agreement between ab initio calculated conformational population values and experimental gas-phase electron diffraction data for the 1,2-dicloroethane. However, for the 1,2-difluorethane species, a reasonable agreement with the experimental anti/gauche population ratio obtained from the analysis of gas-phase far-infrared (50-370 cm(-1)) and low-frequency Raman (70-300 cm(-1)) spectra was not obtained. The results reported here indicate that, for 1,2-difluorethane, and probably other substituted alkanes where the gauche effect is of relevance, a more appropriated treatment of the low-frequency modes must be pursued in order to reproduce experimental conformational population data. PMID- 26621089 TI - Structural and Energetic Study of Cisplatin and Derivatives: Comparison of the Performance of Density Funtional Theory Implementations. AB - In this work, we compare the performance of different DFT implementations, using analytical and numerical basis sets for the expansion of the atomic wave function, in determining structural and energetic parameters of Cisplatin and some biorelevant derivatives. Characterization of the platinum-containing species was achieved at the HF, MP2, and DFT (PBE1PBE, mPW1PW91, B3LYP, B3PW91, and B3P86) levels of theory, using two relativistic effective core potentials to treat the Pt atom (LanL2DZ and SBK), together with analytical Gaussian-type basis sets as implemented in Gaussian03. These results were compared with those obtained with the SIESTA code that employs a pseudopotential derived from the Troullier-Martins procedure for the Pt atom and numerical pseudoatomic orbitals as basis set. All modeled properties were also compared with the experimental values when available or to the best theoretical calculations known to date. On the basis of the results, SIESTA is an excellent alternative to determine structure and energetics of platinum complexes derived from Cisplatin, with less computational efforts. This validates the use of the SIESTA code for this type of chemical systems and thus provides a computationally efficient quantum method (capable to linear scaling at large sizes and available in QM/MM implementations) for exploring larger and more complex chemical models which shall reproduce more faithfully the real chemistry of Cisplatin in physiological conditions. PMID- 26621090 TI - Development and Validation of the B3LYP/N07D Computational Model for Structural Parameter and Magnetic Tensors of Large Free Radicals. AB - Extensive calculations on a large set of free radicals containing atoms of the second and third row show that the B3LYP/N07D computational model provides remarkably accurate structural parameters and magnetic tensors at reasonable computational costs. The key of this success is the optimization of core-valence s functions for hyperfine coupling constants, while retaining (and even improving) the good performances of the parent 6-31+G(d,p) basis set for valence properties through reoptimization of polarization and diffuse p functions. PMID- 26621091 TI - CHARMM Additive All-Atom Force Field for Acyclic Carbohydrates and Inositol. PMID- 26621092 TI - Car-Parrinello Molecular Dynamics Simulations of CaCl2 Aqueous Solutions. AB - Car-Parrinello molecular dynamics (CPMD) simulations are used to investigate the structural properties of 1 and 2 molal (m) CaCl2 aqueous solutions and, in particular, the radial distribution functions, coordination numbers, and dipole moments of water molecules in the first solvation shell. According to these simulations, the first solvation shell of the Ca(2+) ion consists of six water molecules, that are characterized by an increased averaged dipole moment compared to that of bulk water, and a first-shell Ca-O radial distribution function peak at 2.39 A. The results are compared to those of CPMD simulations of Ca(2+) (no counterions), and no significant differences are found. This indicates that the homogeneous neutralizing background charge density implicitly included in simulations of non-neutral systems appropriately mimics the presence of the counterions (at least in terms of reproducing the solvation structure properties and for the box sizes considered). Classical molecular dynamics (MD) simulations of aqueous Ca(2+) using varying box sizes confirm this suggestion. The CPMD simulations at 2 m concentration also reveal additional possibilities for the structural arrangement of water molecules and chloride ions around Ca(2+). In particular, they support the stability of Ca(2+)-Cl(-) (contact) and Ca(2+)-H2O Cl(-) (solvent-separated) ion pairs. In addition, the solvent-separated cation pair is found to occur in a deprotonated Ca(2+)-OH(-)-Ca(2+) form. The existence of such a species has, to our knowledge, never been invoked previously to account for experimental data on CaCl2 solutions. PMID- 26621093 TI - Electrostatically Embedded Multiconfiguration Molecular Mechanics Based on the Combined Density Functional and Molecular Mechanical Method. AB - We present a new method for generating global or semiglobal potential energy surfaces in the presence of an electrostatic potential; the new method can be used to model chemical reactions in solution or in an enzyme, nanocavity, or other chemical environment. The method extends the multiconfiguration molecular mechanics method so that the energy depends on the electrostatic potential at each atomic center. The charge distribution of the system can also be calculated. We illustrate the method by applying it to the symmetric bimolecular reaction Cl( ) + CH3Cl' -> ClCH3 + Cl'(-) in aqueous solution, where the potential energy information is obtained by the combined density functional and molecular mechanical method, that is, by the combined quantum mechanical and molecular mechanical method (QM/MM) with the QM level being density functional theory. It is found that we can describe a semiglobal potential energy surface in aqueous solution with electronic structure information obtained entirely in the gas phase, including the linear and quadratic responses to variations in the electrostatic potential distribution. The semiglobal potential energy surface calculated by the present method is in good agreement with that calculated directly without any fitting. PMID- 26621094 TI - Tight-Binding Configuration Interaction (TBCI): A Noniterative Approach to Incorporating Electrostatics into Tight Binding. AB - We present a new electronic structure approximation called Tight Binding Configuration Interaction. It uses a tight-binding Hamiltonian to obtain orbitals that are used in a configuration interaction calculation that includes explicit charge interactions. This new method is better capable of predicting energies, ionization potentials, and fragmentation charges than the Wolfsberg-Helmholz Tight-Binding and Many-Body Tight-Binding models reported earlier (Staszewska, G.; Staszewski, P.; Schultz, N. E.; Truhlar, D. Phys. Rev. B 2005, 71, 045423). The method is illustrated for clusters and nanoparticles containing aluminum. PMID- 26621095 TI - The MARTINI Coarse-Grained Force Field: Extension to Proteins. AB - Many biologically interesting phenomena occur on a time scale that is too long to be studied by atomistic simulations. These phenomena include the dynamics of large proteins and self-assembly of biological materials. Coarse-grained (CG) molecular modeling allows computer simulations to be run on length and time scales that are 2-3 orders of magnitude larger compared to atomistic simulations, providing a bridge between the atomistic and the mesoscopic scale. We developed a new CG model for proteins as an extension of the MARTINI force field. Here, we validate the model for its use in peptide-bilayer systems. In order to validate the model, we calculated the potential of mean force for each amino acid as a function of its distance from the center of a dioleoylphosphatidylcholine (DOPC) lipid bilayer. We then compared amino acid association constants, the partitioning of a series of model pentapeptides, the partitioning and orientation of WALP23 in DOPC lipid bilayers and a series of KALP peptides in dimyristoylphosphatidylcholine and dipalmitoylphosphatidylcholine (DPPC) bilayers. A comparison with results obtained from atomistic models shows good agreement in all of the tests performed. We also performed a systematic investigation of the partitioning of five series of polyalanine-leucine peptides (with different lengths and compositions) in DPPC bilayers. As expected, the fraction of peptides partitioned at the interface increased with decreasing peptide length and decreasing leucine content, demonstrating that the CG model is capable of discriminating partitioning behavior arising from subtle differences in the amino acid composition. Finally, we simulated the concentration-dependent formation of transmembrane pores by magainin, an antimicrobial peptide. In line with atomistic simulation studies, disordered toroidal pores are formed. In conclusion, the model is computationally efficient and effectively reproduces peptide-lipid interactions and the partitioning of amino acids and peptides in lipid bilayers. PMID- 26621096 TI - Computational Studies of the X-Linked Inhibitor of Apoptosis Complex Formation with Caspase-9 and a Small Antagonist. AB - Apoptosis is self-programmed cell death. The X-linked inhibitor of apoptosis (XIAP) is known to inhibit caspase proteins, the key players in apoptosis. When this happens, the cells become cancerous as they cannot die naturally. XIAP inhibitors are often overexpressed in cancer tissue. Presented in this article are the results of simulations of XIAP-caspase and XIAP-antagonist complexes. It has been previously established experimentally that low intensity ultrasound promotes apoptosis and increases the therapeutic effect of some XIAP-caspase interaction antagonists. The resulting calculated complex formation energies produced in this work were used with a simple multiscale model as an example of applying such energetic results for estimating the effects of ultrasound on these complexes. The microscopic simulations have been carried out with molecular mechanics employing an all-atom description of the molecules with the OPLS-AA and polarizable force field (PFF) formalisms. It has been determined that the interaction energies in the XIAP-caspase-9 pair with both OPLS and PFF are roughly the same and in the 30-40 kcal/mol range, while PFF predicts a higher magnitude of energy of the XIAP-antagonist complex formation (ca. 100 kcal/mol vs ca. 40 kcal/mol), thus probably being more adequate in reproducing the inhibition abilities of this low molecular weight antagonist. The presented study of the ultrasound effect leads to the conclusion that it is most likely based on the cavitation accompanying the ultrasound irradiation of the cells and not on a simple frequency resonance, as was suggested by some authors. PMID- 26621097 TI - JA, a new type of polyunsaturated fatty acid isolated from Juglans mandshurica Maxim, limits the survival and induces apoptosis of heptocarcinoma cells. AB - Juglans mandshurica Maxim (Juglandaceae) is a famous folk medicine for cancer treatment and some natural compounds isolated from it have been studied extensively. Previously we isolated a type of omega-9 polyunsaturated fatty acid (JA) from the bark of J. mandshurica, however little is known about its activity and the underlying mechanisms. In this study, we studied anti-tumor activity of JA on several human cancer cell lines. Results showed that JA is cytotoxic to HepG2, MDA-MB-231, SGC-7901, A549 and Huh7 cells at a concentration exerting minimal toxic effects on L02 cells. The selective toxicity of JA was better than other classical anti-cancer drugs. Further investigation indicated that JA could induce cell apoptosis, characterized by chromatin condensation, DNA fragmentation and activation of the apoptosis-associated proteins such as Caspase-3 and PARP-1. Moreover, we investigated the cellular apoptosis pathway involved in the apoptosis process in HepG2 cells. We found that proteins involved in mitochondrion (cleaved-Caspase-9, Apaf-1, HtrA2/Omi, Bax, and Mitochondrial Bax) and endocytoplasmic reticulum (XBP-1s, GRP78, cleaved-Caspase-7 and cleaved Caspase-12) apoptotic pathways were up-regulated when cells were treated by JA. In addition, a morphological change in the mitochondrion was detected. Furthermore, we found that JA could inhibit DNA synthesis and induce G2/M cell cycle arrest. The expression of G2-to-M transition related proteins, such as CyclinB1 and phosphorylated-CDK1, were reduced. In contrast, the G2-to-M inhibitor p21 was increased in JA-treated cells. Overall, our results suggest that JA can induce mitochondrion- and endocytoplasmic reticulum-mediated apoptosis, and G2/M phase arrest in HepG2 cells, making it a promising therapeutic agent against hepatoma. PMID- 26621098 TI - Examining the Effectiveness of Climate Change Frames in the Face of a Climate Change Denial Counter-Frame. AB - Prior research on the influence of various ways of framing anthropogenic climate change (ACC) do not account for the organized ACC denial in the U.S. media and popular culture, and thus may overestimate these frames' influence in the general public. We conducted an experiment to examine how Americans' ACC views are influenced by four promising frames for urging action on ACC (economic opportunity, national security, Christian stewardship, and public health)-when these frames appear with an ACC denial counter-frame. This is the first direct test of how exposure to an ACC denial message influences Americans' ACC views. Overall, these four positive frames have little to no effect on ACC beliefs. But exposure to an ACC denial counter-frame does significantly reduce respondents' belief in the reality of ACC, belief about the veracity of climate science, awareness of the consequences of ACC, and support for aggressively attempting to reduce our nation's GHG emissions in the near future. Furthermore, as expected by the Anti-Reflexivity Thesis, exposure to the ACC denial counter-frame has a disproportionate influence on the ACC views of conservatives (than on those of moderates and liberals), effectively activating conservatives' underlying propensity for anti-reflexivity. PMID- 26621099 TI - Towards an automatic early stress recognition system for office environments based on multimodal measurements: A review. AB - Stress is a major problem of our society, as it is the cause of many health problems and huge economic losses in companies. Continuous high mental workloads and non-stop technological development, which leads to constant change and need for adaptation, makes the problem increasingly serious for office workers. To prevent stress from becoming chronic and provoking irreversible damages, it is necessary to detect it in its early stages. Unfortunately, an automatic, continuous and unobtrusive early stress detection method does not exist yet. The multimodal nature of stress and the research conducted in this area suggest that the developed method will depend on several modalities. Thus, this work reviews and brings together the recent works carried out in the automatic stress detection looking over the measurements executed along the three main modalities, namely, psychological, physiological and behavioural modalities, along with contextual measurements, in order to give hints about the most appropriate techniques to be used and thereby, to facilitate the development of such a holistic system. PMID- 26621100 TI - Development and Validation of a Fully Automated Platform for Extended Blood Group Genotyping. AB - Thirty-five blood group systems, containing >300 antigens, are listed by the International Society of Blood Transfusion. Most of these antigens result from a single nucleotide polymorphism. Blood group typing is conventionally performed by serology. However, this technique has some limitations and cannot respond to the growing demand of blood products typed for a large number of antigens. The knowledge of the molecular basis of these red blood cell systems allowed the implementation of molecular biology methods in immunohematology laboratories. Here, we describe a blood group genotyping assay based on the use of TKL immobilization support and microarray-based HIFI technology that takes approximately 4 hours and 30 minutes from whole-blood samples to results analysis. Targets amplified by multiplex PCR were hybridized on the chip, and a revelation step allowed the simultaneous identification of up to 24 blood group antigens, leading to the determination of extended genotypes. Two panels of multiplex PCR were developed: Panel 1 (KEL1/2, KEL3/4; JK1/2; FY1/2; MNS1/2, MNS3/4, FY*Fy et FY*X) and Panel 2 (YT1/2; CO1/2; DO1/2, HY+, Jo(a+); LU1/2; DI1/2). We present the results of the evaluation of our platform on a panel of 583 and 190 blood donor samples for Panel 1 and 2, respectively. Good correlations (99% to 100%) with reference were obtained. PMID- 26621101 TI - Characterization of 137 Genomic DNA Reference Materials for 28 Pharmacogenetic Genes: A GeT-RM Collaborative Project. AB - Pharmacogenetic testing is increasingly available from clinical laboratories. However, only a limited number of quality control and other reference materials are currently available to support clinical testing. To address this need, the Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetic testing community and the Coriell Cell Repositories, has characterized 137 genomic DNA samples for 28 genes commonly genotyped by pharmacogenetic testing assays (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP4F2, DPYD, GSTM1, GSTP1, GSTT1, NAT1, NAT2, SLC15A2, SLC22A2, SLCO1B1, SLCO2B1, TPMT, UGT1A1, UGT2B7, UGT2B15, UGT2B17, and VKORC1). One hundred thirty-seven Coriell cell lines were selected based on ethnic diversity and partial genotype characterization from earlier testing. DNA samples were coded and distributed to volunteer testing laboratories for targeted genotyping using a number of commercially available and laboratory developed tests. Through consensus verification, we confirmed the presence of at least 108 variant pharmacogenetic alleles. These samples are also being characterized by other pharmacogenetic assays, including next-generation sequencing, which will be reported separately. Genotyping results were consistent among laboratories, with most differences in allele assignments attributed to assay design and variability in reported allele nomenclature, particularly for CYP2D6, UGT1A1, and VKORC1. These publicly available samples will help ensure the accuracy of pharmacogenetic testing. PMID- 26621102 TI - The expression of SEIPIN in the mouse central nervous system. AB - Immunohistochemical staining was used to investigate the expression pattern of SEIPIN in the mouse central nervous system. SEIPIN was found to be present in a large number of areas, including the motor and somatosensory cortex, the thalamic nuclei, the hypothalamic nuclei, the mesencephalic nuclei, some cranial motor nuclei, the reticular formation of the brainstem, and the vestibular complex. Double labeling with NeuN antibody confirmed that SEIPIN-positive cells in some nuclei were neurons. Retrograde tracer injections into the spinal cord revealed that SEIPIN-positive neurons in the motor and somatosensory cortex and other movement related nuclei project to the mouse spinal cord. The present study found more nuclei positive for SEIPIN than shown using in situ hybridization and confirmed the presence of SEIPIN in neurons projecting to the spinal cord. The results of this study help to explain the clinical manifestations of patients with Berardinelli-Seip congenital lipodystrophy (Bscl2) gene mutations. PMID- 26621103 TI - Role of renal expression of CD68 in the long-term prognosis of proliferative lupus nephritis. AB - INTRODUCTION: Renal histology of proliferative lupus nephritis (LN) shows increased macrophage infiltration, but its association with renal outcome is a matter of debate. Here, we investigate the potential relationship that macrophage expression has with renal prognosis in patients with proliferative LN. METHODS: Fifty patients newly diagnosed with proliferative LN were followed for a median of 8 years. Laboratory testing was conducted at diagnosis, after induction therapy and at the final follow-up evaluation. Renal biopsies were obtained at diagnosis and underwent immunohistochemical analysis with anti-CD68 and monocyte chemoattractant protein 1 monoclonal antibodies. Patients were stratified at final follow-up evaluation into glomerular filtration rate (GFR) >60 ml/min/1.73 m2 (non-progressor group; n = 24) and GFR <=60 ml/min/1.73 m2 (progressor group; n = 26). All patients were treated with prednisone and six pulses of cyclophosphamide on induction therapy. Conventional maintenance therapy was administered in both groups. RESULTS: Compared to progressors, the non-progressor group showed a lower chronicity index (p = 0.01) and fewer CD68-positive cells in the renal tubules (p = 0.01) and particularly in the renal interstitium (p = 0.0003). Baseline and final serum creatinine correlated positively with the chronicity index (r = 0.3, p = 0.01 and r = 0.3, p = 0.04, respectively), and final serum creatinine correlated positively with interstitial expression of CD68 (r = 0.4, p = 0.0006). CONCLUSION: Renal expression of CD68 and the chronicity index are associated with progression to chronic kidney disease in patients with proliferative LN. PMID- 26621104 TI - Simultaneous abdominal wall defect repair and Tenckhoff catheter placement in candidates for peritoneal dialysis. AB - INTRODUCTION: The presence of pre-existing abdominal wall defect (AWD) could represent a potential contraindication for peritoneal dialysis (PD) treatment. We report the results of our 6-year experience involving simultaneous repair of pre existing AWD and catheter insertion for PD. METHODS: Patients with estimated glomerular filtration rate (e-GFR) 7-10 ml/min attending a single nephrology clinic between January 2008 and December 2014 were evaluated. Simultaneous AWD repair and catheter placement was performed. For inguinal (IH) or umbilical hernia (UH), a prolene mesh repair technique was adopted. Except for one case of total anaesthesia, the surgical procedure was performed under either spinal or local anaesthesia. Ceftazidime alone or in association with quinolones was administered 1 h before surgery in a single dose. Patients were discharged 2 days after surgery, and returned to the clinic twice during the 1st week for peritoneum washing (first volume of peritoneal dialysis solution: 300 ml). From week 3, volume (2000 ml) and dwells were personalized according to the patient's clinical condition; options were: incremental PD, standard PD, or continuous cycling PD. Surgical follow-up was planned at 1, 6, and 12 months. RESULTS: Peritoneal catheters were inserted in 170 patients. IH, UH and incisional hernia were found in 18, 2 and 1 patients, respectively. IH was bilateral in 4 patients; concomitant IH and UH occurred in 1 patient. There were no deaths, nor intra operative complications apart from scrotal haematoma in 1 patient. Over a mean follow-up of 551 days (range 342-1274) no hernia recurrence was registered and the peritoneal catheter continued functioning without problems. CONCLUSIONS: Simultaneous AWD repair and peritoneal catheter placement seems a reliable and safe surgical procedure that allows patients with AWD to benefit from PD treatment. PMID- 26621105 TI - The relationship between contraceptive use and maternal and infant health outcomes in Tajikistan. AB - OBJECTIVE: There has been no evaluation of the association between contraceptive use and maternal and child health (MCH) in Tajikistan, though the government has made concerted efforts to improve accessibility to family planning methods. The aim of this study is to understand the relationship between current contraceptive utilization and specific MCH outcomes in Tajikistan. STUDY DESIGN: Using data from the 2012 Tajikistan Demographic and Health Survey, a total weighted sample of 6716 women aged 15 to 49 years who had at least one child at the time of interview was analyzed. Logistic regression analyses were performed to assess the relationship between current contraceptive utilization and birth spacing, birth limiting and infant mortality. RESULTS: Modern contraceptive use was low among women studied (27.1%). Modern contraceptive users were more likely to present with a longer birth interval [adjusted odds ratio (aOR) = 2.4, 95% confidence interval (CI) = 2.0-2.8] than traditional or nonusers. Women who used modern contraceptives were half as likely to limit births to three or fewer children compared to traditional or nonusers (aOR = 0.5, 95% CI = 0.4-0.6). Among women whose most recent live birth resulted in death, modern contraceptive use was not associated with lower levels of infant mortality. CONCLUSION: Efforts made by the Tajik government to increase utilization of family planning have had mixed effects on overall uptake and the MCH outcomes analyzed in this study. These findings can help to inform the government's policy on family planning. IMPLICATIONS: Contraceptive utilization has not yet translated into beneficial MCH outcomes. Policy makers in Tajikistan might consider placing more emphasis on family planning education, while maximizing accessibility of contraceptive methods. PMID- 26621109 TI - Long Term Follow-up of Pulmonary Vein Isolation Using Cryoballoon Ablation. AB - BACKGROUND: Cryoballoon ablation is an established catheter-based approach to treating atrial fibrillation (AF). There is little data regarding the long-term efficacy of this approach. METHODS: We enrolled 200 consecutive patients with symptomatic AF who had failed therapy with at least one anti-arrhythmic medication and followed them for five years. The primary efficacy endpoint was symptomatic recurrence of AF after a single cryoballoon ablation procedure. RESULTS: Two hundred patients formed the study group. Median follow-up was 56 months. Following a single procedure, 46.7% of patients with paroxysmal AF remained free of symptomatic recurrence of AF compared to 35.6% of patients with persistent AF. When allowing for repeat ablations, at the end of the follow-up period 53.3% of patients in the paroxysmal group remained free of symptomatic AF compared to 47.5% in the persistent group. The rate of complications was low. CONCLUSIONS: Cryoballoon ablation is an effective catheter-based approach for treating symptomatic AF with a low risk of complications. PMID- 26621107 TI - Gut Commensal E. coli Proteins Activate Host Satiety Pathways following Nutrient Induced Bacterial Growth. AB - The composition of gut microbiota has been associated with host metabolic phenotypes, but it is not known if gut bacteria may influence host appetite. Here we show that regular nutrient provision stabilizes exponential growth of E. coli, with the stationary phase occurring 20 min after nutrient supply accompanied by bacterial proteome changes, suggesting involvement of bacterial proteins in host satiety. Indeed, intestinal infusions of E. coli stationary phase proteins increased plasma PYY and their intraperitoneal injections suppressed acutely food intake and activated c-Fos in hypothalamic POMC neurons, while their repeated administrations reduced meal size. ClpB, a bacterial protein mimetic of alpha MSH, was upregulated in the E. coli stationary phase, was detected in plasma proportional to ClpB DNA in feces, and stimulated firing rate of hypothalamic POMC neurons. Thus, these data show that bacterial proteins produced after nutrient-induced E. coli growth may signal meal termination. Furthermore, continuous exposure to E. coli proteins may influence long-term meal pattern. PMID- 26621106 TI - Molecular variability elicits a tunable switch with discrete neuromodulatory response phenotypes. AB - Recent single cell studies show extensive molecular variability underlying cellular responses. We evaluated the impact of molecular variability in the expression of cell signaling components and ion channels on electrophysiological excitability and neuromodulation. We employed a computational approach that integrated neuropeptide receptor-mediated signaling with electrophysiology. We simulated a population of neurons in which expression levels of a neuropeptide receptor and multiple ion channels were simultaneously varied within a physiological range. We analyzed the effects of variation on the electrophysiological response to a neuropeptide stimulus. Our results revealed distinct response patterns associated with low versus high receptor levels. Neurons with low receptor levels showed increased excitability and neurons with high receptor levels showed reduced excitability. These response patterns were separated by a narrow receptor level range forming a separatrix. The position of this separatrix was dependent on the expression levels of multiple ion channels. To assess the relative contributions of receptor and ion channel levels to the response profiles, we categorized the responses into six phenotypes based on response kinetics and magnitude. We applied several multivariate statistical approaches and found that receptor and channel expression levels influence the neuromodulation response phenotype through a complex though systematic mapping. Our analyses extended our understanding of how cellular responses to neuromodulation vary as a function of molecular expression. Our study showed that receptor expression and biophysical state interact with distinct relative contributions to neuronal excitability. PMID- 26621110 TI - A comparison of formalin and GEWF in fixation of colorectal carcinoma specimens: rates of lymph node retrieval and effect on TNM staging. AB - AIMS: The Royal College of Pathologists recommend that a median of at least 12 lymph nodes should be harvested during pathological staging of colorectal cancer. It is not always easy to harvest the required number, especially in patients with rectal cancer receiving neoadjuvant therapy. Lymph node revealing solutions, for example, GEWF, may improve nodal yield. GEWF is safe, cheap and easy to use. METHODS: In a controlled trial, lymph node yields were compared after secondary specimen dissection following either 24 h of further fixation in formalin (n=101) or GEWF immersion (n=99). The number, size and tumour status of additional lymph nodes identified were compared between groups. Twenty-seven cases that received long-course neoadjuvant therapy were also assessed. RESULTS: Median lymph node yield at primary dissection met national standards overall (19) but also in the long-course neoadjuvant therapy group (13). Lymph nodes were smaller in neoadjuvant cases compared with non-neoadjuvant cases (mean size range 1.3-5.6 mm vs 1.5-8.9 mm). The use of further fixation and GEWF detected more nodes at secondary dissection. The mean number of additional nodes harvested was greater with formalin (8.3) than GEWF (7.3). There was no significant difference in the mean size of the additional lymph nodes detected between groups (point estimate 1.02; 95% CI -0.58 to 2.63; p=0.211). Upstaging triggering adjunct chemotherapy occurred in 1% (2/200) of cases. CONCLUSIONS: The routine use of adjunct techniques to identify additional lymph nodes is unnecessary with underlying high quality dissection practice. Emphasis should be placed upon education and training, spending appropriate time dissecting and ensuring specimens are sufficiently fixed beforehand. PMID- 26621111 TI - Food-grade argan oil supplementation in molasses enhances fermentative performance and antioxidant defenses of active dry wine yeast. AB - The tolerance of the yeast Saccharomyces cerevisiae to desiccation is important for the use of this microorganism in the wine industry, since active dry yeast (ADY) is routinely used as starter for must fermentations. Both biomass propagation and dehydration cause cellular oxidative stress, therefore negatively affecting yeast performance. Protective treatments against oxidative damage, such as natural antioxidants, may have important biotechnological implications. In this study we analysed the antioxidant capacity of pure chemical compounds (quercetin, ascorbic acid, caffeic acid, oleic acid, and glutathione) added to molasses during biomass propagation, and we determine several oxidative damage/response parameters (lipid peroxidation, protein carbonylation, protective metabolites and enzymatic activities) to assess their molecular effects. Supplementation with ascorbic, caffeic or oleic acids diminished the oxidative damage associated to ADY production. Based on these results, we tested supplementation of molasses with argan oil, a natural food-grade ingredient rich in these three antioxidants, and we showed that it improved both biomass yield and fermentative performance of ADY. Therefore, we propose the use of natural, food-grade antioxidant ingredients, such as argan oil, in industrial processes involving high cellular oxidative stress, such as the biotechnological production of the dry starter. PMID- 26621112 TI - Neurobiological correlates of internet gaming disorder: Similarities to pathological gambling. AB - The number of massively multiplayer online games (MMOs) is on the rise worldwide along with the fascination that they inspire. Problems occur when the use of MMOs becomes excessive at the expense of other life domains. Although not yet formally included as disorder in common diagnostic systems, internet gaming disorder (IGD) is considered a "condition for further study" in section III of the DSM-5. The current review aims to provide an overview of cognitive and neurobiological data currently available on IGD, with a particular focus on impulsivity, compulsivity, and sensitivity to reward and punishment. Additionally, we also compare these findings on IGD with data from studies on pathological gambling (PG)-so far the only condition officially classified as a behavioral addiction in the DSM-5. Multiple similarities have been observed in the neurobiology of IGD and PG, as measured by alterations in brain function and behavior. Both patients with IGD and those with PG exhibited decreased loss sensitivity; enhanced reactivity to gaming and gambling cues, respectively; enhanced impulsive choice behavior; aberrant reward-based learning; and no changes in cognitive flexibility. In conclusion, the evidence base on the neurobiology of gaming and gambling disorders is beginning to illuminate the similarities between the two. However, as only a few studies have addressed the neurobiological basis of IGD, and some of these studies suffer from significant limitations, more research is required before IGD's inclusion as a second behavioral addiction in the next versions of the ICD and DSM can be justified. PMID- 26621113 TI - Microfluidic assessment of mechanical cell damage by extensional stress. AB - Mammalian cells have been widely used in bioreactors to produce biological products such as pharmaceutical materials. The productivity of such bioreactors is vastly affected by flow-induced cell damage in complicated flow environments, such as agitation-driven turbulence and oxygen bubble bursting at the interface between the culturing medium and air. However, there is no systematic approach to diagnose the cell damage caused by the hydrodynamic stress. In this work, we propose a novel microfluidic method to accurately assess the mechanical cell damage under a controlled extensional stress field, generated in a microfluidic cross-slot geometry. The cell damage in the extensional field is related to the oxygen bubble bursting process. We employed viscoelasticity-induced particle focusing to align the cells along the shear-free channel centerline, so that all the cells experience a similar extensional stress field, which also precludes the cell damage due to wall shear stress. We applied our novel microfluidic sensor to find the critical extensional stress to damage Chinese hamster ovary (CHO) cells; the critical stress is found to be ~250 Pa. Our current results are relevant in the design of practical bioreactors, as our results clearly demonstrate that the control of the bubble bursting process is critical in minimizing cell damage in bioreactor applications. Further, our results will provide useful information on the biophysical cell properties under fluid flow environments. PMID- 26621114 TI - Differential changes in thalamic and cortical excitatory synapses onto striatal spiny projection neurons in a Huntington disease mouse model. AB - Huntington disease (HD), a neurodegenerative disorder caused by CAG repeat expansion in the gene encoding huntingtin, predominantly affects the striatum, especially the spiny projection neurons (SPN). The striatum receives excitatory input from cortex and thalamus, and the role of the former has been well-studied in HD. Here, we report that mutated huntingtin alters function of thalamostriatal connections. We used a novel thalamostriatal (T-S) coculture and an established corticostriatal (C-S) coculture, generated from YAC128 HD and WT (FVB/NJ background strain) mice, to investigate excitatory neurotransmission onto striatal SPN. SPN in T-S coculture from WT mice showed similar mini-excitatory postsynaptic current (mEPSC) frequency and amplitude as in C-S coculture; however, both the frequency and amplitude were significantly reduced in YAC128 T S coculture. Further investigation in T-S coculture showed similar excitatory synapse density in WT and YAC128 SPN dendrites by immunostaining, suggesting changes in total dendritic length or probability of release as possible explanations for mEPSC frequency changes. Synaptic N-methyl-D-aspartate receptor (NMDAR) current was similar, but extrasynaptic current, associated with cell death signaling, was enhanced in YAC128 SPN in T-S coculture. Employing optical stimulation of cortical versus thalamic afferents and recording from striatal SPN in brain slice, we found increased glutamate release probability and reduced AMPAR/NMDAR current ratios in thalamostriatal synapses, most prominently in YAC128. Enhanced extrasynaptic NMDAR current in YAC128 SPN was apparent with both cortical and thalamic stimulation. We conclude that thalamic afferents to the striatum are affected early, prior to an overt HD phenotype; however, changes in NMDAR localization in SPN are independent of the source of glutamatergic input. PMID- 26621115 TI - Effects of 2-Hydroxypropyl-Beta-Cyclodextrin on Cardiovascular Signs of Amitriptyline Poisoning in a Rat Model. AB - The aim of this study was to investigate the efficacy of 2-hydroxypropyl-beta cyclodextrin (HPBCD) as an antidotal treatment for the in vivo cardiovascular effects of amitriptyline poisoning. Experiments were carried out on 33 Wistar rats. To evaluate cardiovascular effects of HPBCD, rats were infused with dextrose or HPBCD. In the poisoning model, amitriptyline (0.94 mg/kg/min) was infused until the mean arterial blood pressure (MAP) dropped to 50 % of the baseline. Following amitriptyline infusion, dextrose, low-dose HPBCD (4.19 mg/kg/min), or high-dose HPBCD (16.76 mg/kg/min) was infused, and MAP, heart rate (HR), and electrocardiogram were recorded for 60 min. Hearts were examined for tissue damage and apoptosis. HPBCD infusion alone did not yield significant difference for MAP, HR, QRS duration, QT interval, and cardiac tissue damage when compared to dextrose (p > 0.05). In the poisoning model, MAP and HR decreased, while QRS duration and QT interval prolonged significantly following amitriptyline infusion (p < 0.0167). Dextrose, low-dose HPBCD, and high-dose HPBCD infusion similarly corrected MAP, HR, QRS duration, and QT interval values at the end-experiment time point (p > 0.05). Histological scores for tissue damage and apoptosis showed no significant difference between the groups (p > 0.05). Based on our results, HPBCD did not show cardiovascular toxicity, while it was not more effective than dextrose for the treatment of amitriptyline poisoning. Further antidotal studies of cyclodextrins with higher doses and/or binding affinities are needed for poisonings. PMID- 26621116 TI - Northern Ireland's abortion law breaches human rights, court rules. PMID- 26621117 TI - Influence of macular pigment optical density spatial distribution on intraocular scatter. AB - PURPOSE: This study evaluated the summed measures of macular pigment optical density (MPOD) spatial distribution and their effects on intraocular scatter using a commercially available device (C-Quant, Oculus, USA). METHODS: A customized heterochromatic flicker photometer (cHFP) device was used to measure MPOD spatial distribution across the central 16 degrees using a 1 degrees stimulus. MPOD was calculated as a discrete measure and summed measures across the central 1 degrees , 3.3 degrees , 10 degrees and 16 degrees diameters. Intraocular scatter was determined as a mean of 5 trials in which reliability and repeatability measures were met using the C-Quant. MPOD spatial distribution maps were constructed and the effects of both discrete and summed values on intraocular scatter were examined. RESULTS: Spatial mapping identified mean values for discrete MPOD [0.32 (s.d.=0.08)], MPOD summed across central 1 degrees [0.37 (s.d.=0.11)], MPOD summed across central 3.3 degrees [0.85 (s.d.=0.20)], MPOD summed across central 10 degrees [1.60 (s.d.=0.35)] and MPOD summed across central 16 degrees [1.78 (s.d.=0.39)]. Mean intraocular scatter was 0.83 (s.d.=0.16) log units. While there were consistent trends for an inverse relationship between MPOD and scatter, these relationships were not statistically significant. Correlations between the highest and lowest quartiles of MPOD within the central 1 degrees were near significance. CONCLUSIONS: While there was an overall trend of decreased intraocular forward scatter with increased MPOD consistent with selective short wavelength visible light attenuation, neither discrete nor summed values of MPOD significantly influence intraocular scatter as measured by the C-Quant device. PMID- 26621118 TI - Phase I, two-way, crossover study to demonstrate bioequivalence and to compare safety and tolerability of single-dose XM17 vs Gonal-f(r) in healthy women after follicle-stimulating hormone downregulation. AB - BACKGROUND: XM17 is a recombinant human follicle-stimulating hormone (rhFSH) intended mainly for use in controlled ovarian hyperstimulation and the treatment of anovulation. The purpose of the current study was to establish bioequivalence, safety and tolerability of single 300-IU subcutaneous (sc) doses of XM17 to that of the reference follitropin alfa (Gonal-f((r))) in healthy young women. METHODS: This open-label, Phase I, single-dose, single-center, two-way crossover study was conducted from February to May 2009. Thirty-six women aged 18-39 years were included, with a study duration of ~27 days per participant. After endogenous FSH downregulation with goserelin (3.6 mg) on study Day 0, XM17 and Gonal-f((r)) were administered on Days 11 and 19 in random sequence. Frequent serum samples were drawn for standard pharmacokinetics until 168 h postdosing. Laboratory values, adverse events (AEs) and local tolerability were assessed throughout the study period. Primary endpoints included Cmax and AUC0-t. Secondary endpoints included additional pharmacokinetic (PK) parameters, safety and tolerability. RESULTS: Ratios of XM17 to Gonal-f((r)) for Cmax and AUC0-t equaled 1.017 (90 % confidence interval [CI]: 0.958, 1.080) and 1.028 (90 % CI: 0.931, 1.134), respectively, with the CIs contained within the predefined interval (0.8, 1.25). Ratios for AUC0-168h, AUC0-infinity and t1/2 were also ~1, and no difference in tmax was detected. Both XM17 and Gonal-f((r)) were well tolerated, with no detectable anti FSH antibodies, serious AEs or AEs leading to discontinuation or dose reduction. CONCLUSIONS: PK bioequivalence of single 300-IU sc doses of XM17 to the reference product Gonal-f(r) was statistically demonstrated. XM17 was well tolerated both systemically and locally. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02592031 ; date of registration: 28 October, 2015. PMID- 26621119 TI - Tessaracoccus rhinocerotis sp. nov., isolated from the faeces of Rhinoceros unicornis. AB - A novel Gram-stain-positive, non-spore-forming, irregular rod-shaped, non-motile and facultatively anaerobic actinobacterium, designated strain YIM 101269T, was isolated from the faeces of Rhinoceros unicornis living in Yunnan Wild Animal Park, Yunnan province, south-west China. The isolate grew at 10-35 degrees C, at pH 6-12 and with 0-9 % (w/v) NaCl. The cell-wall peptidoglycan of the organism contained ll-diaminopimelic acid as the diagnostic diamino acid. The polar lipids detected were diphosphatidylglycerol, phosphatidylglycerol, three unidentified polar lipids, one unidentified aminophospholipid and three unknown glycolipids. The major cellar fatty acid was anteiso-C15 : 0.MK-10(H4) was the predominant menaquinone. The DNA G+C content was 69.5 mol%. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain YIM 101269T belonged to the genus Tessaracoccus, closely related to Tessaracoccus flavescens DSM 18582T (97.4 % similarity). Based on the evidence from the present study, strain YIM 101269T is considered to represent a novel species of the genus Tessaracoccus, for which the name Tessaracoccus rhinocerotis sp. nov. is proposed. The type strain is YIM 101269T ( = DSM 27579T = CCTCC AB 2013217T). PMID- 26621120 TI - Adolescent exposure to cocaine increases anxiety-like behavior and induces morphologic and neurochemical changes in the hippocampus of adult rats. AB - Repeated exposure to cocaine during adolescence may affect both physical and psychological conditions in the brain, and increase the risk of psychiatric disorders and addiction behaviors in adulthood. Adolescence represents a critical development period for the hippocampus. Moreover, different regions of the hippocampus are involved in different functions. Dorsal hippocampus (dHP) has been implicated in learning and memory, whereas ventral hippocampus (vHP) plays an important role in emotional processing. In this study, the rats that were exposed to cocaine during adolescence (postnatal days, P28-P42) showed higher anxiety-like behavior in the elevated plus maze test in adulthood (P80), but displayed normal spatial learning and memory in the Morris water maze test. Furthermore, repeated exposure to cocaine during adolescence lead to alterations in morphology of pyramidal neurons, activities of astrocytes, and levels of proteins that involved in synaptic transmission, apoptosis, inflammation and addiction in both dHP and vHP of adult rats. These findings suggest that repeated exposure to cocaine during adolescence in rats may elicit morphologic and neurochemical changes in the hippocampus when the animals reach adulthood. These changes may contribute to the increased susceptibility for psychiatric disorders and addiction seen in adults. PMID- 26621122 TI - Increased expression of BDNF transcript with exon VI in hippocampi of patients with pharmaco-resistant temporal lobe epilepsy. AB - A putative role of the brain-derived neurotrophic factor (BDNF) in epilepsy has emerged from in vitro and animal models, but few studies have analyzed human samples. We assessed the BDNF expression of transcripts with exons I (BDNFI), II (BDNFII), IV (BDNFIV) and VI (BDNFVI) and methylation levels of promoters 4 and 6 in the hippocampi of patients with pharmaco-resistant temporal lobe epilepsy (TLE) (n=24). Hippocampal sclerosis (HS) and pre-surgical pharmacological treatment were considered as clinical independent variables. A statistical significant increase for the BDNFVI (p<0.05) was observed in TLE patients compared to the autopsy control group (n=8). BDNFVI was also increased in anxiety/depression TLE (N=4) when compared to autopsies or to the remaining group of patients (p<0.05). In contrast, the use of the antiepileptic drug Topiramate (TPM) (N=3) was associated to a decrease in BDNFVI expression (p<0.05) when compared to the remaining group of patients. Methylation levels at the BDNF promoters 4 and 6 were similar between TLE and autopsies and in relation to the use of either Sertraline (SRT) or TPM. These results suggest an up-regulated expression of a specific BDNF transcript in patients with TLE, an effect that seems to be dependent on the use of specific drugs. PMID- 26621121 TI - Beta-arrestin1 and 2 differently modulate metabotropic glutamate receptor 7 signaling in rat developmental sevoflurane-induced neuronal apoptosis. AB - Beta-arrestins (beta-arrs) are initially known as negative regulators of G protein-coupled receptors (GPCRs). Recently, there is increasing evidence suggesting that beta-arrs also serve as scaffolds and adapters that mediate distinct intracellular signal transduction initiated by GPCR activation. In the previous study, we have shown that metabotropic glutamate receptor 7 (mGluR7) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling may be involved in the developmental sevoflurane neurotoxicity. In the present study, we showed that activation of mGluR7 with a group III mGluRs orthosteric agonist LAP4 or an atypical mGluR7 allosteric agonist N,N'-bis(diphenylmethyl)-1,2-ethanediamine dihydrochloride (AMN082) significantly attenuated sevoflurane-induced neuronal apoptosis. Interestingly, this neuroprotective role of LAP4 could be partially reduced by beta-arr1 small interfering RNA (siRNA) or beta-arr2 siRNA transfection. In contrast, beta-arr2 siRNA transfection alone abolished the effects of AMN082 on sevoflurane neurotoxicity. In addition, administration of LAP4 or AMN082 significantly enhanced Phospho-ERK1/2 in sevoflurane neurotoxicity, which could be abrogated by beta-arr2 siRNA transfection, but not by beta-arr1 siRNA transfection. Increased beta-arr2-dependent Phospho-ERK1/2 signaling alleviated sevoflurane neurotoxicity by inhibiting bad phosphorylation. We also found that the neuroprotective role of AMN082 was completely reversed by ERK1/2 inhibitor 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (U0126). Alternatively, treatment with U0126 partially suppressed the neuroprotective of LAP4, suggesting that other mechanisms may be implicated in this process. Further investigation indicated that, in the scenario of sevoflurane neurotoxicity, application of LAP4 (but not AMN082) increased the interaction of beta-arrs with transcriptional factors CREB binding protein (CBP) and p300. LAP4 also enhanced the beta-arr1-dependent H3 and H4 acetylation in sevoflurane neurotoxicity. For the behavior study, treatment with LAP4 or AMN082 significantly improved the emotional and spatial learning and memory disorders induced by postnatal sevoflurane exposure. These results suggested that beta-arr1 and 2 may differently modulate mGluR7 signaling in developmental sevoflurane neurotoxicity. This study also reveals a beta-arr-biased agonism at GPCRs (e.g. mGluR7). PMID- 26621123 TI - Changes of the directional brain networks related with brain plasticity in patients with long-term unilateral sensorineural hearing loss. AB - Previous studies often report that early auditory deprivation or congenital deafness contributes to cross-modal reorganization in the auditory-deprived cortex, and this cross-modal reorganization limits clinical benefit from cochlear prosthetics. However, there are inconsistencies among study results on cortical reorganization in those subjects with long-term unilateral sensorineural hearing loss (USNHL). It is also unclear whether there exists a similar cross-modal plasticity of the auditory cortex for acquired monaural deafness and early or congenital deafness. To address this issue, we constructed the directional brain functional networks based on entropy connectivity of resting-state functional MRI and researched changes of the networks. Thirty-four long-term USNHL individuals and seventeen normally hearing individuals participated in the test, and all USNHL patients had acquired deafness. We found that certain brain regions of the sensorimotor and visual networks presented enhanced synchronous output entropy connectivity with the left primary auditory cortex in the left long-term USNHL individuals as compared with normally hearing individuals. Especially, the left USNHL showed more significant changes of entropy connectivity than the right USNHL. No significant plastic changes were observed in the right USNHL. Our results indicate that the left primary auditory cortex (non-auditory-deprived cortex) in patients with left USNHL has been reorganized by visual and sensorimotor modalities through cross-modal plasticity. Furthermore, the cross modal reorganization also alters the directional brain functional networks. The auditory deprivation from the left or right side generates different influences on the human brain. PMID- 26621124 TI - TRPV1 receptors augment basal synaptic transmission in CA1 and CA3 pyramidal neurons in epilepsy. AB - Temporal lobe epilepsy in human and animals is attributed to alterations in brain function especially hippocampus formation. Changes in synaptic activity might be causally related to the alterations during epileptogenesis. Transient receptor potential vanilloid 1 (TRPV1) as one of the non-selective ion channels has been shown to be involved in synaptic transmission. However, the potential role of TRPV1 receptors in synaptic function in the epileptic brain needs to be elucidated. In the present study, we used quantitative real-time PCR (qRT-PCR), western blotting, and immunohistochemistry to assess hippocampal TRPV1 mRNA expression, protein content, and distribution. Moreover, the effects of pharmacologic activation and inhibition of TRPV1 receptors on the slope of evoked field excitatory postsynaptic potentials (fEPSPs) were analyzed in CA1 and CA3 pyramidal neurons, after 3months of pilocarpine-induced status epilepticus (SE). SE induced an upregulation of TRPV1 mRNA and protein content in the whole hippocampal extract, as well as its distribution in both CA1 and CA3 regions. Activation and inhibition of TRPV1 receptors (via capsaicin 1MUM and capsazepine 10MUM, respectively) did not influence basal synaptic transmission in CA1 and CA3 regions of control slices, however, capsaicin increased and capsazepine decreased synaptic transmission in both regions in tissues from epileptic animals. Taken together, these findings suggest that a higher expression of TRPV1 in the epileptic condition is accompanied by alterations in basal synaptic transmission. PMID- 26621125 TI - The neuronal extracellular matrix restricts distribution and internalization of aggregated Tau-protein. AB - Alzheimer's disease (AD) is a chronic degenerative disorder characterized by fibrillary aggregates of Abeta and Tau-protein. Formation and progression of these pathological hallmarks throughout the brain follow a specific spatio temporal pattern which provides the basis for neuropathological staging. Previously, we could demonstrate that cortical and subcortical neurons are less frequently affected by neurofibrillary degeneration if they are enwrapped by a specialized form of the hyaluronan-based extracellular matrix (ECM), the so called 'perineuronal net' (PN). PNs are composed of large aggregating chondroitin sulfate proteoglycans connected to a hyaluronan backbone, stabilized by link proteins and cross-linked via tenascin-R. Recently, PN-associated neurons were shown to be better protected against iron-induced neurodegeneration compared to neurons without PN, indicating a neuroprotective function. Here, we investigated the role of PNs in distribution and internalization of exogenous Tau-protein by using organotypic slice cultures of wildtype mice as well as mice lacking the ECM components aggrecan, HAPLN1 or tenascin-R. We could demonstrate that PNs restrict both distribution and internalization of Tau. Accordingly, PN-ensheathed neurons were less frequently affected by Tau-internalization, than neurons without PN. Finally, the PNs as well as their three investigated components were shown to modulate the processes of distribution as well as internalization of Tau. PMID- 26621126 TI - Cannabinoid receptor agonists modulate calcium channels in rat retinal Muller cells. AB - While activation of cannabinoid CB1 receptor (CB1R) regulates a variety of retinal neuronal functions by modulating ion channels in these cells, effect of activated cannabinoid receptors on Ca(2+) channels in retinal Muller cells is still largely unknown. In the present work we show that three subunits of T-type Ca(2+) channels, CaV3.1, CaV3.2 and CaV3.3, as well as one subunit of L-type Ca(2+) channels, CaV1.2, were expressed in rat Muller cells by immunofluorescent staining. Consistently, nimodipine- and mibefradil-sensitive Na(+) currents through L- and T-type Ca(2+) channels could be recorded electrophysiologically. The cannabinoid receptor agonist WIN55212-2 significantly suppressed Ca(2+) channel currents, mainly the T-type one, in acutely isolated rat Muller cells in a dose-dependent manner, with an IC50 of 3.98MUM. The WIN55212-2 effect was not blocked by AM251/SR141716, specific CB1R antagonists. Similar suppression of the currents was observed when anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), endogenous ligands of cannabinoid receptors, were applied. Moreover, even though CB2 receptors (CB2Rs) were expressed in rat Muller cells, the effects of WIN55212 2 and 2-AG on Ca(2+) channel currents were not blocked by AM630, a selective CB2R antagonist. However, the effect of AEA could be partially rescued by AM630. These results suggest that WIN55212-2 and 2-AG receptor-independently suppressed the Ca(2+) channel currents in Muller cells, while AEA suppressed the currents partially through CB2Rs. The existence of receptor-dependent and -independent mechanisms suggests that cannabinoids may modulate Muller cell functions through multiple pathways. PMID- 26621127 TI - Understanding the impact of colorectal cancer education: a randomized trial of health fairs. AB - BACKGROUND: Regular screening for colorectal cancer (CRC) reduces morbidity and mortality from this disease. A number of factors play a role in the underutilization of CRC screening; populations with the lowest CRC screening rates are least likely to be aware of the need for screening or have knowledge about screening options. The overall purpose of this project was to assess two methods for increasing knowledge about CRC in a health fair context: one, by using a health educator to provide CRC information at a table, or two, to provide a tour through a giant inflatable, walk-through colon model with physical depictions of healthy tissue, polyps, and CRC. METHODS: We participated in six community health fair events, three were randomized to incorporate the use of the inflatable colon, and three used a standard display table method. We used a pre/post-design to look for changes in knowledge about CRC before and after participating in a health fair. We examined descriptive statistics of participants using frequencies and proportions. McNemar's test for paired binary data was used to test whether there were significant differences in the distribution of correct answer percentage from pre to post and from pre to follow up. Linear regression (GEE) was used to investigate whether there was a significant difference in the change from pre- to post-intervention in the percentage of correct answers on knowledge of tests available to detect CRC and awareness of risk factors for CRC between participants at sites with the inflatable colon compared to participants at sites without the inflatable colon. RESULTS: Participants (n = 273) were recruited at the six health fairs. Participants in health fairs with the inflatable colon had higher knowledge at post-test than participants in health fairs with tabling activities, that is, without the inflatable colon; however, the difference was not significant. One month follow-up after each health fair showed virtually no recollection of information learned at the health fairs. CONCLUSIONS: The use of an inflatable colon may be an innovative way to help people learn about CRC and CRC screening; however, it is not significantly more effective than conventional table display methods. Further research is needed to associate intention to obtain screening after touring the inflatable colon with actual screening. Future research could explore ways to better retain knowledge at long-term follow-up. PMID- 26621128 TI - BAFF inhibition does not significantly impair immunization responses in patients with rheumatoid arthritis. PMID- 26621129 TI - Perceptions and experiences of adolescents, parents and school administrators regarding adolescent-parent communication on sexual and reproductive health issues in urban and rural Uganda. AB - BACKGROUND: Evidence suggests that in spite of some adolescents being sexually active, many parents do not discuss sex-related issues with them due to lack of age-appropriate respectful vocabulary and skills. The likelihood of parent adolescent communication improving sexual and reproductive health outcomes appears plausible. The desire to understand parent-adolescent communication and how to improve it for promotion of healthy sexual behaviours inspired this research. The paper is meant to describe perceptions of adolescents, parents and school administrators about parent-adolescent communication on sexual issues; describe the content of such communication and identify factors that influence this communication. METHODS: The study was done among two urban and two rural secondary school students in their second year of education. Data were collected from 11 focus group discussions and 10 key Informants Interviews. Data management, analysis and interpretation followed thematic analysis principles. Illuminating verbatim quotations are used to illustrate findings. RESULTS: Parental warmth and acceptability of children was perceived by parents to be foundational for a healthy adolescent- parent communication. Perceptions of adolescents tended to point to more open and frequent communication with mothers than fathers and to cordial relationships with mothers. Fathers were perceived by adolescents to be strict, intimidating, unapproachable and unavailable. While adolescents tended to generally discuss sexual issues with mothers, male adolescents communicated less with anyone on sex, relationships and condoms. Much of the parent-adolescent communication was perceived to focus on sexually transmitted infections and body changes. Discussions of sex and dating with adolescents were perceived to be rare. Common triggers of sexuality discussions with female adolescents were; onset of menstruation and perceived abortion in the neighbourhood. Discussion with male adolescents, if it occurred was perceived to be triggered by parental suspicion of having female 'friends' or coming home late. Peers at school and mass media were perceived to the main source of sexuality information. CONCLUSIONS: Communication on sexuality issues between parents and their adolescent children was infrequent and critical elements like sex and specifics of protection against undesirable sexual behaviour consequences were avoided. Peers, schools and mass media should be creatively harnessed to improve parent-adolescent communication about sexuality issues. PMID- 26621130 TI - Local molecular analysis of indeterminate thyroid nodules. AB - BACKGROUND: Thyroid nodules are common but only a minority are malignant. Molecular testing can assist in helping determine whether indeterminate nodules are suspicious for malignancy or benign. The objective of the study was to determine if the analysis of mutations (BRAF, NRAS, KRAS and HRAS) using readily available molecular techniques can help better classify indeterminate thyroid nodules. METHODS: A retrospective cohort of consecutive patients undergoing diagnostic thyroid surgery were analyzed for the presence or absence of specific mutations known to be associated with thyroid malignancy in FNA samples. Markers chosen were BRAF, NRAS, KRAS and HRAS. All were locally available and currently in use at our centre for other clinical indications. Results from the molecular analysis were then compared to the histopathology from thyroidectomy specimens to determine the sensitivity and specificity of these molecular techniques to classify indeterminate thyroid nodules. RESULTS: Sixty consecutive patients with indeterminate FNAs were recruited. Twenty-three patients had malignant tumors while 37 specimens were benign. Multiple different mutations were identified in the FNA samples. Overall 18 cases had a positive mutation (10 malignant and 8 benign). The sensitivity of BRAF, HRAS, KRAS, and NRAS was 8.7, 8.7, 8.7, and 17.4 respectively while the specificity was100, 83.7, 100 and 94.6. CONCLUSION: While molecular analysis remains promising, it requires further refinement. Several markers showed promise as good "rule-in" tests. PMID- 26621131 TI - Synthesis of novel pyridyl containing phospholanes and their polynuclear luminescent copper(i) complexes. AB - A novel type of cyclic P,N-ligands, pyridyl containing phospholanes, has been synthesized in a moderate yield by the reaction of primary phosphines with 1,4 dichlorobutane in a superbasic medium. A series of homo tetranuclear octahedral Cu4I4L2, dinuclear tetrahedral Cu2I2L3, and dinuclear "head-to-tail" Cu2I2L2 luminescent complexes with these ligands were obtained. All the compounds were characterized using a range of spectroscopic and computational techniques, and in the case of some Cu4I4L2 and Cu2I2L3 complexes, by single crystal X-ray diffraction. The structural diversity of the obtained complexes was reflected in their photophysical properties: phosphorescence spectra of the compounds display emission in broad spectral range of 471-615 nm. TD-DFT computations allow the assignment of a single emission band around 550 nm for Cu2I2L3 complexes and 471 nm for Cu2I2L2 complex to a vertical triplet-singlet transition from a metal-to ligand and halide-to-ligand charge-transfer (3)(M + X)LCT excited state, whereas a second band at around 600 nm in the spectra of octahedral Cu4I4L2 complexes was assigned predominantly to Cu4I4 cluster-centered ((3)CC) excited state. PMID- 26621132 TI - Bonfils intubation in parallel with a supraglottic air-Q(r) intubating laryngeal airway. PMID- 26621133 TI - A Case of Heel Cord Pain After Repair of Acute Achilles Tendon Rupture: Treated by Endoscopic Adhesiolysis of the Achilles Tendon. AB - The causes of heel cord pain after repair of acute rupture of the Achilles tendon are unclear. The proposed etiologies include nonabsorbable suture granuloma formation, alteration of the pain receptors threshold in the tendon, and distension of the paratenon by the hypertrophied tendon, underlying tendinopathy, postrepair neovascularization, and peritendinous fibrous adhesion. We present an endoscopic technique of adhesiolysis of the Achilles tendon to deal with the various possible causes of postrepair heel cord pain. LEVELS OF EVIDENCE: Therapeutic, Level 4: Case report. PMID- 26621134 TI - Prevalence of premature ovarian failure in systemic lupus erythematosus patients treated with immunosuppressive agents in Thailand. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease that affects most women of reproductive age. The prevalence of premature ovarian failure (POF) in SLE patients is higher than that in the general population. However, the data on this condition are limited in Asian countries. OBJECTIVES: To determine the prevalence and associated factors of POF in SLE patients who received immunosuppressive therapy. METHODS: Women aged 18-40 years who were diagnosed with SLE according to the 1997 revised criteria for the classification of SLE or patients with biopsy-proven lupus nephritis were evaluated. All patients had received at least one of the following immunosuppressive agents: cyclophosphamide (CYC), azathioprine, mycophenolate mofetil, chlorambucil or cyclosporine for more than six months. POF was diagnosed in those who had sustained amenorrhea for more than six consecutive months, with a level of estradiol <= 110 pmol/L (30 pg/mL) and follicle stimulating hormone >=40 IU/L. RESULTS: Ninety two SLE patients were included in this study. Mean age at enrollment was 30 +/- 6.9 years and disease duration was 103 +/- 67.5 months. The mean Systemic Lupus International Collaborating Clinics/ American College of Rheumatology (SLICC/ACR) damage index was 1.7 +/- 1.7. Seventy five patients (82%) had lupus nephritis. Sixty four patients (70%) received CYC. Eleven patients (12%) with POF were observed. For the binary logistic regression model, CYC cumulative dosage of more than 10 g was the only independent risk factor of POF (hazard ratio 17.0, 95% CI 1.96-147.72, p = 0.01). CONCLUSIONS: From our data, 12% of SLE patients developed POF. A cumulative dose of CYC of more than 10 g was the only risk factor for POF. To prevent these events, systematic evaluation and early recognition of POF should be promoted in the care of SLE patients. PMID- 26621135 TI - The presence or severity of pulmonary hypertension does not affect outcomes for single-lung transplantation. AB - Advanced lung disease (ALD) that requires lung transplantation (LTX) is frequently associated with pulmonary hypertension (PH). Whether the presence of PH significantly affects the outcomes following single-lung transplantation (SLT) remains controversial. Therefore, we retrospectively examined the outcomes of 279 consecutive SLT recipients transplanted at our centre, and the patients were split into four groups based on their mean pulmonary artery pressure values. Outcomes, including long-term survival and primary graft dysfunction, did not differ significantly for patients with versus without PH, even when PH was severe. We suggest that SLT can be performed safely in patients with ALD associated PH. PMID- 26621136 TI - Can procalcitonin levels indicate the need for adjunctive therapies in sepsis? AB - After decades of extensive experimental and clinical research, septic shock and the related multiple organ dysfunction still remain the leading cause of mortality in intensive care units (ICUs) worldwide. Defining sepsis is a difficult task, but what is even more challenging is differentiating infection induced from non-infection-induced systemic inflammatory response-related multiple organ dysfunction. As conventional signs of infection are often unreliable in intensive care, biomarkers are used, of which one of the most frequently investigated is procalcitonin. Early stabilisation of vital functions via adequate supportive therapy and antibiotic treatment has resulted in substantial improvements in outcome over the last decades. However, there are certain patients who may need extra help, hence modulation of the immune system and the host's response may also be an important therapeutic approach in these situations. Polyclonal intravenous immunoglobulins have been used in critical care for decades. A relatively new potential approach could be attenuation of the overwhelming cytokine storm by specific cytokine adsorbents. Both interventions have been applied in daily practice on a large scale, with firm pathophysiological rationale but weak evidence supported by clinical trials. The purpose of this review is to give an overview on the pathophysiology of sepsis as well as the role and interpretation of biomarkers and their potential use in assisting adjunctive therapies in sepsis in the future. PMID- 26621137 TI - Corona mortis: in vivo anatomical knowledge and the risk of injury in totally extraperitoneal inguinal hernia repair. AB - PURPOSE: Corona mortis (CMOR) is the arterial and/or venous vascular communication(s) between the obturator and external iliac vessels. Totally extraperitoneal (TEP) inguinal hernioplasty can be associated with vascular complications especially during the fixation of the mesh. Theoretically, CMOR is an important nominee. But, the data in literature are insufficient about CMOR injury. Additionally, most of the studies about CMOR have been usually performed on cadavers. We aimed to reveal the preperitoneal vascular anatomy of inguinal area and provide in vivo knowledge about CMOR. The risk of arterial injury was also evaluated. MATERIALS: The data of preperitoneal vascular anatomy of 321 patients who underwent TEP procedure between January 2005 and July 2014 were retrospectively evaluated. RESULTS: Mean age was 46 +/- 8.9 years, 53 females vs 268 males. 391 hemipelvises were evaluated. Two types of arterial structure were identified; (1) an aberrant obturator artery forming an anastomosis with branches of ordinary obturator artery; (2) a pubic branch of inferior epigastric artery. The incidence of arterial CMOR was 28.4 % and of any arterial structure was 45.0 %. An arterial CMOR was considered as thick (>=2 mm) or thin (<2 mm). Injury of arterial CMOR during tack stapling on Cooper's ligament was seen in six cases (1.5 %). All of them were thin (<2 mm) in structure. Venous CMOR was visible only under low pressure in work space. CONCLUSION: During TEP hernia repair, CMOR and/or pubic branch of inferior epigastric artery can be damaged. To prevent this complication, tacks should be stapled to Cooper's ligament close to symphysis pubis and dissection should be careful on the posterior surface of superior pubic ramus. Small caliber (<2 mm) arterial CMOR is more prone to be injured during TEP procedure. To explore venous structures properly, pressure in workspace should be kept as low as possible. PMID- 26621138 TI - An implantable sensor device measuring suture tension dynamics: results of developmental and experimental work. AB - PURPOSE: Knowledge about suture tension dynamics after laparotomy closure is limited due to the lack of adequate measurement tools. As a consequence, a miniaturized implantable sensor and data logger were developed and applied experimentally in a porcine model to measure suture tension dynamics after laparotomy closure. MATERIAL AND METHODS: We developed an implantable device (6 * 3 * 1 mm) fitted with silicon strain gauges and an implantable data logger allowing long-term registration. In nine domestic pigs, sensors and loggers were implanted along the suture closing a median laparotomy registering suture tension over a period of 23 h. RESULTS: Fascial closure was achieved by a mean suture tension of 1.07 N. After 30 minutes, suture tension was reduced to 0.81N (-24.3 %, p = 0.0003). After 12 h, tension showed a further decrease to 0.69 N (-35.5 %, n.s.), after 23 h mean suture tension reached 0.56 N, (-47.7 %, p = 0.014). CONCLUSIONS: The aim to develop an implantable miniaturized sensor device registering long-term suture tension dynamics was achieved. The use in the animal experiment was feasible and safe. We observed a loss of almost 50 % of suture tension 23 h after fascial closure. This could mean that up to 50 % of initial suture tension may be an unnecessary surplus not contributing to tissue stability but to the risk of suture failure. PMID- 26621139 TI - The incidence of inguinal hernia and associated risk factors of incarceration in pediatric inguinal hernia: a nation-wide longitudinal population-based study. AB - PURPOSE: This study uses a national database to evaluate the incidence of inguinal hernia and associated risk factors of incarcerated hernia in children from birth to 15 years of age. METHODS: The study selected children born from 1997 to 2005 from a randomly selected cohort of 1,000,000 from an insured population of 23 million. We regarded children that were classified with code 550 and hernia surgery in accordance to the International Classification of Diseases, 9th Revision, as having inguinal hernia. We used the 2 chi-square test and logistic regression modeling for statistical analyses. RESULTS: In total, 79,794 children (41,767 male and 38,027 female) were enrolled in the study. The cumulative incidence of inguinal hernia in males and females from birth to 15 years old were 6.62 and 0.74 %, respectively (p < 0.01). The peak incidence of inguinal hernia was at 0 years of age for males and 5 years of age for females. The ratio of unilateral vs. bilateral repair was 5.54:1. Females tend to have more bilateral inguinal hernia than males (25.4 vs. 12.9 %, p < 0.01). Incarcerated hernia occurred in 4.19 % children with inguinal hernia without significant gender discrepancy. Approximately 40 % of incarcerated hernia underwent hernia repair immediately after visiting the emergent department. In patients who presented with reducible hernia, we did not find significant correlation between waiting time to hernia repair and occurrence of incarceration. CONCLUSIONS: The cumulative incidence of inguinal hernia from birth to 15 years of age was 6.62 and 0.74 % in males and females, respectively. Incarceration was not related to prematurity or the waiting time for surgery. PMID- 26621140 TI - Knowledge and attitudes towards rotavirus diarrhea and the vaccine amongst healthcare providers in Yogyakarta Indonesia. AB - BACKGROUND: Rotavirus has been identified as the most common pathogen associated with severe diarrhoea. Two effective vaccines against the pathogen have been licensed. However, many countries including Indonesia have yet to introduce the vaccine into their national immunisation programs. This study aimed to examine the attitudes of healthcare providers (HCPs) and other health stakeholders towards the pathogen and the vaccine. METHODS: Semi-structured in-depth interviews were undertaken in two districts of Yogyakarta Province, Indonesia with nurses, midwives, primary care providers, pediatricians and other health stakeholders. Thematic analysis was undertaken. RESULTS: Fourteen interviews were conducted between August and October 2013. We identified that while participants do not consider diarrhea to be an important problem in Indonesia, they do acknowledge that it can be serious if not properly treated. While the majority had some level of knowledge about rotavirus, not all participants knew that a vaccine was available. There were mixed feelings towards the need for the vaccine. Some felt that the vaccine is not ranked as a priority as it is not listed on the national program. However, others agreed there is a rationale for its use in Indonesia. The cost of the vaccine (when sold in the private sector) was perceived to be the primary barrier impacting on its use. CONCLUSIONS: The high cost and the low priority given to this vaccine by the public health authorities are the biggest obstacles impacting on the acceptance of this vaccine in Indonesia. HCPs need to be reminded of the burden of disease associated with rotavirus. In addition, reminding providers about the costs associated with treating severe cases versus the costs associated with prevention may assist with improving the acceptance of HCPs towards the vaccine. Promotion campaigns need to target the range of HCPs involved in the provision of care to infants and pregnant women. PMID- 26621141 TI - Multidisciplinary Aortopathy Clinics Should Now Be the Standard of Care in Canada. AB - Thoracic aortic aneurysm is often undiagnosed and has a very poor prognosis when presented with acute aortic dissection. Early diagnosis, expert medical management, and elective aortic surgery are the cornerstones of improvement of long-term survival in thoracic aortic disease (TAD). International guidelines now recommend the acute and long-term management of patients with TAD to occur within multidisciplinary aortopathy clinics under the care of professionals with specific training and experience. Multidisciplinary "heart teams" are recognized to be more focused on patient-centric care, to facilitate faster clinical decision times with increased adherence to guideline-directed therapy, and to improve knowledge translation and physician and patient satisfaction. The range of differential diagnoses for TAD has expanded rapidly over the past decade. Diagnosis of an index case with a syndromic or nonsyndromic familial TAD allows for preventative care. Effective family screening can save lives by allowing for elective management of thoracic aortic aneurysm rather than emergent care of acute aortic complications. Expert cardiac imaging with access to the full range of required imaging modalities is central to all clinical management decisions. Medical and surgical management of TAD is now provided as personalized care according to patient- and disease-specific factors. Special considerations apply to pregnancy management for women with TAD. Multidisciplinary aortopathy clinics should now be the standard of care for the management of TAD in Canada and we should implement best practice guidelines. With the already established and emerging clinics, the stage is now set to build a Canadian Aortopathy Clinics Trials network. PMID- 26621142 TI - Towards More Personalized Surgical Indications for Thoracic Aortic Dilatation: Are We There Yet? AB - Thoracic aortic aneurysms remain an important cause of death in the general population. The key to improving patient prognosis with thoracic aortic dilatation lies in early identification and tailored management strategies. Advances in the understanding of the molecular mechanisms of aneurysm formation, the natural history of disease, and clinical risk factors have led to significant improvements in patient management and overall outcomes. In the past decade, identification of the genetic basis of disease, together with wider availability of molecular testing, ushered in a new era for a tailored approach to the management of patients with thoracic aortic aneurysms. In this viewpoint, we explore these various iterative steps and future challenges. PMID- 26621143 TI - Concomitant Phosphodiesterase 5 Inhibition Enhances Myocardial Protection by Inhaled Nitric Oxide in Ischemia-Reperfusion Injury. AB - Enhanced cyclic guanosine monophosphate (cGMP) signaling may attenuate myocardial ischemia-reperfusion injury (I/R) and improve left ventricular (LV) functional recovery after myocardial infarction (MI). We investigated the cardioprotection afforded by inhaled NO (iNO), the phosphodiesterase 5 (PDE5)-specific inhibitor tadalafil (TAD), or their combination (iNO+TAD) in C57Bl6J mice subjected to 6 minute left anterior descending artery ligation followed by reperfusion. We measured plasma and cardiac concentrations of cGMP during early reperfusion, quantified myocardial necrosis and inflammation by serial troponin-I (TnI) and myeloperoxidase-positive cell infiltration at day 3, and evaluated LV function and remodeling after 4 weeks using echocardiography and pressure-conductance catheterization. Administration of iNO, TAD, or both during I/R was safe and hemodynamically well tolerated. Compared with untreated mice (CON), only iNO+TAD increased plasma and cardiac-cGMP levels during early reperfusion (80 +/- 12 versus 36 +/- 6 pmol/ml and 0.15 +/- 0.02 versus 0.05 +/- 0.01 pmol/mg protein, P < 0.05 for both). Moreover, iNO+TAD reduced TnI at 4 hours to a greater extent (P < 0.001 versus CON) than either alone (P < 0.05 versus CON) and was associated with significantly less myocardial inflammatory cell infiltration at day 3. After 4 weeks and compared with CON, iNO+TAD was associated with increased fractional shortening (43 +/- 1 versus 33 +/- 2%, P < 0.01), larger stroke volumes (14.9 +/- 1.2 versus 10.2 +/- 0.9 MUl, P < 0.05), enhanced septal and posterior wall thickening (P < 0.05 and P < 0.001, respectively), and attenuated LV dilatation (P < 0.001), whereas iNO or TAD alone conferred less benefit. Thus, iNO+TAD has superior efficacy to limit early reperfusion injury and attenuate adverse LV remodeling. Combination of inhaled NO with a long-acting PDE5 inhibitor may represent a promising strategy to reduce ischemic damage following reperfusion and better preserve LV function. PMID- 26621145 TI - Is now the time for probiotics in diabetes management? PMID- 26621146 TI - Is there a pathophysiological link between high arterial stiffness and left ventricular filling pressures in patients with acute myocardial infarction [corrected]? PMID- 26621144 TI - Central GPR109A Activation Mediates Glutamate-Dependent Pressor Response in Conscious Rats. AB - G protein-coupled receptor 109A (GPR109A) activation by its ligand nicotinic acid (NA) in immune cells increases Ca(2+) levels, and Ca(2+) induces glutamate release and oxidative stress in central blood pressure (BP)-regulating nuclei, for example, the rostral ventrolateral medulla (RVLM), leading to sympathoexcitation. Despite NA's ability to reach the brain, the expression and function of its receptor GPR109A in the RVLM remain unknown. We hypothesized that NA activation of RVLM GPR109A causes Ca(2+)-dependent l-glutamate release and subsequently increases neuronal oxidative stress, sympathetic activity, and BP. To test this hypothesis, we adopted a multilevel approach, which included pharmacologic in vivo studies along with ex vivo and in vitro molecular studies in rat pheochromocytoma cell line (PC12) cells (which exhibit neuronal phenotype). We present the first evidence for GPR109A expression in the RVLM and in PC12 cells. Next, we showed that RVLM GPR109A activation (NA) caused pressor and bradycardic responses in conscious rats. The resemblance of these responses to those caused by intra-RVLM glutamate and their attenuation by NMDA receptor (NMDAR) blockade (2-amino-5-phosphonopentanoic acid) and enhancement by l glutamate uptake inhibition (l-trans-pyrrolidine-2,4-dicarboxylic acid, PDC) supported our hypothesis. NA increased Ca(2+), glutamate, nitric oxide and reactive oxygen species (ROS) levels in PC12 cells and increased RVLM ROS levels. The inactive NA analog isonicotinic acid failed to replicate the cardiovascular and biochemical effects of NA. Further, GPR109A knockdown (siRNA) abrogated the biochemical effects of NA in PC12 cells. These novel findings yield new insight into the role of RVLM GPR109A in central BP control. PMID- 26621147 TI - Could we improve thromboembolic risk stratification in patients with atrial fibrillation? PMID- 26621148 TI - Fever and generalized erythema caused by subcutaneous panniculitis-like T-cell lymphoma. PMID- 26621149 TI - Importance of the accurate measurement of carotid intima-media thickness for evaluating the relationship between blood pressure and vascular damage. PMID- 26621150 TI - Erratum to: Predictors of Condom Use Among Iranian Women at Risk of HIV. PMID- 26621152 TI - Assessment of the clinical relevance of 17q25.3 copy number and three-dimensional telomere organization in non-small lung cancer patients. AB - PURPOSE: To identify potential biomarkers that may provide new therapeutic targets or prognostic indicators for non-small cell lung cancer (NSCLC), we investigated the three-dimensional (3D) organization of telomeres and cytoband 17q25.3 copy number in NSCLC tissues. METHODS: NSCLC paraffin-embedded tissue specimens from 18 patients were assessed for 3D telomere organization by 3D nuclear telomere imaging followed by quantitative analysis. Patients were stratified by smoking, histology, and EGFR status. Cytoband 17q25.3 was examined by fluorescent in situ hybridization. Data from comparative genomic hybridization and/or single nucleotide polymorphism arrays for cytoband 17q25.3 were obtained and correlated with Q-FISH and 3D telomere results. RESULTS: 3D telomeric profiling demonstrated that the smokers, EGFR-negative, and squamous cell carcinoma subgroups tended to have higher numbers of lower-intensity telomeres, indicative of shorter telomeres, as well as higher numbers of telomeric aggregations compared to non-smokers, EGFR-positive, and adenocarcinomas, respectively. Gains of cytoband 17q25.3 in conjunction with an increase in the control region 17p11.2 were observed in 7 of 18 (38.9 %) patients, reflecting a gain of chromosome 17. Clonal gains of cytoband 17q25.3 were observed in 11 of 18 (61 %) patients, highlighting a potential biological significance for the genes in this region in NSCLC tumourigenesis. CONCLUSIONS: The 3D telomere profiles may differentiate NSCLC patients with different histologies, EGFR, and smoking statuses, rendering them a potential biomarker for distinguishing these clinically relevant histological and molecular subtypes of lung cancer. Highly frequent clonal gain of cytoband 17q25.3 was also demonstrated, suggesting an important biological role for the genes in this region. PMID- 26621151 TI - Psychometric Properties and Validity of a Multi-dimensional Risk Perception Scale Developed in the Context of a Microbicide Acceptability Study. AB - Currently available risk perception scales tend to focus on risk behaviors and overall risk (vs partner-specific risk). While these types of assessments may be useful in clinical contexts, they may be inadequate for understanding the relationship between sexual risk and motivations to engage in safer sex or one's willingness to use prevention products during a specific sexual encounter. We present the psychometric evaluation and validation of a scale that includes both general and specific dimensions of sexual risk perception. A one-time, audio computer-assisted self-interview was administered to 531 women aged 18-55 years. Items assessing sexual risk perceptions, both in general and in regards to a specific partner, were examined in the context of a larger study of willingness to use HIV/STD prevention products and preferences for specific product characteristics. Exploratory and confirmatory factor analyses yielded two subscales: general perceived risk and partner-specific perceived risk. Validity analyses demonstrated that the two subscales were related to many sociodemographic and relationship factors. We suggest that this risk perception scale may be useful in research settings where the outcomes of interest are related to motivations to use HIV and STD prevention products and/or product acceptability. Further, we provide specific guidance on how this risk perception scale might be utilized to understand such motivations with one or more specific partners. PMID- 26621153 TI - Characterization of miR-146a and miR-155 in blood, tissue and cell lines of head and neck squamous cell carcinoma patients and their impact on cell proliferation and migration. AB - PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies worldwide with an unchanged 5-year survival rate during the last decade. To detect reliable prognostic markers and improve patients' outcome in future, the aim of our study was to detect differences in microRNA (miRNA; miR) expression profile and further on to analyze the functional role of selected miRNAs. METHODS: Blood samples from HNSCC patients and sex- and age-matched healthy volunteers were analyzed by microarrays and validated by quantitative real-time PCR. Data were compared with tumor tissue results and all findings were correlated with clinical parameters. Additionally, the proliferation and migration potential of two cell lines transfected with miRNA mimics and inhibitors for miR-146a and miR-155 were examined. RESULTS: Initial analysis of blood samples showed no significant differences between the miRNA profile of HNSCC patients and healthy controls (p > 0.05). Interestingly, down-regulation of miR-146a and miR-155 in blood of patients correlated with the occurrence of distant metastasis regarding tumor patients only (p = 0.023 and p = 0.028, respectively). Additionally, our investigations in tissue samples revealed a lower expression of miR-155 in tumor cells (p = 0.003) and a correlation with higher cT-classification for down-regulation of miR-146a (p = 0.005). Moreover, functional assays demonstrated that inhibition of miR-146a and miR-155 promoted dramatically proliferation and migration potential, whereas transfection of both mimics had an inhibitory effect. CONCLUSIONS: Characterizing the expression of miR-146a and miR-155 and their functional role in tumor biology underlined significantly their proliferation and migration potential suggesting relevance as potential prognostic markers in HNSCC. PMID- 26621154 TI - Detection of Enterococcus spp. in bronchoalveolar lavage fluid of patients with high-risk neutropenia: May it be ignored? PMID- 26621155 TI - Erratum to: 'The direction of cross affects obesity after puberty in male but not female offspring'. PMID- 26621156 TI - Lisdexamfetamine Dimesylate Effects on Binge Eating Behaviour and Obsessive Compulsive and Impulsive Features in Adults with Binge Eating Disorder. AB - In a published 11-week, placebo-controlled trial, 50 and 70 mg/d lisdexamfetamine dimesylate (LDX), but not 30 mg/d LDX, significantly reduced binge eating days (primary endpoint) in adults with binge eating disorder (BED). This report provides descriptions of LDX effects on secondary endpoints (Binge Eating Scale [BES]; Three-Factor Eating Questionnaire [TFEQ]; Yale-Brown Obsessive Compulsive Scale modified for Binge Eating [Y-BOCS-BE]; and the Barratt Impulsiveness Scale, version 11 [BIS-11]) from that study. Week 11 least squares mean treatment differences favoured all LDX doses over placebo on the BES (p <= 0.03), TFEQ Disinhibition and Hunger subscales (all p < 0.05), and Y-BOCS-BE total, obsessive, and compulsive scales (all p <= 0.02) and on BIS-11 total score at 70 mg/d LDX (p = 0.015) and the TFEQ Cognitive Restraint subscale at 30 and 70 mg/d LDX (both p < 0.05). These findings indicate that LDX decreased global binge eating severity and obsessive-compulsive and impulsive features of BED in addition to binge eating days. PMID- 26621158 TI - Hospital of diagnosis and probability of having surgical treatment for resectable gastric cancer. AB - BACKGROUND: Gastric cancer surgery is increasingly being centralized in the Netherlands, whereas the diagnosis is often made in hospitals where gastric cancer surgery is not performed. The aim of this study was to assess whether hospital of diagnosis affects the probability of undergoing surgery and its impact on overall survival. METHODS: All patients with potentially curable gastric cancer according to stage (cT1/1b-4a, cN0-2, cM0) diagnosed between 2005 and 2013 were selected from The Netherlands Cancer Registry. Multilevel logistic regression was used to examine the probability of undergoing surgery according to hospital of diagnosis. The effect of variation in probability of undergoing surgery among hospitals of diagnosis on overall survival during the intervals 2005-2009 and 2010-2013 was examined by using Cox regression analysis. RESULTS: A total of 5620 patients with potentially curable gastric cancer, diagnosed in 91 hospitals, were included. The proportion of patients who underwent surgery ranged from 53.1 to 83.9 per cent according to hospital of diagnosis (P < 0.001); after multivariable adjustment for patient and tumour characteristics it ranged from 57.0 to 78.2 per cent (P < 0.001). Multivariable Cox regression showed that patients diagnosed between 2010 and 2013 in hospitals with a low probability of patients undergoing curative treatment had worse overall survival (hazard ratio 1.21; P < 0.001). CONCLUSION: The large variation in probability of receiving surgery for gastric cancer between hospitals of diagnosis and its impact on overall survival indicates that gastric cancer decision-making is suboptimal. PMID- 26621159 TI - An embryological point of view on associated congenital anomalies of children with Hirschsprung disease. AB - The most common congenital gut motility disorder is the Hirschsprung disease (HSCR). This anomaly is characterized by absence of neural crest-derived enteric neuronal ganglia. The aim of our study was to analyze the relationship between HSCR and other congenital anomalies or malfunctions. We examined 130 patients with Hirschsprung disease from Slovakia for last 10 years. During patients examination we focused not only on morphological abnormalities, but also functional anomalies. The incidence of associated congenital anomalies in our patients with HSCR was 26.1 %. But if we add functional defects (hypothyroidism, malfunction in cellular immunity, neurological deficit) to the morphological congenital abnormalities, the rate of the patients with HSCR with additional defects achieves 50.1 %. Nine of our patients (6.9 %) had syndromic HSCR. The most frequent disorder (13.6 % of patients) was primary deficiency in cellular immunity. More than 12.3 % of patients with HSCR had genitourinary abnormalities, in 10.0 % of patients variable degree of psychomotor retardation was observed, and skeletal, muscle and limb anomalies involved 7.7 % of patients. In 7.6 % cases of patients we found congenital hypothyroidism (including 2 cases of agenesis of thyroid gland). More than 6.1 % of patients presented with an associated anomaly in gastrointestinal tract (mostly anorectal malformations). Up to 5.5 % patients had congenital anomaly of heart, 3.8 % had ophthalmic and 3.1 % had craniofacial anomalies. Down syndrome was the main diagnosis in 3.8 % patients. We discussed the relationship between HSCR and other anomalies, which are probably caused by abnormal migration, proliferation, or differentiation, of neural crest cells during embryogenesis (Tab. 1, Fig. 2, Ref. 75). PMID- 26621160 TI - Preoperative NT-proBNP values in patients with atrioventricular septal defect and its role as a predictor of early postoperative course. AB - OBJECTIVES: Atrioventricular septal (AVSDC) defect presents by excessive pulmonary blood flow and congestive heart failure in children. This study was designed to identify and compare N-terminal pro-brain natriuretic peptide (NT proBNP) values in complete and incomplete form at the time of surgery, and evaluation of postoperative course. METHODS: The prospective study included thirty-one patients with complete and fifteen with intermediate forms, undergoing surgery in the period from May 2009 to January 2014. Pre- and post-operative variables were statistically analyzed. RESULTS: The median value of NT-proBNP was 1420.0 pg/mL, with elevated levels in complete form (1656.0 vs 488.0 pg/mL, p < 0.001); age and weight with negative correlation. Other preoperative variables (genetic disorder, atrioventricular valve regurgitation, borderline ventricle) were not significant. Higher incidence of postoperative variables was present in complete form, namely mechanical ventilation (p < 0.03), dose and length of vasopressors (p < 0.002), ICU stay (p < 0.04), and complications (p < 0.05). NT proBNP analysis as a predictor of postoperative course showed an association with longer ventilatory (> 48 hours) and inotropic forms of support, ICU stay, and presence of infection. CONCLUSION: NT-proBNP value might be helpful in the decision-making process of early surgical treatment of complete form of AVSDC, and useful as a predictor of early post-operative course (Tab. 4, Fig. 3, Ref. 14). PMID- 26621161 TI - The association of neutrophil to lymphocyte ratio with presence and severity of obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) is characterized by reductions in breathing amplitude during sleep caused by an obstructed or collapsed upper airway. The neutrophil to lymphocyte ratio (NLR) has been proposed as a novel biomarker for systemic inflammatory response. The aim of the present study was to evaluate the relationship between NLR and OSA. METHODS: The study population consisted of 195 consecutive patients with clinical suspicion of OSA. Full night polysomnography was performed for all patients. Patients with an apnea hypopnea index (AHI) >= 5 were considered to have OSA. NLR was calculated as the ratio of neutrophil count to lymphocyte count. RESULTS: While 130 patients (91 male, mean age: 49.9+/-9.8 years) had OSA, 65 patients (42 male, mean age: 48.7 +/- 10.2 years) had normal findings according to AHI scores. Cardiovascular risk factors such as hypertension, hyperlipidemia, diabetes mellitus and smoking were more common in patients with OSA. Patients with OSA had significantly higher NLR than controls (1.87+/-0.80 vs 1.49+/-0.48, p=0.005). AHI score was significantly correlated with NLR (r=0.228, p=0.001). NLR and presence of hyperlipidemia were independent predictors of OSA (OR: 2.451, 2.850, p=0.001, 0.004, respectively). NLR of 1.62 or higher predicted OSA with a sensitivity of 56.2 % and specificity of 63.1 %. CONCLUSIONS: NLR was higher and also correlated with AHI score in patients with OSA which has not been reported previously. NLR more than 1.62 was an independent predictor of OSA. A simple, cheap white blood cell count may also give an idea about the presence and severity of OSA (Tab. 3, Fig. 3, Ref. 30). PMID- 26621162 TI - Plasma oxytocin levels are reduced in Slovak autistic boys. AB - BACKGROUND: Obstructive sleep apnea (OSA) is characterized by reductions in breathing amplitude during sleep caused by an obstructed or collapsed upper airway. The neutrophil to lymphocyte ratio (NLR) has been proposed as a novel biomarker for systemic inflammatory response. The aim of the present study was to evaluate the relationship between NLR and OSA. METHODS: The study population consisted of 195 consecutive patients with clinical suspicion of OSA. Full night polysomnography was performed for all patients. Patients with an apnea hypopnea index (AHI) >= 5 were considered to have OSA. NLR was calculated as the ratio of neutrophil count to lymphocyte count. RESULTS: While 130 patients (91 male, mean age: 49.9 +/- 9.8 years) had OSA, 65 patients (42 male, mean age: 48.7 +/- 10.2 years) had normal findings according to AHI scores. Cardiovascular risk factors such as hypertension, hyperlipidemia, diabetes mellitus and smoking were more common in patients with OSA. Patients with OSA had significantly higher NLR than controls (1.87 +/- 0.80 vs 1.49 +/- 0.48, p=0.005). AHI score was significantly correlated with NLR (r=0.228, p=0.001). NLR and presence of hyperlipidemia were independent predictors of OSA (OR: 2.451, 2.850, p=0.001, 0.004, respectively). NLR of 1.62 or higher predicted OSA with a sensitivity of 56.2 % and specificity of 63.1 %. CONCLUSIONS: NLR was higher and also correlated with AHI score in patients with OSA which has not been reported previously. NLR more than 1.62 was an independent predictor of OSA. A simple, cheap white blood cell count may also give an idea about the presence and severity of OSA (Tab. 3, Fig. 3, Ref. 30). PMID- 26621163 TI - The use of cell-free fetal DNA in maternal plasma for noninvasive prenatal linkage analysis in beta globin gene cluster. AB - OBJECTIVES: To use the PCR-RFLP-based linkage analysis for non-invasive prenatal diagnosis of beta-thalassemia. BACKGROUNDS: Thalassemia is a prevalent genetic disorder occurring throughout the world. Cell-free fetal DNA (cffDNA) in the maternal plasma during pregnancy has been used to develop non-invasive prenatal screening and diagnostic tests. METHODS: PCR-RFLP for six SNPs in the beta-globin gene was executed on paternal and maternal DNA as well as DNA extracted from CVS of the fetuses in seven beta-thalassemic families. Based on the results, two families in which the paternal inherited SNPs in specific loci were different from the maternal one were selected and PCR-RFLP was performed on cffDNA extracted from the maternal plasma. RESULTS: Paternal SNPs in cffDNA were distinguished and the inheritance of paternally normal or mutant beta globin allele was predicted by linkage analysis. CONCLUSION: The use of PCR-RFLP on cffDNA as a simple and inexpensive method was capable to provide similar results achieved by studying CVS of the fetuses. However, there is a limiting factor in this approach, namely that there is the little amount of cffDNA in maternal plasma. The PCR yield was improved either by adding BSA to PCR reaction or increasing the PCR cycles (Tab. 2, Fig. 2, Ref. 18). PMID- 26621164 TI - Surgical treatment of gastric cancer. AB - Gastric cancer is a malignant disease which has generally a very bad prognosis. The frequency of occurence of this disease in the population is dependent on the age and localisation. Most frequently, this disease has occured in Japan, China, countries of South Africa and Eastern Europe for a long time but men are more likely to suffer from this disease than women witha ratio of 2 : 1. METHODS: We retrospectively evaluated the group of patients who had been treated in our complex oncology center in the course of five years RESULTS: We treated 572 patients with gastric cancer in five years period. 218 patients of the total number were admitted, 185 patients of all hospitalized patients were operated (85 %). 53 patients of our group of hospitalized patients underwent adjuvant oncology therapy (24 %). Overall, five-year survival was 18.4 % in our group, the median survival time was 12.9 months. CONCLUSION: Radical surgery is considered to be the only treatment modality which can lead to patient's cure under optimal conditions. Complex care for patients with gastric carcinoma should be centralized in big centers. Personalized oncological treatment should be a way how to get better results (Tab. 2, Fig. 5, Ref. 14). PMID- 26621165 TI - Maggot therapy in treatment of a complex hand injury complicated by mycotic infection. AB - Complex injuries of the hand remain a therapeutic challenge for surgeons. We present the case of a male who suffered a devastating injury of the hand caused by a conveyor belt. The patient developed a progressive Absidia corymbifera infection of the affected soft tissues. Initial treatments with serial surgical debridement and topical and intravenous itraconazole were unsuccessful in eliminating the infection. We decided to use maggot debridement therapy in a new special design to debride all necrotic, devitalized tissue and preserve only healthy tissue and functioning structures. This maneuverer followed by negative pressure therapy allowed progressive healing. In such complex hand injuries, maggot debridement combined with negative pressure therapy could be considered to achieve effective and considerable results, although future functional morbidity may occur (Fig. 4, Ref. 18). PMID- 26621166 TI - Chylothorax - multidisciplinary solution. AB - Surgical treatment is not commonly used in the management of chylothorax. We describe a complicated algorithm that we used in treating a 70-year-old lady with Bechterev disease, who suffered from a blunt chest injury with subsequent right sided serial ribs fracture with hemothorax and thoracic vertebral body fracture. Because of Bechterev disease, hyperextension of the ossified thoracic spine caused an injury of the thoracic lymphatic duct. Simultaneous thoracic spine stabilisation with surgical revision of the thoracic lymphatic duct from an anterior approach was indicated. Despite the urgency of thoracic spine stabilisation, the procedure was postponed due to an acute coronary syndrome, which implied drug eluting stent insertion with a subsequent need of dual anti platelet therapy. Thus, the procedure was done 16 days after stent insertion. The diagnosis of chylotorax must be considered in case of thoracic injury with continuing waste to the chest tube and the finding of well expanded pulmonary parenchyma. Biochemical investigation of the effusion is the cornerstone in establishing the diagnosis of chylothorax (Tab. 2, Fig. 1, Ref. 14). PMID- 26621167 TI - Effects of resveratrol on methotrexate-induced intestinal injury. AB - Methotrexate (MTX) is an anticancer drug. Many studies have reported that MTX causes oxidative stress-associated damage in the small intestine. The purpose of this study was to investigate the possible protective effect of resveratrol (RES), an antioxidant, against MTX-induced damage in the small intestine. MATERIALS AND METHODS: Twenty-four Spraque Dawley rats were randomly divided into four groups; the control group, the RES group given 20 mg/kg RES for 10 days, the MTX group given single dose 30 mg/kg MTX, MTX+RES group given 20 mg/kg RES i.p. for 7 days and 30 mg/ kg MTX i.p. on the 7th day, RES being maintained for 3 further days. All rats were sacrificed on the 10th day, and small intestinal tissue was removed for histopathological and biochemical analysis. Additionally, mucosal apoptosis was analyzed using the TUNEL method. RESULTS: Histopathologically, villar fusion, atrophic villus epithelium, cystic expansion in crypts, hemorrhage and inflammatory cell infiltration were seen in the small intestine in the MTX group. In the MTX+RES group this histopathological damage decreased significantly. Apoptotic score was significantly higher in the MTX group and significantly lower in the MTX+RES group. Tissue malondialdehyde (MDA) level was significantly higher in the MTX group. Superoxide dismutase (SOD) activity was significantly decreased in the MTX group. The MDA level in the MTX+RES group decreased while SOD and catalase (CAT) activities rose, this was not statistically significant. PMID- 26621168 TI - Sodium hydrosulphide against renal ischemia/reperfusion and the possible contribution of nitric oxide in adult male Albino rats. AB - This study evaluates the effects produced by H2S donor; sodium hydrosulfide (NaHS), in a renal ischemia/reperfusion (IR) rat model and assesses the possible mediating role of nitric oxide (NO) in these H2S' effects. BACKGROUND: For several centuries, hydrogen sulfide (H2S) had been known to be a highly toxic agent. Recent studies, however, indicated that apart from NO and CO, H2S is the third "gasotransmitter" involved in the regulation of various physiological functions. Nevertheless, its impact on renal IR injury remains unclear. METHODS: Rats were randomly divided into three groups: sham control; renal IR; and renal IR+NaHS groups.NaHS (100 umol/kg, ip) was administered 30 min prior to the induction of renal ischemia. RESULTS: NaHS was found to attenuate significantly the IR-induced elevations in the serum levels of urea, creatinine and tumor necrosis factor alpha (TNF-alpha) as compared with IR group. NaHS also significantly compensated the deficits in the total antioxidant capacities (TAC) and lowered the elevated malondialdehyde (MDA) levels observed with renal IR in renal, hepatic, pulmonary, and cardiac tissues. Furthermore, NaHS pretreatment down-regulated the renal IR-induced over-expression of inducible nitric oxide synthase (iNOS) and up-regulated the IR-induced suppression of endothelial nitric oxide synthase (eNOS). The loss of normal architecture, hemorrhage, and inflammatory cells infiltration detected by histopathological examination of renal, hepatic, pulmonary, and cardiac tissues in IR rats were markedly ameliorated by pre-ischemic NaHS treatment. CONCLUSION: NaHS protects against the effects of renal IR injury by acting primarily through a decrease in both pro inflammatory cytokines and iNOS expression as well as through up-regulation of the eNOS pathway. Furthermore, H2S has a powerful anti-oxidant and anti-apoptotic effects (Tab. 2, Fig. 6, Ref. 45). PMID- 26621169 TI - Effects of tomato pulp on hepatic steatosis in the rats fed with high fat diet. AB - BACKGROUND: Hepatic steatosis is one of the most common causes of chronic liver injury. OBJECTIVES: This study was aimed to evaluate the protective effects of Solanumlycopersicum (tomato) pulp on high fat diet-induced hepatic steatosis in rats. METHODS: Male Wistar rats were treated in 4 experimental groups including: healthy control group given standard diet, high fat diet group for induction of hepatic steatosis, high fat diet plus Clofibrate as positive control, and high fat diet plus tomato pulp for protection of liver steatosis. Finally, the groups were compared considering serum lipid profile, serum biomarkers of liver tissue injury and liver histopathological changes. The lipid peroxidation product and the activities of antioxidant enzymes were measured as the indicators of antioxidation in liver. RESULTS: Rats fed with the high fat diet showed hypertriglyceridemia, hypercholesterolemia, increased activities of hepatocellular enzymes, significant decline in antioxidants, and elevated lipid peroxidation indices in liver. Tomato pulp treatment significantly reduced elevated markers of liver injury and malondialdehyde level, as well as brought back the liver antioxidants and the excessive accumulation of lipids in serum towards normal. CONCLUSION: The results showed that tomato pulp exerted protective effects against hepatic steatosis in rats fed with high fat diet, possibly through its antioxidant actions (Tab. 5, Fig. 2, Ref. 40). PMID- 26621170 TI - Liposomal formulations of amphotericin B: differences according to the scientific evidence. AB - This article presents an overview of the characteristics of liposomes as drug carriers, particularly in relation to liposomal formulations of amphotericin B. General features regarding structure, liposome-cell interactions, stability, encapsulation of active substances and elimination of liposomes are described. Up to the present time extensive efforts to produce similar or bioequivalent products of amphotericin B formulations, in particular in the case of liposomal amphotericin B, have been unsuccessful in spite of having a very similar composition and even an apparently identical manufacturing process. Guidelines for the development of generic liposomal formulations developed by the FDA and EMA are also summarized. Based on the available evidence of the composition of liposomes, any differences in the manufacturing process even if the same lipid composition is used may result in different final products. Therefore, it seems unreasonable to infer that all amphotericin B liposomal formulations are equal in efficacy and safety. PMID- 26621171 TI - [Potential antimicrobial drug interactions in clinical practice: consequences of polypharmacy and multidrug resistance]. AB - BACKGROUND: Polypharmacy is a growing problem nowadays, which can increase the risk of potential drug interactions, and result in a loss of effectiveness. This is particularly relevant to the anti-infective therapy, especially when infection is produced by resistant bacteria, because therapeutic options are limited and interactions can cause treatment failure. METHODS: All antimicrobial prescriptions were retrospectively reviewed during a week in the Pharmacy Department, in order to detect potential drug-interactions and analysing their clinical significance. A total of 314 antimicrobial prescriptions from 151 patients were checked. RESULTS: There was at least one potential interaction detected in 40% of patients, being more frequent and severe in those infected with multidrug-resistant microorganisms. Drugs most commonly involved were quinolones, azoles, linezolid and vancomycin. CONCLUSIONS: Potential drug interactions with antimicrobial agents are a frequent problem that can result in a loss of effectiveness. This is why they should be detected and avoided when possible, in order to optimize antimicrobial therapy, especially in case of multidrug resistant infections. PMID- 26621172 TI - [Surveillance of resistance of Staphylococcus aureus to antibiotics in Galicia: 2007-2012]. AB - INTRODUCTION: Since 2007 the Galician Surveillance Program on Antimicrobial Resistance has been collected data of Staphylococcus aureus susceptibility patterns. The data from 2007 to 2012 have been analyzed and are reported. METHODS: A total of 4,577 different isolates of S. aureus from cerebrospinal fluid and blood cultures were included. The Institutions involved provided the information about the susceptibility patterns, the assay methods used and the interpretative guidelines followed, and demographic data of patients. RESULTS: The rate of methicillin-resistance S. aureus (MRSA) was 22% in 2007-2010 and 26% in 2011-2012, although in some areas the percentage reached 57% (2007- 2010) or 66% (2011-2012). The higher rates of resistance were found in patients older than 75 years. Gentamycin resistance was less than 9% and for quinolones were about 25%. A strong association between methicillin and quinolone-resistance were observed (91%). The resistance against linezolid and glycopeptides were exceptional. CONCLUSIONS: The percentage of MRSA has evolved slightly along the period of this study reaching no significant differences between Galicia and the global data in Spain in 2012. Nevertheless, there are significant differences among the geographic areas studied. Most MRSA isolates were recovered from hospitalized patients, but an increase in the number of MRSA among outpatients was observed, while old patients from nursing homes are included in the outpatient group, so the MRSA rate in this group could be overestimated. PMID- 26621173 TI - [Analysis of the concordance of antibiotic treatment for patients with severe sepsis in emergencies]. AB - OBJECTIVES: Antibiotic treatment is vital in patients with severe sepsis/septic shock. The objectives were to assess the degree of concordance between antibiotic prescribed in emergencies and post requirements; to relate it to health outcomes (mortality) and to analyze the reasons for disagreement. MATERIAL AND METHODS: Retrospective descriptive study of antibiotic treatment prescribed in emergencies and the subsequent treatment in patients with criteria of severe sepsis/septic shock in 2013. We collected patient demographic characteristics, infectious focus, antibiotic prescribed from emergencies and subsequent changes. It was considered concordant if there were no changes, if there were changes, but the initial antibiotic was right and suspensions for end of treatment. Mortality and evolution were analyzed. RESULTS: Six hundred patients were included. A 60% experienced changes respect to the antibiotic treatment initiated in emergencies (87.6% justified), with a degree of overall antibiotic concordance of 47.5% The mortality rate at end-point was 9.83%, with no statistically significant relationship with the degree of concordance (OR=0.864 (0.503-1.484)/chi2=0.28; p=0.597). Reasons for change of antibiotic: clinical outcome (17.96%), change of spectrum (35.03%), de-escalation (41.32%), sequential therapy (8.68%). An 11% required ICU admission. Clinical outcomes: resolution of the disease (79.2%), readmission after 30 days (7.7%) and transfer to health centers (4.5%). The median hospital stay was 7 days. CONCLUSIONS: The degree of concordance antibiotic was quite high, and the mortality rate was lower than that described in the literature, without relating to the discordance. The presence of concordance was associated with fewer readmissions and ICU admissions. The main reasons for disagreement were inadequate spectrum selection and change after microbiological crops. PMID- 26621174 TI - Use of antibiotics at a University Clinic Hospital: effect of protocolized antibiotic treatment in the evolution of hospital patients with infections. AB - OBJECTIVES: To analyse factors associated to "failure" in patients under antibiotic (AB) treatment at a third level hospital. PATIENTS AND METHODS: All patients receiving an AB treatment along April 2012 were prospectively observed and factors associated to failure were analyzed. Failure was defined as clinical or microbiological failure, relapse or death. Statistically significance was established as p<0.05. RESULTS: 602 of 1,265 admitted patients during the study month included an AB in their medical prescriptions, being 178 considered as prophylactic AB prescriptions, 342 empirical treatments and 82 directed treatments as empiric treatments. Ceftriaxone and levofloxacin were the most used AB; choice of empirical and directed treatments were in line with protocols in 71% (242 of 342 cases) and 67% (55 of 82), respectively. Of all the patients receiving antibiotics for therapy (n=424), 402 had infection criteria (in 22 cases antibiotic treatment was deemed unnecessary since the patient showed no infectious process). Of these, 292 (72%) showed a good evolution, while the others were considered as failed therapies, either because of microbiological persistence in 49 (12.8%), relapse in 31 (7.71%) and death in en 30 (7.46%). Factors associated to "failure" were Charlson score >=3 (OR 3.35; 95%CI 1.602 7.009); empirical and/or directed treatment not in keeping with the protocol (OR 5.68; 95%CI 2.898-11.217); and infection by ESBL and/or ciprofloxacin resistant E. coli (OR 4.43; 95%CI 1.492-13.184). CONCLUSIONS: A high rate of AB prescriptions in admitted patients correspond to empirical infection treatment, being ceftriaxone and levofloxacin the most used AB. Inadequate empirical and/or directed treatment is associated to clinical or microbiological failure and death. PMID- 26621175 TI - Clinical features and outcomes of aspiration pneumonia and non-aspiration pneumonia in octogenarians and nonagenarians admitted in a General Internal Medicine Unit. AB - INTRODUCTION: Pneumonia is a common infectious disease and causes significant morbidity and mortality especially in elderly people. Aspiration as a cause of pneumonia is common in this population. The aim of our study was to describe the clinical features and outcomes of very old patients with aspiration pneumonia (AP) and comparing them with patients with non-AP. MATERIAL AND METHODS: In this prospective cohort study, we analyzed old patients (>=80 years-old) with pneumonia admitted 2014 in the Department of General Internal Medicine. RESULTS: Seventy-six old patients with pneumonia were included in the study, and 46 (60.5%) met criteria of AP. Increasing levels of urea, creatinine and sodium and low estimated glomerular filtrate rate were more common among AP patients. In addition, severity of pneumonia scored by pneumonia severity index and CURB-65 score were significantly greater in AP than in non-AP patients. The 30-days mortality in AP was (44%) quite higher than in non-AP (32%). The only predictor of mortality was high level of sodium (odds ratio: 1.09; 95% confidence intervals: 1.00-1.18). CONCLUSIONS: AP in octogenarian and nonagenarians showed higher levels of sodium and low estimated glomerular filtrate rate and higher severity of pneumonia and slightly higher mortality than non-AP. PMID- 26621176 TI - [Seroprevalence of hepatitis E virus in patients with hepatitis C and / or infected with HIV]. AB - INTRODUCTION: Hepatitis E virus (HEV) can cause chronic infection and cirrhosis. The seroprevalence data of anti-HEV IgG in the patients infected with HIV or with chronic liver disease are scarce. METHODS: To document the seroprevalence of HEV infection in HIV patients or with chronic liver disease population, a retrospective study in serum samples from 625 patients was carried on: 200 HIV infected, 200 HCV infected, 25 coinfected by HIV and HCV and 200 healthy controls. Anti-HVE IgG antibodies were determined in serum samples by a commercial immunoassay (EIA) and all positive samples were studied further for the presence of anti-HEV IgM antibodies (HEV IgM 3.0; DiaSorin, Turin, Italy). Positive HEV IgM antibody specimens were examined for HEV RNA by polymerase chain reaction. RESULTS: Anti-HEV IgG were reactive in 25 (12.5%) of the 200 HIV infected patients, in 47 out of 200 HCV infected patients (23.5%), 10 out of 25 coinfected HIV-HCV group (40%) and 24 out of 200 healthy controls (12%). According to EIA anti-HEV IgM, 11 patients could be considered as acute hepatitis E cases but in only one of them was confirmed recent HEV infection by RT-PCR. CONCLUSIONS: The higher seroprevalence was found in HIV-HCV coinfected patients. The only patient with HEV RNA was HIV-HCV coinfected. PMID- 26621177 TI - [Measurement of antimicrobial consumption using DDD per 100 bed-days versus DDD per 100 discharges after the implementation of an antimicrobial stewardship program]. AB - INTRODUCTION: Monitoring antimicrobial consumption in hospitals is a necessary measure. The indicators commonly employed do not clearly reflect the antibiotic selection pressure. The objective of this study is to evaluate two different methods that analyze antimicrobial consumption based on DDD, per stay and per discharge, before and after the implementation an antimicrobial stewardship program. MATERIAL AND METHODS: Comparative pre-post study of antimicrobial consumption with the implementation of an antimicrobial stewardship program using DDD per 100 bed-days and DDD per 100 discharges as indicators. RESULTS: Hospital bed days remained stable and discharges increased slightly along the period of study Antibiotic consumption in DDD per 100 bed-days decreased by 2.5% versus 3.8% when expressed as DDD per 100 discharges. Antifungal consumption decreased by more than 50%. CONCLUSIONS: When average hospital stay decreases, reductions in the consumption of antimicrobials with an antimicrobial stewardship program system occur at the expense of reducing the number of patients receiving treatment, while increases occur due to longer durations of treatment. PMID- 26621178 TI - [Cellulitis by Neisseria weaveri after a dog bite]. PMID- 26621179 TI - [Gastric cytomegalovirus infection in a patient with non-Hodgkin's lymphoma]. PMID- 26621180 TI - [Urinary tract infection associated with Delftia acidovorans]. PMID- 26621181 TI - [Enhanced recovery of group B Streptococcus in pregnant women screening]. PMID- 26621182 TI - A roadmap for better mental health in New York City. PMID- 26621183 TI - QRS prolongation after cardiac resynchronization therapy is a predictor of persistent mechanical dyssynchrony. AB - PURPOSE: Prolonged QRS duration is the main selection criterion for cardiac resynchronization therapy (CRT) which ameliorates left ventricular mechanical dyssynchrony (MD). However, consequences of post-CRT QRS prolongation and residual MD have been poorly evaluated. We aimed to define the predictors of persistent MD and hypothesized that CRT-induced QRS change (DeltaQRS) might have an impact on residual MD after CRT. METHODS: A total of 80 patients receiving CRT were included in the study. DeltaQRS was calculated as the difference between the baseline and paced QRS intervals. Residual MD was assessed early after device implantation with a longitudinal dyssynchrony index (Yu index). Significant MD was defined as a Yu index >= 33 msec. Two groups were created based on residual MD and compared according to clinical, electrocardiographic and echocardiographic features. RESULTS: Patients with persistent MD had longer paced QRS durations (182.5 +/- 16.2 vs. 165.4 +/- 22.5 msec, p = 0.03) and were less likely to have left ventricular (LV) leads located in the posterolateral vein (53 % vs. 85 %, p = 0.002). The linear correlation between the DeltaQRS and the Yu index values was modest (Spearman's rho = -0.341, p = 0.002); additionally, a prolonged QRS was strongly associated with MD after CRT (p = 0.00008). Both LV lead localization and CRT-induced QRS prolongation emerged as the significant predictors of persistent MD. A biventricularly paced QRS more than 10 msec longer than the pre paced QRS width was predictive of persistent MD after CRT (sensitivity = 80 %, specificity = 62 %). CONCLUSIONS: DeltaQRS was found to be associated with residual MD after CRT. Ten milliseconds of QRS prolongation predicted persistent MD after CRT. PMID- 26621184 TI - Characterization of a novel highly thermostable esterase from the Gram-positive soil bacterium Streptomyces lividans TK64. AB - A novel esterase gene (estW) from soil bacterium Streptomyces lividans TK64 was successfully cloned using a pair of homologous primers. The estW gene encoded a protein (EstW) of 289 amino acid residues with a predicted molecular weight of 31.43 kDa. Sequence alignment revealed that EstW show relatively high levels of homology to other lipolytic enzymes characterized from Streptomyces and phylogenetic analysis suggested EstW belongs to the bacterial lipase/esterase family I. The estW gene was expressed at a high level in Escherichia coli and the recombinant enzyme was purified to homogeneity. The purified EstW was characterized via hydrolysis of various p-nitrophenyl esters and the best substrate was found to be p-nitrophenyl acetate (pNPA). Maximal activity of the recombinant protein was observed at pH 8.0 and 50 degrees C with pNPA as the substrate. The calculated activation energy (Ea ) of the esterase reaction was 9.12 kcal/mol. Half-life of EstW at 95 degrees C was approximately 12.5 H, making it the most thermostable esterase among all of the known lipolytic enzymes from Streptomyces, and the thermostability of EstW was similar to those of some enzymes characterized from the thermophilic bacteria. EstW exhibited relatively high tolerance to several detergents and required no cations for its maximal activity. The unique properties of EstW, namely its high thermostability and stability in the presence of organic solvents, may render it a potential candidate for industrial applications. PMID- 26621186 TI - Highlight report: xenobiotic-metabolizing enzymes in skin models. PMID- 26621185 TI - Controlling the Architecture, Coordination, and Reactivity of Nanoparticle Coating Utilizing an Amino Acid Central Scaffold. AB - We have developed a versatile strategy to prepare a series of multicoordinating and multifunctional ligands optimized for the surface-functionalization of luminescent quantum dots (QDs) and gold nanoparticles (AuNPs) alike. Our chemical design relies on the modification of l-aspartic acid precursor to controllably combine, through simple peptide coupling chemistry, one or two lipoic acid (LA) groups and poly(ethylene glycol) (PEG) moieties in the same ligand. This route has provided two sets of modular ligands: (i) bis(LA)-PEG, which presents two lipoic acids (higher coordination) appended onto a single end-functionalized PEG, and (ii) LA-(PEG)2 made of two PEG moieties (higher branching, with various end reactive groups) appended onto a single lipoic acid. These ligands are combined with a new photoligation strategy to yield hydrophilic and reactive QDs that are colloidally stable over a broad range of conditions, including storage at nanomolar concentration and under ambient conditions. AuNPs capped with these ligands exhibit excellent stability in various biological conditions and improved resistance against NaCN digestion. This route also provides compact nanocrystals with tunable surface reactivity. As such, we have covalently coupled QDs capped with bis(LA)-PEG-COOH to transferrin to facilitate intracellular uptake. We have also characterized and quantified the coupling of dye-labeled peptides to QD surfaces using fluorescence resonance energy transfer interactions in QD-peptide dye assemblies. PMID- 26621189 TI - Response to Editorial Comment to Features, risk factors and clinical outcome of "very late" recurrences after surgery for localized renal carcinoma: A retrospective evaluation of a cohort with a minimum of 10 years of follow up. PMID- 26621188 TI - The role of siderophores in metal homeostasis of members of the genus Burkholderia. AB - Although members of the genus Burkholderia can utilize a high-affinity iron uptake system to sustain growth under iron-limiting conditions, many strains also produce siderophores, suggesting that they may serve alternative functions. Here we demonstrate that the two Burkholderia siderophores pyochelin and ornibactin can protect the cells from metal toxicity and thus play an alternative role in metal homeostasis. We also demonstrate that metals such as copper and zinc induce the production of ornibactin. PMID- 26621187 TI - Feasibility of Neoadjuvant Ad-REIC Gene Therapy in Patients with High-Risk Localized Prostate Cancer Undergoing Radical Prostatectomy. AB - In a phase I/IIa study of in situ gene therapy using an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC), we assessed the inhibitory effects of cancer recurrence after radical prostatectomy (RP), in patients with high risk localized prostate cancer (PCa). After completing the therapeutic interventions with initially planned three escalating doses of 1.0 * 10(10) , 1.0 * 10(11) , and 1.0 * 10(12) viral particles (VP) in 1.0-1.2 mL (n = 3, 3, and 6), an additional higher dose of 3.0 * 10(12) VP in 3.6 mL (n = 6) was further studied. Patients with recurrence probability of 35% or more within 5 years after RP as calculated by Kattan's nomogram, were enrolled. They received two ultrasound guided intratumoral injections at 2-week intervals, followed by RP 6 weeks after the second injection. Based on the findings of MRI and biopsy mapping, as a rule, one track injection to the most prominent cancer area was given to initial 12 patients and 3 track injections to multiple cancer areas in additional 6 patients. As compared to the former group, biochemical recurrence-free survival of the latter showed a significantly favorable outcome. Neoadjuvant Ad-REIC, mediating simultaneous induction of cancer selective apoptosis and augmentation of antitumor immunity, is a feasible approach in preventing cancer recurrence after RP. (199). PMID- 26621190 TI - Tuning of nanoparticle biological functionality through controlled surface chemistry and characterisation at the bioconjugated nanoparticle surface. AB - We have used a silica - PEG based bionanoconjugate synthetic scheme to study the subtle connection between cell receptor specific recognition and architecture of surface functionalization chemistry. Extensive physicochemical characterization of the grafted architecture is capable of capturing significant levels of detail of both the linker and grafted organization, allowing for improved reproducibility and ultimately insight into biological functionality. Our data suggest that scaffold details, propagating PEG layer architecture effects, determine not only the rate of uptake of conjugated nanoparticles into cells but also, more significantly, the specificity of pathways via which uptake occurs. PMID- 26621191 TI - A biomimetic hybrid nanoplatform for encapsulation and precisely controlled delivery of theranostic agents. [Corrected]. AB - Nanoparticles have demonstrated great potential for enhancing drug delivery. However, the low drug encapsulation efficiency at high drug-to-nanoparticle feeding ratios and minimal drug loading content in nanoparticle at any feeding ratios are major hurdles to their widespread applications. Here we report a robust eukaryotic cell-like hybrid nanoplatform (EukaCell) for encapsulation of theranostic agents (doxorubicin and indocyanine green). The EukaCell consists of a phospholipid membrane, a cytoskeleton-like mesoporous silica matrix and a nucleus-like fullerene core. At high drug-to-nanoparticle feeding ratios (for example, 1:0.5), the encapsulation efficiency and loading content can be improved by 58 and 21 times, respectively, compared with conventional silica nanoparticles. Moreover, release of the encapsulated drug can be precisely controlled via dosing near infrared laser irradiation. Ultimately, the ultra-high (up to ~87%) loading content renders augmented anticancer capacity both in vitro and in vivo. Our EukaCell is valuable for drug delivery to fight against cancer and potentially other diseases. PMID- 26621192 TI - Successful treatment with an anti-PD-1 antibody for progressing brain metastases in renal cell cancer. PMID- 26621193 TI - More colors to the palette. PMID- 26621195 TI - District nurses' experiences of preventive home visits to 75-year-olds in Stockholm: a qualitative study. AB - Aims This study had two aims: to describe the dialogue between district nurses (DNs) and older people in preventive home visits (PHVs) from the perspective of the DNs, and to identify barriers to and facilitators of this dialogue as perceived by the DNs. BACKGROUND: The number of older people is rapidly increasing in all western countries, and as people's age increases, the probability that they will have multiple diseases also increases. Planned actions are therefore needed to promote health and prevent diseases among older people so they can remain in good health and live in their homes for as long as possible. In Sweden, PHVs to 75-year-olds by DNs are one such action. METHODS: This qualitative study included five group interviews with 20 DNs. Data were analysed with qualitative content analysis. Findings DNs' experiences of barriers to and facilitators of a successful health dialogue were sorted into five domains. Together, these domains provided a systematic description of the interaction between the DN and the older person in the PHV. The domains included: establishing trustful contact, conducting a structured interview, making an overall assessment, proposing health-promoting activities and offering follow-up. The barriers and facilitators could be related to the older person, the DN or the home environment. The latent content of the interviews was evident in three themes that were related to the DNs' experiences of barriers and facilitators. These themes illustrated professional dilemmas that the DNs had to resolve to achieve the purpose of the PHV. The study demonstrates that the interaction between a DN and an older person in a PHV can be described as a complex social process in which the DN balances a personal and professional approach, combines a person-oriented and a task-oriented approach and employs both a salutogenic and pathogenic perspective. PMID- 26621194 TI - Reduction in diarrhoeal rates through interventions that prevent unnecessary antibiotic exposure early in life in an observational birth cohort. AB - BACKGROUND: Antibiotic treatment early in life is often not needed and has been associated with increased rates of subsequent diarrhoea. We estimated the impact of realistic interventions, which would prevent unnecessary antibiotic exposures before 6 months of age, on reducing childhood diarrhoeal rates. METHODS: In data from a prospective observational cohort study conducted in Vellore, India, we used the parametric g-formula to model diarrhoeal incidence rate differences contrasting the observed incidence of diarrhoea to the incidence expected under hypothetical interventions. The interventions prevented unnecessary antibiotic treatments for non-bloody diarrhoea, vomiting and upper respiratory infections before 6 months of age. We also modelled targeted interventions, in which unnecessary antibiotic use was prevented only among children who had already stopped exclusive breast feeding. RESULTS: More than half of all antibiotic exposures before 6 months (58.9%) were likely unnecessary. The incidence rate difference associated with removing unnecessary antibiotic use before 6 months of age was -0.28 (95% CI -0.46 to -0.08) episodes per 30 child-months. This implies that preventing unnecessary antibiotic exposures in just 4 children would reduce the incidence of diarrhoea by 1 from 6 months to 3 years of age. CONCLUSIONS: Interventions to reduce unnecessary antibiotic use among young children could result in an important reduction in diarrhoeal rates. This work provides an example application of statistical methods which can further the aim of presenting epidemiological findings that are relevant to public health practice. PMID- 26621196 TI - Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy. AB - The macrophage is known to be a multifunctional antigen presenting cells and playing a central role in inflammation. Macrophages infiltrate into malignant tumor tissues in high numbers (the so-called tumor-associated macrophages [TAMs]) and many studies over the past decade have demonstrated that macrophages have protumor functions and are closely related to tumor progression. It has been shown that protumor macrophages that have differentiated through interaction with tumor cells are involved in stem cell niches, immunosuppression, invasion, and metastasis. Consistent with these functions, studies using human tumor samples have demonstrated that a higher density of macrophages, especially macrophages with the M2 phenotype, is closely associated with worse clinical prognosis in many kinds of malignant tumors. Infiltrating TAMs themselves or polarization pathway of TAMs are considered as new therapeutic targets for the therapy of malignant tumors. PMID- 26621197 TI - Infective endocarditis requiring ICU admission: epidemiology and prognosis. AB - BACKGROUND: Very few studies focused on patients with severe infective endocarditis (IE) and multiple complications leading to Intensive Care Unit (ICU) admission. Studied primary outcomes depended on the series and multiple prognostic factors have been identified. Our goal was to determinate characteristics of patients, in-hospital mortality and independent prognostic factors in an overall population of patients admitted to ICU for a left-sided, definite, active and severe IE. METHODS: Retrospective study performed in 9 ICUs during an 11-year period. RESULTS: Data of 248 patients (mean age = 62.4 +/- 13.3 years; 63.7 % male) were studied. Native and prosthetic valves were involved in 195 and 53 patients, respectively. Causative pathogens, identified in 225 patients, were mainly streptococci (45.6 %) and staphylococci (43.4 %). On ICU admission, 127 patients exhibited extra-cardiac involvement. Ninety-five patients had one or more neurological complications, as followed: ischemic stroke (n = 66), cerebral hemorrhage (n = 31), meningitis (n = 16), brain abscess (n = 16), and intracranial mycotic aneurysm (n = 10). Criteria prompting to cardiac surgery appeared during ICU stay for 186 patients and between ICU and hospital discharges in 5 patients. Due to contra-indications, surgery required by IE was only performed during hospitalization in 125 patients. Moreover, surgery was considered adequate according to usual guidelines in 76 of 191 patients with indication(s) of valvular surgery: for patients with surgical procedure considered as emergency (n = 69), 17 surgical procedures underwent within the first 24 h following indication; for patients with urgent surgical indication (n = 102), surgery was performed during the first week following indication in 40 patients; finally, elective surgery (n = 20) was performed for 19 patients. During hospitalization, 103 (41.5 %) patients died. Four independent prognostic factors were identified: SAPS II > 35 (AOR = 2.604; 95 % CI: 1.320-5.136; p = 0.0058), SOFA > 8 (AOR = 3.327; 95 % CI: 1.697-6.521; p = 0.0005), IE due to methicillin resistant Staphylococcus aureus (AOR = 4.981; 95 %CI = 1.433-17.306; p = 0.0115) and native IE (AOR = 0.345; 95 % CI: 0.169-0.703; p = 0.0034). CONCLUSIONS: Mortality in patients admitted to ICU for left-sided IE remains high, especially in cases of endocarditis due to methicillin resistant Staphylococcus aureus, when organ failures occur and ICU scores are high. PMID- 26621198 TI - Platelet transfusions in cancer patients with hypoproliferative thrombocytopenia in the intensive care unit. AB - BACKGROUND: Thrombocytopenia is a frequent finding in critically ill cancer patients for whom indications of platelet transfusions are unclear. We herein addressed the current practices in platelet transfusion and the risk of bleeding in cancer patients with hypoproliferative thrombocytopenia in the intensive care unit (ICU). METHODS: A retrospective monocenter study over a 7-year period was conducted in a medical ICU. Adult patients with malignancies and hypoproliferative thrombocytopenia, and who received at least one platelet concentrate during their ICU stay, were included. RESULTS: 296 patients were included and received a total of 904 platelet transfusions, for prophylactic indications in 300 (33.2 %) episodes, for securing an invasive procedure in 257 (28.4 %), and for treatment of minor to major bleeding manifestations in 347 (38.4 %). Most prophylactic transfusions (80 %) were performed at platelet count thresholds below 10-20 * 10(9)/L. Platelet increments were generally low in all three indications, 10 (interquartile range 2-25), 11 (2-25), and 8 (0-21) * 10(9)/L, respectively. A total of 97 major ICU-acquired bleeding events occurred in 40 patients. About half of those bleeding episodes (54.7 %) occurred at platelet counts below 20 * 10(9)/L. However, neither low admission platelet count nor low nadir platelet counts were predictive of ICU-acquired bleeding. The in ICU mortality rate tended to be higher in patients with severe ICU-acquired bleeding events (50 vs. 36 %). CONCLUSIONS: Most prophylactic platelet transfusions were given using thresholds of 10-20 * 10(9)/L in critically ill thrombocytopenic cancer patients. The individual risk of ICU-acquired severe bleeding appears hardly predictable with the depth of thrombocytopenia. PMID- 26621199 TI - A homochiral vanadium-salen based cadmium bpdc MOF with permanent porosity as an asymmetric catalyst in solvent-free cyanosilylation. AB - A homochiral vanadium-salen based MOF with the pcu topology is constructed via in situ synthesis under solvothermal conditions. The synthesized MOF exhibits BET surface areas of 574 m(2) g(-1), showing the highest H2 adsorption capacity (1.05 wt% at 77 K, 1 bar) and the highest CO2 uptake (51 cm(3) g(-1) at 273 K, 1 bar) for currently known salen-based MOFs. This framework shows excellent performance as an asymmetric catalyst in solvent-free cyanosilylation. PMID- 26621200 TI - Aggression-related alcohol expectancies and barroom aggression among construction tradespeople. AB - INTRODUCTION AND AIMS: Few studies have investigated the relationship of barroom aggression with both general and barroom-specific alcohol expectancies. The present study investigated these associations in a rarely studied and high-risk population: construction tradespeople. DESIGN AND METHODS: Male construction tradespeople (n = 211) aged 18-35 years (M = 21.91, SD = 4.08 years) participated in a face-to-face questionnaire assessing general and barroom-specific alcohol expectancies and perpetration of physical and verbal barroom aggression as well as control variables, age, alcohol consumption and trait aggression. RESULTS: Sequential logistic regression analyses revealed that general alcohol-aggression expectancies of courage or dominance were not predictive of either verbal or physical barroom aggression after controlling for age, alcohol consumption and trait aggression. However, barroom-specific alcohol expectancies were associated with both verbal and physical barroom aggression, with positive associations found for expected hyper-emotionality and protective effects for expected cognitive impairment. DISCUSSION AND CONCLUSIONS: In a population where rates of risky drinking and barroom aggression are high, specific expectations about the effects of drinking in bars may influence subsequent aggressive behaviour in bars. [Zinkiewicz L, Smith G, Burn M, Litherland S, Wells S, Graham K, Miller P. Aggression-related alcohol expectancies and barroom aggression among construction tradespeople. Drug Alcohol Rev 2016;35:549-556]. PMID- 26621201 TI - Alcohol use in shiftworkers. AB - It has been suggested that shiftworkers may consume alcohol to help them sleep, resulting in greater consumption. A large study in Australian workers suggested that those on non-standard schedules (outside 8am-6pm, Monday-Friday) do not drink more, but are at increased odds of binge drinking (heavy periods of drinking followed by abstinence) than workers on standard schedules. However, differences in types of non-standard schedules were not examined in the study. The current study examined the alcohol intake of Australian shiftworkers on fixed and rotating shifts. Shiftworkers (n=118, age=43.4+/-9.9y, 68% male) on 12h rotating (n=29), 8h-rotating (n=29), morning (n=33) and night (n=27) schedules from printing, postal, nursing and oil industries participated. They completed a Cancer Council Dietary Questionnaire, recording frequency and amount of alcohol consumed on average per day over the preceding year. They also completed a shortened Standard Shiftwork Index, including questions on shift schedule, sleep duration, tiredness, gender and age. Average alcohol consumption was 9.6+/-13.1 standard drinks/week. One in six reported using alcohol as a sleep aid between shifts at least sometimes and nearly one third reported consuming 12 or more drinks in 24h. Alcohol consumption was higher for males and decreased with age. Controlling for gender and age, there were no significant differences between shift types in standard drinks/week (p=0.50). However, those on 12-h rotating shifts consumed more drinks per 24h (p=0.04) and had less sleep (p<0.001). Results support the suggestion that shiftworkers are likely to binge drink, particularly younger, male workers and those on long, rotating shifts. Alcohol use in shiftworkers may put increased pressure on already vulnerable physiological systems. PMID- 26621202 TI - Maternal folate deficiency and metabolic dysfunction in offspring. AB - The importance of folate during pregnancy was established more than 80 years ago by Lucy Wills' ground-breaking studies of tropical macrocytic anaemia. More recently, it has become apparent that the adverse consequences of inadequate nutrient supply during early developmental may be exacerbated by over-nutrition postnatally. The present paper aims to review recent evidence that maternal methyl donor (notably folate) supply peri-conceptually and during pregnancy has long-term effects on offspring (metabolic) health. In addition, we propose the hypothesis that epigenetic mechanisms, especially DNA methylation, may mediate the effects of these early life nutritional insults. We discuss evidence from a natural experiment in human subjects which provides proof of principle for the hypothesis. We describe an attempt to test this hypothesis using a mouse model in which female C57Bl/6 mice were randomised to low or normal folate diets prior to, and during, pregnancy and lactation. Low maternal folate supply resulted in offspring that were more susceptible to detrimental metabolic effects of a high fat diet fed from weaning, manifested as increased circulating TAG concentration. Interestingly, this metabolic phenotype in adult offspring occurred without any detectable change in adiposity, suggesting a different aetiological origin from the more commonly reported observation that maternal undernutrition leads to increased offspring adiposity and to symptoms of the Metabolic Syndrome. The widespread prevalence of overweight and obesity and of folate deficiency among women of child-bearing age highlights the possibility that this double nutritional insult may exacerbate the risk of metabolic disease in their offspring. PMID- 26621203 TI - Origin of marine planktonic cyanobacteria. AB - Marine planktonic cyanobacteria contributed to the widespread oxygenation of the oceans towards the end of the Pre-Cambrian and their evolutionary origin represents a key transition in the geochemical evolution of the Earth surface. Little is known, however, about the evolutionary events that led to the appearance of marine planktonic cyanobacteria. I present here phylogenomic (135 proteins and two ribosomal RNAs), Bayesian relaxed molecular clock (18 proteins, SSU and LSU) and Bayesian stochastic character mapping analyses from 131 cyanobacteria genomes with the aim to unravel key evolutionary steps involved in the origin of marine planktonic cyanobacteria. While filamentous cell types evolved early on at around 2,600-2,300 Mya and likely dominated microbial mats in benthic environments for most of the Proterozoic (2,500-542 Mya), marine planktonic cyanobacteria evolved towards the end of the Proterozoic and early Phanerozoic. Crown groups of modern terrestrial and/or benthic coastal cyanobacteria appeared during the late Paleoproterozoic to early Mesoproterozoic. Decrease in cell diameter and loss of filamentous forms contributed to the evolution of unicellular planktonic lineages during the middle of the Mesoproterozoic (1,600-1,000 Mya) in freshwater environments. This study shows that marine planktonic cyanobacteria evolved from benthic marine and some diverged from freshwater ancestors during the Neoproterozoic (1,000-542 Mya). PMID- 26621205 TI - Quantitative shotgun proteomics reveals extensive changes to the proteome of the orbitofrontal cortex in rats that are hyperactive following withdrawal from a high sugar diet. AB - In most Westernized societies, there has been an alarming increase in the consumption of sugar-sweetened drinks. For many adults these drinks represent a substantial proportion of their total daily caloric intake. Here we investigated whether extended exposure to sugar changes behavior and protein expression in the orbitofrontal cortex (OFC). Male adult Sprague-Dawley rats (n = 8 per group) were treated for 26 days with either water or a 10% sucrose solution. Locomotor behavior was measured on the first and last day of treatment, then 1 week after treatment. Following the 1-week period free from treatment, sucrose treated rats were significantly more active than the control. Two hours following final behavioral testing, brains were rapidly removed and prepared for proteomic analysis of the OFC. Label free quantitative shotgun proteomic analyses of three rats from each group found 290 proteins were differentially expressed in the sucrose treated group when compared to the control group. Major changes in the proteome were seen in proteins related to energy metabolism, mitochondrial function and the cellular response to stress. This research does not seek to suggest that sugar will cause specific neurological disorders, however similar changes in proteins have been seen in neurological disorders such as Alzheimer's disease, Parkinson's disease and schizophrenia. PMID- 26621206 TI - Use of high concentrations of dimethyl sulfoxide for cryopreservation of HepG2 cells adhered to glass and polydimethylsiloxane matrices. AB - Animal cells are generally cryopreserved in cryovials in a cell suspension state containing 5%-10% v/v dimethyl sulfoxide (DMSO) used as a cryoprotective agent. However, cryopreservation of cells in an attached state has not been intensively studied, and the effective freezing solution remains unknown. Here we determined the suitable DMSO concentration for the cryopreservation of human hepatoma HepG2 cells attached to glass and polydimethylsiloxane (PDMS) matrices coated with poly l-lysine. With the use of the glass matrix, the rate of cell adhesion increased with the DMSO concentration up to 30% v/v in the freezing solution. In contrast, the cell-adhesion rate remained constant in the case of the PDMS matrix irrespective of the DMSO concentration between 10% v/v and 30% v/v. The viability of post-thawed cells attached to glass or PDMS matrix was also investigated. The viability was highest at the DMSO concentration of 20% v/v in the freezing solution. The DMSO concentration of 30% v/v, however, had a cytotoxic effect on the cell viability. Thus, the 20% v/v DMSO concentration was found to be most suitable for the cryopreservation of HepG2 cells in the attached state. This dose is high compared to the DMSO concentration used for the cryopreservation of cells in the suspended state. PMID- 26621207 TI - Heme oxygenase levels and metaflammation in benign prostatic hyperplasia patients. AB - PURPOSE: To investigate the relationship between intra-prostatic levels of heme oxygenase (HO), metaflammation in benign prostatic hyperplasia (BPH) tissue in patients with MetS and moderate-severe lower urinary tract symptoms (LUTS). METHODS: Between January 2012 and June 2013, 132 consecutive patients, who underwent transurethral resection of the prostate for moderate-severe LUTS, secondary to clinical BPH, were enrolled. Prostate samples were investigated for the presence of an inflammatory infiltrate, according to the Irani score, and for HO-1 and HO-2 levels measurements. Patients were evaluated for the presence of metabolic syndrome (MetS) defined by the International Diabetes Federation. RESULTS: We observed that subjects with MetS exhibited greater Irani score (3.0 vs. 2.0; p < 0.05), Irani grade (2.0 vs. 1.0; p < 0.05) and lower value of HO-1 (4.55 vs. 6.01; p < 0.05) and HO-2 (0.81 vs. 2.66; p < 0.05). HO-1 (3.91 vs. 5.67; p < 0.05) and HO-2 (1.06 vs. 1.37; p < 0.05) were significantly reduced in patients with high intra-prostatic inflammation (Irani score >=4). At the multivariate logistic regression analysis, HO-1 reduction (OR 0.588; p < 0.01), waist circumference (OR 1.09; p < 0.01), triglycerides (OR 1.013; p < 0.05) and HDL (OR 0.750; p < 0.05) were independent predictors of high intra-prostatic inflammation. We also found that HO-1 reduction (OR 0.598; p < 0.01) and the presence of MetS (OR 34.846; p < 0.01) were associated with Irani score >=4. CONCLUSION: MetS-induced inflammation may play a key role in BPH. In detail, prostate metaflammation is inversely related to intra-prostatic HO-1 levels, serum HDL and positively with triglycerides. PMID- 26621208 TI - Balancing risk and benefit of extended pelvic lymph node dissection in patients undergoing radical cystectomy. AB - PURPOSE: The optimal extent of pelvic lymph node dissection (PLND) during radical cystectomy (RC) in patients with urothelial carcinoma of the bladder (UCB) is the subject of ongoing debate. In this study, we compared local recurrence-free and overall survival, in addition to complication rates, after extended PLND (ePLND) compared to standard PLND (sPLND). METHODS: We reviewed the charts of 314 patients who underwent RC for UCB between 2008 and 2013. ePLND was performed in 105 patients, and 105 matched patients who underwent standard PLND (sPLND) were selected based on clinical parameters. Local recurrence-free and overall survival rates were assessed using Kaplan-Meier survival analysis, and Cox proportional hazards models were used to assess potential determinants of these outcomes. Complications were assessed at 30 and 90 days using the Clavien-Dindo reporting system. RESULTS: More lymph nodes were removed by ePLND (median 21) compared to sPLND (median 9; P < 0.001), but the rate of nodal involvement was not different. In multivariable analysis, ePLND was associated with a better local recurrence free survival (HR = 0.63, P = 0.005), but was not an independent predictor of overall survival (HR = 1.06, P = 0.84). Estimated blood loss was greater with ePLND (1047.3 vs. 584.5 ml P < 0.001), but there was no significant difference in complications. CONCLUSIONS: Extended PLND appears to reduce the risk of local recurrence, but was not an independent predictor of overall survival in this cohort. ePLND was associated with greater blood loss compared to sPLND, but not with other perioperative complications. PMID- 26621209 TI - Soil recovery across a chronosequence of restored wetlands in the Florida Everglades. AB - The restoration project in the Hole-in-the-Donut of Everglades National Park in Florida, USA is to reestablish native wetlands by complete removal of the invasive plants and the associated soil. However, there is little information available about changes in properties of the newly formed Marl soils in restored wetlands. In this study, we measured soil physicochemical properties, soil enzymatic activities, and stable isotopes of carbon (delta(13)C) in plants and soil organic carbon (SOC) in an undisturbed natural wetland (UNW) and three wetlands restored respectively in 1989, 1996 and 1999 (WR89, WR96 and WR99). The older restored wetlands (WR89 and WR96) are characterized by greater SOC and mineral nitrogen. The values of soil dehydrogenase and phosphatase activities in the four wetlands follow the order: UNW > WR89 > WR96 > WR99, and are consistent with changes in vegetation coverage. The principal component analysis shows that dehydrogenase and phosphatase activities are the vital variables contributing to the soil of UNW. The similar delta(13)C values of SOC and plants in the restored wetlands suggest the formation of SOC during restoration is mainly derived from the associated plants. These results indicate that the newly restored soils develop toward the soil in the UNW with time since restoration. PMID- 26621210 TI - In vitro and in vivo screening for novel essential cell-envelope proteins in Pseudomonas aeruginosa. AB - The Gram-negative bacterium Pseudomonas aeruginosa represents a prototype of multi-drug resistant opportunistic pathogens for which novel therapeutic options are urgently required. In order to identify new candidates as potential drug targets, we combined large-scale transposon mutagenesis data analysis and bioinformatics predictions to retrieve a set of putative essential genes which are conserved in P. aeruginosa and predicted to encode cell envelope or secreted proteins. By generating unmarked deletion or conditional mutants, we confirmed the in vitro essentiality of two periplasmic proteins, LptH and LolA, responsible for lipopolysaccharide and lipoproteins transport to the outer membrane respectively, and confirmed that they are important for cell envelope stability. LptH was also found to be essential for P. aeruginosa ability to cause infection in different animal models. Conversely, LolA-depleted cells appeared only partially impaired in pathogenicity, indicating that this protein likely plays a less relevant role during bacterial infection. Finally, we ruled out any involvement of the other six proteins under investigation in P. aeruginosa growth, cell envelope stability and virulence. Besides proposing LptH as a very promising drug target in P. aeruginosa, this study confirms the importance of in vitro and in vivo validation of potential essential genes identified through random transposon mutagenesis. PMID- 26621211 TI - Primary stability of inferior tilt fixation of the glenoid component in reverse total shoulder arthroplasty: A finite element study. AB - Glenoid component fixation with inferior tilt has been suggested as one of the surgical methods to decrease scapular notching and improve stability, but its clinically beneficial effect remains a concern. We evaluated the influence of inferior tilt fixation of the glenoid component on primary stability in reverse total shoulder arthroplasty by finite element analysis. Finite element models were constructed from cadaveric scapulae of females over the age of 60 years and glenoid components from reverse total shoulder arthroplasty. The relative micromotion at the bone-glenoid component interface, distribution of bone stress under the glenoid component and around the screws, contact area between the bone and screws, and cut surface area of the cancellous bone exposed after glenoid reaming were analyzed and compared between a neutral and 10 degrees inferior tilt fixation of the glenoid component. The 10 degrees inferior tilt fixation demonstrated greater relative micromotion and higher bone stress than the neutral tilt fixation. Eccentric reaming, which is done to produce the inferior tilt fixation of the glenoid component, increased glenoid cancellous bone exposure and decreased bone-screws contact area. Inferior tilt fixation of the glenoid component may adversely affect primary stability and longevity after reverse total shoulder arthroplasty. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1061-1068, 2016. PMID- 26621213 TI - Easy access to the calf for the lone surgeon. PMID- 26621212 TI - Optogenetics-enabled assessment of viral gene and cell therapy for restoration of cardiac excitability. AB - Multiple cardiac pathologies are accompanied by loss of tissue excitability, which leads to a range of heart rhythm disorders (arrhythmias). In addition to electronic device therapy (i.e. implantable pacemakers and cardioverter/defibrillators), biological approaches have recently been explored to restore pacemaking ability and to correct conduction slowing in the heart by delivering excitatory ion channels or ion channel agonists. Using optogenetics as a tool to selectively interrogate only cells transduced to produce an exogenous excitatory ion current, we experimentally and computationally quantify the efficiency of such biological approaches in rescuing cardiac excitability as a function of the mode of application (viral gene delivery or cell delivery) and the geometry of the transduced region (focal or spatially-distributed). We demonstrate that for each configuration (delivery mode and spatial pattern), the optical energy needed to excite can be used to predict therapeutic efficiency of excitability restoration. Taken directly, these results can help guide optogenetic interventions for light-based control of cardiac excitation. More generally, our findings can help optimize gene therapy for restoration of cardiac excitability. PMID- 26621214 TI - Long-term results of remodelling the facial bones with a soft moulding helmet in beagles: the "reciprocally stimulated growth" hypothesis. AB - Facial deformity is often seen in infants with deformational plagiocephaly and it usually improves with conservative management. However, we know of few studies of the effect of helmet treatment on the facial skeleton. Our aim therefore was to find out its long-term effects on skull remodelling, and on the shape of the face. Seven beagles wore helmets for seven weeks after birth. Seven study beagles and 3 controls were killed and we measured the length, width, and height of the skulls, maxillas, and mandibles. Statistical analysis showed that the total craniofacial length and skull length did not differ significantly, and skull volumes were similar. Maximal craniofacial, skull, maxillary, and mandibular width were all significantly less in the study group. The maximal craniofacial, maxillary, and mandibular widths were strongly correlated with changes in the skull width, and the width:length ratios of the skulls, maxillas, and mandibles did differ significantly. The skull widths in the study group were significantly smaller, which suggests that a soft moulding helmet may change the growth pattern permanently. The effect of a soft moulding helmet on the lateral aspect of the skull affected the width of the face semipermanently. This modulation in the shape of the skull vault and base may change the shape of the maxilla and mandible, which may serve as a background for the use of helmet treatment to change the facial configuration. PMID- 26621215 TI - Damage control surgery and combat-related maxillofacial and cervical injuries: a systematic review. AB - Damage control surgery involves rapid assessment, life-saving resuscitation, and abbreviated surgery for a patient with severe injuries. Traditionally the concept of damage control surgery has been restricted to penetrating abdominal injuries, but more recently it has been expanded to areas outside of the abdomen including the maxillofacial and neck regions. However, we know of little evidence that, when applied to injuries to the face and neck, it changes outcomes. We systematically reviewed published papers to identify those that discussed damage control in the context of combat-related trauma of the face and neck. We identified three papers that discussed the principles of managing combat-related maxillofacial injuries, all three of which were review articles that advocated the use of damage control principles in facial injuries either in isolation or as part of a multisystem approach. Anecdotal experience and opinion indicates that the concept of damage control is applicable when managing combat-related injuries of the face and neck, but no outcomes were confirmed. Further studies are required to validate the concept. PMID- 26621216 TI - Increasing N200 Potentials Via Visual Stimulus Depicting Humanoid Robot Behavior. AB - Achieving recognizable visual event-related potentials plays an important role in improving the success rate in telepresence control of a humanoid robot via N200 or P300 potentials. The aim of this research is to intensively investigate ways to induce N200 potentials with obvious features by flashing robot images (images with meaningful information) and by flashing pictures containing only solid color squares (pictures with incomprehensible information). Comparative studies have shown that robot images evoke N200 potentials with recognizable negative peaks at approximately 260 ms in the frontal and central areas. The negative peak amplitudes increase, on average, from 1.2 MUV, induced by flashing the squares, to 6.7 MUV, induced by flashing the robot images. The data analyses support that the N200 potentials induced by the robot image stimuli exhibit recognizable features. Compared with the square stimuli, the robot image stimuli increase the average accuracy rate by 9.92%, from 83.33% to 93.25%, and the average information transfer rate by 24.56 bits/min, from 72.18 bits/min to 96.74 bits/min, in a single repetition. This finding implies that the robot images might provide the subjects with more information to understand the visual stimuli meanings and help them more effectively concentrate on their mental activities. PMID- 26621217 TI - Constructing herbicide metribuzin sustained-release formulations based on the natural polymer poly-3-hydroxybutyrate as a degradable matrix. AB - Polymer poly(3-hydroxybutyrate) [P(3HB)] has been used as a matrix in slow release formulations of the herbicide metribuzin (MET). Physical P(3HB)/MET mixtures in the form of solutions, powders, and emulsions were used to construct different metribuzin formulations (films, granules, pellets, and microparticles). SEM, X-Ray, and DSC proved the stability of these formulations incubated in sterile water in vitro for long periods of time (up to 49 days). Metribuzin release from the polymer matrix has been also studied. By varying the shape of formulations (microparticles, granules, films, and pellets), we were able to control the release time of metribuzin, increasing or decreasing it. PMID- 26621221 TI - The complex role of NOTCH receptors and their ligands in the development of hepatoblastoma, cholangiocarcinoma and hepatocellular carcinoma. AB - The NOTCH signalling pathway is one of the key molecular pathways of embryonic development and adult tissues homeostasis in mammals. Mammals have four NOTCH receptors and various ligands that modulate their activity. Many cell disorders, whose genesis involves the NOTCH signalling pathway, have been discovered, including cancer. The mechanisms by which these receptors and their ligands affect liver cell transformation are not yet well understood, and they seem to behave as both oncogenes and tumour-suppressor proteins. In this review, we discuss the published data regarding the role of these proteins in the development of hepatoblastoma, cholangiocarcinoma and hepatocellular carcinoma malignancies. The alteration of the NOTCH signalling pathway may be one of the main drivers of hepatic neoplastic growth. However, this signalling pathway might also modulate the development of specific liver tumour features. The complexity of the function of NOTCH receptors and their ligands may be due to their interactions with many other cell signalling pathways. Furthermore, the different levels of expression and activation of these receptors could be a reason for their distinct and sometimes contradictory effects. PMID- 26621218 TI - Rationale and design of A Trial of Sertraline vs. Cognitive Behavioral Therapy for End-stage Renal Disease Patients with Depression (ASCEND). AB - Major Depressive Disorder (MDD) is highly prevalent in patients with End Stage Renal Disease (ESRD) treated with maintenance hemodialysis (HD). Despite the high prevalence and robust data demonstrating an independent association between depression and poor clinical and patient-reported outcomes, MDD is under-treated when identified in such patients. This may in part be due to the paucity of evidence confirming the safety and efficacy of treatments for depression in this population. It is also unclear whether HD patients are interested in receiving treatment for depression. ASCEND (Clinical Trials Identifier Number NCT02358343), A Trial of Sertraline vs. Cognitive Behavioral Therapy (CBT) for End-stage Renal Disease Patients with Depression, was designed as a multi-center, 12-week, open label, randomized, controlled trial of prevalent HD patients with comorbid MDD or dysthymia. It will compare (1) a single Engagement Interview vs. a control visit for the probability of initiating treatment for comorbid depression in up to 400 patients; and (2) individual chair-side CBT vs. flexible-dose treatment with a selective serotonin reuptake inhibitor, sertraline, for improvement of depressive symptoms in 180 of the up to 400 patients. The evolution of depressive symptoms will also be examined in a prospective longitudinal cohort of 90 HD patients who choose not to be treated for depression. We discuss the rationale and design of ASCEND, the first large-scale randomized controlled trial evaluating efficacy of non-pharmacologic vs. pharmacologic treatment of depression in HD patients for patient-centered outcomes. PMID- 26621222 TI - Multiplex lateral flow detection and binary encoding enables a molecular colorimetric 7-segment display. AB - Multiplex expansion in point-of-care diagnostics usually requires a linear increase of premium commodities such as reagents or space. Here we demonstrate the power of binary and molecular encoding to compress device operations. We describe the first colorimetric 7-segment display on a paper-based biosensor, providing compact and intuitive read-outs for multiplex detections. PMID- 26621219 TI - Inhibition of NF-kappaB by deoxycholic acid induces miR-21/PDCD4-dependent hepatocellular apoptosis. AB - MicroRNAs (miRNAs/miRs) are key regulators of liver metabolism, while toxic bile acids participate in the development of several liver diseases. We previously demonstrated that deoxycholic acid (DCA), a cytotoxic bile acid implicated in the pathogenesis of non-alcoholic fatty liver disease, inhibits miR-21 expression in hepatocytes. Here, we investigated the mechanisms by which DCA modulates miR-21 and whether miR-21 contributes for DCA-induced cytotoxicity. DCA inhibited miR-21 expression in primary rat hepatocytes in a dose-dependent manner, and increased miR-21 pro-apoptotic target programmed cell death 4 (PDCD4) and apoptosis. Both miR-21 overexpression and PDCD4 silencing hampered DCA-induced cell death. Further, DCA decreased NF-kappaB activity, shown to represent an upstream mechanism leading to modulation of the miR-21/PDCD4 pathway. In fact, NF-kappaB overexpression or constitutive activation halted miR-21-dependent apoptosis by DCA while opposite results were observed upon NF-kappaB inhibition. In turn, DCA induced oxidative stress resulted in caspase-2 activation and NF-kappaB/miR-21 inhibition, in a PIDD-dependent manner. Finally, modulation of the NF-kappaB/miR 21/PDCD4 pro-apoptotic pathway by DCA was also shown to occur in the rat liver in vivo. These signalling circuits may constitute appealing targets for bile acid associated liver pathologies. PMID- 26621224 TI - The clinical impact of platelet-rich plasma on tendinopathy compared to placebo or dry needling injections: A meta-analysis. AB - OBJECTIVE: The purpose of this meta-analysis was to compare the impact of platelet-rich plasma with that of placebo or dry needling injections on tendinopathy. METHODS: The databases of PubMed, CENTRAL, Scopus, Web of Science, and trial registries, reference lists, and conference abstract books were searched up to December 2014. Adults with tendinopathy in randomized controlled trials were enrolled. The trials compared effect of platelet-rich plasma with that of placebo or dry needling. We used subgroup analysis linked to the anatomical location of the tendinopathy. The primary outcome was pain intensity at two or three and six months after intervention. The secondary outcome was functional disability at three months after treatment. RESULTS: Five trials were included. There was a statistically significant difference in favor of the platelet-rich plasma intervention at the second primary outcome time point (SMD 0.48, 95%CIs -0.86 to -0.10, I(2) = 0%, p = 0.01) and at the secondary outcome time point (SMD -0.47, 95%CIs -0.85 to -0.09, I(2) = 0%, p=0.01). CONCLUSIONS: Platelet-rich plasma did not provide significantly greater clinical benefit versus placebo or dry needling for the treatment of tendinopathy at a six-month follow-up. However, there was a marginal clinical difference in favor of platelet rich plasma injections on rotator cuff tendinopathy. PMID- 26621225 TI - SD-OCT findings in polypoidal choroidal vasculopathy. AB - OBJECTIVE: To examine patients with polypoidal choroidal vasculopathy (PCV), using spectral-domain optical coherence tomography (SD-OCT) to characterise and locate the PCV lesions. PATIENTS AND METHODS: A series of 15 eyes of 10 patients diagnosed with PCV were examined. All eyes were imaged with macular SD-OCT. RESULTS: SD-OCT cross-sectional scan findings included atypical and typical pigment epithelial detachments (PEDs). Polyps and neovascularisation were located above Bruch membrane. All 15 eyes (100%) showed sub-retinal fluid (SRF) in association with PEDs. CONCLUSION: These SD-OCT findings located the vascular lesions of PCV in the sub-retinal pigment epithelium (RPE) space, and strongly suggest that PCV is a variant of type 1 neovascularization. PMID- 26621226 TI - Associations of surgical and nonsurgical weight loss with knee musculature: a cohort study of obese adults. AB - BACKGROUND: Marked weight loss reduces lean body mass and quadriceps thickness. It is unclear whether muscle loss varies according to the method of weight loss. OBJECTIVE: This study compared the association of surgical versus nonsurgical weight loss with change in vastus medialis (VM) properties in obese adults. METHODS: Twenty obese patients (body mass index >= 30 kg/m(2)) who lost weight via laparoscopic gastric banding were matched for weight loss with obese patients who lost weight nonsurgically. The thickness and fat infiltration of VM were assessed at baseline and a mean of 2.4 years later. RESULTS: After adjusting for confounders, the annual change in VM thickness was -2.9% in the surgical group and -.5% for the nonsurgical group (P = .02). There was also a tendency toward an increased risk for VM fat infiltration to be reduced when weight loss occurred nonsurgically (OR 5.1, 95% CI .8-32.8; P = .09). CONCLUSIONS: Compared with nonsurgical weight loss, laparoscopic gastric banding was associated with greater VM muscle thickness loss. Relative to laparoscopic gastric banding, there was also a tendency toward an increased risk for VM fat infiltration to be reduced with nonsurgical weight loss. Close attention to preserving muscle properties at the knee when significant amounts of weight loss have occurred is required. Physical therapy may be important in the management of patients after laparoscopic gastric banding in an attempt to preserve skeletal muscle mass. PMID- 26621228 TI - Perspective on Foundations of Solvation Modeling: The Electrostatic Contribution to the Free Energy of Solvation. PMID- 26621223 TI - Health system and community level interventions for improving antenatal care coverage and health outcomes. AB - BACKGROUND: The World Health Organization (WHO) recommends at least four antenatal care (ANC) visits for all pregnant women. Almost half of pregnant women worldwide, and especially in developing countries do not receive this amount of care. Poor attendance of ANC is associated with delivery of low birthweight babies and more neonatal deaths. ANC may include education on nutrition, potential problems with pregnancy or childbirth, child care and prevention or detection of disease during pregnancy.This review focused on community-based interventions and health systems-related interventions. OBJECTIVES: To assess the effects of health system and community interventions for improving coverage of antenatal care and other perinatal health outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (7 June 2015) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-randomised trials and cluster-randomised trials. Trials of any interventions to improve ANC coverage were eligible for inclusion. Trials were also eligible if they targeted specific and related outcomes, such as maternal or perinatal death, but also reported ANC coverage. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: We included 34 trials involving approximately 400,000 women. Some trials tested community based interventions to improve uptake of antenatal care (media campaigns, education or financial incentives for pregnant women), while other trials looked at health systems interventions (home visits for pregnant women or equipment for clinics). Most trials took place in low- and middle-income countries, and 29 of the 34 trials used a cluster-randomised design. We assessed 30 of the 34 trials as of low or unclear overall risk of bias. Comparison 1: One intervention versus no interventionWe found marginal improvements in ANC coverage of at least four visits (average odds ratio (OR) 1.11, 95% confidence interval (CI) 1.01 to 1.22; participants = 45,022; studies = 10; Heterogeneity: Tau2 = 0.01; I2 = 52%; high quality evidence). Sensitivity analysis with a more conservative intra-cluster correlation co-efficient (ICC) gave similar marginal results. Excluding one study at high risk of bias shifted the marginal pooled estimate towards no effect. There was no effect on pregnancy-related deaths (average OR 0.69, 95% CI 0.45 to 1.08; participants = 114,930; studies = 10; Heterogeneity: Tau2 = 0.00; I2 = 0%; low quality evidence), perinatal mortality (average OR 0.98, 95% CI 0.90 to 1.07; studies = 15; Heterogeneity: Tau2 = 0.01; I2 = 58%; moderate quality evidence) or low birthweight (average OR 0.94, 95% CI 0.82 to 1.06; studies = five; Heterogeneity: Tau2 = 0.00; I2 = 5%; high quality evidence). Single interventions led to marginal improvements in the number of women who delivered in health facilities (average OR 1.08, 95% CI 1.02 to 1.15; studies = 10; Heterogeneity: Tau2 = 0.00; I2 = 0%; high quality evidence), and in the proportion of women who had at least one ANC visit (average OR 1.68, 95% CI 1.02 to 2.79; studies = six; Heterogeneity: Tau2 = 0.24; I2 = 76%; moderate quality evidence). Results for ANC coverage (at least four and at least one visit) and for perinatal mortality had substantial statistical heterogeneity. Single interventions did not improve the proportion of women receiving tetanus protection (average OR 1.03, 95% CI 0.92 to 1.15; studies = 8; Heterogeneity: Tau2 = 0.01; I2 = 57%). No study reported onintermittent prophylactic treatment for malaria. Comparison 2: Two or more interventions versus no interventionWe found no improvements in ANC coverage of four or more visits (average OR 1.48, 95% CI 0.99 to 2.21; participants = 7840; studies = six; Heterogeneity: Tau2 = 0.10; I2 = 48%; low quality evidence) or pregnancy-related deaths (average OR 0.70, 95% CI 0.39 to 1.26; participants = 13,756; studies = three; Heterogeneity: Tau2 = 0.00; I2 = 0%; moderate quality evidence). However, combined interventions led to improvements in ANC coverage of at least one visit (average OR 1.79, 95% CI 1.47 to 2.17; studies = five; Heterogeneity: Tau2 = 0.00; I2 = 0%; moderate quality evidence), perinatal mortality (average OR 0.74, 95% CI 0.57 to 0.95; studies = five; Heterogeneity: Tau2 = 0.06; I2 = 83%; moderate quality evidence) and low birthweight (average OR 0.61, 95% CI 0.46 to 0.80; studies = two; Heterogeneity: Tau2 = 0.00; I2 = 0%; moderate quality evidence). Meta-analyses for both ANC coverage four or more visits and perinatal mortality had substantial statistical heterogeneity. Combined interventions improved the proportion of women who had tetanus protection (average OR 1.48, 95% CI 1.18 to 1.87; studies = 3; Heterogeneity: Tau2 = 0.01; I2 = 33%). No trial in this comparison reported on intermittent prophylactic treatment for malaria. Comparison 3: Two interventions compared head to head. No trials found. Comparison 4: One intervention versus a combination of interventionsThere was no difference in ANC coverage (four or more visits and at least one visit), pregnancy-related deaths, deliveries in a health facility or perinatal mortality. No trials in this comparison reported on low birthweight orintermittent prophylactic treatment of malaria. AUTHORS' CONCLUSIONS: Implications for practice - Single interventions may improve ANC coverage (at least one visit and four or more visits) and deliveries in health facilities. Combined interventions may improve ANC coverage (at least one visit), reduce perinatal mortality and reduce the occurrence of low birthweight. The effects of the interventions are unrelated to whether they are community or health system interventions. Implications for research - More details should be provided in reporting numbers of events, group totals and the ICCs used to adjust for cluster effects. Outcomes should be reported uniformly so that they are comparable to commonly-used population indicators. We recommend further cluster-RCTs of pregnant women and women in their reproductive years, using combinations of interventions and looking at outcomes that are important to pregnant women, such as maternal and perinatal morbidity and mortality, alongside the explanatory outcomes along the pathway of care: ANC coverage, the services provided during ANC and deliveries in health facilities. PMID- 26621227 TI - Changes in the body composition after laparoscopic gastric plication: a short term prospective case series. AB - BACKGROUND: While laparoscopic gastric plication (LGP) results in a rapid weight loss in the first postoperative months, changes in body composition after LGP have not been studied previously. OBJECTIVE: To evaluate the body composition after LGP. SETTING: A tertiary referral hospital. METHOD: This is a consecutive case series. Body composition was measured using bioimpedance analysis with a Tanita BC-418 by 1 nutritionist. Weight, fat mass (FM), fat-free mass (FFM), and total body water (TBW) were measured at baseline and at 1, 3, and 6 months postoperative. RESULTS: Sixteen consecutive patients underwent LGP. No intraoperative or major postoperative complications occurred during the follow-up period. No patient was lost to follow-up at any point during the study period. Mean postoperative total weight loss was 31 kg after 6 months, of which 25.5 kg (83%) was due to FM reduction. %FM was decreased by 15% after 6 months, whereas %TBW increased by 11%. CONCLUSIONS: Most of the weight loss caused by LGP is attributable to FM loss, and FFM loss is minimal after LGP. Therefore, LGP shifts body composition toward normal. PMID- 26621229 TI - Improved Description of Stereoelectronic Effects in Hydrocarbons Using Semilocal Density Functional Theory. AB - Serious and systematic errors with popular density functionals occur for isodesmic stabilization energies of n-alkanes, isomerization, and dimerization energies of hydrocarbons and geometries of sterically overcrowded aromatic systems. These functionals are too biased toward the correct description of free atoms. Changing two parameters within the Perdew-Burke-Ernzerhof approximation leads to a new nonempirical functional, PBEsol, that improves the description of large organic systems. PMID- 26621230 TI - Symmetry-Adapted Perturbation-Theory Interaction-Energy Decomposition for Hydrogen-Bonded and Stacking Structures. AB - This letter reports the computational ab initio studies on the stacked and hydrogen-bonded geometries of the uracil dimer and pyrimidine...p-benzoquinone complex with a special regard to the ratios of different interaction-energy terms calculated by means of the symmetry-adapted perturbation theory (SAPT). In the hydrogen-bonded systems the absolute value of the dispersion term constitutes approximately half of the absolute value of the total SAPT0 interaction energy, while in the stacking complexes the ratio of the dispersion to the total interaction energy is much larger, ca. 1.2-2.0. Our SAPT results are compared with the DFT-SAPT results published recently by the Hobza group (J. Chem. Phys. 2007, 127, 075104), and the role of the dispersion contribution in stacking and hydrogen-bonded arrangements is discussed. The methodological part of this letter presents the influence of counterpoise corrections in the optimization procedure on the geometries of the systems and the calculated SAPT contributions. PMID- 26621231 TI - Microscopic Picture of the Aqueous Solvation of Glutamic Acid. AB - We present molecular dynamics simulations of glutamic acid and glutamate solvated in water, using both density functional theory (DFT) and the Gromos96 force field. We focus on the microscopic aspects of the solvation-particularly on the hydrogen bond structures and dynamics-and investigate the influence of the protonation state and of the simulation method. Radial distribution functions show that the hydrogen bonds are longer in the force field systems. We find that the partial charges of the solutes in the force field simulations are lower than the localized electron densities for the quantum simulations. This lower polarization decreases the hydrogen bond strength. Protonation of the carboxylate group renders glutamic acid a very strong and stable hydrogen bond donor. The donated hydrogen bond is shorter and lives longer than any of the other hydrogen bonds. The solute molecules simulated by the force field accept on average three more hydrogen bonds than their quantum counterparts. The life times of these bonds show the opposite result: the residence times are much longer (up to a factor 4) in the ab initio simulations. PMID- 26621232 TI - All-Electron Scalar Relativistic Basis Sets for Third-Row Transition Metal Atoms. AB - A family of segmented all-electron relativistically contracted (SARC) basis sets for the elements Hf-Hg is constructed for use in conjunction with the Douglas Kroll-Hess (DKH) and zeroth-order regular approximation (ZORA) scalar relativistic Hamiltonians. The SARC basis sets are loosely contracted and thus offer computational advantages compared to generally contracted relativistic basis sets, while their sufficiently small size allows them to be used in place of effective core potentials (ECPs) for routine studies of molecules. Practical assessments of the SARC basis sets in DFT calculations of atomic (ionization energies) as well as molecular properties (geometries and bond dissociation energies for MHn complexes) confirm that the basis sets yield accurate and reliable results, providing a balanced description of core and valence electron densities. CCSD(T) calculations on a series of gold diatomic compounds also demonstrate the applicability of the basis sets to correlated methods. The SARC basis sets will be of most utility in calculating molecular properties for which the core electrons cannot be neglected, such as studies of electron paramagnetic resonance, Mossbauer and X-ray absorption spectra, and topological analysis of electron densities. PMID- 26621233 TI - Reaction Coordinates and the Transition-Vector Approximation to the IRC. AB - The appearance of a reaction profile or potential energy surface (PES) associated with the reaction path (defined as the path of steepest descent from the saddle point) depends on the choice of reaction coordinate onto which the intrinsic reaction coordinate is projected. This provides one with the freedom, but also the problem, of choosing the optimal perspective (i.e., the optimal reaction coordinate) for revealing what is essential for understanding the reaction. Here, we address this issue by analyzing a number of different reaction coordinates for the same set of model reactions, namely, prototypical oxidative addition reactions of C-X bonds to palladium. We show how different choices affect the appearance of the PES, and we discuss which qualities make a particular reaction coordinate most suitable for comparing and analyzing the reactions. Furthermore, we show how the transition vector (i.e., the normal mode associated with a negative force constant that leads from the saddle point to the steepest descent paths) can serve as a useful and computationally much more efficient approximation (designated TV-IRC) for full IRC computations, in the decisive region around the transition state. PMID- 26621234 TI - E2 and SN2 Reactions of X(-) + CH3CH2X (X = F, Cl); an ab Initio and DFT Benchmark Study. AB - We have computed consistent benchmark potential energy surfaces (PESs) for the anti-E2, syn-E2, and SN2 pathways of X(-) + CH3CH2X with X = F and Cl. This benchmark has been used to evaluate the performance of 31 popular density functionals, covering local-density approximation, generalized gradient approximation (GGA), meta-GGA, and hybrid density-functional theory (DFT). The ab initio benchmark has been obtained by exploring the PESs using a hierarchical series of ab initio methods [up to CCSD(T)] in combination with a hierarchical series of Gaussian-type basis sets (up to aug-cc-pVQZ). Our best CCSD(T) estimates show that the overall barriers for the various pathways increase in the order anti-E2 (X = F) < SN2 (X = F) < SN2 (X = Cl) ~ syn-E2 (X = F) < anti-E2 (X = Cl) < syn-E2 (X = Cl). Thus, anti-E2 dominates for F(-) + CH3CH2F, and SN2 dominates for Cl(-) + CH3CH2Cl, while syn-E2 is in all cases the least favorable pathway. Best overall agreement with our ab initio benchmark is obtained by representatives from each of the three categories of functionals, GGA, meta-GGA, and hybrid DFT, with mean absolute errors in, for example, central barriers of 4.3 (OPBE), 2.2 (M06-L), and 2.0 kcal/mol (M06), respectively. Importantly, the hybrid functional BHandH and the meta-GGA M06-L yield incorrect trends and qualitative features of the PESs (in particular, an erroneous preference for SN2 over the anti-E2 in the case of F(-) + CH3CH2F) even though they are among the best functionals as measured by their small mean absolute errors of 3.3 and 2.2 kcal/mol in reaction barriers. OLYP and B3LYP have somewhat higher mean absolute errors in central barriers (5.6 and 4.8 kcal/mol, respectively), but the error distribution is somewhat more uniform, and as a consequence, the correct trends are reproduced. PMID- 26621235 TI - Mechanisms for the Reactions of Hydroxyl Radicals with Acrolein: A Theoretical Study. AB - Three low-energy pathways for the reaction of HO(*) with acrolein, a key reaction in atmospheric environments, have been investigated by means of quantum mechanical electronic structure methods (UQCISD and RQCISD(T)). The first step of all the reaction pathways studied involves the barrierless formation of a prereaction loosely bound complex in the entrance channel, lying a few kcal/mol below the energy of the reactants. The lowest-energy barrier pathway at 0 K is found to be the HO(*) abstraction of the aldehydic H-atom through a transition state structure lying 1.1 kcal/mol below the energy of the reactants. The addition of HO(*) to the terminal carbon atom of the C?C double bond proceeds via a transition-state structure lying 0.7 kcal/mol below the energy of reactants at 0 K, whereas the HO(*) addition to the central carbon atom takes place via a transition-state structure lying 0.8 kcal/mol above the energy of the reactants at 0 K. On the basis of conventional transition-state theory calculations at 298 K, it is predicted that 74.5% of the HO(*) reaction with acrolein proceeds via abstraction of the aldehydic H-atom, 24.2% via HO(*) addition to the terminal carbon atom of the double bond, and 1.3% via HO(*) addition to the central carbon atom of the double bond. These results are in close agreement with available experimental data. PMID- 26621236 TI - Benchmarking pKa Prediction Methods for Residues in Proteins. AB - Methods for estimation of pKa values of residues in proteins were tested on a set of benchmark proteins with experimentally known pKa values. The benchmark set includes 80 different residues (20 each for Asp, Glu, Lys, and His), half of which consists of significantly variant cases (DeltapKa >= 1 pKa unit from the amino acid in solution). The method introduced by Case and co-workers [J. Am. Chem. Soc. 2004, 126, 4167-4180], referred to as the molecular dynamics/generalized-Born/thermodynamic integration (MD/GB/TI) technique, gives a root-mean-square deviation (rmsd) of 1.4 pKa units on the benchmark set. The use of explicit waters in the immediate region surrounding the residue was shown to generally reduce high errors for this method. Longer simulation time was also shown to increase the accuracy of this method. The empirical approach developed by Jensen and co-workers [Proteins 2005, 61, 704-721], PROPKA, also gives an overall rmsd of 1.4 pKa units and is more or less accurate based on residue type the method does very well for Lys and Glu, but less so for Asp and His. Likewise, the absolute deviation is quite similar for the two methods-5.2 for PROPKA and 5.1 for MD/GB/TI. A comparison of these results with several prediction methods from the literature is presented. The error in pKa prediction is analyzed as a function of variation of the pKa from that in water and the solvent accessible surface area (SASA) of the residue. A case study of the catalytic lysine residue in 2-deoxyribose-5-phosphate aldolase (DERA) is also presented. PMID- 26621237 TI - A Systematic Comparison of Second-Order Polarization Propagator Approximation (SOPPA) and Equation-of-Motion Coupled Cluster Singles and Doubles (EOM-CCSD) Spin-Spin Coupling Constants for Selected Singly Bonded Molecules, and the Hydrides NH3, H2O, and HF and Their Protonated and Deprotonated Ions and Hydrogen Bonded Complexes. AB - Second-order polarization propagator approximation (SOPPA) and equation-of-motion coupled cluster singles and doubles (EOM-CCSD) methods have been employed for the calculation of one-bond spin-spin coupling constants in series of small molecules and ions, and of one- and two-bond coupling constants across X-H...Y hydrogen bonds. For isolated molecules, one-bond SOPPA coupling constants (1)J(X-Y) involving (13)C, (15)N, (17)O, and (19)F have larger absolute values than corresponding EOM-CCSD coupling constants, with the EOM-CCSD values being in significantly better agreement with available experimental data. The difference between SOPPA and EOM-CCSD tends to increase as the number of nonbonding electrons on the coupled atoms increases, and the SOPPA values for O-F coupling are significantly in error. Similarly, the absolute values of SOPPA one-bond coupling constants (1)J(X-H) for the hydrides NH3, H2O, and FH and their protonated and deprotonated ions are greater than EOM-CCSD values, with the largest differences occurring for F-H coupling. One- and two-bond coupling constants (1)J(X-H), (1h)J(H-Y), and (2h)J(X-Y) across X-H...Y hydrogen bonds in neutral, protonated, and deprotonated complexes formed from the hydrides are similar at SOPPA and EOM-CCSD, with the largest differences again found for (1)J(F-H) in complexes with F-H as the proton donor, and (2h)J(F-F) for (FHF)(-). The signs of (1)J(X-H), (1h)J(H-Y), and (2h)J(X-Y) are the same at both levels of theory, as is their variation across the proton-transfer coordinate in F-H...NH3. SOPPA would appear to provide a reliable and more cost-effective alternative approach for computing coupling constants across hydrogen bonds, although couplings involving F may be problematic. PMID- 26621238 TI - pH Dependence of a 310-Helix versus a Turn in the M-Loop Region of PDE4: Observations on PDB Entries and an Electronic Structure Study. AB - Available X-ray crystal structures of phosphodiesterase 4 (PDE 4) are classified into two groups based on a secondary structure difference of a 310-helix versus a turn in the M-loop region. The only variable that was discernible between these two sets is the pH at the crystallization conditions. Assuming that at lower pH there is a possibility of protonation, thermodynamics of protonation and deprotonation of the aspartic acid, cysteine side chains, and amide bonds are calculated. The models in the gas phase and in the explicit solvent using the ONIOM method are calculated at the B3LYP/6-31+G* and B3LYP/6-31+G*:UFF levels of theory, respectively. The molecular dynamics (MD) simulations are also performed on the M-loop region of a 310-helix and a turn with explicit water for 10 ns under NPT conditions. The isodesmic equations of the various protonation states show that the turn containing structure is thermodynamically more stable when proline or cysteine is protonated. The preference for the turn structure on protonation (pH = 6.5-7.5) is due to an increase in the number of the hydrogen bonding and electrostatic interactions gained by the surrounding environment such as adjacent residues and solvent molecules. PMID- 26621239 TI - Proton Transfer at Metal Sites in Proteins Studied by Quantum Mechanical Free Energy Perturbations. AB - Catalytic metal sites in enzymes frequently have second-sphere carboxylate groups that neutralize the charge of the site and share protons with first-sphere ligands. This gives rise to an ambiguity concerning the position of this proton, which has turned out to be hard to settle with experimental, as well as theoretical, methods. We study three such proton-transfer reactions in two proteins and show that, in [Ni,Fe] hydrogenase, the bridging Cys-546 ligand is deprotonated by His-79, whereas in oxidized copper nitrite reductase, the His-100 ligand is neutral and the copper-bound water molecule is deprotonated by Asp-98. We show that these reactions strongly depend on the electrostatic interactions with the surrounding protein and solvent, because there is a large change in the dipole moment of the active site (2-6 D). Neither vacuum quantum mechanical (QM) calculations with large models, a continuum solvent, or a Poisson-Boltzmann treatment of the surroundings, nor combined QM and molecular mechanics (QM/MM) optimizations give reliable estimates of the proton-transfer energies (mean absolute deviations of over 20 kJ/mol). Instead, QM/MM free-energy perturbations are needed to obtain reliable estimates of the reaction energies. These calculations also indicate what interactions and residues are important for the energy, showing how the quantum system may be systematically enlarged. With such a procedure, results with an uncertainty of ~10 kJ/mol can be obtained, provided that a proper QM method is used. PMID- 26621240 TI - Gas-Phase Interaction of Calcium (Ca(2+)) with Seleno Derivatives of Uracil. AB - The structures and relative stabilities of the complexes between Ca(2+) and 2 selenouracil, 4-selenouracil, and 2,4-diselenouracil have been investigated through the use of B3LYP/6-311++G(3df,2p)//B3LYP/6-31+G(d,p) density functional theory (DFT) calculations. In those systems where both types of basic centers, a carbonyl or a selenocarbonyl group, are present, Ca(2+) association with the oxygen is favored. For 2,4-diselenouracil the nitrogen atom at position 3 is the most basic site toward Ca(2+) attachment followed by heteroatoms attached to positions 4 and 2. Although the enolic and selenol forms of selenouracils should not be observed in the gas phase, the corresponding Ca(2+) complexes are the most stable ones. More importantly, all the activation barriers associated with the corresponding tautomeric processes are lower than the entrance channel, and therefore not only these complexes should be observed but also they should be the dominant species in the gas phase. Also, Ca(2+) association has a clear catalytic effect on these tautomerization processes, whose activation barriers decrease between 10 and 15 kcal mol(-1). PMID- 26621241 TI - How Is cis-trans Isomerization Controlled in Dronpa Mutants? A Replica Exchange Molecular Dynamics Study. AB - The reversibly photoactivatable green fluorescent protein analog Dronpa holds great promise as a marker for various new cellular imaging applications. Using a replica exchange method which combines both Hamiltonian and temperature exchanges, the ground-state dynamics of Dronpa and two mutants with increased switching kinetics, Val157Gly and Met159Thr, were compared. The dominant chromophore state was found to be the cis isomer in all three proteins. The simulation data suggest that both mutations strongly increase the chromophore flexibility and cis-trans isomerization rate. We identify three key amino acids, Val157, Met159, and Phe173, which are able to impede the bottom hula-twist transition path, depending on their position and rotameric state. We believe our insights will help to understand the switching process and provide useful information for the design of new variants with improved fluorescence properties. PMID- 26621242 TI - Homology Models and Molecular Modeling of Human Retinoic Acid Metabolizing Enzymes Cytochrome P450 26A1 (CYP26A1) and P450 26B1 (CYP26B1). AB - Homology models of cytochrome P450 26A1 and cytochrome P450 26B1 were constructed using the crystal structures of human, CYP2C8, CYP2C9, and CYP3A4 as templates for the model building. The homology models generated were investigated for their docking capacities against the natural substrate all-trans-retinoic acid (atRA), five different tetralone-derived retinoic acid metabolizing blocking agents (RAMBAs), and R115866. Interaction energies (IE) and linear interaction energies (LIE) were calculated for all inhibitors in both homology models after molecular dynamics (MD) simulation of the enzyme-ligand complexes. The results revealed that the homologues had the capacity to distinguish between strong and weak inhibitors. Important residues in the active site were identified from the CYP26A1/B1-atRA complexes. Residues involved in hydrophobic interactions with atRA were Pro113, Phe222, Phe299, Val370, Pro371, and Phe374 in CYP26A1 and Leu88, Pro118, Phe222, Phe295, Ile368, and Tyr272 in CYP26B1. Hydrogen bonding interactions were observed between the atRA carboxylate group and Arg 90 in CYP26A1 and with Arg76, Arg95, and Ser369 in CYP26B1. PMID- 26621243 TI - Genetic predisposition of variants in TLR2 and its co-receptors to severe malaria in Odisha, India. AB - Although the role of TLRs signalling in malaria pathogenesis is well established, contribution of individual TLR to clinical outcome of malaria still remains inconclusive. Given the importance of TLR2 and its co-receptors in recognising distinct structural forms of key malaria toxins and mediating innate immune response, it is essential to delineate their genetic contribution. Variants in TLR1 (I602S) and TLR6 (P249S) were genotyped by PCR-RFLP methods, and TLR2 (I/D) was genotyped by PCR in 200 samples each from uncomplicated malaria (UM) and severe malaria (SM). Further, SM was categorised into its sub-clinical groups (CM and NCSM or SOD and MODS) and analysed. The results showed the PP genotype of TLR6 (P249S) to be significantly more common in UM (P < 0.0001), whereas the 'SS' genotype was the risk factor for SM including its sub-clinical categories. The TLR1 (602S) and TLR2 (D) variants were significantly high in patients with CM; however, negative LD was observed between TLR2 and TLR6 in NCSM and MODS. Haplotype analysis showed significantly high frequency of I-I-S haplotype in all forms of subclinical SM and was associated with low parasite load in SM (P = 0.013). The haplotypes I-D-S and S-I-P were significantly high in SOD and CM, respectively. The TLR6 '249S' variant appeared to be the dominant determinant for genetic predisposition to SM and that its association with either TLR2 'D' or TLR1 '602S' modulates for CM development. The present study opens up several new avenues for their exploration and validation in future studies in different global settings for malaria. PMID- 26621244 TI - The neuroprotective effects of R-phenibut after focal cerebral ischemia. AB - R-phenibut is a gamma-aminobutyric acid (GABA)-B receptor and alpha2-delta subunit of the voltage-dependent calcium channel (VDCC) ligand. The aim of the present study was to test the effects of R-phenibut on the motor, sensory and tactile functions and histological outcomes in rats following transient middle cerebral artery occlusion (MCAO). In this study, MCAO was induced by filament insertion (f-MCAO) or endothelin-1 (ET1) microinjection (ET1-MCAO) in male Wistar or CD rats, respectively. R-phenibut was administrated at doses of 10 and 50mg/kg for 14 days in the f-MCAO or 7 days in the ET1-MCAO. The vibrissae-evoked forelimb-placing and limb-placing tests were used to assess sensorimotor, tactile and proprioceptive function. Quantitative reverse transcriptase-PCR was used to detect brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) gene expression in the damaged brain hemisphere. Both f-MCAO and ET1-MCAO resulted in statistically significant impairment of sensorimotor function and brain infarction. R-phenibut at a dose of 10mg/kg significantly improved histological outcome at day 7 in the ET1-MCAO. R-phenibut treatment at a dose of 50mg/kg significantly alleviated reduction of brain volume in damaged hemisphere in both f-MCAO and ET1-MCAO. In R-phenibut treated animals a trend of recovery of tactile and proprioceptive stimulation in the vibrissae-evoked forelimb-placing test was observed. After R-phenibut treatment at a dose of 50mg/kg statistically significant increase of BDNF and VEGF gene expression was found in damaged brain hemisphere. Taken together, obtained results provide evidence for the neuroprotective activity of R-phenibut in experimental models of stroke. These effects might be related to the modulatory effects of the drug on the GABA-B receptor and alpha2-delta subunit of VDCC. PMID- 26621245 TI - A selective alpha1D-adrenoreceptor antagonist inhibits human prostate cancer cell proliferation and motility "in vitro". AB - The progression of prostate cancer (PC) to a metastatic hormone refractory disease is the major contributor to the overall cancer mortality in men, mainly because the conventional therapies are generally ineffective at this stage. Thus, other therapeutic options are needed as alternatives or in addition to the classic approaches to prevent or delay tumor progression. Catecholamines participate to the control of prostate cell functions by the activation of alpha1 adrenoreceptors (alpha1-AR) and increased sympathetic activity has been linked to PC development and evolution. Molecular and pharmacological studies identified three alpha1-AR subtypes (A, B and D), which differ in tissue distribution, cell signaling, pharmacology and physiological role. Within the prostate, alpha1A-ARs mainly control stromal cell functions, while alpha1B- and alpha1D- subtypes seem to modulate glandular epithelial cell growth. The possible direct contribution of alpha1D-ARs in tumor biology is supported by their overexpression in PC. The studies here presented investigate the "in vitro" antitumor action of A175, a selective alpha1D-AR antagonist we have recently obtained by modifying the potent, but not subtype-selective alpha1-AR antagonist (S)-WB4101, in the hormone refractory PC3 and DU145 PC cell lines. The results indicate that A175 has an alpha1D-AR-mediated significant and dose-dependent antiproliferative action that possibly involves the induction of G0/G1 cell cycle arrest, but not apoptosis. In addition, A175 reduces cell migration and adhesiveness to culture plates. In conclusion, our work clarified some cellular aspects promoted by alpha1D-AR activity modulation and supports a further pharmacological approach in the cure of hormone-refractory PC, by targeting specifically this AR subtype. PMID- 26621246 TI - In vitro pharmacological evaluation of multitarget agents for thromboxane prostanoid receptor antagonism and COX-2 inhibition. AB - PURPOSE: Patients with high cardiovascular risk due to ageing and/or comorbidity (diabetes, atherosclerosis) that require effective management of chronic pain may take advantage from new non-steroidal anti-inflammatory drugs (NSAIDs) that at clinical dosages may integrate the anti-inflammatory activity and reduced gastrointestinal side effects of selective cyclooxygenase-2 (COX-2) inhibitor (coxib) with a cardioprotective component involving antagonism of thromboxane A2 prostanoid (TP) receptor. METHODS: New compounds were obtained modulating the structure of the most potent coxib, lumiracoxib, to obtain novel multitarget NSAIDs endowed with balanced coxib and TP receptor antagonist properties. Antagonist activity at TP receptor (pA2) was evaluated for all compounds in human platelets and in an heterologous expression system by measuring prevention of aggregation and Gq-dependent production of intracellular inositol phosphate induced by the stable thromboxane A2 (TXA2) agonist U46619. COX-1 and COX-2 inhibitory activities were assessed in human washed platelets and lympho monocytes suspension, respectively. COX selectivity was determined from dose response curves by calculating a ratio (COX-2/COX-1) of IC50 values. RESULTS: The tetrazole derivative 18 and the trifluoromethan sulfonamido-isoster 20 were the more active antagonists at TP receptor, preventing human platelet aggregation and intracellular signalling, with pA2 values statistically higher from that of lumiracoxib. Comparative data regarding COX-2/COX-1 selectivity showed that while compounds 18 and 7 were rather potent and selective COX-2 inhibitor, compound 20 was somehow less potent and selective for COX-2. CONCLUSION: These results indicate that compounds 18 and 20 are two novel combined TP receptor antagonists and COX-2 inhibitors characterized by a fairly balanced COX-2 inhibitor activity and TP receptor antagonism and that they may represent a first optimization of the original structure to improve their multitarget activity. PMID- 26621247 TI - 5-HT2A receptors control body temperature in mice during LPS-induced inflammation via regulation of NO production. AB - G protein-coupled 5-HT2A receptors are involved in the regulation of numerous normal and pathological physiological functions. At the same time, its involvement in the regulation of body temperature (Tb) in normal conditions is obscure. Here we study the effect of the 5-HT2A receptor activation or blockade on Tb in sick animals. The experiments were carried out on adult C57BL/6 mouse males. Systemic inflammation and sickness were produced by lipopolysaccharide (LPS, 0.1mg/kg, ip), while the 5-HT2A receptor was stimulated or blocked through the administration of the receptor agonist DOI or antagonist ketanserin (1mg/kg), respectively. LPS, DOI or ketanserin alone produced no effect on Tb. However, administration of LPS together with a peripheral or central ketanserin injection reduced Tb (32.2 degrees C). Ketanserin reversed the LPS-induced expression of inducible NO synthase in the brain. Consequently, an involvement of NO in the mechanism of the hypothermic effect of ketanserin in sick mice was hypothesized. Administration of LPS together with NO synthase inhibitor, l-nitro-arginine methyl ester (60mg/kg, ip) resulted in deep (28.5 degrees C) and prolonged (8h) hypothermia, while administration of l-nitro-arginine methyl ester alone produced no effect on Tb. Thus, 5-HT2A receptors play a key role in Tb control in sick mice. Blockade of this GPCR produces hypothermia in mice with systemic inflammation via attenuation of LPS-induced NO production. These results indicate an unexpected role of 5-HT2A receptors in inflammation and NO production and have a considerable biological impact on understanding the mechanism of animal adaptation to pathogens and parasites. Moreover, adverse side effects of 5-HT2A receptor antagonists in patients with inflammation may be expected. PMID- 26621248 TI - Decreased acylcarnitine content improves insulin sensitivity in experimental mice models of insulin resistance. AB - The important pathological consequences of insulin resistance arise from the detrimental effects of accumulated long-chain fatty acids and their respective acylcarnitines. The aim of this study was to test whether exercise combined with decreasing the content of long-chain acylcarnitines represents an effective strategy to improve insulin sensitivity in diabetes. We used a novel compound, 4 [ethyl(dimethyl)ammonio]butanoate (methyl-GBB), treatment and exercise to decrease acylcarnitine contents in the plasma and muscles in the insulin resistance models of high fat diet (HFD) fed C57BL/6 mice and db/db mice. The methyl-GBB treatment induced a substantial decrease in all acylcarnitine concentrations in both fed and fasted states as well as when it was combined with exercise. In the HFD fed mice methyl-GBB treatment improved both glucose and insulin tolerance. Methyl-GBB administration, exercise and the combination of both improved insulin sensitivity and reduced blood glucose levels in db/db mice. Methyl-GBB administration and the combination of the drug and exercise activated the PPARalpha/PGC1alpha signaling pathway and stimulated the corresponding target gene expression. Insulin insensitivity in db/db mice was not induced by significantly increased fatty acid metabolism, while increased insulin sensitivity by both treatments was not related to decreased fatty acid metabolism in muscles. The pharmacologically reduced long-chain acylcarnitine content represents an effective strategy to improve insulin sensitivity. The methyl-GBB treatment and lifestyle changes via increased physical activity for one hour a day have additive insulin sensitizing effects in db/db mice. PMID- 26621250 TI - Usability and Acceptance of the Librarian Infobutton Tailoring Environment: An Open Access Online Knowledge Capture, Management, and Configuration Tool for OpenInfobutton. AB - BACKGROUND: The Librarian Infobutton Tailoring Environment (LITE) is a Web-based knowledge capture, management, and configuration tool with which users can build profiles used by OpenInfobutton, an open source infobutton manager, to provide electronic health record users with context-relevant links to online knowledge resources. OBJECTIVE: We conducted a multipart evaluation study to explore users' attitudes and acceptance of LITE and to guide future development. METHODS: The evaluation consisted of an initial online survey to all LITE users, followed by an observational study of a subset of users in which evaluators' sessions were recorded while they conducted assigned tasks. The observational study was followed by administration of a modified System Usability Scale (SUS) survey. RESULTS: Fourteen users responded to the survey and indicated good acceptance of LITE with feedback that was mostly positive. Six users participated in the observational study, demonstrating average task completion time of less than 6 minutes and an average SUS score of 72, which is considered good compared with other SUS scores. CONCLUSIONS: LITE can be used to fulfill its designated tasks quickly and successfully. Evaluators proposed suggestions for improvements in LITE functionality and user interface. PMID- 26621249 TI - PPARalpha in lysosomal biogenesis: A perspective. AB - Lysosomes are membrane-bound vesicles containing hydrolytic enzymes, ubiquitously present in all eukaryotic cells. Classically considered to be central to the cellular waste management machinery, recent studies revealed the role of lysosomes in a wide array of cellular processes like, degradation, cellular development, programmed cell death, secretion, plasma membrane repair, nutritional responses, and lipid metabolism. We recently studied the regulation of TFEB, considered to be the master regulator of lysosomal biogenesis, by activation of peroxisomal proliferator activated receptor alpha (PPARalpha), one of the key regulators of lipid metabolism. In this article, we discuss how the recent finding could be put in to perspective with the previous findings that relate lysosomal biogenesis to lipid metabolism, and comment on the possibility of a bi-directional interplay between these two distinct cellular processes upon activation of PPARalpha. PMID- 26621251 TI - Making the transition to workload-based staffing: using the Workload Indicators of Staffing Need method in Uganda. AB - BACKGROUND: Uganda's health workforce is characterized by shortages and inequitable distribution of qualified health workers. To ascertain staffing levels, Uganda uses fixed government-approved norms determined by facility type. This approach cannot distinguish between facilities of the same type that have different staffing needs. The Workload Indicators of Staffing Need (WISN) method uses workload to determine number and type of staff required in a given facility. The national WISN assessment sought to demonstrate the limitations of the existing norms and generate evidence to influence health unit staffing and staff deployment for efficient utilization of available scarce human resources. METHODS: A national WISN assessment (September 2012) used purposive sampling to select 136 public health facilities in 33/112 districts. The study examined staffing requirements for five cadres (nursing assistants, nurses, midwives, clinical officers, doctors) at health centres II (n = 59), III (n = 53) and IV (n = 13) and hospitals (n = 11). Using health management information system workload data (1 July 2010-30 June 2011), the study compared current and required staff, assessed workload pressure and evaluated the adequacy of the existing staffing norms. RESULTS: By the WISN method, all three types of health centres had fewer nurses (42-70%) and midwives (53-67%) than required and consequently exhibited high workload pressure (30-58%) for those cadres. Health centres IV and hospitals lacked doctors (39-42%) but were adequately staffed with clinical officers. All facilities displayed overstaffing of nursing assistants. For all cadres at health centres III and IV other than nursing assistants, the fixed norms or existing staffing or both fell short of the WISN staffing requirements, with, for example, only half as many nurses and midwives as required. CONCLUSIONS: The WISN results demonstrate the inadequacies of existing staffing norms, particularly for health centres III and IV. The results provide an evidence base to reshape policy, adopt workload-based norms, review scopes of practice and target human resource investments. In the near term, the government could redistribute existing health workers to improve staffing equity in line with the WISN results. Longer term revision of staffing norms and investments to effectively reflect actual workloads and ensure provision of quality services at all levels is needed. PMID- 26621252 TI - Socioeconomic predictors and consequences of depression among primary care attenders with non-communicable diseases in the Western Cape, South Africa: cohort study within a randomised trial. AB - BACKGROUND: Socioeconomic predictors and consequences of depression and its treatment were investigated in 4393 adults with specified non-communicable diseases attending 38 public sector primary care clinics in the Eden and Overberg districts of the Western Cape, South Africa. METHODS: Participants were interviewed at baseline in 2011 and 14 months later, as part of a randomised controlled trial of a guideline-based intervention to improve diagnosis and management of chronic diseases. The 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) was used to assess depression symptoms, with higher scores representing more depressed mood. RESULTS: Higher CESD-10 scores at baseline were independently associated with being less educated (p = 0.004) and having lower income (p = 0.003). CESD-10 scores at follow-up were higher in participants with less education (p = 0.010) or receiving welfare grants (p = 0.007) independent of their baseline scores. Participants with CESD-10 scores of ten or more at baseline (56 % of all participants) had 25 % higher odds of being unemployed at follow-up (p = 0.016), independently of baseline CESD-10 score and treatment status. Among participants with baseline CESD-10 scores of ten or more, antidepressant medication at baseline was independently more likely in participants who had more education (p = 0.002), higher income (p < 0.001), or were unemployed (p = 0.001). Antidepressant medication at follow up was independently more likely in participants with higher income (p = 0.023), and in clinics with better access to pharmacists (p = 0.053) and off-site drug delivery (p = 0.013). CONCLUSIONS: Socioeconomic disadvantage appears to be both a cause and consequence of depression, and may also be a barrier to treatment. There are opportunities for improving the prevention, diagnosis and treatment of depression in primary care in inequitable middle income countries like South Africa. TRIAL REGISTRATION: The trial is registered with Current Controlled Trials ( ISRCTN20283604 ). PMID- 26621254 TI - Geometric changes of parotid glands caused by hydration during chemoradiotherapy. AB - BACKGROUND: Plan adaptation during the course of (chemo)radiotherapy of H&N cancer requires repeat CT scanning to capture anatomy changes such as parotid gland shrinkage. Hydration, applied to prevent nephrotoxicity from cisplatin, could temporarily alter the hydrogen balance and hence the captured anatomy. The aim of this study was to determine geometric changes of parotid glands as function of hydration during chemoradiotherapy compared to a control group treated with radiotherapy only. METHODS: This study included an experimental group (n = 19) receiving chemoradiotherapy, and a control group (n = 19) receiving radiotherapy only. Chemoradiotherapy patients received cisplatin with 9 l of saline solution during hydration in the first, fourth and seventh week. The delineations of the parotid glands on the planning CT scan were automatically propagated to Cone Beam CT scans using deformable image registration. Relative volume and position of the parotid glands were determined at the second chemotherapy cycle (week four) and at fraction 35. RESULTS: When saline solution was administrated, the volume temporarily increased on the first day (7.2 %, p < 0.001), second day (10.8 %, p < 0.001) and third day (7.0 %, p = 0.016). The gland positions shifted lateral, the distance between glands increased on the first day with 1.5 mm (p < 0.001), on the second day 2.2 mm (p < 0.001). At fraction 35, with both groups the mean shrinkage was 24 % +/- 11 % (1SD) and the mean medial distance between the parotid glands decreased by 0.47 cm +/- 0.27 cm. CONCLUSIONS: Hydration significantly modulates parotid gland geometry. Unless, in the context of adaptive RT, a repeat CT scan is timed during a chemotherapy cycle, these effects are of minor clinical relevance. PMID- 26621255 TI - Adjuvant Radioactive iodine 131 ablation in papillary microcarcinoma of thyroid: Saudi Arabian experience [corrected]. AB - BACKGROUND: Papillary Microcarcinoma (PMC) of thyroid is a rare type of differentiated thyroid cancer (DTC), which according to the World Health Organization measures 1.0 cm or less. The gold standard of treatment of PMC is still controversy. Our aim was to contribute in resolving the debate on the therapeutic choices of the surgical and adjuvant I-131 (RAI) treatment in PMC. METHODS: From 2000 to 2012, 326 patients were found to have PMC and were retrospectively reviewed for clinicopathological characteristics, treatment outcomes and prognostic factors. RESULTS: Mean age of cohort was 42.6 years (range: 18-76) and the mean tumor size was 0.61 cm +/- 0.24; lymph node involvement was seen in 12.9 % of cases. Median follow up period was 8.05 years (1.62-11.4). Total 23 all site recurrences (7.13 %) were observed; more observed in patients without I-131 ablation (p <0.0001). Ten year DFS rates were 89.6 %. Cox regression Model analysis revealed size, histopathologic variants, multifocality, extrathyroidal extension, lymphovascular space invasion, nodal status, and adjuvant RAI ablation the important prognostic factors affecting DFS. DISCUSSION: Despite excellent DFS rates, a small proportion of patients with PMC develop recurrences after treatment. Adjuvant RAI therapy improves DFS in PMC patients with aggressive histopathologic variants, multifocality, ETE, LVSI, tumor size (> 0.5 cm) and lymph node involvement. Failure of RAI ablation to decrease risk in N1a/b supports prophylactic central neck dissection during thyroidectomy, however more trials are warranted. CONCLUSION: Adjuvant I-131 ablation following thyroidectomy in PMC patients, particularly with poor prognostic factors improves DFS rates. PMID- 26621253 TI - Validation of parent-reported physical activity and sedentary time by accelerometry in young children. AB - BACKGROUND: It is unknown if young children's parent-reported physical activity and sedentary time are correlated with direct measures. The study objectives were to compare parent-reported physical and sedentary activity versus directly measured accelerometer data in early childhood. METHODS: From 2013 to 2014, 117 healthy children less than 6 years of age were recruited to wear Actical accelerometers for 7 days. Accelerometer data and questionnaires were available on 87 children (74%). Average daily physical activity was defined as the sum of activity >=100 counts per minute, and sedentary time as the sum of activity <100 counts per minute during waking hours. Parents reported daily physical activity (unstructured free play in and out of school, and organized activities) and selected sedentary behaviors (screen time, stroller time, time in motor vehicle). Spearman correlation coefficients and Bland-Altman plots were used to assess the validity of parent-reported measures compared to accelerometer data. RESULTS: Total physical activity was significantly greater when measured by accelerometer than parent-report; the median difference was 131 min/day (p < 0.001). Parent reported child physical activity was weak to moderately correlated with directly measured total physical activity (r = 0.39, 95% CI 0.19, 0.56). The correlations between types of physical activity (unstructured free play in and outside of school/daycare, and organized structured activity) and accelerometer were r = 0.30 (95% CI 0.09, 0.49); r = 0.42 (95% CI 0.23, 0.58); r = 0.26 (95% CI 0.05, 0.46), respectively. There was no correlation between parent-reported and accelerometer-measured total sedentary time in children (r = 0.10, 95% CI -0.12, 0.33). When the results were stratified by age group (<18, 18-47, and 48-70 months of age) no statistically significant correlations were observed and some inverse associations were observed. CONCLUSIONS: The correlation between parent report of young children's physical activity and accelerometer-measured activity was weak to moderate depending on type of activity and age group. Parent-report of children's sedentary time was not correlated with accelerometer-measured sedentary time. Additional validation studies are needed to determine if parent reported measures of physical activity and sedentary time are valid among children less than 6 years of age and across these young age groups. PMID- 26621256 TI - Expression of UCP2 in Wistar rats varies according to age and the severity of obesity. AB - Obesity, a complex metabolic disorder, is characterized by mitochondrial dysfunction and oxidative stress. Increased expression of uncoupling protein 2 (UCP2) during obesity is an adaptive response to suppress the production of reactive oxygen species. The aims of this study were to compare the expression of UCP2 in diet-induced obese Wistar rats that differed according to age and their severity of obesity, and to compare UCP2 expression in the liver and muscle of these rats. UCP2 messenger RNA and protein expression was increased 4.6-fold (p < 0.0001) and 3.0-fold (p < 0.05), respectively, in the liver of the older and heavier rats. In contrast, UCP2 expression was decreased twofold (p < 0.005) in the muscle of these rats, while UCP3 messenger RNA (mRNA) was increased twofold (p < 0.01). Peroxisome proliferator-activated receptor alpha (PPARalpha) was similarly increased (3.0-fold, p < 0.05) in the liver of the older and more severe obese rats. Total protein content was increased (2.3-fold, p < 0.0001), while 5' adenosine monophosphate-activated protein kinase (AMPK) activity was decreased (1.3-fold, p = 0.05) in the liver of the older, heavier rats. No difference in total protein content and AMPK expression was observed in the muscle of these rats. This study showed that the expression of UCP2 varies according to age and the severity of obesity and supports the widely held notion that increased UCP2 expression is an adaptive response to increased fatty acid beta-oxidation and reactive oxygen species production that occurs during obesity. An understanding of metabolic adaptation is imperative to gain insight into the underlying causes of disease, thus facilitating intervention strategies to combat disease progression. PMID- 26621257 TI - Self-corrective behavior for turn alternation in pill bugs (Armadillidium vulgare). AB - Pill bugs (Armadillidium vulgare) demonstrate a behavior called turn alternation that keeps their overall direction of movement straight after obstacles in experimental settings force them to deviate from a course. For example, this behavior is seen when they alternate their path choice on successive trials of the T-maze test. However, sometimes pill bugs stop after turning and change their direction (directional change). The function of this directional change has not been investigated because such individuals are usually omitted from the data. The present paper shows that pill bugs use directional changes to prevent them from turning in the same direction on two successive turns, a behavior called turn repetition. We examined the behavior of 36 pill bugs that each completed 130 successive T-maze trials. Directional changes appeared more frequently when individuals had begun a turn repetition than when they had begun a turn alternation. Furthermore, after correcting for turn repetition, turn alternations increased. These results suggest that pill bugs have an inherent mechanism that acts to maintain turn-alternating behavior. PMID- 26621258 TI - Gerbils exhibit stable open-arms exploration across repeated testing on the elevated plus-maze. AB - Repeated testing on the elevated plus-maze (EPM) leads rats and mice to avoid the open-arms of the apparatus. The effect of multiple exposures to the EPM on the behavioral profile of gerbils is unknown. In this study, young and middle-aged gerbils were exposed to the EPM and four retests were carried out 24, 48, 72 and 96h after the first trial in order to determine whether animals exhibited open arms avoidance. In addition, groups of young and middle-aged gerbils were exposed to the EPM for 20-min followed by a 5-min retest trial 24h apart to analyze the effect of a prolonged exposure to the EPM on open-arms exploration during first trial and retest. Gerbils exhibited high exploration of open-arms during the first trial and progressive locomotor decrease across repeated testing. Unlike previous reports for rats and mice, young gerbils showed a stable open-arms exploration both across multiple exposures and during a prolonged exposure to EPM. Middle-aged gerbils also exhibited a stable open-arms exploration during retest prior to the 20-min test. Results suggest a reliable repeated test paradigm for the EPM using our proposed methodology for gerbils. PMID- 26621259 TI - Luminescent dinuclear copper(I) complexes bearing 1,4 bis(diphenylphosphino)butane and functionalized 3-(2'-pyridyl)pyrazole mixed ligands. AB - A family of new dinuclear Cu(i) complexes with 1,4-bis(diphenylphosphino)butane (dppb) and functionalized 3-(2'-pyridyl)pyrazole mixed ligands has been synthesized and characterized. It is revealed that all these Cu(i) complexes include a [Cu2(dppb)2](2+) framework with the two Cu(i) atoms doubly bridged by a pair of dppb to generate a fourteen-membered Cu2P4C8 ring, and functionalized 3 (2'-pyridyl)pyrazole adopts a neutral chelating coordination mode without the N-H bond cleavage of the pyrazolyl ring. All these dinuclear Cu(i) complexes display a relatively weak low-energy absorption in CH2Cl2 solution, which is closely related to the variation of the Cu-N and Cu-P bonds caused by the substituent on the pyrazolyl ring. These dinuclear Cu(i) complexes are all emissive in solution and solid states at ambient temperature, which can be well modulated through structural modification of 3-(2'-pyridyl)pyrazole. It is shown that introduction of the trifluoromethyl group into the pyrazolyl ring is helpful for enhancing the luminescence properties of Cu(i) pyrazole phosphine complexes. PMID- 26621260 TI - New treatment models for compulsive disorders. AB - Obsessive compulsive disorder (OCD) as well as related disorders such as body dysmorphic disorder, tic disorder, and trichotillomania are all common and often debilitating. Although treatments are available, more effective approaches to these problems are needed. Thus this review article presents what is currently known about OCD and related disorders and suggests that understanding OCD more broadly as a compulsive disorder may allow for more effective treatment options. Toward that goal, the review presents new models of psychopharmacology and psychotherapy, as well as new brain stimulation strategies. Treatment advances, grounded in the neuroscience, have promise in advancing treatment response for OCD as well as other disorders of compulsivity. PMID- 26621261 TI - Transcriptomics and the mechanisms of antidepressant efficacy. AB - The mechanisms by which antidepressants have their effects are not clear and the reasons for variability in treatment outcomes are also unknown. However, there is evidence from candidate gene research that indicates gene expression changes may be involved in antidepressant action. In this study, we examined antidepressant induced alterations in gene expression on a transcriptome-wide scale, exploring associations with treatment response. Blood samples were taken from a subset of depressed patients from the GENDEP study (n=136) before and after eight weeks of treatment with either escitalopram or nortriptyline. Transcriptomic data were obtained from these samples using Illumina HumanHT-12 v4 Expression BeadChip microarrays. When analysing individual genes, we observed that changes in the expression of two genes (MMP28 and KXD1) were associated with better response to nortriptyline. Considering connectivity between genes, we identified modules of genes that were highly coexpressed. In the whole sample, changes in one of the ten identified coexpression modules showed significant correlation with treatment response (cor=0.27, p=0.0029). Using transcriptomic approaches, we have identified gene expression correlates of the therapeutic effects of antidepressants, highlighting possible molecular pathways involved in efficacious antidepressant treatment. PMID- 26621262 TI - Telomere length in bipolar disorder and lithium response. AB - Telomeres consist of exanucleotide tandem repeats and proteins complexes at the end of chromosome ends. Telomeres shorten at each cell division, and as such telomere length is a marker of cellular age. Accelerated telomere shortening and cell senescence have been associated with a number of chronic medical conditions, including psychiatric disorders, where increased prevalence of age-related disorders and shorter telomere length have been reported. Shorter telomeres in psychiatric patients are thought to be the consequence of allostatic load, consisting in the overactivation of allostatic systems due to chronic exposure to severe medical conditions and failure to adapt to chronic stressful stimuli. Most of the studies on telomere length in psychiatry have focused on major depressive disorder, but recent findings have shown shorter leukocyte telomere length in bipolar disorder patients and suggested that lithium may counteract telomeres shortening. These findings provided new insights into the pathophysiology of bipolar disorder and the mechanism of action of lithium. In this review we will present findings from the literature on telomere length in bipolar disorder, with a specific focus on lithium. We will also discuss advances and limitations of published work as well as methodological issues and potential confounding factors that should be taken into account when designing research protocols to study telomere length. PMID- 26621263 TI - Erratum to: Association of Autophagy in the Cell Death Mediated by Dihydrotestosterone in Autoreactive T Cells Independent of Antigenic Stimulation. PMID- 26621264 TI - Lay knowledge, social movements and the use of medicines: Personal reflections. AB - This article consists of two personal reflections about the changing status of lay knowledge over the last 20 years. The first reflection is by Nicky Britten from the perspective of a sociologist working in medical schools whose interest in this topic was motivated by my own personal experience of health care and of teaching general practitioners. Starting with the problematic deficit model of 'ignorant patients', I trace the literature on patient-centredness, shared decision-making, lay knowledge, public involvement in research and social movements. Looking at medicines use in particular, I deplore the continued hegemony of the concept of compliance in the face of extensively documented problems with the licensing, regulation, prescribing and monitoring of medicines. I argue that lay knowledge is now taken more seriously, not so much because of advocacy by clinicians and academics, but because of social movements and social action. We may have moved from 'anecdotes' to 'lived experience' but there is still a way to go, particularly when it comes to medicines use. I end with a possible future scenario. The second reflection is by Kath Maguire and is a response from the perspective of someone who came to work in this field with the express purpose of improving engagement with lay knowledge. It questions my own 'layness' and explores the issues raised by Nicky Britten using the lens of lived experience. Finally, it questions the paradigm of social movements and highlights the importance of developing different ways of listening. PMID- 26621265 TI - Using patient admission characteristics alone to predict mortality of critically ill patients: A comparison of 3 prognostic scores. AB - PURPOSE: This study compared the performance of 3 admission prognostic scores in predicting hospital mortality. MATERIALS AND METHODS: Patient admission characteristics and hospital outcome of 9549 patients were recorded prospectively. The discrimination and calibration of the predicted risks of death derived from the Simplified Acute Physiology Score (SAPS III), Admission Mortality Prediction Model (MPM0 III), and admission Acute Physiology and Chronic Health Evaluation (APACHE) II were assessed by the area under the receiver operating characteristic curve and a calibration plot, respectively. MEASUREMENTS AND MAIN RESULTS: Of the 9549 patients included in the study, 1276 patients (13.3%) died after intensive care unit admission. Patient admission characteristics were significantly different between the survivors and nonsurvivors. All 3 prognostic scores had a reasonable ability to discriminate between the survivors and nonsurvivors (area under the receiver operating characteristic curve for SAPS III, 0.836; MPM0 III, 0.807; admission APACHE, 0.845), with best discrimination in emergency admissions. The SAPS III model had a slightly better calibration and overall performance (slope of calibration curve, 1.03; Brier score, 0.09; Nagelkerke R(2), 0.297) compared to the MPM0 III and admission APACHE II model. CONCLUSIONS: All 3 intensive care unit admission prognostic scores had a good ability to predict hospital mortality of critically ill patients, with best discrimination in emergency admissions. PMID- 26621266 TI - Can the revised UK code direct practice? AB - The Nursing and Midwifery Council, the United Kingdom regulator of nursing and midwifery has recently revised its professional code of practice. This article begins by arguing that a professional code must be capable of sustaining close reading and of action guidance. Using four exemplar clauses, it is argued that the new revised code does not meet this purpose. First, I show that in setting out requirements for consent and documentation, the meaning of the relevant clause has changed significantly during the editing process so that a literal reading of the final document bears little relation to established professional practice. Second, I argue that the clause concerning the nature of professional relationships has also been altered during the editing process so that it is inconsistent with other professional groups and established accounts of the professional nurse-patient relationship. Third, I argue that the clause concerning disclosure of confidential information, which survived revision and editing with its meaning intact, is nevertheless factually incorrect and inconsistent with UK law and authoritative guidance. Finally, fourth, I argue that use of the word 'inappropriate' is inappropriate as it amounts to meaningless circularity, discussed in relation to a clause on expressing personal beliefs. Taken together, these examples demonstrate that the Code is seriously flawed and does not fulfil its purpose. One way that simple prescriptive clauses in the Code can be usefully understood is through the provision of detailed guidance. I argue that the Nursing and Midwifery Council has changed its position on its view of the value of guidance and has significantly reduced the amount of written guidance and advice it provides. The article concludes by arguing that in order to meet its action directing function, further clarifying revision and the provision of detailed guidance is required. PMID- 26621267 TI - Informed horses are influential in group movements, but they may avoid leading. AB - In species that move in cohesive groups, animals generally reach decisions through socially distributed processes, and individual knowledge is expected to influence collective decision making. Pooling of information should not be considered a general rule, however, since conflicts of interest may occur between group members. When resources are limited or highly attractive, higher-ranking individuals can prevent others from accessing food, and subordinates may have an interest in withholding information about its location. We investigated the role individual knowledge may play in recruitment processes in four groups of horses (Equus caballus). Animals were repeatedly released in a food search situation, in which one individual had been informed about the location of a preferred food, while another was a naive control subject. Horses that were informed about the location of the feeding site were seen to approach the food source more steadily and were followed by a higher number of group members than their uninformed counterparts. Recruitment processes appeared mostly passive. Among the informed subjects, lower-ranking individuals were overall less followed than the higher ranking ones. Most lower-ranking horses arrived alone at the feeding site. Non followed informed subjects spent less time in active walk and used direct paths less frequently than followed animals, and they were joined by fewer partners at the attractive food source and spent more time feeding alone. This indicates that the influence of informed individuals on the behavior of other group members was a mixed process. Some horses brought nutritional benefits to their conspecifics by leading them to food supplies, whereas the behavior of others might be functionally deceptive. PMID- 26621268 TI - Prophylactic Eculizumab Use in Kidney Transplantation: A Review of the Literature and Report of a Case with Atypical Hemolytic Uremic Syndrome. AB - BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a very rare disease, which presents with microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Progression to end-stage renal disease (ESRD) from acute kidney injury is observed in 60% of aHUS cases. The prognosis of aHUS patients who undergo kidney transplantation (Ktx) is generally poor, but these patients should be treated prophylactically with eculizumab to prevent recurrence after transplantation. CASE REPORT: An 18-year-old man was referred to our center with a history of rapid progression to ESRD with unknown etiology. He had anemia, thrombocytopenia, high levels of LDH, and indirect bilirubin and creatinine on initial laboratory results. Our diagnosis was aHUS due to initial results, normal level of ADAMTS activity, and lack of predisposing factors seen in typical HUS. We planned to perform genetic analysis for the patient and the donor candidate (mother). The variations found on exon 7 of the CFH gene had not been reported previously. According to PolyPhen analysis, this mutation was reported as a potential cause for aHUS. We decided to perform Ktx under eculizumab prophylaxis. Weekly administration of prophylaxis was extended to 1 month. The graft functioned immediately after Ktx. The patient has completed his first year uneventfully in our follow-up, with a creatinine 0.79 mg/dl at his last control visit. CONCLUSIONS: We found favorable results of an aHUS case successfully treated with kidney transplantation combined with short-term prophylactic eculizumab therapy. PMID- 26621270 TI - A Putative Association of COMT Val(108/158)Met with Impulsivity in Binge Eating Disorder. AB - OBJECTIVE: This study aims to investigate the influence of the COMT Val(108/158)Met polymorphism on trait and behavioural impulsivity in binge eating disorder (BED). COMT Val(108/158)Met has been related to impulsivity in previous studies, but so far no study has investigated the role of this polymorphism in the context of BED. METHOD: Impulsivity was assessed via a questionnaire (trait) and on a behavioural level via the antisaccade task in a sample of 69 participants classified into one out of three age-matched groups: (1) obese individuals with BED according to DMS-IV (BED+); (2) obese individuals without BED, matched with the BED+ sample according to body weight (OBED-); and (3) normal-weight healthy controls (NWC). The COMT Val(108/158)Met polymorphism was genotyped in all samples. RESULTS: As expected, the BED+ sample showed higher trait and behavioural impulsivity. Furthermore, within the BED+ group, COMT Met/Met homozygous individuals showed stronger deficits in inhibitory control. DISCUSSION: COMT Met/Met homozygous individuals with BED might represent a specific group in the BED spectrum, which shows a higher behavioural impulsivity. The association between COMT Val(108/158)Met with inhibitory control should be interpreted with caution because of the small sample size. Larger replication studies are needed to further elucidate the role of the COMT Val(108/158)Met polymorphism in the regulation of disordered eating behaviour. PMID- 26621269 TI - Loss of Ezh2 promotes a midbrain-to-forebrain identity switch by direct gene derepression and Wnt-dependent regulation. AB - BACKGROUND: Precise spatiotemporal control of gene expression is essential for the establishment of correct cell numbers and identities during brain development. This process involves epigenetic control mechanisms, such as those mediated by the polycomb group protein Ezh2, which catalyzes trimethylation of histone H3K27 (H3K27me3) and thereby represses gene expression. RESULTS: Herein, we show that Ezh2 plays a crucial role in the development and maintenance of the midbrain. Conditional deletion of Ezh2 in the developing midbrain resulted in decreased neural progenitor proliferation, which is associated with derepression of cell cycle inhibitors and negative regulation of Wnt/beta-catenin signaling. Of note, Ezh2 ablation also promoted ectopic expression of a forebrain transcriptional program involving derepression of the forebrain determinants Foxg1 and Pax6. This was accompanied by reduced expression of midbrain markers, including Pax3 and Pax7, as a consequence of decreased Wnt/beta-catenin signaling. CONCLUSION: Ezh2 is required for appropriate brain growth and maintenance of regional identity by H3K27me3-mediated gene repression and control of canonical Wnt signaling. PMID- 26621271 TI - Serum Glutathione in Patients with Schizophrenia in Dynamics of Antipsychotic Therapy. AB - Serum concentrations of oxidized and reduced glutathione were measured in 73 patients with schizophrenia at admission and in dynamics of therapy with traditional and atypical antipsychotic drugs. The level of reduced glutathione in patients with schizophrenia with manifest clinical symptoms was lower than in normal subjects. Atypical neuroleptics produced virtually no effects on the glutathione system, while therapy with typical antipsychotics led to further decrease in the levels of reduced glutathione, thus aggravating the imbalance of metabolic processes typical of schizophrenia. PMID- 26621272 TI - The Key Proteins of Dopaminergic Neurotransmission of Human Peripheral Blood Lymphocytes: Changed mRNA Level in Alcohol Dependence Syndrome. AB - The expression of dopamine receptor (DRD), Nurr1 transcription factor (NR4A2), and alpha-sinucleine (SNCA) genes in peripheral blood lymphocytes is evaluated. The results indicate that alcohol dependence is associated with high expression of SNCA and DRD4 (signifi cantly higher than in the control group) and is not associated with changes in the work of NR4A2 and DRD3 genes. The levels of DRD3 and DRD4 mRNA form a positive linear correlation (p<=0.05). The expression of SNCA and DRD4 genes can serve as an important peripheral marker of alcohol dependence development, which is essential for antipsychotic therapy. PMID- 26621273 TI - Study of Cytokine Profile of Cultured "Early" and "Late" Endothelial Progenitor Cells in Peripheral Blood of Chronic Heart Failure Patients after Mobilization Course with Granulocyte Colony-Stimulating Factor. AB - The effect of cell culturing protocol with various adhesion proteins and different culture time on the profile of cytokine and growth factors produced by endothelial progenitor cells harvested after mobilization with granulocyte colony stimulating factor was examined in patients with chronic heart failure. The endothelial progenitor cells cultured on fibronectin or gelatin produced a broad and overall similar spectrum of cytokines and growth factors, the levels of which depended on the culture time. On culture day 16, the cells grown on fibronectin diminished the production of cytokines and growth factors (IL-10, IL-18, IL-8, erythropoietin, and VEGF), while the cells grown on gelatin down-regulated the synthesis of TNF-alpha, IL-8, and erythropoietin, although they up-regulated the production of IL-10, IL-18, and VEGF. PMID- 26621274 TI - Successive Administration of Streptococcus Type 5 Group A Antigens and S. typhimurium Antigenic Complex Corrects Elevation of Serum Cytokine Concentration and Number of Bone Marrow Stromal Pluripotent Cells in CBA Mice Induced by Each Antigen Separately. AB - Administration of bacterial antigens to CBA mice induced an increase in serum concentration of virtually all cytokines with a peak in 4 h after administration of S. typhimurium antigens and in 7 h after administration of streptococcus antigens. In 20 h, cytokine concentrations returned to the control level or were slightly below it. In 4 h after administration of S. typhimurium antigens preceded 3 h before by administration of streptococcus antigens, we observed a significant decrease in serum concentrations of IFN-gamma, IL-10, GM-CSF, IL-12, and TNF-alpha, in comparison with injection S. typhimurium antigens alone and IL 5, IL-10, GM-CSF, and TNF-alpha in comparison with injection of streptococcus antigens alone; the concentrations of IL-2 and IFN-gamma, in contrast, increased by 1.5 times in this case. In 20 h after administration of S. typhimurium antigens, the number of multipotential stromal cells (MSC) in the bone marrow and their cloning efficiency (ECF-MSC) increased by 4.8 and 4.4 times, respectively, in comparison with the control, while after administration of streptococcus antigens by 2.6 and 2.4 times, respectively. In 20 h after administration of S. typhimurium antigens preceded 3 h before by administration of streptococcus antigens, these parameters increased by 3.2 and 2.9 times, respectively, in comparison with the control, i.e. the observed increase in the level of MSC count and ECF-MSC is more consistent with the response of the stromal tissue to streptococcus antigens. Thus, successive administration of two bacterial antigens corrected both serum cytokine profiles and MSC response to administration of each antigen separately, which indicates changeability of the stromal tissue in response to changes in the immune response. PMID- 26621275 TI - Association of Apolipoprotein A1 Gene Polymorphisms with Serum Lipid Spectrum in Adolescents in East Siberia. AB - We studied the incidence of genotypes of polymorphic alleles (-75)G>A and (+83)C>T of apolipoprotein A1 gene in healthy Russian adolescents, residents of East Siberia. Genotyping was carried out by PCR with subsequent restriction fragment length polymorphism analysis. The incidence of allele (-75)A was 22.5%, of allele (+83)T - 7.3%. Association of allele (-75) A with high blood cholesterol level was revealed. PMID- 26621276 TI - The Use of Cell Elastography to Study the Biomechanical Properties of Bacillus subtilis. AB - The cytometric, elastic, and adhesion properties of Bacillus subtilis at different terms of culturing were studied. The cytometric parameters of bacterial cells increased by day 6 in culture and decreased at later terms. Analysis of membrane rigidity showed that parameters describing bacterial elastic properties underwent waveform changes: the decrease in bacterial elasticity (from day 1 to 6) was followed by its increase on day 12 in culture. Analysis of adhesion activity showed that this parameter increased during the first 6 days and than decreased at later stages culturing. PMID- 26621277 TI - Antioxidant Effect of Polyoxidonium and Metaprot during Bronchopulmonary Inflammation in Rats. AB - The antioxidant effects of individual or combined application of polyoxidonium and metaprot were examined in rats with acute bronchopulmonary inflammation. By degree of antioxidant potency, polyoxidonium was inferior to metaprot, but their combined application produced more potent antioxidant effect. Polyoxidonium and metaprot in low concentrations increased and in high concentrations suppressed spontaneous biochemiluminescence in the model system of alveolar macrophages. PMID- 26621278 TI - Toxicity and Antiviral Activity of the Extracts of Submerged Mycelium of Nematophagous Duddingtonia flagrans Fungus in Vero Cell Culture. AB - We studied toxicity and antiviral activity of aqueous and ethanol extracts of bioactive substances from the biomass of nematophagous fungus Duddingtonia flagrans prepared by submerged culturing of the mycelium. It is found that both extracts were characterized by low toxicity for cultured Vero cells and inhibited reproduction of DNA-viruses in this cell line. Ethanol extract of the fungus exhibited higher in vitro antiviral activity against Herpes simplex virus type 2, ectromelia virus, and vaccinia virus than water extract, which can be due to higher content of proteins, polysaccharides, flavonols, catechins, or carotenes or more effective their combination. The extracts of cultured mycelium of Duddingtonia flagrans fungus containing a complex of bioactive substances can be used for creation of broad-spectrum antiviral drugs against DNA-viruses. PMID- 26621279 TI - Heart Rate Variability in Nonlinear Rats with Different Orientation and Exploratory Activity in the Open Field. AB - The basic behavioral activity of nonlinear rats was evaluated from the sum of crossed peripheral and central squares and peripheral and central rearing postures in the open fi eld test. This index was low (<20 episodes), intermediate (20-29 episodes), or high (>30 episodes). Male rats with high score of orientation and exploratory activity were characterized by higher indexes of total heart rate variability than rats with low or intermediate activity. Specimens with a greater contribution of VLF waves into the total power spectrum of heart rate variability were shown to dominate among the rats with high behavioral activity. Our results are consistent with the notions of a suprasegmental nature of VLF waves. PMID- 26621280 TI - Behavioral Indexes of Thermal Nociceptive Sensitivity in Rats after Melatonin Administration. AB - We studied the effect of melatonin (10 mg/kg intraperitoneally) on behavioral indexes reflecting changes in nociceptive sensitivity of rats in response to thermal stimulation in the hot plate test. Administration of melatonin to animals suppressed the perceptual component of nociception, which was manifested in an increase in the perception threshold of noxious thermal stimulus. In the follow up period, exogenous melatonin contributed to a decrease in the latency of avoidance reactions and enhanced the behavior of escaping the thermal nociceptive stimulation. Our results suggest that the involvement of melatonin in goal directed behavior of mammals during nociceptive treatment is related to an increase in orientation and exploratory activity, facilitation of memory storage, and improvement of memory retrieval for environmental signals, action program, and reinforcing effect of avoiding the painful stimulus. PMID- 26621281 TI - Mechanisms of Disruptive Action of Dichlorodiphenyltrichloroethane (DDT) on the Function of Thyroid Follicular Epitheliocytes. AB - The mechanism of disruptive action of dichlorodiphenyltrichloroethane (DDT) on the function of thyroid follicular epitheliocytes was examined in mature male Wistar rats administered with a daily dose of DDT (2 MUg/kg) for 6 or 10 weeks. In 6 weeks, the serum level of Na(+)/I(-) symporter responsible for the transport of iodides into follicular thyrocytes decreased, while serum concentration of thyroperoxidase increased. In 10 weeks, both the number of follicles in the thyroid gland and serum level of Na(+)/I(-) symporter increased. In circulating blood, the concentrations of thyroglobulin as well as alpha and beta receptors of the thyroid hormones did not change. DDT down-regulated the iodine-accumulated function of follicular thyrocytes by suppressing Na(+)/I(-) symporter synthesis. Recovery of Na(+)/I (-) symporter production resulted from up-regulation of the proliferative processes in thyroid gland. PMID- 26621282 TI - Scarabaeus cristatus (Coleoptera: Scarabaeidae) as intermediate host of Physocephalus dromedarii (Nematoda: Spirocercidae)--a contribution to the epidemiology of camel physocephalidosis. AB - In UAE, camel Physocephalus dromedarii was diagnosed for the first time in 2011 in dromedaries from a farm that previously had imported animals from foreign countries. The large scarab beetle, Scarabaeus cristatus, was found to be the major intermediate host for this parasite in Dubai. A total of 638 specimens of S. cristatus were collected and examined for the presence of third-stage larvae of nematode larvae at two sites in the Dubai Emirate (Emirates Industry for Camel Milk and Products and horse endurance training track) within a distance of 15 km. Third-stage larvae of P. dromedarii were detected in 94 and 97 % of beetles collected from the territory of the camel milk farm and the endurance training track, respectively. In addition to third-stage larvae, 264 beetles contained second-stage larvae. Only four beetles were infected with other than P. dromedarii larvae. The average larval burden in beetles from camel milk farm was significantly higher compared to those in beetles collected from the other site (1538 vs. 697). Comparison of larval burdens in juvenile and adult beetles collected at the camel milk farm showed a significantly higher intensity in adult specimens (501 vs. 1734) while in beetles found on the horse endurance track, larval burdens were comparable (548 vs. 858). The results suggest that S. cristatus become infected at the camel milk farm, and in search for other sources of food, they fly to places where they were found feeding on feces of other animals. PMID- 26621283 TI - Molecular identification and characterization of prohibitin from Echinococcus granulosus. AB - Prohibitin (PHB) is a widely distributed protein that functions as a molecular chaperone, is involved in the regulation of cell cycle, and maintains mitochondrial structure and functions of the anti-apoptosis, senescence, and proliferation. The aim of this study was to characterize PHB in Echinococcus granulosus (EgPHB), a harmful cestode parasite of humans, many livestock species, and wild animals. We found that EgPHB is a conserved SPFH (stomatin, prohibitin, flotillin, and HflK/C) domain-containing protein, consisting of 289 amino acids, which shares 42.66-99.31% identity with PHBs from other parasites and mammals. EgPHB was located mainly in the tegument issue of protoscoleces, in the inner body of adult worms, and was expressed widely in the germinal layer. This is the first report on prohibitin from E. granulosus, and EgPHB is considered to be a valuable protein to study more in the future. PMID- 26621284 TI - Angiostrongylus cantonensis in the vector snails Pomacea canaliculata and Achatina fulica in China: a meta-analysis. AB - Angiostrongyliasis is a food-borne parasitic disease induced by the nematode Angiostrongylus cantonensis, and has been recognized as the main cause leading to human eosinophilic meningitis. Humans usually acquire infection by digestion of infected Pomacea canaliculata and Achatina fulica, the most predominant intermediate hosts found in China. This meta-analysis was aimed to assess the prevalence of A. cantonensis infection among these two snails in China in the past 10 years. Data were systematically collected in electronic databases such as PubMed, Web of Science, ScienceDirect, CNKI, SinoMed, VIP, CSCD, and Wanfang from 2005 to 2015. Thirty-eight studies with a total of 41,299 P. canaliculata and 21,138 Ac. fulica were included in the present study. The overall infection rate of A. cantonensis in China was estimated to be 7.6 % (95 % confidential interval (CI) = 0.063 to 0.090) in P. canaliculata and 21.5 % in Ac. fulica (95 % CI = 0.184 to 0.245), respectively. No significant difference was observed in prevalence rates among publication year and sample size for both snails. Also, it was found that the prevalence in Ac. fulica is significantly higher than that in P. canaliculata (odds ratio (OR) = 3.946, 95 % CI = 3.070 to 5.073). The present study reveals that snail infection with A. cantonensis is clearly prevalent in China. Further studies are required to improve strategies for control of infections of snails, particularly those of Ac. fulica, and to detect further factors and conditions such as geographic region, temperatures, and diagnosis method. PMID- 26621286 TI - Erratum to: The UBC-40 Urothelial Bladder Cancer Cell Line Index: a genomic resource for functional studies. PMID- 26621285 TI - Hydrothermal synthesis of titanium dioxide nanoparticles: mosquitocidal potential and anticancer activity on human breast cancer cells (MCF-7). AB - Mosquito vectors (Diptera: Culicidae) are responsible for transmission of serious diseases worldwide. Mosquito control is being enhanced in many areas, but there are significant challenges, including increasing resistance to insecticides and lack of alternative, cost-effective, and eco-friendly products. To deal with these crucial issues, recent emphasis has been placed on plant materials with mosquitocidal properties. Furthermore, cancers figure among the leading causes of morbidity and mortality worldwide, with approximately 14 million new cases and 8.2 million cancer-related deaths in 2012. It is expected that annual cancer cases will rise from 14 million in 2012 to 22 million within the next two decades. Nanotechnology is a promising field of research and is expected to give major innovation impulses in a variety of industrial sectors. In this study, we synthesized titanium dioxide (TiO2) nanoparticles using the hydrothermal method. Nanoparticles were subjected to different analysis including UV-Vis spectrophotometry, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), zeta potential, and energy-dispersive spectrometric (EDX). The synthesized TiO2 nanoparticles exhibited dose-dependent cytotoxicity against human breast cancer cells (MCF-7) and normal breast epithelial cells (HBL-100). After 24-h incubation, the inhibitory concentrations (IC50) were found to be 60 and 80 MUg/mL on MCF-7 and normal HBL-100 cells, respectively. Induction of apoptosis was evidenced by Acridine Orange (AO)/ethidium bromide (EtBr) and 4',6-diamidino 2-phenylindole dihydrochloride (DAPI) staining. In larvicidal and pupicidal experiments conducted against the primary dengue mosquito Aedes aegypti, LC50 values of nanoparticles were 4.02 ppm (larva I), 4.962 ppm (larva II), 5.671 ppm (larva III), 6.485 ppm (larva IV), and 7.527 ppm (pupa). Overall, our results suggested that TiO2 nanoparticles may be considered as a safe tool to build newer and safer mosquitocides and chemotherapeutic agents with little systemic toxicity. PMID- 26621288 TI - Development of Guidelines for the Management of Pulmonary Nodules: Toward Better Implementation. PMID- 26621289 TI - Autoimmunity: A Pathway to Usual Interstitial Pneumonia? PMID- 26621287 TI - Neutralizing Antibody Response and Antibody-Dependent Cellular Cytotoxicity in HIV-1-Infected Individuals from Guinea-Bissau and Denmark. AB - The development of therapeutic and prophylactic HIV vaccines for African countries is urgently needed, but the question of what immunogens to use needs to be answered. One approach is to include HIV envelope immunogens derived from HIV positive individuals from a geographically concentrated epidemic with more limited viral genetic diversity for a region-based vaccine. To address if there is a basis for a regional selected antibody vaccine, we have screened two regionally separate cohorts from Guinea-Bissau and Denmark for neutralizing antibody activity and antibody-dependent cellular cytotoxicity (ADCC) against local and nonlocal circulating HIV-1 strains. The neutralizing activity did not demonstrate higher potential against local circulating strains according to geography and subtype determination, but the plasma from Danish individuals demonstrated significantly higher inhibitory activity than that from Guinea Bissau individuals against both local and nonlocal virus strains. Interestingly, an opposite pattern was observed with ADCC activity, where Guinea-Bissau individual plasma demonstrated higher activity than Danish plasma and was specifically against the local circulating subtype. Thus, on basis of samples from these two cohorts, no local-specific neutralizing activity was detected, but a local ADCC response was identified in the Guinea-Bissau samples, suggesting potential use of regional immunogens for an ADCC-inducing vaccine. PMID- 26621290 TI - Adaptive Servoventilation: Answer to a Sleep Physician's Dream? PMID- 26621291 TI - Correction to Dosage in: Antiplatelet Drugs: Antithrombotic Therapy and Prevention of Thrombosis: 9th ed: American College of Chest Physicians Evidence Based Clinical Practice Guidelines. PMID- 26621292 TI - Error in Figure 1 in: Treatment and Prevention of Heparin-Induced Thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. PMID- 26621294 TI - Pemberton Sign: A Recommendation to Perform Arm Elevation Spirometry With Flow Volume Loops. AB - We report a case of intrathoracic goiter with positive Pemberton sign. Conventional spirometry did not show abnormalities, but arm elevation spirometry with flow-volume loops revealed expiratory flow limitation with a plateau. Clinicians should consider repeating flow-volume loops with arm elevation in all cases of intrathoracic goiter with initially normal loops. PMID- 26621295 TI - A Man in His 60s With Renal Failure and Shock Refractory to Vasopressors. PMID- 26621296 TI - A 79-Year-Old Man With Interstitial Lung Disease and Cryptic Area of High 18 Fluorodeoxyglucose Uptake in Left Upper Lobe. AB - Seven years after left hemicolectomy and radical lymph nodal dissection followed by adjuvant chemotherapy for colorectal cancer (histotype, adenocarcinoma; stage, pT3N2M0; grading, G2), a slight increase in carcinoembryonic antigen levels (6.2 ng/mL; range, 0-5 ng/mL) was detected in a 79-year-old man. He was a heavy smoker with history of an interstitial fibrotic lung disease with associated areas of emphysema. PMID- 26621297 TI - A 68-Year-Old Musician With Cough, Wheezing, and a Lung Mass. AB - A 68-year-old man was referred to the pulmonary clinic for evaluation of cough and a 5-cm right upper lobe mass. He was in his usual state of health until 1 year prior when he developed intermittent cough, wheezing, and sinus congestion. He denied any sputum production or hemoptysis. He also denied any fevers, chills, or weight loss. He had received various treatments within the prior 6 months, including short courses of oral prednisone, levofloxacin, and bronchodilators, without any relief of his symptoms. PMID- 26621298 TI - Goals of Care: Role of Physicians in the ICU. PMID- 26621299 TI - Response. PMID- 26621300 TI - Thoracic Ultrasound Limitations in the Differential Diagnosis of Respiratory Failure Causes. PMID- 26621301 TI - Response. PMID- 26621302 TI - Lenalidomide in Nonmalignant Disorders: A New Ray of Hope for Refractory Sarcoidosis. PMID- 26621303 TI - Response. PMID- 26621304 TI - Pulseless Pulse Oximetry. PMID- 26621305 TI - Response. PMID- 26621306 TI - Cytokine Serum Levels and Septic Myocardial Dysfunction: Is This the Key? PMID- 26621307 TI - Outcomes in Patients With Acute Lung Injury/ARDS vs Cardiogenic Pulmonary Edema. PMID- 26621308 TI - Response. PMID- 26621309 TI - Photonic Crystal Microbubbles as Suspension Barcodes. AB - A novel suspension array was developed that uses photonic crystal (PhC) microbubbles as barcode particles. The PhC microbubbles have an outer transparent polymeric shell, a middle PhC shell, and an inner bubble core, and they were achieved by extraction-derived self-assembly of colloidal nanoparticles in semipermeable solid microcapsules. The encoded elements of the microbubbles originated from their PhC structure with a coated shell, which not only improved the stability of the codes but also provided a flexible surface for bioassays. By using multicompartmental microcapsule templates, PhC microbubbles with substantial coding levels and controllable movement could also be achieved. In addition, as the size of the encapsulated bubbles could be tailored, the overall density of the PhC microbubbles could be adjusted to match the density of a detection solution and to remain in suspension. These remarkable properties make the PhC microbubbles excellent barcode particles. PMID- 26621310 TI - Injectable gellan gum-based nanoparticles-loaded system for the local delivery of vancomycin in osteomyelitis treatment. AB - Infection spreading in the skeletal system leading to osteomyelitis can be prevented by the prolonged administration of antibiotics in high doses. However systemic antibiotherapy, besides its inconvenience and often low efficacy, provokes numerous side effects. Thus, we formulated a new injectable nanoparticle loaded system for the local delivery of vancomycin (Vanc) applied in a minimally invasive way. Vanc was encapsulated in poly(L-lactide-co-glycolide) nanoparticles (NPs) by double-emulsification. The size (258 +/- 11 nm), polydispersity index (0.240 +/- 0.003) and surface potential (-25.9 +/- 0.2 mV) of NPs were determined by dynamic light scattering and capillary electrophoresis measurements. They have a spherical morphology and a smooth topography as observed using atomic force microscopy. Vanc loading and encapsulation efficiencies were 8.8 +/- 0.1 and 55.2 +/- 0.5 %, respectively, based on fluorescence spectroscopy assays. In order to ensure injectability, NPs were suspended in gellan gum and cross-linked with Ca(2+); also a portion of dissolved antibiotic was added to the system. The resulting system was found to be injectable (extrusion force 11.3 +/- 1.1 N), reassembled its structure after breaking as shown by rheology tests and ensured required burst release followed by sustained Vanc delivery. The system was cytocompatible with osteoblast-like MG-63 cells (no significant impact on cells' viability was detected). Growth of Staphylococcus spp. reference strains and also those isolated from osteomyelitic joints was inhibited in contact with the injectable system. As a result we obtained a biocompatible system displaying ease of application (low extrusion force), self-healing ability after disruption, adjustable drug release and antimicrobial properties. PMID- 26621311 TI - A promising "TRAIL" of tanshinones for cancer therapy. AB - An ideal cancer therapy specifically targets cancer cells while sparing normal tissues. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) elicits apoptosis by engaging its cognate death receptors (DRs-namely, DR4 and DR5. The cancer cell-selective proapoptotic action of TRAIL is highly attractive for cancer therapy, but clinical application of TRAIL is rather limited due to tumors' inherent or acquired TRAIL resistance. Combining TRAIL with agents that reverse resistance to it has proved promising in the sensitization of TRAIL induced apoptosis. Noteworthy, natural compounds have already been validated as potential resources for TRAIL sensitizers. In this review, we focus on the recently identified TRAILsensitizing effect of tanshinones, the anticancer ingredients of the medicinal plant Salvia miltiorrhiza (Danshen in Chinese). Research from our laboratories and others have revealed the synergy of a tanshinones-TRAIL combination in diverse types of cancer cells through up regulation of DR5 and/or down-regulation of antiapoptotic proteins such as survivin. Thus, in addition to their anticancer mechanisms, tanshinones as TRAIL sensitizers hold great potential to be translated to TRAIL-based therapeutic modalities for combatting cancer. PMID- 26621312 TI - CMV-associated axonal sensory-motor Guillain-Barre syndrome in a child: Case report and review of the literature. AB - BACKGROUND: Guillain-Barre syndrome is the most frequent cause of flaccid paresis in Western countries. Moreover, CMV infection is the most common antecedent viral infection in adult patients and the presence of specific IGM antiganglioside antibodies is often identified. Instead, Guillain-Barre syndrome following CMV infections is rarely reported in childhood and often presents severe symptoms at onset and longer recovery times. MATERIAL AND METHODS: One year of clinical, electrophysiological and serological follow-up of a 9-year old child with axonal sensory-motor Guillain-Barre syndrome following CMV infection is reported. Moreover, the literature data on paediatric sensory-motor axonal GBS and GBS secondary to CMV infection and antiganglioside antibodies are reviewed. RESULTS: Our patient presented with paraesthesias and a pattern of weakness showing proximal predominance and affecting the upper limbs more than the lower limbs. At nadir, unilateral facial palsy was also present and he was unable to walk. Electroneurography showed motor-sensory axonal damage. Both anti-CMV and anti-GM2 IgM were positive. After early treatment with IVIG and IV methylprednisolone the patient recovered deambulation. Six months later, his neurological examination was normal and electroneurography showed normal data. CONCLUSION: The sensory motor axonal form of Guillain-Barre syndrome following CMV infection may present a good prognosis and a prompt full recovery also in children, if adequate treatment is started in time. PMID- 26621313 TI - Chromosomal abnormalities in 1354 Japanese patients with azoospermia due to spermatogenic dysfunction. PMID- 26621315 TI - Aortopulmonary collaterals: Angiogenesis, or a whole lot more? PMID- 26621314 TI - System-wide assembly of pathways and modules hierarchically reveal metabolic mechanism of cerebral ischemia. AB - The relationship between cerebral ischemia and metabolic disorders is poorly understood, which is partly due to the lack of comparative fusing data for larger complete systems and to the complexity of metabolic cascade reactions. Based on the fusing maps of comprehensive serum metabolome, fatty acid and amino acid profiling, we identified 35 potential metabolic biomarkers for ischemic stroke. Our analyses revealed 8 significantly altered pathways by MetPA (Metabolomics Pathway Analysis, impact score >0.10) and 15 significantly rewired modules in a complex ischemic network using the Markov clustering (MCL) method; all of these pathways became more homologous as the number of overlapping nodes was increased. We then detected 24 extensive pathways based on the total modular nodes from the network analysis, 12 of which were new discovery pathways. We provided a new perspective from the viewpoint of abnormal metabolites for the overall study of ischemic stroke as well as a new method to simplify the network analysis by selecting the more closely connected edges and nodes to build a module map of stroke. PMID- 26621316 TI - Interrupted aortic arch: Measure twice, cut once. PMID- 26621317 TI - The evolution of surgical mentorship, or 10 pounds of potatoes in a 5-pound bag. PMID- 26621318 TI - The mesothelioma surgery shift. PMID- 26621320 TI - Discussion. PMID- 26621319 TI - North American single-center experience with a sutureless aortic bioprosthesis. AB - OBJECTIVE: Surgical sutureless aortic valves have the potential for shorter procedural times and could benefit patients with increased risk. The Enable (Medtronic Inc, Minneapolis, Minn) valve is a bioprosthesis housed in a Nitinol cage allowing folding and deployment once implanted. We aimed to evaluate the early clinical and echocardiographic results with the Enable valve. METHODS: Patients with aortic stenosis, Society of Thoracic Surgeons score greater than 5.0%, the need for combined procedures, and frailty were considered for Enable implantation. RESULTS: Between August 2012 and October 2014, 63 patients underwent implantation of the Enable valve (Medtronic Inc, Minneapolis, Minn). Thirty patients underwent isolated aortic valve replacement. Combined procedures were aortic valve replacement/coronary artery bypass grafting (26), aortic valve replacement/mitral valve repair (2), aortic valve replacement/mitral valve repair/coronary artery bypass grafting (2), and aortic valve replacement/ascending aortic graft (3). Predicted Society of Thoracic Surgeons score was 8.06 +/- 7.73 (0.94-41.30). Implant success was 100%. Mean crossclamp time for isolated aortic valve replacement was 44 +/- 14 minutes (30-91). Thirty day mortality was 1.6% (1/63), and late mortality was 3.2% (2/62). No mortality was valve related. Intraoperative need for revision was 6.3% (4/63). Early migration requiring reoperation occurred in 1.6% of patients (1/63). Postoperative indexed aortic valve area was 1.08 +/- 0.22 cm(2)/m(2), and peak and mean gradients were 17 +/- 7 mm Hg and 9 +/- 4 mm Hg, respectively. The rate of complications was as follows: pacemaker 3.1% (2/63), transient ischemic attack 1.6% (1/63), other thromboembolic events 0%, bleeding 0%, and endocarditis 0%. Mean follow-up was 10 +/- 8 months. At latest follow-up, 61 patients were in New York Heart Association class I. Moderate or severe aortic regurgitation did not develop in any patients in the follow-up period. CONCLUSIONS: The Enable bioprosthesis is an acceptable alternative to conventional aortic valve replacement in higher-risk patients. The early hemodynamic performance seems favorable. PMID- 26621321 TI - Discussion. PMID- 26621322 TI - Lung transplantation and concomitant cardiac surgery: Is it justified? AB - OBJECTIVE: Increasing numbers of lung transplant candidates have cardiac conditions that affect their survival after transplantation. Our objective was to determine if patients who undergo concomitant cardiac surgery (CCS) during the lung transplant procedure have similar outcomes, as a cohort of isolated lung transplant recipients. METHODS: This was a retrospective, observational, matched cohort analysis. The records of lung transplant recipients who underwent CCS from August 2000 to August 2013 were reviewed. A cohort of isolated lung transplant recipients, matched on the basis of age, lung allocation score, diagnosis, type of procedure, and era, was identified. The primary endpoint of this trial was 5 year survival. The secondary endpoints were primary graft dysfunction, grade III, at 72 hours, intensive care unit and hospital length of stay, and 5-year major adverse cardiac event rates. RESULTS: A total of 120 patients underwent lung transplantation and CCS. Compared with the isolated lung transplant group, the donor, recipient, and operation characteristics were similar. No difference was found in the survival of the 2 groups for up to 5 years, or in the incidence of primary graft dysfunction Grade III at 72 hours, intensive care unit length of stay, invasive ventilation, hospital length of stay, or incidence of 5-year major adverse cardiac events. CONCLUSIONS: Lung transplant recipients undergoing CCS have early and midterm clinical outcomes similar to those of isolated lung transplant recipients. Given that this report is the largest published experience, offering cardiac surgery at the time of lung transplantation, to selected patients, remains justified. PMID- 26621323 TI - Chronic mucocutaneous candidiasis: characterization of a family with STAT-1 gain of-function and development of an ex-vivo assay for Th17 deficiency of diagnostic utility. AB - Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent and persistent superficial infections, with Candida albicans affecting the mucous membranes, skin and nails. It can be acquired or caused by primary immune deficiencies, particularly those that impair interleukin (IL)-17 and IL-22 immunity. We describe a single kindred with CMC and the identification of a STAT1 GOF mutation by whole exome sequencing (WES). We show how detailed clinical and immunological phenotyping of this family in the context of WES has enabled revision of disease status and clinical management. Together with analysis of other CMC cases within our cohort of patients, we used knowledge arising from the characterization of this family to develop a rapid ex-vivo screening assay for the detection of T helper type 17 (Th17) deficiency better suited to the routine diagnostic setting than established in-vitro techniques, such as intracellular cytokine staining and enzyme-linked immunosorbent assay (ELISA) using cell culture supernatants. We demonstrate that cell surface staining of unstimulated whole blood for CCR6+ CXCR3- CCR4+ CD161+ T helper cells generates results that correlate with intracellular cytokine staining for IL-17A, and is able to discriminate between patients with molecularly defined CMC and healthy controls with 100% sensitivity and specificity within the cohort tested. Furthermore, removal of CCR4 and CD161 from the antibody staining panel did not affect assay performance, suggesting that the enumeration of CCR6+ CXCR3- CD4+ T cells is sufficient for screening for Th17 deficiency in patients with CMC and could be used to guide further investigation aimed at identifying the underlying molecular cause. PMID- 26621325 TI - Soluble epoxide hydrolase: A potential target for metabolic diseases. AB - Epoxyeicosatrienoic acids (EETs), important lipid mediators derived from arachidonic acid, have many beneficial effects in metabolic diseases, including atherosclerosis, hypertension, cardiac hypertrophy, diabetes, non-alcoholic fatty liver disease, and kidney disease. Epoxyeicosatrienoic acids can be further hydrolyzed to less active diols by the enzyme soluble epoxide hydrolase (sEH). Increasing evidence suggests that inhibition of sEH increases levels of EETs, which have anti-inflammatory effects and can prevent the development of hypertension, atherosclerosis, heart failure, fatty liver, and multiple organ fibrosis. Arachidonic acid is the most abundant omega-6 polyunsaturated fatty acid (PUFA) and shares the same set of enzymes with omega-3 PUFAs, such as docosahexaenoic acid and eicosapentaenoic acid. The omega-3 PUFAs and metabolites, such as regioisomeric epoxyeicosatetraenoic acids and epoxydocosapentaenoic acids, have been reported to have strong vasodilatory and anti-inflammatory effects. Therefore, sEH may be a potential therapeutic target for metabolic disorders. In this review, we focus on our and other recent studies of the functions of sEH, including the effects of its eicosanoid products from both omega-3 and omega-6 PUFAs, in various metabolic diseases. We also discuss the possible cellular and molecular mechanisms underlying the regulation of sEH. PMID- 26621324 TI - A redox signalling globin is essential for reproduction in Caenorhabditis elegans. AB - Moderate levels of reactive oxygen species (ROS) are now recognized as redox signalling molecules. However, thus far, only mitochondria and NADPH oxidases have been identified as cellular sources of ROS in signalling. Here we identify a globin (GLB-12) that produces superoxide, a type of ROS, which serves as an essential signal for reproduction in C. elegans. We find that GLB-12 has an important role in the regulation of multiple aspects in germline development, including germ cell apoptosis. We further describe how GLB-12 displays specific molecular, biochemical and structural properties that allow this globin to act as a superoxide generator. In addition, both an intra- and extracellular superoxide dismutase act as key partners of GLB-12 to create a transmembrane redox signal. Our results show that a globin can function as a driving factor in redox signalling, and how this signal is regulated at the subcellular level by multiple control layers. PMID- 26621326 TI - Acute personalized habitual caffeine doses improve attention and have selective effects when considering the fractionation of executive functions. AB - Caffeine is widely used, often consumed with food, and improves simple and complex/executive attention under fasting conditions. We investigated whether these cognitive effects are observed when personalized habitual doses of caffeine are ingested by caffeine consumers, whether they are influenced by nutriments and if various executive domains are susceptible to improvement. This was a double blind, placebo-controlled study including 60 young, healthy, rested males randomly assigned to one of four treatments: placebo fasting, caffeine fasting, placebo meal and caffeine meal. Caffeine doses were individualized for each participant based on their self-reported caffeine consumption at the time of testing (morning). The test battery included measures of simple and sustained attention, executive domains (inhibiting, updating, shifting, dual tasking, planning and accessing long-term memory), control measures of subjective alterations, glucose and insulin levels, skin conductance, heart rate and pupil dilation. Regardless of meal intake, acute habitual doses of caffeine decreased fatigue, and improved simple and sustained attention and executive updating. This executive effect was not secondary to the habitual weekly dose consumed, changes in simple and sustained attention, mood, meal ingestion and increases in cognitive effort. We conclude that the morning caffeine "fix" has positive attentional effects and selectively improved executive updating whether or not caffeine is consumed with food. PMID- 26621327 TI - Time to Positivity of Blood Cultures in Infants 0 to 90 Days Old Presenting to the Emergency Department: Is 36 Hours Enough? AB - Background: Continuous monitoring blood culture systems (CMBCS) now allow for more rapid detection of microbial growth. We aimed to determine whether a 36-hour period was sufficient to detect all blood cultures positive for pathogenic bacteria in infants 0 to 90 days old undergoing a septic workup in the emergency department of a tertiary care pediatric center. Methods: We performed a retrospective study of all positive blood cultures collected in these infants over a 5-year time period (from March 13, 2008 to July 29, 2013). Bottles were incubated in a CMBCS. The time to positivity (TTP) was calculated from time of blood culture registration into the laboratory system to time of Gram stain. Medical charts were reviewed for relevant clinical information. Cultures were classified as pathogenic or contaminant using microorganism type and clinical presentation. Results: Three thousand five hundred fifty-nine blood cultures were collected. Of these, 98 (2.8%) were positive. Fifty-two (53.1%) were deemed pathogenic and 46 (46.9%) were deemed contaminant, for a true prevalence of bacteremia of 1.5%. At 24, 36, 48, and 50 hours, 87.8% (86 of 98), 96.9% (95 of 98), 99% (97 of 98), and 100% (98 of 98) of all cultures were positive. Considering only pathogenic organisms, 96.1% (50 of 52) and 100% (52 of 52) were positive at 24 and 36 hours. Mean TTP for pathogens and contaminants was 14.40 and 23.18 hours, respectively (P < .001). Conclusions: An incubation period of 36 hours is sufficient to detect 100% of blood cultures positive for a pathogenic organism in our population. PMID- 26621328 TI - Eight-Year Review of Bordetella pertussis Testing Reveals Seasonal Pattern in the United States. AB - Review of Bordetella pertussis polymerase chain reaction testing from 2007 through 2014 revealed a yearly spike in positivity rates during the summer throughout the United States. Paradoxically, the highest test volumes occurred outside of this time frame, which provides an opportunity for improved test utilization. PMID- 26621329 TI - Aryl hydrocarbon receptor-dependent up-regulation of the heterodimeric amino acid transporter LAT1 (SLC7A5)/CD98hc (SLC3A2) by diesel exhaust particle extract in human bronchial epithelial cells. AB - The heterodimeric L-type amino acid transporter (LAT) 1/CD98hc is overexpressed in lung cancers with a poor prognosis factor. Factors that contribute to LAT1/CD98hc overexpression in lung cells remain however to be determined, but the implication of atmospheric pollution can be suspected. The present study was therefore designed to analyze the effects of diesel exhaust particle (DEP) extract (DEPe) on LAT1/CD98hc expression in bronchial epithelial BEAS-2B cells. Exposure to DEPe up-regulated LAT1 and CD98hc mRNA levels in a concentration dependent manner, with DEPe EC50 values (around 0.2 MUg/mL) relevant to environmental situations. DEPe concomitantly induced LAT1/CD98hc protein expression and LAT1-mediated leucine accumulation in BEAS-2B cells. Inhibition of the aryl hydrocarbon receptor (AhR) pathway through the use of a chemical AhR antagonist or the siRNA-mediated silencing of AhR expression was next found to prevent DEPe-mediated induction of LAT1/CD98hc, indicating that this regulation depends on AhR, known to be activated by major chemical DEP components like polycyclic aromatic hydrocarbons. DEPe exposure was finally shown to induce mRNA expression and activity of matrix metalloproteinase (MMP)-2 in BEAS-2B cells, in a CD98hc/focal adhesion kinase (FAK)/extracellular regulated kinase (ERK) manner, thus suggesting that DEPe-mediated induction of CD98hc triggers activation of the integrin/FAK/ERK signaling pathway known to be involved in MMP-2 regulation. Taken together, these data demonstrate that exposure to DEPe induces functional overexpression of the amino acid transporter LAT1/CD98hc in lung cells. Such a regulation may participate to pulmonary carcinogenic effects of DEPs, owing to the well-documented contribution of LAT1 and CD98hc to cancer development. PMID- 26621330 TI - The role of microRNAs in the development and progression of chemical-associated cancers. AB - Human exposure to certain natural and man-made chemical carcinogens is one of the major risk factors for cancer development. The effect of chemical carcinogens on genetic and epigenetic alterations and their significance in the development of cancer has been well-established. In contrast, the role of microRNAs (miRNAs) in the etiology of chemical-associated cancers remains relatively unexplored despite extensive reports on changes in miRNA expression upon carcinogen exposure. This review summarizes the current knowledge for the role of miRNAs as drivers of chemical-induced carcinogenesis by bridging the gap between carcinogen exposure and cancer development through functional studies. It also emphasizes the potential for miRNA changes as early indicators of the carcinogenic process, markers for carcinogen exposure, and identification of chemical carcinogenic hazards. PMID- 26621331 TI - Social behaviour of cattle in tropical silvopastoral and monoculture systems. AB - Silvopastoral systems can be a good alternative for sustainable livestock production because they can provide ecosystem services and improve animal welfare. Most farm animals live in groups and the social organization and interactions between individuals have an impact on their welfare. Therefore, the objective of this study was to describe and compare the social behaviour of cattle (Bos indicus*Bos taurus) in a silvopastoral system based on a high density of leucaena (Leucaena leucocephala) combined with guinea grass (Megathyrsus maximus), star grass (Cynodon nlemfuensis) and some trees; with a monoculture system with C. nlemfuensis, in the region of Merida, Yucatan. Eight heifers in each system were observed from 0730 to 1530 h each day for 12 consecutive days during the dry season and 12 consecutive days during the rainy season. The animals followed a rotation between three paddocks, remaining 4 days in each paddock. The vegetation was characterized in the paddocks of the silvopastoral system to estimate the average percentage of shade provided. To make a comparison between systems, we used a t test with group dispersion, and Mann-Whitney tests with the frequency of affiliative and agonistic behaviours. We assessed differences in linearity and stability of dominance hierarchies using Landau's index and Dietz R-test, respectively. The distance of cows with respect to the centroid of the group was shorter, and non-agonistic behaviours were 62% more frequent in the intensive silvopastoral system than in the monoculture one. Heifers in the silvopastoral system had a more linear and non-random dominance hierarchy in both seasons (dry season: h'=0.964; rainy season: h'=0.988), than heifers in the monoculture system (dry season: h'=0.571, rainy season: h'=0.536). The dominance hierarchy in the silvopastoral system was more stable between seasons (R-test=0.779) than in the monoculture system (R-test=0.224). Our results provide the first evidence that heifers in the silvopastoral system maintain more stable social hierarchies and express more sociopositive behaviours, suggesting that animal welfare was enhanced. PMID- 26621332 TI - Fluid deprivation increases isotonic NaCl intake, but not hypertonic salt intake, under normal and heated conditions in obese Zucker rats. AB - In the course of exposure to fluid deprivation and heated environment, mammals regulate their hydromineral balance and body temperature by a number of mechanisms including sweating, water and salt intakes. Here we challenged obese Zucker rats, known to have a predisposition to hypertension, with 0.9%NaCl alone or with 2%NaCl solution + water to drink under fluid deprivation and heated conditions. Food and fluid intakes, body weight, diuresis and natriuresis were measured daily throughout. Serum aldosterone levels and Na(+) concentration were also analyzed. Data showed that obese and lean rats presented similar baseline measurements of food, 0.9%NaCl and fluid intakes, diuresis and fluid balance; whereas hypertonic 2%NaCl consumption was almost absent. Before and during fluid deprivation animals increased isotonic but not hypertonic NaCl intake; the obese showed significant increases in diuresis and Na(+) excretion, whereas, total fluid intake was similar between groups. Heat increased isotonic NaCl intake and doubled natriuresis in obese which were wet on their fur and displayed a paradoxical increase of fluid gain. Fluid deprivation plus heat produced similar negative fluid balance in all groups. Body weight losses, food intake and diuresis reductions were amplified under the combined conditions. Animals exposed to 2%NaCl showed higher circulating levels of aldosterone and obese were lower than leans. In animals which drank 0.9%NaCl, obese showed higher serum levels of Na(+) than leans. We conclude that in spite of their higher sensitivity to high salt and heat obese Zucker rats can control hydromineral balance in response to fluid deprivation and heat by adjusting isotonic NaCl preference with sodium balance and circulating levels of aldosterone. This suggests a key hormonal role in the mechanisms underlying thermoregulation, body fluid homeostasis and sodium intake. PMID- 26621334 TI - Hipersensitivity Reactions to Corticosteroids. AB - Corticosteroids are widely used drugs in the clinical practice, especially by topic application in dermatology. These substances may act as allergens and produce immediate and delayed hypersensitivity reactions. Allergic contact dermatitis is the most frequent presentation of corticosteroid allergy and it should be studied by patch testing in specific units. The corticosteroids included in the Spanish standard battery are good markers but not ideal. Therefore, if those makers are positive, it is useful to apply a specific battery of corticosteroids and the drugs provided by patients. Immediate reactions are relatively rare but potentially severe, and it is important to confirm the sensitization profile and to guide the use of alternative corticosteroids, because they are often necessary in several diseases. In this article we review the main concepts regarding these two types of hypersensitivity reactions in corticosteroid allergy, as well as their approach in the clinical practice. PMID- 26621333 TI - Therapy for ventricular arrhythmias in structural heart disease: a multifaceted challenge. AB - The unpredictable nature and potentially catastrophic consequences of ventricular arrhythmias (VAs) have obligated physicians to search for therapies to prevent sudden cardiac death (SCD). At present, a low left ventricular ejection fraction (LVEF) has been used as a risk factor to predict SCD in patients with structural heart disease and has been consistently adopted as the predominant, and sometimes sole, indication for implantable cardioverter defibrillator (ICD) therapy. Although the ICD remains the mainstay life-saving therapy for SCD, it does not modify the underlying arrhythmic substrate and may be associated with adverse effects from perioperative and long-term complications. Preventative pharmacological therapy has been associated with limited benefits, but anti arrhythmic medications have significant side effects profiles. Catheter ablation of VAs has greatly evolved over the last few decades. Substrate mapping in sinus rhythm has allowed haemodynamically unstable VAs to be successfully treated. Both LVEF as an indication for ICD therapy and electro-anatomical mapping for substrate modification identify static components of underlying myocardial arrhythmogenicity. They do not take into account dynamic factors, such as the mechanisms of arrhythmia initiation and development of new anatomical or functional lines of block, leading to the initiation and maintenance of VAs. Dynamic factors are difficult to evaluate and consequently are not routinely used in clinical practice to guide treatment. However, progress in the treatment of VAs should consider and integrate dynamic factors with static components to fully characterize the myocardial arrhythmic substrate. PMID- 26621335 TI - An unexpected cause for cavitary pneumonia and empyema. AB - Tularemia is an emerging zoonotic disease mainly of the Northern Hemisphere caused by the Gram-negative coccobacillus Francisella tularensis. It is affecting a wide range of animals and causes human disease after insect and tick bites, skin contact, ingestion and inhalation. A 66-year-old man presented to our clinic with cavitary pneumonia and distinct pleural effusion. After failure of empiric antibiotic therapy, thoracoscopic assisted decortication and partial excision of the middle lobe were conducted. Conventional culture methods and broad-range bacterial PCR including RipSeqMixed analysis were performed from the excised biopsies. Culture results remained negative but broad-range PCR targeting the first half of the 16S rRNA gene revealed F. tularensis DNA. This result was confirmed by F. tularensis-specific PCR and by serology. The source of infection could not be explored. To conclude, we report the rare clinical picture of a community-acquired pneumonia followed by pleural effusion and empyema due to F. tularensis. Broad range bacterial PCR proved to be a powerful diagnostic tool to detect the etiologic organism. PMID- 26621336 TI - Mtss1 is a critical epigenetically regulated tumor suppressor in CML. AB - Chronic myeloid leukemia (CML) is driven by malignant stem cells that can persist despite therapy. We have identified Metastasis suppressor 1 (Mtss1/MIM) to be downregulated in hematopoietic stem and progenitor cells from leukemic transgenic SCLtTA/Bcr-Abl mice and in patients with CML at diagnosis, and Mtss1 was restored when patients achieved complete remission. Forced expression of Mtss1 decreased clonogenic capacity and motility of murine myeloid progenitor cells and reduced tumor growth. Viral transduction of Mtss1 into lineage-depleted SCLtTA/Bcr-Abl bone marrow cells decreased leukemic cell burden in recipients, and leukemogenesis was reduced upon injection of Mtss1-overexpressing murine myeloid 32D cells. Tyrosine kinase inhibitor (TKI) therapy and reversion of Bcr-Abl expression increased Mtss1 expression but failed to restore it to control levels. CML patient samples revealed higher DNA methylation of specific Mtss1 promoter CpG sites that contain binding sites for Kaiso and Rest transcription factors. In summary, we identified a novel tumor suppressor in CML stem cells that is downregulated by both Bcr-Abl kinase-dependent and -independent mechanisms. Restored Mtss1 expression markedly inhibits primitive leukemic cell biology in vivo, providing a therapeutic rationale for the Bcr-Abl-Mtss1 axis to target TKI resistant CML stem cells in patients. PMID- 26621337 TI - The TGF-beta/SMAD pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia. AB - Natural killer (NK) cells are key components of the innate immune system, providing potent antitumor immunity. Here, we show that the tumor growth factor beta (TGF-beta)/SMAD signaling pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia (ALL). We characterized NK cells in 50 consecutive children with B-ALL at diagnosis, end induction and during maintenance therapy compared with age-matched controls. ALL NK cells at diagnosis had an inhibitory phenotype associated with impaired function, most notably interferon-gamma production and cytotoxicity. By maintenance therapy, these phenotypic and functional abnormalities partially normalized; however, cytotoxicity against autologous blasts remained impaired. We identified ALL-derived TGF-beta1 to be an important mediator of leukemia-induced NK cell dysfunction. The TGF-beta/SMAD signaling pathway was constitutively activated in ALL-NK cells at diagnosis and end induction when compared with healthy controls and patients during maintenance therapy. Culture of ALL blasts with healthy NK cells induced NK dysfunction and an inhibitory phenotype, mediated by activation of the TGF-beta/SMAD signaling pathway, and abrogated by blocking TGF-beta. These data indicate that by regulating the TGF-beta/SMAD pathway, ALL blasts induce changes in NK cells to evade innate immune surveillance, thus highlighting the importance of developing novel therapies to target this inhibitory pathway and restore antileukemic cytotoxicity. PMID- 26621340 TI - Cardiotrophin-1 is inversely associated with obesity in non-diabetic individuals. AB - Cardiotrophin-1 is known to be a key regulator of energy homeostasis, as well as glucose and lipid metabolism in vivo. However, there are inconsistent results of the association between cardiotrophin-1 and obesity in humans, possibly confounded by hyperglycemia. Therefore, the aim of this study was to investigate the relationships among cardiotrophin-1 levels, overweight and obese individuals without diabetes in a Chinese population. The median (inter-quarter range) serum cardiotrophin-1 levels were 447.9 (230.9, 913.9), 350.6 (201.1, 666.5), and 288.1 (162.3, 572.4) pg/ml in non-diabetic subjects who were of normal weight (n = 522), overweight (n = 203), and obese (n = 93), respectively (trend test p < 0.001). Subjects who were overweight and obese had significantly lower cardiotrophin-1 levels than those with normal weight. The multivariate linear regression analyses showed that overweight (beta = -338.718, 95% CI = -552.786 ~ 124.651, p < 0.01), obese (beta = -530.275, 95% CI = -832.967 ~ -227.583, p < 0.01), and smoking (beta = -377.375, 95% CI = -654.353 ~ -100.397, p < 0.01) were negatively related to cardiotrophin-1 after adjusting for age, gender, HOMA-IR, hypertension, total cholesterol, HDL, triglyceride, eGFR, ALT, and alcohol drinking. The results of this study provided epidemiological evidence that non diabetic subjects who were overweight or obesity had significantly lower cardiotrophin-1 concentrations than those with normal weight, and both obesity and being overweight were inversely associated with cardiotrophin-1 levels. PMID- 26621338 TI - Similar clinical features in follicular lymphomas with and without breaks in the BCL2 locus. AB - Approximately 15% of follicular lymphomas (FLs) lack breaks in the BCL2 locus. The aim of this study was to better define molecular and clinical features of BCL2-breakpoint/t(14;18)-negative FLs. We studied the presence of BCL2, BCL6 and MYC breaks by fluorescence in situ hybridization and the expression of BCL2, MUM1, CD10, P53 and Ki67 in large clinical trial cohorts of 540 advanced-stage FL cases and 116 early-stage disease FL patients treated with chemotherapy regimens and radiation, respectively. A total of 86% and 53% of advanced- and early-stage FLs were BCL2-breakpoint-positive, respectively. BCL2 was expressed in almost all FLs with BCL2 break and also in 86% and 69% of BCL2-breakpoint-negative advanced- and early-stage FLs, respectively. CD10 expression was significantly reduced in BCL2-breakpoint-negative FLs of all stages and MUM1 and Ki67 expression were significantly increased in BCL2-break-negative early-stage FLs. Patient characteristics did not differ between FLs with and without BCL2 breaks and neither did survival times in advanced-stage FLs. These results suggest that the molecular profile differs to some extent between FLs with and without BCL2 breaks and support the notion that FLs with and without BCL2 breaks belong to the same lymphoma entity. PMID- 26621341 TI - iTRAQ proteomics analysis reveals that PI3K is highly associated with bupivacaine induced neurotoxicity pathways. AB - Bupivacaine, a commonly used local anesthetic, has potential neurotoxicity through diverse signaling pathways. However, the key mechanism of bupivacaine induced neurotoxicity remains unclear. Cultured human SH-SY5Y neuroblastoma cells were treated (bupivacaine) or untreated (control) with bupivacaine for 24 h. Compared to the control group, bupivacaine significantly increased cyto inhibition, cellular reactive oxygen species, DNA damage, mitochondrial injury, apoptosis (increased TUNEL-positive cells, cleaved caspase 3, and Bcl-2/Bax), and activated autophagy (enhanced LC3II/LC3I ratio). To explore changes in protein expression and intercommunication among the pathways involved in bupivacaine induced neurotoxicity, an 8-plex iTRAQ proteomic technique and bioinformatics analysis were performed. Compared to the control group, 241 differentially expressed proteins were identified, of which, 145 were up-regulated and 96 were down-regulated. Bioinformatics analysis of the cross-talk between the significant proteins with altered expression in bupivacaine-induced neurotoxicity indicated that phosphatidyl-3-kinase (PI3K) was the most frequently targeted protein in each of the interactions. We further confirmed these results by determining the downstream targets of the identified signaling pathways (PI3K, Akt, FoxO1, Erk, and JNK). In conclusion, our study demonstrated that PI3K may play a central role in contacting and regulating the signaling pathways that contribute to bupivacaine-induced neurotoxicity. PMID- 26621339 TI - Depression as a systemic syndrome: mapping the feedback loops of major depressive disorder. AB - BACKGROUND: Depression is a complex public health problem with considerable variation in treatment response. The systemic complexity of depression, or the feedback processes among diverse drivers of the disorder, contribute to the persistence of depression. This paper extends prior attempts to understand the complex causal feedback mechanisms that underlie depression by presenting the first broad boundary causal loop diagram of depression dynamics. METHOD: We applied qualitative system dynamics methods to map the broad feedback mechanisms of depression. We used a structured approach to identify candidate causal mechanisms of depression in the literature. We assessed the strength of empirical support for each mechanism and prioritized those with support from validation studies. Through an iterative process, we synthesized the empirical literature and created a conceptual model of major depressive disorder. RESULTS: The literature review and synthesis resulted in the development of the first causal loop diagram of reinforcing feedback processes of depression. It proposes candidate drivers of illness, or inertial factors, and their temporal functioning, as well as the interactions among drivers of depression. The final causal loop diagram defines 13 key reinforcing feedback loops that involve nine candidate drivers of depression. CONCLUSIONS: Future research is needed to expand upon this initial model of depression dynamics. Quantitative extensions may result in a better understanding of the systemic syndrome of depression and contribute to personalized methods of evaluation, prevention and intervention. PMID- 26621342 TI - Case series: toxicity from 25B-NBOMe--a cluster of N-bomb cases. AB - Background A new class of hallucinogens called NBOMes has emerged. This class includes analogues 25I-NBOMe, 25C-NBOMe and 25B-NBOMe. Case reports and judicial seizures indicate that 25I-NBOMe and 25C-NBOMe are more prevalently abused. There have been a few confirmed reports of 25B-NBOMe use or toxicity. Report Observational case series. This report describes a series of 10 patients who suffered adverse effects from 25B-NBOMe. Hallucinations and violent agitation predominate along with serotonergic/stimulant signs such as mydriasis, tachycardia, hypertension and hyperthermia. The majority (7/10) required sedation with benzodiazepines. Analytical method 25B-NBOMe concentrations in plasma and urine were quantified in all patients using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Peak plasma levels were measured between 0.7-10.1 ng/ml. Discussion The NBOMes are desired by users because of their hallucinogenic and stimulant effects. They are often sold as LSD or synthetic LSD. Reported cases of 25B- NBOMe toxicity are reviewed and compared to our series. Seizures and one pharmacological death have been described but neither were observed in our series. Based on our experience with cases of mild to moderate toxicity, we suggest that management should be supportive and focused on preventing further (self) harm. High doses of benzodiazepines may be required to control agitation. Patients who develop significant hyperthermia need to be actively managed. Conclusions Effects from 25B-NBOMe in our series were similar to previous individual case reports. The clinical features were also similar to effects from other analogues in the class (25I-NBOMe, 25C-NBOMe). Violent agitation frequently present along with signs of serotonergic stimulation. Hyperthermia, rhabdomyolysis and kidney injury were also observed. PMID- 26621343 TI - Hepatic role in an early glucose-lowering effect by a novel dipeptidyl peptidase 4 inhibitor, evogliptin, in a rodent model of type 2 diabetes. AB - Although multiple dipeptidyl peptidase 4 (DPP4) inhibitors have shown glucose lowering effects by preserving pancreatic cells in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice, the hepatic role in regulation of glucose homeostasis by DPP4 inhibitors in HFD/STZ mice remains elusive. In herein study, parallel comparison of effects on the liver (expression of gluconeogenic genes and the linked signaling molecules) and pancreas (islet morphology and relative area of alpha or beta cells) in combination with glucose lowering effects were made at the end of 2- and 10-week of evogliptin treatment in HFD/STZ mice. Significant control of hyperglycemia was observed from the second week and persisted during 10-week treatment of 0.3% evogliptin in HFD/STZ mice. This effect was accompanied by increased level of plasma glucagon-like peptide-1 and preserved pancreas islet structure. Furthermore, the hepatic increases in gluconeogenic gene expression in HFD/STZ mice was significantly reduced by evogliptin treatment, which was accompanied by the suppression of cAMP response element-binding protein (CREB) phosphorylation and expression of transducer of regulated CREB protein 2. This hepatic effect of evogliptin treatment was reproduced in 2-week study, however, pancreatic beta-cell area was not altered yet although the expression of pancreatic and duodenal homeobox protein 1 was increased. We conclude that the suppression of hepatic gluconeogenesis by evogliptin is followed by preservation of pancreatic islet, leading to remarkable and persistent glucose-lowering effect in HFD/STZ mice. Our findings provide further insight for the hepatic role in DPP4 inhibitor-mediated glucose control in diabetes. PMID- 26621344 TI - Multilayered Graphene Nano-Film for Controlled Protein Delivery by Desired Electro-Stimuli. AB - Recent research has highlighted the potential use of "smart" films, such as graphene sheets, that would allow for the controlled release of a variety of therapeutic drugs. Taking full advantage of these versatile conducting sheets, we investigated the novel concept of applying graphene oxide (GO) and reduced graphene oxide (rGO) materials as both barrier and conducting layers that afford controlled entrapment and release of any molecules of interest. We fabricated multilayered nanofilm architectures using a hydrolytically degradable cationic poly(beta-amino ester) (PAE), a model protein antigen, ovalbumin (OVA) as a building block along with the GO and rGO. We successfully showed that these multilayer films are capable of blocking the initial burst release of OVA, and they can be triggered to precisely control the release upon the application of electrochemical potential. This new drug delivery platform will find its usefulness in various transdermal drug delivery devices where on-demand control of drug release from the surface is necessary. PMID- 26621345 TI - [Complications of deep anterior lamellar keratoplasty. Avoid, recognize and treat]. AB - Deep anterior lamellar keratoplasty (DALK) offers tremendous advantages over penetrating keratoplasty (PK). Intraoperative safety is increased due to reduced opening of the eye interoperatively and the fact that no endothelial graft rejection can take place as the patient's own corneal endothelium is retained. Despite these advantages the number of DALK procedures performed each year in Germany remains constant at a low level. One reason could be that the DALK technique offers some complexity and at the same time intraoperative conversion to PK has to be performed in some cases due to rupture of Descemet's membrane. Moreover, interface-related and DALK-specific complications exist which can contribute to an unfavorable visual outcome. Most of these complications, such as incomplete attachment of Descemet's membrane or opacification within the interface between Descemet's membrane and the posterior corneal stoma can be resolved by adequate measures making PK for revision barely necessary. As visual acuity does not differ between PK and DALK, the benefits of DALK - lack of endothelial immune reaction and increased ocular stability during surgery - outweigh the risk of additional complications and DALK should therefore be performed whenever appropriate. PMID- 26621346 TI - [Unusual masquerade of an ocular carcinoma metastasis]. AB - BACKGROUND: Idiopathic and therapy resistant uveitis especially of unclear origin, is a diagnostic challenge for ophthalmologists. Metastases to the anterior chamber or vitreous body can occasionally mimic the clinical picture of uveitis, a variant on the usual lymphomatous masquerade syndrome. The underlying pathological pathways leading to the metastatic spread of tumor cells within the fluid compartments of the eye remain unclear. CASE REPORT: We present an unusual case of vitreous metastases to the right eye of a patient in whom an underlying primary malignancy was unknown. After recurrent episodes of cortisone-refractive panuveitis with pseudohypopyon, a diagnostic vitreous biopsy was performed. Cytopathological examination of the vitreous sample revealed carcinoma cells with an immune profile suggestive of lung cancer metastasis. Subsequent staging investigations revealed a primary lung adenocarcinoma as well as cerebral, adrenal and osseous metastases. THERAPY: Due to the extent of dissemination of this non-small cell lung cancer (NSCLC), only palliative treatment including external beam irradiation and systemic chemotherapy was possible to reduce pain and to maintain vision as well as an attempt at systemic control of the disease. PMID- 26621347 TI - Erratum to: Cocaine-induced plasticity in the cerebellum of sensitised mice. PMID- 26621348 TI - Pseudoginsenoside-F11 inhibits methamphetamine-induced behaviors by regulating dopaminergic and GABAergic neurons in the nucleus accumbens. AB - RATIONALE: Although dependence to methamphetamine (METH) is associated with serious psychiatric symptoms and is a global health and social problem, no effective therapeutic approaches have been identified. Pseudoginsenoside-F11 (PF11) is an ocotillol-type saponin that is isolated from Panax quinquefolius (American ginseng) and was shown to have neuroprotective effects to promote learning and memory and to antagonize the pharmacological effects of morphine. Furthermore, PF11 also shows protective effects against METH-induced neurotoxicity in mice. However, the effects of PF11 on METH-induced preference and dopamine (DA) release have not been defined. OBJECTIVES: We investigated the effects of PF11 administration on METH-induced hyperlocomotion and conditioned place preference (CPP) in mice. Subsequently, extracellular DA and gamma aminobutyric acid (GABA) levels were determined in the nucleus accumbens (NAc) of mice after co-administration of PF11 and METH using in vivo microdialysis analyses. Moreover, the effects of PF11 administration on the MU-opioid neuronal responses, DAMGO (MU-opioid receptor agonist; [D-Ala(2), N-MePhe(4), Gly-ol] enkephalin)-induced hyperlocomotion and accumbal extracellular DA increase were investigated to elucidate how PF11 inhibits METH-induced dependence by dopaminergic neuronal hyperfunction. RESULTS: Co-administration of PF11 and METH for 6 days attenuated METH-induced locomotor sensitization compared with treatment with METH alone. In the CPP test, PF11 administration also inhibited METH-induced place preference. In vivo microdialysis analyses indicated that co administration of PF11 and METH for 7 days prevented METH-induced extracellular DA increase in the NAc and repeated PF11 administration with or without METH for 7 days increased extracellular GABA levels in the NAc, whereas single administration of PF11 did not. Furthermore, DAMGO-induced hyperlocomotion and accumbal extracellular DA increase were significantly inhibited by acute PF11 administration. CONCLUSIONS: The present data suggest that PF11 inhibits METH induced hyperlocomotion, preference, and accumbal extracellular DA increase by regulating GABAergic neurons and MU-opioid receptors. PMID- 26621350 TI - Id4 Marks Spermatogonial Stem Cells in the Mouse Testis. AB - Mammalian spermatogenesis is a classic adult stems cell-dependent process, supported by the self-renewal and differentiation of spermatogonial stem cells (SSCs). However, the identification of SSCs and elucidation of their behaviors in undisturbed testis has long been a big challenge. Here, we generated a knock-in mouse model, Id4-2A-CreERT2-2A-tdTomato, which allowed us to mark Id4-expressing (Id4(+)) cells at different time points in situ and track their behaviors across distinct developmental stages during steady-state and regenerating spermatogenesis. We found that Id4(+) cells continue to produce spermatogonia, spermatocytes and sperm in mouse testis, showing they are capable of self-renewal and have differentiation potential. Consistent with these findings, ablation of Id4(+) cells in mice results in a loss of spermatogenesis. Furthermore, developmental fate mapping reveals that Id4(+) SSCs originate from neonate Id4(+) gonocytes. Therefore, our results indicate that Id4 marks spermatogonial stem cells in the mouse testis. PMID- 26621349 TI - Cannabis use and cognitive function in first episode psychosis: differential effect of heavy use. AB - RATIONALE: First episode patients and patients with schizophrenia exhibit increased rates of cannabis use compared to the general population. Contrary to what has been reported in studies with healthy people, most of the published studies so far have reported no impairments or even beneficial effects on neurocognition associated with cannabis consumption in psychotic patients. However, these studies did not address the effects of very high cannabis consumption. OBJECTIVES: Our aim in this study was to assess the effects on neurocognition of medium and heavy cannabis consumption in first psychotic episode patients. METHODS: A total of 74 patients were included in the study and assigned to three different groups according to their mean cannabis consumption during the last year (non-users, medium users, and heavy users). Participants were administered verbal memory and other neurocognitive tasks. RESULTS: Heavy cannabis users were significantly impaired in all the verbal memory measures with respect to non-users, including immediate (p = .026), short-term (p = .005), and long-term (p = .002) memory. There were no significant differences between medium and non-users. Moreover, non-users performed better than all cannabis users in the arithmetic task (p = .020). Heavy cannabis consumption was associated with more commission errors in the continuous performance task (CPT) (p = .008) and more time to complete trail making test A (TMT-A) (p = .008), compared to the group of medium users. CONCLUSIONS: Heavy cannabis consumption seems to impair verbal memory in first psychotic episode patients. Heavy users also perform worse than medium users in other neurocognitive tasks. Based on the results and the available evidence, a dose-related effect of cannabis consumption is suggested. PMID- 26621351 TI - Validity of smartphone pedometer applications. AB - BACKGROUND: Given the widespread use of smartphone pedometer applications and the relatively limited number of published validity tests, this study examined the validity of three popular commercial smartphone pedometer applications (i.e., Accupedo, Moves, and Runtastic Pedometer). PARTICIPANTS: Convenience samples of males and females were recruited for laboratory tests [n = 11; mean: aged 24.18 years (+/-3.06)] and a free-living test [n = 18; mean: aged 28.78 years (+/ 9.52)]. METHODS: Five conditions were assessed: (a) 20-step test, (b) 40-step stair climbing, (c) treadmill walking and running at different speeds, (d) driving, and (e) 3-day free-living. The Yamax SW-200 pedometer and observed step counts were used as criterion measures. RESULTS: Analyses identified an unacceptable error percentage in all of the applications compared to the pedometer. CONCLUSIONS: Given the inaccuracy of these applications, caution is required in their promotion to the public for self-monitoring physical activity and in their use as tools for assessing physical activity in research trials. PMID- 26621353 TI - Effect analysis of repeat sternotomy in pediatric cardiac operations. AB - BACKGROUND: Reoperation for congenital heart disease may be associated with cardiac or vascular injuries during repeat sternotomy, resulting in increased mortality and/or morbidity rates. The aim of this study was to determine the frequency of these cardiac injuries and the associated outcome. METHODS: Between January 2012 and December 2013, 4256 sternotomy procedures were performed at the Pediatric Cardiac Center in Fuwai Hospital, including 195 repeat sternotomy procedures (RS). We retrospectively studied the clinical data of 195 RS patients and 250 randomly selected primary sternotomy (PS) patients. Demographic and operative details, major injures (MI), and clinical outcomes were compared between the two groups. We also assessed the risk factors for major injury and in hospital mortality and morbidity. RESULTS: Significant differences were observed between the RS and PS groups in terms of skin incision to cardiopulmonary bypass(CPB) time, overall CPB time, cross-clamp time and blood requirement, and ventilation time (p < 0.001). MI during RS occurred in 7 of the 195 patients (3.6 %), while operative mortality was 1.0 % (2/195). However, in the RS patients, mortality and morbidity rates were not significantly different between the MI subgroup and the non-MI subgroup (p = 1.000 and 0.556, respectively). Additionally, no significant difference was found between the RS and PS groups in terms of mortality (p = 1.000) and morbidity (p = 0.125). CONCLUSIONS: Both RS and MI are not associated with increased risk of operative mortality and morbidity. Outcomes for reoperative pediatric operations in contemporary practice are similar with those for primary operations. PMID- 26621352 TI - Differential expression of galanin in the cholinergic basal forebrain of patients with Lewy body disorders. AB - INTRODUCTION: Depletion of cholinergic neurons within the nucleus basalis of Meynert (nbM) is thought to contribute to the development of cognitive impairments in both Alzheimer's disease (AD) and Lewy body disorders (LBD). It has been reported that, in late stage AD, a network of fibres that contain the neuropeptide galanin displays significant hypertrophy and 'hyperinnervates' the surviving cholinergic neurons. Galanin is considered as a highly inducible neuroprotective factor and in AD this is assumed to be part of a protective tissue response. The aim of this study was to determine if a similar galanin upregulation is present in the nbM in post-mortem tissue from patients with LBD. Gallatin immunohistochemistry was carried out on anterior nbM sections from 76 LBD cases (27 PD, 15 PD with mild cognitive impairment (MCI), 34 PD with dementia (PDD) and 4 aged-matched controls. Galaninergic innervation of cholinergic neurons was assessed on a semi-quantitative scale. RESULTS: The LBD group had significantly higher galaninergic innervation scores (p = 0.016) compared to controls. However, this difference was due to increased innervation density only in a subgroup of LBD cases and this correlated positively with choline acetyltransferase-immunopositive neuron density. CONCLUSION: Galanin upregulation within the basal forebrain cholinergic system in LBD, similar to that seen in AD, may represent an intrinsic adaptive response to neurodegeneration that is consistent with its proposed roles in neurogenesis and neuroprotection. PMID- 26621355 TI - The experience of couples being given an oxygen concentrator to use at home: A longitudinal interpretative phenomenological analysis. AB - This longitudinal study explores the lived experience of four couples where one person from each couple is prescribed an oxygen concentrator to use at home. Transcripts were analysed using interpretative phenomenological analysis. The findings reported here focus on two super-ordinate themes: 'the journey of acceptance' and 'negotiating changing relationships'. Participants described a gradual process of accepting the device into their lives, the impact on couple's relationships and the role that expectations have in mediating that process. These themes suggest that patient education that considers the psychological and social issues may prove useful in facilitating the acceptance process. PMID- 26621354 TI - Naloxone Administration in US Emergency Departments, 2000-2011. AB - Rates of opioid overdose and opioid-related emergency department (ED) visits have increased dramatically. Naloxone is an effective antidote to potentially fatal opioid overdose, but little is known about naloxone administration in ED settings. We examined trends and correlates of naloxone administration in ED visits nationally from 2000 to 2011. Using data from the National Hospital Ambulatory Medical Care Survey, we examined ED visits involving (1) the administration of naloxone or (2) a diagnosis of opioid overdose, abuse, or dependence. We assessed patient characteristics in these visits, including concomitant administration of prescription opioid medications. We used logistic regression to identify correlates of naloxone administration. From 2000 to 2011, naloxone was administered in an estimated 1.7 million adult ED visits nationally; 19 % of these visits recorded a diagnosis of opioid overdose, abuse, or dependence. An estimated 2.9 million adult ED visits were related to opioid overdose, abuse, or dependence; 11 % of these visits involved naloxone administration. In multivariable logistic regression models, patient age, race, and insurance and non-rural facility location were independently associated with naloxone administration. An opioid medication was provided in 14 % of visits involving naloxone administration. Naloxone was administered in a minority of ED visits related to opioid overdose, abuse, or dependence. Among all ED visits involving naloxone administration, prescription opioids were also provided in one in seven visits. Further work should explore the provider decision-making in the management of opioid overdose in ED settings and examine patient outcomes following these visits. PMID- 26621356 TI - Primary Malignant Melanoma of the Rectum: a Case Report of an Extremely Rare Gastrointestinal Cancer. PMID- 26621357 TI - A Two-Dimensional Multiphase Model of Biofilm Formation in Microfluidic Chambers. AB - The bacterial pathogen Xylella fastidiosa is the causal agent of many pathological conditions of economically important agricultural crops. There is no known cure for X. fastidiosa diseases, and management of the problem is based solely in controlling the population of insect vectors, which is somewhat effective. The bacterium causes disease by forming biofilms inside the vascular system of the plant, a process that is poorly understood. In microfluidic chambers, used as artificial xylem vessels, this bacterium has been observed to reproducibly cluster into a distinct, regular pattern of aggregates, spatially separated by channels of non-biofilm components. We develop a multiphase model in two dimensions, which recapitulates this spatial patterning, suggesting that bacterial growth and attachment/detachment processes are strongly influential modulators of these patterns. This indicates plausible strategies, such as the addition of metals and chelators, for mitigating the severity of diseases induced by this bacterial pathogen. PMID- 26621358 TI - An Effect of Landmarks on Territory Shape in a Convict Cichlid. AB - We determine size, shape and location for a territory that is optimal in the sense of minimizing defense costs, when a given proportion of the boundary is landmarked and its primary benefit in terms of fitness is greater ease of detecting intruders across it. Increasing the landmarked proportion of boundary causes the optimal configuration to be smaller and more elongated, and to be located with its center further from the nest, so that the nest is closer to the landmarked boundary. These predictions accord with observations in a recent study of the convict cichlid Amatitlania siquia. Our results thus confirm the consistency of the observed behavior with the hypothesis that A. siquia designs its territory to make intruders easier to spot. Our results also lead us to conjecture that moving the landmark proportionately closer to or further away from the nest would have yielded essentially the same outcome in this study, because the optimal configuration depends only on the angle subtended by the landmark at the nest and hence only on the length of the landmark relative to its distance from the nest, as opposed to its absolute value. PMID- 26621359 TI - Hypoxic culture conditions induce increased metabolic rate and collagen gene expression in ACL-derived cells. AB - There has been substantial effort directed toward the application of bone marrow and adipose-derived mesenchymal stromal cells (MSCs) in the regeneration of musculoskeletal tissue. Recently, resident tissue-specific stem cells have been described in a variety of mesenchymal structures including ligament, tendon, muscle, cartilage, and bone. In the current study, we systematically characterize three novel anterior cruciate ligament (ACL)-derived cell populations with the potential for ligament regeneration: ligament-forming fibroblasts (LFF: CD146(neg) , CD34(neg) CD44(pos) , CD31(neg) , CD45(neg) ), ligament perivascular cells (LPC: CD146(pos) CD34(neg) CD44(pos) , CD31(neg) , CD45(neg) ) and ligament interstitial cells (LIC: CD34(pos) CD146(neg) , CD44(pos) , CD31(neg) , CD45(neg) )-and describe their proliferative and differentiation potential, collagen gene expression and metabolism in both normoxic and hypoxic environments, and their trophic potential in vitro. All three groups of cells (LIC, LPC, and LFF) isolated from adult human ACL exhibited progenitor cell characteristics with regard to proliferation and differentiation potential in vitro. Culture in low oxygen tension enhanced the collagen I and III gene expression in LICs (by 2.8- and 3.3-fold, respectively) and LFFs (by 3- and 3.5-fold, respectively) and increased oxygen consumption rate and extracellular acidification rate in LICs (by 4- and 3.5-fold, respectively), LFFs (by 5.5- and 3-fold, respectively), LPCs (by 10- and 4.5-fold, respectively) as compared to normal oxygen concentration. In summary, this study demonstrates for the first time the presence of three novel progenitor cell populations in the adult ACL that demonstrate robust proliferative and matrix synthetic capacity; these cells may play a role in local ligament regeneration, and consequently represent a potential cell source for ligament engineering applications. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:985-994, 2016. PMID- 26621360 TI - Association of transforming growth factor-beta1 gene C509T, G800A and T869C polymorphisms with intracerebral hemorrhage in North Indian Population: a case control study. AB - Transforming growth factor-beta1 (TGF-beta1) is a multifunctional pro inflammatory cytokine involved in inflammation and pathogenesis of cerebrovascular disease. As per our knowledge, there is no published study investigating the association between variations within the TGF-beta1 gene polymorphisms and risk of intracerebral hemorrhage (ICH). The aim of this study was to investigate the association of the TGF-beta1 gene (C509T, G800A and T869C) polymorphisms, and their haplotypes with the risk of ICH in North Indian population. 100 ICH patients and 100 age- and sex-matched controls were studied. Genotyping was performed using SNaPshot method. Conditional logistic regression analysis was used to calculate the strength of association between TGF-beta1 gene polymorphisms and risk of ICH. Hypertension, diabetes, dyslipidemia, low socioeconomic status, smoking, physical activity were found to be associated with the risk of ICH. The distribution of C509T, G800A and T869C genotypes was consistent with Hardy-Weinberg Equilibrium (HWE) in the ICH and control group. Adjusted conditional logistic regression analysis showed an independent association of TGF-beta1 G800A (OR 9.07; 95% CI 2.3-35.6; P = 0.002) and T869C (OR 5.1; 95 % CI 1.9-13.2; P = 0.001) with the risk of ICH under dominant model. Haplotype analysis showed that C509-G800-C869 and C509-A800-C869 haplotypes were significantly associated with the increased risk of ICH. C509T and T869C were in strong linkage disequilibrium (D' = 0.53, r(2) = 0.23). Our results suggest that TGF-beta1 (G800A, T869C) gene polymorphisms and their haplotypes are significantly associated with the risk of ICH in North Indian population. Further prospective studies with large sample size are required for independent validation. Our findings could be helpful in identifying individuals at increased risk for developing ICH. PMID- 26621361 TI - GIFT-1, a phase IIa clinical trial to test the safety and efficacy of IFNgamma administration in FRDA patients. AB - Friedreich's ataxia is an autosomal recessive progressive degenerative disorder caused by deficiency of the protein frataxin. The most common genetic cause is a homozygotic expansion of GAA triplets within intron 1 of the frataxin gene leading to impaired transcription. Preclinical in vivo and in vitro studies have shown that interferon gamma (IFNgamma) is able to up-regulate the expression of frataxin gene in multiple cell types. We designed a phase IIa clinical trial, the first in Italy, aimed at assessing both safety and tolerability of IFNgamma in Friedreich's patients and ability to increase frataxin levels in peripheral blood mononuclear cells. Nine patients (6 female and 3 males aged 21-38 years) with genetically confirmed disease were given 3 subcutaneous escalating doses (100, 150 and 200 MUg) of IFNgamma (human recombinant interferon 1 b gamma, trade name IMUKIN((r))), over 4 weeks. The primary end-point was the assessment of the safety and tolerability of IFNgamma by means of standard clinical and hematological criteria. The secondary end-point was the detection of changes of frataxin levels in peripheral blood mononuclear cells after each single escalating dose of the drug. IFNgamma was generally well tolerated, the main adverse event was hyperthermia/fever. Although, increases in frataxin levels could be detected in a minority of patients, these changes were not significant. A large phase III multicenter, randomized clinical trial with IFNgamma in Friedreich's ataxia patients is currently ongoing. This study is expected to conclusively address the clinical efficacy of IFNgamma therapy in patients with Friedreich's ataxia. PMID- 26621362 TI - An updated Italian normative dataset for the Stroop color word test (SCWT). AB - The Stroop color and word test (SCWT) is widely used to evaluate attention, information processing speed, selective attention, and cognitive flexibility. Normative values for the Italian population are available only for selected age groups, or for the short version of the test. The aim of this study was to provide updated normal values for the full version, balancing groups across gender, age decades, and education. Two kinds of indexes were derived from the performance of 192 normal subjects, divided by decade (from 20 to 90) and level of education (4 levels: 3-5; 6-8; 9-13; >13 years). They were (i) the correct answers achieved for each table in the first 30 s (word items, WI; color items, CI; color word items, CWI) and (ii) the total time required for reading the three tables (word time, WT; color time, CT; color word time, CWT). For each index, the regression model was evaluated using age, education, and gender as independent variables. The normative data were then computed following the equivalent scores method. In the regression model, age and education significantly influenced the performance in each of the 6 indexes, whereas gender had no significant effect. This study confirms the effect of age and education on the main indexes of the Stroop test and provides updated normative data for an Italian healthy population, well balanced across age, education, and gender. It will be useful to Italian researchers studying attentional functions in health and disease. PMID- 26621363 TI - Epstein-Barr virus infection involving bilateral middle cerebellar peduncles in an old woman: a case report. PMID- 26621364 TI - Incorporating research evidence into decision-making processes: researcher and decision-maker perceptions from five low- and middle-income countries. AB - BACKGROUND: The 'Sponsoring National Processes for Evidence-Informed Policy Making in the Health Sector of Developing Countries' program was launched by the Alliance for Health Policy and Systems Research, WHO, in July 2008. The program aimed to catalyse the use of evidence generated through health policy and systems research in policymaking processes through (1) promoting researchers and policy advocates to present their evidence in a manner that is easy for policymakers to understand and use, (2) creating mechanisms to spur the demand for and application of research evidence in policymaking, and (3) increased interaction between researchers, policy advocates, and policymakers. Grants ran for three years and five projects were supported in Argentina, Bangladesh, Cameroon, Nigeria and Zambia. This paper seeks to understand why projects in some settings were perceived by the key stakeholders involved to have made progress towards their goals, whereas others were perceived to have not done so well. Additionally, by comparing experiences across five countries, we seek to illustrate general learnings to inform future evidence-to-policy efforts in low- and middle-income countries. METHODS: We adopted the theory of knowledge translation developed by Jacobson et al. (J Health Serv Res Policy 8(2):94-9, 2003) as a framing device to reflect on project experiences across the five cases. Using data from the projects' external evaluation reports, which included information from semi-structured interviews and quantitative evaluation surveys of those involved in projects, and supplemented by information from the projects' individual technical reports, we applied the theoretical framework with a partially grounded approach to analyse each of the cases and make comparisons. RESULTS AND CONCLUSION: There was wide variation across projects in the type of activities carried out as well as their intensity. Based on our findings, we can conclude that projects perceived as having made progress towards their goals were characterized by the coming together of a number of domains identified by the theory. The domains of Jacobson's theoretical framework, initially developed for high-income settings, are of relevance to the low- and middle-income country context, but may need modification to be fully applicable to these settings. Specifically, the relative fragility of institutions and the concomitantly more significant role of individual leaders point to the need to look at leadership as an additional domain influencing the evidence-to-policy process. PMID- 26621365 TI - The voice of non-pregnant women on alcohol consumption during pregnancy: a focus group study among women in Sweden. AB - BACKGROUND: Consensus is that fetal exposure to alcohol is harmful. Abstinence while trying to conceive and throughout pregnancy is recommended. Despite this, there are many women who consume alcohol around conception and until pregnancy recognition. The aim of this study was to explore the voice of non-pregnant women concerning alcohol consumption and its relation to pregnancy. METHODS: Data were collected through seven focus groups interviews with 34 women of fertile age, who were neither pregnant nor mothers. Semi-structured interviews were undertaken, recorded and transcribed verbatim and then analysed using thematic analysis. RESULTS: Three main themes were identified in the analysis: an issue that cannot be ignored; awareness and uncertainty concerning alcohol and pregnancy; and transition to parenthood. Alcohol was an integral part of the women's lives. A societal expectation to drink alcohol was prevalent and the women used different strategies to handle this expectation. Most women agreed not to drink alcohol during pregnancy although their knowledge on the specific consequences was scanty and they expressed a need for more information. Most of the participants found drinking alcohol during pregnancy to be irresponsible and saw pregnancy as a start of a new way of life. CONCLUSIONS: Social expectations concerning women's alcohol use change with pregnancy when women are suddenly expected to abstain. Although most study participants shared an opinion for zero tolerance during pregnancy, their knowledge regarding consequences of drinking during pregnancy were sparse. In order for prospective mothers to make informed choices, there is a need for public health initiatives providing information on the relationship between alcohol consumption and reproduction. PMID- 26621366 TI - Reducing The Cost of Transport and Increasing Walking Distance After Stroke: A Randomized Controlled Trial on Fast Locomotor Training Combined With Functional Electrical Stimulation. AB - Background Neurorehabilitation efforts have been limited in their ability to restore walking function after stroke. Recent work has demonstrated proof-of concept for a functional electrical stimulation (FES)-based combination therapy designed to improve poststroke walking by targeting deficits in paretic propulsion. Objectives To determine the effects on the energy cost of walking (EC) and long-distance walking ability of locomotor training that combines fast walking with FES to the paretic ankle musculature (FastFES). Methods Fifty participants >6 months poststroke were randomized to 12 weeks of gait training at self-selected speeds (SS), fast speeds (Fast), or FastFES. Participants' 6-minute walk test (6MWT) distance and EC at comfortable (EC-CWS) and fast (EC-Fast) walking speeds were measured pretraining, posttraining, and at a 3-month follow up. A reduction in EC-CWS, independent of changes in speed, was the primary outcome. Group differences in the number of 6MWT responders and moderation by baseline speed were also evaluated. Results When compared with SS and Fast, FastFES produced larger reductions in EC (Ps <=.03). FastFES produced reductions of 24% and 19% in EC-CWS and EC-Fast (Ps <.001), respectively, whereas neither Fast nor SS influenced EC. Between-group 6MWT differences were not observed; however, 73% of FastFES and 68% of Fast participants were responders, in contrast to 35% of SS participants. Conclusions Combining fast locomotor training with FES is an effective approach to reducing the high EC of persons poststroke. Surprisingly, differences in 6MWT gains were not observed between groups. Closer inspection of the 6MWT and EC relationship and elucidation of how reduced EC may influence walking-related disability is warranted. PMID- 26621367 TI - Pregnancy and estrogen enhance neural progenitor-cell proliferation in the vomeronasal sensory epithelium. AB - BACKGROUND: The hormonal state during the estrus cycle or pregnancy produces alterations on female olfactory perception that are accompanied by specific maternal behaviors, but it is unclear how sex hormones act on the olfactory system to enable these sensory changes. RESULTS: Herein, we show that the production of neuronal progenitors is stimulated in the vomeronasal organ (VNO) epithelium of female mice during a late phase of pregnancy. Using a wide range of molecular markers that cover the whole VNO cell maturation process in combination with Ca(2+) imaging in early postmitotic neurons, we show that newly generated VNO cells adopt morphological and functional properties of mature sensory neurons. A fraction of these newly generated cells project their axons to the olfactory forebrain, extend dendrites that contact the VNO lumen, and can detect peptides and urinary proteins shown to contain pheromone activity. High throughput RNA-sequencing reveals concomitant differences in gene expression in the VNO transcriptomes of pregnant females. These include relative increases in expression of 20 vomeronasal receptors, of which 17 belong to the V1R subfamily, and may therefore be considered as candidate receptors for mediating maternal behaviors. We identify the expression of several hormone receptors in the VNO of which estrogen receptor alpha (Esr1) is directly localized to neural progenitors. Administration of sustained high levels of estrogen, but not progesterone, is sufficient to stimulate vomeronasal progenitor cell proliferation in the VNO epithelium. CONCLUSIONS: Peripheral olfactory neurogenesis driven by estrogen may contribute to modulate sensory perception and adaptive VNO-dependent behaviors during pregnancy and early motherhood. PMID- 26621368 TI - Novel mutations in EVC cause aberrant splicing in Ellis-van Creveld syndrome. AB - Ellis-van Creveld syndrome (EvC) is a rare autosomal recessive disorder characterized by disproportionate chondrodysplasia, postaxial polydactyly, nail dystrophy, dental abnormalities and in a proportion of patients, congenital cardiac malformations. Weyers acrofacial dysostosis (Weyers) is another dominantly inherited disorder allelic to EvC syndrome but with milder phenotypes. Both disorders can result from loss-of-function mutations in either EVC or EVC2 gene, and phenotypes associated with the two gene mutations are clinically indistinguishable. We present here a clinical and molecular analysis of a Chinese family manifested specific features of EvC syndrome. Sequencing of both EVC and EVC2 identified two novel heterozygous splice site mutations c.384+5G>C in intron 3 and c.1465-1G>A in intron 10 in EVC, which were inherited from mother and father, respectively. In vitro minigene expression assay, RT-PCR and sequencing analysis demonstrated that c.384+5G>C mutation abolished normal splice site and created a new cryptic acceptor site within exon 4, whereas c.1465-1G>A mutation affected consensus splice junction site and resulted in full exon 11 skipping. These two aberrant pre-mRNA splicing processes both produced in-frame abnormal transcripts that possibly led to abolishment of important functional domains. To our knowledge, this is the first report of EVC mutations that cause EvC syndrome in Chinese population. Our data revealed that EVC splice site mutations altered splicing pattern and helped elucidate the pathogenesis of EvC syndrome. PMID- 26621369 TI - Extracorporeal membrane oxygenation to support repeated whole-lung lavage in a patient with pulmonary alveolar proteinosis in life threatening dyspnoe--a case report. AB - BACKGROUD: Pulmonary alveolar proteinosis is a rare disorder that is characterized by a large accumulation of lipoproteinaceous material within the alveoli. This causes respiratory failure due to a restriction of gas exchange and changes in the ventilation/perfusion ratio. Clinical symptoms are variable and depend on the severity of damage of the lung parenchyma. Treatment method is whole-lung lavage, where the accumulated lipoproteinaceous material is removed using large quantities of saline. CASE PRESENTATION: This case report describes a 45 year old patient with advanced pulmonary alveolar proteinosis. Due to the presence of severe global respiratory insufficiency, this patient could not undergo the classic whole-lung lavage using a double-lumen tube and selective lung ventilation. The whole-lung lavage was performed with the support of veno venous extracorporeal membrane oxygenation. A total of 27 l of warm saline was used. CONCLUSION: According to the current published literature, whole-lung lavage with extra-corporeal membrane oxygenation support is a very rare treatment method. Even when taking into account all of the risks associated with whole-lung lavage and v-v extracorporeal membrane oxygenation support, we found that this technique is very effective and, without a doubt, it saved the life of our patient. PMID- 26621370 TI - Nano-transfersomal formulations for transdermal delivery of asenapine maleate: in vitro and in vivo performance evaluations. AB - CONTEXT: Asenapine maleate (ASPM) is an antipsychotic drug for the treatment of schizophrenia and bipolar disorder. Extensive metabolism makes the oral route inconvenient for ASPM. OBJECTIVE: The objective of this study is to increase ASPM bioavailability via transdermal route by improving the skin permeation using combined strategy of chemical and nano-carrier (transfersomal) based approaches. MATERIALS AND METHODS: Transfersomes were prepared by the thin film hydration method using soy-phosphatidylcholine (SPC) and sodium deoxycholate (SDC). Transfersomes were characterized for particle size, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency, surface morphology, and in vitro skin permeation studies. Various chemical enhancers were screened for skin permeation enhancement of ASPM. Optimized transfersomes were incorporated into a gel base containing suitable chemical enhancer for efficient transdermal delivery. In vivo pharmacokinetic study was performed in rats to assess bioavailability by transdermal route against oral administration. RESULTS AND DISCUSSION: Optimized transfersomes with drug:SPC:SDC weight ratio of 5:75:10 were spherical with an average size of 126.0 nm, PDI of 0.232, ZP of -43.7 mV, and entrapment efficiency of 54.96%. Ethanol (20% v/v) showed greater skin permeation enhancement. The cumulative amount of ASPM permeated after 24 h (Q24) by individual effect of ethanol and transfersome, and in combination was found to be 160.0, 132.9, and 309.3 MUg, respectively, indicating beneficial synergistic effect of combined approach. In vivo pharmacokinetic study revealed significant (p < 0.05) increase in bioavailability upon transdermal application compared with oral route. CONCLUSION: Dual strategy of permeation enhancement was successful in increasing the transdermal permeation and bioavailability of ASPM. PMID- 26621371 TI - A Novel Assay to Identify the Trafficking Proteins that Bind to Specific Vesicle Populations. AB - Here we describe a method capable of identifying interactions between candidate trafficking proteins and a defined vesicle population in intact cells. The assay involves the expression of an FKBP12-rapamycin binding domain (FRB)-tagged candidate vesicle-binding protein that can be inducibly linked to an FKBP-tagged molecular motor. If the FRB-tagged candidate protein binds the labeled vesicles, then linking the FRB and FKBP domains recruits motors to the vesicles and causes a predictable, highly distinctive change in vesicle trafficking. We describe two versions of the assay: a general protocol for use in cells with a typical microtubule-organizing center and a specialized protocol designed to detect protein-vesicle interactions in cultured neurons. We have successfully used this assay to identify kinesins and Rabs that bind to a variety of different vesicle populations. In principle, this assay could be used to investigate interactions between any category of vesicle trafficking proteins and any vesicle population that can be specifically labeled. PMID- 26621372 TI - Fractionation of Subcellular Organelles. AB - This unit provides both a theoretical and a practical background to all the techniques associated with the application of differential and density gradient centrifugation for the analysis of subcellular membranes. The density gradient information focuses on the use of the modern gradient solute iodixanol, chosen for its ease of use, versatility, and compatibility with biological particles. Its use in both pre-formed discontinuous and continuous gradients and in self generated gradients is discussed. Considerable emphasis is given to selection of the appropriate centrifuge rotors and tubes and their influence on the methods used for creation, fractionation, and analysis of density gradients. Without proper consideration of these critical ancillary procedures, the resolving power of the gradient can be easily compromised. PMID- 26621373 TI - Immunofluorescence Staining. AB - This unit provides a protocol for indirect immunofluorescence, which is a method that provides information about the locations of specific molecules and the structure of the cell. Antibody molecules for a specific target molecule are exposed to the cell or tissue being investigated. The binding of these molecules is detected by incubating the sample with a secondary antibody specific for immunoglobulin molecules and conjugated to a fluorophore. This provides both a visible signal and amplification of the signal and the results are observed with a fluorescence microscope. This unit describes the widely used and powerful technique of localization of proteins in cells by immunofluorescence. The location can be determined by double labeling with an antibody directed against a protein of known location. The technique can be used as a supplement to immunolocalization by electron microscopy and subcellular fractionation. It allows not only identification of the antigen distribution in the cell but also a survey of the dynamic aspects of protein movements in the cell-on and off membranes, into and out of the nucleus, and through membrane traffic pathways. PMID- 26621374 TI - Midwifery 2030: a woman's pathway to health. What does this mean? AB - The 2014 State of the World's Midwifery report included a new framework for the provision of woman-centred sexual, reproductive, maternal, newborn and adolescent health care, known as the Midwifery2030 Pathway. The Pathway was designed to apply in all settings (high-, middle- and low-income countries, and in any type of health system). In this paper, we describe the process of developing the Midwifery2030 Pathway and explain the meaning of its different components, with a view to assisting countries with its implementation. The Pathway was developed by a process of consultation with an international group of midwifery experts. It considers four stages of a woman's reproductive life: (1) pre-pregnancy, (2) pregnancy, (3) labour and birth, and (4) postnatal, and describes the care that women and adolescents need at each stage. Underpinning these four stages are ten foundations, which describe the systems, services, workforce and information that need to be in place in order to turn the Pathway from a vision into a reality. These foundations include: the policy and working environment in which the midwifery workforce operates, the effective coverage of sexual, reproductive, maternal, newborn and adolescent services (i.e. going beyond availability and ensuring accessibility, acceptability and high quality), financing mechanisms, collaboration between different sectors and different levels of the health system, a focus on primary care nested within a functional referral system when needed, pre- and in-service education for the workforce, effective regulation of midwifery and strengthened leadership from professional associations. Strengthening of all of these foundations will enable countries to turn the Pathway from a vision into reality. PMID- 26621375 TI - Authors' reply: Intrapartum and neonatal mortality in primary midwife-led and secondary obstetrician-led care in the Amsterdam region of the Netherlands: A retrospective cohort study'. PMID- 26621376 TI - Quality of life of mothers at the sixth week and sixth month post partum and type of infant feeding. AB - INTRODUCTION: there is little scientific evidence on the relationship between maternal quality of life and type of infant feeding. The purpose of this study was to determine if there were differences in mother's quality of life by type of infant feeding. MATERIAL AND METHODS: longitudinal prospective study with 364 women who gave birth at a public hospital at Madrid, Spain, between February and October 2013. To be included, the participants had to be a healthy primigravida aged 18-45 years who gave birth to a healthy newborn with a gestational age between 36 and 42 completed weeks, regardless of birth type. The hospital interviews were performed between 36 and 48 hours post partum in women who had case of vaginal/instrumental births and 60-72 hours post partum for women who had a caesarean birth. Telephone interviews were conducted at the sixth week and sixth month post partum, and included the SF-36 to measure quality of life. SF-36 scores were compared between breast feeding and artificial milk feeding. We also analysed the longitudinal change in SF-36 scores in both groups. RESULTS: at the sixth week post partum, regardless of the infant feeding modality, an increased mental health score was recorded for mothers who reported that their children ate and slept well and for those who did not go to the emergency hospital service because of concern over their baby's health. No significant differences in quality of life were found between the two groups at six months post partum. Between the sixth week and sixth month post partum, quality of life improved significantly in both groups. DISCUSSION: at the sixth week post partum, the proportion of children who ate and slept well and did not have to attend in an emergency hospital service was higher in the breast feeding group. This observation was associated with greater maternal quality of life. This positive indirect relationship between breast feeding and quality of life should be considered an additional maternal health benefit in the short term. PMID- 26621377 TI - The potential for carbon bio-sequestration in China's paddy rice (Oryza sativa L.) as impacted by slag-based silicate fertilizer. AB - Rice is a typical silicon-accumulating plant. Silicon (Si), deposited as phytoliths during plant growth, has been shown to occlude organic carbon, which may prove to have significant effects on the biogeochemical sequestration of atmospheric CO2. This study evaluated the effects of silicate fertilization on plant Si uptake and carbon bio-sequestration in field trials on China's paddy soils. The results showed (1) Increased Si concentrations in rice straw with increasing application rates of silicate fertilizer; (2) Strong positive correlations between phytolith contents and straw SiO2 contents and between phytolith contents and phytolith-occluded carbon (PhytOC) contents in rice straw; (3) Positive correlations between the phytolith production flux and either the above-ground net primary productivity (ANPP) or the PhytOC production rates; (4) Increased plant PhytOC storage with increasing application rates of silicate fertilizer. The average above-ground PhytOC production rates during China's rice production are estimated at 0.94 * 10(6) tonnes CO2 yr(-1) without silicate fertilizer additions. However, the potential exists to increase PhytOC levels to 1.16-2.17 * 10(6) tonnes CO2 yr(-1) with silicate fertilizer additions. Therefore, providing silicate fertilizer during rice production may serve as an effective tool in improving atmospheric CO2 sequestration in global rice production areas. PMID- 26621378 TI - Characterization of H2 photoproduction by marine green alga Tetraselmis subcordiformis integrated with an alkaline fuel cell. AB - OBJECTIVES: To investigate the feasibility of coupling carbonyl cyanide m chlorophenylhydrazone-regulated photohydrogen production by Tetraselmis subcordiformis in a photobioreactor to an alkaline fuel cell (AFC). RESULTS: H2 evolution kinetics in the AFC integrated process was characterized. The duration of H2 evolution was prolonged and its yield was improved about 1.5-fold (to 78 +/ 5 ml l(-1)) compared with that of the process without AFC. Improved H2 yield was possibly caused by removal of H2 feedback inhibition by H2 consumption in situ. Decreases in the H2 production rate correlated with the gradual deactivation of PSII and hydrogenase activities. The H2 yield was closely associated with catabolism of starch and protein. CONCLUSION: A marine green algal CO2 supplemented culture integrated with in situ H2-consumption by an AFC system was developed as a viable protocol for the H2 production. PMID- 26621379 TI - Reply to the letter to the editor "Sleep disorders breathing in chronic heart failure. Is adaptive servoventilation really the answer?". PMID- 26621380 TI - NICE guidance on pembrolizumab for advanced melanoma. PMID- 26621381 TI - Molecular characterization and expression analyses of cDNAs encoding the thioredoxin-interacting protein and selenoprotein P genes and histological changes in Nile tilapia (Oreochromis niloticus) in response to silver nanoparticle exposure. AB - Herein, Nile tilapia thioredoxin-interacting protein (On-TXNIP) and selenoprotein P (On-SEPP) cDNAs were cloned and characterized. The full-length On-TXNIP cDNA contained 2 arrestin domains, 2 conserved cysteine residues that bind to thioredoxin to inhibit thioredoxin function, and 2 PPXY motifs, which negatively regulate the protein by stimulating binding to E3 ubiquitin ligase. The On-SEPP cDNA contained 17 selenocysteines (Sec) encoded by the TGA codon, which can be recognized as either a stop codon or a Sec codon. The On-SEPP cDNA also carried 2 typical SECIS elements located in the 3'UTR that are important for selenocysteine translation. Evolutionary analyses of both the On-TXNIP and On-SEPP genes revealed that these genes are closely related to the TXNIP and SEPP genes in zebrafish (Danio rerio), with amino acid similarities of 91.8% and 61.9%, respectively. A normal tissue distribution analysis indicated that the On-TXNIP and On-SEPP genes were ubiquitously expressed in all tissues examined, and the highest expression levels of these genes were observed in peripheral blood leukocytes (PBLs) and the trunk kidney, respectively. The expression levels of On TXNIP and On-SEPP transcripts were acutely and chronically analyzed following the injection of fish with 1, 10 or 100mg/kg silver nanoparticles (Ag NPs). Significant up-regulation of On-TXNIP and On-SEPP transcripts was observed in the liver, spleen, and head kidney at the early phase of Ag NP exposure (hours 6 through 48). Down-regulation of On-SEPP transcripts was clearly observed in the liver at weeks 1 to 4. Histopathology analysis demonstrated that the fish livers exhibited a dramatic infiltration of Kupffer cells, elevated bi-nucleated cells, expanded sinusoidal blood congestion and severe necrosis in a dose-dependent manner. Based on these findings, coupling of the expression analysis of these two cellular stress response genes and histopathological observation of fish exposed to Ag NPs should be reliable for the assessment of Ag NP contamination in teleost fish. PMID- 26621382 TI - Candidate genes involved in the susceptibility of primary open angle glaucoma. AB - PURPOSE: Glaucoma is a common disease often identified by high intraocular pressure, characteristic optic neuropathy and vision loss. It is currently a leading cause of blindness worldwide with no known cure. Primary open angle glaucoma (POAG) is the most common type of glaucoma worldwide. It is a multifactorial disease where both genetic as well as environmental factors are involved in the pathogenesis. RESULTS: Till date, at least 29 genetic loci have been found to be linked to POAG. However, the role of only three underlying genes Myocilin (MYOC), Optineurin (OPTN) and WD repeat Domain 36, (WDR36) is well established. Also, the role of Cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1), Glutathione S-transferase mu 1 (GSTM1) and Neurotrophin (NTF4) has been fairly identified. Association studies have found that 66 loci with 76 genes associated to POAG till date, but even more studies are required to confirm their role in the disease pathology. Gene mutations in various populations have been identified by genetic studies to establish that about 5% of POAG is currently attributed to single-gene or Mendelian forms of glaucoma and others caused by the combined effects of many genetic and environmental risk factors, each of which do not act alone to cause glaucoma. CONCLUSION: Although the clinical progression of the disease is well defined, the molecular events responsible for glaucoma are poorly understood and thus the etiology of POAG remains a mystery. Despite strong genetic influence in POAG pathogenesis, only a small part of the disease can be explained in terms of genetic aberration. This review is an overview and update on the latest research and progress of genetic studies associated with POAG. PMID- 26621383 TI - Testis-specific products of the Drosophila melanogaster sbr gene, encoding nuclear export factor 1, are necessary for male fertility. AB - The evolutionarily conserved nuclear export factor 1 (NXF1) provides mRNA export from the nucleus to the cytoplasm. We described several testis-specific transcripts of the Drosophila melanogaster nxf1 gene designated "sbr" in this species via different PCR approaches and CAGE-seq analysis. Characteristically, most of them have truncated 3'UTRs compared with those in other organs. In addition to regular transcripts, there are shorter transcripts that begin in intron 3 of the sbr gene. These short, 5'-truncated testis-specific transcripts vary in terms of transcription start site and their ability to exclude or retain the last 237 nucleotides of intron 3 in their 5'UTR. Using an anti-SBR antibody against the C-terminal portion of this protein, we detected the major SBR protein (74 kDa) in all analyzed organs of the fly as well as a new smaller protein (60 kDa) found only in the testes. This protein corresponds to the detected sbr transcripts that start in intron 3, based on its molecular mass. We investigated the sbr12 allele of the sbr gene, which is lethal in homozygous females and causes dominant sterility in heterozygous males. Sequencing of the sbr12 gene allele revealed a 30-bp deletion in exon 9 without a frame shift.Western blot analysiswith an SBR-specific antibody revealed two bands of the expected size in the testes of heterozygous males. Thus, a mutant protein along with the normal protein presents in the testes of lethal allele-bearing flies and the described shorter testis-specific variant of SBR may account for male sterility. PMID- 26621384 TI - The role of active site aromatic residues in substrate degradation by the human chitotriosidase. AB - Human chitotriosidase (HCHT) is a glycoside hydrolase family 18 chitinase synthesized and secreted in human macrophages thought be an innate part of the human immune system. It consists of a catalytic domain with the (beta/alpha)8 TIM barrel fold having a large area of solvent-exposed aromatic amino acids in the active site and an additional family 14 carbohydrate-binding module. To gain further insight into enzyme functionality, especially the effect of the active site aromatic residues, we expressed two variants with mutations in subsites on either side of the catalytic acid, subsite -3 (W31A) and +2 (W218A), and compared their catalytic properties on chitin and high molecular weight chitosans. Exchange of Trp to Ala in subsite -3 resulted in a 12-fold reduction in extent of degradation and a 20-fold reduction in kcat(app) on chitin, while the values are 5-fold and 10-fold for subsite +2. Moreover, aromatic residue mutation resulted in a decrease of the rate of chitosan degradation contrasting previous observations for bacterial family 18 chitinases. Interestingly, the presence of product polymers of 40 sugar moieties and higher starts to disappear already at 8% degradation for HCHT50-W31A. Such behavior contrast that of the wild type and HCHT-W218A and resembles the action of endo-nonprocessive chitinases. PMID- 26621386 TI - Outcomes of octogenarian (>= 80 yo) patients with advanced non-small cell lung cancer (NSCLC): A single institution experience at the Christie Hospital. PMID- 26621385 TI - The spider hemolymph clot proteome reveals high concentrations of hemocyanin and von Willebrand factor-like proteins. AB - Arthropods include chelicerates, crustaceans, and insects that all have open circulation systems and thus require different properties of their coagulation system than vertebrates. Although the clotting reaction in the chelicerate horseshoe crab (Family: Limulidae) has been described in details, the overall protein composition of the resulting clot has not been analyzed for any of the chelicerates. The largest class among the chelicerates is the arachnids, which includes spiders, ticks, mites, and scorpions. Here, we use a mass spectrometry based approach to characterize the spider hemolymph clot proteome from the Brazilian whiteknee tarantula, Acanthoscurria geniculata. We focused on the insoluble part of the clot and demonstrated high concentrations of proteins homologous to the hemostasis-related and multimerization-prone von Willebrand factor. These proteins, which include hemolectins and vitellogenin homologous, were previously identified as essential components of the hemolymph clot in crustaceans and insects. Their presence in the spider hemolymph clot suggests that the origin of these proteins' function in coagulation predates the split between chelicerates and mandibulata. The clot proteome reveals that the major proteinaceous component is the oxygen-transporting and phenoloxidase-displaying abundant hemolymph protein hemocyanin, suggesting that this protein also plays a role in clot biology. Furthermore, quantification of the peptidome after coagulation revealed the simultaneous activation of both the innate immune system and the coagulation system. In general, many of the identified clot-proteins are related to the innate immune system, and our results support the previously suggested crosstalk between immunity and coagulation in arthropods. PMID- 26621387 TI - Therapeutic strategies for circadian rhythm and sleep disturbances in Huntington disease. AB - Aside from the well-known motor, cognitive and psychiatric signs and symptoms, Huntington disease (HD) is also frequently complicated by circadian rhythm and sleep disturbances. Despite the observation that these disturbances often precede motor onset and have a high prevalence, no studies are available in HD patients which assess potential treatments. In this review, we will briefly outline the nature of circadian rhythm and sleep disturbances in HD and subsequently focus on potential treatments based on findings in other neurodegenerative diseases with similarities to HD, such as Parkinson and Alzheimer disease. The most promising treatment options to date for circadian rhythm and sleep disruption in HD include melatonin (agonists) and bright light therapy, although further corroboration in clinical trials is warranted. PMID- 26621388 TI - Changes in medication regimen complexity and the risk for 90-day hospital readmission and/or emergency department visits in U.S. Veterans with heart failure. AB - BACKGROUND: Heart failure (HF) hospitalization is associated with multiple medication modifications. These modifications often increase medication regimen complexity and may increase the risk of readmission and/or emergency department (ED) visit. OBJECTIVES: To determine the association between changes in medication regimen complexity (MRC) during hospitalization of patients with heart failure and the risk of readmission or ED visit at 90 days. Secondary objectives include examining the association between changes in MRC and time to readmission as well as the relationship between number of medications and MRC. METHODS: This was a retrospective cohort study that included U.S. Veterans hospitalized with heart failure. MRC was quantified using the medication regimen complexity index (MRCI). The change in MRCI was the difference between admission MRCI and discharge MRCI recorded during the index hospitalization. Demographic and clinical data were collected to characterize the study population. Patient data for up to one year after discharge was recorded to identify hospital readmissions and ED visits. RESULTS: A total of 174 patients were included in the analysis. Sixty-two patients (36%) were readmitted or had an ED visit at 90 days from the index hospitalization. The mean change (SD) in MRCI during the index hospitalization among the cohort was 4.7 (8.3). After multivariate logistic regression analysis, each unit increase in MRCI score was associated with a 4% lower odds of readmission or ED visit at 90 days but this finding was not statistically significant (OR 0.955; 95% CI 0.911-1.001). In the cox proportional hazard model, the median time to hospital readmission or ED visit was 214 days. Each unit increase in MRCI score was associated with a modest but non-significant increase in probability of survival from readmission or ED visit (HR 0.978; 95% CI 0.955, 1.001). CONCLUSION: Changes in medication regimen complexity that occur during hospitalization may also be associated with optimization of medical therapy and do not necessarily portend worse outcomes in patients with HF. PMID- 26621389 TI - Reduction of clinically irrelevant alarms in patient monitoring by adaptive time delays. AB - The problem of high rates of false alarms in patient monitoring in anesthesiology and intensive care medicine is well known but remains unsolved. False alarms desensitize the medical staff, leading to ignored true alarms and reduced quality of patient care. A database of intra-operative monitoring data was analyzed to find characteristic alarm patterns. The original data were re-evaluated to find relevant events and to rate the severity of these events. Based on this analysis an adaptive time delay was developed that individually delays the alarms depending on the grade of threshold deviation. The conventional threshold algorithm led to 4893 alarms. 3515 (71.84 %) of these alarms were annotated as clinically irrelevant. In total 81.0 % of all clinically irrelevant alarms were caused by only mild and/or brief threshold violations. We implemented the new algorithm for selected parameters. These parameters equipped with adaptive validation delays led to 1729 alarms. 931 (53.85 %) alarms were annotated as clinically irrelevant. 632 alarms indicated the 645 clinically relevant events. The positive predictive value of occurring alarms improved from 28.16 % (conventional algorithm) to 46.15 % (new algorithm). 13 events were missed. The false positive alarm reduction rate of the algorithm ranged from 33 to 86.75 %. The overall reduction was 73.51 %. The implementation of this algorithm may be able to suppress a large percentage of false alarms. The effect of this approach has not been demonstrated but shows promise for reducing alarm fatigue. Its safety needs to be proven in a prospective study. PMID- 26621390 TI - [Cervical cerclage in Reunion island: Evaluation of physicians' practice patterns]. AB - Cervical incompetency is one of the direct causes of neonatal morbidity and mortality; a unique and efficient treatment of which is cervical cerclage. The objective of this study was the evaluation of physicians' practice patterns concerning cerclage in Reunion Island, in order to reinforce the management and information of patients at risk. The indications and complications of cerclages effectuated in 2010 and 2011 were compared to the literature. MATERIAL AND METHODS: In this retrospective study, all the medical records of cerclage realized in Reunion Island during two years were collected and analyzed, specifically data concerning patients' cerclage, the complications, and the outcome of the pregnancy. RESULTS: We listed 200 cerclages, which were predominantly prophylactic cerclages (75.5%) and represented 0.71% of all births. A total of 71% of the indications of cerclage in Reunion Island did not take into account the recommendations of the literature. Analysis revealed the frequent use of prophylactic cerclage and subsequently reflected the insufficient use of therapeutic cerclage. In those cases, the rate of premature delivery was indeed lower (P=0.003), as well as the rate of chorioamniotitis (P=0.003). CONCLUSION: Cerclage is an efficient treatment to extend the length of the pregnancy. Nevertheless, it is important to comply with the recommendations given by the literature, by spotting the patients at risk of premature delivery, and recommend cerclage only in case of real cervical incompetency, for the sake of improving their management and reducing the rate of complications. PMID- 26621391 TI - Breast reconstruction using a latissimus dorsi flap after mastectomy. AB - INTRODUCTION: The latissimus dorsi (LD) myocutaneous flap has long been regarded as the second choice flap for autologous breast reconstruction following a mastectomy in our department. Despite uncertainty about donor-site morbidity, it is regarded as a relatively safe procedure; moreover, in contrast to our first choice, the deep inferior epigastric perforator flap, no microsurgical expertise is needed. METHODS: This is a systematic review of patient files for all LD breast reconstructions performed in the 2004-2013 period, at Rigshospitalet, Copenhagen, Denmark. RESULTS: A total of 135 unilateral LD breast reconstructions were performed in 126 women during the ten-year period. The median age of the women was 48.5 years, and they mainly had secondary reconstruction (90%). The average time to removal of the last drain was 6.3 days, and the average time to discharge was 6.9 days. A total of 13 patients (10%) had local complications and were re-operated within the first 30 days. We observed one flap loss and only one systemic complication; a urinary tract infection. In all, 38 patients (28%) received antibiotic treatment after the operations and 27 (20%) developed a seroma at the donor site on the back. Patients who developed seroma were four times as likely as those who did not to be readmitted for antibiotic treatment. CONCLUSIONS: LD breast reconstruction remains a safe choice for autologous breast reconstruction. Prevention of donor-site seroma as well as improvement of the clinical pathway and post-operative regimen could be future focus-points for this procedure. FUNDING: The review was performed as part of the pre-graduate research year project, "Donor-site morbidity after m. latissimus dorsi reconstruction", funded by Concordiafonden. TRIAL REGISTRATION: not relevant. PMID- 26621392 TI - Translation and validation of the Stop-Bang Questionnaire for obstructive sleep apnoea into Danish. AB - INTRODUCTION: Obstructive sleep apnoea (OSA) is a growing problem as more and more consequences of the condition become unveiled owing to continued research on the subject. It is essential to establish relevant, fast and accurate screening options, both in the primary sector and for preoperative screening in hospitals if we are to diagnose and treat this condition and thereby avoid the consequences of the untreated disease. METHODS: We have translated the Stop-Bang Questionnaire (SBQ) into Danish (SBQD) according to the guidelines presented by Guillemin et al in 1993. A validation study was performed including 43 consecutive patients. RESULTS: Most of the patients were men (79%). The overall median age was 54 years (range: 21-83 years). The median SBQD score for the group with an Apnoea Hypopnoea Index value (AHI) > 5 SBQD was 4 (range: 2-5), AHI > 15 SBQD score 5 (range: 4-7) and AHI > 30 SBQD score 7 (range: 4-8). Setting the SBQD cut-off at three, thereby defining scores 0-2 as normal as proposed by the authors, we observed the following sensitivity: AHI > 5 = 96.6%, AHI > 15 = 100% and AHI > 30 = 100%. The area under the curve was calculated and significant p-values achieved. CONCLUSIONS: The translation of the SBQ into Danish was validated as the results achieved were comparable to those reported from other studies and as acceptable sensitivity and specificity were observed. To avoid too many false positives, we recommend that the SBQD cut-off is set to >= 3 when screening preoperative patients and to >= 5 at primary physicians when screening high-risk patients. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26621393 TI - Validation of post-operative atrial fibrillation in the Western Denmark Heart Registry. AB - INTRODUCTION: Post-operative new-onset atrial fibrillation and flutter (POAF) is associated with increased morbidity and mortality following cardiac surgery. Registers and databases are important data sources for observational studies in this research area; hence, the aim was to assess the data validity of the POAF diagnosis in the Western Denmark Heart Registry (WDHR). METHODS: We studied a 25% random sample (n = 1,381) from a cohort of 5,532 patients who underwent coronary artery bypass grafting, valve surgery or combinations between 1 January 2011 and 31 December 2013. Registrations of POAF diagnoses in the WDHR were compared with the actual clinical course as documented in the medical records. The positive predictive value for new-onset POAF in the WDHR was calculated. RESULTS: A positive predictive value of 82.5% (95% confidence interval: 78.8-85.7) was found with a sensitivity and specificity of 75.2% and 90.9%, respectively. CONCLUSIONS: A diagnosis of new-onset POAF in the WDHR is relatively valid and may be used for contemporary epidemiological studies. Improvements may optimise the registry's validity even further, emphasising the importance of continuous validation and maintenance of the registry. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26621394 TI - Low adherence to cervical cancer screening after subtotal hysterectomy. AB - INTRODUCTION: A reason for not recommending subtotal hysterectomy is the risk of cervical pathology. We aimed to evaluate cervical cancer screening and to describe cervical pathology after subtotal and total hysterectomy for benign indications. METHODS: Data regarding adherence to screening and pathology results from the national Danish registry (Patobank) were obtained on women from a randomised clinical trial and an observational study of subtotal versus total abdominal hysterectomy from the time of surgery until 2014. RESULTS: We included 501 women (259 subtotal hysterectomies and 242 total hysterectomies). The mean follow-up time was 14.1 years, and the mean age at follow-up was 62.1 years. After subtotal hysterectomy, 9.7% were not invited for screening. Adherence to screening was 61.4%; 8.5% were not screened. After total hysterectomy, 14.5% were not invited, 6.6% adhered to screening and 65.7% were not screened. We found a minimum of one abnormal test in 28 (10.8%) after subtotal hysterectomy and one after total hysterectomy. No cervical cancers were found. CONCLUSIONS: Adherence to cervical cancer screening after subtotal hysterectomy in a Danish population is suboptimal and some patients have unnecessary tests performed after total hysterectomy. Clarification of the use of cervical/vaginal smears after hysterectomy is needed to identify women at risk of cervical dysplasia or cancer. FUNDING: Research Foundation of Region Zealand, University of Southern Denmark, Nykobing Falster Hospital, Rigs-hospitalet and Roskilde Hospital, Denmark. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01880710. PMID- 26621395 TI - C-reactive protein and white blood cell count do not improve clinical decision making in acute appendicitis. AB - INTRODUCTION: Acute appendicitis (AA) remains a diagnostic challenge as indicated by the high rate of unnecessary surgery. Blood samples, primarily C-reactive protein (CRP) and leucocyte counts, are used as a diagnostic supplement despite their relatively low sensitivities and specificities. However, their influence on diagnostic decision-making has not previously been investigated. The aim of the present study was to investigate if the results of CRP and leucocytes had any positive or negative influence on the decision-making of surgeons handling patients with suspected AA. METHODS: This was a prospective, observational cohort study including patients (>= 15 years of age) admitted on suspicion of AA. The surgeons were instructed to perform their physical examination and to register whether they found the patient more or less than 50% likely to have AA. Thereafter, the surgeons had to assess the blood results and re-evaluate their diagnosis. The surgeon's diagnosis before and after was compared with the final diagnosis defined by surgical findings or follow-up. The gold standard was any degree of appendicitis on histology. RESULTS: A total of 226 patients were included of whom 91 (40.3%) had appendicitis on histology. The surgeons changed their diagnosis in nine cases after assessing blood samples. The changes in the proportion of correct diagnoses, sensitivity, specificity and predictive values after assessing blood samples were not significant. CONCLUSIONS: The results of CRP and leucocyte counts did not influence clinical decision-making. FUNDING: Financial support was obtained from the Danish Council for Independent Research (Ref. no. 12-132020). TRIAL REGISTRATION: Clinicaltrials.gov: NCT02304653. PMID- 26621396 TI - Favourable results of Mohs micrographic surgery for basal cell carcinoma. AB - INTRODUCTION: Basal cell carcinoma (BCC) is the most common malignant neoplasm with an annual incidence approaching 200/100,000 person-years. Mohs micrographic surgery (MMS) is widely used in North America and in Europe for treatment of BCC. This technique ensures radical tumour removal, sparing of the surrounding healthy skin, and it also offers higher cure rates than standard tumour excision with a predefined margin of healthy skin. The superiority of MMS relies on the fact that the entire (100%) margin of the excised tissue is examined microscopically for residual tumour in contrast to the traditional histopathological examination, in which 2% of the margin is examined. METHODS: In Denmark, MMS was first introduced by us in 2012. In the present study, we retrospectively included all patients who underwent MMS from May 2012 to June 2015. RESULTS: A total of 231 patients with 263 BCC were included. The mean age was 66.1 years. The most common localisations were the forehead (31.3%), the nose (31.0%) and the cheek (14.7%). Primary BCC comprised 54.0%; the remaining cases were relapses, most frequently after curettage (36.9%), radiotherapy (18.9%) and photodynamic therapy (11.7%). MMS leads to 40% smaller skin defects than standard excisions with 4 or 6 mm margins. Closure of skin defects was achieved by side-to-side closure in 49% and by local flaps in 40%. There were no relapses during the observation time. The safety, cosmetic and functional outcome were excellent. CONCLUSIONS: We recommend that MMS be included in the Danish BCC treatment guidelines, especially for high-risk BCC in the face, in line with standard practice in Europe and the United States. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 26621397 TI - Danish experience with paediatric epilepsy surgery. AB - INTRODUCTION: Epilepsy surgery is increasingly used to treat children with medically intractable epilepsy. This study investigates the aetiology and seizure outcome in Danish children operated between 1996 and 2010. METHODS: Retrospectively collected data on structural magnetic resonance imaging (MRI) diagnoses, surgical procedures and seizure outcomes classified according to the Engel Classification were used. Changes over time grouped as 1996-2000, 2001-2005 and 2006-2010 were analysed. RESULTS: A total of 95 children underwent epilepsy surgery. Sixty-three operations were performed in Denmark and 50 abroad. In all, 14 children needed reoperation. The median follow-up period was four years. At the latest follow-up, Engel class I (indicating no disabling seizures) was found in 67% of the patients. Cortical dysplasia, mesial temporal sclerosis and tumour were the most common MRI findings. The percentage of tumours operated decreased over time, and frontal lobe resections increased. In the 2006-2010 period, resections with normal MRI were performed, resulting in a less favourable Engel outcome. Persistent, unexpected complications were seen in three of 113 operations. CONCLUSIONS: The majority of children who undergo epilepsy surgery have a good, worthwhile seizure outcome. The seizure outcome for Danish children corresponds to that of other epilepsy surgery centres. The clinical criteria for selection of patients changed over time. FUNDING: none. TRIAL REGISTRATION: The Danish Data Protection Agency approved the project with record number: 2013-41 2459. PMID- 26621398 TI - Difficult to predict early failure after major lower-extremity amputations. AB - INTRODUCTION: The successful outcome of a major amputation depends on several factors, including stump wound healing. The purpose of this study was to examine the criteria upon which the index amputation was based and to identify factors associated with early amputation failure after major non-traumatic lower extremity amputation. METHODS: We studied a consecutive one-year series of 36 men and 34 women with a median (25-75% quartiles) age of 72 (63-83) years who were treated in an acute orthopaedic ward; 44 below-knee and 26 above-knee amputees of whom 47 had an American Society of Anesthesiologists rating above two. Patient characteristics and other factors potentially influencing early amputation failure within 30 days were evaluated. RESULTS: Eleven patients died (16%) and 11 (16%) had a re-amputation at a higher level, whereas four (6%) had a major revision at the same level within 30 days. Amputations were performed by a house officer (n = 29), a specialist registrar (n = 27) or a consultant (n = 14). A total of 28 surgeons performed the included operations. Neither a preoperative skin perfusion test (only measured for 25 patients), nor any of the many other factors evaluated predicted early amputation failure. Patients with one or more failures stayed in the ward for a median of 45 (33-57) days versus 20 (14-25) days for those without failures. CONCLUSIONS: The rate of short-term amputation failures was high, and no clear explanation for this was established. A pre amputation algorithm to support the right choice of amputation level is needed. FUNDING: none. TRIAL REGISTRATION: This trial was registered with the Danish Data Protection Agency (R. no. 01975 HVH-2012-053). PMID- 26621399 TI - ONSTEP versus laparoscopy for inguinal hernia repair: protocol for a randomised clinical trial. AB - INTRODUCTION: The optimal repair of inguinal hernias remains controversial. It is recommended that an inguinal hernia be repaired using a mesh, either with a laparoscopic or an open approach. In Denmark, the laparoscopic approach is used in an increasing number of cases. The laparoscopic repair has a learning curve of about 50-100 cases and decreases chronic pain, but slightly increases the risk of serious complications compared with open mesh repairs. Therefore, a simpler kind of operation is needed. The ONSTEP technique is a possible solution to this problem. The objective of the present randomised clinical trial described in this protocol is to evaluate chronic pain after inguinal hernia repair using the ONSTEP method versus the laparoscopic approach. METHODS: This study is designed as a non-inferiority, two-arm, multicentre, randomised clinical trial, with a 1:1 allocation to ONSTEP or laparoscopic repair. Patients are recruited from surgical departments in Denmark and follow-up is one year. In total, 188 patients will be included. DISCUSSION: This protocol describes one of the first randomised clinical trials investigating the ONSTEP technique. To our knowledge, it is the first clinical trial comparing the ONSTEP technique with the laparoscopic technique. The results from this study are needed before it can be decided whether the ONSTEP technique should replace the laparoscopic technique in general surgical practice. FUNDING: This study has not received external funding. TRIAL REGISTRATION: NCT01960777 (clinicaltrials.gov). PMID- 26621400 TI - Prevention of post-operative anaemia in hip and knee arthroplasty--a systematic review. AB - INTRODUCTION: Patient blood management strategies for total hip and knee arthroplasty are controversial. They range from pre-operative haemoglobin optimisation to intra- and post-operative interventions. The aim of this study was to assess the various treatment modalities with respect to blood loss, haemoglobin levels and blood transfusions. METHODS: The analysis was based on the principles of a systematic review. The literature was searched in PubMed for the period from 2004 to November 2014. The articles were reviewed with respect to blood loss, post-operative haemoglobin drop, blood transfusions and length of hospital stay. The papers were evidence-graded. Non-randomised clinical studies and papers not concerning total hip or knee arthroplasty were excluded as were studies lacking a control group. Subanalyses were performed for tranexamic acid, tourniquet and fibrin use. RESULTS: A total of 49 studies were found eligible which is equivalent to a total of 4,752 patients. Tranexamic acid administered either orally, topically, intravenously or in combination decreased blood loss, increased the post-operative haemoglobin level, decreased the number of patients receiving blood transfusions and minimised the length of stay. A similar result was found for fibrin spray in total hip arthroplasty. However, for total knee arthroplasty, the outcome was blurred. Tourniquet use was uniformly not significant in the measured parameters. CONCLUSIONS: Tranexamic acid is useful in managing anaemia and blood loss. Fibrin sealant also has this potential, but is not more potent than tranexamic acid. Tourniquet use is not advantageous. PMID- 26621401 TI - Groin injuries in athletes--development of clinical entities, treatment, and prevention. AB - The doctoral thesis is based on eight papers published in peer-reviewed journals and a review of the literature. The papers are published between 1997 and 2013 in cooperation with Sankt Elisabeth Hospital, Herlev Hospital, Glostrup Hospital, Rigshospitalet, Hvidovre Hospital, Amager Hospital, Copenhagen Trial Unit, and Institute of Preventive Medicine, Copenhagen. Groin injuries in sport are very common and in football they are among the most common and most time-consuming injuries. These injuries are treated very differently around the world. There is no consensus in the literature regarding definitions, examination methods, diagnosis or treatment and in general the level of evidence is very low. There is a need for identification of the painful anatomical structures, how to examine them and how to define clinical entities to develop effective treatment and prevention. The aim of these studies were: - To review the literature to create an overview of the ideas and the knowledge in order to plan future studies in this field. - Develop and test clinical examination techniques of the relevant tendons and muscles in the region. - Since no evidence-based diagnosis exist; to develop a set of clinical entities to identify the different groups of patients. To test the effect of a dedicated exercise program developed for treatment of long-standing adductor-related groin pain in athletes in a randomised clinical trial comparing it to the treatment modalities used at that time. - To examine the long-term effect of the above mentioned training program for treatment of long-standing adductor-related groin pain. - To develop a training program for prevention of groin injuries in soccer and test it in a randomised clinical trial. - To describe the occurrence and presentation in clinical entities of groin injuries in male football and to examine the characteristics of these injuries. - Evaluate if radiological signs of femuro-acetabular impingement (FAI) or dysplasia affect the clinical outcome of treatment of long-standing adductor related groin pain, initially and at 8-12 year follow-up. The main findings of the eight papers were: - No randomised trials existed in this area; there was no consensus in the literature and the majority of the literature was Level 4 and 5. From the existing literature and the author' experience an injury mechanism was suggested and the term ''adductor-related groin injury'' was suggested. - A well defined clinical examination of the adductor-, iliopsoas, and abdominal muscles and the symphysis joint for pain, strength, and flexibility was reproducible with only limited intra- and inter-observer variation. - By utilising a well-defined classification long-standing groin injuries could be classified with a system of clinical entities. PMID- 26621402 TI - Near infrared spectroscopy--investigations in neurovascular diseases. AB - The purpose of this thesis was to explore and develop methods, where continuous wave near infrared spectroscopy (CW-NIRS) can be applied in different neurovascular diseases, in order to find biological markers that are useful in clinical neurology. To develop a new method to detect changes in cerebral blood flow (CBF), the first study investigated a multi-source detector separation configuration and indocyanine green (ICG) as a tracer to calculate a corrected blood flow index (BFI) value. The study showed no correlation between CBF changes measured by 133Xenon single photon emission computer tomography (133Xe-SPECT) and the corrected BFI value. It was concluded, that it was not possible to obtain reliable BFI data with the ICG CW-NIRS method. NIRS measurements of low frequency oscillations (LFOs) may be a reliable method to investigate vascular alterations in neurovascular diseases, but this requires an acceptable LFOs variation between hemispheres and over time in the healthy brain. The second study therefore investigated day-to-day and hemispheric variations in LFOs with NIRS. It was shown that NIRS might be useful in assessing LFOs between hemispheres, as well as interhemispheric phase and gain directly and over time. Migraine may be associated with persistent impairment of neurovascular coupling, but there is no experimental evidence to support this. The third study therefore investigated interictal neurovascular coupling during a mental task by a Stroop test in migraine without aura (MO) patients, which is the most common type of migraine. The study showed intact neurovascular coupling in the prefrontal cortex outside of attacks in patients with MO. The fourth study aimed to investigate possible changes in LFOs amplitude following nitric oxide (NO) donor infusion in familial hemiplegic migraine (FHM), which is a rare Mendelian subtype of migraine with aura. This study showed increased LFOs amplitude only in FHM patients with co existing common type of migraine, but not in patients with pure FHM phenotype. This suggests that the sensitivity to NO resides within the common migraine phenotypes rather than the FHM phenotype. Stimulation of the sphenopalatine ganglion (SPG) may lead to parasympathetic outflow and cause pain in cluster headache (CH). The fifth study therefore investigated pain and autonomic symptoms in relation to high or low SPG frequency stimulation in chronic CH patients. Cortical changes in oxygenated hemoglobin (HbO) were also recorded with NIRS and showed a moderate HbO increase, which was most pronounced on the ipsilateral CH side following high frequency stimulation. A possible application of NIRS to assess cerebral vascular changes due to sympathetic activity was investigated in obstructive sleep apnoea (OSA) patients, who have increased sympathetic activity and risk of stroke. Following successful continuous positive airway pressure (CPAP) therapy, OSA patients decreased their LFOs amplitude, which was interpreted as a marker of decreased sympathetic activity in cortical vessels. Finally, a novel hybrid technique, combining NIRS and ultrasound, was tested to detect CBF changes after acetazolamide injection in healthy volunteers using a cerebral flow index (CFI). The study showed an increase in CFI, which correlated with CBF measured with 133Xe-SPECT at 15 min. but not 60 min. Further methodological and explorative clinical studies are needed to assess the feasibility of ultrasound-tagged NIRS in clinical neurology. In summary, the thesis presents several novel approaches, by which NIRS may be used in clinical neurology, and potentials of NIRS to investigate complex mechanisms in neurovascular diseases. PMID- 26621403 TI - EHealth: self-management in inflammatory bowel disease and in irritable bowel syndrome using novel constant-care web applications. EHealth by constant-care in IBD and IBS. AB - BACKGROUND: Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are chronic gastrointestinal disorders of unknown aetiology of increasing incidence and changing disease activity or severity. Approximately 60-80% of IBD patients suffer from IBS. Monitoring and treatment goals of IBD are to optimise the disease course by prolonging remission periods and preventing or shortening periods of active disease. Constant-care web-monitoring and treatment approaches with active patient involvement have been proven effective in UC, increasing patients' adherence and improving the disease outcomes. AIM: To assess the feasibility and efficacy of the novel constant-care eHealth applications in: i) CD patients treated with infliximab (IFX), ii) UC patients with active disease on mesalazine, iii) IBS patients and iv) IBD patients with IBS on a low FODMAP diet (LFD). METHODS: New constant-care web applications www.cd.constant-care.dk, www.meza.constant-care.dk and www.ibs.constant-care.dk in IBD patients were developed and assessed in this thesis. An integrated inflammatory burden measure of disease activity, consisting of a subjective (clinical indices) and of an objective (faecal calprotectin) part and a treatment guide to drug doses and intervals, was incorporated into the web applications and used by patients. RESULTS: Web-guided IFX treatment in CD demonstrated patients' inter- and intra individual variability in infusion intervals and provided patients with individualised treatment according to their needs. Web-guided treatment with multimatrix mesalazine was efficacious in a majority of UC patients with mild-to moderate disease activity. Web-guided IBS-monitoring in IBD and in IBS patients on LFD was shown to be a feasible method that actively involved patients in their disease management and had a positive short-term impact on the disease. Moreover, the new constant-care concepts were demonstrated to be safe and to have a positive impact on quality of life and adherence to treatment and helped to reduce the costs. CONCLUSIONS: The novel constant-care web applications have proven feasible in improving the disease outcomes in CD patients on IFX, in UC patients on mesalazine, and in monitoring IBS. These applications are expected to be implemented in the clinical practice of gastroenterology in Denmark in the coming years. Future studies will help to assess whether the natural disease course can be improved in the long-term. PMID- 26621404 TI - Syphilis and HIV co-infection. Epidemiology, treatment and molecular typing of Treponema pallidum. AB - The studies included in this PhD thesis examined the interactions of syphilis, which is caused by Treponema pallidum, and HIV. Syphilis reemerged worldwide in the late 1990s and hereafter increasing rates of early syphilis were also reported in Denmark. The proportion of patients with concurrent HIV has been substantial, ranging from one third to almost two thirds of patients diagnosed with syphilis some years. Given that syphilis facilitates transmission and acquisition of HIV the two sexually transmitted diseases are of major public health concern. Further, syphilis has a negative impact on HIV infection, resulting in increasing viral loads and decreasing CD4 cell counts during syphilis infection. Likewise, HIV has an impact on the clinical course of syphilis; patients with concurrent HIV are thought to be at increased risk of neurological complications and treatment failure. Almost ten per cent of Danish men with syphilis acquired HIV infection within five years after they were diagnosed with syphilis during an 11-year study period. Interestingly, the risk of HIV declined during the later part of the period. Moreover, HIV-infected men had a substantial increased risk of re-infection with syphilis compared to HIV uninfected men. As one third of the HIV-infected patients had viral loads >1,000 copies/ml, our conclusion supported the initiation of cART in more HIV-infected MSM to reduce HIV transmission. During a five-year study period, including the majority of HIV-infected patients from the Copenhagen area, we observed that syphilis was diagnosed in the primary, secondary, early and late latent stage. These patients were treated with either doxycycline or penicillin and the rate of treatment failure was similar in the two groups, indicating that doxycycline can be used as a treatment alternative - at least in an HIV-infected population. During a four-year study period, the T. pallidum strain type distribution was investigated among patients diagnosed by PCR testing of material from genital lesions. In total, 22 strain types were identified. HIV-infected patients were diagnosed with nine different strains types and a difference by HIV status was not observed indicating that HIV-infected patients did not belong to separate sexual networks. In conclusion, concurrent HIV remains common in patients diagnosed with syphilis in Denmark, both in those diagnosed by serological testing and PCR testing. Although the rate of syphilis has stabilized in recent years, a spread to low-risk groups is of concern, especially due to the complex symptomatology of syphilis. However, given the efficient treatment options and the targeted screening of pregnant women and persons at higher risk of syphilis, control of the infection seems within reach. Avoiding new HIV infections is the major challenge and here cART may play a prominent role. PMID- 26621405 TI - Central and peripheral defects in motor units of the diaphragm of spinal muscular atrophy mice. AB - Spinal muscular atrophy (SMA) is characterized by motoneuron loss and muscle weakness. However, the structural and functional deficits that lead to the impairment of the neuromuscular system remain poorly defined. By electron microscopy, we previously found that neuromuscular junctions (NMJs) and muscle fibres of the diaphragm are among the earliest affected structures in the severe mouse SMA model. Because of certain anatomical features, i.e. its thinness and its innervation from the cervical segments of the spinal cord, the diaphragm is particularly suitable to characterize both central and peripheral events. Here we show by immunohistochemistry that, at postnatal day 3, the cervical motoneurons of SMA mice receive less stimulatory synaptic inputs. Moreover, their mitochondria become less elongated which might represent an early stage of degeneration. The NMJs of the diaphragm of SMA mice show a loss of synaptic vesicles and active zones. Moreover, the partly innervated endplates lack S100 positive perisynaptic Schwann cells (PSCs). We also demonstrate the feasibility of comparing the proteomic composition between diaphragm regions enriched and poor in NMJs. By this approach we have identified two proteins that are significantly upregulated only in the NMJ-specific regions of SMA mice. These are apoptosis inducing factor 1 (AIFM1), a mitochondrial flavoprotein that initiates apoptosis in a caspase-independent pathway, and four and a half Lim domain protein 1 (FHL1), a regulator of skeletal muscle mass that has been implicated in several myopathies. PMID- 26621407 TI - Introduction: Defining, measuring, and predicting quality in neurosurgery. PMID- 26621406 TI - A subset of interneurons required for Drosophila larval locomotion. AB - Efforts to define the neural circuits generating locomotor behavior have produced an initial understanding of some of the components within the spinal cord, as well as a basic understanding of several invertebrate motor pattern generators. However, how these circuits are assembled during development is poorly understood. We are defining the neural circuit that generates larval locomotion in the genetically tractable fruit fly Drosophila melanogaster to study locomotor circuit development. Forward larval locomotion involves a stereotyped posterior to-anterior segmental translocation of body wall muscle contraction and is generated by a relatively small number of identified muscles, motor and sensory neurons, plus an unknown number of the ~270 bilaterally-paired interneurons per segment of the 1st instar larva. To begin identifying the relevant interneurons, we have conditionally inactivated synaptic transmission of interneuron subsets and assayed for the effects on locomotion. From this screen we have identified a subset of 25 interneurons per hemisegment, called the lateral locomotor neurons (LLNs), that are required for locomotion. Both inactivation and constitutive activation of the LLNs disrupt locomotion, indicating that patterned output of the LLNs is required. By expressing a calcium indicator in the LLNs, we found that they display a posterior-to-anterior wave of activity within the CNS corresponding to the segmental translocation of the muscle contraction wave. Identification of the LLNs represents the first step toward elucidating the circuit generating larval locomotion. PMID- 26621408 TI - Impact of antibiotic prophylaxis for intrathecal baclofen pump surgery in pediatric patients. AB - OBJECT This study explored antibiotic prophylaxis (AP) in pediatric patients undergoing intrathecal baclofen pump (ITBP) surgery and factors associated with perioperative AP compliance with clinical guidelines. METHODS Data were obtained from the Pediatric Health Information System. The study cohort comprised patients who underwent ITBP surgery within 3 days of admission, between July 1, 2004, and March 31, 2014, with a minimum prior screening period and follow-up of 180 days. Exclusion criteria were prior infection, antibiotic use within 30 days of admission, and/or missing financial data. Chi-square tests and multivariate logistic regressions were used to determine factors associated with compliance with AP guidelines in ITBP surgeries. RESULTS A total of 1,534 patients met the inclusion criteria; 91.5% received AP and 37.6% received dual coverage or more. Overall bundled compliance comprised 2 components: 1) perioperative antibiotic administration and 2) < 24-hour postoperative antibiotic course. The most frequently used antibiotics in surgery were cefazolin (n = 873, 62.2%) and vancomycin (n = 351, 25%). Documented bundled AP compliance rates were 70.2%, 62.0%, 66.0%, and 55.2% in West, South, Midwest, and Northeast regions of the US, respectively. Compared with surgeries in the Northeast, procedures carried out in the West (OR 2.0, 95% C11.4-2.9, p < 0.001), Midwest (OR 1.6, 95% C11.1-2.3, p = 0.007), and South (OR 1.5, 95% C11.1-2.0, p = 0.021) were more likely to have documented AP compliance. Black (OR 0.74, 95% CI 0.55-1.00, p = 0.05) and Hispanic (OR 0.63, 95% CI 0.47-0.86, p = 0.004) patients were less likely to have documented AP compliance in ITBP surgeries than white patients. There were no significant differences in compliance rate by age, sex, type of insurance, and diagnosis. AP process measures were associated with shorter length of stay, lower hospitalization costs, and lower 6-month rates of surgical infection/complication. One of the 2 noncompliance subgroups, missed preoperative antibiotic administration, was correlated with a significantly higher 6-month surgical complication/infection rate (27.03%) compared with bundled compliance (20.00%, p = 0.021). For the other subgroup, prolonged antibiotic use > 24 hours postoperatively, the rate was insignificantly higher (22.00%, p = 0.368). Thus, of direct relevance to practicing clinicians, missed preoperative antibiotics was associated with 48% higher risk of adverse complication/infection outcome in a 6 month time frame. Adjusted hospitalization costs associated with baclofen pump surgery differed significantly (p < 0.001) with respect to perioperative antibiotic practices: 22.83, 29.10, 37.66 (* 1000 USD) for bundled compliance, missed preoperative antibiotics, and prolonged antibiotic administration, respectively. CONCLUSIONS Significant variation in ITBP antibiotic prophylaxis was found. Documented AP compliance was associated with higher value of care, showing favorable clinical and financial outcomes. Of most impact to clinical outcome, missed preoperative antibiotics was significantly associated with higher risk of 6-month surgical complication/infection. Prolonged antibiotic use was associated with significantly higher hospital costs compared with those with overall bundled antibiotic compliance. Future research is warranted to examine factors associated with practice variation and how AP compliance is associated with outcomes and quality, aiming for improving delivery of care to pediatric patients undergoing ITBP procedures. PMID- 26621409 TI - Complications after craniosynostosis surgery: comparison of the 2012 Kids' Inpatient Database and Pediatric NSQIP Database. AB - OBJECT Research conducted using large administrative data sets has increased in recent decades, but reports on the fidelity and reliability of such data have been mixed. The goal of this project was to compare data from a large, administrative claims data set with a quality improvement registry in order to ascertain similarities and differences in content. METHODS Data on children younger than 12 months with nonsyndromic craniosynostosis who underwent surgery in 2012 were queried in both the Kids' Inpatient Database (KID) and the American College of Surgeons Pediatric National Surgical Quality Improvement Program (Peds NSQIP). Data from published clinical craniosynostosis surgery series are reported for comparison. RESULTS Among patients younger than 12 months of age, a total of 1765 admissions were identified in KID and 391 in Peds NSQIP in 2012. Only nonsyndromic patients were included. The mean length of stay was 3.2 days in KID and 4 days in Peds NSQIP. The rates of cardiac events (0.5% in KID, 0.3% in Peds NSQIP, and 0.4%-2.2% in the literature), stroke/intracranial bleeds (0.4% in KID, 0.5% in Peds NSQIP, and 0.3%-1.2% in the literature), infection (0.2% in KID, 0.8% in Peds NSQIP, and 0%-8% in the literature), wound disruption (0.2% in KID, 0.5% in Peds NSQIP, 0%-4% in the literature), and seizures (0.7% in KID, 0.8% in Peds NSQIP, 0%-0.8% in the literature) were low and similar between the 2 data sets. The reported rates of blood transfusion (36% in KID, 64% in Peds NSQIP, and 1.7%-100% in the literature) varied between the 2 data sets. CONCLUSIONS Both the KID and Peds NSQIP databases provide large samples of surgical patients, with more cases reported in KID. The rates of complications studied were similar between the 2 data sets, with the exception of blood transfusion events where the retrospective chart review process of Peds NSQIP captured almost double the rate reported in KID. PMID- 26621410 TI - Length of hospital stay after craniotomy for tumor: a National Surgical Quality Improvement Program analysis. AB - OBJECT Although the length of hospital stay is often used as a measure of quality of care, data evaluating the predictors of extended hospital stay after craniotomy for tumor are limited. The goals of this study were to use multivariate regression to examine which preoperative characteristics and postoperative complications predict a prolonged hospital stay and to assess the impact of length of stay on unplanned hospital readmission. METHODS Data were extracted from the National Surgical Quality Improvement Program (NSQIP) database from 2007 to 2013. Patients who underwent craniotomy for resection of a brain tumor were included. Stratification was based on length of hospital stay, which was dichotomized by the upper quartile of the interquartile range (IQR) for the entire population. Covariates included patient age, sex, race, tumor histology, comorbidities, American Society of Anesthesiologists (ASA) class, functional status, preoperative laboratory values, preoperative neurological deficits, operative time, and postoperative complications. Multivariate logistic regression with forward prediction was used to evaluate independent predictors of extended hospitalization. Thereafter, hierarchical multivariate logistic regression assessed the impact of length of stay on unplanned readmission. RESULTS The study included 11,510 patients. The median hospital stay was 4 days (IQR 3-8 days), and 27.7% (n = 3185) had a hospital stay of at least 8 days. Independent predictors of extended hospital stay included age greater than 70 years (OR 1.53, 95% CI 1.28%-1.83%, p < 0.001); African American (OR 1.75, 95% CI 1.44%-2.14%, p < 0.001) and Hispanic (OR 1.68, 95% CI 1.36%-2.08%) race or ethnicity; ASA class 3 (OR 1.52, 95% CI 1.34%-1.73%) or 4-5 (OR 2.18, 95% CI 1.82%-2.62%) designation; partially (OR 1.94, 95% CI 1.61%-2.35%) or totally dependent (OR 3.30, 95% CI 1.95%-5.55%) functional status; insulin-dependent diabetes mellitus (OR 1.46, 95% CI 1.16%-1.84%); hematological comorbidities (OR 1.68, 95% CI 1.25%-2.24%); and preoperative hypoalbuminemia (OR 1.78, 95% CI 1.51%-2.09%, all p <= 0.009). Several postoperative complications were additional independent predictors of prolonged hospitalization including pulmonary emboli (OR 13.75, 95% CI 4.73% 39.99%), pneumonia (OR 5.40, 95% CI 2.89%-10.07%), and urinary tract infections (OR 11.87, 95% CI 7.09%-19.87%, all p < 0.001). The C-statistic of the model based on preoperative characteristics was 0.79, which increased to 0.83 after the addition of postoperative complications. A length of stay after craniotomy for tumor score was created based on preoperative factors significant in regression models, with a moderate correlation with length of stay (p = 0.43, p < 0.001). Extended hospital stay was not associated with differential odds of an unplanned hospital readmission (OR 0.97, 95% CI 0.89%-1.06%, p = 0.55). CONCLUSIONS In this NSQIP analysis that evaluated patients who underwent craniotomy for tumor, much of the variance in hospital stay was attributable to baseline patient characteristics, suggesting length of stay may be an imperfect proxy for quality. Additionally, longer hospitalizations were not found to be associated with differential rates of unplanned readmission. PMID- 26621411 TI - Prediction model for outcome after low-back surgery: individualized likelihood of complication, hospital readmission, return to work, and 12-month improvement in functional disability. AB - OBJECT Lumbar spine surgery has been demonstrated to be efficacious for many degenerative spine conditions. However, there is wide variability in outcome after spine surgery at the individual patient level. All stakeholders in spine care will benefit from identification of the unique patient or disease subgroups that are least likely to benefit from surgery, are prone to costly complications, and have increased health care utilization. There remains a large demand for individual patient-level predictive analytics to guide decision support to optimize outcomes at the patient and population levels. METHODS One thousand eight hundred three consecutive patients undergoing spine surgery for various degenerative lumbar diagnoses were prospectively enrolled and followed for 1 year. A comprehensive patient interview and health assessment was performed at baseline and at 3 and 12 months after surgery. All predictive covariates were selected a priori. Eighty percent of the sample was randomly selected for model development, and 20% for model validation. Linear regression was performed with Bayesian model averaging to model 12-month ODI (Oswestry Disability Index). Logistic regression with Bayesian model averaging was used to model likelihood of complications, 30-day readmission, need for inpatient rehabilitation, and return to work. Goodness-of-fit was assessed via R(2) for 12-month ODI and via the c statistic, area under the receiver operating characteristic curve (AUC), for the categorical endpoints. Discrimination (predictive performance) was assessed, using R(2) for the ODI model and the c-statistic for the categorical endpoint models. Calibration was assessed using a plot of predicted versus observed values for the ODI model and the Hosmer-Lemeshow test for the categorical endpoint models. RESULTS On average, all patient-reported outcomes (PROs) were improved after surgery (ODI baseline vs 12 month: 50.4 vs 29.5%, p < 0.001). Complications occurred in 121 patients (6.6%), 108 (5.9%) were readmitted within 30 days of surgery, 188 (10.3%) required discharge to inpatient rehabilitation, 1630 (88.9%) returned to work, and 449 (24.5%) experienced an unplanned outcome (no improvement in ODI, a complication, or readmission). There were 45 unique baseline variable inputs, derived from 39 clinical variables and 38 questionnaire items (ODI, SF-12, MSPQ, VAS-BP, VAS-LP, VAS-NP), included in each model. For prediction of 12-month ODI, R(2) was 0.51 for development and 0.47 for the validation study. For prediction of a complication, readmission, inpatient rehabilitation, and return to work, AUC values ranged 0.72-0.84 for development and 0.79-0.84 for validation study. CONCLUSIONS A novel prediction model utilizing both clinical data and patient interview inputs explained the majority of variation in outcome observed after lumbar spine surgery and reliably predicted 12-month improvement in physical disability, return to work, major complications, readmission, and need for inpatient rehabilitation for individual patients. Application of these models may allow clinicians to offer spine surgery specifically to those who are most likely to benefit and least likely to incur complications and excess costs. PMID- 26621412 TI - Predicting functional impairment in brain tumor surgery: the Big Five and the Milan Complexity Scale. AB - OBJECT The Milan Complexity Scale-a new practical grading scale designed to estimate the risk of neurological clinical worsening after performing surgery for tumor removal-is presented. METHODS A retrospective study was conducted on all elective consecutive surgical procedures for tumor resection between January 2012 and December 2014 at the Second Division of Neurosurgery at Fondazione IRCCS Istituto Neurologico Carlo Besta of Milan. A prospective database dedicated to reporting complications and all clinical and radiological data was retrospectively reviewed. The Karnofsky Performance Scale (KPS) was used to classify each patient's health status. Complications were divided into major and minor and recorded based on etiology and required treatment. A logistic regression model was used to identify possible predictors of clinical worsening after surgery in terms of changes between the preoperative and discharge KPS scores. Statistically significant predictors were rated based on their odds ratios in order to build an ad hoc complexity scale. For each patient, a corresponding total score was calculated, and ANOVA was performed to compare the mean total scores between the improved/unchanged and worsened patients. Relative risk (RR) and chi-square statistics were employed to provide the risk of worsening after surgery for each total score. RESULTS The case series was composed of 746 patients (53.2% female; mean age 51.3 +/- 17.1). The most common tumors were meningiomas (28.6%) and glioblastomas (24.1%). The mortality rate was 0.94%, the major complication rate was 9.1%, and the minor complication rate was 32.6%. Of 746 patients, 523 (70.1%) patients improved or remained unchanged, and 223 (29.9%) patients worsened. The following factors were found to be statistically significant predictors of the change in KPS scores: tumor size larger than 4 cm, cranial nerve manipulation, major brain vessel manipulation, posterior fossa location, and eloquent area involvement (Nagelkerke R(2) = 0.286). A grading scale was obtained with scores ranging between 0 and 8. Worsened patients showed mean total scores that were significantly higher than the improved/unchanged scores (3.24 +/- 1.55 vs 1.47 +/- 1.58; p < 0.001). Finally, a grid was developed to show the risk of worsening after surgery for each total score: scores higher than 3 are suggestive of worse clinical outcome. CONCLUSIONS Through the evaluation of the 5 aforementioned parameters-the Big Five-the Milan Complexity Scale enables neurosurgeons to estimate the risk of a negative clinical course after brain tumor surgery and share these data with the patient. Furthermore, the Milan Complexity Scale could be used for research and educational purposes and better health system management. PMID- 26621413 TI - Patient variables and referral paradigms associated with osteoporosis screening and treatment in neurosurgical patients undergoing kyphoplasty. AB - OBJECT Vertebral fractures are the most common osteoporotic fracture. Bone density testing and medical treatment with bisphosphonates or parathormone are recommended for all patients with an osteoporotic fracture diagnosis. Inadequate testing and treatment of patients presenting with low-impact fractures have been reported in various specialties. Similar data are not available from academic neurosurgery groups. The authors assessed compliance with treatment and testing of osteoporosis in patients with vertebral compression fractures evaluated by the authors' academic neurosurgery service, and patient variable and health-systems factors associated with improved compliance. METHODS Data for patients who underwent percutaneous kyphoplasty for compression fractures was retrospectively collected. Diagnostic and medical interventions were tabulated. Pre-, intra-, and posthospital factors that had been theorized to affect the compliance of patients with osteoporosis-related therapies were tabulated and statistically analyzed. RESULTS Less than 50% of patients with kyphoplasty received such therapies. Age was not found to correlate with other variables. Referral from a specialist rather than a primary care physician was associated with a higher rate of bone density screening, as well as vitamin D and calcium therapy, but not bisphosphonate/parathormone therapy. Patients who underwent preoperative evaluation by their primary care physician were significantly more likely to receive bisphosphonates compared with those only evaluated by a hospitalist. Patients with unprovoked fractures were more likely to undergo multiple surgeries compared with those with minor trauma. CONCLUSIONS These results suggest poor compliance with current standard of care for medical therapies in patients with osteoporotic compression fractures undergoing kyphoplasty under the care of an academic neurosurgery service. PMID- 26621414 TI - Neurosurgery clinical registry data collection utilizing Informatics for Integrating Biology and the Bedside and electronic health records at the University of Rochester. AB - In a population health-driven health care system, data collection through the use of clinical registries is becoming imperative to continue to drive effective and efficient patient care. Clinical registries rely on a department's ability to collect high-quality and accurate data. Currently, however, data are collected manually with a high risk for error. The University of Rochester's Department of Neurosurgery in conjunction with the university's Clinical and Translational Science Institute has implemented the integrated use of the Informatics for Integrating Biology and the Bedside (i2b2) informatics framework with the Research Electronic Data Capture (REDCap) databases. PMID- 26621415 TI - Patient-reported outcomes 3 months after spine surgery: is it an accurate predictor of 12-month outcome in real-world registry platforms? AB - OBJECT The health care landscape is rapidly shifting to incentivize quality of care rather than quantity of care. Quality and outcomes registry platforms lie at the center of all emerging evidence-driven reform models and will be used to inform decision makers in health care delivery. Obtaining real-world registry outcomes data from patients 12 months after spine surgery remains a challenge. The authors set out to determine whether 3-month patient-reported outcomes accurately predict 12-month outcomes and, hence, whether 3-month measurement systems suffice to identify effective versus noneffective spine care. METHODS All patients undergoing lumbar spine surgery for degenerative disease at a single medical institution over a 2-year period were enrolled in a prospective longitudinal registry. Patient-reported outcome instruments (numeric rating scale [NRS], Oswestry Disability Index [ODI], 12-Item Short Form Health Survey [SF-12], EQ-5D, and the Zung Self-Rating Depression Scale) were recorded prospectively at baseline and at 3 months and 12 months after surgery. Linear regression was performed to determine the independent association of 3- and 12-month outcome. Receiver operating characteristic (ROC) curve analysis was performed to determine whether improvement in general health state (EQ-5D) and disability (ODI) at 3 months accurately predicted improvement and achievement of minimum clinical important difference (MCID) at 12 months. RESULTS A total of 593 patients undergoing elective lumbar surgery were included in the study. There was a significant correlation between 3-month and 12-month EQ-5D (r = 0.71; p < 0.0001) and ODI (r = 0.70; p < 0.0001); however, the authors observed a sizable discrepancy in achievement of a clinically significant improvement (MCID) threshold at 3 versus 12 months on an individual patient level. For postoperative disability (ODI), 11.5% of patients who achieved an MCID threshold at 3 months dropped below this threshold at 12 months; 10.5% of patients who did not meet the MCID threshold at 3 months continued to improve and ultimately surpassed the MCID threshold at 12 months. For ODI, achieving MCID at 3 months accurately predicted 12-month MCID with only 62.6% specificity and 86.8% sensitivity. For postoperative health utility (EQ-5D), 8.5% of patients lost an MCID threshold improvement from 3 months to 12 months, while 4.0% gained the MCID threshold between 3 and 12 months postoperatively. For EQ-5D (quality-adjusted life years), achieving MCID at 3 months accurately predicted 12-month MCID with only 87.7% specificity and 87.2% sensitivity. CONCLUSIONS In a prospective registry, patient reported measures of treatment effectiveness obtained at 3 months correlated with 12-month measures overall in aggregate, but did not reliably predict 12-month outcome at the patient level. Many patients who do not benefit from surgery by 3 months do so by 12 months, and, conversely, many patients reporting meaningful improvement by 3 months report loss of benefit at 12 months. Prospective longitudinal spine outcomes registries need to span at least 12 months to identify effective versus noneffective patient care. PMID- 26621416 TI - Editorial. Can big data bridge the chasm? Issues, opportunities, and strategies for the evolving value-based health care environment. PMID- 26621417 TI - The present and future of quality measures and public reporting in neurosurgery. AB - Quality measurement and public reporting are intended to facilitate targeted outcome improvement, practice-based learning, shared decision making, and effective resource utilization. However, regulatory implementation has created a complex network of reporting requirements for physicians and medical practices. These include Medicare's Physician Quality Reporting System, Electronic Health Records Meaningful Use, and Value-Based Payment Modifier programs. The common denominator of all these initiatives is that to avoid penalties, physicians must meet "generic" quality standards that, in the case of neurosurgery and many other specialties, are not pertinent to everyday clinical practice and hold specialists accountable for care decisions outside of their direct control. The Centers for Medicare and Medicaid Services has recently authorized alternative quality reporting mechanisms for the Physician Quality Reporting System, which allow registries to become subspecialty-reporting mechanisms under the Qualified Clinical Data Registry (QCDR) program. These programs further give subspecialties latitude to develop measures of health care quality that are relevant to the care provided. As such, these programs amplify the power of clinical registries by allowing more accurate assessment of practice patterns, patient experiences, and overall health care value. Neurosurgery has been at the forefront of these developments, leveraging the experience of the National Neurosurgery Quality and Outcomes Database to create one of the first specialty-specific QCDRs. Recent legislative reform has continued to change this landscape and has fueled optimism that registries (including QCDRs) and other specialty-driven quality measures will be a prominent feature of federal and private sector quality improvement initiatives. These physician- and patient-driven methods will allow neurosurgery to underscore the value of interventions, contribute to the development of sustainable health care solutions, and actively participate in meaningful quality initiatives for the benefit of the patients served. PMID- 26621419 TI - Neurosurgery value and quality in the context of the Affordable Care Act: a policy perspective. AB - Neurosurgeons provide direct individualized care to patients. However, the majority of regulations affecting the relative value of patient-related care are drafted by policy experts whose focus is typically system- and population-based. A central, prospectively gathered, national outcomes-related database serves as neurosurgery's best opportunity to bring patient-centered outcomes to the policy arena. In this study the authors analyze the impact of the Affordable Care Act (ACA) on the determination of quality and value in neurosurgery care through the scope, language, and terminology of policy experts. The methods by which the ACA came into law and the subsequent quality implications this legislation has for neurosurgery will be discussed. The necessity of neurosurgical patient-oriented clinical registries will be discussed in the context of imminent and dramatic reforms related to medical cost containment. In the policy debate moving forward, the strength of neurosurgery's argument will rest on data, unity, and proactiveness. The National Neurosurgery Quality and Outcomes Database (N(2)QOD) allows neurosurgeons to generate objective data on specialty-specific value and quality determinations; it allows neurosurgeons to bring the patient-physician interaction to the policy debate. PMID- 26621418 TI - The National Neurosurgery Quality and Outcomes Database Qualified Clinical Data Registry: 2015 measure specifications and rationale. AB - Meaningful quality measurement and public reporting have the potential to facilitate targeted outcome improvement, practice-based learning, shared decision making, and effective resource utilization. Recent developments in national quality reporting programs, such as the Centers for Medicare & Medicaid Services Qualified Clinical Data Registry (QCDR) reporting option, have enhanced the ability of specialty groups to develop relevant quality measures of the care they deliver. QCDRs will complete the collection and submission of Physician Quality Reporting System (PQRS) quality measures data on behalf of individual eligible professionals. The National Neurosurgery Quality and Outcomes Database (N(2)QOD) offers 21 non-PQRS measures, initially focused on spine procedures, which are the first specialty-specific measures for neurosurgery. Securing QCDR status for N(2)QOD is a tremendously important accomplishment for our specialty. This program will ensure that data collected through our registries and used for PQRS is meaningful for neurosurgeons, related spine care practitioners, their patients, and other stakeholders. The 2015 N(2)QOD QCDR is further evidence of neurosurgery's commitment to substantively advancing the health care quality paradigm. The following manuscript outlines the measures now approved for use in the 2015 N(2)QOD QCDR. Measure specifications (measure type and descriptions, related measures, if any, as well as relevant National Quality Strategy domain[s]) along with rationale are provided for each measure. PMID- 26621420 TI - Interrupted time-series analysis: studying trends in neurosurgery. AB - OBJECT Neurosurgery studies traditionally have evaluated the effects of interventions on health care outcomes by studying overall changes in measured outcomes over time. Yet, this type of linear analysis is limited due to lack of consideration of the trend's effects both pre- and postintervention and the potential for confounding influences. The aim of this study was to illustrate interrupted time-series analysis (ITSA) as applied to an example in the neurosurgical literature and highlight ITSA's potential for future applications. METHODS The methods used in previous neurosurgical studies were analyzed and then compared with the methodology of ITSA. RESULTS The ITSA method was identified in the neurosurgical literature as an important technique for isolating the effect of an intervention (such as a policy change or a quality and safety initiative) on a health outcome independent of other factors driving trends in the outcome. The authors determined that ITSA allows for analysis of the intervention's immediate impact on outcome level and on subsequent trends and enables a more careful measure of the causal effects of interventions on health care outcomes. CONCLUSIONS ITSA represents a significant improvement over traditional observational study designs in quantifying the impact of an intervention. ITSA is a useful statistical procedure to understand, consider, and implement as the field of neurosurgery evolves in sophistication in big-data analytics, economics, and health services research. PMID- 26621421 TI - The Michigan Spine Surgery Improvement Collaborative: a statewide Collaborative Quality Initiative. AB - OBJECT Given the scrutiny of spine surgery by policy makers, spine surgeons are motivated to demonstrate and improve outcomes, by determining which patients will and will not benefit from surgery, and to reduce costs, often by reducing complications. Insurers are similarly motivated. In 2013, Blue Cross Blue Shield of Michigan (BCBSM) and Blue Care Network (BCN) established the Michigan Spine Surgery Improvement Collaborative (MSSIC) as a Collaborative Quality Initiative (CQI). MSSIC is one of the newest of 21 other CQIs that have significantly improved-and continue to improve-the quality of patient care throughout the state of Michigan. METHODS MSSIC focuses on lumbar and cervical spine surgery, specifically indications such as stenosis, disk herniation, and degenerative disease. Surgery for tumors, traumatic fractures, deformity, scoliosis, and acute spinal cord injury are currently not within the scope of MSSIC. Starting in 2014, MSSIC consisted of 7 hospitals and in 2015 included another 15 hospitals, for a total of 22 hospitals statewide. A standardized data set is obtained by data abstractors, who are funded by BCBSM/BCN. Variables of interest include indications for surgery, baseline patient-reported outcome measures, and medical history. These are obtained within 30 days of surgery. Outcome instruments used include the EQ-5D general health state score (0 being worst and 100 being the best health one can imagine) and EQ-5D-3 L. For patients undergoing lumbar surgery, a 0 to 10 numeric rating scale for leg and back pain and the Oswestry Disability Index for back pain are collected. For patients undergoing cervical surgery, a 0 to 10 numeric rating scale for arm and neck pain, Neck Disability Index, and the modified Japanese Orthopaedic Association score are collected. Surgical details, postoperative hospital course, and patient-reported outcome measures are collected at 90-day, 1-year, and 2-year intervals. RESULTS As of July 1, 2015, a total of 6397 cases have been entered into the registry. This number reflects 4824 eligible cases with confirmed surgery dates. Of these 4824 eligible cases, 3338 cases went beyond the 120-day window and were considered eligible for the extraction of surgical details, 90-day outcomes, and adverse events. Among these 3338 patients, there are a total of 2469 lumbar cases, 862 cervical cases, and 7 combined procedures that were entered into the registry. CONCLUSIONS In addition to functioning as a registry, MSSIC is also meant to be a platform for quality improvement with the potential for future initiatives and best practices to be implemented statewide in order to improve quality and lower costs. With its current rate of recruitment and expansion, MSSIC will provide a robust platform as a regional prospective registry. Its unique funding model, which is supported by BCBSM/BCN, will help ensure its longevity and viability, as has been observed in other CQIs that have been active for several years. PMID- 26621422 TI - Effect of complications within 90 days on patient-reported outcomes 3 months and 12 months following elective surgery for lumbar degenerative disease. AB - OBJECT There is a paradigm shift toward rewarding providers for quality rather than volume. Complications appear to occur at a fairly consistent frequency in large aggregate data sets. Understanding how complications affect long-term patient-reported outcomes (PROs) following degenerative lumbar surgery is vital. The authors hypothesized that 90-day complications would adversely affect long term PROs. METHODS Nine hundred six consecutive patients undergoing elective surgery for degenerative lumbar disease over a period of 4 years were enrolled into a prospective longitudinal registry. The following PROs were recorded at baseline and 12-month follow-up: Oswestry Disability Index (ODI) score, numeric rating scales for back and leg pain, quality of life (EQ-5D scores), general physical and mental health (SF-12 Physical Component Summary [PCS] and Mental Component Summary [MCS] scores) and responses to the North American Spine Society (NASS) satisfaction questionnaire. Previously published minimum clinically important difference (MCID) threshold were used to define meaningful improvement. Complications were divided into major (surgicalsite infection, hardware failure, new neurological deficit, pulmonary embolism, hematoma and myocardial infarction) and minor (urinary tract infection, pneumonia, and deep venous thrombosis). RESULTS Complications developed within 90 days of surgery in 13% (118) of the patients (major in 12% [108] and minor in 8% [68]). The mean improvement in ODI scores, EQ-5D scores, SF-12 PCS scores, and satisfaction at 3 months after surgery was significantly less in the patients with complications than in those who did not have major complications (ODI: 13.5 +/- 21.2 vs 21.7 +/- 19, < 0.0001; EQ-5D: 0.17 +/- 0.25 vs 0.23 +/- 0.23, p = 0.04; SF-12 PCS: 8.6 +/- 13.3 vs 13.0 +/- 11.9, 0.001; and satisfaction: 76% vs 90%, p = 0.002). At 12 months after surgery, the patients with major complications had higher ODI scores than those without complications (29.1 +/- 17.7 vs 25.3 +/- 18.3, p = 0.02). However, there was no difference in the change scores in ODI and absolute scores across all other PROs between the 2 groups. In multivariable linear regression analysis, after controlling for an array of preoperative variables, the occurrence of a major complication was not associated with worsening ODI scores 12 months after surgery. There was no difference in the percentage of patients achieving the MCID for disability (66% vs 64%), back pain (55% vs 56%), leg pain (62% vs 59%), or quality of life (19% vs 14%) or in patient satisfaction rates (82% vs 80%) between those without and with major complications. CONCLUSIONS Major complications within 90 days following lumbar spine surgery have significant impact on the short-term PROs. Patients with complications, however, do eventually achieve clinically meaningful outcomes and report satisfaction equivalent to those without major complications. This information allows a physician to counsel patients on the fact that a complication creates frustration, cost, and inconvenience; however, it does not appear to adversely affect clinically meaningful long-term outcomes and satisfaction. PMID- 26621423 TI - Quality analysis of anterior cervical discectomy and fusion in the outpatient versus inpatient setting: analysis of 7288 patients from the NSQIP database. AB - OBJECT In an era of escalating health care cost and universal pressure of improving efficiency and cost of care, ambulatory surgery centers (ASCs) have emerged as lower cost options for many surgical therapies. Anterior cervical discectomy and fusion (ACDF) is one of the most prevalent spine surgeries performed and is rapidly increasing with an expanding aging population. While ASCs offer cost advantages for ACDF, there is a scarcity of evidence that ASCs allow for equivalent quality and thus superior health care value. Therefore, the authors analyzed a nationwide, prospective quality improvement registry (National Surgical Quality Improvement Program [NSQIP]) to compare the quality of ACDF surgery performed in the outpatient ASC versus the inpatient hospital setting. METHODS Patients undergoing ACDF (2005-2011) were identified from the NSQIP database based on the primary Current Procedural Terminology codes. Patients were divided into 2 cohorts (outpatient vs inpatient) based on the acute care setting documented in the NSQIP database. All 30-day surgical morbidity and mortality rates were compared between the 2 groups. Propensity score matching and multivariate logistic regression analysis were used to adjust for confounding factors and to identify the independent association of outpatient ACDF with perioperative outcomes and morbidity. RESULTS A total of 7288 ACDF cases were identified (inpatient = 6120, outpatient = 1168). Unadjusted rates of major morbidity (0.94% vs 4.5%, p < 0.001) and return to the operating room (OR) within 30 days (0.3% vs 2.0%, p < 0.001) were significantly lower in outpatient versus inpatient ACDF. After propensity matching 1442 cases (inpatient = 650, outpatient = 792) based on baseline 32 covariates, rates of major morbidity (1.4% vs 3.1%, p = 0.03), and return to the OR (0.34% vs 1.4%, p = 0.04) remained significantly lower after outpatient ACDF. Adjusted comparison using multivariate logistic regression demonstrated that ACDF performed in the outpatient setting had 58% lower odds of having a major morbidity and 80% lower odds of return to the OR within 30 days. CONCLUSIONS An analysis of a nationwide, prospective quality improvement registry representing more than 250 hospitals demonstrates that 1- to 2-level ACDF can be safely performed in the outpatient ambulatory surgery setting in patients who are appropriate candidates. In an effort to decrease cost of care, surgeons can safely consider performing ACDF in an ASC environment. PMID- 26621424 TI - [Inflammatory tumor of the great omentum after ingestion of a bone fragment]. AB - The ingestion of a foreign body is one of the most common accidents in children. It comes in extremely varied clinical presentations in which radiological imaging plays an important role in diagnosis. Colonic perforations are particularly serious because of the major risk for septic fecal peritonitis. Management depends on the nature of the ingested object, its location, the child's age and the child's clinical status. We report a child presenting an inflammatory tumor of the omentum on an ingested bone fragment that had perforated the transverse colon. PMID- 26621425 TI - The effects of 1% prednisolone acetate on pupil diameter and intraocular pressure in healthy dogs treated with 0.005% latanoprost. AB - PURPOSE: Prostaglandin analogs contribute to blood-aqueous barrier breakdown and may exacerbate uveitis. As these analogs induce de novo synthesis of endogenous prostaglandins, their therapeutic, hypotensive effect could potentially be inhibited by anti-inflammatory treatment. We therefore evaluated whether topical 1% prednisolone acetate alters the effects of 0.005% latanoprost on pupil diameter (PD) and intraocular pressure (IOP). ANIMALS STUDIED: Ten healthy Labrador retriever dogs from the Israel Guide Dog Center for the Blind. METHODS: Pupil diameter and IOP were measured hourly, 8 AM-4 PM, with the right and left eyes serving as control (CE) and treated (TE) eyes, respectively. Measurements were conducted during four sessions: (1) without treatment (n = 10), (2) following latanoprost treatment (n = 10) at 8 AM, (3) following prednisolone treatment (n = 7) at 8 AM, and (4) bilateral latanoprost treatment at 8 AM, prednisolone treatment in TE at 11 AM (n = 8). The different number of dogs in sessions 3 and 4 is because some dogs were matched with their new owners earlier than expected. RESULTS: Pupil diameters were not affected by the addition of prednisolone and, at 4 PM, were 3.82 +/- 0.47 and 3.97 +/- 0.36 mm in TE and CE, respectively (P = 0.175, Wilcoxon). IOPs were not affected by the addition of prednisolone and, at 4 PM, were 9.0 +/- 0.8 and 9.3 +/- 0.8 mm Hg in TE and CE, respectively (P = 0.339, Wilcoxon). CONCLUSION: Prednisolone did not alter latanoprost's miotic and hypotensive effects in normal dogs during this study period. PMID- 26621426 TI - Causal Inference and Explaining Away in a Spiking Network. AB - While the brain uses spiking neurons for communication, theoretical research on brain computations has mostly focused on non-spiking networks. The nature of spike-based algorithms that achieve complex computations, such as object probabilistic inference, is largely unknown. Here we demonstrate that a family of high-dimensional quadratic optimization problems with non-negativity constraints can be solved exactly and efficiently by a network of spiking neurons. The network naturally imposes the non-negativity of causal contributions that is fundamental to causal inference, and uses simple operations, such as linear synapses with realistic time constants, and neural spike generation and reset non linearities. The network infers the set of most likely causes from an observation using explaining away, which is dynamically implemented by spike-based, tuned inhibition. The algorithm performs remarkably well even when the network intrinsically generates variable spike trains, the timing of spikes is scrambled by external sources of noise, or the network is mistuned. This type of network might underlie tasks such as odor identification and classification. PMID- 26621428 TI - Stability and Dissociation Energies of Open-Chain N4C2. AB - Complex forms of nitrogen are of interest due to their potential as high-energy materials. Many forms of nitrogen, including open-chain and cage molecules, have been studied previously. While many all-nitrogen molecules Nx have been shown to be too unstable for high-energy applications, it has been shown that certain heteroatoms (including carbon) can stabilize a nitrogen structure. A molecule that is not 100% nitrogen will be less energetic, but that energy loss is a tradeoff for the improved stability. In this study, open-chain N4C2 (70% nitrogen by mass) isomers are studied by theoretical calculations to determine isomer stability and dissociation energies. Calculations are carried out with density functional theory (PBE1PBE), perturbation theory (MP2), and coupled-cluster theory (CCSD(T)). Trends in stability of the molecules are calculated and discussed. PMID- 26621427 TI - Body Image in Anorexia Nervosa: Body Size Estimation Utilising a Biological Motion Task and Eyetracking. AB - OBJECTIVE: Anorexia nervosa (AN) is a psychiatric condition characterised by a distortion of body image. However, whether individuals with AN can accurately perceive the size of other individuals' bodies is unclear. METHOD: In the current study, 24 women with AN and 24 healthy control participants undertook two biological motion tasks while eyetracking was performed: to identify the gender and to indicate the walkers' body size. RESULTS: Anorexia nervosa participants tended to 'hyperscan' stimuli but did not demonstrate differences in how visual attention was directed to different body areas, relative to controls. Groups also did not differ in their estimation of body size. DISCUSSION: The hyperscanning behaviours suggest increased anxiety to disorder-relevant stimuli in AN. The lack of group difference in the estimation of body size suggests that the AN group was able to judge the body size of others accurately. The findings are discussed in terms of body image distortion specific to oneself in AN. PMID- 26621429 TI - Dissecting the Hydrogen Bond: A Quantum Monte Carlo Approach. AB - We present a Quantum Monte Carlo study of the dissociation energy and the dispersion curve of the water dimer, a prototype of hydrogen bonded system. Our calculations are based on a wave function which is a modern and fully correlated implementation of the Pauling's valence bond idea: the Jastrow Antisymmetrised Geminal Power (JAGP) [Casula et al. J. Chem. Phys. 2003, 119, 6500-6511]. With this variational wave function we obtain a binding energy of -4.5(0.1) kcal/mol that is only slightly increased to -4.9(0.1) kcal/mol by using the Lattice Regularized Diffusion Monte Carlo (LRDMC). This projection technique allows for the substantial improvement in the correlation energy of a given variational guess and indeed, when applied to the JAGP, yields a binding energy in fair agreement with the value of -5.0 kcal/mol reported by experiments and other theoretical works. The minimum position, the curvature, and the asymptotic behavior of the dispersion curve are well reproduced both at the variational and the LRDMC level. Moreover, thanks to the simplicity and the accuracy of our variational approach, we are able to dissect the various contributions to the binding energy of the water dimer in a systematic and controlled way. This is achieved by appropriately switching off determinantal and Jastrow variational terms in the JAGP. Within this scheme, we estimate that the dispersive van der Waals contribution to the electron correlation is substantial and amounts to 1.5(0.2) kcal/mol, this value being comparable with the intermolecular covalent energy that we find to be 1.1(0.2) kcal/mol. The present Quantum Monte Carlo approach based on the JAGP wave function is revealed as a promising tool for the interpretation and the quantitative description of weakly interacting systems, where both dispersive and covalent energy contributions play an important role. PMID- 26621430 TI - Beyond Point Charges: Dynamic Polarization from Neural Net Predicted Multipole Moments. AB - Intramolecular polarization is the change to the electron density of a given atom upon variation in the positions of the neighboring atoms. We express the electron density in terms of multipole moments. Using glycine and N-methylacetamide (NMA) as pilot systems, we show that neural networks can capture the change in electron density due to polarization. After training, modestly sized neural networks successfully predict the atomic multipole moments from the nuclear positions of all atoms in the molecule. Accurate electrostatic energies between two atoms can be then obtained via a multipole expansion, inclusive of polarization effects. As a result polarization is successfully modeled at short-range and without an explicit polarizability tensor. This approach puts charge transfer and multipolar polarization on a common footing. The polarization procedure is formulated within the context of quantum chemical topology (QCT). Nonbonded atom-atom interactions in glycine cover an energy range of 948 kJ mol(-1), with an average energy difference between true and predicted energy of 0.2 kJ mol(-1), the largest difference being just under 1 kJ mol(-1). Very similar energy differences are found for NMA, which spans a range of 281 kJ mol(-1). The current proof-of concept enables the construction of a new protein force field that incorporates electron density fragments that dynamically respond to their fluctuating environment. PMID- 26621431 TI - Geometries of Third-Row Transition-Metal Complexes from Density-Functional Theory. AB - A set of 41 metal-ligand bond distances in 25 third-row transition-metal complexes, for which precise structural data are known in the gas phase, is used to assess optimized and zero-point averaged geometries obtained from DFT computations with various exchange-correlation functionals and basis sets. For a given functional (except LSDA) Stuttgart-type quasi-relativistic effective core potentials and an all-electron scalar relativistic approach (ZORA) tend to produce very similar geometries. In contrast to the lighter congeners, LSDA affords reasonably accurate geometries of 5d-metal complexes, as it is among the functionals with the lowest mean and standard deviations from experiment. For this set the ranking of some other popular density functionals, ordered according to decreasing standard deviation, is BLYP > VSXC > BP86 ~ BPW91 ~ TPSS ~ B3LYP ~ PBE > TPSSh > B3PW91 ~ B3P86 ~ PBE hybrid. In this case hybrid functionals are superior to their nonhybrid variants. In addition, we have reinvestigated the previous test sets for 3d- (Buhl M.; Kabrede, H. J. Chem. Theory Comput. 2006, 2, 1282-1290) and 4d- (Waller, M. P.; Buhl, M. J. Comput. Chem. 2007, 28, 1531-1537) transition-metal complexes using all-electron scalar relativistic DFT calculations in addition to the published nonrelativistic and ECP results. For this combined test set comprising first-, second-, and third-row metal complexes, B3P86 and PBE hybrid are indicated to perform best. A remarkably consistent standard deviation of around 2 pm in metal-ligand bond distances is achieved over the entire set of d-block elements. PMID- 26621432 TI - Torsional Barriers and Equilibrium Angle of Biphenyl: Reconciling Theory with Experiment. AB - The barriers of internal rotation of the two phenyl groups in biphenyl are investigated using a combination of coupled cluster and density functional theory. The experimental barriers are for the first time accurately reproduced; our best estimates of the barriers are 8.0 and 8.3 kJ/mol around the planar and perpendicular conformations, respectively. The use of flexible basis sets of at least augmented quadruple-zeta quality is shown to be a crucial prerequisite. Further, to finally reconcile theory with experiment, extrapolations of both the basis set toward the basis set limit and electron correlation toward the full configuration-interaction limit are necessary. The minimum of the torsional angle is significantly increased by free energy corrections, which are needed to reach an agreement with experiment. The density functional B3LYP approach is found to perform well compared with the highest level ab initio results. PMID- 26621433 TI - Nonenzymatic Pathway of PUFA Oxidation. A First-Principles Study of the Reactions of OH Radical with 1,4-Pentadiene and Arachidonic Acid. AB - The oxidation of polyunsaturated hydrocarbons by .OH radical can play an important role in lipid oxidation of polyunsaturated fatty acids (PUFA) such as arachidonic acid (AA). As a prototype of this oxidation, the reaction of 1,4 pentadiene with the .OH radical is studied using the QCISD(T)/cc-pVTZ//BH&HLYP/6 31G(d) level of theory. One of the prereaction complexes is shown to be a springboard for the indirect bisallylic hydrogen abstraction (AO), terminal (T0O), and nonterminal .OH addition (NT0O) reactions. The enthalpies of the transition states of the AO, T0O, and NT0O reactions are found to be lower than those of the reactants, so all these reactions are expected to be fast. The nonterminal adduct is found to be reactive via two low-lying consecutive reaction channels. The first channel is a five-membered ring closing (NT1O). The second channel is bond scission, which results in an allyl radical and a vinyl alcohol (NT2O). An analogous reaction pathway in which AA takes the place of 1,4 pentadiene was explored using the ONIOM(QCISD(T)/cc-pVTZ:BH&HLYP/6 31G(d))//BH&HLYP/6-31G(d) method. The results show that the formation of the five membered ring (AA-NT1O) is energetically favored. Our results demonstrate for the first time a possible, ab initio-based mechanism for the nonenzymatic biosynthesis of isoprostane-like structures from AA without the presence of molecular oxygen. Furthermore, the energetically low-lying bond scission channel may explain the observed formation of short fatty acids and dieneols (tautomers of unsaturated aldehydes). PMID- 26621434 TI - Karplus Equation for (3)JHH Spin-Spin Couplings with Unusual (3)J(180 degrees ) < (3)J(0 degrees ) Relationship. AB - Vicinal (3)JHH coupling constants for monosubstituted ethane molecules present the unusual relationship (3)JHH (180 degrees ) < (3)JHH (0 degrees ) when the substituent contains bonding and antibonding orbitals with strong hyperconjugative interactions involving bond and antibond orbitals of the ethane fragment. This anomalous behavior is studied as a function of the substituent rotation for three model systems (propanal, thiopropanal, and 1-butene) at the B3LYP/TZVP level. The consistency of this level of theory to study this problem is previously established using different ab initio methods and larger basis sets. The origin of the unusual (3)JHH(180 degrees ) - (3)JHH(0 degrees ) relationship is attributed to simultaneous sigma/pi hyperconjugative interactions sigmaCalpha-Halpha -> pi*Cc?X, and sigmaCalpha-Cbeta -> pi*Cc?X. These interactions depend on the substituent rotation and their effects are different for (3)JHH(180 degrees ) than for (3)JHH(0 degrees ). The modelization carried out shows an increase of those effects as the substituent changes from weaker (CH?CH2) to stronger (CH?S) electron acceptor pi*C?X. PMID- 26621435 TI - Performance of the Density Functional Theory/Multireference Configuration Interaction Method on Electronic Excitation of Extended pi-Systems. PMID- 26621436 TI - Origins of Resistance Conferred by the R292K Neuraminidase Mutation via Molecular Dynamics and Free Energy Calculations. AB - Point mutations in the influenza virus enzyme neuraminidase (NA) have been reported that lead to dramatic loss of activity for known NA inhibitors including the FDA approved sialic acid mimics zanamivir and oseltamivir. A more complete understanding of the molecular basis for such resistance is a critical component toward development of improved next-generation drugs. In this study, we have used explicit solvent all-atom molecular dynamics simulations, free energy calculations (MM-GBSA), and residue-based decomposition to model binding of four ligands with NA from influenza virus subtype N9. The goal is to elucidate which structural and energetic properties change as a result of a mutation at position R292K. Computed binding free energies show strong correlation with experiment (r(2) = 0.76), and an examination of individual energy components reveal that changes in intermolecular Coulombic terms (DeltaEcoul) best describe the variation in affinity with structure (r(2) = 0.93). H-bond populations also parallel the experimental ordering (r = -0.96, r(2) = 0.86) reinforcing the view that electrostatics modulate binding in this system. Notably, in every case, the simulation results correctly predict that loss of binding occurs as a result of the R292K mutation. Per-residue binding footprints reveal that changes in DeltaDeltaEcoul for R292K-wildtype at position 292 parallel the change in experimental fold resistance energies (DeltaDeltaGR292K-WT) with S03 < S00 < S02 < S01. The footprints also reveal that the most potent ligands have (1) less reliance on R292 for intrinsic affinity, (2) enhanced binding via residues E119, E227, and E277, and (3) flatter DeltaEcoul and DeltaH-bond profiles. Improved resistance for S03 appears to be a function of the ligand's larger guanidinium group which leads to an increased affinity for wildtype NA while at the same time a reduction in favorable interactions localized to R292. Overall, the computational results significantly enhance experimental observations through quantification of specific interactions which govern molecular recognition along the N9-ligand binding interface. PMID- 26621437 TI - Is Alanine Dipeptide a Good Model for Representing the Torsional Preferences of Protein Backbones? AB - The conformational preference for different phi/Psi backbone torsion angles is a key determinant of peptide and protein secondary structure. Often, dipeptides are used as models for understanding protein backbone dynamics and to derive force field parameters. Here, the question is examined to what extent the conformational preferences in dipeptides reflect the backbone dynamics in polypeptides and proteins and to what extent an alanine dipeptide-based backbone torsion parametrization can lead to accurate reproduction of amino acid dependent phi/Psi preferences in protein structures. Results from a comparison of the analysis of Protein Data Bank (PDB) structures with long simulations of selected proteins and amino acid dipeptides suggest that a common alanine dipeptide-based torsion potential does in fact lead to excellent agreement between protein simulations and PDB structures. At the same time, the phi/Psi preferences in the dipeptides are significantly different, suggesting that dipeptides are not good model systems for studying protein backbone dynamics. PMID- 26621438 TI - Coordination chemistry and applications of versatile 4,5-diazafluorene derivatives. AB - This perspective review will examine the coordination chemistry and applications of metal complexes of 4,5-diazafluorene derivatives. The versatile derivatives of 4,5-diazafluorene can serve multiple roles, and display a number of coordination modes. The ambidentate derivatives with multiple coordination sites can allow for the syntheses of coordination polymers, multimetallic, and macrocyclic complexes. In addition, certain 4,5-diazafluorene derivatives can serve as spectator ligands to support reactivity at the metal centre, or as reactive actor ligands engaging in atypical reactivity patterns. The applications of metal complexes of 4,5 diazafluorene derivatives in catalysis, photochemistry and photophysics, as well as in bioinorganic chemistry are also surveyed. PMID- 26621439 TI - Complementary and Integrative Medicine at Mayo Clinic. AB - Complementary and alternative medicine (CAM) has gained acceptance throughout the industrialized world. The present study was performed to provide information about the use of CAM at Mayo Clinic, an academic medical center in Northern Midwest of the US. We retrospectively reviewed the electronic medical records of 2680 patients visiting the CAM program at Mayo Clinic, Rochester, between 1 July 2006 and 31 March 2011. Services provided included acupuncture, massage, integrative medical consultations and executive stress management training. Data including age, gender, race, diagnosis and the number of treatment/consultation sessions were collected to describe the use of CAM in our institute over the last several years. It was found that the mean (standard deviation) age of patient was 52.6 (15.5) years. Of those, 73.1% were female and 26.9% were male. Most patients were white. The number of patients referred to CAM increased significantly from 2007 to 2010. The three most common diagnostic categories were back pain (12.9%), psychological disorders (11.8%), and joint pain (9.6%). Back pain was the most common diagnosis for patients receiving acupuncture, and fibromyalgia was the most common for patients receiving massage therapy. Psychological disorders (i.e., stress) were the major diagnosis referred to both integrative medical consults and executive stress management training. These results suggest that the diseases related to pain and psychological disorders are the main fields of CAM use. It also shows the increasing trend of the use of CAM at an academic medical center in the US. PMID- 26621440 TI - Clinical Strategy for Optimal Traditional Chinese Medicine (TCM) Herbal Dose Selection in Disease Therapeutics: Expert Consensus on Classic TCM Herbal Formula Dose Conversion. AB - The clinical therapeutics of traditional Chinese medicine (TCM) constitutes a complicated process which involves theory, diagnosis, and formula prescription with specific herbal dosage. Zhang Zhong-Jing's classic work, Treatise on Febrile and Miscellaneous Diseases, has been influencing TCM practice for almost 2000 years. However, during this extended period of time in Chinese history, the Chinese weight measurement system experienced noticeable changes. This change in the weight measurement system inevitably, and perhaps even negatively, affected TCM herbal dosage determination and treatment outcome. Thus, in modern society, a full understanding of the accuracy of herbal dose selection has a critical importance in the TCM daily practice of delivering the best treatment to the patients suffering from different illnesses. In the 973 Project of the Chinese National Basic Research Program, expert consensus on classic TCM formula dose conversion has been reached based on extensive literature review and discussion on the dose-effect relationship of classic TCM formulas. One "liang" in classic TCM formulas is equivalent to 13.8 g. However, based on many TCM basic and clinical studies of variable herbal formula prescriptions and herbal drug preparations, the rule of one liang equals 13.8 g should be adjusted according to different disease conditions. Recommended by the committee on TCM formula dose effect relationship of the China Association of Chinese Medicine and the World Federation of Chinese Medicine Societies, the following expert consensus has been reached: (i) One liang converts to 6-9 g for the severely and critically ill patients. (ii) One liang converts to 3-6 g for the patients suffering from chronic diseases. (iii) One liang converts to 1-3 g in preventive medicine. The above conversions should be used as a future TCM practice guideline. Using this recommended guideline should enhance the effectiveness of daily TCM practice. PMID- 26621441 TI - The Effects of Qigong for Adults with Chronic Pain: Systematic Review and Meta Analysis. AB - A systematic review was conducted to evaluate the effectiveness of qigong as a treatment for chronic pain. Five electronic databases were searched from their date of establishment until July 2014. The review included 10 randomized clinical trials (RCTs) that compared the impacts of qigong on chronic pain with waiting list or placebo or general care. Random effect models and standard mean differences were used to present pain scores. A total of 10 RCTs met inclusion criteria. There was a statistically significant difference on reducing chronic pain between internal qigong and control (SMD: -1.23 95% CI= -2.23, -0.24p = 0.02), external qigong and general care (SMD: -1.53 95% CI= -2.15, -0.91p < 0.05), external qigong and placebo (SMD: -0.51 95% CI = 0.95, -0.06p = 0.03), and internal qigong for chronic neck pain at 6 months (SMD: -1.00 95% CI= -1.94, 0.06p = 0.04). The differences between external qigong and control, external qigong and waiting list, internal qigong and waiting list, and external for premenstrual syndromes were not significant. This study showed that internal qigong generated benefits on treating some chronic pain with significant differences. External qigong showed nonsignificant differences in treating chronic pain. Higher quality randomized clinical trials with scientific rigor are needed to establish the effectiveness of qigong in reducing chronic pain. PMID- 26621442 TI - Electroacupuncture for Acute Ischemic Stroke: A Meta-Analysis of Randomized Controlled Trials. AB - Electroacupuncture (EA) is an extension technique of acupuncture based on traditional acupuncture combined with modern electrotherapy. Here, we conducted a systematic review specifically to assess the effectiveness and safety of EA for acute ischemic stroke. Eight databases were searched for randomized-controlled clinical trials (RCTs) of EA for acute ischemic stroke published from inception to June 2013. Ultimately, 67 studies claimed to be RCTs. Eighteen studies with 1411 individuals were selected for the analyses, which got >= 4 "yes" in the domains of Cochrane risk of bias tool. The meta-analysis showed a significant effect of EA for improving Barthel Index (p < 0.00001), Fugl-Meyer Assessment (p < 0.00001), National Institutes of Health Stroke Scale (p < 0.00001), and Revised Scandinavian Stroke Scale (p < 0.00001) compared with western conventional treatments (WCTs). In an analysis of the total clinical efficacy rate, there was a significant difference between EA and WCTs (p=0.0002). Adverse effects were monitored in 6 studies, and were well tolerated in all stroke patients. According to the GRADE approach, the quality of evidence was mostly high or moderate. In conclusion, this systematic review revealed the evidence in support of the use of EA for acute ischemic stroke, although further larger sample-size and rigorously designed RCTs are required. PMID- 26621443 TI - Tanshinone IIA Prevents Leu27IGF-II-Induced Cardiomyocyte Hypertrophy Mediated by Estrogen Receptor and Subsequent Akt Activation. AB - IGF-IIR plays important roles as a key regulator in myocardial pathological hypertrophy and apoptosis, which subsequently lead to heart failure. Salvia miltiorrhiza Bunge (Danshen) is a traditional Chinese medicinal herb used to treat cardiovascular diseases. Tanshinone IIA is an active compound in Danshen and is structurally similar to 17[Formula: see text]-estradiol (E[Formula: see text]. However, whether tanshinone IIA improves cardiomyocyte survival in pathological hypertrophy through estrogen receptor (ER) regulation remains unclear. This study investigates the role of ER signaling in mediating the protective effects of tanshinone IIA on IGF-IIR-induced myocardial hypertrophy. Leu27IGF-II (IGF-II analog) was shown in this study to specifically activate IGF IIR expression and ICI 182,780 (ICI), an ER antagonist used to investigate tanshinone IIA estrogenic activity. We demonstrated that tanshinone IIA significantly enhanced Akt phosphorylation through ER activation to inhibit Leu27IGF-II-induced calcineurin expression and subsequent NFATc3 nuclear translocation to suppress myocardial hypertrophy. Tanshinone IIA reduced the cell size and suppressed ANP and BNP, inhibiting antihypertrophic effects induced by Leu27IGF-II. The cardioprotective properties of tanshinone IIA that inhibit Leu27IGF-II-induced cell hypertrophy and promote cell survival were reversed by ICI. Furthermore, ICI significantly reduced phospho-Akt, Ly294002 (PI3K inhibitor), and PI3K siRNA significantly reduced the tanshinone IIA-induced protective effect. The above results suggest that tanshinone IIA inhibited cardiomyocyte hypertrophy, which was mediated through ER, by activating the PI3K/Akt pathway and inhibiting Leu27IGF-II-induced calcineurin and NFATC3. Tanshinone IIA exerted strong estrogenic activity and therefore represented a novel selective ER modulator that inhibits IGF-IIR signaling to block cardiac hypertrophy. PMID- 26621444 TI - p-Hydroxybenzyl Alcohol, an Active Phenolic Ingredient of Gastrodia elata, Reverses the Cycloheximide-Induced Memory Deficit by Activating the Adrenal Gland in Rats. AB - The present study investigated the ameliorating effects of p-hydroxybenzyl alcohol (HBA), an active phenolic ingredient of Gastrodia elata, on cycloheximide (CXM)-induced impairment of passive avoidance response and clarified the role of adrenal glands on the effect of HBA in rats. An adrenalectomy (ADX) caused the memory deficit from 1 to 3 days after surgery. Administration of corticosterone (CORT) plus glucose completely recovered the memory deficit caused by ADX, and this effect was better than that of glucose or CORT alone. HBA ameliorated the memory deficit induced by CXM in sham and ADX rats, but ADX partially blocked it. Furthermore, plasma glucose, epinephrine and adrenal steroid levels of ADX rats significantly decreased. Sham rats who received HBA had an increase in plasma glucose and adrenal steroid levels. Therefore, we suggest that the reversal of CXM-induced memory deficit by HBA was partially dependent on adrenal glands through the increase of the levels of plasma adrenal steroids. PMID- 26621445 TI - Resveratrol Suppresses Cytokine Production Linked to FcepsilonRI-MAPK Activation in IgE-Antigen Complex-Exposed Basophilic Mast Cells and Mice. AB - A complicated interplay between resident mast cells and other recruited inflammatory cells contributes to the development and progression of allergic inflammation entailing the promotion of T helper 2 (Th2) cytokine responses. The current study examined whether resveratrol suppressed the production of inflammatory Th2 cytokines in cultured rat basophilic leukemia RBL-2H3 cells. Cells pre-treated with resveratrol nontoxic at 1-25 MUM were sensitized with anti dinitrophenyl (anti-DNP), and subsequently stimulated by dinitrophenyl-human serum albumin (DNP-HSA) antigen. Resveratrol dose-dependently diminished the secretion of interleukin (IL)-3, IL-4, IL-13 as well as tumor necrosis factor (TNF)-alpha by the antigen stimulation from sensitized cells. It was found that resveratrol mitigated the phosphorylation of p38 MAPK, ERK, and JNK elevated in mast cells exposed to Fc epsilon receptor I (FcepsilonRI)-mediated immunoglobulin E (IgE)-antigen complex. The FcepsilonRI aggregation was highly enhanced on the surface of mast cells following the HSA stimulation, which was retarded by treatment with 1-25 MUM resveratrol. The IgE-receptor engagement rapidly induced tyrosine phosphorylation of c-Src-related focal adhesion protein paxillin involved in the cytoskeleton rearrangement. The FcepsilonRI-mediated rapid activation of c-Src and paxillin was attenuated in a dose-dependent manner. In addition, the paxillin activation entailed p38 MAPK and ERK-responsive signaling, but the JNK activation was less involved. Consistently, oral administration of resveratrol reduced the tissue level of phosphorylated paxillin in the dorsal skin of DNP-HSA-challenged mice. The other tyrosine kinase Tyk2-STAT1 signaling was activated in the dorsal epidermis of antigen-exposed mice, which was associated with allergic inflammation. These results showed that resveratrol inhibited Th2 cytokines- and paxillin-linked allergic responses dependent upon MAPK signaling. Therefore, resveratrol may possess the therapeutic potential of targeting mast cells in preventing the development of allergic inflammation. PMID- 26621446 TI - Potential Wound Healing Activities of Galla Rhois in Human Fibroblasts and Keratinocytes. AB - Wound healing is a complex process orchestrated by the regeneration of the epithelium and the remodeling of the extracellular matrix through processes like collagen deposition. Galla Rhois has been widely used in traditional Korean medicine for its various pharmacological effects, including an anticoccidial effect, however, little is known about its healing activity. The purpose of this study was to determine the effects of Galla Rhois ethanol extract (GRE) on wound healing activities, including H2O2-induced oxidative stress, cell migration, and lactate dehydrogenase (LDH) release assays using human keratinocyte (HaCaT) and dermal fibroblasts (CCD-986SK). In addition, total soluble collagen deposition and collagen gene expression for Type I and III collagen were evaluated in CCD 986SK. Total tannin and flavonoid contents for GRE were measured. GRE induced a significant increase in the number and migration of cells, along with a decrease in cell death and LDH release. In addition, it also induced the over-expression of collagen Type I and III mRNA and caused increased synthesis of total soluble collagen. The contents of total tannin and flavonoid for GRE were 55.7% ([Formula: see text][Formula: see text]mg/g) and 62.9% ([Formula: see text][Formula: see text]mg/g), respectively. The results suggest that GRE can cause accelerated wound healing by increasing cell survival, proliferation, migration, and collagen synthesis along with a potential anti-oxidant property. This evidence provides novel insight into natural therapy for tissue injury. PMID- 26621447 TI - Comparison of Immunomodulatory and Anticancer Activities in Different Strains of Tremella fuciformis Berk. AB - Tremella fuciformis Berk (TF) is a common edible and medicinal mushroom, and has long been used in food and in Chinese medicine. It possesses anticancer, anti inflammation, anti-oxidative, and neuroprotective abilities. Since their cultivation is a problem, TFs in Taiwan are primarily imported from China, which has a problem with pesticide residues. Thus, the question of whether the Taiwan cultivated TFs, T1, and T6 showed similar or even better results than TFs from China (CH) was assessed in the present study. The results of the physicochemical tests of these TFs showed that T1 extracted by hot water (T1H) has the highest concentration of polysaccharide; meanwhile, T6 extracted by cold water (T6C) showed the highest amount of protein. Regarding the immune modulatory effects of these TFs, hot water extracts of these TFs augmented significantly the inducible nitric oxide synthetase (iNOS), interleukin (IL)-6, and tumor necrosis factor (TNF)-[Formula: see text] mRNA expression than those of cold water extracts. On the other hand, the cold water extracts of TFs, especially of T1C, obviously suppressed cancer cell survival better than those of hot water extracts. Interestingly, we found that hot water extracts of TFs may augment necrotic cell death, whereas, cold water extracts of TFs induce apoptosis. Furthermore, we also showed that these TFs activate caspase-3 cleavage, up regulate the Bax/Bcl-2 ratio, and decrease MMP-9 expressions in PC-3 cells. Taken together, our results indicated that T1 and T6 strains of TFs showed the similar immune modulatory and anticancer abilities were better than the CH strain of TFs. PMID- 26621448 TI - Antrodia cinnamomea Inhibits Migration in Human Hepatocellular Carcinoma Cells: The Role of ERp57 and PGK-1. AB - Evidences suggest that ERp57 and PGK-1 signaling lead to cancer cell proliferation and migration. We hypothesized that ERp57 and PGK-1 down-regulation may inactivate matrix metalloproteinase (MMP)-2, -9 expressions and inhibit hepatocellular carcinoma (HCC) migration. Antrodia cinnamomea is widely prescribed as an adjuvant to treat HCC in Taiwan. We aimed to investigate if ethanol extract of fruiting bodies of Antrodia cinnamomea (EEAC) and its active ingredients (i.e., zhankuic acid A, cordycepin, and adenosine) can modulate HCC cancer cells migration through ERp57 and PGK-1 and other molecular pathways such as PI3K/Akt and MAPK. ERp57 and PGK-1 siRNA were transfected into HCC to determine effects on MMP-2/-9 expressions and cell migration. We then examined the inhibitory effects of EEAC and its active ingredients on HCC migration and its related mechanisms including ERp57, PGK-1, PI3K/Akt, and MAPK signaling pathways. Down-regulation of ERp57 and PGK-1 by siRNA decreased MMP-2, -9 expressions and Transwell cell migration in HCC. Nontoxic EEAC markedly inhibited migration of HCC, and significantly inhibited activities and protein expressions of MMP-2 and -9, while the expression of the endogenous inhibitors (TIMP-1 and TIMP-2) of these proteins increased. Nontoxic EEAC and its active ingredients decreased ERp57, GLUD-1, GST-pi, and PGK-1 protein expressions. Finally, nontoxic EEAC inhibited the phosphorylated FAK, PI3K/Akt, and MAPK signaling. Our findings first indicate that EEAC and its ingredients effectively suppress HCC migration. Additionally, the molecular mechanisms appear to be mediated, in part, through the down-regulation of ERp57, PGK-1, MAPK, and PI3K/Akt. PMID- 26621449 TI - The Inhibitory Effect of Abietic Acid on Melanoma Cancer Metastasis and Invasiveness In Vitro and In Vivo. AB - Melanoma cell metastasis is the primary cause of patient death. Thus, various treatment strategies have been developed to prevent metastasis. Abietic acid (AA) is an organic compound commonly found in trees. This study is aimed to investigate the antimetastatic activity of AA in B16F10-xenografted C57BL/6 mice and assess the anticancer activity of AA in combination with Taxol in melanoma cells. AA effectively reduced the formation of lung metastases by approximately 92.8%. AA treatment inhibited migratory potential (p < 0.001), invasion (p < 0.001), and motility (p < 0.001) of highly metastatic B16F10 melanoma cells in vitro. Zymography revealed that AA reduced the proteinase activities of matrix metalloproteinase-2 and urokinase-type plasminogen activator. Molecular analyses showed that AA reduced Akt phosphorylation and activating protein-1 DNA-binding activity by Western blot and electrophoretic mobility shift assay (EMSA), respectively. In summary, AA effectively inhibited B16F10 lung metastasis, and 50[Formula: see text][Formula: see text]M AA did not affect the viability of B16F10 cells. AA improved the efficacy of Taxol and demonstrated strong anticancer activity on melanoma cells. These results suggested that AA could be used as an antimetastatic agent or as an adjuvant for anticancer therapy. PMID- 26621450 TI - Unraveling the Structural Modifications in Lignin of Arundo donax Linn. during Acid-Enhanced Ionic Liquid Pretreatment. AB - Solid acid-enhanced ionic liquid (IL) pretreatment is of paramount importance for boosting the yield of sugars from biomass cost-effectively and environmentally friendly. To unravel the chemical and supramolecular structural changes of lignin after pretreatment, IL-acid lignin (ILAL) and subsequent residual cellulolytic enzyme lignin (RCEL) were isolated from Arundo donax Linn. The structural features were compared with those of the corresponding milled wood lignin (MWL). Results indicated that the pretreatment caused loss of beta-O-4', beta-beta', beta-1' linkages and formation of condensed structures in lignin. A preferential breakdown of G-type lignin may have occurred, evidenced by an increased S/G ratio revealed by 2D HSQC NMR analysis. It was determined that the depolymerization of beta-O-4' linkage, lignin recondensation, and cleavage of ferulate-lignin ether linkages took place. Moreover, a simulation module was first developed to define morphological changes in lignin based on AFM and TEM analyses. Briefly, tree branch like aggregates was destroyed to monodisperse particles. PMID- 26621451 TI - Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy. AB - Pathological activation of the Toll-like receptor signaling adaptor protein MYD88 underlies many autoimmune and inflammatory disease states. In the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), the oncogenic MYD88 L265P mutation occurs in 29% of cases, making it the most prevalent activating mutation in this malignancy. IRAK4 kinase accounts for almost all of the biological functions of MYD88, highlighting IRAK4 as a therapeutic target for diseases driven by aberrant MYD88 signaling. Using innovative structure-based drug design methodologies, we report the development of highly selective and bioavailable small molecule IRAK4 inhibitors, ND-2158 and ND-2110. These small molecules suppressed LPS-induced TNF production, alleviated collagen-induced arthritis, and blocked gout formation in mouse models. IRAK4 inhibition promoted killing of ABC DLBCL lines harboring MYD88 L265P, by down-modulating survival signals, including NF-kappaB and autocrine IL-6/IL-10 engagement of the JAK-STAT3 pathway. In ABC DLBCL xenograft models, IRAK4 inhibition suppressed tumor growth as a single agent, and in combination with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib or the Bcl-2 inhibitor ABT-199. Our findings support pharmacological inhibition of IRAK4 as a therapeutic strategy in autoimmune disorders, in a genetically defined population of ABC DLBCL, and possibly other malignancies dependent on aberrant MYD88 signaling. PMID- 26621452 TI - IKKbeta acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis. AB - Cancer-associated fibroblasts (CAFs) comprise one of the most important cell types in the tumor microenvironment. A proinflammatory NF-kappaB gene signature in CAFs has been suggested to promote tumorigenesis in models of pancreatic and mammary skin cancer. Using an autochthonous model of colitis-associated cancer (CAC) and sporadic cancer, we now provide evidence for a tumor-suppressive function of IKKbeta/NF-kappaB in CAFs. Fibroblast-restricted deletion of Ikkbeta stimulates intestinal epithelial cell proliferation, suppresses tumor cell death, enhances accumulation of CD4(+)Foxp3(+) regulatory T cells, and induces angiogenesis, ultimately promoting colonic tumor growth. In Ikkbeta-deficient fibroblasts, transcription of negative regulators of TGFbeta signaling, including Smad7 and Smurf1, is impaired, causing up-regulation of a TGFbeta gene signature and elevated hepatocyte growth factor (HGF) secretion. Overexpression of Smad7 in Ikkbeta-deficient fibroblasts prevents HGF secretion, and pharmacological inhibition of Met during the CAC model confirms that enhanced tumor promotion is dependent on HGF-Met signaling in mucosa of Ikkbeta-mutant animals. Collectively, these results highlight an unexpected tumor suppressive function of IKKbeta/NF kappaB in CAFs linked to HGF release and raise potential concerns about the use of IKK inhibitors in colorectal cancer patients. PMID- 26621453 TI - IKKbeta in intestinal mesenchymal cells promotes initiation of colitis-associated cancer. AB - The importance of mesenchymal cells in inflammation and/or neoplastic transformation is well recognized, but their role in the initiation of these processes, particularly in the intestine, remains elusive. Using mouse models of colorectal cancer, we show that IKKbeta in intestinal mesenchymal cells (IMCs) is critically involved in colitis-associated, but not spontaneous tumorigenesis. We further demonstrate that IMC-specific IKKbeta is involved in the initiation of colitis-associated cancer (CAC), as in its absence mice develop reduced immune cell infiltration, epithelial cell proliferation, and dysplasia at the early stages of the disease. At the molecular level, these effects are associated with decreased early production of proinflammatory and protumorigenic mediators, including IL-6, and reduced STAT3 activation. Ex vivo IKKbeta-deficient IMCs show defective responses to innate immune stimuli such as LPS, as shown by decreased NF-kappaB signaling and reduced expression of important NF-kappaB target genes. Collectively, our results reveal a hitherto unknown role of mesenchymal IKKbeta in driving inflammation and enabling carcinogenesis in the intestine. PMID- 26621455 TI - The expression of CD44v6 in colon: from normal to malignant. AB - CD44v6, an integral transmembrane protein belonging to a family of adhesion molecule receptors, plays an important role in tumor growth, progression and metastasis. The purpose of this study was to evaluate the expression of CD44v6 in normal, hyperplastic, adenomatous, and malignant colonic epithelium and to determine its correlation with tumor pathologic stage and lymph node metastasis. We examined the immunohistochemical expression of CD44v6 in normal colonic tissue (n = 25), hyperplastic polyps (n = 45), tubular adenomas (n = 57), tubulovillous adenomas (n = 25), villous adenomas (n = 9), adenocarcinomas stage I (n = 26), adenocarcinomas stage III (n = 26), and lymph node metastasis (n = 26). The percentage of positive cells and the staining intensity were assessed and scored. Statistical analysis was performed using logistic regression and McNemar test. All normal colonic tissue and hyperplastic polyps showed CD44v6 staining confined to the base of the crypt. In tubular adenomas, the dysplastic surface adenomatous epithelium expressed CD44v6 in 49 (86%) cases. CD44v6 was expressed in the glandular areas of tubulovillous adenomas in 21 (84%) cases and in the villous portion in 18 (72%) cases. All villous adenomas expressed CD44v6. CD44v6 was expressed in 23 (88%) cases of stage I adenocarcinomas, in 24 (92%) cases of stage III adenocarcinomas, and in 9 (35%) cases of metastatic adenocarcinomas. We concluded that the gain of CD44v6 expression in premalignant and malignant colonic lesions suggests that CD44v6 may be functionally involved in the adenoma to-carcinoma progression. CD44v6 did not correlate to tumor pathologic stage and is lost during the acquisition of migratory function by metastatic tumor cells. PMID- 26621454 TI - Melanocyte antigen triggers autoimmunity in human psoriasis. AB - Psoriasis vulgaris is a common T cell-mediated inflammatory skin disease with a suspected autoimmune pathogenesis. The human leukocyte antigen (HLA) class I allele, HLA-C*06:02, is the main psoriasis risk gene. Epidermal CD8(+) T cells are essential for psoriasis development. Functional implications of HLA-C*06:02 and mechanisms of lesional T cell activation in psoriasis, however, remained elusive. Here we identify melanocytes as skin-specific target cells of an HLA C*06:02-restricted psoriatic T cell response. We found that a Valpha3S1/Vbeta13S1 T cell receptor (TCR), which we had reconstituted from an epidermal CD8(+) T cell clone of an HLA-C*06:02-positive psoriasis patient specifically recognizes HLA C*06:02-positive melanocytes. Through peptide library screening, we identified ADAMTS-like protein 5 (ADAMTSL5) as an HLA-C*06:02-presented melanocytic autoantigen of the Valpha3S1/Vbeta13S1 TCR. Consistent with the Valpha3S1/Vbeta13S1-TCR reactivity, we observed numerous CD8(+) T cells in psoriasis lesions attacking melanocytes, the only epidermal cells expressing ADAMTSL5. Furthermore, ADAMTSL5 stimulation induced the psoriasis signature cytokine, IL-17A, in CD8(+) T cells from psoriasis patients only, supporting a role as psoriatic autoantigen. This unbiased analysis of a TCR obtained directly from tissue-infiltrating CD8(+) T cells reveals that in psoriasis HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation. We propose that HLA-C*06:02 may predispose to psoriasis via this newly identified autoimmune pathway. PMID- 26621456 TI - Anti-Glomerular Basement Membrane Disease Combined with IgA Nephropathy Complicated with Reversible Posterior Leukoencephalopathy Syndrome: An Unusual Case. AB - BACKGROUND: Anti-glomerular basement membrane disease (anti-GBM disease) is an autoimmune glomerulonephritis disease that is characterized by IgG linear deposition along the non-collagen domain of a3 chains of type IV collagen on the GBM. Although anti-GBM disease accompanied with IgA linear deposition along GBMs was discussed previously in some papers, anti-GBM disease combined with IgA granular deposition in the mesangial area, especially complicated with reversible posterior leukoencephalopathy syndrome (RPLS), was rarely reported. RPLS is usually caused by hypertensive encephalopathy, renal decompensation, fluid retention, and adverse effects of immunosuppressive drugs. CASE REPORT: A male patient with the chief complaints of headache, gross hematuria, and nocturia was referred to our hospital. Based on renal biopsy, the diagnosis was finally confirmed as anti-GBM disease combined with IgA nephropathy and, the patient received comprehensive treatment, including cyclophosphamide (CTX), which led to symptom improvement. Two days after the third impulse CTX was given, he suddenly experienced headache and dizziness, which eventually developed into a tonic clonic seizure. RPLS was identified by cranial magnetic resonance imaging (MRI) with reversible neuroimaging. After diazepam and antihypertension management, seizures were controlled. RPLS, a neurological complication, was found in anti GBM disease with IgA nephropathy during our immunosuppressants therapy for the first time. CONCLUSIONS: It is worth paying more attention to patients with rapidly progressive glomerulonephritis (RPGN), as they might be complicated with RPLS during intravenous administration of CTX and methylprednisolone. We suggest the neuroimaging be examined as soon as the seizure happens. PMID- 26621457 TI - MicroRNAs regulate KDM5 histone demethylases in breast cancer cells. AB - MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Alteration of miRNA levels is common in tumors and contributes to the pathogenesis of human malignancies. In the present study we examined the role played by miR-137 in breast tumorigenesis. We found miR-137 levels to be lower in breast cancer cells than in their non-tumorigenic counterparts and observed reduced proliferation and migration of breast cancer cells overexpressing miR-137. We further identified KDM5B, a histone demethylase known to be involved in breast cancer tumorigenesis, as a target of miR-137. As the involvement of histone demethylases in cancer is still poorly understood and as the role of miRNAs in controlling epigenetic mechanisms in cancer is emerging, we broadened our study to the whole KDM5 histone demethylase family to see if the genes coding for these epigenetic enzymes might be regulated by miRNAs in cancer cells. We discovered that KDM5C is overexpressed in breast cancer cells, providing evidence that miR-138 regulates its expression. We found miR-138 overexpression to affect breast cancer cell proliferation. Altogether, our findings suggest that miRNAs may regulate KDM5 histone demethylase levels in breast cancer and thereby control breast cancer cell proliferation and migration. PMID- 26621458 TI - Molecular mechanisms of Tetranychus urticae chemical adaptation in hop fields. AB - The two-spotted spider mite, Tetranychus urticae Koch is a major pest that feeds on >1,100 plant species. Many perennial crops including hop (Humulus lupulus) are routinely plagued by T. urticae infestations. Hop is a specialty crop in Pacific Northwest states, where 99% of all U.S. hops are produced. To suppress T. urticae, growers often apply various acaricides. Unfortunately T. urticae has been documented to quickly develop resistance to these acaricides which directly cause control failures. Here, we investigated resistance ratios and distribution of multiple resistance-associated mutations in field collected T. urticae samples compared with a susceptible population. Our research revealed that a mutation in the cytochrome b gene (G126S) in 35% tested T. urticae populations and a mutation in the voltage-gated sodium channel gene (F1538I) in 66.7% populations may contribute resistance to bifenazate and bifenthrin, respectively. No mutations were detected in Glutamate-gated chloride channel subunits tested, suggesting target site insensitivity may not be important in our hop T. urticae resistance to abamectin. However, P450-mediated detoxification was observed and is a putative mechanism for abamectin resistance. Molecular mechanisms of T. urticae chemical adaptation in hopyards is imperative new information that will help growers develop effective and sustainable management strategies. PMID- 26621459 TI - Metagenomics as a Tool for Enzyme Discovery: Hydrolytic Enzymes from Marine Related Metagenomes. AB - This chapter discusses metagenomics and its application for enzyme discovery, with a focus on hydrolytic enzymes from marine metagenomic libraries. With less than one percent of culturable microorganisms in the environment, metagenomics, or the collective study of community genetics, has opened up a rich pool of uncharacterized metabolic pathways, enzymes, and adaptations. This great untapped pool of genes provides the particularly exciting potential to mine for new biochemical activities or novel enzymes with activities tailored to peculiar sets of environmental conditions. Metagenomes also represent a huge reservoir of novel enzymes for applications in biocatalysis, biofuels, and bioremediation. Here we present the results of enzyme discovery for four enzyme activities, of particular industrial or environmental interest, including esterase/lipase, glycosyl hydrolase, protease and dehalogenase. PMID- 26621460 TI - Investigating Bacterial Protein Synthesis Using Systems Biology Approaches. AB - Protein synthesis is essential for bacterial growth and survival. Its study in Escherichia coli helped uncover features conserved among bacteria as well as universally. The pattern of discovery and the identification of some of the longest-known components of the protein synthesis machinery, including the ribosome itself, tRNAs, and translation factors proceeded through many stages of successively more refined biochemical purifications, finally culminating in the isolation to homogeneity, identification, and mapping of the smallest unit required for performing the given function. These early studies produced a wealth of information. However, many unknowns remained. Systems biology approaches provide an opportunity to investigate protein synthesis from a global perspective, overcoming the limitations of earlier ad hoc methods to gain unprecedented insights. This chapter reviews innovative systems biology approaches, with an emphasis on those designed specifically for investigating the protein synthesis machinery in E. coli. PMID- 26621461 TI - Biology and Assembly of the Bacterial Envelope. AB - All free-living bacterial cells are delimited and protected by an envelope of high complexity. This physiological barrier is essential for bacterial survival and assures multiple functions. The molecular assembly of the different envelope components into a functional structure represents a tremendous biological challenge and is of high interest for fundamental sciences. The study of bacterial envelope assembly has also been fostered by the need for novel classes of antibacterial agents to fight the problematic of bacterial resistance to antibiotics. This chapter focuses on the two most intensively studied classes of bacterial envelopes that belong to the phyla Firmicutes and Proteobacteria. The envelope of Firmicutes typically has one membrane and is defined as being monoderm whereas the envelope of Proteobacteria contains two distinct membranes and is referred to as being diderm. In this chapter, we will first discuss the multiple roles of the bacterial envelope and clarify the nomenclature used to describe the different types of envelopes. We will then define the architecture and composition of the envelopes of Firmicutes and Proteobacteria while outlining their similarities and differences. We will further cover the extensive progress made in the field of bacterial envelope assembly over the last decades, using Bacillus subtilis and Escherichia coli as model systems for the study of the monoderm and diderm bacterial envelopes, respectively. We will detail our current understanding of how molecular machines assure the secretion, insertion and folding of the envelope proteins as well as the assembly of the glycosidic components of the envelope. Finally, we will highlight the topics that are still under investigation, and that will surely lead to important discoveries in the near future. PMID- 26621462 TI - Comparative Genomics and Evolutionary Modularity of Prokaryotes. AB - The soaring number of high-quality genomic sequences has ushered in the era of post-genomic research where our understanding of organisms has dramatically shifted towards defining the function of genes within their larger biological contexts. As a result, novel high-throughput experimental technologies are being increasingly employed to uncover physical and functional associations of genes and proteins in complex biological processes. Through the construction and analysis of physical, genetic and metabolic networks generated for the model organisms, such as Escherichia coli, organizational principles of the genome have been deduced, such as modularity, which has important implications toward understanding prokaryotic evolution and adaptation to novel lifestyles. PMID- 26621463 TI - Predicting Functional Interactions Among Genes in Prokaryotes by Genomic Context. AB - Genomic context methods for finding functions of unannotated genes were implemented very early after the publication of the first few prokaryotic genomes. The ideas behind these methods include gene fusions, conservation of gene adjacency, and the patters of co-occurrence of genes across available genomes. A later addition was the prediction of features related to functional organization, such as operons, stretches of genes co-transcribed into a single messenger RNA. The ideas behind these methods tend to be easy to understand, while the strategies for transforming those basic ideas into predictions can vary in complexity, mostly because genes whose products are known to functionally interact vary in the way they relate to those basic ideas. We present here a view of genomic context methods for predicting functional interactions, with simple examples of their implementation as compared and evaluated using genes whose products are known to functionally interact. PMID- 26621464 TI - Functional Implications of Domain Organization Within Prokaryotic Rhomboid Proteases. AB - Intramembrane proteases are membrane embedded enzymes that cleave transmembrane substrates. This interesting class of enzyme and its water mediated substrate cleavage mechanism occurring within the hydrophobic lipid bilayer has drawn the attention of researchers. Rhomboids are a family of ubiquitous serine intramembrane proteases. Bacterial forms of rhomboid proteases are mainly composed of six transmembrane helices that are preceded by a soluble N-terminal domain. Several crystal structures of the membrane domain of the E. coli rhomboid protease ecGlpG have been solved. Independently, the ecGlpG N-terminal cytoplasmic domain structure was solved using both NMR and protein crystallography. Despite these structures, we still do not know the structure of the full-length protein, nor do we know the functional role of these domains in the cell. This chapter will review the structural and functional roles of the different domains associated with prokaryotic rhomboid proteases. Lastly, we will address questions remaining in the field. PMID- 26621465 TI - Mapping Transcription Regulatory Networks with ChIP-seq and RNA-seq. AB - Bacterial genomes encode numerous transcription factors, DNA-binding proteins that regulate transcription initiation. Identifying the regulatory targets of transcription factors is a major challenge of systems biology. Here I describe the use of two genome-scale approaches, ChIP-seq and RNA-seq, that are used to map transcription factor regulons. ChIP-seq maps the association of transcription factors with DNA, and RNA-seq determines changes in RNA levels associated with transcription factor perturbation. I discuss the strengths and weaknesses of these and related approaches, and I describe how ChIP-seq and RNA-seq can be combined to map individual transcription factor regulons and entire regulatory networks. PMID- 26621466 TI - Quantitative and Systems-Based Approaches for Deciphering Bacterial Membrane Interactome and Gene Function. AB - High-throughput genomic and proteomic methods provide a concise description of the molecular constituents of a cell, whereas systems biology strives to understand the way these components function as a whole. Recent developments, such as genome editing technologies and protein epitope-tagging coupled with high sensitivity mass-spectrometry, allow systemic studies to be performed at an unprecedented scale. Available methods can be successfully applied to various goals, both expanding fundamental knowledge and solving applied problems. In this review, we discuss the present state and future of bacterial cell envelope interactomics, with a specific focus on host-pathogen interactions and drug target discovery. Both experimental and computational methods will be outlined together with examples of their practical implementation. PMID- 26621467 TI - Toward Network Biology in E. coli Cell. AB - E. coli has been a critically important model research organism for more than 50 years, particularly in molecular biology. In 1997, the E. coli draft genome sequence was published. Post-genomic techniques and resources were then developed that allowed E. coli to become a model organism for systems biology. Progress made since publication of the E. coli genome sequence will be summarized. PMID- 26621468 TI - Genetic Interaction Scoring Procedure for Bacterial Species. AB - A genetic interaction occurs when the phenotype of an organism carrying two mutant genes differs from what should have been observed given their independent influence. Such unexpected outcome indicates a mechanistic connection between the perturbed genes, providing a key source of functional information about the cell. Large-scale screening for genetic interactions involves measuring phenotypes of single and double mutants, which for microorganisms is usually done by automated analysis of images of ordered colonies. Obtaining accurate colony sizes, and using them to identify genetic interactions from such screens remains a challenging and time-consuming task. Here, we outline steps to compute genetic interaction scores in E. coli by measuring colony sizes from plate images, performing normalisation, and quantifying the strength of the effect. PMID- 26621469 TI - Mapping the Protein-Protein Interactome Networks Using Yeast Two-Hybrid Screens. AB - The yeast two-hybrid system (Y2H) is a powerful method to identify binary protein protein interactions in vivo. Here we describe Y2H screening strategies that use defined libraries of open reading frames (ORFs) and cDNA libraries. The array based Y2H system is well suited for interactome studies of small genomes with an existing ORFeome clones preferentially in a recombination based cloning system. For large genomes, pooled library screening followed by Y2H pairwise retests may be more efficient in terms of time and resources, but multiple sampling is necessary to ensure comprehensive screening. While the Y2H false positives can be efficiently reduced by using built-in controls, retesting, and evaluation of background activation; implementing the multiple variants of the Y2H vector systems is essential to reduce the false negatives and ensure comprehensive coverage of an interactome. PMID- 26621470 TI - Biogenesis of Escherichia coli DMSO Reductase: A Network of Participants for Protein Folding and Complex Enzyme Maturation. AB - Protein folding and structure have been of interest since the dawn of protein chemistry. Following translation from the ribosome, a protein must go through various steps to become a functional member of the cellular society. Every protein has a unique function in the cell and is classified on this basis. Proteins that are involved in cellular respiration are the bioenergetic workhorses of the cell. Bacteria are resilient organisms that can survive in diverse environments by fine tuning these workhorses. One class of proteins that allow survival under anoxic conditions are anaerobic respiratory oxidoreductases, which utilize many different compounds other than oxygen as its final electron acceptor. Dimethyl sulfoxide (DMSO) is one such compound. Respiration using DMSO as a final electron acceptor is performed by DMSO reductase, converting it to dimethyl sulfide in the process. Microbial respiration using DMSO is reviewed in detail by McCrindle et al. (Adv Microb Physiol 50:147-198, 2005). In this chapter, we discuss the biogenesis of DMSO reductase as an example of the participant network for complex iron-sulfur molybdoenzyme maturation pathways. PMID- 26621471 TI - Microbial Proteome Profiling and Systems Biology: Applications to Mycobacterium tuberculosis. AB - Each year, 1.3 million people die from tuberculosis, an infectious disease caused by Mycobacterium tuberculosis. Systems biology-based strategies might significantly contribute to the knowledge-guided development of more effective vaccines and drugs to prevent and cure infectious diseases. To build models simulating the behaviour of a system in response to internal or external stimuli and to identify potential targets for therapeutic intervention, systems biology approaches require the acquisition of quantitative molecular profiles on many perturbed states. Here we review the current state of proteomic analyses in Mycobacterium tuberculosis and discuss the potential of recently emerging targeting mass spectrometry-based techniques which enable fast, sensitive and accurate protein measurements. PMID- 26621472 TI - Structural Aspects of Bacterial Outer Membrane Protein Assembly. AB - The outer membrane of Gram-negative bacteria is predominantly populated by beta Barrel proteins and lipid anchored proteins that serve a variety of biological functions. The proper folding and assembly of these proteins is essential for bacterial viability and often plays a critical role in virulence and pathogenesis. The beta-barrel assembly machinery (Bam) complex is responsible for the proper assembly of beta-barrels into the outer membrane of Gram-negative bacteria, whereas the localization of lipoproteins (Lol) system is required for proper targeting of lipoproteins to the outer membrane. PMID- 26621473 TI - Substrate Interaction Networks of the Escherichia coli Chaperones: Trigger Factor, DnaK and GroEL. AB - In the dense cellular environment, protein misfolding and inter-molecular protein aggregation compete with protein folding. Chaperones associate with proteins to prevent misfolding and to assist in folding to the native state. In Escherichia coli, the chaperones trigger factor, DnaK/DnaJ/GrpE, and GroEL/ES are the major chaperones responsible for insuring proper de novo protein folding. With multitudes of proteins produced by the bacterium, the chaperones have to be selective for their substrates. Yet, chaperone selectivity cannot be too specific. Recent biochemical and high-throughput studies have provided important insights highlighting the strategies used by chaperones in maintaining proteostasis in the cell. Here, we discuss the substrate networks and cooperation among these protein folding chaperones. PMID- 26621474 TI - Genetic, Biochemical, and Structural Analyses of Bacterial Surface Polysaccharides. AB - Surface polysaccharides are an often essential component of the outer surface of bacteria. They may serve to protect organisms from harsh environmental conditions and to increase virulence. The focus of this review will be to introduce polysaccharide biosynthesis and export from the cell, and the associated techniques used to determine these glycostructures. Protein interactions and proteomics will then be discussed while introducing systems biology approaches used to determine protein-protein and protein-polysaccharide interactions. The final section will address related screening methods used to study gene regulation in bacteria relating to polysaccharide gene clusters and their associated regulators. The goal of this review will be to highlight key studies that have increased our knowledge of glycobiology and discuss novel methods that examine this field at the cellular level using systems biology. PMID- 26621476 TI - Nutritional Value of electron beam irradiated cottonseed meal in broiler chickens. AB - This study was conducted to evaluate the effect of electron beam-irradiated cottonseed meal on performance, carcass characteristics and some blood parameters of broiler chicks. Treatments were cottonseed meal (CSM) at levels of 12% and 24% (raw and irradiated at 30 kGy) and corn-soya bean meal diet (as control, without CSM and without irradiation) that used with five dietary treatments, four replicates and 10 birds of each for 42 days in completely randomized design. Feed intake (FI) and body weight gain (BWG) were recorded weekly. At 42 days of age, two birds per pen were randomly selected for the determination of carcass characteristics and blood parameters. BWG decreased with increasing levels of dietary CSM during the experiment (p < 0.05). In addition, radiation had significant positive effect in broilers fed 12% compared with those fed 24% CSM. FI in chicks fed control and diet containing 24% CSM were increased significantly in starter period. But FI was significantly decreased in broilers consumed CSM compare to the control in grower and during the experiment. Feed conversion ratio (FCR) increased with increasing levels of CSM in the diets. Relative weights of liver, gastrointestinal tract (GI), pancreas, gizzard and abdominal fat were increased by increasing levels of CSM in the diet (p < 0.05). Glucose, cholesterol, HDL, triglyceride and phosphorous concentrations increased, and LDL concentration decreased as the dietary CSM levels increased (p < 0.05). But radiation had not significant effect on blood parameters. Electron irradiation seems to be a good procedure to improve the nutritional quality of CSM, but it seems higher dose of it was needed to improve performance of chickens. PMID- 26621475 TI - Acetoacetate promotes the formation of fluorescent advanced glycation end products (AGEs). AB - Acetoacetate (AA) is an important ketone body, which produces reactive oxygen species (ROS). Advanced glycation end products (AGEs) are defined as final products of glycation process whose production is influenced by the levels of ROS. The accumulation of AGEs in the body contributes to pathogenesis of many diseases including complications of diabetes, and Alzheimer's and Parkinson's disease. Here, we evaluated the impact of AA on production of AGEs upon incubation of human serum albumin (HSA) with glucose. The effect of AA on the AGEs formation of HSA was studied under physiological conditions after incubation with glucose for 35 days. The physical techniques including circular dichroism (CD) and fluorescence spectroscopy were used to assess the impact of AA on formation and structural changes of glycated HSA (GHSA). Our results indicated that the secondary and tertiary structural changes of GHSA were increased in the presence of AA. The fluorescence intensity measurements of AGEs also showed an increase in AGEs formation. Acetoacetate has an activator effect in formation of AGEs through ROS production. The presence of AA may result in enhanced glycation in the presence of glucose and severity of complications associated with accumulation of AGEs. PMID- 26621477 TI - Dengue NS1 antigen contributes to disease severity by inducing interleukin (IL) 10 by monocytes. AB - Both dengue NS1 antigen and serum interleukin (IL)-10 levels have been shown to associate with severe clinical disease in acute dengue infection, and IL-10 has also been shown to suppress dengue-specific T cell responses. Therefore, we proceeded to investigate the mechanisms by which dengue NS1 contributes to disease pathogenesis and if it is associated with altered IL-10 production. Serum IL-10 and dengue NS1 antigen levels were assessed serially in 36 adult Sri Lankan individuals with acute dengue infection. We found that the serum IL-10 levels correlated positively with dengue NS1 antigen levels (Spearman's r = 0.47, P < 0.0001), and NS1 also correlated with annexin V expression by T cells in acute dengue (Spearman's r = 0.63, P = 0.001). However, NS1 levels did not associate with the functionality of T cell responses or with expression of co-stimulatory molecules. Therefore, we further assessed the effect of dengue NS1 on monocytes and T cells by co-culturing primary monocytes and peripheral blood mononuclear cells (PBMC), with varying concentrations of NS1 for up to 96 h. Monocytes co cultured with NS1 produced high levels of IL-10, with the highest levels seen at 24 h, and then declined gradually. Therefore, our data show that dengue NS1 appears to contribute to pathogenesis of dengue infection by inducing IL-10 production by monocytes. PMID- 26621479 TI - Clinical anatomy of the subserous layer: An amalgamation of gross and clinical anatomy. AB - The 1998 edition of Terminologia Anatomica introduced some currently used clinical anatomical terms for the pelvic connective tissue or subserous layer. These innovations persuaded the present author to consider a format in which the clinical anatomical terms could be reconciled with those of gross anatomy and incorporated into a single anatomical glossary without contradiction or ambiguity. Specific studies on the subserous layer were undertaken on 79 Japanese women who had undergone surgery for uterine cervical cancer, and on 26 female cadavers that were dissected, 17 being formalin-fixed and 9 fresh. The results were as follows: (a) the subserous layer could be segmentalized by surgical dissection in the perpendicular, horizontal and sagittal planes; (b) the segmentalized subserous layer corresponded to 12 cubes, or ligaments, of minimal dimension that enabled the pelvic organs to be extirpated; (c) each ligament had a three-dimensional (3D) structure comprising craniocaudal, mediolateral, and dorsoventral directions vis-a-vis the pelvic axis; (d) these 3D-structured ligaments were encoded morphologically in order of decreasing length; and (e) using these codes, all the surgical procedures for 19th century to present-day radical hysterectomy could be expressed symbolically. The establishment of clinical anatomical terms, represented symbolically through coding as demonstrated in this article, could provide common ground for amalgamating clinical anatomy with gross anatomy. Consequently, terms in clinical anatomy and gross anatomy could be reconciled and compiled into a single anatomical glossary. PMID- 26621478 TI - Autocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic effects. AB - Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists have emerged as treatment options for type 2 diabetes mellitus (T2DM). GLP-1R signals through G protein-dependent, and G-protein-independent pathways by engaging the scaffold protein beta-arrestin; preferential signalling of ligands through one or the other of these branches is known as 'ligand bias'. Here we report the discovery of the potent and selective GLP-1R G-protein-biased agonist, P5. We identified P5 in a high-throughput autocrine-based screening of large combinatorial peptide libraries, and show that P5 promotes G-protein signalling comparable to GLP-1 and Exendin-4, but exhibited a significantly reduced beta-arrestin response. Preclinical studies using different mouse models of T2DM demonstrate that P5 is a weak insulin secretagogue. Nevertheless, chronic treatment of diabetic mice with P5 increased adipogenesis, reduced adipose tissue inflammation as well as hepatic steatosis and was more effective at correcting hyperglycaemia and lowering haemoglobin A1c levels than Exendin-4, suggesting that GLP-1R G-protein-biased agonists may provide a novel therapeutic approach to T2DM. PMID- 26621480 TI - Partial Gland Ablation for Prostate Cancer: Report of a Food and Drug Administration, American Urological Association, and Society of Urologic Oncology Public Workshop. AB - OBJECTIVE: To summarize the discussion that took place at a public workshop, co sponsored by the U.S. Food and Drug Administration, the American Urological Association, and Society of Urologic Oncology reviewing the current state of the art for partial gland ablation (PGA) for the management of patients with prostate cancer. The purpose of this workshop was to discuss potential indications, current available evidence, and designs for future trials to provide the evidence needed by patients and providers to decide how and when to use PGA. METHODS: A workshop evaluating PGA for prostate cancer was held in New Orleans, Louisiana, in May 2015. Invited experts representing all stakeholders and attendees discussed the regulatory development of medical products, technology available, potential indications, and designs of trials to evaluate this modality of therapy. RESULTS: The panel presented the current information on the technologies available to perform PGA, the potential indications, and results of prior consensus conferences. Use of magnetic resonance imaging for patient selection, guide therapy, and follow-up was discussed. Designs of trials to assess PGA outcomes were discussed. CONCLUSION: The general consensus was that currently available technologies are capable of selective ablation with reasonable accuracy, but that criteria for patient selection remain debatable, and long-term cancer control remains to be established in properly designed and well-performed prospective clinical trials. Concerns include the potential for excessive, unnecessary use in patients with low-risk cancer and, conversely, that current diagnostic techniques may underestimate the extent and aggressiveness of some cancers, leading to inadequate treatment. PMID- 26621481 TI - Polyethylene glycol marker measured with NIRS gives a reliable estimate of the rangeland intake of grazing sheep. AB - Polyethylene glycol (PEG) measured with NIRS is known to be a valuable faecal marker when used in indoor experiments. In order to verify whether it can be used at pasture, an experiment was conducted with two trials. In trial 1, six Romane breed adult dry ewes placed in metabolism cages were fed daily with natural, freshly cut rangeland from a fertilised or unfertilised paddock for 6 weeks. Three ewes did not receive PEG and the three others were dosed with 10 g of PEG in solution form once daily until the end of the experiment to measure in vivo dry matter digestibility and PEG recovery rate for each forage quality. At the same time (trial 2), 15 ewe lambs and 14 lactating adult ewes suckling one or two lambs were allowed to graze together on the same herbage as that cut for indoor ewes. All animals were initially equipped with faecal bags emptied twice daily for collecting total faeces, and eight ewe lambs and seven adults were dosed once daily with 10 g of PEG. Faecal grab samples were collected for 4 to 5 days for each forage quality grazed. Indoor trial 1 showed that PEG had no effect on dry matter intake (DMI) or on digestibility. PEG recovery rates measured on fertilised (77.7%) and unfertilised (82.1%) forage were not different (P>0.05). PEG recovery rates measured at pasture did not differ (P>0.05) between pasture quality and animal type with an average value of 68.9%. Faecal output measured with bags or estimated with PEG and calculated DMI were not different (P>0.05) when PEG recovery rate measured at pasture was used. Conversely, using indoor PEG recovery values, significantly (P<0.05) or tended to overestimate faecal output. In conclusion, PEG could be used as a faecal marker administered at a minimal dose of 1% of DMI with a recovery rate measured under pasture conditions for pasture intake measurements on a group of animals at the same physiological stage but not for individual measurements. PMID- 26621482 TI - How comparable are rates of malignancies in patients with rheumatoid arthritis across the world? A comparison of cancer rates, and means to optimise their comparability, in five RA registries. AB - BACKGROUND: The overall incidence of cancer in patients with rheumatoid arthritis (RA) is modestly elevated. The extent to which cancer rates in RA vary across clinical cohorts and patient subsets, as defined by disease activity or treatment is less known but critical for understanding the safety of existing and new antirheumatic therapies. We investigated comparability of, and means to harmonise, malignancy rates in five RA registries from four continents. METHODS: Participating RA registries were Consortium of Rheumatology Researchers of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (SRR) (Sweden), Norfolk Arthritis Register (NOAR) (UK), CORRONA International (several countries) and Institute of Rheumatology, Rheumatoid Arthritis (IORRA) (Japan). Within each registry, we analysed a main cohort of all patients with RA from January 2000 to last available data, and sensitivity analyses of sub-cohorts defined by disease activity, treatment change, prior comorbidities and restricted by calendar time or follow-up, respectively. Malignancy rates with 95% CIs were estimated, and standardised for age and sex, based on the distributions from a typical RA clinical trial programme population (fostamatinib). RESULTS: There was a high consistency in rates for overall malignancy excluding non-melanoma skin cancer (NMSC), for malignant lymphomas, but not for all skin cancers, across registries, in particular following age/sex standardisation. Standardised rates of overall malignancy excluding NMSC varied from 0.56 to 0.87 per 100 person years. Within each registry, rates were generally consistent across sensitivity analyses, which differed little from the main analysis. CONCLUSION: In real-world RA populations, rates of both overall malignancy and of lymphomas are consistent. PMID- 26621484 TI - Response to: 'Heterogeneity, consistency and model fit should be assessed in Bayesian network meta-analysis' by Wei et al. PMID- 26621485 TI - CaO nanocrystals grown over SiO2 microtubes for efficient CO2 capture: organogel sets the platform. AB - Materials that can capture and store CO2 are important. Though CaO is a cheap sorbent, it is inefficient for practical purposes due to sintering and poor diffusion of CO2 through the surface-CaCO3 layer. We have developed a high performance, sintering-resistant CaO-based sorbent by uniformly nanofabricating the CaO nanocrystals on SiO2 microtubes made by organogel templated polymerization. PMID- 26621483 TI - Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis based on ANCA type. AB - OBJECTIVE: To evaluate whether the classification of patients with anti neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) according to ANCA type (anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) antibodies) predicts treatment response. METHODS: Treatment responses were assessed among patients enrolled in the Rituximab in ANCA-associated Vasculitis trial according to both AAV diagnosis (granulomatosis with polyangiitis (GPA)/microscopic polyangiitis (MPA)) and ANCA type (PR3-AAV/MPO-AAV). Complete remission (CR) was defined as disease activity score of 0 and successful completion of the prednisone taper. RESULTS: PR3-AAV patients treated with rituximab (RTX) achieved CR at 6 months more frequently than did those randomised to cyclophosphamide (CYC)/azathioprine (AZA) (65% vs 48%; p=0.04). The OR for CR at 6 months among PR3-AAV patients treated with RTX as opposed to CYC/AZA was 2.11 (95% CI 1.04 to 4.30) in analyses adjusted for age, sex and new-onset versus relapsing disease at baseline. PR3-AAV patients with relapsing disease achieved CR more often following RTX treatment at 6 months (OR 3.57; 95% CI 1.43 to 8.93), 12 months (OR 4.32; 95% CI 1.53 to 12.15) and 18 months (OR 3.06; 95% CI 1.05 to 8.97). No association between treatment and CR was observed in the MPO-AAV patient subset or in groups divided according to AAV diagnosis. CONCLUSIONS: Patients with PR3 AAV respond better to RTX than to CYC/AZA. An ANCA type-based classification may guide immunosuppression in AAV. TRIAL REGISTRATION NUMBER: NCT00104299; post results. PMID- 26621486 TI - Neuropeptide Y is a physiological substrate of fibroblast activation protein: Enzyme kinetics in blood plasma and expression of Y2R and Y5R in human liver cirrhosis and hepatocellular carcinoma. AB - Fibroblast activation protein (FAP) is a dipeptidyl peptidase (DPP) and endopeptidase that is weakly expressed in normal adult human tissues but is greatly up-regulated in activated mesenchymal cells of tumors and chronically injured tissue. The identities and locations of target substrates of FAP are poorly defined, in contrast to the related protease DPP4. This study is the first to characterize the physiological substrate repertoire of the DPP activity of endogenous FAP present in plasma. Four substrates, neuropeptide Y (NPY), peptide YY, B-type natriuretic peptide and substance P, were analyzed by mass spectrometry following proteolysis in human or mouse plasma, and by in vivo localization in human liver tissues with cirrhosis and hepatocellular carcinoma (HCC). NPY was the most efficiently cleaved substrate of both human and mouse FAP, whereas all four peptides were efficiently cleaved by endogenous DPP4, indicating that the in vivo degradomes of FAP and DPP4 differ. All detectable DPP specific proteolysis and C-terminal processing of these neuropeptides was attributable to FAP and DPP4, and plasma kallikrein, respectively, highlighting their combined physiological significance in the regulation of these neuropeptides. In cirrhotic liver and HCC, NPY and its receptor Y2R, but not Y5R, were increased in hepatocytes near the parenchymal-stromal interface where there is an opportunity to interact with FAP expressed on nearby activated mesenchymal cells in the stroma. These novel findings provide insights into the substrate specificity of FAP, which differs greatly from DPP4, and reveal a potential function for FAP in neuropeptide regulation within liver and cancer biology. PMID- 26621487 TI - Erratum to: The current landscape of television and movies in medical education. PMID- 26621488 TI - Guidelines: the do's, don'ts and don't knows of feedback for clinical education. AB - INTRODUCTION: The guidelines offered in this paper aim to amalgamate the literature on formative feedback into practical Do's, Don'ts and Don't Knows for individual clinical supervisors and for the institutions that support clinical learning. METHODS: The authors built consensus by an iterative process. Do's and Don'ts were proposed based on authors' individual teaching experience and awareness of the literature, and the amalgamated set of guidelines were then refined by all authors and the evidence was summarized for each guideline. Don't Knows were identified as being important questions to this international group of educators which if answered would change practice. The criteria for inclusion of evidence for these guidelines were not those of a systematic review, so indicators of strength of these recommendations were developed which combine the evidence with the authors' consensus. RESULTS: A set of 32 Do and Don't guidelines with the important Don't Knows was compiled along with a summary of the evidence for each. These are divided into guidelines for the individual clinical supervisor giving feedback to their trainee (recommendations about both the process and the content of feedback) and guidelines for the learning culture (what elements of learning culture support the exchange of meaningful feedback, and what elements constrain it?) CONCLUSION: Feedback is not easy to get right, but it is essential to learning in medicine, and there is a wealth of evidence supporting the Do's and warning against the Don'ts. Further research into the critical Don't Knows of feedback is required. A new definition is offered: Helpful feedback is a supportive conversation that clarifies the trainee's awareness of their developing competencies, enhances their self-efficacy for making progress, challenges them to set objectives for improvement, and facilitates their development of strategies to enable that improvement to occur. PMID- 26621491 TI - Beyond immune density: critical role of spatial heterogeneity in estrogen receptor-negative breast cancer. PMID- 26621489 TI - How computer simulations of the human heart can improve anti-arrhythmia therapy. AB - Over the last decade, the state-of-the-art in cardiac computational modelling has progressed rapidly. The electrophysiological function of the heart can now be simulated with a high degree of detail and accuracy, opening the doors for simulation-guided approaches to anti-arrhythmic drug development and patient specific therapeutic interventions. In this review, we outline the basic methodology for cardiac modelling, which has been developed and validated over decades of research. In addition, we present several recent examples of how computational models of the human heart have been used to address current clinical problems in cardiac electrophysiology. We will explore the use of simulations to improve anti-arrhythmic pacing and defibrillation interventions; to predict optimal sites for clinical ablation procedures; and to aid in the understanding and selection of arrhythmia risk markers. Together, these studies illustrate how the tremendous advances in cardiac modelling are poised to revolutionize medical treatment and prevention of arrhythmia. PMID- 26621492 TI - Analysis of temperature-mediated changes in the wine yeast Saccharomyces bayanus var uvarum. An oenological study of how the protein content influences wine quality. AB - Saccharomyces bayanus var. uvarum plays an important role in the fermentation of red wine from the D.O. Ribera del Duero. This is due to the special organoleptic taste that this yeast gives the wines and their ability to ferment at low temperature. To determine the molecular factors involved in the fermentation process at low temperature, a differential proteomic approach was performed by using 2D-DIGE, comparing, qualitatively and quantitatively, the profiles obtained at 13 and 25 degrees C. A total of 152 protein spots were identified. We detected proteins upregulated at 13 degrees C that were shown to be related to temperature stress, the production of aromatic compounds involved in the metabolism of amino acids, and the production of fusel alcohols and their derivatives, each of which is directly related to the quality of the wines. To check the temperature effects, an aromatic analysis by GC-MS was performed. The proteomic and "aromatomic" results are discussed in relation to the oenological properties of S. bayanus var. uvarum. PMID- 26621493 TI - True and Perceived Synchrony are Preferentially Associated With Particular Sensory Pairings. AB - Perception and behavior are fundamentally shaped by the integration of different sensory modalities into unique multisensory representations, a process governed by spatio-temporal correspondence. Prior work has characterized temporal perception using the point in time at which subjects are most likely to judge multisensory stimuli to be simultaneous (PSS) and the temporal binding window (TBW) over which participants are likely to do so. Here we examine the relationship between the PSS and the TBW within and between individuals, and within and between three sensory combinations: audiovisual, audiotactile and visuotactile. We demonstrate that TBWs correlate within individuals and across multisensory pairings, but PSSs do not. Further, we reveal that while the audiotactile and audiovisual pairings show tightly related TBWs, they also exhibit a differential relationship with respect to true and perceived multisensory synchrony. Thus, audiotactile and audiovisual temporal processing share mechanistic features yet are respectively functionally linked to objective and subjective synchrony. PMID- 26621494 TI - Neuropsychological and social cognitive function in young people at genetic risk of bipolar disorder. AB - BACKGROUND: Impairments in key neuropsychological domains (e.g. working memory, attention) and social cognitive deficits have been implicated as intermediate (endo) phenotypes for bipolar disorder (BD), and should therefore be evident in unaffected relatives. METHOD: Neurocognitive and social cognitive ability was examined in 99 young people (age range 16-30 years) with a biological parent or sibling diagnosed with the disorder [thus deemed to be at risk (AR) of developing BD], compared with 78 healthy control (HC) subjects, and 52 people with a confirmed diagnosis of BD. RESULTS: Only verbal intelligence and affective response inhibition were significantly impaired in AR relative to HC participants; the BD participants showed significant deficits in attention tasks compared with HCs. Neither AR nor BD patients showed impairments in general intellectual ability, working memory, visuospatial or language ability, relative to HC participants. Analysis of BD-I and BD-II cases separately revealed deficits in attention and immediate memory in BD-I patients (only), relative to HCs. Only the BD (but not AR) participants showed impaired emotion recognition, relative to HCs. CONCLUSIONS: Selective cognitive deficits in the capacity to inhibit negative affective information, and general verbal ability may be intermediate markers of risk for BD; however, the extent and severity of impairment in this sample was less pronounced than has been reported in previous studies of older family members and BD cases. These findings highlight distinctions in the cognitive profiles of AR and BD participants, and provide limited support for progressive cognitive decline in association with illness development in BD. PMID- 26621495 TI - Hypoxic preconditioning protects cardiomyocytes against hypoxia/reoxygenation induced cell apoptosis via sphingosine kinase 2 and FAK/AKT pathway. AB - Previous studies have demonstrated that hypoxic preconditioning (HPC) alleviates hypoxia/reoxygenation (H/R) injury. However, the impact and mechanism involved were not fully understood. This study aimed to evaluate the effect of HPC on H/R injury in cardiomyocytes and investigate the molecular mechanisms involved. In our study, primary neonatal rat cardiomyocytes were isolated and characterized by immunofluorescence staining. We established H/R models in vitro to mimic ischemia/reperfusion (I/R) injury in vivo. Primary cardiomyocytes were exposed to HPC and then subjected to H/R. SphK2 expression was determined by quantitative real-time PCR and Western blotting. Cell apoptosis was measured by Hoechst staining. H9c2 cells were transfected with SphK2 siRNA or pcDNA3.1-SphK2 plasmid. The transfection efficiency was evaluated 48h post-transfection. After H/R, cell apoptosis rate was determined by Annexin V-FITC/PI and caspase-3/-9 activity was measured. The activation of FAK/AKT pathway was evaluated by Western blotting. Our results showed that HPC significantly increased SphK2 expression in primary cardiomyocytes under normal or H/R condition and protected against H/R-induced cell apoptosis, whereas SphK2 inhibitor K145 abolished the cardioprotective effect of HPC. HPC markedly reduced the cell apoptosis rate of H9c2, decreased the activities of caspase-3 and -9 and increased p-FAK and p-AKT levels, which were reversed by SphK2 knockdown. Additionally, SphK2 overexpression exerted a similar effect with HPC on cell apoptosis and FAK/AKT. Inhibition of H9c2 cell apoptosis induced by HPC and SphK2 overexpression was abolished by PI3K/AKT inhibitor LY294002. These results indicate that HPC may protect cardiomyocytes against H/R injury via SphK2 and the downstream FAK/AKT signaling pathway. Our findings provided important evidences for the protective role of HPC in ameliorating myocardial H/R injury. PMID- 26621496 TI - Comparative evaluation of the GP5+/6+, MY09/11 and PGMY09/11 primer sets for HPV detection by PCR in oral squamous cell carcinomas. AB - The aim of this study was to evaluate the use of GP5+/6+, MY09/11 and PGMY09/11 primer sets for the detection of human papillomavirus (HPV) DNA by single step polymerase chain reaction (PCR) and nested PCR in formalin-fixed and paraffin embedded (FFPE) tissues from oral squamous cell carcinomas (OSCCs). DNA extracted from FFPE tissues were tested for amplification of the human beta globin gene with PCO3/4 primers. Positive samples for this gene were tested for HPV DNA using single step PCR with GP5+/6+, MY09/11 and PGMY09/11 primer sets. All negative samples at single step PCR with MY09/11 and PGMY09/11 were subjected to a further PCR with GP5+/6+ primers using the non-amplified product in the previously reactions (nested PCR) as samples. Among 26 samples, 23 were positive for the human beta globin gene and were considered viable for HPV DNA detection by PCR. Single step PCR with GP5+/6+ and MY09/11 primers and MY/GP+ nested PCR did not amplify HPV DNA in any samples. PGMY09/11 primers detected HPV DNA in 13.0% of OSCC cases and this rate was raise to 17.4% with the use of PGMY/GP+ nested PCR. According to our results the PGMY/GP+ nested PCR is the most appropriate primer set for the detection of HPV DNA using FFPE samples from OSCC. PMID- 26621497 TI - Tetranectin as a Potential Biomarker for Stable Coronary Artery Disease. AB - This cross-sectional study tested the hypothesis that decreased serum levels of tetranectin (TN), a regulator of the fibrinolysis and proteolytic system, is associated with the presence and severity of CAD. We conducted a systematic serological and immunohistochemical (IHC) analysis to respectively compare the TN levels in serum and artery samples in CAD patients and healthy controls. Our results showed that serum levels of TN were significantly lower in patients with CAD than in healthy controls. Further analysis via trend tests revealed that serum TN levels correlated with the number of diseased arteries. Besides, the multivariate logistic regression model revealed TN as an independent factor associated with the presence of CAD. Additionally, IHC analysis showed that TN expression was significantly higher in atherosclerotic arteries as compared to healthy control tissues. In conclusion, our study suggests that increased serum TN level is associated with the presence and severity of diseased coronary arteries in patients with stable CAD. PMID- 26621498 TI - Comparison of gut hormones and adipokines stimulated by glucagon test among patients with type II diabetes mellitus after metabolic surgery. AB - Laparoscopic Roux-en-Y gastric bypass (RYGB) achieves a higher remission of type 2 diabetes mellitus (T2DM) than laparoscopic sleeve gastrectomy (SG) in non morbidly obese patients. However, the mechanisms of the higher remission are unknown. To compare glucagon-provoked acute insulin responses, as well as changes of gut and pancreatic hormones and adipokines between patients with T2DM after RYGB and SG at one year post-operatively, a total of 14 RYGB and 13 SG patients were followed-up and evaluated for glucose metabolism, gut and pancreatic hormones, and adipokines. One year after surgery, 1-mg intravenous glucagon tests were performed. The differences in each hormone at different time points and the area under the curve (AUC) were compared between the two groups. Glucagon stimulated acute insulin responses were not different between the RYGB and SG groups, nor were they different between the remitters and non-remitters at one year after the metabolic surgery. Plasma des-acyl ghrelin and nesfatin-1 levels significantly decreased at 6 min after glucagon stimulation in the RYGB and SG groups, as well as in the remitters and non-remitters. The glucagon test did not affect intestinal hormones. Plasma resistin was suppressed after intravenous glucagon stimulation in both RYGB and SG groups. In conclusion, intravenous glucagon inhibited plasma levels of des-acyl ghrelin, nesfatin-1, and resistin in T2DM patients at one year after both RYGB and SG, whereas post-glucagon suppression of plasma obestatin and resistin was shown in the remitters but not in the non-remitters. PMID- 26621499 TI - Tunable Magnetization Dynamics in Interfacially Modified Ni81Fe19/Pt Bilayer Thin Film Microstructures. AB - Interface modification for control of ultrafast magnetic properties using low dose focused ion beam irradiation is demonstrated for bilayers of two technologically important materials: Ni81Fe19 and Pt. Magnetization dynamics were studied using an all-optical time-resolved magneto-optical Kerr microscopy method. Magnetization relaxation, precession, damping and the spatial coherence of magnetization dynamics were studied. Magnetization precession was fitted with a single-mode damped sinusoid to extract the Gilbert damping parameter. A systematic study of the damping parameter and frequency as a function of irradiation dose varying from 0 to 3.3 pC/MUm(2) shows a complex dependence upon ion beam dose. This is interpreted in terms of both intrinsic effects and extrinsic two-magnon scattering effects resulting from the expansion of the interfacial region and the creation of a compositionally graded alloy. The results suggest a new direction for the control of precessional magnetization dynamics, and open the opportunity to optimize high-speed magnetic devices. PMID- 26621501 TI - Cinacalcet-associated severe hypocalcemia resulting in torsades de pointes and cardiac arrest: a case for caution. PMID- 26621500 TI - Characterization of vasculogenic potential of human adipose-derived endothelial cells in a three-dimensional vascularized skin substitute. AB - PURPOSE: The need for clinically applicable skin substitutes continues to be a matter of fact. Hypothetically, a laboratory grown autologous skin analog with near normal architecture might be a suitable approach to yield both satisfactory functional and cosmetic long-term results. In this study, we explored the use of human endothelial cells derived from freshly isolated adipose stromal vascular fraction (SVF) in a three-dimensional (3D) co-culture model of vascularized bio engineered skin substitute. METHODS: The SVF was isolated from human white adipose tissue samples and keratinocytes from human skin biopsies. The SVF, in particular endothelial cells, were characterized using flow cytometry and immuofluorescence analysis. Endothelial and mesenchymal progenitors from the SVF formed blood capillaries after seeding into a 3D collagen type I hydrogel in vitro. Subsequently, human keratinocytes were seeded on the top of those hydrogels to develop a vascularized dermo-epidermal skin substitute. RESULTS: Flow cytometric analysis of surface markers of the freshly isolated SVF showed the expression of endothelial markers (CD31, CD34, CD146), mesenchymal/stromal cell-associated markers (CD44, CD73, CD90, CD105), stem cell markers (CD49f, CD117, CD133), and additionally hematopoietic markers (CD14, CD15, CD45). Further analysis of white adipose-derived endothelial cells (watECs) revealed the co expression of CD31, CD34, CD90, CD105, and partially CD146 on these cells. WatECs were separated from adipose-stromal cells (watASCs) using FACS sorting. WatASCs and watECs cultured separately in a 3D hydrogel for 3 weeks did not form any vascular structures. Only if co-cultured, both cell types aligned to develop a ramified vascular network in vitro with continuous endothelial lumen formation. Transplantation of those 3D-hydrogels onto immuno-incompetent rats resulted in a rapid connection of human capillaries with the host vessels and formation of functional, blood-perfused mosaic human-rat vessels within only 3-4 days. CONCLUSIONS: Adipose tissue represents an attractive cell source due to the ease of isolation and abundance of endothelial as well as mesenchymal cell lineages. Adipose-derived SVF cells exhibit the ability to form microvascular structures in vitro and support the accelerated blood perfusion in skin substitutes in vivo when transplanted. PMID- 26621502 TI - Anti-inflammatory effects of vicenin-2 and scolymoside on polyphosphate-mediated vascular inflammatory responses. AB - AIM AND OBJECTIVE: Recent results indicate that polyphosphate (polyP) released by human endothelial cells can function as a pro-inflammatory mediator. Cyclopia subternata is a medicinal plant commonly used in traditional medicine to relieve pain in biological processes. This study was undertaken to investigate whether two structurally related active compounds found in C. subternata, namely vicenin 2 and scolymoside, can modulate polyP-mediated inflammatory responses in human umbilical vein endothelial cells (HUVECs) and in mice. METHODS: The anti inflammatory activities of vicenin-2 and scolymoside were determined by measuring permeability, leukocytes adhesion and migration, and activation of pro inflammatory proteins in polyP-activated HUVECs and mice. In addition, the beneficial effects of vicenin-2 and scolymoside on survival rate in polyP injected mice were determined. RESULTS: We found that vicenin-2 and scolymoside inhibits polyP-mediated barrier disruption, the expressions of cell adhesion molecules, and leukocyte to HUVEC adhesion/migration. Interestingly, polyP induced NF-kappaB activation and the productions of TNF-alpha and IL-6 were inhibited by vicenin-2 and scolymoside in HUVECs. These anti-inflammatory functions of vicenin-2 and scolymoside were confirmed in polyP-injected mice. CONCLUSIONS: These results suggest that vicenin-2 and scolymoside have therapeutic potential for various systemic inflammatory diseases. PMID- 26621503 TI - HDAC9, TWIST1 and FERD3L gene expression in asymptomatic stable and unstable carotid plaques. AB - BACKGROUND AND OBJECTIVES: A variant located at the end of HDAC9 gene within clusters of DNAse I sensitivity zones and histone modification hotspots has been associated with large vessel stroke and could be linked to plaque instability. The aim of the study is to define if an altered expression of HDAC9, TWIST1 and FERD3L genes could be involved in plaque vulnerability. METHODS: Histological classification and gene expression analysis were performed in 6 stable and 16 unstable plaques obtained from asymptomatic patients undergoing endarterectomy. Gene expression was analysed by real-time PCR. RESULTS AND CONCLUSIONS: TWIST1 gene expression resulted higher in stable plaques (P < 0.02). HDAC9 gene expression followed a similar trend (P = 0.11). These results highlighting the significant correlation between TWIST and HDAC9 gene expression suggest that both genes may contribute to plaque stability in a coordinated way. PMID- 26621504 TI - CXCL16 upregulates RANKL expression in rheumatoid arthritis synovial fibroblasts through the JAK2/STAT3 and p38/MAPK signaling pathway. AB - OBJECTIVE: To explore the influence of chemokine, CXCL16, on the expression of the receptor activator nuclear factor kappaB ligand (RANKL) in rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLS). METHODS: The expression of CXCL16/CXCR6 and RANKL in RA or osteoarthritis (OA) patient synovia was examined by Western blot and immunohistochemistry. The serum concentration of CXCL16 and RANKL was measured by enzyme-linked immunosorbent assay (ELISA). RA-FLS were treated with recombinant CXCL16, and RANKL mRNA and protein were measured using PCR, Western blot and ELISA. RESULTS: The synovial expression of CXCL16, CXCR6, and RANKL was higher in RA patients than in patients with OA. The serum CXCL16 and RANKL levels were higher in RA patients compared with OA patients and healthy controls. CXCL16 correlated with erythrocyte sedimentation rate, C reactive protein, disease activity, serum rheumatoid factor, and RANKL. RA-FLS treated with CXCL16 showed markedly increased expression of RANKL. When STAT3 or p38 activation was blocked by an inhibitor, CXCL16 failed to upregulate RANKL expression. In contrast, inhibiting the Akt or Erk pathway did not achieve the same effect. CONCLUSIONS: CXCL16 upregulates RANKL expression in RA-FLS and these effects are mainly mediated by the JAK2/STAT3 and p38/MAPK signaling pathways. PMID- 26621505 TI - Surgical management of vascular anomalies in children at a tertiary care hospital in a resource-limited setting: a Tanzanian experience with 134 patients. AB - BACKGROUND: Vascular anomalies pose major diagnostic and therapeutic challenges among pediatricians and pediatric surgeons practicing in resource limited countries. There is paucity of published data regarding this subject in Tanzania and Bugando Medical Centre in particular. This study describes our experiences on the challenges and outcome of surgical management of childhood vascular anomalies in our environment. METHODS: Between January 2009 and December 2013, a prospective study on the surgical management of vascular anomalies was undertaken at Bugando Medical Centre. RESULTS: A total of 134 patients (M; F = 1:2.5) were studied. The median age at presentation was 6 years. Of the 134 patients, 101 (75.4%) were diagnosed as having vascular tumors and 33 (24.6%) had vascular malformations. The head and the neck were the most frequent anatomical site recorded as having a tumor (56.7% of patients). Out of 134 patients, 129 (96.3%) underwent surgical treatment. Failure to respond to non-operative treatment (86.8%), huge disfiguring/obstructing mass (4.7%), infection (3.1%), ulceration (3.1%) and hemorrhage (2.3%) were indications for surgical intervention. Tumor excision and primary wound closure was the most common type of surgical procedure performed in 80.6% of patients. Surgical site infection was the most frequent complications accounting for 33.8% of cases. Mortality rate was 1.5%. Tumor excision and primary wound closure gave better outcome compared with other surgical options (p < 0.001). Outcome of injection sclerotherapy in 3 (3.7%) children, serial ligation of feeder vessels employed in 2 (1.6%), and conservative treatment in 5 (3.7%), were poor and required conversion to surgical excision. Despite low mortality rate recorded in this study, but ugly scar, 14 (20.6%) and limb deformity, 6 (8.8%) were problems. The overall result of surgical treatment at the end of follow up period was excellent in 108 (87.1%) patients. CONCLUSION: Surgical excision and primary wound closure gave good outcome which could be employed in complicated and vascular anomalies which failed to respond to other treatment in regions with limited resources. PMID- 26621507 TI - Unmet Needs of Asian American and Pacific Islander Cancer Survivors. AB - In the USA, cancer is the leading cause of death for Asian Americans and Pacific Islanders (AAPIs), but little is known about the unmet needs of AAPI cancer survivors, especially from a national perspective. Using a community-based participatory research approach, we partnered with the Asian and Pacific Islander National Cancer Survivors Network and the Asian American Cancer Support Network to design and conduct a cross-sectional survey to understand the unmet needs of a national sample of AAPI cancer survivors. We assessed unmet needs in 10 domains: day-to-day activities, financial expenses, emotional concerns, medical treatment, cancer information, home care, nutrition, physical concerns, family relationships, and spirituality. We also assessed self-reported measures related to quality of life. This national sample of AAPI cancer survivors included people from 14 states and two territories who had been diagnosed with a broad range of cancers, including cancer of the breast, ovary/uterus/cervix, prostate, blood, and other sites. Over 80 % reported at least one unmet need. Participants reported an average of 8.4 unmet needs, spanning an average of 3.9 domains. Most commonly reported were unmet needs pertaining to physical concerns (66 %), day-to day activities (52 %), and emotional concerns (52 %). This is the first report of unmet needs in a national sample of AAPI cancer survivors with a range of different cancer types. It describes the areas of greatest need and points to the importance of devoting more resources to identifying and addressing unmet needs for the underserved population of AAPI cancer survivors. PMID- 26621509 TI - Depression and anxiety in ovarian cancer: a systematic review and meta-analysis of prevalence rates. AB - OBJECTIVES: To systematically review the literature pertaining to the prevalence of depression and anxiety in patients with ovarian cancer as a function of treatment stage. DESIGN: Systematic review and meta-analysis. PARTICIPANTS: 3623 patients with ovarian cancer from primary research investigations. PRIMARY OUTCOME MEASURE: The prevalence of depression and anxiety in patients with ovarian cancer as a function of treatment stage. RESULTS: We identified 24 full journal articles that met the inclusion criteria for entry into the meta-analysis resulting in a pooled sample size of 3623 patients. The meta-analysis of prevalence rates identified pretreatment, on-treatment and post-treatment depression prevalences of 25.34% (CI 22.79% to 28.07%), 22.99% (CI 19.85% to 26.46%) and 12.71% (CI 10.14% to 15.79%), respectively. Pretreatment, on treatment and post-treatment anxiety prevalences were 19.12% (CI 17.11% to 21.30%), 26.23% (CI 22.30% to 30.56%) and 27.09% (CI 23.10% to 31.49%). CONCLUSIONS: Our findings suggest that the prevalence of depression and anxiety in women with ovarian cancer, across the treatment spectrum, is significantly greater than in the healthy female population. With the growing emphasis on improving the management of survivorship and quality of life, we conclude that further research is warranted to ensure psychological distress in ovarian cancer is not underdiagnosed and undertreated. PMID- 26621508 TI - Management of prostate cancer patients following radiation therapy after radical surgery referred from urology to radiation oncology departments in Spain. AB - PURPOSE: To define usual clinical management of prostate cancer (PCa) patients following postoperative radiation therapy (RT) (adjuvant or salvage) and its evolution over time in radiation oncology (RO) departments in Spain. METHODS: An epidemiological, cross-sectional, multicentre study was conducted. 567 PCa patients that had undergone radical prostatectomy (RP) and received postoperative RT between February and December of both 2006 and 2011 participated in the study. In patients from 2006, health-related quality of life (HRQoL) was assessed using the EPIC questionnaire. Investigators completed a specific survey on two clinical cases of adjuvant and salvage RT. RESULTS: 70.6 % of patients received salvage RT versus 29.4 % who received adjuvant RT; no significant differences were found in terms of frequency for each procedure between both the years. Regarding the survey, a positive surgical margin was the main criteria used in adjuvant RT decision making. In terms of salvage RT scenario, 85.7 % of the investigators stated that adjuvant RT should have been offered instead, 81.4 % of the investigators agreed on a PSA score >0.2 ng/mL as the main criteria for identifying biochemical recurrence after RP, and 67.4 % of investigators did not consider any PSA score for ruling out salvage RT treatment. CONCLUSIONS: Most patients are referred to RO departments to receive salvage RT. Despite the publication of three IA evidence level randomized clinical trials, the patterns for using adjuvant and salvage RT did not change from 2006 to 2011, although patients' profile did. A consensus regarding postoperative RT indications should be reached in order to correct this controversial situation. PMID- 26621510 TI - Recorded gonorrhoea rates in Denmark, 1900-2010: the impact of clinical testing activity and laboratory diagnostic procedures. AB - OBJECTIVES: Assessment of the relations between recorded gonorrhoea rates and clinical testing activity and disposable diagnostic tests. METHODS: In Denmark, two sources of information on the epidemiology of gonorrhoea are available: (1) a mandatory clinical notification system (since 1867) comprising summary information about geographic distribution, season, age group and gender; in 1994, more detailed anonymous individualised epidemiological information was included; (2) a voluntary countrywide laboratory surveillance system for culture-confirmed cases (since 1957) comprising information about patient's age and gender, infected anatomical sites and medical setting attended. RESULTS: Both surveillance systems showed marked simultaneous changes in gonorrhoea rates, although periodically considerable under-reporting or under-diagnosing was demonstrated. The annual incidence of notified cases peaked in 1919 (474/100,000), in 1944 (583/100,000) and in 1972 (344/100,000). Since 1995, the incidence has been at a low endemic level (1.5-10/100,000) and the total male/female incidence ratios were from 3 to 7 times higher than previously recorded. Among approximately 2 million persons tested during 1974-1988 78,213 men and 63,143 women with culture-confirmed gonorrhoea were identified. During this period, pharyngeal sampling was performed in 36% of men and 25% of women with gonorrhoea; pharyngeal gonorrhoea was found in 10% and 16%, respectively; 40% and 30% of these patients had no concomitant urogenital gonorrhoea. Among men with gonorrhoea, 34% were sampled from the rectum; 9% had rectal gonorrhoea, among whom the rectum was the only infected site in 67%. CONCLUSIONS: Crucial factors for case finding are clinical sampling tradition and appropriate laboratory diagnostic facilities. When case finding is insufficient, a reservoir of asymptomatic rectal or pharyngeal gonorrhoea remains unrecognised. PMID- 26621506 TI - Altered machinery of protein synthesis is region- and stage-dependent and is associated with alpha-synuclein oligomers in Parkinson's disease. AB - INTRODUCTION: Parkinson's disease (PD) is characterized by the accumulation of abnormal alpha-synuclein in selected regions of the brain following a gradient of severity with disease progression. Whether this is accompanied by globally altered protein synthesis is poorly documented. The present study was carried out in PD stages 1-6 of Braak and middle-aged (MA) individuals without alterations in brain in the substantia nigra, frontal cortex area 8, angular gyrus, precuneus and putamen. RESULTS: Reduced mRNA expression of nucleolar proteins nucleolin (NCL), nucleophosmin (NPM1), nucleoplasmin 3 (NPM3) and upstream binding transcription factor (UBF), decreased NPM1 but not NPM3 nucleolar protein immunostaining in remaining neurons; diminished 18S rRNA, 28S rRNA; reduced expression of several mRNAs encoding ribosomal protein (RP) subunits; and altered protein levels of initiation factor eIF3 and elongation factor eEF2 of protein synthesis was found in the substantia nigra in PD along with disease progression. Although many of these changes can be related to neuron loss in the substantia nigra, selective alteration of certain factors indicates variable degree of vulnerability of mRNAs, rRNAs and proteins in degenerating sustantia nigra. NPM1 mRNA and 18S rRNA was increased in the frontal cortex area 8 at stage 5-6; modifications were less marked and region-dependent in the angular gyrus and precuneus. Several RPs were abnormally regulated in the frontal cortex area 8 and precuneus, but only one RP in the angular gyrus, in PD. Altered levels of eIF3 and eIF1, and decrease eEF1A and eEF2 protein levels were observed in the frontal cortex in PD. No modifications were found in the putamen at any time of the study except transient modifications in 28S rRNA and only one RP mRNA at stages 5-6. These observations further indicate marked region-dependent and stage-dependent alterations in the cerebral cortex in PD. Altered solubility and alpha-synuclein oligomer formation, assessed in total homogenate fractions blotted with anti alpha-synuclein oligomer-specific antibody, was demonstrated in the substantia nigra and frontal cortex, but not in the putamen, in PD. Dramatic increase in alpha-synuclein oligomers was also seen in fluorescent-activated cell sorter (FACS)-isolated nuclei in the frontal cortex in PD. CONCLUSIONS: Altered machinery of protein synthesis is altered in the substantia nigra and cerebral cortex in PD being the frontal cortex area 8 more affected than the angular gyrus and precuneus; in contrast, pathways of protein synthesis are apparently preserved in the putamen. This is associated with the presence of alpha-synuclein oligomeric species in total homogenates; substantia nigra and frontal cortex are enriched, albeit with different band patterns, in alpha-synuclein oligomeric species, whereas alpha-synuclein oligomers are not detected in the putamen. PMID- 26621511 TI - Incidence of knee cartilage surgery in Norway, 2008-2011. AB - OBJECTIVE: A systematic and long-term data collection on the treatment of focal cartilage defects (FCDs) of the knee is needed. This can be achieved through the foundation of a National Knee Cartilage Defect Registry. The aim of this study was to establish the nationwide burden of knee cartilage surgery, defined as knee surgery in patients with an FCD. We also aimed to identify any geographical differences in incidence rates, patient demographics or trends within this type of surgery. SETTING: A population-based study with retrospective identification of patients undergoing knee cartilage surgery in Norway through a mandatory public health database from 2008 to 2011. PARTICIPANTS: We identified all patients undergoing cartilage surgery, or other knee surgery in patients with an FCD. All eligible surgeries were assessed for inclusion on the basis of certain types of ICD-10 and NOMESKO Classification of Surgical Procedures codes. PRIMARY AND SECONDARY OUTCOME MEASURES: The variables were diagnostic and surgical codes, geographic location of the performing hospital, age and sex of the patients. Yearly incidence and incidence rates were calculated. Age-adjusted incidences for risk ratios and ORs between geographical areas were also calculated. RESULTS: A total of 10,830 cases of knee cartilage surgery were identified, with slight but significant decreases from 2008 to 2011 (p<0.0003). The national incidence rate was 56/100 000 inhabitants and varied between regions, counties and hospitals. More than 50% of the procedures were palliative and nearly 400 yearly procedures were reparative or restorative. CONCLUSIONS: Knee cartilage surgery is common in Norway, counting 2500 annual cases with an age-adjusted incidence rate of 68.8/100,000 inhabitants. There are significant geographical variations in incidence and trends of surgery and in trends between public and private hospitals. We suggest that a national surveillance system would be beneficial for the future evaluation of the treatment of these patients. PMID- 26621512 TI - Organisation and function of the primary motor cortex in chronic pain: protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Primary motor cortical (M1) adaptation in the form of altered organisation and function is hypothesised to underpin motor dysfunction observed in chronic pain. The aim of this review is to assess the evidence for altered M1 organisation and function in chronic pain. METHODS AND ANALYSIS: Systematic review and meta-analysis. We will search electronic databases with predetermined search terms to identify relevant studies and evaluate the studies for inclusion and risks of bias. Two independent reviewers will extract data. Any disagreement will be resolved through a third reviewer. Cross-sectional or prospective studies published in English before May 2015 that investigate M1 organisation and function in chronic pain will be included if they meet the eligibility criteria. Primary outcomes will include M1 cortical excitability, spatial cortical representation, the function of inhibitory and facilitatory intracortical networks, cortical reactivity and cortical glucose metabolism. Clinical measures such as pain and disability will be included where the correlation with the primary outcomes of M1 organisation and function were investigated in the included studies. ETHICS AND DISSEMINATION: This systematic review does not require ethical approval. The results of this review will be submitted for peer reviewed publication regardless of outcome and will be presented at relevant conferences. TRIAL REGISTRATION NUMBER: Our systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD42015014823). PMID- 26621513 TI - Patient experience of computerised therapy for depression in primary care. AB - OBJECTIVE: To explore patient experience of computerised cognitive behaviour therapy (cCBT) for depression in a pragmatic randomised controlled trial (Randomised Evaluation of the Effectiveness and Acceptability of Computerised Therapy, REEACT). DESIGN: Qualitative semistructured interviews with 36 participants. PARTICIPANTS: Depressed patients with a Patient Health Questionnaire 9 of 10 or above recruited into the REEACT randomised controlled trial. SETTING: Primary care settings in England. RESULTS: Participant experience was on a continuum, with some patients unable or unwilling to accept psychological therapy without interpersonal contact while others appreciated the enhanced anonymity and flexibility of cCBT. The majority of patients were ambivalent, recognising the potential benefits offered by cCBT but struggling with challenges posed by the severity of their illness, lack of support and limited personalisation of programme content. Low completion rates were commonly reported, although more positive patients reported greater engagement. Both positive and ambivalent patients perceived a need for monitoring or follow-up to support completion, while negative patients reported deliberate non-adherence due to dissatisfaction with the programme. Patients also reported that severity of depression impacted on engagement, and viewed cCBT as unsuitable for patients undergoing more severe depressive episodes. CONCLUSIONS: The study demonstrates both the unique demands and benefits of computerised therapy. cCBT was preferred by some patients and rejected by others, but the majority of patients were ambivalent about the therapy. cCBT could be offered within a menu of options in stepped care if matched appropriately to individual patients or could be offered with enhanced support to appeal to a greater number of patients. TRIAL REGISTRATION NUMBER: ISRCTN91947481. PMID- 26621514 TI - Association between sleeping hours and cardiometabolic risk factors for metabolic syndrome in a Saudi Arabian population. AB - OBJECTIVES: Epidemiological and molecular studies have shown that sleep duration is associated with metabolic syndrome (MtS), a disease that is on the rise in the Kingdom of Saudi Arabia. We aim to investigate the association between sleep duration and selected cardiometabolic risk factors of MtS in a Saudi Arabian population. SETTING: Secondary care was given to the participants. There were 2 participating centres, shopping malls in North and South Jeddah, Saudi Arabia. PARTICIPANTS: We recruited 2686 participants over a 1-year study period. Participants were selected based on their willingness. The only criterion for exclusion was living in the area (North or South Jeddah) for less than 15 years. PLANNED AND PRIMARY OUTCOME MEASURES: Participants were measured for blood sugar levels, blood pressure and body mass index. All participants were asked to fill out a questionnaire. RESULTS: There was a positive association between longer sleep duration and obesity, hypertension and hyperglycaemia. The adjusted ORs for obesity, hypertension and hyperglycaemia were 1.54 (95% CI 1.20 to 1.98), 1.89 (95% CI 1.45 to 2.48) and 1.59 (95% CI 1.19 to 2.13), respectively, in participants sleeping >8 h/night, as compared with those sleeping 7 h. The positive associations between longer sleep duration, defined as sleeping >7 h, and the disease status, did not differ from other risk factors such as physical activity and nutrition. CONCLUSIONS: This is the first epidemiological study reporting on the association between sleep duration and cardiometabolic risk factors of MtS in a Saudi Arabian population. Sleep durations of 8 h or greater were found to be associated with all 3 cardiometabolic risk factors: obesity, hypertension and hyperglycaemia, and this relationship was not confounded by quality of nutrition or physical activity levels. PMID- 26621515 TI - Identification of antithrombotic drugs related to total joint replacement using anonymised free-text notes: a search strategy in the Clinical Practice Research Datalink. AB - OBJECTIVES: We aimed to design and test a method to extract information on antithrombotic therapy from anonymised free-text notes in the Clinical Practice Research Datalink (CPRD). SETTING: General practice database representative of the UK. PARTICIPANTS: All patients undergoing total hip replacement (THR, n=25,898) or total knee replacement (TKR, n=22,231) between January 2008 and October 2012 were included. Antithrombotic drug use related to THR or TKR was identified using anonymised free text and prescription data. PRIMARY AND SECONDARY OUTCOME MEASURES: Internal validity of our newly designed method was determined by calculating positive predictive values (PPVs) of hits for predefined keywords in a random sample of anonymised free-text notes. In order to determine potential detection bias, total joint replacement (TJR) patient characteristics were compared as per their status of exposure to antithrombotics. RESULTS: PPVs ranging between 97% and 99% for new oral anticoagulants (NOAC) or low-molecular weight heparins (LMWH) exposure related to TJR were obtained with our method. Our search strategy increased detection rates by 57%, yielding a total proportion of 18.5% of all THR and 18.6% of all TKR surgeries. Identified users of NOACs and LMWHs were largely similar with regards to age, sex, lifestyle, disease and drug history compared to patients without identified drug use. CONCLUSIONS: We have developed a useful method to identify additional exposure to NOACs or LMWHs with TJR surgery. PMID- 26621516 TI - Factoring in weather variation to capture the influence of urban design and built environment on globally recommended levels of moderate to vigorous physical activity in children. AB - OBJECTIVES: In curbing physical inactivity, as behavioural interventions directed at individuals have not produced a population-level change, an ecological perspective called active living research has gained prominence. However, active living research consistently underexplores the role played by a perennial phenomenon encompassing all other environmental exposures-variation in weather. After factoring in weather variation, this study investigated the influence of diverse environmental exposures (including urban design and built environment) on the accumulation of globally recommended moderate to vigorous physical activity levels (MVPA) in children. DESIGN: This cross-sectional observational study is part of an active living initiative set in the Canadian prairie city of Saskatoon. As part of this study, Saskatoon's neighbourhoods were classified based on urban street design into grid-pattern, fractured grid-pattern and curvilinear types of neighbourhoods. Moreover, diverse environmental exposures were measured including, neighbourhood built environment, and neighbourhood and household socioeconomic environment. Actical accelerometers were deployed between April and June 2010 (spring-summer) to derive MVPA of 331 10-14-year-old children in 25 1-week cycles. Each cycle of accelerometry was conducted on a different cohort of children within the total sample and matched with weather data obtained from Environment Canada. Multilevel modelling using Hierarchical Linear and Non linear Modelling software was conducted by factoring in weather variation to depict the influence of diverse environmental exposures on the accumulation of recommended MVPA. RESULTS: Urban design, including diversity of destinations within neighbourhoods played a significant role in the accumulation of MVPA. After factoring in weather variation, it was observed that children living in neighbourhoods closer to the city centre (with higher diversity of destinations) were more likely to accumulate recommended MVPA. CONCLUSIONS: The findings indicate that after factoring in weather variation, certain types of urban design are more likely to be associated with MVPA accumulation. PMID- 26621517 TI - Home oxygen therapy reduces risk of hospitalisation in patients with chronic obstructive pulmonary disease: a population-based retrospective cohort study, 2005-2012. AB - OBJECTIVE: This study evaluated the effect of home oxygen therapy (HOT) on hospital admissions in chronic obstructive pulmonary disease (COPD) patients. DESIGN AND SETTING: Using nationwide health insurance claims from 2002-2012, we conducted a longitudinal population-based retrospective cohort study. PARTICIPANTS: Individuals who were aged 40 years or above and newly diagnosed with COPD in 2005. OUTCOME MEASURES: The primary outcome was total number of hospitalisations during the study period. Participants were matched using HOT propensity scores and were stratified by respiratory impairment (grade 1: FEV1 <=25% or PaO2 <=55 mm Hg; grade 2: FEV1 <=30% or PaO2 56-60 mm Hg; grade 3: FEV1 <=40% or PaO2 61-65 mm Hg; 'no grade': FEV1 or PaO2 unknown), then a negative binomial regression analysis was performed for each group. RESULTS: Of the 36,761 COPD patients included in our study, 1330 (3.6%) received HOT. In a multivariate analysis of grade 1 patients performed before propensity score matching, the adjusted relative risk of hospitalisation for patients who did not receive HOT was 1.27 (95% CI 1.01 to 1.60). In a multivariate analysis of grade 1 patients performed after matching, the adjusted relative risk for patients who did not receive HOT was 1.65 (95% CI 1.25 to 2.18). In grade 2 or grade 3 patients, no statistical difference in hospital admission risk was detected. In the 'no grade' group of patients, HOT was associated with an increased risk of hospitalisation. CONCLUSIONS: HOT reduces the risk of hospital admission in COPD patients with severe hypoxaemia. However, apart from these patients, HOT use is not associated with hospital admissions. PMID- 26621518 TI - Vitamin D status and associated metabolic risk factors among North Korean refugees in South Korea: a cross-sectional study. AB - OBJECTIVE: Vitamin D deficiency is now recognised as a common health problem associated with various chronic diseases; however, it has not been fully elucidated among the minority groups. Here, we aimed to investigate the prevalence of vitamin D deficiency and its associated metabolic risk factors among North Korean refugees living in South Korea. DESIGN: Cross-sectional analysis from the longitudinal cohort, the North Korean refugee health in South Korea (NORNS) study. PARTICIPANTS: A total of 386 North Korean refugees aged >=30 years, who measured serum 25-hydroxy vitamin D (25(OH)D) level. RESULTS: The prevalence of vitamin D deficiency (25(OH)D <20 ng/mL) was 87% and no participants had an adequate vitamin D level (25(OH)D >=30 ng/mL). Underweight participants (body mass index (BMI) <18 kg/m(2)) had significantly lower 25(OH)D levels than individuals with normal BMI (>=18.5 and<23 kg/m(2)). In the multivariate logistic regression analysis, the lowest 25(OH)D level (<10 ng/mL) was significantly associated with metabolic syndrome (OR, 6.37, 95% CI 1.34 to 30.3), high triglyceride (OR, 6.71, 95% CI 1.75 to 25.7), and low high-density lipoprotein (OR, 5.98, 95% CI 1.54 to 23.2) compared with 25(OH)D levels >=20 ng/mL after adjusting for age, sex, season, length of residence in South Korea, physical activity and BMI. CONCLUSIONS: Vitamin D deficiency is very common among North Korean refugees in South Korea. Despite their lower BMI, vitamin D deficiency was associated with metabolic syndrome in this population. PMID- 26621519 TI - Preventing obesity in infants: the Growing healthy feasibility trial protocol. AB - INTRODUCTION: Early childhood is an important period for establishing behaviours that will affect weight gain and health across the life course. Early feeding choices, including breast and/or formula, timing of introduction of solids, physical activity and electronic media use among infants and young children are considered likely determinants of childhood obesity. Parents play a primary role in shaping these behaviours through parental modelling, feeding styles, and the food and physical activity environments provided. Children from low socio economic backgrounds have higher rates of obesity, making early intervention particularly important. However, such families are often more difficult to reach and may be less likely to participate in traditional programs that support healthy behaviours. Parents across all socio-demographic groups frequently access primary health care (PHC) services, including nurses in community health services and general medical practices, providing unparalleled opportunity for engagement to influence family behaviours. One emerging and promising area that might maximise engagement at a low cost is the provision of support for healthy parenting through electronic media such as the Internet or smart phones. The Growing healthy study explores the feasibility of delivering such support via primary health care services. METHODS: This paper describes the Growing healthy study, a non-randomised quasi experimental study examining the feasibility of an intervention delivered via a smartphone app (or website) for parents living in socioeconomically disadvantaged areas, for promoting infant feeding and parenting behaviours that promote healthy rather than excessive weight gain. Participants will be recruited via their primary health care practitioner and followed until their infant is 9 months old. Data will be collected via web-based questionnaires and the data collected inherently by the app itself. ETHICS AND DISSEMINATION: This study received approval from the University of Technology Sydney Ethics committee and will be disseminated via peer-reviewed publications and conference presentations. PMID- 26621520 TI - Nutrition interventions for children aged less than 5 years following natural disasters: a systematic review protocol. AB - INTRODUCTION: Malnutrition among children is a serious public health problem in the aftermath of any natural disaster. We will review the various nutrition interventions for children aged <5 years in countries where natural disasters occurred and analyse the effect on nutrition-related outcomes. METHODS AND ANALYSIS: We will conduct a systematic review on nutrition intervention studies following natural disasters that were published between January 2000 and December 2015. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The Cochrane Risk of Bias (RoB) tool will be used for randomised controlled trials and Risk of Bias Assessment for Non-Randomized Studies (RoBANS) will be used for non-randomised studies. The quality of evidence will be assessed using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines. If sufficient data are available, we will conduct meta-analyses to establish the relationship between nutrition interventions and nutrition outcome indicators. All statistical analyses will be performed using Review Manager (Rev Man) V.5.3 for Windows. Heterogeneity of the data will be tested using the standard chi(2) test. A fixed-effect model will be used for the studies with high heterogeneity (p value>0.10, I(2)<=50%). For dichotomous and continuous data, relative risk (RR) and mean difference with 95% CI will be used respectively. Subgroup analysis will be performed for studies with low heterogeneity (p value <=0.10). We will use Z score with the level of significance set at p value <0.05 to test the total effect. Funnel plots will be used to detect publication bias. ETHICS AND DISSEMINATION: As primary data will not be collected, formal ethical approval will not be required. The results will be disseminated by publication in peer-reviewed journals, conference presentations and the media. REGISTRATION DETAILS: International Prospective Register for Systematic Reviews (PROSPERO) number CRD42015023243 was registered on 1 June 2015. PMID- 26621522 TI - Erratum to: Clinicopathological factors associated with HER2 status in gastric cancer: results from a prospective multicenter observational cohort study in a Japanese population (JFMC44-1101). PMID- 26621521 TI - YOCAS(c)(r) Yoga Reduces Self-reported Memory Difficulty in Cancer Survivors in a Nationwide Randomized Clinical Trial: Investigating Relationships Between Memory and Sleep. AB - Background Interventions are needed to alleviate memory difficulty in cancer survivors. We previously showed in a phase III randomized clinical trial that YOCAS(c)(r) yoga-a program that consists of breathing exercises, postures, and meditation-significantly improved sleep quality in cancer survivors. This study assessed the effects of YOCAS(c)(r) on memory and identified relationships between memory and sleep. STUDY DESIGN AND METHODS: Survivors were randomized to standard care (SC) or SC with YOCAS(c)(r) . 328 participants who provided data on the memory difficulty item of the MD Anderson Symptom Inventory are included. Sleep quality was measured using the Pittsburgh Sleep Quality Index. General linear modeling (GLM) determined the group effect of YOCAS(c)(r) on memory difficulty compared with SC. GLM also determined moderation of baseline memory difficulty on postintervention sleep and vice versa. Path modeling assessed the mediating effects of changes in memory difficulty on YOCAS(c)(r) changes in sleep and vice versa. RESULTS: YOCAS(c)(r) significantly reduced memory difficulty at postintervention compared with SC (mean change: yoga=-0.60; SC=-0.16; P<.05). Baseline memory difficulty did not moderate the effects of postintervention sleep quality in YOCAS(c)(r) compared with SC. Baseline sleep quality did moderate the effects of postintervention memory difficulty in YOCAS(c)(r) compared with SC (P<.05). Changes in sleep quality was a significant mediator of reduced memory difficulty in YOCAS(c)(r) compared with SC (P<.05); however, changes in memory difficulty did not significantly mediate improved sleep quality in YOCAS(c)(r) compared with SC. CONCLUSIONS: In this large nationwide trial, YOCAS(c)(r) yoga significantly reduced patient-reported memory difficulty in cancer survivors. PMID- 26621523 TI - Pre- and post-ESD discrepancies in clinicopathologic criteria in early gastric cancer: the NECA-Korea ESD for Early Gastric Cancer Prospective Study (N-Keep). AB - BACKGROUND: Discrepancies in the clinicopathologic parameters pre- and post endoscopic submucosal dissection (ESD) sometimes necessitate additional surgical resection. The aim of this study was to assess such discrepancies in clinicopathologic parameters before and after ESD in the context of reducing the risk of failure of curative ESD. METHODS: Data on 712 early gastric cancer patients were prospectively collected from 12 university hospitals nationwide. The inclusion criteria were differentiated carcinoma <3 cm in size, no ulceration, submucosal invasion <500 MUm, and no metastasis. Clinicopathologic factors were compared retrospectively. RESULTS: The discrepancy rate was 20.1 % (148/737) and the most common cause of discrepancy was tumor size (64 cases, 8.7 %). Ulceration, undifferentiated histology, and SM2 invasion were found in 34 (4.6 %), 18 (2.4 %), and 51 cases (6.9 %), respectively. Lymphovascular invasion (LVI) was observed in 34 cases (4.6 %). Cases with lesions exceeding 3 cm in size showed more frequent submucosal invasion, an elevated gross morphology, and upper and middle locations (p < 0.05). In the cases with ulceration, depth of invasion (DOI) was deeper than in the cases without ulceration (p = 0.005). Differentiation was correlated with DOI and LVI (p = 0.021 and 0.007). DOI was correlated with tumor size, ulceration, differentiation, LVI, gross type, and location. There were statistically significant differences between mucosal cancer cases and submucosal cancer cases in tumor size, differentiation, ulceration, LVI, and location. CONCLUSIONS: The overall discrepancy rate was 20.1 %. To reduce this rate, it is necessary to evaluate the DOI very cautiously, because it is correlated with other parameters. In particular, careful checking for SM invasive cancer is required due to the high incidence of LVI irrespective of the depth of submucosal invasion. PMID- 26621524 TI - Auxiliary diagnosis of lymph node metastasis in early gastric cancer using quantitative evaluation of sentinel node radioactivity. AB - BACKGROUND: Sentinel node (SN) mapping using dye and radioisotope (RI) tracer has been reported to be feasible in cases of early gastric cancer. Because accurate diagnosis of micrometastasis is sometimes difficult in the limited time available during surgery, a faster and simpler method of improving the intraoperative diagnostic precision of lymph node metastasis is needed. The amount of tracer deposited in an SN can be determined from its radioactivity; however, the significance of the RI count has not been fully discussed. We investigated the clinical impact of the RI count when used as an adjunct to conventional lymph node dissection when diagnosing lymphatic metastasis in cases of early gastric cancer. METHODS: From 2008 to 2009, patients with clinically diagnosed T1N0M0 gastric cancers who underwent gastrectomy and SN mapping were enrolled. SNs were examined by intraoperative and postoperative pathology. The RI count was measured for each SN with a handheld gamma probe; the correlation between nodal metastasis and the RI count was assessed. RESULTS: A total of 308 SNs were harvested from 72 patients. Patients with SN metastasis had significantly higher total RI counts than those without SN metastasis (p = 0.007). Among cases with SN metastasis, RI counts were also significantly elevated in metastasis-positive nodes, stations, and basins. In these cases, the most of SNs having the highest RI count in each case had metastasis including isolated tumor cells. CONCLUSION: In early gastric cancer patients, a high RI count from an SN was correlated with lymph node metastasis. Therefore, RI counting may aid efficient pathological diagnosis and focused lymph node dissection. PMID- 26621526 TI - Mobilising the alumni of a Master of Public Health degree to build research and development capacity in low- and middle-income settings: The Peoples-uni. AB - BACKGROUND: Peoples-uni (People's Open Access Education Initiative) was established to help build Public Health capacity in low- and middle-income countries (LMICs) through postgraduate level online courses. Graduates are invited to join a virtual alumni group. We report the results of efforts to meet the need for health research capacity building by exploring how the course alumni could be mobilised to perform collaborative research into the health problems of their populations. METHODS: Two online surveys of Peoples-uni graduates were conducted with graduates from the first two and first four cohorts in 2013 and 2014, respectively, to explore the formation of an alumni group that would collaborate to further the research and development agenda in LMICs. This was followed by feedback on research-related activity and outcomes via the online alumni and tutors' forum to estimate early indicators of alumni success in relation to capacity building in both the conduct and utilisation of research. RESULTS: Responses were received from 26 (87% response rate) graduates of the first survey and 42 (60% response rate) of the second survey. Overall, 92% of the respondents to the first survey supported the creation of an alumni group, especially if it helped to develop their own research skills and improve the health of their populations. Findings from the second survey showed that study with Peoples-uni was felt to have had a major or potential impact on the careers of the respondents, with 19% of graduates having progressed to a PhD programme to further their research skills, and a further 48% being in the process of applying or intending to apply for doctoral studies. Further feedback shows that at least one collaborative study has been completed and published by alumni members with other collaborative studies planned. Ongoing support has been provided to graduates to help them publish their work and apply for individual or collaborative research grants. CONCLUSIONS: Harnessing the alumni of a Masters level course to perform collaborative research has considerable potential to build research capacity in LMICs. PMID- 26621525 TI - Tumor-associated macrophages of the M2 phenotype contribute to progression in gastric cancer with peritoneal dissemination. AB - BACKGROUND: Tumor-associated macrophages (TAMs) of the M2 phenotype are known to promote tumor proliferation and to be associated with a poor prognosis in numerous cancers. Here, we investigated whether M2 macrophages participate in the development of peritoneal dissemination in gastric cancer. METHODS: The characteristics of peritoneal macrophages in gastric cancer patients with or without peritoneal dissemination were examined by flow cytometry and the real time quantitative polymerase chain reaction. The effects of M2 macrophages on phenotypic changes of the gastric cancer cell line MKN45 were assessed with a direct or indirect co-culture system in vitro and an in vivo mouse xenograft model. RESULTS: The number of peritoneal macrophages with the M2 phenotype (CD68(+)CD163(+) or CD68(+)CD204(+)) was significantly higher in gastric cancer patients with peritoneal dissemination than in those without peritoneal dissemination. Higher expression of the M2-related messenger RNAs (IL-10, vascular endothelial growth factor A, vascular endothelial growth factor C, matrix metalloproteinase 1, and amphiregulin) and lower expression of M1-related messenger RNAs (TNF-alpha, CD80, CD86, and IL-12p40) were also confirmed in the TAMs. Macrophage co-culture with gastric cancer cells converted M1 phenotype into M2 phenotype. Moreover, the coexistence of MKN45 cells with M2 macrophages resulted in cancer cell proliferation and an acceleration of tumor growth in the xenograft model. CONCLUSIONS: Intraperitoneal TAMs in gastric cancer patients with peritoneal dissemination were polarized to the M2 phenotype, and could contribute to tumor proliferation and progression. Therefore, intraperitoneal TAMs are expected to be a promising target in the treatment of peritoneal dissemination in gastric cancer. PMID- 26621527 TI - The effect of vertebral artery hypoplasia in posterior circulation infarction in young patients. AB - Purpose Vertebral artery hypoplasia (VAH) is prevalent in the asymptomatic population and contributes to posterior circulation ischaemic events. The aims of this study were to determine whether VAH is an independent risk factor for posterior circulation infarction (PCI) stroke in young patients and to evaluate its impact on the clinical prognosis of PCI stroke in young patients. Materials and Methods The medical records of 235 young stroke patients were reviewed retrospectively. All patients underwent digital subtraction angiography (DSA). VAH was defined by a diameter of <2 mm or the absence of the lateral vertebral artery on DSA. Logistic regression analyses were performed to elucidate the independent factors associated with PCI stroke in young patients. Then, an independent two-sample t-test was performed to evaluate the clinical effect of VAH. Results Our study included 235 young patients who experienced acute ischaemic stroke, 64 of whom were diagnosed with PCI stroke and 38 of whom (16.2%) were found to have VAH. The multivariate logistic regression analysis indicated that gender and VAH were independent risk factors for PCI stroke in young patients. The independent two-sample t-test showed that among the young patients who experienced PCI stroke, the National Institute of Health Stroke Scale score was not significantly different between the patients with and without VAH. Conclusions Our study showed that VAH increases the risk of PCI stroke in young patients. However, the influence of VAH on clinical outcomes in young patients following PCI stroke is minor. PMID- 26621528 TI - Charting the evolution of approaches employed by the Global Alliance for Vaccines and Immunizations (GAVI) to address inequities in access to immunization: a systematic qualitative review of GAVI policies, strategies and resource allocation mechanisms through an equity lens (1999-2014). AB - BACKGROUND: GAVI's focus on reducing inequities in access to vaccines, immunization, and GAVI funds, - both between and within countries - has changed over time. This paper charts that evolution. METHODS: A systematic qualitative review was conducted by searching PubMed, Google Scholar and direct review of available GAVI Board papers, policies, and program guidelines. Documents were included if they described or evaluated GAVI policies, strategies, or programs and discussed equity of access to vaccines, utilization of immunization services, or GAVI funds in countries currently or previously eligible for GAVI support. Findings were grouped thematically, categorized into time periods covering GAVI's phases of operations, and assessed depending on whether the approaches mediated equity of opportunity or equity of outcomes between or within countries. RESULTS: Serches yielded 2816 documents for assessment. After pre-screening and removal of duplicates, 552 documents underwent detailed evaluation and pertinent information was extracted from 188 unique documents. As a global funding mechanism, GAVI responded rationally to a semi-fixed funding constraint by focusing on between country equity in allocation of resources. GAVI's predominant focus and documented successes have been in addressing between-country inequities in access to vaccines comparing lower income (GAVI-eligible) countries with higher income (ineligible) countries. GAVI has had mixed results at addressing between-country inequities in utilization of immunization services, and has only more recently put greater emphasis and resources towards addressing within-country inequities in utilization to immunization services. Over time, GAVI has progressively added vaccines to its portfolio. This expansion should have addressed inter-country, inter-regional, inter-generational and gender inequities in disease burden, however, evidence is scant with respect to final outcomes. CONCLUSION: In its next phase of operations, the Alliance can continue to demonstrate its strength as a highly effective multi-partner enterprise, capable of learning and innovating in a world that has changed much since its inception. By building on its successes, developing more coherent and consistent approaches to address inequities between and within countries and by monitoring progress and outcomes, GAVI is well-positioned to bring the benefits of vaccination to previously unreached and underserved communities towards provision of universal health coverage. PMID- 26621529 TI - Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies. AB - BACKGROUND: The neurotrophic hypothesis postulates that mood disorders such as bipolar disorder (BD) are associated with a lower expression of brain-derived neurotrophic factor (BDNF). However, its role in peripheral blood as a biomarker of disease activity and of stage for BD, transcending pathophysiology, is still disputed. In the last few years an increasing number of clinical studies assessing BDNF in serum and plasma have been published. Therefore, it is now possible to analyse the association between BDNF levels and the severity of affective symptoms in BD as well as the effects of acute drug treatment of mood episodes on BDNF levels. METHODS: We conducted a systematic review and meta analysis of all studies on serum and plasma BDNF levels in bipolar disorder. RESULTS: Through a series of meta-analyses including a total of 52 studies with 6,481 participants, we show that, compared to healthy controls, peripheral BDNF levels are reduced to the same extent in manic (Hedges' g = -0.57, P = 0.010) and depressive (Hedges' g = -0.93, P = 0.001) episodes, while BDNF levels are not significantly altered in euthymia. In meta-regression analyses, BDNF levels additionally negatively correlate with the severity of both manic and depressive symptoms. We found no evidence for a significant impact of illness duration on BDNF levels. In addition, in plasma, but not serum, peripheral BDNF levels increase after the successful treatment of an acute mania episode, but not of a depressive one. CONCLUSIONS: In summary, our data suggest that peripheral BDNF levels, more clearly in plasma than in serum, is a potential biomarker of disease activity in BD, but not a biomarker of stage. We suggest that peripheral BDNF may, in future, be used as a part of a blood protein composite measure to assess disease activity in BD. PMID- 26621530 TI - A multi-parametric workflow for the prioritization of mitochondrial DNA variants of clinical interest. AB - Assigning a pathogenic role to mitochondrial DNA (mtDNA) variants and unveiling the potential involvement of the mitochondrial genome in diseases are challenging tasks in human medicine. Assuming that rare variants are more likely to be damaging, we designed a phylogeny-based prioritization workflow to obtain a reliable pool of candidate variants for further investigations. The prioritization workflow relies on an exhaustive functional annotation through the mtDNA extraction pipeline MToolBox and includes Macro Haplogroup Consensus Sequences to filter out fixed evolutionary variants and report rare or private variants, the nucleotide variability as reported in HmtDB and the disease score based on several predictors of pathogenicity for non-synonymous variants. Cutoffs for both the disease score as well as for the nucleotide variability index were established with the aim to discriminate sequence variants contributing to defective phenotypes. The workflow was validated on mitochondrial sequences from Leber's Hereditary Optic Neuropathy affected individuals, successfully identifying 23 variants including the majority of the known causative ones. The application of the prioritization workflow to cancer datasets allowed to trim down the number of candidate for subsequent functional analyses, unveiling among these a high percentage of somatic variants. Prioritization criteria were implemented in both standalone ( http://sourceforge.net/projects/mtoolbox/ ) and web version ( https://mseqdr.org/mtoolbox.php ) of MToolBox. PMID- 26621533 TI - Relation between bandgap and resistance drift in amorphous phase change materials. AB - Memory based on phase change materials is currently the most promising candidate for bridging the gap in access time between memory and storage in traditional memory hierarchy. However, multilevel storage is still hindered by the so-called resistance drift commonly related to structural relaxation of the amorphous phase. Here, we present the temporal evolution of infrared spectra measured on amorphous thin films of the three phase change materials Ag4In3Sb67Te26, GeTe and the most popular Ge2Sb2Te5. A widening of the bandgap upon annealing accompanied by a decrease of the optical dielectric constant epsiloninfinity is observed for all three materials. Quantitative comparison with experimental data for the apparent activation energy of conduction reveals that the temporal evolution of bandgap and activation energy can be decoupled. The case of Ag4In3Sb67Te26, where the increase of activation energy is significantly smaller than the bandgap widening, demonstrates the possibility to identify new phase change materials with reduced resistance drift. PMID- 26621532 TI - A novel homozygous splicing mutation of CASC5 causes primary microcephaly in a large Pakistani family. AB - Primary microcephaly is a disorder characterized by a small head and brain associated with impaired cognitive capabilities. Mutations in 13 different genes encoding centrosomal proteins and cell cycle regulators have been reported to cause the disease. CASC5, a gene encoding a protein important for kinetochore formation and proper chromosome segregation during mitosis, has been suggested to be associated with primary microcephaly-4 (MCPH4). This was based on one mutation only and circumstantial functional evidence. By combining homozygosity mapping and whole-exome sequencing in an MCPH family from Pakistan, we identified a second mutation (NM_170589.4;c.6673-19T>A) in CASC5. This mutation induced skipping of exon 25 of CASC5 resulting in a frameshift and the introduction of a premature stop codon (p.Met2225Ilefs*7). The C-terminally truncated protein lacks 118 amino acids that encompass the region responsible for the interaction with the hMIS12 complex, which is essential for proper chromosome alignment and segregation. Furthermore, we showed a down-regulation of CASC5 mRNA and reduction of the amount of CASC5 protein by quantitative RT-PCR and western blot analysis, respectively. As a further sign of functional deficits, we observed dispersed dots of CASC5 immunoreactive material outside the metaphase plate of dividing patient fibroblasts. Normally, CASC5 is a component of the kinetochore of metaphase chromosomes. A higher mitotic index in patient cells indicated a mitotic arrest in the cells carrying the mutation. We also observed lobulated and fragmented nuclei as well as micronuclei in the patient cells. Moreover, we detected an altered DNA damage response with higher levels of gammaH2AX and 53BP1 in mutant as compared to control fibroblasts. Our findings substantiate the proposed role of CASC5 for primary microcephaly and suggest that it also might be relevant for genome stability. PMID- 26621535 TI - Efficacy of tenofovir-based rescue therapy in patients with lamivudine-resistant hepatitis B virus: A systematic review and meta-analysis. AB - BACKGROUND: Currently, there are no conclusive results on the efficacy of Tenofovir disoproxil fumarate (TDF) monotherapy in chronic hepatitis B (CHB) patients with lamivudine-resistant (LAM-R). OBJECTIVE: The aim of this study was to compare the efficacy between TDF and TDF-based combination therapy against LAM R HBV in CHB patients. METHODS: Randomized and non-randomized control trials directly comparing TDF and TDF-based therapy for treatment of LAM-R CHB patients, were searched in Pubmed, Medline, EMBASE, database up to June 15, 2015. The data were analyzed with Review Manager (v.5.3). RESULTS: Five articles (683 patients in total) met entry criteria. The overall efficacy of tenofovir-based combination therapy was not significantly better with regard to the rates of virological response (85.5% vs. 81.5%; RR=0.95, 95%CI=0.88-1.03, P=0.25), ALT normalization (61.9% vs.72.0%; RR=1.18, 95%CI=0.96-1.44, P=0.11) and HBeAg loss (17.0% vs. 18.1%; RR=1.40, 95%CI=0.78-2.49, P=0.26) compared with TDF monotherapy through 48 week treatment. Additionally, subgroup analysis showed that no significant difference was determined as TDF group compared to TDF-based group at 48weeks, in terms of rates of HBV DNA undetectability, ALT normalization and HBeAg loss in the treatment of LAM-R patients with prior failure of LAM monotherapy. Moreover, the rates of HBV DNA suppression between groups were similar through 24 or 48weeks of treatment in LAM-R patients with prior failure of LAM/ADV therapy. CONCLUSIONS: TDF monotherapy is as effective as TDF-based combination therapy in maintaining viral suppression in LAM-R patients with prior failure of LAM or LAM/ADV therapy. PMID- 26621534 TI - Pre-notification letter type and response rate to a postal survey among women who have recently given birth. AB - BACKGROUND: Surveys are commonly used in health research to assess patient satisfaction with hospital care. Achieving an adequate response rate, in the face of declining trends over time, threatens the quality and reliability of survey results. This paper evaluates a strategy to increase the response rate in a postal satisfaction survey with women who had recently given birth. METHODS: A sample of 2048 Australian women who had recently given birth at seven maternity units in New South Wales were invited to participate in a postal survey about their recent experiences with maternity care. The study design included a randomised controlled trial that tested two types of pre-notification letter (with or without the option of opting out of the survey). The study also explored the acceptability of a request for consent to link survey data with existing routinely collected health data (omitting the latter data items from the survey reduced survey length and participant burden). This consent was requested of all women. RESULTS: The survey had an overall response rate of 46% (913 completed surveys returned, total sample 1989). Women receiving the pre-notification letter with the option of opting out of the survey were more likely to actively decline to participate than women receiving the letter without this option, although the overall numbers of women declining were small (27 versus 12). Letter type was not significantly associated with the return of a completed survey. Among women who completed the survey, 97% gave consent to link their survey data with existing health data. CONCLUSIONS: The two types of pre-notification letters used in our study did not influence the survey response rate. However, seeking consent for record linkage was highly acceptable to women who completed the survey, and represents an important strategy to add to the arsenal for designing and implementing effective surveys. In addition to aspects of survey design, future research should explore how to more effectively influence personal constructs that contribute to the decision to participate in surveys. PMID- 26621536 TI - Assessment of health related quality of life in polish patients with primary biliary cirrhosis. AB - BACKGROUND: Most patients with primary biliary cirrhosis (PBC) have impaired health related quality of life (HRQoL), as assessed by PBC-specific HRQoL (PBC 40) and generic (SF-36) questionnaires. Data on the applicability of PBC-27, a shorter version of PBC-40, have been limited. AIMS: To assess HRQoL in Polish PBC patients, applying PBC-40, PBC-27 and SF-36 and to associate clinical or laboratory parameters with HRQoL factors. METHODS: A total of 205 PBC patients (188 females) were analyzed using PBC-40, PBC-27 and SF-36; 85 disease-free demographically matched (in terms of age, gender, ethnicity) individuals were used as normal controls. RESULTS: When compared to controls, PBC patients had significantly impaired HRQoL across all the domains of SF-36. HRQoL impairment by PBC-40 and PBC-27 was comparable between cirrhotics and non-cirrhotics, except for significantly worse Itch in cirrhotics (6.5+/-4.9 vs 5.1+/-4.3; P=0.03). In PBC-40/27, alkaline phosphatase (ALP) levels correlated with itch (P=0.0003). Female patients had marginally impaired cognitive function compared to males by PBC-40 (P=0.06). Other gender-related differences were not found. Anti-gp210 positive, as well as AMA negative PBC patients, had worse HRQoL features in itch and social/emotional domains of PBC-40/PBC-27 questionnaires. Very strong correlations (P<0.0001) between PBC-40/PBC-27 and SF-36 were seen for several domains. CONCLUSIONS: HRQoL is significantly impaired in Polish patients with PBC, independently of gender and disease severity. PBC-40 and PBC-27 questionnaires are efficient in detecting HRQoL impairment in Polish PBC patients. The striking correlation between PBC-40/PBC-27 and SF-36 confirms the usefulness of the former HRQoL measures in PBC patients from Central-Eastern Europe. PMID- 26621537 TI - Therapeutic apheresis in pregnancy: General considerations and current practice. AB - It is widely known that pregnancy does not represent a contraindication to therapeutic apheresis (TA) techniques. In fact, since the first experiences of TA in pregnancy for the prevention of hemolytic disease of the newborn, several diseases are at present treated with TA, mainly within 6 clinical categories: (a) TA is a priority and has no alternative equally effective treatment (e.g., thrombotic thrombocytopenic purpura); (b) TA is a priority but there are alternative therapies not contraindicated in pregnancy (e.g., myasthenia gravis); (c) TA is an effective tool of saving/avoiding drugs contraindicated in pregnancy (e.g., systemic lupus erythematosus); (d) TA is a treatment of specific conditions/complications of pregnancy with maternal and/or fetal risk (e.g., antiphospholipid syndrome); (e) TA is a treatment of specific conditions of pregnancy with exclusive fetal risk (e.g., hemolytic disease of the newborn); (f) TA is a treatment of disease which is strongly indicated and can exceptionally occur during pregnancy (e.g., Goodpasture's syndrome). When dealing with TA pregnant patients, some technical aspects due to the physiological changes of gestation have to be carefully considered, in particular the increase of the circulating blood volume. Moreover a multidisciplinary medical team, including an obstetrician, a clinical consultant, specialist in TA and in transfusion medicine, and a neonatologist stand as a basic requirement for the proper management of some clinical conditions that may be characterized by high maternal and fetal risk. PMID- 26621538 TI - Erythrocyte exchange and leukapheresis in pregnancy. AB - Hematological diseases in pregnancy should be carefully managed with a multidisciplinary approach, which should include obstetrics, hematology and, in selected patients, apheresis professionals. Hematological malignancies in pregnant women are rare, but the attending physicians should be aware that the use of cytotoxic drugs, tyrosine-kinase inhibitors or differentiating agents such as all-trans retinoic acid (ATRA) during the first trimester of pregnancy might be teratogenic and, in turn, induce fetal abnormalities or abortion. Thus, in pregnant patients with either acute or chronic leukemia presenting with symptomatic hyperleukocytosis, leukocytapheresis (LA) could be considered as a bridge therapeutic option. Furthermore, sickle cell disease (SCD) in pregnant women is usually managed only with supportive care, i.e. packed red blood cell (RBC) transfusion to prevent excessive hemoglobin decrease, hydration and prevention of acute sickling crisis. Nevertheless, selected patients at high risk for placental detachment due to vasoocclusive acute crisis or with multiple pregnancies may benefit from prophylactic erythrocyte exchange (EEX). Both LA and EEX must be carried out by well trained personnel and the patients (and the fetus) must be under close clinical and instrumental monitoring. In the present paper, recent indications for performing either LA or EEX in pregnant patients are reviewed. PMID- 26621531 TI - Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium. AB - Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 * 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 * 10(-3) and 7.0 * 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 * 10(-3), 4.5 * 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry. PMID- 26621539 TI - Neutralization of the neuromuscular inhibition of venom and taipoxin from the taipan (Oxyuranus scutellatus) by F(ab')2 and whole IgG antivenoms. AB - The neuromuscular junction activity of Oxyuranus scutellatus venom and its presynaptic neurotoxin, taipoxin, and their neutralization by two antivenoms were examined in mouse phrenic nerve-diaphragm preparations. The action of taipoxin was also studied at 21 degrees C. The efficacy of the antivenoms was also assessed in an in vivo mouse model. Both antivenoms were effective in neutralizing the neuromuscular blocking activity in preincubation-type experiments. In experiments involving independent addition of venom and antivenoms, neutralization depended on the time interval between venom addition and antivenom application. When taipoxin was incubated for 5, 10 or 20min at 21 degrees C, and antivenom added and temperature increased to 37 degrees C, neutralization was achieved only when the toxin was incubated for 5 or 10min. The neutralization by the two antivenoms in an in vivo model showed that both whole IgG and F(ab')2 antivenoms were effective in neutralizing lethality. Our findings highlight the very rapid action of taipan venom at the nerve terminal, and the poor capacity of antivenoms to revert neurotoxicity as the time interval between venom or taipoxin application and antivenom addition increased. Additionally the disparity between molecular masses of the active substances of the two antivenoms did not result in differences in neutralization. PMID- 26621540 TI - Comparison of the lethal effects of chemical warfare nerve agents across multiple ages. AB - Children may be inherently more vulnerable than adults to the lethal effects associated with chemical warfare nerve agent (CWNA) exposure because of their closer proximity to the ground, smaller body mass, higher respiratory rate, increased skin permeability and immature metabolic systems. Unfortunately, there have only been a handful of studies on the effects of CWNA in pediatric animal models, and more research is needed to confirm this hypothesis. Using a stagewise, adaptive dose design, we estimated the 24h median lethal dose for subcutaneous exposure to seven CWNA in both male and female Sprague-Dawley rats at six different developmental times. Perinatal (postnatal day [PND] 7, 14 and 21) and adult (PND 70) rats were more susceptible than pubertal (PND 28 and 42) rats to the lethal effects associated with exposure to tabun, sarin, soman and cyclosarin. Age-related differences in susceptibility were not observed in rats exposed to VM, Russian VX or VX. PMID- 26621542 TI - The WUSCHEL Related Homeobox Protein WOX7 Regulates the Sugar Response of Lateral Root Development in Arabidopsis thaliana. AB - Sugars promote lateral root formation at low levels but become inhibitory at high C/N or C/P ratios. How sugars suppress lateral root formation is unclear, however. Here we report that WOX7, a member of the WUSCHEL related homeobox (WOX) family transcription factors, inhibits lateral root development in a sugar dependent manner. The number of lateral root primordia increased in wox7 mutants but decreased in plants over-expressing WOX7. Plants expressing the WOX7-VP16 fusion protein produced even more lateral roots than wox7, suggesting that WOX7 acts as a transcriptional repressor in lateral root development. WOX7 is expressed at all stages of lateral root development, but it is primarily involved in lateral root initiation. Consistent with this, the wox7 mutant had a higher mitotic activity only at early stages of lateral root development. Further studies suggest that WOX7 regulates lateral root development through direct repression of cell cycle genes, particularly CYCD6;1. WOX7 expression was enhanced by sugar, reduced by auxin, but did not respond to salt and mannitol. In the wox7 mutant, the effect of sugar on lateral root formation was mitigated. These results together suggest that WOX7 plays an important role in coupling the lateral root development program and sugar status in plants. PMID- 26621541 TI - Sensitivity of neural stem cell survival, differentiation and neurite outgrowth within 3D hydrogels to environmental heavy metals. AB - We investigated the sensitivity of embryonic murine neural stem cells exposed to 10 pM-10 MUM concentrations of three heavy metals (Cd, Hg, Pb), continuously for 14 days within 3D collagen hydrogels. Critical endpoints for neurogenesis such as survival, differentiation and neurite outgrowth were assessed. Results suggest significant compromise in cell viability within the first four days at concentrations >=10 nM, while lower concentrations induced a more delayed effect. Mercury and lead suppressed neural differentiation at as low as 10 pM concentration within 7 days, while all three metals inhibited neural and glial differentiation by day 14. Neurite outgrowth remained unaffected at lower cadmium or mercury concentrations (<=100 pM), but was completely repressed beyond day 1 at higher concentrations. Higher metal concentrations (>=100 pM) suppressed NSC differentiation to motor or dopaminergic neurons. Cytokines and chemokines released by NSCs, and the sub-cellular mechanisms by which metals induce damage to NSCs have been quantified and correlated to phenotypic data. The observed degree of toxicity in NSC cultures is in the order: lead>mercury>cadmium. Results point to the use of biomimetic 3D culture models to screen the toxic effects of heavy metals during developmental stages, and investigate their underlying mechanistic pathways. PMID- 26621543 TI - Breast cancer risk factor associations differ for pure versus invasive carcinoma with an in situ component in case-control and case-case analyses. AB - PURPOSE: Invasive ductal carcinoma (IDC) is diagnosed with or without a ductal carcinoma in situ (DCIS) component. Previous analyses have found significant differences in tumor characteristics between pure IDC lacking DCIS and mixed IDC with DCIS. We will test our hypothesis that pure IDC represents a form of breast cancer with etiology and risk factors distinct from mixed IDC/DCIS. METHODS: We compared reproductive risk factors for breast cancer risk, as well as family and smoking history between 831 women with mixed IDC/DCIS (n = 650) or pure IDC (n = 181), and 1,620 controls, in the context of the Women's Circle of Health Study (WCHS), a case-control study of breast cancer in African-American and European American women. Data on reproductive and lifestyle factors were collected during interviews, and tumor characteristics were abstracted from pathology reports. Case-control and case-case analyses were conducted using unconditional logistic regression. RESULTS: Most risk factors were similarly associated with pure IDC and mixed IDC/DCIS. However, among postmenopausal women, risk of pure IDC was lower in women with body mass index (BMI) 25 to <30 [odds ratio (OR) 0.66; 95 % confidence interval (CI) 0.35-1.23] and BMI >= 30 (OR 0.33; 95 % CI 0.18-0.67) compared to women with BMI < 25, with no associations with mixed IDC/DCIS. In case-case analyses, women who breastfed up to 12 months (OR 0.55; 95 % CI 0.32 0.94) or longer (OR 0.47; 95 % CI 0.26-0.87) showed decreased odds of pure IDC than mixed IDC/DCIS compared to those who did not breastfeed. CONCLUSIONS: Associations with some breast cancer risk factors differed between mixed IDC/DCIS and pure IDC, potentially suggesting differential developmental pathways. These findings, if confirmed in a larger study, will provide a better understanding of the developmental patterns of breast cancer and the influence of modifiable risk factors, which in turn could lead to better preventive measures for pure IDC, which have worse disease prognosis compared to mixed IDC/DCIS. PMID- 26621544 TI - Body mass index and weight change in relation to triple-negative breast cancer survival. AB - The aim of this study was to evaluate the influence of body mass index (BMI), weight change on triple-negative breast cancer (TNBC) prognosis in a population based prospective cohort study. The current analysis included 518 participants diagnosed with TNBC in Shanghai Breast Cancer Survival Study. Weight at 1 year prior to cancer diagnosis, at diagnosis, and at 6, 18 and 36 months after cancer diagnosis and height at 6 months after cancer diagnosis were assessed. Disease free survival (DFS) and overall survival (OS) were evaluated in relation to BMI and weight change using Cox proportional hazard models. Obesity (BMI >= 28.0 kg/m(2)) at 1-year pre-diagnosis was associated with higher risk of total mortality and recurrence/disease-specific mortality, with multivariate hazard ratios (HRs) of 1.79 (95 % CI 1.06-3.03) and 1.83 (95 % CI 1.05-3.21), respectively. The associations between BMI and TNBC prognosis attenuated over time from pre-diagnosis to post-diagnosis. Compared with stable weight (change within 5 %), weight loss >=5 % at 18- or 36-month post-diagnosis was related with higher risk of total mortality and recurrence/disease-specific mortality. Respective multivariate HRs were 2.08 (95 % CI 1.25-3.46) and 1.42 (95 % CI 0.77 2.63) for OS, and 2.50 (95 % CI 1.45-4.30) and 2.17 (95 % CI 1.14-4.12) for DFS. However, the association of weight loss and OS/DFS attenuated after excluding patients whose weight was measured after recurrence. Weight gain >=5 % at 18- or 36-month post-diagnosis was associated with a non-significant increased risk of death. The results showed that obesity pre-diagnosis and weight loss post diagnosis was inversely associated with TNBC prognosis. Emphasis on maintaining stable weight after cancer diagnosis for TNBC patients may be considered. PMID- 26621545 TI - CpG oligodeoxynucleotide-specific goose TLR21 initiates an anti-viral immune response against NGVEV but not AIV strain H9N2 infection. AB - Toll-like receptors (TLRs) recognize components of pathogens and mediate the host innate immune response. TLR21 is a TLR that specifically recognizes exogenous double-stranded DNA and rapidly signals to downstream innate immune factors. This study reports the cDNA of goose TLR21 and identifies its immune characteristics. The goose TLR21 is 3161 base pairs and encodes a 975 amino acid protein. As predicted, the goose transmembrane protein TLR21 has a signal peptide, leucine rich repeat regions, a transmembrane domain, and a Toll/interleukin-1 receptor domain. Multiple sequence alignments and phylogenetic analyses showed that goose TLR21 has homology to chicken TLR21. The tissue distribution of TLR21 suggested that it has high transcript levels in immune-associated tissues, especially in the bursa of Fabricius, the Hadrian gland, and the thymus. After challenge with agonist ODN2006 and new type gosling viral enteritis virus (NGVEV), significant induction of TLR21 production, pro-inflammatory cytokines IL-1beta and IL-6, and interferons were observed in peripheral blood mononuclear cells. Both synthetic DNA (ODN2006) and viral DNA (NGVEV) can be recognized by goose TLR21, which leads to a rapid up-regulation of pro-inflammatory cytokines and anti-viral molecules. In vivo, avian influenza A virus H9N2 and NGVEV were used to infect goslings, which was followed by a significant up-regulation of TLR21 mRNA transcripts in multiple tissues of NGVEV-infected geese. In general, goose TLR21 plays an important role in binding invading pathogenic DNA viruses, which subsequently triggers an innate immune response; furthermore, it acts as a functional homologue of mammalian TLR9, as TLR21 recognizes a mammalian TLR9 agonist. PMID- 26621546 TI - The response of aged mice to primary infection and re-infection with pneumonia virus of mice depends on their genetic background. AB - The pneumonia virus of mice (PVM) model is used to study respiratory syncytial virus (RSV) pathogenesis. The outcome of PVM infection varies in different inbred mouse strains, BALB/c being highly susceptible and C57BL/6 more resistant. As the disease symptoms induced by RSV infection can become more severe as people age, we examined the primary and secondary immune responses to infection with PVM in aged BALB/c and C57BL/6 mice. Based on clinical parameters, aged C57BL/6 mice displayed less severe disease than young adult mice when infected with 3000pfu of PVM-15, while BALB/c mice were equally susceptible at both ages showing significant weight loss and high levels of virus replication. Furthermore, after primary infection the CD4(+) T cell numbers in the lungs were higher in young adult mice, while the CD8(+) T cell numbers were comparable in both age groups and strains. When either C57BL/6 or BALB/c mice were infected with PVM as young adults and then re-infected as aged mice, they were protected from clinical disease, while virus replication was reduced. In contrast to mice with a primary PVM-infection, re-infected mice did not have infiltration of neutrophils or inflammatory mediators in the lung. BALB/c mice had higher virus neutralizing antibody levels in the serum and lung than C57BL/6 mice upon re-infection. Re infection with PVM led to significant influx of effector CD4(+) T cells into the lungs when compared to aged mice with a primary infection, while this cell population was decreased in the lung draining lymph nodes in both mouse strains. After re-infection the effector CD8(+) T cell population was also decreased in the lung draining lymph nodes in both mouse strain when compared to aged mice after primary infection. However, the central memory CD4(+) and CD8(+) T cells were significantly enhanced in numbers in the lungs and draining lymph nodes of both mouse strains after re-infection, and these numbers were higher for C57BL/6 mice. PMID- 26621547 TI - LOTUS, a possible endogenous inhibitor of axonal degeneration, as a new biomarker for multiple sclerosis. PMID- 26621548 TI - The management of antithrombotic agents for patients undergoing GI endoscopy. PMID- 26621549 TI - Oviposition site selection by Gasterophilus pecorum (Diptera: Gasterophilidae) in its habitat in Kalamaili Nature Reserve, Xinjiang, China. AB - Oviposition site selection is an important aspect of the behavioural ecology of insects. A comparison of the habitats used by a species enhances our understanding of their adaptation to altered environments. We collected data on the oviposition behaviours of Gasterophilus pecorum (Diptera: Gasterophilidae) in its habitat in Kalamaili Nature Reserve (KNR), Xinjiang, China between March and October 2014. We found 91 quadrats were used by G. pecorum for oviposition. Examining 13 ecological factors using the t-test, chi-square test, and principal component analysis showed that G. pecorum's oviposition habitat was preferentially on slopes with inclinations of 10-30 degrees that were semi sunny, semi-cloudy slopes, in positions high or low on the slopes, with preferences for total plants lower than 10% and Stipa capillata coverage lower than 10% on the low slopes, but Ceratoides latens coverage on the high and intermediate slopes, when the numbers of plant species and families were lower than five. G. pecorum often selected sites at a distance < 2000 m from a water source and average altitude 900-1000 m. The oviposition site selection by G. pecorum may be correlated with the behaviour of Przewalski's horses (Equus ferus przewalskii), and water and food resources may strongly influence oviposition site selection, as Przewalski's horses rest and forage in these areas. PMID- 26621550 TI - Comparison of beliefs about e-cigarettes' harms and benefits among never users and ever users of e-cigarettes. AB - INTRODUCTION: E-cigarette use is rapidly increasing, especially among youth and young adults. We need to learn what factors are associated with uptake in e cigarettes. One important set of predictors is beliefs about e-cigarettes' potential harms and benefits. METHODS: Online survey data were collected in July, 2014 from 527 U.S. adults from a nationally representative online panel (KnowledgePanel) who reported being aware of e-cigarettes. Participants were asked to rate 7 statements related to e-cigarettes harms or benefits (e.g., breathing vapors from other people's e-cigarettes is harmful to my health; vaping or using e-cigarettes can help people quit smoking regular cigarettes completely). Responses were categorized into agree, disagree, or no opinion. We compared the proportions of agreement between respondents who ever used e cigarettes and those who had never used. Multinomial logistic regression was used to predict agree or no opinion versus disagree (base outcome) for each belief. Relative risk ratios (RRRs) are reported. The analyses were completed in December, 2014 and were weighted to match the general U.S. adult population. RESULTS: Agreement across the 7 beliefs ranged from 33% (vaping can help people quit smoking) to 56% (e-cigarettes make smoking look more acceptable to youth). Ever use of e-cigarettes was associated with lower relative risk of agreeing with statements about potential harms and higher relative risk of agreeing with statements about benefits (versus disagreeing) compared with never users. DISCUSSION: These findings provide timely data on beliefs about e-cigarettes between e-cigarette users and non-users to inform potential message topics for health campaign interventions. PMID- 26621551 TI - Cost-effectiveness analysis of a continuing care intervention for cocaine dependent adults. AB - INTRODUCTION: The study conducts a cost-effectiveness analysis (CEA) of a continuing care Telephone Monitoring and Counseling (TMC) intervention for adults diagnosed with cocaine dependence. Participants were randomly assigned to a control condition of intensive outpatient treatment only (treatment-as-usual, or TAU; N=108), or to one of two treatment conditions featuring TMC (N=106) and TMC plus incentives (TMC-plus; N=107). Follow-up assessments were conducted over a 2 year period. METHODS: Intervention and client costs were collected with the program and client versions of the Drug Abuse Treatment Cost Analysis Program (DATCAP). Effectiveness was measured as the number of days abstinent during follow-up. Secondary analyses consider alternative measures of effectiveness and the reduced societal costs of physical and mental health problems and criminal justice involvement. RESULTS: From the societal perspective, TMC dominates both TAU and TMC-plus as a cost-effective and cost-saving intervention. Results varied by substance-using status, however, with the subgroup of participants in TMC-plus that were using drugs at intake and early in treatment having the greatest number of days of abstinence and generating similar savings during follow-up than the TMC subgroup using drugs at intake. CONCLUSIONS: Telephone monitoring and counseling appears to be a cost-effective and potentially cost-saving strategy for reducing substance use among chronic substance users. Providing client incentives added to total intervention costs but did not improve overall effectiveness. CLINICAL TRIAL REGISTRATION: Clinical Trials.gov Number: NCT00685659. PMID- 26621552 TI - Expression, purification, and characterization of recombinant human L-chain ferritin. AB - Ferritins form nanocage architectures and demonstrate their potential to serve as functional nanomaterials with potential applications in medical imaging and therapy. In our study, the cDNA of human L-chain ferritin was cloned into plasmid pET-28a for its overexpression in Escherichia coli. However, the recombinant human L-chain ferritin (rLF) was prone to form inclusion bodies. Molecular chaperones were co-expressed with rLF to facilitate its correct folding. Our results showed that the solubility of rLF was increased about 3-fold in the presence of molecular chaperones, including GroEL, GroES and trigger factor. Taking advantage of its N-terminal His-tag, rLF was then purified with Ni affinity chromatography. With a yield of 10 mg/L from bacterial culture, the purified rLF was analyzed by circular dichroism spectrometry for its secondary structure. Furthermore, the rLF nanocages were characterized using dynamic light scattering and transmission electron microscopy. PMID- 26621555 TI - Response to the Letter to the Editor by Qiuming Hu, Haiping Li, and Xixi Wu. PMID- 26621554 TI - Recognition and Management of Acute Flaccid Myelitis in Children. AB - BACKGROUND: In 2014-2015, several regions of the United States experienced an outbreak of acute flaccid myelitis in pediatric patients. A common, unique feature was disease localization to the gray matter of the spinal cord. METHODS: We report 11 children, ages 13 months to 14 years (median 9 years), in the Intermountain West who presented with extremity weakness (n = 10) or cranial neuropathy (n = 1) of varying severity without an apparent etiology. RESULTS: All children experienced acute paralysis, and 10 had symptoms or signs that localized to the spinal cord. Maximum paralysis occurred within 4 days of onset in all patients. All had spinal gray matter lesions consistent with acute myelitis detected by magnetic resonance imaging; no single infectious cause was identified. Despite therapy with intravenous immunoglobulin, corticosteroids, or plasma exchange, nine of 10 (90%) children had motor deficits at follow-up. CONCLUSIONS: Recognition of this disorder enables clinicians to obtain appropriate imaging and laboratory testing, initiate treatment, and provide families with accurate prognostic information. In contrast to other causes of acute flaccid paralysis in childhood, most children with acute flaccid myelitis have residual neurological deficits. PMID- 26621553 TI - Immunomodulatory effects of radiation: what is next for cancer therapy? AB - Despite its former reputation as being immunosuppressive, it has become evident that radiation therapy can enhance antitumor immune responses. This quality can be harnessed by utilizing radiation as an adjuvant to cancer immunotherapies. Most studies combine the standard radiation dose and regimens indicated for the given disease state, with novel cancer immunotherapies. It has become apparent that low-dose radiation, as well as doses within the hypofractionated range, can modulate tumor cells making them better targets for immune cell reactivity. Herein, we describe the range of phenotypic changes induced in tumor cells by radiation, and explore the diverse mechanisms of immunogenic modulation reported at these doses. We also review the impact of these doses on the immune cell function of cytotoxic cells in vivo and in vitro. PMID- 26621556 TI - Combinations of phytomedicines with different lipid lowering activity for dyslipidemia management: The available clinical data. AB - BACKGROUND: Cardiovascular diseases are the primary cause of death and the leading cause of disability in industrialized countries. Dyslipidemia is a major independent and reversible risk factor for these diseases: it is estimated that a reduction of 1 mmol/l (38 mg/dl) of LDL cholesterol is associated with a risk of developing a cardiovascular complication reduced by 25%, a reduction potentially achieved by life-style improvement associated to adequate dietary supplementation with bioactive substances. AIM: The aim of this review is to focus on the major phytochemical nutraceuticals combinations supported by clinical trials that have demonstrated positive effects in the treatment of dyslipidemia. MAIN TEXT: There are many nutraceuticals with significant lipid-lowering properties: most of them are used in association with a low dosage, because that permits to reduce the risk of side effects and theoretically to improve efficacy. In fact, natural products with different synergetic lipid-lowering could be combined: they can reduce the absorption of lipids from the bowel and/or increase their excretion (soluble fibers, plant sterols, probiotics), enhance the hepatic uptake of cholesterol (berberine, soybean proteins), inhibit Hydroxy-Methil-Gglutaryl Coenzyme A reductase enzyme and consequently the hepatic synthesis of cholesterol (monacolins, policosanols, allicin, soybean proteins, bergamot); furthermore some products are able to reduce the oxidation of the LDL and increase the thermogenesis and lipid metabolism (chlorogenic acid). CONCLUSION: Rational combinations of nutraceuticals with different lipid-lowering activities, whether associated with an appropriate lifestyle, should provide an alternative to drug treatment in patients in primary cardiovascular disease prevention with mildly added cardiovascular risk and in some statin-intolerant patients. PMID- 26621557 TI - Expanding our Reach: Telehealth and Licensure Implications for Psychologists. AB - This article discusses the background and history of the Association of State and Provincial Psychology Board's (ASPPB) Principles and Standards for Telepsychology. The Principles/Standards are described with comments on each one as they apply to the practice of telepsychology, and with a guide on how they coordinate with the American Psychological Association's Guidelines for the Practice of Telepsychology. Further, barriers to the interjurisdictional practice of telepsychology are reviewed and a proposed solution to them is presented. The ASPPB psychology interjurisdictional compact, known as the PSYPACT is in process of being introduced as an effective vehicle for addressing these barriers. PMID- 26621558 TI - Formation of Enhanced Uniform Chiral Fields in Symmetric Dimer Nanostructures. AB - Chiral fields with large optical chirality are very important in chiral molecules analysis, sensing and other measurements. Plasmonic nanostructures have been proposed to realize such super chiral fields for enhancing weak chiral signals. However, most of them cannot provide uniform chiral near-fields close to the structures, which makes these nanostructures not so efficient for applications. Plasmonic helical nanostructures and blocked squares have been proved to provide uniform chiral near-fields, but structure fabrication is a challenge. In this paper, we show that very simple plasmonic dimer structures can provide uniform chiral fields in the gaps with large enhancement of both near electric fields and chiral fields under linearly polarized light illumination with polarization off the dimer axis at dipole resonance. An analytical dipole model is utilized to explain this behavior theoretically. 30 times of volume averaged chiral field enhancement is gotten in the whole gap. Chiral fields with opposite handedness can be obtained simply by changing the polarization to the other side of the dimer axis. It is especially useful in Raman optical activity measurement and chiral sensing of small quantity of chiral molecule. PMID- 26621559 TI - Effect of dexmedetomidine constant rate infusion on the bispectral index during alfaxalone anaesthesia in dogs. AB - OBJECTIVE: To assess the effect of two rates of infusion of dexmedetomidine on the bispectral index (BIS) in dogs anaesthetized with alfaxalone constant rate infusion (CRI). STUDY DESIGN: Prospective, randomized, 'blinded' experimental study. ANIMALS: Six healthy Beagles (three females and three males). METHODS: Dogs received as premedication saline (group D0), 1 MUg kg(-1) (group D1) or 2 MUg kg(-1) (group D2) dexmedetomidine, intravenously (IV). Anaesthesia was induced with alfaxalone (6 mg kg(-1) to effect IV) and maintained with alfaxalone at 0.07 mg kg(-1) minute(-1) and a CRI of saline (D0) or dexmedetomidine 0.5 MUg kg(-1) hour(-1) (D1) or 1 MUg kg(-1) hour(-1) (D2) for 90 minutes. BIS, electromyography (EMG), signal quality index (SQI) and suppression ratio (SR) were measured at 10 minute intervals and the median values were calculated. Nociceptive stimuli were applied every 30 minutes and BIS and cardiorespiratory values were compared before and after stimuli. Cardiorespiratory parameters were recorded throughout the study. RESULTS: BIS and EMG values differed significantly among groups, being lower in D2 (71 +/- 8) than in D0 (85 +/- 10) and D1 (84 +/- 9). SQI was always over 90% and SR was zero throughout all the treatments. There were no significant differences between pre- and post-stimulus values of BIS, EMG and SQI for any treatment, although in D0 and D1, heart rate, respiratory rate and arterial pressures increased significantly after the nociceptive stimulus. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of dexmedetomidine (2 MUg kg( 1) + CRI 1 MUg kg(-1) hour(-1) ) decreases the BIS values and avoids the autonomic responses of a nociceptive stimulus during alfaxalone anaesthesia at 0.07 mg kg(-1) minute(-1) in dogs. However, further studies are needed to verify whether this combination produces an adequate degree of hypnosis under surgical situations. PMID- 26621560 TI - Sri Lankan National Melioidosis Surveillance Program Uncovers a Nationwide Distribution of Invasive Melioidosis. AB - The epidemiologic status of melioidosis in Sri Lanka was unclear from the few previous case reports. We established laboratory support for a case definition and started a nationwide case-finding study. Suspected Burkholderia pseudomallei isolates were collated, identified by polymerase chain reaction assay, referred for Matrix Assisted Laser Desorption Ionization-Time of Flight analysis and multilocus sequence typing (MLST), and named according to the international MLST database. Between 2006 and early 2014, there were 32 patients with culture confirmed melioidosis with an increasing annual total and a falling fatality rate. Patients were predominantly from rural communities, diabetic, and male. The major clinical presentations were sepsis, pneumonia, soft tissue and joint infections, and other focal infection. Burkholderia pseudomallei isolates came from all parts of Sri Lanka except the Sabaragamuwa Province, the south central hill country, and parts of northern Sri Lanka. Bacterial isolates belonged to 18 multilocus sequence types, one of which (ST 1137) was associated with septicemia and a single-organ focus (Fisher's exact, P = 0.004). Melioidosis is an established endemic infection throughout Sri Lanka, and is caused by multiple genotypes of B. pseudomallei, which form a distinct geographic group based upon related sequence types (BURST) cluster at the junction of the southeast Asian and Australasian clades. PMID- 26621561 TI - Increasing Incidence of Ehrlichiosis in the United States: A Summary of National Surveillance of Ehrlichia chaffeensis and Ehrlichia ewingii Infections in the United States, 2008-2012. AB - Human ehrlichiosis is a potentially fatal disease caused by Ehrlichia chaffeensis and Ehrlichia ewingii. Cases of ehrlichiosis are reported to Centers for Disease Control and Prevention through two national surveillance systems: Nationally Notifiable Diseases Surveillance System (NNDSS) and Case Report Forms. During 2008-2012, 4,613 cases of E. chaffeensis infections were reported through NNDSS. The incidence rate (IR) was 3.2 cases per million person-years (PYs). The hospitalization rate (HR) was 57% and the case fatality rate (CFR) was 1%. Children aged < 5 years had the highest CFR of 4%. During 2008-2012, 55 cases of E. ewingii infection were reported through NNDSS. The national IR was 0.04 cases per million PY. The HR was 77%; no deaths were reported. Immunosuppressive conditions were reported by 26% of cases. The overall rate for ehrlichiosis has increased 4-fold since 2000. Although previous literature suggests E. ewingii primarily affects those who are immunocompromised, this report shows most cases occurred among immunocompetent patients. This is the first report to show children aged < 5 years with ehrlichiosis have an increased CFR, relative to older patients. Ongoing surveillance and reporting of tick-borne diseases are critical to inform public health practice and guide disease treatment and prevention efforts. PMID- 26621562 TI - An Unusual Presentation of Neurocysticercosis: A Space-Occupying Lesion in the Fourth Ventricle Associated with Progressive Cognitive Decline. AB - We communicate a case of a middle-aged Brazilian patient with an unusual presentation of fourth ventricular neurocysticercosis: occurrence of two intraventricular cysts at different locations in the brain within 2 years and cognitive decline as the only neurological symptom. Neurocysticercosis was confirmed by magnetic resonance imaging, serology, histology, and genetic analysis. Neurocysticercosis should be considered as a differential diagnosis in cases with atypical neurologic or psychiatric symptoms, atypical neuroimaging and travel history. Especially, fourth ventricular cysts carry the risk of obstructive hydrocephalus and brainstem compression and therefore should be extirpated completely. If complete removal of the cystic structures cannot be proven in cases with surgically treated neurocysticercosis, anthelminthic therapy and thorough follow-up examinations should be conducted. PMID- 26621563 TI - The Association of Cytokines and Micronutrients with Hepatitis E Virus Infection During Pregnancy and the Postpartum Period in Rural Bangladesh. AB - Hepatitis E virus (HEV) infection is severe during pregnancy, with a pregnant case fatality rate around 30%. In Bangladesh, plasma samples from 1,100 women during the first trimester (TM) and third TM of pregnancy and 3 months postpartum (PP) were tested for anti-HEV IgG. During this time, 40 women developed antibody responses to HEV. These seroconverters are classified as the cases (incidence = 46 infections per 1,000 person-years). All except one seroconversion occurred between the third TM and 3 months PP. The cases and 40 matched non-seroconverters (controls) underwent analysis of a panel of 10 cytokines, 12 vitamins and minerals, and two markers of inflammation. Throughout pregnancy, seroconverting cases displayed higher concentrations of both pro- and anti-inflammatory cytokines compared with the non-seroconverting controls, even prior to infection. In the first TM, seroconverters had lower circulating zinc concentrations (P = 0.03), an increased prevalence of vitamin D deficiency (25-hydroxy vitamin D [25(OH)2D] < 50 nmol/L, P = 0.08), and anemia (hemoglobin < 110 g/L, P = 0.05) compared with controls. There were no differences in C-reactive protein or alpha 1-acid glycoprotein. Antecedent micronutrient deficiencies may lead to dysregulated cytokine expression and immunologic compromise, increasing the risk of HEV infection, especially during pregnancy. This exploratory analysis reveals potential novel associations that deserve further study. PMID- 26621564 TI - Undetermined Human Ehrlichiosis and Anaplasmosis in the United States, 2008-2012: A Catch-All for Passive Surveillance. AB - Human ehrlichiosis and anaplasmosis are potentially severe illnesses endemic in the United States. Several bacterial agents are known causes of these diseases: Ehrlichia chaffeensis, Ehrlichia ewingii, Ehrlichia muris-like agent, Panola Mountain Ehrlichia species, and Anaplasma phagocytophilum. Because more than one agent may be present in one area, cases of human ehrlichiosis and anaplasmosis may be reported as "human ehrlichiosis/anaplasmosis undetermined" when the available evidence does not suggest an etiology to the species level. Here, we present a brief summary of these undetermined cases with onset of symptoms from 2008 to 2012 reported to two passive surveillance systems in the United States. The reported incidence rate during this time was 0.52 cases per million person years. Many cases (24%) had positive polymerase chain reaction results. Enhanced surveillance in an area where several of these etiologic agents are endemic may provide a better understanding of the epidemiology of ehrlichiosis and anaplasmosis in the United States. PMID- 26621565 TI - Case Report: An Outbreak of Food-Borne Typhoid Fever Due to Salmonella enterica Serotype Typhi in Japan Reported for the First Time in 16 Years. AB - For the first time in 16 years, a food-borne outbreak of typhoid fever due to Salmonella enterica serotype Typhi was reported in Japan. Seven patients consumed food in an Indian buffet at a restaurant in the center of Tokyo, while one was a Nepali chef in the restaurant, an asymptomatic carrier and the implicated source of this outbreak. The multiple-locus variable-number tandem repeat analysis showed 100% consistency in the genomic sequence for five of the eight cases. PMID- 26621566 TI - Relationship Among Strongyloides stercoralis Infection, Human T-Cell Lymphotropic Virus Type 1 Infection, and Cancer: A 24-Year Cohort Inpatient Study in Okinawa, Japan. AB - This study evaluated the prevalence of Strongyloides stercoralis infection and human T-cell lymphotropic virus type 1 (HTLV-1) infection in the population. In addition, this study investigated the relationship between S. stercoralis infection or HTLV-1 infection and a patient's risk of developing related cancers. This is a retrospective cohort study of 5,209 patients. The prevalence of S. stercoralis infection was 5.2% among all patients. The prevalence among men (6.3%) was significantly higher than among women (3.6%, P < 0.001). The prevalence of HTLV-1 infection among this population was 13.6% and the prevalence among women (15.5%) was significantly higher than that of men (12.3%, P < 0.001). HTLV-1 seroprevalence was higher in patients with liver cancer (P = 0.003, odds ratio [OR]: 1.91, 95% confidence interval [CI]: 1.24, 2.95) and in those with lymphoma other than adult T-cell leukemia/lymphoma (ATLL) (P = 0.005, adjusted OR: 2.76, 95% CI: 1.36, 5.62) if compared with patients without any neoplasm. The prevalence of both S. stercoralis and HTLV-1 in the Okinawan population has been steadily decreasing over the past 24 years. HTLV-1 infection significantly increases the odds of developing liver cancer and lymphomas other than ATLL. PMID- 26621568 TI - Tuning different kinds of entangled metal-organic frameworks by modifying the spacer group of aliphatic dicarboxylate ligands and the reactant ratio. AB - Taking advantage of the conformational flexibility of the bpp ligand and aliphatic dicarboxylic acids, six interesting entangled coordination polymers, {[Cd(fum)(bpp)(H2O)].(H2O)}n (), {[Cd(fum)(bpp)2].(H2O)5}n (), {[Cd2(suc)1.5(bpp)2(NO3)(H2O)2].6H2O}n (), {[Cd(suc)(bpp)2].(H2O)1.5}n (), {[Cd2(glu)2(bpp)3].10H2O}n (), and {Cd(adp)(bpp)(H2O)}n () have been prepared and structurally characterized (bpp = 1,3-bi(4-pyridyl)propane, fum = fumaric, suc = succinate, glu = glutaric, adp = adipic). Compounds and are comprised of undulated 2D 4(4)-sql networks. In the structure of compound , two identical undulated layers are parallelly interpenetrated with each other to give a 2D -> 2D interpenetrating framework. For , the dangling arms projected from 2D layers are intercalated into the neighboring sheets, producing a 2D -> 3D polythreading framework. Compound shows a rare example of a 2D self-penetrating framework with a (3,4)-connected (4(2).6(3).8)(4(2).6) topology. Compound presents an unusual 2D self-threading network with a novel 4-connected {4(2).6(3).8} topology. Compound displays a 3D self-penetrating system based on a 2D -> 3D parallel polycatenation array. Compound exhibits an unprecedented 3D self-penetrating structure having both 1D + 1D -> 1D polycatenation and 3D + 3D -> 3D interpenetration characteristics. A comparison of these six compounds demonstrates that both the different spacer lengths of the aliphatic dicarboxylates and reactant ratios appear to play a significant role in the assembly of entangled frameworks. In addition, thermal stabilities and photoluminescence properties of have been examined in the solid state at room temperature. PMID- 26621567 TI - A Comparison of Five Different Treatment Regimens as the First-Line Treatment of Helicobacter pylori in Turkey. AB - BACKGROUND: The H. pylori eradication success is low in countries with high antibiotic resistance to H. pylori. OBJECTIVE: We retrospectively assessed the eradication rates achieved by five different regimens and aimed to compare the efficiency of bismuth enhanced sequential therapy and other treatments in a gastroenterology outpatient clinic a university-affiliated hospital. DESIGN: Our study was carried out with a retrospective cohort design. SETTING: This study assessed the gastroscopy examinations of patients. PATIENTS: A total of 621 patients were included in the study. There were 122 patients in the quadruple treatment group, 168 patients in the classical sequential treatment group, 130 patients in the bismuth enhanced sequential therapy, 113 patients in the sequential treatment with levofloxacin, and 88 patients in the hybrid treatment. MEASUREMENTS: Eradication rates of different regimens was analyzed by performing Chi-square and Tukey's honest significant difference test. RESULTS: Eradication rates by ITT and PP analysis achieved by treatment groups were 74.6 and 75.6% in the quadruple treatment; 70.2 and 70.4% in the sequential treatment with clarithromycin, 88.5 and 90.3% in the bismuth enhanced sequential therapy, 77.9 and 78.5% in the sequential treatment with levofloxacin, and 76.1 and 76.2% in the hybrid treatment. LIMITATIONS: The main limitation of our study was its retrospective nature. Different proton pump inhibitors were used in the treatment arms. CONCLUSIONS: Bismuth-enhanced sequential therapy can be recommended to overcome resistance. PMID- 26621569 TI - Medial Prefrontal Aberrations in Major Depressive Disorder Revealed by Cytoarchitectonically Informed Voxel-Based Morphometry. AB - OBJECTIVE: The heterogeneous human frontal pole has been identified as a node in the dysfunctional network of major depressive disorder. The contribution of the medial (socio-affective) versus lateral (cognitive) frontal pole to major depression pathogenesis is currently unclear. The authors performed morphometric comparison of the microstructurally informed subdivisions of human frontal pole between depressed patients and comparison subjects using both uni- and multivariate statistics. METHOD: Multisite voxel- and region-based morphometric MRI analysis was conducted in 73 depressed patients and 73 matched comparison subjects without psychiatric history. Frontal pole volume was first compared between depressed patients and comparison subjects by subdivision-wise classical morphometric analysis. In a second approach, frontal pole volume was compared by subdivision-naive multivariate searchlight analysis based on support vector machines. RESULTS: Subdivision-wise morphometric analysis found a significantly smaller medial frontal pole in depressed patients, with a negative correlation of disease severity and duration. Histologically uninformed multivariate voxel-wise statistics provided converging evidence for structural aberrations specific to the microstructurally defined medial area of the frontal pole in depressed patients. CONCLUSIONS: Across disparate methods, subregion specificity in the left medial frontal pole volume in depressed patients was demonstrated. Indeed, the frontal pole was shown to structurally and functionally connect to other key regions in major depression pathology, such as the anterior cingulate cortex and the amygdala via the uncinate fasciculus. Present and previous findings consolidate the left medial portion of the frontal pole as particularly altered in major depression. PMID- 26621570 TI - A Selective Review of Cerebral Abnormalities in Patients With First-Episode Schizophrenia Before and After Treatment. AB - The question of whether there are significant changes in brain anatomy and function at illness onset and over the early course of schizophrenia is a crucial issue with broad implications for prognosis, patient care, and models of illness pathophysiology. Prefrontal hypoactivity and hippocampal and subcortical hyperactivity at the onset of illness may represent a core illness pathophysiology. Gray matter changes have been most robust within thalamo cortical networks, whereas altered brain activity has been most pronounced in fronto-parietal and default-mode networks. These findings indicate that regional anatomical and functional brain abnormalities are significantly dissociated during the early course of schizophrenia prior to antipsychotic treatment. One possible explanation is that functional MRI may reflect physiological alterations related to acute psychosis or consequences of distal anatomic changes, while changes in brain anatomy reflect more stable and long-standing alterations. The relative stability of brain measures in the early years after illness onset stands in contrast to indirect evidence for moderate progressive changes provided by our recent study of chronic never-treated patients. Our recent cross-sectional study of never-treated patients with chronic schizophrenia found an accelerated age-related decline in cortical thickness, relative to healthy controls, that could not be attributed to medication effects. Studies must consider both the clinical heterogeneity that affects findings of brain changes within schizophrenia and the low specificity of the brain changes, which can occur in other early-onset mental disorders as well. PMID- 26621571 TI - Oligosaccharides in Urine, Blood, and Feces of Piglets Fed Milk Replacer Containing Galacto-oligosaccharides. AB - Human milk oligosaccharides (HMOs) are absorbed into the blood (about 1% of the HMO intake) and subsequently excreted in urine, where they may protect the infant from pathogen infection. As dietary galacto-oligosaccharides (GOS) have partial structural similarities with HMOs, this study investigated the presence of GOS and oligosaccharides originating from milk replacer in blood serum, urine, and cecal and fecal samples of piglets, as a model for human infants. Using liquid chromatography-mass spectrometry and capillary electrophoresis with fluorescence detection, oligosaccharides originating from piglet diet including 3' sialyllactose and specific GOS ranging from degree of polymerization 3 to 6 were detected in blood serum and in urine of piglets. In blood serum, GOS levels ranged from 16 to 23 MUg/mL, representing about 0.1% of the GOS daily intake. In urine, approximately 0.85 g of GOS/g of creatinine was found. Cecum digesta and feces contained low amounts of oligosaccharides, suggesting an extensive GOS intestinal fermentation in piglets. PMID- 26621572 TI - Association between the seminal plasma proteome and sperm functional traits. AB - OBJECTIVE: To analyze the seminal plasma proteome and biological functions associated with sperm functional alterations. DESIGN: Cross-sectional study. SETTING: University andrology and research laboratories. PATIENT(S): A total of 156 normozoospermic men. INTERVENTION(S): Sperm mitochondrial activity, acrosome integrity, and DNA fragmentation were evaluated in a semen aliquot. Remaining semen was centrifuged, and seminal plasma was utilized for proteomic analysis (liquid chromatography-tandem mass spectrometry). Patients were divided into percentiles (15%) to form the following groups: substudy 1, high (control, n = 26) and low (study, n = 23) sperm mitochondrial activity; substudy 2, high (control, n = 23) and low (study, n = 22) sperm acrosome integrity; and substudy 3, low (control, n = 22) and high (study, n = 22) sperm DNA fragmentation. Groups were compared using univariate and multivariate analyses. Differentially expressed proteins were used for functional enrichment analysis. MAIN OUTCOME MEASURE(S): Seminal plasma proteome and postgenomic pathways are associated with several sperm functional traits. RESULT(S): In total, 506, 493, and 464 proteins were observed in substudies 1, 2, and 3, respectively. Enriched functions in substudy 1 were intramolecular oxidoreductase activity, aminoglycans catabolism, endopeptidases inhibition, lysosomes, and acute-phase response (study group). In substudy 2, main enriched functions were phospholipase inhibition, arachidonic acid metabolism, exocytosis, regulation of acute inflammation, response to hydrogen peroxide, and lysosomal transport (study group). In substudy 3, enriched functions were prostaglandin biosynthesis and fatty acid binding (study group). We proposed eight, six, and eight seminal biomarkers for substudies 1, 2, and 3, respectively. CONCLUSION(S): Seminal plasma proteome reflects sperm mitochondrial activity reduction, acrosome damage, and DNA fragmentation, with several postgenomic functions related to these alterations. PMID- 26621573 TI - Cancer: Mitochondrial Origins. AB - The primacy of glucose derived from photosynthesis as an existential source of chemical energy across plant and animal phyla is universally accepted as a core principle in the biological sciences. In mammalian cells, initial processing of glucose to triose phosphate intermediates takes place within the cytosolic glycolytic pathway and terminates with temporal transport of reducing equivalents derived from pyruvate metabolism by membrane-associated respiratory complexes in the mitochondrial matrix. The intra-mitochondrial availability of molecular oxygen as the ultimate electron acceptor drives the evolutionary fashioned chemiosmotic production of ATP as a high-efficiency biological process. The mechanistic bases of carcinogenesis have demonstrated profound alteration of normative mitochondrial function, notably dysregulated respiratory processes. Accordingly, the classic Warburg effect functionally links aerobic glycolysis, aberrant production and release of lactate, and metabolic down-regulation of mitochondrial oxidative processes with the carcinogenetic phenotype. We surmise, however, that aerobic fermentation by cancer cells may also represent a developmental re-emergence of an evolutionarily conserved early phenotype, which was "sidelined" with the emergence of mitochondrial oxidative phosphorylation as a primary mechanism for ATP production in normal cells. Regardless of state dependent physiological status in mixed populations of cancer cells, it has been established that mitochondria are functionally linked to the initiation of cancer and its progression. Biochemical, molecular, and physiological differences in cancer cell mitochondria, notably mtDNA heteroplasmy and allele-specific expression of selected nuclear genes, may represent major focal points for novel targeting and elimination of cancer cells in metastatic disease afflicting human populations. To date, and despite considerable research efforts, the practical realization of advanced mitochondrial targeted therapies has not been forthcoming. PMID- 26621574 TI - Metabolomic analysis of riboswitch containing E. coli recombinant expression system. AB - In this study we have employed metabolomics approaches to understand the metabolic effects of producing enhanced green fluorescent protein (eGFP) as a recombinant protein in Escherichia coli cells. This metabolic burden analysis was performed against a number of recombinant expression systems and control strains and included: (i) standard transcriptional recombinant expression control system BL21(DE3) with the expression plasmid pET-eGFP, (ii) the recently developed dual transcriptional-translational recombinant expression control strain BL21(IL3), with pET-eGFP, (iii) BL21(DE3) with an empty expression plasmid pET, (iv) BL21(IL3) with an empty expression plasmid, and (v) BL21(DE3) without an expression plasmid; all strains were cultured under various induction conditions. The growth profiles of all strains together with the results gathered by the analysis of the Fourier transform infrared (FT-IR) spectroscopy data, identified IPTG-dependent induction as the dominant factor hampering cellular growth and metabolism, which was in general agreement with the findings of GC-MS analysis of cell extracts and media samples. In addition, the exposure of host cells to the synthetic inducer ligand, pyrimido[4,5-d] pyrimidine-2,4-diamine (PPDA), of the orthogonal riboswitch containing expression system (BL21(IL3)) did not display any detrimental effects, and its detected levels in all the samples were at similar levels, emphasising the inability of the cells to metabolise PPDA. The overall results obtained in this study suggested that although the BL21(DE3)-EGFP and BL21(IL3)-EGFP strains produced comparable levels of recombinant eGFP, the presence of the orthogonal riboswitch seemed to be moderating the metabolic burden of eGFP production in the cells enabling higher biomass yield, whilst providing a greater level of control over protein expression. PMID- 26621575 TI - The changing dynamics of coral reef science in Arabia. AB - Six percent of the world's coral reefs occur around the Arabian Peninsula, providing a valuable ecological, economic and scientific resource for the nations bordering its shores. We provide the first region-wide assessment of the current status and historical trends in coral reef research, focusing on research in the Red Sea, Arabian Sea, and Arabian Gulf. In total, 633 regional reef publications have been produced since the 1930s, covering a wide variety of themes and taxa. Our results show a great deal of commonality in regional reef research, but also highlight important differences in research among the various seas as well as knowledge gaps that represent opportunities for future research. A regionally integrated approach to future research is essential. There is a growing need for large-scale research to guide management of reefs and their stressors, as these operate at much larger scales than the national borders within which most research currently occurs. PMID- 26621576 TI - De-facto marine protection from a Navy bombing range: Farallon De Medinilla, Mariana Archipelago, 1997 to 2012. AB - Fourteen surveys were conducted at Farallon De Medinilla (a U.S. Department of Defense bombing range in the Mariana Archipelago) between 1997 and 2012; annual surveys were conducted from 1999 through 2012. There was no evidence that the condition of the biological resources assessed had changed, or been adversely impacted to a significant degree by the training activities being conducted there. Restricted access has resulted in a de-facto preserve effect and outweighs minor negative impacts from training. The health, abundance and biomass of fishes, corals and other marine resources are comparable to or superior to those in similar habitats at other locations within the Mariana Archipelago. Our research suggests that the greatest threat to FDM's marine resources is from fishermen, not military training activities. PMID- 26621577 TI - Plastic ingestion by pelagic and demersal fish from the North Sea and Baltic Sea. AB - Plastic ingestion by marine biota has been reported for a variety of different taxa. In this study, we investigated 290 gastrointestinal tracts of demersal (cod, dab and flounder) and pelagic fish species (herring and mackerel) from the North and Baltic Sea for the occurrence of plastic ingestion. In 5.5% of all investigated fishes, plastic particles were detected, with 74% of all particles being in the microplastic (<5mm) size range. The polymer types of all found particles were analysed by means of Fourier transform infrared (FT-IR) spectroscopy. Almost 40% of the particles consisted of polyethylene (PE). In 3.4% of the demersal and 10.7% of the pelagic individuals, plastic ingestion was recorded, showing a significantly higher ingestion frequency in the pelagic feeders. The condition factor K was calculated to test differences in the fitness status between individuals with and without ingested plastic, but no direct effect was detected. PMID- 26621578 TI - Tight coupling between coral reef morphology and mapped resilience in the Red Sea. AB - Lack of knowledge on the conservation value of different reef types can stymie decision making, and result in less optimal management solutions. Addressing the information gap of coral reef resilience, we produce a map-based Remote Sensed Resilience Index (RSRI) from data describing the spatial distribution of stressors, and properties of reef habitats on the Farasan Banks, Saudi Arabia. We contrast the distribution of this index among fourteen reef types, categorized on a scale of maturity that includes juvenile (poorly aggraded), mature (partially aggraded), and senile (fully aggraded) reefs. Sites with high reef resilience can be found in most detached reef types; however they are most common in mature reefs. We aim to stimulate debate on the coupling that exists between geomorphology and conservation biology, and consider how such information can be used to inform management decisions. PMID- 26621579 TI - Elasticity of Ferropericlase across the Spin Crossover in the Earth's Lower Mantle. AB - Knowing the elasticity of ferropericlase across the spin transition can help explain seismic and mineralogical models of the lower-mantle including the origin of seismic heterogeneities in the middle to lowermost parts of the lower mantle. However, the effects of spin transition on full elastic constants of ferropericlase remain experimentally controversial due to technical challenges in directly measuring sound velocities under lower-mantle conditions. Here we have reliably measured both VP and VS of a single-crystal ferropericlase ((Mg0.92,Fe0.08)O) using complementary Brillouin Light Scattering and Impulsive Stimulated Light Scattering coupled with a diamond anvil cell up to 96 GPa. The derived elastic constants show drastically softened C11 and C12 within the spin transition at 40-60 GPa while C44 is not affected. The spin transition is associated with a significant reduction of the aggregate VP/VS via the aggregate VP softening because VS softening does not visibly occur within the transition. Based on thermoelastic modelling along an expected geotherm, the spin crossover in ferropericlase can contribute to 2% reduction in VP/VS in a pyrolite mineralogical model in mid lower-mantle. Our results imply that the middle to lowermost parts of the lower-mantle would exhibit enhanced seismic heterogeneities due to the occurrence of the mixed-spin and low-spin ferropericlase. PMID- 26621580 TI - A Phase I Dose Escalation Study Demonstrates Quercetin Safety and Explores Potential for Bioflavonoid Antivirals in Patients with Chronic Hepatitis C. AB - The hepatitis C virus (HCV) infects more than 180 million people worldwide, with long-term consequences including liver failure and hepatocellular carcinoma. Quercetin bioflavonoids can decrease HCV production in tissue culture, in part through inhibition of heat shock proteins. If quercetin demonstrates safety and antiviral activity in patients, then it could be developed into an inexpensive HCV treatment for third world countries or other affected populations that lack financial means to cover the cost of mainstream antivirals. A phase 1 dose escalation study was performed to evaluate the safety of quercetin in 30 untreated patients with chronic HCV infection and to preliminarily characterize quercetin's potential in suppressing viral load and/or liver injury. Quercetin displayed safety in all trial participants. Additionally, 8 patients showed a "clinically meaningful" 0.41-log viral load decrease. There was a positive correlation (r = 0.41, p = 0.03) indicating a tendency for HCV decrease in patients with a lower ratio of plasma quercetin relative to dose. No significant changes in aspartate transaminase and alanine transaminase were detected. In conclusion, quercetin exhibited safety (up to 5 g daily) and there was a potential for antiviral activity in some hepatitis C patients. PMID- 26621581 TI - Pathogenic FBN1 variants in familial thoracic aortic aneurysms and dissections. AB - Marfan syndrome (MFS) due to mutations in FBN1 is a known cause of thoracic aortic aneurysms and acute aortic dissections (TAAD) associated with pleiotropic manifestations. Genetic predisposition to TAAD can also be inherited in families in the absence of syndromic features, termed familial TAAD (FTAAD), and several causative genes have been identified to date. FBN1 mutations can also be identified in FTAAD families, but the frequency of these mutations has not been established. We performed exome sequencing of 183 FTAAD families and identified pathogenic FBN1 variants in five (2.7%) of these families. We also identified eight additional FBN1 rare variants that could not be unequivocally classified as disease-causing in six families. FBN1 sequencing should be considered in individuals with FTAAD even without significant systemic features of MFS. PMID- 26621583 TI - CD44 is functionally crucial for driving lung cancer stem cells metastasis through Wnt/beta-catenin-FoxM1-Twist signaling. AB - A novel paradigm in tumor biology suggests that non-small cell lung cancer (NSCLC) metastasis is driven by lung cancer stem cell-like cells (LCSCs), but the underlying mechanisms remain unclear. Here, we aim to investigate biological function of CD44 in regulating metastatic trait of LCSCs and its underlying mechanisms. In this study, we found that CD133+ CD44+ cells which were derived from primary lung adenocarcinoma (LAC) possessed cancer stem cell-like features. Furthermore, CD44 was demonstrated functionally crucial to drive metastatic potential of CD133+ CD44+ LCSCs by in vitro and in vivo experiments. In patient cohorts, high level of CD44 predicted increased probability of metastasis. Significantly, microarray revealed that FoxM1 and key proteins of Wnt/beta catenin pathway were up-regulated in CD133+ CD44+ LCSCs compared with those in CD133+ CD44- cells. Then, we demonstrated that CD44 promoted metastatic activity in CD133+ CD44+ LCSCs through Wnt/beta-catenin pathway and FoxM1 was the downstream target of Wnt/beta-catenin pathway. Meanwhile, our findings indicated that FoxM1 promoted metastatic activity in CD133+ CD44+ LCSCs by inducing EMT and Twist was a direct transcriptional target of FoxM1. Collectively, CD44, both a functional biomarker and therapeutic target, promoted CD133+ CD44+ LCSCs metastasis by Wnt/beta-catenin-FoxM1-Twist signaling. This study provided support for the missing link between EMT and CSCs surface-marker and supplied a promising approach for elimination of LCSCs by targeting CD44-Wnt/beta-catenin-FoxM1-Twist signaling. (c) 2015 Wiley Periodicals, Inc. PMID- 26621584 TI - Cellular Reprogramming in Basic and Applied Biomedicine: The Dawn of Regenerative Medicine. AB - Fertilization triggers a cascade of cellular and molecular events restoring the totipotent state and the potential for all cell types. However, the program quickly directs differentiation and cellular commitment. Under the genetic and epigenetic control of this process, Waddington likened this to a three dimensional landscape where cells could not ascend the slope or traverse once canalized thus leading to cell fate decisions and the progressive restriction of cellular potency. But this is not the only possible outcome at least experimentally. Somatic cell nuclear transfer and overexpression of key transcription factors to generate induced pluripotent cells have challenged this notion. The return to pluripotency and the reinstatement of plasticity and heterogeneity once thought to be the exclusive remit of the developing embryo can now be replicated in vitro. The following chapter introduces some of these ideas and suggests that the fundamental principles learned may constitute the first step toward the opportunity for specific tissue renewal and replacement in healthy aging and the treatment of chronic diseases-the age of regenerative medicine. PMID- 26621582 TI - Social dynamics within decomposer communities lead to nitrogen retention and organic matter build-up in soils. AB - The chemical structure of organic matter has been shown to be only marginally important for its decomposability by microorganisms. The question of why organic matter does accumulate in the face of powerful microbial degraders is thus key for understanding terrestrial carbon and nitrogen cycling. Here we demonstrate, based on an individual-based microbial community model, that social dynamics among microbes producing extracellular enzymes ('decomposers') and microbes exploiting the catalytic activities of others ('cheaters') regulate organic matter turnover. We show that the presence of cheaters increases nitrogen retention and organic matter build-up by downregulating the ratio of extracellular enzymes to total microbial biomass, allowing nitrogen-rich microbial necromass to accumulate. Moreover, increasing catalytic efficiencies of enzymes are outbalanced by a strong negative feedback on enzyme producers, leading to less enzymes being produced at the community level. Our results thus reveal a possible control mechanism that may buffer soil CO2 emissions in a future climate. PMID- 26621585 TI - Synthetic mRNA Reprogramming of Human Fibroblast Cells. AB - Reprogramming of somatic cells, such as skin fibroblasts, to pluripotency was first achieved by forced expression of four transcription factors using integrating retroviral or lentiviral vectors, which result in integration of exogenous DNA into cellular genome and present a formidable barrier to therapeutic application of induced pluripotent stem cells (iPSCs). To facilitate the translation of iPSC technology to clinical practice, mRNA reprogramming method that generates transgene-free iPSCs is a safe and efficient method, eliminating bio-containment concerns associated with viral vectors, as well as the need for weeks of screening of cells to confirm that viral material has been completely eliminated during cell passaging. PMID- 26621586 TI - MicroRNA-Mediated Reprogramming of Somatic Cells into Induced Pluripotent Stem Cells. AB - MicroRNAs or miRNAs belong to a class of small noncoding RNAs that play a crucial role in posttranscriptional regulation of gene expression. Nascent miRNAs are expressed as a longer transcript, which are then processed into a smaller 18-23 nucleotide mature miRNAs that bind to the target transcripts and induce cleavage or inhibit translation. MiRNAs therefore represent another key regulator of gene expression in establishing and maintaining unique cellular fate. Several classes of miRNAs have been identified to be uniquely expressed in embryonic stem cells (ESC) and regulated by the core transcription factors Oct4, Sox2, and Klf4. One such class of miRNAs is the mir-302/367 cluster that is enriched in pluripotent cells in vivo and in vitro. Using the mir-302/367 either by themselves or in combination with the Yamanaka reprogramming factors (Oct4, Sox2, c-Myc, and Klf4) has resulted in the establishment of induced pluripotent stem cells (iPSC) with high efficiencies. In this chapter, we outline the methodologies for establishing and utilizing the miRNA-based tools for reprogramming somatic cells into iPSC. PMID- 26621587 TI - Generation of Footprint-Free Induced Pluripotent Stem Cells from Human Fibroblasts Using Episomal Plasmid Vectors. AB - Human induced pluripotent stem cells (hiPSCs) have provided novel insights into the etiology of disease and are set to transform regenerative medicine and drug screening over the next decade. The generation of human iPSCs free of a genetic footprint of the reprogramming process is crucial for the realization of these potential uses. Here we describe in detail the generation of human iPSC from control and disease-carrying individuals' fibroblasts using episomal plasmids. PMID- 26621588 TI - Reprogramming of Human Fibroblasts with Non-integrating RNA Virus on Feeder-Free or Xeno-Free Conditions. AB - Recent advances in generating induced pluripotent stem cells have radically advanced the field of regenerative medicine by making possible the production of patient-specific pluripotent stem cells from somatic cells. However, a major obstacle to the use of iPSC for therapeutic applications is the potential genomic modifications resulted from viral insertion of transgenes in the cellular genome. Second, the culture of iPSCs and adult cells often requires the use of animal products, which hinder the generation of clinical-grade iPSCs. We report here the generation of iPSCs by an RNA Sendai virus vector that does not integrate transgenes into the cell's genome. In addition, reprogramming can be performed on a feeder-free or xeno-free condition without containing animal products. Generation of an integrant-free iPSCs in these conditions will facilitate the studies of iPSCs in cell-based therapies. PMID- 26621589 TI - Inducing Pluripotency in Cattle. AB - Nuclear reprogramming technologies in general and induced pluripotent stem cells (iPSCs) in particular have opened the door to a vast number of practical applications in regenerative medicine and biotechnology. It also represents a possible alternative to the still evasive achievement of embryonic stem cells (ESCs) isolation from refractory species such as Bos. taurus. Herein, we described a protocol for bovine iPSCs (biPSCs) generation and characterization. The protocol is based on the overexpression of the exogenous transcription factors NANOG, OCT4, SOX2, KLF4 and c-MYC, using a pantropic retroviral system. PMID- 26621590 TI - Generation of Induced Pluripotent Stem Cells (iPSCs) from Adult Canine Fibroblasts. AB - Induced pluripotent stem cells hold great potential in regenerative medicine as it enables to generate pluripotent stem cells from any available cell types. Ectopic expression of four transcription factors (Oct4, Sox2, Klf4, and c-Myc) can reprogram fibroblasts directly to pluripotency as shown in multiple species. Here, we describe detailed protocols for generation of iPSCs from adult canine fibroblasts. Robust canine iPSCs will provide powerful tools not only to study human diseases, but also for the development of therapeutic approaches. PMID- 26621591 TI - Derivation of Equine-Induced Pluripotent Stem Cell Lines Using a piggyBac Transposon Delivery System and Temporal Control of Transgene Expression. AB - The discovery of induced pluripotent stem cells (iPSCs) has had a transforming effect on our understanding of biology and has brought an enormous promise to regenerative medicine. It has opened up a magnitude of unprecedented possibilities to study disease processes in vitro, model them in animal systems, and develop patient-specific cell-based regenerative therapies. iPSCs derived from other than the human species will be instrumental for bringing these prospects to fruition by providing preclinical models and novel treatments for veterinary medicine. In this chapter, we describe the derivation of iPSCs from equine embryonic fibroblasts using a non-viral method developed in our laboratory and originally applied to the murine and human systems (Woltjen et al., Nature 458:766-770, 2009). We will detail the procedures involved and discuss potential pitfalls as well as elaborate on possible variations and future improvements of this technique. PMID- 26621592 TI - Generation of Avian Induced Pluripotent Stem Cells. AB - Avian species are among the most diverse vertebrates on our planet and significantly contribute to the balance of the ecology. They are also important food source and serve as a central animal model to decipher developmental biology and disease principles. Derivation of induced pluripotent stem cells (iPSCs) from avian species would enable conservation of genetic diversity as well as offer a valuable cell source that facilitates the use of avian models in many areas of basic and applied research. In this chapter, we describe methods used to successfully reprogram quail fibroblasts into iPSCs by using human transcription factors and the techniques critical to the characterization of their pluripotency. PMID- 26621593 TI - Generation of Induced Pluripotent Stem Cells from Mammalian Endangered Species. AB - For some highly endangered species there are too few reproductively capable animals to maintain adequate genetic diversity, and extraordinary measures are necessary to prevent their extinction. Cellular reprogramming is a means to capture the genomes of individual animals as induced pluripotent stem cells (iPSCs), which may eventually facilitate reintroduction of genetic material into breeding populations. Here, we describe a method for generating iPSCs from fibroblasts of mammalian endangered species. PMID- 26621594 TI - Generation of Efficient Germ-Line Chimeras Using Embryonic Stem Cell Injection. AB - There are many different reasons for producing germ-line chimeras, so a method for producing these is very important both for the testing of stem cells (SC) and for the production of an animal which may be genetically modified (Voncken, Methods Mol Biol 693:11-36, 2011). As with many scientific procedures the theory behind the process is very simple: in this case injection of cells into the blastocoel cavity of an embryo which has developed to the blastocyst stage so as the injected cells can contribute to the inner cell mass (ICM) and hopefully contribute to the germ line of the animal produced (Schneider et al., Stem Cell Rev 5(4):369-377, 2009). Incorporation of the cells into the gonads of the animal produced will allow the testing of those cells and the resulting animal which may be derived from the injected cells (Bradley et al., Nature 309(5965):255-256, 1984). The problems arise because of the size of the cells and the challenge of injection into the blastocoel cavity of a developing embryo. PMID- 26621595 TI - Generation of Viable Mice from Induced Pluripotent Stem Cells (iPSCs) Through Tetraploid Complementation. AB - Tetraploid complementation assay is the most rigorous criteria for pluripotency characterization of pluripotent stem cells including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Pluripotent stem cells could complement the developmental deficiency of tetraploid embryos and thus support the full-term mice development. Here we describe the protocol for tetraploid complementation using iPSCs to produce viable all-iPSC mice. PMID- 26621596 TI - Cloning Endangered Felids by Interspecies Somatic Cell Nuclear Transfer. AB - In 2003, the first wild felid was produced by interspecies somatic cell nuclear transfer. Since then other wild felid clone offspring have been produced by using the same technique with minor modifications. This chapter describes detailed protocols used in our laboratory for (1) the isolation, culture, and preparation of fibroblast cells as donor nucleus, and (2) embryo reconstruction with domestic cat enucleated oocytes to produce cloned embryos that develop to the blastocyst stage in vitro and, after transfer into synchronized recipients, establish successful pregnancies. PMID- 26621597 TI - Generation of Chimeras from Porcine Induced Pluripotent Stem Cells. AB - Pig induced pluripotent stem cells (piPSCs) offer a great opportunity and a number of advantages in the generation of transgenic animals. These immortalized cells can undergo multiple rounds of genetic modifications (e.g., gene knock-in, knockout) and selection leading to animals that have optimized traits of biomedical or agricultural interests. In this chapter we describe the production and characterization of piPSCs, microinjection of piPSCs into embryos, embryo transfer and production of chimeric animals based on successful protocols. PMID- 26621598 TI - A Novel Method of Somatic Cell Nuclear Transfer with Minimum Equipment. AB - Somatic cell nuclear transfer (SCNT) is an exceptional experimental biology technique with an arguably great contribution to our current understanding of developmental plasticity. Many students and young researchers are interested in taking advantage of SCNT virtues in their experiments but the cost of micromanipulation microscopes, intensive training programs, and also the sophisticated process of SCNT may dissuade them from entering this amazing field of science. Here, we describe the details of a streamlined manual method of SCNT that can be performed using very basic equipment found in every embryology laboratory: the Pasteur pipette and stereomicroscope. The overall method introduced is very simple and a person with no previous experience in cloning can learn and adopt the basic routines of this technique independently. PMID- 26621599 TI - Neonatal Care and Management of Foals Derived by Somatic Cell Nuclear Transfer. AB - There are few reports on the birth of foals resulting from equine adult somatic cell nuclear transfer (NT). On evaluation of reports of 28 live-born adult somatic-cell NT (clone) foals, 3 died within 2 weeks of birth of complications. Approximately 50 % of all reported cloned foals had complications, some requiring aggressive supportive care. The most common abnormalities reported were neonatal maladjustment syndrome, enlarged umbilical remnant, and angular deformity of the forelimbs, similar to problems described in cloned cattle. In contrast, large offspring syndrome and gross abnormalities of the fetal membranes which are described in cloned cattle are not reported in cloned foals. Reports of the health of foals produced by nuclear transfer suggest that NT foals should be treated aggressively as at-risk foals until all parameters are normal. PMID- 26621600 TI - Isolation of Reprogramming Intermediates During Generation of Induced Pluripotent Stem Cells from Mouse Embryonic Fibroblasts. AB - Mature cells of the body can be reprogrammed towards a pluripotent state by forced expression of the transcription factors Oct-4, Klf-4, Sox2, and C-Myc (OKSM) at very low efficiency. To study the reprogramming process in detail the rare intermediates of the reaction need to be separated from the bulk population. Using a genetically engineered reprogrammable mouse strain we describe how to isolate intermediates from reprogramming cultures of mouse embryonic fibroblasts via antibody labeling of cell surface markers and fluorescence-activated cell sorting (FACS). PMID- 26621601 TI - Analysis of Mitochondrial DNA in Induced Pluripotent and Embryonic Stem Cells. AB - The mitochondrial genome has a major role to play in establishing and maintaining pluripotency. Furthermore, mitochondrial DNA (mtDNA) copy is strictly regulated during differentiation. Undifferentiated, pluripotent cells possess fewer than 300 copies of mtDNA, which establishes the mtDNA set point and promotes cell proliferation and, as a result, these cells rely on glycolysis with some support from oxidative phosphorylation (OXPHOS) for the generation of ATP. The mtDNA set point provides the starting point from which cells increase their mtDNA copy number as they differentiate into mature functional cells. Dependent on cell types, mtDNA copy number ranges from ~10 copies in sperm to several thousand in cardiomyocytes. Consequently, differentiating cell types can acquire the appropriate numbers of mtDNA copy to meet their specific requirements for ATP generated through OXPHOS. However, as reprogrammed somatic cells do not always achieve this, it is essential to analyze them for their OXPHOS potential and ability to regulate mtDNA copy number. Here, we describe how to assess mtDNA copy number in pluripotent and differentiating cells using real-time PCR protocols; assess expression of the mtDNA specific replication factors through real-time RT PCR; identify mtDNA variants in embryonic and induced pluripotent stem cells; determine DNA methylation patterns of the mtDNA-specific replication factors; and assess mitochondrial OXPHOS capacity. PMID- 26621602 TI - Genome Modification of Pluripotent Cells by Using Transcription Activator-Like Effector Nucleases (TALENs). AB - Interest is increasing in transcription activator-like effector nucleases (TALENs) as a tool to introduce targeted double-strand breaks into the large genomes of human and animal cell lines. The produced DNA lesions stimulate DNA repair pathways, error-prone but dominant non-homologous end joining (NHEJ) and accurate but less occurring homology-directed repair (HDR), and as a result targeted genes can be modified. Here, we describe a modified Golden-Gate cloning method for generating TALENs and also details for targeting genes in mouse embryonic stem cells. The protocol described here can be used for modifying the genome of a broad range of pluripotent cell lines. PMID- 26621603 TI - TEST performance of a myositis panel in a clinical immunology laboratory in New South Wales, Australia. AB - BACKGROUND: There is increasing recognition of a clinico-serological correlation between the idiopathic inflammatory myopathies and myositis-specific autoantibodies (MSA). We review the use of a line immunoassay-based myositis panel incorporating both MSA and myositis-associated autoantibodies (MAA) in a selected population of patients. METHODS: A retrospective analysis of patients with myositis panel assays performed in 2013 were reviewed and compared against clinical diagnoses. RESULTS: A total of 96 patient samples were evaluated, the clinical indications include 60 patients with suspected idiopathic inflammatory myositis (IIM), 24 patients with suspected interstitial lung disease (ILD) and 12 patients with suspected systemic autoimmune disease (SAD). In the myositis group, there were 21 patients diagnosed with IIM and 18 patients diagnosed with IIM had a positive myositis panel. Of the 39 patients without IIM, nine of these patients had a positive myositis panel. In the ILD group, 10 of 24 patients had a positive myositis panel; of these, two were diagnosed anti-synthetase syndrome (ASS) and five patients with ILD. In the suspected SAD group, three had positive myositis panel and all did not appear associated with their final diagnoses. In patients with a clinical diagnosis of IIM or ILD-associated SAD, four patients with anti PL-12 were detected, three patients with anti-signal recognition protein, two patients with anti-Jo-1, and two patients with anti-Mi2. CONCLUSIONS: The myositis panel is an objective investigative modality with a sensitivity of 80.00% and a specificity of 75.76% in a setting of high pretest clinical suspicion. PMID- 26621604 TI - Optimal surgical cytoreduction of the upper abdomen and the diaphragm for advanced ovarian cancer using PlasmaJetTM energy. AB - OBJECTIVE: To show the contribution of PlasmaJetTM, technology using pur gaz plasma as electrically neutral source of energy to cut and coagulate tissue, in ovarian cancer surgery. METHODS: A forty eight years old patient was diagnosed with an ovarian cancer. The first laparoscopy allowed one to make histological diagnosis (ovarian high-grade serous carcinoma) and determine that the disease was resecable, with a PCI to ten. The film shows the upper abdominal time of the cytoreduction surgery, using PlasmaJetTM. RESULTS: The surgery included: stripping of the peritoneum of the right diaphragm and full thickness diaphragmatic resection, stripping of the peritoneum of left diaphragm splenectomy, resection of the greater and the lesser omentums, pelvic lymphadenectomy and para-aortic lymphadenectomy, posterior pelvectomy (Hudson) and appendicectomy. There were no postoperative complications (short or medium term). CONCLUSION: The PlasmaJet seems to be a very interesting instrument in this type of surgery, particularly in the dissection of adherent pathological areas, as diaphragmatic domes can be. PMID- 26621606 TI - Women, Private Health Insurance, and the Affordable Care Act. PMID- 26621605 TI - Patient and Provider Perceptions of Weight Gain, Physical Activity, and Nutrition Counseling during Pregnancy: A Qualitative Study. AB - OBJECTIVE: This study investigated patient and provider perceptions of weight gain, physical activity, and nutrition counseling during prenatal care visits. METHODS: Individual qualitative interviews were conducted with 30 pregnant women between 20 and 30 weeks gestation (15 African American, 15 White) and 11 prenatal care providers (5 attending physicians, 5 residents, 1 nurse practitioner) in 2014. RESULTS: The majority of patients and providers reported receiving or giving advice on weight gain (87% and 100%, respectively), physical activity (87% and 91%), and nutrition (100% and 91%) during a prenatal visit. Discussion of counseling content was largely consistent between patients and providers. However, counseling was limited and not fully consistent with current weight gain, physical activity, or dietary guidelines during pregnancy. Most patients viewed provider advice positively, but some wanted more detailed information. Providers discussed many barriers to lifestyle counseling, including lack of time, inadequate training, concern about the sensitivity of the topic, lower education or income level of the patient, cultural differences, and lack of patient interest. CONCLUSIONS: Providers discussed weight gain, physical activity, and nutrition during prenatal care visits and patients accurately recalled this advice. However, counseling was limited and not fully consistent with guidelines. Future studies are needed to develop and evaluate the efficacy of interventions to help providers overcome perceived barriers and more effectively counsel women on weight and healthy lifestyles during pregnancy. PMID- 26621607 TI - Practices Regarding Rape-related Pregnancy in U.S. Abortion Care Settings. AB - OBJECTIVE: We aimed to explore current practices regarding screening for rape and response to disclosure of rape-related pregnancy in the abortion care setting. METHODS: We performed a cross-sectional, nonprobability survey of U.S. abortion providers. Individuals were recruited in person and via emailed invitations to professional organization member lists. Questions in this web-based survey pertained to providers' practice setting, how they identify rape-related pregnancy, the availability of support services, and their experiences with law enforcement. Providers were asked their perceptions of barriers to care for women who report rape-related pregnancy. RESULTS: Surveys were completed by 279 providers (21% response rate). Most respondents were female (93.1%), and the majority were physicians in a clinical role (69.4%). One-half (49.8%) reported their practice screens for pregnancy resulting from rape, although fewer (34.8%) reported that screening is the method through which most patients with this history are identified. Most (80.6%) refer women with rape-related pregnancy to support services such as rape crisis centers. Relatively few (19.7%) have a specific protocol for care of women who report rape-related pregnancy. Clinics that screen were 79% more likely to have a protocol for care than centers that do not screen. Although the majority (67.4%) reported barriers to identification of women with rape-related pregnancy, fewer (33.3%) reported barriers to connecting them to support services. CONCLUSION: Practices for identifying and providing care to women with rape-related pregnancy in the abortion care setting are variable. Further research should address barriers to care provision, as well as identifying protocols for care. PMID- 26621608 TI - Genetic association of marbling score with intragenic nucleotide variants at selection signals of the bovine genome. AB - Selection signals of Korean cattle might be attributed largely to artificial selection for meat quality. Rapidly increased intragenic markers of newly annotated genes in the bovine genome would help overcome limited findings of genetic markers associated with meat quality at the selection signals in a previous study. The present study examined genetic associations of marbling score (MS) with intragenic nucleotide variants at selection signals of Korean cattle. A total of 39 092 nucleotide variants of 407 Korean cattle were utilized in the association analysis. A total of 129 variants were selected within newly annotated genes in the bovine genome. Their genetic associations were analyzed using the mixed model with random polygenic effects based on identical-by-state genetic relationships among animals in order to control for spurious associations produced by population structure. Genetic associations of MS were found (P<3.88*10-4) with six intragenic nucleotide variants on bovine autosomes 3 (cache domain containing 1, CACHD1), 5 (like-glycosyltransferase, LARGE), 16 (cell division cycle 42 binding protein kinase alpha, CDC42BPA) and 21 (snurportin 1, SNUPN; protein tyrosine phosphatase, non-receptor type 9, PTPN9; chondroitin sulfate proteoglycan 4, CSPG4). In particular, the genetic associations with CDC42BPA and LARGE were confirmed using an independent data set of Korean cattle. The results implied that allele frequencies of functional variants and their proximity variants have been augmented by directional selection for greater MS and remain selection signals in the bovine genome. Further studies of fine mapping would be useful to incorporate favorable alleles in marker-assisted selection for MS of Korean cattle. PMID- 26621609 TI - The GL service: Web service to exchange GL string encoded HLA & KIR genotypes with complete and accurate allele and genotype ambiguity. AB - Genotype list (GL) Strings use a set of hierarchical character delimiters to represent allele and genotype ambiguity in HLA and KIR genotypes in a complete and accurate fashion. A RESTful web service called genotype list service was created to allow users to register a GL string and receive a unique identifier for that string in the form of a URI. By exchanging URIs and dereferencing them through the GL service, users can easily transmit HLA genotypes in a variety of useful formats. The GL service was developed to be secure, scalable, and persistent. An instance of the GL service is configured with a nomenclature and can be run in strict or non-strict modes. Strict mode requires alleles used in the GL string to be present in the allele database using the fully qualified nomenclature. Non-strict mode allows any GL string to be registered as long as it is syntactically correct. The GL service source code is free and open source software, distributed under the GNU Lesser General Public License (LGPL) version 3 or later. PMID- 26621610 TI - Reply. PMID- 26621612 TI - Comparison of fluoride effects on germination and growth of Zea mays, Glycine max and Sorghum vulgare. AB - BACKGROUND: Fluorosis is a disease caused by over-exposure to fluoride (F). Argentina's rural lands have higher fluorine content than urban lands. Evidence confirms that plants grown in fluoridated areas could have higher F content. We compared F uptake and growth of crops grown in different F concentrations. The effect of 0-8 ppm F concentrations on maize, soybeans and sorghum germination and growth was compared. After 6 days seeding, the germination was determined, the roots and aerial parts lengths were measured, and vigor index was calculated. F content was measured in each part of the plants. Controls with equal concentrations of NaCl were carried out. RESULTS: Significant decrease in roots and aerial parts lengths, and in vigor index of maize and soybeans plants was observed with F concentrations greater than 2 ppm. This was not observed in sorghum seedlings. Also, the amount of F in all crops augmented as F increases, being higher in roots and ungerminated seeds. Sorghum was the crop with the highest F content. CONCLUSION: Fluoride decreased the germination and growth of maize and soybeans and therefore could influence on their production. Conversely, sorghum seems to be resistant to the action of F. (c) 2015 Society of Chemical Industry. PMID- 26621613 TI - Patients' daily life experiences five years after gastric bypass surgery--a qualitative study. AB - AIM AND OBJECTIVE: The objective was to explore and describe patients' daily life experiences five years after gastric bypass surgery. BACKGROUND: Bariatric surgery markedly decreases body weight. Previous studies describe positive consequences, as well as physical, social and emotional challenges during the first few years after surgery. An understanding of how patients adjust to and cope with postsurgical changes in the long term is crucial to help them obtain a successful outcome after bariatric surgery. METHOD: A qualitative method was employed. In-depth interviews with 10 men and women were conducted five years after bariatric surgery in a Norwegian hospital. RESULTS: One overarching theme- a multitude of daily life changes following bariatric surgery--was developed based on three main themes: relational aspects related to weight loss, the new body and changes in self-esteem. Six sub-themes are described. CONCLUSION: Those who undergo gastric bypass surgery experience enormous changes in their daily lives. Their social lives, their relationship to their body and their self-esteem may be altered by the weight loss. RELEVANCE TO CLINICAL PRACTICE: The results of this study suggest directions for patient education, health staff education and peer education. A patient education programme focusing on changes in daily life experiences when undergoing gastric bypass surgery is suggested due to the changes experienced by the patients involved in this study. PMID- 26621614 TI - A year (2014-2015) of plants in Proteomics journal. Progress in wet and dry methodologies, moving from protein catalogs, and the view of classic plant biochemists. AB - The present review is an update of the previous one published in Proteomics 2015 Reviews special issue [Jorrin-Novo, J. V. et al., Proteomics 2015, 15, 1089-1112] covering the July 2014-2015 period. It has been written on the bases of the publications that appeared in Proteomics journal during that period and the most relevant ones that have been published in other high-impact journals. Methodological advances and the contribution of the field to the knowledge of plant biology processes and its translation to agroforestry and environmental sectors will be discussed. This review has been organized in four blocks, with a starting general introduction (literature survey) followed by sections focusing on the methodology (in vitro, in vivo, wet, and dry), proteomics integration with other approaches (systems biology and proteogenomics), biological information, and knowledge (cell communication, receptors, and signaling), ending with a brief mention of some other biological and translational topics to which proteomics has made some contribution. PMID- 26621615 TI - Facile Synthesis of Coaxial CNTs/MnOx-Carbon Hybrid Nanofibers and Their Greatly Enhanced Lithium Storage Performance. AB - Carbon nanotubes (CNTs)/MnOx-Carbon hybrid nanofibers have been successfully synthesized by the combination of a liquid chemical redox reaction (LCRR) and a subsequent carbonization heat treatment. The nanostructures exhibit a unique one dimensional core/shell architecture, with one-dimensional CNTs encapsulated inside and a MnOx-carbon composite nanoparticle layer on the outside. The particular porous characteristics with many meso/micro holes/pores, the highly conductive one-dimensional CNT core, as well as the encapsulating carbon matrix on the outside of the MnOx nanoparticles, lead to excellent electrochemical performance of the electrode. The CNTs/MnOx-Carbon hybrid nanofibers exhibit a high initial reversible capacity of 762.9 mAhg(-1), a high reversible specific capacity of 560.5 mAhg(-1) after 100 cycles, and excellent cycling stability and rate capability, with specific capacity of 396.2 mAhg(-1) when cycled at the current density of 1000 mAg(-1), indicating that the CNTs/MnOx-Carbon hybrid nanofibers are a promising anode candidate for Li-ion batteries. PMID- 26621618 TI - Conductive Graphitic Carbon Nitride as an Ideal Material for Electrocatalytically Switchable CO2 Capture. AB - Good electrical conductivity and high electron mobility of the sorbent materials are prerequisite for electrocatalytically switchable CO2 capture. However, no conductive and easily synthetic sorbent materials are available until now. Here, we examined the possibility of conductive graphitic carbon nitride (g-C4N3) nanosheets as sorbent materials for electrocatalytically switchable CO2 capture. Using first-principle calculations, we found that the adsorption energy of CO2 molecules on g-C4N3 nanosheets can be dramatically enhanced by injecting extra electrons into the adsorbent. At saturation CO2 capture coverage, the negatively charged g-C4N3 nanosheets achieve CO2 capture capacities up to 73.9 * 10(13) cm( 2) or 42.3 wt%. In contrast to other CO2 capture approaches, the process of CO2 capture/release occurs spontaneously without any energy barriers once extra electrons are introduced or removed, and these processes can be simply controlled and reversed by switching on/off the charging voltage. In addition, these negatively charged g-C4N3 nanosheets are highly selective for separating CO2 from mixtures with CH4, H2 and/or N2. These predictions may prove to be instrumental in searching for a new class of experimentally feasible high-capacity CO2 capture materials with ideal thermodynamics and reversibility. PMID- 26621617 TI - Low-frequency stimulation in anterior nucleus of thalamus alleviates kainate induced chronic epilepsy and modulates the hippocampal EEG rhythm. AB - High-frequency stimulation (HFS) of the anterior nucleus of thalamus (ANT) is a new and alternative option for the treatment of intractable epilepsy. However, the responder rate is relatively low. The present study was designed to determine the effect of low-frequency stimulation (LFS) in ANT on chronic spontaneous recurrent seizures and related pathological pattern in intra-hippocampal kainate mouse model. We found that LFS (1 Hz, 100 MUs, 300 MUA), but not HFS (100 Hz, 100 MUs, 30 MUA), in bilateral ANT significantly decreased the frequency of spontaneous recurrent seizures, either non-convulsive focal seizures or tonic clonic generalized seizures. The anti-epileptic effect persisted for one week after LFS cessation, which manifested as a long-term inhibition of the frequency of seizures with short (20-60 s) and intermediate duration (60-120 s). Meanwhile, LFS decreased the frequency of high-frequency oscillations (HFOs) and interictal spikes, two indicators of seizure severity, whereas HFS increased the HFO frequency. Furthermore, LFS decreased the power of the delta band and increased the power of the gamma band of hippocampal background EEG. In addition, LFS, but not HFS, improved the performance of chronic epileptic mice in objection-location task, novel objection recognition and freezing test. These results provide the first evidence that LFS in ANT alleviates kainate-induced chronic epilepsy and cognitive impairment, which may be related to the modulation of the hippocampal EEG rhythm. This may be of great therapeutic significance for clinical treatment of epilepsy with deep brain stimulation. PMID- 26621616 TI - High educational performance is a distinctive feature of bipolar disorder: a study on cognition in bipolar disorder, schizophrenia patients, relatives and controls. AB - BACKGROUND: Schizophrenia is associated with lower intelligence and poor educational performance relative to the general population. This is, to a lesser degree, also found in first-degree relatives of schizophrenia patients. It is unclear whether bipolar disorder I (BD-I) patients and their relatives have similar lower intellectual and educational performance as that observed in schizophrenia. METHOD: This cross-sectional study investigated intelligence and educational performance in two outpatient samples [494 BD-I patients, 952 schizophrenia spectrum (SCZ) patients], 2231 relatives of BD-I and SCZ patients, 1104 healthy controls and 100 control siblings. Mixed-effects and regression models were used to compare groups on intelligence and educational performance. RESULTS: BD-I patients were more likely to have completed the highest level of education (odds ratio 1.88, 95% confidence interval 1.66-2.70) despite having a lower IQ compared to controls (beta = -9.09, S.E. = 1.27, p < 0.001). In contrast, SCZ patients showed both a lower IQ (beta = -15.31, S.E. = 0.86, p < 0.001) and lower educational levels compared to controls. Siblings of both patient groups had significantly lower IQ than control siblings, but did not differ on educational performance. IQ scores did not differ between BD-I parents and SCZ parents, but BD-I parents had completed higher educational levels. CONCLUSIONS: Although BD-I patients had a lower IQ than controls, they were more likely to have completed the highest level of education. This contrasts with SCZ patients, who showed both intellectual and educational deficits compared to healthy controls. Since relatives of BD-I patients did not demonstrate superior educational performance, our data suggest that high educational performance may be a distinctive feature of bipolar disorder patients. PMID- 26621619 TI - In Vitro Pharmacodynamics of Vancomycin against Methicillin-Susceptible and Resistant Staphylococcus aureus: Considering the Variability in Observed Tissue Exposure. AB - Vancomycin is considered a first-line antibiotic for complicated skin and skin structure infections (cSSSI) because of the risk of methicillin-resistant Staphylococcus aureus (MRSA). The vancomycin exposure of tissue can vary widely in patients with cSSSI, yet most models test only the average exposure. The in vitro pharmacodynamic model was used to simulate three tissue exposure levels attained by administering vancomycin at 1 g every 12 h (q12h), based on the median (50th), 25th, and 10th percentile tissue area under the concentration-time curve (AUC) values observed during an in vivo microdialysis study of diabetic patients. Four clinical isolates (two of MRSA [vancomycin MIC, 1 and 2 MUg/ml] and two of methicillin-susceptible S. aureus [MSSA] [MIC, 1 and 2 MUg/ml]) were evaluated. Experiments were performed over 72 h in duplicate. Time-kill curves were constructed, and the area under the bacterial killing and regrowth curve (AUBC) during the final 24-h dosing interval (48 to 72 h) (AUBC48-72) was calculated. Reductions in the 72-h number of CFU/ml and AUBC48-72 at the different exposure levels were compared. Target tissue vancomycin exposure levels for the 50th (AUC0-12, 102.0 +/- 9.1 MUg . h/ml), 25th (AUC0-12, 44.3 +/- 1.8 MUg . h/ml), and 10th (AUC0-12, 25.3 +/- 3.1 MUg . h/ml) percentiles were obtained in all studies. No differences in the 72-h number of CFU or AUBC were observed between exposure levels when all of the isolates were analyzed together. However, for the two MRSA isolates, the 10th percentile exposure level achieved a lower 72 h number of CFU/ml (-1.4 +/- 0.4 log10 CFU/ml, P = 0.007) and a greater AUBC48-72 (97.1 +/- 20.0 log10 CFU . h/ml, P = 0.011) than the higher exposure levels. The majority of the tissue exposure levels achieved with a vancomycin dosing regimen of 1 g q12h resulted in substantial killing of MSSA and MRSA; however, the lowest exposure levels observed in a minority of the population may explain the poor vancomycin response. PMID- 26621620 TI - Geneticin Stabilizes the Open Conformation of the 5' Region of Hepatitis C Virus RNA and Inhibits Viral Replication. AB - The aminoglycoside Geneticin (G418) is known to inhibit cell culture proliferation, via virus-specific mechanisms, of two different virus genera from the family Flaviviridae. Here, we tried to determine whether Geneticin can selectively alter the switching of the nucleotide 1 to 570 RNA region of hepatitis C virus (HCV) and, if so, whether this inhibits viral growth. Two structure-dependent RNases known to specifically cleave HCV RNA were tested in the presence or absence of the drug. One was the Synechocystis sp. RNase P ribozyme, which cleaves the tRNA-like domain around the AUG start codon under high-salt buffer conditions; the second was Escherichia coli RNase III, which recognizes a double-helical RNA switch element that changes the internal ribosome entry site (IRES) from a closed (C) conformation to an open (O) one. While the drug did not affect RNase P activity, it did inhibit RNase III in the micromolar range. Kinetic studies indicated that the drug favors the switch from the C to the O conformation of the IRES by stabilizing the distal double-stranded element and inhibiting further processing of the O form. We demonstrate that, because the RNA in this region is highly conserved and essential for virus survival, Geneticin inhibits HCV Jc1 NS3 expression, the release of the viral genomic RNA, and the propagation of HCV in Huh 7.5 cells. Our study highlights the crucial role of riboswitches in HCV replication and suggests the therapeutic potential of viral-RNA-targeted antivirals. PMID- 26621622 TI - Comparative RNA-seq-Based Transcriptome Analysis of the Virulence Characteristics of Methicillin-Resistant and -Susceptible Staphylococcus pseudintermedius Strains Isolated from Small Animals. AB - Staphylococcus pseudintermedius is often associated with pyoderma, which can turn into a life-threatening disease. The dissemination of highly resistant isolates has occurred in the last 10 years and has challenged antimicrobial treatment of these infections considerably. We have compared the carriage of virulence genes and biofilm formation between methicillin-resistant and methicillin-susceptible S. pseudintermedius (MRSP and MSSP, respectively) isolates and their in vitro gene expression profiles by transcriptome sequencing (RNA-seq). Isolates were relatively unevenly distributed among the four agr groups, and agr type III predominated in MRSP. Five virulence genes were detected in all isolates. Only the spsO gene was significantly associated with MSSP isolates (P = 0.04). All isolates produced biofilm in brain heart infusion broth (BHIB)-4% NaCl. MSSP isolates produced more biofilm on BHIB and BHIB-1% glucose media than MRSP isolates (P = 0.03 and P = 0.02, respectively). Virulence genes encoding surface proteins and toxins (spsA, spsB, spsD, spsK, spsL, spsN, nucC, coa, and luk-I) and also prophage genes (encoding phage capsid protein, phage infection protein, two phage portal proteins, and a phage-like protein) were highly expressed in the MRSP isolate (compared with the MSSP isolate), suggesting they may play a role in the rapid and widespread dissemination of MRSP. This study indicates that MRSP may upregulate surface proteins, which may increase the adherence of MRSP isolates (especially sequence type 71 [ST71]) to corneocytes. MSSP isolates may have an increased ability to form biofilm under acidic circumstances, through upregulation of the entire arc operon. Complete understanding of S. pseudintermedius pathogenesis and host-pathogen signal interaction during infections is critical for the treatment and prevention of S. pseudintermedius infections. PMID- 26621621 TI - Characterization of a Carbapenem-Hydrolyzing Enzyme, PoxB, in Pseudomonas aeruginosa PAO1. AB - Pseudomonas aeruginosa is an opportunistic pathogen often associated with severe and life-threatening infections that are highly impervious to treatment. This microbe readily exhibits intrinsic and acquired resistance to varied antimicrobial drugs. Resistance to penicillin-like compounds is commonplace and provided by the chromosomal AmpC beta-lactamase. A second, chromosomally encoded beta-lactamase, PoxB, has previously been reported in P. aeruginosa. In the present work, the contribution of this class D enzyme was investigated using a series of clean in-frame ampC, poxB, and oprD deletions, as well as complementation by expression under the control of an inducible promoter. While poxB deletions failed to alter beta-lactam sensitivities, expression of poxB in ampC-deficient backgrounds decreased susceptibility to both meropenem and doripenem but had no effect on imipenem, penicillin, and cephalosporin MICs. However, when expressed in an ampCpoxB-deficient background, that additionally lacked the outer membrane porin-encoding gene oprD, PoxB significantly increased the imipenem as well as the meropenem and doripenem MICs. Like other class D carbapenem-hydrolyzing beta-lactamases, PoxB was only poorly inhibited by class A enzyme inhibitors, but a novel non-beta-lactam compound, avibactam, was a slightly better inhibitor of PoxB activity. In vitro susceptibility testing with a clinical concentration of avibactam, however, failed to reduce PoxB activity against the carbapenems. In addition, poxB was found to be cotranscribed with an upstream open reading frame, poxA, which itself was shown to encode a 32-kDa protein of yet unknown function. PMID- 26621624 TI - Preserving Cognition and Attaining Ideal Anesthesia and Surgical Outcomes in Older Adults. PMID- 26621623 TI - Simultaneous Semimechanistic Population Analyses of Levofloxacin in Plasma, Lung, and Prostate To Describe the Influence of Efflux Transporters on Drug Distribution following Intravenous and Intratracheal Administration. AB - Levofloxacin (LEV) is a broad-spectrum fluoroquinolone used to treat pneumonia, urinary tract infections, chronic bacterial bronchitis, and prostatitis. Efflux transporters, primarily P-glycoprotein (P-gp), are involved in LEV's tissue penetration. In the present work, LEV free lung and prostate interstitial space fluid (ISF) concentrations were evaluated by microdialysis in Wistar rats after intravenous (i.v.) and intratracheal (i.t.) administration (7 mg/kg of body weight) with and without coadministration of the P-gp inhibitor tariquidar (TAR; 15 mg/kg administered i.v.). Plasma and tissue concentration/time profiles were evaluated by noncompartmental analysis (NCA) and population pharmacokinetics (popPK) analysis. The NCA showed significant differences in bioavailability (F) for the control group (0.4) and the TAR group (0.86) after i.t. administration. A four-compartment model simultaneously characterized total plasma and free lung (compartment 2) and prostate (compartment 3) ISF concentrations. Statistically significant differences in lung and prostate average ISF concentrations and levels of kidney active secretion in the TAR group from those measured for the control group (LEV alone) were observed. The estimated population means were as follows: volume of the central compartment (V1), 0.321 liters; total plasma clearance (CL), 0.220 liters/h; TAR plasma clearance (CLTAR), 0.180 liters/h. The intercompartmental distribution rate constants (K values) were as follows: K12, 8.826 h(-1); K21, 7.271 h(-1); K13, 0.047 h(-1); K31, 7.738 h(-1); K14, 0.908 h( 1); K41, 0.409 h(-1); K21 lung TAR (K21LTAR), 8.883 h(-1); K31 prostate TAR (K31PTAR), 4.377 h(-1). The presence of P-gp considerably impacted the active renal secretion of LEV but had only a minor impact on the efflux from the lung following intratracheal dosing. Our results strongly support the idea of a role of efflux transporters other than P-gp contributing to LEV's tissue penetration into the prostrate. PMID- 26621625 TI - Saliva versus Plasma for Pharmacokinetic and Pharmacodynamic Studies of Fentanyl in Patients with Cancer. PMID- 26621627 TI - Comment Re: Kapil et al. 2015. PMID- 26621626 TI - The Association of Brain MRI Characteristics and Postoperative Delirium in Cardiac Surgery Patients. AB - PURPOSE: Delirium is common after cardiac surgery and is associated with adverse consequences, including cognitive decline. Identification of vulnerable older adults might allow for early implementation of delirium-prevention strategies. Brain MRI findings provide insight into structural brain changes that may identify vulnerable patients. The purpose of this study was to examine the association between brain MRI characteristics potentially associated with delirium vulnerability and the development of postoperative delirium in a nested cohort of patients undergoing cardiac surgery. METHODS: We identified 79 cardiac surgery patients who had brain MRI imaging after cardiac surgery, as part of an ongoing randomized trial evaluating the efficacy of blood pressure management based on cerebral autoregulation monitoring versus standard management for improving neurological outcomes. Cerebral lateral ventricular size, cortical sulcal width, and white matter hyperintensities (WMH) on brain MRI scans were graded on a validated 0 to 9 scale, and categorized into tertiles. New ischemic lesions were characterized as present or absent. Delirium was assessed using a validated chart-review. Neuropsychological testing performed before surgery was used to establish preoperative cognitive baseline. Multivariable logistic regression was used to assess the independent association between MRI characteristics and postoperative delirium. FINDINGS: The average age of patients was 70.1 +/- 7.8 years old, and 72% were male. Twenty-eight of 79 (35.4%) patients developed postoperative delirium. Patients with delirium had higher unadjusted ventricular size (median 4 vs. 3, P = 0.003), and there was a trend towards higher sulcal sizes and WMH grades. Increasing tertiles of ventricular size (Odds Ratio [OR] 3.59; 95% Confidence Interval [CI] 1.59-8.12; P = 0.002) and sulcal size (OR 2.15; 95%CI 1.13-4.12; P = 0.02) were associated with postoperative delirium, with a trend for tertiles of WMH grade (OR 1.91; 95%CI 0.99-3.68; P = 0.05). In multivariable models adjusted for logistic EuroSCORE, baseline cognitive status, bypass time, and any postoperative complication, each tertile of ventricular size was associated with increased odds of postoperative delirium (OR 3.23 per tertile increase in ventricular size; 95%CI 1.21-8.60; P = 0.02). There were no differences in odds of delirium by tertiles of sulcal grade, tertiles of white matter grade, or presence of new ischemic lesions, in adjusted models. IMPLICATIONS: Increased brain ventricular size was independently associated with delirium after cardiac surgery. These results suggest that cerebral atrophy may contribute to increased vulnerability for postoperative delirium. Baseline brain MRIs may be useful in identifying cardiac surgery patients at high risk for postoperative delirium, who might benefit from targeted perioperative approaches to prevent delirium. ClinicalTrials.gov identifier: NCT00981474. PMID- 26621628 TI - Can Intraoperative Processed EEG Predict Postoperative Cognitive Dysfunction in the Elderly? AB - PURPOSE: Postoperative cognitive dysfunction (POCD) is a serious and costly complication of the elderly; even mild impairment has the potential to impact overall well being. Anesthesiologists continue to search for ways to manipulate intraoperative technique to optimize postoperative cognition in the elderly. Depth of anesthesia during surgery is an area that has shown some promise for short-term outcomes, such as delirium. However, excessive depth has both positive and negative associations with longer-term POCD. We hypothesize that this uncertainty is due to the inability of median depth to capture the amount of burst suppression or electrical silence. In this study, our purpose was to identify the intraoperative processed EEG parameters that are most closely correlated with POCD. METHODS: To explore the association of several processed EEG parameters with POCD, we performed a retrospective analysis of a cohort of 105 patients aged >68 years scheduled for major surgery under general anesthesia. Intraoperative medications, hemodynamics, processed EEG and cerebral oxygen saturation were recorded. All patients had a cognitive battery before surgery and repeated at 3 months afterward. FINDINGS: One hundred and five patients enrolled and 77 (73.3%) patients completed the 3-month cognitive testing. The incidence of POCD was 27%; the median Bispectral Index value for patients who developed POCD was similar to patients who did not (46 vs 42 minutes). However, patients who developed POCD spent less time with Bispectral Index <45 minutes (82.8 vs 122.5 minutes, P = 0.01) and burst suppression (35 vs 96 minutes, P = 0.04). Hypotension, cerebral desaturation, and use of total intravenous anesthesia were similar between patients with and without POCD. IMPLICATIONS: Patients who developed POCD spent less time in EEG burst suppression and less time in deep states. Burst suppression may be protective for POCD. Further work is needed to definitively identify the role of burst suppression in the context of other patient and intraoperative variables to prevent POCD. PMID- 26621629 TI - Saliva versus Plasma for Pharmacokinetic and Pharmacodynamic Studies of Fentanyl in Patients with Cancer. PMID- 26621630 TI - Suppression on plant-parasitic nematodes using a soil fumigation strategy based on ammonium bicarbonate and its effects on the nematode community. AB - Banana production is severely hindered by plant-parasitic nematodes in acidic, sandy soil. This study investigated the possibility of applying a novel fumigation agent based on ammonium bicarbonate as a strategy for controlling plant-parasitic nematodes under sealed conditions. Moreover, its effects on the nematode community in pot and field experiments were also measured using morphology and feeding-habit based classification and the PCR-DGGE method. Results showed that a mixture (LAB) of lime (L) and ammonium bicarbonate (AB) in suitable additive amounts (0.857 g kg(-1) of L and 0.428 g kg(-1) of AB) showed stronger nematicidal ability than did the use of AB alone or the use of ammonium hydroxide (AH) and calcium cyanamide (CC) with an equal nitrogen amount. The nematode community was altered by the different fumigants, and LAB showed an excellent plant-parasitic nematicidal ability, especially for Meloidogyne and Rotylenchulus, as revealed by morphology and feeding-habit based classification, and for Meloidogyne, as revealed by the PCR-DGGE method. Fungivores and omnivore predators were more sensitive to the direct effects of the chemicals than bacterivores. This study explored a novel fumigation agent for controlling plant parasitic nematodes based on LAB and provides a potential strategy to ensure the worldwide development of the banana industry. PMID- 26621631 TI - Consumption of Bifidobacterium animalis subsp. lactis BB-12 in yogurt reduced expression of TLR-2 on peripheral blood-derived monocytes and pro-inflammatory cytokine secretion in young adults. AB - PURPOSE: Probiotic bacteria modulate immune parameters and inflammatory outcomes. Emerging evidence demonstrates that the matrix used to deliver probiotics may influence the efficacy of probiotic interventions in vivo. The aims of the current study were to evaluate (1) the effect of one species, Bifidobacterium animalis subsp. lactis BB-12 at a dose of log10 +/- 0.5 CFUs/day on immune responses in a randomized, partially blinded, 4-period crossover, free-living study, and (2) whether the immune response to BB-12 differed depending on the delivery matrix. METHODS: Healthy adults (n = 30) aged 18-40 years were recruited and received four treatments in a random order: (A) yogurt smoothie alone; smoothie with BB-12 added (B) before or (C) after yogurt fermentation, or (D) BB 12 given in capsule form. At baseline and after each 4-week treatment, peripheral blood mononuclear cells (PBMCs) were isolated, and functional and phenotypic marker expression was assessed. RESULTS: BB-12 interacted with peripheral myeloid cells via Toll-like receptor 2 (TLR-2). The percentage of CD14+HLA-DR+ cells in peripheral blood was increased in male participants by all yogurt-containing treatments compared to baseline (p = 0.0356). Participants who consumed yogurt smoothie with BB-12 added post-fermentation had significantly lower expression of TLR-2 on CD14+HLA-DR+ cells (p = 0.0186) and reduction in TNF-alpha secretion from BB-12- (p = 0.0490) or LPS-stimulated (p = 0.0387) PBMCs compared to baseline. CONCLUSIONS: These findings not only demonstrate a potential anti inflammatory effect of BB-12 in healthy adults, but also indicate that the delivery matrix influences the immunomodulatory properties of BB-12. PMID- 26621633 TI - Role of selected amino acids on plasma IGF-I concentration in infants. AB - PURPOSE: Insulin-like growth factor-I (IGF-I) is related to growth and its secretion is modified by protein intake in early infancy. We examined the relationship of dietary protein and circulating amino acids on plasma IGF-I levels and early growth. METHODS: Healthy formula-fed infants (n = 213) were randomly assigned to receive either a protein-reduced infant formula with alpha lactalbumin-enriched whey and free tryptophan and phenylalanine (IF) or an isocaloric standard formula without free amino acids (CF) for the first 120 days of life. A group of breastfed (BF) infants was studied as a non-randomized reference cohort. Biochemical variables were measured shortly after birth (subpopulation) and at an age of 120 days. A path analysis was used to explore the relationship between IGF-I, insulin and amino acids. Results are derived from secondary analyses of a randomized controlled trial. RESULTS: Plasma concentrations of IGF-I at 120 days were significantly higher in IF than in CF infants [58.5 (15.0) vs. 53.7 (9.95) ng/mL; p = 0.020]. BF infants showed lower IGF-I concentrations of 41.6 (10.7) ng/mL. All amino acids but Thr and Cit had a more marked effect on insulin than on IGF-I level. Considering weight, sex and feeding group, Trp explained an equal percentage of variance of IGF-I and insulin (total R 2 12.5 % of IGF-I and 12.3 % of insulin), while branched-chain AA explained an up to twofold higher variance of insulin than IGF-I. Compared to CF, IF explained 18.9 % of the IGF-I level (p = 0.03), while for insulin no direct effect was detectable. CONCLUSION: Higher IGF-I concentrations and growth velocities in infants receiving protein-reduced IF indicate that the protein concentration of an infant formula alone does not control IGF-I levels and growth. Other components (e.g., selected amino acids) of infant formulae might control directly or indirectly via insulin influence IGF-I. PMID- 26621632 TI - Taurine supplementation regulates Ikappa-Balpha protein expression in adipose tissue and serum IL-4 and TNF-alpha concentrations in MSG obesity. AB - PURPOSE: Obesity is usually associated with low-grade inflammation, which impairs insulin action. The amino acid, taurine (TAU), regulates glucose homeostasis and lipid metabolism and presents anti-inflammatory actions. Here, we evaluated whether inflammatory markers are altered in the serum and retroperitoneal adipose tissue of monosodium glutamate (MSG) obese rats, supplemented or not with TAU. METHODS: Male Wistar rats received subcutaneous injections of MSG (4 mg/kg body weight/day, MSG group) or hypertonic saline (CTL) during the first 5 days of life. From 21 to 120 days of age, half of each of the MSG and CTL groups received 2.5 % TAU in their drinking water (CTAU and MTAU). RESULTS: At 120 days of age, MSG rats were obese and hyperinsulinemic. TAU supplementation reduced fat deposition without affecting insulinemia in MTAU rats. MSG rats presented increased pIkappa-Balpha/Ikappa-Balpha protein expression in the retroperitoneal adipose tissue. TAU supplementation decreased the ratio of pIkappa-Balpha/Ikappa Balpha protein, possibly contributing to the increased Ikappa-Balpha content in MTAU adipose tissue. Furthermore, MSG obesity or supplementation did not alter TNF-alpha, IL-1beta or IL-6 content in adipose tissue. In contrast, MSG rats presented lower serum TNF-alpha, IL-4 and IL-10 concentrations, and these alterations were prevented by TAU treatment. CONCLUSION: MSG obesity in rats was not associated with alterations in pro-inflammatory markers in retroperitoneal fat stores; however, reductions in the serum concentrations of anti-inflammatory cytokines and of TNF-alpha were observed. TAU treatment decreased adiposity, and this effect was associated with the normalization of circulating TNF-alpha and IL 4 concentrations in MTAU rats. PMID- 26621635 TI - The c-Ring of the F1FO-ATP Synthase: Facts and Perspectives. AB - The F1FO-ATP synthase is the only enzyme in nature endowed with bi-functional catalytic mechanism of synthesis and hydrolysis of ATP. The enzyme functions, not only confined to energy transduction, are tied to three intrinsic features of the annular arrangement of c subunits which constitutes the so-called c-ring, the core of the membrane-embedded FO domain: (i) the c-ring constitution is linked to the number of ions (H(+) or Na(+)) channeled across the membrane during the dissipation of the transmembrane electrochemical gradient, which in turn determines the species-specific bioenergetic cost of ATP, the "molecular currency unit" of energy transfer in all living beings; (ii) the c-ring is increasingly involved in the mitochondrial permeability transition, an event linked to cell death and to most mitochondrial dysfunctions; (iii) the c subunit species specific amino acid sequence and susceptibility to post-translational modifications can address antibacterial drug design according to the model of enzyme inhibitors which target the c subunits. Therefore, the simple c-ring structure not only allows the F1FO-ATP synthase to perform the two opposite tasks of molecular machine of cell life and death, but it also amplifies the enzyme's potential role as a drug target. PMID- 26621634 TI - Vitamin D3 supplementation does not modify cardiovascular risk profile of adults with inadequate vitamin D status. AB - PURPOSE: The Nutrition Societies in Germany, Austria, and Switzerland recommend a daily intake of 20 ug vitamin D3 for adults when endogenous synthesis is absent. The current study aimed to elucidate whether this vitamin D3 dose impacts cardiovascular risk markers of adults during the winter months. METHODS: The study was conducted in Halle (Saale), Germany (51o northern latitude) as a placebo-controlled, double-blinded, randomised trial (from January to April). A total of 105 apparently healthy subjects (male and female, 20-71 years old) were included. Subjects were randomly allocated to two groups. One group received a daily 20-ug vitamin D3 dose (n = 54), and the other group received a placebo (n = 51) for 12 weeks. Outcome measures included blood pressure, heart rate, concentrations of renin, aldosterone, serum lipids and vascular calcification markers, and haematologic variables such as pro-inflammatory monocytes. RESULTS: Blood pressure and systemic cardiovascular risk markers remained unchanged by vitamin D3 supplementation, although serum 25-hydroxyvitamin D3 increased from 38 +/- 14 to 73 +/- 16 nmol/L at week 12. The placebo and vitamin D groups did not differ in their final cardiovascular risk profile. CONCLUSION: Daily supplementation of 20 ug vitamin D3 during winter is unlikely to change cardiovascular risk profile. PMID- 26621636 TI - Biomolecular Interactions of Tannin Isolated from Oenothera gigas with Liposomes. AB - We have examined the interaction between hydrolysable tannin 1-O-galloyl-4,6 hexahydroxydiphenoyl-beta-D-glucose (OGbetaDG) with neutral liposomes as a model of cell membranes composed of three lipids: lecithin, 1,2-dipalmitoyl-sn-glycero 3-phosphocholine (DPPC) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) at different mass ratios. OGbetaDG in the concentration range 0.5-15 ug/ml (0.4-12 uM) strongly interacts with liposomal membranes by changing their structure, surface charge and fluidity. Used OGbetaDG molecules decrease and increase the rigidity of hydrophilic surface and hydrophobic parts of liposomes, respectively. At higher concentrations of tannin (>15 uM), liposomes are aggregated. Fourier Transform Infra-Red (FTIR) analysis showed that mainly -OH groups from OGbetaDG and also PO(2-) groups from phospholipids are responsible for the interaction. Obtained data indicate the importance of membrane lipid composition in interactions between tannins and cells. PMID- 26621638 TI - Using Clinical Trial End Points to Risk Stratify Patients With Pulmonary Arterial Hypertension. PMID- 26621639 TI - ECG Response: December 1, 2015. PMID- 26621637 TI - Retrospective Analysis of Long-Term Outcomes After Combat Injury: A Hidden Cost of War. AB - BACKGROUND: During the conflicts in Iraq and Afghanistan, 52,087 service members have been wounded in combat. The long-term sequelae of these injuries have not been carefully examined. We sought to determine the relation between markers of injury severity and the subsequent development of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease. METHODS AND RESULTS: Retrospective cohort study of critically injured US military personnel wounded in Iraq or Afghanistan from February 1, 2002 to February 1, 2011. Patients were then followed until January 18, 2013. Chronic disease outcomes were assessed by International Classification of Diseases, 9th edition codes and causes of death were confirmed by autopsy. From 6011 admissions, records were excluded because of missing data or if they were for an individual's second admission. Patients with a disease diagnosis of interest before the injury date were also excluded, yielding a cohort of 3846 subjects for analysis. After adjustment for other factors, each 5-point increment in the injury severity score was associated with a 6%, 13%, 13%, and 15% increase in incidence rates of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease, respectively. Acute kidney injury was associated with a 66% increase in rates of hypertension and nearly 5-fold increase in rates of chronic kidney disease. CONCLUSIONS: In Iraq and Afghanistan veterans, the severity of combat injury was associated with the subsequent development of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease. PMID- 26621640 TI - Incidental Finding of Solitary Plasmacytoma in Thallium-201 Myocardial Perfusion Scintigraphy. PMID- 26621641 TI - Asymptomatic Takayasu Aortitis Complicated by Type B Dissection. PMID- 26621642 TI - Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Preamble, Principles, and General Considerations: A Scientific Statement From the American Heart Association and American College of Cardiology. PMID- 26621643 TI - Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 1: Classification of Sports: Dynamic, Static, and Impact: A Scientific Statement From the American Heart Association and American College of Cardiology. PMID- 26621644 TI - Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 3: Hypertrophic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy and Other Cardiomyopathies, and Myocarditis: A Scientific Statement From the American Heart Association and American College of Cardiology. PMID- 26621645 TI - Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 4: Congenital Heart Disease: A Scientific Statement From the American Heart Association and American College of Cardiology. PMID- 26621646 TI - Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 5: Valvular Heart Disease: A Scientific Statement From the American Heart Association and American College of Cardiology. PMID- 26621647 TI - Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 6: Hypertension: A Scientific Statement from the American Heart Association and the American College of Cardiology. PMID- 26621648 TI - Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 7: Aortic Diseases, Including Marfan Syndrome: A Scientific Statement From the American Heart Association and American College of Cardiology. PMID- 26621649 TI - Eligibility and Disqualification Recommendations for Competitive Athletes with Cardiovascular Abnormalities: Task Force 8: Coronary Artery Disease: A Scientific Statement from the American Heart Association and American College of Cardiology. PMID- 26621650 TI - Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 9: Arrhythmias and Conduction Defects: A Scientific Statement From the American Heart Association and American College of Cardiology. PMID- 26621651 TI - Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 11: Drugs and Performance-Enhancing Substances: A Scientific Statement From the American Heart Association and American College of Cardiology. PMID- 26621652 TI - Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 12: Emergency Action Plans, Resuscitation, Cardiopulmonary Resuscitation, and Automated External Defibrillators: A Scientific Statement From the American Heart Association and American College of Cardiology. PMID- 26621653 TI - Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 13: Commotio Cordis: A Scientific Statement From the American Heart Association and American College of Cardiology. PMID- 26621654 TI - Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 15: Legal Aspects of Medical Eligibility and Disqualification Recommendations: A Scientific Statement From the American Heart Association and American College of Cardiology. PMID- 26621655 TI - Cardiology Patient Page. Omega-3 Fatty Acids and Heart Health. PMID- 26621656 TI - Letter by Kakkos et al Regarding Article, "Periaortitis as a Rare Complication After Endovascular Aneurysm Repair". PMID- 26621657 TI - Response to Letter Regarding Article, "Periaortitis as a Rare Complication After Endovascular Aneurysm Repair". PMID- 26621658 TI - Letter by Mansencal et al Regarding Article, "Sudden Cardiac Arrest During Sports Activity in Middle Age". PMID- 26621659 TI - Response to Letter Regarding Article, "Sudden Cardiac Arrest During Sports Activity in Middle Age". PMID- 26621660 TI - Letter by Lin et al Regarding Article, "Risk of Stroke in Chronic Heart Failure Patients Without Atrial Fibrillation: Analysis of the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure (GISSI-HF) Trials.". PMID- 26621662 TI - Correction. PMID- 26621663 TI - Correction. PMID- 26621661 TI - Response to Letter Regarding Article, "Risk of Stroke in Chronic Heart Failure Patients Without Atrial Fibrillation: Analysis of the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure (GISSI-HF) Trials.". PMID- 26621664 TI - Correction. PMID- 26621666 TI - Correction. PMID- 26621665 TI - Correction. PMID- 26621667 TI - Correction. PMID- 26621668 TI - Free vascularized tibial periosteal graft with monitoring skin island for limb reconstruction: Anatomical study and case report. AB - Several types of vascularized periosteal flaps have recently been described for the treatment or prevention of complex non-union in pediatric patients. Among them, a vascularized tibial periosteal graft (VTPG), supplied by the anterior tibial vessels (ATV), has been used successfully as a pedicled flap in a few patients. The purpose of the study is to describe the periosteal branches of the ATV, as well as the cutaneous and muscular branches by means of an anatomical study. In addition, to report on the use of VTPG as a free flap with a monitoring skin island in a clinical case. A mean of 6.5 periosteal branches (range 5-7) were found. In all cases we located a cutaneous perforator branching from one of the periosteal branches located at the midlevel of the leg. We performed a two stage reconstruction of a recalcitrant non-union and residual shortening of the right tibia in a 17-year-old boy. After nonunion focus distraction, we used a massive bone allograft fixed with a nail and covered by a VTPG as a biological resource. Allograft consolidation was achieved 5.5 months after surgery. At eighteen months after surgery, no complications were observed and the patient had resumed all his daily activities, despite a residual 2-cm limb-length discrepancy. VTPG may be considered as a valuable surgical option for bone reconstruction in complex biological scenarios in the young population. (c) 2015 Wiley Periodicals, Inc. Microsurgery 37:248-251, 2017. PMID- 26621671 TI - Mechanical Interaction of an Expanding Coiled Stent with a Plaque-Containing Arterial Wall: A Finite Element Analysis. AB - Wall injury is observed during stent expansion within atherosclerotic arteries, related in part to stimulation of the inflammatory process. Wall stress and strain induced by stent expansion can be closely examined by finite element analysis (FEA), thus shedding light on procedure-induced sources of inflammation. The purpose of this work was to use FEA to examine the interaction of a coiled polymer stent with a plaque-containing arterial wall during stent expansion. An asymmetric fibrotic plaque-containing arterial wall model was created from intravascular ultrasound (IVUS) images of a diseased artery. A 3D model for a coil stent at unexpanded state was generated in SolidWorks. They were imported into ANSYS for FEA of combined stent expansion and fibrotic plaque-distortion. We simulated the stent expansion in the plaqued lumen by increasing balloon pressure from 0 to 12 atm in 1 atm step. At increasing pressure, we examined how the expanding stent exerts forces on the fibrotic plaque and vascular wall components, and how the latter collectively resist and balance the expansive forces from the stent. Results show the expanding coiled stent creates high stresses within the plaque and the surrounding fibrotic capsule. Lower stresses were observed in adjacent medial and adventitial layers. High principal strains were observed in plaque and fibrotic capsule. The results suggest fibrotic capsule rupture might occur at localized regions. The FEA/IVUS method can be adapted for routine examination of the effects of the expansion of selected furled stents against IVUS-reconstructed diseased vessels, to improve stent deployment practices. PMID- 26621669 TI - Tissue-specific regulation of flowering by photoreceptors. AB - Plants use various kinds of environmental signals to adjust the timing of the transition from the vegetative to reproductive phase (flowering). Since flowering at the appropriate time is crucial for plant reproductive strategy, several kinds of photoreceptors are deployed to sense environmental light conditions. In this review, we will update our current understanding of light signaling pathways in flowering regulation, especially, in which tissue do photoreceptors regulate flowering in response to light quality and photoperiod. Since light signaling is also integrated into other flowering pathways, we also introduce recent progress on how photoreceptors are involved in tissue-specific thermosensation and the gibberellin pathway. Finally, we discuss the importance of cell-type-specific analyses for future plant studies. PMID- 26621670 TI - Signaling filopodia in vertebrate embryonic development. AB - Next to classical diffusion-based models, filopodia-like cellular protrusions have been proposed to mediate long range signaling events and morphogen gradient formation during communication between distant cells. An increasing wealth of data indicates that in spite of variable characteristics of signaling filopodia in different biological contexts, they represent a paradigm of intercellular crosstalk which is presently being unraveled in a growing literature. Here, we summarize recent advances in investigating the morphology, cellular basis and function of signaling filopodia, with focus on their role during embryonic development in vertebrates. PMID- 26621672 TI - An In Vitro Hemodynamic Flow System to Study the Effects of Quantified Shear Stresses on Endothelial Cells. AB - Numerous in vitro systems have previously been developed and employed for studying the effects of hemodynamics on endothelial cell (EC) dysfunction. In the majority of that work, accurate flow quantification (e.g., uniformity of the flow over the ECs) remains elusive and wall shear stress (WSS) quantifications are determined using theoretical relationships (without considering the flow channel aspect ratio effects). In addition, those relationships are not applicable to flows other than steady laminar cases. The present work discusses the development of a novel hemodynamic flow system for studying the effects of various well quantified flow regimes over ECs. The current work presents a novel hemodynamic flow system applying the concept of a parallel plate flow chamber (PPFC) with live microscopy access for studying the effects of quantified WSS on ECs. A range of steady laminar, pulsatile (carotid wave form) and low-Reynolds number turbulent WSSs were quantified through velocity field measurements by a laser Doppler velocimetry (LDV) system, to validate the functionality of the current hemodynamic flow system. Uniformity of the flow across the channel width can be analyzed with the current system (e.g., the flow was uniform across about 65-75% of the channel width for the steady cases). The WSS obtained from the experiments had higher values in almost all of the cases when compared to the most commonly used theoretical solution (9% < error < 16%), whereas another relationship, which considers the channel dimensions, had better agreement with the experimental results (1% < error < 8%). Additionally, the latter relationship predicted the uniform flow region in the PPFC with an average difference of <5% when compared to the experimental results. The experimental data also showed that the WSS at various locations (D, E and F) at the test section differed by less than 4% for the laminar cases representing a fully developed flow. WSS was also determined for a low-Re (Re = 2750) turbulent flow using (1) the Reynolds shears stress and (2) the time-averaged velocity profile gradient at the wall, with a good agreement (differences <16%) between the two where the first method returned a higher value than the second. Porcine aortic endothelial cell (PAEC) viability in the system and morphological cell response to laminar WSS of about 11 dyne/cm(2), were observed. These results provide performance validation of this novel in vitro system with many improved features compared to previous similar prototypes for investigation of flow effects on ECs. The integration of the LDV technique in the current study and the comparison of the results with those from theory revealed that great care must be taken when using PPFCs since the commonly used theoretical relation for laminar steady flows is unable to predict the flow uniformity (which may introduce significant statistical bias in biological studies) and the predicted WSS was subjected to greater error when compared to a more comprehensive equation presented in the current work. Moreover, application of the LDV technique in the current system is essential for studies of more complex cases, such as disturbed flows, where the WSS cannot be predicted using theoretical or numerical modelling methods. PMID- 26621673 TI - Microcystic/Reticular Schwannoma Arising in the Submandibular Gland: A Rare Benign Entity that Mimics More Common Salivary Gland Carcinomas. AB - Microcystic/reticular schwannoma is a recently described variant of schwannoma with a predilection for the gastrointestinal tract, rarely involving the head/neck region. This is the first reported case involving the submandibular gland. We present a case in a 34 year old man with 4.5 cm submandibular mass. Fine needle aspiration suggested a spindle cell lesion. Frozen section evaluation raised the possibility of mucoepidermoid carcinoma. Resection showed a well circumscribed mass with a mucoid appearance. Histologic findings include a lobular architecture with fibrous septa, a lympho-plasmacytic infiltrate, and scattered lymphoid aggregates at the periphery. There are two distinct histologic patterns with solid areas of spindle cells and areas of spindle/ovoid cells with a microcystic pattern in a myxoid background. The tumor has a pushing border, with extension into adipose and adjacent parenchyma, without cytologic atypia or necrosis. Immunohistochemical stains are positive for S-100 and CD34, and negative for calponin, mammoglobin, ALK1, p63, ER, GFAP, SMA, desmin, cytokeratin 7, cytokeratin AE1/AE3, and C-Kit. Mucicarmine stain is negative. Recognition of this benign unusual variant of schwannoma is paramount for appropriate conservative treatment due to the morphologic and immunohistochemical overlap with primary salivary gland carcinomas. PMID- 26621674 TI - Oral parafunctions, piercing and signs and symptoms of temporomandibular disorders in high school students. AB - OBJECTIVE: The use of chewing-gum and piercing has become common among adolescents and might result in increased oral muscle activity and overloading. Aim To investigate the frequency of oral piercing and parafunctions in relation to symptoms of temporomandibular disorders (TMD) among adolescents. MATERIALS AND METHODS: One hundred and twenty-four third level high school students, living either in a city or in a small town, enrolled in either science or media programmes, were included. The students completed a questionnaire regarding different parafunctions and symptoms of TMD. A clinical examination of the temporomandibular system and estimation of the tooth wear was performed in 116 students. RESULTS: Chewing-gum was used by 86% of the students (25% with a daily use) and 14% had an oral piercing. The science students used more chewing gum than the media students (p = 0.008), while the media students had more piercings (p < 0.001). Symptoms once a week or more were reported with 39% for headache, 18% for clicking, 7% for facial pain and 6% for difficulty to open wide. Girls reported more headaches (p = 0.007) and more severe symptoms (p = 0.003), had more medical consultations and used more analgesics (both p < 0.05) and had more clinical signs (p = 0.01) than boys. Girls had more oral piercings and used more chewing gum than boys (both p < 0.05). The media students had more sick leave (p < 0.01) than the science students. Chewing-gum use was associated with headache (p < 0.01), with difficulty to open wide (p < 0.05) and with tenderness of the temporomandibular joints and muscles (both p < 0.05). Oral piercing was associated with headache and muscle tenderness (both p < 0.05) and daily nail biting with headache (p < 0.05) and tooth wear (p = 0.004). CONCLUSIONS: There is an association between use of chewing gum, nail biting, oral piercing, and symptoms of TMD. PMID- 26621675 TI - Compliance with Evidence-Based Guidelines in Acute Pancreatitis: an Audit of Practices in University of Toronto Hospitals. AB - Despite existing evidence-based practice guidelines for the management of acute pancreatitis, clinical compliance with recommendations is poor. We conducted a retrospective review of 248 patients admitted between 2010 and 2012 with acute pancreatitis at eight University of Toronto affiliated hospitals. We included all patients admitted to ICU (52) and 25 ward patients from each site (196). Management was compared with the most current evidence used in the Best Practice in General Surgery Management of Acute Pancreatitis Guideline. Fifty-six patients (22.6 %) had only serum lipase tested for biochemical diagnosis. Admission ultrasound was performed in 174 (70.2 %) patients, with 69 (27.8 %) undergoing ultrasound and CT. Of non-ICU patients, 158 (80.6 %) were maintained nil per os, and only 18 (34.6 %) ICU patients received enteral nutrition, commencing an average 7.5 days post-admission. Fifty (25.5 %) non-ICU patients and 25 (48.1 %) ICU patients received prophylactic antibiotics. Only 24 patients (22.6 %) with gallstone pancreatitis underwent index admission cholecystectomy. ERCP with sphincterotomy was under-utilized among patients with biliary obstruction (16 [31 %]) and candidates for prophylactic sphincterotomy (18 [22 %]). Discrepancies exist between the most current evidence and clinical practice within the University of Toronto hospitals. A guideline, knowledge translation strategy, and assessment of barriers to clinical uptake are required to change current clinical practice. PMID- 26621676 TI - Dorsal displacement of the facial nerve in acoustic neuroma surgery: clinical features and surgical outcomes of 21 consecutive dorsal pattern cases. AB - In acoustic neuroma surgery, the facial nerve (FN) course varies among patients, but a dorsal pattern is rarely observed. We retrospectively reviewed and classified 556 acoustic neuromas operated on via a lateral suboccipital retrosigmoid (LSO) approach into two groups: dorsal (group D) and non-dorsal (group ND). The clinical features and outcomes including functional preservation of the FN, the extent of tumor resection, and the retreatment rate were compared. Among 556 cases, 21 (3.8%) patients with dorsal patterns were identified. No significant differences in clinical features or preoperative status were noted between groups D and ND. No significant differences in functional FN preservation were found between groups D and ND in the immediate postoperative period (90.5 and 83.0%, respectively) or 1-year postoperatively (95.2 and 97.0%, respectively). Compared with group ND, the extent of tumor resection was significantly less (p < 0.0001) and the retreatment rate was significantly higher in group D (hazard ratio, 33.6; 95% confidence interval [CI], 11.7-96.1; p < 0.0001). In one dorsal pattern case, surgical resection was abandoned based on the intraoperative findings. Dorsal displacement of the FN was accurately predicted with preoperative imaging evaluations in just two cases. Functional preservation of the FN during acoustic neuroma surgery is achievable if the FN runs along the dorsal side of the tumor. However, a dorsal pattern, especially when the FN is broadened, is clearly associated with less complete tumor removal and a higher rate of retreatment than typical pattern cases. PMID- 26621677 TI - Petroclival tumor model--technical note and educational implications. AB - Petroclival area lesions are rare, and their surgery is challenging due to the deep location and to the complex relationships between the tumor and the neurovascular structures. The objective is to present a petroclival tumor model simulating the distorted anatomy of a real petroclival lesion and propose its use to practice microsurgical removal while preserving neurovascular structures. Four embalmed cadaver heads were used in this study. An endoscopic endonasal transclival approach was used to access the dura in front of the trigeminal nerve; a pediatric Foley was inserted above the trigeminal nerve and was gradually inflated (one-balloon technique). If a larger tumor model was desired, an additional balloon was placed below the trigeminal nerve (two-balloon technique). A pre-mixed tumor polymer was injected into the petroclival space and allowed to harden to create an implanted tumor. A post-implant CT scan was done to evaluate the location and volume of the implanted artificial tumor. Tumors were subsequently excised via retrosigmoid and anterior petrosal approaches. Six petroclival tumors were successfully developed: three were small (9.41-10.36 ml) and three large (21.05-23.99 ml). During dissection, distorted anatomy created by the tumor model mimicked that of real surgery. We have established a petroclival tumor model with adjustable size which offers opportunities to study the distorted anatomy of the area and that is able to be used as a training tool to practice microsurgical removal of petroclival lesions. The practice dissection of this tumor model can be a bridge between a normal anatomic dissection and real surgery. PMID- 26621678 TI - Factors influencing the outcome (GOS) in reconstructive cranioplasty. AB - After performing a decompressive craniectomy, a cranioplastic surgery is usually warranted. The complications of this reconstructive procedure may differ from the initial operation. The authors of this study report on their experience to define patient-specific and procedural risk factors for possible complications following cranioplasty influencing the outcome (Glasgow Outcome Scale (GOS)), mobility, shunt dependency, and seizures. A retrospective analysis of 263 patients of all ages and both sexes who had undergone cranioplasty after craniectomy for traumatic brain injury (including chronic subdural hematoma), subarachnoidal hemorrhage (including intracerebral hemorrhage), ischemic stroke, and tumor surgery in one single center in 12 years from January 2000 to March 2012 has been carried out. A multiple logistic regression analysis was performed to identify potential risk factors (age, gender, used cranioplasty material, initial diagnosis, clipped or coil-embolized subarachnoidal hemorrhage (SAH) patients, time interval, complications especially hydrocephalus and seizures, mobility) upon the prognosis described as a dichotomized Glasgow Outcome Scale. Two hundred forty-eight patients met the study criteria. The overall complication rate after cranioplastic surgery was 18.5% (46 patients). Complications included: surgical site infection, epidural hematoma, hydrocephalus with or without former SAH, and new-onset seizures. Logistic regression analysis identified significant correlation between a low GOS (2 or 3) and postoperative seizures (OR 2.37, CI 1.35-4.18, p < 0.05), shunt-depending hydrocephalus (OR 5.83, CI 3.06-11.11, p < 0.05), and age between 51 and 70 years (OR 2.4, 95% CI 1.09-5.29, p = 0.029). However, gender, time interval between craniectomy and cranioplasty, initial diagnosis, and used cranioplasty material had no significant influence on post cranioplasty complications as surgical site infections, hematoma, wound healing disturbance, seizures, or hydrocephalus. Evaluation of treatment modality in aneurysmal SAH clip vs. coil showed no significant relation to postoperative complications either. Complications after cranioplastic surgery are a common problem, as prognostic factors could identify a shunt-depending hydrocephalus and epilepsia to develop a major deficit after cranioplastic surgery (GOS 2 or 3). We detected a significant extra risk of people between the age of 51 and 70 years to end up in GOS level 2 or 3. PMID- 26621679 TI - Targeting TRPV1 for Body Weight Control using TRPV1(-/-) Mice and Electroacupuncture. AB - Obesity is a global social medical problem resulting in morbidity as high as 20 30%. Here we investigated whether the manipulation of TRPV1 can control mice body weight through electroacupuncture (EA). The results demonstrated that body weight increased with time in the control group (108.19 +/- 1.31%, n = 7). The increase of mice body weight was significantly less in the EA group (104.41 +/- 0.76%, p < 0.05, compared with the control group, n = 7) but not in the sham EA group (109.1 +/- 0.63%, p < 0.05, compared with EA group, n = 7). EA did not decrease the gain of body weight in TRPV1 knock mice (107.94 +/- 0.41% and 107.79 +/- 1.04% for TRPV1(-/-) and TRPV1(-/-) with EA, respectively, p > 0.05). The visceral white adipose tissue (WAT) weight was lower in the EA group at 4 weeks after manipulation. Moreover, the protein levels of TRPV1, pPKA, pPKC, and pERK were increased in the dorsal root ganglion (DRG) and spinal cord (SC) after EA treatment but not in the sham EA and TRPV1(-/-) mice. This study suggests that targeting TRPV1 is beneficial in controlling body weight and TRPV1-associated mechanisms in mice. PMID- 26621680 TI - Multiple bronchial artery aneurysms: Successful treatment with ethylene-vinyl alcohol copolymer (Onyx(r)). PMID- 26621681 TI - Sex hormones and multiple sclerosis: another informative failure. PMID- 26621684 TI - The Use of a Mobile Van for School Vision Screening: Results of 63 841 Evaluations. AB - PURPOSE: To present data from an established mobile screening program for children in the amblyogenic age group using gold-standard examination techniques by eye care professionals. DESIGN: Retrospective 12-year, cross-sectional study. METHODS: setting: Single center. STUDY POPULATION: All children enrolled in pre kindergarten, kindergarten, and first grades in public schools in Cleveland, Ohio were eligible for evaluations. intervention procedure: An ophthalmic technician and/or optometrist examined children in a customized van that visits all elementary schools. The initial screening included testing of monocular near and distance visual acuity, stereoacuity, ocular alignment, motility, pupils, and external abnormalities. Children meeting the 2003 American Academy of Pediatrics vision screening referral criteria underwent cycloplegic retinoscopy and ophthalmoscopy by the on-site optometrist and received glasses. In addition, these children were referred to pediatric ophthalmology for ongoing care. MAIN OUTCOME MEASURE: Determination of the proportion of children with refractive errors, amblyopia, and/or strabismus. RESULTS: Between 2002 and 2014, 63 841 evaluations were performed, representing approximately 55% of eligible children. Overall, 6386 (10.0%) of children met 1 or more referral criteria: 5355 (8.39%) received glasses, 873 (1.37%) had amblyopia, and 1125 (1.76%) had strabismus. Over the 12-year period, there was no statistically significant change in the prevalence of strabismus (1.73%-2.24%, P = .91) or amblyopia (0.9%-2.08%, P = .13) among first grade students. CONCLUSIONS: Amblyopia, strabismus, and refractive errors are common in young children. During the study period, the rates of amblyopia and strabismus remained stable, indicating the need for continued vision screening and treatment services. A van-based model, traveling directly to schools, appears to be effective in reaching young children in underserved communities. PMID- 26621682 TI - Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. AB - BACKGROUND: Relapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women. METHODS: We did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurology centres in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18-50 years with relapsing remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 months, with a significance level of p=0.10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00451204. FINDINGS: We enrolled 164 patients: 83 were allocated to the estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0.25 relapses per year (95% CI 0.17-0.37) in the estriol group versus 0.37 relapses per year (0.25-0.53) in the placebo group (adjusted rate ratio 0.63, 95% CI 0.37-1.05; p=0.077). The proportion of patients with serious adverse events did not differ substantially between the estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses were more common in the estriol group than in the placebo group (19 [23%] vs three [4%], p=0.0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0.0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clinical examination, mammogram, uterine ultrasound, or endometrial lining biopsy. INTERPRETATION: Estriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 months. These results warrant further investigation in a phase 3 trial. FUNDING: National Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation. PMID- 26621683 TI - Short-Wavelength Automated Perimetry Parameters at Baseline and Following Remission in Patients With Birdshot Retinochoroidopathy. AB - PURPOSE: To identify changes in short-wavelength automated perimetry patterns and parameters between the active and inactive states. DESIGN: Retrospective cohort study with age-matched, normal controls. METHODS: setting: Private tertiary referral center. STUDY POPULATION: Seventy-five eyes of 38 patients with active birdshot retinochoroidopathy and 37 eyes of 37 historical normal controls. INTERVENTION: Thirty-seven patients received immunomodulatory therapy. A fluocinolone acetonide intravitreal implant (Retisert) was implanted in both eyes of 1 patient as an initial treatment. MAIN OUTCOME MEASURES: Changes in short wavelength automated perimetry total deviation scores, pattern deviation scores, mean deviation, and pattern standard deviation in the active phase and the remission state. RESULTS: Mean deviation (P = .006), pattern standard deviation (P = .001), total deviation score (P = .002), and pattern deviation score (P = .007) were significantly different from the active phase to the remission state. The length of time required to achieve remission did not significantly affect the changes in mean deviation (regression coefficient = 0.01; P = .92), pattern standard deviation (regression coefficient = 0.01; P = .87), total deviation score (regression coefficient = -0.1; P = .32), or pattern deviation score (regression coefficient = 0.1; P = .36) from the active phase to the remission state. CONCLUSION: There was significant improvement in total deviation score, pattern deviation score, mean deviation, and pattern standard deviation on short wavelength automated perimetry as patients achieved remission. Short-wavelength automated perimetry appears to be a useful and complementary modality in monitoring disease activity in birdshot retinochoroidopathy. PMID- 26621685 TI - Systematic Evaluation of Optical Coherence Tomography Angiography in Retinal Vein Occlusion. AB - PURPOSE: To evaluate the clinical utility of optical coherence tomography angiography (OCTA) in patients with retinal vein occlusion (RVO), and to systematically compare OCTA images with changes seen on color fundus photography and fluorescein angiography (FA). DESIGN: Reliability analysis. METHODS: Eighty one eyes of 76 patients with a history of RVO (branch, central, or hemicentral), both acute and chronic, underwent OCTA and color fundus photography. In 29 eyes, data were compared to FA imaging. Comparative and multimodal analysis of the 3 imaging procedures were performed. RESULTS: We identified good agreement between FA and OCTA scans centered on the macula for capillary nonperfusion (intraclass correlation coefficient [ICC] 0.825 for the 3 * 3-mm scan and 0.891 for the 8 * 8 mm scan). Agreement for area of capillary changes (dilation, pruning, and telangiectasia) was also substantial (ICC 0.712 for the 3 * 3-mm scan and 0.787 for the 8 * 8-mm scan). For foveal avascular zone grading, agreement was good for the 3 * 3-mm scan (kappa = 1.000 for radius and kappa = 0.799 for outline) but poor for the 8 * 8-mm scan (kappa = 0.156 for radius and kappa = 0.600 for outline). The quality of the images obtained was an important issue for OCTA, as 15.1% of scans were nongradable, particularly in patients unable to maintain fixation. CONCLUSIONS: OCTA is a quick, reliable, and noninvasive method to evaluate the area of capillary nonperfusion and foveal avascular zone morphology in patients with RVO. However, good fixation is a requirement for acquisition of good-quality images. PMID- 26621686 TI - High-performance liquid chromatography as a technique to determine protein adsorption onto hydrophilic/hydrophobic surfaces. AB - The purpose of this study is to evaluate the potential of simple high performance liquid chromatography (HPLC) setup for quantification of adsorbed proteins on various type of plane substrates with limited area (<3 cm(2)). Protein quantification was investigated with a liquid chromatography chain equipped with a size exclusion column or a reversed-phase column. By evaluating the validation of the method according to guidelines of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), all the results obtained by HPLC were reliable. By simple adsorption test at the contact of hydrophilic (glass) and hydrophobic (polydimethylsiloxane: PDMS) surfaces, kinetics of adsorption were determined and amounts of adsorbed bovine serum albumin, myoglobin and lysozyme were obtained: as expected for each protein, the amount adsorbed at the plateau on glass (between 0.15 MUg/cm(2) and 0.4 MUg/cm(2)) is lower than for hydrophobic PDMS surfaces (between 0.45 MUg/cm(2) and 0.8 MUg/cm(2)). These results were consistent with bicinchoninic acid protein determination. According to ICH guidelines, both Reversed Phase and Size Exclusion HPLC can be validated for quantification of adsorbed protein. However, we consider the size exclusion approach more interesting in this field because additional informations can be obtained for aggregative proteins. Indeed, monomer, dimer and oligomer of bovine serum albumin (BSA) were observed in the chromatogram. On increasing the temperature, we found a decrease of peak intensity of bovine serum albumin as well as the fraction of dimer and oligomer after contact with PDMS and glass surface. As the surface can act as a denaturation parameter, these informations can have a huge impact on the elucidation of the interfacial behavior of protein and in particular for aggregation processes in pharmaceutical applications. PMID- 26621687 TI - A facile system to evaluate in vitro drug release from dissolving microneedle arrays. AB - The use of biological tissues in the in vitro assessments of dissolving (?) microneedle (MN) array mechanical strength and subsequent drug release profiles presents some fundamental difficulties, in part due to inherent variability of the biological tissues employed. As a result, these biological materials are not appropriate for routine used in industrial formulation development or quality control (QC) tests. In the present work a facile system using Parafilm M((r)) (PF) to test drug permeation performance using dissolving MN arrays is proposed. Dissolving MN arrays containing 196 needles (600 MUm needle height) were inserted into a single layer of PF and a hermetic "pouch" was created including the array inside. The resulting system was placed in a dissolution bath and the release of model molecules was evaluated. Different MN formulations were tested using this novel setup, releasing between 40 and 180 MUg of their cargos after 6h. The proposed system is a more realistic approach for MN testing than the typical performance test described in the literature for conventional transdermal patches. Additionally, the use of PF membrane was tested either in the hermetic "pouch" and using Franz Cell methodology yielding comparable release curves. Microscopy was used in order to ascertain the insertion of the different MN arrays in the PF layer. The proposed system appears to be a good alternative to the use of Franz cells in order to compare different MN formulations. Given the increasing industrial interest in MN technology, the proposed system has potential as a standardised drug/active agent release test for quality control purposes. PMID- 26621688 TI - Evaluation of magnetic nanoparticles coated by 5-fluorouracil imprinted polymer for controlled drug delivery in mouse breast cancer model. AB - Nanoparticles (NPs) have been extensively investigated to improve delivery efficiency of therapeutic and diagnostic agents. In this study, magnetic molecularly imprinted polymer (MIP) was synthesized by using polydopamine. Synthesized MIP was used for controlled 5-fluorouracil (5-FU) delivery in a spontaneous model of breast adenocarcinoma in Balb/c mice in the presence of an external magnetic field. Antitumor effectiveness of 5-FU imprinted polymer (5-FU IP) was evaluated in terms of tumor-growth delay, tumor-doubling time, inhibition ratio, and histopathology. Results showed higher efficacy of 5-FU-IP in the presence of magnetic field upon suppressing tumor growth than free 5-FU and 5-FU IP without magnetic field. The 5-FU and Fe distribution among tissues were evaluated by high-performance liquid chromatography and flame atomic absorption spectrometry, respectively. The obtained results, showed significantly deposition of 5-FU in the 5-FU-IP treated group with magnetic field. Thus, magnetic 5-FU-IP is promising for breast cancer therapy with high efficacy. PMID- 26621689 TI - Advanced stable lipid-based formulations for a patient-centric product design. AB - Multiparticulate dosage forms are a recent strategy to meet the special needs of children, elderly people and patients suffering from dysphagia. Our study presents a novel and cost-efficient approach for the manufacturing of a taste masked multiparticulate system with a stable immediate release profile by applying lipid-based excipients in a solvent-free hot melt coating process. The thermosensitive N-acetylcysteine (N-ac) was used as model drug and hot-melt coated with a mixture of tripalmitin and polysorbate 65. A predictive in vitro method for the evaluation of the taste masking efficiency was developed based on the deprotonation of the carboxyl group of N-ac and the decline of pH, responsible for the unpleasant sour taste of the compound. The method was confirmed using in vivo studies. Differential scanning calorimetry and X-ray scattering experiments revealed polymorphic transformation and its dependency on transformation time, temperature and emulsifier concentration. During the process, the coating was transformed almost completely into the stable beta polymorph, leading to an unaltered dissolution profile during storage. A statistical design was conducted that revealed the critical process parameters affecting the taste masking efficiency and drug release. This study shows the successful application of solvent-free hot-melt coating in the development of a taste-masked and stable formulation. PMID- 26621690 TI - Seasonal variations in the stable oxygen isotope ratio of wood cellulose reveal annual rings of trees in a Central Amazon terra firme forest. AB - In Amazonian non-flooded forests with a moderate dry season, many trees do not form anatomically definite annual rings. Alternative indicators of annual rings, such as the oxygen (delta(18)Owc) and carbon stable isotope ratios of wood cellulose (delta(13)Cwc), have been proposed; however, their applicability in Amazonian forests remains unclear. We examined seasonal variations in the delta(18)Owc and delta(13)Cwc of three common species (Eschweilera coriacea, Iryanthera coriacea, and Protium hebetatum) in Manaus, Brazil (Central Amazon). E. coriacea was also sampled in two other regions to determine the synchronicity of the isotopic signals among different regions. The annual cyclicity of delta(18)Owc variation was cross-checked by (14)C dating. The delta(18)Owc showed distinct seasonal variations that matched the amplitude observed in the delta(18)O of precipitation, whereas seasonal delta(13)Cwc variations were less distinct in most cases. The delta(18)Owc variation patterns were similar within and between some individual trees in Manaus. However, the delta(18)Owc patterns of E. coriacea differed by region. The ages of some samples estimated from the delta(18)Owc cycles were offset from the ages estimated by (14)C dating. In the case of E. coriacea, this phenomenon suggested that missing or wedging rings may occur frequently even in well-grown individuals. Successful cross-dating may be facilitated by establishing delta(18)Owc master chronologies at both seasonal and inter-annual scales for tree species with distinct annual rings in each region. PMID- 26621691 TI - Ecological specialisation in habitat selection within a macropodid herbivore guild. AB - Specialist species show stronger resource selection, narrower niches and lower niche overlap than generalist species. We examined ecological specialisation with respect to habitat selection in a macropodid community comprising the western grey kangaroo Macropus fuliginosus, red-necked wallaby M. rufogriseus and swamp wallaby Wallabia bicolor in the Grampians National Park, Victoria, Australia. We used radio tracking to quantify habitat selection. We predicted that because the fitness benefits of generalisation and specialisation differ, there would be a mix of generalised and specialised species in our community. As all three macropodid species show marked sexual dimorphism, we also expected that they would show sex-based specialisation. Finally, because many large herbivores select different habitats for foraging and resting, we predicted that our species would specialise on a subset of their overall selected habitat based on activity period (diurnal or nocturnal). All three species specialised on the available resources to some degree. Western grey kangaroos were specialists, at least during the active period. Niche data for the two wallaby species were harder to interpret so we could not determine their degree of specialisation. Within species, we found no evidence of sex-based specialisation. However, we found clear evidence of specialisation by activity period in western grey kangaroos and red-necked wallabies, but not in swamp wallabies. The strength of behavioural decisions made during the active period in influencing specialisation points to the likelihood that bottom-up processes regulate this community. PMID- 26621692 TI - Strength reliability and in vitro degradation of three-dimensional powder printed strontium-substituted magnesium phosphate scaffolds. AB - Strontium ions (Sr(2+)) are known to prevent osteoporosis and also encourage bone formation. Such twin requirements have motivated researchers to develop Sr substituted biomaterials for orthopaedic applications. The present study demonstrates a new concept of developing Sr-substituted Mg3(PO4)2 - based biodegradable scaffolds. In particular, this work reports the fabrication, mechanical properties with an emphasis on strength reliability as well as in vitro degradation of highly biodegradable strontium-incorporated magnesium phosphate cements. These implantable scaffolds were fabricated using three dimensional powder printing, followed by high temperature sintering and/or chemical conversion, a technique adaptable to develop patient-specific implants. A moderate combination of strength properties of 36.7MPa (compression), 24.2MPa (bending) and 10.7MPa (tension) were measured. A reasonably modest Weibull modulus of up to 8.8 was recorded after uniaxial compression or diametral tensile tests on 3D printed scaffolds. A comparison among scaffolds with varying compositions or among sintered or chemically hardened scaffolds reveals that the strength reliability is not compromised in Sr-substituted scaffolds compared to baseline Mg3(PO4)2. The micro-computed tomography analysis reveals the presence of highly interconnected porous architecture in three-dimension with lognormal pore size distribution having median in the range of 17.74-26.29MUm for the investigated scaffolds. The results of extensive in vitro ion release study revealed passive degradation with a reduced Mg(2+) release and slow but sustained release of Sr(2+) from strontium-substituted magnesium phosphate scaffolds. Taken together, the present study unequivocally illustrates that the newly designed Sr substituted magnesium phosphate scaffolds with good strength reliability could be used for biomedical applications requiring consistent Sr(2+)- release, while the scaffold degrades in physiological medium. STATEMENT OF SIGNIFICANCE: The study investigates the additive manufacturing of scaffolds based on different strontium substituted magnesium phosphate bone cements by means of three-dimensional powder printing technique (3DPP). Magnesium phosphates were chosen due to their higher biodegradability compared to calcium phosphates, which is due to both a higher solubility as well as the absence of phase changes (to low soluble hydroxyapatite) in vivo. Since strontium ions are known to promote bone formation by stimulating osteoblast growth, we aimed to establish such a highly degradable magnesium phosphate ceramic with an enhanced bioactivity for new bone ingrowth. After post-processing, mechanical strengths of up to 36.7MPa (compression), 24.2MPa (bending) and 10.7MPa (tension) could be achieved. Simultaneously, the failure reliability of those bioceramic implant materials, measured by Weibull modulus calculations, were in the range of 4.3-8.8. Passive dissolution studies in vitro proved an ion release of Mg(2+) and PO4(3-) as well as Sr(2+), which is fundamental for in vivo degradation and a bone growth promoting effect. In our opinion, this work broadens the range of bioceramic bone replacement materials suitable for additive manufacturing processing. The high biodegradability of MPC ceramics together with the anticipated promoting effect on osseointegration opens up the way for a patient-specific treatment with the prospect of a fast and complete healing of bone fractures. PMID- 26621693 TI - Reaction of bone nanostructure to a biodegrading Magnesium WZ21 implant - A scanning small-angle X-ray scattering time study. AB - Understanding the implant-bone interaction is of prime interest for the development of novel biodegrading implants. Magnesium is a very promising material in the class of biodegrading metallic implants, owing to its mechanical properties and excellent immunologic response during healing. However, the influence of degrading Mg implants on the bone nanostructure is still an open question of crucial importance for the design of novel Mg implant alloys. This study investigates the changes in the nanostructure of bone following the application of a degrading WZ21 Mg implant (2wt% Y, 1wt% Zn, 0.25wt% Ca and 0.15wt% Mn) in a murine model system over the course of 15months by small angle X ray scattering. Our investigations showed a direct response of the bone nanostructure after as little as 1month with a realignment of nano-sized bone mineral platelets along the bone-implant interface. The growth of new bone tissue after implant resorption is characterized by zones of lower mineral platelet thickness and slightly decreased order in the stacking of the platelets. The preferential orientation of the mineral platelets strongly deviates from the normal orientation along the shaft and still roughly follows the implant direction after 15months. We explain our findings by considering geometrical, mechanical and chemical factors during the process of implant resorption. STATEMENT OF SIGNIFICANCE: The advancement of surgical techniques and the increased life expectancy have caused a growing demand for improved bone implants. Ideally, they should be bio-resorbable, support bone as long as necessary and then be replaced by healthy bone tissue. Magnesium is a promising candidate for this purpose. Various studies have demonstrated its excellent mechanical performance, degradation behaviour and immunologic properties. The structural response of bone, however, is not well known. On the nanometer scale, the arrangement of collagen fibers and calcium mineral platelets is an important indicator of structural integrity. The present study provides insight into nanostructural changes in rat bone at different times after implant placement and different implant degradation states. The results are useful for further improved magnesium alloys. PMID- 26621694 TI - Non-invasive in vitro and in vivo monitoring of degradation of fluorescently labeled hyaluronan hydrogels for tissue engineering applications. AB - Tracking of degradation of hydrogels-based biomaterials in vivo is very important for rational design of tissue engineering scaffolds that act as delivery carriers for bioactive factors. During the process of tissue development, an ideal scaffold should remodel at a rate matching with scaffold degradation. To reduce amount of animals sacrificed, non-invasive in vivo imaging of biomaterials is required which relies on using of biocompatible and in situ gel forming compounds carrying suitable imaging agents. In this study we developed a method of in situ fabrication of fluorescently labeled and injectable hyaluronan (HA) hydrogel based on one pot sequential use of Michael addition and thiol-disulfide exchange reactions for the macromolecules labeling and cross-linking respectively. Hydrogels with different content of HA were prepared and their enzymatic degradation was followed in vitro and in vivo using fluorescence multispectral imaging. First, we confirmed that the absorbance of the matrix-linked near-IR fluorescent IRDye(r) 800CW agent released due to the matrix enzymatic degradation in vitro matched the amount of the degraded hydrogel measured by classical gravimetric method. Secondly, the rate of degradation was inversely proportional to the hydrogel concentration and this structure-degradation relationship was similar for both in vitro and in vivo studies. It implies that the degradation of this disulfide cross-linked hyaluronan hydrogel in vivo can be predicted basing on the results of its in vitro degradation studies. The compliance of in vitro and in vivo methods is also promising for the future development of predictive in vitro tissue engineering models. STATEMENT OF SIGNIFICANCE: The need for engineered hydrogel scaffolds that deliver bioactive factors to endogenous progenitor cells in vivo via gradual matrix resorption and thus facilitate tissue regeneration is increasing with the aging population. Importantly, scaffold should degrade at a modest rate that will not be too fast to support tissue growth nor too slow to provide space for tissue development. The present work is devoted to longitudinal tracking of a hydrogel material in vivo from the time of its implantation to the time of complete resorption without sacrificing animals. The method demonstrates correlation of resorption rates in vivo and in vitro for hydrogels with varied structural parameters. It opens the possibility to develop predictive in vitro models for tissue engineered scaffolds and reduce animal studies. PMID- 26621696 TI - Hybrid hydrogel-aligned carbon nanotube scaffolds to enhance cardiac differentiation of embryoid bodies. AB - Carbon nanotubes (CNTs) were aligned in gelatin methacryloyl (GelMA) hydrogels using dielectrophoresis approach. Mouse embryoid bodies (EBs) were cultured in the microwells fabricated on the aligned CNT-hydrogel scaffolds. The GelMA dielectrophoretically aligned CNT hydrogels enhanced the cardiac differentiation of the EBs compared with the pure GelMA and GelMA-random CNT hydrogels. This result was confirmed by Troponin-T immunostaining, the expression of cardiac genes (i.e., Tnnt2, Nkx2-5, and Actc1), and beating analysis of the EBs. The effect on EB properties was significantly enhanced by applying an electrical pulse stimulation (frequency, 1Hz; voltage, 3V; duration, 10ms) to the EBs for two continuous days. Taken together, the fabricated hybrid hydrogel-aligned CNT scaffolds with tunable mechanical and electrical characteristics offer an efficient and controllable platform for electrically induced differentiation and stimulation of stem cells for potential tissue regeneration and cell therapy applications. STATEMENT OF SIGNIFICANCE: Dielectrophoresis approach was used to rapidly align carbon nanotubes (CNTs) in gelatin methacryloyl (GelMA) hydrogels resulting in hybrid GelMA-CNT hydrogels with tunable and anisotropic electrical and mechanical properties. The GelMA-aligned CNT hydrogels may be used to apply accurate and controllable electrical pulses to cell and tissue constructs and thereby regulating their behavior and function. In this work, it was demonstrated that the GelMA hydrogels containing the aligned CNTs had superior performance in cardiac differentiation of stem cells upon applying electrical stimulation in contrast with control gels. Due to broad use of electrical stimulation in tissue engineering and stem cell differentiation, it is envisioned that the GelMA aligned CNT hydrogels would find wide applications in tissue regeneration and stem cell therapy. PMID- 26621695 TI - Human mesenchymal stem cells cultured on silk hydrogels with variable stiffness and growth factor differentiate into mature smooth muscle cell phenotype. AB - Cell-matrix and cell-biomolecule interactions play critical roles in a diversity of biological events including cell adhesion, growth, differentiation, and apoptosis. Evidence suggests that a concise crosstalk of these environmental factors may be required to direct stem cell differentiation toward matured cell type and function. However, the culmination of these complex interactions to direct stem cells into highly specific phenotypes in vitro is still widely unknown, particularly in the context of implantable biomaterials. In this study, we utilized tunable hydrogels based on a simple high pressure CO2 method and silk fibroin (SF) the structural protein of Bombyx mori silk fibers. Modification of SF protein starting water solution concentration results in hydrogels of variable stiffness while retaining key structural parameters such as matrix pore size and beta-sheet crystallinity. To further resolve the complex crosstalk of chemical signals with matrix properties, we chose to investigate the role of 3D hydrogel stiffness and transforming growth factor (TGF-beta1), with the aim of correlating the effects on the vascular commitment of human mesenchymal stem cells. Our data revealed the potential to upregulate matured vascular smooth muscle cell phenotype (myosin heavy chain expression) of hMSCs by employing appropriate matrix stiffness and growth factor (within 72h). Overall, our observations suggest that chemical and physical stimuli within the cellular microenvironment are tightly coupled systems involved in the fate decisions of hMSCs. The production of tunable scaffold materials that are biocompatible and further specialized to mimic tissue-specific niche environments will be of considerable value to future tissue engineering platforms. STATEMENT OF SIGNIFICANCE: This article investigates the role of silk fibroin hydrogel stiffness and transforming growth factor (TGF-beta1), with the aim of correlating the effects on the vascular commitment of human mesenchymal stem cells. Specifically, we demonstrate the upregulation of mature vascular smooth muscle cell phenotype (myosin heavy chain expression) of hMSCs by employing appropriate matrix stiffness and growth factor (within 72h). Moreover, we demonstrate the potential to direct specialized hMSC differentiation by modulating stiffness and growth factor using silk fibroin, a well-tolerated and -defined biomaterial with an impressive portfolio of tissue engineering applications. Altogether, our study reinforce the fact that complex differentiation protocols may be simplified by engineering the cellular microenvironment on multiple scales, i.e. matrix stiffness with growth factor. PMID- 26621697 TI - Multifunctional cationic polyurethanes designed for non-viral cancer gene therapy. AB - Nano-polyplexes from bioreducible cationic polymers have a massive promise for cancer gene therapy. However, the feasibility of cationic polyurethanes for non viral gene therapy is so far not well studied. In this work, a linear cationic polyurethane containing disulfide bonds, urethane linkages and protonable tertiary amino groups was successfully generated by stepwise polycondensation reaction between 2,2'-dithiodiethanol bis(p-nitrophenyl carbonate) and 1,4-bis(3 aminopropyl)piperazine (BAP). We confirmed that the cationic polyurethane (denoted as PUBAP) displayed superior gene delivery properties to its cationic polyamide analogue, thus causing higher in vitro transfection efficiency in MCF-7 and SKOV-3 cells. Besides, further folate-PEGylation and hydrophobic deoxycholic acid (DCA) conjugation to amino-containing PUBAP can be conducted to afford multifunctional polyurethane gene delivery system. After optimization, folate decorated nano-polyplexes from the PUBAP conjugated with 8 folate-PEG chains and 12 DCA residues exhibited superb colloidal stability under physiological conditions, and performed rapid uptake via folate receptor-mediated endocytosis, efficient intracellular gene release and nucleus translocation into SKOV-3 cells in vitro and in vivo. Importantly, PUBAP based polyplexes possess low cytotoxicity as a result of PUBAP biodegradability. Therefore, marked growth inhibition of SKOV-3 tumor xenografted in Balb/c nude mice was achieved with negligible side effects on the mouse health after intravenous administration of PUBAP based polyplexes with a therapeutic plasmid encoding for TNF-related apoptosis-inducing ligand. This work provides a new insight into biomedical application of bio-responsive polyurethanes for cancer therapy. STATEMENT OF SIGNIFICANCE: In this study, we have confirmed that disulfide-based cationic polyurethane presents a new non-viral vector for gene transfer and cancer gene therapy. The significance of this work includes: (1) design and synthesis of a group of novel disulfide-based cationic polyurethane by non-isocyanate chemistry; (2) comparative study of transfection activity between cationic polyurethanes and cationic polyamides; (3) feasibility of bioreducible cationic polyurethanes for in vivo cancer gene therapy. PMID- 26621698 TI - Triggered release of model drug from AuNP-doped BSA nanocarriers in hair follicles using IRA radiation. AB - Recent advances in the field of dermatotherapy have resulted in research efforts focusing on the use of particle-based drug delivery systems for the stimuli responsive release of drugs in the skin and skin appendages, i.e. hair follicles and sebaceous glands. However, effective and innocuous trigger mechanisms which result in the release of the drugs from the nanocarriers upon reaching the target structures are still lacking. For the first time, the present study demonstrated the photo-activated release of the model drug fluorescein isothiocyanate (FITC) from topically applied gold nanoparticle-doped bovine serum albumin (AuNPs-doped BSA) particles (approx. 545nm) using water-filtered infrared A (IRA) radiation in the hair follicles of an ex vivo porcine skin model. The IRA radiation-induced plasmonic heating of the AuNPs results in the partial decomposition or opening of the albumin particles and release the model drug, while control particles without AuNPs show insignificant release. The results demonstrate the feasibility of using IRA radiation to induce release of encapsulated drugs from plasmonic nanocarriers for the targeting of follicular structures. However, the risk of radiation-induced skin damage subsequent to repeated applications of high infrared dosages may be significant. Future studies should aim at determining the suitability of lower infrared A dosages, such as for medical treatment regimens which may necessitate repeated exposure to therapeutics. STATEMENT OF SIGNIFICANCE: Follicular targeting using nanocarriers is of increasing importance in the prophylaxis and treatment of dermatological or other diseases. For the first time, the present study demonstrated the photo-activated release of the model drug fluorescein isothiocyanate (FITC) from topically applied gold nanoparticle-doped bovine serum albumin (AuNPs-doped BSA) particles using water filtered infrared A (IRA) radiation in the hair follicles of an ex vivo porcine skin model. The results demonstrate the feasibility of using wIRA radiation to induce release of encapsulated drugs for the targeting of follicular structures, and provide a new vision on the development of optically addressable delivery systems for controlled release of drugs in the skin and skin appendages, i.e. hair follicles and sebaceous glands. PMID- 26621699 TI - Decellularized retinal matrix: Natural platforms for human retinal progenitor cell culture. AB - Tissue decellularization strategies have enabled engineering of scaffolds that preserve native extracellular matrix (ECM) structure and composition. In this study, we developed decellularized retina (decell-retina) thin films. We hypothesized that these films, mimicking the retina niche, would promote human retinal progenitor cell (hRPC) attachment, proliferation and differentiation. Retinas isolated from bovine eyes were decellularized using 1% w/v sodium dodecyl sulfate (SDS) and pepsin digested. The resulting decell-retina was biochemically assayed for composition and cast dried to develop thin films. Attachment, viability, morphology, proliferation and gene expression of hRPC cultured on the films were studied in vitro. Biochemical analyses of decell-retina compared to native retina indicated the bulk of DNA (94%) was removed, while the majority of sulfated GAGs (55%), collagen (83%), hyaluronic acid (87%), and key growth factors were retained. The decell-retina films supported hRPC attachment and growth, with cell number increasing 1.5-fold over a week. RT-PCR analysis revealed hRPC expression of rhodopsin, rod outer membrane, neural retina-specific leucine zipper neural and cone-rod homeobox gene on decell-retina films, indicating photoreceptor development. In conclusion, novel decell-retina films show promise as potential substrates for culture and/or transplantation of retinal progenitor cells to treat retinal degenerative disorders. STATEMENT OF SIGNIFICANCE: In this study, we report the development of a novel biomaterial, based on decellularized retina (decell-retina) that mimics the retina niche and promotes human retinal progenitor cell (hRPC) attachment, proliferation and differentiation. We estimated, for the first time, the amounts of collagen I, GAGs and HA present in native retina, as well as the decell-retina. We demonstrated that retinas can be decellularized using ionic detergents and can be processed into mechanically stable thin films, which can act as substrates for culturing hRPCs. Rhodopsin, ROM1, NRL and CRX gene expression on the decell retina films indicated photoreceptor development from RPCs. These results support the potential of decell-retina as a cell delivery platform to treat and manage retinal degenerative disease like AMD. PMID- 26621700 TI - Identifying and defining complications of dermatologic surgery to be tracked in the American College of Mohs Surgery (ACMS) Registry. AB - BACKGROUND: In recent years, increasing emphasis has been placed on value-based health care delivery. Dermatology must develop performance measures to judge the quality of services provided. The implementation of a national complication registry is one such method of tracking surgical outcomes and monitoring the safety of the specialty. OBJECTIVE: The purpose of this study was to define critical outcome measures to be included in the complications registry of the American College of Mohs Surgery (ACMS). METHODS: A Delphi process was used to reach consensus on the complications to be recorded. RESULTS: Four major and one minor complications were selected: death, bleeding requiring additional intervention, functional loss attributable to surgery, hospitalization for an operative complication, and surgical site infection. LIMITATIONS: This article addresses only one aspect of registry development: identifying and defining surgical complications. CONCLUSION: The ACMS Registry aims to gather data to monitor the safety and value of dermatologic surgery. Determining and defining the outcomes to be included in the registry is an important foundation toward this endeavor. PMID- 26621701 TI - ADP-stimulated contraction: A predictor of thin-filament activation in cardiac disease. AB - Diastolic dysfunction is general to all idiopathic dilated (IDCM) and hypertrophic cardiomyopathy (HCM) patients. Relaxation deficits may result from increased actin-myosin formation during diastole due to altered tropomyosin position, which blocks myosin binding to actin in the absence of Ca(2+). We investigated whether ADP-stimulated force development (without Ca(2+)) can be used to reveal changes in actin-myosin blockade in human cardiomyopathy cardiomyocytes. Cardiac samples from HCM patients, harboring thick-filament (MYH7mut, MYBPC3mut) and thin-filament (TNNT2mut, TNNI3mut) mutations, and IDCM were compared with sarcomere mutation-negative HCM (HCMsmn) and nonfailing donors. Myofilament ADP sensitivity was higher in IDCM and HCM compared with donors, whereas it was lower for MYBPC3. Increased ADP sensitivity in IDCM, HCMsmn, and MYH7mut was caused by low phosphorylation of myofilament proteins, as it was normalized to donors by protein kinase A (PKA) treatment. Troponin exchange experiments in a TNNT2mut sample corrected the abnormal actin-myosin blockade. In MYBPC3trunc samples, ADP sensitivity highly correlated with cardiac myosin-binding protein-C (cMyBP-C) protein level. Incubation of cardiomyocytes with cMyBP-C antibody against the actin-binding N-terminal region reduced ADP sensitivity, indicative of cMyBP-C's role in actin-myosin regulation. In the presence of Ca(2+), ADP increased myofilament force development and sarcomere stiffness. Enhanced sarcomere stiffness in sarcomere mutation-positive HCM samples was irrespective of the phosphorylation background. In conclusion, ADP stimulated contraction can be used as a tool to study how protein phosphorylation and mutant proteins alter accessibility of myosin binding on actin. In the presence of Ca(2+), pathologic [ADP] and low PKA-phosphorylation, high actin myosin formation could contribute to the impaired myocardial relaxation observed in cardiomyopathies. PMID- 26621702 TI - Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism like social behavior. AB - Autism spectrum disorders (ASDs) are a group of highly inheritable mental disorders associated with synaptic dysfunction, but the underlying cellular and molecular mechanisms remain to be clarified. Here we report that autism in Chinese Han population is associated with genetic variations and copy number deletion of P-Rex1 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1). Genetic deletion or knockdown of P-Rex1 in the CA1 region of the hippocampus in mice resulted in autism-like social behavior that was specifically linked to the defect of long-term depression (LTD) in the CA1 region through alteration of AMPA receptor endocytosis mediated by the postsynaptic PP1alpha (protein phosphase 1alpha)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling pathway. Rescue of the LTD in the CA1 region markedly alleviated autism-like social behavior. Together, our findings suggest a vital role of P-Rex1 signaling in CA1 LTD that is critical for social behavior and cognitive function and offer new insight into the etiology of ASDs. PMID- 26621703 TI - Genomic data do not support comb jellies as the sister group to all other animals. AB - Understanding how complex traits, such as epithelia, nervous systems, muscles, or guts, originated depends on a well-supported hypothesis about the phylogenetic relationships among major animal lineages. Traditionally, sponges (Porifera) have been interpreted as the sister group to the remaining animals, a hypothesis consistent with the conventional view that the last common animal ancestor was relatively simple and more complex body plans arose later in evolution. However, this premise has recently been challenged by analyses of the genomes of comb jellies (Ctenophora), which, instead, found ctenophores as the sister group to the remaining animals (the "Ctenophora-sister" hypothesis). Because ctenophores are morphologically complex predators with true epithelia, nervous systems, muscles, and guts, this scenario implies these traits were either present in the last common ancestor of all animals and were lost secondarily in sponges and placozoans (Trichoplax) or, alternatively, evolved convergently in comb jellies. Here, we analyze representative datasets from recent studies supporting Ctenophora-sister, including genome-scale alignments of concatenated protein sequences, as well as a genomic gene content dataset. We found no support for Ctenophora-sister and conclude it is an artifact resulting from inadequate methodology, especially the use of simplistic evolutionary models and inappropriate choice of species to root the metazoan tree. Our results reinforce a traditional scenario for the evolution of complexity in animals, and indicate that inferences about the evolution of Metazoa based on the Ctenophora-sister hypothesis are not supported by the currently available data. PMID- 26621704 TI - Neural evidence that three dimensions organize mental state representation: Rationality, social impact, and valence. AB - How do people understand the minds of others? Existing psychological theories have suggested a number of dimensions that perceivers could use to make sense of others' internal mental states. However, it remains unclear which of these dimensions, if any, the brain spontaneously uses when we think about others. The present study used multivoxel pattern analysis (MVPA) of neuroimaging data to identify the primary organizing principles of social cognition. We derived four unique dimensions of mental state representation from existing psychological theories and used functional magnetic resonance imaging to test whether these dimensions organize the neural encoding of others' mental states. MVPA revealed that three such dimensions could predict neural patterns within the medial prefrontal and parietal cortices, temporoparietal junction, and anterior temporal lobes during social thought: rationality, social impact, and valence. These results suggest that these dimensions serve as organizing principles for our understanding of other people. PMID- 26621705 TI - Sex beyond the genitalia: The human brain mosaic. AB - Whereas a categorical difference in the genitals has always been acknowledged, the question of how far these categories extend into human biology is still not resolved. Documented sex/gender differences in the brain are often taken as support of a sexually dimorphic view of human brains ("female brain" or "male brain"). However, such a distinction would be possible only if sex/gender differences in brain features were highly dimorphic (i.e., little overlap between the forms of these features in males and females) and internally consistent (i.e., a brain has only "male" or only "female" features). Here, analysis of MRIs of more than 1,400 human brains from four datasets reveals extensive overlap between the distributions of females and males for all gray matter, white matter, and connections assessed. Moreover, analyses of internal consistency reveal that brains with features that are consistently at one end of the "maleness femaleness" continuum are rare. Rather, most brains are comprised of unique "mosaics" of features, some more common in females compared with males, some more common in males compared with females, and some common in both females and males. Our findings are robust across sample, age, type of MRI, and method of analysis. These findings are corroborated by a similar analysis of personality traits, attitudes, interests, and behaviors of more than 5,500 individuals, which reveals that internal consistency is extremely rare. Our study demonstrates that, although there are sex/gender differences in the brain, human brains do not belong to one of two distinct categories: male brain/female brain. PMID- 26621706 TI - Ventral and dorsal streams for choosing word order during sentence production. AB - Proficient language use requires speakers to vary word order and choose between different ways of expressing the same meaning. Prior statistical associations between individual verbs and different word orders are known to influence speakers' choices, but the underlying neural mechanisms are unknown. Here we show that distinct neural pathways are used for verbs with different statistical associations. We manipulated statistical experience by training participants in a language containing novel verbs and two alternative word orders (agent-before patient, AP; patient-before-agent, PA). Some verbs appeared exclusively in AP, others exclusively in PA, and yet others in both orders. Subsequently, we used sparse sampling neuroimaging to examine the neural substrates as participants generated new sentences in the scanner. Behaviorally, participants showed an overall preference for AP order, but also increased PA order for verbs experienced in that order, reflecting statistical learning. Functional activation and connectivity analyses revealed distinct networks underlying the increased PA production. Verbs experienced in both orders during training preferentially recruited a ventral stream, indicating the use of conceptual processing for mapping meaning to word order. In contrast, verbs experienced solely in PA order recruited dorsal pathways, indicating the use of selective attention and sensorimotor integration for choosing words in the right order. These results show that the brain tracks the structural associations of individual verbs and that the same structural output may be achieved via ventral or dorsal streams, depending on the type of regularities in the input. PMID- 26621707 TI - Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. AB - Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by extraskeletal bone formation through endochondral ossification. FOP patients harbor point mutations in ACVR1 (also known as ALK2), a type I receptor for bone morphogenetic protein (BMP). Two mechanisms of mutated ACVR1 (FOP-ACVR1) have been proposed: ligand-independent constitutive activity and ligand-dependent hyperactivity in BMP signaling. Here, by using FOP patient derived induced pluripotent stem cells (FOP-iPSCs), we report a third mechanism, where FOP-ACVR1 abnormally transduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-beta signaling but not BMP signaling. Activin-A enhanced the chondrogenesis of induced mesenchymal stromal cells derived from FOP-iPSCs (FOP-iMSCs) via aberrant activation of BMP signaling in addition to the normal activation of TGF-beta signaling in vitro, and induced endochondral ossification of FOP-iMSCs in vivo. These results uncover a novel mechanism of extraskeletal bone formation in FOP and provide a potential new therapeutic strategy for FOP. PMID- 26621709 TI - Protein-like proton exchange in a synthetic host cavity. AB - The mechanism of proton exchange in a metal-ligand enzyme active site mimic (compound 1) is described through amide hydrogen-deuterium exchange kinetics. The type and ratio of cationic guest to host in solution affect the rate of isotope exchange, suggesting that the rate of exchange is driven by a host whose cavity is occupied by water. Rate constants for acid-, base-, and water-mediated proton exchange vary by orders of magnitude depending on the guest, and differ by up to 200 million-fold relative to an alanine polypeptide. These results suggest that the unusual microenvironment of the cavity of 1 can dramatically alter the reactivity of associated water by magnitudes comparable to that of enzymes. PMID- 26621708 TI - Human-specific derived alleles of CD33 and other genes protect against postreproductive cognitive decline. AB - The individuals of most vertebrate species die when they can no longer reproduce. Humans are a rare exception, having evolved a prolonged postreproductive lifespan. Elders contribute to cooperative offspring care, assist in foraging, and communicate important ecological and cultural knowledge, increasing the survival of younger individuals. Age-related deterioration of cognitive capacity in humans compromises these benefits and also burdens the group with socially costly members. We investigated the contribution of the immunoregulatory receptor CD33 to a uniquely human postreproductive disease, Alzheimer's dementia. Surprisingly, even though selection at advanced age is expected to be weak, a CD33 allele protective against Alzheimer's disease is derived and unique to humans and favors a functional molecular state of CD33 resembling that of the chimpanzee. Thus, derived alleles may be compensatory and restore interactions altered as a consequence of human-specific brain evolution. We found several other examples of derived alleles at other human loci that protect against age related cognitive deterioration arising from neurodegenerative disease or cerebrovascular insufficiency. Selection by inclusive fitness may be strong enough to favor alleles protecting specifically against cognitive decline in postreproductive humans. Such selection would operate by maximizing the contributions of postreproductive individuals to the fitness of younger kin. PMID- 26621710 TI - Universal brain signature of proficient reading: Evidence from four contrasting languages. AB - We propose and test a theoretical perspective in which a universal hallmark of successful literacy acquisition is the convergence of the speech and orthographic processing systems onto a common network of neural structures, regardless of how spoken words are represented orthographically in a writing system. During functional MRI, skilled adult readers of four distinct and highly contrasting languages, Spanish, English, Hebrew, and Chinese, performed an identical semantic categorization task to spoken and written words. Results from three complementary analytic approaches demonstrate limited language variation, with speech-print convergence emerging as a common brain signature of reading proficiency across the wide spectrum of selected languages, whether their writing system is alphabetic or logographic, whether it is opaque or transparent, and regardless of the phonological and morphological structure it represents. PMID- 26621711 TI - Rudimentary empathy in macaques' social decision-making. AB - Primates live in highly social environments, where prosocial behaviors promote social bonds and cohesion and contribute to group members' fitness. Despite a growing interest in the biological basis of nonhuman primates' social interactions, their underlying motivations remain a matter of debate. We report that macaque monkeys take into account the welfare of their peers when making behavioral choices bringing about pleasant or unpleasant outcomes to a monkey partner. Two macaques took turns in making decisions that could impact their own welfare or their partner's. Most monkeys were inclined to refrain from delivering a mildly aversive airpuff and to grant juice rewards to their partner. Choice consistency between these two types of outcome suggests that monkeys display coherent motivations in different social interactions. Furthermore, spontaneous affilitative group interactions in the home environment were mostly consistent with the measured social decisions, thus emphasizing the impact of preexisting social bonds on decision-making. Interestingly, unique behavioral markers predicted these decisions: benevolence was associated with enhanced mutual gaze and empathic eye blinking, whereas indifference or malevolence was associated with lower or suppressed such responses. Together our results suggest that prosocial decision-making is sustained by an intrinsic motivation for social affiliation and controlled through positive and negative vicarious reinforcements. PMID- 26621712 TI - Conservatives negatively evaluate counterstereotypical people to maintain a sense of certainty. AB - People frequently use physical appearance stereotypes to categorize individuals when their group membership is not directly observable. Recent research indicates that political conservatives tend to use such stereotypes more than liberals do because they express a greater desire for certainty and order. In the present research, we found that conservatives were also more likely to negatively evaluate and distribute fewer economic resources to people who deviate from the stereotypes of their group. This occurred for people belonging to both preexisting and novel groups, regardless of whether the stereotypes were real or experimentally fabricated. Critically, conservatives only negatively evaluated counterstereotypical people when the stereotypes were functional-that is, when they expected that they would need to use the stereotypes at a later point to categorize individuals into groups. Moreover, increasing liberals' desire for certainty led them to negatively evaluate counterstereotypical people just like conservatives did. Thus, conservatives are not only more likely to use stereotypes than are liberals, but are especially likely to negatively evaluate counterstereotypical people to organize the social world with greater certainty. PMID- 26621713 TI - How culture gets embrained: Cultural differences in event-related potentials of social norm violations. AB - Humans are unique among all species in their ability to develop and enforce social norms, but there is wide variation in the strength of social norms across human societies. Despite this fundamental aspect of human nature, there has been surprisingly little research on how social norm violations are detected at the neurobiological level. Building on the emerging field of cultural neuroscience, we combine noninvasive electroencephalography (EEG) with a new social norm violation paradigm to examine the neural mechanisms underlying the detection of norm violations and how they vary across cultures. EEG recordings from Chinese and US participants (n = 50) showed consistent negative deflection of event related potential around 400 ms (N400) over the central and parietal regions that served as a culture-general neural marker of detecting norm violations. The N400 at the frontal and temporal regions, however, was only observed among Chinese but not US participants, illustrating culture-specific neural substrates of the detection of norm violations. Further, the frontal N400 predicted a variety of behavioral and attitudinal measurements related to the strength of social norms that have been found at the national and state levels, including higher culture superiority and self-control but lower creativity. There were no cultural differences in the N400 induced by semantic violation, suggesting a unique cultural influence on social norm violation detection. In all, these findings provided the first evidence, to our knowledge, for the neurobiological foundations of social norm violation detection and its variation across cultures. PMID- 26621714 TI - Biological soil crusts accelerate the nitrogen cycle through large NO and HONO emissions in drylands. AB - Reactive nitrogen species have a strong influence on atmospheric chemistry and climate, tightly coupling the Earth's nitrogen cycle with microbial activity in the biosphere. Their sources, however, are not well constrained, especially in dryland regions accounting for a major fraction of the global land surface. Here, we show that biological soil crusts (biocrusts) are emitters of nitric oxide (NO) and nitrous acid (HONO). Largest fluxes are obtained by dark cyanobacteria dominated biocrusts, being ~20 times higher than those of neighboring uncrusted soils. Based on laboratory, field, and satellite measurement data, we obtain a best estimate of ~1.7 Tg per year for the global emission of reactive nitrogen from biocrusts (1.1 Tg a(-1) of NO-N and 0.6 Tg a(-1) of HONO-N), corresponding to ~20% of global nitrogen oxide emissions from soils under natural vegetation. On continental scales, emissions are highest in Africa and South America and lowest in Europe. Our results suggest that dryland emissions of reactive nitrogen are largely driven by biocrusts rather than the underlying soil. They help to explain enigmatic discrepancies between measurement and modeling approaches of global reactive nitrogen emissions. As the emissions of biocrusts strongly depend on precipitation events, climate change affecting the distribution and frequency of precipitation may have a strong impact on terrestrial emissions of reactive nitrogen and related climate feedback effects. Because biocrusts also account for a large fraction of global terrestrial biological nitrogen fixation, their impacts should be further quantified and included in regional and global models of air chemistry, biogeochemistry, and climate. PMID- 26621715 TI - Augmenting NMDA receptor signaling boosts experience-dependent neuroplasticity in the adult human brain. AB - Experience-dependent plasticity is a fundamental property of the brain. It is critical for everyday function, is impaired in a range of neurological and psychiatric disorders, and frequently depends on long-term potentiation (LTP). Preclinical studies suggest that augmenting N-methyl-d-aspartate receptor (NMDAR) signaling may promote experience-dependent plasticity; however, a lack of noninvasive methods has limited our ability to test this idea in humans until recently. We examined the effects of enhancing NMDAR signaling using d cycloserine (DCS) on a recently developed LTP EEG paradigm that uses high frequency visual stimulation (HFvS) to induce neural potentiation in visual cortex neurons, as well as on three cognitive tasks: a weather prediction task (WPT), an information integration task (IIT), and a n-back task. The WPT and IIT are learning tasks that require practice with feedback to reach optimal performance. The n-back assesses working memory. Healthy adults were randomized to receive DCS (100 mg; n = 32) or placebo (n = 33); groups were similar in IQ and demographic characteristics. Participants who received DCS showed enhanced potentiation of neural responses following repetitive HFvS, as well as enhanced performance on the WPT and IIT. Groups did not differ on the n-back. Augmenting NMDAR signaling using DCS therefore enhanced activity-dependent plasticity in human adults, as demonstrated by lasting enhancement of neural potentiation following repetitive HFvS and accelerated acquisition of two learning tasks. Results highlight the utility of considering cellular mechanisms underlying distinct cognitive functions when investigating potential cognitive enhancers. PMID- 26621718 TI - Correction to Supporting Information for Gadad et al., Administration of thimerosal-containing vaccines to infant rhesus macaques does not result in autism-like behavior or neuropathology. PMID- 26621716 TI - Mitochondrial function in the brain links anxiety with social subordination. AB - Dominance hierarchies are integral aspects of social groups, yet whether personality traits may predispose individuals to a particular rank remains unclear. Here we show that trait anxiety directly influences social dominance in male outbred rats and identify an important mediating role for mitochondrial function in the nucleus accumbens. High-anxious animals that are prone to become subordinate during a social encounter with a low-anxious rat exhibit reduced mitochondrial complex I and II proteins and respiratory capacity as well as decreased ATP and increased ROS production in the nucleus accumbens. A causal link for these findings is indicated by pharmacological approaches. In a dyadic contest between anxiety-matched animals, microinfusion of specific mitochondrial complex I or II inhibitors into the nucleus accumbens reduced social rank, mimicking the low probability to become dominant observed in high-anxious animals. Conversely, intraaccumbal infusion of nicotinamide, an amide form of vitamin B3 known to enhance brain energy metabolism, prevented the development of a subordinate status in high-anxious individuals. We conclude that mitochondrial function in the nucleus accumbens is crucial for social hierarchy establishment and is critically involved in the low social competitiveness associated with high anxiety. Our findings highlight a key role for brain energy metabolism in social behavior and point to mitochondrial function in the nucleus accumbens as a potential marker and avenue of treatment for anxiety-related social disorders. PMID- 26621717 TI - Hydrogel-laden paper scaffold system for origami-based tissue engineering. AB - In this study, we present a method for assembling biofunctionalized paper into a multiform structured scaffold system for reliable tissue regeneration using an origami-based approach. The surface of a paper was conformally modified with a poly(styrene-co-maleic anhydride) layer via initiated chemical vapor deposition followed by the immobilization of poly-l-lysine (PLL) and deposition of Ca(2+). This procedure ensures the formation of alginate hydrogel on the paper due to Ca(2+) diffusion. Furthermore, strong adhesion of the alginate hydrogel on the paper onto the paper substrate was achieved due to an electrostatic interaction between the alginate and PLL. The developed scaffold system was versatile and allowed area-selective cell seeding. Also, the hydrogel-laden paper could be folded freely into 3D tissue-like structures using a simple origami-based method. The cylindrically constructed paper scaffold system with chondrocytes was applied into a three-ring defect trachea in rabbits. The transplanted engineered tissues replaced the native trachea without stenosis after 4 wks. As for the custom-built scaffold system, the hydrogel-laden paper system will provide a robust and facile method for the formation of tissues mimicking native tissue constructs. PMID- 26621721 TI - Correction for Duchez et al., Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A2-IIA. PMID- 26621719 TI - Amyloid fibrils activate B-1a lymphocytes to ameliorate inflammatory brain disease. AB - Amyloid fibrils composed of peptides as short as six amino acids are therapeutic in experimental autoimmune encephalomyelitis (EAE), reducing paralysis and inflammation, while inducing several pathways of immune suppression. Intraperitoneal injection of fibrils selectively activates B-1a lymphocytes and two populations of resident macrophages (MPhis), increasing IL-10 production, and triggering their exodus from the peritoneum. The importance of IL-10-producing B 1a cells in this effective therapy was established in loss-of-function experiments where neither B-cell-deficient (MUMT) nor IL10(-/-) mice with EAE responded to the fibrils. In gain-of-function experiments, B-1a cells, adoptively transferred to MUMT mice with EAE, restored their therapeutic efficacy when Amylin 28-33 was administered. Stimulation of adoptively transferred bioluminescent MPhis and B-1a cells by amyloid fibrils resulted in rapid (within 60 min of injection) trafficking of both cell types to draining lymph nodes. Analysis of gene expression indicated that the fibrils activated the CD40/B-cell receptor pathway in B-1a cells and induced a set of immune-suppressive cell surface proteins, including BTLA, IRF4, and Siglec G. Collectively, these data indicate that the fibrils activate B-1a cells and F4/80(+) MPhis, resulting in their migration to the lymph nodes, where IL-10 and cell-surface receptors associated with immune-suppression limit antigen presentation and T-cell activation. These mechanisms culminate in reduction of paralytic signs of EAE. PMID- 26621720 TI - Nck influences preosteoblastic/osteoblastic migration and bone mass. AB - Migration of the cells in osteoblastic lineage, including preosteoblasts and osteoblasts, has been postulated to influence bone formation. However, the molecular bases that link preosteoblastic/osteoblastic cell migration and bone formation are incompletely understood. Nck (noncatalytic region of tyrosine kinase; collectively referred to Nck1 and Nck2) is a member of the signaling adaptors that regulate cell migration and cytoskeletal structures, but its function in cells in the osteoblastic lineage is not known. Therefore, we examined the role of Nck in migration of these cells. Nck is expressed in preosteoblasts/osteoblasts, and its knockdown suppresses migration as well as cell spreading and attachment to substrates. In contrast, Nck1 overexpression enhances spreading and increases migration and attachment. As for signaling, Nck double knockdown suppresses migration toward IGF1 (insulin-like growth factor 1). In these cells, Nck1 binds to IRS-1 (insulin receptor substrate 1) based on immunoprecipitation experiments using anti-Nck and anti-IRS-1 antibodies. In vivo, Nck knockdown suppresses enlargement of the pellet of DiI-labeled preosteoblasts/osteoblasts placed in the calvarial defects. Genetic experiments indicate that conditional double deletion of both Nck1 and Nck2 specifically in osteoblasts causes osteopenia. In these mice, Nck double deficiency suppresses the levels of bone-formation parameters such as bone formation rate in vivo. Interestingly, bone-resorption parameters are not affected. Finally, Nck deficiency suppresses repair of bone injury after bone marrow ablation. These results reveal that Nck regulates preosteoblastic/osteoblastic migration and bone mass. PMID- 26621722 TI - HSV targeting of the host phosphatase PP1alpha is required for disseminated disease in the neonate and contributes to pathogenesis in the brain. AB - Newborns are significantly more susceptible to severe disease after infection with herpes simplex virus (HSV) compared with adults, with differences in the host response implicated as a major factor. To understand host response differences between these age groups, we investigated the shutoff of protein synthesis by the host and the retargeting of host phosphatase PP1alpha by the HSV 1 protein gamma34.5 for reversal of translational arrest. In a murine newborn model of viral dissemination, infection with the HSV-1 mutant for PP1alpha binding resulted in complete absence of disease. PP1alpha-binding mutant HSV-1 replicated in visceral organs early after inoculation, demonstrating that HSV-1 replication requires PP1alpha-targeting only later in infection. Newborn mice deficient in type I IFN signaling partially rescued the virulence of the PP1alpha binding mutant virus, suggesting an IFN-independent role for eIF2alpha kinases during infection. When we investigated the contribution of PP1alpha targeting to pathogenesis in the brain, we found that the inability of HSV-1 to bind PP1alpha increased survival time in both newborn and adult mice. Unlike disseminated disease, type I IFN signaling in the brain was required to attenuate disease following PP1alpha-mutant virus infection. Furthermore, pharmacologic inhibition of eIF2alpha dephosphorylation reduced HSV-1 replication in a brain slice culture model of encephalitis. Our findings reveal age-dependent differences in gamma34.5 function and tissue-specific reliance on the type I IFN response for protection from HSV disease. These results define an important role for gamma34.5 in neonatal infections in contrast to other studies indicating that the autophagy inhibiting function of gamma34.5 is dispensable for pathogenesis in the newborn brain. PMID- 26621725 TI - Correction for Cagin et al., Mitochondrial retrograde signaling regulates neuronal function. PMID- 26621723 TI - Numb deficiency in cerebellar Purkinje cells impairs synaptic expression of metabotropic glutamate receptor and motor coordination. AB - Protein Numb, first identified as a cell-fate determinant in Drosophila, has been shown to promote the development of neurites in mammals and to be cotransported with endocytic receptors in clathrin-coated vesicles in vitro. Nevertheless, its function in mature neurons has not yet been elucidated. Here we show that cerebellar Purkinje cells (PCs) express high levels of Numb during adulthood and that conditional deletion of Numb in PCs is sufficient to impair motor coordination despite maintenance of a normal cerebellar cyto-architecture. Numb proved to be critical for internalization and recycling of metabotropic glutamate 1 receptor (mGlu1) in PCs. A significant decrease of mGlu1 and an inhibition of long-term depression at the parallel fiber-PC synapse were observed in conditional Numb knockout mice. Indeed, the trafficking of mGlu1 induced by agonists was inhibited significantly in these mutants, but the expression of ionotropic glutamate receptor subunits and of mGlu1-associated proteins was not affected by the loss of Numb. Moreover, transient and persistent forms of mGlu1 plasticity were robustly induced in mutant PCs, suggesting that they do not require mGlu1 trafficking. Together, our data demonstrate that Numb is a regulator for constitutive expression and dynamic transport of mGlu1. PMID- 26621724 TI - Omega-3 and -6 fatty acids allocate somatic and germline lipids to ensure fitness during nutrient and oxidative stress in Caenorhabditis elegans. AB - Animals in nature are continually challenged by periods of feast and famine as resources inevitably fluctuate, and must allocate somatic reserves for reproduction to abate evolutionary pressures. We identify an age-dependent lipid homeostasis pathway in Caenorhabditis elegans that regulates the mobilization of lipids from the soma to the germline, which supports fecundity but at the cost of survival in nutrient-poor and oxidative stress environments. This trade-off is responsive to the levels of dietary carbohydrates and organismal oleic acid and is coupled to activation of the cytoprotective transcription factor SKN-1 in both laboratory-derived and natural isolates of C. elegans. The homeostatic balance of lipid stores between the somatic and germ cells is mediated by arachidonic acid (omega-6) and eicosapentaenoic acid (omega-3) precursors of eicosanoid signaling molecules. Our results describe a mechanism for resource reallocation within intact animals that influences reproductive fitness at the cost of somatic resilience. PMID- 26621727 TI - Correction for Grahammer et al., mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress. PMID- 26621726 TI - Reversion to an embryonic alternative splicing program enhances leukemia stem cell self-renewal. AB - Formative research suggests that a human embryonic stem cell-specific alternative splicing gene regulatory network, which is repressed by Muscleblind-like (MBNL) RNA binding proteins, is involved in cell reprogramming. In this study, RNA sequencing, splice isoform-specific quantitative RT-PCR, lentiviral transduction, and in vivo humanized mouse model studies demonstrated that malignant reprogramming of progenitors into self-renewing blast crisis chronic myeloid leukemia stem cells (BC LSCs) was partially driven by decreased MBNL3. Lentiviral knockdown of MBNL3 resulted in reversion to an embryonic alternative splice isoform program typified by overexpression of CD44 transcript variant 3, containing variant exons 8-10, and BC LSC proliferation. Although isoform specific lentiviral CD44v3 overexpression enhanced chronic phase chronic myeloid leukemia (CML) progenitor replating capacity, lentiviral shRNA knockdown abrogated these effects. Combined treatment with a humanized pan-CD44 monoclonal antibody and a breakpoint cluster region - ABL proto-oncogene 1, nonreceptor tyrosine kinase (BCR-ABL1) antagonist inhibited LSC maintenance in a niche dependent manner. In summary, MBNL3 down-regulation-related reversion to an embryonic alternative splicing program, typified by CD44v3 overexpression, represents a previously unidentified mechanism governing malignant progenitor reprogramming in malignant microenvironments and provides a pivotal opportunity for selective BC LSC detection and therapeutic elimination. PMID- 26621728 TI - Augmented Binary Substitution: Single-pass CDR germ-lining and stabilization of therapeutic antibodies. AB - Although humanized antibodies have been highly successful in the clinic, all current humanization techniques have potential limitations, such as: reliance on rodent hosts, immunogenicity due to high non-germ-line amino acid content, v domain destabilization, expression and formulation issues. This study presents a technology that generates stable, soluble, ultrahumanized antibodies via single step complementarity-determining region (CDR) germ-lining. For three antibodies from three separate key immune host species, binary substitution CDR cassettes were inserted into preferred human frameworks to form libraries in which only the parental or human germ-line destination residue was encoded at each position. The CDR-H3 in each case was also augmented with 1 +/- 1 random substitution per clone. Each library was then screened for clones with restored antigen binding capacity. Lead ultrahumanized clones demonstrated high stability, with affinity and specificity equivalent to, or better than, the parental IgG. Critically, this was mainly achieved on germ-line frameworks by simultaneously subtracting up to 19 redundant non-germ-line residues in the CDRs. This process significantly lowered non-germ-line sequence content, minimized immunogenicity risk in the final molecules and provided a heat map for the essential non-germ-line CDR residue content of each antibody. The ABS technology therefore fully optimizes the clinical potential of antibodies from rodents and alternative immune hosts, rendering them indistinguishable from fully human in a simple, single-pass process. PMID- 26621729 TI - Direct mapping of local director field of nematic liquid crystals at the nanoscale. AB - Liquid crystals (LCs), owing to their anisotropy in molecular ordering, are of wide interest in both the display industry and soft matter as a route to more sophisticated optical objects, to direct phase separation, and to facilitate colloidal assemblies. However, it remains challenging to directly probe the molecular-scale organization of nonglassy nematic LC molecules without altering the LC directors. We design and synthesize a new type of nematic liquid crystal monomer (LCM) system with strong dipole-dipole interactions, resulting in a stable nematic phase and strong homeotropic anchoring on silica surfaces. Upon photopolymerization, the director field can be faithfully "locked," allowing for direct visualization of the LC director field and defect structures by scanning electron microscopy (SEM) in real space with 100-nm resolution. Using this technique, we study the nematic textures in more complex LC/colloidal systems and calculate the extrapolation length of the LCM. PMID- 26621733 TI - Correction for Monteith and Pielak, Residue level quantification of protein stability in living cells. PMID- 26621732 TI - Human autoreactive T cells recognize CD1b and phospholipids. AB - In contrast with the common detection of T cells that recognize MHC, CD1a, CD1c, or CD1d proteins, CD1b autoreactive T cells have been difficult to isolate in humans. Here we report the development of polyvalent complexes of CD1b proteins and carbohydrate backbones (dextramers) and their use in identifying CD1b autoreactive T cells from human donors. Activation is mediated by alphabeta T cell receptors (TCRs) binding to CD1b-phospholipid complexes, which is sufficient to activate autoreactive responses to CD1b-expressing cells. Using mass spectrometry and T-cell responses to scan through the major classes of phospholipids, we identified phosphatidylglycerol (PG) as the immunodominant lipid antigen. T cells did not discriminate the chemical differences that distinguish mammalian PG from bacterial PG. Whereas most models of T-cell recognition emphasize TCR discrimination of differing self and foreign structures, CD1b autoreactive T cells recognize lipids with dual self and foreign origin. PG is rare in the cellular membranes that carry CD1b proteins. However, bacteria and mitochondria are rich in PG, so these data point to a more general mechanism of immune detection of infection- or stress-associated lipids. PMID- 26621731 TI - Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS. AB - Ubiquitous expression of amyotrophic lateral sclerosis (ALS)-causing mutations in superoxide dismutase 1 (SOD1) provokes noncell autonomous paralytic disease. By combining ribosome affinity purification and high-throughput sequencing, a cascade of mutant SOD1-dependent, cell type-specific changes are now identified. Initial mutant-dependent damage is restricted to motor neurons and includes synapse and metabolic abnormalities, endoplasmic reticulum (ER) stress, and selective activation of the PRKR-like ER kinase (PERK) arm of the unfolded protein response. PERK activation correlates with what we identify as a naturally low level of ER chaperones in motor neurons. Early changes in astrocytes occur in genes that are involved in inflammation and metabolism and are targets of the peroxisome proliferator-activated receptor and liver X receptor transcription factors. Dysregulation of myelination and lipid signaling pathways and activation of ETS transcription factors occur in oligodendrocytes only after disease initiation. Thus, pathogenesis involves a temporal cascade of cell type-selective damage initiating in motor neurons, with subsequent damage within glia driving disease propagation. PMID- 26621730 TI - Non-bee insects are important contributors to global crop pollination. AB - Wild and managed bees are well documented as effective pollinators of global crops of economic importance. However, the contributions by pollinators other than bees have been little explored despite their potential to contribute to crop production and stability in the face of environmental change. Non-bee pollinators include flies, beetles, moths, butterflies, wasps, ants, birds, and bats, among others. Here we focus on non-bee insects and synthesize 39 field studies from five continents that directly measured the crop pollination services provided by non-bees, honey bees, and other bees to compare the relative contributions of these taxa. Non-bees performed 25-50% of the total number of flower visits. Although non-bees were less effective pollinators than bees per flower visit, they made more visits; thus these two factors compensated for each other, resulting in pollination services rendered by non-bees that were similar to those provided by bees. In the subset of studies that measured fruit set, fruit set increased with non-bee insect visits independently of bee visitation rates, indicating that non-bee insects provide a unique benefit that is not provided by bees. We also show that non-bee insects are not as reliant as bees on the presence of remnant natural or seminatural habitat in the surrounding landscape. These results strongly suggest that non-bee insect pollinators play a significant role in global crop production and respond differently than bees to landscape structure, probably making their crop pollination services more robust to changes in land use. Non-bee insects provide a valuable service and provide potential insurance against bee population declines. PMID- 26621734 TI - Angptl4 links alpha-cell proliferation following glucagon receptor inhibition with adipose tissue triglyceride metabolism. AB - Type 2 diabetes is characterized by a reduction in insulin function and an increase in glucagon activity that together result in hyperglycemia. Glucagon receptor antagonists have been developed as drugs for diabetes; however, they often increase glucagon plasma levels and induce the proliferation of glucagon secreting alpha-cells. We find that the secreted protein Angiopoietin-like 4 (Angptl4) is up-regulated via Ppargamma activation in white adipose tissue and plasma following an acute treatment with a glucagon receptor antagonist. Induction of adipose angptl4 and Angptl4 supplementation promote alpha-cell proliferation specifically. Finally, glucagon receptor antagonist improves glycemia in diet-induced obese angptl4 knockout mice without increasing glucagon levels or alpha-cell proliferation, underscoring the importance of this protein. Overall, we demonstrate that triglyceride metabolism in adipose tissue regulates alpha-cells in the endocrine pancreas. PMID- 26621736 TI - Correction to Supporting Information for Dolcetti et al., Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis. PMID- 26621735 TI - Identifying an ovarian cancer cell hierarchy regulated by bone morphogenetic protein 2. AB - Whether human cancer follows a hierarchical or stochastic model of differentiation is controversial. Furthermore, the factors that regulate cancer stem-like cell (CSC) differentiation potential are largely unknown. We used a novel microfluidic single-cell culture method to directly observe the differentiation capacity of four heterogeneous ovarian cancer cell populations defined by the expression of the CSC markers aldehyde dehydrogenase (ALDH) and CD133. We evaluated 3,692 progeny from 2,833 cells. We found that only ALDH(+)CD133(+) cells could generate all four ALDH(+/-)CD133(+/-) cell populations and identified a clear branched differentiation hierarchy. We also observed a single putative stochastic event. Within the hierarchy of cells, bone morphologenetic protein 2 (BMP2) is preferentially expressed in ALDH(-)CD133(-) cells. BMP2 promotes ALDH(+)CD133(+) cell expansion while suppressing the proliferation of ALDH(-)CD133(-) cells. As such, BMP2 suppressed bulk cancer cell growth in vitro but increased tumor initiation rates, tumor growth, and chemotherapy resistance in vivo whereas BMP2 knockdown reduced CSC numbers, in vivo growth, and chemoresistance. These data suggest a hierarchical differentiation pattern in which BMP2 acts as a feedback mechanism promoting ovarian CSC expansion and suppressing progenitor proliferation. These results explain why BMP2 suppresses growth in vitro and promotes growth in vivo. Together, our results support BMP2 as a therapeutic target in ovarian cancer. PMID- 26621737 TI - Production of functional small interfering RNAs by an amino-terminal deletion mutant of human Dicer. AB - Although RNA interference (RNAi) functions as a potent antiviral innate-immune response in plants and invertebrates, mammalian somatic cells appear incapable of mounting an RNAi response and few, if any, small interfering RNAs (siRNAs) can be detected. To examine why siRNA production is inefficient, we have generated double-knockout human cells lacking both Dicer and protein kinase RNA-activated. Using these cells, which tolerate double-stranded RNA expression, we show that a mutant form of human Dicer lacking the amino-terminal helicase domain can process double-stranded RNAs to produce high levels of siRNAs that are readily detectable by Northern blot, are loaded into RNA-induced silencing complexes, and can effectively and specifically inhibit the expression of cognate mRNAs. Remarkably, overexpression of this mutant Dicer, but not wild-type Dicer, also resulted in a partial inhibition of Influenza A virus-but not poliovirus-replication in human cells. PMID- 26621738 TI - History of the ribosome and the origin of translation. AB - We present a molecular-level model for the origin and evolution of the translation system, using a 3D comparative method. In this model, the ribosome evolved by accretion, recursively adding expansion segments, iteratively growing, subsuming, and freezing the rRNA. Functions of expansion segments in the ancestral ribosome are assigned by correspondence with their functions in the extant ribosome. The model explains the evolution of the large ribosomal subunit, the small ribosomal subunit, tRNA, and mRNA. Prokaryotic ribosomes evolved in six phases, sequentially acquiring capabilities for RNA folding, catalysis, subunit association, correlated evolution, decoding, energy-driven translocation, and surface proteinization. Two additional phases exclusive to eukaryotes led to tentacle-like rRNA expansions. In this model, ribosomal proteinization was a driving force for the broad adoption of proteins in other biological processes. The exit tunnel was clearly a central theme of all phases of ribosomal evolution and was continuously extended and rigidified. In the primitive noncoding ribosome, proto-mRNA and the small ribosomal subunit acted as cofactors, positioning the activated ends of tRNAs within the peptidyl transferase center. This association linked the evolution of the large and small ribosomal subunits, proto-mRNA, and tRNA. PMID- 26621739 TI - Human genetic basis of interindividual variability in the course of infection. AB - The key problem in human infectious diseases was posed at the turn of the 20th century: their pathogenesis. For almost any given virus, bacterium, fungus, or parasite, life-threatening clinical disease develops in only a small minority of infected individuals. Solving this infection enigma is important clinically, for diagnosis, prognosis, prevention, and treatment. Some microbes will inevitably remain refractory to, or escape vaccination, or chemotherapy, or both. The solution also is important biologically, because the emergence and evolution of eukaryotes alongside more rapidly evolving prokaryotes, archaea, and viruses posed immunological challenges of an ecological and evolutionary nature. We need to study these challenges in natural, as opposed to experimental, conditions, and also at the molecular and cellular levels. According to the human genetic theory of infectious diseases, inborn variants underlie life-threatening infectious diseases. Here I review the history of the field of human genetics of infectious diseases from the turn of the 19th century to the second half of the 20th century. This paper thus sets the scene, providing the background information required to understand and appreciate the more recently described monogenic forms of resistance or predisposition to specific infections discussed in a second paper in this issue. PMID- 26621740 TI - The introduction of RNA-DNA differences underlies interindividual variation in the human IL12RB1 mRNA repertoire. AB - Human interleukin 12 and interleukin 23 (IL12/23) influence susceptibility or resistance to multiple diseases. However, the reasons underlying individual differences in IL12/23 sensitivity remain poorly understood. Here we report that in human peripheral blood mononuclear cells (PBMCs) and inflamed lungs, the majority of interleukin-12 receptor beta1 (IL12RB1) mRNAs contain a number of RNA DNA differences (RDDs) that concentrate in sequences essential to IL12Rbeta1's binding of IL12p40, the protein subunit common to both IL-12 and IL-23. IL12RB1 RDDs comprise multiple RDD types and are detectable by next-generation sequencing and classic Sanger sequencing. As a consequence of these RDDs, the resulting IL12Rbeta1 proteins have an altered amino acid sequence that could not be predicted on the basis of genomic DNA sequencing alone. Importantly, the introduction of RDDs into IL12RB1 mRNAs negatively regulates IL12Rbeta1's binding of IL12p40 and is sensitive to activation. Collectively, these results suggest that the introduction of RDDs into an individual's IL12RB1 mRNA repertoire is a novel determinant of IL12/23 sensitivity. PMID- 26621742 TI - Rotational diffusion affects the dynamical self-assembly pathways of patchy particles. AB - Predicting the self-assembly kinetics of particles with anisotropic interactions, such as colloidal patchy particles or proteins with multiple binding sites, is important for the design of novel high-tech materials, as well as for understanding biological systems, e.g., viruses or regulatory networks. Often stochastic in nature, such self-assembly processes are fundamentally governed by rotational and translational diffusion. Whereas the rotational diffusion constant of particles is usually considered to be coupled to the translational diffusion via the Stokes-Einstein relation, in the past decade it has become clear that they can be independently altered by molecular crowding agents or via external fields. Because virus capsids naturally assemble in crowded environments such as the cell cytoplasm but also in aqueous solution in vitro, it is important to investigate how varying the rotational diffusion with respect to transitional diffusion alters the kinetic pathways of self-assembly. Kinetic trapping in malformed or intermediate structures often impedes a direct simulation approach of a kinetic network by dramatically slowing down the relaxation to the designed ground state. However, using recently developed path-sampling techniques, we can sample and analyze the entire self-assembly kinetic network of simple patchy particle systems. For assembly of a designed cluster of patchy particles we find that changing the rotational diffusion does not change the equilibrium constants, but significantly affects the dynamical pathways, and enhances (suppresses) the overall relaxation process and the yield of the target structure, by avoiding (encountering) frustrated states. Besides insight, this finding provides a design principle for improved control of nanoparticle self-assembly. PMID- 26621741 TI - Functional screen identifies kinases driving prostate cancer visceral and bone metastasis. AB - Mutationally activated kinases play an important role in the progression and metastasis of many cancers. Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations of kinases are rare. Several lines of evidence suggest that nonmutated kinases and their pathways are involved in prostate cancer progression, but few kinases have been mechanistically linked to metastasis. Using a mass spectrometry-based phosphoproteomics dataset in concert with gene expression analysis, we selected over 100 kinases potentially implicated in human metastatic prostate cancer for functional evaluation. A primary in vivo screen based on overexpression of candidate kinases in murine prostate cells identified 20 wild-type kinases that promote metastasis. We queried these 20 kinases in a secondary in vivo screen using human prostate cells. Strikingly, all three RAF family members, MERTK, and NTRK2 drove the formation of bone and visceral metastasis confirmed by positron-emission tomography combined with computed tomography imaging and histology. Immunohistochemistry of tissue microarrays indicated that these kinases are highly expressed in human metastatic castration-resistant prostate cancer tissues. Our functional studies reveal the strong capability of select wild-type protein kinases to drive critical steps of the metastatic cascade, and implicate these kinases in possible therapeutic intervention. PMID- 26621744 TI - Discontinuous shear thickening in Brownian suspensions by dynamic simulation. AB - Dynamic particle-scale numerical simulations are used to show that the shear thickening observed in dense colloidal, or Brownian, suspensions is of a similar nature to that observed in noncolloidal suspensions, i.e., a stress-induced transition from a flow of lubricated near-contacting particles to a flow of a frictionally contacting network of particles. Abrupt (or discontinuous) shear thickening is found to be a geometric rather than hydrodynamic phenomenon; it stems from the strong sensitivity of the jamming volume fraction to the nature of contact forces between suspended particles. The thickening obtained in a colloidal suspension of purely hard frictional spheres is qualitatively similar to experimental observations. However, the agreement cannot be made quantitative with only hydrodynamics, frictional contacts, and Brownian forces. Therefore, the role of a short-range repulsive potential mimicking the stabilization of actual suspensions on the thickening is studied. The effects of Brownian and repulsive forces on the onset stress can be combined in an additive manner. The simulations including Brownian and stabilizing forces show excellent agreement with experimental data for the viscosity eta and the second normal stress difference N2. PMID- 26621743 TI - Autotetraploid rice methylome analysis reveals methylation variation of transposable elements and their effects on gene expression. AB - Polyploidy, or whole-genome duplication (WGD), serves as a key innovation in plant evolution and is an important genomic feature for all eukaryotes. Neopolyploids have to overcome difficulties in meiosis, genomic alterations, changes of gene expression, and epigenomic reorganization. However, the underlying mechanisms for these processes are poorly understood. One of the most interesting aspects is that genome doubling events increase the dosage of all genes. Unlike allopolyploids entangled by both hybridization and polyploidization, autopolyploids, especially artificial lines, in relatively uniform genetic background offer a model system to understand mechanisms of genome-dosage effects. To investigate DNA methylation effects in response to WGD rather than hybridization, we produced autotetraploid rice with its diploid donor, Oryza sativa ssp. indica cv. Aijiaonante, both of which were independently self-pollinated over 48 generations, and generated and compared their comprehensive transcriptomes, base pair-resolution methylomes, and siRNAomes. DNA methylation variation of transposable elements (TEs) was observed as widespread in autotetraploid rice, in which hypermethylation of class II DNA transposons was predominantly noted in CHG and CHH contexts. This was accompanied by changes of 24-nt siRNA abundance, indicating the role of the RNA-directed DNA methylation pathway. Our results showed that the increased methylation state of class II TEs may suppress the expression of neighboring genes in autotetraploid rice that has obtained double alleles, leading to no significant differences in transcriptome alterations for most genes from its diploid donor. Collectively, our findings suggest that chromosome doubling induces methylation variation in TEs that affect gene expression and may become a "genome shock" response factor to help neoautopolyploids adapt to genome-dosage effects. PMID- 26621745 TI - Role of protein dynamics in ion selectivity and allosteric coupling in the NaK channel. AB - Flux-dependent inactivation that arises from functional coupling between the inner gate and the selectivity filter is widespread in ion channels. The structural basis of this coupling has only been well characterized in KcsA. Here we present NMR data demonstrating structural and dynamic coupling between the selectivity filter and intracellular constriction point in the bacterial nonselective cation channel, NaK. This transmembrane allosteric communication must be structurally different from KcsA because the NaK selectivity filter does not collapse under low-cation conditions. Comparison of NMR spectra of the nonselective NaK and potassium-selective NaK2K indicates that the number of ion binding sites in the selectivity filter shifts the equilibrium distribution of structural states throughout the channel. This finding was unexpected given the nearly identical crystal structure of NaK and NaK2K outside the immediate vicinity of the selectivity filter. Our results highlight the tight structural and dynamic coupling between the selectivity filter and the channel scaffold, which has significant implications for channel function. NaK offers a distinct model to study the physiologically essential connection between ion conduction and channel gating. PMID- 26621746 TI - ClpB N-terminal domain plays a regulatory role in protein disaggregation. AB - ClpB/Hsp100 is an ATP-dependent disaggregase that solubilizes and reactivates protein aggregates in cooperation with the DnaK/Hsp70 chaperone system. The ClpB substrate interaction is mediated by conserved tyrosine residues located in flexible loops in nucleotide-binding domain-1 that extend into the ClpB central pore. In addition to the tyrosines, the ClpB N-terminal domain (NTD) was suggested to provide a second substrate-binding site; however, the manner in which the NTD recognizes and binds substrate proteins has remained elusive. Herein, we present an NMR spectroscopy study to structurally characterize the NTD substrate interaction. We show that the NTD includes a substrate-binding groove that specifically recognizes exposed hydrophobic stretches in unfolded or aggregated client proteins. Using an optimized segmental labeling technique in combination with methyl-transverse relaxation optimized spectroscopy (TROSY) NMR, the interaction of client proteins with both the NTD and the pore-loop tyrosines in the 580-kDa ClpB hexamer has been characterized. Unlike contacts with the tyrosines, the NTD-substrate interaction is independent of the ClpB nucleotide state and protein conformational changes that result from ATP hydrolysis. The NTD interaction destabilizes client proteins, priming them for subsequent unfolding and translocation. Mutations in the NTD substrate-binding groove are shown to have a dramatic effect on protein translocation through the ClpB central pore, suggesting that, before their interaction with substrates, the NTDs block the translocation channel. Together, our findings provide both a detailed characterization of the NTD-substrate complex and insight into the functional regulatory role of the ClpB NTD in protein disaggregation. PMID- 26621747 TI - Origin of information-limiting noise correlations. AB - The ability to discriminate between similar sensory stimuli relies on the amount of information encoded in sensory neuronal populations. Such information can be substantially reduced by correlated trial-to-trial variability. Noise correlations have been measured across a wide range of areas in the brain, but their origin is still far from clear. Here we show analytically and with simulations that optimal computation on inputs with limited information creates patterns of noise correlations that account for a broad range of experimental observations while at same time causing information to saturate in large neural populations. With the example of a network of V1 neurons extracting orientation from a noisy image, we illustrate to our knowledge the first generative model of noise correlations that is consistent both with neurophysiology and with behavioral thresholds, without invoking suboptimal encoding or decoding or internal sources of variability such as stochastic network dynamics or cortical state fluctuations. We further show that when information is limited at the input, both suboptimal connectivity and internal fluctuations could similarly reduce the asymptotic information, but they have qualitatively different effects on correlations leading to specific experimental predictions. Our study indicates that noise at the sensory periphery could have a major effect on cortical representations in widely studied discrimination tasks. It also provides an analytical framework to understand the functional relevance of different sources of experimentally measured correlations. PMID- 26621748 TI - Ack1 is a dopamine transporter endocytic brake that rescues a trafficking dysregulated ADHD coding variant. AB - The dopamine (DA) transporter (DAT) facilitates high-affinity presynaptic DA reuptake that temporally and spatially constrains DA neurotransmission. Aberrant DAT function is implicated in attention-deficit/hyperactivity disorder and autism spectrum disorder. DAT is a major psychostimulant target, and psychostimulant reward strictly requires binding to DAT. DAT function is acutely modulated by dynamic membrane trafficking at the presynaptic terminal and a PKC-sensitive negative endocytic mechanism, or "endocytic brake," controls DAT plasma membrane stability. However, the molecular basis for the DAT endocytic brake is unknown, and it is unknown whether this braking mechanism is unique to DAT or common to monoamine transporters. Here, we report that the cdc42-activated, nonreceptor tyrosine kinase, Ack1, is a DAT endocytic brake that stabilizes DAT at the plasma membrane and is released in response to PKC activation. Pharmacologic and shRNA mediated Ack1 silencing enhanced basal DAT internalization and blocked PKC stimulated DAT internalization, but had no effects on SERT endocytosis. Both cdc42 activation and PKC stimulation converge on Ack1 to control Ack1 activity and DAT endocytic capacity, and Ack1 inactivation is required for stimulated DAT internalization downstream of PKC activation. Moreover, constitutive Ack1 activation is sufficient to rescue the gain-of-function endocytic phenotype exhibited by the ADHD DAT coding variant, R615C. These findings reveal a unique endocytic control switch that is highly specific for DAT. Moreover, the ability to rescue the DAT(R615C) coding variant suggests that manipulating DAT trafficking mechanisms may be a potential therapeutic approach to correct DAT coding variants that exhibit trafficking dysregulation. PMID- 26621749 TI - Networks of energetic and metabolic interactions define dynamics in microbial communities. AB - Microorganisms form diverse communities that have a profound impact on the environment and human health. Recent technological advances have enabled elucidation of community diversity at high resolution. Investigation of microbial communities has revealed that they often contain multiple members with complementing and seemingly redundant metabolic capabilities. An understanding of the communal impacts of redundant metabolic capabilities is currently lacking; specifically, it is not known whether metabolic redundancy will foster competition or motivate cooperation. By investigating methanogenic populations, we identified the multidimensional interspecies interactions that define composition and dynamics within syntrophic communities that play a key role in the global carbon cycle. Species-specific genomes were extracted from metagenomic data using differential coverage binning. We used metabolic modeling leveraging metatranscriptomic information to reveal and quantify a complex intertwined system of syntrophic relationships. Our results show that amino acid auxotrophies create additional interdependencies that define community composition and control carbon and energy flux through the system while simultaneously contributing to overall community robustness. Strategic use of antimicrobials further reinforces this intricate interspecies network. Collectively, our study reveals the multidimensional interactions in syntrophic communities that promote high species richness and bolster community stability during environmental perturbations. PMID- 26621753 TI - Unusual Sertoli Cell Tumor Associated With Sex Cord Tumor With Annular Tubules in Peutz-Jeghers Syndrome: Report of a Case and Review of the Literature on Ovarian Tumors in Peutz-Jeghers Syndrome. AB - We report the case of an 11-year-old girl with Peutz-Jeghers syndrome and a unilateral ovarian tumor most consistent with Sertoli cell tumor associated with sex cord tumor with annular tubules. The ovary was replaced by a lobular, solid, yellow tumor. Microscopic examination showed 2 components that focally merged. The first was composed of uniform, cytologically bland cells arranged mostly in diffuse sheets and focally in tubules. The second showed typical sex cord tumor with annular tubules with extensive calcification. The predominant component of the tumor clearly fell in the sex cord category and most closely resembled Sertoli cell tumor. This case adds to the limited information on ovarian sex cord tumors, other than typical sex cord tumor with annular tubules, arising in association with Peutz-Jeghers syndrome, a topic reviewed herein. PMID- 26621754 TI - A Corny Joke. PMID- 26621751 TI - Nrf2 in ischemic neurons promotes retinal vascular regeneration through regulation of semaphorin 6A. AB - Delayed revascularization of ischemic neural tissue is a major impediment to preservation of function in central nervous system (CNS) diseases including stroke and ischemic retinopathies. Therapeutic strategies allowing rapid revascularization are greatly needed to reduce ischemia-induced cellular damage and suppress harmful pathologic neovascularization. However, key mechanisms governing vascular recovery in ischemic CNS, including regulatory molecules governing the transition from tissue injury to tissue repair, are largely unknown. NF-E2-related factor 2 (Nrf2) is a major stress-response transcription factor well known for its cell-intrinsic cytoprotective function. However, its role in cell-cell crosstalk is less appreciated. Here we report that Nrf2 is highly activated in ischemic retina and promotes revascularization by modulating neurons in their paracrine regulation of endothelial cells. Global Nrf2 deficiency strongly suppresses retinal revascularization and increases pathologic neovascularization in a mouse model of ischemic retinopathy. Conditional knockout studies demonstrate a major role for neuronal Nrf2 in vascular regrowth into avascular retina. Deletion of neuronal Nrf2 results in semaphorin 6A (Sema6A) induction in hypoxic/ischemic retinal ganglion cells in a hypoxia-inducible factor-1 alpha (HIF-1alpha)-dependent fashion. Sema6A expression increases in avascular inner retina and colocalizes with Nrf2 in human fetal eyes. Extracellular Sema6A leads to dose-dependent suppression of the migratory phenotype of endothelial cells through activation of Notch signaling. Lentiviral mediated delivery of Sema6A small hairpin RNA (shRNA) abrogates the defective retinal revascularization in Nrf2-deficient mice. Importantly, pharmacologic Nrf2 activation promotes reparative angiogenesis and suppresses pathologic neovascularization. Our findings reveal a unique function of Nrf2 in reprogramming ischemic tissue toward neurovascular repair via Sema6A regulation, providing a potential therapeutic strategy for ischemic retinal and CNS diseases. PMID- 26621750 TI - Severe infectious diseases of childhood as monogenic inborn errors of immunity. AB - This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications. PMID- 26621755 TI - Feasibility of low-concentration iodinated contrast medium with lower-tube voltage dual-source CT aortography using iterative reconstruction: comparison with automatic exposure control CT aortography. AB - To evaluate the feasibility of low-concentration contrast medium (CM) for vascular enhancement, image quality, and radiation dose on computed tomography aortography (CTA) using a combined low-tube-voltage and iterative reconstruction (IR) technique. Ninety subjects underwent dual-source CT (DSCT) operating in dual source, high-pitch mode. DSCT scans were performed using both high-concentration CM (Group A, n = 50; Iomeprol 400) and low-concentration CM (Group B, n = 40; Iodixanol 270). Group A was scanned using a reference tube potential of 120 kVp and 120 reference mAs under automatic exposure control with IR. Group B was scanned using low-tube-voltage (80 or 100 kVp if body mass index >=25 kg/m(2)) at a fixed current of 150 mAs, along with IR. Images of the two groups were compared regarding attenuation, image noise, signal-to-noise ratio (SNR), contrast-to noise ratio (CNR), iodine load, and radiation dose in various locations of the CTA. In comparison between Group A and Group B, the average mean attenuation (454.73 +/- 86.66 vs. 515.96 +/- 101.55 HU), SNR (25.28 +/- 4.34 vs. 31.29 +/- 4.58), and CNR (21.83 +/- 4.20 vs. 27.55 +/- 4.81) on CTA in Group B showed significantly greater values and significantly lower image noise values (18.76 +/ 2.19 vs. 17.48 +/- 3.34) than those in Group A (all Ps < 0.05). Homogeneous contrast enhancement from the ascending thoracic aorta to the infrarenal abdominal aorta was significantly superior in Group B (P < 0.05). Low concentration CM and a low-tube-voltage combination technique using IR is a feasible method, showing sufficient contrast enhancement and image quality. PMID- 26621757 TI - Molecular characterization and functional analysis of tumor necrosis factor receptor-associated factor 2 in the Pacific oyster. AB - Tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) are a family of crucial adaptors, playing vital roles in mediating signal transduction in immune signaling pathways, including RIG-I-like receptor (RLR) signaling pathway. In the present study, a new TRAF family member (CgTRAF2) was identified in the Pacific oyster, Crassostrea gigas. Comparison and phylogenetic analysis revealed that CgTRAF2 could be a new member of the invertebrate TRAF2 family. Quantitative real time PCR revealed that CgTRAF2 mRNA was highly expressed in the digestive gland, gills, and hemocytes, and it was significantly up-regulated after Vibrio alginolyticus and ostreid herpesvirus 1 (OsHV-1) challenge. The CgTRAF2 mRNA expression profile in different developmental stages of oyster larvae suggested that CgTRAF2 could function in early larval development. CgTRAF2 mRNA expression pattern, after the silence of CgMAVS (Mitochondrial Antiviral Signaling) -like, indicated that CgTRAF2 might function downstream of CgMAVS-like. Moreover, the subcellular localization analysis revealed that CgTRAF2 was localized in cytoplasm, and it may play predominately important roles in signal transduction. Collectively, these results demonstrated that CgTRAF2 might play important roles in the innate immunity and larval development of the Pacific oyster. PMID- 26621756 TI - Differences in aortic vortex flow pattern between normal and patients with stroke: qualitative and quantitative assessment using transesophageal contrast echocardiography. AB - The flow in the aorta forms a vortex, which is a critical determinant of the flow dynamics in the aorta. Arteriosclerosis can alter the blood flow pattern of the aorta and cause characteristic alterations of the vortex. However, this change in aortic vortex has not yet been studied. This study aimed to characterize aortic vortex flow pattern using transesophageal contrast echocardiography in normal and stroke patients. A total of 85 patients who diagnosed with ischemic stroke and 16 normal controls were recruited for this study. The 16 normal control subjects were designated as the control group, and the 85 ischemic stroke patients were designated as the stroke group. All subjects underwent contrast transesophageal echocardiography (TEE), and particle image velocimetry was used to assess aortic vortex flow. Qualitative and quantitative analyses of vortex flow morphology, location, phasic variation, and pulsatility were undertaken and compared between the groups. In the control group, multiple irregularly-shaped vortices were observed in a peripheral location in the descending thoracic aorta. In contrast, the stroke group had a single, round, merged, and more centrally located aortic vortex flow. In the quantitative analysis of vortex, vortex depth, which represents the location of the major vortex in the aorta, was significantly higher in the control group than in the stroke group (0.599 +/- 0.159 vs. 0.522 +/- 0.101, respectively, P = 0.013). Vortex relative strength, which is the pulsatility parameter of the vortex itself, was significantly higher in the stroke group than in the control group (0.367 +/- 0.148 vs. 0.304 +/- 0.087, respectively, P = 0.025). It was feasible to visualize and quantify the characteristic morphology and pulsatility of the aortic vortex flow using contrast TEE, and aortic vortex pattern significantly differed between normal and stroke patients. PMID- 26621758 TI - New alpha-glucosidase inhibiting anthracenone from the barks of Harungana madagascariensis Lam. AB - Two new 10-hydroxy-9(10H)-anthracenone, madagascenone A (1) and B (2), were isolated from the barks of Harungana madagascariensis Lam. The structures of the compounds were determined using 1D- and 2D-NMR and mass spectroscopic techniques. Both of the compounds showed an in vitro alpha-glucosidase inhibition with IC50 = 69.9 +/- 4.21 and 122.3 +/- 1.13 MUM, respectively, more potent than the standard acarbose (IC50 = 840 +/- 1.23 MUM). PMID- 26621760 TI - Brain May Prime Metastatic Cell Growth. AB - Metastasizing tumor cells lose expression of the tumor suppressor PTEN at a much higher rate when they enter the brain compared to other organs, suggesting that the brain's unique microenvironment may prime metastatic cells for aggressive growth, a recent study reports. The findings may have implications for developing targeted therapies for brain metastases. PMID- 26621759 TI - Extra-pulmonary manifestations associated with Mycoplasma pneumoniae pneumonia in adults. PMID- 26621761 TI - Novartis Compiles Mouse Avatar "Encyclopedia". AB - Novartis scientists have generated the PDX Encyclopedia, which contains over 1,000 patient-derived tumor xenograft models spanning a range of common solid cancers. They'll use this collection for in vivo drug screens designed to mimic human clinical trials, which they hope improves candidate therapy profiling. PMID- 26621762 TI - Turning Cancer Cells into Cancer Killers. AB - Researchers have changed leukemia cells into natural killer cells by adding a specific antibody to bone marrow cells from patients with acute myeloblastic leukemia. The induced natural killer cells killed leukemia cells in culture. The antibody does not trigger the same conversion in bone marrow from healthy patients. PMID- 26621763 TI - Reconsidering counselling and consent. AB - In the current era patient autonomy is enormously important. However, recently there has also been some movement back to ensure that trust in the doctor's skill, knowledge and virtue is not excluded in the process. These new nuances of informed consent have been referred to by terms such as beneficent paternalism, experience-based paternalism and we would add virtuous paternalism. The purpose of this paper is to consider the history and current problematic nature of counselling and consent. Starting with the tradition founded by Hippocrates we trace and seek to understand how relevant aspects of the patient-doctor relationship have evolved under the influences of subsequent moral theories. Finally we tentatively endorse certain modes of counselling in the current era in order to promote morally sound, good clinical practice. PMID- 26621764 TI - Computer-Guided Deep Brain Stimulation Programming for Parkinson's Disease. AB - OBJECTIVE: Pilot study to evaluate computer-guided deep brain stimulation (DBS) programming designed to optimize stimulation settings using objective motion sensor-based motor assessments. MATERIALS AND METHODS: Seven subjects (five males; 54-71 years) with Parkinson's disease (PD) and recently implanted DBS systems participated in this pilot study. Within two months of lead implantation, the subject returned to the clinic to undergo computer-guided programming and parameter selection. A motion sensor was placed on the index finger of the more affected hand. Software guided a monopolar survey during which monopolar stimulation on each contact was iteratively increased followed by an automated assessment of tremor and bradykinesia. After completing assessments at each setting, a software algorithm determined stimulation settings designed to minimize symptom severities, side effects, and battery usage. RESULTS: Optimal DBS settings were chosen based on average severity of motor symptoms measured by the motion sensor. Settings chosen by the software algorithm identified a therapeutic window and improved tremor and bradykinesia by an average of 35.7% compared with baseline in the "off" state (p < 0.01). CONCLUSIONS: Motion sensor based computer-guided DBS programming identified stimulation parameters that significantly improved tremor and bradykinesia with minimal clinician involvement. Automated motion sensor-based mapping is worthy of further investigation and may one day serve to extend programming to populations without access to specialized DBS centers. PMID- 26621766 TI - Homochiral mononuclear Dy-Schiff base complexes showing field-induced double magnetic relaxation processes. AB - A pair of enantiopure mononuclear dysprosium/salen-type complexes (Et3NH)[Dy((R,R)/(S,S)-3-NO2salcy)2] (/), where 3-NO2salcyH2 represents N,N'-(1,2 cyclohexanediylethylene)bis(3-nitrosalicylideneiminato), are reported. The enantiomer contains two crystallographically independent dysprosium(iii) ions, each chelated by two enantiopure 3-NO2salcy(2-) ligands forming a [DyN4O4] core. Detailed magnetic studies on compound reveal a field-induced dual magnetic relaxation behavior, originating from single ion anisotropy and intermolecular interactions, respectively. PMID- 26621765 TI - Easing the Burden: Describing the Role of Social, Emotional and Spiritual Support in Research Families with Li-Fraumeni Syndrome. AB - This study presents findings of a mixed-method descriptive exploration of the role of friends and spirituality/religiosity in easing the burden of families with the rare inherited disorder, Li-Fraumeni Syndrome (LFS). LFS is caused by germline mutations in the TP53 gene and is associated with very high lifetime risk of developing one or more malignancies. During the first clinical visit we assessed several types of social support among a subset of study participants (N = 66) using an established interactive research tool called the Colored Eco Genetic Relationship Map (CEGRM). We performed both quantitative and qualitative analyses of social relationships with LFS family members and close non-kin. Distress scores (N = 59) were mostly low normal, with some outliers. We found that reported friendships varied widely, that the friendships were often deep and enduring, and were important sources of informational, tangible, emotional and spiritual support. Confidantes tended to be best friends and/or spouses. Organized religion was important in selected families, typically from mainstream traditions. However, a number of people identified themselves as "spiritual" and reported spiritual and humanist explorations. Our results shed preliminary light on how some people in families with LFS cope in the face of tremendous medical, social and emotional challenges. PMID- 26621767 TI - Water filling and electric field-induced enhancement in the mechanical property of carbon nanotubes. AB - The effects of water filling and electric field on the mechanical property of carbon nanotubes (CNTs) are investigated with molecular dynamics simulations. The simulation results indicate that the water filling and electric field could enhance the elastic modulus but reduce the Poisson's ratio of the CNTs. As for the buckling behaviors, a significant enhancement could be observed in the yield stress and average post-buckling stress of the CNTs. In particular, the enhancement in the yield stress induced by the water filling and electric field could be even higher than that resulted from the solid filling. Moreover, a transition mechanism from the rod instability to shell buckling is shown to explain the nonmonotonic variation of yield stress, and the critical diameter can be tuned through filling the water molecules and applying the electric field. The present findings provide a valuable route for the optimized design and application of the nanoscale functional devices based on the water-filled CNTs. PMID- 26621768 TI - [The ambulatory is it future of radical prostatectomy? Probably not...]. PMID- 26621769 TI - A global map of hemispheric influenza vaccine recommendations based on local patterns of viral circulation. AB - Both the Northern and the Southern Hemisphere annual WHO influenza vaccine recommendations are designed to ensure vaccine delivery before the winter-time peak of viral circulation in each hemisphere. However, influenza seasonal patterns are highly diverse in tropical countries and may be out of phase with the WHO recommendations for their respective hemisphere. We modelled the peak timing of influenza activity for 125 countries using laboratory-based surveillance data from the WHO's FLUNET database and compared it with the influenza hemispheric recommendations in place. Influenza vaccine recommendations for respectively 25% and 39% of the Northern and Southern Hemisphere countries were out of phase with peak influenza circulation in their corresponding hemisphere (62% and 53%, respectively, when the analysis was limited to the 52 countries in the tropical belt). These results indicate that routine influenza immunization efforts should be closely tailored to local patterns of viral circulation, rather than a country's hemispheric position. PMID- 26621770 TI - Norcocaine and cocaethylene distribution patterns in hair samples from light, moderate, and heavy cocaine users. AB - Even though hair analysis often seems to be the best choice for retrospective monitoring of cocaine intake, differentiating between incorporated cocaine and external contamination is widely debated. In this study we report results obtained in 90 hair samples from addicts. All samples were analyzed for cocaine, benzoylecgonine, norcocaine, cocaethylene, and tropococaine by gas chromatography mass spectrometry (GC-MS) techniques coupled with direct immersion solid-phase micro-extraction. Cocaine concentrations were stratified into three classes of usage: light (0.5-3 ng/mg), moderate (3.1-10 ng/mg) and heavy (10.1-40 ng/mg). The Substance Abuse and Mental Health Services Administration cut-off criteria for establishing active cocaine use were applied to the results. For all samples criteria were cocaine levels above 0.5 ng/mg (ranging from 1.63 to 39.29 ng/mg, mean 9.49 ng/mg), benzoylecgonine concentrations >= 0.05 ng/mg (ranging from 0.19 to 5.77 ng/mg, mean 1.40), and benzoylecgonine to cocaine % ratio >=5% (from 6.43 to 26.09%). Norcocaine was present in 58.9% of samples (concentration range: 0.22 3.14 ng/mg) and was strongly predictive only of heavy cocaine use (sensitivity 100% for cocaine concentrations above 9.58 ng/mg). Twenty hair samples from moderate and heavy users tested positive for cocaethylene (concentration range: 0.22-1.98 ng/mg, mean 0.73 ng/mg). This study on hair samples with no chance of false positive cases highlights the very limited applications of testing minor cocaine metabolites for definitive proof of active cocaine consumption. (c) 2015 The Authors. Drug Testing and Analysis Published by John Wiley & Sons, Ltd. PMID- 26621771 TI - Synthetic approaches towards alkaloids bearing alpha-tertiary amines. AB - Alkaloids account for some of the most beautiful and biologically active natural products. Although they are usually classified along biosynthetic criteria, they can also be categorized according to certain structural motifs. Amongst these, the alpha-tertiary amine (ATA), i.e. a tetrasubstituted carbon atom surrounded by three carbons and one nitrogen, is particularly interesting. A limited number of methods have been described to access this functional group and fewer still are commonly used in synthesis. Herein, we review some approaches to asymmetrically access ATAs and provide an overview of alkaloid total syntheses where those have been employed. PMID- 26621772 TI - Modal gating of endplate acetylcholine receptors: A proposed mechanism. PMID- 26621773 TI - Impact of single-site axonal GABAergic synaptic events on cerebellar interneuron activity. AB - Axonal ionotropic receptors are present in a variety of neuronal types, and their function has largely been associated with the modulation of axonal activity and synaptic release. It is usually assumed that activation of axonal GABA(A)Rs comes from spillover, but in cerebellar molecular layer interneurons (MLIs) the GABA source is different: in these cells, GABA release activates presynaptic GABA(A) autoreceptors (autoRs) together with postsynaptic targets, producing an autoR mediated synaptic event. The frequency of presynaptic, autoR-mediated miniature currents is twice that of their somatodendritic counterparts, suggesting that autoR-mediated responses have an important effect on interneuron activity. Here, we used local Ca(2+) photolysis in MLI axons of juvenile rats to evoke GABA release from individual varicosities to study the activation of axonal autoRs in single release sites. Our data show that single-site autoR conductances are similar to postsynaptic dendritic conductances. In conditions of high [Cl(-)](i), autoR-mediated conductances range from 1 to 5 nS; this corresponds to ~30-150 GABA(A) channels per presynaptic varicosity, a value close to the number of channels in postsynaptic densities. Voltage responses produced by the activation of autoRs in single varicosities are amplified by a Na(v)-dependent mechanism and propagate along the axon with a length constant of 91 um. Immunolabeling determination of synapse location shows that on average, one third of the synapses produce autoR-mediated signals that are large enough to reach the axon initial segment. Finally, we show that single-site activation of presynaptic GABA(A) autoRs leads to an increase in MLI excitability and thus conveys a strong feedback signal that contributes to spiking activity. PMID- 26621774 TI - Modulation of the slow/common gating of CLC channels by intracellular cadmium. AB - Members of the CLC family of Cl(-) channels and transporters are homodimeric integral membrane proteins. Two gating mechanisms control the opening and closing of Cl(-) channels in this family: fast gating, which regulates opening and closing of the individual pores in each subunit, and slow (or common) gating, which simultaneously controls gating of both subunits. Here, we found that intracellularly applied Cd(2+) reduces the current of CLC-0 because of its inhibition on the slow gating. We identified CLC-0 residues C229 and H231, located at the intracellular end of the transmembrane domain near the dimer interface, as the Cd(2+)-coordinating residues. The inhibition of the current of CLC-0 by Cd(2+) was greatly enhanced by mutation of I225W and V490W at the dimer interface. Biochemical experiments revealed that formation of a disulfide bond within this Cd(2+)-binding site is also affected by mutation of I225W and V490W, indicating that these two mutations alter the structure of the Cd(2+)-binding site. Kinetic studies showed that Cd(2+) inhibition appears to be state dependent, suggesting that structural rearrangements may occur in the CLC dimer interface during Cd(2+) modulation. Mutations of I290 and I556 of CLC-1, which correspond to I225 and V490 of CLC-0, respectively, have been shown previously to cause malfunction of CLC-1 Cl(-) channel by altering the common gating. Our experimental results suggest that mutations of the corresponding residues in CLC 0 change the subunit interaction and alter the slow gating of CLC-0. The effect of these mutations on modulations of slow gating of CLC channels by intracellular Cd(2+) likely depends on their alteration of subunit interactions. PMID- 26621775 TI - Understanding the physiology of the asymptomatic diaphragm of the M1592V hyperkalemic periodic paralysis mouse. AB - The diaphragm muscle of hyperkalemic periodic paralysis (HyperKPP) patients and of the M1592V HyperKPP mouse model rarely suffers from the myotonic and paralytic symptoms that occur in limb muscles. Enigmatically, HyperKPP diaphragm expresses the mutant NaV1.4 channel and, more importantly, has an abnormally high Na(+) influx similar to that in extensor digitorum longus (EDL) and soleus, two hindlimb muscles suffering from the robust HyperKPP abnormalities. The objective was to uncover the physiological mechanisms that render HyperKPP diaphragm asymptomatic. A first mechanism involves efficient maintenance of resting membrane polarization in HyperKPP diaphragm at various extracellular K(+) concentrations compared with larger membrane depolarizations in HyperKPP EDL and soleus. The improved resting membrane potential (EM) results from significantly increased Na(+) K(+) pump electrogenic activity, and not from an increased protein content. Action potential amplitude was greater in HyperKPP diaphragm than in HyperKPP soleus and EDL, providing a second mechanism for the asymptomatic behavior of the HyperKPP diaphragm. One suggested mechanism for the greater action potential amplitude is lower intracellular Na(+) concentration because of greater Na(+) K(+) pump activity, allowing better Na(+) current during the action potential depolarization phase. Finally, HyperKPP diaphragm had a greater capacity to generate force at depolarized EM compared with wild-type diaphragm. Action potential amplitude was not different between wild-type and HyperKPP diaphragm. There was also no evidence for an increased activity of the Na(+)-Ca(2+) exchanger working in the reverse mode in the HyperKPP diaphragm compared with the wild-type diaphragm. So, a third mechanism remains to be elucidated to fully understand how HyperKPP diaphragm generates more force compared with wild type. Although the mechanism for the greater force at depolarized resting EM remains to be determined, this study provides support for the modulation of the Na(+) K(+) pump as a component of therapy to alleviate weakness in HyperKPP. PMID- 26621776 TI - Differential mechanisms of Cantu syndrome-associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel. AB - Cantu syndrome (CS) is a rare disease characterized by congenital hypertrichosis, distinct facial features, osteochondrodysplasia, and cardiac defects. Recent genetic analysis has revealed that the majority of CS patients carry a missense mutation in ABCC9, which codes for the sulfonylurea receptor SUR2. SUR2 subunits couple with Kir6.x, inwardly rectifying potassium pore-forming subunits, to form adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels, which link cell metabolism to membrane excitability in a variety of tissues including vascular smooth muscle, skeletal muscle, and the heart. The functional consequences of multiple uncharacterized CS mutations remain unclear. Here, we have focused on determining the functional consequences of three documented human CS-associated ABCC9 mutations: human P432L, A478V, and C1043Y. The mutations were engineered in the equivalent position in rat SUR2A (P429L, A475V, and C1039Y), and each was coexpressed with mouse Kir6.2. Using macroscopic rubidium ((86)Rb(+)) efflux assays, we show that K(ATP) channels formed with P429L, A475V, or C1039Y mutants enhance K(ATP) activity compared with wild-type (WT) channels. We used inside-out patch-clamp electrophysiology to measure channel sensitivity to ATP inhibition and to MgADP activation. For P429L and A475V mutants, sensitivity to ATP inhibition was comparable to WT channels, but activation by MgADP was significantly greater. C1039Y-dependent channels were significantly less sensitive to inhibition by ATP or by glibenclamide, but MgADP activation was comparable to WT. The results indicate that these three CS mutations all lead to overactive K(ATP) channels, but at least two mechanisms underlie the observed gain of function: decreased ATP inhibition and enhanced MgADP activation. PMID- 26621777 TI - Taxodione and Extracts from Salvia austriaca Roots as Human Cholinesterase Inhibitors. AB - Taxodione, an abietane diterpenoid, was isolated from Salvia austriaca transformed roots grown in in vitro conditions. The compound is known to have antibacterial, cytotoxic and anti-tumour properties. This study evaluates the ability of pure taxodione and extracts obtained from the S. austriaca hairy roots and roots from field-grown plants to inhibit human acetylcholinesterase and butyrylcholinesterase. Both extracts were found to have similar actions against acetylcholinesterase. The IC50 for extracts from transformed and untransformed roots were 142.5 and 139.5 ug ml(-1), respectively. The highest activity towards human acetylcholinesterase was demonstrated by taxodione (IC50 = 54.84 ug ml( 1)). With respect to BChE inhibition, the root extracts demonstrated stronger activity (IC50 = 23.6 ug ml(-1): field-grown plants and 41.6 ug ml(-1): transformed roots) than taxodione (IC50 = 195.9 ug ml(-1)). Taxodione showed significant cytotoxicity against A549 cell line (IC50 = 9.1 ug ml(-1)), whereas the activities for the extracts from S. austriaca roots of field-grown plants (IC50 = 75.7 ug ml(-1)) and hairy roots (IC50 = 86.2 ug ml(-1)) were lower. Computer modelling suggests that taxodione should not demonstrate cardiotoxic or genotoxic activity. It also indicates that taxodione should demonstrate very rapid transport from the body with very good blood-brain barrier penetration, but with no cumulative effect on the human body. The obtained results indicate that taxodione is a safe compound and may be used for further investigations in pharmacological activities. PMID- 26621778 TI - Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis. AB - Experimental autoimmune myocarditis (EAM) is a CD4(+) T-cell-mediated model of human inflammatory dilated cardiomyopathies. Heart-specific CD4(+) T-cell activation is dependent on autoantigens presented by MHC class II (MHCII) molecules expressed on professional APCs. In this study, we addressed the role of inflammation-induced MHCII expression by cardiac nonhematopoietic cells on EAM development. EAM was induced in susceptible mice lacking inducible expression of MHCII molecules on all nonhematopoietic cells (pIV-/- K14 class II transactivator (CIITA) transgenic (Tg) mice) by immunization with alpha-myosin heavy chain peptide in CFA. Lack of inducible nonhematopoietic MHCII expression in pIV-/- K14 CIITA Tg mice conferred EAM resistance. In contrast, cardiac pathology was induced in WT and heterozygous mice, and correlated with elevated cardiac endothelial MHCII expression. Control mice with myocarditis displayed an increase in infiltrating CD4(+) T cells and in expression of IFN-gamma, which is the major driver of nonhematopoietic MHCII expression. Mechanistically, IFN-gamma neutralization in WT mice shortly before disease onset resulted in reduced cardiac MHCII expression and pathology. These findings reveal a previously overlooked contribution of IFN-gamma to induce endothelial MHCII expression in the heart and to progress cardiac pathology during myocarditis. PMID- 26621779 TI - Kinetochore-microtubule attachment is sufficient to satisfy the human spindle assembly checkpoint. AB - The spindle assembly checkpoint (SAC) is a genome surveillance mechanism that protects against aneuploidization. Despite profound progress on understanding mechanisms of its activation, it remains unknown what aspect of chromosome spindle interactions is monitored by the SAC: kinetochore-microtubule attachment or the force generated by dynamic microtubules that signals stable biorientation of chromosomes? To answer this, we uncoupled these two processes by expressing a non-phosphorylatable version of the main microtubule-binding protein at kinetochores (HEC1-9A), causing stabilization of incorrect kinetochore microtubule attachments despite persistent activity of the error-correction machinery. The SAC is fully functional in HEC1-9A-expressing cells, yet cells in which chromosomes cannot biorient but are stably attached to microtubules satisfy the SAC and exit mitosis. SAC satisfaction requires neither intra-kinetochore stretching nor dynamic microtubules. Our findings support the hypothesis that in human cells the end-on interactions of microtubules with kinetochores are sufficient to satisfy the SAC without the need for microtubule-based pulling forces. PMID- 26621780 TI - An in vitro system to characterize prostate cancer progression identified signaling required for self-renewal. AB - Mutations in RB and PTEN are linked to castration resistance and poor prognosis in prostate cancer. Identification of genes that are regulated by these tumor suppressors in a context that recapitulates cancer progression may be beneficial for discovering novel therapeutic targets. Although various genetically engineered mice thus far provided tumor models with various pathological stages, they are not ideal for detecting dynamic changes in gene transcription. Additionally, it is difficult to achieve an effect specific to tumor progression via gain of functions of these genes. In this study, we developed an in vitro model to help identify RB- and PTEN-loss signatures during the malignant progression of prostate cancers. Trp53-/- ; Rbf/f , Trp53-/- ; Ptenf/f , and Trp53-/- ; Rbf/f ; Ptenf/f prostate epithelial cells were infected with AD-LacZ or AD-Cre. We found that deletion of Rb, Pten or both stimulated prostasphere formation and tumor development in immune-compromised mice. The GO analysis of genes affected by the deletion of Rb or Pten in Trp53-/- prostate epithelial cells identified a number of genes encoding cytokines, chemokines and extracellular matrix remodeling factors, but only few genes related to cell cycle progression. Two genes (Il-6 and Lox) were further analyzed. Blockade of Il-6 signaling and depletion of Lox significantly attenuated prostasphere formation in 3D culture, and in the case of IL-6, strongly suppressed tumor growth in vivo. These findings suggest that our in vitro model may be instrumental in identifying novel therapeutic targets of prostate cancer progression, and further underscore IL-6 and LOX as promising therapeutic targets. (c) 2015 Wiley Periodicals, Inc. PMID- 26621781 TI - Relationship between prevalence and severity of restless legs syndrome and anemia in patients with systemic lupus erythematosus. AB - AIM: Our aim was to evaluate the relationship between the prevalence and severity of restless legs syndrome (RLS) and the anemia in patients with systemic lupus erythematosus (SLE). METHODS: This was a case-control study which was conducted at the rheumatology clinic of a university affiliated hospital, including 62 patients with SLE and 62 age- and sex-matched healthy controls. The patients were divided into two groups in terms of their hemoglobin levels. The criterion for anemia was hemoglobin level lower than 12 g/dL in females and 13 g/dL in males. RESULTS: Nineteen patients (30.6%) in the patient group were diagnosed with RLS, and International RLS Study Group Rating Scale (IRLSSG-RS) score was 10.7 +/- 9.5 (median:10.0 [range:0.0-30.0]). Three subjects (4.8%) in the control group had RLS, and the IRLSSG-RS score was 0.7 +/- 3.3 (median:0.0 [range:0.0-18.0]). The prevalence of RLS and the IRLSSG-RS score were higher in the patient group than those in the control group (P < 0.001). Ten SLE patients (50%) with anemia had RLS, and their IRLSSG-RS score was 14.5 +/- 9.9 (median:21.0 [range:11.0-30.0]). Nine SLE patients (21.4%) without anemia had RLS and their IRLSSG-RS was 9.0 +/- 8.9 (median:21.0 [range:11.0-24.0]). Significant differences were present in the prevalence of RLS and the IRLSSG-RS score between SLE patients with and without anemia (P = 0.024, P = 0.044, respectively). CONCLUSION: The present study demonstrated that the prevalence of RLS was higher in patients with SLE than that of the normal population. Results of this study also suggested that anemia was associated with higher frequency of and more severe RLS in patients with lupus. PMID- 26621782 TI - Separation and characterization of bufadienolides in toad skin using two dimensional normal-phase liquid chromatography*reversed-phase liquid chromatography coupled with mass spectrometry. AB - Bufadienolides possess various bioactivities especially antitumor. Due to the high structural diversity, the separation of bufadienolides often suffers from coelution problem on conventional RP columns. In this work, an off-line two dimensional normal-phase liquid chromatography*reversed-phase liquid chromatography (2D-NPLC*RPLC) method was developed to separate and characterize bufadienolides in toad skin. Several RP and NP columns were evaluated with five reference bufadienlides. The XUnion C18 and XAmide columns exhibited superior chromatographic performances for bufadienlide separation, and were selected in RPLC and NPLC, respectively. RPLC was used in the second-dimension for the good compatibility with MS, while NPLC was adopted in the first-dimension. The orthogonality of the 2D-NPLC*RPLC system was investigated by the geometric approach using fifteen bufadienolide mixtures. The result was 49.6%, demonstrating reasonable orthogonality of this 2D-LC system. By combining the 2D LC system with MS, 64 bufadienlides including 33 minor ones and 11 pairs of isomers in toad skin were identified. This off-line 2D-NPLC*RPLC allowed to solve the coelution problem of bufadienlides in one-dimension RPLC, and thus facilitated the identification significantly. PMID- 26621783 TI - Chemical fingerprint and metabolic profile analysis of ethyl acetate fraction of Gastrodia elata by ultra performance liquid chromatography/quadrupole-time of flight mass spectrometry. AB - The chemical fingerprint and metabolic profile of traditional Chinese medicine is very complicated and has been a great challenge. In the present study, chemical fingerprint of ethyl acetate fraction of Gastrodia elata (EtAcGE) and metabolic profile of rat plasma sample after intragastric administration of EtAcGE (2.5g/kg) were investigated using ultra-high performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UPLC/Q-TOF MS). A total of 38 chemical constituents of EtAcGE were identified by comparing their retention time, accurate molecular mass and characteristic fragment ions with those of references, or tentatively characterized by comparing molecular formula, fragment ions with that of known compound or information available in literature. And 40 compounds were detected in dosed rat plasma sample, including 16 prototypes and 24 metabolites underwent metabolic process of glucuronidation, glucosylation, sulfation, methylation, hydroxylation, dehydrogenation or mixed modes. The metabolic "soft spots" was hydroxyl or carboxy group. This is the first research for chemical fingerprint and metabolic profile of EtAcGE, which lay a foundation for the further investigation of EtAcGE. PMID- 26621784 TI - In vivo investigation of escitalopram's allosteric site on the serotonin transporter. AB - Escitalopram is a commonly prescribed antidepressant of the selective serotonin reuptake inhibitor class. Clinical evidence and mapping of the serotonin transporter (SERT) identified that escitalopram, in addition to its binding to a primary uptake-blocking site, is capable of binding to the SERT via an allosteric site that is hypothesized to alter escitalopram's kinetics at the SERT. The studies reported here examined the in vivo role of the SERT allosteric site in escitalopram action. A knockin mouse model that possesses an allosteric-null SERT was developed. Autoradiographic studies indicated that the knockin protein was expressed at a lower density than endogenous mouse SERT (approximately 10-30% of endogenous mouse SERT), but the knockin mice are a viable tool to study the allosteric site. Microdialysis studies in the ventral hippocampus found no measurable decrease in extracellular serotonin response after local escitalopram challenge in mice without the allosteric site compared to mice with the site (p=0.297). In marble burying assays there was a modest effect of the absence of the allosteric site, with a larger systemic dose of escitalopram (10-fold) necessary for the same effect as in mice with intact SERT (p=0.023). However, there was no effect of the allosteric site in the tail suspension test. Together these data suggest that there may be a regional specificity in the role of the allosteric site. The lack of a robust effect overall suggests that the role of the allosteric site for escitalopram on the SERT may not produce meaningful in vivo effects. PMID- 26621785 TI - Diffusion-Weighted MR Imaging of Hepatocellular Carcinoma: Current Value in Clinical Evaluation of Tumor Response to Locoregional Treatment. AB - The established size-based image biomarkers for tumor burden measurement continue to be applied to solid tumors, as size measurement can easily be used in clinical practice. However, in the setting of novel targeted therapies and liver-directed locoregional treatments for hepatocellular carcinoma (HCC), simple tumor anatomic changes can be less informative and usually appear later than biologic changes. Functional magnetic resonance (MR) imaging has the potential to be a promising technique for assessment of HCC response to therapy. Diffusion-weighted MR imaging is now widely used as a standard imaging modality to evaluate the liver. This review discusses the current clinical value of diffusion-weighted MR imaging in the evaluation of tumor response after nonsurgical locoregional treatment of HCC. PMID- 26621787 TI - Optimisation of ultrasound-assisted osmotic dehydration of sweet potato (Ipomea batatas) using response surface methodology. AB - BACKGROUND: Sweet potato is a highly nutritious tuber crop that is rich in beta carotene. Osmotic dehydration is a pretreatment method for drying of fruit and vegetables. Recently, ultrasound technology has been applied in food processing because of its numerous advantages which include time saving, little damage to the quality of the food. Thus, there is need to investigate and optimise the process parameters [frequency (20-50 kHz), time (10-30 min) and sucrose concentration (20-60% w/v)] for ultrasound-assisted osmotic dehydration of sweet potato using response surface methodology. RESULTS: The optimised values obtained were frequency of 33.93 kHz, time of 30 min and sucrose concentration of 35.69% (w/v) to give predicted values of 21.62, 4.40 and 17.23% for water loss, solid gain and weight reduction, respectively. The water loss and weight reduction increased when the ultrasound frequency increased from 20 to 35 kHz and then decreased as the frequency increased from 35 to 50 kHz. CONCLUSION: The results from this work show that low ultrasound frequency favours the osmotic dehydration of sweet potato and also reduces the use of raw material (sucrose) needed for the osmotic dehydration of sweet potato. (c) 2015 Society of Chemical Industry. PMID- 26621788 TI - The characteristics of falls in an inpatient traumatic brain injury rehabilitation setting. AB - AIMS AND OBJECTIVES: To describe the nature of falls in an inpatient traumatic brain injury rehabilitation setting. BACKGROUND: Falls are the most frequently recorded patient safety incident in the inpatient context. However, higher rates of falls are reported in rehabilitation settings compared to acute care settings. In the rehabilitation setting, patients with a traumatic brain injury have been identified as at a high risk of falling. However to date, research into the nature of falls involving this patient population is limited. DESIGN: Five-year retrospective cohort study design. METHODS: Falls data from an inpatient traumatic brain injury rehabilitation unit were retrieved from the NSW Ministry of Health Incident Information Management System and patient clinical notes; nursing shift data were retrieved from the local rostering system. RESULTS: The fall rate was 5.18 per 1000 patient bed days. Over a 24-hour period falls (n = 103) occurred in a trimodal pattern. The median fall free period after admission was 14 days and 22% of traumatic brain injury patients had at least one fall. 53% of falls occurred in the patient's bedroom and 57% were attributed to loss of balance. At time of fall, 93% of fallers had impaired mobility and 85% required assistance for transfers. CONCLUSION: Falls within inpatient traumatic brain injury rehabilitation are a significant and complex clinical issue. While many patients continued to be at risk of falling several months after admission, a repeat faller's first fall occurred earlier in their admission than a single faller's. RELEVANCE TO CLINICAL PRACTICE: Generic falls prevention measures are insufficient for preventing falls in the brain injury rehabilitation population. Falls prevention initiatives should target times of high patient activity and situations where there is decreased nursing capacity to observe patients. Rehabilitation clinicians need to be mindful that a patient's risk of falling is not static and in fact, may increase over time. PMID- 26621789 TI - Enhancing metaproteomics--The value of models and defined environmental microbial systems. AB - Metaproteomics--the large-scale characterization of the entire protein complement of environmental microbiota at a given point in time--has provided new features to study complex microbial communities in order to unravel these "black boxes." New technical challenges arose that were not an issue for classical proteome analytics before that could be tackled by the application of different model systems. Here, we review different current and future model systems for metaproteome analysis. Following a short introduction to microbial communities and metaproteomics, we introduce model systems for clinical and biotechnological research questions including acid mine drainage, anaerobic digesters, and activated sludge. Model systems are useful to evaluate the challenges encountered within (but not limited to) metaproteomics, including species complexity and coverage, biomass availability, or reliable protein extraction. The implementation of model systems can be considered as a step forward to better understand microbial community responses and ecological functions of single member organisms. In the future, improvements are necessary to fully explore complex environmental systems by metaproteomics. PMID- 26621790 TI - The standalone aminopeptidase PepN catalyzes the maturation of blasticidin S from leucylblasticidin S. AB - The peptidyl nucleoside blasticidin S (BS) isolated from Streptomyces griseochromogenes was the first non-mercurial fungicide used on a large scale to prevent rice blast. In the biosynthesis of BS, leucylblasticidin S (LBS) was suggested as the penultimate metabolite with 20-fold less inhibitory activity than the final product BS. Incomplete conversion of LBS to BS at a variable efficiency ranging from 10% to 90% was observed either in the native strain S. griseochromogenes or a heterologous producer Streptomyces lividans WJ2. In this study, we determined that maturation of BS from LBS is not a spontaneous process but is governed by a standalone peptidase PepN, which hydrolyzes LBS in a pH sensitive way with most appropriate of pH 7~8 but is inactive when the pH is below 5 or above 10. PepN1 and PepN2, two neighboring PepN homologs from Streptomyces lividans were purified in E. coli but displayed ca.100-fold difference in LBS hydrolytic activity. Overexpression of pepN1 in WJ2 enhanced BS yield by 100% and lowered the ratio of LBS to BS from 2:1 to 2:3. This work presents the expansion of the biological role for PepN in antibiotic maturation and the first report of hydrolysis of beta amide linkage by this conserved enzyme. PMID- 26621791 TI - Synthesis of nanocrystals by discharges in liquid nitrogen from Si-Sn sintered electrode. AB - The synthesis feasibility of silicon-tin nanocrystals by discharges in liquid nitrogen is studied using a Si-10 at % Sn sintered electrode. Time-resolved optical emission spectroscopy shows that silicon and tin melt almost simultaneously. The presence of both vapours does not lead to the synthesis of alloyed nanocrystals but to the synthesis of separate nanocrystals of silicon and tin with average sizes of 10 nm. These nanocrystals are transformed into amorphous silicon oxide (am-SiO2) and beta-SnO2 by air oxidation, after evaporation of the liquid nitrogen. The synthesis of an am-Si0.95Sn0.05 phase around large silicon crystals (~500 nm) decorated by beta-Sn spheroids is achieved if the current flowing through electrodes is high enough. When the sintered electrode is hit by powerful discharges, some grains are heated and tin diffuses in the large silicon crystals. Next, these grains are shelled and fall into the dielectric liquid. PMID- 26621792 TI - Isolation and characterization of two novel halotolerant Catechol 2, 3 dioxygenases from a halophilic bacterial consortium. AB - Study of enzymes in halophiles will help to understand the mechanism of aromatic hydrocarbons degradation in saline environment. In this study, two novel catechol 2,3-dioxygenases (C23O1 and C23O2) were cloned and overexpressed from a halophilic bacterial consortium enriched from an oil-contaminated saline soil. Phylogenetic analysis indicated that the novel C23Os and their relatives formed a new branch in subfamily I.2.A of extradiol dioxygenases and the sequence differences were further analyzed by amino acid sequence alignment. Two enzymes with the halotolerant feature were active over a range of 0-30% salinity and they performed more stable at high salinity than in the absence of salt. Surface electrostatic potential and amino acids composition calculation suggested high acidic residues content, accounting for their tolerance to high salinity. Moreover, two enzymes were further characterized. The enzymes activity both increased in the presence of Fe(3+), Fe(2+), Cu(2+) and Al(3+) and showed no significant inhibition by other tested metal ions. The optimal temperatures for the C23Os were 40 degrees C and 60 degrees C and their best substrates were catechol and 4-methylcatechol respectively. As the firstly isolated and characterized catechol dioxygenases from halophiles, the two halotolerant C23Os presented novel characteristics suggesting their potential application in aromatic hydrocarbons biodegradation. PMID- 26621793 TI - Classification of Recombinant Biologics in the EU: Divergence Between National Pharmacovigilance Centers. AB - BACKGROUND AND OBJECTIVE: Biological medicinal products (biologics) are subject to specific pharmacovigilance requirements to ensure that biologics are identifiable by brand name and batch number in adverse drug reaction (ADR) reports. Since Member States collect ADR data at the national level before the data is aggregated at the European Union (EU) level, it is important that an unambiguous understanding of which medicinal products belong to the biological product category exists. This study aimed to identify the level of consistency between Member States regarding the classification of biologics by national authorities responsible for ADR reporting. METHODS: A sample list of recombinant biologics from the European Medicines Agency database of European Public Assessment Reports was created to analyze five Member States (Belgium, the Netherlands, Spain, Sweden, and the UK) according to which products were classified as biologics by each Member State. We calculated the Fleiss kappa value to analyze interrater reliability. RESULTS: A considerable divergence was identified regarding the classification of the 146 recombinant biologics from the sample list: one Member State classified 100 % of the recombinant biologics from the sample list as biologics, whereas the classification rates in the remaining four Member States ranged between 70 and 88 % for products available on the national market. The interrater reliability for 87 products available on the market in all five Member States was considered poor. CONCLUSION: Discrepancies exist between Member States in the classification of biologics; less divergence exists for common well-known biologics. These findings highlight the need to think about the best approaches to translate EU legislation into national practices. Additionally, we recommend a publicly available and frequently updated list of centrally authorized biologics. PMID- 26621794 TI - The cross talk between long, non-coding RNAs and microRNAs in gastric cancer. AB - Gastric cancer is one of the most common malignant diseases and remains the second leading cause of cancer-related mortality worldwide. Although great effort has been made during the past decades to facilitate the early detection and treatment of gastric cancer, the prognosis is not yet satisfactory and the underlying molecular mechanisms of gastric cancer pathogenesis are not fully understood. Meanwhile, non-coding RNAs have been established as key players in regulating various biological and pathological processes, such as cell-cycle progression, chromatin remodeling, gene transcription, and posttranscriptional processing. Furthermore, numerous studies have also revealed a complicated interplay among different species of non-coding RNAs; therefore, the cross regulation between long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) has begun to emerge. This lncRNA-miRNA cross talk, which has attracted increasing attention in recent years, is involved in a great number of human diseases including gastric cancer. In this review, we summarize the latest research progress of the interactions between lncRNAs and miRNAs, highlighting their influences on the development and progression of gastric cancer to provide novel approaches for cancer diagnosis and treatment. PMID- 26621796 TI - Predicting the Outcome. PMID- 26621795 TI - Differentiating brain metastases from different pathological types of lung cancers using texture analysis of T1 postcontrast MR. AB - PURPOSE: The goal of this study was to investigate the feasibility of differentiating brain metastases from different types of lung cancers using texture analysis (TA) of T1 postcontrast MR images. METHODS: TA was performed, and four subset textures were extracted and calculated separately. The capability of each texture to classify the different types of lung carcinoma was investigated using the Kruskal-Wallis test and receiver operating characteristic analysis. K-nearest neighbor (KNN) classifier model and back-propagation artificial neural network (BP-ANN) classifier model were used to build models and improve the predictive ability of TA. RESULTS: Texture-based lesion classification was highly specific in differentiating brain metastases originated from different types of lung cancers, with misclassification rates of 3.1%, 4.3%, 5.8%, and 8.1%, respectively, for small cell lung carcinoma, squamous cell carcinoma, adenocarcinoma, and large cell lung carcinoma. The BP-ANN model had a better predictive ability than the KNN model. No texture feature could distinguish between all four types of lung cancer. CONCLUSIONS: TA may predict the differences among various pathological types of lung cancer with brain metastases. The texture parameters, which reflect the tumor histopathology structure, may serve as an adjunct tool for clinically accurate diagnoses and deserves further investigation. Magn Reson Med 76:1410-1419, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26621797 TI - Complications of defibrillation testing. A review of the literature. AB - Defibrillation testing (DT) has traditionally been performed at the time of implantable cardioverter defibrillator (ICD) insertion. However, there has been a trend away from conducting DT, in part due to observational studies showing uncommon but serious complications related to DT. More recently, several randomized trials have shown no improvement in the efficacy of clinical shocks among patients assigned to have DT. These trials also suggest a modest increase in perioperative complications related to DT; however, the overall rate of complications was very low. This review focuses on the prevalence of complications associated with DT and elaborates on a number of indications for DT. PMID- 26621798 TI - Engineering a thermostable Halothermothrix orenii beta-glucosidase for improved galacto-oligosaccharide synthesis. AB - Lactose is produced in large amounts as a by-product from the dairy industry. This inexpensive disaccharide can be converted to more useful value-added products such as galacto-oligosaccharides (GOSs) by transgalactosylation reactions with retaining beta-galactosidases (BGALs) being normally used for this purpose. Hydrolysis is always competing with the transglycosylation reaction, and hence, the yields of GOSs can be too low for industrial use. We have reported that a beta-glucosidase from Halothermothrix orenii (HoBGLA) shows promising characteristics for lactose conversion and GOS synthesis. Here, we engineered HoBGLA to investigate the possibility to further improve lactose conversion and GOS production. Five variants that targeted the glycone (-1) and aglycone (+1) subsites (N222F, N294T, F417S, F417Y, and Y296F) were designed and expressed. All variants show significantly impaired catalytic activity with cellobiose and lactose as substrates. Particularly, F417S is hydrolytically crippled with cellobiose as substrate with a 1000-fold decrease in apparent k cat, but to a lesser extent affected when catalyzing hydrolysis of lactose (47-fold lower k cat). This large selective effect on cellobiose hydrolysis is manifested as a change in substrate selectivity from cellobiose to lactose. The least affected variant is F417Y, which retains the capacity to hydrolyze both cellobiose and lactose with the same relative substrate selectivity as the wild type, but with ~10-fold lower turnover numbers. Thin-layer chromatography results show that this effect is accompanied by synthesis of a particular GOS product in higher yields by Y296F and F417S compared with the other variants, whereas the variant F417Y produces a higher yield of total GOSs. PMID- 26621799 TI - The potential of the endolysin Lysdb from Lactobacillus delbrueckii phage for combating Staphylococcus aureus during cheese manufacture from raw milk. AB - Phage endolysins have received increased attention in recent times as potential antibacterial agents and the biopreservatives in food production processes. Staphylococcus aureus is one of the most common pathogens in bacterial food poisoning outbreaks. In this study, the endolysin Lysdb, one of the two-component cell lysis cassette of Lactobacillus delbrueckii phage phiLdb, was shown to possess a muramidase domain and catalytic sites with homology to Chalaropsis-type lysozymes. Peptidoglycan hydrolytic bond specificity determination revealed that Lysdb was able to cleave the 6-O-acetylated peptidoglycans present in the cell walls of S. aureus. Turbidity reduction assays demonstrated that Lysdb could effectively lyse the S. aureus live cells under acidic and mesothermal conditions. To further evaluate the ability of Lysdb as a potential antibacterial agent against S. aureus in cheese manufacture, Lactobacillus casei BL23 was engineered to constitutively deliver active Lysdb to challenge S. aureus in lab scale cheese making from raw milk. Compared with the raw milk, the viable counts of S. aureus were reduced by 10(5)-fold in the cheese inoculated with the engineered L. casei strain during the fermentation process, and the pathogenic bacterial numbers remained at a low level (10(4) CFU/g) after 6 weeks of ripening at 10 degrees C. Taken together, all results indicated that the Lysdb has the function as an effective tool for combating S. aureus during cheese manufacture from raw milk. PMID- 26621800 TI - In vitro propagation and cell cultures of memory tonic herb Evolvulus alsinoides: a best source for elicited production of scopoletin. AB - Evolvulus alsinoides L. is used for preparation of 'Shankhapushpi', an important popular ayurvedic drug that contributes considerably to the improvement of memory power. The improvement is attributed to the presence of furanocoumarin scopoletin, a metabolite with a wide range of biological activities. This report describes, for the first time, an in vitro culture system for propagation and enhanced production of scopoletin. Different concentrations of auxins and cytokinins individually and in combination were used in Murashige and Skoog (MS) medium to induce shoot regeneration in cotyledonary nodal explants and callus formation in leaf explants. The best response was achieved in MS medium fortified with 5.0 MUM 6-benzyladenine (BA) in which 96 % of cultures produced 7.6 +/- 0.6 shoots per explant. Regenerated shoots were rooted on MS medium with 5.0 MUM indole-3-acetic acid (IAA). Plantlets were successfully acclimatized and established in soil. MS medium fortified with 10 MUM BA + 5.0 MUM IAA showed maximum growth and accumulation of scopoletin in cell cultures. Cell cultures could be maintained over 24 months. The influences of auxins, cytokinins, organic acids, amino acids, and fungal-derived elicitors on production of scopoletin were studied. Presence of either L-arginine, sodium pyruvate, or yeast extract highly promoted scopoletin production as compared with control and achieved 75.02-, 72.13-, and 57.98-fold higher accumulation, respectively. The results presented herein have laid solid foundation for large-scale production of scopoletin and further investigation of its purification and utilization as a novel pharmaceutical drug. PMID- 26621801 TI - Mucosal delivery of allergen peptides expressed by Lactococcus lactis inhibit allergic responses in a BALB/c mouse model. AB - Allergen-specific immunotherapy (SIT) is considered to be the only curative treatment of allergy, but its safety is always affected by immunologic properties and quality of allergen. Recombinant allergen derivative could be a potential therapeutic strategy, but clinical studies showed that macromolecular derivatives could not avoid T cell-mediated side effects. In this study, five Der p2-derived peptides (DPs) containing major T cell epitopes of Der p2 were first artificially synthesized. Compared with Der p2 macromolecular derivative DM, these DPs not only fully eliminated IgE-binding capacity but also reduced T cells reactivity, suggesting these DPs could be better therapeutic molecules. For their application in vivo, Lactococcus lactis was engineered to express these DPs, and their protective effects were evaluated in BALB/c mice models. Western blot showed that all DPs could be produced in the recombinant strains. Mucosal delivery of these strains could inhibit Der p2-induced allergic responses in Der p2-sensitized mice, characterized by a reduction in specific IgE antibody and lung inflammatory responses. These protective effects were associated with an increase of specific IgG2a in serum and regulatory T cells in the mesenteric lymph nodes. On the whole, the suppressive effect induced by the DP mixture could be better than single DP, but a bit weaker than DM. These DPs could be promising candidate molecules for active vaccination and induction of tolerance, and thus promote the development of non-allergenic peptide in the treatment and prevention of allergy. PMID- 26621802 TI - Production, properties, and industrial food application of lactic acid bacteria derived exopolysaccharides. AB - Exopolysaccharides (EPS)-producing lactic acid bacteria (LAB) are industrially important microorganisms in the development of functional food products and are used as starter cultures or coadjutants to develop fermented foods. There is large variability in EPS production by LAB in terms of chemical composition, quantity, molecular size, charge, presence of side chains, and rigidity of the molecules. The main body of the review will cover practical aspects concerning the structural diversity structure of EPS, and their concrete application in food industries is reported in details. To strengthen the food application and process feasibility of LAB EPS at industrial level, a future academic research should be combined with industrial input to understand the technical shortfalls that EPS can address. PMID- 26621803 TI - N- and C-terminal truncations of a GH10 xylanase significantly increase its activity and thermostability but decrease its SDS resistance. AB - XynII from Volvariella volvacea has high sodium dodecyl sulfate (SDS) resistance, with the potential for industrial applications under harsh conditions. It consists of a single glycoside hydrolase family 10 (GH10) catalytic domain but contains an additional unique 10 and 4 amino acid residues at the N- and C terminus, respectively. In this study, five XynII derivatives with N- and/or C terminus deletions were constructed to determine the effects of these regions on enzyme activity, substrate specificity, thermostability, and SDS resistance. Our results revealed that N- and/or C-terminal truncations significantly increased enzyme activity and thermostability, but reduced SDS resistance. Specifically, the XynIIDeltaNC4 mutant had 2.53-fold more catalytic efficiency (k cat/K m) towards beechwood xylan than wild-type and 3.0-fold more thermostability (t 1/2 [55 degrees C]). XynIIDeltaNC4 displayed 3.33-, 4.38-, 1.37-, and 1.98-fold more activity against xylotriose, xylotetraose, xylopentaose, and xylohexaose, respectively, than XynII did. However, its half-life (t 1/2) in 4 % SDS was only 1.72 h, while that of XynII was 4.65 h. Circular dichroism analysis revealed that deletion of N- and C-terminal segments caused minor changes in secondary structure. Our observations suggest that the extra N- and C-terminal segments in wild-type XynII evolved to strengthen the interaction between these regions of the protein, making the local structure more rigid and reducing structural flexibility. In this way, N- and C-terminal truncations increased the thermostability and activity of XynII on different xylans and linear xylooligosaccharides, but reduced its resistance to SDS. PMID- 26621804 TI - Distribution and activity of anaerobic ammonium-oxidising bacteria in natural freshwater wetland soils. AB - Anaerobic ammonium oxidation (anammox) process plays a significant role in the marine nitrogen cycle. However, the quantitative importance of this process in nitrogen removal in wetland systems, particularly in natural freshwater wetlands, is still not determined. In the present study, we provided the evidence of the distribution and activity of anammox bacteria in a natural freshwater wetland, located in southeastern China, by using (15)N stable isotope measurements, quantitative PCR assays and 16S rRNA gene clone library analysis. The potential anammox rates measured in this wetland system ranged between 2.5 and 25.5 nmol N2 g(-1) soil day(-1), and up to 20% soil dinitrogen gas production could be attributed to the anammox process. Phylogenetic analysis of 16S rRNA genes showed that anammox bacteria related to Candidatus Brocadia, Candidatus Kuenenia, Candidatus Anammoxoglobus and two novel anammox clusters coexisted in the collected soil cores, with Candidatus Brocadia and Candidatus Kuenenia being the dominant anammox genera. Quantitative PCR of hydrazine synthase genes showed that the abundance of anammox bacteria varied from 2.3 * 10(5) to 2.2 * 10(6) copies g(-1) soil in the examined soil cores. Correlation analyses suggested that the soil ammonium concentration had significant influence on the activity of anammox bacteria. On the basis of (15)N tracing technology, it is estimated that a total loss of 31.1 g N m(-2) per year could be linked the anammox process in the examined wetland. PMID- 26621805 TI - Editorial. PMID- 26621806 TI - Foreword. PMID- 26621807 TI - Following professional codes of practice and military orders in austere military environments: a controversial debate on ethical challenges. AB - In 2004, the World Medical Association's International Code of Ethics claimed that 'medical ethics in armed conflict is identical to medical ethics in times of peace'. This paper challenges this notion and suggests that the hostile, austere and diverse environments in which military doctors and nurses serve are significantly more problematic and different to a civilian healthcare environment. It debates that there may be some incompatibility and challenges between following military orders such as the protocols written down in a Medical Rules of Eligibility matrix and professional codes of practice in these environments. This is either where fighting takes place or where the mission is for humanitarian purposes. PMID- 26621808 TI - Commentary. PMID- 26621809 TI - Coupled plasma haemofiltration filtration in severe sepsis: systematic review and meta-analysis. AB - INTRODUCTION: Coupled plasma filtration and adsorption (CPFA) has been used in the treatment of severe sepsis with the intention of removing the proinflammatory and anti-inflammatory mediators from the systemic circulation. It is believed that this interrupts and moderates the septic cascade, but there is uncertainty about the benefits of this therapy. METHODS: A systematic review and meta analysis were performed to estimate the effects of CPFA on mortality in severe sepsis. The Cochrane CENTRAL Register of Controlled Trials, CINAHL, EMBASE, MEDLINE-EBSCO-Host, MEDLINE and ProQuest, were searched from 1997 to 2013. Randomised controlled trials, prospective cohort studies and retrospective cohort studies were included using the Centre for Reviews and Dissemination (CRD) framework. Data were abstracted using standard pro forma, and studies independently reviewed by two authors to confirm inclusion criteria. Quality of studies and risk of bias were assessed using the Grading of Recommendations, Assessment, Development and Evaluation Working Group (GRADE) and Critical Appraisal Skills (CASP) criteria, respectively. Meta-analysis was performed using Review Manager (RevMan V.5.1) software. The primary outcome was 28-day mortality. Secondary outcomes were mediator adsorption (picograms/mL), mean arterial BP (mm Hg) and oxygenation ratio. RESULTS: 17 studies met the inclusion criteria (n=441 patients, 242 CPFA). 14 studies reported the primary outcome of 28-day mortality. There were 88 deaths in CPFA patients versus 118 in those receiving haemofiltration: OR 0.34 (95% CI 0.24 to 0.13). Point estimates of effect on the secondary outcomes of mean arterial pressure and oxygen ratio favoured CPFA. Studies were small and heterogenous. CONCLUSIONS: Evidence for CPFA in severe sepsis is sparse, of poor quality and further research is required, however, this meta-analysis noted improvements in survival rates of those patients treated with CPFA. PMID- 26621810 TI - Is the British Army medical grading functional assessment tool effective? AB - Decision Support Aids (DSAs) have been widely used throughout industry and one (known as Table 7) is available to support British Army Medical Officers (MOs) grade soldiers against the Joint Medical Employment Standards. It is unknown how useful this DSA is in practice. An electronic questionnaire was distributed to British Army MOs working within Defence Primary Care facilities enquiring about MOs views on the usefulness of the DSA. Although the response rate was low, informative data were obtained. Between a half and a third of respondents felt that their judgement was affected in the application of the grading system when there were career implications to the grading MOs felt that the DSA allowed subjectivity in the grading. The results of this research suggest that although minor changes to Table 7 may improve service provision, an improvement in training in the application of Table 7 would be of greater benefit to the quality of occupational health service provision in the British Army. PMID- 26621811 TI - Preparing to care for paediatric trauma patients. AB - INTRODUCTION: Considerable evidence has discussed the significant workload and advances in clinical care by UK Defence Medical Services (DMS) during recent conflicts in Iraq and Afghanistan. Although the DMS is not doctrinally staffed to deal with children on operations, severely ill and injured paediatric casualties continue to present to military medical facilities; therefore, staff must be competent to deliver the appropriate level of care. This paper reports the paediatric presentations to the emergency department (ED), at the Role 3 Medical Treatment Facility (MTF) in Camp Bastion, Afghanistan, over a 21-month period. The aim was to provide quantitative, statistical data of paediatric presentations seen by deployed ED nurses, to identify whether the current training was appropriate and to make recommendations for further training requirements for DMS ED nurses. METHOD: All paediatric presentations to the MTF ED between January 2011 and September 2012 were analysed. The following aspects of the admission were analysed: date of admission, mechanism of injury, injury sustained, discharge, length of stay in the ED and length of stay in the R3. RESULTS: There were 159 paediatric presentations to the ED in 2011 of which 56% warranted admission to the intensive treatment unit (ITU). In contrast, over the shorter period in 2012, 79% of 73 paediatric presentations were admitted to the ITU. The most common mechanism of injury was hostile action. 13% of the patients who presented to the ED in 2011 did not survive to discharge, compared with 11% the following year. CONCLUSION: Although the exposure to paediatric polytrauma during the conflicts in Afghanistan and Iraq is not replicated in peace time roles, it is likely that wherever emergency nurses are deployed the treatment of children will continue. Analysis of the service evaluation has led to the recommendations for specific skills that emergency nurses could develop during the pre-deployment phase to better prepare for caring for such patients. These include recognition of the sick child/triage, paediatric drug calculations, awareness of the massive transfusion requirements for children and skills to gain intravenous/intraosseous access in a child. PMID- 26621812 TI - The incidence and prevention of foot problems among male Phase One British Army recruits at an Army Training Regiment. AB - INTRODUCTION: Studies have demonstrated that there is an excessive number of foot problems among personnel entering the military, which leads to disruption to training resulting in an increase in both costs and wastage. Days are lost in training due to foot problems, most commonly blisters, causing a loss of working/training days with a resultant low morale and a financial loss to the army. METHODS: A cohort of Phase One British Army recruits completed a questionnaire in week 3 of training to identify previous and current foot problems and assess what education on the topic they received during their training. Also, 43 foot risk assessment tools were used by the medical staff to identify incidence, severity and working days lost. Questionnaires were completed by 31 instructors to gain data on prevention and management of foot problems. Focus groups were conducted among instructors to investigate their knowledge of prevention and management, and problems identified among recruits. RESULTS: A lack of formal training on foot care exists among recruits and instructors. Blisters were reported to be the main foot problem, and army-issue boots were reported to be the main cause of problems. Sizing of boots was inconsistent, and manufacturers can vary in their sizings. There were no policies available, and only one lesson on foot care was given. CONCLUSIONS: Currently, no policies exist on foot care at the Army Training Regiment (ATR). Foot clinics were available daily, and blisters and foot problems were already present; therefore, foot education is required in the early stages of training. The field craft exercise resulted in half of the recruits reporting blisters. Poor foot hygiene remained a problem when recruits arrived at the ATR for their training. Foot care instruction included in the training would reduce days and hours lost in training. PMID- 26621813 TI - Introducing 'The Diverse Nature of Defence Healthcare' university module for DMS personnel. AB - Over the past 10 years the UK Defence Medical Services has deployed healthcare personnel to a variety of operational areas in support of UK Operations. The unique nature of every operational deployment, in conjunction with the wide variety of roles which healthcare staff undertake, necessitates bespoke educational preparation of the military healthcare force. This paper explores the creation and development of one of the four modules which comprise the BSc (Hons) in Defence Health Care studies, entitled 'The Diverse Nature of Defence Healthcare'. It demonstrates the unique contribution that the Defence School of Healthcare Education makes towards Generation and Preparation of the Force for deployment. PMID- 26621814 TI - An exploration of the experiences of wound healing in military traumatic amputees and its impact on their rehabilitation. AB - The aim of this study was to establish the effect that wounds had on the rehabilitation of traumatic amputees from the military patients' perspective. In particular it established which aspects of wound healing had the greatest impact in relation to living with a wound and the effect that military cohesion had on their recovery. The study was undertaken within the interpretivistic paradigm and followed an ethnographic design using semi-structured interviews. It contributes to the theoretical understanding of rehabilitation of the combat injured as no other study has been undertaken in this area in the UK. It captured the responses of this unique group as they reach the end of their journey through rehabilitation and detailed their reflections on the challenges they had faced and overcome. Analysis revealed that complications including infection, pain, foreign bodies and further surgery prevented the wounds from healing. The participants found this frustrating and they further highlighted time as an important factor in their journey. The military environment formed a culture in which patients learned from, and were supported by, each other. This was compared to a community of practice. In conclusion suggestions were made for practice, policy and education and further research in this area. PMID- 26621815 TI - Mental health stigmatisation in deployed UK Armed Forces: a principal components analysis. AB - INTRODUCTION: UK military research suggests that there is a significant link between current psychological symptoms, mental health stigmatisation and perceived barriers to care (stigma/BTC). Few studies have explored the construct of stigma/BTC in depth amongst deployed UK military personnel. METHOD: Three survey datasets containing a stigma/BTC scale obtained during UK deployments to Iraq and Afghanistan were combined (n=3405 personnel). Principal component analysis was used to identify the key components of stigma/BTC. The relationship between psychological symptoms, the stigma/BTC components and help seeking were examined. RESULTS: Two components were identified: 'potential loss of personal military credibility and trust' (stigma Component 1, five items, 49.4% total model variance) and 'negative perceptions of mental health services and barriers to help seeking' (Component 2, six items, 11.2% total model variance). Component 1 was endorsed by 37.8% and Component 2 by 9.4% of personnel. Component 1 was associated with both assessed and subjective mental health, medical appointments and admission to hospital. Stigma Component 2 was associated with subjective and assessed mental health but not with medical appointments. Neither component was associated with help-seeking for subjective psycho-social problems. CONCLUSIONS: Potential loss of credibility and trust appeared to be associated with help seeking for medical reasons but not for help-seeking for subjective psychosocial problems. Those experiencing psychological symptoms appeared to minimise the effects of stigma by seeking out a socially acceptable route into care, such as the medical consultation, whereas those who experienced a subjective mental health problem appeared willing to seek help from any source. PMID- 26621816 TI - [Pulmonary embolism]. AB - Pulmonary embolism is a potentially fatal disorder and frequently seen in critical care and emergency medicine. Due to a high mortality rate within the first few hours, the accurate initiation of rational diagnostic pathways in patients with suspected pulmonary embolism and timely consecutive treatment is essential. In this review, the current European guidelines on the diagnosis and therapy of acute pulmonary embolism are presented. Special focus is put on a structured patient management based on the individual risk of early mortality. In particular risk assessment and new risk-adjusted treatment recommendations are presented and discussed in this article. PMID- 26621818 TI - Superoxide anions produced by Streptococcus pyogenes group A-stimulated keratinocytes are responsible for cellular necrosis and bacterial growth inhibition. AB - Gram-positive Streptococcus pyogenes (group A Streptococcus or GAS) is a major skin pathogen and interacts with keratinocytes in cutaneous tissues. GAS can cause diverse suppurative and inflammatory infections, such as cellulitis, a common acute bacterial dermo-hypodermitis with a high morbidity. Bacterial isolation yields from the lesions are low despite the strong local inflammation observed, raising numerous questions about the pathogenesis of the infection. Using an in vitro model of GAS-infected keratinocytes, we show that the major ROS produced is the superoxide anion ([Formula: see text]), and that its production is time- and dose-dependent. Using specific modulators of ROS production, we show that [Formula: see text] is mainly synthesized by the cytoplasmic NADPH oxidase. Superoxide anion production leads to keratinocyte necrosis but incomplete inhibition of GAS growth, suggesting that GAS may be partially resistant to the oxidative burst. In conclusion, GAS-stimulated keratinocytes are able to develop an innate immune response based on the production of ROS. This local immune response limits GAS development and induces keratinocyte cell death, resulting in the skin lesions observed in patients with cellulitis. PMID- 26621819 TI - Concomitant Administration of a Histamine2 Receptor Antagonist and Proton Pump Inhibitor Enhances Gastric Acid Suppression. AB - STUDY OBJECTIVE: Because it has been hypothesized that histamine2 receptor antagonists (H2 RAs) might interfere with the action of proton pump inhibitors (PPIs) when the drugs are given concomitantly, we sought to compare the pharmacodynamic effects of simultaneous administration of a PPI and an H2 RA with the effects of each drug administered alone. DESIGN: Prospective, randomized, double-blind, three-way crossover study. SETTING: Esophageal motility laboratory at a large teaching hospital. SUBJECTS: Twenty-one healthy volunteers. INTERVENTION: Subjects were randomized to one of three treatment arms: an H2 RA (ranitidine 300 mg) plus placebo, a PPI (omeprazole 40 mg) plus placebo, or ranitidine 300 mg plus omeprazole 40 mg, all given once/day at 8 a.m., 30 minutes before a standard breakfast, for 1 week. The subjects then received the other two treatments, with each treatment period separated by a 1-week washout period. MEASUREMENTS AND MAIN RESULTS: The primary outcome was length of time that the gastric pH remained higher than 4. Secondary outcomes were median gastric pH higher than 4 and percentage of time that the gastric pH remained higher than 4. On day 7, ambulatory intragastric pH was recorded over an 8-hour period in each treatment arm. The combination of ranitidine and omeprazole resulted in a significantly longer time that the gastric pH remained higher than 4 (median 410.5 min [interquartile range (IQR) 298.5-454.25 min]) versus either omeprazole alone (median 356.7 min [IQR 254.9-419.2 min], p=0.023) or ranitidine alone (134.1 min [IQR 99.9-302.5 min], p<0.0001). Median gastric pH was also significantly higher when omeprazole and ranitidine were given in combination (pH 5.92 [IQR 4.75-6.46]) than either omeprazole alone (pH 4.88 [IQR 4.27-6.11], p=0.001) or ranitidine alone (pH 2.31 [IQR 2.04-5.27], p=0.0003). Likewise, the percentage of time that the gastric pH remained higher than 4 was significantly higher when omeprazole and ranitidine were given in combination (median 85.52%) than either omeprazole alone (74.31%, p=0.027) or ranitidine alone (27.94%, p=0.0002). CONCLUSION: When a PPI and H2 RA were administered concomitantly 30 minutes before breakfast, the H2 RA did not decrease the acid suppressive ability of the PPI; rather, it improved gastric acid control. Thus these results failed to support the initial hypothesis of this study. Further prospective studies are needed to test these findings in patients with gastroesophageal reflux disease as well as those with erosive esophagitis. PMID- 26621820 TI - Primary Tuberculosis of the Elbow joint: A Case Report. PMID- 26621822 TI - Orphaned mitochondria in heart failure. PMID- 26621821 TI - Influence of age, gender, and race on nitric oxide release over acupuncture points-meridians. AB - This study examined the influence of age, gender and race on nitric oxide (NO) release over acupuncture points, meridian without acupoint, and non-meridian regions of the Pericardium (PC) and Bladder (BL) meridian as well as aging on LU meridian in 61 healthy subjects. Biocapture tubes were attached to the skin surface, and total nitrite and nitrate was biocaptured and quantified using chemiluminescence. In elder ages compared to adults, NO levels over the ventral forearm were significantly decreased over LU on radial regions but not altered over PC on medial regions. Conversely, NO content was elevated over BL regions only in overweight/obesity of elder ages. NO levels over PC regions were marginally elevated in overweight/obese males compared to females but did not alter between races. These results suggest a selective reduction of NO release over LU meridian with aging, which is consistent with a progressive decline in lung function and increase in chronic respiratory disease in elder ages. Increased NO levels along the BL meridian in older obese subjects may reflect a modified NO level along somatic-bladder pathway for counteracting bladder dysfunctions with aging. Both of them support somatic-organ connections in the meridian system associated with potential pathophysiological changes with aging. PMID- 26621817 TI - Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1. AB - High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 * 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 * 10(-8)), with the alleles showing opposite effects on the risks of the two cancers. PMID- 26621823 TI - Imaging assessment of traumatic brain injury. AB - Traumatic brain injury (TBI) constitutes injury that occurs to the brain as a result of trauma. It should be appreciated as a heterogeneous, dynamic pathophysiological process that starts from the moment of impact and continues over time with sequelae potentially seen many years after the initial event. Primary traumatic brain lesions that may occur at the moment of impact include contusions, haematomas, parenchymal fractures and diffuse axonal injury. The presence of extra-axial intracranial lesions such as epidural and subdural haematomas and subarachnoid haemorrhage must be anticipated as they may contribute greatly to secondary brain insult by provoking brain herniation syndromes, cranial nerve deficits, oedema and ischaemia and infarction. Imaging is fundamental to the management of patients with TBI. CT remains the imaging modality of choice for initial assessment due to its ease of access, rapid acquisition and for its sensitivity for detection of acute haemorrhagic lesions for surgical intervention. MRI is typically reserved for the detection of lesions that may explain clinical symptoms that remain unresolved despite initial CT. This is especially apparent in the setting of diffuse axonal injury, which is poorly discerned on CT. Use of particular MRI sequences may increase the sensitivity of detecting such lesions: diffusion-weighted imaging defining acute infarction, susceptibility-weighted imaging affording exquisite data on microhaemorrhage. Additional advanced MRI techniques such as diffusion tensor imaging and functional MRI may provide important information regarding coexistent structural and functional brain damage. Gaining robust prognostic information for patients following TBI remains a challenge. Advanced MRI sequences are showing potential for biomarkers of disease, but this largely remains at the research level. Various global collaborative research groups have been established in an effort to combine imaging data with clinical and epidemiological information to provide much needed evidence for improvement in the characterisation and classification of TBI and in the identity of the most effective clinical care for this patient cohort. However, analysis of collaborative imaging data is challenging: the diverse spectrum of image acquisition and postprocessing limits reproducibility, and there is a requirement for a robust quality assurance initiative. Future clinical use of advanced neuroimaging should ensure standardised approaches to image acquisition and analysis, which can be used at the individual level, with the expectation that future neuroimaging advances, personalised to the patient, may improve prognostic accuracy and facilitate the development of new therapies. PMID- 26621824 TI - Superiority trials: statistical trickery or mass blindness? PMID- 26621825 TI - Pathophysiology of type 1 and type 2 diabetes mellitus: a 90-year perspective. AB - Diabetes mellitus is a complex metabolic disorder associated with an increased risk of microvascular and macrovascular disease; its main clinical characteristic is hyperglycaemia. The last century has been characterised by remarkable advances in our understanding of the mechanisms leading to hyperglycaemia. The central role of insulin in glucose metabolism regulation was clearly demonstrated during the early 1920s, when Banting, Best, Collip and Macleod successfully reduced blood glucose levels and glycosuria in a patient treated with a substance purified from bovine pancreata. Later, during the mid-1930s, clinical observations suggested a possible distinction between 'insulin-sensitive' and 'insulin-insensitive' diabetes. Only during the 1950s, when a reliable measure of circulating insulin was available, was it possible to translate these clinical observations into pathophysiological and biochemical differences, and the terms 'insulin-dependent' (indicating undetectable insulin levels) and 'non-insulin dependent' (normal or high insulin levels) started to emerge. The next 30 years were characterised by pivotal progress in the field of immunology that were instrumental in demonstrating an immune-mediated loss of insulin-secreting beta cells in subjects with 'insulin-dependent' diabetes. At the same time, new experimental techniques allowing measurement of insulin 'impedance' showed a reduced peripheral effect of insulin in subjects with 'non-insulin-dependent' diabetes (insulin resistance). The difference between the two types of diabetes emerging from decades of observations and experiments was further formally recognised in 1979, when the definitions 'type I' and 'type II' diabetes were introduced to replace the former 'insulin-dependent' and 'non-insulin-dependent' terms. In the following years, many studies elucidated the natural history and temporal contribution of insulin resistance and beta-cell insulin secretion in 'type II' diabetes. Furthermore, a central role for insulin resistance in the development of a cluster of cardiometabolic alterations (dyslipidaemia, inflammation, high blood pressure) was suggested. Possibly as a consequence of the secular changes in diabetes risk factors, in the last 10 years the limitation of a simple distinction between 'type I' and 'type II' diabetes has been increasingly recognised, with subjects showing the coexistence of insulin resistance and immune activation against beta-cells. With the advancement of our cellular and molecular understanding of diabetes, a more pathophysiological classification that overcomes the historical and simple 'glucocentric' view could result in a better patient phenotyping and therapeutic approach. PMID- 26621826 TI - Urine-derived induced pluripotent stem cells as a modeling tool for paroxysmal kinesigenic dyskinesia. AB - Paroxysmal kinesigenic dyskinesia (PKD) is a monogenic movement disorder with autosomal dominant inheritance. We previously identified the proline-rich transmembrane protein 2 (PRRT2) as a causative gene of PKD. However, the pathogenesis of PKD remains largely unknown so far. In addition, applicable modeling tools to investigate the underlying mechanisms of PKD are still lacking. The combination of disease-specific human induced pluripotent stem cells (iPSCs) and directed cell differentiation offers an ideal platform for disease modeling. In this study, we generated two iPSC lines from the renal epithelial cells of one PKD patient with the hotspot c.649dupC mutation (PKD-iPSCs). These cell lines were positive for alkaline phosphatase Nanog, Tra-1-80, Tra-1-60, SSEA-3 and SSEA 4. Teratomas with three blastoderms including ectoderm, mesoderm, and endoderm were obtained two months after injection of PKD-iPSCs into NOD/SCID mice. The expression of PRRT2 mRNA was decreased in PKD-iPSCs compared with that of the control iPSCs. Furthermore, PKD-iPSCs possessed the differentiation potential of functional glutamatergic, dopaminergic and motor neurons in vitro. Electrophysiological examinations revealed that the current densities of fast activated and deactivated sodium channels as well as voltage gated potassium channels were not different between the neurons from PKD-iPSCs and control iPSCs. Thus, PKD-iPSCs are a feasible modeling tool to investigate the pathogenic mechanisms of PKD. PMID- 26621827 TI - Introducing Pitt-Hopkins syndrome-associated mutations of TCF4 to Drosophila daughterless. AB - Pitt-Hopkins syndrome (PTHS) is caused by haploinsufficiency of Transcription factor 4 (TCF4), one of the three human class I basic helix-loop-helix transcription factors called E-proteins. Drosophila has a single E-protein, Daughterless (Da), homologous to all three mammalian counterparts. Here we show that human TCF4 can rescue Da deficiency during fruit fly nervous system development. Overexpression of Da or TCF4 specifically in adult flies significantly decreases their survival rates, indicating that these factors are crucial even after development has been completed. We generated da transgenic fruit fly strains with corresponding missense mutations R578H, R580W, R582P and A614V found in TCF4 of PTHS patients and studied the impact of these mutations in vivo. Overexpression of wild type Da as well as human TCF4 in progenitor tissues induced ectopic sensory bristles and the rough eye phenotype. By contrast, overexpression of Da(R580W) and Da(R582P) that disrupt DNA binding reduced the number of bristles and induced the rough eye phenotype with partial lack of pigmentation, indicating that these act dominant negatively. Compared to the wild type, Da(R578H) and Da(A614V) were less potent in induction of ectopic bristles and the rough eye phenotype, respectively, suggesting that these are hypomorphic. All studied PTHS-associated mutations that we introduced into Da led to similar effects in vivo as the same mutations in TCF4 in vitro. Consequently, our Drosophila models of PTHS are applicable for further studies aiming to unravel the molecular mechanisms of this disorder. PMID- 26621828 TI - Analysis of neural progenitors from embryogenesis to juvenile adult in Xenopus laevis reveals biphasic neurogenesis and continuous lengthening of the cell cycle. AB - Xenopus laevis is a prominent model system for studying neural development, but our understanding of the long-term temporal dynamics of neurogenesis remains incomplete. Here, we present the first continuous description of neurogenesis in X. laevis, covering the entire period of development from the specification of neural ectoderm during gastrulation to juvenile frog. We have used molecular markers to identify progenitors and neurons, short-term bromodeoxyuridine (BrdU) incorporation to map the generation of newborn neurons and dual pulse S-phase labelling to characterise changes in their cell cycle length. Our study revealed the persistence of Sox3-positive progenitor cells from the earliest stages of neural development through to the juvenile adult. Two periods of intense neuronal generation were observed, confirming the existence of primary and secondary waves of neurogenesis, punctuated by a period of quiescence before metamorphosis and culminating in another period of quiescence in the young adult. Analysis of multiple parameters indicates that neural progenitors alternate between global phases of differentiation and amplification and that, regardless of their behaviour, their cell cycle lengthens monotonically during development, at least at the population level. PMID- 26621829 TI - The LINC complex component Sun4 plays a crucial role in sperm head formation and fertility. AB - LINC complexes are evolutionarily conserved nuclear envelope bridges, physically connecting the nucleus to the peripheral cytoskeleton. They are pivotal for dynamic cellular and developmental processes, like nuclear migration, anchoring and positioning, meiotic chromosome movements and maintenance of cell polarity and nuclear shape. Active nuclear reshaping is a hallmark of mammalian sperm development and, by transducing cytoskeletal forces to the nuclear envelope, LINC complexes could be vital for sperm head formation as well. We here analyzed in detail the behavior and function of Sun4, a bona fide testis-specific LINC component. We demonstrate that Sun4 is solely expressed in spermatids and there localizes to the posterior nuclear envelope, likely interacting with Sun3/Nesprin1 LINC components. Our study revealed that Sun4 deficiency severely impacts the nucleocytoplasmic junction, leads to mislocalization of other LINC components and interferes with the formation of the microtubule manchette, which finally culminates in a globozoospermia-like phenotype. Together, our study provides direct evidence for a critical role of LINC complexes in mammalian sperm head formation and male fertility. PMID- 26621830 TI - Apical constriction and epithelial invagination are regulated by BMP activity. AB - Epithelial invagination is a morphological process in which flat cell sheets transform into three-dimensional structures through bending of the tissue. It is accompanied by apical constriction, in which the apical cell surface is reduced in relation to the basal cell surface. Although much is known about the intra cellular molecular machinery driving apical constriction and epithelial invagination, information of how extra-cellular signals affect these processes remains insufficient. In this study we have established several in vivo assays of placodal invagination to explore whether the external signal BMP regulates processes connected to epithelial invagination. By inhibiting BMP activity in prospective cranial placodes, we provide evidence that BMP signals are required for RhoA and F-actin rearrangements, apical constriction, cell elongation and epithelial invagination. The failure of placode invagination after BMP inhibition appears to be a direct consequence of disrupted apical accumulation of RhoA and F actin, rather than changes in cell death or proliferation. In addition, our results show that epithelial invagination and acquisition of placode-specific identities are two distinct and separable developmental processes. In summary, our results provide evidence that BMP signals promote epithelial invagination by acting upstream of the intracellular molecular machinery that drives apical constriction and cell elongation. PMID- 26621831 TI - Differentiated muscles are mandatory for gas-filling of the Drosophila airway system. AB - At the end of development, organs acquire functionality, thereby ensuring autonomy of an organism when it separates from its mother or a protective egg. In insects, respiratory competence starts when the tracheal system fills with gas just before hatching of the juvenile animal. Cellular and molecular mechanisms of this process are not fully understood. Analyses of the phenotype of Drosophila embryos with malformed muscles revealed that they fail to gas-fill their tracheal system. Indeed, we show that major regulators of muscle formation like Lame duck and Blown fuse are important, while factors involved in the development of subsets of muscles including cardiac and visceral muscles are dispensable for this process, suggesting that somatic muscles (or parts of them) are essential to enable tracheal terminal differentiation. Based on our phenotypic data, we assume that somatic muscle defect severity correlates with the penetrance of the gas filling phenotype. This argues that a limiting molecular or mechanical muscle borne signal tunes tracheal differentiation. We think that in analogy to the function of smooth muscles in vertebrate lungs, a balance of physical forces between muscles and the elasticity of tracheal walls may be decisive for tracheal terminal differentiation in Drosophila. PMID- 26621832 TI - Proteasome inhibition mediates p53 reactivation and anti-cancer activity of 6 gingerol in cervical cancer cells. AB - Human papilloma virus (HPV) expressing E6 and E7 oncoproteins, is known to inactivate the tumor suppressor p53 through proteasomal degradation in cervical cancers. Therefore, use of small molecules for inhibition of proteasome function and induction of p53 reactivation is a promising strategy for induction of apoptosis in cervical cancer cells. The polyphenolic alkanone, 6-Gingerol (6G), present in the pungent extracts of ginger (Zingiber officinale Roscoe) has shown potent anti-tumorigenic and pro-apoptotic activities against a variety of cancers. In this study we explored the molecular mechanism of action of 6G in human cervical cancer cells in vitro and in vivo. 6G potently inhibited proliferation of the HPV positive cervical cancer cells. 6G was found to: (i) inhibit the chymotrypsin activity of proteasomes, (ii) induce reactivation of p53, (iii) increase levels of p21, (iv) induce DNA damage and G2/M cell cycle arrest, (v) alter expression levels of p53-associated apoptotic markers like, cleaved caspase-3 and PARP, and (vi) potentiate the cytotoxicity of cisplatin. 6G treatment induced significant reduction of tumor volume, tumor weight, proteasome inhibition and p53 accumulation in HeLa xenograft tumor cells in vivo. The 6G treatment was devoid of toxic effects as it did not affect body weights, hematological and osteogenic parameters. Taken together, our data underscores the therapeutic and chemosensitizing effects of 6G in the management and treatment of cervical cancer. PMID- 26621833 TI - Doublecortin-like kinase 1 expression associates with breast cancer with neuroendocrine differentiation. AB - Doublecortin-like kinase 1 (DCLK1), a microtubule associated kinase, has recently been proposed to be a putative marker for stemness and adverse prognosis in gastrointestinal cancers. However, it is not clear whether the protein also plays similar roles in breast cancer. Here, the expression of DCLK1 was analyzed in a large cohort of invasive breast cancers (IBC) by immunohistochemistry. DCKL1 was associated with favorable clinico-pathologic features, namely lower histologic grade, absence of lymphovascular invasion, fibrotic focus, necrosis and lower pN stage (p<=0.045). Additionally, independent significant correlations were found with estrogen receptor and neuroendocrine markers (p <=0.019), implicating its relationship with IBC with neuroendocrine differentiation (IBC-NED). In the current cohort, IBC-NED showed worse outcome than luminal cancers without NED (hazard ratio=1.756, p=0.041). Interestingly, within the IBC-NED group, DCLK1 was found to be a good prognostic factor (hazard ratio =0.288, p=0.011). These findings were in contrast to those in gastrointestinal cancers, suggesting different functional roles of DCLK1 in different types of cancers. In clinical practice, NED is not routinely assessed; thus IBC-NED are not well studied. Its poor outcome and significant heterogeneity warrants more attention. DCLK1 expression could aid in the prognostication and management of this special cancer subtype. PMID- 26621834 TI - Genome-wide haplotype association study identify TNFRSF1A, CASP7, LRP1B, CDH1 and TG genes associated with Alzheimer's disease in Caribbean Hispanic individuals. AB - Alzheimer's disease (AD) is an acquired disorder of cognitive and behavioral impairment. It is considered to be caused by variety of factors, such as age, environment and genetic factors. In order to identify the genetic affect factors of AD, we carried out a bioinformatic approach which combined genome-wide haplotype-based association study with gene prioritization. The raw SNP genotypes data was downloaded from GEO database (GSE33528). It contains 615 AD patients and 560 controls of Caribbean Hispanic individuals. Firstly, we identified the linkage disequilibrium (LD) haplotype blocks and performed genome-wide haplotype association study to screen significant haplotypes that were associated with AD. Then we mapped these significant haplotypes to genes and obtained candidate genes set for AD. At last, we prioritized AD candidate genes based on their similarity with 36 known AD genes, so as to identify AD related genes. The results showed that 141 haplotypes on 134 LD blocks were significantly associated with AD (P<1E 4), and these significant haplotypes were mapped to 132 AD candidate genes. After prioritizing these candidate genes, we found seven AD related genes: APOE, APOC1, TNFRSF1A, LRP1B, CDH1, TG and CASP7. Among these genes, APOE and APOC1 are known AD risk genes. For the other five genes TNFRSF1A, CDH1, CASP7, LRP1B and TG, this is the first genetic association study which showed the significant association between these five genes and AD susceptibility in Caribbean Hispanic individuals. We believe that our findings can provide a new perspective to understand the genetic affect factors of AD. PMID- 26621835 TI - Negative correlation of ITCH E3 ubiquitin ligase and miRNA-106b dictates metastatic progression in pancreatic cancer. AB - Pancreatic cancer is one of the major malignancies and cause for mortality across the world, with recurrence and metastatic progression remaining the single largest cause of pancreatic cancer mortality. Hence it is imperative to develop novel biomarkers of pancreatic cancer prognosis. The E3 ubiquitin ligase ITCH has been previously reported to inhibit the tumor suppressive Hippo signaling by suppressing LATS1/2 in breast cancer and chronic lymphocytic leukemia. However, the role of ITCH in pancreatic cancer progression has not been described. Here we report that ITCH transcript and protein expression mimic metastatic trait in pancreatic cancer patients and cell lines. Loss-of-function studies of ITCH showed that the gene product is responsible for inducing metastasis in vivo. We furthermore show that hsa-miR-106b, which itself is down regulated in metastatic pancreatic cancer, directly interacts and inhibit ITCH expression. ITCH and hsa miR-106b are thus potential biomarkers for pancreatic cancer prognosis. PMID- 26621836 TI - BAG3 elevation inhibits cell proliferation via direct interaction with G6PD in hepatocellular carcinomas. AB - Bcl-2 associated athanogene 3 (BAG3) contains multiple protein-binding motifs to mediate potential interactions with chaperons and/or other proteins, which is possibly ascribed to the multifaceted functions assigned to BAG3. The current study demonstrated that BAG3 directly interacted with glucose 6 phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP). BAG3 suppressed the PPP flux, de novo DNA synthesis and cell growth in hepatocellular carcinomas (HCCs). The growth defect of HCCs with forced BAG3 expression can be rescued by enforced G6PD expression. However, BAG3 elevation did not cause a reduction in cellular NADPH concentrations, another main product of G6PD. In addition, supplement of nucleosides alone was sufficient to recover the growth defect mediated by BAG3 elevation. Collectively, the current study established a tumor suppressor-like function of BAG3 via direct interaction with G6PD in HCCs at the cellular level. PMID- 26621837 TI - Common variations in TERT-CLPTM1L locus are reproducibly associated with the risk of nasopharyngeal carcinoma in Chinese populations. AB - Associations between single nucleotide polymorphisms (SNPs) at 5p15 (TERT CLPTM1L) and multiple cancer types have been reported. We examined whether polymorphisms in the TERT-CLPTM1L locus were related to the risk of developing nasopharyngeal carcinoma (NPC) among Chinese populations. In the first stage, 26 tag SNPs were genotyped in a Guangxi population (855 patients and 1036 controls). In the second stage, the SNPs, which showed significant association, were further genotyped in a Guangdong population (997 patients and 972 controls). Functional analyses were conducted to verify the biological relevance of the associated polymorphism. In the 1st stage, four SNPs (rs2736098, rs2735845, rs402710, and rs401681) were significantly associated with the risk of developing NPC. After the 2nd stage validation, rs2735845 and rs401681 were independently associated with the risk of developing NPC in the additive model (rs2735845, OR = 1.19, 95% CI = 1.04-1.37, P = 0.011; rs401681, OR = 0.85, 95% CI = 0.74-0.99, P = 0.034). Furthermore, we observed higher CLPTM1L messenger RNA levels in fetal mesenchymal stem cells from the rs2735845 G allele carriers compared with that from non carriers. In addition, using an immunohistochemistry assay, we observed higher TERT and CLPTM1L levels in NPC tissues compared with that in non-cancerous nasopharyngeal tissues. Our findings suggest that polymorphisms in the TERT CLPTM1L locus may play a role in mediating the susceptibility to NPC in Chinese populations. PMID- 26621838 TI - The anti-tumor NC1 domain of collagen XIX inhibits the FAK/ PI3K/Akt/mTOR signaling pathway through alphavbeta3 integrin interaction. AB - Type XIX collagen is a minor collagen associated with basement membranes. It was isolated for the first time in a human cDNA library from rhabdomyosarcoma and belongs to the FACITs family (Fibril Associated Collagens with Interrupted Triple Helices). Previously, we demonstrated that the NC1 domain of collagen XIX (NC1(XIX)) exerts anti-tumor properties on melanoma cells by inhibiting their migration and invasion. In the present work, we identified for the first time the integrin alphavbeta3 as a receptor of NC1(XIX). Moreover, we demonstrated that NC1(XIX) inhibits the FAK/PI3K/Akt/mTOR pathway, by decreasing the phosphorylation and activity of the major proteins involved in this pathway. On the other hand, NC1(XIX) induced an increase of GSK3beta activity by decreasing its degree of phosphorylation. Treatments targeting this central signaling pathway in the development of melanoma are promising and new molecules should be developed. NC1(XIX) seems to have the potential for the design of new anti-cancer drugs. PMID- 26621839 TI - A HLA-A2-restricted CTL epitope induces anti-tumor effects against human lung cancer in mouse xenograft model. AB - Cancer immunotherapy is attractive for antigen-specific T cell-mediated anti tumor therapy, especially in induction of cytotoxic T lymphocytes. In this report, we evaluated human CTL epitope-induced anti-tumor effects in human lung cancer xenograft models. The tumor associated antigen L6 (TAL6) is highly expressed in human lung cancer cell lines and tumor specimens as compared to normal lung tissues. TAL6 derived peptides strongly inhibited tumor growth, cancer metastasis and prolonged survival time in HLA-A2 transgenic mice immunized with a formulation of T-helper (Th) peptide, synthetic CpG ODN, and adjuvant Montanide ISA-51 (ISA-51). Adoptive transfer of peptide-induced CTL cells from HLA-A2 transgenic mice into human tumor xenograft SCID mice significantly inhibited tumor growth. Furthermore, combination of CTL-peptide immunotherapy and gemcitabine additively improved the therapeutic effects. This pre-clinical evaluation model provides a useful platform to develop efficient immunotherapeutic drugs to treat lung cancer and demonstrates a promising strategy with benefit of antitumor immune responses worthy of further development in clinical trials. PMID- 26621840 TI - Dosimetric comparisons of VMAT, IMRT and 3DCRT for locally advanced rectal cancer with simultaneous integrated boost. AB - The simultaneous integrated boost radiotherapy for preoperative locally advanced rectal cancer (LARC) can improve the local control and overall survival rates. The purpose of this study is to compare the dosimetric differences among volumetric modulated arc therapy (VMAT), fixed-field intensity modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3DCRT) for the LARC. Ten LARC patients treated in our department using the simultaneous escalate strategy were retrospectively analyzed in this study. All patients had T3 with N+/- and were treated with IMRT. Two additional VMAT and 3DCRT plans were created for each patient. VMAT plans were designed using SmartArc planning module. Both IMRT and SmartArc had similar optimization objectives. The prescription was 50 Gy to the planning clinical target volume (PTV-C) and 56 Gy to the planning gross target volume (PTV-G). The target coverage and organs at risk (OARs) were compared for all the techniques. The paired, two-tailed Wilcoxon signed-rank test was applied for statistical analysis. Results of this study indicate that IMRT and SmartArc were all significantly superior to 3DCRT in most of the relevant values evaluated of target response, OARs and normal tissue sparing. They provided comparable dosimetric parameters for target volume. But IMRT shows better sparing for OARs and normal tissue. PMID- 26621841 TI - Implications of a peroxisome proliferator-activated receptor alpha (PPARalpha) ligand clofibrate in breast cancer. AB - Inflammatory and invasive breast cancers are aggressive and require better understanding for the development of new treatments and more accurate prognosis. Here, we detected high expression of PPARalpha in human primary inflammatory (SUM149PT) and highly invasive (SUM1315MO2) breast cancer cells, and tissue sections of human breast cancer. PPARalpha ligands are clinically used to treat dyslipidemia. Among lipid lowering drugs clofibrate, fenofibrate and WY14643, clofibrate showed high chemo-sensitivity towards breast cancer cells. Clofibrate treatment significantly induced PPARalpha DNA binding activity, and remarkably reduced cyclooxygenase-2/PGE2 and 5-lipoxygenase/LTB4 inflammatory pathways. Clofibrate treatment reduced the proliferation of breast cancer cells probably by inhibiting NF-kappaB and ERK1/2 activation, reducing cyclinD1, cyclinA, cyclinE, and inducing pro-apoptotic P21 levels. Surprisingly, the expression of lipogenic pathway genes including SREBP-1c (sterol regulatory element-binding protein-1c), HMG-CoA synthase, SPTLC1 (serine palmitoyltransferase long-chain), and Acyl-CoA oxidase (ACO) decreased with a concurrent increase in fatty acid oxidation genes such as CPT-1a (carnitine palmitoyltransferase 1a) and SREBP-2 (Sterol regulatory element-binding protein-2). Clofibrate treatment induced secretion of free fatty acids and effectively decreased the level of phosphorylated active form of fatty acid synthase (FASN), an enzyme catalyzing de novo synthesis of fatty acids. High level of coactivators steroid receptor coactivator-1 (SRC-1) and histone acetylase CBP-300 (CREB binding protein-300) were observed in the nuclear complexes of clofibrate treated breast cancer cells. These findings implicate that stimulating PPARalpha by safe, well-tolerated, and clinically approved clofibrate may provide a safer and more effective strategy to target the signaling, lipogenic, and inflammatory pathways in aggressive forms of breast cancer. PMID- 26621842 TI - MicroRNA-20a in human faeces as a non-invasive biomarker for colorectal cancer. AB - OBJECTIVE: Detection of microRNA (miRNA) aberrations in human faeces is a new approach for colorectal cancer (CRC) screening. The aim of this study was to characterise miR-20a in faeces as a non-invasive biomarker for diagnosis of CRC. RESULTS: miR-20a expression was significantly higher in the 40 CRC tumours compared to their respective adjacent normal tissues (P = 0.0065). Levels of miR 20a were also significantly higher in faecal samples from CRC patients (P < 0.0001). The area under receiver operating characteristic (AUROC) curve for miR 20a was 0.73, with a sensitivity of 55% and specificity of 82% for CRC patients compared with controls. No significant difference in the level of miR-20a was found between patients with proximal, distal, and rectal cancer. The use of antibiotics did not influence faecal miR-20a levels. PATIENTS AND METHODS: miR 20a was selected from an expression microarray containing 667 miRNAs. Further verification of miR-20a was performed in 40 pairs of primary CRC tissues, as well as 595 faecal samples (198 CRCs, 199 adenomas, and 198 healthy controls) using TaqMan probe based quantitative Real-Time PCR (qRT-PCR). CONCLUSIONS: Faecal based miR-20a can be utilised as a potential non-invasive biomarker for CRC screening. PMID- 26621844 TI - Bcl-2 family proteins as regulators of cancer cell invasion and metastasis: a review focusing on mitochondrial respiration and reactive oxygen species. AB - Although Bcl-2 family proteins were originally identified as key regulators of apoptosis, an impressive body of evidence has shown that pro-survival members of the Bcl-2 family, including Bcl-2, Bcl-XL, and Bcl-w, can also promote cell migration, invasion, and cancer metastasis. Interestingly, cell invasion was recently found to be suppressed by multidomain pro-apoptotic members of the Bcl-2 family, such as Bax and Bak. While the mechanisms underlying these new functions of Bcl-2 proteins are just beginning to be studied, reactive oxygen species (ROS) have emerged as inducers of cell invasion and the production of ROS from mitochondrial respiration is known to be promoted and suppressed by the pro survival and multidomain pro-apoptotic Bcl-2 family members, respectively. Here, I review the evidence supporting the ability of Bcl-2 proteins to regulate cancer cell invasion and metastasis, and discuss our current understanding of their underlying mechanisms, with a particular focus on mitochondrial respiration and ROS, which could have implications for the development of strategies to overcome tumor progression. PMID- 26621845 TI - Spatial measurement error and correction by spatial SIMEX in linear regression models when using predicted air pollution exposures. AB - Spatial modeling of air pollution exposures is widespread in air pollution epidemiology research as a way to improve exposure assessment. However, there are key sources of exposure model uncertainty when air pollution is modeled, including estimation error and model misspecification. We examine the use of predicted air pollution levels in linear health effect models under a measurement error framework. For the prediction of air pollution exposures, we consider a universal Kriging framework, which may include land-use regression terms in the mean function and a spatial covariance structure for the residuals. We derive the bias induced by estimation error and by model misspecification in the exposure model, and we find that a misspecified exposure model can induce asymptotic bias in the effect estimate of air pollution on health. We propose a new spatial simulation extrapolation (SIMEX) procedure, and we demonstrate that the procedure has good performance in correcting this asymptotic bias. We illustrate spatial SIMEX in a study of air pollution and birthweight in Massachusetts. PMID- 26621843 TI - The erbB3- and IGF-1 receptor-initiated signaling pathways exhibit distinct effects on lapatinib sensitivity against trastuzumab-resistant breast cancer cells. AB - Both erbB3 and IGF-1 receptor (IGF-1R) have been shown to play an important role in trastuzumab resistance. However, it remains unclear whether erbB3- and IGF-1R initiated signaling pathways possess distinct effects on the sensitivity of lapatinib, a dual tyrosine kinase inhibitor against both EGFR and erbB2, in trastuzumab-resistant breast cancer. Here, we show that the trastuzumab-resistant SKBR3-pool2 and BT474-HR20 breast cancer sublines, as compared the parental SKBR3 and BT474 cells, respectively, exhibit refractoriness to lapatinib. Knockdown of erbB3 inhibited Akt in SKBR3-pool2 and BT474-HR20 cells, significantly increased lapatinib efficacy, and dramatically re-sensitized the cells to lapatinib-induced apoptosis. In contrast, specific knockdown of IGF-1R did not alter the cells' responsiveness to lapatinib. While the levels of phosphorylated Src (P-Src) were reduced upon IGF-1R downregulation, the P-Akt levels remained unchanged. Furthermore, a specific inhibitor of Akt, but not Src, significantly enhanced lapatinib-mediated anti-proliferative/anti-survival effects on SKBR3-pool2 and BT474-HR20 cells. These data indicate that erbB3 signaling is critical for both trastuzumab and lapatinib resistances mainly through the PI-3K/Akt pathway, whereas IGF-1R-initiated Src activation results in trastuzumab resistance without affecting lapatinib sensitivity. Our findings may facilitate the development of precision therapeutic regimens for erbB2-positive breast cancer patients who become resistant to erbB2-targeted therapy. PMID- 26621846 TI - Quantitative Histone Mass Spectrometry Identifies Elevated Histone H3 Lysine 27 (Lys27) Trimethylation in Melanoma. AB - Normal cell growth is characterized by a regulated epigenetic program that drives cellular activities such as gene transcription, DNA replication, and DNA damage repair. Perturbation of this epigenetic program can lead to events such as mis regulation of gene transcription and diseases such as cancer. To begin to understand the epigenetic program correlated to the development of melanoma, we performed a novel quantitative mass spectrometric analysis of histone post translational modifications mis-regulated in melanoma cell culture as well as patient tumors. Aggressive melanoma cell lines as well as metastatic melanoma were found to have elevated histone H3 Lys(27) trimethylation (H3K27me3) accompanied by overexpressed methyltransferase EZH2 that adds the specific modification. The altered epigenetic program that led to elevated H3K27me3 in melanoma cell culture was found to directly silence transcription of the tumor suppressor genes RUNX3 and E-cadherin. The EZH2-mediated silencing of RUNX3 and E cadherin transcription was also validated in advanced stage human melanoma tissues. This is the first study focusing on the detailed epigenetic mechanisms leading to EZH2-mediated silencing of RUNX3 and E-cadherin tumor suppressors in melanoma. This study underscores the utility of using high resolution mass spectrometry to identify mis-regulated epigenetic programs in diseases such as cancer, which could ultimately lead to the identification of biological markers for diagnostic and prognostic applications. PMID- 26621847 TI - Immobilized Metal Affinity Chromatography Coupled to Multiple Reaction Monitoring Enables Reproducible Quantification of Phospho-signaling. AB - A major goal in cell signaling research is the quantification of phosphorylation pharmacodynamics following perturbations. Traditional methods of studying cellular phospho-signaling measure one analyte at a time with poor standardization, rendering them inadequate for interrogating network biology and contributing to the irreproducibility of preclinical research. In this study, we test the feasibility of circumventing these issues by coupling immobilized metal affinity chromatography (IMAC)-based enrichment of phosphopeptides with targeted, multiple reaction monitoring (MRM) mass spectrometry to achieve precise, specific, standardized, multiplex quantification of phospho-signaling responses. A multiplex immobilized metal affinity chromatography- multiple reaction monitoring assay targeting phospho-analytes responsive to DNA damage was configured, analytically characterized, and deployed to generate phospho pharmacodynamic curves from primary and immortalized human cells experiencing genotoxic stress. The multiplexed assays demonstrated linear ranges of >=3 orders of magnitude, median lower limit of quantification of 0.64 fmol on column, median intra-assay variability of 9.3%, median inter-assay variability of 12.7%, and median total CV of 16.0%. The multiplex immobilized metal affinity chromatography multiple reaction monitoring assay enabled robust quantification of 107 DNA damage-responsive phosphosites from human cells following DNA damage. The assays have been made publicly available as a resource to the community. The approach is generally applicable, enabling wide interrogation of signaling networks. PMID- 26621848 TI - Analysis of Monoclonal Antibody Sequence and Post-translational Modifications by Time-controlled Proteolysis and Tandem Mass Spectrometry. AB - Methodology for sequence analysis of ~150 kDa monoclonal antibodies (mAb), including location of post-translational modifications and disulfide bonds, is described. Limited digestion of fully denatured (reduced and alkylated) antibody was accomplished in seconds by flowing a sample in 8murea at a controlled flow rate through a micro column reactor containing immobilized aspergillopepsin I. The resulting product mixture containing 3-9 kDa peptides was then fractionated by capillary column liquid chromatography and analyzed on-line by both electron transfer dissociation and collisionally activated dissociation mass spectrometry (MS). This approach enabled identification of peptides that cover the complete sequence of a murine mAb. With customized tandem MS and ProSightPC Biomarker search, we verified 95% amino acid residues of this mAb and identified numerous post-translational modifications (oxidized methionine, pyroglutamylation, deamidation of Asn, and several forms ofN-linked glycosylation). For disulfide bond location, native mAb is subjected to the same procedure but with longer digestion times controlled by sample flow rate through the micro column reactor. Release of disulfide containing peptides from accessible regions of the folded antibody occurs with short digestion times. Release of those in the interior of the molecule requires longer digestion times. The identity of two peptides connected by a disulfide bond is determined using a combination of electron transfer dissociation and ion-ion proton transfer chemistry to read the two N terminal and two C-terminal sequences of the connected peptides. PMID- 26621849 TI - Metformin suppresses hypoxia-induced stabilization of HIF-1alpha through reprogramming of oxygen metabolism in hepatocellular carcinoma. AB - Overexpression of hypoxia-induced factor 1alpha (HIF-1alpha) has been shown to be involved in the development and progression of hepatocellular carcinoma (HCC). HIF-1alpha should therefore be a promising molecular target for the development of anti-HCC agents. Metformin, an established antidiabetic drug, has proved to also be effective in treating cancer although the precise underlying mechanisms of this activity are not fully elucidated. The aim of this study was to investigate the effects of metformin on the expression of HIF-1alpha and oxygen metabolism in HCC. The results showed that metformin inhibited hypoxia-induced HIF-1alpha accumulation and activation independent of AMP-activated protein kinase (AMPK). Moreover, this decrease in HIF-1alpha accumulation was accompanied by promotion of HIF-1alpha protein degradation. In addition, metformin significantly decreased oxygen consumption, ultimately leading to increased intracellular oxygen tension and decreased staining with the hypoxia marker pimonidazole. In vivo studies demonstrated that metformin delayed tumor growth and attenuated the expression of HIF-1alpha in HCC tumor xenografts. Together, these findings suggest that metformin decreases hypoxia-induced HIF-1alpha accumulation by actively suppressing mitochondrial oxygen consumption and enhancing cellular oxygenation ability, providing a fundamental mechanism of metformin activity against HCC. PMID- 26621850 TI - Antibiotic drug tigecycline inhibits melanoma progression and metastasis in a p21CIP1/Waf1-dependent manner. AB - Antibiotics are common drugs with low toxicity but high effectiveness. They have been suggested to be drug candidates for cancer therapy in recent years. Here, we tried to investigate the antitumour effect of tigecycline on malignant melanoma. We showed that tigecycline dramatically inhibited cell proliferation and induced cell cycle arrest at G0/G1 phase. At the same time, tigecycline suppressed cell invasion and migration through preventing epithelial-mesenchymal transition (EMT) process. In addition, tigecycline also significantly blocked tumor growth in vivo. Expression of cell cycle-related proteins were investigated and resulted in downregulation of G1/S checkpoint proteins, such as CDK2 and Cyclin E. However, cyclin-dependent kinase inhibitor 1 (CDKN1A, p21(CIP1/Waf1)) was downregulated after tigecycline treatment, which was not conformed to its conventional function. To explain this, we overexpressed p21 in melanoma cells. We found that p21 overexpression significantly rescued tigecycline-induced cell proliferation inhibition as well as migration and invasion suppression. Taken together, our results revealed that the essential role of p21 in the inhibitory effect of tigecycline on proliferation, migration and invasion of melanoma. Tigecycline might act as a candidate therapeutic drug for treatment of patients suffering from malignant melanoma. PMID- 26621851 TI - Luminal long non-coding RNAs regulated by estrogen receptor alpha in a ligand independent manner show functional roles in breast cancer. AB - Estrogen Receptor alpha (ERalpha) activation by estrogenic hormones induces luminal breast cancer cell proliferation. However, ERalpha plays also important hormone-independent functions to maintain breast tumor cells epithelial phenotype. We reported previously by RNA-Seq that in MCF-7 cells in absence of hormones ERalpha down-regulation changes the expression of several genes linked to cellular development, representing a specific subset of estrogen-induced genes. Here, we report regulation of long non-coding RNAs from the same experimental settings. A list of 133 Apo-ERalpha-Regulated lncRNAs (AER-lncRNAs) was identified and extensively characterized using published data from cancer cell lines and tumor tissues, or experiments on MCF-7 cells. For several features, we ran validation using cell cultures or fresh tumor biopsies. AER lncRNAs represent a specific subset, only marginally overlapping estrogen-induced transcripts, whose expression is largely restricted to luminal cells and which is able to perfectly classify breast tumor subtypes. The most abundant AER-lncRNA, DSCAM-AS1, is expressed in ERalpha+ breast carcinoma, but not in pre-neoplastic lesions, and correlates inversely with EMT markers. Down-regulation of DSCAM-AS1 recapitulated, in part, the effect of silencing ERalpha, i.e. growth arrest and induction of EMT markers. In conclusion, we report an ERalpha-dependent lncRNA set representing a novel luminal signature in breast cancer cells. PMID- 26621853 TI - Development and characterization of a novel long-acting recombinant follicle stimulating hormone agonist by fusing Fc to an FSH-beta subunit. AB - STUDY QUESTION: Does a novel long-acting recombinant human FSH, KN015, a heterodimer composed of FSHalpha and FSHbeta-Fc/Fc, offer a potential FSH alternative? SUMMARY ANSWER: KN015 had in vitro activity and superior in vivo bioactivity than recombinant human FSH (rhFSH), suggesting KN015 could serve as a potential FSH agonist for clinical therapy. WHAT IS KNOWN ALREADY: rhFSH has very short half-life so that repeat injections are needed, resulting in discomfort and inconvenience for patients. The longest-acting rhFSH available in clinics is corifollitropin alpha (FSH-CTP), but its half-life is not long enough to sustain the whole therapy period, and additional injections of rhFSH are needed. STUDY DESIGN, SIZE, DURATION: Plasmids containing FSHalpha, FSHbeta-Fc and Fc cDNA were transfected into Chinese hamster ovary (CHO) cells for KN015 production. The pharmacokinetics of KN015 was investigated in 6-week-old SD rats (n = 6/group) and healthy Cynomolgus monkeys in two different dose groups (n = 2/group). A series of experiments were designed for in vitro and in vivo characterization of the bioactivity of KN015 relative to rhFSH. PARTICIPANTS/MATERIALS, SETTING, METHODS: The purity and molecular weight of KN015 were determined by reducing and non-reducing SDS-PAGE. To measure KN015 half-life, sera were collected at increasing time points and the remaining FSH concentration was measured by enzyme linked immunosorbent assay. To assess the bioactivity of KN015 versus rhFSH in vitro, firstly cAMP production was assessed in CHO cells expressing FSH receptor (FSHR) with the treatment of Fc/Fc, rhFSH or KN015 at eight different doses (0.03, 0.09, 0.28, 0.83, 2.5, 7.5, 22.5, 67.5 nM), and secondly cumulus oocyte complexes (COCs; n = 20/group) of ICR mice (primed-PMSG 44 h before sacrificed) were collected and cultured in medium containing 1.25 pM Fc/Fc, rhFSH or KN015 at 37 degrees C and then germinal vesicle breakdown (GVBD) and COC expansion were observed at 4 and 16 h, respectively. The in vivo activity of KN015 was compared with rhFSH by ovary weight gain and ovulation assays. In the former, ovary weight gains in 21-day-old female SD rats, after a single subcutaneous injection of KN015, were compared with those after several injections of rhFSH over a range of doses (n = 8/group). Sera were harvested for estradiol (E2) analysis, and the ovaries were processed for hematoxylin and eosin (HE) staining, immunohistochemistry (IHC), TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labeling (TUNEL), RT-PCR and western blot. In the latter, 26-day old female SD rats (n = 8/group) were injected with different doses of KN015 or rhFSH, and were sacrificed at 24 h after an injection of hCG (20 IU/rat). Moreover, the molecular responses stimulated by KN015 or rhFSH in the ovary were also analyzed through detecting expression of the FSH target genes (Cyp19a1, Fshr and Lhcgr) and phosphatidylinositide 3-kinase (PI3K) pathway activation. MAIN RESULTS AND THE ROLE OF CHANCE: KN015 has a molecular weight of 82 kD and its half-life is 84 h in SD rats (10-fold longer than that of rhFSH) and 215 h in Cynomolgus monkeys. The EC50 value of the cAMP induction in CHO cells (KN015 versus rhFSH, 1.84 versus 0.87 nM), COC expansion and oocyte maturation assays showed KN015 had approximately half of rhFSH's activity in vitro. A single dose of KN015 (1.5 pmol/rat, 166.1 +/- 19.7 mg, P < 0.01) stimulated significantly larger ovary weight gain than several injections of rhFSH (1.5 pmol/rat, 59.3 +/- 28.1 mg, P < 0.01). The serum E2 level in the KN015 group was significantly higher than that in rhFSH group. The number of oocytes obtained by ovulation induction was comparable with or higher in the KN015 group than in the rhFSH group. KN015 was more effective than rhFSH in inducing FSH target genes (Cyp19a1, Fshr, Lhcgr) or activating the PI3K pathway in vivo. Moreover, a single injection of KN015 promoted granulosa cell proliferation and prevented follicle atresia to the same extent as several injections of rhFSH. LIMITATIONS, REASONS FOR CAUTION: All assays in this study were operated only in animals and clinical trials are needed to confirm they can be extrapolated to humans. WIDER IMPLICATIONS OF THE FINDINGS: KN015 is a valuable alternative to FSH and may have great potential for therapeutic applications. STUDY FUNDING/COMPETING INTERESTS: This study was supported by National Basic Research Program of China (2011|CB944504, 2012CB944403) and National Natural Science Foundation of China (81172473, 31371449). The authors have no conflicts of interest to declare. PMID- 26621854 TI - Tramadol versus Celecoxib for reducing pain associated with outpatient hysteroscopy: a randomized double-blind placebo-controlled trial. AB - STUDY QUESTION: Which is better, Tramadol or Celecoxib, in reducing pain associated with outpatient hysteroscopy? SUMMARY ANSWER: Both Tramadol and Celecoxib are effective in reducing pain associated with outpatient hysteroscopy but Celecoxib may be better tolerated. WHAT IS KNOWN ALREADY: Pain is the most common cause of failure of outpatient hysteroscopy. A systematic review and meta analysis showed that local anaesthetics were effective in reducing pain associated with hysteroscopy but there was insufficient evidence to support the use of oral analgesics, opioids and non-steroidal anti-inflammatory drugs, to reduce hysteroscopy-associated pain and further studies were recommended. STUDY DESIGN, SIZE, DURATION: This was a randomized double-blind placebo-controlled trial with balanced randomization (allocation ratio 1:1:1) conducted in a university hospital from May 2014 to November 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two hundred and ten women who had diagnostic outpatient hysteroscopy were randomly divided into three equal groups: Group 1 received oral Tramadol 100 mg, group 2 received Celecoxib 200 mg and group 3 received an oral placebo. All the drugs were given 1 h before the procedure. A patient's perception of pain was assessed during the procedure, immediately afterwards and 30 min after the procedure with the use of a visual analogue scale (VAS). MAIN RESULTS AND THE ROLE OF CHANCE: There was a significant difference in the pain scores among the groups during the procedure, immediately afterwards and 30 min after the procedure (P< 0.001, 0.001, <0.001 respectively). Tramadol had significantly lower pain scores when compared with the placebo during the procedure (mean difference = 1.54, 95% confidence interval (CI) (0.86, 2.22), P < 0.001), immediately after the procedure (mean difference = 1.09; 95% CI (0.5, 1.68), P < 0.001) and 30 min later (mean difference = 0.95, 95% CI (0.48, 1.41), P < 0.001). Celecoxib administration also led to significantly lower pain scores than the placebo during the procedure (mean difference = 1.28, 95% CI (0.62, 1.94), P < 0.001), immediately after the procedure (mean difference = 0.72; 95% CI (0.13, 1.32), P = 0.016) and 30 min later (mean difference = 0.77, 95% CI (0.3, 1.24), P = 0.001). There were no significant differences in pain scores between Tramadol and Celecoxib at any time. Time until no pain differed significantly among the groups (P = 0.01); it was shorter with both Tramadol and Celecoxib groups when compared with placebo (P = 0.002 and 0.046, respectively). The procedure failed to be completed in one patient in the placebo group but no failure to complete the procedure occurred in Tramadol and Celecoxib groups. Four women in the Tramadol group reported nausea but no side effects were reported with Celecoxib group and no complications were reported in any group of patients. LIMITATIONS, REASONS FOR CAUTION: All results were based on the subjective perception of pain, which varies among individuals and is related to the individuals' previous pain experience and level of anxiety. WIDER IMPLICATIONS OF THE FINDINGS: Tramadol and Celecoxib are effective in reducing pain in outpatient hysteroscopy. Celecoxib may be better tolerated as no side effects were reported in the study, however further research on a larger sample size is required before drawing firm conclusions about lack of side effects. STUDY FUNDING/COMPETING INTERESTS: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: www.clinicaltrials.gov - NCT02071303. PMID- 26621855 TI - Human embryos commonly form abnormal nuclei during development: a mechanism of DNA damage, embryonic aneuploidy, and developmental arrest. AB - STUDY QUESTION: What is the prevalence and developmental significance of morphologic nuclear abnormalities in human preimplantation embryos? SUMMARY ANSWER: Nuclear abnormalities are commonly found in human IVF embryos and are associated with DNA damage, aneuploidy, and decreased developmental potential. WHAT IS KNOWN ALREADY: Early human embryonic development is complicated by genomic errors that occur after fertilization. The appearance of extra-nuclear DNA, which has been observed in IVF, may be a result of such errors. However, the mechanism by which abnormal nuclei form and the impact on DNA integrity and embryonic development is not understood. STUDY DESIGN, SIZE, DURATION: Cryopreserved human cleavage-stage embryos (n = 150) and cryopreserved blastocysts (n = 105) from clinical IVF cycles performed between 1997 and 2008 were donated for research. Fresh embryos (n = 60) of poor quality that were slated for discard were also used. Immunohistochemical, microscopic and cytogenetic analyses at different developmental stages and morphologic grades were performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Embryos were fixed and stained for DNA, centromeres, mitotic activity and DNA damage and imaged using confocal microscopy. Rates of abnormal nuclear formation were compared between morphologically normal cleavage-stage embryos, morphologically normal blastocysts, and poor quality embryos. To control for clinical and IVF history of oocytes donors, and quality of frozen embryos within our sample, cleavage-stage embryos (n = 52) were thawed and fixed at different stages of development and then analyzed microscopically. Cleavage-stage embryos (n = 9) were thawed and all blastomeres (n = 62) were disaggregated, imaged and analyzed for karyotype. Correlations were made between microscopic and cytogenetic findings of individual blastomeres and whole embryos. MAIN RESULTS AND THE ROLE OF CHANCE: The frequency of microscopic nuclear abnormalities was lower in blastocysts (5%; 177/3737 cells) than in cleavage-stage embryos (16%, 103/640 blastomeres, P < 0.05) and highest in arrested embryos (65%; 44/68 blastomeres, P < 0.05). DNA damage was significantly higher in cells with microscopic nuclear abnormalities (gammaH2AX (phosphorylated (Ser139) histone H2A.X): 87.1%, 74/85; replication protein A: 72.9%, 62/85) relative to cells with normal nuclear morphology (gammaH2AX: 9.3%, 60/642; RPA: 5.6%, 36/642) (P < 0.05). Blastomeres containing nuclear abnormalities were strongly associated with aneuploidy (Fisher exact test, two tailed, P < 0.01). LIMITATIONS, REASONS FOR CAUTION: The embryos used were de identified, and the clinical and IVF history was unknown. WIDER IMPLICATIONS OF THE FINDINGS: This study explores a mechanism of abnormal embryonic development post-fertilization. While most of the current data have explored abnormal meiotic chromosome segregation in oocytes as a primary mechanism of reproductive failure, abnormal nuclear formation during early mitotic cell division in IVF embryos also plays a significant role. The detection of abnormal nuclear formation may have clinical application in noninvasive embryo selection during IVF. STUDY FUNDING/COMPETING INTERESTS: The study was supported by Columbia University and the New York Stem Cell Foundation. Authors declare no competing interest. PMID- 26621856 TI - The impact of the Rasouli decision: a Survey of Canadian intensivists. AB - INTRODUCTION: In a landmark 2013 decision, the Supreme Court of Canada (SCC) ruled that the withdrawal of life support in certain circumstances is a treatment requiring patient or substitute decision maker (SDM) consent. How intensive care unit (ICU) physicians perceive this ruling is unknown. OBJECTIVES: To determine physician knowledge of and attitudes towards the SCC decision, as well as the self-reported changes in practice attributed to the decision. METHODS: We surveyed intensivists at university hospitals across Canada. We used a knowledge test and Likert-scale questions to measure respondent knowledge of and attitudes towards the ruling. We used vignettes to assess decision making in cases of intractable physician-SDM conflict over the management of patients with very poor prognoses. We compared management choices pre-SCC decision versus post-SCC decision versus the subjective, respondent-defined most appropriate choice. Responses were compared across predefined subgroups. We performed qualitative analysis on free-text responses. RESULTS: We received 82 responses (response rate=42%). Respondents reported providing high levels of self-defined inappropriate treatment. Although most respondents reported no change in practice, there was a significant overall shift towards higher intensity and less subjectively appropriate management after the SCC decision. Attitudes to the SCC decision and approaches to disputes over end-of-life (EoL) care in the ICU were highly variable. There were no significant differences among predefined subgroups. CONCLUSIONS: Many Canadian ICU physicians report providing a higher intensity of treatment, and less subjectively appropriate treatment, in situations of dispute over EoL care after the Supreme Court of Canada's ruling in Cuthbertson versus Rasouli. PMID- 26621858 TI - Host Foxp3+CD4+ Regulatory T Cells Act as a Negative Regulator of Dendritic Cells in the Peritransplantation Period. AB - Host Foxp3+CD4+ regulatory T cells (Tregs) have been shown to suppress graft versus-host disease (GVHD) in experimental bone marrow transplantation (BMT) models; however, the detailed mechanism is unknown. To address this issue, we established a murine MHC-haploidentical BMT model (BDF1 (H-2b/d) -> B6C3F1 (H 2b/k)), in which transplantation following conditioning with high-dose (13 Gy) or low-dose (5 Gy) total body irradiation corresponds to myeloablative stem cell transplantation (MAST) or reduced-intensity stem cell transplantation (RIST) BMT. All MAST recipients died of GVHD within 70 d, whereas RIST recipients developed almost no GVHD and survived for at least 3 mo. In this BMT model, we investigated the kinetics of immune cells in the mesenteric lymph nodes because GVHD was most prominent in the intestines. Host Tregs that survived after total body irradiation could proliferate transiently by day 4. Comparing the kinetics of immune cells among MAST, RIST, and anti-CD25 mAb-treated RIST, we found that the transiently surviving host Tregs were fully functional, closely contacted with host dendritic cells (DCs), and significantly restrained the maturation (CD80 and CD86 expression) of DCs in a dose-dependent manner. There was a positive correlation between the ratio of DCs to host Tregs and the extent of maturation of DCs. Host Tregs suppressed alloresponse mainly by contact inhibition. Host Tregs are already active in lymph nodes before transplantation and restrain the maturation of host DCs, thereby dampening the ability of DCs to activate allogeneic donor T cells and consequently reducing the magnitude of graft-versus host reaction. Thus, host Tregs are negative regulators of host DCs that act in the peritransplantation period. PMID- 26621857 TI - Alcohol Consumption Modulates Host Defense in Rhesus Macaques by Altering Gene Expression in Circulating Leukocytes. AB - Several lines of evidence indicate that chronic alcohol use disorder leads to increased susceptibility to several viral and bacterial infections, whereas moderate alcohol consumption decreases the incidence of colds and improves immune responses to some pathogens. In line with these observations, we recently showed that heavy ethanol intake (average blood ethanol concentrations > 80 mg/dl) suppressed, whereas moderate alcohol consumption (blood ethanol concentrations < 50 mg/dl) enhanced, T and B cell responses to modified vaccinia Ankara vaccination in a nonhuman primate model of voluntary ethanol consumption. To uncover the molecular basis for impaired immunity with heavy alcohol consumption and enhanced immune response with moderate alcohol consumption, we performed a transcriptome analysis using PBMCs isolated on day 7 post-modified vaccinia Ankara vaccination, the earliest time point at which we detected differences in T cell and Ab responses. Overall, chronic heavy alcohol consumption reduced the expression of immune genes involved in response to infection and wound healing and increased the expression of genes associated with the development of lung inflammatory disease and cancer. In contrast, chronic moderate alcohol consumption upregulated the expression of genes involved in immune response and reduced the expression of genes involved in cancer. To uncover mechanisms underlying the alterations in PBMC transcriptomes, we profiled the expression of microRNAs within the same samples. Chronic heavy ethanol consumption altered the levels of several microRNAs involved in cancer and immunity and known to regulate the expression of mRNAs differentially expressed in our data set. PMID- 26621859 TI - GIMAP1 Is Essential for the Survival of Naive and Activated B Cells In Vivo. AB - An effective immune system depends upon regulation of lymphocyte function and homeostasis. In recent years, members of the GTPases of the immunity associated protein (GIMAP) family were proposed to regulate T cell homeostasis. In contrast, little is known about their function and mode of action in B cells. We used a combination of transgenic mice and in vivo and in vitro techniques to conditionally and electively ablate GIMAP1 in resting and activated peripheral B cells. Our data suggest that GIMAP1 is absolutely essential for the survival of peripheral B cells, irrespective of their activation state. Together with recent data showing increased expression of GIMAP1 in B cell lymphomas, our work points to the possible potential of GIMAP1 as a target for manipulation in a variety of B cell-mediated diseases. PMID- 26621860 TI - Progression from Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Is Marked by a Higher Frequency of Th17 Cells in the Liver and an Increased Th17/Resting Regulatory T Cell Ratio in Peripheral Blood and in the Liver. AB - Nonalcoholic fatty liver disease is increasing in prevalence. It can be subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Five to twenty percent of cases progress from NAFL to NASH. Increased hepatic Th17 cells and IL-17 expression were observed in NASH mice and patients, respectively. We analyzed CD4(+) effector T cells and regulatory T cells (Tregs) from peripheral blood and livers of NAFL and NASH patients. A total of 51 NAFL patients, 30 NASH patients, 31 nonalcoholic fatty liver disease patients (without histology), and 43 healthy controls were included. FACS analysis was performed on PBMCs and intrahepatic lymphocytes. Compared with healthy controls, a lower frequency of resting Tregs (rTregs; CD4(+)CD45RA(+)CD25(++)) and higher frequencies of IFN-gamma(+) and/or IL-4(+) cells were detected among CD4(+) T cells of peripheral blood in NASH, and to a lesser degree in NAFL. In hepatic tissue, NAFL to NASH progression was marked by an increase in IL-17(+) cells among intrahepatic CD4(+) T cells. To define immunological parameters in peripheral blood to distinguish NAFL from NASH, we calculated different ratios. Th17/rTreg and Th2/rTreg ratios were significantly increased in NASH versus NAFL. The relevance of our findings for NASH pathogenesis was highlighted by the normalization of all of the changes 1 y after bariatric surgery. In conclusion, our data indicate that NAFL patients show changes in their immune cell profile compared with healthy controls. NAFL to NASH progression is marked by an increased frequency of IL-17(+) cells among intrahepatic CD4(+) T cells and higher Th17/rTreg and Th2/rTreg ratios in peripheral blood. PMID- 26621861 TI - The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions. AB - Effector memory (EM) CD4(+) T cells recirculate between normoxic blood and hypoxic tissues to screen for cognate Ag. How mitochondria of these cells, shuttling between normoxia and hypoxia, maintain bioenergetic efficiency and stably uphold antiapoptotic features is unknown. In this study, we found that human EM CD4(+) T cells had greater spare respiratory capacity (SRC) than did naive counterparts, which was immediately accessed under hypoxia. Consequently, hypoxic EM cells maintained ATP levels, survived and migrated better than did hypoxic naive cells, and hypoxia did not impair their capacity to produce IFN gamma. EM CD4(+) T cells also had more abundant cytosolic GAPDH and increased glycolytic reserve. In contrast to SRC, glycolytic reserve was not tapped under hypoxic conditions, and, under hypoxia, glucose metabolism contributed similarly to ATP production in naive and EM cells. However, both under normoxic and hypoxic conditions, glucose was critical for EM CD4(+) T cell survival. Mechanistically, in the absence of glycolysis, mitochondrial membrane potential (DeltaPsim) of EM cells declined and intrinsic apoptosis was triggered. Restoring pyruvate levels, the end product of glycolysis, preserved DeltaPsim and prevented apoptosis. Furthermore, reconstitution of reactive oxygen species (ROS), whose production depends on DeltaPsim, also rescued viability, whereas scavenging mitochondrial ROS exacerbated apoptosis. Rapid access of SRC in hypoxia, linked with built-in, oxygen-resistant glycolytic reserve that functionally insulates DeltaPsim and mitochondrial ROS production from oxygen tension changes, provides an immune metabolic basis supporting survival, migration, and function of EM CD4(+) T cells in normoxic and hypoxic conditions. PMID- 26621862 TI - Type I IFN Contributes to the Phenotype of Unc93b1D34A/D34A Mice by Regulating TLR7 Expression in B Cells and Dendritic Cells. AB - TLR7 recognizes pathogen-derived and self-derived RNA, and thus a regulatory system for control of the TLR7 response is required to avoid excessive activation. Unc93 homolog B1 (Unc93B1) is a regulator of TLR7 that controls the TLR7 response by transporting TLR7 from the endoplasmic reticulum to endolysosomes. We have previously shown that a D34A mutation in Unc93B1 induces hyperactivation of TLR7, and that Unc93b1(D34A/D34A) mice (D34A mice) have systemic inflammation spontaneously. In this study, we examined the roles of inflammatory cytokines such as IFN-gamma, IL-17A, and type I IFNs to understand the mechanism underlying the phenotype in D34A mice. mRNAs for IFN-gamma and IL I7A in CD4(+) T cells increased, but inflammatory phenotype manifesting as thrombocytopenia and splenomegaly was still observed in Ifng(-/-) or Il17a(-/-) D34A mice. In contrast to T cell-derived cytokines, Ifnar1(-/-) D34A mice showed an ameliorated phenotype with lower expression of TLR7 in B cells and conventional dendritic cells (cDCs). The amount of TLR7 decreased in B cells from Ifnar1(-/-) D34A mice, but the percentage of TLR7(+) cells decreased among CD8alpha(-) cDCs. In conclusion, type I IFNs maintain expression of TLR7 in B cells and cDCs in different ways; total amount of TLR7 is kept in B cells and TLR7(+) population is retained among cDCs. Our results suggested that these TLR7 expressing cells are activated initially and influence TLR7-dependent systemic inflammation. PMID- 26621864 TI - A cerebral abscess at first internist glance. AB - A 73-year-old man was transferred to the neurosurgery ward, with a presumptive diagnosis of cerebral abscess. The case was also discussed with the internists as internal medicine consultants. The neurosurgeons pointed out a right temporal lobe abscedated lesion on CT, but we noticed that the hypodense attenuation that usually surrounds the abscess wall (vasogenic oedema) extended to a broader, well delimitated area, suggesting medium cerebral artery territory. The patient had left-sided hemiplegia with a confusional state and low-grade fever. Considering possible haematogenous dissemination, an echocardiography was performed, confirming mitral endocarditis. Blood cultures and aspirated pus isolated Escherichia coli. Investigating the patient's medical history, we learned he had been submitted to bladder catheterisation 7 weeks before for acute urinary retention due to benign prostatic hyperplasia, and empirically medicated for urinary tract infection. E. coli had also been isolated in a urine specimen at the time. The clinical history of the patient cancelled the pathogenesis of cerebral abscess. PMID- 26621863 TI - IgG-Immune Complexes Promote B Cell Memory by Inducing BAFF. AB - Memory B cell responses are vital for protection against infections but must also be regulated to prevent autoimmunity. Cognate T cell help, somatic hypermutation, and affinity maturation within germinal centers (GCs) are required for high affinity memory B cell formation; however, the signals that commit GC B cells to the memory pool remain unclear. In this study, we identify a role for IgG-immune complexes (ICs), FcgammaRs, and BAFF during the formation of memory B cells in mice. We found that early secretion of IgG in response to immunization with a T dependent Ag leads to IC-FcgammaR interactions that induce dendritic cells to secrete BAFF, which acts at or upstream of Bcl-6 in activated B cells. Loss of CD16, hematopoietic cell-derived BAFF, or blocking IC:FcgammaR regions in vivo diminished the expression of Bcl-6, the frequency of GC and memory B cells, and secondary Ab responses. BAFF also contributed to the maintenance and/or expansion of the follicular helper T cell population, although it was dispensable for their formation. Thus, early Ab responses contribute to the optimal formation of B cell memory through IgG-ICs and BAFF. Our work defines a new role for FcgammaRs in GC and memory B cell responses. PMID- 26621865 TI - Bug on the back: vertebral osteomyelitis secondary to fluoroquinolone resistant Salmonella typhi in an immunocompetent patient. AB - Although Salmonella osteomyelitis is commonly seen in immunocompromised patients, it may occasionally affect an immunocompetent host. Symptoms are usually non specific, such as fever, abdominal or back pain; hence it should be considered in the differential diagnosis of patients with a history of travel to endemic regions. Fluoroquinolone resistance is rising and non-responsive patients should be treated with ampicillin, trimethoprim-sulfamethoxazole and ceftriaxone. We present a case of acute T8-T11 osteomyelitis with cord compression caused by a fluoroquinolone resistant strain of Salmonella typhi. PMID- 26621866 TI - Systemic lupus erythaematosus presenting as spontaneous splenic rupture. AB - Systemic lupus erythaematosus (SLE) is known to involve the reticuloendothelial system, but spontaneous splenic rupture (SSR) in the context of the disease is a very rare complication. We observed a 61-year-old woman with an unremarkable previous medical history who presented with SSR and underwent an emergency splenectomy. The histopathological analysis of the specimen revealed signs of vasculitis. On review of symptoms with the patient, a history of oligoarthralgia, photosensitivity, xerostomia and Raynaud phenomenon was elicited. Laboratory investigations revealed lymphopaenia, mild proteinuria and positive antinuclear and anti-dsDNA antibodies. The patient was started on hydroxychloroquine and the disease has since remained silent. This article addresses the rare association between SLE and SSR. PMID- 26621867 TI - Penetrating neck injury from a screwdriver: can the No Zone approach be applied to Zone I injuries? AB - The newer approach to management of penetrating neck injuries (PNI) involves the No Zone approach: comprehensive physical examination combined with CT angiography for triage to effectively identify or exclude vascular and aerodigestive injury. This approach, however, has a low negative exploration rate; there is risk of missing occult injuries especially Zone I and III PNI. We report a case of a patient with PNI to Zone I of the neck who was haemodynamically stable at presentation; CT scan revealed complete occlusion of the common carotid artery. Immediate surgical exploration revealed an occult hypopharyngeal injury in addition to the arterial trauma, which was missed on the CT scan. Hence the No Zone approach needs cautious clinical application, especially in Zone I injuries. PMID- 26621869 TI - Mitochondrial outer membrane permeabilization increases reactive oxygen species production and decreases mean sperm velocity but is not associated with DNA fragmentation in human sperm. AB - STUDY HYPOTHESIS: Does induction of mitochondrial outer membrane permeabilization (MOMP) in vitro affect specific functional parameters of human spermatozoa? STUDY FINDING: Our findings show that MOMP induction increases intracellular reactive oxygen species (ROS) and decreases mean sperm velocity but does not alter DNA integrity. WHAT IS KNOWN ALREADY: MOMP in somatic cells is related to a variety of apoptotic traits, such as alteration of mitochondrial membrane potential (DeltaPsim), and increase in ROS production and DNA fragmentation. Although the presence of these apoptotic features has been reported in spermatozoa, to date the effects of MOMP on sperm function and DNA integrity have not been analysed. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: The study included spermatozoa from fertile donors. Motile sperm were obtained using the swim-up method. The highly motile sperm were collected and diluted with human tubal fluid to a final cell concentration of 5 * 10(6) ml(-1). To induce MOMP, selected sperm were treated at 37 degrees C for 4 h with a mimetic of a Bcl-2 pro-apoptotic protein, ABT-737. MOMP was evaluated by relocating of cytochrome c. In addition, the effect of ABT 737 on mitochondrial inner membrane permeabilization was assessed using the calcein-AM/cobalt chloride method. In turn, DeltaPsim was evaluated with JC-1 staining, intracellular ROS production with dihydroethidium, sperm motility was analysed by computer-assisted sperm analysis and DNA fragmentation by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) assay. Measurements were performed by flow cytometry. MAIN RESULTS AND THE ROLE OF CHANCE: MOMP was associated with DeltaPsim dissipation (P < 0.05), increased ROS production (P < 0.05) and decreased mean sperm velocity (P < 0.05), but it was not associated with DNA fragmentation. MOMP did not induce a large increase in ROS, which could explain the negligible effect of MOMP on sperm DNA fragmentation under our experimental conditions. LIMITATIONS, REASONS FOR CAUTION: The study was carried out in vitro using highly motile sperm, selected by swim-up, from healthy donors. WIDER IMPLICATIONS OF THE FINDINGS: The results obtained in this study reveal that the alterations of sperm functions caused by MOMP are sufficiently relevant to justify its future study in male infertility. LARGE SCALE DATA: None. STUDY FUNDING AND COMPETING INTERESTS: The study was funded by grant DI12-0102 from the Universidad de La Frontera (J.V.V.) and a doctoral scholarship from CONICYT (F.T.). The authors declare no conflict of interest. PMID- 26621868 TI - ML264, A Novel Small-Molecule Compound That Potently Inhibits Growth of Colorectal Cancer. AB - Colorectal cancer is one of the leading causes of cancer mortality in Western civilization. Studies have shown that colorectal cancer arises as a consequence of the modification of genes that regulate important cellular functions. Deregulation of the WNT and RAS/MAPK/PI3K signaling pathways has been shown to be important in the early stages of colorectal cancer development and progression. Kruppel-like factor 5 (KLF5) is a transcription factor that is highly expressed in the proliferating intestinal crypt epithelial cells. Previously, we showed that KLF5 is a mediator of RAS/MAPK and WNT signaling pathways under homeostatic conditions and that it promotes their tumorigenic functions during the development and progression of intestinal adenomas. Recently, using an ultrahigh throughput screening approach we identified a number of novel small molecules that have the potential to provide therapeutic benefits for colorectal cancer by targeting KLF5 expression. In the current study, we show that an improved analogue of one of these screening hits, ML264, potently inhibits proliferation of colorectal cancer cells in vitro through modifications of the cell-cycle profile. Moreover, in an established xenograft mouse model of colon cancer, we demonstrate that ML264 efficiently inhibits growth of the tumor within 5 days of treatment. We show that this effect is caused by a significant reduction in proliferation and that ML264 potently inhibits the expression of KLF5 and EGR1, a transcriptional activator of KLF5. These findings demonstrate that ML264, or an analogue, may hold a promise as a novel therapeutic agent to curb the development and progression of colorectal cancer. PMID- 26621870 TI - Identification of novel members of the bacterial azoreductase family in Pseudomonas aeruginosa. AB - Azoreductases are a family of diverse enzymes found in many pathogenic bacteria as well as distant homologues being present in eukarya. In addition to having azoreductase activity, these enzymes are also suggested to have NAD(P)H quinone oxidoreductase (NQO) activity which leads to a proposed role in plant pathogenesis. Azoreductases have also been suggested to play a role in the mammalian pathogenesis of Pseudomonas aeruginosa. In view of the importance of P. aeruginosa as a pathogen, we therefore characterized recombinant enzymes following expression of a group of putative azoreductase genes from P. aeruginosa expressed in Escherichia coli. The enzymes include members of the arsenic resistance protein H (ArsH), tryptophan repressor-binding protein A (WrbA), modulator of drug activity B (MdaB) and YieF families. The ArsH, MdaB and YieF family members all show azoreductase and NQO activities. In contrast, WrbA is the first enzyme to show NQO activity but does not reduce any of the 11 azo compounds tested under a wide range of conditions. These studies will allow further investigation of the possible role of these enzymes in the pathogenesis of P. aeruginosa. PMID- 26621871 TI - Soluble CD109 binds TGF-beta and antagonizes TGF-beta signalling and responses. AB - Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine implicated in many diseases, including tissue fibrosis and cancer. TGF-beta mediates diverse biological responses by signalling through type I and II TGF beta receptors (TbetaRI and TbetaRII). We have previously identified CD109, a glycosylphosphatidylinositol (GPI)-anchored protein, as a novel TGF-beta co receptor that negatively regulates TGF-beta signalling and responses and demonstrated that membrane-anchored CD109 promotes TGF-beta receptor degradation via a SMAD7/Smurf2-mediated mechanism. To determine whether CD109 released from the cell surface (soluble CD109 or sCD109) also acts as a TGF-beta antagonist, we determined the efficacy of recombinant sCD109 to interact with TGF-beta and inhibit TGF-beta signalling and responses. Our results demonstrate that sCD109 binds TGF-beta with high affinity as determined by surface plasmon resonance (SPR) and cell-based radioligand binding and affinity labelling competition assays. SPR detected slow dissociation kinetics between sCD109 and TGF-beta at low concentrations, indicating a stable and effective interaction. In addition, sCD109 antagonizes TGF-beta-induced Smad2/3 phosphorylation, transcription and cell migration. Together, our results suggest that sCD109 can bind TGF-beta, inhibit TGF-beta binding to its receptors and decrease TGF-beta signalling and TGF-beta-induced cellular responses. PMID- 26621872 TI - The crystal structure of an inverting glycoside hydrolase family 9 exo-beta-D glucosaminidase and the design of glycosynthase. AB - Exo-beta-D-glucosaminidase (EC 3.2.1.165) from Photobacterium profundum (PpGlcNase) is an inverting GH (glycoside hydrolase) belonging to family 9. We have determined the three-dimensional structure of PpGlcNase to describe the first structure-function relationship of an exo-type GH9 glycosidase. PpGlcNase has a narrow and straight active-site pocket, in contrast with the long glycan binding cleft of a GH9 endoglucanase. This is because PpGlcNase has a long loop, which blocks the position corresponding to subsites -4 to -2 of the endoglucanase. The pocket shape of PpGlcNase explains its substrate preference for a beta1,4-linkage at the non-reducing terminus. Asp(139), Asp(143) and Glu(555) in the active site were located near the beta-O1 hydroxy group of GlcN (D-glucosamine), with Asp(139) and Asp(143) holding a nucleophilic water molecule for hydrolysis. The D139A, D143A and E555A mutants significantly decreased hydrolytic activity, indicating their essential role. Of these mutants, D139A exclusively exhibited glycosynthase activity using alpha-GlcN-F (alpha-D glucosaminyl fluoride) and GlcN as substrates, to produce (GlcN)2. Using saturation mutagenesis at Asp(139), we obtained D139E as the best glycosynthase. Compared with the wild-type, the hydrolytic activity of D139E was significantly suppressed (<0.1%), and the F(-)-release activity also decreased (<3%). Therefore the glycosynthase activity of D139E was lower than that of glycosynthases created previously from other inverting GHs. Mutation at the nucleophilic water holder is a general strategy for creating an effective glycosynthase from inverting GHs. However, for GH9, where two acidic residues seem to share the catalytic base role, mutation of Asp(139) might inevitably reduce F(-)-release activity. PMID- 26621874 TI - Palmitate-induced impairment of glucose-stimulated insulin secretion precedes mitochondrial dysfunction in mouse pancreatic islets. AB - It has been well established that excessive levels of glucose and palmitate lower glucose-stimulated insulin secretion (GSIS) by pancreatic beta-cells. This beta cell 'glucolipotoxicity' is possibly mediated by mitochondrial dysfunction, but involvement of bioenergetic failure in the pathological mechanism is the subject of ongoing debate. We show in the present study that increased palmitate levels impair GSIS before altering mitochondrial function. We demonstrate that GSIS defects arise from increased insulin release under basal conditions in addition to decreased insulin secretion under glucose-stimulatory conditions. Real-time respiratory analysis of intact mouse pancreatic islets reveals that mitochondrial ATP synthesis is not involved in the mechanism by which basal insulin is elevated. Equally, mitochondrial lipid oxidation and production of reactive oxygen species (ROS) do not contribute to increased basal insulin secretion. Palmitate does not affect KCl-induced insulin release at a basal or stimulatory glucose level, but elevated basal insulin release is attenuated by palmitoleate and associates with increased intracellular calcium. These findings deepen our understanding of beta-cell glucolipotoxicity and reveal that palmitate-induced GSIS impairment is disconnected from mitochondrial dysfunction, a notion that is important when targeting beta-cells for the treatment of diabetes and when assessing islet function in human transplants. PMID- 26621873 TI - Autism-associated R451C mutation in neuroligin3 leads to activation of the unfolded protein response in a PC12 Tet-On inducible system. AB - Several forms of monogenic heritable autism spectrum disorders are associated with mutations in the neuroligin genes. The autism-linked substitution R451C in neuroligin3 induces local misfolding of its extracellular domain, causing partial retention in the ER (endoplasmic reticulum) of expressing cells. We have generated a PC12 Tet-On cell model system with inducible expression of wild-type or R451C neuroligin3 to investigate whether there is activation of the UPR (unfolded protein response) as a result of misfolded protein retention. As a positive control for protein misfolding, we also expressed the mutant G221R neuroligin3, which is known to be completely retained within the ER. Our data show that overexpression of either R451C or G221R mutant proteins leads to the activation of all three signalling branches of the UPR downstream of the stress sensors ATF6 (activating transcription factor 6), IRE1 (inositol-requiring enzyme 1) and PERK [PKR (dsRNA-dependent protein kinase)-like endoplasmic reticulum kinase]. Each branch displayed different activation profiles that partially correlated with the degree of misfolding caused by each mutation. We also show that up-regulation of BiP (immunoglobulin heavy-chain-binding protein) and CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous protein] was induced by both mutant proteins but not by wild-type neuroligin3, both in proliferative cells and cells differentiated to a neuron-like phenotype. Collectively, our data show that mutant R451C neuroligin3 activates the UPR in a novel cell model system, suggesting that this cellular response may have a role in monogenic forms of autism characterized by misfolding mutations. PMID- 26621876 TI - Human Reproduction Update: double digits and beyond. PMID- 26621875 TI - Emodin inhibits coxsackievirus B3 replication via multiple signalling cascades leading to suppression of translation. AB - CVB3 (coxsackievirus 3) is a primary causal agent of viral myocarditis. Emodin is a natural compound isolated from certain plant roots. In the present study, we found that emodin inhibited CVB3 replication in vitro and in mice, and now we report an unrecognized mechanism by which emodin inhibits CVB3 replication through suppression of viral protein translation via multiple pathways. On one hand, emodin treatment inhibited Akt/mTOR (mammalian target of rapamycin) signalling and activated 4EBP1 (eukaryotic initiation factor 4R-binding protein 1), leading to suppression of translation initiation of ribosomal protein L32 encoded by a 5'-TOP (terminal oligopyrimidine) mRNA. On the other hand, emodin treatment differentially regulated multiple signal cascades, including Akt/mTORC1/p70(S6K) (p70 S6 kinase), ERK1/2 (extracellular-signal-regulated kinase 1/2)/p90(RSK) (p90 ribosomal S6 kinase) and Ca(2+)/calmodulin, leading to activation of eEF2K (eukaryotic elongation factor 2 kinase) and subsequent inactivation of eEF2 (eukaryotic elongation factor 2), resulting in inhibition of CVB3 VP1 (viral protein 1) synthesis. These data imply that eEF2K is a major factor mediating cross-talk of different arms of signalling cascades in this signal network. This notion was verified by either overexpressing eEF2K or treating the cells with siRNAs or eEF2K inhibitor A484954. We showed further that the emodin-induced decrease in p70(S6K) phosphorylation plays a dominant positive role in activation of eEF2K and in turn in conferring the antiviral effect of emodin. This finding was further solidified by expressing constitutively active and dominant-negative Akt. Collectively, our data reveal that emodin inhibits viral replication through impairing translational machinery and suppression of viral translation elongation. PMID- 26621877 TI - Sex, the brain and hypertension: brain oestrogen receptors and high blood pressure risk factors. AB - Hypertension is a major contributor to worldwide morbidity and mortality rates related to cardiovascular disease. There are important sex differences in the onset and rate of hypertension in humans. Compared with age-matched men, premenopausal women are less likely to develop hypertension. However, after age 60, the incidence of hypertension increases in women and even surpasses that seen in older men. It is thought that changes in levels of circulating ovarian hormones as women age may be involved in the increase in hypertension in older women. One of the key mechanisms involved in the development of hypertension in both men and women is an increase in sympathetic nerve activity (SNA). Brain regions important for the regulation of SNA, such as the subfornical organ, the paraventricular nucleus and the rostral ventral lateral medulla, also express specific subtypes of oestrogen receptors. Each of these brain regions has also been implicated in mechanisms underlying risk factors for hypertension such as obesity, stress and inflammation. The present review brings together evidence that links actions of oestrogen at these receptors to modulate some of the common brain mechanisms involved in the ability of hypertensive risk factors to increase SNA and blood pressure. Understanding the mechanisms by which oestrogen acts at key sites in the brain for the regulation of SNA is important for the development of novel, sex-specific therapies for treating hypertension. PMID- 26621878 TI - Is it time to move beyond the "O" in early COPD? PMID- 26621879 TI - Response to pulmonary rehabilitation: toward personalised programmes? PMID- 26621880 TI - Foxp3+ cells are running the show in patients with surgically resected nonsmall cell lung cancer. PMID- 26621881 TI - In the name of ventilator-associated pneumonia prevention: lung microbiota blown away by colistin! PMID- 26621882 TI - Circulating free DNA, new dynamic marker in nonsmall cell lung cancer patients? PMID- 26621883 TI - Risk stratification of pulmonary embolism: clinical evaluation, biomarkers or both? PMID- 26621884 TI - Measuring the breathless brain: is real life too noisy? PMID- 26621885 TI - Ataxia telangiectasia: why should the ERS care? PMID- 26621886 TI - Remembering Philippe Leuenberger. PMID- 26621887 TI - Numbers needed to treat to prevent tuberculosis. PMID- 26621888 TI - Numbers needed to treat to prevent tuberculosis. PMID- 26621889 TI - Accelerating tuberculosis elimination in low-incidence settings: the role of genomics. PMID- 26621890 TI - Accelerating tuberculosis elimination in low-incidence settings: the role of genomics. PMID- 26621891 TI - Linezolid in drug-resistant tuberculosis: haste makes waste. PMID- 26621892 TI - Linezolid in drug-resistant tuberculosis: haste makes waste. PMID- 26621893 TI - Mediastinoscopy after negative endoscopic mediastinal nodal staging: can it be omitted? PMID- 26621894 TI - Mediastinoscopy after negative endoscopic mediastinal nodal staging: can it be omitted? PMID- 26621895 TI - Pulmonary arterial hypertension in patients treated with interferon. PMID- 26621896 TI - Pulmonary arterial hypertension in patients treated with interferon. PMID- 26621897 TI - "Pulmonary arterial hypertension in patients treated with interferon." Laurent Savale, Caroline Sattler, Sven Gunther, David Montani, Marie-Camille Chaumais, Swanny Perrin, Xavier Jais, Andrei Seferian, Roland Jovan, Sophie Bulifon, Florence Parent, Gerald Simonneau, Marc Humbert and Olivier Sitbon. Eur Respir J 2014; 44: 1627-1634. PMID- 26621898 TI - "GINA 2015: the latest iteration of a magnificent journey." Jean Bousquet and Marc Humbert. Eur Respir J 2015; 46: 579-582. PMID- 26621899 TI - "2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)." Nazzareno Galie, Marc Humbert, Jean-Luc Vachiery, Simon Gibbs, Irene Lang, Adam Torbicki, Gerald Simonneau, Andrew Peacock, Anton Vonk Noordegraaf, Maurice Beghetti, Ardeschir Ghofrani, Miguel Angel Gomez Sanchez, Georg Hansmann, Walter Klepetko, Patrizio Lancellotti, Marco Matucci, Theresa McDonagh, Luc A. Pierard, Pedro T. Trindade, Maurizio Zompatori and Marius Hoeper. Eur Respir J 2015; 46: 903-975. PMID- 26621901 TI - Spontaneous sternal fracture due to multiple myeloma requiring extensive surgical repair. AB - Spontaneous sternal fracture is a well-known complication of multiple myeloma due to osteolytic bone lesions. The possibility of a multiple myeloma should be thoroughly investigated in patients presenting with a spontaneous sternal fracture. This work up should go beyond protein electrophoresis alone as a monoclonal paraprotein is not always present. In some cases, the myeloma plasma cell clone produces only the free light chain (kappa or lambda) or may even be non-secretory. The underlying plasma cell dyscrasia is treated with chemotherapy and, if needed, local radiotherapy. However, for patients with a fracture causing persistent pain and physical discomfort, internal fixation may be additionally required. We present a case of a patient who presented with a displaced pathological sternal fracture. She was treated with chemotherapy, radiotherapy and an open reduction and internal fixation with a Locking Compression Plate (LCP). This technique offers a feasible option for rigid fixation of pathological fractures. PMID- 26621902 TI - Bilateral central toxic keratopathy after laser in situ keratomileusis. AB - One week after LASIK, our patient presented with bilateral haloes and reduced vision. Examination revealed the typical central toxic keratopathy triad: corneal thinning, hyperopic shift and a reduction in best corrected visual acuity to 6/12, which, after commencing high-dose topical steroids, improved 6 months later to 6/6. PMID- 26621903 TI - Serratia marcescens osteomyelitis in Cushing's disease. AB - We report a case of a 46-year-old man with fever, hypotension and arthralgias of the ankles and knees after brain surgery for a pituitary tumour causing Cushing's disease. Blood and urine cultures isolated Serratia marcescens; antibiotic susceptibility testing showed sensitivity to piperacillin-tazobactan and ciprofloxacin. Articular MRI showed inflammation and necrosis of both knees and ankles, and left hip and right elbow (compatible with osteomyelitis). Culture of an ankle abscess on the ankle joint was positive for Serratia marcescens. Bone scintigraphy confirmed osteomyelitic lesions. Medical treatment included antibiotics and strong opioid therapy for 14 weeks. The patient was discharged clinically improved maintaining ciprofloxacin for 24 additional weeks based on clinical and analytic recovery. PMID- 26621904 TI - Gliosarcoma with neuroaxis metastases. AB - Gliosarcomas are rare tumours of the central nervous system, with a well-known capacity for metastasis. When they metastasise, the dissemination occurs more frequently via the haematogenous route to extraneural sites. Metastasis-spread through the cerebrospinal fluid is extremely rare. We present the case of a 58 year-old man who underwent a gross total resection of a lesion in the left temporal lobe. The histological findings revealed a gliosarcoma and the patient received radiotherapy followed by chemotherapy. Seven months after surgery, while the patient remained neurologically intact, brain and spinal cord MRI revealed tumour recurrence and neuroaxis metastases through the traffic routes of the cerebrospinal fluid. The patient died 8 months after the diagnosis. A PubMed search regarding metastatic gliosarcoma up to June 2015 was also carried out. To the best of our knowledge, this is the first case report of gliosarcoma metastases to the brain and spinal cord leptomeninges. PMID- 26621905 TI - POEMS syndrome: complex factors contributing to a delayed diagnosis. AB - POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) syndrome is a rare paraneoplastic syndrome due to an underlying plasma cell disorder. The chronically evolving nature of this syndrome and diverse clinical manifestations make it a challenging diagnosis, especially in the early stages of the disease. We present a case that illustrates well how these confounding factors can delay recognition of the disorder. We describe the presentation of some of the classical symptoms, and discuss how investigations can be optimised in order to fit together the clinical picture. Recent advances in the understanding of nerve conduction studies and electromyography in POEMS may help improve the early identification of this disease. This is of great importance, as early recognition and the initiation of appropriate treatment can reduce morbidity and mortality in POEMS. PMID- 26621906 TI - Septic cavernous sinus thrombosis with infectious arteritis of the internal carotid artery. PMID- 26621907 TI - Dellen and corneal perforation after bilateral pterygium excision in a patient with no risk factors. AB - Corneal perforation associated with dellen is a rare but serious complication of a primary pterygium excision. In this case report, we describe a 60-year-old man who underwent a corneal perforation in the centre of corneal dellen in his right eye and corneal dellen in his left eye after the surgical treatment of a bilateral pterygium with a bare sclera technique without adjunctive therapy. He was successfully treated with lamellar keratoplasty in his right eye and a conservative approach in his left eye, consisting of the use of artificial tears, antibiotic ointment and a patch. The clinical evidence from this brief interventional case report indicates that topical lubricants are proper therapy for corneal dellen. However, if corneal perforation is observed, lamellar keratoplasty is a good option. PMID- 26621908 TI - Hepatitis B Virus (HBV) Core-Related Antigen During Nucleos(t)ide Analog Therapy Is Related to Intra-hepatic HBV Replication and Development of Hepatocellular Carcinoma. AB - BACKGROUND: Although nucleos(t)ide analog (NA) therapy effectively reduces the hepatitis B virus (HBV) DNA load in the serum of patients with chronic hepatitis B, it does not completely reduce the incidence of hepatocellular carcinoma (HCC). METHODS AND RESULTS: A total of 109 patients who had chronic hepatitis B and were receiving NA therapy were analyzed. Multivariate Cox regression analysis showed that age (>60 years had a hazard ratio [HR] of 2.66), FIB-4 index (an index of >2.1 had a HR of 2.57), and the presence of HBV core-related antigen (HBcrAg; HR, 3.53) during treatment were significantly associated with the development of HCC. The amount of HBV DNA and pregenomic RNA in liver were significantly higher in 16 HBcrAg-positive patients, compared with 12 HBcrAg-negative patients, suggesting active HBV replication in HBcrAg-positive livers. Hepatic gene expression profiling showed that HBV-promoting transcriptional factors, including HNF4alpha, PPARalpha, and LRH1, were upregulated in HBcrAg-positive livers. HepAD38 cells overexpressing LRH1 increased HBV replication, characterized by higher HBV DNA and pregenomic RNA levels, during long-term exposure to entecavir. Conversely, overexpression of precore/core in HepG2 cells increased levels of these transcriptional factors. Metformin efficiently repressed HBV replication in primary human hepatocytes. CONCLUSIONS: Modulating HBV transcriptional factors by metformin in combination with NA therapy would potentiate anti-HBV activity and reduce the incidence of HCC in HBcrAg-positive patients. PMID- 26621910 TI - Yersinia enterocolitica Affects Intestinal Barrier Function in the Colon. AB - Infection with Yersinia enterocolitica causes acute diarrhea in early childhood. A mouse infection model presents new findings on pathological mechanisms in the colon. Symptoms involve diarrhea with watery feces and weight loss that have their functional correlates in decreased transepithelial electrical resistance and increased fluorescein permeability. Y. enterocolitica was present within the murine mucosa of both ileum and colon. Here, the bacterial insult was of focal nature and led to changes in tight junction protein expression and architecture. These findings are in concordance with observations from former cell culture studies and suggest a leak flux mechanism of diarrhea. PMID- 26621909 TI - Persistently Elevated C-Reactive Protein Level in the First Year of Antiretroviral Therapy, Despite Virologic Suppression, Is Associated With HIV Disease Progression in Resource-Constrained Settings. AB - A case-cohort analysis of human immunodeficiency virus (HIV)-infected individuals receiving antiretroviral therapy (ART) was performed within a multicountry randomized trial (PEARLS) to assess the prevalence of persistently elevated C reactive protein (CRP) levels, based on serial measurements of CRP levels, and their association with HIV clinical failure. A persistently elevated CRP level in plasma (defined as >= 5 mg/L at both baseline and 24 weeks after ART initiation) was observed in 50 of 205 individuals (24%). A persistently elevated CRP level but not an elevated CRP level only at a single time point was independently associated with increased clinical failure, compared with a persistently low CRP level, despite achievement of virologic suppression. Serial monitoring of CRP levels could identify individuals who are at highest risk of HIV progression and may benefit from future adjunct antiinflammatory therapies. PMID- 26621912 TI - Uropathogenic Escherichia coli Epigenetically Manipulate Host Cell Death Pathways. AB - Urinary tract infections caused by uropathogenic Escherichia coli (UPEC) pathovars belong to the most frequent infections in human. It is well established that UPEC can subvert innate immune responses, but the role of UPEC in interfering with host cell death pathways is not known. Here, we show that UPEC abrogates activation of the host cell prosurvival protein kinase B signaling pathway, which results in the activation of mammalian forkhead box O (FOXO) transcription factors. Although FOXOs were localized in the nucleus and showed increased DNA-binding activity, no change in the expression levels of FOXO target genes were observed. UPEC can suppress BIM expression induced by LY249002, which results in attenuation of caspase 3 activation and blockage of apoptosis. Mechanistically, BIM expression appears to be epigenetically silenced by a decrease in histone 4 acetylation at the BIM promoter site. Taken together, these results suggest that UPEC can epigenetically silence BIM expression, a molecular switch that prevents apoptosis. PMID- 26621911 TI - Association of HIV, Hepatitis C Virus, and Liver Fibrosis Severity With the Enhanced Liver Fibrosis Score. AB - BACKGROUND: Liver disease is common during human immunodeficiency virus (HIV) infection, but valid serum fibrosis markers are lacking. We hypothesize that HIV monoinfection and HIV/hepatitis C virus (HCV) coinfection is associated with an enhanced liver fibrosis (ELF) score higher than that for uninfected controls and examine whether this association is affected by factors other than liver injury. METHODS: The association of HIV and HIV/HCV coinfection with the ELF score was evaluated using multivariable regression after controlling for transient elastography-measured liver stiffness and traditional and HIV-related factors in a cross-sectional analysis of 297 women. RESULTS: HIV/HCV-coinfected and HIV monoinfected women had higher median ELF scores than controls (9.6, 8.5, and 8.2, respectively). After adjustment for demographic, behavioral, and metabolic factors and for inflammatory markers, HIV/HCV coinfection remained associated with a 9% higher ELF score (95% confidence interval [CI], 5%-13%), while the association of HIV monoinfection was substantially attenuated (1% higher ELF score; 95% CI, -2% to 4%). After further adjustment for liver stiffness, HIV/HCV coinfection remained associated with 6% higher levels (95% CI, 3%-10%). In HIV/HCV-coinfected and HIV-monoinfected women, higher liver stiffness values were associated with higher ELF scores, as were older age and a nadir CD4(+) T-cell count of <200 cells/mm(3). CONCLUSIONS: Our findings suggest that the ELF score can be used to assess liver fibrosis severity in HIV-infected women. However, higher ELF scores may reflect extrahepatic fibrosis in HIV-infected patients with a history of severe immunosuppression or advanced age. PMID- 26621914 TI - Mapping search terms to review goals is essential. PMID- 26621913 TI - Automated physics-based design of synthetic riboswitches from diverse RNA aptamers. AB - Riboswitches are shape-changing regulatory RNAs that bind chemicals and regulate gene expression, directly coupling sensing to cellular actuation. However, it remains unclear how their sequence controls the physics of riboswitch switching and activation, particularly when changing the ligand-binding aptamer domain. We report the development of a statistical thermodynamic model that predicts the sequence-structure-function relationship for translation-regulating riboswitches that activate gene expression, characterized inside cells and within cell-free transcription-translation assays. Using the model, we carried out automated computational design of 62 synthetic riboswitches that used six different RNA aptamers to sense diverse chemicals (theophylline, tetramethylrosamine, fluoride, dopamine, thyroxine, 2,4-dinitrotoluene) and activated gene expression by up to 383-fold. The model explains how aptamer structure, ligand affinity, switching free energy and macromolecular crowding collectively control riboswitch activation. Our model-based approach for engineering riboswitches quantitatively confirms several physical mechanisms governing ligand-induced RNA shape-change and enables the development of cell-free and bacterial sensors for diverse applications. PMID- 26621915 TI - Patient safety room of horrors: a novel method to assess medical students and entering residents' ability to identify hazards of hospitalisation. AB - BACKGROUND: Patient safety curricula in undergraduate medical education (UME) are often didactic format with little focus on skills training. Despite recent focus on safety, practical training in residency education is also lacking. Assessments of safety skills in UME and graduate medical education (GME) are generally knowledge, and not application-focused. We aimed to develop and pilot a safety focused simulation with medical students and interns to assess knowledge regarding hazards of hospitalisation. METHODS: A simulation demonstrating common hospital-based safety threats was designed. A case scenario was created including salient patient information and simulated safety threats such as the use of upper extremity restraints and medication errors. After entering the room and reviewing the mock chart, learners were timed and asked to identify and document as many safety hazards as possible. Learner satisfaction was assessed using constructed response evaluation. Descriptive statistics, including per cent correct and mean correct hazards, were performed. RESULTS: All 86 third-year medical students completed the encounter. Some hazards were identified by a majority of students (fall risk, 83% of students) while others were rarely identified (absence of deep venous thrombosis prophylaxis, 13% of students). Only 5% of students correctly identified pressure ulcer risk. 128 of 131 interns representing 49 medical schools participated in the GME implementation. Incoming interns were able to identify a mean of 5.1 hazards out of the 9 displayed (SD 1.4) with 40% identifying restraints as a hazard, and 20% identifying the inappropriate urinary catheter as a hazard. CONCLUSIONS: A simulation showcasing safety hazards was a feasible and effective way to introduce trainees to safety-focused content. Both students and interns had difficulty identifying common hazards of hospitalisation. Despite poor performance, learners appreciated the interactive experience and its clinical utility. PMID- 26621916 TI - Addressing basic resource needs to improve primary care quality: a community collaboration programme. AB - BACKGROUND: Unmet basic resource needs, such as difficulty affording healthcare, medications, food and housing, may contribute to worse healthcare quality indicators, but interventions are hampered by lack of specific knowledge regarding the distribution of unmet basic resource needs and their association with priority clinical conditions and health service use patterns. METHODS: Cross sectional study of primary care patients in two urban academic practices from 1 October 2013 to 30 April 2014. Patients were screened for unmet needs and enrolled in a programme to link them with community resources. Key measures included patient report of unmet basic resource needs, clinical conditions prioritised by quality improvement programmes (hypertension, diabetes and depression), and health service use patterns such as frequent emergency department (ED) visits (>2 in the preceding year) and frequent clinic 'no-shows' (>1 in the preceding year). RESULTS: 416 patients with unmet needs were included, and compared with 2750 patients who did not report needs. The most common types of needs reported were: difficulties affording healthcare (46.5%), food (40.1%) and utilities (36.3%). Patients who reported unmet needs were more likely to have depression (17.8% vs 9.5%, p<0.0001), diabetes (32.7% vs 20.4%, p<0.0001), hypertension (54.3% vs 46.3%, p=0.002), be frequent ED users (11.3% vs 5.4%, p<0.0001), and have frequent 'no-shows' to clinic (21.6% vs 11.9%, p<0.0001). CONCLUSIONS: Difficulty affording healthcare and food are particularly common needs among patients with priority conditions. Strategies to identify and address unmet needs as part of routine care may be an important way to improve healthcare quality. PMID- 26621917 TI - Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an IRE1alpha-dependent manner. AB - Nonalcoholic steatohepatitis (NASH) is a lipotoxic disease wherein activation of endoplasmic reticulum (ER) stress response and macrophage-mediated hepatic inflammation are key pathogenic features. However, the lipid mediators linking these two observations remain elusive. We postulated that ER stress-regulated release of pro-inflammatory extracellular vesicles (EVs) from lipotoxic hepatocytes may be this link. EVs were isolated from cell culture supernatants of hepatocytes treated with palmitate (PA) to induce lipotoxic ER stress, characterized by immunofluorescence, Western blotting, electron microscopy, and nanoparticle tracking analysis. Sphingolipids were measured by tandem mass spectrometry. EVs were employed in macrophage chemotaxis assays. PA induced significant EV release. Because PA activates ER stress, we used KO hepatocytes to demonstrate that PA-induced EV release was mediated by inositol requiring enzyme 1alpha (IRE1alpha)/X-box binding protein-1. PA-induced EVs were enriched in C16:0 ceramide in an IRE1alpha-dependent manner, and activated macrophage chemotaxis via formation of sphingosine-1-phosphate (S1P) from C16:0 ceramide. This chemotaxis was blocked by sphingosine kinase inhibitors and S1P receptor inhibitors. Lastly, elevated circulating EVs in experimental and human NASH demonstrated increased C16:0 ceramide. PA induces C16:0 ceramide-enriched EV release in an IRE1alpha-dependent manner. The ceramide metabolite, S1P, activates macrophage chemotaxis, a potential mechanism for the recruitment of macrophages to the liver under lipotoxic conditions. PMID- 26621919 TI - Morphokinetics of cloned mouse embryos treated with epigenetic drugs and blastocyst prediction. AB - Time-lapse monitoring of somatic cell nuclear transfer (SCNT) embryos may help to predict developmental success and increase birth and embryonic stem cells (ESC) derivation rates. Here, the development of ICSI fertilized embryos and of SCNT embryos, non-treated or treated with either psammaplin A (PsA) or vitamin C (VitC), was monitored, and the ESC derivation rates from the resulting blastocysts were determined. Blastocyst rates were similar among PsA-treated and VitC-treated SCNT embryos and ICSI embryos, but lower for non-treated SCNT embryos. ESC derivation rates were higher in treated SCNT embryos than in non treated or ICSI embryos. Time-lapse microscopy analysis showed that non-treated SCNT embryos had a delayed development from the second division until compaction, lower number of blastomeres at compaction and longer compaction and cavitation durations compared with ICSI ones. Treatment of SCNT embryos with PsA further increased this delay whereas treatment with VitC slightly reduced it, suggesting that both treatments act through different mechanisms, not necessarily related to their epigenetic effects. Despite these differences, the time of completion of the third division, alone or combined with the duration of compaction and/or the presence of fragmentation, had a strong predictive value for blastocyst formation in all groups. In contrast, we failed to predict ESC derivation success from embryo morphokinetics. Time-lapse technology allows the selection of SCNT embryos with higher developmental potential and could help to increase cloning outcomes. Nonetheless, further studies are needed to find reliable markers for full-term development and ESC derivation success. PMID- 26621918 TI - Association of NMT2 with the acyl-CoA carrier ACBD6 protects the N myristoyltransferase reaction from palmitoyl-CoA. AB - The covalent attachment of a 14-carbon aliphatic tail on a glycine residue of nascent translated peptide chains is catalyzed in human cells by two N myristoyltransferase (NMT) enzymes using the rare myristoyl-CoA (C(14)-CoA) molecule as fatty acid donor. Although, NMT enzymes can only transfer a myristate group, they lack specificity for C(14)-CoA and can also bind the far more abundant palmitoyl-CoA (C(16)-CoA) molecule. We determined that the acyl-CoA binding protein, acyl-CoA binding domain (ACBD)6, stimulated the NMT reaction of NMT2. This stimulatory effect required interaction between ACBD6 and NMT2, and was enhanced by binding of ACBD6 to its ligand, C(18:2)-CoA. ACBD6 also interacted with the second human NMT enzyme, NMT1. The presence of ACBD6 prevented competition of the NMT reaction by C(16)-CoA. Mutants of ACBD6 that were either deficient in ligand binding to the N-terminal ACBD or unable to interact with NMT2 did not stimulate activity of NMT2, nor could they protect the enzyme from utilizing the competitor C(16)-CoA. These results indicate that ACBD6 can locally sequester C(16)-CoA and prevent its access to the enzyme binding site via interaction with NMT2. Thus, the ligand binding properties of the NMT/ACBD6 complex can explain how the NMT reaction can proceed in the presence of the very abundant competitive substrate, C(16)-CoA. PMID- 26621920 TI - Postnatal pituitary and follicular activation: a revisited hypothesis in a sheep model. AB - The importance of postnatal pituitary activation as regards female reproductive development is not yet understood. By taking advantage of the experimental model developed in a previous study, i.e. ewe lambs expressing markedly different ovarian phenotypes at 50 days of age, we designed this study to determine whether differences found in ovarian status during the early prepubertal period are due to different patterns of postnatal pituitary activation, and to assess whether these differences have long lasting effects on subsequent reproductive performance. Results showed that ewe lambs with high antral follicle count (AFC) at 50 days of age had significantly lower plasma FSH concentrations and higher anti-Mullerian hormone (AMH) concentrations during the first 9 weeks of age compared with low AFC ewe lambs (P<0.0001). With a longitudinal experiment we showed that a high AFC in the early prepubertal period is associated with consistently higher AMH concentrations and numbers of antral follicles up to the postpubertal period, and with higher pregnancy rates in the first breeding season. In addition, the effect of age in decreasing AMH concentrations was more marked in the low AFC group. Results of the present study demonstrate that ewe lambs undergo different patterns of postnatal pituitary activation. A high AFC at 50 days of age indicates an advanced phase of ovarian maturation, which was accompanied by constantly higher AMH concentrations up to the postpubertal period, a greater ovarian response to FSH stimulation and by higher pregnancy rates at first mating, as compared with the low AFC group. PMID- 26621921 TI - Single-centre experience of mitral valve surgery via right lateral mini thoracotomy in octogenarians. AB - OBJECTIVES: According to demographic changes in the industrialized world, the average age of patients referred to cardiac surgery is increasing. These patients typically display numerous comorbidities, associated with increased perioperative risk. Therefore, the indication for a catheter-based therapy is progressively extended, including interventions on the mitral valve (MV). In this context, we evaluated a contemporary series of octogenarians undergoing minimally invasive MV surgery at our institution using right lateral minithoracotomy to elucidate the preoperative risk profile and the postoperative course in this particular cohort. METHODS: Between October 2009 and October 2014, 34 patients aged 80 years and older (82.5 +/- 2.0) undergoing minimally invasive MV surgery were identified with a subgroup of 15 patients (44.1%) receiving concomitant surgery on the tricuspid valve (TV). We analysed the preoperative profile, perioperative course and functional outcome. RESULTS: Preoperative comorbidities included insulin dependent diabetes mellitus (17.6%), COPD (17.6%), active endocarditis (2.9%) and previous neurological events (2.9%). The mean left ventricular ejection fraction was 59.7 +/- 6.9%. Mean European System for Cardiac Outcome Risk Evaluation II was 5.2 +/- 5.3%. The repair rate of all treated MVs and TVs in isolated and combined procedures was 81.6% (73.5% for MV and 100.0% for TV surgery). Postoperatively, 4 patients (11.8%) required new-onset intermittent haemodialysis. Prolonged ventilation (>12 h) was necessary in 9 patients (26.5%). The 30-day mortality rate was 5.9%. CONCLUSIONS: Minimally invasive right lateral MV surgery in octogenarians results in favourable outcomes. Therefore, MV surgery represents a valid option in this cohort, providing established and durable concepts of valve reconstruction. PMID- 26621924 TI - A Focus on Quality: Editorial Impact. PMID- 26621922 TI - Reconstruction of massive post-sternotomy defects with allogeneic bone graft: four-year results and experience using the method. AB - OBJECTIVES: Deep sternal wound infection poses a serious problem in cardiac surgery, with an up to 40% risk of mortality. Massive loss of sternum bone tissue and adjacent ribs results in major chest wall instability causing respiratory insufficiency and defects of soft tissue healing. Proposals for managing the situation have been published but the complexity of the issue precludes unequivocal resolution. Capitalizing on orthopaedic experience, we used allogeneic bone graft of sternum as a viable option. METHODS: We performed the transplantation of allogeneic bone graft in 10 patients. In 9 cases, an allograft of sternum was used and in 1 case an allograft of calva bone. After the primary cardiac surgery, a massive post-sternotomy defect of the chest wall had developed in all 10 patients. Vacuum wound drainage was applied in the treatment of all patients. To stabilize the transverse, titanium plates were used. Bone allograft was prepared by the official Tissue Centre. Crushed allogeneic spongy bone was applied to reinforce the line of contact of the graft and the edges of residual skeleton. In 9 cases, the soft tissue was closed by direct suture of mobilized pectoral flaps. In 1 case, V-Y transposition of pectoral flap was performed. RESULTS: In 6 cases, healing of the reconstructed chest wall occurred without further complications. In 3 cases, additional re-suture of the soft tissues and skin in the lower pole of the wound was necessary. Excellent chest wall stability along with the adjustment of respiratory insufficiency and good cosmetic effect was achieved in all cases. In 1 case, severe concomitant complications and no healing of the wound resulted in death within 6 months after the reconstruction. Median follow-up of all patients in the series was 14.1 months (1-36 months). In 4 patients, scintigraphy of the chest wall was performed. CONCLUSIONS: Our existing results show that allogeneic bone graft transplantation is a promising and easily applied method in the management of serious tissue loss in sternal dehiscence with favourable functional and cosmetic effects. The relatively small number of patients with such severe healing complications of sternotomy however puts critical limits to a more detailed comparison with other practices and evaluation of long-term results. PMID- 26621925 TI - Letter to the Editor on "Myringotomy and Ventilation Tube Insertion with Endoscopic or Microscopic Technique in Adults: A Pilot Study". PMID- 26621926 TI - Re: "Myringotomy and Ventilation Tube Insertion with Endoscopic or Microscopic Technique in Adults". PMID- 26621927 TI - Clinically Significant Rhinosinusitis Can Be Asymptomatic. PMID- 26621928 TI - Response to "Clinically Significant Rhinosinusitis Can Be Asymptomatic". PMID- 26621929 TI - Letter to Editor on "Factors Associated with Hypertrophy of the Lingual Tonsils". PMID- 26621930 TI - Response to Commentary on "Factors Associated with Hypertrophy of the Lingual Tonsils". PMID- 26621931 TI - Critical Points Regarding Hypocalcemia after Total Thyroidectomy. PMID- 26621932 TI - Response to "Critical Points Regarding Hypocalcemia after Total Thyroidectomy". PMID- 26621933 TI - Corrigendum. PMID- 26621934 TI - Smoke and mirrors. PMID- 26621935 TI - Dermatology: a specialty in crisis. PMID- 26621936 TI - Consultant perception of general internal medicine: a survey of consultant physicians. AB - The Future Hospital Commission has highlighted the need for increased general medical skills in the medical workforce in order to meet the increasing demands on the NHS in terms of patients with increasing age, frailty and complex comorbidities. However there continues to be a lack of clarity around the concept of generalism and general internal medicine (GIM), with differing views on the physician's role in GIM. This survey sought to explore further the roles in which current physicians perceive they are practising GIM as well as views on training in GIM. The survey highlights three key points: (i) that consultant perception and practice of GIM continues to vary dependent on physician specialty; (ii) that the practice of GIM is not limited to the front door but includes the management of patients under the care of a specialty team with general medical needs, be that in an inpatient, outpatient or acute care setting; and (iii) that training in GIM needs to reflect this variation in roles and practice. PMID- 26621937 TI - What makes a good clinical app? Introducing the RCP Health Informatics Unit checklist. AB - Doctors increasingly rely on medical apps running on smart phones or tablet computers to support their work. However, these apps vary hugely in the quality of their data input screens, internal data processing, the methods used to handle sensitive patient data and how they communicate their output to the user. Inspired by Donabedian's approach to assessing quality and the principles of good user interface design, the Royal College of Physicians' Health Informatics Unit has developed and piloted an 18-item checklist to help clinicians assess the structure, functions and impact of medical apps. Use of this checklist should help clinicians to feel more confident about using medical apps themselves, about recommending them to their staff or prescribing them for patients. PMID- 26621938 TI - Management of high-risk non-ST elevation myocardial infarction in the UK: need for alternative models of care to reduce length of stay and admission to angiography times. AB - The roll out of the primary percutaneous coronary intervention pathway as the default treatment for patients with ST elevation myocardial infarction (STEMI) across the NHS has led to a paradigm shift in the model of care resulting in a significant improvement in mortality. In comparison, a similar care plan does not exist for non-ST elevation acute coronary syndrome (NSTE-ACS) despite the fact that patients presenting with high-risk non-STEMI carry a similar if not higher mortality at six months in comparison to STEMI. In this article we focus on the contemporary management of NSTE-ACS in the NHS and also look at some of the dedicated pathways already developed and implemented successfully in expediting treatment and decreasing hospital stay without compromising the safety of patients. PMID- 26621939 TI - Improvements in the management of neutropenic sepsis: lessons learned from a district general hospital. AB - Neutropenic sepsis is a life-threatening condition with mortality rates reported to range between 2 and 21% in adults. It can occur following chemotherapy treatment, due to disease (such as haematological conditions affecting the bone marrow) and in patients on disease-modifying agents (such as patients receiving methotrexate for rheumatoid arthritis). Appropriate emergency treatment is essential and achieving intravenous antibiotic door-to-needle time of less than 1 hour is a key target. Shortfalls in the management of patients presenting to teams with limited expertise in this area were identified in the National Confidential Enquiry into Patient Outcome and Death report in 2008, leading to recommendations including the need for an acute oncology service (AOS) at all hospitals with either an emergency department or medical admissions unit. Practice at Weston General Hospital has been audited at three time points since 2008 (in 2008, 2011 and 2013-14) during which there have been several service developments relevant to the management of neutropenic sepsis, including the introduction of an AOS in June 2013. The percentage of patients in which intravenous antibiotic 1-hour door-to-needle time was achieved has improved from 14% (2008) to 31% (2011) to 79% (2013-14) and neutropenic sepsis mortality has decreased from 39% (2008) to 14% (2011) to 0% (2013-14). PMID- 26621940 TI - The Royal College of Physicians' Fallsafe care bundles applied trustwide: the Northumbria experience 2013. AB - The Royal College of Physicians' FallSafe care bundles constitute measures of good practice, some of which are recommended for all patients, some are additional measures for older and more vulnerable patients admitted to hospital, and there is another bundle for after an inpatient fall, to reduce the number of inpatient falls. In 2013 a dedicated healthcare assistant, trained by the falls team, started a monthly spot audit looking at preventative measures, on all inpatients on every ward of the trust. Monthly results were fed back to the ward managers, ward falls liaison nurses, doctors, therapists and pharmacy staff on each ward, to discuss at the monthly ward governance meetings. Training and advice on specific aspects of falls prevention were provided by falls nurse practitioners. In total, 9,679 patient episodes were recorded over the year. Compliance with the measures recommended by the FallSafe care bundles has improved following regular spot audit and training. This has led to an overall reduction in the number of inpatient falls. Despite this however, in the real world of changing patient demographics, ward closures and the increasing use of ambulatory care, the number of falls/1,000 bed days has increased. PMID- 26621941 TI - Management of bile acid malabsorption using low-fat dietary interventions: a useful strategy applicable to some patients with diarrhoea-predominant irritable bowel syndrome? AB - This study evaluates the efficacy of low-fat dietary interventions in the management of gastrointestinal (GI) symptoms due to bile acid malabsorption. In total, 40 patients with GI symptoms and a 7-day (75)selenium homocholic acid taurine (SeHCAT) scan result of <20%, were prospectively recruited and then advised regarding a low-fat dietary intervention. Before and after dietary intervention, patients rated their GI symptoms using a 10-point numerical scale, and recorded their intake in 7-day dietary diaries. After dietary intervention, the median scores for all GI symptoms decreased, with a significant reduction for urgency, bloating, lack of control, bowel frequency (p >=: 0.01). Mean dietary fat intake reduced to 42 g fat after intervention (p >=: 0.01). Low-fat dietary interventions in patients with a SeHCAT scan result of <20% leads to clinically important improvement in GI symptoms and should be widely used. PMID- 26621942 TI - Sticks and stones: investigating rude, dismissive and aggressive communication between doctors. AB - Destructive communication is a problem within the NHS; however previous research has focused on bullying. Rude, dismissive and aggressive (RDA) communication between doctors is a more widespread problem and underinvestigated. We conducted a mixed method study combining a survey and focus groups to describe the extent of RDA communication between doctors, its context and subsequent impact. In total, 606 doctors were surveyed across three teaching hospitals in England. Two structured focus groups were held with doctors at one teaching hospital. 31% of doctors described being subject to RDA communication multiple times per week or more often, with junior and registrar doctors affected twice as often as consultants. Rudeness was more commonly experienced from specific specialties: radiology, general surgery, neurosurgery and cardiology. 40% of respondents described that RDA moderately or severely affected their working day. The context for RDA communication was described in five themes: workload, lack of support, patient safety, hierarchy and culture. Impact of RDA communication was described as personal, including emotional distress and substance abuse, and professional, including demotivation. RDA communication between doctors is a widespread and damaging behaviour, occurring in contexts common in healthcare. Recognition of the impact on doctors and potentially patients is key to change. PMID- 26621943 TI - What is the quality of smoking cessation advice in guidelines of tobacco-related diseases? AB - Smoking is a major risk factor for a range of diseases, and quitting smoking provides considerable benefits to health. It therefore follows that clinical guidelines on disease management, particularly for diseases caused by smoking, should include smoking cessation. The aim of this study was to determine the extent to which this is the case. We conducted a systematic review investigating clinical guidelines and recommendations issued by UK national or European transnational medical speciality associations and societies issued between 2000 and 2012 on a range of diseases caused by smoking. We then investigated whether selected guidelines contained reference to smoking cessation and smoking cessation advice. Although the extent to which smoking and smoking cessation was mentioned in the guidelines varied between diseases, only 60% of guidelines identified recognised that smoking is a risk factor for the development of the disease and 40% recommended smoking cessation. Only 19% of guidelines provided detailed information on how to deliver smoking cessation support. Smoking cessation is not comprehensively addressed in current UK and transnational European clinical practice guidelines and recommendations. PMID- 26621944 TI - Drug therapies to delay the progression of chronic kidney disease. AB - Chronic kidney disease (CKD) is associated with significant morbidity and mortality, impacted not alone by progression to end-stage kidney disease, but also by the high associated incidence of cardiovascular events and related mortality. Despite our current understanding of the pathogenesis of CKD and the treatments available, the reported incidence of CKD continues to rise worldwide, and is often referred to as the silent public healthcare epidemic. The significant cost to patient wellbeing and to the economy of managing the later stages of CKD have prompted efforts to develop interventions to delay the development and progression of this syndrome. In this article, we review established and novel agents that may aid in delaying the progression of CKD and improve patient outcomes. PMID- 26621945 TI - Faints, fits and funny turns for the physician. AB - The diagnosis and management of the dizzy patient presents the physician with significant challenges. Dizziness and imbalance are common complaints among the general population, affecting around one-third of people over the age of 65 years, and can result from a range of causes spanning many medical disciplines. The ability to take a thorough, accurate history with a logical framework for formulating a differential diagnosis is essential given the many ways that symptoms of dizziness can present. An understanding of the key features of the vestibular examination, and consideration of other pathologies including neurological and cardiac, are important. This conference was held with the aim of demystifying the dizzy patient by providing physicians with a practical approach to the assessment and management of dizziness, imbalance and 'funny turns'. PMID- 26621946 TI - An IVF pregnancy, a neck lump and shortness of breath. AB - We present the case of a young primigravida, conceived with in vitro fertilisation, referred with unilateral neck swelling and pleuritic chest pain. Our case highlights the potential complexity of the management of the complications of assisted conception techniques. The discussion explores important considerations in the management of such patients. PMID- 26621947 TI - Sexual health issues in adolescents and young adults. PMID- 26621948 TI - Tackling emerging infections: clinical and public health lessons from the West African Ebola virus disease outbreak, 2014-2015. PMID- 26621949 TI - UK medical selection: lottery or meritocracy? PMID- 26621950 TI - Conservative care of the patient with end-stage renal disease. AB - 'Conservative care' is the management of end-stage kidney disease without dialysis, ie a palliative approach. It is now well established as the fourth treatment option alongside haemodialysis, peritoneal dialysis and transplantation, in the majority of UK renal centres. PMID- 26621951 TI - HIV and the kidney in the acute medical unit. AB - Acute kidney injury (AKI) is encountered commonly in HIV-positive patients admitted to the acute medical unit. The spectrum of AKI has changed in the era of combination anti-retroviral therapy, and now includes adverse effects of commonly used anti-retroviral drugs in addition to traditional precipitants such as severe sepsis or exposure to nephrotoxic antimicrobials. An accurate diagnosis requires careful integration of clinical data including volume status, history of potentially nephrotoxic exposures and consideration of immuno-virological status. This article provides an overview of common causes of AKI in HIV and presents a framework by which the acute care physician may approach the finding of an elevated serum creatinine in a patient with HIV. PMID- 26621952 TI - Isolated microscopic haematuria of glomerular origin: clinical significance and diagnosis in the 21st century. AB - Isolated microscopic, or non-visible, haematuria of glomerular origin was previously regarded a benign finding, but it is now known that, even in the absence of proteinuria, hypertension or renal impairment at presentation, haematuria is associated with increased risk of kidney failure in the long term. The most common causes of isolated microscopic haematuria among children and young adults are IgA nephropathy, Alport syndrome (AS), and thin basement membrane nephropathy (TBMN). AS, which is usually inherited as an X-linked or autosomal recessive trait, and TBMN, which is usually autosomal dominant, are caused by mutations in the genes encoding type-IV collagen, an abundant component of the glomerular basement membrane. A detailed family history with screening of at-risk relatives is important, allowing prompt diagnosis of affected relatives and helping determine the mode of transmission. As costs fall and availability increases, genetic testing is increasingly being used in clinical practice to provide diagnostic and predictive information for patients and their families. PMID- 26621953 TI - Acute kidney injury. AB - Acute kidney injury (AKI) - an abrupt deterioration in renal function - causes a rise in serum creatinine (SCr) or fall in urine output. It is common, occurring in up to 20% of hospital admissions. Importantly, even small rises in SCr are associated with increased risk of death and longer hospital stays. A 2009 National Confidential Enquiry into Patient Outcome and Death report found that a proportion of AKI in secondary care was avoidable. In addition, management of established AKI was 'good' less than half the time. In practice, AKI represents a heterogeneous group of conditions, encompassing impairments in both kidney structure and function. Delivering disease-specific treatment early in the course of AKI may improve outcomes. The provision of best-practice care for all will rely on a better understanding of risk, and frameworks of care that can be applied across a diverse patient group. PMID- 26621954 TI - The health impacts of dietary sodium and a low-salt diet. AB - High salt intake is now endemic worldwide. It contributes to the generation and maintenance of high blood pressure, which is now the biggest risk factor for global disease. There is now compelling evidence to support salt reduction in hypertensives and a substantial body of evidence to support salt reduction in the general population to reduce risk of death from cardiovascular disease. In specific diseases such as heart failure and chronic kidney disease, guidelines support the World Health Organization target for reduced salt intake at 5 g daily. Achieving a diet that is lower in salt has challenges, but is more likely to be achieved through salt reduction strategies particularly focused on processed food and through educational programs. To be effective, these interventions require collaboration between industry, health agencies and governments. PMID- 26621956 TI - Pneumonitis and pulmonary haemorrhage after acute myocardial infarction. AB - A 55-year-old man presented with acute ST-elevation myocardial infarction. He received rescue angioplasty with one drug eluting stent. He developed marked breathlessness and haemoptysis two days later. Investigations led to the diagnosis of pulmonary haemorrhage, possibly from pneumonitis caused by ticagrelor. He was successfully managed with high-dose steroids and ticagrelor was replaced with clopidogrel. On stopping the steroids a month later, mild haemoptysis recurred and this was managed conservatively. Pneumonitis and pulmonary haemorrhage is rarely reported with acute myocardial infarction, but poses serious challenge to the patient and the clinician. Diagnosis may be delayed as breathlessness can occur due to myriad causes after myocardial infarction. Interrupting dual anti-platelet therapy after angioplasty could lead to devastating stent thrombosis. PMID- 26621957 TI - Lesson of the month 2: Non-uraemic calciphylaxis - an unexpected differential diagnosis for a necrotic ulcer. AB - Calciphylaxis is an uncommon cause of skin necrosis seen almost exclusively in patients with end-stage renal disease. We present an unexpected diagnosis of calciphylaxis in a patient with normal renal and parathyroid function. The patient presented with a month-long history of painful bilateral necrotic leg ulcers, resistant to conventional treatment. She developed severe sepsis requiring admission to the intensive care unit, and despite escalation of antibiotic therapy and meticulous wound care management, eventually died. A biopsy confirmed a diagnosis of calciphylaxis. We suspect that warfarin therapy may have contributed to the development of this condition. Through this case we aim to raise awareness of calciphylaxis as a differential diagnosis of non healing necrotic skin ulcers, especially in patients with known risk factors including established warfarin therapy. PMID- 26621958 TI - The Mount Fuji sign. PMID- 26621959 TI - From Darzi to Keogh: are doctors under 'report fatigue'. PMID- 26621960 TI - Upper gastrointestinal cancer misses: could we do better? PMID- 26621961 TI - Venous thromboembolism: a role for weight-stratified thromboprophylaxis? PMID- 26621962 TI - The limited role of cranial computerised tomography in the assessment of a medical patient. PMID- 26621963 TI - Facial Skin Smoothness as an Indicator of Perceived Trustworthiness and Related Traits. AB - Facial texture has typically been studied as an umbrella phenomenon comprising several properties, such as skin tone and smoothness. Furthermore, texture has normally been addressed within complex models including also structural and dynamic properties and focusing on the extraction of perceptual dimensions from large numbers of physical and personality traits. It is yet unclear how individual facial textural properties affect the perception of individual physical and personality traits. We took a step in this direction by showing that the manipulation of a single facial textural property (skin smoothness) affected explicit evaluations of trustworthiness, competence, attractiveness, and health independently and in combination. Within the context of skin smoothness, our data also suggest a direct perceptual route for physical and an indirect perceptual route for personality traits. PMID- 26621964 TI - Quick Thinkers Are Smooth Talkers: Mental Speed Facilitates Charisma. PMID- 26621966 TI - Protein modification for immune regulation. PMID- 26621965 TI - Effects of Lipopolysaccharide and Progesterone Exposures on Embryonic Cerebral Cortex Development in Mice. AB - Our objective was to determine if progesterone pretreatment could ameliorate the detrimental effects of lipopolysaccharide (LPS)-induced inflammation on cortical neurogenesis. Timed pregnant mouse dams (n = 8) were given intraperitoneal injections of progesterone (42 mg/kg) or vehicle on embryonic day 17.5. Two hours later, mice were given intraperitoneal LPS (140 MUg/kg) or vehicle. Mice were sacrificed 16 hours later on embryonic day 18. Two-color immunofluorescence was performed with primary antibodies T-box transcription factor 2 (Tbr2), ionized calcium binding adapter molecule 1 (Iba1), cleaved caspase 3 (CC3), and 5-bromo 2'-deoxyuridine (BrdU). Cells were counted, and statistical analysis was determined using analysis of variance and Tukey-Kramer method. The Tbr2 intermediate neural progenitor cell density decreased after LPS exposure (P = .0022). Pre-exposure to progesterone statistically increased Tbr2 intermediate neural progenitors compared to LPS treatment alone and was similar to controls (P = .0022). After LPS exposure, microglia displayed an activated phenotype, and cell density was increased (P < .001). Cell death rates were low among study groups but was increased in LPS exposure groups compared to progesterone alone (P = .0015). Lipopolysaccharide-induced systemic inflammation reduces prenatal neurogenesis in mice. Pre-exposure with progesterone is associated with increased neurogenesis. Progesterone may protect the preterm brain from defects of neurogenesis induced by inflammation. PMID- 26621967 TI - Retraction of: A calreticulin/gC1qR complex prevents cells from dying: a conserved mechanism from arthropods to humans. PMID- 26621968 TI - The European Respiratory Review: farewell from the editor with confidence for the future. PMID- 26621969 TI - Improving patient outcomes in pulmonary hypertension. PMID- 26621970 TI - Multiple cystic lung disease. AB - Multiple cystic lung disease represents a diverse group of uncommon disorders that can present a diagnostic challenge due to the increasing number of diseases associated with this presentation. High-resolution computed tomography of the chest helps to define the morphological aspects and distribution of lung cysts, as well as associated findings. The combination of appearance upon imaging and clinical features, together with extrapulmonary manifestations, when present, permits confident and accurate diagnosis of the majority of these diseases without recourse to open-lung biopsy. The main diseases in this group that are discussed in this review are lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis and folliculin gene-associated syndrome (Birt-Hogg-Dube); other rare causes of cystic lung disease, including cystic metastasis of sarcoma, are also discussed. Disease progression is unpredictable, and understanding of the complications of cystic lung disease and their appearance during evolution of the disease are essential for management. Correlation of disease evolution and clinical context with chest imaging findings provides important clues for defining the underlying nature of cystic lung disease, and guides diagnostic evaluation and management. PMID- 26621971 TI - ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia. AB - Ataxia telangiectasia (A-T) is a rare, progressive, multisystem disease that has a large number of complex and diverse manifestations which vary with age. Patients with A-T die prematurely with the leading causes of death being respiratory diseases and cancer. Respiratory manifestations include immune dysfunction leading to recurrent upper and lower respiratory infections; aspiration resulting from dysfunctional swallowing due to neurodegenerative deficits; inefficient cough; and interstitial lung disease/pulmonary fibrosis. Malnutrition is a significant comorbidity. The increased radiosensitivity and increased risk of cancer should be borne in mind when requesting radiological investigations. Aggressive proactive monitoring and treatment of these various aspects of lung disease under multidisciplinary expertise in the experience of national multidisciplinary clinics internationally forms the basis of this statement on the management of lung disease in A-T. Neurological management is outwith the scope of this document. PMID- 26621972 TI - Second-line combination therapies in nonsmall cell lung cancer without known driver mutations. AB - In advanced nonsmall cell lung cancer (NSCLC) patients, platinum-based combination chemotherapy is standard treatment in the first-line setting; however, the large majority of patients ultimately progress. For more than a decade, single-agent therapy with docetaxel, pemetrexed or erlotinib has been the standard of care after failure with platinum salts, showing some benefit over best supportive care. Nonetheless, prognosis remains poor and new second-line strategies are urgently needed. Combinations of cytotoxic agents, including rechallenge with platinum salts, do not offer clear benefit over single-agent therapy for the majority of patients. In patients without a known tumoural oncogenic driver mutation, regimens based on combinations of targeted agents have shown promising results; however, a clear role in therapeutic management is yet to be established. Some success has been reported in recent research combining a cytotoxic agent with targeted therapies.In this review, we summarise published data for the various strategies evaluated over the past decade in second-line treatment of NSCLC patients without a known driver mutation. We focus on combination treatments and consider future perspectives, including the need to identify predictive markers to support personalised therapeutic strategies. PMID- 26621973 TI - Anti-IgE treatment, airway inflammation and remodelling in severe allergic asthma: current knowledge and future perspectives. AB - Asthma is a disorder of the airways involving various inflammatory cells and mediators and characterised by bronchial hyperresponsiveness, chronic inflammation and structural alterations in the airways, also known as remodelling. IgE is an important mediator of allergic reactions and has a central role in allergic asthma pathophysiology, as it is implicated in both the early and late phase allergic response. Moreover, clinical and mechanistic evidence has lately emerged, implicating IgE in the development of airway remodelling. The use of monoclonal antibodies targeting IgE, such as omalizumab, has proven very effective in improving respiratory symptoms and quality of life, while reducing asthma exacerbations, emergency room visits and the use of systemic corticosteroids in allergic severe asthma. These effects are believed to be mainly mediated by omalizumab's inhibitory effect on the initiation and further propagation of the allergic inflammation cascade. However, there is evidence to suggest that anti-IgE treatment remains effective long after it has been discontinued. In part, these findings could be attributed to the possible ameliorating effects of anti-IgE treatment on airway remodelling. In this review, we discuss recent findings supporting the notion that anti-IgE treatment modulates the complex immune responses that manifest clinically as asthma and ameliorates airway remodelling changes often observed in allergic severe asthma phenotypes. PMID- 26621974 TI - Sleep apnoea and driving risk: the need for regulation. AB - Obstructive sleep apnoea syndrome (OSAS) is a highly prevalent chronic respiratory disorder with prevalence among adult males of >=10%. The most common daytime symptom associated with OSAS is excessive sleepiness, which in more severe manifestations can result in sleepiness at the wheel while driving and probably contributes to the substantial increase in accident risk among patients with OSAS. Fortunately, current evidence indicates that successful therapy of OSAS, particularly with continuous positive airway pressure, can bring the accident risk down to levels similar to an equivalent general population. The recognition of the increased driving accident risk in OSAS prompted the Transport and Mobility Directorate of the European Commission to establish a working group on this topic in 2012, which ultimately led to a revision of Annex III of the EU Driving Licence Directive, which is subject to mandatory implementation by European Union member states by December 2015. This directive specifies that patients with moderate or severe OSAS associated with significant daytime sleepiness should be prohibited from driving until effective therapy is established. These new regulations are designed to balance the legitimate objective of public safety with not penalising OSAS patients who are complying with effective therapy. Successful implementation of regulations on driving in OSAS patients must also include measures to educate relevant stakeholders including patients, medical personnel, traffic police and employers in the transport industry. The key objective is to encourage patients with possible OSAS to seek diagnosis and treatment and not to inhibit OSAS patients from coming forward. PMID- 26621975 TI - Pulmonary alveolar microlithiasis: review of the 1022 cases reported worldwide. AB - Pulmonary alveolar microlithiasis (PAM) is a rare disease characterised by the widespread intra-alveolar accumulation of minute calculi called microliths. It is caused by mutation of the SLC34A2 gene encoding the type IIb sodium phosphate cotransporter in alveolar type II cells. The present study explores the epidemiological, familial, genetic, clinical, diagnostic, radiological and therapeutic aspects with the aim of contributing to a better understanding of this uncommon disease.We searched articles on PAM published up to December 2014 and 544 papers were found, accounting for 1022 cases.PAM is present in all continents and in many nations, in particular in Turkey, China, Japan, India, Italy and the USA. Familiality is frequent. The clinical course is not uniform and the causes of this clinical variability seem to be largely nongenetic. The optimal diagnostic procedure is the association of chest high-resolution computed tomography (HRCT) with bronchoalveolar lavage, but a chest radiograph may suffice in families in which a case has already been diagnosed. Moreover, chest radiography and HRCT allow the classification of the evolutionary phase of the disease and its severity. At present lung transplantation is the only effective therapy. However, better knowledge of the gene responsible offers hope for new therapies. PMID- 26621976 TI - Pulmonary arterial hypertension: the burden of disease and impact on quality of life. AB - Pulmonary arterial hypertension (PAH) is a debilitating disease that pervades all aspects of a patient's daily life. It is also increasingly acknowledged that the burden of PAH extends to older patients and carers. Until recently, the adverse effect of disease symptoms on the physical, emotional and social factors governing patient health-related quality of life (HRQoL) remained largely unrecognised. With a shift in therapeutic objectives to longer term improvements and HRQoL benefits, clinical trials now frequently include HRQoL measures as study end-points. Most HRQoL instruments used in patients with PAH are generic or non-disease-specific questionnaires and therefore may not accurately capture PAH disease burden. New PAH-specific HRQoL instruments currently undergoing validation include emPHasis-10 and Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland). Using various HRQoL measures, pharmacological therapies have been shown to improve HRQoL in patients with PAH. Patients also derive HRQoL benefits from nonpharmacological strategies, which include the emotional support provided by multidisciplinary care and support groups that is fundamental to patient wellbeing. Looking to the future, validated PAH-specific HRQoL instruments together with dedicated guidelines and procedures are essential to support the translation of HRQoL scores to the clinic, thus enabling a holistic treatment approach to the management of patients with PAH. PMID- 26621977 TI - Recent advances in targeting the prostacyclin pathway in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a severe disease characterised by increased pulmonary vascular resistance, which leads to restricted pulmonary arterial blood flow and elevated pulmonary arterial pressure. In patients with PAH, pulmonary concentrations of prostacyclin, a prostanoid that targets several receptors including the IP prostacyclin receptor, are reduced. To redress this balance, epoprostenol, a synthetic prostacyclin, or analogues of prostacyclin have been given therapeutically. These therapies improve exercise capacity, functional class and haemodynamic parameters. In addition, epoprostenol improves survival among patients with PAH. Despite their therapeutic benefits, treatments that target the prostacyclin pathway are underused. One key factor is their requirement for parenteral administration: continuous intravenous administration can lead to embolism and thrombosis; subcutaneous administration is associated with infusion-site pain; and inhalation is time consuming, requiring multiple daily administrations. Nevertheless, targeting the prostacyclin pathway is an important strategy for the management of PAH. The development of oral therapies for this pathway, as well as more user-friendly delivery devices, may alleviate some of the inconveniences. Continued improvements in therapeutic options will enable more patients with PAH to receive medication targeting the prostacyclin pathway. PMID- 26621979 TI - Imaging the heart in pulmonary hypertension: an update. AB - Noninvasive imaging of the heart plays an important role in the diagnosis and management of pulmonary hypertension (PH), and several well-established techniques are available for assessing performance of the right ventricle, the key determinant of patient survival. While right heart catheterisation is mandatory for establishing a diagnosis of PH, echocardiography is the most important screening tool for early detection of PH. Cardiac magnetic resonance imaging (CMRI) is also a reliable and practical tool that can be used as part of the diagnostic work-up. Echocardiography can measure a range of haemodynamic and anatomical variables (e.g. pericardial effusion and pulmonary artery pressure), whereas CMRI provides complementary information to echocardiography via high resolution, three-dimensional imaging. Together with echocardiography and CMRI, techniques such as high-resolution computed tomography and positron emission tomography may also be valuable for screening, monitoring and follow-up assessments of patients with PH, but their clinical relevance has yet to be established. Technological advances have produced new variants of echocardiography, CMRI and positron emission tomography, and these permit closer examination of myocardial architecture, motion and deformation. Integrating these new tools into clinical practice in the future may lead to more precise noninvasive determination of diagnosis, risk and prognosis for PH. PMID- 26621978 TI - Right heart catheterisation: best practice and pitfalls in pulmonary hypertension. AB - Right heart catheterisation (RHC) plays a central role in identifying pulmonary hypertension (PH) disorders, and is required to definitively diagnose pulmonary arterial hypertension (PAH). Despite widespread acceptance, there is a lack of guidance regarding the best practice for performing RHC in clinical practice. In order to ensure the correct evaluation of haemodynamic parameters directly measured or calculated from RHC, attention should be drawn to standardising procedures such as the position of the pressure transducer and catheter balloon inflation volume. Measurement of pulmonary arterial wedge pressure, in particular, is vulnerable to over- or under-wedging, which can give rise to false readings. In turn, errors in RHC measurement and data interpretation can complicate the differentiation of PAH from other PH disorders and lead to misdiagnosis. In addition to diagnosis, the role of RHC in conjunction with noninvasive tests is widening rapidly to encompass monitoring of treatment response and establishing prognosis of patients diagnosed with PAH. However, further standardisation of RHC is warranted to ensure optimal use in routine clinical practice. PMID- 26621980 TI - Under pressure: pulmonary hypertension associated with left heart disease. AB - Pulmonary hypertension (PH) associated with left heart disease (PH-LHD) is the most common type of PH, but its natural history is not well understood. PH-LHD is diagnosed by right heart catheterisation with a mean pulmonary arterial pressure >=25 mmHg and a pulmonary capillary wedge pressure >15 mmHg. The primary causes of PH-LHD are left ventricular dysfunction of systolic and diastolic origin, and valvular disease. Prognosis is poor and survival rates are low. Limited progress has been made towards specific therapies for PH-LHD, and management focuses on addressing the underlying cause of the disease with supportive therapies, surgery and pharmacological treatments. Clinical trials of therapies for pulmonary arterial hypertension in patients with PH-LHD have thus far been limited and have provided disappointing or conflicting results. Robust, long-term clinical studies in appropriate target populations have the potential to improve the outlook for patients with PH-LHD. Herein, we discuss the knowledge gaps in our understanding of PH-LHD, and describe the current unmet needs and challenges that are faced by clinicians when identifying and managing patients with this disease. PMID- 26621981 TI - Challenges in pulmonary hypertension: managing the unexpected. AB - The diverse challenges associated with diagnosis and management of patients with pulmonary hypertension are illustrated in this case-based review. Case 1 describes a patient diagnosed with pulmonary arterial hypertension (PAH) with right heart failure and active systemic lupus erythematosus who was effectively treated with an up-front triple combination of PAH therapies and immunosuppressive therapy. In case 2, a diagnosis of pulmonary veno-occlusive disease was reached after a combined approach of clinical suspicion, physical examination, and invasive and noninvasive tests. Cautious PAH therapy and high dose diuretics provided clinical benefit in this patient and served as a bridge to lung transplantation. These cases highlight the need for ongoing follow-up of patients with PAH, comprising frequent assessment of treatment success and continued diagnostic evaluation. PMID- 26621982 TI - A skin rash with multiple pulmonary nodules. PMID- 26621983 TI - New fundamental evidence of non-classical structure in the combination of natural concepts. AB - We recently performed cognitive experiments on conjunctions and negations of two concepts with the aim of investigating the combination problem of concepts. Our experiments confirmed the deviations (conceptual vagueness, underextension, overextension etc.) from the rules of classical (fuzzy) logic and probability theory observed by several scholars in concept theory, while our data were successfully modelled in a quantum-theoretic framework developed by ourselves. In this paper, we isolate a new, very stable and systematic pattern of violation of classicality that occurs in concept combinations. In addition, the strength and regularity of this non-classical effect leads us to believe that it occurs at a more fundamental level than the deviations observed up to now. It is our opinion that we have identified a deep non-classical mechanism determining not only how concepts are combined but, rather, how they are formed. We show that this effect can be faithfully modelled in a two-sector Fock space structure, and that it can be exactly explained by assuming that human thought is the superposition of two processes, a 'logical reasoning', guided by 'logic', and a 'conceptual reasoning', guided by 'emergence', and that the latter generally prevails over the former. All these findings provide new fundamental support to our quantum theoretic approach to human cognition. PMID- 26621984 TI - Comparing quantum versus Markov random walk models of judgements measured by rating scales. AB - Quantum and Markov random walk models are proposed for describing how people evaluate stimuli using rating scales. To empirically test these competing models, we conducted an experiment in which participants judged the effectiveness of public health service announcements from either their own personal perspective or from the perspective of another person. The order of the self versus other judgements was manipulated, which produced significant sequential effects. The quantum and Markov models were fitted to the data using the same number of parameters, and the model comparison strongly supported the quantum over the Markov model. PMID- 26621985 TI - Team decision problems with classical and quantum signals. AB - We study team decision problems where communication is not possible, but coordination among team members can be realized via signals in a shared environment. We consider a variety of decision problems that differ in what team members know about one another's actions and knowledge. For each type of decision problem, we investigate how different assumptions on the available signals affect team performance. Specifically, we consider the cases of perfectly correlated, i.i.d., and exchangeable classical signals, as well as the case of quantum signals. We find that, whereas in perfect-recall trees (Kuhn 1950 Proc. Natl Acad. Sci. USA 36, 570-576; Kuhn 1953 In Contributions to the theory of games, vol. II (eds H Kuhn, A Tucker), pp. 193-216) no type of signal improves performance, in imperfect-recall trees quantum signals may bring an improvement. Isbell (Isbell 1957 In Contributions to the theory of games, vol. III (eds M Drescher, A Tucker, P Wolfe), pp. 79-96) proved that, in non-Kuhn trees, classical i.i.d. signals may improve performance. We show that further improvement may be possible by use of classical exchangeable or quantum signals. We include an example of the effect of quantum signals in the context of high frequency trading. PMID- 26621986 TI - The importance of imagination (or lack thereof) in artificial, human and quantum decision making. AB - Enlarging upon experiments and analysis that I did jointly some years ago, in which artificial (symbolic, neural-net and pattern) learning and generalization were compared with that of humans, I will emphasize the role of imagination (or lack thereof) in artificial, human and quantum cognition and decision-making processes. Then I will look in more detail at some of the 'engineering details' of its implementation (or lack thereof) in each of these settings. In other words, the question posed is: What is actually happening? For example, we previously found that humans overwhelmingly seek, create or imagine context in order to provide meaning when presented with abstract, apparently incomplete, contradictory or otherwise untenable decision-making situations. Humans are intolerant of contradiction and will greatly simplify to avoid it. They can partially correlate but do not average. Human learning is not Boolean. These and other human reasoning properties will then be taken to critique how well artificial intelligence methods and quantum mechanical modelling might compete with them in decision-making tasks within psychology and economics. PMID- 26621987 TI - 'Social Laser': action amplification by stimulated emission of social energy. AB - The problem of the 'explanation' of recent social explosions, especially in the Middle East, but also in Southern Europe and the USA, has been debated actively in the social and political literature. We can mention the contributions of P. Mason, F. Fukuyama, E. Schmidt, J. Cohen and I. Krastev to this debate. We point out that the diversity of opinions and conclusions is really amazing. At the moment, there is no consistent and commonly acceptable theory of these phenomena. We present a model of social explosions based on a novel approach for the description of social processes, namely the quantum-like approach. Here quantum theory is treated simply as an operational formalism-without any direct relation to physics. We explore the quantum-like laser model to describe the possibility of action amplification by stimulated emission of social energy. PMID- 26621988 TI - Is there contextuality in behavioural and social systems? AB - Most behavioural and social experiments aimed at revealing contextuality are confined to cyclic systems with binary outcomes. In quantum physics, this broad class of systems includes as special cases Klyachko-Can-Binicioglu-Shumovsky type, Einstein-Podolsky-Rosen-Bell-type and Suppes-Zanotti-Leggett-Garg-type systems. The theory of contextuality known as contextuality-by-default allows one to define and measure contextuality in all such systems, even if there are context-dependent errors in measurements, or if something in the contexts directly interacts with the measurements. This makes the theory especially suitable for behavioural and social systems, where direct interactions of 'everything with everything' are ubiquitous. For cyclic systems with binary outcomes, the theory provides necessary and sufficient conditions for non contextuality, and these conditions are known to be breached in certain quantum systems. We review several behavioural and social datasets (from polls of public opinion to visual illusions to conjoint choices to word combinations to psychophysical matching), and none of these data provides any evidence for contextuality. Our working hypothesis is that this may be a broadly applicable rule: behavioural and social systems are non-contextual, i.e. all 'contextual effects' in them result from the ubiquitous dependence of response distributions on the elements of contexts other than the ones to which the response is presumably or normatively directed. PMID- 26621989 TI - Quantum probability and quantum decision-making. AB - A rigorous general definition of quantum probability is given, which is valid not only for elementary events but also for composite events, for operationally testable measurements as well as for inconclusive measurements, and also for non commuting observables in addition to commutative observables. Our proposed definition of quantum probability makes it possible to describe quantum measurements and quantum decision-making on the same common mathematical footing. Conditions are formulated for the case when quantum decision theory reduces to its classical counterpart and for the situation where the use of quantum decision theory is necessary. PMID- 26621990 TI - The visualizable, the representable and the inconceivable: realist and non realist mathematical models in physics and beyond. AB - The project of this article is twofold. First, it aims to offer a new perspective on, and a new argument concerning, realist and non-realist mathematical models, and differences and affinities between them, using physics as a paradigmatic field of mathematical modelling in science. Most of the article is devoted to this topic. Second, the article aims to explore the implications of this argument for mathematical modelling in other fields, in particular in cognitive psychology and economics. PMID- 26621991 TI - Statistical microeconomics and commodity prices: theory and empirical results. AB - A review is made of the statistical generalization of microeconomics by Baaquie (Baaquie 2013 Phys. A 392, 4400-4416. (doi:10.1016/j.physa.2013.05.008)), where the market price of every traded commodity, at each instant of time, is considered to be an independent random variable. The dynamics of commodity market prices is given by the unequal time correlation function and is modelled by the Feynman path integral based on an action functional. The correlation functions of the model are defined using the path integral. The existence of the action functional for commodity prices that was postulated to exist in Baaquie (Baaquie 2013 Phys. A 392, 4400-4416. (doi:10.1016/j.physa.2013.05.008)) has been empirically ascertained in Baaquie et al. (Baaquie et al. 2015 Phys. A 428, 19 37. (doi:10.1016/j.physa.2015.02.030)). The model's action functionals for different commodities has been empirically determined and calibrated using the unequal time correlation functions of the market commodity prices using a perturbation expansion (Baaquie et al. 2015 Phys. A 428, 19-37. (doi:10.1016/j.physa.2015.02.030)). Nine commodities drawn from the energy, metal and grain sectors are empirically studied and their auto-correlation for up to 300 days is described by the model to an accuracy of R(2)>0.90-using only six parameters. PMID- 26621992 TI - Probabilistic frames for non-Boolean phenomena. AB - Classical probability theory, as axiomatized in 1933 by Andrey Kolmogorov, has provided a useful and almost universally accepted theory for describing and quantifying uncertainty in scientific applications outside quantum mechanics. Recently, cognitive psychologists and mathematical economists have provided examples where classical probability theory appears inadequate but the probability theory underlying quantum mechanics appears effective. Formally, quantum probability theory is a generalization of classical probability. This article explores relationships between generalized probability theories, in particular quantum-like probability theories and those that do not have full complementation operators (e.g. event spaces based on intuitionistic logic), and discusses how these generalizations bear on important issues in the foundations of probability and the development of non-classical probability theories for the behavioural sciences. PMID- 26621993 TI - An investigation of a quantum probability model for the constructive effect of affective evaluation. AB - The idea that choices can have a constructive effect has received a great deal of empirical support. The act of choosing appears to influence subsequent preferences for the options available. Recent research has proposed a cognitive model based on quantum probability (QP), which suggests that whether or not a participant provides an affective evaluation for a positively or negatively valenced stimulus can also be constructive and so, for example, influence the affective evaluation of a second oppositely valenced stimulus. However, there are some outstanding methodological questions in relation to this previous research. This paper reports the results of three experiments designed to resolve these questions. Experiment 1, using a binary response format, provides partial support for the interaction predicted by the QP model; and Experiment 2, which controls for the length of time participants have to respond, fully supports the QP model. Finally, Experiment 3 sought to determine whether the key effect can generalize beyond affective judgements about visual stimuli. Using judgements about the trustworthiness of well-known people, the predictions of the QP model were confirmed. Together, these three experiments provide further support for the QP model of the constructive effect of simple evaluations. PMID- 26621994 TI - Basis for binary comparisons and non-standard probabilities. AB - To analyse paired comparison outcomes, such as with non-standard probabilities, a basis is created for the space of all binary interactions, whether from probabilities, correlations, etc. In this manner, the source of all transitive and non-transitive behaviours (e.g. path dependencies) can be identified. PMID- 26621995 TI - Quantum probability and the mathematical modelling of decision-making. PMID- 26621996 TI - Instability of political preferences and the role of mass media: a dynamical representation in a quantum framework. AB - We search to devise a new paradigm borrowed from concepts and mathematical tools of quantum physics, to model the decision-making process of the US electorate. The statistical data of the election outcomes in the period between 2008 and 2014 is analysed, in order to explore in more depth the emergence of the so-called divided government. There is an increasing urge in the political literature which indicates that preference reversal (strictly speaking the violation of the transitivity axiom) is a consequence of the so-called non-separability phenomenon (i.e. a strong interrelation of choices). In the political science literature, non-separable behaviour is characterized by a conditioning of decisions on the outcomes of some issues of interest. An additional source of preference reversal is ascribed to the time dynamics of the voters' cognitive states, in the context of new upcoming political information. As we discuss in this paper, the primary source of political information can be attributed to the mass media. In order to shed more light on the phenomenon of preference reversal among the US electorate, we accommodate the obtained statistical data in a classical probabilistic (Kolmogorovian) scheme. Based on the obtained results, we attribute the strong ties between the voters non-separable decisions that cannot be explained by conditioning with the Bayes scheme, to the quantum phenomenon of entanglement. Second, we compute the degree of interference of voters' belief states with the aid of the quantum analogue of the formula of total probability. Lastly, a model, based on the quantum master equation, to incorporate the impact of the mass media bath is proposed. PMID- 26621997 TI - Editorial. PMID- 26621998 TI - Physicians and knowledge translation of statistics: Mind the gap. PMID- 26621999 TI - Medical students now choosing wisely. PMID- 26622000 TI - Streamlining the ethics review system. PMID- 26622002 TI - Rubella in a returned traveller. PMID- 26622003 TI - GPs challenge seven-day NHS proposal. PMID- 26622001 TI - Recommendations on screening for cognitive impairment in older adults. PMID- 26622004 TI - A forgotten pandemic. PMID- 26622005 TI - Spontaneous remission of a large thyroid tumour. PMID- 26622007 TI - Better outbreak research response needed. PMID- 26622006 TI - Sensitivity and specificity of administrative mortality data for identifying prescription opioid-related deaths. AB - BACKGROUND: Comprehensive systems for surveilling prescription opioid-related harms provide clear evidence that deaths from prescription opioids have increased dramatically in the United States. However, these harms are not systematically monitored in Canada. In light of a growing public health crisis, accessible, nationwide data sources to examine prescription opioid-related harms in Canada are needed. We sought to examine the performance of 5 algorithms to identify prescription opioid-related deaths from vital statistics data against data abstracted from the Office of the Chief Coroner of Ontario as a gold standard. METHODS: We identified all prescription opioid-related deaths from Ontario coroners' data that occurred between Jan. 31, 2003, and Dec. 31, 2010. We then used 5 different algorithms to identify prescription opioid-related deaths from vital statistics death data in 2010. We selected the algorithm with the highest sensitivity and a positive predictive value of more than 80% as the optimal algorithm for identifying prescription opioid-related deaths. RESULTS: Four of the 5 algorithms had positive predictive values of more than 80%. The algorithm with the highest sensitivity (75%) in 2010 improved slightly in its predictive performance from 2003 to 2010. INTERPRETATION: In the absence of specific systems for monitoring prescription opioid-related deaths in Canada, readily available national vital statistics data can be used to study prescription opioid-related mortality with considerable accuracy. Despite some limitations, these data may facilitate the implementation of national surveillance and monitoring strategies. PMID- 26622008 TI - Staying Safe. PMID- 26622009 TI - Access to primary care: creative solutions are needed. PMID- 26622010 TI - Patient safety research in primary care: where are we now? PMID- 26622011 TI - Euthanasia, ethics, and the Gordian Knot: is the Hippocratic Code obsolete? PMID- 26622012 TI - Growing trends in the pursuit of muscularity: what healthcare professionals should be aware of. PMID- 26622013 TI - Clinical signs in elbow pain. PMID- 26622014 TI - Give us a reason to be a GP. PMID- 26622015 TI - The diagnostic accuracy of faecal calprotectin in investigations for suspected inflammatory bowel disease in children. PMID- 26622016 TI - The FGM enhanced dataset: how are we going to discuss this with our patients? PMID- 26622018 TI - Addendum. PMID- 26622017 TI - Meetings between experts. PMID- 26622019 TI - Viewpoint: The subtle value of GP trainees. PMID- 26622020 TI - Yonder: Appraisal, district nurses, problem gambling, and Nora Batty. PMID- 26622021 TI - The concept of the 'undeserving poor': pejorative stereotypes and worsening inequalities undermine welfare reform. PMID- 26622022 TI - Saint Luke: chronicler of the first Christmas and most published of any doctor. PMID- 26622023 TI - Healthcare professionals have special needs when they become patients. PMID- 26622024 TI - Beyond patient reassurance. PMID- 26622029 TI - The lurch of progress. PMID- 26622030 TI - We need more guidance on shared decision making. PMID- 26622031 TI - Achilles tendon rupture: how to avoid missing the diagnosis. PMID- 26622032 TI - General practice funding underpins the persistence of the inverse care law: cross sectional study in Scotland. AB - BACKGROUND: Universal access to health care, as provided in the NHS, does not ensure that patients' needs are met. AIM: To explore the relationships between multimorbidity, general practice funding, and workload by deprivation in a national healthcare system. DESIGN AND SETTING: Cross-sectional study using routine data from 956 general practices in Scotland. METHOD: Estimated numbers of patients with multimorbidity, estimated numbers of consultations per 1000 patients, and payments to practices per patient are presented and analysed by deprivation decile at practice level. RESULTS: Levels of multimorbidity rose with practice deprivation. Practices in the most deprived decile had 38% more patients with multimorbidity compared with the least deprived (222.8 per 1000 patients versus 161.1; P<0.001) and over 120% more patients with combined mental-physical multimorbidity (113.0 per 1000 patients versus 51.5; P<0.001). Practices in the most deprived decile had 20% more consultations per annum compared with the least deprived (4616 versus 3846, P<0.001). There was no association between total practice funding and deprivation (Spearman rho -0.09; P = 0.03). Although consultation rates increased with deprivation, the social gradients in multimorbidity were much steeper. There was no association between consultation rates and levels of funding. CONCLUSION: No evidence was found that general practice funding matches clinical need, as estimated by different definitions of multimorbidity. Consultation rates provide only a partial estimate of the work involved in addressing clinical needs and are poorly related to the prevalence of multimorbidity. In these circumstances, general practice is unlikely to mitigate health inequalities and may increase them. PMID- 26622033 TI - Online data on opening hours of general practices in England: a comparison with telephone survey data. AB - BACKGROUND: The NHS Choices website (www.nhs.uk) provides data on the opening hours of general practices in England. If the data are accurate, they could be used to examine the benefits of extended hours. AIM: To determine whether online data on the opening times of general practices in England are accurate regarding the number of hours in which GPs provide face-to-face consultations. DESIGN AND SETTING: Cross-sectional comparison of data from NHS Choices and telephone survey data reported by general practice staff, for a nationally representative sample of 320 general practices (December 2013 to September 2014). METHOD: GP face-to face consultation times were collected by telephone for each sampled practice for each day of the week. NHS Choices data on surgery times were available online. Analysis was based on differences in the number of surgery hours (accounting for breaks) and the times of the first and last consultations of the day only between the two data sources. RESULTS: The NHS Choices data recorded 8.8 more hours per week than the survey data on average (40.1 versus 31.2; 95% confidence interval [CI] = 7.4 to 10.3). This was largely accounted for by differences in the recording of breaks between sessions. The data were more similar when only the first and last consultation times were considered (mean difference = 1.6 hours; 95% CI = 0.9 to 2.3). CONCLUSION: NHS Choices data do not accurately measure the number of hours in which GPs provide face-to-face consultations. They better record the hours between the first and last consultations of the day. PMID- 26622034 TI - Digital communication between clinician and patient and the impact on marginalised groups: a realist review in general practice. AB - BACKGROUND: Increasingly, the NHS is embracing the use of digital communication technology for communication between clinicians and patients. Policymakers deem digital clinical communication as presenting a solution to the capacity issues currently faced by general practice. There is some concern that these technologies may exacerbate existing inequalities in accessing health care. It is not known what impact they may have on groups who are already marginalised in their ability to access general practice. AIM: To assess the potential impact of the availability of digital clinician-patient communication on marginalised groups' access to general practice in the UK. DESIGN AND SETTING: Realist review in general practice. METHOD: A four-step realist review process was used: to define the scope of the review; to search for and scrutinise evidence; to extract and synthesise evidence; and to develop a narrative, including hypotheses. RESULTS: Digital communication has the potential to overcome the following barriers for marginalised groups: practical access issues, previous negative experiences with healthcare service/staff, and stigmatising reactions from staff and other patients. It may reduce patient-related barriers by offering anonymity and offers advantages to patients who require an interpreter. It does not impact on inability to communicate with healthcare professionals or on a lack of candidacy. It is likely to work best in the context of a pre-existing clinician patient relationship. CONCLUSION: Digital communication technology offers increased opportunities for marginalised groups to access health care. However, it cannot remove all barriers to care for these groups. It is likely that they will remain disadvantaged relative to other population groups after their introduction. PMID- 26622035 TI - Improving patient safety culture in general practice: an interview study. AB - BACKGROUND: When improving patient safety a positive safety culture is key. As little is known about improving patient safety culture in primary care, this study examined whether administering a culture questionnaire with or without a complementary workshop could be used as an intervention for improving safety culture. AIM: To gain insight into how two interventions affected patient safety culture in everyday practice. DESIGN AND SETTING: After conducting a randomised control trial of two interventions, this was a qualitative study conducted in 30 general practices to aid interpretation of the previous quantitative findings. METHOD: Interviews were conducted at practice locations (n = 27) with 24 GPs and 24 practice nurses. The theory of communities of practice--in particular, its concepts of a domain, a community, and a practice--was used to interpret the findings by examining which elements were or were not present in the participating practices. RESULTS: Communal awareness of the problem was only raised after getting together and discussing patient safety. The combination of a questionnaire and workshop enhanced the interaction of team members and nourished team feelings. This shared experience also helped them to understand and develop tools and language for daily practice. CONCLUSION: In order for patient safety culture to improve, the safety culture questionnaire was more successful when accompanied by a practice workshop. Initial discussion and negotiation of shared goals during the workshop fuelled feelings of coherence and belonging to a community wishing to learn about enhancing patient safety. Team meetings and day to-day interactions enhanced further liaison and sharing, making patient safety a common and conscious goal. PMID- 26622036 TI - Harms from discharge to primary care: mixed methods analysis of incident reports. AB - BACKGROUND: Discharge from hospital presents significant risks to patient safety, with up to one in five patients experiencing adverse events within 3 weeks of leaving hospital. AIM: To describe the frequency and types of patient safety incidents associated with discharge from secondary to primary care, and commonly described contributory factors to identify recommendations for practice. DESIGN AND SETTING: A mixed methods analysis of 598 patient safety incident reports in England and Wales related to 'Discharge' from the National Reporting and Learning System. METHOD: Detailed data coding (with 20% double-coding), data summaries generated using descriptive statistical analysis, and thematic analysis of special-case sample of reports. Incident type, contributory factors, type, and level of harm were described, informing recommendations for future practice. RESULTS: A total of 598 eligible reports were analysed. The four main themes were: errors in discharge communication (n = 151; 54% causing harm); errors in referrals to community care (n = 136; 73% causing harm); errors in medication (n = 97; 87% causing harm); and lack of provision of care adjuncts such as dressings (n = 62; 94% causing harm). Common contributory factors were staff factors (not following referral protocols); and organisational factors (lack of clear guidelines or inefficient processes). Improvement opportunities include developing and testing electronic discharge methods with agreed minimum information requirements and unified referrals systems to community care providers; and promoting a safety culture with 'safe discharge' checklists, discharge coordinators, and family involvement. CONCLUSION: Significant harm was evident due to deficits in the discharge process. Interventions in this area need to be evaluated and learning shared widely. PMID- 26622037 TI - Missed opportunities for diagnosis: lessons learned from diagnostic errors in primary care. AB - BACKGROUND: Because of the difficulties inherent in diagnosis in primary care, it is inevitable that diagnostic errors will occur. However, despite the important consequences associated with diagnostic errors and their estimated high prevalence, teaching and research on diagnostic error is a neglected area. AIM: To ascertain the key learning points from GPs' experiences of diagnostic errors and approaches to clinical decision making associated with these. DESIGN AND SETTING: Secondary analysis of 36 qualitative interviews with GPs in Oxfordshire, UK. METHOD: Two datasets of semi-structured interviews were combined. Questions focused on GPs' experiences of diagnosis and diagnostic errors (or near misses) in routine primary care and out of hours. Interviews were audiorecorded, transcribed verbatim, and analysed thematically. RESULTS: Learning points include GPs' reliance on 'pattern recognition' and the failure of this strategy to identify atypical presentations; the importance of considering all potentially serious conditions using a 'restricted rule out' approach; and identifying and acting on a sense of unease. Strategies to help manage uncertainty in primary care were also discussed. CONCLUSION: Learning from previous examples of diagnostic errors is essential if these events are to be reduced in the future and this should be incorporated into GP training. At a practice level, learning points from experiences of diagnostic errors should be discussed more frequently; and more should be done to integrate these lessons nationally to understand and characterise diagnostic errors. PMID- 26622038 TI - Special unlicensed medicines: what we do and do not know about them. PMID- 26622039 TI - Research into practice: accessing primary care. PMID- 26622040 TI - A THIN-LAYER LIF THERMOLUMINESCENCE DOSEMETER SYSTEM WITH FAST READOUT FOR THE USE IN PERSONAL DOSIMETRY SERVICES. AB - A newly developed thermoluminescence dosemeter system is presented that is suitable for application in fields where personal monitoring of a large number of users is required. The system presented here is intended to be used as the upcoming main dosemeter for whole body dosimetry at the dosimetry service of the MPA NRW (Germany) with ~110,000 evaluations per month. PMID- 26622041 TI - MULTICENTRE COMPARISON OF IMAGE QUALITY FOR LOW-CONTRAST OBJECTS AND MICROCATHETER TIPS IN X-RAY-GUIDED TREATMENT OF ARTERIOVENOUS MALFORMATION IN THE BRAIN. AB - The treatment of brain arteriovenous malformations (AVMs) can be performed as a minimally invasive X-ray-guided procedure using a microcatheter for navigation to reach the target site. The performance of the interventional vascular surgery devices used for AVM was compared in four hospitals. The relation between image quality and the entrance surface air kerma (ESAK) was assessed for the default protocols for digital subtraction angiography (DSA) and fluoroscopy. A custom phantom, built with PMMA and aluminium plates was used to mimic the attenuation properties of the patient head. Image quality was assessed using low-contrast objects and catheters embedded in two phantoms. Differences were found in the ESAK values, especially for the fluoroscopy, whereas for DSA, the ESAK values were similar. The differences in image quality can be related to acquisition parameters, such as kV and filtration, and post-processing. The proposed method can be used to optimise the existing AVM protocols. PMID- 26622042 TI - SYSTEM UPGRADE ON PHILIPS ALLURA FD20 ANGIOGRAPHY SYSTEMS: EFFECTS ON PATIENT SKIN DOSE AND STATIC IMAGE QUALITY. AB - Fluoroscopically guided procedures might be highly irradiating for patients, possibly leading to skin injuries. In such a context, every effort should be done to lower patient exposure as much as possible. Moreover, patient dose reduction does not only benefit to the patient but also allows reducing staff exposure. In this framework, Philips Healthcare recently introduced a system upgrade for their angiography units, called 'AlluraClarity'. The authors performed air kerma rate measurements for all available fluoroscopy modes and air kerma per frame measurements for the digital subtraction angiography protocols, along with subjective spatial resolution and low-contrast detectability assessments using a standard QA phantom. Air kerma reductions ranging from 25.5 to 84.4 % were found, with no significant change in image quality when switching from a standard operating mode to an upgraded version. These results are confirmed by the comparison of actual patient exposures for similar procedures. PMID- 26622043 TI - CAN AN ENERGY-COMPENSATED SOLID-STATE X-RAY DETECTOR BE USED FOR RADIATION PROTECTION APPLICATIONS AT HIGHER PHOTON ENERGIES? AB - The objective of this study was to investigate the characteristics of a solid state detector commonly available at hospitals for parallel use as a real-time personal radiation monitor following radiation emergency situations. A solid state detector probe with an inherent filtration (R100, RTI Electronics AB, Molndal, Sweden) was chosen for evaluation. The energy dependence and the linearity in signal response with kerma in air were examined, and the detector was exposed to both X-ray beams using a conventional X-ray unit with effective photon energies ranging between 28.5 and 48.9 keV and to gamma rays 1.17 and 1.33 MeV from (60)Co. The R100 exhibited ~1.7 times over-response at the lowest X-ray energy relative to the (60)Co source. The detector demonstrated a linear response (R(2) = 1) when irradiated with (60)Co to air kerma values in the range of 20-200 mGy. The conclusion is that high-energy photons such as those from (60)Co can be detected by the R100 with an energy response within a factor of <2 over the energy range examined and that the detector can provide real-time dose measurements following nuclear or radiological events. PMID- 26622044 TI - EXPERIMENTAL STUDY ON ASSESSING INTERNAL RADIOACTIVE CONTAMINANTS BY USE OF NASAL SWAB. AB - Nasal swab analysis is an effective method to provide valuable information for early and fast estimates of alpha radionuclide intakes and resultant doses. In this study, an inhalation environment was built by use of lead nitrate aerosol to simulate alpha radioactive aerosol inhalation. The result of exposure and swabbing experiments with guinea pigs shows that the lead smeared on nasal swabs represents ~13 % of intake if samples are acquired within 90 min after exposure and declines over time with a half-time of 1.4 h. The results also indicate a decreasing swabbing efficiency with post-exposure time. This study could provide useful information for the method of nasal swab used in nuclear and radiological emergencies. PMID- 26622045 TI - A NEW SEMI-EMPIRICAL AMBIENT TO EFFECTIVE DOSE CONVERSION MODEL FOR THE PREDICTIVE CODE FOR AIRCREW RADIATION EXPOSURE (PCAIRE). AB - The Predictive Code for Aircrew Radiation Exposure (PCAIRE) is a semi-empirical code that estimates both ambient dose equivalent, based on years of on-board measurements, and effective dose to aircrew. Currently, PCAIRE estimates effective dose by converting the ambient dose equivalent to effective dose (E/H) using a model that is based on radiation transport calculations and on the radiation weighting factors recommended in International Commission on Radiological Protection (ICRP) 60. In this study, a new semi-empirical E/H model is proposed to replace the existing transport calculation models. The new model is based on flight data measured using a tissue-equivalent proportional counter (TEPC). The measured flight TEPC data are separated into a low- and a high-lineal energy spectrum using an amplitude-weighted 137Cs TEPC spectrum. The high-lineal energy spectrum is determined by subtracting the low-lineal-energy spectrum from the measured flight TEPC spectrum. With knowledge of E/H for the low- and high lineal-energy spectra, the total E/H is estimated for a given flight altitude and geographic location. The semi-empirical E/H model also uses new radiation weighting factors to align the model with the most recent ICRP 103 recommendations. The ICRP 103-based semi-empirical effective dose model predicts that there is a ~30 % reduction in dose in comparison with the ICRP 60-based model. Furthermore, the ambient dose equivalent is now a more conservative dose estimate for jet aircraft altitudes in the range of 7-13 km (FL230-430). This new semi-empirical E/H model is validated against E/H predicted from a Monte Carlo N Particle transport code simulation of cosmic ray propagation through the Earth's atmosphere. Its implementation allows PCAIRE to provide an accurate semi empirical estimate of the effective dose. PMID- 26622046 TI - Detection of Neisseria gonorrhoeae in the pharynx and saliva: implications for gonorrhoea transmission. AB - OBJECTIVES: This study aimed to determine the proportion of untreated pharyngeal swabs or saliva samples positive by culture or nucleic acid amplification tests (NAATs) for Neisseria gonorrhoeae up to 14 days after an initial culture-positive pharyngeal swab. METHODS: Men who have sex with men who tested positive for pharyngeal gonorrhoea at Melbourne Sexual Health Centre (MSHC) and returned to MSHC for treatment within 14 days between 13 October 2014 and 25 March 2015 were included in this study. Pharyngeal swabs and saliva samples were collected for culture and NAAT. RESULTS: Of 33 initially culture-positive pharyngeal swabs, 32 saliva samples and 31 pharyngeal swabs were positive by NAAT and 14 pharyngeal and 6 saliva samples were positive by culture within 14 days. There was a significant decline in the proportion of repeated pharyngeal culture samples positive by culture over time (p<0.001). CONCLUSIONS: The rapid decline suggests pharyngeal gonorrhoea is short-lived, and the finding of gonorrhoea commonly in the saliva implicates this body fluid in its transmission without direct throat inoculation. PMID- 26622047 TI - The New Shape of EC. AB - The journal Eukaryotic Cell has served the eukaryotic microbiology community since 2002. It will continue to do so as it merges into the new broad-scope open access journal mSphere in 2016. PMID- 26622050 TI - Editor's Choice-Progress in the chain of survival and its impact on outcomes of patients admitted to a specialized high-volume cardiac arrest center during the past two decades. AB - AIM: Cardiac arrest (CA) is still associated with high mortality and morbidity. Data on the changes in management and outcomes over a long period of time are limited. Using data from a single emergency department (ED), we assessed changes over two decades. METHODS: In this single-center observational study, we prospectively included 4133 patients receiving cardiopulmonary resuscitation and being admitted to the ED of a tertiary care hospital between January 1992 and December 2012. RESULTS: There was a significant improvement in both 6-month survival rates (+10.8%; p < 0.001) and favorable neurological outcome (+4.7%; p < 0.001). While the number of witnessed CA cases decreased (-4.7%; p < 0.001) the proportion of patients receiving bystander basic life support increased (+8.3%; p < 0.001). The proportion of patients with initially shockable ECG rhythms remained unchanged, but cardiovascular causes of CA decreased (-9.6%; p < 0.001). Interestingly, the time from CA until ED admission increased (+0.1 hours; p = 0.024). The use of percutaneous coronary intervention and therapeutic hypothermia were significantly associated with survival. CONCLUSIONS: Outcomes of patients with CA treated at a specialized ED have improved significantly within the last 20 years. Improvements in every link in the chain of survival were noted. PMID- 26622051 TI - Insulin Resistance and Inflammation in Hypogonadotropic Hypogonadism and Their Reduction After Testosterone Replacement in Men With Type 2 Diabetes. AB - OBJECTIVE: One-third of men with type 2 diabetes have hypogonadotropic hypogonadism (HH). We conducted a randomized placebo-controlled trial to evaluate the effect of testosterone replacement on insulin resistance in men with type 2 diabetes and HH. RESEARCH DESIGN AND METHODS: A total of 94 men with type 2 diabetes were recruited into the study; 50 men were eugonadal, while 44 men had HH. Insulin sensitivity was calculated from the glucose infusion rate (GIR) during hyperinsulinemic-euglycemic clamp. Lean body mass and fat mass were measured by DEXA and MRI. Subcutaneous fat samples were taken to assess insulin signaling genes. Men with HH were randomized to receive intramuscular testosterone (250 mg) or placebo (1 mL saline) every 2 weeks for 24 weeks. RESULTS: Men with HH had higher subcutaneous and visceral fat mass than eugonadal men. GIR was 36% lower in men with HH. GIR increased by 32% after 24 weeks of testosterone therapy but did not change after placebo (P = 0.03 for comparison). There was a decrease in subcutaneous fat mass (-3.3 kg) and increase in lean mass (3.4 kg) after testosterone treatment (P < 0.01) compared with placebo. Visceral and hepatic fat did not change. The expression of insulin signaling genes (IR beta, IRS-1, AKT-2, and GLUT4) in adipose tissue was significantly lower in men with HH and was upregulated after testosterone treatment. Testosterone treatment also caused a significant fall in circulating concentrations of free fatty acids, C-reactive protein, interleukin-1beta, tumor necrosis factor-alpha, and leptin (P < 0.05 for all). CONCLUSIONS: Testosterone treatment in men with type 2 diabetes and HH increases insulin sensitivity, increases lean mass, and decreases subcutaneous fat. PMID- 26622052 TI - Using the BacMam Baculovirus System to Study Expression and Function of Recombinant Efflux Drug Transporters in Polarized Epithelial Cell Monolayers. AB - The ATP-binding cassette (ABC) transporter superfamily includes several membrane bound proteins that are critical to drug pharmacokinetics and disposition. Pharmacologic evaluation of these proteins in vitro remains a challenge. In this study, human ABC transporters were expressed in polarized epithelial cell monolayers transduced using the BacMam baculovirus gene transfer system. The purpose of the study was to evaluate the efficacy of BacMam baculovirus to transduce cells grown in monolayers. In a porcine kidney cell line, LLC-PK1 cells, baculoviral transduction is successful only via the apical side of a polarized monolayer. We observed that recombinant ABC transporters were expressed on the cell surface with post-translational modification. Furthermore, sodium butyrate played a critical role in recombinant protein expression, and preincubation in the presence of tunicamycin or thapsigargin enhanced protein expression. Cells overexpressing human P-glycoprotein (P-gp) showed vectorial basolateral-to-apical transport of [(3)H]-paclitaxel, which could be reversed by the inhibitor tariquidar. Similarly, coexpression of human P-gp and ABCG2 in LLC PK1 cells resulted in higher transport of mitoxantrone, which is a substrate for both transporters, than in either P-gp- or ABCG2-expressing cells alone. Taken together, our results indicate that a high level of expression of efflux transporters in a polarized cell monolayer is technically feasible with the BacMam baculovirus system. PMID- 26622053 TI - Novel electrocardiographic criteria for the diagnosis of arrhythmogenic right ventricular cardiomyopathy. AB - AIMS: In order to improve the electrocardiographic (ECG) diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC), we evaluated novel quantitative parameters of the QRS complex and the value of bipolar chest leads (CF leads) computed from the standard 12 leads. METHODS AND RESULTS: We analysed digital 12-lead ECGs in 44 patients with ARVC, 276 healthy subjects including 44 age and sex-matched with the patients and 36 genotyped members of ARVC families. The length and area of the terminal S wave in V1 to V3 were measured automatically using a common for all 12 leads QRS end. T wave negativity was assessed in V1 to V6 and in the bipolar CF leads computed from the standard 12 leads. The length and area of the terminal S wave were significantly shorter, whereas the S wave duration was significantly longer in ARVC patients compared with matched controls. Among members of ARVC families, those with mutations (n = 15) had shorter QRS length in V2 and V3 and smaller QRS area in lead V2 compared with those without mutations (n = 20). In ARVC patients, the CF leads were diagnostically superior to the standard unipolar precordial leads. Terminal S wave duration in V1 >48 ms or major T wave negativity in CF leads separated ARVC patients from matched controls with 90% sensitivity and 86% specificity. CONCLUSION: The terminal S wave length and area in the right precordial leads are diagnostically useful and suitable for automatic analysis in ARVC. The CF leads are diagnostically superior to the unipolar precordial leads. PMID- 26622054 TI - Sex difference in appropriate shocks but not mortality during long-term follow-up in patients with implantable cardioverter-defibrillators. AB - AIMS: Implantable cardioverter-defibrillators (ICDs) have been shown to improve survival, although a considerable number of patients never receive therapy. Implantable cardioverter-defibrillators are routinely implanted regardless of sex. There is continuing controversy whether major outcomes differ between men and women. METHODS AND RESULTS: In this retrospective single-centre study, 1151 consecutive patients (19% women) undergoing ICD implantation between 1998 and 2010 were followed for mortality and first appropriate ICD shock over 4.9 +/- 2.7 years. Sex-related differences were investigated using multivariable Cox models adjusting for potential confounders. During follow-up, 318 patients died, a rate of 5.9% per year among men and 4.6% among women (uncorrected P = 0.08); 266 patients received a first appropriate ICD shock (6.3% per year among men vs. 3.6% among women, P = 0.002). After multivariate correction, independent predictors of all-cause mortality were age (hazard ratio, HR = 1.04 per year of age, 95% confidence interval (CI) [1.03-1.06], P < 0.001), left ventricular ejection fraction (HR = 0.98 per %, 95% CI [0.97-1.00], P = 0.025), renal function (HR = 0.99 per mL/min/1.73 m(2), 95% CI [0.99-1.00], P = 0.009), use of diuretics (HR = 1.81, 95% CI [1.29-2.54], P = 0.0023), peripheral arterial disease (HR = 2.21, 95% CI [1.62-3.00], P < 0.001), and chronic obstructive pulmonary disease (HR = 1.48, 95% CI [1.13-1.94], P = 0.029), but not sex. Female sex (HR = 0.51, 95% CI [0.33-0.81], P = 0.013), older age (HR = 0.98, 95% CI [0.97-0.99], P < 0.001), and primary prophylactic ICD indication (HR = 0.69, 95% CI [0.52-0.93], P = 0.043) were independent predictors for less appropriate shocks. CONCLUSION: Women receive 50% less appropriate shocks than men having similar mortality in this large single-centre population. These data may pertain to individually improved selection of defibrillator candidates using risk factors, e.g. sex as demonstrated in this study. PMID- 26622057 TI - Diagnostic performance of CT, MRI and PET/CT in patients with suspected colorectal liver metastases: the superiority of MRI. AB - BACKGROUND: Meticulous imaging of colorectal liver metastases (CRLM) is mandatory to optimize outcome after liver resection. However, the detection of CRLM is still challenging. PURPOSE: To evaluate prospectively if magnetic resonance imaging (MRI) with diffusion-weighted and Gd-EOB-DTPA-enhanced sequences had a better diagnostic performance for CRLM compared to computed tomography (CT) and fluorine-18 fluorodeoxyglucose positron emission tomography (PET/CT). MATERIAL AND METHODS: Forty-six patients scheduled for resection of suspected CRLM were evaluated prospectively from September 2011 to January 2013. None of the patients had undergone previous treatment for their CRLM. Multiphase CT, liver MRI with diffusion-weighted and dynamic Gd-EOB-DTPA-enhanced sequences and low-dose PET/CT were performed. Two independent, blinded readers evaluated the examinations. The reference standard was histopathological confirmation (81/140 CRLM) or follow-up. RESULTS: A total of 140 CRLM and 196 benign lesions were identified. On a per lesion basis, MRI had the significantly highest sensitivity overall and for CRLM < 10 mm (P < 0.001). Overall sensitivity/specificity and PPV/NPV were 68%/94% and 89%/81% for CT, 90%/87% and 82%/93% for MRI, and 61%/99% and 97%/78% for PET/CT. For CRLM < 10 mm it was 16%/96% and 54%/80% for CT, 74%/88% and 64%/93% for MRI, and 9%/98% and 57%/79% for PET/CT. CONCLUSION: MRI had the significantly highest sensitivity compared with CT and PET/CT, particularly for CRLM < 10 mm. Therefore, detection of CRLM should be based on MRI. PMID- 26622055 TI - Human-based approaches to pharmacology and cardiology: an interdisciplinary and intersectorial workshop. AB - Both biomedical research and clinical practice rely on complex datasets for the physiological and genetic characterization of human hearts in health and disease. Given the complexity and variety of approaches and recordings, there is now growing recognition of the need to embed computational methods in cardiovascular medicine and science for analysis, integration and prediction. This paper describes a Workshop on Computational Cardiovascular Science that created an international, interdisciplinary and inter-sectorial forum to define the next steps for a human-based approach to disease supported by computational methodologies. The main ideas highlighted were (i) a shift towards human-based methodologies, spurred by advances in new in silico, in vivo, in vitro, and ex vivo techniques and the increasing acknowledgement of the limitations of animal models. (ii) Computational approaches complement, expand, bridge, and integrate in vitro, in vivo, and ex vivo experimental and clinical data and methods, and as such they are an integral part of human-based methodologies in pharmacology and medicine. (iii) The effective implementation of multi- and interdisciplinary approaches, teams, and training combining and integrating computational methods with experimental and clinical approaches across academia, industry, and healthcare settings is a priority. (iv) The human-based cross-disciplinary approach requires experts in specific methodologies and domains, who also have the capacity to communicate and collaborate across disciplines and cross-sector environments. (v) This new translational domain for human-based cardiology and pharmacology requires new partnerships supported financially and institutionally across sectors. Institutional, organizational, and social barriers must be identified, understood and overcome in each specific setting. PMID- 26622056 TI - Integration of family planning with maternal health services: an opportunity to increase postpartum modern contraceptive use in urban Uttar Pradesh, India. AB - BACKGROUND: Maternal health (MH) services provide an invaluable opportunity to inform and educate women about family planning (FP). It is expected that this would enable women to choose an appropriate method and initiate contraception early in the postpartum period. In this study we examined interactions with health providers for MH services, and the effect of FP information provision during these interactions on the postpartum use of modern contraceptive methods. METHODS: This study used midline data collected from 990 women who had delivered a live birth between January 2010 and the date of the midline survey in 2012. These women were asked a series of questions about their last delivery, including interactions with health providers during pregnancy, delivery and the postpartum period, if they received FP information during these interactions, and their contraceptive use during the postpartum period. RESULTS: The study found that FP information provision as part of antenatal care in the third trimester, delivery and the postpartum period have a positive association with postpartum modern contraceptive use in urban Uttar Pradesh. However, health providers often miss these opportunities. Despite a high proportion of women coming into contact with health providers when utilising MH services, only a small proportion received FP information during these interactions. CONCLUSIONS: Integration of FP with MH services can increase postpartum modern contraceptive use. With the launch of the National Urban Health Mission, there now exists appropriate policy and programmatic environments for integration of FP and MH services in urban settings in India. However, this will require a concentrated effort both to enhance the capacity of health providers and encourage supportive supervision. PMID- 26622058 TI - Application of T2 relaxometry in lateralization and localization of mesial temporal lobe epilepsy and corresponding comparison with MR volumetry. AB - BACKGROUND: Magnetic resonance (MR) volumetry is insensitive to subtle mesial temporal sclerosis (MTS), while T2 relaxometry is potential useful in detecting MTS, especially MTS in early course. PURPOSE: To explore and compare the feasibility of T2 relaxometry and MR volumetry in evaluation of mesial temporal lobe epilepsy (MTLE) and lateralization of the epileptogenic zone, so as to optimize and enhance lesion depiction. MATERIAL AND METHODS: For the 17 unilateral MTLE patients and 14 normal participants, the hippocampus and amygdala were contoured on axial T2-weighted (T2W) images and then co-registered onto T2 relaxation maps. Abnormal is defined as an elevated asymmetric ratio of larger than 2 SD. Visual and quantitative volumetric assessment were combined as outcomes of MR volumetry to distinguish MR-positive and MR-negative lesions. Operative and pathological findings were used as gold standard. RESULTS: T2 values of lesions were significantly elevated. In lateralizing the epileptogenic zones, T2 relaxometry yielded an overall accuracy of 94.1% (sensitivity 92.6%, specificity 100%), and MR volumetry yielded an overall accuracy of 82.4% (sensitivity 88.9%, specificity 57.1%), meaning a better performance of T2 relaxometry (P < 0.001, by chi-square test). For pathologically sclerotic structures, most (25/27) were recognized by T2 relaxometry, while 24 of 27 sclerotic structures were detected via MR volumetry. MR volumetry wrongly discerned three normal regions as MTS, while one MR-negative sclerotic hippocampus was detected by T2 relaxometry. CONCLUSION: T2 relaxometry is feasible in non-invasive lateralization of epileptogenic zone, and more advantaged than MR volumetry in detecting MR-negative lesions, facilitating prompt diagnosis and longitudinal disease monitoring. PMID- 26622059 TI - Are patients ready for communication with radiologists? Results of the R2P2 survey. AB - BACKGROUND: Patient empowerment requires that patients have enough information to make decisions concerning their own health. If patients are to discuss imaging results with radiologists, they have to know who these medical professionals are and what they do. PURPOSE: To examine whether patients understand the role of radiologists, and if particular subgroups are better informed than other ones. MATERIAL AND METHODS: Consecutive radiology outpatients in eight radiology centers could complete a web-based or printed questionnaire. Respondents indicated on a five-point Likert scale their level of agreement with 18 statements on the role of radiologists and their preferences concerning contacts with radiologists. Results were rearranged to allow comparison of predetermined subgroups. Dichotomous results were analyzed using chi(2) statistics. RESULTS: A total of 1,146 questionnaires were found eligible for analysis. Results showed confusion as to the question whether radiologists are medically qualified and enjoy all the privileges thereof. Medically qualified or highly educated respondents were modestly better informed. Patients in private practice were better informed than outpatients in hospitals. CONCLUSION: Patient empowerment requires better understanding of the role of radiologists. Different population subgroups necessitate specific information strategies. PMID- 26622060 TI - Cervical cancer response to neoadjuvant chemoradiotherapy: MRI assessment compared with surgery. AB - BACKGROUND: Imaging findings of residual cervical tumor after chemoradiotherapy can closely resemble those of post-irradiation inflammation. PURPOSE: To determine the diagnostic performance of magnetic resonance imaging (MRI) in evaluating residual disease after chemoradiotherapy in patients with locally advanced cervical carcinoma (LACC). MATERIAL AND METHODS: Retrospective analysis of prospectively collected data from 41 patients with histopathologically proven LACC (International Federation of Gynecology and Obstetrics stage >=IB2) who underwent MRI before and after chemoradiotherapy. At each examination, a qualitative and semi-quantitative analysis of primary tumor, including tumor volume and signal intensity were assessed on T2-weighted (T2W) images. All patients had surgery after post-chemoradiotherapy MRI. MRI and histopathologic results were compared. RESULTS: All patients showed significant difference in tumor volume and signal intensity between pre- and post-chemoradiotherapy MRI (P < 0.0001). According to pathology, 27/41 (66%) patients had true negative and 2/41 (5%) had true positive post-chemoradiotherapy MRI. Eleven out of 41 (27%) patients showed inflammation with false positive post-chemoradiotherapy MRI and 1/41 (2%) had a false negative post-chemoradiotherapy MRI. Sensitivity, specificity, accuracy, positive predictive values, and negative predictive values of post-chemoradiotherapy MRI in predicting residual disease were 69%, 71%, 71%, 15%, and 96%, respectively. CONCLUSION: The differentiation of residual tumor from post-irradiation inflammation with early post- chemoradiotherapy MRI (within 28-60 days) is difficult with a high risk of false positive results. Combination of qualitative and semi-quantitative analysis does not improve the accuracy. Conversely, post-chemoradiotherapy MRI has a high negative predictive value with a low risk of false negative results. The role of conventional MRI combined with functional techniques should be evaluated. PMID- 26622061 TI - Genotyping-by-sequencing map permits identification of clubroot resistance QTLs and revision of the reference genome assembly in cabbage (Brassica oleracea L.). AB - Clubroot is a devastating disease caused by Plasmodiophora brassicae and results in severe losses of yield and quality in Brassica crops. Many clubroot resistance genes and markers are available in Brassica rapa but less is known in Brassica oleracea. Here, we applied the genotyping-by-sequencing (GBS) technique to construct a high-resolution genetic map and identify clubroot resistance (CR) genes. A total of 43,821 SNPs were identified using GBS data for two parental lines, one resistant and one susceptible lines to clubroot, and 18,187 of them showed >5* coverage in the GBS data. Among those, 4,103 were credibly genotyped for all 78 F2 individual plants. These markers were clustered into nine linkage groups spanning 879.9 cM with an average interval of 1.15 cM. Quantitative trait loci (QTLs) survey based on three rounds of clubroot resistance tests using F2 : 3 progenies revealed two and single major QTLs for Race 2 and Race 9 of P. brassicae, respectively. The QTLs show similar locations to the previously reported CR loci for Race 4 in B. oleracea but are in different positions from any of the CR loci found in B. rapa. We utilized two reference genome sequences in this study. The high-resolution genetic map developed herein allowed us to reposition 37 and 2 misanchored scaffolds in the 02-12 and TO1000DH genome sequences, respectively. Our data also support additional positioning of two unanchored 3.3 Mb scaffolds into the 02-12 genome sequence. PMID- 26622062 TI - Improvement of barley genome annotations by deciphering the Haruna Nijo genome. AB - Full-length (FL) cDNA sequences provide the most reliable evidence for the presence of genes in genomes. In this report, detailed gene structures of barley, whole genome shotgun (WGS) and additional transcript data of the cultivar Haruna Nijo were quality controlled and compared with the published Morex genome information. Haruna Nijo scaffolds have longer total sequence length with much higher N50 and fewer sequences than those in Morex WGS contigs. The longer Haruna Nijo scaffolds provided efficient FLcDNA mapping, resulting in high coverage and detection of the transcription start sites. In combination with FLcDNAs and RNA Seq data from four different tissue samples of Haruna Nijo, we identified 51,249 gene models on 30,606 loci. Overall sequence similarity between Haruna Nijo and Morex genome was 95.99%, while that of exon regions was higher (99.71%). These sequence and annotation data of Haruna Nijo are combined with Morex genome data and released from a genome browser. The genome sequence of Haruna Nijo may provide detailed gene structures in addition to the current Morex barley genome information. PMID- 26622063 TI - Constructing a linkage-linkage disequilibrium map using dominant-segregating markers. AB - The relationship between linkage disequilibrium (LD) and recombination fraction can be used to infer the pattern of genetic variation and evolutionary process in humans and other systems. We described a computational framework to construct a linkage-LD map from commonly used biallelic, single-nucleotide polymorphism (SNP) markers for outcrossing plants by which the decline of LD is visualized with genetic distance. The framework was derived from an open-pollinated (OP) design composed of plants randomly sampled from a natural population and seeds from each sampled plant, enabling simultaneous estimation of the LD in the natural population and recombination fraction due to allelic co-segregation during meiosis. We modified the framework to infer evolutionary pasts of natural populations using those marker types that are segregating in a dominant manner, given their role in creating and maintaining population genetic diversity. A sophisticated two-level EM algorithm was implemented to estimate and retrieve the missing information of segregation characterized by dominant-segregating markers such as single methylation polymorphisms. The model was applied to study the relationship between linkage and LD for a non-model outcrossing species, a gymnosperm species, Torreya grandis, naturally distributed in mountains of the southeastern China. The linkage-LD map constructed from various types of molecular markers opens a powerful gateway for studying the history of plant evolution. PMID- 26622064 TI - KIT D816V-mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression. AB - Multilineage involvement of bone marrow (BM) hematopoiesis by the somatic KIT D816V mutation is present in a subset of adult indolent systemic mastocytosis (ISM) patients in association with a poorer prognosis. Here, we investigated the potential involvement of BM mesenchymal stem cells (MSCs) from ISM patients by the KIT D816V mutation and its potential impact on disease progression and outcome. This mutation was investigated in highly purified BM MSCs and other BM cell populations from 83 ISM patients followed for a median of 116 months. KIT D816V-mutated MSCs were detected in 22 of 83 cases. All MSC-mutated patients had multilineage KIT mutation (100% vs 30%, P = .0001) and they more frequently showed involvement of lymphoid plus myeloid BM cells (59% vs 22%; P = .03) and a polyclonal pattern of inactivation of the X-chromosome of KIT-mutated BM mast cells (64% vs 0%; P = .01) vs other multilineage ISM cases. Moreover, presence of KIT-mutated MSCs was associated with more advanced disease features, a greater rate of disease progression (50% vs 17%; P = .04), and a shorter progression-free survival (P <= .003). Overall, these results support the notion that ISM patients with mutated MSCs may have acquired the KIT mutation in a common pluripotent progenitor cell, prior to differentiation into MSCs and hematopoietic precursor cells, before the X-chromosome inactivation process occurs. From a clinical point of view, acquisition of the KIT mutation in an earlier BM precursor cell confers a significantly greater risk for disease progression and a poorer outcome. PMID- 26622065 TI - Health committee backs sugar tax on soft drinks in fight against child obesity. PMID- 26622066 TI - Intermittent pneumatic compression is effective in reducing proximal DVT. PMID- 26622067 TI - Soil moisture and chemistry influence diversity of ectomycorrhizal fungal communities associating with willow along an hydrologic gradient. AB - Influences of soil environment and willow host species on ectomycorrhizal fungi communities was studied across an hydrologic gradient in temperate North America. Soil moisture, organic matter and pH strongly predicted changes in fungal community composition. In contrast, increased fungal richness strongly correlated with higher plant-available phosphorus. The 93 willow trees sampled for ectomycorrhizal fungi included seven willow species. Host identity did not influence fungal richness or community composition, nor was there strong evidence of willow host preference for fungal species. Network analysis suggests that these mutualist interaction networks are not significantly nested or modular. Across a strong environmental gradient, fungal abiotic niche determined the fungal species available to associate with host plants within a habitat. PMID- 26622068 TI - Aging and Financial Decision Making. AB - This study examines how cognitive changes associated with aging impact the financial decision making capability of older Americans. We find that a decrease in cognition is associated with a decrease in financial literacy. Decreases in episodic memory and visuospatial ability are associated with a decrease in numeracy, and a decrease in semantic memory is associated with a decrease in financial knowledge. A decrease in cognition also predicts a drop in self confidence in general, but importantly, it is not associated with a drop in confidence in managing one's own finances. Participants experiencing decreases in cognition do show an increased likelihood of getting help with financial decisions; however, many participants experiencing significant drops in cognition still do not get help. PMID- 26622069 TI - In vitro controlled release of antigen in dendritic cells using pH-sensitive liposome-polymeric hybrid nanoparticles. AB - A hybrid nanoparticle (NP) consisting of a pH sensitive lipid shell and a poly(lactic-co-glycolic) acid (PLGA) core was constructed. This hybrid NP has a mean size of 120.1 +/- 8.8 nm and positively charged surface (zeta potential of 14.2 +/- 1.4 mV). The lipid shell of the hybrid NP was quickly disintegrated in buffer with a pH of 5.5, which resembles the acidic environment of endosomes in dendritic cell (DC). Less than 20% of the antigen enclosed in pH-sensitive hybrid NP was released into human serum at physiological pH within 24 h, but more than 40% of the enclosed antigen was released within 8 h after pH was adjusted to 5.5. Fast uptake of the pH sensitive hybrid NP by DC was also observed. It was found that pH sensitive hybrid NP displayed faster degradation and antigen release compared to regular hybrid NPs after uptake by DC. PMID- 26622070 TI - Ocular Perfusion Pressure vs Estimated Trans-Lamina Cribrosa Pressure Difference in Glaucoma: The Central India Eye and Medical Study (An American Ophthalmological Society Thesis). AB - PURPOSE: To test the hypothesis that taking translamina pressure difference into consideration changes associations between ocular perfusion pressure and glaucomatous optic neuropathy. METHODS: The population-based Central India Eye and Medical Study included 4711 subjects. Ocular perfusion pressure was calculated as follows: 2/3 [diastolic blood pressure + 1/3 * (systolic blood pressure - diastolic blood pressure)] - IOP. Cerebrospinal fluid pressure (mm Hg) was estimated as follows: 0.44 body mass index (kg/m(2)) + 0.16 diastolic blood pressure (mm Hg) - 0.18 * age (years) - 1.91. Translamina pressure difference was IOP minus cerebrospinal fluid pressure. RESULTS: In multivariate analysis, higher open-angle glaucoma prevalence was associaed with higher IOP (P<.001; odds ratio [OR], 1.19; 95% CI, 1.15, 1.24) or with higher translamina pressure difference (P<.001; OR, 1.15; 95% CI, 1.10, 1.19), but not with ocular perfusion pressure (P<.37). A smaller neuroretinal rim area was correlated with higher IOP (P<.001; standardized coefficient beta -0.09) or larger translamina pressure difference (P<.001; beta -0.10), but not with ocular perfusion pressure (P=.26). Greater prevalence of angle-closure glaucoma was associated with higher IOP (P<.001; OR, 1.22; 95% CI, 1.15, 1.28) or higher translamina pressure difference (P<.001; OR, 1.19; 95% CI, 1.13, 1.25) or lower ocular perfusion pressure (P<.04; OR, 0.95; 95% CI, 0.90, 0.996). Correlation coefficients were highest for the association with IOP and lowest for ocular perfusion pressure. A smaller rim area was correlated with higher IOP (P<.001; beta -0.08) and higher translamina pressure difference (P<.001; beta -0.08); rim area and ocular perfusion pressure were not significantly associated (P=.25). CONCLUSIONS: The present study provides information on the relationship of translamina pressure difference to the development of optic nerve damage in what is presently called glaucoma. It does not provide support of the idea that ocular perfusion pressure plays a major role in the pathogenesis of optic neuropathy. PMID- 26622071 TI - Phenotypes of Recessive Pediatric Cataract in a Cohort of Children with Identified Homozygous Gene Mutations (An American Ophthalmological Society Thesis). AB - PURPOSE: To assess for phenotype-genotype correlations in families with recessive pediatric cataract and identified gene mutations. METHODS: Retrospective review (2004 through 2013) of 26 Saudi Arabian apparently nonsyndromic pediatric cataract families referred to one of the authors (A.O.K.) and for which recessive gene mutations were identified. RESULTS: Fifteen different homozygous recessive gene mutations were identified in the 26 consanguineous families; two genes and five families are novel to this study. Ten families had a founder CRYBB1 deletion (all with bilateral central pulverulent cataract), two had the same missense mutation in CRYAB (both with bilateral juvenile cataract with marked variable expressivity), and two had different mutations in FYCO1 (both with bilateral posterior capsular abnormality). The remaining 12 families each had mutations in 12 different genes (CRYAA, CRYBA1, AKR1E2, AGK, BFSP2, CYP27A1, CYP51A1, EPHA2, GCNT2, LONP1, RNLS, WDR87) with unique phenotypes noted for CYP27A1 (bilateral juvenile fleck with anterior and/or posterior capsular cataract and later cerebrotendinous xanthomatosis), EPHA2 (bilateral anterior persistent fetal vasculature), and BFSP2 (bilateral flecklike with cloudy cortex). Potential carrier signs were documented for several families. CONCLUSIONS: In this recessive pediatric cataract case series most identified genes are noncrystallin. Recessive pediatric cataract phenotypes are generally nonspecific, but some notable phenotypes are distinct and associated with specific gene mutations. Marked variable expressivity can occur from a recessive missense CRYAB mutation. Genetic analysis of apparently isolated pediatric cataract can sometimes uncover mutations in a syndromic gene. Some gene mutations seem to be associated with apparent heterozygous carrier signs. PMID- 26622072 TI - Predictors of Physical Altercation among Adolescents in Residential Substance Abuse Treatment. AB - This study tested the hypothesis that basic social information-processing components represented by family conflict, peer aggression, and pro-aggression cognitive scripts are related to aggression and social problems among adolescents in substance abuse treatment. The sample consisted of 547 adolescents in two community-based residential facilities. Correlation results indicated that more peer aggression is related to more pro-aggression scripts; scripts, peer aggression, and family conflict are associated with social problems; and in treatment physical altercation involvement is predicted by higher peer aggression. Findings suggest that social information-processing components are valuable for treatment research. PMID- 26622073 TI - Using Automatic Speech Recognition to Assess Spoken Responses to Cognitive Tests of Semantic Verbal Fluency. AB - Cognitive tests of verbal fluency (VF) consist of verbalizing as many words as possible in one minute that either start with a specific letter of the alphabet or belong to a specific semantic category. These tests are widely used in neurological, psychiatric, mental health, and school settings and their validity for clinical applications has been extensively demonstrated. However, VF tests are currently administered and scored manually making them too cumbersome to use, particularly for longitudinal cognitive monitoring in large populations. The objective of the current study was to determine if automatic speech recognition (ASR) could be used for computerized administration and scoring of VF tests. We examined established techniques for constraining language modeling to a predefined vocabulary from a specific semantic category (e.g., animals). We also experimented with post-processing ASR output with confidence scoring, as well as with using speaker adaptation to improve automated VF scoring. Audio responses to a VF task were collected from 38 novice and experienced professional fighters (boxing and mixed martial arts) participating in a longitudinal study of effects of repetitive head trauma on brain function. Word error rate, correlation with manual word count and distance from manual word count were used to compare ASR based approaches to scoring to each other and to the manually scored reference standard. Our study's results show that responses to the VF task contain a large number of extraneous utterances and noise that lead to relatively poor baseline ASR performance. However, we also found that speaker adaptation combined with confidence scoring significantly improves all three metrics and can enable use of ASR for reliable estimates of the traditional manual VF scores. PMID- 26622074 TI - Coupling bounds for approximating birth-death processes by truncation. AB - Birth-death processes are continuous-time Markov counting processes. Approximate moments can be computed by truncating the transition rate matrix. Using a coupling argument, we derive bounds for the total variation distance between the process and its finite approximation. PMID- 26622075 TI - Design, development, and evaluation of an MRI-guided SMA spring-actuated neurosurgical robot. AB - In this paper, we present our work on the development of a magnetic resonance imaging (MRI)-compatible Minimally Invasive Neurosurgical Intracranial Robot (MINIR) comprising of shape memory alloy (SMA) spring actuators and tendon-sheath mechanism. We present the detailed modeling and analysis along with experimental results of the characterization of SMA spring actuators. Furthermore, to demonstrate image-feedback control, we used the images obtained from a camera to control the motion of the robot so that eventually continuous MR images could be used in the future to control the robot motion. Since the image tracking algorithm may fail in some situations, we also developed a temperature feedback control scheme which served as a backup controller for the robot. Experimental results demonstrated that both image feedback and temperature feedback can be used to control the motion of MINIR. A series of MRI compatibility tests were performed on the robot and the experimental results demonstrated that the robot is MRI compatible and no significant visual image distortion was observed in the MR images during robot operation. PMID- 26622076 TI - Impact of Comorbidity on Early Outcome of Patients with Subarachnoid Hemorrhage Caused by Cerebral Aneurysm Rupture. AB - BACKGROUND: One of the complications aneurysms subarachnoid hemorrhage is the development of vasospasm, which is the leading cause of disability and death from ruptured cerebral aneurysm. AIM: To evaluate the significance of previous comorbidities on early outcome of patients with subarachnoid hemorrhage caused by rupture of a cerebral aneurysm in the prevention of vasospasm. PATIENTS AND METHODS: The study had prospective character in which included 50 patients, whose diagnosed with SAH caused by the rupture of a brain aneurysm in the period from 2011to 2013. Two groups of patients were formed. Group I: patients in addition to the standard initial treatment and "3H therapy" administered nimodipine at a dose of 15-30 mg / kg bw / h (3-10 ml) for the duration of the initial treatment. Group II: patients in addition to the standard initial treatment and "3H therapy" administered with MgSO4 at a dose of 12 grams in 500 ml of 0.9% NaCl / 24 h during the initial treatment. RESULTS: Two-thirds of the patients (68%) from both groups had a good outcome measured with values according to GOS scales, GOS IV and V. The poorer outcome, GOS III had 20% patients, the GOS II was at 2% and GOS I within 10% of patients. If we analyze the impact of comorbidity on the outcome, it shows that there is a significant relationship between the presence of comorbidity and outcomes. The patients without comorbidity (83.30%) had a good outcome (GOS IV and V), the same outcome was observed (59.4%) with comorbidities, which has a statistically significant difference (p = 0.04). Patients without diabetes (32%) had a good outcome (GOS IV and V), while the percentage of patients with diabetes less frequent (2%) with a good outcome, a statistically significant difference (p = 0.009). CONCLUSION: The outcome of treatment 30 days after the subarachnoid hemorrhage analyzed values WFNS and GOS, is not dependent on the method of prevention and treatment of vasospasm. Most concomitant diseases in patients with SAH which, requiring additional treatment measures are arterial hypertension and diabetes mellitus. The best predictors in the initial treatment of patients with subarachnoid hemorrhage caused by rupture of a cerebral aneurysm has the presence of comorbidity, which has statistical significance. PMID- 26622077 TI - Molecular Characterization of Glucose-6-phosphate Dehydrogenase Deficiency in Families from the Republic of Macedonia and Genotype-phenotype Correlation. AB - INTRODUCTION: Glucose-6-phospahte dehydrogenase deficiency (G6PD) is one of the most common inherited disorders affecting around 400 million people worldwide. Molecular analysis of the G6PD gene identified more than 140 distinct mutations, the majority being single base missense mutations. G6PD Mediterranean is the most common variant found in populations of the Mediterranean area. AIM: The aim of our study was to perform molecular characterization of G6PD deficiency in families from the Republic of Macedonia and correlate the findings to disease phenotype. PATIENTS AND METHODS: Six patients and seven other family members were selected for genetic characterization, the selection procedure involved clinical evaluation and G6PD quantitative testing. All patients were first screened for the Mediterranean mutation, and subsequently for the Seattle mutation. Mutations were detected using PCR amplification and appropriate restriction endonuclease cleavage. RESULTS: Four hemizygote and 3 heterozygous carriers for G6PD Mediterranean were detected. All G6PD deficient patients from this group showed clinical picture of hemolysis, and in 66.6% neonatal jaundice was confirmed based on history data. To our knowledge, this is the first study concerned with molecular aspects of the G6PD deficiency in R. Macedonia. CONCLUSION: This study represents a step towards a more comprehensive genetic evaluation in our population and better understanding of the health issues involved. PMID- 26622078 TI - The Effect of Midazolam on Decreasing the Duration of Intussusception Hydrostatic Reduction in Children. AB - BACKGROUND AND OBJECTIVE: The use of sedative medications may be effective in the success and facilitation of the intussusception non-surgical treatment. Therefore, the purpose of this study was to examine the effect of midazolam on decreasing the duration of intussusception hydrostatic reduction in children. MATERIALS AND METHODS: In a double-blind clinical trial, 32 children were diagnosed with ileocolic intussusception based on sonographic findings, were studied and randomly divided into two groups. After obtaining written informed consent from the parents, 5 minutes before reduction, an intravenous Midazolam at the concentration of 1.0 mg/kg (up to 3 mg) was infused, and then barium reduction was performed under fluoroscopy guideline. In the control group, sterile water was injected as placebo and the remaining reduction steps were performed compared with the experiment group. RESULTS: Of 16 patients that received Midazolam, 15 patients demonstrated successful reduction; and of 16 patients that received distilled water, only 11 patients showed successful reduction (P=0.07). The mean duration of a successful reduction in the Midazolam group and placebo was 34.8+/-11.35 and 32.73+/-19.2 min, respectively (P=0.733). CONCLUSIONS: The use of Midazolam as a benzodiazepine with known sedative and muscle relaxant effects can increase the success rate of enema reduction in intussusception. PMID- 26622079 TI - Evaluation of 6 Patients with Genital Melanoma from Onset of Symptoms to Death: Evaluate the Factors Affecting the Prognosis of the Disease. AB - BACKGROUND: Genital melanoma is a rare but deadly cancer in women and the prognosis is often poor. PURPOSE: This study assesses the impact of possible risk factors on the end prognosis of the patients, with the ultimate goal of improving survival of disease. METHODS: This is a report of 6 patients diagnosed and treated as genital melanoma. Parameters reviewed included: age at diagnose, presenting symptoms, location size and Breslow depth of lesion, stage at diagnose, adjuvant therapies, hysterectomy and salpingo-oophorectomy, metastasis or recurrence in follow-up, chemotherapy for metastatic disease. RESULTS: The mean age at the time of diagnosis, was 44.67 years, the average size of lesion was 2.91 cm; the average Breslow depth of lesion was 1.93 mm. The mean interval between the onsets of symptoms to diagnosis was 16.7 months; the average life expectancy was 23.5 months. There is no significant relationship between the initial location of the lesion and prognosis (P: 0.98). Patients diagnosed in < 7 months, were in lower stages at diagnose (P: 0.018), and the survival of them was better (P: 0.035). Patients diagnosed in early stages had better survival at last (P: 0.035) Adjuvant radiotherapy improves survival markedly (P: 0.018). Hysterectomy and salpingo-oophorectomy had no significant effect on prognosis (P: 0.7). Chemotherapy in metastatic disease had no significant effect on prognosis (P: 0.46). CONCLUSION: The survival markedly improved if the disease diagnosed in a short distance from onset of symptoms and specially in early stages. Adjuvant radiotherapy can improve the survival significantly, but for the early hysterectomy and salpingo-oophorectomy and also for chemotherapy in metastatic disease, the impact on prognosis is uncertain, but positive. PMID- 26622080 TI - Open Rotator Cuff Tear Repair Using Deltopectoral Approach. AB - BACKGROUND: The goal of this study was to evaluate the outcome of the open repair of rotator cuff tears via the deltopectoral approach in patients unable to afford arthroscopic repair costs. METHODS: We evaluated 80 consecutive patients who were treated for full-thickness rotator cuff tears by open repair through the deltopectoral approach. There were 48 men and 32 women at a mean age of 60.1 years (range, 35-80 years). Preoperative and postoperative clinical assessments were performed with the Constant score, American Shoulder and Elbow Surgeons (ASES) score, modified University of California Los Angeles (UCLA) score, and pain visual analog scale. RESULTS: The mean follow-up period was 30.6 months (range, 18-48 months). At final follow-up visits, the ASES, Constant score, and modified UCLA score were found to have improved significantly from 33.56, 39.24, and 13.0 to 85.64, 81.46, and 32.2, respectively (P <0.01). Pain, as measured on a visual analog scale, was improved significantly (P <0.01). The mean time for recovering the full range of motion was 2.5 months. Postoperative pain at 48 hours and at 6 weeks was relatively low. There were no cases of intractable stiffness. CONCLUSION: The deltopectoral approach for open rotator cuff repair produced satisfactory results and reduces rate of shoulder stiffness and postoperative pain. PMID- 26622081 TI - Emergency Room Treatment of Hypertensive Crises. AB - AIM: The aim of the study was to evaluate efficiency of hypertensive urgency treatment using inhibitors of alpha1-adrenergic receptors and angiotensin converting enzyme inhibitors-ACE inhibitors in the Emergency Room of Outpatient Hospital and Polyclinic "dr Mustafa Sehovic" Tuzla in relation to age, duration and severity of hypertension. METHODS: The study was conducted from June 2011 to May 2012 and included 120 patients of both sexes diagnosed with arterial hypertension, aged 40 to 80 with verified hypertensive urgency. The patients were divided into two groups: the control group treated with sublingual captopril and the experimental group treated intravenously with urapidil. RESULTS: The results show that the largest number of patients belonged to age group from 60 to 69 years (34,16%), and the average age was 58 (11). The largest number of patients (38,0%) had verified hypertension for 11 to 20 years. The average systolic/diastolic artery blood pressure at reception was 213 (19) / 130 (4) mmHg. The average systolic/diastolic artery blood pressure after the first dose of 12,5 mg captopril in the control group was 177,42 (10,91) / 112,33 (3,50) mmHg, while after the first dose of 12,5 mg urapidil it was 179,25 (16,62) / 110,33 (8,78) mmHg. The average systolic/diastolic artery blood pressure after the second dose of 12,5 mg of captopril in the control group was 152,00 (6,32) / 95,50 (3,76) mmHg, while after the second dose of 12,5 mg of urapidil it was 152,55 (7,17) / 95,29 (5,04) mmHg. CONCLUSION: Urapidil is more efficient in hypertensive urgency treatment, since the decrease of middle artery pressure (MAP) in the group treated with urapidil was statistically significant (p<0,001). No statistical significance was found between the efficiency of urapidil and the patient's age, while captopril was more efficient in older patients (p=0,02). Also, no statistically significant difference was found between the efficiency of captopril and urapidil in relation to duration of hypertension. PMID- 26622082 TI - Inflammatory Markers and Procoagulants in Chronic Renal Disease Stages 1-4. AB - INTRODUCTION: Starting from the point that the chronic kidney disease (CKD) is chronic, inflammatory and hypercoagulable state characterized by an increase in procoagulant and inflammatory markers high cardiovascular morbidity and mortality in these patients could be explained. AIM: The aim of the research was to monitor inflammatory markers and procoagulants in various stages of kidney disease (stage 1-4). MATERIALS AND METHODS: The research included 120 subjects older than 18 years with CKD stages 1-4 examined and monitored in Clinic of Nephrology, University Clinical Centre Sarajevo over a period of 24 months. The research included determining the following laboratory parameters: serum creatinine, serum albumin, C-reactive protein, leukocytes in the blood, plasma fibrinogen, D-dimer, antithrombin III, coagulation factors VII (FC VII) and coagulation factor VIII (FC VIII). RESULTS: With the progression of kidney disease (CKD stages 1-4), there was a significant increase of inflammatory and procoagulant markers: CRP, fibrinogen and coagulation factor VIII, and an increase in the average values of leukocytes and a reduction in the value of antithrombin III, but without statistical significance. Also, there were no significant differences in the values of D-dimer and coagulation factor VII. CONCLUSION: The progression of kidney disease is significantly associated with inflammation, which could in the future be useful in prognostic and therapeutic purposes. Connection of CKD with inflammation and proven connection of inflammation with cardiovascular risk indicates the potential value of some biomarkers, which could in the future identify as predictors of outcome and could have the benefit in the early diagnosis and treatment of cardiovascular disease in CKD. PMID- 26622083 TI - Health Effects of the Programmed Physical Activities on Lipid Profile in Peripheral Arterial Disease of the Lower Extremities. AB - AIMS: Determine health effects of programmed physical activities on blood fats in peripheral arterial disease of lower limbs or in examinees on medication therapy and examinees performing programmed physical activities along with the medication therapy. METHODS: Overall research has been carried out at the Clinic for Vascular Disease CCUS. Before involvement into the study, examinees had to meet the inclusion criteria. Research was carried out as randomized controlled trial including 100 patients with arterial disease of lower limbs, who meet inclusion criteria: control group (CG, n=50) and test group (TG, n=50). Total level of cholesterol was used for effects assessment of 28 weeks of applied programmed activity in patients. RESULTS: Values of total cholesterol (tCh) and triglycerides before and after treatment in patients of CG and TG showed statistically significant change of its mean values. Significant decrease were marked in tCh and triglycerides levels in TG compared to CG. CONCLUSION: Adequate programmed physical activities in patients with peripheral vascular disease appeared as very successful in treated patients. Results indicate statistically significant decrease of the cholesterol and triglycerides after the treatment. Physical activity used in the treatment made partial regression of arterial diseases and saved patients for undergoing to surgery. Lower level of total cholesterol represents a ten year period prevention of initial stage in progress of arterial diseases. PMID- 26622084 TI - Urinary Problems Amongst Gynecological Consultations. Association Between Prolapse, Gynecological Surgery and Diabetes. AB - BACKGROUND: Urinary incontinence is the inability of a woman to maintain bladder control. Symptoms range from urgency, frequency, nocturia to urge incontinence (1). It limits functional and social activities and leads to depression and social withdrawal. (2). This observational study aimed to describe the common urinary problems amongst gynecological consultations. It also describes the relationship of urinary incontinence with history of diabetes, previous gynecological surgery and prolapse. METHODS: The study was conducted as a descriptive cross sectional study from Jan-May 2015 at Qassim University Clinic, Buraidah. Women with urinary problem and those without urinary problems were compared for risk factors including diabetes, prolapse and previous gynecological surgery. The Statistical Package for the Social Sciences 22 (SPSS 22) was used to conduct proportion z-tests to determine the association of prolapse, gynecological surgeries and diabetes with urinary incontinence. To test the hypothesis, differences between two groups on the aforementioned factors were examined. The groups included participants that reported having urinary problems (n = 111) and those who do not have urinary problems (n = 100). RESULTS: The most frequent complaints of participants with urinary problems were urgency (n = 66, 59.46%), Stress incontinence (SI) (n = 65, 58.56%) and frequency (n = 62, 55.86%). For participants with a urinary problem, 89.19% have not had a gynecological surgery (n = 99) and the remaining 10.81% of participants had a gynecological surgery (n = 12). For participants without a urinary problem, 97.0% have not had a gynecological surgery (n = 97) and the remaining 3.0% had a gynecological surgery (n = 3). For participants with a urinary problem, 72.97% did not have diabetes (n = 81) and the remaining 27.03% of participants did have diabetes (n = 30). For participants without a urinary problem, 92.0% did not have diabetes (n = 92) and the remaining 8.0% did report having diabetes (n = 8). For participants with a urinary problem, 91.89% had not experienced a prolapse (n = 102) and the remaining 8.11% of participants had experienced a prolapse (n = 9). For participants without a urinary problem, 98.0% have not experienced a prolapse (n = 98) and the remaining two participants had experienced a prolapse. CONCLUSION: Gynecological conditions such as prolapse of the uterus, surgery involving the pelvic floor as well as medical conditions such as diabetes mellitus are some of the key risk factors for urinary incontinence. Therefore control of these risk factors can avoid development of urinary incontinence. Bladder retraining, Kegel exercises, drinking of less fluids are some of the preventive measures to avoid development of this embarrassing condition. PMID- 26622085 TI - Electrocardiographic and Echocardiographic Imaging of the Heart of Athletes and Patients with Hypertension. AB - INTRODUCTION: "Athlete's heart syndrome" is a condition characterized by structural, electrophysiologic and functional adaptation of the myocardium to physical activity (training), depending on the activity intensity, duration and type. In athletes left ventricular hypertrophy often resembles comorbid conditions (hypertension or hypertrophic cardiomyopathy) so the differential diagnosis of the disease is very important and crucial, especially in people who are in active training. In fact, if an athlete has finding which indicate thickening of the left ventricle walls, should be distinguished hypertrophy which occurred as a result of many years of training from accidental existence of hypertension or hypertrophic cardiomyopathy in the same person. Therefore, it is important to make a diagnostic difference between healthy and sick heart. MATERIAL AND METHODS: The study involved male persons aged 20-45 which have increased muscle mass of the left ventricle due to different etiology. Definite sample included 80 respondents divided into two groups. All respondent underwent interview, clinical examination, ECG and echocardiography. RESULTS: Average systolic blood pressure (SBP) for the athletes were 115.8+/-7.2 mmHg, and in patients, with hypertension 154.4+/-3.5 mmHg, average values of diastolic blood pressure (DBP) for the athletes were 74.2+/-8.1 mmHg in patients, hypertensive 96.2 +/- 3.9 mmHg. Values of SBP and DBP were significantly lower in the group of athletes compared to patients with hypertension (p=0.001). The value of the SFO/min was significantly lower in the group of athletes compared to patients with hypertension (p <0.001). There was a statistically significant difference in the sum of SV2 RV5 and between groups of athletes and groups of patients with hypertension (p<0.05). There was no significant difference in the echocardiography parameters between two groups. There was a statistically significant difference in the sum of SV2 and RV5 between groups of athletes and groups of patients with hypertension (p<0.05). CONCLUSION: ECG parameters, PQ, QRS, QT did not prove to be useful in the differentiation between the groups because no statistically significant differences in their values were found. Echocardiography is a reliable diagnostic tool in differentiating physiologic hypertrophy of athletes compared to hypertrophy in patients with hypertension. PMID- 26622086 TI - Clinical Impact of Chronic Tonsillitis on Weight and Height Parameters. AB - AIM: The aim of the study was to determine the impact of chronic tonsillitis before and after the surgical intervention with physiological values of the physiological parameters, such as the weight and height. MATERIAL AND METHODS: The clinical study was of a transversal type (cross-sectional). In the study participated 85 patients, who fulfilled the criteria of the study. RESULTS: Mean age of the participants in the study was 7.15 (7.11 years, for the boys and 7.19 years for the girls). There were no significant statistical changes in the boys and girls included in the study according to age. Connections between the weight and height resulted very strong and statistically important for each phase of the measurements performing in the study. CONCLUSION: I propose careful treatment of patients with chronic tonsillitis, especially for the young age patients as well as measurement taking for an adequate treatment on time (adenotonsillectomy) since it is the only method to complication prevention in the organism including the physiological parameters like weight and height. PMID- 26622087 TI - Treatment of Infertility in Men with Post-traumatic Stress Disorder (PTSD) with the Method of Intrauterine Insemination. AB - OBJECTIVE: Our objective was to determine the effect of PTSD on changing the quality of sperm in veterans with PTSD, and the percentage of successful procedures intrauterine insemination (IUI) as a first-line treatment of male infertility patients with post-traumatic stress disorder (PTSD). PATIENTS AND METHODS: The study is designed as a prospective observational study. The study was started from February 2013 until May of 2014. Our study included a total of 51 patients who were treatment for infertility in private Hospital for gynecology, endocrinology and infertility, IVF Center in Peja, and those who were outpatients treated for chronic PTSD in the Polyclinic, Biolab-Zafi, in Klina the Republic of Kosovo. All subjects divide into two groups; The first, consisting of 21 respondents to the participants of the war in Kosovo, which was established diagnosis of PTSD. The second group of 30 who have not lived in Kosovo for the time War, and without signs of PTSD. RESULTS: Subjects with PTSD were somewhat older than the control group (p = 0.235) but it was not a significant difference (44.5 +/- 5.6 vs 43.8 +/- 2.3). When the question of type of infertility, secondary infertility is significantly higher in patients with PTSD (62% vs 20%). The total number of sperm and semen volume no significant differences between the two groups (p > 0.05). Sperm motility showed a significant reduction in cases of PTSD (p <0.0001), from observation semen parameters were found more abnormal forms of spermatozoa in the ejaculate cases with PSD (p < 0.0001) (Table 2). The percentage of pregnancies IUI procedure was slightly higher in patients with PTSD than the control group without PTSD (19% vs. 16.6%). CONCLUSION: A combination of analytical oriented psychotherapy techniques and assisted reproductive techniques (ART) such as IUI procedures, increases the chances for healing infertility in patients with PTSD. PMID- 26622088 TI - Gender Representation of Osteoporosis in Patients with Urolithiasis. AB - INTRODUCTION: A great number of clinical studies has indicated that the patients with calcium urolithiasis have a reduced mineral bone density. AIM: The aim of our research was to establish representation of osteoporosis, by measuring mineral bone density using the DEXA method, in patients with calcium urolithiasis, by gender. MATERIAL AND METHODS: The research was a prospective one, performed at the University Hospital of the Clinical Center of Banja Luka, at the Urology Clinic and Clinic for Endocrinology, Diabetes and Metabolic Diseases. The material in this research were the patients divided into two groups: a working group (the patients suffering from calcium urolithiasis) and a control group (the patients without calcium urolithiasis). One hundred and twenty (120) patients were included in both these groups, divided in three age subgroups: 20-40, 40-60 and over 60. The total working group consisted of 63 men (52.2%) and 57 (47.5%) women. In the control group, the number of women was 72 (60%) and 48 (40%) of men. Establishing of mineral bone density at L2-L4 of lumbal spine vertebrae and hip was done for the patients in both these groups, using DEXA method. RESULTS: Analysis of mineral bone density using DEXA method in patients by gender of working and control groups has shown that osteoporosis and osteopenia in patients of the working group is significantly more present in women (14% and 22.8%) compared to men (1.6% and 17.5%). When compared by gender in the control group, osteoporosis was present a lot more in women (36.1%) compared to men (2.1%). When observed for the total sample of both the working and control group, there was a statistically significant difference (p<0,01) related to gender structure, where the share of women with osteoporosis/osteopenia was significantly higher (36.1%) compared to men (4.2%). CONCLUSION: Representation of osteoporosis in women with urolithiasis, particularly of older age, is very expressed and this is why prevention measures should start as soon as possible, so as to avoid severe complications of this illness. PMID- 26622089 TI - Intraocular Pressure Measurements Referring to the Corneal Thickness in Keratoconic Eyes After Corneal Crosslinking with Riboflavin and Ultraviolet A. AB - AIM: To determine the possible relation between intraocular pressure (IOP), central corneal thickness (CCT) and corneal resistance (CR) in kerotoconic eyes before, 3,6 and 12 months after collagen crosslinking procedure (CXL) with aim to find out does the thicker cornea means already more resistance cornea followed with higher IOP. METHODS: Thirty eyes (30 patients) with central keratoconus (KC)were evaluated in retrospective cross sectional study. The corneal biomechanical parameters were taken with Wave Light Allegro Oculyzer produced by Alcon before the CXL, 3, 6 and 12 months after the procedure. IOP were checked by Goldmann applanation tonometry (GAT) before, 3, 6 and 12 months after CXL. RESULTS: The value of IOP before the CXL was 12,0 mmHg (10,62-15,25 mmHg), 3 months later 13,5 mmHg (11,0-16,0 mmHg), 6 months 14,0 mmHg (11,0-16,0 mmHg) and 12 months later 15,0 mmHg (10,37-17,25 mmHg) and was statistically significant higher (p=0,015) comparing to the value of IOP 3 months after the CXL, IOP 12 months after CXL procedure was statistically significant higher comparing to preoperative values (p=0,010). There were no statistically significant difference between the values 3 and 6 months after CXL. The CCT before the CXL procedure was 449 (433-505,75 microns), 3 months after CXL was 420 (383-473microns, p < 0,005), 6 months later 437 (401,25-480,25, p=0,001), 12 months after CXL 437 (401-503 microns, p=0,001). However there is statistically significant difference in CCT 12 months after CXL 437 (401-503microns p=0,032) and the value of CCT 3 months later the procedure (p=0,004) and the CCT 12 months after CXL and the value of CXL 6 months after CXL (p=0,036). The value of CCT did not show any statistically significant difference 3 and 6 months postoperatively. CONCLUSION: After riboflavin-UVA CXL in eyes with KC there was significant decrease in central corneal thickness 3 and 6 months after the procedure and the thickness is almost the same 12 months later. However IOP is low before CXL, raising up 3 and 6 months after CXL but significant increase is seen 12 months later. It means the regular measurement of IOP could be the serious and confident indicator of increasing of corneal resistance which is the main goal of CXL treatment. PMID- 26622091 TI - Familial Pompe Disease. AB - INTRODUCTION: Pompe disorder is a rare glycogen storage disorder that is due to a deficiency of the lysosomal alpha glycosidase enzyme. The heart, skeletal muscle, liver and nervous system can be affected from the lysosomal glycogen accumulation. Symptoms such as muscle weakness, hypotony, myopathy and respiratory failure develop. The onset may be at the infantile, adolescent or adult period depending on the enzyme level. The CK level is high in almost all patients. The diagnosis is made with enzyme level measurement and genetic analysis. CASE REPORT: We present a family with Pompe disease consisting of the asymptomatic mother and two siblings who presented with muscle weakness and respiratory failure and who had been followed-up with a diagnosis of muscular dystrophy for a long time. PMID- 26622090 TI - Atherogenic Dyslipidemia and Residual Vascular Risk in Practice of Family Doctor. AB - OBJECTIVE: Timely recognition and optimal management of atherogenic dyslipidemia (AD) and residual vascular risk (RVR) in family medicine. BACKGROUND: The global increase of the incidence of obesity is accompanied by an increase in the incidence of many metabolic and lipoprotein disorders, in particular AD, as an typical feature of obesity, metabolic syndrome, insulin resistance and diabetes type 2. AD is an important factor in cardio metabolic risk, and is characterized by a lipoprotein profile with low levels of high-density lipoprotein (HDL), high levels of triglycerides (TG) and high levels of low-density lipoprotein (LDL) cholesterol. Standard cardiometabolic risk assessment using the Framingham risk score and standard treatment with statins is usually sufficient, but not always that effective, because it does not reduce RVR that is attributed to elevated TG and reduced HDL cholesterol. RVR is subject to reduction through lifestyle changes or by pharmacological interventions. In some studies it was concluded that dietary interventions should aim to reduce the intake of calories, simple carbohydrates and saturated fats, with the goal of reaching cardiometabolic suitability, rather than weight reduction. Other studies have found that the reduction of carbohydrates in the diet or weight loss can alleviate AD changes, while changes in intake of total or saturated fat had no significant influence. In our presented case, a lifestyle change was advised as a suitable diet with reduced intake of carbohydrates and a moderate physical activity of walking for at least 180 minutes per week, with an recommendation for daily intake of calories alignment with the total daily (24-hour) energy expenditure (24-EE), depending on the degree of physical activity, type of food and the current health condition. Such lifestyle changes together with combined medical therapy with Statins, Fibrates and Omega-3 fatty acids, resulted in significant improvement in atherogenic lipid parameters. CONCLUSION: Unsuitable atherogenic nutrition and insufficient physical activity are the new risk factors characteristic for AD. Nutritional interventions such as diet with reduced intake of carbohydrates and calories, moderate physical activity, combined with pharmacotherapy can improve atherogenic dyslipidemic profile and lead to loss of weight. Although one gram of fat release twice more kilo calories compared to carbohydrates, carbohydrates seems to have a greater atherogenic potential, which should be explored in future. PMID- 26622093 TI - Trainees and Private Practice: Our Greatest Contribution from Academia. PMID- 26622092 TI - Tinea Corporis, Caused by Microsporum Canis - a Case Report From Kosovo. AB - INTRODUCTION: Tinea corporis (B35.6) caused by Microsporum canis which is fungal species that causes numerous forms of disease. It is part of a group of fungi known as Dermatophytes. Though mostly well known for ringworm in pets, it is also known to infect humans. This fact makes this pathogen both anthrophilic and zoophilic in nature. Microsporum canis is a communicable pathogen. CASE REPORT: We will report about a case, 22-year-old female, residing in a village, with typical changes of a mycotic infection caused by M. Canis. Dermatological description can be summarized with polymorphic erythematous, papulosquamous changes, erosions mainly on genital organ and spread to the thighs and lower abdomen which are accompanied with itching and burning. Diagnosis B35.6 was determined on the basis of clinical appearance complemented with anamnesis, microscopic examination and culture. The patient was treated successfully with general and local antimycotics and antibiotics. PMID- 26622094 TI - The EmprintTM Ablation System with ThermosphereTM Technology: One of the Newer Next-Generation Microwave Ablation Technologies. AB - Microwave ablation is a recent development in the field of tumor ablation that uses electromagnetic waves to establish a microwave near-field with direct tissue heating. Some of the limitations of the earlier generation devices had been unpredictable size and shape of the ablation zones with changes in the surrounding tissue environment as well as differences across various different tissue types. The Emprint Ablation System with Thermosphere Technology (Covidien, Boulder, CO) is the most recent generation ablation system that attempts to produce predictable large spherical zones of ablation despite varying tissue environments across different tissue types such as liver, lung, and bone to name a few. This article will discuss these recent device developments as well as review some basic microwave characteristics. PMID- 26622095 TI - Vascular Imaging with Carbon Dioxide: Confidence in a Safe, Efficacious, User Friendly System. AB - Carbon dioxide (CO2) has been used as an imaging agent since the early 1900s. The intravascular use of CO2 for imaging began in the 1960s. Its use was limited, as the available technology for imaging and safe delivery was poor. Even until today its use as an imaging agent has not reached its potential because of non-user friendly and cumbersome delivery methods. Confusing tanks, valves, and assembly of do-it-yourself systems create an aversion to its use. As an invisible agent with properties vastly different from liquid contrast, well-seasoned interventionalists are hesitant to use it because of perceived often unrealistic potential complications. Despite many of the advantages of a gaseous imaging agent, insecurity has translated to its lack of use and availability to the benefit of patients. With the development of the new CO2mmander/AngiAssist delivery system (AngioAdvancements, Inc; Ft. Meyers, FL), a compact, unwieldy, easily understood, closed system that does not require assembly is replacing the various makeshift systems in the CO2 community. This system combines a small multiuse disposable cylinder, compact regulator, and a dual syringe delivery system to the patient. A unique proprietary valve (K-valve) prevents the possibility of CO2 overload during delivery. Because of one-way valves and the prepackaged complete setup, operator error and air contamination with inadvertent connections are eliminated. Noncompressed CO2 is administered in the volume of choice in a nonexplosive manner. This simple, yet safe and effective, delivery system will undoubtedly promote the greater use of intravascular CO2. This in turn will translate into improved patient care in both the diagnostic and interventional arena. PMID- 26622096 TI - Hydrogel-Coated Coils: Product Description and Clinical Applications. AB - Hydrogel-coated coils are truly detachable coils with a platinum core covered with hydrogel. The coils are available in 0.018- and 0.035-in systems. These coils have the ability to expand up to four times their size ~20 minutes after deployment, thus providing a very effective mechanical vascular occlusion effect. The vessel-occlusive effect of these coils is a volume, space-occupying effect, not a thrombotic effect, as seen in fibered coils. Hydrogel-coated coils were originally developed and designed to treat brain aneurysms; however, their use has expanded to peripheral applications. Hydrogel-coated coils have been used in the management of visceral aneurysms, high-flow vascular arteriovenous fistulae, and endoleaks after endovascular thoracic and abdominal aneurysm repair. The purpose of this article is to describe the hydrogel-coated coil system, the mechanism of action, technical details for optimal deployment, and clinical applications. PMID- 26622097 TI - Irreversible Electroporation. AB - Irreversible electroporation (IRE) is a predominantly nonthermal ablative technology that uses high-voltage, low-energy DC current pulses to induce cell death. Thermal ablative technologies such as radiofrequency ablation, microwave ablation, and cryoablation have several applications in oncology but have limitations that have been established. IRE has shown promise to overcome some of these limitations. This article reviews the basics of the technology, patient selection, clinical applications, practical pointers, and the published data. PMID- 26622099 TI - Treatment of Chronic Total Occlusions Using the Avinger Ocelot Crossing Catheter. AB - Peripheral arterial disease is becoming more prevalent as the population ages. In addition, the severity of the disease seems to be progressing from simple narrowing of vessels to chronic total occlusions (CTOs). Treatment of CTOs of the infrainguinal peripheral arteries remains a challenge even for experienced endovascular specialists. Many crossing techniques have been described ranging from standard guidewire and catheter-based techniques including subintimal recanalization to specialized CTO crossing devices. One of the newest technologies, the Avinger Ocelot catheter (Avinger, Inc., Redwood City, CA), employs optical coherence tomography imaging on the tip of a rotating crossing catheter to allow visual confirmation of luminal passage. This article will review this new technology for crossing CTOs, review the results of the multicenter CONNECT II trial, and discuss the potential benefits of direct visualization while crossing occlusions. PMID- 26622098 TI - The Amplatzer Vascular Plug: Review of Evolution and Current Applications. AB - The Amplatzer Vascular Plug (AVP) was created for peripheral embolization as a modification of the family of Amplatz septal occluders used in the treatment of congenital heart malformations. The device has evolved over the years and multiple versions have been launched into the market. Each of the versions of the device has some important modifications in terms of the size of the introducer's system, number of layers, and resultant thrombogenicity. It is very important for the operator to become familiar with the unique features of the AVP, and to understand the advantages and limitations of each model in the AVP family to achieve an optimal embolic result. The purpose of this article is to review the evolution and current clinical applications of the AVP in the field of interventional radiology, with emphasis on the advantages and limitations of this device in comparison with other embolization agents. PMID- 26622100 TI - Venous Thromboembolic Disease: The Use of the Aspiration Thrombectomy Device AngioVac. AB - Central venous thrombosis is a complex problem, particularly in cases where the thrombus burden is large. Several interventional techniques and devices have been developed over the past 15 to 20 years to manage this entity, but the vast majority of them still need the concomitant use of thrombolytics to achieve an optimal result. AngioVac (AngioDynamics, Latham, NY) is the first aspiration thrombectomy device capable to remove a larger burden of undesired intravascular material such as thrombus, tumor, and foreign bodies without the need of lytics. This review focuses on the AngioVac device in the management of iliocaval thrombosis and pulmonary embolism. PMID- 26622101 TI - Retrievable Filter Update: The Denali Vena Cava Filter. AB - Over the past decade, there has been a gradual evolution of the retrievable inferior vena cava (IVC) filter, as the indications for caval filtration have expanded since the first such filters came into use. However, the particular design of retrievable or optional filters has introduced a subset of both symptomatic and asymptomatic device failures that have prompted a reassessment in the approach to patient selection as well as a new lexicon of technical considerations when considering retrieval. The Denali Vena Cava Filter (Bard Peripheral Vascular, Inc., Tempe, AZ) represents one of the latest filters to come to market that specifically addresses the various issues of its predecessors. While the body of published experience with this filter is still relatively sparse, the incidence of filter tilt, strut perforation, strut fracture, and filter migration appears acceptably low and the filters remain relatively easy to retrieve even after long dwell times. PMID- 26622102 TI - Endovascular Management of Acute Pulmonary Embolism Using the Ultrasound-Enhanced EkoSonic System. AB - Acute, symptomatic pulmonary embolism (PE) in the massive and submassive categories continues to be a healthcare concern with significant risk for increased morbidity and mortality. Despite increased awareness and venous thromboembolism prophylaxis, endovascular treatment is still an important option for many of these patients. There are a variety of techniques and devices used for treating PE, but none have been evaluated as extensively as the EkoSonic endovascular system that is also currently the only FDA-approved device for the treatment of pulmonary embolism. This article describes the use of the EkoSonic device for this patient population. PMID- 26622103 TI - Yttrium-90 Radioembolization of Hepatocellular Carcinoma-Performance, Technical Advances, and Future Concepts. AB - Hepatocellular carcinoma (HCC) is a lethal tumor, claiming over half a million lives per year. Treatment of HCC is commonly performed without curative intent, and palliative options dominate, including catheter-based therapies, namely, transarterial chemoembolization and yttrium-90 ((90)Y) radioembolization. This review will showcase the performance of (90)Y radioembolization for the treatment of HCC, focusing on recent seminal data and technical advances. In particular, novel radioembolization treatment concepts are discussed and compared with conventional HCC therapy. PMID- 26622105 TI - Navigational Tools for Interventional Radiology and Interventional Oncology Applications. AB - The interventional radiologist is increasingly called upon to successfully access challenging biopsy and ablation targets, which may be difficult based on poor visualization, small size, or the proximity of vulnerable regional anatomy. Complex therapeutic procedures, including tumor ablation and transarterial oncologic therapies, can be associated with procedural risk, significant procedure time, and measurable radiation time. Navigation tools, including electromagnetic, optical, laser, and robotic guidance systems, as well as image fusion platforms, have the potential to facilitate these complex interventions with the potential to improve lesion targeting, reduce procedure time, and radiation dose, and thus potentially improve patient outcomes. This review will provide an overview of currently available navigational tools and their application to interventional radiology and oncology. A summary of the pertinent literature on the use of these tools to improve safety and efficacy of interventional procedures compared with conventional techniques will be presented. PMID- 26622104 TI - High-Intensity Focused Ultrasound: Current Status for Image-Guided Therapy. AB - Image-guided high-intensity focused ultrasound (HIFU) is an innovative therapeutic technology, permitting extracorporeal or endocavitary delivery of targeted thermal ablation while minimizing injury to the surrounding structures. While ultrasound-guided HIFU was the original image-guided system, MR-guided HIFU has many inherent advantages, including superior depiction of anatomic detail and superb real-time thermometry during thermoablation sessions, and it has recently demonstrated promising results in the treatment of both benign and malignant tumors. HIFU has been employed in the management of prostate cancer, hepatocellular carcinoma, uterine leiomyomas, and breast tumors, and has been associated with success in limited studies for palliative pain management in pancreatic cancer and bone tumors. Nonthermal HIFU bioeffects, including immune system modulation and targeted drug/gene therapy, are currently being explored in the preclinical realm, with an emphasis on leveraging these therapeutic effects in the care of the oncology patient. Although still in its early stages, the wide spectrum of therapeutic capabilities of HIFU offers great potential in the field of image-guided oncologic therapy. PMID- 26622106 TI - Planning Arteriography for Yttrium-90 Microsphere Radioembolization. PMID- 26622107 TI - Superior Vena Cava Rupture and Cardiac Tamponade Complicating the Endovascular Treatment of Malignant Superior Vena Cava Syndrome: A Case Report and Literature Review. PMID- 26622109 TI - Watch what I do, not what I say I do: Computer-based avatars to assess behavioral inhibition, a vulnerability factor for anxiety disorders. AB - Behavioral inhibition (BI), a tendency to withdraw from or avoid novel social and non-social situations, is a personality trait which can confer risk for anxiety disorders. Like many personality traits, BI is often assessed via self-report questionnaires where respondents rate themselves for frequency of certain behaviors or feelings. However, questionnaires have inherent limitations, particularly in psychiatric populations where there may be unawareness of deficit. A viable alternative may be virtual environments, in which the participant guides an on-screen "avatar" through a series of onscreen events meant to simulate real-world situations. Here, we report on initial development of such an assessment tool, involving several onscreen scenarios with choice points where the participant can select from response options corresponding to inhibited or uninhibited behaviors. In two experiments involving over 300 college students, scores on the computer-based task were strongly correlated with BI scores attained through self-report questionnaire (r>.780, p<.001); this relationship held regardless of participant gender and experience with computer games. The results suggest that virtual environments may hold promise as alternative formats for assessment of personality traits in populations unsuited to traditional paper-and-pencil questionnaire formats due to psychopathology, limited attention span, or poor vocabulary and/or literacy skills. PMID- 26622110 TI - Residual gallbladder stones after cholecystectomy: A literature review. AB - BACKGROUND: Incomplete gallbladder removal following open and laparoscopic techniques leads to residual gallbladder stones. The commonest presentation is abdominal pain, dyspepsia and jaundice. We reviewed the literature to report diagnostic modalities, management options and outcomes in patients with residual gallbladder stones after cholecystectomy. MATERIALS AND METHODS: Medline, Google and Cochrane library between 1993 and 2013 were reviewed using search terms residual gallstones, post-cholecystectomy syndrome, retained gallbladder stones, gallbladder remnant, cystic duct remnant and subtotal cholecystectomy. Bibliographical references from selected articles were also analyzed. The parameters that were assessed include demographics, time of detection, clinical presentation, mode of diagnosis, nature of intervention, site of stone, surgical findings, procedure performed, complete stone clearance, sequelae and follow-up. RESULTS: Out of 83 articles that were retrieved between 1993 and 2013, 22 met the inclusion criteria. In most series, primary diagnosis was established by ultrasound/computed tomography scan. Localization of calculi and delineation of biliary tract was performed using magnetic resonance imaging/magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography. In few series, diagnosis was established by endoscopic ultrasound, intraoperative cholangiogram and percutaneous transhepatic cholangiography. Laparoscopic surgery, endoscopic techniques and open surgery were the most common treatment modalities. The most common sites of residual gallstones were gallbladder remnant, cystic duct remnant and common bile duct. CONCLUSION: Residual gallbladder stones following incomplete gallbladder removal is an important sequelae after cholecystectomy. Completion cholecystectomy (open or laparoscopic) is the most common treatment modality reported in the literature for the management of residual gallbladder stones. PMID- 26622111 TI - The procedure outcome of laparoscopic resection for 'small' hepatocellular carcinoma is comparable to vlaparoscopic radiofrequency ablation. AB - BACKGROUND: The aim of this study was to compare the effectiveness of laparoscopic liver resection (LLR) and laparoscopic radiofrequency ablation (LRFA) in the treatment of small nodular hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We enrolled 50 cirrhotic patients with similar baseline characteristics that underwent LLR (n = 26) or LRFA (n = 24), in both cases with intraoperative ultrasonography. Operative and peri-operative data were retrospectively evaluated. RESULTS: LLR included anatomic resection in eight cases and non-anatomic resection in 18. In LRFA patients, a thermoablation of 62 nodules was achieved. Between LLR and LRFA groups, a significant difference was found both for median diameters of treated HCC nodules (30 vs. 17.1 mm; P < 0.001) and the number of treated nodules/patient (1.29 +/- 0.62 vs. 2.65 +/- 1.55; P < 0.001). A conversion to laparotomy occurred in two LLR patient (7.7%) for bleeding. No deaths occurred in both groups. Morbidity rates were 26.9% in the LLR group versus 16.6% in the LRFA group (P = 0.501). Hospital stay in the LLR and LRFA group was 8.30 +/- 6.52 and 6.52 +/- 2.69 days, respectively (P = 0.022). The surgical margin was free of tumour cells in all LLR patients, with a margin <5 mm in only one case. In the LRFA group, a complete response was achieved in 90.3% of thermoablated HCC nodules at the 1-month post-treatment computed tomography evaluation. CONCLUSIONS: LLR for small peripheral HCC in patients with chronic liver disease represents a valid alternative to LRFA in terms of patient toleration, surgical outcome of the procedure, and short-term morbidity. PMID- 26622108 TI - Hepatorenal Syndrome: A Review of Pathophysiology and Current Treatment Options. PMID- 26622112 TI - Laparoscopic reconstruction of ureteral strictures involving solitary renal units 1 year and 5 year outcomes. AB - CONTEXT: Long-term outcome following a laparoscopic reconstruction of ureteral strictures (US) involving solitary renal units (SRU) are scarcely reported. AIMS: The aim was to report short-term (1 year) and long-term (5 years) outcomes following a laparoscopic reconstruction of US in a solitary kidney. SETTINGS AND DESIGN: Retrospective. MATERIALS AND METHODS: Records of patients operated for similar scenarios between January 2004 and January 2014 were evaluated. Clinical, biochemical and radiological profile were noted. Operative and post-operative profile were recorded. Follow-ups were scheduled at regular intervals (3 months post-procedure, 6 monthly for 2 years and yearly thereafter. Imaging was repeated at yearly intervals). Outcome was assessed by comparing pre-operative and post operative clinical, biochemical, and radiological parameters. STATISTICAL ANALYSIS USED: SAS software 9.2 version. A P < 0.05 was inferred as statistically significant. RESULTS: Seven patients underwent a laparoscopic reconstruction. Stricture location was upper ureter (n = 1), mid ureter (n = 2), lower ureter (n = 4). Surgeries performed were ureteroureterostomy, Boari flap ureteroneocystostomy and ureteroneocystostomy with psoas hitch. Four patients reported prior contralateral nephrectomy. Three patients underwent prior endoscopic correction. Four patients presented with elevated serum creatinine (>1.4 mg/dl). Till last follow-up, improvement in symptomatology and improvement or stabilisation of serum creatinine was perceived in all. Ureteral patency with resolution of hydronephrosis was observed in five patients at 1 year follow-up. Two patients revealed ureteral patency with persistence of hydronephrosis. Clinical, biochemical and radiological outcomes were maintained till long-term follow-up. CONCLUSION: Laparoscopic reconstruction of US in SRU offers impressive short- and long-term outcome. PMID- 26622113 TI - Towards a better knot: Using mechanics methods to evaluate three knot-tying techniques in laparo-endoscopic single-site surgery. AB - INTRODUCTION: Knot tying is difficult but important for laparo-endoscopic single site surgery (LESS). There are several techniques for LESS knot-tying. However, objective assessment of these skills has not yet been established. The aim of this study was to assess three different knot-tying techniques in LESS using mechanical methods. MATERIALS AND METHODS: The subject tied 24 knots, eight knots with each of the three techniques in an inanimate box laparoscopic trainer while the movements of their instruments were evaluated using a LESS mechanical evaluation platform. The operations were assessed on the basis of the time, average load of the dominant hand. Then, forces caused the knots to rupture were measured using a material testing system and used to compare the knots's strength. RESULTS: The intracorporeal one-hand knot-tying technique presented significantly better time and average load scores than the extracorporeal knot tying technique (P < 0.01), and the intracorporeal side winding technique was more time and average load consuming in comparison to other techniques during the performance of knot-tying (P < 0.01). The intracorporeal one-handed knot-tying knots can tolerate better distraction forces compared with the intracorporeal side winding knot-tying knots and the extracorporeal knot-tying knots (P < 0.05). CONCLUSIONS: The intracorporeal one-hand knot-tying technique and knots showed better results than the intracorporeal "side winding" technique and the extracorporeal knot-tying technique in terms of the time, average load taken and the force caused the knot to rupture. PMID- 26622114 TI - Laparoscopic approach is safe and effective in the management of Mirizzi syndrome. AB - CONTEXT: Mirizzi syndrome (MS), an unusual complication of gallstone disease is due to mechanical obstruction of the common hepatic duct and is associated with clinical presentation of obstructive jaundice. Pre-operative identification of this entity is difficult and surgical management constitutes a formidable challenge to the operating surgeon. AIM: To analyse the clinical presentation, pre-operative diagnostic strategies, operative management and outcome of patients operated for MS in a tertiary care centre. MATERIALS AND METHODS: This retrospective study identified patients operated for MS between January 2006 and August 2013 and recorded and analysed their pre-operative demographics, pre operative diagnostic strategies, operative management, and outcome. RESULTS: A total of 20 patients was identified out of 1530 cholecystectomies performed during the study period giving an incidence of 1.4%. There were 11 males and 9 females with a mean age of 55.6 years. Abdomen pain and jaundice were predominant symptoms and alteration of liver function test was seen in 14 patients. Endoscopic retrograde cholangiopancreatography (ERCP) the mainstay of diagnosis was diagnostic of MS in 72% of patients, while the rest were identified intra operatively. The most common type of MS was Type II with an incidence of 40%. Cholecystectomy was completed by laparoscopy in 14 patients with a conversion rate of 30%. A choledochoplasty was sufficed in most of the patients and none required a hepaticojejunostomy. The laparoscopic cohort had a shorter length of hospital stay when compared to the entire group. CONCLUSION: MS, a rare complication of cholelithiasis is a formidable diagnostic and therapeutic challenge and pre-operative ERCP as a main diagnostic strategy enables the surgeon to identify and minimize bile duct injury. A choledochoplasty might be sufficient in the majority of the types of MS, while a laparoscopic approach is feasible and safe in most cases as well. PMID- 26622115 TI - I-gel as an alternative to endotracheal tube in adult laparoscopic surgeries: A comparative study. AB - BACKGROUND: The tracheal tube is always considered to be the gold standard for laparoscopic surgeries. As conventional laryngoscopy guided endotracheal intubation evokes significant hypertension and tachycardia, we have used I-gel, second generation extraglottic airway device, in an attempt to overcome these drawbacks. We conducted this study to compare haemodynamic changes during insertion, efficacy of ventilation, and complications with the use of I-gel when compared with endotracheal tube (ETT) in laparoscopic surgeries. MATERIALS AND METHODS: A total of 60 American Society of Anaesthesiologists physical status I and II adult patients undergoing elective laparoscopic surgeries were randomly allocated to one of the two groups of 30 patients each: Group-A (I-gel) in which patients airway was secured with appropriate sized I-gel, and Group-B (ETT) in which patients airway was secured with laryngoscopy - guided endotracheal intubation. Ease, attempts and time for insertion of airway device, haemodynamic and ventilatory parameters at different time intervals, and attempts for gastric tube insertion, and perioperative complications were recorded. RESULTS: There was significant rise in pulse rate and mean blood pressure during insertion with use of ETT when compared to I-gel. Furthermore, time required for I-gel insertion was significantly less when compared with ETT. However ease and attempts for airway device insertion, attempts for gastric tube insertion and efficacy of ventilation were comparable between two groups. CONCLUSION: We concluded that I-gel requires less time for insertion with minimal haemodynamic changes when compared to ETT. I gel also provides adequate positive-pressure ventilation, comparable with ETT. Hence I-gel can be a safe and suitable alternative to ETT for laparoscopic surgeries. PMID- 26622116 TI - Anorectal function and outcomes after transanal minimally invasive surgery for rectal tumors. AB - BACKGROUND: Transanal endoscopic microsurgery is a minimally invasive technique that allows full-thickness resection and suture closure of the defect for large rectal adenomas, selected low-risk rectal cancers, or small cancers in patients who have a high risk for major surgery. Our aim, in the given prospective study was to report our initial clinical experience with TAMIS, and to evaluate its effects on postoperative anorectal functions. MATERIALS AND METHODS: In 10 patients treated with TAMIS for benign and malignant rectal tumors, preoperative and postoperative anorectal function was evaluated with anorectal manometry and Cleveland Clinic Incontinence Score. RESULTS: The mean distance of the tumors from the anal verge was 5.6 cm, and mean tumor diameter was 2.6 cm. All resection margins were tumor free. There was no difference in preoperative and 3-week postoperative anorectalmanometry findings; only mean minimum rectal sensory volume was lower at 3 weeks after surgery. The Cleveland Clinic Incontinence Score was normal in all patients except one which resolved by 6 weeks after surgery.The mean postoperative follow-up was 28 weeks without any recurrences. CONCLUSION: Transanal minimally invasive surgery is a safe and effective procedure for treatment of rectal tumors and can be performed without impairing anorectal functions. PMID- 26622117 TI - Laparoscopic cystojejunostomy for type I cystic biliary atresia in children. AB - PURPOSE: The use of laparoscopy in the treatment of biliary atresia (BA) is still debated. We report our strategy using laparoscopy in type I cystic BA. MATERIALS AND METHODS: We reviewed the records of patients treated for BA from 2002-2013. When the diagnosis was suspected, an ultrasound was performed. If it showed a cyst > 5 mm in the hilum with no patent gallbladder, we performed an initial explorative laparoscopy. In the case of a patent biliary tree above the cyst, a laparoscopic cystojejunostomy was performed. In cases of absent communication (type III), conversion and portoenterostomy were performed. Pre and postoperative data and overall survival rate with the native liver were reviewed. RESULTS: Forty-four children were treated for BA. Six presented with a cystic form diagnosed by US. Three children had type I BA; three had type III BA. No postoperative complications were noted. Median follow-up was 62.2 months (22.7 93.5). One patient died of a cardiac malformation. The five remaining patients are alive with their native liver. Of the 38 treated for noncystic BA, 16 were transplanted. CONCLUSION: We confirmed the prognosis of cystic BA, which is less severe than noncystic BA. Our strategy using laparoscopy allowed for the confirmation and qualification of the type of BA. In type I, complete treatment by laparoscopy has been performed safely. PMID- 26622118 TI - A novel reconstruction method for giant incisional hernia: Hybrid laparoscopic technique. AB - BACKGROUND AND OBJECTIVES: Laparoscopic reconstruction of ventral hernia is a popular technique today. Patients with large defects have various difficulties of laparoscopic approach. In this study, we aimed to present a new reconstruction technique that combines laparoscopic and open approach in giant incisional hernias. MATERIALS AND METHODS: Between January 2006 and August 2012, 28 patients who were operated consequently for incisional hernia with defect size over 10 cm included in this study and separated into two groups. Group 1 (n = 12) identifies patients operated with standard laparoscopic approach, whereas group 2 (n = 16) labels laparoscopic technique combined with open approach. Patients were evaluated in terms of age, gender, body mass index (BMI), mean operation time, length of hospital stay, surgical site infection (SSI) and recurrence rate. RESULTS: There are 12 patients in group 1 and 16 patients in group 2. Mean length of hospital stay and SSI rates are similar in both groups. Postoperative seroma formation was observed in six patients for group 1 and in only 1 patient for group 2. Group 1 had 1 patient who suffered from recurrence where group 2 had no recurrence. DISCUSSION: Laparoscopic technique combined with open approach may safely be used as an alternative method for reconstruction of giant incisional hernias. PMID- 26622119 TI - Recurrent intussusception in a gastric bypass patient with incidental Meckel's diverticulum: A case report. AB - Most cases of intussusception in adults are secondary to a pathologic condition that serves as a lead point. Intussusception has been reported in the bariatric literature, typically due to intussusception of the jejunojejunostomy. However, other causes of intussusception should be considered, including a Meckel's diverticulum (MD). Simple diverticulectomy or segmental resection is the preferred treatment since the malignancy rate is low. We present an interesting case of a patient with past surgical history of open Roux-en-Y gastric bypass who presented with intussusception. Intraoperatively, an MD was encountered and treated with diverticulectomy. 4 months later, she re-presented with recurrent intussusception and was subsequently taken back to the operating room for revision of her jejunojejunostomy. The postoperative course was uncomplicated. PMID- 26622120 TI - Laparoscopic hysterectomy with bilateral orchidectomy for Persistent Mullerian duct syndrome with seminoma testes: Case report. AB - Persistent Mullerian duct syndrome (PMDS) is one of the three rare intersex disorders caused by defective anti-mullerian hormone or its receptor, characterized by undescended testes with presence of underdeveloped derivatives of mullerian duct in genetically male infant or adult with normal external genitals and virilization. This population will essentially have normal, 46(XY), phenotype. We hereby present a case of PMDS, presented with incarcerated left inguinal hernia associated with cryptorchidism and seminoma of right testes. Patient underwent laparoscopic hernia repair with bilateral orchidectomy and hysterectomy with uneventful postoperative recovery. Here we highlight the importance of minimal access approach for this scenario in terms of better visualization, less blood loss, combining multiple procedures along with early return to work and excellent cosmetic outcome. PMID- 26622121 TI - Portomesenteric venous thrombosis after laparoscopic sleeve gastrectomy: A case report and a call for prevention. AB - Postoperative portomesenteric venous thrombosis (PMVT) is being increasingly reported after bariatric surgery. It is variable and often a nonspecific presentation along with its potential for life-threatening and life-altering outcomes makes it imperative that it is prevented, detected early and treated optimally. We report the case of a 50-year-old morbidly obese man undergoing a laparoscopic sleeve gastrectomy who developed symptomatic PMVT two weeks postsurgery, which was successfully treated by anticoagulant therapy. We provide postulates to the etiopathological mechanism for this thrombotic entity. The growing recognition that obesity and bariatric surgery create a procoagulant state regionally and systemically provides impetus for designing the ideal protocol for PMVT prophylaxis, which could be more common than currently believed. We support the early screening for PMVT in the postbariatric surgical patient with unexplainable or intractable abdominal symptoms. The role of routine surveillance and the ideal duration of post-PMVT anticoagulation is yet to be elucidated. PMID- 26622122 TI - Laparoscopic resection of a bulky primary adrenal hydatid cyst. AB - A 55-year-old man with no medical history of relevance was referred to our department for chronic back pain. Plain radiographs of the abdomen showed a round calcified image with liquid level inside in the upper-left quadrant. On computed tomography (CT) a bulky solid-cystic mass with calcified wall of 65 * 34 mm was shown in the left adrenal gland with no-contrast enhancement. The patient underwent a laparoscopic approach. Intraoperatively there was a large hard stony mass depending on the left adrenal gland, which was entirely supplanted by the tumor. Complete excision was done. The patient underwent uneventful recovery. Histopathology examination showed a solid-cystic mass with a thick fibrous wall and calcified areas compatible with hydatid cyst. To date there have been published few cases of adrenal hydatid cyst. To our awareness it is the fourth case issued in all literature resected by the laparoscopic approach. PMID- 26622123 TI - Laparoscopic excision of infra-renal PEComa. AB - Perivascular epitheloid cell tumors (PEComas) are rare tumors of malignant potential. There is no normal cell variant to these cells. The family is large and includes angiomyolipoma, clear cell "sugar" tumor amongst others. Imaging modalities are not very diagnostic. The diagnosis hence is often postoperative. A 55-year old female presented to us with ultrasonographic diagnosis of solid mass in the right infrarenal region. Contrast-enhanced computerized sonography (CECT) suggested paraganglioma or a soft tissue retroperitoneal tumor. Laparoscopic excision was successful. The rarity of this pathology and laparoscopic modality of excision prompted us to publish this report. PMID- 26622124 TI - Robotic surgery: A step forward in the wide spread of minimally invasive colorectal surgery. PMID- 26622125 TI - Biomechanical evaluation of inferior scapula notching of reverse shoulder arthroplasty depending on implant configuration and scapula neck anatomy. AB - PURPOSE: The presence of inferior scapula notching is significantly affected by the anatomy the scapula and can be influenced by the glenosphere design and position and the onlay type. MATERIALS AND METHODS: A biomechanical study was undertaken with 13 human shoulder specimens in a robot-assisted shoulder simulator. Inferior scapula contact during adduction of the humerus was detected using a contact pressure film. Computed tomography scans with three-dimensional reconstructions of each specimen were performed. RESULTS: The greatest improvement of the scapula notching angle (SNA) was achieved by simultaneous implantation of a shallow humeral onlay and an eccentric glenosphere design: 16.3 19.0 degrees (P < 0.005). The SNA was significantly decreased by 5.8 degrees when shifting from a 38 mm centric glenosphere to a 42 mm centric glenosphere (P < 0.005) and by 8.9 degrees comparing the 38 mm centric glenosphere with 38 mm eccentric glenosphere (P < 0.005). The solitary implantation of a shallow onlay significantly decreased the SNA depending on the glenosphere size between 7.4 degrees and 8.0 degrees (P = 0.001). A more inferior position of the metaglene as well as a long scapula neck (P = 0.029) and a large lateral scapula pillar angle (P = 0.033) were correlated with a lower SNA. CONCLUSION: This study demonstrates the importance of inferior glenosphere placement and the benefit of eccentric glenosphere and shallow humeral cup design to reduce the adduction deficit of the reverse shoulder. The presence of a short neck of the scapula can have a negative prognostic effect on inferior impingement during adduction of the arm. LEVEL OF EVIDENCE: Basic Science Study. PMID- 26622126 TI - In-hospital mortality risk for total shoulder arthroplasty: A comprehensive review of the medicare database from 2005 to 2011. AB - INTRODUCTION: The in-hospital mortality rate after total shoulder arthroplasty (TSA) is unknown. The purpose of this study is to quantify the in-patient mortality rates and associated demographic risk factors for patients undergoing a TSA from 2005 to 2011 using a comprehensive Medicare registry database. MATERIALS AND METHODS: We conducted a retrospective review of the Medicare database within the PearlDiver database. The PearlDiver database is a publicly available Health Insurance Portability and Accountability Act-compliant national database that captures 100% of the Medicare hospital data for TSA between 2005 and 2011. Using International Classification of Diseases, Ninth Revision codes for TSA we identified a dataset of patients undergoing TSA as well as a subset of those for whom there was a death discharge (i.e., in-patient death). Risk for this outcome was further quantified by age, gender and year. Linear regression was performed to identify risk factors for the primary outcome. RESULTS: A total of 101,323 patients underwent 125,813 TSAs between 2005 and 2011. There were 113 in-patient mortalities during this period. Thus the incidence of death was 0.09%. Increasing age was a significant risk factor for mortality (P = 0.03). Gender and year of procedure were not significant risk factors for mortality. CONCLUSION: The incidence of in-patient mortality for Medicare patients undergoing TSA between 2005 and 2011 was <1 in 1000 surgeries. Increased age is a significant predictor of mortality. LEVEL 4: Retrospective analysis. PMID- 26622127 TI - Can an extracorporeal glenoid aiming device be used to optimize the position of the glenoid component in total shoulder arthroplasty? AB - PURPOSE: Successful total shoulder arthroplasty (TSA) requires a correct position of the glenoid component. This study compares the accuracy of the positioning with a new developed glenoid aiming device and virtual three-dimensional computed tomography (3D-CT) scan positioning. MATERIALS AND METHODS: On 39 scapulas from cadavers, a K-wire (KDev) was positioned using the glenoid aiming device. It consists of glenoid components connected to the aiming device, which cover 150 degrees of the inferior glenoid circle, has a fixed version and inclination and is available with several different radii. The aiming device is stabilized at the most medial scapular point. The K-wire is drilled from the center of the glenoid component to this most medial point. All scapulas were also scanned with CT and 3D reconstructed. A virtual K-wire (Kct) was positioned in the center of the glenoid and in the scapular plane. Several parameters were compared. Radius of the chosen glenoid component (rDev) and the virtual radius of the glenoid circle (rCT), spinal scapular length with the device (SSLdev) and virtual (SSLct), version and inclination between KDev and Kct, difference between entry point and exit point ("Matsen"-point). RESULTS: Mean rDev: 14 mm +/- 1.7 mm and mean rCT: 13.5 mm +/- 1.6 mm. There was no significant difference between SSLdev (110.6 mm +/- 7.5 mm) and SSLct (108 mm +/- 7.5 mm). The version of KDev and Kct was -2.53 degrees and -2.17 degrees and the inclination 111.29 degrees and 111.66 degrees , respectively. The distance between the "Matsen-point" device and CT was 1.8 mm. CONCLUSION: This glenoid aiming device can position the K-wire on the glenoid with great accuracy and can, therefore, be helpful to position the glenoid component in TSA. The level of evidence: II. PMID- 26622128 TI - Catastrophic failure of a low profile metal-backed glenoid component after total shoulder arthroplasty. AB - CONTEXT: The longevity of the glenoid component in total shoulder arthroplasty (TSA) continues to be problematic. All polyethylene glenoid components have been most widely used, but loosening rates with time and the need for revision has resulted in high-profile metal-backed components with the potential for a more stable prosthesis bone interface and liner exchange. High revision rates in the high profile metal backed designs led us to evaluate a low profile metal backed component. AIMS: To examine the rate and mode of failure of a TSA in a single surgeon consecutive series that has been identified by the Australian National Joint Replacement Registry to have a higher than anticipated rate of revision. MATERIALS AND METHODS: This is a single surgeon retrospective consecutive series of 51 arthroplasties undertaken in 50 patients (18 males and 32 females) with an average age of 70.4 ears (range 51-90) and mean follow-up of 5.5 years (range 3.7 8.1). RESULTS: We observed a very high (29%) rate of revision of the metal-backed glenoid components in this series. The primary mode of failure was glenoid baseplate nonintegration which with a well-fixed central cage screw led to bone resorption and implant breakage or disassembly. CONCLUSION: Analysis of the mode of failure of implants identified by robust registries is essential for the development of new prostheses and the pursuit of prosthesis longevity. This low profile metal backed prosthesis has been withdrawn, but without a published mechanism of failure. We feel that any prosthesis withdrawal should be accompanied by appropriate published mechanisms to prevent future component design errors based on similar design problems. PMID- 26622129 TI - Periprosthetic humeral fracture after Copeland resurfacing and the role of revision arthroplasty: A report of three cases. AB - Follow-up series of the Copeland resurfacing hemiarthroplasty have reported few postoperative fractures around the prosthesis. We report three cases of periprosthetic fracture around a Copeland resurfacing arthroplasty. Due to prosthetic loosening and tuberosity comminution, all cases were managed with revision shoulder arthroplasty. All patients had good functional outcome and range of movement on early follow-up. PMID- 26622130 TI - Posterior shoulder instability following anatomic total shoulder arthroplasty: A case report and review of management. AB - We report a case of posterior shoulder instability following anatomic total shoulder arthroplasty (TSA). In addition, we present guidelines to aid in the management of posterior instability after TSA. A 50-year-old male underwent anatomic TSA for glenohumeral osteoarthritis. Postoperatively, the patient developed posterior instability secondary to glenoid retroversion. He did not improve despite conservative treatment. He underwent an arthroscopic posterior bone block procedure, 4-month after his index arthroplasty. At 14-month follow up, the patient had regained near full motion and strength, and radiographs demonstrated osseous integration with no evidence of component loosening. Posterior instability following TSA is a relatively rare complication and challenging to manage. The posterior, arthroscopic iliac crest bone block grafting procedure represents a treatment option for posterior instability in the setting of a stable glenoid prosthesis following TSA. PMID- 26622131 TI - Giant cell tumor of the humeral head treated by denosumab: Implication to shoulder surgeons. AB - Giant cell tumor is a benign bone tumor that is commonly encountered. The optimal treatment of a giant cell tumor which causes extensive bony destruction is controversial. Recent studies on the receptor activator of nuclear factor kappaB ligand antagonist denosumab may offer a new treatment option for these patients. We presented a patient with giant cell tumor of the humeral head. He was initially treated with denosumab and subsequently with the operation. The shoulder joint was successfully salvaged. But there are potential difficulties that surgeons may face in patients treated with denosumab. PMID- 26622132 TI - Propionibacterium acnes infection after shoulder surgery. AB - Propionibacterium acnes has been implicated as a cause of infection following shoulder surgery, may occur up to 2 years after the index operation and has been shown to be responsible for up to 56% of shoulder infections after orthopedic implant. Male patients within the population undergoing shoulder surgery are particularly at risk, especially if their shoulder surgery involved prosthesis or was posttraumatic. P. acnes infection can be difficult to diagnose clinically and laboratory techniques require prolonged and specialized cultures. Usual inflammatory markers are not raised in infection with this low virulence organism. Delayed diagnosis with P. acnes infection can result in significant morbidity prior to prosthesis failure. Early diagnosis of P. acnes infection and appropriate treatment can improve clinical outcomes. It is important to be aware of P. acnes infection in shoulder surgery, to evaluate risk factors, to recognize the signs of P. acnes infection, and to promptly initiate treatment. The signs and symptoms of P. acnes infection are described and discussed. Data were collected from PubMedTM, Web of Science, and the NICE Evidence Healthcare Databases - AMED (Ovid), BNI (Ovid), CINAHL (EBSCO), Embase (Ovid), HMIC: DH-Data and Kings Fund (Ovid), Medline (Ovid), and PsycINFO (Ovid). The search terms used were "P. acnes," "infection," "shoulder," and "surgery." In this review, we summarize the current understanding of the prevention and management of P. acnes infection following shoulder surgery. PMID- 26622133 TI - Recent trends: Medical management of infectious keratitis. AB - This review article highlights the newer diagnostic modalities and approaches in the medical management of infectious keratitis. A Medline literature search conducted to March 2014 has been included. Recent studies or publications were selected from international indexed journals using suitable key words. Development of specular microscopy and polymerase chain reaction (PCR) has a promising role as diagnostic modalities in infectious keratitis, especially in refractory cases. Previously fortified antibiotics have been the mainstay of treatment for bacterial keratitis. Recently, the advent of fourth-generation fluoroquinolones monotherapy has shown promising results in the management of bacterial keratitis. Corneal collagen cross-linking is being considered in the refractory cases. Topical natamycin and amphotericin B should be considered as the first choice anti-fungal agents in suspected filamentous or yeast infection respectively. Voriconazole and newer routes of administration such as intrastromal and intracameral injection of conventional anti-fungal agents have demonstrated a positive clinical response. Ganciclovir is a newer anti-viral agent with promising results in herpes simplex keratitis. Thus, introduction of newer diagnostic modalities and collagen cross-linking along with fourth generation fluoroquinolones and newer azoles have a promising role in the management of infectious keratitis. PMID- 26622135 TI - Morphological and functional outcomes following modified early treatment diabetic retinopathy study laser in diabetic macular edema. AB - AIM: The aim was to report morphological and functional outcomes following modified early treatment diabetic retinopathy study (ETDRS) laser in diabetic macular edema (DME). MATERIALS AND METHODS: Structural and functional changes using spectral domain optical coherence tomography (OCT) and microperimetry (MP) were studied before and 4 months after laser in 37 eyes with clinically significant macular edema (ME) requiring modified ETDRS laser treatment. Paired t test was used to compare pre and postlaser outcomes P < 0.05 was considered statistically significant. RESULTS: Central foveal thickness showed a significant reduction after laser P = 0.004. There was a significant reduction in mean retinal thickness (MRT) and retinal volume in all the quadrants of ETDRS except for the temporal and nasal quadrants in outer 6 mm ring. Maximum reduction in MRT was seen in eyes with DME having neurosensory detachment (382.66 MU to 292.61 MU). Retinal sensitivities reduced in all quadrants following laser, however, fixation patterns showed improvements. The change in VA was positively correlated to change in MRT (r = 0.468, P = 0.032). CONCLUSION: Laser not only causes structural benefits such as reduction of retinal thickness and volume, it also causes improvement of fixation patterns. PMID- 26622134 TI - Corneal cross-linking treatment of keratoconus. AB - Keratoconus as the most common cause of ectasia is one of the leading cause of corneal transplants worldwide. The current available therapies do not modify the underlying pathogenesis of the disease, and none of the available approaches but corneal transplant hinder the ongoing ectasia. Several studies document Crosslink defect between collagen fibrils in the pathogenesis of keratoconus. Collagen cross link is a relatively new approach that with the application of the riboflavin and ultraviolet A, new covalent bands reform. Subjective and objective results following this method seem to be promising. Endothelial damage besides other deep structural injury, which is the major concern of this technique have not yet been reported, when applying the standard method. PMID- 26622136 TI - Visual function of children with visual and other disabilities in Oman: A case series. AB - BACKGROUND: We assessed visual functioning of the children with special needs in Oman between 2009 and 2012. We present the methods of assessing different visual functions, outcomes and interventions carried out to improve their functioning. MATERIALS AND METHODS: In this case series type of study, optometrists assessed visual functions of children of "day care centers" in Oman. Experts further assessed them and provided low vision care. Ocular movements, refractive corrections, near, distance, contrast color, motion, field of vision and cognitive, visual function test results were noted. Feedback to caregivers was given to improving visual functioning of these children. RESULTS: We grouped 321 participants, (196 (61.1%) boys, age range of 3-18 years) into 61; Down syndrome (DS), 72 with intellectual disabilities, 67; hearing impaired and 121 with other conditions. Refractive error and lag of accommodation was 26 (42.6%) and 14 (22.6%) among children with DS. Contrast sensitivity was impaired in 8 (12.7%) among hearing impaired children. Defective distant and near vision was in 162 (70%) and 104 (42%) of our cohort. Children with intellectual disability were most difficult to assess. Children in group of other disabilities" had a higher proportion of impaired visual functioning. They were given low vision aids (telescopes (22), filters (7) and magnifiers (3)) in large numbers compared to those in other groups. CONCLUSIONS: The outcomes of assessment of visual functioning of children with other disabilities show great variation and difficult to group. The care therefore should be individual. All visual functions cannot be assessed at one time. PMID- 26622137 TI - Ocular response analyzer parameters in healthy, keratoconus suspect and manifest keratoconus eyes. AB - BACKGROUND: To evaluate and compare corneal biomechanical indices and their specificity among keratoconus (KC), keratoconus suspect (KCS), and normal eyes (NL) before and after controlling potential confounders. MATERIALS AND METHODS: A total of 160 eyes in three groups were included prospectively: NL, KC, and KCS groups based on clinical examination and topography. Corneal hysteresis (CH) and corneal resistance factor (CRF) were measured by the ocular response analyzer. CH and CRF were compared between the three groups by analysis of variances test. RESULTS: The three groups consisted of 80 NL, 48 KC, and 32 KCS eyes. The mean CH measured was 10.4 +/- 1.25, 7.83 +/- 1.28 and 10.17 +/- 1.80 mm Hg in NL, KC and KCS eyes, respectively. The mean CRF was 10.23 +/- 1.75, 6.5 +/- 1.63 and 9.98 +/ 2.00 mm Hg in NL, KC and KCS eyes, respectively. Mean CH and CRF were significantly different between the NL and KC (P < 0.05); however after controlling for central corneal thickness and sex; there was no significant difference between NL and KCS (P > 0.05). CONCLUSION: CH and CRF can be helpful in differentiating KC from NL eyes; however, they are not valuable for detecting KCS that is the main concern for refractive surgery. Future studies focusing on more accurate tests for identifying KCS, using a consistent grading scale for defining KC and KCS are still warranted. PMID- 26622138 TI - A novel strategy for management of uncorrected refractive errors in urban slums. AB - BACKGROUND: Blindness and Vision impairment remains a major public health issue not only in rural but also in urban areas. Concept of using peripheral health centers to render primary health care services to the community was a WHO proposed model. However, establishing them in urban slums is a challenge as most of the slums are illegal establishments. So, aim was to establish vision centers for providing primary eye care services in the urban slums of Mumbai, West India. METHODS: Vision centers were established in various slum pockets of Mumbai from the year 2008 till 2009. Refraction and screening for ocular morbidity were carried out for those who attended this center and management for uncorrected refractive errors was done. RESULTS: Data from 6 such vision centers located in various slum pockets of Mumbai city from April 9 to March 2011 were collected and analyzed. Of the 19,550 adults, 2270 (11.61%) had moderate vision impairment with presenting visual acuity of <0.5 LogMAR in both eyes. Severe Visual impairment was seen in (723) 3.70%. Blindness was seen in (357) 1.82%. Of the 2993, which were moderately and severely visually impaired, 1893 subjects that is, 63.24% of them improved to 0.2 LogMAR or better with spectacle correction. CONCLUSIONS: About 63.24% of visual impairment was due to uncorrected refractive errors, these included both moderately and severely vision impaired. Totally, 357 (1.82%) were also identified as blind. This model of vision centers has a role in the identification and management of sight-threatening problems. PMID- 26622139 TI - Microbial keratitis following accelerated corneal collagen cross-linking. AB - A deep stromal infiltrate with hypopyon appeared in central cornea of right eye of a 15-year-old boy postoperatively after 2 days, who underwent uneventful accelerated corneal collagen crosslinking (C3R) with riboflavin and ultraviolet-A (UVA) for the treatment of keratoconus. Staphylococcus aureus keratitis was confirmed by the microbiological studies, which guided intense treatment with topical and systemic antibiotics. Before C3R, the best corrected visual acuity (BCVA) in the ocular dexter was 20/30 with the refraction of - 1.00 DS/-5.00 DC * 30 degrees with drop to 20/400 following the infection. After intensive treatment BCVA recovered to 20/40 with the refraction of -4.0 DC * 60 degrees at 6 months postprocedure. Slit lamp examination at this stage revealed a faint nebulo-macular grade scar in the central cornea involving visual axis. Collagen crosslinking with riboflavin-UVA is a minimally invasive method, but traditionally requires epithelial removal, which could be a predisposing factor to bacterial keratitis. PMID- 26622140 TI - Metastatic Serratia endophthalmitis associated with extravasation injury in a preterm neonate. AB - The authors report a case of a preterm neonate who presented with lid edema, corneal edema, and an inflammatory membrane with whitish exudates in the pupillary area, suggestive of endophthalmitis. There was also a cutaneous ulcer with an eschar on the right wrist at the site of extravasation associated with previous intravenous catheter. Cultures from the ulcer and vitreous samples both grew Serratia marcescens with identical antibiotic sensitivity and resistance patterns. The ocular infection was rapidly progressive and did not respond to administered medical and surgical therapy leading to subsequent phthisis bulbi. Serratia can cause endophthalmitis refractory to antibiotics and despite aggressive and timely treatment can have an unfavorable outcome. This report aims at highlighting the possibility of metastatic infection from an extravasation injury with a potentially fatal outcome. PMID- 26622142 TI - Surgical management of glaucoma secondary to idiopathic elevated episcleral venous pressure. AB - Idiopathic elevated episcleral venous pressure is characterized by dilated episcleral veins and open angle glaucoma. Trabeculectomies in these eyes are often complicated by uveal effusions (intraoperative or postoperative) at nonhypotonous pressures. We highlight the ability to avoid the need for sclerostomies by preventing intraoperative shallowing of the anterior chamber and the use of tight scleral sutures which should be adjusted postsurgery to gradually reach the target intraocular pressure in a step-wise manner. PMID- 26622141 TI - Brown's syndrome with ocular albinism: Case report of a rare presentation and literature review. AB - We report a rare case of Brown's syndrome associated with ocular albinism in a 10 year-old boy. This report highlights the importance of further analysis of cases of Brown's syndrome and throws some light on the etiology and association of this rare condition. PMID- 26622143 TI - Spontaneous ophthalmic artery occlusion in children due to Hyperhomocysteinemia. AB - Ophthalmic artery occlusion usually presents as a sudden onset profound decrease in vision in the middle-aged and elderly patients following periocular procedures (retrobulbar injection/glabellar fat injection), embolism from the heart or after prolonged systemic surgery. In this report, we describe three children with spontaneous ophthalmic artery occlusion who presented with unilateral loss of vision and diagnosed elsewhere as optic atrophy whose detailed history and examination were suggestive of ophthalmic artery occlusion. Detailed systemic and laboratory evaluation revealed hyperhomocysteinemia as the only potential risk factor. To the best of our knowledge, this is the first report of the association of hyperhomocysteinemia and spontaneous ophthalmic artery occlusion. PMID- 26622144 TI - Melanoma associated retinopathy: A new dimension using adaptive optics. AB - We report a 56-year-old male patient, complaining of metamorphopsia in his left eye nevertheless visual acuity, slit lamp, and fundus examinations were within normal limits. Microperimetry (MAIA, Centervue, Italy) revealed central field loss and spectral domain optical coherence tomography (Spectralis, Heidelberg, Germany) showed disrupted cone outer segment tip layer. The patient had a diagnosis of cutaneous melanoma in his foot for which an excision biopsy with lymph node dissection was performed 5 months earlier. Our clinical diagnosis was melanoma-associated retinopathy. Electrophysiology confirmed the diagnosis. Adaptive optics retinal imaging (Imagine eyes, Orsay) was performed to assess the cone mosaic integrity across the central retina. This is the first report on the investigation of autoimmune retinopathy using adaptive optics ophthalmoscopy. This case highlights the viability of innovative diagnostic modalities that aid early detection and subsequent management of vision threatening retinal. PMID- 26622145 TI - Neonatal orbital abscess. AB - Orbital abscess generally occurs in older children but it can rarely affect infants and neonates too. We report a case of community acquired methicillin resistant staphylococcus aureus (CA-MRSA) neonatal orbital abscess in a 12-day old term female neonate with no significant past medical history or risk factor for developing the infection. The case highlights the importance of consideration of CA-MRSA as a causative agent of neonatal orbital cellulitis even in a neonate without any obvious predisposing condition. Prompt initiation of appropriate medical therapy against MRSA and surgical drainage of the abscess prevents life threatening complications of orbital cellulitis which more often tend to be fatal in neonates. PMID- 26622146 TI - Fissure, fluid, and functional loss. PMID- 26622147 TI - Is transcanalicular laser dacryocystorhinostomy using low energy 810 nm diode laser better than 980 nm diode laser? PMID- 26622148 TI - A case of decompressive retinopathy. PMID- 26622149 TI - Cataract surgery as a risk factor for non-arteritic anterior ischemic optic neuropathy and the intra-operative use of intravitreal corticosteroid. PMID- 26622150 TI - Assessment of Oxidative Stress in Patients with Premature Canities. AB - CONTEXT: Premature canities is a common, yet unexplored disorder. Oxidative stress levels have been evaluated within the greying hair follicle but not in the sera of patients with premature canities. AIMS: To evaluate the oxidative stress parameters in the sera of patients with premature canities. SETTINGS AND DESIGN: A pilot case-controlled study, conducted in a tertiary care setup in Delhi during November 2011 to December 2012. MATERIALS AND METHODS: Fifty-two self-reporting cases of premature canities (age of onset <20 years) and 30 healthy controls were recruited from outpatient Department of Dermatology. Oxidative stress parameters (serum malonaldehyde (MDA), whole blood reduced glutathione (rGSH) and serum ferric reducing antioxidant potential [FRAP]) were assessed in cases and controls. Mann-Whitney test was used to compare the oxidative stress parameters between the two groups (SPSS version 17.0, SPSS Inc, Chicago, USA; P < 0.05 considered as significant). RESULTS: The age and sex distribution of cases and controls was comparable. The mean serum levels of MDA were higher in cases than controls (3.7 +/- 1.6 nmol/ml vs. 2.8 +/- 1.5 nmol/ml; P = 0.01). The GSH levels were lower in the cases than controls (31.5 +/- 8.9 mg/dl vs. 36.6 +/- 16.9 mg/dl; P = 0.064). Similarly, the mean FRAP levels were lower in the cases than controls (400 +/- 70 nmol/ml vs. 430 +/- 80 nmol/ml; P = 0.038). CONCLUSIONS: Patients with premature canities had a higher level of pro-oxidants and lower levels of antioxidants than controls. This is the first humble attempt to document the oxidative stress parameters in sera of patients with premature canities, further studies with larger sample size are required to reach a definite conclusion. PMID- 26622151 TI - Involvement of Mechanical Stress in Androgenetic Alopecia. AB - CONTEXT: Androgenetic alopecia (AGA) is a frequent disorder characterized by progressive hair miniaturization in a very similar pattern among all affected men. The pathogenesis is related to androgen-inducible overexpression of transforming growth factor beta-1 from balding dermal papilla cells, which is involved in epithelial inhibition and perifollicular fibrosis. Recent research shows that hair follicle androgen sensitivity is regulated by Hic-5, an androgen receptor co-activator which may be activated by the mechanical stimulation. Moreover, the dermis of scalp susceptible to be affected by AGA is firmly bounded to the galea aponeurotica, so the physical force exerted by the occipitofrontalis muscle is transmitted to the scalp skin. AIMS: To know whether mechanical stress supported by hair follicles is involved in AGA phenomenon. MATERIALS AND METHODS: It is performed with a finite element analysis of a galea model and a schematic representation of AGA progression according to Hamilton-Norwood scale in order to establish the correlation between elastic deformation in scalp and clinical progression of male pattern baldness. RESULTS: The result was a highly significant correlation (r: -0.885, P < 0.001) that clearly identifies a mechanical factor in AGA development. CONCLUSIONS: All these data suggest that mechanical stress determines AGA patterning and a stretch-induced and androgen mediated mechanotransduction in dermal papilla cells could be the primary mechanism in AGA pathogenesis. PMID- 26622152 TI - Possible Relationship between Chronic Telogen Effluvium and Changes in Lead, Cadmium, Zinc, and Iron Total Blood Levels in Females: A Case-Control Study. AB - INTRODUCTION: Hair loss is a common and distressing problem that can affect both males and females of all ages. Chronic telogen effluvium (CTE) is idiopathic diffuse scalp hair shedding of at least 6 months duration. Hair loss can be one of the symptoms of metal toxicity. Lead (Pb) and cadmium (Cd) are highly toxic metals that can cause acute and chronic health problems in human. The aim of the present study is to determine if there is a relationship between these metals and CTE in women and if CTE is also associated with changes in zinc (Zn) or iron (Fe) blood levels. MATERIALS AND METHODS: Pb, Cd, Fe and Zn total blood levels were determined in 40 female patients fulfilling the criteria of CTH and compared with total blood levels of same elements in 30 well-matched healthy women. RESULTS: Quantitative analysis of total blood Fe, Zn, Pb and Cd revealed that there were no significant differences between patients and controls regarding Fe, Zn, and Pb. Yet, Cd level was significantly higher in patients than controls. In addition, Cd level showed significant positive correlation with the patient's body weight. CONCLUSION: Estimation of blood Pb and Cd levels can be important in cases of CTE as Cd toxicity can be the underlying hidden cause of such idiopathic condition. PMID- 26622153 TI - Clinical, Trichoscopic, and Histopathological Features of Primary Cicatricial Alopecias: A Retrospective Observational Study at a Tertiary Care Centre of North East India. AB - BACKGROUND: The primary cicatricial alopecias (PCAs) are a rare group of diseases where hair follicle is the primary target of destruction. There are a few studies on histopathological and trichoscopic features of PCA. AIMS: To study the clinical, trichoscopic, and histopathological characteristics of PCAs of the scalp and to find out the concordance between trichoscopic and histopathological diagnosis. MATERIALS AND METHODS: We retrospectively analyzed the clinical, trichoscopic, and histopathological features of 24 PCA patients. Fisher's Chi square exact test was done to find the significant trichoscopic and histopathological features. Cohen's kappa coefficient was used to determine the agreement between histopathological and trichoscopic diagnosis. RESULTS: A total of 24 patients of PCA were seen with a male: female ratio of 2:1. There were 10 (41.7%) patients of discoid lupus erythematosus (DLE), 5 (20.8%) of lichen planopilaris (LPP), 3 (12.5%) of dissecting cellulitis of scalp, and 2 (8.3%) each of pseudopelade of brocq, folliculitis decalvans, and frontal fibrosing alopecia. The important histopathological findings of DLE were follicular plugging, vacuolar changes in the basal layer, necrotic keratinocytes, and superficial and deep perifollicular and perivascular lymphocytic infiltrate. Histopathology of LPP showed vacuolar changes in the basal layer and lichenoid infiltrate involving the infundibulum and isthmus. Trichoscopy of DLE showed follicular plugging, yellow dots, and thick arborizing blood vessels. The peripilar cast was important finding in LPP. The characteristic yellow dot with three-dimensional structure was noted in dissecting cellulitis of the scalp. The Cohen's kappa agreement was 0.89 between histopathological and trichoscopic diagnosis. CONCLUSION: The diagnosis of PCA is challenging because of overlapping features clinically and histopathologically. Trichoscopy may provide quick and reliable diagnosis and obviate the necessity of scalp biopsy in busy clinics. PMID- 26622155 TI - Facial Papules in Fibrosing Alopecia in a Pattern Distribution (Cicatricial Pattern Hair Loss). AB - Frontal fibrosing alopecia (FFA) and fibrosing alopecia in a pattern distribution (FAPD) represent clinically distinctive conditions characterized by pattern hair loss with evidence of follicular inflammation and fibrosis. Since Kossard's original description, the condition has been recognized to represent a rather generalized than localized process, with extension well beyond the frontotemporal hairline. More recently, peculiar facial papules have been reported in FFA representing facial vellus hair involvement. We report the case of a 42-year-old woman with FAPD associated with the same facial papules, supporting that both entities belong to the same spectrum of cicatricial pattern hair loss. PMID- 26622154 TI - Autistic Trait, Empathy, and Attention-Deficit/Hyperactivity Symptoms in Women with Idiopathic Hirsutism. AB - AIM: Many psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), disruptive behavioral disorders, autism spectrum disorders, and some psychiatric characteristics, such as poor empathizing, are regarded to be related to elevated levels of androgens or androgen sensitivity. Thus, numerous studies have investigated the potential association between androgen-related physical diseases and these psychiatric conditions. Idiopathic hirsutism (IH) is a disease characterized by an increased sensitivity of the pilosebaceous unit to circulating androgens in women. The purpose of this study was to examine whether IH has a relationship with androgen-related psychiatric conditions. MATERIALS AND METHODS: Totally 37 females with IH and 33 healthy female controls were included in this study. Childhood and present ADHD symptoms of the participants were assessed using the Wender Utah Rating Scale (WURS) and the Adult ADHD Self-Report Scale, respectively. The Autism-spectrum quotient and the interpersonal reactivity index were used to assess autistic traits and different aspects of empathy. Hirsutism severity was measured using the Ferriman-Gallwey scoring system. RESULTS: No significant difference was found between the patients and controls on psychiatric questionnaire scores, except for a trend for subjects with IH to show higher levels of the school-associated problems than controls according to WURS. The severity of hirsutism was strongly correlated with the WURS irritability and behavioral problems/impulsivity subscores and WURS total score, and moderately correlated with the WURS attentional deficit subscore. CONCLUSIONS: This study provides preliminary evidence that common etiological factors may be involved in both the severity of IH, ADHD, and coexisting disruptive behavioral problems. PMID- 26622156 TI - A Case of Woolly Hair Nevus Associated with Pigmentary Demarcation Lines and Heterochromia Iridis: Coincidence or a New Association? AB - We report a case of woolly hair nevus with pigmentary demarcation lines and heterochromia iridis. Woolly hair nevus is a rare abnormality of the scalp hair characterized by the patch of hair, which is curlier and light colored than the rest of the scalp hair. Association of woolly hair nevus with some other ectodermal defects effecting skin and eyes has been reported before. Here, woolly hair nevus associated with demarcation lines and heterochromia iridis, to our knowledge, have not been previously reported. PMID- 26622157 TI - Keratosis Follicularis Spinulosa Decalvans: A Report of Three Cases. AB - Keratosis follicularis spinulosa decalvans is a disorder affecting the hair follicles characterized by scarring alopecia of the scalp, eyebrows, and axillae, sometimes associated with photophobia and keratoderma. Being X-linked, it is more commonly seen in males but can be rarely seen in females also. We report three cases of this rare disorder including one in a female. PMID- 26622158 TI - Severe Facial Hirsutism Following Isotretinoin Therapy: An Under-reported Entity. AB - Hirsutism is usually a manifestation of hyperandrogenism, and iatrogenic causes for excess hair growth are uncommon. Here, we report on a 48-year-old female patient, who developed severe excess facial hair following treatment with isotretinoin for papulopustular rosacea. To the best of our knowledge, only one case has been reported before, and not in the dermatology literature. Taking into consideration the fact that isotretinoin is a widely prescribed medication in the dermatology practice, information on its possible adverse effects is of major importance for the treating dermatologist. PMID- 26622159 TI - A Rare Presentation and Histopathologic Findings of Woolly Hair Nevus. AB - Woolly hair nevus is a rare disease whose diagnosis is challenging. We present a case of this condition presenting in a 27-year-old healthy male. We describe a histology pattern consisting in the presence of several terminal hair follicles ending in the same dilated follicular infundibulum, a perifollicular lymphocytic infiltrate and an excessive amount of normal apocrine glands in deep reticular dermis, some findings non-previously reported. Clinicopathological correlation is very important for making a correct diagnosis. PMID- 26622160 TI - Silvery Hair with Speckled Dyspigmentation: Chediak-Higashi Syndrome in Three Indian Siblings. AB - Silvery hair is a common feature of Chediak-Higashi syndrome (CHS), Griscelli syndrome, and Elejalde syndrome. CHS is a rare autosomal recessive disorder characterized by partial oculocutaneous albinism, frequent pyogenic infections, and the presence of abnormal large granules in leukocytes and other granule containing cells. A 6-year-old girl had recurrent respiratory infections, speckled hypo- and hyper-pigmentation over exposed areas, and silvery hair since early childhood. Clinical features, laboratory investigations, hair microscopy, and skin biopsy findings were consistent with CHS. Her younger sisters aged 4 and 2 years had similar clinical, peripheral blood picture, and hair microscopy findings consistent with CHS. This case is reported for its rare occurrence in all the three siblings of the family, prominent pigmentary changes, and absent accelerated phase till date. Awareness, early recognition, and management of the condition may prevent the preterm morbidity associated. PMID- 26622161 TI - A Solitary Asymptomatic Tumor on the Knee. PMID- 26622162 TI - Loose Anagen Hair Syndrome. PMID- 26622163 TI - Reflections on the Adaptive Designs Accelerating Promising Trials Into Treatments (ADAPT-IT) Process-Findings from a Qualitative Study. AB - CONTEXT: The context for this study was the Adaptive Designs Advancing Promising Treatments Into Trials (ADAPT-IT) project, which aimed to incorporate flexible adaptive designs into pivotal clinical trials and to conduct an assessment of the trial development process. Little research provides guidance to academic institutions in planning adaptive trials. OBJECTIVES: The purpose of this qualitative study was to explore the perspectives and experiences of stakeholders as they reflected back about the interactive ADAPT-IT adaptive design development process, and to understand their perspectives regarding lessons learned about the design of the trials and trial development. MATERIALS AND METHODS: We conducted semi-structured interviews with ten key stakeholders and observations of the process. We employed qualitative thematic text data analysis to reduce the data into themes about the ADAPT-IT project and adaptive clinical trials. RESULTS: The qualitative analysis revealed four themes: education of the project participants, how the process evolved with participant feedback, procedures that could enhance the development of other trials, and education of the broader research community. DISCUSSION AND CONCLUSIONS: While participants became more likely to consider flexible adaptive designs, additional education is needed to both understand the adaptive methodology and articulate it when planning trials. PMID- 26622164 TI - Native American Children and Their Reports of Hope: Construct Validation of the Children's Hope Scale. AB - Child reports of hope continue to be utilized as predictors of positive adjustment; however, the utilization of the hope construct has not been assessed within the culturally diverse Native American child group. The present study investigated the applicability of the Hope theory among 96 Native American children in the Midwest. Measures included the Children's Hope Scale and a Hope Interview. Native American children in the current sample appear to conceptualize hope as a way to reach goals as did the children in the normative sample. Results from the factor analysis demonstrate that the factor structure found in the current study was similar to the factor structure found in the standardization sample. Because of the similar Hope theory conceptualization and factor structure, interventions focused on the positive psychology construct of hope may be applicable within a Native American child population. PMID- 26622165 TI - Experimental Limiting Oxygen Concentrations for Nine Organic Solvents at Temperatures and Pressures Relevant to Aerobic Oxidations in the Pharmaceutical Industry. AB - Applications of aerobic oxidation methods in pharmaceutical manufacturing are limited in part because mixtures of oxygen gas and organic solvents often create the potential for a flammable atmosphere. To address this issue, limiting oxygen concentration (LOC) values, which define the minimum partial pressure of oxygen that supports a combustible mixture, have been measured for nine commonly used organic solvents at elevated temperatures and pressures. The solvents include acetic acid, N-methylpyrrolidone, dimethyl sulfoxide, tert-amyl alcohol, ethyl acetate, 2-methyltetrahydrofuran, methanol, acetonitrile, and toluene. The data obtained from these studies help define safe operating conditions for the use of oxygen with organic solvents. PMID- 26622166 TI - Association of ZEB1 and TCF4 rs613872 changes with late onset Fuchs endothelial corneal dystrophy in patients from northern India. AB - PURPOSE: Fuchs endothelial corneal dystrophy (FECD) results in loss of vision associated with progressive corneal edema and loss of corneal transparency. The aim of the study was to evaluate changes in ZEB1, COL8A2, SLC4A11, and TCF4 rs613872 and correlate them with clinical findings. METHODS: Eighty-two patients with clinically diagnosed FECD and 143 controls were recruited during the period 2007-2012. Clinical details, pedigree information up to three generations, and 5 ml of blood samples were collected. Histopathological and transmission electron microscopy studies were performed on host corneal buttons from patients who underwent keratoplasty. Genomic DNA from blood was processed for PCR amplification followed by direct sequencing to screen genetic changes in the candidate genes. The pathogenic nature of the genetic variants was assessed using Sorting Intolerant From Tolerant (SIFT) and MutationTaster. RESULTS: The mean age at the onset of symptoms was 59.14+/-1.41years, the male to female ratio was 1:1.5, and the mean specular count (endothelial cell density) was 1629+/-93.62 cells/mm(2) with a mean central corneal thickness (CCT) of 617.30+/-15.73 um. ZEB1 showed a novel variant IVS2+276 C/T in 14% of the cases, a novel nonsense p.Leu947stop mutation in one patient, two novel missense mutations (p.Glu733Lys, p.Ala818Val) in one patient each, and one novel synonymous variation (p.Ser234Ser) in two patients. Reported mutation p.Gln840Pro and five polymorphisms were also identified. The TCF4 single nucleotide polymorphism (SNP) rs613872 was significantly higher in patients with FECD. CONCLUSIONS: This is the first report of genetic variations in ZEB1 and TCF4 SNP rs613872 in patients with FECD from northern India that suggests a possible role in disease pathogenesis and the regulation of endothelial cell density. PMID- 26622167 TI - Could the FDA-approved anti-HIV PR inhibitors be promising anticancer agents? An answer from enhanced docking approach and molecular dynamics analyses. AB - Based on experimental data, the anticancer activity of nelfinavir (NFV), a US Food and Drug Administration (FDA)-approved HIV-1 protease inhibitor (PI), was reported. Nevertheless, the mechanism of action of NFV is yet to be verified. It was hypothesized that the anticancer activity of NFV is due to its inhibitory effect on heat shock protein 90 (Hsp90), a promising target for anticancer therapy. Such findings prompted us to investigate the potential anticancer activity of all other FDA-approved HIV-1 PIs against human Hsp90. To accomplish this, "loop docking" - an enhanced in-house developed molecular docking approach followed by molecular dynamic simulations and postdynamic analyses were performed to elaborate on the binding mechanism and relative binding affinities of nine FDA-approved HIV-1 PIs against human Hsp90. Due to the lack of the X-ray crystal structure of human Hsp90, homology modeling was performed to create its 3D structure for subsequent simulations. Results showed that NFV has better binding affinity (DeltaG =-9.2 kcal/mol) when compared with other PIs: this is in a reasonable accordance with the experimental data (IC50 3.1 MUM). Indinavir, saquinavir, and ritonavir have close binding affinity to NFV (DeltaG =-9.0, -8.6, and -8.5 kcal/mol, respectively). Per-residue interaction energy decomposition analysis showed that hydrophobic interaction (most importantly with Val534 and Met602) played the most predominant role in drug binding. To further validate the docking outcome, 5 ns molecular dynamic simulations were performed in order to assess the stability of the docked complexes. To our knowledge, this is the first account of detailed computational investigations aimed to investigate the potential anticancer activity and the binding mechanism of the FDA-approved HIV PIs binding to human Hsp90. Information gained from this study should also provide a route map toward the design, optimization, and further experimental investigation of potential derivatives of PIs to treat HER2+ breast cancer. PMID- 26622168 TI - Apatinib for molecular targeted therapy in tumor. AB - As tumor angiogenesis is one of the hallmarks of cancer, the inhibition of vascular endothelial growth factor signaling has become an attractive anticancer approach. Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor-2, has demonstrated encouraging anticancer activity across a broad range of malignancies, including gastric cancer, non-small-cell lung cancer, breast cancer, and hepatocellular carcinoma. In this up-to-date review, focus is not only on the structure, mechanisms, and pharmacokinetics of apatinib, but also on summarizing clinical trials and making recommendations of apatinib for patients with advanced solid tumors. PMID- 26622170 TI - Scales for assessment of patients with traumatic brain injury. PMID- 26622169 TI - Profile of paritaprevir/ritonavir/ombitasvir plus dasabuvir in the treatment of chronic hepatitis C virus genotype 1 infection. AB - Over the last several years, many advances have been made in the treatment of chronic hepatitis C virus (HCV) infection with the development of direct-acting antivirals. Paritaprevir/ritonavir/ombitasvir with dasabuvir (PrOD) is a novel combination of a nonstructural (NS) 3/4A protein inhibitor boosted by ritonavir, an NS5A protein inhibitor, and an NS5B nonnucleoside polymerase inhibitor. This review aims to discuss the pharmacology, efficacy, safety, drug interactions, and viral drug resistance of PrOD in the treatment of HCV genotype 1 infections. Phase I, II, and III human and animal studies that describe the pharmacology, pharmacokinetics, efficacy, and safety of PrOD for HCV were identified and included. Studies that evaluated patients without cirrhosis (n=2,249) and with cirrhosis (n=422) demonstrated that PrOD for 12 or 24 weeks was effective at achieving sustained virologic response rates (>90%) in patients with genotype 1a or 1b HCV infection. Although indicated for the treatment of HCV genotype 1 infection, PrOD is also recommended for the treatment of HCV in patients coinfected with HIV. Additionally, promising data exist for the use of PrOD in liver-transplant recipients. The most common adverse drug events associated with PrOD included nausea, pruritus, insomnia, diarrhea, asthenia, dry skin, vomiting, and anemia. The high efficacy rates seen coupled with a favorable side effect profile seen with PrOD with or without ribavirin have led to its addition as a recommended treatment regimen for HCV genotype 1 infection. PMID- 26622171 TI - Associated factors vs risk factors in cross-sectional studies. PMID- 26622173 TI - Importance of hypoglycemia on the risk of Alzheimer's disease in elderly subjects with diabetes mellitus. PMID- 26622172 TI - Real-world evaluation of compliance and preference in Alzheimer's disease treatment. AB - PURPOSE: Rivastigmine transdermal patch has shown higher caregiver satisfaction and greater preference than oral formulation in patients with Alzheimer's disease. However, there is limited literature available related to caregiver preference or treatment compliance in real-world clinical settings. To date, no such data are available from Asia and the Middle East, which account for a sizeable proportion of patients with Alzheimer's disease. The objective of this study was to evaluate treatment preference and compliance with oral and transdermal medications in daily clinical practice in an ethnically diverse patient population from Asia and the Middle East with mild-to-moderate Alzheimer's disease. PATIENTS AND METHODS: RECAP (Real-world Evaluation of Compliance And Preference in the treatment of Alzheimer's disease) was a 24-week, multicenter, prospective, noninterventional study. Two treatment cohorts were observed during the study: oral (cholinesterase inhibitors or memantine) and transdermal (rivastigmine patch). Caregiver preference, physician preference, and patient compliance were evaluated at week 24. RESULTS: A total of 978 of 1,931 enrolled patients (mean age: 72.8 years; 50.5% female) were in the transdermal cohort. For patients with exposure to both oral and transdermal monotherapy (n=330), a significant caregivers' preference for the transdermal monotherapy was observed (82.7%; P<0.0001). Of the 89 participating physicians, 71 indicated preference for transdermal monotherapy. Patient compliance was also significantly higher for transdermal than oral monotherapy (P<0.0001). CONCLUSION: Our study showed higher caregiver and physician preference and greater patient compliance with transdermal monotherapy in daily practice. PMID- 26622174 TI - Effectiveness of elastic band-type ankle-foot orthoses on postural control in poststroke elderly patients as determined using combined measurement of the stability index and body weight-bearing ratio. AB - PURPOSE: Poor recovery of postural stability poststroke is the primary cause of impairment in activities and social participation in elderly stroke survivors. The purpose of our study was to experimentally evaluate the effectiveness of our new elastic ankle-foot orthosis (AFO), compared to a traditional AFO fabricated with hard plastic, in improving postural stability in elderly chronic stroke survivors. PATIENTS AND METHODS: Postural stability was evaluated in ten chronic stroke patients, 55.7+/-8.43 years old. Postural stability was evaluated using the standardized methods of the Biodex Balance System combined with a foot pressure system, under three experimental conditions, no AFO, rigid plastic AFO, and elastic AFO (E-AFO). The following dependent variables of postural stability were analyzed: plantar pressure under the paretic and nonparetic foot, area of the center of balance (COB) and % time spent in each location, distance traveled by the COB away from the body center, distance traveled by the center of pressure, and calculated index of overall stability, as well as indices anterior posterior and medial-lateral stability. RESULTS: Both AFO designs improved all indices of postural stability. Compared to the rigid plastic AFO, the E-AFO produced additional positive effects in controlling anterior-posterior body sway, equalizing weight bearing through the paretic and nonparetic limbs, and restraining the displacement of the center of pressure and of the COB. CONCLUSION: Based on our outcomes, we recommend the prescription of E-AFOs as part of a physiotherapy rehabilitation program to promote recovery of postural stability poststroke. When possible, therapeutic outcomes should be documented using the Biodex Balance System and foot pressure system, as used in our study, to provide evidence needed to support the development of a larger controlled trial to generate high-quality evidence on the effectiveness of E-AFOs. PMID- 26622175 TI - The risk of burn injury during long-term oxygen therapy: a 17-year longitudinal national study in Sweden. AB - BACKGROUND: Long-term oxygen therapy (LTOT) improves the survival time in hypoxemic chronic obstructive pulmonary disease. Despite warnings about potential dangers, a considerable number of patients continue to smoke while on LTOT. The incidence of burn injuries related to LTOT is unknown. The aim of this study was to estimate the rate of burn injury requiring health care contact during LTOT. METHODS: Prospective, population-based, consecutive cohort study of people starting LTOT from any cause between January 1, 1992 and December 31, 2009 in the Swedish National Register of Respiratory Failure (Swedevox). RESULTS: In total, 12,497 patients (53% women) were included. The mean (standard deviation) age was 72+/-9 years. The main reasons for starting LTOT were chronic obstructive pulmonary disease (75%) and pulmonary fibrosis (15%). Only 269 (2%) were active smokers when LTOT was initiated. The median follow-up time to event was 1.5 years (interquartile range, 0.55-3.1). In total, 17 patients had a diagnosed burn injury during 27,890 person-years of LTOT. The rate of burn injury was 61 (95% confidence interval, 36-98) per 100,000 person-years. There was no statistically significant difference in the rate of burn injury between ever-smokers and never smokers, or between men and women. CONCLUSION: The rate of burn injuries in patients on LTOT seems to be low in Sweden. The strict requirements in Sweden for smoking cessation before LTOT initiation may contribute to this finding. PMID- 26622176 TI - Categorization of COPD patients in Turkey via GOLD 2013 strategy document: ALPHABET study. AB - OBJECTIVE: To determine distribution of COPD assessment categories and physicians' adherence to Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2013 strategy in Turkish COPD patients. METHODS: A total of 1,610 COPD patients (mean [standard deviation] age: 62.6 [9.9] years, 85.7% were males) were included in this multicenter, non-interventional, cross-sectional study. Patients were categorized via GOLD 2013 strategy document. Consistency between reported and re-classified GOLD categories, and measures used for symptom evaluation and exacerbation was analyzed. RESULTS: Overall, 41.1% of patients were assigned to GOLD A, while 13.2% were assigned to GOLD C categories. Long-acting beta-2 agonist + long-acting muscarinic antagonist + inhaled corticosteroid regimen was the most common treatment (62.0%). Over-treatment was noted in >70% of GOLD A, B, and C patients. A high consistency between measures of symptom evaluation (Kappa coefficient =0.993, P<0.0001) and a low-moderate consistency between exacerbation risk measures (Kappa coefficient =0.237, P<0.0001) were noted. CONCLUSION: Our findings revealed GOLD A as the most prevalent category in Turkish cohort of COPD patients. Group assignment was altered depending on the chosen measure for symptom and risk assessment. Physician non-adherence to treatment recommendations in GOLD 2013 document leading to over-treatment in patients assigned to GOLD A, B, and C categories was also detected. PMID- 26622177 TI - Silver nanoparticles cause complications in pregnant mice. AB - BACKGROUND: Silver nanoparticles (AgNPs) have attracted much interest and have been used for antibacterial, antifungal, anticancer, and antiangiogenic applications because of their unique properties. The increased usage of AgNPs leads to a potential hazard to human health. However, the potential effects of AgNPs on animal models are not clear. This study was designed to investigate the potential impact of AgNPs on pregnant mice. METHODS: The synthesis of AgNPs was performed using culture extracts of Bacillus cereus. The synthesized AgNPs were characterized by X-ray diffraction, Fourier transform infrared spectroscopy, and transmission electron microscopy. AgNPs were administrated into pregnant mice via intravenous infusion at 1.0 mg/kg doses at 6.5 days postcoitum (dpc). At 13.5, 15.5, and 17.5 dpc, the pregnant mice were euthanized, and the embryo and placenta were isolated. The meiotic status of oocytes was evaluated. DNA methylation studies were performed, and aberrant imprinting disrupted fetal, placental, and postnatal development. Quantitative real-time polymerase chain reaction analysis and Western blot were used to analyze various gene expressions. RESULTS: The synthesized AgNPs were uniformly distributed and were spherical in shape with an average size of 8 nm. AgNPs exposure increased the meiotic progression of female germ cells in the fetal mouse ovaries, and maternal AgNP exposure significantly disrupted imprinted gene expression in 15.5 dpc embryos and placentas, such as Ascl2, Snrpn, Kcnq1ot1, Peg3, Zac1, H19, Igf2r, and Igf2; DNA methylation studies revealed that AgNPs exposure significantly altered the methylation levels of differentially methylated regions of Zac1. CONCLUSION: The results from this study indicated that early exposure to AgNPs has the potential to disrupt fetal and postnatal health through epigenetic changes in the embryo and abnormal development of the placenta. These results can contribute to research involved in the safe use of various biomedical applications of AgNPs and improves the understanding of the development of AgNPs in biomedical applications. PMID- 26622178 TI - Paroxetine ameliorates changes in hippocampal energy metabolism in chronic mild stress-exposed rats. AB - The molecular mechanisms underlying stress-induced depression have not been fully outlined. Hence, the current study aimed at testing the link between behavioral changes in chronic mild stress (CMS) model and changes in hippocampal energy metabolism and the role of paroxetine (PAROX) in ameliorating these changes. Male Wistar rats were divided into three groups: vehicle control, CMS-exposed rats, and CMS-exposed rats receiving PAROX (10 mg/kg/day intraperitoneally). Sucrose preference, open-field, and forced swimming tests were carried out. Corticosterone (CORT) was measured in serum, while adenosine triphosphate and its metabolites, cytosolic cytochrome-c (Cyt-c), caspase-3 (Casp-3), as well as nitric oxide metabolites (NOx) were measured in hippocampal tissue homogenates. CMS-exposed rats showed a decrease in sucrose preference as well as body weight compared to control, which was reversed by PAROX. The latter further ameliorated the CMS-induced elevation of CORT in serum (91.71+/-1.77 ng/mL vs 124.5+/-4.44 ng/mL, P<0.001) as well as the changes in adenos-ine triphosphate/adenosine diphosphate (3.76+/-0.02 nmol/mg protein vs 1.07+/-0.01 nmol/mg protein, P<0.001). Furthermore, PAROX reduced the expression of Cyt-c and Casp-3, as well as restoring NOx levels. This study highlights the role of PAROX in reversing depressive behavior associated with stress-induced apoptosis and changes in hippocampal energy metabolism in the CMS model of depression. PMID- 26622179 TI - Association between insulin and executive functioning in alcohol dependence: a pilot study. AB - Alcohol dependence is a disorder ascribable to multiple factors and leads to cognitive impairment. Given that insulin dysregulation can cause cognitive impairment, patients with alcohol dependence are likely to develop insulin dysregulation such as that in diabetes. The purposes of this study are to identify an association between cognitive functioning and insulin and to investigate insulin as the biomarker of cognitive functioning in alcohol dependent patients. Serum insulin levels were measured and cognitive functions were assessed in 45 patients with chronic alcoholism. The Korean version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-K), a battery of cognitive function tests, was used to assess cognitive functioning. Serum insulin levels were not significantly correlated with most CERAD-K scores, but there was a significant negative correlation with scores on the Trail Making Test B, which is designed to measure executive functioning. Lower serum insulin levels were associated with slower executive functioning responses on the Trail Making Test B, suggesting that executive functioning may be in proportion to serum insulin levels. Thus, in patients with alcohol dependence, insulin level is associated with cognitive functioning. In addition, the present findings suggest that insulin level is a potential biomarker for determining cognitive functioning. PMID- 26622180 TI - Clinical development of nintedanib for advanced non-small-cell lung cancer. AB - Angiogenesis is an essential process in the development, growth, and metastasis of malignant tumors including lung cancer. Several angiogenesis inhibitors have been developed as potential therapies for non-small-cell lung cancer (NSCLC). Nintedanib is a small-molecule tyrosine kinase inhibitor that targets receptors for vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor as well as RET (rearranged during transfection) and Flt3. When administered as monotherapy, nintedanib was well tolerated at doses up to 250 mg or 200 mg twice daily in European and Japanese patients, respectively, with liver toxicity featuring prominently among dose-limiting toxicities in both populations. A recent Phase III trial demonstrated that treatment with the combination of nintedanib and docetaxel resulted in a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with docetaxel alone in predefined NSCLC patients with adenocarcinoma tumor histology. Although the incidence of elevated alanine aminotransferase or aspartate aminotransferase as well as of diarrhea was higher in patients treated with nintedanib plus docetaxel, most of these adverse events were manageable with supportive treatment or dose reduction. The results of completed and ongoing clinical trials of nintedanib monotherapy and combination therapy for the treatment of NSCLC are summarized in this study. PMID- 26622181 TI - Cardiovascular risk assessment in type 2 diabetes mellitus: comparison of the World Health Organization/International Society of Hypertension risk prediction charts versus UK Prospective Diabetes Study risk engine. AB - INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) are at higher risk of developing cardiovascular diseases, and assessment of their cardiac risk is important for preventive strategies. PURPOSE: The Ministry of Health of Sri Lanka has recommended World Health Organization/International Society of Hypertension (WHO/ISH) charts for cardiac risk assessment in individuals with T2DM. However, the most suitable cardiac risk assessment tool for Sri Lankans with T2DM has not been studied. This study was designed to evaluate the performance of two cardiac risk assessments tools; WHO/ISH charts and UK Prospective Diabetes Study (UKPDS) risk engine. METHODS: Cardiac risk assessments were done in 2,432 patients with T2DM attending a diabetes clinic in Southern Sri Lanka using the two risk assessment tools. Validity of two assessment tools was further assessed by their ability to recognize individuals with raised low-density lipoprotein (LDL) and raised diastolic blood pressure in a cohort of newly diagnosed T2DM patients (n=332). RESULTS: WHO/ISH charts identified 78.4% of subjects as low cardiac risk whereas the UKPDS risk engine categorized 52.3% as low cardiac risk (P<0.001). In the risk categories of 10%-<20%, the UKPDS risk engine identified higher proportions of patients (28%) compared to WHO/ISH charts (7%). Approximately 6% of subjects were classified as low cardiac risk (<10%) by WHO/ISH when UKPDS recognized them as cardiac risk of >20%. Agreement between the two tools was poor (kappa value =0.144, P<0.01). Approximately 82% of individuals categorized as low cardiac risk by WHO/ISH had higher LDL cholesterol than the therapeutic target of 100 mg/dL. CONCLUSION: There is a significant discrepancy between the two assessment tools with WHO/ISH risk chart recognizing higher proportions of patients having low cardiac risk than the UKPDS risk engine. Risk assessment by both assessment tools demonstrated poor sensitivity in identifying those with treatable levels of LDL cholesterol and diastolic blood pressure. PMID- 26622182 TI - Consolidation therapy of arsenic trioxide alternated with chemotherapy achieves remarkable efficacy in newly diagnosed acute promyelocytic leukemia. AB - BACKGROUND: Currently, all-trans retinoic acid (ATRA) combined with daunorubicin and ATRA combined with arsenic trioxide (ATO) therapies are considered the standard induction therapy regimens for adult patients newly diagnosed with acute promyelocytic leukemia (APL). However, there is no consensus concerning the optimal consolidation and maintenance therapies after induction therapy. In this study, we explored a new therapeutic strategy for APL that may be simple, effective, and safe. METHODS: The patients in our study were divided into high white blood cell (WBC) group and low WBC group according to the numeration of leukocytes at the first visit. The low WBC group received ATRA and ATO until complete remission (CR), and the high WBC group received anthracycline, ATRA, and ATO until CR. After achieving hematologic CR, ATO was alternated with chemotherapy for consolidation therapy. Three cycles were completed in the 1st year with no maintenance therapy. The patients were followed for a median of 5 years after their initial treatment. RESULTS: After induction therapy, the rate of CR for the 18 patients was 100%. The rate of negativity for the PML/RARalpha fusion gene following induction therapy was 100%. There was no mortality during the treatment. Both the 5-year event-free survival rate and 5-year overall survival rate were 100%. No relapses occurred during the follow-up period. CONCLUSION: This study proposes a novel treatment for APL that is efficient, well tolerated, and very simple to perform. PMID- 26622183 TI - Utility of gonadotropin-releasing hormone agonists for prevention of chemotherapy induced ovarian damage in premenopausal women with breast cancer: a systematic review and meta-analysis. AB - BACKGROUND: Premature ovarian failure and infertility following chemotherapy are major concerns for premenopausal women with breast cancer. A potential ovarian function preservation strategy is administration of gonadotropin-releasing hormone (GnRH) agonists during adjuvant chemotherapy; however, studies of the clinical efficacy of GnRH agonists to protect chemotherapy-induced ovarian damage have shown mixed results. OBJECTIVE: This meta-analysis study was designed to estimate the efficacy of GnRH agonists administered concurrently with chemotherapy to prevent chemotherapy-induced ovarian damage in premenopausal women with breast cancer. METHODS: Electronic literature databases (PubMed, EMBASE, MEDLINE, Cochrane Library databases searching, China National Knowledge Infrastructure, Web of Science, and the Wanfang Data) were searched for relevant randomized controlled trials (RCTs) published until September 2015. Only RCTs that examined the effect of GnRH agonists for chemotherapy-induced ovarian failure in premenopausal women with breast cancer were selected. The rate of spontaneous resumption of menses and spontaneous pregnancy were collected. All data were analyzed by RevMan 5.3 (Cochrane Collaboration, Copenhagen, Denmark) and Stata 12.0 (StataCorp, College Station, TX, USA). RESULTS: Eleven RCTs with a total of 1,062 participants (GnRH agonists administered concurrently with chemotherapy, n=541; chemotherapy alone, n=521) were included in the meta analysis. A significantly greater number of women treated with GnRH agonist experienced spontaneous resumption of menses after the adjuvant chemotherapy, yielding a pooled odds ratio of 2.57 (versus chemotherapy alone, 95% confidence interval (CI)=1.65, 4.01; P<0.0001). A subgroup analysis showed that addition of GnRH agonists significantly improved the resumption of menses rate in patients who were hormone-insensitive. However, the two treatment groups experienced similar spontaneous pregnancy (odds ratio =0.177; 95% CI=0.92, 1.40; P=0.09). CONCLUSION: GnRH agonists cotreatment with chemotherapy in premenopausal women with breast cancer plays a beneficial role in resumption of ovarian function, with a higher rate of resumption of menses. However, treatment with GnRH agonists does not appear to exhibit its protective effects in fertility. PMID- 26622184 TI - Dynamin-related protein 1 is involved in micheliolide-induced breast cancer cell death. AB - Dynamin-related protein 1 (Drp1) is a newly discovered therapeutic target for tumor initiation, migration, proliferation, and chemosensitivity. Thus, therapeutic strategies that focus on targeting Drp1 and its related signaling pathway pave a new way to address the ineffectiveness of traditional cancer therapies. Micheliolide (MCL), a guaianolide sesquiterpene lactone, can selectively eradicate acute myeloid leukemia stem or progenitor cells. But the effect of MCL on the mitochondrial dynamics of cancer cells is still not well demonstrated. In this study, we show that MCL inhibited the growth of MCF-7 human breast cancer cells, accompanied by increased mitochondrial fission and upregulation of Drp1. The results obtained from overexpression experiments of wild or dominant-negative mutant type of Drp1 demonstrate that Drp1 is both necessary and sufficient to induce MDA-MB-231 and MCF-7 cell death. Furthermore, mitochondrial membrane potential decreased, whereas reactive oxygen species (ROS) generation, cytochrome c release, and PARP cleavage were enhanced after overexpression of Drp1 wild type. On the other hand, overexpression of Drp1-K38A (a dominant-negative mutant of Drp1) rescued cells from increased apoptosis, confirming the role of MCL-induced Drp1 in the observed apoptosis. Finally, MCL induced Drp1-mediated cell death could be reversed by N-acetyl-L-cysteine (the ROS scavenger) in breast cancer cells. Taken together, the present study shows a novel role for Drp1 in MCL-induced breast cancer cell death, potentially through regulation of ROS-mitochondrial apoptotic pathway. PMID- 26622185 TI - The expenditures related to the use of antifungal drugs in patients with hematological cancers: a cost analysis. AB - OBJECTIVE: The aim of this study is to analyze the expenditures related to the use of antifungal drugs in patients with hematological malignancies. METHODS: In this retrospective study, the expenditures related to use of antifungal drugs for treatment of invasive fungal infections in patients with hematological malignancies between November 2010 and November 2012 were analyzed. Expenditures of antifungal drugs were calculated by converting the price billed to the Republic of Turkey Social Security Institution per patient using the US dollar ($) exchange rate. RESULTS: We retrospectively analyzed the expenditures related to the use of antifungal drugs in 282 febrile episodes of 126 neutropenic patients. Voriconazole (VOR), caspofungin, and liposomal amphotericin B (L-AmB) were administered as a first-line antifungal therapy to treat 72 febrile episodes of 65 neutropenic patients, 45 febrile episodes of 37 neutropenic patients, and 34 febrile episodes of 32 neutropenic patients, respectively. The expenditures related to the use of antifungal drugs per febrile neutropenic episode were $3,857.85 for VOR; $15,783.34 for caspofungin, and $21,561.02 for L-AmB, respectively. The expenditure related to the use of posaconazole (POS) was $32,167.39 per patient for primary or secondary prophylaxis. CONCLUSION: Improving conditions in the patient's room, choosing pre-emptive antifungal treatment instead of empirical antifungal treatment, switching to tablet form of VOR after initiation of its intravenous form, secondary prophylaxis with VOR against invasive aspergillosis, primary prophylaxis with POS in high-risk patients, and choosing less L-AmB as being an alternative to other antifungal drugs, may reduce expenditures related to the use of antifungal drugs in the treatment of invasive fungal infections during febrile neutropenic episodes of patients with hematological malignancies. PMID- 26622186 TI - The financial burden of sickle cell disease on households in Ekiti, Southwest Nigeria. AB - BACKGROUND: Studies on economic impact of sickle cell disease (SCD) are scanty despite its being common among children in developing countries who are mostly Africans. OBJECTIVE: To determine the financial burden of SCD on households in Ado Ekiti, Southwest Nigeria. METHODS: A longitudinal and descriptive study of household expenditures on care of 111 children with SCD managed at the pediatric hematology unit of the Ekiti State University Teaching Hospital was conducted between January and December 2014. RESULTS: There were 64 male and 47 female children involved, aged between 15 and 180 months. They were from 111 households, out of which only eight (7.2%) were enrolled under the National Health Insurance Scheme. The number of admissions and outpatients' consultations ranged from 1 to 5 and 1 to 10 per child, respectively. Malaria, vaso-occlusive crisis, and severe anemia were the leading comorbidities. The monthly household income ranged between ?12,500 and ?330,000 (US$76 and US$2,000) with a median of ?55,000 (US$333), and health expenditure ranged between ?2,500 and ?215,000 (US$15 and US$1,303) with a mean of ?39,554+/-35,479 (US$240+/-215). Parents of 63 children lost between 1 and 48 working days due to their children's ill health. Parents of 23 children took loans ranging between ?6,500 and ?150,000 (US$39 and US$909) to offset hospital bills. The percentage of family income spent as health expenditure on each child ranged from 0.38 to 34.4. Catastrophic health expenditure (when the health expenditure >10% of family income) occurred in 23 (20.7%) households. Parents who took loan to offset hospital bills, low social class, and patients who took ill during the study period significantly had higher odds for catastrophic health expenditure (95% confidence interval [CI] 5.399 87.176, P=0.000; 95% CI 2.322-47.310, P=0.002; and 95% CI 1.128-29.694, P=0.035, respectively). CONCLUSION: SCD poses enormous financial burden on parents and households. PMID- 26622187 TI - Clinical evaluation of a water-in-oil emulsion with protective and regenerative properties for the anogenital area. AB - Inadequate hygiene, aggressive cleansing, and chafing skin folds, as well as urine, feces, and sweat may trigger irritative contact dermatitis in the anogenital area. Serious recommendations for protection of the skin toward irritants include hygienic aspects and the use of appropriate skin care. Furthermore, preventing an accumulation of irritants on unprotected skin is mandatory. An intraindividual comparison study with 30 participants (17 female, 13 male; age: 44.2+/-8.3 years) was performed to evaluate the properties of a newly developed water-in-oil (W/O) balm on artificial sodium dodecyl sulfate damaged epidermal barrier. The balm was applied 14 days twice daily, and transepidermal water loss and erythema were investigated. A significant improvement of both parameters after 12 days and even after 21 days could be confirmed. Two major clinical trials were performed to evaluate the safety and efficacy regarding protective and regenerative properties of the W/O balm on irritated skin in the anogenital area. Therefore, 29 children were enrolled (14 male, 15 female, age: 15.5+/-7.8 months) in an open-labeled 4-week clinical study. The balm was used in the area under disposable diapers at least after diaper change or if required. Furthermore, in a second open, multicenter study, 43 women (mean age: 46.2+/-16.9) with predisposition to skin irritation in the outer anogenital region were included. The product was applied for 4 weeks 1-2 times daily. In both studies, skin tolerability, applicability, scent, spreadability, and removability of the balm were evaluated by participants and practitioners predominantly as good or even very good, also skin hydration, protection, and regeneration were judged positively. The studies confirmed that the newly developed W/O balm exhibits excellent tolerability and is easy to remove. At the same time, excellent properties with respect to efficacy regarding regeneration and protection could be observed, without any undesired effects at any time. PMID- 26622188 TI - Demographics, clinical disease characteristics, and quality of life in a large cohort of psoriasis patients with and without psoriatic arthritis. AB - INNOVATION: What is already known about the topic: psoriasis (PsO) is a common skin disease with major impact on quality of life (QoL). Patient-reported data on QoL from large number of PsO patients with and without psoriatic arthritis (PsA) are limited. WHAT THIS STUDY ADDS: In a large cohort referred to a university psoriasis center, patients with PsO and concomitant PsA (~30% in this group) had greater degrees of skin and nail involvement and experienced greater negative impacts on QoL. Despite large numbers of patients with moderate-to-severe disease, use of systemic therapy by community practitioners was uncommon. BACKGROUND: PsO and PsA are common diseases that have marked adverse impacts on QoL. The disease features and patient-reported QoL data comparing PsO and PsA patients are limited. OBJECTIVE: To identify and compare demographics, clinical disease characteristics, and QoL scores in a large cohort of PsO patients with and without PsA. METHODS: All PsO patients seen in a psoriasis specialty clinic, named the Center of Excellence for Psoriasis and Psoriatic Arthritis, were enrolled in an observational cohort. Demographic, QoL, and clinical data were collected from patient-reported questionnaires and from physical examinations performed by Center of Excellence for Psoriasis and Psoriatic Arthritis dermatologists and a rheumatologists. Cross sectional descriptive data were collected and comparisons between patients with PsO alone and those with concomitant PsA are presented. RESULTS: A total of 568 patients were enrolled in the database. Mean age of PsO onset was 28 years and mean disease duration was 18 years. Those with family history had an earlier onset of PsO by ~7 years. Mean body surface area involvement with PsO was 14%. Mean body mass index was 30.7. Prevalence of PsA was 29.8%. PsA patients had a higher mean body surface area compared to patients with PsO alone (16.7% vs 13.4%, P<0.05), higher prevalence of psoriatic nail changes (54.4% vs 36%, P<0.0002), and worse QoL scores as assessed by the Short Form-12 (67 vs 52, P<0.00001), Psoriasis Quality of Life-12 questionnaire (62 vs 71, P<0.01), and Routine Assessment of Patient Index Data 3 (2.3 vs 4.7, P<0.01). Strikingly, 49% of patients with PsO had never received any systemic therapy. CONCLUSION: These data highlight that PsO has marked negative impacts on QoL, while those patients with concomitant PsA are affected to a much greater degree. Despite large numbers of patients presenting with moderate-to severe disease, use of systemic therapy for both PsO and PsA was uncommon. PMID- 26622190 TI - Personalized treatment options for ALK-positive metastatic non-small-cell lung cancer: potential role for Ceritinib. AB - The fusion of echinoderm microtubule-associated protein-like 4 with the anaplastic lymphoma kinase (EML4-ALK) is found in 3%-7% of non-small-cell lung cancer (NSCLC) cases and confers sensitivity to crizotinib, the first United States Food and Drug Administration (FDA)-approved ALK inhibitor drug. Although crizotinib has an excellent initial therapeutic effect, acquired resistance to this drug invariably develops within the first year of treatment. Resistance may involve secondary gatekeeper mutations within the ALK gene interfering with crizotinib-ALK interactions, or compensatory activation of aberrant bypass signaling pathways. New therapeutic strategies to overcome crizotinib resistance are needed. Ceritinib, a second-generation ALK inhibitor, overcomes several crizotinib-resistant ALK mutations and has demonstrated efficacy against tumor growth in several in vitro and in vivo preclinical models of crizotinib resistance. Notably, the dose-escalation Phase I ASCEND-1 trial has shown a marked activity of ceritinib in both crizotinib-naive and crizotinib-resistant ALK-rearranged lung cancer. The overall response rate was 58% in a subgroup of patients with ALK-rearranged late-stage NSCLC. Drug discontinuation rate due to toxicity was 10%. The standard dose was established at 750 mg daily. This paper outlines the pathogenesis and treatment of ALK-positive lung cancer, focuses on the preclinical and clinical results surrounding the accelerated FDA approval of ceritinib for the treatment of ALK-positive metastatic NSCLC patients who have progressed on/or are crizotinib intolerant, and discusses the potential efforts seeking to maximize ceritinib efficacy and expand its usage to other indications in cancer therapy. PMID- 26622191 TI - A pharmacogenomic prospective randomized controlled trial of CYP2B6 polymorphisms and efavirenz dose adjustment among HIV-infected Thai patients: a pilot study. AB - OBJECTIVE: We aimed at comparing clinical/immunological outcomes in human immunodeficiency virus (HIV)-infected patients who were treated with CYP2B6 guided and conventional efavirenz (EFV) therapy. METHODS: This study was a 24 week prospective randomized controlled trial. Eligible patients were HIV-infected adults yet to start antiretroviral therapy. Twenty-four HIV-infected patients were recruited and randomly assigned to genotype CYP2B6 polymorphism before ART initial dose. Patients with CYP2B6 *6/*6 received 400 mg EFV-based regimen and those with other genotypes received 600 mg EFV-based therapy. RESULTS: For CYP2B6 polymorphism, 12 patients were extensive metabolizers, ten patients were intermediate metabolizers, and only two patients were poor metabolizers (*6/*6). The overall mean EFV plasma concentrations were similar in both groups. The mean drug concentrations (standard deviation) were 1.675 (0.963), 1.445 (0.778), and 1.899 (0.808) ug/mL at week 4, 12, and 24, respectively. The CYP2B6 *6/*6 patient who received low dose of EFV had lower mean EFV level than those who received a normal dose, 1.916 versus 3.915 ug/mL (P<0.001), respectively. Seventy percent of the patients had neuropsychiatric adverse events, especially dizziness. DISCUSSION: There was a trend toward association of the CYP2B6 polymorphism and plasma EFV concentrations in this study. Reduced EFV dose should be considered in CYPB6 *6/*6 carrier to keep the drug concentration in therapeutic range. PMID- 26622189 TI - Translational utility of experimental autoimmune encephalomyelitis: recent developments. AB - Multiple sclerosis (MS) is a complex autoimmune condition with firmly established genetic and environmental components. Genome-wide association studies (GWAS) have revealed a large number of genetic polymorphisms in the vicinity of, and within, genes that associate to disease. However, the significance of these single nucleotide polymorphisms in disease and possible mechanisms of action remain, with a few exceptions, to be established. While the animal model for MS, experimental autoimmune encephalomyelitis (EAE), has been instrumental in understanding immunity in general and mechanisms of MS disease in particular, much of the translational information gathered from the model in terms of treatment development (glatiramer acetate and natalizumab) has been extensively summarized. In this review, we would thus like to cover the work done in EAE from a GWAS perspective, highlighting the research that has addressed the role of different GWAS genes and their pathways in EAE pathogenesis. Understanding the contribution of these pathways to disease might allow for the stratification of disease subphenotypes in patients and in turn open the possibility for new and individualized treatment approaches in the future. PMID- 26622193 TI - Students as facilitators in a teacher training program: motivation for leadership roles. AB - INTRODUCTION: Although students often partake in peer-teaching activities during medical school, they are rarely provided with formal training in teaching. We have previously described our teacher training (TT) program for medical students. The TT program is delivered face-to-face across two sessions. In order to alleviate academic teaching load required to run the course, and at the same time provide our final-year students with practical opportunities to develop their leadership skills, we engaged five senior students as co-facilitators alongside academic staff. By developing an understanding of our students' motivation to participate as facilitators, we may be able to promote an interest within leadership in teaching among other students. Our study sought to examine students' motivation to take part as facilitators in the TT program. METHODS: Data were collected through a focus group session with the five student facilitators. Self-determination theory, which poses that there are three elements key to intrinsic motivation, including autonomy, competence, and relatedness, was used as a conceptual lens to identify and code recurrent themes in the data. RESULTS: Elements that motivated students to assist in facilitation included an opportunity to review and build on their knowledge and skills in teaching practices; the recognition and acknowledgement received from school staff and fellow students; the opportunity to develop these relationships; and a desire to increase their peer-teaching responsibilities. CONCLUSION: By actively involving our students in leadership practices, we were able to not only engage the students, but also develop our student community and contribute to the promotion of a culture of excellence in teaching within the hospital. PMID- 26622194 TI - Nurse uniform wearing practices and associated factors among nurses working in Northwest Ethiopia: a cross-sectional institution based study. AB - BACKGROUND: Wearing uniforms help in the formation of professional identity in healthcare. It fosters a strong self image and professional identity which can lead to good confidence and better performance in nursing practice. However, most nurses in Ethiopia are not wearing nursing uniforms and the reasons remain unclear. Therefore, the aim of this research is to assess nurse uniform wearing practices among nurses and factors associated with such practice in hospitals in Northwest Ethiopia. METHODS: A hospital based cross-sectional study was conducted from March to April, 2014 in five hospitals located in Northwest Ethiopia. A total 459 nurses participated in the study. Data was collected using a pre-tested self-administered questionnaire. Descriptive statistics were analyzed in order to characterize the study population. Bivariate and multiple logistic regression models were fitted. Odds ratios with 95 % confidence intervals were computed to identify factors associated with nursing uniform practice. RESULTS: Nurse uniform wearing practice was found to be 49.2 % of the total sample size. Around 35 % of the respondents that did not implement nurse uniform wearing practices stated that there was no specific uniform for nurses recommended by hospital management. In addition to this, nurse uniform wearing practices were positively associated with being female [AOR = 1.58, 95 % CI (1.02, 2.44)], studying nursing by choice [AOR =3.16, 95 % CI (2.03, 4.92)], and the appeal of nursing uniforms to nurses [AOR = 3.43 95 % CI (1.96, 5.98)]. CONCLUSION: Nurse uniform wearing practices were not exceptionally prevalent in Northwest Ethiopian hospitals. However, encouraging students to pursue interest-based careers and implementing a nurse uniform wearing policy may have the potential to improve such practices. PMID- 26622192 TI - Potential of minimally invasive procedures in the treatment of uterine fibroids: a focus on magnetic resonance-guided focused ultrasound therapy. AB - Minimally invasive treatment options are an important part of the uterine fibroid treatment arsenal, especially among younger patients and in those who plan future pregnancies. This article provides an overview of the currently available minimally invasive therapy options, with a special emphasis on a completely noninvasive option: magnetic resonance-guided focused ultrasound (MRgFUS). In this review, we describe the background of MRgFUS, the patient-selection criteria for MRgFUS, and how the procedure is performed. We summarize the published clinical trial results, and review the literature on pregnancy post-MRgFUS and on the cost-effectiveness of MRgFUS. PMID- 26622195 TI - QUALITY OF LIFE IN HEMODIALYSIS PATIENTS. AB - PURPOSE: To explore the quality of life in hemodialysis patients. MATERIAL AND METHODS: The sample studied consisted of 320 patients undergoing hemodialysis in one-day dialysis center. Data were collected by the completion of a specially designed questionnaire which apart from the sociodemographic and clinical variables, it also included the scale Missoula-VITAS Quality of Life Index (MVQOLI) for assessing quality of life. RESULTS: Of the 320 hemodialysis patients, 57,2% were men while 28,1% of the participants were 71-80 years old. The average total score of quality of life was found to be 17.43 (in a range 0 30). The total score of quality of life was found to be higher in participants <60 years (p= 0,009), of higher educational level (p=0.001), being very informed about the health problem (p=0,013), complied with therapeutic recommendations and the proposed diet (p=0,025 & p=0,012, respectively), having very good relations with the medical and nursing staff or other patients (p<0,001), not experiencing difficulties with social or family environment (p=0,001), had help at home (p <0,001) and in those who did not conceal their health problem from the social environment (p<0.001). Furthermore, it was found that the increasing duration of hemodialysis session entailed poorer quality of life (p<0,001). These results were largely confirmed by multiple linear regression. CONCLUSIONS: Sociodemographic and clinical characteristics seems to influence the quality of life in hemodialysis patients. PMID- 26622196 TI - LIFE QUALITY RELATED TO SPIRITUAL HEALTH AND FACTORS AFFECTING IT IN PATIENTS AFFLICTED BY DIGESTIVE SYSTEM METASTATIC CANCER. AB - INTRODUCTION: Spiritual health is of the basic elements in chronic patients. This concept can be considered as an important approach in promoting physical & spiritual health & life quality. GOAL: The present study has been planned aiming to study life quality related to metastatic phase gastrointestinal (digestive) cancer referring to Mazandaran Medical Science University Educational Center in Iran. MATERIAL AND METHODS: This research has been done by descriptive-analytical method with 250 patients through available sampling method. The data has been collected via spiritual health & life quality questionnaire. The data analysis has been performed by calculating X2, T Test, variance analysis and Pearson correlation coefficient. RESULTS: The mean & standard deviation of the patients were 12.56 +/-94/47. The highest relationship between age & spirituality was related to ages over 60. There was a meaningful statistical relationship between spirituality & life quality scale (p<0.001), between spirituality & respiratory disorder (p<0.047), anorexia (p<0.004), exhaustion (p<0.006), financial problems (p<0.006). CONCLUSION: regarding the results, we can perceive the necessity behind improving spiritual health aspect as an influencing factor on the patients' life quality. Through enhancing spiritual beliefs, it is possible to help the patients' spiritual quality get promoted. PMID- 26622197 TI - CLINICAL-EPIDEMIOLOGICAL STUDY ON STROKE PRESENCE IN THE POPULATION OF HERZEGOVINA-NERETVA CANTON INFLUENCED BY INVESTIGATED RISK FACTORS. AB - INTRODUCTION: Stroke is a rapid loss of brain function due to disturbance blood flow to the brain. The existence of multiple risk factors, the length of their duration, and severity of each factor individually, is positively correlated with the occurrence of stroke. Stroke is the third cause of disability and premature death for men and women. AIM: The aim of this research is that through clinical and epidemiological studies the origin and development of stroke to inspect the same level of representation in the population of the Herzegovina-Neretva Canton. MATERIAL AND METHODS: This survey covers the entire population of residents in the Herzegovina-Neretva Canton, and the number of patients who had a need for primary and secondary treating the symptoms of stroke. The very setting of this model of anthropological research modern human groups and theoretical estimates of the impact of genetic and / or environmental risk factors in the formation of phenotypic expression of complex traits of stroke, at the population level, resulted in the realization of the very methodology of this research. The study was conducted at the Department of Neurology, Regional Medical Center (RMC) "Dr. Safet Mujic" and the Department of Neurology, Clinical Center Mostar. These two health institutions, in addition to primary care are at the disposal for entire population of the Herzegovina-Neretva Canton and beyond. Data were collected by examining the details of the history of the board of hospitalized patients in the period from 1 January 2010-to 31 December 2014. The processed are 10 risk factors potential causes of stroke. We also as research material, used records of hospital morbidity-the disease-illness statistics form (form number: 03-21-61; 03/02/60; 03/02/61; 09/03/60). RESULTS: In our study, stroke is the second most frequent in the period of investigation, and noted the rapid growth that is in 2010 and 10.21% to 14.52% in 2014. There was a slight statistically significant differences in relation to the number of infected men and women, and the same is in favor of the patients are female. The number of patients with ischemic stroke, 954 of them or 48.38% was male and 1,018 or 51.62% were female. Of the 10 possible risk factors, factor 6 has a statistically significant canonical factor value, of which hypertension-CVI and the level of P = 0009 *, p = secondary hypertension, 0034 *, hypertensive heart disease, p =, * 0021, Diabetes mellitus of P = 0029 *, p = Anemia, 0052 * and C-reactive protein (CRP) of p = 0049 *, respectively, these canonical factors carry the entire amount of information about the relations impact of certain risk factors in the onset and development of the brain shock. CONCLUSION: We conclude that there is a statistically significant correlation between the studied risk factors in the genesis of the origin and development of different types of stroke. PMID- 26622198 TI - A COMPARISON OF SERUM LEVELS OF 25-HYDROXY VITAMIN D IN PREGNANT WOMEN AT RISK FOR GESTATIONAL DIABETES MELLITUS AND WOMEN WITHOUT RISK FACTORS. AB - BACKGROUND: During pregnancy, Low serum 25-hydroxyvitamin-D [25(OH)D] concentration is even more critical. This deficiency leads to higher incidences of preeclampsia, gestational diabetes, preterm birth, bacterial vaginosis, and also affects the health of the infants. The aim of this study was to evaluate the relationships between serum levels of 25-hydroxyvitamin D (25[OH]D) and gestational diabetes mellitus (GDM) and differences in high-risk pregnant women and women without risk factors for GDM. METHODS: This cross sectional study including 155 pregnant women, who are still in the first trimester of pregnancy (less than 12 weeks gestation), were randomized to two groups of high and low risk for GDM. For these people, once at the gestational age less than 12 times a week and once at for 24 to 28 weeks of pregnancy, tests of FBS / BS / HbA1C / 25OHD / insulin / Ca / Albumin was requested. Besides, the OGTT test was performed with 75 g glucose at 24 and 28 weeks of pregnancy to diagnose GDM. RESULTS: Serum levels of 25(OH)D in the second trimester of pregnancy ng / ml (24.1 +/- 39.5) was significantly lower than that of the first trimester ng / ml (25.9 +/- 45.6) (p <0.001). But serum 25(OH)D levels in the first and second trimester of pregnancy was significantly different in women at high risk for GDM than women who had no risk factors (p =0.584 and p =0.99). Serum levels of 25(OH)D has an inverse and significant relationship with HbA1C at the beginning of pregnancy (p=0.007). In addition, a significant and inverse relationship was shown between serum levels of 25(OH)D in the second trimester with insulin (p=0.047) and blood sugar 2 hours after ingestion of 75 g glucose (p=0.045) at 24 28 weeks of gestation. CONCLUSION: Regarding to the relationship between serum levels of 25(OH)D and blood sugar and insulin at the second trimester of pregnancy, it is recommended for pregnant women to take vitamin D supplementation. PMID- 26622199 TI - HOW MANY REPETITIONS OF CHILD CARE SKILLS ARE REQUIRED FOR HEALTH WORKER STUDENTS TO ACHIEVE PROFICIENCY? LEARNING CURVE PATTERNS IN CHILD CARE SKILLS ACQUISITION. AB - INTRODUCTION: The vulnerability of children under 5 years old requires paying more attention to the health of this group. In the Iranian health care system, health workers are the first line of human resources for health care in rural areas. Because most health workers begin working in conditions with minimal facilities, their clinical qualifications are crucial. The aim of this study was to determine the number of repetitions of child care skills, required for health worker students to achieve proficiency based on the learning curve. METHODS: A time series research design was used. Participants in this study were first year health worker students enrolled in three health schools in 2011. Data were collected using a questionnaire consisting of demographic information and a checklist evaluating the health worker students' clinical skills proficiency for child care. Data were analyzed using SPSS version 16.0 software (SPSS Inc., Chicago, IL) using descriptive and inferential statistics including Kruskal Wallis and Pearson correlation coefficient tests. RESULTS: Learning curve patterns in child care skills acquisition showed that for less than 20 and between 20 to 29 times, the level of skill acquisition had an upward slope. Between 30- 39 the learning curve was descending, however the slope became ascending once more and then it leveled off (with change of less than 5%). CONCLUSION: It seems that 40 repetitions of child care skills are sufficient for health worker students to achieve proficiency. This suggests that time, resources and additional costs for training health worker students' trainees can be saved by this level of repetition. PMID- 26622200 TI - RETROSPECTIVE STUDY OF MEASURING TUBERCULOSIS THERAPY COMPLIANCE: GREECE AS A HOST COUNTRY FOR VULNERABLE POPULATIONS BEFORE AND DURING THE FINANCIAL CRISIS. AB - BACKGROUND: For the realization of "2015 UN Millennium Development Goals", a question arises pertaining to the course of tuberculosis in Greece and its relationship to patient adherence to treatment, given the fact that the country is undergoing a financial crisis and is a gateway for economic migrants. METHODS: The study concerned 1179 patients of the anti-TBdepartment, "Sotiria" General Chest Diseases Hospital, Athens, Greece collaborating with the National Reference Centre of Mycobacteria, covering a year before the financial crisis, 2007 and 2010-11, the first years of the crisis. A special recording form was used, on the basis of a specific protocol. RESULTS: Out of 954 patients were diagnosed with tuberculosis disease, 657 of which were foreigners. Out of 791 patients residing in the same area, 632 were foreigners. Of the patients who proceeded to a first self-discontinuation of the medication, only 38.3% (n=18) completed the treatment, while 40.4% of them self-discontinued within the first month. Duration of treatment was 6.68+/-3.54 months for those (n=805) with no discontinuation and 7.48+/-3.68 months for those (n=149) with at least one discontinuation, regardless of the etiology p= 0,032. Cases increased during financial crisis, with gradual decrease in mean treatment duration for patients with first line treatment to 7.77+/-3.81 months in 2007, and 6.53+/-3.47 and 6.40+/-3.31 months in 2010 and 2011, respectively. CONCLUSIONS: Since the beginning of treatment measurable signs of either adherent/non-adherent behavior appeared, affecting mean treatment duration and completion. Duration of treatment decreased in the years of financial crisis. Migrants ghettoization calls for implementation of DOTS. PMID- 26622201 TI - THE ASSESSMENT OF CAREGIVER BURDEN IN CAREGIVERS OF HEMODIALYSIS PATIENTS. AB - BACKGROUND: Chronic renal failure is among the chronic disease which due to persistence of the disease and long treatment process has various effects on the physiological, psychological, functional ability, lifestyle changes, and independence status of the patient and his family. This may result in the burden feeling in caregivers. According to the importance of the subject, this study is to assess the level of caregiver burden in caregivers of hemodialysis patients. METHODS: This is a cross-sectional analytical descriptive study that was conducted in 2014 on the caregivers of hemodialysis patients. Research instruments were consisted of two parts: demographic data check list and caregiver burden questionnaire. Data were analyzed by SPSS statistical software and Pearson correlation coefficient tests. A p value of less than 0.05 was considered statistically significant. RESULTS: In this study, 72.5% of caregivers reported moderate to severe levels of caregiver burden. A significant relationship was observed between gender of the patient with caregiver burden score of (p=0.031) and type of the income with caregiver burden score of (p=0.000). Caregivers of male patients and patients with inadequate income had a higher caregiver burden score. CONCLUSIONS: Our results showed that more than half of the caregivers of hemodialysis patients had moderate to severe levels of caregiver burden, therefore it is worthy that health officials and nurses pay special attention to this issue by communicating with these patients and their caregivers. PMID- 26622202 TI - CLASSIFICATION OF IRANIAN NURSES ACCORDING TO THEIR MENTAL HEALTH OUTCOMES USING GHQ-12 QUESTIONNAIRE: A COMPARISON BETWEEN LATENT CLASS ANALYSIS AND K-MEANS CLUSTERING WITH TRADITIONAL SCORING METHOD. AB - BACKGROUND: Nurses constitute the most providers of health care systems. Their mental health can affect the quality of services and patients' satisfaction. General Health Questionnaire (GHQ-12) is a general screening tool used to detect mental disorders. Scoring method and determining thresholds for this questionnaire are debatable and the cut-off points can vary from sample to sample. This study was conducted to estimate the prevalence of mental disorders among Iranian nurses using GHQ-12 and also compare Latent Class Analysis (LCA) and K-means clustering with traditional scoring method. METHODOLOGY: A cross sectional study was carried out in Fars and Bushehr provinces of southern Iran in 2014. Participants were 771 Iranian nurses, who filled out the GHQ-12 questionnaire. Traditional scoring method, LCA and K-means were used to estimate the prevalence of mental disorder among Iranian nurses. Cohen's kappa statistic was applied to assess the agreement between the LCA and K-means with traditional scoring method of GHQ-12. RESULTS: The nurses with mental disorder by scoring method, LCA and K-mean were 36.3% (n=280), 32.2% (n=248), and 26.5% (n=204), respectively. LCA and logistic regression revealed that the prevalence of mental disorder in females was significantly higher than males. CONCLUSION: Mental disorder in nurses was in a medium level compared to other people living in Iran. There was a little difference between prevalence of mental disorder estimated by scoring method, K-means and LCA. According to the advantages of LCA than K-means and different results in scoring method, we suggest LCA for classification of Iranian nurses according to their mental health outcomes using GHQ-12 questionnaire. PMID- 26622203 TI - THE REGRESSION MODEL OF IRAN LIBRARIES ORGANIZATIONAL CLIMATE. AB - BACKGROUND: The purpose of this study was to drawing a regression model of organizational climate of central libraries of Iran's universities. METHODS: This study is an applied research. The statistical population of this study consisted of 96 employees of the central libraries of Iran's public universities selected among the 117 universities affiliated to the Ministry of Health by Stratified Sampling method (510 people). Climate Qual localized questionnaire was used as research tools. For predicting the organizational climate pattern of the libraries is used from the multivariate linear regression and track diagram. RESULTS: of the 9 variables affecting organizational climate, 5 variables of innovation, teamwork, customer service, psychological safety and deep diversity play a major role in prediction of the organizational climate of Iran's libraries. The results also indicate that each of these variables with different coefficient have the power to predict organizational climate but the climate score of psychological safety (0.94) plays a very crucial role in predicting the organizational climate. Track diagram showed that five variables of teamwork, customer service, psychological safety, deep diversity and innovation directly effects on the organizational climate variable that contribution of the team work from this influence is more than any other variables. CONCLUSIONS: Of the indicator of the organizational climate of climateQual, the contribution of the team work from this influence is more than any other variables that reinforcement of teamwork in academic libraries can be more effective in improving the organizational climate of this type libraries. PMID- 26622204 TI - PROCESS DOCUMENTATION: A MODEL FOR KNOWLEDGE MANAGEMENT IN ORGANIZATIONS. AB - BACKGROUND: Continuous and interconnected processes are a chain of activities that turn the inputs of an organization to its outputs and help achieve partial and overall goals of the organization. These activates are carried out by two types of knowledge in the organization called explicit and implicit knowledge. Among these, implicit knowledge is the knowledge that controls a major part of the activities of an organization, controls these activities internally and will not be transferred to the process owners unless they are present during the organization's work. Therefore the goal of this study is identification of implicit knowledge and its integration with explicit knowledge in order to improve human resources management, physical resource management, information resource management, training of new employees and other activities of Isfahan University of Medical Science. METHODS: The project for documentation of activities in department of health of Isfahan University of Medical Science was carried out in several stages. First the main processes and related sub processes were identified and categorized with the help of planning expert. The categorization was carried out from smaller processes to larger ones. In this stage the experts of each process wrote down all their daily activities and organized them into general categories based on logical and physical relations between different activities. Then each activity was assigned a specific code. The computer software was designed after understanding the different parts of the processes, including main and sup processes, and categorization, which will be explained in the following sections. RESULTS: The findings of this study showed that documentation of activities can help expose implicit knowledge because all of inputs and outputs of a process along with the length, location, tools and different stages of the process, exchanged information, storage location of the information and information flow can be identified using proper documentation. CONCLUSION: A documentation program can create a complete identifier for every process of an organization and also acts as the main tool for establishment of information technology as the basis of the organization and helps achieve the goal of having electronic and information technology based organizations. In other words documentation is the starting step in creating an organizational architecture. Afterwards, in order to reach the desired goal of documentation, computer software containing all tools, methods, instructions and guidelines and implicit knowledge of the organization was designed. This software links all relevant knowledge to the main text of the documentation and identification of a process and provides the users with electronic versions of all documentations and helps use the explicit and implicit knowledge of the organization to facilitate the reengineering of the processes in the organization. PMID- 26622205 TI - LUNG CANCER AND PULMONARY THROMBOEMBOLISM. AB - INTRODUCTION: Malignant diseases including lung cancer are the risk for development of pulmonary thromboembolism (PTE). OBJECTIVE: To show the number of PTE in patients with lung cancer treated in Clinic for pulmonary diseases and TB "Podhrastovi" in three-year period: from 2012-2014. MATERIAL AND METHODS: This is the retrospective study in which we present the number of various types of lung cancer treated in three-year period, number and per cent of PTE in different types of lung carcinoma, number and per cent of PTE of all diagnosed PTE in lung carcinoma according to the type of carcinoma. RESULTS: In three-year period (from 2012 to 2014) 1609 patients with lung cancer were treated in Clinic for pulmonary diseases and TB "Podhrastovi" Clinical Centre of Sarajevo University. 42 patients: 25 men middle -aged 64.4 years and 17 women middle- aged 66.7 or 2.61% of all patients with lung cancer had diagnosed PTE. That was the 16. 7% of all patients with PTE treated in Clinic "Podhrastovi "in that three-year period. Of all 42 patients with lung cancer and diagnosed PTE 3 patients (7.14%) had planocellular cancer, 4 patients (9.53%) had squamocellular cancer, 9 (21.43%) had adenocarcinoma, 1 (2.38%) had NSCLC, 3 (7.14 %) had microcellular cancer, 1 (2.38%) had neuroendocrine cancer, 2 (4.76%) had large cell-macrocellular and 19 (45.24%) had histological non-differentiated lung carcinoma. CONCLUSION: Malignant diseases, including lung cancer, are the risk factor for development of PTE. It is important to consider the including anticoagulant prophylaxis in these patients and so to slow down the course of diseases in these patients. PMID- 26622207 TI - DENTAL CONSIDERATIONS FOR LEUKEMIC PEDIATRIC PATIENTS: AN UPDATED REVIEW FOR GENERAL DENTAL PRACTITIONER. AB - The early signs of leukemia can usually manifest in the oral cavity due to infiltration of leukemic cells or due to associated decline in normal marrow elements, especially in the acute phase of leukemia, as common lesions at this stage of the disease can be screened and diagnosed by the dentist. Therefore, the dental community should be aware of the oral manifestations of leukemia and oral complications of anticancer treatment. This can eliminate the oral symptoms of the disease and to improve quality of life for these patients. An extensive search in PubMed line using a combination of terms like "leukemia, children, dental, Acute lymphoblastic leukemia, pediatric" for last ten years was made. Reviews and case reports concerned about acute lymphoblastic leukemia in children were all collected and analyzed and data were extracted. Accordingly, the aim of this review is to highlight on the oral presentations of leukemia in children attending dental clinics and the management of its undesirable side effects. PMID- 26622206 TI - INTEGRATING CHRONIC KIDNEY DISEASE PATIENT'S SPIRITUALITY IN THEIR CARE: HEALTH BENEFITS AND RESEARCH PERSPECTIVES. AB - INTRODUCTION: Patients who suffer from chronic renal disease face problems in many aspects of their life; problems such as physical and social as well as mental such as stress, anxiety, depression. In addition, they exhibit an amount of spiritual needs, which relate and influence the psychological adaptation to the illness. AIM: The aim of this article is to examine evidence from the international literature regarding the possible relation of spirituality and health outcomes, mostly in the complex codex of a chronic and life treathing disease such as CKD. RESULTS: Spirituality is a very debatable issue and the term has no single and widely agreed definition. The key components of spirituality were 'meaning', 'hope', 'relatedness/connectedness', and 'beliefs/beliefs systems'. Spirituality has been characterized as the quest for meaning in life, mainly through experiences and expressions of mind, in a unique and dynamic process different for each individual. For many individuals spirituality and religion are important aspects of their existence, constituting a source support contribute to wellbeing and coping with life's daily difficulties. CONCLUSION: Considering, assessing and addressing chronic kidney disease patient's spirituality and spiritual needs is necessary and it can have a positive outcome in health related quality of life, mental health and life expectancy. PMID- 26622208 TI - Concentric Tube Robots as Steerable Needles: Achieving Follow-the-Leader Deployment. AB - Concentric tube robots can enable new clinical interventions if they are able to pass through soft tissue, deploy along desired paths through open cavities, or travel along winding lumens. These behaviors require the robot to deploy in such a way that the curved shape of its shaft remains unchanged as the tip progresses forward (i.e., "follow-the-leader" deployment). Follow-the-leader deployment is challenging for concentric tube robots due to elastic (and particularly torsional) coupling between the tubes that form the robot. However, as we show in this paper, follow-the-leader deployment is possible, provided that tube precurvatures and deployment sequences are appropriately selected. We begin by defining follow-the-leader deployment and providing conditions that must be satisfied for a concentric tube robot to achieve it. We then examine several useful special cases of follow-the-leader deployment, showing that both circular and helical precurvatures can be employed, and provide an experimental illustration of the helical case. We also explore approximate follow-the-leader behavior and provide a metric for the similarity of a general deployment to a follow-the-leader deployment. Finally, we consider access to the hippocampus in the brain to treat epilepsy, as a motivating clinical example for follow-the leader deployment. PMID- 26622209 TI - Power Amplifier Linearizer for High Frequency Medical Ultrasound Applications. AB - Power amplifiers (PAs) are used to produce high-voltage excitation signals to drive ultrasonic transducers. A larger dynamic range of linear PAs allows higher contrast resolution, a highly desirable characteristic in ultrasonic imaging. The linearity of PAs can be improved by reducing the nonlinear harmonic distortion components of high-voltage output signals. In this paper, a linearizer circuit is proposed to reduce output signal harmonics when working in conjunction with a PA. The PA performance with and without the linearizer was measured by comparing the output power 1-dB compression point (OP1dB), and the second- and third-order harmonic distortions (HD2 and HD3, respectively). The results show that the PA with the linearizer circuit had higher OP1dB (31.7 dB) and lower HD2 (-61.0 dB) and HD3 (-42.7 dB) compared to those of the PA alone (OP1dB (27.1 dB), HD2 (-38.2 dB), and HD3 (-36.8 dB)) at 140 MHz. A pulse-echo measurement was also performed to further evaluate the capability of the linearizer circuit. The HD2 of the echo signal received by the transducer using a PA with the linearizer (-24.8 dB) was lower than that obtained for the PA alone (-16.6 dB). The linearizer circuit is capable of improving the linearity performance of PA by lowering harmonic distortions. PMID- 26622210 TI - [Not Available]. AB - Experimentally-induced total sleep deprivation (TSD) and chronic partial sleep restriction (CPSR) leads to the emergence of cognitive impairments. This is hypothesized to result from a consequent neuroinflammation which may also hasten the neurodegenerative processes. Neuroinflammatory markers such as tumor necrosis factor-alpha (TNFalpha) are thought to be potential culprits in SD-induced neurodegeneration. The effect of TSD and CPSR on memory and anxiety-related behaviors (using the Elevated Plus-Maze test-retest protocol) and serum level of brain derived neurotrophic factor (BDNF) and corticosterone were assessed in male Wistar rats subjected to the modified disk-over-water (DOW) apparatus. In addition, an immunohistochemical (IHC) study was done to possibly detect the amyloid-beta (Abeta) and hyper-phosphorylated tau protein (HPtau) deposition in the dentate gyrus (DG) of the examined rats' hippocampi. Histomorphology and neuronal numerical density assessments were done at the same level across control and experimental animals. We also studied the above parameters in rats after intraperitoneal injection of the TNFalpha neutralizing antibody, infliximab (IFX). Rats subjected to TSD and CPSR which did not receive IFX, showed a more pronounced impairment of memory, elevated serum corticosterone and decreased BDNF levels. CPSR rats which underwent delayed brain excision following behavioral testing, showed deposition of the HPtau and revealed the least numerical density in the hippocampal DG neurons. Meanwhile, IHC study revealed no Abeta deposition in the hippocampal DG of all examined rats. Interestingly, treatment with IFX, abrogated sleep restriction-induced cognitive decline, biochemical changes and the immunohistopathology in the hippocampal DG. Taken together, our findings indicated that CPSR (the SD model mimicking shift work) induces not only cognitive and biochemical changes, but also pathology in the hippocampal DG. This is possibly via activation of the inflammatory mechanisms in part through TNFalpha-dependent pathways. PMID- 26622212 TI - Evaluation of chromosome aberrations induced by digoxin in Chinese hamster ovary cells. AB - Digoxin is a cardiac glycoside that has been reported to inhibit growth of multiple tumor cell types in vitro. The present study was assessing the cytogenetic effects of this drug on Chinese Hamster Ovary (CHO) cells. All experiments were performed in triplicate. The IC50 was 22.5 +/- 0.8 ug/ml. To investigate the clastogenic effects of drug, chromosomal aberration in metaphase cells were analyzed. Chromatid breaks and polyploidy were the main types of aberration. Mitomycin-C and sodium arsenite were used as positive controls. CHO cells were exposed to different concentration of drug (5, 10, 15, 20 ug/ml) in 24 hours. All of the study aberrations and frequency of aberrant cells significantly increased as a function of digoxin concentration (for chromatid breaks: r = 0.881, df = 13, P < 0.001; for polyploidy: r = 0.777, df = 13, P = 0.001; for cells with aberrations: r = 0.926, df = 13, P < 0.001). The mitotic index negatively correlated with the concentration of digoxin (r = -0.978, df = 13, P < 0.001). All concentrations that cause chromosomal aberrations are in the cytotoxic range of the drug. The peak serum digoxin concentration (5 - 20 ng/ml) was very lower than concentrations we used in the present experiments. Further studies on valuation of chromatid breaks, micronuclei, and sister chromatid exchange in lymphocytes of patients who received digoxin, were recommended. PMID- 26622211 TI - Irrational antibiotic prescribing: a local issue or global concern? AB - Resistance to antibiotics is a major public-health concern and antibiotic use is being ever more recognized as the main discriminatory pressure driving this resistance. The aim was to assess the outpatient usage of antibiotics in teaching hospitals in various parts of capital city of Iran, Tehran and its association with resistance. 600 outpatient antibiotic prescriptions between December 2011 and May 2012 were reviewed in our teaching hospitals. All prescriptions were scrutinized in order to evaluate the antibiotic prescribing. The medical doctors from all grades were asked to note the chief complaints and the most possible diagnosis on each prescription. Clinical data, patient demographic and ultimately the total quantities of antibiotics were recorded. Our data was then compared against the major antibiotic guidelines and similar studies in other countries. The most common prescribed antibiotics are Penicillins (Penicillin, Co-Amoxiclav and Amoxicillin) (40 %), Cephalosporins (Cefixime, Cephalexin and Ceftriaxone) (24.5 %) and Macrolides (particularly Azithromycin) (15.3 %). In total, 18.2 % of cases were combinational antibacterial therapies (>= 2). The most common diagnosis was upper respiratory tract infections as common cold (29.2 %) and sore throat (11.8 %). Directions (instructions for use) of 58 % of selected antibiotics were acceptable. Parenteral administration remains the common route of administration with 22 % of all reviewed prescriptions. Based on Cochrane reviews the antibiotic prescribing was unjustified in 42.7 % of the cases. The prescribing habit, correct diagnosis and the use of antibiotics need instant consideration. These data can provide useful information for assessing public health policy that aims to reduce the antibiotic use and resistance levels. PMID- 26622213 TI - Quantitative population-health relationship (QPHR) for assessing metabolic syndrome. AB - Metabolic syndrome (MS) is a condition that predisposes individuals to the development of cardiovascular diseases and type 2 diabetes mellitus. A cross sectional investigation of 15,365 participants residing in metropolitan Bangkok who had received an annual health checkup in 2007 was used in this study. Individuals were classified as MS or non-MS according to the International Diabetes Federation criteria using BMI cutoff of >= 25 kg/m(2) plus two or more MS components. This study explores the utility of quantitative population-health relationship (QPHR) for predicting MS status as well as discovers variables that frequently occur together. The former was achieved by decision tree (DT) analysis, artificial neural network (ANN), support vector machine (SVM) and principal component analysis (PCA) while the latter was obtained by association analysis (AA). DT outperformed both ANN and SVM in MS classification as deduced from its accuracy value of 99 % as compared to accuracies of 98 % and 91 % for ANN and SVM, respectively. Furthermore, PCA was able to effectively classify individuals as MS and non-MS as observed from the scores plot. Moreover, AA was employed to analyze individuals with MS in order to elucidate pertinent rule from MS components that occur frequently together, which included TG+BP, BP+FPG and TG+FPG where TG, BP and FPG corresponds to triglyceride, blood pressure and fasting plasma glucose, respectively. QPHR was demonstrated to be useful in predicting the MS status of individuals from an urban Thai population. Rules obtained from AA analysis provided general guidelines (i.e. co-occurrences of TG, BP and FPG) that may be used in the prevention of MS in at risk individuals. PMID- 26622214 TI - Synthesis and computational investigation of molecularly imprinted nanospheres for selective recognition of alpha-tocopherol succinate. AB - Molecularly imprinted polymers (MIPs) are macromolecular matrices that can mimic the functional properties of antibodies, receptors and enzymes while possessing higher durability. As such, these polymers are interesting materials for applications in biomimetic sensor, drug synthesis, drug delivery and separation. In this study, we prepared MIPs and molecularly imprinted nanospheres (MINs) as receptors with specific recognition properties toward tocopherol succinate (TPS) in comparison to tocopherol (TP) and tocopherol nicotinate (TPN). MIPs were synthesized using methacrylic acid (MAA) as functional monomer, ethylene glycol dimethacrylate (EGDMA) as crosslinking agent and dichloromethane or acetronitrile as porogenic solvent under thermal-induced polymerization condition. Results indicated that imprinted polymers of TPS-MIP, TP-MIP and TPN-MIP all bound specifically to their template molecules at 2 folds greater than the non imprinted polymers. The calculated binding capacity of all MIP was approximately 2 mg per gram of polymer when using the optimal rebinding solvent EtOH:H2O (3:2, v/v). Furthermore, the MINs toward TPS and TP were prepared by precipitation polymerization that yielded particles that are 200-400 nm in size. The binding capacities of MINs to their templates were greater than that of the non-imprinted nanospheres when using the optimal rebinding solvent EtOH:H2O (4:1, v/v). Computer simulation was performed to provide mechanistic insights on the binding modalities of template-monomer complexes. In conclusion, we had successful prepared MIPs and MINs for binding specifically to TP and TPS. Such MIPs and MINs have great potential for industrial and medical applications, particularly for the selective separation of TP and TPS. PMID- 26622215 TI - Anti-apolipoprotein A-I antibodies and paraoxonase 1 activity in Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus (SLE) patients have an increased risk of atherosclerosis. Identification of at-risk patients and the pathogenesis of atherosclerosis in SLE remain elusive. Paraoxonase 1 (PON1) and anti apolipoprotein A-I antibody (anti-Apo A-I) appear to have a potential role in premature atherosclerosis in SLE. The aim of this work was to study PON1 activity and anti-Apo A-I antibody in SLE female patients and to demonstrate their relations to disease activity as well as disease related damage. Forty SLE female patients and 40 apparently healthy volunteers were included. Anti-Apo A-I antibodies levels and PON1 activity levels were assessed. Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and systemic Lupus International Collaboration Clinics (SLICC)/American College of Rheumatology (ACR) damage index were preformed in all patients. Compared with controls, SLE patients showed significantly lower PON1 activity and significantly higher titers of anti-Apo A I. Anti-Apo A-I antibody titers correlated inversely with PON1 activity. Elevated titers of anti-Apo A-I antibody and reduced PON activity were related to increased SLEDAI and (SLICC/ACR) damage index scores. We concluded that there is decreased PON1 activity and formation of anti-Apo A-I antibodies in female patients with SLE. SLE-disease activity assessed by SLEDAI and SLE disease related organ damage assessed by SLICC/ACR damage index are negatively correlated with PON1 activity and positively correlated with anti-Apo A-I antibodies. PON1 activity and anti-Apo A-I antibodies might be involved in the pathogenesis of atherosclerosis in SLE patients. PMID- 26622216 TI - Pulmonary phthalate exposure and asthma - is PPAR a plausible mechanistic link? AB - Due to their extensive use as plasticisers in numerous consumer products, phthalates have become ubiquitous environmental contaminants. An increasing number of epidemiological studies suggest that exposure to phthalates may be associated with worsening or development of airway diseases. Peroxisome Proliferation Activated Receptors (PPAR)s, identified as important targets for phthalates in early studies in rodent liver, have been suggested as a possible mechanistic link. In this review we discuss the likelihood of an involvement of PPARs in asthma development and exacerbation due to pulmonary phthalate exposure. First, we go through the literature on indoor air levels of phthalates and pulmonary phthalate kinetics. These data are then used to estimate the pulmonary phthalate levels due to inhalation exposure. Secondly, the literature on phthalate-induced activation or modulation of PPARs is summarized. Based on these data, we discuss whether pulmonary phthalate exposure is likely to cause PPAR activation, and if this is a plausible mechanism for adverse effects of phthalates in the lung. It is concluded that the pulmonary concentrations of some phthalates may be sufficient to cause a direct activation of PPARs. Since PPARs mainly mediate anti-inflammatory effects in the lungs, a direct activation is not a likely molecular mechanism for adverse effects of phthalates. However, possible modulatory effects of phthalates on PPARs deserve further investigation, including partial antagonist effects and/or cross talk with other signalling pathways. Moreover other mechanisms, including interactions between phthalates and other receptors, could also contribute to possible adverse pulmonary effects of phthalates. PMID- 26622217 TI - Protective effect of ginseng against gamma-irradiation-induced oxidative stress and endothelial dysfunction in rats. AB - This study investigated the potential protective effects of ginseng on gamma irradiation-induced oxidative stress and endothelial dysfunction in rats. Twenty four male albino rats were divided into four groups. In the control group, rats were administered vehicle by tube for 7 consecutive days. The second group was administered ginseng extract (100 mg/kg, by gavage) for 7 consecutive days. Animals in the third group were administered vehicle by tube for 7 consecutive days, then exposed to single dose gamma-irradiation (6 Gy). The Fourth group received ginseng extract for 7 consecutive days, one hour later rats were exposed to gamma-irradiation. Oral administration of ginseng extract prior to irradiation produced a significant protection which was evidenced by a significant reduction in serum creatine kinase (CPK) and lactate dehydrogenase (LDH) activities and asymmetric dimethylarginine (ADMA), urea and creatinine levels with significant increase in serum total nitrate/nitrite (NO(x)) level. Moreover, ginseng significantly increased cardiac and renal superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) activities, and reduced glutathione (GSH) content, associated with a significant depletion in malondialdehyde (MDA) and NO(x) levels compared to irradiated group. This study suggests that ginseng may serve as a potential protective agent against gamma-irradiation-induced cardio nephrotoxicity via enhancing the antioxidant activity and inhibition of endothelial dysfunction. PMID- 26622218 TI - Heme oxygenase effect on mesenchymal stem cells action on experimental Alzheimer's disease. AB - The objective is to evaluate the effect of heme oxygenase-1 (HO-1) enzyme inducer and inhibitor on Mesenchymal Stem Cells (MSCs) in Alzheimer disease. 70 female albino rats were divided equally into 7 groups as follows: group 1: healthy control; group 2: Aluminium chloride induced Alzheimer disease; group 3: induced Alzheimer rats that received intravenous injection of MSCs; group 4: induced Alzheimer rats that received MSCs and HO inducer cobalt protoporphyrin; group 5: induced Alzheimer rats that received MSCs and HO inhibitor zinc protoporphyrin; group 6: induced Alzheimer rats that received HO inducer; group7: induced Alzheimer rats that received HO inhibitor. Brain tissue was collected for HO-1, seladin-1 gene expression by real time polymerase chain reaction, heme oxygenase activity, cholesterol estimation and histopathological examination. MSCs decreased the plaque lesions, heme oxygenase induction with stem cells also decreased plaque lesions however there was hemorrhage in the brain. Both heme oxygenase inducer alone or with stem cells increased seladin-1 expression and decreased cholesterol level. MSCs alone or with HO-1 induction exert a therapeutic effect against the brain lesion in Alzheimer's disease possibly through decreasing the brain cholesterol level and increasing seladin-1 gene expression. PMID- 26622219 TI - Chemical composition, antioxidant and antigenotoxic activities of different fractions of Gentiana asclepiadea L. roots extract. AB - The aim of this study was to evaluate the antioxidant and antigenotoxic activities of chloroform, ethyl acetate and n-butanol fractions obtained from Gentiana asclepiadea L. roots methanolic extract. The main secondary metabolites sweroside, swertiamarin and gentiopicrine were quantified in G. asclepiadea root extracts using HPLC-DAD analysis. Amount of total phenols, flavonoids, flavonols and gallotannins was also determined. The antigenotoxic potential of extracts from roots of G. asclepiadea was assessed using the standard in vivo procedure for the detection of sex linked recessive lethal mutations in Drosophila melanogaster males treated with ethyl methanesulfonate (EMS). The results showed that the most abundant secoiridoid in G. asclepiadea roots was gentiopicrine and its content in the n-butanol fraction (442.89 mg/g) was the highest. Among all extracts, ethyl acetate fraction showed the highest antioxidant activity, as well as total phenolics (146.64 GAE/g), flavonoids (44.62 RUE/g), flavonols (22.71 RUE/g) and gallotannins (0.99 mg GAE/g) content. All the fractions showed antioxidant activity using in vitro model systems and the results have been correlated with total phenolics, flavonoids, flavonols and gallotannins content. In addition to antioxidant activity, G. asclepiadea root extract fractions possess an antigenotoxic effect against DNA damage induced by alkylation with EMS. The antioxidant activity exhibited by G. asclepiadea depended on the phenolic compounds content of the tested extracts, while there was no significant difference in the antigenotoxic potential between fractions. PMID- 26622220 TI - Embelia ribes extract reduces high fat diet and low dose streptozotocin-induced diabetic nephrotoxicity in rats. AB - Nephropathy associated with type 2 diabetes is the single most common cause of end-stage renal disease. The aim of the present study was to evaluate the preventive effect of ethanolic extract of Embelia ribes fruit (EER) against high fat diet (HFD) and low dose streptozotocin (STZ)-induced diabetic nephrotoxicity in Wistar rats. HFD-fed and low dose STZ (35 mg/kg, i.p)-induced diabetic rats were treated with EER (100 and 200 mg/kg/day) for 21 days while continuing on HFD. Preventive effects of EER were demonstrated by significant reduction (p< 0.01) in body weight gain, fasting blood glucose, blood pressure, serum lactate dehydrogenase (LDH), creatinine, alkaline phosphatase (ALP), total cholesterol and triglyceride levels, while elevation in serum albumin and total protein levels. Insulin sensitizing effects were seen during oral glucose tolerance testing. Further, EER treatment significantly (p< 0.01) decreased the kidney thiobarbituric acid-reactive substance (TBARS) levels, while increasing the superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) levels in diabetic rats. Histological studies of kidney also supported the experimental findings. Taken together, our data suggest that EER attenuates renal injury in type 2 diabetic rats, possibly by improvement in glucose and lipid metabolism, enhancement of insulin sensitivity, blood pressure lowering, and inhibition of lipid peroxidation process. PMID- 26622221 TI - Diastereoselective Oxidative C-N/C-O and C-N/C-N Bond Formation Tandems Initiated by Visible Light: Synthesis of Fused N-Arylindolines. AB - The synthesis of fused N-arylindolines using visible light photoredox catalysis has been developed. We previously described that photogenerated amine radical cations generate substituted indoles through an intermediate benzylic carbocation. Herein, we expand the application of this chemistry by trapping the benzylic carbocation with tethered heteronucleophiles. The reactivity of the photogenerated benzylic carbocation is explored and applied to a range of substrates with various electronic characters and ring constraints. The method described provides C2 and C3 fused indolines bearing a tetrasubstituted carbon stereocenter with greater than 99:1 diastereoselectivity in moderate to good yields. PMID- 26622222 TI - Palladium-Catalyzed Alkene Carboamination Reactions of Electron-Poor Nitrogen Nucleophiles. AB - Modified reaction conditions that facilitate Pd-catalyzed alkene carboamination reactions of electron-deficient nitrogen nucleophiles are reported. Pent-4 enylamine derivatives bearing N-tosyl or N-trifluoroacetyl groups are coupled with aryl triflates to afford substituted pyrrolidines in good yield. These reactions proceed via a mechanism involving anti-aminopalladation of the alkene, which differs from previously reported analogous reactions of N-aryl and N-boc pentenylamines. The application of these conditions to a formal synthesis of (+/ )-aphanorphine is also described. PMID- 26622223 TI - Exploiting Enzymatic Dynamic Reductive Kinetic Resolution (DYRKR) in Stereocontrolled Synthesis. AB - Over the past two decades, the domains of both frontline synthetic organic chemistry and process chemistry and have seen an increase in crosstalk between asymmetric organic/organometallic approaches and enzymatic approaches to stereocontrolled synthesis. This review highlights the particularly auspicious role for dehydrogenase enzymes in this endeavor, with a focus on dynamic reductive kinetic resolutions (DYRKR) to "deracemize" building blocks, often setting two stereocenters in so doing. The scope and limitations of such dehydrogenase-mediated processes are overviewed, as are future possibilities for the evolution of enzymatic DYRKR. PMID- 26622225 TI - Safety and efficacy of salvage low-dose-rate brachytherapy for prostate bed recurrences following radical prostatectomy. AB - PURPOSE: To report efficacy in our series of nodular recurrences in the post surgical bed that underwent salvage low-dose-rate (LDR) brachytherapy. MATERIAL AND METHODS: Patients with radical prostatectomy (RP) who had biochemical failure with nodular recurrence detected by DRE, ultrasound, and pelvic CT and then salvaged with LDR (125)I brachytherapy were included. Nodular recurrences were biopsy confirmed adenocarcinoma, and patients had no evidence of nodal or distant metastasis on imaging including bone scan. Follow up was at least every 6 months with a serial prostate specific antigen (PSA). RESULTS: Twelve patients had salvage LDR brachytherapy with median age 69 years (range 59-86) and median pre salvage PSA of 4.22 ng/ml. Nodule biopsy Gleason score was 7, 8, or undifferentiated. Median rectal V100 was 0.00 cc. Compared to pre-salvage, patients reported no additional genitourinary (GU) toxicity. After a median 35 months post-salvage follow up (range 10-81 months), patients had a median PSA nadir of 0.72 ng/ml (range 0.01-22.4). At 6 months post salvage, 90% of patients had a PSA below pre-salvage levels. At last follow up, 4 patients had PSA control. CONCLUSIONS: There was a trend to improved biochemical relapse free survival for lower Gleason score and pre-salvage PSA, which may be indicative of the lack of or only low volume metastatic disease. LDR brachytherapy is an effective salvage technique and can be considered in well selected patients allowing for dose escalation to the nodular recurrence. PMID- 26622226 TI - Effect of constipation on dosimetry after permanent seed brachytherapy for prostate cancer. AB - PURPOSE: A major concern in prostate brachytherapy is rectal toxicity, which mainly depends on the dose and volume of rectum involved by radiation. We hypothesize that the rectal distension, as produced by constipation, influences the dosimetric parameters of the rectum and other pelvic organs. MATERIAL AND METHODS: An open, controlled, prospective, paired trial (pre-post test) was designed and conducted. Twenty-three patients treated with prostate brachytherapy were recruited, of which 21 were evaluated. All of them underwent two CT scans, the first one with empty rectum and the second with rectum distended by a catheter balloon. Target volumes and organs at risk were delineated, and dosimetric parameters were calculated and then compared for each patient between both CT. RESULTS: For rectum, D2cc increased 15.8% (p < 0.001) and D0.1cc 24.05% (p = 0.002) when the rectum was full. A significant difference was also found in dose distribution to prostate, when rectum is distended, a 1% decrease in V100 (p = 0.031) and a 3.25% in D90 (p = 0.033) was registered. CONCLUSIONS: The status of rectal distension, as occurs in constipation, has a deleterious influence on prostate brachytherapy dosimetry. This situation increases the radiation to rectum and modifies dose distribution to prostate. We recommend prevention of constipation for at least two half lives of the radioactive seeds. PMID- 26622224 TI - NMDA Receptors Mediate Stimulus-Timing-Dependent Plasticity and Neural Synchrony in the Dorsal Cochlear Nucleus. AB - Auditory information relayed by auditory nerve fibers and somatosensory information relayed by granule cell parallel fibers converge on the fusiform cells (FCs) of the dorsal cochlear nucleus, the first brain station of the auditory pathway. In vitro, parallel fiber synapses on FCs exhibit spike-timing dependent plasticity with Hebbian learning rules, partially mediated by the NMDA receptor (NMDAr). Well-timed bimodal auditory-somatosensory stimulation, in vivo equivalent of spike-timing-dependent plasticity, can induce stimulus-timing dependent plasticity (StTDP) of the FCs spontaneous and tone-evoked firing rates. In healthy guinea pigs, the resulting distribution of StTDP learning rules across a FC neural population is dominated by a Hebbian profile while anti-Hebbian, suppressive and enhancing LRs are less frequent. In this study, we investigate in vivo, the NMDAr contribution to FC baseline activity and long term plasticity. We find that blocking the NMDAr decreases the synchronization of FC- spontaneous activity and mediates differential modulation of FC rate-level functions such that low, and high threshold units are more likely to increase, and decrease, respectively, their maximum amplitudes. Three significant alterations in mean learning-rule profiles were identified: transitions from an initial Hebbian profile towards (1) an anti-Hebbian; (2) a suppressive profile; and (3) transitions from an anti-Hebbian to a Hebbian profile. FC units preserving their learning rules showed instead, NMDAr-dependent plasticity to unimodal acoustic stimulation, with persistent depression of tone-evoked responses changing to persistent enhancement following the NMDAr antagonist. These results reveal a crucial role of the NMDAr in mediating FC baseline activity and long-term plasticity which have important implications for signal processing and auditory pathologies related to maladaptive plasticity of dorsal cochlear nucleus circuitry. PMID- 26622227 TI - Reduced dose to urethra and rectum with the use of variable needle spacing in prostate brachytherapy: a potential role for robotic technology. AB - PURPOSE: Several robotic delivery systems for prostate brachytherapy are under development or in pre-clinical testing. One of the features of robotic brachytherapy is the ability to vary spacing of needles at non-fixed intervals. This feature may play an important role in prostate brachytherapy, which is traditionally template-based with fixed needle spacing of 0.5 cm. We sought to quantify potential reductions in the dose to urethra and rectum by utilizing variable needle spacing, as compared to fixed needle spacing. MATERIAL AND METHODS: Transrectal ultrasound images from 10 patients were used by 3 experienced planners to create 120 treatment plans. Each planner created 4 plan variations per patient with respect to needle positions: (125)I fixed spacing, (125)I variable spacing, (103)Pd fixed spacing, and (103)Pd variable spacing. The primary planning objective was to achieve a prostate V100 of 100% while minimizing dose to urethra and rectum. RESULTS: All plans met the objective of achieving prostate V100 of 100%. Combined results for all plans show statistically significant improvements in all assessed dosimetric variables for urethra (Umax, Umean, D30, D5) and rectum (Rmax, Rmean, RV100) when using variable spacing. The dose reductions for mean and maximum urethra dose using variable spacing had p values of 0.011 and 0.024 with (103)Pd, and 0.007 and 0.029 with (125)I plans. Similarly dose reductions for mean and maximum rectal dose using variable spacing had p values of 0.007 and 0.052 with (103)Pd, and 0.012 and 0.037 with (125)I plans. CONCLUSIONS: The variable needle spacing achievable by the use of robotics in prostate brachytherapy allows for reductions in both urethral and rectal planned doses while maintaining prostate dose coverage. Such dosimetric advantages have the potential in translating to significant clinical benefits with the use of robotic brachytherapy. PMID- 26622228 TI - Comparison of permanent (125)I seeds implants with two different techniques in 500 cases of prostate cancer. AB - PURPOSE: To perform a comparative study of 500 consecutive (125)I seeds implants for intracapsular prostate carcinoma with two techniques differing in terms of both strand implantation and planning. MATERIAL AND METHODS: From 2002 to 2007 we performed 250 implants with fixed stranded seeds (RapidStrandTM) and a preplanning system and from 2007 to 2010, 250 with real-time and ProLinkTM system. Mean age was 68 and 66, respectively, median PSA (prostate-specific antigen) 7.3 and 7.2, stage T1-T2a in 98% and 94%, and Gleason <= 6 in 96% and 86%. Low risk cases were 81% and 71%. The prescribed dose was 145 Gy to the prostate volume, or 108 Gy plus EBRT 46 Gy in some intermediate risk cases. Hormonal treatment was given to 42% and 28%. RESULTS: Median follow-up was 48 and 47 months, respectively, 14 patients in the first group and 7 patients in the second developed biochemical failure (BF). Actuarial biochemical relapse-free survival (bRFS) at 5 years increased from 90.2% to 97.2% (low risk from 91.3% to 97.2%, intermediate risk from 84.2% to 97.1%). Biochemical failure was independent of hormone treatment. Rectal complications were G1-2 in 1.2% and 5.2%, respectively. A urinary catheter was necessary in 6.9% and 9.6%, and urethral resection in 1.9% and 4.4%. Genitourinary toxicity was G1-2 in 4.6% and 12%, G3-4 in 1.9% and 4.8%. An assessment of mean D90 in a sample of patients showed that the dosimetry in postoperative planning based on CT improved from a mean D90 of 143 Gy to 157 Gy. CONCLUSIONS: The outcome of patients with low risk prostate carcinoma treated with (125)I seed is very good with low complications rate. The real-time approach in our hands achieved a more precise seed implantation, better dosimetry, and a statistically non-significant better biochemical control. We have made this our standard technique. PMID- 26622229 TI - A new template for MRI-based intracavitary/interstitial gynecologic brachytherapy: design and clinical implementation. AB - PURPOSE: To describe the potential clinical use of a new brachytherapy applicator for gynecological tumors, with special attention to locally advanced cervical carcinoma. This device allows the combination of intracavitary radiotherapy and MRI-compatible transperineal interstitial needles. The design of this template addresses the disadvantages of currently commercially available templates: the inability of the intracavitary component to reach deep into the cervix (MUPIT), and the MRI-incompatibility of these templates (MUPIT and Syed), which necessitates use of CT imaging for the dosimetry. MATERIAL AND METHODS: The newly developed Benidorm Template applicator allows titanium needles in a template with straight and angled holes to provide different angles of divergence to be used with currently existing MRI-compatible intrauterine tubes. It can provide total coverage of the craniocaudal and lateral extension of the tumor (intrautherus, parametrial, and paravaginal). This method is mainly indicated in advanced cervical carcinoma with bulky parametrial invasion (medial or distal), with bulky primary disease that responds poorly to external beam radiotherapy extensive paravaginal involvement (tumor thickness greater than 0.5 cm) extending to the middle or lower third of the vagina, or for disease that has invaded the bladder or rectum (stage IVA). RESULTS: Between April 2013 until December 2014, we treated 15 patients with locally advanced cervical carcinoma employing the Benidorm Template. The median dose at D90 for the CTV was 79.8 Gy (71.5-89.9 Gy), at D2cc for the bladder it was 77.6 Gy (69.8-90.8 Gy), and at D2cc for the rectum it was 71.9 Gy (58.3-83.7 Gy). Values expressed in EQD2, assuming alpha/beta of 10 for CTV and 3 for OAR. CONCLUSIONS: This new applicator allows the use of MRI based dosimetry, thus providing the advantages of MRI volume definition. As such, it facilitates determination of complete intracavitary and interstitial CTV coverage and the sparing of normal tissues. PMID- 26622230 TI - Dosimetric comparison of AcurosTM BV with AAPM TG43 dose calculation formalism in breast interstitial high-dose-rate brachytherapy with the use of metal catheters. AB - PURPOSE: Radiotherapy for breast cancer includes different techniques and methods. The purpose of this study is to compare dosimetric calculations using TG 43 dose formalism and Varian AcurosTM BV (GBBS) dose calculation algorithm for interstitial implant of breast using metal catheters in high-dose-rate (HDR) brachytherapy, using (192)Ir. MATERIAL AND METHODS: Twenty patients who were considered for breast conservative surgery (BCS), underwent lumpectomy and axillary dissection. These patients received perioperative interstitial HDR brachytherapy as upfront boost using rigid metal implants. Whole breast irradiation was delivered TG-43 after a gap of two weeks. Standard brachytherapy dose calculation was done by dosimetry. This does not take into account tissue heterogeneity, attenuation and scatter in the metal applicator, and effects of patient boundary. AcurosTM BV is a Grid Based Boltzmann Solver code (GBBS), which takes into consideration all the above, was used to compute dosimetry and the two systems were compared. RESULTS: Comparison of GBBS and TG-43 formalism on interstitial metal catheters shows difference in dose prescribed to CTV and other OARs. While the estimated dose to CTV was only marginally different with the two systems, there is a significant difference in estimated doses of starting from 4 to 53% in the mean value of all parameters analyzed. CONCLUSIONS: TG-43 algorithm seems to significantly overestimate the dose to various volumes of interest; GBBS based dose calculation algorithm has impact on CTV, heart, ipsilateral lung, heart, contralateral breast, skin, and ribs of the ipsilateral breast side; the prescription changes occurred due to effect of metal catheters, inhomogeneities, and scatter conditions. PMID- 26622231 TI - Performance and suitability assessment of a real-time 3D electromagnetic needle tracking system for interstitial brachytherapy. AB - PURPOSE: Accurate insertion and overall needle positioning are key requirements for effective brachytherapy treatments. This work aims at demonstrating the accuracy performance and the suitability of the Aurora((r)) V1 Planar Field Generator (PFG) electromagnetic tracking system (EMTS) for real-time treatment assistance in interstitial brachytherapy procedures. MATERIAL AND METHODS: The system's performance was characterized in two distinct studies. First, in an environment free of EM disturbance, the boundaries of the detection volume of the EMTS were characterized and a tracking error analysis was performed. Secondly, a distortion analysis was conducted as a means of assessing the tracking accuracy performance of the system in the presence of potential EM disturbance generated by the proximity of standard brachytherapy components. RESULTS: The tracking accuracy experiments showed that positional errors were typically 2 +/- 1 mm in a zone restricted to the first 30 cm of the detection volume. However, at the edges of the detection volume, sensor position errors of up to 16 mm were recorded. On the other hand, orientation errors remained low at +/- 2 degrees for most of the measurements. The EM distortion analysis showed that the presence of typical brachytherapy components in vicinity of the EMTS had little influence on tracking accuracy. Position errors of less than 1 mm were recorded with all components except with a metallic arm support, which induced a mean absolute error of approximately 1.4 mm when located 10 cm away from the needle sensor. CONCLUSIONS: The Aurora((r)) V1 PFG EMTS possesses a great potential for real-time treatment assistance in general interstitial brachytherapy. In view of our experimental results, we however recommend that the needle axis remains as parallel as possible to the generator surface during treatment and that the tracking zone be restricted to the first 30 cm from the generator surface. PMID- 26622232 TI - Interstitial brachytherapy technique for chest wall refractory recurrence of breast cancer. AB - PURPOSE: To report the treatment effect of interstitial brachytherapy for chest wall locoregional recurrence of breast cancer. MATERIAL AND METHODS: This 44-year old female presented with chest wall recurrence seven years after modified radical mastectomy for stage II breast cancer. Despite external beam radiation and chemotherapy, the lesion expanded as 5.3 * 5.1 * 3.0 cm(3), and 8.0 * 5.1 * 4.0 cm(3). The locoregional recurrent tumor was treated with interstitial brachytherapy under ultrasound guidance. The brachytherapy dose was 30 Gy in 6 fractions of 5 Gy each. RESULTS: Removal of the recurrent tumor was securely achieved by interstitial brachytherapy guided with ultrasound scanning. The refractory tumor in patient healed uneventfully after interstitial brachytherapy without recurrence during the 7 months of follow-up. CONCLUSIONS: The ultrasound guided interstitial brachytherapy may be effective for refractory recurrence of breast cancer. PMID- 26622233 TI - Brachytherapy in the treatment of lung cancer - a valuable solution. AB - The majority of patients with lung cancer are diagnosed with clinically advanced disease. Many of these patients have a short life expectancy and are treated with palliative aim. Because of uncontrolled local or recurrent disease, patients may have significant symptoms such as: cough, dyspnea, hemoptysis, obstructive pneumonia, or atelectasis. Brachytherapy is one of the most efficient methods in overcoming difficulties in breathing that is caused by endobronchial obstruction in palliative treatment of bronchus cancer. Efforts to relieve this obstructive process are worthwhile, because patients may experience improved quality of their life (QoL). Brachytherapy plays a limited but specific role in definitive treatment with curative intent in selected cases of early endobronchial disease as well as in the postoperative treatment of small residual peribronchial disease. Depending on the location of the lesion, in some cases brachytherapy is a treatment of choice. This option is fast, inexpensive, and easy to perform on an outpatient basis. Clinical indications, different techniques, results, and complications are presented in this work. PMID- 26622235 TI - Comments on: "Clinical implementation of a new electronic brachytherapy system for skin brachytherapy". PMID- 26622234 TI - Brachytherapy for malignancies of the vagina in the 3D era. AB - Vaginal cancer is an uncommon malignancy and can be either recurrent or primary. In both cases, brachytherapy places a central role in the overall treatment course. Recent technological advances have led to more advanced brachytherapy techniques, which in turn have translated to improved outcomes for patients with malignancies of the vagina. The aim of this manuscript is to outline the incorporation of modern brachytherapy into the treatment of patients with vaginal cancer including patient selection along with the role of brachytherapy in conjunction with other treatment modalities, various brachytherapy techniques, treatment planning, dose fractionation schedules, and normal tissue tolerance. PMID- 26622236 TI - In reply to the Letter to the Editor titled: "Comments on: Clinical implementation of a new electronic brachytherapy system for skin brachytherapy". PMID- 26622237 TI - Image-guided high-dose-rate brachytherapy: preliminary outcomes and toxicity of a joint interventional radiology and radiation oncology technique for achieving local control in challenging cases. AB - PURPOSE: To determine the ability of image-guided high-dose-rate brachytherapy (IG-HDR) to provide local control (LC) of lesions in non-traditional locations for patients with heavily pre-treated malignancies. MATERIAL AND METHODS: This retrospective series included 18 patients treated between 2012 and 2014 with IG HDR, either in combination with external beam radiotherapy (EBRT; n = 9) or as monotherapy (n = 9). Lesions were located in the pelvis (n = 5), extremity (n = 2), abdomen/retroperitoneum (n = 9), and head/neck (n = 2). All cases were performed in conjunction between interventional radiology and radiation oncology. Toxicity was graded based on CTCAE v4.0 and local failure was determined by RECIST criteria. Kaplan-Meier analysis was performed for LC and overall survival. RESULTS: The median follow-up was 11.9 months. Two patients had localized disease at presentation; the remainder had recurrent and/or metastatic disease. Seven patients had prior EBRT, with a median equivalent dose in 2 Gy fractions (EQD2) of 47.0 Gy. The median total EQD2s were 34 Gy and 60.9 Gy for patients treated with monotherapy or combination therapy, respectively. Image-guided high-dose rate brachytherapy was delivered in one to six fractions. Six patients had local failures at a median interval of 5.27 months with a one-year LC rate of 59.3% and a one-year overall survival of 40.7%. Six patients died from their disease at a median interval of 6.85 months from the end of treatment. There were no grade >= 3 acute toxicities but two patients had serious long term toxicities. CONCLUSIONS: We demonstrate a good one year LC rate of nearly 60%, and a favorable toxicity profile when utilizing IG-HDR to deliver high doses of radiation with high precision into targets not readily accessible by other forms of local therapy. These preliminary results suggest that further studies utilizing this approach may be considered for patients with difficult to access lesions that require LC. PMID- 26622238 TI - MITHRA - multiparametric MR/CT image adapted brachytherapy (MR/CT-IABT) in anal canal cancer: a feasibility study. AB - PURPOSE: The aim of this study is to test a novel multiparametric imaging guided procedure for high-dose-rate brachytherapy in anal canal cancer, in order to evaluate the feasibility and safety. MATERIAL AND METHODS: For this analysis, we considered all consecutive patients who underwent magnetic resonance/computed tomography image adapted brachytherapy (MR/CT-IABT) treated from February 2012 to July 2014. To conduct this project, we formed a working group that established the procedure and identified the indicators and benchmarks to evaluate the feasibility and safety. We considered the procedure acceptable if 90% of the indicators were consistent with the benchmarks. Magnetic resonance imaging with contrast and diffusion weighted imaging were performed with an MRI-compatible dummy applicator in the anus to define the position of the clinical target volume disease and biological information. A pre-implantation treatment planning was created in order to get information on the optimal position of the needles. Afterwards, the patient underwent a simulation CT and the definite post implantation treatment planning was created. RESULTS: We treated 11 patients (4 men and 7 women) with MR/CT-IABT and we performed a total of 13 procedures. The analysis of indicators for procedure evaluation showed that all indicators were in agreement with the benchmark. The dosimetric analysis resulted in a median of V200, V150, V100, V90, V85, respectively of 24.6%, 53.4%, 93.5%, 97.6%, and 98.7%. The median coverage index (CI) was 0.94, the median dose homogeneity index (DHI) was 0.43, the median dose non-uniformity ratio (DNR) resulted 0.56, the median overdose volume index (ODI) was 0.27. We observed no episodes of common severe acute toxicities. CONCLUSIONS: Brachytherapy is a possible option in anal cancer radiotherapy to perform the boost to complete external beam radiotherapy (EBRT). Magnetic resonance can also have biological advantages compared to the US. Our results suggest that the multiparametric MR/CT-IABT for anal cancer is feasible and safe. This new approach paves the way to prospective comparison studies between MRI and ultrasound-guided brachytherapy (USBT) in anal canal cancer. PMID- 26622239 TI - Californium versus cobalt brachytherapy combined with external-beam radiotherapy for IIB stage cervical cancer: long-term experience of a single institute. AB - PURPOSE: The purpose of this paper was to observe and compare long-term curative effects and complications of FIGO stage IIB cervical cancer patients (n = 232) treated with high-dose-rate (HDR) californium ((252)Cf) neutron or cobalt ((60)Co) photon intracavitary brachytherapy (ICBT) combined with external-beam radiotherapy (EBRT). MATERIAL AND METHODS: The EBRT dose to the small pelvis was 50 Gy in both groups. The brachytherapy component of (252)Cf or (60)Co was added in the 3(rd) week of EBRT, 5 fractions were performed once per week resulting in a total ICBT dose of 40 Gy/Gyeq (point A). RESULTS: Overall survival (OS) at 5, 10 and 15 years was 63.6%, 50.4% and 38.8% in the (252)Cf group and 62.2%, 50.5%, 39.9%, in the (60)Co group, respectively (p = 0.74). The percentage of tumour recurrence was statistically significantly lower in the (252)Cf group with 7.4% versus 17.1% in the (60)Co group (p = 0.02). Second primary cancers have developed similarly 9.1% and 8.1% cases for (252)Cf and (60)Co groups, respectively. CONCLUSIONS: Our long-term retrospective study comparing (252)Cf and (60)Co isotopes with brachytherapy in combined treatment of FIGO IIB stage cervix carcinoma patients shows, that overall survival in the both groups are similar. However, the recurrence of tumour was significantly lower in the (252)Cf group. The incidence of second primary cancers was similar in both groups. PMID- 26622240 TI - Routine use of ultrasound guided tandem placement in intracavitary brachytherapy for the treatment of cervical cancer - a South Indian institutional experience. AB - PURPOSE: Intracavitary brachytherapy necessitates the insertion of a tandem applicator through the cervical os into the uterine cavity. Blind insertion of the tandem may result in suboptimal tandem placement. This decreases the control of the tumor locally and may result in uterine perforation. Although routine real time ultrasound guided tandem placement has shown better results, it is seldom practised. The aim of this work is to evaluate the role of routine real-time intraoperative trans-abdominal ultrasound guided tandem placement in intracavitary brachytherapy for the treatment of cervical cancer. MATERIAL AND METHODS: This is a prospective single institutional study conducted from April 2013 to May 2015. A total of 96 patients of locally advanced cervical cancer were treated with routine ultrasound guided brachytherapy amounting to a total of 282 intracavitary applications. RESULTS: In 78 of the study patients, the cervical os could be easily identified visually, which was then confirmed with ultrasound guidance. In another 12 patients, though the os could be identified visually, uterine sounding was only possible under ultrasound guidance. In another 4 patients, the cervical os could not be identified visually as the cervix was flushed with vagina and ultrasound guidance was necessary for accurate os identification. In 2 of the study patients, intraoperative ultrasound helped in identifying the patients suitable for interstitial brachytherapy rather than intracavitary brachytherapy. Out of the 96 study patients, the length of the uterine canal changed in 15 patients during the subsequent brachytherapy application. CONCLUSIONS: This procedure is strongly advocated for proper placement of the tandem applicator and to avoid perforations. It is an accurate, fast, easily available, and cost-effective method. Hence, it can be incorporated in intracavitary applications for cervical cancers even in the developing countries where cost, accessibility, and time are important issues. PMID- 26622241 TI - Bladder (ICRU) dose point does not predict urinary acute toxicity in adjuvant isolated vaginal vault high-dose-rate brachytherapy for intermediate-risk endometrial cancer. AB - PURPOSE: High-dose-rate brachytherapy (HDR-BT) alone is an adjuvant treatment option for stage I intermediaterisk endometrial cancer after complete surgical resection. The aim of this study was to determine the value of the dose reported to ICRU bladder point in predicting acute urinary toxicity. Oncologic results are also presented. MATERIAL AND METHODS: One hundred twenty-six patients were treated with postoperative HDR-BT 24 Gy (4 * 6 Gy) per ICRU guidelines for dose reporting. Cox analysis was used to identify variables that affected local control. The mean bladder point dose was examined for its ability to predict acute urinary toxicity. RESULTS: Two patients (1.6%) developed grade 1 gastrointestinal toxicity and 12 patients (9.5%) developed grades 1-2 urinary toxicity. No grade 3 or greater toxicity was observed. The mean bladder point dose was 46.9% (11.256 Gy) and 49.8% (11.952 Gy) for the asymptomatic and symptomatic groups, respectively (p = 0.69). After a median follow-up of 36.8 months, the 3-year local failure and 5-year cancer-specific and overall survival rates were 2.1%, 100%, and 94.6%, respectively. No pelvic failure was seen in this cohort. Age over 60 years (p = 0.48), lymphatic invasion (p = 0.77), FIGO histological grade (p = 0.76), isthmus invasion (p = 0.68), and applicator type (cylinder * ovoid) (p = 0.82) did not significantly affect local control. CONCLUSIONS: In this retrospective study, ICRU bladder point did not correlate with urinary toxicity. Four fractions of 6 Gy HDR-BT effected satisfactory local control, with acceptable urinary and gastrointestinal toxicity. PMID- 26622242 TI - A total EQD2 greater than 85 Gy for trachea and main bronchus D2cc being associated with severe late complications after definitive endobronchial brachytherapy. AB - PURPOSE: The endobronchial brachytherapy (EBBT) is an established treatment method for tumors of the tracheobronchial system, however, little is known about the tolerance dose for organ at risk (OAR) in EBBT. The purpose of this study is to analyze patients with superficial bronchial carcinoma treated with definitive EBBT, and to investigate a relationship between late complications and dose for OAR. MATERIAL AND METHODS: Endobronchial brachytherapy was performed 6 Gy per fraction for three to four fractions with or without external beam radiation therapy (EBRT). For the purpose of dosimetric analysis, the wall of the lower respiratory tract (LRT: trachea, main bronchus, and lobar bronchiole), trachea, and main bronchus (TMB) was extracted. D0.5cc, D1cc, and D2cc of LRT and TMB were calculated in each EBBT session and added together. V100, V150, and V200 of LRT were also calculated. RESULTS: Between March 2008 and April 2014, EBBT was performed in 14 patients for curative intent. The 2-year overall survival (OS), progression-free survival (PFS), and local recurrence free survival (LRFS) was 82.1%, 77.9%, and 91.7%, respectively. There was one patient with grade 5, one grade 4, and three grade 3 obstruction of trachea or bronchus. The mean EQD2 of LRT D2cc, TMB D2cc, D1cc, and D0.5cc of patients with or without late severe respiratory complications was significantly different between two groups (p = 0.018, 0.008, 0.009, and 0.013, respectively). The 2-year incidence rates of late severe complications in patients with TMB D2cc <= 85 Gy in EQD2 and > 85 Gy were 0% and 83.3%, respectively with a statistically significance (p = 0.014). CONCLUSIONS: It was discovered that TMB D2cc > 85 Gy in EQD2 is a strong risk factor for severe late respiratory complication after EBBT. PMID- 26622243 TI - Superficial ocular malignancies treated with strontium-90 brachytherapy: long term outcomes. AB - PURPOSE: The incidence of conjunctival malignancies is less than 1%. Though surgical excision remains the mainstay of treatment, the incidence of positive surgical margins and local recurrence rates are high, which is approximately up to 33% in negative margins and 56% in positive margins. Radiotherapy reduces the risk of recurrence in these cases. Brachytherapy using beta emitters such as strontium-90 ((90)Sr) is an ideal treatment technique for these tumors with the advantage of treating only a few millimeters of tissue while sparing the underlying normal eye. We report the long term outcomes in the form of local control and late sequelae of patients with conjunctival malignancies treated with (90)Sr applicator brachytherapy. MATERIAL AND METHODS: During 1999-2013, 13 patients with conjunctival tumors, treated using (90)Sr brachytherapy were analyzed. Brachytherapy was either in a post-operative adjuvant or in a recurrent setting. Local control (LC), disease free survival (DFS), overall survival (OS), and late sequelae were evaluated. RESULTS: The median age at presentation was 47 years (range: 11-71 years). Thirteen patients with 15 tumors were treated. The commonest histology was squamous cell carcinoma. The median dose was 44 Gy over 11 fractions. The median follow up of all the patients was 51 months (range: 3 139 months). The median follow up of patients with carcinoma only was 64 months with a LC and DFS of 90.9% at 5 years. None of the patients developed >= grade II Radiation Therapy Oncology Group (RTOG) acute toxicities. One patient developed a focal scar and another developed corneal opacification at the limbus. Vision was not impaired in any of the patients. CONCLUSIONS: Strontium-90 brachytherapy used in early invasive conjunctival malignancies as an adjunct to surgery in primary and recurrent settings, results in optimal disease control and ocular functional outcomes. PMID- 26622244 TI - A pilot study of ultrasound-guided electronic brachytherapy for skin cancer. AB - PURPOSE: Electronic brachytherapy (eBT) has gained acceptance over the past 5 years for the treatment of non-melanomatous skin cancer (NMSC). Although the prescription depth and radial margins can be chosen using clinical judgment based on visual and biopsy-derived information, we sought a more objective modality of measurement for eBT planning by using ultrasound (US) to measure superficial (< 5 mm depth) lesions. MATERIAL AND METHODS: From December 2013 to April 2015, 19 patients with 23 pathologically proven NMSCs underwent a clinical examination and US evaluation of the lesions prior to initiating a course of eBT. Twenty lesions were basal cell carcinoma and 3 lesions were squamous cell carcinoma. The most common location was the nose (10 lesions). A 14 or 18 MHz US unit was used by an experienced radiologist to determine depth and lateral extension of lesions. The US-measured depth was then used to define prescription depth for eBT planning without an added margin. A margin of 7 mm was added radially to the US lateral extent measurements, and an appropriate cone applicator size was chosen to cover the target volume. RESULTS: The mean depth of the lesions was 2.1 mm with a range of 1-3.4 mm, and the mean largest diameter of the lesions was 8 mm with a range of 2.6-20 mm. Dose ranged from 32-50 Gy in 8-20 fractions with a median dose of 40 Gy in 10 fractions. All patients had a complete response and no failures have occurred with a median follow-up of 12 months (range of 6-22 months). Also, no prolonged skin toxicities have occurred. CONCLUSIONS: A routinely available radiological US unit can objectively determine depth and lateral extension of NMSC lesions for more accurate eBT treatment planning, and should be considered in future eBT treatment guidelines. PMID- 26622245 TI - Physical and psychosocial side-effects of brachytherapy: a questionnaire survey. AB - PURPOSE: Brachytherapy (BT) plays an important role in cancer treatment. Like any other medical therapy it may, however, induce side effects whose recognition can affect the patient's quality of life. Therefore, the present study evaluated the frequency and severity of physical and psychosocial adverse effects of BT. MATERIAL AND METHODS: Patients (n = 70) undergoing high-dose-rate (HDR) BT or low dose-rate (LDR) of head and neck, breast, and prostate cancers were interviewed face-to-face at the end of their course of treatment. Interviews concerned the occurrence of 35 physical (dermatological, gastroenterological, neurological, ocular, pulmonological, and urological) and 10 psychosocial side effects of BT. RESULTS: A high percentage of patients reported that BT decreased their life satisfaction (54.3%), sense of security (41.4%), and self-esteem (34.3%). The highest frequency of gastroenterological and urological symptoms was reported by prostate cancer patients. Cigarette smoking increased the frequency of nausea, dyschezia, and weight loss. Overweight patients were characterized by an increased rate of urinary incontinence and dyschezia, as well as more pronounced decrease of self-esteem and sense of security following BT treatment. CONCLUSIONS: These findings are not only highly relevant to the way patients can be prepared for the therapy but also have a bearing on ways to minimize the number and severity of BT side effects. PMID- 26622246 TI - Dosimetric impact of source-positioning uncertainty in high-dose-rate balloon brachytherapy of breast cancer. AB - PURPOSE: To evaluate the dosimetric impact of source-positioning uncertainty in high-dose-rate (HDR) balloon brachytherapy of breast cancer. MATERIAL AND METHODS: For 49 HDR balloon patients, each dwell position of catheter(s) was manually shifted distally (+) and proximally (-) with a magnitude from 1 to 4 mm. Total 392 plans were retrospectively generated and compared to corresponding clinical plans using 7 dosimetric parameters: dose (D95) to 95% of planning target volume for evaluation (PTV_EVAL), and volume covered by 100% and 90% of the prescribed dose (PD) (V100 and V90); skin and rib maximum point dose (Dmax); normal breast tissue volume receiving 150% and 200% of PD (V150 and V200). RESULTS: PTV_EVAL dosimetry deteriorated with larger average/maximum reduction (from +/- 1 mm to +/- 4 mm) for larger source position uncertainty (p value < 0.0001): from 1.0%/2.5%, 3.3%/5.9%, 6.3%/10.0% to 9.8%/14.5% for D95; from 1.0%/2.6%, 3.1%/5.7%, 5.8%/8.9% to 8.7%/12.3% for V100; from 0.2%/1.5%, 1.0%/4.0%, 2.7%/6.8% to 5.1%/10.3% for V90. >= +/- 3 mm shift reduced average D95 to < 95% and average V100 to < 90%. While skin and rib Dmax change was case specific, its absolute change (?Delta(Value)?) showed that larger shift and high dose group had larger variation compared to smaller and lower dose group (p value < 0.0001), respectively. Normal breast tissue V150 variation was case-specific and small. Average ?Delta(V150)? was 0.2 cc for the largest shift (+/- 4 mm) with maximum < 1.7 cc. V200 was increased with higher elevation for larger shift: from 6.4 cc/9.8 cc, 7.0 cc/10.1 cc, 8.0 cc/11.3 cc to 9.2 cc/ 13.0 cc. CONCLUSIONS: The tolerance of +/- 2 mm recommended by AAPM TG 56 is clinically acceptable in most clinical cases. However, special attention should be paid to a case where both skin and rib are located proximally to balloon, and the orientation of balloon catheter(s) is vertical to these critical structures. In this case, sufficient dosimetric planning margins are required. PMID- 26622247 TI - Monte Carlo dosimetry of a new (90)Y brachytherapy source. AB - PURPOSE: In this study, we attempted to obtain full dosimetric data for a new (90)Y brachytherapy source developed by the College of Chemistry (Sichuan University) for use in high-dose-rate after-loading systems. MATERIAL AND METHODS: The dosimetric data for this new source were used as required by the dose calculation formalisms proposed by the AAPM Task Group 60 and Task Group 149. The active core length of the new (90)Y source was increased to 4.7 mm compared to the value of 2.5 mm for the old (90)Sr/(90)Y source. The Monte Carlo simulation toolkit Geant4 was used to calculate these parameters. The source was located in a 30-cm-radius theoretical sphere water phantom. RESULTS: The dosimetric data included the reference absorbed dose rate, the radial dose function in the range of 1.0 to 8.0 mm in the longitudinal axis, and the anisotropy function with a theta in the range of 0 degrees to 90 degrees at 5 degrees intervals and an r in the range of 1.0 to 8.0 mm in 0.2-mm intervals. The reference absorbed dose rate for the new (90)Y source was determined to be equal to 1.6608 +/- 0.0008 cGy s(-1) mCi(-1), compared to the values of 0.9063 +/ 0.0005 cGy s(-1) mCi(-1) that were calculated for the old (90)Sr/(90)Y source. A polynomial function was also obtained for the radial dose function by curve fitting. CONCLUSIONS: Dosimetric data are provided for the new (90)Y brachytherapy source. These data are meant to be used commercially in after loading system. PMID- 26622248 TI - A practical MRI-based reconstruction method for a new endocavitary and interstitial gynaecological template. AB - PURPOSE: There are perineal templates for interstitial implants such as MUPIT and Syed applicators. Their limitations are the intracavitary component deficit and the necessity to use computed tomography (CT) for treatment planning since both applicators are non-magnetic resonance imaging (MRI) compatibles. To overcome these problems, a new template named Template Benidorm (TB) has been recently developed. Titanium needles are usually reconstructed based on their own artifacts, mainly in T1-weighted sequence, using the void on the tip as the needle tip position. Nevertheless, patient tissues surrounding the needles present heterogeneities that complicate the accurate identification of these artifact patterns. The purpose of this work is to improve the titanium needle reconstruction uncertainty for the TB case using a simple method based on the free needle lengths and typical MRI pellets markers. MATERIAL AND METHODS: The proposed procedure consists on the inclusion of three small A-vitamin pellets (hyperintense on MRI images) compressed by both applicator plates defining the central plane of the plate's arrangement. The needles used are typically 20 cm in length. For each needle, two points are selected defining the straight line. From such line and the plane equations, the intersection can be obtained, and using the free length (knowing the offset distance), the coordinates of the needle tip can be obtained. The method is applied in both T1W and T2W acquisition sequences. To evaluate the inter-observer variation of the method, three implants of T1W and another three of T2W have been reconstructed by two different medical physicists with experience on these reconstructions. RESULTS AND CONCLUSIONS: The differences observed in the positioning were significantly smaller than 1 mm in all cases. The presented algorithm also allows the use of only T2W sequence either for contouring or reconstruction purposes. The proposed method is robust and independent of the visibility of the artifact at the tip of the needle. PMID- 26622250 TI - Quality of life in patients with primary axillary hyperhidrosis before and after treatment with fractionated microneedle radiofrequency. AB - BACKGROUND: Primary axillary hyperhidrosis (PAH) is a common condition with a great impact on the patient's quality of life (QOL). It is associated with serious social, emotional, and occupational distress. The aim of this study was to investigate the QOL in patients with PAH before and after treatment with fractionated microneedle radiofrequency (FMR). MATERIALS AND METHODS: We evaluated 25 patients with severe PAH. Each patient had three sessions of FMR treatment using a novel applicator at 3-week intervals. The study was based on Dermatology Life Quality Index (DLQI) Questionnaires. Patients were evaluated at baseline and 3 months after the last session. RESULTS: Our patients included 32% males and 68% females. The mean +/- standard deviation (SD) age of subjects was 30.2 +/- 6.27 years. The mean +/- SD of the DLQI before and after treatment was 12.96 +/- 5.93, and 4.29 +/- 2.21, respectively. There was a statistically significant difference between the before and after intervention (P < 0.001). No major, permanent adverse effects were shown. CONCLUSION: Treatment with FMR can improve the DLQI of patients with PAH. PMID- 26622251 TI - Frequency distribution of gastro esophageal reflux disease in inhalation injury: A historical cohort study. AB - BACKGROUND: There is no data on the prevalence and the association of gastro esophageal reflux disease (GERD) with toxic fume inhalation. Therefore, we aimed to evaluate the frequency distribution of GERD symptoms among the individuals with mild respiratory disorder due to the past history of toxic fume exposure to sulfur mustard (SM). MATERIALS AND METHODS: In a historical cohort study, subjects were randomly selected from 7000 patients in a database of all those who had a history of previous exposure to a single high dose of SM gas during war. The control group was randomly selected from adjacent neighbors of the patients, and two healthy male subjects were chosen per patient. In this study, we used the validated Persian translation of Mayo Gastroesophageal Reflux Questionnaire to assess the frequency distribution of reflux disease. RESULTS: Relative frequency of GERD symptoms, was found to be significantly higher in the inhalation injury patients with an odds ratio of 8.30 (95% confidence interval [CI]: 4.73-14.55), and after adjustment for cigarette smoking, tea consumption, age, and body mass index, aspirin and chronic cough the odds ratio was found to be 4.41 (95% CI: 1.61-12.07). CONCLUSION: The most important finding of our study was the major GERD symptoms (heartburn and/or acid regurgitation once or more per week) among the individuals with the past history of exposure to SM toxic gas is substantially higher (4.4-fold) than normal populations. PMID- 26622249 TI - Magnetic resonance imaging-guided brachytherapy for cervical cancer: initiating a program. AB - Over the past decade, the application of magnetic resonance imaging (MRI) has increased, and there is growing evidence to suggest that improvements in accuracy of target delineation in MRI-guided brachytherapy may improve clinical outcomes in cervical cancer. To implement a high quality image guided brachytherapy program, a multidisciplinary team is required with appropriate expertise as well as an adequate patient load to ensure a sustainable program. It is imperative to know that the most important source of uncertainty in the treatment process is related to target delineation and therefore, the necessity of training and expertise as well as quality assurance should be emphasized. A short review of concepts and techniques that have been developed for implementation and/or improvement of workflow of a MRI-guided brachytherapy program are provided in this document, so that institutions can use and optimize some of them based on their resources to minimize their procedure times. PMID- 26622252 TI - Epidermal hydration and skin surface lipids in patients with long-term complications of sulfur mustard poisoning. AB - BACKGROUND: Despite almost the three decades passed since the chemical attacks of Iraqi's army against the Iranian troops, some veterans are still suffering from long-term complications of sulfur mustard (SM) poisoning, including certain skin complaints specially dryness, burning, and pruritus. We thus aimed to evaluate the skin's water and lipid content in patients with a disability of >25% due to complications of SM poisoning and compare them with a matched control group. MATERIALS AND METHODS: Sixty-nine male participants were included in this study; 43 SM-exposed patients, and 26 normal controls from their close relatives. The water and lipid content was measured in four different locations: Extensor and flexor sides of forearms and lateral and medial sides of legs by the Corneometer CM 820/Sebumeter SM 810. Collected data was analyzed and P <= 0.05 was considered as statistically significant. RESULTS: The mean age of the patients and controls was 49.53 +/- 11.34 (ranges: 40-71) and 29.08 +/- 8.836 (ranges: 15-49 years), respectively. In the veterans group, the main cutaneous complaint was itching and skin dryness. Cherry angioma, dry skin, and pruritus were significantly more common in the SM-exposed cases than in the controls. (P = 0.01, 0.05, and 0.04, respectively). The moisture and lipid content of all areas were lower in the SM exposed group, but it was only significant in skin sebum of lateral sides of legs (P = 0.02). CONCLUSION: Exposure to SM could decrease the function of stratum corneum and lipid production as a barrier, even after several years of its exposure. PMID- 26622253 TI - A nationwide report on blood pressure of children and adolescents according to socioeconomic status: The CASPIAN-IV study. AB - BACKGROUND: Hypertension is a major leading factor for global burden of diseases. Blood pressure (BP) tracks from childhood to adulthood. So, it is important to investigate its aff ecting factors. In this study we aimed to compare the BP status in the Iranian pediatric population according to the socioeconomic status (SES) of their living area. MATERIALS AND METHODS: In this nationwide study, a representative sample of 14,880 students, aged 6-18 years was chosen by multistage random cluster sampling from 30 provinces in Iran. Anthropometric indices and BP were measured. A validated questionnaire, including the questions of the World Health Organization Global School-based Student Health Survey was completed. Findings were compared across the four regions of the country, categorized based on their elevating SES: Southeast, north-northeast, west, and central. RESULTS: Participants consisted of 13,486 children and adolescents, that is, a participation rate of 90.6%, composed of 49.2% girls and 75.6% urban residents. The mean (standard deviation) age of participants was 12.47 (3.36) years. The region with highest SES (central) had the lowest rate of high BP (HBP), that is, 3.0% (95% of confidence interval [CI]: 2.4-3.9), and the region with lowest SES (southeast) had the highest rate, that is, 7.4% (4.4-12.2). The mean (95% CI) values of systolic BP for the four regions from lowest to highest SES were 100.5 (99.6-101.3), 100.9 (100.3-101.4), 101.7 (101.3-102), and 101.7 (101.2-102.1) mmHg. The corresponding mean Diastolic BP values were as follows: 65.4 (64.6-66.1), 63.4 (62.9-63.8), 65.6 (65.3-65.8), and 64.4 (64.0-64.7) mmHg. CONCLUSION: We found significant differences in mean BP and the frequency of HBP according to the SES of the living area. Further studies are necessary to find the underlying factors resulting in such differences. PMID- 26622254 TI - Favorable results after conservative management of 316 valproate intoxicated patients. AB - BACKGROUND: Valproic acid (VPA) is an effective antiepileptic drug widely used worldwide. Despite several studies indicating the usefulness of intravenous L carnitine in the treatment of VPA poisoning, this drug is not readily available in Iran. The aim of this study was to determine whether supportive care without antidote would result in acceptable outcomes in VPA poisoned patients. MATERIALS AND METHODS: In an observational, retrospective, single-center case series, all patients >12-year-old with VPA overdose who had referred to a tertiary center between 2009 and 2013 were consecutively enrolled. Patients' demographic and presenting features, physical examinations, clinical management, laboratory data, and outcomes were recorded. RESULTS: A total of 316 patients were enrolled with pure VPA toxicity. The most common presenting signs/symptoms were drowsiness, nausea and vomiting, vertigo, and headache. In the course of the disease, 14 patients (4.4%) were intubated and three (0.9%) required hemodialysis with mean dialysis sessions of two. Fourteen patients were admitted to Intensive Care Unit, and seizures occurred in five. The initial level of consciousness was lower in patients with poor outcome. The median ingested dose of VPA in patients who required dialysis was significantly higher (20 vs. 6 g; P = 0.006). Multivariate analyses revealed that coma on presentation was associated with a worse outcome (P = 0.001; odds ratio = 61.5, 95% CI = 5.8-646.7). CONCLUSION: Prognosis of VPA poisoned patients appears to be good even with supportive care. According to our study, older age, ingestion of higher amounts of VPA and lower PCO2, HCO3, base excess, and CPK levels prone the patients to more severe toxicities in univariate analysis, but the main poor prognostic factor is coma on presentation in multivariate analysis. PMID- 26622255 TI - Relationship between obstructive sleep apnea and 30-day mortality among patients with pulmonary embolism. AB - BACKGROUND: Pulmonary embolism (PE) is the most life-threatening form of venous thrombosis which causes the majority of mortalities in this category. Obstructive sleep apnea (OSA) has been indicated as one of the risk factors for thromboembolism because of hemostatic alterations. The present study was designed to seek for the relationship between OSA and 30-day mortality of patients with PE. MATERIALS AND METHODS: This prospective cohort study was conducted among 137 consecutive patients referred to hospital with symptoms of PE and preliminary stable hemodynamic. Confirmation of PE was made by multislice computed tomography pulmonary angiography and in the case of contraindication; V/Q lung scan and Doppler sonography were done. A STOP-Bang Questionnaire was used to determine patients with high- and low-risk of OSA. Patients were followed up for 1-month, and their survivals were recorded. RESULTS: This study showed that there was no relationship between OSA and 30-day mortality (P = 0.389). Chronic kidney disease (P = 0.004), hypertension (P = 0.003), main thrombus (P = 0.004), and segmental thrombus (P = 0.022) were associated with 30-day mortality. In the logistic regression analysis, history of chronic kidney disease was diagnosed as a risk factor for 30-day mortality among the PE patients (P = 0.029, odds ratio = 4.93). CONCLUSION: Results of this study showed 30-day mortality was not affected by OSA directly. In fact, it was affected by complications of OSA such as hypertension and thrombus. Also, positive history of chronic kidney disease increased the risk of 30-day mortality. PMID- 26622256 TI - Serum anti-inflammatory cytokines for the evaluation of inflammatory status in endometriosis. AB - BACKGROUND: Endometriosis is a frequent gynecologic disease with a severe impact on the quality of life in the affected women; its pathogenesis is yet to be fully understood, with an altered immunity as a possible key factor. The present study aimed to investigate the serum anti-inflammatory cytokine profile in the patients with endometriosis compared with the healthy controls. MATERIALS AND METHODS: One hundred and sixty women were included, divided into two study groups (Group I - endometriosis; Group 2 - healthy women). We evaluated the serum levels of interleukin-1 receptor antagonist (IL-1Ra), IL-2, IL-2R, IL-4, IL-10, IL-13, and IL-15 with the use of Human multiplex cytokine panels. Statistical analyses (normality distribution analysis, independent t-test, Mann-Whitney U-test) were performed using IBM SPSS software (version 22.0) and GraphPad Prism (version 5.00); receiver operating characteristic curve were used to demonstrate the diagnostic performance of the studied markers. RESULTS: The mean serum level of IL-1Ra, IL-4, and IL-10 were significantly higher in women with endometriosis compared to women free of disease from the control group (30.155, 138.459, and 1.489, respectively, compared to 14.109, 84.710, and 0.688, respectively; P < 0.001, P < 0.001, and P = 0.002, respectively.). No significant differences in the mean serum levels of IL-2, IL-13, and IL-15 were observed between the studied groups and IL-2R had a very low detection rate. CONCLUSION: Endometriosis is associated with elevated levels of anti-inflammatory cytokines, IL-1Ra, IL-4, and IL-10, markers that have a potential role as a prognostic factor for endometriosis. PMID- 26622257 TI - D-dimer testing for safe exclusion and risk stratification in patients with acute pulmonary embolism in primary care. AB - BACKGROUND: Safe exclusion and risk stratification are currently recommended for the initial management of patients with acute pulmonary embolism (APE). The aim of this study was to assess the safe exclusion and risk stratification value of D dimer (DD) for APE when tested at the beginning of admission. MATERIALS AND METHODS: All consecutive Chinese APE patients and controls were recruited from January 2010 to December 2012. All measurements of serum indexes were made in duplicate and blinded to the patients' status. All the 40 patients with the first episode of APE were confirmed by multi-detector computed tomographic pulmonary angiography. The plasma prothrombin time (PT), activated partial thromboplastin time, thrombin time, fibrinogen, and DD levels were measured within 24 h of admission. We used the Mann-Whitney U-test to determine the differences between groups and drew receiver operator characteristic curve to evaluate the indexes' value in the APE screening. RESULTS: The PT and DD in the APE group were significantly higher than those in the disease control group (P < 0.05). Taking PT and DD as the useful screening tests for APE and AUC was 0.765 and 0.822, respectively. DD yielded the higher screening efficiency, with DD >1820 MUg/L as cut-off value, the sensitivity, specificity, positive and negative predictive value was 82.5%, 75.2%, 56.9%, and 91.6%, respectively. CONCLUSION: The patients with APE showed significant higher DD levels compared with disease controls, suggesting a negative qualitative DD test result can safely and efficiently exclude APE in primary care. PMID- 26622258 TI - Effect of supplements: Probiotics and probiotic plus honey on blood cell counts and serum IgA in patients receiving pelvic radiotherapy. AB - BACKGROUND: Radiotherapy is frequently used in treatment approaches of pelvic malignancies. Nevertheless, it has some known systemic effects on blood cells and the immune system that possibly results in their susceptibility to infection. Probiotics are live microbial food ingredients that provide a health advantage to the consumer. Honey has prebiotic properties. The aim of this clinical trial was to investigate probable effects of probiotic or probiotics plus honey on blood cell counts and serum IgA levels in patients receiving pelvic radiotherapy. MATERIALS AND METHODS: Sixty-seven adult patients with pelvic cancer were enrolled. Patients were randomized to receive either: (1) Probiotic capsules (including: Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus bulgaricus, Bifidobacterium breve, Bifidobacterium longum, and Streptococcus thermophiles) (n = 22), (2) probiotic capsules plus honey (n = 21) or (3) placebo capsules (n = 24) all for 6 weeks. Blood and serum samples were collected for one week before radiotherapy and 24-72 h after the end of radiotherapy. RESULTS: White blood cells (WBC), red blood cells (RBC), platelet counts, and serum IgA level were not significantly changed in patients taking probiotic (alone or plus honey) during pelvic radiotherapy. The mean decrease in RBC count was 0.52, 0.18, and 0.23 * 10(6) cells/MUL, WBC count was 2.3, 1.21, and 1.34 * 10(3) cells/MUL and platelet count was, 57.6, 53.3, and 66.35 * 10(3) cells/MUL for the probiotic, probiotic plus honey, and placebo groups, respectively. The mean decrease of serum IgA was 22.53, 29.94, and 40.73 mg/dL for the probiotic, probiotic plus honey, and placebo groups, respectively. CONCLUSION: The observed nonsignificant effect of probiotics may be in favor of local effects of this product in the gut rather than systemic effects, however, as a trend toward a benefit was indicated, further studies are necessary in order to extract effects of probiotics or probiotic plus honey on hematologic and immunologic parameters in patients receiving pelvic radiotherapy. PMID- 26622259 TI - Effects of blackberry (Morus nigra L.) consumption on serum concentration of lipoproteins, apo A-I, apo B, and high-sensitivity-C-reactive protein and blood pressure in dyslipidemic patients. AB - BACKGROUND: This study investigated blackberry (Persian mulberry) effects on apo A-I, apo B, high-sensitivity-C-reactive protein (hs-CRP), and systolic blood pressure (SBP) and diastolic blood pressure (DBP) in dyslipidemic patients. MATERIALS AND METHODS: In this 8-week randomized clinical trial, 72 dyslipidemic patients were randomly divided into two groups: Intervention (300 mL/day blackberry juice with pulp) and control group (usual diets). Before and after the intervention, fasting blood samples were taken from both groups and serum concentration of lipoprotein, apo A-I and apo B, serum lipids (total cholesterol, low-density lipoprotein, high-density lipoprotein [HDL], and triglyceride), hs CRP were measured. Blood pressure before and after the study was measured with a mercury manometer. RESULTS: At week 8 in the intervention group, apo A-I and HDL increased significantly (P = 0.015, P = 0.001, respectively), apo B and hs-CRP decreased significantly (P = 0.044, P = 0.04, respectively). Mean changes in apo A-I and HDL and apo B/apo A-I ratio were significant between the groups (P = 0.005, P = 0.014, and P = 0.009, respectively). After 8 weeks, there was a significant difference between hs-CRP mean values (P = 0.01) of the groups. At week 8, SBP decreased significantly (P = 0.005) in the intervention group with no significant differences for SBP mean values between the groups. No significant changes were observed in other lipid parameters and DBP in the intervention group and between the groups. CONCLUSION: Blackberry consumption may exert beneficial effects on apolipoproteins, blood pressure, and inflammatory markers in individuals with lipid disorders. PMID- 26622260 TI - Evaluation of intravenous hydroxylethyl starch, intravenous albumin 20%, and oral cabergoline for prevention of ovarian hyperstimulation syndrome in patients undergoing ovulation induction. AB - BACKGROUND: The purpose of this study was to compare the three different strategies, intravenous (IV) hydroxylethyl starch (HES), IV human albumin (HA), and oral Cabergoline (Cb) in the prevention of ovarian hyperstimulation syndrome (OHSS). MATERIALS AND METHODS: In this prospective randomized clinical trial, 91 women at high risk of developing OHSS were allocated into the three groups, group one received 2 vial (2 * 50 ml) IV HAs, in group two, 1000 ml of 6% HES was administered IV, both groups 30 min after oocyte retrieval within 4 h. Group three, 31 infertile patients received oral Cb 0.5 mg daily for 7 days after oocyte retrieval. Patients were visited 14 +/- 1 days after in-vitro fertilization and if beta-human chorionic gonadotropin level >10, transvaginal ultrasonography was performed 2 weeks later to confirm intrauterine pregnancy. Patients were followed up weekly for 3 months for signs of OHSS and were also informed about the signs of OHSS and asked to contact immediately if any symptoms of were detected. RESULTS: None of the participants in group HES developed severe OHSS and only 3 patients (10%) developed mild to moderate OHSS. The incident of severe OHSS was significantly higher in albumin group compared to Cb and HES group (P = 0.033 and P < 0.001, respectively). Also, the probability of developing severe OHSS was higher in Cb group than group HES (P = 0.031). CONCLUSION: The findings from this study suggest that administration of 1000 ml of HES 6% has a higher prophylactic effect compared to administration of IV HA and oral Cb. PMID- 26622261 TI - Pulmonary function tests and impulse oscillometry in severe chronic obstructive pulmonary disease patients' offspring. AB - BACKGROUND: Several studies have showed an increased prevalence of airflow obstruction in first degree relatives of individuals with chronic obstructive pulmonary disease (COPD). Considering no specific research had evaluated airway resistance in offspring of patients with severe COPD, we utilized a spirometry and a impulse oscillometry (IO) to evaluate this population. MATERIALS AND METHODS: In this case control study, from November 2011 to July 2012, we consecutively evaluated 54 offsprings of severe COPD patients (case group) admitted in the pulmonary ward, affiliated to the Isfahan University of Medical Sciences and control group. Pulmonary function tests and the IO were obtained for both groups. Student's t-test was used for inter-group comparisons, and P values below 0.05 were taken as significant. RESULTS: Abnormal increased airway resistance was seen in cases in comparison with controls (R5 Hz [46.29%, P = 0.01], R25 Hz [42.59%, P < 0.001]). Also, considering the spirometry, case group had pulmonary function parameters less than control group (forced vital capacity [FVC]; P = 0.02, forced expiratory volume in 1(st) s; P < 0.001, forced expiratory flow (FEF) 25-75; P < 0.001, FEF 25-75/FVC; P < 0.001) but they were in normal range. CONCLUSION: This study demonstrated increased airway resistance among the severe COPD offsprings. The IO may be a sensitive tool for detection of high risk subjects in families with COPD. PMID- 26622262 TI - Diagnostic accuracy of pleural fluid tumor necrosis factor-alpha in tuberculous pleurisy: A meta-analysis. AB - BACKGROUND: Pleurisy is a common extra pulmonary complication of tuberculosis, but current methods for diagnosing it are fairly crude. Here we product a meta analysis for the available evidence on the ability of tumor necrosis factor-alpha (TNF-alpha) in pleural fluid to serve as a diagnostic marker of tuberculous pleurisy (TP). MATERIALS AND METHODS: We searched the PubMed, EMBASE, and Google Scholar databases systematically for studies measuring sensitivity, specificity and other measures of diagnostic accuracy of pleural fluid TNF-alpha in the diagnosis of TP were meta-analyzed by Stata, version 12 and meta-disc. RESULTS: A total of six publications reporting seven case-control studies were identified. Pooled results indicated that pleural fluid TNF-alpha showed a diagnostic sensitivity of 0.89 (95% confidence interval [95% CI] 0.83-0.93; range, 0.42-1.0) and a diagnostic specificity of 0.82 (95% CI: 0.78-0.86; range, 0.58-0.98). The pooled positive likelihood ratio was 4.78 (95% CI: 3.32-6.89); the negative likelihood ratio, 0.16 (95% CI: 0.1-0.27); the diagnostic odds ratio, 32.43 (95% CI: 14.48-72.6); and the area under the curve was 0.8556 (standard error of mean 0.0559). CONCLUSION: Pleural fluid TNF-alpha levels shows relatively high sensitivity but insufficient specificity for diagnosing TP. Pleural fluid TNF alpha measurement may be useful in combination with clinical manifestations and conventional tests such as microbiological examination or pleural biopsy. PMID- 26622264 TI - Prevalence of intellectual disability in Iran: Toward a new conceptual framework in data collection. PMID- 26622263 TI - Dietary approach to stop hypertension (DASH): diet components may be related to lower prevalence of different kinds of cancer: A review on the related documents. AB - BACKGROUND: Dietary approaches to stop hypertension (DASH) eating plan is a healthy dietary pattern. Our object is to review surveys in the field of major components of DASH diet and different kinds of cancers. MATERIALS AND METHODS: Our search result from PubMed search engine recruited to find related articles. RESULTS: Adherence to the DASH diet components was significantly related to lower prevalence of various cancers due to their high content of fiber, nutrients, vitamins, mineral, and antioxidant capacity. CONCLUSION: In this review, positive association of DASH diet components and different cancers were observed. However, the exact association of DASH with cancers should be clarified in future longitudinal studies due to potential interaction among foods and nutrients. PMID- 26622265 TI - World Health Organization: Do we have to intensify global tobacco control efforts? PMID- 26622266 TI - Much more is expected from nations to counter antimicrobial resistance: World Health Organization. PMID- 26622267 TI - Effect of Er:YAG Laser on Shear Bond Strength of Composite to Enamel and Dentin of Primary Teeth. AB - OBJECTIVES: Bond strength of composite resin to enamel and dentin of primary teeth is lower than that to permanent teeth; therefore, it may compromise the adhesive bonding. New methods, such as laser application have been recently introduced for tooth preparation. The purpose of this study was to evaluate the effect of tooth preparation with bur and Er:YAG laser on shear bond strength of composite to enamel and dentin of primary teeth. MATERIALS AND METHODS: Seventy five primary molar teeth were collected and 150 specimens were obtained by mesiodistal sectioning of each tooth. In each of the enamel and dentin groups, the teeth were randomly assigned to 3 subgroups with the following preparations: bur preparation + etching (37% H3PO4), laser preparation + etching, and laser preparation without etching. Single Bond adhesive and Z250 composite were applied to all samples. After thermocycling, the shear bond strength testing was preformed using the Instron Testing Machine. Data were analysed using SPSS-17 and two-way ANOVA. RESULTS: The bond strength of enamel specimens was significantly higher than that of dentin specimens, except for the laser-non-etched groups. The enamel and dentin laser-non-etched groups had no significant difference in bond strength. In both enamel and dentin groups, bur preparation + etching yielded the highest bond strength, followed by laser preparation + etching, and the laser preparation without etching yielded the lowest bond strength (P < 0.001). CONCLUSION: In both enamel and dentin groups, laser preparation caused lower shear bond strength compared to bur preparation. PMID- 26622268 TI - Improving Knowledge of General Dental Practitioners on Antibiotic Prescribing by Raising Awareness of the Faculty of General Dental Practice (UK) Guidelines. AB - OBJECTIVES: Cases of antimicrobial resistance are increasing, partly due to inappropriate prescribing practices by dentists. The purpose of this study was to investigate the prescribing practices and knowledge of dentists with regards to antibiotics. Moreover, this study aimed to determine whether the prescriptions comply with the recommended guidelines and whether clinical audit can alter the prescribing practices of dentists leading to better use of antibiotics in the dental service. MATERIALS AND METHODS: A clinical audit (before/after non controlled trial) was carried out in two dental clinics in the northeast of England. Retrospective data were collected from 30 antibiotic prescriptions, analysed and compared with the recommended guidelines. Data collected included age and gender of patients, type of prescribed antibiotics and their dosage, frequency and duration, clinical condition and reason for prescribing. The principles of appropriate prescribing based on guidance by the Faculty of General Dental Practice in the United Kingdom (UK), FGDP, were discussed with the dental clinicians. Following this, prospective data were collected and similarly managed. Pre and post audit data were then compared. Changes were tested for significance using McNemar's test and P value<0.05 was considered statistically significant. RESULTS: After intervention, data revealed that antibiotic prescribing practices of dentists improved, as there was an increase in the percentage of prescriptions that were in accordance with the FGDP (UK) guidelines. CONCLUSION: In view of the limited data collected, this study concludes that there are inappropriate antibiotic prescribing practices amongst general dental practitioners and that clinical audit can address this situation, leading to a more rational use of antibiotics in dental practice. PMID- 26622269 TI - A Simplified Method for the Restoration of Severely Decayed Primary Incisors. AB - OBJECTIVES: Caries and dental trauma are common reasons for primary anterior teeth restorations in children. This non-control clinical trial was designed to evaluate crown restorations reinforced with a sectioned file post for the restoration of severely damaged primary maxillary incisors. MATERIALS AND METHODS: Thirty-eight primary maxillary incisors of 12 children (3-5 years old) with early childhood caries (ECC) received composite restorations with a custom made post. The restorations were evaluated using the modified United State Public Health Service (USPHS) criteria. The results were statistically analyzed by descriptive -analytical tests. RESULTS: In this trial, the quality of marginal adaptation decreased after three and 12 months intervals. Recurrent carious lesions were observed during intervals. In terms of restoration retention, only one patient lost both the post and the restoration at the 12-month follow up. CONCLUSION: The sectioned file post technique showed good retention and aesthetics for restoring severely damaged primary maxillary anterior teeth. PMID- 26622270 TI - Comparison of Bone Loss around Bone Platform Shift and Non-Bone Platform Shift Implants After 12 Months. AB - OBJECTIVES: The aim of the present randomized clinical trial was to evaluate marginal bone loss around two types of implants modified at the neck area: Nobel Active and Nobel Replace Groovy, both manufactured by Nobel Biocare. MATERIALS AND METHODS: A total of 25 Nobel Active and 21 Nobel Replace Groovy implants were included in the present study. The implants were placed based on the relevant protocol and patient inclusion and exclusion criteria. The amount of bone loss around implants was compared at 6 and 12-month intervals using digital periapical radiographs. RESULTS: The mean bone loss values in the Nobel Active and Nobel Replace Groovy groups were 0.682 mm and 0.645 mm, respectively, with no statistically significant difference based on the results of independent t-test (P=0.802). CONCLUSION: Use of both implant types yielded favorable results, with high durability. The two implant types exhibited no superiority over each other in terms of bone loss. PMID- 26622271 TI - How Is the Enamel Affected by Different Orthodontic Bonding Agents and Polishing Techniques? AB - OBJECTIVES: The objective of this study was to assess the effect of new bonding techniques on enamel surface. MATERIALS AND METHODS: Sixty upper central incisors were randomly divided into two equal groups. In the first group, metal brackets were bonded using TransbondXT and, in the second group, the same brackets were bonded with Maxcem Elite. The shear bond strength (SBS) of both agents to enamel was measured and the number and length of enamel cracks before bonding, after debonding and after polishing were compared. The number of visible cracks and the adhesive remnant index (ARI) scores in each group were also measured. RESULTS: There were significantly more enamel cracks in the Transbond XT group after debonding and polishing compared to the Maxcem Elite group. There was no significant difference in the length of enamel cracks between the two groups; but, in each group, a significant increase in the length of enamel cracks was noticeable after debonding. Polishing did not cause any statistically significant change in crack length. The SBS of Maxcem Elite was significantly lower than that of Transbond XT (95% confidence interval). CONCLUSION: Maxcem Elite offers clinically acceptable bond strength and can thus be used as a routine adhesive for orthodontic purposes since it is less likely to damage the enamel. PMID- 26622272 TI - Computerized Analysis of Digital Photographs for Evaluation of Tooth Movement. AB - OBJECTIVES: Various methods have been introduced for evaluation of tooth movement in orthodontics. The challenge is to adopt the most accurate and most beneficial method for patients. This study was designed to introduce analysis of digital photographs with AutoCAD software as a method to evaluate tooth movement and assess the reliability of this method. MATERIALS AND METHODS: Eighteen patients were evaluated in this study. Three intraoral digital images from the buccal view were captured from each patient in half an hour interval. All the photos were sent to AutoCAD software 2011, calibrated and the distance between canine and molar hooks were measured. The data was analyzed using intraclass correlation coefficient. RESULTS: Photographs were found to have high reliability coefficient (P > 0.05). CONCLUSION: The introduced method is an accurate, efficient and reliable method for evaluation of tooth movement. PMID- 26622273 TI - Relationship of Halitosis with Gastric Helicobacter Pylori Infection. AB - OBJECTIVES: Gastric infection with Helicobacter pylori may be one of the main causes of halitosis. This study was performed to evaluate the relationship of Helicobacter pylori infection with halitosis. MATERIALS AND METHODS: This case control study was performed on 44 dyspeptic patients with a mean age of 34.29+/ 13.71 years (range 17 to 76 years). The case group included 22 patients with halitosis and no signs of diabetes mellitus, renal or liver failure, upper respiratory tract infection, malignancies, deep carious teeth, severe periodontitis, coated tongue, dry mouth or poor oral hygiene. Control group included 22 patients without halitosis and the same age, sex, systemic and oral conditions as the case group. Halitosis was evaluated using organoleptic test (OLT) and Helicobacter pylori infection was evaluated by Rapid Urease Test (RUT) during endoscopy. The data were statistically analyzed using chi square, Mann Whitney and t-tests. RESULTS: Helicobacter pylori infection was detected in 20 (91%) out of 22 halitosis patients, and 7 control subjects (32%) (P<0.001). CONCLUSION: Helicobacter pylori gastric infection can be a cause of bad breath. Dentists should pay more attention to this infection and refer these patients to internists to prevent further gastrointestinal (GI) complications and probable malignancies. PMID- 26622274 TI - Efficacy of Disinfection of Dental Stone Casts: Virkon versus Sodium Hypochlorite. AB - OBJECTIVES: The purpose of this experimental study was to compare the disinfection efficacy of sodium hypochlorite and peroxygenic acid (Virkon) solutions for dental stone casts contaminated with microbial strains. MATERIALS AND METHODS: A total of 960 spherical stone beads with a diameter of 10 mm were prepared and used as carriers of bacterial inoculums. They were individually inoculated by soaking in broth culture media containing each of the four understudy microorganisms. Different concentrations of Virkon and hypochlorite solutions were prepared using distilled water and then were sprayed on the surfaces of dental casts contaminated with Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis and Candida albicans. The pour plate technique was used to evaluate the antimicrobial efficacy of each solution. Microbicidal effect (ME) was calculated according to the log10 of control colony counts minus the log10 of the remaining colony counts after the antimicrobial procedure. Statistical difference was assessed using the Kruskal Wallis and the Man Whitney U tests with a significance of 95%. RESULTS: We observed different bactericidal effects of Virkon at various concentrations; 1% Virkon killed S. aureus, P aeruginosa, and Candida albicans, while 3% Virkon solution was required to kill B. subtilis. For S. aureus, P. aeruginosa, and C. albicans, no significant difference was observed between 1% Virkon and 0.525% sodium hypochlorite (P >0.05). For B. subtilis, the efficacy of 3% Virkon and 0.525% sodium hypochlorite was not significantly different (P >0.999). CONCLUSION: According to the obtained results for Virkon and based on its low toxicity and good environmental compatibility, it may be recommended as an antimicrobial disinfectant for dental stone casts as non-critical items. PMID- 26622275 TI - Asymmetric Outer Bow Length and Cervical Headgear Force System: 3D Analysis Using Finite Element Method. AB - OBJECTIVES: This study sought to assess distal and lateral forces and moments of asymmetric headgears by variable outer bow lengths. MATERIALS AND METHODS: Four 3D finite element method (FEM) models of a cervical headgear attached to the maxillary first molars were designed in SolidWorks 2010 software and transferred to ANSYS Workbench ver. 11 software. Models contained the first molars, their periodontal ligament (PDL), cancellous and cortical bones, a mesiodistal slice of the maxillae and the headgear. Models were the same except for the outer bow length in headgears. The headgear was symmetric in model 1. In models 2 to 4, the headgears were asymmetric in length with differences of 5mm, 10mm and 15mm, respectively. A 2.5 N force in horizontal plane was applied and the loading manner of each side of the outer bow was calculated trigonometrically using data from a volunteer. RESULTS: The 15mm difference in outer bow length caused the greatest difference in lateral (=0.21 N) and distal (= 1.008 N) forces and also generated moments (5.044 N.mm). CONCLUSION: As the difference in outer bow length became greater, asymmetric effects increased. Greater distal force in the longer arm side was associated with greater lateral force towards the shorter arm side and more net yawing moment. CLINICAL RELEVANCE: A difference range of 1mm to 15 mm of length in cervical headgear can be considered as a safe length of outer bow shortening in clinical use. PMID- 26622276 TI - Comparative Scanning Electron Microscopic Study of the Marginal Adaptation of Four Root-End Filling Materials in Presence and Absence of Blood. AB - OBJECTIVES: The aim of this study was to evaluate marginal adaptation of mineral trioxide aggregate (MTA), calcium enriched mixture (CEM) cement, Biodentine and BioAggregate in presence of normal saline and human blood. MATERIALS AND METHODS: In this in-vitro experimental study, 80 extracted single-rooted human teeth were instrumented and filled with gutta-percha. After resecting the root-end, apical cavity preparation was done and the teeth were randomly divided into 4 groups (N=20)(a total of 8 subgroups). Root-end filling materials were placed in 3mm root-end cavities prepared ultrasonically. Half the specimens in each group were exposed to normal saline and the other half to fresh whole human blood. After 4 days, epoxy resin replicas of the apical portion of samples were fabricated and scanning electron microscopy (SEM) analysis was performed to find gaps in the adaptation of the root-end filling materials at their interface with dentin. The Kruskal-Wallis and Mann-Whitney tests were used for statistical analysis of data with P<0.05 as the limit of significance. RESULTS: There were no significant differences in marginal adaptation of the 8 tested groups (P>0.05). CONCLUSION: Based on the results, blood contamination does not affect the marginal adaptation of MTA, CEM cement, Biodentine or BioAggregate. PMID- 26622277 TI - Pneumatized Articular Eminence and Assessment of Its Prevalence and Features on Panoramic Radiographs. AB - OBJECTIVES: Pneumatized articular eminence or tubercle (PAT) is an air cell cavity in the zygomatic process of the temporal bone. Pneumatization of articular eminence may be seen incidentally on panoramic radiographs (PRs) as a unilocular or multilocular radiolucent defect. The aim of this study was to assess the prevalence and the pattern of PAT on PR in an Iranian population. MATERIALS AND METHODS: A total of 3,098 PRs belonging to 1,735 females and 1,363 males were retrospectively investigated for the presence and radiographic features of PAT. All PRs were taken for routine dental examination. Chi-square test, univariate odds ratio (OR) and corresponding 95% confidence interval (95% CI) and binary logistic regression were used for statistical analysis. RESULTS: Overall, PAT was found in 2.1 % of cases including 41 females and 23 males (with a mean age of 33.23+/-12.43 and 35.64+/-13.24 years, respectively, range 19-69 years). There were 40 unilateral and 24 bilateral cases (total: 88 PATs) including 49 unilocular and 39 multilocular cases. There was no significant difference in PAT between males and females or different age groups (P>0.05 and all CIs included 1.00). Binary logistic regression indicated that there was no relationship between the presence of PAT and age or sex. CONCLUSION: Knowledge about this anatomical variation is helpful for clinicians who are planning to perform temporomandibular joint surgery. They should assess the radiographic imaging thoroughly before the surgery. It can also provide valuable information to understand the differential diagnosis of pathological entities in this region. PMID- 26622278 TI - Accuracy of an Electronic Apex Locator for Working Length Determination in Primary Anterior Teeth. AB - OBJECTIVES: Correct determination of working length is an important step for success of endodontic therapy. Conventional radiography has limitations in providing the accurate location of apical foramen. For this reason, electronic apex locators (EALs) were developed to shorten the treatment time and decrease the radiation dose. The aim of this study was to evaluate the accuracy of Root ZX EAL for working length determination in primary anterior teeth. MATERIALS AND METHODS: In this in-vitro study, 50 extracted primary anterior teeth with root resorption were selected with no obstructed canals or history of previous root canal therapy. Working lengths were measured by direct observation of actual length (AL), radiography and Root ZX EAL. A variation of +/-0.5 mm from the AL was considered acceptable. The results were analyzed statistically using paired t test and interclass correlation coefficient (ICC) at 0.05 level of significance. RESULTS: Considering an acceptable 0.5 mm margin from AL (direct measurement), the accuracy of Root ZX EAL and radiography was found to be 86% and 76%, respectively. Absolute value of error from AL was significantly lower for ZX compared to radiography (P<0.001). Interclass correlation comparing both radiography and Root ZX with AL showed strong correlations. CONCLUSION: Root ZX EAL can be used as a reliable tool for obtaining root canal length in primary anterior teeth with resorption. PMID- 26622279 TI - Effect of Low-Level Laser Therapy on Orthodontic Tooth Movement: A Clinical Investigation. AB - OBJECTIVES: One major drawback of orthodontic treatment is its long duration due to slow tooth movement and the pain at the onset of treatment following application of forces. There is controversy regarding the efficacy of laser for decreasing the treatment time and pain of orthodontic treatment. The purpose of this study was to investigate the effect of low level diode laser on the rate of orthodontic tooth movement and the associated pain. MATERIALS AND METHODS: In this double blind randomized controlled clinical trial, 12 orthodontic patients referring to Shahid Beheshti School of Dentistry for first premolar extraction were randomly selected and allocated to gallium aluminum-arsenide laser (GA-AL-AS diode laser, 880 nm, 100 mW, 5 j/cm(2), 8 points, 80 seconds, continuous mode) or control group. The patients initially underwent leveling and alignment using the sectional system. Force (150 gr) was applied to each canine tooth via sectional closing loops. The loops were activated every month. The rate of tooth movement and pain were monitored over the treatment period and recorded on days 1, 3, 7, 30, 33, 37, 60, 63 and 67. Two-way ANOVA was used for comparison of groups. RESULTS: There was no significant difference in terms of tooth movement and pain scores between the irradiated and non-irradiated sides at any time point (P>0.05). CONCLUSION: Although laser enhanced orthodontic tooth movement in the upper jaw, we failed to provide solid evidence to support the efficacy of laser for expediting tooth movement or reducing the associated pain. PMID- 26622280 TI - Effect of Saliva pH on Shear Bond Strength of Orthodontic Brackets. AB - OBJECTIVES: The purpose of this study was to evaluate the effect of salivary pH on the shear bond strength (SBS) of orthodontic brackets to tooth surface. MATERIALS AND METHODS: Eighty intact premolars were randomly divided into four groups of 20. After bonding a bracket on each tooth, the groups one to four were stored in artificial saliva at a pH of 3.8, 4.8, 5.8, and 6.8, respectively for two months. The artificial saliva solutions were refreshed weekly. Each tooth was then embedded in an acrylic block so that the crown was exposed and its buccal surface was parallel to the direction of the force during SBS testing. All brackets were debonded using Dartec universal testing machine, and the mean values of SBS in different groups were compared using one-way analysis of variance (ANOVA). RESULTS: The mean SBS value in group one (pH 3.8) was significantly lower than that in other groups (P<0.05). The differences between other groups were not significant (P>0.05). CONCLUSION: Decreased salivary pH due to poor oral hygiene and/or frequent consumption of acidic beverages may be responsible for orthodontic bracket bond failure. PMID- 26622281 TI - Comparison of Serum and Salivary Antioxidants in Patients with Temporomandibular Joint Disorders and Healthy Subjects. AB - OBJECTIVES: Temporomandibular dysfunction (TMD) is a group of disorders in the facial region and temporomandibular joint (TMJ). Biomarkers are assumed to play a role in pain and early detection of destruction. The aim of this study was to compare the saliva and serum antioxidant levels in patients with TMD and healthy subjects. MATERIALS AND METHODS: This case-control study was conducted on 28 TMD patients without pain, 28 TMD patients with pain and 28 healthy controls. The total antioxidant capacity of saliva and serum of patients was measured. Data were analyzed using ANOVA and Tamhane's test. RESULTS: The mean (+/-SD) total antioxidant capacity of serum (plasma TAC) was 0.8900 (+/-0.11627) mmol/L in TMD patients with pain, 1.2717 (+/-0.18711) mmol/L in TMD patients without pain and 1.7500(+/-0.18711) mmol/L in the control group. Based on ANOVA, the difference in this regard among the three groups was statistically significant (P=0.000). The mean salivary TAC was 1.34 (+/-0.06721) mmol/L in TMD patients with pain, 1.42 (+/-0.16677) mmol/L in TMD patients without pain and 1.35 (+/-0.11627) mmol/L in the control group. The difference in this respect among the three groups was not significant (P>0.05). CONCLUSION: The mean plasma TAC in TMD patients with/without pain was significantly lower than that in the control group but no significant difference was detected in salivary TAC among the three groups. PMID- 26622282 TI - Unilateral Outer Bow Expanded Cervical Headgear Force System: 3D Analysis Using Finite Element Method. AB - OBJECTIVES: Headgears are among the effective orthodontic appliances to achieve treatment goals. Unilateral molar distal movement is sometimes needed during an orthodontic treatment, which can be achieved by an asymmetric headgear. Different unilateral headgears have been introduced. The main goal of this study was to analyze the force system of unilateral expanded outer bow asymmetric headgears by the finite element method (FEM). MATERIALS AND METHODS: Six 3D finite element models of a mesiodistal slice of the maxilla containing upper first molars, their periodontal ligaments (PDLs), cancellous bone, cortical bone, and a cervical headgear with expanded outer bow attached to maxillary first molars were designed in SolidWorks 2010 and meshed in ANSYS Workbench ver. 12.1. The models were the same except for the degree of outer bow expansion. The outer bow ends were loaded with 2 N force. The distal driving force and the net moment were evaluated. RESULTS: A decrease in the distalizing force in the normal side molar from 1.69 N to 1.37 N was shown by increasing the degree of unilateral expansion. At the same time, the force increased from 2.19 N to 2.49 N in the expanded side molar. A net moment increasing from 2.26 N.mm to 4.64 N.mm was also shown. CONCLUSION: Unilateral outer bow expansion can produce different distalizing forces in molars, which increase by increasing the expansion. PMID- 26622283 TI - Effect of Four Methods of Surface Treatment on Shear Bond Strength of Orthodontic Brackets to Zirconium. AB - OBJECTIVES: Providing reliable attachment between bracket base and zirconia surface is a prerequisite for exertion of orthodontic force. The purpose of the present study was to evaluate the effect of four zirconium surface treatment methods on shear bond strength (SBS) of orthodontic brackets. MATERIALS AND METHODS: One block of zirconium was trimmed into four zirconium surfaces, which served as our four study groups and each had 18 metal brackets bonded to them. Once the glazed layer was removed, the first group was etched with 9.6% hydrofluoric acid (HF), and the remaining three groups were prepared by means of sandblasting and 1W, and 2W Er: YAG laser, respectively. After application of silane, central incisor brackets were bonded to the zirconium surfaces. The SBS values were measured by a Dartec testing machine with a crosshead speed of 1 mm/min. Data were analyzed using one-way ANOVA and Tukey's HSD for multiple comparisons. RESULTS: The highest SBS was achieved in the sandblasted group (7.81+/-1.02 MPa) followed in a descending order by 2W laser group (6.95+/-0.87 MPa), 1W laser group (6.87+/-0.92 MPa) and HF acid etched group (5.84+/-0.78 MPa). The differences between the study groups were statistically significant except between the laser groups (P<0.05). CONCLUSION: In terms of higher bond strength and safety, sandblasting and Er: YAG laser irradiation with power output of 1W and 2W can be considered more appropriate alternatives to HF acid etching for zirconium surface treatment prior to bracket bonding. PMID- 26622284 TI - Accuracy of Digital Bitewing Radiography versus Different Views of Digital Panoramic Radiography for Detection of Proximal Caries. AB - OBJECTIVES: Dental caries are common and have a high incidence among populations. Radiographs are essential for detecting proximal caries. The best technique should be recognized for accurate detection of caries. The aim of this study was to compare the accuracy of detection of proximal caries using intraoral bitewing, extraoral bitewing, improved interproximal panoramic, improved orthogonality panoramic and conventional panoramic radiographs. MATERIALS AND METHODS: In this descriptive cross sectional study, 100 extracted human teeth with and without proximal caries were used. Intra and extraoral radiographs were taken. Images were evaluated and scored by two observers. Scores were compared with the histological gold standard. The diagnostic accuracy of radiographs was assessed by means of receiver operating characteristic (ROC) curve analysis (P<0.05). RESULTS: Microscopic evaluation of proximal surfaces revealed that 54.8% of the surfaces were sound and 45.2% were carious (with different depths). The differences in the area under the ROC curve (Az value) among the five techniques were not statistically significant. CONCLUSION: Improved interproximal panoramic and extraoral bitewing radiographs were superior to conventional panoramic radiography for detection of proximal caries ex vivo and should be considered for patients with contraindications for intraoral radiographs. PMID- 26622285 TI - Three-Dimensional Finite Element Analysis of Stress Distribution and Displacement of the Maxilla Following Surgically Assisted Rapid Maxillary Expansion with Tooth and Bone-Borne Devices. AB - OBJECTIVES: The aim of this study was to investigate the displacement and stress distribution during surgically assisted rapid maxillary expansion under different surgical conditions with tooth- and bone-borne devices. MATERIALS AND METHODS: Three-dimensional (3D) finite element model of a maxilla was constructed and an expansion force of 100 N was applied to the left and right molars and premolars with tooth-borne devices and the left and right of mid-palatal sutures at the first molar level with bone-borne devices. Five computer-aided design (CAD) models were simulated as follows and surgical procedures were used: G1: control group (without surgery); G2: Le Fort I osteotomy; G3: Le Fort I osteotomy and para-median osteotomy; G4: Le Fort I osteotomy and pterygomaxillary separation; and G5: Le Fort I osteotomy, para-median osteotomy, and pterygomaxillary separation. RESULTS: Maxillary displacement showed a gradual increase from G1 to G5 in all three planes of space, indicating that Le Fort I osteotomy combined with para-median osteotomy and pterygomaxillary separation produced the greatest displacement of the maxilla with both bone- and tooth-borne devices. Surgical relief and bone-borne devices resulted in significantly reduced stress on anchored teeth. CONCLUSION: Combination of Le Fort I and para-median osteotomy with pterygomaxillary separation seems to be an effective procedure for increasing maxillary expansion, and excessive stress side effects are lowered around the anchored teeth with the use of bone-borne devices. PMID- 26622286 TI - Maturogenesis of Two Maxillary Central Incisors: A Case Report with 10 Years of Follow Up. AB - This case report describes the treatment of two immature maxillary central incisors in a 7-year-old female patient. She suffered complicated crown fracture because of trauma, and the root formation was incomplete. White mineral trioxide aggregate (MTA) was selected as the pulp-capping material after cervical pulpotomy to preserve the pulp tissue vitality and achieve maturogenesis. Follow up evaluations showed successful treatment in terms of preservation of pulp vitality and demonstrated marked continuous physiological root development. During 10 years of follow-up, both teeth were clinically asymptomatic, and radiographic evaluations showed apparent root regeneration with apical root-end closure without pulp or periapical pathosis. PMID- 26622288 TI - Current Understandings of Molecular Biology of Echinococcus multilocularis, a Pathogen for Alveolar Echinococcosis in Humans- a Narrative Review Article. AB - BACKGROUND: Echinococcus multilocularis is a tiny tapeworm, responsible for 0.3~0.5 million alveolar echinococcosis in humans. METHODS: We searched relevant papers published between 1981 and 2013 based on the database sources such as PubMed and Google scholar, and collected and integrated the data for analysis. RESULTS: The parasite is able to use host-originated molecules to modulate its development and has complex signalling pathways than expected previously. E. multilocularis utilizes many types of alternative splicing approaches to generate transcript isoforms. Recently, the genome of E. multilocularis has been deciphered. CONCLUSION: These data will give us a profound understanding of biology of E. multilocularis, which will promote the use as a model to study helminths. PMID- 26622289 TI - A Bibliometric and Trend Analysis on the Water-Related Risk Assessment Studies for Cryptosporidium Pathogen. AB - BACKGROUND: The bibliometric methods have been used in many disciplines of sciences to study the scientific production and research trends. In this study, they were used to investigate research trends related to the risk assessment of Cryptosporidium pathogen in water field. METHODS: Data were obtained on the Scopus database from 1993 to 2013. Research tendency was investigated by analyzing the distribution of languages, countries, journals, author keywords, authorship pattern and co-authorship relations. RESULTS: The English language was dominant language of all publications (96.36%). Number of articles in this field increased from 2 in 1993 to 29 papers in 2007 and then received to 19 at the end of 2013. United States produced 35.41% of all pertinent articles followed by United Kingdom with 10.76% and Australia with 9.92%. Water Research Journal published the most papers in this field, taking 11.62% of all, followed by Journal of Water and Health (10.92%) and Water Science and Technology (10.21%). The most productive authors were Ashbolt NJ form Canada that accounts about 1.51% of the total publications followed by Rose JB and Haas CN from United States. Authorship pattern analysis results show that literature does follow Lotka's law (P=0.627). CONCLUSION: A downward trend in the number of publications is likely to occur in future. The results of this bibliometric analysis may help relevant researchers realize the scope of the microbial risk assessment research of Cryptosporidium, and establish the further research direction. PMID- 26622287 TI - The Status of Human and Animal Fascioliasis in Iran: A Narrative Review Article. AB - BACKGROUND: The public health importance of human fascioliasis has increased during last few decades due to the appearance of new emerging and re-emerging foci in many countries. Iran, as the most important focus of human disease in Asia, has been included among six countries known to have a serious problem with fascioliasis by WHO. Various aspects of the disease in Iran are discussed in this review. METHODS: This narrative review covers all information about human and animal fascioliasis in Iran, which has been published in local and international journals from 1960 to 2014 using various databases including PubMed, SID, Google Scholar, Scopus, Science Direct. RESULTS: During the period of the study the infection rates of 0.1% to 91.4% was noted in various livestock. Despite the higher infection rates of livestock in southern areas in past decades, human disease has been mostly encountered in northern Provinces especially in Guilan. Recent studies indicate noticeable decrease in prevalence rates of veterinary fascioliasis in Iran, however the prevalence rates of fascioliasis in livestock in northern Provinces of Guilan and Mazandaran seem to remain at a higher level in comparison to other parts. New foci of the disease have also been reported recently. CONCLUSION: While the prevalence of animal fascioliasis has decreased during last decades, human fascioliasis emerged as a public health problem in the country. The validity of new foci of human fascioliasis needs complementary standard studies. PMID- 26622290 TI - Double-Blind Randomized Efficacy Field Trial of Alum Precipitated Autoclaved Leishmania major (Alum-ALM) Vaccine Mixed With BCG Plus Imiquimod Vs. Placebo Control Group. AB - BACKGROUND: Canine visceral leishmaniasis (CVL) is not only an emerging veterinary concern but also a public health threat in endemic areas. The aim of this study was to assess the efficacy, immunogenicity and safety of two doses of aluminum hydroxide (alum) precipitated Leishmania major (Alum-ALM) mixed with BCG plus imiquimod against CVL. METHODS: A total of 560 ownership dogs were serologically tested and 234 healthy dogs with no clinical signs of CVL, no anti Leishmania antibodies and negative leishmanin skin test were selected and double blind randomly injected intradermally either with 0.1 ml Alum-ALM (200ug protein) mixed with BCG (2 * 10(6) CFUs) plus imiquimod (121 dogs) or with 0.1 ml of normal saline (113 dogs). RESULTS: The follow-up examinations showed that there was no side effect associated with the vaccination except one case. Strong skin test conversion were seen in vaccinated group (30.3%) compared to the control group (6.6%) at 22-24 weeks after the booster injection (p<0.001). The seroconversion was 16.3% (18/110) in vaccinated group and 26.4% (28/106) in control group after two transmission cycles but the difference was not significant (P=0.095). The efficacy rate based on seroconversion was 40.4 %. CONCLUSION: Two injections of Alum-ALM mixed with BCG and imiquimod is safe, although decreases the seroconversion rate of CVL, but the overall efficacy was low. PMID- 26622291 TI - Modification on Direct Agglutination Antigen Preparation for Simplified Sero Diagnosis of Human and Canine Visceral Leishmaniasis. AB - BACKGROUND: Visceral leishmaniasis is systematic serous parasitic disease with public health importance. Zoonotic form of visceral leishmaniasis is wide spread in Mediterranean basin and South America regions. Direct agglutination test (DAT) is an accurate, reliable and non-expensive serological test for the diagnosis of visceral leishmaniasis in human and canines but the antigen preparation involves some limitations. This study aimed to compare the conventional production of DAT antigen with our modified DAT antigen and then assessed on human and dog pooled sera. METHODS: Conventional DAT antigen has been prepared at the School of Public Health, Tehran University of Medical Sciences and some modifications were carried out on it, which named as modified DAT antigen. Three positive and one negative human and dog pooled serum were separately used for the comparison of modified DAT with conventional DAT antigen batches with one-month interval for a period of 9 months. RESULTS: A good concordance was observed between modified DAT compared to conventional DAT antigens for the detection of visceral leishmaniasis on human (100%) and dog (94.4%) pooled sera, respectively. CONCLUSION: Since the modified DAT antigen could be reduced the preparation time from 3 days to several hours and a good degree of agreement was found between modified DAT and convention DAT antigen batches, it can be used as a simple and easy tool for screening and serodiagnosis of human and canine L. infantum infection. PMID- 26622292 TI - Comparative Proteomic Profiling of Leishmania tropica: Investigation of a Case Infected with Simultaneous Cutaneous and Viscerotropic Leishmaniasis by 2 Dimentional Electrophoresis and Mass Spectrometry. AB - BACKGROUND: Viscerotropic leishmaniasis caused by Leishmania tropica poses a significant problem in the diagnosis and treatment management. Since differential gene expression is more important in outcome of the infection, we employed proteomic approach to identify potential proteins involved in visceralization of L. tropica. METHODS: The proteomes profiling of L. tropica isolated from cutaneous and visceral tissues of one host were compared by 2-DE/MS proteomics study. Moreover, the transcript level of some identified proteins was confirmed using real-time RT-PCR. RESULTS: Of the 700 protein spots that were detected reproducibly on each gel, 135 were found to be differentially expressed (P<= 0.05). Most of responsive proteins in visceral isolate changed in less abundant compared to cutaneous isolate. Among differentially expressed proteins, 56 proteins were confidently identified and classified according to the biological process. The largest groups consist of proteins involved in carbohydrate metabolism and protein synthesis. Most of the identified proteins, which implicated in energy metabolism, cell signaling and virulence were down regulated, whereas some proteins that have a role in protein folding, antioxidant defense and proteolysis were up-regulated in visceral form. Moreover, the transcript level of some identified proteins such as co-chaperon was confirmed using real-time RT-PCR. CONCLUSION: L. tropica probably uses different mechanisms for survival and multiplication in viscera to establish viscerotropic leishmaniasis. The current study provides some clues into the mechanisms underlying the dissemination of L. tropica . PMID- 26622293 TI - Molecular Detection and Identification of Zoonotic Microsporidia Spore in Fecal Samples of Some Animals with Close-Contact to Human. AB - BACKGROUND: Microsporidia species are obligatory intracellular agents that can infect all major animal groups including mammals, birds, fishes and insects. Whereas worldwide human infection reports are increasing, the cognition of sources of infection particularly zoonotic transmission could be helpful. We aimed to detect zoonotic microsporidia spore in fecal samples from some animals with close - contact to human. METHODS: Overall, 142 fecal samples were collected from animals with closed-contact to human, during 2012-2013. Trichrome - blue staining were performed and DNA was then extracted from samples, identified positive, microscopically. Nested PCR was also carried out with primers targeting SSU rRNA gene and PCR products were sequenced. RESULTS: From 142 stool samples, microsporidia spores have been observed microscopically in 15 (10.56%) samples. En. cuniculi was found in the faces of 3 (15%) small white mice and 1 (10%) laboratory rabbits(totally 2.81%). Moreover, E. bieneusi was detected in 3 (10%) samples of sheep, 2 (5.12%) cattle, 1 (10%) rabbit, 3 (11.53%) cats and 2 (11.76%) ownership dogs (totally 7.74%). Phylogenetic analysis showed interesting data. This is the first study in Iran, which identified E. bieneusi and En. Cuniculi in fecal samples of laboratory animals with close - contact to human as well as domesticated animal and analyzed them in phylogenetic tree. CONCLUSION: E. bieneusi is the most prevalent microsporidia species in animals. Our results can also alert us about potentially zoonotic transmission of microsporidiosis. PMID- 26622294 TI - Interleukin-18 Antagonism Improved Histopathological Conditions of Malaria Infection in Mice. AB - BACKGROUND: Interleukin 18 (IL-18) exerts pleiotropic roles in many inflammatory related diseases including parasitic infection. Previous studies have demonstrated the promising therapeutic potential of modulating IL-18 bioactivity in various pathological conditions. However, its involvement during malaria infection has yet to be established. In this study, we demonstrated the effect of modulating IL-18 on the histopathological conditions of malaria infected mice. METHODS: Plasmodium berghei ANKA infection in male ICR mice was used as a model for malaria infection. Modulation of IL-18 release was carried out by treatment of malarial mice with recombinant mouse IL-18 (rmIL-18) and recombinant mouse IL 18 Fc chimera (rmIL-18Fc) intravenously. Histopathological study and analysis were performed on major organs including brain, liver, spleen, lungs and kidney. RESULTS: Treatment with rmIL-18Fc resulted in significant improvements on the histopathological conditions of the organs in malaria-infected mice. CONCLUSION: IL-18 is an important mediator of malaria pathogenesis and targeting IL-18 could prove beneficial in malaria-infected host. PMID- 26622295 TI - Influence of Toxoplasma gondii Infection on Male Fertility: A Pilot Study on Immunocompetent Human Volunteers. AB - BACKGROUND: This study was conducted to investigate the influence of Toxoplasma gondii infection on spermatic and hormonal parameters in a pilot sample of immunocompetent human male subjects. METHODS: This cross sectional, observational pilot study on 60 immunocompetent human male subjects aged between 18 and 60 yr old was conducted between 2012 -2013. Blind evaluation of serological markers of past T. gondii infection (TOX-IgG, TOX-IgM) was performed, along with individual spermiograms and determinations of follicle-stimulating hormone (FSH) and testosterone serum levels. RESULTS: The overall prevalence of past T. gondii infection in the investigated immunocompetent male subjects was 25%. No statistically significant influence of T. gondii infection on sperm characteristics (ejaculate quantity, sperm count, motility, morphology) and serum levels of FSH or testosterone were found. Among possible predictors of a modified spermiogram studied by multiple logistic regression along with the T. gondii infection (age, smoking, alcohol consumption, fertility influencing malformations, infections, trauma or medication), only the presence of varicocele in the medical history of the studied subjects was found to significantly participate in the prediction of a modified spermiogram (P=0.0154). A necessary sample size of 994 subjects was computed in order to achieve a test power of 0.8 (80%) to discriminate an effect size of 8.89% estimated by our pilot study. CONCLUSIONS: Although our investigation did not demonstrate an influence of latent T. gondii infection on spermatic and hormonal parameters of immunocompetent male humans, the absence of such an influence cannot be affirmed, due to the limited sample size of our pilot study. PMID- 26622296 TI - Evaluation of Ozone Application in Dental Unit Water Lines Contaminated with Pathogenic Acanthamoeba. AB - BACKGROUND: In this study morphological and molecular characterization of Acanthamoeba strains, isolated from dental unit waterlines (DUWLs) were surveyed and the levels of disinfection achievable in vitro by the application of ozone disinfectant to DUWLs were evaluate. METHODS: Water samples were collected from air-water syringes, cup fillers and tap water before and at the end of the working day. They were cultured on non-nutrient agar (NNA) plates. Species identification was carried out with a PCR assay based on sequence analysis of the 18S rRNA gene. The cellular response to ozone was tested on Acanthamoeba cyst with different doses at different contact time in vitro twice. RESULTS: Prevalence rates for Acanthamoeba contamination were 100, 100 and 72% for air water syringes, cup fillers and tap water, respectively. The morphological analysis revealed the presence of A. castellanii, A. griffin, A. hatchitti and A. lenticulata. Phylogenetic analysis of the sequences showed the four strains to be closely related to a sequence type (T3, T4, T5 and T11). Acanthamoeba cells were stained with trypan blue, which revealed killed of Acanthamoeba instantaneously after 10 minutes in ozonized water. There was no growth of Acanthamoeba occurred after ozone treatment in water bottles for 5 minutes with a flow rate of 500 mg/hour. Conclusion : Ozone can play an important role in controlling the problem of contamination of DUWLs as a potent disinfectant. PMID- 26622297 TI - Phenolic Acid Composition and Anti-Parasitic Effects of Four Peucedanum Species on Entamoeba histolytica Trophozoites. AB - BACKGROUND: The aim of this study was to determine phenolic acid composition and anti-parasitic effects of Peucedanum caucasicum, P. palimbioides, P. longibracteolatum and P. chryseum on Entamoeba histolytica. METHODS: Methanol extracts of the plant species were prepared by soxhlet extraction. Phenolic acid compositions were determined by HPLC. Anti-proliferative effect of extracts on trophozoites was determined by using trypan blue dye exclusion test. For counting the cells, approximately a hundred of E. histolytica trophozoites were examined in each time. The data were presented as mean values with standard deviations and analyzed by repeated measures of ANOVA followed by Tukey test for post-hoc pairwise comparisons. The P-value was set at 0.05 for significance level. RESULTS: All of the extracts showed a time and dose dependent amoebicidal action on trophozoites. Among the extracts tested, P. longibracteolatum showed the strongest amoebicidal effect on the trophozoites. As expected, this plant species also exhibited time and dose dependent activity on the trophozoites. At 4.0 mg/ml extract concentration, all of the trophozoites were killed by the extract in 72(nd) hour. Gallic (11.144 mg/g), P-hydroxybenzoic (17.646 mg/g), and o-coumaric acids (14.442 mg/g) were determined as the major phenolic acids of P. longibracteolatum. Gallic and P-hydroxybenzoic acids found in P. longibracteolatum could not be determined in other extracts. Therefore, high activity potential of this plant could probably be attributed to the presence of these phytochemicals. CONCLUSION: P. longibracteolatum can be further evaluated as potential therapeutic drugs for the treatment of Entamoeba infections. PMID- 26622298 TI - Prevalence, Clinical Criteria and Sociodemographic Predictors of Trichomonas vaginalis Infection in Suspected Egyptian Women, Using Direct Diagnostic Techniques. AB - BACKGROUND: The present study aimed to determine the prevalence and associated risk factors of vaginal trichomoniasis in women referred to gynecologic clinic in Benha University Hospital, Egypt. METHODS: Two hundred female patients enrolled in the study. Vaginal samples were obtained from them and examined for T. vaginalis by wet mount, Giemsa stain, Acridine orange (AO) stain and culture on modified Diamond's medium. For analysis of accuracy of the methods used, the receiver operating characteristic (ROC) curve concept with culture as a gold standard was applied. RESULTS: Out of 200 patients, T. vaginalis was found in 22 (11%) patients by any of the diagnostic methods used. The accuracy of AO staining comes next to Diamond's culture (AUC 0.909, sensitivity 81.8%, specificity 100%, CI 0.81-1.0) followed by Giemsa staining (AUC 0.835, sensitivity 68.2%, specificity 98.9%, CI 0.72-0.95). The wet mount was the least accurate method (AUC 0.795, sensitivity 59.1%, specificity 100%, CI 0.67-0.92). There was no significant association between potentially supposed risk factors and trichomoniasis except patients complaining of either dysuria and dyspareunia or back pain and abdominal pain. CONCLUSION: Trichomoniasis is a common disease in our community. Sociodemographic factors do not seem to affect the prevalence among different Egyptian population. For accurate diagnosis, laboratory investigation is essential. A positive wet smear is diagnostic, but negative samples should be examined by methods that are more sensitive. PMID- 26622299 TI - Prevalence and Genetic Characterization of Cryptosporidium Spp. In Diarrheic Children from Gonbad Kavoos City, Iran. AB - BACKGROUND: Cryptosporidium is an intestinal protozean parasite causing waterborne and foodborne outbreaks of diarrheal diseases. The present study was performed in order to find prevalence and subtypes of Cryptosporidium among children with diarrhea in Gonbad Kavoos City, Northern Iran. METHODS: Diarrheic samples were collected from 547 children. The initial parasitological diagnosis was made based on detection of oocysts using the modified Ziehl-Neelsen acid-fast staining method. The positive microscopically samples were selected for sequence analysis of partial 60 kDa glycoprotein (gp60) gene. RESULTS: Out of 547 collected samples, 27 (4.94%) were positive for Cryptosporidium oocysts. Fifteen from 27 positive samples successfully amplified in PCR. Sequences analysis of gp60 gene in 15 Cryptosporidium isolates revealed that all of them (100%) were C. parvum. The results showed three subtypes of IIa subtype family (7 cases) including IIaA16G2R1, IIaA17G1R1, IIaA22G3R1 and one subtype of IId subtype family (8 cases). The most common allele was IId A17G1d (53.3%). CONCLUSION: The predominance of zoonotic subtype families of C. parvum species (IIa, IId) in the present study is in concordance with previous studies in Iran and emphasizes the significance of zoonotic transmission of cryptosporidiosis in the country. PMID- 26622300 TI - Characterization of Specific RAPD Markers of Virulence in Trichomonas vaginalis Isolates. AB - BACKGROUND: As for human trichomoniasis the host-parasite relationship is very complex, and the broad ranges of clinical symptoms are unlikely be attributable to a single pathogenic mechanism. Specific Random Amplified Polymorphic DNA (RAPD) markers of 490 bp, 720 bp and 460 bp using the primers Tv-5, OPA-6 and OPA 11, respectively, were reported. This was the first description of possible genetic virulence markers of the infection by T. vaginalis. The aim of this study was to characterize the specific RAPD markers in order to elucidate their importance on virulence of this illness. METHODS: The selected specific RAPD fragments were cloned and sequenced. The obtained sequences were compared by the BLAST algorithm. RESULTS: The nucleotide sequence of the Tv-5490 RAPD marker exhibited significant similarity to T. vaginalis hypothetical G3 leucine rich repeat (LRR) family protein (e-value: 6e-14) and Giardia lamblia leucine rich repeat protein 1 virus receptor protein (e-value: 6e-14 and 2e-12) ; however, the OPA-6720 and OPA-11460 showed no significant similarity with any coding published sequence. All the evaluated strains showed the presence of the LRR gene. CONCLUSION: These results demonstrate a possible role of this gene in the virulence of T. vaginalis and in the parasite infection with Trichomonas virus as a possible virus receptor. Further analysis of this gene and encoded protein will allow determining the role that they play in the isolates virus susceptible or resistant phenotypes. PMID- 26622301 TI - Recombinant LPG3 Stimulates IFN-Gamma and TNF-Alpha Secretion by Human NK Cells. AB - BACKGROUND: Natural killer (NK) cells play an important role in early stages of innate immune responses against viral and tumoral attacks. Activation of NK cells by leishmaniasis results in secretion of cytokines such as interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, which enhance the phagocytosis and clearance of parasite. Lipophosphoglycan 3 (LPG3), the Leishmania homologous with GRP94 (glucose regulated protein 94), a member of HSP90 family, contributes to LPG assembly as the most abundant macromolecule on the surface of Leishmania promastigotes. METHODS: We purified NK cells from healthy individuals (n=10) using magnetic-activated cell sorting (MACS) technology. Purified NK cells were co-incubated with different concentrations of recombinant LPG3 (rLPG3), and its N terminal (NT) and C-terminal (CT) fragments. Finally, the production of IFN-gamma and TNF-alpha by NK cells were measured by ELISA. RESULTS: Recombinant LPG3 but not its fragments (CT and NT), could significantly enhance the production of TNF alpha by NK cells (P<0.05). Moreover, rLPG3, CT, and NT fragments were markedly stimulated the secretion of IFN-gamma by NK cells (P<0.001). CONCLUSION: The Leishmania LPG3 antigen could effectively activate NK cells, in vitro. Leishmania LPG3 participates in the innate immunity against leishmaniasis and thereby improves the effective parasite destruction. However, its efficiency should be tested in vivo. PMID- 26622302 TI - Genotyping Characterization of Toxoplasma gondii in Cattle, Sheep, Goats and Swine from the North of Portugal. AB - BACKGROUND: Epidemiological investigations on Toxoplasma gondii infection have found a significant association between human toxoplasmosis and consumption of raw or undercooked meat. The present study aimed to characterize genotypes of T. gondii in 20 cattle, 40 sheep, 15 goats and 16 pigs from the North of Portugal. METHODS: Nested PCR amplified the surface antigen 2 (SAG2) gene. Sequencing analysis was performed in order to assess the prevalence of SAG2 type strains (I, II and III). RESULTS: Three and 4 strains of SAG2 type II were identified in heart samples of cattle and sheep, respectively. Three SAG2 type II strains were detected in brain, diaphragm and heart of 3 pigs. Three strains detected in heart samples of 3 goats belonged to SAG2 types I or II; with the same result being observed in heart samples from 2 sheep and in 2 brain and 1 heart samples from 3 pigs. CONCLUSION: SAG2 type II has been shown for the first time to infect cattle in North of Portugal. In addition, SAG2 type II has also been confirmed as the predominant strain in sheep and pigs in the same region. This is the first molecular report of T. gondii in goats from Portugal. PMID- 26622303 TI - Seroepidemiological Study of Toxocariasis among Volunteers Animal Husbandry Workers and Veterinary in Southern Anatolia in Turkey in 2014. AB - BACKGROUND: Human toxocariasis is a parasitic infection caused by the larvae of Toxocara canis. We examine the Toxocara seroprevalance in veterinarians and animal husbandry workers living in the Mugla Province, Turkey to evaluate better the risk factors for Toxocara exposure. METHODS: In 2014, 376 volunteers participated in the study in 2014. All blood specimens were tested using a commercial enzyme immunoassay kit and ELISA positive samples were confirmed by Western Blot (WB) method. RESULTS: The seroprevalence of Toxocara, as determined by WB, was 8%. A statistically significant correlation was evident between patient age and Toxocara positivity among animal husbandry workers (P = 0.029). A strong association was also evident between sex and seropositivity in the animal husbandry group (P=0.024). Veterinarians working in pet clinics did in fact exhibit higher Toxocara seropositivities relative to those of other groups (P = 0.029). A statistically significant difference was detected between the rural geographic areas surveyed (P = 0.04). CONCLUSION: In Mugla Province, seroprevalence of Toxocara is lower than other regions. Despite the low seroprevalence observed, especially in high risk professions toxocariasis remains an important medical concern within the region. PMID- 26622304 TI - Seroprevalence and Associated Risk Factors of Toxocariasis among College Students in Taipei City, Taiwan. AB - BACKGROUND: Infection by Toxocara spp. is known to be significantly associated with partial epilepsy. It has become popular for people to raise dogs/cats as pets and consume roasted meat/viscera, and the status of Toxocara spp. infection, epilepsy awareness, and associated risk factors among the general population are currently unknown in Taiwan. METHODS: A seroepidemiological investigation among 203 college students (CSs), consisting of 110 males and 93 females with an average age of 21.5 +/- 1.2 years, was conducted in 2009 in Taipei City. A Western blot analysis based on excretory-secretory antigens derived from Toxocara canis larvae (TcESs) was applied to determine the positivity of serum immunoglobulin G antibodies. A self-administered questionnaire was also given to obtain information about demographic characteristics, epilepsy awareness, and risk factors. A logistic regression model was applied for the statistical analysis using SPSS software. RESULTS: The overall seropositive rate of Toxocara spp. infection was 8.4% (17/203). As to epilepsy awareness, a non-significantly higher seroprevalence was found in CSs who claimed to "know" about epilepsy compared to those who did not know (P > 0.05). CONCLUSIONS: It appears that appropriate educational programs are urgently needed to provide correct knowledge related to the prevention and control measures against Toxocara spp. infections to avoid potential threats by this parasite to the general population in Taiwan. PMID- 26622305 TI - A Diagnostic and Symptomatological Study on Trichomoniasis in Symptomatic Pregnant Women in Rafsanjan, South Central Iran in 2012-13. AB - BACKGROUND: Trichomonas vaginalis, the causative agent of trichomoniasis, is responsible for more than half of all sexually transmitted infections (STIs). The present study aimed to determine the frequency of T. vaginalis infection and its clinical manifestations in symptomatic pregnant women in the area based on four different diagnostic methods. METHODS: A total of 162 pregnant women with at least one sign or symptom of vaginosis, referred to two gynecologic and obstetrics clinics in Rafsanjan City, south central Iran, were randomly selected in 2012-13. Through speculum examination of patients by gynecologists, clinical diagnosis determined, vaginal discharge were collected by using two sterile cotton swabs from the posterior fornix and vagina pH was measured. Samples were examined by three diagnostic methods including wet mount, culture in TYI-S-33 medium and polymerase chain reaction (PCR). RESULTS: T. vaginalis was detected in 19.5%, 27.2%, 56.2% and 51.6% of subjects according to diagnostic methods of clinical diagnosis, wet mount, culture and PCR, respectively. There was statistically significant relationship between T. vaginalis infection and patients' age, gestational age, marriage age, residence, educational level, parity. The symptomatological pattern in the 91 women infected with T. vaginalis was as follows: leukorrhea, 96.7%; urine frequency, 65.9%; odorous secretion, 63.3%; urogenital itching and irritation, 53.8%; vaginal inflammation, 47.3%; dyspareunia, 39.6%; and dysuria, 16.5%. CONCLUSION: Our results indicated a high prevalence of T. vaginalis in symptomatic pregnant women, very low sensitivity and relative high specificity of clinical diagnosis and wet mount technique compared to culture and PCR, as well as thatpregnancy increases the susceptibility to the infection in a gestational age-dependent manner. PMID- 26622307 TI - The Effect of Educational Intervention based on BASNEF Model on Decreasing the Cesarean Section Rate among Pregnant Women in Khomain Country. AB - OBJECTIVE: Over the past two decades, the incidence of cesarean section in most countries has increased. Cesarean section increases the risk of death and complications in the mother and fetus. Educational interventions based on behavior change models can play an important role in reduce the rate of cesarean section. The aim of our study is investigation the effect of educational intervention based on BASNEF Model on decreasing of cesarean section rate among pregnant women in Khomain County, from June to November 2013. MATERIALS AND METHODS: In this interventional study, 140 nulliparous women who were in their last trimester of pregnancy were randomly allocated to case and control groups. Data gathering instrument was a questionnaire based on BASNEF framework. Data were analyzed by SPSS 14 software. RESULTS: The scores of knowledge, attitudes, subjective norms, and enabling factors in the intervention group than the control group showed a significant difference (p < 0.001). After the study, it was found that 18 women (25.7%) in case group and 42 women (60%) in the control group underwent cesarean section. By Chi-square test showed that the difference in the type of delivery between the two groups was statistically significant (p < 0.001). CONCLUSION: Design and implement curriculum based on BASNEF can be effective in reducing elective cesarean section. PMID- 26622306 TI - The effects of Ostertagia occidentalis somatic antigens on ovine TLR2 and TLR4 expression. AB - BACKGROUND: Recognition of helminth-derived pathogen associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), including toll like receptors (TLRs) is the first step towards initiating anti-helminth immune responses. Methods : Using somatic antigens of Ostertagia occidentalis, an important abomasal parasite of ruminants, the expression of ovine TLR2 and TLR4 in peripheral blood mononuclear cells (PBMCs) was analyzed by real-time quatitative reverse-transcription polymerase chain reaction (qRT-PCR). Somatic antigens of O. occidentalis were prepared to stimulate ovine PBMCs in a time and dose dependent manner. Results : A high expression of TLR2 and TLR4 was observed in PBMCs cultured with somatic antigens of the parasites specially when PBMCs were cultured with 100 ug/ml of somatic antigens and incubated for 2h. Up regulation of TLR2 expression was more pronounced and evident in our study. Conclsusion : Somatic antigens of O. occidentalis have immunostimulatory and dominant role on peripheral immune cells. This study provide for the first time evidence of induction of TLRs in ovine PBMCs by somatic antigen of O. occidentalis. PMID- 26622308 TI - G-CSF Intrauterine for Thin Endometrium, and Pregnancy Outcome. AB - OBJECTIVE: To evaluate effects of G-CSF on a cancelled ART cycle due to thin endometrium. MATERIALS AND METHODS: In a nonrandomized clinical trial from January 2011 to January 2013 in two tertiary university based hospitals fifteen patients undergoing embryo transfer and with the history of cycle cancellation due to thin endometrium were studied. Intrauterine infusion of G-CSF was done on the day of oocyte pick-up or 5 days before embryo transfer. The primary outcome to be measured was an endometrium thickened to at least 6 mm and the secondary outcome was clinical pregnancy rate and consequently take-home baby. All previous cycles were considered as control for each patient. RESULTS: The G-CSF was infused at the day of oocyte retrieval or 5 days before embryo transfer. The endometrial thickness reached from 3.593+/-0.251 mm to 7.120 +/- 0.84 mm. The mean age, gravidity, parity, and FSH were 35.13+/- 9.531 years, 3, 1 and 32.78 +/ 31.10 mIU/ml, respectively. The clinical pregnancy rate was 20%, and there was one missed abortion, a mother death at 34 weeks, and a preterm labor at 30 weeks due to PROM. CONCLUSION: G-CSF may increase endometrial thickness in the small group of patients who had no choice except cycle cancellation or surrogacy. PMID- 26622309 TI - The Relationship between Maternal Vitamin D Deficiency and Low Birth Weight Neonates. AB - OBJECTIVE: Maternal hypovitaminosis D may impair fetal growth and cause adverse pregnancy outcomes including intrauterine growth restriction and neonatal low birth weight. The aim of this study is to evaluate the relationship between maternal vitamin D status and neonate's birth weight. MATERIALS AND METHODS: A cross-sectional, descriptive analytical study was carried out in the nursery ward of 2 hospitals (Tehran-Iran) during one year (January 2011- January 2012). One hundred and two neonates were categorized into two groups, neonates with birth weight< 2500 gr (n=52) and neonates with birth weight>2500 gr (n = 50). Data regarding medical history, physical examination and anthropometric measurements of neonates were noted in a questionnaire. Birth time blood samples of their mothers were analyzed for serum 25-(OH)-vitamin D by ELISA method. Maternal vitamin D status was compared in two groups. RESULTS: Mean maternal vitamin D (vit D) level was 31.46 nmol/L. Forty eight percent of mothers had vitamin D deficiency, 27.5% had vit D insufficiency and 24.5% were normal. Mean maternal vitamin D level of LBW neonates was lower than other group; 25.05 vs. 38.13 (p = 0.001). All mothers of neonates with head circumference <= 33 cm also had vitamin D deficiency (p = 0.007). CONCLUSION: Maternal Vitamin D deficiency may increase the risk of low birth weight neonate and modifying maternal nutrition behavior and their vit D level could be beneficial on pregnancy outcome. PMID- 26622310 TI - Clarification of Safe Delivery by Iranian Experts Based on Clinical Governance: A Qualitative Study. AB - OBJECTIVE: To clarify the principles of a safe delivery based on Clinical Governance Criteria, as recommended by the pertinent experts. MATERIALS AND METHODS: The current study was part of a qualitative research conducted by content analysis method in 2013 and purposive sampling, performing 24 in-depth interviews based on semi-structured questions and analyzed using thematic content analysis. The participants in this research included midwives, obstetricians, managers, and hospital doctors. The data were under continuous consideration and comparative analysis in order to achieve data saturation. RESULTS: The main concepts derived from interpretations of the pertinent experts include: Patient & Public involvement; Risk Management; Education; Clinical efficiency; Clinical audit; Personnel & Management. CONCLUSION: In a safe delivery, there is a vicious cycle of causes the elimination of which is only possible through benchmarking patterns that attend to most aspects of a safe delivery. Changes to services require utilization of appropriate change management strategies. PMID- 26622311 TI - Comparison of Maternal and Umbilical Cord Blood Selenium Levels in Low and Normal Birth Weight Neonates. AB - OBJECTIVE: To compare the maternal and umbilical cord serum selenium concentrations in Low and normal birth weight neonates. MATERIALS AND METHODS: A case-control study was carried out in Vali-Asr and Akbarabadi Hospitals (Jan. to Dec. 2013). Two groups; case group; 91 mothers who delivered a low birth weight (LBW) neonate and control group; 86 subjects who delivered a normal birth weight neonate were selected. Immediately after birth, 5 ml of maternal blood and umbilical cord blood were collected, and sent to laboratory to assay Se concentrations. To compare both groups' blood Se concentration, data were analyzed in SPSS 16.0. RESULTS: Eighty six (48.6%) mothers with normal birth weight neonates and 91 (51.4%) mothers with low birth weight infants entered the study. Mean maternal mothers' age and mean maternal blood Se were 28.55 + 5.90 years and 79.3756+26.46915. A significant association was seen between maternal blood and cord blood Se level in control and case group (P value < 0.0001, r = 0.69) and (P value<0.001, r = 0.79). On the other hand no differences were seen between 2 groups' maternal blood Se level (P Value = 0.65). Umbilical Cord blood Se concentration was not also different between case and control group (P value = 0.46). CONCLUSION: We found that maternal and umbilical cord blood Se concentrations were not different in low and adequate birth weight infants, however; umbilical cord Se concentrations were positively correlated with maternal blood Se concentrations. PMID- 26622312 TI - Induced Abortion Practices in an Urban Indian Slum: Exploring Reasons, Pathways and Experiences. AB - OBJECTIVE: To explore the context, experiences and pathways of seeking abortion care among married women in a minority dominated urban slum community in Mumbai city of India. MATERIALS AND METHODS: A mixed-method study was conducted using a systematic random sampling method to select 282 respondents from the slum community. One fifth of these womenreported undergoing at least one induced abortion over past five years. A quantitative survey was conducted among these women (n = 57) using structured face-to-face interviews. Additionally, in-depths interviews involving 11 respondents, 2 community health workers and 2 key informants from the community were conducted for further exploration of qualitative data. RESULTS: The rate of induced abortion was 115.6 per 1000 pregnancies in the study area with an abortion ratio of 162.79 per 1000 live births. Frequent pregnancies with low birth spacing and abortions were reported among the women due to restricted contraception use based on religious beliefs. Limited supportfrom husband and family compelled the women to seek abortion services, mostly secretly, from private, unskilled providers and unregistered health facilities. Friends and neighbors were main sources of advice and link to abortion services. Lack of safe abortion facilities within accessible distance furtherintensifies the risk of unsafe abortions. CONCLUSION: Low contraception usage based on rigid cultural beliefs and scarcely accessible abortion services were the root causes of extensive unsafe abortions.Contraception awareness and counseling with involvement of influential community leaders as well as safe abortion services need to be strengthened to protect these deprived women from risks of unwanted pregnancies and unsafe abortions. PMID- 26622313 TI - Frequency of "Nursing Strike" among 6-Month-Old Infants, at East Tehran Health Center and Contributing Factors. AB - OBJECTIVE: An abrupt refusal by the infant to breastfeed is often called "nursing strike". In fact a common reason for cessation of nursing is infant's refusal to breast feed. This problem can often be overcome. This paper has aimed to identify the causes of "breast feeding refusal" or "nursing strike" in 6 month old infants visiting the East Tehran health center for their scheduled vaccination of 6 months old. MATERIALS AND METHODS: Totally 175 six month old infants were enrolled in this study. A questionnaire was filled by mother for each child and later the infants with "nursing strike" were compared with all others. RESULTS: In this study prevalence of breast feeding refusal in infants was 24%.There was significant relation between the "breastfeeding refusal" and maternal academic education or working status. In this study mothers reported various reasons associated with "refusal breast feeding. According to the mothers playful infant and nasal obstructions were the probable causes for refusal. CONCLUSION: There is a diverse variety of factors influencing nursing strike. Most of these factors can be prevented by identifying the background reasons and proper training. PMID- 26622314 TI - Fixed versus Flexible Gonadotropin Releasing Hormone Antagonist Protocol in Controlled Ovarian Stimulation for Invitro Fertilization in Women with Polycystic Ovary Syndrome. AB - OBJECTIVE: This study was conducted to compare the results of fixed versus flexible GnRH antagonist protocols in controlled ovarian stimulation for Intra Cytoplasmic Sperm Injection (ICSI) in patients with PCOS. MATERIALS AND METHODS: A randomized clinical trial was performed on 100 PCOS women, who were admitted to a tertiary infertility clinic and were candidate for IVF/ICSI. They were divided into two groups based on the GnRH antagonist protocol. We started GnRH antagonist 0.25mg in flexible protocol when a follicle >= 14 mm in diameter was seen in transvaginalsonography (Group 1). In fixed protocol, GnRH antagonist was administered from day 6 of stimulation (Group 2). Number of oocytes in methapase 2, number of developed and frozen embryo as main outcome and days of stimulation, number of gonadotropin and antagonist used assecondry outcome measures were assessed and compared between the two groups. RESULTS: The days of stimulation and the number of antagonist used was not significantly different between fixed and flexible group (p >= 0.05).Although the number of gonadotropin injections was significantly lower in flexible group (p = 0.03), the number of oocyte retrieved and the number of embryo which cryopreserved was significantly higher in flexible compared to fixed protocol (p < 0.01). CONCLUSION: It seems using flexible antagonist protocol in PCOS infertile patients is in favor of better outcomes in terms of number of good quality oocytes and embryo and possibility for cryopreservation for future cycles. PMID- 26622315 TI - miR-23b as a potential tumor suppressor and its regulation by DNA methylation in cervical cancer. AB - BACKGROUND: The aberrant expression of miR-23b is involved in the development and progression of cancer. The aim of this study was to evaluate the potential role of methylation in the silencing of miR-23b in cervical cancer cell lines and to determine its expression in stages of malignant progression and in cervical cancer tissues HPV16-positive. METHODS: The methylation of the miR-23b promoter was determined in HeLa, SiHa, CaSki and C33A cells using a Human Cancer miRNA EpiTectMethyl II Signature PCR Array(r). The cells were treated with 5-Aza-2' deoxycytidine, and the expression of miR-23b, uPa, c-Met and Zeb1 was determined by qRT-PCR. miR-92a and GAPDH were used as controls. The expression of miR-23b was determined in cervical scrapes and biopsies of women without squamous intraepithelial lesions, with precursor lesions and with cervical cancer, all were HPV16-positive. The Fisher exact and Mann-Whitney tests were used to compare the differences of the expression of miR-23b, uPa, c-Met and Zeb1 among cell groups, and the difference among patients, respectively. The association between the expression of miR-23b and cervical cancer was determined by logistic regression with a confidence level of 95 %. A value of p < 0.05 was considered statistically significant. RESULTS: In C33A, HeLa and CaSki cells, methylation was associated with decreased expression of miR-23b. After treatment with 5-Aza CdR, the expression of miR-23b increased in all cell lines and the expression of c-Met decreased in HeLa cells, while uPa and Zeb1 decreased in C33A and CaSki cells. In SiHa cells the expression of uPa, c-Met and Zeb1 increased. The expression of miR-23b decreased in relation to the increase in the severity of the lesion and was significantly lower in cervical cancer. In women with premalignant lesions HPV16-positive, decreased levels of miR-23b increased the risk of cervical cancer (OR = 36, 95 % CI = 6.7-192.6, p < 0.05). CONCLUSIONS: The results suggest that the expression of miR-23b is regulated by the methylation of its promoter and is possible that this microRNA influence the expression of uPa, c-Met and Zeb1 in cervical cancer cells lines. In women with premalignant lesions and cervical cancer infected with HPV16, the expression level of miR-23b agree with a tumor suppressor gene. PMID- 26622316 TI - Celecoxib for the prevention of nonmuscle invasive bladder cancer: results from a matched control study. AB - OBJECTIVES: New targets and approaches are under investigation for the treatment of nonmuscle invasive bladder cancer (NMIBC). Preclinical data suggest cyclooxygenase-2 (COX-2) as a promising target. Celecoxib, a COX-2 selective inhibitor, inhibits tumor development and enhances survival, both in vitro and in vivo models of bladder cancer. Therefore, we conducted a pilot study of celecoxib to prevent recurrence in patients with intermediate risk NMIBC. METHODS: Treatment with celecoxib was administered orally for 12 months and compared with a contemporary series of patients treated with intravesical mitomycin C (MMC), given weekly for 4 weeks and then monthly for 11 months. Primary endpoints were time to first recurrence and adverse events. RESULTS: From 2003 through 2006, 58 patients were treated with celecoxib and compared with 66 patients receiving MMC. After a median follow up of 75 months, 49 patients were disease free, including 23 (34.85%) in the MMC group and 26 (44.8%) in the celecoxib group. Median disease-free interval was 67 months [95% confidence interval (CI) 35.8 to NA] versus 41 months (95% CI 27.1-67.1; log-rank p = 0.25) for patients treated with MMC and celecoxib, respectively. In the multivariate analysis, treatment was not found to be an independent predictor for recurrence [hazard ratio (HR) 0.76, 95% CI 0.47-1.22, p = 0.25). Overall, 45 AEs were recorded in 35/124 patients. There were no differences between the two groups. CONCLUSIONS: Our data support a clinical benefit of celecoxib and encourage future trials in which COX-2 inhibitors may be tested in selected patients with NMIBC. PMID- 26622318 TI - Diseases masking and delaying the diagnosis of urogenital tuberculosis. AB - As urogenital tuberculosis (UGTB) has no specific clinical features, it is often overlooked. To identify some of the reasons for misdiagnosing UGTB we performed a systematic review. We searched in Medline/PubMed papers with keywords 'urogenital tuberculosis, rare' and 'urogenital tuberculosis, unusual'. 'Urogenital tuberculosis, rare' presented 230 articles and 'urogenital tuberculosis, unusual' presented 81 articles only, a total of 311 papers. A total of 34 papers were duplicated and so were excluded from the review. In addition, we excluded from the analysis 33 papers on epidemiological studies and literature reviews, papers describing non-TB cases and cases of TB another than urogenital organs (48 articles), cases of congenital TB (three articles), UGTB as a case of concomitant disease (16 articles), and UGTB as a complication of BCG-therapy (eight articles). We also excluded 22 articles dedicated to complications of the therapy, which made a total of 164 articles. Among the remaining 147 articles we selected 43 which described really unusual, difficult to diagnose cases. We also included in our review a WHO report from 2014, and one scientific monograph on TB urology. The most frequent reasons for delayed diagnosis were absence typical clinical features of UGTB, and the tendency of UGTB to hide behind the mask of another disease. We can conclude that actually UGTB is not rare disease, but it is often an overlooked disease. The main reasons for delayed diagnosis are vague, atypical clinical features and a low index of suspicion. PMID- 26622317 TI - Muscle-invasive urothelial bladder cancer: an update on systemic therapy. AB - Urothelial carcinoma is a common malignancy that carries a poor prognosis when the disease includes muscle invasion. Metastatic urothelial carcinoma is almost uniformly fatal. The evidence behind treatment options in the neoadjuvant, adjuvant and metastatic settings are discussed in this manuscript, with a focused review of standard and investigational cytotoxic, targeted, and immunotherapy approaches. We have focused especially on neoadjuvant cisplatin-based therapy (supported by level one evidence) and on novel immunotherapy agents such as checkpoint inhibitors, which have shown great promise in early clinical studies. PMID- 26622319 TI - Hexaminolevulinate hydrochloride in the detection of nonmuscle invasive cancer of the bladder. AB - Clinical trials have shown that hexaminolevulinate (HAL) fluorescence cystoscopy improves the detection of bladder tumors compared with standard white-light cystoscopy, resulting in more efficacious treatment. However, some recent meta analyses report controversially on recurrence-free rates with this procedure. A systematic review of literature was performed from December 2014 to January 2015 using the PubMed, Embase and Cochrane databases for controlled trials on photodynamic diagnosis (PDD) with HAL. A total of 154 publications were found up to January 2015. Three of the authors separately reviewed the records to evaluate eligibility and methodological quality of clinical trials. A total of 16 publications were considered eligible for analysis. HAL-PDD-guided cystoscopy increased overall tumor detection rate (proportion difference 19%, 95% confidence interval [CI] 0.152-0.236) although the benefit was particularly significant in patients with carcinoma in situ (CIS) lesion (proportion difference 15.7%, 95% CI 0.069-0.245) and was reduced in papillary lesions (Ta proportion difference 5.9%, 95% CI 0.014-0.103 and T1 proportion difference 1.2%, 95% CI 0.033-0.057). Moreover, there were 15% of patients (95% CI 0.098-0.211) with at least one additional tumor seen with PDD. With regard to recurrence rates, the data sample was insufficient for a statistical analysis, although the evaluation of raw data showed a trend in favor of HAL-PDD. This meta-analysis confirms the increased tumor detection rate by HAL-PDD with a most pronounced benefit for CIS lesion. PMID- 26622321 TI - Targeting PD-1/PD-L1 in the treatment of metastatic renal cell carcinoma. AB - Immunostimulatory therapies have been a cornerstone of treatment for metastatic renal cell carcinoma (RCC) since the 1990s. However, the use of traditional immunotherapeutic approaches for RCC, such as high-dose interleukin-2 and interferon-alpha, has been limited by significant systemic toxicities and the need to deliver these therapies at centers of expertise. Furthermore, in spite of the success of these immunostimulatory therapies for some patients with RCC, it is clear that most patients fail to respond to cytokine therapy. More effective immune therapy for RCC has therefore been necessary. The interaction between programmed death-1 (PD-1, present on T cells), and one of its ligands (PD-L1, present on antigen-presenting cells and tumor cells) constitutes an immune checkpoint through which tumors can induce T-cell tolerance and avoid immune destruction. Monoclonal antibodies that disrupt the PD-1/PD-L1 interaction serve as inhibitors of this immune checkpoint, and have demonstrated favorable activity in RCC as monotherapy and in combination with other active agents. This review summarizes the current landscape of anti-PD-1/PD-L1 therapy for RCC, and highlights challenges for the future development of this promising approach. PMID- 26622320 TI - Management of carcinoma in situ of the bladder: best practice and recent developments. AB - Management of carcinoma in situ of the bladder remains a complex and challenging endeavor due to its high rate of recurrence and progression. Although it is typically grouped with other nonmuscle invasive bladder cancers, its higher grade and aggressiveness make it a unique clinical entity. Intravesical bacillus Calmette-Guerin is the standard first-line treatment given its superiority to other agents. However, high rates of bacillus Calmette-Guerin failure highlight the need for additional therapies. Radical cystectomy has traditional been the standard second-line therapy, but additional intravesical therapies may be more appealing for non-surgical candidates and patients refusing cystectomy. The subject of this review is the treatment strategies and available therapies currently available for carcinoma in situ of the bladder. It discusses alternative intravesical treatment options for patients whose condition has failed to respond to bacillus Calmette-Guerin therapy and who are unfit or unwilling to undergo cystectomy. PMID- 26622322 TI - Testosterone and prostate cancer: an evidence-based review of pathogenesis and oncologic risk. AB - Testosterone plays a central role in male development and health. Likewise, androgen deficiency, or hypogonadism, is associated with a variety of symptoms including decreased energy, diminished libido and erectile dysfunction, among others. Male androgen levels steadily decline with age, and, in a subset of symptomatic older men, can result in late-onset hypogonadism (LOH). Over the last decade, increased awareness of hypogonadism among patients and providers has led to a significant rise in the use of testosterone replacement therapy (TRT) for hypogonadism, and especially in LOH. Accompanying the rise in TRT are concerns of potential adverse effects, including cardiovascular risks and the promotion of prostate cancer. The 'androgen hypothesis' asserts that prostate cancer development and progression is driven by androgens, and thus TRT has the theoretical potential to drive prostate cancer development and progression. In this review, we examine existing data surrounding testosterone and prostate cancer. There is significant evidence that androgens promote prostate cancer in experimental systems. However, there is no clear evidence that elevations in endogenous testosterone levels promote the development of prostate cancer in humans. As a result of experimental and historical data on the progression of prostate cancer following TRT, there has been widespread belief that TRT will promote disease progression in prostate cancer patients. Despite these fears, there are a growing number of studies demonstrating no increase in prostate cancer incidence among men on TRT. Furthermore, in studies involving a small number of patients, there has been no discernable increase in disease progression in prostate cancer patients on TRT. While data from large, prospective, randomized, controlled trials are absent, TRT in select prostate cancer patients is likely safe. In the end, the use of TRT in prostate cancer patients is still considered experimental and should only be offered after well-informed shared decision making and with close monitoring. PMID- 26622323 TI - Histone deacetylase inhibitors in castration-resistant prostate cancer: molecular mechanism of action and recent clinical trials. AB - Historically, androgen-deprivation therapy has been the cornerstone for treatment of metastatic prostate cancer. Unfortunately, nearly majority patients with prostate cancer transition to the refractory state of castration-resistant prostate cancer (CRPC). Newer therapeutic agents are needed for treating these CRPC patients that are unresponsive to androgen deprivation and/or chemotherapy. The histone deacetylase (HDAC) family of enzymes limits the expression of genomic regions by improving binding between histones and the DNA backbone. Modulating the role of HDAC enzymes can alter the cell's regulation of proto-oncogenes and tumor suppressor genes, thereby regulating potential neoplastic proliferation. As a result, histone deacetylase inhibitors (HDACi) are now being evaluated for CRPC or chemotherapy-resistant prostate cancer due to their effects on the expression of the androgen receptor gene. In this paper, we review the molecular mechanism and functional target molecules of different HDACi as applicable to CRPC as well as describe recent and current clinical trials involving HDACi in prostate cancer. To date, four HDAC classes comprising 18 isoenzymes have been identified. Recent clinical trials of vorinostat, romidepsin, and panobinostat have provided cautious optimism towards improved outcomes using these novel therapeutic agents for CPRC patients. Nevertheless, no phase III trial has been conducted to cement one of these drugs as an adjunct to androgen-deprivation therapy. Consequently, further investigation is necessary to delineate the benefits and drawbacks of these medications. PMID- 26622324 TI - Hyperuricaemia with deposition: latest evidence and therapeutic approach. AB - This article reviews recent evidence on urate deposition and the opportunity for a therapeutic approach. We reviewed Pubmed 2013-2015 literature using the search terms 'deposition' with 'hyperuricaemia', 'gout', 'ultrasonography', 'DECT' (dual energy computed tomography), 'radiography', 'CT'(computed tomography), 'MRI' (magnetic resonance imaging), or 'cardiovascular', in addition to a digital bibliographic library compiled by the authors with 2072 papers on hyperuricaemia and gout. Relevant papers on the topic were selected. Recent evidence, mostly based on imaging studies, showed a continuum from hyperuricaemia to deposition and clinical manifestations. Chronic inflammation and structural damage may be present even in asymptomatic patients with crystal-proved deposition. The impact of early intervention in patients with asymptomatic deposition either on vascular outcomes or further structural joint damage has not been demonstrated yet. In conclusion, a worldwide definition of gout is still lacking, stages from hyperuricaemia to clinical gout not being definitively defined. Although there is increasing interest on the impact of early deposits on joint damage and cardiovascular outcomes, robust evidence is still lacking to fully support interventions. PMID- 26622325 TI - Key issues in the management of patients with systemic lupus erythematosus: latest developments and clinical implications. AB - Systemic lupus erythematous (SLE) is a chronic multisystem disease with significant associated morbidity and mortality. A deeper understanding of the pathogenesis of SLE has led to the development of biologic agents, primarily targeting B cells and others inhibiting costimulatory molecules, type I interferons and cytokines such as interleukin-6. Several of these agents have been studied in clinical trials; some have shown promise while others have yielded disappointing results. Economic and regulatory issues continue to hamper the availability of such therapies for SLE patients. With increasing recognition that recurrent flares of disease activity lead to long-term damage accrual, one of the most important recent developments in patient management has been the concept of treat-to-target in SLE while minimizing patient exposure to excessive corticosteroid and other immunosuppressive therapy. This article reviews these key issues in SLE management, outlining recent developments and clinical implications for patients. PMID- 26622327 TI - RNA interference-based therapeutics for inherited long QT syndrome. AB - Inherited long QT syndrome (LQTS) is an electrical heart disorder that manifests with syncope, seizures, and increased risk of torsades de pointes and sudden cardiac death. Dominant-negative current suppression is a mechanism by which pathogenic proteins disrupt the function of ion channels in inherited LQTS. However, current approaches for the management of inherited LQTS are inadequate. RNA interference (RNAi) is a powerful technique that is able to suppress or silence the expression of mutant genes. RNAi may be harnessed to knock out mRNAs that code for toxic proteins, and has been increasingly recognized as a potential therapeutic intervention for a range of conditions. The present study reviews the literature for RNAi-based therapeutics in the treatment of inherited LQTS. Furthermore, this review discusses the combined use of RNAi with the emerging technology of induced pluripotent stem cells for the treatment of inherited LQTS. In addition, key challenges that must be overcome prior to RNAi-based therapies becoming clinically applicable are addressed. In summary, RNAi-based therapy is potentially a powerful therapeutic intervention, although a number of difficulties remain unresolved. PMID- 26622328 TI - Immunological effect induced by mesenchymal stem cells in a rat liver transplantation model. AB - The aim of the present study was to investigate the immunological effect induced by bone marrow mesenchymal stem cells (MSCs) in rats that had undergone an orthotopic liver transplantation (OLT). MSCs were isolated and cultured from the bone marrow tissue of Lewis rats. In total, 42 rat OLT models were established and equally distributed into three groups. Group A received an OLT only, group B were also intramuscularly injected with tacrolimus (FK506), while group C were not only administered FK506, but also received MSCs. On day 7 post-surgery, the blood levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) were measured. In addition, pathological changes were observed in the liver, levels of immune cytokines, including transforming growth factor (TGF)-alpha1, interleukin (IL)-10 and IL-12, were determined using immunohistochemistry, MSC homing was assessed and the survival times of the patients were recorded. Liver function, as assessed by the levels of ALT, AST and TBIL, was shown to improve in group C when compared with groups B and A (both P<0.01). In addition, survival analysis revealed that the survival times in groups B (median, 44 days) and C (median, 63 days) were significantly longer compared with group A (median, 11 days; both P<0.01). The survival rate of group C was also higher compared with group B (P<0.01). Pathological examination demonstrated strong acute rejection in group A, a mild acute rejection in group B and the mildest reaction in group C. In addition, immunohistochemistry revealed that TGF-alpha1 and IL-10 expression was stronger in groups C and B, with group C exhibiting more significant expression than group B. By contrast, expression levels of IL-12 in groups A, B and C were positive, weak-positive and negative, respectively. Therefore, postoperative immunosuppression induced by MSCs is important for the alleviation of immune rejection from recipient-to-graft, and may induce immune tolerance in rat OLT models. PMID- 26622326 TI - Treatment of rheumatoid arthritis-associated interstitial lung disease: a perspective review. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting 0.5-1% of the worldwide population. Whilst predominantly causing chronic pain and inflammation in synovial joints, it is also associated with significant extra articular manifestations in a large proportion of patients. Among the various pulmonary manifestations, interstitial lung disease (ILD), a progressive fibrotic disease of the lung parenchyma, is the commonest and most important, contributing significantly to increased morbidity and mortality. The most frequent patterns of RA-associated ILD (RA-ILD) are usual interstitial pneumonia and nonspecific interstitial pneumonia. New insights during the past several years have highlighted the epidemiological impact of RA-ILD and have begun to identify factors contributing to its pathogenesis. Risk factors include smoking, male sex, human leukocyte antigen haplotype, rheumatoid factor and anticyclic citrullinated protein antibodies (ACPAs). Combined with clinical information, chest examination and pulmonary function testing, high-resolution computed tomography of the chest forms the basis of investigation and allows assessment of subtype and disease extent. The management of RA-ILD is a challenge. Several therapeutic agents have been suggested in the literature but as yet no large randomized controlled trials have been undertaken to guide clinical management. Therapy is further complicated by commonly prescribed drugs of proven articular benefit such as methotrexate, leflunomide (LEF) and anti-tumour necrosis factor alpha agents having been implicated in both ex novo occurrence and acceleration of existing ILD. Agents that offer promise include immunomodulators such as mycophenolate and rituximab as well as newly studied antifibrotic agents. In this review, we discuss the current literature to evaluate recommendations for the management of RA-ILD and discuss key gaps in our knowledge of this important disease. PMID- 26622329 TI - Establishment of a new animal model of allergic rhinitis with biphasic sneezing by intranasal sensitization with Staphylococcal enterotoxin B. AB - Allergic rhinitis (AR) is a global health problem. The effectiveness of currently available medications is limited and therefore investigation for more effective drugs is essential. The aim of the present study was to establish a model of AR in guinea pigs that can be utilized for the further investigation of new drugs. Guinea pigs were intranasally sensitized with 1 ug Staphylococcal enterotoxin B (SEB) dissolved in 40 ul saline once daily for 14 days. One week after the last sensitization, the same treatment was applied intranasally once every four days for a total of 30 times. In the treatment group, terfenadine was administered orally 70 min before the 4th, 14th and 24th challenge. Sneezing and nasal scratching were evaluated following each of the 30 challenges. The quantity of antigen-specific antibodies in the serum was measured. Between the 19th and 30th challenges, the guinea pigs in the model group produced significant biphasic elevations in sneezing number, with peaks 10 min-2 h and 4-8 h after the SEB challenges. In addition, the guinea pigs produced significantly more sneezing in the first peak during the 19th to 30th challenges than during the first to 18th challenges (P<0.01). Terfenadine significantly inhibited the early- and late phase sneezing at all challenge times. The serum levels of SEB-specific immunoglobulin (Ig) E and IgG1 were higher in the model group in comparison with those in the control group (P<0.01). This experiment demonstrated that SEB can induce typical AR with biphasic sneezing in guinea pigs. Histamine may play an important role in the early- and the late-phase sneezing in the model of AR. This model can be potentially used for the investigation of new drugs. PMID- 26622330 TI - Erythropoietin pretreatment suppresses inflammation by activating the PI3K/Akt signaling pathway in myocardial ischemia-reperfusion injury. AB - Erythropoietin (EPO), a glycoprotein originally known for its important role in the stimulation of erythropoiesis, has recently been shown to have significant protective effects in animal models of kidney and intestinal ischemia-reperfusion injury (IRI). However, the mechanism underlying these protective effects remains unclear. The aim of the current study was to evaluate the effects of EPO on myocardial IRI and to investigate the mechanism underlying these effects. A total of 18 male Sprague Dawley rats were randomly divided into three groups, namely the sham, IRI-saline and IRI-EPO groups. Rats in the IRI-EPO group were administered 5,000 U/kg EPO intraperitoneally 24 h prior to the induction of IRI. IRI was induced by ligating the left descending coronary artery for 30 min, followed by reperfusion for 3 h. Pathological changes in the myocardial tissue were observed and scored. The levels of the proinflammatory cytokines, interleukin (IL)-6, IL-1beta and tumor necrosis factor (TNF)-alpha, were evaluated in the serum and myocardial tissue. Furthermore, the effects of EPO on phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling and EPO receptor (EPOR) phosphorylation were measured. Pathological changes in the myocardial tissue, increased expression levels of TNF-alpha, IL-6 and IL-1beta in the myocardium, and increased serum levels of these mediators, as a result of IRI, were significantly decreased by EPO pretreatment. The effects of EPO were found to be associated with the activation of PI3K/Akt signaling, which suppressed the inflammatory responses, following the initiation of EPOR activation by EPO. Therefore, EPO pretreatment was demonstrated to decrease myocardial IRI, which was associated with activation of EPOR, subsequently increasing PI3K/Akt signaling to inhibit the production and release of inflammatory mediators. Thus, the results of the present study indicated that EPO may be useful for preventing myocardial IRI. PMID- 26622331 TI - Expression of glucocorticoid receptor-alpha in the epidermis of patients with psoriasis vulgaris. AB - Expression of glucocorticoid receptor (GR)-alpha is observed in almost all tissues and cells of the body; thus, investigating the expression of the receptor in the epidermis of patients with psoriasis vulgaris. The aim of the present study was to investigate GR-alpha expression in the epidermis of psoriasis vulgaris patients The study population consisted of 26 patients with psoriasis vulgaris and 10 normal control cases. None of the patients had received any prior treatment with glucocorticoids. Epithelial tissue samples were detected using a streptavidin peroxidation-enzymatic method for biopsy. Non-lesional tissue samples from within a range of 3 cm of lesions formed the non-lesional group, and lesional tissue samples formed the lesional group. Pathological image analysis system (named CMIAS) was used to convert image signals into numeric values, according to the optical density per unit area. GR-alpha expression was observed within the nucleus in the normal control group; however, cytoplasmic expression was observed in the lesions of the psoriatic group. The optical density values were significantly lower in the psoriatic group when compared with the normal control group, indicating a statistically significant difference in GR-alpha expression between the two groups (P<0.001), and this decreasing correlation was unaffected by the administration of steroids for 6 months. Therefore, decreased expression of GR-alpha may play an important role in the degeneration of keratinocytes in patients with psoriasis vulgaris. PMID- 26622332 TI - Expression of vascular cell adhesion molecule-1 in the aortic tissues of atherosclerotic patients and the associated clinical implications. AB - The aim of this study was to investigate the expression level of vascular cell adhesion molecule-1 (VCAM-1) in the aortic tissues of atherosclerotic patients and to explore the associated clinical implications. Full-thickness aortic wall tissue samples were collected from atherosclerotic patients. Biochemical analysis was used for the detection of the serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), lipoprotein (a) [Lp (a)], apolipoprotein (Apo) AI and Apo-B. Coronary angiography and SYNTAX scoring were used to determine the extent and severity of the disease. Immunohistochemistry was employed for the detection of the VCAM-1 protein expression levels in the arterial tissues. Significant differences were observed in the blood lipid levels between atherosclerotic patients and control subjects. Immunohistochemistry indicated that the aortic VCAM-1 expression level in atherosclerotic patients was 0.23+/ 0.06 optical density (OD) units, which was significantly higher than that in the control subjects (0.08+/-0.03 OD units). In the atherosclerotic patients, the aortic VCAM-1 expression was positively correlated with the serum levels of TG (r=0.347), TC (r=0.469), LDL-C (r=0.463), Lp (a) (r=0.507) and Apo-B (r=0.384), while VCAM-1 and HDL-C were negatively correlated (r=-0.319). Furthermore, a higher SYNTAX score was accompanied by a higher VCAM-1 expression level (r=0.532), and an elevated aortic VCAM-1 expression was associated with certain cardiovascular risk factors. In conclusion, aortic VCAM-1 expression is associated with the severity of atherosclerosis and cardiovascular risk factors, indicating that VCAM-1 plays a role in the pathogenesis of atherosclerosis. PMID- 26622333 TI - siRNA targeting of Trop2 suppresses the proliferation and invasion of lung adenocarcinoma H460 cells. AB - The aim of the present study was to investigate the effect of the small interfering RNA (siRNA)-induced inhibition of the Trop2 gene on the proliferation and invasion of lung adenocarcinoma H460 cells. A recombinant adenovirus expression vector, which contained siRNA targeting open reading frames for Trop2 (rAd5-siTrop2), was transfected into lung adenocarcinoma H460 cells. Three groups were included in the study, namely the Ctrl (non-transfected control), rAd5 siCtrl (native control) and rAd5-siTrop2 (knockdown Trop2 gene) groups. The mRNA and protein expression levels of Trop2 were detected using quantitative polymerase chain reaction and western blot analysis, respectively. In addition, the expression levels of cyclin Dl and phospho-extracellular signal regulated kinase (p-ERK)-1 were detected using western blot analysis. The effects of Trop2 inhibition on the proliferation and invasion of lung adenocarcinoma H460 cells were investigated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assay. Trop2-targeted siRNA recombinant plasmids were successfully constructed. The recombinant adenovirus vector, rAd5-siTrop2, significantly downregulated the mRNA and protein expression levels of Trop2 in the lung adenocarcinoma H460 cells, with cyclin D1 and p-ERK-1 expression downregulated simultaneously. In addition, following the silencing of Trop2, the proliferation and invasion rates of the lung adenocarcinoma H460 cells were reduced. Therefore, the results indicated that Trop2 serves a key function in the proliferation and invasion of lung adenocarcinoma H460 cells in vitro. PMID- 26622334 TI - High prevalence of diabetic retinopathy and lack of association with integrin alpha2 gene polymorphisms in patients with type 2 diabetes from Northeastern Mexico. AB - Diabetic retinopathy (DR) is one of the primary causes of blindness in the working age population and is characterized by angiogenesis in the retina. Platelets have been suggested to be involved in the pathogenesis of diabetic microvascular complications. The integrin receptor for collagen/laminin, alpha2beta1, mediates platelet primary adhesion to subendothelial tissues, which is an essential first step in thrombus formation. The gene encoding the alpha2 subunit of alpha2beta1 integrin has >=8 polymorphisms, including a BglII/NdeI restriction fragment length polymorphism. To explore the prevalence of DR in a population from Northeastern Mexico, unrelated, hospitalized patients who had received a diagnosis of type 2 diabetes mellitus (DM2) at least 10 years previously were recruited (n=177). DR was diagnosed in a masked manner by independent ophthalmologists using fundus images captured using a non-mydriatic retinal camera. A total of 121 patients with DM2 (68%) had some degree of DR development (DR patients), and 56 patients with DM2 (32%) did not exhibit any sign of DR (No-DR patients). The results showed that after 15 years of DM2 progression, there is an increased risk of DR (P=0.0497; odds ratio, 1.993). In addition, insulin therapy and family history of DM2 were significantly associated with DR. In order to detect a possible association between DR and BglII/NdeI alpha2 gene polymorphisms, a comparative cross-sectional study between DR and No DR patients was conducted. The alpha2 gene was genotyped by polymerase chain reaction-restriction fragment length polymorphism assay. Statistical analysis revealed no association between BglII/NdeI genotypes and the development of DR in this group of patients. In conclusion, the present data indicate a high prevalence of DR in the Mexican population and suggest that the damage in DR is due to other factors, such as the duration of the DM2, and is not linked to BglII/NdeI alpha2 gene polymorphisms. PMID- 26622335 TI - Brainstem edema caused by traumatic carotid-cavernous fistula: A case report and review of the literature. AB - Brainstem edema caused by traumatic carotid-cavernous fistula (TCCF) is rare, and there is little information available regarding its clinical characteristics. The present report describes the case of a 51-year-old man with TCCF, who presented with right exophthalmos and intracranial bruit for 1 week. One month prior to admission at hospital, he fractured the frontal and ethmoid sinuses. Digital subtraction angiography confirmed the diagnosis of TCCF, and magnetic resonance imaging (MRI) suggested edema on the right side of the pons. Five days after admission, the patient exhibited left hemiparesis, and MRI revealed aggravation of the brainstem edema. Following treatment with transarterial balloon embolization, the clinical symptoms, including hemiparesis, were relieved; at the 1-month follow-up, the brain edema had disappeared. The patient was normal at the 6-month follow-up. Following the report of the present case, we reviewed six additional cases previously reported in the literature and discussed the potential mechanisms of TCCF-associated brainstem edema. We conclude that occlusion of the superior petrosal sinus may contribute to brainstem edema caused by TCCF. Relief of the brainstem edema and brainstem edema-associated clinical symptoms can be achieved with transarterial coil or balloon embolization of the TCCF to reduce the drainage pressure in the brainstem veins. PMID- 26622336 TI - Biological effects of pyrroloquinoline quinone on liver damage in Bmi-1 knockout mice. AB - Pyrroloquinoline quinone (PQQ) has been demonstrated to function as an antioxidant by scavenging free radicals and subsequently protecting the mitochondria from oxidative stress-induced damage. The aim of the present study was to investigate whether PQQ is able to rescue premature senescence in the liver, induced by the deletion of B cell-specific Moloney MLV insertion site-1 (Bmi-1), by inhibiting oxidative stress. In vivo, the mice were allocated into three groups that underwent the following treatment protocols. WT mice received a normal diet, while BKO mice also received a normal diet. An additional group of BKO mice were fed a PQQ-supplemented diet (BKO + PQQ; 4 mg PQQ/kg in the normal diet). The results indicated that PQQ partially rescued the liver damage induced by the deletion of Bmi-1. PQQ was demonstrated to exhibit these therapeutic effects on liver damage through multiple aspects, including the promotion of proliferation, antiapoptotic effects, the inhibition of senescence, the upregulation of antioxidant ability, the downregulation of cell cycle protein expression, the scavenging of reactive oxygen species and the reduction of DNA damage. The results of these experiments indicated that treatment of BKO mice with a moderate dose of PQQ significantly protected the liver from deleterious effects by inhibiting oxidative stress and participating in DNA damage repair. Therefore, PQQ has great potential as a therapeutic agent against oxidative stress during liver damage. PMID- 26622338 TI - Viral encephalitis complicated by acute retinal necrosis syndrome: A case report. AB - Acute retinal necrosis syndrome (ARN) is a viral infection characterized by focal retinal necrosis. Viral meningitis complicated by ARN is relatively rare. In the present case study, a 44-year-old male presented with fever, headache and mental disorder. After four days, the patient developed blurred vision. The patient was diagnosed with viral encephalitis complicated by bilateral ARN, based on the examination results. After treatment with antivirals and systemic glucocorticoids, the symptoms of the patient improved. Viral encephalitis may be an important risk factor for ARN. For a patient with viral encephalitis who experiences decreased visual acuity or vitreous opacification, the possibility of ARN should be considered. PMID- 26622337 TI - Acute myocarditis mimicking ST-elevation myocardial infarction: A case report and review of the literature. AB - The present study describes the case of a young man aged 22 who had acute retrosternal pain, elevated cardiac markers and electrocardiographic ST-T changes, which led to an original misdiagnosis of acute myocardial infarction. The patient underwent immediate coronary angiography, which revealed normal coronary arteries. Finally, the diagnosis of viral myocarditis was made on consideration of his fever, scattered red dots on his arms and legs and other auxiliary examination results obtained in the following days, which were supportive of the diagnosis. The patient improved on antiviral and myocardial protection therapy and was discharged 2 weeks later. Viral myocarditis is a common disease with a variable natural history. It remains challenging for doctors to differentiate between acute myocarditis and myocardial infarction, particularly in the early stages. A diagnosis of myocarditis should be made on the basis of synthetic evaluation of the evidence, including medical history, clinical presentation and results of the available auxiliary tests, in order to provide guidelines for treatment. PMID- 26622339 TI - Human adipose-derived mesenchymal stem cells repair cisplatin-induced acute kidney injury through antiapoptotic pathways. AB - Cisplatin has been hypothesized to induce nephrotoxicity through triggering the apoptosis of tubular cells; however, the drug remains widely administered for the treatment of tumors. Recently, mesenchymal stem cells (MSCs) have been demonstrated to protect the kidney from the adverse effects induced by cisplatin. The aim of the present study was to investigate the mechanisms underlying the protective effects of human adipose-derived MSCs (AD-MSCs) on kidney function and tubular cells. Sprague-Dawley rats were divided into three groups, which included the healthy controls, those subjected to cisplatin-induced acute kidney injury (AKI) for 24 h without subsequent treatment and those subjected to cisplatin induced AKI for 24 h, followed by AD-MSC engraftment. The rats were sacrificed at day 5 and the effects were analyzed using various methods, including biochemical analysis, structural examination and cell tracking experiments. In addition, an in vitro experiment with NRK-52E cells was performed. The cells were divided into three groups, including the healthy control, cisplatin induction and cisplatin induction with co-culture of AD-MSCs, and were subsequently assessed with a Transwell assay. After culture for four days, the cells were lysed and the total protein extract was subjected to western blot analysis. Cisplatin-induced renal dysfunction and tissue damage was shown to recover following AD-MSC infusion, although there were few AD-MSCs observed around the injured kidney tubules in the kidney. When the cisplatin-treated NRK-52E cells were co-cultured with AD-MSCs, the activation of p38 and BAX were inhibited, while the expression of Bcl-2 was upregulated, as compared with the cisplatin-treated NRK-52E cells that were not co-cultured. Therefore, AD-MSCs were shown to markedly improve cisplatin-induced renal failure and tubular cells necrosis through the secretion of certain factors, which subsequently inhibited the apoptosis pathway in vitro. It was hypothesized that AD-MSC secretion was triggered by the injured tubular cells. Thus, AD-MSCs may be important for the therapy of patients with renal injury due to their antiapoptotic capacity. PMID- 26622340 TI - Effect of autologous platelet-rich plasma on the chondrogenic differentiation of rabbit adipose-derived stem cells in vitro. AB - This study aimed to isolate rabbit adipose-derived stem cells (ADSCs) and explore the potential of platelet-rich plasma (PRP) in the chondrogenic differentiation of ADSCs, thereby potentially providing a new approach for the repair and regeneration of cartilage injury. Rabbit ADSCs were isolated and characterized by induction towards adipogenic, osteogenic and chondrogenic lineages in vitro. The isolated ADSCs were also cultured with or without 10% PRP. Immunofluorescence staining, toluidine blue staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to detect type II collagen (Col II) and aggrecan (AGC) expression. Col II immunofluorescence staining and toluidine blue staining indicated that following induction by autologous PRP, ADSCs manifested Col II and AGC expression. The expression of Col II and AGC mRNA was significantly upregulated in the PRP-treated cells when compared with that in control cells. Autologous PRP produced by laboratory centrifugation was able to promote the chondrogenic differentiation of rabbit ADSCs in vitro. PMID- 26622341 TI - Factors affecting sphincter-preserving resection treatment for patients with low rectal cancer. AB - The aim of the present study was to identify the factors associated with the use of sphincter-preserving resection (SPR) surgery for the treatment of low rectal cancer. A total of 330 patients with histopathologically confirmed low rectal cancer were divided into two groups, namely the abdominoperineal resection (APR) and sphincter-preserving (SP) groups. For SPR factor analysis, the chi2 test was performed as the univariate analysis, while a logistic regression test was conducted as the multivariate analysis. Of the 330 patients, 192 cases (58.18%) received SPR surgery and 138 cases (41.82%) underwent an APR. Univariate analysis results revealed that the sphincter-preserving factor was significantly associated with age, gender, ethnicity, body mass index (BMI), total infiltrated circumference, distance of the tumor from the anal verge (DTAV), depth of invasion and tumor grade (P<0.05). However, there were no statistically significant associations with family medical history, diabetes history, venous tumor embolism, growth type, tumor length, lymphatic metastasis and level of preoperative carcinoembryonic antigen (P>0.05). Multivariate analysis indicated that the sphincter-preserving factor was strongly associated with DTAV and the depth of invasion, with significant statistical difference (P<0.05). Therefore, selecting SPR surgery for patients with low rectal cancer is dependent on age, gender, ethnicity, BMI, the total infiltrated circumference, DTAV, depth of invasion and tumor grade. In addition, DTAV and the depth of invasion are independent risk factors for the selection of SPR surgery. PMID- 26622342 TI - Interleukin-17A promotes the formation of inflammation in the lung tissues of rats with pulmonary fibrosis. AB - The aim of the present study was to investigate the effects of interleukin (IL) 17A in a rat model of pulmonary fibrosis. In total, 20 female Wistar rats were randomly divided into a normal saline (NS group) and a bleomycin group (BLM group). The BLM group rats were intratracheally instilled with BLM, while the NS group rats were intratracheally instilled with saline. In each group, half the rats were sacrificed at day 7 and day 28, respectively, following intratracheal instillation. Subsequently, hematoxylin and eosin and Masson's trichrome staining were performed to observe the pathological changes in the lung tissue, while the expression of IL-17A in the lung tissue was detected by immunohistochemistry. In addition, the bronchoalveolar lavage fluid (BALF) was collected and divided into two sections. One section was used for cell counting and classification, and an ELISA was performed to detect the concentration of IL-17A in the BALF. The additional section was used to separate, purify and cultivate alveolar macrophages (AMs). The concentration of IL-17A in the cultivating supernatant was detected by ELISA, and the mRNA expression levels of IL-17A in the AMs were detected using reverse transcription-polymerase chain reaction (RT-PCR). The results revealed that a considerable number of inflammatory cells had infiltrated into the alveolar cavity in the BLM group at day 7, and less alveolitis and more serious fibrosis were observed at day 28, as compared with the NS group. Furthermore, when compared with the NS group, the protein expression levels of IL 17A in the lung tissue were markedly higher in the BLM group at days 7 and 28 (higher at day 7; P<0.05). In addition, the total number of BALF cells in the BLM group was clearly higher at day 7 when compared with the NS group (P<0.05), although a normal level was re-established by day 28. The level of IL-17A in the BALF increased significantly at days 7 and 28 in the BLM group; however, when compared with the level at day 7, the concentration had decreased at day 28. When compared with the NS group, the protein expression levels of IL-17A in the BLM group were notably higher after 12, 24 and 48 h. In addition, the results of the RT-PCR assay revealed that the mRNA expression levels of IL-17A increased significantly at days 7 and 28 in the BLM group when compared with the NS group (P<0.05). Therefore, IL-17A was demonstrated to promote the development of pulmonary inflammation, which may be involved in the development of pulmonary fibrosis. PMID- 26622343 TI - Methylation of Werner syndrome protein is associated with the occurrence and development of invasive meningioma via the regulation of Myc and p53 expression. AB - The aim of the present study was to investigate the positive rate of Werner syndrome protein (WRN) methylation in meningioma patients, and further assess the association between WRN methylation and the occurrence of meningioma. A total of 56 consecutive meningioma patients and 26 healthy individuals were enrolled in the study. A methylation-specific polymerase chain reaction assay was performed to detect the positive rate of WRN methylation in the peripheral blood and tissue samples collected from the recruited subjects. In addition, western blot analysis was performed to determine the protein expression levels of WRN, Myc and p53 in the peripheral blood and tissue samples. The positive rate of WRN methylation in the peripheral blood of the meningioma group was increased when compared with the control group (P<0.05). In addition, the protein expression levels of WRN were significantly decreased in the peripheral blood and tissue samples collected from the individuals with a positive WRN methylation status (P<0.05), as compared with the samples without WRN methylation. Furthermore, the protein expression levels of Myc and p53 were increased in the peripheral blood and tissue samples that exhibited positive WRN methylation when compared with those without WRN methylation (P<0.05). Therefore, WRN methylation was demonstrated to be associated with the occurrence and development of invasive meningioma, possibly through the regulation of Myc and p53 expression. PMID- 26622344 TI - Silibinin attenuates methotrexate-induced pulmonary injury by targeting oxidative stress. AB - The aim of the present study was to assess the protective effect of silibinin against methotrexate (MTX)-induced pulmonary toxicity. Rats were divided into four groups (MTX, MTX + silibinin, silibinin and control. MTX was injected intraperitoneally (i.p) into female Wistar rats (10 mg/kg/day for 3 days), which resulted in significant increases in the serum levels of alanine aminotransferase, aspartate aminotransferase and oxidant enzymes, including nitric oxide and myeloperoxidase. Furthermore, significant reductions were detected in the serum activity levels of the antioxidative enzymes, glutathione peroxidase and superoxide dismutase, when compared with the control group. However, administration of silibinin (100 mg/kg/day for 10 days, i.p.) was shown to ameliorate the MTX-induced pulmonary toxicity, as indicated by the normalization of the oxidative stress parameters. Furthermore, silibinin treatment was demonstrated to reduce the histopathological changes associated with MTX. In conclusion, silibinin exhibited protective effects against MTX induced pulmonary toxicity, which may be attributed to its antioxidant activity. PMID- 26622345 TI - Clinical application of computed tomographic angiography in patients with renal arterial hemorrhage: Diagnostic accuracy and subsequent therapeutic outcome. AB - The aim of the present study was to determine the accuracy of multi-section computed tomographic angiography (CTA) for the diagnosis of renal arterial h=emorrhage in comparison with digital subtraction angiography (DSA) and the effect of diagnostic outcome on therapeutic patient management. A retrospective analysis was conducted of the records of all patients undergoing DSA for acute renal hemorrhage between August 2005 and June 2014. A total of 74 patients were identified in whom CTA was performed prior to the DSA. DSA detected a renal arterial lesion in 68 cases and no bleeding was demonstrated in 6 cases. CTA correctly identified the bleeding site in 59 of the 68 DSA-positive cases. There were 14 patients with negative CTA results that underwent DSA after 2-10 days because of persistent hematuria, and 9 of them were found to have positive DSA results. The sensitivity, specificity, positive predictive value and negative predictive value of CTA for the detection of arterial lesions in the context of acute renal hemorrhage were 0.868, 0.833, 0.983 and 0.357, respectively. All patients with bleeding sites identified by DSA underwent superselective embolization in a single session. Five patients underwent a secondly embolization for recurrent hemorrhage. These results indicate that CTA is an accurate technique for the detection of major arterial hemorrhage and supports its use in the initial examination of these patients. PMID- 26622346 TI - Ischemic postconditioning attenuates inflammation in rats following renal ischemia and reperfusion injury. AB - Ischemic postconditioning (IPoC) involves a series of brief rapid intermittent ischemic episodes applied at the onset of reperfusion in the previously ischemic tissue or organ. Previous studies have demonstrated that IPoC attenuates tissue damage induced by ischemia and reperfusion (I/R) injury. The aim of the present study was to investigate whether IPoC has a beneficial effect on inflammation in a rat model of renal I/R injury. Wistar rats were subjected to 45 min of ischemia followed by 24, 72 or 120 h of reperfusion (I/R group). In the IPoC group, rats subjected to I/R were treated with six cycles of 10 sec reperfusion followed by a 10-sec ischemic episode. Blood samples were collected for the determination of blood urea nitrogen (BUN) and creatinine (Cr) levels. Furthermore, histological examination and immunohistochemical staining for the localization of nuclear factor-kappaB (NF-kappaB) were performed. In addition, quantitative polymerase chain reaction (qPCR) analysis was used to determine the expression levels of intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), while western blot analysis was used to detect the protein expression levels of NF-kappaB. The results indicated that the BUN and Cr levels increased significantly in the I/R group, while the IPoC rats showed evidently reduced renal damage. Immunohistochemical analysis revealed that the expression levels of NF-kappaB were decreased by IPoC. In addition, the qPCR results revealed that IPoC significantly inhibited the increased mRNA expression levels of ICAM-1, IL-6 and TNF-alpha, induced by I/R injury. Western blot analysis indicated that the expression levels of NF-kappaB were upregulated in the I/R group, while IPoC was shown to inhibit the expression. In conclusion, IPoC was demonstrated to exhibit potent anti-inflammatory properties against renal I/R injury. PMID- 26622347 TI - Clinical characteristics and treatment outcome of Stevens-Johnson syndrome and toxic epidermal necrolysis. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are erythematous skin lesions with blister formation accompanied by mucosal involvement. These conditions are considered to be life-threatening illnesses. Understanding the clinical presentation, risk factors, treatment options and results will be advantageous for physicians in the management of patients in the future. The aim of the present study was to review and analyze the clinical manifestations, drug implications, treatment and outcome of patients with SJS and/or TEN who had been hospitalized in a tertiary care center. All hospitalized patients with SJS and/or TEN during a 5-year period were retrospectively reviewed. The clinical severity was graded according to the score of toxic epidermal necrolysis (SCORTEN) scale. Clinical symptoms, diagnosis, possible precipitating factors, management and outcome data were collected for analysis. A total of 43 patients (mean age, 49.5 years) were hospitalized and classified into the SJS group (55.8%), SJS/TEN overlap group (20.9%) and TEN group (23.3%). The majority of the patients (90.7%) had mucocutaneous eruptions associated with oral drug administration. Allopurinol, anticonvulsants and antibiotics were the most common causative agents for the mucocutaneous eruption. Twenty-eight patients (65.1%) were treated with corticosteroids. The mortality rate was 6.9%. Comparison between the survival group and the non-survival group revealed that patient age >70 years (P=0.014) and body surface area involvement >20% (P<0.01) were the significant factors associated with mortality. The use of systemic steroids was higher in the survival group in comparison with the non-survival group (65.1 vs. 0%, respectively; P=0.014). The mucocutaneous eruptions in SJS and TEN are mostly caused by medication. With early recognition and treatment, the mortality rate in this study was lower than that in previous reports. Patient age and the area of mucocutaneous involvement were significant factors associated with mortality. PMID- 26622350 TI - Effects of IgG anti-GM1 monoclonal antibodies on neuromuscular transmission and calcium channel binding in rat neuromuscular junctions. AB - Guillain-Barre syndrome is a type of acute inflammatory neuropathy that causes ataxia and is associated with the IgG anti-GM1 antibody. However, the pathogenic role of the IgG anti-GM1 antibody and calcium channels in neuromuscular junctions (NMJs) remains unclear. Thus, the aim of the present study was to investigate the effects of the IgG anti-GM1 monoclonal antibody (mAb) on spontaneous muscle action potentials (SMAPs), and the effects of calcium channel blockers, in a rat spinal cord-muscle co-culture system. In addition, the binding of IgG anti-GM1 mAb to calcium channels was investigated in the rat hemidiaphragm. The frequency of SMAPs in the innervated muscle cells was acutely inhibited by the IgG anti-GM1 mAb; however, this effect was blocked by the N-type calcium channel blocker, omega-conotoxin GVIA (30 nM). Furthermore, the P/Q-type calcium channel blocker, omega-agatoxin IVA (10 nM), was found to partially block the IgG anti-GM1 mAb induced inhibitory effect in the spinal cord-muscle co-culture system. Immunohistochemical analysis of the rat hemidiaphragm indicated that IgG anti-GM1 mAb binding overlapped with anti-Cav2.2 (alpha1B) antibody binding in the nerve terminal. In addition, IgG anti-GM1 mAb binding partially overlapped with anti Cav2.1 (alpha1A) antibody binding. Thus, the results demonstrated that the IgG anti-GM1 mAb binds to calcium channels in the nerve terminals of NMJs. Therefore, the inhibitory effect of IgG anti-GM1 mAb on SMAPs may involve N-type and P/Q type calcium channels in motor nerve terminals at the NMJ. PMID- 26622349 TI - Diagnosis of an aneurysmal bone cyst of the cricoid cartilage: A case report. AB - An aneurysmal bone cyst (ABC) is a type of reactive reparative bone neoplasm that rarely occurs in the head and neck. To date, only a small number of cases have been previously reported. The present study reports the case of a 58-year-old male who presented with a tumor in the laryngeal cricoid cartilage, a rare position for a tumor, who subsequently underwent treatment by surgical resection. Based on the observations of the present study and a literature review, it was concluded that an ABC of the larynx can be identified based on a combination of radiology and postoperative histopathology examinations. However, following a tracheotomy and excision, the difficulty of performing tracheal cannula removal is inevitable. The present study described in detail a rare disease, ABC, occurring in the larynx. More cases are required for follow-up studies. PMID- 26622348 TI - Resveratrol relieves ischemia-induced oxidative stress in the hippocampus by activating SIRT1. AB - Resveratrol, a naturally occurring phytoalexin, acts as an activator of sirtuin 1 (SIRT1) and has been shown to have a neuroprotective role in various models. Healthy adult male Sprague-Dawley rats were subjected to cerebral ischemia in order to study the protective effect of resveratrol on the brain following ischemia, and to investigate the effects of SIRT1 activation on the hippocampus. Untreated and resveratrol-treated rats were anesthetized prior to undergoing surgery to induce middle cerebral artery occlusion followed by reperfusion. SIRT1 expression was evaluated by immunohistochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction, and SIRT1 activity was also evaluated. In addition, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Nissl staining assays were conducted and the levels of reactive oxygen species were determined. It was observed that resveratrol significantly decreased the number of TUNEL-positive cells and increased the expression of SIRT1 mRNA in a dose-dependent manner. This was accompanied by increases in SIRT1 protein expression levels and SIRT1 activity. The results demonstrate the neuroprotective and antioxidant effects of resveratrol against ischemia-induced apoptosis in the rat hippocampus. PMID- 26622351 TI - Electroacupuncture at the governor vessel and bladder meridian acupoints improves postmenopausal osteoporosis through osteoprotegerin/RANKL/RANK and Wnt/beta catenin signaling pathways. AB - Previous studies have demonstrated that pretreatment with electroacupuncture (EA) at the zusanli/ST36 and sanyinjiao/SP6 acupoints prevents ovariectomy-induced osteoporosis in rats; however, the therapeutic effects of EA at the governor vessel (GV) and bladder meridian (BL) acupoints remain unclear. In the present study, the effects of EA at the GV4, GV6, BL20 and BL23 acupoints on the bones of ovariectomized (OVX) rats were investigated to identify the pathways that mediate the action of EA on the bones. A postmenopausal osteoporosis model was established by performing an ovariectomy in six-month-old female Sprague Dawley rats. Following the ovariectomy, EA treatment was administered once per day for 90 days, with an interval of 5 days per 10 days. The changes in the serum levels of estradiol (E2) and the bone turnover markers, osteocalcin (OC) and tartrate resistant acid phosphatase 5b (TRACP 5b), were determined, while the bone mineral density (BMD) of the lumbar vertebra and the histomorphology of the femur were observed. Furthermore, the expression of osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL), which are involved in the OPG/RANKL pathway, were detected by ELISA. In addition, the protein expression levels of low-density lipoprotein receptor-related protein (LRP) 5, beta-catenin and runt-related transcription factor (Runx) 2, which are involved in the Wnt/beta-catenin signaling pathway, were detected by western blot analysis. The results revealed that the GV and BL EA treatment groups significantly increased the serum levels of E2 and OC, decreased the serum levels of TRACP 5b and increased the BMD of the lumbar vertebra when compared with the OVX group. With regard to the histomorphology of the bone tissue, an ordered arrangement and a slight thinning of the trabeculae, with no evident hairline fractures, was observed in the femurs following EA treatment in the OVX rats. Furthermore, histomorphological analysis revealed that EA treatment significantly increased the values of the bone histomorphometry indices, trabecular area percentage, trabecular thickness and trabecular number, and reduced the value of trabecular separation, as compared with the OVX group. In addition, the ratio of OPG/RANKL expression was significantly upregulated, and the expression levels of LRP5, beta catenin and Runx2 were significantly upregulated in the EA treatment groups. Therefore, these results demonstrated that long-term stimulation with EA treatment at the GV and BL acupoints was able to alleviate osteoporosis induced by an ovariectomy through regulating the OPG/RANKL and Wnt/beta-catenin signaling pathways. PMID- 26622352 TI - Expression and significance of annexin A2 in patients with gastric adenocarcinoma and the association with E-cadherin. AB - Annexin A2 is a calcium-dependent phospholipid-binding protein, involved in invasion, angiogenesis and migration in cancer cells. The aims of the present study were to evaluate the expression levels of annexin A2 and E-cadherin in gastric adenocarcinoma (GAC), and to investigate the association between the expression of annexin A2 and that of E-cadherin and Ki67, in addition to various clinicopathological factors. This study included 126 patients that were histopathologically diagnosed with GAC. Tissue samples were acquired by surgical resection, and annexin A2 mRNA expression levels were determined using reverse transcription-quantitative polymerase chain reaction. Annexin A2, E-cadherin and Ki67 protein expression levels were detected using western blot analysis and/or immunohistochemical staining. The expression of annexin A2 mRNA and protein was significantly upregulated in the GAC tissues. Annexin A2 expression was detected in 52/126 cases (41.3%) of gastric cancer (GC), and correlations were identified between annexin A2 expression and Tumor, Node, Metastasis (TNM) stage (P=0.002), lymph node metastasis (P=0.016) and distal metastasis (P=0.005). The positive expression rates of E-cadherin and Ki67 in the tumor tissue of patients with GAC were 27.8% (35/126) and 56.2% (71/126), respectively. A negative correlation was observed between the expression of annexin A2 and E-cadherin (P<0.001). No significant association was detected between the expression levels of annexin A2 and Ki67 (P=0.801). In conclusion, upregulated annexin A2 expression was associated with lymph node metastasis, distal metastasis, advanced TNM stage and E-cadherin expression in patients with GAC. The association between the expression of annexin A2 and that of E-cadherin may indicate an underlying mechanism by which annexin A2 contributes to the metastasis in GC, and thus annexin A2 may represent a potential target for the treatment of GAC. PMID- 26622353 TI - Polycythemia vera associated with IgA nephropathy: A case report and literature review. AB - A case of polycythemia vera (PV) associated with immunoglobulin A nephropathy (IgAN) in a 57-year-old man is described. The patient had a mild enlargement of the kidneys and elevated serum creatinine level, whereas the glomerular filtration rate was normal. Pathological observation under a light microscope showed mild mesangial hyperplasia. The urinary protein level was found to be positively correlated with changes in blood cell counts. After controlling blood pressure, anti-platelet, hydroxyurea treatment, the patient's proteinuria decreased and renal function remained in the normal range. PV associated with renal disease is rare and generally considered to be associated with hypervolemia or high-viscosity-induced renal hyperperfusion and hyperfiltration. This is a rare case of PV associated with IgAN without a high filtration rate. A review of the clinical features of PV associated with renal disease from previous literature was also conducted. The histological results of the cases varied and included IgAN, focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis. PMID- 26622354 TI - Premature rupture of the fetal membrane combined with subclinical chorioamnionitis negatively affects pregnancy outcomes by a mechanism associated with reduced levels of matrix metalloproteinase-2. AB - The present study aimed to investigate whether premature rupture of the fetal membrane, combined with subclinical chorioamnionitis, affects pregnancy outcomes. In addition, the association between premature rupture of the fetal membrane (PROM) and the levels of matrix metalloproteinase-2 (MMP-2), an inactive proenzyme that can be activated by other factors or signals in humans, was examined. In total, 80 pregnant patients with PROM were classified into the experimental and control groups, according to their final placental pathological diagnosis results. The 40 patients in the experimental group suffered from subclinical chorioamnionitis, while the 40 patients in the control group exhibited no lesions of the placenta or fetal membrane. Tissue samples were collected and the total protein and mRNA were extracted for western blot and quantitative polymerase chain reaction analyses. ELISA was performed in order to detect the levels of MMP-2 in the serum of the two groups of patients. The rates of cesarean section, puerperal infection, postpartum hemorrhage, preterm incidence, placenta accreta, residual placental blood and stillbirth were all significantly higher in the experimental group compared with the control group. In addition, the mRNA and protein expression levels of MMP-2 were reduced in the experimental group compared with the control group. ELISA results indicated that the serum MMP-2 concentrations were also reduced in the patients with PROM. Therefore, the present study demonstrated that the PROM, combined with subclinical chorioamnionitis, significantly affected pregnancy outcomes and was associated with reduced levels of MMP-2. PMID- 26622355 TI - Hemoglobin discriminates stages of chronic kidney disease in elderly patients. AB - The prevalence of chronic kidney disease (CKD) increases with age, and anemia is known to affect the outcome of subjects with CKD. However, little is known with regard to the associations between metabolic complications and stages of CKD among elderly patients. Thus, the aim of the present study was to investigate the prevalence of CKD in elderly Chinese patients, as well as the associations between stages of CKD and clinically important complications of anemia. In total, 2,258 individuals with CKD, divided into younger (n=989) and elderly (n=1,269) groups, were enrolled in the study between June 2009 and December 2011. The glomerular filtration rate (GFR) was assessed using a 99mTc-DTPA renal dynamic imaging method (modified Gate's method). The levels of serum creatinine (SCr) and hemoglobin (Hb), and the hematocrit (HCT) were measured simultaneously per manufacturer's instructions. In the elderly group, the levels of SCr and proportional ratios were higher, while the GFR, Hb level, HCT and proportional ratios were lower when compared with the values in the younger group. Statistically significant differences were observed in the Hb concentrations when comparing individuals classified with different stages of CKD in the younger and elderly groups. In the younger group, there was no significant difference in the Hb concentrations between the stage 3a and 3b CKD patients. However, in the elderly group, the Hb concentrations were significantly higher in patients classified with stage 3a CKD when compared with those with stage 3b, whose GFR cutoff point was <60 ml/min/1.73 m2. In conclusion, the results indicated that Hb levels may be used to discriminate stages of CKD in elderly patients; thus, Hb may be used as a biomarker to assess the severity of CKD. PMID- 26622356 TI - Pharmacodynamic study of 131I-labeled CA215 antibody on an animal model of estrogen-resistant OC-3-VGH ovarian cancer. AB - The aim of the present study was to explore the inhibitory effect of 131I-labeled ovarian cancer antigen 215 (131I-CA215) antibody on human OC-3-VGH ovarian cancer. A subcutaneous transplanted tumor model of estrogen-resistant human OC-3 VGH ovarian cancer in nude mice was established. The model mice were randomly divided into seven groups, which were the negative control (NC), positive control (PC; 60 mg/kg cyclophosphamide), high-dose CA215 antibody (HA; 10 mg/kg), low dose CA215 antibody (LA; 2 mg/kg), high-dose 131I-CA215 antibody (131I-HA; 10 mg/kg + 125 MUCi), medium-dose 131I-CA215 antibody (131I-MA; 6 mg/kg + 75 MUCi) and low-dose 131I-CA215 antibody (131I-LA; 2 mg/kg + 25 MUCi) groups. Each group received intraperitoneal administration for 14 consecutive days. At 24 h after the final administration, the tumor was removed and weighed to calculate the tumor inhibition rate (TIR) and the relative tumor increase rate (T/C). Compared with the NC group, the HA group, as well as the 31I-HA and 131I-MA antibody groups, exhibited significantly inhibited tumor growth. The relative T/C values were 54, 30 and 48%, respectively, and the TIRs were 33.59, 64.89 and 45.80%, respectively. All differences were statistically significant. The difference between the HA and 131I-HA groups also presented statistical significance. CA215 and 131I-CA215 antibodies can markedly inhibit OC-3-VGH ovarian cancer. The high dose 131I-CA215 antibody demonstrated a clear synergetic effect. PMID- 26622357 TI - Effect of quercetin on the proliferation of the human ovarian cancer cell line SKOV-3 in vitro. AB - Quercetin is a hydrophobic agent that demonstrates potential anticancer activity. The aim of the present study was to observe the effects of quercetin on the proliferation and apoptosis of the ovarian cancer cell line SKOV-3, and to provide a foundation for the treatment of ovarian cancer using this agent. Ovarian cancer SKOV-3 cells were treated with quercetin at different doses. The inhibitory effect of quercetin on proliferation was detected using the MTT assay and the inhibition rate was calculated. Cell apoptosis was determined using Hoechst staining, and western blot analysis was used to analyze changes in the expression levels of survivin protein. The effects of quercetin on the cell cycle and apoptosis of the SKOV-3 cell line were analyzed using flow cytometry. Quercetin inhibited the proliferation of SKOV-3 cells in a time- and dose dependent manner. Furthermore, Hoechst staining showed that quercetin induced SKOV-3 cell apoptosis. The protein expression levels of survivin were reduced as the concentration of quercetin increased. Flow cytometric analysis showed that quercetin caused ovarian cancer SKOV-3 cell cycle arrest in the G0/G1 phase and a significant decrease in the percentage of cells at the G2/M phase; furthermore, the apoptosis rate was observed to increase following quercetin treatment. The results in combination indicated that Quercetin could inhibit the proliferation of ovarian cancer SKOV-3 cells, inhibit cell cycle progression from G0/G1 to G2/M and induce cell apoptosis in vitro. PMID- 26622358 TI - Small interfering RNA targeting receptor for advanced glycation end products suppresses the generation of proinflammatory cytokines. AB - The aim of the present study was to investigate the effect of receptor for advanced glycation end products (RAGE)-specific small interfering (si)RNA on the generation of proinflammatory cytokines in primary rat hepatic stellate cells (HSCs) and hepatic fibrotic (HF) rats. The RAGE-specific siRNA expression vector pAKD-GR126 was constructed, and then transfected into primary rat HSCs. Reverse transcription-quantitative polymerase chain reaction and western blot analyses were conducted to determine the mRNA and protein expression levels, respectively, of RAGE, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in the primary HSCs. In addition, a CCl4-induced Sprague Dawley (SD) rat model of hepatic fibrosis was established, and pAKD-GR126 was injected into the SD rats via the tail vein. Serum TNF-alpha and IL-6 concentrations were determined using radioimmunoassay. The mRNA and protein expression levels of RAGE (mRNA, F=7.791; protein, F=36.513), TNF-alpha (mRNA, F=474.568; protein, F=123.500) and IL-6 (mRNA, F=203.463; protein, F=320.555) in the pAKD-GR126-transfected primary HSCs were significantly reduced compared with those in the control and pAKD-NC groups (P<0.05). Serum TNF-alpha and IL-6 levels in the low-, medium- and high-dose pAKD GR126 treatment groups were reduced compared with those in the fibrotic model group (TNF-alpha, F=416.397; IL-6, F=1,716.659; P<0.05). In summary, the RAGE specific siRNA was able to effectively suppress the generation of the proinflammatory cytokines TNF-alpha and IL-6 in primary rat HSCs and HF rats. PMID- 26622359 TI - Nitric oxide content and apoptosis rate in steroid-induced avascular necrosis of the femoral head. AB - The aim of the present study was to explore the effect on nitric oxide (NO) content and osteocyte apoptosis of steroid-induced avascular necrosis of the femoral head (SANFH) in an animal model of SANFH. A total of 40 Japanese white rabbits, 5 months of age and weighing 2.5+/-0.5 kg, were randomly divided into groups A (hormone + endotoxin group), B (endotoxin + normal saline group), C (normal saline + hormone group) and D (control group). Following the establishment of the model, a blood sample was taken from the heart of each animal and centrifuged; the levels of NO in the serum were detected. The bilateral femoral heads were conventionally dissected, fixed, decalcified and stained with hematoxylin and eosin. Subsequently, the empty bone lacunae were counted under an optical microscope. Changes in osteocyte morphology were observed using electron microscopy and osteocyte apoptosis was detected with a terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The percentage of empty bone lacunae in group A was significantly higher compared with that in groups B, C and D (P<0.01); however, there was no significant difference in percentage among groups B, C and D. The NO content in group A was significantly higher compared with that in groups B, C and D (P<0.01); however, there was no significant difference in NO content among groups B, C and D. The osteocyte apoptosis index in group A was significantly higher compared with that in the other groups (P<0.01); there was no significant difference among groups B, C and D. NO content was positively correlated with osteocyte apoptosis index (r=0.707). Thus, the present study found that NO content and the osteocyte apoptosis index were increased in SANFH, and that they play an important role in SANFH. The content of NO was positively correlated with the osteocyte apoptosis index, indicating that NO induces apoptosis. PMID- 26622360 TI - Mitomycin-C suppresses mucus secretion in an ileal neobladder rat model. AB - The aim of the present study was to investigate the mucus secretion status of mature goblet cells following the application of mitomycin-C (MMC) in ileal neobladder rat models. Bladder substitution models were established in Sprague Dawley rats, which had been divided into five groups, namely the control (sham), normal saline (NS), high-dose MMC (HMMC), low-dose MMC (LMMC) and dehydrated alcohol (DA) groups. To evaluate the total protein concentration and level of sialic acid following the therapy, urine from the rats in each group was collected on days 8, 11 and 14. In addition, to observe the variances between mucus secretion and the ileum goblet cells, immunohistochemistry and hematoxylin and eosin staining were conducted in the different groups on day 17. The results indicated that the ileal neobladder mucosas in the MMC groups were clearly undamaged, as compared with the DA group. Furthermore, the MMC and DA groups were shown to inhibit the proliferation of goblet cells. The concentration of protein and sialic acid in the LMMC group was found to be lower compared with the NS group, while the concentration in the HMMC group was considerably lower. In conclusion, HMMC was demonstrated to evidently reduce the mucin and sialic acid concentration in the urine, without visible damage to the ileal neobladder mucus membrane. Therefore, MMC may provide a novel therapeutic approach for the treatment of certain bladder conditions. PMID- 26622361 TI - Recombinant ING4 suppresses the migration of SW579 thyroid cancer cells via epithelial to mesenchymal transition. AB - Thyroid cancer is a common endocrine malignancy that has rapidly increased in global incidence. Inhibitor of growth 4 (ING4) has been identified in various types of carcinoma; however, to the best of our knowledge, no previous studies have investigated the effects of ING4 on thyroid cancer. In the present study, SW579 thyroid cancer cells were treated with recombinant ING4 protein, and the results confirmed that recombinant ING4 protein was able to reduce the rate of proliferation, increase the rate of apoptosis and inhibit the mobility of SW579 cells. These results were obtained using a colony formation, fluoroscein isothiocyanate/propidium iodide double staining and Transwell assays, respectively. Furthermore, in the western blot analysis assays, ING4 was demonstrated to inhibit the Wnt/beta catenin signaling pathway and epithelial to mesenchymal transition (EMT). Therefore, the present study demonstrated the antitumor activities of recombinant ING4 and identified ING4 could inhibit EMT in thyroid cancer cell. However, additional studies are required to confirm these results in other cell types. PMID- 26622362 TI - Idiopathic basal ganglia calcification presenting as schizophrenia-like psychosis and obsessive-compulsive symptoms: A case report. AB - Idiopathic basal ganglia calcification (IBGC) is a rare neurodegenerative disorder characterized by the deposition of calcium in the brain and variable combinations of movement disorders, gait impairment and neuropsychiatric symptoms. Few reports have described psychiatric manifestations as early symptoms of IBGC. The present study reports the case of a middle-aged man with schizophrenia-like psychosis and obsessive-compulsive symptoms as the first manifestations of IBGC. The response of the patient to olanzapine and fluoxetine suggests that low-dose olanzapine is effective and should be increased cautiously to avoid worsening parkinsonism and that fluoxetine is an effective drug for the treatment of obsessive-compulsive symptoms in IBGC. PMID- 26622363 TI - Estrogen therapy to treat retinopathy in newborn mice. AB - The aim of the present study was to treat retinopathy of prematurity (ROP) with estrogen (E2) so as to elucidate the role of E2 in the pathogenesis of ROP. A total of 120 postnatal 7-day-old (P7) C57BL/6J mice were selected and raised in a high-oxygen environment (75% oxygen) for 5 days, followed by 5 days in normal room air. Different doses of E2 or normal saline (NS) were injected intraperitoneally during different time-periods, and the mice were divided into 14 groups according dose of E2 injection (0.5-1.5 ug/0.05 ml) and dosing time. Blood vessel changes and hyperplasia were evaluated in flat-mounted retina and retinal slices. All mice that were exposed to room air, whether they were administered E2 or NS, showed good vascular development in the flat-mounted retina at P17. No increase in the number of endothelial cell nuclei in the new blood vessels was observed. In ascending order of E2 dose the numbers of cell nuclei were as follows: 0.18+/-0.129, 0.28+/-0.086 and 0.55+/-0.110. The number in the NS group was 2.12+/-0.373. When the results of the room-air groups were compared with those of the hyperoxia groups, a highly significant difference was found in each comparison (P<0.0001). All mice showed varying degrees of neovascularization and vascular obstruction in the flat-mounted retina at P17, and it was difficult to compare the blood vessels morphologically among these groups. The number of endothelial cell nuclei decreased following E2 injection, and the difference from the NS group exposed to hyperoxia was highly significant (P<0.0001). For all dose levels, the number of cell nuclei was the lowest when the drug was administered during P7-16, and the difference from the other two time-periods was statistically significant (P<0.05). When E2 was administered during P7-16, the number of cell nuclei was 15.5+/-1.993 in the 0.5-ug group, 14.23+/-2.49 in the 1.0-ug group and 18.05+/-1.62 in the 1.5-ug group. No significant difference was found among these three groups (P>0.05). In conclusion, E2 treatment during the development of retinopathy can improve symptoms in neonatal mice, suggesting that E2 plays an important role at the two initial stages in the pathogenesis of ROP. This may indicate new pharmacological measures to prevent and treat ROP. PMID- 26622364 TI - Effect of bone marrow stem cell mobilisation on the expression levels of cellular growth factors in a rat model of acute tubular necrosis. AB - The aim of the present study was to observe the mobilisation effects of stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) on bone marrow stem cells (BMSCs) in rats with renal ischaemia-reperfusion injury. In addition, the effects of the BMSCs on the expression levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) were investigated, with the aim to further the understanding of the protective mechanisms of SCF and G-CSF in renal ischaemia-reperfusion injury. The model and treatment groups were established using a model of unilateral renal ischaemia-reperfusion injury, in which the treatment group and the treatment control group were subcutaneously injected once a day with 200 ug/kg SCF and 50 ug/kg G-CSF, 24 h after the modelling, for five consecutive days. The CD34+ cell count was measured in the peripheral blood using flow cytometry. The mRNA expression levels of HGF and EGF were determined using polymerase chain reaction analysis, while the protein expression levels of HGF and EGF were detected using immunohistochemistry. The CD34+ cell count in the peripheral blood of the treatment and treatment control groups was significantly higher compared with that in the model group (P<0.05). However, CD34 expression levels in the cells from the renal tissues of the model and treatment groups were significantly higher compared with that of the control and treatment control groups (P<0.05), with the greatest increase observed in the treatment group. The mRNA and protein expression levels of HGF and EGF in the treatment group were significantly higher compared with the model group (P<0.05). Therefore, the results indicated that a combination of SCF and G-CSF can promote the repair of acute tubular necrosis. This combination, which can mobilise sufficient numbers of BMSCs to migrate back to the injured site, is a key factor in promoting the repair of renal tubular injury. Upregulation of HGF and EGF was also shown to promote the repair of renal tubular injury. PMID- 26622365 TI - Cytotoxicity of the saponin TTB2 on Ewing sarcoma cells. AB - The steroidal saponin TTB2 can be isolated from the n-BuOH extracts of Trillium tschonoskii Maxim. The aim of the present study was to observe whether this saponin exerted any cytotoxic effects on malignant sarcoma cells, and to further investigate the possible underlying molecular mechanisms. The cell viability, cell cycle arrest and phosphorylation of certain important signal molecules in the sarcoma cell line were investigated. It was found that TTB2 inhibited the growth of the Ewing sarcoma cell line and arrested cells in the G2/M and S phases of the cell cycle in a dose- and time-dependent manner. Furthermore, the phosphorylation of extracellular signal-regulated kinase was inhibited by TTB2. In conclusion, the results showed that the saponin TTB2 isolated from T. tschonoskii Maxim exerts anticancer effects and may be a potential candidate for the development of anticancer drugs for use in the treatment of cancer. PMID- 26622366 TI - Evaluation of the effects of Cimicifugae Rhizoma on the morphology and viability of mesenchymal stem cells. AB - Cimicifugae Rhizoma is a traditional herbal medicine used to treat various diseases in Korea, China and Japan. Cimicifugae Rhizoma is primarily derived from Cimicifuga heracleifolia Komarov or Cimicifuga foetida Linnaeus. Cimicifugae Rhizoma has been used as an anti-inflammatory, analgesic and antipyretic remedy. The present study was performed to evaluate the extracts of Cimicifugae Rhizoma on the morphology and viability of human stem cells derived from gingiva. Stem cells derived from gingiva were grown in the presence of Cimicifugae Rhizoma at final concentrations that ranged from 0.001 to 1,000 ug/ml. The morphology of the cells was viewed under an inverted microscope and the analysis of cell proliferation was performed using a Cell Counting kit-8 (CCK-8) assay on days 1, 3, 5 and 7. Under an optical microscope, the control cells exhibited a spindle shaped, fibroblast-like morphology. The shapes of the cells in the groups treated with 0.001, 0.01, 0.1, 1 and 10 ug/ml Cimicifugae Rhizoma were similar to the shapes in the control group. Significant alterations in morphology were noted in the 100 and 1,000 ug/ml groups when compared with the control group. The cells in the 100 and 1,000 ug/ml groups were rounder, and fewer cells were present. The cultures that were grown in the presence of Cimicifugae Rhizoma at a concentration of 0.001 ug/ml on day 1 had an increased CCK-8 value. The cultures grown in the presence of Cimicifugae Rhizoma at a concentration of 10 ug/ml on day 7 had a reduced CCK-8 value. Within the limits of this study, Cimicifugae Rhizoma influenced the viability of stem cells derived from the gingiva, and its direct application onto oral tissues may have adverse effects at high concentrations. The concentration and application time of Cimicifugae Rhizoma should be meticulously controlled to obtain optimal results. PMID- 26622367 TI - Effect of Wujia Shenghua capsule on uterine bleeding following medically-induced incomplete abortion in rats during early pregnancy. AB - The Wujia Shenghua capsule (WSC) is derived from Sheng-Hua-Tang, a well-known traditional Chinese medicine compound prescription that has been widely applied during the postpartum period in Chinese communities for a number of years. The aim of the present study was to investigate the effect of WSC on uterine bleeding following medically-induced incomplete abortion in rats during early pregnancy. Incomplete abortions were induced in Wistar rats during early pregnancy using mifepristone combined with misoprostol. The effects of WSC treatment were investigated in terms of the duration and volume of uterine bleeding, the uterine index and shape, and various hemodynamic indexes. In addition, blood samples were collected to measure the levels of estradiol (E2), fibronectin (FN) and laminin (LM) via a radioimmunoassay or enzyme-linked immunosorbent assay, while the expression levels of FN, estrogen receptor (ER) and progesterone receptor (PR) in the uterine tissues were determined by immunohistochemistry. The in vivo results demonstrated that WSC treatment markedly shortened the duration and reduced the volume of uterine bleeding when compared with the model group. Furthermore, WSC treatment significantly elevated the E2 level in the serum and the expression of the ER and PR in the uterine tissues, while notably decreasing the FN and LM levels in the serum and uterine tissues. In addition, the hemodynamic indexes were shown to improve with WSC treatment. These results demonstrated that WSC exerted an inhibitory effect on the bleeding caused by medical abortion, possibly through modulating the E2, ER, PR, FN and LM levels. PMID- 26622368 TI - Vascular effects and safety of supplementation with shark liver oil in middle aged and elderly males. AB - Shark liver oil (SLO) has long been used as a traditional health food, with a particular benefit for vascular health, in Japan. The aim of this study was to assess the effect of dietary supplementation with SLO on arterial stiffness and peripheral microvascular function in otherwise healthy middle-aged and older males with slightly increased arterial stiffness. A randomized, double-blind, placebo-controlled, parallel study design was used to assign 41 healthy males with a mean age of 59.0+/-4.0 years (range, 45-69 years) to either SLO (n=21) or placebo (n=20) treatment for eight weeks. The effects on arterial stiffness and peripheral microvascular function were assessed by the cardio-ankle vascular index (CAVI) and by measurement of hand blood flow to cutaneous tissues using a laser Doppler perfusion imaging (LDPI) technique, respectively. Although the magnitude of the changes in the CAVI value during the eight-week intervention for the SLO group did not significantly differ from that for the placebo group, the changes in the CAVI value for the former group were significantly associated (r=0.575, P<0.01) with age. It was also found that the LDPI values at week 8 were significantly lowered (P<0.05) compared with the baseline values in the placebo group, while no change was observed in the SLO group, resulting in a significant difference in the changes between the two groups (P=0.002). Neither SLO supplementation-related adverse side-effects nor any abnormal changes in routine laboratory tests, including lipid profiles and anthropometric and haemodynamic parameters, were observed throughout the intervention. SLO may have the potential to safely improve vascular health in middle-aged and elderly males. PMID- 26622369 TI - Protective effects of dexmedetomidine on intestinal ischemia-reperfusion injury. AB - Dexmedetomidine (DEX) has been hypothesized to possess anti-oxidative properties that may mitigate the damage caused by ischemia-reperfusion (IR) injury. The aim of the present study was to examine the effects of DEX on intestinal contractile activity, inflammation and apoptosis following intestinal IR injury. Intestinal IR injury was induced in rats by complete occlusion of the superior mesenteric artery for 60 min, followed by a 60-min reperfusion period. Rats received an intraperitoneal injection of 25 ug/kg DEX at 30 min prior to the mesenteric IR injury. Following reperfusion, segments of the terminal ileum were rapidly extracted and transferred into an isolated organ bath. The contractile responses to receptor-mediated acetylcholine (Ach) and non-receptor-mediated potassium chloride (KCl) were subsequently examined. Nitric oxide (NO) levels were determined and the expression levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, Bax and Bcl-2 were measured using an enzyme-linked immunosorbent assay. The levels of telomerase and caspase-3 were determined using reverse transcription-quantitative polymerase chain reaction. The results indicated that DEX treatment produced a significant reduction in the IR-induced contractile response to Ach and KCl in the intestinal tissue. Furthermore, DEX appeared to significantly ameliorate intestinal IR injury, in addition to reducing the production of NO. Similar reductions were observed in the intestinal expression levels of TNF-alpha and IL-6. In addition, DEX treatment resulted in a reduction in the expression levels of Bax in the intestinal tissues, while increasing those of Bcl-2, in addition to significantly increasing the mRNA levels of telomerase and caspase-3. Therefore, the present study indicated that NO, TNF-alpha and IL-6 may partially contribute to the pathogenesis of intestinal IR injury in addition to the increased expression levels of Bax, Bcl-2, telomerase and caspase-3. These findings suggest that DEX possesses beneficial anti-apoptotic and anti-inflammatory effects in intestinal tissue following bowel injury. PMID- 26622370 TI - gamma-aminobutyric acid transporter-1 is involved in anxiety-like behaviors and cognitive function in knockout mice. AB - The aim of the present study was to investigate the effect of gamma-aminobutyric acid transporter-1 (GAT-1) on the anxiety-like behaviors and cognitive function in knockout mice. In total, 20 adult male mice were divided into two groups, namely the GAT-1 knockout (GAT-1-/-) and wild-type (WT) groups. The open field test, elevated 0-maze (EZM) and Morris water maze were used to evaluate changes in anxiety-like behaviors and cognitive function. Compared with the WT mice, GAT 1-/- mice made more entries and spent a longer time within the central area, traveling a greater distance, during the open field test (P<0.05). The EZM revealed that GAT-1-/- mice spent more time in the open sectors and made more total entries when compared with the WT mice (P<0.01). Observations from the two tests indicated reduced anxiety-like behaviors in the GAT-1-/- mice. During the learning session using a Morris water maze, the latency to find the platform was significantly longer in the GAT-1-/- mice when compared with the WT mice (P<0.01). In addition, during the probe test, the GAT-1-/- mice spent less time in the target quadrant and more time in the opposite quadrant when compared with the WT mice (P<0.01); thus, the cognitive function in the GAT-1-/- mice was impaired. Therefore, the results demonstrated that the anxiety-like behaviors were reduced and cognitive function was impaired in GAT-1 knockout mice, indicating that GAT-1 is involved in anxiety and cognitive functions. PMID- 26622371 TI - Evaluation of discomfort and tolerability to bronchoscopy according to different sedation procedures with midazolam. AB - Patients frequently experience great discomfort during a bronchoscopy for the diagnosis of lung neoplasms. Sedation is generally recommended during bronchoscopy; however, few studies have evaluated the discomfort and tolerability of patients to a bronchoscopy with regard to the administration procedures. The aim of the present study was to evaluate the discomfort and tolerability of patients undergoing a bronchoscopy using different sedation procedures with midazolam. The retrospective survey of sedation during bronchoscopy involved the comparison of two periods: January-March 2012 (first period) and July-September 2012 (second period). A numerical rating score, which ranged between 1 (best) and 5 (worst) according to the subjective view of the patients, was used to rate patient discomfort, pain, sensation, time and tolerability to the bronchoscopy. In the first period, 2.5 mg midazolam was administered prior to the initiation of surgery, and additional doses of midazolam was added in 2.5-mg increments whenever the patient deviated from the target sedation level. In the second period, 2.0 or 3.0 mg midazolam was administered prior to the initiation of surgery, and additional midazolam doses were administered in 1.0-mg increments until the patients were sedated to the target sedation level. In total, 60 and 68 valid responses were obtained in the first and second periods, respectively. The patients in the second period exhibited significantly improved discomfort and pain scores during the bronchoscopy and higher rates of consent to re examination, as compared with the patients in the first period (1.89+/-1.40 vs. 2.78+/-1.52, P<0.001; 1.48+/-1.13 vs. 2.00+/-1.37, P=0.005; 2.45+/-1.62 vs. 3.13+/-1.47, P=0.013, respectively). The amount of midazolam administered was significantly higher in the second period. There were no fatal complications during the bronchoscopy in either period. In conclusion, the present study observed that the administration of additional midazolam in small doses, until the target sedation level is achieved, is a safe procedure that is associated with significantly less discomfort and pain during bronchoscopy and a greater consent to re-examination when compared with the administration of a fixed dose of midazolam. PMID- 26622372 TI - Neutrophil elastase and fetal fibronectin levels as predictors of single-birth prematurity. AB - The aim of this study was to investigate the predictive values (PVs) of neutrophil elastase (NE) and fetal fibronectin (fFN) in cervical secretions for single-birth premature delivery. Samples of cervical secretions were obtained from 144 women with high-risk singleton pregnancies at 20-34 weeks' gestation and premature Creasy scores of >12 points for NE and fFN level testing, and the PVs of the two indicators for premature birth (PB) were retrospectively analyzed. NE and fFN had high negative PVs (NPVs) for PB; the NPV of NE and fFN for delivery 7 days after detection was significantly higher than the positive PV (P<0.01). In addition, the sensitivity of the combined use of NE and fFN levels for PB prediction was high if both were present, and the PB rate of the double-positive group was higher than that of the single-positive group (P<0.01). Clinical intervention could turn the NE and fFN values negative in certain cases; in these cases, the PB rate was significantly lower than that in the sustained-positive group. In conclusion, NE and fFN in cervical secretions could be used as objective predictors of premature delivery, and their combined application could improve the prediction sensitivity. Effective clinical intervention could then reduce the incidence of PB. PMID- 26622373 TI - Efficacy of 3D conformal thoracic radiotherapy for extensive-stage small-cell lung cancer: A retrospective study. AB - The aim of the present study was to evaluate the effect of 3-dimensional conformal thoracic radiotherapy (TRT) on extensive-stage small-cell lung cancer (ES-SCLC). A total of 165 patients with ES-SCLC were enrolled in the present study, including 82 patients receiving chemotherapy combined with TRT (the ChT/TRT group) and 83 patients receiving chemotherapy alone (the ChT group). The overall survival (OS) and progression-free survival (PFS) rates were compared between the ChT/TRT and ChT groups, and the prognostic factors for OS rate were identified. It was found that the patients had a median OS time of 15 months, and 2- and 5-year OS rates of 31.5 and 2.4%, respectively. The 2- and 5-year OS rates were 35.3 and 2.4% in the ChT/TRT group, and 14.5 and 2.4% in the ChT group, respectively (P<0.05). The 1- and 2-year PFS rates were 35.4 and 6.0% in the ChT/TRT group, and 20.5 and 6.0% in the ChT group, respectively (P<0.05). The median PFS was 11 months in the 20 patients receiving TRT at 45 Gy/30 fractions twice daily, and 9 months in the 22 patients receiving TRT at 60 Gy/30 fractions daily (P=0.043). Multivariate analysis revealed that receiving >=4 cycles of chemotherapy (P=0.001) and TRT (P=0.008) were favorable prognostic factors for OS. It was concluded that the addition of TRT improves the OS and PFS rates of patients with ES-SCLC, and TRT administration at 45 Gy/30 fractions twice daily is feasible and tolerable for the treatment of ES-SCLC. Thus, TRT and receiving >=4 cycles of chemotherapy are independent, favorable prognostic factors for OS in patients with ES-SCLC. PMID- 26622374 TI - Changes in the cytokine expression of peripheral Treg and Th17 cells in children with rotavirus enteritis. AB - The aim of the present study was to investigate the changes in the cytokine expression of peripheral regulatory T cells (Treg) and T helper 17 (Th17) cells in children with rotavirus (RV) enteritis. In total, 102 children with RV enteritis were recruited for the observation group, while 30 healthy cases were included in the control group. Peripheral blood samples were collected from the individuals in the two groups, after which flow cytometry was conducted to detect the proportion of Treg and Th17 cells. In addition, ELISA was used to determine the levels of the cytokines, interleukin (IL)-10, transforming growth factor (TGF)-beta, IL-17 and IL-6. When compared with the control group, the proportion of Treg cells and level of TGF-beta in the peripheral blood of the children with RV enteritis were significantly decreased (P<0.05); however, the proportion of Th17 cells and the serum levels of IL-17 and IL-6 in the peripheral blood of children with RV enteritis were significantly increased (P<0.05). In conclusion, the present study identified an imbalance in the proportion of peripheral blood Treg/Th17 cells, and subsequently in the expression of cytokines, in children with RV enteritis. Thus, detecting the proportion of peripheral blood Treg/Th17 cells in children with RV enteritis, or the changes in the levels of serum cytokines, is of clinical significance for further investigation into the pathogenesis of RV enteritis. PMID- 26622375 TI - microRNA-20a enhances the epithelial-to-mesenchymal transition of colorectal cancer cells by modulating matrix metalloproteinases. AB - The mortality rates associated with colorectal cancer (CRC) are high due to metastasis. Epithelial-to-mesenchymal transition (EMT) is a key step in tumor metastasis. The aim of the present study was to investigate the function of microRNA-20a (miR-20a) in EMT. The expression of miR-20a was analyzed in CRC tissues and cell lines using the reverse transcription-quantitative polymerase chain reaction. Plasmids containing miR-20a short hairpin RNA and miR-20a mimics were transfected into SW620 and LS174T cell lines, respectively. Cell counting kit-8, Transwell(r) and wound healing assays were performed to assess the effects of miR-20a on cell proliferation, invasion and migration. EMT markers and matrix metalloproteinases (MMPs) were identified using western blotting. The results showed that increased expression of miR-20a in CRC tissues was associated with tumor invasion and lymph node metastasis (P<0.05). Further experiments indicated that miR-20a-knockdown inhibited the proliferation, invasion and migration of CRC cells, upregulated the expression of vimentin and tissue inhibitor of metalloproteinases-2 (TIMP-2) and downregulated the expression of E-cadherin, MMP 2 and MMP-9. The opposite effects were observed in CRC cell lines overexpressing miR-20a. In conclusion, these results have shown that the upregulation of miR-20a suppresses TIMP-2 expression, which subsequently increases the expression of MMP 2 and MMP-9, thereby promoting the EMT of CRC cells. These findings suggest that miR-20a represents a potential therapeutic target for patients with CRC. PMID- 26622376 TI - Early-stage lupus nephritis treated with N-acetylcysteine: A report of two cases. AB - The oxidative-antioxidative status is closely associated with the progression of systemic lupus erythematosus (SLE), and oxidative stress is customarily found in patients with SLE. N-acetylcysteine (NAC), a typical antioxidant, is reliable and often applied for clinical treatment. Lupus nephritis (LN) is a kidney disorder associated with SLE, but the treatment of LN with antioxidants is rarely documented. The present report describes two cases of early-stage LN that were orally treated with 1,200 mg NAC in addition to the standard therapy with hydroxychloroquine and calcitriol. Following the NAC administration, the glutathione level largely increased while the level of the lipid peroxidation biomarker 8-iso-prostaglandin F2alpha declined in both cases. In addition, the routine blood counts, 24-h urine protein, erythrocyte sedimentation rate and the SLE disease activity index were markedly improved. In conclusion, the present report of two cases has shown that NAC, as an antioxidant, may exert a beneficial effect to modulate the oxidative status in LN; however, the underlying mechanisms require further investigation. PMID- 26622377 TI - Association between hepatitis B virus infection and diabetes mellitus: A meta analysis. AB - Hepatitis B virus (HBV) infection has been shown by certain studies to be associated with diabetes mellitus (DM); however, the results of these studies were controversial. For that reason, a meta-analysis of the literature was performed in order to determine the association between HBV infection and the prevalence of DM more accurately. The PubMed, Embase, Chinese National Knowledge Infrastructure and Wan Fang databases, as well as the Chinese Science and Technology Journal Database, were searched for literature published until June 2014. The reference lists of all relevant articles were also searched. The summary odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were calculated based on a random-effects model. Heterogeneity was assessed using the I2 statistic. Subgroup analyses were conducted based on study type and region for the purpose of assessing the factors that could potentially affect the outcome. A total of 15 eligible studies (in 14 articles) were selected for the meta-analysis, involving 12,974,690 HBV-infected patients and 231,776,232 controls. The OR for the prevalence of DM was 1.33 (95% CI, 1.09-1.62; P=0.005) between the patients with HBV infection and the controls. The subgroup analysis based on study type revealed a significantly higher prevalence of DM in the HBV infected group than that in the control group in both case-control (OR, 1.89; 95% CI, 1.08-3.30; P=0.025) and cross-sectional (OR, 1.41; 95% CI, 1.04-1.90; P=0.027) studies. The subgroup analysis based on region revealed a significantly higher prevalence of DM in the HBV-infected group than in the control group in the Asia-Pacific region (OR, 1.67; 95% CI, 1.08-2.58; P=0.022). Compared with uninfected patients, the pooled results suggest that HBV-infected patients have a higher risk of developing DM; however, given the fact that this is a meta analysis of observational studies, further randomized controlled trials are required in order to reach a more accurate conclusion. PMID- 26622378 TI - Effect of hyperbaric oxygen preconditioning on peri-hemorrhagic focal edema and aquaporin-4 expression. AB - The aim of the present study was to investigate the effect of hyperbaric oxygen preconditioning (HBO-PC) on peri-hemorrhagic focal edema and aquaporin-4 (AQP-4) expression in an experimental intracerebral hemorrhage (ICH) rat model. Sixty-six Sprague Dawley(r) rats were divided into three groups: The sham-surgery group (SHG; n=6); the control group (A-ICH; n=30), in which the rats were injected with autologous blood; and the experimental HBO-PC group (P-HBO; n=30). The rats underwent brain edema and AQP-4 detection at 5 postoperative time-points (24, 48 and 72 h and 5 and 7 days). The water content in the brain tissues of the A-ICH animals was higher than that in the brain tissues of the SHG rats at each time point (P<0.05), and the edema in the P-HBO was significantly more severe 24 and 48 h postoperatively than that at 7 days postoperatively (P<0.05). The difference between the P-HBO and A-ICH was significant at 48 and 72 h postoperatively (P<0.05). AQP-4 was expressed in the post-hemorrhagic rat brains of all groups; the SHG animals exhibited low expression, while the A-ICH animals exhibited an increased expression 24 h postoperatively. In the A-ICH, expression peaked at 48 h postoperatively and began to decrease gradually after 72 h. At the 7-day time point, the expression level in the A-ICH was closer to but still higher than that of the SHG animals (P<0.05). The differences between the P-HBO and A-ICH animals at the postoperative 24-h, 48-h and 7-day time-points were statistically significant (P<0.05). In conclusion, HBO-PC may downregulate AQP-4 expression to reduce the intracerebral edema, thus strengthening tolerance to ICH and protecting the nerves. PMID- 26622379 TI - Improvement of liver function by the administration of oyster extract as a dietary supplement to habitual alcohol drinkers: A pilot study. AB - Alcoholic liver disease (ALD) is characterized by elevated serum gamma glutamyltransferase (GGT) activity with hepatic steatosis, hepatitis or occasionally fibrosis that may progress to cirrhosis. The potential therapeutic role of oyster extract (OE) or OE-containing dietary supplements (OE supplement) in ALD has seldom been evaluated. In the present study, 84 adults who had an alcohol-drinking habit and marginally high serum GGT levels were enrolled in a randomized, double-blind, placebo-controlled feeding trial to study the effect on alcohol-impaired liver function as reflected by an increased serum level of GGT, as well as the safety, of an OE supplement. The subjects were randomized to receive either an OE supplement (OE group) or placebo (placebo group). There were 42 subjects (31 males and 11 females) in each group, and all the enrolled subjects entered the study. Four individuals (5%) dropped out for reasons unassociated with the study and 6 other subjects were excluded from the efficacy analysis because they did not maintain the required frequency of alcohol intake. As a result, 38 subjects in the placebo group and 36 in the OE group underwent efficacy assessment. Assays of GGT and other liver enzymes were performed at baseline (week 0) and at weeks 4, 8 and 12 of the intervention period. The mean serum levels of GGT in the placebo group gradually increased, while those in the OE group tended to decrease, although no significant within-group differences were observed for either group. A significant between-group difference in the change of mean GGT from baseline was, however, found at week 12 (P=0.049). No OE supplement-associated untoward side-effects nor any abnormal changes in routine laboratory tests and anthropometric parameters were observed throughout the 12 week intervention. An OE supplement shows promise in reducing risk factors associated with ALD in adults with an alcohol intake habit. PMID- 26622380 TI - Genomic and proteomic investigation of preeclampsia. AB - The aim of this study was to use proteomic and transcriptomic approaches to examine differences in protein and gene expression in maternal plasma between normal and preeclamptic pregnancies. Preeclampsia and control groups were compared with respect to the expression of CD34 and CD133 genes by quantitative polymerase chain reaction (qPCR) and heat shock protein (Hsp)27 and 70 by western blotting in blood samples from the pregnant women. Blood samples were obtained at gestational week 12-14 from 65 healthy pregnant women. Fetal DNA was isolated from the maternal blood and CD34 and CD133 were amplified by qPCR. Western blot analysis was used to examine the expression levels of Hsp27 and Hsp70 proteins. The analysis of CD133 by qPCR was unsuccessful in 7 women as the levels of fetal DNA were in the collected maternal blood samples were insufficient. Measurements of CD34 and CD133 were performed in 57 and 50 women, respectively. Preeclampsia developed in 6 (10.5%) of 57 women. qPCR results of 8 healthy pregnant women were used for the calibration of CD34 and CD133 levels, and the results for the remaining women were compared with the calibration values. CD34 expression was decreased in 30 (52.6%) and increased in 27 (47.4%) of 57 women. CD133 expression was decreased in 14 (28%) and increased in 36 (72%) of 50 women. CD34 expression was increased in 2 (33%) and 25 (49%) and decreased in 4 (66%) and 25 (51%) women with and without preeclampsia, respectively (P=0.467). CD133 expression was increased in 4 (66%) and 32 (72%); and decreased in 2 (33%) and 12 (28%) women with and without preeclampsia, respectively (P=0.756). Western blotting showed that the expression of Hsp27 and Hsp70 in the maternal serum of the preeclampsia group was significantly higher than that in the normal pregnancy group. CD34 and CD133 were found to be inadequate for use in the prediction of preeclampsia. However, it is noteworthy that CD133 levels were increased in 66 and 72% of women with and without preeclampsia, respectively. Hsps are expressed under various pathological conditions. These results suggest that conditions of oxidative stress increased the Hsp27 and Hsp70 protein levels. PMID- 26622381 TI - microRNA-18a regulates gastric carcinoma cell apoptosis and invasion by suppressing hypoxia-inducible factor-1alpha expression. AB - Hypoxia is associated with various pathophysiological events, including cancer, lung and cardiovascular diseases. A number of studies have indicated that alterations in microRNA (miRNA) expression may be involved in the regulation of the cellular response to hypoxia. In the present study, miR-18a expression was revealed to be markedly downregulated under hypoxic conditions in MGC-803 and HGC 27 gastric carcinoma cell lines. Furthermore, miR-18a was demonstrated to affect the rate of cell apoptosis and the cell invasion ability in MGC-803 and HGC-27 cells under hypoxic conditions. Cell apoptosis was were analyzed using flow cytometry and cell invasiveness was evaluated using a Transwell-matrigel assay. The results showed that miR-18a overexpression was able to promote cell apoptosis and inhibit cell invasion. Using bioinformatic analysis, hypoxia-inducible factor (HIF)-1alpha was identified as one of the target genes of miR-18a, and based on the function of HIF-1alpha in hypoxia, miR-18a was predicted to regulate HIF 1alpha expression. This hypothesis was confirmed by a further luciferase assay and the detection of the mRNA and protein expression levels of HIF-1alpha following the induction of miR-18a overexpression. In addition, the expression levels of mitochondrial apoptosis-associated genes were detected following the induction of miR-18a overexpression. In the cells overexpressing miR-18a, the Bcl 2 protein expression level was downregulated, while the protein expression levels of Bax, caspase 3 and caspase 9 were upregulated in the MGC-803 and HGC-27 cell lines. Therefore, miR-18a was hypothesized to induce apoptosis through the HIF 1alpha/mitochondrial apoptosis pathway. PMID- 26622382 TI - A rare case of focal nesidioblastosis causing adult-onset hypoglycemia. AB - Nesidioblastosis is a major cause of persistent hyperinsulinemic hypoglycemia of infancy and is caused by hypertrophy of the pancreatic endocrine islands. The disease can be categorized histologically into diffuse and focal forms. The condition rarely occurs in adults and only one adult case of suspected, but not histologically confirmed, focal nesidioblastosis has been reported. The present study describes the case of a 62-year-old man suffering from symptomatic hypoglycemia for 3 years and exhibiting a nodule in the pancreatic tail. Pathological evaluation following surgical enucleation of the pancreatic body and tail revealed focal nesidioblastosis. The hypoglycemic symptoms of the patient disappeared postoperatively. To the best of our knowledge, this is the first histologically-confirmed case of focal adult nesidioblastosis, suggesting that the possibility of nesidioblastosis should be taken into account in adult patients with persistent hypoglycemia. PMID- 26622383 TI - Hydrogen-rich saline promotes motor functional recovery following peripheral nerve autografting in rats. AB - Despite the application of nerve grafts and considerable microsurgical innovations, the functional recovery across a long peripheral nerve gap is generally partial and unsatisfactory. Thus, additional strategies are required to improve nerve regeneration across long nerve gaps. Hydrogen possesses antioxidant and anti-apoptotic properties, which could be neuroprotective in the treatment of peripheral nerve injury; however, such a possibility has not been experimentally tested in vivo. The aim of the present study was to investigate the effectiveness of hydrogen-rich saline in promoting nerve regeneration after 10-mm sciatic nerve autografting in rats. The rats were randomly divided into two groups and intraperitoneally administered a daily regimen of 5 ml/kg hydrogen-rich or normal saline. Axonal regeneration and functional recovery were assessed through a combination of behavioral analyses, electrophysiological evaluations, Fluoro GoldTM retrograde tracings and histomorphological observations. The data showed that rats receiving hydrogen-rich saline achieved better axonal regeneration and functional recovery than those receiving normal saline. These findings indicated that hydrogen-rich saline promotes nerve regeneration across long gaps, suggesting that hydrogen-rich saline could be used as a neuroprotective agent for peripheral nerve injury therapy. PMID- 26622384 TI - Isolated spleen recurrence in a patient with lung adenocarcinoma: A case report. AB - Spleen metastasis is extremely rare in patients with lung cancer. However, recent improvements in imaging modalities may enable the antemortem diagnosis of spleen metastasis. The present study reports the case of a female patient with lung adenocarcinoma and spleen metastasis. The patient developed isolated spleen metastasis in the postoperative course. This rare metastasis was detected in a follow-up abdominal computed tomography (CT) scan without any symptoms, and was confirmed by fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan. Although very rare, chest physicians and thoracic surgeons should be alert to the possibility of spleen metastasis development when evaluating the follow-up abdominal CT scan. FDG-PET/CT scanning and an interventional approach should be considered to clarify the possibility of spleen metastasis. PMID- 26622385 TI - Efficacy of celecoxib for acute pain management following total hip arthroplasty in elderly patients: A prospective, randomized, placebo-control trial. AB - The aim of the present study was to determine whether celecoxib is able to ameliorate pain intensity, provide a narcotic-sparing effect, achieve early ambulation and improve rehabilitation following total hip arthroplasty (THA) in elderly patients. Peri- and post-operative oral celecoxib was administered to verify the efficacy of celecoxib for acute pain management in a multimodal analgesic strategy. All 64 eligible patients were randomly allocated to either the celecoxib group, who took an oral 400 mg capsule of celecoxib peri operatively and 200 mg per 12 h post-operatively for the first 5 days, or the control group, who were orally treated with a placebo capsule having the same appearance. A multimodal analgesic technique was used in which oral celecoxib or placebo capsule was combined with intravenous patient-controlled analgesia (PCA) morphine pump for peri- and post-operative pain management. Pain assessments were recorded at 6, 12, 24, 48 and 72 h, and 7 and 14 days after THA using the visual analog scale (VAS). PCA morphine consumption; 6, 12, 24 and 48-h post-operative Harris hip score (HHS); time interval until initial ambulation; rates of urinary retention and post-operative nausea and vomiting (PONV) within 72 h; and intra- and post-operative blood loss were also documented. The celecoxib and control groups comprised 34 and 30 patients, respectively. Baseline demographics were comparable between the two groups. The post-operative VAS in the celecoxib group was significantly lower than that in the control group at 12, 24, 48 and 72 h after THA. The post-operative HHS had no significant difference between the two groups, while the time interval until initial ambulation in the celecoxib group (4.5+/-1.2 days) was significantly less than that in the control group (5.83+/ 2.04 days; P<0.05). Morphine consumption was significantly decreased in the celecoxib group when compared with the control group at 6, 12, 24 and 24 h. Although the 72-h post-operative rates of urinary retention and PONV were lower in the celecoxib group than in the control group, there were no significant differences in these rates between the two groups. The intra- or post-operative blood loss was not significantly different between groups. In conclusion, pre-and post-operative oral celecoxib in a multimodal analgesic strategy can achieve favorable pain relief, reduce opioid consumption, and provide earlier ambulation and improved rehabilitation when compared with PCA morphine alone following THA in elderly patients. PMID- 26622386 TI - Crosstalk analysis of pathways in breast cancer using a network model based on overlapping differentially expressed genes. AB - Multiple signal transduction pathways can affect each other considerably through crosstalk. However, the presence and extent of this phenomenon have not been rigorously studied. The aim of the present study was to identify strong and normal interactions between pathways in breast cancer and determine the main pathway. Five sets of breast cancer data were downloaded from the high-throughput Gene Expression Omnibus (GEO) and analyzed to identify differentially expressed (DE) genes using the Rank Product (RankProd) method. A list of pathways with differential expression was obtained by gene set enrichment analysis (GSEA) of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The DE genes that overlapped between pathways were identified and a crosstalk network diagram based on the overlap of DE genes was constructed. A total of 1,464 DE genes and 26 pathways were identified. In addition, the number of DE genes that overlapped between specific pathways were determined, and the greatest degree of overlap was between the extracellular matrix (ECM)-receptor interaction and Focal adhesion pathways, which had 22 overlapping DE genes. Weighted pathway analysis of the crosstalk between pathways identified that Pathways in cancer was the main pathway in breast cancer. PMID- 26622387 TI - Anti-neutrophil cytoplasmic antibody-negative microscopic polyangiitis: A case report and literature review. AB - The aim of this study was to investigate the clinical characteristics, diagnosis and treatment of anti-neutrophil cytoplasmic antibody (ANCA)-negative microscopic polyangiitis (MPA). We described the case of a patient with ANCA-negative MPA and conducted analyses and a review of the relevant literature. Based on the collected data, the epidemiology, diagnosis and treatment of ANCA-negative MPA were discussed. The patient, a 69-year-old male, was initially diagnosed with pneumonia and interstitial lung disease (ILD) based on his clinical symptoms. The patient was ANCA-negative. The follow-up and consultations with the relevant departments after the ANCA testing led to a diagnosis of MPA being considered. The administration of glucocorticoids and immunosuppressant drugs was found to improve the symptoms of the patient. The clinical symptoms of MPA are unspecific. The majority of MPA cases are ANCA-positive, but misdiagnosis should be considered as a possibility in ANCA-negative cases. When patients are suspected to have MPA, therefore, ANCA tests should be immediately performed. Test results should be analyzed for the early diagnosis of MPA in order to enable the provision of immediate treatment, improve patient prognosis and reduce mortality rate. PMID- 26622388 TI - Sodium houttuyfonate inhibits biofilm formation and alginate biosynthesis associated gene expression in a clinical strain of Pseudomonas aeruginosa in vitro. AB - The increasing multidrug resistance of Pseudomonas aeruginosa has become a serious public-health problem. In the present study, the inhibitory activities of sodium houttuyfonate (SH) against biofilm formation and alginate production in a clinical strain of P.aeruginosa (AH16) were investigated in vitro using crystal violet dying and standard curve methods, respectively. The cellular morphology of P. aeruginosa treated with SH was observed using a scanning electron microscope. Furthermore, reverse transcription-quantitative polymerase chain reaction was used to identify differences in the expression levels of genes associated with alginate biosynthesis as a result of the SH treatment. The results indicated that SH significantly inhibited biofilm formation, and decreased the levels of the primary biofilm constituent, alginate, in P. aeruginosa AH16 at various stages of biofilm development. In addition, scanning electron microscopy observations demonstrated that SH markedly altered the cellular morphology and biofilm structure of P. aeruginosa. Furthermore, the results from the reverse transcription-quantitative polymerase chain reaction analysis indicated that SH inhibited biofilm formation by mitigating the expression of the algD and algR genes, which are associated with alginate biosynthesis. Therefore, the present study has provided novel insights into the potent effects and underlying mechanisms of SH-induced inhibition of biofilm formation in a clinical strain of P. aeruginosa. PMID- 26622389 TI - Successful treatment of a case of acute myocardial infarction due to type A aortic dissection by coronary artery stenting: A case report. AB - Acute type A aortic dissection (AD) has been recognized as a potentially life threatening condition, which sometimes involves the ostium of the coronary artery and may lead to acute myocardial infarction (AMI). In patients with acute type A AD presenting with clinical signs of AMI, it is crucial to establish the diagnosis rapidly in order to proceed with the correct treatment. The present study reports the diagnosis of a rare case of acute type A AD with the typical presentation of acute inferior MI and cardiogenic shock, which was accidentally diagnosed during catheterization and treated by right coronary ostial occlusion stenting, allowing for further surgical interventions. PMID- 26622390 TI - Overexpression of the pituitary tumor transforming gene upregulates metastasis in malignant neoplasms of the human salivary glands. AB - Salivary gland malignant neoplasms (SGMNs) represent a group of malignant solid tumors with heterogeneity in their cellular make-up, which causes difficulty with regard to the immunohistochemical confirmation of their cytological features. In the present study, overexpression of the pituitary tumor transforming gene (PTTG) was evaluated in human mucoepidermoid carcinoma specimens with a submaxillary salivary gland origin by immunohistochemical analysis, western blot analysis and reverse transcription quantitative polymerase chain reaction. In addition, a SGMN cell line was constructed, namely A-253 PTTG (+), which overexpressed PTTG. Subsequently, the regulatory role of PTTG in the proliferation and migration of A 253 cells was investigated. The immunohistochemical results demonstrated that there was a higher rate of PTTG-positive cells in the SGMN tissues when compared with the control submaxillary salivary gland tissues. Furthermore, PTTG expression at a mRNA and protein level was significantly higher in the SGMN specimens when compared with the control specimens. In addition, the rates of proliferation and migration of the A-253 PTTG (+) cells were significantly higher compared with the A-253 PTTG (-) cells. Therefore, PTTG was demonstrated to play an important role in SGMN cell proliferation and migration, and may subsequently be a notable marker for SGMN diagnosis and a potential target for anticancer therapy. PMID- 26622391 TI - Definitive radiotherapy with concurrent oncothermia for stage IIIB non-small-cell lung cancer: A case report. AB - Hyperthermia enhances the susceptibility of tumors to radiotherapy (RT) and chemotherapy. Oncothermia, also known as electro-hyperthermia, is a new treatment modality developed to overcome the problems of traditional hyperthermia by selectively delivering energy to the malignant tissues. The present study reports the outcome of combined oncothermia and RT in a 75-year-old patient with stage IIIB non-small-cell lung cancer (NSCLC). Due to the advanced age and the performance status of the patient, the combination of systemic chemotherapy and RT was deemed infeasible; therefore, the patient instead decided to undergo oncothermia concurrently with definitive RT. The RT was administered at a dose of 64.8 Gy in 36 fractions using a three-dimensional conformal plan technique. Oncothermia was started concomitantly with RT and was performed for 60 min per session, two sessions per week, for a total of 12 sessions. No severe toxicities developed, with the exception of mild odynophagia, which resolved soon after the treatments. Follow-up computed tomography showed complete tumor response, and the patient was alive with no evidence of the disease 18 months after the completion of the treatment. In conclusion, the present case report suggests that oncothermia combined with RT, with the former possessing radiosensitizing potential and no additional toxicities, may be a promising alternative for advanced-age and/or frail patients with locally advanced NSCLC. PMID- 26622392 TI - Genetic polymorphisms of short tandem repeat loci D13S305, D13S631 and D13S634 in the Han population of Tianjin, China. AB - Short tandem repeat (STR) markers, also known as microsatellites, are extensively used in mapping studies, forensics and disease diagnosis due to their small dimension and low mutation and high polymorphism rates. In recent years quantitative fluorescence polymerase chain reaction (QF-PCR) has been successfully used to amplify STR markers in the prenatal diagnosis of common chromosomal abnormalities. This method provides a diagnosis of common aneuploidies 24-48 h after sampling with low error rates and cost; however, the size of different alleles, frequency, heterozygosity and distribution of STR markers vary among different populations. In the present study three STR markers, D13S305, D13S631 and D13S634, on chromosome 13 were analyzed in 350 unrelated individuals (200 males and 150 females) from the Han population of Tianjin, China using QF-PCR. Eleven, seven and 11 alleles of each marker were observed, respectively. The frequencies of the genotypes were in good agreement with Hardy Weinberg equilibrium (P>0.05). The results showed that these three STR markers were highly polymorphic in the Han population of Tianjin, China. The study has provided basic data for use in the prenatal diagnosis of Patau syndrome. PMID- 26622393 TI - Jinmaitong decreases sciatic nerve DNA oxidative damage and apoptosis in a streptozotocin-induced diabetic rat model. AB - Diabetic peripheral neuropathy (DPN) is a common chronic complication of diabetes. Jinmaitong (JMT), a Traditional Chinese Medicine, improves certain symptoms of DPN, such as limb pain and numbness. The aim of the present study was to investigate the effects of JMT on DNA oxidative damage and apoptosis in the sciatic nerve of diabetic rats. The rats were divided into a normal and a diabetic group. Diabetes was induced using streptozotocin (60 mg/kg). The diabetic model (DM) rats received vitamin C (0.05 g/kg/day) or JMT [low-dosage (L), 0.44 g/kg/day; medium-dosage (M), 0.88 g/kg/day or high-dosage (H), 1.75 g/kg/day]. After 16 weeks, the mechanical pain threshold of the rats was evaluated. The expression of 8-hydroxy-deoxyguanosine (8-OHdG), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p22phox, B-cell lymphoma 2 (Bcl 2), caspase 3 and cleaved-poly(ADP-ribose) polymerase 1 (PARP-1) in the sciatic nerve tissues was measured using the reverse transcription-quantitative polymerase chain reaction, immunohistochemistry and western blotting. JMT had no effect on body weight and fasting blood glucose levels. Following treatment, the rats in the JMT groups had an improved pain threshold compared with the DM controls (JMT-L, 52.9+/-6.5 g; JMT-M, 74.7+/-9.3 g; and JMT-H, 61.7+/-2.0 g vs. DM control, 35.32+/-12.06 g; all P<0.01), while the threshold in the JMT-M rats was similar to that of normal controls (P>0.05). 8-OHdG and NADPH oxidase p22phox expression was significantly decreased in the three JMT groups compared with that in the DM controls (all P<0.05). Following JMT treatment, Bcl-2 levels were increased, while caspase 3 and cleaved-PARP-1 levels were decreased compared with those in the DM controls (all P<0.01). In conclusion, JMT may reduce DNA oxidative damage to the sciatic nerve in diabetic rats, as well as regulate genes involved in peripheral neuronal cell apoptosis, suggesting that JMT could be used to prevent or treat DPN in diabetic patients. PMID- 26622394 TI - Association between macrophage migration inhibitory factor in the endometrium and estrogen in endometriosis. AB - Recent studies have shown that macrophage migration inhibitory factor (MIF) has a possible role in endometriosis-related pain and infertility, yet it has not been explored whether the mRNA level of MIF is altered in endometrial tissues from patients with endometriosis. The aim of the present study was to compare the expression of MIF in endometrial tissues from women with and without endometriosis, and to analyze the association between endometrial MIF expression and 17beta-estradiol (E2). The protein and mRNA expression of MIF in the human endometrial tissue was assessed by western blotting and reverse transcription polymerase chain reaction analysis, respectively. The MIF expression of women with endometriosis was found to be significantly higher than that of the controls. A positive correlation was noted between the serum E2 level and MIF expression. In endometrial cells from women with endometriosis, the level of E2 induced MIF upregulation was significantly higher than that in cells from women without endometriosis. In conclusion, this study demonstrated a significant increase in MIF expression in the endometrial tissues of women with endometriosis and an association between MIF expression and E2 level. MIF expression in endometrial cells from patients with endometriosis showed an increased sensitivity to stimulation by E2. PMID- 26622395 TI - Prognostic value of natriuretic peptides in severe trauma patients with multiple organ dysfunction syndrome. AB - The aim of the present study was to evaluate the prognostic values of the N terminal peptide of pro-atrial natriuretic peptide (NT-proANP) and the N-terminal fragment of B-type natriuretic peptide (NT-proBNP) in severe trauma patients developing multiple organ dysfunction syndrome (MODS). Out of the 126 severe trauma patients that were admitted to the Emergency Intensive Care Unit of the General Hospital of Shenyang Military Region between January 2009 and December 2011, 26 patients with multiple injuries and an injury severity score (ISS) of >16 points were included in the study. The MODS score was calculated on admission as well as 24, 48 and 72 h after the injury. Patients were divided into two groups: Group A consisted of patients with minor signs of organ dysfunction (MODS score, <=4 points) and group B of patients with major organ dysfunction (MODS score, >4 points). Venous blood (5 ml) was extracted from the patients on admission and 6, 12, 24, 48 and 72 h after the injury. The Elecsys proBNP(r) and proANP(r) assays were used to determine the NT-proBNP and NT-proANP levels, respectively. The changes in the levels of C-reactive protein, white blood cells and neutrophils were detected and analyzed on admission. Acute physiology and chronic health evaluation II scores and ISSs were collected 72 h after the injury. The hemodynamic monitoring of cardiac index (CI) was performed using The Pulse index Continuous Cardiac Output system. The serum NT-proANP and NT-proBNP concentrations were elevated in all 26 patients. Upon admission, the serum NT proANP and NT-proBNP values were 637.3+/-8.9 and 137.3+/-8.9 pmol/l, respectively, in group A and 1,185.0+/-7.2 and 185.0+/-7.2 pmol/l, respectively, in group B. The NT-proANP and NT-proBNP levels in group A were significantly lower than those in group B at all subsequent time-points (P<0.001). By contrast, the CI in group A was significantly higher than that in group B at all time points (P<0.001). An inverse correlation was observed between the NT-proANP or NT proBNP concentration and CI at 24, 48 and 72 h after the injury (r=-0.679 and 0.772, respectively; P<0.001). In conclusion, the serum NT-proANP and NT-proBNP concentrations following multiple injuries have been found to be significantly correlated with the clinical signs of MODS, and a distinct correlation has been observed between the levels of serums NT-proANP and NT-proBNP and decreased CI. The data of this pilot study suggest that NT-proANP and NT-proBNP levels may be of value in the diagnosis of post-traumatic cardiac impairment. PMID- 26622396 TI - Simvastatin reverses cardiomyocyte hypertrophy via the upregulation of phosphatase and tensin homolog expression. AB - The aim of the present study was to investigate the effects of simvastatin on the protein kinase B (PKB) signaling pathway and the expression of phosphatase and tensin homolog (PTEN). The effects of simvastatin were analyzed by administering the drug orally to male spontaneously hypertensive rats (SHRs) at a dose of 10 mg/kg/day, while the control animals received an equal volume of saline. The systolic pressure (mmHg) of the rat tail artery was measured prior to the initiation of the experiment, and once a week until the end of the experiment. At the end of the experiment, the animals were euthanized and the hearts were removed. The left ventricular and interventricular septum were weighed, after which the left ventricular mass/body mass ratio was calculated. In addition, cardiomyocytes isolated from Sprague Dawley rats were cultured with 15% fetal bovine serum to induce hypertrophy, following which the cells were treated with different doses of simvastatin. The in vitro effects were assessed by measuring the surface area of the cardiomyocytes, while the rate of protein synthesis was measured using a 3H-leucine incorporation assay and western blot analyses. Simvastatin was demonstrated to inhibit cardiomyocyte hypertrophy in the in vivo and in vitro experiments. Notably, simvastatin increased PTEN expression and inhibited PKB expression in the SHR model, as well as in the cardiomyocytes in culture. In addition, the use of PTEN antisense oligodeoxynucleotides was revealed to inhibit the effects of simvastatin on cardiomyocytes. Therefore, these results indicated that simvastatin was able to reverse cardiomyocyte hypertrophy in vivo and in vitro, possibly by increasing the expression of PTEN. PMID- 26622397 TI - Paraptosis triggers mitochondrial pathway-mediated apoptosis in Alzheimer's disease. AB - In previous years, increasing evidence has indicated that paraptosis and mitochondrial-mediated apoptosis may be associated with Alzheimer's disease (AD). However, the association between paraptosis and mitochondrial-mediated apoptosis, and the pathological processes underlying AD, remain elusive. In the present study, the beta-amyloid precursor protein gene, and the gene mutations PS1M146L and L286V, were transfected to an SH-SY5Y cell line to establish an AD cell model. Subsequently, an MTT assay was used to examine the cell viability of the AD cell model, while a TUNEL assay was employed to observe the number of positively stained apoptotic cells. Cytoplasmic vacuolization was examined using light microscopy and images were photographed. Furthermore, western blot analysis was utilized to detect the expression of golden biomarkers of the mitochondrial pathway, including Bcl-2 and Bax. The paraptosis inhibitor, cycloheximide, was selected to treat the AD model cells in order to observe the association between paraptosis and mitochondrial-mediated apoptosis. The results indicated that the decrease in the cell viability of the AD cells was initiated at 24 h, as compared with the normal cells (P<0.05). TUNEL-positive stained cells were observed at 48 h, which was later compared with the cell death initiation. In addition, examination of cytoplasmic vacuolization using microscopy indicated that there were a small number of paraptosis cells present at 24 h. The expression levels of Bcl-2 was significantly decreased, while Bax was significantly increased at 48 h. Furthermore, cycloheximide treatment was demonstrated to significantly increase Bcl-2 expression, while decreasing Bax expression (P>0.05). In conclusion, the occurrence of paraptosis was demonstrated in the early pathological stages of AD, which may subsequently damage the mitochondria and trigger mitochondrial pathway mediated apoptosis. Thus, paraptosis may trigger programmed cell death directly, or indirectly through the regulation of Bcl-2 and Bax protein expression. PMID- 26622398 TI - Association between mobilization of circulating endothelial progenitor cells and time or degree of injury from angioplasty in patients with exertional angina: A prospective study. AB - The aim of the present study was to investigate the effect of coronary artery angioplasty on the recruitment of circulating endothelial progenitor cells (EPCs) in patients with angina pectoris. A total of 66 patients treated by coronary stenting were enrolled in the PCI group and 17 patients that underwent angiography alone were enrolled in the control group. The EPC count in the blood was measured by flow cytometry prior to and at 1, 3, 5, 7 and 24 h following angioplasty in the percutaneous coronary intervention (PCI) group, and at three time-points following angiography in the control group. Differences between the two groups included the characteristics of the coronary artery lesions, the incidence of diabetes and family history of coronary heart disease. The mean surface area of the stent deployed was 335.59+/-234.99 mm2. No significant change in EPC count was measured in the control group. In the PCI group, a moderate and delayed increase in the number of cluster of differentiation (CD)34+/kinase domain receptor (KDR)+ EPCs occurred at 24 h post-balloon inflation compared with the baseline level. The CD133-/CD34+/KDR+ subpopulations showed undulating changes at 3, 7 and 24 h post-PCI (P=0.016, P=0.01 and P=0.032, respectively). An arch shape was displayed in CD133+/KDR+ cells; initially, a reduction occurred at 3 h and was maintained constantly until 7 h (P=0.003, P=0.013 and P=0.033 at 3, 5 and 7 h, respectively), after which a slight increase to the baseline level occurred at 24 h (P=0.084). The CD133+/CD34+ cells increased in stepwise manner until 24 h. The CD34+/KDR+ EPC change magnitude correlated significantly with a global damage index by partial correlation analysis (P<0.001). The results suggested that a time-dependent mobilization of EPCs may be initiated by PCI; the change magnitude of the CD34+/KDR+ cells was associated particularly with endothelial injury degree from the PCI procedure. PMID- 26622399 TI - Effect of catheter ablation versus antiarrhythmic drugs on atrial fibrillation: A meta-analysis of randomized controlled trials. AB - The aim of the present study was to compare the health outcomes of catheter ablation therapy against those of antiarrhythmic drugs (AADs) in the management of atrial fibrillation (AF). The effects of catheter ablation and AADs on a number of parameters were compared, including AF recurrence, all-cause mortality, stroke/transient ischemic attack (TIA) and quality of life (QoL). A systematic literature search of PubMed, Embase and the Cochrane Central Register of Controlled Trials was conducted to obtain relevant randomized controlled trials. The relative risks (RRs) and 95% confidence intervals (CIs) of AF recurrence, all cause mortality and stroke/TIA between catheter ablation and AADs were subsequently calculated. Weighted mean differences (WMDs) and 95% CIs were used to evaluate the QoL between the two therapy groups. In total, 11 randomized trials, which included 1,763 AF patients, were eligible for the meta-analysis. Overall, the results indicated that catheter ablation produces superior outcomes compared with AADs in reducing AF recurrence (RR, 0.47; 95% CI, 0.38-0.58; P<0.001) and improving the QoL (physical component summary: WMD, 2.23; 95% CI, 0.24-4.21; P=0.03; mental component summary: WMD, 2.69; 95% CI, 0.04-5.35; P=0.05). However, no statistically significant difference was identified between the two groups with regard to the incidence of all-cause mortality (RR, 0.87; 95% CI, 0.37-2.06; P=0.76) and stroke/TIA (RR, 1.83; 95% CI, 0.73-4.55; P=0.20). In summary, catheter ablation was demonstrated to markedly reduce AF recurrence and improve QoL when compared with AAD therapy. However, the incidence rates of all cause mortality and stroke/TIA were comparable between catheter ablation and AAD therapy. PMID- 26622400 TI - Saikosaponin A protects against experimental sepsis via inhibition of NOD2 mediated NF-kappaB activation. AB - The excessive production of inflammatory cytokines during invasive infection primarily mediates the pathophysiology of sepsis. To improve the survival of septic patients, many selective or mediator-specific anti-inflammatory agents have been developed. Saikosaponin A (SsA), a triterpenoid saponin isolated from Radix Bupleuri, inhibits the production of proinflammatory mediators in several cell types and protects against CCl4-induced liver injury in rats. However, whether SsA treatment provides protective effects against sepsis remains unknown. The aim of the present study was to investigate the anti-inflammatory role of SsA in septic rats and the possible involvement of the nucleotide-binding oligomerization domain 2 (NOD2)/NF-kappaB signaling pathway in the regulation of inflammatory cytokine expression. Sixty male Wistar rats were randomly divided into six groups (10 rats per group): Sham surgery, cecal ligation and puncture (CLP), CLP plus SsA (1.0 mg/kg), CLP plus SsA (2.5 mg/kg), CLP plus SsA (5.0 mg/kg) and sham surgery plus SsA (2.5 mg/kg) groups. Rats in the SsA groups were intraperitoneally (i.p.) injected with different doses of SsA following the CLP surgery. Tissues from the ileum were harvested 8 h after CLP or sham surgery and the levels of inflammatory cytokines and NOD2 mRNA, and the activation of NF kappaB were measured. The concentrations of the cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, as well as the NOD2 mRNA expression levels and NF-kappaB activation in the intestinal tissues were significantly increased in the septic rats of the CLP group compared with those in the sham group. SsA administration effectively suppressed the increase in the levels of TNF-alpha and IL-6. Moreover, the upregulation of NOD2 mRNA expression and phospho-NF-kappaB p65 levels was significantly inhibited following the administration of SsA. SsA may exert a protective role in the septic process by suppressing TNF-alpha and IL 6 concentrations in the intestines of septic rats and these effects appear to be mediated, at least partly, via inhibition of the NOD2/NF-kappaB signaling pathway. PMID- 26622401 TI - Role of (-)-epigallocatechin-3-gallate in the osteogenic differentiation of human bone marrow mesenchymal stem cells: An enhancer or an inducer? AB - Epidemiological investigations have revealed that the consumption of green tea, which is a rich source of (-)-epigallocatechin-3-gallate (EGCG), is associated with a reduced risk of osteoporosis. A number of in vitro and in vivo studies have also demonstrated that EGCG exerts a significant positive effect on osteogenesis; however, the single effect of EGCG on osteogenic differentiation has been seldom studied. EGCG was hypothesized to function as an enhancer or an inducer. In the present study, the effect of EGCG on the osteogenic differentiation of primary human bone marrow mesenchymal stem cells (hBMSCs), without other additives, was investigated. Three groups of stem cells were analyzed, which included a negative control group (hBMSCs cultured with culture medium only), an experimental group (cells treated with culture medium containing 2.5, 5 and 10 uM EGCG), and a positive control group (cells cultured with osteogenesis-induced culture medium). After 3, 7, 14 and 21 days, cell proliferation, alkaline phosphatase (ALP) activity and the expression of associated osteogenic genes were analyzed. The results revealed that ALP activity and the expression of associated osteogenic genes, with the exception of bone morphogenetic protein 2 (BMP2), were not affected by EGCG treatment alone. These results indicated that EGCG itself had little effect on the osteogenic differentiation of MSCs; however, EGCG was able to enhance osteogenesis in the presence of osteoinductive agents through the upregulation of BMP2 expression. Additionally, EGCG was shown to promote cell growth, demonstrating its safety as a therapeutic agent. Therefore, the present study indicated that treatment with EGCG was dependent on other osteogenic inducers. PMID- 26622402 TI - CORRIGENDUM. AB - [This corrects the article DOI: 10.3892/etm.2012.503.]. PMID- 26622403 TI - Effect of vitamin K2 on the development of stress-induced osteopenia in a growing senescence-accelerated mouse prone 6 strain. AB - Vitamin K2 (VK2) has been used as a therapeutic agent for osteoporosis, since it has been suggested to be able to reduce the frequency of fractures by improving bone quality; however, bone turnover is strictly regulated by various cytokines and hormones. In the present study, the effect of menaquinone-4 (MK-4) on bone turnover was investigated using the senescence-accelerated mouse prone 6 (SAMP6) strain. Since water-immersion restraint stress (WRS) causes a significant decrease in bone mineral density (BMD), WRS was used as the bone resorption model in the SAMP6 strain. Six-week-old SAMP6 male mice were divided into the following three groups: Control, WRS and WRS + MK-4. WRS was performed for 6 h per day, 5 times a week, for 4 weeks. Following WRS, MK-4 (30 mg/kg) was injected subcutaneously 3 times a week for 4 weeks. No growth retardation was observed in the WRS groups as compared with the control group. In the WRS groups, the BMD was significantly lower than that in the control group. The levels of bone formation and resorption markers were increased in the WRS groups, indicating that WRS reduced the BMD by promoting high bone turnover. A bone histomorphometrical examination showed that the trabecular (Tb) bone mass in the secondary spongiosa at the distal femur was significantly reduced in the WRS mice, and this reduction was abrogated by MK-4 treatment. Specifically, the Tb bone reduction was caused by the activation of osteoclasts (Ocs), and Oc activity was suppressed by MK-4. The number of osteoblasts and the mineral apposition rate were significantly increased in the WRS and WRS + MK-4 mice, suggesting that WRS triggered a significantly higher mineral apposition rate. These results indicate that MK-4 can induce recovery from the bone mineral loss caused by WRS treatment. Further studies are required to clarify the association between bone quality and MK-4. PMID- 26622404 TI - Effects of autologous bone marrow-derived stem cell mobilization on acute tubular necrosis and cell apoptosis in rats. AB - The aim of this study was to investigate the effects of stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) on bone marrow-derived stem cell (BMSC) mobilization in rat models of renal ischemia/reperfusion (I/R) injury. In addition, the effects of SCF and G-CSF on cellular apoptosis were explored in order to determine the protective mechanism of the two factors against renal I/R injury. A unilateral renal I/R injury model was established for the model and treatment groups. The treatment and treatment control groups were subcutaneously injected with SCF (200 ug/kg/day) and G-CSF (50 ug/kg/day) 24 h after the establishment of the model for five consecutive days. The total number of leukocytes in the peripheral blood and the cellular percentages of cluster of differentiation (CD)34+, renal CD34+ and apoptotic cells were detected. The total number of leukocytes in the peripheral blood and the percentages of CD34+ cells in the treatment and treatment control groups reached maximum levels on the fifth postoperative day and were significantly higher than those in the normal control and model groups. The number of renal CD34+ cells in the treatment group was significantly increased compared with that in the treatment control and model groups. The apoptotic indices (AIs) of the model and treatment groups were higher than those of the normal control and treatment control groups. The AI of the model group was significantly higher than that of the treatment group. In conclusion, the combined application of SCF and G-CSF can mobilize sufficient numbers of BMSCs and cause cellular 'homing' to the injured site, thus inhibiting apoptosis and promoting the repair of renal tubular injury. PMID- 26622405 TI - Association between miR-181b and PKG 1 in myocardial hypertrophy and its clinical implications. AB - The aim of this study was to explore the microRNA (miR)-181b expression in myocardial hypertrophy and to investigate its association with cGMP-dependent protein kinase type I (PKG 1) in an in vitro model. The miR-181b level in the peripheral blood was determined in patients with myocardial hypertrophy, and an in vitro model was established via phenylephrine (PE) treatment. Reverse transcription-quantitative polymerase chain reaction analysis and western blotting were performed to detect the expression levels of miR-181b, PKG 1 and hypertrophy-related genes. The results revealed that the expression of miR-181b was elevated in the peripheral blood of patients with myocardial hypertrophy, and this may have contributed to the pathology and progression of the disease. When the primary myocardial cells were treated with PE, microscopic observation and flow cytometry revealed significant hypertrophy. Furthermore, upregulation of myocardial hypertrophy-related genes, including beta-myosin heavy chain, alpha sarcomeric actinin and atrial natriuretic peptide, was observed. The miR-181b expression level in the PE-treated cells was elevated, while the mRNA and protein expression levels of PKG 1 were decreased, indicating a negative correlation between miR-181b and PKG 1 in myocardial hypertrophy. In addition, when the PE treated primary myocardial cells were transfected with miR-181b inhibitor, the reduced PKG 1 expression was restored and the myocardial hypertrophy alleviated, as indicated by the reduced cellular sizes and decreased expression levels of the myocardial hypertrophy-related genes. In conclusion, miR-181b expression has been shown to be upregulated in myocardial hypertrophy, and this may play a role in the pathogenesis of the disease by regulating the expression of PKG 1. The present findings suggest that miR-181b is a promising molecular indicator for the clinical diagnosis and treatment of cardiac hypertrophy. PMID- 26622406 TI - Expression and interaction of TNF-alpha and VEGF in chronic stress-induced depressive rats. AB - The incidence of depression increases annually but the pathogenesis is not yet fully understood. The aim of the present study was to explore the expression and interaction of tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor (VEGF) in chronic stress-induced depressive rats. A total of 20 adult healthy Sprague Dawley rats (180-220 g) were randomly divided into the control and experimental depression groups. The depression model was established with a chronic stress method, and the success of model construction was assessed through weigh measurements and the sugar consumption and open-field tests. The expression of TNF-alpha and VEGF was detected using the reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blotting and immunohistochemistry. Compared with the control group, the weight of the rats in the experimental group was found to be reduced (P<0.05). The open-field test showed significant differences in the horizontal and vertical motion of the rats between the two groups, and the rats in the experimental group exhibited a significantly reduced ability to adapt to a new environment (P<0.05). Furthermore, the sensitivity of the rats in the experimental group to reward stimulation was decreased. The relative mRNA expression levels of TNF-alpha and VEGF in the hippocampus of the experimental group were lower than those in the control group, and western blot analysis revealed that the protein expression of VEGF and TNF-alpha was reduced in the experimental group. Neurons of the experimental group exhibited reduced immunohistochemical staining compared with neurons from the normal hippocampus in the control group. In conclusion, the present study investigated the association between the occurrence of depression and TNF-alpha and VEGF at the mRNA and protein levels using RT-qPCR, western blotting, immunohistochemistry and animal behavior experiments. The results provide a fundamental basis for follow-up clinical research. PMID- 26622407 TI - Renoprotective effects of berberine as adjuvant therapy for hypertensive patients with type 2 diabetes mellitus: Evaluation via biochemical markers and color Doppler ultrasonography. AB - Diabetes and hypertension are complex and serious diseases that may ultimately lead to renal complications. Adequate control of blood glucose and blood pressure contributes to decreased renal risks, but may not be sufficient for certain patients. The current study was undertaken to investigate the renoprotective effects of berberine as an adjuvant therapy to standard hypotensive and hypoglycemic treatment in hypertensive patients with type 2 diabetes mellitus (T2DM). In this 2-year clinical study, 69 hypertensive patients with T2DM, whose blood pressure and fasting plasma glucose (FPG) were adequately controlled by hypotensive and oral hypoglycemic agents prior to the study, were enrolled and randomly assigned into control (33 cases) and add-on (36 cases) groups. Berberine was orally administrated to the patients in the add-on group concomitantly with standard hypotensive and hypoglycemic treatment. Baseline characteristics, including the levels of FPG, glycated hemoglobin, systolic blood pressure, diastolic blood pressure, serum creatinine, urinary albumin-to-creatine ratio (UACR), urinary osteopontin and kidney injury molecule-1 (KIM-1) were determined. Furthermore, the oxidative stress markers malondialdehyde, urinary 8-hydroxy-2' deoxyguanosine, superoxide dismutase, glutathione peroxidase and total antioxidant capacity, and the inflammatory parameters vascular adhesion molecule 1, C-reactive protein and high molecular weight-adiponectin were evaluated. In addition, ultrasonographic parameters, including peak systolic velocity, end diastolic velocity and renal arterial resistance index were determined. After treatment, it was observed that the control and add-on treatments were able to adequately control blood pressure and blood glucose. Patients in the add-on group exhibited significant reductions in renal damage biochemical markers (UACR, urinary osteopontin and KIM-1) and improved renal hemodynamics, in addition to reduced inflammation and oxidative stress. The present results suggest that berberine is beneficial for hypertensive patients with T2DM as add-on therapy to standard hypotensive and hypoglycemic agents. PMID- 26622408 TI - Preconditioning with Gua Lou Gui Zhi decoction enhances H2O2-induced Nrf2/HO-1 activation in PC12 cells. AB - Spasticity is common in various central neurological conditions, including after a stroke. Such spasticity may cause additional problems, and often becomes a primary concern for afflicted individuals. A number of studies have identified nuclear factor (erythroid-derived 2)-like 2 (Nrf2) as a key regulator in the adaptive survival response to oxidative stress. Elevated expression of Nrf2, combined with heme oxygenase 1 (HO-1) resistance, in the central nervous system is known to elicit key internal and external oxidation protection. Gua Lou Gui Zhi decoction (GLGZD) is a popular traditional Chinese formula with a long history of clinical use in China for the treatment of muscular spasticity following a stroke, epilepsy or a spinal cord injury. However, the mechanism underlying the efficacy of the medicine remains unclear. In the present study, the antioxidative effects of GLGZD were evaluated and the underlying molecular mechanisms were investigated, using hydrogen peroxide (H2O2)-induced rat pheochromocytoma cells (PC12 cells) as an in vitro oxidative stress model of neural cells. Upon application of different concentrations of GLGZD, a 3-(4,5 dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay and ATP measurement were conducted to assess the impact on PC12 cell proliferation. In addition, inverted microscopy observations, and the MTT and ATP assessments, revealed that GLGZD attenuated H2O2-induced oxidative damage and signaling repression in PC12 cells. Furthermore, the mRNA and protein expression levels of Nrf2 and HO-1, which are associated with oxidative stress, were analyzed using reverse transcription quantitative polymerase chain reaction (PCR) and confocal microscopy. Confocal microscopy observations, as well as the quantitative PCR assay, revealed that GLGZD exerted a neuroprotective function against H2O2 induced oxidative damage in PC12 cells. Therefore, the results demonstrated that GLGZD protected PC12 cells injured by H2O2, which may be associated with the upregulation of Nrf2 and HO-1 mRNA and protein expression levels in PC12 cells. PMID- 26622409 TI - Window of opportunity: A new insight into sequential bevacizumab and paclitaxel in two cases of metastatic triple-negative breast cancer. AB - Bevacizumab, an antiangiogenic monoclonal antibody against vascular endothelial growth factor, was designed to normalize tumor vasculature and reduce intratumoral pressure. It can create a 'normalization window' during which the cancer can be attacked the most effectively, and the effects of chemotherapeutic drugs are enhanced. Representative trials (E2100, AVADO, RIBBON-1, RIBBON-2 and TURANDOT) have shown that the addition of bevacizumab to chemotherapy has significant benefits on progression-free survival for metastatic breast cancer, but not on overall survival. The present study describes two patients with metastatic triple-negative breast cancer who received 6 courses of bevacizumab containing chemotherapy. Each course comprised 5-7.5 mg/kg bevacizumab administered on days 1 and 15, and 20-24 h after bevacizumab delivery, 80 mg/m2 paclitaxel was administered for 3 weeks on days 2, 9 and 16, followed by 1 week of rest. Following sequential treatment with bevacizumab and paclitaxel, the results of computed tomography showed that the tumors were rapidly reduced in size. Based on the imaging findings from three-dimension power Doppler ultrasonography in one of the breast cancer patients who received neoadjuvant chemotherapy with bevacizumab, the possible timing of the normalization window was 20-24 h after the administration of bevacizumab. The normalization window may provide an opportunity to enhance the effect of chemotherapy with the aid of bevacizumab. PMID- 26622410 TI - Augmented anti-angiogenesis activity of polysulfated heparin-endostatin and polyethylene glycol-endostatin in alkali burn-induced corneal ulcers in rabbits. AB - Endostatin (ES) is an endogenous angiogenesis inhibitor that has the ability to inhibit tumor growth and metastasis. However, its clinical application is limited by a number of disadvantages, such as poor stability, short half-life and the requirement of high doses to maintain its efficacy. The chemical modification on ES may offer a solution to these disadvantages. The aim of the present study was to evaluate the effects of ES, polysulfated heparin-endostatin (PSH-ES) and polyethylene glycol-endostatin (PEG-ES) on the endothelial cell proliferation and angiogenesis associated with corneal neovascularization (CNV) and to determine their mechanisms of action. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) was used to study the effects of ES and its derivatives on endothelial cell proliferation in vitro, and rabbits were used to evaluate the effects of ES and its derivatives on CNV in vivo. In the evaluation of CNV, the expression of vascular endothelial growth factor in the cornea was measured via immunohistochemistry and microvessels were counted. ES and its derivatives significantly inhibited endothelial cell proliferation in vitro (P<0.05) and suppressed CNV in vivo. Among the compounds examined, ES most effectively inhibited endothelial cell proliferation in vitro (P<0.05); however, PSH-ES and PEG-ES most effectively inhibited CNV in vivo (P<0.05). These results indicate that PSH-ES and PEG-ES are candidate anti-angiogenesis drugs. PMID- 26622411 TI - RANKL, OPG and CTR mRNA expression in the temporomandibular joint in rheumatoid arthritis. AB - The calcitonin receptor (CTR) and receptor activator of nuclear factor kappaB ligand (RANKL) have been found to be involved in the differentiation of osteoclasts. The association between the RANKL:osteoprotegerin (OPG) expression ratio and the pathogenesis of bone-destructive rheumatoid arthritis (RA) has been described in several joints, but the available data for the temporomandibular joint (TMJ) are limited. The aim of the present study was to investigate the involvement of osteoclasts at sites of bone erosion by determining the CTR expression and the RANKL:OPG expression ratio in the TMJ in a collagen-induced arthritis (CIA) model. Forty-eight male Wistar rats were randomly divided into two groups: Control group, injected with saline solution for 6 weeks; and CIA group, injected with emulsion. The RANKL and OPG mRNA expression was significantly increased in immunized rats compared with that in non-immunized rats. The RANKL:OPG expression ratio on the trabecular bone surface was 9.0 and 6.4 in the CIA group at weeks 4 and 6, respectively, while the RANKL:OPG expression ratio in the controls was 1.0:2. CTR mRNA expression was significantly upregulated in immunized rats compared with that in non-immunized rats; the level of CTR mRNA in the CTR-positive osteoclasts on the trabecular bone surface was 10.9- and 7.8-fold higher in the CIA rats than that in the control rats at weeks 4 and 6, respectively. In conclusion, focal bone destruction in an experimental model of arthritis in the TMJ can be attributed to cells expressing CTR, a defining feature of osteoclasts. The expression of RANKL and OPG mRNA within the inflamed synovium provides an insight into the mechanism of osteoclast differentiation and function at the border of bone erosion in arthritis. PMID- 26622412 TI - Effect of a nutrient mixture on the localization of extracellular matrix proteins in HeLa human cervical cancer xenografts in female nude mice. AB - Cervical cancer is one of the most commonly diagnosed cancers and a significant cause of mortality in women worldwide. Although cervical cancer is fully treatable in the early stages, once it has metastasized, patient outcome is poor. The objective of the present study was to investigate the effect of dietary supplementation with a nutrient mixture (NM) containing lysine, ascorbic acid, proline, green tea extract and other micronutrients on the expression of extracellular matrix (ECM) proteins in HeLa cell xenografts in nude female mice. After housing for 1 week, female athymic nude mice between 5 and 6 weeks of age (n=12) were inoculated subcutaneously with 3*106 HeLa cells in phosphate-buffered saline and Matrigel and randomly divided into two groups. These were the control group, in which the mice were fed with regular mouse chow, and the NM group, in which the mice were fed with the regular diet supplemented with 0.5% NM (w/w). After 4 weeks, the tumors were excised and processed for histology. Tumor growth was evaluated and the tumors were stained for the ECM proteins collagen I, collagen IV, fibronectin, laminin, periodic acid-Schiff (PAS) and elastin. NM strongly inhibited (by 59%, P=0.001) the growth of HeLa xenografts in nude mice. Tumors from control mice exhibited little to no collagen I expression either internally or in the fibrous capsule, while tumors from the NM group expressed collagen I in the fibrous capsule and within the tumor. Tumors from the control group showed diffuse cytoplasmic and capsular collagen IV with abundant nucleated cells. NM treatment substantially increased collagen IV production and induced a dense fibrous network of collagen IV with chambers that surrounded live nucleated cells and large amounts of necrotic cell debris. Tumors from the mice fed with the NM exhibited a well-defined border of fibronectin in the capsule and intense areas of staining internally whereas control group tumors showed less overall fibronectin with sporadic internal staining and little in the fibrous capsule. Although laminin appeared abundantly in control and NM-treated tumors, the NM group tumors exhibited a chamber-like network of laminin internally. Tumors from the control group exhibited internal areas of intense PAS staining, whereas tumors from the NM-treated group exhibited a more uniform diffuse pattern of PAS staining. In conclusion, NM supplementation of HeLa xenograft-bearing female nude mice demonstrated a potent inhibition of tumor growth and enhancement of ECM proteins, suggesting the therapeutic value of this specific nutrient complex in the treatment of cervical cancer. PMID- 26622413 TI - Genetic variants of endothelial PAS domain protein 1 are associated with susceptibility to acute mountain sickness in individuals unaccustomed to high altitude: A nested case-control study. AB - The endothelial PAS domain protein 1 (EPAS1) gene functions to sense the blood oxygen level by regulating the hypoxia-inducible transcription factor pathway, and single nucleotide polymorphisms (SNPs) of EPAS1 have been found to have a strong and positive selection in the adaptation of the native Tibetan highland population to high-altitude hypoxia. The aim of the present study was to investigate the effect of EPAS1 SNPs on the risk of acute mountain sickness (AMS) and the physiological responses to acute high-altitude hypoxia in lowland humans. Three tag SNPs (rs6756667, rs13419896 and rs4953354; minor allele frequency, >=5%) were selected and genotyped in 603 unrelated Han Chinese men, who had traveled to Lhasa (a high-altitude hypoxia environment) by plane, using a matrix assisted laser desorption/ionization time-of-flight mass spectrometry method. The data showed that the EPAS1 rs6756667 wild-type GG homozygous genotype was associated with elevated AMS risk compared with the AA and AG genotypes (odds ratio, 1.815; 95% confidence interval, 1.233-2.666; P=0.0023) using the dominant model analysis. EPAS1 rs6756667 GG genotypes were also associated with higher levels of hemoglobin, red blood cells and hematocrit than those carrying the AG heterozygote during AMS development. These findings indicate that EPAS1 SNPs play a role in the physiological effects of AMS, and these effects could be further evaluated as a therapeutic strategy to control acute hypoxia-related human diseases. PMID- 26622414 TI - Significance of the changes occurring in the levels of interleukins, SOD and MDA in rat pulmonary tissue following exposure to different altitudes and exposure times. AB - The aim of the present study was to investigate the changes occurring in the levels of interleukin, superoxide dismutase (SOD) and malondialdehyde (MDA) in rat lung tissue at different altitudes and times, and to determine the significance of such changes. A total of 88 Wistar rats were randomly divided into 3 groups as follows: the control group [low altitude (LA), 1,500 m; n=8], the moderate altitude group (MA group, 2,260 m; n=40) and the high altitude group (HA group, 5,000 m; n=40). The moderate and high altitude groups were subdivided into the 1, 3, 7, 15 and 30 day groups (MA1, 3, 7, 15, 30 and HA1, 3, 7, 15, 30; n=8). The levels of interleukins (IL-6, IL-8 and IL-10) in the rat lung tissue were determined by ELISA. The WST-1 Cell Proliferation Assay kit and total bile acids assay were used to determine the activity levels of SOD and the content of MDA, respectively. Compared to the control group, the levels of IL-6/IL-8/IL-10 were higher in the MA1 group; however, no significant differences were observed between the other MA subgroups. In addition, no significant differences were detected in SOD activity and the MDA content in the MA subgroups. The levels of IL-6/IL-8 in all the HA subgroups were higher compared to those of the control group, and with the passing of time, the levels of IL-6/IL-8 decreased, but were still higher than those of the control group. However, the level of IL-10 decreased with the passing of time, and was lower in all the HA subgroups compared to the control group. With the passing of time, SOD activity decreased, and the MDA content gradually increased. On the whole, the findings of this study indicate that hypoxia due to high altitude induces lung inflammation and oxidative damage, which subsequently causes severe damage to lung tissue. PMID- 26622415 TI - High expression of microRNA-208 is associated with cardiac hypertrophy via the negative regulation of the sex-determining region Y-box 6 protein. AB - The aim of this study was to investigate the expression levels of microRNA-208 (miR-208) and sex-determining region Y-box 6 (SOX6) in patients with progressive cardiac hypertrophy. A total of 50 patients with essential hypertension accompanied by left ventricular hypertrophy, and 30 healthy individuals were enrolled. Peripheral blood samples were collected in order to compare miR-208 expression levels between the cardiac hypertrophy patients and healthy individuals. In addition, an in vitro cellular model of cardiac hypertrophy was established to determine the association between miR-208 and SOX6 expression. Rat cardiomyocytes were treated with phenylephrine (PE) to induce cardiac hypertrophy. Some of the hypertrophic cardiomyocytes were subsequently transfected with antagomiR-208, an miR-208 antagonist, in order to determine the effects of silencing miR-208 expression. Differences between healthy and hypertrophic cardiomyocyte morphology were evaluated using immunofluorescence staining. The mRNA expression levels of the hypertrophy-associated genes beta myosin heavy chain, alpha-sarcomeric actin and atrial natriuretic peptide were determined using quantitative polymerase chain reaction (qPCR). The mRNA and protein expression levels of miR-208 and SOX6 in peripheral blood and cardiomyocytes were detected using qPCR and western blot analysis, respectively. The expression levels of miR-208 were significantly increased in the peripheral blood of patients with left ventricular hypertrophy (P<0.05). PE-stimulated cardiomyocytes were significantly increased in size compared with normal cardiomyocytes. In the PE-stimulated cardiomyocytes, miR-208 expression levels were significantly increased (P<0.05). However, SOX6 expression levels were significantly decreased compared with those in normal cardiomyocytes (P<0.05). Following transfection with antagomiR-208, SOX6 expression levels in the PE stimulated cardiomyocytes significantly increased, while the total mRNA and protein expression levels of hypertrophy-associated genes significantly decreased (P<0.05). miR-208 expression levels are increased in the peripheral blood of patients with cardiac hypertrophy. Therefore, the results of this study suggest that the expression levels of miR-208 are associated with cardiac hypertrophy by the negative regulation of SOX6. PMID- 26622416 TI - Extracellular polymeric substance from Aphanizomenon flos-aquae induces apoptosis via the mitochondrial pathway in A431 human epidermoid carcinoma cells. AB - Extracellular polymeric substance (EPS) is a substance secreted during algal growth, which has been found to have numerous health-promoting effects. In the present study, A431 human epidermoid carcinoma cells were selected as target cells and cultivated in vitro as an experimental model to investigate the anti cancer effect of extracellular polymeric substances from Aphanizomenon flos-aquae (EPS-A) and the possible underlying mechanism. Apoptosis- and cell cycle associated molecules as well as the mitochondrial membrane potential of the cells were quantified using flow cytometry (FCM). FCM showed that EPS-A induced cell cycle arrest, which led to a loss of mitochondrial function of the A431 cells and an increase in necrotic and late apoptotic cells. In order to evaluate the apoptosis and cell viability, acridine orange/ethidium bromide staining was used, morphological changes were observed using fluorescence microscopy and typical apoptotic characteristics were observed. Following treatment with a high dose of EPS-A, transmission electron microscopy showed nuclear fragmentation, chromosome condensation, cell shrinkage and expansion of the endoplasmic reticulum; apoptotic bodies were also observed. In conclusion, EPS-A caused cell cycle arrest, stimulated cell apoptosis via the mitochondrial pathway and exhibited important anti-cancer activity. PMID- 26622417 TI - Detection of AmpC beta-lactamases in Acinetobacter baumannii in the Xuzhou region and analysis of drug resistance. AB - The aim of the present study was to determine the prevalence and related drug resistance of AmpC beta-lactamases in Acinetobacter baumannii in tertiary-level hospitals in the Xuzhou region in China. A total of 134 clinical isolates of non repetitive Acinetobacter baumannii were collected from different hospitals in the Xuzhou region, and multiplex polymerase chain reaction (PCR) was employed to determine the genotype of AmpC. The PCR products were purified and sequenced. The susceptibility to antibiotics was tested using the biometrics automated microbiological-assay system, VITEK-2. Amongst the 134 isolated strains, 96 strains were found to produce AmpC beta-lactamases, and the positive rate was 72%, all of which carried acinetobacter-derived cephalosporinase (ADC) type AmpC resistance genes. The drug sensitivity tests indicated that the positive Acinetobacter baumannii strains were resistant to the majority of extended spectrum beta-lactam antibiotics, but were only sensitive to polymyxin. In conclusion, the incidence of AmpC enzymes in Acinetobacter baumannii strains in tertiary-level hospitals in the Xuzhou area is relatively high, and resistance to the majority of extended-spectrum beta-lactam antibiotics may be related to the ADC type of AmpC. PMID- 26622418 TI - Prognostic significance of the mRNA expression of ERCC1, RRM1, TUBB3 and TYMS genes in patients with non-small cell lung cancer. AB - The present study aimed to investigate the prognostic value of excision repair cross-complementing 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), class III beta-tubulin (TUBB3) and thymidylate synthase (TYMS) in patients with non small cell lung cancer (NSCLC) receiving platinum-based adjuvant chemotherapy. The mRNA expression of these genes was assessed in 72 tumor tissue samples obtained following surgery, using multiplex branched-DNA technology. Subsequent to surgery, all 72 patients with NSCLC were treated with platinum-based chemotherapy. The expression of these five genes was analyzed and the correlation with clinical characteristics and patient survival was investigated. Among the 72 samples, the incidence rate of mRNA expression of ERCC1 was 38.9% (28/72), RRM1 was 55.6% (40/72), TUBB3 was 47.2% (34/72) and TYMS was 62.5% (45/72). The incidence rate of ERCC1 expression in adenocarcinoma (34.2%) was significantly lower than that in non-adenocarcinoma (44.1%; P<0.05). Furthermore, the incidence rates of TYMS and TUBB3 expression in the high-median differentiation tissue samples were significantly lower than those in the low differentiation tissue samples (P<0.05). When the correlation of gene expression and patient survival was analyzed, high expression of ERCC1, RRM1, TUBB3 or TYMS was found to be associated with poor prognosis (P<0.001, P=0.001, P=0.001 and P=0.001, respectively). ERCC1, RRM1, TUBB3 and TYMS are key factors involved in survival following surgical treatment in patients with NSCLC. The mRNA expression of these genes may have prognostic value for patients with NSCLC treated with platinum based chemotherapy. PMID- 26622419 TI - Association between low expression levels of interleukin-9 and colon cancer progression. AB - Although interleukin (IL)-9 has been extensively studied in inflammation and autoimmune diseases, the expression level of IL-9 in colon cancer and its clinical significance are less well established. In total, 15 healthy donors (HDs) and 60 patients who had been diagnosed with colon cancer that had undergone a surgical resection were enrolled in the study. The plasma levels of IL-9 in the HDs and cancer patients were detected by the liquid chip technique, while the expression levels of IL-9 in the colon cancer tissues and normal tissues were analyzed using immunohistochemistry (IHC) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Finally, the difference in the expression levels of IL-9 between the patients classified as tumor-node-metastasis stage I II and stage III-IV was compared. The results demonstrated that the plasma levels of IL-9 in the patients with colon cancer were significantly lower when compared with the HDs (1.29 vs. 2.53 pg/ml, P<0.05). Furthermore, according to the IHC and RT-qPCR results, low expression levels of IL-9 were observed in the colon cancer tissues when compared with the normal tissues (P<0.05). With regard to the plasma and tumor tissue samples, patients diagnosed with stage III-IV colon cancer expressed lower levels of IL-9 compared with the stage I-II patients (P<0.05). In conclusion, low expression levels of IL-9 were observed in the tissue and plasma samples collected from the colon cancer patients, and the decreased expression of IL-9 was shown to correlate with colon cancer progression. PMID- 26622420 TI - Protective effects of monosialotetrahexosylganglioside sodium on H2O2-induced human vascular endothelial cells. AB - Monosialotetrahexosylganglioside sodium (GM1) is widely used in the treatment of central and peripheral neurological injuries. In addition to its neuroprotective activity, GM1 exerts protective effects on brain microvascular endothelial cells, although the mechanisms underlying these effects remain unclear. The aim of the present study was to clarify the protective effects and underlying mechanisms of GM1 on human umbilical vein endothelial cells (HUVECs). In this study, hydrogen peroxide (H2O2) was applied to induce the HUVEC injury. HUVECs in a logarithmic growth phase were divided into five groups, namely the control, H2O2-treated, 10 mg/l GM1, 5-mg/l GM1 and 1-mg/l GM1 groups. In all the groups, cell proliferation was detected using a Cell Counting Kit-8 assay, a flow cytometric method was applied to analyze the cell cycle and nuclear factor (NF)-kappaB expression was evaluated using immunofluorescence analysis. In addition, the protein expression levels of NF-kappaB, phosphatidylinositol 3-kinase (PI3K) and glycogen synthase kinase (GSK)-3 were detected via western blot analysis. The results indicated that GM1 exerted significant protective effects on H2O2-injured cells by increasing the ratio of cells in the S/G2 phase. Furthermore, western blot analysis revealed that PI3K expression levels were markedly increased after 24 h, as a result of the GM1 treatment, while the expression of both GSK-3 markedly decreased. In addition, the ratio of nuclear-to-cytoplasmic NF-kappaB expression increased in the GM1-treated cells. In summary, GM1 exhibited marked protective effects on the HUVECs, possibly due to the ability of GM1 in maintaining the integrity of the endothelium and increasing the proportion of cells undergoing mitosis, a process in which the PI3K/GSK-3 and NF-kappaB pathways are crucially involved. PMID- 26622421 TI - Combination of vascular endothelial growth factor-loaded microspheres and hyperbaric oxygen on random skin flap survival in rats. AB - The present study aimed to investigate the role of hyperbaric oxygen (HBO) and treatment with vascular endothelial growth factor (VEGF)-loaded microspheres, and HBO plus VEGF on the survival of random skin flaps in rats. The modified McFarlane flap model was established in 40 rats and evaluated within four groups: VEGF (n=10), HBO (n=10), HBO plus VEGF (n=10) and controls (n=10). Seven days following treatment, the necrotic area of the flap was measured. The specimens were stained with hematoxylin and eosin for histological analysis. Immunohistochemical staining was used to analyze the positive expression levels of VEGF. The percentages of necrosis of the skin flaps in all groups were: 49.66+/-2.64% in controls, 26.85+/-1.77% in VEGF, 28.27+/-2.21% in HBO and 10.44+/-2.48% in the combination group. Histological analysis demonstrated angiogenesis with mean vessel density per mm2 in the groups were: 16.68+/-2.69 in controls, 22.96+/-3.29 in VEGF, 24.74+/-3.19 in HBO and 34.81+/-3.93 in the combination group. The expression of VEGF of the controls, VEGF, HBO and the combination group were 28.33+/-4.98, 52.54+/-4.55, 49.32+/-4.62 and 78.97+/-4.90 integral absorbance, respectively. For all measurements, the combination group showed greater improvement in random skin flap survival than others (P<0.05). No significant difference was detected between the VEGF and HBO group. The control group exhibited lower survival rates compared with the other groups (P<0.05). Combination of VEGF and HBO improved random skin flap survival compared with the effect of VEGF or HBO alone, suggesting these two agents exhibited a synergistic effect. PMID- 26622422 TI - Effect of non-genomic actions of thyroid hormones on the anaesthetic effect of propofol. AB - Hyperthyroidism is a common disease of the endocrine system and it is known that additional propofol anaesthesia is required during surgery for patients with hyperthyroidism compared with those with normal thyroid function. The aim of the present study was to determine the mechanism through which thyroid hormones (THs) inhibit the effect of propofol anaesthesia. Immunofluorescence techniques were used to verify the difference between the expression quantities of gamma aminobutyric acid type A (GABAA) receptor subunits alpha2 and beta2 in the dorsal root ganglions (DRGs) of rats with hyperthyroidism and those in normal rats. Perforated patch clamp recordings in the whole-cell mode were performed to detect the GABA-activated current in acutely isolated rat DRG neurons from rats with hyperthyroidism and normal rats. This method was also used to evaluate the change in the GABA-activated currents following the pre-perfusion of propofol with and without 3,3',5-L-triiodothyronine (T3). Compared with normal rats, rats with hyperthyroidism expressed same quantities of GABAA receptor alpha2 and beta2 subunits in DRGs. In addition, no difference in GABA-activated currents in the acutely isolated DRG neurons from the two types of rat was observed (P>0.05). T3 inhibits or minimises the augmentation effect of propofol on the GABA-activated currents (P<0.05). The inhibitory effect of T3 on propofol was minimised by increasing the propofol concentration (P<0.05). The inhibitory effect of T3 on the anaesthetic effect of propofol is achieved through the inhibition of the function of GABAA receptors through the non-genomic actions of the THs, rather than by changing the number of GABAA receptors. This inhibitory effect can be mitigated by increasing the propofol concentration. In conclusion, rats with hyperthyroidism require a larger dose of propofol to induce anaesthesia since the non-genomic actions of THs suppress GABA receptors, which in turn inhibits the anaesthetic action of propofol. PMID- 26622423 TI - Impact of perioperative probiotic treatment for surgical site infections in patients with colorectal cancer. AB - The aim of the present study was to estimate the effect of the perioperative administration of probiotics in patients undergoing colorectal cancer (CRC) surgery. The study focused on a total of 156 consecutive surgeries carried out from among all the elective CRC surgeries performed between April 2009 and March 2013. The patients involved in surgeries undertaken between April 2009 and October 2011 were placed in the non-probiotic group (group A, 81 patients) and those involved in surgeries between November 2011 and March 2013 were placed in the probiotic group (group B, 75 patients). Postoperative infectious complications were recorded, and the immune responses and fecal microbiota were determined. A breakdown of infectious complications showed that 21 (13.5%) patients experienced superficial incisional surgical site infections (SSIs), of which 16 patients were from group A (19.8%), and five patients from group B (6.7%) (P=0.016). The ImmuKnow(r) adenosine triphosphate values peaked on the first postoperative day (POD) in both groups. In group A, the ImmuKnow value of the first POD was increased significantly compared with the preoperative value (P=0.022). In group B, the value of the first POD did not increase compared with the preoperative value (P=0.28). In conclusion, probiotic treatment can reduce superficial incisional SSIs in patients undergoing CRC surgery. Perioperative probiotic treatment can enhance immune responses and improve the intestinal microbial environment. PMID- 26622424 TI - Chemoembolization and stenting combined with iodine-125 seed strands for the treatment of hepatocellular carcinoma with inferior vena cava obstruction. AB - The aim of the present study was to investigate the efficacy and safety of stenting combined with radioactive iodine-125 seed strands following chemoembolization for the treatment of patients with hepatocellular carcinoma and inferior vena cava (IVC) obstruction. A retrospective analysis was conducted of 52 hepatocellular carcinoma patients with IVC obstruction. All patients received chemoembolization of tumor-supplying arteries and IVC stents, and 18 patients additionally received iodine-125 seed strands, which were fixed to the stents. Improvement of IVC obstruction and the tumor response rates were compared between the two groups with a median follow-up time of 2.5 months. In both groups the stents were successfully deployed. At the 2-month post-procedural follow-up, the mean diameter of the IVC obstruction site, the mean pressure difference between the distal IVC obstructive segment and the right atrium as well as the obstruction scoring did not differ significantly between the two groups. By contrast, the tumor response rate of the iodine-125 seed strand group was 94.4%, whereas for the group without iodine-125 seed strands it was 35.3% (P<0.001). The combination of stent and iodine-125 seed strands was effective and safe for the treatment of hepatocellular carcinoma with IVC obstruction. PMID- 26622425 TI - Different training status may alter the continuous blood glucose kinetics in self paced endurance running. AB - The main purpose of the systemic energy metabolism is to provide a source of energy, mainly glucose, for the brain; therefore, blood glucose levels would be expected to correlate with exercise performance. The individual training status may also affect the blood glucose levels. The aim of the present study was to assess the association between blood glucose levels and running velocity during prolonged running in athletes with different training statuses. Two female college athletes, a triathlete and a tennis player, ran a course that was 247.4 m in circumference for 5 h while wearing a continuous glucose monitoring system. Blood was obtained at time-points of -1, 1, 3 and 5 h. The athletes had free access to food and fluids throughout the run. The athletes ran at almost the same pace without a sudden decrease in pace. The blood glucose levels increased and remained high in the triathlete, whereas the tennis player remained hypoglycemic throughout the run. Carbohydrate ingestion did not affect the blood glucose levels. The magnitude of hormonal changes, e.g. insulin, adrenaline and cortisol, was greater in the tennis player. The blood glucose concentration did not correlate with the running velocity or the carbohydrate ingestion; however, a discrepancy in blood glucose transition was observed between the triathlete and the tennis player, indicating a possible association between the adaptation to endurance exercise and the blood glucose kinetics during prolonged running. PMID- 26622426 TI - Clinical value of real-time elastography quantitative parameters in evaluating the stage of liver fibrosis and cirrhosis. AB - The aim of the present study was to assess the value of real-time elastography (RTE) quantitative parameters, namely the liver fibrosis (LF) index and the ratio of blue area (%AREA), in evaluating the stage of liver fibrosis. RTE quantitative analysis software was used to examine 120 patients with chronic hepatitis in order to obtain the values for 12 quantitative parameters from the elastic images. The diagnostic performance of two such parameters, the LF index and %AREA, were assessed with a receiver operating characteristic (ROC) curve to determine the optimal diagnostic cut-off values for liver cirrhosis and fibrosis. A good correlation was observed between the LF index and %AREA with the fibrosis stage. The areas under the ROC curve for the LF index were 0.985 for the diagnosis of liver cirrhosis and 0.790 for liver fibrosis. With regard to %AREA, the areas under the ROC curve for the diagnosis of liver cirrhosis and fibrosis were 0.963 and 0.770, respectively. An LF index of >3.25 and a %AREA of >28.83 for the diagnosis of cirrhosis stage resulted in sensitivity values of 100 and 100%, specificity values of 88.9 and 85.9% and accuracy values of 90.8 and 88.3%, respectively. The LF index and %AREA parameters exhibited higher reliability in the diagnosis of liver cirrhosis compared with the diagnosis of the liver fibrosis stage. However, the two parameters possessed a similar efficacy in the diagnosis of liver cirrhosis and the stage of liver fibrosis. Therefore, the quantitative RTE parameters of the LF index and %AREA may be clinically applicable as reliable indices for the early diagnosis of liver cirrhosis, without the requirement of an invasive procedure. PMID- 26622427 TI - Effect of adenosine on GLAST expression in the retina of a chronic ocular hypertension rat model. AB - This study was performed to evaluate the effect of adenosine and an adenosine receptor antagonist on the expression of the L-glutamate/L-aspartate transporter (GLAST) in the retina of a chronic ocular hypertension (COH) rat model. COH models were established via the cauterization of three episcleral veins. Measurements of the intraocular pressure of the right eye (COH eye) were taken weekly by a handheld digital tonometer. A total of 10 uM adenosine or 10 uM adenosine + 100 nM SCH442416 solution (2 ul) was injected into the rat vitreous space. The reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemistry were used to detect GLAST expression. Compared with the COH group, GLAST mRNA expression was decreased by 33.6% in the group treated with adenosine (n=6, P=0.020) and was increased by 159.6% in the group treated with SCH442416 (n=6, P=0.001). Administration of adenosine decreased GLAST protein expression by 34.7% (n=6, P<0.001), while treatment with the adenosine A2A receptor antagonist SCH442416 increased GLAST protein expression by 48.3% compared with the control COH group (n=6, P<0.001). Immunohistochemical experiments showed that administration of adenosine decreased GLAST protein expression, as compared with expression in the control COH rat retina. Administration of SCH442416 markedly increased GLAST protein expression. The results of the present study may provide a novel method for retinal neuron protection. PMID- 26622428 TI - Effects of TGF-beta1 and alginate on the differentiation of rabbit bone marrow derived mesenchymal stem cells into a chondrocyte cell lineage. AB - The aim of the present study was to investigate the effect of a three-dimensional (3D) culture system of sodium alginate gel on the directional differentiation induction of bone marrow-derived mesenchymal stem cells (BMSCs) into chondrocytes, as well as the in vitro gene transfection technique. The biological characteristics of the passage and proliferation of rabbit BMSCs were investigated under conditions of in vitro monolayer and 3D culture of sodium alginate gel. Transforming growth factor (TGF)-beta1 gene recombinant adenoviral cosmid vectors and the recombinant adenoviral vector Ad.TGF-beta1 were constructed, and the effect of Ad.TGF-beta1 transfection on the differentiation of BMSCs into chondrocytes was investigated. The whole bone marrow rinsing method was used to obtain, separate and purify the rabbit BMSCs, and the in vitro monolayer and 3D culture of sodium alginate gel were thus successfully and stably established. A safe, stable and efficient method of constructing Ad.TGF-beta1 TGF beta1 gene recombinant adenoviral vectors was established. Following TGF-beta1 transfection, BMSCs were able to continuously secrete significantly increased amounts of specific extracellular matrix components of chondrocytes, such as collagen II and proteoglycans. Furthermore, the effects in the post-gene transfection 3D culture group were found to be enhanced compared with those in the monolayer culture group. In conclusion, the 3D culture system of sodium alginate gel and in vitro gene transfection exhibited significant inductive effects on differentiation, which could be used to promote BMSCs to differentiate into chondrocytes. PMID- 26622429 TI - High-dose immunosuppressant alters the immunological status of New Zealand white rabbits following skin transplantation. AB - The aim of this study was to investigate the effect of an immunosuppressant on the immunological status of New Zealand white rabbits after skin grafting, and to evaluate a method for monitoring the immunological status of subjects with skin transplants. The rabbits were randomly divided into allograft rejection, autograft tolerance, nontransplant, allograft low-dose immunosuppressant and allograft high-dose immunosuppressant groups. The rabbits in the low- and high dose immunosuppressant groups were treated with cyclosporine A intravenously 8 h prior to skin transplantation and once daily following transplantation at doses of 2 and 25 mg/kg, respectively. At 12 days after skin transplantation, the spleens of donor (female) rabbits and recipient (male) rabbits were harvested for the preparation of single-cell suspensions. The splenocytes from recipient and donor rabbits were labeled with 0.3 or 6 uM carboxy fluorescein diacetate succinimidyl ester, respectively, and a mixed cell suspension was prepared. The final preparation was intravenously injected into recipient New Zealand white rabbits. The ratio of the two fluorescently labeled cell populations in the peripheral blood was measured using flow cytometry at 1, 2, 4 and 8 h after the injection, and the cell death rate was calculated. Histological analysis was also performed on samples collected at the time of splenectomy. The cell death rates of the allograft rejection and low-dose immunosuppressant groups reached their highest levels 8 h after the injection of spleen cell suspension. Allogeneic spleen cells from donor male rabbits were almost completely removed within 8 h of injection. The cell death rate increased slowly in the nontransplant, autograft and high-dose immunosuppressant groups without specificity. This study provides a specific method for the in vivo monitoring of the immunological status of patients after skin grafting. This method can quickly and accurately detect the immunological status of recipients following the injection of a mixed splenocyte suspension, thereby indicating the strength of immune rejection by the immune systems of the recipients. PMID- 26622430 TI - Microgranular variant of acute promyelocytic leukemia with der(17) ins(17;15): A case report and review of the literature. AB - Acute promyelocytic leukemia (APL) with variant translocations is rare. The patient of the present case report, a 2-year-old male with a microgranular variant of APL carrying der(17) ins(17;15) translocation, exhibited fever and epistaxis. The complete blood count showed marked leukocytosis with 72% atypical promyelocytes, anemia and thrombocytopenia. Conventional cytogenetic analysis of the bone marrow cells revealed a karyotype of 47, XY, add(3)(q29), -7, ins(17;15)(q12;q14q22),+21,+mar. The promyelocytic leukemia/retinoic acid receptor alpha (PML/RARalpha) rearrangement and insertion were confirmed by fluorescence in situ hybridization. The PML/RARalpha transcripts were not detected by the reverse transcription polymerase chain reaction, and the patient was diagnosed with microgranular variant M3 APL. The patient achieved remission after a 30-day treatment and was still in remission during a recent follow-up. The present findings suggest that the ins(17;15) variant in APL may not be associated with an unfavorable prognosis. In summary, we reported an extremely rare case of APL with der(17) ins(17;15) abnormality in a pediatric patient and reviewed the literature. PMID- 26622431 TI - Efficacy of low-dose 90Sr-90Y therapy combined with topical application of 0.5% timolol maleate solution for the treatment of superficial infantile hemangiomas. AB - The aim of the present study was to investigate the clinical efficacy and safety of low-dose 90Sr-90Y therapy combined with the topical application of 0.5% timolol maleate solution for the treatment of superficial infantile hemangiomas (IHs). A total of 72 infants with hemangiomas were allocated at random into the observation group (17 cases aged <=3 months, 20 cases aged >3 months) or the control group (15 cases aged <=3 months, 20 cases aged >3 months). The observation group was treated with low-dose 90Sr-90Y combined with timolol, while the control group received an identical dose of 90Sr-90Y with physiological saline. Data were collected for statistical analysis, and treatment efficacy was compared between the two groups. In the observation group, 100% (37/37) of subjects exhibited an 'excellent' response to the treatment, while 94.1% (16/17) of patients aged <=3 months and 85.0% (17/20) aged >3 months were classed as being cured. In the control group, the treatment was classed as 'effective' in 100% (35/35) of the subjects, while the excellent response rate was 86.7% (13/15) among the infants aged <=3 months and 75.0% (15/20) among the infants aged >3 months. The 'cure' rates in the control group were 66.7% (10/15) and 60.0% (12/20) for the <=3-month- and >3-month-old subjects, respectively. The excellent response and cure rates were notably higher in the observation group than those in the control group. Comparison between the two groups revealed a chi2 value of 13.90 (P<0.01) for excellent responses in subjects aged <=3 months, while for patients aged >3 months the chi2 value was 28.57 (P<0.01). Analysis of the cure responses gave similar results [<=3 months, chi2=23.22 (P<0.01); >3 months, chi2=15.67 (P<0.01)]. At 3-4 months after the first course of treatment, the cure rate was 33.3% (11/33) in the observation group, which was significantly higher than the rate of 18.32% (4/22) in the control group (chi2=5.92, P<0.05). No serious adverse reactions were observed in either group. In summary, low-dose 90Sr-90Y therapy combined with the topical application of 0.5% timolol maleate induces a rapid response in superficial IH, with excellent efficacy and no obvious adverse reactions, and may represent a clinically applicable intervention. PMID- 26622432 TI - Effect of shRNA-mediated knockdown of vascular endothelial growth factor on the proliferation of choroid-retinal endothelial cells under hypoxic conditions. AB - The aim of the present study was to investigate the role of vascular endothelial growth factor (VEGF) in cell proliferation under hypoxic conditions. Gene knockdown of VEGF was conducted in the choroid-retinal endothelial RF/6A cell line by transfection with short hairpin RNA (shRNA), in which a shRNA fragment against VEGF was synthesized and cloned into the vector, pSilencer 2.1-U6 neo. Subsequently, a model of hypoxia was established in the RF/6A cell line via treatment with CoCl2, into which the recombinant plasmids, containing the VEGF targeting shRNA (p-shRNA), were transfected. The study included four treatment groups, namely a control group (normal group), a hypoxia group treated with CoCl2 (CoCl2 group), a control plasmid group that were subjected to CoCl2 treatment and transfection with a pSilencer 2.1-U6 neo plasmid without the shRNA (CoCl2 + p-NC group), and a group treated with CoCl2 and transfected with a pSilencer 2.1-U6 neo plasmid containing the VEGF-targeting shRNA (CoCl2 + p-shRNA group). Subsequent to treatment, the mRNA and protein expression levels of VEGF were evaluated using quantitative polymerase chain reaction and western blot analysis, respectively, In addition, cell proliferation was assessed. RF/6A cells treated with CoCl2 reduced cell connectivity, irregular morphology and reduced thickness compared with the cells in the normal group. However, cells in the CoCl2 + p shRNA group exhibited an improved morphology compared with the CoCl2 and CoCl2 + p-NC groups. Cell proliferation in the CoCl2 group was enhanced in a time dependent manner. However, the hypoxia-induced increase in cell proliferation was significantly inhibited in the CoCl2 + p-shRNA group, with inhibition rates of 16, 32 and 38% at 24, 48 and 72 h, respectively. The mRNA and protein expression levels of VEGF were increased in the CoCl2 group when compared with the normal group, and these hypoxia-induced increases in VEGF expression were reduced in the CoCl2 + p-shRNA group. Therefore, the results indicated that the targeted knockdown of VEGF in vascular endothelial cells may be effective for the treatment of retinal neovascularization diseases. PMID- 26622433 TI - Adult systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease: A case report. AB - Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease (EBV+ T-LPD) occurs mainly in Asia and South America and is extremely rare in adults. The disease is characterized by a clonal proliferation of EBV-infected T cells with a cytotoxic immunophenotype and is associated with a poor clinical outcome and can be life-threatening. The majority of the patients have evidence of systemic disease, often with lymph node, liver and spleen involvement. The present study describes a case of adult systemic EBV+ T-LPD with high fever, systemic lymphadenopathy, hepatosplenomegaly, nose-pharynx neoplasm, pancytopenia, EB virus infection and proliferative bone marrow, with the aim of improving the understanding of the condition. PMID- 26622434 TI - Management of extracranial carotid artery aneurysm: A report of four cases. AB - Extracranial carotid artery aneurysm (ECAA) is an uncommon type of peripheral artery aneurysm. The treatment of this disease requires surgical intervention. Due to the limited number of large studies, the safety and efficacy of surgical and interventional management of ECAA is not well characterized. The optimum treatment has not been clearly defined. The present study reports four cases of ECAA. The patients received end-to-end anastomosis, carotid artery stents and balloon occlusion, respectively. These four cases demonstrate that ECAA may be successfully managed using end-to-end anastomosis. Furthermore, end-to-end anastomosis is a better intervention compared with endovascular treatment as it facilitates the removal of lesions under direct observation. The advantage of open surgery is the surgical repair of end-to-end anastomosis under direct observation. However, few studies have investigated the effect of the timing of resection of an aneurysm on patient outcome and the control of bleeding remains a challenge for surgeons. Therefore, the proximal and distal ends of aneurysm should be under direct observation during surgery. PMID- 26622435 TI - Construction of orthotopic xenograft mouse models for human pancreatic cancer. AB - Animal models are indispensable for the study of tumorigenesis and the development of anti-cancer drugs for human pancreatic cancer. In the present study, two orthotopic xenograft mouse models were developed. AsPC-1 human pancreatic cancer cells were stably labeled with red fluorescent protein (RFP) and injected subcutaneously into nude mice. For the orthotopic tumor mass model, the formed subcutaneous tumors were cut into blocks and implanted into the pancreas of nude mice via laparotomy. For the MatrigelTM tumor block model, solidified Matrigel containing RFP-labeled AsPC-1 cells was cut into blocks and implanted into the pancreas of nude mice. A subcutaneous tumor xenograft model was used as a control. Tumor growth and metastasis were assessed using an in vivo fluorescence imaging system. Thirty-six days after implantation, all mice from the two orthotopic xenograft models (n=20 per group) and 55% of the subcutaneous xenograft mice (n=20) developed tumors. The tumor growth rate was significantly higher in the orthotopic models than that in the subcutaneous model (P<0.01). Metastasis to organs such as the liver was observed in the orthotopic tumor models. Histological examination showed that the tumors were poorly differentiated adenocarcinomas. In conclusion, two orthotopic xenograft mouse models of human pancreatic cancer were established; these exhibited greater tumor growth and metastasis than the subcutaneous xenograft mouse model. PMID- 26622436 TI - 1alpha,25-Dihydroxyvitamin D3 inhibits the differentiation and bone resorption by osteoclasts generated from Wistar rat bone marrow-derived macrophages. AB - The steroid hormone 1alpha,25-dihydroxyvitamin D3 [1alpha,25-(OH)2D3] plays an important role in maintaining a balance in calcium and bone metabolism. To study the effects of 1alpha,25-(OH)2D3 on osteoclast (OC) formation and bone resorption, OC differentiation was induced in bone marrow-derived mononuclear cells from Wistar rats with the addition of macrophage colony stimulating factor and receptor activator for nuclear factor-kappaB ligand in vitro. Cells were then treated with 1alpha,25-(OH)2D3 at 10-9, 10-8 or 10-7 mol/l. OCs were identified using tartrate-resistant acid phosphatase staining and activity was monitored in the absorption lacunae by scanning electron microscopy. Expression levels of functional proteins associated with bone absorption, namely carbonic anhydrase II, cathepsin K and matrix metalloproteinase-9 were evaluated by western blot analysis. The results showed that 1alpha,25-(OH)2D3 inhibited the formation and activation of OCs in a dose-dependent manner and downregulated the expression levels of bone absorption-associated proteins. PMID- 26622438 TI - Effect of exogenous adipose-derived stem cells in the early stages following free fat transplantation. AB - Cotransplantation of adipose-derived stem cells (ASCs) is an effective therapeutic approach for enhancing the survival of transplanted fat tissue; however, the role of ASCs in free fat transplantation remains unclear. In the present study, fat harvested from C57BL/6 mice expressing green fluorescent protein was injected subcutaneously into the back of C57BL/6 mice, who also received ASCs (group A) or received the fat tissue only (group B). The grafts were harvested at days 1, 4, 7, 14, 30 and 90 following the transplantation. Graft volume and histology were evaluated, and the secretion levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) were quantified using enzyme-linked immunosorbent assays. No statistically significant difference was identified between groups A and B in the graft survival rate up to day 14 following the aspirated fat transplantation; however, the graft survival rate decreased during the following 14-90 days. Initially, group =A exhibited a higher graft survival rate and a greater degree of angiogenesis compared with group B. The ratio of dead cells was not significantly different between the two groups on day 1; however, group A had a greater number of living interstitial cells compared with group B at the later time points. The secretion of VEGF by the ASCs had an earlier peak time in group A (day 4) compared with group B (day 7). In addition, the secretion of HGF in group A was greater compared with group B. Therefore, the role of exogenous ASCs in free fat transplantation may not directly participate in angiogenesis and adipogenesis, but may promote the survival ratio of the graft-resident interstitial cells, which are involved in angiogenesis and adipogenesis, via a paracrine effect. PMID- 26622437 TI - Analysis of mutation of the c-Kit gene and PDGFRA in gastrointestinal stromal tumors. AB - The aim of the present study was to investigate mutation status of the c-Kit gene (KIT) and PDGFRA in patients with a gastrointestinal stromal tumor (GIST). In total, 93 patients with a GIST were included in the study, in which polymerase chain reaction amplification and gene sequencing were used to detect the sequences of exons 9, 11, 13 and 17 in KIT and exons 12 and 18 in PDGFRA. KIT mutations were detected in 64 cases (68.82%), of which exon 11 mutations were detected in 56 cases (60.22%), exon 13 mutations were detected in three cases (3.23%) and one case (1.08%) was shown to have a mutation in exon 17. The most common mutation in exon 11 was a deletion, which accounted for 55.36% (31/56) of the cases, followed by a point mutation observed in 26.79% (15/56) of the cases, while an insertion (tandem repeats) was identified in 14.29% (8/56) of the cases, and 3.57% (2/56) of the exon 11 mutations were deletions associated with a point mutation. The majority of the mutations were heterozygous, with only a few homozygous mutations. Mutational analysis revealed the mutations to be more concentrated in the classic hot zone at the 5'-end, followed by the tandem repeat frame at the 3'-end. In four cases, a mutation was detected in exon 18 of PDGFRA, of which one was associated with a mutation in KIT. The remaining three cases (10.34%, 3/29) were not associated with mutations in KIT and accounted for 37.5% (3/8) of the CD117-negative GIST cases. Therefore, the majority of the GIST cases were characterized by mutations in KIT or PDGFRA, which were directly associated with the disease. Pairs of different mutations in the same exon of KIT, or KIT mutations coupled with pairs of mutations in PDGFRA, were detected in a small number of patients. Imatinib is a small molecule tyrosine kinase inhibitor and is the first line targeted treatment for GIST, resulting in markedly improved survival rates. Thus, gene mutation genotyping may provide inspiration and guidance for imatinib-based targeted cancer therapy. PMID- 26622439 TI - Intracoronary administration of anisodamine and nicorandil in individuals undergoing primary percutaneous coronary intervention for acute inferior myocardial infarction: A randomized factorial trial. AB - In acute inferior myocardial infarction (AIMI), numerous conventional drugs that are used to improve the myocardial microcirculation can significantly reduce blood pressure (BP) and coronary perfusion pressure, aggravate bradyarrhythmia and cause a deterioration in the hemodynamic state of the whole body, which greatly limits the application of these drugs in clinical settings. The aim of the present study was to assess the effect of anisodamine and nicorandil regimens on the prevention of no-reflow (NR) and the amelioration of myocardial reperfusion in patients with AIMI undergoing primary percutaneous coronary intervention (PCI). A total of 104 consecutive patients with AIMI were included in this study and randomly assigned to one of four groups: A (control group), B (anisodamine group), C (nicorandil group) and D (anisodamine and nicorandil group). Patients underwent PCI via transradial artery access and the angiographic results were evaluated. Coronary diastolic BP (DBP) and systolic and mean BPs were measured by invasive catheterization. The primary end-point was a post-PCI Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion grade (TMPG) of 3. Composite end-points (mortality + new MI + target vessel revascularization) were evaluated during the hospital stay and 30 days after discharge. Following the procedure, the proportion of patients achieving TMPG 3 was significantly higher in group D than that in the other groups (P=0.014); furthermore, the incidence of a postprocedural TIMI score of 3 was the highest in group D. Three days after the procedure, the peak creatine kinase-MB and cardiac troponin I levels were the lowest and the left ventricular ejection fraction was the highest in group D. A thrombus score of 3/4 and low DBP were the independent risk factors for poor myocardial reperfusion (expressed as TMPG <3), while 2 mg anisodamine plus 2 mg nicorandil prior to PCI was protective for optimal myocardial reperfusion following the procedure. The combination of anisodamine and nicorandil can effectively ameliorate myocardial reperfusion and protect cardiac function in patients with AIMI undergoing primary PCI. PMID- 26622440 TI - Wogonin inhibits osteoclast differentiation by inhibiting NFATc1 translocation into the nucleus. AB - The aim of the present study was to identify a natural product with the ability to inhibit nuclear factor of activated T cells c1 (NFATc1) translocation from the cytoplasm to the nucleus by high-throughput screening, and to investigate the effect of the natural product upon osteoclast differentiation and its underlying mechanism. An NFATc1 antagonist redistribution assay was performed in U2OS-NFATc1 cells against a natural product library, and Wogonin was found to have the ability to inhibit the NFATc1 translocation from the cytoplasm to the nucleus. The effect of Wogonin on NFATc1 transcription activation was further determined by luciferase assay. An osteoclast differentiation assay was executed to evaluate the effect of Wogonin on osteoclast differentiation. The effect of Wogonin upon the vital genes in osteoclast differentiation was investigated using fluorescent quantitative polymerase chain reaction analysis. The natural product Wogonin significantly inhibited the translocation of NFATc1 from the cytoplasm to the nucleus and its transcriptional activation activity. Wogonin also significantly inhibited osteoclast differentiation and decreased the transcription of osteoclast-associated immunoglobulin-like receptor, tartrate-resistant acid phosphatase and calcitonin receptor. In conclusion, the natural product Wogonin inhibited osteoclast differentiation through the inhibition of NFATc1 translocation from the cytoplasm to the nucleus, and thus the downregulation of genes associated with osteoclast differentiation, which marked Wogonin as a potential treatment for osteoporosis. PMID- 26622441 TI - Efficacy of nutritional treatment in patients with psoriasis: A case report. AB - Psoriasis is a chronic inflammatory skin disease characterized by thickened, silvery-scaled patches. There is currently no cure and treatments only attempt to reduce the severity of symptoms. This study reports the case of a 36-year-old female who presented to the clinic with severe psoriasis and had been treated with topical steroid cream for the past 14 years. After adherence to prescribed dietary changes for 6 months, including abundant intake of vegetables, minimal consumption of meat, and avoidance of junk food and sugar in food or drinks, as well as nutritional supplementation with Vitacor Plus, ProLysinC, VitaCforte and LysinC Drink mix, the patient experienced complete resolution of psoriatic patches on her body. PMID- 26622442 TI - Helium-neon laser therapy in the treatment of hydroxyapatite orbital implant exposure: A superior option. AB - The aim of the present study was to evaluate the efficacy of helium-neon laser therapy in the treatment of hydroxyapatite orbital implant exposure and compare the results with those of a combined drugs and surgery regimen. A total of 70 patients with hydroxyapatite orbital implant exposure in 70 eyes were randomly divided into two groups: Helium-neon laser therapy (group A) and drugs plus surgery (group B). Each group contained 35 patients. The healing rates and times of the conjunctival wound were recorded and compared following helium-neon laser treatment or the drugs plus surgery regimen. Changes in the hydroxyapatite orbital implant prior to and following helium-neon laser irradiation were analyzed. A similar animal study was conducted using 24 New Zealand white rabbits, which received orbital implants and were then received drug treatment or helium-neon therapy. In the human experiment, the rates for conjunctival wound healing were 97.14% in group A and 74.29% in group B, with a significant difference between the groups (chi2=5.71, P<0.05). Patients with mild exposure were healed after 7.22+/-2.11 days of helium-neon laser therapy and 14.33+/-3.20 days of drugs plus surgery. A statistically significant difference was found between the groups (t=8.97, P<0.05). Patients with moderate to severe exposure were healed after 18.19+/-2.12 days of helium-neon laser therapy and 31.25+/-4.21 days of drugs plus surgery. The difference between the groups was statistically significant (t=7.91, P<0.05). Enhanced magnetic resonance imaging showed that the helium-neon laser therapy significantly promoted vascularization of the hydroxyapatite orbital implant. These results, combined with pathological findings in animals, which showed that a helium-neon laser promoted vascularization and had anti-inflammatory effects, suggest that helium-neon laser irradiation is an effective method for treating hydroxyapatite orbital implant exposure, thereby avoiding secondary surgery. PMID- 26622443 TI - Clinical efficacy of propranolol in the treatment of hemangioma and changes in serum VEGF, bFGF and MMP-9. AB - The aim of this study was to observe the clinical efficacy and safety of propranolol in the treatment of hemangioma, and to reveal its possible mechanism. A total of 129 cases of proliferative hemangioma were divided into two groups: i) Treatment (n=97), in which the patients received oral propranolol therapy and ii) observation (n=32), in which the patients underwent clinical observation. The changes in the hemangiomas were noted and compared between the two groups. In addition, the heart rate, blood glucose levels, liver, kidney and thyroid function of the patients in the treatment group were monitored prior to and following treatment; the ELISA method was used for the measurement of the patients' serum concentrations of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and matrix metalloproteinase-9 (MMP-9) at the same time-points. A significant difference in curative effect was found between the treatment and observation group. The concentration of free thyroxine and sensitive thyroid-stimulating hormone and the heart rate of the treatment group exhibited significant changes prior to and following medication, but no statistical significance was found in the changes in blood glucose, liver and kidney function and free triiodothyronine concentration. Furthermore, the serum concentrations of VEGF, bFGF and MMP-9 in the treatment group 8 weeks after medication were decreased significantly compared with those before treatment. In conclusion, oral propranolol has a good curative effect in the treatment of proliferative hemangioma, with few side effects and a high level of safety. The mechanism underlying the effects of propranolol may be associated with the downregulation of VEGF, bFGF and MMP-9 expression. PMID- 26622444 TI - Retrospective analysis of the clinicopathological characteristics of gastrointestinal neuroendocrine neoplasms. AB - The aim of the present study was to analyze and summarize the clinicopathological characteristics and factors affecting prognosis for patients with gastrointestinal neuroendocrine neoplasms (GINENs). Retrospective analysis was conducted on the clinicopathological data of 74 patients who were diagnosed with GINEN, and immunohistochemical methods were used to detect the expression levels of relevant markers [synaptophysin (Syn), chromogranin A (CgA) and Ki-67]. Among the 74 cases with GINEN, there were 39 males and 35 females, with an average age of 56.9 years. There were 32 neoplasms in the rectum, 29 in the stomach, 6 in the colon, 2 in the small intestine and 5 in the appendix. All 74 cases underwent surgical resection. According to the World Health Organization Classification of Tumors of the Digestive System (2010), the diagnosis of the 74 cases showed 41 cases (55.4%) of neuroendocrine tumor (NET; 25 cases of G1 and 16 cases of G2), 21 cases (28.4%) of neuroendocrine carcinoma (NEC) and 12 cases (16.2%) of mixed adenoneuroendocrine carcinoma (MANEC). Additionally, 19 cases had metastasis to lymph nodes. During 10-34 months of follow-up, 15 patients had distant metastasis and 24 patients succumbed, and the accumulative survival rate in 1 or 2 years was 87.8 and 74.3%, respectively. Six factors, namely neoplasm size, depth of invasion, lymph node metastasis, distant metastasis, pathological type and the expression or lack of expression of CgA, significantly affected the survival time of patients. Definitive diagnosis of GINEN mainly relies on pathological diagnosis. GINENs with different histopathological types and grading have different clinicopathological characteristics and prognosis: NETs are mainly early lesions with a good prognosis, whereas NECs and MANECs have high malignancy and strong invasion with a worse prognosis. PMID- 26622445 TI - Effect of serum from postmenopausal women with osteoporosis exhibiting the Kidney Yang deficiency pattern on bone formation in an hFOB 1.19 human osteoblastic cell line. AB - The aim of the present study was to investigate the underlying mechanism of the Kidney-Yang deficiency (KYD) pattern of osteoporosis in postmenopausal women of a certain age range by comparing the effect of serum from postmenopausal women with osteoporosis exhibiting the KYD pattern with that of serum from postmenopausal women without osteoporosis on bone formation in an hFOB 1.19 human osteoblastic cell line. A random selection of 30 female, postmenopausal volunteers aged 60-70 years, including 15 cases without osteoporosis and 15 cases with the KYD pattern of osteoporosis, were enrolled at the Physical Examination Center of the Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine. Venous blood was extracted and the serum was separated. The hFOB 1.19 cells were treated with 10% KYD pattern-serum or control serum from postmenopausal women of the same age range without osteoporosis. It was found that the KYD pattern-serum significantly decreased the cell viability, activity of alkaline phosphatase and number of calcified nodules, as well as downregulated the expression of osteocalcin and osteoprotegerin (OPG) and upregulated that of receptor activator of nuclear factor kappaB ligand (RANKL) in the hFOB 1.19 cells. In addition, the present results showed that the concentrations of estradiol (E2), OPG and insulin like factor-1 (IGF-1) in the KYD pattern-serum were lower than those in the control serum. In combination, these findings suggest that the downregulation of E2, OPG and IGF-1 in the KYD pattern-serum inhibits the OPG/RANKL system, leading to a decrease in bone formation in the hFOB 1.19 cells. This indicates that the alterations in E2, OPG and IGF-1 may account for the susceptibility of certain postmenopausal women to the KYD pattern of osteoporosis. PMID- 26622446 TI - Clinical efficacy of 'Spleen-kidney-care' Yiqi Huayu and Jiangzhuo traditional Chinese medicine for the treatment of patients with diabetic nephropathy. AB - The aim of the present study was to investigate the effect of the traditional Chinese medicine (TCM), 'Spleen-kidney-care' Yiqi Huayu and Jiangzhuo decoction (SKC-YJ), as an adjuvant therapy in diabetic nephropathy (DN) treatment. In total, 72 patients with DN were randomly divided into control (n=54) and experimental (n=18) groups, with the latter administered SKC-YJ treatment. Indicators for determining the condition of the patients included the levels of proteinuria, blood glucose, glycosylated hemoglobin, blood lipids, blood viscosity and C-reactive protein, which were used to analyze the treatment protocols for DN. Following SKC-YJ treatment, the urinary albumin excretion rate, fasting blood glucose, 2 h-postprandial blood glucose, glycosylated hemoglobin, triglyceride, total cholesterol, blood viscosity, fibrinogen and C-reactive protein levels were detected in the two groups, and were all demonstrated to decrease significantly following treatment with SKC-YJ. Furthermore, the results revealed that SKC-YJ treatment exhibited no significant side-effects on the blood, liver and renal functions or gastrointestinal reactions. By contrast, SKC YJ improved the symptoms of nausea, vomiting and diarrhea in the patients with DN, while showing no allergic reaction during the observation period. Therefore, SKC-YJ treatment was shown to significantly improve the clinical efficacy of DN treatment, illustrating novel roles for TCM in DN treatment. PMID- 26622447 TI - microRNA-195 inhibits cell proliferation in bladder cancer via inhibition of cell division control protein 42 homolog/signal transducer and activator of transcription-3 signaling. AB - microRNA (miR)-195 acts as a suppressor in multiple types of malignant tumors, including bladder cancer; however, the detailed function of miR-195 in bladder cancer remains largely unknown. The aim of the present study was to investigate the role of miR-195 in the regulation of bladder cancer cell proliferation and to determine whether cell division control protein 42 homolog (Cdc42)/signal transducer and activator of transcription-3 (STAT3) signaling acts as a downstream effector of miR-195 in bladder cancer cells. Reverse transcription quantitative polymerase chain reaction was used to determine the expression levels of miR-195 in bladder cancer tissues and normal adjacent tissue. The results revealed that the expression of miR-195 was significantly downregulated in bladder cancer tissues compared with that in the normal adjacent tissues. A luciferase reporter assay was then conducted, which identified Cdc42 as a direct target of miR-195, and the expression of Cdc42 was significantly upregulated in bladder cancer tissues, as determined by western blotting. Furthermore, miR-195 negatively regulated the protein expression of Cdc42 in bladder cancer cells. An MTT assay was also conducted to determine the rate of cell proliferation. Upregulation of miR-195 or the inhibition of Cdc42 could inhibit bladder cancer cell proliferation, possibly through activation of STAT3 signaling. In addition, restoration of Cdc42 could reverse the inhibitory effect of miR-195 upregulation on bladder cancer cell proliferation. In conclusion, the results of the present study suggest that miR-195 plays an inhibitory role in the regulation of bladder cancer cell proliferation by directly targeting Cdc42/STAT3 signaling. PMID- 26622448 TI - Pioglitazone is an effective treatment for patients with post-stroke depression combined with type 2 diabetes mellitus. AB - The antidepressive effects of the antidiabetic medicine, pioglitazone, were recently reported in several studies. These effects may ameliorate the depressive symptoms of patients with post-stroke depression (PSD). The present study aimed to evaluate the antidepressive effect of pioglitazone in patients with PSD combined with type 2 diabetes. A total of 118 consecutive patients with stroke who had depression were studied for an average of 3 months. The Diagnostic and Statistical Manual of Mental Disorders (fourth edition) was used to assess whether a patient was depressed or not. The severity of depression was evaluated by the Hamilton depression rating scale (HAMD). In accordance with their HAMD scores, the 118 patients were divided into a severe depression group (n=40) and a mild and moderate (MM) depression group (n=78). These subjects were then divided into pioglitazone [30 mg once daily (qd)] and metformin (0.5 g twice daily) subgroups. All patients were given fluoxetine (20 mg qd). Follow-up evaluations, which included HAMD scores, activities of daily living (ADL) scores, fasting blood glucose (FBG) levels and fasting insulin (FINS) levels, were conducted on the first and third month following the beginning of the treatment. In the MM depression group, the HAMD score in the pioglitazone subgroup was lower than that in the metformin subgroup following treatment for 1 or 3 months. In the severe depression group, the HAMD score in the pioglitazone subgroup was lower than that in the metformin subgroup following 3 months of treatment. The FINS levels of the pioglitazone subgroup gradually decreased in the 3 months of treatment. No noticeable improvement was observed in the ADL scores and FBG values. In conclusion, the results of the current study demonstrate that pioglitazone effectively decreased HAMD scores and FINS values in patients with PSD, suggesting that pioglitazone may be useful for the treatment of patients with PSD combined with type 2 diabetes. PMID- 26622449 TI - Impact of daily lifestyle on coronary heart disease. AB - Limited data are available with regard to the impact of daily lifestyle choices in patients with coronary heart disease (CHD) who have undergone stent placement. Thus, the aim of the present study was to investigate the impact of daily lifestyle factors in patients with CHD following stent implantation. Between March 2005 and March 2006, 129 consecutive patients with CHD were admitted to Cangzhou Central Hospital at Hebei Medical University (Cangzhou, China). The patients underwent coronary stenting and participated in a 7-year clinical follow up that analyzed the impact of their daily lifestyle choices on CHD following the stent placement. Rates of dinner satiety [95% confidence interval (CI), 1.121 10.97, P=0.005], smoking (95% CI, 4.05-34.90, P=2.01*10-7) and heavy alcohol use (95% CI, 1.32-11.05, P=0.006) were significantly higher in the repeated (re) revascularization group when compared with the non-revascularization group. In addition, the exercise rate was significantly lower in the re-revascularization group when compared with the non-revascularization group (95% CI, 0.02-0.65, P=0.005). However, no statistically significant differences were observed between the groups with regard to sleeping patterns (95% CI, 0.03-0.71, P=0.270) or anxiety rates (P=0.289). A coronary angiography performed during re revascularization revealed in-stent restenosis in 26% of the patients, stenoses at the entrance to or exit from the stent in 29% of the patients and new lesions in 19% of the patients. Furthermore, original lesions exhibited deterioration in 26% of the patients. The clinical endpoint was reached in 55% of the patients between 3 and 5 years of the follow-up period. In conclusion, poor daily lifestyle habits can increase the in-stent restenosis rate, accelerate the progression of the original lesion and promote the emergence of new lesions in patients with CHD following stent placement. PMID- 26622451 TI - Mechanism of protective immunity by vaccination with recombinant Echinococcus granulosus glutathione S-transferase (Chinese strain) in mice. AB - The aim of this study was to investigate the immunoprotective effects of recombinant Echinococcus granulosus glutathione S-transferase (rEgGST) against the development of protoscolices (PSCs), and to determine the mechanisms underlying this protection. ICR mice were subcutaneously immunized three times with rEgGST at weeks 0, 2 and 4, followed by the intraperitoneal administration of E. granulosus PSCs at week 10. Six mice in each group were sacrificed at 0, 2, 4, 6, 10, 18 and 30 weeks following the initial vaccination in order to observe the macroscopic and microscopic effects of parasite development. Various analyses were subsequently conducted, including determination of the levels of immunoglobulins (Igs) and cytokines. Significant differences were observed a number of indices of immune response following immunization with rEgGST. These included reduced cyst formation and elevated levels of IgG1, IgG2a, IgG3, IL-2, IL-4, IL-10 and IFN-gamma, which indicated an increased percentage of immune helper cells. The results of the present study suggest that immunization with rEgGST in mice is able to successfully reduce the PSC-induced formation of cysts and to stimulate an immune response, suggesting that rEgGST possesses potential value as a candidate vaccine for PSC infection. PMID- 26622450 TI - Therapeutic effect of intravitreal injections of ranibizumab for the treatment of macular choroidal neovascularization caused by pathological myopia. AB - The aim of the present study was to evaluate the clinical efficacy and safety of intravitreal ranibizumab injections for the treatment of macular choroidal neovascularization (CNV) caused by pathological myopia. Between one and four intravitreal injections of ranibizumab were administered to 61 eyes from 61 patients who were diagnosed with macular CNV caused by pathological myopia. Following injection, the best-corrected visual acuity (BCVA), central macular thickness (CMT) and fundus fluorescein angiography (FFA) findings were evaluated monthly for a period of 6 months. Among the 61 eyes, 10 eyes received one injection, 44 received two injections, six received three injections and one received four injections (average, 1.97 injections). The BCVA was 0.02+/-0.01 prior to treatment and 0.30+/-0.03 subsequent to treatment, and this difference was statistically significant (P<0.01). The CMT was reduced by an average of 45.1 um. Regarding the FFA results, 56 eyes had no CNV fluorescence leakage and five eyes had CNV fluorescence leakage following treatment; however, the intensity of CNV fluorescence leakage in the five eyes following treatment was lower than that prior to treatment. As a treatment for pathological myopia-induced macular CNV, intravitreal injections of ranibizumab may improve eyesight as well as the macular retinal tissue structure; thus, this is a safe and effective treatment method. PMID- 26622452 TI - Lipid emulsion mitigates local anesthesia-induced central nervous system toxicity in rats. AB - The aim of the present study was to investigate the effect of intravenously administered lipid emulsion on local anesthetic (LA)-induced central nervous system (CNS) toxicity. A total of 100 male Sprague Dawley rats were allocated at random into the following groups: Sham (A), lidocaine (B), levobupivacaine (C) and ropivacaine (D). Groups B-D were each subdivided into three subgroups: Toxic, post-conditioning and pre-conditioning. Intracerebroventricular injections of 0.9% normal saline (sham group) or LA were administered via microsyringe; in addition, a 20% lipid emulsion was injected into tail vein prior to the LA injection (pre-conditioning subgroups) or following rat respiratory arrest (post conditioning subgroups). The heart rate, blood pressure, neurological behavior scores, neuronal density and time from LA injection to respiratory arrest, apnea and start of arrhythmia were measured. Rats in the toxic groups died due to respiratory arrest following the injection of LA into the lateral ventricle. Rats in the post-conditioning subgroups were resuscitated from the LA-induced respiratory arrest, while the pre-conditioning subgroup rats exhibited no respiratory arrest. No significant differences in heart rate were observed between the toxic and post-conditioning subgroups in the levobupivacaine and ropivacaine groups (P>0.05); however, a significant difference was observed between these treatment groups and the rats treated with lidocaine (P<0.01). A significant difference was also observed in the time from the LA injection to the onset of arrhythmia among the rats in groups B, C and D (P<0.01). No significant differences in the neurological behavior scores and neuronal density were observed in the hippocampal CA1 zone among group C and D rats in the post- and pre-conditioning subgroups at various time-points following treatment. Beyond that, the same phenomena regarding neurological behavior scores was observed in post- and pre-conditioning subgroups of group B at 12 and 24 h treatment, contrasting with the statistically significant difference between post- and pre conditioning subgroups at 6 h treatment (P<0.01). The results of the present study therefore indicate that pre- and post-conditioning with lipid emulsion effectively mitigates LA-induced CNS toxicity in rats. PMID- 26622453 TI - Clinical features and risk factors for blood stream infections of Candida in neonates. AB - Candida species are the leading cause of invasive fungal infections in children admitted to hospital. However, few data exist with regard to the clinical features, risk factors and prognosis for candidemia in neonates. The present retrospective study included 40 neonates from the Affiliated Children's Hospital of the Capital Institute of Pediatrics (Beijing, China) in the time period between January 1, 2006 and December 31, 2010 (candidemia group, n=19; non candidemia group, n=21). The clinical characteristics, prognosis and previously identified risk factors for the two groups were recorded. According to the forward stepwise multivariate logistic regression analysis, administration of antibiotics >2 weeks prior, the use of glycopeptide antibiotics, maternal candidal vaginitis and secondary gastrointestinal surgery were identified as predictors of candidiasis. When compared with the non-gastrointestinal dysfunction group, the proportion of neonates that had been subjected to parenteral nutrition, central venous catheters, gastrointestinal surgery, secondary gastrointestinal surgery, repeated tracheal intubation and glycopeptide antibiotic administration was significantly higher in the gastrointestinal dysfunction group (P<0.05). Long-term application of antibiotics, use of glycopeptide antibiotics, maternal candidal vaginitis and secondary gastrointestinal surgery appeared to be the risk factors of candidemia in neonates. The neonates co-existed with gastrointestinal dysfunction suffering from candidemia were likely to experience growth retardation at 6 months after hospital discharge. Candidemia is potentially life-threatening situation for neonates, and if patients do not succumb it may affect their early development. PMID- 26622454 TI - Primary hepatic sarcomatoid carcinoma: A case report. AB - Sarcomatoid carcinoma (SC) is a malignant tumor type of unclear pathogenesis, which rarely occurs in the liver. The present study reports the case of a 60-year old woman who presented with multiple masses in her liver, with no fever, abdominal pain or jaundice. Serological markers for hepatitis B and C virus were negative, as was the test for alpha fetoprotein. Abdominal enhanced magnetic resonance imaging examination confirmed multiple lesions in the liver, and liquefactive necrosis was observed. The patient underwent a right hepatectomy, in addition to a cholecystectomy. Cytokeratin 8 (CK8), cluster of differentiation 117, pancytokeratin and vimentin were positively detected using immunohistochemistry, and thus the diagnosis of primary hepatic SC (PHSC) was established. During the follow-up period, characteristic imaging manifestations of tumor recurrence were detected, including peripheral enhancement, central necrosis, variable enhancement, venous invasion and intrahepatic metastasis. The immunohistochemical detection of CK, epithelial membrane antigen and vimentin, with CK8 as a critical indicator, may be useful for the diagnosis of PHSC. The preferred treatment for PHSC is surgical resection and the prognosis is poor. PMID- 26622455 TI - Investigation of CYP 3A5 and ABCB1 gene polymorphisms in the long-term following renal transplantation: Effects on tacrolimus exposure and kidney function. AB - The clinical use of tacrolimus (Tac) is complicated by the large inter-individual variability in its pharmacokinetics as well as by chronic adverse effects on renal function. The main goal of this study was to evaluate the potential influence of cytochrome P450 3A5 (CYP 3A5) and ATP-binding cassette transporter B1 (ABCB1) gene polymorphisms on Tac dose requirements and dose-adjusted concentrations in different long-term periods following renal transplantation. Another aim was to investigate whether these polymorphisms affect renal function in late post-transplant period. A total of 91 renal transplant recipients were enrolled for genotyping analysis, and 53 of these entered into a pharmacokinetic pharmacogenetic study. Allele-specific polymerase chain reaction was used for CYP 3A5 and ABCB1 polymorphism determination. Pharmacokinetic data (dose, trough concentration and dose-adjusted concentration of Tac) and renal function parameters [creatinine (Cre) clearance and serum Cre level] were analyzed in relation to patient genotype at 6, 12 and 24 months after transplantation. Also, linear regression analysis was performed to evaluate the effect of CYP 3A5 and ABCB1 genotypes on Tac exposure and renal function up to 24 months post transplant. Individuals carrying the CYP 3A5*1/*3 genotype had higher Tac dose requirements than CYP 3A5*3/*3 carriers at 6, 12 and 24 months after renal transplantation. The results revealed that ABCB1 polymorphism did not influence Tac dose requirements independently. Regression analysis showed that CYP 3A5 influenced the Tac dose-adjusted concentration as well as renal function up to 24 months post-transplant. These findings confirmed that CYP 3A5 polymorphism represents the most important determinant of Tac dose and exposure in the late period following renal transplantation. Furthermore, the obtained results indicate that the decline in renal function may be more pronounced in patients with CYP 3A5*1 in the long-term period after renal transplantation. PMID- 26622456 TI - Systemic air embolism as a complication of CT-guided percutaneous core needle lung biopsy: A case report and review of the literature. AB - Computed tomography (CT)-guided percutaneous core needle biopsy (PCNB) of the lung is a widely accepted and frequently performed interventional radiological procedure for the diagnosis of various pulmonary lesions. Common complications are usually mild and self-limited; however, air embolism is an extremely rare but potentially fatal complication. This study reports a case of fatal air embolism in the coronary and spinal arteries that resulted from a complex CT-guided PCNB of the lung. The present case suggests that multiple precautions may not eliminate the risk of the fatal air embolism resulting from the procedure of CT guided PCNB. Prompt recognition and urgent resuscitation are crucial for initial stabilization, allowing subsequent diagnostic confirmation and appropriate treatment. The common characteristics of symptomatic air embolism, based on the case reported and a review of the literature, are summarized in the present study in order to provide recommendations for clinical practice. PMID- 26622457 TI - Carotid stump syndrome: A case report. AB - Carotid stump syndrome (CSS) is known to be one of the causes of recurrent ipsilateral ischemic stroke following the occlusion of the internal carotid artery (ICA). The present study describes a case of left CSS in a 50-year-old patient presenting with a central retinal artery embolism following internal carotid and middle cerebral artery occlusion. The central retinal artery embolism was believed to be a consequence of microemboli, which originated from the stump of the occluded ICA, passing into the ophthalmic artery due to external carotid internal carotid anastomotic channels, although the other possible pathophysiological causes of this condition are discussed. Digital subtraction angiography of the patient showed trickle flow in the occluded ICA during the venous phase, by which the stump emboli may have been transported to the ophthalmic artery. The patient was successfully treated with anticoagulation therapy without surgical or endovascular treatment. PMID- 26622458 TI - MicroRNA-18a regulates invasive meningiomas via hypoxia-inducible factor-1alpha. AB - The aim of the present study was to investigate the effects of microRNA-18a (miR 18a) on the invasiveness and metastasis of invasive meningiomas and the underlying mechanism. A total of 69 patients with meningiomas (30 patients in the invasive meningioma group and 39 patients in the non-invasive meningioma group) and 48 cases in the control group were enrolled. Samples of meningioma tissues, serum and cerebrospinal fluid were collected. Reverse transcription-quantitative polymerase chain reaction was performed to quantify the expression levels of hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA and miR-18a. Western blot analysis was used to determine protein expression levels of HIF-1alpha. The expression levels of HIF-1alpha mRNA and protein in all three types of sample from the invasive meningioma group were significantly higher compared with those in the control and non-invasive meningioma groups (P<0.05), and the expression levels of HIF-1alpha mRNA in the serum and cerebrospinal fluid of the non invasive meningioma group were significantly higher compared with those in the control group (P<0.05). The expression levels of miR-18a in the invasive meningioma group were significantly reduced compared with those in the control and non-invasive meningioma groups (P<0.05), whereas the levels of miR-18a in the non-invasive meningioma group were significantly lower compared with those in the control group (P<0.05). The expression of HIF-1alpha is significantly upregulated in patients with invasive meningiomas, possibly due to the downregulation of miR 18a expression. Therefore, miR-18a may regulate invasive meningiomas via HIF 1alpha. PMID- 26622459 TI - Assessment of carboprost tromethamine for reducing hemorrhage in laparoscopic intramural myomectomy. AB - The aim of the present study was to evaluate the effect of carboprost tromethamine on blood loss during laparoscopic myomectomy (LM) in females. Ninety women, who were scheduled for LM due to symptomatic uterine myomas, were randomly divided into three groups. Twenty-four women were intramyometrially injected with 12 IU diluted vasopressin (vasopressin group), 30 cases received a deep intramuscular injection of 250 ug carboprost tromethamine 30 min prior to myomectomy (carboprost group), and 36 cases received an intramuscular injection of 250 ug carboprost tromethamine followed by a 20 IU oxytocin intravenous infusion at a rate of 120 mU/min during the procedure (carboprost plus oxytocin group). The procedure time, amount of hemorrhage, postoperative reduction in hemoglobin levels, adverse effects, bowel deflation time and time of postoperative hospital stay were compared. The procedure time, amount of hemorrhage and postoperative reduction in hemoglobin levels were not significantly different between the carboprost group and the vasopressin group (P>0.05). In the carboprost plus oxytocin group, the procedure time, amount of hemorrhage and postoperative reduction in hemoglobin levels were 24.3+/-2.6 min, 51.1+/-8.4 ml and 6.9+/-1.5 g/l, respectively, which were significantly less than those in the vasopressin and carboprost groups (all P<0.05). In the carboprost and carboprost plus oxytocin groups, the incidence of mild uterine contraction pain was significantly higher than in the vasopressin group (chi2=12.913, P=0.002). The incidences of other side-effects were not significantly different among the three groups. The times for bowel deflation and postoperative hospital stay were marginally increased in both the carboprost and carboprost plus oxytocin groups, compared with the vasopressin group, although no significant differences were found among the three groups (P>0.05). Deep intramuscular injections of carboprost tromethamine prior to performing myomectomy could be an effective approach for reducing blood loss from intramural LM, in particular when combined with oxytocin intravenous infusion. PMID- 26622460 TI - Correlation between the protein expression of A-kinase anchor protein 95, cyclin D3 and AKT and pathological indicators in lung cancer tissues. AB - The aim of the present study was to investigate the correlation between the protein expression of A-kinase anchor protein 95 (AKAP95), cyclin D3 and AKT with pathological indicators in lung cancer tissues. Immunohistochemistry was used to detect the protein expression levels of the proteins in 51 lung cancer tissue samples and 15 pericarcinoma tissue samples. The percentage of cyclin D3 positive samples in the lung cancer and pericarcinoma tissues was 68.63 and 28.57%, respectively, and the difference was statistically significant (P<0.01). However, cyclin D3 expression was not shown to correlate with differentiation grade, histological type or lymph node metastasis. In addition, the percentage of AKT positive samples in the cancer and pericarcinoma tissues was 76.47 and 38.46%, respectively, and the difference was statistically significant (P<0.05). AKT expression was found to significantly correlate with the grade of cancer tissue differentiation (P<0.05); however, no correlations were observed with histological type or lymph node metastasis (P>0.05). AKAP95 expression was shown to correlate with cyclin D3 and AKT expression in the lung cancer tissue (P<0.05); however, there was no correlation between cyclin D3 and AKT expression. The present study provided evidence suggesting that AKAP95 may have a role in regulation of the cell cycle. PMID- 26622461 TI - Brucella melitensis 16MDeltaTcfSR as a potential live vaccine allows for the differentiation between natural and vaccinated infection. AB - Brucellosis is a zoonotic disease that poses a serious threat to public health and safety. Although the live attenuated vaccines targeting brucellosis, such as M5-90, are effective, there are a number of drawbacks to their use. For example, the vaccines are unable to differentiate between the natural and vaccinated forms of the infection, and these vaccines have also been shown to cause abortion in pregnant animals. Therefore, a safer and more potent vaccine is required. In the present study, a B. melitensis 16M TcfSR promoter mutant (16MDeltaTcfSR) was constructed in an attempt to overcome these drawbacks. A TcfSR mutant was derived from B. melitensis 16M and tested for virulence and protection efficiency. Levels of immuoglobulin G (IgG), and cytokine production were determined. In addition, TcfS was assessed as a diagnostic marker for brucellosis. The survival capacity of the 16MDeltaTcfSR mutant was shown to be attenuated in the RAW 264.7 murine macrophage cell line and BALB/c mice, and the vaccination was shown to induce a high level of protective immunity in BALB/c mice. In addition, the 16MDeltaTcfSR vaccination elicited an anti-Brucella-specific IgG response and induced the secretion of interferon-gamma. Thus, the TcfS antigen allowed for the serological differentiation between the natural and vaccinated infection in animals. In conclusion, the results demonstrated that the 16MDeltaTcfSR mutant was attenuated in murine macrophage cells and BALB/c mice; therefore, 16MDeltaTcfSR is a potential candidate for a live attenuated vaccine against B. melitensis infection. PMID- 26622462 TI - Differences in 23S ribosomal RNA mutations between wild-type and mutant macrolide resistant Chlamydia trachomatis isolates. AB - The aim of the present study was to determine the in vitro susceptibility of wild type and mutant clinical isolates of Chlamydia (C.) trachomatis strains to erythromycin, azithromycin and josamycin, and to identify the resistance conferring 23S ribosomal (r)RNA mutations in the isolates. The wild-type resistant isolates were defined as those with minimum inhibitory concentration values above the tissue concentration of the antibiotic in the urogenital system. Furthermore, all resistant C. trachomatis isolates were exposed to sub-inhibitory concentrations of macrolides, and 13 resistant mutants were selected following serial passages. Among the 8 wild-type isolates that were resistant to erythromycin, 3 isolates had a mutation at T2611C in the 23S rRNA gene while the others did not show any 23S rRNA mutations. The selected mutant isolates showed a 4- to 16-fold reduction in in vitro sensitivities. With regard to the mutant strains, the T2611C mutation was found in 10 isolates, A2057G mutation in 6 isolates, and A2059G mutation in 1 isolate. Thus, the macrolide-resistant isolates of the wild-type strain had different mutations from those selected by exposure to sub-inhibitory concentrations of macrolides. Also, since 23S rRNA mutations were not identified in certain isolates, it was considered that other molecular mechanisms may also be responsible for the macrolide resistance of C. trachomatis. PMID- 26622464 TI - Cutaneous Rosai-Dorfman disease in a middle-aged man: A case report. AB - The present study describes a case of cutaneous Rosai-Dorfman disease (CRDD). The clinical manifestations and therapeutic options of CRDD vary, and the etiology of the disease is still unknown. The clinical manifestations include single or multiple yellow-red to brown or purple papules, nodules and/or plaques, with the face being the most frequently affected site. A 52-year-old man presented with an 8-month history of multiple lesions on his face. Physical examination revealed a number of yellow-red papules and nodules, the majority of which had coalesced into plaques. The histological finding from a red papule showed a dense, dermal infiltrate, which was predominantly composed of large histiocytes, strongly positive for S-100 and cluster of differentiation (CD)68 but negative for CD1a, mixed with aggregates of lymphocytes and scattered plasma cells and eosinophils. The patient showed only a marginal improvement with a month of oral, low-dose prednisone. PMID- 26622463 TI - Clinical efficacy of 5-aminolevulinic acid photodynamic therapy in the treatment of moderate to severe facial acne vulgaris. AB - Acne vulgaris is considered as a therapeutic challenge in terms of managing ongoing symptoms and preventing scar formation. Although there are many available treatments for alleviating acne, therapies for resistant or moderate-to-severe forms have been limited to systemic agents that are accompanied by potentially severe side-effects. While, aminolevulinic acid (ALA) photodynamic therapy (PDT) has increasingly been used as a simple and safe therapeutic option of acne vulgaris, the clinical efficacy requires confirmation in further studies. The aim of this study was to investigate the efficacy and safety of 5-ALA-PDT in the treatment of moderate-to-severe facial acne vulgaris. A total of 50 patients with moderate-to-severe facial acne were enrolled in the study and randomly divided equally into a therapy group and a control group. In the therapy group, the patients were treated with 5% 5-ALA for 1.5 h, followed by three 20-min doses of infrared radiation once a week; in the control group, the patients were treated with three 20 min doses of infrared radiation without 5-ALA once a week. Both treatments lasted for 3 weeks. The clinical efficacy was determined by evaluating acne lesion counts at weeks 0, 2, 4 and 6. Total efficacy rate (TER) was the primary endpoint of the study, and was defined as the proportion of the patients whose treatment effectiveness evaluation was cured (>=90% of skin lesions improved) and excellent (60-89% improvement). Adverse effects were recorded throughout the study. The study was completed by 24 patients in the therapy group and 23 patients in the control group. The numbers of acne lesions significantly decreased. The TER of the therapy group was significantly higher than that of the control group at weeks 4 and 6. Adverse effects were observed in 12 patients of the therapy group and 2 patients of the control group. In the therapy group the most common adverse effect was a burning sensation (n=7), followed by transient hyperpigmentation (n=3) and acute acneform lesions (n=2), while in control group, the 2 patients experienced flushing and dryness. The adverse effects were all cured by a symptomatic approach prior to the end of the study. 5-ALA-PDT combined with infrared radiation is an effective and safe therapy for moderate-to-severe facial acne. PMID- 26622465 TI - Treatment of nasal microcystic adnexal carcinoma with an expanded rotational forehead skin flap: A case report and review of the literature. AB - Microcystic adnexal carcinoma (MAC) is a rare and locally aggressive adenocarcinoma with low-grade malignancy. The present study describes the first reported case and treatment of a Chinese male with a MAC located on the nasal dorsum and nosewing. A 44-year-old man presented with a nasal deformity caused by local repeated infections following an accidental injury to the nose 20 years previously. The nose had been injured by a brick, and treatment at a local hospital 12 years previously had resulted in a nasal scar and a gradually enlarging mass. A physical examination revealed a hypertrophic deformity of the nose and an indurated scar plaque, measuring 2.0*2.0 cm, on the nasal dorsum and nosewing. Microscopic examination revealed a tumor consisting of solid cell nests and a cystic structure with a capsular space. In addition, ductal cells of an adnexal cell origin were visible in the outer epithelium. The medial portion exhibited a microductal structure and invasion of deeper tissues without evident atypia. The tumor cells presented normal nuclear to cytoplasmic ratios and minimal mitotic activity. Pathological examination verified that the tumor was a MAC of low-grade malignancy. A complete surgical resection was performed via Mohs micrographic surgery (MMS), and reconstruction was achieved using an expanded rotational forehead skin flap. No tumor recurrence was detected after a three year follow-up period. Therefore, for effective treatment of similar MAC cases, complete surgical resection using MMS is recommended, and successful reconstruction may be achieved using an expanded skin flap. PMID- 26622466 TI - Long-term improvement of arterial wall characteristics in patients with diabetes mellitus type 1 using cyclic, intermittent treatment with a low-dose fluvastatin and valsartan combination. AB - Improvement of arterial wall (AW) characteristics decreases cardiovascular risk. In a previous study, it was observed that AW characteristics in patients with diabetes mellitus type 1 are significantly improved by short-term treatment with a low-dose combination of fluvastatin and valsartan. Additionally, a unique phenomenon of prolonged effect after treatment discontinuation was suggested. The present study tested whether repeated treatm ent after a certain period results in the same beneficial effect, th ereby advancing the hypothesis that cyclic treatment can provide a long-term improvement of AW characteristics. A total of 44 patients with diabetes mellitus type 1 that participated in the previous study were recruited. Six months after the discontinuation of the initial treatment, the same treatment with a low-dose fluvastatin (10 mg daily) and valsartan (20 mg daily) combination (n=22) or placebo (n=22) was repeated. Brachial artery flow mediated dilation (FMD), pulse wave velocity (PWV) and carotid artery beta stiffness were measured. It was found that the beneficial effect achieved with an initial 1-month treatment was completely regained following treatment repetition: FMD improved by 50.9% (P<0.01), PWV by 5.7% (P<0.001) and beta-stiffness by 9.9% (P<0.001). In addition, a gradual decline of the obtained effects was observed, reaching the level of 9.6% for FM D, 6.3% for PWV and 9.5% for beta-stiffness 6 months after treatm ent discontinuation. It was observed that repetition of treatment was similarly effective as the initial intervention. The benefits achieved by treatment steadily declined with time. Combining these findings, cyclic intermittent treatment with a low-dose fluvastatin and valsartan combination is proposed as a new cardiovascular preventive strategy in patients with DM1. PMID- 26622467 TI - Effect of Huaier on the proliferation and apoptosis of human gastric cancer cells through modulation of the PI3K/AKT signaling pathway. AB - The aim of the present study was to investigate the effect of Huaier on the proliferation and apoptosis of the MKN45 and SGC7901 gastric cancer cell lines. The MTT assay was used to measure the effects of Huaier on the growth of the cells, while cell cycle distribution and apoptosis levels were analyzed using flow cytometry. Western blotting was used to assess the levels of proteins associated with the apoptotic pathway. It was found that cell survival decreased with the increase in the concentration of Huaier, and the apoptosis rates were increased in a dose-dependent manner both in MKN45 and SGC7901 cells. The number of cells in the G2/M phase in the Huaier-treated groups was increased in a dose dependent manner compared with that in the control group. Huaier inhibited phosphorylated- (p-)AKT1, phosphatidylinositol 3-kinase (PI3K), pyruvate dehydrogenase kinase isoform 1, p-phosphatidylinositol 3,4,5-trisphosphate 3 phosphatase and dual-specificity protein phosphatase and B-cell lymphoma 2 expression and upregulated cleaved-caspase-9 expression in a dose-dependent manner. In conclusion, Huaier can strongly inhibit gastric cancer cell proliferation by inhibiting cyclin B1 expression, promoting G2/M-phase arrest and modulating the PI3K/AKT signaling pathway, and can induce gastric cancer cell apoptosis by modulating the PI3K/AKT signaling pathway in dose-dependent manner. PMID- 26622468 TI - Bortezomib inhibits cell proliferation in prostate cancer. AB - Despite the improvement in chemotherapeutic agents, the outcome of patients with prostate cancer remains poor. It is therefore imperative that new anticancer drugs are explored. The aim of the present study was to investigate the inhibitory effect of bortezomib on DU145 prostate cancer cells. The DU145 cell proliferation rate was detected via MTT assay prior to and following exposure to various concentrations of bortezomib, and the level of cell apoptosis and the cell cycle distribution were tested using flow cytometry. In addition, western blotting was used to measure the expression of Bcl-2-interacting killer (Bik) and active-caspase-3. The results showed that bortezomib inhibited the proliferation of DU145 cells in a time- and dose-dependent manner. Following treatment with 1.6 umol/l bortezomib, the DU145 cells showed marked nuclear condensation, chromatin condensation and fragmentation. Analysis of the cell cycle revealed a significantly increased percentage of cells in the G0/G1 phase and a decreased percentage in the S and G2/M phases. The rate of DU145 cell apoptosis was significantly higher in the bortezomib group than that in the control group, and this was accompanied by an enhanced expression of Bik and active-caspase-3. It can be concluded that bortezomib inhibits the proliferation of DU145 cells by inducing apoptosis. The underlying mechanism may involve the upregulation of Bik and active-caspase-3 expression. PMID- 26622469 TI - TGF-beta1 induces apoptosis of bone marrow-derived mesenchymal stem cells via regulation of mitochondrial reactive oxygen species production. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) are the most promising seed cells in regenerative medicine. Our previous study demonstrated that transforming growth factor (TGF)-beta1 induced BMSC senescence in vitro. Whether TGF-beta1 affects the apoptosis of BMSCs has not been examined; therefore the aim of the present study was to investigate this effect. BMSCs were isolated from mouse bone marrow, and the third-passage cells were exposed to 0, 10 and 20 ng/ml TGF-beta1 for 24 h. Cell proliferation was measured by MTT assay; apoptosis was assessed using DAPI staining; and the apoptotic signals Annexin V, B-cell lymphoma (Bcl)-2 and Bcl-2-associated X protein (Bax) were measured using western blotting. Mitochondrial reactive oxygen species (ROS) were measured by flow cytometry following staining with MitoSOXTM Red mitochondrial superoxide indicator. The MTT assay showed that 10 and 20 ng/ml TGF-beta1 inhibited BMSC proliferation. DAPI staining demonstrated that 10 and 20 ng/ml TGF-beta1 promoted BMSC apoptosis, which was further confirmed by a western blotting assay showing a significant increase in the pro-apoptotic signals Annexin V and Bax but a decrease in the anti-apoptotic signal Bcl-2. It was also found that TGF-beta1 markedly increased the mitochondrial ROS levels in BMSCs. It is well known that mitochondrial ROS are strong stimulators of cell apoptosis. These findings indicate that TGF-beta1 can induce BMSC apoptosis, and the mechanism may involve mitochondrial ROS generation. PMID- 26622470 TI - Role and mechanism of vascular cell adhesion molecule-1 in the development of rheumatoid arthritis. AB - The aim of the present study was to investigate the role and mechanism of vascular cell adhesion molecule-1 (VCAM-1) in the development of rheumatoid arthritis (RA). One hundred and twenty patients with RA who had been admitted to the Huaihe Hospital of Henan University between January and December 2013 were enrolled in the study as the observation group, while, in the corresponding period, 30 healthy volunteers were enrolled as the control group. The serum levels of VCAM-1 and rheumatoid factor (RF) were detected using ELISA. The patients underwent conventional treatment and their serum VCAM-1 and RF levels were detected at different time-points to determine their correlation. The observation group exhibited significantly higher serum VCAM-1 and RF levels than the control group (P<0.01). Twenty-four hours after treatment, the serum VCAM-1 levels of the patients peaked (1,269.47+/-128.76 ug/l); 36 h after treatment, the serum RF levels peaked (34.42+/-8.45 U/ml); 1 month after treatment, the VCAM-1 and serum RF levels of the patients were lower than those prior to treatment (P<0.05). Pearson correlation analysis indicated that there was a significant, positive correlation between the serum VCAM-1 and RF levels in the patients with RA (r=0.852, P<0.01). In conclusion, the serum VCAM-1 levels of patients with RA increased and subsequently decreased as the condition was relieved, which could possibly be associated with the autoimmune and inflammatory reactions found in RA. Serum VCAM-1 levels can therefore reflect the disease condition and curative effects of treatment. PMID- 26622471 TI - Systemic lupus erythematosus with intestinal perforation: A case report. AB - Systemic lupus erythematosus (SLE) is a systemic autoimmune inflammatory disease, which can affect almost all systems and organs. Gastrointestinal disorder is one of the most noteworthy complications of patients with SLE. However, gastrointestinal disorder with intestinal perforation is rare, but potentially life-threatening if not treated promptly. The present study reported a case of SLE with intestinal perforation, where surgical intervention was performed and a crevasse (~3 cm in diameter) was detected in the ileum, ~60 cm from the ileocecal valve. Following surgery, the patient suffered from difficult ventilator weaning, septic shock and intestinal obstruction. The patient was successfully treated and discharged from the hospital after ~4 months of treatment. Intestinal perforation in SLE patients is potentially life-threatening; early diagnosis and prompt treatment are crucial to the management of this rare complication of SLE. PMID- 26622472 TI - CORRIGENDUM. AB - [This corrects the article DOI: 10.3892/etm.2014.2158.]. PMID- 26622473 TI - Is acupuncture no more than a placebo? Extensive discussion required about possible bias. AB - Numerous randomized controlled trials (RCTs) of acupuncture have been conducted in recent years. The results of several studies implied that acupuncture was only a powerful placebo; however, certain studies demonstrated that verum acupuncture had a greater effect than placebo and the mechanisms between a verum acupuncture group and a placebo/sham group were different. Researchers attempted to investigate the inherent factors that may potentially influence the results of trials. Certain problems observed in acupuncture RCTs also occurred in RCTs in other fields, including insufficient sample size, high dropout rates, inadequate follow-up and randomization. The study of acupuncture is so complex that specific methodological challenges are raised, which are frequently overlooked, including sham interventions, blinding, powerful placebo effects (even stronger than an inert pill) and variations in acupuncture administration. The aforementioned problems may contribute to bias, and researchers systematically attempt to solve these problems. The present review aimed to suggest techniques to design high quality studies, minimize the placebo effect and optimize acupuncture administration in acupuncture studies. If these problems are addressed, then the results of acupuncture studies may be different. PMID- 26622475 TI - Amplification efficiency and thermal stability of qPCR instrumentation: Current landscape and future perspectives. AB - Quantitative polymerase chain reaction (qPCR) is a method of amplifying and detecting small samples of genetic material in real time and is in routine use across many laboratories. Speed and thermal uniformity, two important factors in a qPCR test, are in direct conflict with one another in conventional peltier driven thermal cyclers. To overcome this, companies are developing novel thermal systems for qPCR testing. More recently, qPCR technology has developed to enable its use in point-of-care testing (POCT), where the test is administered and results are obtained in a single visit to a health provider, particularly in developing countries. For a system to be suitable for POCT it must be rapid and reliable. In the present study, the speed and thermal uniformity of four qPCR thermal cyclers currently available were compared, two of which use the conventional peltier/block heating method and two of which use novel heating and cooling methods. The time required to complete 40 cycles varied between 12 and 58 min, and the Ct values were comparable, ranging between 13.6 and 16.8. Therefore, the novel technologies investigated in the present study for qPCR instrumentation performed equally well compared with conventional qPCR instruments, in terms of amplification efficiency and thermal uniformity. PMID- 26622474 TI - Protective effects of quercetin and taraxasterol against H2O2-induced human umbilical vein endothelial cell injury in vitro. AB - Due to the association between inflammation and endothelial dysfunction in atherosclerosis, the blockage of the inflammatory process that occurs on the endothelial cells may be a useful way of preventing atherosclerosis. In the present study, human umbilical vein endothelial cells (HUVECs) were used to investigate the protective effects of quercetin and taraxasterol against H2O2 induced oxidative damage and inflammation. HUVECs were pretreated with quercetin or taraxasterol at concentrations ranging between 0 and 210 uM for 12 h, prior to being administered different concentrations of H2O2 for 4 h. Cell viability and levels of apoptosis were assessed through cell counting kit-8 (CCK-8) and terminal deoxynucleotidyl transferase dUTP nick end labeling assays, respectively, to determine the injury to the HUVECs. The viability loss in the H2O2-induced HUVECs was markedly restored in a concentration-dependent manner by pretreatment with quercetin or taraxasterol. This effect was accompanied by significantly decreased expression of vascular cell adhesion molecule 1 (VCAM-1) and cluster of differentiation (CD)80 for taraxasterol and that of CD80 for quercetin. In conclusion, the present study showed the protective effects of quercetin and taraxasterol against cell injury and inflammation in HUVECs and indicated that the effects were mediated via the downregulation of VCAM-1 and CD80 expression. This study has therefore served as a preliminary investigation on the anti-atherosclerotic and cardiovascular protective effects of quercetin and taraxasterol as dietary supplements. PMID- 26622476 TI - Rosiglitazone modulates collagen deposition and metabolism in atherosclerotic plaques of fat-fed ApoE-knockout mice. AB - Abnormal collagen deposition, as well as collagen metabolism, plays a crucial role in the formation and progression of vulnerable atherosclerotic plaques (VAPs), which are susceptible to rupture. According to our previous findings, rosiglitazone, a thiazolidinedione, can promote the stability of atherosclerotic plaques in fat-fed ApoE-knockout mice; however, it is unknown whether it can modulate collagen deposition and metabolism in VAPs. The present study was designed to determine the effect of rosiglitazone on collagen deposition and metabolism in the plaques of fat-fed ApoE-knockout mice. Following 13 weeks of the high-fat diet, the mice were randomized into three groups (10 mice/group) and intragastrically administered rosiglitazone, simvastatin and distilled water, respectively, for a further 13 weeks. The category of the collagen present in the plaques was evaluated using the picro-Sirius red polarization method. Additionally, the protein expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the plaques was determined using immunohistochemistry. The results showed that rosiglitazone reduced the lipid to collagen and type III to type I collagen ratios in the plaques, and these reductions were correlated with the reduction in the plaque MMP-9 to TIMP-1 ratio. These results suggest that rosiglitazone can modulate collagen deposition and metabolism and promote the stabilization of VAPs. PMID- 26622477 TI - Effects of As2O3 nanoparticles on cell growth and apoptosis of NB4 cells. AB - The aim of the present study was to explore the preparation of arsenic trioxide (As2O3) nanoparticles and examine the antitumor effects of these nanoparticles on NB4 cells. As2O3 nanoparticles were prepared using the sol-gel method and characterized using transmission electron microscopy and energy dispersive spectroscopy. The results indicated that the As2O3 nanoparticles prepared in the present study were round or elliptical, well dispersed and had an ~40-nm or <10 nm diameter. The antitumor effects of As2O3 nanoparticles at various concentrations were analyzed by flow cytometry and the MTT assay, and were compared with those of traditional As2O3 solution. At the same concentration and incubation time (48 h), the survival rate of cells treated with As2O3 nanoparticles was significantly lower than that of cells treated with the As2O3 solution. The growth inhibition rate under both treatments was time- and dose dependent. In addition, at the same concentration and incubation time, the apoptosis rate of the cells treated with As2O3 nanoparticles was significantly higher than that of the cells treated with the As2O3 solution. Furthermore, As2O3 nanoparticles resulted in a greater reduction in the expression of the anti apoptotic protein B-cell lymphoma 2 compared with the As2O3 solution. In conclusion, As2O3 nanoparticles, prepared using the sol-gel method, were found to produce a stronger cytotoxic effect on tumor cells than that produced by the As2O3 solution, possibly by inhibiting Bcl-2 expression. PMID- 26622478 TI - Identification of AAAS gene mutation in Allgrove syndrome: A report of three cases. AB - Allgrove syndrome (AS) is an autosomal recessive congenital disease, caused by mutations in the AAAS gene, and is characterized by the triad of Addison's disease, achalasia and alacrima. The present study describes three newly diagnosed cases of AS, in which genetic analysis of the AAAS gene was used to identify AAAS gene mutations, to enhance the understanding of the pathogenesis and clinical manifestations of AS in the Chinese population. Two of the cases exhibited homozygous mutations of c.771delG (p.Arg258GlyfsX33) in exon 8 and one case exhibited a homozygous mutation of c.1366C>T (p.Q456X) in exon 15. A review of the current literature suggests that the AAAS c.771delG mutation has only been reported in the Chinese population. Genetic analysis of the AAAS gene in Chinese AS patients at a young age may facilitate an earlier diagnosis and the timely initiation of the appropriate treatment, ultimately improving the patient outcome. PMID- 26622479 TI - Heterogeneity of clinical features and corresponding antibodies in seven patients with anti-NMDA receptor encephalitis. AB - Anti-N-methyl D-aspartate (NMDA) receptor encephalitis is the most common type of encephalitis in the spectrum of autoimmune encephalitis defined by antibodies targeting neuronal surface antigens. In the present study, the clinical spectrum of this disease is presented using instructive cases in correlation with the anti NMDA receptor antibody titers in the cerebrospinal fluid (CSF) and serum. A total of 7 female patients admitted to the hospital of Hannover Medical School (Hannover, Germany) between 2008 and 2014 were diagnosed with anti-NMDA receptor encephalitis. Among these patients, 3 cases were selected to illustrate the range of similar and distinct clinical features across the spectrum of the disease and to compare anti-NMDA antibody levels throughout the disease course. All patients received immunosuppressive treatment with methylprednisolone, intravenous immunoglobulin and/or plasmapheresis, followed in the majority of patients by second-line therapy with rituximab and cyclophosphamide. The disease course correlated with NMDA receptor antibody titers, and to a greater extent with the ratio between antibody titer and protein concentration. A favorable clinical outcome with a modified Rankin Scale (mRS) score of <=1 was achieved in 4 patients, 1 patient had an mRS score of 2 after 3 months of observation only, whereas 2 patients remained severely impaired (mRS score 4). Early and aggressive immunosuppressive treatment appears to support a good clinical outcome; however, the clinical signs and symptoms differ distinctively and treatment decisions have to be made on an individual basis. PMID- 26622480 TI - Nitrogen mustard hydrochloride-induced acute respiratory failure and myelosuppression: A case report. AB - Nitrogen mustards are chemical agents that are similar to sulfur mustards, with similar toxicities. The present study describes a case of nitrogen mustard induced acute respiratory failure and myelosuppression in a 33-year-old man. The patient, who was accidentally exposed to nitrogen mustard hydrochloride in a pharmaceutical factory, exhibited severe inhalation injury and respiratory symptoms. Laboratory tests revealed reduced white blood cell counts and lowered platelet levels during the first 6 days after the skin exposure to nitrogen mustard. Following treatment with mechanical ventilation, immunity-enhancing agents and nutritional supplements for 1 month, the patient successfully recovered and was released from hospital. PMID- 26622481 TI - Randomized controlled trial comparing letrozole with laparoscopic ovarian drilling in women with clomiphene citrate-resistant polycystic ovary syndrome. AB - The aim of the present study was to compare the reproductive outcomes of letrozole and laparoscopic ovarian drilling (LOD) in women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). A total of 141 women with CC-resistant PCOS were enrolled and randomly allocated into groups A and B. Group A (n=71) received 2.5 mg letrozole from days 5 to 10 of menses for up to six cycles, and group B (n=70) underwent LOD. A 6-month follow-up was performed. No statistically significant difference was found in the baseline clinical characteristics and the major serum hormone profiles, including luteinizing hormone, follicle-stimulating hormone, estradiol and free testosterone, between the two groups. Women receiving letrozole had a lower rate of spontaneous abortion (6.9 vs. 15.8%) and higher clinical pregnancy (40.8 vs. 27.1%) and live birth (38.0 vs. 22.9%) rates; however, the differences were not statistically significant. Letrozole had superior reproductive outcomes compared with LOD in women with CC-resistant PCOS; therefore, letrozole could be used as the first line treatment for women with CC-resistant PCOS. PMID- 26622482 TI - Efficacy and safety evaluation of citalopram and doxepin on sleep quality in comorbid insomnia and anxiety disorders. AB - Anxiety disorders are frequently comorbid with insomnia, and sleep disturbance in patients with anxiety disorders is the most common complaint. Antidepressants can affect sleep quality; however, their effect in patients with comorbid insomnia and anxiety disorders is unclear. The aim of the present study was to comprehensively evaluate the dose, treatment duration, treatment efficacy and safety of clinical citalopram and doxepin application in patients with comorbid insomnia and anxiety disorders. It was found that both citalopram (20 mg/day) and low-dose doxepin (12.5 mg/day) significantly improved sleep latency, duration and disturbances, as well as daytime dysfunction and the global Pittsburgh Sleep Quality Index during the 12-week treatment period. Notably, low-dose doxepin significantly improved sleep latency in patients after treatment for 8 and 12 weeks as compared with citalopram. It was further observed that both citalopram and low-dose doxepin improved anxiety. A significant and positive correlation was found between the improvement in the sleep quality and anxiety in the two treatment groups. Citalopram and low-dose doxepin both showed good efficacy and a low adverse reaction rate in the treated patients. These data support a potential application of citalopram and low-dose doxepin in the treatment of patients with comorbid insomnia and anxiety disorders. PMID- 26622483 TI - Bipolar button-electrode plasma vaporization of the prostate: An effective option for patients with post-brachytherapy retention. AB - Urinary retention is a common urinary complication following brachytherapy for prostate cancer. When conservative therapy has failed, surgical intervention, such as transurethral resection of the prostate (TURP), is performed. In the present case, it was found that conventional bipolar TURP was an inappropriate choice of therapy, since the electrical loop could easily rupture and discharge sparks when encountering the seeds intraoperatively; however, bipolar button electrode plasma vaporization of the prostate was proven to be a much safer technique. The 'button-type' electrode, which has a larger contacting surface, was firm enough to tolerate the transient high levels of energy generated by the short circuit and enable the safe completion of the procedure. PMID- 26622484 TI - EBP50 inhibits pancreatic cancer cell growth and invasion by targeting the beta catenin/E-cadherin pathway. AB - Ezrin-radixin-moesin (ERM)-binding phosphoprotein 50 (EBP50) has previously been demonstrated to be associated with the malignant transformation of numerous types of human cancer. The aim of the present study was to investigate the effect of EBP50 overexpression on pancreatic cancer and the underlying mechanism. Reverse transcription-quantitative polymerase chain reaction was used to detect the expression of EBP50 in human pancreatic cancer tissue specimens. Furthermore, pBK CMV-HA-EBP50 and the pBK-CMV-HA vectors were transfected into pancreatic cancer cells and the effect of EBP50 upregulation on the proliferation and invasion of the cells was investigated. In addition, the effect of EBP50 overexpression on beta-catenin and E-cadherin expression was evaluated. The results revealed that overexpression of EBP50 suppressed cell growth and invasion in two human pancreatic cancer cell lines. Overexpression of EBP50 also suppressed beta catenin expression and increased E-cadherin expression. Thus, the present study demonstrated that EBP50 inhibits pancreatic cancer cell growth and invasion through targeting the beta-catenin/E-cadherin pathway. The results suggest that EBP50 may function as a potential tumor suppressor and thus may serve as a potential therapeutic target. PMID- 26622485 TI - Effect of siRNA-Livin on drug resistance to chemotherapy in glioma U251 cells and CD133+ stem cells. AB - The aim of the present study was to observe the effect of siRNA-Livin on the expression of multidrug resistance-associated protein (MRP) genes in a U251 cell line and U251 stem cells. CD133+ cancer stem cells were identified and isolated from the U251 glioblastoma cells, and morphological observations were used to detect the cell survival conditions. In addition, quantitative polymerase chain reaction was used to detect the mRNA expression levels of Livin, MRP1 and MRP3. Following transfection with the lentivirus containing the siRNA-Livin, the expression of Livin was significantly inhibited in the U251 cells and stem cells (P<0.01). Following temozolomide intervention, the proliferation of the U251 cells and U251 stem cells was restrained, with a lot of cell debris present and the structure of the cell spheres destroyed. The inhibitory effect was more significant following transfection with siRNA-Livin. Prior to siRNA-Livin transfection, the expression of MRP1 presented an increasing trend in the U251 cells and U251 stem cells with increasing drug concentrations and intervention times (P<0.05). Following siRNA-Livin transfection, the expression of MRP1 decreased in the U251 cells and U251 stem cells under the same drug concentration and intervention time (P<0.05), while the expression of MRP3 increased in the U251 stem cells under the same intervention concentration and time (P<0.05). Therefore, siRNA-Livin was shown to decrease the expression of MRP1 in U251 cells and U251 stem cells, increase the expression of MRP3 in U251 stem cells and decrease the proliferation of U251 cells and U251 stem cells. Thus, Livin may be associated with the high expression of MRP1, and siRNA-Livin may be used to lower the expression of MRP1 in order to reduce the drug resistance to chemotherapy in cases of glioblastoma. PMID- 26622486 TI - Differential diagnosis of a carcinoma of the maxillary sinus that resembles a sparganum infection: A case report. AB - Primary malignant tumors of the maxillary sinuses are rare. The present study reports the case of a maxillary sinus adenocarcinoma that was misdiagnosed as a frog sparganum infection, and discusses the differential diagnosis between the two diseases. The patient was ultimately diagnosed with a carcinoma of the left maxillary sinus that presented as a progressive mass in the left eye and the maxillary sinus. Eosinophilic infiltration was observed in the subcutaneous tissue, and the patient had experienced previous exposure to undercooked frog. Although an anti-sparganum ELISA was performed and the results were negative, a sparganosis infection was initially diagnosed. However, following the application of anti-sparganosis treatment, no improvements were observed. Histological examination of an orbital mass resection revealed an adenocarcinoma with bone metastases. To the best of our knowledge, the present study is the first to report a maxillary sinus carcinoma misdiagnosed as sparganosis. Therefore, the findings of the current study should be considered in the differential diagnosis between a carcinoma of the maxillary sinus and sparganosis. Avoidance of misdiagnosis at an early stage is crucial for effective diagnosis and treatment of sinonasal malignancies. PMID- 26622487 TI - Rapamycin-induced autophagy activity promotes bone fracture healing in rats. AB - Autophagy is a crucial mediating process for normal bone cell function and metabolism in physiology or pathology. Rapamycin has been demonstrated to induce the autophagy pathway by inhibiting the mammalian target of rapamycin (mTOR) pathway. However, the contribution of autophagy in orthopedic diseases is rarely reported. The aim of the present study was to evaluate the capacity of pharmacologically induced autophagy to modify disease function in a rat model of bone fracture. A femur fracture model was established via surgery in adult male Sprague-Dawley rats. Rapamycin (n=63 rats) or dimethyl sulfoxide (DMSO) vehicle control (n=63 rats) was administered intraperitoneally for 2, 4 and 6 weeks, and 21 randomly selected rats were sacrificed in each group at each time point. X-ray micro-computed tomography and hematoxylin and eosin staining were used to evaluate the extent of fracture healing in each group. The effects of rapamycin on autophagy, mTOR signaling and the expression levels of vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA) were analyzed using immunohistochemistry, immunofluorescence staining and western blot analysis. Rapamycin affected the mTOR signaling pathway in rats following fracture, as indicated by the inhibition of the phosphorylation of ribosomal protein S6, a target of mTOR, and activation of microtubule-associated protein 2 light chain 3, a key marker of autophagy. Histomorphometry and image examination indicated that the number of osteoblasts in each section was significantly (P<0.01) increased in the rapamycin group compared with the control group, and this was associated with a significant (P<0.05) increase in mineralized callus fraction. Furthermore, rapamycin treatment increased the expression levels of VEGF and PCNA in the rat callus tissue. These results suggest that rapamycin may serve a beneficial function in fracture healing, and that the underlying mechanism may involve the activation of autophagy. PMID- 26622488 TI - Telaprevir-based triple therapy following partial splenic arterial embolization for chronic hepatitis C with thrombocytopenia can reduce carcinogenesis and improve hepatic function reserve. AB - Thrombocytopenia in patients with chronic hepatitis C negatively impacts interferon (IFN)-based treatment. The aim of this study was to evaluate the efficacy and safety of telaprevir (TVR)-based triple therapy including IFN for patients who have undergone partial splenic arterial embolization (PSE). Ten patients with thrombocytopenia who were infected with hepatitis C virus (HCV) genotype 1b received 12 weeks of TVR in combination with 24 weeks of pegylated interferon (PEG-IFN)alpha2b and ribavirin following PSE. A sustained virological response (SVR) was seen in 9 of the 10 patients who could be assessed. Early relapse was seen in 1 patient who had the IL-28B minor allele and a null response to pretreatment. The alpha-fetoprotein levels of the patients decreased from 17.94+/-7.30 ng/ml prior to PSE to 4.33+/-2.41 ng/ml at 6 months after triple therapy (P=0.08). Furthermore, serum albumin levels improved significantly from 3.68+/-0.49 g/dl pre-PSE to 4.13+/-0.34 g/dl at 12 months after triple therapy (P=0.043). PSE contributed to the treatment success of triple therapy, particularly for patients who were either treatment-naive, had a history of relapse or the IL28B major allele. This strategy can reduce carcinogenesis and improve hepatic function reserve. PMID- 26622489 TI - Novel cardioprotective strategy combining three different preconditioning methods to prevent ischemia/reperfusion injury in aged hearts in an improved rabbit model. AB - The use of ischemic preconditioning (IPC) to protect the myocardium is usually not effective in elderly patients. The aim of the present study was to design new methods to achieve enhanced myocardial protection, based on the differential role of endogenous adenosine (ADO) and ADO receptors (ARs) in the effects of IPC on young and old animals. An improved New Zealand white rabbit model of ischemia/reperfusion was established based on the Langendorff model. Adult or elderly rabbit hearts, with or without exposure to IPC, were used in order to assess the roles of ADO and ARs in the different effects of IPC. Different protective methods were designed based on a combination of endogenous and exogenous interventions. Cardiac function, as well as biochemical, histopathological and apoptotic indices, were measured in the different intervention groups. The improved Langendorff model was stable, reliable and suitable for the undertaking of the experiments. The ADO levels in the aged rabbit hearts pre- and post-IPC were lower than those in the adult hearts, indicating that ADO levels may be an endogenous factor influencing IPC. A new protection strategy combining ADO-enhanced IPC, A1AR agonist 2-chloro-N(6) cyclopentyladenosine preconditioning and cold crystalloid cardioplegia had a significant protective effect in aged hearts. The results of the present study suggested that endogenous ADO enhancement, A1AR agonist preconditioning and exogenous treatment yield an additive effect in aged rabbit hearts. The simultaneous application of these three types of intervention provided the most effective myocardial protection in the improved aged rabbit heart model. PMID- 26622490 TI - Effects of Shenmai injection and its bioactive components following ischemia/reperfusion in cardiomyocytes. AB - The aim of the present study was to determine whether the myocardial protective function of Shenmai injection (SM) during ischemia/reperfusion (I/R) is attributable to its regulation of intracellular calcium (Ca2+) and phospholamban (PLB) levels. Cultured neonatal Sprague Dawley rat cardiomyocytes were used to compare the effects of normoxia, total saponins of Panax ginseng (TSPG), ginsenoside Rg1 (Rg1) and SM treatments in rat myocardial cells following I/R. For each of these treatment groups, the mRNA and protein levels of PLB and the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) were evaluated, in addition to the cytoplasmic Ca2+ concentration [Ca2+]i and the rate of apoptosis. The results indicated that I/R markedly decreased phosphorylated PLB and SERCA expression and that SM was able to mitigate this effect, while TPSG and Rg1 were not. Furthermore, SM appeared to prevent aberrant apoptosis and restore the depleted [Ca2+]i resulting from I/R. The protective efficacy of SM against heart disease following I/R may, therefore, be due in part to its effect on intracellular Ca2+ homeostasis. SM may exert its protective effects by relieving PLB inhibition, and the pharmacodynamic actions of SM appear to be significantly more effective than those of its bioreactive components, TPSG and Rgl. PMID- 26622492 TI - Clinical characteristics and therapeutic analysis of 51 patients with Marjolin's ulcers. AB - Marjolin's ulcers, which are epidermoid carcinomas arising on non-healing scar tissue, may be of various pathological types, including squamous cell carcinoma. The pathogenesis of squamous cell carcinoma arising in an ulcer differs from that of the primary cutaneous squamous cell carcinoma. This squamous cell carcinoma is aggressive in nature, and has a high rate of metastasis. Between January 2001 and September 2013, 51 patients with Marjolin's ulcers were admitted to the Departments of Plastic Surgery of the Affiliated Foshan Hospital and the Second Affiliated Hospital of Sun Yat-sen University. The ulcers included 43 cases of squamous cell carcinoma, six of melanoma, one of basal cell carcinoma and one of epithelioid sarcoma. The clinical data of these patients were retrospectively analyzed. Patients were followed until mortality. Among the patients with squamous cell carcinoma, 30.23% exhibited sentinel lymph node metastasis and 11.63% had distant metastasis. Among the patients with melanoma, 66.67% had sentinel lymph node metastasis and 33.33% had distant metastasis. Sentinel lymph node metastasis was successfully detected in 11 patients with Marjolin's ulcer using 18F-fluorodeoxyglucose positron emission tomography-computed tomography and B-mode ultrasound guided biopsy. Squamous cell carcinoma was often treated by extended resection and skin grafting or skin flap repair. Patients with deep, aggressive squamous cell carcinoma of an extremity and sentinel lymph node metastasis underwent amputation and lymph node dissection. This treatment was also used for melanoma type Marjolin's ulcers. PMID- 26622491 TI - Relief of diabetes by duodenal-jejunal bypass sleeve implantation in the high-fat diet and streptozotocin-induced diabetic rat model is associated with an increase in GLP-1 levels and the number of GLP-1-positive cells. AB - A recently invented duodenal-jejunal bypass sleeve (DJBS) implanted in the duodenum and proximal jejunum has exhibited good glycemic control in diabetes mellitus. However, the specific mechanism by which DJBS placement induces the remission of diabetes is not well known. Previous studies have indicated that changes in the pattern of gut hormone secretion may play a role. The aim of the present study was to explore the role of intestinal L cells and the production of glucagon-like peptide-1 (GLP-1) by these cells in DJBS implantation-induced glycemic control in diabetic rats. A DJBS was placed in the proximal small intestine of rats with diabetes induced by a high-fat diet and low-dose streptozotocin (STZ), and the effects of the DJBS on the remission of diabetes and the GLP-1 levels of plasma and intestinal tissues were investigated 12 weeks after DJBS placement. The number of intestinal GLP-1 positive cells was also counted. When the DJBS had been in place for 12 weeks, the plasma glucose level of the DJBS-implanted rats decreased significantly from 23.33+/-1.56 mmol/l prior to surgery to 7.70+/-0.84 mmol/l and the diabetes mellitus was relieved completely; however, diabetic control rats and diabetic rats subjected to sham surgery did not show any improvement. Parallel with the remission of diabetes, the plasma and distal ileum GLP-1 levels of rats in the DJBS implantation group were also higher than those of rats in the diabetic control and sham surgery groups. The number of GLP-1-positive cells in the distal ileum was also higher in the DJBS implantation group than in the diabetic control and sham surgery groups (31.0+/-2.6 vs. 23.5+/-4.4 vs. 23.0+/-3.2 respectively; P<0.01). DJBS implantation effectively led to the remission of diabetes in rats with diabetes induced by a high-fat diet and low-dose STZ when implanted for 12 weeks. The remission of diabetes may be associated with the increase in the number of L cells and elevation of GLP-1 levels induced by DJBS implantation. PMID- 26622493 TI - Papillary tumor of the pineal region: A case report and review of the literature. AB - Papillary tumor of the pineal region (PTPR) was first described as a distinct tumor entity in 2003 and was introduced into the World Health Organization classification of central nervous system tumors in 2007. This tumor is rare and, to the best of our knowledge, only 7 cases have been reported in children <16 years of age, while the youngest documented patient was a 15-month-old boy. The present study reported a case of PTPR in a 10-year-old girl who underwent magnetic resonance imaging and surgical resection of tumors. Histological and immunohistochemical staining results were presented. Patients with PTPR require long-term follow-up, and the patient of the present study has continued to do well, with no recurrence of the tumor at the 15-month follow-up examination. In addition, a review of the literature on this unusual neoplasm was performed, along with discussion of their differential diagnosis. PMID- 26622495 TI - Characterization of human periodontal ligament cells cultured on three dimensional biphasic calcium phosphate scaffolds in the presence and absence of L ascorbic acid, dexamethasone and beta-glycerophosphate in vitro. AB - The aim of this study was to evaluate the effect of porous biphasic calcium phosphate (BCP) scaffolds on the proliferation and osteoblastic differentiation of human periodontal ligament cells (hPDLCs) in the presence and absence of osteogenic inducer (L-ascorbic acid, dexamethasone and beta-glycerophosphate). The cell growth within the scaffolds in the absence of osteogenic inducers was studied by cell counting kit-8 (CCK-8) assay and scanning electron microscopy (SEM). Alkaline phosphatase (ALP) activity and osteoblastic differentiation markers of hPDLCs in BCP scaffolds were examined in the presence and absence of osteogenic inducers. The cell number of hPDLCs in the BCP scaffolds was less than that of hPDLCs cultured in microplates (control). SEM images showed that cells successfully adhered to the BCP scaffolds and spread amongst the pores; they also produced abundant extracellular cell matrix. In the presence and absence of osteogenic inducers, the ALP activity of hPDLCs within BCP scaffolds was suppressed in varying degrees at all time-points. In the absence of osteogenic inducers, hPDLCs in BCP scaffolds express significant higher levels of osteopontin (OPN) mRNA than the control, and there were no significant differences for Runx2 and osteocalcin (OCN) mRNA levels compared with those cultured in microplates. In the presence of osteogenic inducers, Runx2 expression levels were significantly higher than those in control. OPN and OCN mRNA levels were downregulated slightly. Three-dimensional porous BCP scaffolds are able to stimulate the osteoblastic differentiation of hPDLCs in the presence and absence of osteogenic inducer and may be capable of supporting hPDLC-mediated bone formation. PMID- 26622494 TI - Establishment of immortalized mesenchymal stem cells derived from the submandibular glands of tdTomato transgenic mice. AB - Transgenic mice that overexpress the red fluorescent protein tdTomato (tdTomato mice) are well suited for use in regenerative medicine studies. Cultured cells from this murine model exhibit strong red fluorescence, enabling real-time in vivo imaging through the body surface of grafted animals. Mesenchymal stem cells (MSCs) have marked potential for use in cell therapy and regenerative medicine; however, the mechanisms that regulate their dynamics in vivo are poorly understood. In the present study, an MSC line was derived from the submandibular gland fibroblasts of tdTomato mice. The fluorescent signal from this cell line was observed in organs throughout the body, as well as in salivary glands. Primary culture cells derived from the submandibular gland were immortalized with SV40 large T antigen (GManSV cells); these cells exhibited increased migratory ability, as compared with those isolated from the sublingual gland. GManSV cells were tdTomato-positive and exhibited spindle-shaped fibroblastic morphology; they also robustly expressed mouse MSC markers: Stem cell antigen-1 (Sca-1), CD44, and CD90. This cell line retained multipotent stem cell characteristics, as evidenced by its ability to differentiate into both osteogenic and adipogenic lineages. These results indicate that Sca-1+/CD44+/CD90+-GManSV cells may be useful for kinetic studies of submandibular gland-derived MSCs in the context of in vitro co culture with other types of salivary gland-derived cells. These cells may also be used for in vivo imaging studies, in order to identify novel cell therapy and regenerative medicine for the treatment of salivary gland diseases. PMID- 26622496 TI - Protective effect of allicin on high glucose/hypoxia-induced aortic endothelial cells via reduction of oxidative stress. AB - This study was designed to explore the protective effect of allicin on aortic endothelial cell injury induced by high glucose/hypoxia and to investigate the corresponding mechanisms. The primary-cultured murine aortic endothelial cells were subcultured. The third passage of cells was adopted and randomly divided into five groups: The normal group (NG), the mannitol group (MG), the high glucose/hypoxia group (HG), the allicin group (AG) and the protein kinase C (PKC) inhibitor group (GG). The general morphology was observed under an inverted phase contrast microscope and cell viability was assessed using the MTT assay. Intracellular reactive oxygen species (ROS) levels in the endothelial cells were quantified using dihydroethidium staining. The levels of 8-hydroxydeoxyguanosine (8-OHdG), nuclear factor-kappaB (NF-kappaB), NADPH oxidase 4 (Nox4) and hypoxia inducible factor-1alpha (HIF-1alpha) and the activity of PKC were measured using ELISA. A quantitative polymerase chain reaction (qPCR) was adopted to evaluate the mRNA expression of Nox4, HIF-1alpha and NF-kappaB. The altered cell morphology observed in HG was notably ameliorated in the AG and GG. The protein levels of 8-OHdG, NF-kappaB, Nox4, HIF-1alpha and PKC in the HG were higher than those in the other groups. Furthermore, the cell viability in the AG was significantly increased and the protein levels of 8-OHdG, NF-kappaB, Nox4, HIF 1alpha and PKC were significantly decreased compared with those in the HG. The ROS production was found to be increased in the HG cells, while there was a significant decrease in the AG cells. These data indicate that allicin exerts a protective effect against high glucose/hypoxia-induced injury in aortic endothelial cells through its antioxidative action, which may involve the inhibition of the PKC pathway and regulation of HIF-1alpha. PMID- 26622497 TI - Mycobacterium heraklionense sp. nov.: A case series. AB - Mycobacterium heraklionense sp. nov. (M. heraklionense) is a novel non tuberculous mycobacterium belonging to the Mycobacterium terrae complex that has recently been described. It has a world-wide distribution. Recently, a case of tenosynovitis in an immunocompetent individual caused by M. heraklionense was reported, indicating that it has the ability to cause diseases. In the present study, in order to provide a more detailed profile of this mycobacterium and to obtain a more complete overall picture of its clinical significance, we report all available data regarding the initial 12 cases of its isolation. Of the 12 patients, 5 (42%) eventually died within a period of 3 months following the isolation of the mycobacterium. However, any connection between the presence of M. heraklionense and these deaths could not be documented. These 5 patients were all males with a mean age of 74.6 years suffering from serious underlying diseases, which most probably were the cause of death. Additional data from possible new cases of M. heraklionense isolation are anticipated. PMID- 26622498 TI - Fenofibrate inhibits the expression of VEGFC and VEGFR-3 in retinal pigmental epithelial cells exposed to hypoxia. AB - The aim of the present study was to examine the mechanisms through which fenofibrate inhibits the ability of human retinal pigment epithelial cells (RPE cells) exposed to hypoxia to stimulate the proliferation and migration of human umbilical vein endothelial cells (HUVECs). For this purpose, RPE cells and HUVECs were divided into the following groups: RPE-normoxia, RPE + fenofibrate, RPE hypoxia, RPE hypoxia + fenofibrate; HUVECs normal culture and HUVECs + RPE hypoxia culture supernatant. RPE cell hypoxia was induced by cobalt(II) chloride (CoCl2). A superoxide anion probe was used to measure the production of superoxide anion, which is indicative of hypoxic conditions. Cell proliferation was assessed by MTT assay, and the expression of vascular endothelial growth factor C (VEGFC) and vascular endothelial growth factor receptor-3 (VEGFR-3) in the RPE cell culture supernatant was measured by enzyme-linked immunosorbent assay (ELISA). The migration ability of the HUVECs was determined by scratch wound assay, and the angiogenic ability of the HUVECs was examined by measuring cell lumen formation. The mRNA and protein expression levels of VEGFC and VEGFR-3 in the RPE cells were measured by RT-qPCR and western blot analysis, respectively. Our results revealed that fenofibrate inhibited the increase in the expression and release of VEGFC and VEGFR-3 into the RPE cell culture supernatant induced by exposure to hypoxia. The culture of HUVECs in medium supernatant of RPE cells epxosed to hypoxia enhanced the viability and migration ability of the HUVECs and promoted lumen formation; these effects were inhibited by fenofibrate. In conclusion, our data demonstrated that the exposure of RPE cells to hypoxia induced the expression and release of VEGFC and VEGFR-3 into the cell culture supernatant. The culture of HUVECs in conditioned medium from RPE cells exposed to hypoxia increased VEGFC and VEGFR-3 expression, and promoted the proliferation and migration of the HUVECs, as well as capillary tube formation, suggesting that RPE cells play an important role in the formation of choroidal neovascularization resulting from hypoxia. Fenofibrate inhibited the upregulation of VEGFC and VEGFR 3 in the RPE cells exposed to hypoxia, and thus reduced the ability of HUVECs to form new blood vessels. PMID- 26622499 TI - Silencing of TGM2 reverses epithelial to mesenchymal transition and modulates the chemosensitivity of breast cancer to docetaxel. AB - Epithelial to mesenchymal transition (EMT) plays a critical role in drug resistance. The aim of the present study was to further elucidate its role by examining the effect of tissue transglutaminase (TG2) on EMT and drug resistance in breast cancer. An antisense lentiviral (LV) short hairpin (sh)RNA construct specific to the TG2 gene (TGM2) was designed, synthesized and stably transfected into MDA-MB-231 cells to silence TGM2 by RNA interference (RNAi). The transfected cells expressed low levels of TG2 and constituted the RNAi (TGM2-shRNA) group. A control (NC) group was also established by transfecting MDA-MB-231 cells with scrambled shRNA. The expression levels of TG2, E-cadherin, vimentin and B-cell lymphoma (Bcl)-2 in the cells were examined via western blotting. The transfected MDA-MB-231 cells were divided into four groups, two of which were treated with doxetaxel (TXT): NC, RNAi, TXT and RNAi + TXT groups,. Cell proliferation was analyzed by MTT assay and cell apoptosis was detected by flow cytometry. An in vivo assay was also conducted, in which MDA-MB-231 cells transfected with scrambled shRNA or TGM2-shRNA were subcutaneously implanted into nude mice. After 2 weeks, TXT or vehicle was intraperitoneally administered at a dose of 10 mg/kg on day 1 of every week and tumor growth was monitored. Following the silencing of TGM2 in the MDA-MB-231 cells, the cells showed changes in morphology, indicating that an increased expression of TG2 was associated with a mesenchymal morphology. Transfection of the cells with TGM2-shRNA affected the expression of TG2, E cadherin, vimentin and Bcl-2. In the MTT assay, the proliferation of MDA-MB-231 cells was significantly inhibited in the RNAi group compared with the control group (P<0.05), and the inhibitory effect increased in a time-dependent manner. Following treatment with TXT for 48 h, apoptosis was significantly promoted in the RNAi + TXT group compared with that in the other groups (P<0.05). Measurement of the tumors in the nude mice indicated that the combination of RNAi and TXT brought about a stronger antitumor effect than either treatment alone. These results suggest that the downregulation of TG2 reversed EMT and modulated the chemosensitivity of breast cancer to TXT. TG2 may be an important predictive and prognostic factor for the treatment efficacy of chemotherapy in patients with breast cancer. PMID- 26622500 TI - Anti-mitochondrial M2 antibody-positive autoimmune hepatitis. AB - Anti-mitochondrial M2 antibody (AMA-M2) is specific to primary biliary cirrhosis (PBC), but can also be found in certain patients with autoimmune hepatitis (AIH). Effective methods of differentiating between PBC and AIH are required, as their clinical course and management are different. Titers of AMA-M2 were analyzed before and after follow-up in patients with PBC or AIH. Patients who underwent liver biopsy and were diagnosed with either AIH (10 patients) or PBC (3 patients) were enrolled in the study. The AMA-M2 antibody titers of these patients were analyzed upon hospital admission. AMA-M2 reacted with the pyruvate dehydrogenase complex-E2, branched-chain 2-oxo acid dehydrogenase complex and 2-oxoglutaric acid dehydrogenase complex in the assay utilized for this study. The cut-off value for AMA-M2 was 5. Six AIH patients were AMA-M2(-) and 4 were AMA-M2(+). The titer for the AIH patients who were AMA-M2(+) was 24.8+/-14.8, compared with 324+/-174 in the patients with PBC (P=0.0138). Three AMA-M2(+) AIH patients were followed-up after liver biopsy. The AMA-M2 levels had decreased in all 3 patients, becoming undetectable in 2 of them. In conclusion, certain patients with AIH in this study were found to be AMA-M2(+), but the titers were significantly lower than those in the patients with PBC. At follow-up, the AIH patients exhibited decreased AMA-M2 titers. PMID- 26622501 TI - Association among the expression of beta-catenin, cyclin D1 and estrogen receptor beta in human breast cancer. AB - beta-catenin, cyclin D1 and estrogen receptor (ER)-beta are closely associated with the pathogenesis of breast cancer. In the present study, tissue samples were collected from 226 patients with breast cancer. Subsequently, immunohistochemical analysis was performed to detect the expression of beta-catenin, cyclin D1 and ER beta, and the Kaplan-Meier method was used for survival analysis. The abnormal expression rate of beta-catenin was 75.2%, while the cyclin D1 positive expression rate was 77.0% and the ER-beta positive expression rate was 43.4%. In the tissue samples exhibiting abnormal expression of beta-catenin, the positive expression rate of cyclin D1 (85.9%) was significantly higher compared with the samples that expressed beta-catenin normally (50.0%). Furthermore, the positive expression rate of ER-beta (35.7%) in the beta-catenin normal expression tissues was significantly lower compared with that in the beta-catenin abnormal expression tissues (45.9%). In the tissues with positive cyclin D1 expression, the positive expression rate of ER-beta (48.4%) was significantly higher compared with the cyclin D1 negative expression samples (26.9%). In addition, patients with normal expression of beta-catenin and positive expression of cyclin D1 exhibited longer tumor-free survival times. Therefore, an association exists among the abnormal expression of beta-catenin and the positive expression of cyclin D1 and ER-beta, which may contribute to the development of breast cancer. PMID- 26622502 TI - Effects of ultrasound on estradiol level, bone mineral density, bone biomechanics and matrix metalloproteinase-13 expression in ovariectomized rabbits. AB - The aim of the present study was to observe the effect of ultrasound (US) on estradiol level, bone mineral density (BMD), bone biomechanics and matrix metalloproteinase-13 (MMP-13) expression in ovariectomized (OVX) rabbits. A total of 28 virgin New Zealand white rabbits were randomly assigned into the following groups: Control (control group), ovariectomy (OVX group), ovariectomy with ultrasound therapy (US group) and ovariectomy with estrogen replacement therapy group (ERT group). At 8 weeks after ovariectomy, the US group received ultrasound treatment while the ERT group were orally treated with conjugated estrogens, and the control and OVX groups remained untreated. The estradiol level, BMD and bone biomechanics, cartilage histology and the MMP-13 expression were analyzed after the intervention. The results indicate that the US treatment increased estradiol level, BMD and bone biomechanical function. Furthermore, the US treatment appeared to improve the recovery of cartilage morphology and decreased the expression of MMP-13 in OVX models. Furthermore, the results suggest that 10 days of US therapy was sufficient to prevent the reduction of estradiol, BMD and bone biomechanical function, to protect osteoarthritis cartilage structure, and to reduce MMP-13 transcription and expression in OVX rabbits. Therefore, US treatment may be a potential treatment for postmenopausal osteoarthritis and osteoporosis. PMID- 26622503 TI - Role of matrix metalloproteinases in radiation-induced lung injury in alveolar epithelial cells of Bama minipigs. AB - Radiation-induced lung injury (RILI) is a common complication associated with thoracic radiotherapy. The aim of the present study was to investigate the effects of a single 15-Gy dose of right-thoracic lung irradiation on the expression levels of matrix metalloproteinases (MMPs) and other proteins in the alveolar epithelial type II (AE2) cells of Bama minipigs. All minipigs received either right-thoracic irradiation or sham irradiation under anesthesia, and were sacrificed at 4, 8, 12 or 24 weeks after irradiation. Collagen deposition was measured using Massons trichrome staining. Surfactant protein A (SP-A), transforming growth factor beta1 (TGFbeta1), MMP2, MMP9, vimentin and E-cadherin protein expression levels were evaluated using western blot analysis, and the MMP2 and MMP9 gelatinase activities were tested using gelatin zymography. SP-A and alpha-smooth muscle actin (alpha-SMA) co-localization was visualized using double immunofluorescence staining. At each time-point following irradiation, a significant increase in TGFbeta1, alpha-SMA, MMP2, MMP9 and vimentin protein expression levels and MMP2 and MMP9 gelatinase activity were observed in the irradiated lungs compared with the sham-irradiated controls. By contrast, SP-A and E-cadherin protein expression levels decreased in a time-dependent manner post-irradiation. SP-A and alpha-SMA co-localization was observed in irradiated alveolar epithelial cells. These data demonstrate that E-cadherin, SP-A, MMP2 and MMP9 may function as sensitive predictors of RILI. Epithelial-mesenchymal transition (EMT) occurs in the irradiated lungs of Bama minipigs, and MMP2 and MMP9 may contribute to EMT in AE2 cells by regulating TGFbeta1. Therefore, EMT may serve a crucial function in the development of RILI. PMID- 26622504 TI - Collagen type III glomerulopathy: A case report and review of 20 cases. AB - Collagen type III glomerulopathy is a non-immune-mediated glomerular disease, characterized by abnormal accumulation of type III collagen fibrils within the mesangial matrix and subendothelial space. The clinical manifestations of this disease are proteinuria, peripheral edema, hypertension and occasional progression to end-stage renal disease. Collagen type III glomerulopathy is extremely rare, and its etiology and pathogenesis remain elusive. To date, only case reports are available and the majority of these are from Japan. To investigate the idiographic features of collagen type III glomerulopathy in China, we report a case of collagen type III glomerulopathy with two differing renal biopsies and review 20 cases in China. The majority of the Chinese patients were adults. Thirty percent of the patients had nephrotic syndrome, and hypertension was observed in 75% of cases. Elevated creatinine was present in 45% of patients. The pathology of collagen type III glomerulopathy in the Chinese cases was similar to that observed in other ethnicities, although certain cases were IgA-positive by immunofluorescence microscopy, and electron-dense material could be observed in the mesangial area. The onset age, clinical manifestations and pathological features of the disease are not exactly the same in China as worldwide. PMID- 26622505 TI - Association between Parkinson's disease and G2019S and R1441C mutations of the LRRK2 gene. AB - In recent genome-wide association studies (GWAS), 11 risk loci were identified in patients with familial and sporadic Parkinson's disease (PD) in different populations. The LRRK2 gene was found to be a mutation hot spot in European and Asian populations. The aim of the present study was to investigate the incidence of G2019S and R1441C mutations in the LRRK2 gene in individuals from the Xinjiang region of China, and to explore the associations between LRRK2 gene single nucleotide mutations and susceptibility to PD in the Uyghur and Han populations of Xinjiang. A case-control study was conducted with a group of 312 patients with PD, including 130 Uyghur and 182 Han individuals. The control group comprised 359 subjects, including 179 Uyghur and 180 Han individuals. Polymerase chain reaction restriction fragment length polymorphism and DNA sequencing methods were used to detect the G2019S and R1441C mutations in the LRRK2 gene in the Uyghur and Han populations. No known mutations or new hybrids were found. Thus, there was no evidence that Uyghur and Han patients with PD possess the G2019S or R1441C mutations of the LRRK2 gene. This does not exclude the possibility of the presence other LRRK2 gene mutations that are associated with PD in the Uyghur and Han populations. In the future, the association of the LRRK2 gene with PD development in different regions and populations requires further study, in addition to the regulatory effects of the G2019S and R1441C mutations on gene expression. PMID- 26622506 TI - Subclavian steal syndrome decreases neurogenesis in the cerebellar cortex and affects cognitive function in rabbits. AB - Subclavian steal syndrome (SSS) is a condition characterized by a steno-occlusive impairment of the proximal subclavian artery. The majority of patients with SSS are asymptomatic, while symptomatic patients present with neurological symptoms. SSS is a risk factor for cerebral ischemia, which reacts badly upon cognitive function; however, it remains unknown whether SSS is able to cause progressive cognitive impairment. In the present study, the potential effects of SSS on cognitive function were investigated using atherosclerotic rabbits as a model of SSS. A total of 48 male New Zealand rabbits were divided into the control, sham and SSS groups. The results of eyeblink experiments indicated no significant differences among the three groups; however, SSS did appear to exert a negative impact on neurogenesis in the cerebellar cortex. In order to further clarify the mechanisms underlying this SSS-mediated reduction in cell proliferation, the energy metabolism, immune function and oxidative stress statuses were evaluated by determining the levels of adenosine triphosphate (ATP), adenosine, interleukin (IL)-1beta, IL-6, malondialdehyde, 8-hydroxy-2'-deoxyguanosine, CuZn-superoxide dismutase and catalase. The results showed that the levels of extracellular ATP in the cerebellar cortex had decreased, while levels of adenosine had also decreased. These findings suggest that SSS is able to inhibit neurogenesis in the cerebellar cortex by decreasing the extracellular ATP levels. Furthermore, these changes may result in an impairment of the cognition of the rabbits. The early diagnosis and treatment of SSS may, therefore, prevent or mitigate cognitive impairment in the future. PMID- 26622507 TI - Multiple courses of immunotherapy with different immune cell types for patients with hepatocellular carcinoma after microwave ablation. AB - The aim of the present study was to investigate the therapeutic efficacy of immunotherapy after microwave ablation (MWA), which was used to improve liver function, reduce the recurrence rate and enhance survival period in patients with hepatocellular carcinoma (HCC). Between February 2009 and December 2010, 14 patients received immunotherapy after MWA (immunotherapy group) and 15 patients received MWA alone with no post-ablated adjuvant therapy (control group). Immune and liver parameters, recurrence rate and survival time were recorded. The absolute lymphocyte count in the immunotherapy group exceeded that in the control group after 3 courses of immunotherapy (P<0.05). No significant differences were detected in the lymphocyte subset distribution in the control and immunotherapy patients prior to ablation (P>0.05); however, certain cytotoxic subsets (CD3+/CD8+, CD8+CD28+ and CD3+CD16+CD56+ T cells) were over-represented and negative regulatory or helper subsets (CD4+CD8+, CD4+, CD4+CD25+) were under represented in the immunotherapy group between 1 and 12 months after immunotherapy (P<0.05). After 2 courses of immunotherapy the proliferation rate of myeloid dendritic cells and T lymphocytes, including CD3+/CD8+ lymphocytes, significantly increased (P<0.05 and P<0.01, respectively). In addition, the level of albumin in the immunotherapy group exceeded that in the control group after 3 courses of immunotherapy (P<0.05). However, the rate of disease-free survival and overall survival within 16 months of MWA did not differ significantly between the two groups (P>0.05). In conclusion, the results of the present study indicate that immunotherapy improves the immune status and liver function of patients with HCC. PMID- 26622508 TI - Modular flexible ureteroscopy and holmium laser lithotripsy for the treatment of renal and proximal ureteral calculi: A single-surgeon experience of 382 cases. AB - To determine the safety and efficacy of modular flexible ureteroscopy and holmium laser lithotripsy for the treatment of renal and proximal ureteral calculi, a retrospective chart review of a single surgeon's 3-year modular flexible ureteroscopy experience was performed. All of the patients were treated with modular flexible ureteroscopy and holmium laser lithotripsy by a single surgeon. Stone-free status was defined as no fragments or a single fragment <=4 mm in diameter at the 3-month follow-up. The procedure number, operative time, stone free rates, repeat usage of the multilumen catheter, and perioperative complications were documented. The present study included 215 male patients and 167 female patients, with an average age of 48.5+/-13.7 years (range, 17-84 years). The mean stone size was 11.5+/-4.1 mm (range, 4-28 mm), and the mean total stone burden was 17.5+/-5.7 mm (range 15-46 mm). A total of 305 patients (79.8%) had a stone burden <=20 mm, and 77 patients (20.2%) had a stone burden >20 mm. The mean number of primary procedures was 1.3+/-0.2 (range, 1-3). The stone-free rate following the first and the second procedure was 73.4 and 86.9%, respectively. The mean postoperative hospital stay was 3.1+/-1.2 days (range, 2-6 days). The highest clearance rates were observed for proximal ureteral stones (100%) and renal pelvic stones (88.7%), whereas the lowest clearance rates were observed for lower calyx stones (76.7%) and multiple calyx stones (77.8%). The higher the initial stone burden, the lower the postoperative stone-free rate (<=20 vs. >20 mm; 89.8 vs. 75.3%). The overall complication rate was 8.1%. The results of the present study suggest that modular flexible ureteroscopy with holmium laser lithotripsy may be considered the primary method for the treatment of renal and proximal ureteral calculi in select patients, due to its acceptable efficacy, low morbidity, and relatively low maintenance costs. PMID- 26622509 TI - Expression of P2X7R in breast cancer tissue and the induction of apoptosis by the gene-specific shRNA in MCF-7 cells. AB - The aim of the present study was to investigate the effects of P2X7R short hairpin (sh)RNA on the proliferation and apoptosis of MCF-7 cells, and to detect the expression of P2X7R in breast cancer and MCF-7 cells. In order to detect the expression of P2X7R in normal breast and breast cancer tissues, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blot analysis and immunohistochemistry were performed. A P2X7-targeted shRNA sequence and a scrambled sequence were inserted into the pLKO.1 expression vector, and MCF-7 cells with stable transfection of P2X7R-shRNA and P2X7R-scrambled shRNA (control) were selected. qRT-PCR was used to detect the mRNA expression levels of P2X7R in the MCF-7 cells transfected with P2X7R-shRNA and scrambled shRNA. In addition, protein expression levels of P2X7R in the fresh tumor tissues were detected by western blot analysis. An MTT assay was used to detect the proliferation rate at different time points, while flow cytometry was used to detect the growth inhibition and apoptosis rate of the stably transfected MCF-7 cells. P2X7R expression levels in the breast cancer tissues were higher when compared with the normal breast tissue, and a positive correlation was observed with the estrogen receptor (ER+), as shown by qRT-PCR, western blot analysis and immunohistochemistry. Plasmids expressing P2X7 gene-specific shRNA and scrambled shRNA were constructed and transfected into MCF-7 cells. The qRT-PCR results revealed lower mRNA expression levels of P2X7 in the P2X7R-shRNA cells when compared with the scrambled shRNA cells. Furthermore, western blot analysis demonstrated that P2X7 protein was highly expressed in the MCF-7 cells transfected with scrambled shRNA, while low expression was observed in the P2X7R shRNA-transfected cells. Following transfection of the recombinant plasmids into the MCF-7 cells, the proliferation rate in each group was analyzed. The P2X7R shRNA and KN-62 groups were shown to have significantly reduced rates of proliferation when compared with the normal control group. In addition, flow cytometry revealed that the P2X7R-shRNA and KN-62 groups exhibited a reduced level of cell proliferation and a higher rate of apoptosis. In conclusion, P2X7R was shown to be overexpressed in breast cancer tissues and positively associated with ER expression. A P2X7R-shRNA expression vector effectively inhibited P2X7R expression in MCF-7 breast cancer cells, which subsequently induced cell apoptosis and reduced the levels of cell proliferation. These results indicated that P2X7R may serve as a potential target for breast cancer treatment and prevention. PMID- 26622510 TI - Nilotinib rapidly reverses breakpoint cluster region-Abelson oncogene fusion gene and M244V mutations in a patient with chronic myelogenous leukemia: A case report. AB - Chronic myelogenous leukemia (CML) is a condition characterized by a balanced genetic translocation, t (9;22) (q34;q11.2), which leads to a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is referred to as the Philadelphia chromosome. At a molecular level, this translocation results in the formation of the BCR-ABL fusion oncogene, which translates into a BCR-ABL oncoprotein. Imatinib, nilotinib and dasatinib are three tyrosine kinase inhibitors that have been approved by the US Food and Drug Administration for the treatment of patients diagnosed with CML in the chronic phase (CML-CP). The present study describes the case of a patient with imatinib-resistant CML who, following two months of treatment with nilotinib, no longer exhibited detectable BCR-ABL fusion genes or M244V mutations. This suggests that nilotinib may be effective for treating CML cases in which the BCR-ABL fusion protein has an M244V mutation. PMID- 26622511 TI - Phenotypic characterization of type II collagen-induced arthritis in Wistar rats. AB - The aim of the present study was to determine a more specific, efficient and simple method for the induction of collagen-induced arthritis (CIA) in rats. Different strains of rats were injected at the base of the tail with bovine type II collagen (CII) emulsified in incomplete Freund's adjuvant (IFA). The onset and severity of arthritis were evaluated by clinical assessment. The established CIA model was analyzed using a comprehensive examination of clinical, hematological, histological and radiological parameters. The results demonstrated that Wistar rats were the most susceptible strain to CIA followed by Wistar Furth rats, with Sprague Dawley rats being the least susceptible. Following primary and booster immunization, female Wistar rats developed severe arthritis, with an incidence of >83% and low variability in clinical signs. The development of arthritis was accompanied by a significantly elevated erythrocyte sedimentation rate compared with that in the control rats. The radiographic examination revealed bone matrix resorption, considerable soft tissue swelling, periosteal new bone formation and bone erosion in the arthritic joints of the CIA rats. Histopathologically, the synovial joints of CIA rats were characterized by synovial hyperplasia, pannus formation, marked cellular infiltration, bone and cartilage erosion and narrowing of the joint space. The administration of an intradermal injection of only 200 ug bovine CII emulsified in IFA at the base of the tail therefore leads to the successful development of a CIA rat model. This well-characterized CIA rat model could be specifically used to study the pathophysiology of human rheumatoid arthritis as well as to test and develop anti-arthritic agents for humans. PMID- 26622512 TI - Effects of paroxetine on spatial memory function and protein kinase C expression in a rat model of depression. AB - The aim of the present study was to investigate the effects of paroxetine on the spatial memory and expression level of protein kinase C (PKC) in a rat model of depression. Rat models of depression were established by chronic unpredictable mild stress. The spatial learning and memory function of the rats were assessed by the Morris water maze test. The expression levels of PKC in the hippocampus were detected by western blotting. The results showed that, compared with the control group, the escape latency was prolonged and the percentage of time in the target quadrant and the number of times the rats crossed the platform were reduced in the model group; however, the impaired spatial learning and memory function in these rat models could be restored by paroxetine, almost to a level comparable with that in the normal control animals. In addition, the expression of PKC in the model group was significantly decreased compared with that in the control group, and the expression could also be elevated by paroxetine treatment. These results suggest an association between PKC levels and the pathogenesis of depression. The application of paroxetine can improve the spatial memory and reverse the changes in PKC levels in the hippocampus in the rat model of depression. The present findings have enhanced the understanding of the pathogenesis of depression, and provide experimental evidence for the treatment of depression with paroxetine. PMID- 26622514 TI - A case of mushroom-shaped anaplastic oligodendroglioma resembling meningioma and arteriovenous malformation: Inadequacies of diagnostic imaging. AB - Magnetic resonance imaging (MRI) is the most widely discussed and clinically employed method for the differential diagnosis of oligodendrogliomas; however, MRI occasionally produces unclear results that can hinder a definitive oligodendroglioma diagnosis. The present study describes the case of a 34-year old man that suffered from headache and right upper-extremity weakness for 2 months. Based on the presurgical evaluation, it was suggested that the patient had a World Health Organization (WHO) grade II-II glioma, meningioma or arteriovenous malformation (AVM), with unclear radiological manifestations. Postsurgical pathological assessment confirmed the tumor to be an anaplastic oligodendroglioma (WHO grade III). This case is notable due to the confusing radiological manifestation of a mushroom-shaped anaplastic oligodendroglioma in the parietal-temporal-occipital region, which provided a potential source of misdiagnosis for meningioma and AVM. PMID- 26622515 TI - Percutaneous transhepatic biliary drainage and stenting for malignant obstructive jaundice: A report of two cases. AB - Malignant obstructive jaundice comprises a group of diseases that can be caused by primary biliary and extra-biliary carcinomas. Generally, surgical resection is the primary treatment for malignant obstructive jaundice; however, for the patients that are unable to undergo surgery, urgent treatment is required to improve hepatic function. Percutaneous transhepatic biliary drainage (PTBD) and stenting are emerging alternative treatments for malignant obstructive jaundice. PTBD and stenting have exhibited good efficacy for the treatment of malignant obstructive jaundice, with few complications and reduced associated pain. PMID- 26622513 TI - Reduction of the systemic inflammatory induced by acute cerebral infarction through ultra-early thrombolytic therapy. AB - Acute ischemic stroke induces systemic inflammation, exhibited as changes in body temperature, white blood cell counts and C-reactive protein (CRP) levels. The aim of the present study was to observe the effects of intravenous thrombolytic therapy on inflammatory indices in order to investigate the hypothesis that post stroke systemic inflammatory response occurs in response to the necrosis of brain tissues. In this study, 62 patients with acute cerebral infarction and indications for intravenous thrombolysis were divided into three groups on the basis of their treatment and response: Successful thrombolysis (n=36), failed thrombolysis (n=12) and control (n=14) groups. The body temperature, white blood cell counts and high-sensitivity (hs)-CRP levels were recorded pre-treatment and on post-stroke days 1, 3, 5 and 7. Spearman's correlation analysis showed that the pre-treatment National Institutes of Health Stroke Scale (NIHSS) score positively correlated with body temperature, white blood cell count and hs-CRP levels. On day 3 of effective intravenous thrombolysis, the body temperature and white blood cell were decreased and on days 3 and 5, the serum levels of hs-CRP were reduced compared with those in the failed thrombolysis and control groups. The results indicate that the systemic inflammatory response following acute cerebral infarction was mainly caused by ischemic injury of local brain tissue; the more serious the stroke, the stronger the inflammatory response. Ultra-early thrombolytic therapy may inhibit the necrosis of brain tissue and thereby reduce the inflammatory response. PMID- 26622516 TI - Network analysis of microRNAs and genes in human osteosarcoma. AB - To date, numerous studies have suggested that microRNAs (miRNAs) and genes play key roles in osteosarcoma (OS); however, the majority of these studies have been conducted with a specific focus on either the genes or the miRNAs, which has made the regulatory mechanisms of OS difficult to decipher. The aim of the present study was to systematically investigate the elements [genes, miRNAs and transcription factors (TFs)] associated with the morbidity of OS and to explore the associations among these elements, instead of focusing on one or several elements. The scattered data were collected from existing studies of OS, and three regulatory networks (abnormally expressed, related and global) were constructed to explore OS at a macroscopic level. The abnormally expressed network showed the numerous incorrect data linkages that are present when OS emerges, making it useful as a map of the faults in OS. In theory, the correction of these errors could lead to the prevention and even cure of the disease. Unlike studies in which cancer networks have been formed based purely on gene data, the present study focused on genes and miRNAs, as well as the associations among them, to form the regulatory networks of OS. The constructed regulatory networks were shown to contain numerous self-adaptation associations, which may aid in the analysis of the pathogenesis of OS. By comparing and analyzing the similarities and differences, a number of important pathways were highlighted. A notable finding was the predicted TFs obtained by the P-Match method, which could be used to further study the pathogenesis of OS. In the present study, the mechanism of OS has been systematically analyzed and a theoretical foundation for the mechanism has been provided, which may assist the development of gene therapy targeting OS. PMID- 26622517 TI - Upregulation of peroxiredoxin III in doxorubicin-induced cytotoxicity and the FoxO3a-dependent expression in H9c2 cardiac cells. AB - Doxorubicin (DOX) is an efficient drug used in cancer therapy; however, it produces reactive oxygen species (ROS) that induce severe cytotoxicity, limiting its clinical application. The aim of the present study was to investigate the role of peroxiredoxin III (Prx III) in DOX-induced H9c2 cell injuries. Following DOX treatment, the expression of phosphorylated-FoxO3a (p-FoxO3a) was decreased and Prx III expression was increased in H9c2 cells. In order to detect whether oxidative stress was involved in the induction of Prx III expression by FoxO3a, exogenous H2O2 was used to induce oxidative stress in the H9c2 cells. Apoptosis of H9c2 cardiomyocytes was assessed using methyl thiazolyl tetrazolium assay and Hoechst staining. The levels of Prx III and p-FoxO3a were evaluated using western blot analysis. As expected, H2O2 was found to mimic the effect of DOX, decreasing the expression of p-FoxO3a and increasing the expression of Prx III. In addition, the study evaluated whether the transcription factor FoxO3a was essential for the expression of Prx III. Pretreatment of H9c2 cells with N-acetyl-L-cysteine (NAC), a scavenger of ROS, prior to exposure to DOX dramatically increased the phosphorylation of FoxO3a and led to a marked reduction in Prx III expression in the H9c2 cells. In conclusion, the results of the current study suggest that FoxO3a mediates the expression of Prx III in DOX-induced injuries. PMID- 26622518 TI - Correlation between metabolic enzyme GSTP1 polymorphisms and susceptibility to lung cancer. AB - The aim of the present study was to determine the frequency distribution and characteristics of polymorphic alleles and genotypes in glutathione S-transferase pi 1 (GSTP1) exon 5, and to explore the correlation between GSTP1 exon 5 polymorphisms and susceptibility to lung cancer using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Patients were diagnosed with lung cancer from May 2006 to October 2008 by postoperative pathological examination. A total of 150 patients, including 115 males and 35 females, aged 31-76 years (mean, 57.1 years) were enrolled. The control group consisted of 152 healthy volunteers who received physical examination at outpatient clinics. Genomic DNA was extracted from the peripheral venous blood of the 302 subjects, and the GSTP1 genotype was determined by PCR-RFLP and restricted enzyme digestion of PCR products. GSTP1 polymorphisms were analyzed in the 302 subjects. The C and G allele frequencies of GSTP1 in the control and lung cancer groups showed no significant difference (P=0.135); the frequencies of three different genotypes, A/A, A/G and G/G, of GSTP1 in the control and lung cancer groups exhibited no significant differences between the two groups (P=0.223). GSTP1 genotype frequencies in the study population fitted the Hardy Weinberg equilibrium, demonstrating that the genotype results of this study conform to this genetic law. Overall, 50.7% of the subjects in the lung cancer group carried the non-A/A genotype of GSTP1, which was higher than the 43.4% of the control group. The risk of lung cancer in subjects with the non-A/A genotype was 1.43-fold higher than that in those with the A/A genotype, but no statistical significance was found (P=0.138). GSTP1 exon 5 polymorphisms were demonstrated to be associated with lung cancer susceptibility on the whole. However, stratified analysis suggested the correlation of GSTP1 exon 5 polymorphisms with lung squamous cell carcinoma risk, and that exon 5 polymorphisms might increase the risk of lung squamous cell carcinoma. Exon 5 GSTP1 polymorphisms were not found to be a strong influencing factor in lung cancer risk, but may play a certain role. PMID- 26622519 TI - Angiotensin II stimulates melanogenesis via the protein kinase C pathway. AB - Melanogenesis is a physiological process that results in the synthesis of melanin pigments, which serve a crucial function in hyperpigmentation. The aim of the present study was to determine the effects of angiotensin II (Ang II) on melanogenesis and to elucidate the molecular events of Ang II-induced melanogenesis. Experiments were performed on human melanocytes to elucidate the pigmenting effect of Ang II and the underlying mechanisms. The elements involved in melanogenesis, including melanin content, tyrosinase (TYR) activity, and microphthalmia-associated transcription factor (MITF) and TYR expression at the mRNA and protein levels were evaluated. Melanin content and TYR activity increased in response to Ang II treatment in a concentration-dependent manner. MITF and TYR mRNA and protein expression levels were increased significantly in response to Ang II in a concentration-dependent manner. The Ang II-induced increase in melanin synthesis was reduced significantly in response to co treatment with Ro-32-0432, a protein kinase C (PKC) inhibitor, whereas co treatment with H-89, a PKA inhibitor, did not attenuate the Ang II-induced increase in melanin levels. These results suggest that PKC is required for Ang II induced pigmentation in human melanocytes and that the mechanism involves the PKC pathway and MITF upregulation. PMID- 26622520 TI - A case of crusted scabies combined with bullous scabies. AB - Scabies is a contagious skin disease that causes extremely itching. It is a parasitic disease caused by the mite Sarcoptes scabiei and characterized by polymorphous lesions. Vesicular and bullous lesions in cases of scabies are rather rare. Bullous scabies has a pemphigoid presentation. Crusted scabies, also known as Norwegian scabies, is a rare and severe form of the disease. The large number of mites present in and on the skin cause scabies to be highly contagious. The present study reports a case of crusted scabies combined with bullous scabies, the clinical and histopathological manifestations of which mimicked those of bullous pemphigoid. Direct and indirect immunofluorescence test results were negative. Bullae recurred and persisted despite systemic corticosteroids and antihistamine medication. The patient was successfully treated with 10% sulfur cream and remained free of recurrence during the 12 months of follow-up. Differential diagnosis with bullous pemphigoid and the mechanism of formation of bullae are also discussed. PMID- 26622521 TI - Association between toll-like receptor 6 expression and auxiliary T cells in the peripheral blood of pediatric patients with allergic purpura. AB - The aim of the present study was to investigate the correlations between toll like receptor 6 (TLR6) expression in the peripheral blood mononuclear cells (PBMCs) and auxiliary T cells of children with purpura. A total of 42 children with acute Henoch-Schonlein purpura (HSP) were selected for the study, and a further 30 healthy children were selected as a control group. Enzyme-linked immunosorbent assays were performed to detect the levels of plasma interferon (IFN)-gamma, interleukin (IL)-4 and IL-17, and flow cytometry was performed to detect the TLR6 protein expression levels in PBMCs. The plasma levels of IL-4, IFN-gamma and IL-17 in the HSP group were significantly higher compared with those in the normal control group. TLR6 protein expression was significantly increased in the PBMCs of the HSP patients. The TLR6 protein expression levels in the monocytes of the HSP group significantly positively correlated with the serum IL-4 and IL-17 levels, but not with the serum levels of IFN-gamma. Therefore, the results of the present study suggest that the activation of TLR6 may be involved in the immunopathogenesis of HSP, and that the activated TLR6 may mediate this process by upregulating the immune responses of type 2 T helper (Th2) and Th17 cells. PMID- 26622522 TI - Transient unilateral facial paralysis induced by perimesencephalic non-aneurysmal subarachnoid hemorrhage: A case report and review of the literature. AB - The present study is, to the best of our knowledge, the first report of a rare, transient form of unilateral facial paralysis induced by perimesencephalic non aneurysmal subarachnoid hemorrhage. The paralysis may have resulted from the compression of a part of the facial nerve by the flow of the hemorrhage into the cavum subarachnoidale; alternatively, the paralysis may have been caused by disorder of the blood supply of the facial nucleus, with the hemorrhage leading to brainstem vasospasm. The patient underwent hemostatic therapy, administration of a symptomatic antiemetic and dehydration. The facial nerve compression was released due to the absorption of the hemorrhage or the rapid improvement of the facial nucleus blood supply following the resolution of the vasospasm. Consequently, the facial nerve function was fully recovered, and the facial paralysis disappeared. PMID- 26622523 TI - Expression of E-cadherin in oral lichen planus. AB - Oral lichen planus (OLP) is a common lesion of the oral mucosa that can progress to cancer. E-cadherin is involved in intercellular adherence and the pathogenesis, development and metastasis of tumors, and is considered to be an important indicator of tumor progression and prognosis. The aim of this study was to investigate the expression of E-cadherin in OLP in order to elucidate its role in the pathogenesis and malignant transformation of OLP and provide evidence to support the early diagnosis and treatment of OLP with malignant potential. OLP specimens (n=52) and samples of normal oral mucosa (n=41) as the control were collected. Immunohistochemical staining was conducted to reveal the expression of E-cadherin in the OLP samples and normal oral mucosa. It was observed that 25 of the 52 OLP specimens exhibited normal positive expression of E-cadherin and 27 exhibited abnormal positive expression, corresponding to an abnormal positive rate of 51.92%. In the normal oral mucosa group, 39 of the 41 cases exhibited normal positive expression and 2 exhibited abnormal positive expression. The abnormal positive rate in the normal oral mucosa was 4.88%, which was significantly lower than that in the OLP group. The significantly elevated rate of abnormal positive expression of E-cadherin in the OLP group indicates the involvement of E-cadherin in the malignant transformation of OLP and supports the malignant potential of OLP. PMID- 26622525 TI - Role of the glucocorticoid receptor in the recurrence of primary nephrotic syndrome. AB - The present study aimed to investigate the changes in the expression levels of the glucocorticoid receptor (GR) and its subtypes in patients with recurrent renal syndrome. In addition, the effects of tumour necrosis factor alpha (TNF alpha) and a TNF-alpha monoclonal antibody on these receptors in peripheral blood mononuclear cells (PBMCs) isolated from the patients was analysed. Furthermore, a new treatment method for recurrent renal syndrome was explored. The serum levels of TNF-alpha in the normal (A), stable renal syndrome (B) and renal syndrome recurrence (C) groups of patients were determined by enzyme-linked immunosorbent assay (ELISA). The mRNA and protein expression levels of GR, GRalpha and GRbeta were determined by ELISA, western blot analysis and quantitative polymerase chain reaction in PBMC cultures from the three groups in the absence of intervention (blank control) and following stimulation with methylprednisolone, TNF-alpha and/or TNF-alpha monoclonal antibody. Group C exhibited higher expression levels of TNF-alpha and GRbeta but a lower level of GRalpha expression (P<0.05) compared with the other groups. Regardless of methylprednisolone intervention, the expression levels of GR and GRbeta in the three groups following stimulation by TNF-alpha were significantly higher compared with those in the respective blank control, whereas in group C, the GRalpha expression levels following TNF-alpha treatment were lower compared with those in the control group (P<0.05). The treatment of group C with TNF-alpha monoclonal antibodies resulted in higher GRalpha expression but lower GRbeta expression compared with those in the blank control (P<0.05). The change in the ratios of the GR subtypes may be associated with renal syndrome recurrence. TNF-alpha may be involved in renal syndrome relapse by changing the levels of GR as well as the proportion of the GR subtypes. TNF-alpha monoclonal antibodies may mitigate the changes in the ratios of these subtypes. PMID- 26622524 TI - Promoter methylation of p16 and RASSF1A genes may contribute to the risk of papillary thyroid cancer: A meta-analysis. AB - The aim of the present meta-analysis was to investigate the correlation of promoter methylation of the p16 and Ras association domain family 1 isoform A (RASSF1A) genes with the risk of the development of papillary thyroid cancer (PTC). A number of electronic databases were searched without language restrictions as follows: Medline (1966-2013), the Cochrane Library database (Issue 12, 2013), Embase (1980-2013), CINAHL (1982-2013), Web of Science (1945 2013) and the Chinese Biomedical Database (CBM; 1982-2013). A meta-analysis was performed with the use of Stata statistical software. The odds ratios (ORs), ratio differences (RDs) and 95% confidence intervals (95% CIs) were calculated. In the present meta-analysis, eleven clinical cohort studies with a total of 734 patients with PTC were included. The results of the current meta-analysis indicated that the frequency of promoter methylation of p16 in cancer tissues was significantly higher compared with that in normal, adjacent and benign tissues (cancer tissues vs. normal tissues: OR=7.14; 95% CI, 3.30-15.47; P<0.001; cancer tissues vs. adjacent tissues: OR=11.90; 95% CI, 5.55-25.52; P<0.001; cancer tissues vs. benign tissues: OR=2.25; 95% CI, 1.67-3.03; P<0.001, respectively). The results also suggest that RASSF1A promoter methylation may be implicated in the pathogenesis of PTC (cancer tissues vs. normal tissues: RD=0.53; 95% CI, 0.42 0.64; P<0.001; cancer tissues vs. adjacent tissues: RD=0.39; 95% CI, 0.31-0.48; P<0.001; cancer tissues vs. benign tissues: RD=0.39; 95% CI, 0.31-0.47; P<0.001; respectively). Thus, the present meta-analysis indicates that aberrant promoter methylation of p16 and RASSF1A genes may play a crucial role in the pathogenesis of PTC. PMID- 26622526 TI - Unexpected unrelated umbilical cord blood stem cell engraft in two patients with severe aplastic anemia that received immunosuppressive treatment: A case report and literature review. AB - Severe aplastic anemia (SAA) is a life-threatening bone marrow disorder. Bone marrow transplantation is the primary therapy for SAA; however, its efficacy is limited by numerous factors, including lack of histocompatible sibling donor, patient age and graft-versus-host-disease (GVHD) following transplantation. Immunosuppressive treatment (IST) is the first procedure developed for patients without a sibling donor. Our previous study reported that patients administered enhanced IST, in addition to a regime of unrelated umbilical cord blood (UCB) transfusion, exhibited higher efficiency and a reduced rate of relapse. Therefore, the present study reported the cases of 2 patients that received enhanced IST plus unrelated UCB transfusion. These patients exhibited complete hematological recovery with an increased rate of mixed chimerism and demonstrated no signs of GVHD or relapse during the 2-year follow-up period. Thus, enhanced immunosuppressive treatment (low-dose cyclophosphamide and antithymocyte globulin) combined with UCB transfusion may be an effective treatment for patients with SAA. PMID- 26622527 TI - Dynamic changes of five neurotransmitters and their related enzymes in various rat tissues following beta-asarone and levodopa co-administration. AB - The aim of the present study was to investigate the dynamic changes of five neurotransmitters and their associated enzymes in the rat plasma and brain tissues following the co-administration of beta-asarone and levodopa (L-dopa). The rats were divided into five groups, including the control group and four treatment groups that were intragastrically co-administered beta-asarone and L dopa and sacrificed at 1, 5, 18 and 48 h, respectively. Neurotransmitter levels in the brain tissues and plasma were detected using high performance liquid chromatograph and the related enzymes of dopamine (DA) were measured using an enzyme-linked immunosorbent assay. The results indicated that the striatal levels of L-dopa and 3,4-dihydroxyphenylacetic acid (DOPAC) peaked at 1 h and then returned to the normal levels, while the striatal levels of DA were stable within 48 h. In the cortex and hippocampus tissue, L-dopa, DA, DOPAC and homovanillic acid (HVA) levels peaked at 1 h and then returned to normal levels. In the plasma, L-dopa, DA, DOPAC and HVA levels peaked at 1 h. Compared with the control group, L-dopa, DA and HVA levels were higher between 18 and 48 h, whereas the DOPAC level was lower. By contrast, no statistically significant differences were observed in the serotonin (5-HT) levels among the plasma, hippocampus, cortex and striatum. Furthermore, the DA/L-dopa ratio in the brain tissues and plasma increased in the first 5 h, while (DOPAC + HVA)/DA ratios demonstrated a significant reduction. Striatal tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC) levels were higher compared with the control group; however, catechol-O-methyltransferase (COMT) and monoamine oxidase B levels were reduced. In the rat plasma, TH and COMT peaked at 1 h, while AADC peaked at 5 h. In conclusion, the results of the present study indicate that the co-administration of L-dopa and beta-asarone may be used to maintain a stable striatal DA level within 48 h. In addition, this treatment may promote DA generation by AADC and reduce the metabolism of DA by COMT. PMID- 26622529 TI - Superior mesenteric artery syndrome caused by surgery and radiation therapy for a brain tumor: A case report. AB - Superior mesenteric artery syndrome (SMAS) is defined as an obstruction of the third part of duodenum due to compression by the superior mesenteric artery. Although traumatic brain injury is a risk factor for SMAS, few cases of SMAS resulting from brain surgery have been reported. SMAS has been observed to occur following neurosurgical surgery in pediatric patients but, to the best of our knowledge, no such cases have been reported in adults. The present study reports the case of a 21-year-old female patient who developed SMAS after persistent vomiting and prolonged weight loss following cerebellar tumor resection and cranial irradiation. The SMAS was confirmed by computed tomography and resolved following successful nutritional management. PMID- 26622528 TI - Effect of TNF-alpha inhibitors on transcriptional levels of pro-inflammatory interleukin-33 and Toll-like receptors-2 and -9 in psoriatic plaques. AB - Tumor necrosis factor (TNF)-alpha inhibitors are considered to be effective in the treatment of psoriatic plaques, although the precise therapeutic pathway is not clear. Pro-inflammatory molecules, such as Toll-like receptor (TLR)-2 and -9 and interleukin (IL)-33, a member of the IL-1 receptor/TLR superfamily, have been found to be expressed in psoriatic plaques. The aim of the present study was to investigate whether TNF-alpha inhibitor treatment has an effect on the expression of IL-33 and TLR-2 and -9 in psoriatic plaques. Seventeen patients with psoriatic plaques were treated with a TNF-alpha inhibitor (etanercept or infliximab) for 12 weeks in an open-label study, and the transcriptional levels of IL-33 and TLR-2 and -9 were determined by reverse transcription-quantitative polymerase chain reaction in paired biopsies of psoriatic plaques obtained at baseline (B) and following the 12 weeks of treatment (P). The psoriasis area severity index (PASI) score was also determined. At B, elevated IL-33 and TLR-2 mRNA levels were observed in all cases, while TLR-9 showed elevated mRNA levels in 76% of cases. At P, reductions in the mRNA levels of IL-33, TLR-2 and TLR-9 were observed, with TLR-2 and -9 levels exhibiting significant reductions (P<0.0001, Wilcoxon signed rank test). PASI scores were significantly reduced by the treatment (P<0.0001, Wilcoxon signed-rank test) and the changes in PASI scores exhibited a significant positive Pearson's correlation with the P/B mRNA expression ratios of TLR-2 or -9 in males (P<0.05), particularly in the etanercept group (P<0.0001). The findings support the efficacy of anti-TNF-alpha treatment on the innate immune response in psoriatic skin, with a focus on TLR-2 and -9 inhibition, suggesting their role in the pathogenic mechanism of plaque psoriasis, which may be associated with gender. PMID- 26622530 TI - Extra-articular tenosynovial chondromatosis of the left ring finger in a 23-year old man: A case report and literature review. AB - Tenosynovial chondromatosis is an extra-articular version of articular synovial chondromatosis and a relatively rare condition that can affect the tendon sheath, bursa, or joint synovial tissue. Tenosynovial chondromatosis is rarely reported in the literature and is often misdiagnosed. In the present study, a case of extra-articular tenosynovial chondromatosis of the left ring finger in a 23-year old man is reported. Three different-sized nodules were identified upon surgery and all were removed via synovectomy. The patient was symptom free 6 months postoperatively, and there were no signs of recurrence after 1.5 years of follow up. The literature describing tenosynovial chondromatosis in the fingers is also reviewed. PMID- 26622531 TI - MicroRNA-181b stimulates inflammation via the nuclear factor-kappaB signaling pathway in vitro. AB - Acute lung injury (ALI) is characterized by severe lung edema and an increase in the inflammatory reaction. Considerable evidence has indicated that microRNAs (miRNAs or miRs) are involved in various human diseases; however, the expression profile and function of miRNAs in ALI have been rarely reported. The present study used miRNA microarray and reverse transcription-quantitative polymerase chain reaction to demonstrate that miR-181b is the one of the most significantly upregulated miRNA after lipopolysaccharide (LPS) stimulation in human bronchial epithelial cells, BEAS-2B. To elaborate the role of miR-181b in ALI, an assay was performed to investigate the overexpression of miR-181b in BEAS-2B cells, and the expression of inflammatory factors was then analyzed. The overexpression of miR 181b resulted in the induction of an increment in interleukin (IL)-6 levels. p65 was identified to be a primary component of NF-kappaB, since it was upregulated in the miR-181b overexpression in the BEAS-2B cells, while pyrrolidine dithiocarbamate, a specific inhibitor of NF-kappaB, was found to be able to abrogate the upregulation of the expression of p65. In conclusion, the findings of the present study suggested that miR-181b may be involved in the process of LPS-induced inflammation in BEAS-2B cells by activating the NF-kappaB signaling pathway, which implies that it may serve as a potential therapeutic target for ALI. PMID- 26622532 TI - Extubation outcome after a successful spontaneous breathing trial: A multicenter validation of a 3-factor prediction model. AB - The aim of the present study was to validate, and if necessary update, a predictive model previously developed using a classification and regression tree (CART) algorithm for predicting successful extubation (ES) using a new cohort. This prospective cohort study enrolled adults admitted to 10 intensive care units, who had successfully passed a spontaneous breathing trial (SBT) and were considered ready for extubation. After extubation, the patients were followed up for 48 h. The primary outcome measure was ES, defined as the ability to maintain spontaneous unassisted breathing for >48 h after extubation. The 3-factor CART model was applied to patients in this cohort. The predicted probability of ES for each patient in this validation cohort was calculated based on the original CART model using the Laplace correction method. The performance was assessed by discrimination and calibration. A decision curve analysis was used assess the clinical net benefit (NB). Extubation failure (EF) occurred in 90/530 patients (17%). Among the 90 patients, 72 (13.6%) were reintubated, while 18 patients remained on rescue noninvasive ventilation within 48 h after extubation. The original CART model showed high discrimination but only moderate calibration with predicted probabilities that were systematically lower than expected. The original CART model was updated, and the updated model preserved excellent discrimination (area under the receiver operating characteristic curve, 0.91; 95% confidence interval, 0.87 to 0.93), but exhibited near-perfect calibration (calibration slope, 1; intercept, 0). Between threshold probabilities of 50 and 80%, the NB of using this updated model is significantly improved compared with the current strategy. The updated CART model may be used to estimate the predicted probability of ES after a successful SBT for individual patients. Applying this model appears to produce a substantial clinical consequence with regard to potential reduction in unexpected EFs. PMID- 26622534 TI - CORRIGENDUM. AB - [This corrects the article DOI: 10.3892/etm.2015.2351.]. PMID- 26622533 TI - Scutellaria barbata D. Don inhibits growth and induces apoptosis by suppressing IL-6-inducible STAT3 pathway activation in human colorectal cancer cells. AB - One of the most critical cellular signal transduction pathways known to malfunction in colorectal cancer is the interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) pathway. Scutellaria barbata D. Don (SB) is well-known traditional medicine in China that targets STAT3 signaling, and it has long been used to treat various types of cancer; however, the precise mechanism of its antitumor activity remains largely unclear. In order to further elucidate this underlying mechanism, an ethanol extract of SB (EESB) in cancer treatment. The aim of the present study was to evaluate the effects of EESB on the IL-6-inducible STAT3 pathway. We tested the dose-response association between EESB, IL-6-induced proliferaion and apoptosis using an MTT assay, colony formation and flow cytometry analysis in vitro. In addition, caspase-9 and caspase-3 activation was determined using a colorimetric assay, the activity of IL-6-induced STAT3 pathway was evaluated using western blot analysis, and the expression levels of cyclin D1, cyclin-dependent kinase 4, Bcl2 and Bcl2 associated X were determined using reverse transcription-polymerase chain reaction and western blot analysis. In the present study it was found that EESB could significantly inhibit the IL-6-mediated increase in STAT3 phosphorylation levels and transcriptional activity in HT-29 human colon carcinoma cells, resulting in the suppression of cell proliferation and the induction of apoptosis. In addition, treatment with EESB markedly inhibited the IL-6-induced upregulation of cyclin D1 and B-cell lymphoma-2, two key target genes of the STAT3 pathway. These results suggest that treatment with EESB could effectively inhibit the proliferation and promote the apoptosis of human colon carcinoma cells via modulation of the IL-6/STAT3 signaling pathway and its target genes. PMID- 26622535 TI - Checkpoint kinase 1 inhibitors as targeted molecular agents for clear cell carcinoma of the ovary. AB - In clear cell carcinoma of the ovary, chemoresistance frequently results in treatment failure. The present study aimed to review the potential association of transcription factor hepatocyte nuclear factor (HNF)-1beta with cell cycle checkpoint machinery, as a mechanism for chemoresistance. The English-language literature on the subject was reviewed to identify genomic alterations and aberrant molecular pathways interacting with chemoresistance in clear cell carcinoma. Oxidative stress induced by repeated hemorrhage induces greater susceptibility of endometriotic cells to DNA damage, and subsequent malignant transformation results in endometriosis-associated ovarian cancer. Molecular changes, including those in HNF-1beta and checkpoint kinase 1 (Chk1), may be a manifestation of essential alterations in cell cycle regulation, detoxification and chemoresistance in clear cell carcinoma. Chk1 is a critical signal transducer in the cell cycle checkpoint machinery. DNA damage, in turn, increases persistent phosphorylation of Chk1 and induction of G2/M phase cell cycle arrest in cells overexpressing HNF-1beta. HNF-1beta deletion induces apoptosis, suggesting that enhanced levels of HNF-1beta may be associated with chemoresistance. Targeted therapy with Chk1 inhibitors may be explored as a potential treatment modality for patients with clear cell carcinoma. This provides a novel direction for combination therapy, including targeting of Chk1, which may overcome drug resistance and improve treatment efficacy. PMID- 26622536 TI - Clinical benefits of metformin in gynecologic oncology. AB - Evidence has suggested that diabetes may contribute to the initiation and progression of specific types of cancer. Metformin, a biguanide, has become the preferred first-line therapy for the treatment of type 2 diabetes. Metformin is inexpensive, has a proven safety profile and is able to be safely combined with additional antidiabetic agents. In addition to the well-established antidiabetic effects of metformin, there has also been notable interest in its antitumor properties. The present review discusses the emerging role of metformin as an example of an existing drug, used worldwide in the treatment of diabetes, which has been demonstrated to exert significant in vitro and in vivo anticancer activities and has thus been investigated in clinical trials. In gynecologic oncology, metformin has been suggested to exhibit significant treatment efficacy against endometrial cancer. Three studies have demonstrated the potential therapeutic effects of metformin on the survival outcome of patients with ovarian cancer and in ovarian cancer prevention. However, this evidence was based on observational studies. Metformin has been shown to exert no statistically significant beneficial effect on cervical cancer incidence or mortality. By cancer site, the current limited insights highlight the need for clinical investigations and better-designed studies, along with evaluation of the effects of metformin on cancer at other sites. PMID- 26622537 TI - BMI-1, a promising therapeutic target for human cancer. AB - BMI-1 oncogene is a member of the polycomb-group gene family and a transcriptional repressor. Overexpression of BMI-1 has been identified in various human cancer tissues and is known to be involved in cancer cell proliferation, cell invasion, distant metastasis, chemosensitivity and patient survival. Accumulating evidence has revealed that BMI-1 is also involved in the regulation of self-renewal, differentiation and tumor initiation of cancer stem cells (CSCs). However, the molecular mechanisms underlying these biological processes remain unclear. The present review summarized the function of BMI-1 in different human cancer types and CSCs, and discussed the signaling pathways in which BMI-1 is potentially involved. In conclusion, BMI-1 may represent a promising target for the prevention and therapy of various cancer types. PMID- 26622538 TI - Impaired glucose metabolism treatment and carcinogenesis. AB - Carbohydrate metabolism disorders increase the risk of carcinogenesis. Diabetes mellitus alters numerous physiological processes that may encourage cancer growth. However, treating impaired glucose homeostasis may actually promote neoplasia; maintaining proper glucose plasma concentrations reduces metabolic stresses, however, certain medications may themselves result in oncogenic effects. A number of previous studies have demonstrated that metformin reduces the cancer risk. However, the use of sulfonylurea derivatives correlates with an increased risk of developing a malignancy. Another form of treatment, insulin therapy, involves using various forms of insulin that differ in pharmacodynamics, pharmacokinetics and efficacy. Previous studies have indicated that certain insulin variants also affect the cancer risk. The results from analyses that address the safety of long-lasting insulin types raise the most concern regarding the increased risk of malignancy. Rapid development of novel diabetic medications and their widespread use carries the risk of potentially increased rates of cancer, unnoticeable in limited, randomized, controlled trials. In the present review, the results of clinical and epidemiological studies are evaluated to assess the safety of anti-hyperglycemic medications and their effect on cancer risk and outcomes. PMID- 26622539 TI - Apoptosis and inhibition of proliferation of cancer cells induced by cordycepin. AB - Cordycepin, a 3-deoxyadenosine, is the predominant functional component of the fungus Cordyceps militaris, a traditional Chinese medicine. Previous studies investigating the inhibition of cancer cells by cordycepin identified that it not only promotes cell apoptosis, but also controls cell proliferation. Furthermore, studies have elucidated the molecular mechanisms of inhibiting cell proliferation by cordycepin binding the A3 adenosine receptor, activating G protein, inhibiting cAMP formation, decreasing glycogen synthase kinase-3beta/beta-catenin activation and suppressing cyclin D1 and c-myc expression. The most significant signaling pathway in which cell apoptosis is induced by cordycepin is the caspase pathway. Cordycepin induces cell apoptosis via binding the DR3 receptor and consequently activating caspase-8/-3. Taken together, these studies demonstrate that cordycepin may be used as a natural medicine, as it can not only control tumor cell proliferation, but also induce cancer cell apoptosis. PMID- 26622540 TI - Effect of human papillomavirus infection on the immune system and its role in the course of cervical cancer. AB - Human papillomavirus (HPV) is widely known as a cause of cervical intraepithelial neoplasia (CIN) and cervical cancer. The mechanisms involved have been studied by numerous studies. The integration of the virus genome into the host cells results in the abnormal regulation of cell cycle control. HPV can also induce immune evasion of the infected cells, which enable the virus to be undetectable for long periods of time. The induction of immunotolerance of the host's immune system by the persistent infection of HPV is one of the most important mechanisms for cervical lesions. The present review elaborates on the roles of several types of immune cells, such as macrophages and natural killer cells, which are classified as innate immune cells, and dendritic cells (DCs), cluster of differentiation (CD)4+/CD8+ T cells and regulatory T cells, which are classified as adaptive immune cells. HPV infection could effect the differentiation of these immune cells in a unique way, resulting in the host's immune tolerance to the infection. The immune system modifications induced by HPV infection include tumor-associated macrophage differentiation, a compromised cellular immune response, an abnormal imbalance between type 1 T-helper cells (Th1) and Th2 cells, regulatory T cell infiltration, and downregulated DC activation and maturation. To date, numerous types of preventative vaccines have been created to slow down carcinogenesis. Immune response activation-based therapeutic vaccine is becoming more and more attractive for the treatment of HPV-associated diseases. PMID- 26622541 TI - AKT plays a crucial role in gastric cancer. AB - The AKT protein is involved in the phosphatidylinositol-3 kinase signaling pathway and is a vital regulator of survival, proliferation and differentiation in various types of cells. Helicobacter pylori infection induces epithelial cell proliferation and oxidative stress in chronic gastritis. These alterations lead to telomere shortening, resulting in the activation of telomerase. AKT, in particular, is activated by H. pylori-induced inflammation. AKT then promotes the expression of human telomerase reverse transcriptase, which encodes a catalytic subunit of telomerase, and induces telomerase activity, an essential component of the process of carcinogenesis. AKT activation is increased in gastric mucosa with carcinogenic properties and is associated with the low survival of patients with gastric cancer. The findings of the present study suggest that AKT is pivotal in gastric carcinogenesis and progression. PMID- 26622543 TI - BTG1 potentiates apoptosis and suppresses proliferation in renal cell carcinoma by interacting with PRMT1. AB - B-cell translocation gene 1 (BTG1) is a member of the BTG/transducer of Erb family. BTG1 regulates cell cycle progression, inhibits proliferation, promotes apoptosis and stimulates cellular differentiation in multiple cell types. However, the functions of BTG1 in renal cell carcinoma (RCC) remain unclear. Therefore, the present study investigated the role of BTG1 in RCC tissue samples and 786-O RCC cells. RCC tissues and cells exhibited significantly weaker BTG1 protein and mRNA expression compared with para-carcinoma control tissues (P<0.05). Upregulated BTG1 expression induced significant G0/G1 cell cycle arrest, apoptosis and inhibition of cell proliferation in 786-O cells (P<0.05). Furthermore, BTG1 interacted with protein arginine N-methyltransferase 1 (PRMT1), and blocking the action of PRMT1 in 786-O cells resulted in inhibition of BTG1 function. These findings indicate that BTG1 may inhibit cell growth and promote apoptosis by interacting with PRMT1 in RCC; the identification of this mechanism may aid in the production of novel therapies for RCC. PMID- 26622542 TI - Novel biomarker candidates for the diagnosis of ovarian clear cell carcinoma. AB - Ovarian clear cell carcinoma can arise from endometriosis; however, it is distinct from other types of epithelial ovarian carcinoma in terms of its clinicopathological and molecular features. Cancer antigen 125 lacks the sensitivity and specificity required for accurate clinical diagnosis of clear cell carcinoma. Therefore, the aim of the current review was to identify novel biomarker candidates for the immunohistochemical and serological diagnosis of clear cell carcinoma. A search of the relevant English language literature published between 1966 and 2014 was conducted using the PubMed MEDLINE online database. High-throughput tissue microarray technology and proteomic screening combined with mass spectrometry may provide additional information regarding diagnostic biomarker candidates for ovarian clear cell carcinoma. The present review summarizes the characteristics of potential genomic alterations that activate cancer signaling pathways and, thus, contribute to carcinogenesis. The major signaling pathways activated in clear cell carcinoma are associated with cell cycle regulation (hepatitis A virus cellular receptor 1 and tumor protein D52), growth factor signaling (insulin-like growth factor binding protein 1; KiSS 1 metastasis-suppressor; erb-b2 receptor tyrosine kinase 2; and fibroblast growth factor receptor 2), anti-apoptosis and survival pathways [sialidase 3 (membrane sialidase)], metabolism (gamma-glutamyltransferase 1), chemoresistance (napsin A aspartic peptidase, glutathione peroxidase 3; and aldehyde dehydrogenase 1 family, member A1), coagulation [coagulation factor III (thromboplastin, tissue factor); and tissue factor pathway inhibitor 2], signaling (lectin, galactoside binding and soluble, 3), and adhesion and the extracellular matrix [cadherin 1, type 1, E-cadherin (epithelial); versican; and laminin, alpha 5]. The present review of the relevant literature may provide a basis for additional clinical investigation of the ovarian clear cell carcinoma serum biomarker candidate proteins identified herein. PMID- 26622544 TI - Different methods for target volume delineation of glandular breast tissue following breast-conserving surgery in breast cancer: A comparative study. AB - The present study aimed to investigate an optimal and feasible method for delineating the target volume of glandular breast tissue following breast conserving surgery. A total of 15 patients who underwent radiotherapy following breast-conserving surgery were recruited into the study. Clinical target volume was delineated by the following three methods based on computed tomography (CT): Anatomical landmarks (CTVan), breast palpation (CTVpa) and CT scan images (CTVgl). The target volume, degree of inclusion (DI) and conformal index (CI) defined by these methods were compared. The difference was significant between CTVan and CTVgl, and CTVpa and CTVgl (P<0.0001). The CI between CTVan and CTVpa was 0.644+/-0.122, significantly higher than that between CTVan and CTVgl (0.264+/-0.108; P<0.0001) or between CTVpa and CTVgl (0.328+/-0.115; P<0.0001). The DI of CTVpa in CTVan was 0.890+/-0.08 and the opposite was 0.709+/-0.144, while that of DI of CTVgl in CTVan or CTVpa was 0.994+/-0.005 and 0.989+/-0.008, respectively. The boundary difference between CTVan and CTVpa was 3.35+/-7.23, 5.57+/-13.37, 1.75+/-11.62 and 11.25+/-4.07 mm for the medial, lateral, cephalic and caudal boundaries, respectively. A significant difference was observed in the target volume of the breast defined by the three methods. The target volume defined by CTVgl was significantly smaller than that identified by the other two methods. Overall, the combination of palpation marks and anatomical landmarks to define the contouring scope of the breast was indicated to be a relatively rational method for delineating the target volume of the breast. PMID- 26622545 TI - Significance of ATP-binding cassette transporter proteins in multidrug resistance of head and neck squamous cell carcinoma. AB - According to the cancer stem cell theory, a small subpopulation of cancer cells, known as cancer stem cells (CSCs), exist that are self-renewing and are involved in tumor invasion, metastasis and recurrence. A number of studies have reported that certain cancer cells are able to efflux the Hoechst 33342 dye. These cells are termed side population (SP) cells and share characteristic features of CSCs. The results of the present study revealed that 2.7% of primary head and neck squamous cell carcinoma (HNSCC) cells were SP cells. This was reduced to 0.7% following treatment with verapamil. The immunofluorescence and reverse transcription polymerase chain reaction analysis revealed that SP cells have an enhanced expression of the ATP-binding cassette (ABC) transporter protein ABC subfamily G, member 2 (ABCG2), which has been identified to be actively involved in drug exclusion. Similarly, the mRNA level of the oncogene B lymphoma Mo-MLV insertion region-1 and the stem cell surface proteins nestin and octamer-binding transcription factor-4 were highly expressed in the SP cells compared with the non-SP cells. In addition, it was demonstrated that HNSCC SP cells exhibited increased proliferation and were highly resistant to multiple drugs. These findings suggest that the presence of CSCs, such as SP cells, may be responsible for chemotherapy failure and tumor relapse in patients with HNSCC. Therefore, the identification of a novel therapeutic drug that could effectively target CSCs may help to eradicate refractory tumors. PMID- 26622546 TI - Laryngeal function reconstruction with hyoid osteomuscular flap in partial laryngectomy for laryngeal cancer. AB - The present study aimed to evaluate the clinical outcome of using a hyoid osteomuscular flap to repair the laryngeal defect after extended vertical partial laryngectomy. A total of 26 glottic cancer patients underwent reconstruction with osteomuscular hyoid flaps following tumor resections. Ipsilateral arytenoid cartilage was resected in all cases, and the upper region of the cricoid cartilage was resected in 11 cases. Selective ipsilateral level II, III and IV neck dissections were performed in node (N)-positive patients and ipsilateral level II, and III neck dissections in N0 patients. The bone grafts were then fixed to the cricoid and contralateral thyroid cartilages. Invasion of the thyroid cartilage endochorium was present in 12 cases and lymph nodes metastases was present in 11 cases. The extubation rate of the tracheostomy tube was 100%. The glottides of all patients were almost symmetrical. Patients were followed up for 2-7 years. One patient developed local recurrence, ipsilateral regional recurrence, contralateral regional recurrence and lung metastasis, respectively. The disease-free survival rates at 3 and 5 years were 100% (20/20) and 79% (11/14), respectively. Overall, laryngeal function recovered well upon hyoid osteomuscular flap reconstruction following extended vertical partial laryngectomy, with a high extubation rate and good sound quality. PMID- 26622547 TI - Cigarette smoke induces the expression of Notch3, not Notch1, protein in lung adenocarcinoma. AB - The aim of the present study was to determine the effect of cigarette smoke on the expression of Notch proteins in lung adenocarcinoma (LAC). Protein expression levels of Notch1 and Notch3 were analyzed using immunohistochemistry in 102 human LAC specimens. Of these, 52 were obtained from smokers and 50 from non-smokers. In addition, cigarette smoke extract (CSE) at varying concentrations (1, 2.5 and 5%) was administered to A549 cells. The expression of Notch1 and Notch3 protein was then detected by western blot analysis at different time points (0, 8, 24 and 48 h). Of the 102 LAC specimens, 42 (41.2%) were positive for Notch1 and 63 (61.8%) were positive for Notch3. There was no significant difference in the level of Notch1 expression between smokers and non-smokers with LAC (P>0.05). The positive rate and staining intensity of Notch3 expression were increased in the smokers compared with the non-smokers (P<0.05). The expression of Notch3 protein in A549 cells increased in a time- and dose-dependent manner following treatment with CSE, whilst the expression of Notch1 protein appeared stable. The results suggested that cigarette smoke was able to induce the expression of Notch3, not Notch1, protein in LAC. The data revealed an upregulation of Notch3 in LAC following cigarette smoke exposure. Such findings may provide a novel therapeutic target for the treatment of LAC. PMID- 26622548 TI - Aberrant methylation of CDH11 predicts a poor outcome for patients with bladder cancer. AB - DNA methylation is one of the major mechanisms via which tumor suppressor gene inactivation occurs. For example, hypermethylation of the promoter region of cadherin 11 (CDH11), a novel tumor suppressor gene, frequently occurs in human cancer. In the current study, the methylation status of CDH11 was investigated in bladder cancer tissue samples, and the correlation with clinicopathological features and patient outcome was assessed. The methylation status of CDH11 was detected in 146 bladder cancer tissues and 37 normal bladder epithelial tissues using methylation-specific polymerase chain reaction (PCR). In addition, CDH11 mRNA expression levels were examined by quantitative PCR. Subsequently, associations between CDH11 methylation and specific clinicopathological characteristics, as well as patient outcome, were analyzed. Aberrant CDH11 promoter hypermethylation was detected in 63.0% (92/146) of bladder cancer tissues, however, no CDH11 methylation was identified in the control samples; this difference was significant (P<0.05). Furthermore, CDH11 mRNA expression levels were significantly lower in the tumor samples with methylated CDH11 compared with the normal bladder epithelium and tumor samples with unmethylated CDH11 (P<0.05). When the methylation status of CDH11 was correlated with the clinicopathological features, it was identified that CDH11 methylation was significantly associated with poor differentiation (P=0.0440), an advanced disease stage (P=0.0350), a larger tumor size (P=0.0013) and multiple tumors (P=0.0390). In addition, patients with methylated CDH11 exhibited significantly poorer outcomes than patients with unmethylated CDH11 (P=0.0004). Furthermore, multivariate Cox proportional hazard analysis indicated that CDH11 methylation was independently associated with a poor outcome in the patients with bladder cancer, with a relative risk of mortality of 6.852 (P=0.0082; 95% confidence interval, 3.461-16.177). The current findings indicate that aberrant CDH11 methylation frequently occurs in bladder cancer, and correlates with malignant behavior and poor outcome. Thus, CDH11 methylation status may be used as an independent prognostic biomarker for patients with bladder cancer. PMID- 26622549 TI - An integrated approach of predicted miR-34a targets identifies a signature for gastric cancer. AB - microRNA-34a (miRNA/miR-34a) functions as a tumor suppressor gene in gastric cancer and may be involved in system-wide regulatory networks. To clarify the expression of all predicted target genes of this miRNA, a comprehensive and systematic analysis of miR-34a-target genes in gastric cancer was conducted in the present study. In the initial analysis, the potential functions, pathways and networks of gastric cancer-associated molecules and miR-34a targets were identified. In the final integrative analysis of gastric cancer-associated miR 34a targets, 30 hub genes were identified using overlap calculations, indicating that miR-34a may be significant in the development and progression of gastric cancer through the Smad signaling pathway, the cell cycle, the mitogen-activated protein kinase signaling pathway, apoptosis, the Notch signaling pathway and other pathways. The present study provides a bioinformatic analysis of miR-34a targets in gastric cancer, describes numerous target genes and novel coregulatory networks, and may provide an opportunity to identify a critical regulatory network for predicting the molecular mechanisms of miR-34a in the development and progression of gastric cancer. PMID- 26622550 TI - Dimethyl sulfoxide induces chemotherapeutic resistance in the treatment of testicular embryonal carcinomas. AB - Dimethyl sulfoxide (DMSO) is an amphipathic molecule that is used as a solvent in biological studies and as a vehicle for drug therapy. The present study was designed to evaluate the potential effects of DMSO as a solvent in the treatment of testicular embryonal carcinomas (ECs). DMSO was applied to two human EC cell lines (NEC8 and NEC14), with the treated cells evaluated in relation to cisplatin (CDDP) resistance, differentiation (using Vimentin, Fibronectin, TRA-1-60, and SSEA-1 and -3 as markers) and stemness (denoted by expression of SOX2 and OCT3/4). Furthermore, DNA methyltransferase (DNMT-1, -3A and -3L) expression and methylation status were analyzed. DMSO induced resistance to CDDP, aberrant differentiation and reduction of stemness-related markers in each of the EC cell lines. The expression levels of DNMT-3L and -3A were reduced in response to DMSO, while this treatment also affected DNA methylation. The data demonstrated that DMSO perturbed differentiation, reduced stemness and induced resistance to CDDP in human EC cells. Therefore, DMSO could reduce drug efficacy against EC cells and its use should be carefully managed in the clinical application of chemotherapy. PMID- 26622551 TI - Differential expression of vascular endothelial growth factor-A, -C and -D for the diagnosis and prognosis of cancer patients with malignant effusions. AB - Elevated levels of vascular endothelial growth factor (VEGF) contribute to angiogenesis and serous cavity effusions. The present study evaluated the diagnostic and prognostic values of VEGF-A, -C and -D proteins in the serum, supernatant fluid and exfoliated cells of cancer patients with malignant effusions compared with patients with benign effusions. An enzyme-linked immunosorbent assay was used to detect levels of VEGF-A, -C and -D proteins in the sera of 79 cases (30 lung cancer, 21 gastric cancer and 28 benign effusions) and the supernatant fluid of 96 cases (38 lung cancer, 30 gastric cancer, and 28 benign effusion). Immunocytochemistry detected the expression of VEGF-A, -C and D proteins in effusion cells from 71 cases (34 lung cancer, 17 gastric cancer and 20 benign effusions). The data were further investigated to determine whether there was an association between VEGF subtype expression and clinicopathological characteristics and prognosis. The expression levels of VEGF-A in the supernatant fluid were increased in the lung and gastric cancer patient samples compared with the benign effusions (P<0.05). The VEGF-A level in the supernatant fluid was significantly increased compared with the corresponding sera of patients with malignant effusion (P<0.05). VEGF-A, -C and -D proteins in the exfoliated cells from primary lung or gastric cancer effusions were expressed at 52.94, 70.58 and 82.35%, respectively, whereas their expression was not detected in the exfoliated cells from benign effusion, with the exception of mesothelial cells. The levels of VEGF-A and VEGF-C in the supernatant fluid levels and the cell levels of VEGF A were inversely associated with age; in addition, VEGF-A levels in the supernatant fluid were associated with malignant and bloody effusion, and only cavity metastasis (P<0.05). Survival analysis demonstrated a relatively reduced survival time for patients with VEGF-A levels of >406.19 pg/ml in the supernatant fluid compared with patients with VEGF-A levels of <=406.19 pg/ml (P=0.066). Serum VEGF-A, -C and -D levels exhibited no evident clinical significance in the diagnosis and prognosis of serous cavity effusions. VEGF-A in the supernatant fluid merits further study as a tumor marker in the clinical setting to discriminate benign from malignant effusions, while cellular VEGF-C and -D may contribute to the formation of malignant effusions. PMID- 26622553 TI - miR-125a inhibits the migration and invasion of liver cancer cells via suppression of the PI3K/AKT/mTOR signaling pathway. AB - In order to explore the regulation of the invasive ability of hepatocellular carcinoma cells and the underlying mechanism, mimics sequences of microRNA (miR) 125a (miR-125a-3p/5p) and scramble sequences (miR-125a-3p-s/5p-s) were transfected into human hepatocellular carcinoma cell lines, HCC-LM3 and HepG2, and the non-malignant epithelioid hepatic cell line QZG. To inhibit and upregulate the expression of miR-125a individually. Protein expression was detected by western blotting, and the cell proliferation and migration abilities were evaluated by soft agar colony formation and Transwell assay, respectively. It was revealed that the expression of miR-125a was downregulated in HepG2 and HCC-LM3 cells compared with that of QZG cells, and expression was markedly lower in HCC-LM3 cells than that in HepG2 cells (P<0.01). The colony formation and migration rates of the cells transfected with miR-125a-3p/5p were decreased compared with negative controls, but were increased in cells transfected with miR 125a-3p-3/5p-s (P<0.01). The protein and messenger RNA expression of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) was decreased following transfection with miR-125a-5p, whereas expression was increased compared with negative controls following transfection with miR-125a-5p s (P<0.01). Furthermore, the proliferation and migration abilities of cells were attenuated following inhibition of the PI3K/AKT/mTOR pathway by LY294002. The results of the present study indicated that miR-125a inhibits the invasive ability of hepatocellular carcinoma cells via regulation of the PI3K/AKT/mTOR pathway. PMID- 26622552 TI - Recurrent inflammatory myofibroblastic tumor of the inguinal region: A case report and review of the literature. AB - Inflammatory myofibroblastic tumors (IMTs) of the inguinal region are exceptionally rare. The current study reported the case of a 49 year-old male patient with IMT, who presented with a fever, night sweats, anorexia, loss of weight and frequent urination. Computed tomography (CT) revealed a lesion occupying the soft tissue of the right inguinal region and surgery was performed to resect the lesion. Histopathological analysis of the lesion revealed a composition of spindle and inflammatory cells, including plasma cells and lymphocytes. In addition, immunohistochemical analysis demonstrated that the tumor cells were positive for CD34, vimentin, actin, Ki-67, B cell lymphoma-2, CD99, epithelial membrane antigen and CD38; however, tumor cells were negative for CD117, desmin, anaplastic lymphoma kinase and creatine kinase. Thus, the patient was diagnosed with IMT and was advised to return for regular follow-up appointments. Subsequently, the patient developed a local recurrence 12 months following the initial surgery. Of note, the histopathological characteristics of the recurrent lesions were consistent with those of the initial specimen. Thus, a second surgery was performed, followed by fractionated radiotherapy (FRT). At 3 and 6 months following the FRT, magnetic resonance imaging scans did not indicate tumor recurrence or metastasis. In conclusion, surgical excision is the current recommended treatment for IMT; however, for cases similar to that of the current study, which are not successfully controlled by surgical excision, radiotherapy should be considered and long-term follow-up is essential. PMID- 26622554 TI - Caspase-dependent drug-induced apoptosis is regulated by cell surface sialylation in human B-cell lymphoma. AB - The important role of sialic acid in various biological phenomena is well established. In order to further clarify the role of sialic acid in cell death induced by various stimuli, the present study compared the cell survival of the HBL-2 human diffuse large B-cell lymphoma cell line upon anticancer drug-induced cell death, with or without neuraminidase pretreatment: Cell survival was assessed using flow cytometry. Upon treatment with doxorubicin or etoposide, the HBL-2 cell viability decreased. In etoposide-induced cell death, the HBL-2 cells demonstrated nuclear fragmentation, which was consistent with morphologically apoptotic cells. In addition, a higher decrease in the cell viability of etoposide-treated HBL-2 cells was observed in cells pretreated with neuraminidase compared with cells that were not pretreated. Furthermore, the caspase-3, caspase 8 and caspase-9 activities in etoposide-induced apoptosis demonstrated a greater increase upon neuraminidase pretreatment compared with no neuraminidase pretreatment. In conclusion, cell surface sialylation appears to protect lymphoma cells from anticancer drug-induced apoptosis. PMID- 26622555 TI - Expression of Oct-4 is significantly associated with the development and prognosis of colorectal cancer. AB - Octamer-binding transcription factor 4 (Oct-4), is an essential transcription factor, which is required for pluripotency and self-renewal in embryonic stem cells and germ cells. It is also involved in maintaining cancer stem-like properties in certain types of tumor, and is an important biomarker for cancer stem cells. The present study investigated whether Oct-4 expression was associated with colorectal cancer (CRC). In order to achieve this, primary CRC tissues, matched non-tumor tissues and benign polyp tissues, representing different stages of carcinogenesis, were obtained, and Oct-4 expression was analyzed using reverse transcription-quantitative polymerase chain reaction, flow cytometry analysis and immunohistochemistry. Furthermore, the medical records of patients with CRC were reviewed, and clinicopathological analysis was performed in order to assess the association between Oct-4 expression and certain clinicopathological parameters. It was shown that the transcription and translation of Oct-4 increased in a stepwise manner, from non-tumor to benign polyp tissues, and from benign polyps to CRC tissues. Oct-4 expression in CRC was significantly correlated with histological grade (P=0.007), lymph node metastasis (P=0.027), distant metastasis (P=0.017) and TNM stage (P=0.041). Kaplan-Meier survival curve analysis demonstrated that Oct-4+ cases had a shorter median survival time (37.0 months) compared with Oct-4- cases (76.0 months; P=0.001). These results indicated that aberrant expression of Oct-4 may be involved in the development of CRC. Thus, Oct-4 may be a biomarker for the prediction, diagnosis or assessment of prognosis in CRC, in addition to a potential target for the treatment of this disease. PMID- 26622556 TI - The role of mechano-growth factor E peptide in the regulation of osteosarcoma. AB - Osteosarcoma is one of the most common bone tumors, and exhibits a high degree of malignancy. Gene therapy is a novel approach to its treatment, however, specific target genes are required to enable effective use of this therapy. In order to investigate the effects of the mechano-growth factor E (MGF-E) peptide, which is derived from the IGF-I alternative splicing isoform, on the regulation of the development of osteosarcoma, the expression of MGF was detected in osteosarcoma cell lines with different degrees of malignancy. Concomitantly, exogenous MGF-E peptide was used to stimulate these osteosarcoma cell lines. The results demonstrated that MGF was overexpressed in malignant osteosarcoma cells, while it was not expressed in the least malignant osteosarcoma cells. Furthermore, MGF-E treatment altered the cell cycle distribution, and promoted the proliferation, migration and invasion of osteosarcoma cells. The possible mechanisms underlying these effects were detected by quantitative polymerase chain reaction and western blotting. Based on these results, it was hypothesized that MGF may be a suitable biomarker for malignant osteosarcoma phenotypes. PMID- 26622557 TI - Desmoplastic small-round-cell tumor of the abdomen: A report of two rare cases. AB - Desmoplastic small-round-cell tumor (DSRCT) is an uncommon type of malignancy, which primarily occurs in adolescent males and develops in the abdominal cavity. The present study reports the case of two manifestations of DSRCT complicated with other diseases, which involved the invasion of the pelvis or abdominal vessels. The first case was of a 25-year-old man with repeated diarrhea and abdominal distension for 9 months; the second case was of a 68-year-old man who presented with persistent abdominal pain for 20 days. In each patient, a mass was identified in the abdomen and biopsies were performed in order to reach a diagnosis. Immunohistochemical staining of the biopsy material revealed a diagnosis of DSRCT in each case. In addition, the present study aimed to discuss the use of imaging techniques in providing evidence for the early diagnosis of DSRCT. PMID- 26622558 TI - JNK signaling pathway is involved in piperlongumine-mediated apoptosis in human colorectal cancer HCT116 cells. AB - Piperlongumine (PPLGM), an alkaloid isolated from the long pepper (Piper longum L.), can selectively trigger cancer cell death in colorectal cancer cells. The present study investigated whether the c-Jun NH2-terminal kinase (JNK) signaling pathway is involved in PPLGM-induced apoptosis in the human colorectal cancer HCT116 cell line. The results demonstrated that PPLGM reduced the cell viability and induced cell apoptosis in a time- and concentration-dependent manner, without a significant effect on cell cycle distribution. Meanwhile, treatment with 10 uM PPLGM resulted in JNK activation within 1 h, and a marked and sustained increase in c-Jun phosphorylation in the HCT116 cells. In addition, SP600125, a general inhibitor of JNK, inhibited PPLGM-induced apoptosis in the HCT116 cells by inhibiting PPLGM-induced c-Jun phosphorylation. Altogether, it can be concluded that the JNK signaling pathway, at least in part, is involved in PPLGM-mediated apoptosis in HCT116 cells. PMID- 26622559 TI - Calligonum comosum extract inhibits diethylnitrosamine-induced hepatocarcinogenesis in rats. AB - Calligonum comosum (C. comosum) is an Egyptian desert plant that contains polyphenol antioxidants. The present study examined the chemopreventive effect of an extract of C. comosum in a rat model of hepatocarcinogenesis. Male Wistar rats (n=40) were administered 100 mg/kg diethylnitrosamine (DEN) by intraperitoneal (i.p.) injection once a week for 3 weeks. Subsequently, depending on whether the rats received further administration of 0.8 mg/kg carbon tetrachloride (CCl4) i.p. once a week for 7 weeks and 100 mg/kg C. comosum extract in their diet for 7 weeks, the rats were divided into four groups as follows: Group 1, treatment with DEN alone; group 2, treatment with DEN and C. comosum extract; group 3, treatment with DEN and CCl4; and group 4, treatment with DEN, CCl4 and C. comosum extract. The supplementation of C. comosum extract significantly suppressed the elevation in serum liver enzyme levels, including aspartate aminotransferase, alanine transaminase and gamma-glutamyl transferase, and reduced the degree of oval cell proliferation induced by DEN and CCl4. In addition, C. comosum extract significantly decreased the number and area of glutathione S-transferase placental form-positive preneoplastic hepatic foci induced by DEN, with or without CCl4 treatment. To the best of our knowledge, the present study is the first to provide definitive evidence of the hepatoprotective and chemopreventive effects of C. comosum. PMID- 26622560 TI - Expression of cluster of differentiation 34 and vascular endothelial growth factor in breast cancer, and their prognostic significance. AB - The aim of the present study was to investigate the immunohistochemical expression of cluster of differentiation (CD) 34 and vascular endothelial growth factor (VEGF) in breast cancer tissue, and their prognostic significance. High CD34 expression levels (microvessel density, >15/HPF) were identified in 27.3% (12/44) of cases, exhibiting no significant correlation with the clinicopathological characteristics of the patients. However, Kaplan-Meier analysis demonstrated that the survival time of patients with high CD34 expression was significantly shorter than that of patients with low CD34 expression (50.0 vs. 90.6%; P=0.003). Samples with high VEGF expression levels (++ or +++) accounted for 63.6% (28/44) of the total number of cases. High VEGF expression was significantly prevalent in patients aged >=50 years compared with patients aged <50 years (<=78.6 vs. 37.5%; P=0.006). Furthermore, all patients with vascular invasion exhibited high VEGF expression levels; thus, patients with vascular invasion presented with significantly higher VEGF expression rates compared with patients with no vascular invasion (100.0 vs. 55.6%; P=0.018). However, Kaplan-Meier analysis demonstrated that high VEGF expression was not correlated with the overall survival of the patients (P=0.366). By contrast, Cox multivariate analysis identified that clinical stage, triple-negative subtype and age were independent prognostic factors for patients with breast cancer (P=0.005, P=0.006 and P=0.032, respectively), and that CD34 expression was a potential independent prognostic factor (P=0.055). Therefore, the present study determined that for patients with breast cancer, a high level of CD34 expression may be a potential indicator of a poor prognosis. PMID- 26622561 TI - Effect of adipose-derived stem cell-conditioned medium on the proliferation and migration of B16 melanoma cells. AB - Adipose-derived stem cells (ASCs) are a population of cells derived from adipose tissue. ASCs exhibit multilineage development potential and are able to secrete various factors, which influence adjacent cells. Previous studies have reported the effectiveness of ASC-conditioned medium (ASC-CM) in wound healing, anti melanogenesis, wrinkle improvement and hair growth. In the present study, the anticancer function of ASC-CM was investigated in vitro and in vivo. An MTT assay revealed that ASC-CM significantly decreased the proliferation of B16 melanoma cells in a time- and dose-dependent manner (P<0.01). Cell cycle analysis indicated that ASC-CM significantly increased the number of cells in G1 phase while reducing the number of cells in the S and G2/M phases (P<0.01). Furthermore, a wound migration model demonstrated that ASC-CM treatment significantly decreased the migration ability of B16 melanoma cells (P<0.01). In addition, C57BL/6 mice were administered with a single intratumoral injection of ASC-CM, daily or every other day, and a significant reduction in the volume of the tumor mass was observed compared with that of the control group (P<0.01). Thus, the findings of the present study indicated that ASC-CM has an anti tumorigenic effect on B16 melanoma cells in vitro and in vivo, and may potentially be used to support the treatment of melanoma in the future. PMID- 26622562 TI - AID, p53 and MLH1 expression in early gastric neoplasms and the correlation with the background mucosa. AB - A number of tumor-associated genes have been associated with gastric cancer development. The present study evaluated differences in tumor-associated protein expression and phenotype among early gastric neoplasms, and correlated these data with those of the background mucosa. The expression of activation-induced cytidine deaminase (AID), p53 and MLH1 in 151 early gastric neoplasms [22 gastric adenomas, 92 intramucosal carcinomas (MCs), and 37 submucosal carcinomas (SMCs)] was examined immunohistochemically and compared with that of the corresponding background mucosal condition. The cellular phenotypes of the neoplasms and the corresponding background intestinal metaplasia were also determined. Aberrant AID, p53 and MLH1 expression was detected in 36.4, 0 and 0% of the adenomas, in 35.9, 32.6 and 16.3% of the MCs, and in 56.8, 62.2 and 21.6% of the SMCs, respectively. The frequency of aberrant AID and p53 expression in the SMCs was significantly increased compared with that in the MCs (AID, P<0.05; p53, P<0.01). Aberrant AID expression was significantly associated with p53 overexpression in the SMCs (P<0.01), but not in the adenomas or MCs. In addition, AID expression was associated with the severity of mononuclear cell activity in the non cancerous mucosa adjacent to the tumor (P<0.05), particularly in the SMC cases. The percentage of MCs (34.8%) and SMCs (24.3%) that were of the gastric phenotype was higher compared with the percentage of adenomas (18.2%). These results indicated that p53 and MLH1 expression and a gastric phenotype may be important for carcinogenesis, and that chronic inflammation and AID and p53 expression are associated with submucosal progression. PMID- 26622563 TI - Efficacy of primary tumour volume as a predictor of survival compared with size alone in pancreatic ductal adenocarcinoma. AB - Tumour size (TSize) predicts outcome in pancreatic ductal adenocarcinoma (PDAC), but little is known regarding three-dimensional tumour volume (TVol) associations. We hypothesised that TVol would more accurately predict outcome following pancreatoduodenectomy (PD) for PDAC. Clinicopathological and outcome data was reviewed for all PDs performed in the Royal North Shore Hospital (St. Leonards, NSW, Australia), between April 2004 and November 2010, in patients whose three tumour dimensions were recorded (n=103). TVol was quantified using the ellipsoidal volume formula, 4/3pi(r1*r2*r3), and was correlated with clinicopathological indices/outcome. Over a median follow-up time of 20.5 months, TVol failed to significantly predict post-resection mortality [odds ratio (OR), 1.0; 95% confidence interval (CI), 0.99-1.00; P=0.438)]. Neural invasion remained an overall independent predictor of mortality following multivariate analysis (OR, 3.94; 95% CI, 1.36-11.40; P=0.011). Patients with higher TVol were more likely to require a vascular resection (P=0.007), had longer surgical times (P<0.001), larger intraoperative blood losses (P=0.007) and a trend toward worse survival (P=0.068). TVol inclusion in a multivariate model resulted in a small improvement in mortality prediction versus TSize (14.9 vs. 14.7%). A higher TVol results in a more complex perioperative course. Although TVol improved the mortality prediction beyond simple TSize alone, this difference was not significant. Studies normalising TVol for body composition are required. PMID- 26622564 TI - Inability of PET/CT to identify a primary sinonasal inverted papilloma with squamous cell carcinoma in a patient with a submandibular lymph node metastasis: A case report. AB - The present study describes the first reported case of a sinonasal inverted papilloma (IP) with squamous cell carcinoma (SCC) that presented as a cancer of unknown primary in the English-language literature. In July 2010, a 66-year old male presented with a 6-month history of a painless, progressive mass in the right submandibular region. Physical examination revealed a 3*4-cm smooth, non tender mass and subsequently, excision of the right submandibular gland was performed. Post-operative pathological examination indicated poorly differentiated SCC of the submandibular lymph node. Positron-emission tomography/computed tomography (PET/CT) was unable to identify the primary tumour site in this case, and 14 months later the patient presented with nasal obstruction, leading to the diagnosis of right sinonasal IP with coexistent SCC. The patient received pre-operative radiotherapy, a right total maxillectomy and post-operative radiotherapy. However, the patient succumbed to a distant metastasis 37 months after the initial presentation. 18F-fluorodeoxyglucose uptake on PET/CT may be not a reliable predictor of malignancy in sinonasal IPs. Therefore, we suggest emphasis of the use of multiple biopsies for suspected sinonasal IPs in order to improve diagnostic accuracy. PMID- 26622565 TI - Low local blood perfusion, high white blood cell and high platelet count are associated with primary tumor growth and lung metastasis in a 4T1 mouse breast cancer metastasis model. AB - It was originally thought that no single routine blood test result would be able to indicate whether or not a patient had cancer; however, several novel studies have indicated that the median survival and prognosis of cancer patients were markedly associated with the systemic circulation features of cancer patients. In addition, certain parameters, such as white blood cell (WBC) count, were largely altered in malignant tumors. In the present study, routine blood tests were performed in order to observe the change of blood cells in tumor-bearing mice following the implantation of 4T1 breast cancer cells into the mammary fat pad; in addition, blood flow in breast tumor sites was measured indirectly using laser Doppler perfusion imaging (LDPI), in an attempt to explain the relevance between the blood circulation features and the growth or metastasis of breast cancer in mice model. The LDPI and blood test results indicated that the implantation of 4T1 breast cancer cells into BALB/c mice led to thrombosis as well as high WBC count, high platelet count, high plateletcrit and low blood perfusion. Following implantation of the 4T1 cells for four weeks, the lung metastatic number was determined and the Pearson correlation coefficient revealed that the number of visceral lung metastatic sites had a marked negative association with the ratio of basophils (BASO%; r=-0.512; P<0.01) and the mean corpuscular hemoglobin was significantly correlated with primary tumor weight (r=0.425; P<0.05). In conclusion, the results of the present study demonstrated that tumor growth led to thrombosis and acute anemia in mice; in addition, when blood BASO% was low, an increased number of lung metastases were observed in tumor-bearing mice. PMID- 26622566 TI - Acquired resistance to decitabine and cross-resistance to gemcitabine during the long-term treatment of human HCT116 colorectal cancer cells with decitabine. AB - The aim of the present study was to determine the effects of long-term exposure of decitabine (DAC) to HCT116 colorectal cancer (CRC) cells on the acquisition of resistance to DAC as well as cross-resistance to anticancer drugs used for CRC or other epigenetic modifiers. In the present study, DAC-resistant HCT116 CRC cells were established through long-term treatment with increasing concentrations of DAC (10 to 540 nM); and the cross-resistance to other drugs was subsequently examined. DAC-resistant HCT116 cells were obtained following a 104-day treatment with DAC, including DAC-free intervals. The results demonstrated that the IC50 value of DAC was increased ~100-fold in DAC-resistant HCT116 cells. Messenger (m)RNA expression of secreted frizzed-related protein 1 (SFRP1), which is regulated by DNA methylation, was not detected in DAC-resistant cells; however, SFRP1 mRNA was present in HCT116 cells treated with DAC for 52 days. DNA methyltransferase 1 (DNMT1) protein levels were slightly decreased until day 81 and then returned to control levels in DAC-resistant cells. Further experiments using DAC-resistant HCT116 cells revealed that these cells exhibited cross resistance to gemcitabine (Gem); however, cross-resistance was not observed for other DNMT inhibitors (azacitidine and zebularine), histone deacetylase inhibitors (trichostatin A, vorinostat and valproic acid) or anticancer drugs for CRC (5-fluorouracil, irinotecan and oxaliplatin). Furthermore, the protein expression levels of cytidine deaminase (CDA) were increased, while those of deoxycytidine kinase (dCK) were decreased in DAC-resistant HCT116 cells; by contrast, the mRNA expression levels for these proteins were not significantly altered. In conclusion, the results of the present study indicated that the long term treatment of HCT116 cells with DAC led to the acquisition of resistance to both DAC and Gem. In addition, these results may be partly attributed to changes in CDA and/or dCK, which are involved in metabolic pathways common to these two drugs. PMID- 26622567 TI - Combining CXCL10 gene therapy and radiotherapy improved therapeutic efficacy in cervical cancer HeLa cell xenograft tumor models. AB - Radiotherapy is an important treatment method for cervical cancer, but the efficacy requires improvement. Therefore, novel methods of treatment are required. Previous data have demonstrated that the CXC chemokine ligand 10 (CXCL10) inhibits angiogenesis, induces apoptosis and causes avoidance of the S phase of the cell cycle in cervical cancer cells. The aim of the present study was to evaluate the anti-tumor effect of radiotherapy combined with CXCL10 gene therapy. Mouse models of cervical carcinoma were created by inoculation with HeLa cells, and were treated by combining intravenously administered plasmid-encoding CXCL10, administered 5 times (days 12, 15, 18, 21 and 24 following inoculation), with direct radiation (20 Gy/5 fractions) administered on 5 consecutive days (~day 27 after inoculation). The vessel density and tumor cell proliferation were observed by immunostaining, and apoptosis was determined using a TUNEL assay. The results revealed a significant increase in the inhibition of tumor growth, reduced vessel density, decreased cell proliferation and increased apoptosis in the tumor cells of the combination therapy group. Overall, these findings resulted in the conclusion that CXCL10 gene therapy in combination with radiotherapy is a novel effective therapeutic strategy for cervical cancer. PMID- 26622568 TI - Paraneoplastic hypocalcemia-induced heart failure in advanced breast cancer: A case report and literature review. AB - Hypocalcemia is an uncommon clinical symptom of patients with malignant tumors, and a number of factors may be involved in its development. The present study describes the case of a 67-year-old Caucasian female, presenting with severe refractory hypocalcemia and heart failure. The patient was subsequently diagnosed with breast cancer and bone metastases. The paraneoplastic origin of the syndrome was confirmed by its complete resolution once the tumor responded to specific antineoplastic treatments, comprising weekly paclitaxel and aromatase inhibitor administration. The present case report suggested the need for greater awareness of the possibility of paraneoplastic hypocalcemia in breast cancer patients, and suggested that this condition may also contribute to the occurrence of heart failure. The mechanisms potentially responsible for this event were discussed and a brief review of the literature presented. PMID- 26622569 TI - Targeting hypoxia-inducible factor-2alpha enhances sorafenib antitumor activity via beta-catenin/C-Myc-dependent pathways in hepatocellular carcinoma. AB - Sorafenib is a type of multikinase inhibitor that exhibits antiangiogenic and antiproliferative effects; in addition, sorafenib is a unique first-line drug recommended for the treatment of advanced hepatocellular carcinoma (HCC). However, the effectiveness of HCC treatment remains poor due to acquired drug resistance. It has been suggested that hypoxia, induced as a results of the antiangiogenic effects of sustained sorafenib treatment, may be an important factor in sorafenib resistance. The transcription factor hypoxia-inducible factor (HIF)-2alpha has been reported to be associated with cell proliferation under hypoxic conditions; therefore, it was hypothesized that hypoxia may enhance tumor cell proliferation via this mechanism. The present study aimed to evaluate whether the knock-down of HIF-2alpha was able to enhance the therapeutic efficacy of sorafenib in order to effectively treat HCC. The results demonstrated that hypoxia protected HCC cells against sorafenib; however, short hairpin RNA-HIF 2alpha transfection in combination with sorafenib treatment exhibited a significantly synergistic effect against HCC cell proliferation. In addition, HCC cells acquired increased beta-catenin/C-Myc expression, which enhanced proliferation under hypoxic conditions; however, targeted knock-down of HIF 2alpha or C-Myc markedly decreased cell proliferation in HCC cells. In conclusion, the results of the present study indicated that the targeted knock down of HIF-2alpha in combination with sorafenib may be a promising strategy for the treatment of HCC. PMID- 26622570 TI - Simultaneous occurrence of keratocystic odontogenic tumor and ameloblastoma in the mandible: A case report. AB - Keratocystic odontogenic tumors (KCOTs) and ameloblastomas are benign odontogenic tumors that primarily occur in the molar region of the mandible. However, it is uncommon for these tumors to arise simultaneously in a patient's jaw. The present study reported the diagnostic process and features of a rare case of the simultaneous occurrence of KCOT and ameloblastoma in the mandible of a 45-year old male. Image-based diagnosis was challenging due to several conditions, including the intactness of the teeth and bone cortex as well as the sizes and locations of the lesions. Based on radiographic evidence, the patient was initially misdiagnosed and underwent a biopsy for a radicular cyst and a simple bone cyst prior to the correct diagnoses of KCOT and ameloblastoma, respectively. In addition, the present study discussed the diagnostic process of the present case and reviewed previous literature regarding the simultaneous occurrence of benign tumors of the jaw. PMID- 26622571 TI - Iris metastasis from esophageal squamous cell carcinoma: A case report. AB - Carcinoma metastatic to the eye is a rare condition, typically associated with a poor prognosis. Breast and lung cancers are the most common sources of intraocular metastases, and the majority of metastatic lesions involve the posterior uvea, with <8% of reported cases arising in the iris. Intraocular metastasis as the presenting form of esophageal carcinoma is highly uncommon. In the present report, a rare case of metastatic iris tumor resulting from esophageal squamous cell carcinoma is discussed. A 64-year-old patient presented with a progressively distending pain in the right eye, with associated blurred vision. Local and systemic evaluation was performed, followed by treatment. Multiple examinations identified a neoplasm in the right iris and postoperative pathology revealed that the iris lesion was a metastasis of esophageal squamous cell cancer origin. The patient was treated with adjuvant radiation. To the best of our knowledge, this was only the second reported case of esophageal squamous cell carcinoma metastasizing to the iris. PMID- 26622572 TI - Pancreatic hemangioendothelioma, an extremely rare vascular anomaly in children: A case report and literature review. AB - The current study presents the case of a female infant with pancreatic hemangioendothelioma (HE) and discusses this rare disease in terms of the clinical features, treatment principle and prognosis. An 8-month-old female with pancreatic HE was admitted to the Department of General Surgery in The Children's Hospital (Zhejiang University School of Medicine, Hangzhou, Zhejiang, China) on January 3, 2011, due to yellow skin and sclera that had been apparent for 1 week. Magnetic resonance imaging (MRI) showed dilatation in the left and right hepatic, common hepatic and common bile ducts, a pancreatic head mass of ~4.7*5.2 cm with a strong signal, and close linkage of the portal vein and mesenteric vessels to the mass. Laparotomy was performed on January 11, 2011. An intraoperative frozen specimen showed a benign tumor. Finally, Whipple surgery retaining the tumor was chosen. The patient was treated by fasting, gastrointestinal decompression, antibiotics and supportive treatment post-surgery. Jaundice disappeared rapidly following the surgery. The patient started eating at 1 week post-surgery and was discharged 1 week later. From the pathological results, a diagnosis of pancreatic HE was made, with no tumor invasion of the hepatic lymph nodes. During the follow up visit at 28 months post-surgery, the child showed good growth and development. MRI showed that the mass size was ~2.4*2.0*1.5 cm, which was a significantly decrease from previously. Additionally, a literature search showed that from 1973 to the present date, only 9 studies on children with HE of the pancreas have been reported. Childhood pancreatic HE is a rare form of pancreatic vascular anomaly, mainly occurring in infants. If the tumor oppresses the duodenum and invades the mesenteric vessels, Whipple surgery retaining the tumor could be performed. PMID- 26622573 TI - Identification of a rare case of intra-articular osteochondroma manifesting as three loose bodies in a patient with hereditary multiple osteochondromas: A case report. AB - Hereditary multiple osteochondromas (HMO) is an autosomal dominant bone disorder characterised by the presence of multiple benign cartilage-capped tumours. Exostosin-1 (EXT1) and EXT2 are the major morbigenous genes associated with HMO, mutations in which are responsible for 90% of all HMO cases. In patients with HMO, osteochondromas arise adjacent to the metaphysis and typically remain in the metaphyseal region of the long bones. Therefore, it is rare for osteochondromas to be identified intra-articularly, although they may manifest as loose bodies. The present study describes a rare case of HMO manifesting as limited flexing range in the right knee joint of a 27-year-old male patient. Computed tomography and magnetic resonance imaging (MRI) revealed three intra-articular osteochondromas located in the intercondylar fossa of the patient's right knee. The intra-articular osteochondromas and protuberant extra-articular osteochondromas around the right knee were resected, resulting in improved right knee function and no postoperative recurrence. Pathological analysis revealed that the intra-articular osteochondromas had a thinner cartilage cap layer than the extra-articular osteochondromas. In addition, genetic analysis of the patient and the patient's mother was conducted. From this, it was determined that a nonsense mutation, c.115G>T (p.E39X) in exon 1 of the EXT1 gene, was the cause of HMO in this case. Thus, it is proposed that osteochondromas with a pedicle within the knee, may tear and become loose intra-articular bodies, resulting in limited joint function and thereby contributing to the progression of HMO. PMID- 26622574 TI - Utilization of arsenic trioxide as a treatment of cisplatin-resistant non-small cell lung cancer PC-9/CDDP and PC-14/CDDP cells. AB - Cisplatin is a commonly used drug in combination chemotherapy. However, various malignant tumors frequently acquire resistance to cisplatin. Arsenic trioxide (ATO) has been approved as a chemotherapeutic drug for the treatment of acute promyelocytic leukemia, and the combination of ATO and cisplatin has been revealed to demonstrate synergistic effects in ovarian and small cell lung cancer cells. Thus, it was hypothesized that ATO may also be active against cisplatin resistant non-small cell lung cancer (NSCLC) PC-9/CDDP and PC-14/CDDP cells. The present study also evaluated the effects of ATO on the cisplatin-sensitive NSCLC PC-9 and PC-14 cell lines. Notably, ATO demonstrated a markedly decreased IC50 in the cisplatin-resistant PC-9/CDDP and PC-14/CDDP cells compared with the IC50 in the cisplatin-sensitive parental PC-9 and PC-14 cells. Additionally, it was found that arsenite accumulation in the PC-9 cell line was affected through the downregulation of GS-X pump systems. Although it is likely that cisplatin resistance in PC-9 cells does not depend on the GS-X pump systems, ATO was effective against cisplatin-resistant NSCLC PC-9/CDDP and PC-14/CDDP cells in combination chemotherapy. PMID- 26622575 TI - Zinc finger protein X-linked is overexpressed in colorectal cancer and is associated with poor prognosis. AB - Zinc finger protein X-linked (ZFX) is a zinc finger transcription factor and plays a significant role in the self-renewal ability of embryonic stem cells and various cancers. However, its expression and function in colorectal cancer (CRC) remain unclear. In the present study, we evaluated the expression of ZFX in CRC using quantitative polymerase chain reaction (qPCR), western blot analysis and immunohistochemistry (IHC), and further explored its potential functions in CRC cell lines using cell counting kit-8 and Transwell invasion assays. qPCR and western blot analysis revealed that ZFX was significantly upregulated in CRC tissues; IHC further confirmed this finding, revealing that higher expression of ZFX was significantly associated with larger tumor size (P=0.01), higher pathological stage (P=0.02), depth of invasion (P=0.047), lymph node invasion (P=0.02) and higher American Joint Committee on Cancer (AJCC) stage (P=0.04). CRC patients with higher ZFX expression also exhibited significantly shorter survival times (P=0.019). Moreover, knockdown of ZFX significantly suppressed proliferation and invasion in CRC cell lines HCT116 and LoVo. These results suggest that ZFX plays a notable role in CRC tumorigenicity and may serve as a novel marker and therapeutic target for CRC. PMID- 26622576 TI - Ethanol induces upregulation of the nerve growth factor receptor CD271 in human melanoma cells via nuclear factor-kappaB activation. AB - Alcohol consumption is one of the most important, and potentially avoidable, risk factors of human cancer, accounting for 3.6% of all types of cancer worldwide. In a recent meta-analysis, a 20% increased risk of melanoma was linked with regular alcohol consumption. In the present study, the effect of ethanol exposure on the expression of the nerve growth factor receptor, CD271, in human FEMX-I melanoma cells was investigated. Consistent with the derivation of melanocytes from the neural crest, the majority of melanomas express CD271, a protein that is crucial for maintaining the melanoma stem cell properties, including the capacity of self renewal and resistance to chemotherapy and radiotherapy. Analysis of CD271-sorted subpopulations and clones of FEMX-I cells indicated no hierarchical organization of CD271+ and CD271- cells. In addition, CD271 expression was lost upon growth of FEMX-I melanoma cells in cancer stem cell-like conditions, while it was greatly increased upon CD133 knockdown or exposure to ethanol. After 24-h exposure to 100, 200 and 400 mM ethanol, the percentage of CD271+ cells increased from 14% in control cells to 24, 35 and 88%, respectively. An increase in the percentage of CD271+ cells was already evident 8 h after ethanol exposure and reached a maximum at 48 h. Ethanol-induced upregulation of CD271 was mediated by nuclear factor kappaB (NF-kappaB). In fact, exposure of FEMX-I cells to 100-400 mM ethanol for 24 h resulted in a concentration- and time-dependent increase in NF-kappaB activity, up to 900% that of control cells. NF-kappaB activation was due to a decrease in p50 homodimers, which occupy the NF-kappaB binding site, blocking transactivation. No effects of ethanol on 9 additional signaling pathways of FEMX I cells were observed. In the presence of CD271 blocking antibodies, NF-kappaB activation was not prevented, indicating that ethanol did not target CD271 directly. These data demonstrate that ethanol induces expression of CD271 in FEMX I cells via NF-kappaB activation and indicate a possible molecular link between ethanol exposure and melanoma formation. PMID- 26622577 TI - Assessment of cell proliferation in renal cell carcinoma using dual-phase 18F fluorodeoxyglucose PET/CT. AB - The present study aimed to examine the association between 18F-fluorodeoxyglucose (18F-FDG) uptake and cell proliferation markers; in addition, the correlation between 18F-FDG uptake and biological characteristic in patients with renal cell carcinoma (RCC) was investigated using dual-phase 18F-FDG-positron emission tomography/computed tomography (PET/CT). Dual-phase 18F-FDG PET/CT was performed on 31 RCC patients and the maximum standardized uptake values at 1 h (SUV1) and 2 h (SUV2) as well as the retention index (RI; %) in the primary tumors were calculated. Monoclonal antibodies for Ki-67, minichromosome maintenance 2 (MCM2) and topoisomerase II alpha (topo II alpha) were used to assess the expression levels of their respective proteins in excised tumor tissue using immunohistochemistry. The results demonstrated that RI and SUV2 in patients with Stage I/II + grade 1 (G1) RCC were significantly decreased compared with all patients with other stages/grades (RI, P=0.0065; SUV2, P=0.043); in addition, significantly increased uptake and RI were detected in patients with metastases compared with patients without metastases (SUV1, P=0.029; SUV2, P=0.0003; RI, P<0.001). All proliferation markers significantly correlated with RI (Ki-67, r=0.501, P=0.004; MCM2, r=0.359, P=0.047; topo II alpha, r=0.402, P=0.024), while SUV1 and SUV2 correlated with Ki-67 only. In conclusion, the results of the present study demonstrated that dual-phase 18F-FDG-PET/CT was more useful for predicting cell proliferation in RCC compared with single-phase imaging alone. However, follow-ups are required in order to determine whether dual-phase 18F-FDG PET/CT provides independent prognostic information. PMID- 26622578 TI - S6K1 inhibition enhances the apoptotic cell death of breast cancer cells in response to Bcl-2/Bcl-xL inhibition by the downregulation of survivin. AB - Breast cancer cells possess a deregulated apoptotic pathway with increased expression levels of anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins and ribosomal S6 kinase 1 (S6K1) protein activity. Therefore, combined interference of anti-apoptotic Bcl-2 family and S6K1 protein expression may be a reasonable therapeutic strategy for the treatment of patients with breast cancer. In the present study, it was identified that the administration of a combination of ABT263 [navitoclax; a Bcl-2/Bcl-extra large (Bcl-xL) inhibitor] and PF4708671 (an S6K1 inhibitor) markedly increased apoptotic cell death in the BT474 breast cancer cells compared with the administration of either agent alone. Furthermore, the downregulation of Bcl-2/Bcl-xL and S6K1 with small interfering RNA induced a significant increase in cell death compared with RNA interference of either agent alone. Notably, combination treatment with ABT263 and PF4708671 decreased the expression level of survivin protein, with this ectopic expression of survivin attenuating cell death. Thus, the present study determined that the combined inhibition of Bcl-2/Bcl-xL and S6K1 may be a good strategy for treating patients with breast cancer. PMID- 26622579 TI - Hypoxia promotes C-X-C chemokine receptor type 4 expression through microRNA-150 in pancreatic cancer cells. AB - Hypoxia promotes pancreatic cancer progression by triggering cancer cell invasion. However, the mechanism underlying this process remains unclear, hindering the development of effective therapies. The present study aimed to delineate the molecular mechanisms underlying the prometastatic effect of hypoxia in pancreatic cancer cells. The expression of microRNA-150 (miRNA-150) was detected using reverse transcription-quantitative polymerase chain reaction in pancreatic cancer samples and in the hypoxia-induced CaPan2 human pancreatic cancer cell line. The target gene was identified using bioinformatics and a luciferase reporter assay. Inhibition of the expression of C-X-C chemokine receptor type 4 (CXCR4) by miRNA-150 was confirmed using transfection with miRNA 150 mimics. The prometastatic effect of hypoxia was detected using migration assays. The expression of miRNA-150 was shown to be downregulated in pancreatic cancer samples compared with that in normal pancreatic tissue samples. Furthermore, its expression was reduced in hypoxia-induced CaPan2 cells, compared with that in control cells. Bioinformatics and the results of the luciferase reporter assay, demonstrated that miRNA-150 inhibited the expression of CXCR4 by directly targeting the 3' untranslated region of CXCR4 mRNA. The results of the migration assay showed that hypoxia promotes cell migration and invasion. However, this prometastatic effect was reversed by transfection with miRNA-150 mimics. The present results suggest that hypoxia promotes pancreatic cancer migration by downregulating miRNA-150. PMID- 26622580 TI - Clinical characteristics of patients with large and deep soft tissue sarcomas. AB - In the present study, the incidence of surgical wound complications in patients with large and deep high-grade soft tissue sarcoma (STS) was investigated. In addition, the disease-specific and event-free survival rates were examined in these patients. In total, 30 adult patients with primary high-grade deep STS with a size of 10 cm or greater were treated in the current study. Of the 30 patients, 16 (53%) developed a total of 19 wound complications. In addition, 10 cases of wound dehiscence, 5 cases of infections, 3 cases of hematomas and 1 case of lymphorrhea were reported, while 3 patients with postoperative infections underwent additional surgical treatment. Longer surgery duration was associated with wound complications (P=0.04). The disease-specific survival was 58.5% at 3 years and 46.1% at 5 years after treatment. Furthermore, local recurrence was detected in 13 patients and distant metastasis was identified in 17 patients as the first relapse. The 3- and 5-year event-free survival rates were 24.4 and 16.3%, respectively. In conclusion, patients with large and high-grade, deep STSs presented a high complication rate; therefore, careful wound care is required in these patients. Furthermore, it should be also taken into account that these patients have a greater risk of tumor-associated events and mortality. PMID- 26622581 TI - Leukemia cells are sensitized to temozolomide, carmustine and melphalan by the inhibition of O6-methylguanine-DNA methyltransferase. AB - The cytotoxicity of the monofunctional alkylator, temozolomide (TMZ), is known to be mediated by mismatch repair (MMR) triggered by O6-alkylguanine. By contrast, the cytotoxicity of bifunctional alkylators, including carmustine (BCNU) and melphalan (MEL), depends on interstrand crosslinks formed through O6 alkylguanine, which is repaired by nucleotide excision repair and recombination. O6-alkylguanine is removed by O6-methylguanine-DNA methyltransferase (MGMT). The aim of the present study was to evaluate the cytotoxicity of TMZ, BCNU and MEL in two different leukemic cell lines (HL-60 and MOLT-4) in the context of DNA repair. The transcript levels of MGMT, ERCC1, hMLH1 and hMSH2 were determined using reverse transcription-quantitative polymerase chain reaction. In addition, the proliferation was measured using the trypan blue exclusion assay. Drug sensitivity was found to vary between the two cell lines. Treatment of the cells with TMZ, BCNU or MEL in combination with O6-benzylguanine, an MGMT inhibitor, was demonstrated to sensitize the two cell lines to these agents. However, the extent of sensitization was not found to be correlated with the expression levels of MGMT transcripts. Furthermore, the drug sensitivity was also not associated with the transcript levels of ERCC1, hMLH1 and hMSH2. Thus, leukemic cells were sensitized to alkylating agents by the inhibition of MGMT. PMID- 26622582 TI - Nestin expression as an independent indicator of poor prognosis for patients with anaplastic thyroid cancer. AB - The protein nestin, a neuronal stem cell marker, has been reported to indicate a poor prognosis in various tumours. Anaplastic thyroid cancer (ATC) is one of the most aggressive malignancies in humans, and its molecular background has not been identified. The present study evaluated the expression of nestin and its significance in ATC. Tissue samples from 23 patients with ATC were subjected to immunohistochemical staining and the staining intensity of nestin in the cytoplasm was evaluated. The expression of nestin in the tumour cytoplasm was confirmed in 6 of the 23 tissue samples (26.1%). Between the nestin-positive group (n=6) and the nestin-negative group (n=17), there were no significant differences in the clinicopathological factors of the patients. However, the nestin-positive group exhibited significantly worse prognoses than the nestin negative group (median survival time, 86.5 vs. 306 days; P<0.01, log-rank test). The multivariate analysis indicated that nestin expression was a prognostic indicator for the ATC patients (hazard ratio, 5.59; 95% confidence interval, 1.63 19.50; P<0.01), which is independent of the known clinical indicators. Nestin expression has the potential to be an independent indicator of a poor prognosis for patients with ATC. PMID- 26622584 TI - Expression of wingless-type mouse mammary tumor virus integration site family pathway effectors in lymphatic and hepatic metastases of patients with colorectal cancer: Associations with the primary tumor. AB - The wingless-type mouse mammary tumor virus integration site family (Wnt) pathway plays a major role in the carcinogenesis of colorectal cancer (CRC). Its most important effector, the nuclear beta-catenin, influences not only transcription but also the proliferation and dedifferentiation of the colonic mucosa. This induces an epithelial-mesenchymal transition which ultimately can lead to the development of cancer and the formation of metastases. However, little is known about the exact interaction and context-sensitive expression of Wnt-pathway effectors in the primary tumor and corresponding metastasis. Therefore, this study assessed the expression of the three most important effectors of the Wnt pathway, beta-catenin, adenomatous polyposis coli (APC) and Wnt-1, in the primary tumor and corresponding metastasis of patients with CRC. Immunohistochemical staining of beta-catenin, APC and Wnt-1 was performed in paraffin-embedded tissue samples of the primary tumor, and the corresponding hepatic and nodal metastasis samples from 24 patients with metastatic CRC. Isotype antibodies were used as negative controls. The results were visualized using the ABC-method. Analysis of the primary tumor comprised of a separate evaluation of the central tumor area as well as the invasion front. There was a significant overexpression of nuclear beta-catenin at the tumor invasion front (P<0.001). Compared to normal colonic mucosa, expression of cytoplasmic beta-catenin was significantly higher in the primary tumor (P<0.001) as well as all the corresponding hepatic and lymphatic metastases (hepatic metastases, P=0.001; nodal metastases, P=0.017). By contrast, APC expression was significantly lower in all analyzed tumor compartments compared with normal colonic mucosa (primary tumor, P=0.022; hepatic metastases, P=0.006; nodal metastases, P=0.012). Finally, Wnt-1 protein expression was significantly lower in liver metastases but not in the primary tumor or lymphatic metastases compared with normal colonic mucosa (P=0.003). The present study demonstrates that the major Wnt-effector proteins, beta-catenin, APC and Wnt-1, are heterogeneously expressed in the primary tumor and corresponding hepatic as well as nodal metastases of patients with CRC. This context-sensitive diverse expression of Wnt-effector proteins may be important for future individualized targeted therapies. PMID- 26622583 TI - Prognostic significance of histone methyltransferase enhancer of zeste homolog 2 in patients with cervical squamous cell carcinoma. AB - Histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been reported to be associated with certain malignant phenotypes in cervical cancer. However, clinicopathological parameters and clinical outcomes of EZH2 in cervical cancer, particularly in cervical squamous cell carcinoma (CSCC) remain largely unknown. The retrospective cohort comprising of 117 consecutive patients with CSCC was incorporated into a tissue microarray which also included 23 paired normal tissues. Immunohistochemical analysis was performed to evaluate the correlation between EZH2 expression and clinicopathological implications. Aberrant overexpression of EZH2 was frequently observed in CSCCs as compared with adjacent normal tissues (P=0.0005). Expression of EZH2 is associated with poor tumor differentiation grade (P=0.020) and lymphovascular invasion (P=0.012). Univariate analysis revealed that the patients with CSCC whose tumors exhibited higher EZH2 levels had inferior overall survival (OS) compared to those whose tumors expressed lower EZH2 (log rank P=0.004). In the multivariate analysis, EZH2 expression was an independent predictor of OS (hazard ratio = 1.836, 95% confidence interval: 1.090-2.993, P=0.022). EZH2 overexpression is common in the development of CSCC and is a promising prognostic predictor for patients with CSCC. PMID- 26622585 TI - Serum microRNA profiles as prognostic or predictive markers in the multimodality treatment of patients with gastric cancer. AB - Despite the implementation of multimodality treatment strategies, the persistently poor prognosis of gastric cancer patients is predominantly caused by the lack of predictive markers for response assessment in the neoadjuvant setting, preventing individualized therapy. Therefore, the identification of novel predictive and prognostic markers for application in the multimodality treatment of gastric cancer patients is required. The aim of the present study was to characterize the serum microRNA (miRNA/miR) profile of gastric cancer patients undergoing multimodality therapy to identify possible prognostic and predictive markers. The study consisted of 32 patients with gastric cancer who had undergone either primary surgical resection (n=14) or neoadjuvant therapy followed by surgical resection (n=18). Histopathological regression was defined as a major histopathological response when the resected specimens contained <10% vital residual tumor cells. Intratumoral miRNA was isolated from pre-operative or post-neoadjuvant blood serum samples. Initially, microarray analyses were performed in six of the patients that received neoadjuvant treatment (three responders versus three non-responders), to assess the amplification profile of dysregulated miRNAs. Based on these findings, possible predictive or prognostic markers were validated in all study patients by performing single reverse transcription-polymerase chain reaction (RT-PCR) analysis. Depending on the extent of the histopathological regression, a differential miRNA expression profile was identified in the microarray analyses. Based on the amplification profile, miR-21, miR-29a and miR-221 were selected for additional validation. However, the single RT-PCR measurements of the three selected miRNAs did not exhibit any prognostic or predictive value in the patients treated with primary resection or neoadjuvant therapy and resection. Thus, the current pilot study failed to identify a prognostic or predictive value in selected miRNAs using single RT-PCR measurements, however, the microarray results revealed a differential microRNA expression profile depending on the histopathological regression. The findings of the present study may have been affected by the small sample size. PMID- 26622586 TI - Successful treatment of gastrointestinal stromal tumor with multiple liver metastases with radiofrequency ablation and imatinib: A case report. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract, and typically metastasize to the liver. In patients with recurrent metastatic GISTs, no single treatment is effective. The current study reports a case of GIST with 27 metastases in the liver, which was successfully treated using radiofrequency ablation (RFA) combined with surgical resection and imatinib therapy. The patient remains tumor-free 36 months after the first RFA treatment. This case suggests that comprehensive therapy including surgical resection, RFA and imatinib, may be an effective strategy for the treatment of GIST with multiple liver metastases. PMID- 26622587 TI - Therapeutic effect of lymphokine-activated killer cells treated with low-dose ionizing radiation on osteosarcoma. AB - The aim of the present study was to investigate the effect of lymphokine activated killer (LAK) cells, which received low-dose ionizing radiation, on the treatment of osteosarcoma in rats. The cultured UMR-106 cells were inoculated under the anterior chest skin of 24 rats to establish an osteosarcoma model. In addition, the LAK cells from 24 mice were exposed to doses of 0 (control group), 0.65 or 3.25 mGy X-ray radiation. The tritiated thymidine (3H-TdR) release method and Winn assay were performed to determine the antitumor effects of the LAK cells. The proliferation of the mouse LAK cells treated with 3.25 mGy radiation was significantly higher than that for those treated with 0 or 0.65 mGy radiation, which suggested that low-dose ionizing radiation stimulates the proliferation of LAK cells. The tumor-bearing rats were divided into three groups and injected with LAK cells that had already received 0, 0.65 or 3.25 mGy radiation. The mean survival time of the 3.25-mGy group was longer than that of the 0- and 0.65-mGy groups. After 30 days, tumors with weights of ~6.25 and 2.0 g were identified in the rats of the 0- and 0.65-mGy groups, respectively. However, tumor proliferation was not detectable in the rats of the 3.25-mGy radiation group. Therefore, low-dose ionizing radiation effectively kills osteosarcoma cells in rats by stimulating the proliferation and enhancing the cytotoxicity of LAK cells. PMID- 26622588 TI - Increased survival time of a patient with metastatic malignant melanoma following immunotherapy: A case report and literature review. AB - Metastatic malignant melanoma is treated with chemotherapy and radiotherapy. A number of previous studies have indicated that cytokine-induced killer cells (CIK cells) are a heterogeneous cell population that express cluster of differentiation (CD)3 and CD56, in addition to the natural killer cell NKG2D activating receptor. CIK cells possess major histocompatibility complex unrestricted cytotoxicity towards cancer, but not towards normal targets. The present study investigated whether the addition of CIK cells resulted in an improved therapeutic response in a patient with metastatic malignant melanoma. In the current case, a patient with metastatic malignant melanoma received CIK therapy, which resulted in a relatively long survival time of 28 months. To the best of our knowledge, there have been no previous studies reporting such positive effects in a patient who received CIK cell immunotherapy. Based on the findings of the present study, CIK cell therapy may be an option that results in a good prognosis in certain patients with metastatic malignant melanoma. PMID- 26622589 TI - Primary small cell neuroendocrine carcinoma of the oral cavity: A case report and review of the literature. AB - Small cell neuroendocrine carcinoma (SNEC) of the oral cavity is a rare and distinctive tumor with aggressive clinical behavior. Thus far, only a small number of cases have been reported and no definitive standard treatment strategy has been determined. The current study reports a case of oral SNEC arising in the lower gingiva in a 73-year-old male. Computed tomography displayed a relatively well-defined mass measuring 2.8*2*1.4 cm in size. The mass was located in the buccal side of the right mandibular posterior gingiva and exhibited no bony involvement. Histopathological examination revealed a proliferation of small cells with ovoid- to spindle-shaped nuclei, fine granular chromatin, inconspicuous nucleoli, scant cytoplasm and high mitotic activity. Immunohistochemically, the tumor cells were positive for cytokeratin AE1/AE3, chromogranin A, synaptophysin and neuron-specific enolase. Surgical resection and radical neck dissection were performed prior to the administration of adjuvant chemotherapy with a combination of cisplatin and etoposide. No evidence of local recurrence or metastasis was observed at 14 months post-surgery. PMID- 26622590 TI - Treatment of esophageal-gastric double primary cancer by pedunculated remnant gastric interposition, esophageal-gastric anastomosis and gastrojejunal Billroth II anastomosis: A case report. AB - With the continuous advancement of clinical diagnostic techniques, including imaging technology, the incidence of confirmed multiple primary cancers or double primary carcinoma increases yearly. However, studies reporting synchronization surgery performed for primary dual esophageal gastric cancer are rare. The present study reports the case of a patient with double primary esophageal gastric cancer, located in the thoracic cavity segment of the esophagus and gastric antrum of the stomach, respectively. The gastric cancer was diagnosed by endoscopy biopsy with concomitant esophageal cancer. The patient underwent gastric cancer resection, and pedunculated remnant gastric interposition esophagogastric side anastomosis was performed with gastrojejunostomy Billroth II anastomosis behind the colon. Abdominal cavity lymph node dissection was also performed. The esophageal-gastric double primary cancer was simultaneously excised and the gastric regions were used in the construction of the upper gastrointestinal tract: The surgery was successful. However, two weeks after surgery, upper gastrointestinal imaging revealed esophagogastric anastomotic leakage. Subsequently, an esophageal stent was inserted and antibiotics and additional treatment was administered. Follow-up one year after surgery revealed that the patient was well and remained in a stable condition. PMID- 26622591 TI - Downregulated expression of PHLDA1 protein is associated with a malignant phenotype of cholangiocarcinoma. AB - Cholangiocarcinoma is one of the most aggressive types of malignancy, and is associated with poor patient prognosis. Recent findings suggest that a decrease in pleckstrin homology-like domain family A, member 1 (PHLDA1) expression is significant in the induction of cell migration and tumor invasion. The clinicopathological significance of the expression of PHLDA1, and its potential correlation with the expression of CD133 in cholangiocarcinoma have remained to be elucidated. In the present study, PHLDA1 protein expression was investigated by immunohistochemical analysis of 218 cholangiocarcinoma tissue samples, as well as 30 para-neoplastic and 20 normal bile ducts. The expression status of PHLDA1 and CD133 was determined, and these results were analyzed against the age, gender, tumor location and size, histological grade, clinical stage and overall mean survival time of the patients. The expression of PHLDA1 protein was markedly decreased in 35.3% of cholangiocarcinomas, compared with that of the para neoplastic and normal cholangiocytes. Carcinomas with loss of expression of PHLDA1 were significantly correlated with the tumor site (P=0.001), histological grade (P=0.020) and clinical stage (P=0.0001), but not with age (P=0.085), gender (P=0.456) or size (P=0.413), respectively. Kaplan-Meier survival analysis indicated that the loss of expression of PHLDA1 was significantly correlated with the overall survival time (Log rank=193.861; P=0.0001). Furthermore, the expression of PHLDA1 was found to be inversely correlated with the expression of CD133 (gamma=-0.142; P=0.036). These findings suggested that the decreased expression of PHLDA1 may be significant in the carcinogenesis and progression of cholangiocarcinoma, and may represent a novel adjunct marker of disease prognosis. PMID- 26622594 TI - Decreased expression of ferroportin in prostate cancer. AB - The present study examined the expression levels of ferroportin, a transmembrane protein that transports iron from the inside of a cell to the outside, in the prostate cancer PC3, DU145 and LNCAP cell lines, in the normal prostate RWPE2 cell line, and in tissue samples from different differentiation stages of prostatic carcinoma and prostatic hyperplasia. The study also investigated the role of ferroportin protein expression in the diagnosis and prognosis of prostate cancer. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were employed to measure the mRNA and protein expression levels of ferroportin in the PC3, DU145, LNCAP and RWPE2 cells. Immunohistochemistry was used to determine ferroportin protein expression in the prostate cancer and prostatic hyperplasia tissues. Compared with the normal prostate RWPE2 cells, ferroportin protein expression was significantly lower in the prostate cancer PC3, DU145 and LNCAP cells (P<0.05). Compared with the prostatic hyperplasia tissues, ferroportin protein expression was significantly reduced in the prostate cancer tissues (P<0.05). Overall, the expression levels of ferroportin in the prostate cancer tissues were lower than those in the normal prostate tissues, which may provide valuable clinical information for the diagnosis and prediction of disease progression in prostate cancer, and may indicate a potential therapeutic target for treating prostate cancer by regulating iron metabolism. PMID- 26622592 TI - Epidermal growth factor receptor protein overexpression and gene amplification are associated with aggressive biological behaviors of esophageal squamous cell carcinoma. AB - Alterations of the epidermal growth factor receptor (EGFR), including overexpression or gene mutations, contribute to the malignant transformation of human epithelial cells. The aim of this study was to assess EGFR overexpression or gene amplification in esophageal squamous cell carcinoma (ESCC) tissue samples and investigate their correlations with biological behaviors. Tissue specimens from 56 patients with surgically resected ESCC were obtained for immunohistochemical analysis of EGFR expression and fluorescence in situ hybridization analysis of EGFR amplification. The data were statistically analyzed to determine the associations with patient clinicopathological and survival data. EGFR was overexpressed in 30 of the 56 (53.6%) ESCC samples and was associated with poor tumor differentiation (P=0.047). EGFR amplification was detected in 13 cases (23.2%) and was associated with advanced pathological stage (P=0.042) and tumor lymph node metastasis (P=0.002). The univariate analysis identified no association between EGFR overexpression and the overall survival (OS) of the patients. By contrast, EGFR amplification predicted ESCC prognosis (P=0.031), while the multivariate analysis revealed a marginal statistical significance for the association between EGFR amplification and OS (P=0.056). EGFR overexpression and increased EGFR copy number were common events in ESCC and contributed to malignant biological behaviors, including tumor dedifferentiation and lymph node metastasis. EGFR amplification may therefore be useful in predicting OS in patients with ESCC. PMID- 26622593 TI - DNA methylation is involved in the aberrant expression of miR-133b in colorectal cancer cells. AB - The dysregulation of microRNA (miRNA) expression is highly involved in cancer. Recently, a number of studies have demonstrated that the silencing of specific miRNAs is associated with DNA methylation. The muscle-specific miRNA-113b (miR 133b) is markedly downregulated in human colorectal cancer (CRC) compared with healthy colon cells, and is critical in the regulation of CRC cell proliferation and apoptosis. However, the mechanism of miR-133b downregulation in CRC has yet to be elucidated. Therefore, the aim of the present study was to determine the existence of an association between DNA methylation and miR-133b expression in CRC cells. It was identified that miR-133b promoter hypermethylation is upregulated in CRC tissues. To investigate the role of miR-133b methylation in CRC cells, the survival, cell cycle and invasion were analyzed in HT-29 and SW620 CRC cells treated with 5-aza-2'-deoxycytidine (5-Aza-CdR), 4-phenylbutyric acid (PBA) and 5-Aza-CdR/PBA. Functional analysis demonstrated that demethylation increased the expression of miR-133b, which restored migration and apoptosis in CRC cells. Thus, these results indicate that the regulation of miR-133b methylation may provide a novel therapeutic strategy for CRC treatment. PMID- 26622595 TI - A novel combination of triple metachronous malignancies of the kidney, oropharynx and prostate: A case report. AB - Synchronous or metachronous malignancies are a rare event, with an incidence rate that increases with age. The present study reports the case of a 70-year-old Caucasian male who was referred to the outpatient office of the Urology Unit, Sapienza University of Rome (Latina, Italy) due to lower urinary tract symptoms. An abdominal ultrasound investigation was performed that demonstrated the presence of a right renal mass. The patient underwent right radical nephrectomy, which resulted in the definitive diagnosis of clear cell type renal cell carcinoma. The patient was eventually diagnosed with triple primary metachronous cancer consisting of renal clear cell carcinoma, prostate adenocarcinoma and squamous cell carcinoma of the oropharynx (palatine tonsil). To the best of our knowledge, this combination of primary neoplasms has not previously been documented. PMID- 26622596 TI - Inhibitory effect of Embelin on human acute T cell lymphoma Jurkat cells through activation of the apoptotic pathway. AB - It has previously been shown that Embelin inhibits proliferation, promotes apoptosis, and increases sensitivity and reduces resistance to chemotherapy drugs, in various types of tumor cells. The present study examined the effects of Embelin on the proliferation of human acute T cell lymphoma Jurkat cells. Jurkat cells were treated with various concentrations of Embelin and the effects of Embelin on the inhibition of growth of Jurkat cells were evaluated. Expression of X-linked inhibitor of apoptosis protein (XIAP); poly ADP ribose polymerase; caspase-3; caspase-8; caspase-9; the proapoptotic protein, Bax; and the antiapoptotic proteins, Bcl-xl and Bcl-2, were assessed. The results showed that Embelin significantly inhibited the growth of human acute T cell lymphoma Jurkat cells. Following treatment with 5, 10 or 20 mM Embelin for 48 h, cell viability was 82.31, 58.65 and 37.62%, respectively, which was significantly reduced compared with that of the control group and the 0.1% DMSO control group (P<0.01). Furthermore, the caspase-3 inhibitor, z-DEVD-fmk, and the caspase-9 inhibitor, Ac LEHD-CHO, reversed this inhibitory effect. It was also shown that the apoptotic rate of cells treated with Embelin was significantly elevated. Subsequently, it was demonstrated that Embelin downregulated the expression of XIAP and the proapoptotic Bcl2 family members, Bcl-2 and Bcl-xl, while it concomitantly upregulated that of the antiapoptotic protein, Bax. These results showed that Embelin inhibited growth and induced apoptosis of Jurkat cells in vitro, by activating the endogenous caspase-dependent apoptotic pathway through inhibition of XIAP and proapoptotic Bcl-2 family members. PMID- 26622597 TI - Epithelial-myoepithelial carcinoma of the nasopharynx: A case report and review of the literature. AB - An 80-year-old female with complaints of right-sided nose blockage and occasional epistaxis for several months was referred to Sanggye Paik Hospital (Seoul, Korea). Nasal examination revealed a hemorrhagic mass protruding towards the right posterior nasal cavity, for which the patient was subjected to excisional biopsy. The pathological diagnosis was epithelial-myoepithelial carcinoma, as immunohistochemical analysis revealed that the inner cells stained positive for cytokeratin 7, an epithelial cell marker, whereas the outer cells stained positive for smooth muscle actin and P63, consistent with a myoepithelial phenotype. The patient received concurrent chemoradiation therapy followed by systemic chemotherapy. Following the achievement of a partial response, the patient's treatment course was uneventful. Follow-up at 24 months revealed a stable status at partial response, with no subsequent progression. PMID- 26622598 TI - Bilateral dissecting aneurysms of the internal carotid arteries misdiagnosed as skull base tumors: A case report. AB - A 45-year-old female presented with a five-year history of intermittent headaches and a two-month history of left hypoglossal nerve palsy. Computed tomography and magnetic resonance imaging of the head revealed space-occupying lesions in the base of the skull with accompanying bone erosion, which were suggestive of skull base chordomas. However, an endoscopic endonasal transsphenoidal biopsy was also performed and pathological analysis of the lesion suggested a thrombosis. Cranial magnetic resonance angiography revealed old dissecting aneurysms of the bilateral internal carotid arteries (ICAs), which led to a definitive diagnosis. The patient was successfully treated with anticoagulants and antiplatelet agents. The present case study suggests that, for patients with space-occupying lesions of the skull base and symptoms of cranial nerve palsy, the possibility of an ICA dissection should be prioritized during the differential diagnosis. PMID- 26622599 TI - Cytoplasmic c-ros oncogene 1 receptor tyrosine kinase expression may be associated with the development of human oral squamous cell carcinoma. AB - The c-ros oncogene 1 receptor tyrosine kinase (ROS1) gene encodes a proto oncogenic protein that has been demonstrated to be involved in the pathogenesis of several types of cancer. The present study aimed to analyze the expression of ROS1 in human oral squamous cell carcinomas (OSCCs), and investigate the association between its expression and the clinicopathological parameters of patients with OSCC. Paraffin-embedded OSCC tissues from 31 patients were obtained and the expression of ROS1 was analyzed by immunohistochemistry. The cellular location of ROS1 was determined by immunofluorescence in human oral cancer CAL-27 cells. The association of clinicopathological characteristics and survival rates with ROS1 expression were assessed. The results revealed that ROS1 was exclusively localized in the cytoplasm of the OSCC tissues (24/30, 80.0%), and in the cytoplasm of adjacent dysplastic epithelial tissues (2/15, 13.3%) (P<0.001). The moderate to strong expression of ROS1 in the cytoplasm was higher in OSCC tissues than in the normal epithelial tissues adjacent to the tumor (67.7 vs. 0%, P=0.001). The results of the Kaplan-Meier analysis and multivariate Cox regression analysis indicated that there was no association between the 5-year survival rate of patients and the cytoplasmic (P=0.28 and P=0.60, respectively) or nuclear expression (P=0.90 and P=0.31, respectively) of ROS1. These results suggest that the cytoplasmic expression level of ROS1 may be associated with the development of OSCC. PMID- 26622600 TI - Effects of the novel heat shock protein 90 inhibitor AUY922 in renal cell carcinoma ACHN and 786-O cells. AB - The aim of the present study was to investigate the effects of the heat shock protein (HSP)90 inhibitor AUY922 on the proliferation and migratory ability of renal cell carcinoma (RCC) cells. The expression of HSP90 was measured in vitro using western blotting and quantitative polymerase chain reaction in the ACHN and 786-O cell RCC lines, and also in the immortalized normal human proximal tubule epithelium HK-2 cell line. The effects of the time and concentration of AUY922 administration were investigated in the ACHN and 786-O cells, and the cell proliferation was measured using an MTT assay. A Transwell assay was performed to evaluate the migratory ability of ACHN cells following treatment with AUY922 at concentrations of 10, 50 and 100 nM. Western blot analysis and reverse transcription polymerase chain reaction revealed that HSP90 mRNA and protein were overexpressed in the two RCC cell lines compared with the HK-2 cell line. AUY922 inhibited the proliferation of the ACHN and 786-O cells in a time- and concentration-dependent manner, and the migratory ability of the ACHN cells was markedly suppressed subsequent to treatment with AUY922. The present data suggest that the pathogenesis of human RCC may be mediated by HSP90. It was also indicated that the specific HSP90 inhibitor AUY922 plays a therapeutic role in the treatment of RCC, and therefore, HSP90 may be a selective target for molecular-targeted treatments of RCC. PMID- 26622601 TI - Minichromosome maintenance complex component 7 has an important role in the invasion of papillary urothelial neoplasia. AB - The aims of the present study were to investigate the expression of minichromosome maintenance complex component 7 (MCM7) and determine its association with tumor proliferation and invasion in pathological tumor (pT)a and pT1 papillary urothelial neoplasia. The MCM7, MCM3 and Ki67 proteins were detected in 154 cases of urothelial neoplasia using immunohistochemical analysis. The expression of MCM7 significantly increased (P<0.001) as the pathological stage and grade progressed between inverted papilloma, papillary urothelial neoplasm of low malignant potential (PUNLMP), pTa tumor and pT1 tumor. However, no statistically significant difference in MCM7 staining was observed between low grade pTa tumors and PUNLMP (P=0.2294). In contrast to MCM7, MCM3 was highly expressed in all stages of urothelial neoplasia, with no statistically significant differences observed between the tumor types (P=0.2993, 0.3885 and 0.8489 for pTa tumors, PUNLMP and inverted papiloma, respectively). Furthermore, MCM7 expression was elevated with increased tumor grade and was positively correlated with Ki67 expression (rs =0.9106, P<0.001). However, MCM3 expression was not correlated with MCM7 or Ki67 expression (rs =0.0734, P=0.3657 and rs =0.0638, P=0.4318, respectively). In conclusion, MCM7 overexpression may simultaneously promote tumor proliferation and invasion. Furthermore, it may be a reliable marker for the pathological differential diagnosis of pTa and pT1 papillary urothelial neoplasms; therefore, MCM7 expression may be used to predict tumor prognosis and behavior. PMID- 26622602 TI - Macrodystrophia lipomatosa of the foot: A case report. AB - Macrodystrophia lipomatosa is a sporadic, nonhereditary developmental anomaly and a rare form of congenital localized gigantism. It is characterized by the proliferation of all the mesenchymal elements of a digit or digits, and a disproportionate increase of fibroadipose tissue involving the nerve sheath, muscle, periosteum and bone marrow. In the present study, a 9-month-old boy was referred to Gazi University Hospital (Ankara, Turkey) with congenital unilateral enlargement of the right forefoot, particularly involving the second and third toes. X-ray and magnetic resonance imaging (MRI) scans were performed in order to assess the skeletal structures. The present study described the characteristic imaging features, with an emphasis on the MRI findings, of this rare congenital form of gigantism. PMID- 26622603 TI - Eyelash trichomegaly following treatment with erlotinib in a non-small cell lung cancer patient: A case report and literature review. AB - Inhibitors of epidermal growth factor receptor (EGFR), including tyrosine kinase inhibitors (TKIs), present significant clinical benefits in the treatment of non small cell lung cancer (NSCLC), particularly in patients with an EGFR mutation. However, TKI treatment also results in unwanted cutaneous toxic side effects, such as a skin rash. Eyelash trichomegaly is rarely reported as a side effect; however, it causes cosmetic issues or eyeball irritation in patients, which may result in the early termination of TKI treatment. Therefore, although TKI-induced eyelash trichomegaly is rare, it should be considered carefully by lung cancer physicians. The present study reported a case of erlotinib-induced eyelash trichomegaly in a 65-year-old Chinese female patient suffering from NSCLC with an EGFR mutation. To the best of our knowledge, this is the first reported case of erlotinib-induced trichomegaly in a Chinese patient. PMID- 26622604 TI - Suppression of MAL gene expression is associated with colorectal cancer metastasis. AB - Mal, T-cell differentiation protein (MAL) is a candidate tumor suppressor gene that functions in membrane trafficking processes in polarized epithelial cells. The aim of the present study was to determine its clinical significance in colorectal cancer (CRC). The RNA and protein expression levels of MAL in 30 colorectal specimens were detected by semi-quantitative polymerase chain reaction and immunohistochemistry analysis. Statistical analysis was performed using SPSS software. The RNA level of MAL was significantly downregulated in the CRC tissues compared with the adjacent healthy tissue (P<0.05). MAL was only positively expressed in 20% of the CRC tissues, but in 66.7% of the adjacent tissues, as determined by immunohistochemistry analysis. The expression of the MAL RNA transcript exhibited a positive correlation with protein expression. The expression levels of MAL were significantly associated with different tumor-node metastasis stages and lymph node metastasis (P<0.05), but not with age, gender, tumor site, differentiation status and pathological type (P>0.05). Suppression of MAL expression was significantly correlated with metastasis in CRC. The present study indicated that MAL may function as an anti-metastasis factor and represent a potential biomarker for malignant colorectal tumors. PMID- 26622605 TI - Bilobol inhibits the lipopolysaccharide-induced expression and distribution of RhoA in HepG2 human hepatocellular carcinoma cells. AB - Recent studies have revealed the localization of RhoA protein in the cell nucleus, in addition to its distribution in the cytosol and cell membrane. The results of previous studies by our group indicated that nuclear RhoA expression is increased, or RhoA is transported into the nucleus, when cells become cancerous or damaged. Furthermore, application of the anticancer agent Taxol appeared to reduce nuclear RhoA localization, indicating an association between the nuclear translocation of RhoA and tumor progression. Bilobol is a traditional Chinese medicine ingredient, however, its anticancer effect has remained unclear. The present study aimed to demonstrate the anticarcinogenic action of bilobol against hepatocellular carcinoma, in order to lay the foundations for subsequent research into the mechanisms underlying its anticancer effects. In the present study, HepG2 cells were treated with lipopolysaccharide (LPS), to induce inflammation, and/or bilobol. By performing an ELISA, it was observed that bilobol was able to suppress the inflammation induced by LPS. In addition, immunofluorescence and western blot analyses indicated that bilobol may reduce the expression of RhoA, suppress translocation of RhoA into the nucleus and inhibit the RhoA/Rho-associated protein kinase signaling pathway. In conclusion, the present study revealed the potential anticancer effects of bilobol. PMID- 26622606 TI - Microvascular density and endothelial area correlate with Ki-67 proliferative index in surgically-treated pancreatic ductal adenocarcinoma patients. AB - Previous experimental and clinical data have indicated that tumour cell proliferation is associated with angiogenesis; in addition, an increased microvascular density (MVD) of tumours has been associated with poor prognosis in solid and haematological malignancies. However, limited data exists regarding the association between tumour cell proliferation and angiogenesis in primary tumour tissue from pancreatic ductal adenocarcinoma (PDAC) patients; therefore, the present study aimed to investigate this association. A series of 31 PDAC patients with stage Tumour (T)2-3 Node (N)0-1 Metastasis (M)0 were recruited into the present study and subsequently underwent surgery. PDAC tissue and adjacent normal tissue (ANT), resected during surgery, were evaluated using immunohistochemistry and image analysis methods to determine MVD, endothelial area (EA) and Ki-67 expression, which is an indicator of cell proliferation rate. The results demonstrated a correlation between the above parameters with each other as well as the main clinico-pathological features of PDAC. Significant differences were identified in MVD, EA and Ki-67 proliferation index between PDAC and ANT. It was demonstrated that MVD, EA and Ki-67 proliferation index were significantly correlated with each other in tumour tissue (r=0.69-0.81; P=0.001-0.003). However, no other significant correlations were identified. These data therefore suggested that angiogenesis and cell proliferation rate were significantly increased in PDAC compared with ANT, which provides a biological basis for the potential use of novel combinations of angiogenesis inhibitors and anti proliferative chemotherapeutic drugs in the treatment of PDAC. PMID- 26622607 TI - Pazopanib monotherapy in a patient with a malignant granular cell tumor originating from the right orbit: A case report. AB - Granular cell tumors are uncommon, usually benign tumors of Schwann cell origin. The malignant variant is extremely rare, representing <2% of all granular cell tumors. Therefore, standard systemic chemotherapy for this disease does not exist. The present study reports the case of a 40-year-old female with a malignant granular cell tumor that originally arose in the right orbit and subsequently relapsed. The patient was started on pazopanib monotherapy following treatment with two investigational drugs, a smoothened inhibitor and then a phosphatidylinositol 3-kinase inhibitor, as part of a clinical trial. Although additional radiotherapy for local control was necessary, the lung metastases remained stable during the pazopanib monotherapy, which lasted for 7 months, following which a clinically stable disease state was determined. This case suggests that pazopanib can be a treatment option for the stabilization of disease progression in metastatic malignant granular cell tumor. PMID- 26622608 TI - In vitro and in vivo targeting of bladder carcinoma with metformin in combination with cisplatin. AB - Bladder cancer is the ninth most common carcinoma worldwide, and improving the sensitivity of this cancer to chemotherapy is a current clinical challenge. Metformin is a potentially useful therapeutic agent for the treatment of certain types of cancer. In the present study, metformin and cisplatin (a first-line chemotherapeutic agent for the treatment of bladder cancer) were administered to T24 and BIU-87 bladder cancer cells lines alone or in combination, prior to undergoing MTT assay and fluorescence-activated cell sorting analysis to determine cell viability and cell cycle distribution, respectively. Western blotting was used to examine the expression of proteins associated with the AMP activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling pathways. In addition, a xenograft model was constructed to evaluate the antitumor efficacy of metformin and cisplatin treatment, alone or in combination. Immunohistochemistry was performed to detect the expression levels of proteins associated with xenograft growth and angiogenesis. Furthermore, western blotting was performed to observe the expression of proteins associated with the AKT/mTOR signaling pathway in the xenograft model. The results demonstrated that the treatment of T24 and BIU-87 cells with metformin or cisplatin resulted in decreased tumor cell proliferation. However, the joint application of metformin and cisplatin was significantly more effective than that of each compound alone (P<0.05). Similarly, cells more markedly accumulated in the sub-G1 phase following joint treatment with metformin and cisplatin, compared with metformin or cisplatin treatment alone. In addition, human cell cycle signaling pathway western blotting arrays were performed, which identified the marked downregulation of phosphorylated (p)-mTOR and unchanged expression of p AMPK, AMPK and mTOR following combined treatment with cisplatin and metformin. Concurrently, combined use of metformin and cisplatin markedly inhibited the growth and angiogenesis of xenografts generated from BIU-87 cells. Immunohistochemical analysis revealed that downregulation of the expression of specific proteins associated with AMPK promoted xenograft growth and angiogenesis, while western blotting revealed inhibition of the AKT/mTOR signaling pathway in xenografts treated with metformin in combination with cisplatin. Overall, the results of the present study demonstrated that the concurrent administration of metformin and cisplatin may result in enhanced antitumor efficacy compared with that of one agent alone, thus, providing a potential novel therapeutic strategy for the treatment of bladder cell carcinoma. PMID- 26622609 TI - Accessory spleen appearing as an intrasplenic pseudo-tumoral mass: A rare case report. AB - The current study presents a rare case of an accessory spleen that manifested as a solid intrasplenic pseudotumor. The affected patient was previously healthy. Upon examination with computed tomography (CT), an ovoid, soft-tissue mass of ~4.1 cm in diameter was found on the upper pole of the spleen. Biochemical indices, such as blood routine and coagulation tests, and tumor marker analysis, revealed no abnormalities. Another CT scan was performed, but this failed to indicate whether the mass was benign or malignant. Therefore, the lesion was resected along with the spleen by laparoscopic surgery. The resected sample was subject to pathological examinations for final validation, and was finally diagnosed as an accessory spleen. The patient was followed up for six months with no signs of recurrence. PMID- 26622610 TI - RhoC is essential in TGF-beta1 induced epithelial-mesenchymal transition in cervical cancer cells. AB - Epithelial-mesenchymal transition (EMT) is a critical process in the promotion of epithelial tumor progression and metastasis. The present study aimed to investigate the role of Ras homolog gene family, member C (RhoC) guanosine triphosphatase (GTPase) in transforming growth factor (TGF)-beta1 induced EMT. EMT occurred in human cervical carcinoma SiHa cells following TGF-beta1 stimulation for 4 days, as demonstrated by the appearance of mesenchymal morphology, reorganization of the actin cytoskeleton, reduced E-cadherin expression and increased Vimentin expression, which was associated with increased RhoC expression and activity. However, EMT was not observed in cells that were pretreated with RhoC siRNA prior to TGF-beta1 stimulation. Downregulation of RhoC 4 days following TGF-beta1 stimulation was not able to reverse the existing EMT. In addition, TGF-beta1 promoted the invasion of the control SiHa cells but not that of the cells in which RhoC was downregulated. In conclusion, RhoC expression is activated by TGF-beta1, and sufficient RhoC expression levels are essential for TGF-beta1-induced EMT. PMID- 26622611 TI - Upregulation of SOX9 promotes cell proliferation, migration and invasion in lung adenocarcinoma. AB - Sex determining region Y-box 9 (SOX9) is an important transcription factor in development and has been implicated in several types of cancer. Although the association between upregulation of SOX9 and lung adenocarcinoma (ADC) has been reported previously, the role of SOX9 in the proliferation, migration and invasion of cancer cells remains unclear. Therefore, in the present study, SOX9 expression was detected in 163 human lung adenocarcinoma tissues by immunohistochemistry and western blotting. It was found that the SOX9 protein was over-expressed in the majority of lung adenocarcinoma. The full-length human SOX9 plasmid was then transfected into the lung ADC A549 cell line. An MTT assay was used to investigate the role of SOX9 in cell proliferation. Scratch and extracellular matrix cell invasion assays were performed to investigate whether SOX9 promotes the migration and invasion of lung ADC cells. The results revealed that ectopic overexpression of SOX9 in the lung adenocarcinoma cell line resulted in a marked increase in cell proliferation, migration and invasion. Accordingly, knockdown of SOX9 by RNA interference resulted in the inhibition of cell growth, migration and invasion. The present data indicate that SOX9 may act as a novel marker for lung adenocarcinoma and perform an important role in cell proliferation, migration and invasion. PMID- 26622612 TI - Association of p73 G4C14-to-A4T14 polymorphism with non-small cell lung cancer risk. AB - The p73 gene is a structural and functional homolog of the p53 gene, which has a crucial role in mediating cell cycle arrest and apoptosis. Numerous previous studies have investigated the polymorphism of p73 G4C14-to-A4T14 at exon 2, as it was suggested to affect gene expression and result in functional significance. However, the correlation of this polymorphism with clinicopathological variables of patients with non-small cell lung cancer (NSCLC) remains to be elucidated. The aim of the present study was to examine the association between the gene polymorphism of p73 G4C14-to-A4T14 and the risk of developing NSCLC. The single nucleotide polymorphisms of p73 G4C14-to-A4T14 were genotyped using polymerase chain reaction with confronting two-pair primers and direct DNA sequencing in 186 NSCLC patients and 196 cancer-free controls. chi2-tests and logistic regression analysis were used to analyze the experimental data, including the determination of odds ratio (OR), 95% confidence intervals (95% CIs) and P-values. The results demonstrated that the AT/AT genotype was associated with a significantly decreased risk of NSCLC (P=0.010; OR=0.370; 95% CI=0.170-0.806) compared with the GC allele genotypes including GC/GC and GC/AT. In addition, carriers of the AT allele exhibited a significantly reduced risk of NSCLC (P=0.038; OR=0.713; 95% CI=0.517-0.983) compared with non-carriers. In conclusion, these results indicated that the p73 G4C14-to-A4T14 polymorphism was a potential marker of NSCLC genetic susceptibility. However, further studies with a larger population are required in order to confirm these results. PMID- 26622613 TI - Primary thyroid paraganglioma mimicking medullary thyroid carcinoma: A case report. AB - Primary thyroid paraganglioma (TP) is an uncommon tumor, and in rare cases, this disease tends to mimic medullary thyroid carcinoma (MTC). The present study reports a rare case of primary TP mimicking thyroid carcinoma, accompanied by hyperthyroidism. A 30-year-old female presented with an anterior cervical mass. Pre-operative radiological studies and operative frozen section analysis indicated an atypical MTC. Primary TP was finally diagnosed by pathology and immunohistochemical staining. Laboratory examinations (thyroid hormones tests) and Tc99m emission computed tomography revealed hyperthyroidism. Gene analysis of TP-associated gene mutations was negative. Surgical resection was performed as a curative approach and there is currently no metastasis after 36 months of follow up. Surgeons must be aware of this disease in order to ensure a correct diagnosis and to prevent them from performing unnecessary procedures. The current study presents a case of primary TP mimicking MTC, discusses the radiographic results and histological characteristics, and provides a review of the associated literature. PMID- 26622614 TI - Expression and clinical significance of focal adhesion kinase and adrenomedullin in epithelial ovarian cancer. AB - The aim of the present study was to investigate the expression of focal adhesion kinase (FAK) and adrenomedullin (ADM) and determine their clinical significance and cooperative role in human epithelial ovarian cancer. The expression of FAK and ADM was investigated in epithelial ovarian cancer, benign ovarian tumors and normal control tissues by immunohistochemical staining and optical microscopy. The FAK and ADM expression and correlation with clinicopathological parameters was analyzed using SPSS 13.0 software. The expression of FAK and ADM in epithelial ovarian cancer was significantly higher compared with that in benign tumors or normal ovarian tissues (P<0.01); however, no significant difference was observed between benign tumors and normal tissues (P>0.05). The expression of FAK was found to be correlated with histological grade, clinical stage, lymph node metastasis and prognosis (P<0.05), but exhibited no significant association with patient age or histological type (P>0.05). The expression of ADM was significantly correlated with pathological grade, lymph node metastasis and prognosis (P<0.05), but not with age, clinical stage or histological type (P>0.05). The Spearman's rank correlation analysis revealed a positive correlation between FAK and ADM expression (r=0.314). FAK and ADM were more highly expressed in epithelial ovarian cancer compared with benign tumors or normal ovarian tissues. Furthermore, FAK and ADM may play a cooperative role; specifically, FAK may upregulate ADM in the invasion and migration of epithelial ovarian cancer. Thus, FAK and ADM may represent potential biomarkers for evaluating the malignant potential and prognosis of ovarian cancer. PMID- 26622615 TI - Acute intussusception and polyp with malignant transformation in Peutz-Jeghers syndrome: A case report. AB - Intussusception is one of the most frequent complications of Peutz-Jeghers syndrome, and has been well described in previous studies. More attention has been paid to malignancy, which is another complication of Peutz-Jeghers syndrome and which leads to increased mortality. Few cases of intussusception combined with malignant polyps in Peutz-Jeghers syndrome have been reported to date. In the present study, we report a case of intussusception and malignant polyps occurring in various parts of the small intestine in a 43-year-old male. In addition to repair of the intussusception and partial resection of the small intestine with malignant polyps, we also simultaneously performed polypectomy of as many polyps as possible without resection of the small intestine. Our aim is to make clinicians aware of intussusception and malignant polyps coexisting in Peutz-Jeghers syndrome when performing emergency surgery. Prophylaxis and polypectomy of the entire small bowel is an effective way to reduce the frequency of laparotomies in patients with this disease. PMID- 26622616 TI - Effect of vascular endothelial growth factor-C expression on lymph node metastasis in human cholangiocarcinoma. AB - The present study aimed to evaluate the expression of vascular endothelial growth factor C (VEGF-C) in human cholangiocarcinoma tissues and its role in metastasis in vitro. A total of 65 biopsy samples of cholangiocarcinoma, plus the FRH-0201 cell line, were investigated. The expression of VEGF-C in the human cholangiocarcinoma specimens was evaluated by immunohistochemistry (IHC). The effect of VEGF-C on tumor cell migration and proliferation was measured by MTT and Transwell assays in the FRH-0201 cell line. According to the IHC results, the biopsies of human cholangiocarcinoma were stained positively for VEGF-C, with a positive rate of 75.4% (49/65). Moreover, VEGF-C was expressed at a higher level in the patients with lymph node metastasis than in those without lymph node metastasis. In vitro, VEGF-C exhibited marked growth stimulation below the concentration of 5 ng/ml and was able to promote cholangiocarcinoma cell migration significantly. These findings suggested that VEGF-C may be a useful factor to predict lymph node metastasis in cholangiocarcinoma tissues and indicates that VEGF-C plays a significant role in proliferation and migration in cholangiocarcinoma cells. PMID- 26622617 TI - Tumstatin induces apoptosis mediated by Fas signaling pathway in oral squamous cell carcinoma SCC-VII cells. AB - Oral squamous cell carcinoma is a cancer originating in the tissues lining the mouth and lips. The present study investigated the effects of recombinant tumstatin, an anti-angiogenic agent with distinct antitumor activity, on oral squamous cell carcinoma SCC-VII cells. Apoptosis was characterized by YO-PRO-1 staining, sub-G1 population, and DNA fragmentation analysis. Apoptotic mechanism of tumstatin was also investigated. The antitumor activity of tumstatin was further evaluated using an SCC-VII animal model. Recombinant tumstatin was found to decrease the viability of SCC-VII cells in a dose-dependent manner. The number of cells stained with the apoptotic marker YO-PRO-1, the sub-G1 cell population and the level of apoptotic DNA fragmentation increased in the SCC-VII cells following treatment with recombinant tumstatin. In addition, recombinant tumstatin treatment increased the expression of the Fas gene at the transcript and protein levels, and the inhibition of cell viability by recombinant tumstatin was suppressed by a neutralizing anti-Fas antibody. Furthermore, treatment with recombinant tumstatin decreased the volume and weight of tumors in C3H/HeJ mice implanted with SCC-VII cells. In conclusion, the results indicated that tumstatin induced apoptosis that is mediated by the Fas signaling pathway in SCC-VII cells and inhibited tumor growth in an SCC-VII animal model. PMID- 26622618 TI - Retroperitoneal cystic immature teratoma: A case report. AB - Retroperitoneal cystic immature teratoma (RCIT) is a rare disease. RCITs manifest as solid and cystic masses. In pathological sections, cysts of various sizes, with internal hemorrhage and necrosis, are observed. Components of all germ layer tissue are also observed, the majority of which is located within the endoderm. As the tumor contains undifferentiated immature tissue components, RCITs are also termed malignant teratomas. Immature teratomas grow rapidly, often invading adjacent tissue to cause serious symptoms, and transfer through the blood and lymph vessels, often resulting in glandular cancer. The present study reports the case of an infant with RCIT. The female patient, aged six months and six days, was hospitalized due to an abdominal mass. Physical examination revealed a large mass (10*8 cm) below the xiphoid in the epigastrium. The mass, which ranged from the xiphoid to the umbilical region, was friable, and possessed a smooth surface, clear boundaries and poor activity, without tenderness. Upper abdominal computed tomography (CT) revealed a large, solid, cystic mass in the left, middle and lower retroperitoneum. The patient was admitted to the Yantai Yuhuangding Hospital for surgery. The pre-operative examination was improved following admission by documenting parameters that included the results from routine blood tests, bleeding and clotting times and cardiography. Retroperitoneal tumor resection was then performed. During resection, the tumor was found to originate from the retroperitoneum. As the tumor involved the gastric wall, a section of the gastric wall was resected, in addition to the tumor. The resection surface was yellow and friable. Pathological examination of tumor tissue sections revealed the involvement of immature nerves and mesenchymal components, confirming the diagnosis of a grade II immature teratoma. Subsequent to six months of outpatient follow-up, the patient had recovered well, without recurrence. RCIT is a clinically rare disease, and the present study adds to the current understanding of this rare condition in infants. PMID- 26622619 TI - Secondary osteosarcoma arising from osteochondroma following autologous stem cell transplantation with total-body irradiation for neuroblastoma: A case report. AB - The present study reports the first case of malignant transformation to osteosarcoma arising from osteochondroma following childhood total-body irradiation (TBI). The association between TBI and later development of osteochondroma is well-known; however, malignant degeneration arising from radiation-induced osteochondroma is rare. The current study describes the case of a 17-year-old boy with osteosarcoma arising from osteochondroma of the left distal humerus, which developed following TBI. TBI was administered as part of a conditioning regimen received prior to autologous peripheral hematopoietic stem cell transplantation (HSCT) at the age of 6 years, following an initial diagnosis of neuroblastoma at the age of 5 years. The patient subsequently underwent preoperative chemotherapy followed by wide local excision and reconstruction with an extracorporeally irradiated autograft. Postoperative chemotherapy was administered, and the patient demonstrated no clinical or radiographic evidence of recurrence after 40 months of follow-up. To the best of our knowledge, this is only the second reported case of malignant degeneration of osteochondroma following childhood TBI, and the first reported case of transformation to osteosarcoma. The current case highlights the importance of close observation for secondary malignancies in this patient population. PMID- 26622620 TI - Breast carcinoma metastasis to the lacrimal gland: Two case reports. AB - A 77-year-old female, with proptosis, reduced eye motility and diplopia which had developed over two to three months and a 69-year-old female with proptosis, oedema of the eyelid, reduced motility and ptosis, which had developed over three weeks, are presented in the present study. Computed tomography scans revealed irregular lacrimal gland tumours in the two patients. The two patients had history of breast cancer. The first breast cancer metastasis in the lacrimal gland demonstrated a cribriform growth pattern containing ductal elements. The epithelial tumour cells stained positive for cytokeratin (1-8, 10, 14-16, 18 and 19), oestrogen receptor, epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA) and gross cystic disease fluid protein 15 (GCDFP-15). The second metastatic tumour was positive for EMA and estrogen receptor, but variably positive for CEA and GCDFP-15. The metastasis in the lacrimal gland was a pleomorphic tumour. The tumour cells were positive for EMA and variably positive for oestrogen and CEA. Metastases to the lacrimal gland are extremely rare, and metastases to the lacrimal gland should be considered in the diagnoses of lacrimal gland tumours. The present study aimed to describe two such cases and draw attention to breast carcinomas as a differential diagnosis and the most frequent cause of lacrimal gland metastasis. PMID- 26622621 TI - First-line combination of GELOX followed by radiation therapy for patients with stage IE/IIE ENKTL: An updated analysis with long-term follow-up. AB - In recent years, asparaginase-based chemotherapy regimens have produced excellent short-term efficacy in patients with extranodal natural killer/T-cell lymphoma (ENKTL). However, few long-term outcomes have been reported to date. A phase II clinical trial evaluating the efficacy and safety of a combination of gemcitabine, oxaliplatin and asparaginase (GELOX), followed by radiotherapy (RT) in the treatment of localized ENKTL, was reported by this group in 2012. By the time of the present analysis, detailed information had been collected for all 27 patients in the phase II trial, over an extended follow-up period. The median follow-up time was 63.15 months. The 5-year overall survival and progression-free survival were 85.0 and 74.0%, respectively. Recurrence within the RT field was observed in three patients, and the planning target-volume control rate at 5 years was 88.9%. One patient with confirmed lung invasion who did not respond to autologus stem cell transplantation (ASCT) was successfully treated by salvage therapy with lenalidomide monotherapy, and the EBV DNA load in this individual reflected disease progression and treatment response. No clinically significant late toxicities were identified during follow-up visits. In conclusion, this updated analysis confirmed the long-term benefit of the GELOX regimen followed by RT, and demonstrated a good safety profile for this treatment. This strategy may be one of the most suitable options for the treatment of early stage ENKTL. PMID- 26622622 TI - Castleman's disease presenting in the lungs: A report of two cases. AB - Castleman's disease (CD) is a rare disease that most commonly occurs in the mediastinum. The lung is a rare site in which CD may occur. The current study reported 2 cases of CD localized in the lungs. Computed tomography imaging identified a high-density mass in the lungs of the two patients. Biopsy and pathological examinations indicated that one case presented features of two CD types (hyaline-vascular and plasma cell types), while the other case suffered from multicentric CD. The present study highlighted the typical clinical features of CD in the lungs. In addition, it is proposed that a diagnosis of CD should be considered for certain patients with masses in the lungs, and a biopsy should be performed to facilitate diagnosis and treatment. PMID- 26622623 TI - Salvage helical tomotherapy for prostate cancer recurrence following definitive external beam radiotherapy: A case report. AB - Salvage prostatectomy for recurrent prostate cancer after external beam radiotherapy (EBRT) has resulted in positive outcomes; however, it is technically challenging and is associated with a number of risks. When a patient exhibits recurrent prostate cancer following definitive EBRT and presents with comorbidities meaning that they cannot receive a prostatectomy, it is difficult to treat due to the numerous limitations of current salvage therapies. In the present study, two cases of salvage reirradiation using helical tomotherapy for locally recurrent prostate cancer following definitive EBRT are presented. The two patients received EBRT without severe complications. Local recurrence was confirmed by serum levels of prostate-specific antigen, repeat prostate biopsy, prostate magnetic resonance imaging and a bone scan. Salvage reirradiation using helical tomotherapy was performed and resulted in promising outcomes without any complications. In conclusion, helical tomotherapy can be a safe and effective salvage treatment modality for locally recurrent prostate cancer following definitive EBRT. PMID- 26622624 TI - High-dose chemotherapy combined with autologous peripheral blood stem cell transplantation in children with advanced malignant solid tumors: A retrospective analysis of 38 cases. AB - The aim of the present study was to assess the toxicity and efficacy of autologous peripheral blood stem cell (APBSC) transplantation in children with advanced malignant solid tumors. The outcomes of 38 children with advanced malignant solid tumor, who were treated with high-dose chemotherapy and autologous peripheral blood stem cell transplantation in Beijing Tongren Hospital (Capital Medical University, Beijing, China) between September 2005 and November 2011, were retrospectively analyzed. The effects of treatment were evaluated according to the standard Bearman's criteria. The mean count of collected mononuclear cells and the cluster of differentiation 34+ cell count from 38 patients was 5.6+/-2.2*108/kg and 3.8+/-2.6*106/kg, respectively. From these 38 patients, the number of stem cells collected from 31 cases (81.6%) accorded with the transplantation standards. Three and 14 days after pretreatment in these 38 cases, there were 19 cases of grade I, 11 cases of grade II, five cases of grade III and three cases of grade IV (one case succumbed) adverse reaction. Following the treatment (23-40 days after pretreatment, during organ injury recovery), 37 cases obtained bone marrow reconstitution with a mean time of 12.3+/-3.1 days after APBSC reinfusion. The median survival time of the 37 patients was 49 months, and the survival rate at one, three and five years post-treatment was 91.9, 68.2 and 36.6%, respectively. PMID- 26622625 TI - Clinico-epidemiology of neuroblastoma in north east Egypt: A 5-year multicenter study. AB - Neuroblastoma, an embryonal malignancy of the sympathetic nervous system, is the most frequent extracranial solid tumor The clinico-epidemiological features of neuroblastoma in infants and children were investigated between January 2005 and January 2010 at the Pediatric Oncology units of Mansoura, Zagazig, and Tanta University Children's Hospitals (Egypt). Of 142 cases of neuroblastoma, 10 were omitted from the study due to defective data. The median age of the patients was 30 months, with 75.8% aged >=1 year and 24.2% aged <1 year at time of diagnosis. The male-to-female ratio was 1.06. Suprarenal glands were the most common primary tumor site (72.7%). The majority of the patients (76.7%) had stage IV disease. Favorable pathology was observed in 43.8% of patients, while 56.2% exhibited unfavorable pathology. The estimated survival rate of patients was 30.7+/-10.0%, and mean survival time was 24.2+/-5.2 months. The rate of mortality was 28.6% for patients aged <1 year, and 81.8% for those aged >=1 year (P=0.005). For patients with favorable pathology, the rate of mortality was significantly lower (28.6%) compared with that of patients with unfavorable pathology (77.8%; P=0.049). Although the association between outcome and each of the primary tumor sites, children's oncology group risk and gender was statistically insignificant, a large effect size was identified between outcome and primary tumor site, as well as children's oncology group risk and a medium effect size was identified between outcome and gender. Additionally, an age of >=1 year was associated with unfavorable pathology (P=0.024), stage IV disease (P=0.026) and a suprarenal primary tumor site (P=0.001). PMID- 26622627 TI - Obligate anaerobic Salmonella typhimurium strain YB1 treatment on xenograft tumor in immunocompetent mouse model. AB - The present authors have previously reported a novel approach to genetically engineer Salmonella typhimurium for the medically important therapeutic strategy of using bacterial agents to target malignant tumors in a breast cancer tumor bearing nude mouse model. However, studying an immunocompromised mouse model for cancer therapy is insufficient, as certain crucial information about the influence of the immune system may be missing. In the present study, inoculation of the Salmonella strain, YB1, into a colon cancer tumor-bearing immunocompetent mouse model was investigated. The present study determined the tumor targeting efficiency, antitumor potential, the effects of multiple treatments and the systemic toxicity. Intravenous inoculation of YB1 in BALB/c mice exhibited high antitumor effects and also greatly increased the tumor targeting ability and safety compared with the previously-reported nude mouse model. In addition, repeated administration of YB1 further enhanced this effect. Furthermore, no marked toxicity was observed with YB1 treatment, while the VNP20009 and SL7207 strains demonstrated certain adverse effects. The findings of the present study indicate that the YB1 strain is effective and safe in targeting a colon cancer tumor in an immunocompetent mouse model. PMID- 26622626 TI - Expression levels of B7-H3 and TLT-2 in human oral squamous cell carcinoma. AB - The aim of the present study was to investigate the role of immune regulatory molecules B7-H3 [also known as cluster of differentiation 276] and triggering receptor expressed on myeloid cell-like transcript-2 (TLT-2) in patients with oral squamous cell carcinoma (OSCC). Human OSCC samples were obtained from 76 patients (female, 32; male, 44; age range, 23-81 years; median age, 50.9 years) that underwent resection for OSCC at Peking University Shenzhen Hospital (Shenzhen, China) between 2007 and 2010. In addition, control oral mucosal samples were obtained from 76 healthy individuals (female, 36; male, 40; age range, 21-62 years; median age, 45.3 years) during wisdom tooth extraction. Protein and gene expression levels of B7-H3 and TLT-2 were determined by immunohistochemical analysis and reverse transcription-polymerase chain reaction (RT-PCR). In the healthy oral mucosa samples, B7-H3 expression was identified to be weak, while the expression of TLT-2 was only detected sporadically in the cell membrane and cytoplasm. By contrast, the two regulatory molecules were widely expressed in the aforementioned localizations in human OSCC specimens upon immunohistochemical examination. Furthermore, quantitative RT-PCR confirmed the presence of significantly higher B7-H3 and TLT-2 expression levels in OSCC specimens compared with the oral mucosa of healthy individuals. The significantly higher expression levels of B7-H3 and TLT-2 in human OSCC specimens may indicate an inhibitory role of these molecules in the antitumoral immune response. To investigate interactions between these two molecules and individual antitumoral immune response in OSCC patients, prospective clinical studies with an adequate sample size are required. PMID- 26622628 TI - Primary mesenchymal chondrosarcoma with bilateral kidney invasion and calcification in renal pelvis: A case report and review of the literature. AB - Mesenchymal chondrosarcoma (MC) is a rare malignant cartilaginous forming tumor. MC of the kidney is extremely rare, with only seven cases reported in the literature. The present study described the case of a 17-year-old male, who presented with sudden severe pain in the right flank and a high fever. Imaging studies demonstrated a large soft heterogeneous mass (7.8*9.5*15 cm) located between the liver and right kidney with no clear demarcation, and a well demarcated mass (1.3*2.4 cm) with patchy dense calcification occupying the left renal pelvis. Following the diagnosis of a Wilms' tumor, the patient underwent a right radical nephrectomy and the pathological diagnosis was MC of the kidney. To the best of our knowledge, the current study presents the first case of MC with bilateral kidney invasion and calcification in the renal pelvis. In addition, the clinical, radiological and pathological features, and the management of this unusual neoplasm were discussed. PMID- 26622629 TI - Immune checkpoints: Cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1 in breast cancer surgery. AB - Immune checkpoints refer to a plethora of inhibitory pathways built into the immune system, and recent studies have emphasized the role of these checkpoints in carcinogenesis. The aim of the present study was to evaluate two major immune checkpoints, the cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), in the serum of 35 patients with stage I and II breast cancer. Serum concentrations of CTLA-4 and PD-1 were measured at three time points: i) Preoperatively; ii) during anesthesia following the harvesting of sentinel nodes (SNs); and iii) 24 h postoperatively. Control samples were obtained from 25 healthy, age-matched females. Assessment of CTLA-4 and PD-1 expression levels was conducted using flow cytometry. A statistically significant difference in PD-1 expression was identified between breast cancer patients preoperatively and healthy controls (26.31+/-11.87 vs. 12.72+/-8.15; P<0.0001). In addition, a statistically significant association was found between CTLA-4 and PD-1 levels prior to surgery (P=0.0084). In addition, CTLA-4 expression was associated with age (P=0.0453), with elevated levels of CTLA-4 detected in older breast cancer patients. Higher PD-1 expression levels were observed in T2 tumors compared with T1 tumors prior to surgery and intraoperatively; however, the differences were not statistically significant. Furthermore, a decrease in PD-1 levels was observed subsequent to harvesting SNs with metastasis, but not in SN negative patients (P=0.05). A negative correlation was also observed between PD-1 expression and progesterone receptor (PR) status following surgery (P=0.024). These results provided a basis for further investigation of immune checkpoints in breast cancer. Breast cancer patients exhibit an altered profile of immune checkpoint markers, with higher concentrations of PD-1 observed in larger, PR negative tumors. PMID- 26622630 TI - Advanced renal cell carcinoma associated with von Hippel-Lindau disease: A case report and review of the literature. AB - The autosomal dominant hereditary disorder von Hippel-Lindau (VHL) disease is caused by a germline mutation in the VHL gene. The symptoms of VHL include hemangioblastoma of the central nervous system, retinal angiomas, visceral tumors and multiple visceral cysts. However, advanced renal cell carcinoma (RCC) occurs in few VHL patients at initial diagnosis; in addition, sporadic VHL disease with de novo germline mutation is rare. The current study reports the clinical case of a 33-year-old Asian male patient diagnosed with advanced bilateral multicentric renal carcinomas. The patient underwent radical nephrectomy with embolectomy of the right kidney for treatment of T3b-stage RCC and laparoscopic nephron-sparing surgery of the left kidney. Sunitinib was administered following histological diagnosis and during follow-up. Genetic analysis revealed a missense mutation, c.194C>G (p.Ser65Trp). In addition, genetic analysis of the patient's parents and brothers, who were unaffected, confirmed a diagnosis of de novo VHL disease. To the best of our knowledge, the present study reports the first known case of a sporadic de novo germline mutation of VHL at c.194C>G. Current understanding of the molecular genetics and pathophysiology of VHL disease, as well as developments in surgical and target therapies for RCC have advanced in recent years; however, early detection through genetic screening and regular clinical surveillance of VHL disease patients and their families continues to be the primary basis for managing the disease. PMID- 26622631 TI - Effect of insulin on the mRNA expression of procollagen N-proteinases in chondrosarcoma OUMS-27 cells. AB - Chondrosarcoma is one of the most common bone tumors, and at present, there is no non-invasive treatment option for this cancer. The chondrosarcoma OUMS-27 cell line produces proteoglycan and type II, IX, and XI collagens, which constitutes cartilage tissue. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) proteases are a group of secreted proteases, which include the procollagen N-proteinases ADAMTS-2, -3 and -14. These procollagen N-proteinases perform a role in the processing of procollagens to collagen and the maturation of type I collagen. The present study aimed to improve the understanding of the causes of metastasis, local invasion and resistance to chemo- and radiotherapy in chondrosarcoma, as well as the effect of insulin on cancer cells. The present study was designed to reveal the effects of insulin on procollagen N-proteinases in chondrosarcoma OUMS-27 cells. The cells were cultured in Dulbecco's modified Eagle's medium (DMEM) alone or in DMEM containing 10 ug/ml insulin. The medium was changed every other day for 11 days. The cells were harvested on days 1, 3, 7 and 11, and total RNA isolation was performed immediately following harvesting. The expression levels of ADAMTS2, ADAMTS3 and ADAMTS14 mRNA were estimated by reverse transcription-quantitative polymerase chain reaction using appropriate primers. ADAMTS2 mRNA expression was found to be decreased on day 7 (P=0.028) and increased at day 11 compared with the control group (P=0.016). The increase in mRNA concentration at day 11 was significantly different compared to the concentrations on days 3 (P=0.047) and 7 (P=0.008). The expression of ADAMTS3 mRNA decreased immediately subsequent to insulin induction on day 1 compared with the control group (P=0.008). The most evident decrease in mRNA concentration was seen at day 7 subsequent to insulin induction (P=0.008). The present results demonstrated that ADAMTS2 and ADAMTS3 may perform a role in the invasion and metastasis of tumors, and may also possess proteolytic activity that results in the breakdown of the extracellular matrix (ECM). Insulin itself can modulate the biosynthesis of ECM macromolecules that are altered in diabetes through various pathways. PMID- 26622632 TI - Advantage of transurethral resection with narrow band imaging for non-muscle invasive bladder cancer. AB - The aim of the present study was to compare the benefits of transurethral resection (TUR) under narrow band imaging (NBI-TUR) and TUR under conventional white light imaging (WLI-TUR) for non-muscle invasive bladder cancer (NMIBC). The study cohort consisted of 135 patients with NMIBC who were followed up for >=1 year after TUR and who received no additional post-operative treatment. In the WLI-TUR group (n=78), systematic intravesical observation under WLI was followed by a multiple site biopsy (MSB), after which lesions detected as positive findings were resected completely under WLI. In the NBI-TUR group (n=57), similar observation under WLI was followed by systematic intravesical observation under NBI. Following MSB under NBI, TUR was performed for all lesions detected as positive findings under NBI. The sensitivity, specificity, positive-predictive value, negative-predictive value (NPV) and accuracy in the NBI-TUR group were calculated using results from the cystoscopical and pathological examinations of MSB samples under WLI and NBI. The tumor recurrence rate was analyzed in the two groups. Background factors did not differ significantly between the two groups, with the exception of the observation period (31.0 vs. 15.0 months; P<0.01). The procedure under NBI exhibited significantly higher sensitivity (95.0 vs. 70.0%; P<0.01) and NPV (97.1 vs. 86.8%; P<0.01) compared with the procedure under WLI. The 1-year recurrence rate in the NBI-TUR group was significantly lower than that in the WLI-TUR group (21.1 vs. 39.7%; P=0.016). In conclusion, the present study indicated that NBI-TUR is more advantageous than conventional WLI-TUR for patients with NMIBC. PMID- 26622633 TI - Requirement for novel surgical and clinical protocols for the treatment of desmoplastic small round cell tumor: A report of two cases and a review of the literature. AB - Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive neoplasm that was initially described in 1989. DSRCT predominantly affects young men and typically occurs in the intra-abdominal area. The present study describes the cases of two patients with DSRCT. The first patient was a 23-year-old male who presented with abdominal pain in the right flank, coupled with difficulty urinating and bowel dysfunction. The second patient was 12-year-old female who presented with abdominal pain, emesis and loss of appetite. A computed tomography scan of the abdomen revealed the presence of an extensive pelvic mass in each patient, however, a visceral origin was not clearly identifiable in the first patient. In the second patient, a large soft-tissue tumor was located posterior to the pancreatic tail and the stomach, with no anatomical line visible between the stomach and splenic vein. Ultrasound-guided biopsy in the first patient and videolaparoscopy in the second patient followed by immunohistochemical analysis clarified the presence of a malignant neoplasm composed of small, blue, round cells. Due to right ureter involvement and hydronephrosis in the first patient, a treatment strategy of surgical debulking of the tumor was selected. The surgical procedure involved en bloc resection of the lesion associated with a pelvic peritonectomy, followed by post-operative radiotherapy. However, the second patient exhibited extensive disease, therefore, a chemotherapeutic protocol of vincristine, doxorubicin and cyclophosphamide, as well as radiation therapy, was scheduled. Disease relapse was observed in the abdominal cavity of the first patient after one year, while the second patient remains asymptomatic. Following analysis of present two cases, it was concluded that aggressive treatment regimens may induce tumor regression. However, relapse of the disease is frequent and long-term survival is rare with the currently available therapeutic strategies. PMID- 26622634 TI - Number of cerebral lesions predicts freedom from new brain metastases after radiosurgery alone in lung cancer patients. AB - Numerous patients with few brain metastases receive radiosurgery, either alone or in combination with whole-brain irradiation. The addition of whole-brain irradiation to radiosurgery reduces the rate of intracerebral failures, particularly the development of new cerebral lesions distant from those treated with radiosurgery. Less intracerebral failures mean less neurocognitive deficits. However, whole-brain irradiation itself may lead to a decline in neurocognitive functions. Therefore, a number of physicians have reservations with regard to adding whole-brain irradiation to radiosurgery. Prognostic factors that allow an estimation of the risk of developing new cerebral metastases can facilitate the decision regarding additional whole-brain irradiation. Since primary tumors show a different biology and clinical course, prognostic factors should be identified separately for each primary tumor leading to brain metastasis. The present study investigated 10 characteristics in a series of 98 patients receiving radiosurgery alone for 1-2 cerebral metastases from lung cancer, the most common primary tumor associated with brain metastasis. These characteristics included radiosurgery dose, age, gender, performance status, histology, number of cerebral lesions, maximum total diameter of cerebral lesions, main location of cerebral lesions, extracranial spread and interval from first diagnosis of lung cancer to administration of radiosurgery. On univariate analysis, the number of cerebral lesions prior to radiosurgery (1 vs. 2 lesions) was the only characteristic significantly associated with freedom from new brain metastases (P=0.002). In cases of 2 lesions, 73% of patients developed new cerebral lesions within 1 year. On multivariate analysis, the number of brain metastases remained significant (risk ratio, 2.46; 95% confidence interval, 1.34-4.58; P=0.004). Given the high rates of new cerebral lesions in patients with 2 brain metastases, these patients should be strongly considered for additional whole-brain irradiation. PMID- 26622635 TI - Glucagonoma syndrome: A case report. AB - Necrolytic migratory erythema (NME), diabetes mellitus and glucagon-secreting tumors form the hallmarks of glucagonoma syndrome, and represent the major clinical manifestations of glucagonoma. NME is usually presented as the initial complaint of patients. Due to the rare incidence of glucagonoma, its diagnosis is often delayed, which leads to its progression. Here, we report a case of NME with a typical skin rash, which was misdiagnosed and treated with corticosteroids for two years. Removal of the tumor in the pancreatic body led to the rapid relief of the symptoms. The aim of the present study is to demonstrate the typical characteristics of glucagonoma syndrome to clinicians in order to improve its diagnosis and treatment. PMID- 26622636 TI - Anti-metastatic effect of jolkinolide B and the mechanism of activity in breast cancer MDA-MB-231 cells. AB - Tumor metastasis is the main cause of mortality in cancer patients. However, no effective therapies are currently available to prevent metastasis. Cell adhesion to the extracellular matrix (ECM) is crucial in cancer progression and metastasis. Thus, suppression of cell adhesion may be an effective therapeutic strategy for the prevention of metastasis. In the present study, the anti adhesion and anti-invasion effects of jolkinolide B, a diterpenoid compound from Euphorbia fischeriana Steud, that were exerted through suppression of beta1 integrin expression and phosphorylation of focal adhesion kinase (FAK) were examined in human breast cancer MDA-MB-231 cells. Jolkinolide B inhibited the adhesion of MDA-MB-231 cells to fibronectin but not to poly-L-lysine. In addition, jolkinolide B inhibited extracellular signal-regulated kinase (ERK) phosphorylation. U0126, an ERK inhibitor, also suppressed the invasion and adhesion of MDA-MB-231 cells. Overall, the present data demonstrated that jolkinolide B is a novel inhibitor of FAK-mediated signaling pathways that is involved in decreasing cell adhesion and invasion. Mitogen-activated protein kinase/ERK kinase may play a critical role in these effects, indicating that jolkinolide B possesses therapeutic potential for the treatment of breast cancer metastasis. PMID- 26622637 TI - Evaluation of the efficacy and safety of a neoadjuvant gemcitabine and nedaplatin regimen followed by radiotherapy or concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma. AB - The aim of the present study was to evaluate the efficacy and safety of a neoadjuvant gemcitabine and nedaplatin chemotherapy regimen, followed by concurrent chemoradiotherapy or radiotherapy alone, in locoregionally advanced nasopharyngeal carcinoma (NPC). Eighty-six patients with stage III, IVA or IVB NPC, who received neoadjuvant chemotherapy [gemcitabine, 1,000 mg/m2 on day 1 (d1) and d5; nedaplatin, 25 mg/m2 on d 1-3] every 3 weeks for at least two cycles, followed by intensity-modulated radiotherapy every 3 weeks, with or without concurrent nedaplatin (25 mg/m2, d1-3) between September 2010 and December 2013, were retrospectively analyzed. By comparing pretreatment and post treatment MRI images, it was shown that seven patients achieved a complete response (8.5%), while 66 achieved a partial response (80.5%), following completion of neoadjuvant chemotherapy (combined response rate, 89.0%). Grade 3-4 toxicities following neoadjuvant chemotherapy included neutropenia (29.1%), leukopenia (11.6%), liver dysfunction (9.3%), thrombocytopenia (9.3%) and nausea/vomiting (8.1%). The median follow-up was 18 months (range, 5-44 months). The 2-year relapse-free survival, distant metastasis-free survival, progression free survival and overall survival rates were 96.6, 85.4, 83.3 and 96.1%, respectively. Compared with alternative neoadjuvant chemotherapy regimens in combination with radiotherapy or concurrent chemoradiotherapy, the present gemcitabine and nedaplatin did not provide additional survival benefit and led to a higher frequency of liver dysfunction. Therefore, neoadjuvant gemcitabine and nedaplatin should be used with caution in locoregionally advanced NPC. PMID- 26622638 TI - Radionuclide imaging in the diagnosis of osteoid osteoma. AB - Oseteoid osteoma is a well-known type of benign bone-forming tumor, which has previously been diagnosed using plain radiograph imaging. However, diagnosis of osteoid osteoma may be delayed due to ambiguities on plain radiograph images; despite the increasing use of magnetic resonance imaging (MRI), this type of misdiagnosis is not uncommon. The aim of the present study was to evaluate the effectiveness of radionuclide imaging scans for the diagnosis of osteoid osteoma, as this form of imaging was proposed to be a more sensitive test. The characteristics of 18 cases of osteoid osteoma were analyzed based on diagnostic imaging and the time from initial recognition of symptoms by the patient to diagnosis. Diagnostic modalities included plain radiograph, computed tomography (CT), MRI and radionuclide imaging. Among the 18 patients, 14 patients had unique positive findings in plain radiographs. The mean duration between initial cognition of symptoms to the diagnosis for these patients was 5.2 months (range, 3.8-9.3 months). A total of 4 patients exhibited no radiographic abnormalities in the initial plain radiographs and were diagnosed a mean of 18.5 months (range, 17 20 months) following the onset of symptoms. Overall, radionuclide imaging was performed on 16 patients and all of the cases demonstrated positive findings. In these cases, 28.6% of osteoid osteoma patients with clinical indications revealed no abnormal findings in plain radiographs. Therefore, in situations such as these, radionuclide imaging may be a useful indicator for diagnosis, as these results have demonstrated that it positively identified all cases of osteoid osteoma. In addition, the results of the present study indicated that if the radionuclide imaging was positive, CT scan was a more valuable diagnostic tool, whereas if the radionuclide imaging was negative, MRI should be recommended for the diagnosis of other undiscovered disease entities. PMID- 26622639 TI - Similar survival benefits of a good response and stable disease to platinum-based chemotherapy in non-small cell lung cancer. AB - The present study aimed to evaluate the similar survival benefits of a good response [complete response or partial response (CR/PR)] and stable disease (SD) to chemotherapy in non-small cell lung cancer (NSCLC) patients in clinical practice. All 322 patients who were treated between 1999 and 2012 with first-line platinum-based chemotherapy were retrospectively analyzed. Tumor responses were classified according to the response evaluation criteria for solid tumors. A total of 67 (20.8%) patients experienced CR/PR and 165 (51.2%) achieved SD. There was no difference in progression-free survival between the patients with CR/PR and those with SD (P=0.347). There was also no difference between the two groups with regard to overall survival time (P=0.878). In multivariate analysis, disease control (more than SD) was one of the favorable prognostic factors. In clinical practice, a survival benefit would be provided not only for the patients who have good response, but also for those with SD. PMID- 26622640 TI - Pleural synovial sarcoma patient treated with combined chemotherapy and Endostar, plus sunitinib maintenance therapy: A case report and review of the literature. AB - Synovial sarcoma is a rare, highly malignant soft-tissue tumor that occurs primarily in the extremities. At present, there is no effective clinical treatment for this condition. The present study reports the case of a 49-year-old male who was diagnosed with pleural synovial sarcoma and treated with recombinant human endostatin (Endostar) combined with chemotherapy for a total of six cycles, followed by sunitinib maintenance therapy. To the best of our knowledge, this is the first reported use of sunitinib for maintenance therapy in pleural synovial sarcoma. The patient survived for 25 months after the recurrence of the disease following surgery. The results indicate that this combination therapy was effective in the treatment of pleural synovial sarcoma. The present study also briefly reviews the literature on pleural synovial sarcoma, and the features and treatments for this rare case are discussed. PMID- 26622641 TI - Gd-EOB-DTPA-enhanced and diffusion-weighted magnetic resonance findings in hepatic epithelioid angiomyolipoma: A case report. AB - The present study reports a case of histologically proven hepatic epithelioid angiomyolipoma that was evaluated with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging and diffusion weighted imaging. A 23-year-old female was admitted to the Northern Jiangsu People's Hospital (Yangzhou, Jiangsu, China) due to a 5.6-cm mass in the liver, and a right partial hepatectomy was performed. Magnetic resonance imaging (MRI) revealed a hypointense mass on T1-weighted imaging, and a hyperintense mass on T2 weighted and diffusion-weighted imaging, with a higher apparent diffusion coefficient value compared with normal liver parenchyma. On the dynamic Gd-EOB DTPA-enhanced MRI scan, the lesion manifested as hypervascular with multiple filiform vessels and a pseudocapsule image, and in the hepatobiliary phase the lesion demonstrated a lack of contrast retention, thus appearing hypointense compared with the background liver. Pre-operatively, EMAL was diagnosed on the basis of these findings in the tumor. The optimum treatment is complete surgical excision and subsequent follow-up. The patient was healthy and free from recurrence at 6 months and 1 year post-surgery. Therefore, knowledge of EAML specific features on dynamic Gd-EOB-DTPA-enhanced and DWI scans may improve the diagnostic accuracy of hypervascular hepatic tumors and may facilitate treatment selection. PMID- 26622642 TI - Expression of human protection of telomere 1 correlates with telomere length and radiosensitivity in the human laryngeal cancer Hep-2 cell line. AB - The close association between telomere length and radiosensitivity has been established by several studies. There is also a hypothesis that telomere length may be regulated by human protection of telomere 1 (hPOT1) in human carcinoma cells. In the present study, the hPOT1 level between the radioresistant Hep-2R cells and the wild-type were compared, and the results showed that the hPOT1 gene was upregulated in the radioresistant Hep-2R cell lines compared with the wild type. This suggested that the expression level of hPOT1 correlates with radiosensitivity. Additionally, an hPOT1-directed short hairpin (sh)RNA plasmid was constructed and transferred into the Hep-2R cells, which lead to telomere shortening, an increase in apoptosis and markedly decreased growth of the RNAi Hep-2R cell line. These results demonstrate that hPOT1-directed shRNAs are associated with telomere length and radiosensitivity, and maybe a potent sensitizer for laryngeal cancer radiotherapy. PMID- 26622643 TI - Alterations of immune cell subsets in relapsed, thymoma-associated minimal change disease: A case report. AB - The most frequently described glomerulopathy in patients with thymoma is minimal change disease (MCD). The present study reports the case of a 63-year-old female with recurrent thymoma and poorly-controlled paraneoplastic MCD, who was enrolled on a phase I/II clinical trial (no. NCT01100944) and treated with the histone deacetylase inhibitor, belinostat, in combination with cisplatin, doxorubicin and cyclophosphamide. Treatment resulted in a complete radiological response, a dramatic reduction in proteinuria and changes in immune cell subset composition, consisting of a reduction in the number of T helper (Th)1, Th2, Th17 and regulatory T cells. Changes in T-cell polarization were also observed with an increase in the Th1/Th2 ratio. To the best of our knowledge, the current study is the first to provide a detailed description of changes in immune cell subset composition in thymoma-associated MCD. Early administration of effective antitumor therapy should be considered in these cases, particularly when proteinuria is poorly controlled despite the use of steroids and other immunosuppressive therapies. PMID- 26622644 TI - Association between the MTHFR C677T polymorphism and gastric cancer susceptibility: A meta-analysis of 5,757 cases and 8,501 controls. AB - Current data regarding the association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of developing gastric cancer are insufficient to draw definite conclusions. Therefore, the present meta analysis was conducted to achieve a more precise estimation of the association. MEDLINE, EMBASE and Wanfang database searches resulted in the identification of 28 eligible studies describing 5,757 cases and 8,501 controls. The strength of the association between the MTHFR C677T polymorphism and gastric cancer risk were evaluated using crude odds ratios (ORs), with 95% confidence intervals (CIs). The pooled ORs were determined using homozygous (TT vs. CC), heterozygous (CT vs. CC), dominant (TT+CT vs. CC) and recessive (TT vs. CC+CT) models. When all studies were pooled into the meta-analysis, significant associations were identified between the MTHFR C677T polymorphism and the risk of gastric cancer (homozygous model: OR, 1.39; 95% CI, 1.20-1.62; heterozygous model: OR, 1.18; 95% CI, 1.05-1.32; dominant model: OR, 1.23; 95% CI, 1.10-1.38; recessive model: OR, 1.26; 95% CI, 1.12-1.42). Stratification of the data by ethnicity identified a statistically significantly elevated risk of gastric cancer in Asian MTHFR C677T polymorphism populations (homozygous model: OR, 1.64; 95% CI, 1.43-1.90; heterozygous model: OR, 1.30; 95% CI, 1.16-1.45; dominant model: OR, 1.39; 95% CI, 1.25-1.54; recessive model: OR, 1.41; 95% CI, 1.25-1.51), but not in Caucasian populations (homozygous model: OR, 1.15; 95% CI, 0.89-1.48; heterozygous model: OR, 1.03; 95% CI, 0.84-1.25; dominant model: OR, 1.05; 95% CI, 0.86-1.28; recessive model: OR, 1.09; 95% CI, 0.91-1.31). Following adjustment for heterogeneity, the current meta-analysis demonstrated that the MTHFR C677T polymorphism was not associated with the risk of gastric cancer in Caucasian individuals. Furthermore, no evidence of publication bias was observed. Thus, the current meta-analysis indicates that the MTHFR C677T allele may be a low-penetrant risk factor for the development of gastric cancer in Asian populations. PMID- 26622645 TI - Clinical analysis of 29 cases of nasal mucosal malignant melanoma. AB - The present study aimed to investigate the clinical features of nasal mucosa malignant melanoma, including the histopathological features and factors affecting prognosis. A retrospective analysis of the clinical data obtained from the Department of Otolaryngology Head and Neck Surgery, Tianjin Huanhu Hospital (Tianjin, China) between October 1999 and June 2013 was performed using the Kaplan-Meier method. In total, 29 cases of nasal mucosal malignant melanoma were analyzed. The overall 3- and 5-year survival rates were 48.3 and 27.6%, respectively. The study group consisted of 18 males and 11 females, with a median age of 61.5 years. Overall, 19 patients underwent surgery, 28 received radiotherapy and 17 received chemotherapy. The American Joint Committee on Cancer staging system (AJCC) was used to retrospectively stage the tumors. In total, 8 were tumor stage (T)1, 10 were T2, 6 were T3 and 5 were T4. The results revealed that the T stage, surgical treatment, location of the tumor and the presence of black pigmentation affected the 5-year survival rate of the patients. By contrast, radiotherapy and chemotherapy had no effect on the overall survival rate. Overall, endoscopic or endoscopic-assisted surgery were the preferred methods of treatment, and histological features, including the presence of tumor melanin pigmentation, affected the prognosis of the patients. This study indicated that the AJCC staging system is able to effectively predict the prognosis of patients with nasal mucosa malignant melanoma. PMID- 26622646 TI - Effect of CYP2C19 and CYP3A4 gene polymorphisms on the efficacy of bortezomib based regimens in patients with multiple myeloma. AB - Bortezomib is used to treat patients with multiple myeloma. It is primarily metabolized by the enzyme cytochrome P450 (CYP). Variations in the capacity of bortezomib metabolism affect the treatment outcomes and the side-effects experienced by patients. In the present study, polymorphisms in the CYP3A4 and CYP2C19 genes were analyzed by polymerase chain reaction in 56 newly-diagnosed patients with multiple myeloma. The polymorphisms analyzed included the c.681G>A, c.636G>A and c.-806C>T polymorphisms of CYP2C19. The CYP3A4 gene was sequenced after amplification and was classified into normal and mutant types. Associations between the metabolizer genotypes of CYP3A4 and CYP2C19, the therapeutic efficacy of bortezomib-based regimens, and the occurrence of peripheral neuropathy were studied. The results identified no significant differences in gender, serum beta2 microglobulin, creatinine, blood albumin, isotypes, and the Durie-Salmon and International Staging System stages between the CYP2C19 poor + intermediate metabolizer types and the extensive + ultrarapid metabolizer types. In addition, it was revealed that the CYP2C19 and CYP3A4 phenotypes did not affect the efficacy of bortezomib-based regimens, nor were they correlated with peripheral neuropathy. Additional large-scale studies are required in order to evaluate the role of CYP enzymes in bortezomib treatments for patients with multiple myeloma. PMID- 26622647 TI - Primary malignant hepatic paraganglioma mimicking liver tumor: A case report. AB - An extra-adrenal pheochromocytoma is also known as a paraganglioma. The present study reported the case of a 47-year-old female patient with an extremely rare primary nonfunctioning hepatic paraganglioma without any clinical signs and symptoms. A computed tomography scan of the entire abdomen region revealed a hyper-enhanced, well-marginated round mass located in segment 3 of the liver. A preoperative diagnosis of hepatocellular carcinoma was established and a left lateral hepatic lobectomy was performed. During the removal of the mass, the patient experienced extreme fluctuations in blood pressure. Analysis of hepatic and peripheral venous blood test results confirmed the increase of noradrenaline secretion. Postoperatively, the patient's blood pressure and catecholamine level returned to the normal range. However, three years after surgery, a plasma catecholamine examination revealed a high noradrenaline level. Abdominal magnetic resonance imaging scans revealed two metastases, located in the spleen and below the right posterior lobe of the liver, which were identified as malignant paragangliomas. Therefore, the patient was diagnosed with primary malignant hepatic paraganglioma recurrence three years after hepatic resection. PMID- 26622648 TI - Diffuse-type giant cell tumor of the tendon sheath in the temporal region incidentally diagnosed due to a temporal tumor: A report of two cases and review of the literature. AB - Diffuse-type tenosynovial giant cell tumor (D-GCTS) is a rare benign lesion that not only frequently occurs in the fingers, but also along the tendon sheaths of the foot and ankle. The present study reports the cases of two middle-aged patients that were diagnosed with D-GCTS. The presentation of the D-GCTS lesions was extremely rare, as the tumors were located in the temporal fossa and threatened the skull base and external auditory canal. There were similarities and differences between the two patients in their clinical symptoms, disease progressions and invading sites. The patients' disease course occurred unnoticed with the absence of pain, was protracted and became infiltrative. However, the female patient was admitted to the hospital due to the occurrence of pain in the left temporal region, and the male patient presented at the doctor due to a painless left temporal mass and external auditory canal bleeding. Therefore, the operation area of the two patients was not the same. This type of illness should be considered in the differential diagnosis for masses occurring in the temporal region. Total tumor removal is the best treatment for D-GCTS, and the careful monitoring of recurrence can achieve a good clinical outcome subsequent to the surgical resection. PMID- 26622649 TI - Long-term outcome of 31 cases of refractory acute promyelocytic leukemia treated with compound realgar natural indigo tablets administered alternately with chemotherapy. AB - The aim of the present study was to investigate the long-term survival of patients with refractory acute promyelocytic leukemia (APL) that were administered alternately with compound realgar natural indigo tablet (CRNIT) treatment and chemotherapy. In total, 31 patients with refractory APL were administered with CRNIT treatment alternately with chemotherapy. The complete remission (CR) and relapse rates were estimated by bone marrow (BM) examination. The expression of the promyelocytic leukemia-retinoic acid receptor alpha (PML RARalpha) fusion protein and the apoptosis rate in the retinoic acid (RA) resistant NB4-R1 cell line administered with CRNIT treatment in vitro were measured by western blot analysis and flow cytometry, respectively. The patients were followed up for 12-60 months, with a median follow-up time of 43 months. The total continuous CR rate was 90.32% (28/31), and the duration of response was between 10.3 and 60 months (median, 42.4 months). The total relapse rate was 9.68% (3/31), and the median time of relapse was 13 months (range, 8-27 months). During the treatment with CRNITs, there was no evident BM depression and only limited side-effects were experienced. Additionally, in vitro cell molecular biology results revealed that CRNIT treatment resulted in a marked induction of apoptosis and degradation of the PML-RARalpha fusion protein. The present results revealed that CRNIT treatment in combination with chemotherapy is an effective and feasible therapy for the treatment of patients with refractory APL. PMID- 26622650 TI - Sigmoid adenocarcinoma with metastases to the kidney: Report of a rare case and review of the literature. AB - Distant metastases from colorectal cancer (CRC) most frequently spread to the liver and lungs. CRC metastasis to the kidney is extremely rare and may be generally associated with an unfavorable prognosis. Thus, patients with metastatic CRC and kidney metastasis are a diagnostic and therapeutic challenge. The present study reported the case of a 42-year-old male with a local recurrence of CRC following sigmoid resection with partial mesorectal excision, which had infiltrated the urinary bladder, requiring partial resection of the urinary bladder wall. After 4 years, the patient developed a recurrent tumor localized in the upper pole of the left kidney and underwent left nephrectomy. The patient remained disease-free 6 months after the surgery. PMID- 26622651 TI - MRI and MR spectroscopy findings of the evolution of an intracranial germinoma: A case report. AB - Intracranial germinomas (IG) are rare tumors that typically occur in the pineal gland and suprasellar region of the brain. IG can be successfully treated with radiation therapy and its recurrence is rare. The present study reports the case of a patient with IG involving the pineal and suprasellar regions. The patient was treated with radiotherapy, achieving significant remission. However, recurrence was discovered 10 months later. The patient was subsequently treated with chemotherapy and radiotherapy, resulting in gradual remission. The patient had recovered 2 months later and was in good health. The entire evolution process, including magnetic resonance (MR) imaging and MR spectroscopy findings, are described herein. The present case suggests that MR spectroscopy may be useful for monitoring the effects of treatment. PMID- 26622652 TI - microRNA-182 inhibits the proliferation and migration of glioma cells through the induction of neuritin expression. AB - Astrocytomas are the most common type of glial tumors and carry a poor prognosis. However, the pathogenesis of astrocytomas remains to be elucidated. Neuritin, a novel member of the neurotrophic factors family, has been shown to be associated with tumor malignancy, via the regulation of apoptosis and proliferation. In the present study, microRNA-182 (miR-182) was cloned and transfected into the U251 human astrocytoma cell line, in order to investigate its regulatory effects on the proliferation and migration of these cells, as well as its association with the expression of neuritin. The results showed that miR-182 specifically targets the gene encoding neuritin, NRN1, as demonstrated by a reduction in the protein and mRNA levels of NRN1. In addition, overexpression of miR-182 affected cell cycle regulation and cell migration capacity in vitro, which may have been associated with the promotion of apoptosis by this molecule. In conclusion, endogenous miR-182 may be involved in the pathogenesis of astrocytoma, which is associated with the miR-182-regulated gene, NRN1. PMID- 26622653 TI - Triplet cytotoxic chemotherapy with gemcitabine, 5-fluorouracil and cisplatin for advanced pancreatic cancer. AB - In advanced or relapsed pancreatic cancer, mono- or duo-therapy has shown modest efficacy at best. The present study evaluated the efficacy of a triplet combination in relapsed or advanced pancreatic cancer. A total of 37 patients with adenocarcinoma of the pancreas in stage III/IV or with relapsed disease were treated with a gemcitabine, 5-fluorouracil and cisplatin (GFP) regimen every 3 weeks. Only 29 out of 37 patients were evaluable for response due to early treatment interruption in 8 patients. The overall response rate was 24.1% and the disease control rate was 68.9%. The progression-free survival (PFS) rate was 61.5, 30.9 and 17.6% at 3, 6 and 9 months, respectively, and the overall survival (OS) rate was 46.5 and 30.6% at 6 and 12 months, respectively. Grade 3/4 leukopenia, neutropenia and thrombocytopenia occurred in 18.4, 29.9 and 24.5% of 147 cycles, respectively. Old age and a poor performance status (PS) were associated with the early discontinuation of chemotherapy (P=0.038 and P=0.036, respectively). In patients <65 years old and with a PS of <2, the median PFS and OS times were 5.3 months and 10.3 months, respectively. Overall, although GFP resulted in acceptable response and survival rates, it does not appear to have marked superiority to gemcitabine-based single or duplet chemotherapy. PMID- 26622654 TI - Melanoma-associated antigen expression and the efficacy of tyrosine kinase inhibitors in head and neck cancer. AB - Melanoma-associated antigen (MAGE) has been identified in a variety of types of cancer. The expression of several MAGE subgroups is correlated with poor prognosis and chemotherapeutic resistance. One target of chemotherapeutic treatment in head and neck cancer is the epidermal growth factor receptor (EGFR). The efficacy of tyrosine kinase inhibitors (TKI) in the context of melanoma associated antigens is discussed in the present study. Five human squamous cell carcinoma cell lines were treated with the EGFR TKIs, erlotinib and gefitinib. The efficacy of these agents was measured using a crystal violet assay. Furthermore, the expression levels of MAGE-A1, -A5, -A8, -A9, -A11 and -A12 were determined by reverse transcription-quantitative polymerase chain reaction. The association between TKI efficacy and MAGE-A expression was analyzed by linear regression. The cell lines revealed inhomogeneous expression patterns for the MAGE-A subgroups. Four of the five cell lines demonstrated a good response to erlotinib and gefitinib. However, treatment with erlotinib induced better results than those of gefitinib, and revealed a concentration-dependent effect. The expression of MAGE-A5 and -A11 were significantly correlated with lower efficacy of erlotinib and gefitinib. By contrast, MAGE-A12 was associated with a superior response to these two drugs. One cell line, which expressed all investigated MAGE A subgroups, was entirely resistant to the two TKIs. These results revealed a notable correlation between MAGE-A5 and -A11 and lower efficacy of EGFR TKIs. Pretreatment analysis of MAGE-A status may therefore aid improvement of chemoprevention using erlotinib and gefitinib in head and neck cancer. PMID- 26622655 TI - C-X-C motif receptor 7 in gastrointestinal cancer. AB - Chemokine receptors are key mediators of normal physiology and numerous pathological conditions, including inflammation and cancer. This receptor family is an emerging target for anticancer drug development. C-X-C motif receptor 7 (CXCR7) is an atypical chemokine receptor that was first cloned from a canine cDNA library as an orphan receptor and was initially named receptor dog cDNA 1 (RDC1). Shortly after demonstrating that RDC1 binds with its ligand, stromal cell derived factor-1alpha and interferon-inducible T-cell alpha chemoattractant, RDC1 was officially deorphanized and renamed CXCR7, as the seventh receptor in the CXC class of the chemokine receptor family. Recent accumulating evidence has demonstrated that CXCR7 expression is augmented in the majority of tumor cells compared with their normal counterparts and is involved in cell proliferation, survival, migration, invasion and angiogenesis during the initiation and progression of breast, lung and prostate cancer. In the present review, the expression and role of CXCR7, as well as its clinical relevance in cancer of the gastrointestinal system, were investigated. In addition, the potential of this chemokine receptor as a therapeutic target in the treatment of gastrointestinal cancer was discussed. PMID- 26622656 TI - Breast cancer metastasis and the lymphatic system. AB - Breast cancer remains the leading cause of cancer mortality worldwide, despite a significant decline in death rates due to early detection. The majority of cancer mortalities are due to the metastasis of tumor cells to other organs. Metastasis or tumor cell dissemination occurs via the hematogenous and lymphatic systems. For many carcinomas, the dissemination of tumor cells via lymphatic drainage of the tumor is the most common metastatic route. Such lymphatic drainage collects at the regional lymph nodes and the dissection and pathological examination of these nodes for lodged cancer cells is the gold standard procedure to detect metastasis. The present report provides an overview of the lymphatic system and its clinical significance as a prognostic factor, in addition to the interactions between the primary tumor and its microenvironment, and the influence of genomic subtypes on the resulting organ-specific pattern of tumor cell dissemination. It also examines the seemingly protracted asymptomatic period, during which the disseminated cells remain dormant, leading to the manifestation of metastasis decades after the successful treatment of the primary tumor. PMID- 26622658 TI - A rare gastric neuroendocrine carcinoma coexisting with Brunner's gland adenoma: A case report. AB - Gastric neuroendocrine carcinoma (G-NEC) is a rare neoplasm known for its aggressive behavior and poor prognosis. Brunner's gland adenoma (BGA) is a rare benign proliferative lesion that develops most commonly in the duodenum. To the best of our knowledge, no cases of G-NEC coexisting with BGA have previously been reported. The present study therefore reports the first case of G-NEC combined with BGA. A 67-year-old female presented with upper abdominal discomfort. No distant metastases were detected upon pre-operative abdominal computed tomography imaging. The patient underwent a radical distal gastrectomy, D2 lymphadenectomy and Billroth I gastroenterostomy. The resected masses were histologically confirmed to be G-NEC and BGA, respectively. The patient did not receive neoadjuvant or adjuvant chemotherapy or radiotherapy, and remains alive with no evidence of metastasis or recurrence at four years post-surgery. PMID- 26622659 TI - Aspiration cytology of an ectopic cervical thymoma misinterpreted as a lymphoproliferative lesion of the thyroid: A case report. AB - Ectopic cervical thymoma is a rare tumor that originates from ectopic thymic tissue trapped during the migration of the embryonic thymus. To the best of our knowledge, only 14 cases of ectopic cervical thymoma, which include descriptions of the cytological features based on fine-needle aspiration (FNA), have been reported thus far. The current study describes the case of a 52-year-old male presenting with an enlarging anterior neck mass that been apparent for a number of years and was now accompanied by shortness of breath. FNA cytology revealed large numbers of small lymphocytes admixed with rare groups of large, polygonal cells that were interpreted to be reactive lymphocytes or possible follicular dendritic cells. However, no definite follicular or Hurthle cells were identified. Therefore, the overall cytological features were misinterpreted as a lymphoproliferative lesion. However, subsequent histological analysis of the resected left total lobectomy specimen determined a diagnosis of thymoma, type B1. Thus, awareness of this entity combined with a careful search for thymic epithelial cells may aid in determining a correct diagnosis when FNA is performed for the evaluation of a neck mass. PMID- 26622657 TI - Traditional Chinese medicine in the prevention and treatment of cancer and cancer metastasis. AB - Traditional Chinese medicine (TCM) has been a major part of healthcare in China, and has extensively affected medicine and healthcare in surrounding countries over a long period of time. In the fight against cancer, certain anticancer remedies using herbs or herbal formulas derived from TCM have been developed for the management of malignancies. Furthermore, there are clinical trials registered for the use of herbal remedies in cancer management. Herbal medicine has been used as part of combined therapies to reduce the side-effects of chemotherapy, including bone marrow suppression, nausea and vomiting. Herbal remedies have also been used as chemopreventive therapies to treat precancerous conditions in order to reduce the incidence of cancer in high-risk populations. Emerging evidence has revealed that herbal remedies can regulate the proliferation, apoptosis, adhesion and migration of cancer cells. In addition to this direct effect upon cancer cells, a number of herbal remedies have been identified to suppress angiogenesis and therefore reduce tumour growth. The inhibition of tumour growth may also be due to modifications of the host immune system by the herbal treatment. However, the precise mechanisms underlying the therapeutic effects of herbal remedies remain poorly understood and are yet to be fully elucidated. The present study aims to summarize the current literature and clinical trial results of herbal remedies for cancer treatment, with a particular focus on the recent findings and development of the Yangzheng Xiaoji capsule. PMID- 26622660 TI - Peroxisome proliferator-activated receptor-gamma is downregulated in ulcerative colitis and is involved in experimental colitis-associated neoplasia. AB - The aim of the present study was to evaluate the expression of peroxisome proliferator-activated receptor (PPAR)-gamma in inflammatory bowel disease (IBD), and to also identify the association between PPAR-gamma and the clinical features of patients with IBD. An azoxymethane (AOM)/dextran sodium sulfate (DSS) animal model of colitis-associated neoplasia was established to investigate the protective effect of 5-aminosalicylic acid (5-ASA) and to explore the changes in the expression of PPAR-gamma during this process. A total of 66 specimens of colorectal tissue obtained from biopsy performed on IBD patients and 30 healthy control individuals were immunohistochemically stained for PPAR-gamma. An AOM/DSS animal model of colitis-associated neoplasia was then established. Reverse transcription quantitative polymerase chain reaction was conducted and it was found that, compared with the control group and patients with Crohn's disease (CD), the expression of PPAR-gamma in the intestinal tissue of patients with ulcerative colitis (UC) was significantly decreased (P=0.027 and 0.046, respectively). The expression of PPAR-gamma was found to be negatively associated with the disease activity of UC and was not associated with the severity of disease, site of lesions or CD characteristics. Administration of 5-ASA decreased the colitis and tumor burden of colons. The expression level of PPAR-gamma in the intestinal tissue was also increased in the AOM/DSS/5-ASA group compared with AOM/DSS group (P<0.001). PPAR-gamma is an important factor in the pathogenesis of UC and colitis-associated cancer. The present study found that 5-ASA significantly alleviates the colitis and tumor burden in a mouse model of AOM/DSS induced colitis-associated neoplasia, and promotes the expression of PPAR-gamma in the intestinal tract. PMID- 26622661 TI - Management of nasopharyngeal angiofibroma in a 72-year-old male through a sublabial and buccolabial incision approach: A case report and literature review. AB - Nasopharyngeal angiofibroma (NA) primarily affects adolescent males. The incidence of NA in the elderly, however, is extremely low. The present study describes a 72-year-old male with NA that presented with typical symptoms and radiological findings. The location and extension of the tumor was too lateral and inferior to be effectively resected by an endoscopic approach. Therefore, a combination of endoscopic and open approaches was considered. The tumor was completely resected using an image-guided endoscopic-assisted sublabial and buccolabial incision approach. The post-operative histopathological and immunohistochemical analysis confirmed the diagnosis of NA. The present study demonstrated the occurrence of NA in the elderly, and highlighted the potential of an image-guided endoscopic-assisted sublabial and buccolabial incision approach for the treatment of NA in the elderly. PMID- 26622662 TI - Expression of cyclin D1 and cyclin E in urothelial bladder carcinoma detected in tissue chips using a quantum dot immunofluorescence technique. AB - The present study aimed to investigate the expression of cyclin D1 and cyclin E in tissue chips of bladder cancer using quantum dots (QDs), as well as examine its clinicopathological significance. The QD-based immunofluorescence tissue chemical technique was adopted to detect cyclin D1 and cyclin E expression in 75 tissue chips of human urothelial bladder carcinoma (including 70 cases of urothelial bladder carcinoma and 5 cases of cystitis), and its correlation with clinicopathological features was analyzed. The positive rates of cyclin D1 and cyclin E expression in urothelial bladder carcinoma were 68.6% (48/70) and 70.0% (49/70), respectively; however, no expression was observed in cystitis. Based on the results of statistical analysis, the difference in the positive rates of cyclin D1 and cyclin E expression between urothelial bladder carcinoma and cystitis was significant (P<0.05). QD staining and statistical analysis revealed that the expression of cyclin D1 and cyclin E in urothelial bladder carcinoma was significantly higher compared with that in cystitis (P<0.05). However, no statistically significant difference (P>0.05) in cyclin D1 expression was observed in relation to pathological stage, clinical stage or invasion of urothelial bladder carcinoma; however, there was a significant difference (P<0.05) in cyclin E expression with respect to these factors. These results demonstrated that overexpression of cyclin D1 may be an early event in the occurrence of urothelial bladder carcinoma. Cyclin D1 may play a role in the initial stage where cell proliferation is a necessary step, without invasion or metastasis. In addition, overexpression of cyclin E was correlated with the stage and depth of invasion of urothelial bladder carcinoma. In conclusion, the abnormal expression of cyclin D1 and cyclin E may be involved in the occurrence and development of urothelial bladder carcinoma. PMID- 26622663 TI - Gefitinib-induced intestinal obstruction in advanced non-small cell lung carcinoma: A case report. AB - Gefitinib is an epidermal growth factor receptor (EGFR) inhibitor, which is used to treat patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations. Dermatological reactions are the most common adverse events associated with gefitinib treatment; other adverse effects, including diarrhea, nausea, stomatitis and an asymptomatic elevation of liver enzymes have also been reported. The present study describes a patient with intestinal obstruction who was successfully undergoing treatment with gefitinib for primary and metastatic neoplasms. Gefitinib-induced intestinal obstruction has not been previously reported; therefore, careful monitoring of gastrointestinal symptoms should be conducted throughout the course of gefitinib-treated malignancies. PMID- 26622664 TI - Evaluation of spheroid head and neck squamous cell carcinoma cell models in comparison to monolayer cultures. AB - Two-dimensional (2D) monolayer cell culture models are the most common method used to investigate tumor cells in vitro. In the few last decades, a multicellular spheroid model has gained attention due to its adjacency to tumors in vivo. The aim of the present study was to investigate immunohistochemical differences between these two cell culture systems. The FaDu, CAL27 and SCC25 head and neck squamous cell carcinoma (HNSCC) cell lines were seeded out in monolayer and multicellular spheroids. The FaDu and SCC25 cells were treated with increasing doses of cisplatin and irradiation. CAL27 cells were not used in theproliferation experiments, since the spheroids of CAL27 cells were not able to process the reagent in CCK-8 assays. Furthermore, they were stained to present alterations of the following antigens: Ki-67, vascular endothelial growth factor receptor, epithelial growth factor and survivin. Differences in growth rates and expression patterns were detected in certain HNSCC cell lines. The proliferation rates showed a significant divergence of cells grown in the three-dimensional model compared with cells grown in the 2D model. Overall, multicellular spheroids are a promising method to reproduce the immunohistochemical aspects and characteristics of tumor cells, and may show different response rates to therapeutic options. PMID- 26622665 TI - Promoter demethylation of nuclear factor-erythroid 2-related factor 2 gene in drug-resistant colon cancer cells. AB - The mechanisms underlying drug resistance in colorectal cancer (CRC) treatment remain to be fully elucidated. Therefore, the present study aimed to investigate the underlying mechanism resistance to a widely used anticancer drug, 5 Fluorouracil (5-FU). Nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important transcription factor involved in cellular protection. In the present study, it was hypothesized that the epigenetic modification of Nrf2 may be a potential target for 5-FU resistance in CRC treatment. Protein and messenger RNA levels of Nrf2, heme oxygenase-1 (HO-1), DNA methylases and DNA methyltransferases were determined and DNA methylation analysis for the Nrf2 promoter was performed in a human CRC control (SNU-C5) and resistant (SNU-C5R) cell line. The results demonstrated that Nrf2 expression levels, nuclear translocation and promoter binding were significantly increased in SNU-C5R cells compared with SNU-C5 cells. Elevated levels of activated Nrf2 in SNU-C5R cells resulted in the increased protein expression and activity of HO-1. In addition, increased production of reactive oxygen species (ROS) and upregulation of ten eleven translocation (TET)1 were observed in SNU-C5R cells compared with SNU-C5 cells. Furthermore, methylation analysis revealed Nrf2 promoter cytosine phosphate-guanine island hypomethylation in 5-FU-treated cells. In conclusion, the results indicated that 5-FU-induced ROS production resulted in the upregulation of TET1 expression and function. In addition, these results indicated that TET-dependent demethylation of the Nrf2 promoter upregulated Nrf2 and HO-1 expression, which induced cellular protection mechanisms, ultimately leading to drug resistance. PMID- 26622666 TI - L858R-positive lung adenocarcinoma with KRAS G12V, EGFR T790M and EGFR L858R mutations: A case report. AB - Improvement in the current understanding of the molecular basis of lung cancer at multiple levels, including the genetic, epigenetic and protein levels, has the potential to impact the diagnosis, prognosis and treatment of lung cancer. The mutation status of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) is known to be a predictor of the response to gefitinib in lung cancer. Furthermore, mutations in the EGFR and KRAS genes appear to be mutually exclusive. The present study reports a rare case of a patient harboring two EGFR mutations (L858R and T790M) and a KRAS mutation (G12V). The development of gefitinib resistance was detected in the subsequent treatment. The present study indicates that EGFR and KRAS mutational analysis should be recommended for all patients with non-small-cell lung carcinoma. PMID- 26622667 TI - Curcumin suppresses migration and invasion of human endometrial carcinoma cells. AB - Curcumin, a widely used Chinese herbal medicine, has historically been used in anti-cancer therapies. However, the anti-metastatic effect and molecular mechanism of curcumin in endometrial carcinoma (EC) are still poorly understood. The purpose of this study was to detect the anti-metastatic effects of curcumin and the associated mechanism(s) in EC. Based on assays carried out in EC cell lines, it was observed that curcumin inhibited EC cell migration and invasion in vitro. Furthermore, following treatment with curcumin for 24 h, there was a decrease in the expression levels of matrix metalloproteinase (MMP)-2 and -9 as well as proteinase activity in EC cells. Moreover, curcumin treatment significantly decreased the levels of the phosphorylated form of extracellular signal-regulated kinase (ERK) 1/2. MEK1 overexpression partially blocked the anti metastatic effects of curcumin. Combined treatment with ERK inhibitor U0126 and curcumin resulted in a synergistic reduction in MMP-2/-9 expression; the invasive capabilities of HEC-1B cells were also inhibited. In conclusion, curcumin inhibits tumor cell migration and invasion by reducing the expression and activity of MMP-2/9 via the suppression of the ERK signaling pathway, suggesting that curcumin is a potential therapeutic agent for EC. PMID- 26622668 TI - Clinicopathological features and prognostic implications of Raf kinase inhibitor protein downregulation in tongue squamous cell carcinoma. AB - Raf kinase inhibitor protein (RKIP) is recognized as a suppressor of metastasis, and the downregulation of RKIP is associated with aggressive events and a poor outcome in a variety of solid tumors. However, the clinical relevance of RKIP expression in tongue squamous cell carcinoma (TSCC) remains unclear. In the present study, the expression of RKIP in 85 pairs of TSCC and corresponding adjacent non-cancerous tissues, 30 matched metastatic lesions from the cervical lymph nodes and 32 oral leukoplakia samples were assessed using immunohistochemical methods. The association between RKIP expression and clinicopathological features was then evaluated. Kaplan-Meier survival analysis and Cox proportional hazards model were used to estimate the effect of RKIP expression on the survival time of patients with TSCC. The results revealed that RKIP expression was dramatically downregulated in TSCC, and to an even greater extent in metastatic lesions. RKIP downregulation was significantly associated with the presence of lymphatic metastasis and the clinical stage of TSCC. Furthermore, patients with low RKIP expression demonstrated a significantly shorter overall survival time. Multivariate analysis indicated that RKIP expression may be an independent prognostic factor in TSCC. In conclusion, the present findings indicate that the lack of RKIP expression is of clinical significance and may serve as a prognostic biomarker in TSCC. PMID- 26622669 TI - Expression analysis of apolipoprotein E and its associated genes in gastric cancer. AB - Gastric cancer is a common type of cancer worldwide, and has a poor prognosis, in part due to the low rates of early diagnosis and the limited treatment methods available. Apolipoprotein E (ApoE) is involved in exogenous cholesterol transport and may be important in enabling tumor cells to fulfill their high cholesterol requirements. A number of reports have indicated that ApoE affects the development and prognosis of gastric cancer. Therefore, the aim of the present study was to investigate the genes and transcription factors that interact with ApoE during the development of gastric cancer. Using gene expression profiling, the BioGRID database and the transcriptional regulatory element database, gene expression and regulatory networks in gastric cancer tissues and adjacent normal tissues were analyzed. The data demonstrated that eight genes associated with ApoE were differentially expressed, with six of these upregulated and two downregulated. Functionally, these genes were involved in the JAK-STAT cascade, acute-phase response, acute inflammatory response, and the steroid hormone response. Among these ApoE-associated genes, expression of the signal transducer and activator of transcription 2 (STAT2) and STAT3 transcription factors was upregulated. To the best of our knowledge, this is the first study to demonstrate the network of ApoE-related genes and transcription factors in gastric cancer. Additional studies are required in order to confirm these data and to translate the results into the identification of clinical biomarkers and novel treatment strategies for gastric cancer. PMID- 26622670 TI - Association of chemokine and chemokine receptor expression with the invasion and metastasis of lung carcinoma. AB - The chemokine system has been reported to be utilized and manipulated by tumor cells in order to promote local tumor growth and distant dissemination. The present study aimed to investigate the expression of three chemokine ligand receptor axes in lung carcinoma tissues. Tumor and healthy normal tissue samples were obtained from 120 lung carcinoma patients following surgical resection. Immunohistochemistry and reverse transcription quantitative polymerase chain reaction were used in order to identify the protein and messenger (m)RNA expression of chemokines, including chemokine (C-X-C motif) ligand (CXCL)12/stromal cell-derived factor (SDF)-1, CXCL8/interleukin (IL)-8, chemokine (C-C motif) ligand (CCL)19 and CCL21, and the corresponding chemokine receptors, chemokine (C-X-C motif) receptor (CXCR)4, CXCR1, CXCR2 and chemokine (C-C motif) receptor (CCR)7, respectively. The results revealed that compared with the normal lung tissues, lung carcinoma tissues expressed significantly higher mRNA levels of CXCL12/SDF-1, CXCR4, CXCL8/IL-8, CXCR2, CCL19 and CCR7 (P<0.01). In four histological subtypes, adenocarcinoma presented dominant expression of CXCR4, CXCR2, CXCL8/IL-8 and CCL19 (P<0.05). In addition, it was demonstrated that tumor staging was inversely correlated with chemokine receptor CCR7 and CXCR2 mRNA expression as well as positively correlated with CXCL12/SDF-1, CXCL8/IL-8 and CCL19 mRNA levels (P<0.05). Lymph node metastasis presented a positive correlation with CXCR4, CXCR2 and CXCL8/IL-8 expression and a negative correlation with CCL19 and CCR7 expression (P<0.05). Furthermore, vascular invasion was more prevalent in patients with higher expression levels of CXCR4, CCR7 or CCL19 (P<0.01). In conclusion, these data suggested that the ligand receptor interaction of CXCL8-CXCR2, CXCL12-CXCR4 and CCL19-CCR7 may be involved in the tumorigenesis of lung carcinoma. Higher expression levels of chemokines and lower expression of chemokine receptors indicated poor tumor staging. The CXC chemokine receptors, CXCR4 and CXCR2, promoted lymphatic metastasis through the activation of their specific ligands, while CCL19 and its receptor CCR7 had an essential role in hematogenous metastasis of lung carcinoma. PMID- 26622672 TI - Role of RNA-interference-induced zinc finger protein 139 suppression in gastric cancer cell sensitivity to chemotherapeutic agents. AB - Zinc finger proteins (ZNFs) are a class of proteins widely distributed in the human genome, which have been found to play a role in the regulation of gene transcription and the occurrence and development of gastric cancer (GC). ZNF139 was found to be associated with GC in our previous experiments. The present study aimed to analyse the differences in ZNF139 protein expression in SGC7901 GC cells and in situ grafted GC tumors in nude mice prior to and following RNA interference inhibition, and to investigate the mechanisms underlying ZNF139 involvement in the occurrence, development and chemosensitivity of GC. A ZNF139 targeted small interfering (si)RNA plasmid was constructed and transfected into the cancer cells and in situ grafted tumors. The MTT assay was used to investigate the alterations in chemosensitivity prior to and following transfection of siRNA-ZNF139. The two-dimensional difference gel electrophoresis and liquid chromatography-mass spectrometry techniques were used to identify the different protein points prior to and following siRNA-ZNF139 transfection. Western blot analysis was performed to confirm the identified proteins. In the siRNA-ZNF139 group, the growth of the cancer cells and in situ grafted tumors significantly decreased. However, the post-interference chemosensitivity to 5 fluorouracil, cisplatin and mitomycin C significantly increased. In the in vivo and in vitro experiments, the expression of pyridoxal kinase (PDXK) was upregulated, whereas the expression levels of annexin A2 (ANXA2) and fascin were downregulated following transfection. Western blot analysis confirmed the results for PDXK, ANXA2 and fascin by proteomics. Therefore, ZNF139 may participate in the occurrence, development and chemosensitivity of GC by promoting the expression of ANXA2 and fascin, while inhibiting the expression of PDXK. PMID- 26622671 TI - Anticancer potential of selected Fallopia Adans species. AB - The aim of the present study was to determine the anticancer potential of three species belonging to the Fallopia genus (Polygonaceae): Fallopia convolvulus (F. convolvulus, Fallopia dumetorum (F. dumetorum) and Fallopia aubertii (F. aubertii). For this purpose, crude extracts were obtained and characterized for their phenolic and flavonoid total content and examined for their anticancer activity on three tumor cell lines: breast cancer (MCF7), colon carcinoma (Caco 2) and cervical cancer (HeLa) cells. The cytotoxic potential of the three species was assessed by MTT assay, cell cycle analysis and by the evaluation of mitochondrial membrane potential (MMP). The acute toxicity of the extracts was evaluated using one in vitro cell model (Vero cells, an African Green monkey kidney cell line) and two invertebrate in vivo models (Daphnia magna and Artemia salina). The highest total phenolic and flavonoid content was found in the F. aubertii flower extracts. The cytotoxic effects of the extracts from F. aubertii and F. convolvulus on all three cell lines were examined at concentrations ranging from 3 to 300 ug/ml. G2/M cell cycle arrest was induced by all the extracts, and a significant increase in the subG1 cell population was observed. The hydroethanolic extract from the flowers of F. aubertii induced cell apoptosis more rapidly than the other extracts. The MMP indicates the involvement of the mitochondria in the induction of apoptosis. A positive correlation between the total phenolic content of the extracts and the IC50 values against the HeLa cells was also noted. None of the extracts exhibited significantly toxic effects. Considering the antitumor potential of F. aubertii and F. convolvulus, these two species may represent a good source of plant extracts with anticancer properties. PMID- 26622673 TI - Lambert-Eaton myasthenic syndrome in a patient with small-cell lung cancer: A case report. AB - Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular junction disorder characterized by fluctuating proximal limb muscle weakness, decreased deep tendon reflexes and various autonomic symptoms. LEMS is reportedly the most common neurological paraneoplastic syndrome. This is the case report of a patient with small-cell lung cancer (SCLC) who developed LEMS. A 68-year-old male patient presented with a 6-month history of progressive weakness of the proximal limbs and a 2-month history of xerostomia. The patient was admitted to the Department of Neurology of the People's Liberation Army General Hospital of Shenyang Military Region (Shenyang, China). The symptoms of the patient were not relieved with supportive therapy. Further laboratory tests, electrodiagnostic studies, chest computed tomography and immunohistochemical staining confirmed the diagnosis of LEMS in the presence of SCLC. Following administration of two cycles of rescue chemotherapy with a combination of etoposide and cisplatin, the symptoms of the patient were gradually relieved and, after six cycles of therapy, the primary malignancy completely regressed. In conclusion, a diagnosis of LEMS may lead to the timely detection of SCLC, significantly improving patient prognosis and survival. PMID- 26622674 TI - Metformin inhibits growth of lung adenocarcinoma cells by inducing apoptosis via the mitochondria-mediated pathway. AB - Metformin is commonly used to treat type II diabetes, although it may also reduce the risk of cancer and improve the associated prognosis. However, its mode of action in cancer remains unclear. The present study evaluated the effects of metformin on lung adenocarcinoma A549 cells and identified molecular mechanisms of metformin activity. The A549 cells were treated with metformin at different concentrations and cell viability was assayed by using an MTT assay. The cell cycle and the apoptosis rate were assayed by flow cytometry. Nude mice were transplanted with A549 cells and the tumor growth inhibition rate was detected. Once the A549 cells had been treated with 20 mM metformin for 48 h, the cell cycle was arrested in the G0/Gl phase and the apoptosis rate was 20.57+/-3.16%. The expression of the B-cell lymphoma (Bcl)-2 and Bcl-extra large proteins was downregulated following metformin treatment, while Bax protein expression was significantly increased. Tumor size in the high-dose metformin and cisplatin plus metformin groups was significantly smaller, and the inhibition rates were 41.3 and 72.9%, respectively, compared with the control group. These results indicated that metformin displays anticancer activity against lung adenocarcinoma by causing G1 arrest of the cell cycle and subsequent cell apoptosis through the mitochondria-dependent pathway in A549 cells. Furthermore, it was found that metformin dramatically inhibited lung adenocarcinoma tumor growth in vivo. These data suggest that metformin may become a potential cytotoxic drug in the prevention and treatment of lung adenocarcinoma. PMID- 26622675 TI - Pathogenic mechanisms of lung adenocarcinoma in smokers and non-smokers determined by gene expression interrogation. AB - Cigarette smoking is the leading risk factor for lung cancer, which accounts for the highest number of cancer-related mortalities worldwide in men and women. Individuals with a history of smoking are 15-30 times more likely to develop lung cancer compared with those who do not smoke. However, our understanding of the underlying molecular mechanisms that contribute to lung tumorigenesis in smokers versus non-smokers remains incomplete. In order to investigate such mechanisms, the present study aimed to systemically interrogate microarray datasets from tumor biopsies and matching normal tissues from stage I and II lung adenocarcinoma patients who had never smoked or were current smokers. The gene expression analysis identified 422 (99 upregulated and 323 downregulated) and 534 (174 upregulated and 360 downregulated) differentially-expressed genes from the never-smokers and current smokers, respectively, and the two groups shared 277 genes that exhibited similar trends of alteration. These genes encode regulators that are involved in a variety of cellular functions, including collagen metabolism and homeostasis of caveolae plasma membranes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes characterization indicated that biological pathways, including extracellular matrix-receptor interaction and cell migration and proliferation, were all affected in the lung cancer patients regardless of the smoking status. However, smoking induced a unique gene expression pattern characterized by upregulation of cell cycle regulators (CDK1, CCNB1 and CDC20), as well as significantly affected biological networks, including p53 signaling pathways. Taken together, these findings suggest novel mechanistic insights, and provide an improved understanding of the smoking-induced molecular alterations that contribute to the pathogenesis of lung adenocarcinoma. PMID- 26622676 TI - Clinical value of elasticity imaging and contrast-enhanced ultrasound in the diagnosis of papillary thyroid microcarcinoma. AB - The present study aimed to evaluate the value of elasticity imaging and contrast enhanced ultrasonography (CEUS) in the differential diagnosis of papillary thyroid microcarcinoma (TMC). In total, 73 patients exhibiting a total of 80 small thyroid nodules, which were difficult to diagnose using conventional ultrasonography, underwent elasticity imaging and CEUS. The diagnostic findings were subsequently clarified by intraoperative and pathological examination, and the accuracy of the 2 diagnostic methods was compared. The correct diagnostic rate of CEUS was 85% (68/80 nodules), of which 6 cases of TMC were misdiagnosed as benign lesions and 6 benign nodules were misdiagnosed as TMC. By contrast, the accuracy rate of the elasticity imaging, based on the 5-point diagnostic method, was 92.5% (74/80 nodules), of which 3 cases of TMC were misdiagnosed as benign nodules and 3 benign nodules were misdiagnosed as TMC. Furthermore, elasticity imaging in the diagnosis of TMC was determined to have sensitivity, specificity and accuracy rates of 94.0, 90.0 and 92.5%, respectively, whereas the corresponding rates for CEUS were 88.0, 80.0 and 85.0%, respectively. Thus, ultrasonographic elasticity imaging exhibited significant advantages in the diagnosis of TMC compared with CEUS (P<0.05). The use of CEUS demonstrates no evident advantage in the diagnosis of TMC; however, an elasticity score of >=3 is of high clinical value as a diagnostic criterion for TMC. PMID- 26622677 TI - Overexpression of short TRPM8 variant alpha promotes cell migration and invasion, and decreases starvation-induced apoptosis in prostate cancer LNCaP cells. AB - The aim of the present study was to investigate the function of a transient receptor potential melastatin 8 (TRPM8) splice variant, short TRMP8alpha (sM8alpha), in the androgen-dependent prostate cancer LNCaP cell line, and to evaluate the potential involvement of the mitogen-activated protein kinase (MAPK) signaling pathway. The coding DNA for sM8alpha was cloned and transfected into LNCaP cells to generate cells that overexpress this isoform of TRPM8. Cellular proliferation was determined by performing an MTT assay, and flow cytometry was used to analyze apoptosis and cell cycle distribution. Furthermore, cellular migration and invasion were evaluated using Transwell(r) migration assays. The subcellular location of recombinant sM8alpha was detected by quantum dots-based immunofluorescent imaging, western blotting was performed to examine the expression levels of proteins in the MAPK signaling pathway and reverse transcription-polymerase chain reaction was used to determine the expression of sM8alpha mRNA transcripts. The present study demonstrated that sM8alpha mRNA was expressed at a low level in the LNCaP, DU145 and PC-3 prostate cancer cell lines. Additionally, the recombinant sM8alpha protein was located in the cytoplasm of LNCaP cells and its overexpression significantly reduced starvation-induced apoptosis in these cells (P<0.05), possibly by means of reduced activation of phosphorylated-c-Jun N-terminal kinase (p-JNK). The migration and invasion of the LNCaP cells were markedly enhanced by the overexpression of sM8alpha, possibly via activation of MMP-2. Furthermore, overexpression of sM8alpha in LNCaP cells did not alter the expression of full-length TRPM8 and had no effect on cellular proliferation. Overall, the results of the present study indicate that sM8alpha may be important in the regulation of prostate cancer cell migration and invasion through the activation of matrix metalloproteinase-2, as well as in the regulation of apoptosis through the activation of p-JNK in the MAPK signaling pathway. PMID- 26622678 TI - Sarcomatoid carcinoma of the stomach: A case report and literature review. AB - Sarcomatoid carcinoma of the stomach is a rare type of malignant tumor, characterized by distinct cellular morphology. This type of tumor is even more rare in giant size. The present study reports a case of giant sarcomatoid carcinoma, which developed in the distal stomach. A 49-year-old male underwent medical investigation for gastrointestinal hemorrhage. Endoscopic examination, computed tomography (CT) and positron emission tomography-CT scan identified a giant neoplasm, which involved the gastric antrum and body, gallbladder and hepatic flexure of the colon. Surgery was performed to excise the tumor, which was ~14*13*8 cm in size. A diagnosis of sarcomatoid carcinoma was made since the tumor was positive for epithelial markers, even within the mesenchymal elements. To the best of our knowledge, only 5 cases of sarcomatoid carcinoma of the stomach have been previously reported, and a tumor that has been able to be resected despite such a large size has never been reported. PMID- 26622679 TI - Alternatively activated macrophages are associated with metastasis and poor prognosis in prostate adenocarcinoma. AB - Recent studies have revealed that alternatively activated macrophages (AAMs) are involved in tumor progression. However, the effect of AAMs on the metastasis of prostate cancer is poorly understood. In the present study, the prostate tissues of 42 patients with prostate adenocarcinoma (PCa) were used in the analysis of tumor associated macrophages (TAMs) and AAMs by immunofluorescence. The patients were followed up for 5 years. The associations of TAMs and AAMs with the clinicopathological features and outcome in these cases were evaluated. Immunofluorescent analysis indicated that the mean number of TAMs (CD68-positive cells) in the prostate tissues of PCa patients with metastasis [45.29+/-7.25 cells/high-power field (HPF)] was significantly higher compared with that of PCa patients without metastasis (33.57+/-5.25 cells/HPF; P<0.01). The mean numbers of AAMs (CD68- and CD206-positive cells) in the tissues of PCa patients with and without metastasis were 29.43+/-5.68 and 9.14+/-5.29 cells/HPF, respectively. In addition, the percentage of AAMs (number of AAMs/number of TAMs) was 65.11+/-9.68 and 27.32+/-7.85% in patients with and without metastasis, respectively. The differences in the number and percentage of AAMs between the two groups were statistically significant (P<0.01). The number and percentage of AAMs was positively correlated with tumor grade and serum prostate-specific antigen (PSA) level. Univariate analysis indicated that the level of PSA, Gleason score, metastatic status, T grade, number of TAMs, number of AAMs and percentage of AAMs were predictors of the overall survival. Furthermore, multivariate analyses revealed that Gleason score, level of PSA and number of TAMs were predictors for overall survival rate. These results indicate that TAMs and AAMs may be important in the metastasis of PCa, and that TAMs and AAMs may be used as potential biomarkers of poor prognosis in late-stage PCa patients. PMID- 26622680 TI - Fibroadenoma with an unexpected lobular carcinoma in situ: A case report and review of the literature. AB - Fibroadenoma (FA) is the most common type of breast lesion in young female individuals. Although malignant transformation in FA is rare, there is evidence of an association with breast carcinoma, particularly in middle-aged females with associated risk factors, such as a strong family history and/or BRCA-1/2 mutations. The current study presents the case of a 44-year-old female exhibiting lobular carcinoma in situ (LCIS) arising within an FA. Over the previous 20 years, numerous lumps were detected in the patient's breasts, all of which were clinically diagnosed as FA and expectantly managed. One year prior to presentation, the patient's father was diagnosed with esophageal cancer, older sister with kidney cancer and the patient herself with a benign ovarian teratoma. The patient presented with one lump in each breast and monitoring was performed using ultrasonography (US). US detected an increase in the size of the two lumps and analysis of the images was used to propose a diagnosis of FA. Therefore, a lumpectomy was performed. Analysis of the frozen section indicated a diagnosis of FA in the right breast, however, a 5-mm LCIS was identified within the FA of the left breast. Subsequent to the identification of three additional lumps in the left breast, a left mastectomy was performed. During a five-year follow-up period, no local recurrence or contralateral breast carcinoma occurred. The present study showed that FAs containing foci of carcinoma in situ can be indistinguishable from benign lesions following imaging, therefore, despite the incidence of carcinoma within FA is estimated at 0.1-0.3%, it should be considered a long-term risk factor for invasive breast cancer. The present describes a case of LCIS arising within an FA and conducts a review of the relevant literature. PMID- 26622681 TI - Genomic profiling screens small molecules of metastatic prostate carcinoma. AB - The aim of the present study was to investigate the pathogenesis of metastatic prostate carcinoma, to find the metabolic pathways changed in the disease and to screen out the potential therapeutic drugs. GSE38241 was downloaded from Gene Expression Omnibus; the Geoquery package was applied to preprocessed expression profiling, and the differentially-expressed genes (DEGs) were selected with limma (linear regression model packages). Next, WikiPathways cluster analysis was performed for DEGs on a Gene Set Analysis Toolkit V2 platform, and DEGs with hypergeometric algorithms were calculated through gene set enrichment analysis. A total of 1,126 DEGs were identified between the normal prostate and metastatic prostate carcinoma. In addition, KPNA4, SYT1, PLCB1, SPRED1, MBNL2, RNF165, MEF2C, MBNL1, ZFP36L1 and CELF2, were found to be likely to play significant roles in the process of metastatic prostate carcinoma. The small molecules STOCK1N-35874 and 5182598 could simulate the state of normal cells well, while the small molecules MS-275 and quinostatin could simulate the state of metastatic prostate carcinoma cells. In conclusions, the small molecules STOCK1N-35874 and 5182598 were identified to be good potential therapeutic drugs for the treatment of metastatic prostate carcinoma, while the two small molecules MS-275 and quinostatin could cause metastatic prostate carcinoma. PMID- 26622682 TI - Clinical implications of PTEN and VEGF expression status, as well as microvessel density in esophageal squamous cell carcinoma. AB - There are limitations to the use of single biomarker levels, for example phosphate and tensin homology (PTEN) or vascular endothelial growth factor (VEGF), in the diagnosis of esophageal squamous cell carcinoma (ESCC). The present study therefore aimed to evaluate the clinical implications of combined detection of multiple biomarkers. The associations between PTEN and VEGF expression status, microvessel density (MVD), and the pathological characteristics of 50 patients with ESCC were determined using chi2, analysis of variance, and t-tests. The results indicated that the PTEN-positive rate was negatively correlated with ESCC histological grade (P<0.01), depth of ESCC invasion (P<0.01) and lymph node metastasis status. Furthermore, the VEGF positive rate was correlated with lymph node metastasis status, while MVD was correlated with the depth of ESCC invasion (P<0.01) and lymph node metastasis status (P<0.05). The PTEN-positive rate was negatively correlated with the VEGF positive rate. A higher MVD was identified in ESCC samples than that of the normal esophageal mucosa, particularly in VEGF-positive ESCC specimens compared with those of VEGF-negative specimens, and PTEN-negative ESCC specimens compared with that of the PTEN-positive ESCC specimens. These results suggested that combined detection of PTEN and VEGF levels, as well as evaluation of MVD in patients with ESCC may provide essential information for improvements in the diagnosis and prognosis of ESCC. PMID- 26622683 TI - Guggulsterone inhibits human cholangiocarcinoma Sk-ChA-1 and Mz-ChA-1 cell growth by inducing caspase-dependent apoptosis and downregulation of survivin and Bcl-2 expression. AB - Guggulsterone has recently been reported to demonstrate anti-tumor effects in a variety of cancers. The present study aims to investigate the biological roles and underlying mechanism of the action of guggulsterone in cholangiocarcinoma. The immortalized human cholangiocarcinoma Sk-ChA-1 and Mz-ChA-1 cell lines were treated with various concentrations of the trans isomer of guggulsterone, Z guggulsterone. Cellular proliferation was determined using the XTT assay. The apoptotic status of cholangiocarcinoma cells was assessed by Hoechst 33258 staining, DNA fragmentation assay and flow cytometry. Specific caspase inhibitor was used to explore the role of caspase in guggulsterone-induced apoptosis. A colorimetric assay was performed to measure the alterations of the activities of caspase-3, -8 and -9. Western blot analysis was used to detect the protein expression of survivin, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein and cleaved poly (adenosine diphosphate-ribose) polymerase (PARP). As revealed by the present data, guggulsterone significantly inhibited the growth of the two human cholangiocarcinoma cell lines by inducing cellular apoptosis. In addition, guggulsterone-induced apoptosis of cholangiocarcinoma cells was demonstrated to be partially inhibited by the caspase inhibitors z-VAD-fmk, z-LEHD-fmk and z-IETD fmk, accompanied by the activation of caspases-3, -8 and -9, accumulation of cleaved PARP and decreased expression of survivin and Bcl-2. In conclusion, the present study demonstrated that guggulsterone was able to suppress the proliferation of cholangiocarcinoma by inducing caspase-dependent apoptosis and downregulating survivin and Bcl-2. PMID- 26622684 TI - Mutation of the PIK3CA gene as a prognostic factor in patients with colorectal cancer. AB - Colorectal cancer (CRC) is one of the most common cancers worldwide, with ~700,000 mortalities occurring due to CRC in 2012. The treatment options are effective in a small percentage of patients, and it is important to identify specific biomarkers in order to determine patients for whom the available therapies will be beneficial. It has been hypothesised that the PIK3CA gene mutation may affect the response to therapy of patients with metastatic CRC. In the present study, primary tumour specimens were collected from 156 patients with CRC who were treated in the Military Institute of Medicine in Warsaw (Warsaw, Poland). Codons 12 and 13 of exon 1 of KRAS, exons 11 and 15 of BRAF and exons 9 and 20 of PIK3CA were analysed for mutation using direct sequencing. The prognostic value of each mutation and the clinical and pathological variables of these tumours were estimated. The results revealed that PIK3CA mutations were present in 15 patients (9.6%), of whom seven (46.7%) possessed mutations in codon 9 and eight (53.3%) possessed mutations in codon 20. Mutation in the PIK3CA gene was detected in six patients with KRAS gene mutations, which accounted for 40% of PIK3CA-mutated tumours, and in one patient with BRAF mutations, which accounted for 6.6% of PIK3CA-mutated tumours. No significant differences were identified between the overall survival (OS) rates of patients with PIK3CA mutations (median OS, 56.7 months) and those with wild-type PIK3CA genes (median OS, 47.6 months) (P=0.1270). Univariate analysis identified that the following prognostic factors affected the OS rate in the current patient cohort: Gender, female patients survived for 57.5 months compared with 39.3 months for male patients (P=0.0111); and lymph node involvement grade, as survival of patients without lymph node metastases was 61.4 months compared with 45.4 months in patients presenting with metastases (P=0.0122). The findings of the present analysis indicate that PIK3CA mutation status is not a prognostic factor in CRC patients. In addition, no statistically significant association exists between tumours with PIK3CA mutations and clinical or pathological factors. PMID- 26622685 TI - Characterization of the role of the photosensitizer, deuteporfin, in the detection of lymphatic metastases in a pancreatic cancer xenograft model. AB - Currently, the use of photosensitizers as tracer agents to detect lymphatic metastases is a developing area of study in the field of pancreatic cancer treatment. In the present study, deuteporfin, a novel photosensitizer, was used as a tracer agent to detect lymphatic metastases in a pancreatic cancer xenograft model. The biodistribution and pharmacokinetics of deuteporfin, following intravenous administration and injection of deuteporfin into the left rear footpad, were investigated in Sprague-Dawley rats. The increased difference in deuteporfin concentration between the cancerous and normal tissues was directly observed through the application of a Wood's lamp. In addition, the highly lymphatic BxPC-3-LN5 human metastatic pancreatic cancer cell line was generated from BxPC-3 cells using a continuous screening and seeding method in vivo. A xenograft model of the BxPC-3-LN5 human pancreatic cancer cell line transplanted into the left rear footpad of nude mice, was established. The effects of deuteporfin as a tracer agent in the detection of lymphatic metastases were then characterized in the pancreatic cancer xenograft model. Following intravenous administration, deuteporfin was rapidly enriched in the pancreas and popliteal fossa lymph nodes compared with that of the left rear footpad administration group. In addition, deuteporfin appeared to be selectively enriched in the cancerous pancreatic lymph nodes of the pancreatic cancer xenograft model. These results indicated that deuteporfin may be developed as a novel photosensitizer tracer agent for the detection of lymphatic metastases in pancreatic cancer. The advantages of deuteporfin are that it has a selective tumor-targeting effect due to high tissue uptake, and that it may be administered intravenously and is therefore suitable for surgery. PMID- 26622686 TI - Significance of MUC1 expression in biopsy specimens of submucosal invasive gastric carcinoma: The association with lymph node metastasis. AB - Mucin 1, cell surface associated (MUC1) is a tumor-associated glycoprotein that has been reported to have an important role in lymphatic invasion and metastasis. The present study aimed to investigate the significance of MUC1 expression in endoscopic biopsy specimens of submucosal invasive gastric carcinomas and the association with lymph node metastasis. The clinicopathological features of 144 cases of surgically resected submucosal invasive gastric carcinomas and their paired endoscopic biopsy specimens were reviewed. Immunohistochemical staining for MUC1 was performed for the 144 endoscopic biopsy specimens. Positive MUC1 expression was identified in 70 (49%) cases. In addition, univariate analysis revealed that MUC1 expression was significantly associated with the presence of poorly-differentiated (P=0.001) and poorly-cohesive (P=0.015) carcinoma cells, undifferentiated type by Japanese classification (P<0.001), diffuse type of Lauren classification (P<0.001) and lymph node metastasis (P=0.024). By multivariate analysis, diffuse type of Lauren classification (P<0.001) and lymph node metastasis (P=0.035) were identified as independent factors for MUC1 expression. Furthermore, MUC1 expression (P=0.007), tumor size (P=0.018) and lymphatic invasion (P<0.001) were demonstrated to be independent factors for lymph node metastasis under multivariate analysis. In conclusion, the results of the present study indicated that positive MUC1 expression in endoscopic biopsy specimens may be a predictive factor of lymph node metastasis in submucosal invasive gastric carcinoma. PMID- 26622687 TI - Undiagnosed giant cystic pheochromocytoma: A case report. AB - Giant cystic pheochromocytomas (GPCCs) are rare adrenal tumors and the majority of them present as asymptomatic. As a result GPCCs often remain undiagnosed until surgery and therefore the surgical team face a greater challenge in perioperative management. The present study describes the case of a 36 year-old woman with an undiagnosed GPCC, which was successfully resected despite the occurrence of perioperative cardiovascular events, including hypertension, hypotension, ventricular arrhythmias, acute heart failure, acute myocardial infarction, and the patient was discharged home without any recurrence. It should be considered in retroperitoneal tumour of patients with nonspecific symptoms and given adequate treatment to promote the perioperative safety. PMID- 26622688 TI - MicroRNA-577 inhibits gastric cancer growth by targeting E2F transcription factor 3. AB - The incidence and mortality rates of gastric cancer are one of the highest of all types of cancers. Emerging evidence has demonstrated that altered expression of micro (mi)RNAs may be implicated in the tumorigenesis of numerous types of cancer. Therefore, miRNAs may have potential as important tools in cancer diagnostics and therapeutics. miRNAs regulate the expression of genes involved in mediating cell proliferation and developmental timing, among numerous other processes. Altered expression levels of miRNAs may result in the ability of cells to proliferate aberrantly and migrate. The present study used reverse transcription-quantitative polymerase chain reaction assays to analyze miRNA-577 expression in gastric cancer tissues and cell lines, MTT and cell cycle analysis to examine cell proliferation in vitro, and luciferase assays and western blot to investigate miRNA-577's downstream targets. The results demonstrated that miRNA 577 was significantly downregulated in gastric cancer patient samples and cell lines. In addition, miRNA-577 affected an important regulator of E2F transcription factor 3 expression and that altered miRNA-577 expression resulted in the aberrant proliferation of gastric cancer cells. PMID- 26622689 TI - Acute airway obstruction due to benign asymptomatic nodular goiter in the cervical region: A case report. AB - Benign nodular goiter is a common disease. Although large goiters with obstructive symptoms including shortness of breath and dyspnea are a clear indication for surgery, acute upper airway obstruction, particularly in benign cervical goiter cases, is rare. We herein report the case of 46-year-old female with acute upper airway obstruction due to benign nodular goiter. The patient had a large and elastic goiter which was more pronounced on the left side of her neck, and surgery was scheduled for within a few months. Three months after the initial presentation, while still waiting for surgery, the patient was brought to the emergency room due to loss of consciousness and breathing difficulty and was immediately intubated. A computed tomography (CT) scan revealed that the trachea was markedly compressed by a nodular lesion in the left lobe, and bilateral pneumonia was also evident. Total thyroidectomy was immediately performed via the supraclavicular approach. The patient had an uneventful postoperative course and recovered well. The resected specimen included a well-encapsulated solid and cystic mass. Histopathological examination mainly revealed adenomatous goiter. The present case suggests that benign asymptomatic nodular goiter mostly located in the neck may cause acute airway obstruction, even if the nodules are not large. Early surgery should be performed when tracheal deviation and stenosis due to a large goiter is prominent by CT scan. PMID- 26622690 TI - Survivin expression in lung cancer: Association with smoking, histological types and pathological stages. AB - Survivin is expressed in the nucleus and/or cytoplasm of various malignant cells. Nuclear survivin is critical for the completion of mitosis, while cytoplasmic survivin functions as an inhibitor of apoptosis. The expression of survivin has been reported to be associated with the aggressiveness of certain types of cancer. The present study examined the association between cigarette smoking history and the expression of survivin and Ki-67 in lung adenocarcinomas of pathological (p) stages I, II and III. The expression of survivin and Ki-67 in adenocarcinomas was also compared with that of other p-stage I lung cancers, including squamous cell carcinoma (SqCC), large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SmCCs), of patients with a smoking history. In adenocarcinomas at p-stage I, labeling indices (LIs) of nuclear survivin and Ki 67 were significantly higher in tissue samples from smokers than those from non smokers; however, the nuclear survivin and Ki-67 LIs in p-stage II and III adenocarcinomas from non-smokers and smokers were similar to those in p-stage I adenocarcinomas of smokers. The nuclear survivin and Ki-67 LIs in adenocarcinomas of smokers at p-stage I were lower than those in SqCCs, LCNECs and SmCCs of smokers at the same stage. Smokers with adenocarcinoma also exhibited a higher survival rate compared with that of smokers with SqCCs, LCNECs and SmCCs. The present results indicated that a history of smoking is associated with increased nuclear survivin and Ki-67 expression in lung adenocarcinomas of p-stage I, but not p-stages II or III. In addition it was revealed that, in smokers, the nuclear survivin and Ki-67 expression in p-stage I adenocarcinomas was lower than that of other p-stage I lung cancer types, and was associated with an enhanced survival rate. In conclusion, smoking is associated with the histogenesis of lung adenocarcinoma but not with the development of lung adenocarcinoma, based on the nuclear expression levels of Ki-67 and survivin. PMID- 26622691 TI - Anticancer effects of fucoxanthin and fucoxanthinol on colorectal cancer cell lines and colorectal cancer tissues. AB - Colorectal cancer is one of the most malignant neoplasms worldwide. Fucoxanthin is a carotenoid present in the chloroplasts of brown seaweeds. In the present study, the anticancer effects of fucoxanthin and its metabolite, fucoxanthinol, on 6 colorectal cancer cell lines and 20 tissue samples from surgically resected clinical colorectal cancer specimens were examined using a collagen-gel droplet embedded culture drug sensitivity test (CD-DST). The in vitro sensitivity to fucoxanthin, fucoxanthinol and the anticancer drugs is expressed as T/C (%), where T is the absorbance of cells which stained by neutral red treated with carotenoids and C is the absorbance of non-staining cells. Fucoxanthin and fucoxanthinol decreased the T/C (%) of Caco-2, WiDr, HCT116, and DLD-1 cell lines at doses of 20 uM. Fucoxanthinol also decreased the T/C (%) of SW620 cells, while the T/C (%) of Colo205 cells was not reduced by treatment with either carotenoid. Specifically, the T/C (%) of Caco-2 and WiDr cells, which were incubated in carotenoid-free medium for 6 days following treatment with 20 uM fucoxanthinol for 24 h, was markedly decreased to 1.4+/-0.2 and 12.0+/-0.3%, respectively. Furthermore, fucoxanthin and fucoxanthinol decreased the T/C (%) in colorectal cancer tissue samples. Notably, 20 uM fucoxanthinol treatment resulted in a higher proportion of colorectal cancer samples with a T/C (%) of <50% (13/20, 65%) compared with samples treated with 20 uM fucoxanthin (2/20, 10%). The median T/C (%) value of 35.1% for the 20 cancers specimens treated with 20 uM fucoxanthinol was lower than the median T/C (%) values of 86.3% and 75.8% for those treated with fluorouracil and paclitaxel, respectively. These results suggested that fucoxanthin and fucoxanthinol may be of use as chemotherapeutic agents in colorectal cancer. PMID- 26622692 TI - SU11274 suppresses proliferation and motility of pancreatic cancer cells. AB - Mesenchymal-epithelial transition factor (c-Met) is associated with the proliferation and motility of cancer cells. c-Met expression has been detected in surgical pancreatic cancer specimens, and its overexpression is associated with a poor prognosis. SU11274 is a specific inhibitor of c-Met. In the present study, the cell proliferation and motility of pancreatic cancer cells treated with SU11274 was investigated. The PANC-1, MIA-Paca2, NOR-P1, PK-45H, PK-1 and PK-59 pancreatic cancer cell lines were used. The expression of c-Met and cyclin D1 was analyzed by quantitative polymerase chain reaction. In addition, a 3-(4,5 dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt assay was performed to assess cell proliferation, and a scratch assay was performed to assess cell motility. c-Met expression was higher in PANC-1, PK 45H, PK-1 and PK-59 cell lines compared with that in normal pancreatic tissue. Following treatment with 30 uM SU11274, the proliferation of MIA-Paca2 and PK-45H cells was suppressed to 19.8+/-10.7% (P<0.05) and 45.8+/-14.8% (P<0.05) of the control level, respectively. Furthermore, cyclin D1 expression was downregulated to 43.7+/-17.9% (P<0.05) and 53.2+/-18.6% (P<0.05) of the control level in the MIA-Paca2 and PK-45H cell lines, respectively, following treatment with 30 uM SU11274. In addition, cell motility was reduced to 1.0+/-0.3% in MIA-Paca2 (P<0.05) and 14.7+/-3.5% in PK-45H (P<0.05) following treatment with 30 uM SU11274, compared with the motility of untreated cells. These results indicated that SU11274 suppresses the proliferation of pancreatic cancer cells via the downregulation of cyclin D1. The present study also demonstrated that cell motility was suppressed by treatment with SU11274. PMID- 26622693 TI - Radiosensitivity in HeLa cervical cancer cells overexpressing glutathione S transferase pi 1. AB - The aims of the present study were to investigate the effect of overexpressed exogenous glutathione S-transferase pi 1 (GSTP1) gene on the radiosensitivity of the HeLa human cervical cancer cell line and conduct a preliminarily investigation into the underlying mechanisms of the effect. The full-length sequence of human GSTP1 was obtained by performing a polymerase chain reaction (PCR) using primers based on the GenBank sequence of GSTP1. Subsequently, the gene was cloned into a recombinant eukaryotic expression plasmid, and the resulting construct was confirmed by restriction analysis and DNA sequencing. A HeLa cell line that was stably expressing high levels of GSTP1 was obtained through stable transfection of the constructed plasmids using lipofectamine and screening for G418 resistance, as demonstrated by reverse transcription-PCR. Using the transfected HeLa cells, a colony formation assay was conducted to detect the influence of GSTP1 overexpression on the cell radiosensitivity. Furthermore, flow cytometry was used to investigate the effect of GSTP1 overexpression on cell cycle progression, with the protein expression levels of the cell cycle regulating factor cyclin B1 detected using western blot analysis. Colony formation and G2/M phase arrest in the GSTP1-expressing cells were significantly increased compared with the control group (P<0.01). In addition, the expression of cyclin B1 was significantly reduced in the GSTP1-expressing cells. These results demonstrated that increased expression of GSTP1 inhibits radiosensitivity in HeLa cells. The mechanism underlying this effect may be associated with the ability of the GSTP1 protein to reduce cyclin B1 expression, resulting in significant G2/M phase arrest. PMID- 26622694 TI - Analysis of p16 gene mutations and their expression using exhaled breath condensate in non-small-cell lung cancer. AB - The aim of the present study was to investigate the mutational status of exons 1 and 2 of the p16 gene in the exhaled breath condensate (EBC) of patients with non small-cell lung cancer (NSCLC) and determine the feasibility and clinical significance of applying EBC in the diagnosis of NSCLC. Polymerase chain reaction and DNA sequencing were applied to detect exon 1 and 2 alterations of the p16 gene in EBC by comparing 58 samples from NSCLC patients and 30 from healthy controls. Of the 58 EBC samples from NSCLC patients, 54 were successfully tested and 8 cases of mutations were identified, of which 3 were in exon 1 and 5 in exon 2. The mutation rate was 14.81% (8/54). There were no p16 gene mutations in the 30 samples obtained from healthy controls. EBC p16 gene mutations exhibited no statistically significant differences according to gender, smoking history, pathological type, degree of differentiation and presence or absence of lymph node metastasis. The p16 gene mutation rate was proportional to the tumor stage (P<0.05). Therefore, the detection of the p16 gene mutation in EBC may be used as a novel molecular marker to assist in the diagnosis of NSCLC. PMID- 26622695 TI - Role of five small nucleotide polymorphisms in the VEGF gene on the susceptibility to osteosarcoma and overall survival of patients. AB - The present study aimed to investigate the association between five common small nucleotide polymorphisms (SNPs) in the VEGF gene and the risk of osteosarcoma. An additional aim was to investigate the role of these five SNPs on the prognosis of osteosarcoma. A total of 186 patients with osteosarcoma and 186 age- and sex matched healthy controls were enrolled into the present study. A polymerase chain reaction-restriction fragment length polymorphism assay was conducted to determine the incidence of the VEGF-2578 C/A, -1156 G/A, +1612 G/A, +936 C/T and 634 G/C polymorphisms. Conditional logistic regression analyses revealed that individuals carrying the -634 GG genotype possessed a significantly increased risk of osteosarcoma, with an adjusted odds ratio [(95% confidence interval (CI)] of 2.00 (1.07-3.75). In the Cox proportional hazards model, subsequent to adjusting for potential confounding factors, patients with osteosarcoma carrying the -634 GG genotype were found to demonstrate a shorter overall survival time (hazard ratio, 3.10; 95% CI, 1.17-8.38). The VEGF-634 G/C polymorphism may therefore be used as a genetic marker for the prediction of the risk and clinical outcome of osteosarcoma. PMID- 26622696 TI - Forkhead box J1 expression is upregulated and correlated with prognosis in patients with clear cell renal cell carcinoma. AB - The forkhead box (FOX) family of transcription factors are considered to have a role in tumorigenesis. FOXJ1 is a member of the FOX family; however, its function in human renal cell carcinoma (RCC) has remained to be elucidated. Therefore, the present study evaluated the expression of FOXJ1 in human clear cell RCC and the effect of FOXJ1 on the proliferative ability of RCC cells. The RCC specimens analyzed in the present study were obtained from 286 patients with RCC who underwent nephrectomy. FOXJ1 mRNA expression levels were determined using reverse transcription-quantitative polymerase chain reaction, and FOXJ1 protein expression levels were determined using immunohistochemistry and western blot analysis. To determine the effect of FOXJ1 on the proliferative ability of RCC cells, the expression of FOXJ1 was decreased using small interfering (si)RNA, and a FOXJ1 vector was stably transfected into RCC cell lines. The proliferative ability of RCC cells was then examined using a WST-1 assay and xenograft experiments with BALB/c nude mice, where the association between FOXJ1 expression and patient survival was determined using Kaplan-Meier analysis. FOXJ1 expression was significantly higher in RCC tissues compared with that of healthy renal tissues. Furthermore, FOXJ1 expression was associated with tumor stage, histologic grade and size. In addition, FOXJ1 significantly enhanced the proliferation of RCC cells in vitro and in vivo. The present study identified that FOXJ1 expression was upregulated in RCC and enhanced the proliferative ability of RCC cells. Therefore, FOXJ1 may serve as an independent prognostic marker and a therapeutic target for the treatment of patients with RCC. PMID- 26622697 TI - RNA interference for epidermal growth factor receptor enhances the radiosensitivity of esophageal squamous cell carcinoma cell line Eca109. AB - The present study investigated the effects of small interfering RNAs (siRNAs) specific to the epidermal growth factor receptor (EGFR) gene, on the radiosensitivity of esophageal squamous cell carcinoma cells. EGFR gene siRNAs (EGFR-siRNA) were introduced into esophageal cancer Eca109 cells using Lipofectamine(r) 2000. The EGFR messenger (m)RNA expression levels, EGFR protein expression and cell growth were assessed using reverse transcription-polymerase chain reaction analysis, western blot analysis and a Cell Counting Kit-8 (CCK-8), respectively. In addition, colony assays were used to determine the inhibitory effects of X-ray radiation on EGFR-silenced cells. EGFR mRNA and protein levels were reduced in the Eca109 cells transfected with EGFR-siRNA. The relative EGFR mRNA expression levels were reduced to 26.74, 9.52 and 4.61% in Eca109 cells transfected with EGFR-siRNA1, 2 and 3, respectively. These mRNA levels were significantly reduced compared with the those of the control group (42.44%; P<0.0001). Transfection with siRNA3 resulted in the greatest reduction in EGFR mRNA expression, with an inhibition rate of 85%. The relative EGFR protein expression levels were reduced to 24.05, 34.91 and 34.14% in Eca109 cells transfected with EGFR-siRNA1, 2 and 3, respectively. These protein levels were significantly reduced compared with those of the control group (78.57%; P<0.0001). Transfection with siRNA1 resulted in the greatest reduction in EGFR protein expression, with an inhibition rate of 72.84%. This reduction in EGFR expression inhibited the proliferation of Eca109 cells, which was identified using the CCK-8 assay. The proliferation inhibition ratio was 28.2%. The cells treated with irradiation in addition to EGFR-siRNA, demonstrated reduced radiobiological parameters (D0, Dq and SF2) compared with those of cells treated with irradiation only, with a sensitization enhancing ratio of 1.5. In conclusion, suppression of EGFR expression may enhance the radiosensitivity of esophageal cancer Eca109 cells and therefore may represent a promising approach for future clinical practice. PMID- 26622698 TI - PAX6 overexpression is associated with the poor prognosis of invasive ductal breast cancer. AB - Paired box 6 (PAX6) plays a significant role in the development of human neuroectodermal epithelial tissues. Previous studies have suggested that the PAX6 promoter is hypermethylated in breast cancer and that it is involved in breast cancer cell proliferation. The present study aimed to investigate the expression of PAX6 in invasive breast cancer tissues, and to evaluate its prognostic significance. Immunohistochemistry (IHC) was used to detect PAX6 expression on a breast cancer tissue microarray containing tissues from 111 patients. Associations of PAX6 expression with staging and prognosis were analyzed. PAX6 was mainly expressed in the nucleus. The PAX6 staining intensity was not associated with age, histological grade, lymph node status, tumor size, or progesterone receptor and human epidermal growth factor receptor 2 expression (all P>0.05). A high level of PAX6 staining was more frequent in estrogen receptor (ER)-negative cases compared with ER-positive cases (43.9 vs. 25.7%; P=0.049). After a median follow-up time of 110 months, the patients with low PAX6 expression exhibited an improved survival rate compared with the patients with high PAX6 expression (P<0.001). Cox analysis showed a worse survival rate in the patients with high PAX6 staining (hazard ratio, 3.458; 95% confidence interval, 1.575-7.593; P=0.002). In conclusion, high tumor PAX6 staining intensity by IHC was associated with a poor prognosis in breast cancer patients. PMID- 26622699 TI - Expression and clinical significance of tyrosine phosphatase SHP2 in thyroid carcinoma. AB - Protein-tyrosine phosphatase SHP2 is encoded by the gene PTPN11. SHP2 is hypothesized to have a critical role in cancer, via the activation of mutations that have been detected in several types of leukaemia and in certain solid tumours, including liver, breast, gastric and cervical cancer. However, to the best of our knowledge, there have been no previous reports evaluating the significance of SHP2 expression in thyroid cancer. The present study evaluated SHP2 expression in 65 thyroid cancer specimens, 40 specimens of self-matched adjacent peritumour tissues and 40 specimens of normal thyroid tissue, using immunohistochemical and western blot analyses with an anti-SHP2 antibody. Western blotting was also used to assess SHP2 expression in thyroid cancer cell lines (SW579, IHH-4, FTC-133, TPC-1, DRO, TA-K, and ML-1) and Nthy-ori3-1 normal thyroid cells. In addition, SHP2 antisense oligonucleotides were used to block SHP2 expression in SW579 cells, and growth inhibition assays were conducted. Increased SHP2 expression was detected in the tumour tissues compared with that of the normal thyroid tissues (P<0.05). SHP2 expression was significantly correlated with poor tumour differentiation (P<0.05), late TNM stage (P<0.05) and lymph node metastasis (P<0.05), suggesting that SHP2 may represent a potential target for thyroid cancer therapy. PMID- 26622700 TI - Bilateral breast cancer with a unilateral carcinoma within a fibroadenoma: A case report. AB - Fibroadenomas are a type of benign tumor that occur in young women below the age of 35 years old. The tumors are the second most common type of tumor after fibrocystic disease. The chance of carcinoma arising in a fibroadenoma is extremely low. To date, <130 such cases have been reported. Previous studies have reported that fibroadenomas can evolve into a number of different types of malignancy. The present study is the first to describe a case of bilateral primary breast cancer with a unilateral invasive ductal carcinoma within a fibroadenoma. The current study presents a case of a 48-year-old female who presented with 2 stiff lumps on bilateral breasts, diagnosed as bilateral breast carcinoma, with a unilateral invasive ductal carcinoma within a fibroadenoma in the right breast. The patient underwent a bilateral mastectomy and subsequently received 4 cycles of chemotherapy (epirubicin, 60 mg/m2 and cyclophosphamide, 600 mg/m2) every 21 days, followed by 4 cycles of docetaxel chemotherapy (100 mg/m2) every 21 days. The patient then received maintenance endocrine therapy (tamoxifen, 20 mg, twice daily) for 19 months. The patient was followed up every 3 months, and at the last follow-up examination in May 2015, the patient exhibited no signs of recurrence. PMID- 26622701 TI - Ectopic expression of p33ING1b suppresses proliferation and induces apoptosis in colonic adenocarcinoma cells. AB - Inhibitor of growth 1b (ING1b) is considered to be a class II tumor suppressor gene. Although decreased expression of p33ING1b has previously been reported in colorectal cancer (CRC), its role in CRC has remained to be elucidated. The present study was designed to assess the function of p33ING1b in CRC and to further evaluate its underlying mechanisms of action. Western blot analysis confirmed that ING1b gene expression was significantly decreased in CRC tissues compared with that of adjacent non-tumorous colorectal tissues. Furthermore, recombinant adenovirus-mediated ectopic expression of p33ING1b resulted in growth inhibition, G1-phase cell cycle arrest and apoptosis in the SW480, HT29 and LoVo colorectal adenocarcinoma cell lines. The results suggested that the downregulation of ING1b contributes to colorectal carcinogenesis and that ectopic expression of ING1b may be a potentially useful therapeutic approach for CRC. PMID- 26622702 TI - Interleukin-12 in patients with cancer is synthesized by peripheral helper T lymphocytes. AB - The production of cytokines by helper T lymphocytes is a critical event in the immune response, as alterations in the regulation of this process may result in an appropriate immune response, persistent infection or the development of autoimmune disease. Previously, this group has used flow cytometry to demonstrate the expression of interleukin-12 (IL-12) in peripheral blood CD4+ T lymphocytes from patients and mice with advanced cancer. The aim of the present study was to investigate whether CD4+ T lymphocytes from the peripheral blood (PB) of patients with cancer produce IL-12, using molecular approaches, flow cytometry and cellular imaging techniques. CD3+ and CD4+ cells, and cells producing IL-12, were isolated from the PB obtained from patients with cancer, using a cell sorting flow cytometry technique. The positivity of cells for CD3, CD4 and IL-12, which were identified by cell sorting, was visualized using immunofluorescent cellular imaging. Total RNA was extracted from the CD3+CD4+IL-12+ cells, obtained by cell sorting, for confirmation of the presence of IL-12 mRNA, using reverse transcription-polymerase chain reaction (RT-PCR). RT-PCR demonstrated the presence of IL-12 mRNA in all patients (n=14), in contrast to the control group, in whom IL-12 expression was not detected. Immunofluorescent analysis of CD4+ T lymphocytes showed positive intracytoplasmatic IL-12 staining. These results demonstrated that CD3+CD4+ T lymphocytes in the PB of patients with cancer have the capacity to synthesize and express IL-12. PMID- 26622703 TI - Metformin upregulates E-cadherin and inhibits B16F10 cell motility, invasion and migration. AB - Malignant melanoma is a highly metastatic cancer, and has a poor prognosis once metastasis has occurred. E-cadherin downregulation is associated with a poorer prognosis in various types of cancer, including lung, ovarian, cervical and prostate. In the majority of cancer cell lines, E-cadherin upregulation inhibits cell motility, migration and invasiveness, and reduces tumor metastasis in in vivo models. In the present study, the inhibitory effects of metformin on the motility, invasion and migration of the B16F10 murine melanoma cell line, and the possible molecular mechanisms underlying this effect were investigated. B16F10 cells were treated with various concentrations of metformin for 24 h and their motility, migration and invasion were tested using a wound-healing assay, a migration assay and a matrigel invasion assay, respectively. Furthermore, the expression of E-cadherin was measured by immunocytochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction. The results showed that metformin effectively upregulated the expression of E-cadherin, and inhibited B16F10 cell motility, migration and invasion, in a dose-dependent manner. This suggested that the inhibition of motility, migration and invasion of B16F10 cells by metformin may be associated with the upregulation of E-cadherin expression, indicating that metformin may have a role in the treatment of melanoma. PMID- 26622704 TI - NLRC5 expression in tumors and its role as a negative prognostic indicator in stage III non-small-cell lung cancer patients. AB - Major histocompatibility complex (MHC) class I molecules have a crucial role in tumor immune evasion; however, the association of MHC class I molecules with outcomes in cancer patients remains controversial. Nucleotide-binding oligomerization-like receptor family caspase recruitment domain-containing 5 (NLRC5) has been reported to be a MHC class I transactivator. However, the expression and function of NLRC5 in cancer remains to be elucidated. The present study aimed to retrospectively examine NLRC5 expression in human tumor tissues and its association with clinical outcomes of non-small-cell lung cancer (NSCLC) stage III patients. The expression of MHC class I and NLRC5 in NSCLC were detected using immunohistochemistry (IHC). The association between their expression levels was assessed using the Pearson's chi2 test and their association with survival was assessed using Kaplan-Meier analysis and the log rank test. In addition, the expression of NLRC5 and MHC class I were examined in 323 cases of seven other types of tumors and their correlations were studied. The results revealed that the expression of NLRC5 was correlated with that of MHC class I in NSCLC patients (P=0.008). MHC class I-positive and nuclear NLRC5 positive NSCLC patients were found to have shorter overall survival (OS) rates (log-rank, P=0.032 and P=0.039, respectively). In addition, in the seven different tumor types, there was a significant correlation between MHC class I and NLRC5 nuclear expression (P<0.001) as well as MHC class I and NLRC5 cytoplasmic expression (P=0.003). In conclusion, NLRC5 was demonstrated to be widely expressed in eight tumor tissues and its expression was correlated with that of MHC class I. Of note, nuclear NLRC5-negative and MHC class I-negative stage III NSCLC patients had improved OS rates compared to those with positive expression. Therefore, NLRC5 and MHC class I may be negative prognostic indicators in NSCLC stage III patients. PMID- 26622705 TI - Contrast-enhanced ultrasound aids in the detection of prostate rhabdomyosarcoma: A case report and literature review. AB - Prostate sarcoma is a rare malignancy with an extremely poor prognosis. The extremely low morbidity and atypical clinical symptoms contribute to a missed diagnosis. The typical features of prostate sarcoma in transrectal ultrasound (US) and magnetic resonance imaging, such as a markedly enlarged volume and irregular prostatic contours, cannot usually be found until dysuria or even uroschesis occurs, and may then be too late to treat. However, there appears to no specific tumor marker for the disease in the serum. The present study reports a case of a young male patient who was diagnosed with prostate rhabdomyosarcoma. This was, to the best of our knowledge, the first case of this diagnosis using contrast-enhanced US (CEUS) when the symptoms were not severe. In this case, the intralesional non-enhancement areas and rim-like hyper-enhancement around the lesion were considered to be the main CEUS features of prostate rhabdomyosarcoma. The present study also reviews the associated literature. PMID- 26622706 TI - Insulin and hypoxia-inducible factor-1 cooperate in pancreatic cancer cells to increase cell viability. AB - The aim of the present study was to investigate whether interstitial insulin and cancer-induced hypoxia-inducible factor-1 (HIF-1) cooperate in pancreatic cancer cells. A population of 45 nude mice were divided into one intact control group and six pancreatic tumor-carrier groups. Pancreatic tumors were generated using HIF-1-positive wild-type MiaPaCa2 (wt-MiaPaCa2) pancreatic cancer cells in three groups of carriers and MiaPaCa2 cells transfected with small interfering RNA against HIF-1alpha (si-MiaPaCa2 cells) in the other three carrier groups. To vary the intrapancreatic insulin levels, tumor-carrying mice were subjected to one of the following conditions: i) Untreated, ii) single injection of the beta-cell toxin streptozotosin prior to cancer cell transplantation and iii) daily injection of insulin following cancer cell transplantation. After 12 weeks, tumor viability was assessed by histological analysis. Western blotting of the tumor grafts was performed to determine the protein expression levels of insulin receptor (IR) and two downstream proteins, hexokinase-II (HK-II) and vascular endothelial growth factor (VEGF). Histologically, the greatest viability was observed in wt-MiaPaCa2 tumors with carriers that remained untreated. These tumors also exhibited greater IR expression than their si-MiaPaCa2 counterparts, indicating that HIF-1 is necessary for basal expression of IR. However, IR expression was increased in wt-MiaPaCa2 and si-MiaPaCa2 tumors when the carriers were treated with exogenous insulin. This indicates that the insulin-induced IR expression was independent of HIF-1. Notably, the insulin-induced IR expression was associated with increased HK-II and VEGF expression in wt-MiaPaCa2 tumors but not si-MiaPaC2 tumors. Therefore, the present study proposes that insulin and HIF 1 may cooperate to increase pancreatic cancer cell viability. Furthermore, the HIF-1 signaling pathway is required for insulin-induced HK-II and VEGF expression, as well as basal IR expression levels in pancreatic cancer cells. PMID- 26622707 TI - Hodgkin's lymphoma associated with myelofibrosis: A case report. AB - In the present study, the case of a patient with nodular sclerosing Hodgkin's lymphoma (NSHL) presenting with diffuse fibrosis of the bone marrow (BM) was reported. A 30-year-old male complained of fever for 1 year, as well as lumbago, lymph node swelling and night sweats for 3 months. A biopsy of the lymph nodes established a diagnosis of NSHL. Aspiration of BM was a dry tap, and the BM biopsy demonstrated marked myelofibrosis with increased proliferation of reticulin fiber. Multiple skeletal lesions were detected in the patient's vertebra, pelvis, sternum and bilateral femur by magnetic resonance imaging and computed tomography. Following numerous courses of chemotherapy and radiotherapy, remission of the lymphoma was achieved. Subsequently, the BM aspiration became possible, and BM biopsy demonstrated a reduction in fibrosis. PMID- 26622708 TI - A case of CD10-negative angioimmunoblastic T cell lymphoma with leukemic change and increased plasma cells mimicking plasma cell leukemia: A case report. AB - Angioimmunoblastic T cell lymphoma (AITL) is a peripheral T cell lymphoma, known to express CD3 and CD4, and, frequently, also CD10 and c-Maf-1. Hypergammaglobulinemia is not particularly rare in patients with AITL. However, AITL in conjunction with plasmacytosis in the peripheral blood is rare. The current report presents a case of CD10-negative AITL demonstrating leukemic change and plasmacytosis in the peripheral blood mimicking plasma cell leukemia. A 78-year-old male was admitted to hospital due to systemic lymph node enlargement, high serum IgG and IgA, and increased counts of plasmacytoid cells and lymphoid cells with atypical nuclei in the peripheral blood. Initially, plasma cell leukemia was suspected, due to the extreme increase in the number of plasma cells in the peripheral blood. However, the plasma cells did not show clonal expansion on examination by flow cytometry. Based on histological analyses, following a biopsy of an enlarged lymph node, the patient was diagnosed with AITL. This case suggests that when hypergammaglobulinemia and increases in B lineage cells are observed, AITL should be considered in addition to disorders of B-lineage cells. PMID- 26622709 TI - Atypical teratoid/rhabdoid tumor with hereditary multiple exostoses in an 18-year old male: A case report. AB - Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive embryonic brain tumor that is predominantly found in young children. The present study reports the unusual case of an adult male AT/RT patient with a history of another type of tumor, hereditary multiple exostoses (EXT or HME), who survived for 18 years. The patient's first and chief complaint was a 1-month history of progressive projectile vomiting. The patient was admitted twice for treatment, and on the second admission, a craniotomy was performed to remove a intracranial mass. However, no radiotherapy or chemotherapy treatment was administered. Pathology revealed monotonous medium- to large-sized neoplastic cells. The patient succumbed to a pulmonary infection and respiratory failure 14 days after the initial treatment. The prognosis for AT/RT is extremely poor; furthermore, the patient presented with another tumor. There may have been an association between the two tumors that worsened the clinical phenotype and prognosis of this patient. Additionally, symptomatic treatment for this condition is insufficient; early surgery and radiotherapy may be more useful for preventing the aggressive progression of these tumors. PMID- 26622710 TI - Hepatocellular carcinoma metastasis to the gingival soft tissues: A case report and review of the literature. AB - Metastases to the gingival soft tissues are rare in hepatocellular carcinoma (HCC). To the best of our knowledge, only 13 cases have been reported in English literature to date. The present study described the case of a 43-year-old Chinese man who was admitted to Tangdu Hospital (Xi'an, China) due to the presence of a gingival tumor that was initially diagnosed as granulation tissue by a dental surgeon. Examination of the patient's medical history revealed that a solid mass, measuring 1.5 cm in diameter, was identified in the right lobe of the liver 2 years prior to presentation at the current hospital; however, no biopsy was performed. Thus, the tumor was resected and histological examination resulted in an initial diagnosis of atypical squamous cell carcinoma. However, the histopathological characteristics, immunohistochemical features and serum alpha fetoprotein expression levels supported a diagnosis of metastatic HCC. In conclusion, the present case study highlights the difficulties in diagnosing metastatic HCC without a history of primary HCC, and the importance of excluding a diagnosis of metastatic tumor when a lesion is identified in the gingival. Furthermore, it was determined that a final diagnosis of gingival metastasis of HCC predominantly depends on pathological characteristics and immunohistochemical features. PMID- 26622711 TI - Expression of TYMS in lymph node metastasis from low-grade glioma. AB - The aim of the present study was to investigate the expression of thymidylate synthase (TYMS) in the primary foci and metastatic lymph nodes of low-grade glioma, and to analyze the function of TYMS in the lymph node metastases from low grade glioma. The study included 93 cases of surgically resected and pathologically confirmed low-grade glioma, form patients treated at Huaihe Hospital of Henan University (Kaifeng, China). The following clinical data was obtained from each patient: Gender, age, subjective symptoms (dizziness, headache, a feeling of pressure in the head, etc.), site of disease, tumor type, pathological stage, degree of differentiation and lymph node involvement. The surgically resected gliomas and dissected cervical lymph nodes were immunohistochemically stained, and DNA was extracted from the tumor and lymph node tissues samples for polymerase chain reaction sequencing and amplification. The expression of TYMS in the primary foci and metastatic lymph nodes of low grade glioma was examined. Additionally, the association between pathological features and the postoperative survival rate of the patients was analyzed. The primary lesions of all 93 cases exhibited positive TYMS expression and 43/157 (27.39%) lymph nodes exhibited positive TYMS expression. Factors that significantly influenced the postoperative survival rate of the patients, included the metastasis of the cervical lymph nodes (P<0.01), the number of dissected cervical lymph nodes (P<0.01) and the degree of differentiation (P<0.05). The metastasis of the cervical lymph nodes was the only independent risk factor affecting postoperative disease-free survival. The risk of recurrence in patients with metastasis of the cervical lymph nodes was 6.3-fold higher than in those without metastasis (P<0.01). Thus, the results of the present study provide a theoretical basis for accurately predicting the prognosis of patients with low-grade malignant brain glioma, reducing the conjecture involved in selecting postoperative treatment strategies and improving therapeutic efficacy. PMID- 26622712 TI - A marked response to icotinib in a patient with large cell neuroendocrine carcinoma harboring an EGFR mutation: A case report. AB - The present study reports the case of an 84-year-old male with primary pulmonary large cell neuroendocrine carcinoma (LCNEC) harboring an epidermal growth factor receptor (EGFR) gene mutation that exhibited a long-lasting response to the EGFR tyrosine kinase inhibitor (EGFR-TKI) icotinib. The patient had an extensive smoking history, a poor performance status, and presented with an irregular mass in the middle lobe of the right lung on computed tomography (CT) and an enlarged left supraclavicular lymph node on physical examination. Right middle lobe bronchial brushing during fiberoptic bronchoscopy identified poorly differentiated cancer cells. The left supraclavicular lymph node was biopsied and a diagnosis of metastatic LCNEC was determined. Furthermore, an EGFR exon 19 deletion was identified by DNA sequencing. Following diagnosis, icotinib was administered at a dose of 125 mg three times a day. Chest CT scans were performed after 1 month of treatment, which indicated that the tumor was in partial remission. This marked response to icotinib lasted for 8 months. Thus, the present case illustrates the possibility of identifying EGFR mutations in LCNEC and indicates that EGFR-tyrosine kinase inhibitors may be an alternative treatment strategy for patients with LCNEC harboring activating EGFR mutations. PMID- 26622713 TI - Malignant lymphoma occurring simultaneously in the urinary bladder wall and bilateral renal parenchyma: A case report. AB - A 67-year-old man was admitted to hospital with acid regurgitation, acute right lower abdominal pain and mild fever. Multiple suspicious mass lesions were detected in the patient's kidneys, the right side wall of his bladder and the right lower ureter, using CT urography and PET-CT. He underwent palliative surgery of the bladder and percutaneous renal biopsy. Postoperative histopathological examination and immunohistochemical staining indicated that the tumor was consistent with diffuse large B-cell lymphoma (DLBCL). Although DLBCL is by far the most common type of non-Hodgkin's lymphoma, it is rare for DLBCL to simultaneously involve the kidneys, bladder and the lower ureteric tract. PMID- 26622714 TI - High expression levels of unc-51-like kinase 1 as a predictor of poor prognosis in colorectal cancer. AB - Colorectal cancer (CRC) is one of the most common and lethal cancers worldwide. Unc-51-like kinase 1 (ULK1) plays an important role in autophagy, which is widely involved in human CRC. The aim of the present study was to investigate the clinical and prognostic significance of the expression of ULK1 in human CRC. Expression of ULK1 in 339 CRC specimens (tumor-node-metastasis stages I-IV) was assessed by immunohistochemistry. The optimal cutpoint of the expression of ULK1 was assessed by the X-tile program, and the patients were divided into 2 groups of high or low expression levels of ULK1, accordingly. Correlation analysis between the expression of ULK1 and the clinicopathological variables in CRC demonstrated that the expression of ULK1 was significantly associated with gender and tumor differentiation. Univariate Cox regression analysis indicated that high expression levels of ULK1 were a risk factor for overall and disease-free survival. Therefore, the high expression levels of ULK1 may be a useful independent biomarker for predicting a poor prognosis in patients with CRC. PMID- 26622715 TI - Expression of p16 protein in infantile hemangioma. AB - The present study aimed to investigate the expression and significance of p16 in the occurrence, development and regression of infantile hemangioma (IH). The expression of p16 was examined in proliferating, involuting hemangioma and normal tissues using immunohistochemical techniques. The expression of p16 was significantly lower in proliferating hemangioma than in involuting hemangioma, and was significantly lower in the involuting hemangioma than in normal tissues. Significant differences were found between the three groups (P<0.05). The results indicate that p16 may be important in the regression of IH endothelial cells and in anti-angiogenesis. There is a certain association between p16 expression and the regression of hemangioma. This provides a theoretical basis for the further study of the pathological mechanisms of p16 in hemangioma and potential gene therapies that may treat this disease. PMID- 26622716 TI - Soluble purified recombinant C2ORF40 protein inhibits esophageal cancer cell proliferation by inducing cell cycle G1 phase block. AB - Chromosome 2 open reading frame 40 (C2ORF40) plays a significant role in numerous processes, including cell differentiation, senescence, apoptosis, inflammation and neuroendocrine hormone regulation. Moreover, C2ORF40 is a candidate tumor suppressor gene in a variety of tumors, and is closely associated with prognosis. Bioinformatics analysis has indicated that pro-C2ORF40 is a secreted protein with a signal peptide. Secreted C2ORF40 protein (sC2ORF40) exists in cancer cell medium. However, thus far, the exact biological function of sC2ORF40 in carcinogenesis has not been thoroughly researched. In the present study, the signal peptide sequence of the C2ORF40 complementary DNA was initially cut off to produce secreted recombinant human C2ORF40 protein (rhC2ORF40). The soluble rhC2ORF40 was expressed, purified and examined for tumor-suppressing function for the first time. The results revealed that the soluble purified rhC2ORF40 protein was concentrated with a purity of >95%. Furthermore, the rhC2ORF40 inhibited esophageal cancer cell proliferation in vitro (P<0.05) and caused cell cycle G1 phase block, as determined by flow cytometric analysis (P<0.05). Overall, the soluble rhC2ORF40 protein with high purity and biological activity was obtained, which suppressed esophageal cancer cells proliferation by inducing cell cycle G1 phase block in vitro. Therefore, the soluble rhC2ORF40 protein could be potential biological therapy drug for esophageal carcinoma. PMID- 26622717 TI - A potential oral anticancer drug candidate, Moringa oleifera leaf extract, induces the apoptosis of human hepatocellular carcinoma cells. AB - It has previously been reported that cold water-extracts of Moringa oleifera leaf have anticancer activity against various human cancer cell lines, including non small cell lung cancer. In the present study, the anticancer activity of M. oleifera leaf extracts was investigated in human hepatocellular carcinoma HepG2 cells. By the analysis of apoptotic signals, including the induction of caspase or poly(ADP-ribose) polymerase cleavage, and the Annexin V and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays, it was demonstrated that M. oleifera leaf extracts induce the apoptosis of HepG2 cells. In the hollow fiber assay, oral administration of the leaf extracts significantly reduced (44-52%) the proliferation of the HepG2 cells and A549 non-small cell lung cancer cells. These results support the potential of soluble extracts of M. oleifera leaf as orally administered therapeutics for the treatment of human liver and lung cancers. PMID- 26622718 TI - Hepatoid adenocarcinoma of the stomach: Nine case reports and treatment outcomes. AB - Hepatoid adenocarcinoma (HAC), an extrahepatic tumor, has notable morphological similarities to hepatocellular carcinoma, which has been reported in gastrointestinal tract organs, including the rectum, gallbladder, lung, ovary and urinary bladder. HAC of the stomach (GHAC) is a rare variant of gastric cancer, characterized by aggressive behavior and extremely poor prognosis. Correct diagnosis depends on clinicopathological and immunohistochemical studies. In the present study, we reported nine cases of GHAC who were treated in the First Affiliated Hospital of Zhejiang University, China, from January 2009 to December 2013. All patients underwent radical gastrectomy; among them, one patient had stage I, one had stage II and seven had stage III. Elevated serum alpha fetoprotein was observed in eight cases. Until now, only one patient has succumbed, four patients have liver metastases, one has lung metastasis and four remain disease-free. Relatively longer survival requires accurate diagnosis at an earlier stage and active multimodality treatment, including radical gastrectomy and adjuvant chemotherapy. PMID- 26622719 TI - Nuclear medicine techniques in Merkel cell carcinoma: A case report and review of the literature. AB - Merkel cell carcinoma (MCC) is a rare and aggressive type of neuroendocrine cancer of the skin. It predominantly affects the elderly, with a predilection for the sun-exposed skin of the head and neck. Risk factors include immune suppressing diseases, such as human immunodeficiency virus (HIV), chronic lymphocytic leukemia and multiple myeloma, organ transplantation, and the presence of the newly-identified Merkel cell polyomavirus (MCPyV). Diagnosis is based on pathological findings, primarily the immunohistochemical determination of cytokeratin 20 positivity. By contrast, staging relies on conventional imaging methods, such as ultrasonography, computed tomography (CT) and magnetic resonance imaging, and nuclear medicine techniques, such as sentinel lymph node scintigraphy, somatostatin receptor scintigraphy (SRS), and positron emission tomography (PET)/CT with 18F-fluorodeoxyglucose (FDG) or alternative radiopharmaceuticals. The treatment of MCC is primarily surgical, with possible adjuvant radiation, while the use of chemotherapy appears to be an alternative therapeutic option that is used only in specific cases. The present study describes the case of a 43-year-old HIV-positive Caucasian man with MCC located on the posterior surface of the left thigh, which was identified by cytological and histological examination of tissue sampled by fine needle aspiration and biopsy performed under CT. SRS demonstrated a high uptake of 111In-diethylene triamine pentaacetic acid-octreotide at the affected site. Therefore, the lesion was surgically excised, and the patient received chemotherapy and adjuvant radiotherapy. Three months subsequent to treatment, the patient underwent a PET/CT scan with 18F-FDG that demonstrated uptake in the cervical lymph nodes and the area of the excised lesion. These findings indicated that the disease was in remission. The aim of the present study was to highlight the value and contribution of nuclear medicine in the diagnosis, staging and follow-up, using PET/CT, octreoscan and sentinel lymph node scintigraphy, of patients with MCC, as well as the therapeutic strategy of radiolabelled somatostatin analogue scintigraphy. PMID- 26622720 TI - Solitary fibrous tumors of the prostate: A case report. AB - Increasing numbers of extrapleural solitary fibrous tumours (SFTs), including the prostate SFT, have been reported over the last 10-years. Prostate SFT is relatively uncommon, with <20 cases reported in the literature worldwide. In the present study, a prostate SFT case, which was initially misdiagnosed as benign prostatic hyperplasia, is presented. The patient was subjected to three surgeries (cystoscopy and per urethra lithocystotomy, transurethral resection of the prostate and nerve-sparing retropubic radical prostatectomy) prior to SFT diagnosis. It was demonstrated that histopathological and immunohistochemical factors (positive staining for CD34 and B cell lyphoma-2 expression) were of significant diagnostic value. Thus, nerve-sparing retropubic radical prostatectomy for total resection may be the best therapeutic strategy to treat prostate SFT, allowing the preservation of sexual function and reducing the risk of locoregional recurrence. PMID- 26622721 TI - Decreased expression of protein tyrosine phosphatase non-receptor type 12 is involved in the proliferation and recurrence of bladder transitional cell carcinoma. AB - Protein tyrosine phosphatase non-receptor type 12 (PTPN12) has been shown to be involved in the development of a number of types of carcinoma. However, the effect of PTPN12 on the proliferation and recurrence of human bladder transitional cell carcinoma (TCC) is unclear. The present study aimed to investigate the expression and function of PTPN12 in human TCC. Samples from 164 patients with TCC, in addition to 146 patients undergoing bladder surgery for indications other than TCC, were examined. PTPN12 protein expression was examined using immunohistochemistry and western blotting, and PTPN12 mRNA expression was examined using reverse transcription-quantitative polymerase chain reaction. PTPN12 expression was increased following transfection with the PTPN12 expressing, pcDEF3 vector, and PTPN12 expression was decreased by RNA interference, in four TCC cell lines. The proliferation of TCC cells was analyzed by a WST-1 assay and in xenografts on BALB/C nude mice. The effect of PTPN12 on tumor recurrence was analyzed by adhesion, migration and invasion assays in TCC cell lines. PTPN12 expression was significantly decreased in TCC tissues compared with that in normal urothelium, and the level of PTPN12 expression was negatively correlated with tumor size, pathological grade, clinical stage and tumor recurrence. Furthermore, decreased expression of PTPN12 significantly enhanced the proliferation of TCC cells in vitro and in vivo. TCC cells with lower levels of PTPN12 exhibited greater adhesion, migration and invasion. In conclusion, PTPN12 expression is downregulated in human TCC. Restoring PTPN12 activity may represent a novel therapeutic strategy for this disease. PMID- 26622723 TI - Signet-ring cell carcinoma of the colon: A case report of a 9-year-old boy. AB - Colorectal carcinomas are common in adults; however, they rarely occur in children. The present study reported the case of a colorectal carcinoma diagnosed as signet-ring cell carcinoma in a 9-year-old boy. The patient presented with acute intestinal obstruction symptoms, which persisted following 3 days of conservative treatment. The diagnosis was determined by emergency laparotomy and a mass was identified in the transverse colon proximal to the splenic flexure. Histological examination of the mass revealed signet-ring cell carcinoma. In addition, the present study aimed to discuss the diagnostic establishment and treatment of this rare disease in children. Due to the high mortality rate caused by delays in accurate diagnoses, signet-ring cell carcinoma in children promotes a specific diagnostic and surgical challenge. PMID- 26622722 TI - Silencing of survivin by YM155 induces apoptosis and growth arrest in hepatocellular carcinoma cells. AB - Survivin overactivation is a frequent event in human hepatocellular carcinoma (HCC), due to its function in the induction of hepatocyte proliferation and apoptotic dysfunction. Recently, a novel survivin inhibitor named YM155, has demonstrated broad antitumor effects against various malignant tumors. Therefore, the present study aimed to explore how this agent may impact on HCC and elucidate its underlying mechanism of action. Immunohistochemical analysis was performed on 8 specimens of human HCC, to assess the protein expression of survivin and phosphorylated retinoblastoma tumor suppressor (p-Rb). In addition, in vitro, HepG2 and Huh7 human HCC cell lines were exposed to 100 uM YM155 for up to 72 h and the cell viability was subsequently determined using MTT assay. Furthermore, the apoptotic status of YM155-treated HCC cells was investigated by flow cytometry, and the protein levels of survivin, procaspase-3 and p-Rb in YM155 treated HCC cells were assessed by immunoblotting analysis. The results demonstrated that HCC specimens expressed high levels of survivin and p-Rb protein compared with those of adjacent noncancerous liver tissues. In vitro, YM155 significantly induced HCC cell apoptosis and growth arrest. At the protein level, YM155 markedly inhibited survivin and p-Rb expression, and elevated procaspase-3. YM155 demonstrated significant antitumor effects on HCC cells in the present study. These effects were associated with its anti-proliferative and apoptosis-induction activities. YM155 requires further investigation as a novel agent for potential use as a therapeutic strategy for the treatment of HCC. PMID- 26622724 TI - Vasculogenic mimicry is a major feature and novel predictor of poor prognosis in patients with orbital rhabdomyosarcoma. AB - Vasculogenic mimicry (VM) is a key developmental program, frequently activated during cancer invasion and metastasis. The aim of the present study was to evaluate the role of VM in orbital rhabdomyosarcoma (RMS), the correlation between VM and tumor differentiation, recurrence and survival duration, as well as the contribution of epithelial cell kinase (EphA2) and matrix metalloproteinase-2 (MMP-2) in VM initiation. A total of 32 patients were enrolled to investigate the associations between VM in orbital RMS tumors and clinical characteristics, as well as its impact on overall survival. VM was identified and confirmed by CD31/periodic acid-Schiff double staining, while the presence of EphA2 and MMP-2 were examined by immunohistochemical analysis. VM was identified in eleven patients, particularly those with poorly differentiated orbital RMS (P=0.001). Patients with VM exhibited significantly worse survival rates (P=0.001, log-rank test), a significantly increased risk of mortality (P=0.008) and EphA2 and MMP-2 expression levels were enhanced (P=0.005 and 0.001, respectively). The VM and mitotic rate were independent predictors of poor prognosis (P=0.001 and 0.004, respectively), indicated by multivariate Cox proportional hazards models. These results demonstrated that VM is present in orbital RMS and represents an independent prognostic factor for overall survival. In addition, overexpression of EphA2 and MMP-2 may promote VM formation in orbital RMS. PMID- 26622725 TI - Knockdown of Aurora-B inhibits the growth of non-small cell lung cancer A549 cells. AB - Elevated expression of Aurora-B affects cell apoptosis and proliferation in a variety of solid tumors. However, the role of Aurora-B has been poorly evaluated in non-small cell lung cancer (NSCLC). In the present study, it was found that Aurora-B was overexpressed in tissue specimens obtained from 174 patients with lung cancer. It was also demonstrated that knockdown of Aurora-B induces apoptosis and inhibits the growth of lung cancer A549 cells in vitro and in vivo. Furthermore, it was found that silencing Aurora-B decreased the activity of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Therefore, it was concluded that knockdown of Aurora-B induces apoptosis and inhibits growth in NSCLC A549 cells, in addition to inhibiting the activity of the PI3K/AKT signaling pathway. Targeting Aurora-B may provide a novel target for lung cancer therapy. PMID- 26622726 TI - Paclitaxel combined with harmine inhibits the migration and invasion of gastric cancer cells through downregulation of cyclooxygenase-2 expression. AB - Cyclooxygenase-2 (COX-2) has a critical role in the invasiveness and metastasis of gastric cancer. In addition, paclitaxel (PTX) and harmine (HM) were reported to be potential therapeutic drug candidates for cancer therapy; however, the synergistic antitumor effect of PTX and HM combined treatment on the human gastric cancer cells remains to be elucidated. The aim of the present study was to evaluate the effects of PTX and/or HM on the cell migration and invasion in two human gastric cancer cell lines, SGC-7901 and MKN-45. MTT assay was used to detect the growth inhibition induced by PTX and HM. The Transwell assay was employed to assess the effects of PTX and HM on the cell migration and invasion. The expression levels of COX-2 and matrix metalloproteinase-9 (MMP-9) were analyzed by western blot analysis. The results demonstrated that PTX and HM inhibited cell proliferation in a dose-dependent manner. Individually PTX and HM were able to inhibit the migration and invasion of two human gastric cancer cells; however, the combination of PTX and HM exerted synergistic effects on migration and invasion inhibition, with downregulation of COX-2 and matrix metalloproteinase (MMP)-9. In conclusion, the results of the present study indicated that combination chemotherapy using PTX with HM exerted an antitumor effect, which may be implicated for the treatment of gastric cancer. Of note, the combination of the two drugs inhibited migration and invasion more effectively compared with each drug alone, the mechanism of which proceeded via the downregulation of COX-2 expression. PMID- 26622727 TI - Rheb phosphorylation is involved in p38-regulated/activated protein kinase mediated tumor suppression in liver cancer. AB - Ras homolog enriched in brain (Rheb) is a key regulator of mammalian target of rapamycin complex 1 (mTORC1). The Rheb-mTORC1 axis is a pivotal pathway that mediates cell growth. It was previously reported that upon energy-stress stimulation, the phosphorylation of Rheb at serine 130 by p38-regulated/activated protein kinase (PRAK) results in the impaired nucleotide binding ability of Rheb and inhibits Rheb-mediated mTORC1 activation. However, the role of Rheb phosphorylation in cancer development remains to be elucidated. The aim of the present study was to determine the effect of Rheb phosphorylation on tumor growth in vitro and in vivo. In addition, tissue samples were obtained from 70 hepatocellular carcinoma (HCC) patients in order to determine any associations between Rheb phosphorylation and the clinicopathological characteristics of patients. In vitro and ex vivo kinase assays were performed to determine the phosphorylation of Rheb by PRAK. A xenograft assay was performed to assess tumorigenicity of MEF cell lines. In addition, western blot and immunohistochemical analyses were performed to detect Rheb protein expression and phosphorylation. The results of the present study revealed that Rheb phosphorylation may be induced through Ras overexpression. In addition, kinase dead PRAK and dominant-negative PRAK mutation were demonstrated to abolish the Rheb phosphorylation induced by Ras overexpression. Xenograft assays in nude mice revealed that Rheb phosphorylation was involved in PRAK-mediated tumor suppression. Of note, the clinicopathological analysis of 70 HCC samples determined that Rheb phosphorylation was associated with poor proliferation and the progression of HCC. In conclusion, the results of the present study suggested that Rheb phosphorylation may have an important role as an intracellular barrier to cancer development. PMID- 26622729 TI - Serum thymidine kinase 1 is a reliable maker for the assessment of the risk of developing malignancy: A case report. AB - With regard to different types of malignancies, thymidine kinase 1 (TK1) is a useful prognostic marker in clinical oncology, both as a serum proliferation marker and in immunohistochemistry. The present study investigated the use of serum TK1 protein (STK1p) for the identification of multiple proliferating diseases linked to the risk of developing cancer, by following one patient during the period of 2003-2014. The patient presented with adenomatous polyps in the stomach in 2003, follicular cervicitis in 2007 and hyperplasia of the breast/fibrocystic breasts in 2010. The breast cysts increased from 4*5 mm in size in 2010 to 8*7 mm in size in 2013, and were assessed as a suspicious malignancy at the end of this period. In parallel, the STK1p values increased from 2.0 to 7.6 pM. Based on this information, a minimally invasive surgery using the Mammotome(r) Biopsy System was performed. Immunohistochemistry on the cyst tissue showed strong staining of TK1 in the ductal epithelial cells and thus confirmed the abnormal proliferation in the lesion. One week after the surgery, the STK1p value had decreased to almost normal values (1.6 pM), but then fluctuated above 2.0 pM for the next 7 months. After the surgery, the patient was re-examined and small foci with squamous cell hyperplasia and a suspected ulcerated cervix, as well as flat gastric erosive, were identified, but not treated; this may explain why the STK1 P-values did not return to within normal values. The patient is currently being followed up using STK1p analysis combined with imaging/pathology in order to begin therapeutic intervention as early as possible to avoid the risk of developing cancer. Overall, STK1p is useful in health screening to identify individuals at risk of developing premalignancy/malignancy. PMID- 26622728 TI - MicroRNA screening identifies circulating microRNAs as potential biomarkers for osteosarcoma. AB - MicroRNAs (miRNAs) are a family of small non-protein coding RNAs, which regulate the expression of a wide variety of genes at the post-transcriptional level to control numerous biological and pathological processes. Various circulating miRNAs have been identified as potential diagnostic and prognostic biomarkers in multiple types of cancer and disease. The aim of the present study was to identify potential miRNA biomarkers for the early diagnosis and relapse prediction of osteosarcoma (OS). miRNA profiling was performed on serum from patients with osteosarcoma and healthy controls. All putative miRNAs were verified by reverse transcription-quantitative polymerase chain reaction analysis of 20 pre-therapeutic OS patients and 20 healthy individuals. The expression of miR-106a-5p, miR16-5p, miR-20a-5p, miR-425-5p, miR451a, miR-25-3p and miR139-5p was demonstrated to be downregulated in the serum of OS patients when compared with that of the healthy controls. Receiver-operating characteristic curve analyses indicated that these 7 miRNAs may be used as diagnostic biomarkers with the ability to discriminate between the healthy cohort and patients with OS. These results provide novel insights into the use of miRNAs in early blood screening for OS. PMID- 26622730 TI - Metastatic lung adenocarcinoma to the bladder: A case report. AB - Urothelial cancer is the most frequently diagnosed type of malignant tumor in the bladder, of which primary adenocarcinoma accounts for a small percentage. Secondary malignancies, in particular metastatic adenocarcinoma from the lung, are exceedingly rare, with only six cases previously reported in the literature. The present study describes the case of a 71-year-old Chinese male patient with known lung cancer for >2 years, who was diagnosed with metastatic adenocarcinoma to the bladder. The histopathological characteristics and immunohistochemical features of the patient are reported. It was proposed that pathologists should consider the possibility of metastatic adenocarcinoma from the lung, rather than assume a diagnosis of primary adenocarcinoma of the bladder or direct invasion of adenocarcinoma from the surrounding organs. Furthermore, it is essential to determine the medical history of each patient and observe the immunohistochemical features of all tumors prior to diagnosis. PMID- 26622731 TI - Insights into the roles of hnRNP A2/B1 and AXL in non-small cell lung cancer. AB - Lung cancer has long been one of the most serious types of malignant tumor, and is associated with high incidence and mortality rates. Despite advancements in the comprehensive treatment of the disease, particularly with targeted therapeutic agents, there has been little improvement in the 5-year survival rates of patients. One of the leading causes of mortality in lung cancer is the lack of effective early diagnostic criteria. On this basis, the present study aimed to identify an index with potential in the early diagnosis and prognosis of lung cancer. The current study determined the expression of heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 and AXL proteins in non-small cell lung cancer (NSCLC) tumor samples, and performed prognostic analysis of the collected clinical data to identify any association. In addition, RNA interference was performed to silence the expression of hnRNP A2/B1, allowing evaluation of its molecular and cellular functions, and determination of the mechanism of hnRNP A2/B1 in NSCLC by means of AXL mediation. It was identified that the positive expression rate of hnRNP A2/B1 and AXL proteins were significantly higher in NSCLC compared with paracancerous lung tissues (P<0.05). Furthermore, the expression of hnRNP A2/B1 protein was correlated with the expression AXL. Thus, the expression of hnRNP A2/B1 and AXL protein are factors affecting prognosis in patients with NSCLC. Of these, hnRNP A2/B1 appears to be an independent risk factor. PMID- 26622732 TI - Non-Hodgkin's lymphoma with uncommon clinical manifestations: A case report. AB - Extranodal lymphoma occurs in ~40% of all patients with lymphoma and has been described in virtually all organs and tissue. However, diffuse large B-cell lymphoma (DLBCL), which is the most common histological subtype of non-Hodgkin's lymphoma (NHL), primarily arising in the retroperitoneal region has been rarely reported. Primary retroperitoneal lymphoma without renal or ureteral involvement affecting the genitourinary system has not been reported until now. In this article, we report the rare case of a young female suffering with primary DLBCL located simultaneously in the retroperitoneal and gastrointestinal region. The first sign of this disease was renal colic. Pathological assessment was performed using immunohistochemistry staining, revealing positivity for CD20 and Ki67. DLBCL was the final confirmed diagnosis. Obtaining a definitive histological diagnosis by surgery and using exactly chemotherapy played an essential role in the treatment of our patient. This case serves as a reminder to include the differential diagnosis of primary retroperitoneal NHL when a patient presents with a retroperitoneal mass and the first symptom is renal colic. PMID- 26622733 TI - T-box 2 expression predicts poor prognosis in gastric cancer. AB - T-Box 2 (TBX2) plays a critical role in embryonic development. Previously, TBX2 has been suggested to be involved in malignancies. However, the role of TBX2 in gastric cancer (GC) remains unclear. In the present study, TBX2 expression was found to be evidently upregulated in GC compared with the expression in the corresponding adjacent non-cancerous tissues at the mRNA and protein levels. Using immunohistochemical analysis on the tissue samples obtained from 266 patients with GC, TBX2 expression was found to be significantly associated with the clinical stage and incidence of vascular invasion and metastasis. Patients with GC that expressed TBX2 demonstrated a shorter overall survival time compared with the patients without TBX2 expression. Multivariate analysis revealed that TBX2 expression was an independent prognostic factor for overall survival (hazard ratio, 3.930; 95% confidence interval, 2.041-7.917; P=0.009). These results indicated that TBX2 is a prognostic marker for patients with GC. PMID- 26622734 TI - Chronic neutrophilic leukemia with overexpression of EVI-1, and concurrent CSF3R and SETBP1 mutations: A case report. AB - Chronic neutrophilic leukemia (CNL) is a rare type of myeloproliferative neoplasm, characterized by sustained neutrophilia, splenomegaly, bone marrow granulocytic hyperplasia (without evidence of dysplasia) and an absence of the Philadelphia chromosome. Thus far, ~150 cases of CNL have been described in the literature; however, none have demonstrated overexpression of the ecotropic viral integration site-1 (EVI-1, also known as MECOM) gene. The present study describes a case that fulfilled the World Health Organization diagnostic criteria for CNL, and was associated with overexpression of EVI-1, as well as novel concurrent mutations of colony stimulating factor 3 receptor (CSF3R) and SET binding protein 1 (SETBP1). In addition, the current study briefly reviewed the relevant literature regarding novel genetic findings associated with the diagnosis and treatment of CNL. To the best of our knowledge, this is the first case report of CNL with associated EVI-1 overexpression, and concurrent CSF3R and SETBP1 mutations. PMID- 26622735 TI - Primary pancreatic lymphoma: A rare cause of pancreatic mass. AB - Primary pancreatic lymphoma (PPL) is a rare entity, most likely to be clinically misdiagnosed as pancreatic cancer. The cure rate of PPL is higher compared with that of pancreatic adenocarcinoma. This is the case report of a 57-year-old male patient who was hospitalized with complaints of abdominal pain, weight loss and jaundice. The radiological evaluation revealed a pancreatic head mass and, following endoscopic ultrasound-guided fine-needle aspiration biopsy, the tumor was diagnosed as diffuse large B-cell lymphoma. The final diagnosis was PPL, and the patient went into remission after receiving three cycles of treatment with rituximab, doxorubicin, cyclophosphamide, vincristine and prednisolone (R-CHOP regimen). Therefore, PPL should be considered in the differential diagnosis of pancreatic masses and its management differs from that of other types of pancreatic tumor. PMID- 26622736 TI - A 10-gene expression signature of Notch pathway predicts recurrence in ovarian carcinoma. AB - Patients with ovarian carcinoma are at high risk of tumor recurrence. In the present study, 81 Notch pathway genes were selected to find recurrence-related genes in The Cancer Genome Atlas dataset. A 10-gene signature (FZD4, HES1, PSEN2, JAG2, PPARG, FOS, HEY1, CDC16, MFNG, and EP300) was identified and validated that is associated with recurrence-free survival time, but not with overall survival time, in the TCGA dataset and in other two independent datasets, GSE9891 and GSE30161. This gene signature gave a significant performance in discriminating patients at high risk of recurrence from those at low risk, as measured by the area under the receiver operating characteristic curve. Cox proportional hazards regression analyses demonstrated that the prognostic value of this 10-gene set is independent of other clinical variables in all three datasets. The potential as a biomarker for predicting high- and low-risk subgroups for recurrence in ovarian cancer patients deserves further investigation in prospective patient cohorts in the future. PMID- 26622737 TI - SMAD4 expression in breast ductal carcinoma correlates with prognosis. AB - The present study examined SMAD4 expression in fine-needle aspiration cell blocks from patients with breast ductal carcinoma, in order to assess its viability as a prognostic marker. Using immunohistochemistry, the SMAD4 protein status of 86 breast ductal carcinoma fine-needle biopsies, from patients who underwent tumor resection at Beihua University Affiliated Hospital (Jilin, China) between 2002 and 2008, was characterized. The association between SMAD4 expression and clinicopathological parameters, as well as prognosis was assessed using the Mantel-Haenszel method and Cox proportional hazards regression. SMAD4 staining was observed in the cytoplasm and nucleus, and its expression was found to be decreased in ductal breast carcinoma as compared with adjacent normal breast epithelia. Patients with reduced SMAD4 expression levels tended to exhibit more poorly differentiated tumors, a higher risk of recurrence and shorter overall survival. These results demonstrated that the evaluation of SMAD4 protein status in fine-needle biopsy specimens of breast ductal carcinoma may provide additional prognostic information. PMID- 26622738 TI - Expression and mutation analysis of Cyclin A and Ki-67 in glioma and their correlation with tumor progression. AB - The present study aimed to analyze the expression and mutation of Cyclin A and Ki 67 in gliomas, and determine their correlation with tumor progression. Tissue samples of 186 diagnosed glioma patients were examined immunohistochemically for Cyclin A and Ki-67 expression. Gene mutation analysis was performed on genomic DNA extracted from patient samples, using polymerase chain reaction amplification and sequencing. Cyclin A and Ki-67 expression were observed in the glioma and lymphatic metastasis tissues, and were analyzed using SPSS 14.0 statistical software. Of the total patients, 64 (34.41%) were Cyclin A-positive and 68 (36.56%) were Ki-67-positive. The expression of Cyclin A and Ki-67 in glioma was positively correlated with lymphatic metastasis. Statistically significant differences were observed in the mutation rate of Ki-67 (P<0.05), but not Cyclin A (P>0.05), between the gliomas and metastatic tumors. In conclusion, Cyclin A and Ki-67 are highly expressed in glioma tissues, and their expression and mutation are associated with the lymphatic metastasis of glioma in the brain. It may be concluded that Cyclin A and Ki-67 may be used as biomarkers to guide the diagnosis of glioma and evaluate the prognosis of affected patients. PMID- 26622739 TI - Combined paclitaxel, cisplatin and fluorouracil therapy enhances ionizing radiation effects, inhibits migration and induces G0/G1 cell cycle arrest and apoptosis in oral carcinoma cell lines. AB - Although taxels (in particular paclitaxel), cisplatin and fluorouracil (TPF) chemotherapy has been approved for use in the treatment of head and neck squamous cell carcinoma (HNSCC), little is known with regard to the cellular mechanisms of this novel drug association. In order to investigate the reaction of cells to this novel treatment, the present study aimed to examine the cytotoxic effect of TPF in HNSCC cell lines in combination with irradiation, to analyze its effect on cell cycle progression and cell death, and to evaluate its ability to alter cell migration. An MTT assay was used to determine cell viability following TPF and cisplatin treatments in two human HNSCC cell lines (FaDu and SCC-9) and one keratinocyte cell line (HaCaT). The concurrent use of TPF or cisplatin and irradiation was also analyzed. Flow cytometric analysis was utilized to determine the cell cycle distribution and to verify the induction of apoptosis. The capacity of the drugs to alter oral cancer cell migration was also evaluated using a Transwell migration assay. The results indicated that TPF and cisplatin were cytotoxic to all cell lines, and enhanced the effects of ionizing radiation. FaDu cells were significantly more sensitive to the two treatments, and TPF was more cytotoxic than cisplatin for all cells. Flow cytometric analysis revealed that TPF increased the number of cells in G0/G1 phase in the SCC-9 cell line, and indicated apoptotic cell death. The results of the Transwell assay demonstrated that TPF inhibited migration in oral carcinoma cell lines. The results of the present study indicated that TPF functions in oral carcinoma cell lines through the enhancement of ionizing radiation effects, inducing cell cycle arrest at G0/G1 and apoptosis, in addition to inhibiting migration. PMID- 26622740 TI - Three-way complex variant translocation involving short arm chromosome (1;9;22)(p36;q34;q11) in a chronic myeloid leukemia patient. AB - Chronic myeloid leukemia (CML) is a disease of the clonal hematopoietic stem cells caused by a balanced translocation between the long arms of chromosomes 9 and 22. Overall, 90-95% of CML patients present with a Philadelphia (Ph) chromosome t(9;22)(q34;q11) translocation and in addition, variant complex translocations, involving a third chromosome, are observed in 5-8% of CML patients. Cytogenic testing using bone marrow sample was performed and the FISH test was used for the detection of BCR-ABL fusion gene and complete blood analysis of CML patient was also performed. Results of hematological analysis showed the induced values of white blood cells (168,5000/mm3) and platelets (300,000/mm3) and FISH analysis test showed that 98% cells were positive for BCR/ABL gene translocation. The present study describes a three-way (1;9;22)(p36;q34;q11) Ph chromosome translocation in a 24-year-old female with CML. The patient, who was in the chronic phase of the disease, was treated with daily dose of 400 mg/dl with imatinib mesylateand was monitored constantly at various intervals over a 6-month period. Many studies reported that certain CML patents with variant translocation responded poorly to imatinib. In the current case report, the CML patient exhibited a suboptimal response to imatinib, denoting a poor prognosis. PMID- 26622741 TI - Marginal zone B-cell lymphoma of the pulmonary mucosa-associated lymphoid tissue: A case report. AB - Marginal zone B-cell lymphoma of the pulmonary mucosa-associated lymphoid tissue (pulmonary MALT-MZL) is a common type of primary pulmonary lymphoma, but is rare as a pulmonary malignant tumor. In the present study, a 49-year-old male patient was admitted to The First Affiliated Hospital of Xi'an JiaTong University (Xi'an, China) with a pulmonary lesion in the right upper lung. The patient was diagnosed with pulmonary MALT-MZL subsequent to undergoing chest computed tomography (CT), a routine blood test, pathological and histological examinations, a transbronchial lung biopsy and bronchoscopy. A chest CT scan revealed right middle lobe consolidation and inflammatory signs, accompanied by mediastinal lymphadenopathy in the anterior basal segment of the upper lobe and CT angiogram signs. Bronchial stenosis and swollen mucosa were observed by bronchoscopy. The tissue section of the transbronchial lung biopsy specimens revealed diffusely infiltrated monocytoid B-cell lymphocytes and a lymphoepithelial lesion. The tissue was found to be positive for cluster of differentiation (CD)20, B-cell lymphoma 2 and CD79a expression, but negative for CD3, CD5, cyclin D1 and kappa light chain expression. CD21 and CD23, located in the residual follicular dendritic cells, were detected by immunohistochemical staining. The clinical manifestations of pulmonary MALT-MZL are non-specific and misdiagnosis frequently occurs in clinical practice. Therefore, an appropriate invasive biopsy procedure is necessary for early and accurate diagnosis of pulmonary MALT-MZL. Clinical presentation that includes periodic fever and distended bronchi in pulmonary consolidation may indicate a diagnosis of MALT-MZL. Pulmonary MALT-MZL belongs to the category of indolent lymphoma and accurate clinical diagnosis is challenging. The results in the present study may provide additional evidence for the accurate diagnosis of this rare entity. PMID- 26622742 TI - Piwil2 modulates the invasion and metastasis of prostate cancer by regulating the expression of matrix metalloproteinase-9 and epithelial-mesenchymal transitions. AB - Piwi-like RNA-mediated gene silencing 2 (Piwil2) is an oncogene that is highly expressed in breast, gastric, colorectal and papillary thyroid cancer. As a candidate oncogene, its role in prostrate cancer has yet to be elucidated. In the present study, 30 tumor specimens and four prostate cancer cell lines were analyzed. The total RNA and protein from the specimens and the cells were analyzed using quantitative polymerase chain reaction and western blotting, respectively. The expression of Piwil2 in PC-3 cells was knocked down using specific small hairpin RNA. Transwell assays and wound-healing models were used to assess cell invasion and migration. In addition, the expression of several factors associated with epithelial-mesenchymal transitions (EMT) were evaluated by western blotting. The results revealed that the Piwil2 gene was associated with the Gleason score and the tumor-node-metastasis stage of the tumor tissues. Cell invasion and migration decreased significantly in PC-3 cells with knocked down Piwil2. In addition, silencing Piwil2 downregulated the expression of N cadherin, Twist and vimentin and upregulated the expression of E-cadherin, factors associated with EMT, and also reduced the expression of matrix metalloproteinase-9. Piwil2 was demonstrated to possess an important role in the invasive ability of prostate cancer, and therefore, may be a potential therapeutic target for the treatment of this cancer. PMID- 26622743 TI - Associations and indications of Ki67 expression with clinicopathological parameters and molecular subtypes in invasive breast cancer: A population-based study. AB - Ki67 has potential prognostic and predictive values for breast cancer patients, and has become an important biomarker in routine clinical practice. The aims of the present study were to investigate the distribution of Ki67 expression and its correlation with other clinicopathological parameters in central China. In total, 1,259 patients with newly-diagnosed invasive breast cancer were included in the present study. The clinical information was obtained from the electronic medical records. The expression levels of Ki67, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) were detected by immunohistochemical analysis. The associations between Ki67 scores and other prognostic factors were evaluated as continuous and categorical variables. The mean value of the Ki67 scores of all patients was 31%. In total, ~36% (456/1,259) of the patients demonstrated a low expression of Ki67. A statistically significant correlation was identified between the mean Ki67 scores and the lymph node status, tumor grade, ER, PR and HER2 status, and clinical stage or molecular subtypes (all P<0.001). When Ki67 was categorized into high (>14%) and low (<=14%) level groups, the chi2 test was used to verify these results. The Ki67 scores demonstrated no statistically significant differences between the HER2 positive (non-luminal) and three negative subtypes, with the exception of patients with a tumor size of >2 cm (P=0.02). In conclusion, the results revealed the presence of significant correlations between Ki67 and other clinicopathological parameters. PMID- 26622744 TI - Association between prognostic factors and clinical outcome of well differentiated thyroid carcinoma: A retrospective 10-year follow-up study. AB - Differentiated thyroid carcinoma (DTC) is one of the most common metabolic disorders and accounts for 98% of all cases of thyroid cancer. Previously, a number of studies have investigated the prognostic factors associated with well differentiated thyroid carcinoma (WDTC); however, these studies yielded conflicting results. The current study used a retrospective study design to collect data from WDTC patients who had received the same treatment regimen from the same institute, with a minimum follow-up of 10 years. The De Groot staging system was used to classify WDTC in a total of 320 patients (240 females and 80 males). Among the subjects, the pathological subtypes identified were as follows: Papillary carcinoma (240 cases, 75%), follicular carcinoma (67 cases, 21%) and Hurthle cell carcinoma (13 cases, 4%). Prognostic factors that significantly affected the clinical outcome of the disease were advanced age (P=0.001), tumor size (P=0.03), presence of thyroglobulin (P=0.001) and De Groot stage (P=0.005). The 10-year follow-up study revealed that WDTC is associated with a high survival rate of 96% (307/320 patients survived) and a low mortality rate (4%). PMID- 26622745 TI - Primary cerebellopontine angle ependymoma with spinal metastasis in an adult patient: A case report. AB - Subtentorial ependymoma is a common central nervous system tumor in young children, but is uncommon in adults. Ependymoma often arises from the cells lining the fourth ventricle. The present study reports a rare case of primary ependymoma that originated from the cerebellopontine angle, with local extension to the two internal auditory canals and remote spinal metastasis, in an adult male. A 50-year-old male presented with headache, tinnitus and bilateral hearing loss that had persisted for 4 months. Magnetic resonance imaging (MRI) revealed a mass in each of the cerebellopontine angles, which had spread to each internal auditory canal and wrapped the VII/VIII cranial nerve complex. A gross total resection was performed to remove the mass in the right side. Histological examination confirmed that the tumor was a World Health Organization grade II papillary ependymoma. Notably, the patient complained of urine retention post surgery and massive occupational lesions in T3-T4 and L5-S2 were found on full spinal cord MRI. The patient then received combination therapy consisting of temozolomide, and whole-brain and spinal cord radiation. In the final follow-up examination, performed 13 months after treatment, slight shrinkage of the T3 lesion was observed, and no progression of the left cerebellopontine angle and S5 L2 lesions were identified on MRI. In summary, although this clinical entity is rare, the diagnosis of ependymoma and the possibility of spinal cord metastasis should be considered in subtentorial tumors. PMID- 26622746 TI - Transcatheter arterial chemoembolization as an examination method for hepatocellular carcinoma undetected by B-mode ultrasound, computed tomography and digital subtratcion angiography: A case report. AB - Transcatheter arterial chemoembolization (TACE) is the conventional treatment for patients with unresectable hepatocellular carcinoma (HCC), but few studies to date have demonstrated the use of TACE as an examination method for uneasily detected HCC. The present study describes an unusual case of HCC with TACE as an examination method. A 41-year-old male presented with an elevated alpha fetoprotein level (AFP) of 3,635 ng/ml, however, no tumor lesions were detected by B-mode ultrasound, computed tomography (CT) or digital subtraction angiography. During TACE treatment, two tumor lesions of ~0.5 and 0.8 cm were revealed in the right liver lobe, with no tumors in the left liver lobe. A month after TACE, a liver CT scan found 11 lesions (8 in the right liver lobe and 3 in the left liver lobe). The HCC patient's AFP levels decreased to an almost normal level following the TACE treatment. This study provokes consideration of the application of TACE in the diagnosis and treatment of HCC patients with liver lesions that are hard to detect by conventional means. PMID- 26622747 TI - Cerebral tumefactive demyelinating lesions. AB - Tumefactive demyelinating lesions (TDLs), are a rare demyelinating pathological disease in the central neurological system, which have been proven to be a diagnostic dilemma to neurosurgeons. The clinical presentation and radiographic appearance of these lesions often results in their misdiagnosis as intracranial tumors, such as gliomas, which leads to unnecessary surgical resection and adjunct radiation. In the present study, the clinical and radiographic features of 14 patients with cerebral TDLs who underwent surgical treatment between January 2004 and January 2009 were reviewed and analyzed. The surgical methods used included biopsy and resection, while steroid therapy was indicated when TDLs were confirmed by histopathological analysis. The patients were followed-up and the outcomes were evaluated using the Karnofsky performance scale (KPS). The main clinical presentations included: Hemiplegia (8 cases), increased intracranial pressure (4 cases) and seizures (general in 1 case; partial in 3 cases). On magnetic resonance imaging scans, 12/14 TDL cases demonstrated an isolated local subcortical mass and 6/14 cases (42.9%) demonstrated enhancing veins coursing undistorted through the lesion. The postoperative complications included: Hemiplegia (2 cases) and mortality (1 case). A total of 9 cases underwent microsurgical total resection, and 5 cases received stereotactic biopsy that was followed with high-dose methylprednisolone therapy. The follow-up study demonstrated that 2 cases presented recurrence with multiple sclerosis and the KPS scores for 13/14 patients (92.9%) were >=80. In conclusion, the clinical and radiographic features of TDLs may help to establish the correct diagnosis prior to surgery, in order to avoid unnecessary resection or adjunctive therapy. Using steroid therapy, the majority of patients with TDLs appeared to achieve satisfactory prognosis. PMID- 26622748 TI - Alteration of DNA damage signaling pathway profile in radiation-treated glioblastoma stem-like cells. AB - The present study aimed to investigate the alteration of the DNA damage signaling pathway profile in radiation-treated glioblastoma stem-like cells (GSLCs), and also aimed to explore potential targets for overcoming glioblastoma radioresistance. Serum-free medium was used to isolate and culture GSLCs. Cell growth was detected using a cell counting kit-8 assay and cell sorting analysis was performed by flow cytometry. X-ray irradiation was produced by a Siemens Primus linear accelerator. Reverse transcription-quantitative polymerase chain reaction (qPCR)was performed to investigate target genes. SPSS 15.0 was used for all statistical analyses. Human glioblastoma U251 and U87 cells were cultured in serum-free medium supplemented with epidermal growth factor and fibroblast growth factor 2, which constitutes tumor sphere medium, and demonstrated sphere formation, with significantly increased the proportion of CD133+ and Nestin+ cells, which are referred to as GSLCs. The present data revealed that treatment with 10 Gy X-ray radiation alters the expression profile of DNA damage-associated genes in GSLCs. The expression levels of 12 genes demonstrated a >=2-fold increase in the irradiated U87 GSLCs compared with the untreated U87 GSLCs. Three genes, consisting of XPA, RAD50 and PPP1R15A, were selected from the 12 genes by gene functional searching and qPCR confirmatory studies, as these genes were considered to be potential targets for overcoming radioresistance. The expression of XPA, RAD50 and PPP1R15A is significantly increased in U87 and U251 radiation resistant GSLCs, indicating three potential targets for overcoming the radioresistance of GSLCs. PMID- 26622749 TI - Ethnicity affects EGFR and KRAS gene alterations of lung adenocarcinoma. AB - Mutations or copy number gains (CNGs) of the EGFR and KRAS genes are representative alterations in lung adenocarcinomas that are individually associated with patient characteristics such as ethnicity, smoking status and gender. However, the effects of combinations of these genetic alterations have not been statistically examined. The present study analyzed previously examined lung adenocarcinoma cases in Asian (n=166) and non-Asian (n=136) individuals in whom all four EGFR and KRAS alterations had been studied. The polynomial logistic regression models were used following adjustment for gender and smoking status, and using patients without any type of EGFR/KRAS alterations as a reference. Between the two ethnic groups, EGFR CNGs (gEGFR) occurred more frequently than EGFR mutations (mEGFR) (46 vs. 38% in Asians; 21 vs. 10% in non-Asians), whereas KRAS mutations (mKRAS) were more frequent than KRAS CNGs (gKRAS) (13 vs. 7% and 35 vs. 4%, respectively). Additionally, gEGFR and gKRAS occurred significantly more frequently in respective mutant cases, and all EGFR alterations were almost exclusive of all KRAS alterations. The polynomial logistic regression models confirmed that all types of EGFR alterations were significantly more frequent among Asian individuals than among non-Asian individuals, independent of gender and smoking status (odds ratios, 2.36-6.67). KRAS alterations occurred less frequently among Asian individuals than among non-Asian individuals, although a significant difference was not detected. The present study results indicated that the EGFR and KRAS profiles, including mutations and CNGs, differ between Asian and non-Asian individuals with lung adenocarcinoma, suggesting that ethnicity strongly affects the molecular characteristics of lung adenocarcinoma. PMID- 26622750 TI - Diagnosis and treatment of accessory breast cancer in 11 patients. AB - The present study aimed to investigate the clinical characteristics, diagnosis and treatment of accessory breast cancer, and contribute valuable information regarding this rare tumour to the current literature, ultimately facilitating the development of improved treatment strategies. The present study reported the cases of 11 patients with accessory breast cancer. The patients with accessory breast cancer were admitted between January 2002 and June 2014, and the patient records were retrospectively analysed. All patients presented with a tumour that was localised in the axilla. Out of these patients, there were 8 patients with invasive ductal carcinoma and 3 patients with invasive lobular carcinoma. The follow-up periods for patients ranged between 4 and 54 months. Out of the 5 patients that experienced neoplasm metastases, 4 patients succumbed to the disease. In total, 6 patients remain alive with no evidence of disease. Accessory breast cancer is a progressive tumour, and long-term follow-up is required. A comprehensive treatment strategy may be an effective treatment option for patients; however, the optimal time at which to commence chemotherapy and the role of combined radiotherapy and endocrine therapy require additional investigation. PMID- 26622751 TI - POEMS syndrome with vascular transformation of the lymph node sinuses: A case report. AB - POEMS syndrome is a rare multisystem disorder associated with the clinical signs of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes. However, there is often a delay in the diagnosis due to a lack of overall consideration of the symptoms collectively. For this reason, POEMS syndrome is frequently mistaken for other diseases, such as chronic inflammatory demyelinating polyneuropathy. The present study reports the case of a 40-year-old female patient, who presented with a progressive lack of strength in the lower limbs and a unilateral cervical lump. The patient's enlarged cervical lymph nodes were mistaken for local hemangioma. However, subsequently POEMS syndrome with vascular transformation of the lymph node sinuses (VTS) was diagnosed. The patient received glucocorticoid treatment (20 mg prednisone acetate, daily), which is ongoing. The most recent follow-up examination revealed that the patient's strength had improved and at the time of writing the patient remained alive. The study discusses the clinical manifestations, auxiliary examinations and reason for the misdiagnosis. Hematoxylin and eosin staining and cluster of differentiation 31 immunostaining were adopted to identify the VTS. To the best of our knowledge, this is the first report of POEMS syndrome with VTS. PMID- 26622752 TI - A phase II double-blinded study to evaluate the efficacy of EW02 in reducing chemotherapy-induced neutropenia in breast cancer. AB - EW02, a polysaccharide-enriched crude extract from black soybean, has been shown to assist hematopoiesis in chemotherapy-treated animals. The present study aimed to clarify the safety, quality of life (QOL) and efficacy for myelopoiesis of EW02 administration in early breast cancer (EBC) patients receiving adjuvant chemotherapy. A total of 60 eligible EBC patients were enrolled in a randomized, double-blinded trial, 40 of whom were prescribed 700 mg oral EW02 three times daily for 15 days in chemotherapy cycle (C)2. The remainder were prescribed a placebo. All subjects took EW02 in C3 for 15 days. Blood samples were collected at different time-points for determining the blood cell count, and the serum level of granulocyte colony-stimulating factor (G-CSF) and interleukin (IL)-6. All patients tolerated EW02 well without severe side-effects. QOL evaluation showed that only the score of one questionnaire section (QLQ-C30) was significantly increased at C1 day (D)8 to C2D8 when the EW02 and placebo groups were compared (P=0.045). No significant myelopoiesis recovery, and no incremental change in IL-6 and G-CSF levels were found in C2. Subgroup analysis showed a slightly lower decrease in absolute neutrophil count (ANC) in the EW02 patients who underwent Adriamycin + cyclophosphamide treatment compared with the placebo group. Although EW02 failed to show efficacy for myelopoiesis in the present study, EW02 was still well tolerated in EBC patients who underwent adjuvant chemotherapy. PMID- 26622753 TI - Prognostic factors for elderly patients with primary malignant bone and soft tissue tumors. AB - The number of patients with primary malignant bone and soft tissue tumors in Japan is increasing in line with the increasing size of the elderly population. The aim of the present study was to determine the prognostic factors of primary malignant bone or soft tissue tumors in elderly patients. Clinical data was obtained from 90 patients, aged >=65 years, with primary malignant bone or soft tissue tumors (bone, 20 cases; and soft tissue, 70 cases), treated at the Osaka City University Hospital between 1993 and 2013. Clinical information prior to treatment and tumor type, location, size, depth, grade and American Society of Anesthesiologists-Physical Status (ASA-PS) score were evaluated in order to identify prognostic factors using the Cox proportional hazards regression model. In addition, 5-year survival rates were evaluated using the Kaplan-Meier method. The average follow-up period was 44.8 months and the 5-year overall survival rate was 77.5%. In the multivariate analysis, ASA-PS score and high-grade sarcoma were found to be associated with a poorer overall survival. No significant differences were observed between the patient group aged 65-74 years and that aged >=75 years. In general, aging is associated with physically reduced function and an increased prevalence of comorbidities. It was therefore expected that increasing age may be a predictive factor for poor prognosis. However, the results of the present study suggested that ASA-PS score and tumor grade were significant factors associated with poor prognosis, whereas increasing age was not. Therefore, the treatment of elderly patients with primary bone and soft tissue tumors should not be based on age. PMID- 26622754 TI - Nasopharyngeal chordoma in a patient with a severe form of sleep-disordered breathing: A case report. AB - Nasopharyngeal chordoma is a rare type of malignant neoplasm that originates in the remnants of the notochord, a primitive tissue of embryonic origin preserved outside the axial skeleton. Approximately one-third of chordomas are located in the base of the skull, in the midline of the body. The slow growth rate of the tumor, which gradually fills the nasopharyngeal cavity, contributes to a delayed oncological diagnosis. Among its isolated and non-specific symptoms, the obstruction of the nasopharynx is dominant, thus, sleep-disordered breathing (SDB) may occur. The current study presents the case of a 32-year-old female patient who was incidentally diagnosed with a nasopharyngeal chordoma during a diagnostic examination for SDB. The diagnostic examination was performed as a part of a research program for pathologically obese patients who qualified for bariatric surgery. Following tumor resection, a significant improvement in various polysomnographic parameters occurred, including a decrease in the apnea hypopnea index from 53.5 to 6.4 and an increase in the mean saturation rate from 92.5 to 95%, confirming that an association exists between tumor obstruction of the nasopharynx and SDB. The incidental diagnosis of this rare type of neoplasm drew attention to diagnostic and therapeutic problems associated with nasopharyngeal chordomas. Furthermore, it indicated the necessity for the accurate laryngological examination of patients with SDB. PMID- 26622755 TI - Ruptured thymoma causing a hemothorax: A case report. AB - A thymoma is a neoplasm that arises from the epithelial cells of the thymus, and may cause various signs and symptoms dependent upon its local extent. A non traumatic hemothorax is extremely rare. The present study reports the case of a 77-year-old female who presented with an acute onset of chest pain. Imaging procedures revealed a mass occupying the anterior mediastinum and left hemithorax, and a left pleural effusion. Progressive anemia was noted following admission. Left hemothorax due to rupture of the anterior mediastinal mass was suspected, and emergency surgery was performed. Hemorrhage was observed on the cut surface of the tumor. An analysis of frozen sections indicated a thymoma, and a thymo-partial thymectomy was subsequently performed to remove as much of the hematoma as possible. The patient was discharged on post-operative day 13 following an uneventful recovery. The present case suggests that in previously healthy individuals, sudden-onset dyspnea and chest pain co-occurring with an acute widening of the mediastinum observed on roentgenograph may be indicative of a ruptured thymoma. PMID- 26622756 TI - Receptor activator of nuclear factor kappaB expression is a prognostic factor in human osteosarcoma. AB - Receptor activator of nuclear factor kappaB (RANK), a member of the tumour necrosis factor family, is activated by its ligand and regulates the differentiation of osteoclasts and dendritic cells. Local growth of osteosarcoma involves destruction of the host bone by osteoclasts and proteolytic mechanisms. Although the prognosis of patients with osteosarcoma has been improved by advances in chemotherapy over the last four decades, the issues of non responders, and the lack of effective prognostic markers have remained. The present study aimed to investigate the prognostic and predictive value of RANK expression in human osteosarcoma. The expression of RANK was immunohistochemically evaluated in biopsies of 43 patients (mean age 25.4 years) with high-grade osteosarcoma, and was found to be correlated with histological response to chemotherapy, disease-free status and overall survival. RANK expression was detected in eight of the 43 osteosarcoma specimens (18%), whereas the remaining specimens were negative for RANK. A statistically significant correlation was detected between RANK expression and the overall survival of patients. A total of 7/8 patients with RANK-expressing tumours succumbed to the disease (88% mortality rate amongst patients with RANK-positive tumours vs. 37% with RANK-negative tumours; P<0.05). No significant difference was found when comparing RANK expression status with response to chemotherapy; 50% of RANK positive patients exhibited a poor response to chemotherapy, compared with 66% in the RANK negative group. In addition, the appearance of metastases was not correlated with RANK expression status (38% metastases in RANK-positive tumours vs. 34% in RANK-negative tumours). In conclusion, the results of the present study suggested that RANK expression is likely to be of prognostic, but not of predictive, value. PMID- 26622757 TI - Metanephric adenoma with diffuse calcifications: A case report. AB - Metanephric adenoma is a rare and benign renal neoplasm originating in the epithelial cells of the kidney. The tumor has a benign course and a characteristic histopathological appearance, typically exhibiting a solid and poorly-demarcated margin with rare cystic components or calcifications. However, it is often difficult to distinguish metanephric adenoma from malignant neoplasms prior to surgical resection. To the best of our knowledge, only one case of metastasis to the lymph nodes has been described in the literature thus far. The present study retrospectively analyzed one case of surgically and pathologically confirmed atypical metanephric adenoma. Clinical and pathological analysis, as well as computed tomography scans, revealed a mass with a clearly defined margin and diffuse calcifications. The mass was subsequently resected and the patient recovered well following the procedure. PMID- 26622758 TI - Bak Foong pills combined with metformin in the treatment of a polycystic ovarian syndrome rat model. AB - The aim of the present study was to investigate the treatment effects and associated mechanism of Bak Foong pills (BFPs) combined with metformin in the treatment of polycystic ovarian syndrome (PCOS). BFPs and/or metformin were administrated to treat the PCOS rats, and the weights and morphologies of the ovary, uterus and adrenal gland were measured. The levels of fasting blood glucose (FBG), serum testosterone (T), luteinizing hormone, fasting insulin (FIN) and insulin-like growth factor-1 were also measured, and the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. The expression level of androgen receptor (AR) in the ovarian tissue, and the cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc) mRNA levels in the ovary and adrenal tissues were detected. The levels of T, FIN, FBG and HOMA-IR in the combination group were significantly reduced; the wet weights of the ovary and the adrenal gland were decreased significantly, while that of the uterus was increased, and the histological morphology benignly recovered. The rats of each treatment group all experienced restored ovulation. The AR expression level in the treatment group was reduced, and the P450scc mRNA levels in the ovary and the adrenal gland of the combined treatment group were decreased. BFPs combined with metformin significantly affected PCOS, and the possible mechanism involved in the treatment may have been through the reduction of P450scc generation. BFPs may reduce the androgen levels, thus allowing the ovary to restore ovulation. PMID- 26622759 TI - Autologous peripheral blood stem cell transplantation in children and adolescents with non-Hodgkin lymphoma. AB - The aim of this study was to evaluate the effect and safety of autologous peripheral blood stem cell transplantation (APBSCT) in children and adolescents with non-Hodgkin lymphoma (NHL). Ten patients with NHL were analyzed retrospectively. In all the patients, lymph node enlargement was most frequently detected. Patients with a mediastinal mass presented with a cough, palpitation and shortness of breath. Extranodal patients presented with abdominal pain, inability to walk and vaginal bleeding. All patients underwent APBSCT with conditioning regimens BEAM or BuCy. Among them, four patients with B-cell NHL received rituximab in addition to the conditioning regimen. Hematopoietic reconstitution was observed in all patients. Severe toxicity and transplant related mortality were not observed. Prior to APBSCT, nine patients with a status of complete response (CR) and CR unconfirmed achieved continuing complete remission. Only one patient with partial response succumbed to progressive disease. APBSCT in children and adolescents with NHL is a safe, convenient and efficient treatment. The BEAM conditioning regimen was shown to be effective and tolerable for children and adolescents with NHL. Rituximab is a safe agent in the transplantation. The CR status at the time of transplantation demonstrated a higher survival rate. PMID- 26622760 TI - Wogonoside induces apoptosis in Bel-7402, a hepatocellular carcinoma cell line, by regulating Bax/Bcl-2. AB - The anticancer effect of Scutellaria baicalensis extract has recently become a topic of interest. In this study, the anticancer effects and underlying mechanisms of wogonoside, the main constituent of Scutellaria baicalensis, were investigated in a human hepatocellular carcinoma (HCC) cell line in vitro. The effects of wogonoside on the proliferation, cell cycle progression and apoptosis of hepatocellular carcinoma cells were examined. Western blotting was employed to analyze the proteins associated with the biological effects of wogonoside. Wogonoside exerted anti-proliferation properties in vitro. HCC cell growth was attenuated by wogonoside (8 uM) treatment. Cell cycle progression analysis and DNA ladder assay revealed that apoptosis was enhanced in wogonoside-treated cells and that cell cycle arrest occurred in the G2/M phase. It was also demonstrated that increased apoptosis was accompanied by increased levels of Bax protein and decreased levels of Bcl-2 protein. The results of this study suggest that wogonoside may represent a potential therapeutic agent against HCC. PMID- 26622761 TI - Treatment with near-infrared radiation promotes apoptosis in pancreatic cancer cells. AB - Cancer remains one of the leading causes of human mortality worldwide. Radiation and chemotherapy are commonly used for cancer treatment; however, the combination of these therapies and surgery do not completely eradicate cancer cells. Near infrared radiation (NIR) is a low-energy form of radiation that exerts multiple effects on mammalian cells. Previous studies have reported that NIR induces DNA double-strand breaks and apoptosis of cancer cells. In the present study, a 915 nm laser was used to examine the effects of NIR on pancreatic cancer cells. Irradiation of pancreatic cancer cells using a 915-nm laser significantly induced caspase-3 activation and apoptosis. In addition, the combination of gemcitabine treatment and a 915-nm laser synergistically increased the number of apoptotic cells. The results of the present study indicate the use of infrared irradiation and chemotherapy may be a possible therapy for the treatment of cancer. PMID- 26622762 TI - Peroxiredoxin 1 suppresses apoptosis via regulation of the apoptosis signal regulating kinase 1 signaling pathway in human oral leukoplakia. AB - Peroxiredoxin 1 (Prx1) has a significant role in several malignant types of tumor. However, the role of Prx1 in oral leukoplakia (OLK) has remained to be elucidated. OLK is a common precancerous lesion of the oral mucosa that has a very high malignant transformation rate. The aim of the present study was to investigate the roles of Prx1, and its association with apoptosis signal regulating kinase 1 (ASK1) and p38 in OLK. A total of 20 OLK samples and 10 normal oral mucosa samples were obtained from patients at the Beijing Stomatological Hospital (Beijing, China). The messenger RNA (mRNA) and protein expression levels of Prx1, ASK1 and p38 were determined by polymerase chain reaction and western blot analysis, respectively. Flow cytometry was used to detect cell apoptosis. The interaction between Prx1 and ASK1 was examined in H2O2 treated DOK cells by glutathione-S-transferase pull-down assays and by co immunoprecipitation in vitro. Compared with those of the normal oral mucosa, the mRNA levels of Prx1, ASK1 and p38 were elevated in OLK tissues (P<0.05). The protein expression levels of Prx1, phosphorylated-ASK1 (p-ASK1) and p-p38 were also significantly enhanced in OLK tissues compared with those of the normal mucosa (P<0.05). In Prx1-knockdown DOK cells, ASK1 and p38 were activated, leading to enhanced levels of apoptosis in response to H2O2. No clear interaction between Prx1 and ASK1 was detected in H2O2-treated DOK cells. Prx1 was suggested to be involved in OLK pathogenesis by providing resistance against extracellular damages from oxidative stress via inhibition of the ASK1-induced apoptotic signaling pathway. Targeting Prx1 may provide a novel therapeutic strategy for the treatment of patients with OLK. PMID- 26622763 TI - Identification and functional study of osteosarcoma metastasis marker genes. AB - To date, osteosarcoma metastasis genes, which are key for accurate initial diagnosis of the disease, have not been well identified. In the present study, osteosarcoma samples with and without metastasis were collected from 31 patients. Specific complementary DNA subtraction techniques were used to identify the osteosarcoma metastasis transcripts, which are responsible for the metastasis of osteosarcoma. The specific differentially expressed transcripts were identified by Basic Local Alignment Search Tool analysis and the results were validated by immunoblotting. Specifically, ezrin and beta4 integrin were employed as markers to detect osteosarcoma metastasis in the initial stages. The results of the present study indicated that the two transcripts, ezrin and beta4 integrin, were highly expressed in patients with osteosarcoma metastasis, and concluded that these were osteosarcoma metastasis genes. These results indicate that beta4 integrin and/or ezrin may be used as a novel marker for the detection of osteosarcoma metastasis in the initial stages. PMID- 26622764 TI - Common molecularcytogenetic alterations in tumors originating from the pineal region. AB - Tumors of the pineal region (PR) are rare and can be subdivided into four main histomorphological groups: Pineal-parenchymal tumors (PPT), germ cell tumors (GCT), glial tumors and miscellaneous tumors. The appropriate pathological classification and grading of these malignancies is essential for determining the clinical management and prognosis. However, an early diagnosis is often delayed due to unspecific clinical symptoms, and histological support is not always decisive to identify the diversity of tumors of the PR. The present study aimed to characterize 18 tumors of the PR using comparative genomic hybridization. All the tumors were primarily surgically resected without any previous irradiation or chemotherapy. In addition to chromosomal aberrations in PPT and different GCTs of the PR, the present study described, for the first time, the chromosomal changes in a few rare entities (solitary-fibrous and neuroendocrine tumors) of the PR. The tumors in the study, regardless of histology and World Health Organization grade, were characterized by frequent gains at 7, 9q, 12q, 16p, 17 and 22q, and losses at 13q. While the detection of chromosomal aberrations in these tumors appears not to be indicative enough of histological entities and their grade of malignancy, the present data may be of use to select genes of interest for higher resolution genomic analyses. PMID- 26622765 TI - Acute promyelocytic leukemia harbouring rare FLT3-TKD and WT1 mutations: A case report. AB - The involvement of the central nervous system (CNS) is rare in acute promyelocytic leukemia (APL). The present study reported the case of a 34-year old male patient with APL that possessed a rare point mutation (p.Asn841Gly, c.2523C>A) in the tyrosine kinase domain of the FMS-like tyrosine kinase 3 (FLT3) gene and a novel Wilm tumor gene mutation (c.1209_1210insT/p.K404X). The patient suffered central nervous system and systemic relapses twice during systemic and intrathecal chemotherapy. At present, the patient is undergoing alternative induction and consolidation therapies, including the administration of FLT3 inhibitor, tetraarsenic tetrasulfide and novel cytotherapy, and is prepared for salvage allogeneic hematopoietic stem cell transplantion (allo-HSCT). The present study indicated that patients with APL that are at a high risk of relapse and unfavorable gene mutations should receive immediate allo-HSCT, whenever possible. PMID- 26622766 TI - Cyclooxygenase-2 gene polymorphisms and the risk of colorectal cancer: A population-based study. AB - The aim of the present study was to determine the association between polymorphisms in the cyclooxygenase-2 (COX-2) gene promoter region, rs20417 G/C and rs2745557 G/A, and the susceptibility to colorectal cancer (CRC) in a Han Chinese population in Shaanxi, China. Polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) were used to detect the polymorphisms of COX-2, rs20417 G/C and rs2745557 G/A, in 300 patients with CRC and 300 healthy individuals in the present case-control study. The results revealed that for the COX-2 rs20417 G/C polymorphism, the GC+CC allele frequency was 80% in CRC patients and 71% in healthy controls [odds ratio (OR)=1.63; 95% confidence interval (CI), 1.12-2.38; P=0.01]. For the COX-2 rs2745557 G/A polymorphism, the GA+AA allele frequency was 84% in CRC patients and 73% in healthy controls (OR=1.94; 95% CI, 1.30-2.90; P<0.01). In addition, among individuals with a smoking history, drinking history or family history of CRC, those who were COX-2 rs20417 (GC+CC) or COX-2 rs2745557 (GA+AA) carriers had a significantly increased risk of developing CRC compared with that of GG genotype carriers (P<0.05). Furthermore, the allelic frequencies of COX-2 rs20417 G/C and rs2745557 G/A in patients with lymph node metastasis in stage III/IV of CRC were significantly different from those of COX-2 rs20417 G/C and rs2745557 G/A in patients without lymph node metastasis in stage I/II (P<0.05). In conclusion, the results of the present study revealed that COX-2 rs20417 C allele carriers and rs2745557 A allele carriers have a significantly increased risk of CRC compared with GG genotype carriers; in addition, the frequencies of these alleles were demonstrated to be associated with lymph node metastasis and CRC progression. PMID- 26622767 TI - Osterix transcriptional factor is involved in the metastasis of human breast cancers. AB - The transcriptional factor Osterix is specifically expressed in bone tissues to regulate the differentiation and maturation of osteoblasts. Recent studies have also identified the expression of Osterix in a number of cancer tissues, such as kidney and lung cancers. However, the association of Osterix with the metastasis of breast cancers has never been reported. The present study, for the first time, provides evidence supporting the involvement of Osterix in breast cancer metastasis. Western blotting was employed to investigate the expression of Osterix in a number of human breast cancer cell lines with different metastatic features. Gain-of-function and loss-of-function experiments were performed in MCF7 cells (low level of metastasis) and MDA-MB-361 cells (high level of metastasis). The expression of several metastasis-associated genes was analyzed by western blotting and quantitative polymerase chain reaction. A firefly luciferase-based reporter gene assay was conducted in order to study whether Osterix regulated the promoter activities of the MMP2 and MMP9 genes, which play critical roles in cancer metastasis. The results showed that Osterix was highly expressed in the MDA-MB-231 and MDA-MB-361 cells, but was not detectable in the MCF7 cells. The overexpression of Osterix in the MCF7 cells promoted the expression of VEGF, MMP9 and beta-catenin, while downregulating the expression of E-cadherin. In addition, suppression of Osterix expression in the MDA-MB-361 cells reversed the alteration of VEGF, MMP9, beta-catenin and E-cadherin expression. A reporter gene assay suggested that Osterix activated MMP2 and MMP9 promoter activity. In conclusion, Osterix is involved in the metastasis of human breast cancer and may be a target for the efficient treatment of human breast cancers. PMID- 26622768 TI - RAS/BRAF mutational status in familial non-medullary thyroid carcinomas: A retrospective study. AB - There are contrasting views on whether familial non-medullary thyroid carcinomas (FNMTCs) are characterized by aggressive behavior, and limited evidence exists on the prognostic value of BRAF and RAS mutations in these tumors. Thus, in the present study, clinicopathological features were analyzed in 386 non-medullary thyroid carcinomas (NMTCs), subdivided in 82 familial and 304 sporadic cases. Furthermore, the RAS and BRAF mutational statuses were investigated in a subgroup of 34 FNMTCs to address their clinical and biological significance. The results demonstrated that, compared with sporadic NMTCs, FNMTCs are characterized by significantly higher rates of multicentricity and bilaterality and are more frequently associated with chronic autoimmune thyroiditis. Notably, a statistically significant difference in the rates of multicentricity was observed by subgrouping familial tumors according to the number of relatives involved; those with >=3 affected relatives were more likely to be multicentric. Furthermore, the FNMTC cohort exhibited higher rates of tumors >4 cm in size with extrathyroidal or lymph node involvement. However, no significant difference was observed. Similarly, no differences were observed with respect to the age of onset or the patient outcome. The mutational profiling exhibited a rate of 58.8% for BRAF V600E mutations in familial tumors, which is at the upper limit of the mutational frequency observed in historical series of sporadic thyroid cancer. A high rate of NRAS mutations (17.6%) was also observed, mostly in the follicular variant histotype. Notably, compared with BRAF/RAS-wild type FNMTCs, the familial carcinomas bearing BRAF or NRAS mutations exhibited slightly higher rates of bilaterality and multicentricity, in addition to increased frequency of locally advanced stage or lymph node involvement. The present data support the theory that FNMTCs are characterized by clinicopathological features that resemble a more aggressive phenotype and suggest that RAS/BRAF mutational analysis deserves to be further evaluated as a tool for the identification of FNMTCs with a potentially unfavorable prognosis. PMID- 26622769 TI - Associations of the BRAF (V600E) mutation and p53 protein expression with clinicopathological features of papillary thyroid carcinomas patients. AB - The BRAF (V600E) mutation is the most prevalent type of genetic alteration that has been identified in papillary thyroid carcinoma (PTC); in addition, previous immunohistochemical studies have revealed the overexpression of p53 protein in PTC. The aim of the present study was to investigate the prevalence of the BRAF (V600E) mutation and the expression of p53 in PTC, as well as to determine any associations between these two factors and the clinicopathological features of PTC. The study was performed on 66 PTC patients who underwent surgical tumor resection between January and December 2012. Polymerase chain reaction-based DNA amplification was used to analyze extracted DNA from the tumor specimens in order to determine the prevalence of the BRAF (V600E) mutation. In addition, immunohistochemical analysis was employed in order to evaluate the protein expression of p53 in sections of tumor tissue. Furthermore, statistical analysis was performed in order to determine any associations among the BRAF (V600E) mutation prevalence, p53 overexpression and the clinicopathological features of PTC patients, including age, gender, tumor size, multiplicity, lymph node metastasis and extrathyroidal extension. The results revealed that the BRAF (V600E) mutation was observed in 50 (75.8%) of the 66 PTC patients and overexpression of p53 was found in 52 (78.8%) of 66 cases. No significant correlations were observed between the BRAF (V600E) mutation or p53 protein overexpression and the clinicopathological features of patients. However, the BRAF (V600E) mutation demonstrated noteworthy, but non-significant, correlations with the overexpression of p53 (P=0.0854) and extrathyroidal extension (P=0.0661). In addition, a significant correlation was observed between lymph node metastasis and bilaterality (P=0.0280). In conclusion, the present study demonstrated that the BRAF (V600E) mutation and overexpression of p53 were not significantly correlated with clinicopathological features of PTC, although notable associations were identified between BRAF (V600E) mutation and overexpression of p53 as well as extrathyroidal extension. In addition, lymph node metastasis was significantly associated with bilaterality. PMID- 26622770 TI - Transarterial embolization for pelvic hematoma following laparoscopic radical prostatectomy: A case report and review of the literature. AB - The present study reports a case of hemorrhage from branches of the right obturator artery following laparoscopic radical prostatectomy. On post-operative day 9, the patient complained of lower abdominal pain, and the hemoglobin and hematocrit levels had decreased. Emergency computed tomography angiography showed a large pelvic hematoma suggesting active bleeding. Transarterial embolization (TAE) was performed using microcoils. There were no post-procedure complications. At 3 months post-surgery, using computed tomography, the pelvic hematoma was shown to have been absorbed. To the best of our knowledge, TAE for a hemorrhage from the obturator artery following laparoscopic prostatectomy has not previously been described. TAE is a safe and minimally invasive treatment compared with surgical intervention, and should be considered as a treatment for post-operative arterial hemorrhage. PMID- 26622771 TI - Prognostic significance of combining VEGFA, FLT1 and KDR mRNA expression in lung cancer. AB - Angiogenesis is important in cancer progression. Promising results in clinical trials have indicated that targeting vascular epidermal growth factor (VEGF) signaling may prolong lung cancer patient survival. In particular, various studies have implicated VEGFA as a potential prognostic marker in lung cancer, although prognostication using the expression of VEGF receptors (VEGFRs), such as fms-related tyrosine kinase 1 (FLT1; also known as VEGFR1) and kinase insert domain receptor (KDR; also known as VEGFR2), has produced varied results in different lung cancer studies. The present study aimed to investigate the prognostic significance of these three factors, alone or in combination. mRNA expression data were extracted from four independent lung cancer cohorts totaling 583 patients, and the association between mRNA expression and survival was investigated by performing statistical analyses. When VEGFA, FLT1 and KDR expression were considered alone, only VEGFA demonstrated a significant association with patient survival consistently across all four datasets (P<0.05). Patients with a high expression of VEGFA and one of the two receptors were associated with significantly worse survival than patients expressing low levels of VEGFA and the particular receptor (P<0.05). Notably, patients with a high level expression of all three genes in their tumor specimens were associated with a significantly shorter survival time compared with patients exhibiting a low level expression of one, two or all three genes (P<0.05). The results indicate that a high level of VEGFA expression and its receptors may be required for cancer progression. Therefore, these three factors should be considered together as a prognostic indicator for lung cancer patients. PMID- 26622772 TI - Endocrine MPA enhances the effects of TAC chemotherapy on improvement of prognosis and increase in long-term survival rates for patients with endometrial cancer. AB - The aim of the present study was to investigate the effect of taxol, adriamycin and carboplatin (TAC) chemotherapy combined with endocrine medroxyprogesterone acetate (MPA) therapy for the treatment of patients with endometrial cancer. A retrospective analysis of 124 patients with endometrial cancer was performed by dividing the cohort into an experimental and control group. The 64 patients in the experimental group received TAC and MPA chemotherapy, whereas the 60 patients in the control group were treated with TAC chemotherapy only. Tissue samples scraped from the uterus were used to extract the total proteins and RNAs for the western blot and reverse transcription-quantitative polymerase chain reaction analyses, respectively. All the patients were followed up for 20-45 months, during which time prognostic data, and one- to three-year survival rates were recorded and compared. The rate of recurrence or metastasis was significantly lower in the experimental group compared with that in the control group (P<0.05) and the three-year survival rate of the experimental group was significantly higher than that of the control group (P<0.05). Furthermore, the mean metastasis associated 1 (MTA1) protein and RNA expression levels were significantly lower in the experimental group compared with the control group (P<0.05), exhibiting ~30 and ~15% of the levels in the control group, respectively. Therefore, a treatment strategy of TAC chemotherapy combined with endocrine MPA therapy appears to effectively improve the prognosis and increase the long-term survival rates of patients with endometrial cancer. Such an enhancing effect may be mediated by the transcriptional downregulation of MTA1 expression. PMID- 26622773 TI - Inhibition of p38 mitogen-activated protein kinase potentiates the apoptotic effect of berberine/tumor necrosis factor-related apoptosis-inducing ligand combination therapy. AB - It was previously reported that berberine (BBR) and tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) exhibited a synergistic apoptotic effect on triple negative breast cancer (TNBC) cells. In addition, the BBR/TRAIL combination treatment sensitized TRAIL-resistant TNBC cells to TRAIL. The aim of the present study was to investigate a novel pathway for enhancing the apoptotic effect of BBR/TRAIL through mitogen-activated protein kinases (MAPKs). Selective inhibitors and small interfering RNAs were utilized to understand the role of p38 MAPK in this pathway. The results demonstrated that p38 MAPK was activated in response to the combination therapy in TRAIL-resistant TNBC cells. In addition, it was revealed that the inhibition of p38 enhanced apoptosis in epidermal growth factor receptor (EGFR)-overexpressing MDA-MB-468 TNBC cells and EGFR-mutant PC-9 non-small-cell lung carcinoma cells, which was associated with the downregulation of EGFR serine phosphorylation. Viability assays for these two cell lines also confirmed the significant reduction of cell viability following p38 inhibition in BBR/TRAIL-treated cells. In conclusion, the present study provided novel evidence for the role of p38 in suppressing BBR/TRAIL-mediated apoptosis and its association with EGFR, which may explain the mechanism of treatment resistance in certain types of cancer. PMID- 26622774 TI - PU.1 affects proliferation of the human acute myeloid leukemia U937 cell line by directly regulating MEIS1. AB - The transcription factor PU.1 is a member of the ETS family, which is expressed in a wide variety of hematopoietic lineages. Accumulating evidence has indicated that PU.1 plays a key role in hematopoiesis, and reduced expression of PU.1 leads to the pathogenesis of human myeloid leukemia. As a multi-functional factor, PU.1 is also required for mixed lineage leukemia (MLL) stem cell potential and the development of MLL. However, the function of PU.1 in human non-MLL leukemia and its molecular mechanism remains poorly understood. In the present study, PU.1 siRNA was demonstrated to efficiently inhibit the transcription level of oncogene MEIS1 in the human acute myeloid non-MLL leukemia U937 cell line. In addition, PU.1, as a positive regulator of MEIS1, performed a crucial role in maintaining cell proliferation. Using electrophoretic mobility shift assay, chromatin immunoprecipitation analysis and luciferase reporter assay, previously unexplored evidence that PU.1 activated the MEIS1 promoter through a conserved binding motif in vitro and in vivo was further defined. Overall, the present study provides insight into the molecular mechanism of the contribution of PU.1 to the pathogenesis of non-MLL U937 cells, which is mediated by direct regulation of MEIS1 transcription. The present data reveal the possibility of developing an alternative therapy for non-MLL leukemia by targeting PU.1-mediated MEIS1 gene activation. PMID- 26622775 TI - The effect of two nucleoside antitumor drugs on the proliferation and DNA methylation of human gastric cancer cells. AB - Fluorouracil (5-Fu) and 5-azacitidine (5-aza) are two types of nucleoside analog, which have been widely applied in the treatment of several types of cancer. However, the effect of these two types of drug on the proliferation and DNA methylation of cancer cells has not been compared in a single study. In the present study, in vitro cultured human gastric cancer cells (hGCCs) were treated with various concentrations of 5-Fu and 5-aza, and cell counting, MTT assay and methyl-sensitive amplified polymorphism were used to evaluate the resulting levels of proliferation and DNA methylation of hGCCs. The results revealed that the two drugs were able to inhibit the proliferation of hGCCs, but that the effect of 5-aza was weaker than that of 5-Fu. However, 5-aza decreased the level of DNA methylation in hGCCs, whereas 5-Fu did not alter DNA methylation. These results indicated that 5-Fu was able to more efficiently inhibit the proliferation of hGCCs than 5-aza, and that this difference may be due to differences in the anticancer mechanism of these two types of drug. PMID- 26622776 TI - FIGO stage IV gestational choriocarcinoma misdiagnosed as pulmonary tuberculosis: A case report. AB - Choriocarcinoma is a rare, highly malignant neoplasm, which may occur during or following any type of pregnancy. This tumor often demonstrates rapid hematogenous spread to multiple organs, and is associated with high human chorionic gonadotropin (HCG) levels and a good response to chemotherapy. In the present study, the case of a 29-year-old female with distant metastatic choriocarcinoma [International Federation of Gynecology and Obstetrics (FIGO) stage IV; World Health Organization score, 15], who was misdiagnosed with pulmonary tuberculosis at a local hospital is presented. The major failure in the diagnosis of this case was that the patient's serum beta-HCG levels were ignored initially. However, the patient received combined treatment with systematic multi-agent chemotherapy, whole-brain radiation therapy and gross total resection of the brain lesion at West China Second Hospital, and achieved complete remission. In conclusion, the accurate and prompt diagnosis of choriocarcinoma is crucial for a good outcome. Furthermore, in young female patients exhibiting symptoms such as pulmonary bleeding or neurological disturbances following a hydatidiform mole or a normal pregnancy, even in the absence of abnormal uterine bleeding, serum beta-HCG levels must be analyzed and a diagnosis of choriocarcinoma must be considered. PMID- 26622777 TI - Downregulation of Rab25 activates Akt1 in head and neck squamous cell carcinoma. AB - Several studies have suggested that Ras-associated binding 25 protein (Rab25) is involved in the pathogenesis of human cancer. Although it has been demonstrated that the development of head and neck squamous cell carcinoma (HNSCC) is the result of an accumulation of multiple sequential genetic and epigenetic alterations in key genes with important functions in cell growth and the cell cycle, recent studies have indicated that HNSCC is a complex and heterogenous disease. To the best of our knowledge, there is no data regarding the regulation of the Rab25 gene at the mRNA or protein level in HNSCC. Furthermore, available data on Rab25 expression in other types of cancer are conflicting. The aim of the present study was to investigate whether Rab25 is involved in the development and/or progression of HNSCC, and to analyze the mechanisms underlying its effects in this type of cancer. The expression of Rab25 mRNA in HNSCC tissues and adjacent non-tumor tissue samples was measured using reverse transcription quantitative polymerase chain reaction, while the level of the Rab25, Akt1 and phosphorylated-Akt1 proteins was measured using western blotting. Expression of Rab25 mRNA and protein was downregulated in 69.1% and 56.1% of tumor tissue samples, respectively. This downregulation was associated with an increase in p Akt1 expression, in the absence of a change in total Akt1 protein levels, in tumor tissues compared with normal tissues. The current findings suggest that Rab25 acts as a tumor suppressor in HNSCC. PMID- 26622778 TI - Sentinel lymph node biopsy in patients with breast ductal carcinoma in situ: Chinese experiences. AB - The axillary treatment of patients with ductal carcinoma in situ (DCIS) remains controversial. The aim of the present study was to evaluate the roles of sentinel lymph node biopsy (SLNB) in patients with breast DCIS. A database containing the data from 262 patients diagnosed with breast DCIS and 100 patients diagnosed with DCIS with microinvasion (DCISM) who received SLNB between January 2002 and July 2014 was retrospectively analyzed. Of the 262 patients with DCIS, 9 presented with SLN metastases (3 macrometastases and 6 micrometastases). Patients with large tumors diagnosed by ultrasound or with tumors of high histological grade had a higher positive rate of SLNs than those without (P=0.037 and P<0.0001, respectively). Of the 100 patients with DCISM, 11 presented with metastases. Younger patients had a higher positive rate of SLNs (P=0.028). According to the results of this study and the systematic review of recent studies, the indications of SLNB for patients with DCIS are as follows: SLNB should be performed in all DCISM patients and in those DCIS patients who received mastectomy, and could be avoided in those who received breast-conserving surgery. However, SLNB should be recommended to patients who have high risks of harboring invasive components. The risk factors include a large, palpable tumor, a mammographic mass or a high histological grade. PMID- 26622779 TI - Role of annexin A6 in cancer. AB - Annexin A6 (AnxA6) is a member of a conserved superfamily of Ca2+-dependent membrane-binding annexin proteins. It participates in membrane and cytoskeleton organization, cholesterol homeostasis, membrane trafficking, cell adhesion and signal transduction. The expression levels of AnxA6 are closely associated with melanoma, cervical cancer, epithelial carcinoma, breast cancer, gastric cancer, prostate cancer, acute lymphoblastic leukemia, chronic myeloid leukemia, large cell lymphoma and myeloma. AnxA6 exhibits dual functions in cancer, acting either as a tumor suppressor or promoter, depending on the type of cancer and the degree of malignancy. In several types of cancer, AnxA6 acts via Ras, Ras/MAPK and/or FAK/PI3K signaling pathways by mainly mediating PKCalpha, p120GAP, Bcr-Abl and YY1. In the present review, the roles of AnxA6 in different types of cancer are summarized. PMID- 26622780 TI - Long non-coding RNA growth arrest-specific transcript 5 in tumor biology. AB - The recognition of the biological relevance of long non-coding RNA (lncRNA) molecules has only recently been recognized as one of the most significant advances in contemporary molecular biology. A growing body of evidence indicates that lncRNAs act not only as the intermediary between DNA and protein but also as significant protagonists of cellular functions. The dysregulation of lncRNAs has increasingly been linked to numerous human diseases, particularly cancers. Recent studies have demonstrated that the lncRNA growth arrest-specific transcript 5 (GAS5) was pervasively downexpressed in most human cancers compared with non cancerous adjacent tissues including gastric, breast, lung and prostate cancer. In addition, patients with decreased GAS5 expression have a significantly poorer prognosis than those with higher expression. Furthermore, GAS5 is involved in the control of cell apoptosis, proliferation, metastasis, angiogenesis, DNA repair and tumor cell metabolism. This review provides an overview of the current knowledge concerning the role of GAS5 in tumor expression and biology function. PMID- 26622782 TI - Role of hypoxia-inducible factor-1alpha, carbonic anhydrase-IX, glucose transporter-1 and vascular endothelial growth factor associated with lymph node metastasis and recurrence in patients with locally advanced cervical cancer. AB - The aim of the present study was to determine whether the expression of hypoxia inducible factor-1alpha (HIF-1alpha), carbonic anhydrase-IX (CA-IX), glucose transporter-1 (GLUT-1) or vascular endothelial growth factor (VEGF) was associated with the clinicopathological characteristics, lymph node metastasis or progression-free survival of patients with cervical cancer. Tumor tissue samples were obtained from 54 cervical cancer patients who had undergone radical hysterectomy. The expression of HIF-1alpha, CA-IX, GLUT-1 and VEGF was analyzed by immunohistochemical staining. Of the 54 cases, 28 were positive for HIF 1alpha, 35 for CA-IX, 40 for GLUT-1 and 23 for VEGF. It was revealed that HIF 1alpha expression was correlated with tumor stage and histology, CA-IX expression with tumor stage, tumor size, lymph node metastasis and lymph-vascular space involvement, GLUT-1 expression with tumor stage and lymph-vascular space involvement, and VEGF expression with microvessel density. The multivariate regression analysis indicated that CA-IX expression and lymph-vascular space involvement were independent variables associated with lymph node metastasis. Progression-free survival was shorter for patients who were positive for CA-IX or VEGF expression than for those who were negative for CA-IX or VEGF expression. The progression-free survival of patients treated with radiotherapy or chemo radiotherapy following radical hysterectomy was also shorter for patients with positive CA-IX expression. These findings suggest that CA-IX expression is a possible risk factor for lymph node metastasis and disease recurrence in locally advanced cervical cancer patients. PMID- 26622781 TI - Interplay between unfolded protein response and autophagy promotes tumor drug resistance. AB - The endoplasmic reticulum (ER) is involved in the quality control of secreted protein via promoting the correct folding of nascent protein and mediating the degradation of unfolded or misfolded protein, namely ER-associated degradation. When the unfolded or misfolded proteins are abundant, the unfolded protein response (UPR) is elicited, an adaptive signaling cascade from the ER to the nucleus, which restores the homeostatic functions of the ER. Autophagy is a conserved catabolic process where cellular long-lived proteins and damaged organelles are engulfed and degraded for recycling to maintain homeostasis. The UPR and autophagy occur simultaneously and are involved in pathological processes, including tumorigenesis, chemoresistance of malignancies and neurodegeneration. Accumulative data has indicated that the UPR may induce autophagy and that autophagy is able to alleviate the UPR. However, the detailed mechanism of interplay between autophagy and UPR remains to be fully understood. The present review aimed to depict the core pathways of the two processes and to elucidate how autophagy and UPR are regulated. Moreover, the review also discusses the molecular mechanism of crosstalk between the UPR and autophagy and their roles in malignant survival and drug resistance. PMID- 26622783 TI - Antitumor action of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone in hepatocellular carcinoma. AB - The inhibition of apoptosis in cancer cells is the major pathological feature of hepatic carcinoma. Rosiglitazone (RGZ), a ligand for peroxisome proliferator activated receptor gamma (PPAR-gamma), has been shown to induce apoptosis in hepatic carcinoma cells. However, the mechanism underlying this effect remains to be elucidated. The present study aimed to investigate the effect of RGZ on cell viability and apoptosis, and its mechanisms in cultured HepG2 cells using MTT assay, flow cytometry and western blotting. The results revealed that treatment with RGZ may attenuate HepG2 cell viability and induce the apoptosis of the cells. The mechanism of RGZ-induced apoptosis involves an increase in the level of activated PPAR-gamma (p-PPAR-gamma) and a decrease in p85 and Akt expression. In addition, the PPAR-gamma antagonist GW9662 suppressed the effect of RGZ in the HepG2 cells. Taken together, the results suggest that RGZ induces the apoptosis of HepG2 cells through the activation of PPAR-gamma, suppressing the activation of the PI3K/Akt signaling pathway. Such mechanisms may contribute to the favorable effects of treatment using RGZ in HepG2 cells. PMID- 26622784 TI - miR-215 functions as a tumor suppressor and directly targets ZEB2 in human non small cell lung cancer. AB - MicroRNA-215 (miR-215) has previously been demonstrated to be dysregulated in a number of human malignancies and to be correlated with tumor progression. However, the expression and function of miR-215 in non-small cell lung cancer (NSCLC) has remained to be elucidated. Therefore, the present study aimed to investigate the effects of miR-215 in NSCLC tumorigenesis and development. Reverse transcription-quantitative polymerase chain reaction was used to evaluate miR-215 expression in NSCLC cell lines and primary tumor tissues. The association between miR-215 expression and certain clinicopathological factors was also determined, and the effects of miR-215 on the biological behavior of NSCLC cells were investigated. In addition, the potential regulatory function of miR-215 on zinc finger E-box-binding homeobox 2 (ZEB2) expression was examined. miR-215 expression was significantly downregulated in NSCLC cell lines and clinical specimens. Reduced miR-215 expression was significantly associated with lymph node metastasis and advanced TNM stage. Overexpression of miR-215 inhibited NSCLC cell proliferation, invasion and migration, and promoted cell apoptosis in vitro, and suppressed tumorigenicity in vivo. Furthermore, luciferase reporter assay analysis identified ZEB2 as a direct target of miR-215. These findings indicated that miR-215 may act as a tumor suppressor in NSCLC and may serve as a novel therapeutic agent for miR-based therapy. PMID- 26622785 TI - Intrathoracic extramedullary hematopoiesis presenting as tumor-simulating lesions of the mediastinum in alpha-thalassemia: A case report. AB - Extramedullary hematopoiesis (EMH) is a rare disease, where hematological disorder drives extramedullary hematopoietic tumor formation in multiple regions of the body. The present study reports a case of EMH presenting as multiple tumor like lesions of mediastinum in a 61-year-old male with alpha-thalassemia, which was subjected to a video-assisted thoracoscopic surgery tissue biopsy to differentiate it from other mediastinal tumors. To date, only three cases of EMH in patients with alpha-thalassemia have been described in the literature. Patients with EMH typically exhibit no hematological disorder preoperatively and therefore EMH is frequently misdiagnosed. In the present study, along with a literature review of the clinicopathological features of EMH, the diagnosis and treatment of this rare case was discussed, in order to differentiate diagnosis, and particularly to distinguish EHM from extramedullary myeloid sarcoma. PMID- 26622786 TI - Genetic variability of DNA repair mechanisms influences treatment outcome of gastric cancer. AB - The aim of the current study was to investigate the role of polymorphisms in DNA repair pathways on the clinical outcome of gastric cancer patients treated with platinum-based chemotherapy. A total of 380 gastric cancer patients treated with platinum-based chemotherapy were included in the present study. The genotypes of ERCC1 rs11615 (Asn118Asn) and rs3212986 (*197G>T), ERCC2 rs1799793 (Asn312Asp) and rs13181 (Lys751Gln), NBN rs1805794 (Gln185Gln) and rs1063054 (*1209A>C), RAD51 rs1801321 (-61G>T) and rs12593359 (*502T>G), and XRCC3 rs861539 (Thr241Met) were determined by polymerase chain reaction-restriction fragment length polymorphism, according to the manufacturer's instructions. The TC+CC genotypes of ERCC1 rs11615 and GA+AA genotypes of ERCC2 rs1799793 were found to be associated with improved response to chemotherapy, with an adjusted odds ratio of 1.66 (95% CI, 1.07-2.56) and 1.61 (95% CI, 1.05-2.49), respectively. Based on the results of Cox analysis, patients with TC+CC genotypes of ERCC1 rs11615 and GA+AA genotypes of ERCC2 rs1799793 exhibited a significantly decreased risk of mortality, with hazard ratios of 1.71 (95% CI, 1.06-2.72) and 1.97 (95% CI, 1.28 3.03), respectively. In conclusion, these results suggest that ERCC1 rs11615 and ERCC2 rs1799793 in the DNA repair pathways may be used as predictive factors of the clinical outcome in gastric cancer patients. PMID- 26622787 TI - Overexpression of FGFR2 contributes to inherent resistance to MET inhibitors in MET-amplified patient-derived gastric cancer xenografts. AB - Gastric cancer is one of the most malignant diseases and one of the leading causes of cancer-associated mortality worldwide. Although advances have been made in surgical techniques, perioperative management and the combined use of surgery with chemotherapy and/or radiotherapy, patients with advanced stage gastric cancer continue to face poor outcomes. Furthermore, it was reported that MET gene amplification and overexpression predicted the sensitivity to MET inhibitors in gastric cancer. However, the identification of drug-resistant tumors has encouraged the pre-emptive elucidation of the possible mechanisms of clinical resistance. The current study assessed a number of patient-derived gastric cancer models with MET amplification and overexpression, including CNGAS028. The tumor tissues were subjected to microarray analysis (using single nucleotide polymorphism 6.0 and human genome U133 arrays) followed by western blotting. The results demonstrated that CNGAS028 xenograft tumors did not respond to treatment with a selective MET inhibitor. Additional analysis indicated that FGFR2 overexpression contributed to the resistance to MET inhibitors. Furthermore, treatment with a combination of fibroblast growth factor receptor 2 and MET inhibitors inhibited the growth of CNGAS028 xenograft tumors in vivo. In conclusion, the current results aid in understanding the mechanism of inherent resistance to selective MET inhibitors as well as provide important information for patient selection and clinical treatment strategies. PMID- 26622788 TI - Carbogen gas-challenge blood oxygen level-dependent magnetic resonance imaging in hepatocellular carcinoma: Initial results. AB - The present study aimed to evaluate the feasibility of performing carbogen gas challenge blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) measurements in patients with hepatocellular carcinoma (HCC). A total of 25 patients with HCC underwent T2* mapping derived from multi-echo gradient-recalled echo imaging prior to and following breathing carbogen (95% O2 and 5% CO2) for 10 min. Follow-up T2* mapping was performed in 5 patients 1 day after transarterial chemoembolization (TACE). T2*, R2* and ?R2* values (R2*air - R2*carb) of the whole tumor, the solid region of the tumor and the adjacent liver parenchyma were measured and compared in the patients with HCC. The T2* value of the solid region of the tumor following carbogen breathing was higher than the value following room air breathing (P<0.05), and the R2* value of room air breathing was higher than that following carbogen breathing (P<0.05). ?R2* values of the tumor and the adjacent liver parenchyma prior to and following carbogen breathing were 2.4+/ 7.8, 8.1+/-14.7 and 2.0+/-11.0 sec-1, respectively. R2* values were significantly decreased in 2 cases 1 day after TACE (17.8 vs. -3.4 sec-1 and 10.2 vs. 2.4 sec 1). Overall, carbogen gas-challenge BOLD MRI measurements are feasible in clinical settings and may serve as a novel functional biomarker for monitoring the treatment efficacy of embolic therapies for HCC. PMID- 26622789 TI - High expression of the putative cancer stem cell marker, DCLK1, in rectal neuroendocrine tumors. AB - Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein, is known to regulate neuronal differentiation, migration and neurogenesis. Recent evidence suggests that the protein is a putative marker for intestinal and pancreatic stem cells, including their cancer stem cell counterparts. The present study conducted immunohistochemical analyses for DCLK1 and the stemness marker, NANOG, in human intestinal neuroendocrine tumors (NETs), as their expression had not been previously investigated in these tumors. Eighteen patients with endoscopically resected rectal NETs were enrolled in the study. The mean age of the patients was 51 years old. The mean diameter of the resected tumors was 5.2 mm, and a histological diagnosis of NET grade G1 was formed for all tumors. Immunohistochemical analysis was performed not only for DCLK1, but also for the known NET markers, synaptophysin, chromogranin A and cluster of differentiation (CD)56. The intensity and distribution of staining were scored on a scale of 0-3 and 0-2, respectively. The sum of the scores was calculated for each specimen. Co expression of DCLK1 and NANOG was also examined. The mean scores for DCLK1 and synaptophysin were significantly higher than those for chromogranin A (P<0.0001) and CD56 (P<0.01). There were no significant differences in the scores between DCLK1 and synaptophysin or between chromogranin A and CD56. Notably, NANOG was expressed in high quantities in all the tumor tissues studied, showing clear co expression with DCLK1. In conclusion, DCLK1 may be a novel marker for rectal NET, potentially indicating the presence of the stemness gene product, NANOG. PMID- 26622790 TI - High expression level of T-box transcription factor 5 predicts unfavorable survival in stage I and II gastric adenocarcinoma. AB - The expression of T-box transcription factor 5 (TBX5) has previously been observed in human cancer. The aim of the present study was to investigate TBX5 expression and its potential clinical significance in gastric cancer (GC). Using reverse transcription-quantitative polymerase chain reaction, the TBX5 mRNA expression levels in 30 pairs of surgically resected healthy gastric tissues and early stage (stages I and II) GC tissues were evaluated. The TBX5 mRNA expression levels were increased in GC stage I and II tumor tissues (P=0.01, n=30) compared with the matched adjacent non-tumor tissue. However, no significant difference was observed in TBX5 mRNA expression levels in matched adjacent non-tumor tissue compared with the tumor tissue from stage III and IV GC samples (P=0.318, n=30). Immunohistochemical analysis for TBX5 expression was performed on 161 paraffin embedded stage I and II GC tissue blocks. Statistical analysis was performed to evaluate the associations between TBX5 expression, clinicopathological factors and prognosis. Patients with stage I and II GC and tumors with high TBX5 expression levels presented poor overall survival (OS) rate (P=0.024). The Cox proportional hazards model analysis demonstrated that TBX5 expression was an independent risk factor (P=0.017). The present study indicates that high expression of TBX5 is associated with unfavorable OS rates in patients with stage I and II GC. In conclusion, the expression of TBX5 may be a valuable biomarker for the selection of cases of high-risk stage I and II GC. PMID- 26622791 TI - Immunohistochemical study of vascular endothelial growth factor-C/vascular endothelial growth factor receptor-3 expression in oral tongue squamous cell carcinoma: Correlation with the induction of lymphangiogenesis. AB - The aim of the present study was to elucidate the associations between the expression of the vascular endothelial growth factor-C (VEGF-C)/VEGF receptor-3 (VEGFR-3) axis and lymphangiogenesis, regional lymph node metastasis and clinicopathological factors in oral tongue squamous cell carcinoma (OTSCC) using immunohistochemistry. The expression of VEGF-C, VEGFR-3 and podoplanin was immunohistochemically evaluated in specimens obtained from 65 patients with OTSCC (T1-2, N0) who had undergone radical surgery alone. The associations between the expression of VEGF-C, VEGFR-3 and podoplanin, and lymphangiogenesis, regional lymph node metastasis and clinocopathological factors were determined by immunohistochemical analysis. VEGF-C, VEGFR-3 and combined VEGF-C/VEGFR-3 expression was significantly higher in cases with regional recurrence compared with those without lymph node involvement (P<0.001). As regards lymphangiogenesis, a significant correlation was observed between podoplanin expression and VEGF-C, VEGFR-3 and combined VEGF-C/VEGFR-3 expression (P<0.001). Therefore, lymphangiogenesis in the peritumoral stroma was associated with lymph node metastasis. However, podoplanin expression did not exhibit a significant correlation with the progression of lymph node metastasis. The results of the present study suggest that the VEGF-C/VEGFR-3 axis may be associated with lymph node metastasis through lymphangiogenesis. Determining the VEGF-C/VEGFR-3 expression status may help predict which patients will develop regional recurrence and provide novel targets for therapies to suppress lymph node metastasis in the treatment of OTSCC. PMID- 26622792 TI - Effect and prognostic significance of the KAI1 gene in human gastric carcinoma. AB - The present study aimed to explore the effect and mechanism of the Kangai 1 (KAI1) gene in regulating the migration and invasion of gastric carcinoma cells, and the prognostic significance of this gene in gastric cancer patients. Immunohistochemistry and in situ hybridization were used to investigate the role of KAI1 in the progression and prognosis of gastric cancer. The pEGFP-N1-KAI1 plasmid was transfected into human gastric carcinoma SGC7901 cells using liposomes. The effect of transfection with the KAI1 gene was measured using a reverse transcription-semi-quantitative polymerase chain reaction (RT-sqPCR) assay. The Transwell chamber assay was used to study the metastatic and invasive ability of SGC7901 cells. Gastric cancer metastasis-associated genes, including hypoxia-inducible factor (HIF)-1alpha, matrix metalloproteinase (MMP)-2, MMP-9, basic fibroblast growth factor (bFGF), and urease plasminogen activator (uPA) were measured by RT-sqPCR prior to and following transfection with the KAI1 gene. The expression of KAI1 protein and mRNA was associated with the differentiation degree of gastric cancer, presence of lymph node metastasis, tumor-node metastasis stage, depth of invasion and the survival time of patients. The migratory and invasive abilities of SGC7901 cells were significantly decreased subsequent to transfection with the KAI1 gene, and the expression of bFGF and uPA was downregulated. It was concluded that the tumor suppressor gene KAI1 inhibits the migration and invasion of gastric carcinoma cells, possibly by suppressing the expression of uPA. Patients that expressed KAI1 may demonstrate an improved prognosis. PMID- 26622793 TI - A feedback constraint optimization method for intensity-modulated radiation therapy of nasopharyngeal carcinoma. AB - Intensity-modulated radiation therapy (IMRT) is able to achieve good target conformance with a limited dose to organs at risk (OARs); however, IMRT increases the irradiation volume and monitor units (MUs) required. The present study aimed to evaluate the use of an IMRT plan with fewer segments and MUs, while maintaining quality in the treatment of nasopharyngeal carcinoma. In the present study, two types of IMRT plan were therefore compared: The direct machine parameter optimization (DMPO)-RT method and the feedback constraint DMPO-RT (fc_DMPO-RT) method, which utilizes compensative feedback constraint in DMPO-RT and maintains optimization. Plans for 23 patients were developed with identical dose prescriptions. Each plan involved synchronous delivery to various targets, with identical OAR constraints, by means of 7 coplanar fields. The average dose, maximum dose, dose-volume histograms of targets and the OAR, MUs of the plan, the number of segments, delivery time and accuracy were subsequently compared. The fc_DMPO-RT exhibited superior dose distribution in terms of the average, maximum and minimum doses to the gross tumor volume compared with that of DMPO-RT (t=62.7, 20.5 and 22.0, respectively; P<0.05). The fc_DMPO-RT also resulted in a smaller maximum dose to the spinal cord (t=7.3; P<0.05), as well as fewer MUs, fewer segments and decreased treatment times than that of the DMPO-RT (t=6.2, 393.4 and 244.3, respectively; P<0.05). The fc_DMPO-RT maintained plan quality with fewer segments and MUs, and the treatment time was significantly reduced, thereby resulting in reduced radiation leakage and an enhanced curative effect. Therefore, introducing feedback constraint into DMPO may result in improved IMRT planning. In nasopharyngeal carcinoma specifically, feedback constraint resulted in the improved protection of OARs in proximity of targets (such as the brainstem and parotid) due to sharp dose distribution and reduced MUs. PMID- 26622794 TI - Imatinib-based therapy in adult Philadelphia chromosome-positive acute lymphoblastic leukemia: A case report and literature review. AB - Acute lymphoblastic leukemia (ALL) has a rapid onset and rarely occurs with exclusive prodrome of general osteoporosis and vertebral compression fractures. However, Philadelphia chromosome-positive (Ph+) ALL has a poor prognosis, even when patients are treated with intensive chemotherapy, and the first-line effective treatment requires further elucidation. The present study focused on a 56-year-old Chinese male patient who initially presented with spontaneous bone fractures and was ultimately diagnosed as Ph+ ALL after 6 months, which required to preliminarily exclude a working diagnosis of myeloma. Apart from intensive chemotherapy, the patient successfully completed an imatinib-based regimen and achieved complete remission (CR) 2 weeks later. Subsequently, the patient was subjected to consolidation treatment using the same imatinib regimen combined with interferon-alpha 2b for 9 courses. In November 2013, the patient had achieved persistent hematological and molecular genetic normality for ~16 months after the initial CR. In conclusion, Ph+ ALL must be considered in the differential diagnosis of adults experiencing unexplained bone disease. PMID- 26622795 TI - microRNA-32 induces radioresistance by targeting DAB2IP and regulating autophagy in prostate cancer cells. AB - The aberrant expression of microRNAs (miRNAs/miRs) has been found in numerous cancer types. miR-32 is an oncomiR in prostate cancer (PCa), however, the mechanisms by which miR-32 functions as a regulator of radiotherapy response and resistance in PCa are largely unknown. In the present study, it was found that DAB2 interacting protein (DAB2IP), the miR-32-dependent tumor-suppressor gene, was downregulated and induced autophagy and inhibited radiotherapy-induced apoptosis in PCa cells. miR-32 expression was upregulated or overexpressed in PCa, and miR-32 inhibited DAB2IP expression through a direct binding site within the DAB2IP 3' untranslated region. miR-32 mimics enhanced tumor cell survival and decreased radiosensitivity in the PCa cells, which were reversed by miR-32 inhibitor. Flow cytometric analysis revealed that overexpressed miR-32, consistent with the DAB2IP-knockdown results, reduced ionizing radiation (IR) induced cell apoptosis, which was restored by 4 nM brefeldin A treatment. More significantly, the overexpression of miR-32 and the knockdown of DAB2IP enhanced autophagy in the IR-treated PCa cells. miR-32 regulated the expression of autophagy-related proteins, such as DAB2IP, Beclin 1 and Light chain 3beta I/II, as well as phosphorylation of S6 kinase and mammalian target of rapamycin. In conclusion, these data provide novel insights into the mechanisms governing the regulation of DAB2IP expression by miR-32 and their possible contribution to autophagy and radioresistance in PCa. PMID- 26622796 TI - Combined therapy with EGFR TKI and gambogic acid for overcoming resistance in EGFR-T790M mutant lung cancer. AB - Although patients with non-small cell lung cancer (NSCLC) experience an initial response to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib, those individuals with activating mutations in EGFR develop resistance. Gambogic acid (GA), a polyprenylated xanthone, has strong antitumor activities. In the present study, the therapeutic efficacy of gefitinib with GA was evaluated in a gefitinib-resistant NSCLC model. The NCI-H1975 cell line with EGFR-T790M mutation was subcutaneously injected into immunocompromised mice. The mice were randomly assigned to receive treatment with gefitinib, GA, gefitinib plus GA, or vehicle for 4 weeks, then all mice were sacrificed and their tumor tissues were subjected to caspase activity detection and western blot analysis. Gefitinib and GA alone slightly inhibited the tumor growth of NCI-H1975. However, the combined treatment significantly enhanced their antitumor effects, without any marked adverse events. In addition, gefitinib plus GA enhanced the level of apoptosis in the tumor tissues. Western blot analysis also revealed that the combination treatment reduced the phosphorylation level of AKT, MEK1/2 and ERK1/2, while an increased expression ratio of Bax/Bcl-2 was observed. In the current study, gefitinib in combination with GA resulted in antitumor growth in the EGFR-T790M secondary mutation NCI-H1975 tumor model due to an enhanced apoptotic effect. This novel therapeutic strategy may be a practical approach for the treatment of patients who show gefitinib resistance. PMID- 26622797 TI - Ewing's sarcoma of the ulna treated with sub-total resection and reconstruction using a non-vascularized, autogenous fibular graft and hernia mesh: A case report. AB - Ewing's sarcoma of the bone is the second most frequently occurring malignant bone tumor in children and adolescents. Ewing's sarcoma in the ulna are extremely rare. Thus, the surgical options for reconstruction of the elbow are limited and technically challenging. In the current study, a 29-year-old male with Ewing's sarcoma of the ulna was treated with a sub-total resection and reconstruction using a non-vascularized, autogenous fibular graft and hernia mesh. At the 2-year follow-up, the patient had returned to his previous occupation with no evidence of local recurrence or distant metastasis. The functional recovery was satisfactory, and the patient could perform active movement of the elbow from 0 degrees to 135 degrees , forearm pronation to 30 degrees , supination to 85 degrees and had full hand function. The grip power of the left hand was 36 kg, which was 86% of the contralateral side (42 kg). PMID- 26622798 TI - Surgical treatment of primary cardiac tumors in children: Experience of a single institute. AB - In order to review the surgical experience of a single institute with regard to the treatment of primary cardiac tumors, data was collected on patients with a histopathological diagnosis of a primary cardiac tumor (with the exception of myxoma) in a retrospective analysis of those treated between 2004 and 2013. In total, 11 patients were identified, with a mean age at diagnosis of 23 months and a mean weight of 13 kg. The most frequent cause of referral was a cardiac murmur and the most frequent cardiac tumor was rhabdomyoma (5 cases), followed by fibroma (3 cases), angiofibroma (2 cases) and fibrosarcoma (1 case). Surgical removal of the tumor was performed in all patients due to the respective clinical symptoms. A subtotal resection was performed in a single patient (with angiofibroma invading the aortic root, superior vena cava and sinus node) due to financial constraints. This patient succumbed to tumor invasion 2 years later. Another of the patients (pericardial fibrosarcoma) succumbed 1 year after the total resection, as they were unable to undergo a repeat surgery for the relapsed tumor due to financial inadequacy. The remaining 9 patients have survived in good condition during the 1-6 year follow-up. Surgery is the preferred treatment for patients with symptomatic primary cardiac tumors, and has good early- and long term outcomes. However, due to the current health care system inadequacies in China, certain parents cannot afford the medical expenses, thus, more comprehensive social security and medical insurance may require consideration. PMID- 26622799 TI - ATPase inhibitory factor 1 is a potential prognostic marker for the migration and invasion of glioma. AB - Adenosine triphosphatase inhibitory factor 1 (IF1) has previously been considered to be a driving oncogene in human cancers. Several studies have revealed that IF1 overexpression is present in a variety of tumor types and promotes tumor growth and metastasis. The present study aimed to investigate the clinical significance of IF1 in glioma and the role of IF1 in cell migration and invasion. The mRNA and protein expression of IF1 in glioma tissues was found to be significantly increased compared with the expression in normal brain tissues (P<0.05). The presence of IF1 expression was significantly associated with an advanced clinical stage in glioma (P<0.05). Furthermore, the presence of IF1 expression was found to be associated with a reduced overall survival rate of glioma patients (P<0.05). Multivariate Cox regression analysis indicated that IF1 was an independent factor for predicting the overall survival rate of patients with glioma (P<0.05). IF1 knockdown also significantly reduced the number of migratory and invasive U251 and U87 cells (P<0.05). In addition, IF1 knockdown inhibited the expression of nuclear factor-kappaB (NF-kappaB) and Snai1, and led to increased E-cadherin expression and reduced vimentin expression. In conclusion, the presence of IF1 expression is associated with poor clinicopathological features in glioma. IF1 expression is an independent prognostic marker for predicting the overall survival rate of patients with glioma. Mechanistically, IF1 may promote glioma cell migration and invasion through the NF-kappaB/Snai1 axis. PMID- 26622800 TI - Feasibility and safety of laparoscopic resection for gastric GISTs larger than 5 cm: Results from a prospective study. AB - The role of laparoscopic resection for large gastric gastrointestinal stromal tumors (GISTs), particularly those >5 cm, remains under debate due the possibility of intraoperative tumor rupture. To determine the feasibility and safety of the laparoscopic approach in the treatment of large gastric GISTs, a prospective study was performed between March 2011 and March 2014. Intraoperative tumor rupture was studied as the primary outcome. Secondary outcomes were the conversion rate, surgical duration, estimated blood loss, time to tolerate fluid and solid diets, length of post-operative hospital stay and recurrence rate at the end of the follow-up. A total of 16 patients were included in this study, with a tumor size of 7.04+/-1.53 cm (range, 5.2-10.8 cm). No intraoperative tumor rupture occurred. The median duration of surgery was 88.1+/-31.9 min, with an estimated blood loss volume of 37.1+/-18.7 ml. No patient required a blood transfusion. The mean time until the start of oral intake for fluid and solid diets was 1.1+/-0.6 and 2.5+/-0.9 days, respectively. The median length of post operative hospital stay was 5.4+/-5.8 days. The follow-up period for all patients was 16.9+/-11.2 months (range, 2-38 months). No local or distant recurrence was observed. The study indicates that laparoscopic resection for large gastric GISTs is feasible and safe. Laparoscopic surgery should be considered as the standard approach in all cases, irrespective of tumor size or location. PMID- 26622801 TI - Delayed neurological deterioration after surgery for intraspinal meningiomas: Ischemia-reperfusion injury in a rat model. AB - Delayed neurological deterioration in the absence of direct cord insult following surgical removal and cord decompression is a rare but severe postoperative complication in a small subset of patients with intraspinal meningiomas. To date, the underlying pathophysiology of such a finding remains unclear and ischemia reperfusion injury (IRI) is considered as the potential etiology in the literature. However, no experimental research has been reported to prove this hypothesis. The present study investigated whether IRI occurs following decompression surgery using an experimental rat model of chronic compressive spinal cord injury (SCI). A chronic spinal cord compression model was developed with various sizes of polymer sheets (mild and severe compression) that were microsurgically implanted underneath the T8-9 laminae, and occurrence of IRI in the spinal cord following decompression was determined by measuring superoxide dismutase (SOD) level and malondialdehyde (MDA) concentration. In the mild compression groups, after decompression SOD activities significantly increased along with a reduction in MDA content compared with the non-decompression group (P<0.05), which exhibited diminishment of lipid peroxidation and relief of the secondary injury. These findings indicated that decompression is effective to improve neurological recovery and may deliver improved outcomes for chronic mild compression of the spinal cord. However, in severe compression groups, after decompression, SOD activities markedly reduced further along with a significant increase in MDA content compared with non-decompression group (P<0.05). The results indicated that lipid peroxidation increased immediately after decompression surgery which resulted from reperfusion of the spinal cord. These findings demonstrated IRI may occur as a result of chronic severe compression of the spinal cord. In clinical practice, sudden cord expansion and reperfusion may have lead to disruption in the blood spinal cord barrier, and triggered a cascade of IRI resulting in postoperative neurologic deterioration. Recognition of this neurological deterioration following removal for intraspinal meningiomas may improve preoperative patient counseling and merits further study for determination of the precise pathophysiology. PMID- 26622802 TI - Extraskeletal myxoid chondrosarcoma of the vulva: A case report. AB - Extraskeletal myxoid chondrosarcoma (ESMC) of the vulva is an extremely rare tumor and currently, there is little available information on its biological behavior and treatment strategy. The present study reports a case of recurrent ESMC of the vulva in a 32-year-old female. The patient presented with an increasingly painful mass of the right vulva, at the site of an exision which had been performed 7-months previously. The tumor mass was histopathologically diagnosed as primary ESMC of the vulva and subsequently, vulvectomy was performed. Cytological examination showed negative surgical margins. Intraoperative radiation therapy at a single dose of 10 Gy was administered to the bed of the removed tumor. The patient refused chemotherapy and five months after surgery, a new lesion was identified in the inguinal region. Bilateral inguinal-femoral lymph node dissection was performed and external beam radiation therapy at a dose of 40 Gy was administered to the inguinal region. Follow-up examination seven months after surgery revealed no evidence of disease progression and at present, the patient remains alive. This study highlights the importance of analyzing each clinical case of ESMC as this may lead to the development of guidelines for the optimal treatment of this rare tumor. PMID- 26622803 TI - Comparative genomic hybridization analysis of invasive ductal breast carcinomas in the Chinese population. AB - Breast cancer is the most common malignancy in Chinese women. The aim of the present study was to investigate the genetic alterations that occur in breast cancer cells in Chinese women. Comparative genomic hybridization (CGH) analysis was performed on 34 tumors obtained from patients with primary invasive ductal breast carcinoma (IDC). Recurrent genetic alterations in breast cancer include gains on chromosomes 1q (59%), 16p (50%), 17q (44%), 8q (38%), 11q (32%), 20q (32%), 1p (24%), 20p (24%), 19q (21%) and 19p (18%). Losses are common on chromosomes 6q (15%), 8p (12%), 18 (12%), 4q (9%), X (9%) and 17p (9%). In the present study, high-level amplifications were observed on chromosomes 1q32, 8p, 11q13, 17q and 20q. Overall, the chromosomal DNA gains observed were consistent with the changes reported in Caucasian populations. However, the incidence of chromosomal DNA loss was lower in the present study compared with the incidence reported in the literature. The present results demonstrate the pattern of chromosomal imbalances in the invasive ductal breast carcinomas of Chinese females. PMID- 26622805 TI - Photodynamic hyperthermal chemotherapy with indocyanine green in feline vaccine associated sarcoma. AB - The anticancer effects of photodynamic hyperthermal chemotherapy (PHCT), which consists of a combination of indocyanine green photodynamic hyperthermal therapy and local chemotherapy, have previously been reported. The present study investigated the effect of PHCT in six cases of feline vaccine-associated sarcoma (FVAS) following conservative surgical resection. No recurrence was observed in three out of six (50%) cases, while recurrence was observed in the remaining three cases. Of note, each feline with recurrences had previously undergone surgical resection more than three times, whereas those without recurrence had undergone no or one previous resection. In addition, the three animals in which there was no recurrence survived between 893 and 1,797 days following surgery. In conclusion, the results of the present study suggested that PHCT may be a candidate as a novel adjuvant cancer therapy for FVAS. PMID- 26622804 TI - A concordant expression pattern of fatty acid synthase and membranous human epidermal growth factor receptor 2 exists in gastric cancer and is associated with a poor prognosis in gastric adenocarcinoma patients. AB - Fatty acid synthase (FAS) and human epidermal growth factor receptor 2 (HER2) are overexpressed in gastric cancer (GC), and certain interactions have been found between FAS and HER2. A total of 94 patients were enrolled in the present study, each of whom underwent a D2 radical surgery in Zhongshan Hospital affiliated with Fudan University (Shanghai, China) between 2000 and 2005. The expression of FAS and HER2 was assessed by immunohistochemistry analysis of tissue microarrays generated from GC and non-tumor tissues. All data were analyzed by GraphPad Prism 5.0 to investigate the association between FAS and HER2 and to detect the potential association with prognosis. FAS (P<0.0001) and membranous HER2 (mHER2; P=0.0021) were overexpressed in the GC tissues, and a bidirectional and strong correlation was demonstrated between FAS and mHER2 in the tumor tissues. The expression of cytoplasmic HER2 (cHER2) was significantly lower in the GC tissues compared with the non-tumor tissues (P=0.0005), and cHER2 was expressed at a higher level in tumors that had better differentiation compared with poorly differentiated tissues (P=0.0503). Patients with a concordant expression pattern of FAS and mHER2 showed a significantly poorer prognosis than the non-concordant group (P=0.0096; hazards ratio, 3.2801; 95% confidence interval, 1.5781-6.8176). GC tissues significantly overexpress FAS and mHER2 and the expression of these two markers is associated. Patients with a concordant expression of FAS and mHER2 are more likely to suffer a poor prognosis. PMID- 26622806 TI - Aberrant CXCR4 and beta-catenin expression in osteosarcoma correlates with patient survival. AB - To determine the clinical significance of C-X-C chemokine receptor type 4 (CXCR4) and beta-catenin in osteosarcoma, their protein expression levels were assessed in 96 osteosarcoma and 20 osteochondroma cases using immunohistochemistry. Additionally, CXCR4 and beta-catenin mRNA expression levels were measured in 16 fresh osteosarcoma and 16 adjacent healthy tissue samples using fluorescent reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In the osteosarcoma samples, the positive CXCR4 protein expression rate was significantly higher than the rate in the osteochondroma samples (68.75 vs. 20.00%; P<0.01). Furthermore, beta-catenin protein expression was detected in 61.46% of osteosarcoma cases and 25.00% of osteochondroma cases. Similarly, the RT-qPCR data identified increased CXCR4 and beta-catenin mRNA expression levels in the osteosarcoma compared with adjacent control tissues. It was determined that CXCR4 (P<0.01) and beta-catenin (P<0.05) expression were significantly associated with the clinical Enneking stage, metastasis and survival of osteosarcoma. Furthermore, multivariate analysis identified CXCR4 and beta catenin protein expression levels, as well as clinical stage and metastasis, as significant risk factors for survival in patients with osteosarcoma (P<0.05). In conclusion, the present study determined that CXCR4 and beta-catenin are abnormally expressed in osteosarcoma tissues, and, therefore, may be important during osteosarcoma progression. PMID- 26622807 TI - Epithelioid angiomyolipoma mimicking adrenal cortical carcinoma: A diagnostic pitfall. AB - Epithelioid angiomyolipoma (EAML) is a rare mesenchymal neoplasmic variant of angiomyolipoma characterized by aggressive growth and unpredictable outcome. Cases of local recurrence and distant metastasis have been described. The histopathological diagnosis may be difficult, as EAML often mimics other neoplasms. This is the case report of a 39-year-old male patient with EAML, which was initially diagnosed as adrenal cortical carcinoma, due to the lack of cooperation between clinicians and pathologists. PMID- 26622808 TI - MicroRNA-33a-5p suppresses growth of osteosarcoma cells and is downregulated in human osteosarcoma. AB - A body of evidence has indicated that microRNAs (miRNAs) may have significant roles in cancer. Aberrant expression of miRNAs has frequently been observed in various human malignancies, including osteosarcoma (OS). However, the roles of miRNAs in OS remain poorly understood. In the present study, high-throughput deep sequencing was performed to screen for deregulated miRNAs in OS. Screening identified 310 miRNAs which were significantly overexpressed and 41 miRNAs which were significantly downregulated (>2-fold) in OS samples, compared with adjacent non-tumor bone tissues. Among these miRNAs, miR-33a-5p was notably downregulated. TaqMan reverse transcription-polymerase chain reaction analysis further verified that miR-33a-5p expression was significantly reduced in a large cohort of human OS samples. Enhancing miR-33a-5p expression via transfection with miR-33a-5p precursor significantly inhibited OS cell growth, suggesting potential antitumor properties of miR-33a-5p. The results of the present study provide novel insights into the miRNAs involved in OS, and suggest that miR-33a-5p may function as a tumor suppressor in OS. Therefore, miR-33a-5p may be able to serve as a diagnostic and therapeutic target for OS treatment. PMID- 26622809 TI - Development of an orthotopic model of human metastatic prostate cancer in the NOD SCIDgamma mouse (Mus musculus) anterior prostate. AB - Prostate cancer is one of the most prevalent oncological diseases in males worldwide, and the mortalities resulting from this type of cancer are mainly due to metastasis. The most common models for the study of metastasis are transgenic and immunocompromised mice, which enable the study of the metastatic process in a controlled way by the injection of prostate cancer cells into the mice. In the present study, NOD-SCIDgamma mice were injected orthotopically with PC3 cells in the anterior prostate in order to establish a metastatic model. The results demonstrated the development and growth of a primary tumor that preceded the formation of micrometastases in the lung, liver and pancreas, followed by macrometastases in the liver. This model adequately represents the dynamics of the metastatic process, and may be useful for novel therapeutic assays and post surgical relapse studies. PMID- 26622810 TI - Cell surface GRP78: A potential marker of good prognosis and response to chemotherapy in breast cancer. AB - The 78-kDa glucose-regulated protein (GRP78) is a stress induced heat shock protein which, under limiting conditions, functions as a cell surface signaling receptor. Tumor cells are considered to be subjected to a physiologically stressful microenvironment due to their excessive growth. The role of GRP78 in tumor survival has been of notable interest. The present study aimed to assess the potential prognostic and predictive value of cell surface GRP78 expression in breast cancer tumor cells. Cell surface and cytoplasmic expression of GRP78 was examined by immunohistochemical staining of GRP78 in breast cancer archival paraffin-embedded tumor specimens. The cohort studied included breast cancer patients with operable T1,2, estrogen receptor-positive, node-negative cancer who were assessed using the Oncotype DX gene profile, as well as patients with locally advanced disease prior to and following neoadjuvant systemic treatment. GRP78 values were compared between the 2 groups, and prior to and following systemic treatment. Association analyses between GRP78 expression and prognostic markers were also performed. Cox regression analysis was used to examine the impact of these variables on disease-free survival (DFS). No differences in cytoplasmic GRP78 expression were observed. By contrast, the rates of cell surface GRP78 expression were 74.1% in the early stage operable patients, 36% in neoadjuvant systemic treatment patients prior to treatment and 62.5% in patients following systemic treatment (P<0.039). Positive cell surface GRP78 expression was associated with increased expression of the progesterone receptor (P=0.024), p53 expression (P=0.022) and improved DFS (P=0.047). In the case of GRP78 positivity, a trend for a superior response to chemotherapy was observed (P=0.19). The results of the present study indicated that cell surface GRP78 may be used as a marker for good prognosis in breast cancer and a potential marker for response to chemotherapy. PMID- 26622811 TI - Primary skeletal muscle diffuse large B cell lymphoma: A case report and review of the literature. AB - The occurrence of primary extranodal non-Hodgkin's lymphoma (NHL) of soft tissue is rare, particularly in skeletal muscle. The present study describes a case of diffuse large B cell lymphoma of the right lower extremity and provides a detailed review of the literature associated with this disorder, with the aim of improving the future diagnosis and therapy of extranodal NHL. The present case report was of a 76-year-old woman who presented with a right thigh and calf mass. In view of the tumor's location and the patient's age, soft tissue tumors were considered to be soft tissue sarcoma. Imaging scans were performed to determine the location and size of the tumor, followed by a biopsy of the muscle. Histopathological examination then yielded a diagnosis of diffuse large B cell lymphoma. The patient then underwent 4 cycles of chemotherapy. There was evident relief of pain and swelling in the right extremity; however, positron emission tomography/computed tomography (PET/CT) determined insufficient treatment efficacy. Chemotherapy was adjusted for 2 cycles; however, the patient suffered an aggravation of edema, so a different chemotherapy regimen of bleomycin, cytarabine, vincristine, cyclosphamide and dexamethasone (BCOAD) was performed for a further 2 cycles. The edema was alleviated and magnetic resonance imaging revealed shrinkage of the lower limb mass and the right thigh mass was undetectable. In conclusion, the present case report demonstrated that PET/CT may help determine the efficacy of chemotherapy treatment and that the BCOAD chemotherapy regimen may be more effective than standard treatments in certain cases. PMID- 26622812 TI - Squamous cell carcinoma of unknown primary site presenting with an abdominal wall lesion as the primary symptom: A case report and review of the literature. AB - Squamous cell carcinoma of unknown primary site (SC CUP) is a rare malignant tumor, and its histogenesis and appropriate treatment are unclear. To the best of our knowledge, this type of carcinoma with abdominal wall lesions as the primary presenting symptom 3 months after laparoscopic surgery, has not been previously described in the literature. In the present study, a postmenopausal 54-year-old female patient was diagnosed with pain from the right abdominal puncture site 3 months after laparoscopic unilateral left salpingo-oophorectomy at a local hospital, at which time the left ovary and Fallopian tube were free of malignant tumor. Computed tomography (CT) imaging showed a subcutaneous nodule with a size of 6.2*3.3 cm. A wide excision of the lesion with safety margins and repair of the abdominal wall was performed, and the histopathological results and various investigations lead to the diagnosis of metastatic well-differentiated SC CUP. The patient underwent three surgeries and eight cycles of Taxol and cisplatin/carboplatin chemotherapy, and received a total of 10.8 Gy palliative radiation. However, the patient succumbed to intestinal bleeding, thrombocytopenia and multiple organ failure with pelvic recurrence and liver metastases at 10 months post-diagnosis. The prognosis of SC CUP, particularly with multiple metastases, is extremely poor. Although chemotherapy, surgery and radiotherapy have a certain role in the treatment, no regimen has been established as a standard therapy and palliative care could be recommended. PMID- 26622813 TI - Sarcoidosis manifesting as hepatic and splenic nodules mimicking ovarian cancer metastases: A case report. AB - The current study presents a case of sarcoidosis manifesting as hepatic and splenic nodules, which was difficult to differentiate from ovarian cancer metastases. A 24-year-old female, who was previously diagnosed with right ovarian cancer and underwent surgery at the age of 21, was found to have two nodules in the spleen revealed by contrast-enhanced computed tomography (CT). 18F fluorodeoxyglucose positron emission tomography/CT revealed two abnormal high uptake lesions in the spleen and one abnormal high uptake lesion in the liver. Under a diagnosis of hepatic and splenic metastases from right ovarian cancer, a laparoscopic splenectomy and partial hepatectomy were performed. Histopathological examination showed that a large number of non-caseating epithelioid cell granulomas formed these nodules, which was compatible with sarcoidosis. This case indicates that it is difficult to distinguish sarcoidosis from metastatic disease even using the latest modalities, and that laparoscopic surgery is a minimally invasive and useful tool for forming a differential diagnosis. PMID- 26622814 TI - Intracranial malignant melanoma: A report of 7 cases. AB - The aim of the present study was to investigate the clinical diagnosis and treatment of intracranial malignant melanoma. For this purpose, the clinical manifestation, signs, cerebrospinal fluid (CSF) contents, imageology, pathological features, treatment and prognosis of 7 cases of intracranial malignant melanoma were analyzed in The Chinese PLA General Hospital (Beijing, China) from 1996 to 2013. All the melanoma cases were confirmed by histopathology, and CSF cytopathology demonstrated that there were 5 cases of primary malignant melanoma and 2 cases of secondary malignant melanoma. Among the patients, 4 presented with >1 pigmented nevus in the skin, and 1 presented with skin melanoma. Intracranial malignant melanoma mostly affects middle-aged males. CSF cytopathology and imageology (particularly enhanced magnetic resonance), are important tools in the diagnosis of the disease. Particularly, when a patient presents with a pigmented nevus in the skin and an abnormal lesion in the brain, a diagnosis of intracranial malignant melanoma should be considered. PMID- 26622815 TI - Determination of EGFR and KRAS mutational status in Greek non-small-cell lung cancer patients. AB - It has been reported that certain patients with non-small-cell lung cancer (NSCLC) that harbor activating somatic mutations within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene may be effectively treated using targeted therapy. The use of EGFR inhibitors in patient therapy has been demonstrated to improve response and survival rates; therefore, it was suggested that clinical screening for EGFR mutations should be performed for all patients. Numerous clinicopathological factors have been associated with EGFR and Kirsten-rat sarcoma oncogene homolog (KRAS) mutational status including gender, smoking history and histology. In addition, it was reported that EGFR mutation frequency in NSCLC patients was ethnicity-dependent, with an incidence rate of ~30% in Asian populations and ~15% in Caucasian populations. However, limited data has been reported on intra-ethnic differences throughout Europe. The present study aimed to investigate the frequency and spectrum of EGFR mutations in 1,472 Greek NSCLC patients. In addition, KRAS mutation analysis was performed in patients with known smoking history in order to determine the correlation of type and mutation frequency with smoking. High-resolution melting curve (HRM) analysis followed by Sanger sequencing was used to identify mutations in exons 18-21 of the EGFR gene and in exon 2 of the KRAS gene. A sensitive next-generation sequencing (NGS) technology was also employed to classify samples with equivocal results. The use of sensitive mutation detection techniques in a large study population of Greek NSCLC patients in routine diagnostic practice revealed an overall EGFR mutation frequency of 15.83%. This mutation frequency was comparable to that previously reported in other European populations. Of note, there was a 99.8% concordance between the HRM method and Sanger sequencing. NGS was found to be the most sensitive method. In addition, female non-smokers demonstrated a high prevalence of EGFR mutations. Furthermore, KRAS mutation analysis in patients with a known smoking history revealed no difference in mutation frequency according to smoking status; however, a different mutation spectrum was observed. PMID- 26622816 TI - Association of molecular biomarkers expression with biochemical recurrence in prostate cancer through tissue microarray immunostaining. AB - The aim of the present study was to investigate the prognostic role of metallothionein-2A (MT-2A), E-cadherin, interleukin-6 (IL-6), cyclin-E, proliferating cell nuclear antigen (PCNA) and B cell lymphoma (Bcl)-2 in the biochemical recurrence of prostate cancer (PCa) using tissue microarray immunostaining. Tissue specimens from 128 PCa patients who underwent radical prostatectomy were processed and transferred onto tissue microarrays. The clinicopathological parameters of PCa patients were also recorded. Following immunohistochemical examination of MT-2A, E-cadherin, IL-6, cyclin-E, PCNA and Bcl-2 expression in PCa specimens, association analysis of biomarkers expression with the biochemical recurrence of PCa was performed. The results revealed that the overall rate of biochemical recurrence was 30.5% (39/128) and the median biochemical recurrence-free time was 19 months (range, 6-35 months). The biochemical recurrence rates in low-, intermediate- and high-risk PCa classification were 14.8 (8/54), 38.7 (24/62) and 58.3% (7/12), respectively. Survival analysis demonstrated that a decreased biochemical recurrence-free survival rate was noted in PCa cases with positive MT-2A and cyclin E expression as well as those with negative E-cadherin expression (P=0.022, 0.028 and 0.011, respectively). Subsequent multivariate Cox analysis revealed that MT-2A [hazard ratio (HR)=2.01; 95% confidence interval (CI)=1.08-3.15; P=0.005], E-cadherin (HR=1.79; 95% CI=1.08-2.21; P=0.042) and cyclin E (HR=1.92; 95% CI=1.22-2.45; P=0.020) were independent predictors of the biochemical recurrence of PCa. In conclusion, the present study provided clinical evidence that evaluation of molecular biomarkers expression may improve clinical prognostic accuracy for the biochemical recurrence of PCa. Of note, the expression of MT-2A, cyclin E and E cadherin may serve as independent predictors for biochemical recurrence of PCa. PMID- 26622817 TI - Bortezomib attenuates HIF-1- but not HIF-2-mediated transcriptional activation. AB - Bortezomib is the first proteasomal inhibitor (PI) to be used therapeutically for treating relapse cases of multiple myeloma and mantle cell lymphoma. A proposed mechanism for its action is that it prevents the proteasomal degradation of proapoptotic proteins, leading to enhanced apoptosis. Although the alpha subunit of hypoxia-inducible factor (HIF)-1 is not degraded with bortezomib treatment, the heterodimeric HIF-1 fails to transactivate target genes. HIF-1 and HIF-2 are related hypoxia-inducible transcription factors that are important for the survival of hypoxic tumor cells. The majority of reports have focused on the effects of bortezomib on the transcriptional activities of HIF-1, but not HIF-2. The present study investigated the effects of bortezomib on HIF-2 activity in cancer cells with different levels of HIF-1alpha and HIF-2alpha subunits. HIF alpha subunit levels were detected using specific antibodies, while HIF transcriptional activities were evaluated using immunodetection, reverse transcription-polymerase chain reaction and luciferase reporter assay. Bortezomib treatment was found to suppress the transcription and expression of CA9, a HIF-1 specific target gene; however, it had minimal effects on EPO and GLUT-1, which are target genes of both HIF-1 and HIF-2. These data suggest that bortezomib attenuates the transcriptional activity only of HIF-1, and not HIF-2. This novel finding on the lack of an inhibitory effect of bortezomib on HIF-2 transcriptional activity has implications for the improvement of design and treatment modalities of bortezomib and other PI drugs. PMID- 26622818 TI - Analysis of the correlation between P53 and Cox-2 expression and prognosis in esophageal cancer. AB - The present study aimed to explore the importance of P53 and Cox-2 protein expression in esophageal cancer and assess their influence on prognosis. The expression of P53 and Cox-2 was assessed in esophageal cancer samples from 195 patients subjected to radical surgery at Changzhou First People's Hospital (Changzhou, China) between May 2010 and December 2011. Expression of P53 and Cox 2 proteins were detected in 60.5% (118/195) and 69.7% (136/195) of the samples, respectively, and were co-expressed in 43.1% (84/195) of the samples. A correlation was identified between P53 expression and overall survival (OS) (P=0.0351) as well as disease-free survival (DFS) (P=0.0307). In addition, the co expression of P53 and Cox-2 also correlated with OS (P=0.0040) and DFS (P=0.0042). P53 expression (P=0.023), TNM staging (P<0.001) and P53/Cox-2 co expression (P=0.009) were identified as independent factors affecting OS in patients with esophageal cancer via a Cox multivariate regression model analysis. A similar analysis also identified P53 expression (P=0.020), TNM staging (P<0.001) and P53/Cox-2 co-expression (P=0.008) as independent prognostic factors influencing DFS in these patients. Binary logistic regression analysis demonstrated a correlation between P53 expression (P=0.012), TNM staging (P<0.001), tumor differentiation level (P=0.023) and P53/Cox-2 co-expression (P=0.021), and local recurrence or distant esophageal cancer metastasis. The results of the present study indicate that P53 and Cox-2 proteins may act synergistically in the development of esophageal cancer, and the assessment of P53/Cox-2 co-expression status in esophageal cancer biopsies may become an important diagnostic criterion to evaluate the prognosis of patients with esophageal cancer. PMID- 26622819 TI - Differential expression of 2IgB7-H3 and 4IgB7-H3 in cancer cell lines and glioma tissues. AB - B7-H3 protein is an important tumor antigen, but the expression of its isoforms, 4IgB7-H3 and 2IgB7-H3, in tumor tissues remains unknown due to the lack of specific monoclonal antibodies (mAbs). In the present study, a mAb (9C3) specifically recognizing 2IgB7-H3, but not 4IgB7-H3, was prepared. Using 9C3 and a previously prepared mAb (4H7) that recognizes 4IgB7-H3 and 2IgB7-H3, the differential expression of 2IgB7-H3 and 4IgB7-H3 was analyzed in a variety of tumor cell lines by flow cytometry. It was found that 4IgB7-H3 had a more broad spectrum of expression among the cell lines compared with 2IgB7-H3. The expression of the two isoforms was further examined in glioma tissues using reverse transcription-polymerase chain reaction and immunohistochemistry techniques. The data revealed that 2IgB7-H3, but not 4IgB7-H3, was specifically expressed in glioma. Taken together, these results demonstrated for the first time that 2IgB7-H3 is a valuable biomarker for the diagnosis of glioma. PMID- 26622820 TI - Compound Radix Sophorae Flavescentis exerts antitumor effects by inhibiting the proliferation and inducing the apoptosis of esophageal carcinoma TE-8 cells. AB - The aim of this study was to examine the effects of compound Radix Sophorae Flavescentis on the proliferation of esophageal carcinoma TE-8 cells and to elucidate the mechanisms involved. For this purpose, we incubated TE-8 cells in medium containing various concentrations (0, 0.0125, 0.025, 0.05, 0.1, 0.2, 0.4 and 0.8 mg/ml) of the compound Radix Sophorae Flavescentis injection and its effects on the proliferation of TE-8 cells were examined by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, we observed the morphological changes and measured the expression levels of apoptosis-related genes (caspase-3, Bcl-2 and Bax) in the cells treated with different doses of the compound (low-dose group, 0.05 mg/ml; medium-dose group, 0.2 mg/ml; and high-dose group, 0.8 ng/ml) by reverse transcription-quantitative PCR (RT-qPCR). The apoptotic index of the cancer cells treated with different doses of the compound was determined by TUNEL assay. Our results revealed that compared with the control group (untreated cells), the proliferation of the cancer cells treated with the compound was significantly inhibited (P<=0.05); the inhibition of the proliferation of the cancer cells occured in a dose-dependent manner. Compared with the control group, the apoptotic rate of the cells in the low-dose, medium-dose and high-dose groups increased significantly (P<0.05) in a dose-dependent manner. In addition, compared with the control group, the mRNA expression of caspase-3 and Bax increased significantly in the cells treated with the compound. However, the mRNA expression of Bcl-2 markedly decreased (P<0.05). With the gradual increase in the drug concentration, the mRNA expression levels of caspase-3, Bcl-2 and Bax in the cancer cells were altered in a dose-dependent manner. In conclusion, our data demonstrate that compound Radix Sophorae Flavescentis injection significantly enhances the expression of pro-apoptotic genes in esophageal carcinoma TE-8 cells by increasing apoptosis and inhibiting cell proliferation. Thus, this study provides a theoretical basis for the clinical treatment of esophageal carcinoma. PMID- 26622821 TI - SC1, an immunoglobulin-superfamily cell adhesion molecule, is involved in the brain metastatic activity of lung cancer cells. AB - SC1 is a cell adhesion molecule that belongs to the immunoglobulin superfamily; this molecule was initially purified from the chick embryonic nervous system and was reported to exhibit homophilic adhesion activity. SC1 is transiently expressed in various organs during development and has been identified in numerous neoplastic tissues, including lung cancer and colorectal carcinomas. The present study focused on the encephalic metastasis of lung cancer cells with respect to the potential function of SC1, as this molecule is known to be consistently expressed in the central nervous system as well as lung cancers. SC1 complementary DNA was introduced into A549 cells, a human lung cancer-derived cell line. The stable overexpression of the SC1 protein in A549 cells was demonstrated to enhance the self-aggregation of the cells. In addition, the SC1 transfectants enhanced the metastatic and invasive potential to the encephalic parenchyma following implantation into nude mice. In conclusion, the results of the present study demonstrated that cell adhesion due interactions between SC1 on brain tissue and SC1 on lung cancer cells was involved in the malignant aspects of lung cancer, including invasion and metastasis to the brain. PMID- 26622822 TI - Early rectal cancer accompanied by multiple systemic abscesses: A case report. AB - A 70-year-old man undergoing treatment for diabetes presented with a cough and pyrexia that has lasted one week. Laboratory tests demonstrated evidence of inflammation. The patient was hospitalized and antibiotic treatment was initiated, but the condition of the patient did not improve. After 2 weeks, computerized tomography scanning demonstrated the presence of multiple small nodules in the lungs and a liver abscess. The patient also developed neck pain and numbness of the upper extremities and was then transferred to Tokai University Hachioji Hospital (Tokyo, Japan). Percutaneous transhepatic drainage (PTD) of the liver abscess was performed and antibiotic treatment was initiated. Detailed examination revealed there was pyogenic spondylitis of the cervical spine, therefore abscess drainage and an anterior cervical spinal fusion were performed. Culture of each lesion resulted in Klebsiella pneumoniae growth. While continuing antibiotic treatment and rehabilitation, the gastrointestinal tract was investigated and evidence of early rectal cancer was observed. The pulmonary nodules disappeared during treatment, indicating that these were multiple lung abscesses. Four weeks following abscess drainage and anterior cervical spinal fusion, lower anterior resection was performed. The present case report describes a patient who developed multiple abscesses associated with early rectal cancer and discusses the case with reference to the literature. PMID- 26622823 TI - Thrombotic thrombocytopenic purpura following salvage chemotherapy with paclitaxel, ifosfamide and cisplatin in a patient with a refractory germ cell tumor: A case report and review of the literature. AB - Thrombotic thrombocytopenic purpura (TTP) is a rare form of thrombotic microangiopathy that is characterized by microvascular thrombosis, thrombocytopenia, hemolysis and end organ damage. An extensive variety of drugs, including certain chemotherapeutic agents, have been associated with TTP. However, paclitaxel, cisplatin and ifosfamide regimen (TIP)-induced TTP has not previously been described. The present study reports the case of a 43-year-old patient with a refractory testicular germ cell tumor who developed acute TTP during TIP chemotherapy. Following the third cycle of TIP chemotherapy, the patient developed fever, anemia, thrombocytopenia and confusion. A diagnosis of TTP was established. Plasmapheresis was initiated as daily treatment in the first week, then continued every other day for 4 weeks. TIP chemotherapy was discontinued. The patient's clinical and neurological symptoms improved markedly after a week. Renal function and hemolysis improved, and the patient was discharged in a stable condition. The patient did not develop any complications and has been in remission for 5 months. The Naranjo adverse drug reaction probability scale indicated a likely association between TTP and the TIP chemotherapy regimen in this patient. This case is also investigated with regard to the associated literature to increase the awareness of TTP following chemotherapy. PMID- 26622824 TI - BRD4 induces cell migration and invasion in HCC cells through MMP-2 and MMP-9 activation mediated by the Sonic hedgehog signaling pathway. AB - Hepatocellular carcinoma (HCC) is a highly aggressive form of carcinoma with poor prognosis, and HCC-associated mortality primarily occurs due to migration and invasion of HCC cells. The manipulation of epigenetic proteins, such as BRD4, has recently emerged as an alternative therapeutic strategy. The present study aimed to investigate the novel mechanism of BRD4 involvement in the migration and invasion of HCC cells. Reverse transcription-quantitative polymerase chain reaction was used to assess BRD4 mRNA expression levels in HCC cell lines. This analysis demonstrated that BRD4 was significantly overexpressed in HCC cell lines compared with a human immortalized normal liver cell line. A short hairpin RNA (shRNA) was then used to suppress BRD4 expression in HCC cells, and resulted in impaired HCC cell proliferation, migration and invasion. When the HepG2 HCC cell line was treated with recombinant human sonic hedgehog (SHH) peptide, the migration and invasion capabilities of HepG2 cells that were inhibited by BRD4 silencing were restored. BRD4 induced cell migration and invasion in HepG2 cells through the activation of matrix metalloproteinase (MMP)-2 and MMP-9, mediated by the SHH signaling pathway. Taken together, the results of the present study demonstrated the importance of BRD4 in HCC cell proliferation and metastasis. Thus, BRD4 is a potential novel target for the development of therapeutic approaches against HCC. PMID- 26622825 TI - Clinicopathological characteristics of hepatitis B surface antigen-negative and hepatitis C antibody-negative hepatocellular carcinoma. AB - The present study investigated the clinicopathological characteristics of resected hepatitis B virus surface antigen (HBs-Ag)-negative, hepatitis C virus antibody (HCV-Ab)-negative hepatocellular carcinoma (NBNC HCC). The clinicopathological characteristics of 164 patients with NBNC HCC, 144 patients with HBs-Ag-positive HCC (HBV group) and 550 patients with HCV-Ab-positive HCC (HCV group) were compared. In the NBCN HCC group, 61 patients succumbed after 2 years. Subsequently, NBCN HCC patients were compared according to survival time (<2 years, 39 patients vs. >=2 years, 64 patients) to identify prognostic factors. Finally, the clinicopathological characteristics of NBNC HCC were compared according to history of alcohol abuse/pathological results: Non alcoholic steatohepatitis HCC (NASH group, 40 patients), alcohol abuse HCC (AL group, 80 patients) and other HCCs (non-NASH/non-AL group, 44 patients). Age, diabetes prevalence and body mass index were significantly higher for NBNC HCC compared with virus-related HCC. Among stage II cases, the prognosis was significantly better for the NBNC compared with that for the HCV group. A high alpha-fetoprotein level, poorly differentiated HCC and advanced liver fibrosis were independent risk factors for the prognosis of NBNC HCC. The proportion of female patients was significantly higher among NASH compared with AL HCC patients. The cumulative survival rates following surgery were similar in the NASH, AL and non-NASH/non-AL groups. NBNC HCC is considered to be a lifestyle disease, with better prognosis for stage II patients. The prognostic factors for NBNC HCC patients undergoing hepatectomy were similar to those with virus-related HCC and did not differ according to alcohol abuse history or pathological results. PMID- 26622826 TI - Germline and somatic mutations of the APC gene in papillary thyroid carcinoma associated with familial adenomatous polyposis: Analysis of three cases and a review of the literature. AB - Patients with familial adenomatous polyposis (FAP), which is caused by the dysfunction of the adenomatous polyposis coli (APC) protein, have the possibility of developing extracolonic manifestations, including thyroid cancer (TC), congenital hypertrophy of the retinal pigment epithelium, desmoid tumors, and gastric and duodenal adenomas. The pathogenesis of these disorders associated with FAP is considered to be affected by the site of the germline mutation on the APC gene as a genotype-phenotype correlation. Moreover, beta-catenin binding sites consist of 20-amino acid repeats (20-AARs) in the APC protein, and they are essential for the development of colorectal adenomas and certain other extracolonic manifestations. The present study retrospectively analyzed the germline and somatic mutations of the APC gene in three papillary TC patients with FAP to analyze the association between the remaining number of 20-AARs and the development of TC. The mutation sites of two TCs did not include 20-AARs in each allele. In one patient, the remaining number of 20-AARs was two in the germline mutation and zero in the somatic mutation. Together with the data on 13 FAP-associated thyroid cancerous lesions in 3 FAP patients reported previously, the majority of the remaining numbers of 20-AARs was zero in the TC patients with FAP (13/16; 81.3%). Consequently, the APC/beta-catenin signaling pathway may be strongly involved with the pathogenesis of TC with FAP. Further accumulation of FAP patients with TC will be required to confirm the molecular pathogenesis of TC. PMID- 26622827 TI - Prediction of chemotherapeutic efficacy using the ratio of neutrophils to lymphocytes in patients with unresectable or recurrent gastric cancer. AB - In cancer patients, the balance between neutrophil (N) and lymphocyte (L) cell counts fluctuates with the tumor load. The objective of the present study was to determine the implications of the chemotherapy effect by the fluctuations of N/L ratio in patients with unresectable or recurrent gastric cancer. The study participants were identified from a prospective cohort of patients with unresectable or recurrent gastric cancer (n=135). The median N/L ratio was 3.23 (range: 0.76-20.45) prior to chemotherapy (pre-chemo-N/L ratio) and 2.55 (range: 1.17-13.45) following 2-4 weeks from when the chemotherapy was completed (post chemo-N/L ratio), respectively. The median overall survival was 7.9 months. The results demonstrated that the N/L ratio of the post-chemotherapy was significantly reduced compared with the pre-chemotherapy group (P<0.001). The survival rate for the pre-chemo-N/L ratio >=4.0 group was significantly reduced compared to the N/L <4.0 group (P=0.01). The difference of the pre-chemo-N/L ratio subtracted from the post-chemo-N/L ratio can inflect the chemotherapy effect, respectively. These results indicate that the N/L ratio may be used to predict the potential chemotherapy efficacy in unresectable or recurrent gastric cancer. PMID- 26622828 TI - Temporal bone meningioma involving the middle ear: A case report. AB - Meningioma is a common intracranial tumor involving the meninges. The localization of this type of tumor is rarely extracranial due to its typically low invasive properties. Furthermore, invasion of the middle ear is exceptional. The present study reported a case of meningioma extending into the middle ear from the middle cranial fossa through the tegmen tympani. The clinical and pathological characteristics, as well as the outcome of the patient, were described. PMID- 26622829 TI - Imaging of human pancreatic cancer xenografts by single-photon emission computed tomography with 99mTc-Hynic-PEG-AE105. AB - The elevated expression of urokinase-type plasminogen activator receptor (uPAR) is associated with the poor prognosis of pancreatic cancer patients. Thus, uPAR is a promising candidate as a molecular target for the non-invasive imaging of pancreatic cancer. The present study aimed to develop a technetium-99m (99mTc) labeled uPAR-binding peptide for non-invasive single-photon emission computed tomography (SPECT) assessment of uPAR expression in pancreatic cancer xenograft models. A linear high-affinity uPAR peptide antagonist, Hynic-PEG-AE105, was labeled with 99mTc. Human uPAR-positive pancreatic cancer BxPC-3 cells were inoculated into nude mice. SPECT was performed in the pancreatic cancer xenograft mice models. The results showed that the rate of the 99mTc labeling of Hynic-PEG AE105 was 97.72+/-1.73%. The tumor uptake of 99mTc-Hynic-PEG-AE105 was higher than the control inactive peptide 99mTc-Hynic-PEG-AE105mut at 4 h (3.37+/-0.11 vs. 1.36+/-0.18; P<0.001) and 6 h (3.64+/-0.25 vs. 1.28+/-0.20; P<0.001) (n=10). Moreover, a significant correlation was observed between the tumor uptake of 99mTc-Hynic-PEG-AE105 and uPAR expression (r=0.791, P=0.006). In conclusion, in the present study, a peptide-based SPECT tracer, 99mTc-Hynic-PEG-AE105, with a high purity and specific radioactivity was synthesized. 99mTc-Hynic-PEG-AE105 is a promising agent for the non-invasive determination of uPAR expression in pancreatic cancer. PMID- 26622830 TI - Ultraviolet light exposure, skin cancer risk and vitamin D production. AB - The danger of overexposure to solar ultraviolet radiation has been widely reviewed since the 1980s due to the depletion of the ozone layer. However, the benefits of mild exposure of the skin to ultraviolet (UV) light have not been widely investigated. Numerous reports have demonstrated that an association exists between low light exposure to the sun, non-melanoma skin cancer and a lack of vitamin D synthesis. As vitamin D synthesis in the body depends on skin exposure to UVB radiation from the sun (wavelength, 290-320 nm), experimental measurements for this type of solar radiation are important. The present study analyzed data obtained from a laboratory investigating UV radiation from the sun at the University of Tarapaca (Arica, Chile), where systematic experimental UVB measurements had been performed using a calibrated biometer instrument since 2006. These data were compared with skin cancer data from the local population. The results demonstrated that the incidence of skin cancer systematically increased from 7.4 to 18.7 in men and from 10.0 to 21.7 in women between 2000 and 2006 in Arica, respectively; this increase may be due to multiple factors, including the lack of adequate levels of vitamin D in risk groups such as post menopausal women and senior age. This marked increase may also be due to the high levels of UV radiation measured in this region throughout the year. However, it is not certain that the local population has adequate vitamin D levels, nor that their skin has been predominantly exposed to artificial light that does not allow adequate vitamin D synthesis. Thus, the current study presents the association between skin type IV, the time to induce solar erythema and the time required to produce 1,000 international units of vitamin D. PMID- 26622831 TI - A rare case of pure primary hemangioma of the scapula: A case report. AB - Hemangioma is a benign vascular tumor, which may occur in any bone of the body. The most common locations are the spine and craniofacial bone; however, occurrence is extremely rare in the scapula. The current study presented the case of a 58-year-old female, with scapula hemangioma in the left shoulder who presented with joint ache that had lasted for ~1 year. The main clinical manifestations included local tenderness, an osseous lump and limited shoulder movement with a little pain, which was alleviated by rest. Roentgenogram, computed tomography and magnetic resonance imaging of the left acromion revealed a mass along the inner surface of the scapula of the left shoulder with polycystic expansion and bone destruction. The results of computed tomography and magnetic resonance imaging indicated a pure primary tumor and the lesion was subsequently resected. Notably, the postoperative pathological diagnosis was capillary hemangioma. The aim of the present study was to analyze the clinical and imaging features of scapula hemangioma, which must be considered for the differential diagnosis of scapula tumors. In the present case, no recurrence was identified by X-ray examination 1 year after surgery. The long-term efficacy of surgical treatment requires continuous observation of the patient. PMID- 26622832 TI - Reduced PTEN expression and overexpression of miR-17-5p, -19a-3p, -19b-3p, -21 5p, -130b-3p, -221-3p and -222-3p by glioblastoma stem-like cells following irradiation. AB - Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene that induces cell apoptosis by inhibiting the PI3K/Akt signaling pathway. Glioblastoma (GBM) is a brain tumor that is resistant to irradiation and chemotherapy and, thus, is difficult to cure. GBM stem-like cells (GSCs) have been implicated as a cause of this resistance. microRNA (miRNA/miR) inhibits the expression of proteins. The objective of the present study was to identify miRNAs that target PTEN, which induces apoptosis, in irradiation-resistant GSCs. When the expression of miRNAs was examined in GSCs irradiated at 60 Gy using the human GBM A172 cell line, the expression of PTEN-targeting miR-17-5p, -19a-3p, -19b-3p, -21-5p, -130b-3p, -221-3p and -222-3p was significantly higher in irradiated GSCs than in non-irradiated cells, and the PTEN expression levels, as revealed by immunostaining, were lower in the irradiated GSCs than in the non-irradiated cells. These results suggested that the expression of PTEN was suppressed through the overexpression of PTEN-targeting miRNAs in GSCs following irradiation. PMID- 26622833 TI - Optimal treatment for primary benign intratracheal schwannoma: A case report and review of the literature. AB - A 53-year-old male was admitted to Xinhua Hospital (Shanghai, China) due to coughing and dyspnea that had persisted for half a year, with aggravation of chest tightness and dyspnea for 1 week. Chest computed tomography (CT) revealed a mass within the distal third of the trachea. Flexible bronchoscopy confirmed an ~2.0 cm, smooth, tan-colored mass in the trachea, 2 cm above the carina. Endoscopic resection by argon plasma coagulation combined with electronic snaring was applied, however, recurrence was found 2 weeks later. Finally, the tumor was completely removed by surgery and the post-operative course was uneventful. Since schwannoma is rare in the intrapulmonary region and extremely rare in the trachea, a review of 51 cases of primary tracheal schwannoma previously reported in the English literature was performed. The majority of cases occurred in adults and were usually located in the distal third of the trachea. The predominant tumor size was 1-3 cm and airway obstruction symptoms were common. Half of the patients were misdiagnosed with asthma, and CT scan and bronchoscopy were contributory to the correct diagnosis. The treatment of choice depended on the patient's condition, however, surgery should be chosen in the event of local recurrence following endoscopic treatment. PMID- 26622834 TI - Effect of phosphorylation and methylation on the function of the p16INK4a protein in non-small cell lung cancer A549 cells. AB - The p16INK4a protein (p16) has been reported to be a tumor suppressor gene that suppresses the proliferation of cells through the direct inhibition of cell cycle progression. Accordingly, p16 is a potential target for cancer gene therapy. In the present study, the arginine 22, 131 and 138 residues of p16 were found to be methylation sites, as the mutation of these arginine residues to lysine resulted in the hypomethylation of p16. Furthermore, the protein arginine methyltransferases (PRMTs), such as PRMT1, PRMT4 and PRMT6, were determined to be involved in the methylation of the p16 arginine residues. PRMT6 effectively reduced the intensity of the association between p16 and CDK4, and also weakened the function of p16 in preventing cell proliferation. In addition, the p16 protein was found to be phosphorylated in various cell lines, and mutations in the serine residues weakened the cell cycle arrest and induction of apoptosis mediated by p16. Preliminarily, the crosstalk between the phosphorylation and arginine methylation modification of p16 was examined. These findings predict a role for serine phosphorylation against arginine methylation of p16. PMID- 26622835 TI - Tripartite motif-containing 29 as a novel biomarker in non-small cell lung cancer. AB - Tripartite motif-containing 29 (TRIM29) is a member of the tripartite motif (TRIM) protein family. TRIM29 has been reported to be deregulated in a number of cancer types, suggesting the oncogenic function of TRIM29. However, its clinical significance in non-small cell lung cancer (NSCLC) has not been fully elucidated. In the present study, the TRIM29 expression status was investigated by immunohistochemical analysis in paraffin-embedded specimens obtained from 320 patients with surgically resected NSCLC, treated between 2000 and 2007. High TRIM29 expression was significantly associated with smoking (P=0.012), T stage (P=0.015) and M stage (P=0.003). Furthermore, elevated TRIM29 expression level was correlated with reduced overall (OS) and disease-free survival. In addition, high TRIM29 expression was an independent prognostic factor for OS [P=0.003, hazard ratio (HR)=2.102, 95% confidence interval (CI), 1.069-3.193]. In conclusion, these results suggest that TRIM29 may be a useful prognostic marker in NSCLC patients and a potential molecular target for NSCLC treatment. PMID- 26622836 TI - Expression of ALDH1A1 and CD44 in primary head and neck squamous cell carcinoma and their value for carcinogenesis, tumor progression and cancer stem cell identification. AB - In head and neck squamous cell carcinoma (HNSCC), aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) and hyaluronan receptor cluster of differentiation 44 (CD44) are often used as cancer stem cell (CSC) markers. The aim of the present study was to examine the relevance of these proteins for HNSCC in general and for the identification of CSCs. Tumors from 48 patients with primary HNSCC were analyzed for the expression of ALDH1A1 and CD44. Additionally, the association of the proteins with the proliferation rate and epidermal growth factor receptor (EGFR) expression was analyzed. ALDH1A1 was expressed in 54.2% of the carcinoma samples while CD44 was expressed in 89.6% of the carcinoma samples. Most notably, these proteins were often not expressed exclusively in a subpopulation, but also in the majority of tumor cells (ALDH1A1: 30.8% of ALDH1A1+ tumors; CD44: 65.1% of CD44+ tumors). Furthermore, patients with ALDH1A1+ tumors exhibited worse survival rates. CD44 and EGFR expression patterns were overlapping within the tumors and the expression rates were significantly connected. Ki-67+ tumor cells often expressed CD44. ALDH1A1 and CD44 expression patterns only partly overlapped. Consequently, ALDH1A1 and CD44 play significant roles in carcinogenesis and tumor progression. Within the present study, CD44 appeared to interact with EGFR and was more often expressed in primary HNSCC than the marker ALDH1A1. However, ALDH1A1 was a better marker to define a subpopulation of tumor cells. Finally, neither ALDH1A1 nor CD44, alone or combined, were sufficient to determine the CSC population in HNSCC. PMID- 26622837 TI - Medulloblastoma with soft-tissue and skeletal metastases in an adult: A case report. AB - Medulloblastoma (MB) is a highly malignant primary brain tumor, which occurs in the cerebellum or posterior cranial fossa. MB is most commonly identified in children <10 years of age. The disease is rare in adults, affecting patients aged between 30 and 50 years of age, with an incidence of 0.5 cases per 1,000,000 individuals. Extraneural metastases are reported in 7-10% of cases, most commonly involving the bones and more rarely involving the lymph nodes, visceral organs and bone marrow. The current study presents the case of a 36-year-old male who underwent a gross total resection followed by radiation therapy to the craniospinal axis for the treatment of MB. The patient subsequently developed widespread metastasis, which involved the soft tissue of the occipital bone. Subsequently, the patient was administered palliative radiotherapy and initially exhibited a good clinical response. However, the patient succumbed at 18 months post-diagnosis due to dissemination of the disease. The literature on the extraneural metastasis of MB is also reviewed in the current study. PMID- 26622838 TI - Synthesis and positron emission tomography evaluation of 18F-Glu-Urea-Lys, a prostate-specific membrane antigen-based imaging agent for prostate cancer. AB - In recent years, single-photon emission computed tomography and positron emission tomography (PET) have also been used, in addition to computed tomography and magnetic resonance imaging, in targeting the diagnosis of prostate cancer. The aim of this study was to synthesize the prostate-specific membrane antigen (PSMA) based imaging agent 2-{3-[1-Carboxy-5-(4-[18F] fluoro-benzoylamino)-pentyl] ureido}-pentanedioic acid (18F-Glu-Urea-Lys, [18F]3) and to detect its PET imaging efficiency for high PSMA expression in prostate cancer. In this study, 18F-Glu-Urea-Lys was synthesized in two steps from the p-methoxybenzyl-protected Glu-Urea-Lys precursor using N-Hydroxysuccinimidyl-4-[18F] fluorobenzoate ([18F]SFB). PET imaging evaluation was conducted in nude mice using LNCaP (PSMA+), and PC-3, 231 and A549 (all PSMA-) xenograft models. The results indicated that 18F-Glu-Urea-Lys was produced in radiochemical yields of 28.7%. The radiochemical purity was 99.1% and the mean total synthesis time was 168 min. In nude mice models 18F-Glu-Urea-Lys clearly delineated PSMA+ LNCaP prostate tumor xenografts on PET imaging. At 4 h post-injection, the contrast agents were only observed in renal, liver, bladder and PSMA+ LNCaP tumors. The PSMA- tumor (PC-3, 231 and A549) was clear. In conclusion, 18F-Glu-Urea-Lys was found to be easily synthesized. This radiotracer demonstrated high tumor and low-to-normal tissue uptake, fast clearance from non-target tissues and retention in PSMA+ prostate tumor xenografts. PMID- 26622839 TI - Adenoid cystic carcinoma of the larynx: A report of two cases. AB - Laryngeal adenoid cystic carcinoma (ACC) is extremely rare, worldwide. From January 1994 to January 2014, all cases of laryngeal ACC that were diagnosed in the four largest hospitals in Hainan province, were reviewed. Only two such cases were identified. The first patient had a tumor in the subglottic region and the second patient, in the glottic region. The patient with subglottic ACC, who had experienced ongoing symptoms for 3 years, had previously been diagnosed with asthma, at a local hospital. Both presented at an advanced stage. The patient with subglottic disease received a total laryngectomy with a positive surgical margin, was treated with adjuvant radiotherapy, and later succumbed to a pleural effusion as a result of pulmonary metastases. The patient with glottic disease received a partial laryngectomy and declined adjuvant radiotherapy. Subsequently, she developed recurrent disease and passed away following an episode of asphyxia at 14 months post-surgery. Each of these cases had a poor prognosis at presentation. For patients with locoregionally advanced laryngeal ACC, more effective management strategies are required. PMID- 26622840 TI - Acute monocytic leukaemia with t(11; 12) (p15; q13) chromosomal changes: A case report and literature review. AB - Acute myeloid leukaemia (AML) is a type of heterogeneous disease derived from haematopoietic stem cells. Cytogenetic characterisation is essential for diagnosis and prognosis stratification. Here, we present the case of a 43-year old female diagnosed with leukaemia, who demonstrated a rare chromosomal change of t(11; 12) (p15; q13) along with a positive FLT3-ITD mutation. The patient had a white blood cell count of 76.41*109/l. Bone marrow morphology revealed that monoblasts accounted for 25.5% of cells, and premonocytes accounted for 49.0%. This patient strongly responded to idarubicin and Ara-c (cytarabine) chemotherapy, which rapidly eliminated the leukaemia cell clones. However, the proliferation rate of the leukaemia cells was high during the intermission of chemotherapy. Subsequently, following two courses of chemotherapy, full haematological remission could not be attained. AML patients with t(11; 12) (p15; q13) combined with FLT3-ITD mutations are expected to have a short life expectancy; however, early haematopoietic stem cell transplantation therapy may improve the treatment outcome for these patients. PMID- 26622841 TI - A single center clinical analysis of children with neuroblastoma. AB - In the present study, the cases of 59 children diagnosed with neuroblastoma (NB) were retrospectively analyzed to assess the association between the short-term efficacy of treatment and prognostic factors. In total, 59 patients with NB that were diagnosed between July 1, 2008 and June 30, 2013 at Shanghai Children's Hospital were enrolled in the present study. The follow-up was performed until December 31, 2013, and the data revealed that 43 patients (72.9%) achieved complete remission (CR) or partial remission (PR). The 3-year overall survival (OS) rate of patients with stage I, II, III, IV and IVs disease was 100, 100, 65.6, 34.8 and 85.7%, respectively (P=0.02). The 3-year OS and event-free survival rates were evidently increased in patients with favorable histology compared with the rates in the patients with unfavorable histology (P=0.046 and 0.030, respectively). Univariate statistical analysis revealed that the factors significantly associated with prognosis were patient age, tumor stage and risk group (P=0.004, 0.02 and 0.001, respectively). The present study identified that tumor stage, risk group and patient age are important prognostic factors for NB. An age of 18 months was also hypothesized to be the cut-off for the prognosis of patients. PMID- 26622842 TI - Association between functional variants in BIRC5/survivin gene 3' untranslated region and mRNA expression in lymphoblastoid cell lines. AB - Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5)/survivin genetic microRNA (miRNA) binding site variants in the 3' untranslated region (3'UTR) are known to be significantly associated with cancer risk. However, the roles of genetic variants in BIRC5/survivin gene 3'UTRs and post-transcriptional regulation have not been elucidated. In the present study, we revealed that rs1042489, rs1042542, rs17882360, rs2239680, rs2661694 and rs4789560 in the BIRC5/survivin 3'UTR have potential miRNA binding sites using bioinformatics analysis. However, only rs1042489 was significantly associated with BIRC5/survivin mRNA expression in lymphoblastoid cell lines (P=0.030); rs1042489 may be a putative variant mediating the post-transcriptional regulation of the target BIRC5/survivin gene. An in-depth understanding of how 3'UTR variants regulate BIRC5/survivin activity is expected to pave the way to targeting the BIRC5/survivin pathway in cancer therapy. PMID- 26622844 TI - Myxoma of the upper leg originating from an appendiceal mucinous neoplasm: A case report. AB - Myxoma is rare in the upper leg. The current study presents the case of a large tumor in the right upper leg. The tumor extended to pelvic cavity and was found to be connected with a cystic and solid neoplasm that was adjacent to the ascending colon in the right lower quadrant. The large tumor of the upper leg had existed for 15 years and had ulcerated through the skin 4 days prior to admittance. Palliative surgery was performed, with histological findings of a myxoma. Since appendiceal mucinous neoplasms may invade organizations outside of the mucous layer of the appendix and cause secondary peritoneal myxoma, this myxoma of the upper leg probably originated from an appendiceal mucinous neoplasm. PMID- 26622843 TI - Primary extragonadal germ cell tumor: A case report on prostate seminoma. AB - Primary extragonadal germ cell tumors are rare, and 60% of such cases are seminomas. While the tumors can occur in the mediastinum, thymus, retroperitoneal organs and pineal gland, seminoma originating in the prostate tissue is extremely rare. The present study reports the case of a 54-year-old male with prostate seminoma. The patient was followed up at the First Affiliated Hospital of Dalian Medical University (Dalian, Liaoning, China) from 2001 onwards. The patient received chemotherapy with cyclophosphamide following total resection of the pelvic organs, pelvic lymph node dissection, continent detenial cecum-ascending colic bladder and orchidectomy. The patient experienced considerable post operative quality of life for >10 years and the disease did not reappear. The study indicated that extragonadal seminoma is sensitive to chemotherapy, and that radical surgery and post-operative adjuvant chemotherapy with cyclophosphamide is a reasonable and feasible treatment method. PMID- 26622845 TI - Complete regression of adult pineoblastoma following radiotherapy: A case report and review of the literature. AB - Adult pineoblastomas (PBs) are rare central nervous system tumors. Little is known with regard to the clinical features and outcomes of adult PB, and optimal treatment strategies for adult PB remain to be determined. The current report describes a case of PB in a 46-year-old male, who presented with obstructive hydrocephalus due to a large pineal region mass. Considering the potential effect on quality of life, the patient underwent a partial resection. Postoperative radiotherapy, comprising prophylactic craniospinal irradiation at a dose of 34.2 Gy followed by a local 25.3-Gy 'boost' to the tumor site for a total dose of 59.5 Gy, resulted in the complete regression of the tumor without neurological deficits. The patient has remained free of recurrence for 36 months after radiotherapy. This case highlights a minimally invasive strategy to treat a rare pineal region tumor with significant involvement of critical structures that resulted in a favorable response and an excellent neurological outcome. The radiographic and histopathological features of PB are also reviewed, and the various treatment options reported in the literature are discussed. PMID- 26622846 TI - Hepatocellular carcinoma presenting as thoracic spinal canal metastasis with no clinical primary foci: A report of a rare case and review of the literature. AB - Hepatocellular carcinoma (HCC) is the third most common malignant tumor worldwide and has a poor survival rate. The poor prognosis can be attributed to several of the characteristics of HCC, such as fast infiltrating growth, early-stage metastasis, high-grade malignancy and poor therapeutic efficacy. The current study presents a case of HCC that was metastatic to the spinal canal with an unknown primary site and discusses the diagnostic probabilities. The patient was a 48-year-old female who presented with chest paraesthesis of the back and numbness of the right lower limb. Computed tomography (CT) and magnetic resonance imaging indicated a possible lipomyoma in the thoracic spinal canal. Surgery was performed to remove the mass and the post-operative pathological diagnosis indicated a moderately-differentiated HCC. Subsequent abdominal CT scans and B mode ultrasound failed to localize the primary foci in the liver and the tumor markers were normal. The patient had no history of chronic liver disease in the past. The patient refused any further examinations after surgery and was discharged from hospital. A post-operative follow-up 1.5 years later found that the patient was healthy and that the level of discomfort had been significantly reduced following the surgery. HCC presenting as thoracic spinal canal metastasis with an unknown primary site is extremely rare. The present study additionally reports the results of a literature review and provides a rational deduction for the unknown primary foci of HCC. PMID- 26622847 TI - Multiple myeloma with intracranial extension and bilateral renal infiltration: A case report and review of the literature. AB - Multiple myeloma (MM) is a rare hematological malignancy, characterized by uncontrolled proliferation of plasma cells in the bone marrow. MM is usually confined to the bone marrow, however, it may occasionally infiltrate other tissues, which is known as extramedullary plasmacytoma (EMP). The majority of EMPs involve the head and neck region, although different anatomical sites, including the gastrointestinal tract, central nervous system, thyroid gland and breast may also be affected. The simultaneous presentation of EMP in the kidney and head is rare, presenting diagnostic challenges due to its unusual location and non-specific or absent symptoms. To the best of our knowledge, no case of extramedullary plasmacytoma presenting with simultaneous renal and intracranial infiltration has been reported in the literature thus far. However, the present study reports a case of primary renal and intracranial extramedullary plasmacytoma in a 76-year-old male patient. The patient presented with a swelling over the right side of the forehead, which had slowly increased in size prior to hospital admission. The swelling was associated with dizziness and weakness, without bone pain. Contrast magnetic resonance imaging suggested an osteolytic skull lesion with intracranial extension. Abdominal enhanced computed tomography scanning revealed a large tumor mass extending around and into the kidneys. Immunohistochemical examination of the renal tumor biopsy, and blood and serum samples, as well as immunoelectrophoresis of serum proteins, resulted in a diagnosis of EMP being proposed. Therefore, the patient was administered with two cycles of cyclophosphamide and thalidomide in combination with dexamethasone. Follow-up imaging performed 4 months later revealed almost complete disappearance of the intracranial tumor mass and renal infiltration. The current study also presented a review of the literature. This study revealed that EMPs may co-exist with MM or present as the main symptom of MM. The diagnosis of an EMP is complex and requires radiological, hematological, biochemical and histological investigation. At present, no guidelines for EMP treatment have been established and thus, treatment options include surgery, chemotherapy and radiotherapy, either alone or in combination. We hypothesize that combined treatment may provide the best patient outcome. PMID- 26622848 TI - Cytoplasm estrogen receptor beta5 as an improved prognostic factor in thymoma and thymic carcinoma progression. AB - A number of previous studies have reported that sex steroid hormones, including estrogens, are involved in the regulation of the thymic function. The aim of the present study was to investigate the expression of estrogen receptor beta5 (ERbeta5) in thymic tumors and the correlation between ERbeta5 expression and thymoma biological characteristics. The expression levels of ERbeta5 in thymic epithelial tumors was evaluated in 103 patents using immunohistochemical staining and reverse transcription-quantitative polymerase chain reaction. In addition, an indirect immunofluorescence assay was performed to evaluate the ERbeta5 expression levels in the TC1889 and T1682 cell lines. The survival outcome was estimated using Kaplan-Meier plots. The results indicated that ERbeta5 expression was mainly located in the thymic tumor cell cytoplasm (87.37%; 90/103 cases) and overexpression was observed in thymic tumors compared with normal thymic tissues (P=0.001). Using the Kruskal-Wallis test, a statistically significant association was observed between cytoplasmic ERbeta5 (cERbeta5) expression and thymic tumor subtypes (P=0.024) and stages (P=0.003 and R=-0.376). The Kaplan-Meier plots revealed that cERbeta5 expression was significantly associated with improved overall and progression-free survival (P=0.008 and P=0.004, respectively). The present study suggested that overexpression of cERbeta5 may indicate an improved prognosis and may be involved in the underlying mechanism through which estrogen inhibits thymoma and thymic carcinoma development. PMID- 26622849 TI - Mitochondrial reactive oxygen species and complex II levels are associated with the outcome of hepatocellular carcinoma. AB - In the present study, two oxidative stress parameters, reactive oxygen species (ROS) and mitochondrial respiratory complex II, were evaluated in the mitochondria of hepatocellular carcinoma (HCC) cells to determine the association between these parameters and the carcinogenesis and clinical outcome of HCC. High levels of ROS and low levels of complex II were found to be associated with reduced post-operative survival in HCC patients using the log-rank test. Furthermore, multivariate analysis confirmed that the levels of ROS [relative risk (RR)=2.867; 95% confidence interval (CI), 1.062-7.737; P=0.038] and complex II (RR=5.422; 95% CI, 1.273-23.088; P=0.022) were independent predictors for the survival of patients with HCC. Therefore, the analysis of ROS and complex II levels may provide a useful research and therapeutic tool for the prediction of HCC prognosis and treatment. PMID- 26622850 TI - Multiple-phase spiral CT findings of pancreatic vasoactive intestinal peptide secreting tumor: A case report. AB - The present study reports a case of pancreatic vasoactive intestinal peptide secreting tumor (VIPoma), of 2.2 cm in diameter, arising from the region of the uncus of the pancreas with liver metastases in a 50-year-old patient, which demonstrated unusual multiple-phase spiral computed tomography (MPSCT) results. The pancreatic lesion was isodense compared with the pancreatic parenchyma. During the hepatic artery phase and portal venous phase, the mass was hypodense compared with the enhanced pancreas, with the mean CT attenuation (HU) values being 56 HU and 66 HU, respectively. During the hepatic parenchymal phase, the mass became hyperdense with the mean CT attenuation values being 74 HU. The process of contrast-enhanced MPSCT demonstrated progressive strengthening. Pancreaticoduodenectomy and wedge resection of a number of the liver metastases was performed. There are only a limited number of studies reporting CT findings of pancreatic VIPoma and no MPSCT findings have been described previously. PMID- 26622851 TI - Gastric heterotopic pancreas masquerading as a stromal tumor: A case report. AB - Heterotopic pancreas (HP), a rare condition that is generally asymptomatic, is an aberration in the developmental profile of the pancreas. While it can occur in any location in the gastrointestinal tract, it is most typically found in the antrum of the stomach and is usually wrongly considered to be a submucosal tumor (SMT). Despite advances in diagnostic modalities, a HP still poses a diagnostic dilemma to clinicians. Invasive surgery or endoscopic resection have often been inappropriately applied in cases of an ectopic pancreas due to the difficulty in distinguishing it from neoplastic SMTs, such as gastrointestinal stromal tumors (GISTs). The present study reports the unusual case of a middle-aged female with an SMT at the lesser curve of the mid-body of the stomach, which was initially diagnosed as a GIST through endoscopic ultrasonography and computed tomography. However, following removal by endoscopic submucosal dissection, this lesion was finally histopathologically confirmed as an HP. Therefore, although it is rare, the possibility of an HP should always be considered when diagnosing an extramucosal gastric mass. The precise pre-operative diagnosis of this entity may avoid unnecessary extensive treatment intervention. PMID- 26622852 TI - Afzelin exhibits anti-cancer activity against androgen-sensitive LNCaP and androgen-independent PC-3 prostate cancer cells through the inhibition of LIM domain kinase 1. AB - Prostate cancer presents high occurrence worldwide. Medicinal plants are a major source of novel and potentially therapeutic molecules; therefore, the aim of the present study was to investigate the possible anti-prostate cancer activity of afzelin, a flavonol glycoside that was previously isolated from Nymphaea odorata. The effect of afzelin on the proliferation of androgen-sensitive LNCaP and androgen-independent PC-3 cells was evaluated by performing a water soluble tetrazolium salt-1 assay. In addition, the effect of afzelin on the cell cycle of the LNCaP and PC-3 prostate cancer cell lines was evaluated. Western blot analysis was performed to evaluate the effect of afzelin on the kinases responsible for the regulation of actin organization. Afzelin was identified to inhibit the proliferation of LNCaP and PC3 cells, and block the cell cycle in the G0 phase. The anticancer activity of afzelin in these cells was determined to be due to inhibition of LIM domain kinase 1 expression. Thus, the in vitro efficacy of afzelin against prostate cancer is promising; however, additional studies on different animal models are required to substantiate its anticancer potential. PMID- 26622853 TI - Primary gastrointestinal stromal tumor of the liver in an anorectal melanoma survivor: A case report. AB - The majority of gastrointestinal stromal tumors (GISTs) arise in the stomach and small intestine; primary GIST of the liver is extremely rare. GISTs share specific immunohistological features with melanoma, therefore, determining a definitive diagnosis can be difficult. However, electron microscopy can be used to aid the differential diagnosis of GIST. The present study reports the first case of a KIT/platelet-derived growth factor receptor alpha (PDGFRA) wild-type, primary GIST arising from the liver in a long-term survivor of anorectal melanoma. The patient underwent APR for treatment of malignant melanoma of the anorectum in 2001 with no adjuvant therapy and remained disease-free until 2009. In 2009, the patient presented with a solitary, rapidly growing hypervascular liver tumor, which was subsequently diagnosed as a primary GIST of the liver. Imatinib treatment (400 mg/day) was initially administered for two months, however, disease progression occurred. Therefore, the patient underwent chemotherapy with doxorubicin (50 mg/m2) and cisplatin (50 mg/m2) every three weeks. Although this temporarily resulted in stable disease, progression occurred five months later. Finally, oral sunitinib (37.5 mg/day) was administered; however, the patient succumbed to the disease one month later. Despite the current GIST patient exhibiting a poor response to imatinib, the present study highlights the importance of considering a second primary malignancy and performing immunohistochemical analysis upon the occurrence of a newly developed lesions in long-term remission cancer survivors. PMID- 26622854 TI - Ethanolic extract of Tulipa edulis Bak induces apoptosis in SGC-7901 human gastric carcinoma cells via the mitochondrial signaling pathway. AB - Tulipa edulis Bak (TEB) is an active ingredient in various traditional Chinese medicine compounds and is commonly used to treat swelling and redness, remove toxicity and eliminate stagnation, as well as to prevent and treat certain cancer types. However, the underlying molecular mechanism of the anticancer activity of TEB remains unclear. The aim of the current study was to investigate the effect and underlying mechanism of the ethanolic extract of TEB (EETEB) on SGC-7901 human gastric carcinoma cells. An MTT assay was performed to analyze cell viability. In addition, transmission electron microscopy, an Annexin V/fluorescein isothiocyanate assay, a JC-1 assay and laser scanning confocal microscopy with DAPI staining were used to determine the rate of apoptosis. Furthermore, reverse transcription-polymerase chain reaction and western blot analysis were used to detect the expression levels of the apoptosis gene and protein. EETEB was identified to inhibit the growth of SGC-7901 cells in a dose dependent manner and induce changes in cell morphology. At the molecular level, EETEB induced SGC-7901 cell DNA fragmentation, loss of plasma membrane and asymmetrical collapse of the mitochondrial membrane potential, while it increased the expression of pro-apoptotic B-cell lymphoma-2 (Bcl-2)-associated X protein and reduced expression of anti-apoptotic Bcl-2. Thus, the results of the current study revealed that the application of EETEB may inhibit the growth of the SGC 7901 cells due to mitochondria-mediated apoptosis. PMID- 26622855 TI - Paclitaxel induces apoptosis and reduces proliferation by targeting epidermal growth factor receptor signaling pathway in oral cavity squamous cell carcinoma. AB - Oral cavity cancer is common worldwide. Furthermore, the epidermal growth factor receptor (EGFR) signaling pathway is considered to be constitutively activated in oral cancers. Paclitaxel is widely accepted as an antitumor drug as it effectively inhibits the cell cycle. This study predominantly explores the possible molecule mechanism of paclitaxel on oral cancer treatment. Cell viability was first detected using an MTT assay. Cell apoptosis was examined by Hoechst staining and flow cytometry using an annexin-V and propidium iodide kit. Specific EGFR signaling pathways were further explored through western blot analysis. Abnormal protein expression levels were determined via immunofluoresence. Additionally, the protein levels of matrix metalloproteinase (MMP)-2 and 9 were determined using ELISA. Paclitaxel significantly inhibited oral cancer cell viability in a time- and dose-dependent manner. Paclitaxel also enhanced oral cancer cell apoptosis via increased Bim and Bid protein expression. Furthermore, paclitaxel was observed to inhibit oral cancer cell proliferation through increased MMP-2 and MMP-9 protein levels. Paclitaxel inhibited the growth of the oral cancer cell line, tea8113 malignant proliferation and enhanced tea8113 cell apoptosis through inhibiting the EGFR signaling pathway. PMID- 26622856 TI - Knockdown of Pin1 leads to reduced angiogenic potential and tumorigenicity in glioblastoma cells. AB - Glioblastoma is the most common and most aggressive type of primary brain tumor. Current approaches in the treatment of glioblastoma are not effective enough to increase patient survival or prevent recurrence following surgery. Consequently, the search for potential drug targets is ongoing. Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1), an isomerase that is overexpressed in various tumors, has become an attractive molecule in cancer research. Pin1 has been reported to regulate proteins involved in essential cellular pathways that mediate cell proliferation, cell cycle progression, differentiation and apoptosis, by altering their stability and function. The results of the present study revealed that knockdown of Pin1 in glioblastoma cells using RNA interference or the selective Pin1 inhibitor, juglone, suppressed the tumorigenic features by reducing cell growth, migration and angiogenic potential. Furthermore, knockdown of Pin1 decreased the levels of vascular endothelial growth factor and matrix metallopeptidase 9, and also triggered apoptosis. Due to the fundamental roles of Pin1 in promoting tumorigenesis, Pin1 inhibitory molecules, including juglone, or alternative synthetic derivatives hold potential for the development of clinical countermeasures against glioblastoma. PMID- 26622857 TI - Normal platelet counts mask abnormal thrombopoiesis in patients with chronic myeloid leukemia. AB - Increased platelet heterogeneity has been reported in myeloproliferative neoplasms (MPN) with thrombocytosis. However, whether abnormal thrombopoiesis occurs in patients with chronic myeloid leukemia (CML) who have normal platelet counts, remains unclear. In order to explore this question, 25 patients with CML with normal platelet counts (CML-N), 40 patients with CML with elevated platelet counts (CML-E) and 33 healthy adults were recruited. The association of platelet count with mean platelet volume (MPV), platelet large cell ratio (P-LCR) and platelet distribution width (PDW) was examined. Bone marrow smears were also reviewed to assess the proliferation and abnormal lobation of megakaryocytes. The results showed that the two CML groups exhibited higher MPV, P-LCR and PDW values than those of the controls (P<0.05). Furthermore, the CML-N group was more heterogeneous in terms of thrombopoiesis than the CML-E group, as demonstrated by a higher PDW (P<0.05) and higher ratio of multinucleated dysmegakaryocytes (12.17 vs. 4.69%; chi2=29.79; P=0.000). In addition, no correlation between platelet count and MPV, P-LCR or PDW was observed in the CML-N group (r=-0.102, -0.051 and -0.049, and P=0.619, 0.828 and 0.810, respectively). The results suggested that patients in the CML-N group have more heterogeneous thrombopoiesis of megakaryocytes and platelets, and that apparently normal platelet counts may mask the abnormal thrombopoiesis in these patients. PMID- 26622858 TI - Inverted (hobnail) high-grade prostatic intraepithelial neoplasia and invasive inverted pattern. AB - High-grade prostatic intraepithelial neoplasia (HGPIN) is considered to be an important precursor for prostatic adenocarcinoma. The present study aimed to investigate the histological features of the uncommon inverted (hobnail) pattern of HGPIN in transrectal ultrasonographic (TRUS) prostatic needle biopsies from 13 cases. These 13 diagnosed cases of inverted HGPIN were identified out of a total of 2,034 TRUS biopsies (0.63%), obtained from patients suspected to have prostate cancer. The hobnail pattern is comprised of secretory cell nuclei, which are histologically localized at the luminal surface of the prostate gland, rather than the periphery, and exhibit reverse polarity. Histological examinations were performed and the results demonstrated that 5 of the 13 cases exhibited pure inverted histology, while HGPIN was observed to be histologically associated with other patterns in the remaining 8 patients. In addition, an association with adenocarcinoma was identified in 7 of the 13 cases. All 7 carcinomas accompanied by inverted HGPIN were conventional acinar adenocarcinoma cases; of note, for these 7 cases, the Gleason score was 7 for each. One acinar adenocarcinoma case accompanying inverted HGPIN demonstrated hobnail characteristics in large areas of the invasive component. It was observed that nuclei were proliferated in the invasive cribriform glands, which was comparable to that of inverted HGPIN, and were located on the cytoplasmic luminal surface; a similar morphology was also observed in individual glands. In conclusion, the results of the present study suggested that the hobnail HGPIN pattern may be of diagnostic importance due to its high association with adenocarcinoma and the high Gleason scores in the accompanying carcinomas. PMID- 26622859 TI - Rare presentation of a right retroperitoneal accessory spleen: A case report. AB - An accessory spleen is a congenital malformation, which is defined as ectopic splenic parenchyma. Here, an extremely rare case of a right retroperitoneal accessory spleen, mimicking a retroperitoneal neoplasm, is reported. A 40-year old woman was referred following the incidental detection of a retroperitoneal neoplasm. Computed tomography and magnetic resonance imaging scans confirmed the presence of a retroperitoneal neoplasm at the hepatorenal recess. Retroperitoneoscopic excision was conducted, with excellent results. Pathological examination of the resected specimen revealed splenic tissue. In conjunction with a review of the literature and a discussion of the salient radiological features, the present case highlights the requirement for accurate preoperative diagnosis of an accessory spleen in the right retroperitoneal space, in order to avoid unnecessary surgical intervention. PMID- 26622860 TI - Analysis of soluble urokinase plasminogen activator receptor in multiple myeloma for predicting prognosis. AB - Multiple myeloma is a type of malignancy, which affects the plasma cells of the bone marrow. Recent studies have found that malignant plasma cells may express urokinase plasminogen activator (uPA) and uPA receptor (uPAR), and that initiation of proteolytic events by this system contributes to the process of invasion and destruction of the bone marrow. Studies have also suggested that the level of the soluble form of uPAR (suPAR) may act as a marker for prognosis in patients with multiple myeloma, and that there is an association between uPAR/suPAR expression, and clinical characteristics, efficacy of treatment in disease control and patient survival. In order to investigate this, the present study used flow cytometry to detect the monoclonal antibodies associated with multiple myeloma, specifically, uPAR (CD87), CD56 and CD38. Patients with multiple myeloma were divided into the following groups: The effective groups (remission and stable disease) and the ineffective group (progressive disease). suPAR expression in the effective groups was 257.6+/-32.47 pg/ml and 331.0+/ 99.80 pg/ml respectively, which was not significantly different from that of the normal control group (P>0.05). By contrast, the suPAR level in the invalid group was 562.2+/-291.0 pg/ml, which was significantly different from the levels in the normal control group (P<0.01) and the effective groups (P<0.05). suPAR levels were positively correlated with disease stage (P<0.01), renal function (P<0.05), C-reactive protein (P<0.005), beta2-microglobulin (P<0.001), extramedullary involvement (P<0.001), chromosome 13 deletion (P<0.01) and survival >2 years (P<0.01). They were was negatively correlated with hemoglobin concentration. No correlation was observed between uPAR expression and suPAR levels. The present study also indicated that the stage of disease and suPAR expression were independent factors, which predicted survival of <2 years. In conclusion, high suPAR expression appears to predict disease progression, a shortened survival period and early extramedullary infiltration. PMID- 26622861 TI - Overexpression of long non-coding RNA HOTAIR predicts a poor prognosis in patients with acute myeloid leukemia. AB - The long non-coding RNA, HOX transcript antisense intergenic RNA (HOTAIR), has been indicated to have involvement in a number of cancers, however, its role in acute myeloid leukemia (AML) is unknown. The present study aimed to investigate the pattern of HOTAIR expression in AML and to evaluate its clinical significance in tumor progression. Quantitative polymerase chain reaction was performed to examine the HOTAIR expression in mononuclear cells from the bone marrow (BM) or peripheral blood specimens of 85 patients with newly diagnosed AML. The association of HOTAIR expression with the clinicopathological factors and prognosis of AML patients was statistically analyzed. The expression of HOTAIR was significantly upregulated in the AML patients compared with the healthy controls (mean expression value, 3.87+/-0.29 vs. 1.28+/-0.09; P<0.001), and markedly decreased in the patients post-treatment compared with pre-treatment (4.76+/-0.47 vs. 2.81+/-0.27; P<0.001). Moreover, high levels of HOTAIR were associated with higher white blood cell and BM blast counts (P<0.001 and P=0.001, respectively), and lower hemoglobin and platelet counts (P=0.007 and 0.001, respectively). Patients with a high level of HOTAIR expression had relatively poor overall survival (OS; 20.5 vs. 32.1 months, P=0.001) and relapse-free survival (21.5 vs. 33.6 months, P=0.001) times compared with those with a low level of HOTAIR expression. These data demonstrated that HOTAIR expression was upregulated in newly diagnosed AML patients and was associated with leukemic burden, and DFS and OS times. HOTAIR may represent a biomarker of a poor prognosis and is a potential therapeutic target for AML treatment. PMID- 26622863 TI - Effects of siRNA Livin on EJ human bladder cancer cells treated with mitomycin-C. AB - The aim of this study was to observe the inhibitory and therapeutic effects of small interfering RNA (siRNA) targeting Livin in EJ human bladder cancer cells. Specific siRNA targeting Livin was synthesized and transfected into EJ human bladder cancer cells treated or not treated with mitomycin-C (MMC). Livin mRNA and protein, as well as proliferation and apoptosis of EJ cells was examined with reverse transcription-polymerase chain reaction, western blotting, Cell Counting Kit-8 assay and flow cytometry, respectively. The results indicated that the expression of Livin mRNA and protein in EJ cells was significantly decreased by siRNA Livin. The proliferation of EJ cells was significantly inhibited by treatment with MMC and transfection of siRNA Livin. The inhibition of cell proliferation by treatment with MMC was further enhanced by transfection of siRNA Livin. The apoptotic rate of cells transfected with siRNA Livin and treated with MMC was significantly higher than those cells receiving a single transfection of siRNA Livin and single treatment of MMC. In conclusion, the present study demonstrates that transfection of siRNA Livin induces growth suppression and apoptosis in EJ human bladder cancer cells, and increases the chemotherapeutic sensitivity of cells to MMC. PMID- 26622862 TI - Potentiation of the antitumor activity of adriamycin against osteosarcoma by cannabinoid WIN-55,212-2. AB - Osteosarcoma is the most frequent primary malignant bone tumor that occurs in children and adolescents. The present study aimed to identify novel therapeutic strategies for osteosarcoma, by assessing the antitumor activity of the cannabinoid WIN-55,212-2 and its combined effect with adriamycin (ADM) against the MG-63 human osteosarcoma cell line. To evaluate the antiproliferative action of these molecules, a Cell Counting kit-8 (CCK-8) assay was used. The ability of cannabinoid to inhibit the migration, invasion and angiogenic activity of MG-63 cells were assessed by scratch, Transwell(r) chamber and angiogenesis assays, respectively, in vitro. To examine the alterations in expression of targeted genes, quantitative polymerase chain reaction and western blot analysis were used. The administration of cannabinoid combined with ADM was demonstrated to inhibit the growth of MG-63 cells, resulting in a cell viability of 32.12+/ 3.13%, which was significantly lower (P<0.05) compared with the cell viability following treatment with cannabinoid (70.86+/-7.55%) and ADM (62.87+/-5.98%) alone. Greater antimetastasis and antiangiogenic activities were also observed following the coadministration of the two agents compared with individual treatments and controls. In addition, the expression levels of Notch-1, matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) in MG 63 cells were downregulated following the treatments with cannabinoid alone or in combination with ADM. In conclusion, the present findings demonstrated that cannabinoid WIN-55,212-2 may significantly potentiate the antiproliferative, antimetastasis and antiangiogenic effects of ADM against MG-63 cells via the downregulation of Notch-1, MMP-2 and VEGF. These findings may offer a novel strategy for the treatment of osteosarcoma. PMID- 26622864 TI - Screening of potential biomarkers for chemoresistant ovarian carcinoma with miRNA expression profiling data by bioinformatics approach. AB - The aim of the present study was to screen out the biomarkers associated with chemoresistance in ovarian carcinomas and to investigate the molecular mechanisms. microRNA (miRNA) expression data was obtained from published microarray data of the GSE43867 dataset from Gene Expression Omnibus (GEO), including the data of 86 chemotherapy-treated patients with serous epithelial ovarian carcinomas (response group, 36 complete response cases and 12 partial response cases; non-response group, 10 stable cases and 28 progressive disease cases), and identification of differentially-expressed miRNAs were conducted with a GEO2R online tool based on R language. TargetScan 6.2 was used to predict the targets of differentially-expressed miRNAs. Protein-protein interaction network analysis was conducted by STRING 9.1, while functional enrichment [Gene Ontology (GO) biological process terms] and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted by GeneCodis3 for the target genes. A total of 6 differentially-expressed miRNAs were screened out, with 317 target genes obtained. It was found that 67 interactions existed among 76 genes/proteins through the PPI network analysis, and that 6 of these were potential key genes (PIK3R5, MAPK3, PTEN, S1PR3, BDKRB2 and NCBP2). The main biological processes involved in chemoresistant ovarian carcinoma were apoptosis, programmed cell death, cell migration, cell death and cell motility. The miRNA target genes were found to be associated with the ErbB signaling pathway, the gonadotropin releasing hormone signaling pathway and other pathways in cancer. IK3R5, MAPK3 and PIK3R5 are involved in the majority of GO terms and KEGG pathways associated with chemoresistance in ovarian carcinoma. PMID- 26622865 TI - Efficacy of quercetin against chemically induced murine oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer, and oxidative damage is associated with the development of OSCCs. Antioxidants have therefore been proposed for use as chemoprotective agents against different types of cancer. In the present study, the effect of the antioxidant quercetin, administered at doses of 10 and 100 mg/kg/day, was investigated in an experimental murine model of 4-nitroquinoline 1-oxide (4-NQO) induced carcinogenesis. The survival of the treated animals, the plasmatic levels of reduced glutathione and the type and severity of lesions (according the International Histological Classification of Tumors and Bryne's Multifactorial Grading System for the Invasive Tumor Front) were assessed. Additionally, the organization of the extracellular matrix was analyzed by carbohydrate and collagen histochemistry, and immunohistochemistry was used to assess the expression of the tumor markers proliferating cell nuclear antigen and mutated p53. The results indicate that, despite the promising effect of quercetin in other studies, this drug is ineffective as a chemoprotective agent against 4-NQO induced OSCC in mice at the assayed doses. PMID- 26622866 TI - Invasive urothelial carcinoma within a calyceal diverticulum associated with renal stones: A case report. AB - Calyceal diverticula are rare outpouchings of the upper collecting system lying within the renal parenchyma. These often contain stones, however, carcinoma within a calyceal diverticulum is uncommon. The present study reports a case of invasive urothelial carcinoma within a calyceal diverticulum associated with renal stones. A 70-year-old male with a left renal mass identified by abdominal computed tomography was referred to the Department of Urology, Kanazawa University Hospital. Pre-operative diagnosis was difficult owing to an atypical imaging finding of a hypovascular renal mass with calcification. A laparoscopic nephroureterectomy was performed, and the surgical specimens showed invasive high grade urothelial carcinoma within a calyceal diverticulum, and the calcifications were renal stones consisting of 97% calcium oxalate. Urothelial carcinoma in calyceal diverticula is a rare condition, however, a pre-operative definite diagnosis is difficult and a high potential for invasion of the renal parenchyma is suspected in this disease. PMID- 26622867 TI - Distribution and characterization of tumor-associated macrophages/microglia in rat C6 glioma. AB - Immunity responses and immunotherapy are novel areas of research for the pathological development and treatment of glioma, the most common brain cancer. Characterization of the subpopulations of infiltrated immune cells may aid in our understanding of the tumor immune response and contribute to the identification of cellular targets for selective immunotherapy. Using a rat C6 glioma model, the present study observed a significant heterogeneity of active macrophages and microglia, including cluster of differentiation 8 (CD8)+, endothelial monocyte activating polypeptide II (EMAPII)+ and ED1+ cells, mostly in the areas of compact tumor growth and inside or around the pannecrosis. Moreover, the CD8+ cells were similar to reactive ED1+ and EMAPII+ microglia/macrophages in morphology and distribution, but different from the W3/13+ T cells. These observations suggest that different subtypes of macrophages and microglia are involved in glioma development and thus, may be potential targets for immunotherapeutic antitumor strategies. PMID- 26622868 TI - Granulocytic sarcoma of the breast: A case report. AB - Granulocytic sarcoma (GS) is an unusual type of tumor composed of immature cells outside the bone marrow. The disease exhibits a correlation with acute myeloid leukemia and other myeloproliferative disorders. Although it can invade a number of areas of the body, the involvement of the breast is uncommon. The present study reports the case of a 58-year-old female with a mildly tender lump in the left breast that had been apparent for one year. Available diagnostic techniques, including ultrasound, magnetic resonance imaging and mammography, were systematically used to determine a diagnosis of GS, and lumpectomy and systemic chemotherapy were performed. The patient was satisfied with the result of no local recurrence at the one year follow-up examination. The present study discusses the clinical and pathological characteristics of the present case of GC. PMID- 26622869 TI - Total nephrectomy with nephron-sparing surgery for a giant bilateral renal angiomyolipoma: A case report. AB - The current report presents the case of a 50-year-old female who presented with a giant bilateral renal angiomyolipoma (AML). After assessing the patient's symptoms, the tumor size and renal function, the patient underwent a total nephrectomy for the right AML, which measured 28*20*14 cm and nephron-sparing surgery was performed without preoperative selective angiographic embolization for a further 3 AMLs in the left kidney, the largest of which had a diameter of 12 cm. The introperative bleeding volume was at an acceptable level and the renal function was stable. No local recurrence was observed and no dialysis was required during follow-up. The strategy of the treatment in this report should be considered when treating similar tumors. PMID- 26622870 TI - Low-grade cribriform cystadenocarcinoma of the palatal gland: A case report. AB - Low-grade cribriform cystadenocarcinoma (LGCCC) is a malignant salivary gland tumor. LGCCC occurs rarely, with the parotid gland being the most commonly afflicted site. Few cases arise in other sites. The present study reports a case of LGCCC that occurred at the palatal gland of the hard palate. A 56-year-old female was referred to Saitama Medical University Hospital (Moroyama, Saitama, Japan) due to an intraoral mass. Since cytological examination and biopsy led to a diagnosis favoring a neoplasm, but with uncertain malignant potential, the tumor was resected with a safe surgical margin. The specimen was thoroughly examined. Microscopically, there was a well-demarcated, unilocular cyst with the lumen lined by tumor cells. The tumor cells were arranged in tubular, cribriform and solid structures in the area of the intracystic mass lesions. Nuclear atypia was inconspicuous, although mitotic figures were observed throughout the tumor. Neither local nor perineural invasion was present. On immunohistochemistry, the tumor cells were diffusely positive for S-100 protein. Myoepithelial markers, calponin and p63, highlighted the cells rimming the cystic mass. The final histopathological diagnosis was of LGCCC. The tumor was completely resected. At 1 year post-resection, the patient exhibited no recurrence or distant metastasis. LGCCC is regarded as clinically indolent. However, there is little literature available to aid with prognosis prediction due to the rarity of LGCCC cases. Thus, greater experience and longer follow-up periods are necessary to find the optimal/curative treatment for patients with LGCCC and to clarify the pathophysiology. PMID- 26622871 TI - CXCL1 expression is correlated with Snail expression and affects the prognosis of patients with gastric cancer. AB - Gastric cancer (GC) continues to result in a poor survival rate and prognostic biomarkers for the disease are lacking. Chemokine (C-X-C motif) ligand (CXCL1) expression plays a critical role in tumor metastasis, and Snail promotes epithelial-mesenchymal transition (EMT) to promote metastasis. Therefore, the present study aimed to investigate the correlation between CXCL1 and Snail expression and the effect of CXCL1 expression on the survival of patients with GC. CXCL1 and Snail expression in paraffin-embedded tissue sections from 127 patients with GC were each assessed by immunohistochemistry. Cox regression and Kaplan-Meier analyses were performed to evaluate the prognostic significance of CXCL1 and Snail. Evaluation of the association between CXCL1 and Snail expression and clinical characteristics was based on the chi2 test. Spearman's rank correlation coefficient and Fisher's exact test were used to explore the association between CXCL1 and Snail expression in GC tissues. CXCL1 was found to be significantly associated with tumor invasion (P=0.003), tumor-node-metastasis (TNM) staging (P=0.001), tumor size (P=0.013) and lymph node metastasis (P=0.022) in GC. Snail overexpression was also significantly associated with tumor invasion (P=0.001), TNM staging (P=0.005), tumor size (P=0.026), lymph node metastases (P=0.014) and perineural invasion (P=0.009). CXCL1 and Snail expression were independent factors for a worse overall survival rate, as determined by multivariate analysis (P=0.011 and P=0.018; respectively). The combined expression of CXCL1 and Snail resulted in a worse prognosis compared with the other three groups (P=0.005). Furthermore, there was a significantly positive correlation between CXCL1 and Snail expression in GC (r=0.431; P<0.001). The expression of CXCL1 is significantly associated with Snail expression and may be used as a predictive co-biomarker for patient prognosis and tumor aggressiveness in GC. CXCL1 may promote GC metastasis by regulating EMT. PMID- 26622872 TI - Desmoplastic fibroma in the proximal femur: A case report with long-term follow up. AB - Desmoplastic fibroma of the bone is an extremely rare primary benign tumor. The present study reports a case of desmoplastic fibroma of the bone with the longest published follow-up. A 21-year-old female presented to The First Hospital of Jilin University (Changchun, Jilin, China) with thigh pain. Radiography demonstrated a lytic expansile lesion in the proximal femur. Curettage was performed, followed by use of an allogeneic graft. One month later, the patient suffered a pathological fracture and was treated with an open reduction and internal fixation. There was no recurrence of the tumor over a 28-year follow-up period. In conclusion, desmoplastic fibroma in the proximal femur is rare and an intralesional resection is strongly recommended to prevent recurrence. The disease may be misdiagnosed as a bone cyst, so the diagnosis should be confirmed with a histological examination. PMID- 26622873 TI - Desmoplastic trichoepithelioma: A clinicopathological study of three cases and a review of the literature. AB - Desmoplastic trichoepithelioma (DTE) is a rare benign adnexal tumor with the characteristic features of asymptomatic, solitary, annular, indurated and centrally depressed papules or plaques, most commonly occurring in younger individuals on the face. Microscopically and clinically, DTE may be difficult to distinguish from other cutaneous adnexal neoplasms, particularly syringoma, cutaneous metastatic breast cancer, morpheaform basal cell carcinoma and microcystic adnexal carcinoma. The present study reports three cases of DTE. The first case was of a 45-year-old male with an asymptomatic flesh-colored plaque below the right edge of the outer canthus that had been present for seven years. The second case was of a 23-year-old female with an asymptomatic skin lesion on the right cheek that had slowly and progressively increased in size. The third case was of a 26-year-old female who presented with a hard yellowish-white plaque, which gradually grew and formed a rectangular, 3*4-cm patch, on the tip of the left brow. This plaque was present for three years without evident cause or subjective symptoms. In all three cases, the routine systemic examinations and laboratory findings were normal. Histopathological and immunohistochemical findings from incisional biopsies of the lesions were consistent with a diagnosis of DTE. DTE treatment methods and immunohistochemical markers were analyzed by reviewing clinical pathological aspects in order to avoid a misdiagnosis and to provide the best available treatment approach for DTE. PMID- 26622874 TI - Gastric diverticulum simulating a left adrenal mass: A case report and review of the literature. AB - Gastric diverticulum (GD) is a pouch protruding from the gastric wall. It is rare and in the majority of cases, asymptomatic. Usually GDs are detected incidentally by gastrointestinal study. The current study reports one case and a literature review of GD mimicking an adrenal mass. A 49-year-old male presented with a low density lesion in the left adrenal area, but no symptoms of an adrenal adenoma. The lesion was identified as a gastric diverticulum in the fundus of the stomach following enhancement of computed tomography (CT) imaging using an oral contrast agent. Although the majority of previously reported cases utilized upper gastrointestinal barium studies to confirm the presence of GD, the current study demonstrated that CT scanning enhanced with oral contrast material may aid in the differentiation of adrenal masses from other gastrointestinal abnormalities. PMID- 26622875 TI - Impact of the availability of active cytotoxic agents on the survival of patients with advanced gastric cancer. AB - Several cytotoxic agents, including fluoropyrimidines, platinums, taxanes and irinotecan, are effective in the treatment of advanced gastric cancer (AGC). However, the effect of the availability of cytotoxic agents on survival has not yet been evaluated. Therefore, the present study assessed the impact of the availability of active cytotoxic agents on the survival of patients with AGC. The records of 216 patients with newly diagnosed AGC that were treated with palliative chemotherapy between March 2002 and November 2012 at Chungbuk National University Hospital were reviewed. For the present study, the patients were divided according to the availability of active cytotoxic agents over the course of treatment: Group 1 received fluoropyrimidine and platinum; group 2 received fluoropyrimidine, platinum and taxane or irinotecan; and group 3 received fluoropyrimidine, platinum, taxane and irinotecan. The median overall survival times for groups 1, 2 and 3 were 6.3, 9.9 and 14.3 months, respectively (P<0.0001). Multivariate analysis revealed that the Eastern Cooperative Oncology Group (ECOG) performance status and the availability of active cytotoxic agents were independent prognostic factors, as the hazard ratios for mortality were 3.25 for patients with an ECOG performance status of 2-3 [95% confidence interval (CI), 1.99-5.30; P<0.0001], 0.58 for patients in group 2 (95% CI, 0.42-0.80; P=0.0009), and 0.40 for patients in group 3 (95% CI, 0.28-0.58; P<0.0001). The present study reveals that the availability of active cytotoxic agents is associated with an improved survival time in patients with AGC. PMID- 26622876 TI - Upregulation of Beclin-1 expression in DU-145 cells following low-frequency ultrasound irradiation combined with microbubbles. AB - Castration-resistant prostate cancer (PCa) is difficult to treat. Autophagy, which is an evolutionarily conserved mechanism, plays an important role in cancer development. The balance between cell death and survival in different stages varies in cancer development. The role of autophagy in PCa development has not yet been fully elucidated. Ultrasound may be of value in the treatment of PCa. The aim of the present study was to investigate the association between autophagy and ultrasound combined with microbubbles. The MTT assay was used to evaluate cell viability. Autophagy was observed by transmission electron microscopy. Reverse transcription-polymerase chain reaction and western blot analysis were used to assess the expression of autophagy-related genes. The results revealed that cell viability was significantly reduced by ultrasound combined with microbubbles in DU145 PCa cells. The present study demonstrated that ultrasound combined with microbubbles induced autophagy and autophagy-related DU-145 cell death. Notably, these findings highlighted additional mechanisms that suggest the potential of ultrasound-modulated autophagy as a novel therapeutic strategy for PCa. PMID- 26622877 TI - Radiological and clinical results following high-dose intensity-modulated radiotherapy in recurrent craniopharyngioma: A case report. AB - Craniopharyngiomas (CPs) are rare benign suprasellar tumors. The standard treatment for CP is complete surgical resection or partial resection followed by adjuvant radiotherapy (RT). Adjuvant RT is typically administered at a total dose of 54 Gy with 1.8 Gy/fraction. The current study reported the case of a young patient affected by recurrent craniopharyngioma, who was treated with irradiation subsequent to several surgical resections. Image fusion and intensity-modulated radiation therapy techniques were employed to deliver a high total dose (63 Gy with 2.1 Gy/fraction) with no severe acute toxicities recorded. At the 6-year follow-up, no radiological or clinical signs of disease progression or late sequelae were observed. PMID- 26622878 TI - Male accessory breast cancer successfully treated with endocrine therapy: A case report. AB - Male accessory breast cancer is an extremely rare tumor. Several risk factors have been identified, including genetic and hormonal abnormalities. Accessory breast carcinoma usually occurs under the axilla or in the inguinal region. Clinical diagnosis is frequently delayed due to the general lack of awareness among physicians and patients. In the present study, the case of a 63-year-old male patient who was diagnosed with accessory breast cancer at a local advanced stage was reported. However, the patient was successfully treated with endocrine therapy. PMID- 26622879 TI - FOXQ1 is overexpressed in laryngeal carcinoma and affects cell growth, cell cycle progression and cell invasion. AB - Forkhead box Q1 (FOXQ1) is a forkhead transcription factor that is involved in numerous biological processes and has been shown to participate in tumorigenesis. However, the clinical significance of the expression of this protein in laryngeal carcinoma, and the mechanisms underlying its regulation in this disease remain unclear. The aim of present study was to measure the expression of FOXQ1 in laryngeal carcinoma, and to examine its effect on tumorigenesis. In the present study, reverse transcription-quantitative polymerase chain reaction and western blotting were employed to measure FOXQ1 expression in laryngeal carcinoma tissue samples, small interfering RNA specific to FOXQ1, was transfected into Hep2 cells and its effect on cell proliferation, cell cycle progression and cell migration was examined, using a CCK-8 assay, flow cytometry and a transwell migration assay, respectively. The results showed overexpression of FOXQ1 mRNA and protein in laryngeal cancer tissue samples. Inhibition of FOXQ1 suppressed cell growth and invasion, and arrested cells in the G0/G1 phase. Overexpression of FOXQ1 is associated with the development of laryngeal carcinoma and may enhance tumorigenesis through its effects on cell proliferation, cell cycle progression and cell migration. PMID- 26622880 TI - Application of eupatilin in the treatment of osteosarcoma. AB - 5,7-dihydroxy-3',4',6-trimethoxyflavone, commonly known as eupatilin, is a traditional Asian medicinal plant, which is mainly used for the treatment of gastritis, as well as its use as an anti-inflammatory agent. Eupatilin is a bioactive compound; however, its effects on osteosarcoma (OS) have remained to be elucidated. Therefore, the present study aimed to investigate the effects of eupatilin on this malignant bone tumor, using the U-2 OS cell line. The experimental results revealed that eupatilin inhibited U-2 OS cell growth in a concentration-dependent manner and induced G2/M phase cell cycle arrest and apoptosis. Additionally, western blot analysis indicated that eupatilin was able to trigger the mitochondrial apoptotic pathway, demonstrated by the enhanced Bax/B cell lymphoma-2 ratio, decrease in mitochondrial membrane potential, release of cytochrome c, caspase-3 and -9 activation and poly(ADP ribose)polymerase cleavage detected in the U-2 OS cells. These results indicated that eupatilin was able to inhibit U-2 OS cancer cell proliferation by the induction of apoptosis via the mitochondrial intrinsic pathway. Eupatilin may therefore represent a novel anticancer drug for use in the treatment of osteosarcoma. PMID- 26622881 TI - Effect of temozolomide on the viability of musculoskeletal sarcoma cells. AB - Musculoskeletal sarcomas (MSS) are a heterogeneous group of malignancies with relatively high mortality rates. The prognosis for patients with MSS is poor, with few drugs inducing measurable activity. Alkylating agents, namely ifosfamide and dacarbazine, which act nonspecifically on proliferating cells, are the typical therapy prescribed for advanced MSS. A novel alkylating agent, temozolomide (TMZ), has several advantages over existing alkylating agents. TMZ induces the formation of O6-methylguanine in DNA, thereby inducing mismatches during DNA replication and the subsequent activation of apoptotic pathways. However, due to conflicting data in the literature, the mechanism of TMZ action has remained elusive. Therefore, the present study aimed to evaluate apoptosis in MSS cells treated with TMZ, and to evaluate the correlation between TMZ action and survival pathways, including the phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK)1/2 mitogen activated protein kinase (MAPK) pathways. Cell proliferation was evaluated by performing an XTT (sodium 3' [1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis (4-methoxy-6-nitro) benzene sulfonic acid hydrate) assay. Apoptotic morphological changes, for example chromatin condensation, were evaluated by fluorescence confocal microscopy. The expression of the apoptosis-associated proteins caspase-3, poly adenosine diphosphate ribose polymerase (PARP), Akt and ERK1/2, was determined by western blotting. The results of the present study indicated that, in certain MSS cells, the IC50 value was lower than that in TMZ-sensitive U-87 MG cells. Furthermore, TMZ treatment was associated with apoptotic morphological changes and the expression levels of pro-apoptotic cleaved caspase-3 and PARP were also increased in TMZ-treated MSS cells. In addition, the results indicated that PI3K/Akt and ERK1/2 MAPK were constitutively phosphorylated in MSS cells, and phosphorylation of PI3K/Akt was suppressed in certain cells, and maintained in other cells, by TMZ. These observations emphasized the plasticity of MSS cells, and suggested that this plasticity may contribute to the variance in cell sensitivity to TMZ and TMZ-resistance in MSS. PMID- 26622882 TI - Prevalence of KRAS, BRAF, PI3K and EGFR mutations among Asian patients with metastatic colorectal cancer. AB - Mutations in oncogenes along the epidermal growth factor receptor (EGFR) signaling pathway have been implicated in the resistance to cetuximab in patients with metastatic colorectal cancer (mCRC). However, the relative significance of these mutations based on their frequencies of occurrence in the Singaporean population remains unclear. In the present study, the prevalence of Kirsten rat sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B (BRAF), phosphoinositide 3-kinase (PI3K) and EGFR somatic mutations were determined among Singaporean patients with mCRC. DNA extracted from 45 pairs of surgically resected tumor and normal mucosa samples was subjected to direct sequencing or restriction fragment length polymorphism. Associations of the genetic mutations with various clinicopathological parameters were further explored. Mutations in either codon 12 or 13 of KRAS were confirmed as prominent phenomena among the included Singaporean mCRC patients, at a prevalence comparable with that of Caucasian and patients of other Asian ethnicities [33.3% (90% confidence interval, 21.8-44.9%)]. KRAS mutation was not associated with clinicopathological features, including age, gender and ethnicity of patients, or the tumor site, differentiation and mucinous status. Conversely, the prevalence of BRAF (0%), PI3K (2.2%) and EGFR (0%) mutations were low. The results of the present study indicate that KRAS mutations are prevalent among the studied population, and confirm the low prevalence of BRAF, PI3K and EGFR mutations. KRAS should be prioritized as an investigational gene for future studies of predictive biomarkers of cetuximab response among Singaporean patients with mCRC. PMID- 26622883 TI - Evaluation of MMP-2, MMP-9, TIMP-1, TIMP-2, NGAL and MMP-9/NGAL complex in urine and sera from patients with bladder cancer. AB - The identification of biomarkers in urine or serum samples from patients with bladder cancer is urgently required for the development of non-invasive methods for the diagnosis of bladder carcinoma and to facilitate follow-up surveillance, to combat the high progression and recurrence rates of this type of cancer. The current study measured the content of matrix metalloproteinase (MMP)-2 and -9, as well as tissue inhibitor of metalloproteinase (TIMP)-1 and -2 in the urine and sera of 41 patients with bladder cancer by ELISA. The association between levels of MMP-2 and -9 and TIMP-1 and -2, and tumor grade and stage were investigated to verify whether these molecules are involved in tumor differentiation. Statistical analysis of the data revealed that urinary TIMP-1 levels were significantly higher in the high grade group compared with those of the low grade samples (P=0.022). The results also revealed a significantly differing distribution of TIMP-1 expression between Ta and T1 stage specimens (P=0.040). The corresponding area under the curves (AUCs) were 0.72, with a sensitivity of 0.70 and specificity of 0.75. In addition, neutrophil gelatinase-associated lipocalin (NGAL) and MMP-9/NGAL complex levels in the sera were measured. All molecules evaluated were detected in the sera of the patients studied. In particular, tumors staged as non-muscle invasive (Ta and T1), demonstrated significantly higher NGAL levels compared with those of muscle invasive (>T1) bladder cancer (32.8 ng/ml vs. 16.2 ng/ml; P=0.029). The discriminatory ability of NGAL expression was confirmed by receiver operating characteristic curve analysis that revealed an AUC of 0.75, a sensitivity of 0.88 and a specificity of 0.67. These data indicated that urinary TIMP-1 and serum NGAL may be useful non-invasive biomarkers to provide clinical information for bladder cancer disease management. Multicenter, prospective studies are required to confirm these preliminary results. PMID- 26622884 TI - Primary neuroendocrine tumors of the ear, nose and throat: A report of three cases and a review of the literature. AB - The aim of the present study was to review all cases of neuroendocrine tumors of the ear, nose and throat in a tertiary care center, as well as the data published in the literature. The study presents all the cases of neuroendocrine tumors (NETs) in the Hotel Dieu De France Hospital (Beirut, Lebanon) between January 2004 and January 2014. The data reported in the English and French literature is also reviewed with regard to the typical clinical presentation and management of these tumors. Three cases of NETs presented to the Department of Otolaryngology Head and Neck Surgery during the study period. One case was of an atypical carcinoid (AC) tumor of the larynx, one case was of a typical carcinoid tumor in the middle ear and the third case was, to the best of our knowledge, the first reported case of an AC tumor of the nasopharynx. Overall, NETs are rare in the head and neck. The clinical presentation can mimic any other tumor in the same localization in the absence of a carcinoid syndrome. Management of these tumors remains controversial, but a complete excision of the tumor is crucial, followed by possible adjuvant treatment. PMID- 26622885 TI - Percutaneous biliary stenting combined with radiotherapy as a treatment for unresectable hilar cholangiocarcinoma. AB - Hilar cholangiocarcinoma is often unresectable at the time of the initial diagnosis, and the provision of a definite palliative benefit is important in patients with unresectable hilar cholangiocarcinoma. The aim of the present study was to evaluate the safety of percutaneous biliary stenting and to analyze whether percutaneous biliary stenting combined with radiotherapy (RT) prolonged the stent patency and survival time of patients. In total, the cases of 38 patients with unresectable hilar cholangiocarcinoma that underwent percutaneous biliary stenting at the Navy General Hospital were retrospectively reviewed in the present study. Uncovered metallic stenting (UMS) combined with RT was administered to 25 patients, and UMS alone was administered to 13 patients. The records of early complications subsequent to percutaneous biliary stenting were collected, and the stent patency and survival times of patients were analyzed and compared between the two groups. The technical success rate of the procedure was 100% and the successful drainage rate was 86.8%. The overall early complication rate was 15.8% and the procedure-associated mortality rate was 2.6%. The median stent patency was 326 days in the UMS+RT group and 196 days in the UMS group (P=0.022). The UMS+RT group (median, 367 days) demonstrated a longer survival time compared with the UMS group (median, 267 days; P=0.025). Percutaneous biliary stenting offers a safe and effective method for the palliative treatment of patients with unresectable hilar cholangiocarcinoma, and percutaneous biliary stenting combined with RT may prolong stent patency and patient survival time. PMID- 26622886 TI - Metastasis of myxoid liposarcoma to fat-bearing areas: A case report of unusual metastatic sites and a hypothesis. AB - Sarcoma is a rare disease that always metastasizes to the lungs and bones. Myxoid liposarcoma (MLPS), in comparison with other sarcomas, has a distinct biological characteristic. Recent studies have suggested that MLPS expresses high levels of adipophilin and chemokine (C-X-C motif) receptor 4 (CXCR4), which are correlated with adipogenesis and metastasis. In addition, the Ewing sarcoma breakpoint region 1-DNA damage-inducible transcript 3 (EWSR1-DDIT3) fusion transcript, recently identified in MLPS, was shown to selectively repress the osteoblastic transcription in multipotent mesenchymal cells. The present study reported a rare case of MLPS with metastasis in fat-bearing areas, including the bones, epidural region, orbits and abdominal cavity, while the lungs were not involved. Bone metastasis was diagnosed by magnetic resonance imaging and proven by histology. However, bone scanning lacked sufficient sensitivity to detect the bone metastasis. Based on these findings, we hypothesized that molecular adipophilin and molecular CXCR4 may contribute to the fat-bearing area metastasis pattern. Furthermore, the EWSR1-DDIT3 fusion transcript may repress the osteoblastic activity in the bone metastases, ultimately resulting in a low detection rate by bone scans. PMID- 26622888 TI - Detecting abnormal methylation of tumor suppressor genes GSTP1, P16, RIZ1, and RASSF1A in hepatocellular carcinoma and its clinical significance. AB - Hepatocellular carcinoma (HCC) has a high rate of mortality. Further studies into epigenetic changes in HCC, particularly the abnormal methylation of tumor suppressor genes (TSGs), are required, since these changes may provide novel biomarkers for early screening and diagnosis of HCC. By using methylation specific polymerase chain reaction (MSP), the present study detected the methylation status in the promoter region of 4 candidate TSGs, GSTP1, P16, RIZ1, and RASSF1A, respectively, in 35 paired HCC and tumor-adjacent liver tissues in addition to 20 normal liver tissues. Their effect on the initiation and progression of HCC was also investigated by analyzing the clinicopathological data. The results of the present study revealed that the methylation level of RIZ1 and GSTP1 genes in HCC was significantly increased compared with that in the adjacent tissues (P<0.01) and the normal liver tissues (P<0.01). The methylation frequency of P16 and RASSF1A genes was not significantly increased compared with that observed in the adjacent tissues (P>0.05) but was significantly increased compared with the normal tissues (P<0.01). In HCC tissues, the methylation frequency of the GSTP1 gene in tumors with capsular invasion was significantly increased compared with that in tumors without capsular invasion (P<0.05). The methylation frequency of P16 gene in hepatitis B surface antigen (HbsAg)-positive HCC patients was significantly increased compared with that in HbsAg-negative patients (P<0.05). The methylation status of RIZ1 and RASSF1A genes was not significantly correlated with the clinicopathological data (P>0.05). Previous studies have demonstrated that the methylation status of RIZ1 and GSTP1 genes is HCC-specific, and thus may be used as a biomarker to assist the clinical diagnosis of HCC. While the methylation of GSTP1 gene promoter may associate with the invasiveness of HCC, chronic hepatitis B virus infection may be the cause of methylation-induced P16 inactivation. PMID- 26622887 TI - Occupational type affects the receipt of breast cancer adjuvant chemotherapy in China. AB - Adjuvant chemotherapy has been demonstrated to improve the prognosis of patients with early-stage breast cancer; however, the high cost and side effects associated with this treatment may discourage patients from receiving it. The present study assessed the candidate factors that may influence decisions regarding postoperative adjuvant chemotherapy in females with early-stage breast cancer. Patients diagnosed with invasive breast cancer between January 2000 and December 2007 were enrolled in the study. Information about the patients, including socio-demographic factors, clinicopathological characteristics and receipt of adjuvant chemotherapy, was obtained from their medical records. Overall, 434 out of 1,296 (33.5%) patients with breast cancer decided against receiving adjuvant chemotherapy. Receipt of chemotherapy was significantly associated with the age of the patient at the time of diagnosis (P=0.029), occupational type (P=0.023), and lymph node status (P<0.001). Moderate associations were also observed between receipt of adjuvant chemotherapy and the patients family history of cancer (P=0.055) and hormone-receptor status (P=0.075). The results of the present study suggest that the occupational type of the patient is associated with receipt of adjuvant chemotherapy in China. This observation may provide a novel strategy for physicians to improve patients compliance regarding adjuvant chemotherapy. Further studies in additional developing countries are required in order to validate these observations. PMID- 26622889 TI - Prediction of central lymph node metastasis in 392 patients with cervical lymph node-negative papillary thyroid carcinoma in Eastern China. AB - Central lymph node metastasis (CLNM) is common in papillary thyroid microcarcinoma (PTMC). The aim of the present study was to investigate the risk factors associated with CLNM in clinical lateral cervical lymph node-negative (cN0) PTMC in Eastern China. A total of 392 patients with confirmed PTMC by histological examination who underwent thyroidectomy and central neck lymph node dissection (CND) between May 2011 and October 2012 at the First Affiliated Hospital of Wenzhou Medical University (Wenzhou, China) were enrolled. The clinicopathological and ultrasonographic data from the patients were analyzed retrospectively. A scoring system was developed on the basis of independent predictive factors for CLNM. Male gender, age <45 years, maximum tumor diameter >5 mm, lower lobe location, multifocal carcinoma with total tumor diameter >10 mm and extracapsular spread were independent predictive factors for CLNM according to logistic regression analysis. The clinicopathological score was statistically significant, with an index point >=2 indicating CLNM with 86.2% sensitivity and 70.4% specificity. The findings of the present study indicate that CND may be recommended to be routinely performed when the clinicopathological index point >=2. PMID- 26622890 TI - Diagnostic utility of diffusion-weighted magnetic resonance imaging in two common renal tumors. AB - The aim of the present study was to evaluate the utility of diffusion-weighted magnetic resonance imaging (DWI) in the diagnosis of common renal tumors. Conventional magnetic resonance imaging and DWI were performed on 85 patients with renal lesions (54 renal carcinoma and 31 renal angiomyolipoma cases). The apparent diffusion coefficient (ADC) values in each case at b=800 sec/mm2 were measured in the ADC maps using a statistical software package. The 54 cases of renal cell carcinoma showed a high signal intensity in the parenchyma, and the 31 renal angiomyolipoma cases showed a well-defined mixed signal intensity on DWI. The soft-tissue component showed a high signal intensity and the fat tissue showed a low signal intensity on DWI. When the b-value was set to 800 sec/mm2, the mean ADC was significantly lower in the renal carcinoma cases than in the renal angiomyolipoma cases. In conclusion, the measurement of ADC on DWI can reveal the structure of renal tumors, which is beneficial in diagnosing and determining the prognosis of benign and malignant renal tumors. PMID- 26622891 TI - Loss of heterozygosis on chromosome 18q21-23 and muscle-invasive bladder cancer natural history. AB - Loss of heterozygosis (LOH) on chromosome (Chr) 18q21-23 was reported to be one of the most common genetic alterations identified in bladder cancer. The current study aimed to determine the prognostic role of LOH on Chr 18q21-23 in patients diagnosed with muscle-invasive urothelial bladder carcinoma (MIBC). A total of 34 consecutive patients were enrolled in the present prospective study. LOH on Chr 18 was assessed by performing multiplex polymerase chain reaction on paired blood and tumour tissue samples from each patient. The following primers were used in the present study: D18S51, MBP LW and MBP H. These data were then compared with follow-up information. The main outcome measure was patient status at the end of the follow-up. Cox regression was used to evaluate the impact of each parameter on cancer-specific survival and the Kaplan Meier test for disease-free survival was plotted in order to estimate survival. Out of 34 patients, 18 (52.9%) exhibited >=1 alteration in one of the loci analysed on chromosome 18, while 16 (47.1%) revealed no alterations. No correlation was identified with stage (P=0.18) or grade (P=0.06); however, LOH on Chr 18q21-23 was significantly associated with a lower recurrence-free probability (P<0.0001). Kaplan-Meier curves demonstrated a significant association between patient status at follow-up and LOH on Chr 18 (P<0.001). In addition, multivariate analysis identified LOH on Chr 18 (P<0.001) and stage (P=0.01) as independent survival predictors. Furthermore, artificial neural network analysis was consistent with the results of the multivariate analysis. In conclusion, the present study highlighted the role of LOH on Chr 18q21-23 in predicting the clinical outcome of patients with MIBC. PMID- 26622893 TI - Optimal cytoreductive surgery for underlying ovarian cancer associated with deep venous thrombosis without placement of inferior vena cava filter: A case report and literature review. AB - Ovarian cancer associated with deep venous thrombosis (DVT) is an uncommon, potentially life-threatening condition. The primary therapeutic strategy for the treatment of this condition is up-front primary cytoreductive surgery, with placement of an inferior vena cava (IVC) filter prior to surgery to prevent fatal pulmonary embolism. The present study describes the case of a 49-year-old female, who presented with DVT unresponsive to anticoagulant therapy in the lower extremities prior to the diagnosis of ovarian cancer. During the search for the underlying malignancy, transvaginal sonography (TVS) revealed a cystic solid mass in the pelvic cavity. Subsequently, the patient underwent up-front primary cytoreductive surgery without placement of a preoperative IVC filter, followed by six cycles of chemotherapy. The patient was diagnosed with ovarian clear cell adenocarcinoma stage IIIC, complicated by DVT, and had survived >3 years without relapse at the time of completion of the present study. The successful outcome of the present case demonstrated that occult primary cancer should be suspected in patients with DVT unresponsive to anticoagulant therapy. The present study also indicated that up-front primary cytoreductive surgery without placement of an IVC filter represents an effective potential strategy for the treatment of advanced ovarian cancer associated with DVT, as the thrombus strongly adheres to the vessel wall following organization. PMID- 26622892 TI - Anti-inflammatory drugs and uterine cervical cancer cells: Antineoplastic effect of meclofenamic acid. AB - Uterine cervical cancer (UCC) is one of the main causes of cancer-associated mortality in women. Inflammation has been identified as an important component of this neoplasia; in this context, anti-inflammatory drugs represent possible prophylactic and/or therapeutic alternatives that require further investigation. Anti-inflammatory drugs are common and each one may exhibit a different antineoplastic effect. As a result, the present study investigated different anti inflammatory models of UCC in vitro and in vivo. Celecoxib, sulindac, nimesulide, dexamethasone, meclofenamic acid, flufenamic acid and mefenamic acid were tested in UCC HeLa, VIPA, INBL and SiHa cell lines. The cytotoxicity of the drugs was evaluated in vitro. Celecoxib, sulindac, nimesulide, mefenamic acid and flufenamic acid presented with slight to moderate toxicity (10-40% of cell death corresponding to 100 uM) in certain cell lines, while meclofenamic acid exhibited significant cytotoxicity in all essayed cell lines (50-90% of cell death corresponding to 100 uM). The meclofenamic acid was tested in murine models (immunodeficient and immunocompetent) of UCC, which manifested a significant reduction in tumor growth and increased mouse survival. It was demonstrated that of the evaluated anti-inflammatory drugs, meclofenamic acid was the most cytotoxic, with a significant antitumor effect in murine models. Subsequent studies are necessary to evaluate the clinical utility of this drug. PMID- 26622894 TI - Expression of the copper transporters hCtr1, ATP7A and ATP7B is associated with the response to chemotherapy and survival time in patients with resected non small cell lung cancer. AB - Copper transporter family proteins may regulate the chemoresistance of non-small cell lung cancer (NSCLC) to platinum-based anticancer drugs. The present study aimed to investigate the expression of these proteins in lung cancer tissue specimens for association with clinicopathological data and patient responses to chemotherapy and survival. A total of 54 patients with surgically resected NSCLC that received first-line platinum-based doublet chemotherapy were recruited in the present study, and the paraffin-embedded pre-treatment tumor tissue specimens were subjected to immunohistochemical analysis for the expression of human copper transporter 1 (hCtr1) and copper-transporting p-type adenosine triphosphatase 1 (ATP7A) and 2 (ATP7B). This cohort of patients with NSCLC received platinum-based chemotherapy subsequent to the surgical removal of tumor lesions. ATP7B expression was found to be significantly associated with tumor cell differentiation, while hCtr1 expression was significantly associated with improved chemotherapeutic responses. The median survival time was 20 months in patients possessing tumors with high ATP7A expression, but >66 months in patients possessing tumors with low ATP7A expression at the end of the follow-up (P<0.001). The median survival time at the end of the follow-up was 15 months in patients with low tumor hCtr1 expression, but >66 months in patients with high tumor hCtr1 expression (P<0.001). High hCtr1 and low ATP7A expression were each favorable prognostic factors subsequent to chemotherapy for patients with resected NSCLC. Multivariate analysis revealed that high hCtr1 expression combined with low ATP7A expression, good tumor differentiation and female gender were all favorable independent predictive and prognostic factors for patients with resected NSCLC following chemotherapy. High hCtr1 expression combined with low ATP7A expression was associated with an improved prognosis in patients with resected NSCLC that received platinum-based chemotherapy. Surgery combined with neoadjuvant chemotherapy may improve the survival time of patients with NSCLC. PMID- 26622895 TI - Inflammatory mediators, tumor necrosis factor-alpha and interferon-gamma, induce EMT in human PTC cell lines. AB - Inflammatory mediators, tumor necrosis factor (TNF)-alpha and interferon (IFN) gamma, promote adverse outcomes in numerous types of cancer; however, their role in papillary thyroid cancer (PTC) remains unclear. The aim of the present study was to investigate the influence of TNF-alpha and IFN-gamma on the migration, invasion and epithelial-mesenchymal transition (EMT) of the three PTC cell lines, TPC-1, BCPAP and K1. The effect of TNF-alpha and IFN-gamma on cell migration and invasion was assessed by wound-healing and Transwell assays. In addition, the mRNA and protein expression levels of the EMT makers, E-cadherin, N-cadherin and vimentin, were analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunoblot analysis. The wound-healing and Transwell experiments revealed that TNF-alpha and IFN-gamma increased the migratory and invasive behavior of PTC cells (P<0.05). RT-qPCR revealed that TNF-alpha and IFN gamma downregulated E-cadherin mRNA, while they upregulated N-cadherin and vimentin mRNA expression levels. These results were further confirmed by the immunoblot analysis. The results of the present study suggest that TNF-alpha and IFN-gamma induce EMT and malignant progression in human PTC cells. PMID- 26622896 TI - Capecitabine maintenance therapy following docetaxel/capecitabine combination treatment in patients with metastatic breast cancer. AB - The present study aimed to analyze the efficacy of maintenance therapy with single agent capecitabine for human epidermal growth factor receptor (HER2) negative metastatic breast cancer (MBC) patients following disease control with 6 cycles of docetaxel plus capecitabine chemotherapy as the first-line treatment. As an initial treatment, 6 cycles of docetaxel plus capecitabine followed by maintenance therapy with capecitabine were administered. A total of 55 patients received combination therapy and 48 patients proceeded to maintenance therapy: Of these, 32 patients (66.7%) were postmenopausal and 37 (77.1%) had estrogen and progesterone receptor positive disease. The median progression-free survival rate with maintenance therapy was 5.5 months (95% CI, 0-11.4 months) and the median overall survival (OS) was 26.6 months (95% CI, 21.8-30.1 months). The use of maintenance therapy improved previous responses in 4 patients (8.3%; 2 partial and 2 complete responses) and 32 patients (66.7%) had stable disease. The median number of maintenance therapy cycles applied was 6.5 (range 1-28, total 441). The observation of side effects, including grade 3/4 neutropenia, febrile neutropenia and fatigue was more common during combination therapy. The results of the present study indicate that maintenance with single agent capecitabine therapy is an effective and tolerable treatment option for HER2 negative MBC patients in which disease control with 6 cycles of docetaxel plus capecitabine chemotherapy is achieved in the first-line setting. PMID- 26622897 TI - MicroRNA-650 in a copy number-variable region regulates the production of interleukin 6 in human osteosarcoma cells. AB - Copy number variation is a well-known genetic variation. microRNAs (miRNAs/miRs) are non-coding RNAs that mediate gene expression by regulating target mRNAs. In the present study, copy number deletions encompassing miRNA coding regions were investigated to determine the association between the deletion of miRNA and its phenotypic effects. A total of 38 human miRNAs in copy number variants were identified and miR-650, which is functional in the human osteosarcoma MG-63 cell line, was selected. Overexpression of miR-650 decreased the expression of inhibitor of growth family member 4 (ING4) in the MG-63 cells and increased interleukin (IL)6 transcription, as well as IL6 secretion in IL1B-stimulated cells. Furthermore, miR-650 downregulated the amount of nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha and increased the transcriptional activity of nuclear factor (NF)kappaB. Downregulation of ING4 also increased the production of IL6, similar to miR-650 overexpression. Taken together, these data indicate that miR-650 plays a significant role in the production of IL6 by regulating ING4 expression and NFkappaB signaling in IL1B stimulated MG-63 osteosarcoma cells. PMID- 26622898 TI - Expression and clinical significance of microRNA-21, maspin and vascular endothelial growth factor-C in bladder cancer. AB - The present study aimed to explore the expression and clinical significance of microRNA-21 (miR-21), maspin and vascular endothelial growth factor C (VEGF-C) in bladder cancer (BC). A total of 53 BC samples and 12 normal bladder tissue samples were collected. Total messenger RNA (mRNA) was extracted, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to evaluate the expression of miR-21 and maspin in BC and normal bladder tissues. Immunohistochemistry was used for the detection of maspin and VEGF-C protein expression. Furthermore, the correlations between these molecules and certain clinicopathological parameters were investigated, and survival analysis was performed to assess their prognostic significance. miR-21 mRNA expression and VEGF-C protein expression were increased in BC tissues compared with those in normal bladder tissues, whereas maspin mRNA and protein expression levels in BC tissues were significantly decreased (P<0.01). miR-21, maspin and VEGF-C expression were significantly associated with the stage, grade and lymph node metastasis of BC (P<0.05), but not the other clinicopathological features evaluated. There was a marked inverse correlation between the mRNA expression of miR-21 and maspin, with a coefficient of -0.978 (P<0.001). Similarly, there was a significant inverse correlation between the protein expression of maspin and VEGF C, with a coefficient of -0.589 (P<0.001). Overexpression of miR-21 and VEGF-C, as well as decreased maspin expression, were associated with a poorer prognosis. These results suggested that upregulation of miR-21, decreased maspin expression and enhanced VEGF-C in BC may promote tumor progression. miR-21, maspin and VEGF C may therefore have significant roles as biomarkers for prognosis and as therapeutic targets of BC. PMID- 26622899 TI - Renal clear cell carcinoma with thyroid and parotid metastases: A case report. AB - The present study reports a rare case of a renal clear cell carcinoma with thyroid and parotid metastases. A 56-year-old female, with a painless, right preauricular mass present for 6 months was referred to Renji Hospital (Shanghai, China). Physical examination revealed a mass of 3*3 cm, which was smooth, firm, immobile and non-tender. There was no accompanying facial weakness. Parotid ultrasonography revealed a hypoechoic mass within the right parotid gland, which was potentially a parotid mixed tumor. In July 2011, the patient underwent a superficial parotidectomy with preservation of the facial nerve. Pathology confirmed as right parotid clear cell carcinoma (metastasis). The patient's relevant medical history included a right radical nephrectomy for renal clear cell carcinoma (clinical stage III) in 2004. Additionally, in 2009, the patient underwent a resection of thyroid metastatic renal cell carcinoma. To the best of our knowledge, no similar case has previously been reported in English-language literature. The present study discusses a case report, and investigates the clinical features and treatment strategy. PMID- 26622900 TI - Effect of BMAP-28 on human thyroid cancer TT cells is mediated by inducing apoptosis. AB - Thyroid cancer is the most common malignant endocrine tumor, with significant morbidity and mortality. Bovine myeloid antimicrobial peptide 28 (BMAP-28) is a cathelicidin that is found in bovine neutrophils. In the present study, the effect and relative mechanism of BMAP-28 on the human thyroid cancer TT cell line in vitro and in vivo were investigated. A 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay, flow cytometry and a TT-xenograft mouse model were used in this study. The data obtained indicated that BMAP-28 significantly inhibited the proliferation of the TT cells in vitro. In addition, the Annexin V fluorescein isothiocyanate/propidium iodide assay detected that BMAP-28 induced apoptotic effects in the TT cells. Moreover, the expression of activated caspase 3 and -9 was upregulated at the transcriptional and translational levels. Simultaneously, the expression of matrix metalloproteinase (MMP)3 and MMP9 was downregulated following BMAP-28 treatment. Finally, BMAP-28 significantly prevented the tumor growth in the TT-xenograft mouse model. These results indicated that BMAP-28 could be a potential agent for the treatment of thyroid cancer. PMID- 26622901 TI - Effects of orientin and vitexin from Trollius chinensis on the growth and apoptosis of esophageal cancer EC-109 cells. AB - Orientin and vitexin are the monomers of total flavonoids in Trollius chinensis Bunge. Orientin and vitexin have the same chemical constitution. Modern studies on pharmacology have indicated that the total flavonoids of this plant have antitumor actions. The aim of the present study was to investigate the effects of orientin and vitexin on the growth and apoptosis of EC-109 cells, to investigate the expression of p53 and B-cell lymphoma (bcl-2), and to discuss the associated antitumor activity, in vitro. This data provides experience for the basis of the selection and structure-activity associations of antineoplastic agents, and analysis of the efficacy of the total flavonoids in Trollius chinensis. In this study, EC-109 cells in the logarithmic growth phase were treated with different concentrations of orientin and vitexin. The inhibitory effect on cell growth and proliferation was detected by MTT method. Cell nuclei were assayed by the cell death detection using Hoechst 33258 staining, cell apoptosis was detected by DNA agarose gel electrophoresis, and the apoptosis rate of the EC-109 cells was examined using an Annexin V-fluorescein isothiocyanate/propidium iodide double labeled technique of flow cytometry (FCM). The protein expression of p53 and bcl 2 in the EC-109 cells was detected by FCM. Orientin and vitexin exhibited marked inhibitory effects on the proliferation of the EC-109 cells. The inhibition rate increased with the increase in concentration and reaction time, and orientin and vitexin were able to induce the apoptosis of the EC-109 cells. The gene expression levels of p53 and bcl-2 were upregulated and downregulated, respectively. Additionally, the antitumor effects of orientin were stronger than that of vitexin using the same concentration. These experimental findings indicated that orientin and vitexin engender antitumor effects that may be associated with the regulation of the apoptosis-related gene expression of p53 and bcl-2. Therefore, orientin and vitexin may serve as therapeutic agents for the treatment of esophageal cancer. PMID- 26622902 TI - Sequencing study on familial lung squamous cancer. AB - Lung cancer is the leading cause of cancer-related mortality worldwide. The majority of lung cancers are sporadic, and familial cases are extremely rare. Previous studies have mainly focused on sporadic lung cancer and identified a large quantity of driver genes. However, familial lung cancers are rarer and studied less. The present study recruited a Chinese family in which multiple members had developed lung squamous carcinoma. To find the causative mutations, whole exome sequencing was conducted using a peripheral blood sample of one lung squamous carcinoma patient, and certain variants were validated in more samples. Whole exome sequencing analysis obtained ~2.0 Gb of data (an average of 60x depth for each targeted base), and further validation experiments identified two functional variants in two cancer-related genes (c.1218delA:p.E406fs in PDE4DIP and C1342A:p.L448I in CLTCL1). This study therefore provides useful sources for the further study of hereditary lung cancer. PMID- 26622903 TI - microRNA-195 inhibits the proliferation, migration and invasion of cervical cancer cells via the inhibition of CCND2 and MYB expression. AB - The functions of microRNAs (miRNA/miR) in the development of cervical cancer remain largely undefined. The present study investigated the role of miR-195 in cervical cancer development. The expression of miR-195 mimics in the cervical cancer HeLa cell line significantly decreased the cell proliferation, migration and invasion capacities in vitro. Using miRNA target prediction algorithms and reporter assays, cyclin D2 (CCND2) and v-myb avian myeloblastosis viral oncogene homolog (MYB) were identified as direct targets of miR-195. Moreover, miR-195 repressed the expression of CCND2 and MYB in the HeLa cells at the mRNA and protein levels. Finally, the expression of miR-195 was downregulated in cervical cancer tissues compared with normal tissues. Together, these data suggest that miR-195 is a tumor suppressor in cervical cancer. PMID- 26622904 TI - Pigment epithelium-derived factor inhibits caveolin-induced interleukin-8 gene expression and proliferation of human prostate cancer cells. AB - Caveolin-1 (Cav), a primary protein component of caveolae, is overexpressed in prostate cancer, thereby promoting growth and metastasis of this tumor. By contrast, pigment epithelium-derived factor (PEDF) has been shown to inhibit tumor growth and metastasis, including that of prostate cancer, via its anti angiogenic and anti-inflammatory effects. Although it was recently demonstrated that PEDF binds to Cav and blocks its pro-inflammatory actions in endothelial cells, it remains unclear whether PEDF also inhibits the tumor-promoting effects of Cav in cultured prostate cancer cells. The present study examined the effects of PEDF on cell growth, in addition to the gene expression of interleukin-8 (IL 8), which is involved in prostate cancer progression, in the PC-3 human prostate cancer cell line. Exogenous Cav led to a dose-dependent upregulation of the mRNA expression of IL-8 in PC-3 cells, which was blocked by treatment with 1 or 10 nM PEDF, or following the overexpression of small interfering RNAs directed against Cav. Cav (10 nM) increased DNA synthesis in PC-3 cells, which was again suppressed by the administration of 10 nM PEDF. The results of the present study indicated that PEDF may inhibit Cav-induced increases in IL-8 gene expression and proliferation of PC-3 cells. Therefore, the suppressive effects of PEDF in prostate cancer may, in part, be ascribed to its inhibitory actions on Cav. PMID- 26622905 TI - Retroperitoneal teratoma causing ptosis: A case report. AB - The present study reports the case of a patient who had undergone unsuccessful hormone therapy for ocular myasthenia gravis 14-years prior to the current presentation. The diagnosis of ocular myasthenia gravis was once again confirmed by a neostigmine test and repeat nerve stimulation study. Computed tomography scans in an external institution revealed a retroperitoneal cystic tumor with calcification above the left adrenal gland. The tumor was removed via a transperitoneal laparoscopic resection and was diagnosed as a mature cystic teratoma upon pathological examination. A teratoma is a common form of germ cell tumor, but primary teratomas of the retroperitoneum are quite rare in the adult population. Post-operative observation of the patient showed resolution of the ptosis and improved movement of the eyeballs. The potential mechanism was unclear, but the patient's teratoma was mature and may have contained myoid cells with antigenicity for anti-acetylcholine receptor (anti-AchR), as has been established in the thymus. Therefore, the anti-AchR antibody may have been involved. PMID- 26622906 TI - Synergistic interaction between MEK inhibitor and gefitinib in EGFR-TKI-resistant human lung cancer cells. AB - With the increasing use of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) in patients with advanced non-small cell lung cancer (NSCLC), acquired resistance has become a major clinical problem. A combination of different signaling pathway inhibitors is a promising strategy to overcome this. In the present study, the mitogen-activated protein kinase kinase 1/2 inhibitor, AZD6244, was used in combination with gefitinib to investigate the efficacy of this treatment in NSCLC cell lines, particularly in gefitinib resistant cells. The EGFR-TKI-sensitive PC-9 (mutant EGFR/wild-type K-Ras) and EGFR-TKI-resistant A549 (wild-type EGFR/mutant K-Ras) human NSCLC cell lines were treated with AZD6244 alone, gefitinib alone or the combination of the two drugs, and the effects were evaluated using cell proliferation assays, with alterations in signaling pathways analyzed by western blotting. It was found that the growth inhibitory effect of combination treatment with gefitinib and AZD6244 was greater than that of gefitinib alone in the EGFR-TKI-resistant A549 cells. Treatment of A549 cells with gefitinib alone reduced the expression level of the activated form of Akt, and the combination of the two drugs showed stronger inhibition of phosphorylated-Akt and phosphorylated-extracellular signal-regulated kinases. The data showed that the combination of AZD6244 and gefitinib exhibited dose dependent synergism in gefitinib-resistant NSCLC cells. Thus, a preclinical rationale exists for the use of AZD6244 to enhance the efficacy of gefitinib in patients with EGFR-TKI-resistant NSCLC. PMID- 26622907 TI - Gene expression profiling and its use in adenocarcinomas of unknown primary origin: A case report. AB - Carcinomas of unknown primary origin account for 3-5% of all malignancies. The current literature suggests that metastatic dissemination is able to occur in the absence of primary tumor growth. In metastatic disease that is difficult to diagnose, the origin usually remains unknown even after an exhaustive evaluation of immunohistochemistry (IHC) markers. In the current study, a 49-year-old male presented with lymph nodes metastases of unknown origin. The excisional biopsy of an inguinal node revealed an adenocarcinoma growth pattern, but the IHC could not determine the primary origin. A gene profiling test was performed to complete the diagnosis and a salivary gland adenocarcinoma was diagnosed with 90% probability. Subsequently, the patient underwent appropriate chemotherapy for salivary gland adenocarcinoma, and exhibited an improved partial response. The present case study highlights the importance of an accurate diagnosis of the primary tumor and the use of all the current tools available in order to provide patients with the best treatment possible. PMID- 26622908 TI - FOLFIRINOX-induced reversible dysarthria: A case report and review of previous cases. AB - FOLFIRINOX is a standard chemotherapeutic regimen for patients with advanced pancreatic cancer who have a good performance status. In this study, we present the case of a 64-year-old male who developed dysarthria following FOLFIRINOX treatment, and review all four cases of dysarthria encountered among the nine patients who received this treatment in our hospital. In all cases, dysarthria occurred during the infusion of irinotecan in the first course of treatment, persisted for several hours, and then resolved rapidly without any sequelae. Physical and neurological examinations at the onset of dysarthria revealed no other abnormalities. Imaging studies revealed no abnormal findings. Atropine was prophylactically administered in the second and subsequent courses of treatment and effectively prevented or alleviated dysarthria. This acute neurological symptom is surprising and uncommon in traditional cancer chemotherapy, and medical oncologists may initially suspect the onset of stroke or cerebrovascular disease. However, consistent with our experience, all reported cases resolved completely, with no need for dose reduction or treatment interruption. PMID- 26622909 TI - Sustained use of an occupational sun safety program in a recreation industry: follow-up to a randomized trial on dissemination strategies. AB - The sustainability of evidence-based programs is needed to obtain long-term benefits. To assess sustainability of Go Sun Smart (GSS), an occupational skin cancer prevention program disseminated to the North American ski industry. Fifty three of the 68 ski areas from the original dissemination trial participated in 2012 and 2013, 5 to 7 years after program distribution by enhanced or basic dissemination strategies. Sustained use was measured by: (1) on-site observation of sun protection communication and (2) an online survey with senior managers. In the sustainability assessment, sun safety communication had declined, and dissemination strategy did not affect continued use. Managers held weaker attitudes about skin cancer importance and program fit, but more managers provided free/reduced-cost sunscreen than in the dissemination trial. Manager turnover was a key factor in program discontinuance. Sustainability remains a challenge. Additional research is needed to determine the best strategies for sustainability. PMID- 26622910 TI - Bridging barriers to clinic-based HIV testing with new technology: translating self-implemented testing for African American youth. AB - Numerous barriers to clinic-based HIV testing exist (e.g., stigmatization) for African American youth. These barriers may be addressed by new technology, specifically HIV self-implemented testing (SIT). We conducted a series of formative phase 3 translation studies (49 face-to-face interviews, 9 focus groups, 1 advisory panel review) among low-income African American youth (15-19 years) and providers of adolescent services in two US cities to identify potential translation difficulties of the OraQuick SIT. Based on content analysis, we found that providers and African American youth viewed SITs positively compared to clinic-based testing. Data suggest that SITs may reduce social stigma and privacy concerns and increase convenience and normalization of HIV testing. Challenges with SIT implementation include difficulties accessing confirmatory testing, coping with adverse outcomes, and instructional materials that may be inappropriate for low socioeconomic status (SES) persons. Study results underscore the need for translation studies to identify specific comprehension and implementation problems African American youth may have with oral SITs. PMID- 26622911 TI - Using the Primary Care Behavioral Health Provider Adherence Questionnaire (PPAQ) to identify practice patterns. AB - Primary care-mental health integration (PC-MHI) is growing in popularity. To determine program success, it is essential to know if PC-MHI services are being delivered as intended. The investigation examines responses to the Primary Care Behavioral Health Provider Adherence Questionnaire (PPAQ) to explore PC-MHI provider practice patterns. Latent class analysis was used to identify clusters of PC-MHI providers based on their self-report of adherence on the PPAQ. Analysis revealed five provider clusters with varying levels of adherence to PC-MHI model components. Across clusters, adherence was typically lowest in relation to collaboration with other primary care staff. Clusters also differed significantly in regard to provider educational background and psychotherapy approach, level of clinic integration, and previous PC-MHI training. The PPAQ can be used to identify PC-MHI provider practice patterns that have relevance for future clinical effectiveness studies, development of provider training, and quality improvement initiatives. PMID- 26622912 TI - Survivorship care planning after participation in communication skills training intervention for a consultation about lymphoma survivorship. AB - A survivorship care plan refers to a written summary of the treatment received and recommendations regarding surveillance and management of late effects. To provide evaluation of a communication skills training (CST) intervention to enhance the transition of lymphoma survivors to cancer survivorship. Nineteen oncologists specializing in lymphoma treatment were recruited and completed a survivorship CST workshop, and two standardized patient assessments (SPAs), one pretraining and one posttraining. Significant improvements in SPA scores were observed in six of the seven SPA assessment categories: use of survivorship care plan, review of disease and treatment details, long-term effects, potential late effects, specific physician recommendations, and additional health maintenance recommendations. The intervention had significant effects on physicians' uptake of new strategies and skills, as measured through pre- and posttraining SPAs, as well as on the physicians' self-efficacy about having these conversations. PMID- 26622915 TI - Interpersonal communication outcomes of a media literacy alcohol prevention curriculum. AB - Media literacy intervention efficacy literature has focused on media-relevant (e.g., knowledge and realism) and behavior-relevant outcomes (e.g., attitudes and behaviors), without much attention paid to interpersonal communication outcomes. This project examined interpersonal communication after participation in two versions (analysis plus analysis and analysis plus planning) of the Youth Message Development (YMD) intervention, a brief media literacy curriculum targeted at preventing high school student alcohol use. Participants attended a 75-mins media literacy YMD workshop and completed a delayed posttest questionnaire 3 to 4 months later. Overall, 68 % participants replied affirmatively to interpersonal communication about the YMD intervention. Communication about the workshop moderated the effects of the type of workshop (analysis plus analysis or analysis plus planning) on self-efficacy to counter-argue (but not critical thinking). Interpersonal communication moderated the effects of the YMD intervention on self efficacy to counter-argue, thereby signaling the importance of including interpersonal communication behaviors in intervention evaluation. PMID- 26622914 TI - Community health workers assisting Latinos manage stress and diabetes (CALMS-D): rationale, intervention design, implementation, and process outcomes. AB - Latinos have high rates of diabetes and mental distress, but lack appropriate services. A study was designed to compare enhanced standard diabetes care with enhanced standard care plus community health worker (CHW) delivered stress management for Latinos with type 2 diabetes. This paper reports intervention design and process outcomes. A formative process was used to develop and implement an eight-session, group stress management intervention. One hundred twenty-one participants completed baseline assessments; n = 107 attended diabetes education and were then randomized. Recruits reported high credibility and treatment expectancies. Treatment fidelity was high. Participants reported high treatment satisfaction and therapeutic alliance and their diabetes knowledge and affect improved over the short term. Retention and attendance at group sessions was challenging but successful relative to similar trials. This comprehensive and culturally sensitive stress management intervention, delivered by a well-trained CHW, was successfully implemented. PMID- 26622913 TI - A review of diabetes prevention program translations: use of cultural adaptation and implementation research. AB - The Diabetes Prevention Program (DPP) has been shown to prevent type 2 diabetes through lifestyle modification. The purpose of this study was to describe the literature on DPP translation, synthesizing studies using cultural adaptation and implementation research. A systematic search was conducted. Original studies evaluating DPP implementation and/or cultural adaptation were included. Data about cultural adaptation, implementation outcomes, and translation strategies was abstracted. A total of 44 were included, of which 15 reported cultural adaptations and 38 explored implementation. Many studies shortened the program length and reported a group format. The most commonly reported cultural adaptation (13 of 15) was with content. At the individual level, the most frequently assessed implementation outcome (n = 30) was adoption. Feasibility was most common (n = 32) at the organization level. The DPP is being tested in a variety of settings and populations, using numerous translational strategies and cultural adaptations. Implementation research that identifies, evaluates, and reports efforts to translate the DPP into practice is crucial. PMID- 26622916 TI - Texercise select effectiveness: an examination of physical activity and nutrition outcomes. AB - Given the role of physical activity (PA) and good nutrition to delay the onset and progression of most chronic conditions, effective interventions are needed to influence lifestyle behaviors of community-dwelling populations. The purpose of this study is to examine the effectiveness of Texercise Select to improve health indicators, PA, and dietary behaviors, and confidence to engage in healthful behaviors. Texercise Select, a 12-week exercise program, was delivered. Baseline and 12-week follow-up assessments were collected from 220 participants with baseline data who were aged 45 years and older for this non-randomized one-group pre-post design trial. Linear mixed models were fitted for continuous outcome variables and GEE models with logit link function for binary outcome variables. Significant improvements (P < 0.05) were seen in physical activity scores (d = 0.64 for aerobic activity), weekly fruit/vegetable consumption (d = 0.31), daily water consumption (d = 0.29), as well as PA- and nutrition-related confidence (d =0.38 and 0.21, respectively) and social support (d =0.45). Programs rooted in best practices show promise for positively impacting large numbers of participants and becoming sustainably embedded in communities over time. PMID- 26622917 TI - Development of the Health Incentive Program Questionnaire (HIP-Q) in a cardiac rehabilitation population. AB - The purpose of this study was to develop a questionnaire to facilitate the design of acceptable financial health incentive programs. A multiphase psychometric questionnaire development method was used. Theoretical and literature reviews and three focus groups generated a pool of content areas and items. New items were developed to ensure adequate content coverage. Field testing was conducted with a convenience sample of cardiac rehabilitation (CR) patients (n = 59) to establish face and construct validity (p = 0.021) and reliability (intraclass coefficients = 0.42-0.87). The final questionnaire is comprised of 23 items. This questionnaire builds on previous attempts to explore acceptability by sampling a wider range of instrumental and affective attitudes and by measuring the effect of program features on the likelihood of incentive program participation. Future research is now needed to examine whether tailoring incentives to preferences assessed by the questionnaire improves uptake and effectiveness. PMID- 26622918 TI - Assessing intervention fidelity in a multi-level, multi-component, multi-site program: the Children's Healthy Living (CHL) program. AB - Addressing complex chronic disease prevention, like childhood obesity, requires a multi-level, multi-component culturally relevant approach with broad reach. Models are lacking to guide fidelity monitoring across multiple levels, components, and sites engaged in such interventions. The aim of this study is to describe the fidelity-monitoring approach of The Children's Healthy Living (CHL) Program, a multi-level multi-component intervention in five Pacific jurisdictions. A fidelity-monitoring rubric was developed. About halfway during the intervention, community partners were randomly selected and interviewed independently by local CHL staff and by Coordinating Center representatives to assess treatment fidelity. Ratings were compared and discussed by local and Coordinating Center staff. There was good agreement between the teams (Kappa = 0.50, p < 0.001), and intervention improvement opportunities were identified through data review and group discussion. Fidelity for the multi-level, multi component, multi-site CHL intervention was successfully assessed, identifying adaptations as well as ways to improve intervention delivery prior to the end of the intervention. PMID- 26622921 TI - News from the NIH: using an experimental medicine approach to facilitate translational research. PMID- 26622920 TI - Society of Behavioral Medicine (SBM) position statement: SBM supports increased efforts to integrate community health workers into the patient-centered medical home. AB - Integrating community health workers (CHWs) into health care systems has been associated with enhanced patient experience, improved population health, and reduced costs and unnecessary utilization of resources. Under the Affordable Care Act (ACA), care provided by CHWs is eligible for reimbursement. However, optimal integration of CHWs into health care requires purposeful implementation. This health policy brief is focused on the benefits of integrating CHWs specifically into the patient-centered medical home (PCMH). CHWs in the PCMH can serve as primary providers of culturally relevant information and advocacy, assist providers in understanding the influence of patients' environment on disease management, and enhance motivation for self-care management among patients with chronic diseases. Despite the important role of CHWs, there are some barriers to integration into existing systems of care. The Society of Behavioral Medicine (SBM) recommends overcoming these barriers by establishing standards that ensure a skilled CHW workforce, clearly defining roles for CHWs, and expanding the scope of reimbursable prevention and primary care services to include those provided by CHWs. PMID- 26622919 TI - Self-report measures of medication adherence behavior: recommendations on optimal use. AB - Medication adherence plays an important role in optimizing the outcomes of many treatment and preventive regimens in chronic illness. Self-report is the most common method for assessing adherence behavior in research and clinical care, but there are questions about its validity and precision. The NIH Adherence Network assembled a panel of adherence research experts working across various chronic illnesses to review self-report medication adherence measures and research on their validity. Self-report medication adherence measures vary substantially in their question phrasing, recall periods, and response items. Self-reports tend to overestimate adherence behavior compared with other assessment methods and generally have high specificity but low sensitivity. Most evidence indicates that self-report adherence measures show moderate correspondence to other adherence measures and can significantly predict clinical outcomes. The quality of self report adherence measures may be enhanced through efforts to use validated scales, assess the proper construct, improve estimation, facilitate recall, reduce social desirability bias, and employ technologic delivery. Self-report medication adherence measures can provide actionable information despite their limitations. They are preferred when speed, efficiency, and low-cost measures are required, as is often the case in clinical care. PMID- 26622922 TI - Prenatal Diagnosis of Nasal Glioma Associated with Metopic Craniosynostosis: Case Report and Review of the Literature. AB - Nasal gliomas (nasal glial heterotopia) are rare benign congenital frontonasal lesions occurring in approximately 1:20.000-40,000 live births. The diagnosis is rarely reported prenatally. Nasal gliomas are typically isolated lesions, with syndromic association being exceedingly rare. Metopic craniosynostosis can occur as an isolated abnormality or in association with multiple syndromes. This case is the first reported case of nasal glioma in association with craniosynostosis in the published literature. PMID- 26622923 TI - Incarcerated Grynfeltt-Lesshaft Hernia. AB - Superior lumbar triangle hernia, also known as Grynfeltt-Lesshaft hernia, denotes a subtype of abdominal wall hernia, and more specifically of lumbar hernia, occurring between the 12th rib, the internal oblique muscle, and the quadratus lumborum muscle. We report the case of a 92-year-old female patient in which this form of hernia occurred, complicated by incarceration and acute bowel obstruction. The discussion contains a short resume of the different kinds of abdominal wall hernias. PMID- 26622924 TI - Placental site trophoblastic tumor: a case report and review of the literature. AB - We present a case of a gravida 1 para 1 woman, who presented with an 11-month history of amenorrhea after cesarean delivery. The patient was taking birth control pills at the time of presentation. She was observed with a slight elevation of serum beta-hCG level, an enlarged heterogeneous uterus and hematometra. A biopsy was performed, and the patient was diagnosed with placental site trophoblastic tumor; the patient then underwent surgery. Placental site trophoblastic tumor is the rarest form of gestational trophoblastic disease, derived from intermediate trophoblast cells. It does not have a pathognomonic appearance; therefore, correlation with medical history, as well as results of laboratory tests and pathological analysis is mandatory. It is a relatively chemoresistant tumor, posing considerable therapeutic challenges; patients with localized disease are managed with surgery and those with metastatic disease require additional chemotherapy. Herein, we review the main features of this entity and top differential diagnosis, as the rarity of this tumor is associated with imaging and pathological pitfalls, reinforcing the need for further experience in this field. PMID- 26622925 TI - Popliteal vein aneurysm presenting as recurrent pulmonary embolism. AB - Although rare, popliteal vein aneurysms can lead to pulmonary emboli, which can be fatal. We present a case of a popliteal vein aneurysm in a 39-year-old female who presented with her third episode of pulmonary embolism despite being on anticoagulants. Computed Tomography Venogram demonstrated a large Popliteal Vein Aneurysm measuring 71*36*77 mm which was surgically repaired. According to the current literature, anticoagulation is insufficient therefore early surgical intervention is recommended as it is safe and effective. PMID- 26622926 TI - 18-FDG Uptake in Pulmonary Dirofilariasis. AB - Solitary pulmonary nodules are a common finding on chest radiography and CT. We present the case of an asymptomatic 59-year-old male found to have a 13 mm left upper lobe nodule on CT scan. The patient was asymptomatic and the CT was performed to follow up mediastinal and hilar lymphadenopathy that had been stable on several previous CT scans. He had a history of emphysema and reported a 15 pack-year smoking history. PET-CT was performed which demonstrated mild 18-FDG uptake within the nodule. Given his age and smoking history, malignancy was a consideration and he underwent a wedge resection. Pathological examination revealed a necrobiotic granulomatous nodule with a central thrombosed artery containing a parasitic worm with internal longitudinal ridges and abundant somatic muscle, consistent with pulmonary dirofilariasis. Dirofilaria immitis, commonly known as the canine heartworm, rarely affects humans. On occasion it can be transmitted to a human host by a mosquito bite. There are two major clinical syndromes in humans: pulmonary dirofilariasis and subcutaneous dirofilariasis. In the pulmonary form, the injected larvae die before becoming fully mature and become lodged in the pulmonary arteries. PMID- 26622927 TI - Internal Carotid Artery Web: Doppler Ultrasound with CT Angiography correlation. AB - We present a case of an internal carotid web, detected on duplex ultrasound and confirmed by CT angiography. To our knowledge, this is only the third reported ultrasound case in the imaging literature. This vascular abnormality can cause a clinically significant carotid stenosis and is a risk factor for recurrent embolic cerebrovascular events. Due to small size and poor awareness among radiologists, carotid webs are often under-diagnosed on non-invasive imaging modalities. Improved awareness including knowledge of salient imaging features is useful as early diagnosis leading to appropriate intervention can eliminate the risk of future cerebrovascular events. PMID- 26622928 TI - Magnetic Resonance Imaging of the Lung as an Alternative for a Pregnant Woman with Pulmonary Tuberculosis. AB - We report a case of a pregnant 21-year-old woman with pulmonary tuberculosis in which magnetic resonance imaging of the lung was used to assess the extent and characteristics of the pathological changes. Although the lung has been mostly ignored in magnetic resonance imaging for many decades, today technical development enables detailed examinations of the lung. The technique is now entering the clinical arena and its indications are increasing. Magnetic resonance imaging of the lung is not only an alternative method without radiation exposure, it can provide additional information in pulmonary imaging compared to other modalities including computed tomography. We describe a successful application of magnetic resonance imaging of the lung and the imaging appearance of post-primary tuberculosis. This case report indicates that magnetic resonance imaging of the lung can potentially be the first choice imaging technique in pregnant women with suspected pulmonary tuberculosis. PMID- 26622929 TI - Combined Undifferentiated and Neuroendocrine Carcinomas of the Gallbladder Appearing as Two Separate Lesions: A Case Report with Radiological-Pathological Correlation. AB - We report herein a rare case of incidentally detected combined undifferentiated and neuroendocrine carcinomas of the gallbladder. An incidental gallbladder malignancy was revealed on abdominal ultrasound and multi-detector computed tomography in a 54-year-old man. A short distance from the main polypoid hypoechoic mass at the fundus of the gallbladder, focal wall thickening was noted with prominently increased power Doppler flow. Extended cholecystectomy was performed, and histology confirmed the main polypoid mass as undifferentiated carcinoma and the separate nodule as neuroendocrine carcinoma. To our knowledge, this is the first report presenting two separate lesions of combined gallbladder carcinomas by radiological features. PMID- 26622930 TI - Peroneus Brevis Tendon Variant Insertion on the Calcaneus. AB - Insertion of the peroneus brevis tendon normally occurs at the lateral aspect of the fifth metatarsal base. However, there is new evidence that congenital variant insertion of the tendon on the calcaneal peroneal tubercle occurs in a small segment of the population. We report a case of 24-year old male presenting with non-traumatic ankle pain who underwent ankle magnetic resonance imaging. Imaging demonstrated insertion of the peroneus brevis tendon on the calcaneal peroneal tubercle with absence of the tendon distal to the calcaneus. Furthermore, in reviewing 200 consecutive ankle magnetic resonance examinations, the authors discovered one additional case of this variant. We discuss the magnetic resonance imaging characteristics of this anatomic variant, the implications for clinical management, and review the literature on peroneal anatomic variations. PMID- 26622931 TI - Skeletal and Brain Abnormalities in Fucosidosis, a Rare Lysosomal Storage Disorder. AB - Fucosidosis is a rare genetic lysosomal storage disorder caused by a deficiency in alpha- L-fucosidase. We present a case of a 4-year, 11-month-old girl with developmental delay, as well as skeletal and brain abnormalities as shown on X ray and MRI. Her spinal X- rays demonstrated lumbar kyphosis and anterior beaking of lumbar vertebral bodies. Lower iliac segment constriction, increased angulation of the acetabular roof, and widening of the ribs were apparent on abdominal X-ray. Her brain MRI illustrated symmetric T1 hyperintensity and T2 hypointensity of the bilateral globi pallidi. The case report highlights clinical and imaging findings of this rare disease. PMID- 26622932 TI - Thalamic Massa Intermedia Duplication in a Dysmorphic 14 month-old Toddler. AB - The massa intermedia is an inconstant parenchymal band connecting the medial thalami. It may be thickened in various disease processes such as Chiari II malformation or absent in other disease states. However, the massa intermedia may also be absent in up to 30% of normal human brains. To the best of my knowledge, detailed imaging findings of massa intermedia duplication have only been described in a single case report. An additional case of thalamic massa intermedia duplication discovered on a routine brain MR performed for dysmorphic facial features is reported herein. PMID- 26622933 TI - Delayed Myocardial Enhancement in Cardiac Magnetic Resonance Imaging. AB - Delayed myocardial enhancement MRI is a highly valuable but non-specific imaging technique that is ancillary in the diagnosis of a variety of diseases including myocardial viability, cardiomyopathy, myocarditis and other infiltrative myocardial processes. The lack of specificity stems from the wide variety of differential diagnoses that may present with overlapping patterns of delayed enhancement. Many of these differential diagnoses have been presented and discussed in this article. PMID- 26622934 TI - Solitary Neurofibroma Of The Spermatic Cord: A Case Report. AB - We report the ultrasound, computerized tomography, positron emission tomography and magnetic resonance imaging findings of a 38-year-old man with a biopsy proven solitary neurofibroma of the spermatic cord. Solitary neurofibromas of the male genital tract are exceedingly rare benign peripheral nerve sheath neoplasms composed of Schwann cells and fibroblasts. In contrast to schwannomas they are not bound by a capsule thus allowing infiltration between the nerve fascicles. Although they are benign lesions whose potential for malignant degeneration is very low, especially in the absence of neurofibromatosis type 1, accurate diagnosis is important as neurofibromas in this location can cause significant morbidity and psychological distress. Despite the extensive differential diagnosis of masses in the male inguinal canal, including both benign and malignant entities, a diagnosis of benign peripheral nerve sheath tumor can be potentially suggested based on imaging, particularly if MRI is performed. Surgical resection is the treatment of choice and the final diagnosis should be provided by histopathology, as was the case with this patient. PMID- 26622935 TI - A pictorial review of reconstructive foot and ankle surgery: hallux abductovalgus. AB - This pictorial review focuses on basic procedures performed within the field of podiatric surgery, specifically for the hallux abductovalgus or "bunion" deformity. Our goal is to define objective radiographic parameters that surgeons utilize to initially define deformity, lead to procedure selection and judge post operative outcomes. We hope that radiologists will employ this information to improve their assessment of post-operative radiographs following reconstructive foot surgeries. First, relevant radiographic measurements are defined and their role in procedure selection explained. Second, the specific surgical procedures of the distal metatarsal, metatarsal shaft, metatarsal base, and phalangeal osteotomies are described in detail. Additional explanations of arthrodesis of the first metatarsal-phalangeal and metatarsal-cuneiform joints are also provided. Finally, specific plain film radiographic findings that judge post operative outcomes for each procedure are detailed. PMID- 26622936 TI - Sialadenitis following low dose I-131 diagnostic thyroid scan with Thyrogen(r) (recombinant human thyroid stimulating hormone--thyrotropin alfa). AB - Salivary dysfunction and sialadenitis are well known complications of radioiodine treatment for thyroid cancer. The parotid gland is more frequently affected and the salivary gland injury is dose related. The symptoms may develop shortly after therapeutic Iodine 131(I-131) administration or months later and progress with time. The development of unilateral parotiditis following a low dose, diagnostic I-131 scan performed following Thyrogen stimulation in a patient without prior history of sialadenitis is rare in our experience, and has not been reported in the medical literature. PMID- 26622937 TI - Pancreatic CSCs and microenvironment. PMID- 26622938 TI - The complexity of microenvironment-mediated drug resistance. PMID- 26622939 TI - TNF-R1, an immune checkpoint in melanoma? PMID- 26622940 TI - WWP2 is required for normal cell cycle progression. AB - WWP2 is a ubiquitin E3 ligase belonging to the Nedd4-like family. Given that WWP2 target proteins including PTEN that are crucial for regulating cell proliferation or suppressing tumorigenesis, we have asked whether WWP2 plays a role in controlling cell cycle progression. Here we report that WWP2 is necessary for normal cell cycle progression as its silencing significantly reduces the cell proliferation rate. We have identified that an isoform of WWP2 (WWP2-V4) is highly expressed in the M phase of the cell cycle. Silencing of WWP2 accelerates the turnover of cyclin E, which is accompanied by increased levels of phospho histone H3 (p-H3) and cyclin B. Moreover, silencing of WWP2 results in compromised phosphorylation of Akt(S473), a residue whose phosphorylation is tightly associated with the activation of the kinase. Combined, these results strongly suggest that WWP2 is an important component in regulating the Akt signaling cascade, as well as cell cycle progression. PMID- 26622942 TI - Immuno-stimultory/regulatory gene expression patterns in advanced ovarian cancer. AB - It has been established that a high degree of tumor-infiltrating T cells is associated with ovarian cancer prognosis. We hypothesized that tumors display an immune-related program of transcription that can act in a stimulatory or a regulatory manner. We analyzed transcriptome-wide gene expression data from 503 ovarian tumors from the Cancer Genome Atlas to identify genes that show differential prognoses when stratified by CD3 expression. Genes with immunological functions and tumor antigen genes were selected for analysis. We repeated our analysis in an independent validation study. Five genes showed stimulatory/regulatory patterns at a high level of confidence (Bonferroni p < 0.05). Three of these (MAGEA8, MPL, AMHR2) were validated and one (WT1) could not be evaluated. These patterns show specific prognostic effect only in conjunction with CD3 expression. When patients express multiple transcripts in poor prognosis directions, there is a dose response: increasingly regulatory type tumors are associated with higher stage, lower treatment response and shorter overall survival and progression free survival. The high-confidence set of transcripts (MAGEA8, MPL, AMHR2, WT1) and selected low-confidence hits (EPOR, TLR7) alone or in combination represent candidate prognosis markers for further investigation. PMID- 26622941 TI - Novel high-grade serous epithelial ovarian cancer cell lines that reflect the molecular diversity of both the sporadic and hereditary disease. AB - Few cell line models of epithelial ovarian cancer (EOC) have been developed for the high-grade serous (HGS) subtype, which is the most common and lethal form of gynaecological cancer. Here we describe the establishment of six new EOC cell lines spontaneously derived from HGS tumors (TOV2978G, TOV3041G and TOV3291G) or ascites (OV866(2), OV4453 and OV4485). Exome sequencing revealed somatic TP53 mutations in five of the cell lines. One cell line has a novel BRCA1 splice-site mutation, and another, a recurrent BRCA2 nonsense mutation, both of germline origin. The novel BRCA1 mutation induced abnormal splicing, mRNA instability, resulting in the absence of BRCA1 protein. None of the cell lines harbor mutations in KRAS or BRAF, which are characteristic of other EOC subtypes. SNP arrays showed that all of the cell lines exhibited structural chromosomal abnormalities, copy number alterations and regions of loss of heterozygosity, consistent with those described for HGS. Four cell lines were able to produce 3D spheroids, two exhibited anchorage-independent growth, and three (including the BRCA1 and BRCA2 mutated cell lines) formed tumors in SCID mice. These novel HGS EOC cell lines and their detailed characterization provide new research tools for investigating the most common and lethal form of EOC. PMID- 26622943 TI - A novel MeCP2 acetylation site regulates interaction with ATRX and HDAC1. AB - Methyl-CpG-binding protein-2 (MeCP2) regulates gene expression by recruiting SWI/SNF DNA helicase/ATPase (ATRX) and Histone Deacetylase-1 (HDAC1) to methylated gene regions and modulates heterochromatin association by interacting with Heterochromatin protein-1. As MeCP2 contributes to tumor suppressor gene silencing and its mutation causes Rett Syndrome, we investigated how novel post translational-modification contributes to its function. Herein we report that upon pharmacological inhibition of SIRT1 in RKO colon and MCF-7 breast cancer cells, endogenous MeCP2 is acetylated at sites critical for binding to DNA and transcriptional regulators. We created an acetylation mimetic mutation in MeCP2 and found it to possess decreased binding to ATRX and HDAC1. Conditions inducing MeCP2 acetylation do not alter its promoter occupancy at a subset of target genes analyzed, but do cause decreased binding to ATRX and HDAC1. We also report here that a specific inhibitor of SIRT1, IV, can be used to selectively decrease H3K27me3 repressive marks on a subset of repressed target gene promoters analyzed. Lastly, we show that RKO cells over-expressing MeCP2 mutant show reduced proliferation compared to those over-expressing MeCP2-wildtype. Our study demonstrates the importance of acetylated lysine residues and suggests their key role in regulating MeCP2 function and its ability to bind transcriptional regulators. PMID- 26622944 TI - Combinations of genetic data in a study of oral cancer. AB - In the single locus strategy a number of genetic variants are analyzed, in order to find variants that are distributed significantly different between controls and patients. A supplementary strategy is to analyze combinations of genetic variants. A combination that is the genetic basis for a polygenic disorder will not occur in in control persons genetically unrelated to patients, so the strategy is to analyze combinations of genetic variants present exclusively in patients. In a previous study of oral cancer and leukoplakia 325 SNPs were analyzed. This study has been supplemented with an analysis of combinations of two SNP genotypes from among the 325 SNPs. Two clusters of combinations containing 95 patient specific combinations were significantly associated with oral cancer or leukoplakia. Of 373 patients with oral cancer 205 patients had a number of these 95 combinations in their genome, whereas none of 535 control persons had any of these combinations in their genome. PMID- 26622945 TI - Inhibitor of p52 NF-kappaB subunit and androgen receptor (AR) interaction reduces growth of human prostate cancer cells by abrogating nuclear translocation of p52 and phosphorylated AR(ser81). AB - Accumulating evidence shows that androgen receptor (AR) activation and signaling plays a key role in growth and progression in all stages of prostate cancer, even under low androgen levels or in the absence of androgen in the castration resistant prostate cancer. Sustained activation of AR under androgen-deprived conditions may be due to its interaction with co-activators, such as p52 NF kappaB subunit, and/or an increase in its stability by phosphorylation that delays its degradation. Here we identified a specific inhibitor of AR/p52 interaction, AR/p52-02, via a high throughput screen based on the reconstitution of Gaussia Luciferase. We found that AR/p52-02 markedly inhibited growth of both castration-resistant C4-2 (IC50 ~6 MUM) and parental androgen-dependent LNCaP (IC50 ~4 MUM) human prostate cancer cells under low androgen conditions. Growth inhibition was associated with significantly reduced nuclear p52 levels and DNA binding activity, as well as decreased phosphorylation of AR at serine 81, increased AR ubiquitination, and decreased AR transcriptional activity as indicated by decreased prostate-specific antigen (PSA) mRNA levels in both cell lines. AR/p52-02 also caused a reduction in levels of p21(WAF/CIP1), which is a direct AR targeted gene in that its expression correlates with androgen stimulation and mitogenic proliferation in prostate cancer under physiologic levels of androgen, likely by disrupting the AR signaling axis. The reduced level of cyclinD1 reported previously for this compound may be due to the reduction in nuclear presence and activity of p52, which directly regulates cyclinD1 expression, as well as the reduction in p21(WAF/CIP1), since p21(WAF/CIP1) is reported to stabilize nuclear cyclinD1 in prostate cancer. Overall, the data suggest that specifically inhibiting the interaction of AR with p52 and blocking activity of p52 and pARser81 may be an effective means of reducing castration resistant prostate cancer cell growth. PMID- 26622946 TI - Otoacoustic Emissions in Smoking and Nonsmoking Young Adults. AB - OBJECTIVES: The present study investigates the usefulness of transiently evoked otoacoustic emissions (TEOAEs) and distortion product OAEs (DPOAEs) in detecting small changes in the hearing of young smoking adults. METHODS: Otoacoustic emissions were acquired from the ears of 48 young adults (age, 20 to 27 years). The dataset was divided into two groups, smoking (24 persons/48 ears) and nonsmoking (24 persons/48 ears). The level of smoking was relatively small in comparison to previous studies, an average of 3.8 years and 8.7 cigarettes per day. In each ear three OAE measurements were made: TEOAEs, DPOAEs, and spontaneous OAEs (SOAEs). Pure tone audiometry and tympanometry were also conducted. Audiometric thresholds did not differ significantly between the datasets. Half-octave-band values of OAE signal to noise ratios and response levels were used to assess statistical differences. RESULTS: Averaged data initially revealed that differences between the two study groups occurred only for TEOAEs at 1 kHz. However when the datasets were divided into ears with and without SOAEs more differences became apparent, both for TEOAEs and DPOAEs. In ears that exhibited SOAEs, both smokers and nonsmokers, there were no statistically significant differences between evoked OAEs; however in all ears without SOAEs, evoked OAEs were higher in the ears of nonsmokers, by as much as 5 dB. These differences were most prominent in the 1-2 kHz range. CONCLUSION: A general decrease in OAE levels was found in the group of smokers. However, in ears which exhibited SOAEs, there was no difference between the evoked OAEs of smokers and nonsmokers. We conclude that smoking had not yet measurably affected the ears of those with acute hearing (i.e., those who exhibit SOAEs). However, in ears without SOAEs, smokers exhibited smaller evoked OAE amplitudes than nonsmokers, even though their audiometric thresholds were within the norm. PMID- 26622948 TI - Anatomic Variants on Computed Tomography in Congenital Aural Atresia and Stenosis. AB - OBJECTIVES: To quantitatively analyzing the anatomic variants on temporal computed tomography (CT) in congenital external auditory canal stenosis (EACS), congenital aural atresia (CAA), and normal ear structure. METHODS: Through a retrospective study, we analyzed 142 temporal high-resolution CT studies performed in 71 microtia patients. The following 6 parameters were compared among the three groups: Marx classification, medial canal diameter, vertical facial nerve (VFN) anterior displacement, tegmen mastoideum position, tympanic cavity volume, and malleus-incus joint or malleus-incus complex (MIC) area. RESULTS: The results showed that the microtia distributions in the Marx classification in these three groups were significantly different, as 86% (31 of 35) of ears with major microtia (third-degree dysplasia) had an atresia, and in 54.8% (23 of 42) of the minor microtic (first-degree or second-degree) ears, the bony or cartilaginous part of the external auditory canal was stenotic. Measurement data also showed that the potential medial canal diameter of the atresia group was obviously shorter than that of the stenosis group. The VFN anterior displacement and temporomandibular joint backward-shift together lead to medial canal diameters in ears with atresic canals that is smaller than those with stenotic canals. The tegmen mastoideum position was not significantly different between the three groups. CONCLUSION: The mal-development of the external auditory canal is significantly associated with auricle and middle ear developmental anomalies. Compared with CAA ears, EACS have better development of the auricle, canal, tympanic cavity and MIC and relatively safer surgical operation except for the position of the tegmen mastoideum and the VFN. PMID- 26622947 TI - An Evaluation of the Protective Effects of Thymoquinone on Amikacin-Induced Ototoxicity in Rats. AB - OBJECTIVES: In this study we investigated the probable protective effects of thymoquinone on amikacin-induced ototoxicity in rats. METHODS: Thirty-two healthy rats were divided into four groups (amikacin, amikacin+thymoquinone, thymoquinone, and no treatment). Thymoquinone was fed to the rats via oral gavage in a dose of 40 mg/kg/day throughout the study period of 14 days. Amikacin was given by the intramuscular route in a dose of 600 mg/kg/day. Audiological assessment was conducted by the distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) tests, administered to all rats at the beginning of the study, and also on days 7 and 15. Biochemical parameters were calculated at the termination of the study to evaluate the oxidative status. RESULTS: There were significant decreases in DPOAE values and significant increases in ABR thresholds of the amikacin group on days 7 and 15, as compared to the amikacin+thymoquinone group. While ABR thresholds of the amikacin group increased significantly on days 7 and 15 as compared to their initial values, there were no significant differences between the initial and the 7th and 15th day values of ABR thresholds in the amikacin+thymoquinone group. Total oxidant status and oxidative stress index values of the amikacin+thymoquinone group were significantly lower than those of the amikacin group. Total antioxidant status values of the amikacin+thymoquinone group were significantly higher than those of the amikacin group. CONCLUSION: Our study has demonstrated that the ototoxic effect brought forth by amikacin could be overcome with the concurrent use of thymoquinone. PMID- 26622949 TI - Cochlear Implantation for Profound Hearing Loss After Multimodal Treatment for Neuroblastoma in Children. AB - OBJECTIVES: Neuroblastoma (NBL) predominantly affects children under 5 years of age. Through multimodal therapy, including chemotherapy, radiotherapy, surgery, and peripheral blood stem cell transplantation, the survival rate in patients with NBL have improved while treatment-related complications have also increased. Treatment-related ototoxicity, mainly from cisplatin, can result in profound hearing loss requiring cochlear implantation (CI). We analyzed the effectiveness and hearing preservation of CI recipients who had treated with multimodal therapy due to NBL. METHODS: Patients who received multimodal therapy for NBL and subsequent CIs were enrolled. A detailed review of the perioperative hearing test, speech evaluation, and posttreatment complications was conducted. Speech performance was analyzed using the category of auditory performance (CAP) score and the postoperative hearing preservation of low frequencies was also compared. Patients who were candidates for electro-acoustic stimulation (EAS) used an EAS electrode for low frequency hearing preservation. RESULTS: Three patients were identified and all patients showed improvement of speech performance after CI. The average of CAP score improved from 4.3 preoperatively to 5.8 at 1 year postoperatively. Two patients who were fitted with the Flex electrode showed complete hearing preservation and the preserved hearing was maintained over 1 year. The one remaining patient was given the standard CI-512 electrode and showed partial hearing preservation. CONCLUSION: Patients with profound hearing loss resulting from NBL multimodal therapy can be good candidates for CI, especially for EAS. A soft surgical technique as well as a specifically designed electrode should be applied to this specific population during the CI operation in order to preserve residual hearing and achieve better outcomes. PMID- 26622950 TI - Is Hypozincemia Related to Tinnitus?: A Population Study Using Data From the Korea National Health and Nutrition Examination Survey. AB - OBJECTIVES: The aim of present study was to determine the relationship between serum zinc level and tinnitus using data from the Korea National Health and Nutrition Examination Survey (KNHANES). METHODS: The present study examined the relationship between serum zinc level and tinnitus using data from the KNHANES. A total of 2,225 KNHANES participants responded to the tinnitus questionnaire and provided blood samples to measure serum zinc concentration. Based on questionnaire responses, participants were categorized into control, mild tinnitus, moderate tinnitus, and severe tinnitus subgroups. RESULTS: There were no significant differences between groups in serum zinc level after adjustment for sex, age, and hearing loss. CONCLUSION: It was concluded that hypozincemia is not related to tinnitus in a large population. PMID- 26622951 TI - Anatomical Factors Influencing Pneumatization of the Petrous Apex. AB - OBJECTIVES: Aim of the present study was to define the relationship between petrous apex pneumatization and the nearby major anatomical landmarks using temporal bone computed tomography (CT) images. METHODS: This retrospective, Institutional Review Board-approved study analyzed CT images of 84 patients that showed normal findings bilaterally. Pneumatization of the petrous apex was classified using two methods. Eight parameters were as follows: angle between the posterior cranial fossa and internal auditory canal, Morimitsu classification of anterior epitympanic space, distance between the carotid canal and jugular bulb, distance between the cochlear modiolus and carotid canal, distance between the tympanic segment and jugular bulb, high jugular bulb, distance between the vertical segment and jugular bulb, and distance between the lateral semicircular canals and middle cranial fossa. RESULTS: There was a significant difference in Morimitsu classification of the anterior epitympanic space between the two classification methods. Poorly pneumatic upper petrous apices were distributed uniformly in three types of Morimitsu classification, but more pneumatic upper petrous apices were found more often in anterior type. Lower petrous apex was well pneumatized regardless of the types of anterior epitympanic space, but the largest amount of pneumatization was found more frequently in the anterior type of anterior epitympanic space. CONCLUSION: This study showed that there was no reliable anatomic marker to estimate petrous apex pneumatization and suggests that the pneumatization of the petrous apex may be an independent process from other part of the temporal bone, and may not be influenced by the nearby major anatomical structures in the temporal bone. In this study, the anterior type of anterior epitympanic space was found to be closely related to more well pneumatized petrous apices, which implies that the anterior saccule of the saccus medius may be the main factor influencing pneumatization of the petrous apex. PMID- 26622952 TI - Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. AB - OBJECTIVES: The primary aim of this study is to evaluate the gene expression profile of Asian sand dust (ASD)-treated human middle ear epithelial cell (HMEEC) using microarray analysis. METHODS: The HMEEC was treated with ASD (400 ug/mL) and total RNA was extracted for microarray analysis. Molecular pathways among differentially expressed genes were further analyzed. For selected genes, the changes in gene expression were confirmed by real-time polymerase chain reaction. RESULTS: A total of 1,274 genes were differentially expressed by ASD. Among them, 1,138 genes were 2 folds up-regulated, whereas 136 genes were 2 folds down regulated. Up-regulated genes were mainly involved in cellular processes, including apoptosis, cell differentiation, and cell proliferation. Down-regulated genes affected cellular processes, including apoptosis, cell cycle, cell differentiation, and cell proliferation. The 10 genes including ADM, CCL5, EDN1, EGR1, FOS, GHRL, JUN, SOCS3, TNF, and TNFSF10 were identified as main modulators in up-regulated genes. A total of 11 genes including CSF3, DKK1, FOSL1, FST, TERT, MMP13, PTHLH, SPRY2, TGFBR2, THBS1, and TIMP1 acted as main components of pathway associated with 2-fold down regulated genes. CONCLUSION: We identified the differentially expressed genes in ASD-treated HMEEC. Our work indicates that air pollutant like ASD, may play an important role in the pathogenesis of otitis media. PMID- 26622953 TI - Idiopathic Sudden Sensorineural Hearing Loss With Minimal Hearing Impairment. AB - OBJECTIVES: The aim of the study was to determine the characteristics of patients who did not match the audiometric criteria of idiopathic sudden sensorineural hearing loss (SSNHL) but complained of acute hearing loss. METHODS: By thorough medical chart reviews, historical cohort study was performed with consecutive data of 589 patients complaining of acute unilateral sensorineural hearing loss without identifiable causes between 2005 and 2013. Those patients demonstrating a hearing loss of at least 30 dB at three consecutive frequencies based on pure tone audiometry were classified as group I; the others were classified as group II. Patients' characteristics, final hearing, and hearing improvement rate (HIR) between the two groups were compared. RESULTS: Group II exhibited distinctive characteristics, including an early age of onset of the hearing loss (P<0.01), an absence of accompanying diabetes (P<0.01) and hypertension (P<0.01), and better unaffected hearing and final hearing compared with group I (P<0.001). However, the HIR of the patients in the two groups was not significantly different (P>0.05). CONCLUSION: Patients who did not meet the audiological criteria of SSNHL exhibited distinctive characteristics compared to SSNHL patients. PMID- 26622954 TI - Comparison of Short- and Long-term Hearing Outcomes of Successful Inlay Cartilage Tympanoplasty Between Small and Large Eardrum Perforations. AB - OBJECTIVES: To compare the short- and long-term hearing outcomes after successful inlay cartilage tympanoplasty between patients with small (<=25%) and large (>=50%) eardrums perforations. METHODS: This is a retrospective case series study conducted in a tertiary referral center. Twenty-five patients who underwent 27 procedures were enrolled. Their mean age was 60.26 years (range, 42 to 76 years). The mean follow-up time was 18.86 months (range, 12.30 to 35.83 months). The preoperative, initial postoperative, and long-term hearing results in patients with total repair of the eardrum were analyzed. RESULTS: In the small size group, the average (+/-standard deviation) air-bone gap (ABG) closure was 1.08+/-7.53 dB in the short-term and 2.33+/-11.56 dB in the long-term hearing examinations. There was no difference between short- and long-term ABG closure (P=0.689). In the large size group, the average ABG closure was 9.77+/-9.40 dB in the short term and 16.25+/-6.01 dB in the long-term hearing examinations. There was a significant difference between short- and long-term ABG closure (P=0.029). CONCLUSION: Patients with large perforations have continuous hearing improvement and ABG closure for more than one year. In contrast, the short- and long-term postoperative ABGs are almost the same in patients with small perforations. More long-term postoperative follow-up of hearing results is necessary for large perforations. PMID- 26622955 TI - Unidentified Bright Objects on Brain Magnetic Resonance Imaging Affect Vestibular Neuritis. AB - OBJECTIVES: The aim of this study was to investigate the differences in clinical manifestations of in two groups of vestibular neuritis (VN) patients with or without unidentified bright objects (UBOs). METHODS: A prospective, observational study with 46 patients diagnosed with VN between May 2013 and November 2013 was executed. A caloric test, a cervical vestibular-evoked myogenic potentials (cVEMPs) test, brain magnetic resonance imaging (MRI), spontaneous nystagmus test, head impulse test, and head-shaking nystagmus test were performed. RESULTS: Of the patients, 56.5% (n=26) were classified as UBO-positive by MRI. These showed lower caloric weakness and more prominent cVEMP asymmetry compared with the UBO-negative group (P<0.05). Total VN (TVN) was the most common in the UBO positive group (45.0%), followed by superior VN (SVN, 30.0%), and inferior VN (IVN, 25.0%). However, in the UBO-negative group, SVN (75.0%) was the most common, followed by TVN and IVN (P<0.05). The recovery rate was not influenced by UBOs (P>0.05). CONCLUSION: UBOs on T2-weighted or fluid attenuated inversion recovery MRI may affect the patterns of the vestibular nerve in patients with VN. PMID- 26622956 TI - Five-Year Subjective Outcomes of Obstructive Sleep Apnea Surgery: A Multiinstitutional Study. AB - OBJECTIVES: To evaluate the effect of obstructive sleep apnea (OSA) surgery on long-term (5-year) subjective outcomes, including sleep disordered breathing (SDB) symptoms and other complications, in patients with OSA. METHODS: We enrolled patients who underwent diagnostic polysomnography for OSA between January 2006 and December 2006 in ten hospitals. Patients either were treated for OSA or were not treated for OSA. All patients completed a brief telephone survey regarding their SDB signs and symptoms (e.g., snoring, apnea, nocturnal arousals, and daytime sleepiness), positive airway pressure (PAP) compliance, and any adverse effects of either the surgery or PAP. A positive subjective outcome for either surgery or no treatment was taken to be the alleviation of apnea, defined as a >=50% increase in score. A positive subjective outcome (compliance) for PAP was defined as a PAP usage of >=4 hours per night and >=5 days per week. RESULTS: A total of 229 patients were included in this study. Patients were divided into three groups: a surgery group (n=87), a PAP group (n=68), and a control (untreated) group (n=74). The surgery group exhibited significant improvement in all SDB symptoms compared with the control group. The long-term subjective outcomes of the surgery (52.9%) and PAP (54.4%) groups were significantly better than those of the control group (25.0%). The subjective outcome of the surgery group was not significantly different from that of the PAP group. The overall surgical complication rate was 23.0% (20 of 87) in the surgery group, and 55.0% (22 of 40) of all patients with PAP experienced adverse effects. CONCLUSION: The extent of SDB symptoms was consistently improved in patients with OSA at 5 years postsurgery. Information about the potential long-term subjective outcomes should be provided to patients when considering surgery. PMID- 26622957 TI - Relationship Between Snoring Intensity and Severity of Obstructive Sleep Apnea. AB - OBJECTIVES: The aim of this study was to determine the relationship between the intensity of snoring and severity of sleep apnea using Watch-PAT (peripheral arterial tone) 100. METHODS: A total of 404 patients (338 males and 66 females) who underwent home-based portable sleep study using Watch-PAT 100 for obstructive sleep apnea (OSA) from January 2009 through December 2011 were included in this study. Subjects were divided into 4 groups; no OSA (PAT apnea hypopnea index [pAHI]<5/hour), mild OSA (5<=pAHI<15/hour), moderate OSA (15<=pAHI<30/hour), or severe OSA groups (pAHI>=30/hour). Mean snoring intensity and percent sleep time with snoring intensity greater than 40, 50, and 60 dB were measured by Watch-PAT 100. Correlations of these parameters with apnea hypopnea index (AHI), respiratory disturbance index (RDI), and oxygen desaturation index were assessed. RESULTS: The mean age and body mass index were 46.5+/-14.8 years and 24.7+/-3.4 kg/m(2), respectively. Mean AHI and RDI were 16.5+/-15.3/hour and 20.8+/ 14.3/hour, respectively. The mean snoring intensity in the no, mild, moderate, and severe OSA groups was 44.0+/-2.7, 45.4+/-6.0, 47.7+/-5.0, and 50.5+/-5.6 dB, respectively (P<0.001). There was a positive correlation between snoring intensity and pAHI or PAT RDI (pRDI) (r=0.391 and r=0.385, respectively, both P<0.001). There was also a positive correlation between percent sleep time with the snoring intensity greater than 50 dB and pAHI or pRDI (r=0.423 and r=0.411, respectively, both P<0.001). CONCLUSION: This study revealed that the intensity of snoring increased with the severity of sleep apnea, which suggests that the loudness of snoring might be an indicator of the severity of OSA. PMID- 26622958 TI - Decreased Serum Epinephrine in Children With Positive Skin Prick Test. AB - OBJECTIVES: To evaluate the association between catecholamine levels and skin prick test results among children. METHODS: Two hundred eight first grade children from one elementary school were invited to participate in this study. Skin prick test (SPT) for six allergens (2 house dust mites, cat, dog, mugwort, and pollen mixture) was performed, and patient demographic information was recorded. The parents were surveyed using questionnaires about rhinitis-related symptoms. Finally, venous blood sampling was done to measure catecholamine levels (epinephrine, norepinephrine, and dopamine) by high-performance liquid chromatography. RESULTS: Out of 208 children, 174 (106 boys and 68 girls) enrolled in this study. Ninety-six of the children (55%) had negative SPT (nonsensitization group), while 78 (45%) had a positive SPT to at least one of six allergens (sensitization group). The diagnosis of chronic rhinitis was more prevalent in the sensitization group (35.9%) than nonsensitization group (26.0%), however the finding was not significant (P=0.186). Epinephrine levels were decreased between the sensitization group compared to the nonsensitization group (P=0.004). There was no difference in norepinephrine and dopamine levels (P>0.05). CONCLUSION: Epinephrine levels are lower in children with positive SPT compared to controls, however, the level of the catecholamine was not associated with the presence or absence of rhinitis symptoms. PMID- 26622959 TI - Comparison of Component-Resolved Diagnosis by Using Allergen Microarray With the Conventional Tests in Allergic Rhinitis Patients: The First Using in Korea. AB - OBJECTIVES: The aim of this study was to evaluate the component-resolved diagnosis using a microarray allergen chip (Immuno Solid-phase Allergen Chip, ImmunoCAP ISAC) and to compare this new diagnostic tool with the established ImmunoCAP methods for allergen-specific IgE detection in allergic rhinitis patients. METHODS: One hundred sixty-eight allergic rhinitis patients were included in this study. All the patients were diagnosed with allergic rhinitis according to their clinical symptoms, physical examination and a positive skin prick test. We analyzed their specific IgEs for house dust mites (Dermatophagoides farine [DF] and Dermatophagoides pteronyssinus [DP]), Alternaria alternata, birch, and mugwort using ImmunoCAP and ImmunoCAP ISAC in the same patient sample. We compared the sensitivity and correlation between the two tests. RESULTS: In cases of allergies to DP and DF, the sensitivity of the specific IgE was 80% and that of the allergen microarray was 78.9%. The correlation between the two tests was significant for both DP and DF (P<0.001). For the A. alternata, birch and mugwort allergens, the sensitivity of ImmunoCAP ISAC was slightly lower than that of ImmunoCAP. CONCLUSION: These results suggest that the allergen microarray chip method is a reliable new method to diagnose the components of an allergen in patients with allergic rhinitis sensitive to house dust mites. Further study about the utility of the allergen microarray is needed. PMID- 26622960 TI - Effectiveness of Recombinant Human Growth Hormone for Pharyngocutaneous Fistula Closure. AB - OBJECTIVES: In laryngeal cancer, which comprises 25% of head and neck cancer, chemotherapy has come into prominence with the increase in organ-protective treatments. With such treatment, salvage surgery has increased following recurrence; the incidence of pharyngocutaneous fistula has also increased in both respiratory and digestive system surgery. We investigated the effects of recombinant human growth hormone on pharyngocutaneous fistula closure in Sprague Dawley rats, based on an increase in amino acid uptake and protein synthesis for wound healing, an increase in mitogenesis, and enhancement of collagen formation by recombinant human growth hormone. METHODS: This study was experimental animal study. Forty Sprague-Dawley rats were separated into two groups, and pharyngoesophagotomy was performed. The pharyngoesophagotomy was sutured with vicryl in both groups. Rats in group 1 (control group) received no treatment, while those in group 2 were administered a subcutaneous injection of recombinant human growth hormone daily. On day 14, the pharynx, larynx, and upper oesophagus were excised and examined microscopically. RESULTS: Pharyngocutaneous fistula exhibited better closure macroscopically in the recombinant human growth hormone group. There was a significant difference in collagen formation and epithelisation in the recombinant human growth hormone group compared to the control group. CONCLUSION: This study is believed to be the first in which the effect of recombinant human growth hormone on pharyngocutaneous fistula closure was evaluated, and the findings suggest the potential of use of growth hormone for treatment of pharyngocutaneous fistula. PMID- 26622961 TI - Usefulness of Rigid Bronchoscopic Intervention Using Argon Plasma Coagulation for Central Airway Tumors. AB - OBJECTIVES: Argon plasma coagulation (APC) is a noncontact form of electrocautery that utilizes ionized argon as the electrical current. A rigid bronchoscopic use of APC for the management of central airway obstruction could be safe and rapidly effective. This study evaluated the usefulness of rigid bronchoscopy with APC for the management of central airway obstructions due to benign or malignant tumors. METHODS: Twenty patients with obstructing central airway tumors were retrospectively reviewed from February 2008 to February 2013 at Chonnam National University Hospital. All patients received rigid bronchoscopic tumor removal under general anesthesia. APC was applied before and after tumor removal. RESULTS: The median age of patients was 59 years (interquartile range [IQR], 51 to 67 years) and 70% were female. The causes of airway obstruction included malignancy (n=8) and benign tumor (n=12). Airway tumors comprised intraluminal lesions (n=11, 55%) and mixed intraluminal/extraluminal lesions (n=9, 45%). The median tumor size was 15 mm (IQR, 10 to 18 mm). The median degree of airway obstruction was significantly reduced after intervention (90% [IQR, 88% to 96%] vs. 10% [IQR, 0% to 20%], P<0.001). The median American Thoracic Society dyspnea grade (3 [IQR, 1 to 4] vs. 1 [IQR, 0 to 1], P<0.001) and forced expiratory volume in one second (1.03 L [IQR, 0.52 to 1.36 L] vs. 1.98 L [IQR, 1.57 to 2.64 L], P=0.004) were significantly improved after intervention. There were no procedure related acute complications and deaths. CONCLUSION: Rigid bronchoscopy with APC is an effective and safe procedure to alleviate central airway obstruction caused by tumors. PMID- 26622962 TI - Laryngeal Compensation for Voice Production After CO2 Laser Cordectomy. AB - OBJECTIVES: Carbon dioxide (CO2) laser cordectomy is considered one of the modalities of choice for treatment of early glottic carcinoma. In addition to its comparable oncological results with radiotherapy and open surgical procedures, it preserves of laryngeal functions including voice production. The aim of this study was to detect how the larynx compensates for voice production after different types of CO2 laser cordectomy for early glottic carcinoma together with assessment of the vocal outcome in each compensation mechanism. METHODS: One hundred twelve patients treated with CO2 laser cordectomy were classified according to their main postoperative phonatory site. Perceptual analysis of voice samples using GRBAS (grade, roughness, breathiness, asthenia, and strain) scale was done for 88 patients after exclusion of the voice samples of all female patients to make the study population homogenous and the samples of 18 male patients due to bad quality (4 patients) or unavailability (14 patients) of their voice samples and the results were compared with those obtained from control group that included 25 age-matched euphonic male subjects. RESULTS: Five types of laryngeal compensation were defined including: vocal fold to vocal fold, vocal fold to vocal neofold, vocal fold to vestibular fold, vestibular fold, to vestibular fold, and arytenoids hyper adduction. Characters changes of voice produced by each compensation type were found to be statistically significant except for breathiness, asthenia and strain changes in vocal fold to vocal fold compensation type. CONCLUSION: The larynx can compensate for voice production after CO2 laser cordectomy by five different compensation mechanisms with none of them producing voice quality comparable with that of controls. PMID- 26622963 TI - Association of Oversized Tracheal Tubes and Cuff Overinsufflation With Postintubation Tracheal Ruptures. AB - OBJECTIVES: Postintubation tracheal ruptures (PTR) are rare but cause severe complications. Our objective was to investigate the tracheal pattern of injury resulting from cuff inflation of the tracheal tube, to study the two main factors responsible for PTR (cuff overinsufflation and inapplicable tube sizes), and to explain the context, why small women are particularly susceptible to PTR. METHODS: Experimental study performed on 28 fresh human laryngotracheal specimens (16 males, 12 females) within 24 hours post autopsy. Artificial ventilation was simulated by using an underwater construction and a standard tracheal tube. Tube sizes were selected according to our previously published nomogram. Tracheal lesions were detected visually and tracheal diameters measured. The influence of body size, sex difference and appropriate tube size were investigated according to patient height. RESULTS: In all 28 cases, the typical tracheal lesion pattern was a longitudinal median rupture of the posterior trachea. Appropriate tube sizes according to body size caused PTR with significantly higher cuff pressure when compared with oversized tubes. An increased risk of PTR was found in shorter patients, when oversized tubes were used. Sex difference did not have any significant influence. CONCLUSION: This experimental model provides information about tracheal patterns in PTR for the first time. The model confirms by experiment the observations of case series in PTR patients, and therefore emphasizes the importance of correct tube size selection according to patient height. This minimizes the risk of PTR, especially in shorter patients, who have an increased risk of PTR when oversized tubes are used. PMID- 26622964 TI - Tumor Regression Patterns Based on Follow-up Duration in Patients With Head and Neck Squamous Cell Carcinoma Treated With Radiotherapy or Chemoradiotherapy. AB - OBJECTIVES: We describe patterns of tumor regression based on follow-up duration after radiotherapy (RT) or chemo-RT in patients with head and neck squamous cell carcinoma. METHODS: Thirty-one patients with head and neck squamous cell carcinoma were included in this study and received definitive RT or chemo-RT. The pattern of primary tumor regression after treatment was evaluated every 1 to 2 months. Predictive factors for the length of time to full regression were also analyzed. RESULTS: Among all patients, 27 patients showed regression of the primary tumor, 24 patients showed >50% regression, and 15 patients showed total regression. The primary tumor gradually regressed during the course of follow-up. The median time to full regression was 5.2 months (range, 1.3 to 17.9 months). In the 24 patients who showed >50% regression, the rate of >50% regression increased over time as follows: 25.0% at 1 month, 62.5% at 2 months, 75.0% at 3 months, 91.7% at 4 months, and 95.8% at 5 months. Higher total RT dose and shorter RT duration were associated with longer time to full regression. CONCLUSION: A substantial number of patients showed continuous regression of the primary tumor for more than 2 months after treatment. The timing for evaluation of tumor regression must be greater than 2 months from the completion of RT or chemo-RT in patients with head and neck squamous cell carcinoma. PMID- 26622965 TI - Scapular Tip Free Flap for Head and Neck Reconstruction. AB - OBJECTIVES: Head and neck reconstruction is still challenging in terms of esthetic and functional outcomes. This study investigated the feasibility of the angular branch-based scapular tip free flap (STFF). METHODS: This was a retrospective study of 17 patients undergoing maxillectomy and mandibulectomy and either primary or secondary reconstruction by STFF. This study included surgical, esthetic, and functional outcomes, and detailed data are presented regarding the flap, such as pedicle length, size of the harvested bone, and failure rate. Medical photographs were used to estimate the esthetic outcome, and computed tomography was used to check the flap status postoperatively. RESULTS: The data were collected from April 2013 to April 2014. Eight patients underwent maxillary reconstruction, and nine underwent mandibular reconstruction. Maxillary defects usually included unilateral alveolar structures and the palate; mandibular defects were usually those involving mandibular angle and short segment. Vein grafting was not required in any of the patients. Flap failure occurred in one of the 17 patients (5.9%) with successful reconstruction after revision. Of the eight maxillectomy patients, orbital revisions for diplopia after maxillary reconstruction were performed in two patients (25%), and oroantral fistula repair was performed in one patient (12.5%). CONCLUSION: This study demonstrated the reconstructive advantages of the angular branch-based STFF, long pedicle, low flap failure, 3-dimensional nature of bone and soft tissues (chimeric flap), and small rate of donor site morbidity with free ambulation. This flap is an excellent option for use in complex three-dimensional head and neck reconstruction. PMID- 26622966 TI - Frequency of methicillin-resistant Staphylococcus aureus nasal carriage in healthy children. AB - BACKGROUND AND OBJECTIVE: The prevalence of community acquired methicillin resistant Staphylococcus aureus (CA-MRSA) is increasing around the world. It involves healthy people and causes a variety of diseases. MATERIAL AND METHODS: This cross sectional study was conducted from September 2010-June 2011 on children less than 14 years of Ahvaz, southwest Iran. The participants were selected with two staged cluster sampling. A sterile cotton nasal swab was used to collect the samples from the 864 participants. MRSA isolates were identifed by catalase and coagulase tests and 1 MUg oxacillin disk method. Polymerase chain reaction (PCR) was performed on all the MRSA colonies to detect the mecA gene. Data was put in SPSS 16 software and descriptive statistics and chi-square test were used for analysis. RESULTS: Out of 864 children, 471 (54.51%) were male and 393 (45.49%) were female. 235 children (27.1%) had Staphylococcus aureus and 11 (1.3%) of all children diagnosed with MRSA. PCR showed that 7 colonies (0.8%) had the mecA gene. CONCLUSION: The results of this study indicate that MRSA exists in healthy children of Ahvaz. Although the prevalence of CA-MRSA is lower than many other regions, it still needs close attention to prevent its transmission. Further studies are needed to identify the risk factors of CA-MRSA. PMID- 26622967 TI - Study on imipenem resistance and prevalence of blaVIM1 and blaVIM2 metallo-beta lactamases among clinical isolates of Pseudomonas aeruginosa from Mashhad, Northeast of Iran. AB - BACKGROUND AND OBJECTIVES: The main cause of serious nosocomial infections is a Gram-negative pathogen known as Pseudomonas aeruginosa (P. aeruginosa). Carbapenems are widely used as an appropriate treatment for these infections, however resistance to these agents has been observed and is increasing. Metallo beta-lactamase (MBLs) enzyme is one of the main causes of resistance to carbapenem. In the current study the frequency and production of VIM1 and VIM2 by imipenem-resistant P. aeruginosa isolates of patients hospitalized in Imam Reza hospital were evaluated. MATERIALS AND METHODS: In this study, 131 clinical samples were collected from patients hospitalized in Imam Reza hospital in Mashhad during a 15-month period from May 2011 to November 2012. After verification of P. aeruginosa isolates, antibiotic resistance patterns of isolates were determined for 14 antibiotics by Kirby-Bauer standard disk diffusion according to the CLSI guidelines. Combined-disk test was used for phenotypic determination of MBLs-producing isolates and after DNA extraction, genotypic determination of VIM1 and VIM2 metallo beta-lactamase genes was carried out using Multiplex-PCR. RESULTS: Of 63 imipenem-resistant isolates (48.5%), 56 (88.8%) were MBL-producing in phenotypic assessments. Also amongst imipenem resistant isolates, the frequency of VIM1 and VIM2 genes were 58.7 and 3.17%, respectively. CONCLUSION: The results of the current study along with the results of the other conducted studies in Iran in recent years demonstrate that the average resistance to imipenem in P. aeruginosa isolates was 51.3% which has increased in comparison with the results in 2006 (32.9%). It was also determined that the frequency of VIM1 gene was more than VIM2 gene. In phenotypic assessment by using CD method, 49.6% of isolates were determined as MBLs-producing. The sensitivity and specificity of this method were verified in comparison with the results of PCR test. PMID- 26622968 TI - Effect of alum co-adjuvantation of oil adjuvant vaccine on emulsion stability and immune responses against haemorhagic septicaemia in mice. AB - BACKGROUND AND OBJECTIVES: Haemorrhagic septicaemia (HS), caused by Pasteurella multocida, is the most important bacterial disease of cattle and buffaloes in India. Oil adjuvant vaccine (OAV) is the most potent vaccine available for the control of HS. The study aims to evaluate the effect of alum co-adjuvantation of OAV on emulsion stability and immune response. MATERIALS AND METHODS: Two different oil adjuvant vaccines viz., standard oil adjuvant vaccine (OAV) and alum precipitated oil adjuvant vaccine (A-OAV) were prepared with Pasteurella multocida antigen. Emulsion stability was tested by centrifugation, storage at 37 degrees C for 3 months and microscopy. Immune responses were evaluated by ELISA antibody titer, CD4, CD8 T cell populations and survival post challenge by P. multocida in mice. RESULTS: The separation of aqueous and oil phase of emulsion by centrifugation and storage test were 0 and 6.76% in A-OAV as compared to 11.00 and 26.39% in OAV, respectively. The mean droplet size was significantly smaller (p<0.01) in A-OAV as compared to OAV. The A-OAV recorded higher ELISA antibody titer (p<0.05) up to 21st days post vaccination, and higher CD4 (p>0.05) and CD8 T cell (p<0.05) populations compared to OAV. The A-OAV group conferred 100% protection after challenge with both 100 LD50 and 1000 LD50 as compared to 100 and 60% respective protection by OAV group. CONCLUSION: The results indicates that A-OAV had better emulsion stability, produces higher level of CD4, CD8 T cells and antibody titer with better protection compared to oil adjuvant vaccine. PMID- 26622969 TI - Nosocomial emerging of (VIM1) carbapenemase-producing isolates of Klebsiella pneumoniae in North of Iran. AB - BACKGROUND AND OBJECTIVES: The rapid emergence and dissemination of carbapenemase producing Klebsiella pneumoniae strains and other members of the Enterobacteriaceae poses a considerable threat to the care of hospitalized patients and to public health. The aim of this study was to determine the frequency of metallo-beta-lactamases (MBL) and VIM-1 gene in multidrug-resistant strains of K. pneumoniae. METHODS: 50 isolates of non - duplicated K. pneumoniae cultured from patients at intensive care units were tested for their susceptibilities to 13 different antibiotics using microbroth dilution assay. Isolates showing resistance to at least one of the carbapenems were checked for production of metallo-beta-lactamase (MBLs) using imipenem-EDTA synergy tests. PCR was used to detect the gene encoding VIM-1 metallo-beta-lactamase (MBL). RESULTS: Of 50 clinical isolates, 26 (52%) were resistant to imipenem in disk diffusion method. Using imipenem-EDTA synergy tests, production of MBL was detected in 15 (30%) isolates. PCR assay showed that 15 isolates were positive for VIM and these included 10 and 5 isolates showing positive and negative results in phenotypic method of MBL detection test respectively. Amikacin was found as the most effective antibiotic against the MBL producers in this study. CONCLUSION: The emergence of bla(VIM-1) producing K. pneumoniae in North of Iran is concerning. Microorganisms producing bla(VIM-1) constitute the prevalent multidrug-resistant population of K. pneumoniae in that region. PMID- 26622970 TI - High potential application in bioremediation of selenate by Proteus hauseri strain QW4. AB - BACKGROUND AND OBJECTIVE: Selenium is essential for biological systems at low concentrations and toxic at higher levels. Heavy metals and metalloids such as selenium are major contaminants in 40% of hazardous waste sites. Thus, bioremediation has been considered as an effective means of cleaning up of selenium-contaminated sites. MATERIALS AND METHODS: In this study, 30 strains were isolated from wastewater samples collected from selenium-contaminated sites in Qom, Iran using the enrichment culture technique. One bacterial strain designated QW4, identified as Proteus hauseri by morphological, biochemical and 16S rRNA gene sequencing was studied for its ability to tolerate different concentrations of sodium selenate (100-800 mM). Also, the disk diffusion method was performed to determine resistance to some antibiotics. RESULTS: Strain QW4 showed maximum minimum inhibitory concentration (MIC) to selenate (760 mM). The maximum selenate removal was exhibited at 35 degrees C, while the removal activity reduced by 30.7% and 37% at 25 degrees C and 40 degrees C, respectively. The optimum pH and shaking incubator for removal activity was shown to be 7.0 and 150 rpm, with 60.2% and 60.3%, respectively. This bacterial strain was resistant to some antibiotics. CONCLUSION: The concentration of toxic sodium selenate (1000 MUg/ml) in the supernatant of the bacterial culture medium decreased by 100% after 2 days and the color of the medium changed to red due to the formation of less toxic elemental selenium. Also, our results imply that heavy metal pollution may contribute to increased antibiotic resistance through indirect selection. PMID- 26622971 TI - Hepatitis E virus seroprevalence in HIV positive individuals in Shiraz, Southern Iran. AB - BACKGROUND AND OBJECTIVES: Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis in the world. It is usually a self-limited disease but may leads to the deaths of about 20% of pregnant women in developing countries. This study was conducted to determine the prevalence of HEV infection among HIV individuals . MATERIALS AND METHODS: This is a cross-sectional survey of HIV positive individuals in voluntary counselling and testing center of Shiraz in 2013 Using the systematic random sampling method, 158 patients enrolled for the research. They were asked about their age, gender, area of residence, marital status, number of children, education level, occupation, history of imprisonment, mode of HIV transmission, and viral hepatitis co-infection Three ml venous blood sample was drawn from each subject and transferred to the laboratory of voluntary counselling and testing center. RESULTS: The overall seroprevalence of hepatitis E was 26 (16.4%), where it increased significantly with age ranging from zero in subjects less than 30 years of age to 47.4% in those aged 50 years or older. CONCLUSION: Co-infection of HIV positive individuals with HEV is an issue that should be of concern to health care providers. PMID- 26622973 TI - Frosted branch angiitis caused by Varicella Zoster virus in an immunocompetent patient. AB - INTRODUCTION: Frosted branch angiitis(FBA) is a panuveitis with sheating of all retinal vesssels. CASE PRESENTATION: Herein we report an immunocompetent person who presented with fever, headache, atypical rash, and hazy vision. Ophthalmoscopy of both eyes revealed perivascular sheathing with frosted branch angiitis pattern in veins, patchy retinal hemorrhages. Aqueous PCR analysis turned positive for VZV. DISCUSSION: This case illustrates that VZV should be considered in the differential diagnosis of retinal perivasculitis. Since a rapid and accurate diagnosis is crucial for prompt administration of antiviral therapy, PCR-based analysis of aqueous humor is a valuable tool for detecting viruses. PMID- 26622972 TI - Molecular epidemiology of hepatitis C virus and its relation with persistence or clearance of infection in Hamadan, West-Iran. AB - BACKGROUND AND OBJECTIVES: Hepatitis C Virus genotyping appears to be vital for predicting the response to antiviral therapy. The present study aimed to analyze the HCV genotypes in relation to persistence or clearance of the virus in residents of Hamadan Province, West-Iran. MATERIAL AND METHODS: A total of 1159 recorded questionnaires of HCV infected people were evaluated in this prospective study. Several parameters including HCV genotypes, anti-HCV antibodies, viral load, drug treatment, response to therapy and amount of ALT and AST were analyzed. RESULTS: HCV genotyping in 637 samples revealed a predominance of type 1a (52.1%) followed by 3a (42.4%), type 1b (2.7%) and type 2 (0.2%) respectively. Mixed genotypes (3a-1a) were detected in 0.9%, and 1.7% had untypable genotype. High frequency of genotypes 1a and 3a were observed in drug-resistant (group-a) and drug-sensitive (group-b) patients respectively (P<0.0001). Additionally, duration of drug treatment was significantly higher in group-a than group-b (P<0.0001). During follow-up period, 92 cases showed spontaneous clearance of HCV infection and more importantly 86 of 92 cases were positive for anti-HCV antibodies compared with 59 of 455 antibody positive cases with treatment-induced clearance of HCV infection (P<0.0001). CONCLUSION: HCV genotyping and also antibody screening could be useful for proper therapeutic intervention in HCV infected subjects. PMID- 26622974 TI - The Modified Hodge Test: Is it an appropriate method for detection of KPC enzyme or not? PMID- 26622975 TI - Effects of early intervention of swallowing therapy on recovery from dysphagia following stroke. AB - BACKGROUND: Dysphagia is common after stroke. The onset time of swallowing rehabilitation following stroke has an important role in the recovery of dysphagia and preventing of its complications, but it was either highly variable or was not stated in previous trials. The aim of this study was investigation effects of onset time of swallowing therapy on recovery from dysphagia following stroke. METHODS: Sixty dysphagia patients due to stroke range of age 60-74 (67.1 +/- 3.8), participated in this randomized clinical trial study. The patients allocated in Early, Medium and Late groups, on the base of initiation of swallowing therapy after the stroke. After basic clinical and video fluoroscopic swallowing study assessments, traditional swallowing therapy was initiated 3 times per week for 3 months. The outcome measures were North-Western dysphagia patient check sheet, functional oral intake scale, video fluoroscopy, and frequency of pneumonia. Statistical analysis was done by repeated measure ANOVA, Bonferroni and chi(2) tests. RESULTS: Three groups of patients in terms of demographic and clinical characteristics were similar in the pre-treatment P > 0.050. Onset time of swallowing therapy after stroke was effective on swallowing recovery on the main outcome variables. So that in first group patients, recovery was rather than other groups P < 0.050. Furthermore, the frequency of pneumonia in the early group was less than other groups and in the early group no patients experienced pneumonia P = 0.002. CONCLUSION: Our data suggested that early interventions for dysphagia in stroke have an important role in recovery from dysphagia and prevention of complications like aspiration pneumonia. PMID- 26622976 TI - Association of Helicobacter pylori antibodies and severity of migraine attack. AB - BACKGROUND: Recent studies have shown a positive correlation between Helicobacter pylori infection and migraine headache. The aim of this study was to evaluate the role of H. pylori infection in migraine headache with (MA) and without aura (MO). METHODS: This is a case-control study containing information on 84 patients (including MA, MO) and 49 healthy individuals. The enzyme-linked immunosorbent assay (ELISA) test was used to measure immunoglobulin G (IgG,) immunoglobulin M (IgM) titer in two groups. Headache severity was evaluated according to Headache Impact Test (HIT6) questionnaire. RESULTS: Mean +/- SD of IgM antibody in Migrainous patients 26.3 (23.1) showed significantly difference with control group 17.5 (11.2) (P = 0.004). In addition, the mean +/- SD HIT6 in Migrainous patients differed significantly between MA and MO groups 65.5 (4.7), 54.9 (5.3) respectively, P < 0.001). The only significant correlation was found for IgG antibody and HIT6 in MA patients (r = 0.407, P = 0.011) and MO group (r = 0.499, P = 0.002). The risk of migraine occurrence in patients did not significantly associate with the level of IgG and IgM antibodies. CONCLUSION: The results give a hope that definite treatment and eradication of this bacterium could be a cure or to reduce the severity and course of migraine headaches. PMID- 26622977 TI - Knowledge and attitudes toward epilepsy among school teachers in West of Iran. AB - BACKGROUND: Epilepsy comprised the highest proportion of neurological problem of childhood stage, which observed mostly in the first decade of life. The dramatic effect of having a seizure in the classroom can be very traumatic for any child. The knowledge and attitude of teachers toward epilepsy have a direct impact on the life of students with epilepsy. METHODS: A cross-sectional descriptive survey was conducted in Kermanshah (West of Iran). 305 teachers from 25 public schools were randomly participated in this study. The questionnaire included 39 items and three sections (demographic information, knowledge, and attitude about epilepsy). RESULTS: In this study, 97% participants had heard or read about epilepsy. Attitude and knowledge about epilepsy was positive in weighted sum of the item responses, but there were deficits in individual items and first-aid management of seizure attacks. There was no meaningful relationship between attitude scores and demographic items, but higher level of education, female gender, and marital status had a positive influence on teachers' knowledge toward children with epilepsy. CONCLUSION: The main findings indicated a good knowledge and positive attitude about epilepsy among school's teachers. Nevertheless, there is still a need to improve certain aspects of knowledge and attitude and first aid management of an epileptic attack among teachers. PMID- 26622979 TI - Emotional stress recognition using a new fusion link between electroencephalogram and peripheral signals. AB - BACKGROUND: This paper proposes a new emotional stress assessment system using multi-modal bio-signals. Electroencephalogram (EEG) is the reflection of brain activity and is widely used in clinical diagnosis and biomedical research. METHODS: We design an efficient acquisition protocol to acquire the EEG signals in five channels (FP1, FP2, T3, T4 and Pz) and peripheral signals such as blood volume pulse, skin conductance (SC) and respiration, under images induction (calm neutral and negatively excited) for the participants. The visual stimuli images are selected from the subset International Affective Picture System database. The qualitative and quantitative evaluation of peripheral signals are used to select suitable segments of EEG signals for improving the accuracy of signal labeling according to emotional stress states. After pre-processing, wavelet coefficients, fractal dimension, and Lempel-Ziv complexity are used to extract the features of the EEG signals. The vast number of features leads to the problem of dimensionality, which is solved using the genetic algorithm as a feature selection method. RESULTS: The results show that the average classification accuracy is 89.6% for two categories of emotional stress states using the support vector machine (SVM). CONCLUSION: This is a great improvement in results compared to other similar researches. We achieve a noticeable improvement of 11.3% in accuracy using SVM classifier, in compared to previous studies. Therefore, a new fusion between EEG and peripheral signals are more robust in comparison to the separate signals. PMID- 26622978 TI - Injury-related characteristics and quality-of-life among Iranian individuals with spinal cord injury. AB - BACKGROUND: Health-related quality-of-life (HR-QOL) may be affected by various factors including injury-related characteristics among individuals with spinal cord injury (SCI). However, the impact of the influence of these variables has not yet been fully described in Iranian population. Here, we assessed the relationships between injury-related characteristics and HR-QOL among Iranian people with SCI. METHODS: HR-QOL was assessed using short-form health survey (SF 36). Referred patients to Brain and Spinal Injury Research Center between 2010 and 2012 were invited to participate in this investigation. Injury-related characteristics including injury level and completeness, time since injury, plegia type, and American Spinal Injury Association (ASIA) Impairment Scale were evaluated. RESULTS: Total of 104 patients (85 men and 19 women) entered the study. The majority of patients had a complete injury (77.9%). The most frequent ASIA score was A (75%), and the most common level of injury was at thoracic sections (61.5%). Lower injury levels were associated with higher scores in physical component summary (P = 0.040), mental component summary (P = 0.010) and subsequently total score (P = 0.006). Mean age and time since injury were 52.58 +/- 12.69 and 10.88 +/- 16.68 years, respectively, and were not related with HR QOL (P = 0.70 and 0.220, respectively). There was no difference in terms of HR QOL between patients with complete and incomplete injury. Paraplegic individuals had significantly higher scores in the domain of physical functioning compared to patients with tetraplegia (P = 0.007). CONCLUSION: lower injury level is a significant predictor of better QOL among individuals with SCI whereas other injury-related characteristics including completeness, time since injury and plegia type may not influence HR-QOL. PMID- 26622980 TI - Observation of c.260A > G mutation in superoxide dismutase 1 that causes p.Asn86Ser in Iranian amyotrophic lateral sclerosis patient and absence of genotype/phenotype correlation. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder in European populations. ALS can be sporadic ALS (SALS) or familial ALS (FALS). Among 20 known ALS genes, mutations in C9orf72 and superoxide dismutase 1 (SOD1) are the most common genetic causes of the disease. Whereas C9orf72 mutations are more common in Western populations, the contribution of SOD1 to ALS in Iran is more than C9orf72. At present, a clear genotype/phenotype correlation for ALS has not been identified. We aimed to perform mutation screening of SOD1 in a newly identified Iranian FALS patient and to assess whether a genotype/phenotype correlation for the identified mutation exists. METHODS: The five exons of SOD1 and flanking intronic sequences of a FALS proband were screened for mutations by direct sequencing. The clinical features of the proband were assessed by a neuromuscular specialist (SN). The phenotypic presentations were compared to previously reported patients with the same mutation. RESULTS: Heterozygous c.260A > G mutation in SOD1 that causes Asn86Ser was identified in the proband. Age at onset was 34 years and site of the first presentation was in the lower extremities. Comparisons of clinical features of different ALS patients with the same mutation evidenced variable presentations. CONCLUSION: The c.260A > G mutation in SOD1 that causes Asn86Ser appears to cause ALS with variable clinical presentations. PMID- 26622981 TI - Epidemiology of stroke in Shiraz, Iran. AB - BACKGROUND: Stroke is the main cause of physical disability and the second leading cause of death worldwide. Two-thirds of all strokes occur in the developing countries. Despite being preventable, stroke is increasingly becoming a major health issue in these countries. The aim of this study was to evaluate the epidemiology of stroke in Shiraz, Iran, one of the main referral centers in the southwestern part of Iran. METHODS: A cross-sectional study was conducted on all stroke patients admitted to the Namazee Hospital, affiliated to Shiraz University of Medical Sciences, between August 2010 and January 2011. Patients' demographic data, atherosclerosis risk factors, type of stroke, drug history, outcomes, and neurological signs were recorded. Chi-square test, Kolmogorov Smirnov test, t-test, and Mann-Whitney U-test were used to analyze the data. RESULTS: A total of 305 patients with stroke, aged 27-97 years (mean +/- SD = 68.33 +/- 12.99), 269 patients (88.2%) had ischemic stroke (IS) and 36 (11.8%) had hemorrhagic stroke (HS). 133 patients (43.6%) were men and 172 (56.4%) were women. 11.4% of the patients with IS and 40.6% with HS died during hospitalization, causing 12.1% death in all stroke patients [Odds ratio (Or) = 5.34, 95% Confidence intervals (CI) = 2.35-12.11]. Hypertension, ischemic heart disease, diabetes, and recurrent stroke were the most common risk factors. CONCLUSION: This study provides evidence that the epidemiology of stroke in the southwestern part of Iran may be similar to other places. However, it seems necessary and helpful to design a registration system for patients with stroke in Shiraz Namazee Hospital. PMID- 26622983 TI - Effects of carbamazepine on semen parameters in men with newly diagnosed epilepsy. AB - BACKGROUND: We investigated the effects of carbamazepine (CBZ) on semen parameters in men with newly diagnosed epilepsy, by performing semen analysis before starting any antiepileptic drugs, and then after starting CBZ, to determine the role and effects of CBZ in creating abnormalities in sperm analysis in these patients. METHODS: In this prospective study, eight male patients 20-40 years of age who were referred to the outpatient epilepsy clinic at Shiraz University of Medical Sciences, Iran, from 2009 to 2012, due to new-onset seizure(s) were studied. A semen analysis was performed. CBZ was started and after at least 3 months of taking CBZ, another semen analysis was requested to determine the changes in semen quality. Statistical analyses were performed using non-parametric Wilcoxon test. RESULTS: Mean age of the patients was 28.5 +/- 3.5 years. 7 (87.5%) patients had temporal lobe epilepsy and 1 (12.5%) had parietal lobe epilepsy. The mean follow-up period was 5.5 +/- 0.9 months. We observed that semen quality (concentration, progressive motility, morphology) has significantly changed in patients with newly-diagnosed epilepsy after being treated with CBZ (P = 0.012 for all indices). CONCLUSION: This study shows the direct effects of CBZ in causing changes in semen quality in men with epilepsy. Abnormalities in sperm concentration, morphology and motility, which were observed in the current study, might play a significant role in causing reduced fertility in men with epilepsy. PMID- 26622982 TI - Alterations in semen parameters in men with epilepsy treated with valproate. AB - BACKGROUND: Besides the well-known adverse effects of valproate (VPA), disorders related to male reproductive functions have been reported. Furthermore, only a limited number of previous studies have reported the relationship between VPA dose and impairment of the hormonal axis and semen quality. A patient with reversible changes that occurred in the sperm parameters after a dose increment of VPA. METHODS: A 34-year-old male patient who was diagnosed with juvenile myoclonic epilepsy almost 15 years ago was admitted to our clinic. His seizures responded well to high doses of VPA treatment. RESULTS: As the VPA dose was increased, consecutive semen analyses were performed and averaged for each dose; the results showed a remarkable decline in the sperm count and a manifest loss of sperm motility. VPA treatment was gradually diminished and stopped; meanwhile, treatment with another antiepileptic (lamotrigin) was initiated to control the patient's seizures. Nine months later, the patient's semen analysis was within normal ranges. After modification of the patient's treatment regimen, he and his wife had a healthy baby. CONCLUSION: We suggest that VPA-dependent impairments in the hormone and semen analysis parameters were reversible after the termination of medical treatment, and that the VPA treatment did not cause permanent hormonal deregulation and, these side effects are dose dependent. PMID- 26622984 TI - Juvenile dermatomyositis without skin lesions. PMID- 26622985 TI - Disseminated cryptococcosis and active pulmonary tuberculosis co-infection in an otherwise healthy adult. PMID- 26622986 TI - Wilson's disease presenting with unusual radiological features. PMID- 26622987 TI - Neurocinema: A brief overview. AB - Cinema is a multidimensional art capable of affecting our neurophysiologic structure in different ways. Studies show that different parts of the brain are activated while watching a structured film and consequently, the movie imitates consciousness structure. This imitation of the consciousness structure enables cinema to deeply influence the brain. The effect and its manner are the main themes of the newly-emerged science of neurocinema. PMID- 26622989 TI - Prevalence of Hepatitis B Virus Infection in Isfahan Province. AB - Hepatitis B virus (HBV) is a serious global health problem. It is estimated that 1.5-2.5 million people are suffering from this infection in Iran. A review on HBV infection prevalence in Isfahan, Iran is conducted in this article. It will help researchers for further studies and also will be helpful for control the infection. Medline, Embase, Ovid, Google Scholar, Scientific Information Database, Iranmedex, Magiran and Scientific Journal of Iran Blood Transfusion Organization and also students' thesis and projects of Isfahan and Kashan universities of medical sciences were searched for key words "HBV," "HBsAg," "prevalence," "Isfahan," "Esfahan," and "Kashan in titles and/or abstracts. Overall, 24 articles, including 4, 14, 5 and 1 were assessed in Isfahan province, and Isfahan, Kashan, and Foulad-shahr cities, respectively. The highest and lowest participants were 542705 and 73, respectively. The highest prevalence of HBsAg was reported in HIV-infected patients and the lowest one was seen in the thalassemic patients. We collected the articles about the prevalence of HBV in Isfahan to help researchers and determine prevalence HBV in Isfahan province. The similar studies in other province of Iran are necessary for marking decision. PMID- 26622988 TI - Benign and Malignant Hematological Manifestations of Chronic Hepatitis C Virus Infection. AB - Chronic hepatitis C virus (HCV) infection, that affects 3% of world's population, is associated with several hematological manifestations mainly benign cytopenias, coagulopathy and lymphoproliferative diseases. Immune or non-immune-mediated thrombocytopenia is a major challenge in chronic HCV infected patients especially in the setting of an advanced liver disease, with average prevalence of nearly 24%. Although several treatment modalities such as steroids, intravenous immunoglobulin, splenectomy and immunosuppresants have been tried with some success, their efficacy is not impressive and can result in an increase in viral load or other thrombotic complications. Even though a recent phase 2 study has shown promising role of a platelet growth factor, eltrombopag, in boosting platelets counts prior to antiviral treatment, its use in pre-operative setting had unexpected complications. Unlike thrombocytopenia, anemia and neutropenia are more frequently seen in treated patients and are often the result of antiviral therapy. HCV infection also pre-disposes to lymphoproliferative diseases, mainly non-Hodkings lymphomas, likely as a result of chronic antigenic stimulation and mutation of several genes involved in carcinogenesis. Understanding of the role of HCV infection in these conditions has therapeutic implications. Whereas antiviral therapy has shown therapeutic role in HCV-associated indolent lymphomas, monitoring of hepatic function and viral load is important in the management of diffuse large B-cell lymphoma in HCV-infected patients. Although our knowledge about the HCV infection and hematological manifestations has substantially grown in last few decades, further studies are important to advance our therapeutic approach. PMID- 26622990 TI - Prevention and Management of Chronic Hepatitis B. AB - Chronic hepatitis B virus (HBV) infection affects an estimated 370 million people worldwide. HBV is endemic throughout the world, and insidiously causes liver damage over years and decades without any warning symptoms or signs. Up to 25-35% of infected individuals eventually die due to complications of liver cirrhosis and hepatocellular carcinoma (HCC) induced by HBV. Screening those individuals at risk of acquiring hepatitis B, and universal vaccination for prevention, would help in limiting the spread and public health repercussions of the virus. Although many new antiviral therapies have been developed for the management of hepatitis B, they still do not offer the possibility of cure. Most individuals who begin oral suppressive therapy will be indefinitely treated. Continuous suppression of HBV replication in individuals with advanced liver disease prolongs life, decreases the need for liver transplantation, and potentially reduces the risk for HCC. In this clinical review, we present a practical approach to prevention of HBV, its natural history and life cycle, as well as its management. PMID- 26622991 TI - Hepatitis A Seropositivity among First-Year Students of the Medical University in Isfahan, Iran. AB - BACKGROUND: Students of medicine are prone to contact with various infectious agents such as hepatitis A virus (HAV). Infection with HAV may lead to morbidity and in rare cases, mortality. We evaluated the seroprevalence of HAV among 1(st) year medical students to assess the necessity of vaccination/preventive immunoglobulin in this at-risk population. METHODS: This cross-sectional study was carried out in 2007 among 403 1(st)-year medical students in Isfahan, Iran. Participants filled out a questionnaire including items on demographic characteristics, medical history, and hygiene. Then, the anti-HAV IgG antibody was assessed using the ELISA method (Diagnostic Bioprobes, Dia-Pro, Milan, Italy). RESULTS: Among the 403 students invited to attend the study, 361 ones (89.5%) agreed to participate (61.1% female), with a mean age of 19.8 +/- 2.6 years. Of the participants, 272 (75.3%) students were seropositive. Seropositivity was not associated with gender (P = 0.222), but was associated with the number of family members (P < 0.001), residence place (P = 0.003), age (P < 0.001), and the type of drinking water (P = 0.008). CONCLUSIONS: One of the four medical college students of our society is prone to hepatitis A infection. Accordingly, vaccination/preventive immunoglobulin is suggested for this population; however, whether a prior serological screening is cost-effective needs further evaluation by epidemiologic data from our society. PMID- 26622992 TI - Hepatitis B surface antigen prevalence in pregnant women: A cross-sectional survey in Iran. AB - BACKGROUND: Vertical transmission of hepatitis B virus (HBV) from infected mothers to their neonates is one of the most important routes of infection. The exact prevalence rate of HBV in Iranian pregnant mothers is not well known but based on different studies it is estimated between 0.35% and 6.5%. The aim of this study was to determine the seroprevalence of hepatitis B surface antigen (HBsAg) in pregnant women of selected provinces in Iran. METHODS: At this cross sectional study, seven provinces supposed to be of high and low prevalence of hepatitis B in the general population selected. Multistage sampling was used to enroll 5261 parturient women who attended the target provinces birth facilities, during January to March of 2011, were recruited to study. To determine the statistically significant mean and proportion differences, t-test and chi (2) test were used, respectively. RESULTS: Overall 1.2% was positive HBsAg of which 11% of them were hepatitis B e-antigen positive as well. The eastern and north eastern provinces were considerably higher in HBsAg seropositivity than the west and northwest of the country. CONCLUSIONS: In view of the considerable prevalence of hepatitis B in pregnant women, screening all pregnant women prioritizing the eastern and north-eastern provinces is strongly recommended. PMID- 26622993 TI - Hepatitis G virus exposure in dialysis patients and blood donors in Isfahan-Iran. AB - BACKGROUND: Hepatitis G virus (HGV) is transmitted mainly by parenteral route and patients on maintenance hemodialysis (HD) are at risk for this infection. This study was conducted to estimate prevalence of infection through the presence of anti-HGV and to evaluate the clinical significance of HGV envelope protein E2 (anti-E2) in HD patients in compare with volunteer blood donors in Isfahan-Iran. METHODS: In a cross-sectional study, a total of 40 HD patients as cases and 40 healthy volunteer blood donors as negative controls were selected randomly in summer 2008. The epidemiological data were obtained in all subjects, and duration of HD was obtained in HD patients as well. All samples were tested for anti-E2 antibodies, hepatitis C virus (HCV)-antibody and hepatitis B virus surface antigen (HBs-Ag) by an enzyme-linked immunosorbent assay and a recombinant immunoblot assay was employed to confirm anti-HCV reactivity. Student's t-test, Chi-square test or Fisher exact test was used for data analysis and P < 0.05 was considered as statistically significant. RESULTS: Ten of the 40 HD patients tested positive for anti-E2 (25%) and of 40 voluntary blood donors, 10 (5%) were positive for anti-E2 (P = 0.012). Anti-HCV antibodies and HBs-Ag were found in 4 and 1 HD patients, respectively. In anti-E2-positive patients, co-infection with HCV or hepatitis B virus was not significant. Furthermore, the mean duration of hemodialysis in anti-E2 positive and anti-E2 negative patients did not have significant differences. CONCLUSIONS: HD patients are at increased risk of HGV infection in Isfahan-Iran. Since hepatitis G is a good predictor for parenteral transmission, it is suggested to test all of the blood for transfusion for HGV infection. PMID- 26622995 TI - Hepatitis E: Risk and Prevention. PMID- 26622994 TI - The Seroprevalence of Hepatitis B in Akbar Abad Village, Kavar, Southern Iran. AB - BACKGROUND: About 2 billion people were reported to be infected with hepatitis B virus (HBV) and among them; 350 million are chronically infected cases. This study was performed to determine the prevalence of hepatitis B in Kavar, southern Iran. METHODS: From August 2008 to March 2009, 3739 individuals aged between 1 and 88 years were screened for infection with HBV in Akbar Abad Village, Kavar, Southern Iran. A questionnaire was used to record demographic data, history of vaccination and the correlated risk factors. Ten milliliter of the blood sample was taken from each subject. Sera were checked for hepatitis B surface antigen (HBs Ag) and hepatitis B core antibody (HBC Ab). RESULTS: Among subjects, 7.1% were positive for HBC Ab and 2.2% for HBS Ag. Out of positive cases for HBC Ab, 7.3% were female, and 7.6% were male. Out of positive cases for HBS Ag, 2.2% were female, and 2.5% were male. The minimal rates of HBC Ab and HBS Ag were noticed in the age group 1-15 year old. The highest positivity was observed among unemployed individuals. Among subjects with low educational level, 7.5% were positive for HBC Ab and 2.4% for HBS Ag. The highest prevalence was visible in the widow group and the lowest in married persons. Opium addiction had a significant relationship with HBC Ab. The prevalence of HBV seropositivity was higher among drivers, those with a history of dental treatments and family history of liver diseases blood transfusion tattooing recipients. CONCLUSIONS: Our results showed that screening of pregnant women for HBs Ag and vaccination of high-risk individuals including family members of patients with hepatitis B should be implemented in future planning. PMID- 26622996 TI - The evolving role of biosimilars in haematology-oncology: a practical perspective. AB - The loss of patents covering many biopharmaceutical/biological agents in the mid 1990s led to the introduction of a new generation of drugs: biosimilars. These new agents, produced by living cells just as the originator drugs, are chemically highly similar to endogenous human proteins; characterized by three-dimensionally complex, high molecular weight compounds. Among the first biosimilars used in haematology-oncology were erythropoietin and granulocyte colony-stimulating factor. After five years of use in clinical practice, the efficacy and safety profile of biosimilars approved by the European Medicines Agency is excellent. Over the next year or two, biosimilar monoclonal antibodies (MoAbs) will become available; the first will be rituximab and trastuzumab. Not only are MoAbs more complex in terms of molecular weight and number of amino acids than the first biosimilars, but they are also anticancer drugs, not merely supportive treatments like their predecessors. This opens up important questions. How are regulatory agencies to assess their clinical efficacy, immunogenicity and safety? Is the neoadjuvant clinical setting the best to evaluate them? What will regulatory agencies decide in terms of switching an originator molecule for a biosimilar or extrapolating efficacy results from one pathology to another? Once biosimilars of rituximab and trastuzumab are approved, several challenging issues will need to be addressed such as how to maintain appropriate pharmacovigilance, how to extrapolate across indications, and issues concerning automatic substitution. There is currently no consensus in any of these areas. This review addresses all these issues: new challenges that the oncology community will face in the near future. PMID- 26622997 TI - Recent advances in the development of Aurora kinases inhibitors in hematological malignancies. AB - Over the last two decades, since the discovery of Drosophila mutants in 1995, much effort has been made to understand Aurora kinase biology. Three mammalian subtypes have been identified thus far which include the Aurora A, B and C kinases. These regulatory proteins specifically work at the cytoskeleton and chromosomal structures between the kinetochores and have vital functions in the early phases of the mitotic cell cycle. Today, there are multiple phase I and phase II clinical trials as well as numerous preclinical studies taking place looking at Aurora kinase inhibitors in both hematologic and solid malignancies. This review focuses on the preclinical and clinical development of Aurora kinase inhibitors in hematological malignancy and discusses their therapeutic potential. PMID- 26622999 TI - Characteristics and survival of BCR/ABL negative chronic myeloid leukemia: a retrospective analysis of the Surveillance, Epidemiology and End Results database. PMID- 26622998 TI - Adoptive T-cell therapies for refractory/relapsed leukemia and lymphoma: current strategies and recent advances. AB - Despite significant advancements in the treatment and outcome of hematologic malignancies, prognosis remains poor for patients who have relapsed or refractory disease. Adoptive T-cell immunotherapy offers novel therapeutics that attempt to utilize the noted graft versus leukemia effect. While CD19 chimeric antigen receptor (CAR)-modified T cells have thus far been the most clinically successful application of adoptive T immunotherapy, further work with antigen specific T cells and CARs that recognize other targets have helped diversify the field to treat a broad spectrum of hematologic malignancies. This article will focus primarily on therapies currently in the clinical trial phase as well as current downfalls or limitations. PMID- 26623001 TI - Effects on lipid profile of supplementation with vitamin D in type 2 diabetic patients with vitamin D deficiency. AB - BACKGROUND: Epidemiological studies suggest that vitamin D status may have an influence on lipid profile. PATIENTS AND METHODS: We studied consecutive type 2 diabetic patients with vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) lower than 20 ng/ml). They were treated with 16,000 IU of calcifediol orally once a week for a minimum of 8 weeks. RESULTS: A total of 28 patients were treated for a mean time of 84.1 days (range 56-120 days). All patients achieved serum levels of 25(OH)D higher than 20 ng/ml. There was significant reduction in total cholesterol (172.1 +/- 32.4 versus 164.4 +/- 27.3 mg/dl, p = 0.04). There were nonsignificant reductions in low-density lipoprotein (LDL) cholesterol, non-high density lipoprotein (non-HDL) cholesterol and triglycerides. There was no change in HDL cholesterol. CONCLUSIONS: Correction of vitamin D deficiency in type 2 diabetic patients decreases total cholesterol. Our results do not rule out reductions in LDL cholesterol, non-HDL cholesterol and triglycerides. PMID- 26623002 TI - Vitamin D as a risk factor for premature atherosclerosis in patients with type 2 diabetes. AB - BACKGROUND: Several cardiovascular risk factors have been recognized in patients with diabetes and vitamin D deficiency is emerging as a new risk. The aim of this study was to determine the effect of vitamin D deficiency on the incidence of premature atherosclerosis in patients with type 2 diabetes. METHODS: A total of 78 patients with type 2 diabetes were subjected to history taking, physical examination, fasting glucose level, homeostasis model assessment of insulin resistance, lipid profile, 25(OH) vitamin D measurement, and carotid Doppler. RESULTS: Patients with normal carotid intima-media thickness (CIMT) had sufficient vitamin D. Of those with increased CIMT 23.1% had insufficient vitamin D while 76.9% had sufficient vitamin D (six patients had plaques, one of them had vitamin D insufficiency, and the other five patients had sufficient vitamin D). There was a statistically significant difference in the serum level of vitamin D between patients with increased CIMT, and those with normal intima, with a decreased level in the first group. There was a significant negative correlation between vitamin D and fasting blood glucose. There was a statistically significant correlation in left CIMT between the vitamin D sufficiency group and the vitamin D insufficiency group, with higher values in the second group. There was no statistically significant difference in serum cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol in patients with increased CIMT and those with normal intima. CONCLUSIONS: Decreased vitamin D levels in patients with diabetes lead to increased CIMT. The absence of a statistically significance difference in lipid profile between increased and normal CIMT groups raises the possibility of underlying causes for atherosclerosis in patients with diabetes other than dyslipidemia. PMID- 26623003 TI - Comparison of conventional risk factors in middle-aged versus elderly diabetic and nondiabetic patients with myocardial infarction: prediction with decision analytic model. AB - BACKGROUND: We sought to predict occurrence of myocardial infarction (MI) by means of a classification and regression tree (CART) model by conventional risk factors in middle-aged versus elderly (age ?65years) diabetic and nondiabetic patients from the Modares Heart Study. METHOD: A total of 469 patients were randomly selected and categorized into two groups according to clinical diabetes status. Group I consisted of 238 diabetic patients and group II consisted of 231 nondiabetic patients. Our population was MI positive. The outcome investigated was diabetes mellitus. We used a decision-analytic model to predict the diagnosis of patients with suspected MI. RESULTS: We constructed 4 predictive patterns using 12 input variables and 1 output variable in terms of their sensitivity, specificity and risk. The differences among patterns were due to inclusion of predictor variables. The CART model suggested different variables of hypertension, mean cell volume, fasting blood sugar, cholesterol, triglyceride and uric acid concentration based on middle-aged and elderly patients at high risk for MI. Levels of biochemical measurements identified as best risk cutoff points. In evaluating the precision of different patterns, sensitivity and specificity were 47.9-84.0% and 56.3-93.0%, respectively. CONCLUSIONS: The CART model is capable of symbolizing interpretable clinical data for confirming and better prediction of MI occurrence in clinic or in hospital. Therefore, predictor variables in pattern could affect the outcome based on age group variable. Hyperglycemia, hypertension, hyperlipidemia and hyperuricemia were serious predictors for occurrence of MI in diabetics. PMID- 26623004 TI - Pregnancy in acromegaly. AB - With advances in surgical and medical treatment and the availability of assisted reproductive techniques, pregnancy in women with acromegaly is more frequently encountered. Diagnosis of acromegaly during pregnancy is difficult because of changes in growth hormone and insulin like growth factor-1 (IGF-1) axis secondary to placental production of growth hormone. The difficulty is compounded by the inability of routine hormone assays to detect placental growth hormone. In the majority of patients with acromegaly, pregnancy does not have an adverse effect on mother or fetus and pituitary mass does not increase in size. The level of IGF 1 usually remains stable because of the effect of estrogen causing a growth hormone resistant state. In patients with pituitary macroadenoma, the possibility of an increase in size of the pituitary mass needs to be kept in mind and more frequent monitoring is required. In case of tumor enlargement, pituitary surgery can be considered in the mid trimester. Experience with the use of medical treatment for acromegaly during pregnancy is increasing. Dopamine agonists, somatostatin analogs or growth hormone receptor antagonists have been used without any adverse consequences on mother or fetus. At present, it is advisable to stop any medical treatment after confirmation of pregnancy till more data are available on the safety of these drugs. PMID- 25949807 TI - Behavioural evidence for self-medication in bumblebees? AB - The presence of antimicrobial secondary metabolites in nectar suggests that pollinators, which are threatened globally by emergent disease, may benefit from the consumption of nectars rich in these metabolites. We tested whether nicotine, a nectar secondary metabolite common in Solanaceae and Tilia species, is used by parasitized bumblebees as a source of self-medication , using a series of toxicological, microbiological and behavioural experiments. Caged bees infected with Crithidia bombi had a slight preference for sucrose solution laced with the alkaloid and behavioural tests showed that the parasite infection induced an increased consumption of nicotine during foraging activity, though nicotine had an appetite-reducing effect overall. When ingested, nicotine delayed the progression of a gut infection in bumblebees by a few days, but dietary nicotine did not clear the infection, and after 10 days the parasite load approached that of control bees. Moreover, when pathogens were exposed to the alkaloid prior to host ingestion, the protozoan's viability was not directly affected, suggesting that anti-parasite effects were relatively weak. Nicotine consumption in a single dose did not impose any cost even in starved bees but the alkaloid had detrimental effects on healthy bees if consistently consumed for weeks. These toxic effects disappeared in infected bees, suggesting that detoxification costs might have been counterbalanced by the advantages in slowing the progression of the infection. Nicotine consumption did not affect bee lifespan but the reduction in the parasite load may have other likely unexplored subtle benefits both for individual bees and their colony. Potential evidence for self-medication is discussed. The contention that secondary metabolites in nectar may be under selection from pollinators, or used by plants to enhance their own reproductive success, remains to be confirmed. PMID- 26623005 TI - The obesity of bone. AB - During the last decades, obesity and osteoporosis have become important global health problems, and the belief that obesity is protective against osteoporosis has recently come into question. In fact, some recent epidemiologic and clinical studies have shown that a high level of fat mass might be a risk factor for osteoporosis and fragility fractures. Several potential mechanisms have been proposed to explain the complex relationship between adipose tissue and bone. Indeed, adipose tissue secretes various molecules, named adipokines, which are thought to have effects on metabolic, skeletal and cardiovascular systems. Moreover, fat tissue is one of the major sources of aromatase, an enzyme that synthesizes estrogens from androgen precursors, hormones that play a pivotal role in the maintenance of skeletal homeostasis, protecting against osteoporosis. Moreover, bone cells express several specific hormone receptors and recent observations have shown that bone-derived factors, such as osteocalcin and osteopontin, affect body weight control and glucose homeostasis. Thus, the skeleton is considered an endocrine target organ and an endocrine organ itself, likely influencing other organs as well. Finally, adipocytes and osteoblasts originate from a common progenitor, a pluripotential mesenchymal stem cell, which has an equal propensity for differentiation into adipocytes or osteoblasts (or other lines) under the influence of several cell-derived transcription factors. This review will highlight recent insights into the relationship between fat and bone, evaluating both potential positive and negative influences between adipose and bone tissue. It will also focus on the hypothesis that osteoporosis might be considered the obesity of bone. PMID- 25713698 TI - Subdivisions of the adult zebrafish pallium based on molecular marker analysis. AB - BACKGROUND: The telencephalon shows a remarkable structural diversity among vertebrates. In particular, the everted telencephalon of ray-finned fishes has a markedly different morphology compared to the evaginated telencephalon of all other vertebrates. This difference in development has hampered the comparison between different areas of the pallium of ray-finned fishes and the pallial nuclei of all other vertebrates. Various models of homology between pallial subdivisions in ray-finned fishes and the pallial nuclei in tetrapods have been proposed based on connectional, neurochemical, gene expression and functional data. However, no consensus has been reached so far. In recent years, the analysis of conserved developmental marker genes has assisted the identification of homologies for different parts of the telencephalon among several tetrapod species. RESULTS: We have investigated the gene expression pattern of conserved marker genes in the adult zebrafish ( Danio rerio) pallium to identify pallial subdivisions and their homology to pallial nuclei in tetrapods. Combinatorial expression analysis of ascl1a, eomesa, emx1, emx2, emx3, and Prox1 identifies four main divisions in the adult zebrafish pallium. Within these subdivisions, we propose that Dm is homologous to the pallial amygdala in tetrapods and that the dorsal subdivision of Dl is homologous to part of the hippocampal formation in mouse. We have complemented this analysis be examining the gene expression of emx1, emx2 and emx3 in the zebrafish larval brain. CONCLUSIONS: Based on our gene expression data, we propose a new model of subdivisions in the adult zebrafish pallium and their putative homologies to pallial nuclei in tetrapods. Pallial nuclei control sensory, motor, and cognitive functions, like memory, learning and emotion. The identification of pallial subdivisions in the adult zebrafish and their homologies to pallial nuclei in tetrapods will contribute to the use of the zebrafish system as a model for neurobiological research and human neurodegenerative diseases. PMID- 26594341 TI - NetMatchStar: an enhanced Cytoscape network querying app. AB - We present NetMatchStar, a Cytoscape app to find all the occurrences of a query graph in a network and check for its significance as a motif with respect to seven different random models. The query can be uploaded or built from scratch using Cytoscape facilities. The app significantly enhances the previous NetMatch in style, performance and functionality. Notably NetMatchStar allows queries with wildcards. PMID- 26623009 TI - Reported incidence of fever for under-5 children in Zambia: a longitudinal study. AB - BACKGROUND: Childhood fever is the most common clinical sign of Plasmodium falciparum infection. It is used as a measure of burden of the disease and the effectiveness of control programs for malaria. This study aimed to determine the incidence of fever in under-5 children of Magoye and Chivuna rural areas of Mazabuka district, Zambia. METHODS: Incidence of fever was evaluated longitudinally over a period of 16 months (July 2006 and November 2007) among children aged 12-59 months in Magoye and Chivuna rural communities. The data was collected for a study on community directed treatment of soil-transmitted helminth infections in under-five children. Data from caretakers of 1221 children were collected using a structured interviewer-administered questionnaire. Cox proportion hazard regression was used to determine predictors of multiple episodes of fever and Kaplan-Meier survival curves was used to compare survival between two groups. RESULTS: A total of 1221 under-5 children [median age 32 months; IQR 12-58] participated in the study and 696 (57 %) were from Magoye and 525 (43 %) from Chivuna. The incidence rate of fever was 162.4 per month per 1000 children for the 16 months period. The proportion of fever was not statistically related to children' age [p = 0.779] and sex [p = 0.546]. Predictors of multiple episodes of fever were: age (37-48 vs. 12-24 months) [HR 0.81; 95 % CI 0.67, 0.98; p = 0.030]; location (Chivuna vs. Magoye) [HR 1.35; 95 % CI 1.17, 1.56; p < 0.001]; and season (dry vs. rainy) [HR 0.17; 95 % CI 0.12, 0.23; p < 0.001]. CONCLUSION: The study has shown that the incidence of fever was high in the study areas. Febrile illnesses like malaria still have a significant effect on the health of under-5 children in the study population. There still exists the need for interventions aimed at reducing the incidence of fever in under five children, more especially in rural areas. PMID- 26623010 TI - Diagnostic markers of acute myocardial infarction. AB - Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. The highest risk of fatality occurs within the initial hours of onset of AMI. Thus, early diagnosis of cardiac ischemia is critical for the effective management of patients with AMI. Improper diagnosis of patients with chest pain often leads to inappropriate admission of patients without AMI and vice versa. In addition to clinical history, physical examination, accurate electrocardiogram findings and assessment of cardiac biomarkers have an important role in the early diagnosis of acute ischemia. The present review discusses in detail the various cardiac biomarkers released during the event of an AMI. PMID- 26623011 TI - Application of the cell sheet technique in tissue engineering. AB - The development and application of the tissue engineering technique has shown a significant potential in regenerative medicine. However, the limitations of conventional tissue engineering methods (cell suspensions, scaffolds and/or growth factors) restrict its application in certain fields. The novel cell sheet technique can overcome such disadvantages. Cultured cells can be harvested as intact sheets without the use of proteolytic enzymes, such as trypsin or dispase, which can result in cell damage and loss of differentiated phenotypes. The cell sheet is a complete layer, which contains extracellular matrix, ion channel, growth factor receptors, nexin and other important cell surface proteins. Mesenchymal stem cells (MSCs), which have the potential for multiple differentiation, are promising candidate seed cells for tissue engineering. The MSC sheet technique may have potential in the fields of regenerative medicine and tissue engineering in general. Additionally, induced pluripotent stem cell and embryonic stem cell-derived cell sheets have been proposed for tissue regeneration. Currently, the application of cell sheet for tissue reconstruction includes: Direct recipient sites implantation, superposition of cell sheets to construct three-dimensional structure for implantation, or cell sheet combined with scaffolds. The present review discusses the progress in cell sheet techniques, particularly stem cell sheet techniques, in tissue engineering. PMID- 26623012 TI - Non-pathogenic microflora of a spring water with regenerative properties. AB - The Comano spring water (Comano, Italy) has been demonstrated to improve skin regeneration, not only by increasing keratinocyte proliferation and migration, but also by modulating the regenerated collagen and elastic fibers in the dermis. However, such biological properties may not be entirely explained by its mineral composition only. As the non-pathogenic bacterial populations have demonstrated an active role in different biological processes, the potential presence of non pathogenic bacterial species within the Comano spring water was investigated in order to identify any possible correlation between these bacterial populations and the demonstrated biological properties of this water. The water was collected at the spring using an aseptic procedure and multiple cultures were carried out. A total of 9 different strains were isolated, which were Aeromonas hydrophila, Brevundimonas vesicularis, Chromobacterium violaceum, Citrobacter youngae, Empedobacter brevis, Pantoea agglomerans, Pseudomonas putida, Pseudomonas stutzeri and Streptococcus mitis. All the isolated bacterial strains, although showing a rare potential virulence, demonstrated peculiar and favorable metabolic attitudes in controlling environmental pollution. The therapeutical effects of certain spring waters are currently being proven as correlated not only to their peculiar mineral composition, but also to the complex activity of their resident non-pathogenic bacterial populations. Although the present study provided only preliminary data, some of the non-pathogenic bacterial populations that were identified in the Comano spring water are likely to produce molecular mediators with a role in the wound healing process that, thus far, remain unknown. Numerous other unknown bacterial species, comprehensively termed DNA-rich 'dark matter', are likely to contribute to the Comano water regenerative properties as well. Therefore, the non-pathogenic bacterial populations of the Comano spring water are possibly credited for its demonstrated regenerative properties. PMID- 26623013 TI - Tripterygium glycosides inhibit inflammatory mediators in the rat synovial RSC 364 cell line stimulated with interleukin-1beta. AB - Tripterygium glycosides (TG) are extracted from a traditional Chinese medicinal herb. Using the compound, progress has been made in the treatment of rheumatoid arthritis (RA), but the underlying mechanism of its action is poorly understood. The purpose of the present study was to investigate the role of TG in preventing inflammatory arthritis. An inflammatory cell model was established in the rat synovial RSC-364 cell line via induction with interleukin (IL)-1beta. The expression of IL-32 and matrix metalloproteinases (MMP-1 and MMP-9) was determined using an enzyme-linked immunosorbent assay. Compared with the control group (without IL-1beta), IL-1beta in the treatment group induced the expression of IL-32, MMP-1 and MMP-9 in RSC-364 cells. When a different dose of TG was added to RSC-364 cells stimulated with IL-1beta, TG decreased the expression levels of IL-32, MMP-1 and MMP-9 in a dose-dependent manner. These results indicated that TG suppressed the inflammation response in RSC-364 cells. Taken together, these findings may contribute to a better understanding of the role of TG in the anti inflammatory therapeutics for RA. PMID- 26623014 TI - Age-related changes in clinical parameters and their associations with common complex diseases. AB - The aim of the present study was to clarify the age-related changes in 13 clinical parameters and their associations with common complex diseases. Study subjects comprised 6,027 community-dwelling individuals who were recruited to a population-based longitudinal genetic epidemiological study. Bonferroni's correction was applied to compensate for multiple comparisons of association and P<0.0011 was considered statistically significant. Body mass index and waist circumference increased with age up to ~50 years and decreased thereafter in men, whereas the two parameters increased linearly with age in women. The prevalence of obesity was highest (41.1%) in men aged 40-49 years, after which it decreased with age. The prevalence of obesity in women increased with age to <=32.2% in those aged >=70 years. Systolic and mean blood pressure (BP), as well as pulse pressure, increased linearly with age in all subjects, whereas diastolic BP increased with age up to ~60 years and subsequently decreased. The prevalence of hypertension increased with age to <=69.9 or 68.5% at age >=70 years in men and women, respectively. The fasting plasma glucose level, blood hemoglobin A1c content and the prevalence of type 2 diabetes mellitus increased gradually with age in men and women. The serum triglyceride concentration increased with age up to ~50 years and decreased thereafter in men, whereas it increased linearly with age in women. The prevalence of hypertriglyceridemia increased to a peak of 56.8% at age 50-59 years and subsequently decreased in men, whereas in women it increased with age to <=34.9% at >=70 years. The serum high-density lipoprotein (HDL)-cholesterol concentration increased with age up to ~50 years and decreased thereafter in women. The prevalence of hypo-HDL-cholesterolemia increased gradually with age in women. The serum concentration of low-density lipoprotein (LDL)-cholesterol increased with age up to ~50 years and subsequently declined in men, whereas it increased linearly with age in women. The prevalence of hyper-LDL cholesterolemia increased with age to <=53.4% at 50-59 years in men and <=63.9% at 60-69 years in women and it decreased thereafter in the two genders. The serum creatinine concentration and the estimated glomerular filtration rate increased or decreased linearly with age, respectively. The prevalence of chronic kidney disease (CKD) increased with age to <=45.1 or 39.6% at >=70 years in men and women, respectively. Therefore, these results indicate that 13 clinical parameters, as well as the prevalence of obesity, hypertension, type 2 diabetes mellitus, dyslipidemia and CKD, were significantly associated with age. They may therefore prove informative for the prevention of these diseases and contribute to the achievement of a healthy long life and successful aging. PMID- 26623015 TI - Suppression of the increasing level of acetylcholine-stimulated intracellular Ca2+ in guinea pig airway smooth muscle cells by mabuterol. AB - The present study aimed to establish an effective method for the in vitro culture of guinea pig airway smooth muscle (ASM) cells, and also investigate the suppressive effect of mabuterol hydrochloride (Mab) on the increased level of intracellular Ca2+ in ASM cells induced with acetylcholine (Ach). Two different methods, i.e. with or without collagenase to pretreat tracheal tissues, were applied to the manufacture of ASM cells. Cell viability was determined with the 3 (4,5-dimethylthinazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Immunocytochemistry and immunofluorescence were used for the identification of ASM cells. Different concentration levels (10-3, 10-4, 10-5, 10-6 and 10-7 mmol/l) of Mab were administered 5 min before Ach (10-4 M) treatment, respectively. The Ca2+ fluorescent probe, Fura-2/AM or Fluo-3/AM were applied to the inspection of Ca2+ fluorescent intensity with Varioskan Flash, immunocytometry systems and an inverted system microscope, respectively. The results showed that the fresh method, in which isolated tracheal tissues were previously treated with collagenase for 20 min, was more advantageous for the preparation of guinea pig ASM cells compared to when the enzyme was not used. The time for the ASM cells to initially migrate out of the 'tissue blocks' and the culture having to be generated due to the thick cell density was significantly less. On identification with immunocytochemistry or immunofluorescent staining, >95% of the cells were ASM cells. Mab (10-3-10-7 mmol/l) significantly suppressed the elevation of intracellular Ca2+ induced by Ach in a concentration-dependent manner. The inhibitory rates of intracellular Ca2+ by different concentrations of Mab, from low to high, were 14.93, 24.73, 40.06, 48.54 and 57.13%, respectively, when Varioskan Flash was used for determination. In conclusion, this novel method has a shorter harvesting period for ASM cells. Mab can suppress the increasing level of intracellular Ca2+ induced by Ach in guinea pig ASM cells. Further investigation into the precise mechanisms of action is required. PMID- 26623016 TI - Supplemental fermented plant product ('Manda Koso') reduces succinate and deoxycholate, as well as elevates IgA and mucin levels, in rats fed a high-fat diet. AB - 'Manda Koso' is a commercial fermented plant product (FPP) made from 53 types of fruits and vegetables that have been fermented for >3 years and 3 months. We hypothesized that FPP intake improves the luminal environment of rats fed a high fat diet. Thus, the present study examined the effects of consumption of 5% FPP diet for 3 weeks on colonic luminal parameters in rats fed a 30% beef tallow diet. Food intake and body weight gain were unaffected. Consumption of the FPP diet did not influence the proportions of Bifidobacterium, Lactobacillus, Bacteroides, Prevotella or Clostridium in cecal contents. However, the FPP diet caused a significant reduction (-88%) in the level of cecal succinate, a putative inflammatory signal (P<0.01), but did not affect the levels of n-butyrate, propionate, acetate and lactate. The fecal levels of deoxycholate and hyodeoxycholate, which are toxic bile acids, were also significantly reduced by the FPP diet (P<0.05). The FPP diet significantly increased fecal immunoglobulin A and mucins responsible for intestinal immune and barrier functions (P<0.05). The results suggest that the consumption of FPP is beneficial for the colonic luminal environment in rats fed a high-fat diet. PMID- 26623017 TI - Quantification of preeclampsia-related microRNAs in maternal serum. AB - To identify the specific serum preeclampsia (PE)-related biomarkers, 10 microRNAs (miRNAs) were selected based on their reported aberrant (4 upregulated and 6 downregulated) expression in PE placenta. A total of 1,035 pregnant patients were enrolled. Finally, 32 pregnancies with PE and 32 healthy pregnancies were incorporated in the study. The expression of these 10 miRNAs in the different trimesters was determined by SYBR-Green reverse transcription-quantitative polymerase chain reaction. Compared with that in the healthy controls, the expression levels of miR-152, miR-183 and miR-210 in PE serum were higher in the second and third trimester, whereas the expression of miR-182 was only higher in the third trimester. The expression levels of 6 miRNAs (miR-1, miR-328, miR-363, miR-377, miR-500 and miR-584) that were downregulated in PE placenta showed no significant differences between pregnancies complicated by PE and healthy pregnancies throughout the 3 trimesters. Areas under the receiver operating characteristic [standard error (SE)] during the 20-24th gestational week for predicting PE were miR-152: 0.94 (SE, 0.026), miR-183: 0.97 (SE, 0.031) and miR 210: 0.93 (SE, 0.018). In conclusion, the expression levels of serum miR-152, miR 183 and miR-210 were elevated since the second trimester in pregnancies complicated with PE, indicating their potentials as serum biomarkers for forecasting PE. PMID- 26623018 TI - Bortezomib and belinostat inhibit renal cancer growth synergistically by causing ubiquitinated protein accumulation and endoplasmic reticulum stress. AB - There is no curative treatment for advanced renal cancer, and a novel treatment approach is urgently required. Inducing ubiquitinated protein accumulation and endoplasmic reticulum (ER) stress has recently emerged as a new approach in the treatment of malignancies. In the present study, we hypothesized that the histone deacetylase inhibitor belinostat would increase the amount of unfolded proteins in cells by inhibiting heat-shock protein (HSP) 90, and that the proteasome inhibitor bortezomib would inhibit their degradation by inhibiting the proteasome, thus causing ubiquitinated protein accumulation and ER stress synergistically. The combination of bortezomib and belinostat induced significant increases in apoptosis and inhibited renal cancer growth synergistically (combination indexes <1). The combination also suppressed colony formation significantly (P<0.05). As co-treatment with the pan-caspase inhibitor Z-VAD-FMK changed the number of Annexin V-positive cells, this combination-induced apoptosis was considered caspase dependent. Mechanistically, the combination synergistically caused ubiquitinated proteins to accumulate and induced ER stress, as evidenced by the increased expression of glucose-regulated protein 78 and HSP70. To the best of our knowledge, this is the first study demonstrating the beneficial combined effect of bortezomib and belinostat in renal cancer cells. The study provides a basis for clinical studies with the combination in patients with advanced renal cancer. PMID- 26623019 TI - Effect of electroconvulsive stimulation on messenger RNA expression in the prefrontal cortex in a rat pain model. AB - Previous reports have shown that electroconvulsive therapy (ECT) is efficacious in the treatment of neuropathic pain; however, its mechanism of action remains unclear. The present study aimed to understand these mechanisms by investigating the alterations in the expression of neuropeptide Y (NPY) and interleukin-1beta (IL-1beta) in the prefrontal cortex. A rat model of neuropathic pain produced by chronic constrictive injury of the sciatic nerve was used, and mechanical and thermal hyperalgesia were evaluated starting 2 days after the injury. Using a pulse generator, ECT was administered to the rodents for 6 days from days 7-12 after the injury. Thermal and mechanical stimulation were administered to assess pain thresholds. Quantitative polymerase chain reaction, used to measure gene expression levels in the prefrontal cortex, showed that NPY and IL-1beta gene expression levels in the prefrontal cortex increased following the injury. The present results indicate that these gene expression level variations may be associated with the mechanisms underlying the effect of ECT in treating neuropathic pain. PMID- 26623020 TI - Effects of curcumin on ovarian ischemia-reperfusion injury in a rat model. AB - Ischemia-reperfusion injury is a significant problem following reperfusion treatment for ovarian torsion. It is generally caused by reactive oxygen species induced damage. Antioxidant agents, such as curcumin, may protect ovaries from this adverse effect. The aim of the present randomized, controlled study was to evaluate the short-term protective effect of curcumin on a rat model of ovarian ischemia-reperfusion injury. A total of 30 female Wistar albino rats, weighing 160-230 g, were divided into 2 groups depending upon the time of unilateral, left ovary ischemia/reperfusion (group 1, 2 h ischemia/2 h reperfusion and group 2, 4 h ischemia/4 h reperfusion). These groups were subdivided into 3 subgroups (sham, control and curcumin). The sham subgroups were not subjected to ischemia/reperfusion. Control and curcumin subgroups were performed under ischemia for 2 h plus 2 h reperfusion or 4 h ischemia plus 4 h reperfusion. Curcumin, 200 mg/kg, was intraperitoneally administered simultaneously with reperfusion to the curcumin subgroups. Serum nitric oxide (NO), NO synthase (NOS), xanthine oxidase (XO), total antioxidant status (TAS), total oxidant status (TOS) and histological scores were measured and compared between subgroups. For group 1, no significant differences were observed between NO, NOS, XO, TAS or TOS. The left ovary histological grade was significantly higher in the control and curcumin subgroups compared with the sham subgroup (P=0.036). For group 2, TOS was significantly higher in the control group compared with the sham and curcumin groups (P=0.023). However, TAS was also significantly higher in the control subgroup compared with the other 2 subgroups (P=0.005). Left ovary histological grade was significantly higher in the control and curcumin subgroups compared with the sham subgroup (P=0.038). No significant differences were observed between NO, NOS or XO between the group 2 subgroups. The results showed that curcumin exerted no major significant protective effect on ischemia reperfusion injury in the rat ovary. PMID- 26623022 TI - Measurement of interleukins in vitreous infusion fluid. AB - Measurements of interleukin (IL)-6 and -10 concentrations in the vitreous can be used to differentiate intraocular lymphoma (IOL) from uveitis. This is the first study reporting the IL-6 and -10 concentrations in the undiluted vitreous fluid and vitreous infusion fluid, which were simultaneously examined in the patients. A total of 2 females presented with intraocular inflammation, and underwent pars plana vitrectomy. Undiluted anterior vitreous and vitreous infusion fluid were collected simultaneously. IL concentrations were determined by enzyme-linked immunosorbent assay systems. Vitreous infusion fluid of 20 ml was eventually collected following completion of core vitrectomy in the two patients. IL-6 concentrations of the first patient were 513 and 106 pg/ml in the undiluted vitreous and the infusion fluid, respectively, while those of the second patient were 263 and 29 pg/ml. By contrast, IL-10 was under the detectable levels in all the fluids. The IL-10/-6 ratio was <1 in both fluids in the patients. Cytological examination revealed the presence of reactive inflammatory cells in the vitreous fluid. The two patients were eventually diagnosed with uveitis. Measurements of IL concentrations in the vitreous infusion fluid provided significant evidence on the differential diagnosis between IOL and uveitis, when considering how vitreous infusion fluid was diluted. The present study highlighted a novel application of cytokine analyses using the vitreous infusion fluid, which may contribute to the development of future translational researches on uveitis/IOL patients. PMID- 26623021 TI - Expression and significance of telomerase in the nucleus pulposus tissues of degenerative lumbar discs. AB - The pathogenesis of lumbar disc degeneration is extremely complex, and the expression and role of telomerase in degenerative lumbar disc tissues remains unclear. The aim of the present study was to detect telomerase expression in nucleus pulposus tissues of degenerative lumbar discs and to explore the correlation between telomerase expression and other factors typical of disc degeneration. A total of 8 patients with degenerative nucleus pulposus were included as the experimental group and compared with 8 control patients without evident lumbar disc degeneration. The expression of telomerase in nucleus pulposus tissues was detected by immunohistochemical staining. ELISA was performed to determine the differential expression of telomerase, type II collagen and chondroitin sulfate between the two groups. In addition, a correlation analysis was performed to form associations between these factors. Finally, 5 cases in the experimental group and 5 in the control group were involved in the analysis. Immunohistochemistry results showed that telomerase expression in the experimental group was significantly lower compared to the control group and the percentage in the unit field of view showed significant differences between the two groups (P<0.05). Similarly, the ELISA test results showed lower expression levels of telomerase, type II collagen and chondroitin sulfate in the experimental group when compared with the control group (P<0.05). The correlation analysis revealed that telomerase was positively correlated with type II collagen and chondroitin sulfate (correlation coefficients, 0.673 and 0.528, respectively; P<0.01). In conclusion, telomerase is involved in the degeneration process of nucleus pulposus tissue in lumbar discs and has a positive correlation with other factors typically associated with degeneration. PMID- 26623023 TI - Molecular characterization of human Torque Teno virus. AB - The present study analyzed the presence of human Torque Teno virus (TTV) in hospitalized patients from different departments. In total, 378 serum specimens were collected from the patients (171 with cardiovascular disease, 192 with tumor and 15 with gastroenteritis) and analyzed by ELISA and nest-polymerase chain reaction (PCR) to detect the presence of TTV. The results showed that 64 specimens (17%) were TTV positive from detection with the human ELISA kit, and the patients aged <30 years have a higher prevalence. TTV in males was more common than in female patients. In addition, nest-PCR was used to detect TTV within different phylogenetic groups among the 64 specimens, and the results showed that groups 1 (TA278 strain), 4 (KC009) and 5 (CT39) were much more prevalent than groups 2 (PMV isolate) and 3 (11 genotypes) in the different departmental patients. PMID- 26623024 TI - Topiramate effects lipolysis in 3T3-L1 adipocytes. AB - Studies have shown that topiramate (TPM)-induced weight loss can be dependent on the central nervous system (CNS). However, the direct action of TPM on adipose tissue has not been tested previously. Thus, the present study aimed to examine whether TPM modulates lipolysis in 3T3-L1. The 3T3-L1 cells were incubated in 50 uM TPM for 30 min. The beta-adrenergic stimulator, isoproterenol, was used as a positive control. The release of lactate dehydrogenase, non-esterified fatty acid, glycerol and incorporation of 14C-palmitate to lipid were analyzed. The phosphorylation of protein kinase A (PKA), hormone-sensitive lipase (HSL), adipocyte triglyceride lipase (ATGL) and perilipin A, as well as the protein levels of comparative genetic identification 58 (CGI-58) were assessed. The levels of glycerol and non-esterified fatty acid increased markedly when the cells were treated with TPM. The TPM effects were similar to the isoproterenol positive control. Additionally, TPM reduced lipogenesis. These results were observed without any change in cell viability. Finally, the phosphorylation of PKA, HSL, ATGL and perilipin A, as well as the protein levels of CGI-58 were increased compared to the control cells. These results were similar to those observed in the cells treated with isoproterenol. The present results show that TPM increased the phosphorylation of pivotal lipolytic enzymes, which induced lipolysis in 3T3-L1 adipocytes, suggesting that this drug may act directly in the adipose tissue independent from its effect on the CNS. PMID- 26623025 TI - Assessment of autonomic nervous system function in nursing students using an autonomic reflex orthostatic test by heart rate spectral analysis. AB - Nursing students experience academic demands, such as tests, theoretical and practical coursework, research activities, various aspects of professional practice, and contact with health professionals and patients. Consequently, nursing students face numerous types of stress, and increased stress levels contribute to physical and psychological distress in nursing students. The aim of the present study was to investigate the autonomic nervous system function of nursing students by assessing active standing load using the autonomic reflex orthostatic tolerance test, which enables quantitative analysis of dynamic autonomic nervous system function. The autonomic nervous system activity in the resting state was low in fourth-year students, they had parasympathetic hypotension, and there was a tendency towards higher sympathetic nervous system activity of fourth-year students compared with first-, second- and third-year students. In the standing state, there was a trend towards a higher autonomic nervous system activity response of fourth-year students compared with first-, second- and third-year students. These results suggest that stress may influence autonomic nervous activity in fourth-year nursing students. By correcting stress in fourth-year nursing students, it may be possible to prevent the development of health problems. PMID- 26623027 TI - Anti-allergic effect of the naturally-occurring conjugated linolenic acid isomer, jacaric acid, on the activated human mast cell line-1. AB - The present study aimed to investigate the immunomodulatory effect of jacaric acid, a naturally-occurring conjugated linolenic acid isomer that can be found in jacaranda seed oil, on the activated human mast cell line-1 (HMC-1). Our previous studies have demonstrated that jacaric acid only exerted minimal, if any, cytotoxicity on normal murine cells. In the present study, jacaric acid at concentrations <=100 uM did not exhibit direct cytotoxicity on human peripheral blood mononuclear cells after 72 h of incubation, as determined by the MTT reduction assay. By contrast, jacaric acid could alleviate the calcium ionophore A23187 and phorbol 12-myristate 13-acetate-triggered allergic response in the HMC 1 cells at concentrations that were non-cytotoxic to the HMC-1 cells. Following pre-treatment with jacaric acid, the secretion of two inflammatory mediators, beta-N-acetylglucosaminidase and tryptase, as well as the T helper 2 cytokines [interleukin (IL)-4 and IL-13] was significantly reduced in HMC-1 cells. The alleviation of allergic response was accompanied by downregulation of the matrix metalloproteinase-2 and -9 proteins and upregulation of the tissue inhibitor of metalloproteinase-1 protein. Collectively, the results indicated that the naturally-occurring jacaric acid exhibits a suppressive effect on the allergic response in activated human mast cells in vitro, and this could not be attributed to the direct cytotoxicity of jacaric acid on the treated cells. PMID- 26623026 TI - Flos Albiziae aqueous extract and its active constituent quercetin potentiate the hypnotic effect of pentobarbital via the serotonergic system. AB - Flos albiziae (FA) is reportedly used for treatment of insomnia and anxiety in traditional medicine. The hypnotic effect of an extract of FA (FAE) and its constituent quercetin [2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one, QR] was examined in mice. QR is a widely distributed natural flavonoid abundant in FA flowers and other tissues. The possible mechanisms underlying the hypnotic effects of FAE and QR were investigated using behavioral pharmacology. FAE and QR significantly potentiated pentobarbital-induced [50 mg/kg, intraperitoneal (ip)] sleep (prolonged sleeping time; shortened sleep latency) in a dose-dependent manner, and these effects were augmented by administration of 5-hydroxytryptophan (5-HTP), a precursor of 5-hydroxytryptamine. With a sub-hypnotic dose of pentobarbital (28 mg/kg, ip), FAE and QR significantly increased the rate of sleep onset and were synergistic with 5-HTP (2.5 mg/kg, ip). Pretreatment with p chlorophenylalanine, an inhibitor of tryptophan hydroxylase, significantly decreased sleeping time and prolonged sleep latency in pentobarbital-treated mice, whereas FAE and QR significantly reversed this effect. Data show that FAE and QR have hypnotic activity, possibly mediated by the serotonergic system. The present study offers a rationale for the use of FA in treating sleep disorders associated with serotonin system dysfunction. PMID- 26623028 TI - Effects of risedronate on the morphology and viability of gingiva-derived mesenchymal stem cells. AB - Risedronate has been used for the prevention and treatment of postmenopausal and corticosteroid-induced osteoporosis. The present study was performed to evaluate the effects of risedronate on the morphology and viability of human stem cells derived from the gingiva. Stem cells derived from the gingiva were grown in the presence of risedronate at concentrations that ranged from 1 to 10 uM. The morphology of the cells was viewed under an inverted microscope, and cell proliferation was analyzed with a cell counting kit-8 (CCK-8) on days 2, 4 and 7. The untreated control group showed a spindle-shaped, fibroblast-like morphology. The shapes of the cells treated with 1 and 5 uM risedronate were similar to that of the control group on day 2. However, morphology of the 10 uM group markedly differed from that of the control group. The shapes of the cells in the 1, 5 and 10 uM groups were rounder, and pronounced alterations when compared with the untreated control group were noted in all groups on day 7. The cultures growing in the presence of risedronate showed decreased CCK-8 values on day 7. In conclusion, risedronate produced notable alterations in the morphology of the cells and reduced the viability of gingival mesenchymal stem cells. PMID- 26623029 TI - Candidate single-nucleotide polymorphisms and cerebral palsy: A case-control study. AB - Certain genetic polymorphisms have been suggested to be associated with cerebral palsy; the candidate genes are involved in thrombophilia, inflammation and preterm labor, but the mechanism remains to be elucidated. The aim of the present study was to investigate the associations between selected single-nucleotide polymorphisms (SNPs) and cerebral palsy among children. A case-control study was conducted, including 74 infants with cerebral palsy (case group) and 99 healthy infants (control group). The distributions of the allele and genotype frequencies were examined for the total cerebral palsy patient population in addition to subgroups divided according to gestational age (preterm versus full-term). The results showed that the rs1042714 variant in adrenergic receptor beta-2 (ADRB2) and heterozygosity for ADRB2 were associated with the cerebral palsy risk among the preterm infants. No significant differences in the allele or genotype frequencies were observed between the total cerebral palsy patient population and controls for the eight SNPs investigated. PMID- 26623030 TI - A predictive model for the development of chronic obstructive pulmonary disease. AB - The screening of a person at risk for chronic obstructive pulmonary disease (COPD) and timely treatment may provide opportunities to delay the progressive destruction of lung function. Therefore, a model to predict the disease is required. We hypothesized that demographic and clinical information in combination with genetic markers would aid in the prediction of COPD development, prior to its onset. The aim of the present study was to create a predictive model for COPD development. Demographic, clinical presentation and genetic polymorphisms were recorded in COPD patients and control subjects. Nighty-six single-nucleotide polymorphisms of 46 genes were selected for genotyping in the case-control study. A predictive model was produced using logistic regression with a stepwise model-building approach and was validated. A total of 331 patients and 351 control subjects were included. The logistic regression identified the following predictors: Gender, respiratory infection in early life, low birth weight, smoking history and genotype polymorphisms (rs2070600, rs10947233, rs1800629, rs2241712 and rs1205). The model was established using the following formula: COPD = 1/[1 + exp (-2.4933-1.2197 gender + 1.1842 respiratory infection in early life + 2.4350 low birth weight + 1.8524 smoking - 1.1978 rs2070600 + 2.0270 rs10947233 + 1.1913 rs10947233 + 0.6468 rs1800629 + 0.5272 rs2241712 + 0.4024 rs1205)] (when the value is >0.5). The Hosmer-Lemeshow test showed no significant deviations between the observed and predicted events. Validation of the model in 50 patients showed a modest sensitivity and specificity. Therefore, a predictive model based on demographic, clinical and genetic information may identify COPD prior to its onset. PMID- 26623031 TI - Serum levels of nicotinamide-adenine dinucleotide phosphate oxidase 4 are associated with non-valvular atrial fibrillation. AB - Recent evidence indicates that nicotinamide-adenine dinucleotide phosphate oxidase (NOX)-derived reactive oxygen species have a pivotal role in the development of atrial fibrillation (AF). The present study aimed to investigate the potential association between serum levels of NOX4, as well as inflammatory biomarkers and AF. In total, 108 patients with AF (71 with paroxysmal AF and 37 with persistent/permanent AF) and 68 patients without AF, as the controls, were enrolled. The demographic, clinical, laboratory, electrocardiographic and echocardiographic characteristics were carefully recorded. Serum levels of myeloperoxidase (MPO), high-sensitivity C-reactive protein (hs-CRP) and NOX4 were assessed. Left atrial diameter (LAD), left ventricular end-diastolic diameter and P-wave dispersion were significantly increased in patients with paroxysmal AF and persistent/permanent AF compared with the controls, while NOX4 levels were significantly higher in patients with paroxysmal AF and persistent/permanent AF compared to the controls (155.57+/-90 and 155.88+/-64.79 vs. 126.72+/-23.51 pg/ml, respectively, P<0.05). A significant correlation between serum NOX4 levels and hs-CRP, and between NOX4 levels and MPO was also evident (r=0.170; r=0.227, P<0.05, respectively). Multivariate analysis demonstrated that the baseline serum NOX4 level was independently associated with paroxysmal AF [odds ratio (OR)=1.014; 95% confidence interval (CI), 1.001-1.027; P<0.05] and with persistent/permanent AF (OR=1.022; 95% CI, 1.000-1.044; P<0.05). There appears to be an association between increased NOX4 levels and AF, suggesting NOX4 involvement in the pathophysiology of human AF. Further studies are required to elucidate its role in atrial remodeling and to examine its potential prognostic impact. PMID- 26623032 TI - Elevated hsa-miR-99a levels in maternal plasma may indicate congenital heart defects. AB - The current standard for prenatal screening is mostly based on biochemical marker tests and the use of ultrasonography. There is no secure stand-alone screening marker for congenital heart defects (CHDs). MicroRNAs (miRNAs) that are associated with cardiogenesis enter the maternal peripheral bloodstream during pregnancy and allow non-invasive prenatal testing (NIPT). The present study investigated the plasma expression profile of fetal hsa-miR-99a in maternal blood. Peripheral blood samples were collected from 39 pregnant patients, comprising 22 with CHD-positive fetuses and 17 with CHD-free controls. miRNAs were isolated from the maternal serum and reverse transcription-quantitative polymerase chain reaction was carried out to determine the expression of hsa-miR 99a. While the miRNA concentrations were almost identical among the affected and control groups (5.54 vs. 6.40 ng/ul), significantly upregulated hsa-miR-99a levels were identified in the affected group (1.78*10-2+/-3.53*10-2 vs. 1.09*10 3+/-3.55*10-3 ng/ul, P=0.038). In conclusion, according to the present study, hsa miR-99a is involved in cardiac malformation and may serve as a biomarker during fetal development, and therefore presents as a candidate for monitoring cardiomyogenesis and potential use as a NIPT-biomarker for fetal CHD. PMID- 26623033 TI - Association between nm23 gene polymorphisms and the risk of endometriosis. AB - The first tumor metastasis-suppressor gene, nm23, may have an important role in the pathogenesis of endometriosis (EM). The present study aimed to evaluate whether nm23 gene polymorphisms are correlated with the risk of the development of EM in North Chinese women, as a preliminary study. The case-control study was conducted with 379 EM patients and 384 unrelated healthy controls. Genotyping of two polymorphisms within the nm23 gene promoter region (rs16949649 T/C and rs2302254 C/T) were performed using polymerase chain reaction-restriction fragment length polymorphism. The data showed that the rs16949649 and rs2302254 polymorphisms within the nm23 gene were not associated with the risk of developing EM. There were no statistical differences in the distribution of nm23 genotypes between patients with EM and the control group (P=0.490 and P=0.440, respectively). For the rs16949649 T/C, compared with the C/T + T/T genotype, the C/C genotype did not increase the risk of EM [odds ratio (OR)=0.81; 95% confidence interval (CI), 0.57-1.17]. For the rs2302254 C/T, compared with the C/T + C/C genotype, the T/T genotype did not increase the risk of EM (OR=1.46; 95% CI, 0.81-2.64). In conclusion, the findings in the present pilot study suggest that nm23 polymorphisms do not contribute to EM susceptibility. However, more studies in larger populations are required to confirm these results. PMID- 26623034 TI - Association and prediction of severe 5-fluorouracil toxicity with dihydropyrimidine dehydrogenase gene polymorphisms: A meta-analysis. AB - The aim of the present study was to evaluate the association and prediction of dihydropyrimidine dehydrogenase gene (DPYD) polymorphisms and the risk of 5 fluorouracil (5-FU) severe toxicity in cancer patients. A meta-analysis of the published literature was conducted to summarize evidence for DPYD gene polymorphisms associated with an increased risk of severe 5-FU toxicity in patients with cancer from an Asian population. Relevant literature was identified using the PubMed and Cochrane databases on April 11, 2014. Combined risk ratios and 95% confidence intervals (CIs) were calculated in a fixed-effects model. A total of 5 clinical studies were retrieved in the meta-analysis, including 764 cancer patients with DPYD gene polymorphisms who received 5-FU-based chemotherapy. Overall, DPYD gene polymorphisms were associated with the increased risk of 5-FU severe toxicity [risk ratio=2.54 (2.15-3.00); 95% CI, 19.46-84.57; P=0.0001]. In conclusion, the present meta-analysis suggested that polymorphisms of several DPYD gene polymorphisms are associated with an increased risk of severe toxic response to 5-FU. PMID- 26623035 TI - Predictive value of the efficacy of tolvaptan in liver cirrhosis patients using free water clearance. AB - Tolvaptan, an arginine vasopressin V2 antagonist, is available for patients with refractory ascites. Free water clearance was evaluated as a predictor of tolvaptan efficacy. Twenty-one patients with refractory ascites were enrolled in the present study. Liver function test, renal function test, urine volume, free water clearance and osmotic pressure were measured at baseline (day 0) and for each dose of tolvaptan (1.875, 3.75 and 7.5 mg), and compared for efficacy. Tolvaptan increased urine volume and free water clearance decreased osmotic pressure at each dose of tolvaptan, compared to pretreatment levels. Compared to baseline, an increased volume of free water clearance at 1.875 mg of tolvaptan showed a significant correlation with body weight reduction (r=0.480 and P=0.028). Any factors (age, liver function test and renal function test) at pretreatment showed no significant correlation with body weight reduction. An increased volume of urine and osmotic pressure at each dose was not significantly correlated with the tolvaptan effect. Compared to baseline, an increased volume of free water clearance at 1.875 mg of tolvaptan in responders was significantly increased, compared to non-responders (270+/-241 ml/day: 27+/-257 ml/day; P=0.042). In conclusion, an increased volume of free water clearance on day 1 was significantly associated with body weight reduction. Free water clearance could be a simple and useful marker for the prediction of tolvaptan efficacy. PMID- 26623036 TI - A Surveillance, Epidemiology and End Results-Medicare data analysis of elderly patients with glioblastoma multiforme: Treatment patterns, outcomes and cost. AB - The Surveillance, Epidemiology and End Results (SEER) database was used to determine the treatment patterns, outcomes and cost of therapy in elderly patients with glioblastoma multiforme (GBM). The SEER-Medicare linked database was used to identify patients aged >66 years with GBM diagnosed between 1997 and 2009. The patients were stratified by initial treatment following diagnostic surgery (resection or biopsy) into 6 groups as follows: No treatment, standard radiation therapy (SRT) with and without concurrent temozolomide (TMZ), hypofractionated RT (HRT) with and without concurrent TMZ, or TMZ alone. The 3,759 patients identified had a median age of 74 years (range, 66-97 years). A total of ~48% of the patients received SRT without TMZ; ~10% received SRT with concurrent TMZ; ~29% received no treatment; ~10% received HRT without TMZ; ~1% received HRT with TMZ; and <1% received TMZ alone. Untreated patients had a median survival of 2 months (range, 0-89 months). Patients treated with SRT with and without concurrent TMZ had a median survival of 11 and 9 months, respectively (P=0.01). Patients treated with HRT with and without TMZ or TMZ alone had a median survivals of 3 months [adjusted hazard ratio (AHR)=0.48; 95% confidence interval (CI): 0.36-0.66], 4 months (AHR=0.55; 95% CI: 0.49-0.62) and 6 months (AHR=0.43; 95% CI: 0.29-0.62), respectively. The median post-surgery total treatment cost for patients receiving HRT with and without TMZ or TMZ alone was 63,915, 42,834 and 48,298 USD, respectively. Standard RT with concurrent TMZ was associated with improved survival, even in patients aged >75 years. HRT with and without concurrent TMZ and TMZ alone improved survival compared to the no treatment group. Therefore, in certain cases, HRT or TMZ alone may be more cost effective, with similar survival outcomes. The various treatment options highlight the need for geriatric assessment tools to aid in therapeutic decision making. PMID- 26623037 TI - Oral gastrografin radiography for the evaluation of the functional impact of peritoneal carcinomatosis: Correlation with clinicopathological findings. AB - This study was conducted to evaluate the functional impact of peritoneal carcinomatosis (PC) on the gastrointestinal system by oral gastrografin radiography (OGR). OGR was performed on 105 patients with PC from abdominal malignancies. The OGR characteristics were analyzed and compared with intraoperative observations. OGR provided real-time dynamic information on the functional impacts of PC. The OGR findings were normal in 9 (8.6%) and abnormal in 96 (91.4%) cases. In terms of frequency, 33 cases (31.4%) exhibited mild intestinal aggregation and flattening of the intestinal mucosa; 29 cases (27.6%) exhibited limited intestinal invasion, marginally stenotic small bowel and mucosal deformities; 26 cases (24.8%) exhibited only mild mesenteric contracture and mild slowing of gastrointestinal peristalsis; 5 cases (4.8%) exhibited obvious mesenteric contracture, ball-like changes, fixed position and disappearance of the intestinal mucosa; 2 cases (1.9%) exhibited complete pyloric obstruction; and 1 case (0.9%) exhibited duodenal obstruction. Gastric PC was associated with a higher percentage of stomach filling defects and small intestinal aggregates compared with PC from other malignancies (P<0.01 for both). In 87 cases, the ORG findings were in accordance with the intraoperative findings (kappa=0.726, P<0.001), whereas 17 cases (16.2%) were underestimated and 1 (0.9%) was overestimated by OGR. This study indicated that OGR may be a useful technique for the evaluation of the functional impacts of PC on the gastrointestinal system and may help optimize the selection of patients for treatment. PMID- 26623038 TI - Superior antitumor activity of trastuzumab combined with capecitabine plus oxaliplatin in a human epidermal growth factor receptor 2-positive human gastric cancer xenograft model. AB - In the treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastroesophageal junction cancer, it has been reported that the combination of trastuzumab with capecitabine plus cisplatin, or with 5 fluorouracil (5-FU) plus cisplatin, significantly increased overall survival compared with chemotherapy alone (ToGA trial). In addition, adjuvant therapy with capecitabine plus oxaliplatin (XELOX) improved the survival of patients who received curative D2 gastrectomy (CLASSIC trial). However, the efficacy of the combination of trastuzumab with XELOX for patients with HER2-positive gastric cancer remains unknown. The aim of this study, was to investigate the efficacy of the combination of trastuzumab with XELOX in a HER2-positive human gastric cancer xenograft model. Combination treatment with these three agents (trastuzumab 20 mg/kg, capecitabine 359 mg/kg and oxaliplatin 10 mg/kg), was found to exhibit a significantly stronger antitumor activity in NCI-N87 xenografts compared with either trastuzumab or XELOX alone. In this model, treatment with trastuzumab alone or trastuzumab plus oxaliplatin enhanced the expression of thymidine phosphorylase (TP), a key enzyme in the generation of 5-FU from capecitabine in tumor tissues. In in vitro experiments, trastuzumab induced TP mRNA expression in NCI-N87 cells. In addition, NCI-N87 cells co-cultured with the natural killer (NK) cell line CD16(158V)/NK-92 exhibited increased expression of TP mRNA. When NCI-N87 cells were cultured with CD16(158V)/NK-92 cells in the presence of trastuzumab, the mRNA expression of cytokines reported to have the ability to induce TP was upregulated in tumor cells. Furthermore, a medium conditioned by CD16(158V)/NK-92 cells also upregulated the expression of TP mRNA in NCI-N87 cells. These results suggest that trastuzumab promotes TP expression, either by acting directly on NCI-N87 cells, or indirectly via a mechanism that includes trastuzumab-mediated interactions between NK and NCI-N87 cells. Therefore, the combination of trastuzumab with XELOX may be a potent therapy for HER2-positive gastric cancer. PMID- 26623039 TI - Association between delta-aminolevulinate dehydratase G177C polymorphism and blood lead levels in brain tumor patients. AB - As the delta-aminolevulinic acid dehydratase (ALAD) G177C polymorphism affects the toxicokinetics of lead in the body, and the corresponding exposure to lead may increase the risk of adult brain tumors, we hypothesize that there is a possible association of the ALAD G177C genotype and the risk of brain tumors in human. Therefore, the aim of the present study was to clarify the role of the ALAD enzyme gene polymorphism at position G177C in the pathogenesis of brain tumors and its correlation to lead exposure. The ALAD gene polymorphism at position G177C was genotyped using the polymerase chain reaction with restriction fragment length polymorphism method and measured the blood lead level by atomic absorption in 81 brain tumor patients and compared the results with 81 controls. The frequency of the GC genotype (ALAD1-2) was significantly increased in primary brain tumor patients compared to the control group. The genotype frequency of ALAD2 (ALAD1-2 and ALAD2-2) was significantly higher in the meningioma patients but was not significant in glioma patients. There was no significant difference in the number of patients and blood lead level when compared with the control. There was a significant increase when compared to ALAD1 regarding a mean value of the lead level. The genotyping of the ALAD G177C polymorphism in the present study revealed a significant association between ALAD2 and brain tumors. The ALAD G177C polymorphism may modify the lead kinetics in the blood, is associated with higher blood lead burden and may provide a biomarker of neurotoxic risk. PMID- 26623040 TI - Pretreatment platelet-lymphocyte ratio is an independent predictor of cervical cancer recurrence following concurrent chemoradiation therapy. AB - The aim of the present study was to identify the correlations between inflammation markers such as neutrophil-lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR) and C-reactive protein (CRP) and the prognosis in patients with recurrent cervical cancer. The associations among NLR, PLR and CRP and clinical characteristics and prognosis were examined in 32 patients receiving chemotherapy with recurrent cervical cancer following concurrent chemoradiation therapy (CCRT). The patient median survival time was 198 days (range, 42-1,022 days). Pretreatment NLR and PLR were significantly correlated with the recurrence of cervical cancer following CCRT (R=-0.538, P=0.002; and R=-0.542, P=0.001, respectively). Pretreatment PLR >322.0 was significantly associated with a poor prognosis for recurrent cervical cancer following CCRT by univariate and multivariate analyses (P=0.015 and P=0.029). These findings indicate that pretreatment PLR is an important predictor of prognosis in patients with recurrent cervical cancer following CCRT. PMID- 26623041 TI - Diagnostic value of cyclin-dependent kinase/cyclin-dependent kinase inhibitor expression ratios as biomarkers of locoregional and hematogenous dissemination risks in oral squamous cell carcinoma. AB - The aim of the present study was to investigate the diagnostic value of cell cycle-related genes in oral squamous cell carcinoma (OSCC) by examining the expression of the following genes in 77 OSCC tissues by quantitative polymerase chain reaction: Cyclin genes (CCNA1, CCND1, CCND2 and CCNE1), cyclin-dependent kinase (CDK) genes (CDK1, CDK2 and CDK4), CDK inhibitor genes (CDKN2A, CDKN1A, CDKN1B and CDKN1C), and integrin and associated genes that we previously reported (ITGA3, ITGB4, CD9 and JUP). The expression ratios of 66 combinations of the 11 cell cycle-related genes were analyzed to examine their associations with major clinical events using Mann-Whitney U and log-rank tests. Three expression ratios (CDK1/CDKN1B, CDK2/CDKN1A and CCNE1/CDK2) showed associations on univariate analyses and their diagnostic value was re-analyzed with integrin gene expression biomarkers (ITGA3/CD9 and ITGB4/JUP) using the Cox proportional hazards model and Kaplan-Meier estimates. Lymph node metastasis occurred in >90% of double-positive cases (high-ITGA3/CD9 and high-CDK1/CDKN1B) irrespective of tumor size (P<0.0001). Primary site recurrence was found in >30% of double-positive cases (high-ITGA3/CD9 and high-CDK2/CDKN1A) with tumors >20 mm (P=0.003). Triple positive (high-ITGB4/JUP, high-ITGA3/CD9 and high-CDK2/CDKN1A) was associated with distant metastasis (P<0.0001), but not with other clinical parameters. Disease-specific death occurred in 55% of double-positive cases (high-ITGA3/CD9 and high-CDK2/CDKN1A) (P<0.0001) and a positive surgical margin was a significant factor for fatality in these cases. Reliable prediction of locoregional and hematogenous dissemination risks in OSCC using the four CDK and integrin gene expression ratios is a promising biomarker system. Clinical use of these parameters may improve the control rate with the use of new therapeutic strategies. PMID- 26623042 TI - Modified Miccoli's thyroid surgery for thyroid diseases. AB - Minimally invasive video-assisted thyroidectomy (MIVAT), originally described by Miccoli, is considered to be the most widely practiced and easily reproducible procedure for selected patients with benign and/or malignant thyroid nodules. Modified techniques based on MIVAT, namely modified Miccoli's thyroid surgery (MMTS), were developed based on MIVAT. This study aimed to evaluate the preliminary results of MMTS compared with those of MIVAT. The enrolling criteria included a benign nodule <3.5 cm in diameter, a malignant tumor <2 cm, no previous neck surgery and no evidence of any suspected lymph node metastasis or local invasion. Unilateral lobectomy was considered for benign lesions and the additional dissection of central compartment (level VI) lymph nodes was applied for malignant disease. The modified techniques included carefully selecting the operative incision, expanding the operative space, embedding a drainage tube in situ and delicately suturing every layer inwards and crosswise, as well as measuring cervical motion. In addition to the comparison of surgical outcomes between MMTS and MIVAT, other surgical parameters, including operative time, blood loss, postoperative drainage, cosmetic satisfaction, peak angle of cervical rotation, length of hospitalization and complications, were retrospectively analyzed. A consecutive series of 70 patients, including 54 cases of benign and 16 cases of malignant disease, initially underwent MIVAT between April, 2008 and May, 2012, while 127 patients, including 98 benign and 29 malignant cases, subsequently underwent MMTS between September, 2011 and October, 2014. Patients who received MMTS exhibited significantly less blood loss (20.3+/-11.3 vs. 32.3+/ 12.6 ml, P<0.01), lower volume of postoperative drainage (42.77+/-15.2 vs. 50.48+/-23.2 ml, P<0.01) and higher cosmetic satisfaction (94.6+/-3.5 vs. 88.9+/ 2.7%, P<0.01), but a longer operative time (102+/-36 vs. 50.48+/-23.2 min, P<0.01) when compared with MIVAT. In addition, a better peak angle of cervical rotation (38.6+/-4.1 degrees vs. 35.3+/-3.8 degrees , P=0.25) and shorter length of hospitalization (4.25+/-1.08 vs. 4.51+/-1.30 days, P=0.52) was observed in the MMTS group, although the differences with the MIVAT group were not statistically significant. No complications were observed, apart from 2 cases of recurrent laryngeal nerve palsy and 1 case of transient hypocalcemia at the beginning of MIVAT. In conclusion, both MMST and MIVAT are safe and feasible methods of thyroidectomy; however, MMST is associated with less trauma and higher cosmetic satisfaction compared with MIVAT. Therefore, MMST may be used as a standard operative method and prospectively applicable for thyroidectomy, even for early stage malignancies. PMID- 26623043 TI - Characteristics of colorectal tumours in asymptomatic patients with negative immunochemical faecal occult blood test results. AB - The immunochemical faecal occult blood test (iFOBT) is a simple, non-invasive colorectal cancer (CRC) screening method for reducing CRC-related mortality. However, the sensitivity of iFOBT is imperfect and certain colonic neoplasms that require removal may be missed. The aim of this study was to investigate the incidence and characteristics of CRC in asymptomatic, iFOBT-negative patients who underwent opportunistic screening. A total of 919 subclinical patients (276 iFOBT positive and 643 iFOBT-negative) in the health screening program of our hospital underwent total colonoscopy (TCS) within 2 years after iFOBT. The patients were divided into an iFOBT-positive and an iFOBT-negative group and the TCS findings were compared between the two groups. Although the incidence of advanced neoplasia (CRC, high-grade dysplasia, adenoma sized >=10 mm and tubulovillous adenoma) was significantly higher in the iFOBT-positive group, these lesions were also found in 6.3% of iFOBT-negative patients. The lesions tended to be proximally located and non-protruding. In conclusion, screening with iFOBT remains clinically significant. However, colonoscopy is indispensable for reducing the incidence and mortality of CRC. PMID- 26623044 TI - Metachronous second primary lung cancer surgically treated five years or more after the initial surgery. AB - Surgical treatment for metachronous second primary lung cancer following curative resection of primary lung cancer may be challenging. Standard surgical strategies for metachronous second primary lung cancer have not yet been established. The purpose of this study was to evaluate the outcomes of patients who underwent surgical resection for metachronous second primary lung cancer. A total of 12 patients surgically treated for metachronous second primary lung cancer >=5 years after the initial surgery were retrospectively analyzed. The overall 5-year survival after the second surgery was 56.5%. There was no operative mortality. Patients with T1aN0M0 metachronous second primary lung cancer experienced a significantly higher 5-year overall survival rate compared with other patients (100 vs. 26.7%, respectively; P=0.0336). Among patients who underwent sublobar resection, all 3 patients with T1aN0M0 disease remained alive at the last follow up, while 4 of the 5 patients (80%) with non-T1aN0M0 disease had developed recurrence. Surgery for metachronous second primary lung cancer may be safely performed. Early-stage metachronous second primary lung cancer was associated with a good prognosis, even among patients who underwent sublobar resection. Early detection of metachronous second primary lung cancer with close long-term follow-up following initial surgery may improve surgical outcomes. PMID- 26623045 TI - Predictability of antitumor efficacy of cetuximab plus irinotecan based on skin rash severity according to observation period in patients with metastatic colorectal cancer following failure of fluorouracil, irinotecan and oxaliplatin. AB - The efficacy of cetuximab correlates with the severity of skin toxicity, although its onset may vary. The AIM of this retrospective study was to investigate the optimal observation period for skin rash as a predictor of the efficacy of cetuximab plus irinotecan. The subjects comprised 33 patients with KRAS wild-type metastatic colorectal cancer (mCRC) who had received prior chemotherapy with fluorouracil, irinotecan and oxaliplatin. The response rate (RR), progression free survival (PFS) and overall survival (OS) were compared according to the presence or absence of >=grade 2 skin rash within 2, 4, 6, or 8 weeks following cetuximab initiation. The overall RR was 45% (15/33) and the median PFS and OS were 188 and 383 days, respectively. A total of 26 patients experienced >=grade 2 skin rash within 8 weeks. The proportion of responders among patients who developed >=grade 2 skin rash (severe group) decreased depending on the duration of the observation period (50% within 8 weeks), whereas the proportion of non responders among patients with =grade 2 skin rash within 8 weeks may be predictive of unfavorable efficacy of cetuximab plus irinotecan in mCRC patients. PMID- 26623046 TI - Predicted extracapsular invasion of hilar lymph node metastasis by fusion positron emission tomography/computed tomography in patients with lung cancer. AB - Intraoperative detection of hilar lymph node metastasis, particularly with extracapsular invasion, may affect the surgical procedure in patients with lung cancer, as the preoperative estimation of hilar lymph node metastasis is unsatisfactory. The aim of this study was to investigate whether fusion positron emission tomography/computed tomography (PET/CT) is able to predict extracapsular invasion of hilar lymph node metastasis. Between April, 2007 and April, 2013, 509 patients with primary lung cancer underwent surgical resection at our institution, among whom 28 patients exhibiting hilar lymph node metastasis (at stations 10 and 11) were enrolled in this study. A maximum lymph node standardized uptake value of >2.5 in PET scans was interpreted as positive. A total of 17 patients had positive preoperative PET/CT findings in their hilar lymph nodes, while the remaining 11 had negative findings. With regard to extracapsular nodal invasion, the PET/CT findings (P=0.0005) and the histological findings (squamous cell carcinoma, P=0.05) were found to be significant predictors in the univariate analysis. In the multivariate analysis, the PET/CT findings were the only independent predictor (P=0.0004). The requirement for extensive pulmonary resection (sleeve lobectomy, bilobectomy or pneumonectomy) was significantly more frequent in the patient group with positive compared with the group with negative PET/CT findings (76 vs. 9%, respectively, P=0.01). Therefore, the PET/CT findings in the hilar lymph nodes were useful for the prediction of extracapsular invasion and, consequently, for the estimation of possible extensive pulmonary resection. PMID- 26623048 TI - Neurotoxicity due to prophylactic cranial irradiation for small-cell lung cancer: A retrospective analysis. AB - Prophylactic cranial irradiation (PCI) is an established part of standard therapy for small-cell lung cancer (SCLC). However, the concerns regarding severe late neurotoxicity following PCI have not yet been systematically investigated. Therefore, the aim of this study was to investigate the neurocognitive functioning of SCLC patients treated with PCI. Limited-disease SCLC (LD-SCLC) patients (n=40) treated at Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital (Tokyo, Japan) between January, 2004 and December, 2011 were retrospectively reviewed. A total of 18 LD-SCLC patients were treated with PCI (median age, 65.5 years; range, 52-75 years), whereas 22 LD-SCLC patients did not receive PCI (median age, 65.5 years; range, 57-84 years). The median follow up for PCI and non-PCI patients was 22 months (range, 4-85 months) and 14.5 months (range, 2-49 months), respectively. Brain metastases occurred in 6 (33%) PCI patients and 11 (50%) non-PCI patients. In the PCI group, dementia occurred in 5 of the 12 PCI patients without brain metastases (42%, 3-40 months after PCI) and in 1 of the 11 non-PCI patients without brain metastases (9%, 4 months after initial treatment). The frequency of dementia in the PCI group was significantly higher compared with that in the non-PCI group (P=0.0357). In the PCI group, all the patients who developed dementia were aged >65 years (range, 66-75 years). Gait disturbance appeared in 25% of the PCI patients without brain metastases (9 27 months after PCI); these patients were also aged >65 years. Patients aged >65 years were significantly more likely to develop dementia (P=0.0028) and gait disturbance (P=0.0291). Therefore, neurotoxicity due to PCI tends to appear more frequently in older patients. PMID- 26623047 TI - Predictors and outcome of complete removal of colorectal cancer with synchronous lung metastases. AB - The prognosis-improving effect of radical surgery has been demonstrated in patients with colorectal cancer (CRC) with liver metastases. However, few studies have examined the effectiveness of treatments for CRC with metastases in organs other than the liver. The aim of the present study was to evaluate the outcome of surgical treatment for CRC with lung metastases. The study retrospectively examined 57 primary CRC patients (28 men, median age of 65 years) with synchronous lung metastases who underwent surgery between 2003 and 2012. Data such as clinicopathological parameters, metastasized organs, and the details of surgery, recurrence and survival periods were extracted and analyzed. Curative resection was performed in 10 patients ('curative group'). Primary tumors were resected without metastasectomy in 37 patients ('non-curative group'), whereas 10 underwent stoma surgery ('stoma group'). All the metastasized lesions were confined to the lung and liver in the curative group. By contrast, 43% of the non curative/stoma groups had metastases in organs other than the lung and liver. Multivariate analyses indicated the absence of extrahepatic metastases as the only predictor of curative resection in CRC patients with lung metastases. The 3 year overall survival rates for the curative, non-curative and stoma groups were estimated as 74, 20 and 17%, respectively (P=0.0007). In conclusion, curative resection was possible in CRC patients with lung metastases if other disseminated lesions were limited to the liver and this treatment resulted in a longer survival time. Furthermore, palliative resection may contribute to a better prognosis compared to stoma surgery alone in selected cases. PMID- 26623049 TI - Cetuximab treatment for metastatic colorectal cancer with KRAS p.G13D mutations improves progression-free survival. AB - A number of previous studies have reported that 30-50% of patients with colorectal cancer (CRC) harbor Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, which is a major predictive biomarker of resistance to epidermal growth factor (EGFR)-targeted therapy. Treatment with an anti-EGFR inhibitor is recommended for patients with KRAS wild-type metastatic colorectal cancer (mCRC). A recent retrospective study of cetuximab reported that patients with KRAS p.G13D mutations had better outcomes compared with those with other mutations. The aim of this retrospective study was to assess the prevalence of KRAS p.G13D mutations and evaluate the effectiveness of cetuximab in mCRC patients with KRAS p.G13D or other KRAS mutations. We reviewed the clinical records of 98 mCRC patients with KRAS mutations who were treated between August, 2004 and January, 2011 in four hospitals located in Tokyo and Kyushu Island. We also investigated KRAS mutation subtypes and patient characteristics. In the patients who received cetuximab, univariate and multivariate analyses were performed to assess the effect of KRAS p.G13D mutations on progression-free survival (PFS) and overall survival (OS). Of the 98 patients, 23 (23.5%) had KRAS p.G13D-mutated tumors, whereas 75 (76.5%) had tumors harboring other mutations. Of the 31 patients who received cetuximab, 9 (29.0%) had KRAS p.G13D mutations and 22 (71.0%) had other mutations. There were no significant differences in age, gender, primary site, pathological type, history of chemotherapy, or the combined use of irinotecan between either of the patient subgroups. The univariate analysis revealed no significant difference in PFS or OS between the patients with KRAS p.G13D mutations and those with other mutations (median PFS, 4.5 vs. 2.8 months, respectively; P=0.65; and median OS, 15.3 vs. 8.9 months, respectively; P=0.51). However, the multivariate analysis revealed a trend toward better PFS among patients harboring p.G13D mutations (PFS: HR=0.29; 95% CI: 0.08-1.10; P=0.07; OS: HR=0.23; 95% CI: 0.04-1.54; P=0.13). In conclusion, treatment with cetuximab may be more clinically beneficial in mCRC patients with a KRAS p.G13D mutation, compared with those harboring other mutations. However, further investigation is required to clearly determine the benefits of cetuximab treatment in patients with KRAS p.G13D mutation-positive mCRC. PMID- 26623051 TI - Herald bleeding from a ruptured primary hepatic angiosarcoma: A case report. AB - Primary hepatic angiosarcomas (PHAs) are rare tumours with an estimated annual incidence of 0.05 per million in the Caribbean, which is similar to that reported in Western countries. Although a number of cases are detected post-mortem, the most common clinical presentation is with tumour rupture and herald bleeding. This is the case report of a 60-year old female patient who presented with vague upper abdominal pain, found via imaging examinations to be due to a ruptured hepatic tumour in segment III of the liver. The tumour was removed via laparoscopic left lateral sectionectomy, with clear resection margins. The histopathological and immunohistochemical examination established the diagnosis of PHA. Therefore, an index of suspicion should be maintained in selected patients and, when detected ante-mortem, PHAs should be treated aggressively with complete surgical resection to achieve microscopically clear margins, as the response of these tumours to other forms of adjuvant therapy may be unpredictable. PMID- 26623050 TI - Thymoma exhibiting spontaneous regression in size, pleural effusion and serum cytokeratin fragment level: A case report. AB - A 30-year-old man was admitted to Toho University Omori Medical Center for assessment of right chest pain and fever. Chest computed tomography (CT) revealed an anterior mediastinal tumor sized 11.0*6.0*5.0 cm, with right pleural effusion. The laboratory analysis revealed elevated white blood cell count (11,000/ul), C reactive protein (4.1 mg/dl) and cytokeratin fragment (CYFRA; 12.7 ng/ml; normal, <2 ng/ml). The level of CYFRA in the pleural effusion was also markedly elevated (143 ng/ml). On the first day after admission (6 days after the initial CT), there was a mild regression on CT (10.0*5.5*4.4 cm; reduction rate, 26.7%), with decrease of the pleural effusion volume. A CT-guided needle biopsy was performed, but the findings were not conclusive, as most of the tissue was necrotic. Seven days later (13 days after the initial CT), a CT revealed further regression (9.5*5.4*4.2 cm; reduction rate, 34.7%) with disappearance of the pleural effusion. The patient was followed up on an outpatient basis. At 35 days after the initial CT, the tumor continued to shrink without treatment (8.0*3.6*3.0 cm; reduction rate, 73.8%) and the serum CYFRA level had decreased to 0.8 ng/ml, although it had not returned to normal levels. At 62 days after the initial CT, the patient underwent surgical resection. The resected specimen was diagnosed as thymoma (World Health Organization type B2; Masaoka classification, stage II), with prominent degeneration and necrosis. One possible cause of the spontaneous regression may be increased internal pressure, probably associated with rapid tumor growth, leading to massive necrosis with resulting chest pain, inflammatory reaction with pleural effusion and subsequent tumor regression. The serum CYFRA level may be a useful marker for the evaluation of the clinical course of thymoma with extensive necrosis. PMID- 26623052 TI - Cadherin-11 mRNA and protein expression in ovarian tumors of different malignancy: No evidence of oncogenic or tumor-suppressive function. AB - Cadherin-11 (CDH11, OB-cadherin) is a mesenchymal cadherin found to be upregulated in various types of tumors and implicated in tumor progression and metastasis. In order to determine the role of CDH11 expression in ovarian tumors, we performed a combined reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blot analysis and immunohistochemical study on a large cohort of benign, borderline and invasive ovarian tumors. The RT-qPCR and western blot analysis demonstrated that the CDH11 expression was high in benign cystadenomas and decreased with increasing malignancy. This may be explained by the different tumor-stroma ratios, since immunohistochemistry revealed strong staining of stromal cells, particularly vascular smooth muscle cells and endothelial cells, but only weak cytoplasmic or nuclear immunoreactivity of cancer cells. Within the group of invasive carcinomas, high CDH11 protein expression, as detected by western blot analysis, was found to be significantly correlated with advanced stage and nodal involvement. However, the recurrence free and overall survival analyses did not reveal any prognostic or predictive significance. In conclusion, in contrast to other tumor types, CDH11 does not play an important role in ovarian cancer progression. PMID- 26623053 TI - Mutational analysis of the insulin-like growth factor 1 receptor tyrosine kinase domain in non-small cell lung cancer patients. AB - The insulin-like growth factor 1 receptor (IGF1R) pathway plays an important role in the pathogenesis of non-small cell lung cancer (NSCLC) and also provides a mechanism of resistance to targeted therapies. IGF1R is therefore an ideal therapeutic target and several inhibitors have entered clinical trials. However, thus far the response to these inhibitors has been poor, highlighting the importance of predictive biomarkers to identify patient cohorts who will benefit from these targeted agents. It is well-documented that mutations and/or deletions in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain predict sensitivity of NSCLC patients to EGFR TK inhibitors. Single-nucleotide polymorphisms (SNPs) in the IGF pathway have been associated with disease, including breast and prostate cancer. The aim of the present study was to elucidate whether the IGF1R TK domain harbours SNPs, somatic mutations or deletions in NSCLC patients and correlates the mutation status to patient clinicopathological data and prognosis. Initially 100 NSCLC patients were screened for mutations/deletions in the IGF1R TK domain (exons 16-21) by sequencing analysis. Following the identification of SNP rs2229765, a further 98 NSCLC patients and 866 healthy disease-free control patients were genotyped using an SNP assay. The synonymous SNP (rs2229765) was the only aberrant base change identified in the IGF1R TK domain of 100 NSCLC patients initially analysed. SNP rs2229765 was detected in exon 16 and was found to have no significant association between IGF1R expression and survival. The GA genotype was identified in 53.5 and 49.4% of NSCLC patients and control individuals, respectively. No significant difference was found in the genotype (P=0.5487) or allele (P=0.9082) frequencies between the case and control group. The present findings indicate that in contrast to the EGFR TK domain, the IGF1R TK domain is not frequently mutated in NSCLC patients. The synonymous SNP (rs2229765) had no significant association between IGF1R expression and survival in the cohort of NSCLC patients. PMID- 26623055 TI - Comparison of semi-extended and standard lymph node dissection in radical prostatectomy: A single-institute experience. AB - Standard lymphadenectomy for prostate cancer is limited to the obturator lymph nodes (LNs), although the internal and external iliac LNs represent the primary landing zone for prostatic lymphatic drainage. We performed anatomically semi extended pelvic lymph node dissection (PLND) to assess the incidence of LN metastasis in cases of clinically localized prostate cancer. A total of 730 consecutive patients underwent radical prostatectomy with either semi-extended PLND, comprising 6 selective fields, namely the external iliac, internal iliac and obturator LNs bilaterally, or standard LND (obturator LNs alone). A total of 131 patients undergoing semi-extended PLND were compared with 599 patients undergoing standard LND. The patients were stratified into high-risk [prostate specific antigen (PSA)>20 ng/ml, Gleason score (GS)>=8], intermediate-risk (PSA 10-20 ng/ml, GS=4+3) and low-risk (PSA<10 ng/ml, GS<=3+4) subgroups. Following semi-extended LND, positive LNs were detected in 12/61 (20%) of the high-risk, 1/30 (3%) of the intermediate-risk and 0/40 (0%) of the low-risk cases. Following standard LND, positive LNs were detected in 13/182 (7%) of the high-risk, 1/164 (0.6%) of the intermediate-risk and 0/253 (0%) of the low-risk cases. In high risk patients, the detection rate of LN metastasis was significantly higher following extended LND compared with standard LND (P<0.01). In 9 of 13 patients (69%), metastases were identified in the internal and external iliac regions, despite negative obturator LNs. There were no significant differences regarding intraoperative and postoperative complications or blood loss in the two groups. There was no lymphocele formation in patients undergoing either standard or semi extended LND. Extended pelvic LND (PLND) is associated with a high rate of LN metastasis detection outside the fields of standard LND in cases with clinically localized prostate cancer. Therefore, LND including the internal and external iliac LNs should be performed in all patients with high-risk prostate cancer; however, in the low-risk group, PLND may be omitted. PMID- 26623054 TI - Angiopoietin-like protein 2 as a potential biomarker for colorectal cancer. AB - Colorectal cancer (CRC) is the third most common malignancy worldwide. Disease progression leads to its spread to other organs, such as the liver, and is associated with higher mortality rates. Early CRC detection is therefore crucial for maximizing the chances of complete cure. The measurement of serum-based tumor biomarkers has shown great potential for the detection of CRC. In this study, we investigated the feasibility of using angiopoietin-like protein 2 (ANGPTL2) as a candidate biomarker for CRC. We first investigated ANGPTL2 expression in 7 CRC cell lines, among which Colo320, NCC-CoCK-115P, Caco-2 and Colo205 exhibited comparatively high ANGPTL2 expression. The serum levels of ANGPTL2 in CRC patients (3.45+/-1.30 ng/ml) were higher compared with those in healthy controls (2.74+/-0.64 ng/ml) (P<0.05). A receiver operating characteristic analysis demonstrated that the diagnostic performance of ANGPTL2 was marginally lower compared with that of the established biomarker C-reactive protein, but higher compared with that of carbohydrate antigen 19-9. These results suggested that the simultaneous measurement of ANGPTL2, along with previously established serum biomarkers, may increase the likelihood of early detection of CRC. PMID- 26623056 TI - Cyclophosphamide, epirubicin and fluorouracil chemotherapy-induced alteration of haemostasis markers in breast cancer patients. AB - The occurrence of chemotherapy-induced alterations in markers of haemostasis during chemotherapy has been reported previously. However, the change of the haemostasis markers in the cyclophosphamide, epirubicin and fluorouracil (CEF) regimen remains unclear. The aim of the present study was to identify the change of the haemostasis markers during systemic chemotherapy (600 mg/m2 cyclophosphamide, 80 mg/m2 epirubicin and 500 mg/m2 fluorouracil; four courses over 21 days) to investigate its influence on the haemostasis markers of breast cancer patients and to discuss the requirement of anticoagulation therapy. D dimer, activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen (FIB) values were obtained before chemotherapy and on days 1, 4, 7 and 21. The results show that PT, D-dimer and FIB were not prolonged prior to chemotherapy compared to that under the control. APTT was prolonged until day 4. The levels of D-dimer and APTT were significantly higher compared to those of the breast cancer patients before receiving chemotherapy and controls on days 1, 4, 7 and 21 after chemotherapy. Alteration of the haemostasis markers occurred in the breast cancer patients under the CEF chemotherapy regimen. As there is an increased risk of deep vein thrombosis and pool prognosis of cancer patients, anticoagulant therapy should be considered. PMID- 26623057 TI - Clinicopathological characteristics and prognosis of stage IV colorectal cancer. AB - The aim of this study was to determine the role of curative resection in metastatic colorectal cancer (CRC) and determine the subset of patients who may benefit from concurrent curative resection of primary and metastatic lesions. A total of 103 patients diagnosed with synchronous liver and/or lung metastatic CRC at the Osaka Medical Center for Cancer and Cardiovascular Diseases between 1983 and 2010 were retrospectively investigated. All the patients underwent curative resection of the primary and metastatic lesions. The median follow-up time was 5.69 years. A total of 83 and 13 patients had only liver or lung metastasis, respectively, whereas 7 patients had synchronous liver and lung metastases. A total of 25 patients (24.2%) had no recurrence following curative resection and 14 patients (13.5%) received more than one re-resection for disease recurrence and survived without any further recurrence thereafter. The 5-year survival of liver or lung metastatic CRC was 43.7 or 90.0%, respectively. However, the median overall survival (OS) in patients with synchronous liver and lung metastases was 20.7 months. In the univariate and multivariate analyses, tumour invasion, synchronous liver and lung metastases and time-to-recurrence after the first curative resection were significantly associated with OS and disease-free survival. In conclusion, curative resection confers longer-term survival in patients with liver or lung metastatic CRC. PMID- 26623058 TI - A multicenter, phase II study of the RAF-kinase inhibitor sorafenib in patients with advanced renal cell carcinoma. AB - The treatment of advanced renal cell carcinoma (RCC) has advanced significantly over the last two decades. This multicenter study was designed with the primary objective to evaluate the efficacy and safety of sorafenib as first-line treatment in patients with advanced or metastatic RCC in the Middle East, who were considered to be ineligible for other approved first-line therapies. A total of 75 eligible patients from 8 centers in the Middle East were included in this study. The patients comprised 48 men and 27 women, with a median age of 52 years (range, 19-78 years). A total of 50 patients had clear cell carcinoma, 17 had papillary carcinoma and 8 had other pathological subtypes. At enrollment, 55 of the 75 patients had undergone previous nephrectomy. A total of 67 patients presented with metastatic disease, while 8 patients had regional residual lesions or local recurrence. The patients were treated with 400 mg oral sorafenib twice daily on a continuous basis as a single agent. Treatment was discontinued upon disease progression, prohibitive toxicity, surgical complications, loss to follow up, or refusal to continue therapy. The median treatment duration was 21 weeks (range, 1-137 weeks). Sorafenib was tolerated by the majority of the patients. Grade 3/4 hand-foot syndrome occurred in 17 patients; diarrhea, elevated liver enzymes and fatigue were observed in 3 patients each; and grade 3/4 vomiting, hypertension and anemia, in 1 patient each. Of the 75 patients included in this study, 60 were evaluable for response. One patient achieved a complete response for 91 weeks and 6 patients exhibited a partial response (median duration of 23 weeks) with an overall response rate of 11.7%. Disease stabilization occurred in 37 patients (61.7%). Thus, disease control was achieved in 44 of the 60 patientrs (73%). At a median follow-up period of 53.5 weeks (range, 8.5-192 weeks), an intention-to-treat analysis demonstrated a median time-to-disease progression of 25.7 weeks, with a median overall survival of 54.8 weeks. In conclusion, sorafenib was found to be tolerable and effective as first-line therapy in patients with advanced RCC. PMID- 26623059 TI - High vascular endothelial growth factor gene expression predicts poor outcome in patients with non-luminal A breast cancer. AB - Breast cancer is the most frequent type of cancer among women worldwide. Vascular endothelial growth factor (VEGF), the key modulator of angiogenesis, has been implicated in breast cancer susceptibility and aggressiveness. VEGF expression was determined in 99 breast cancer tissue samples using reverse transcription polymerase chain reaction and the human epidermal growth factor receptor 2 (HER2) status was determined by immunohistochemistry. Subsequently, the associations of VEGF, HER2 and hormone receptor status with clinicopathological data were evaluated. High VEGF expression was found to be significantly correlated with the presence of lymphovascular invasion. In hormone receptor-positive/HER2-positive, HER2-positive and triple-negative breast cancer, high VEGF expression was correlated with the presence of axillary nodal metastasis and lower overall survival rates. Therefore, the assessment of the VEGF status along with the hormone receptor and HER2 status may help identify high-risk patients who may benefit from anti-VEGF treatment. PMID- 26623060 TI - Factors affecting disease-free survival in patients with human epidermal growth factor receptor 2-positive breast cancer who receive adjuvant trastuzumab. AB - Breast cancer is the most frequently diagnosed cancer in women worldwide and the second cause of cancer-related mortality. A total of 20-30% of patients with early-stage breast cancer develop recurrence within the first 5 years following diagnosis. Trastuzumab significantly improves overall survival and disease-free survival (DFS) in women with human epidermal growth factor receptor 2 (HER2) positive early and locally advanced breast cancer. This study aimed to determine the factors that affect DFS following adjuvant transtuzumab therapy. A total of 62 patients treated with trastuzumab for early and locally advanced breast cancer were included in our study. Data, including pathology, treatment and treatment outcome, rate of recurrence and laboratory tests, were retrospectively collected. There was no significant association between DFS and age, menopausal status, disease stage and hormone receptor status. The median follow-up was 48.4 months. The median DFS of patients treated with adjuvant trastuzumab was 64.1 months. In addition, the median DFS was 44.3 vs. 66.8 months in patients with platelet lymphocyte ratio (PLR) <=200 vs. >200, respectively (log-rank test; P=0.001), and 70 vs. 45 months in patients with eosinophil count <=70 vs. >70*103/mm3 (log-rank test; P=0.001). Our data revealed the prognostic relevance of a decrease in the peripheral blood eosinophil count and PLR value following trastuzumab therapy in breast cancer. PLR and eosinophil count measurements are cost-effective, readily available worldwide, non-invasive and safe. Combined with other markers, such as patient age, tumor stage and tumor histology, may be effectively used for patients with breast cancer. PMID- 26623061 TI - Pyuria predicts poor prognosis in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin. AB - This study was conducted to evaluate the utility of pyuria as a predictive marker of bacillus Calmette-Guerin (BCG) treatment for non-muscle-invasive bladder cancer (NMIBC). A cohort of 243 NMIBC patients treated with BCG through intravesical instillation between 1994 and 2007 at the Tokyo Metropolitan Tama Medical Center were enrolled in this retrospective study. Pyuria was defined as urine containing >=10 white blood cells per high-power field. A total of 30 of the patients with pyuria (30/37, 81%) and 87 patients of those without pyuria (87/206, 42%) exhibited recurrence following BCG treatment. The 3-year recurrence free survival rate of patients with and without pyuria following BCG treatment was 20 and 62%, respectively. The multivariate Cox proportional hazards regression model indicated that pyuria was an independent predictor of disease recurrence following BCG treatment. Patients with inflammatory NMIBC exhibited resistance to therapy with intravesical instillation of BCG. PMID- 26623062 TI - Predictors of pathological complete response to neoadjuvant chemotherapy in stage II and III breast cancer: The impact of chemotherapeutic regimen. AB - In this study, we sought to determine the predictors of pathological complete response (pCR) and compare the chemotherapeutic regimens administered to breast cancer patients with and those without pCR. We retrospectively reviewed the data of 879 patients treated at the Alvin J. Siteman Cancer Center between 2006 and 2010, to identify patients who were diagnosed with primary stage II or III breast cancer and received neoadjuvant chemotherapy. Patients who received only neoadjuvant endocrine therapy were considered to be ineligible. Patient, tumor, and treatment characteristics, including type of chemotherapy, were compared between patients who did and those who did not achieve pCR using Chi-square or Fishers exact tests and multivariate logistic regression analysis. Two-sided P values of <0.05 were considered significant. Of the 333 patients who met the inclusion criteria, 61 (18.3%) had documented pCR. Compared with patients not achieving pCR, a greater proportion of patients with pCR had stage II disease (80.3 vs. 68%, P=0.057), had poorly differentiated (grade 3) tumors (82 vs. 59.2%, P<0.001), had negative lymph node involvement (41 vs. 34%, P=0.0004) and had tumors that were HER2-amplified (41 vs. 23.5%, P=0.0054). A greater proportion of patients with pCR received taxane-based chemotherapy (23 vs. 12.5%, P=0.016) or trastuzumab in conjunction with chemotherapy (41.0 vs. 16.9%, P<0.001). No patients receiving solely anthracycline-based therapy achieved pCR in our study. Our study demonstrated that, for stage II and III breast cancer, lower stage, negative lymph node involvement and HER2 receptor amplification were each associated with pCR. Taxane therapy and the concurrent use of trastuzumab were also associated with a higher likelihood of pCR. PMID- 26623063 TI - EGFR and K-RAS mutations and ERCC1, TUBB3, TYMS, RRM1 and EGFR mRNA expression in non-small cell lung cancer: Correlation with clinical response to gefitinib or chemotherapy. AB - Personalizing medicines has refined the traditional treatments for non-small-cell lung cancer (NSCLC). In the present study, efforts towards personalizing delivery of care based on the status of EGFR and K-RAS mutations, and mRNA expression levels of ERCC1, TUBB3, TYMS, RRM1 and EGFR by choosing appropriate treatments for 52 patients with NSCLC were discussed. Among these 52 NSCLC patients, there were 14 patients treated with gefitinib. Ten patients with EGFR exon 21 point mutations or exon 19 deletions had better treatment outcomes following gefitinib treatment (71.4%). There were 38 patients treated with platinum-based chemotherapy. Docetaxel-platinum based chemotherapy was chosen as the first-line treatment when the patients had low or median ERCC1/TUBB3 expression and gemcitabine-platinum based chemotherapy was chosen when the patients had low or median ERCC1/RRM1 expression. In total, 26 cases had mRNA expression levels of ERCC1/TUBB3 or ERCC1/RRM1 that could be used to predict the treatment outcomes of chemotherapy (68.4%). The present results indicated that the mutation status of EGFR, as well as the mRNA expression levels of ERCC1, TUBB3 and RRM1, could be used as predictors of the response to gefitinib or chemotherapy. PMID- 26623064 TI - Diffusion-weighted magnetic resonance imaging for prediction of tumor response to neoadjuvant chemoradiotherapy using irinotecan plus S-1 for rectal cancer. AB - The purpose of this study was to investigate the clinical value of diffusion weighted (DW) magnetic resonance imaging (MRI) as a predictor of tumor response in patients receiving neoadjuvant chemoradiotherapy (NA-CRT) for rectal cancer (RC) through measurement of the apparent diffusion coefficient (ADC) value in each tumor. Neoadjuvant radiotherapy with a total dose of 45 Gy in 25 fractions was performed in all 16 patients with RC, combined with irinotecan and S-1. MRI was performed before and after NA-CRT. Multiple factors were assessed to predict the pathological response to NA-CRT. The pathological response rate was determined in 9 patients (56.3%). Statistical analyses indicated that the ADC value prior to NA-CRT was significantly lower in patients with a better response to NA-CRT (P=0.023). A cut-off value of 0.750*10-3 mm2/sec obtained by a receiver operating characteristic curve analysis indicated a sensitivity of 77.8% and specificity of 85.7% for pathological responders to NA-CRT. In addition, the patients with lower ADC values exhibited a greater pathological response to NA CRT (P=0.041). In conclusion, the ADC value of MRI of RC patients treated with NA CRT followed by surgery may provide valuable information to predict the response to NA-CRT. PMID- 26623065 TI - Efficacy and toxicity of nimotuzumab combined with radiotherapy in elderly patients with esophageal squamous cell carcinoma. AB - This study was conducted to assess the efficacy and toxicity of nimotuzumab combined with radiotherapy (RT) in elderly patients with esophageal squamous cell carcinoma. The clinical data of 16 esophageal squamous cell carcinoma patients, aged >70 years, who were initially treated with nimotuzumab combined with RT, were collected and retrospectively reviewed. The overall response and treatment toxicity were analyzed using SPSS software. All the patients completed the treatment schedule. The response to treatment was assessed at treatment completion and reassessed after 1-2 months: 1 patient achieved complete response (CR), 10 patients achieved partial response (PR), 4 patients exhibited stable disease and 1 patient developed disease progression and succumbed to radiation pneumonitis (RP) 1 month later. The overall response rate (CR+PR) was 68.8%. All 16 patients experienced grade 1-2 radiation esophagitis; no grade 3-4 toxicities were reported. There was one case of treatment-related mortality due to RP during the study. One patient developed a rash on the forearm. No hematological, gastrointestinal, hepatic or renal toxicities were observed. In conclusion, the toxicity of combined nimotuzumab with RT in elderly patients with esophageal cancer was tolerable. However, due to limitations associated with the retrospective nature of this study, the limited number of enrolled cases and the epidermal growth factor receptor expression determination prior to treatment, the efficacy of this treatment modality requires further investigation. PMID- 26623066 TI - Palliative chemotherapy followed by methylation inhibitor in high-risk acute myeloid leukemia: An in vitro and clinical study. AB - Decitabine (5-aza-2'-deoxycytidine; DAC) is a well-tolerated alternative to aggressive chemotherapy for leukemia, which induces differentiation and apoptosis of leukemic cells as a DNA hypomethylating agent. The aim of the present study was to investigate the feasibility of DAC sequentially combined with chemotherapy to reverse drug resistance. HL-60/ADR multidrug-resistant leukemia cells cultured in 96-well plates were pretreated with DAC for 72 h; varying concentrations of aclacinomycin (ACLA) were then added to the wells, cell proliferation was tested using the Cell Counting Kit-8 assay, and DNA methyltransferase 1 (DNMT1) protein expression was detected by western blot analysis. Furthermore, we analyzed the therapeutic efficacy in 7 patients with high-risk acute myeloid leukemia (AML) receiving induction therapy with DAC sequentially combined with cytarabine, ACLA and granulocyte-colony stimulating factor (CAG regimen). The proliferation inhibition rate of HL-60/ADR cells treated with DAC at concentrations of 0.5 and 1.0 umol/l sequentially combined with ACLA was significantly higher compared with that with ACLA alone (P<0.001 for both). DNMT1 expression was significantly repressed following treatment with 1.0 umol/l DAC. Of the 11 patients, 8 (72.7%) received induction therapy with DAC sequentially combined with CAG agents and achieved complete remission (CR) after 2 cycles of treatment; however, 3 (27.3%) patients did not achieve remission. Myelosuppression was observed in all 11 patients and pulmonary infections developed in 9 patients (81.8%) during the course of the study. At the last follow-up, 7 of the 8 patients who achieved CR remained in remission. The median follow-up was 6 months (range, 3-18 months). Therefore, pretreatment with DAC may increase the sensitivity of HL-60/ADR cells to ACLA via the epigenetic modulation of demethylation and the sequential administration of DAC and CAG regimen appears to be safe and effective for the treatment of patients with high-risk AML. PMID- 26623067 TI - Efficacy of vinorelbine-based neoadjuvant chemotherapy in breast cancer: A systematic review and meta-analysis of randomized controlled trials. AB - The present study aimed to compare the effects of vinorelbine-based neoadjuvant chemotherapy and vinorelbine-free regimens. A meta-analysis of all the relevant randomized controlled trials was performed to investigate the improvement in pathological complete response (pCR), overall response rate (ORR) and breast conserving surgery (BCS). The PubMed and Embase databases were searched for relevant studies reporting randomized controlled trials comparing vinorelbine based neoadjuvant chemotherapy with vinorelbine-free regimens until July 2013. Risk ratios/odds ratio and 95% confidence intervals (CIs) were used to estimate the association between vinorelbine in neoadjuvant chemotherapy and various efficacy outcomes. Fixed- or random-effect models were adopted to pool the data. Five eligible studies with a total of 1,495 patients were included in the meta analysis. Compared to vinorelbine-free chemotherapy, vinorelbine-based regimens demonstrated no significant improvement in clinical outcomes including: pCR [relative risk (RR)=1.016; 95% CI, 0.738-1.399; P=0.922], ORR (RR=1.048; 95% CI, 0.969-1.133; P=0.239) and BCS (RR=1.764; 95% CI, 0.734-4.239; P=0.205). However, vinorelbine-based regimens were associated with a lower incidence of grade 3-4 alopecia (OR, 0.617; 95% CI, 0.448-0.848; P=0.003). In a hierarchical analysis for patients who received neoadjuvant chemotherapy, the proportion of subjects achieving pCR was significantly increased when HER2-amplified (RR=2.31; 95% CI, 1.20-4.43; P=0.01) and hormone receptor negative (RR=0.488; 95% CI, 0.263-0.908; P=0.023). The present review confirms that neoadjuvant chemotherapy vinorelbine based regimens are unlikely to emerge as superior to pCR, ORR and BCS. Hierarchical analysis indicated that the HER2-amplified and hormone receptor negative patients were significantly associated with a pathological response rate. PMID- 26623068 TI - An unusual cause of respiratory failure in a colon cancer patient. AB - Permanent central venous catheters (CVC), such as Port-a-Cath(r), Hickmann(r) or PICC(r), are widely used in oncology patients for cancer treatment. Thrombosis is a frequent complication that should be ruled out, as it is associated with potentially severe infection and hemodynamic consequences. This is the case report of a male patient who was undergoing chemotherapy for colon cancer. The patient presented with an atrial mass secondary to a CVC-related organized thrombus located inside the atrial cavity. The mass was inducing a massive right to-left intracardial shunt due to a persistent foramen ovale and signs of respiratory failure that required surgical intervention to remove the intracardial mass. PMID- 26623069 TI - Short-term outcomes between laparoscopy-assisted and open colorectomy for colorectal cancer in elderly patients: A case-matched control study. AB - With the increase in life expectancy, surgical intervention for colorectal cancer (CRC) is more frequently performed in elderly patients. This retrospective study was designed to compare short-term outcomes between laparoscopy-assisted colorectomy (LC) and open colorectomy (OC) in elderly patients with CRC. A total of 89 CRC patients aged >=75 years undergoing LC were matched with 89 counterparts undergoing OC. The matching criteria included general information and preoperative status. The operative data and short-term postoperative outcomes were compared. Following analysis, patients in the LC and OC groups were comparable for the matching criteria. Compared with the OC group, the operative time was longer (P=0.046), but the estimated blood loss (P<0.001) and intraoperative transfusion (P=0.042) were less in the LC group. As regards short term postoperative outcomes, the duration of postoperative hospital stay was shorter (P=0.001) and the incidence of wound complications was lower (P=0.044) with LC. The overall complication, other complications, reoperation and mortality rates were comparable between the two groups. In conclusion, considering the operative variables and short-term outcomes, LC is a safe procedure and appears to be superior to OC for elderly patients with CRC. PMID- 26623070 TI - Comparative analysis of the efficacy and safety of modified FOLFOX-6 and DCF regimens as first-line treatment in advanced gastric cancer. AB - The aim of this study was to retrospectively compare the efficacy and toxicity of the oxaliplatin + 5-fluorouracil (5-FU) + leucovorin (LV) regimen [modified (m)FOLFOX-6] with that of the docetaxel + cisplatin + 5-FU regimen (DCF) in patients with advanced gastric cancer (AGC). A total of 72 patients received DCF (75 mg/m2 docetaxel and 75 mg/m2 cisplatin on day 1 and 750 mg/m2 5-FU on days 1 5) every 21 days, whereas 54 patients received mFOLFOX-6 (85 mg/m2 oxaliplatin and 400 mg/m2 LV as a 2-h infusion, followed by a 5-FU bolus of 400 mg/m2 and 2,400 mg/m2 5-FU as a 46-h continuous infusion) every 14 days. In the DCF arm, 55 (76.4%) of the patients received prophylactic granulocyte colony-stimulating factor (G-CSF), 48-72 h following completion of chemotherapy. The median follow up of the study was 12.1 months. The overall response rate (ORR) was 37.0% for mFOLFOX-6 and 40.3% for DCF (P=0.72). The median time to progression was 6.5 and 6.2 months in the mFOLFOX-6 and DCF arms, respectively (P=0.70). The median overall survival was 11.4 and 13.5 months in the mFOLFOX-6 and DCF arms, respectively (P=0.72). The rates of hematological toxicity did not differ between the two arms. However, in the subgroup analysis, grade 3-4 neutropenia and febrile neutropenia were significantly more common among patients who had not received G-CSF prophylaxis in the DCF arm. The incidence of grade 3-4 nausea/vomiting and diarrhea were significantly higher in the DCF arm. In conclusion, the present study demonstrated that the efficacy of the mFOLFOX-6 regimen was comparable to that of the DCF regimen in AGC patients. In addition, the benefit of G-CSF prophylaxis in conjunction with the DCF regimen was demonstrated. PMID- 26623071 TI - Diagnostic accuracy of serum squamous cell carcinoma antigen and squamous cell carcinoma antigen-immunoglobulin M for hepatocellular carcinoma: A meta-analysis. AB - A number of individual studies have evaluated the diagnostic efficiency of serum squamous cell carcinoma antigen (SCCA) and SCCA-immunoglobulin (IgM) for diagnosing hepatocellular carcinoma (HCC), but the results have been conflicting. The aim of this study was to determine the diagnostic accuracy of serum SCCA and SCCA-IgM for HCC. A systematic review of related studies was conducted and relevant data on the accuracy of serum SCCA and SCCA-IgM in the diagnosis of HCC were pooled using random-effects models. Summary receiver operating characteristic curve (SROC) analysis was used to summarize the overall test performance. A total of 12 studies were included in our meta-analysis. The summary estimates for serum SCCA and SCCA-IgM for HCC diagnosis in the included studies were as follows: Sensitivity = 0.59 (95% CI: 0.56-0.62) vs. 0.60 (95% CI: 0.56-0.63); specificity = 0.76 (95% CI: 0.73-0.79) vs. 0.70 (95% CI: 0.67-0.73); diagnostic odds ratio (DOR) = 6.68 (95% CI: 3.71-12.03) vs. 7.32 (95% CI: 3.31 16.15); and area under the SROC curve = 0.7826 vs. 0.7955. Therefore, SCCA and SCCA-IgM exhibited moderate diagnostic accuracy for HCC. Due to the design limitations, the results of published studies should be interpreted with caution. In addition, well-designed studies including larger sample sizes should be conducted to rigorously evaluate the diagnostic value of SCCA and SCCA-IgM. PMID- 26623072 TI - Efficacy of the smaller target volume for stage III non-small cell lung cancer treated with intensity-modulated radiotherapy. AB - The present study reports the local recurrence, distant metastasis, progression free survival, overall survival and radiation toxicity between two arms of stage III non-small cell lung cancer (NSCLC) treated with intensity-modulated radiotherapy (IMRT); one arm with clinical target volume (CTV) and the other without CTV. The two arms of local recurrence, distant metastasis, progression free survival, overall survival, grade 3-4 radiation esophagitis and hematological toxicity had no statistical significance. However, the grade 3-4 radiation pneumonia rate of the group without CTV was significantly decreased. This supports the concept that stage III NSCLC treated with IMRT, which omitted CTV, can reduce the occurrence of radiation pneumonia. The aim of the present study was to analyze the feasibility of the smaller target volume for stage III NSCLC treated with IMRT. Data from 105 patients with stage III NSCLC who were hospitalized and received IMRT between January 1, 2008 and November 30, 2012 were retrospectively analyzed. A total of 55 cases were irradiated with target volume without CTV and 50 cases were irradiated with CTV. Dose prescription was 100% PTV at 54-63 Gy/27-35 F/5.4-7 weeks. The two arms of the patient characteristics and treatment deliveries had no statistical significance. The two arms of the patients were compared for local recurrence, distant metastasis, progression-free survival, overall survival and radiation-related toxicity. In the arms without and with CTV, the local relapse and distant metastases rates were 32.7 and 32.0% (P=1.000) and 56.4 and 48.0% (P=0.946), respectively. The median progression-free survival time for the two arms was 9 months (P=0.619). The 1-, 2- and 3-year survival rates of the arms without and with CTV were 74.5, 43.6 and 23.6%, and 70.0, 46.0 and 20.0% (P=0.956), respectively. In the two arms, grade 3-4 radiation esophagitis and hematological toxicity had no statistical significance. However, in the arm without CTV, grade 3-4 radiation pneumonia was only 5.5%, compared with 18.0% in the arm with CTV (P=0.044). In conclusion, the smaller target volume for stage III NSCLC treated with IMRT was feasible. PMID- 26623073 TI - Investigation of the potential role of preoperative chemotherapy in treatment for gastric cancer with outlet obstruction. AB - Preoperative chemotherapy is currently recognized as the recommended treatment for advanced gastric cancer. Whether there is a role of preoperative chemotherapy in the treatment for advanced gastric cancer with gastric outlet obstruction (GOO) is unknown. In order to explore the potential feasibility of preoperative chemotherapy for advanced gastric cancer with GOO, and to encourage the probe into optimal treatment strategies for advanced gastric cancer with GOO in the current era of preoperative chemotherapy prevailing, a systematic literature search was conducted with a multistage process. The characteristics of the retrieved publications were summarized and the essential information was extracted. Only 11 studies associated with preoperative chemotherapy for advanced gastric cancer with GOO were identified. Among them, 9 were case reports, while the other 2 were research reports of retrospective studies. None were of prospective studies. The paucity of the literature in this field is a marked finding of the present study, which reports the emerging attempts at preoperative chemotherapy for advanced gastric cancer patients with GOO, as no high-quality data are available. The definite role of chemotherapy as an initial treatment for advanced gastric cancer patients with GOO remains unclear. Clinical trials are expected to be conducted in order to explore the feasibility, safety and efficacy of preoperative chemotherapy for advanced gastric cancer patients with GOO. PMID- 26623074 TI - S-1 treatment leading to complete remission of advanced duodenal adenocarcinoma: A case report. AB - Primary duodenal adenocarcinoma (DA) is a rare malignant neoplasm, accounting for 1% of all gastrointestinal tract carcinomas. This is the case report of a 40-year old male patient with a duodenal lesion detected on abdominal magnetic resonance imaging and diagnosed by endoscopy and biopsy as DA. Following surgical resection and histopathological examination, the tumor was confirmed as differentiated duodenal neuroendocrine carcinoma with liver metastasis (TxNxM1). The patient received 8 cycles of palliative chemotherapy with oxaliplatin and S-1 and achieved a clinically complete response, with a treatment-related toxicity profile that was considered as tolerable. Therefore, this regimen exhibited favorable efficacy and a tolerable toxicity profile for the treatment of DA in this case. PMID- 26623075 TI - Factors associated with health-related quality of life in Korean older workers. AB - OBJECTIVES: The prevalence of aged individuals in the Korean workforce continues to increase. This research determined the health and working conditions of Korean older wage workers and confirmed the effects of factors on the health-related quality of life of Korean older workers. METHODS: Of the 25,534 persons surveyed in the fifth Korea National Health and Nutrition Examination Survey, 1368 older (>55 years of age) wage workers without missing variables were selected. Their general characteristics, health status (cardiovascular disease, musculoskeletal disease, and mental health), working conditions (type of occupation, employment status, full- or part-time work, weekly average working hours, and shift work), and health-related quality of life assessed by the EQ-5D questionnaire were examined. RESULTS: The mean values of the EQ-5D index of the male and female older workers were 0.956 +/- 0.087 and 0.917 +/- 0.124, respectively (p < 0.001). The factors that caused statistically significant differences in the EQ-5D index for all subjects were age, education, household income, cerebro-cardiovascular event, osteoarthritis, musculoskeletal pain, stress, occupation type, employment status, and working hours. In logistic regression analysis, the factors that associated with perceived problems in each EQ-5D dimensions were age, musculoskeletal pain, stress, diabetes, smoking, occupation type, employment status, and working hours. CONCLUSIONS: To eventually raise the quality of life of older workers through health maintenance and management, it is necessary to manage related factors that include of musculoskeletal pain and diseases, stress, diabetes, smoking, occupation, employment status, and working hours. PMID- 26623076 TI - Tomato expressing Arabidopsis glutaredoxin gene AtGRXS17 confers tolerance to chilling stress via modulating cold responsive components. AB - Chilling stress is a production constraint of tomato, a tropical origin, chilling sensitive horticultural crop. The development of chilling tolerant tomato thus has significant potential to impact tomato production. Glutaredoxins (GRXs) are ubiquitous oxidoreductases, which utilize the reducing power of glutathione to reduce disulfide bonds of substrate proteins and maintain cellular redox homeostasis. Here, we report that tomato expressing Arabidopsis GRX gene AtGRXS17 conferred tolerance to chilling stress without adverse effects on growth and development. AtGRXS17-expressing tomato plants displayed lower ion leakage, higher maximal photochemical efficiency of photosystem II (Fv/Fm) and increased accumulation of soluble sugar compared with wild-type plants after the chilling stress challenge. Furthermore, chilling tolerance was correlated with increased antioxidant enzyme activities and reduced H2O2 accumulation. At the same time, temporal expression patterns of the endogenous C-repeat/DRE-binding factor 1 (SlCBF1) and CBF mediated-cold regulated genes were not altered in AtGRXS17 expressing plants when compared with wild-type plants, and proline concentrations remained unchanged relative to wild-type plants under chilling stress. Green fluorescent protein -AtGRXS17 fusion proteins, which were initially localized in the cytoplasm, migrated into the nucleus during chilling stress, reflecting a possible role of AtGRXS17 in nuclear signaling of chilling stress responses. Together, our findings demonstrate that genetically engineered tomato plants expressing AtGRXS17 can enhance chilling tolerance and suggest a genetic engineering strategy to improve chilling tolerance without yield penalty across different crop species. PMID- 26623078 TI - Optimal interventional strategy for the treatment of coronary in-stent restenosis. PMID- 26623077 TI - Gene expression of the zinc transporter ZIP14 (SLC39a14) is affected by weight loss and metabolic status and associates with PPARgamma in human adipose tissue and 3T3-L1 pre-adipocytes. AB - BACKGROUND: The expansion and function of adipose tissue are important during the development of insulin resistance and inflammation in obesity. Zinc dyshomeostasis is common in obese individuals. In the liver, zinc influx transporter ZIP14, affects proliferation and glucose metabolism but the role of ZIP14 in adipose tissue is still unknown. This study investigates ZIP14 gene expression in human adipose tissue before and after weight loss as well as the regulation of ZIP14 during early adipogenesis. METHODS: Fourteen obese individuals were investigated before and after a 10 week weight loss intervention and compared to 14 non-obese controls. Gene expressions of ZIP14 and peroxisome proliferator-activated receptor gamma (PPARgamma) were measured in subcutaneous adipose tissue and correlated with metabolic and inflammatory markers. Further, we investigated gene expression of ZIP14 and PPARgamma during early adipogenesis of 3T3-L1 pre-adipocytes, together with an in silico analysis of PPARgamma binding motifs in the promoter sequence of ZIP14. RESULTS: ZIP14 was down regulated in obese individuals compared to non-obese controls (p = 0.0007) and was up-regulated after weight loss (p = 0.0005). Several metabolic markers of clinical importance, including body mass index, triglyceride, and insulin resistance, were inversely correlated with ZIP14. During early adipogensis an up regulation of ZIP14 gene expression was found. PPARgamma gene expression was positively correlated with the ZIP14 gene expression in both adipose tissue and during adipogenesis. However, in silico analysis revealed that the ZIP14 promoter does not contain PPARgamma-binding motifs. CONCLUSIONS: We hypothesize that ZIP14 mediated zinc influx might directly influence PPARgamma activity and that ZIP14 may regulate expansion and function of adipose tissue and serve as a potential biomarker for metabolic stress. PMID- 26623079 TI - Treatment of coronary in-stent restenosis-evidence for universal recommendation? PMID- 26623080 TI - Aortic regurgitation and heart valve disease in mice. PMID- 26623081 TI - Network meta-analyses on in-stent restenosis treatment: dealing with complexity to clarify efficacy and safety. PMID- 26623082 TI - The use of etomidate for rapid sequence induction in septic patients. AB - There is continued debate about the clinical ramifications of single-dose etomidate for rapid sequence induction (RSI) in patients with sepsis. This history of this debate includes early studies identifying an association between etomidate infusions and mortality with adrenal suppression as a hypothesized mechanism. More recent data describing the high prevalence of adrenal insufficiency in patients with sepsis has prompted additional investigation as to the clinical effects of single-dose etomidate when utilized as an agent in RSI. Acknowledging the small number and heterogeneity of studies on this topic, we feel that the recent meta-analysis by Gu et al. provides an accurate and complete assessment of the existing literature on this topic. We continue to utilize etomidate for the purposes of RSI in this critically ill patient population and feel that the current data supports this position. PMID- 26623083 TI - The use of statins in patients with heart failure: more questions than answers. AB - The use of statins to treat patients with heart failure (HF) is controversial due to conflicting results from large, prospective, randomized, placebo-controlled trials and other smaller studies. A recent comprehensive, well-conducted meta analysis from Preiss and colleagues sought to determine whether statin therapy had an effect on major HF outcomes such as hospitalization and death. Although the study demonstrated a significant effect of statin therapy on HF hospitalizations, several limitations involving the participant data and nature of statin used in the analyzed trials raise questions about the inferences that can be drawn from the study results. PMID- 26623085 TI - Hyperglycemic endothelial dysfunction: does it happen and does it matter? PMID- 26623084 TI - In-stent restenosis: local drug delivery with a stent or balloon? PMID- 26623086 TI - The case of stroke prevention by left atrial appendage occlusion in patients with atrial fibrillation-can we close the file? PMID- 26623087 TI - Etomidate in sepsis: understanding the dilemma. PMID- 26623088 TI - Statin therapy for heart failure: to prescribe or not? PMID- 26623089 TI - Safer lung biopsy techniques: fewer patients with pneumothorax, fewer chest tube insertions. PMID- 26623090 TI - Comments on characterization of solitary pulmonary nodules with 18F-FDG PET/CT relative activity distribution analysis. PMID- 26623091 TI - Rapid needle-out patient-rollover approach after CT-guided lung biopsy: challenges and future directions. PMID- 26623092 TI - High risk percutaneous coronary interventions-significance of left ventricular assist device for clinical practice. PMID- 26623093 TI - Digital versus traditional air leak evaluation after elective pulmonary resection: a prospective and comparative mono-institutional study. AB - BACKGROUND: The increased demand to reduce costs and hospitalization in general pushed several institution worldwide to develop fast-tracking protocols after pulmonary resections. One of the commonest causes of protracted hospital stay remains prolonged air leaks (ALs). We reviewed our clinical practice with the aim to compare traditional vs. digital chest drainages in order to evaluate which is the more effective to correctly manage the chest tube after pulmonary resection. METHODS: All patients submitted to elective pulmonary resection for lung malignancies, between April to December, 2014 in our General Thoracic Surgery Department were included in the study. The primary outcome was the chest tube duration, the secondary the postoperative overall hospitalization. Significant differences between traditional and digital groups were investigated with logistic regression models. Numerical variables between the groups were compared by means of the unpaired Wilcoxon-Mann-Whitney test. RESULTS: Both series of patients were comparable for clinical, surgical and pathological characteristics. Chest tube duration showed to be significantly shorter in the digital group (3 vs. 5 days, P=0.0009), while the hospitalization was longer in traditional one [8 vs. 7 days in digital drainage (DD); P=0.0385]. No chest drainage replacement was required at 30-day, in both groups. CONCLUSIONS: We were able to demonstrate that patients managed with a digital system experienced a shorter chest tube duration as well as a lower overall hospital length of stay, compared to those who received the traditional drainage (TD). PMID- 26623094 TI - Effects of long-term smoking on the activity and mRNA expression of CYP isozymes in rats. AB - BACKGROUND: To investigate the effect of long-term smoking on the activity and mRNA expression of cytochrome P450 (CYP) enzymes. METHODS: Sprague-Dawley rats were exposed to passive smoking 6 cigarettes per day for 180 days. A cocktail solution which contained phenacetin (20 mg/kg), tolbutamide (5 mg/kg), chlorzoxazone (20 mg/kg) and midazolam (10 mg/kg) was given orally to rats. Blood samples were collected at pre-specified time points and the concentrations of probe drugs in plasma were determined by HPLC-MS/MS. The corresponding pharmacokinetic parameters were calculated by DAS 3.0. In addition, real-time RT PCR was used to analyze the mRNA expression of CYP1A2, CYP2C11, CYP2E1 and CYP3A1 in rat liver. RESULTS: There were no significant influences of pharmacokinetic profiles of chlorzoxazone in long-term smoking pretreated rats. But many pharmacokinetic profiles of phenacetin, tolbutamide, and midazolam in long-term smoking pretreated rats were affected significantly (P<0.05). The results suggested that long-term smoking had significant inhibition effects on CYP2C11 and CYP3A1 while CYP1A2 enzyme activity was induced. Furthermore, Long-term smoking had no effects on rat CYP2E1. The mRNA expression results were consistent with the pharmacokinetic results. CONCLUSIONS: Alterations of CYP450 enzyme activities may fasten or slow down excretion with corresponding influence on drug efficacy or toxicity in smokers compared to nonsmokers, which may lead to clinical failures of lung cancer therapy or toxicity in smokers. PMID- 26623095 TI - High mobility group box 1: a novel mediator of Th2-type response-induced airway inflammation of acute allergic asthma. AB - BACKGROUND: High mobility group box 1 (HMGB1) is an inflammatory mediator involved into the advanced stage of systemic inflammatory response syndrome (SIRS), and is over-expressed in bacterial sepsis and hemorrhagic shock. Recently, it has been found that the HMGB1 was abnormally expressed in induced sputum and plasma of asthmatic patients. However, the precise role of HMGB1 in the acute allergic asthma is unclear. Therefore, we aim to investigate the role HMGB1 in regulating airway inflammation of acute allergic asthma and its possible mechanism in this study. METHODS: Forty-eight BALB/c female mice were randomly divided into four groups: control group (Control), asthma group (Asthma), HMGB1 group (HMGB1) and anti-HMGB1 (HMGB1 monoclonal antibody of mice) group (Anti HMGB1). Acute allergic asthma mice models were established by ovalbumin (OVA) challenge. Then, we measured the levels of HMGB1 in bronchoalveolar lavage fluid (BALF) and lung tissue of mice. Finally, after exogenous HMGB1 and/or anti-HMGB1 administration, pulmonary function test, histological analysis, Western blot, cytological analysis and ELISA assay were performed to explore the effect of HMGB1 in acute allergic asthma. RESULTS: The levels of HMGB1 in BALF and lung tissue and the expression of HMGB1 protein in the lung tissue of asthma group were significantly higher than those in control group, respectively (P<0.01). Moreover, the HMGB1 group was showed an increased mucus secretion and infiltration of eosinophils and neutrophils in the airway of asthma mice, and a decrease of pulmonary function, compared to control group (P<0.01, respectively). Meanwhile, exogenous HMGB1 could increase the levels of IL-4, IL-5, IL-6, IL-8 and IL-17, whereas could reduce the IFN-gamma in the BALF and lung tissue (P<0.05, respectively). Exogenous HMGB1 could enhance GATA3 expression of Th2 cells and attenuate the T-bet expression of Th1 cells (P<0.05, respectively), which could be abrogated after inhibiting HMGB1. CONCLUSIONS: HMGB1 could aggravate eosinophilic inflammation in the airway of acute allergic asthma through inducing a dominance of Th2-type response and promoting the neutrophilic inflammation. PMID- 26623096 TI - Bronchial sleeve resection or pneumonectomy for non-small cell lung cancer: a propensity-matched analysis of long-term results, survival and quality of life. AB - BACKGROUND: No randomized studies exist comparing pneumonectomy (PN) and sleeve lobectomy (SL). We evaluated surgical results and long-term quality of life in patients operated on for central non-small cell lung cancer (NSCLC) using either SL or PN. METHODS: A total of 641 NSCLC patients underwent surgery 2000-2010. SL was performed in 40 (6.2%) and PN in 67 (10.5%). In 2011, all surviving patients were sent a 15D Quality of Life Questionnaire which 83% replied. Propensity-score matching analysis was utilized to compare the groups. RESULTS: Thirty-two bronchial (18 right/14 left), seven vasculobronchial (3 right/4 left), one right wedge SL, and 18 right and 22 left PN were performed. Preoperatively, the Charlson Comorbidity Index (CCI) score, forced expiratory volume in 1 s (FEV1) and diffusion capacity did not differ between groups. The perioperative complication rate and pattern were similar, but SL group had less major complications (P<0.027). One perioperative death (2.5%) occurred in SL group and four (6%) in PN. The 90-day mortality rate was 5% (n=2) for SL and 7.5% (n=5) for PN. In the follow-up total cancer recurrence did not differ (P=0.187). Quality of life measured by 15D showed no significant difference in separate dimensions or total score, except tendency to favor SL in moving or breathing. The 5-year survival did not differ between groups (P=0.458), but no deaths were observed in SL group after 5 years. CONCLUSIONS: Due to less major operative complications and better long-term survival, we would advocate using SL when feasible, but in patients tolerating PN it should be considered if SL seems not to be oncologically sufficiently radical. PMID- 26623097 TI - The efficacy and toxicities of combined lobaplatin with paclitaxel as a first line chemotherapy for advanced esophageal squamous cell carcinoma. AB - BACKGROUND: To assess the efficacy and toxicities of combined lobaplatin with paclitaxel (LP) as a first line chemotherapy in esophageal cancer. METHODS: The clinical data of 45 patients with esophageal squamous cell carcinoma treated initially with lobaplatin-paclitaxel chemotherapy were collected and reviewed retrospectively. The overall response, treatment toxicities and dysphagia relief were analyzed with SPSS software. RESULTS: The overall response rate was 42.2%, with 1 patient (2.2%) showing complete remission, 18 patients (40.0%) with partial remission, 19 (42.2%) with stable disease (SD), and 7 (15.6%) with progressive disease, respectively. The most common hematological toxicity was leucopenia with grade 0, I, II, III and IV in 16 (35.6%), 10 (22.2%), 11 (24.4%), 7 (15.6%), and 1 patient (2.2%), respectively. Thirty-seven patients (82.2%) experienced grade I-II nausea/vomiting without grade III-IV instances occurring. Four patients (8.9%) experienced grade I hepatotoxicity. No nephrotoxicity was observed. Five in thirteen patients treated with concurrent chemoradiotherapy (CRT) suffered severe radiation pneumonitis. The dysphagia resolved or improved in 32 patients (71%). CONCLUSIONS: Lobaplatin-paclitaxel showed a significant antitumor effect to squamous esophageal cancer with manageable toxicities. Limitation of the surveillance time and the retrospective nature, the effect that based on these data formal prospective trials appear warranted and are needed prior to routine first line use of this regimen. PMID- 26623098 TI - Lower airway inflammation and hyperresponsiveness in non-asthmatic patients with non-allergic rhinitis. AB - BACKGROUND: Potential associations between non-allergic rhinitis (NAR) and asthma have been verified epidemiologically, but these associations remain not very clear. It is necessary to further explore the possible implication of lower airway abnormities in NAR patients but without asthma. This study aims to determine lower airway hyperresponsiveness (AHR), inflammation and lung function in non-asthmatic patients with NAR. METHODS: We recruited 262 non-asthmatic patients with NAR, 377 with AR and 264 healthy subjects. All subjects were non smokers who underwent meticulous history taking, nasal examination, allergen skin prick test (SPT), blood routine test, measurement of fractional exhaled nitric oxide (FeNO), methacholine bronchial challenge test and induced sputum eosinophil count, in this order. RESULTS: Compared with healthy subjects, non-asthmatic patients with NAR yielded markedly lower FEV1/FVC, maximal mid-expiratory flow (MMEF), mid-expiratory flow when 50% of FVC has been expired (MEF50%) and mid expiratory flow when 75% of FVC has been expired (MEF25%) (P<0.05). Differences in spirometry between group AR and NAR were unremarkable (P>0.05). Patients with NAR yielded higher rate of AHR and higher FeNO levels than healthy subjects but lower than those with AR. The proportion of lower airways disorders (sputum eosinophilia, high FeNO levels or AHR) was highest in group AR (70.8%), followed by NAR (53.4%) and healthy subjects (24.2%) (P<0.01). However, sputum eosinophils in NAR patients were not higher compared with healthy subjects (P>0.05). Sputum eosinophils and FeNO had significant correlation with positive AHR and MMEF in group AR but not in NAR. CONCLUSIONS: Non-asthmatic patients with NAR harbor lower AHR, small airways dysfunction and inflammation, despite being less significant than those with AR. This offers clues to unravel the link between NAR and asthma. PMID- 26623099 TI - Pharmacological treatment response according to the severity of symptoms in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Pharmacological management of chronic obstructive pulmonary disease (COPD) is recommended according to the individualized assessment of symptoms and exacerbation risks. The aim of this study was to determine the relationship between the baseline Modified British Medical Research Council (mMRC) dyspnea scale and the COPD Assessment Test (CAT) score and pharmacological treatment response in patients with COPD. METHODS: A total of 102 stable COPD patients who were enrolled in prospective cohort studies were analyzed. Pharmacological treatment responses after a 3-month treatment were assessed by changes on the mMRC dyspnea scale, CAT scores, and spirometric pulmonary functions. RESULTS: Sixty-two patients with a mMRC dyspnea scale <=1 were classified as having "less dyspnea" and 40 patients with a mMRC dyspnea scale >=2 as having "more dyspnea". After a 3-month treatment, the mean mMRC dyspnea scale in the "more dyspnea" group was significantly decreased versus the "less dyspnea" group; however, there were no significant differences in CAT score changes or spirometric pulmonary function changes between the two groups. Baseline mMRC scales (Spearman's rho = 0.591, P<0.001) and baseline CAT scores (Pearson's r =-0.337, P=0.001) were significantly correlated with their changes after a 3-month treatment. Multiple logistic regression analysis demonstrated that baseline mMRC scale and CAT score were the only independent predictors of improvement greater than a minimal clinically significant difference after treatment. CONCLUSIONS: The severity of COPD symptoms is associated with their response to pharmacotherapy. COPD patients with a higher baseline mMRC dyspnea scale and CAT score experience greater symptom reduction by pharmacotherapy. PMID- 26623100 TI - Clinical feasibility and efficacy of video-assisted thoracic surgery (VATS) anatomical resection in patients with central lung cancer: a comparison with thoracotomy. AB - BACKGROUND: The aim of this study is to evaluate the clinical feasibility and efficacy of video-assisted thoracoscopic surgery (VATS) anatomical pulmonary resection in patients with central lung cancer. METHODS: Between July 2004 and December 2011, 465 patients underwent anatomical pulmonary resection and systematic mediastinal lymph node sampling or dissection for central lung cancer. Because patients were not randomized to receive VATS, clinical outcomes were compared using a propensity score matching design, giving 88 patients in each group. RESULTS: A lobectomy was attempted in 69 patients of the thoracotomy group and 64 of the VATS group, bilobectomy in 19 patients of the thoracotomy group and 21 of the VATS group, and segmentectomy in 3 patients of the VATS group. There were no differences in the anatomical distribution of pulmonary resections between the two groups. There was no operation related in-hospital mortality. There were 34 postoperative complications in 30 patients, without significant differences between the two groups. The median hospital stay and chest tube indwelling period of the VATS group were shorter than those of the thoracotomy group by 2 days and 1 day, respectively (P<0.05). During a median follow-up of 32.5 months (range, 0.5-95.8 months), there was no difference between the two groups in 3-year recurrence-free or overall survivals (OS). CONCLUSIONS: VATS anatomical pulmonary resection is safe and feasible for central lung cancer, providing a low operative mortality and favorable outcomes in selected patients. Further case studies with long-term outcome data are necessary to verify our conclusions. PMID- 26623101 TI - Comparison of clinicopathologic features and survival between eastern and western population with esophageal squamous cell carcinoma. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the major histologic subtype of esophageal cancer, characterized by a high mortality rate and geographic differences in incidences. It is unknown whether there is difference between "eastern" ESCC and "western" ESCC. This study is attempted to demonstrate the hypothesis by comparing ESCC between Chinese residents and Caucasians living in the US. METHODS: The data sources of this study are from United States SEER limited-use database and Shanghai Cancer Registries by Shanghai Municipal Center for Disease Control (SMCDC). Consecutive, non-selected patients with pathologically diagnosed ESCC, between January 1, 2002 and December 31, 2006, were included in this analysis. 1-year, 3-year and 5-year survival estimates were computed and compared between two populations. A Cox proportional hazards model was used to determine factors affecting survival differences. RESULTS: A total of 1,718 Chinese, 1,624 Caucasians ESCC patients with individual American Joint Commission on Cancer (AJCC) staging information were included in this study. The Caucasian group had a significantly higher proportion of female patients than Chinese (38.24% vs. 18.68% P<0.01). ESCC was diagnosed in Chinese patients at an earlier age and stage than Caucasians. Generally, Chinese patients had similar overall survival rate with Caucasian by both univariate and multivariate analysis. Overall survival was significantly worse only in male Caucasians compared to Chinese patients (median survival time, 12.4 vs. 14.5 months, P<0.01, respectively). CONCLUSIONS: ESCC from eastern and western countries might have some different features. These differences need to be taken into account for the management of ESCC patients in different ethnic groups. PMID- 26623102 TI - Asiatic acid inhibits cardiac hypertrophy by blocking interleukin-1beta-activated nuclear factor-kappaB signaling in vitro and in vivo. AB - BACKGROUND: Activated interleukin (IL)-1beta signaling pathway is closely associated with pathological cardiac hypertrophy. This study investigated whether asiatic acid (AA) could inhibit IL-1beta-related hypertrophic signaling, and thus suppressing the development of cardiac hypertrophy. METHODS: Transverse aortic constriction (TAC) induced cardiac hypertrophy in C57BL/6 mice and cultured neonatal cardiac myocytes stimulated with IL-1beta were used to evaluate the role of AA in cardiac hypertrophy. The expression of atrial natriuretic peptide (ANP) was evaluated by quantitative polymerase chain reaction (qPCR) and the nuclear factor (NF)-kappaB binding activity was measured by electrophoretic mobility shift assays (EMSA). RESULTS: AA pretreatment significantly attenuated the IL 1beta-induced hypertrophic response of cardiomyocytes as reflected by reduction in the cardiomyocyte surface area and the inhibition of ANP mRNA expression. The protective effect of AA on IL-1beta-stimulated cardiomyocytes was associated with the reduction of NF-kappaB binding activity. In addition, AA prevented TAC induced cardiac hypertrophy in vivo. It was found that AA markedly reduced the excessive expression of IL-1beta and ANP, and inhibited the activation of NF kappaB in the hypertrophic myocardium. CONCLUSIONS: Our data suggest that AA may be a novel therapeutic agent for cardiac hypertrophy. The inhibition of IL-1beta activated NF-kappaB signaling may be the mechanism through which AA prevents cardiac hypertrophy. PMID- 26623103 TI - A comparative analysis of lung cancer patients treated with lobectomy via three dimensional video-assisted thoracoscopic surgery versus two-dimensional resection. AB - BACKGROUND: Three-dimensional (3D) vision systems are now available for thoracic surgery. It is unclear whether 3D video-assisted thoracic surgery (VATS) is superior to 2D VATS systems. This study aimed to compare the operative and perioperative data between 2D and 3D VATS lobectomy (VTL) and to identify the actual role of 3D VTL in thoracic surgery. METHODS: A two-institutional comparative study was conducted from November 2013 to November 2014 at Liaoning Cancer Hospital & Institute and the First Affiliated Hospital of Guangzhou Medical University, China, of 300 patients with resectable non-small cell lung cancer (NSCLC). Patients were assigned to receive either the 3D VATS (n=150) or 2D VATS (n=150) lobectomy. The operative and perioperative data between 2D VATS and 3D VATS were compared. RESULTS: Although there was no significant difference between the two groups regarding the incidence of each single complication, a significantly less operative time was found in the 3D VATS group (145 min) than in the 2D VATS group (176 min) (P=0.006). Postoperative mortality rates in 3D VATS and 2D VATS groups were both 0%.No significant difference was found between groups for estimated blood loss (P=0.893), chest drainage tube placement time (P=0.397), length of hospital stay (P=0.199), number of lymph nodes resected (P=0.397), postoperative complications (P=0.882) and cost of care (P=0.913). CONCLUSIONS: Early results of this study demonstrate that the 3D VATS lobectomy procedure can be performed with less operative time. 3D VATS and 2D VATS lobectomy are both safe procedures in first-line surgical treatment of NSCLC. PMID- 26623104 TI - Phosphatidylethanolamine-binding protein 4 promotes lung cancer cells proliferation and invasion via PI3K/Akt/mTOR axis. AB - BACKGROUND: While phosphatidylethanolamine-binding protein 4 (PEBP4) is a key factor in the malignant proliferation and metastasis of tumor cells, the exact regulatory network governing its roles remains unclear. This study was designed to investigate the effect of PEBP4 on PI3K/Akt/mTOR pathway and explore its molecular network that governs the proliferation and metastasis of tumor cells. METHODS: After the recombinant plasmid pcDNA3.1-PEBP4 was constructed, the recombinant plasmid pcDNA3.1-PEBP4 and PEBP4-targeting siRNA were transfected into lung cancer HCC827 cell line. The expressions of PI3K/Akt/mTOR pathway components in HCC827 cells in each group were determined using Western blotting. In the HCC827 cells, the effect of PI3K pathway inhibitor LY294002 on the expressions of PI3K/Akt/mTOR pathway components under the effect of PEBP4 was determined using Western blotting, and the effects of LY294002 on the cell viability, proliferation, and migration capabilities under the overexpression of PEBP4 were determined using MTT method, flow cytometry, and Transwell migration assay. Furthermore, the effect of mTOR inhibitor rapamycin (RAPA) on the expressions of PI3K/Akt/mTOR pathway components under the effect of PEBP4 was determined using Western blotting, and the effects of RAPA on the cell viability, proliferation, and migration capabilities under the overexpression of PEBP4 were determined using MTT method, flow cytometry, and Transwell migration assay. RESULTS: As shown by Western blotting, the protein expressions of p-Akt and phosphorylated mTOR (p-mTOR) were significantly higher in the pcDNA3.1-PEBP4 transfected group than in the normal control group and PEBP4 siRNA group (P<0.05); furthermore, the protein expressions of p-Akt and p-mTOR significantly decreased in the PEBP4 targeting siRNA-transfected group (P<0.05). Treatment with LY294002 significantly inhibited the protein expressions of p-Akt and p-mTOR in HCC827 cells (P<0.05). In contrast, treatment with RAPA only significantly inhibited the protein expression of p-mTOR (P<0.05). As shown by MTT, flow cytometry, and Transwell migration assay, both LY294002 and RAPA could significantly lower the viability of HCC827 cells and inhibit their proliferation and invasion (P<0.05); meanwhile, they could reverse the effect of PEBP4 in promoting the proliferation and migration of HCC827 cells (P<0.05). CONCLUSIONS: The overexpression of PEBP4 increases the phosphorylation levels of Akt and mTOR in lung cancer cells. The PI3K/Akt/mTOR signaling axis may be a key molecular pathway via which PEBP4 promotes the proliferation and invasion of non-small cell lung cancer (NSCLC) cells; also, it may serve as a potential therapeutic target. PMID- 26623105 TI - Clinical experience of spontaneous pneumomediastinum: diagnosis and treatment. AB - BACKGROUND: Spontaneous pneumomediastinum (SPM) is a benign disease with a variety degree of severity but definite treatment modality is not clearly identified with its rarity. The purpose of this study was to review our experience and discuss the management of SPM according to the severity of disease. METHODS: From March 1996 to December 2012, total 64 patients were enrolled and classified as mild, moderate and severe groups and subsequent clinical courses were analyzed retrospectively. RESULTS: Fifty-one were males and 13 were females (M:F =3.9:1) with a mean age of 18 years old (range: 10-30 years old). Thirty-six patients were in mild, 22 in moderate and 6 in severe group. Chief complaints were chest pain (50 cases; 78.1%), neck pain (35 cases; 54.7%), dyspnea (18 cases; 28.1%), odynophagia (9 cases; 14.1%) and precipitating factors were coughing in 12 cases, feeding problems in 9 cases, and vomiting in 7 cases; however, 34 patients (53.1%) had no precipitating signs. All patients received oxygen therapy (100%), prophylactic antibiotics in 57 patients (89.1%), and pain medications in 47 patients (73.4%). The mean hospital stay was 4.6 days (range: 1 10 days). There was an increased linear trend according to time to visit (P=0.023) but clinical course demonstrated no significant trend between groups. CONCLUSIONS: These data demonstrated that there was no difference in symptom, clinical course and SPM was adequately treated with conservative management regardless of the degree of severity of SPM. PMID- 26623106 TI - A randomized controlled trial evaluating airway inspection effectiveness during endobronchial ultrasound bronchoscopy. AB - BACKGROUND: Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) has revolutionized the evaluation of patients with mediastinal and hilar adenopathy. Limitations of conventional endobronchial ultrasound (C-EBUS) bronchoscopes include the inability to perform a complete airway inspection, low definition optics, and limited maneuverability. These limitations require the use of a standard bronchoscope to perform an airway examination prior to the EBUS procedure. Recently, a hybrid endobronchial ultrasound (H-EBUS) bronchoscope with high definition optics and increased maneuverability has been introduced. Our objective was to assess the ability of H-EBUS to perform a full airway inspection and TBNA. METHODS: Patients referred for EBUS-TBNA were prospectively randomized to either form of EBUS from November 2013 to January 2014. The primary outcome was the airway segment visualization in each lobe using an EBUS bronchoscope. Secondary outcomes included the number of bronchoscopes used per procedure, procedure length, diagnostic yield and specimen adequacy. RESULTS: Sixty-two consecutive patients undergoing EBUS-TBNA were randomized to H-EBUS (n=30) or C EBUS (n=32). In cases in which EBUS-TBNA was the only procedure performed (n=32), use of a second bronchoscope to perform an adequate airway inspection was significantly higher in C-EBUS compared to H-EBUS (5 vs. 0, P=0.046). There was better segmental visualization achieved in multiple lobes when using H-EBUS (P<0.01). No differences in TBNA sample diagnostic yield, specimen adequacy or procedure time were noted when comparing bronchoscopes (P= NS). CONCLUSIONS: Use of an H-EBUS may improve the ability to perform an adequate airway inspection potentially obviating the need for a conventional bronchoscope. PMID- 26623107 TI - Establishment of a mathematic model for predicting malignancy in solitary pulmonary nodules. AB - BACKGROUND: The aim of this study was to establish a model for predicting the probability of malignancy in solitary pulmonary nodules (SPNs) and provide guidance for the diagnosis and follow-up intervention of SPNs. METHODS: We retrospectively analyzed the clinical data and computed tomography (CT) images of 294 patients with a clear pathological diagnosis of SPN. Multivariate logistic regression analysis was used to screen independent predictors of the probability of malignancy in the SPN and to establish a model for predicting malignancy in SPNs. Then, another 120 SPN patients who did not participate in the model establishment were chosen as group B and used to verify the accuracy of the prediction model. RESULTS: Multivariate logistic regression analysis showed that there were significant differences in age, smoking history, maximum diameter of nodules, spiculation, clear borders, and Cyfra21-1 levels between subgroups with benign and malignant SPNs (P<0.05). These factors were identified as independent predictors of malignancy in SPNs. The area under the curve (AUC) was 0.910 [95% confidence interval (CI), 0.857-0.963] in model with Cyfra21-1 significantly better than 0.812 (95% CI, 0.763-0.861) in model without Cyfra21-1 (P=0.008). The area under receiver operating characteristic (ROC) curve of our model is significantly higher than the Mayo model, VA model and Peking University People's (PKUPH) model. Our model (AUC =0.910) compared with Brock model (AUC =0.878, P=0.350), the difference was not statistically significant. CONCLUSIONS: The model added Cyfra21-1 could improve prediction. The prediction model established in this study can be used to assess the probability of malignancy in SPNs, thereby providing help for the diagnosis of SPNs and the selection of follow-up interventions. PMID- 26623108 TI - Characterization of a new subtype of allergen in dermatophagoides farinae-Der f 28. AB - BACKGROUND: House dust mites (HDMs) are the major sources of indoor allergens which induce asthma, dermatitis, rhinitis, and some other allergic diseases. Close to 30 sub-allergens have been identified. METHODS: Through analyzing the full genome sequence of dust mite, a new allergen whose primary structure belongs to the heat shock protein family was identified. The sequence of this allergen was determined by cDNA cloning. The allergenicity was assayed by skin prick test, Western-blot and enzyme-linked immunosorbent assay (ELISA). RESULTS: r-Der f 28 bound to serum IgE from mite allergic patients. Positive responses to r-Der f 28 were shown in 11.5% by skin prick testing from 26 DM-allergic patients. Airway hyperresponsiveness, serum specific IgE and IL-4 were significantly increased in allergic asthma mouse model sensitized to r-Der f 28. CONCLUSIONS: Der f 28 is a new subtype of allergen in dermatophagoides farinae. PMID- 26623109 TI - Percutaneous trans-jugular vein closure of atrial septal defect with steerable introducer under echocardiographic guidance. AB - BACKGROUND: The aim of this study is to discuss a novel surgical approach of percutaneous trans-jugular vein closure of atrial septal defect (ASD) with steerable introducer under echocardiographic guidance. METHODS: From January 2015 to June 2015, ten ASD patients underwent percutaneous trans-jugular vein ASD closure, the occluder placement could be perpendicular to the plane of ASD using the steerable introducer. RESULTS: All cases succeeded. The average procedure time was 27.4+/-5.6 minutes; and the average intracardiac operation time was 6.7+/-5.2 minutes. No patient showed the residual shunt after the procedure. There was no clinical death, no arrhythmia, no hemolysis, no infection, no jugular vein damage or occlusion during patients' hospitalization. The post operation follow up after one month of the operation showed that there was no residual shunt, no falling off or detachment of occluders or other complications. CONCLUSIONS: It is a new surgical method with easy operation, mild damage and wider indication. Compared with the traditional percutaneous and transthoracic closure of ASD, it has obvious advantages. PMID- 26623111 TI - Totally robotic-assisted non-circumferential tracheal resection and anastomosis for leiomyoma in an elderly female. AB - We describe a novel technique of totally robotic-assisted non-circumferential tracheal resection and running anastomosis with coverage of anastomosis with anterior mediastinal fat flap. A 71-year-old female presented with cough and CT scan revealed a mass at the intra-thoracic trachea. A complete robotic-assisted tracheal resection and anastomosis was performed. The postoperative course was uneventful. The final pathologic examination confirmed the diagnosis of primary tracheal leiomyoma. PMID- 26623110 TI - Single-port thoracoscopic right main bronchial tumor sleeve resection and secondary carinal reconstruction. AB - We describe herein a case of single-port thoracoscopic right main bronchial tumor sleeve resection and secondary carinal reconstruction. A 66-year-old male patient had a right main bronchial tumor longer than 12 months, who had been received endobronchial cryosurgery twice before. However, the tumor relapsed quickly. Then the patient transferred to our department. He was underwent a single-port complete thoracoscopic right main bronchial tumor sleeve resection and secondary carinal reconstruction. He recovered smoothly, without any perioperative complications. On the 5th postoperative day (POD), he was discharged in good condition. PMID- 26623112 TI - Video-assisted thoracoscopic right upper lobe sleeve lobectomy combined with carinal resection and reconstruction. AB - We report a case of right upper lobe sleeve lobectomy in combination with carinal resection and reconstruction via video-assisted thoracoscopy surgery (VATS). A squamous cell carcinoma of stage T4N1M0 was identified on pathological examination. The bronchial anastomosis and carinal reconstruction were performed using a running suture with 3-0 prolene and an interrupted suture. The postoperative course was uneventful. PMID- 26623113 TI - Left lower sleeve lobectomy and systematic lymph node dissection by single incision video-assisted thoracic surgery. AB - Sleeve lobectomy for selected cases of intratracheal tumor has better parenchyma preservation compared to pneumonectomy. And the left lower sleeve lobectomy is considered one of the most complex resections. Thanks to the advancement of equipment and accumulation of skills, video-assisted thoracic surgery (VATS) sleeve lobectomy has become safe and feasible. Typically, 3-4 ports are used, but the surgery can also be completed through one incision. A 51-year-old male patient with left lower central lung cancer underwent sleeve lobectomy and systematic mediastinal lymphadenectomy by single-incision VATS and recovered uneventfully. Sleeve lobectomy by single-incision video-assisted thoracic surgery is feasible and safe. PMID- 26623114 TI - Endoscopic intervention of lower airway foreign matter in adults-a different perspective. AB - BACKGROUND: Lower airway foreign matter (FM) is uncommonly encountered in adults. This study reviews FM in the lower airway that required bronchoscopic intervention. METHODS: A retrospective review of patients with FM in the lower airway seen at a tertiary hospital between 1996 and 2014 was undertaken. RESULTS: Lower airway FM was removed in 80 out of 18,650 bronchoscopies performed. Forty seven were males, with mean age of 50.8 (range, 29-78) years and mean symptom duration of 10.3 months (range, 1 day -20 years). The most common symptoms were persistent cough, followed by dyspnea, hemoptysis, episodes of choking and fever. Three-quarters of the patients had risk factors of either aspiration or iatrogenic cause for FM in the airway. FM identified following bronchoscopy was classified as: organic (31.3%), inorganic (46.3%) and endogenous matter (22.4%). Iatrogenic etiology was evident in four-fifths of the patients with inorganic FM (stents being the most common). Forty-eight (60.0%) patients had FM removed via flexible bronchoscopy, and the remainder via rigid bronchoscopy. The majority (27 out of 32) of FM removed by rigid bronchoscopy could not be removed using the flexible scope. This was primarily due to retrieval of stents [24] could only be done with the rigid bronchoscope. There were four FM-related complications (three bronchostenosis, one actinomycosis). CONCLUSIONS: There is an increasing indication for bronchoscopists to retrieve FM, particularly of iatrogenic and endogenous sources, lodging in the lower airway of adults. There may be a reversing trend in the utilization of rigid bronchoscopy, mainly due to the increasing need to remove airway stents as more are deployed. PMID- 26623115 TI - The Journal of Visualized Surgery has been established as the Official Journal of the Asia Thoracoscopic Surgery Education Program. PMID- 26623116 TI - Pre-analytic variability in cardiovascular biomarker testing. AB - The impact of laboratory medicine on clinical cardiology has dramatically increased over the years and a lot of cardiovascular biomarkers have been recently proposed. In order to avoid clinical mistakes, physicians should be well aware of all the aspects, which could affect the quality of laboratory results, remembering that pre-analytic variability is an often overlooked significant source of bias, determining the vast majority of laboratory errors. This review addresses the determinants of pre-analitycal variability in cardiovascular biomarker testing, focusing on the most widespread biomarkers, which are cardiac troponins and natriuretic peptides. PMID- 26623117 TI - Red blood cell distribution width and cardiovascular diseases. AB - BACKGROUND: The red blood cell distribution width (RDW) is a rather simple measure of red blood cell (RBC) size heterogeneity (i.e., anisocytosis), which is easily calculated by dividing the standard deviation (SD) of erythrocyte volumes for the mean corpuscular volume (MCV). Emerging evidence suggests that, besides RBC abnormalities, many human disorders may be frequently associated with a high degree of anisocytosis. METHODS: In this narrative review, we analyzed the current scientific literature about the putative role and the potential epidemiologic association between RDW and cardiovascular diseases. The findings of the most representative epidemiological studies were summarized and discussed. RESULTS: Overall, considerable and convincing evidence has been brought that an increased RDW value is associated with acute coronary syndrome (ACS) [including acute myocardial infarction (AMI)], ischemic cerebrovascular disease (including stroke), peripheral artery disease (PAD), as well as with atrial fibrillation (AF), heart failure (HF) and hypertension. Higher anisocytosis also significantly and independently predicts adverse outcomes in patients with these conditions. CONCLUSIONS: Although the role of anisocytosis in the pathogenesis of cardiovascular diseases remains uncertain, the considerable evidence available so far suggests that the clinical use of RDW may be broadened beyond the conventional boundaries of erythrocyte disorders, in particular for assisting the diagnosis and prognostication of patients with ACS, ischemic cerebrovascular disease, PAD, HF and AF. PMID- 26623118 TI - Pollutional haze as a potential cause of lung cancer. AB - Along with fast economic growth over the past few decades, the world is faced with cumulatively serious environmental pollution and now is paying increased attention to pollutional haze. In the last few years, multiple epidemiological studies and animal models have provided compelling evidences that inhalation of pollutional haze could be linked to several adverse health effects. Since the respiratory tract is the crucial passageway of entry of pollutional haze, the lung is the main affected organ. Therefore, here, we reviewed some of the important information around long-term exposure to pollutional haze and lung cancer, as well as highlight important roles of pollutional haze in human lung carcinogenesis, providing evidence for pollutional haze acting as another risk factor for lung cancer. PMID- 26623121 TI - Cardiopulmonary resuscitation using electrically driven devices: a review. AB - In the treatment of sudden cardiac arrest (SCA) immediate resuscitation with chest compressions and ventilation is crucial for survival. As manual resuscitation is associated with several drawbacks, mechanical resuscitation devices have been developed to support resuscitation teams. These devices are able to achieve better perfusion of heart and brain in laboratory settings, but real world experience showed no significant improved survival in comparison to manual resuscitation. This review will focus on two mechanical resuscitation devices, the Lund University Cardiac Assist System (LUCAS) and AutoPulse devices and the actual literature available. In conclusion, the general use of mechanical resuscitation devices cannot be recommended at the moment. PMID- 26623123 TI - A primer on medical education in the United States through the lens of a current resident physician. AB - Physician training and standards for medical licensure differ widely across the globe. The medical education process in the United States (US) typically involves a minimum of 11 years of formal training and multiple standardized examinations between graduating from secondary school and becoming an attending physician with full medical licensure. Students in the US traditionally enter a 4-year medical school after completing an undergraduate bachelor's degree, in contrast to most other countries where medical training begins after graduation from high school. Medical school seniors planning to practice medicine in the US must complete postgraduate clinical training, referred to as residency, within the specialty of their choosing. The duration of residency varies depending on specialty, typically lasting between 3 and 7 years. For subspecialty fields, additional clinical training is often required in the form of a fellowship. Many experts have called for changes in the medical education system to shorten medical training in the US, and reforms are ongoing in some institutions. However, physician education in the US generally remains a progression from undergraduate premedical coursework to 4 years of medical school, followed by residency training with an optional subspecialty fellowship. PMID- 26623122 TI - China experts consensus on icotinib for non-small cell lung cancer treatment (2015 version). PMID- 26623124 TI - Mismatching of population groups in thoracic surgery case control studies. PMID- 26623120 TI - Ultrasound techniques in the evaluation of the mediastinum, part 2: mediastinal lymph node anatomy and diagnostic reach of ultrasound techniques, clinical work up of neoplastic and inflammatory mediastinal lymphadenopathy using ultrasound techniques and how to learn mediastinal endosonography. AB - Ultrasound imaging has gained importance in pulmonary medicine over the last decades including conventional transcutaneous ultrasound (TUS), endoscopic ultrasound (EUS), and endobronchial ultrasound (EBUS). Mediastinal lymph node (MLN) staging affects the management of patients with both operable and inoperable lung cancer (e.g., surgery vs. combined chemoradiation therapy). Tissue sampling is often indicated for accurate nodal staging. Recent international lung cancer staging guidelines clearly state that endosonography should be the initial tissue sampling test over surgical staging. Mediastinal nodes can be sampled from the airways [endobronchial ultrasound combined with transbronchial needle aspiration (EBUS-TBNA)] or the esophagus [endoscopic ultrasound fine needle aspiration (EUS-FNA)]. EBUS and EUS have a complementary diagnostic yield and in combination virtually all MLNs can be biopsied. Additionally endosonography has an excellent yield in assessing granulomas in patients suspected of sarcoidosis. The aim of this review in two integrative parts is to discuss the current role and future perspectives of all ultrasound techniques available for the evaluation of mediastinal lymphadenopathy and mediastinal staging of lung cancer. A specific emphasis will be on learning mediastinal endosonography. Part 1 deals with an introduction into ultrasound techniques, MLN anatomy and diagnostic reach of ultrasound techniques and part 2 with the clinical work up of neoplastic and inflammatory mediastinal lymphadenopathy using ultrasound techniques and how to learn mediastinal endosonography. PMID- 26623119 TI - Muscle dysfunction in chronic obstructive pulmonary disease: update on causes and biological findings. AB - Respiratory and/or limb muscle dysfunction, which are frequently observed in chronic obstructive pulmonary disease (COPD) patients, contribute to their disease prognosis irrespective of the lung function. Muscle dysfunction is caused by the interaction of local and systemic factors. The key deleterious etiologic factors are pulmonary hyperinflation for the respiratory muscles and deconditioning secondary to reduced physical activity for limb muscles. Nonetheless, cigarette smoke, systemic inflammation, nutritional abnormalities, exercise, exacerbations, anabolic insufficiency, drugs and comorbidities also seem to play a relevant role. All these factors modify the phenotype of the muscles, through the induction of several biological phenomena in patients with COPD. While respiratory muscles improve their aerobic phenotype (percentage of oxidative fibers, capillarization, mitochondrial density, enzyme activity in the aerobic pathways, etc.), limb muscles exhibit the opposite phenotype. In addition, both muscle groups show oxidative stress, signs of damage and epigenetic changes. However, fiber atrophy, increased number of inflammatory cells, altered regenerative capacity; signs of apoptosis and autophagy, and an imbalance between protein synthesis and breakdown are rather characteristic features of the limb muscles, mostly in patients with reduced body weight. Despite that significant progress has been achieved in the last decades, full elucidation of the specific roles of the target biological mechanisms involved in COPD muscle dysfunction is still required. Such an achievement will be crucial to adequately tackle with this relevant clinical problem of COPD patients in the near-future. PMID- 26623125 TI - COPD diagnosis: genome first. PMID- 26623126 TI - Underrated value of repeated right heart catheterization in pulmonary hypertension with heart failure-a case of persisted pulmonary arterial hypertension after treatment for biventricular failure. AB - Pulmonary hypertension (PH) is a common complication of left heart disease and its presence in patients with heart failure predicts worse clinical outcomes. Specific agents targeting pulmonary arterial hypertension (PAH) have been developed over the last few years, but the efficacy of these agents in pulmonary hypertension due to left heart disease (PH-LHD) is uncertain. We report a case of idiopathic pulmonary arterial hypertension (IPAH) initially presented with biventricular failure, which was misdiagnosed as PH-LHD. A 31-year-old man who had a history of recurrent hemoptysis was referred to our center with biventricular failure. Right heart catheterization (RHC) showed elevated mean pulmonary arterial pressure (mPAP) and pulmonary capillary wedge pressure (PCWP). He was diagnosed as having PH-LHD, specifically combined post-capillary and precapillary PH (CpcPH). We treated him for 2 years with diuretics, a beta blocker, an angiotensin-converting enzyme (ACE) inhibitor, and sildenafil, which was added to treat CpcPH. A follow-up echocardiography showed that biventricular function had improved, but not PH. A second RHC revealed elevated mPAP and normal PCWP, which made us change the diagnosis to IPAH. In conclusion, it is important to perform repeated RHC in CpcPH patients after the improvement of left heart dysfunction to distinguish CpcPH from IPAH. PMID- 26623127 TI - Deep-seated intramuscular lipoma penetrates the intercostal muscle. AB - Deep-seated intramuscular lipomas are rare, and most exhibit an infiltrating behavior. This study reports serial radiographs of a lipoma in chest wall muscles which penetrated the intercostal muscle for a 6-year period. Although this lipoma did not involve the parietal pleura, it compressed lung. To the authors' knowledge, the present study is the first report to show the growth of a deep seated chest wall lipoma into the thoracic cavity through serial radiographs. We consider the surgical treatment is needed before deep-seated intramuscular chest wall lipoma compress intrathoracic structures. PMID- 26623128 TI - Primary pericardial synovial sarcoma. AB - A 57-year-old man was admitted to our hospital with cardiomegaly on a chest roentgenogram. A mediastinal tumor was observed during a chest computed tomographic scan and the patient was diagnosed with pericardial synovial sarcoma as a result of a tumor biopsy. Surgery, radiotherapy and chemotherapy were carried out, and although the tumor temporarily decreased in size, it subsequently increased and the patient died approximately 3 years following the initial medical examination. Most synovial sarcomas commonly occur in the vicinity of the joints of the extremities. Therefore, we herein report a rare case of synovial sarcoma which occurred in the pericardium. PMID- 26623129 TI - Intranodal lymphangiography as a possible therapeutic option for patients with isolated thoracic duct injury from penetrating chest trauma. AB - A 49-year-old female presented to the emergency department after multiple stab injuries. Bilateral thoracostomy was performed due to a right hemopneumothorax and a left pneumothorax without tracheoesophageal and vascular injury. On admission day 4, a significant amount of milky fluid was collected in the drain after initiation of regular diet. Under suspicion of chylothorax, conservative management was initiated, but failed. Surgery was considered, but ruled out due to the patient's refusal. As an alternative, lymphangiography was performed, which resulted in decreased thoracic drainage and eventual removal of the chest tube. This is an unusual case of an isolated thoracic duct injury that was successful treated by closure of the duct after intranodal lymphangiography. PMID- 26623130 TI - A rare case of anomalous venous drainage of the right upper lobe. AB - We present an unusual case of partial anomalous venous drainage in which the vein of the right upper lobe drains into the superior vena cava, together with the azygos vein. This was discovered during surgery for a lung tumor of the right upper lobe. We present the embryological background, functional consequences and literature on this rare anatomical anomaly. PMID- 26623131 TI - A rare case of mediastinal metastasis of ovarian carcinoma diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). AB - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has become a minimally invasive tool with excellent diagnostic accuracy and low risk of complications in the diagnosis of thoracic diseases, including lung cancers and primary mediastinal lesions. Occasionally, EBUS-TBNA may be useful in identifying thoracic metastasis from distant tumors. Here we report an interesting and rare case of mediastinal metastasis of ovarian carcinoma diagnosed by EBUS-TBNA. PMID- 26623132 TI - Potentially disseminated solitary fibrous tumor of the pleura: a case report. AB - We report a case involving a female patient with frequent relapse, pleural dissemination, and port site recurrence (PSR) of a pleural solitary fibrous tumor (SFT). At the age of 55 years, she underwent tumor resection via video-assisted thoracoscopic surgery (VATS). The tumor arose from the mediastinal pleura; it was 7 cm in diameter and well demarcated. Histological examination showed neither hemorrhage nor necrosis, but moderate cellularity was present, and the Ki-67 labeling index was 15%. Despite complete resection, the tumor relapsed in the ipsilateral thoracic cavity 3 years postoperatively, and thoracoscopic complete tumor resection was performed; however, pleural lavage cytology (PLC) showed the presence of tumor cells. Multiple pleural dissemination and PSR developed 7 years after the initial surgery. The port site recurrent tumor was resected with the intercostal muscle via VATS. This case illustrates that a SFT may disseminate despite the fact that histological examination shows no evidence of malignancy. PMID- 26623133 TI - Epithelioid inflammatory myofibroblastic sarcoma: a case report. AB - Inflammatory myofibroblastic tumor (IMT) of the lung is a rare malignancy with few cases reported in the literature. Histologically, it is composed by spindle cells and an infiltrate of inflammatory cells. Children and young, non-smoking adults constitute the majority of cases, the clinical behavior ranges from a benign entity to a malignant process with rapid recurrence and metastatic progression. We present a case of epithelioid inflammatory myofibroblastic sarcoma (EIMS) of the pleura, a malignant variant of IMT, which was initially treated with debulking surgical resection followed by systemic chemotherapy. The tumor was found to have an anaplastic lymphoma kinase (ALK) gene rearrangement. An ALK directed tyrosine kinase inhibitor was used with an impressive response, the patient remains in remission nearly 1 year after presentation. The pathogenesis, pathologic findings, clinical behavior and imaging of pulmonary EIMS are discussed. PMID- 26623134 TI - Fatal bleeding due to sternal steel wire fracture following open-heart surgery. AB - Nowadays, stainless steel wires suturing is the most common and safety way for the median sternotomy closure. And it is also accepted by our center. Albeit, in July 2014, a patient who underwent left ventricular outflow tract plus mitral valvuloplasty in extracorporeal circulation suffered a fatal bleeding due to fractured steel wire. The fractured steel wire punctured the free wall of right ventricle and left a 3 mm diameter wound, thus caused the 1,000 mL drainage within half an hour. In our opinion, it was the instant increase in yield strength after strong cough that makes the steel wire fractured. PMID- 26623135 TI - Erratum to link between environmental air pollution and allergic asthma: East meets West. AB - [This corrects the article on p. 14 in vol. 7, PMID: 25694814.]. PMID- 26623136 TI - Erratum to mechanistic impact of outdoor air pollution on asthma and allergic diseases. AB - [This corrects the article on p. 23 in vol. 7, PMID: 25694815.]. PMID- 26623137 TI - Subxiphoid uniportal thoracoscopic extended thymectomy. AB - The aim of this article is to present a thoracoscopic technique of extended thymectomy through a subxiphoid incision. Six consecutive patients were successively treated with this approach, which provided a good view of the bilateral pleural cavities. The procedure is safe and technically feasible and yields excellent cosmetic results. We believe that subxiphoid uniportal thoracoscopic approach is a satisfactory procedure for performing extended thymectomy in well selected patients. PMID- 26623138 TI - A case of multiple pleural cryptococcosis without pleural effusion. AB - Pulmonary cryptococcosis is most likely to occur in immunocompromised patients. The radiological manifestations generally include pulmonary parenchymal lesions, namely, pulmonary nodules, cavitary lesions, and consolidation; thus, multiple pleural nodules are unusual presentation. Here, we report a woman who presented with multiple pleural cryptococcosis without pleural effusion. The patient had previously undergone surgery for stage II rectal cancer. In addition, she received 6 cycles of chemotherapy for follicular lymphoma. Computed tomography (CT) revealed multiple small nodules involving the pleura without pleural effusion, which suggested possible recurrence of rectal cancer or malignant lymphoma as pleural dissemination. Thoracoscopic examination was performed, and pleural cryptococcosis was diagnosed. Although pleural cryptococcosis without pleural effusion is extremely rare presentation, clinicians should consider it when an immunocompromised patient presents with multiple pleural nodules. Thoracoscopic exploration should be the best procedure for the definitive diagnosis of multiple pleural nodules. PMID- 26623139 TI - Dynamic obstruction induced by systolic anterior motion of the mitral valve in a volume-depleted left ventricle: an unexpected cause of acute heart failure in a patient with chronic obstructive pulmonary disease. AB - Systolic anterior motion (SAM) of the mitral valve (MV) and left ventricular outflow tract (LVOT) dynamic obstruction (DO) typically occur in hypertrophic cardiomyopathy; however, they can appear in an apparently normal heart in association with changes in cardiac loading conditions and/or hyperdynamic left ventricular (LV) performance. Meanwhile, chronic obstructive pulmonary disease (COPD) can impair LV filling by elevating pulmonary vascular resistance. The authors report a case of transient acute heart failure caused by LVOT DO resulting from SAM of the MV in a severely volume-depleted LV in a patient with acute COPD exacerbation. PMID- 26623140 TI - Pleural dissemination of a mixed ground-glass opacity nodule treated as a nontuberculous mycobacterial infection for 6 years without growing remarkably. AB - Pulmonary ground-glass opacity (GGO) nodules, which do not grow remarkably, are often observed without treatment. Lung tumors coexisting with inflammation and infection are difficult to diagnose. In this paper, we describe a very rare case of a pulmonary mixed GGO nodule with pleural dissemination. In 67-year-old female, chest computed tomography (CT) showed a mixed GGO nodule that had not grown remarkably in the right lung. For 6 years, the mixed GGO had been treated as nontuberculous mycobacterial infection. She was referred to our department for further investigation of the mixed GGO. We suspected lung cancer and performed lung segmentectomy. The tissue showed pleural dissemination. Coexisting nontuberculous mycobacteria (NTM) delayed the clinical diagnosis. Peripheral lung nodules should be resected or diagnosed as soon as possible, despite manifesting as a slow growth. PMID- 26623141 TI - Endobronchial valve to treat large bulla at right middle lobe in chronic obstructive pulmonary disease patients. AB - We have used endobronchial valve (EBV) to treat large bulla at right middle lobe (RML) on three chronic obstructive pulmonary disease (COPD) patients and presented the clinical datum of three COPD patients with RML bulla. The improvement of lung function was significant on two patients, whose lung parenchyma was preserved well in lobes other than RML. On one patient, whose lung function did not show improvement after EBV treatment, the parenchyma of bilateral lungs was destructed heavily by chronic inflammation of COPD, and the RML bulla did not collapse because right major and/or minor fissures are incomplete. EBV may be used to treat large RML bulla in selected patients, whose parenchyma of other parts of the lung was conserved well and right major and minor fissures are complete. PMID- 26623142 TI - Multifunctional 1050 nm Spectral Domain OCT System at 147 kHz for Posterior Eye Imaging. AB - We report a newly developed multifunctional 1050 nm spectral domain optical coherence tomography (SD-OCT) system working at 147 kHz A-scan rate for posterior eye imaging. It is demonstrated through in-vivo experiments that this system delivers not only superior performance of posterior eye structural imaging but also detailed visualization of microcirculation network in retina. The choroid of the eye with either myopic or normal conditions can clearly be visualized through the entire scanning volume. These results indicate great potential in applying this new system for clinical studies. PMID- 26623143 TI - The use of non-contrast computed tomography and color Doppler ultrasound in the characterization of urinary stones - preliminary results. AB - OBJECTIVE: To investigate the role of density value in computed tomography (CT) and twinkling artifact observed in color Doppler analysis for the prediction of the mineral composition of urinary stones. MATERIAL AND METHODS: A total of 42 patients who were operated via percutaneous or endoscopic means and had undergone abdominal non-contrast CT and color Doppler ultrasonography examinations were included in the study. X-ray diffraction method was utilized to analyze a total of 86 stones, and the correlations between calculated density values and twinkling intensities with stone types were investigated for each stone. RESULTS: Analyses of extracted stones revealed the presence of 40 calcium oxalate monohydrate, 12 calcium oxalate dihydrate, 9 uric acid, 11 calcium phosphate, and 14 cystine stones. The density values were calculated as 1499+/-269 Hounsfield Units (HU) for calcium oxalate monohydrate, 1505+/-221 HU for calcium oxalate dihydrate, 348+/-67 HU for uric acid, 1106+/-219 HU for calcium phosphate, and 563+/-115 HU for cystine stones. The artifact intensities were determined as grade 0 in 15, grade 1 in 32, grade 2 in 24, and grade 3 in 15 stones. CONCLUSION: In case the density value of the stone is measured below 780 HU and grade 3 artifact intensity is determined, it can be inferred that the mineral composition of the stone tends to be cystine. PMID- 26623144 TI - Percutaneous nephrolithotomy for isolated calyceal stones: How important is the stone location? AB - OBJECTIVE: To evaluate the effect of percutaneous access site on the success and complication rates of isolated calyceal stones. MATERIAL AND METHODS: We retrospectively evaluated 2700 patients who underwent percutaneous nephrolithotomy (PNL) in our clinic between October 2002 and August 2014. We selected only the patients with isolated lower, middle or upper calyceal stones and we grouped the patients according to the location of their stones. Successful operation was defined as complete stone clearence or retention of stone fragments smaller than 4 mm which do not lead to infection, obstruction or pain requiring treatment. Intraoperative and postoperative complications were also recorded. RESULTS: Totally 360 patients underwent PNL for their isolated upper, middle and lower calyceal stones. Access sites for those patients were selected based on stone location. The stones were localized in the lower (n=304), middle (n=14), and upper (n=42) calices. There was no statistically significant difference between the groups with respect to operation and scopy times. Hemoglobin drop was seen more frequently in the upper calyceal access group, without any significant intergroup difference. Thoracic complications including hemothorax, pneumothorax and pleural effusion were more common in the upper calyceal access group (11.9%; p<0.001). Complete stone clerance was accomplished in 81.9%, 92.9% and 78.6% of the patients with lower, middle and upper calyceal stones respectively without any significant intergroup difference (p=0.537). CONCLUSION: PNL is an effective and safe treatment modality for isolated calyceal kidney stones and upper calyceal access causes thoracic complications more than other access sites. PMID- 26623145 TI - Effect of body mass index on operative time, hospital stay, stone clearance, postoperative complications, and postoperative analgesic requirement in patients undergoing percutaneous nephrolithotomy. AB - OBJECTIVE: To compare the effect of body mass index (BMI) on operative time, hospital stay, stone clearance, postoperative complications, and postoperative analgesic requirement in patients undergoing percutaneous nephrolithotomy (PCNL) by comparing three BMI groups. MATERIAL AND METHODS: This is a retrospective analysis of 129 patients who underwent PCNL from January 2010 to August 2013. All the patients underwent PCNL by a standard technique. The patients were divided into three groups: patients having a BMI <=24 kg/m(2) were included in the normal group, those having a BMI of 24.1-30.0 kg/m(2) were included in the overweight group, and those having a BMI >30 kg/m(2) were included in the obese group. Three groups were compared for operative time, hospital stay, stone clearance, postoperative complications, and postoperative analgesic requirement. RESULTS: A total of 129 patients including 44 females and 85 males were included with a mean age of 45.00+/-1.44 years. The mean age in the normal group was 43.29+/-1.69 years, 47.08+/-1.29 years in the overweight group, and 43.61+/-1.25 years in the obese group. The mean stone size in the normal group was 25.46+/-8.92 mm, 28.01+/ 8.40 mm in the overweight group, and 26.84+/-7.41 mm in the obese group. Our results showed no statistically significant difference with respect to mean operative time, mean hospital stay, and stone clearance in the normal, obese, and overweight patients undergoing PCNL. Postoperative complications and analgesia requirement were also similar in all the three groups. CONCLUSION: There was no effect of BMI on operative time, hospital stay, stone clearance, postoperative complications, and postoperative analgesic requirement in patients undergoing PCNL. PCNL is a safe and effective procedure for the removal of renal stones in obese patients. PMID- 26623146 TI - Comparison of transperitoneal laparoscopic nephrectomy outcomes in atrophic and hydronephrotic kidneys. AB - OBJECTIVE: To compare the results of transperitoneal laparoscopic nephrectomy in patients with atrophic and hydronephrotic kidneys. MATERIAL AND METHODS: Clinical data were collected from 35 patients who had undergone laparoscopic nephrectomies for atrophic or hydronephrotic non-functioning kidneys between January 2010 and March 2014. Comparative analysis was carried out between the two groups examining demographic characteristics, imaging modalities, etiology, operative times, port numbers, conversion to open surgery, complications, pre-and post-operative hemoglobin and creatinine values, transfusion rates and length of hospital stays. RESULTS: Laparoscopic nephrectomy was performed for atrophic kidneys in 20 (57%) patients and for hydronephrotic kidneys in 15 (42%) patients. In the atrophic group, 3 patients (15%) required transfusion because of bleeding but none of the patients required conversion to open surgery. In the hydronephrotic group one patient (6.6%) required transfusion and conversion to open surgery because of bleeding. Both of the groups were similar in terms of postoperative hospital stay but compared to the atrophic kidneys, hydronephrotic ones were associated with a longer total operative times (90.1 min vs. 73.6 min, p=0.03). Any serious complication (except for bleeding) and mortality were not encountered in both groups. CONCLUSION: Laparoscopic nephrectomy is a safe and effective minimally invasive technique that can be used in atrophic and hydronephrotic non functioning kidneys. PMID- 26623147 TI - Laparoscopic ureterolithotomy; which is better: Transperitoneal or retroperitoneal approach? AB - OBJECTIVE: This was a prospective study to compare the outcome of laparoscopic transperitoneal ureterolithotomy (LTU) with laparoscopic retroperitoneal ureterolithotomy (LRU) as a primary treatment for a large stone in the proximal ureter. MATERIAL AND METHODS: A total of 24 patients with a solitary, large (>1.5 cm), and impacted stone in the proximal ureter was selected and randomly divided into two groups. The first group included 13 patients who were treated by LTU, and the second group included 11 patients who were treated by LRU. Patient demographics and stone characteristics as well as the operative and postoperative data of both groups were compared and statistically analyzed. RESULTS: There was no significant difference between the two groups regarding patient demographics and stone characteristics. The mean operative time was significantly shorter in the LTU group than in the LRU group [116.2+/-21.8 min vs 137.3+/-17.9 min, respectively (p=0.02)]. The mean time to oral intake was significantly longer in the LTU group than in the LRU group [21.2+/-4.9 h vs 15.5+/-2.8 h, respectively (p=0.002)]. There was significant higher rate (27.3%) of changing to open surgery in LRU (p=0.04). The stone-free rate was significantly higher in the LTU group than in the LRU group [100% vs. 72.8%, respectively (p=0.03)]. There was no statistically significant difference between the two groups regarding the mean blood loss, mean hospital stay, mean analgesia dose, blood transfusion rate, postoperative fever, and stone migration during surgery. CONCLUSION: Both approaches of laparoscopic ureterolithotomy are effective in treating large impacted stones in the proximal ureter. LTU has significantly shorter operative time and lower rate of open conversion but has a significantly longer time to oral intake. PMID- 26623148 TI - Analysis of the correlation between sperm DNA integrity and conventional semen parameters in infertile men. AB - OBJECTIVE: A male factor is responsible in approximately 30-40% of couples receiving infertility treatment. Routinely, such couples undergo semen analysis including parameters such as sperm count, motility and morphology. Generally, the analysis of sperm DNA damage, shown to have a significant clinical importance by many studies, is recognized as an advanced test that is not included in routine infertility tests. Intracytoplasmic sperm injection method, commonly employed in the current infertility treatment protocols, lowers the fertilization rate, however, fertilization can occur even with a damaged DNA which is known to pose a risk in the subsequent pregnancy period. The relation between sperm morphology and the degree of sperm DNA damage has not yet been understood clearly. In this study, we aimed to investigate the association between routine semen analysis and sperm DNA integrity assay, another advanced but costly method. MATERIAL AND METHODS: The degree of DNA damage was compared with the results of semen analysis, based on the WHO criteria, in 399 male patients who received comet assay for sperm DNA integrity. The statistical correlation analyses were performed with Windows SPPS statistical package program. RESULTS: Accordingly, the sperm DNA damage was found to be correlated with all 3 parameters (sperm count, forward motility, and morphology) examined by the semen analysis (p<0.001). Total sperm DNA Damage Count was 226, 216, and 210 arbitrary units in patients with a sperm count <15 mil/mL, forward moving motility <32%, and normal morphology <4%, respectively. The difference with the normal individuals was statistically significant (p<0.001). CONCLUSION: In light of the comet assay results, higher degree of sperm DNA damage is associated with significant impairment of all seminal parameters. PMID- 26623149 TI - Oxidative stress markers: Can they be used to evaluate human sperm quality? AB - OBJECTIVE: To study the effects of an acute lifestyle change in human semen oxidative stress (OS) by applying seminal parameters and OS markers and to study the feasibility of mid-infrared spectroscopy with Fourier transform infrared spectroscopy (FT-IR) as a complementary tool to evaluate the effects of OS on human sperm samples. MATERIAL AND METHODS: Sperm samples were collected from healthy male students (n=8) who voluntarily submitted themselves to acute lifestyle changes during academic festivities. The samples were obtained before and after the academic festivities and were compared by basic semen analyses and OS markers, namely with thiobarbituric acid reactive species (TBARS) and total thiol (SH) groups by spectrophotometric assays and carbonyl (CO) groups by slot blot. The samples were also submitted for spectroscopic analysis to evaluate the feasibility of FT-IR coupled with multivariate analysis to calibrate OS biomarkers. Statistical analysis was performed applying paired Wilcoxon tests. RESULTS: Acute lifestyle alterations during academic week festivities were associated with a significant decrease in the percentage of normal spermatozoa in the ejaculate (p=0.011) and a decrease in sperm concentration and in semen volume. Regarding OS, acute lifestyle changes promoted a significant increment of TBARS (p=0.018) and an increasing trend in the SH group. With FT-IR and multivariate analysis, it was possible to develop calibration models to the following protein OS biomarkers: SH groups and CO. CONCLUSIONS: Acute lifestyle changes during academic festivities have negative effects on sperm quality, in both conventional seminal parameters and OS markers. The evaluation of OS biomarkers and FT-IR could improve andrology diagnosis and therapeutic follow-up. PMID- 26623151 TI - Rapid changes in the incidence of urinary system cancers in Turkey. AB - Estimation of national cancer incidence for major cancer sites in Turkey has been carried out by analyzing the data obtained from active cancer registry, and published regularly by Institute of Public Health of Ministry of Health. In the light of these statistics, the incidence of urinary cancers in both sexes and their age related distributions have been discussed, paying special attention to prostate, kidney and bladder cancers. The annual incidence of all cancer cases increased gradually, reaching to 221.5 per 100,000 population in 2009, the latest confirmed figure available at present. Among males the most frequent cancers were those of the lung, prostate and bladder. The incidence rates of urinary cancers among males were 36.1, 21.4 and 6.3 per 100,000 for prostate, bladder and kidney respectively. The reliability of current data concerning the incidence of cancer has been discussed by comparing them with the previously reported national cancer data. PMID- 26623150 TI - Role of percutaneous posterior tibial nerve stimulation either alone or combined with an anticholinergic agent in treating patients with overactive bladder. AB - OBJECTIVE: To evaluate the efficacy of percutaneous tibial nerve stimulation (PTNS), either alone or combined with an anticholinergic agent, in treating patients with an overactive bladder (OAB) in whom previous conservative treatment failed. MATERIAL AND METHODS: In this study, we included a total of 30 female patients with OAB in whom all conventional therapies failed between January 2010 and April 2011. Patients were randomly divided into three groups: Group 1, PTNS group; Group 2, patients receiving an anticholinergic agent; and Group 3, patients receiving both PTNS and anticholinergic agent. PTNS treatment continued for 12 weeks with each session lasting 30 min. RESULTS: All parameters of the bladder diary significantly improved in all groups (p<0.05). Similarly, all scores measured by questionnaires (UDI-6, IIQ-7, and OABSS) revealed significant improvements in all groups. When the improvements in symptoms were compared among the groups, there was a statistically significantly higher improvement in groups 1 and 3 than in Group 2. CONCLUSION: PTNS is a safe, simple, and minimally invasive treatment modality in patients with OAB, and it may be suggested either alone or in combination with anticholinergics when conventional treatments fail. PMID- 26623152 TI - Botulinum toxin injections for treating neurogenic detrusor overactivity. AB - Neurogenic detrusor overactivity (NDO) is a disorder that can cause high intravesical pressure, decreased capacity, decreased bladder compliance, and upper urinary system damage. The current treatment options for NDO are established on the basis of agents that block parasympathetic innervation of the detrusor and inhibit involuntary bladder contractions. Several side effects, such as dryness of mouth, constipation, dyspepsia, changes in visual accommodation, somnolence, and being unable to obtain consistently favorable results, caused by anticholinergic agents, which are frequently used for this purpose, decrease the patient's compliance to treatment. Procedures such as neuromodulation, auto augmentation, and enterocystoplasty are surgical options, and they could be used as the last alternative. Thus, botulinum toxin (BTX) injections to the detrusor have been commonly performed in recent years and lead to satisfactory results. The mechanism of action of BTX in NDO is based on the principal of smooth muscle relaxation in the bladder by the transient inhibition of neuromuscular nerve signals. The aim is to decrease acetylcholine secretion by blocking presynaptic vesicles in the neuromuscular junction. When studies were evaluated, it was observed that BTX injections to the detrusor muscle are a necessary and effective option in patients with incontinence caused by NDO. This treatment option could be indicated in situations where anticholinergic agents are not effective or could not be tolerated, and it could be a valuable alternative to major surgical treatments. In this review, we evaluated the effectiveness and reliability of BTX in patients with NDO. PMID- 26623153 TI - Undifferentiated metastatic renal cell carcinoma presenting as a cutaneous nodular lesion. AB - Cutaneous metastases may be the first sign of clinically silent visceral cancer. Approximately 30% of patients with primary renal cell carcinoma present with metastatic disease, and only 8% of them have skin metastases. We present the case of a 59-year-old male patient with a subcutaneous nodular on the upper chest extending to the jugular region. The lesion appeared skin colored and was not painful and 5 cm * 3.5 cm in diameter. The histological examination of the cutaneous biopsy showed an infiltration of undifferentiated epithelial cells positive to cytokeratins AE1/AE3, whereas they were negative to CK-20, CK5/6, cluster of differentiation 10, vimentin, thyroid transcription factor-1, S-100, human melanoma black-45, hepatocyte-specific antigen, carcinoembryonic antigen, and chromogranin A. A total-body computed tomography (CT) showed the presence of a tumoral lesion in the left kidney with multiple metastases in the lung, brain, and bones. According to the cutaneous biopsy and total-body CT, a final diagnosis of an undifferentiated renal carcinoma presenting as a subcutaneous metastasis was made. A chemotherapeutic treatment with gemcitabine and cisplatin resulted in the stabilization of the renal and metastatic lesions with an improvement in the quality of life of the patient. Considering that the prognosis of patients with cutaneous metastases is very poor, it is necessary to obtain an appropriate diagnosis in order to identify patients with treatable disease with the purpose of starting a therapeutic protocol. PMID- 26623154 TI - Spontaneous rupture of the kidney in the patients with synchronous renal hemangioma and nephrogenic hypertension. AB - Most renal neoplasms in adults are epithelial in origin and mesenchymal tumors are rarely encountered. Vascular tumors and tumor-like lesions account for a very small subset. Hemangioma of the kidney is a rarely seen benign vascular neoplasm that probably arises from angioblastic cells. Its general sign is macroscopic hematuria with or without pain. Preoperative diagnosis is difficult or impossible. Previously, spontaneous rupture of the kidney caused by renal hemangioma was not reported in the English literature. In this study, two cases with a history of nephrogenic hypertension who presented with spontaneous renal rupture are presented. There wasn't any trauma history in the background of our patients. A long-standing nephrogenic hypertension was present in both patients. Patients underwent radical nephrectomy due to rupture of the renal tumor. In histopathological examination, capillary hemangioma was detected in the renal medulla in both cases. Patients didn't need antihypertensive therapy during the postoperative period. PMID- 26623155 TI - A practical approach for the correction of iatrogenic penile skin loss in children: Scrotal embedding technique. AB - The aim of this particular study is to determine the efficacy of scrotal embedding technique in children with overly deficient penile shaft skin, which takes advantage of the rich vascular supply of the scrotal layers and provides adequate tissue coverage. We give the operative and clinical details of two consecutive cases for which we preferred scrotal embedding technique to replace deficient penile skin. The mean operative time for the first and second stages was 72.5 and 52.5 min, respectively. Intraoperative and postoperative courses and convalescences were uneventful. The patients were hospitalized for a mean duration of 2 days. After a mean follow-up of 29 months, cosmetic and functional results were satisfactory. Scrotal embedding technique should be considered as a feasible surgical alternative while reconstructing the penile shaft in iatrogenic cases with overly deficient shaft skin. PMID- 26623156 TI - Operative Mortality After Arthroplasty for Femoral Neck Fracture and Hospital Volume. AB - BACKGROUND: The purpose of the present study is to use a statewide, population based data set to identify mortality rates at 30-day and 1-year postoperatively following total hip arthroplasty (THA) and hemiarthroplasty (HA) for displaced femoral neck fractures. The secondary aim of the study is to determine whether arthroplasty volume confers a protective effect on the mortality rate following femoral neck fracture treatment. METHODS: New York's Statewide Planning and Research Cooperative System was used to identify 45 749 patients older than 60 years of age with a discharge diagnosis of femoral neck fracture undergoing THA or HA from 2000 through 2010. Comorbidities were identified using the Charlson comorbidity index. Mortality risk was modeled using Cox proportional hazards models while controlling for demographic and comorbid characteristics. High volume THA centers were defined as those in the top quartile of arthroplasty volume, while low-volume centers were defined as the bottom quartile. RESULTS: Patients undergoing THA for femoral neck fracture rather than HA were younger (79 vs 83 years, P < .001), more likely to have rheumatoid disease, and less likely to have heart disease, dementia, cancer, or diabetes (all P < .05). Thirty-day mortality after HA was higher (8.4% vs 5.7%; P < .001) as was 1-year mortality (25.9% vs 17.8%; P < .001). After controlling for age, gender, ethnicity, and comorbidities, risk of mortality following THA was 21% lower (hazard ratio [HR] 0.79; P = .003) at 30 days and 22% lower (HR 0.78; P < .001) at 1 year than HA. Patients undergoing THA at high-volume arthroplasty centers had improved 1-year mortality when compared to those undergoing THA at low-volume hospitals (HR 0.55; P = .008). CONCLUSIONS: Based on this large, population-based study, there is no basis to assume THA carries a greater mortality risk after hip fracture than does standard HA, even when accounting for institutional volume of hip arthroplasty. PMID- 26623157 TI - Evaluation of Patients' Response Toward Osteoporosis Letter Intervention Versus Phone Call Plus Letter Intervention. AB - INTRODUCTION: The aim of this study was to compare the effectiveness of 2 interventions in prompting patients to obtain osteoporosis follow-up after a fracture. Our hypothesis was that a phone call plus letter would yield greater response toward osteoporosis evaluation versus a letter alone to patients after sustaining a fragility fracture. MATERIALS AND METHODS: Prospective study randomized 141 patients age 50 years and older with a fragility fracture into 3 groups for comparison. Group 1 (letter only) patients received a letter 3 months after their diagnosis of fracture indicating their risk for osteoporosis and urging them to follow-up for evaluation. Group 2 (phone call plus letter) patients were contacted via phone 3 months after their diagnosis of fracture. A letter followed the phone call. Group 3 (control) patients were neither contacted via phone nor sent a letter. All groups were contacted via phone 6 months after their initial visit to determine if they followed up for evaluation. RESULTS: In group 1, 23 (52.27%) of 44 had follow-up, and 21 (47.73%) of 44 did not follow up. In group 2, 30 (62.5%) of 48 had follow-up, and 18 (37.50%) of 48 did not follow-up. In group 3, 6 (12.24%) of 49 had some sort of follow-up, and 43 (87.76%) of 49 did not have any follow-up. A statistical significance was achieved between group 3 (control) and both groups 1 and 2 with regard to follow up (P < .0001). The results did not show a statistically significant difference between Groups 1 and 2, however, there was a trend toward improved response with a phone call plus letter (P = .321). CONCLUSION: A more personalized approach with a phone call plus follow-up letter to patients increased osteoporosis follow up care by an additional 10%, however, this was not a statistically significant difference from just sending out a letter alone. PMID- 26623158 TI - Longer-Term Outcomes of Geriatric Odontoid Fracture Nonunion. AB - INTRODUCTION: Longer-term outcomes of patients with geriatric type II odontoid fracture nonunion remain unclear. METHODS: Thirty-four consecutive geriatric patients (>70 years old) with minimally displaced (<50% displacement) type II odontoid fractures were treated 24 hours a day for 12 weeks with rigid collar immobilization between the years 2003 and 2011. Radiographic and medical record reviews were performed on all 34 patients. Additionally, 7 patients were available for clinical longer-term follow-up (>4 years). RESULTS: In all, 30 (88%) of the 34 patients had nonunion after 12 weeks of treatment, 2 (6%) patients had union, and 2 (6%) patients died during the first 12 weeks. Twenty one of the 30 patients with nonunion had a displaced or mobile nonunion (70%), and 4 (12%) patients were lost to follow-up. At longer-term follow-up, 23 (68%) patients had died. The average time death occurred was 3.8 years with a range of 0.17 years to 9.42 years postinjury. Twenty of the 23 deaths were attributed to medical comorbidities not related to the patient's odontoid nonunion. We were unable to determine the cause of death in 3 patients. None of the patients who died had identifiable clinical myelopathy prior to their death on chart review. Of the 7 patients who were alive, all were determined to have odontoid nonunion, of which 5 (70%) were mobile odontoid nonunion. Visual Analog Scale (VAS) and Neck Disability Index (NDI) scores were low (VAS averaged 0.57 and NDI averaged 6.9%) and treatment satisfaction was high (averaged 9.7 of 10). Scores for pain and function did not differ significantly when compared to age-matched controls (P = .08, t test). CONCLUSION: Rates of odontoid nonunion are high in patients with geriatric odontoid fractures that are treated with continuous rigid collar for 12 weeks. The majority of patients with nonunion appear to achieve high functional outcomes. In this study, mortality did not appear to be related to adverse neurologic events after treatment. PMID- 26623159 TI - Fixation Versus Replacement in Geriatric Hip Fractures: Does Functional Outcome and Independence in Self-Care Differ? AB - INTRODUCTION: Although there is evidence of improved functional outcomes with our "integrated care pathway" for geriatric hip fractures, we do not know if there is a significant difference in functional recovery of activities of daily living and attainment of independence in self-care between patients who underwent fixation and those treated with arthroplasty. OBJECTIVE: To determine whether such a difference exists in surgically fixed hip fractures. MATERIALS AND METHODS: Patients with hip fracture treated surgically were divided into group A (internal fixation, n = 213) and group B (arthroplasty, n = 199). Demographic data, Charlson comorbidity index (CCI) score, time to surgery, and length of stay were recorded. Inpatient complications and mortality rates were also documented. Modified Barthel Index (MBI) scores were recorded for the following intervals: prefall, discharge, 6-month, and at 1-year follow-up. RESULTS: The mean age (A: 80 years and B: 81years), CCI (A: 5.41 and B: 5.43), and length of stay (A: 13.6 days and B: 15.2 days) were not significantly different. However, there was a significant difference (P < .05) in time to surgery (A: 102.2 hours and B: 86.6 hours). Complication rates were about 6% in both groups (A = 6.57%: urinary infections = 13, wound infections = 1 and B = 6.03%: urinary infections = 10, wound infections = 1, pressure ulcer = 1). The preinjury MBI scores were significantly different (P < .05; A: 91.65 and B: 88.19), however, there was no significant difference in scores measured at discharge (A: 60.79 and B: 59.39), 6 months (A: 77.65 and B: 77.47) and 1 year (A: 80.71 and B: 83.03). Patients who underwent surgery for hip fracture had overall recovered 90.9% of their preinjury function (overall MBI at 1 year: 81.83). CONCLUSION: The MBI scores reflect the extent of attainment of independence in self-care, and actual functional recovery is gauged from the percentage of recovery of preinjury function at 1 year postsurgery. We conclude that the type of surgery may not be a significant factor in determining independence in self-care although patients who had arthroplasty had recovered more function at 1 year postsurgery than those who underwent fixation (percentage recovery of preinjury function-A: 88.1% and B: 94.1%). PMID- 26623160 TI - "Early Trigger" Intravenous Vitamin K: Optimizing Target-Driven Care in Warfarinised Patients With Hip Fracture. AB - Best practice tariff (BPT) was introduced as a financial incentive model to improve compliance with evidence-based care, such as operation for hip fracture within 36 hours of admission. We previously evaluated the impact of warfarin on patients with hip fracture, revealing significant delay to operation and subsequent loss of revenue. As a result of this, an "early trigger" intravenous vitamin K (IVK) pathway was introduced and the service reaudited a year later. The first cycle was a retrospective audit of all cases with hip fracture against BPT standards over a 32-month period. Subsequent protocol change resulted in all warfarinised cases being given 2 mg IVK in the emergency department prior to blood testing. This protocol was reaudited against the same BPT standards 12 months later. An intention-to-treat approach was used, despite breaches of protocol and other reasons for patients not progressing to theater. The data were analyzed with parametric tools to establish true clinical and statistical impact of the introduction of the protocol. In the first cycle, 80 patients were admitted on warfarin with a mean time to theater of 53.71 hours. Of these patients, 79% breached BPT due to anticoagulation. Twelve months following protocol introduction, 42 patients had a mean time to theater of 37.61 hours. Of these patients, 34% breached BPT due to anticoagulation. These data are both clinically and statistically significant (P < .001). No adverse events occurred. We have shown for the first time that "early-trigger" IVK can reduce delay to theater and maximize tariff payments in warfarinised patients with hip fracture. This is in addition to other established benefits associated with early surgery such as decreasing risk of pressure lesions and pneumonia. It affords high quality patient-centered care while ensuring trauma units achieve maximal financial reimbursement through pay for improved performance and supports a culture of change behavior. PMID- 26623161 TI - Effects of Osteoarthritis on Quality of life in Elderly Population of Bhubaneswar, India: A Prospective Multicenter Screening and Therapeutic Study of 2854 Patients. AB - INTRODUCTION: Osteoarthritis (OA) is the most common age-related joint disease affecting >80% people beyond 55 years of age. It is a leading cause of elderly visit to outpatient departments and accounts for almost half of all nonsteroidal anti-inflammatory drug prescriptions. The burden and impact of knee OA in Indian population and extent of public health services usage by people with OA are not known. METHODS: We performed a prospective blinded multicenter screening and therapeutic study from June 2013 to June 2014 at 3 centers to screen patients >55 years with knee OA to assess quality of life, functional disability, and limitation of functions and to compare the effectiveness of hip and leg strengthening exercise programs in these patients. Functional disability was assessed by Western Ontario and McMaster's Universities OA index (WOMAC), Friedman, and Wyman Scores; locomotor function was assessed by walking status, Visual Analog Scale (VAS), and 30-second timed chair stand tests; and quality of life was assessed by Short Form-36 (SF-36). RESULTS: Of 2854 patients screened, 2054 (72%) patients had OA (male:female-1.9:1) with mean age of 63 years and standard deviation of 8. Of 2054 patients, 226 patients were randomly selected for therapeutic study. In remaining 1828 patients, baseline 10-meter walk test (10MWT) was 0.3 m/s, mean SF-36 Physical Component Score (PCS) was 31.3, and Mental Component Score (MCS) was 34.2. At 3 months, 79% patients were comfortable with significant VAS, WOMAC, Friedman-Wyman Scores, 10MWT, and timed chair test improvements in patients who performed lifestyle modifications and exercises (P = .04). Short Form-36 improved, mean PCS was 43.6, and MCS was 54.2. At 3 months, 274 (15%) patients were unsatisfied among whom 26% and 74% were treated with arthroscopic procedures and arthroplasty, respectively. Isolated hip and leg strengthening exercise programs similarly improved knee pain, function, and quality of life. CONCLUSION: Motivation and counseling with hip and leg strengthening exercises should be incorporated with pharmacotherapy in each OA prescription. Physical fitness and weight reduction should be promoted as first line management of OA. PMID- 26623162 TI - The NYU Osteoporosis Model of Care Experience. AB - INTRODUCTION: Participants who sustain a fragility fracture are at increased risk for subsequent fractures. Despite the consequences of recurrent fractures, bone mineral density (BMD) testing and treatment rates for osteoporosis after a fracture remain low. The New York University (NYU) Langone Osteoporosis Model of Care was developed to identify women at increased risk for recurrent fractures and to reduce the rates of subsequent fracture through patient and physician education. METHODS: Women aged 50 years and older who had a fracture and received their care at NYU affiliated hospitals were contacted via mail after discharge. Participants were provided educational materials explaining decreased bone strength and its possible relationship to their fracture and were asked to complete a questionnaire. One year postfracture, participants were sent follow-up questionnaires requesting their most recent fracture treatment and BMD information. Educational material was also provided to the treating orthopedic surgeons. RESULTS: Overall, 524 patients were contacted and 210 (40%) enrolled. By the end of 24 months, 92 participants completed their 1-year questionnaire (44% of the enrollees). Forty-two (46%) participants had undergone new BMD testing and 37 (40%) were receiving antiresorptive medications, including 6 (6%) who had not been prescribed these medications before enrolling in the program. CONCLUSIONS: The Osteoporosis Model of Care is a simple and cost-effective educational program, which improved comprehensive fracture care in an actual clinical setting. Patient enrollment remains a challenge in implementing the program. Our program highlights difficulties in providing community-dwelling participants with appropriate postfracture care. With increasing concern among the public regarding the use of bone strengthening medications and continued low postfracture treatment rates, educating patients with high fracture risk is critical to reducing the rate of subsequent fracture. Our Model of Care Program demonstrates both the success and limitations of a postfracture educational approach using discharge diagnosis data to identify patients with fracture. PMID- 26623163 TI - Cross-Cultural Adaptation and Validation of the Lower Extremity Measure Into German. AB - INTRODUCTION: The Lower Extremity Measure (LEM) was developed to provide a specific instrument to detect changes in physical function in patients with hip fracture. Of 29 questions, 3 have a valid "not applicable" answer option. The goal of this study was to validate the LEM in German and to determine the added value to the physical functioning (pf) subscale of the Short Form 36 (SF-36). MATERIALS AND METHODS: The LEM was translated according to published guidelines and administered to patients with hip fracture (31 A1-A3 and 31 B1-B3) shortly after surgery (baseline), at 3 months (3M), and for reliability testing at 3 months plus 1 week (3M+). The reproducibility, internal consistency, floor and ceiling effects, construct validity, and responsiveness of the German LEM were assessed. RESULTS: A total of 106 patients completed the LEM and SF-36 (mean age 75.5; 67% women) at baseline (mean of 4.9 days after operation), and 88 completed both questionnaires at both the 3M and 3M+ assessments. At each assessment time point, between 6% and 23% of the patients answered 7 questions as "not applicable." Reproducibility and internal consistency were high (intraclass correlation coefficient = 0.93; Cronbach's alpha = .96). No floor effect (0%) and a minor ceiling effect (7.87%) were found for the total LEM score. The strongest correlation was found between the LEM and the SF-36 subscale pf (Spearman rho = .93). Responsiveness was similar for the SF-36 pf subscale and the LEM when using effect size (SF-36 pf 0.71 vs LEM 0.72) and better for the LEM when using standardized response mean (SF-36 pf 0.65 vs LEM 0.76). DISCUSSION: The German LEM is a reliable, valid, and responsive measure for the self-assessment of patients after hip fracture surgery. As a number of questions are not applicable to elderly patients, the added value of this lengthy questionnaire in these often frail, sometimes cognitively impaired patients is still open for debate. PMID- 26623164 TI - Current Practices Regarding Perioperative Management of Patients With Fracture on Antiplatelet Therapy: A Survey of Orthopedic Surgeons. AB - OBJECTIVE: There continues to be controversy over whether operative delay is necessary for patients on antiplatelet therapy, particularly for elderly patients with hip fractures. This study sought to assess current clinical practices of orthopedic surgeons regarding perioperative management of these patients. METHODS: A 12-question, Web-based survey was distributed to orthopedic surgeons via e-mail. Questions regarding timing of surgery assumed patients were on antiplatelet therapy and assessed attitudes toward emergent and nonemergent orthopedic cases as well as operative delay for specific closed fracture types. Responses were compared using unpaired, 2-tailed Student t tests for continuous variables and Pearson chi-square tests with odds ratios (ORs) and 95% confidence intervals (CIs) for categorical variables. Statistical significance was defined as a P value <.05. RESULTS: Overall 67 orthopedic surgeons responded. Fifty-two percent (n = 35) of the respondents described their practice as academic. Thirty nine percent (n = 25) of the surgeons indicated that no delay was acceptable for urgent but nonemergent surgery, and 78% (n = 50) reported no delay for emergent surgery was acceptable. Sixty-eight percent (n = 46) of respondents felt patients on antiplatelet therapy with closed hip fractures did not require operative delay. Surgeons who opted for surgical delay in hip fractures were more likely to delay surgery in other lower extremity fracture types (OR = 16.4, 95% CI 4.48 60.61, P < .001). Sixty-four percent (n = 41) of the surgeons indicated there was no protocol in place at their institution. CONCLUSIONS: There continues to be wide variability among orthopedic surgeons with regard to management of patients with fracture on antiplatelet therapy. Over a quarter of surgeons continue to opt for surgical delay in patients with hip fracture. This survey highlights the need to formulate and better disseminate practice management guidelines for patients with fracture on antiplatelet therapy, particularly given the aging population in the United States. PMID- 26623165 TI - Older Patients Are Immunocompromised by Cytokine Depletion and Loss of Innate Immune Function After HIP Fracture Surgery. AB - PURPOSE/INTRODUCTION: We have examined the immune status of elderly patients who underwent surgery for a hip fracture, an injury associated with poor postoperative outcomes, to identify specific immune defects. METHODS: In a cohort observational study, 16 patients undergoing surgery for hip fractures had immune function evaluation prior to surgery, and then at 3 and 7 days postoperatively, using flow cytometry for phenotype and for monocyte and granulocyte phagocytic function and respiratory burst. Serum samples were stored and batch analyzed using a human cytokine 25-plex panel. RESULTS: We report significant loss of innate immune function, related specifically to reduced granulocyte numbers by day 7 (P < .0001, flow cytometry; P < .05 white blood cells), and although granulocyte ability to take up opsonized Escherichia coli was increased (P < .05), the ability of those cells to generate a respiratory burst was reduced at days 3 and 7 (P < .05). Monocyte respiratory burst was also significantly reduced (P < .05). Serum cytokine levels indicated very poor T-cell function. CONCLUSION: We have demonstrated that the antimicrobial immune response is profoundly reduced after surgery in elderly patients with hip fractures. The effect was sustained up to 7 days postoperatively, identifying these patients as particularly vulnerable to bacterial infections. PMID- 26623166 TI - Race, Rehabilitation, and 30-Day Readmission After Elective Total Knee Arthroplasty. AB - INTRODUCTION: To examine racial variations in access to postacute care (PAC) and rehabilitation (Rehab) services following elective total knee arthroplasty and whether where patients go after surgery for PAC/Rehab is associated with 30-day readmission to acute care facility. MATERIALS AND METHODS: Sample consisted of 129 522 patients discharged from 169 hospitals in the State of Pennsylvania between fiscal years 2008 and 2012. We used multinomial regression models to assess the relationship between patient race and discharge destination after surgery, for patients aged 18 to 64 years and for those aged 65 and older. We used multivariable (MV) regression and propensity score (PS) approaches to examine the relationship between patient discharge destination after surgery for PAC/Rehab and 30-day readmission, controlling for key individual- and facility level factors. RESULTS: Lower proportions of younger patients compared to those older than 65 were discharged to inpatient rehabilitation facilities (IRFs; 5.8% vs 12.6%, respectively) and skilled nursing facilities (SNFs; 15.2% vs 32.7%, respectively) compared to home-based Rehab (self-care; 23.3% vs 14.2%, respectively). Compared to whites, African American patients had significantly higher odds of discharge to IRF (age < 65, odds ratio = 2.04; age >= 65, odds ratio = 1.64) and to SNF (age < 65, odds ratio = 2.86; age >= 65, odds ratio = 2.19) and discharge to home care in patients younger than 65 years (odds ratio = 1.31). The odds of 30-day readmission among patients discharged to an IRF (MV odds ratio = 7.76; PS odds ratio = 8.34) and SNF (MV odds ratio = 2.01; PS odds ratio = 1.83) were significantly higher in comparison to patients discharged home with self-care. CONCLUSION: African American patients with knee replacement are more likely to be discharged to inpatient Rehab settings following surgery. Inpatient Rehab is significantly associated with 30-day readmission to acute care facility. PMID- 26623167 TI - Comparison of Short-Term Outcomes of Geriatric Distal Femur and Femoral Neck Fractures: Results From the NSQIP Database. AB - PURPOSE: To compare and contrast postoperative complications in the geriatric population following open reduction and internal fixation (ORIF) for (DF) fractures relative to femoral neck (FN) fractures. METHODS: Patients aged 65 years and older in the American College of Surgeons National Surgical Quality Improvement Program database who underwent ORIF for FN fractures or DF fractures from 2005 to 2012 were identified. Differences in rates of any adverse events (AAEs), serious adverse events (SAEs), infectious complications, and mortality between groups were explored using univariate and multivariate analyses. RESULTS: The DF cohort had a higher proportion of females (81.95% vs 71.35%, P < .001), were younger (79.41 +/- 7.93 vs 82.11 +/- 7.26 years old, P < .001), and had a lower age adjusted modified Charlson comorbidity index score (4.22 +/- 1.32 vs 4.49 +/- 1.35, P = .02). Cases with DF and FN did not differ in AAE (20.05% vs 20.20%, P = .94), SAE (12.03% vs 13.19%, P = .51), infectious complication (4.26% vs 4.22%, P = .97), hospital length of stay (7.32 +/- 6.73 days vs 7.02 +/- 10.67 days, P = .59), or mortality rates (4.51% vs 5.99%, P = .23). Multivariate analyses revealed that fracture type did not impact AAE (P = .28), SAE (P = .58), infectious complications (P = .83), or mortality (P = .85) rates. CONCLUSION: Postoperative morbidity and mortality of geriatric patients who sustain DF and FN fractures treated operatively were comparable. This information can be used when risk stratifying and prognosticating for elderly patients undergoing these procedures. PMID- 26623168 TI - Enhancing Postoperative Rehabilitation Following Knee Arthroplasty Using a New Cryotherapy Product: A Prospective Study. AB - To compare a novel cooling product, Physicool (P, Physicool Ltd, London, England, UK) with a well-established cryotherapy system, Cryocuff (C, Aircast, DJO Global, Vista, California, USA) using pain scores, range of movement (ROM), and cost as outcome measures in the early phase following total knee arthroplasty. We prospectively studied 90 consecutive patients undergoing unilateral total knee arthroplasty by a single surgeon. Following exclusions, 40 patients were recruited to each group. Visual analogue scale (VAS) for pain and ROM before and after application of cooling device was recorded at 24 and 48 hours after surgery. The cost of treatment per patient was also calculated. The VAS were significantly reduced in P on day 1 postsurgery (p = 0.013) and day 2 (p = 0.001) compared to C. A significant increase in ROM was recorded in P at 24 hours (p = 0.004) and at 48 hours (p = 0.009) postsurgery compared to C. The cost benefit of using P over C was approximately L25 per patient. The Physicool system is a safe and effective cooling method for improving pain and ROM in the early postoperative phase following total knee arthroplasty. Furthermore, it offers substantial cost savings. PMID- 26623169 TI - Prediction of Reoperation of Femoral Neck Fractures Treated With Cannulated Screws in Elderly Patients. AB - BACKGROUND: Reoperation of femoral neck fractures in elderly patients is frequent. Our aim was to determine predictors of reoperations following primary internal fixation with 3 cannulated screws. MATERIALS AND METHODS: A follow-up study included all patients aged 65+ years old patients consecutively admitted to an orthopedic ward with femoral neck fracture in the period from January 1, 2007, to December 31, 2010, and fixed with cannulated screws. We retrospectively obtained all available data from patient databases related to potential predictors of reoperations: gender, age, dwelling, dementia, body mass index, vitamin D, albumin, prednisolone treatment, walking aid, performance of activities of daily living, low-energy trauma, initial displacement, and surgery quality. Outcome was reoperation due to fixation failure/prominent screws, nonunion, or avascular necrosis of femoral head within 2 years after surgery. By multivariate Cox proportional hazards regression, including mortality as a competing risk, we estimated crude and adjusted hazards ratios (HRs) with 95% confidence intervals (CIs) for reoperation. RESULTS: Two years after surgery, 29% of 322 elderly patients underwent reoperation. Reoperation was associated with primary fracture displacement (HRadjusted 1.61; 95% CI: 1.01-2.55; P = .04) compared to undisplacement. A poor quality of primary reduction was associated with a higher risk of reoperations than a good quality (HRadjusted 1.95; 95% CI: 1.02-3.72; P = .04). Elderly individuals in own homes and sheltered housings had a higher risk of reoperation (HRadjusted 2.67; 95% CI 1.35-5.31; P = .005) compared to nursing home residents. CONCLUSION: Our findings support the evidence of a higher incidence of reoperation in displaced femoral neck fractures compared to the nondisplaced and is associated with poor quality of fracture reduction. Reoperations are most frequent in younger and more independent patients living at home. PMID- 26623170 TI - Upper Cervical Epidural Abscess in a Patient With Parkinson Disease: A Case Report and Review. AB - To our knowledge, there are no reports in the literature of patients with Parkinson disease (PD) developing upper cervical spine infections. Our objective is to present a case of upper cervical epidural abscess in a patient with PD and to review upper cervical spine infection. We present the patient's presentation, physical examination, imaging findings, and management as well a review of the literature. A 66-year-old male with PD presented to the emergency department (ED) following referral by a neurologist for a presumed C2 fracture. The preceding history was 1 week of severe neck pain requiring a magnetic resonance imaging (MRI), which was initially interpreted as a C2 fracture. On admission from the ED, further review of the MRI appeared to show anterior prevertebral abscess and an epidural abscess. The patient's neurological examination was at baseline. In the span of 2 days, the patient developed significant motor weakness. A repeat MRI demonstrated expansion of the epidural collection and spinal cord compression. Surgical management consisting of C1 and C2 laminectomy, irrigation, and debridement from anterior and posterior approaches was performed. Postoperatively, the patient did not recover any motor strength and elected to withdraw care and died. Spinal epidural abscess requires a high index of suspicion and needs prompt recognition to prevent neurological impairment. Upper cervical spine infections are rare but can lead to lethal consequences. PMID- 26623171 TI - Self-Reduction of Displaced Bucket-Handle Medial Meniscal Tear in a 71-Year-Old Patient: A Case Report. AB - BACKGROUND: Bucket-handle meniscal tears are rare in geriatric patients. Displaced bucket-handle meniscal tears are usually treated operatively. Due to the rarity of these tears in elderly patients and conflicting evidence regarding the use of arthroscopy versus conservative treatment, it is valuable to report the clinical presentation, treatment, and outcome of these injuries in elderly patients. CASE DESCRIPTION: We describe a 71-year-old man who presented with an acute, displaced, magnetic resonance imaging (MRI)-confirmed right medial meniscal bucket-handle tear with mild effusion and no signs of degenerative joint disease. On physical examination, the patient was unable to fully extend the right leg due to locking of the knee. At 2-month follow-up, MRI showed mild degenerative changes and an anatomically reduced tear. At 6-month follow-up, the patient reported normal, pain-free knee function, and MRI showed the tear healing in anatomic position with minimal inferior surface changes and no effusion. He returned to his pain-free baseline level of physical activity. LITERATURE REVIEW: Upon review of the English literature, this 71-year-old patient is an exceptional case and one of the oldest patients reported to have sustained a displaced medial meniscal bucket-handle tear treated successfully with nonoperative means. Two reported cases of spontaneously reduced meniscal bucket-handle tears were found in the English literature, although both cases were seen in much younger males and involved the lateral meniscus. CLINICAL RELEVANCE: This case suggests that in elderly patients with displaced medial meniscus bucket-handle tears that reduce spontaneously, the physician can safely and efficaciously use conservative, nonoperative management to achieve restoration of baseline knee function and anatomic meniscal healing while avoiding the risks of arthroscopic surgery. Surgical intervention for reduction without repair may be an available option, but no literature is present to direct care; however, complete documentation as in the current case would be instructive. Katz et al have reported that physical therapy was as efficacious as surgical intervention, although the specific displaced bucket-handle tear was not reported. PMID- 26623172 TI - Evaluating Problems With Footwear in the Geriatric Population. AB - Foot pathologies are common in nearly 80% of all elderly patients, and studies have indicated inappropriate footwear as one of the major underlying cause. It has been postulated that ill-fitting shoe wear affects plantar pressure, thus exacerbating weak balance. Complications arising from foot pathologies, which include difficulty in maintaining balance, have increased the risk of falls that can result in fractures and other serious injuries. The link between footwear and the onset or progression of certain foot pathologies has emphasized the need to explore and promote preventative measures to combat the issue. Wider and higher toe boxed shoes, along with sneakers, are examples of footwear documented to evenly distribute plantar pressure, increase comfort, and facilitate appropriate balance and gait. Ultimately, the use of appropriate footwear can help to better stabilize the foot, thus reducing the risk of sustaining debilitating physical injuries known to drastically decrease the quality of life among the geriatric population. PMID- 26623173 TI - Nonuniform update for sparse target recovery in fluorescence molecular tomography accelerated by ordered subsets. AB - Fluorescence molecular tomography (FMT) is a promising imaging modality and has been actively studied in the past two decades since it can locate the specific tumor position three-dimensionally in small animals. However, it remains a challenging task to obtain fast, robust and accurate reconstruction of fluorescent probe distribution in small animals due to the large computational burden, the noisy measurement and the ill-posed nature of the inverse problem. In this paper we propose a nonuniform preconditioning method in combination with L (1) regularization and ordered subsets technique (NUMOS) to take care of the different updating needs at different pixels, to enhance sparsity and suppress noise, and to further boost convergence of approximate solutions for fluorescence molecular tomography. Using both simulated data and phantom experiment, we found that the proposed nonuniform updating method outperforms its popular uniform counterpart by obtaining a more localized, less noisy, more accurate image. The computational cost was greatly reduced as well. The ordered subset (OS) technique provided additional 5 times and 3 times speed enhancements for simulation and phantom experiments, respectively, without degrading image qualities. When compared with the popular L (1) algorithms such as iterative soft-thresholding algorithm (ISTA) and Fast iterative soft-thresholding algorithm (FISTA) algorithms, NUMOS also outperforms them by obtaining a better image in much shorter period of time. PMID- 26623174 TI - Targeting Cathepsin B for Cancer Therapies. AB - Cathepsin B is a member of the papain family of cysteine proteases normally present in the lysosome, but it can translocate and function to degrade components of the extracellular matrix. It exhibits carboxyopeptidase, peptidyldipepidase, and endopeptidase activity. Aberrant overexpression of cathepsin B has been reported in invasive and metastatic cancers, including breast cancer, melanoma and colorectal cancer. It has been shown that oncogenic activation, such as the signaling of the ErbB pathways, can lead to cathepsin B overexpression. The degradation of the extracellular matrix is a key factor for cathepsin B to contribute to development and metastasis of tumors. An example of substrates for cathepsin B is E-cadherin, which is involved in adherens junctions, and the downregulation of E-cadherin in cancer is directly linked to invasion and metastasis. Recent studies also point to a role for cathepsin B in macrophages in the tumor microenvironment. The structure of cathepsin B is crystallographically solved, and several highly selective and potent inhibitors for cathepsin B have been developed. Yet it remains to be a challenge to demonstrate the clinical utility or benefit of any cathepsin B inhibitor. As cathepsin B is required for a cellular process called lysosomal membrane permeabilization (LMP), inhibition of cathepsin B would protect cancer cells from cell death induced by chemotherapeutic agents. It is expected that combining cathepsin B inhibitors with other approaches, such as nanoparticles, to direct the inhibition to the extracellular space may lead to better clinical approaches to treat cancers and metastasis. PMID- 26623175 TI - Successful childhood obesity management in primary care in Canada: what are the odds? AB - Background. The management of a child presenting with obesity in a primary care setting can be viewed as a multi-step behavioral process with many perceived and actual barriers for families and primary care providers. In order to achieve the goal of behavior change and, ultimately, clinically meaningful weight management outcomes in a child who is considered obese, all steps in this process should ideally be completed. We sought to review the evidence for completing each step, and to estimate the population effect of secondary prevention of childhood obesity in Canada. Methods. Data from the 2009/2010 Canadian Community Health Survey and from a review of the literature were used to estimate the probabilities for completion of each step. A flow chart based on these probabilities was used to determine the proportion of children with obesity that would undergo and achieve clinically meaningful weight management outcomes each year in Canada. Results. We estimated that the probability of a child in Canada who presents with obesity achieving clinically meaningful weight management outcomes through secondary prevention in primary care is around 0.6% per year, with a range from 0.01% to 7.2% per year. The lack of accessible and effective weight management programs appeared to be the most important bottleneck in the process. Conclusions. In order to make progress towards supporting effective pediatric obesity management, efforts should focus on population-based primary prevention and a systems approach to change our obesogenic society, alongside the allocation of resources toward weight management approaches that are comprehensively offered, equitably distributed and robustly evaluated. PMID- 26623176 TI - Replacement of native by non-native animal communities assisted by human introduction and management on Isla Victoria, Nahuel Huapi National Park. AB - One of the possible consequences of biological invasions is the decrease of native species abundances or their replacement by non-native species. In Andean Patagonia, southern Argentina and Chile, many non-native animals have been introduced and are currently spreading. On Isla Victoria, Nahuel Huapi National Park, many non-native vertebrates were introduced ca. 1937. Records indicate that several native vertebrates were present before these species were introduced. We hypothesize that seven decades after the introduction of non-native species and without appropriate management to maintain native diversity, non-native vertebrates have displaced native species (given the known invasiveness and impacts of some of the introduced species). We conducted direct censuses in linear transects 500 m long (n = 10) in parallel with camera-trapping (1,253 camera-days) surveys in two regions of the island with different levels of disturbance: high (n = 4) and low (n = 6) to study the community of terrestrial mammals and birds and the relative abundances of native and non-native species. Results show that currently non-native species are dominant across all environments; 60.4% of census records and 99.7% of camera trapping records are of non-native animals. We detected no native large mammals; the assemblage of large vertebrates consisted of five non-native mammals and one non-native bird. Native species detected were one small mammal and one small bird. Species with the highest trapping rate were red and fallow deer, wild boar, silver pheasant (all four species are non-native) and chucao (a native bird). These results suggest that native species are being displaced by non-natives and are currently in very low numbers. PMID- 26623177 TI - No apparent correlation between honey bee forager gut microbiota and honey production. AB - One of the best indicators of colony health for the European honey bee (Apis mellifera) is its performance in the production of honey. Recent research into the microbial communities naturally populating the bee gut raise the question as to whether there is a correlation between microbial community structure and colony productivity. In this work, we used 16S rRNA amplicon sequencing to explore the microbial composition associated with forager bees from honey bee colonies producing large amounts of surplus honey (productive) and compared them to colonies producing less (unproductive). As supported by previous work, the honey bee microbiome was found to be dominated by three major phyla: the Proteobacteria, Bacilli and Actinobacteria, within which we found a total of 23 different bacterial genera, including known "core" honey bee microbiome members. Using discriminant function analysis and correlation-based network analysis, we identified highly abundant members (such as Frischella and Gilliamella) as important in shaping the bacterial community; libraries from colonies with high quantities of these Orbaceae members were also likely to contain fewer Bifidobacteria and Lactobacillus species (such as Firm-4). However, co-culture assays, using isolates from these major clades, were unable to confirm any antagonistic interaction between Gilliamella and honey bee gut bacteria. Our results suggest that honey bee colony productivity is associated with increased bacterial diversity, although this mechanism behind this correlation has yet to be determined. Our results also suggest researchers should not base inferences of bacterial interactions solely on correlations found using sequencing. Instead, we suggest that depth of sequencing and library size can dramatically influence statistically significant results from sequence analysis of amplicons and should be cautiously interpreted. PMID- 26623178 TI - Grunt variation in the oyster toadfish Opsanus tau: effect of size and sex. AB - As in insects, frogs and birds, vocal activity in fishes tends to be more developed in males than in females, and sonic swimbladder muscles may be sexually dimorphic, i.e., either larger in males or present only in males. Male oyster toadfish Opsanus tau L produce a long duration, tonal boatwhistle advertisement call, and both sexes grunt, a short duration more pulsatile agonistic call. Sonic muscles are present in both sexes but larger in males. We tested the hypothesis that males would call more than females by inducing grunts in toadfish of various sizes held in a net and determined incidence of calling and developmental changes in grunt parameters. A small number of fish were recorded twice to examine call repeatability. Both sexes were equally likely to grunt, and grunt parameters (sound pressure level (SPL), individual range in SPL, number of grunts, and fundamental frequency) were similar in both sexes. SPL increased with fish size before leveling off in fish >200 g, and fundamental frequency and other parameters did not change with fish size. Number of grunts in a train, grunt duration and inter-grunt interval were highly variable in fish recorded twice suggesting that grunt parameters reflect internal motivation rather than different messages. Grunt production may explain the presence of well-developed sonic muscles in females and suggests that females have an active but unexplored vocal life. PMID- 26623179 TI - miRMOD: a tool for identification and analysis of 5' and 3' miRNA modifications in Next Generation Sequencing small RNA data. AB - In the past decade, the microRNAs (miRNAs) have emerged to be important regulators of gene expression across various species. Several studies have confirmed different types of post-transcriptional modifications at terminal ends of miRNAs. The reports indicate that miRNA modifications are conserved and functionally significant as it may affect miRNA stability and ability to bind mRNA targets, hence affecting target gene repression. Next Generation Sequencing (NGS) of the small RNA (sRNA) provides an efficient and reliable method to explore miRNA modifications. The need for dedicated software, especially for users with little knowledge of computers, to determine and analyze miRNA modifications in sRNA NGS data, motivated us to develop miRMOD. miRMOD is a user friendly, Microsoft Windows and Graphical User Interface (GUI) based tool for identification and analysis of 5' and 3' miRNA modifications (non-templated nucleotide additions and trimming) in sRNA NGS data. In addition to identification of miRNA modifications, the tool also predicts and compares the targets of query and modified miRNAs. In order to compare binding affinities for the same target, miRMOD utilizes minimum free energies of the miRNA:target and modified-miRNA:target interactions. Comparisons of the binding energies may guide experimental exploration of miRNA post-transcriptional modifications. The tool is available as a stand-alone package to overcome large data transfer problems commonly faced in web-based high-throughput (HT) sequencing data analysis tools. miRMOD package is freely available at http://bioinfo.icgeb.res.in/miRMOD. PMID- 26623180 TI - The vibrating reed frequency meter: digital investigation of an early cochlear model. AB - The vibrating reed frequency meter, originally employed by Bekesy and later by Wilson as a cochlear model, uses a set of tuned reeds to represent the cochlea's graded bank of resonant elements and an elastic band threaded between them to provide nearest-neighbour coupling. Here the system, constructed of 21 reeds progressively tuned from 45 to 55 Hz, is simulated numerically as an elastically coupled bank of passive harmonic oscillators driven simultaneously by an external sinusoidal force. To uncover more detail, simulations were extended to 201 oscillators covering the range 1-2 kHz. Calculations mirror the results reported by Wilson and show expected characteristics such as traveling waves, phase plateaus, and a response with a broad peak at a forcing frequency just above the natural frequency. The system also displays additional fine-grain features that resemble those which have only recently been recognised in the cochlea. Thus, detailed analysis brings to light a secondary peak beyond the main peak, a set of closely spaced low-amplitude ripples, rapid rotation of phase as the driving frequency is swept, frequency plateaus, clustering, and waxing and waning of impulse responses. Further investigation shows that each reed's vibrations are strongly localised, with small energy flow along the chain. The distinctive set of equally spaced ripples is an inherent feature which is found to be largely independent of boundary conditions. Although the vibrating reed model is functionally different to the standard transmission line, its cochlea-like properties make it an intriguing local oscillator model whose relevance to cochlear mechanics needs further investigation. PMID- 26623181 TI - Persistent and extreme outliers in causes of death by state, 1999-2013. AB - In the United States, state-specific mortality rates that are high relative to national rates can result from legitimate reasons or from variability in coding practices. This paper identifies instances of state-specific mortality rates that were at least twice the national rate in each of three consecutive five-year periods (termed persistent outliers), along with rates that were at least five times the national rate in at least one five-year period (termed extreme outliers). The resulting set of 71 outliers, 12 of which appear on both lists, illuminates mortality variations within the country, including some that are amenable to improvement either because they represent preventable causes of death or highlight weaknesses in coding techniques. Because the approach used here is based on relative rather than absolute mortality, it is not dominated by the most common causes of death such as heart disease and cancer. PMID- 26623182 TI - Two continents and two names for a Neotropical colletid bee species (Hymenoptera: Colletidae: Neopasiphaeinae): Hoplocolletes ventralis (Friese, 1924). AB - Neopasiphaeine bees (Apoidea: Colletidae) are known for their Amphinotic distribution in the Australian and Neotropical regions. Affinities between colletid taxa in Australia and South America have been speculated for decades, and have been confirmed by recent phylogenetic hypotheses that indicate a biogeographic scenario compatible with a trans-Antarctic biotic connection during the Paleogene. No neopasiphaeine species occurs on both sides of the Pacific Ocean, but the Neotropical species Hoplocolletes ventralis (Friese, 1924) was described as an Australian taxon due to an error in the specimen labels. This mistake was recognized by CD Michener 50 years ago. We herein report that the same labeling problem also happened with Dasycolletes chalceus Friese, 1924, which remained as a tentatively placed species in the Australian genus Leioproctus until now. Moreover, Dasycolletes chalceus is interpreted as a synonym of Hoplocolletes ventralis. We also provide a revised diagnosis for Hoplocolletes, describe the male of H. ventralis in detail for the first time, including a comparative study of its genitalia and associated sterna. PMID- 26623183 TI - Epidemiological evidence on extra-medical use of prescription pain relievers: transitions from newly incident use to dependence among 12-21 year olds in the United States using meta-analysis, 2002-13. AB - Background. When 12-to-21-year-olds start using prescription pain relievers extra medically, some of them transition into opioid dependence within 12 months after such use. Our main aim for this epidemiological research on 12-to-21-year-olds in the United States (US) is to estimate the risk of becoming a newly incident case of opioid dependence within 12 months after onset of using prescription pain relievers extra-medically (EMPPR). Methods. Meta-analyses from multiple independent replication samples now are possible, based upon nationally representative survey samples of US adolescents age 12-21 years. All 12-to-21 year-olds were sampled and recruited for the US National Surveys on Drug Use and Health, with standardized assessments of EMPPR use and opioid dependence (NSDUH, 2002-2013). Results. Peak risk for a transition from start of EMPPR use to opioid dependence within 12 months is seen at mid-adolescence among 14-to-15-year-olds (6.3%, 8.7% per year), somewhat earlier than peak risk for starting EMPPR use (seen for 16-to-19-year-olds at 4.1%, 5.9% per year). Applied to 12-to-21-year olds in the US between 2002-2013, an estimated 8 million started using PPR extra medically. Each year, roughly 42,000 to 58,000 transitioned into opioid dependence within 12 months after onset of such use. Discussion. These epidemiological estimates for the US in recent years teach us to expect one transition into adolescent-onset opioid dependence within 12 months for every 11 16 newly incident EMPPR users, yielding perhaps 120 newly incident opioid dependent cases in need of practitioner attention or treatment services, each day of each year. This evidence can be used to motivate more effective public health prevention, outreach, and early intervention programs as might prevent or delay occurrence of EMPPR use and opioid dependence. PMID- 26623184 TI - What do giant titanosaur dinosaurs and modern Australasian megapodes have in common? AB - Titanosauria is a globally distributed clade of sometimes extremely large Mesozoic herbivorous sauropod dinosaurs. On the basis of current evidence these giant dinosaurs seem to have reproduced in specific and localized nesting sites. However, no investigations have been performed to understand the possible ecological and geological biases that acted for the selection of these nesting sites worldwide. In this study, observations were performed on the best-known Cretaceous nesting sites around the world. Our observations strongly suggest their eggs were incubated with environmental sources of heat, in burial conditions. Taking into account the clutch composition and geometry, the nature and properties of the sediments, the eggshells' structures and conductance, it would appear that titanosaurs adopted nesting behaviors comparable to the modern Australasian megapodes, using burrow-nesting in diverse media and mound-building strategies. PMID- 26623187 TI - A predictive screening tool to detect diabetic retinopathy or macular edema in primary health care: construction, validation and implementation on a mobile application. AB - The most described techniques used to detect diabetic retinopathy and diabetic macular edema have to be interpreted correctly, such that a person not specialized in ophthalmology, as is usually the case of a primary care physician, may experience difficulties with their interpretation; therefore we constructed, validated and implemented as a mobile app a new tool to detect diabetic retinopathy or diabetic macular edema (DRDME) using simple objective variables. We undertook a cross-sectional, observational study of a sample of 142 eyes from Spanish diabetic patients suspected of having DRDME in 2012-2013. Our outcome was DRDME and the secondary variables were: type of diabetes, gender, age, glycated hemoglobin (HbA1c), foveal thickness and visual acuity (best corrected). The sample was divided into two parts: 80% to construct the tool and 20% to validate it. A binary logistic regression model was used to predict DRDME. The resulting model was transformed into a scoring system. The area under the ROC curve (AUC) was calculated and risk groups established. The tool was validated by calculating the AUC and comparing expected events with observed events. The construction sample (n = 106) had 35 DRDME (95% CI [24.1-42.0]), and the validation sample (n = 36) had 12 DRDME (95% CI [17.9-48.7]). Factors associated with DRDME were: HbA1c (per 1%) (OR = 1.36, 95% CI [0.93-1.98], p = 0.113), foveal thickness (per 1 um) (OR = 1.03, 95% CI [1.01-1.04], p < 0.001) and visual acuity (per unit) (OR = 0.14, 95% CI [0.00-0.16], p < 0.001). AUC for the validation: 0.90 (95% CI [0.75-1.00], p < 0.001). No significant differences were found between the expected and the observed outcomes (p = 0.422). In conclusion, we constructed and validated a simple rapid tool to determine whether a diabetic patient suspected of having DRDME really has it. This tool has been implemented on a mobile app. Further validation studies are required in the general diabetic population. PMID- 26623185 TI - ProCS15: a DFT-based chemical shift predictor for backbone and Cbeta atoms in proteins. AB - We present ProCS15: a program that computes the isotropic chemical shielding values of backbone and Cbeta atoms given a protein structure in less than a second. ProCS15 is based on around 2.35 million OPBE/6-31G(d,p)//PM6 calculations on tripeptides and small structural models of hydrogen-bonding. The ProCS15 predicted chemical shielding values are compared to experimentally measured chemical shifts for Ubiquitin and the third IgG-binding domain of Protein G through linear regression and yield RMSD values of up to 2.2, 0.7, and 4.8 ppm for carbon, hydrogen, and nitrogen atoms. These RMSD values are very similar to corresponding RMSD values computed using OPBE/6-31G(d,p) for the entire structure for each proteins. These maximum RMSD values can be reduced by using NMR-derived structural ensembles of Ubiquitin. For example, for the largest ensemble the largest RMSD values are 1.7, 0.5, and 3.5 ppm for carbon, hydrogen, and nitrogen. The corresponding RMSD values predicted by several empirical chemical shift predictors range between 0.7-1.1, 0.2-0.4, and 1.8-2.8 ppm for carbon, hydrogen, and nitrogen atoms, respectively. PMID- 26623186 TI - Are neonicotinoid insecticides driving declines of widespread butterflies? AB - There has been widespread concern that neonicotinoid pesticides may be adversely impacting wild and managed bees for some years, but recently attention has shifted to examining broader effects they may be having on biodiversity. For example in the Netherlands, declines in insectivorous birds are positively associated with levels of neonicotinoid pollution in surface water. In England, the total abundance of widespread butterfly species declined by 58% on farmed land between 2000 and 2009 despite both a doubling in conservation spending in the UK, and predictions that climate change should benefit most species. Here we build models of the UK population indices from 1985 to 2012 for 17 widespread butterfly species that commonly occur at farmland sites. Of the factors we tested, three correlated significantly with butterfly populations. Summer temperature and the index for a species the previous year are both positively associated with butterfly indices. By contrast, the number of hectares of farmland where neonicotinoid pesticides are used is negatively associated with butterfly indices. Indices for 15 of the 17 species show negative associations with neonicotinoid usage. The declines in butterflies have largely occurred in England, where neonicotinoid usage is at its highest. In Scotland, where neonicotinoid usage is comparatively low, butterfly numbers are stable. Further research is needed urgently to show whether there is a causal link between neonicotinoid usage and the decline of widespread butterflies or whether it simply represents a proxy for other environmental factors associated with intensive agriculture. PMID- 26623188 TI - Datziinae as a new subfamily name for the unavailable name Protopsychodinae Stebner et al., 2015, (Diptera: Psychodidae). AB - In a recent paper a new subfamily of Psychodidae was inadequately named Protopsychodinae. This nomenclatural act cannot be considered as a valid name under ICZN regulations because the subfamily name is not based on the type genus Datzia Stebner et al., 2015, and furthermore the fossil genus Protopsychoda Azar et al., 1999 was originally described under the subfamily Psychodinae. Therefore, the new family-group name Datziinae is herein proposed. PMID- 26623189 TI - Radiocesium concentrations in wild mushrooms collected in Kawauchi Village after the accident at the Fukushima Daiichi Nuclear Power Plant. AB - It is well known from the experience after the 1986 accident at the Chernobyl Nuclear Power Plant that radiocesium tends to concentrate in wild mushrooms. In this study, we collected wild mushrooms from the Kawauchi Village of Fukushima Prefecture, located within 30 km of the Fukushima Daiichi Nuclear Power Plant, and evaluated their radiocesium concentrations to estimate the risk of internal radiation exposure in local residents. We found that radioactive cesium exceeding 100 Bq/kg was detected in 125 of 154 mushrooms (81.2%). We calculated committed effective doses based on 6,278 g per year (age > 20 years, 17.2 g/day), the average intake of Japanese citizens, ranging from doses of 0.11-1.60 mSv, respectively. Although committed effective doses are limited even if residents eat contaminated foods several times, we believe that comprehensive risk communication based on the results of the radiocesium measurements of food, water, and soil is necessary for the recovery of Fukushima after this nuclear disaster. PMID- 26623190 TI - Dynamics in benthic community composition and influencing factors in an upwelling exposed coral reef on the Pacific coast of Costa Rica. AB - Seasonal upwelling at the northern Pacific coast of Costa Rica offers the opportunity to investigate the effects of pronounced changes in key water parameters on fine-scale dynamics of local coral reef communities. This study monitored benthic community composition at Matapalo reef (10.539 degrees N, 85.766 degrees W) by weekly observations of permanent benthic quadrats from April 2013 to April 2014. Monitoring was accompanied by surveys of herbivore abundance and biomass and measurements of water temperature and inorganic nutrient concentrations. Findings revealed that the reef-building corals Pocillopora spp. exhibited an exceptional rapid increase from 22 to 51% relative benthic cover. By contrast, turf algae cover decreased from 63 to 24%, resulting in a corresponding increase in crustose coralline algae cover. The macroalga Caulerpa sertularioides covered up to 15% of the reef in April 2013, disappeared after synchronized gamete release in May, and subsequently exhibited slow regrowth. Parallel monitoring of influencing factors suggest that C. sertularioides cover was mainly regulated by their reproductive cycle, while that of turf algae was likely controlled by high abundances of herbivores. Upwelling events in February and March 2014 decreased mean daily seawater temperatures by up to 7 degrees C and increased nutrient concentrations up to 5- (phosphate) and 16-fold (nitrate) compared to mean values during the rest of the year. Changes in benthic community composition did not appear to correspond to the strong environmental changes, but rather shifted from turf algae to hard coral dominance over the entire year of observation. The exceptional high dynamic over the annual observation period encourages further research on the adaptation potential of coral reefs to environmental variability. PMID- 26623191 TI - Measuring health disparities: a comparison of absolute and relative disparities. AB - Monitoring national trends in disparities in different diseases could provide measures to evaluate the impact of intervention programs designed to reduce health disparities. In the US, most of the reports that track health disparities provided either relative or absolute disparities or both. However, these two measures of disparities are not only different in scale and magnitude but also the temporal changes in the magnitudes of these measures can occur in opposite directions. The trends for absolute disparity and relative disparity could move in opposite directions when the prevalence of disease in the two populations being compared either increase or decline simultaneously. If the absolute disparity increases but relative disparity declines for consecutive time periods, the absolute disparity increases but relative disparity declines for the combined time periods even with a larger increase in absolute disparity during the combined time periods. Based on random increases or decreases in prevalence of disease for two population groups, there is a higher chance the trends of these two measures could move in opposite directions when the prevalence of disease for the more advantaged group is very small relative to the prevalence of disease for the more disadvantaged group. When prevalence of disease increase or decrease simultaneously for two populations, the increase or decrease in absolute disparity has to be sufficiently large enough to warrant a corresponding increase or decrease in relative disparity. When absolute disparity declines but relative disparity increases, there is some progress in reducing disparities, but the reduction in absolute disparity is not large enough to also reduce relative disparity. When evaluating interventions to reduce health disparities using these two measures, it is important to consider both absolute and relative disparities and consider all the scenarios discussed in this paper to assess the progress towards reducing or eliminating health disparities. PMID- 26623192 TI - A critical survey of vestigial structures in the postcranial skeletons of extant mammals. AB - In the Mammalia, vestigial skeletal structures abound but have not previously been the focus of study, with a few exceptions (e.g., whale pelves). Here we use a phylogenetic bracketing approach to identify vestigial structures in mammalian postcranial skeletons and present a descriptive survey of such structures in the Mammalia. We also correct previous misidentifications, including the previous misidentification of vestigial caviid metatarsals as sesamoids. We also examine the phylogenetic distribution of vestigiality and loss. This distribution indicates multiple vestigialization and loss events in mammalian skeletal structures, especially in the hand and foot, and reveals no correlation in such events between mammalian fore and hind limbs. PMID- 26623193 TI - Spatial patterns of coral survivorship: impacts of adult proximity versus other drivers of localized mortality. AB - Species-specific enemies may promote prey coexistence through negative distance- and density-dependent survival of juveniles near conspecific adults. We tested this mechanism by transplanting juvenile-sized fragments of the brooding corals Pocillopora damicornis and Seriatopora hystrix 3, 12, 24 and 182 cm up- and down current of conspecific adults and monitoring their survival and condition over time. We also characterized the spatial distribution of P. damicornis and S. hystrix within replicate plots on three Fijian reef flats and measured the distribution of small colonies within 2 m of larger colonies of each species. Juvenile-sized transplants exhibited no differences in survivorship as a function of distance from adult P. damicornis or S. hystrix. Additionally, both P. damicornis and S. hystrix were aggregated rather than overdispersed on natural reefs. However, a pattern of juveniles being aggregated near adults while larger (and probably older) colonies were not suggests that greater mortality near large adults could occur over longer periods of time or that size-dependent mortality was occurring. While we found minimal evidence of greater mortality of small colonies near adult conspecifics in our transplant experiments, we did document hot-spots of species-specific corallivory. We detected spatially localized and temporally persistent predation on P. damicornis by the territorial triggerfish Balistapus undulatus. This patchy predation did not occur for S. hystrix. This variable selective regime in an otherwise more uniform environment could be one mechanism maintaining diversity of corals on Indo-Pacific reefs. PMID- 26623194 TI - Assessing the utility of the Oxford Nanopore MinION for snake venom gland cDNA sequencing. AB - Portable DNA sequencers such as the Oxford Nanopore MinION device have the potential to be truly disruptive technologies, facilitating new approaches and analyses and, in some cases, taking sequencing out of the lab and into the field. However, the capabilities of these technologies are still being revealed. Here we show that single-molecule cDNA sequencing using the MinION accurately characterises venom toxin-encoding genes in the painted saw-scaled viper, Echis coloratus. We find the raw sequencing error rate to be around 12%, improved to 0 2% with hybrid error correction and 3% with de novo error correction. Our corrected data provides full coding sequences and 5' and 3' UTRs for 29 of 33 candidate venom toxins detected, far superior to Illumina data (13/40 complete) and Sanger-based ESTs (15/29). We suggest that, should the current pace of improvement continue, the MinION will become the default approach for cDNA sequencing in a variety of species. PMID- 26623195 TI - A tide prediction and tide height control system for laboratory mesocosms. AB - Experimental mesocosm studies of rocky shore and estuarine intertidal systems may benefit from the application of natural tide cycles to better replicate variation in immersion time, water depth, and attendant fluctuations in abiotic and edaphic conditions. Here we describe a stand-alone microcontroller tide prediction open source software program, coupled with a mechanical tidal elevation control system, which allows continuous adjustment of aquarium water depths in synchrony with local tide cycles. We used this system to monitor the growth of Spartina foliosa marsh cordgrass and scale insect herbivores at three simulated shore elevations in laboratory mesocosms. Plant growth decreased with increasing shore elevation, while scale insect population growth on the plants was not strongly affected by immersion time. This system shows promise for a range of laboratory mesocosm studies where natural tide cycling could impact organism performance or behavior, while the tide prediction system could additionally be utilized in field experiments where treatments need to be applied at certain stages of the tide cycle. PMID- 26623196 TI - Challenges to a molecular approach to prey identification in the Burmese python, Python molurus bivittatus. AB - Molecular approaches to prey identification are increasingly useful in elucidating predator-prey relationships, and we aimed to investigate the feasibility of these methods to document the species identities of prey consumed by invasive Burmese pythons in Florida. We were particularly interested in the diet of young snakes, because visual identification of prey from this size class has proven difficult. We successfully extracted DNA from the gastrointestinal contents of 43 young pythons, as well as from several control samples, and attempted amplification of DNA mini-barcodes, a 130-bp region of COX1. Using a PNA clamp to exclude python DNA, we found that prey DNA was not present in sufficient quality for amplification of this locus in 86% of our samples. All samples from the GI tracts of young pythons contained only hair, and the six samples we were able to identify to species were hispid cotton rats. This suggests that young Burmese pythons prey predominantly on small mammals and that prey diversity among snakes of this size class is low. We discuss prolonged gastrointestinal transit times and extreme gastric breakdown as possible causes of DNA degradation that limit the success of a molecular approach to prey identification in Burmese pythons. PMID- 26623197 TI - Thyrotoxic Periodic Paralysis: An Underdiagnosed and Under-recognized Condition. AB - Thyrotoxic hypokalemic periodic paralysis (TPP) is a condition characterized by the triad of acute hypokalemia without total body potassium deficit, episodic muscle paralysis, and thyrotoxicosis. We describe two cases of thyrotoxic periodic paralysis who presented to our hospital with potassium values of 1.3 MeQ/l and 1.2 MeQ/l, respectively. Surprisingly, the two patients had no documented past medical history. Based on the clinical features of high heart rate, palpitations (seen in both the patients), and exophthalmos (seen in one patient), thyrotoxic periodic paralysis was suspected. A thorough laboratory workup confirmed the diagnosis of thyrotoxicosis. Beta blockers were initiated promptly, along with intravenous potassium chloride, and the patients eventually improved symptomatically. These patients were eventually diagnosed with Graves' disease and were placed on methimazole, which prevented further attacks. Thyroid periodic paralysis (TPP) is a rare clinical manifestation of hyperthyroidism. Patients present with sudden onset paralysis associated with severe hypokalemia. The presence of paralysis and hypokalemia in a patient who has a history of hyperthyroidism should prompt the physician about thyrotoxic periodic paralysis. A high index of suspicion, prompt diagnosis, and management of the condition can prevent severe complications, such as cardiac arrhythmias. PMID- 26623198 TI - Long-term Outcomes and Late Effects of Definitive Chemoradiotherapy in Patients with Cervical Cancer in Nova Scotia. AB - PURPOSE: To determine the long-term oncologic outcomes and toxicity of patients treated with definitive chemo-radiotherapy for cervical cancer. METHODS AND MATERIALS: The study period was January 1, 2000 to December 31, 2009. All patients diagnosed with cervical cancer who received curative-intent chemoradiotherapy were included. Patients were excluded if they resided out of the province, received surgery as an initial treatment, or were treated with palliative intent. A retrospective chart review was performed. RESULTS: Four hundred and eighty-six patients were diagnosed with cervical cancer; 190 met eligibility criteria. Median follow-up for all patients was 3.2 years (interquartile range 1.1-5.6 years). Clinical stage was FIGO IIB or higher in 139 of 190 patients (73.2%). One hundred and fifty-eight (82.7%) received concurrent cisplatin chemotherapy (mean # cycles = 4.8). The most common external beam radiotherapy (EBRT) dose/fractionation schedule was 45 Gray (Gy) in 25 fractions (149 pts, 78.0%). One hundred and thirty-six (71.2%) received low-dose-rate (LDR) brachytherapy (BT: most common dose = 35 Gy). High-dose-rate (HDR) BT was implemented in 2008; the most common HDR dose was 24 Gy in 8 fractions over five days. Five-year overall survival (OS) and progression-free survival (PFS) were 69.4% and 61.4%, respectively. OS and PFS were significantly higher in patients who received chemotherapy vs. radiotherapy alone. For those receiving HDR-BT, there was a significantly higher OS, but not PFS. The rate of late RTOG Grade 3/4 toxicity at five years was 23.3% (gastrointestinal - 26 events, 13% of patients; genitourinary - 13 events, 8% of patients). Fourteen patients had Grade 3 radiation proctitis as the only late toxicity. EBRT dose above 45 Gy was the only factor associated with late toxicity on multivariate analysis. CONCLUSION: Outcomes of patients treated with chemoradiotherapy for cervical cancer are in keeping with those reported in other series. Chemotherapy improved OS and PFS. External beam radiotherapy dose above 45 Gy was the only predictor of late toxicity. PMID- 26623199 TI - Abscopal Effects: Case Report and Emerging Opportunities. AB - The abscopal effect is a phenomenon observed in the treatment of metastatic cancer where localized irradiation of a particular tumor site causes a response in a site distant to the irradiated volume. The mechanisms of the abscopal effect are speculated to be of several origins, including distant effects on p53, elaboration of inflammatory agents including cytokines, and, most recently, secondary to immune mechanisms. In this case report, we present a rare report of a patient with hepatocellular carcinoma with lung metastases who, after receiving radiation treatment to the liver, had a treatment response in the liver and a complete response in the lung. Recent advances in the understanding of the primary role of immune-modulated cytotoxicity, especially with the success of immune checkpoint inhibitors, have the potential to turn the abscopal effect from a rare phenomenon into a tool to guide antineoplastic therapy and provide a new line of research. PMID- 26623200 TI - Comparing Radiation Dose from Conventional Fluoroscopy to Intraoperative Cone Beam CT (O-arm) during Percutaneous Lesioning Procedures of the Gasserian Ganglion. AB - INTRODUCTION: The use of intraoperative CT-guidance during the percutaneous treatment of trigeminal neuralgia has become increasingly popular due to the greater ease of foramen ovale cannulation and decreased procedure times. Concerns regarding radiation dose to the patient, however, remain unaddressed. We sought to compare the emitted radiation dose from fluoroscopy with intraoperative CT for these procedures. METHODS: A retrospective review of percutaneous lesioning procedures for trigeminal neuralgia performed between 2010 until 2012 at our institution was conducted and radiation doses to the patient were recorded. We subsequently simulated four separate percutaneous trigeminal rhizotomies using the O-arm intraoperative CT (Medtronics, Minneapolis, MN, USA) to cannulate the foramen ovale bilaterally in two formalin-fixed cadaver heads. RESULTS: Seventeen successful percutaneous treatments for trigeminal neuralgia were performed during the study period. Eleven procedures containing complete records were included in the final analysis. For procedures using fluoroscopy, the mean dosage was 15.2 mGys (range: 1.15 - 47.95, 95% CI 7.34 - 22.99). Radiation dosage from the O-arm imaging system was 16.55 mGy for all four cases. An unequal variance t-test did not reach statistical significance (p=0.42). CONCLUSIONS: We did not observe a significant difference in radiation dose delivered to subjects when comparing CT guided foramen ovale cannulation relative to fluoroscopy for percutaneous lesioning of the Gasserian ganglion. Additional study is required under operational settings. PMID- 26623201 TI - Isolated Spinal Metastasis with Spinal Cord Compression Leads to a Diagnosis of a Follicular Thyroid Carcinoma. AB - INTRODUCTION: Thyroid carcinoma initially presents with clinical symptoms due to metastatic lesions in less than 5% of cases. Spinal cord compression from an epidural metastatic lesion as a first symptom is extremely rare. One would expect such a presentation to occur much later in the course of the disease. METHODS: We are presenting a case report of a follicular thyroid carcinoma that presented with spinal cord compression from a thoracic epidural metastatic lesion in a previously healthy 55-year-old male. A single metastasis of follicular thyroid carcinoma presenting with posterior spinal cord compression is rare. In this particular case, our management included a mid-thoracic laminectomy, followed by resection of the epidural lesion. Once the surgical pathology confirmed the diagnosis of a follicular thyroid carcinoma, the general surgery team performed a near total thyroidectomy, after which he received radioactive iodine therapy. The patient is symptom-free at his three-year follow-up. CONCLUSION: Initial presentation of follicular thyroid carcinoma with symptomatic thoracic myelopathy from an epidural metastasis is very uncommon. An early diagnosis and prompt surgical intervention provided an excellent outcome. PMID- 26623202 TI - Stand-alone LLIF Lateral Cage Migration: A Case Report. AB - Lateral approaches to the lumbar disc space have become popular in recent years with very few reported complications. We report on a rare case of a stand-alone cage migration. A 77-year-old female presented with a right L2-3 radiculopathy that was refractory to maximum medical management. This was secondary to foraminal compression at L2-3 and L3-4 due to degenerative disc disease and levoscoliosis, as well as Grade 1 spondylolisthesis at both levels. A left-sided approach lateral lumbar interbody fusion was performed at L2-3 and L3-4 using a lordotic polyetheretherketone (PEEK) graft (50 mm length x 18 mm width x 9 mm height) packed with demineralized bone matrix (DBM). A contralateral release of the annulus fibrosis was performed during the decompression prior to graft insertion. Postoperative anteroposterior and lateral x-ray imaging confirmed good position of interbody grafts, correction of scoliosis as well as spondylolisthesis, and restoration of disc height achieving foraminal indirect decompression. A routine postoperative x-ray at three months demonstrated asymptomatic ipsilateral cage migration at the L2-3 level with evidence of arthrodesis in the disc space. This was managed conservatively without further surgical intervention. Placement of a lateral plate or interbody intradiscal plating system in patients with scoliosis and significant coronal deformity is an option that can be considered to prevent this rare LLIF complication. Moreover, asymptomatic cage migration may be conservatively managed without reoperation. PMID- 26623204 TI - The Mathematics of Four or More N-Localizers for Stereotactic Neurosurgery. AB - The mathematics that were originally developed for the N-localizer apply to three N-localizers that produce three sets of fiducials in a tomographic image. Some applications of the N-localizer use four N-localizers that produce four sets of fiducials; however, the mathematics that apply to three sets of fiducials do not apply to four sets of fiducials. This article presents mathematics that apply to four or more sets of fiducials that all lie within one planar tomographic image. In addition, these mathematics are extended to apply to four or more fiducials that do not all lie within one planar tomographic image, as may be the case with magnetic resonance (MR) imaging where a volume is imaged instead of a series of planar tomographic images. Whether applied to a planar image or a volume image, the mathematics of four or more N-localizers provide a statistical measure of the quality of the image data that may be influenced by factors, such as the nonlinear distortion of MR images. PMID- 26623203 TI - Hypersexuality Addiction and Withdrawal: Phenomenology, Neurogenetics and Epigenetics. AB - Hypersexuality has been defined as abnormally increased sexual activity. Epidemiological and clinical studies have shown that this non-paraphilic condition consists of "excessive" sexual behaviors and disorders accompanied by personal distress and social and medical morbidity. It is a very controversial and political topic in terms of how best to categorize it as similar or not similar to addictive behaviors including substance abuse. Hypersexual disorder is conceptualized as a non-paraphilic sexual desire disorder with impulsivity. Pathophysiological perspectives include dysregulation of sexual arousal and desire, sexual impulsivity, and sexual compulsivity. The nucleus accumbens, situated within the ventral striatum, mediates the reinforcing effects of drugs of abuse, such as cocaine, alcohol, nicotine, and food as well as music. Indeed, it is believed that this structure mandates behaviors elicited by incentive stimuli. These behaviors include natural rewards like feeding, drinking, sexual behavior, and exploratory locomotion. An essential rule of positive reinforcement is that motor responses will increase in magnitude and vigor if followed by a rewarding event. Here, we are hypothesizing that there is a common mechanism of action (MOA) for the powerful effects drugs, music, food, and sex have on human motivation. The human drive for the three necessary motivational behaviors "hunger, thirst, and sex" may all have common molecular genetic antecedents that, if impaired, lead to aberrant behaviors. We hypothesize that based on a plethora of scientific support hypersexual activity is indeed like drugs, food, and music that activate brain mesolimbic reward circuitry. Moreover, dopaminergic gene and possibly other candidate neurotransmitter-related gene polymorphisms affect both hedonic and anhedonic behavioral outcomes. There is little known about both the genetics and epigenetics of hypersexuality in the current literature. However, we anticipate that future studies based on assessments with clinical instruments combined with genotyping of sex addicts will provide evidence for specific clustering of sexual typologies with polymorphic associations. There have been some studies using electrophysiological techniques that do not support the view that hypersexuality is indeed similar to substance abuse and other behavioral addictions. The authors are also encouraging both clinical and academic scientists to embark on research using neuroimaging tools to examine natural dopaminergic agonistic agents targeting specific gene polymorphisms to "normalize" hypersexual behavior. PMID- 26623205 TI - Cognitive Remediation Therapy for Brain Tumor Survivors with Cognitive Deficits. AB - Cognitive deficits have been widely observed in patients with primary brain tumors consequent to diagnosis and treatment. Given the early onset and the relatively long survival rate of patients, it seems pertinent to study and refine the techniques used to treat these deficits. The purpose of this article is to discuss cognitive deficits that follow neurosurgical treatment for low-grade gliomas as well as to outline a neuropsychological intervention to treat these deficits, specifically working memory and attention. Cognitive remediation therapy is a neuropsychological intervention that aims to enhance attention, working memory, and executive functioning, thereby diminishing the impact of these deficits on daily functioning. Computerized cognitive remediation training programs facilitate access to treatment through providing online participation. The authors include preliminary results of three participants who have completed the computerized training program as part of an ongoing study that is investigating the efficacy of this program in patients who have undergone treatment for low-grade gliomas. The results so far suggest some improvement in working memory and attention from baseline scores. It is the hope of the present authors to highlight the importance of this treatment in the continuity of care of brain tumor survivors. PMID- 26623206 TI - Oblique Lateral Lumbar Interbody Fusion (OLLIF): Technical Notes and Early Results of a Single Surgeon Comparative Study. AB - BACKGROUND CONTEXT: Lower back pain is one of the most prevalent and expensive health conditions in the Western world. The standard treatment, interbody fusion, is an invasive procedure that requires the stripping of muscles and soft tissue, leading to surgical morbidity. Current minimally invasive (MI) spinal fusions are technically demanding and suffer from technical limitations. PURPOSE: Oblique lumbar lateral interbody fusion (OLLIF) is a new technique for fusion of the lumbar spine that overcomes these complications. Outcome measures include patient demographics, reported outcomes, and surgical outcomes. STUDY DESIGN/SETTING: Kambin's Triangle can easily be located as a silent window with an electrophysiological probe. Discectomy is performed through a single access portal with a 10 mm diameter. After a discectomy, the disc space is packed with beta-tricalcium phosphate soaked in autologous bone marrow, aspirated, and the cage is inserted. Finally, a minimally invasive posterior fixation is performed. METHODS: OLLIF's major innovation is to approach the disc through Kambin's Triangle, aided by bilateral fluoroscopy. RESULTS: We present data from 69 consecutive OLLIF surgeries on 128 levels with a control group of 55 consecutive open transformational lumbar interbody fusions (TLIFs) on 125 levels. For a single level OLLIF, the mean surgery time is 69 minutes (min) and blood loss is 29 ml. Surgery time was approximately twice as fast as open TLIF (mean: 135 min) and blood loss is reduced by over 80% compared to TLIF (mean: 355 ml). CONCLUSIONS: OLLIF is a minimally invasive fusion that significantly reduces surgery times compared to open surgery. OLLIF overcomes the difficulties of traditional open fusions, making it a safe and technically less demanding surgery than open or minimally invasive TLIF. PMID- 26623207 TI - Bilateral Blindness Following Chemoradiation for Locally Advanced Oropharyngeal Carcinoma. AB - Wernicke's encephalopathy is a life-threatening neurologic complication of thiamine deficiency. Though the presentation of symptoms can vary widely, the classical triad is founded on ophthalmoplegia, alteration of mental status, and gait disturbance. We describe a case of Wernicke's encephalopathy in an oncology patient shortly after concurrent 5-fluorouracil, carboplatin, and radiotherapy for locally advanced oropharyngeal cancer, presenting as complete bilateral blindness, ataxia, nystagmus, and confusion. Thiamine was given based on clinical suspicion and rapid improvement of clinical findings occurred. An MRI performed later supported the diagnosis of Wernicke's encephalopathy. A multifactorial etiology of thiamine deficiency from nutritional deficits and neurotoxic effects of chemotherapy are hypothesized. PMID- 26623208 TI - Grade 3 Radiation Recall Sigmoiditis after Treatment for Locally Advanced Cervical Cancer: A Case Report. AB - We report a case of Grade 3 radiation recall sigmoiditis after administration of a combination of carboplatin, paclitaxel, and bevacizumab, following irradiation for a locally advanced cervical cancer. A 50-year-old woman was diagnosed with an FIGO Stage IIIb squamous cell carcinoma of the cervix with bilateral pelvic and para-aortic lymph nodes. She underwent concurrent chemoradiation followed by high dose rate (HDR) intracavitary brachytherapy. She had a complete loco-regional response. A supraclavicular recurrence was diagnosed three months after completing treatment and two cycles of carboplatin, docetaxel, and bevacizumab were given in April 2014. Shortly after the second cycle, she was admitted to the hospital for significant abdominal pain, diarrhea followed by symptoms of bowel subocclusion. The CT scan and endoscopic images revealed thickening of the sigmoid wall with important edema and telangiectasia. The biopsy was consistent with acute radiation-induced colitis. Because of persistent digestive symptoms, a diverting ileostomy was done few months later. The location, timing, pathology, and its association with a high-dose region are analyzed in this case report. PMID- 26623209 TI - Paraganglioma of the Filum Terminale: Case Report, Pathology and Review of the Literature. AB - Spinal paragangliomas are very rare neuroendocrine tumors often presenting with low back pain and radicular symptoms; once resected, they often show benign clinical outcomes. Radiographically spinal paragangliomas mimic more commonly described tumors, such as ependymomas, schwannomas, meningiomas, and even hemangiomas, but a "salt and pepper" appearance related to a serpiginous vascular structure is instructive. Indeed, the rarity of this tumor makes the diagnosis rather challenging radiographically. Graded as a WHO Grade I tumor, they are slow growing with low proliferation indices. Gross total resection is the mainstay of operative treatment but is often limited by tumor adherence to functional nerves. Here, we present a case of this rare tumor and its management, including a review of the pathology and literature related to this tumor. PMID- 26623210 TI - Male Breast Cancer Prognostic Factors Versus Female Counterparts with Propensity Scores and Matched-Pair Analysis. AB - OBJECTIVE: To assess the effect of prognostic factors and their impact on survival in male and female breast cancer. METHODS: Medical records for men and women diagnosed with breast cancer referred to the cancer center for treatment were reviewed. Patients with distant metastatic diseases were excluded. Data on prognostic factors including age, nodal status, resection margin, use of hormonal therapy, chemotherapy with and without hormone and radiation therapy (RT), survival, and recurrence were analyzed. Survival estimates were obtained using Kaplan-Meier methodology. The Cox regression interaction was used to compare male and female differences in prognostic factors. Male breast cancer (MBC) and female breast cancer (FBC) were matched according to propensity scores and survival compared using Cox regression. RESULTS: From 1963-2006, there were 75 MBC and 1,313 FBC totaling 1,388 breast cancers. The median age of the cohort was 53 (range: 23-90) years. Median follow-up was 90 (range: 0.4-339) months. Prognostic factors of patients were balanced among the groups after adjusting for propensity scores. A Cox model adjusting for propensity scores showed that overall survival (OS) (HR= 2.52 (1.65, 3.86), P<0.001) and distant disease recurrence-free survival (DDRFS) (HR= 2.39 (0.75, 3.04), P=0.003) were significantly different for MBC and FBC. Analyses that stratified by propensity score quintiles had similar findings: OS HR=2.41 (1.67, 3.47), P<0.001); DDRFS HR=2.89 (1.81, 4.60), P<0.001). When MBC and FBC were matched (1:3) by propensity scores, differences between MBC and FBC were again observed in OS (HR=1.94, 95%CI:1.18-3.19, P=0.009) and DDRFS (HR=2.79, 95%CI:1.36-5.75, P=0.005) with MBC at a higher risk of death and disease recurrence compared to FBC . CONCLUSION: This large series showed that MBC and FBC survivals are not similar, with MBC having a worse outcome. The finding of this study needs confirmation from a complete prospective database. PMID- 26623211 TI - Application of Pipeline Embolization Device for Iatrogenic Pseudoaneurysms of the Extracranial Vertebral Artery: A Case Report and Systematic Review of the Literature. AB - Traumatic pseudoaneurysms of the vertebral artery (VA) are uncommon vascular lesions and definitive management is often challenging. Between 0% and 8% of craniocervical fusions are complicated by VA injury. In these cases, preserving the vertebral artery while treating the pseudoaneurysm is the goal of any treatment option. We describe the second known case of a patient with and iatrogenic extracranial vertebral artery pseudoaneurysm treated effectively using the Pipeline Embolization Device (PED) (Ev3 Neurovascular, Irvine, CA). Although there have been only two cases reported, the use of flow-diverting stents appears to be efficacious for the treatment of non-actively bleeding traumatic pseudoaneurysms. PMID- 26623212 TI - Endoscopic Endonasal Transsphenoidal Treatment of Pituitary Apoplexy: Outcomes in a Series of 20 Patients. AB - OBJECTIVE: Pituitary apoplexy is a rare clinical entity and few cases treated with an endonasal endoscopic approach (EEA) have been reported. We report our experience of treating pituitary apoplexy using an EEA approach. METHODS: We performed a retrospective chart review on all the patients who underwent EEA skull base and pituitary surgery between December 2003 and March 2012 performed by the senior authors (THS and VKA) and identified patients with pituitary apoplexy. The extent of resection was determined volumetrically and the visual and endocrine outcome was evaluated. RESULTS: From a total of 488 skull base surgeries, there were 241 pituitary cases, of which 20 had apoplexy. The most common presenting symptoms included headaches (80%), endocrinopathy (95%), and visual symptoms (60%). Surgery was performed within 24 hours in 15% of patients, and > one month after ictus in 40% due to late referral. Gross-total resection (GTR) was achieved in 18 (90%) patients. There was one (5%) postoperative cerebrospinal fluid (CSF) leak treated with lumbar drainage. Of 12 patients with preoperative visual disturbances, seven had improvements. For those patients with visual field cuts, only 33.3% showed improvement. There was no postoperative visual deterioration. Two patients developed new transient postoperative diabetes insipidus (DI) but there was no new permanent DI. The mean duration of follow-up was 22 months (range: 6 days - 72 months). CONCLUSION: The endoscopic endonasal transsphenoidal approach is an effective modality to treat pituitary apoplexy with a high rate of GTR and minimal risk. Delayed surgery may result in lower rates of visual field defect improvement. PMID- 26623213 TI - Musculoskeletal Manifestations of Sickle Cell Disease: A Review. AB - Sickle cell disease (SCD) is an inherited disorder of abnormal haemoglobin commonly encountered in the West African sub-region. It has varied osteoarticular and non-osseous complications that mimic some surgical conditions. The most common orthopaedic complications include avascular necrosis, osteomyelitis, septic arthritis, etc. A cautious and painstaking evaluation is required in handling these patients. Acute care and anaesthetic precautions are vital in ensuring an uneventful postoperative period. PMID- 26623214 TI - Cephalosporin-Induced Toxic Epidermal Necrolysis Treated with Intravenous Immunoglobulin. AB - Toxic epidermal necrolysis (TEN) is a life-threatening cutaneous reaction to various medications, including antipsychotics and antibiotics. While cephalosporin-induced TEN is very rare, we present a case of cefepime-induced TEN. There are several commonly used therapies for TEN, including immunosuppressive agents and intravenous immunoglobulin (IVIG), but their true efficacy has not been proven. In this case, the patient was treated with IVIG. The role of IVIG as therapy for TEN is currently being investigated. Prior observational studies suggest IVIG infers clinic benefit; however, recent meta analyses have not shown any benefit. Our patient initially showed clinical improvement with IVIG therapy but, unfortunately, later succumbed to sepsis. We will provide a brief review of the current research of the pathological mechanism of Stevens-Johnson syndrome (SJS)/TEN and the mechanism of action of IVIG specifically in TEN/SJS. PMID- 26623215 TI - Thermal Burns and Smoke Inhalation: A Simulation Session. AB - In recent years, simulation-based training has seen increased application in medical education. Emergency medicine simulation uses a variety of educational tools to facilitate trainee acquisition of knowledge and skills in order to help achieve curriculum objectives. In this report, we describe the use of a highly realistic human patient simulator to instruct emergency medicine senior residency trainees on the management of a burn patient. PMID- 26623216 TI - Burnout and Sleep Quality: A Cross-Sectional Questionnaire-Based Study of Medical and Non-Medical Students in India. AB - Introduction It is well documented that on entering college, students experience a multitude of changes in sleep habits. Very few studies have been conducted that explore sleep quality in Indian undergraduate students; fewer still study the effects of burnout in the same population. Medical students, in particular, are believed to be more stressed, sleep deprived, and burnt out than their non medical peers. Methods A cross-sectional study was conducted to study sleep disturbances and burnout in a sample of 214 Indian undergraduate students (112 medical, 102 non-medical). The instruments used to measure the sleep quality and burnout were the PSQI (Pittsburgh Sleep Quality Index) and OLBI (Oldenburg Burnout Inventory), respectively. Differences between continuous variables were analysed using Wilcox Mann Whitney U-tests. Bivariate Spearman's rho correlations were done to identify correlations between the individual burnout components and the PSQI sleep quality components. Results Of the students surveyed, 62.6% were found to be poor sleepers with an average score of 6.45 +/- 2.85. It was seen that 20% of the students (n = 43) slept less than five hours a day. Medical students, in particular, were found to have more poor sleep (72.9%) than their non-medical peers (51.9%; p < 0.001). Of the sampled women, 65.8% were poor sleepers, as compared to 62.1% of the sampled men, but the difference was not statistically significant. The average scores of the burnout dimensions were 2.43 +/- 0.57 for exhaustion and 2.32 +/- 0.53 for disengagement. Both exhaustion and disengagement correlated with PSQI sleep scores (Rho 0.21, p 0.001) and (Rho = 0.18, p = 0.008), respectively. The exhaustion dimension of burnout was higher in medical students (2.46 +/- 0.55) than in non-medical students (2.38 +/- 0.59), but was seen to correlate more with the PSQI sleep score in the non-medical group (Rho = 0.62, p < 0.001). The PSQI scores showed a weak but significant correlation with academic year (rho = -0.19, p = 0.004). Unlike the sleep scores, the burnout dimensions did not correlate well with the academic year. Conclusions Burnout and sleep quality are both uncommonly studied topics in India. Fostering a healthier and more proactive approach to tackling burnout and poor sleep quality may help unearth culture specific causes for some of the results we have demonstrated. PMID- 26623217 TI - Minimally Invasive Approach For Extraforaminal Synovial Cyst L5-S1. AB - Symptoms from synovial cysts are produced by neural compression in the spinal canal or the foramen. Few cases of extraforaminal synovial cyst have been published in the literature. This is a case report of a 65-year-old female who presented with a three-month history of sciatic pain and no relief with conservative treatment. MRI showed a left-sided extraforaminal synovial cyst at L5-S1 with compression of the L5 nerve root at the lateral portion of the foramen. Minimally invasive surgery for resection was performed using an extraforaminal tubular microscopic endoscopy-assisted approach. The patient improved clinically and remained symptom-free for the entire follow-up of 30 months. PMID- 26623218 TI - Unexpected Symptomatic Pneumonitis Following Breast Tangent Radiation: A Case Report. AB - Symptomatic radiation pneumonitis (RP) following radiation therapy (RT) to the breast alone is very uncommon. We report a case of an 80-year-old female who presented with fatigue, exertional dyspnea, fever, and cough 11.5 weeks following adjuvant breast RT with tangent fields alone. Imaging was consistent with RP, and she responded to a tapering course of steroids. PMID- 26623220 TI - Complete PSA Response Following Stereotactic Ablative Radiotherapy for a Bony Metastasis in the Setting of Castrate-Resistant Prostate Cancer. AB - A majority of patients with castrate-resistant prostate cancer ultimately develop distant metastases, with bone being the most common site of spread. Classically, systemic therapy has been considered the standard of care for patients with metastatic cancer. Emerging evidence, however, suggests that an intermediate oligometastatic state, between limited disease and widespread metastases, exists; theoretically, with locally ablative treatment, patients may be curable. We describe a complete PSA response following aggressive management, using stereotactic body radiotherapy (SBRT), of an oligometastatic spine lesion in the setting of castrate-resistant prostate cancer (CRPC). This case report supports the use of SBRT in oligometastatic CRPC and suggests that management of limited metastases may provide good long-term outcomes in well-selected patients. PMID- 26623219 TI - Concurrent or Sequential Hormonal and Radiation Therapy in Breast Cancer: A Literature Review. AB - BACKGROUND AND OBJECTIVES: Adjuvant hormonal therapy is frequently used in the treatment of women with estrogen receptor (ER)/progesterone receptor (PR) positive breast cancer. When radiotherapy is given, hormone therapy may be delivered in a concurrent or sequential manner. Hormonal blockade with tamoxifen or aromatase inhibitors is thought to arrest hormonally dependent cancer cells in the early G1 phase of the cell cycle. This has been theorized to reduce the efficacy of radiation, which is known to be more effective in cells that are actively dividing. Therefore, there has been a reluctance by many to treat with concurrent hormonal and radiation therapy. METHODS: We performed a search of the Medline database that led to the identification of 39 studies. Abstract and full text review of these studies led to the identification of seven English non review studies in peer-reviewed literature between 1995 and 2015 that addressed the question of timing of radiation and hormonal therapy. Outcome measures were captured from each of the studies. RESULTS: No difference in survival or local regional recurrence was identified between concurrent versus sequential treatment. Furthermore, no difference in cosmetic outcome or adverse effects was noted for either approach. However, when comparing radiation alone or radiation and hormonal therapy, there was an increased risk of breast and lung fibrosis with combined treatment. CONCLUSIONS: Hormone therapy, concurrent or sequential, with radiation results in comparable disease-related outcomes, including survival and recurrence. However, given the theoretical reduction in efficacy and increased rates of fibrosis with concurrent use, it is reasonable to support the use of sequential therapy. PMID- 26623221 TI - Synchronous Oligometastatic Non-Small Cell Lung Cancer and Isolated Renal Cell Carcinoma: A Case Report and Literature Review. AB - A 58-year-old gentleman presenting with a progressive headache, visual disturbance, decreased appetite, and weight loss was found to have a localized clear cell carcinoma of the kidney and synchronous Stage IV non-small cell lung cancer with a solitary brain metastasis. This case illustrates the challenges in distinguishing between primary and metastatic disease in a patient with both renal cell carcinoma and lung cancer. We highlight the uncertainties in the diagnosis and management of this unique clinical scenario and the potential implications on prognosis. PMID- 26623222 TI - Selective Patch Angioplasty and Intraoperative Shunting in Carotid Endarterectomy: A Single-Center Review of 141 Procedures. AB - OBJECTIVE: Open surgical treatment of carotid artery stenosis, namely, carotid endarterectomy (CEA), has evolved since its inception in 1953. Despite improvements in the treatment of carotid occlusive disease through technological and surgical innovations, the use of patch grafting in CEA's remains controversial. We evaluate the durability of the primary closure and the safety of selective shunting during carotid endarterectomy (CEA) as determined by intraoperative EEG and postoperative outcomes. METHODS: A consecutive series of CEA's performed by the senior author at a single academic medical center from 2001 to 2012 were reviewed. All cases were performed under continuous intraoperative electroencephalography (EEG). Patch angioplasty was used in cases where there was tortuosity of the vessel within the region of the endarterectomy and narrow vessel diameter at the distal end of the arteriotomy. Shunting was used when intraoperative EEG showed a > 50% reduction in a waveform in any lead. Patients were evaluated for restenosis via imaging or ultrasound at six months and subsequently annual follow-up. RESULTS: One hundred and forty-one CEA's were performed on 132 (76 male, 56 female) patients with an average age of 71 years (range: 40-95 years). Four (3%) cases required patch angioplasty and three (2%) required intraoperative shunts. The cross-clamp time ranged from 22 to 74 minutes, and the duration increased with the use of shunts and patches. Complications were rare and included recurrent stenosis (n=2), postoperative transient ischemic attack (n=1), ischemic stroke in (n=1), temporary hypoglossal nerve weakness (n=2), temporary marginal mandibular nerve weakness (n=6), and neck hematoma (n=1). CONCLUSION: Intraoperative EEG data suggests that primary closure and selective shunting in CEA can result in outcomes comparable with routine patch angioplasty and shunting. PMID- 26623223 TI - Knowledge and Perceptions of College Students Regarding the Physician Assistant Profession. AB - PURPOSE: Physician assistants (PAs) are nationally certified and state-licensed medical professionals who practice medicine on healthcare teams with physicians and other providers. Despite the increasing popularity and utility of the profession, knowledge of the role of PAs remains scarce among many segments of the population. The purpose of this study was to determine the knowledge and perceptions of the PA profession among undergraduate college students, as well as what factors are associated with better knowledge and perception of the profession. METHODS: Using a cross-sectional survey, information was gathered regarding knowledge and perception of PAs. A total of 364 students were surveyed from randomly selected undergraduate courses at a Connecticut public university. RESULTS: Knowledge scores were significantly higher (p<0.05) in older students, female students, those with plans to pursue a healthcare career, those majoring in health and human services, and those satisfied with care received from a PA. Significantly better perceptions (p<0.05) of PAs were found in older students, those with plans for a future career in healthcare, those majoring in health and human services, those who received prior care from a PA, and those who were satisfied with prior care from a PA. After a short educational intervention, improvements in perceptions were statistically significant (p<0.001) in the surveyed population. CONCLUSION: This study identifies areas of needed improvement in knowledge and perception of PAs and also provides impetus for educational and marketing-based interventions to improve knowledge and perception of the PA profession in the college student population. PMID- 26623224 TI - Retrosigmoid Versus Translabyrinthine Approach for Acoustic Neuroma Resection: An Assessment of Complications and Payments in a Longitudinal Administrative Database. AB - Object Retrosigmoid (RS) and translabyrinthine (TL) surgery remain essential treatment approaches for symptomatic or enlarging acoustic neuromas (ANs). We compared nationwide complication rates and payments, independent of tumor characteristics, for these two strategies. Methods We identified 346 and 130 patients who underwent RS and TL approaches, respectively, for AN resection in the 2010-2012 MarketScan database, which characterizes primarily privately insured patients from multiple institutions nationwide. Results Although we found no difference in 30-day general neurological or neurosurgical complication rates, in TL procedures there was a decreased risk for postoperative cranial nerve (CN) VII injury (20.2% vs 10.0%, CI 0.23-0.82), dysphagia (10.4% vs 3.1%, CI 0.10 0.78), and dysrhythmia (8.4% vs 2.3%, CI 0.08-0.86). Overall, there was no difference in surgical repair rates of CSF leak; however, intraoperative fat grafting was significantly higher in TL approaches (19.8% vs 60.2%, CI 3.95 9.43). In patients receiving grafts, there was a trend towards a higher repair rate after RS approach, while in those without grafts, there was a trend towards a higher repair rate after TL approach. Median total payments were $16,856 higher after RS approaches ($67,774 vs $50,918, p < 0.0001), without differences in physician or 90-day postoperative payments. Conclusions Using a nationwide longitudinal database, we observed that the TL, compared to RS, approach for AN resection experienced lower risks of CN VII injury, dysphagia, and dysrhythmia. There was no significant difference in CSF leak repair rates. The payments for RS procedures exceed payments for TL procedures by approximately $17,000. Data from additional years and non-private sources will further clarify these trends. PMID- 26623225 TI - Anterior Transsternal Approach for Treatment of Upper Thoracic Vertebral Osteomyelitis: Case Report and Review of the Literature. AB - Direct ventral access to the cervicothoracic spine (C7-T4) poses a technical challenge in spine surgery, given the vital neurovascular structures residing anterior to the cervicothoracic junction (CTJ). The transsternal approach is a feasible surgical option that allows for direct anterior exposure of the lower cervical and upper thoracic vertebrae. Here, the authors report a case of an elderly gentleman with upper thoracic (T1-2) vertebral osteomyelitis and epidural abscess who underwent a transsternal full median sternotomy for ventral decompression and fusion of C7-T2. We also detail our operative procedure and review relevant literature on different transsternal approaches to the CTJ. PMID- 26623226 TI - Extradural Dermoid Cyst of the Anterior Infratemporal Fossa. Case Report. AB - Dermoid cysts are rare in the skull base. There have been 10 reported cases of dermoid cysts in the cavernous sinus, two in the petrous apex, and one in the extradural Meckel cave. This is the first case report of a dermoid cyst in the anterior infratemporal fossa attached to the anterior dura of the foramen ovale. The clinical presentation, radiologic findings, histologic features, tumor origin, and operative technique are described along with a review of the literature. PMID- 26623227 TI - Three-Dimensional Hand-to-Gland Combat: The Future of Endoscopic Surgery? AB - Objective To compare two dimensional (2D), three-dimensional (3D) non-high definition (HD), and 3D HD endoscopic surgical techniques. Methods We describe our initial operative experience with a novel 3D HD endoscopic endonasal approach involving a pituitary adenoma resection, provide a case series, and review the current literature. This is the first case in Europe using the new 3D HD endoscope. Results Although research evidence remains limited, there are no significant negative perioperative or postoperative outcomes when compared with 2D endoscopic techniques. In our experience the narrow operating corridors of endoscopic surgery cannot be addressed with 3D endoscopic techniques. The new 3D HD endoscope creates imaging quality similar to conventional 2D HD systems. Conclusion Three-dimensional endoscopic endonasal techniques provide an exciting new avenue, effectively addressing potential depth perception difficulties with current 2D systems. PMID- 26623228 TI - Pituitary Apoplexy After Intravitreal Injection of Vascular Endothelial Growth Factor Inhibitor: A Novel Complication. AB - Pituitary adenomas are common in the general population. They can be complicated by intratumoral hemorrhage, otherwise known as apoplexy, which frequently presents with neurologic deficits that may necessitate urgent surgical decompression. Many risk factors for pituitary apoplexy have been suggested in the literature. We present a case of symptomatic apoplexy in a woman following the intravitreal administration of the vascular endothelial growth factor (VEGF) inhibitor ranibizumab. Ophthalmoplegia resolved and visual acuity significantly improved following gross total resection of the tumor via an endoscopic endonasal surgical approach. The association between intravitreal injection of a VEGF inhibitor and pituitary apoplexy has not been previously described, but physicians performing these procedures should be aware of this potential complication. PMID- 26623229 TI - Partial Hearing Preservation after Translabyrinthine Vestibular Schwannoma Resection: Case Report and Review of the Literature. AB - Objectives To describe a unique case report of a patient who had partial hearing preservation after translabyrinthine (TL) removal of a vestibular schwannoma (VS). Study Design Case report. Methods The patient's chart was reviewed for hearing levels before and after surgery. Preoperative magnetic resonance imaging (MRI) was compared with postoperative MRI for determination of completeness of tumor removal. The literature on hearing preservation after TL resection is reviewed. Results A 42-year-old woman underwent a TL removal of a VS. The patient's preoperative pure tone average (PTA) was 70 dB and word recognition score (WRS) was 40%. Postoperatively, the patient was able to hear ambient noise in the surgical ear. Her bone conduction PTA was 70 dB, but the WRS score dropped to 2%. One year later, she continues to hear ambient noise and sound in the operative ear. Discussion This is the fifth reported case of partial hearing preservation after TL VS resection. It suggests that by preserving the vestibule and the fluids within the vestibule when possible, there maybe enough residual auditory neural structures for a traditional cochlear implant to benefit such a patient. In addition, preserving the incus when possible may help maintain air conduction to help patients with sound localization. PMID- 26623231 TI - Management of Ruptured and Rapidly Progressive Mycotic Cerebral Aneurysms in the Setting of Unilateral Carotid Occlusion and Endocarditis with Valve Failure. AB - Mycotic cerebral aneurysms can present unique neurosurgical challenges. We report a patient with left carotid occlusions, a ruptured left middle cerebral artery mycotic aneurysm, and a rapidly appearing unruptured left anterior cerebral artery/anterior communicating artery (ACA/ACom) mycotic aneurysm in the setting of mitral valve endocarditis with a perivalvular leak and evolving congestive heart failure. Following medical stabilization and antibiotic administration, a combined endovascular (with contralateral access via the ACom) and open surgical approach was used to selectively secure both aneurysms with preservation of distal flow, allowing lifesaving cardiac valve replacement. This case illustrates the therapeutic complexity of mycotic cerebral aneurysms, which we discuss in the context of an increasing reliance on endovascular approaches. PMID- 26623230 TI - Giant Aneurysmal Bone Cyst of the Anterior Cranial Fossa and Paranasal Sinuses Presenting in Pregnancy: Case Report and Literature Review. AB - Background and Purpose Aneurysmal bone cysts (ABCs) rarely involve the cranium and have seldom been reported in pregnancy. Clinical Presentation We describe a case of a 28-year-old woman who presented at 37 weeks of gestation with 3 months of gradually worsening vision, 10 months of proptosis, and restricted ocular motility on the left. Brain imaging revealed a multicystic enhancing mass measuring 5.9 * 5.3 * 3.7 cm, centered on the cribriform plate on the left, extending into the anterior cranial fossa superiorly as well as the left nasal cavity, maxillary, sphenoid, and frontal sinuses. Her clinical course is described in detail; 3-month postoperative imaging demonstrated no residual mass. Conclusion A literature review revealed five previous cases of ABCs associated with pregnancy. We report a rare case of a giant ABC of fibrous dysplasia involving the paranasal sinuses and anterior cranial fossa. We postulate on the possible influence of pregnancy on the clinical course. PMID- 26623232 TI - Third Ventricular Glioblastoma Multiforme: Case Report and Literature Review. AB - Background Glioblastoma multiforme (GBM) typically presents in the supratentorial white matter, commonly within the centrum semiovale as a ring-enhancing lesion with areas of necrosis. An atypical presentation of this lesion, both anatomically as well as radiographically, is significant and must be part of the differential for a neoplasm in this anatomical location. Case Description We present a case of a 62-year-old woman with headaches, increasing somnolence, and cognitive decline for several weeks. Magnetic resonance imaging demonstrated mild left ventricular dilatation with a well-marginated, homogeneous, and nonhemorrhagic lesion located at the ceiling of the third ventricle within the junction of the septum pellucidum and fornix, without exhibiting the typical radiographic features of hemorrhage or necrosis. Final pathology reports confirmed the diagnosis of GBM. Conclusion This case report describes an unusual location for the most common primary brain neoplasm. Moreover, this case identifies the origin of a GBM related to the paracentral ventricular structures infiltrating the body of the fornix and leaves of the septum pellucidum. To our knowledge this report is the first reported case of a GBM found in this anatomical location with an entirely atypical radiographic presentation. PMID- 26623233 TI - Sinonasal Phosphaturic Mesenchymal Tumor: A Rare and Misinterpreted Entity. AB - Objectives Oncogenic osteomalacia is a paraneoplastic syndrome in which the tumor secretes a peptide-like hormone, fibroblast growth factor, resulting in urinary loss of phosphates. Methods We present the case of a 50-year-old woman with a benign phosphaturic mesenchymal tumor (PMT) involving the ethmoid sinus with obstruction of the ostiomeatal complex causing unilateral nasal airway obstruction. Results The tumor was initially thought to be an esthesioneuroblastoma based on primary pathology interpretation and on clinical and radiographic appearance. However, a benign PMT was later confirmed by further testing. Conclusion The tumor was removed entirely by the endoscopic transnasal approach, leading to a full resolution of symptoms. PMID- 26623234 TI - Severe Edema and Venous Congestion Following Sphenoorbital Meningioma Resection in a Meningiomatosis Case: Importance of Predicting Venous Disturbances. AB - To achieve local disease control, radical removal is the best option for sphenoorbital meningiomas. Preservation of the venous system is crucial during the resection of skull base meningiomas. This vascular injury represents a major risk both for life and neurologic function. We present a case of a severe postoperative frontotemporal venous disturbance and cerebral edema following the radical removal of a giant sphenoorbital meningioma in a patient with meningiomatosis and occlusion of the superior sagittal sinus. The anatomical, radiologic, and surgical aspects are reviewed and discussed, with the aim of preventing such a serious complication. PMID- 26623235 TI - Borderline Intracranial Hypertension Manifesting as Chronic Fatigue Syndrome Treated by Venous Sinus Stenting. AB - Chronic fatigue syndrome and cases of idiopathic intracranial hypertension without signs of raised intracranial pressure can be impossible to distinguish without direct measurement of intracranial pressure. Moreover, lumbar puncture, the usual method of measuring intracranial pressure, can produce a similar respite from symptoms in patients with chronic fatigue as it does in idiopathic intracranial hypertension. This suggests a connection between them, with chronic fatigue syndrome representing a forme fruste variant of idiopathic intracranial hypertension. If this were the case, then treatments available for idiopathic intracranial hypertension might be appropriate for chronic fatigue. We describe a 49-year-old woman with a long and debilitating history of chronic fatigue syndrome who was targeted for investigation of intracranial pressure because of headache, then diagnosed with borderline idiopathic intracranial hypertension after lumbar puncture and cerebrospinal fluid drainage. Further investigation showed narrowings at the anterior ends of the transverse sinuses, typical of those seen in idiopathic intracranial hypertension and associated with pressure gradients. Stenting of both transverse sinuses brought about a life-changing remission of symptoms with no regression in 2 years of follow-up. This result invites study of an alternative approach to the investigation and management of chronic fatigue. PMID- 26623236 TI - Trochlear Nerve Schwannoma Treated with Gamma Knife after Excision: A Case Report and Review of the Literature. AB - Trochlear nerve schwannomas are extremely rare. We present a surgically excised case of trochlear nerve schwannoma followed by Gamma Knife (ELEKTA, Stockholm, Sweden) after histologic confirmation. A 52-year-old man presented with diplopia, gait disturbance, and sensory disturbance. Magnetic resonance imaging demonstrated a large cystic mass at ambient cistern on the right side. Subtotal excision followed by Gamma Knife surgery was undertaken. His neurologic symptoms disappeared with radiologic reduction in size at 15-month follow-up. Because Gamma Knife can manage trochlear nerve schwannomas well, surgical excision should be reserved for large ones and limited to subcapsular or subtotal removal with the expectation of possible recovery of neurologic dysfunction. PMID- 26623237 TI - Nasopharyngeal Masses Arising from Embryologic Remnants of the Clivus: A Case Series. AB - Objectives This study aims to (1) discuss rare nasopharyngeal masses originating from embryologic remnants of the clivus, and (2) discuss the embryology of the clivus and understand its importance in the diagnosis and treatment of these masses. Design and Participants This is a case series of three patients. We discuss the clinical and imaging characteristics of infrasellar craniopharyngioma, intranasal extraosseous chordoma, and canalis basilaris medianus. Results Case 1: A 16-year-old male patient with a history of craniopharyngioma resection, who presented with nasal obstruction. A nasopharyngeal cystic mass was noted to be communicating with a patent craniopharyngeal canal. Histology revealed adamantinomatous craniopharyngioma. Case 2: A 43-year-old male patient who presented with nasal obstruction and headache. Computed tomography (CT) and magnetic resonance imaging revealed an enhancing polypoid mass in the posterior nasal cavity abutting the clivus. Histopathology revealed chondroid chordoma. Case 3: A 4-year-old female patient with a recurrent nasopharyngeal polyp. CT cisternogram showed that this mass may have risen from a bony defect of the middle clivus suggestive of canalis basilaris medianus. Conclusions Understanding the embryology of the clivus is crucial when considering the differential diagnosis of a nasopharyngeal mass. Identification of characteristic findings on imaging is critical in the diagnosis and treatment of these lesions. PMID- 26623238 TI - Chondroblastoma of the Clivus: Case Report and Review. AB - Background and Importance Chondroblastoma is a benign primary bone tumor that typically develops in the epiphyses of long bones. Chondroblastoma of the craniofacial skeleton is extremely rare, with most cases occurring in the squamosal portion of the temporal bone. In this report, we describe the first case of chondroblastoma of the clivus presenting with cranial neuropathy that was treated with endoscopic endonasal resection. We review the literature on craniofacial chondroblastomas with particular emphasis on extratemporal lesions. Case Presentation A 27-year-old woman presented with severe headache, left facial dysesthesias, and diplopia. Physical examination revealed hypesthesia in the left maxillary nerve dermatome, and complete left abducens nerve palsy. Imaging demonstrated an expansile intraosseous mass originating in the upper clivus with extension superiorly into the sella turcica and laterally to involve the medial wall of the left cavernous sinus. The tumor was completely resected via an endoscopic endonasal approach, with postoperative improvement in lateral gaze palsy. Histopathology was consistent with chondroblastoma. Conclusion Chondroblastoma is a rare tumor of the craniofacial skeleton that should be included in the differential diagnosis of an osteolytic lesion of the clivus. Complete surgical resection remains the mainstay of treatment. PMID- 26623239 TI - Probable Immunoglobulin Subtype-G4-Related Disease in the Head and Neck from Foreign Body Injection: A Case Report. AB - Introduction Immunoglobulin subtype G4-related disease (IgG4-RD) is a fibroinflammatory disease of unknown etiology, with manifestations involving nearly every organ system. Its association with foreign bodies is not established. Here, we present a novel case of IgG4-RD in response to foreign body injection. Case Description A 58-year-old woman presented with history of persistent left facial pain, xerophthalmia, blurred vision, and trismus. The patient's medical history was significant for left-sided temporomandibular joint (TMJ) reconstruction with silicone injection into the joint. Magnetic resonance imaging revealed a lesion in the left skull base. Biopsies demonstrated the cardinal histopathological features of IgG4-RD. The patient was treated with a tapering dose of prednisolone followed by rituximab, resulting in tumor shrinkage and resolution of her symptoms. Discussion This is the first reported case of IgG4-RD potentially precipitated by a foreign body, in this case injected silicone into the TMJ. The pathogenesis and etiology of IgG4-RD is still not fully elucidated, but allergic and reactive inflammatory reactions have been implicated in the disease process. This case report should raise the idea of reactive foreign bodies as a causative agent for IgG4-RD. PMID- 26623240 TI - Primary Osteosarcoma of the Skull Base Treated with Endoscopic Endonasal Approach: A Case Report and Literature Review. AB - Introduction Giant cell-rich osteosarcoma (GCRO) is a rare pathologic diagnosis, and most cases have involved the appendicular skeleton. We present a challenging diagnosis of GCRO of the skull base treated with an endoscopic endonasal approach. Case Presentation An 18-year-old female patient presented with acute monocular visual loss. Imaging revealed a large clival mass encasing the internal carotid arteries bilaterally with pituitary and optic nerve compression. The lesion was resected via a staged endoscopic endonasal approach and the patient's vision normalized postoperatively. The final pathological diagnosis was challenging and, after consultation with multiple North American centers, was concluded as GCRO. The tumor recurred and further surgery was performed, followed by adjuvant chemoradiation. Conclusion We highlight diagnostic challenges of GCRO of the skull base, and describe, with intraoperative pictures, successful surgical resection via an endoscopic endonasal approach. Based on our literature review, this is the first published case report of GCRO of the skull base. PMID- 26623241 TI - Tailored PICA Revascularization for Unusual Ruptured Fusiform Vertebro-PICA Origin Aneurysms: Rationale and Case Illustrations. AB - Ruptured fusiform aneurysms of the vertebral artery involving posterior inferior cerebellar artery (PICA) origin are difficult to manage without sacrificing PICA. In this report, two very unusual cases are described which highlight different revascularization strategies that may be required. The first case initially appeared to be a small saccular PICA origin aneurysm, but detailed angiography showed a serpentine recanalization of a fusiform aneurysm. This was treated with PICA-PICA anastomosis and trapping of the aneurysm. The second case is a dissecting vertebral aneurysm with both PICA and the anterior spinal artery originating from the dome. PICA was found to be a bihemispheric variant, so no in situ bypass was available, and an occipital artery to PICA bypass was performed. The vertebral artery was occluded proximally only and follow-up angiography showed remodeling of the distal vertebral artery with the anterior spinal artery filling by retrograde flow from the distal vertebral artery. These cases illustrate both the anatomic variability of this region as well as the need to be familiar with multiple treatment strategies including revascularization techniques to be able to successfully treat these aneurysms. PMID- 26623242 TI - Treatment of Hyponatremia with Tolvaptan in a Patient after Neurosurgical Treatment of a Pituitary Tumor: Case Report and Review of Literature. AB - Hyponatremia is a frequent complication following pituitary surgery. We report a case with hyponatremia after surgery of a pituitary adenoma that was successfully treated with tolvaptan. A 68-year-old man with a pituitary tumor presented with mild hyponatremia (133 mEq/L) before surgery. The patient developed hyponatremia (125 mEq) 4 days postsurgery, and 10% sodium chloride was infused. Seven 7 days postsurgery, hyponatremia was improved (132 mEq/L), and tolvaptan 15 mg was given orally as a single dose instead of the 10% sodium chloride infusion. His serum sodium remained within normal limits. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) after pituitary surgery most probably led to the hyponatremia, and tolvaptan was effective because it is an oral vasopressin receptor antagonist. PMID- 26623243 TI - Metastatic Renal Cell Carcinoma Mimicking Trigeminal Schwannoma in a Patient Presenting with Trigeminal Neuralgia. AB - We present an unusual case of a metastatic renal cell carcinoma (RCC) mimicking trigeminal schwannoma. The patient, with no prior history of RCC, presented with clinical symptoms and imaging consistent with trigeminal neuralgia secondary to trigeminal schwannoma. Magnetic resonance imaging of the brain showed a large bilobed cystic/solid mass primarily in the cerebellopontine angle cistern, with extension into the left middle cranial fossa, Meckel cave, and left cavernous sinus. Following surgical excision, histopathology revealed the tumor to be an RCC infiltrating into the trigeminal nerve fascicles. Further imaging and investigation revealed widespread metastasis to the vertebral bodies and long bones. Metastatic RCC to the trigeminal nerve is rare. Despite the development of more effective treatment modalities, the prognosis of metastatic RCC remains poor. To our knowledge, this is the first reported case of RCC metastasizing to the trigeminal nerve fascicles. PMID- 26623244 TI - Clopidogrel-Associated Thrombotic Thrombocytopenic Purpura following Endovascular Treatment of Spontaneous Carotid Artery Dissection. AB - Thrombotic thrombocytopenic purpura (TTP) is a life-threatening multisystem disease secondary to platelet aggregation. We present a patient who developed profound thrombocytopenia and anemia 8 days following initiation of therapy with clopidogrel after stent placement for carotid artery dissection. She did not have a disintegrin and metalloproteinase with thrombospondin domain 13 (ADAMTS 13) deficiency. Management included steroids and therapeutic plasma exchange. Clopidogrel has rarely been associated with TTP. Unlike other causes of acquired TTP, the diagnosis of early clopidogrel-associated TTP is largely clinical given the infrequent reduction in ADAMTS 13 activity. PMID- 26623245 TI - Multiportal Combined Transorbital and Transnasal Endoscopic Resection of Fibrous Dysplasia. AB - Introduction Historically, access to the anterior skull base was achieved with open procedures. The paradigms to this approach were challenged with the advent of minimally disruptive endoscopic surgical techniques and supporting technology. The next step in the evolution of minimally disruptive surgery was the combination of multiportal endoscopic surgery. Results The patient was an 18-year old man who presented with right-sided proptosis. Further diagnostic tests revealed a fibrous dysplasia (FD) occupying the skull base and orbit. The lesion was successfully resected. Conclusions The location of the tumor in this case was challenging, in which surgeons at some centers would have opted to have performed as an open procedure instead of endoscopically. The combined transnasal/transorbital approach is an uncommonly used technique that we have used to remove this tumor successfully. The patient also had a unique disease (FD) in a unique location that was treated without complications. This case report highlights how surgeons may use an expanded armamentarium in dealing with complex pathologies. PMID- 26623246 TI - Giant Prolactinoma Presenting with Neck Pain and Structural Compromise of the Occipital Condyles. AB - Prolactinomas are the most common form of endocrinologically active pituitary adenoma; they account for ~ 45% of pituitary adenomas encountered in clinical practice. Giant adenomas are those > 4 cm in diameter. Less than 0.5% of pituitary adenomas encountered in neurosurgical practice are giant prolactinomas. Patients with giant prolactinomas typically present with highly elevated prolactin levels, endocrinologic disturbances, and neurologic symptoms from mass induced pressure. Described here is an unusual case of a giant prolactinoma presenting with neck pain and structural compromise of the occipital condyles. Transnasal biopsy of the nasopharyngeal portion of the mass obtained tissue consistent with an atypical prolactinoma with p53 reactivity and a high Ki-67 index of 5%. Despite the size and invasiveness of the tumor, the patient had resolution of his clinical symptoms, dramatic reduction of his hyperprolactinemia, and near-complete disappearance of his tumor following medical treatment. PMID- 26623247 TI - Penetrating Trauma to the Ureter, Bladder, and Urethra. AB - We describe the epidemiology, diagnosis, and management of adult civilian penetrating trauma to the ureter, bladder, and urethra. Trauma is a significant source of death and morbidity. Genitourinary injuries are present in 10% of penetrating trauma cases. Prompt recognition and appropriate management of genitourinary injuries, which are often masked or overlooked due to concomitant injuries, is essential to minimize morbidity. Penetrating trauma most commonly results from gunshot wounds or stab wounds. Compared to blunt trauma, these typically require surgical exploration. An understanding of anatomy and a high index of suspicion are necessary for prompt recognition of genitourinary injuries. PMID- 26623248 TI - Cancer Chemoprevention with Korean Angelica: Active Compounds, Pharmacokinetics, and Human Translational Considerations. AB - Angelica gigas Nakai (AGN) is a major medicinal herb used in Korea and several other Asian countries. Traditionally, its dried root has been used to treat anemia, pain, infection and articular rheumatism, most often through boiling in water to prepare the dosage forms. AGN extract or AGN-containing herbal mixtures are sold in the US and globally as dietary supplements for pain killing, memory enhancement and post-menopausal symptom relief. Decursin (D) and its isomer decursinol angelate (DA) are the major chemicals in the alcoholic extracts of the root of AGN. The anti-cancer activity of AGN alcoholic extract has been established in a number of animal cancer models, including a transgenic model of prostate carcinogenesis. Cell culture structure-activity studies have uncovered distinct cellular and molecular effects of D and DA vs. their pyranocoumarin core decursinol (DOH) with respect to cancer cells and those associated with their microenvironment. Pharmacokinetic (PK) study by us and others in rodent models indicated that DOH is the major and rapid in vivo first-pass liver metabolite of D and DA. Cognizant of metabolic differences among rodents and humans, we carried out a first-in-human PK study of D/DA to inform the translational relevance of efficacy and mechanism studies with rodent models. The combined use of vigorous animal tests and human PK studies can provide stronger scientific rationale to inform design and execution of translational studies to move AGN toward evidence based herbal medicine. PMID- 26623249 TI - Predictive value of antinuclear antibodies in autoimmune diseases classified by clinical criteria: Analytical study in a specialized health institute, one year follow-up. AB - INTRODUCTION: Determination of antinuclear antibodies (ANA) by indirect immunofluorescence (IIF) is usually the initial test for the diagnosis of systemic rheumatic diseases (SRD). Assigning predictive values to positive and negative results of the test is vital because lack of knowledge about ANAs and their usefulness in classification criteria of SRD leads to inappropriate use. METHODS: Retrospective study, ANA tests requested by different specialties, correlation to patients' final diagnosis. RESULTS: The prevalence of autoimmune disease was relatively low in our population yielding a low PPV and a high NPV for the ANA test. 40% of the patients had no clinical criteria applied prior to test. Coexistence of two or more autoimmune disorders affects prevalence and predictive values. CONCLUSION: Application of the test after careful evaluation for clinical criteria remarkably improves the positive likelihood ratio for the diagnosis. PMID- 26623251 TI - Appendicitis Presenting Concurrently with Cecal Arteriovenous Malformation in a Child. AB - Acute appendicitis is a commonly diagnosed surgical problem in the pediatric population. Arterio-venous malformations (AVM) of the colonic tract are rarely reported in the pediatric literature. A 13-year old boy who presented with acute appendicitis with concurrent cecal AVM is reported in whom appendectomy was done. Later on radiological investigations AVM was confirmed. PMID- 26623252 TI - Recurrent Monophasic Wilms' Tumor in Pelvic Kidney - A Therapeutic Challenge. AB - Wilms' tumor in the current era of multimodality treatment has promising outcome, but approximately 10-15% of the patients with favorable-histology, experience tumor progression or relapse. We hereby present an unusual case of repeated loco regional recurrences in a patient with stage I intermediate-risk monophasic (epithelial variant) Wilms' tumor (WT) of pelvic kidney requiring aggressive therapy over a decade and lay emphasis on the importance of initial completion of therapy and need for long term follow-up. PMID- 26623250 TI - Expression and regulation of Schlafen (SLFN) family members in primary human monocytes, monocyte-derived dendritic cells and T cells. AB - Schlafen (SLFN/Slfn) family members have been investigated for their involvement in fundamental cellular processes including growth regulation, differentiation and control of viral replication. However, most research has been focused on the characterization of Slfns within the murine system or in human cell lines. Since little is known about SLFNs in primary human immune cells, we set out to analyze the expression and regulation of the six human SLFN genes in monocytes, monocyte derived dendritic cells (moDCs) and T cells. Comparison of SLFN gene expression across these three cell types showed high mRNA expression of SLFN11 in monocytes and moDCs and high SLFN5 expression in T cells, indicating functional importance within these cell types. Differentiation of monocytes to moDCs leads to the gradual upregulation of SLFN12L and SLFN13 while SLFN12 levels were decreased by differentiation stimuli. Stimulation of moDCs via human rhinovirus, lipopolysaccharide, or IFN-alpha lead to strong upregulation of SLFN gene expression, while peptidoglycan poorly stimulated regulation of both SLFNs and the classical interferon-stimulated gene MxA. T cell activation was found to downregulate the expression of SLFN5, SLFN12 and SLFN12L, which was reversible upon addition of exogenous IFN-alpha. In conclusion, we demonstrate, that SLFN gene upregulation is mainly dependent on autocrine type I interferon signaling in primary human immune cells. Rapid decrease of SLFN expression levels following T cell receptor stimulation indicates a role of SLFNs in the regulation of human T cell quiescence. PMID- 26623253 TI - Pseudoaneurysm of Left Ventricle following Staphylococcal Pericarditis in a Child. AB - Formation of pseudo-aneurysm of the left ventricle is a rare entity particularly in the pediatric age group. We report a case of a pseudo-aneurysm of the left ventricle in a 6-year-old boy who initially presented to us with staphylococcus aureus septicemia. The left ventricular pseudo-aneurysm was surgically resected and the boy was discharged in a healthy condition. PMID- 26623254 TI - Partial Hepatectomy for the Resistant Fasciola Hepatica Infection in a Child. AB - Fascioliasis is an emerging and important chronic parasitic disease caused by two trematode liver fluke species: Fasciola hepatica (F. hepatica) and Fasciola gigantica (F. gigantica) infecting several herbivorous mammals including cattle, goats, sheep, and humans. We report a 9-year-old girl who suffered from F. hepatica infection and underwent right hepatectomy because of increasing abdominal pain resistant to anthelmintic chemotherapy. When anthelmintic drug treatment is not effective and abdominal pain persists, surgical resection including hepatectomy should be kept in mind for resistant F. hepatica infection. PMID- 26623255 TI - Endoscopic Removal of 15 Gastrointestinal Foreign Bodies. AB - Foreign body ingestion occurs commonly in children, elderly, mentally impaired or alcoholic, and psychiatric patients. We present a 15-year-old boy with mental retardation and uncontrolled psychiatric disorder admitted to the hospital with abdominal and chest pain. He was diagnosed with foreign body ingestion and 15 foreign objects, including a sharp knife, were successfully removed endoscopically by using an over-tube. PMID- 26623256 TI - Gastric Perforation Following Dog Bite in a Child. AB - Gastric perforation following dog bite is exceedingly rare event in pediatric population that requires emergency surgery. We report a 26 month old male who presented 36 hours after a dog bite over abdomen with pneumoperitoneum. At laparotomy, two perforations were found on the anterior surface of the stomach. The perforations were repaired primarily. The child made an uneventful postoperative recovery. PMID- 26623257 TI - Endobronchial Carcinoid Tumor in a Girl with Initial Histologic Diagnosis of Leiomyoma. AB - Endobronchial tumors represent the rarest cause of airway obstruction in pediatric population. Due to rarity of the condition, a high index of suspicion is required for early diagnosis. We report a patient in whom diagnostic bronchoscopic biopsy was reported as leiomyoma while post resection histopathology showed an atypical carcinoid. PMID- 26623258 TI - Protruding Enlarged Hymen with Pubic Hairs: A Sign Suggestive of Precocious Puberty! PMID- 26623259 TI - Laparoscopic Reduction of Ileo-Ileal Intussusception in an Infant Operated for Wilms Tumor. PMID- 26623260 TI - Penile Skin Bridges after Circumcision. PMID- 26623261 TI - Morgagni Hernia presenting as Obstructive Jaundice. PMID- 26623262 TI - Effect of Treatment for CHC on Liver Disease Progression and Hepatocellular Carcinoma Development in African Americans. AB - BACKGROUND AND AIMS: African Americans (AA) historically have a low response rate to hepatitis C therapies, and there is limited information available for this patient population regarding the development and treatment of chronic hepatitis C (CHC). The aim of this study was to evaluate liver disease progression and hepatocellular carcinoma (HCC) development in AA with CHC. METHODS: Between 1995 and 2008, 246 AA patients with CHC were identified from a database of patients and followed until 2012-2013 (average 8 years) or the development of HCC after 2008. RESULTS: Viral clearance (intent to treat; sustained virus response (SVR)) was achieved in 15% of patients with interferon based therapies with or without ribavirin. AA patients who achieved an SVR (n=22) did not develop HCC or new onset cirrhosis, whereas the HCC incidence in untreated AA patients was 23% (51/203). Patients who achieved an SVR also had improved fibrosis, as defined by the AST Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4) score, relative to nonresponders and untreated patients. CONCLUSIONS: The severity of liver disease at the first visit (except for cirrhosis) correlated with the development of HCC, but because of the overlap in values between patients, these measurements were not useful for predicting individual risk. Since cirrhosis at the first visit was not a predictive factor, treatment with newer antiviral therapies is the best option for reducing the incidence of advanced liver disease and its harmful outcomes in the AA population. PMID- 26623263 TI - Hepatobiliary Tumors: Update on Diagnosis and Management. AB - Tumors of the liver and biliary tree, mainly hepatocellular carcinoma and cholangiocarcinoma, are the second leading cause of cancer related death worldwide and the sixth leading cause of cancer related death among men in developed countries. Recent developments in biomarkers and imaging modalities have enhanced early detection and accurate diagnosis of these highly fatal malignancies. These advances include serological testing, micro-ribonucleic acids, fluorescence in situ hybridization, contrast-enhanced ultrasound, and hepatobiliary-phase magnetic resonance imaging. In addition, there have been major developments in the surgical and nonsurgical management of these tumors, including expansion of the liver transplantation criteria, new locoregional treatments, and molecularly targeted therapies. In this article, we review various types of hepatobiliary tumors and discuss new developments in their diagnosis and management. PMID- 26623264 TI - Risk Factors for the Development of Hepatocellular Carcinoma in Thailand. AB - Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. The incidence of HCC is on the rise in Thailand, where it has become the most common malignancy in males and the third most common in females. Here, we review some of the risk factors that have contributed to this increase in HCC incidence in the Thai population. Hepatitis B virus (HBV) is the main etiologic risk factor for HCC, followed by hepatitis C virus (HCV). Patients with HBV genotype C have a higher positive rate of hepatitis B early antigen (HBeAg) and progress to cirrhosis and HCC earlier than genotype B. For HCV patients, 16% developed HCC associated cirrhosis by year 5 after diagnosis, and the cumulative risk for death from HCC at year 10 was 60%. Dietary exposure to the fungal hepatocarcinogen aflatoxin B1 has been shown to interact synergistically with HBV infection to increase the risk of early onset HCC. Chronic alcohol abuse remains an important risk factor for malignant transformation of hepatocytes, frequently in association with alcohol-induced cirrhosis. In recent years, obesity and metabolic syndrome have markedly increased the incidence of HCC and are important causes of HCC in some resource-rich regions. PMID- 26623265 TI - Thrombotic Venous Diseases of the Liver. AB - Thrombotic venous diseases of the liver do not occur frequently, but when they do, they can present as difficult diagnostic and therapeutic challenges. The aim of this article is to review the epidemiology, pathogenesis, diagnosis, and therapeutic options of these serious vascular problems. PMID- 26623266 TI - Acute Kidney Injury in Patients with Cirrhosis. AB - Acute kidney injury (AKI) occurs commonly in patients with advanced cirrhosis and negatively impacts pre- and post-transplant outcomes. Physiologic changes that occur in patients with decompensated cirrhosis with ascites, place these patients at high risk of AKI. The most common causes of AKI in cirrhosis include prerenal injury, acute tubular necrosis (ATN), and the hepatorenal syndrome (HRS), accounting for more than 80% of AKI in this population. Distinguishing between these causes is particularly important for prognostication and treatment. Treatment of Type 1 HRS with vasoconstrictors and albumin improves short term survival and renal function in some patients while awaiting liver transplantation. Patients with HRS who fail to respond to medical therapy or those with severe renal failure of other etiology may require renal replacement therapy. Simultaneous liver kidney transplant (SLK) is needed in many of these patients to improve their post-transplant outcomes. However, the criteria to select patients who would benefit from SLK transplantation are based on consensus and lack strong evidence to support them. In this regard, novel serum and/or urinary biomarkers such as neutrophil gelatinase-associated lipocalin, interleukins-6 and 18, kidney injury molecule-1, fatty acid binding protein, and endothelin-1 are emerging with a potential for accurately differentiating common causes of AKI. Prospective studies are needed on the use of these biomarkers to predict accurately renal function recovery after liver transplantation alone in order to optimize personalized use of SLK. PMID- 26623267 TI - Direct-acting Antivirals and Host-targeting Agents against the Hepatitis A Virus. AB - Hepatitis A virus (HAV) infection is a major cause of acute hepatitis and occasionally leads to acute liver failure in both developing and developed countries. Although effective vaccines for HAV are available, the development of new antivirals against HAV may be important for the control of HAV infection in developed countries where no universal vaccination program against HAV exists, such as Japan. There are two forms of antiviral agents against HAV: direct-acting antivirals (DAAs) and host-targeting agents (HTAs). Studies using small interfering ribonucleic acid (siRNA) have suggested that the HAV internal ribosomal entry site (IRES) is an attractive target for the control of HAV replication and infection. Among the HTAs, amantadine and interferon-lambda 1 (IL 29) inhibit HAV IRES-mediated translation and HAV replication. Janus kinase (JAK) inhibitors inhibit La protein expression, HAV IRES activity, and HAV replication. Based on this review, both DAAs and HTAs may be needed to control effectively HAV infection, and their use should continue to be explored. PMID- 26623268 TI - Asymptomatic Hepadnaviral Persistence and Its Consequences in the Woodchuck Model of Occult Hepatitis B Virus Infection. AB - Woodchuck hepatitis virus (WHV) is molecularly and pathogenically closely related to hepatitis B virus (HBV). Both viruses display tropism towards hepatocytes and cells of the immune system and cause similar liver pathology, where acute hepatitis can progress to chronic hepatitis and to hepatocellular carcinoma (HCC). Two forms of occult hepadnaviral persistence were identified in the woodchuck-WHV model: secondary occult infection (SOI) and primary occult infection (POI). SOI occurs after resolution of a serologically apparent infection with hepatitis or after subclinical serologically evident virus exposure. POI is caused by small amounts of virus and progresses without serological infection markers, but the virus genome and its replication are detectable in the immune system and with time in the liver. SOI can be accompanied by minimal hepatitis, while the hallmark of POI is normal liver morphology. Nonetheless, HCC develops in about 20% of animals with SOI or POI within 3 to 5 years. The virus persists throughout the lifespan in both SOI and POI at serum levels rarely greater than 100 copies/mL, causes hepatitis and HCC when concentrated and administered to virus-naive woodchucks. SOI is accompanied by virus-specific T and B cell immune responses, while only virus-specific T cells are detected in POI. SOI coincides with protection against reinfection, while POI does not and hepatitis develops after challenge with liver pathogenic doses >1000 virions. Both SOI and POI are associated with virus DNA integration into the liver and the immune system genomes. Overall, SOI and POI are two distinct forms of silent hepadnaviral persistence that share common characteristics. Here, we review findings from the woodchuck model and discuss the relevant observations made in human occult HBV infection (OBI). PMID- 26623271 TI - Using light and melatonin in the management of New Zealand White rabbits. AB - Lighting system is a stimulant for reproduction in some species (Horses) and an inhibitor for others (Sheep). This study started on September 1(st) and planned to study the effects of different lighting regimes and melatonin treatment on the receptivity and performance of 78 (60-does and 18-bucks) New Zealand White rabbits, which were reared in a private Rabbitary in Menuofia Governorate, Egypt. These rabbits were randomly assigned to six treatment groups of 10 does and three bucks for each (8, 10, 12, 14 and 16 hours light (HL) and melatonin- treated). Ejaculate traits, sexual activity of bucks, sexual receptivity and reproductive performance of does were recorded. Results revealed that exposure of rabbits to long photoperiods (14 and 16HL) or treatment with melatonin improved the quantity and quality of ejaculate traits and buck sexual activity. Moreover, does sexual receptivity, feed intake, litter size and weight at birth and weaning were increased by long photoperiods (14 and 16HL) or treatment with melatonin. On the other hand, gestation period and pre-weaning mortality rate were decreased. It can be concluded that application of long photoperiods is beneficial to rabbit producers and 14HL:10 hours dark is optimal for satisfying the biological requirements of the rabbits. Finally, the light schedules can be used for biostimulation instead of melatonin. PMID- 26623272 TI - Physical and morphometric characterization of indigenous cattle of Assam. AB - The present investigation was undertaken to study the physical and morphometric characteristics in indigenous cattle of Assam. The data pertain to 339 indigenous cattle of different categories. The physical characteristics included colour pattern of body coat, muzzle, tail switch, hoof and horn. Body length, height at wither, heart girth, pouch girth, length of tail, switch, neck, ear and head were taken up for morphometric characterization. The main body coat colour of indigenous cattle was brown (31.18%) followed by white (28.53%), fawn (15.29%), grey (13.53%), black (4.41%) and mixed (7.06%). The prominent colour of tail switch was black (74.53%). Most of animals had black muzzle (86.47%), black hooves (84.71%) and black horn (100%). Morphometric characteristics data obtained were classified according to location, age group and sex of the animal. The means for body length, height at wither, heart girth, pouch girth, length of tail, switch, neck, ear and head were 83.668+/-0.590, 91.942+/-0.55, 113.146+/-0.738, 121.181+/-0.761, 54.196+/-0.527, 26.098+/-0.186, 32.705+/-0.166, 18.131+/-0.111 and 35.035+/-0.195 cm, respectively. Age and sex had significant effect on all the morphometric characters however, location effect was non-significant. The indigenous cattle of Assam are comparatively smaller in size than most of the recognized breeds of cattle however coat colour showed sizeable variation. The data generated for indigenous cattle of Assam would be useful to characterize them. PMID- 26623270 TI - Treatment of Nonalcoholic Fatty Liver Disease: The Role of Medical, Surgical, and Endoscopic Weight Loss. AB - Nonalcoholic fatty liver disease (NAFLD) represents a rapidly growing cause of chronic liver disease in the United States and is associated with significant morbidity and mortality, including progression to liver cirrhosis and hepatocellular carcinoma. NAFLD comprises a spectrum of liver conditions, ranging from simple steatosis to steatosis with inflammation (steatohepatitis) and progressive fibrosis. Weight loss represents a first line therapeutic modality for the management of NAFLD. Herein, we review the evidence base for medical, surgical, and endoscopic approaches to weight loss and their potential impact on the natural history of NAFLD. PMID- 26623273 TI - Caesarean of Lion (Panthera leo) at Dulahajra Safari Park, Bangladesh. AB - A six years eight months pregnant lioness at the Dulahajara Safari Park, Chakoria, Cox's Bazar, Bangladesh, was presented with dystocia. This paper described the pre-, intra- and postoperative procedures including anesthetic protocol carried out and performing a caesarean section to remove dead fetuses and the successful recovery of the lioness without complications. PMID- 26623269 TI - Hepatitis B and Delta Virus: Advances on Studies about Interactions between the Two Viruses and the Infected Hepatocyte. AB - The mechanisms determining persistence of hepatitis B virus (HBV) infection and long-term pathogenesis of HBV-associated liver disease appear to be multifactorial. Although viral replication can be efficiently suppressed by the antiviral treatments currently available, viral clearance is generally not achieved since HBV has developed unique replication strategies, enabling persistence of its genome within the infected hepatocytes. Moreover, no direct antiviral therapy exists for the more than 15 million people worldwide that are also coinfected with the hepatitis delta virus (HDV), a defective virus that needs the HBV envelope proteins for propagation. The limited availability of robust HBV and HDV infection systems has hindered the understanding of the complex network of virus-virus and virus-host interactions that are established in the course of infection and slowed down progress in drug development. Since chronic HBV/HDV coinfection leads to the most severe form of chronic viral hepatitis, elucidation of the molecular mechanisms regulating virus-host interplay and pathogenesis are urgently needed. This article summarizes the current knowledge regarding the interactions among HBV, HDV, and the infected target cell and discusses the dependence of HDV on HBV activity and possible future therapeutic approaches. PMID- 26623274 TI - Hematology and serum chemistry reference values of stray dogs in Bangladesh. AB - Hematology and serum chemistry values were obtained from 28 male and 22 female stray dogs in Chittagong Metropolitan area, Bangladesh. The goal of the study was to establish reference value for hematology and serum chemistry for these semi wild animals in relation to age, sex, reproductive stage and body condition. No significant differences were found for mean values of hemoglobin, packed cell volume, mean corpuscular hemoglobin concentration, white blood cell, differential leukocyte count, total protein, albumin, glucose, cholesterol, phosphorus and potassium among or between sexes, ages, reproductive states or body conditions. Significant differences were noted for erythrocyte sedimentation rate (p<0.02) between sexes. Among different age groups significant differences were found for total red blood cell count (p<0.001). Different body conditions have significant differences in red blood cell count, mean corpuscular volume and mean corpuscular hemoglobin (p<0.001). Pregnant and non-pregnant females differed significantly in their red blood cell count, mean corpuscular volume and mean corpuscular hemoglobin (p<0.001). PMID- 26623275 TI - Chlorpyrifos chronic toxicity in broilers and effect of vitamin C. AB - An experiment was conducted to study chlorpyrifos chronic toxicity in broilers and the protective effect of vitamin C. Oral administration of 0.8 mg/kg body weight (bw) (1/50 LD50) chlorpyrifos (Radar((r))), produced mild diarrhea and gross lesions comprised of paleness, flaccid consistency and slightly enlargement of liver. Histopathologically, chlorpyrifos produced degenerative changes in various organs. Oral administration of 100 mg/kg bw vitamin C partially ameliorated the degenerative changes in kidney and heart. There was insignificant alteration in biochemical and haematological profiles. It is concluded that supplementation of vitamin C reduced the severity of lesions induced by chronic chlorpyrifos toxicity in broilers. PMID- 26623276 TI - Studies on the antidiarrhoeal, antimicrobial and cytotoxic activities of ethanol extracted leaves of yellow oleander (Thevetia peruviana). AB - This study screened the antidiarrhoeal, antimicrobial and cytotoxic effects of ethanol-extracted leaves of yellow oleander (Thevetia peruviana). The extract was tested against castor oil-induced diarrhoea in a model of albino rats and showed significant antidiarrhoeal activity (P<0.01). Disc diffusion technique was used to test the in vitro antibacterial activities of the extract and exhibited poor antibacterial activities against both Gram positive and Gram negative bacteria (mainly Bacillus sp). Ethanol-extracted leaves of yellow oleander showed narrow zone of inhibition in the bacterial lawns of Shigella flexineri, Salmonella typhi, Klebsiella sp, Staphylococcus aureus and Shigella sonnei. Cytotoxicty was determined against brine shrimp nauplii and LC50 of the plant extract was determined as 627.21MUg/ml. The wide range of LC50 value denotes the safety effect of the extract. PMID- 26623277 TI - Pregnancy diagnosis by laparoscopy in free range rhesus macaques (Macaca mulatta). AB - The present study involved 50 adult female rhesus macaques (Macaca mulatto) of age ranging between 4 to 15 years. Pregnancy diagnosis was done by using laparoscopic method. Anesthesia was achieved by using xylazine (2mg/kg) and ketamine (10mg/kg) intramuscularly. The gravid uterus was located close to the urinary bladder in early pregnancy and in abdominal cavity in the mid and late stage of pregnancy. The procedure was completed within 10 - 12 minutes. There were no complications after the surgery and recovery of animal was smooth and uneventful. The results of this study showed that laparoscopic method is also one of the methods of pregnancy diagnosis in rhesus macaques and it can be a precise and a reliable method of pregnancy diagnosis in rhesus macaques. PMID- 26623278 TI - Raw cow's milk relatively inhibits quorum sensing activity of Cromobacterium violaceum in comparison to raw she-camel's milk. AB - Milk from different animal species has variable levels of antimicrobial factors against some of spoilage bacteria. For example, they are significantly present in higher concentration in she-camel's milk than in cattle or buffalo and they are more heat-resistant than their counterparts in cattle and buffalo. Spoilage bacteria are known to communicate with each other by release of signaling molecules, a phenomenon described as quorum sensing (QS). Some food matrices inhibit these signaling compounds. In this study we screened QS inhibitory activities in raw milk of cattle and camel. Ten samples each of fresh raw cow's milk and she-camel's milk from apparently healthy animals were screened using the bacterial model Cromobacterium violaceum. The tested cow's raw milk samples were able to inhibit the production of QS signalling molecules acyl-homoserine lactones (AHLs) produced by C. violaceum. However, she-camel's milk samples were less effective in inhibiting such AHLs. Thus, one of the factors which influence the inhibitory activity could be derived from variation in milk chemical composition, especially in the percentage of fat which is significantly higher in tested cow's milk samples (2.22+/-0.12) than in tested she-camel's milk samples (1.44+/-0.35). Natural inhibition of QS signaling by cow's milk may offer a unique means to control foodborne pathogens and reduce microbial spoilage. PMID- 26623279 TI - Antibiogram and heavy metal tolerance of bullfrog bacteria in Malaysia. AB - Bacterial isolates from 30 farmed bullfrogs (Lithobates catesbeianus) weighing 500-600 g at Johore, Malaysia with external clinical signs of ulcer, red leg and torticollis were tested for their antibiograms and heavy metal tolerance patterns. A total of 17 bacterial species with 77 strains were successfully isolated and assigned to 21 antibiotics and 4 types of heavy metal (Hg(2+), Cr(6+), Cd(2+), Cu(2+)). Results revealed that bacteria were resistant against lincomycin (92%), oleandomycin (72.7%) and furazolidone (71.4%) while being susceptible to chloramphenicol and florfenicol at 97.4%. The multiple antibiotic resistance (MAR) index for C. freundii, E. coli and M. morganii was high with the value up to 0.71. Bacterial strains were found to exhibit 100 % resistance to chromium and mercury. High correlation of resistance against both antibiotics and heavy metals was found (71.4 to 100%) between bullfrog bacteria isolates, except bacteria that were resistant to kanamycin showed only 25% resistance against Cu(2+). Based on the results in this study, bacterial pathogens of bullfrog culture in Johore, Malaysia, were highly resistant to both antibiotics and heavy metals. PMID- 26623280 TI - A case of non-regenerative immune-mediated anemia treated by combination therapy of human immune globulin and mycophenolate mofetil in a dog. AB - A 12-year-old female Shih Tzu dog was referred with diarrhea. Hematological examination indicated severe non-regenerative anemia. Bone marrow aspiration smears and core biopsy specimens revealed normal bone marrow. Based on those results, non-regenerative immune-mediated anemia was diagnosed. The dog was initially treated using prednisolone and cyclosporine. However, this treatment regimen did not prove effective. Nevertheless, the patient achieved a good hematological response after the administration of a combination therapy of human immune globulin and mycophenolate mofetil. Such a combination therapy may prove effective against non-regenerative immune-mediated anemia. PMID- 26623281 TI - Ovine rotaviruses. AB - Rotavirus has been recognized as a predominant cause of acute diarrhea in young animals and humans. Rotavirus has segmented genome composed of 11 segments of double stranded RNA. The virus has a triple layered protein shell consisting of a core, an inner capsid and an outer capsid. The inner capsid protein is responsible for group specificity and based on it rotaviruses are classified into seven groups. Ovine rotavirus strains have only been identified into two serogroups (A and B). The two outer capsid proteins (VP7 and VP4) are responsible for G and P typing of rotavirus, respectively. Although rotavirus has been frequently reported in many animal species, data regarding ovine rotavirus strains is very scanty and limited. Only a few ovine rotaviruses have been isolated and characterized so far. Recently, the G and P types circulating in ovines have been identified. The ovine rotavirus strain NT isolated from a diarrheic lamb in China is being considered as a promising vaccine candidate for human infants. PMID- 26623282 TI - Effects of timed artificial insemination following estrus synchronization in postpartum beef cattle. AB - The objectives of this study were to evaluate estrus response and pregnancy rates resulting from timed artificial insemination (AI) following estrus synchronization using CIDR in postpartum beef cattle. A total of 100 cows were randomly divided into three groups. Groups 1, 2 and 3 were artificially inseminated at 48-50 h (n=30), 53-55 h (n=30) and 58-60 h (n=40) after CIDR removal, respectively. Estrus synchronization was carried out using a CIDR containing 1.38 mg progesterone. All cows were given 2 mg estradiol benzoate, intramuscularly on the day of CIDR insertion (D 0). The CIDR was removed after 8 days and 125 MUg of prostaglandin F2alpha (PGF2alpha) was injected intramuscularly. One day after CIDR removal all cows were given 1 mg of estradiol benzoate intramuscularly (D 9). Cows were observed visually for estrus after removal of CIDR. Between 30 and 32 days after timed AI, pregnancy was determined using transrectal ultrasonography. The first estrus observation which is approximately 32 h after CIDR removal showed no significant difference (P>0.05) among the three groups. The onset response of estrus after 32 h removal of CIDR was less than 10% in all three groups 6.6% (G1), 6.8% (G2) and 7.3% (G3). Furthermore, percentages of estrus response (D 10) following CIDR removal were 76.6%, 75.0% and 77.5%. The difference between on D 9 and D 10 estrus response were statistically significant (P<0.05). The pregnancy rates were 23.3% (G1), 26.6% (G2) and 37.5% (G3), which were not significant (P>0.05). PMID- 26623283 TI - No-scalpel vasectomy by electrocauterization in free range rhesus macaques (Macaca mulatta). AB - The objective of the study was to standardize a new method of vasectomy in male rhesus macaques (Macaca mulatta). A total of 208 free range male rhesus macaques captured from different locations in Shivalik Hills in a population control programme of the rhesus macaques in India. General anaesthesia was achieved by using a combination of ketamine hydrochloride at 8 mg/kg body weight and xylazine hydrochloride at 2mg/kg body weight intramuscularly in squeeze cage. Surgical procedure of vasectomy was carried out by single-hole no-scalpel technique using a single pre-scrotal skin incision above the median raphae. Spermatic cord was grasped with ringed forceps and was pulled out through the single-hole incision. Vas deferens was separated from the artery-vein complexus and about 3-4 cm portion of vas deferens was resected. Cauterization of both ends of the vas deferens was achieved with electrocautery. The induction time for anaesthesia was 1.40+/-0.18 min while surgical time for vasectomy was found to be 5.09+/-0.22 min. Recovery from general anaesthesia was without side-effects after a mean duration of 36.07+/-1.22 min, whereas the duration of anaesthesia was observed to be 82.27+/-4.96 min. There were no major complications following the surgery and recovery of animals was smooth. Animals were kept in postoperative care for five days and released at the same capturing site. PMID- 26623284 TI - A three years retrospective study on the nature and cause of ocular dermoids in cross-bred calves. AB - Nature and cause of ocular dermoids were investigated by field studies, pedigree analysis, clinical examination and light microscopy. It was determined that ocular dermoids in cross-bred calves are genetically-transmitted defects. Calves typically were affected unilaterally or bilaterally with multiple, connected ocular growths that clinically and histologically mimicked normal haired skin. Sites most commonly involved included ventro-lateral limbus, third eyelid, medial canthus, eyelid and conjunctiva. Centro-corneal and anterior segmental dermoids were also observed. It is postulated from this study that bilateral ocular dermoids are genetically-transmitted defects in Hereford cattle. Characteristics of both autosomal recessive and polygenic inheritance were observed. However, mode of inheritance and role of environment in the pathogenesis of these peculiar and important developmental defects remain undefined. Extensive breeding trials utilizing superovulation, embryo transfer, and pre-terminal caesarean section as well as further field studies might be mandatory to confirm sex incidence, significance of associated somatic defects, role of environment in phenotypic expression, and mode of transmission of ocular dermoids in cross-bred calves. PMID- 26623285 TI - Levels of heavy metals in liver and kidney of dogs from urban environment. AB - Lead, cadmium and mercury were detected in liver and kidney tissue of dogs from an urban habitat. Samples were digested in a microwave system and analyzed by atomic absorption spectroscopy. Results of the current study showed that at least one of the three heavy metals was detected in tissues of all examined dogs. These findings make us suppose that humans are exposed to the same heavy metals similar to those of dogs that are exposed since they share the same environment. Mercury concentrations detected in kidney of household dogs were higher than stray dogs, therefore the involvement of pet food in exposure to mercury can be supposed. PMID- 26623286 TI - Agarose cell block technique as a complementary method in the diagnosis of fungal osteomyelitis in a dog. AB - A 7-year-old Labrador Retriever female dog presenting left forelimb lameness for one day was admitted to the Veterinary Hospital (UNESP-Botucatu) for clinical evaluation. Several tests, including blood and image analysis, microbiological culture and cytology of lytic areas of affected bone were made in order to establish a diagnosis. Serum biochemical profile revealed increased levels of liver enzymes, plasma globulin, creatine kinase (CK) and calcium. Hemogram revealed anemia and leukocytosis; left humerus image analysis revealed an osteolytic lesion and cytology revealed a suppurative periostitis. Differential diagnosis was a nonspecific infectious inflammatory process or osteosarcoma. Since it was not possible to achieve a definitive diagnosis and there was a highly suspicious for an infectious agent, an agarose cell block of the bone marrow fine-needle aspiration was made. The cytological examination of cell block presented similar findings as described previously. However, additional stains including periodic acid-Schiff (PAS) were positive for fungal hyphae, which rendered a diagnosis of fungal osteomyelitis due to Aspergillus spp. This case report illustrates an uncommon cause of osteomyelitis for breed that was diagnosed by an underused method in veterinary medicine. PMID- 26623287 TI - Ankyloglossia and its surgical correction by frenuloplasty in a she-camel calf (Camelus dromedarius). AB - A rare case of ankyloglossia in a one-humped camel and its successful surgical correction by horizontal to vertical frenuloplasty is reported. Seven-month-old she-camel calf, with a history of excessive salivation and inability to chew and swallow hay, was referred to Al Qattara veterinary hospital. Solid food was regurgitated, whereas milk and water could be swallowed. On examination; the animal could not protrude its tongue which was attached by a thin tissue band between the ventral surface of the tongue and the floor of the oral cavity. The tissue band was corrected by frenuloplasty and the incisions were sutured. The animal recovered well as the salivation and regurgitation stopped and the animal became able to chew and swallow solid food including hay. It was concluded that ankyloglossia can occur in one-humped camel in which a horizontal to vertical frenuloplasty may improve full function of tongue movement. PMID- 26623288 TI - Inter relationship between some routine semen evaluation parameters in Jersey X local hill cattle crossbred bulls. AB - The present study was conducted with an objective of establishing a relationship between various routine semen evaluation parameters. Work was conducted at Sperm Station Palampur, Himachal Pradesh, on the semen from five Jersey X local hill cattle crossbred breeding bulls. A total of 40 ejaculates (8 from each bull), were analysed at five different stages of processing namely post dilution, post equilibration, post thaw and after 1 and 2 hours incubation post thaw at 37 degrees C for progressive motility, live dead count, reaction to hypo-osmotic solution, acrosomal integrity and gross morphological abnormalities. The results of the study revealed a highly significant (P<0.01) correlation between the various semen evaluation parameters except for the gross morphological abnormalities where there was a significant (P<0.05) negative correlation between the acrosomal integrity and gross morphological abnormalities. PMID- 26623290 TI - Estimating fermentation characteristics and nutritive value of ensiled and dried pomegranate seeds for ruminants using in vitro gas production technique. AB - The purpose of this study was to determine the chemical composition and estimation of fermentation characteristics and nutritive value of ensiled and dried pomegranate seeds using in vitro gas production technique. Samples were collected, mixed, processed (ensiled and dried) and incubated in vitro with rumen liquor taken from three fistulated Iranian native (Taleshi) steers at 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 h. The results showed that ensiling lead to significant increase in gas production of pomegranate seeds at all incubation times. The gas volume at 24 h incubation, were 25.76 and 17.91 ml/200mg DM for ensiled and dried pomegranate seeds, respectively. The gas production rate (c) also was significantly higher for ensiled groups than dried (0.0930 vs. 0.0643 ml/h). The organic matter digestibility (OMD), metabolizable energy (ME), net energy for lactation (NEL) and short chain fatty acids (SCFA) of ensiled pomegranate seeds were significantly higher than that of dried samples (43.15%, 6.37 MJ/kg DM, 4.43 MJ/kg DM, 0.5553 mmol for ensiled samples vs. 34.62%, 5.10 MJ/kg DM, 3.56 MJ/kg DM, 0.3680 mmol for dried samples, respectively). It can be concluded that ensiling increases the nutritive value of pomegranate seeds. PMID- 26623289 TI - Effects of Watercress (Nasturtium nasturtium) extract on selected immunological parameters of rainbow trout (Oncorhynchus mykiss). AB - Watercress (Nasturtium nasturtium) is a medical plant containing diverse chemically-active substances with biological properties. The present study was conducted to investigate the immunomodulatory effects of watercress extract on immunological and hematological parameters of rainbow trout (Oncorhynchus mykiss). Fish were fed for 21 days with diet supplemented with 0.1% and 1% of watercress extract per 1 kg food and with a normal diet as control. Hematological parameters such as red blood cells (RBC) and white blood cells (WBC), hematocrit (Hct), hemoglobin (Hb), RBC index like mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) as well as immunological parameters such as peroxidase, lysozyme and complement activities, total protein, albumin and globulin levels were measured after 21 days of watercress extract treatment. The results indicated that oral administration of 1 % watercress extract in fish may enhance some hematological and immunological parameters including Hb and MCHC, lysozyme and complement activities, total protein and globulin levels, compared to the controls after 21 days of experimental period. In conclusion, on the basis of these results, oral administration of watercress extract may be useful to improve fish's immune system. PMID- 26623292 TI - Determining nutrients degradation kinetics of chickpea (Cicer arietinum) straw using nylon bag technique in sheep. AB - Straw a by-product from grain legume crops is produced in large quantities in Iran. Straw is constant component of ruminant diets on small holder farms; however, there is little information about its nutritive value. Accordingly experiment was conducted to determine the chemical composition and ruminal organic matter (OM) and crude protein (CP) degradability of chickpea straw using nylon bags (in situ) technique. Replicated samples were incubated at 0, 2, 4, 8, 12, 24, 48 and 72 hours in three rumen canulated Ghezel rams with 50+/-3 kg body weight. Dry matter (DM), CP, ether extract (EE), OM, crude fiber (CF) and nitrogen free extract (NFE) content of chickpea straws were 92.2, 6.1, 5.5, 92.0, 34.3 and 46.2%, respectively. The soluble fraction (a) of the OM and CP of chickpea straw was 17.5 and 40.8% and potential degradability (a+b) of OM and CP was 56.7 and 72.0%, respectively. Effective degradability at different passage rates (2, 5 and 8% per hours) for OM was 51.0 44.9 and 40.7% and for CP were 68.4, 64.3 and 61.3%, respectively. In conclusion, based on chemical composition and degradation characteristics, chickpea straw could have moderate nutritive value for ruminants. PMID- 26623291 TI - Role of bovine herpesvirus type 5 (BoHV-5) in diseases of cattle. Recent findings on BoHV-5 association with genital disease. AB - Bovine herpesvirus type 5 (BoHV-5) belongs to the family Herpesviridae, subfamily Alphaherpesvirinae, genus Varicellovirus. This virus is a major causative agent of non-suppurative meningoencephalitis in young cattle. It was first isolated in 1962 from a neurological disease outbreak in Australia. BoHV-5 is genetically and antigenically related to bovine herpesvirus type 1 (BoHV-1), a highly prevalent virus responsible for respiratory and genital disease in cattle. Initially, BoHV 5 was considered a subtype of BoHV-1 (BoHV-1.3). However, the exclusive presentation of outbreaks of neurological disease suggested that the virus was a new agent with characteristics of neuropathogenicity. Even though both are neurotropic viruses, only BoHV-5 is capable of replicating extensively in the central nervous system and inducing neurological disease. Occasionally, encephalitis caused by BoHV-1 has been reported. Like other alpha-herpesviruses, BoHV-5 can establish latency in nervous ganglia and, by stress factors or glucocorticoid treatment, latent virus can be reactivated. During episodes of reactivation, the virus is excreted in nasal, ocular and genital secretions and transmitted to other susceptible hosts. Recently, BoHV-5 has been associated with infection of the reproductive tract. The virus has been isolated and the presence of viral DNA has been demonstrated in semen samples from Brazil and Australia and natural transmission of the virus through contaminated semen has also been described. Embryos and oocytes are permissive for BoHV-5 infection and BoHV-5 DNA has been detected in the central nervous system of aborted fetuses. The objective of this review is to compile the limited information on the recent association between BoHV-5 and reproductive disorders in cattle. PMID- 26623293 TI - Cytokine expression in malaria-infected non-human primate placentas. AB - Malaria parasites are known to mediate the induction of inflammatory immune responses at the maternal-foetal interface during placental malaria (PM) leading to adverse consequences like pre-term deliveries and abortions. Immunological events that take place within the malaria-infected placental micro-environment leading to retarded foetal growth and disruption of pregnancies are among the critical parameters that are still in need of further elucidation. The establishment of more animal models for studying placental malaria can provide novel ways of circumventing problems experienced during placental malaria research in humans such as inaccurate estimation of gestational ages. Using the newly established olive baboon (Papio anubis)-Plasmodium knowlesi (P. knowlesi) H strain model of placental malaria, experiments were carried out to determine placental cytokine profiles underlying the immunopathogenesis of placental malaria. Four pregnant olive baboons were infected with blood stage P. knowlesi H strain parasites on the one fiftieth day of gestation while four other uninfected pregnant olive baboons were maintained as uninfected controls. After nine days of infection, placentas were extracted from all the eight baboons through cesarean surgery and used for the processing of placental plasma and sera samples for cytokine sandwich enzyme linked immunosorbent assays (ELISA). Results indicated that the occurrence of placental malaria was associated with elevated concentrations of tumour necrosis factor alpha (TNF-alpha) and interleukin 12 (IL 12). Increased levels of IL-4, IL-6 and IL-10 and interferon gamma (IFN-gamma) levels were detected in uninfected placentas. These findings match previous reports regarding immunity during PM thereby demonstrating the reliability of the olive baboon-P. knowlesi model for use in further studies. PMID- 26623294 TI - DNA damage in peripheral blood mononuclear cells and neutrophils of dairy cows during the transition period. AB - This study was designed to investigate the apoptotic process in peripheral blood mononuclear cells (PBMC) and polymorphonuclear neutrophil leukocytes (PMN) in dairy cattle during the transition period. Blood samples were collected from 4 dairy cattle at 3 weeks before the expected parturition (wk -3), parturition (wk 0) and 3 weeks after parturition (wk +3). The DNA damage of PBMC and PMN was evaluated based on the comet assay using visual scoring (arbitrary units). Undamaged DNA remained within the core (score 0) and the broken DNA migrated from the core towards the anode forming the tail of a comet (scores 1-4). Significantly higher scores in PBMC at wk 0 and wk +3 were observed compared with those in PMN although there were no significant changes of scores in either cell type during the experimental period. It is suggested that the apoptotic rate of PBMC is accelerated compared with that of PMC during the transition period. PMID- 26623295 TI - Rare congenital absence of tail (anury) and anus (atresia ani) in male camel (Camelus dromedarius) calf. AB - A one-day old male camel calf was presented to the Al-Qattara Veterinary Hospital with complaints of abdominal straining and lack of defecation. On examination it was found that the calf had no tail, the posterior sacral margin was blunt and the anal opening was absent. The case was diagnosed as congenital anury with atresia ani. The animal was sedated with 0.1 mg/kg of xylazine administered intramuscularly and under local infiltration with 2% lidocaine a circular incision was made at the anal area to create an anal opening. The animal passed plenty of meconium. The cut edges were sutured with horizontal mattress sutures. The animal was administered penicillin and streptomycin for 5 days and had an uneventful recovery. It is reported that congenital anury rarely occurs in one humped camel and accompanied atresia ani can be surgically treated. PMID- 26623296 TI - Efficacy of different methanolic plant extracts on anti-methanogenesis, rumen fermentation and gas production kinetics in vitro. AB - The present study was carried out to evaluate the effect of methanolic extracts of three plants, mehandi (Lawsonia inermis), jaiphal (Myristica fragrans) and green chili (Capsicum annuum) on methanogenesis, rumen fermentation and fermentation kinetic parameters by in vitro gas production techniques. Single dose of each plant extract (1 ml / 30 ml buffered rumen fluid) and two sorghum fodder containing diets (high and low fiber diets) were used for evaluating the effect on methanogenesis and rumen fermentation pattern, while sequential incubations (0, 1, 2, 3, 6 9, 12, 24, 36, 48, 60, 72 and 96 h) were carried out for gas production kinetics. Results showed that methane production was reduced, ammonia nitrogen was increased significantly, while no significant effect was found on pH and protozoal population following addition of different plant extracts in both diets except mehandi. Green chili significantly reduced digestibility of dry matter, total fatty acid and acetate concentration at incubation with sorghum based high and low fiber diets. Among all treatments, green chili increased potential gas production, while jaiphal decreased the gas production rate constant significantly. The present results demonstrate that methanolic extracts of different plants are promising rumen modifying agents. They have the potential to modulate the methane production, potential gas production, gas production rate constant, dry matter digestibility and microbial biomass synthesis. PMID- 26623297 TI - Trypanosoma evansi: A clinical, parasitological and immunological evaluation of trypanosomosis using a chronic rabbit model. AB - We evaluated the clinical, parasitological and immunological effects of a Venezuelan strain of Trypanosoma evansi (T. evansi) throughout in experimentally inoculated rabbits over the course of infection and compared them with the same aspect in healthy animals. Body temperature was recorded in degrees Celsius, animal weight in kilograms, serum proteins in g/dl using a refractometer, haematocrit percentage by capillary centrifugation and the anti-T. evansi IgG titer by indirect ELISA immunoassay, from both infected animals and controls for 95 days. Infected animals showed a higher body temperature, total serum protein and anti- T. evansi antibody titer, and a lower haematocrit and weight gain than controls. These differences were related to the presence of the parasites in the blood as detected micro-haematocrit centrifugation technique (MHCT) and direct microscopic examination (DME). This study confirms the usefulness of rabbits as a model for the study of trypanosomosis; the clinical features of the disease can be observed and the three characteristic stages, prepatent period, acute and chronic phase clearly defined over the course of the infection. PMID- 26623298 TI - Determination of feed value of cherry, apricot and almond tree leaves in ruminant using in situ method. AB - In the present study, chemical composition and in situ rumen dry matter degradability (DMD) of some tree species (cherry, apricot and almond tree leaves) were determined. Crude protein (CP) concentration varied from 6.76% for almond tree to 2.76% for cherry tree, neutral detergent fiber (NDF) and acid detergent fiber (ADF), from 29.2, 20.8% for apricot tree to 20.8 and 15.8% for almond tree leaves respectively. Polyphenol and tannin composition measured from 3.49, 1.2% for almond tree to 1.51 and 0.61% for apricot tree, respectively. In situ rumen degradability was carried out in three fistulaed Taleshi native male cattle which were incubated at times of 0, 4, 8, 16, 24, 48, 72 and 96-hour. Almond leaves had higher potential degradation (a+b) for dry matter (92.37%) and cherry leaves showed lower potential degradation (84.12%), respectively. Effective rumen degradable dry matter at rate of 0.05/h varied from 69.86% for almond tree to 52.20% for cherry leaves. Results showed that the almond leaves were higher in nutritive value than cherry and apricot leaves. Therefore, almond tree leaves could be used with forage in ruminant diets to reduce cost of animals feed requirements. Overall, it seemed that the tree leaves used in this study, had a higher nutritive value in ruminant's nutrition, however more experiments are needed for an accurate determination of nutritional values of these resources. PMID- 26623299 TI - Nutritional value of raw soybeans, extruded soybeans, roasted soybeans and tallow as fat sources in early lactating dairy cows. AB - Thirty multiparous Holstein cows (29.8 +/- 4.01days in milk; 671.6 +/- 31.47 kg of body weight) were used in a completely randomized design to compare nutritional value of four fat sources including tallow, raw soybeans, extruded soybeans and roasted soybeans for 8 weeks. Experimental diets were a control containing 27.4 % alfalfa silage, 22.5% corn silage, and 50.1% concentrate, and four diets with either tallow, raw soybean, extruded soybean, or roasted soybean added to provide 1.93% supplemental fat. Dry matter and NEL intakes were similar among treatments, while cows fed fat diets had significantly (P<0.05) high NEL intakes when compared to control with no fat. Supplemental fat, whether tallow or full fat soybeans increased milk production (1.89-2.45 kg/d; P<0.01) and FCM production (1.05-2.79; P<0.01). Milk fat yield and percentage of cows fed fat supplemented diets were significantly (P<0.01 and P<0.05 respectively) higher than control. Between fat-supplemented diets, roasted soybean caused highest milk fat yield and extruded soybean caused lowest milk fat yield. There was no significant effect of supplemental fat on the milk protein and lactose content and yield. Feed efficiency of fat-supplemented diets was significantly (P<0.01) higher than control. Body weight, body weight change and BCS (body condition score) of cows, as well as energy balance and energy efficiency were similar between treatments. In conclusion, while there was no significant effect of fat sources on production response of cows, fat originating from heat-treated soybean help to minimize imported RUP (rumen undegradable protein) sources level as fish meal in comparison with tallow and raw soybean oil. In the Current study, there was no statistical significance among nutritional values of oil from extruded soybeans and roasted soybeans. PMID- 26623301 TI - Castration of dromedary camel through prescrotal midline incision. AB - A total of 165 camels of different ages were castrated through a small, prescrotal midline incision between January, 2010 and December, 2011. The incision was closed with one interrupted, horizontal mattress suture using USP-2 chromic catgut. In 14/165 animals (8.5%) postoperative infection (sepsis) developed, which healed in two to three weeks after open wound management. The remaining 151 animals had an uneventful recovery, but a slight edematous swelling of the scrotum was observed in 8 of the 151 animals (5.3%), which was self limiting and of no significance. No primary or secondary postoperative bleeding was noticed in any of the animals. It was concluded that this technique was less time consuming with negligible postoperative care and complications when performed under standard surgical principles. PMID- 26623300 TI - Tsetse fly saliva: Could it be useful in fly infection when feeding in chronically aparasitemic mammalian hosts. AB - Sleeping sickness and nagana are two important diseases cuased by African trypanosomes in humans and animals respectively, in tropical african countries. A number of trypanosome species are implicated in these diseases, but it is the Trypanosoma brucei group that is responsible for the chronic form of sleeping sickness. During the course of this chronic infection the parasite shows a clear tropism for organs and tissues and only sporadically appears in the blood stream. Notwithstanding this feature, tsetse flies normally get infected from chronically infected apparasitemic hosts. For some pathogens like the microfilaria, it has already shown that the saliva of the vector, black fly saliva contribute to orient the pathogen to the site of the vector bite. Chemotaxis of tsetse saliva may perhaps stimulate movement of Trypanosoma brucei parasites from tissues to the bloodstream and via the vascular to the tsetse feeding site, and could explain the relatively high infection rate of tsetse flies feeding on chronically infected animals. This review paper looks into the possible role of trypanosome vector saliva in ensuring parasite acquisition and its application in the tsetse trypanosome interaction at the host skin interphase. PMID- 26623302 TI - Collection, analysis and cryopreservation of semen from Malayan gaur (Bos gaurus hubbacki): A preliminary study. AB - The Malayan gaur (Bos gaurus hubbacki) or Seladang is classified as vulnerable by the International Union for Conservation of Nature and Natural Resources (IUCN). The Malayan gaur is mainly distributed in the tropical woodlands of Peninsular Malaysia and Southern Thailand. The aim of this study was to collect, analyze and cryopreserve the semen of wild Malayan gaur. Transrectal massage (TM) and electroejaculation (EEJ) technique was applied in semen collection of the Malayan gaur. The semen was then cryopreserved in liquid nitrogen using slow freezing technique. Makler counting chamber was used to evaluate sperm concentration and motility, while the sperm viability and morphology of fresh and post-thaw sperm was determined using eosin-nigrosin staining protocol. As a result, we have successfully collected the Malayan gaur semen using EEJ technique. Sperm motility, viability and morphological changes of the post-thaw semen of Malayan gaur were found undesirable due to the complication of the cryopreservation process. On the basis of current study it can be concluded that Malayan gaur bulls semen can be obtain by EEJ with no evidence of rectal trauma. Optimization of the process of cryopreservation for Malayan gaur sperm is needed to maintain the cryoviability of the good sperm quality. The data generated in this study would be useful in conservation of genetic diversity program for Malayan gaur. PMID- 26623303 TI - Surgical replacement of iatrogenically prolapsed penis in a dromedary camel. AB - Prolapse of the penis through an iatrogenic incision on the right side of the preputial base in a five year old dromedary camel was handled surgically and the organ was successfully replaced into the preputial cavity. The condition occurred as a result of draining an abscess at the base of the prepuce by a quack about eight months earlier. The reason to report this case lies in its peculiarity that although the penis remained outside the preputial cavity for about eight months exposed to the external environment, yet no complications pertaining to its fragile tissue and urination occurred during this long period as seen in cases of paraphimosis. PMID- 26623304 TI - Influence of different storage times and temperatures on blood gas and acid-base balance in ovine venous blood. AB - The present study was designed to investigate the effects of storage temperature and time on blood gas and acid-base balance of ovine venous blood. Ten clinically healthy sheep were used in this study. A total number of 30 blood samples, were divided into three different groups, and were stored in a refrigerator adjusted to +4 oC (Group I, n = 10), at RT of about 22-25 oC (Group II, n = 10) and in an incubator adjusted to 37 oC (Group III, n = 10) for up to 48 h. Blood samples were analysed for blood gas and acid-base indices at 0, 1, 2, 3, 4, 5, 6, 12, 24 and 48 h of storage. In comparison to the baseline value (0), there were significant decreases of blood pH of samples stored at RT and in the incubator after 1 h (p<0.05), the pH value of refrigerated blood samples exhibited insignificant changes during the study (p<0.05). Mean values of pCO2 showed a significant increase in Group I and Group III after 1 h then a progressive decrease after 12 h in all Groups. Mean pO2 values were significantly higher for Group I after 2 h and for Groups II and III after 1 h (p<0.05). In general, base excess decreased significantly for all the groups during the study especially in Groups II and III. In comparison with baseline values, in all groups, bicarbonate (HCO3) increased between 1 h and 6 h (p<0.05), and later decreased at the end of the study (p<0.05). In conclusion, status of acid-base indices of the samples stored at refrigerator and RT were found within normal reference range and it may be of clinical diagnostic use for up to 6 h. PMID- 26623305 TI - Rare fetal monster in Holstein crossbred cow. AB - This report describes a rare case of conjoined female twin monster (Monocephalus Thoracopagus Tetrabrachius Tetrapus Dicaudatus) in a Holstein Friesian pluriparous crossbred cow. PMID- 26623306 TI - Clinical and ultrasonographic findings of some ocular conditions in sheep and goats. AB - This study was carried out to describe the ultrasonographic findings in relation to the clinical symptoms of some common ocular conditions in sheep and goats. Fifty animals (32 goats and 18 sheep) with different ocular problems were examined. Ultrasonographic examination was performed using a B-mode ocular ultrasound unit, and the structure of the globe was evaluated at a depth of 4-6 cm. Early cases (n=35, 70%) showed varying ocular conditions; hypopyon, (n=8, 16%), stromal abscesses, (n=4, 8%), and anterior uveitis (n=23, 46%). Hypopyon appeared clinically as a white or yellowish material in the anterior chamber, and ultrasonographically as a hyperechoic mass in the anterior chamber. Severe iridocyclitis was noticed in acute cases of infectious keratoconjunctivitis (IKC) accompanied by blepharospasm, photophobia, excessive tearing and eyelid margin crust formation. Ultrasonographically, the pupil appeared constricted with increased hyperechoic thickening of the ciliary body. In chronic cases of IKC, corneal pigmentation (n=5, 10%) and cataract (n=10, 20%) were seen. Ultrasonographically the type and degree of cataract were diagnosed. The present study provides an inside view of the inner ocular structures during the course of certain eye diseases where ophthalmoscopic examination is not possible. Our findings, although preliminary, are relevant for the more complete diagnosis of certain external ocular conditions in sheep and goat herds. PMID- 26623307 TI - Fixation of metatarsal fracture with bone plate in a dromedary heifer. AB - An oblique fracture of the distal third of the right metatarsus in a three-year old dromedary heifer weighing about 300 kilograms was immobilized with a 4.5 mm broad-webbed 12-hole dynamic compression bone plate and two interfragmental compression screws. The animal showed slight lameness after 16 weeks of surgery that disappeared after removal of the plate. The result was quite encouraging and the fracture healed in 16 weeks without major complications. It is concluded that the fracture of this bone can be successfully handled with bone plating at least in young, light weight animals. PMID- 26623308 TI - Fluorescent multiple staining and CASA system to assess boar sperm viability and membranes integrity in short and long-term extenders. AB - The aim of this study was to assess the effect on boar spermatozoa quality of in vitro storage in short and long-term extenders by fluorescent multiple staining (FMS) and computer assisted semen analyzer (CASA). Fresh ejaculates from three healthy, sexually mature boars were diluted with equal volumes of six short-term or three long-term commercial extenders and stored at 19 degrees C for 6 days (short-term) or 12 days (long-term). The integrity of spermatozoa membranes was analyzed by FMS using propidium iodide, 5,5',6,6'-tetrachloro-1,1',3,3' tetraethylbenzimidazolyl-carbocyanine iodide (JC-1) and fluorescein isothiocyanate-conjugated peanut agglutinin (PNA). The results obtained from this staining were compared with spermatozoa motility assessed by CASA. Our study showed that the number of viable spermatozoa with non-reacted acrosomes and intact mitochondria was positively correlated with the rate of motile spermatozoa (r(2)>0.9) irrespective of the extender used. In all extenders the number of motile spermatozoa significantly decreased as preservation period increased (P<0.05). FMS test is a potent indicator of sperm motility because it analyses mitochondrial integrity independently from observable alterations in motility. The best performing extenders were BTS for short-term storage and TRI-x-Cell for long-term storage. PMID- 26623309 TI - Histopathological changes induced by paraquat on some tissues of gourami fish (Trichogaster trichopterus). AB - Paraquat is a contact and non-selective herbicide which is used for controlling a wide range of terrestrial weeds and aquatic plants. A long-term contact with this xenobiotic can potentially lead to injuries in fishes as live non-target organisms. Therefore, the current study aimed to investigate the effect of sub lethal toxicity of paraquat on the pathology of gill, liver, and spleen tissues in gourami fish (Trichogaster trichopterus). In this study, sub-lethal concentration is determined based on lethal concentration (LC50 : 7.16+/-0.69, 4.46+/-0.43, 2.19+/-0.27 and 1.41+/-0.17 mg/l of paraquat within 24, 48, 72 and 96 hours, respectively). The experiment was done with four varied concentrations of paraquat (0.0, 0.07, 0.15, and 0.3 mg/l equal 0.0%, 5%, 10% and 20% of nominal value of 96 h LC50) during 3 weeks. The exposed fish displayed erratic swimming and became lethargic. The changes in gills were characterized by hypertrophy, epithelial, epithelium increase of gill filament, edema and secondary gill lamella. The liver showed hypotrophy of liver cells, cloudy swelling and formation of cytoplasmic vacuoles in the liver tissue of fish treated with 0.15 and 0.3 mg/l concentrations of paraquat. Disorder in the ellipsoid cell and hemosiderin accumulation in melano-macrophage centers was observed in the spleen tissue of fish exposed to 0.15 and 0.3 mg/l of paraquat. PMID- 26623310 TI - Efficacy of a combined protocol for re-insemination of open cows after early pregnancy diagnosis using ultrasonography and its effect on fertility. AB - The objective of the present field study was to establish the beneficial effects of re-insemination of non-pregnant cows using ultrasonography 20 to 23 days after the artificial insemination. A total of 245 Japanese Black cows were artificially inseminated and early pregnancy diagnosis (EPD) was performed on 92 cows 20 days after insemination, using ultrasonography. The remaining 153 cows were considered as negative controls in which routine rectal palpation was performed for pregnancy diagnosis 45-50 days post-insemination. EPD revealed that eleven of the 92 cows (12%) were infertile due to ovarian abnormalities and were thus excluded from the rest of the study. Forty-eight (59%) of the remaining 81 cows were diagnosed as pregnant, while the other 33 (41%) were diagnosed as non-pregnant. Of these non-pregnant cows, 17 of them received a dose of an analogue of the gonadotropin-releasing hormone (GnRH analogue) and were then timed-inseminated, while the other 16 were observed for estrus signs, and 13 of them (81%) were artificially inseminated. Rates of conception were 35% and 38% in the GnRH and the artificially inseminated groups, respectively (P>0.05). Total pregnancy rate for the EPD group increased significantly (74%) (P<0.01) when compared to the control cows (54%) within the same period. In conclusion, our field study demonstrated that re-insemination of non-pregnant cows following EPD is highly efficacious not only in improving the rate of fertility via reducing inter insemination and inter-calving intervals, but also aids in the early detection of ovarian disorders. PMID- 26623311 TI - The effects of addition of omega-3, 6, 9 fatty acids on the quality of bovine chilled and frozen-thawed sperm. AB - This study was aimed to investigate the effects of omega-3, 6, 9 fatty acids on the characteristics of bovine chilled and frozen-thawed semen. For this purpose, oil containing different levels of omega-3, 6, 9 fatty acids were added to semen extender. To emulsify the oil in semen extender, polyethylene glycol (PEG) was added as a suitable solvent and the solution was finally sonicated. Five proven Holstein bulls were randomly selected and their ejaculates were collected using an artificial vagina. Groups were designed as control, treatments 1, 2, 3 and 4. The control group contained only the basic extender (Tris-citrate buffer, egg yolk and glycerol) without any additives. In treatment 1, only 5% PEG was added to the diluent; while in treatments 2, 3 and 4 different concentrations of omega 3, 6, 9 fatty acids (1.0, 2.5 and 5.0%) in combination with PEG were added to the basic extender. After dilution, the semen samples were packaged into 0.5 ml straws, a process that was followed by cooling the semen straws. Motility, viability and morphology of semen samples were evaluated after 24 and 48 h of storage in refrigerator (5 degrees C) or after one month of storage in the liquid nitrogen. Immotility was increased and all the other parameters including motility, viability and morphology were significantly decreased in all the groups compared with fresh samples during cold storage and freezing-thawing. Our results demonstrated the following: 1) PEG has significant detrimental effects, especially on the sperm motility; 2) addition of omega-3, 6, 9 fatty acids could not improve the sperm motility in chilled storage condition and after freezing thawing; and 3) omega-3, 6, 9 fatty acidscould not also attenuate the other deleterious effects of PEG. In conclusion, our findings reveal that addition of these fatty acids to the semen extender does not enhance the resistance of the bovine sperm membrane to cooling and freezing-thawing and that further studies are required to find suitable candidate compounds that can boost the quality of semen that is chilled and freeze-thawed. PMID- 26623312 TI - Digit loss due to Demodex spp. infestation in a dog: clinical and pathological features. AB - Here we describe a rare clinical manifestation of canine pododemodicosis. A dog was presented with pedal erythema, scaling, crusting, severe edema and digit loss. The following diseases were taken into account for the differential diagnosis: pododemodicosis, lethal acrodermatitis, zinc responsive dermatosis and pemphigus foliaceus. Results from skin biopsies revealed the presence of Demodex spp. of mites in the follicular infundibula and a severe inflammatory process (pododemodicosis). Upon the acaricidal treatment, the patient exhibited favorable signs of clinical improvement. PMID- 26623313 TI - Efficacy of free glutathione and niosomal glutathione in the treatment of acetaminophen-induced hepatotoxicity in cats. AB - Acetaminophen (APAP) administration results in hepatotoxicity and hematotoxicity in cats. The response to three different treatments against APAP poisoning was evaluated. Free glutathione (GSH) (200mg/kg), niosomal GSH (14 mg/kg) and free amino acids (180 mg/kg of N-acetylcysteine and 280 mg/kg of methionine) were administered to cats that were intoxicated with APAP (a single dose of 150 mg/kg, p.o.). Serum concentration of alanine aminotransferase (ALT) along with serum, liver and erythrocyte concentration of GSH and methemoglobin percentage were measured before and 4, 24 and 72 hours after APAP administration. Free GSH (200 mg/kg) and niosomal GSH (14 mg/kg) were effective in reducing hepatotoxicity and hematotoxicity in cats intoxicated with a dose of 150 mg/kg APAP. We conclude that both types of treatments can protect the liver and haemoglobin against oxidative stress in APAP intoxicated cats. Furthermore, our results showed that treatment with niosomal GSH represents an effective therapeutic approach for APAP poisoning. PMID- 26623314 TI - Frequency and type of toenail tumors in the dromedary camel. AB - A total of 275 dromedary camels (16 males and 259 females) of local "Arabiyat" breed suffering from different types and degrees of severity of toenail tumors were surgically treated. Histopathological examination of the tissue samples removed from 50 tumor-like growths (2 males and 48 females) revealed three types of tumors; squamous cell carcinoma (70%), spiny keratoderma (22%) and fibroma (8%). An increased incidence of tumors was recorded in the medial when compared to the lateral toenails in both sexes. In females, the incidence in the medial toenails was 90/259 (34.75%) and 71/259 (27.41%) in the right and left forelimbs respectively when compared to the lateral toenails which was 25/259 (9.65%) and 5/259 (1.93%) for the respective right and left forelimbs. In the hind limbs, this ratio was 29/259 (11.20%) and 20/259 (7.72%) for right and left medial toenails respectively, whereas it was 17/259 (6.56%) and 2/259 (0.77%) for the right and left lateral toenails respectively. Similar to the observations in female camels, male camels also showed a higher incidence of these tumors in the medial when compared to the lateral toenails in both fore and hind limbs. Based on these findings, we conclude that in the dromedary camels, the medial toenails of the fore limbs are most commonly affected with tumors; with the most common tumor being the squamous cell carcinoma. PMID- 26623315 TI - Involvement of a putative intercellular signal-recognizing G protein-coupled receptor in the engulfment of Salmonella by the protozoan Tetrahymena. AB - In an effort to investigate the molecular basis of protozoa engulfment-mediated hypervirulence of Salmonella in cattle, we evaluated protozoan G protein-coupled receptors (GPCRs) as transducers of Salmonella engulfment by the model protozoan Tetrahymena. Our laboratory previously demonstrated that non-pathogenic protozoa (including Tetrahymena) engulf Salmonella and then exacerbate its virulence in cattle, but the mechanistic details of the phenomenon are not fully understood. GPCRs were investigated since these receptors facilitate phagocytosis of particulates by Tetrahymena, and a GPCR apparently modulates bacterial engulfment for the pathogenic protozoan Entamoeba histolytica. A database search identified three putative Tetrahymena GPCRs, based on sequence homologies and predicted transmembrane domains, that were the focus of this study. Salmonella engulfment by Tetrahymena was assessed in the presence of suramin, a non-specific GPCR inhibitor. Salmonella engulfment was also assessed in Tetrahymena in which expression of putative GPCRs was knocked-down using RNAi. A candidate GPCR was then expressed in a heterologous yeast expression system for further characterization. Our results revealed that Tetrahymena were less efficient at engulfing Salmonella in the presence of suramin. Engulfment was reduced concordantly with a reduction in the density of protozoa. RNAi-based studies revealed that knock-down of one the Tetrahymena GPCRs caused diminished engulfment of Salmonella. Tetrahymena lysates activated this receptor in the heterologous expression system. These data demonstrate that the Tetrahymena receptor is a putative GPCR that facilitates bacterial engulfment by Tetrahymena. Activation of the putative GPCR seemed to be related to protozoan cell density, suggesting that its cognate ligand is an intercellular signaling molecule. PMID- 26623316 TI - Occurrence and surgical repair of third degree perineal lacerations in adult female camels (Camelus dromedarius) by one-stage (Goetz) technique. AB - Retrospective analysis of third degree perineal lacerations in 7 female camels (6 17 yrs of age) that were surgically corrected by one stage repair (Goetz technique) is presented. Majority (3/7) of the camels was primiparous and all parturitions had a history of calving assistance. Six (6/7) camels recovered by first intention of healing. Dehiscence of perineal structure occurred in only one camel due to infection and healed by second intention. Subsequent matings resulted in pregnancy in four camels and one camel died due to unrelated causes. We conclude that perineal lacerations can occur in primiparous camels with difficult assisted deliveries and that one stage repair of perineal lacerations in camels improves the perineal conformation and such camels may easily regain normal fertility. PMID- 26623317 TI - Non-invasive assessment of equine muscular function: A case study. AB - Assessment of muscle function after an injury or during recovery is of great importance in the veterinary field. Accelerometry, bioimpedance analysis and mechanomyography/acoustic myography have been used to assess human muscular problems, but have not been applied to the veterinary clinic. We report the clinical use of these techniques in a 12-year-old Danish Warmblood horse presenting with recurring and shifting lameness. Acoustic myography, assessing both the amplitude and frequency of active muscles, was employed to locate the specific area of muscle injury, the right hip, which exhibited minimal fibre recruitment giving rise to considerable weakness. This specific region was assessed by accelerometry which revealed a normal step interval for the injured leg when compared with the contralateral, but a weaker acceleration and strike force. Finally, an assessment of muscle resistance (R) and reactance (Xc) using bioimpedance confirmed a regional loss of muscle mass and a loss of cellular integrity compared with the contralateral limb. PMID- 26623318 TI - Occurrence of Trichinella spp. in wild animals in northwestern Libya. AB - The present study determined the occurrence of Trichinella spp. in captured and some perished wildlife animals which included 70 hedgehogs, 19 red foxes, 13 common jackals and 8 crested porcupines in northwestern Libya. Muscle samples of these animals were examined by trichinoscopy. Trichinella larvae were detected only in 4 (5.7%) of the hedgehogs (Erinaceus algirus) and 2 (10.5%) of the red foxes (Vulpes vulpes). Larvae were found in the muscles of the diaphragm, abdomen, tongue, forelimb, hindlimb and intercostal muscles. Examination of tissue sections revealed the presence of numerous cysts within the muscle fibers containing one or more coiled or elongated larvae. Inflammatory cell infiltration was observed around the cysts especially at their poles. Results indicated the importance of wild animals as reservoirs of Trichinella larvae and their role in the transmission of the disease to other wild and domestic animals as well as humans. PMID- 26623319 TI - First report of blood parasites in fishes from Kashmir and their effect on the haematological profile. AB - Cyprinus carpio communis Linnaeus, Carassius carassius Linnaeus, Schizothorax curvifrons Heckel and Triplophysa marmorata species of fishes were captured from Anchar Lake and river Jhelum of Kashmir Himalaya for hematological and parasitological analysis. During the investigation haemoflagellates from the genus Babesiosoma and Trypanosoma were recorded in the blood smears. Trypanosomes were present in all the species except C. carpio, whereas Babesiosoma were only found in T. marmorata. Haematological analysis revealed a significant (p<0.01) reduction in red blood cell count in the fishes infected with Babesiosoma and Trypanosoma. A significant decrease (p<0.05) was recorded in haemoglobin value and packed cell volume in the infected fishes in comparison to the non-infected fishes. PMID- 26623320 TI - Corprological and haematological parameters of albino mice (Mus musculus) concurrently infected with Heligmosomoides bakeri and Trypanosoma brucei. AB - The effect of concurrent infection with Trypanosoma brucei (T. brucei) and Heligmosomoides bakeri (H. bakeri) was investigated in this study. Thirty adult male albino mice were used for the study. The mice were divided into six groups of five mice each. Group 1 served as uninfected control, Groups 2 and 3 were infected with H. bakeri and T. brucei respectively, Group 4 received both T. brucei and H. bakeri on the same day, Group 5 was experimentally infected with H. bakeri three days after T. brucei infection, while Group 6 was infected with T. brucei three days after H. bakeri infection. Blood and faecal samples were collected and analyzed weekly to determine the faecal egg counts (FEC), packed cell volume (PCV) and level of parasitaemia (LP). Weekly body weights (BW) were also recorded. FEC and parasitaemia increased in all the infected groups during the study, but these were significantly (p<0.05) higher in the multiple-infection (groups 4, 5 and 6) than those with the single infection (groups 2 and 3). The same trend was also observed in the BW and PCV (p<0.05). The level of infection produced by single infection with T. brucei and H. bakeri respectively were similar (p<0.05). All treatment groups were significantly (p<0.05) different from the control group. From the results, it was concluded that concurrent helminth and protozoan parasite infections produced more deleterious effect on the host when compared with single infection with either parasite. However, the pathology produced by concurrent infection was more severe when the host was exposed to the protozoan parasite before the helminth parasite. PMID- 26623321 TI - Rickettsia rickettsii isolation from naturally infected Amblyomma parvum ticks by centrifugation in a 24-well culture plate technique. AB - Rocky Mountain spotted fever is an acute illness caused by Rickettsia rickettsii (R. rickettsii) and is transmitted by the bite of ticks of the genera Dermacentor, Amblyomma and Rhipicephalus. The illness results in a high mortality rate and may be easily confused with other febrile syndromes. In Yucatan State, Mexico, childhood cases with a high mortality have been reported. In this work we report the isolation of a Mexican R. rickettsii strain from a tick egg mass using an alternative method for Rickettsia isolation with 24-well plates. We also identified a potential vector of R. rickettsii in the southeast of Mexico, which is Amblyomma parvum. PMID- 26623322 TI - A comparison of surgical outcomes of perineal urethrostomy plus penile resection and perineal urethrostomy in twelve calves with perineal or prescrotal urethral dilatation. AB - The clinical diagnosis, ultrasonographic findings, surgical management, outcome, and survival rate of perineal or prescrotal urethral dilatation in 12 male calves are described. All calves were crossbred and intact males. The most noticeable clinical presentations were perineal (n= 10) or prescrotal (n= 2) swellings and micturition problems. The main ultrasonographic findings were oval shaped dilatation of the urethra in all animals with dimensions of 40-75 X 30-62 mm. The calves with perineal urethral dilatation were treated by perineal urethrostomy (n= 4) and partial penile transection including the dilated urethra and urethral fistulation (n= 6). Prescrotal urethral dilatations were treated by penile transection proximal to the dilatation site (n= 2). Cystitis and stricture of the urethra were recorded postoperatively for two of the calves that underwent perineal urethrostomy. Nine animals were slaughtered at normal body weight approximately 6-8 months after the surgical treatment. Three animals were slaughtered after approximately three to four months, two of them having gained insufficient body weight. Our study shows that ultrasonography is a useful tool for the diagnosis of urethral dilatation in bovine calves. Our study also shows that the partial penile transection may be a suitable and satisfactory choice of surgical treatment for correcting the urethral dilatation in bovine calves. PMID- 26623323 TI - Effect of irrigation fluid temperature on body temperature during arthroscopic elbow surgery in dogs. AB - This prospective randomised clinical trial evaluated the effect of warmed irrigation fluid on body temperature in anaesthetised dogs undergoing arthroscopic elbow surgery. Nineteen dogs undergoing elbow arthroscopy were included in the study and were randomly allocated to one of two groups. Group RT received irrigation fluid at room temperature (RT) while dogs in group W received warmed (W) irrigation fluid (36 degrees C). A standardised patient management and anaesthetic protocol was used and body temperature was measured at four time points; (T1) pre-anaesthetic examination, (T2) arrival into theatre, (T3) end of surgery and (T4) arrival into recovery. There was no significant difference in body temperature at any time point between the groups. The mean overall decrease in body temperature between pre-anaesthetic examination (T1) and return to the recovery suite (T4) was significant in both groups, with a fall of 1.06+/-0.58 degrees C (p<0.001) in group RT and 1.53+/-0.76 degrees C (p<0.001) group W. There was no significant difference between the groups. At the end of surgery (T3) 4/19 (21.1%) of dogs were hypothermic (<37 degrees C). The addition of warmed irrigation fluids to a temperature management protocol in dogs undergoing elbow arthroscopy during general anaesthesia did not lead to decreased temperature losses. PMID- 26623324 TI - Endocardiosis and congestive heart failure in a captive ostrich (Struthio camelus). AB - A seven-year-old blue-necked male ostrich was found dead after a few days of illness. The animal was living in an open yard of 25 square meters along with three other females. They were given concentrate-rich ration with free access to green leaves and water. Autopsy revealed cardiac enlargement due to left ventricular hypertrophy and right ventricular dilatation. The left aterioventricular valves were irregularly thickened and contracted. The lungs were engorged with blood and the liver had nutmeg appearance. The small intestine showed segmental sub-serosal petechial hemorrhages. Histological examination revealed myxomatous degeneration of the left aterioventricular valves, pulmonary congestion and edema, congestion of periacinar hepatic zone and fatty degeneration of outer zones, renal glomerulosclerosis and arteriosclerosis. The affected parts of the small intestine showed villous atrophy with lacteal distention. The venules in the affected intestinal segment were severely dilated while the arterioles had narrow lumen and irregular wall thickening with hyaline deposition. The current article reports an endocardiosis in ostrich and discusses other vascular disorders. PMID- 26623325 TI - Search for the genome of bovine herpesvirus types 1, 4 and 5 in bovine semen. AB - Bovine herpesvirus type 1 (BoHV-1) causes respiratory and reproductive disorders in cattle. Recently, bovine herpesvirus type 5 (BoHV-5) and bovine herpesvirus type 4 (BoHV-4) have been identified to be associated with genital disease. In this study, the presence of the genome of BoHV-1, BoHV-4 and BoHV-5 in bovine semen of Argentinean and international origin was analyzed by PCR assays. The most important finding of this study is the detection of the genome of BoHV-1 and BoHV-4 in semen of bulls maintained at artificial insemination centers. It is particularly relevant that BoHV-1 DNA was also identified in one sample of international origin suggesting the need for extensive quality control measures on international transport of bovine semen. PMID- 26623326 TI - Ovine paratuberculosis: a confirmed case of Johne's disease in Libya. AB - Paratuberculosis (Johne's disease) was suspected in a herd of approximately 300 sheep after weight loss and scouring had increased in adult animals despite repeated treatment with anthelmintics, antibiotics, multivitamins and minerals. The herd is located near Tarhouna city. Herd history revealed that a total of 60 ewes showed clinical symptoms and deaths during the last two years. The last case that we attended was submitted to the National Center of Animal Health (NCAH) for a detailed laboratory examination. Gross pathological and histological examination of tissue samples revealed results that were highly comparable with Johne's disease. A definitive diagnosis was made only by histopathological identification of Mycobacterium paratuberculosis in the intestines using Ziehl Neelsen stain. This is the first documented case of M. paratuberculosis in sheep in Libya. PMID- 26623327 TI - Chlamydia psittaci genotype B in a pigeon (Columba livia) inhabiting a public place in San Jose, Costa Rica. AB - Human chlamydiosis is a zoonotic disease of avian origin caused by Chlamydia psittaci. The highest infection rates have been detected in parrots (Psittacidae) and pigeons (Columbiformes), the latter most frequently carry the genotypes B and E. These genotypes have been shown to also infect humans. Because pigeons (Columba livia) cohabit with humans in urban areas, C. psittaci present in the dust from dry feces of infected pigeons may be transmitted by inhalation and represent a significant public health problem. Between 2012 and 2013 a total of 120 fecal samples were collected from pigeons at four public places (Plaza de la Cultura, Parque Morazan, Parque Central de Guadalupe, Plaza de las Garantias Sociales) in San Jose, Costa Rica. A nested polymerase chain reaction (PCR) was used to amplify a region of the outer membrane protein A gene of C. psittaci. Only one sample was positive in PCR and the positive sample was further subjected to sequencing and genotyping. Sequencing identified this sample as C. psittaci genotype B. This study is the first report to show the presence of this organism in pigeons of Costa Rica, and shows that the infected pigeons may represent a significant risk for humans who visit public places that are inhabited by pigeons. PMID- 26623328 TI - Effects of vitamin B12 supplementation on the quality of Ovine spermatozoa. AB - The present study was undertaken to investigate the effect of various levels of vitamin B12 in Tris extender on semen quality of Dallagh rams following the cooling and freeze/thawing process. Semen was collected from six healthy and mature rams with an average body weight of 60.0 +/- 5.0 Kg using an electro ejaculator. High quality samples were mixed and diluted in Tris extender supplemented with different concentrations of vitamin B12 (0, 1, 2 and 3 mg/ml). The semen aliquots were cooled and preserved at 5 degrees C and their qualities were evaluated during pre-freezing and then the cooled semen samples were packaged into 0.25 ml straws. Straws were frozen in the vapor of liquid nitrogen, and were then stored at -196oC. Straws were thawed seven days later and the characteristics of spermatozoa were examined. Results of this study showed that the effect of vitamin B12 on characteristics such as viability, motility, progressive motility and normality of spermatozoa were significant in pre and post freezing conditions (P<0.05). In conclusion, for long term storage of semen of Dallagh rams, we recommend using 2 mg/ml of vitamin B12 in semen extender. PMID- 26623329 TI - Histopathological changes in the head kidney induced by cadmium in a neotropical fish Colossoma macropomum. AB - We evaluated the effect of cadmium (Cd) on the structure and function of the head kidney in the freshwater fish Colossoma macropomum (C. macropomum). Juveniles were exposed to 0.1 mg/L CdCl2 for 31 days. Blood samples were examined using hematological tests and head kidney histology was determined by light microscopy. The concentration of Cd in the head and trunk kidneys was measured using an atomic absorption spectrophotometer. Cd produced histopathological changes in the head kidney, the most evident of these being: the thickening of the vein wall, an increase in the number of basophils/mast cells close to blood vessels and a severe depletion of hematopoietic precursors especially the granulopoietic series. In the blood, a decrease in the total leucocytes and hemoglobin concentration was observed. Cd-exposed fish showed higher Cd concentrations in the trunk kidney than the head kidney. In conclusion, exposure to Cd affected precursor hematopoietic cells in C. macropomum. PMID- 26623330 TI - Fibroblastic osteosarcoma in a lion (Panthera leo). AB - This report describes a case of spontaneous fibroblastic osteosarcoma in the humerus of a lion from a private park in Perugia, Italy. The tumor had an irregular, smooth, brown surface and a generally firm, rubbery consistence with gritty to hard areas interspersed. The mass was poorly vascularized with areas of necrosis at the periphery. The cut surface showed a multilobulated mass that had breached the humeral cortex, with periosteal production of reactive bone. The mass invaded the epiphysis, the synovial membrane, the joint capsule and ligaments. A mild hemorrhagic effusion appeared in the joint space. Clinical signs, gross and histopathologic findings are described in this rare case of a malignant bone tumor. PMID- 26623331 TI - Comparison of effects of age and sex on serum protein electrophoretic pattern in one-humped camels (Camelus dromedarius) in Semnan, Iran. AB - The aim of this study was to evaluate the influence of age and sex on the concentration of total serum protein measured by the biuret method and protein fractions determined using cellulose acetate electrophoresis in apparently healthy camels (Camelus dromedarius). Blood samples were collected from 21 camels (12 males and 9 females). The camels were further divided into two groups: 12 young camels at the age of 3 months to 2 years and 9 adult camels at the age of 3 15 years. Cellulose acetate electrophoresis of serum proteins identified five protein fractions in adult camels as young camels, these five protein fractions include albumin, alpha1 and alpha2, beta and gamma-globulins. In adult camels, serum levels (g/l) of total protein, albumin, alpha1-globulins, alpha2-globulins, beta-globulins and gamma-globulins were 80.9+/-3.10, 42.9+/-3.10, 1.3+/-0.22, 2.2+/-0.30, 11.8+/-0.30 and 22.6+/-0.20, respectively. However, in young camels, these levels (g/l) were 66.8+/-2.90, 40.2+/-2.40, 1.0+/-0.14, 2.6+/-0.30, 10.6+/ 0.80 and 12.3+/-1.20, respectively. The albumin/globulin (A/G) ratio was 2.08+/ 0.28 in adult camels and 3.77+/-0.53 in young ones. The mean serum concentrations of total protein and gamma-globulins were significantly (P<0.05) higher and the A/G ratio was significantly lower in adult camels compared to young camels. The mean concentrations of gamma-globulins were significantly higher and the A/G ratio was significantly (P<0.05) lower in females compared to male camels. The results of the present study indicate a significant effect of age and sex on the concentrations of some of the serum protein fractions in dromedary camels. PMID- 26623332 TI - Multilobular tumor of the zygomatic bone in a dog. AB - Multilobular tumor of bone (MTB) (also known as Multilobular Osteochondrosarcoma) is an uncommon bone tumor frequently located on the skull of dogs, rarely on the ribs or pelvis. These neoplasms are slow growing, locally invasive, and have the potential to compress and invade the brain. A 10-year-old mixed breed dog was presented with a history of approximately 4 months of progressive growth of a left zygomatic mass. Radiographic investigation revealed a finely granular or stippled non homogeneous radiopaque mass involving the zygomatic arch. After surgery, grossly the neoplasm consisted of multiple, variably sized, grayish white to yellow nodules separated by collagenous septa of different thickness. Histologically, the tumor was characterized by the presence of multiple lobules containing osteoid and cartilage, separated by a net of fibrous septae. This neoplastic pattern was consistent with a typical multilobular tumor of bone and based on clinical, radiographical, gross and light microscopic findings the definitive diagnosis was made. While reviewing veterinary literature only few cases of MTB were found in dogs. PMID- 26623333 TI - Ectoparasites infestation of free-ranging hedgehog (Etelerix algirus) in north western Libya. AB - The aim of this study was to assess the prevalence of ectoparasites in hedgehogs (Etelerix algirus) in north western region of Libya. Seventy hedgehogs were sampled, and 39 (55.7%) were infested with external parasites. A total of 44 ticks, 491 fleas were collected from the infested hedgehogs and four species of ectoparasites were identified, one mite (Sarcoptes scabiei), one tick (Rhipicephalus appendiculatus) and two fleas (Xenopsylla cheopis and Ctenocephalides canis). For ectoparasites, 10/39 (25.6%) were infested by S. scabiei, 8/39 (20.5%) by Rh. appendiculatus and 11/39 (28.2%) by fleas. The prevalence of mixed infestation with S. scabiei and C. canis was 3(7.7%), Rh. appendiculatus and C. canis was 2 (5.1%) and infestation by two species of fleas was 5 (12.8%). The overall mixed infestation was 10 (25.6%). We concluded that the hedgehogs may play an important role in spreading external parasites and transmission of diseases from one region to another and from wildlife animals to domestic animals and human. PMID- 26623334 TI - Molecular identification of nontuberculous mycobacteria isolated from pyogenic bovine tissues in South Darfur State and Alsabalouga slaughterhouse at Omdurman area, Sudan. AB - This study identified nontuberculous mycobacteria (NTM) recovered from bovine pyogenic affections obtained at necropsy using the molecular target 16S-23S rDNA internal transcribed spacer region. Postmortem inspection of cattle was conducted at South Darfur State abattoirs and Alsabalouga Slaughterhouse at Omdurman area during 2007-2009. Specimens were examined for the presence of acid fast bacteria (AFB) using microscopic and standard culturing techniques. AFB were identified phenotypically and confirmed by 16S-23S rDNA ITS. Fifty nine NTM were recovered and confirmed as acid fast filaments out of 165 positive AFB specimens, of which 52 isolates were identified as bovine farcy causative agents, while 7 cultures were excluded due to drying. 16S-23S rDNA ITS of NTM revealed three different amplicons 500 bp. (32) isolates, 550 bp. (2) isolates and 600 bp. (14) isolates. Four isolates were contaminated. PMID- 26623335 TI - TRIXcell+, a new long-term boar semen extender containing whey protein with higher preservation capacity and litter size. AB - It was the aim of the present study to test whey as protective protein for the sperm cell in the long-term boar semen preservation medium TRIXcell. Analyses of sperm cell motility using computer-assisted semen analysis (CASA) indicated that the whey protein Porex has a similar protective effect as bovine serum albumin (BSA) in maintaining viability of stored boar sperm. Boar sperm diluted in TRIXcell+ maintains commercially acceptable motility (>60%) for 10 days, while swine sperm diluted in the semen preservation medium Beltsville Thawing Solution (BTS) maintains commercially acceptable motility (>60%) for 3-5 days for most boars. To test the on-farm fertility performance of TRIXcell+ compared to BTS, inseminations were started on 35 commercial pig production farms in the summer of 2006. During the period of July 2006 until July 2012 for each farm and each calendar year the mean farrowing rate and litter size for semen diluted in TRIXcell+ and stored for 3-5 days was found higher than that of semen stored for 1-2 days in BTS. Based on data gained from a total of 583.749 sows inseminated through the years 2006-2012, the mean farrowing rate for semen diluted in TRIXcell+ and BTS was 90.4 +/- 4.0 and 87.9 +/- 3.6, respectively, which is not significantly different. Based on the same data, the mean total number of piglets born alive for semen diluted in TRIXcell+ and BTS was 14.2 +/- 0.7 and 13.6 +/- 0.6, respectively, which is significantly different. We conclude that whey protein can effectively be used in the long-term preservation medium TRIXcell resulting in a higher litter size. PMID- 26623338 TI - Retrobulbar chondrosarcoma in a dog. AB - This paper presents a review of a dog, with a retrobulbar chondrosarcoma, which was admitted for surgery for visible changes in his eye during inspection. Orbital neoplasia in dogs may be primary and secondary. Sixty percent of orbital neoplasia in dogs are primary, ninety percent of which are malignant. Retrobulbar neoplasms are rare and in their early stage represent a diagnostic challenge. Chondrosarcoma of the skull is a slow-progressing malignant disease which occurs locally, aggressive with invasion into the surrounding tissues. Dogs with chondrosarcoma of the skull have life expectancy between 210 and 580 days - in our case it was 180 days - after the first alterations on the eye of the dog occurred. PMID- 26623336 TI - Fosfomycin: Uses and potentialities in veterinary medicine. AB - Fosfomycin (FOS) is a natural bactericidal broad-spectrum antibiotic which acts on proliferating bacteria by inhibiting cell wall and early murein/peptidoglycan synthesis. Bactericidal activity is evident against Gram positive and Gram negative bacteria and can also act synergistically with other antibiotics. Bacterial resistance to FOS may be natural or acquired. Other properties of this drug include inhibition of bacterial adhesion to epithelial cells, exopolysaccharide biofilm penetration, immunomodulatory effect, phagocytosis promotion and protection against the nephrotoxicity caused by other drugs. FOS has chemical characteristics not typically observed in organic phosphoric compounds and its molecular weight is almost the lowest of all the antimicrobials. It tends to form salts easily due to its acidic nature (disodium salt, for intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration; calcium and trometamol salt: for oral (PO) administration). FOS has a very low protein binding (<0.5%) which, along with its low molecular weight and water solubility, contributes to its good diffusion into fluids (cerebrospinal fluid, aqueous and vitreous humor, interstitial fluid) and tissues (placenta, bone, muscle, liver, kidney and skin/fat). In all species, important differences in the bioavailability have been found after administration in relation to the various derivatives of FOS salts. Pharmacokinetic profiles have been described in humans, chickens, rabbits, cows, dogs, horses and weaning piglets. The low toxicity and potential efficacy of FOS are the main factors that contribute to its use in humans and animals. Thus, it has been used to treat a broad variety of bacterial infections in humans, such as localized peritonitis, brain abscesses, severe soft tissue infections, cystitis and other conditions. In veterinary medicine, FOS is used to treat infectious diseases of broiler chickens and pigs. In broilers, it is administered for the treatment of E. coli and Salmonella spp. infections. In piglets, the drug is prescribed to treat a wide variety of bacterial infections. FOS penetration is demonstrated in phagocytic, respiratory (HEP-2) and intestinal (IPEC-J2) cells. Although not widely used in animals, the drug has shown good results in human medicine. The potentialities of FOS suggest that this drug is a promising candidate for the treatment of infections in veterinary medicine. For these reasons, the aim of this work is to provide animal health practitioners with information on a drug that is not extensively recognized. PMID- 26623337 TI - Histopathologic and Radiographic evaluation of the electroacupuncture effects on ulna fracture healing in dogs. AB - Acupuncture can affect bone healing by stimulation of sensory nerves and releasing of local and systemic neuropeptides. The purpose of this experimental study was to evaluate the effects of electroacupuncture on ulna fracture healing in dogs. In this study, 12 healthy dogs were randomly divided in to four equal groups, where group 1 was kept as control group and evaluated for 45 days, group 2: treatment group and evaluated for 45 days, group3: control group of 90 days and group 4: treatment group of 90 days. After induction of anesthesia, the ulna was cut with Gigli wire saw in each groups, 10 days after operation, the treatment (acupuncture) group was treated with 10 minutes electroacupuncture stimulations on the acupoints Kid1, Kid3, Kid6 and Kid7, for 10 days. Histopathologic samples of all dogs were harvested from bone osteotomized site in 45 and 90 days after surgery. Indices like, count of inflammatory cells, cartilaginous tissue, fibrotic tissue and deposition of collagen were evaluated on samples and classified with 0, 1, 2, and 3 degrees. Also, radiographic evaluation of the patients was applied using radiographic scoring system on days: 7, 15, 30, 45, 60 and 90 after surgery. This study revealed that, acupuncture had no effect on bone healing (p>0.05). Cause of non-significant difference changes between the control and treatment groups, and lack of complete healing in both groups may be due to lack of ulna bone fixation. Alternatively, selection of other acupoints in acupuncture could have a better healing role. PMID- 26623339 TI - Type 1 Achilles tendon rupture caused by grooming trauma in a young dog. AB - Achilles tendon rupture is uncommon in small animal practice. A 9-month-old, female, mixed breed dog (weighing 2.2kg) was referred to our hospital with a primary complaint of right hind limb lameness. Complete right Achilles tendon rupture was diagnosed by physical examination and radiography. The tendon was surgically repaired the next day by using a three-loop and single near-far-far near suture methods. Complete healing was achieved by 97 days post-surgery. This report describes the surgical technique used for complete Achilles tendon rupture repair in a young dog. PMID- 26623340 TI - Toxic effects of glibenclamide in fetuses of normoglycemic rats: an alternative therapy for gestational diabetes mellitus. AB - Gestational diabetes mellitus (GDM) is defined as glucose intolerance first diagnosed during the second or third trimester of pregnancy. The treatment aims at glycemic control through changes in the patient's diet with or without exercise, but some patients need insulin therapy. An alternative would be to use oral hypoglycemic agents such as glibenclamide (GLIB). The present study aims to analyze the toxic effects of GLIB in fetuses of pregnant rats which received 5 or 20mg/kg doses of GLIB. Glycemic dosage reveals no significant difference between control (deionized water) and treated groups, showing that these concentrations of GLIB were not effective to cause hypoglycemia in rats. The vitality of the fetuses in all groups was 100%. GLIB administration promoted increase in weight and significant changes in measures of external morphological parameters of treated fetuses. Histological analysis revealed that liver lobes, lobules and central lobular veins were well defined for all treatments. However, GLIB animals presented a light brownish precipitate into the center-lobular veins and in the liver parenchyma among the hepatocytes. These results indicated a possible passage of the drug through the blood-placental membrane, without serious changes that impair the development of neither bone tissue, nor the liver of these animals. PMID- 26623341 TI - Affections of the salivary ducts in buffaloes. AB - The aim of the present study was to determine different affections of the salivary ducts in buffaloes with special reference to diagnosis and treatment. The study was carried out on 39 buffaloes suffering from different affections of the salivary ducts. The recorded affections of the salivary ducts in buffaloes include; ectasia of the parotid duct (21 cases), parotid duct fistula (15 cases) and sialocele (3 cases). Each case was subjected to full study including case history, clinical examination, diagnosis, and treatment whenever possible. Exploratory puncture and radiography were used for confirmation of diagnosis. Intraoral marsupialization was performed for treatment of parotid duct ectasia. Salivary fistula was corrected by one of two successful techniques; the first by reconstruction of the parotid duct and the second by ligation of the parotid duct just caudal to the fistula opening. Sialoceles were corrected by removal of the mandibular salivary gland of the affected side. PMID- 26623342 TI - The physicochemical properties and antioxidative potential of raw thigh meat from broilers fed a dietary medicinal herb extract mixture. AB - A 6-wk feeding study was conducted to evaluate the antioxidative potential, indices such as quality of the thigh meat and liver of broiler chickens fed with a dietary medicinal herb extract mixture (HEM, consisting: Iranian green tea, cinnamon, garlic and chicory at a ratio of 25:15:45:15). A total of 320, one-d old Ross (male) broiler chickens were used to investigate the effects of 0.0, 2.5, 5.0 and 7.5 g/kg HEM in the diet, on aforementioned factors. The HEM supplementation did not influence the composition of raw thigh meat except for the total phenols and crude ash (P<0.05). Furthermore, pH, water-holding capacity (WHC) and acceptability of thigh meat were affecting by administration of HEM in diets (P<0.05). Meat flavor increased in the supplemented groups (P<0.05). According to our data, HEM supplementation decreased the amount of thiobarbituric acid reactive substance (TBARS) in various times of storage and improved the liver lipid peroxides and superoxide dismutase (SOD) activities at week 6 (P<0.05), but did not influence the catalase activity. Our results reveal that the addition of 7.5 g/kg or higher HEM in diet could be sufficient to increase the antioxidative activity and 2.5 g/kg for meat taste of broilers in maximum levels. PMID- 26623344 TI - Simultaneous pyometra and viable puppies' gestation in a bitch. AB - Here we describe a case of pyometra coexisting with gestation in a 4.5 year-old miniature short-haired Dachshund. The dog exhibited depression, vaginal discharge, polydipsia and dehydration. Ultrasound examination revealed the presence of low to moderate anechoic fluid collection in the left uterine horn. Blood analysis revealed mild neutrophilia with a left shift. Based on these findings a presumptive diagnosis of pyometra was made and the bitch was treated using amoxicillin-clavulanate with dopaminergic agonist (cabergoline). A second ultrasound scan revealed the presence of two gestational vesicles in the right uterine horn that were successfully carried to term. Unusually, while pyometra persisted in the left uterine horn, two viable puppies were delivered by caesarean section from the right uterine horn. PMID- 26623343 TI - The palmar metric: A novel radiographic assessment of the equine distal phalanx. AB - Digital radiographs are often used to subjectively assess the equine digit. Recently, quantitative and objective radiographic measurements have been reported that give new insight into the form and function of the equine digit. We investigated a radio-dense curvilinear profile along the distal phalanx on lateral radiographs we term the Palmar Curve (PC) that we believe provides a measurement of the concavity of the distal phalanx of the horse. A second quantitative measurement, the Palmar Metric (PM) was defined as the percent area under the PC. We correlated the PM and age from 544 radiographs of the distal phalanx from the left and right front feet of various breed horses of known age, and 278 radiographs of the front feet of Quarter Horses. The PM was negatively correlated with age and decreased at a rate of 0.28 % per year for horses of various breeds and 0.33 % per year for Quarter Horses. Therefore, veterinarians should be aware of age related change in the concave, parietal solar aspect of the distal phalanx in the horse. PMID- 26623345 TI - Effects of xylazine-ketamine anesthesia on plasma levels of cortisol and vital signs during laparotomy in dogs. AB - This study was designed to evaluate effects of xylazine-ketamine anesthesia on plasma levels of cortisol and vital signs during and after laparotomy in dogs. Eight clinically healthy, adult male dogs, weighing 20 kg were used. All dogs were initially sedated by acepromazine. Thirty minutes later, ketamine plus xylazine was used to induce anesthesia. Surgical incision of laparotomy was done. After a 5 min manipulation of the abdominal organs, the incision was sutured. Vital signs including heart rate, respiratory rate and rectal temperature (RT) were recorded at the times of -30: premedication, 0: induction and Surgical incision, 30: End of surgery, 60, 90 and 120 min. Blood was sampled at the above mentioned times and analyzed using a commercial ELISA kit for cortisol. A significant decreasing trend in RT was observed during the studied times. No significant changes were observed in heart rate and respiratory rate (p>0.05), except at the time of 60 respiratory rate significantly decreased when compared to the time of 90 (p=0.026) and 120 (p=0.041). A non-significant but increasing trend in plasma levels of cortisol was observed. PMID- 26623346 TI - Information prescriptions: A tool for veterinary practices. AB - The Internet has become a major source of health information and has the potential to offer many benefits for both human and animal health. In order for impact to be positive, however, it is critical that users be able to access reliable, trustworthy information. Although more pet owners are using the Internet to research animal health information than ever before, there remains limited research surrounding their online activities or the ability to influence owners' online search behaviors. The current study was designed to assess the online behaviors and perceptions of pet owners after receiving either general or topic-specific information prescriptions as part of their veterinary appointment. Results indicate that nearly 60% of clients accessed the suggested websites and nearly all of these clients reported positive feelings about this addition to their veterinary services. These results suggest that offering information prescriptions to clients can facilitate better online searches by clients and positively impact both animal health and client satisfaction. PMID- 26623347 TI - Innocuity and immune response to Brucella melitensis Rev.1 vaccine in camels (Camelus dromedarius). AB - A field trial was conducted in a camel brucellosis-free herd to evaluate antibody response to the Brucella melitensis Rev.1 vaccine in camels and assess shedding of the vaccine strain in milk. Twenty eight camels were divided into four groups according to their age and vaccination route. Groups A (n=3) and B (n=3) consisted of non-pregnant lactating female camels, vaccinated through subcutaneous and conjunctival routes, respectively. Groups C (n=10) consisted of 8-11 months old calves vaccinated through conjunctival route. The rest of the herd (n=12) composed of female and young camels were not vaccinated and were considered as the control group. Each animal from groups A, B and C was given the recommended dose of 2 * 10(9) colony forming units of Rev.1 vaccine irrespective of age or route of vaccination. Blood samples were collected from all the animals at the time of vaccination and at weekly, bi-weekly and monthly interval until 32 weeks post vaccination and from controls at weeks 8 and 24. The serological tests used were modified Rose Bengal Test, sero-agglutination test, and an indirect Enzyme Linked Immunosorbent Assay. Milk samples were collected from all vaccinated female camels and tested for the presence of Rev.1 vaccine strain. Most vaccinated animals started to show an antibody response at week 2 and remained positive until week 16. By week 20 post-vaccination all animals in the three groups were tested negative for Brucella antibodies. Bacteriological analysis of milk samples did not allow any isolation of Brucella melitensis. All samples were found Brucella negative in PCR analysis. The results of this study indicate that the Rev.1 vaccine induces seroconversion in camels. Rev.1 vaccine strain is not excreted in the milk of camels. These findings are promising as to the safe use of the Rev.1 vaccine in camels. PMID- 26623348 TI - Reproductive health status of north western Himalayan Gaddi sheep: An abattoir study. AB - The study was aimed to provide basic information regarding reproductive status of Gaddi sheep reared by nomadic tribe of Himachal Pradesh. Female genitalia of Gaddi sheep (n=190) were collected from unorganized abattoirs around Palampur over a period of one and half years. Out of total genitalia examined, 80.53% were grossly normal and 19.47% had one or more genital abnormalities. Genital abnormalities were categorized as ovarian (5.26%), uterine (10.53%) and miscellaneous (3.68%). Amongst ovarian abnormalities are follicular cysts (3.16%) and ovaro-bursal adhesions (2.10%), which were recorded in Gaddi ewes. Uterine abnormalities include hydrometra (4.74%), pyometra (2.63%), mucometra (2.10%), endometritis (0.53%) and mummification (0.53%). Miscellaneous abnormalities include parovarian cysts (2.10%), parasitic cysts (1.05%) and nodules on both uterine horns (0.53%). Among the genital abnormalities in sheep, highest incidence (24.32%) was observed with hydrometra and lowest (2.7%) with each of endometritis, mummification and nodular growth on both uterine horns. Thus the uterus (54.07%) was most commonly affected, followed by the ovary (27.02%) and miscellaneous (18.91%) in ewes. In present study, 8.95% pregnant sheep were also slaughtered, with fetal age in majority of cases two months or less on the basis of CRL measurement which represents a huge economic loss. PMID- 26623349 TI - Serosurveillance of infectious agents in equines of the Central Valley of Costa Rica. AB - Blood samples from 181 equines from the Central Valley of Costa Rica were collected in the year 2012 to determine the presence of antibodies against selected infectious agents in horses and to determine the risk factors associated with these agents. The presence of antibodies against Equine Infectious Anemia Virus (EIAV), Equine Herpes Virus 1 and 4 (EHV-1 and EHV-4), West Nile Virus (WNV), Influenza A Virus (IAV), Equine Viral Arteritis Virus (EVAV), Babesia caballi, Theileria equi, Neospora caninum and Chlamydia abortus was determined using commercial assays, and risk factors associated with seropositivity to the different infectious agents was established. The most seroprevalent agent detected was EHV-4 (96.7%), followed by WNV (44.2%), and IAV (41.8%). Horses >3 years, used for work or sports, and with access to pastures, had significantly increased probability to be seropositive to WNV, whereas horses used for breeding and recreational purposes, being stabled, and without access to pastures, had significantly greater probability to be seropositive to IAV. Seroprevalence to B. caballi (19.9%) was lower than to T. equi (38.1%). For B. caballi, access to pastures was determined as a risk factor, whereas being older than 3 years was established as a risk factor for T. equi. Low seroprevalences were determined for EHV-1 (5.0%), EVAV (5.0%), C. abortus (4.8%), and N. caninum (4.4%). Mares having history of abortion were more likely to be seropositive to EHV-1, whereas horses >3 years, used for work and sports, and mares having multiple parturitions, were more likely to be seropositive to N. caninum. None of the horses were seropositive to EIAV. Earlier, only diseases caused by EIAV, WNV and piroplasmosis were reported in Costa Rica. The present study however, determined the presence of carriers for EHV-1, EHV-4, and EIAV. PMID- 26623350 TI - Arthroscopy of septic carpitis in donkeys (Equus asinus). AB - Experimental septic arthritis was induced in the radiocarpal joint of 18 donkeys by intra-articular injection of Staphylococcus aureus (3-4X10(6) CFU). The inoculated animals were divided into three groups (6 donkeys in each group). The arthroscopic examination was carried out before induction of septic carpitis and 3 days (group I), 14 days (group II), and 28 days (group III) after induction of infection. The arthroscopic examination of group I revealed hyperemia of synovial membrane and hypertrophied villi. In group II, severe hyperemia of synovial membrane, hypertrophied villi, pannus in the joint cavity and beginning of articular cartilage erosion were found. In group III, severe hyperemia of synovial membrane, hypertrophied villi and more prominent articular cartilage erosion were present. PMID- 26623352 TI - A detailed systematic anatomical study of monocephalic conjoined symmetric twin lambs. AB - A case of conjoined twins with monocephalus, thoracopagus, partial abdominopagus, tetrabrachius and tetrascelus in lambs complicated with several defects of skeletal, cardiovascular, gastrointestinal, and urogenital systems is reported. The twins were dead and delivered by cesarean section. This case report highlights the detailed anatomical study of defects in different systems due to an abnormal birth defect. PMID- 26623351 TI - Liver abscesses in dromedary camels: Pathological characteristics and aerobic bacterial aetiology. AB - The study was carried out at Nyala abattoirs, South Darfur State, Sudan during a period from 2009 to 2011. Slaughtered camels (822) were examined for pathological changes of liver abscesses and identification of the involved aerobic bacteria. Grossly, a total of 111 (13.5%) liver abscesses were recorded in different camel ages; 90 (81.1%) were less than seven years old and 21 (18.9%) were more than seven years old. Histopathology of sectioned tissues revealed necrotic abscesses with infiltration of inflammatory cells, hydropic degeneration with swelling of hepatocytes comprising the sinusoid and different size of vacuoles in the hepatic cells. Proliferation of bile ducts with fibrous tissue and infiltration of inflammatory cells was also recorded. Investigation of bacteria revealed 90 aerobic isolates; they were identified to 52 (57.8%) gram positive cocci, 20 (22.2%) gram positive rods and 18 (20.0%) gram negative rods. Staphylococcus spp. (41.1%), Corynebacterium spp. (17.9%) and Streptococcus spp. (13.3%) were the most frequently identified bacteria involved in liver abscesses of camels in the region. Further studies are required to assess the pathogenicity of bacterial isolates from camel livers. This is particularly important from a public health perspective, since some people of Sudan are known to consume raw camel liver. PMID- 26623353 TI - Evaluation of bovine (Bos indicus) ovarian potential for in vitro embryo production in the Adamawa plateau (Cameroon). AB - An abattoir study was conducted to evaluate the ovarian potential of 201 local zebu cattle from Ngaoundere, Adamawa region (Cameroon) for in vitro embryo production (IVEP). The ovaries were excised, submerged in normal saline solution (0.9%) and transported to the laboratory for a detailed evaluation. Follicles on each ovary were counted, their diameters (Phi) measured and were grouped into 3 categories: small (Phi < 3 mm), medium (3 >= Phi <= 8 mm) and large (Phi > 8 mm). Each ovary was then sliced into a petri dish; the oocytes were recovered in Dulbecco's phosphate buffered saline, examined under a stereoscope (x10) and graded into four groups based on the morphology of cumulus oophorus cells and cytoplasmic changes of the oocytes. Grade I (GI): oocytes with more than 4 layers of bunch of compact cumulus cells mass with evenly granulated cytoplasm; grade II (GII): oocyte with at least 2-4 layers of compact cumulus cell mass with evenly granulated cytoplasm; grade III (GIII): oocyte with at least one layer of compact cumulus cell mass with evenly granulated cytoplasm; grade IV (GIV): denuded oocyte with no cumulus cells or incomplete layer of cumulus cell or expanded cells and having dark or unevenly granulated cytoplasm. The effects of both ovarian (ovarian localization, corpus luteum, size and weight of ovary) and non ovarian factors (breed, age, body condition score (BCS) and pregnancy status of cow) on the follicular population and oocyte recovery rate were determined. There were an average of 16.75+/-0.83 follicles per ovary. The small, medium and large follicles were 8.39+/-0.60, 8.14+/-0.43 and 0.21+/-0.02 respectively. Oocyte recovery was 10.97+/-0.43 per ovary (65%). Oocytes graded I, II, III and IV were 3.53+/-0.19 (32.21%), 2.72+/-0.15 (24.82%), 2.24+/-0.15 (20.43%) and 2.47+/-0.20 (22.54%) respectively. The oocyte quality index was 2.26. Younger non pregnant cows having BCS of 3 and large ovaries presented higher number of follicles and oocyte quality (P < 0.05) compared with other animals. Oocytes with quality (grade I and II) acceptable for IVEP constituted 57.15% of the harvest. This study indicated that factors such as age, pregnancy status, BCS and ovarian size must be taken into account to increase the potential of the ovary for IVEP. PMID- 26623354 TI - Histopathological alterations in spleen of freshwater fish Cyprinus carpio exposed to sublethal concentration of sodium cyanide. AB - Aquatic ecosystems in areas with intense mining activity are often subject to cyanide contamination; the present study was aimed to evaluate the harmful effects of sodium cyanide on histoarchitechtural aspect of spleen of freshwater fish Cyprinus carpio using an in vivo approach. The fishes were exposed to a sublethal concentration of 0.2 mg/L of sodium cyanide for duration of 10 and 20 days and were further allowed to undergo recovery for 14 days in a toxicant free medium. From the present investigation findings like occurrence of haemosiderin pigment, melanomacrophage centers, vacuolation and necrotic eosinophils were evident in all the fishes exposed to sodium cyanide. However, changes were more pronounced in fish subjected to 10 days of exposure, which was followed by 20 days of exposure and 14 days of recovery. The study revealed that there seemed to be the presence of homeostatic mechanism in fish that allows them to stabilize and overcome stress, which in present case is caused by sublethal concentration of sodium cyanide. Since the recovery phenomenon may be adaptive and even strategic, the present investigation also throws a light on adaptive behaviour of fish under stressful environments. PMID- 26623355 TI - Review on mechanisms of dairy summer infertility and implications for hormonal intervention. AB - In dairy cows and buffaloes, summer heat stress (HS) reduces milk yield and delays return to pregnancy leading to financial loss. Clues for effective interventions against summer infertility (SI) lie in understanding the underlying mechanisms. This article reviews current knowledge on the mechanisms of bovine SI and their implication for hormonal management. Under HS dairy animals encounter anestrous, silent cycles and repeat breeding which extend their open period. These effects are attributed mainly to HS induced disturbances in luteinizing hormone (LH) secretion, follicular dominance and estrogen secretion, ovulation and oocyte competence, luteal development and progesterone secretion, utero placental function and embryo-fetal development. Hormonal timed artificial insemination protocols and LH support around estrous improved summer pregnancy rates by avoiding need for estrus detection, assisting follicular development and ovulation, enhancing quality oocytes and stimulating luteal function. Progesterone supplementation to enhance embryonic development did not produce significant improvement in summer pregnancy rates. There is need for evaluating integrated approaches combining hormones, metabolic modifier and cyto-protective agents. PMID- 26623356 TI - Comparison of several methods of sires evaluation for total milk yield in a herd of Holstein cows in Yemen. AB - A total of 956 lactation records of Holstein cows kept at Kaa Albon station, Imuran Governorate, Yemen during the period from 1991 to 2003 were used to investigate the effect of some genetic and non-genetic factors (Sire, parity, season of calving, year of calving and age at first calving as covariate) on the Total Milk Yield (TMY), Lactation Length (LL), and Dry Period (DP). Components of variance for the random effects (mixed model) were estimated by Restricted Maximum Likelihood (REML) methodology. Sires were evaluated for the TMY by three methods, Best Linear Unbiased Prediction (BLUP) using Harvey program, Transmitting Ability (TA) according to the Least Square Means of sire progeny (TALSM) and according to Means (TAM). Results showed that TMY and DP were affected significantly (P < 0.01) by all factors except season of calving and age at first calving, while LL was affected significantly (P< 0.01) only by year of calving and parity. The averages of the TMY, LL, and DP were 3919.66 kg, 298.28 days, and 114.13 days respectively. The corresponding estimates of heritability (h(2)) were 0.35, 0.06, and 0.14 respectively. The highest and lowest BLUP values of sires for the TMY were - 542.44 kg and 402.14 kg, while the corresponding estimates for TALSM and TAM were - 470.38, 380.88 kg and - 370.12, 388.50 kg respectively. The Spearman rank correlation coefficients among BLUP, TALSM and TAM ranged from 0.81 to 0.67. These results provide evidence that the selection of sires will improve the TMY in this herd because of the wide differences in genetic poetical among sires, and a moderate estimation of heritability. PMID- 26623357 TI - Uterine involution and progesterone level during the postpartum period in Barbary ewes in north Libya. AB - The objectives of the present study were to determine the time of uterine involution and ovarian activity using ultrasound examination and progesterone assay. Weekly progesterone levels were measured starting one week postpartum until two weeks after the 1(st) postpartum estrus in Barbary ewes lambed during winter in AL-Bayda city, north of Libya. A total of 15 Barbary ewes were used in the present study distributed in three groups according to the month of lambing as group 1 (lambed in January), group 2 (lambed in February) and group 3 (lambed in March). Ewes were examined weekly by trans-rectal ultrasound to check involution of the uterus starting one week after lambing until complete uterine involution. Blood samples were collected from the jugular vein, and serum was separated and stored at -20 degrees C until measuring progesterone using ELISA. Results showed that uterine involution completed at day 35 postpartum in groups 1 and 2, while it occurred at day 28 in group 3. The mean progesterone level was basal (less than 1 ng/ml) for a long period and started to increase at days 119, 99 and 77 postpartum in group 1, 2 and 3, respectively. One ewe did not show estrus at all during the period of study in group 2 and there were no growing follicles on their ovaries. The obtained results indicate that, uterine involution as determined by ultrasound completed earlier in ewes lambed in March than those lambed in February or January. Also, progesterone level and ultrasound examination showed that there was no ovarian activity for a longtime after parturition indicating that reproduction in Barbary ewes tends to be seasonal in AL-Bayda city, north Libya. PMID- 26623358 TI - Contribution to reconstruction of third degree rectovestibular lacerations in mares. AB - The study was conducted on ten mares suffering from third degree rectovestibular laceration. Four uterine washes were performed in all cases by using diluted betadine (mixing 5ml of betadine antiseptic solution in 1 liter of sterile saline) to control vaginal and uterine infections before surgery. Surgical repair of third degree rectovestibular laceration was done by one-stage Goetz technique after four to six weeks of initial injury, with the lateral dissection continued extensively until the two flaps were created and brought to the midline without any tension. Primary healing occurred in all cases without significant complications. The obtained results indicate that mares with third degree rectovestibular lacerations are candidates for uterine wash and one-stage Goetz technique with excessive lateral continuation of the flap. PMID- 26623359 TI - Expression of Bcl-2 in canine osteosarcoma. AB - Osteosarcoma (OS) is the most common primary malignancy of bone. It is responsible for 80-85% of the primary bone tumors affecting dogs and it is characterized by aggressive and invasive behavior, with a high metastatic potential. Several studies on cancer and related tumorigenesis, show an involvement of the mechanisms of programmed cell death and cell survival. Many signals seem to be involved in the related mechanism of autophagy and in particular, our interest is focused on the expression of a family of Bcl-2 that seems to be involved either in the control of biomolecular mechanisms like autophagy and apoptosis. In this study we investigated the expression of Bcl-2 in different cases of spontaneous canine osteosarcoma and the related preliminary results are described. We found Bcl-2 activity was increased in OS tissue compared to normal bone tissue. These results suggested that Bcl-2 activity may play an important role in the formation of OS and as a diagnostic for neoplastic activity. However, further research is needed to confirm the role of Bcl-2 activity in OS in canines. PMID- 26623360 TI - Clinical management of dietary induced urolithiasis associated with balanoposthitis in a Boer goat. AB - A Boer-Kajang cross male goat was presented to the Veterinary Hospital, University Malaysia Kelantan with a history of dysuria, hematuria and restlessness. The goat was intensively managed (confined to the pen) and fed with only palm kernel cake for the last three months. Physical examination revealed that the goat was dull, depressed, having an inflamed penis and prepuce with blood stained urine dripping from the penis. The differential diagnoses were obstructive urolithiasis, urinary tract infection and balanoposthitis. Based on the history, clinical signs, physical examination, urinalysis, ultrasonagraphy and feed analysis, the goat was diagnosed with obstructive urolithiasis and balanoposthitis. Treatment was instituted by amputation of the urethral process and retrograde urohydropulsion to relieve the blockade. Sulfadiazine-trimethoprim (Norodine((r))24) 15mg/kg, I.M; flunixin meglumine 2.2mg/kg, I.M; vitamin B complex 1ml/10kg, I.M and ammonium chloride 300mg/kg orally were administered. The goat responded well to treatment and was recovering well during a follow up visit. PMID- 26623361 TI - Foreign body-induced changes in the reticular contraction pattern of sheep observed with M-mode ultrasonography. AB - In the pre-experimental period of a clinical trial, an apparently clinically healthy sheep fitted with ruminal and abomasal cannulas showed changes in the reticular contraction pattern visualized in M-mode ultrasonogram. Radiographic examination revealed a blunt metal screw in its reticulum. By the time change in the reticular motility through the ultrasound examination was detected, the animal had still not expressed any behavioral changes. A description of the clinical case, follow-up of the findings and laboratory data, like white blood cell count, serum pepsinogen and fibrinogen concentrations, were presented. The foreign body was removed through the ruminal cannula and reticular contraction tended to normal. An association of the contraction pattern with measured clinical data was possible, leading to the conclusion that use of M-mode ultrasonography has a potential application in similar clinical situations. PMID- 26623362 TI - Experimental treatment of recurrent otitis externa. AB - The aim of this research is to determine the effect of the hybrid material based on polyvinyl alcohol and silver nanoparticles (PVA/AgNps) in the treatment of the otitis externa as an additional component in the commercial product "Betazon Trio". It was established that the experimental creamy formula with silver concentration 600 mg/L is suitable for recovery of the microbial homeostasis when it is administrated once daily in dose 1 ml over a period of 14 days. PMID- 26623363 TI - Extraocular myositis in a female puppy. AB - Extraocular myositis (EOM) is not commonly encountered in dogs. It is generally diagnosed based on clinical features of exophthalmos without third eyelid protrusion, pain or vision loss. The traditional treatment of choice is prednisolone. This report describes a case of a mixed-breed puppy with clinical signs consistent with EOM, the use of ascorbic acid as an adjuvant to traditional corticosteroid therapy and rapid resolution of the condition without recurrence. It also shows that prolapse of the third eyelid and ptosis of the lower eyelids are possible signs of EOM during recovery. This is the first report of this sort from Africa and therefore the report is of epidemiological significance. PMID- 26623364 TI - Comparative studies between four chemicals for long-term preservation of Trichinella spiralis larvae's. AB - A comparative evaluation of four conservation chemicals (96% ethanol, 1% sodium benzoate, 10% formalin and glycerol), used to preserve Trichinella spiralis larvae's over 120 days, was performed. The results obtained after conservation with 96% ethanol, 1% sodium benzoate and glycerol showed no statistically significant differences in both the shape and the diameter in coiled Trichinella spiralis larvae's over the tested period. Additional advantage of glycerol as conservation liquid toward formalin is a lack of toxicity. PMID- 26623365 TI - Metastatic anal sac carcinoma with hypercalcaemia and associated hypertrophic osteopathy in a dog. AB - A seven-year-old male neutered Irish setter was treated for a metastatic anal sac adenocarcinoma (ASAC) and hypercalcaemia by complete surgical excision of the primary tumour and partial excision of the sublumbar lymph nodes. Further enlargement of the sublumbar lymph nodes was linked to recurrent hypercalcaemia 3 months after surgical treatment. Medical treatment with Toceranib and Clodronate showed modest results in the treatment of the tumour and the hypercalcaemia. Radiotherapy of the sublumbar lymph nodes and later concurrent carboplatin chemotherapy resulted in partial tumour remission with marked reduction in size of the lymph nodes and normalization of the calcaemia. Unfortunately, concurrently with subsequent relapse of the hypercalaemia, the dog developed hypertrophic osteopathy (HO) and lumbar spinal metastasis and the dog was euthanized. To the authors' knowledge, this is the second case of metastatic apocrine gland carcinoma of the anal sac associated with HO and the first case that describe the development of HO late in the stage of the disease. PMID- 26623366 TI - Haemangiosarcoma in a captive Asiatic lion (Panthera leo persica). AB - A 2.7-year-old male captive Asiatic lion (Panthera leo persica) died unexpectedly without preceding symptoms. Gross necropsy revealed liver and lung tumours, which proved to be haemangiosarcomas by histopathology. Some of the liver tumours were ruptured, leading to massive intra-abdominal haemorrhage and death. Haemangiosarcomas are rare in domestic and exotic felids, occurring in skin, thoracic-abdominal cavity and bones. Although these tumours mainly appear to be occurring in older cats, they are sometimes observed in younger animals, as in the present case. This is the first description of haemangiosarcoma in a young Asiatic lion. PMID- 26623367 TI - Medicinal management of corneal opacity in free ranging rhesus macaques (Macaca mulatta) of Shivalik hills in Western Himalayas, Northern India. AB - Corneal opacification was diagnosed in 17 free ranging rhesus macaques during detailed ophthalmic examination as a part of clinical health examination, at the monkey rescue sterilization centre in Hamirpur Himachal Pradesh, India. The cornea was completely opaque permitting only a little vision with respect to the affected eye. Medical management with topical ciprofloxacin and prednisolone along with ketoprofen and vitamin A was instituted. The corneal lesions subsided completely within one week following treatment. The treatment protocol successfully eliminated the discomfort and intraocular lesions with no serious subsequent irritation due to the treatment in these animals. PMID- 26623368 TI - Microscopic analysis of MTT stained boar sperm cells. AB - The ability of sperm cells to develop colored formazan by reduction of MTT was used earlier to develop a spectrophotometric assay to determine the viability of sperm cells for several mammalian species. It was the objective of the present study to visualize microscopically the location of the formazan in boar sperm cells. The MTT staining process of boar sperm cells can be divided into a series of morphological events. Incubation of the sperm cells in the presence of MTT resulted after a few min in a diffuse staining of the midpiece of the sperm cells. Upon further incubation the staining of the midpiece became more intense, and gradually the formation of packed formazan granules became more visible. At the same time, a small formazan stained granule appeared medially on the sperm head, which increased in size during further incubation. After incubation for about 1 h the midpiece granules were intensely stained and more clearly distinct as granules, while aggregation of sperm cells occurred. Around 90% of the sperm cells showed these staining events. At the end of the staining the formazan granules have disappeared from both the sperm cells and medium, whereas formazan crystals appeared as thin crystal threads, that became heavily aggregated in the incubation medium. It was concluded that formazan is taken up by lipid droplets in the cytoplasm. Further, the use of the MTT assay to test for sperm viability should be regarded as a qualitative assay, whereas its practical use at artificial insemination (AI) Stations is limited. PMID- 26623369 TI - Assessment of reproductive and growth performances of pig breeds in the peri urban area of Douala (Equatorial Zone). AB - The aim of this study was to evaluate the reproductive and growth performances of pig breeds in Douala, Cameroon. The reproductive performance of gilts and multiparous sows (38 per group) from 8 selected farms were monitored and controlled. Thereafter, piglets were controlled from birth to weaning age. The age at first service (AFS), fertility index (FI), fecundity, age at first farrowing (AFF), weight at first farrowing (WtFF) and litter size (LS) of gilts were 179.97 +/- 25.40 days; 1.76 +/- 0.77; 100 +/- 0.00; 350.47 +/- 40.58 days; 107.26 +/- 31.85 kg and 7.18 +/- 1.93 piglets, respectively. In sows, the FI, fecundity, LS and farrowing interval (FarI) were 1.13 +/- 0.34; 100 +/- 0.00; 9.03 +/- 2.14 piglets and 179.63 +/- 25.14 days, respectively. FI and LS were better in sows compared to gilts (P = 0.000). The sex ratio was 0.63. Local breed animals reared in semi-modern farms and fed mixed feed showed the lowest WtFF. In piglets, the average birth weight (kg), the average weaning weight (kg), age at weaning (days) and survival rate (%) until weaning were 1.32 +/- 0.20, 10.60 +/- 1.41, 56.86 +/- 8.24 and 48.43, respectively. These results indicated that reproductive performance is strongly influenced by breed, feed and farm type. PMID- 26623371 TI - Historical analysis of Newfoundland dog fur colour genetics. AB - This article makes use of digitized historic newspapers to analyze Newfoundland dog fur colour genetics, and fur colour variations over time. The results indicate that contrary to the accepted view, the 'Solid' gene was introduced into the British population of Newfoundland dogs in the 1840s. Prior to that time, the dogs were white and black (Landseer) or white and brown, and thus spotted/spotted homozygotes. Due to 'Solid' being dominant over 'spotted', and selective breeding, today the majority of Newfoundland dogs are solid black. Whereas small white marks on the chest and/or paw appears to be a random event, the historical data supports the existence of an 'Irish spotted' fur colour pattern, with white head blaze, breast, paws and tail tip, in spotted/spotted homozygotes. PMID- 26623370 TI - Perceptions of veterinary admissions committee members of undergraduate credits earned from community colleges or online compared to traditional 4-year institutions. AB - Veterinary admission committees are asked to create and implement a fair, reliable, and valid system to select the candidates most likely to succeed in veterinary school from a large pool of applicants. Although numerous studies have explored grade point average (GPA) as a predictive value of later academic success, there has been little attention paid to how and where an applicant acquires his/her undergraduate coursework. Quality of academic program is an important component of applicant files, and it is suggested that the source of a candidate's coursework might influence admissions committee decisions, perhaps even outside of the committee's immediate awareness. Options for undergraduate education include taking classes at a traditional four-year institution, a community college, or online. This study provides an overview of the current state of online courses and community colleges in the US as a foundation to explore the views of veterinary admissions committee members pertaining to coursework completed at traditional residential 4-year schools or at community colleges and whether they are delivered on campus or online (at either type of institution). Survey participants reported a pattern of preference for traditional four-year residential coursework compared to online or community college courses. These results are interesting given the exponential growth of students taking online courses and data showing community colleges are providing a successful gateway to obtaining a four-year degree. This also points to the need for admission committees to discuss potential biases since the information about type of school and/or course may not be consistently available for all applicants. Finally, at a time when admitting a diverse class of students is a goal of many programs, it is of special concern that there are potential biases against courses taken online or from community colleges - venues that tend to draw a more diverse population than traditional 4-year universities. PMID- 26623372 TI - Early detection of Haemonchus contortus infection in sheep using three different faecal occult blood tests. AB - Haemonchus contortus is a blood-sucking parasite causing the presence of faecal occult blood (FOB). The objective was to study three different FOB tests in order to have a new indicator of H. contortus infection in sheep that could be included in the genetic evaluation system as an alternative selection criterion to faecal worm egg count (FEC). A total of 29 Corriedale lambs were experimentally infected with 10.000 larvae of H. contortus. Stool samples were recorded for FEC and FOB tests (Hexagon, Hematest((r)) and Multistix((r))), blood for packed cell volume (PCV), haemoglobin, white and red blood cell count (RBC), and FAMACHA((c)) for scoring anaemia. At the end of the experiment lambs were slaughtered to worm burden count. Field infection was achieved in 309 Merino lambs under natural parasite challenge. FEC data were normalized through logarithmic transformation (LnFEC). Pearson correlation was estimated to examine the relationship between all traits. The three tests were able to detect the presence of FOB at day 11. FEC, PCV and RBC decreased to sub-normal values from day 18. FAMACHA((c)) score 3 was considered to be indicative of anaemia. Most of the correlations were of high magnitude, with the exception of Multistix((r)) test that was moderately correlated with haematological parameters, LnFEC and FEC. In field infection, most samples were negative to FOB tests and the correlations were lower than those calculated under experimental infection. In conclusion, FOB tests were able to detect haemonchosis earlier than FEC under high experimental parasite challenge. However, they were not able to detect FOB under natural mixed parasite challenge. FAMACHA((c)) and PCV demonstrated to be good indicators of Haemonchosis, having moderate to high correlations with FEC. PMID- 26623373 TI - Growth performance and certain body measurements of ostrich chicks as affected by dietary protein levels during 2-9 weeks of age. AB - The present work was conducted to examine the effects of dietary crude protein (CP) levels (18, 21 and 24%) on growth performance (Initial and final body weight, daily body weight gain, feed consumption, feed conversion and protein efficiency ratio) during 2-9 weeks of age and certain body measurements (body height, tibiotarsus length and tibiotarsus girth) at 9 weeks of age. A total of 30 African Black unsexed ostrich chicks were used in the present study in simple randomized design. The results of the present work indicated that initial and final live body weight, body weight gain, feed consumption, feed conversion of ostrich chicks were insignificantly affected by dietary protein level used. Protein efficiency ratio was high in the group of chicks fed diet contained 18% CP. Results obtained indicated that tibiotarsus girth was decreased (P<=0.01) with the increasing dietary protein level, where the highest value of tibiotarsus girth (18.38 cm) was observed in chicks fed 18% dietary protein level. Body height and tibiotarsus length were not significantly different. In conclusion, the results of the present study indicate that ostrich chicks (during 2-9 weeks of age) could grow on diets contain lower levels of CP (18%). PMID- 26623374 TI - Haemato-biochemical and endocrine profiling of north western Himalayan Gaddi sheep during various physiological/reproductive phases. AB - The study was aimed to provide baseline data regarding haemato-biochemical and endocrine profiling of Gaddi sheep found in north western Himalayan region of Himachal Pradesh, India. Each random sample was collected from 45 Gaddi sheep reared in government sheep breeding farm Tal, Hamirpur, India, during various reproductive phases viz. anestrus, breeding season and post partum period. Haematology revealed significantly higher (P<0.05) RBC as well as haematocrit values in pregnant animals (n=23) during breeding season than during other reproductive phases. The number of platelets were significantly lower (P<0.05) and MCH, MCHC values were statistically higher (P<0.05) during postpartum period than during other reproductive phases. Blood biochemistry revealed significantly higher (P<0.05) concentrations of plasma cholesterol (83.98+/-3.68 mg/dl), plasma calcium (71.06+/-1.52 mg/l), magnesium (18.21+/-0.53 mg/l), potassium (5.10+/ 0.13 mEq/l) and significantly lower (P<0.05) concentrations of plasma total protein (5.75+/-0.31 gm/dl), globulin (3.04+/-0.29 gm/dl) and sodium (138.83+/ 1.83 mEq/l) during postpartum period in comparison to other reproductive phases. Endocrine profile revealed significantly higher (P<0.05) serum estrogen (60.97+/ 1.24 pg/ml) and T4 (6.0+/-0.27 ug/ml) concentrations during postpartum phase. Similarly, significantly higher (P<0.05) serum progesterone (5.16+/-0.76 ng/ml) as well as TSH (0.70+/-0.14 ug/ml) concentration were recorded during pregnancy. From the study it can be concluded that physiological status significantly affects the blood metabolic and endocrine profile in Gaddi sheep. PMID- 26623375 TI - Double filtration plasmapheresis in a dog with multiple myeloma and hyperviscosity syndrome. AB - A 12 year old, 38 kg, mix-breed, intact male dog presented with a 20 day history of clinical signs consistent with hyperviscosity syndrome secondary to multiple myeloma. The dog received three double filtration plasmapheresis treatments on day 0, 7 and 22 after presentation. A significant (p<0.05) reduction in serum total protein, alpha-2 and gamma globulins was found following each treatment. These reductions were accompanied by a complete resolution, although temporary, of the clinical signs of hyperviscosity syndrome. The present study reported for the first time the use of double filtration plasmapheresis to reduce clinical signs of hyperviscosity syndrome in a dog with multiple myeloma. PMID- 26623376 TI - Intravenous lipid emulsion and dexmedetomidine for treatment of feline permethrin intoxication: a report from 4 cases. AB - Four cases of feline permethrin intoxication are described. The cause of intoxication is the application of canine permethrin spot-on product (Advantix(r), Bayer) by the owners. Principal clinical guidelines recommends the use of anticonvulsant drugs to treat seizures or neurological symptoms after initial stabilization and dermal decontamination. The use of lipid emulsion had an increasing interest in the last decade for treatment of toxicosis caused by lipophylic drugs as reported in human and in veterinary medical practices. All cats presented in this study, were treated with intravenous lipid emulsion (ILE) at variable dosages, and dexmedetomidine was also administered by intravenous way. No adverse reaction such as thrombophlebitis, overload circulation or others was noticed during and after administration of ILE. Dexmedetomidine was proved to be helpful in tranquillizing the cats. All cats were discharged in good condition faster than other cases treated without their use. PMID- 26623377 TI - Detection of antibodies against Chlamydophila abortus in Costa Rican sheep flocks. AB - A total of 359 sheep samples from 15 flocks were analyzed for the presence of antibodies against Chlamydophila abortus using a commercial Enzyme linked Immunosorbent Assay (ELISA). Antibodies were detected in 19 (5.29%) sheep from 12 (80%) flocks. Seropositive animals were found in all analyzed regions (Central, Chorotega, Atlantic Huetar, North Huetar and Central Pacific) determining prevalence between 0.28% and 4.4%, and intra-flock positivity between 3.7% and 25.0%. The survey revealed two risk factors associated with seropositivity; introducing animals (males and females), embryos, or semen from other farms or from abroad without any sanitary certification, and flocks not having quarantine areas or separated boxes for diseased animals. No clinical signs of disease were observed in positive seroreactors. C. abortus seems to be present in Costa Rica in a very low prevalence in sheep flocks. Further studies, to isolate the bacteria are required. Finally, implementation of control measures to prevent the spread of C. abortus is recommended. PMID- 26623378 TI - Pyloro-duodenal hernia with formation of enterocutaneous fistula in a buffalo calf following a dog attack. AB - A body wall hernia entrapping abomasum and concurrent duodenal fistula in a buffalo calf aged about 8 months, secondary to a dog bite was successfully treated by closure of fistulous orifice and ventro lateral herniorrhaphy. PMID- 26623379 TI - Determination of cadmium, lead and mercury residual levels in meat of canned light tuna (Katsuwonus pelamis and Thunnus albacares) and fresh little tunny (Euthynnus alletteratus) in Libya. AB - Surveillance for mercury (Hg), lead (Pb) and cadmium (Cd) contamination in tuna products is crucial for consumer food safety. Hg, Pb and Cd contaminants were monitored in a total of 60 specimens of fresh little tunny (Euthynnus alletteratus) and popular brands of skipjack and yellowfin (Katsuwonus pelamis and Thunnus albacares) canned tuna commercially available in Tripoli, Libya. Direct Mercury Analyzer (DMA-80) was implemented for determination of total Hg level and graphite furnace atomic absorption spectrometry (GFAAS) was employed for determination of Cd and Pb concentrations. The results indicated that Hg had the highest concentration level and Cd had the lowest concentration level either in tested canned tuna or fresh little tunny samples. The average concentration of Hg in fresh little tunny samples was 1.185 +/- 0.968 mg kg(-1) wet weight (ww) and often exceeded the standard permissible limit. In addition, canned yellowfin tuna had the lowest levels of Cd (0.027 +/- 0.026 mg kg(-1) ww), Pb (0.075 +/- 0.071) and Hg (0.163 +/- 0.122 mg kg(-1) ww). Results of the current surveillance indicated that canned skipjack and yellowfin tuna sold in Tripoli markets show contaminant levels well under the European thresholds adopted for Cd, Pb and Hg. However, consumption of large quantities of Mediterranean little tunny products significantly increases human exposure to the risk of Hg toxicity. PMID- 26623380 TI - Dual function of the hemagglutinin H5 fused to chicken CD154 in a potential strategy of DIVA against avian influenza disease: preliminary study. AB - In this study we demonstrated that the vaccine candidate against avian influenza virus H5N1 based on the hemagglutinin H5 (HA) fused to the chicken CD154 (HACD) can also be used for differentiating infected from vaccinated animals (DIVA). As the strategy of DIVA requires at least two proteins, we obtained a variant of the nucleoprotein (NP49-375) in E. coli. After its purification by IMAC, the competence of the proteins NP49-375 and HACD as coating antigens in indirect ELISA assays were tested by using the sera of chickens immunized with the proteins HA and HACD and the reference sera from several avian influenza subtypes. Together with these sera, the sera from different species of birds and the sera of chickens infected with other avian viral diseases were analyzed by competition ELISA assays coated with the proteins NP49-375 and HACD. The results showed that the segment CD154 in the chimeric protein HACD did not interfere with the recognition of the molecule HA by its specific antibodies. Also, we observed variable detection levels when the reference sera were analyzed in the ELISA plates coated with the protein NP49-375. Moreover, only the antibodies of the reference serum subtype H5 were detected in the ELISA plates coated with the protein HACD. The competition ELISA assays showed percentages of inhibition of 88 91% for the positives sera and less than 20% for the negative sera. We fixed the cut-off value of these assays at 25%. No antibody detection was observed in the sera from different species of birds or the sera of chickens infected with other avian viral diseases. This study supported the fact that the ELISA assays using the proteins NP49-375 and HACD could be valuable tools for avian influenza surveillance and as a strategy of DIVA for counteracting the highly pathogenic avian influenza virus H5N1 outbreaks. PMID- 26623381 TI - Human Staphylococcus aureus lineages among Zoological Park residents in Greece. AB - Staphylococcus aureus is a part of the microbiota flora in many animal species. The clonal spread of S. aureus among animals and personnel in a Zoological Park was investigated. Samples were collected from colonized and infected sites among 32 mammals, 11 birds and eight humans. The genes mecA, mecC, lukF/lukS-PV (encoding Panton-Valentine leukocidin, PVL) and tst (toxic shock syndrome toxin 1) were investigated by PCR. Clones were defined by Multilocus Sequence Typing (MLST), spa type and Pulsed-Field Gel Electrophoresis (PFGE). Seven S. aureus isolates were recovered from four animals and one from an employee. All were mecA, mecC and tst-negative, whereas, one carried the PVL genes and was isolated from an infected Squirrel monkey. Clonal analysis revealed the occurrence of seven STs, eight PFGE and five spa types including ones of human origin. Even though a variety of genotypes were identified among S. aureus strains colonizing zoo park residents, our results indicate that colonization with human lineages has indeed occurred. PMID- 26623382 TI - Aging effect on plasma metabolites and hormones concentrations in riding horses. AB - Age effects on plasma metabolites, hormone concentrations, and enzyme activities related to energy metabolism were investigated in 20 riding horses. Animals were divided into two groups: Young (3-8 years) and aged (11-18 years). They were clinically healthy, and not obese. Plasma adiponectin (ADN) concentrations in aged horses were significantly lower than those in young horses (mean+/-SE, 6.5+/ 1.3 ug mL(-1) vs, 10.9+/-1.7 ug mL(-1), Mann-Whitney U test, respectively; P=0.0233). Plasma non-esterified fatty acid levels and Insulin and malondialdehyde concentrations in aged group tended to increase compared to those in young group although there were not significant differences statistically. In aged group, malate dehydrogenase/lactate dehydrogenase (M/L) ratio, which is considered an energy metabolic indicator, did not change significantly compared to that in young group. Present data suggest that aging may negatively affect nutrition metabolism, but not induce remarkable changes in M/L ratio in riding horses. PMID- 26623383 TI - Effectiveness of slow motion video compared to real time video in improving the accuracy and consistency of subjective gait analysis in dogs. AB - Objective measures of canine gait quality via force plates, pressure mats or kinematic analysis are considered superior to subjective gait assessment (SGA). Despite research demonstrating that SGA does not accurately detect subtle lameness, it remains the most commonly performed diagnostic test for detecting lameness in dogs. This is largely because the financial, temporal and spatial requirements for existing objective gait analysis equipment makes this technology impractical for use in general practice. The utility of slow motion video as a potential tool to augment SGA is currently untested. To evaluate a more accessible way to overcome the limitations of SGA, a slow motion video study was undertaken. Three experienced veterinarians reviewed video footage of 30 dogs, 15 with a diagnosis of primary limb lameness based on history and physical examination, and 15 with no indication of limb lameness based on history and physical examination. Four different videos were made for each dog, demonstrating each dog walking and trotting in real time, and then again walking and trotting in 50% slow motion. For each video, the veterinary raters assessed both the degree of lameness, and which limb(s) they felt represented the source of the lameness. Spearman's rho, Cramer's V, and t-tests were performed to determine if slow motion video increased either the accuracy or consistency of raters' SGA relative to real time video. Raters demonstrated no significant increase in consistency or accuracy in their SGA of slow motion video relative to real time video. Based on these findings, slow motion video does not increase the consistency or accuracy of SGA values. Further research is required to determine if slow motion video will benefit SGA in other ways. PMID- 26623385 TI - Electronic informed consenting: A boon to modernize consenting process. PMID- 26623384 TI - Cadmium affects the mitochondrial viability and the acid soluble thiols concentration in liver, kidney, heart and gills of Ancistrus brevifilis (Eigenmann, 1920). AB - The freshwater fish Ancistrus brevifilis, which is found in Venezuelan rivers, is considered a potential sentinel fish in ecotoxicological studies. The cadmium (Cd) effect on the mitochondrial viability (MV) and acid soluble thiols levels (AST) in A. brevifilis tissues (liver, kidney, heart, and gill) was evaluated. Forty-two fish with similar sizes and weights were randomly selected, of which 7 fish (with their respective replicate) were exposed for 7 and 30 days to a Cd sublethal concentration (0.1 mg.l(-1)). We determined the MV through a Janus Green B colorimetric assay and we obtained the concentration of AST by Ellman's method. Mitochondrial viability decreased in fish exposed to Cd for 30 days with the liver being the most affected tissue. We also detected a significant decrease in AST levels was in fishes exposed to Cd for 7 days in liver and kidney tissues; these results suggests that AST levels are elevated in some tissues may act as cytoprotective and adaptive alternative mechanism related to the ROS detoxification, maintenance redox status and mitochondrial viability. Organ specifics variations were observed in both assays. We conclude that the Cd exposure effect on AST levels and MV, vary across fish tissues and is related to the exposure duration, the molecule dynamics in different tissues, the organism and environmental conditions. PMID- 26623386 TI - Clinical operations generation next... The age of technology and outsourcing. AB - Huge cost pressures and the need to drive faster approvals has driven a technology transformation in the clinical trial (CT) industry. The CT industry is thus leveraging mobile data, cloud computing, social media, robotic automation, and electronic source to drive efficiencies in a big way. Outsourcing of clinical operations support services to technology companies with a clinical edge is gaining tremendous importance. This paper provides an overview of current technology trends, applicable Food and Drug Administration (FDA) guidelines, basic challenges that the pharma industry is facing in trying to implement such changes and its shift towards outsourcing these services to enable it to focus on site operations. PMID- 26623387 TI - Clinical Data Acquisition Standards Harmonization importance and benefits in clinical data management. AB - In the clinical trial process, precise and concise data collection at the source is imperative and requires statistical analysis to be performed to derive the primary and secondary endpoints. The quality of raw data collection has a direct impact on the statistical outputs generated as per the statistical analysis plan. Hence, the data collection tools used for data transcription must be clear, understandable, and precise, which helps the investigator to provide the accurate subject data. Clinical Data Acquisition Standards Harmonization (CDASH) provides guidance to develop the case report form (CRF) for domains that are commonly used for the majority of the clinical trials across the therapeutic areas. This white paper describes the importance of CDASH standards, its advantages and its impact on the efforts and the cost in designing the CRF. PMID- 26623388 TI - Elderly patients' participation in clinical trials. AB - The elderly population is a large and the fastest-growing portion of the population worldwide. The elderly make up the lion's share of patients for certain health conditions including cancer, cardiovascular disease, arthritis, and Parkinson's disease, among others in most parts of the world. Furthermore, elderly make up the majority of patients for many medications treating chronic conditions. Typically, clinical trials conducted in adult population include patients between the ages of 18 and 64 years. However, drugs should be studied in all age groups and trial participants should be representative of the patient population receiving the therapy in daily medical practice. Elderly patients are poorly represented in clinical trials. Hence, there is inadequate evidence and knowledge about responses of geriatric patients to medications. Regulatory authorities in developed countries urge to avoid arbitrary upper age limits and advise researchers and industry not to exclude elderly people from clinical trials without a valid reason. Since last few years Indian regulatory authority has been stipulating upper age limit for studies conducted in India. The Central Drugs Standard Control Organization (CDSCO) will be doing a great contribution to the researchers if it changes its view on stipulating upper age restrictions in clinical studies. This article describes the need for including elderly patients in the clinical trials in order to garner data from geriatric patients who form major medication users in most of the chronic diseases. PMID- 26623389 TI - Reasons why patients fail screening in Indian breast cancer trials. AB - INTRODUCTION: An increased number of screen failure patients in a clinical trial increases time and cost required for the recruitment. Assessment of reasons for screen failure can help reduce screen failure rates and improve recruitment. MATERIALS AND METHODS: We collected retrospective data of human epidermal growth factor receptor (HER2) positive Indian breast cancer patients, who failed screening for phase 3 clinical trials and ascertained their reasons for screen failure from screening logs. Statistical comparison was done to ascertain if there are any differences between private and public sites. RESULTS: Of 727 patients screened at 14 sites, 408 (56.1%) failed screening. The data on the specific reasons for screen failures was not available at one of the public sites (38 screen failures out of 83 screened patients). Hence, after excluding that site, further analysis is based on 644 patients, of which 370 failed screening. Of these, 296 (80%) screen failure patients did not meet selection criteria. The majority -266 were HER2 negative. Among logistical issues, 39 patients had inadequate breast tissue sample. Sixteen patients withdrew their consent at private sites as compared to six at public sites. The difference between private and public sites for the above three reasons was statistically significant. CONCLUSION: Use of prescreening logs to reduce the number of patients not meeting selection criteria and protocol logistics, and patient counseling to reduce consent withdrawals could be used to reduce screen failure rate. PMID- 26623390 TI - Exploiting the potential of intranet for managing drug spectrum a web base publication in a Tertiary Care Hospital in Mumbai. AB - OBJECTIVE: The study surveyed the availability of the intranet in campus and also the knowledge related to drug spectrum an intranet publication. MATERIALS AND METHODS: Institutional ethics committee permission was obtained. Verbal consent was taken from the faculty and resident doctors of departments where all the facilities were available. Universal sampling method was used for recruitment. Pre-validated questionnaires were given to approximately 100 faculty and 500 resident doctors in the year 2012-2013. The questionnaire contained 15 items. Content analysis was done. The study questionnaire focused on a survey to obtain participants feedback on the use of the intranet and to evaluate the use of intranet as a source of knowledge. It also dealt on the relevance of the drug spectrum in the context of their subject. The responses were taken after giving the participants sufficient time. Data was entered into an Excel 2003 spread sheet and analyzed by using descriptive statistics. RESULTS: The total number of respondents who participated in our study was 134 including faculty and residents from various departments. A total of 117 (89.66%) respondents stated that their departments have access to the internet. Departments having access to intranet was 103 (76.29%). 67 (49.62%) respondents have accessed. 67 (49.62%) did not have the time to visit intranet site whereas 67 (49.62%) have not accessed intranet. 89 (65.92%) respondents were not aware of the drug spectrum. 101 (74.81%) respondents felt that drug spectrum is a useful activity on intranet. 45 (33.33%) knew about the intranet periodical drug spectrum, but most of the respondents (33.33%) explained the meaning of the word drug spectrum according to their understanding, but never knew about the online intranet journal drug spectrum. CONCLUSION: The study found that the intranet is available in the campus, but it is not being utilized. The awareness and knowledge regarding drug spectrum is lacking, but the participants had a lot of suggestions. Thus, intranet has immense utility, and to make drug spectrum more readable suggestions of the respondents needs to be incorporated which in turn can benefit the medical fraternity as a whole. PMID- 26623391 TI - An evaluation of knowledge, attitude, and practice of adverse drug reaction reporting in a tertiary care teaching hospital of Sikkim. AB - AIM: Spontaneous voluntary adverse drug reaction (ADR) reporting is paramount to the success of the Pharmacovigilance Programme of India. There has however been minimal and sporadic voluntary reporting of ADR's at the ADR Monitoring Centre (AMC) Gangtok, Sikkim. Knowledge, perception, attitude, and awareness of health professionals are determinants of reporting practices. This questionnaire study aims at evaluating these indicators in the teaching hospital attached to the Medical Institute and find out methods to improve existing reporting practices. MATERIALS AND METHODS: This is a cross-sectional questionnaire-based observational study carried out in the Medical, Surgical and Pathology Departments of the Teaching Hospital, Gangtok, Sikkim over a period of 2 months. The questionnaires were filled by the respondents and returned back to us within the next 24 h. Data obtained from filled questionnaires were thereby analyzed. RESULTS: The overall correct response rate to the knowledge-based questions was 56.3%. While 97% of respondents were of the view that ADR reporting was necessary, 35% of the respondents felt that the difficulty in deciding the causality of an ADR discouraged them from reporting. 79% of the respondents were not aware of the presence of an AMC affiliated to the hospital, and 87% of the respondents admitted that they were not sending filled ADR forms to the AMC. CONCLUSIONS: The study indicates that the respondents have an average knowledge and positive attitude toward ADR reporting and pharmacovigilance. There is however a lack of awareness and poor ADR reporting practices. Efforts are required to enhance awareness and attitude toward pharmacovigilance and ADR reporting. PMID- 26623392 TI - Pilot studies: Are they appropriately reported? AB - INTRODUCTION: Pilot studies play a pivotal role in deciding whether a main study can be undertaken thereby helping in appropriate framing of time, cost and study methods. However, they cannot be employed for testing a hypothesis and are underpowered in detecting clinically significant differences between the treatment arms. Literature from the west has shown serious lacunae on the part of researchers in reporting pilot studies. The present study assessed the reporting quality of pilot studies published from India. MATERIALS AND METHODS: All the journal articles with a pilot study design published in Indian Journals between January and December 2013 were identified through PubMed search and were assessed for the following: Reason for undertaking the pilot study; report about intention of further work; mention about sample size calculation; statement on other studies evaluating the same hypothesis published elsewhere; whether any hypothesis was tested in the present study; use of inferential statistics including the total number of statistical analyses performed and whether confidence intervals were reported; post-hoc power calculation; application of randomization and/or blinding; total number of study participants and presence of a control group. RESULTS: A total of 93 articles were considered in the present study. None of these reported reasons for undertaking the present pilot study and intention to carry of carrying out further work depending on their results. Also, none of them discussed the feasibility of conducting such studies in the given set-up. A total of 69/93 (67.7%) studies tested a hypothesis and had employed at least one of the statistical tests to infer whether any significant difference exist between various groups. None of the 93 articles mentioned confidence intervals and calculation of the sample size despite all mentioning the presence of previous studies evaluating a similar hypothesis. Similarly, none of these studies mentioned post-hoc analysis of power and median (range) of times of statistical analyses performed includes 5 (0-57). CONCLUSION: Pilot studies have been poorly reported in Indian biomedical journals, and more attention is required from all the stakeholders of research; researchers, peer reviewers and journal editors. PMID- 26623393 TI - Comparative evaluation of oral gabapentin versus clonidine as premedication on preoperative sedation and laryngoscopic stress response attenuation for the patients undergoing general anesthesia. AB - BACKGROUND: Laryngoscopy and endotracheal intubation (L and I) is associated with rise in blood pressure (BP), heart rate (HR), leading to adverse cardiological outcome especially in susceptible individuals. To compare the BP, HR during L and I as well as to evaluate the preoperative sedation status between oral clonidine (Group C) and oral gabapentine (Group G) as premedication for the patients undergoing major surgery under general anesthesia (GA). MATERIALS AND METHODS: From April 2008 to December 2009; in a prospective, double-blinded, and randomized controlled study; 100 adult patients of either sex, aged 20-45, of American Society of Anesthesiologists status I and II scheduled to undergo major surgery of >1 hour duration, randomly allocated into groups C and G were pre treated with oral clonidine (200 ug) and gabapentin (800 mg) respectively 2 h prior to induction. Preoperative sedation was assessed 2 h after premedication administration. Hemodynamic parameters were noted just before induction, during L and I 1,3,5,7, and10 min after intubation. The results obtained were then analyzed with statistical unpaired "t" test and Chi-square test and compared. RESULTS AND ANALYSIS: Preoperative sedation between two groups were similar but group C attenuated HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean blood pressure (MBP) more significantly before induction, during L and I, 1, 3, and 5 min, following L and I, while comparing with group G. Again gabapentin-reduced HR, BP, (SBP, DBP, MBP) significantly more at 7 and 10 min after L and I on comparison clonidine. CONCLUSION: Oral clonidine is equally effective in producing preoperative sedation in comparison to oral gabapentin, while on the contrary oral clonidine is more efficacious in reducing laryngoscopic stress response than oral gabapentin. PMID- 26623394 TI - A questionnaire based study to assess knowledge, attitude and practice of pharmacovigilance among undergraduate medical students in a Tertiary Care Teaching Hospital of South India. AB - OBJECTIVES: Spontaneous reporting of adverse drug reaction (ADR) is the backbone of pharmacovigilance program. Under reporting by prescribers is still exist. This study was done to assess the knowledge, attitude, and practice (KAP) of undergraduate students about pharmacovigilance. MATERIALS AND METHODS: It was a questionnaire-based cross-sectional study. Study tool was a validated questionnaire containing 21 questions to evaluate KAP of pharmacovigilance among undergraduate medical students in a Tertiary Care Teaching Hospital of South India. RESULTS: All data were analyzed by using Microsoft Excel sheet, Chi square, and ANOVA. The mean score of final, prefinal, and 2(nd) year students is respectively (4.76, 5.63, and 4.73) for knowledge, (4.26, 4.95, and 4.53) for attitude and (1.66, 1.55, and 1.28) for the practice. There is a significant difference in mean score between three groups for knowledge and attitude, but not for practice. They have a better attitude, but poor in knowledge and practice regarding pharmacovigilance. CONCLUSION: Students lack adequate knowledge and skill of reporting ADR, but they have a positive attitude toward pharmacovigilance program. The integration of pharmacovigilance with undergraduate curriculum may help in improving ADR monitoring and reporting. PMID- 26623395 TI - Common pitfalls in statistical analysis: Odds versus risk. AB - In biomedical research, we are often interested in quantifying the relationship between an exposure and an outcome. "Odds" and "Risk" are the most common terms which are used as measures of association between variables. In this article, which is the fourth in the series of common pitfalls in statistical analysis, we explain the meaning of risk and odds and the difference between the two. PMID- 26623396 TI - Relevance of health economics to the Indian healthcare system: A perspective. PMID- 26623397 TI - Comparison of the accuracy of cardiac computed tomography angiography and transthoracic echocardiography in the diagnosis of mitral valve prolapse. AB - BACKGROUND: Cardiac multidetector computed tomography (MDCT) has been mainly applied in the diagnosis of valvular heart morphology and function along with the assessment of coronary artery disease. This study aimed to evaluate the diagnostic performance of coronary MDCT angiography for the diagnosis of mitral valve prolapse (MVP), as compared to transthoracic echocardiography (TTE). MATERIALS AND METHODS: A total of 40 patients who had undergone both TTE and MDCT within a three-month period were included in the study. Two parameters of mitral valve leaflet thickness and leaflet billowing were measured using both techniques. The MDCT results were compared with those of TTE, which was the reference standard. RESULTS: Implementing the Receiver Operating Characteristic (ROC) test on the data for MDCT-measured leaflet billowing received from MDCT angiography suggests that the area under the ROC curve is 96% for a declared variable, which is absolutely significant (P < 0.001), and MDCT-measured leaflet billowing is an appropriate index for the diagnosis of mitral valve prolapse. On the basis of the achieved cut-off point from the ROC analysis (which equals 2.5 mm leaftlet billowing) the MDCT-measured leaflet billowing takes a sensitivity and specificity of 68.4 and 95.2%. The false positive and false negative results are 4.8 and 31.6%. The positive and negative predictive values (PPV and NPV) of the revealed test indicate 92.9 and 76.9%, respectively. Finally, the consistency of the MDCT measured leaflet billowing for diagnosing the mitral valve prolapse is 82.5%. Based on the mentioned test, the consistency of the MDCT-measured leaflet thickness test is 47.5%. CONCLUSION: Along with the assessment of coronary arteries, the presence or absence of MVP can be reliably evaluated by MDCT angiography. PMID- 26623398 TI - Changes in blood glucose level during and after light sedations using propofol fentanyl and midazolam-fentanyl in diabetic patients who underwent cataract surgery. AB - BACKGROUND: Surgeries may trigger the stress response which leads to changes in blood glucose level, and studies suggest that different sedation and anesthesia methods have different effects on blood glucose level. The aim of this study was to investigate changes of blood glucose levels in diabetic patients and compare them in two sedation methods of propofol + fentanyl and midazolam + fentanyl. MATERIALS AND METHODS: Totally, 80 diabetic candidates for cataract surgery who had all the inclusion criteria, underwent cataract surgery using two methods of propofol (1 mg/kg/h) + fentanyl (2 MUg/kg) (Group P) and midazolam (0.03 mg/kg) + fentanyl (2 MUg/kg) (Group M) for light sedation. In the end, 70 patients (Group P n = 35 and Group M n = 35) remained in the study. Patients' blood glucose levels, vital signs, and hemodynamic data were assessed 30 min prior to the surgery, each 15 min during surgery and at the end of surgery. RESULTS: Hemodynamic parameters did not have a statistically significant difference between the two groups mean blood glucose level in Group M was 149.15 mg/dl and in Group P was 149.2 mg/dl, and based on repeated measures analysis of variance test, significant differences were not observed between the two groups (P = 0.99). T-test showed no significant differences in the blood glucose level at any time of the study between the two groups. CONCLUSIONS: Light sedation methods of propofol + fentanyl and midazolam + fentanyl did not have any differences in alteration of blood glucose level. PMID- 26623399 TI - Rolipram: Eotaxin and phosphodiesterase IV inhibitor versus bronchial hyper reactivity response. PMID- 26623400 TI - Sexual dysfunctions in the patients hospitalized in psychiatric wards compared to other specialized wards in Isfahan, Iran, in 2012. AB - BACKGROUND: Having pleasurable sexual intercourses plays a major role in marital life satisfaction. Many of the medical and psychiatric disorders may affect the sexual function of the patients. The present study aims to investigate the relative frequency of sexual dysfunctions in the patients hospitalized in psychiatric wards and that of the patients in other specialized wards. MATERIALS AND METHODS: This study is a descriptive-analytical, cross-sectional one, carried out on 900 patients hospitalized in psychiatric, cardiac, orthopedic, ophthalmology, and dermatology and plastic surgery wards of 5 hospitals in Isfahan. Data collection tools included demographic questionnaire and Arizona Sexual Experiences Scale (ASEX). RESULTS: Sexual dysfunction in the patients hospitalized in psychiatric wards (38%) was significantly higher than in the patients in other wards (27%), (P = 0.00). Among the patients hospitalized in psychiatric wards, those with bipolar disorder (37.3%) had the highest prevalence rate of sexual dysfunction. The patients with schizophrenia, major depression, substance abuse, and anxiety disorders had the following rates respectively. Among the patients in non-psychiatric wards, those in cardiac wards (37.1%) had the highest prevalence rate of sexual dysfunction. There was a significant relationship between the drug uses, mostly psychiatric drugs especially anti psychotics, and the occurrence of sexual dysfunction. CONCLUSION: Considering the significant relative frequency of sexual dysfunction in psychiatric patients and undesired effects of simultaneous occurrence of both of these disorders in the patients, more emphasis is recommended to be placed on the prevention and proper treatment of these disorders in the patients. PMID- 26623401 TI - Can maximal aerobic running speed be predicted from submaximal cycle ergometry in soccer players? The effects of age, anthropometry and positional roles. AB - BACKGROUND: Considering maximal aerobic running speed (MAS) as a useful tool to evaluate aerobic capacity and monitor training load in soccer, there is an increasing need to develop indirect assessment methods of MAS, e.g., submaximal tests. The aim of this study was to examine the prediction of MAS from the physical working capacity (PWC) in heart rate (HR) 170 beat/min test (PWC170). MATERIALS AND METHODS: This cross-sectional study was done on adolescent (n = 67) and adult soccer players (n = 82) were examined for anthropometric characteristics, PWC170 and performed Conconi test to assess MAS. RESULTS: Midfielders scored higher than goalkeepers (GKs) and defenders in MAS while GKs scored lower than all the other playing positions. Although this trend was also observed in PWC170, statistical difference was only observed between midfielders and GKs. Players with higher MAS had also higher PWC170 in both age groups (P < 0.05). The odds ratio of a player of the best PWC170 group to belong also to the best MAS group was 3.96 (95% confidence interval 2.00; 7.84). That is players with high-performance in the PWC170 were about 4 times more likely than those with low PWC170 to achieve a high score in MAS. Regression analysis suggested body fat (BF) percentage, PWC170, maximal HR and age as predictors of MAS (R = 0.61, R (2) = 0.37 and standard error of estimate [SEE] =1.3 km/h, in total; R = 0.74, R (2) = 0.55 and SEE = 1.2 km/h, in adolescents; R = 0.55, R (2) = 0.30 and SEE = 1.3 km/h, in adults). CONCLUSIONS: While there was only moderate correlation between MAS and PWC170, the former can be predicted from the latter when BF, HRmax, and age are considered (large to very large multiple correlation coefficients). PMID- 26623402 TI - Effect of cholecystokinin on learning and memory, neuronal proliferation and apoptosis in the rat hippocampus. AB - BACKGROUND: Cholecystokinin (CCK) has roles in learning and memory, but the cellular mechanism is poorly understood. This study investigated the effect of CCK on spatial learning and memory, neuronal proliferation and apoptosis in the hippocampus in rats. MATERIALS AND METHODS: Experimental groups were control and CCK. The rats received CKK octapeptide sulfated (CCK-8S, 1.6 MUg/kg, i.p.) for 14 days. Spatial learning and memory were tested by Morris water maze and finally immunohistochemical study was performed; neurogenesis by Ki-67 method and apoptosis by Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling (TUNEL) assay in hippocampal dentate gyrus (DG). RESULTS: Cholecystokinin increased Ki-67 positive cells and reduced TUNEL positive cells in the granular layer of hippocampal DG. CCK failed to have a significant effect on spatial learning and memory. CONCLUSION: Results indicate neuroprotective and proliferative effects of CCK in the hippocampus; however, other factors are probably involved until the newly born neurons achieve necessary integrity for behavioral changes. PMID- 26623404 TI - Preventive effect of ilioinguinal nerve block on postoperative pain after cesarean section. AB - BACKGROUND: Cesarean section is a major operation that can be the predictor of postoperative pain and discomfort and, therefore, providing the effective postoperative analgesia is an important factor to facilitate sooner movement of the patient, better care of infants. The aim of this study was to determine the preventive effect of ilioinguinal nerve block on pain after cesarean section. MATERIALS AND METHODS: In a randomized clinical trial study, 80 female candidates for cesarean section under general anesthesia were selected and divided into two groups. In the first group, ilioinguinal nerve was blocked and in the control group, ilioinguinal nerve block was not done. Finally, postoperative pain was compared between the two groups. RESULTS: The mean pain intensity at 6 and 24 h after operation had no significant difference between two groups but in the rest of the times, it was different between two groups. Furthermore, in sitting position, except for 6 h, the pain intensity at the rest of the time had a significant difference between two groups. The pain intensity in 12 h after operation had a significant difference while in 24 h after operation; there was no difference between two groups. Doing repeated measures, ANOVA also indicated that the process of changes in the pain intensity in three positions of rest, sitting and walking had no significant difference up to 24 h after operation (P < 0.001). CONCLUSION: Control of pain after cesarean as one of the most common factors for abdominal surgery will lead to decrease the staying of the patient in hospital, reduce morbidity and lower use of narcotics and analgesics after surgery. PMID- 26623403 TI - Efficacy of topical azathioprine and betamethasone versus betamethasone-only emollient cream in 2-18 years old patients with moderate-to-severe atopic dermatitis: A randomized controlled trial. AB - BACKGROUND: Atopic dermatitis is a chronic skin disease with increasing prevalence worldwide and a considerable burden especially among children. To circumvent the problems related to oral azathioprine (AZT) we aimed to evaluate its topical variant and assess its efficacy in patients aged 2-18. MATERIALS AND METHODS: In a single-blind trial, we randomized the patients into two groups, one treated with topical emollient containing AZT and betamethasone (BM), and the other treated solely with topical emollient of BM. The treatments were administered twice a day for 8 weeks in both groups. The efficacy, recurrence, and the presence of side effects were evaluated using SPSS 20. RESULTS: The amount of reduction in severity scoring for atopic dermatitis (SCORAD) score was significantly greater in the group treated with the topical AZT (P = 0.024). Incidentally, there were no difference between two treatments in difference in proportions of recurrence and adverse effects as well as SCORAD reduction in subgroups of sex and age (all P > 0.05). CONCLUSIONS: Our results showed the superiority of topical AZT over BM with a low recurrence and adverse effects. No expectation of severe side effects, like those of oral AZT, is the major advantage of topical AZT. The sample size was an issue in uncovering the value of AZT in the subgroups. Conducting prolonged studies of quality-of-life and comparing the topical AZT potency relative to the common alternatives are recommended areas of future work. PMID- 26623405 TI - Comparing the effect of intravenous dexamethasone, intravenous ondansetron, and their combination on nausea and vomiting in cesarean section with spinal anesthesia. AB - BACKGROUND: Nausea and vomiting are frequently seen in patients undergoing cesarean section (CS) under regional anesthesia. We aimed to compare the antiemetic efficacy of ondansetron and dexamethasone combination with that of the use of each agent alone to decrease the incidence of postdelivery intra- and post operative nausea and vomiting during CS under spinal anesthesia. MATERIALS AND METHODS: A randomized, prospective, double-blind study was performed on 90 patients undergoing planned CS under spinal anesthesia. The patients received 4 mg ondansetron in Group O, 8 mg dexamethasone in Group D, and 4 mg ondansetron +8 mg dexamethasone in Group OD intravenously within 1-2 min after the umbilical cord was clamped. Frequency of postdelivery intra- and post-operative nausea and vomiting episodes was recorded. RESULTS: A total of 90 eligible patients were included in the study. There were 30 patients in Group O, 30 patients in Group D, and 30 patients in Group OD. Intraoperative nausea in Group D was more than the other two groups. Postoperative nausea in group OD was lesser than the other two groups. Intraoperative vomiting in Group OD was lesser than the other two groups. There was no statistically significant difference among the groups in postoperative vomiting (P > 0.05). CONCLUSION: Combined use of dexamethasone and ondansetron for the same indication seems to increase the antiemetic efficacy. PMID- 26623406 TI - Comparison of the performance of screening test for gestational diabetes in singleton versus twin pregnancies. AB - OBJECTIVE: We compared the performance of the 50-g glucose challenge test (GCT) in singleton versus twin pregnancies and investigated the need for adjusting GCT cutoff values for gestational diabetes mellitus (GDM) in twin pregnancies among Korean women. METHODS: A retrospective chart review was performed in women who underwent GCT at 24 to 28 weeks' gestation and delivered in our department between January 2000 and April 2008. GCT performance was compared between singleton and twin pregnancies for an ideal cutoff value of the GCT for GDM screening. RESULTS: GCT results were available in 3,578 pregnancies (3,435 singleton and 143 twin pregnancies). The mean GCT value was higher in the twin group than in the singleton group. Women in the twin group had a higher mean GCT value (P=0.043) and a higher incidence of GCT >=130, >=135, and >=140 mg/dL (P=0.014, 0.005, and 0.015, respectively). The false positive rate for GCT >=140 mg/dL was significantly higher in the twin than in the singleton group (P=0.042). The optimal GCT screening cutoff value appears to be >=145 mg/dL in twin pregnancies. CONCLUSION: Our study demonstrates that the GCT is associated with a higher false positive rate in twin rather than singleton pregnancies. This study suggests we should consider adjusting the GCT cutoff value for GDM in Korean twin pregnancies. PMID- 26623407 TI - The practice patterns of second trimester fetal ultrasonography: A questionnaire survey and an analysis of checklists. AB - OBJECTIVE: To analyze practice patterns and checklists of second trimester ultrasonography, and to investigate management plans when soft markers are detected among Korean Society of Ultrasound in Obstetrics and Gynecology (KSUOG) members. METHODS: An internet-based self-administered questionnaire survey was designed. KSUOG members were invited to the survey. Checklists of the second trimester ultrasonography were also requested. In the questionnaire survey, general practice patterns of the second trimester ultrasonography and management schemes of soft markers were asked. In the checklists analysis, the number of items were counted and also compared with those recommended by other medical societies. RESULTS: A total of 101 members responded. Eighty-seven percent routinely recommended second trimester fetal anatomic surveillance. Most (91.1%) performed it between 20+0 and 23+6 weeks of gestation. Written informed consents were given by 15.8% of respondents. Nearly 60% recommended genetic counseling when multiple soft markers and/or advanced maternal age were found. Similar tendencies were found in the managements of individual soft markers. However, practice patterns were very diverse and sometimes conflicting. Forty-eight checklists were analyzed in context with the number and content of the items. The median item number was 46.5 (range, 17 to 109). Of 49 items of checklists recommended by International Society of Ultrasound in Obstetrics and Gynecology and/or American Congress of Obstetricians and Gynecologists, 14 items (28.6%) were found in less than 50% of the checklists analyzed in this study. CONCLUSION: Although general practice patterns were similar among KSUOG members, some of which were conflicting, and there is a need for standardization of the practice patterns and checklists of second trimester ultrasonography, which also have very wide range of spectrum. PMID- 26623408 TI - Uterine blood flow indices, antinuclear autoantibodies and unexplained recurrent miscarriage. AB - OBJECTIVE: To study the correlation between 2D and 3D uterine flow indexes and the presence or the absence of antinuclear antibodies (ANA) in women with unexplained recurrent miscarriage (uRM). METHODS: Fifty-two subjects (26 uRM and 26 control women) underwent 2D Doppler measurement of pulsatility index and resistance index of the uterine arteries in both the follicular and midluteal phase of the cycle. Additionally, 3D ultrasonography determination of vascularisation index, flow index, and vascularisation flow index was carried out with the aid of the VOCAL technique. Serum assay for the presence of ANA was performed in all women. RESULTS: Pulsatility index of ANA+ uRM women was higher than that of ANA- uRM women and control ANA+ and ANAwomen, both in the follicular and in the midluteal phase of the cycle. Vascularisation index in ANA- uRM women was significantly higher than that in ANA+ control women. Flow index in uRM ANA+ women was significantly lower than that of each of the other groups. CONCLUSION: ANA might be involved in uRM by determining an impairment in uterine blood flow hemodynamic, particularly in uterine blood flow intensity and uterine artery impedance. PMID- 26623409 TI - Comparison of the effects of gestational weight gain on pregnancy outcomes between non-diabetic and diabetic women. AB - OBJECTIVE: Appropriate gestational weight gain (GWG) is important in diabetic women. Current GWG guideline is for US general population, but not specific for diabetic women. We compared the effect of GWG on perinatal outcomes between diabetic and non-diabetic women. METHODS: Fifty two hundred and twelve women who delivered live singleton infants at Korea University Medical Center from January 2009 to December 2013 were included. One hundred twenty-nine overt diabetes women and 322 gestational diabetes women were categorized as diabetic women, and the others were categorized as none-diabetic women. 5,212 women were categorized by GWG (low 1,081; adequate 2,102; or high 2,029; according to the 2009 Institute of Medicine guidelines), and each of the 3 GWG groups was categorized into 2 groups; diabetic or non-diabetic women. And then, we compared perinatal outcomes between diabetic and non-diabetic groups. RESULTS: In each 3 GWG groups, primary cesarean section delivery, high birth weight, and large for gestational age rates were significantly higher in diabetic women than non-diabetic women. Only in adequate GWG group, preterm birth rate was significantly higher in diabetic women than non diabetic women. CONCLUSION: Our study shows that diabetic women had higher rates of adverse perinatal outcomes than non-diabetic women, although they achieved same GWG. It suggests that current GWG guideline may not be adequate for diabetic women, and that diabetic women may need more strict GWG control than normal population. PMID- 26623410 TI - Endometrial cancer arising from atypical complex hyperplasia: The significance in an endometrial biopsy and a diagnostic challenge. AB - OBJECTIVE: We investigated the features of endometrial hyperplasia with concurrent endometrial cancer that had been diagnosed by endometrial sampling. Further, we attempted to identify an accurate differential diagnostic method. METHODS: We retrospectively studied 125 patients who underwent a diagnostic endometrial biopsy or were diagnosed after the surgical treatment of other gynecological lesions, such as leiomyoma or polyps. Patients were diagnosed between January 2005 and December 2013 at Busan Paik Hospital. Clinical and histopathological characteristics were compared in patients who had atypical endometrial hyperplasia with and without concurrent endometrial cancer. RESULTS: The patients were grouped based on the final pathology reports. One hundred seventeen patients were diagnosed with endometrial hyperplasia and eight patients were diagnosed with endometrioid adenocarcinoma arising from atypical hyperplasia. Of the 26 patients who had been diagnosed with atypical endometrial hyperplasia by office-based endometrial biopsy, eight (30.8%) were subsequently diagnosed with endometrial cancer after they had undergone hysterectomy. The patients with endometrial cancer arising from endometrial hyperplasia were younger (39.1 vs. 47.2 years, P=0.0104) and more obese (body mass index 26.1+/ 9.6 vs. 23.8+/-2.8 kg/m(2), P=0.3560) than the patients with endometrial hyperplasia. The correlation rate between the pathology of the endometrial samples and the final diagnosis of endometrial hyperplasia was 67.3%. CONCLUSION: In patients with atypical endometrial hyperplasia, the detection of endometrial cancer before hysterectomy can decrease the risk of suboptimal treatment. The accuracy of endometrial sampling for the diagnosis of concurrent endometrial carcinoma was much lower than that for atypical endometrial hyperplasia. Therefore, concurrent endometrial carcinoma should be suspected and surgical intervention should be considered in young or obese patients who present with atypical endometrial hyperplasia. PMID- 26623411 TI - Risk factors for malignant transformation of mature cystic teratoma. AB - OBJECTIVE: The aim of this study was to investigate the preoperative characteristics of benign mature cystic teratoma (MCT) and struma ovarii and their risk factors associated malignancies, and determine the appropriate treatment options for these tumors. METHODS: This was a retrospective study on 248 patients who were pathologically diagnosed with ovarian MCT, struma ovarii, or malignant transformations of these tumors at Inje University Haeundae Paik Hospital from March 2010 to January 2015. Routinely evaluated results of adnexal masses before surgery were compared. RESULTS: A total of six patients (2.4%) were confirmed to have malignant tumors. Of the struma ovarii patients, two out of five patients (40%) were confirmed to have malignancy. The mean age at the diagnosis of patients with malignant transformation of teratomas was 43.0 years (range, 27 to 67 years), which was higher than that of patients with benign teratomas (36.5 years). The mean diameter of the tumor before surgery in the malignant tumor group was 11.4 cm and larger than 6.5 cm of benign group (P=0.003). The mean CA-125 level in the malignant tumor group was higher than that in the benign tumor group (P=0.01). CONCLUSION: Risk factors for malignant transformation of MCT include elevated CA-125 levels, older age, large tumor masses, and postmenopausal status. PMID- 26623412 TI - Effect of second-line surgery on in vitro fertilization outcome in infertile women with ovarian endometrioma recurrence after primary conservative surgery for moderate to severe endometriosis. AB - OBJECTIVE: To evaluate the effect of second-line conservative surgery on in vitro fertilization (IVF) outcome in comparison with IVF without second-line surgery in infertile women with ovarian endometrioma recurrence after primary conservative surgery. METHODS: In this retrospective cohort study, 121 consecutive IVF/intracytoplasmic sperm injection cycles that were performed after second-line surgery (n=53) or without second-line surgery (control group, n=68) between January 2006 and December 2011 in 121 infertile women with ovarian endometrioma(s) recurrence after primary conservative surgery for moderate to severe endometriosis were included. The two groups were compared in terms of controlled ovarian stimulation and IVF outcomes. RESULTS: There were no differences in patients' characteristics between the two groups. Total dose and days of gonadotropins administered were significantly higher in the second-line surgery group than in the control group (P<0.001, P=0.008). The numbers of oocytes retrieved, mature oocytes and grade 1 or 2 embryos were significantly lower in the second-line surgery group (P=0.007, P=0.001, P<0.001, respectively). Clinical pregnancy rate per cycle and embryo implantation rate were also significantly lower in the second-line surgery group of 24.5% and 11.8% compared with 48.5% and 25.3% in the control group (P=0.008, P=0.005, respectively). CONCLUSION: Ovarian response to controlled ovarian stimulation and IVF outcome after second-line surgery is worse than those in IVF cycles without second-line surgery in infertile women with ovarian endometrioma recurrence after primary surgery for moderate or severe endometriosis. PMID- 26623413 TI - Contraceptive failure after hysteroscopic sterilization: Analysis of clinical and demographic data from 103 unplanned pregnancies. AB - OBJECTIVE: This investigation examined data on unplanned pregnancies following hysteroscopic sterilization (HS). METHODS: A confidential questionnaire was used to collect data from women with medically confirmed pregnancy (n=103) registered after undergoing HS. RESULTS: Mean (+/-SD) patient age and body mass index (BMI) were 29.5+/-4.6 years and 27.7+/-6.1 kg/m(2), respectively. Peak pregnancy incidence was reported at 10 months after HS, although <3% of unplanned pregnancies occurred within the first three months following HS. Mean (+/-SD) interval between HS and pregnancy was 19.6+/-14.9 (range, 2 to 84) months. Patients age >=30 years and BMI <25 reported conception after HS somewhat sooner than younger patients, although the differences in time to pregnancy were not significant (P=0.24 and 0.09, respectively). The recommended post-HS hysterosalpingogram (to confirm proper placement and bilateral tubal occlusion) was obtained by 66% (68/103) of respondents. CONCLUSION: This report is the first to provide patient-derived data on contraceptive failures after HS. While adherence to backup contraception 3 months after HS can be poor, many unintended pregnancies with HS occur long after the interval when alternate contraceptive is required. Many patients who obtain HS appear to ignore the manufacturer's guidance regarding the post-procedure hysterosalpingogram to confirm proper device placement, although limited insurance coverage likely contributes to this problem. The greatest number of unplanned pregnancies occurred 10 months after HS, but some unplanned pregnancies were reported up to 7 years later. Age, BMI, or surgical history are unlikely to predict contraceptive failure with HS. Further follow-up studies are planned to capture additional data on this issue. PMID- 26623414 TI - Maternal antimullerian hormone as a predictor of fetal aneuploidy occurring in an early pregnancy loss. AB - OBJECTIVE: The purpose of the study was to examine the relationship between the parameter representing ovarian reserve and the fetal aneuploidy in early spontaneous miscarriage. METHODS: A multicenter retrospective cohort study was performed in patients who were diagnosed with early pregnancy loss (<=13 gestational weeks) and examined for fetal karyotype at the CHA Gangnam Medical Center, CHA Bundang Medical Center, and CHA Gumi Medical Center between January 2011 and December 2012. Karyotyping was performed by the Genetic Laboratory of the Fertility Center of CHA Gangnam Medical Center. Medical records were reviewed for demographics, karyotype analysis and hormonal assay of ovarian reserve including antimullerian hormone (AMH) and follicle stimulating hormone. Statistical analysis was performed using SPSS software. RESULTS: A total 462 patients were included in this study. The mean age of the patients was 35.31+/ 4.12 years and the mean AMH level was 3.88+/-3.50 ng/mL (n=195). Two hundred eleven conceptuses (45.7%) of patients showed the euploid and 251 (54.3%) showed the aneuploid. There are significant differences in maternal age, AMH and gestational age between fetal euploid and aneuploid groups (34.46+/-4.35 vs. 36.04+/-3.78 years, P<0.001; 4.60+/-3.86 vs. 3.43+/-3.18 ng/mL, P=0.022; 7.67+/ 1.54 vs. 8.27+/-1.46 weeks, P<0.001, respectively). Multivariate analysis revealed that low AMH level and early gestational age were maternal age independent markers for fetal aneuploid (P<0.001 and P=0.045, respectively). CONCLUSION: Low maternal AMH level might be a predicting marker for fetal aneuploid in early pregnancy loss. PMID- 26623415 TI - Safety of laparoscopically assisted vaginal hysterectomy for women with anterior wall adherence after cesarean section. AB - OBJECTIVE: To evaluate the safety and surgical outcomes of laparoscopically assisted vaginal hysterectomy (LAVH) for women with anterior wall adherence after cesarean section. METHODS: We conducted a retrospective study of 328 women with prior cesarean section history who underwent LAVH from March 2003 to July 2013. The subjects were classified into two groups: group A, with anterior wall adherence (n=49); group B, without anterior wall adherence (n=279). We compared the demographic, clinical characteristics, and surgical outcomes of two groups. RESULTS: The median age and parity of the patients were 46 years (range, 34 to 70 years) and 2 (1 to 6). Patients with anterior wall adherence had longer operating times (175 vs. 130 minutes, P<0.05). There were no significant differences in age, parity, number of cesarean section, body mass index, specimen weight, postoperative change in hemoglobin concentration, or length of hospital stay between the two groups. There was one case from each group who sustained bladder laceration during the vaginal portion of the procedure, both repaired vaginally. There was no conversion to abdominal hysterectomy in either group. CONCLUSION: LAVH is effective and safe for women with anterior wall adherence after cesarean section. PMID- 26623416 TI - Factors affecting medication discontinuation in patients with overactive bladder symptoms. AB - OBJECTIVE: To find out the factors affecting medication discontinuation in patients with overactive bladder (OAB) symptoms. METHODS: The clinical data of 125 patients with OAB symptoms who had taken antimuscarinics and behavioral therapy were retrospectively reviewed. Antimuscarinics related outcomes were evaluated by an independent observer with telephone interview. All patients were asked about duration of medication and reason of continuation or discontinuation of antimuscarinics. To determine pre-treatment factors predicting self-report discontinuation of antimuscarinics, variables of only those with P-values <0.25 on the univariate analysis were included in the Cox proportional hazard modeling. RESULTS: Mean follow-up was 39.6 months and the proportion of discontinuation of antimuscarinics was 60.0% (75/125). The mean duration of medication was 21.2 months in the continuation group and 3.3 months in the discontinuation group. The reasons of discontinuation of antimuscarinics were improved OAB symptoms (46.7%), tolerable OAB symptoms (33.3%), no change of OAB symptoms (1.3%), side-effects (8.0%) and no desire to take long-term medication (10.7%). The variables affecting remaining cumulative probability of antimuscarinics were age, history of anti-incontinence surgery or vaginal surgery, and having stress predominant urinary incontinence on urodynamic study. CONCLUSION: The lower rate of cumulative continuation of antimuscarinics encourages us to give a more detailed counseling and education to the patients with OAB symptoms before prescription. And explorations about newer agent and non-pharmacologic treatment with good efficacy and lower side-effects are needed. PMID- 26623417 TI - Inherited thrombophilia profile in patients with recurrent miscarriages: Experience from a tertiary care center in north India. AB - The cause of recurrent miscarriage (RM) remains unexplained in approximately 30% to 50% cases. The association of inherited thrombotic factors and RM patients has not been documented from the northern part of India. A total of 40 patients had been investigated for inherited thrombophilia workup (protein C, protein S [PS], antithrombin III, and factor V Leiden [FVL] mutation) over a period of 10 years (2005 to 2014). RM patients were divided in to three groups. Group I (only 1st trimester loss), group II (only 2nd and 3rd trimester), and group III (mixed). Each group comprised of the following numbers of patients respectively: I, 24; II, 2; III, 14. Heterozygous FVL mutation was found in 10% (4/40) cases. PS deficiency was detected in 2.7% (1/37) cases. In the present study FVL and PS were seems to be associated with a subset of patients however further studies with larger numbers of patients are recommended for better evaluation. PMID- 26623418 TI - Two pregnancy cases of uterine scar dehiscence after laparoscopic myomectomy. AB - Uterine scar dehiscence following laparoscopic myomectomy rarely occurs but can compromise both maternal and fetal well-being in subsequent pregnancy. We here present two cases of pregnancy complicated by preterm birth that resulted from uterine scar dehiscence following laparoscopic myomectomy. First case was a nulligravida who had scar dehiscence at 26 weeks of gestation after having a laparoscopic myomectomy 3 months prior to conception. Two weeks later, we observed her fetal leg protruding through the defect. The other case was a primigravida with a history of prior cesarean delivery, whose sonography revealed myomectomy scar dehiscence at 31 weeks of gestation. Within a few hours after observing, the patient complained of abdominal pain that was aggravating as fetal leg protruded through the defect. In both cases, babies were born by emergency cesarean section. Conservative management can be one of treatment options for myomectomy scar dehiscence in preterm pregnancy. However, clinicians should always be aware of the possibility of obstetric emergencies. PMID- 26623419 TI - Intraoperative bleeding control during cesarean delivery of complete placenta previa with transient occlusion of uterine arteries. AB - There are few methods to control heavy intra-operative bleeding during cesarean delivery of placenta previa. Transient occlusion of uterine arteries (TOUA) during operation has previously been reported as a quick and safe method to control intra-operative uterine bleeding. We reported 2 cases of cesarean delivery with complete placenta previa in which TOUA was performed to safely reduce intra-operative complication, especially heavy intra-operative bleeding. In the 2 cases, cesarean deliveries were safe and without any complications under the TOUA method. TOUA can be a good method to control heavy intra-operative bleeding during cesarean delivery of complete placenta previa with risk of heavy bleeding. PMID- 26623420 TI - Alternative surgical approaches for aggressive angiomyxoma at different sites in the pelvic cavity. AB - Aggressive angiomyxoma, a rare soft tissue benign neoplasm, predominantly occurs in the female pelvic peritoneum and perineum region during reproductive age. It is slow growing, locally infiltrative, and has a high risk of local recurrence and the neoplastic character of blood vessels. The standard treatment is surgery. We report three unusual aggressive angiomyxoma cases. The first case was a pedunculated mass of the left labium major; the second, a left perineal mass that infiltrated into the paravesical area via the obturator foramen; and the third, a big mass in the retroperitoneal cavity, found that growing aggressive angiomyxoma looked like lava expulsion in the pelvic area. After a thorough examination and full radiologic workup, we performed surgical excision in each patient via different approaches. Histopathologic findings were consistent with diagnosis of aggressive angiomyxoma. To date, no relapse has been observed. PMID- 26623421 TI - Abnormally high level of CA-19-9 in a benign ovarian cyst. AB - CA-19-9 antigen is mainly elevated in cases of gastrointestinal tract malignancy, including of the pancreas, colorectum, and biliary tract. CA 19-9 antigen can also be elevated in ovarian mucinous neoplasms, however, as well as in many benign conditions. Markedly raised levels of more than 10,000 U/mL were almost observed in advanced stage of malignancy. We report herein the case of a 37-year old woman who presented with an abnormally high level of CA 19-9 antigen associated with benign mucinous cystadenoma. PMID- 26623422 TI - Primary borderline parovarian tumor in pregnancy. AB - There are few reports of pregnancy complicated by a primary borderline parovarian tumor. A 32-year-old pregnant woman was found to have an ovarian tumor. At 13 weeks of gestation, cystectomy was performed and a diagnosis of primary borderline parovarian tumor was made. At 38 weeks of gestation, she underwent cesarean section combined with a restaging operation. A normal infant was delivered and there were no signs of recurrence. Currently, the patient is being followed for 24 months after the initial treatment and all imaging data show no evidence of recurrence. This report includes a short review of the existing literature on this topic and documents this case in detail. This case demonstrates the appropriate procedure for evaluating and treating a primary borderline parovarian tumor during pregnancy. PMID- 26623423 TI - Mature oocyte retrieval during laparotomic debulking surgery following random start controlled ovarian stimulation for fertility preservation in a patient with suspected ovarian cancer. AB - Herein, we report a case of successful mature oocyte retrieval during laparotomy after random-start controlled ovarian stimulation (COS) in a 21-year-old nulliparous woman with suspected recurrent ovarian immature teratoma. The patient had been diagnosed with stage IIIC immature teratoma two years earlier following a staging operation, including right oophorectomy and left ovarian cystectomy. And she had subsequently undergone four rounds of postoperative adjuvant chemotherapy with bleomycin, etoposide, and cisplatin. Approximately two years after the initial surgery, she was strongly suspected of having recurrent ovarian immature teratoma on radiologic follow-up. We performed random-start COS and in vivo oocyte retrieval during laparotomic debulking surgery including left oophorectomy. Eight mature oocytes were successfully retrieved and vitrified for fertility preservation. The final pathologic diagnosis was mature cystic teratoma of the ovary and peritoneal implants consistent with gliomatosis peritonei. This is the first case report in which random-start COS and in vivo oocyte retrieval were performed. PMID- 26623424 TI - Three cases of complications after high-intensity focused ultrasound treatment in unmarried women. AB - High-intensity focused ultrasound (HIFU) has been regarded as a non-surgical, minimally invasive therapeutic option for patients who prioritize uterus conservation. Although many studies have shown that HIFU therapy is a safe and effective treatment of uterine fibroid, not all fibroids are suitable for HIFU due to risks of serious complications. We experienced three cases of complications after the HIFU ablation for huge uterine fibroids, including two cases of rapid myoma enlargement and one case of heavy vaginal bleeding. PMID- 26623426 TI - Vectors of Crimean Congo Hemorrhagic Fever Virus in Iran. AB - BACKGROUND: Ticks are important vectors and reservoirs of Crimean Congo Hemorrhagic Fever (CCHF) virus. Human beings may be infected whenever the normal life cycle of the infected ticks on non-human vertebrate hosts is interrupted by the undesirable presence of humans in the cycle. A total of 26 species of Argasid and Ixodid ticks have been recorded in Iran; including nine Hyalomma, two Rhipicephalus, two Dermacentor, five Haemaphysalis, two Boophilus, one Ixodes and two Argas as well as three Ornithodoros species as blood sucking ectoparasites of livestock and poultries. The present paper reviews tick vectors of CCHF virus in Iran, focusing on the role of ticks in different provinces of Iran using reverse transcription polymerase chain reaction (RT-PCR) assay. METHODS: During ten years study, 1054 tick specimens; including two species of Argasidae and 17 species of Ixodidae were examined for their infection to CCHF virus genome. The output of all studies as well as related publications were discussed in the current paper. RESULTS: The results show that Rhipicephalus sanguineus, Hyalomma marginatum, H. anatolicum, H. asiaticum and H. dromedarii were known as the most frequent species which were positive for CCHF virus. CONCLUSION: The status of ticks which were positive for CCHF virus revealed that unlike the most common idea that Hyalomma species are the most important vectors of CCHF virus, other ticks including Rhipicephalus, Haemaphysalis and Dermacentor can be reservoir of this virus; thus, considering geographical distribution, type of host and environmental conditions, different tick control measurements should be carried out in areas with high incidence of CCHF disease. PMID- 26623427 TI - Dynamic Relations between Incidence of Zoonotic Cutaneous Leishmaniasis and Climatic Factors in Golestan Province, Iran. AB - BACKGROUND: Zoonotic Cutaneous Leishmaniasis (ZCL), an important public health problem in Iran, is sensitive to climate conditions. This study aimed to examine dynamic relations between the climate factors and incidence of ZCL in Golestan Province, northern Iran during 2010-2012. METHODS: Data of monthly climatic factors, including temperature variables, relative humidity variables, evaporation, total rainfall, and number of freezing and rainy days together with monthly ZCL incidence were used. Spear-man rank correlation was carried out to explain associations between the monthly ZCL incidence rate and climate factors at 0, 1, 2, 3 and 4 months lagged periods. Pearson's correlation analysis was conducted to examine the type and strength of relationships between the spatially averaged climate factors and ZCL incidence rate in district level. Stepwise multiple regression was used to find the best combination of independent climatic variables, which predict the ZCL incidence. RESULTS: Spearman correlation analysis indicated that the highest correlations between climate factors and monthly ZCL incidence were established when the climate time-series lagged the ZCL incidence series, especially two month prior to disease incidence. Based on the results of the both Spearman rank correlation and Pearson correlation analyses, ZCL incidences in Golestan Province tend to be more prevalent in areas with higher temperature, lower relative humidity, lower total rainfall, higher evaporation and lower number of rainy days. The results of stepwise regression analysis indicated that minimum temperature, mean humidity, and rainfall had considerable effect on ZCL incidence. CONCLUSION: Climate factors are major determinants of ZCL incidence rate in Golestan Province and such climate conditions provide favourable conditions for propagation and transmission of ZCL in this endemic area. PMID- 26623428 TI - A Checklist of Iranian Cockroaches (Blattodea) with Description of Polyphaga sp as a New Species in Iran. AB - BACKGROUND: Cockroaches are of vital importance medically and hygienically. They are able to contaminate foods and act as vectors of pathogenic agents such as bacteria, protozoa, and parasites to human environment either mechanically or through their digestive system. Cockroaches belong to the phylum Arthropoda, class Insecta, and order Blattodea or Blattaria. To date, over 4,500 cockroach species have been reported from different parts of the world. We overviewed the documents involved Iranian cockroaches to up-to-date checklist of cockroach species distributed in various provinces of Iran. METHODS: An extensive literature review was performed in 2013 on Iranian handbooks, reports and published data available since 1986 to obtain a comprehensive list of Iranian cockroaches. Furthermore, in an entomological survey in Tehran, cockroach specimens were collected and identified based on morphological and the DNA sequences of the mitochondrial cytochrome oxidase subunit II (COII) gene (mt-DNA COII) characteristics. RESULTS: Morphological characterization revealed presence of an un-described species very similar to Polyphaga aegyptiaca, P. indica and somehow to Pycnoscelus surinamensis, however, supplementary molecular analysis revealed the species was associated with Polyphaga of Corydiidae (Polyphagidae). With regards to the report of the un-described species, the cockroach fauna of Iran includes three families, 14 genera, and 26 species. CONCLUSION: Some species has not been collected or reported recently and also many geographical regions of the country have not been studied yet, hence a systematic research is required to reveal the real cockroach list of the country. Geographical distributions, nomination changes, and synonyms of cockroach species are presented. PMID- 26623425 TI - Pathological conditions re-shape physiological Tregs into pathological Tregs. AB - CD4+FOXP3+ regulatory T cells (Tregs) are a subset of CD4 T cells that play an essential role in maintaining peripheral immune tolerance, controlling acute and chronic inflammation, allergy, autoimmune diseases, and anti-cancer immune responses. Over the past 20 years, significant progress has been made since Tregs were first characterized in 1995. Many concepts and principles regarding Tregs generation, phenotypic features, subsets (tTregs, pTregs, iTregs, and iTreg35), tissue specificity (central Tregs, effector Tregs, and tissue resident Tregs), homeostasis (highly dynamic and apoptotic), regulation of Tregs by receptors for PAMPs and DAMPs, Treg plasticity (re-differentiation to other CD4 T helper cell subsets, Th1, Th2, Tfh and Th17), and epigenetic regulation of Tregs phenotypes and functions have been innovated. In this concise review, we want to briefly analyze these eight new progresses in the study of Tregs. We have also proposed for the first time a novel concept that "physiological Tregs" have been re-shaped into "pathological Tregs" in various pathological environments. Continuing of the improvement in our understanding on this important cellular component about the immune tolerance and immune suppression, would lead to the future development of novel therapeutics approaches for acute and chronic inflammatory diseases, allergy, allogeneic transplantation-related immunity, sepsis, autoimmune diseases, and cancers. PMID- 26623429 TI - Antigenic Cross-Reactivity Anti-Birtoxin Antibody against Androctonus crassicauda Venom. AB - BACKGROUND: Antivenom is still widely used in the treatment of envenomation as there are no vaccines or other effective agents available against animal venoms. Recently, neurotoxins named birtoxin family have been described from Parabuthus transvaalicus and Androctonus crassicauda. The aim of the present study was to test the anti-birtoxin antibodies for their ability to neutralize the lethal effects of A. crassicauda scorpion venom. METHODS: SDS-PAGE and Western blotting used the presence of components from A. crassicauda and P. transvaalicus scorpion venoms and to determine the degree of cross-reactivity. The Minimum Lethal Dose (MLD) of venom was assessed by subcutaneously (sc) injections in mice. RESULTS: The MLD of the A. crassicauda venom was 35 MUg/ 20g mouse by sc injection route. Western blotting showed the presence of components from A. crassicauda and P. transvaalicus scorpion venoms strongly cross react with the A. crassicauda antivenom. However, Western blotting of the A. crassicauda scorpion venom using the Refik Saydam Public Health Agency (RSPHA) generated antibody showed that not all the venom components cross reacted with the anti-birtoxin antibody. The antibodies only cross reacted with components falling under the 19 kDa protein size of A. crassicauda venom. CONCLUSION: The bioassays and Western blotting of A. crassicauda venom with the anti-birtoxin antibodies produced against a synthetic peptide showed that these antibodies cross reacted but did not neutralize the venom of A. crassicauda. PMID- 26623430 TI - Seroprevalence and Risk Factors of Ehrlichia canis Infection among Companion Dogs of Mashhad, North East of Iran, 2009-2010. AB - BACKGROUND: The aims of this study were to determine the seroprevalence of canine ehrlichiosis and risk factors of this disease in companion dogs' population of Mashhad, North East of Iran. Canine Monocytic Ehrlichiosis (CME) is a zoonotic disease transmitted by ticks, Rhipicephalus sanguineus, and caused by an obligate intracellular bacterium, Ehrlichia canis. METHODS: During September 2009 until November 2010, 250 companion dogs from Mashhad, North-East of Iran, were examined for serum antibody detection against E. canis by means of immunofluorescence assay test (IFAT) and factors associated with a positive antibody response. RESULTS: There was a very low prevalence of anti-E. canis antibodies (0.8%, 2/250) among studied dogs. The antibody titers for two seropositive dogs were 1:80 and 1:160, respectively. One (0.4%) of seropositive dogs was infested with, R. sanguineus. In blood smears from one of infested dogs (0.4%), typical morulae of E. canis was observed in lymphocytes. The results confirm that the lowest occurrence of reactive dogs indoors probably related to low tick infestion. CONCLUSION: This is the first report that describes serological evidences of canine monocytic ehrlichiosis in North-East of Iran. Results suggested that E. canis infection in owned pet dogs from North of Khorasan was not endemic from 2009 to 2010. Additional molecular studies are necessary to confirm E. canis infection and to identify the local strains of the organism. PMID- 26623431 TI - Bovine Ephemeral Fever in Iran: Diagnosis, Isolation and Molecular Characterization. AB - BACKGROUND: Bovine ephemeral fever (BEFV) is an arthropod-borne disease of cattle and water buffaloes. BEFV occurs seasonally in tropical, subtropical and temperate regions of Africa, Asia and Australia. It has been known for the past decades in Iran based on clinical signs but lack of an accurate diagnosis has made the real feature of disease obscured. This is the first scientific report on isolation and identification of the agent in which molecular diagnosis of BEFV was also set up with high sensitivity and specificity. METHODS: The viral agent was successfully isolated through serial passages in brain of suckling mice and cell culture. In addition, the circulating virus during the autumn 2012 in Iran was molecularly characterized based on partial G gene. RESULTS: Alignment of 3 virus sequences from different parts of Iran revealed that they are identical suggesting that the circulating viruses were most likely the same in this period. Phylogenetic analysis of the Iranian sequences with 17 sequences in the GenBank from the world showed that it is identical to the virus circulated in Turkey during the same period suggesting that the virus was circulated in a large geographic region. CONCLUSION: These results offer primary information about BEFV in Iran. To better understanding the epidemiology of the virus, further studies based on seroepidemiology, molecular epidemiology, entomology and meteorology together with finding the model of animal transportation in the region are necessary. PMID- 26623432 TI - Pfcrt Gene in Plasmodium falciparum Field Isolates from Muzaffargarh, Pakistan. AB - BACKGROUND: The aim of the study was to identify the prevalence of different species of Plasmodium and haplotypes of pfcrt in Plasmodium falciparum from the selected area. METHODS: Overall, 10,372 blood films of suspected malarial patients were examined microscopically from rural health center Sinawan, district Muzaffargarh, Pakistan from November 2008 to November 2010. P. falciparum positive samples (both whole blood and FTA blood spotted cards) were used for DNA extraction. Nested PCR was used to amplify the pfcrt (codon 72-76) gene fragment. Sequencing was carried out to find the haplotypes in the amplified fragment of pfcrt gene. RESULT: Over all slide positivity rate (SPR), P. vivax and P. falciparum positivity rate was 21.40 %, 19.37 % and 2.03% respectively. FTA blood spotted cards were equally efficient in the blood storage for PCR and sequencing. Analysis of sequencing results of pfcrt showed only one type of haplotype SagtVMNT (AGTGTAATGAATACA) from codon 72-76 in all samples. CONCLUSION: The results show high prevalence of CQ resistance and AQ resistant genes. AQ is not recommended to be used as a partner drug in ACT in this locality, so as to ward off future catastrophes. PMID- 26623433 TI - Cardiotoxic and Arrhythmogenic Effects of Hemiscorpius lepturus Scorpion Venom in Rats. AB - BACKGROUND: Envenomation by Hemiscorpius lepturus is not painful and the clinical manifestations include bloody urine due to hemoglobinuria or hematuria, dermonecrotic reactions, cardiac arrhythmia and in minority of cases acute renal failure which may lead to death following disseminated intravascular coagulation in infants. Cardiac effects of envenomation by H. lepturus venom including inotropic, chronotropic and arrhythmogenic properties are not studied as now in rat hearts with Langendorff apparatus. METHODS: Rat hearts were allowed to equilibrate in its buffer and cardiotropic plus arrhythmogenic effects induced by injection of different doses of H. lepturus venom were detected and recorded by computer acquisition based data in Langendorff apparatus. The neutralizing effects of Razi Institute antivenom and autonomic drugs were assayed in parallel studies. RESULTS: Hemiscorpius lepturus venom (25 MUg/100 l) treatment caused a negative inotropic (65.4 +/- 3.2 versus 110.2 +/- 3.4) and chronotropic effects (186.3 +/- 4.2 versus 302 +/- 6.3) in comparison to normal saline. Arrhythmogenic aspects including bradycardia, QRS widening and ST depression were induced by venom injection. Pre venom treatment (20 min) of Razi Institute antivenom (10 MUl) neutralized cardiotropic effects but post venom injection (15 min later) had no therapeutic role. Pre (10 min before) and post (15 min after) injection of adrenaline (10 MUl) neneutralized cardiotropic effects while pre venom injection (20 min) of propanolol (10 MUl) had aggravating effects. CONCLUSION: Our study paves the way for further in vivo investigation of cardiovascular effects of this venom for finding suitable treatments instead of its ordinary antivenom medication in cardiogenic shock induced by the venom. PMID- 26623434 TI - Laboratory Evaluations of the Fractions Efficacy of Annona senegalensis (Annonaceae) Leaf Extract on Immature Stage Development of Malarial and Filarial Mosquito Vectors. AB - BACKGROUND: Within the framework to control mosquitoes, ovicidal, larvicidal and pupicidal activity of Annona senegalensis leaf extract and its 4 fractions against Anopheles gambiae and Culex quinquefasciatus were evaluated in the laboratory conditions. METHODS: Ovicidal test was performed by submitting at least 100 eggs of mosquitoes to 125, 250, 500, 1000 and 2000 ppm concentrations, while larvicidal and pupicidal effects were assessed by submitting 25 larvae or pupae to the concentrations of 2500, 1250, 625 and 312.5 ppm of plant extract or fractions of A. senegalensis. RESULTS: The eggs of An. gambiae were most affected by N-hexane (0.00% hatchability) and chloroform (03.67% hatchability) fractions compared to Cx. quinquefasciatus where at least 25 % hatchability were recorded at 2000 ppm. For larvicidal test, N-hexane (LC50= 298.8 ppm) and chloroform (LC50= 418.3 ppm) fractions were more effective than other fractions on An. gambiae larvae while, a moderate effectiveness was also observed with N-hexane (LC50= 2087.6 ppm), chloroform (LC50= 9010.1 ppm) fractions on Cx. quinquefasciatus larvae. The highest mortality percent of the pupae were also recorded with N-hexane and chloroform fractions on An. gambiae at 2500 ppm. As for Cx. quinquefasciatus only 50 % and 36 % mortality were recorded with N-hexane and chloroform fractions respectively. CONCLUSION: The extract of A. senegalensis was toxic on immature stage of mosquito species tested. By splitting methanolic crude extract, only N-hexane and chloroform fractions were revealed to possess a mosquitocidal effects and could be considered and utilized for future immature mosquito vectors control. PMID- 26623435 TI - Determination of the Median Lethal Dose and Electrophoretic Pattern of Hottentotta saulcyi (Scorpiones, Buthidae) Scorpion Venom. AB - BACKGROUND: In this study, we investigated the lethal potency, electrophoretic protein pattern and in vivo effects of Hottentotta saulcyi scorpion venom in mice. METHODS: Scorpions were collected at night, by using a UV lamp from Mardin Province, Turkey. Venom was obtained from mature H. saulcyi scorpions by electrical stimulation of the telson. The lethality of the venom was determined by i.v. injections using Swiss mice. In vivo effects of the venom were assessed by using the intraperitoneal route (ip) injections into mice (20+/-1g) and monitored for 24 h. The protein profiles of the scorpion venom were analyzed by NuPAGE((r)) Novex((r)) 4-12 % gradient Bis-Tris gel followed by Coomassie blue staining. RESULTS: The lethal assay of the venom was 0.73 mg/kg in mice. We determined the electrophoretic protein pattern of this scorpion venom to be 4, 6, 9, 31, 35, 40, 46 and 69 kDa by SDS-PAGE. Analysis of electrophoresis indicated that H. saulcyi scorpion intoxicated mice exhibited autonomic nervous system symptoms (tachypnea, restlessness, hyperexcitability, convulsions, salivation, lacrimation, weakness). CONCLUSIONS: Hottentotta saulcyi scorpion venom includes short-chain neurotoxins and long-chain neurotoxins according to the electrophoretic protein patterns. The stings of H. saulcyi scorpion must be considered of risk for humans in the southeastern region, Turkey. PMID- 26623436 TI - Determination of Prevalence and Risk Factors of Infection with Babesia ovis in Small Ruminants from West Azerbaijan Province, Iran by Polymerase Chain Reaction. AB - BACKGROUND: Small ruminants' babesiosis caused by Babesia ovis, is transmitted during blood feeding by infected ticks and is the most economically important tick-borne disease in tropical and subtropical areas. This study was carried out to to estimate the infection rate of B. ovis in sheep and goats by PCR. We have analysed risk factors that might influence infection of sheep and goats with B. ovis. METHODS: A total 402 blood samples were examined microscopically for the presence of Babesia infection. All samples were tested by PCR. During sampling, whole body of each animal and farm dogs was examined for the presence of ticks. RESULTS: Forty-two animals (10.4%) were positive for Babesia spp. upon microscopic examination, whereas 67 animals (16.7%) yielded the specific DNA for B. ovis of which 52 animals were sheep and 15 animals were goats. Twenty-nine farms (72.5%) were found positive for B. ovis. The percentage of positive animals in each location varied from 13 % to 20 %. The relative risk of the presence of ticks in sheep and goats (P< 0.01) and farm dogs (P< 0.01) for PCR- positive results for B. ovis in sheep and goats was found 3.8 and 2.9, respectively. A total of 747 ticks identified as Rhipicephalus bursa, R. sanguineus and R. turanicus on the basis of morphological features. CONCLUSION: Other animal species besides dogs may also be risk factors for babesiosis in sheep and goats. Also, R. bursa may play an important role as a vector of the parasite in Iran. PMID- 26623437 TI - Fauna and Larval Habitat Characteristics of Mosquitoes in Neka County, Northern Iran. AB - BACKGROUND: Ecological studies on mosquitoes are very important in vector control programs. There are a few studies about the ecology of mosquitoes in northern Iran. This study was carried out to detect fauna and larval habitat characteristics of mosquitoes. METHODS: This study aimed to determine fauna and the ecology of mosquitoes in Neka County, Mazandaran Province, northern Iran from April to December, 2009. The larval collection was conducted using standard dipper, and the characteristics of larval habitat were investigated based on degree of transparency of water, type of water (stagnant or running), plant vegetation, sunny or shady, temperature and altitude of the natural or artificial breeding places. RESULTS: The mosquito larvae were collected from 72 habitats and identified using systematic keys. Nine species of mosquitoes were identified: Anopheles claviger (0.31%), An. maculipennis (0.54%), An. plumbeus (10.28%), An. superpictus (0.01%), Culiseta annulata (1.07%), Cs. longiareolata (8.91%), Culex mimeticus (0.03%), Cx. pipiens (63.99%), and Ochlerotatus geniculatus (14.85%). The range of temperature in the larval habitats was 19.6-22.5 degrees C. Significant difference was observed in the rate of temperature among the species in the larval habitats (P< 0.05). A checklist of mosquitoes including seven genera and 32 species has been provided for Mazandaran Province. CONCLUSION: The most dominant species were Cx. pipiens. They were collected from the larval habitats like Border Rivers, ponds, rain water pools, discarded tires and tree holes. Culiseta annulata was included to the checklist of mosquitoes in Mazandaran Province. PMID- 26623438 TI - Ectoparasites of Rodents Captured in Hamedan, Western Iran. AB - BACKGROUND: Rodents with a population greater than the entire population of other mammals on earth are the source of economic losses and health conflicts. One of the major health problems with the rodents is their role as reservoir hosts of zoonotic diseases. The aim of this study was to assess the infestation of commensal rodents with ectoparasites in Hamedan City, Western Iran. METHODS: The samples were collected by live traps during years 2012-2013. After transferring the samples to the Entomological Laboratory of Hamedan University of Medical Sciences, their ectoparasites were collected and identified. RESULTS: A total of 171 slides were prepared from 105 captured commensal rodents: Mus musculus, Rattus rattus and R. norvegicus comprising three orders namely Mesostigmata: Hypoaspis (Laelaspis) astronomica, Dermanyssius sp, Pachylaelapidae (male). Metastigmata: Rhipicephalus sp and Anoplura: Polyplax spinulosa were recovered in Hamedan City. Seventy (66.6%) rodents were found infested with at least one species of ectoparasites. CONCLUSION: The results of our study indicate that ectoparasites infestation in commensal rodents of Hamedan city is high and more attention by local health authorities is needed to prevent zoonotic diseases. PMID- 26623439 TI - First Record of Urogenital Myiasis Induced by Megaselia scalaris (Diptera: Phoridae) from Iran. AB - Myiasis is the infestation of organs and tissues of human and animals with fly larvae. This article reports an 18 year-old man with urogenital myiasis, the passing of live Megaselia scalaris larvae in the urine, from Zanjan City, northwest of Iran. We discourse the importance of diagnosis and management of urogenital myiasis in medicine. PMID- 26623440 TI - Membrane-stabilizing copolymers confer marked protection to dystrophic skeletal muscle in vivo. AB - Duchenne muscular dystrophy (DMD) is a fatal disease of striated muscle deterioration. A unique therapeutic approach for DMD is the use of synthetic membrane stabilizers to protect the fragile dystrophic sarcolemma against contraction-induced mechanical stress. Block copolymer-based membrane stabilizer poloxamer 188 (P188) has been shown to protect the dystrophic myocardium. In comparison, the ability of synthetic membrane stabilizers to protect fragile DMD skeletal muscles has been less clear. Because cardiac and skeletal muscles have distinct structural and functional features, including differences in the mechanism of activation, variance in sarcolemma phospholipid composition, and differences in the magnitude and types of forces generated, we speculated that optimized membrane stabilization could be inherently different. Our objective here is to use principles of pharmacodynamics to evaluate membrane stabilization therapy for DMD skeletal muscles. Results show a dramatic differential effect of membrane stabilization by optimization of pharmacodynamic-guided route of poloxamer delivery. Data show that subcutaneous P188 delivery, but not intravascular or intraperitoneal routes, conferred significant protection to dystrophic limb skeletal muscles undergoing mechanical stress in vivo. In addition, structure-function examination of synthetic membrane stabilizers further underscores the importance of copolymer composition, molecular weight, and dosage in optimization of poloxamer pharmacodynamics in vivo. PMID- 26623441 TI - Cell-to-cell variability in the propensity to transcribe explains correlated fluctuations in gene expression. AB - Random fluctuations in gene expression lead to wide cell-to-cell differences in RNA and protein counts. Most efforts to understand stochastic gene expression focus on local (intrinisic) fluctuations, which have an exact theoretical representation. However, no framework exists to model global (extrinsic) mechanisms of stochasticity. We address this problem by dissecting the sources of stochasticity that influence the expression of a yeast heat shock gene, SSA1. Our observations suggest that extrinsic stochasticity does not influence every step of gene expression, but rather arises specifically from cell-to-cell differences in the propensity to transcribe RNA. This led us to propose a framework for stochastic gene expression where transcription rates vary globally in combination with local, gene-specific fluctuations in all steps of gene expression. The proposed model better explains total expression stochasticity than the prevailing ON-OFF model and offers transcription as the specific mechanism underlying correlated fluctuations in gene expression. PMID- 26623443 TI - Micronutrients: A double-edged sword in microbial-induced gastric carcinogenesis. AB - Epidemiologic studies throughout the world have uniformly demonstrated significant relationships between the intake of dietary micronutrients and gastric cancer risk. An exciting concept that has gained considerable traction recently is that micronutrients modulate gene expression within Helicobacter pylori, the strongest identified risk factor for gastric carcinogenesis. We present evidence here that essential micronutrients have a direct effect on H. pylori virulence, which subsequently affects interactions at the host-pathogen interface, thereby facilitating the development of premalignant and malignant lesions in the stomach. Further, these fundamental concepts provide a framework for understanding mechanisms driving the development of other malignancies that arise from foci of gastrointestinal inflammation. PMID- 26623442 TI - Diversity of approaches in assessment of executive functions in stroke: limited evidence? AB - Stroke is a leading cause of disability worldwide. Cognitive functions and, in particular, executive function, are commonly affected after stroke, leading to impairments in performance of daily activities, decrease in social participation and in quality of life. Appropriate assessment and understanding of executive dysfunction are important, firstly to develop better rehabilitation strategies for executive functions per se and secondly to consider executive function abilities on rehabilitation strategies in general. The purpose of this review was to identify the most widely used assessment tools of executive dysfunction for patients with stroke, and their psychometric properties. We systematically reviewed manuscripts published in English in databases from 1999 to 2015. We identified 35 publications. The most frequently used instruments were the Stroop, Digit Span and Trail making tests. Psychometric properties were described for the Executive Function Performance Test, Executive Clock Drawing Task, Chinese Frontal Assessment Battery and Virtual Action Planning - Supermarket, and two subtests of the Cambridge Cognitive Examination - Revised. There is a paucity of tools to reliably measure executive dysfunction after stroke, despite the fact that executive dysfunction is frequent. Identification of the best tools for executive dysfunction assessment is necessary to address important gaps in research and in clinical practice. PMID- 26623445 TI - Detecting Rumors Through Modeling Information Propagation Networks in a Social Media Environment. AB - In the midst of today's pervasive influence of social media content and activities, information credibility has increasingly become a major issue. Accordingly, identifying false information, e.g. rumors circulated in social media environments, attracts expanding research attention and growing interests. Many previous studies have exploited user-independent features for rumor detection. These prior investigations uniformly treat all users relevant to the propagation of a social media message as instances of a generic entity. Such a modeling approach usually adopts a homogeneous network to represent all users, the practice of which ignores the variety across an entire user population in a social media environment. Recognizing this limitation of modeling methodologies, this study explores user-specific features in a social media environment for rumor detection. The new approach hypothesizes that whether a user tends to spread a rumor is dependent upon specific attributes of the user in addition to content characteristics of the message itself. Under this hypothesis, information propagation patterns of rumors versus those of credible messages in a social media environment are systematically differentiable. To explore and exploit this hypothesis, we develop a new information propagation model based on a heterogeneous user representation for rumor recognition. The new approach is capable of differentiating rumors from credible messages through observing distinctions in their respective propagation patterns in social media. Experimental results show that the new information propagation model based on heterogeneous user representation can effectively distinguish rumors from credible social media content. PMID- 26623446 TI - End-of-life discussions. PMID- 26623444 TI - HPV vaccine completion and dose adherence among commercially insured females aged 9 through 26 years in the US. AB - BACKGROUND: Although HPV vaccination has been recommended for use in girls and young women since 2007, HPV vaccine uptake is low in the US. METHODS: We conducted a retrospective cohort study using the 2008-2011 MarketScan data to examine HPV vaccine completion and dose adherence among commercially insured females aged 9-26 years. We performed multivariable logistic regression models to examine factors related to HPV vaccine completion and HPV vaccine dose adherence. RESULTS: Among 378,484 females aged 9-26 years who initiated HPV vaccination, only 29.4% completed HPV vaccination. Compared with females receiving vaccines from primary care providers, those receiving vaccines from OB/GYN providers were more likely to complete the vaccine series. Age at HPV vaccine initiation, health insurance plan, seasonal pattern, and flu vaccination were also significantly associated with vaccine completion. Among 111,286 females who completed HPV vaccination, 62.4% received all doses within 30 days of the recommended schedules. Similar factors relating to HPV vaccine completion were consistently associated with HPV vaccine dose adherence. However, younger age (<22 years) and receipt of flu vaccine were negatively related to HPV vaccine dose adherence. CONCLUSIONS: Intervention programs to improve HPV vaccine reminding system and reduce logistic barriers for both physicians and patients are warranted. PMID- 26623447 TI - Aid in Dying: Considering the Options. Support grows as CA becomes fifth state to pass legislation in cases of terminal illness. PMID- 26623448 TI - Neurorehabilitation: achieving recovery after neural injuries. PMID- 26623449 TI - Concussions and Brain Injuries in Youth Sports. PMID- 26623450 TI - The Role of Speech-Language Pathologists in Stroke Rehabilitation. PMID- 26623451 TI - Low back pain, radiculopathy, and bilateral proximal hamstring ruptures: a case report. AB - Low back pain (LBP) is a common complaint in the United States, with an incidence of 6.3%-15.4% and yearly recurrence in 54%-90% of patients.1 Trends show more frequent diagnostic testing, opioid use, and surgical intervention as the incidence of LBP increases.2 LBP is defined as pain at and near the lumbosacral region that can vary with physical activity and time. LBP is usually related to pathology of muscles, ligaments, spinal column joints, nerve roots, and the spinal cord. During the assessment of LBP, practitioners must also consider less common causes of pain in that region. For instance, patients with indolent or nighttime pain may have infectious or malignant processes. Referred pain from injuries to pelvic musculature or abdominal contents should be considered, especially following a traumatic event. One of these injuries, which can present as acute low back pain, is rupture of the proximal hamstring tendon. On rare occasion, concomitant LBP, radiculopathy, and hamstring injuries can occur;. This diagnostic challenge is described in the following case. PMID- 26623452 TI - Orthopaedic Management of Spasticity. AB - Spasticity is a common manifestation of many neurological conditions including multiple sclerosis, stroke, cerebral palsy, traumatic brain injury, and spinal cord injuries. Management of spasticity seeks to reduce its burden on patients and to limit secondary complications. Non-operative interventions including stretching/splinting, postural management, physical therapy/strengthening, anti spasticity medications, and botulinum toxin injections may help patients with spasticity. Surgical management of these conditions, however, is often necessary to improve quality of life and prevent complications. Orthopaedic surgeons manage numerous sequelae of spasticity, including joint contractures, hip dislocations, scoliosis, and deformed extremities. When combined with the efforts of rehabilitation specialists, neurologists, and physical/occupational therapists, the orthopaedic management of spasticity can help patients maintain and regain function and independence as well as reduce the risk of long-tem complications. PMID- 26623453 TI - Heterotopic Ossification in Neurorehabilitation. AB - Neurogenic heterotopic ossification (NHO) involves deposition of bone in extraskeletal tissue in the setting of a neurological disorder, and its pathophysiology is incompletely understood. NHO can lead to significant disability and functional impairment. NHO initially manifests as pain and joint stiffness. Early diagnosis requires appropriate suspicion and imaging studies to detect the uncalcified collagen matrix that forms in the early stages of NHO. If diagnosis is made in the early phase of NHO, progression may be halted with bisphosphonates, indomethacin or radiation therapy. If NHO progresses to its final stages without intervention, it may restrict joints and render them dysfunctional. Surgical treatment of NHO may restore function, but complications may occur, and prophylaxis and aggressive rehabilitation are essential. PMID- 26623454 TI - Barriers to Health Insurance Pre- and Post-Affordable Care Act Implementation in Providence, RI. AB - The impact of healthcare reform under the Affordable Care Act (ACA) on individuals living in cities has not yet been quantified by local Departments of Health. This makes it difficult for safety net sources of healthcare, such as free clinics, to plan for the future. Therefore, members of Clinica Esperanza/Hope Clinic conducted a survey in predominantly Latino communities of South and West Providence, RI, using a convenience sample method (N = 206). Survey results were compared to a prior survey conducted in the same communities prior to ACA implementation. Despite gains due to Obamacare, a much higher level of uninsurance was reported in this survey than has been reported statewide. In 2014, as compared to 2010, 48% vs. 95% of respondents reported being uninsured, and more held private (20% vs. 5%) or government-subsidized health insurance (32% vs. 1%). Undocumented immigration status and cost were the two most commonly reported reasons for remaining uninsured under the ACA. First-generation immigrants living in urban centers are still reporting significantly higher rates of uninsurance (48%) than the general population in RI (7.4%). PMID- 26623455 TI - Hypertriglyceridemia-Induced Pancreatitis: A Decade of Experience in a Community Based Teaching Hospital. AB - INTRODUCTION: Hypertriglyceridemia is the third most common cause of acute pancreatitis. The current evidence on the management of hypertriglyceridemia induced pancreatitis (HTGP) is mainly derived from case series. It has been suggested that insulin, and plasmapheresis have a role in the management of acute HTGP. We present a retrospective review of patients seen at a community-teaching hospital between 2005 and 2015. RESULTS: Out of the 549 admissions for acute pancreatitis, fourteen patients met our inclusion criteria. The mean age of presentation was 39+/- 8 years and there was a predominance of men (57%). More than two-thirds of the patients were admitted to the intensive care unit. The majority of the patients were treated with insulin drip (n=8), and the rest by subcutaneous insulin (n=3) and insulin drip + plasmapheresis (n=3). In the insulin drip group we noted a gradual decrease of the admission serum triglycerides by 50.6 +/-16.0 % at 24 hours, 65.9+/-16.9% at 48 hours, and then 85.2+/- 7.1% at discharge. Serum triglycerides decreased by 79.8% and 92.6%, at discharge in the subcutaneous insulin and insulin + plasmapheresis cohorts, respectively. The insulin + plasmapheresis cohort stayed in the hospital longer (20.7+/-3.1 days) compared to the insulin drip (10.3+/-5.4 days) and subcutaneous insulin (5.7 +/- 1.2 days) cohorts. CONCLUSION: Our study strengthens the evidence for using insulin (infusion or subcutaneous) with or without plasmapheresis in the treatment of hypertriglycerimia-induced pancreatitis. PMID- 26623456 TI - Placing Bundled Payments in Perspective: A Survey of the New England Ophthalmological Society. AB - OBJECTIVE: To determine ophthalmologists' views on the Medicare bundled payment model for specialty physicians in the outpatient setting. DESIGN AND METHODS: The New England Ophthalmology Society (NEOS) was emailed an anonymous survey. Views of bundled payments and demographic characteristics were analyzed. RESULTS: Of responding members, 72% (115/160) strongly opposed bundled payments; 68% (108/160) believed bundled payments will lead to financial losses, and the majority did not support including costs of prescription drugs (69%, 109/159) or preoperative (77%, 123/159) or postoperative complications (59%, 94/159) in the bundle. Respondents who held office in a medical society, were in private practice, solely billed for income, and had mostly conservative political views were significantly more likely to oppose bundling. CONCLUSION: The majority of NEOS ophthalmologists were opposed to bundled payments. Personal beliefs and practice type may influence the level of ophthalmologist support of bundled payments. PMID- 26623457 TI - Pott's Puffy Tumor in a 12-year-old boy. PMID- 26623458 TI - Perinatal Mental Distress in Rhode Island: Data to Guide Decision-Making. PMID- 26623459 TI - A Logic Model for Understanding and Reducing Preventable Hospitalizations. AB - Identifying and understanding the root causes of preventable hospitalization (PH) is important for improving health outcomes and reducing unnecessary healthcare costs. Thus far, however, the desire to address this issue has been impeded by a general lack of research on factors associated with PH. To begin to address this gap, we propose an evidence-based logic model of individual, environmental, and systemic factors related to PH. We aim to use this logic model to design public health interventions to reduce PH in the State of Rhode Island and to stimulate an industry-wide discussion of the problem and its possible solutions. PMID- 26623460 TI - Application of inductively coupled plasma mass spectrometry in the study of apoptosis: determination of caspase-3 using a gold nanoparticle tag. AB - Apoptosis is a main type of cell death in which caspase-3 plays a key role. In this work, a simple, fast and sensitive immunoassay for caspase-3 is established by using inductively coupled plasma mass spectrometry (ICP-MS) detection and signal enhancement gold nanoparticle (Au-NP) labelling of the secondary antibody (IgG). After the immunoreaction of caspase-3, primary antibody and Au-NP labeled IgG, the concentration of caspase-3 was determined by ICP-MS analysis of the Au NPs released from the immunocomplex. Under the optimized conditions, a limit of detection (LOD, 3sigma) of 0.42 ng mL(-1) (0.31 nM) was obtained for caspase-3, with a dynamic range of 1-200 ng mL(-1) and a relative standard deviation of 4.1% (c = 5 ng mL(-1), n = 11). The proposed method has good specificity towards caspase-3. To demonstrate the application potential of the proposed method, the cell lysates of Hg(2+)-induced HepG2 cells were analyzed, and it was found that the concentration of caspase-3 increased when increasing the incubation concentration of Hg(2+). This method is easy, sensitive and selective, and has excellent capability of tolerating a complex biological matrix, indicating the potential of the ICP-MS-based assay in the study of apoptosis. PMID- 26623461 TI - pH- and NIR light responsive nanocarriers for combination treatment of chemotherapy and photodynamic therapy. AB - The side effects of antitumor drugs and low treatment efficacy are two major challenges of current chemotherapy. To address these issues, we developed a new kind of smart nanocarriers that combine pH-responsive chemotherapy and near infrared (NIR) light triggered photodynamic therapy. These nanocarriers were based on upconversion nanoparticle (UCN)-loaded folate-conjugated polymeric lipid vesicles (UFPLVs). Merocyanine 540 (MC540), as a photosensitizer, was loaded in the UFPLVs; doxorubicin hydrochloride (DOX), as an antitumor drug, was conjugated to the surfaces of UFPLVs by pH-sensitive hydrazone bonds. The newly developed MC540&DOX-UFPLVs had a nanosized structure with targeting ligand modification, so they had the potential to accumulate into tumor sites via a combination of passive and active targeting effects. An in vitro singlet oxygen test showed that the nanocarriers can generate cytotoxic singlet oxygen successfully under the irradiation of NIR light. In vitro DOX release profiles demonstrated that the nanocarriers can achieve a pH-triggered drug release. It has been demonstrated by a cellular uptake study that the nanocarriers can efficiently deliver drugs and photosensitizers into tumor cells. In vitro and in vivo combination treatments evidenced the high antitumor effects of MC540&DOX-UFPLVs under NIR light irradiation. These results suggest that the MC540&DOX-UFPLVs may be promising nanocarriers for tumor combination therapy applications. PMID- 26623462 TI - Is it safe to breastfeed while taking methylphenidate? AB - QUESTION: My patient has narcolepsy and is currently breastfeeding her 3-month old infant. Lately she has had difficulties adjusting to caring for her baby, especially staying alert with the demands of breastfeeding. If she starts taking methylphenidate again, should I advise her to switch to formula? ANSWER: Methylphenidate is excreted in breast milk only in small amounts, and to date there have been no reports of breastfed infants demonstrating any adverse effects. Based on the available data, methylphenidate appears to be compatible with breastfeeding; however, the long-term neurodevelopmental effects have not been adequately studied. PMID- 26623463 TI - Family medicine residents' barriers to conducting scholarly work. AB - OBJECTIVE: To identify family medicine residents' barriers to conducting high quality research for the mandatory family medicine resident scholarly project, as well as to determine possible strategies to encourage research activity among family medicine residents. DESIGN: Descriptive study using an online survey. SETTING: Department of Family Medicine at the University of Ottawa in Ontario. PARTICIPANTS: A total of 54 first- and second-year residents. MAIN OUTCOME MEASURES: Family medicine residents' involvement in research activities, perceived quality of their mandatory scholarly project, intentions for publication and presentation, and attitudes toward potential barriers to and facilitators of conducting high-quality research. RESULTS: Of the 54 residents, 20 (37%) reported that their project was of high quality, 6 (11%) intended to publish their findings, and 2 (4%) intended to present their findings. Respondents indicated that the main barriers to conducting high-quality research were lack of time, interest, and scholarly skills. The proposed solutions to increase participation in scholarly work were to allow full research days to be used in half-day increments and to offer a journal club where residents could learn scholarly activities. CONCLUSION: Family medicine residents found several factors to be considerable barriers to completing the required family medicine resident scholarly project. This indicates that there is a need to change the current approach to developing scholarly skills in family medicine. Greater allotment of and flexibility in protected research time and more sessions focused on developing scholarly skills might facilitate scholarly activity among family medicine residents. PMID- 26623464 TI - Age of first exposure to football and later-life cognitive impairment in former NFL players. PMID- 26623465 TI - Age of first exposure to football and later-life cognitive impairment in former NFL players. PMID- 26623466 TI - Author Response. PMID- 26623467 TI - The British Cardiovascular Society Annual Conference 2015. PMID- 26623469 TI - Wellness and what causes it? PMID- 26623468 TI - Research providing new insights into myocardial infarction injury. PMID- 26623470 TI - Music and the heart. PMID- 26623471 TI - [Memories of I.S. Babchine (the 120th anniverasary)]. PMID- 26623473 TI - Editorial: Valuing the Past, Investing in the Future. PMID- 26623472 TI - Mental health: The mindful way. PMID- 26623474 TI - Cognitive Rehabilitation After Traumatic Brain Injury: A Reference for Occupational Therapists. AB - Nearly 1.7 million Americans sustain a traumatic brain injury (TBI) each year. These injuries can result in physical, emotional, and cognitive consequences. While many individuals receive cognitive rehabilitation from occupational therapists (OTs), the interdisciplinary nature of TBI research makes it difficult to remain up-to-date on relevant findings. We conducted a literature review to identify and summarize interdisciplinary evidence-based practice targeting cognitive rehabilitation for civilian adults with TBI. Our review summarizes TBI background, and our cognitive remediation section focuses on the findings from 37 recent (since 2006) empirical articles directly related to cognitive rehabilitation for individuals (i.e., excluding special populations such as veterans or athletes). This manuscript is offered as a tool for OTs engaged in cognitive rehabilitation and as a means to highlight arenas where more empirical, interdisciplinary research is needed. PMID- 26623475 TI - Looking Backward, Thinking Forward: Occupational Therapy and Autism Spectrum Disorders. AB - As autism spectrum disorders become more prevalent and comprise a growing percentage of occupational therapists' caseloads, it is important to examine trends in the literature. The purpose of this scoping review is to provide a historical analysis to illuminate changes and gaps in the occupational therapy literature related to autism spectrum disorders to inform the direction of research and practice. A total of 115 articles published in five occupational therapy journals in the United States from 1980 to 2013 were reviewed. Publications were coded by article type, with intervention studies coded in detail. Results indicated a consistent increase in number of publications as years progressed. Analysis by decade highlighted a shift from a biomedical focus to an occupation focus. Suggestions for future research include building a stronger evidence base, developing occupation-based assessments and interventions, and addressing needs of individuals with autism spectrum disorders and their families across the life span. PMID- 26623476 TI - Psychometrics of the Fitness-to-Drive Screening Measure. AB - We employed item response theory (IRT), specifically using Rasch modeling, to determine the measurement precision of the Fitness-to-Drive Screening Measure (FTDS), a tool that can be used by caregivers and occupational therapists to help detect at-risk drivers. We examined unidimensionality through the factor structure (how items contribute to the central construct of fitness to drive), rating scale (use of the categories of the rating scale), item/person-level separation (distinguishing between items with different difficulty levels or persons with different ability levels) and reliability, item hierarchy (easier driving items advancing to more difficult driving items), rater reliability, rater effects (severity vs. leniency of a rater), and criterion validity of the FTDS to an on-road assessment, via three rater groups (n = 200 older drivers; n = 200 caregivers; n = 2 evaluators). The FTDS is unidimensional, the rating scale performed well, has good person (> 3.07) and item (> 5.43) separation, good person (> 0.90) and item reliability (> 0.97), with < 10% misfitting items for two rater groups (caregivers and drivers). The intraclass correlation (ICC) coefficient among the three rater groups was significant (.253, p < .001) and the evaluators were the most severe raters. When comparing the caregivers' FTDS rating with the drivers' on-road assessment, the areas under the curve (index of discriminability; caregivers .726, p < .001) suggested concurrent validity between the FTDS and the on-road assessment. Despite limitations, the FTDS is a reliable and accurate screening measure for caregivers to help identify at-risk older drivers and for occupational therapy practitioners to start conversations about driving. PMID- 26623477 TI - The road to ratios. PMID- 26623478 TI - 'Not Now, Not Ever' report highlights bleak reality. PMID- 26623480 TI - A New Gd(3+) Spin Label for Gd(3+)-Gd(3+) Distance Measurements in Proteins Produces Narrow Distance Distributions. AB - Gd(3+) tags have been shown to be useful for performing distance measurements in biomolecules via the double electron-electron resonance (DEER) technique at Q- and W-band frequencies. We introduce a new cyclen-based Gd(3+) tag that exhibits a relatively narrow electron paramagnetic resonance (EPR) spectrum, affording high sensitivity, and which yields exceptionally narrow Gd(3+)-Gd(3+) distance distributions in doubly tagged proteins owing to a very short tether. Both the maxima and widths of distance distributions measured for tagged mutants of the proteins ERp29 and T4 lysozyme, featuring Gd(3+)-Gd(3+) distances of ca. 6 and 4 nm, respectively, were well reproduced by simulated distance distributions based on available crystal structures and sterically allowed rotamers of the tag. The precision of the position of the Gd(3+) ion is comparable to that of the nitroxide radical in an MTSL-tagged protein and thus the new tag represents an attractive tool for performing accurate distance measurements and potentially probing protein conformational equilibria. PMID- 26623479 TI - Intracellular Target-Specific Accretion of Cell Penetrating Peptides and Bioportides: Ultrastructural and Biological Correlates. AB - Cell penetrating peptide (CPP) technologies provide a viable strategy to regulate the activities of intracellular proteins that may be intractable to other biological agents. In particular, the cationic helical domains of proteins have proven to be a reliable source of proteomimetic bioportides, CPPs that modulate the activities of intracellular proteins. In this study we have employed live cell imaging confocal microscopy to determine the precise intracellular distribution of a chemically diverse set of CPPs and bioportides. Our findings indicate that, following efficient cellular entry, peptides are usually accreted at intracellular sites rather than being freely maintained in an aqueous cytosolic environment. The binding of CPPs to proteins in a relatively stable manner provides a molecular explanation for our findings. By extension, it is probable that many bioportides influence biological processes through a dominant negative influence upon discrete protein-protein interactions. As an example, we report that bioportides derived from the leucine-rich repeat kinase 2 discretely influence the biology and stability of this key therapeutic target in Parkinson's disease. The intracellular site-specific accretion of CPPs and bioportides can also be readily modulated by the attachment of larger cargoes or, more conveniently, short homing motifs. We conclude that site-specific intracellular targeting could be further exploited to expand the scope of CPP technologies. PMID- 26623481 TI - Biodegradable Photonic Melanoidin for Theranostic Applications. AB - Light-absorbing nanoparticles for localized heat generation in tissues have various biomedical applications in diagnostic imaging, surgery, and therapies. Although numerous plasmonic and carbon-based nanoparticles with strong optical absorption have been developed, their clearance, potential cytotoxicity, and long term safety issues remain unresolved. Here, we show that "generally regarded as safe (GRAS)" melanoidins prepared from glucose and amino acid offer a high light to-heat conversion efficiency, biocompatibility, biodegradability, nonmutagenicity, and efficient renal clearance, as well as a low cost for synthesis. We exhibit a wide range of biomedical photonic applications of melanoidins, including in vivo photoacoustic mapping of sentinel lymph nodes, photoacoustic tracking of gastrointestinal tracts, photothermal cancer therapy, and photothermal lipolysis. The biodegradation rate and renal clearance of melanoidins are controllable by design. Our results confirm the feasibility of biodegradable melanoidins for various photonic applications to theranostic nanomedicines. PMID- 26623482 TI - Bicarbonate and Alkyl Carbonate Radicals: Structural Integrity and Reactions with Lipid Components. AB - The elusive neutral bicarbonate radical and the carbonate radical anion form an acid/conjugate base pair. We now report experimental studies for a model of bicarbonate radical, namely, methyl carbonate (methoxycarbonyloxyl) radical, complemented by DFT computations at the CAM-B3LYP level applied to the bicarbonate radical itself. Methyl carbonate radicals were generated by UV irradiation of oxime carbonate precursors. Kinetic EPR was employed to measure rate constants and Arrhenius parameters for their dissociation to CO2 and methoxyl radicals. With oleate and cholesterol lipid components, methyl carbonate radicals preferentially added to their double bonds; with linoleate and linolenate substrates, abstraction of the bis-allylic H atoms competed with addition. This contrasts with the behavior of ROS such as hydroxyl radicals that selectively abstract allylic and/or bis-allylic H atoms. The thermodynamic and activation parameters for bicarbonate radical dissociation, obtained from DFT computations, predicted it would indeed have substantial lifetime in gas and nonpolar solvents. The acidity of bicarbonate radicals was also examined by DFT methods. A noteworthy linear relationship was discovered between the known pKa's of strong acids and the computed numbers of microsolvating water molecules needed to bring about their ionization. DFT computations with bicarbonate radicals, solvated with up to eight water molecules, predicted that only five water molecules were needed to bring about its complete ionization. On comparing with the correlation, this indicated a pKa of about -2 units. This marks the bicarbonate radical as the strongest known carboxylic acid. PMID- 26623495 TI - Vibrational Spectroscopy and Phonon-Related Properties of the L-Aspartic Acid Anhydrous Monoclinic Crystal. AB - The infrared absorption and Raman scattering spectra of the monoclinic P21 l aspartic acid anhydrous crystal were recorded and interpreted with the help of density functional theory (DFT) calculations. The effect of dispersive forces was taken into account, and the optimized unit cells allowed us to obtain the vibrational normal modes. The computed data exhibits good agreement with the measurements for low wavenumbers, allowing for a very good assignment of the infrared and Raman spectral features. The vibrational spectra of the two lowest energy conformers of the l-aspartic molecule were also evaluated using the hybrid B3LYP functional for the sake of comparison, showing that the molecular calculations give a limited description of the measured IR and Raman spectra of the l-aspartic acid crystal for wavenumbers below 1000 cm(-1). The results obtained reinforce the need to use solid-state calculations to describe the vibrational properties of molecular crystals instead of calculations for a single isolated molecule picture even for wavenumbers beyond the range usually associated with lattice modes (200 cm(-1) < omega < 1000 cm(-1)). PMID- 26623496 TI - Cost-Effectiveness of a Community-Based Exercise Programme in COPD Self Management. AB - INTRODUCTION: Information regarding cost-effectiveness of community-based exercise programmes in COPD is scarce. Therefore, we have investigated whether a community-based exercise programme is a cost-effective component of self management for patients with COPD after 2 years of follow-up. METHODS: All included COPD patients participated in four self-management sessions. Additionally, patients in the COPE-active group participated in an 11-month community-based exercise programme led by physiotherapists. Patients trained 3 times/week for 6 months and two times/week during the subsequent 5 months. In both periods, one of these weekly training sessions was home-based (unsupervised). No formal physiotherapy sessions were offered to COPE-active patients in the second year. A decision analytical model with a 24-month perspective was used to evaluate cost-effectiveness. Incremental cost effectiveness ratios (ICER) were calculated and cost-effectiveness planes were created. RESULTS: Data of 77 patients participating in the exercise programme and 76 patients in the control group were analysed. The ICER for an additional patient prevented from deteriorating at least 47.5 meters on the ISWT was ?6257. The ICER for an additional patient with a clinically relevant improvement (>= 500 steps/day) in physical activity was ?1564, and the ICER for an additional quality adjusted life year (QALY) was ?10 950. CONCLUSION: Due to a lack of maintenance of beneficial effects on our primary outcome exercise capacity after 2 years of follow-up and higher costs of the programme, the community-based exercise programme cannot be considered cost-effective compared to self-management programmes only. Nevertheless, the ICERs for the secondary outcomes physical activity and QALY are generally considered acceptable. PMID- 26623497 TI - Subacute Invasive Pulmonary Aspergillosis Associated with Ankylosing Spondylitis. PMID- 26623498 TI - Fluorescence Spectroscopy of the Retina for the Screening of Bovine Spongiform Encephalopathy. AB - Transmissible spongiform encephalopathies (TSE) are progressive, neurodegenerative disorders, of which bovine spongiform encephalopathy (BSE) is of special concern because it is infectious and debilitating to humans. The possibility of using fluorescence spectroscopy to screen for BSE in cattle was explored. Fluorescence spectra from the retinas of experimentally infected BSE positive cattle with clinical disease were compared with those from both sham inoculated and non-inoculated BSE-negative cattle. The distinct intensity difference of about 4-10-fold between the spectra of the BSE-positive and the BSE negative (sham-inoculated and non-inoculated) eyes suggests the basis for a means of developing a rapid, noninvasive examination of BSE in particular and TSEs in general. PMID- 26623509 TI - Lipoxygenase-modified Ru-bpy/graphene oxide: Electrochemical biosensor for on farm monitoring of non-esterified fatty acid. AB - Elevated concentrations of non-esterified fatty acids (NEFA) in biological fluids are recognized as critical biomarkers for early diagnosis of dairy cow metabolic diseases. Herein, a cost-effective, electrochemically active, and bio-friendly sensor element based on ruthenium bipyridyl complex-modified graphene oxide nanosheets ([Ru(bpy)3](2+)-GO) is proposed as a biosensor platform for NEFA detection. Electrochemical analysis demonstrates that the [Ru(bpy)3](2+)-GO electrodes exhibit superior and durable redox properties compared to the pristine carbon and GO electrodes. Target specificity is accomplished through immobilization of the enzyme, lipoxygenase, which catalyzes the production of redox active species from NEFA. Lipoxygenases retain their catalytic ability upon immobilization and exhibit changes to amperometric signals upon interaction with various concentrations of standard NEFA and serum samples. Our study demonstrates that the [Ru(bpy)3](2+)-GO electrode has the potential to serve as a biosensor platform for developing a field deployable, rapid, and user-friendly detection tool for on-farm monitoring of dairy cow metabolic diseases. PMID- 26623510 TI - Enhanced simultaneous detection of ractopamine and salbutamol--Via electrochemical-facial deposition of MnO2 nanoflowers onto 3D RGO/Ni foam templates. AB - In this paper, we report a facile method to successfully fabricate MnO2 nanoflowers loaded onto 3D RGO@nickel foam, showing enhanced biosensing activity due to the improved structural integration of different electrode materials components. When the as-prepared 3D hybrid electrodes were investigated as a binder-free biosensor, two well-defined and separate differential pulse voltammetric peaks for ractopamine (RAC) and salbutamol (SAL) were observed, indicating the simultaneous selective detection of both beta-agonists possible. The MnO2/RGO@NF sensor also demonstrated a linear relationship over a wide concentration range of 17 nM to 962 nM (R=0.9997) for RAC and 42 nM to 1463 nM (R=0.9996) for SAL, with the detection limits of 11.6 nM for RAC and 23.0 nM for SAL. In addition, the developed MnO2/RGO@NF sensor was further investigated to detect RAC and SAL in pork samples, showing satisfied comparable results in comparison with analytic results from HPLC. PMID- 26623511 TI - A plasmonic colorimetric strategy for biosensing through enzyme guided growth of silver nanoparticles on gold nanostars. AB - A plasmonic colorimetric strategy was designed for sensitive detection of biomolecules through enzyme guided silver nanoparticles (AgNPs) growth on gold nanostars (AuNS). The growth of AgNPs on AuNS led to a substantial blue shift of the localized surface plasmon resonance (LSPR) peak and the color change of AuNS from blue to dark blue, purple and ultimately orange. Both the LSPR blueshift wavelength and the color of detection solution containing AuNS, Ag(+) and ascorbic acid 2-phosphate (AAP) depend on the amount of enzyme that catalyzed the dephosphorylation of AAP to reduce Ag(+) on AuNS surface. Thus this strategy could be used for LSPR and naked-eye detections of both the enzyme such as alkaline phosphatase (ALP) and other biomolecules involved in biorecognition events using ALP as a tag. The LSPR detection method for ALP showed a linear range from 1.0 pM to 25 nM with a detection limit of 0.5 pM. Using DNA as a mode target molecule, this technique showed a detection range from 10 fM to 50 pM DNA with a detection limit of 2.6 fM through the convenient combination with hybridization chain reaction amplification. The proposed plasmonic colorimetric strategy could be extended as a general analytical platform for design of immunosensors and aptasensors with ALP as a label. PMID- 26623512 TI - Facile development of Au-ring microelectrode for in vivo analysis using non-toxic polydopamine as multifunctional material. AB - In this study, we describe a facile and fast wet deposition technique to bottom up fabricate Au-ring microelectrodes (Au-RMEs) using non-toxic polydopamine as multifunctional grafting material instead of commonly used (3-aminopropyl) trimethoxysilane (APTMS). The Au-RMEs are fabricated by growing Au film uniformly inside of a pulled glass capillary. Au-RMEs with tip apex diameter ranging from 15 to 50 MUm were fabricated involving four consequent steps, i.e. hydroxylating the inside wall of a pulled glass capillaries, grafting adhesive polydopamine (PDA) film to hydroxyl group surface, seeding gold nanoparticles (AuNPs) onto PDA surface and finally growing thickness-tunable gold layer on top of gold nanoparticles. After 3-mercaptopropionic acid (MPA) self-assembled monolayers (SAMs) modification, the Au-RMEs obtain improved specificity and sensitivity for monitoring of dopamine (DA) with respect to alleviating ascorbic acid (AA) interference. The current response is in wide linearity to DA concentration in the range of 0.2-100.0 MUM with a correlation coefficient of 0.998 and the detection limit as low as 50.0 nM (S/N=3). In addition, the designed glass substrates of Au-RMEs were mechanically stronger and their tips can be further sharped by adjusting the pulling program. In order to demonstrate the utility of these fabricated microelectrodes in neurochemistry, Au-RMEs were used for electrochemical monitoring of DA release stimulated by K(+) in the striatum of rats. Thus, this study offers a novel and reliable strategy for preparing Au microelectrodes and maybe an attractive alternative to the traditional options for continuous and in vivo electrochemical monitoring of DA in various physiological processes. PMID- 26623513 TI - The 3-I framework: a framework for developing public policies regarding pharmacogenomics (PGx) testing in Canada. AB - The 3-I framework of analyzing the ideas, interests, and institutions around a topic has been used by political scientists to guide public policy development. In Canada, there is a lack of policy governing pharmacogenomics (PGx) testing compared to other developed nations. The goal of this study was to use the 3-I framework, a policy development tool, and apply it to PGx testing to identify and analyze areas where current policy is limited and challenges exist in bringing PGx testing into wide-spread clinical practice in Canada. A scoping review of the literature was conducted to determine the extent and challenges of PGx policy implementation at federal and provincial levels. Based on the 3-I analysis, contentious ideas related to PGx are (i) genetic discrimination, (ii) informed consent, (iii) the lack of knowledge about PGx in health care, (iv) the value of PGx testing, (v) the roles of health care workers in the coordination of PGx services, and (vi) confidentiality and privacy. The 3-I framework is a useful tool for policy makers, and applying it to PGx policy development is a new approach in Canadian genomics. Policy makers at every organizational level can use this analysis to help develop targeted PGx policies. PMID- 26623514 TI - Auxiliary subunits of the CKAMP family differentially modulate AMPA receptor properties. AB - AMPA receptor (AMPAR) function is modulated by auxiliary subunits. Here, we report on three AMPAR interacting proteins-namely CKAMP39, CKAMP52 and CKAMP59 that, together with the previously characterized CKAMP44, constitute a novel family of auxiliary subunits distinct from other families of AMPAR interacting proteins. The new members of the CKAMP family display distinct regional and developmental expression profiles in the mouse brain. Notably, despite their structural similarities they exert diverse modulation on AMPAR gating by influencing deactivation, desensitization and recovery from desensitization, as well as glutamate and cyclothiazide potency to AMPARs. This study indicates that AMPAR function is very precisely controlled by the cell-type specific expression of the CKAMP family members. PMID- 26623515 TI - Mechanical stress contributes to the expression of the STM homeobox gene in Arabidopsis shoot meristems. AB - The role of mechanical signals in cell identity determination remains poorly explored in tissues. Furthermore, because mechanical stress is widespread, mechanical signals are difficult to uncouple from biochemical-based transduction pathways. Here we focus on the homeobox gene SHOOT MERISTEMLESS (STM), a master regulator and marker of meristematic identity in Arabidopsis. We found that STM expression is quantitatively correlated to curvature in the saddle-shaped boundary domain of the shoot apical meristem. As tissue folding reflects the presence of mechanical stress, we test and demonstrate that STM expression is induced after micromechanical perturbations. We also show that STM expression in the boundary domain is required for organ separation. While STM expression correlates with auxin depletion in this domain, auxin distribution and STM expression can also be uncoupled. STM expression and boundary identity are thus strengthened through a synergy between auxin depletion and an auxin-independent mechanotransduction pathway at the shoot apical meristem. PMID- 26623517 TI - Sampling the conformational space of the catalytic subunit of human gamma secretase. AB - Human gamma-secretase is an intra-membrane protease that cleaves many different substrates. Aberrant cleavage of Notch is implicated in cancer, while abnormalities in cutting amyloid precursor protein lead to Alzheimer's disease. Our previous cryo-EM structure of gamma-secretase revealed considerable disorder in its catalytic subunit presenilin. Here, we describe an image classification procedure that characterizes molecular plasticity at the secondary structure level, and apply this method to identify three distinct conformations in our previous sample. In one of these conformations, an additional transmembrane helix is visible that cannot be attributed to the known components of gamma-secretase. In addition, we present a gamma-secretase structure in complex with the dipeptidic inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t butyl ester (DAPT). Our results reveal how conformational mobility in the second and sixth transmembrane helices of presenilin is greatly reduced upon binding of DAPT or the additional helix, and form the basis for a new model of how substrate enters the transmembrane domain. PMID- 26623516 TI - An essential role of acetylcholine-glutamate synergy at habenular synapses in nicotine dependence. AB - A great deal of interest has been focused recently on the habenula and its critical role in aversion, negative-reward and drug dependence. Using a conditional mouse model of the ACh-synthesizing enzyme choline acetyltransferase (Chat), we report that local elimination of acetylcholine (ACh) in medial habenula (MHb) neurons alters glutamate corelease and presynaptic facilitation. Electron microscopy and immuno-isolation analyses revealed colocalization of ACh and glutamate vesicular transporters in synaptic vesicles (SVs) in the central IPN. Glutamate reuptake in SVs prepared from the IPN was increased by ACh, indicating vesicular synergy. Mice lacking CHAT in habenular neurons were insensitive to nicotine-conditioned reward and withdrawal. These data demonstrate that ACh controls the quantal size and release frequency of glutamate at habenular synapses, and suggest that the synergistic functions of ACh and glutamate may be generally important for modulation of cholinergic circuit function and behavior. PMID- 26623519 TI - The impact of a context switch and context instructions on the return of verbally conditioned fear. AB - BACKGROUND AND OBJECTIVES: Repeated exposure to a conditioned stimulus can lead to a reduction of conditioned fear responses towards this stimulus (i.e., extinction). However, this reduction is often fragile and sensitive to contextual changes. In the current study, we investigated whether extinction of fear responses established through verbal threat instructions is also sensitive to contextual changes. We additionally examined whether verbal instructions can strengthen the effects of a context change. METHODS: Fifty-two participants were informed that one colored rectangle would be predictive of an electrocutaneous stimulus, while another colored rectangle was instructed to be safe. Half of these participants were additionally informed that this contingency would only hold when the background of the computer screen had a particular color but not when it had another color. After these instructions, the participants went through an unannounced extinction phase that was followed by a context switch. RESULTS: Results indicate that extinguished verbally conditioned fear responses can return after a context switch, although only as indexed by self-reported expectancy ratings. This effect was stronger when participants were told that CS US contingency would depend on the background color, in which case a return of fear was also observed on physiological measures of fear. LIMITATIONS: Extinction was not very pronounced in this study, possibly limiting the extent to which return of fear could be observed on physiological measures. CONCLUSIONS: Contextual cues can impact the return of fear established via verbal instructions. Verbal instructions can further strengthen the contextual control of fear. PMID- 26623518 TI - Oviductal estrogen receptor alpha signaling prevents protease-mediated embryo death. AB - Development of uterine endometrial receptivity for implantation is orchestrated by cyclic steroid hormone-mediated signals. It is unknown if these signals are necessary for oviduct function in supporting fertilization and preimplantation development. Here we show that conditional knockout (cKO) mice lacking estrogen receptor alpha (ERalpha) in oviduct and uterine epithelial cells have impaired fertilization due to a dramatic reduction in sperm migration. In addition, all successfully fertilized eggs die before the 2-cell stage due to persistence of secreted innate immune mediators including proteases. Elevated protease activity in cKO oviducts causes premature degradation of the zona pellucida and embryo lysis, and wild-type embryos transferred into cKO oviducts fail to develop normally unless rescued by concomitant transfer of protease inhibitors. Thus, suppression of oviductal protease activity mediated by estrogen-epithelial ERalpha signaling is required for fertilization and preimplantation embryo development. These findings have implications for human infertility and post coital contraception. PMID- 26623520 TI - Dispositional Mindfulness and Aggression Among Women in Residential Substance Use Treatment. AB - There is a large literature on substance misuse and interpersonal aggression, including aggression perpetrated by women in treatment for substance misuse. There is also a growing body of literature on mindfulness and substance use, as well as mindfulness and aggression. However, to date, there has been little research on whether dispositional mindfulness is associated with increased aggression among women in treatment for substance misuse. The current study, therefore, examined whether dispositional mindfulness was associated with aggression, above and beyond substance use and demographic characteristics, in women in residential substance misuse treatment (N = 137). Results showed that lower dispositional mindfulness was associated with increased aggression (physical, verbal, and aggressive attitude). Moreover, this relationship between dispositional mindfulness and aggression remained even after controlling for alcohol problems, drug problems, and age, all known predictors of aggression. Our results provide the first empirical evidence that dispositional mindfulness is negatively associated with aggression in women in treatment for substance misuse. Pending replication, this could have important implications for treatment. Specifically, mindfulness-based interventions may prove helpful for the concurrent treatment of substance misuse and aggression. PMID- 26623521 TI - Understanding Onychomycosis Treatment: Mechanisms of Action and Formulation. AB - Historically, the eradication of onychomycosis has been a frustrating and often unsuccessful endeavor. However, new understanding about the mechanisms of action of antifungal agents, the introduction of two new topical agents, and the drugs and devices now being investigated offer greatly improved options for current and future management of these infections. The mechanisms of action of systemic and topical antifungal agents and devices effective against the most common dermatophyte and nondermatophyte causes of onychomycosis are discussed. Semin Cutan Med Surg 34(supp3):S51-S53 (c) 2015 published by Frontline Medical Communications. PMID- 26623522 TI - Changes in tumour expression of programmed death-ligand 1 after neoadjuvant concurrent chemoradiotherapy in patients with squamous oesophageal cancer. AB - BACKGROUND: Programmed death-ligand 1 (PD-L1) expression has been suggested as a potential predictive biomarker of response to anti-PD-1/PD-L1 therapy. In this study, we investigated whether the expression of PD-L1 in tumour cells is affected by neoadjuvant concurrent chemoradiotherapy (CCRT) or chemotherapy in oesophageal squamous cell carcinoma. PATIENTS AND METHODS: Between 2004 and 2014, we collected the medical records of locally advanced oesophageal cancer patients consecutively diagnosed and treated with neoadjuvant CCRT or chemotherapy, followed by curative resection. PD-L1 expression in acquired tissue specimens was evaluated by immunohistochemistry using the H-score. The changes in PD-L1 expression between paired samples were evaluated and we also analysed PD-L1 expression in surgical tumour specimens to evaluate its prognostic role. RESULTS: Twenty-eight paired tumour tissues that were acquired before and after neoadjuvant therapy were available: 19 patients with CCRT and 9 with chemotherapy before complete oesophagectomy. The PD-L1 H-score increased significantly from baseline tumour tissues to surgical tumour tissues after neoadjuvant CCRT (P = 0.007, median H-score from 28 to 52), whereas it decreased significantly after neoadjuvant chemotherapy (P = 0.048, median H-score from 53 to 22). In a total of 73 patients, including 45 additional cases for the prognosis analysis, patients with higher PD-L1 H-scores (>= 20) had poorer overall survival (median 16.7 versus 32.9 months, P = 0.02) than those with lower H-scores (<20). CONCLUSIONS: PD-L1 expression in tumour cells increased in oesophageal cancer patients who received neoadjuvant CCRT. Further studies with more cases are necessary to validate these findings. PMID- 26623523 TI - Using handgrip strength to screen for diabetes in developing countries. AB - Lack of access to healthcare in the developing world has created a need for locally-based primary and pre-primary healthcare systems. Many regions of the world have adopted Community Health Worker (CHW) programmes, but volunteers in these programmes lack the tools and resources to screen for disease. Because of its simplicity of operation, handgrip strength (HGS) measurements have the potential to be an affordable and effective screening tool for conditions that cause muscle weakness in this context. In the study described in this report, translators were used to collect data on age, gender, height, weight, blood pressure, HGS and key demographic data. HGS was significantly lower for diabetics than patients without diabetes. A simple binary logistic model was created that used HGS, age, blood pressure and BMI to predict a patient's probability of having diabetes. This study develops a predictive model for diabetes using HGS and other basic health measurements and shows that HGS-based screening is a viable method of early detection of diabetes. PMID- 26623531 TI - Unexpected Activity: Evidence for Obesogenicity of a BPA Metabolite. PMID- 26623532 TI - Dose-surface analysis for prediction of severe acute radio-induced skin toxicity in breast cancer patients. AB - BACKGROUND: Severe acute radiation-induced skin toxicity (RIST) after breast irradiation is a side effect impacting the quality of life in breast cancer (BC) patients. The aim of the present study was to develop normal tissue complication probability (NTCP) models of severe acute RIST in BC patients. PATIENTS AND METHODS: We evaluated 140 consecutive BC patients undergoing conventional three dimensional conformal radiotherapy (3D-CRT) after breast conserving surgery in a prospective study assessing acute RIST. The acute RIST was classified according to the RTOG scoring system. Dose-surface histograms (DSHs) of the body structure in the breast region were extracted as representative of skin irradiation. Patient, disease, and treatment-related characteristics were analyzed along with DSHs. NTCP modeling by Lyman-Kutcher-Burman (LKB) and by multivariate logistic regression using bootstrap resampling techniques was performed. Models were evaluated by Spearman's Rs coefficient and ROC area. RESULTS: By the end of radiotherapy, 139 (99%) patients developed any degree of acute RIST. G3 RIST was found in 11 of 140 (8%) patients. Mild-moderate (G1-G2) RIST was still present at 40 days after treatment in six (4%) patients. Using DSHs for LKB modeling of acute RIST severity (RTOG G3 vs. G0-2), parameter estimates were TD50=39 Gy, n=0.38 and m=0.14 [Rs = 0.25, area under the curve (AUC) = 0.77, p = 0.003]. On multivariate analysis, the most predictive model of acute RIST severity was a two variable model including the skin receiving >=30 Gy (S30) and psoriasis [Rs = 0.32, AUC = 0.84, p < 0.001]. CONCLUSIONS: Using body DSH as representative of skin dose, the LKB n parameter was consistent with a surface effect for the skin. A good prediction performance was obtained using a data-driven multivariate model including S30 and a pre-existing skin disease (psoriasis) as a clinical factor. PMID- 26623533 TI - Self-Concept Clarity and Emotion Dysregulation in Nonsuicidal Self-Injury. AB - Recent research has linked identity instability with engagement in nonsuicidal self-injury (NSSI; Claes, Luyckx, & Bijttebier, 2014; Claes et al., 2015). This study examined the relationship between self-concept clarity (SCC), an index of identity stability, and NSSI in a sample of 147 college students, using a cross sectional survey design. The relationship between SCC and emotion dysregulation in NSSI severity was also examined. SCC was significantly negatively associated with NSSI engagement, as well as NSSI frequency and versatility, above negative affect or age. SCC fully accounted for the variance originally explained by emotion dysregulation in NSSI versatility. NSSI frequency was not significantly predicted by emotion regulation, but self-concept clarity reached marginal significance. These findings provide preliminary support for identity instability as a contributing factor to a relationship between emotion dysregulation and NSSI severity. Possible explanations and future research directions are discussed. PMID- 26623534 TI - Affective Instability and Reactivity in Depressed Patients With and Without Borderline Pathology. AB - The quality of depression in borderline personality disorder (BPD) was reported to differ from that in patients with major depressive disorder (MDD) only. However, little is known about affect dynamics in "borderline-depression." The authors assessed affective instability and reactivity in 20 MDD patients with BPD and in 21 MDD patients without BPD by Ambulatory Assessment. Participants reported on current affect, daily events, and attribution of affective states to events five times per day over a 7-day period. The results do not indicate higher affective instability in MDD patients with BPD comorbidity. Depressed patients with BPD reported less subjectively perceived affective reactivity, while observed associations between events and affect were not different between groups, except for one finding: In depressed patients with BPD, overall mood was lower after being alone. These findings suggest impaired attribution of mood changes and less tolerance of being alone as specific for depression in BPD. PMID- 26623535 TI - Diagnostic Agreement Between Clinicians and Clients: The Convergent and Discriminant Validity of the SWAP-200 and MCMI-III Personality Disorder Scales. AB - A particularly controversial aspect in the field of personality assessment is the use of self-report measures, versus clinicians' evaluations, for diagnosing personality disorder (PD). No studies have systematically documented the agreement between these sources for the entire array of DSM-5 PDs using comprehensive measures and experienced clinicians' judgments. The present work fills this gap by indexing the agreement between patients' self-descriptions and clinicians' judgments, relying on standardized and thorough PD instruments. The Shedler-Westen Assessment Procedure-200 (SWAP-200; Westen & Shedler, 1999a, 1999b) and the Millon Clinical Multiaxial Inventory-III (Millon, Davis, & Millon, 1997) were both completed in a clinical series of 56 adult outpatients. Analyses highlighted moderate correlations between the two measures for the 10 DSM-5 PDs (Mdn = .35). Agreement was highest for psychological features that are more easily observable by the clinicians. Furthermore, results revealed problematic discriminant validity between the two instruments. PMID- 26623536 TI - Insensitivity to the Magnitude of Potential Gains or Losses When Making Risky Choices: Women With Borderline Personality Disorder Compared With Bipolar Disorder and Controls. AB - Poor decision-making is a feature of borderline personality disorder (BPD) and bipolar disorder (BD). Twenty women with BPD, 20 women with BD, and 20 healthy females completed a risky choice task. Those with BPD exhibited altered processing of information about potential gains and losses, with a bias toward large compared to small gains, large compared to small losses, and a tendency to choose outcomes with a negative expected value. This failure to use explicit reinforcement signals was not observed in those with BD. Difficulties using reward information to make decisions may impair day-to-day function. Such impairments offer new treatment targets in BPD. PMID- 26623537 TI - Diagnosing, Disclosing, and Documenting Borderline Personality Disorder: A Survey of Psychiatrists' Practices. AB - Borderline personality disorder (BPD) is a valid and reliable diagnosis with effective treatments. However, data suggest many patients remain unaware they carry the diagnosis, even when they are actively engaged in outpatient psychiatric treatment. The authors conducted a survey of 134 psychiatrists practicing in the United States to examine whether they had ever withheld and/or not documented their patients' BPD diagnosis. Fifty-seven percent indicated that at some point during their career they failed to disclose BPD; 37 percent said they had not documented the diagnosis. For those respondents with a history of not disclosing or documenting BPD, most agreed that either stigma or uncertainty of diagnosis played a role in their decisions. The findings highlight the need for clinical training programs to address these issues. The research also invites further research to identify other reasons why psychiatrists are hesitant to be fully open about the diagnosis of BPD. PMID- 26623538 TI - Interpersonal Problems and Their Relationship to Depression, Self-Esteem, and Malignant Self-Regard. AB - DSM-5 Section III recommends that level of personality functioning be assessed. This requires an assessment of self and other representations. Malignant self regard (MSR) is a way of assessing the level of functioning of those with a masochistic, self-defeating, depressive, or vulnerably narcissistic personality. In Study 1, 840 undergraduates were assessed for MSR, depressive symptoms, self esteem, anaclitic and introjective depression, and interpersonal problems. MSR, self-esteem, depressive symptoms, and anaclitic and introjective depression were correlated with multiple dimensions of interpersonal problems, and MSR predicted the most variance in interpersonal scales measuring social inhibition, nonassertion, over-accommodation, and excessive self-sacrifice. MSR, anaclitic, and introjective depression predicted unique variance in six of the eight domains of interpersonal problems assessed. In Study 2, 68 undergraduates were provided positive or negative feedback. Consistent with theory, MSR predicted unique variance in state anxiety but not state anger. Results support the validity of the MSR construct. PMID- 26623539 TI - Identifying Two Groups of Entitled Individuals: Cluster Analysis Reveals Emotional Stability and Self-Esteem Distinction. AB - The present study hypothesized that there exist two distinct groups of entitled individuals: grandiose-entitled, and vulnerable-entitled. Self-report scores of entitlement were collected for 916 individuals using an online platform. Model based cluster analyses were conducted on the individuals with scores one standard deviation above mean (n = 159) using the five-factor model dimensions as clustering variables. The results support the existence of two groups of entitled individuals categorized as emotionally stable and emotionally vulnerable. The emotionally stable cluster reported emotional stability, high self-esteem, more positive affect, and antisocial behavior. The emotionally vulnerable cluster reported low self-esteem and high levels of neuroticism, disinhibition, conventionality, psychopathy, negative affect, childhood abuse, intrusive parenting, and attachment difficulties. Compared to the control group, both clusters reported being more antagonistic, extraverted, Machiavellian, and narcissistic. These results suggest important differences are missed when simply examining the linear relationships between entitlement and various aspects of its nomological network. PMID- 26623540 TI - Effortful Control, Rejection Sensitivity, and Borderline Personality Disorder Features in Adulthood. AB - This investigation examined the moderating role of effortful control (EC) in the association between rejection sensitivity (RS) and its subsequent interpersonal distress (IP-distress) on borderline personality disorder (BPD) features. In total, 625 multicultural undergraduates (Study 1) and 562 community international adults (Study 2) completed scales evaluating EC, RS, IP-distress, and BPD features; Study 2 participants also self-reported both anxious and angry expectations of rejection. In both samples, EC moderated the mediating effect of IP-distress in the link between RS and BPD-related psychopathology. The extent to which RS was associated with BPD symptoms through increased IP-distress was greater for individuals with low EC and less so for those with high EC. Thus, low self-regulatory abilities may foster the association between RS and BPD by magnifying interpersonal distress. The implications and limitations of findings are discussed. PMID- 26623541 TI - Identifying the Manipulative Mating Methods Associated With Psychopathic Traits and BPD Features. AB - Psychopathy and borderline personality disorder (BPD) traits are associated with coercion and manipulation within relationships. The authors investigated whether BPD traits were uniquely associated with manipulation for emotional closeness whereas psychopathy was used for the purpose of attaining physical closeness. A community sample (N = 164) reported on mating behaviors, psychopathic traits, and BPD traits. Hierarchical regressions were conducted to predict mating behaviors that would account for the overlap between psychopathy and BPD. Total psychopathic traits were associated with lower levels of relationship exclusivity, greater use of partner poaching, and perpetration of sexual coercion. Specifically, callousness and egocentricity were related to lower relationship exclusivity. BPD traits were associated with the use of mate retention strategies, mate poaching, and victimization in sexual coercion. These findings indicate that manipulative mating behaviors encompass tools to achieve sex and intimacy. Those with BPD traits use these tools for emotional closeness, whereas those with psychopathic traits use them to obtain physical closeness and gratification. PMID- 26623543 TI - Towards biome-specific analysis of meta-omics data. PMID- 26623542 TI - Transcriptome dynamics of a broad host-range cyanophage and its hosts. AB - Cyanobacteria are highly abundant in the oceans and are constantly exposed to lytic viruses. The T4-like cyanomyoviruses are abundant in the marine environment and have broad host-ranges relative to other cyanophages. It is currently unknown whether broad host-range phages specifically tailor their infection program for each host, or employ the same program irrespective of the host infected. Also unknown is how different hosts respond to infection by the same phage. Here we used microarray and RNA-seq analyses to investigate the interaction between the Syn9 T4-like cyanophage and three phylogenetically, ecologically and genomically distinct marine Synechococcus strains: WH7803, WH8102 and WH8109. Strikingly, Syn9 led a nearly identical infection and transcriptional program in all three hosts. Different to previous assumptions for T4-like cyanophages, three temporally regulated gene expression classes were observed. Furthermore, a novel regulatory element controlled early-gene transcription, and host-like promoters drove middle gene transcription, different to the regulatory paradigm for T4. Similar results were found for the P-TIM40 phage during infection of Prochlorococcus NATL2A. Moreover, genomic and metagenomic analyses indicate that these regulatory elements are abundant and conserved among T4-like cyanophages. In contrast to the near-identical transcriptional program employed by Syn9, host responses to infection involved host-specific genes primarily located in hypervariable genomic islands, substantiating islands as a major axis of phage cyanobacteria interactions. Our findings suggest that the ability of broad host range phages to infect multiple hosts is more likely dependent on the effectiveness of host defense strategies than on differential tailoring of the infection process by the phage. PMID- 26623544 TI - Selective consumption and metabolic allocation of terrestrial and algal carbon determine allochthony in lake bacteria. AB - Here we explore strategies of resource utilization and allocation of algal versus terrestrially derived carbon (C) by lake bacterioplankton. We quantified the consumption of terrestrial and algal dissolved organic carbon, and the subsequent allocation of these pools to bacterial growth and respiration, based on the delta(13)C isotopic signatures of bacterial biomass and respiratory carbon dioxide (CO2). Our results confirm that bacterial communities preferentially remove algal C from the terrestrially dominated organic C pool of lakes, but contrary to current assumptions, selectively allocate this autochthonous substrate to respiration, whereas terrestrial C was preferentially allocated to biosynthesis. The results provide further evidence of a mechanism whereby inputs of labile, algal-derived organic C may stimulate the incorporation of a more recalcitrant, terrestrial C pool. This mechanism resulted in a counterintuitive pattern of high and relatively constant levels of allochthony (~76%) in bacterial biomass across lakes that otherwise differ greatly in productivity and external inputs. PMID- 26623547 TI - Zinc Amide Catalyzed Regioselective Allenylation and Propargylation of Ketones with Allenyl Boronate. AB - Zinc amide catalyzed, regioselective allenylation and propargylation of ketones with allenyl boronate is reported. Tertiary allenyl and homopropargyl alcohols were obtained, respectively, in high selectivities, from the same starting materials, simply by changing the reaction conditions. The substrate scope was wide. Mechanistic studies suggest that the reactions are controlled under kinetic and thermodynamic conditions. PMID- 26623546 TI - Privatization of cooperative benefits stabilizes mutualistic cross-feeding interactions in spatially structured environments. AB - Metabolic cross-feeding interactions are ubiquitous in natural microbial communities. However, it remains generally unclear whether the production and exchange of metabolites incurs fitness costs to the producing cells and if so, which ecological mechanisms can facilitate a cooperative exchange of metabolites among unrelated individuals. We hypothesized that positive assortment within structured environments can maintain mutualistic cross-feeding. To test this, we engineered Acinetobacter baylyi and Escherichia coli to reciprocally exchange essential amino acids. Interspecific coculture experiments confirmed that non cooperating types were selectively favoured in spatially unstructured (liquid culture), yet disfavoured in spatially structured environments (agar plates). Both an individual-based model and experiments with engineered genotypes indicated that a segregation of cross-feeders and non-cooperating auxotrophs stabilized cooperative cross-feeding in spatially structured environments. Chemical imaging confirmed that auxotrophs were spatially excluded from cooperative benefits. Together, these results demonstrate that cooperative cross feeding between different bacterial species is favoured in structured environments such as bacterial biofilms, suggesting this type of interactions might be common in natural bacterial communities. PMID- 26623545 TI - Microbial, host and xenobiotic diversity in the cystic fibrosis sputum metabolome. AB - Cystic fibrosis (CF) lungs are filled with thick mucus that obstructs airways and facilitates chronic infections. Pseudomonas aeruginosa is a significant pathogen of this disease that produces a variety of toxic small molecules. We used molecular networking-based metabolomics to investigate the chemistry of CF sputa and assess how the microbial molecules detected reflect the microbiome and clinical culture history of the patients. Metabolites detected included xenobiotics, P. aeruginosa specialized metabolites and host sphingolipids. The clinical culture and microbiome profiles did not correspond to the detection of P. aeruginosa metabolites in the same samples. The P. aeruginosa molecules that were detected in sputum did not match those from laboratory cultures. The pseudomonas quinolone signal (PQS) was readily detectable from cultured strains, but absent from sputum, even when its precursor molecules were present. The lack of PQS production in vivo is potentially due to the chemical nature of the CF lung environment, indicating that culture-based studies of this pathogen may not explain its behavior in the lung. The most differentially abundant molecules between CF and non-CF sputum were sphingolipids, including sphingomyelins, ceramides and lactosylceramide. As these highly abundant molecules contain the inflammatory mediator ceramide, they may have a significant role in CF hyperinflammation. This study demonstrates that the chemical makeup of CF sputum is a complex milieu of microbial, host and xenobiotic molecules. Detection of a bacterium by clinical culturing and 16S rRNA gene profiling do not necessarily reflect the active production of metabolites from that bacterium in a sputum sample. PMID- 26623548 TI - Intraoral 3D Scanning or Dental Impressions for the Assessment of Dental Arch Relationships in Cleft Care: Which is Superior? AB - OBJECTIVE: This study was undertaken to evaluate intraoral 3D scans for assessing dental arch relationships and obtain patient/parent perceptions of impressions and intraoral 3D scanning. MATERIALS & METHODS: Forty-three subjects with nonsyndromic unilateral cleft lip and palate (UCLP) had impressions taken for plaster models. These and the teeth were scanned using the R700 Orthodontic Study Model Scanner and Trios(r) Digital Impressions Scanner (3Shape A/S, Copenhagen, Denmark) to create indirect and direct digital models. All model formats were scored by three observers on two occasions using the GOSLON and modified Huddart Bodenham (MHB) indices. Participants and parents scored their perceptions of impressions and scanning from 1 (very good) to 5 (very bad). Intra- and interexaminer reliability were tested using GOSLON and MHB data (Cronbach's Alpha >0.9). Bland and Altman plots were created for MHB data, with each model medium (one-sample t tests, P < .05) and questionnaire data (Wilcoxon signed ranks P < .05) tested. RESULTS: Intra- and interexaminer reliability (>0.9) were good for all formats with the direct digital models having the lowest interexaminer differences. Participants had higher ratings for scanning comfort (84.8%) than impressions (44.2%) (P < .05) and for scanning time (56.6%) than impressions (51.2%) (P > .05). None disliked scanning, but 16.3% disliked impressions. Data for parents and children positively correlated (P < .05). CONCLUSIONS: Reliability of scoring dental arch relationships using intraoral 3D scans was superior to indirect digital and to plaster models; Subjects with UCLP preferred intra-oral 3D scanning to dental impressions, mirrored by parents/carers; This study supports the replacement of conventional impressions with intra-oral 3D scans in longitudinal evaluations of the outcomes of cleft care. PMID- 26623549 TI - Update on New and Emerging Therapies in the Management of Psoriasis. AB - Tumor necrosis factor inhibitors are a mainstay of treatment for patients with psoriasis who require systemic therapy. Since the approval of several of these agents, other biologic agents and small molecules have been developed; some of these have been approved recently by the US Food and Drug Administration, and others have shown great promise in clinical trials. The currently available and emerging treatments for psoriasis offer clinicians and patients an expanded list of options for individualizing treatment, potentially resulting in higher levels of improvement in both the disease process and quality of life. Semin Cutan Med Surg 34(supp2):S34-S36 (c) 2015 published by Frontline Medical Communications. PMID- 26623550 TI - Accurate lung volume measurements in vitro using a novel inert gas washout method suitable for infants. AB - BACKGROUND: Multiple breath washout (MBW) in infants presents a number of technical challenges. Conventional MBW is based on simultaneous measurement of flow and gas concentrations. These two signals are aligned and combined to derive expired gas volumes from which lung volumes and measures of ventilation inhomogeneity are calculated. Accuracy of measurement becomes increasingly vulnerable to errors in gas signal alignment at fast respiratory rates. In this paper we describe an alternative method of performing MBW in infants. Expired gas is collected and analyzed to derive functional residual capacity (FRC) and lung clearance index (LCI). This eliminates the need for simultaneous measurement of flow, and integration of flow and gas signals, and significantly reduces deadspace. METHODS: A highly accurate lung model incorporating BTPS conditions was used to generate realistic infant breathing parameters: FRC of 100-250 mls with respiratory rate of 20-60 min(-1) . In vitro accuracy of FRC measurement using the novel MBW method was assessed using the model. RESULTS: Overall mean error (standard deviation) of FRC measurement was -1.0 (3.3)% with 90% of tests falling within +/-5%. DISCUSSION: FRC measurement using the novel method has superior accuracy in vitro than previously described systems. By uncoupling the measurement of gas volumes from real-time flow and gas measurement, this system offers an alternative method of MBW which is well suited to infants. PMID- 26623552 TI - [Psychosocial Care of Refugees - A Challenge for the Health Care System, Research and Postgraduate Training]. PMID- 26623553 TI - [Subjective Weight Perception in Normal-Weight Adults - Results of the German Health Interview and Examination Survey for Adults (DEGS1)]. AB - This study investigates the prevalence and socio-demographic distribution of subjective weight perceptions in 2,552 subjects aged 18-79 years with normal weight (according to the WHO classification) who took part in the nationally representative DEGS1 study of the Robert Koch Institute, Berlin. In total, barely half of normal-weight adults-both men and women- considered themselves "a little/much too thick" or "a little/much too thin" (discordant weight perception). Normal-weight women assessed themselves predominantly as too thick (38,6%; 95% CI: 35,7-41,6). A quarter of normal-weight men assessed themselves as too thin, whereas another fifth of normal-weight men considered themselves too thick. The proportion of discordant weight perceptions declined with rising age. In multivariate assessment, socio-economic status was no significant predictor. Results are discussed in reference to potential implications for prevention programs. PMID- 26623551 TI - Trunk Postural Muscle Timing Is Not Compromised In Low Back Pain Patients Clinically Diagnosed With Movement Coordination Impairments. AB - Trunk muscle timing impairment has been associated with nonspecific low back pain (NSLBP), but this finding has not been consistent. This study investigated trunk muscle timing in a subgroup of patients with NSLBP attributed to movement coordination impairment (MCI) and matched asymptomatic controls in response to a rapid arm-raising task. Twenty-one NSLBP subjects and 21 matched controls had arm motion and surface EMG data collected from seven bilateral trunk muscles. Muscle onset and offset relative to deltoid muscle activation and arm motion, duration of muscle burst and abdominal-extensor co-contraction time were derived. Trunk muscle onset and offset latencies, and burst and co-contraction durations were not different (p > .05) between groups. Patterns of trunk muscle activation and deactivation relative to arm motion were not different. Task performance was similar between groups. Trunk muscle timing does not appear to be an underlying impairment in the subgroup of NSLBP with MCI. PMID- 26623554 TI - [Are there Associations between Embitterment and Clinical as well as Personality Variables by Psychosomatically Ill Inpatients]. AB - BACKGROUND: Understanding of bitterness ranges from a negative general human emotion to a destructive complex affekt due to a non adequate processed affront or resentment. OBJECTIVE: Relevant associations between kinds of bitterness and clinical as well as personality-related variables in hospitalized psychosomatic patients were examined. METHOD: Prospective naturalistic study over 14 months of consecutive admitted psychosomatic patients without exclusion criteria (N=166). General bitterness and 4 subscales were investigated on the basis of the Berner Verbitterungs-Inventar (BVI), personality traits on the basis of BFI-10, and clinical variables mainly on the basis of validated instruments (HoNOS, BDI, HADS, GAF, CGI, IIP-D, BSCL, comorbidity, duration of illness and structure as well as conflict-load according to OPD-2). Differences among levels of bitterness were examined with ANOVA tests, relationships between bitterness and clinical as well as personality-related variables using multivariate linear and multinomial regression models. RESULTS: The general bitterness falls within the average range. ANOVA models show higher scores for neuroticism, IIP, BDI, HADS, and BSCL when bitterness is above-average. In multivariate regression analyses, BDI, BSCL and neuroticism are positively associated with bitterness, whereas GAF, illness duration, and conscientiousness are negatively associated with bitterness. Diagnoses, severity of disease and burden of conflicts as well as level of organization of personality are not associated with bitterness. Models explain 11 39% of variance of bitterness. DISCUSSION: Bitterness in psychosomatic patients is hardly associated with personality variables, diagnoses, and psychopathological burden with the exception of depressiveness and neuroticism. Burden of interpersonal concerns may better explain bitterness than psychopathology or personality. CONCLUSIONS: Bitterness could be interpreted as a theoretical construct widely independent from severity of disease, personality, and diagnosis, showing importance in clinical practice. PMID- 26623555 TI - [Providing Care for Migrants]. PMID- 26623556 TI - [In Process Citation]. PMID- 26623557 TI - [In Process Citation]. PMID- 26623558 TI - Integration of tissue metabolomics, transcriptomics and immunohistochemistry reveals ERG- and gleason score-specific metabolomic alterations in prostate cancer. AB - Integrated analysis of metabolomics, transcriptomics and immunohistochemistry can contribute to a deeper understanding of biological processes altered in cancer and possibly enable improved diagnostic or prognostic tests. In this study, a set of 254 metabolites was determined by gas-chromatography/liquid chromatography mass spectrometry in matched malignant and non-malignant prostatectomy samples of 106 prostate cancer (PCa) patients. Transcription analysis of matched samples was performed on a set of 15 PCa patients using Affymetrix U133 Plus 2.0 arrays. Expression of several proteins was immunohistochemically determined in 41 matched patient samples and the association with clinico-pathological parameters was analyzed by an integrated data analysis. These results further outline the highly deregulated metabolism of fatty acids, sphingolipids and polyamines in PCa. For the first time, the impact of the ERG translocation on the metabolome was demonstrated, highlighting an altered fatty acid oxidation in TMPRSS2-ERG translocation positive PCa specimens. Furthermore, alterations in cholesterol metabolism were found preferentially in high grade tumors, enabling the cells to create energy storage. With this integrated analysis we could not only confirm several findings from previous metabolomic studies, but also contradict others and finally expand our concepts of deregulated biological pathways in PCa. PMID- 26623559 TI - Interleukin-6 suppression reduces tumour self-seeding by circulating tumour cells in a human osteosarcoma nude mouse model. AB - Tumour self-seeding by circulating tumour cells (CTCs) enhances tumour progression and recurrence. Previously, we demonstrated that tumour self-seeding by CTCs occurs in osteosarcoma and revealed that interleukin-6 (IL-6) may promote CTC attraction. Here, we investigated the underlying mechanisms of IL-6 in tumour self-seeding by CTCs. IL-6 suppression inhibited in vitro cell proliferation, migration, and invasion. In addition, rhIL-6 activated the Janus-activated kinase/signal transducers and activators of transcription 3 (JAK/STAT3) and mitogen-activated protein kinase/extracellular-signal regulated kinase1/2 (MAPK/ERK1/2) pathways in vitro. Both pathways increased cell proliferation, but only the JAK/STAT3 pathway promoted migration. Suppressing IL-6 inhibited in vivo tumour growth and metastasis. IL-6 suppression or JAK/STAT3 pathway inhibition reduced CTC seeding in primary tumours. Collectively, IL-6 promotes tumour self seeding by CTCs in a nude mouse model. This finding may provide a novel strategy for future therapeutic interventions to prevent osteosarcoma progression and recurrence. PMID- 26623560 TI - Potent efficacy of metronomic topotecan and pazopanib combination therapy in preclinical models of primary or late stage metastatic triple-negative breast cancer. AB - Metronomic chemotherapy has shown promising activity in numerous preclinical studies and also some phase II clinical studies involving various tumor types, and is currently undergoing phase III trial evaluation. Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Herein, we evaluated the potential therapeutic impact and molecular mechanisms of topotecan administered in a continuous low-dose metronomic (LDM) manner, alone or in concurrent combination with pazopanib, an antiangiogenic tyrosine kinase inhibitor (TKI), in a triple-negative, primary and metastatic breast cancer orthotopic model; potential molecular mechanisms of efficacy were also studied, especially the impact of hypoxic conditions. The combination of metronomic topotecan and pazopanib significantly enhanced antitumor activity compared to monotherapy with either drug and prolonged survival, even in the advanced metastatic survival setting, with a marked decrease in tumor vascularity, proliferative index, and the induction of apoptosis. Significant changes in tumor angiogenesis, cancer cell proliferation, apoptosis, HIF1alpha levels, HIF-1 target genes and ABCG2 were found both in vitro and in tumor tissue. Notably, the pazopanib and metronomic topotecan combination treatment inhibited expression of HIF1alpha and ABCG2 genes in cells grown under hypoxic conditions, and this was associated with an increased intracellular concentration of the active form of topotecan. Our results suggest a potential novel therapeutic option for the treatment of metastatic triple negative breast cancer patients. PMID- 26623561 TI - The BMI1 inhibitor PTC-209 is a potential compound to halt cellular growth in biliary tract cancer cells. AB - BMI1 is a core component of the polycomb repressive complex 1 (PRC1) and is up regulated in biliary tract cancer (BTC), contributing to aggressive clinical features. In this study we investigated the cytotoxic effects of PTC-209, a recently developed inhibitor of BMI1, in BTC cells. PTC-209 reduced overall viability in BTC cell lines in a dose-dependent fashion (0.04 - 20 uM). Treatment with PTC-209 led to slightly enhanced caspase activity and stop of cell proliferation. Cell cycle analysis revealed that PTC-209 caused cell cycle arrest at the G1/S checkpoint. A comprehensive investigation of expression changes of cell cycle-related genes showed that PTC-209 caused significant down-regulation of cell cycle-promoting genes as well as of genes that contribute to DNA synthesis initiation and DNA repair, respectively. This was accompanied by significantly elevated mRNA levels of cell cycle inhibitors. In addition, PTC-209 reduced sphere formation and, in a cell line-dependent manner, aldehyde dehydrogease-1 positive cells. We conclude that PTC-209 might be a promising drug for future in vitro and in vivo studies in BTC. PMID- 26623564 TI - WITHDRAWN: Interventions for replacing missing teeth: denture chewing surface designs in edentulous people. PMID- 26623565 TI - Endoscopic features associated with development of metachronous gastric cancer in patients who underwent endoscopic resection followed by Helicobacter pylori eradication. AB - OBJECTIVES: The preventive effect of Helicobacter pylori (HP) eradication on metachronous gastric cancer development after endoscopic resection remains controversial. The aim of this study was to identify specific endoscopic features that correlated with the risk of metachronous gastric cancer development after endoscopic submucosal dissection (ESD) using both endoscopic findings before ESD and changes of findings after HP eradication. METHODS: This retrospective study investigated 122 consecutive patients who underwent ESD for early gastric cancer and successful HP eradication after ESD. Endoscopic findings linked with HP before ESD and changes after HP eradication were evaluated according to the development of metachronous cancer. RESULTS: Most patients showed severe atrophy and intestinal metaplasia (IM) before ESD (97% and 83%, respectively). Improvement of spotty redness, improvement of diffuse redness, emergence of patchy redness, and emergence of map-like redness were frequent findings after HP eradication (52%, 50%, 54%, and 32%, respectively). Kaplan-Meier curves indicated that patients without IM before ESD never developed metachronous cancer, while patients with emergence of map-like redness after HP eradication were significantly more likely to develop metachronous cancer (log-rank test, p = 0.031 and p < 0.001, respectively). Multivariate analysis indicated that emergence of map-like redness after HP eradication was the only predictive factor for development of metachronous cancer (hazard ratio, 3.61; 95% confidence interval, 1.41-9.21; p = 0.007). CONCLUSIONS: Absence of IM before ESD and emergence of map-like redness after HP eradication were useful endoscopic findings in the negative and positive prediction of metachronous gastric cancer developing after ESD. PMID- 26623566 TI - Understanding Effects of Flexible Spending Accounts on People with Disabilities: The Case of a Consumer-Directed Care Program. AB - This study set out to explore the saving behavior, barriers, and facilitators along with effects of participating in a consumer-directed care program among people with disabilities in the state of West Virginia (N = 29). Results suggest that respondents were able to save money through the program to enable them to purchase goods and services they needed to enhance their welfare and quality of life. Generally, items saved for fell into 3 broad categories: household equipment, individual functioning, and home modification. Facilitators and barriers to saving were also indicated and so were the benefits of program participation. Program and policy implications are presented. PMID- 26623567 TI - Evaluation of vitamin D levels in allergic fungal sinusitis, chronic rhinosinusitis, and chronic rhinosinusitis with polyposis. AB - BACKGROUND: Vitamin D3 (VD3 ) levels have been recently found to be responsible for a number of immunological, anti-inflammatory and anti-infectious roles. Some studies reported that some forms of allergic fungal rhinosinusitis (AFRS), occurs more commonly in patients who are more susceptible to VD3 deficiency. The aim of this work was to measure VD3 levels in patients with AFRS and chronic rhinosinusitis (CRS). METHODS: We report a prospective case control study conducted at Ain Shams University. It included 74 participants divided into 4 groups: group A, 25 patients with AFRS; group B, 15 patients with CRS with nasal polyps (CRSwNP); group C: 15 patients with CRS without nasal polyps (CRSsNP); and group D, 19 controls. RESULTS: There was a statistically significant (p < 0.001) difference of VD3 between groups A and B compared with groups C and D. There were no statistically significant differences between the 4 groups regard calcium levels. Finally, there was a statistically significant difference in phosphate levels when we compared groups A and B with groups C and D (p = 0.001). CONCLUSION: Serum level of VD3 in patient with CRSwNP and AFRS is significantly lower than that of patients with CRSsNP and control subjects. Although these results do not imply a specific etiological or therapeutic relationship, VD3 levels may constitute an inexpensive prophylactic and cost-effective option in the therapeutic armamentarium in the control of AFRS and CRSwNP, either by itself or as a synergistic agent with traditional agents. PMID- 26623562 TI - The role of the oncofetal H19 lncRNA in tumor metastasis: orchestrating the EMT MET decision. AB - Long non-coding RNA (lncRNA) genes are emerging as key players in the metastatic cascade. Current evidence indicate that H19 lncRNA and the microRNA(miRNA) miR 675, which is processed from it, play crucial roles in metastasis, through the regulation of critical events specifically the epithelial to mesenchymal (EMT) and the mesenchymal to epithelial transitions (MET). This review summarizes recent mechanistic pathways and tries to put together seemingly conflicting data from different reports under one proposed general scheme underlying the various roles of H19/miR-675 in the metastatic cascade. We propose several approaches to harnessing this knowledge for translational medicine. PMID- 26623568 TI - HelixFlex: bioinspired maneuverable instrument for skull base surgery. AB - Endoscopic endonasal surgery is currently regarded as the 'gold standard' for operating on pituitary gland tumors, and is becoming more and more accepted for treatment of other skull base lesions. However, endoscopic surgical treatment of most skull base pathologies, including certain pituitary tumors, is severely impaired by current instruments lack of maneuverability. Especially, gaining access to, and visibility of, difficult-to-reach anatomical corners without interference with surrounding neurovascular structures or other instruments, is a challenge. In this context there is the need for instruments that are able to provide a stable shaft position, while both the orientation and the position of the end-effector can be independently controlled. Current instruments that allow for this level of maneuverability are usually mechanically complex, and hence less suitable for mass production. This study therefore focuses on the development of a new actuation technique that allows for the required maneuverability while reducing the construction complexity. This actuation technique, referred to as multi-actuation, integrates multiple cable routings into a single steerable structure. Multi-actuation has been successfully integrated and tested in a handheld prototype instrument called HelixFlex. HelixFlex contains a 4 degrees of freedom maneuverable 5.8 mm (diameter) tip and shows promising results concerning its maneuverability and potential rigidity. PMID- 26623570 TI - Contribution to the knowledge of Terpidinae Kluge 2009 (Ephemeroptera: Leptophlebiidae). AB - Three new species of Terpides s.str. from Peru are described as larvae, reared subimagoes and imagoes of both sexes, and eggs extracted from female imagoes: T. ornatodermis sp. n., T. echinovaris sp. n. and T. contamanensis sp. n. Besides hitherto known characters, Terpides s.str. is characterized by unusual structure of eggs and differs from Fittkaulus and Tikuna by arrangement of microtrichia and microlepides on subimaginal legs. Tergalii and eggs of Tikuna bilineata (Needham & Murphy 1924) and eggs of Fittkaulus amazonicus (Kluge 2009) are described for the first time. Comments about structure, phylogenetic position and classification of Terpidinae are given. PMID- 26623571 TI - Studies of Bolivian Ptiliidae (Coleoptera) 2: The subfamily Acrotrichinae including two new genera Petrotrichis and Microtrichis, and eight new species of Acrotrichis. AB - This is the second report on a collection of Ptiliidae from Bolivian forest leaf litter made by Dr Petr Banar of the Brno Museum (Czech Republic) in 2013. A small collection of Bolivian Acrotrichis in the Natural Museum, London, made by H. Mendel and M.V.L. Barclay in 2004 is also included. Two new monotypic genera are described Petrotrichis gen. n. (Acrotrichini), type species P. rotundata sp. n., and Microtrichis gen. n. (Nephanini), type species M. pectana sp. n., together with eight new species of Acrotrichis: A. armillata sp. n., A. cincinna sp. n., A. cornuta sp. n., A. corpulenta sp. n., A. inlecebrosa sp. n., A. linea sp. n., A. nashi sp. n. and A. segmenta sp. n.. PMID- 26623569 TI - Protein kinase CK2 regulates metal toxicity in neuronal cells. AB - Protein kinase CK2 is a pleiotropic tetrameric enzyme, regulating numerous biological processes from cell proliferation to stress response. This study demonstrates for the first time that CK2 is involved in the regulation of metal uptake and toxicity in neuronal cells. After the determination of inhibitory concentrations (IC50) for a range of metal salts (ZnSO4, Al(mal)3, CoCl2, CrO3, NaAsO2 and CaCl2) in Neuro-2a mouse neuroblastoma cells, the effect of CK2 on metal toxicity was investigated by three lines of experiments using CK2 inhibitors, metal ion specific fluorophores and siRNA-mediated knockdown of CK2 expression. The results showed that both CK2 inhibitors, 4,5,6,7 tetrabromobenzotriazole (TBB) and quinalizarin, markedly reduced the toxicity of Zn(ii), Al(iii), Co(ii), Cr(vi) and As(iii). Confocal microscopy imaging revealed that Zn(ii) uptake was accompanied by the increase of intracellular Ca(ii) in Neuro-2a cells treated with IC50 of ZnSO4 (240 MUM), and such concurrent elevation of intracellular Zn(ii) and Ca(ii) was blocked by TBB and quinalizarin. The role of CK2 in metal uptake was further characterised using specific siRNA against each of the three subunits (CK2alpha, alpha' and beta) and the data demonstrate that CK2alpha' is the prominent subunit regulating the metal toxicity. Finally, the role of CK2 in metal toxicity was found to be conserved in the distant species-Saccharomyces cerevisiae by employing the complete deletion mutants of CK2 (cka1Delta, cka2Delta, ckb1Delta and ckb2Delta). Taken together, these findings shed light on a new facet of CK2 functionality and provide a basis for further research on the regulation of Zn(ii) and Ca(ii) homeostasis by CK2. PMID- 26623572 TI - Taxonomy and systematics of the herichthyins (Cichlidae: Tribe Heroini), with the description of eight new Middle American Genera. AB - In recent years great strides have been made for improving our understanding of the evolutionary relationships among neotropical cichlids, particularly within the clade Heroini and its crown clade the herichthyins. Most phylogenetic studies have largely converged on congruent topologies for relationships among species and major lineages within the herichthyins. One major aspect missing from previous studies of these cichlids is a formal taxonomic revision, including the redefining of genera. Based on analysis of 52 species and three mitochondrial and two nuclear loci, we generate a Bayesian phylogeny for the herichthyin cichlids, and formally revise the taxonomy for genera within this clade using morphological features. Eight new genera are recognized and a key to all 16 genera of herichthyin cichlids is also presented. PMID- 26623573 TI - A new species of the genus Odorrana (Amphibia: Ranidae) and the first record of Odorrana bacboensis from China. AB - The genus Odorrana currently contains at least 56 recognized species that inhabits montane streams in subtropical and tropical Asia. Twenty new species have been described in the last decade, indicating the potential cryptic species diversity of this genus. We collected several specimens of Odorrana species from Southern China from 2007 to 2014, and on the basis of a combined morphological characters and phylogenetic analysis, we described the new species Odorrana fengkaiensis sp. nov. herein. The new species is very similar to O. hainanensis and O. bacboensis, but can be consistently separated by morphology, and allopatric distribution. It is further reciprocally monophyletic to O. hainanensis in a mitochondrial gene trees with an average genetic divergence of 2.1% (1.9%-2.4%). The new species inhabits in lowland broad streams, rivers, pools and near the riparian areas, but its general ecology remains poorly known. The new species is characterized by its body length of adult females approximately twice as long as adult males (SVL 77.8-111.9 mm in females, 37.4 51.8 mm in males); eye large in males, eye diameter 1.01-1.16 times as long as snout length; tympanum of males large and distinct, extremely close to the eye, 0.7-1.4 mm in tympanum-eye distance; dorsolateral folds absent; dorsal skin shagreened, with several large tubercles in males; flanks with tubercles and scattered larger pustules, 8-10 of which usually arranged in a dorsolateral row; ventral skin smooth, with spines in adult males during the breeding season; the tibio-tarsal articulation stretched forward beyond the tip of snout; relative finger lengths: II < I < IV < III; dorsum brown with irregularly reticulated green markings in males and young females, uniformly brown in some old adult females; males with velvety nuptial pad on thumb, paired gular pouches; mature oocytes almost purely black in life, showed dark grey animal pole and olive vegetative pole in preservative. In addition, we found O. bacboensis, a new country record from China, indicating a range extension from north-central Vietnam to southeast Yunnan and adjacent area in Guangxi. PMID- 26623574 TI - Description of a new species and redescriptions of two rare species of Parapercis (Perciformes: Pinguipedidae) from the tropical Pacific Ocean. AB - Parapercis johnsoni sp. nov. is described based on 19 specimens from Marquesas Islands, French Polynesia. It differs from congeners in having a combination of the following characters: dorsal-fin rays V, 21; anal-fin rays I, 17; pectoral fin rays modally 17; pored lateral-line scales modally 52 or 53; predorsal scales 7 or 8; transverse scale rows 3.5 or 4 + 14 or 15; total gill rakers on 1st gill arch 13-16; single row of teeth on vomer; 6 large canines at front of lower jaw; and a distinct coloration. Two rare species, P. flavescens Fourmanoir & Rivaton, 1979 and P. fuscolineata Fourmanoir, 1985, are redescribed based on the types and newly identified specimens. Comments on other species occurring in the area are provided. PMID- 26623575 TI - On the genus Limnocassis Spaeth, with description of two new species from South Africa (Coleoptera: Chrysomelidae: Cassidinae). AB - Limnocassis compacta sp. nov. and L. regularis sp. nov. are described from South Africa. They are well distinguished from Limnocassis pumilio (Boheman, 1854), the only known species in the genus, in fine and mostly regular elytral punctation. Colour photographs of all species and new distribution data for L. pumilio are given. PMID- 26623576 TI - Taxonomic review of Kuzicus Gorochov, 1993 (Tettigoniidae: Meconematinae), with two new species from Thailand and key to species. AB - The taxonomy of genus Kuzicus Gorochov, 1993 (Tettigoniidae: Meconematinae) is reviewed. Two new species are described from Thailand: Kuzicus pakthongchai sp. n. Tan et al. and Kuzicus multidenticulatus sp. n. Tan et al. Kuzicus denticuloides (Kevan, 1993) comb. nov. is transferred from genus Xiphidiopsis. Parakuzicus is removed as a subgenus and considered a distinct genus. A key to species of Kuzicus is provided. PMID- 26623577 TI - Repatriating a lost name: notes on McClelland and Griffith's Cobitis boutanensis (Cypriniformes: Nemacheilidae). PMID- 26623578 TI - Designation of a neotype for the kyphosid fish Kyphosus sectatrix (Linnaeus, 1758). PMID- 26623579 TI - Discovery of the genus Vanhartenidia Lelej, 2006 (Hymenoptera: Mutillidae) in Egypt, with description of a new species. AB - The genus Vanhartenidia Lelej, 2006 is newly recorded from Egypt. A new species, V. mandishaensis El-Torkey & Soliman, sp. nov. is described and illustrated from Bahariya Oasis (Giza, Egypt). PMID- 26623580 TI - An evaluated list of Cenozic-Recent radiolarian species names (Polycystinea), based on those used in the DSDP, ODP and IODP deep-sea drilling programs. AB - A first reasonably comprehensive evaluated list of radiolarian names in current use is presented, covering Cenozoic fossil to Recent species of the primary fossilising subgroup Polycystinea. It is based on those species names that have appeared in the literature of the Deep Sea Drilling Project and its successor programs, the Ocean Drilling Program and Integrated Ocean Drilling Program, plus additional information from the published literature, and several unpublished taxonomic database projects. 1192 names are recognised as valid, and several hundred additional names including synonyms and mispellings are given as well. A brief list of valid names is provided in the main paper, while the full list, with synonyms, author, year of publication, family assignment, geologic age interval and notes is provided as a SOM spreadsheet table. PMID- 26623581 TI - A review of the millipede genus Typhloiulus Latzel, 1884 (Diplopoda: Julida: Julidae), with a description of three new species from Bulgaria and Greece. AB - The mostly cavernicolous and endogean millipede genus Typhloiulus Latzel, 1884 (Julida: Julidae) is hitherto known to comprise 33-36 species distributed in the Balkan and Apennine peninsulas, as well as the adjacent parts of the Alps and the Carpathian Arch. Here we describe three new species, T. bulgaricus sp. n., T. orpheus sp. n. and T. rhodopinus sp. n., collected from caves and other subterranean habitats in Bulgaria and Greece. Furthermore, the taxonomic descriptions of some poorly known species are emended and/or new distribution data given. T. staregai Strasser, 1973, is synonymized with T. strictus (Latzel, 1882). A neotype of T. kotelensis Jawlowski, 1938, of which the original type material is thought to be lost, is designated, and a checklist of Typhloiulus species is provided. PMID- 26623582 TI - Morphological and molecular taxonomic analysis of Pseudopoda Jager, 2000 (Araneae: Sparassidae: Heteropodinae) in Sichuan Province, China. AB - The genus Pseudopoda Jager, 2000 is revised from material collected in Sichuan province. A molecular analysis shows the utility of DNA markers to support taxonomic hypotheses in Sparassidae. Two new species are described: Pseudopoda coenobium spec. nov. from Emeishan (male, female) and Pseudopoda wu spec. nov. from Lugu Lake at the border to Yunnan (male, female). The latter species exhibits a unique reduction of the conductor and a strongly developed embolus. The female of Pseudopoda virgata (Fox, 1936) is described for the first time, the male is redescribed, the known range of the geographical distribution is considerably extended to the East (Baoxing and Tienqiang County), the vertical distribution range is extended from 300 m to slightly more than 2000 m. The male of Pseudopoda signata Jager, 2001 is described for the first time, the female is redescribed, the known distribution range of this species is extended from Muge Cuo Lake over Kangding town to the valleys of Paomashan, Gonggashan and Yanzi. It shows a strong morphological variation, which may be interpreted as developing subspecies status in different valleys. However, according to results from a molecular analysis it is clearly considered intraspecific variability. Three further species are recorded from Sichuan: Pseudopoda emei Zhang et al., 2013, Pseudopoda sp. cf. yunnanensis (Yang & Hu, 2001) and Pseudopoda rivicola Jager and Vedel, 2007. PMID- 26623583 TI - New and little known Limacodidae (Lepidoptera) from Xizang, China. AB - Five new and little known species of Limacodidae are reported from Xizang, China. Among them, Pseudohampsonella bayizhena Wu & Pan, sp. nov. and Squamosa monosa Wu & Pan, sp. nov. are described as new, Pseudocaissa Solovyev & Witt and P. marvelosa (Yoshimoto) are newly recorded in China, and Miresa urga Hering and Scopelodes kwangtungensis Hering are reported for the first time in Xizang. The female genitalia are described for the first time in the genus Squamosa Bethune Baker. Photographs of moths and the genitalia of new species and newly recorded species are given. A list of the Limacodidae known from Xizang, China is also included. PMID- 26623584 TI - Taxonomy 2.0: Sequencing of old type specimens supports the description of two new species of the Lasiocampa decolorata group from Morocco (Lepidoptera, Lasiocampidae). AB - The type of Lasiocampa decolorata (KLUG, 1830), collected in 1820, was successfully barcoded to generate a 658bp COI-fragment after 194 years. The resulting molecular data allowed the description of two closely related species from Morocco: Lasiocampa hannae SPEIDEL, MOOSER & WITT sp. n. from the Anti Atlas and Lasiocampa editae SPEIDEL, MOOSER & WITT sp. n. from the High Atlas. PMID- 26623585 TI - A new species of Lamiogethes and a new species of Meligethes from China (Coleoptera: Nitidulidae: Meligethinae). AB - A new species of Lamiogethes Audisio & Cline, 2009, L. nyingchiensis sp. nov., and a new species of Meligethes Stephens, 1830, M. (Odontogethes) scrobescens sp. nov. are described and illustrated from China. The differences between these new species and closely related species are discussed. The materials examined are deposited in the Institute of Zoology, Chinese Academy of Sciences, Beijing, China (IZAS). PMID- 26623586 TI - New data on the subgenus Gnathopaederus of the genus Paederus (Coleoptera: Staphylinidae: Paederinae) of mainland China. AB - Paederus (Gnathopaederus) xuei Peng & Li sp. n. (Yunnan: Dawei Shan) and P. (G.) cheni Peng & Li sp. n. (Hunan: Badagong Shan) are described and illustrated. Additional records of P. (G.) bursavacua Willers, 2001, P. (G.) szechuanus (Chapin, 1927) and P. (G.) yunnanensis Willers, 2001 are reported. PMID- 26623587 TI - Leafhopper genus Kolla Distant (Hemiptera: Cicadellidae: Cicadellinae) with descriptions of four new species from China. AB - Four new species of the genus Kolla from China, Kolla emphysematosa, K. prolongata, K. procerula and K. petalina spp. nov. are described and illustrated. A key to the males of Chinese species and a checklist of the known species worldwide are provided. PMID- 26623588 TI - A revised subgeneric position for Polypedilum (Probolum) simantokeleum, with description of a new Uresipedilum species in Japan (Diptera: Chironomidae). AB - Two Japanese Polypedilum species including a new species are redescribed and described based on the males. Polypedilum (Probolum) simantokeleum, Sasa, Suzuki et Sakai, 1998, is transferred to the subgenus Uresipedilum. Polypedilum (Uresipedilum) dissimilum sp. nov. is easily distinguished from other members of Uresipedilum by having a T-shaped tergal band. Definition of the subgenus Probolum is briefly discussed: we suggest Probolum should be defined as the species with the superior volsella bearing inner lobe pending adequate larval information. PMID- 26623589 TI - Tosta Evans, 1953 (Lepidoptera: Hesperiidae): a new species from northeast Brazil, first description of the female of Tosta tosta Evans, 1953, and placement of the genus within Achlyodini. AB - A new species of Tosta Evans, 1953 from northeast Brazil is described: T. pseudospeculum Siewert, Mielke & Casagrande, sp. nov. Additionally, the female of Tosta tosta Evans, 1953, the type species of the genus, is described for the first time. Illustrations of adults and male and female genitalia for all studied species are provided, as well as a discussion of the placement of the genus within the tribe Achlyodini. PMID- 26623590 TI - New species of cynipid inquilines of the genus Synergus (Hymenoptera: Cynipidae: Synergini) from the Eastern Palaearctic. AB - Eight new species of cynipid inquilines, Synergus abei Melika & Schweger, S. belizinellus Schweger & Melika, S. changtitangi Melika & Schweger, S. formosanus Schweger & Melika, S. ishikarii Melika & Schweger, S. kawakamii Tang & Melika, S. khazani Melika & Schweger and S. symbioticus Schweger & Melika, from the Eastern Palaearctic are described. Descriptions, diagnoses, biology, and host associations for the new species and a key to all known Eastern Palaearctic Synergus species are given. All taxa are supported by morphological and molecular data. We discuss the status of all previously described Eastern Palaearctic Synergus species, and provide validation and synonymization of some species. PMID- 26623591 TI - Two new species of Parasaveljevia Wieser, 1953 (Thoracostomopsidae, Nematoda) from Argentinean coasts (Chubut, Argentina). AB - Two new Parasavaljevia species are described, one from Puerto Madryn, and one from El Limite beach San Jorge Gulf, Chubut Province, Argentina. The two species are characterised by a combination of characters. Parasavaljevia uncinoa n. sp. is characterised by having a long rectangular cirrus, positioned at the level of the inner labial setae, rectangular mandibles with prominent lateral hooks bearing denticles in three lines of nine each and six cephalic setae of the same length, inserted at the anterior end of a small head capsule. Parasavaljevia limitense n. sp. is characterized by having a cirrus posterior positioned, between labial and cephalic setae, rectangular-arched mandibles bearing denticles in five lines of ten each in a gradient of sizes; small buccal cavity, small cephalic capsule and abundant cervical setae (4+10). An emendation of the genus diagnosis and a new key are given and discussed. PMID- 26623592 TI - New species of Edessa Fabricius, 1803 (Hemiptera: Pentatomidae) from Costa Rica. AB - The edessines from Costa Rica are little known; only 18 species have been registered or described from this country so far. Mainly based in a large sample from Instituto Nacional de Biodiverdidad (INBio), Costa Rica, we decided to update the information concerning Edessinae from Costa Rica. We present a list of species from Costa Rica raising the number of known species from Costa Rica to 65. We are also describing nine new species: Edessa bella Fernandes & Silva, E. bruneolineata Fernandes & Correia, E. curvata Fernandes & Nunes, E. lewisi Fernandes & Silva, E. nigroangulata Fernandes & Silva, E. osae Fernandes & Nunes, E. oxcarti Fernandes & Correia, E. pallidoangulata Fernandes & Nunes and E. puravida Fernandes & Correia. Species were described, illustrated and photographed. Distribution maps for the species are also provided. PMID- 26623593 TI - Contributions to the study of the genus Hephathus Ribaut, 1952 (Homoptera: Auchenorrhyncha: Cicadellidae: Macropsinae) of Russia and adjacent countries. AB - In Russia and the adjacent territories, the genus Hephathus includes three species, H. nanus (Herrich-Schaffer, 1835), H. freyi (Fieber, 1868) = H. tshakaranus Dlabola, 1957, syn. n., and H. achilleae Mityaev, 1967. They are indistinguishable in genitalia shape, but differ in male calling signal structure and black pattern of face. Photos of habitus and face, drawings of genitalia and male 2(nd) abdominal apodemes, signal oscillograms, and distribution maps for all species are provided. H. orientalis Linnavuori, 1953 is indistinguishable from H. freyi in coloration and genitalia shape; therefore, investigation of male calling signals is necessary for elucidation of its status. Macropsis fergusoni Evans, 1942 from Tasmania and Asmaropsis troilos Linnavuori, 1978 from Eritrea differ from Palaearctic Hephathus in the shape of head, pro-, and mesonotum and apparently belong to other genera. PMID- 26623594 TI - Two new myrmecophilous species of the genus Petalomium (Acari: Pygmephoroidea: Neopygmephoridae). AB - Two new myrmecophilous species of the genus Petalomium Cross, 1965 (Acari: Pygmephoroidea: Neopygmephoridae), P. crossi sp. nov. and P. reductus sp. nov. are described from ants Myrmicaria distincta Santschi, 1925 (Hymenoptera: Formicidae: Myrmicinae) in Ethiopia. The presence and shape of the postpalpal setae in species of the genus Petalomium are discussed. PMID- 26623595 TI - First record of the fossil snakefly genus Mesoraphidia (Insecta: Raphidioptera: Mesoraphidiidae) from the Middle Jurassic of China, with description of a new species. AB - Mesoraphidia daohugouensis sp. nov. is described from the Middle Jurassic Jiulongshan Formation of Inner Mongolia, China. It is diagnosed by the following character states: subquadrate pronotum, narrowly elliptical forewing, distally darkened pterostigma closed respectively by a proximal costal crossvein and a distal radial veinlet, absence of pterostigmal crossvein. The new species represents the first record of Mesoraphidiinae from the Middle Jurassic of China. PMID- 26623596 TI - No millipede endemics north of the Alps? DNA-Barcoding reveals Glomeris malmivaga Verhoeff, 1912 as a synonym of G. ornata Koch, 1847 (Diplopoda, Glomerida, Glomeridae). AB - In order to evaluate the status of the only species of pill millipede (Glomerida) endemic to Germany, Glomeris malmivaga Verhoeff, 1912, a DNA barcoding study based on the COI mitochondrial gene was conducted. Sequences of G. malmivaga were compared to those of G. ornata Koch, 1847 from Slovenia, of which the former was previously described as a variety of the latter before being elevated to subspecies- and, recently, species-rank. Included in the analysis were specimens of G. helvetica Verhoeff, 1894, also originally described as a variety of G. ornata, which was supposed to be closely related to G. malmivaga based on its morphology, as well as geographical proximity of occurrence. Additionally, G. valesiaca Rothenbuhler, 1899, which occurs in sympatry and looks quite similar to G. helvetica was also sequenced for the first time and included in the study. Sequences of four widespread Glomeris species, all occurring in close proximity to G. malmivaga, G. marginata Villers, 1789, G. connexa Koch, 1847, G. klugii Brandt, 1833 and G. intermedia Latzel, 1884 were downloaded from Genbank and incorporated in the analysis. While G. helvetica and G. valesiaca were found to be clearly separate from G. ornata (11.8-14.6% p-distance), G. malmivaga is almost identical to the latter (0.5% p-distance), despite the large geographical distance between both species. Because of their great morphological and genetical similarity, G. malmivaga n. syn. is synonymised under G. ornata. PMID- 26623597 TI - A new look at the holotype and type locality of Setopagis maculosa (Todd, 1920) Aves: Caprimulgidae), with remarks on its systematic relationships. AB - Setopagis maculosa (Todd, 1920) (Aves: Caprimulgidae) was described based on a single male specimen collected by Samuel Milton Klages in French Guiana, northeastern South America. Since then, no new specimens have been collected nor have any reliable records been made, and the validity of the species has been questioned. A detailed analysis of the holotype reveals that it has unique and distinctive morphological traits that support the validity and taxonomic status of the species, which is provisionally placed in Setopagis. We present new information on the type locality at the time of its collection, which may shed some light on the habitat preferences of the species, and we provide details on its plumage that have been largely overlooked and that will be important for future field identification. PMID- 26623598 TI - Redescription of Lutzomyia (Lutzomyia) renei Martins, Falcao & Silva, 1957 (Diptera: Psychodidae: Phlebotominae). AB - The male genitalia of Lutzomyia (Lutzomyia) renei (Martins, Falcao & Silva, 1957) have four bristles, three fine and one semi-foliaceous, inserted basomesally on the gonocoxite. Nonetheless, in the original description and in other taxonomic studies, these bristles have been illustrated and described in varying formats. In order to clarify the morphology of this species, both sexes are here redescribed based on three males and one female from the type series. A lectotype and two paralectotypes are here designated. PMID- 26623599 TI - AWAL RIYANTO, L. LEE GRISMER & PERRY L. WOOD, JR. (2015) Cyrtodactylus rosichonariefi sp. nov. (Squamata: Gekkonidae), a new swamp-dwelling bent-toed gecko from Bunguran Island (Great Natuna), Indonesia. Zootaxa, 3964 (1): 114-124. PMID- 26623600 TI - Annotated checklist of the Blennidus subgenus Agraphoderus species from Peru with description of B. bombonensis n. sp. and synonymic notes (Coleoptera: Carabidae: Pterostichinae). AB - Forty species belonging to the subgenus Agraphoderus of Blennidus have been recorded so far from Peru. An annotated checklist is provided with information about their type locality, distribution and habitat. The nomenclature of each species is also provided, together with some notes on their systematic status. Blennidus bombonensis n. sp. from Cerro de Pasco is described; Blennidus pseudangularis nomen novum for Ogmopleura angularis Straneo, 1993 (nec Straneo, 1985) is proposed and the following synonymies are stated: Blennidus pseudangularis Allegro & Giachino, nomen novum = Blennidus rectangulus (Straneo, 1993) syn. nov.; Ogmopleura minor Straneo, 1993 = Blennidus rectangulus (Straneo, 1993) syn. nov. Type specimens of most species are illustrated, as well as male genitalia. Finally, a revised key to all the Agraphoderus species from Peru is provided. PMID- 26623601 TI - The Nearctic genera of Agathidinae (Hymenoptera: Braconidae) with a phylogenetic analysis, illustrated generic key, and the description of three new genera. AB - The genera of Nearctic Agathidinae are revised based on a phylogenetic analysis of COI and 28S sequence data; 151 ingroup taxa are included. Three new genera are proposed, i.e., Aphelagathis Sharkey n. gen., Pneumagathis Sharkey n. gen. and Gelastagathis Sharkey n. gen.. The enigmatic species Agathis verticalis Cresson is identified and placed in Aphelagathis, Aphelagathis verticalis (Cresson) n. comb., and a neotype for the species is designated. Two species are described, i.e., Gelastagathis grisselli Sharkey n. sp. and G. frosti Sharkey n. sp. Two new combinations are proposed, Bassus spiracularis Muesebeck and Bassus brooksi Sharkey are transferred to Pneumagathis, Pneumagathis spiracularis (Muesebeck) n. comb., Pneumagathis brooksi (Sharkey) n. comb. An illustrated key to the Nearctic genera of Agathidinae is provided. PMID- 26623602 TI - Revision of Aphelagathis (Hymenoptera, Braconidae, Agathidinae, Agathidini). AB - One previously described (Aphelagathis verticalis) and ten new species (A. bonnieirwinae, A. ceciliapinedae, A. ericgrisselli, A. genehalli, A. mclintocki, A. mikeirwini, A. rociofernandezae, A. schlingeri, A. stangei, and A. wendymooreae) are included. Aphelagathis is limited to the Nearctic and the northern part of the Neotropics. A. rociofernandezae parasitizes the caterpillars of grass-feeding Hesperiidae (Lepidoptera) as does A. verticalis. PMID- 26623603 TI - Lepidodactylus lugubris (Dumeril & Bibron 1836) (Reptilia: Gekkonidae), an introduced lizard new for Brazil, with remarks on and correction of its distribution in the New World. AB - Recently seven specimens of the gecko Lepidodactylus lugubris were collected or observed in Belem, Para, northern Brazil. This is the first vouchered occurrence in Brazil of a widely dispersed (Pacific area) and invasive species (much of the Pacific, parts of northern South America and southern Central America and Florida, U.S.A.). In Suriname the species has already spread into the interior. The distribution of the species is corrected and the history of its introduction in the New World is reconstructed, with an estimation of the state of invasiveness for each country. Some possible routes of introduction are discussed. PMID- 26623604 TI - Discovery of the genus Leptophion Cameron, 1901, from Japan and the Palaearctic region, with description of two new species (Hymenoptera: Ichneumonidae: Ophioninae). AB - The genus Leptophion Cameron, 1901, which belongs to the subfamily Ophioninae Shuckard, 1840, is recorded from Japan and the Palaearctic region for the first time based on two new species, L. parvus sp. nov. from Amamioshima Island and L. septentrionis sp. nov. from Yakushima and Amamioshima Island. A key to the Japanese and Taiwanese species is also provided. PMID- 26623605 TI - New synonyms, combinations and faunistic records in the genus Denierella Kaszab (Coleoptera: Meloidae). AB - Taxonomy of the genus Denierella Kaszab, 1952 (Coleoptera: Meloidae: Epicautini) is evaluated. The following new synonyms and combinations (all from the genus Epicauta Dejean, 1834) are established: Denierella thailandica (Dvorak, 1996) comb. nov. = D. striolata Yang & Ren, 2007 syn. nov.; Denierella emmerichi (Pic, 1934) comb. nov. = D. serrata Kaszab, 1952 syn. nov.; Denierella promerotricha (Dvorak, 1996) comb. nov. A lectotype is designated for Epicauta emmerichi. Epicauta emmerichi yunnanensis Kaszab, 1960 is provisionally raised to E. yunnanensis stat. nov., until its status can be confirmed by the study of the holotype specimen. Five new country records, one new Chinese province record and two new Indian state records of six Denierella species are provided, and the distribution of all species included in this study is outlined. A checklist of the genus Denierella is provided and general problems in the taxonomy of Asiatic Epicautini are discussed. PMID- 26623606 TI - A new species of Nemoura (Plecoptera: Nemouridae) from South of the Russian Far East. AB - A new species of Plecoptera from the Nemoura ovocercia group, Nemoura khasanensis sp. n. from the Primorsky Region, south of the Russian Far East, is described and illustrated. The diagnostic characters for separation from other members of the oviocercia group are provided. PMID- 26623607 TI - The tadpole of Chiasmocleis schubarti Bokermann, 1952 (Amphibia, Anura: Microhylidae). PMID- 26623608 TI - A new species of the genus Serrundabracon van Achterberg (Hymenoptera: Braconidae: Braconinae) from Namibia. AB - A second species of the braconine genus Serrundabracon is described and illustrated and distinguished from the type species, S. maraisi Braet. Both species possess the unique combination of a multiple-arched ovipositor and dentate posterior margin to the metasomal tergite 5. Corrections are made to the redescription of S. maraisi. The relationships of, and possible evolutionary transitions to, the genus are discussed. PMID- 26623609 TI - A remarkable structure in a peculiar species of Sarcophagidae (Diptera): description of the male of Lepidodexia (Harpagopyga) albida Lopes. PMID- 26623610 TI - A review of the genus Drymeia Meigen, 1826 (Diptera: Muscidae) in Russia. AB - A key is provided to the 26 species of the genus Drymeia Meigen, 1826 known from Russia and four additional species that may be found in Russia (D. brumalis (Rondani, 1866), D. cantabrigensis (Huckett, 1965), D. gymnophthalma (Hennig, 1963), D. similis (Malloch, 1918)). The key includes the 10 new species here described from the mountains of South Siberia (D. acrostichalis sp. nov., D. aristata sp. nov., D. cilitarsis sp. nov., D. glabra sp. nov., D. grandis sp. nov., D. grisea sp. nov., D. longiseta sp. nov., D. phaonina sp. nov., D. puchokana sp. nov., D. triseta sp. nov.,) and other two new species from the Russian Arctic (D. cristata sp. nov., D. taymirensis sp. nov.). Five species (D. fasciculata (Stein, 1916), D. firthiana (Huckett, 1965), D. groenlandica (Lundbeck, 1901), D. quadrisetosa (Malloch, 1919), D. neoborealis (Snyder, 1949)) are newly recorded from Russia. Three new synonymies are proposed: D. pribilofensis (Malloch, 1921) (syn: D. inaequalis (Malloch, 1922)), D. setibasis (Huckett, 1965) (syn: D. gymnophthalma sibirica (Lavciev, 1971, unavailable junior secondary homonym) and D. quadrisetosa (Malloch, 1919) (syn: D. amurensis (Lavciev, 1971)). The male terminalia and the female ovipositors of the new species are illustrated. New faunistic data are given for some previously described species of Russian Drymeia. PMID- 26623611 TI - Hypolestes hatuey sp. nov.: a new species of the enigmatic genus Hypolestes (Odonata, Hypolestidae) from Hispaniola. AB - Both sexes of Hypolestes hatuey Torres-Cambas, sp. nov. (Odonata: Zygoptera: Hypolestidae) from Hispaniola are described and illustrated here. This newly described species differs from H. trinitatis and H. clara, the other two species within the genus, by the morphology of the genital ligula and male cerci. Females of H. hatuey sp. nov. differ from H. clara by the shape of the female antehumeral stripe and wing venation. Morphological distinctiveness in males is supported by genetic differences in the 16S mitochondrial gene. Following the categories and criteria of the IUCN Red List of Threatened Species, we suggest this species should be listed as Data Deficient (DD), given that available data on its distribution are too limited to assess its risk of extinction. PMID- 26623612 TI - Revision of the Australian Sphaerodoridae (Annelida) including the description of four new species. AB - A revision of the complete sphaerodorid (Sphaerodoridae, Annelida) collections housed in the three major Australian museums (The Australian Museum, Museum and Art Gallery of the Northern Territory and Museum Victoria) has been performed. Specimens of three of the four species described to date from Australian waters, Ephesiella australiensis, Sphaerodoropsis exmouthensis and Sphaerodoropsis fauchaldi, have been re-encountered, resulting in changes to their previously reported distribution range. Four additional species are herein described as new: Sphaerephesia hutchingsae n. sp., Sphaerodoropsis longofalcigera n. sp., Sphaerodoropsis megatuberculata n. sp. and Sphaerodoropsis wilsoni n. sp. Moreover, Sphaerodoropsis multipapillata heteropapillata is elevated to the rank of species. A formal description of other specimens, most likely belonging to undescribed species, is not possible due to insufficient material, but information about some of their morphological features is provided. Descriptions, iconography, geographical and ecological information of all species part of this revision is provided together with a key for identification to all Australian species. An evaluation of some of the traditional generic taxonomic features is made, considering the variation observed within the Australian species. PMID- 26623613 TI - New record of the genus Israelimeria Weiner & Kaprus', 2005 (Collembola: Neanuridae: Pseudachorutinae) from Iran, with description of a new species. AB - Israelimeria persica sp. nov. is described from Iran. The genus Israelimeria can be easily identified due to a reduction of the number of eyes and the complete absence of the postantennal organ and the furca. The new taxon, and also the second species of the genus, differs from I. poliakovae Weiner & Kaprus', 2005, known only from Judean Mts. in Israel, in size and shape of mandibles and many chaetotactic characters, especially number of setae in ocular area of the head, ventral tube, subcoxae "1" and microchaetae number in furcal area. PMID- 26623614 TI - Preembobracon gen. nov. (Hymenoptera: Braconidae: Doryctinae: Ypsistocerini: Embobraconina) from Brazil. AB - Preembobracon zaldivarriveroni gen et sp. nov. from Brazil is described and illustrated. It belongs to the poorly known tribe Ypsistocerini for which biology, is only partly known and then only for the genera of nominal subtribe which are both associated with termite colonies. Preembobracon displays both derived and plesiomorphic character states relative to Embobracon the only other genus of its tribe, and its position in relation to the other genera discussed. Its biology is unknown. PMID- 26623615 TI - Jumping spiders of the genus Scopocira Simon, 1900 (Araneae: Salticidae: Amycoida) from Colombia, with the description of a new species. PMID- 26623616 TI - Morphological description and DNA barcoding of Hydrobaenus majus sp. nov. (Diptera: Chironomidae: Orthocladiinae) from the Russian Far East. AB - Illustrated descriptions of adult male, pupa and fourth instar larva, as well as DNA barcoding, of Hydrobaenus majus sp. nov. in comparison with the close related species H. sikhotealinensis Makarchenko et Makarchenko from the Russian Far East are provided. The species-specificity of H. majus sp. nov. COI sequences is analyzed and the sequences are presented as diagnostic characters--molecular markers of H. majus and H. sikhotealinensis. PMID- 26623617 TI - A new species of Callyntra (Coleoptera: Tenebrionidae) from central Chile. AB - Callyntra Solier, 1836 is a genus mainly from Chile, with one species occurring in Argentina, which currently contains 20 described species. Recent explorations in the Andes Mountain Range in Chile, have resulted in the collection of specimens morphologically different from all previously described species. The aim of this paper is to describe a new species of Callyntra, discuss its relationship with other species in the genus, and highlight sexual dimorphism and potential conservation status. PMID- 26623618 TI - Change of name for the Oriental robber fly Nyssomyia Hull, 1962 (Diptera: Asilidae, Asilinae), nec Nyssomyia Barretto, 1962 (Diptera: Psychodidae, Phlebotominae). AB - A new name for the Oriental genus Nyssomyia Hull, 1962 (Diptera: Asilidae) is proposed. Homonymy exists between this Oriental robber fly genus and the more senior Neotropical phlebotomine sand fly genus Nyssomyia Barretto, 1962 (sensu Galati 2003) (Diptera: Psychodidae), and the following replacement name is proposed: Ekkentronomyia nom. nov. for Nyssomyia Hull (nec Barretto 1962). Accordingly, a new combination is herein proposed for the only species currently included in this genus: Ekkentronomyia ochracea (Hull, 1962) comb. nov. PMID- 26623619 TI - Amblyosyllis, Eusyllis, Odontosyllis, Perkinsyllis and Streptodonta (Annelida: Syllidae) from Brazil, with descriptions of two new species and new records for the country. AB - We present herein the first records for Amblyosyllis, Eusyllis and Perkinsyllis from northeastern Brazil, describing and illustrating Amblyosyllis sp., Eusyllis kupfferi and E. lamelligera, which are compared to the morphologically most similar congeners; a brief diagnosis is provided for Eusyllis nonatoi, Odontosyllis aracaensis, O. guarauensis, O. guillermoi and Perkinsyllis biota, described from southeastern Brazil. In addition, a new species of Odontosyllis is described, O. brevichaetosa sp. n., characterized by having short, bidentate falciger blades with inverted dorso-ventral gradation in length, and shafts of ventralmost falcigers from midbody parapodia onwards subdistally inflated, with sigmoid tip. A key for the valid Brazilian species of Odontosyllis is provided. Finally, this is also the first account of the genus Streptodonta for the South Atlantic, with the description of S. fauchaldi sp. n., characterized by a distinct distribution pattern of cilia along body, presence of spiniger-like chaetae, and morphology of falciger blades. PMID- 26623620 TI - On the taxonomy of Afrotropical Coleophoridae (II) (Lepidoptera, Coleophoridae). AB - Eight new species of the genus Coleophora Hubner, 1822 are described: Coleophora kenyaensis sp. nov., C. vansoni sp. nov., C. elegans sp. nov., C. namaqua sp. nov., C. kamiesella sp. nov., C. kunenensis sp. nov., C. creola sp. nov., and C. hirsutella sp. nov. The genitalia of three previously described species are described and illustrated for the first time: Coleophora niphocrossa Meyrick, 1920, C. enchitis Meyrick, 1920 and C. textoria Meyrick, 1921. The larval case of C. enchitis is illustrated and data about its biology are given. PMID- 26623621 TI - New taxonomic assignments of Calisiinae with description of two new genera (Hemiptera, Heteroptera, Aradidae). AB - Examination of type species of Calisius pallipes Stal 1860 from Brazil and Calisius ghiliani (A.Costa 1864) from Europe has revealed essential morphological differences warranting their placement into different genera. Stal's pallipes is the genotype of Calisius, and ghiliani that of Aradosyrtis A.Costa, whose generic status is revived. A neotype is designated for Aradosyrtis ghiliani A.Costa 1864. Clearly distinguished from Calisius sensu Stal are the Neotropical Calsius farri Kormilev 1964 and the African Calisius lativentris Horvath 1913, for which the new genera Caribocalisius n.gen and Afrocalsius n.gen are established, respectively. PMID- 26623622 TI - A new genus and two new species of Rhopalophorini Blanchard, 1845 (Coleoptera, Cerambycidae, Cerambycinae). AB - A new genus and two new species of Rhopalophorini Blanchard, 1845 are described, and figured: Allorhopaliella boliviana, gen. nov, sp. nov., from Bolivia; and Rhopalophora peruana sp. nov., from Peru. The new species of Rhopalophora Audinet Serville, 1834 is included in a previous key. PMID- 26623623 TI - The description of the female of Platycheirus troll Mutin (Diptera, Syrphidae) with a preliminary key to the Northern Palaearctic females of the Platycheirus clypeatus group. AB - The female of Platycheirus troll Mutin is described. A preliminary key to the females of the Northern Palaearctic species of the Platycheirus clypeatus group is presented. The possibility to identify the undescribed female of Platycheirus magadanensis Mutin is discussed. PMID- 26623624 TI - A new Neotropical genus of Blastini (Psocodea: 'Psocoptera': Psocidae: Amphigerontiinae). AB - A monotypic genus of Psocidae (Amphigerontiinae: Blastini) from Santiago de Cali, Colombia, is here described and illustrated. It differs from Chaetopsocidus Badonnel, from the Paramo de Monserrate, near Bogota, in having setae on the forewing veins. PMID- 26623625 TI - On the males of the orb-weaving spiders Alpaida nigrofrenata (Simon, 1895), A. machala Levi, 1988, and A. cisneros Levi, 1988 (Araneae, Araneidae) and a new synonymy. AB - The araneid spider genus Alpaida O.P.-Cambridge, 1889 has, until now, 148 described species (WSC 2015). The males of A. nigrofrenata (Simon, 1895), A. machala Levi, 1988, and A. cisneros Levi, 1988 are described here for the first time. A. moka Levi, 1988, based on female specimens, is synonymized with A. xavantina Levi, 1988, based on the study of specimens of both sexes. I.L.F. de Magalhaes (MACN) is thanked for reviewing an early revision of this manuscript. We also thank to M. Machado (PUCRS) for the pictures of A. moka, and M. Kolmann (University of Toronto) and A. Londono Burbano (PUCRS) for review the English. We are grateful to G. Hormiga for helping to improve this manuscript. M.R.M. Poeta was financially supported by CAPES at PPG-Zoo, PUCRS. PMID- 26623626 TI - Bordetella pertussis diagnosis in children under five years of age in the Regional Hospital of Cajamarca, Northern Peru. AB - INTRODUCTION: Bordetella pertussis is an important human pathogen that causes whooping cough (pertussis), an endemic illness responsible of significant morbidity and mortality, especially in infants and children. Worldwide, there are an estimated of 16 million cases of pertussis, resulting in about 195,000 child deaths per year. In Peru, pertussis is a major health problem that has been on the increase despite immunization efforts. The objective of this study was to determine the prevalence of B. pertussis among children under five years of age suspected to have whopping cough in Cajamarca, Peru. METHODOLOGY: Children diagnosed with whooping cough admitted to the Hospital Regional de Cajamarca from August 2010 to July 2013 were included. Nasopharyngeal samples were obtained for B. pertussis culture and polymerase chain reaction (PCR) detection. RESULTS: In 133 children, the pertussis toxin and IS481 gene were detected in 38.35% (51/133) of the cases by PCR, while only 9.02% (12/133) of the Bordetella cultures were positive. The most frequent symptoms in patients with positive B. pertussis were paroxysm of coughing 68.63% (35/51), cyanosis 56.86% (29/51), respiratory distress 43.14% (22/51), and fever 39.22% (20/51). Pneumonia and acute bronchial obstructive syndrome were present in 17.65% (9/51) and 13.72% (7/51) of the cases, respectively. CONCLUSIONS: B. pertussis is responsible for an important proportion of whooping cough in hospitalized children in Cajamarca. Epidemiologic surveillance programs for B. pertussis are essential in Peru, especially in children who could most benefit from the vaccine. PMID- 26623627 TI - Ramadan fasting and infectious diseases: a systematic review. AB - Ramadan represents the fourth of the five pillars of the Islamic creed. Although patients are exempted from observing this duty, they may be eager to share this moment of the year with their peers. However, there are no guidelines that can help physicians to address the concerns of patients with infectious diseases fasting during Ramadan. For this purpose, we performed a systematic review. of 51 articles. Our main findings are that: 1) patients suffering from diabetes at risk of developing infectious complications should not fast; 2) Ramadan fasting has little impact on diarrheal patients; 3) HIV represents a challenge, and ad hoc drug combinations should be recommended to patients, and the patients should be advised not to take fatty meals that could interfere with the treatment; 4) Ramadan has no effect on the effectiveness of anti-helminthic therapy; and 5) patients with active ulcers should not fast, as they have a higher probability of developing complications. PMID- 26623629 TI - Prevalence of Listeria monocytogenes in raw bovine milk and milk products from central highlands of Ethiopia. AB - INTRODUCTION: Listeria monocytogenes is of major significance in human and veterinary medicine. Most human Listeria infections are foodborne and the association of contaminated milk and dairy produce consumption with human listeriosis is noteworthy. In Ethiopia, there is limited data regarding the prevalence of L. monocytogenes in raw bovine milk and dairy products. The aim of this study was, therefore, to determine the prevalence of L. monocytogenes in raw bovine milk and dairy produce. METHODOLOGY: A total of 443 milk and milk product samples were microbiologically analyzed following methods recommended by the U.S. Food and Drug Administration Bacteriological Analytical Manual to isolate Listeria spp. RESULTS: The overall prevalence of Listeria spp. was 28.4% and specifically that of L. monocytogenes was 5.6%. Taking the prevalence of Listeria spp. into consideration, cheese was found to be highly contaminated at 60%, followed by pasteurized milk samples (40%), raw milk (18.9%) and yoghurt (5%). Considering the prevalence of Listeria monocytogenes only, raw milk had the lowest contamination while cheese had the highest, followed by pasteurized milk and yoghurt. CONCLUSIONS: Raw milk and milk products produced in urban and peri urban areas of central Ethiopia were contaminated with pathogenic bacteria, L. monocytogenes. The detection of this pathogen in raw milk and milk products warrants an urgent regulatory mechanism to be put in place and also the potential role of milk processing plants in the contamination of dairy products should be investigated. PMID- 26623628 TI - Clinical and microbiological features of bacteremia caused by Enterococcus faecalis. AB - INTRODUCTION: Enterococcus faecalis is a frequent etiologic agent of invasive infections in hospitalized patients. The aim of this study was to analyze clinical and microbiological features of bacteremia caused by E. faecalis. METHODOLOGY: Between 2011 and 2013, significant bacteremia caused by E. faecalis in hospitalized patients was studied. Patient characteristics, comorbid conditions, and 14-day mortality were recorded. Virulence genes esp, gelE, and cylA; opsonophagocytosis resistance; resistance to bactericidal effect of normal serum; beta lactamase production; and susceptibility to ampicillin, vancomycin, teicoplanin, gentamicin, and streptomycin were investigated. RESULTS: E. faecalis strains were recovered from 33 bacteremic patients. Polymicrobial bacteremia was diagnosed in 2 patients; 10 patients died. Virulence genes were found in strains from both deceased patients and survivors. Sources of bacteremia included urinary tract infections (36.4%), vascular catheters (15.1%), abscesses (9.1%), and unknown (48.5%). Underlying diseases included cancer (30.3%), diabetes (36.4%), cirrhosis (6.1%), renal (36.4%), and chronic obstructive pulmonary disease (2.0%). Co-morbidities included alcohol use (26.1%); glucocorticoid therapy (19.0%); prior antibiotic therapy (60.6%); and central venous (21.2%), arterial (12.1%), and urinary (63.6%) catheters. Also, 57.6% of patients came from the intensive care unit (ICU); 33.3% had mechanical ventilation. Significant mortality-associated conditions included polymicrobial bacteremia, oncological disease, APACHE II score <= 20, ICU stay, renal disease, central venous catheter, and mechanical ventilation. CONCLUSIONS: Outcome of patients was associated with their status and not with the presence of virulence genes in E. faecalis strains. A significant percentage of bacteremia had undetermined origin. An alternate origin may be the gastrointestinal tract, through translocation. PMID- 26623630 TI - Characterization of H5N1 influenza A virus that caused the first highly pathogenic avian influenza outbreak in Saudi Arabia. AB - INTRODUCTION: Saudi Arabia (SA) experienced a highly pathogenic avian influenza (HPAI) H5N1 outbreak in domesticated birds in 2007. METHODOLOGY: Forty-three hemagglutinin (HA) and 41 neuraminidase (NA) genes of HPAI H5N1 viruses were sequenced and phylogenetic analyses of completely sequenced genes were performed to compare with other viral HA and NA gene sequences available in the public databases. RESULTS: Molecular characterization of the H5N1 viruses revealed two genetically distinct clades, 2.2.2 and 2.3.1, of H5N1 viruses circulating in the area. Amino acid sequence analysis of the HA gene indicated that the virus from 2.2.2 contained the sequence SPQGERRRK-R/G at the cleavage site, while the virus from 2.3.1 contained the sequence SPQRERRRK-R/G. Additionally, a few mutations with amino acid substitutions such as M226I at N-link glycosylation site were identified in two of these isolates. Amino acid sequence of the NA gene showed a 20-amino-acid deletion in the NA stalk region, required for enhanced virulence of influenza viruses and its adaptation from wild birds to domestic chickens. As close contact between humans and birds is unavoidable, there is a need for a thorough understanding of the virus epidemiology, factors affecting the spread of the virus, and molecular characterization such as phylogeny and substitution rates of H5N1 viruses circulating in the region. CONCLUSION: Two genetically distinct clades were found to be circulating in the country, which could likely result in recombination and emergence of more virulent viral strains. These findings could be helpful for the authorities devising control measures against these viruses. PMID- 26623631 TI - Seroprevalence and predictors of hepatitis E infection in Nigerian children. AB - INTRODUCTION: Hepatitis E is a hepatotropic virus transmitted through the fecal oral route and is prevalent in developing countries where sanitation is still a public health issue. There is no epidemiological data about this virus in Nigerian children. All the existing studies are hospital based, with obvious limitations. This study was conducted to establish the seroprevalence and predictors of viral hepatitis E antibody in children in Akpabuyo Local Government Area of Cross River State, Nigeria. METHODOLOGY: This was a community-based, cross-sectional study. A multi-staged sampling technique was used to select ten communities from which 406 children were recruited. The study period was April to June 2012. A structured interviewer-administered questionnaire was used for data collection. Blood samples were screened for anti-HEV IgG antibody using the enzyme-linked immunoassay technique. Multivariate logistic regression was used to identify factors that independently predicted the occurrence of the anti-HEV IgG antibody. A p value of < 0.05 was considered significant. RESULTS: The seroprevalence rate of anti-HEV IgG antibody was 7.7% (95% CI = 5.1-10.3). The study population mainly (94.1%) comprised the lower social class. Levels of social amenities in these communities were generally poor, with virtually no piped water and modern sewage disposal systems. After multivariate analysis, the predictor of infection was the duration of residence in the study communities. CONCLUSIONS: HEV infection was prevalent in the study population. Educational campaigns and provision of good sewage disposal and piped water are of high necessity. PMID- 26623632 TI - Virology research in a Latin American developing country: a bibliometric analysis of virology in Colombia (2000-2013). AB - INTRODUCTION: Bibliometric analysis demonstrates that the virology research in Latin America has increased. For this reason, the objective of this study was to evaluate Colombian publications on viruses and viral diseases in indexed journals during the period from 2000 to 2013. METHODOLOGY: The bibliographic data were collected from MedLine, SciELO, LILACS and Scopus databases. The database was constructed in Excel descriptive statistics. The SCImago Journal Rank (SJR) was evaluated using the SCImago Journal & Country Rank in 2013 and was used as an indicator of the quality of the journals used by the Colombian researchers. RESULTS: The total number of papers published was 711, of which 40.4% were published in local journals, and 59.6% were published in foreign journals. Most (89.2%) were original papers. Moreover, 34.2% of the papers were published in collaboration with international researchers, with the United States being the most represented. Of the journals used, 85.6% had an SJR, and 14.4% did not. The median SJR of the papers was 0.789, and the median of the papers with international collaborators was higher compared to the SJR of the papers without international collaboration. Papers were most frequently published in journals whose categories were medicine (miscellaneous), virology, and infectious diseases. The viruses that appeared in the papers more frequently were HIV, dengue, and papillomavirus. CONCLUSIONS: This study provides data for use in research, health planning, and policy analysis as it relates to virology in Colombia and other developing Latin American countries. PMID- 26623633 TI - Monoclonal antibodies for characterization of rabies virus isolated from non hematophagous bats in Brazil. AB - INTRODUCTION: In Brazil, various isolates of rabies virus (RABV) show antigenic profiles distinct from those established by the reduced panel of eight monoclonal antibodies (MAbs) determined by the Centers for Disease Control and Prevention (CDC), utilized for the antigenic characterization of RABV in the Americas. The objective of this study was to produce MAbs from RABV isolates from insectivorous bats with an antigenic profile incompatible with the pre-established one. METHODOLOGY: An isolate of RABV from the species Eptesicus furinalis that showed an antigenic profile incompatible with the panel utilized was selected. Hybridomas were produced utilizing the popliteal lymph nodes of mice immunized with ribonucleoproteins purified from the isolate. RESULTS: Two MAbs-producing clones were obtained, BR/IP1-3A7 and BR/IP2-4E10. Fifty-seven isolates of RABV from different species of animals and different regions of Brazil were analyzed utilizing the MAbs obtained. In the analysis of 23 RABV isolates from non hematophagous bats, the MAbs cross-reacted with ten isolates, of which four were of the species Nyctinomops laticaudatus, one of the species Eptesicus furinalis, and five of the genus Artibeus. Of the nine isolates of non-hematophagous isolates that displayed an incompatible profile analyzed, characteristic of insectivorous bats, BR/IP1-3A7 reacted with five (55.55%) and BR/IP2-4E10 with four (44.44%). CONCLUSIONS: The MAbs obtained were able to recognize epitopes common between the three genera, Artibeus, Eptesicus, and Nyctinomops, thereby allowing the antigenic characterization of RABV isolates in Brazil. PMID- 26623634 TI - Molecular detection of DHFR gene polymorphisms in Pneumocystis jirovecii isolates from Indian patients. AB - INTRODUCTION: Pneumocystis pneumonia (PCP) is an opportunistic life-threatening infection, especially for immunocompromised individuals. A trimethoprim sulfamethoxazole (TMP-SMX) combination is commonly used for the treatment of PCP, targeting both dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) enzymes. Several studies have already shown that polymorphisms in the DHPS gene are associated with drug resistance. The present study analyzed DHFR gene polymorphisms in Pneumocystis jirovecii recovered from clinical samples from patients admitted to a tertiary care health center in New Delhi, India. METHODOLOGY: Detection of P. jirovecii was performed using Gomori methenamine silver staining (GMS) and nested polymerase chain reaction (PCR) assay targeting the mitochondrial large subunit ribosomal RNA (mt LSU rRNA) gene. The DHFR gene was amplified using nested PCR protocol and was sequenced for detection of polymorphisms. RESULTS: Of 180 clinical samples, only 4% (7/180) were positive by GMS staining, and 10% (18/180) were positive by mt LSU rRNA PCR assay. Of these 18 positive samples, only 77% (14/18) were amplified by the DHFR gene PCR assay. A total of 16 nucleotide substitutions were observed in 42% (6/14) samples targeted for the DHFR gene, of which 8 nucleotide substitutions were synonymous and the rest were non-synonymous. CONCLUSIONS: The DHFR gene mutations found in this study may possibly indicate an association of process likely to contribute to therapeutic failure or an evolutionary process, and warrant continuous monitoring. PMID- 26623635 TI - Malaria and associated co-morbidity in children admitted with fever manifestation in Western Ghana: A retrospective study. AB - INTRODUCTION: Children under five years of age are highly vulnerable to malaria infection and often face dire consequences such as severe malaria if they are not promptly and adequately treated with effective anti-malarial medications. We set out to evaluate malaria and associated co-morbidity among children admitted with febrile illness in Sekondi-Takoradi, Ghana. METHODOLOGY: This retrospective study focused on children admitted with fever over a three-year period at the pediatric unit of Effia-Nkwanta Regional Hospital. The children were identified, and the medical records of those who were successfully treated and discharged were searched, retrieved, and reviewed. RESULTS: A total of 1,193 children were identified and selected for analysis. The mean duration of admission increased from 2.17 days in 2010 to 3.36 in 2012. Conversely, the mean age decreased from 3.85 years in 2010 to 2.74 in 2012. Overall, laboratory-confirmed malaria prevalence decreased; however, this decrease was only observed among children five years of age or younger, while malaria prevalence increased among children one year of age or younger. The proportion of children with severe malarial anemia significantly increased, while the proportion of those with mild malaria decreased significantly. CONCLUSIONS: Despite the general decrease in malaria morbidity seen in this study, children younger than one year of age remain at increased risk of malaria morbidity. With an increase in malaria prevalence among children younger than one year of age over the three years of study, integrated and targeted control measures are highly needed for this age group. PMID- 26623636 TI - Antibiotics in surgical wards: use or misuse? A newly industrialized country's perspective. AB - INTRODUCTION: Studies exploring the appropriateness of therapeutic antibiotic use among surgical patients are limited, particularly in developing countries. Therefore, the aim of our study was to determine the appropriateness of antibiotics prescribed in a surgical setting in Malaysia. METHODOLOGY: A prospective observational study was conducted in two surgical wards at a tertiary hospital in Malaysia from November 2012-July 2013. Data was collected using a case report form. The appropriateness of antibiotic therapy was based on compliance with either the Malaysian National Antibiotic Guidelines 2008 or International Clinical Practice Guidelines and determined by an expert panel (consisting of two infectious disease consultants and a pharmacist). RESULTS: Over the study period, a total of 593 antibiotic courses were prescribed for 129 patients (4.6+/-3.4 antibiotics/patient). Only 34 (26.4%) patients received appropriate antibiotic therapy, whilst 95 (73.6%) patients received at least one course of inappropriate antibiotic therapy. The prevalence of inappropriate antibiotic use was 214 (66.3%) and 55 (42.0%) for prophylactic and therapeutic purposes, respectively. The most common causes of inappropriate prophylactic antibiotics were inappropriate timing 20 (36.4%) and inappropriate duration of prophylaxis 19 (34.5%). In cases of inappropriate timing, 9 (45%) were administered too late while 6 (30%) were too early. In contrast, inappropriate choice of antibiotics (42.1%) and inappropriate indication (40.7%) were the most common reasons encountered for inappropriate therapeutic antibiotics. CONCLUSION: Our study suggests considerable inappropriate use of both prophylactic and therapeutic antibiotics in the surgical wards; highlighting an urgent need for antibiotic stewardship initiatives in this setting. PMID- 26623637 TI - Low prevalences of HIV infection and HSV genital shedding in the general adult female population in Senegal. AB - INTRODUCTION: Herpes simplex virus (HSV) is the main co-factor for heterosexual transmission of the human immunodeficiency virus (HIV) in sub-Saharan Africa, and could be involved in the dynamics of the HIV epidemic in Senegal. METHODOLOGY: Genital shedding of HSV was evaluated in adult females who had visited the provincial healthcare centres in Diass, Louga, and Kebemer in Senegal. Study subjects were interviewed by a healthcare worker for sociodemographic characteristics and sexual behavior, and HIV serology was offered. In addition, cervical secretion lavage samples were evaluated for HSV DNA by real-time polymerase chain reaction (PCR), the melting curve analysis of which permitted distinction between HSV type 1 (HSV-1) and HSV type 2 (HSV-2). RESULTS: Among 302 women (mean age, 40 years) enrolled, none were infected by HIV. The mean age at first sexual intercourse was 20 years, and the mean number of sexual partners in the previous year was 1.3 (range, 1-7). Only 6 of 302 (1.9%) women had cervico vaginal secretions positive for HSV DNA. No association between HSV DNA shedding and any sociodemographic or biological variables was found. Surprisingly, genital shedding of HSV-1 was found in two (0.7%) women, representing 33% of herpes shedding women, and HSV-2 in four (1.5%) women. CONCLUSIONS: Taken together, our observations indicate a low prevalence of HSV DNA genital shedding in adult Senegalese women. PMID- 26623638 TI - Relationship between vitamin D and human immunodeficiency virus (HIV) viral load among HIV-infected patients in Kazakhstan. AB - INTRODUCTION: Human immunodeficiency virus (HIV) is associated with inflammation. An association between vitamin D deficiency and inflammation also exists. Our study attempts to examine whether there may be a relationship between vitamin D and HIV viral load (HIV RNA) by: 1) characterizing the distribution of 25 hydroxyvitamin D (25-OHD), and 2) determining if 25-OHD is independently associated with HIV RNA. METHODOLOGY: A cross-sectional study among HIV-infected adults was conducted. Demographics, clinical / social / HIV characteristics and data on antiretroviral therapy were collected by questionnaire, medical records and laboratory testing. All patients provided blood samples. Bivariate and multivariate analyses were conducted to quantify the relationship between vitamin D and HIV RNA. RESULTS: Among the 564 patients, the median (interquartile range, IQR) 25-OHD value was 24.42 (16.22 - 34.10) ng/mL. The mean (standard deviation, SD) log-HIV RNA was 3.51 (1.11) copies/mL. There were 304 patients (53.9%) with an undetectable HIV RNA (< 500 copies/mL). In the bivariate analyses, no differences were observed between patients with and without an undetectable HIV RNA in mean (SD) 25-OHD, 25-OHD insufficiency (< 30 ng/mL), or 25-OHD deciles. In the log-binomial regression analyses, there was no association between 25-OHD and an undetectable HIV RNA (prevalence ratio: 1.00, 95% confidence interval: 0.99 - 1.01, p = 0.67). CONCLUSIONS: No relationship was observed between 25-OHD and HIV RNA among HIV-infected patients in Kazakhstan. PMID- 26623639 TI - Vancomycin susceptibility trends of methicillin-resistant Staphylococcus aureus isolated from burn wounds: a time for action. AB - INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin poses a threat for patients in burn units throughout the world. This study aimed to investigate the reduced susceptibility to vancomycin of MRSA isolated from wounds of patients admitted to the Burns and Plastic Surgery Centre in Tripoli, Libya. METHODOLOGY: All isolates were initially identified by chromagen medium then confirmed by PCR. The minimum inhibition concentration (MIC) was determined by E-test glycopeptide resistance detection (GRD). RESULTS: During the study, 210 isolates were obtained from 560 patients representing 132 (62.9%) and 78 (37.1%) of total samples received during years 2009 and 2010, respectively. MIC levels for vancomycin ranged from 0.5 to 2 ug/ml during the study, 13% of isolates displayed MIC of 1.5 ug/ml and 9% of the isolates displayed 2 ug/ml. Although MRSA isolates decreased dramatically during 2010 (37.1%) compared to 2009 (62.9%), overall, there was a significant increase in the proportion of MRSA isolates exhibiting higher vancomycin MICs during 2010 compared to 2009 (P = 0.0155). There was a significant increase of MICs at 1 ug/ml during 2010 compared with 2009 (P = 0.36). No vancomycin intermediate or resistant strains were found. CONCLUSION: There was a significant increase in the proportion of MRSA isolates exhibiting higher vancomycin MICs. We recommend that MRSA isolates should be monitored. Furthermore, implementation of infection control measures is urgently needed to prevent the spread of MRSA. PMID- 26623640 TI - Neurologic melioidosis presented as encephalomyelitis and subdural collection in two male labourers in India. AB - Two distinct and potentially deceitful cases of neurologic melioidosis are reported. Case 1: A 39-year-old alcoholic and uncontrolled diabetic male presented with cough, fever, and left focal seizures with secondary generalization. An magnetic resonance imaging (MRI) brain scan revealed a small peripherally enhancing subdural collection along the interhemispheric fissure suggestive of minimal subdural empyema. Blood culture grew Burkholderia pseudomallei. Patient was diagnosed with disseminated bacteraemic melioidosis with subdural empyema. He was successfully treated with ceftazidime-cotrimoxazole doxycycline. Case 2: A 45-year-old male presented with left lower limb weakness, difficulty in passing urine and stool, and back pain radiating to lower limbs. Neurological examination revealed flaccid left lower limb with absent deep tendon reflexes and plantar reflex. Spinal MRI showed T2 hyperintensity from D9 to L1 suggestive of demyelination. Patient was treated with high dose methylprednisolone. By day 3 of steroid treatment, lower limb weakness progressed. Subsequent MRI showed extensive cord hyperintensity on T2 weighted sequence extending from C5 to conus medullaris consistent with demyelination. Cerebrospinal fluid (CSF) culture grew B. pseudomallei, and the patient was given meropenem-cotrimoxazole. After three weeks of parenteral treatment, the lower limbs remained paralyzed. Patient was discharged on oral cotrimoxazole doxycycline. CONCLUSIONS: Melioidosis should be considered as a differential in focal suppurative central nervous system (CNS) lesions, meningoencephalitis, or encephalomyelitis in endemic areas. CNS infections must be ruled out prior to steroid administration. The role of corticosteroids in demyelinating CNS melioidosis has been refuted. This is a rare documentation of effect of unintentional corticosteroid treatment in melioidosis. PMID- 26623641 TI - Association of blaCTX-M-15 and qnr genes in multidrug-resistant Salmonella Typhimurium and Shigella spp from India. PMID- 26623642 TI - Heterogeneous Evolution of HIV-1 CRF01_AE in Men Who Have Sex with Men (MSM) and Other Populations in China. AB - INTRODUCTION: The HIV epidemic in men who have sex with men (MSM) continues to grow in most countries. However, the phylodynamic and virological differences among HIV-1 strains circulating in MSM and other populations are not well characterized. METHODS: Nearly full-length genomes (NFLGs) of the HIV-1 CRF01_AE were obtained from the Los Alamos HIV database. Phylogenetic analyses were conducted using the NFLG, gag, pol and env genes, using the maximum likelihood method. Selection pressure analyses at the codon level were performed for each gene in the phylogenetic clusters using PAML. RESULTS: Sequences isolated from MSM in China clustered in Clusters 1 (92.5%) and 2 (85.71%). The major risk factor for Cluster 3 was heterosexual transmission (62.16%). The ratio of non synonymous to synonymous substitutions in the env gene (0.7-0.75) was higher than the gag (0.26-0.34) or pol (0.21-0.26) genes. In env gene, Cluster 1 (4.56*10(-3) subs/site/year) and 2 (6.01*10(-3) subs/site/year) had higher evolutionary rates than Cluster 3 (1.14*10(-3) subs/site/year). Positive selection affected 4.2 6.58% of the amino acid sites in the env gene. Two sites (HXB2:136 and 316) evolved similarly in Clusters 1 and 2, but not Cluster 3. CONCLUSION: The HIV-1 CRF01_AE in MSM is evolving differently than in other populations. PMID- 26623643 TI - Molecular Diagnosis of Pathogenic Sporothrix Species. AB - BACKGROUND: Sporotrichosis is a chronic (sub)cutaneous infection caused by thermodimorphic fungi in the order, Ophiostomatales. These fungi are characterized by major differences in routes of transmission, host predilections, species virulence, and susceptibilities to antifungals. Sporothrix species emerge in the form of outbreaks. Large zoonoses and sapronoses are ongoing in Brazil and China, respectively. Current diagnostic methods based on morphology and physiology are inaccurate due to closely related phenotypes with overlapping components between pathogenic and non-pathogenic Sporothrix. There is a critical need for new diagnostic tools that are specific, sensitive, and cost-effective. METHODOLOGY: We developed a panel of novel markers, based on calmodulin (CAL) gene sequences, for the large-scale diagnosis and epidemiology of clinically relevant members of the Sporothrix genus, and its relative, Ophiostoma. We identified specific PCR-based markers for S. brasiliensis, S. schenckii, S. globosa, S. mexicana, S. pallida, and O. stenoceras. We employed a murine model of disseminated sporotrichosis to optimize a PCR assay for detecting Sporothrix in clinical specimens. RESULTS: Primer-BLAST searches revealed candidate sequences that were conserved within a single species. Species-specific primers showed no significant homology with human, mouse, or microorganisms outside the Sporothrix genus. The detection limit was 10-100 fg of DNA in a single round of PCR for identifying S. brasiliensis, S. schenckii, S. globosa, S. mexicana, and S. pallida. A simple, direct PCR assay, with conidia as a source of DNA, was effective for rapid, low-cost genotyping. Samples from a murine model of disseminated sporotrichosis confirmed the feasibility of detecting S. brasiliensis and S. schenckii DNA in spleen, liver, lungs, heart, brain, kidney, tail, and feces of infected animals. CONCLUSIONS: This PCR-based method could successfully detect and identify a single species in samples from cultures and from clinical specimens. The method proved to be simple, high throughput, sensitive, and accurate for diagnosing sporotrichosis. PMID- 26623644 TI - Clinical Performance of a New Soluble CD14-Subtype Immunochromatographic Test for Whole Blood Compared with Chemiluminescent Enzyme Immunoassay: Use of Quantitative Soluble CD14-Subtype Immunochromatographic Tests for the Diagnosis of Sepsis. AB - We previously reported that a soluble CD14-subtype (sCD14-ST) immunochromatographic test (ICT) for plasma is more convenient than chemiluminescent enzyme immunoassay (CLEIA), but plasma separation makes bedside measurements difficult. We developed a new sCD14-ST ICT for whole blood and investigated whether quantitative determinations of sCD14-ST by ICT were useful for diagnosing sepsis and severe sepsis/septic shock. We studied 20 patients who fulfilled two or more systemic inflammatory response syndrome (SIRS) criteria and 32 patients who had been diagnosed with sepsis or severe sepsis/septic shock. Whole blood was collected on day 0 (on admission) and day 7, and the sCD14-ST concentration was quantitatively measured by CLEIA and ICT for whole blood. The patients' Acute Physiology and Chronic Health Evaluation (APACHE) II, Sequential Organ Failure Assessment (SOFA), and Mortality in Emergency Department Sepsis (MEDS) scores were also calculated. The cut-off values obtained by the quantitative measurements made by ICT were 464.5 pg/mL for sepsis and 762.7 pg/mL for severe sepsis/septic shock (P < 0.0001). A Bland-Altman plot showed that no fixed bias or proportional bias was detected between CLEIA and quantitative ICT for whole blood. sCD14-ST concentrations were significantly correlated with APACHE II, SOFA, and MEDS scores (P < 0.0001). These results suggest that the new sCD14-ST ICT for whole blood may be a useful tool for the convenient, rapid bedside diagnosis and treatment of sepsis. PMID- 26623645 TI - Maximizing Sensory Dynamic Range by Tuning the Cortical State to Criticality. AB - Modulation of interactions among neurons can manifest as dramatic changes in the state of population dynamics in cerebral cortex. How such transitions in cortical state impact the information processing performed by cortical circuits is not clear. Here we performed experiments and computational modeling to determine how somatosensory dynamic range depends on cortical state. We used microelectrode arrays to record ongoing and whisker stimulus-evoked population spiking activity in somatosensory cortex of urethane anesthetized rats. We observed a continuum of different cortical states; at one extreme population activity exhibited small scale variability and was weakly correlated, the other extreme had large scale fluctuations and strong correlations. In experiments, shifts along the continuum often occurred naturally, without direct manipulation. In addition, in both the experiment and the model we directly tuned the cortical state by manipulating inhibitory synaptic interactions. Our principal finding was that somatosensory dynamic range was maximized in a specific cortical state, called criticality, near the tipping point midway between the ends of the continuum. The optimal cortical state was uniquely characterized by scale-free ongoing population dynamics and moderate correlations, in line with theoretical predictions about criticality. However, to reproduce our experimental findings, we found that existing theory required modifications which account for activity-dependent depression. In conclusion, our experiments indicate that in vivo sensory dynamic range is maximized near criticality and our model revealed an unanticipated role for activity-dependent depression in this basic principle of cortical function. PMID- 26623646 TI - Live Bird Exposure among the General Public, Guangzhou, China, May 2013. AB - BACKGROUND: A novel avian-origin influenza A(H7N9) caused a major outbreak in Mainland China in early 2013. Exposure to live poultry was believed to be the major route of infection. There are limited data on how the general public changes their practices regarding live poultry exposure in response to the early outbreak of this novel influenza and the frequency of population exposure to live poultry in different areas of China. METHODOLOGY: This study investigated population exposures to live birds from various sources during the outbreak of H7N9 in Guangzhou city, China in 2013 and compared them with those observed during the 2006 influenza A(H5N1) outbreak. Adults were telephone-interviewed using two-stage sampling, stratified by three residential areas of Guangzhou: urban areas and two semi-rural areas in one of which (Zengcheng) A(H7N9) virus was detected in a chicken from wet markets. Logistic regression models were built to describe practices protecting against avian influenza, weighted by age and gender, and then compare these practices across residential areas in 2013 with those from a comparable 2006 survey. PRINCIPAL FINDINGS: Of 1196 respondents, 45% visited wet markets at least daily and 22.0% reported buying live birds from wet markets at least weekly in April-May, 2013, after the H7N9 epidemic was officially declared in late March 2013. Of those buying live birds, 32.3% reported touching birds when buying and 13.7% would slaughter the poultry at home. Although only 10.1% of the respondents reported raising backyard birds, 92.1% of those who did so had physical contact with the birds they raised. Zengcheng respondents were less likely to report buying live birds from wet markets, but more likely to buy from other sources when compared to urban respondents. Compared with the 2006 survey, the prevalence of buying live birds from wet markets, touching when buying and slaughtering birds at home had substantially declined in the 2013 survey. CONCLUSION/SIGNIFICANCE: Although population exposures to live poultry were substantially fewer in 2013 compared to 2006, wet markets and backyard poultry remained the two major sources of live bird exposures for the public in Guangzhou in 2013. Zengcheng residents seemed to have reduced buying live birds from wet markets but not from other sources in response to the detection of H7N9 virus in wet markets. PMID- 26623647 TI - Glucose Homeostatic Law: Insulin Clearance Predicts the Progression of Glucose Intolerance in Humans. AB - Homeostatic control of blood glucose is regulated by a complex feedback loop between glucose and insulin, of which failure leads to diabetes mellitus. However, physiological and pathological nature of the feedback loop is not fully understood. We made a mathematical model of the feedback loop between glucose and insulin using time course of blood glucose and insulin during consecutive hyperglycemic and hyperinsulinemic-euglycemic clamps in 113 subjects with variety of glucose tolerance including normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). We analyzed the correlation of the parameters in the model with the progression of glucose intolerance and the conserved relationship between parameters. The model parameters of insulin sensitivity and insulin secretion significantly declined from NGT to IGT, and from IGT to T2DM, respectively, consistent with previous clinical observations. Importantly, insulin clearance, an insulin degradation rate, significantly declined from NGT, IGT to T2DM along the progression of glucose intolerance in the mathematical model. Insulin clearance was positively correlated with a product of insulin sensitivity and secretion assessed by the clamp analysis or determined with the mathematical model. Insulin clearance was correlated negatively with postprandial glucose at 2h after oral glucose tolerance test. We also inferred a square-law between the rate constant of insulin clearance and a product of rate constants of insulin sensitivity and secretion in the model, which is also conserved among NGT, IGT and T2DM subjects. Insulin clearance shows a conserved relationship with the capacity of glucose disposal among the NGT, IGT and T2DM subjects. The decrease of insulin clearance predicts the progression of glucose intolerance. PMID- 26623648 TI - Use and Utility of Hemostatic Screening in Adults Undergoing Elective, Non Cardiac Surgery. AB - INTRODUCTION: One view of value in medicine is outcome relative to cost of care provided. With respect to operative care, increased attention has been placed on evaluation and optimization of patients prior to undergoing an elective surgery. We examined more than 2 million patients having elective, non-cardiac surgery to assess the incidence and utility of pre-operative hemostatic screening, compared with a composite of history variables that may indicate a propensity for bleeding, to assess several important outcomes of surgery. MATERIALS & METHODS: We queried the NSQIP database to identify 2,020,533 patients and compared hemostatic tests (PT, aPTT, platelet count) and history covariables indicative of potential for abnormal hemostasis. We compared outcomes across predictor values; used Person's chi-square tests to compare differences, and logistic regression to model outcomes. RESULTS: Approximately 36% of patients had all three tests pre operatively while 16% had none of them; 11.2% had a history predictive of potential abnormal bleeding. Outcomes of interest across the cohort included death in 0.7%, unplanned return to the operating room or re-admission within 30 days in 3.8% and 6.2% of patients; 5.3% received a transfusion during or after surgery. Sub-analyses in each of the nine surgical specialties' most common procedures yielded similar results. CONCLUSION: The limited predictive value of each hemostatic screening test, as well as excess costs associated with them, across a broad spectrum of elective surgeries, suggests that limiting pre operative testing to a more select group of patients may be reasonable, equally efficacious, efficient, and cost-effective. PMID- 26623649 TI - Adequacy of Using Consensus Guidelines for Diagnosis of Dementia with Lewy Bodies in Clinical Trials for Drug Development. AB - BACKGROUND/AIMS: To evaluate the adequacy of using the consensus diagnostic criteria for dementia with Lewy bodies (DLB) to recruit patients with homogeneous characteristics in future clinical trials, where multiple departments of multinational centres are expected to participate with a long enrolment period, and additionally, to contribute to the possible future criteria revision. METHODS: Using data from 2 trials of donepezil for DLB, conducted 3 years apart, characteristics in patients with probable DLB were analysed and compared between studies and between psychiatric and neurological centres. RESULTS: In 273 patients (phase II: 135, phase III: 138; psychiatric: 73, neurological: 184), clinical characteristics overall were very similar between studies, and between specialty centres, excluding distinctive parkinsonism in the neurological versus psychiatric centres: incidence of parkinsonism (91.8 vs. 71.2%, p < 0.001), Hoehn and Yahr stage (III: 55.0 vs. 21.2%, p < 0.001), and concomitant anti-Parkinson medication (24.5 vs. 11.0%, p = 0.017). Rapid eye movement sleep behaviour disorder, depression, and delusion, suggestive or supportive features, were observed in 35-40%. Additionally, a high prevalence (55.3%) of anxiety was observed. CONCLUSION: Employing the consensus criteria is adequate to enrol homogeneous DLB patients into future clinical trials regardless of the specialty of centres and time. Further discussion could involve adding anxiety to future criteria. PMID- 26623650 TI - Visual Benefits in Apparent Motion Displays: Automatically Driven Spatial and Temporal Anticipation Are Partially Dissociated. AB - Many behaviourally relevant sensory events such as motion stimuli and speech have an intrinsic spatio-temporal structure. This will engage intentional and most likely unintentional (automatic) prediction mechanisms enhancing the perception of upcoming stimuli in the event stream. Here we sought to probe the anticipatory processes that are automatically driven by rhythmic input streams in terms of their spatial and temporal components. To this end, we employed an apparent visual motion paradigm testing the effects of pre-target motion on lateralized visual target discrimination. The motion stimuli either moved towards or away from peripheral target positions (valid vs. invalid spatial motion cueing) at a rhythmic or arrhythmic pace (valid vs. invalid temporal motion cueing). Crucially, we emphasized automatic motion-induced anticipatory processes by rendering the motion stimuli non-predictive of upcoming target position (by design) and task-irrelevant (by instruction), and by creating instead endogenous (orthogonal) expectations using symbolic cueing. Our data revealed that the apparent motion cues automatically engaged both spatial and temporal anticipatory processes, but that these processes were dissociated. We further found evidence for lateralisation of anticipatory temporal but not spatial processes. This indicates that distinct mechanisms may drive automatic spatial and temporal extrapolation of upcoming events from rhythmic event streams. This contrasts with previous findings that instead suggest an interaction between spatial and temporal attention processes when endogenously driven. Our results further highlight the need for isolating intentional from unintentional processes for better understanding the various anticipatory mechanisms engaged in processing behaviourally relevant stimuli with predictable spatio-temporal structure such as motion and speech. PMID- 26623651 TI - Tilt Table Therapies for Patients with Severe Disorders of Consciousness: A Randomized, Controlled Trial. AB - One major aim of the neurological rehabilitation of patients with severe disorders of consciousness (DOC) is to enhance patients' arousal and ability to communicate. Mobilization into a standing position by means of a tilt table has been shown to improve their arousal and awareness. However, due to the frequent occurrence of syncopes on a tilt table, it is easier to accomplish verticalization using a tilt table with an integrated stepping device. The objective of this randomized controlled clinical trial was to evaluate the effectiveness of a tilt table therapy with or without an integrated stepping device on the level of consciousness. A total of 50 participants in vegetative or minimally conscious states 4 weeks to 6 month after injury were treated with verticalization during this randomized controlled trial. Interventions involved ten 1-hour sessions of the specific treatment over a 3-week period. Blinded assessors made measurements before and after the intervention period, as well as after a 3-week follow-up period. The coma recovery scale-revised (CRS-R) showed an improvement by a median of 2 points for the group receiving tilt table with integrated stepping (Erigo). The rate of recovery of the group receiving the conventional tilt table therapy significantly increased by 5 points during treatment and by an additional 2 points during the 3-week follow-up period. Changes in spasticity did not significantly differ between the two intervention groups. Compared to the conventional tilt table, the tilt table with integrated stepping device failed to have any additional benefit for DOC patients. Verticalization itself seems to be beneficial though and should be administered to patients in DOC in early rehabilitation. Trial Registration: Current Controlled Trials Ltd (www.controlled-trials.com), identifier number ISRCTN72853718. PMID- 26623652 TI - Removing of Disinfection By-Product Precursors from Surface Water by Using Magnetic Graphene Oxide. AB - The magnetic graphene oxide (MGO) was successfully synthesised by the in situ chemical co-precipitation method with Fe3+, Fe2+ and graphene oxide (GO) in laboratory and, was used as an adsorbent for disinfection by-product (DBP) precursors removing from four natural surface water samples. The results indicate that various DBPs formation significantly decreased by 7-19% to 78-98% for the four samples after MGO treatment and, the treatment process was rapidly reached equilibrium within 20 minutes. The DBP precursors removal efficiency decreased with the increasing pH value from 4 to 10. Hydrophobic compounds (humic acid and fulvic acid) are more sensitive to MGO, whereas hydrophilic and nitrogenous compounds (aromatic proteins) are more insensitive. MGO could be regenerated by using 20% (v/v) ethanol and, the DBP precursors removal efficiency can stay stable after five cycles. These results indicate that MGO can be utilized as a promising adsorbent for the removal of DBP precursors from natural surface water. PMID- 26623653 TI - The Bone Marrow-Mediated Protection of Myeloproliferative Neoplastic Cells to Vorinostat and Ruxolitinib Relies on the Activation of JNK and PI3K Signalling Pathways. AB - The classical BCR-ABL-negative Myeloproliferative Neoplasms (MPN) are a group of heterogeneous haematological diseases characterized by constitutive JAK-STAT pathway activation. Targeted therapy with Ruxolitinib, a JAK1/2-specific inhibitor, achieves symptomatic improvement but does not eliminate the neoplastic clone. Similar effects are seen with histone deacetylase inhibitors (HDACi), albeit with poorer tolerance. Here, we show that bone marrow (BM) stromal cells (HS-5) protected MPN-derived cell lines (SET-2; HEL and UKE-1) and MPN patient derived BM cells from the cytotoxic effects of Ruxolitinib and the HDACi Vorinostat. This protective effect was mediated, at least in part, by the secretion of soluble factors from the BM stroma. In addition, it correlated with the activation of signalling pathways important for cellular homeostasis, such as JAK-STAT, PI3K, JNK, MEK-ERK and NF-kappaB. Importantly, the pharmacological inhibition of JNK and PI3K pathways completely abrogated the BM protective effect on MPN cell lines and MPN patient samples. Our findings shed light on mechanisms of tumour survival and may indicate novel therapeutic approaches for the treatment of MPN. PMID- 26623654 TI - A Randomised Controlled Trial to Reduce Sedentary Time in Young Adults at Risk of Type 2 Diabetes Mellitus: Project STAND (Sedentary Time ANd Diabetes). AB - AIMS: Type 2 diabetes mellitus (T2DM), a serious and prevalent chronic disease, is traditionally associated with older age. However, due to the rising rates of obesity and sedentary lifestyles, it is increasingly being diagnosed in the younger population. Sedentary (sitting) behaviour has been shown to be associated with greater risk of cardio-metabolic health outcomes, including T2DM. Little is known about effective interventions to reduce sedentary behaviour in younger adults at risk of T2DM. We aimed to investigate, through a randomised controlled trial (RCT) design, whether a group-based structured education workshop focused on sitting reduction, with self-monitoring, reduced sitting time. METHODS: Adults aged 18-40 years who were either overweight (with an additional risk factor for T2DM) or obese were recruited for the Sedentary Time ANd Diabetes (STAND) RCT. The intervention programme comprised of a 3-hour group-based structured education workshop, use of a self-monitoring tool, and follow-up motivational phone call. Data were collected at three time points: baseline, 3 and 12 months after baseline. The primary outcome measure was accelerometer-assessed sedentary behaviour after 12 months. Secondary outcomes included other objective (activPAL) and self-reported measures of sedentary behaviour and physical activity, and biochemical, anthropometric, and psycho-social variables. RESULTS: 187 individuals (69% female; mean age 33 years; mean BMI 35 kg/m2) were randomised to intervention and control groups. 12 month data, when analysed using intention-to treat analysis (ITT) and per-protocol analyses, showed no significant difference in the primary outcome variable, nor in the majority of the secondary outcome measures. CONCLUSIONS: A structured education intervention designed to reduce sitting in young adults at risk of T2DM was not successful in changing behaviour at 12 months. Lack of change may be due to the brief nature of such an intervention and lack of focus on environmental change. Moreover, some participants reported a focus on physical activity rather than reductions in sitting per se. The habitual nature of sedentary behaviour means that behaviour change is challenging. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN08434554. PMID- 26623655 TI - Follicular Dendritic Cells Retain Infectious HIV in Cycling Endosomes. AB - Despite the success of antiretroviral therapy (ART), it does not cure Human Immunodeficiency Virus (HIV) and discontinuation results in viral rebound. Follicular dendritic cells (FDC) are in direct contact with CD4+ T cells and they retain intact antigen for prolonged periods. We found that human FDC isolated from patients on ART retain infectious HIV within a non-degradative cycling compartment and transmit infectious virus to uninfected CD4 T cells in vitro. Importantly, treatment of the HIV+ FDC with a soluble complement receptor 2 purges the FDC of HIV virions and prevents viral transmission in vitro. Our results provide an explanation for how FDC can retain infectious HIV for extended periods and suggest a therapeutic strategy to achieve cure in HIV-infected humans. PMID- 26623658 TI - Large-Scale Quantum-Mechanical Molecular Dynamics Simulations Using Density Functional Tight-Binding Combined with the Fragment Molecular Orbital Method. AB - The fully analytic gradient is developed for density-functional tight-binding (DFTB) combined with the fragment molecular orbital (FMO) method (FMO-DFTB). The response terms arising from the coupling of the electronic state to the embedding potential are derived, and the gradient accuracy is demonstrated on water clusters and a polypeptide. The radial distribution functions (RDFs) obtained with FMO-DFTB are found to be similar to those from conventional DFTB, while the computational cost is greatly reduced; for 256 water molecules one molecular dynamics (MD) step takes 73.26 and 0.68 s with full DFTB and FMO-DFTB, respectively, showing a speed-up factor of 108. FMO-DFTB/MD is applied to 100 ps MD simulations of liquid hydrogen halides and is found to reproduce experimental RDFs reasonably well. PMID- 26623657 TI - Rapamycin Promotes the Autophagic Degradation of Oxidized Low-Density Lipoprotein in Human Umbilical Vein Endothelial Cells. AB - BACKGROUND/AIMS: Oxidized low-density lipoprotein (ox-LDL) has been extensively implicated in the initiation of atherosclerosis. Our previous studies reported that ox-LDL could activate autophagy in human umbilical vein endothelial cells (HUVECs). Because of this, subsequent studies were designed to elucidate the possible role of the autophagic inducer, rapamycin, on ox-LDL degradation in endothelial cells. METHODS: Intracellular cholesterol content was measured using a tissue total cholesterol assay kit. ox-LDL trafficking within endothelial cells was analyzed by flow cytometry. Levels of proteins involved in the autophagic process, microtubule-associated protein 1 light chain 3 (MAP1-LC3), lysosome associated membrane protein 1 (LAMP1), Beclin 1 and p62, were assessed by Western blot analysis. RESULTS: We discovered that rapamycin could decrease the ox-LDL content in HUVECs at the 3-hour time point. Rapamycin also mediated an obvious increase in Dil-labeled ox-LDL (Dil-ox-LDL)/LC3 and Dil-ox-LDL/LAMP1 co localization, which was inhibited by 3-methyladenine (3-MA), an autophagic inhibitor. In addition, significant co-localization of LC3 and LAMP1 occurred in cells pretreated with rapamycin. In the presence of rapamycin, p62 levels were reduced, and autophagic flux was enhanced. CONCLUSION: These data demonstrate that the activation of the autophagy-lysosome pathway by rapamycin may accelerate ox-LDL degradation. PMID- 26623656 TI - Modelling of Thyroid Peroxidase Reveals Insights into Its Enzyme Function and Autoantigenicity. AB - Thyroid peroxidase (TPO) catalyses the biosynthesis of thyroid hormones and is a major autoantigen in Hashimoto's disease--the most common organ-specific autoimmune disease. Epitope mapping studies have shown that the autoimmune response to TPO is directed mainly at two surface regions on the molecule: immunodominant regions A and B (IDR-A, and IDR-B). TPO has been a major target for structural studies for over 20 years; however, to date, the structure of TPO remains to be determined. We have used a molecular modelling approach to investigate plausible modes of TPO structure and dimer organisation. Sequence features of the C-terminus are consistent with a coiled-coil dimerization motif that most likely anchors the TPO dimer in the apical membrane of thyroid follicular cells. Two contrasting models of TPO were produced, differing in the orientation and exposure of their active sites relative to the membrane. Both models are equally plausible based upon the known enzymatic function of TPO. The "trans" model places IDR-B on the membrane-facing side of the myeloperoxidase (MPO)-like domain, potentially hindering access of autoantibodies, necessitating considerable conformational change, and perhaps even dissociation of the dimer into monomers. IDR-A spans MPO- and CCP-like domains and is relatively fragmented compared to IDR-B, therefore most likely requiring domain rearrangements in order to coalesce into one compact epitope. Less epitope fragmentation and higher solvent accessibility of the "cis" model favours it slightly over the "trans" model. Here, IDR-B clusters towards the surface of the MPO-like domain facing the thyroid follicular lumen preventing steric hindrance of autoantibodies. However, conformational rearrangements may still be necessary to allow full engagement with autoantibodies, with IDR-B on both models being close to the dimer interface. Taken together, the modelling highlights the need to consider the oligomeric state of TPO, its conformational properties, and its proximity to the membrane, when interpreting epitope-mapping data. PMID- 26623659 TI - Out of the Woods. PMID- 26623660 TI - Anti-MoS2 Nanostructures: Tl2S and Its Electrochemical and Electronic Properties. AB - Layered transition metal dichalcogenides are catalytically important compounds. Unlike the mounting interest in transition metal dichalcogenides such as MoS2 and WS2 for electrochemical applications, other metal chalcogenides with layered structure but different chemical composition have received little attention among the scientific community. One such example is represented by thallium(I) sulfide (Tl2S), a Group 13 chalcogenide, which adopts the peculiar anti-CdCl2 type structure where the chalcogen is sandwiched between the metal layers. This is the exact opposite of a number of transition metal dichalcogenides like 1T-MoS2 adopting the regular CdCl2 structure type. The electronic structure of Tl2S thus differs from MoS2. Such structure may provide a useful insight and understanding toward its electrochemical behavior in relation to the electrochemical properties of MoS2. We thus investigated the intrinsic electroactivity of Tl2S and its implications for sensing and energy generation, specifically the electrocatalytic properties toward the hydrogen evolution reaction (HER). We show that Tl2S exhibits four distinct redox signals at ca. 0.4 V, -0.5 V, -1.0 V and -1.5 V vs Ag/AgCl as a result of its inherent cathodic and anodic processes. We also demonstrate that Tl2S possesses slow electron transfer abilities with a rate (k(0)obs) as low as 6.3 * 10(-5) cm s(-1). Tl2S displays a competent performance as a HER electrocatalyst compared to a conventional glassy carbon electrode. However, the poor conductivity of Tl2S renders the HER electrocatalytic behavior second-rate compared to MoS2. Furthermore, we investigated the electronic properties of Tl2S and found that Tl2S exhibits an unusually narrow band dispersion around the Fermi level. We show here that anti-MoS2 structure of Tl2S is accompanied by highly unusual features. PMID- 26623662 TI - Geminal Diazides Derived from 1,3-Dicarbonyls: A Protocol for Synthesis. AB - Geminal diazides constitute a rare class of compounds where only a limited number of methods are available for their synthesis. We present the reaction of 1,3 dicarbonyl compounds (as exemplified by malonates, 3-oxoesters, and 1,3 diketones) with molecular iodine and sodium azide in aqueous DMSO providing a general access to geminal diazides. A broad range of geminal diazides with various structural motifs including sterically demanding substituents and ordinary functional groups were synthesized, and it was shown that the diazidation of 1,3-dicarbonyls can be selectively achieved even in the presence of other 1,3-dicarbonyls with substituents at 2-position. Additionally, several diazides were studied regarding their thermal stability. PMID- 26623661 TI - Tunable Affinity and Molecular Architecture Lead to Diverse Self-Assembled Supramolecular Structures in Thin Films. AB - The self-assembly behavior of specifically designed giant surfactants is systematically studied in thin films using grazing incidence X-ray scattering and transmission electron microscopy, focusing on the effects of molecular nanoparticle (MNP) functionalities and molecular architectures on nanostructure formation. Two MNPs with different surface functionalities, i.e., hydrophilic carboxylic acid functionalized [60]fullerene (AC60) and omniphobic fluorinated polyhedral oligomeric silsesquioxane (FPOSS), are utilized as the head portions of the giant surfactants. By covalently tethering these functional MNPs onto the end point or junction point of polystyrene-block-poly(ethylene oxide) (PS-b-PEO) diblock copolymer, linear and star-like giant surfactants with different molecular architectures are constructed. With fixed length of the PEO block, changing the molecular weight of the PS block leads to the formation of various ordered phases and phase transitions. Due to the distinct affinity, the AC60 based and FPOSS-based giant surfactants form two- or three-component morphologies, respectively. A stretching parameter for the PS block is introduced to characterize the PS chain conformation in the different morphologies. The highly diverse self-assembled nanostructures with high etch resistance between components in small dimensions obtained from the giant surfactant thin films suggest that these macromolecules could provide a promising and robust platform for nanolithography applications. PMID- 26623663 TI - Isotope Dependence and Quantum Effects on Atomic Hydrogen Diffusion in Liquid Water. AB - Relative diffusion coefficients were determined in water for the D, H, and Mu isotopes of atomic hydrogen by measuring their diffusion-limited spin-exchange rate constants with Ni(2+) as a function of temperature. H and D atoms were generated by pulse radiolysis of water and measured by time-resolved pulsed EPR. Mu atoms are detected by muonium spin resonance. To isolate the atomic mass effect from solvent isotope effect, we measured all three spin-exchange rates in 90% D2O. The diffusion depends on the atomic mass, demonstrating breakdown of Stokes-Einstein behavior. The diffusion can be understood using a combination of water "cavity diffusion" and "hopping" mechanisms, as has been proposed in the literature. The H/D isotope effect agrees with previous modeling using ring polymer molecular dynamics. The "quantum swelling" effect on muonium due to its larger de Broglie wavelength does not seem to slow its "hopping" diffusion as much as predicted in previous work. Quantum effects of both the atom mass and the water librations have been modeled using RPMD and a qTIP4P/f quantized flexible water model. These results suggest that the muonium diffusion is very sensitive to the Mu versus water potential used. PMID- 26623664 TI - Molybdenum-Carbide-Modified Nitrogen-Doped Carbon Vesicle Encapsulating Nickel Nanoparticles: A Highly Efficient, Low-Cost Catalyst for Hydrogen Evolution Reaction. AB - Despite being promising substitutes for noble metal catalysts used in hydrogen evolution reaction (HER), the nonprecious metal catalysts (NPMCs) based on inexpensive and earth-abundant 3d transition metals (TMs) are still practically unfeasible due mainly to unsatisfactory activity and durability. Herein, a highly active and stable catalyst for HER has been developed on the basis of molybdenum carbide-modified N-doped carbon vesicle encapsulating Ni nanoparticles (MoxC Ni@NCV). This MoxC-Ni@NCV material was synthesized simply by the solid-state thermolysis of melamine-related composites of oxalate and molybdate with uniform Ni ions doping (Ni@MOM-com). Notably, the prepared MoxC-Ni@NCV was almost the most efficient NPMCs for HER in acidic electrolyte to date. Besides good long term stability, MoxC-Ni@NCV exhibited a quiet low overpotential that was comparable to Pt/C. Thus, this work opens a new avenue toward the development of highly efficient, inexpensive HER catalysts. PMID- 26623665 TI - PEGylated Nanoparticles Obtained through Emulsion Polymerization as Paclitaxel Carriers. AB - Polymer nanoparticles (NPs) represent a promising way to deliver poorly water soluble anticancer drugs without the use of unwanted excipients, whose presence can be the cause of severe side effects. In this work, a Cremophor-free formulation for paclitaxel (PTX) has been developed by employing PEGylated polymer nanoparticles (NPs) as drug delivery carriers based on modified poly(epsilon-caprolactone) macromonomers and synthesized through free radical emulsion polymerization. Paclitaxel was loaded in the NPs in a postsynthesis process which allowed to obtain a drug concentration suitable for in vivo use. In vivo experiments on drug biodistribution and therapeutic efficacy show comparable behavior between the NPs and the Cremophor formulation, also showing good tolerability of the new formulation proposed. PMID- 26623666 TI - Sphere-Like Protein-Glycopolymer Nanostructures Tailored by Polyassociation. AB - Key parameters allow a reproducible polyassociation between avidin and biotinylated glycopolymers in order to fabricate defined supramolecular nanostructures for future (bio)medical and biotechnological applications. Thus, the polymerization efficiency of biotinylated glycopolymers in the fabrication of biohybrid structures (BHS) was investigated with regard to the influence of (i) the degree of biotinylation of the dendritic glycoarchitectures, (ii) two biotin linkers, (iii) the dendritic scaffold (perfectly branched vs hyperbranched), and (iv) the ligand-receptor stoichiometry. The adjustment of all these parameters opens the way to fabricate defined sizes of the final biohybrid structures as a multifunctional platform ready for their use in different applications. Various analytical techniques, including purification of BHS, were used to gain fundamental insights into the structural properties of the resulting protein glycopolymer BHS. Finally, the elucidation of pivotal conformational properties of isolated BHS with defined sizes by asymmetrical flow field flow fractionation study revealed that they mainly possess spherical-/star-like properties. From this study, the fundamental knowledge can be likely transferred to other assemblies formed by molecular recognition processes (e.g., adamantane-beta cyclodextrin). PMID- 26623668 TI - Review of the effect of intravenous lipid emulsion on laboratory analyses. AB - CONTEXT: Although the clinical use of intravenous lipid emulsion therapy for the treatment of lipophilic drug toxicity is increasing, the focus of most publications is on outcome in laboratory animals or in patients. An unintended consequence of intravenous lipid emulsion is the creation of extremely lipemic blood, which may interfere with the laboratory analysis or interpretation of common analytes. OBJECTIVE: The American Academy of Clinical Toxicology has established a lipid emulsion workgroup to review the evidence and produce recommendations on the use of this novel therapy for drug toxicity. The aim of this subgroup is to review the available evidence regarding the effect of intravenous lipid emulsion on common laboratory testing, which often forms the basis of the appraisal of the balance between benefits and potential adverse events. METHODS: We performed a comprehensive review of the literature. Relevant articles were determined based upon a predefined methodology. Package inserts of manufacturers' assays were collected. Article inclusion required that the article met predefined inclusion criteria with the agreement of at least two members of the subgroup. RESULTS: We included thirty-six articles in the final analysis. Evaluation of the reviewed analytes revealed heterogeneity with regards to the assessment of the effect of intravenous lipid emulsion in terms of consistency and magnitude of effect across the different analytic platforms. CONCLUSIONS: The measurements of a number of common analytes can be markedly affected by the lipemia produced by lipid emulsions such that they cannot always be interpreted in the way that most physicians use this information in typical clinical situations. In fact, a lack of appreciation of this effect may lead to unintentional treatment errors. Because the effect of the lipemia produced is dependent on the reagents and laboratory platform used, it would be useful for all future reports to clearly document sample handling, reagents and laboratory platform used, as well as any procedures employed to reduce the lipid content. PMID- 26623667 TI - Suppression of transcriptional drift extends C. elegans lifespan by postponing the onset of mortality. AB - Longevity mechanisms increase lifespan by counteracting the effects of aging. However, whether longevity mechanisms counteract the effects of aging continually throughout life, or whether they act during specific periods of life, preventing changes that precede mortality is unclear. Here, we uncover transcriptional drift, a phenomenon that describes how aging causes genes within functional groups to change expression in opposing directions. These changes cause a transcriptome-wide loss in mRNA stoichiometry and loss of co-expression patterns in aging animals, as compared to young adults. Using Caenorhabditis elegans as a model, we show that extending lifespan by inhibiting serotonergic signals by the antidepressant mianserin attenuates transcriptional drift, allowing the preservation of a younger transcriptome into an older age. Our data are consistent with a model in which inhibition of serotonergic signals slows age dependent physiological decline and the associated rise in mortality levels exclusively in young adults, thereby postponing the onset of major mortality. PMID- 26623676 TI - Susceptibility Profile of Staphylococcus epidermidis and Staphylococcus haemolyticus Isolated from Blood Cultures to Vancomycin and Novel Antimicrobial Drugs over a Period of 12 Years. AB - The aim of this study was to evaluate the antimicrobial susceptibility profile of 85 Staphylococcus epidermidis and 84 Staphylococcus haemolyticus strains isolated from blood cultures to oxacillin, vancomycin, tigecycline, linezolid, daptomycin, and quinupristin/dalfopristin over a period of 12 years. S. epidermidis and S. haemolyticus isolated from blood cultures of inpatients, attended at a teaching hospital, were analyzed for the presence of the mecA gene and by SCCmec typing. The minimum inhibitory concentration (MIC) values of tigecycline, linezolid, daptomycin, quinupristin/dalfopristin, and vancomycin were determined. Isolates exhibiting vancomycin MICs of >=2 MUg/ml were typed by pulsed-field gel electrophoresis (PFGE). The rate of mecA positivity was 92.9% and 100% in S. epidermidis and S. haemolyticus, respectively. The most frequent SCCmec types were type III (53.2%) in S. epidermidis and type I (32.1%) in S. haemolyticus. All isolates were susceptible to linezolid and daptomycin, but 7.1% of S. haemolyticus and 2.3% of S. epidermidis isolates were resistant to tigecycline, and 1.2% each of S. haemolyticus and S. epidermidis were resistant and intermediately resistant to quinupristin/dalfopristin, respectively. S. epidermidis exhibited higher vancomycin MICs (40% with MIC of >=2 MUg/ml). Clonal typing of strains with vancomycin MIC of >=2 MUg/ml revealed the presence of different PFGE types of S. epidermidis and S. haemolyticus over a period of up to 4 years (2002-2004, 2005-2008, 2006-2009, 2010-2011). Despite the observation of a high prevalence of mecA, the clinical strains were fully susceptible to vancomycin and to the new drugs linezolid, daptomycin, tigecycline, and quinupristin/dalfopristin. The PFGE types with vancomycin MIC of >=2 MUg/ml exhibited a great diversity of SCCmec cassettes, demonstrating that S. epidermidis and S. haemolyticus may easily acquire these resistance-conferring genetic elements. PMID- 26623677 TI - The complete chloroplast genome sequence of Salix babylonica. AB - The complete chloroplast genome of the Salix babylonica has been reconstructed from the whole-genome Illumina sequencing data. The circular genome is 156 819 bp in size, and comprises a pair of inverted repeat (IR) regions of 27 624 bp each, a large single-copy (LSC) region of 85 255 bp, and a small single-copy (SSC) region of 16 316 bp. The chloroplast genome contains 130 genes, including 83 protein-coding genes (76 PCG species), eight ribosomal RNA genes (4 rRNA species), and 38 transfer RNA genes (30 tRNA species). The overall GC content of the chloroplast genome is 36.7%, while the corresponding values of the LSC, SSC, and IR regions are 34.4%, 31.0%, and 41.8%, respectively. By comparing four willow chloroplast genomes, this study found that RNA genes were more conservative than protein-coding genes. PMID- 26623678 TI - Management Strategies for Onychomycosis in Special Patient Populations. AB - Clinicians must be aware of characteristics unique to certain populations when diagnosing and treating onychomycosis. For example, although onychomycosis is uncommon in children, it should be considered in the differential diagnosis when young patients have nail changes, particularly if a family history of onychomycosis is present. In elderly patients, comorbid medical conditions may complicate systemic treatment, and physical impairments may interfere with topical therapy. Nondermatophyte molds and yeasts should be considered as possible pathogens in patients with diabetes and psoriasis. Patients who are immunosuppressed for any reason are at increased risk for nail infections. Semin Cutan Med Surg 34(supp3):S54-S55 (c) 2015 published by Frontline Medical Communications. PMID- 26623680 TI - Exposure to Endotoxin in Household Dust. To Wheeze or Not to Wheeze. PMID- 26623679 TI - Phytonutrients Differentially Stimulate NAD(P)H:Quinone Oxidoreductase, Inhibit Proliferation, and Trigger Mitotic Catastrophe in Hepa1c1c7 Cells. AB - Phytonutrients have rapidly emerged as natural food chemicals possessing multifaceted biological actions that may support beneficial health outcomes. Among the vast array of phytonutrients currently being studied, sulforaphane, curcumin, quercetin, and resveratrol have been frequently reported to stimulate the expression of endogenous detoxification enzymes and may thereby facilitate the neutralization of otherwise harmful environmental agents. Some of these same phytonutrients, however, have also been implicated in disrupting normal cell proliferation and hence may possess toxic properties in and of themselves. In this study, we characterize the respective minimum threshold concentrations of the aforementioned phytonutrients in Hepa1c1c7 cells that stimulate NAD(P)H: quinone oxidoreductase (NQO1), a key enzyme in the hepatic neutralization of menadione, other biological oxidants, and some environmental carcinogens. Moreover, our findings demonstrate that relatively low concentrations of either sulforaphane or curcumin significantly (P < .05) increase NQO1 protein expression and activity without triggering G2/M cell cycle arrest or mitotic catastrophe. The minimal quercetin concentration inducing NQO1, however, was 100-fold higher than that which disrupted mitosis. Also, while resveratrol modestly stimulated NQO1, the minimally effective resveratrol concentration concomitantly induced evidence of cellular apoptosis. Taken together, these findings indicate that only particular phytonutrients are likely efficacious in upregulating NQO1 activity without also leading to hepatic cytotoxicity. PMID- 26623681 TI - Continuous beta-Lactam Infusion to Optimize Antibiotic Use for Severe Sepsis. A Knife Cutting Water? PMID- 26623682 TI - Those Who Aren't Counted Still Count. PMID- 26623683 TI - Fatty Acids Secreted by Anaerobes. Fueling Inflammation in Cystic Fibrosis Lungs. PMID- 26623684 TI - Allocating Organs for Lung Transplantation. Two Sides of the Coin. PMID- 26623685 TI - Toward Precision Medicine in Pulmonary Arterial Hypertension. PMID- 26623686 TI - An Official American Thoracic Society/European Respiratory Society Policy Statement: Enhancing Implementation, Use, and Delivery of Pulmonary Rehabilitation. AB - RATIONALE: Pulmonary rehabilitation (PR) has demonstrated physiological, symptom reducing, psychosocial, and health economic benefits for patients with chronic respiratory diseases, yet it is underutilized worldwide. Insufficient funding, resources, and reimbursement; lack of healthcare professional, payer, and patient awareness and knowledge; and additional patient-related barriers all contribute to the gap between the knowledge of the science and benefits of PR and the actual delivery of PR services to suitable patients. OBJECTIVES: The objectives of this document are to enhance implementation, use, and delivery of pulmonary rehabilitation to suitable individuals worldwide. METHODS: Members of the American Thoracic Society (ATS) Pulmonary Rehabilitation Assembly and the European Respiratory Society (ERS) Rehabilitation and Chronic Care Group established a Task Force and writing committee to develop a policy statement on PR. The document was modified based on feedback from expert peer reviewers. After cycles of review and revisions, the statement was reviewed and formally approved by the Board of Directors of the ATS and the Science Council and Executive Committee of the ERS. MAIN RESULTS: This document articulates policy recommendations for advancing healthcare professional, payer, and patient awareness and knowledge of PR, increasing patient access to PR, and ensuring quality of PR programs. It also recommends areas of future research to establish evidence to support the development of an updated funding and reimbursement policy regarding PR. CONCLUSIONS: The ATS and ERS commit to undertake actions that will improve access to and delivery of PR services for suitable patients. They call on their members and other health professional societies, payers, patients, and patient advocacy groups to join in this commitment. PMID- 26623687 TI - A Phase I/IIa Safety and Efficacy Study of Nebulized Liposome-mediated Gene Therapy for Cystic Fibrosis Supports a Multidose Trial. PMID- 26623688 TI - Effects of Extracorporeal CO2 Removal on Inspiratory Effort and Respiratory Pattern in Patients Who Fail Weaning from Mechanical Ventilation. PMID- 26623689 TI - Lung Cancer Susceptibility, Ethnicity, and the Benefits of Computed Tomography Screening. PMID- 26623690 TI - Reply: Lung Cancer Susceptibility, Ethnicity, and the Benefits of Computed Tomography Screening. PMID- 26623691 TI - Excess Risk of Cancer from Computed Tomography Scan Is Small but Not So Low as to Be Incalculable. PMID- 26623692 TI - Reply: Excess Risk of Cancer from Computed Tomography Scan Is Small but Not So Low as to Be Incalculable. PMID- 26623693 TI - Risk-based Heterogeneity of Treatment Effect in Trials and Implications for Surveillance of Clinical Effectiveness Using Regression Discontinuity Designs. PMID- 26623694 TI - Reply: Risk-based Heterogeneity of Treatment Effect in Trials and Implications for Surveillance of Clinical Effectiveness Using Regression Discontinuity Designs. PMID- 26623697 TI - Psychiatric Comorbidity and Substance Use Outcomes in an Office-Based Buprenorphine Program Six Months Following Hurricane Sandy. AB - BACKGROUND: On October 2012, Hurricane Sandy struck New York City, resulting in unprecedented damages, including the temporary closure of Bellevue Hospital Center and its primary care office-based buprenorphine program. OBJECTIVES: At 6 months, we assessed factors associated with higher rates of substance use in buprenorphine program participants that completed a baseline survey one month post-Sandy (i.e. shorter length of time in treatment, exposure to storm losses, a pre-storm history of positive opiate urine drug screens, and post-disaster psychiatric symptoms). METHODOLOGY: Risk factors of interest extracted from the electronic medical records included pre-disaster diagnosis of Axis I and/or II disorders and length of treatment up to the disaster. Factors collected from the baseline survey conducted approximately one month post-Sandy included self reported buprenorphine supply disruption, health insurance status, disaster exposure, and post-Sandy screenings for PTSD and depression. Outcome variables reviewed 6 months post-Sandy included missed appointments, urine drug results for opioids, cocaine, and benzodiazepines. RESULTS: 129 (98%) patients remained in treatment at 6 months, and had no sustained increases in opioid-, cocaine-, and benzodiazepine-positive urine drug tests in any sub-groups with elevated substance use in the baseline survey. Contrary to our initial hypothesis, diagnosis of Axis I and/or II disorders pre-Sandy were associated with significantly less opioid-positive urine drug findings in the 6 months following Sandy compared to the rest of the clinic population. CONCLUSION: These findings demonstrate the adaptability of a safety net buprenorphine program to ensure positive treatment outcomes despite disaster-related factors. PMID- 26623712 TI - Prognostic value of hypoxia-regulated gene expression in loco-regional gastroesophageal cancer. PMID- 26623698 TI - Antimicrobial Treatment for Systemic Anthrax: Analysis of Cases from 1945 to 2014 Identified Through a Systematic Literature Review. AB - Systemic anthrax is associated with high mortality. Current national guidelines, developed for the individualized treatment of systemic anthrax, outline the use of combination intravenous antimicrobials for a minimum of 2 weeks, bactericidal and protein synthesis inhibitor antimicrobials for all cases of systemic anthrax, and at least 3 antimicrobials with good blood-brain barrier penetration for anthrax meningitis. However, in an anthrax mass casualty incident, large numbers of anthrax cases may create challenges in meeting antimicrobial needs. To further inform our understanding of the role of antimicrobials in treating systemic anthrax, a systematic review of the English-language literature was conducted to identify cases of systemic anthrax treated with antimicrobials for which a clinical outcome was recorded. A total of 149 cases of systemic anthrax were identified. Among the identified 59 cases of cutaneous anthrax, 33 were complicated by meningitis (76% mortality), while 26 simply had evidence of the systemic inflammatory response syndrome (4% mortality); 21 of 26 (81%) of this latter group received monotherapy. Subsequent analysis regarding combination antimicrobial therapy was restricted to the remaining 123 cases of more severe anthrax (overall 67% mortality). Recipients of combination bactericidal and protein synthesis inhibitor therapy had a 45% survival versus 28% in the absence of combination therapy (p = 0.07). For meningitis cases (n = 77), survival was greater for those receiving 3 or more antimicrobials over the course of treatment (3 of 4; 75%), compared to receipt of 1 or 2 antimicrobials (12 of 73; 16%) (p = 0.02). Median parenteral antimicrobial duration was 14 days. Combination bactericidal and protein synthesis inhibitor therapy may be appropriate in severe anthrax disease, particularly anthrax meningitis, in a mass casualty incident. PMID- 26623713 TI - Examining BPA's Mechanisms of Action: The Role of c-Myc. PMID- 26623714 TI - Comment on "In Vitro Effects of Bisphenol A beta-D-Glucuronide (BPA-G) on Adipogenesis in Human and Murine Preadipocytes". PMID- 26623715 TI - Identification and Biosynthetic Characterization of Natural Aromatic Azoxy Products from Streptomyces chattanoogensis L10. AB - Aromatic azoxy compounds recently attracted wide interest for their unique liquid crystalline properties. However, biosynthetic pathways of natural azoxy products have rarely been reported. Three novel aromatic azoxy compounds, azoxymycins A, B, and C, have been isolated and identified from Streptomyces chattanoogensis L10, and their biosynthetic pathways have been reported. PMID- 26623717 TI - Imaging of Irreversible Loss of Brain Function. AB - The updated guidelines for the determination of irreversible loss of brain function include a substantial innovation, i. e., the use of CT angiography as a supplementary technical examination. Adherence to a standardized protocol is the prerequisite for the application of CT angiography. The guidelines for standardized execution of perfusion scintigraphy are unchanged and still valid. Requirements regarding the quality of examining physicians are specified. KEY POINTS: * The guidelines for determining irreversible loss of brain function were updated.* The approval of CT angiography as a supplementary examination method is a major innovation.* CT angiography is to be performed to determine the cessation of cerebral blood circulation according to a standard protocol.* The guidelines for the standardized implementation of perfusion scintigraphy continue to be valid.* Quality requirements regarding examining physicians were specified. PMID- 26623716 TI - Application of diagnostic and treatment criteria for common variable immunodeficiency disorder. AB - Common variable immunodeficiency disorder (CVID) is the most frequent symptomatic primary immune deficiency disorder in adults. It probably comprises a spectrum of polygenic disorders, with hypogammaglobulinemia being the overarching feature. While the majority of patients with CVID can be identified with relative ease, a significant proportion can present with minimal symptoms in spite of profound laboratory abnormalities. Here we discuss three patients who were presented to the Auckland Hospital immunoglobulin treatment committee to determine if they qualified for immunoglobulin replacement. Two were asymptomatic with profound laboratory abnormalities while the third patient was severely ill with extensive bronchiectasis. The third patient had less severe laboratory abnormalities compared with the two asymptomatic patients. We have applied four sets of published diagnostic and treatment criteria to these patients to compare their clinical utility. We have chosen these patients from the broad phenotypic spectrum of CVID, as this often illustrates differences in diagnostic and treatment criteria. PMID- 26623718 TI - Lactococcus lactis subsp. lactis JCM 5805 activates natural killer cells via dendritic cells. AB - Lactococcus lactis subsp. lactis JCM 5805 (JCM5805) has been shown to stimulate plasmacytoid dendritic cells (pDC). Here, we investigated the effect of JCM5805 on NK cells. In vitro studies suggested that JCM5805 activated natural killer (NK) cells via dendritic cells including pDC. Furthermore, the oral administration of JCM5805 enhanced the cytotoxic activity of NK cells. PMID- 26623719 TI - The miR27b-CCNG1-P53-miR-508-5p axis regulates multidrug resistance of gastric cancer. AB - Multidrug resistance (MDR) correlates with treatment failure and poor prognosis among gastric cancer (GC) patients. In a previous study using high-throughput functional screening, we identified 11 microRNAs (miRNAs) that regulate MDR in GC and found that miR-508-5p reversed MDR by targeting ABCB1 and ZNRD1. However, the mechanism by which miR-508-5p was decreased in chemo-resistant GC cells was unclear. In this study, we found that ectopic miR-27b is sufficient to sensitize tumors to chemotherapy in vitro and in vivo. Moreover, miR-27b directly targets the 3' untranslated regions (3'-UTRs) of CCNG1, a well-known negative regulator of P53 stability. Interestingly, miR-27b up-regulation leads to increased miR-508 5p expression, and this phenomenon is mediated by CCNG1 and P53. Further investigation indicated that miR-508-5p is directly regulated by P53. Thus, the miR-27b/CCNG1/P53/miR-508-5p axis plays important roles in GC-associated MDR. In addition, miR-27b and miR-508-5p expression was detected in GC tissues with different chemo-sensitivities, and we found that tissues in which miR-27b and miR 508-5p are up-regulated are more sensitive to chemotherapy. Together, these data suggest that the combination of miR-27b and miR-508-5p represents a potential marker of MDR. Restoring the miR-27b and miR-508-5p levels might contribute to MDR reversion in future clinical practice. PMID- 26623720 TI - Immunohistochemical prediction of lapatinib efficacy in advanced HER2-positive breast cancer patients. AB - Molecular mechanisms of lapatinib resistance in breast cancer are not well understood. The aim of this study was to correlate expression of selected proteins involved in ErbB family signaling pathways with clinical efficacy of lapatinib. Study group included 270 HER2-positive advanced breast cancer patients treated with lapatinib and capecitabine. Immunohistochemical expression of phosphorylated adenosine monophosphate-activated protein (p-AMPK), mitogen activated protein kinase (p-MAPK), phospho (p)-p70S6K, cyclin E, phosphatase and tensin homolog were analyzed in primary breast cancer samples. The best discriminative value for progression-free survival (PFS) was established for each biomarker and subjected to multivariate analysis. At least one biomarker was determined in 199 patients. Expression of p-p70S6K was independently associated with longer (HR 0.45; 95% CI: 0.25-0.81; p = 0.009), and cyclin E with shorter PFS (HR 1.83; 95% CI: 1.06-3.14; p = 0.029). Expression of p-MAPK (HR 1.61; 95% CI 1.13-2.29; p = 0.009) and cyclin E (HR 2.99; 95% CI: 1.29-6.94; p = 0.011) was correlated with shorter, and expression of estrogen receptor (HR 0.65; 95% CI 0.43-0.98; p = 0.041) with longer overall survival. Expression of p-AMPK negatively impacted response to treatment (HR 3.31; 95% CI 1.48-7.44; p = 0.004) and disease control (HR 3.07; 95% CI 1.25-7.58; p = 0.015). IN CONCLUSION: the efficacy of lapatinib seems to be associated with the activity of downstream signaling pathways - AMPK/mTOR and Ras/Raf/MAPK. Further research is warranted to assess the clinical utility of these data and to determine a potential role of combining lapatinib with MAPK pathway inhibitors. PMID- 26623721 TI - Dasatinib induces DNA damage and activates DNA repair pathways leading to senescence in non-small cell lung cancer cell lines with kinase-inactivating BRAF mutations. AB - Improved therapies are greatly needed for non-small cell lung cancer (NSCLC) that does not harbor targetable kinase mutations or translocations. We previously demonstrated that NSCLC cells that harbor kinase-inactivating BRAF mutations (KIBRAF) undergo senescence when treated with the multitargeted kinase inhibitor dasatinib. Similarly, treatment with dasatinib resulted in a profound and durable response in a patient with KIBRAF NSCLC. However, no canonical pathways explain dasatinib-induced senescence in KIBRAF NSCLC. To investigate the underlying mechanism, we used 2 approaches: gene expression and reverse phase protein arrays. Both approaches showed that DNA repair pathways were differentially modulated between KIBRAF NSCLC cells and those with wild-type (WT) BRAF. Consistent with these findings, dasatinib induced DNA damage and activated DNA repair pathways leading to senescence only in the KIBRAF cells. Moreover, dasatinib-induced senescence was dependent on Chk1 and p21, proteins known to mediate DNA damage-induced senescence. Dasatinib also led to a marked decrease in TAZ but not YAP protein levels. Overexpression of TAZ inhibited dasatinib-induced senescence. To investigate other vulnerabilities in KIBRAF NSCLC cells, we compared the sensitivity of these cells with that of WTBRAF NSCLC cells to 79 drugs and identified a pattern of sensitivity to EGFR and MEK inhibitors in the KIBRAF cells. Clinically approved EGFR and MEK inhibitors, which are better tolerated than dasatinib, could be used to treat KIBRAF NSCLC. Our novel finding that dasatinib induced DNA damage and subsequently activated DNA repair pathways leading to senescence in KIBRAF NSCLC cells represents a unique vulnerability with potential clinical applications. PMID- 26623722 TI - miR-302b enhances breast cancer cell sensitivity to cisplatin by regulating E2F1 and the cellular DNA damage response. AB - The identification of the molecular mechanisms involved in the establishment of the resistant phenotype represents a critical need for the development of new strategies to prevent or overcome cancer resistance to anti-neoplastic treatments.Breast cancer is the leading cause of cancer-related deaths in women, and resistance to chemotherapy negatively affects patient outcomes. Here, we investigated the potential role of miR-302b in the modulation of breast cancer cell resistance to cisplatin.miR-302b overexpression enhances sensitivity to cisplatin in breast cancer cell lines, reducing cell viability and proliferation in response to the treatment. We also identified E2F1, a master regulator of the G1/S transition, as a direct target gene of miR-302b. E2F1 transcriptionally activates ATM, the main cellular sensor of DNA damage. Through the negative regulation of E2F1, miR-302b indirectly affects ATM expression, abrogating cell cycle progression upon cisplatin treatment. Moreover miR-302b, impairs the ability of breast cancer cells to repair damaged DNA, enhancing apoptosis activation following cisplatin treatment.These findings indicate that miR-302b plays a relevant role in breast cancer cell response to cisplatin through the modulation of the E2F1/ATM axis, representing a valid candidate as therapeutic tool to overcome chemotherapy resistance. PMID- 26623723 TI - Aberrant modulation of the BRCA1 and G1/S cell cycle pathways in alcoholic hepatitis patients with Mallory Denk Bodies revealed by RNA sequencing. AB - Mallory-Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding DDC. Liver injury from alcohol administration causes balloon hepatocytes and MDB formation impeding liver regeneration. By comparing AH livers where MDBs had formed with normal liver transcriptomes obtained by RNA sequencing (RNA-Seq), there was significant upregulation of BRCA1-mediated signaling and G1/S cell cycle checkpoint pathways. The transcriptional architecture of differentially expressed genes from AH livers reflected step-wise transcriptional changes progressing to AH. Key molecules such as BRCA1, p15 and p21 were significantly upregulated both in AH livers and in the livers of the DDC re-fed mice model where MDBs had formed. The increase of G1/S cell cycle checkpoint inhibitors p15 and p21 results in cell cycle arrest and inhibition of liver regeneration, implying that p15 and p21 could be exploited for the identification of specific targets for the treatment of liver disease. Provided here for the first time is the RNA-Seq data that represents the fully annotated catalogue of the expression of mRNAs. The most prominent alterations observed were the changes in BRCA1-mediated signaling and G1/S cell cycle checkpoint pathways. These new findings expand previous and related knowledge in the search for gene changes that might be critical in the understanding of the underlying progression to the development of AH. PMID- 26623726 TI - SnoRNPs, ZNHIT proteins and the R2TP pathway. PMID- 26623724 TI - Prohibitin overexpression improves myocardial function in diabetic cardiomyopathy. AB - Prohibitin (PHB) is a highly conserved protein implicated in various cellular functions including proliferation, apoptosis, tumor suppression, transcription, and mitochondrial protein folding. However, its function in diabetic cardiomyopathy (DCM) is still unclear. In vivo, type 2 diabetic rat model was induced by using a high-fat diet and low-dose streptozotocin. Overexpression of the PHB protein in the model rats was achieved by injecting lentivirus carrying PHB cDNA via the jugular vein. Characteristics of type 2 DCM were evaluated by metabolic tests, echocardiography and histopathology. Rats with DCM showed severe insulin resistance, left ventricular dysfunction, fibrosis and apoptosis. PHB overexpression ameliorated the disease. Cardiofibroblasts (CFs) and H9c2 cardiomyoblasts were used in vitro to investigate the mechanism of PHB in altered function. In CFs treated with HG, PHB overexpression decreased expression of collagen, matrix metalloproteinase activity, and proliferation. In H9c2 cardiomyoblasts, PHB overexpression inhibited apoptosis induced by HG. Furthermore, the increased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was significantly decreased and the inhibited phosphorylation of Akt was restored in DCM. Therefore, PHB may be a new therapeutic target for human DCM. PMID- 26623725 TI - Targeting the EWS-ETS transcriptional program by BET bromodomain inhibition in Ewing sarcoma. AB - Ewing sarcomas (ES) are highly malignant bone or soft tissue tumors. Genetically, ES are defined by balanced chromosomal EWS/ETS translocations, which give rise to chimeric proteins (EWS-ETS) that generate an oncogenic transcriptional program associated with altered epigenetic marks throughout the genome. By use of an inhibitor (JQ1) blocking BET bromodomain binding proteins (BRDs) we strikingly observed a strong down-regulation of the predominant EWS-ETS protein EWS-FLI1 in a dose dependent manner. This was further enhanced by co-treatment with an inhibitor of the PI3K pathway. Microarray analysis further revealed JQ1 treatment to block a typical ES associated expression program. The effect on this expression program was mimicked by RNA interference with BRD3 or BRD4 expression, indicating that the EWS-FLI1 mediated expression profile is at least in part mediated via such epigenetic readers. Consequently, contact dependent and independent proliferation of different ES lines was strongly inhibited. Mechanistically, treatment of ES resulted in a partial arrest of the cell cycle as well as induction of apoptosis. Tumor development was suppressed dose dependently in a xeno-transplant model in immune deficient mice, overall indicating that ES may be susceptible to treatment with epigenetic inhibitors blocking BET bromodomain activity and the associated pathognomonic EWS-ETS transcriptional program. PMID- 26623727 TI - Novel and potent anti-tumor and anti-metastatic di-2-pyridylketone thiosemicarbazones demonstrate marked differences in pharmacology between the first and second generation lead agents. AB - Di(2-pyridyl)ketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di(2 pyridyl)ketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) are novel, highly potent and selective anti-tumor and anti-metastatic drugs. Despite their structural similarity, these agents differ in their efficacy and toxicity in vivo. Considering this, a comparison of their pharmacokinetic and pharmaco/toxico dynamic properties was conducted to reveal if these factors are involved in their differential activity. Both compounds were administered to Wistar rats intravenously (2 mg/kg) and their metabolism and disposition were studied using UHPLC-MS/MS. The cytotoxicity of both thiosemicarbazones and their metabolites was also examined using MCF-7, HL-60 and HCT116 tumor cells and 3T3 fibroblasts and H9c2 cardiac myoblasts. Their intracellular iron-binding ability was characterized by the Calcein-AM assay and their iron mobilization efficacy was evaluated. In contrast to DpC, Dp44mT undergoes rapid demethylation in-vivo, which may be related to its markedly faster elimination (T1/2 = 1.7 h for Dp44mT vs. 10.7 h for DpC) and lower exposure. Incubation of these compounds with cancer cells or cardiac myoblasts did not result in any significant metabolism in-vitro. The metabolism of Dp44mT in-vivo resulted in decreased anti-cancer activity and toxicity. In conclusion, marked differences in the pharmacology of Dp44mT and DpC were observed and highlight the favorable pharmacokinetics of DpC for cancer treatment. PMID- 26623729 TI - ASXL1 mutation correction by CRISPR/Cas9 restores gene function in leukemia cells and increases survival in mouse xenografts. AB - Recurrent somatic mutations of the epigenetic modifier and tumor suppressor ASXL1 are common in myeloid malignancies, including chronic myeloid leukemia (CML), and are associated with poor clinical outcome. CRISPR/Cas9 has recently emerged as a powerful and versatile genome editing tool for genome engineering in various species. We have used the CRISPR/Cas9 system to correct the ASXL1 homozygous nonsense mutation present in the CML cell line KBM5, which lacks ASXL1 protein expression. CRISPR/Cas9-mediated ASXL1 homozygous correction resulted in protein re-expression with restored normal function, including down-regulation of Polycomb repressive complex 2 target genes. Significantly reduced cell growth and increased myeloid differentiation were observed in ASXL1 mutation-corrected cells, providing new insights into the role of ASXL1 in human myeloid cell differentiation. Mice xenografted with mutation-corrected KBM5 cells showed significantly longer survival than uncorrected xenografts. These results show that the sole correction of a driver mutation in leukemia cells increases survival in vivo in mice. This study provides proof-of-concept for driver gene mutation correction via CRISPR/Cas9 technology in human leukemia cells and presents a strategy to illuminate the impact of oncogenic mutations on cellular function and survival. PMID- 26623731 TI - Transportation Self-Efficacy and Social Problem-Solving of Persons Who Are Blind or Visually Impaired. AB - Social problem-solving skills and transportation self-efficacy were assessed for 48 vocational rehabilitation consumers with visual disabilities who required assistance securing work transportation. Social problem solving was at the upper end of the normed average; transportation self-efficacy averaged 101.5 out of 140. Level of vision loss was not associated with score differences; urban residence related to slightly higher self-efficacy than suburban or rural residency. Participants appeared to have the skills necessary to secure employment transportation, but were less confident about transportation-seeking activities that required more initiative of social interaction. Training and information might help consumers gain confidence in these tasks and increase viable transportation options. PMID- 26623732 TI - Uterine-Derived CD11b Cells Significantly Increase Vasculogenesis and Promote Myocardial Healing in Ischemic Cardiomyopathy. AB - Ischemic heart disease is the leading cause of mortality in industrialized countries. Cell transplantation could restore function of the ischemic heart likely through the mechanism of cell-induced angiogenesis. We have previously shown that cells isolated from uteri increase angiogenesis and alleviate cardiac dysfunction when transplanted after MI. However, which uterine cell type contributes to angiogenesis is unknown. Here we report that uterine-derived CD11b cells significantly increase vasculogenesis and promote myocardial healing in ischemic cardiomyopathy. We have established a novel and simple methodology for uterine CD11b cell isolation and enrichment and demonstrate that this technique can be used for purifying and establishing viable CD11b cell cultures in rats. The isolated fresh CD11b cells were transplanted into ischemic rat hearts 5 days after injury. Following transplantation, vasculogenesis significantly increased in ischemic cardiac tissue, which reduced infarct size and restored myocardial function and perfusion compared with controls. Thus, uterine CD11b cells have the potential to promote functional healing when implanted after ischemic cardiomyopathy. Importantly, we have demonstrated a novel means by which CD11b cells can be easily purified and cultured for cell transplantation. PMID- 26623733 TI - Description and phylogenetic relationships of a new genus and two new species of lizards from Brazilian Amazonia, with nomenclatural comments on the taxonomy of Gymnophthalmidae (Reptilia: Squamata). AB - We describe a new genus and two new species of gymnophthalmid lizards based on specimens collected from Brazilian Amazonia, mostly in the "arc of deforestation". The new genus is easily distinguished from other Gymnophthalmidae by having very wide, smooth, and imbricate nuchals, arranged in two longitudinal and 6-10 transverse rows from nape to brachium level, followed by much narrower, strongly keeled, lanceolate, and mucronate scales. It also differs from all other Gymnophthalmidae, except Iphisa, by the presence of two longitudinal rows of ventrals. The new genus differs from Iphisa by having two pairs of enlarged chinshields (one in Iphisa); posterior dorsal scales lanceolate, strongly keeled and not arranged in longitudinal rows (dorsals broad, smooth and forming two longitudinal rows), and lateral scales keeled (smooth). Maximum parsimony, maximum likelihood, and Bayesian phylogenetic analyses based on morphological and molecular data indicate the new species form a clade that is most closely related to Iphisa. We also address several nomenclatural issues and present a revised classification of Gymnophthalmidae. PMID- 26623734 TI - A new species of Anoplodactylus (Pycnogonida: Phoxichilidiidae) from Brazil, with a case of gynandromorphism in Anoplodactylus eroticus Stock, 1968. AB - A new species of Anoplodactylus was discovered in coral reefs from the State of Paraiba, northeastern Brazil. A. mirim sp. nov. is very small and is characterized for having 3 teeth on the cheliphores and a very small cement gland. It belongs to the A. pygmaeus complex, which contains very small species. A. batangensis is recorded for the first time along the Brazilian coast, and A. eroticus is recorded for the first time in the South Atlantic. We record the fifth known case of gynandromorphism, the fourth for Anoplodactylus, based on two specimens of A. eroticus. PMID- 26623730 TI - Lack of survival advantage with autologous stem-cell transplantation in high-risk neuroblastoma consolidated by anti-GD2 immunotherapy and isotretinoin. AB - Since 2003, high-risk neuroblastoma (HR-NB) patients at our center received anti GD2 antibody 3F8/GM-CSF + isotretinoin - but not myeloablative therapy with autologous stem-cell transplantation (ASCT). Post-ASCT patients referred from elsewhere also received 3F8/GM-CSF + isotretinoin. We therefore accrued a study population of two groups treated during the same period and whose consolidative therapy, aside from ASCT, was identical. We analyzed patients enrolled in 1st complete/very good partial remission (CR/VGPR). Their event-free survival (EFS) and overall survival (OS) were calculated from study entry. Large study size allowed robust statistical analyses of key prognosticators including MYCN amplification, minimal residual disease (MRD), FCGR2A polymorphisms, and killer immunoglobulin-like receptor genotypes of natural killer cells. The 170 study patients included 60 enrolled following ASCT and 110 following conventional chemotherapy. The two cohorts had similar clinical and biological features. Five year rates for ASCT and non-ASCT patients were, respectively: EFS 65% vs. 51% (p = .128), and OS 76% vs. 75% (p = .975). In multivariate analysis, ASCT was not prognostic and only MRD-negativity after two cycles of 3F8/GM-CSF correlated with significantly improved EFS and OS. Although a trend towards better EFS is seen with ASCT, OS is near identical. Cure rates may be similar, as close surveillance detects localized relapse and effective salvage treatments are applied. ASCT may not be needed to improve outcome when anti-GD2 immunotherapy is used for consolidation after dose-intensive conventional chemotherapy. PMID- 26623735 TI - Eremocoris juquilianus a new bug species from the mountains in Oaxaca, Mexico (Hemiptera: Rhyparochromidae: Drymini): with description of the immature stages. AB - The genus Eremocoris Fieber is represented by 43 species, and three subspecies, 14 and 3 are Palearctic, 5 Oriental, 3 Afrotropical and 21 Nearctic. 14 species are recorded in Mexico. This contribution contains descriptions and illustrations of the adult and all immature stages of Eremocoris juquilianus sp. nov. and notes on its biology, habitat, and distribution in Mexico. PMID- 26623736 TI - Phylogenetic positions of four hypotrichous ciliates (Protista, Ciliophora) based on SSU rRNA gene, with notes on their morphological characters. AB - The morphology and infraciliature of the four hypotrichous ciliates; Rigidohymena inquieta (Stokes, 1887) Berger, 2011, Pattersoniella vitiphila Foissner, 1987, Notohymena australis Foissner & O' Donoghue, 1990, and Cyrtohymena (Cyrtohymenides) australis (Foissner, 1995) Foissner, 2004, collected from east China, were investigated by using live observation and protargol impregnation method. An improved diagnosis for R. inquieta was supplied based on descriptions of present and previous populations. New morphology and morphogenesis information based on Chinese populations of another three hypotrichids were also supplemented. The Small-subunit rRNA (SSU rRNA) gene sequences of the four species were characterized and their phylogenetic positions were revealed by means of Bayesian inference and Maximum-likelihood analysis. The analyses shows that R. inquieta clusters with other members of the subfamily Stylonychinae, which confirms the monophyly of the subfamily and verified R. inquieta as a separated species from R. candens though it differs from others mainly by body size. C. (C.) australis occupying the basal position of the clade which contains cyrtohymenids and some other groups, declines the idea of separating Cyrtohymena into two subgenus. Notohymena australis and China population of Pattersoniella vitiphila respectively clustering with their congeners correspond well with the systematics revealed by morphological similarities. PMID- 26623737 TI - A new species of Deutonura (Collembola: Neanuridae: Neanurinae) from Algeria, with revised diagnosis of the genus and key to western Palaearctic species. AB - Deutonura adriani sp. nov. is described from the region of Tizi-Ouzou (Algeria). The species is morphologically similar to D. deficiens deficiens Deharveng, 1979 from southwestern France, differing by not having De3 chaetae integrated into the dorso-external tubercle on abdominal tergites I and II. The genus Deutonura is re diagnosed and a key to its Western Palaearctic species is provided. PMID- 26623728 TI - MicroRNAs as growth regulators, their function and biomarker status in colorectal cancer. AB - Gene expression is in part regulated by microRNAs (miRNAs). This review summarizes the current knowledge of miRNAs in colorectal cancer (CRC); their role as growth regulators, the mechanisms that regulate the miRNAs themselves and the potential of miRNAs as biomarkers. Although thousands of tissue samples and bodily fluids from CRC patients have been investigated for biomarker potential of miRNAs (>160 papers presented in a comprehensive tables), none single miRNA nor miRNA expression signatures are in clinical use for this disease. More than 500 miRNA-target pairs have been identified in CRC and we discuss how these regulatory nodes interconnect and affect signaling pathways in CRC progression. PMID- 26623738 TI - Descriptions of two new and one newly recorded enchytraeid species (Clitellata, Enchytraeidae) from the Ozegahara Mire, a heavy snowfall highmoor in Central Japan. AB - Three species of semi-aquatic freshwater Enchytraeidae of the genera Mesenchytraeus Eisen, 1878, Chamaedrilus Friend, 1913 and Globulidrilus Christensen & Dozsa-Farkas, 2012 are described from stream, wet soil or snow habitats in the Ozegahara Mire, an extensive high moor in heavy snowfall area in central Japan. Among Mesenchytraeus speies, Mesenchytraeus nivalis sp. nov. is distinguished by not having enlarged chaetae and spermathecal diverticula, vas deferens with atrial glands 3 or 4 in number and club-shaped, spermathecal ental duct short, with sperm bundles in the sperm sack. Chamaedrilus ozensis sp. nov. closely resembles C. floridae, but the length of the sperm funnel and character of the coelomocytes are different. Globulidrilus helgei Christensen & Dozsa Farkas, 2012 is recorded for the first time from Japan. PMID- 26623739 TI - Taxonomy of 'Euconnus complex'. Part IV. Review of Euconnus subgenus Rhomboconnus (Coleoptera, Staphylinidae, Scydmaeninae). AB - Morphological structures of the type species of Euconnus (Rhomboconnus Franz) are described and illustrated, and compared with those of Euconnus s. str. Rhomboconnus, although showing several peculiar character states (e.g., rudimentary or lacking basal elytral foveae) is maintained as a subgenus of Euconnus, and its revised diagnosis is given. Two species currently placed in Rhomboconnus, E. perplexus Franz (Venezuela) and E. trianguliceps Franz (Ecuador) are redescribed. A surprising and striking similarity of the aedeagus of Rhomboconnus to that of Plaumanniola Costa Lima (Plaumanniolini) is discussed as yet another structural evidence supporting a previously postulated close relationship between the enigmatic Plaumanniolini and the 'Euconnus complex'. PMID- 26623740 TI - The rare mantis shrimp Areosquilla indica (Hansen, 1976) (Crustacea, Stomatopoda) from the Great Barrier Reef: first Australian records of the genus and species. AB - The rare mantis shrimp genus Areosquilla is recorded from Australia for the first time based on nine specimens of A. indica (Hansen, 1926) collected from the Great Barrier Reef. Morphological variation beyond that observed in previous accounts is reported. The present record and other recent discoveries bring the Australian stomatopod fauna to 152 species and 68 genera. PMID- 26623741 TI - New species and first records of Macunahyphes Dias, Salles & Molineri, 2005 (Ephemeroptera: Leptohyphidae) from Bahia state, Brazil. AB - A new species of Macunahyphes Dias, Salles & Molineri (Leptohyphidae) is described based on male imagos collected in the Michelin Ecological Reserve, Igrapiuna, Bahia state, Brazil, located in a preserved area of Atlantic Forest. The male of the new species can be distinguished from all congeners by the shape of the penes, which have a pair of unusual spines, and are elongated with lateral hook-shaped projections distributed from the base to the middle region. This new species represents the first record for the genus from Bahia State. PMID- 26623742 TI - New species of Tauala Wanless, 1988 from Australia (Araneae: Salticidae: Astioida: Astiae), with a redefinition of the genus. AB - Five species of the genus Tauala Wanless, 1988, namely T. zborowskii sp. nov. (f), T. ottoi sp. nov. (f), T. palumaensis sp. nov. (m), T. bilobatus sp. nov. (m) and T. setosus sp. nov. (m), are diagnosed, described and illustrated. Additional colour plates with the females of T. lepidus Wanless, 1988 and T. athertonensis Gardzinska, 1996 and the male of T. splendidus Wanless, 1988 are provided, as well as distributional maps for these three species. Tauala elongata Peng & Li, 2002 is considered a non-congener. A revised definition of the genus is proposed and its distribution and relationships are discussed. PMID- 26623743 TI - Description of two new species of Laubuka (Teleostei: Cyprinidae) from River Cauvery, southern Iandia. AB - Fishes currently identified as Laubuka laubuca from the Cauvery River and its tributaries in the Western Ghats of India are shown to represent two different species: Laubuka trevori, sp. nov., and L. latens, sp. nov., distinguished from all species of Chela and Laubuka by possessing 71/2 branched dorsal-fin rays; 14 precaudal vertebrae; 17-18 predorsal scales; 5 branched pelvic-fin rays and 5+4+2 teeth on the fifth ceratobranchial. Laubuka trevori is further distinguished from its congeners by possessing 141/2-151/2 branched anal-fin rays; 1/26/1/11/2 scales in transverse line on body; a short pelvic fin (10.1-16.3% SL) and two longitudinal stripes: a golden and a bluish-green stripe on the body, running from behind the opercle to the base of the caudal fin, the latter broken and less distinct in the anterior half of the body. Laubuka latens is further distinguished by its long pelvic fin (23.2-26.9% SL) and the absence of any markings on the side of the body other than a humeral spot and a caudal-peduncle spot. PMID- 26623744 TI - Molecular and morphological characterization of Veleshkinema iranicum n. gen., n. sp. (Nematoda: Hexatylina, Sphaerularioidea) from Iran. AB - Veleshkinema iranicum n. gen., n. sp. is described and illustrated based on morphological, morphometric and molecular characters. The new genus is characterized by having slender females and males, stylet with asymmetrical knobs, dorsal gland orifice just posterior to subventral knob, lip region with flattened apex and eight sectors, pharynx with a non-muscular and non-valvular median bulb, pharyngeal glands slightly overlapping intestine dorsally, visible cellular cardia, female with a single gonad having a quadricolumellate crustaformeria with 8-10 cells in each column, no postvulval uterine sac and rounded and offset spermatheca containing spheroid sperm cells, males with arcuate tylenchoid spicules and subterminal bursa. The new genus is morphologically compared with four genera: Abursanema, Deladenus, Prothallonema and Sphaerularia. Molecular phylogenetic studies of the new genus using 808 bp partial sequences of SSU ribosomal RNA gene placed the new genus in a clade with Sphaerularia spp. In phylogenetic analyses using 756 bp partial sequences of the 28S ribosomal RNA gene (D2-D3 segments), the new genus formed a monophyletic group with Abursanema iranicum and Sphaerularia spp. PMID- 26623745 TI - A new Chthamalus (Crustacea: Cirripedia) from the challengeri subgroup on Taiwan rocky intertidal shores. AB - The present study describes a new barnacle, Chthamalus williamsi sp. nov., from rocky shores in Taiwan. Chthamalus williamsi sp. nov. belongs to the challengeri subgroup of Chthamalus due to cirrus I having no conical spines and the setae on cirri II having no basal guards. Within the challengeri sub-group, C. williamsi sp. nov. differs from C. challengeri Hoek, 1883, C. dalli Pilsbry, 1916 and C. montagui Southward, 1976 by its scutum and the tergum both having straight articular margins. Chthamalus moro Pilsbry, 1916 differs from C. williamsi sp. nov. in having strong ribbing on the shell surface, and C. williamsi sp. nov. differs from C. antennatus Darwin, 1854 by having a normal form cirrus III, rather than an antenniform cirrus III as in C. antennatus. The external morphology and size of C. williamsi sp. nov. are similar to C. sinensis Ren, 1984 (C. neglectus Yan & Chan, 2004 is a synonym of C. sinensis, from molecular data presented in the present study) but the scutum of C. williamsi sp. nov. has a height similar to its width, whilst the scutum of C. sinensis is much depressed, being wider than high. From molecular analysis of a mitochondrial COI region, C. williamsi sp. nov. formed a distinct clade (divergence >15%) from other described species in the challengeri subgroup including C. challengeri, C. sinensis, C. moro, C. montagui and C. dalli, suggesting that it is a new species. PMID- 26623746 TI - A new invasive weed-feeding species of Polypedilum (Pentapedilum) Kieffer from South Africa (Diptera: Chironomidae, Chironominae). AB - Polypedilum (Pentapedilum) tuburcinatum Andersen et Bello Gonzalez sp. n. is described and figured as male, female, pupa and larva based on material collected in the Eastern Cape Province in South Africa, imported into quarantine in Ireland and reared in the laboratory. The species feeds on the aquatic weed Lagarosiphon major (Ridl.) Moss ex Wager and is regarded as a promising candidate agent for biological control of this invasive weed. PMID- 26623747 TI - Five new species of Ishiharella Dworakowska (Hemiptera: Cicadellidae: Typhlocybinae) with a key to worldwide species of the genus. AB - Detailed morphological descriptions and illustrations of five new species of the empoascine leafhopper genus Ishiharella Dworakowska (Typhlocybinae: Emposascini): I. dentidensa Yu & Yang, sp. nov., I. falcata Yu, Yang & Dietrich, sp. nov., I. hirsuta Yu, Yang & Dietrich, sp. nov., I. inflata Yu & Yang, sp. nov. and I. multiprotrusa Yu, Yang & Dietrich, sp. nov. are provided and a key to species of the genus is given. PMID- 26623748 TI - Cladocera (Crustacea: Branchiopoda) of Sabah state in Borneo Island, Malaysia. AB - Fauna of Cladocera (Crustacea: Branchiopoda) of Sabah state of Malaysia, Borneo Island, was evaluated for the first time. Samples from 40 locations were studied, and 31 species of Cladocera were revealed, including three species of Sididae, one species of Daphnidae, one species of Moinidae, four species of Macrothricidae, two species of Ilyocryptidae, and 20 species of Chydoridae. One species of Ilyocryptidae, Ilyocryptus yooni Jeong, Kotov and Lee, 2012, is recorded for Malaysia for the first time, and one more, Anthalona sp., is probably new for science. Of 31 species recorded for Sabah, only three are true planktonic species and 28 are substrate-associated species. Absence of large natural lakes, habitats with most rich cladoceran fauna, can be an important factor limiting diversity of Cladocera in Sabah. PMID- 26623750 TI - Defragmentation of journals enhances access and collaboration: commentary on the occasion of Zootaxa 4,000. AB - Scientific literature in all fields of science are fragmented over many journals and other publications. This is mainly due to the diversity in scientific disciplines and publishers around the world. Databases, abstracting/indexing publications and review journals have helped defragment widely dispersed publications. With the rapid development and wider availability of the internet in the last two decades, many traditional paper-based journals have become online, along with the development of online-only journals. A new form of defragmentation (the development of mega-journals) emerged and Zootaxa was at its forefront (Zhang 2006b). On the occasion of Zootaxa 4,000, I herein discuss the mega-journals, defragmentation in scientific publications in general, and the development and achievements of Zootaxa in biodiversity sciences. PMID- 26623749 TI - A new species of Isopsestis (Lepidoptera: Thyatiridae) from Yunnan, China. AB - A new species of genus Isopsestis Werny, 1968 (Lepidoptera: Thyatiridae), Isopsestis poculiformis sp. nov., is described from the locality 2660m elevation in Northeast Yunnan, China, and compared with its closest ally. Male adult and genitalia of the new species are illustrated and a distribution map of the genus Isopsestis Werny, 1968 is provided. PMID- 26623751 TI - New species of Simona Moulds, 2012 and Chelapsalta Moulds, 2012 cicadas (Cicadidae: Cicadettinae: Cicadettini) from Australia: comparative morphology, songs, behaviour and distributions. AB - In 2012, Moulds established the morphologically similar cicada genera Simona and Chelapsalta, each with one Australian species (sancta Distant and puer Walker, respectively). In this paper, two new species are described within the genus Simona Moulds 2012, S. erema sp. nov. and S. retracta sp. nov., and one within the genus Chelapsalta Moulds 2012, C. myoporae sp. nov. The type species of Simona (female holotype), S. sancta (Distant, 1913), is redescribed based on a contemporary male, nominated a plesiotype, held in the Australian National Insect Collection. Melampsalta subgulosa Ashton 1914 is supported as a junior synonym of S. sancta. The species within the two genera of Simona and Chelapsalta are morphologically very similar. S. erema occurs widely through the arid regions of inland Australia, extending west from western Queensland through the Northern Territory, to central-western Western Australia, a linear distance of approximately 2200 km. S. retracta is known from a single semi-arid locality in southern inland Queensland. C. myoporae occurs widely through southeast, central and southwest Queensland, extending southwards into inland and western N.S.W. and southeastern South Australia. It tends to occur most commonly within vegetation associated with seasonal riverine floodplains, and in some areas of poorly drained and clay-rich soils. The calling songs of these three species, together with those of S. sancta and C. puer, are described. Detailed comparisons made of the songs of S. erema and C. myoporae, each from three widely separated locations, clearly exhibit structural consistency in their calling songs across their distributions. The Simona songs are complex and contain multiple elements; the species are very mobile and wary, and inhabit low dense shrubland. The songs of the two Chelapsalta species, both relatively sedentary in behaviour, in contrast consist of relatively uniform chirping and buzzing elements. It is suggested that, although the two genera are morphologically similar, the calling songs, behaviour and habitats do distinguish them, at least as represented by these species documented. MaxEnt modeling of the species climatic envelope for the widely distributed species Simona erema suggests an association with summer peak rainfall and diurnal temperature range. Modeling under estimated conditions of the Last Glacial Maximum (22 ky) suggests the possibility of an even more widespread distribution at that time. PMID- 26623752 TI - Annotated catalogue of the carabid beetles of the Republic of Macedonia (Coleoptera: Carabidae). AB - The catalogue of the ground beetles (Coleoptera: Carabidae) of the Republic of Macedonia is the result of our permanent investigation during 15 years. It is based on the critical review of the data in 255 scientific publications and the revision of the collections deposited in the museums in Macedonia (Skopje and Struga), other European countries (Berlin, Budapest, Vienna, Sofia) and the first author's private collection. For all of the species and subspecies we have presented the known literature references, precise data for the studied material and overall distribution in the Republic of Macedonia. The study of the material resulted in new country records of 10 genera, 101 species and 25 subspecies. First detailed records are provided for another 47 species and subspecies, and additional material was studied of 482 species and subspecies. Type material of 18 species and subspecies was also examined. Thirteen species and one subspecies were rejected from the list of Macedonian ground beetles. Six more species are treated as questionable and were not included in the present list. As a result, the presence of 571 species and 234 subspecies (626 taxa in total) in Macedonia is confirmed. These taxa are arranged in 104 genera, 31 subtribes, 35 tribes and 13 subfamilies. The most numerous in term of the species are the genera Bembidion (60), Harpalus (48) and Amara (46), as well as Pterostichus (26), Ophonus (19), Carabus (16), Trechus (16), Brachinus (16) and Dyschirius (15). PMID- 26623753 TI - Revision of the Neotropical species of the subgenus Atrichopogon (Psilokempia) (Diptera: Ceratopogonidae). AB - This revision of the midges in the subgenus Psilokempia Enderlein of Atrichopogon Kieffer provides a brief description of the subgenus, diagnoses, descriptions, illustrations and a key to adult males and females of the 17 species from the Neotropical region, as well as distributional records of both new and previously described species. Six new species are described and illustrated: A. arti, A. javieri, A. longirostris, A. nahuelbutensis, A. sergioi and A. woodruffi (n. spp.). The type materials of all previously known Neotropical species except A. penicillatus Delecolle & Rieb were examined. Atrichopogon altivolans Macfie, A. aridus Spinelli & Marino, A. domizii Spinelli, A. glaber Macfie, A. gordoni Macfie, A. insigniventris Macfie, A. pectinatus Macfie and A. penicillatus are redescribed and illustrated, and notes on the types of A. echinodes Macfie, A. harrisi Macfie and A. sanctaeclarae Macfie are provided. Lectotypes are designated for A. glaber, A. insigniventris and A. pectinatus. The previously unknown males of A. altivolans, A. pectinatus and A. penicillatus are described and illustrated, and A. fimbriatus Macfie is recognized as a junior synonym of A. gordoni. PMID- 26623754 TI - Phylogenetic systematics of egg-brooding frogs (Anura: Hemiphractidae) and the evolution of direct development. AB - Egg-brooding frogs (Hemiphractidae) are a group of 105 currently recognized Neotropical species, with a remarkable diversity of developmental modes, from direct development to free-living and exotrophic tadpoles. Females carry their eggs on the back and embryos have unique bell-shaped gills. We inferred the evolutionary relationships of these frogs and used the resulting phylogeny to review their taxonomy and test hypotheses on the evolution of developmental modes and bell-shaped gills. Our inferences relied on a total evidence parsimony analysis of DNA sequences of up to 20 mitochondrial and nuclear genes (analyzed under tree-alignment), and 51 phenotypic characters sampled for 83% of currently valid hemiphractid species. Our analyses rendered a well-resolved phylogeny, with both Hemiphractidae (sister of Athesphatanura) and its six recognized genera being monophyletic. We also inferred novel intergeneric relationships [((Cryptobatrachus, Flectonotus), (Stefania, (Fritziana, (Hemiphractus, Gastrotheca))))], the non-monophyly of all species groups previously proposed within Gastrotheca and Stefania, and the existence of several putative new species within Fritziana and Hemiphractus. Contrary to previous hypotheses, our results support the most recent common ancestor of hemiphractids as a direct developer. Free-living aquatic tadpoles apparently evolved from direct-developing ancestors three to eight times. Embryos of the sister taxa Cryptobatrachus and Flectonotus share a pair of single gills derived from branchial arch I, while embryos of the clade including the other four genera have two pairs of gills derived from branchial arches I and II respectively. Furthermore, in Gastrotheca the fusion of the two pairs of gills is a putative synapomorphy. We propose a revised taxonomy concordant with our optimal topologies. PMID- 26623756 TI - Mites and ticks (Acari) in Shanxi Province, China: an annotated checklist. AB - This paper reviews the research on mites and ticks in Shanxi Province before 1 January 2015. We provided a checklist of 189 species belonging to 4 orders Ixodida: 24 species in 2 families and 9 genera; Mesostigmata: 74 species in 12 families and 34 genera; Sarcoptiformes: 17 species in 10 families and 14 genera and Trombidiformes: 74 species in 15 families and 47 genera. Information on the host/habitat and distribution is given for each species. Historical mistakes in records are corrected and the classification of the known species is updated. PMID- 26623755 TI - Revision of the genus Melanagromyza in California, with descriptions of three new species (Diptera: Agromyzidae). AB - The 27 Californian species of the genus Melanagromyza Hendel (Diptera: Agromyzidae) are reviewed, including descriptions of three new species (Melanagromyza californiana sp. nov., M. chemsaki sp. nov. and M. gonzalesina sp. nov.) and the first record for one species (Melanagromyza martini Spencer) for California and the USA. All species in California are described or redescribed, with illustrations and photographs, and a key to the species is presented. Maps for the species in California, along with host distributions, are provided, with comments on biology and host plants. PMID- 26623757 TI - The genus Leucophenga (Diptera, Drosophilidae), part V: the mutabilis species group from East Asia, with morphological and molecular evidence. AB - A total of seven known species of the Leucophenga mutabilis species group are resurveyed from the East Asia: L. angusta Okada, 1956; L. bellula Bergroth, 1894; L. magnipalpis Duda, 1924; L. nigripalpis Duda, 1924; L. orientalis Lin & Wheeler, 1972; L. striatipennis Okada, 1989 and L. taiwanensis Lin & Wheeler, 1972. The diagnosis of the mutabilis group is revised, and a key to the seven species of this group is provided. DNA sequences of the mitochondrial COI (cytochrome c oxidase subunit I) gene with BOLD process ID and GenBank accession numbers are provided for these species. The pairwise intra- and interspecific Kimura two-parameter COI distances among the aforementioned seven known species are summarized; and the utility of DNA barcoding in the genus Leucophenga is discussed. PMID- 26623758 TI - A new species and subgenus of Elseya (Testudines: Pleurodira: Chelidae) from New Guinea. AB - The New Guinea freshwater turtle, Elseya novaeguineae (senu lato) is a long-term, widespread resident of New Guinea and has been subject to substantial vicariance in one of the most geologically dynamic regions on earth. Thus, it should come as no surprise that the taxonomy of this turtle is poorly resolved. Elseya novaeguineae has long been recognized as a species complex, though which elements of this taxon warrant recognition as separate species has been debated. In this paper, we restrict Elseya novaeguineae to the Birds Head region of New Guinea, west of the Langguru Thrust and Fold Belt; we resurrect from synonymy Elseya schultzei for the populations north of the Central Ranges; and we describe a new species for the populations to the south of the Central Ranges. We revisit the classification of the genus Elseya throughout its range in the light of our work and recently published reports, and erect three subgenera that recognize the three major clades within this genus. Subgenus Elseya is the nominate subgenus, to which we assign Elseya dentata, E. branderhorsti and undescribed E. sp. aff. dentata [Sth Alligator]. Elseya novaeguineae, E. schultzei and our new species are assigned to a new subgenus, Hanwarachelys. Species of northern and eastern Queensland, E. albagula, E. irwini, E. lavarackorum and the fossil taxa E. uberrima and E. nadibajagu, are assigned to subgenus Pelocomastes, resurrected from synonymy. PMID- 26623759 TI - First records of interstitial leptocytherids (Crustacea, Ostracoda): two new species and a redescription of Callistocythere ventricostata Ruan & Hao, 1988 collected from the Okinawa Islands, southern Japan. AB - Two new and one known species belonging to the genus Callistocythere of the family Leptocytheridae from interstitial environments of the Okinawa Islands are fully described. Callistocythere intermedia sp. nov. is regarded as belonging to the C. japonica group, and Callistocythere ryukyuensis sp. nov. belongs to the C. minor group (these groups were established by Hanai 1957 based on carapace morphology). The redescribed Callistocythere ventricostata Ruan & Hao, 1988 clearly differs from known leptocytherid species in the morphologies of the carapace and the male copulatory organ. The habitats of C. intermedia sp. nov. and C. ryukyuensis sp. nov. are found along the shoreline zone and the mid to high tide levels of the littoral zone, respectively, and C. ventricostata is found from the shoreline to the sub-tidal zone. These species are the first global records of interstitial leptocytherids. PMID- 26623760 TI - The family Caprellidae (Amphipoda: Caprelloidea: Caprellidae) from Campos Basin, Southwestern Atlantic, with a key of species occurring in Brazil. AB - Caprellid material of the present study was collected between 25-3000 m depth from the Campos Basin area, Southwestern Atlantic. As a result, Deutella incerta was found as a new record to the Southwestern Atlantic and two new species are described: Liropus guerragarciai sp. nov. and Mayerella sittropiae sp. nov. Besides, Paracaprella pusilla is herein redescribed as a common component of the Campos Basin amphipod community. Caprellids are a diverse and abundant group that can be found among algae and general biological substrates of the continental shelf area. As more deep sea samples are coming into light, they are turning out to be also a common component in this habitat. Including the present data, there are 25 caprellid species recorded in Brazil, being four of them restricted to the slope areas and 14 endemic to the Brazilian coast. A key to the Caprellidae species from Brazil is provided. PMID- 26623761 TI - A new species of Bambusaspis Cockerell (Hemiptera: Sternorrhyncha: Coccomorpha) colonising bamboo in Malaysia. AB - All life stages (adult female and male, first-instar nymph, second-instar male and female nymphs, and prepupa and pupa) of a new species of Asterolecaniidae, Bambusaspis transversa Lagowska & Martin sp. n., from bamboo in Malaysia, are described and illustrated. The adult female and first-instar nymphs are compared with those Bambusaspis species considered to be closest to the new species. PMID- 26623762 TI - A new leaf-tailed gecko of the Uroplatus ebenaui group (Squamata: Gekkonidae) from Madagascar's central eastern rainforests. AB - We describe a new leaf-tailed gecko species of the Uroplatus ebenaui group from the eastern central rainforests of Madagascar, which had previously been considered as a confirmed candidate species. Our description of Uroplatus fiera sp. nov. relies on integrating evidence from molecular and morphological characters and is based on newly collected material from two localities. A phylogenetic analysis based on multiple mitochondrial DNA fragments places the new species as sister to a lineage of uncertain status (Uroplatus ebenaui [Ca8]), and the clade consisting of these two lineages is sister to a further undescribed candidate species (U. ebenaui [Ca1]). This entire clade is sister to U. phantasticus plus another candidate species. The new species differs from these close relatives, and all other congenerics, by strong differences in DNA sequences of mitochondrial genes (>8.5% uncorrected p-distance in 16S rDNA to all nominal species of the genus) and lacks shared alleles with any of the nominal species in the nuclear CMOS gene. From its closest relatives the new species further differs in its much smaller tail size (relative to U. phantasticus), and a narrower tail, fewer supralabials, and more toe lamellae (relative to U. ebenaui [Ca1]). Morphologically the new species is most similar to U. ebenaui but differs in its larger body size and unpigmented oral mucosa. Given its distribution in central eastern Madagascar, with records from near Fierenana and Ambatovy, its range overlaps with that of U. phantasticus. Based on examination of the U. phantasticus holotype, we confirm that this latter has a blackish pigmented oral mucosa as do those specimens typically attributed to this nomen, thereby confirming its distinctness from U. fiera sp. nov., in which the mucosa is unpigmented. PMID- 26623763 TI - Scale insect species names that have been combined with the genus name Dactylopius Costa (Hemiptera: Sternorrhyncha: Coccomorpha). AB - The genus Dactylopius is the only genus at present in the family Dactylopiidae. Since the name Dactylopius was proposed in 1829, however, numerous other species names belonging to different families of scale insects have been combined with it and these are also listed. The present status and the family placement are also given for each species. PMID- 26623764 TI - New enchytraeid species (Enchytraeidae, Oligochaeta) from Korea. AB - We give descriptions of five new enchytraeid species (Enchytraeidae, Oligochaeta) from Korea: Henlea magnaampullacea sp. n., Fridericia sphaerica sp. n., F. cusanicaformis sp. n., F. granulocyta sp. n. and Mesenchytraeus calyx sp. n., with morphological and molecular (mitochondrial cytochrome c oxidase subunit I, nuclear histone 3 genes and nuclear ribosomal ITS region sequences) data. In total, 19 enchytraeid species belonging to seven genera have been found in the studied woodland and agronomical soil samples. Apart from the five new species, three further species are new for the Korean enchytraeid fauna, Enchytraeus christenseni, E. dichaetus, and Achaeta cf. brevivasa. Molecular taxonomical analyses show that the Korean species resembling H. ventriculosa is not identical with the European species, furthermore sequence analysis of individuals morphologically identified as F. seoraksani indicate the possibility of species complexity and the presence of cryptic species. PMID- 26623765 TI - A new species of the genus Arcoptilia Arenberger (Lepidoptera, Pterophoridae) from Angola. AB - The new species Arcoptilia naumanni sp. nov. (Lepidoptera, Pterophoridae) is described and illustrated from males found in Angola. Platyptilia rufamaculata Gielis, 2011, syn. nov. is established as a junior synonym of Arcoptilia pongola Ustjuzhanin & Kovtunovich, 2010. PMID- 26623766 TI - A review of the Oriental species of Cothornobata Czerny (Diptera, Micropezidae, Eurybatinae). AB - The Oriental species of the genus Cothornobata Czerny are reviewed, with a revision of the species occurring in the northern Oriental region, and descriptions of the following 16 new species from China and Vietnam: C. atra sp. nov.; C. breviseta sp. nov.; C. bubengensis sp. nov.; C. curva sp. nov.; C. elegantula sp. nov.; C. fusca sp. nov.; C. ingensfurca sp. nov.; C. longifurca sp. nov.; C. longigonitea sp. nov.; C. mentogensis sp. nov.; C. paieroi sp. nov.; C. pugnoa sp. nov.; C. shuimanensis sp. nov.; C. uniseta sp. nov.; C. vietnamensis sp. nov.; C. zhangae sp. nov. Cothornobata nigrigenu Enderlein is newly reported from China and Nestima meijerei (Frey) is given as a new combination for Cothornobata meijerei Frey. A key to the 19 Oriental species of the genus is provided. PMID- 26623767 TI - Review of the genus Miloderes Casey, 1888 (Coleoptera: Curculionidae: Entiminae), with desciptions of three new species. AB - The genus Miloderes Casey, 1888 is reviewed and three new species are described. The genus now has eight valid species: M. amargosensis sp. nov., M. mercuryensis Tanner, M. nelsoni Kissinger, M. panamintensis sp. nov., M. setosus Casey, M. tingi Tanner, M. ubehebensis sp. nov. and M. viridis Pierce. Miloderes allredi Tanner, 1974 is a new junior synonym of M. viridis Pierce, 1910. The relationships of the species are discussed based on morphological characters from external morphology as well as from the endophallus. A key to species is provided. PMID- 26623768 TI - Morphological and molecular variation in Tylototriton (Caudata: Salamandridae) in Laos, with description of a new species. AB - The salamandrid genus Tylototriton is poorly known in Laos, with one described species and unverified reports of two others. We undertook new fieldwork and obtained samples of Tylototriton at six localities across northern Laos during 2009-2013. Bayesian phylogenetic analysis of mitochondrial DNA, principal component analyses of 13 mensural characters, and qualitative morphological comparisons with samples from across the geographic range of Tylototriton were performed. Samples from Laos fell into four molecular and morphological groups, consisting of T. notialis, T. panhai, T. anguliceps, and a fourth lineage that is hypothesized here to be an undescribed species. Tylototriton podichthys sp. nov. is distinguished from its congeners by having distinct mitochondrial DNA haplotypes and in characteristics of the glandular skin on the head and body, shape of the rib nodules, and coloration of the body and limbs. This study expands the number of confirmed Tylototriton species in Laos from one to four, with the description of one species and extension of the ranges of T. panhai and T. anguliceps to Laos. An improved understanding of the geographic ranges of T. podichthys sp. nov. and T. anguliceps within Laos is needed. PMID- 26623769 TI - Taxonomic review of the genus Indomyrlaea Roesler & Kuppers 1979 of China, with descriptions of five new species (Lepidoptera: Pyralidae: Phycitinae). AB - The taxonomy of the Chinese species of the genus Indomyrlaea Roesler & Kuppers, 1979 is revised. Five new species, namely I. bannensis Ren & Li sp. nov., I. fastigipalpa Ren & Li sp. nov., I. nigra Ren & Li sp. nov., I. proceripalpa Ren & Li sp. nov., and I. sinuapalpa Ren & Li sp. nov., are described. The following taxonomic changes are proposed: Sandrabatis Ragonot, 1893 and its type species Sandrabatis crassiella Ragonot, 1893 are synonymized with Ceroprepes Zeller, 1867 and Ceroprepes ophthalmicella (Christoph, 1881), respectively; Indomyrlaea phaeella (Hampson, 1903) comb. nov. is transferred from Sandrabatis. The original combination Nephopterix eugraphella Ragonot, 1888 is resurrected from its previous affiliation with Indomyrlaea. A checklist and a key to all the known species of the world are included. PMID- 26623770 TI - First record of genus Orbiniella Day, 1954 (Polychaeta: Orbiniidae) in North Atlantic Ocean with the description of a new species. AB - A new species of the genus Orbiniella Day, 1954 (Polychaeta: Orbiniidae), collected during the BIOICE programme on sedimentary bottoms off Iceland, is described. Orbiniella petersenae sp. nov. is a shelf and slope species (107 to 1,915 m) chiefly characterized by having notopodial postchaetal papilla from first chaetiger, long crenulated capillary chaetae and several acicular chaetae on each parapodial rami, and pygidium with four lobes. External micromorphology and gross internal anatomy were studied using, respectively, SEM and micro-CT; this is the first time these techniques are used for any species in this genus. A key to all species of this genus worldwide is provided. PMID- 26623771 TI - Larval descriptions of Annitella esparraguera (Schmid 1952) and Annitella iglesiasi Gonzalez & Malicky 1988 (Trichoptera: Limnephilidae), two endemic species from Southern Europe. AB - Descriptions of the previously unknown larvae of Annitella esparraguera and A. iglesiasi, two European endemic species from the southern Iberian Peninsula are presented. The most important diagnostic features are illustrated and some taxonomic, zoogeographical and ecological notes are given. In addition, a previous key is modified to include these two new Iberian Limnephilidae larvae. PMID- 26623772 TI - Revision of the genus Ferkeria Roewer, 1947, with the description of a new species (Opiliones: Laniatores: Cosmetidae). AB - A new diagnosis for the cosmetid genus Ferkeria Roewer, 1947 is proposed. The type species, F. vestita Roewer, 1947 is redescribed and a new species, Ferkeria flavicoxae sp. nov., is described from Zongo, La Paz, Bolivia. The new species differs from the only other species of the genus by: yellow-white colored coxa IV (orange-brown in F. vestita); armature of scutal areas I-III with rounded tubercles (spiniform in F. vestita) and conspicuous tarsal process (reduced in F. vestita). PMID- 26623773 TI - Revision of Neodeuterus Schaufuss and description of a new allied genus from Borneo (Coleoptera: Staphylinidae: Pselaphinae). AB - The Sumatran genus Neodeuterus is revised, and the two included species are synonymized (i.e., N. admirandus = N. alter syn. n.). In addition, Borneodeuterus gen. n. is erected to accommodate B. sannio sp. n. from Borneo. PMID- 26623774 TI - An enigmatic Rhachotropis (Crustacea: Amphipoda: Eusiridae) from New Zealand. AB - The eusirid genus Rhachotropis S.I. Smith, 1883 has a worldwide distribution and the largest bathymetric range known from any amphipod genus. A large, charismatic, colourful species was collected below 800 m at two sites 1000 km apart on the southern Kermadec Ridge and on the Chatham Rise in the south-western Pacific off eastern New Zealand. The new species, Rhachotropis oweni is described, increasing the total number of Rhachotropis to 61 species worldwide, including six species from New Zealand waters. PMID- 26623775 TI - First record of the genus Leptanilloides (Hymenoptera: Formicidae: Dorylinae) from the United States. AB - We describe a new species of the Neotropical genus Leptanilloides, L. chihuahuaensis sp. n., based on male specimens from the Davis Mountains in western Texas. Known males of species of Leptanilloides are compared with L. chihuahuaensis. This is the first report of the genus from the United States and the Nearctic region. Previously, the Leptanilloides genus-group was only known to occur from southern Mexico to southeastern Brazil; and thus, this record from Texas represents a remarkable extension of the known range of the genus. PMID- 26623776 TI - Integrative taxonomic revision of mantellid frogs of the genus Aglyptodactylus (Anura: Mantellidae). AB - Molecular genetic studies have in recent years revealed the presence of hidden species diversity in Madagascar's amphibians, and numerous genera contain candidate species awaiting description. We here revise the taxonomy of one such genus within the endemic Malagasy-Comorian family Mantellidae. The target taxon, Aglyptodactylus, is classified in the subfamily Laliostominae and to date contained three recognized nominal species. We focus in particular on clarifying the status of three candidate species proposed for the genus, and for this purpose integrate evidence from molecular genetics, bioacoustics and morphology. We furthermore summarize the information available for all species in the genus concerning their taxonomic identities, distributions and advertisement calls. Our analyses of advertisement calls revealed significant differences coinciding with major clades revealed by phylogenetic analysis of the mitochondrial 16S rRNA gene. Together with the new molecular dataset this provides clear evidence for evolutionary lineage divergence and supports the three candidate species previously characterized by mtDNA divergence of single specimens only. We also observed morphological differences among some of the lineages but these were in most cases not unambiguously diagnostic. As a taxonomic consequence we describe two new species: Aglyptodactylus australis sp. nov. from Andohahela rainforest in southeastern Madagascar, which so far is the largest species known in the genus with females reaching 82.5 mm snout-vent length; and Aglyptodactylus chorus sp. nov. from northeastern lowland rainforests in the Maroantsetra region. For the third proposed and confirmed candidate species we resurrect the name Rana inguinalis Gunther, 1877 as Aglyptodactylus inguinalis (Gunther, 1877) from the synonymy of A. madagascariensis. This name is applied to populations distributed in lowlands along most of the east coast of Madagascar, from Marojejy in the north southward to Tolagnaro. Genetic data indicate strong differentiation of A. inguinalis with three sub-lineages receiving support, and we cannot exclude that A. inguinalis as defined herein is a complex of species warranting further partition in the future. As a result of the revised taxonomy, A. madagascariensis remains restricted to rainforests at higher elevations (650-1500 m a.s.l.) ranging from northern to south-central Madagascar, and showing some further differentiation with respect to a northern and a southern sub-lineage. Difficulties in the assignment of historical type specimens are discussed, as well as the biogeography and conservation status of the recognized species. PMID- 26623777 TI - Revision of the species of the Merodon nanus group (Diptera: Syrphidae) including three new species. AB - The nanus group of the genus Merodon Meigen (Diptera, Syrphidae) is revised, yielding an illustrated key, a discussion of taxonomic characters and morphological diagnosis for the five species of this group. Three new cryptic species are described, Merodon kopensis Vujic et Hayat sp. n., M. neonanus Vujic et Taylor sp. n. and M. rasicus Vujic et Radenkovic sp. n. New diagnostic characters are given for M. nanus Sack and M. telmateia Hurkmans. In addition, environmental profiles for each investigated species have been defined and compared, and maps of distribution and richness created. Niche dissimilarity was found for each species. Eastern Anatolia and the southern Aegean region of Turkey are reported as the most species rich regions for the nanus group. PMID- 26623778 TI - First record and five new species of Xylographellini (Coleoptera: Ciidae) from China, with online DNA barcode library of the family. AB - We report the first record of the beetle tribe Xylographellini (Ciidae) from the continental Palaearctic Region, represented by five new species discovered in Yunnan and Sichuan provinces, China: Scolytocis danae sp. nov., Syncosmetus euryale sp. nov., Sync. medusa sp. nov., Sync. perseus sp. nov. and Sync. stheno sp. nov. Illustrations and identification keys are provided for these new species, and in order to facilitate further research of Ciidae we present an open access DNA barcode library (dx.doi.org/10.5883/DS-SYNCOSM) containing 114 records (of 44 species in 14 genera), 15 of which belong to the newly described species. A phylogenetic analysis based on the barcode fragment of the cytochrome oxidase I gene did not recover much tree structure within Ciidae, however both Xylographus Mellie and Syncosmetus Sharp were recovered as clades, with a single Scolytocis Blair being the sister to the latter. PMID- 26623779 TI - Hidden diversity of endoparasitic eriophyoid mites: two new Novophytoptus Roivainen, 1947 (Acari: Eriophyoidea: Phytoptidae) species from the parenchymatous tissues of rushes (Juncaceae). AB - The monogeneric subfamily Novophytoptinae is a separate lineage of phytoptids restricted to endoparasitism on herbaceous monocots of the order Poales. Novophytoptines live under the epidermis of their hosts where they feed on parenchymatous cells and reproduce therein. It is unknown yet how novophytoptines penetrate the plant epidermis, but preliminary observations indicate that they might be able to penetrate through circular holes which they cut in the epidermis using their modified gnathosoma. Two new species, Novophytoptus luzulis n. sp. from Luzula pilosa L. and Novophytoptus maritimus n. sp. from Juncus maritimus Lam., are described and illustrated. Two small pores, presumably representing external openings of spermathecal tubes, were found in the postero-medial genital cuticle (sensu Chetverikov 2014b) at the level between the posterior margin of the genital coverflap and the genital rim, in both new species. This is the first documented report of such structures in slide-mounted eriophyoid mites. CLSM and DIC microscopy-based observations showed that novophytoptines possess a peculiar spermathecal apparatus, including greatly expanded sack-shaped spermathecae and thick, bent spermathecal tubes directed anteriad, and a semicircular anterior genital apodeme perpendicular to the long body axis. Similarity in the structure of the spermathecal apparatus among novophytoptines, phytoptines and sierraphytoptines (all Phytoptidae from angiosperms) apparently supports their assignment to a common group. Additional examples of endoparasitism among Eriophyoidea are listed. The hypothesis of a primary endoparasitic life style in the eriophyoid basal stalk and a secondary shift to free living forms on exposed surfaces of plants is briefly discussed. Research on grass-associated endoparasitic mites is important because they may include new vectors of pathogens. SketchUp Free Software is recommended as one of the most simple and promising 3D drawing tools for modeling the internal genitalia and other complex anatomical structures of microarthropods (especially eriophyoids) based on digital data obtained using various microscopic techniques such as CLSM. PMID- 26623780 TI - Heterangaeus Alexander, 1925 crane flies (Diptera: Pediciidae) of Korea. AB - The Korean crane fly species of the genus Heterangaeus Alexander, 1925 (Diptera: Pediciidae) is taxonomically revised. H. gloriosus gloriosus (Alexander, 1924) is redescribed. A new species Heterangaeus koreanus n. sp., which is the first species of Pediciidae from South Korea, is described and illustrated. PMID- 26623781 TI - Records of Pauropoda (Pauropodidae, Brachypauropodidae, Eurypauropodidae, Sphaeropauropodidae) from China, with a key to the species and descriptions of three new species of Decapauropus. AB - The arthropod class Pauropoda was not recognized from China until 1988, but currently 36 known species are now recorded from 27 sites in 18 provinces. This paper contains descriptions of three new species of Decapauropus Remy, 1931: D. biclavula sp. n., D. annulcordatus sp. n. and D. tribulosus sp. n. from Jiangsu, Hunan, Jiangxi and Guangxi Provinces, respectively. These three new species bring the known pauropod fauna of China to 39 species in 11 genera and four families. In addition, Dasongius (Sun & Guo, 2010) nom. nov. is proposed to replace the invalid junior homonym of Songius Sun & Guo, 2010. PMID- 26623782 TI - Description of four new species of the tiger moth genus Dysschema Hubner (Lepidoptera: Erebidae, Arctiinae, Arctiini, Pericopina). AB - Description of four new species of the tiger moth genus Dysschema Hubner (Lepidoptera: Erebidae, Arctiinae, Arctiini, Pericopina). Four new species of Pericopina are described, three from southeast of Brazil: Dysschema uriasi Moraes, sp. nov., Dysschema wayneri Moraes, sp. nov., Dysschema amapoarum Moraes & Duarte sp. nov., and one from Mexico: Dysschema tarsoi Moraes sp. nov. Detailed species descriptions are based upon morphological characters. Photographs of habitus, illustrations of genitalia and comments on morphology are provided. PMID- 26623784 TI - Cladocera of Hainan Island, China. AB - The cladoceran fauna of Hainan Island (China) was investigated. Samples were collected in January 2013 and in April 2014 from over hundred water bodies, including large and small reservoirs, ponds and pools, rivers, streams, and paddy fields. There are no large natural lakes on the island. We found 53 species of Cladocera: 9 species of Sididae; 5 Daphniidae; 2 Moinidae; 2 Macrothricidae; 2 Ilyocryptidae; 3 Bosminidae; and 30 Chydoridae. Planktonic communities were dominated by Diaphanosoma dubium Manuilova, 1964, D. excisum Sars, 1885, D. sarsi Richard, 1894, Moina micrura Kurz, 1874 and Bosminopsis deitersi (Richard, 1895). Six Chydoridae species are first records for China. The fauna consists mostly of Oriental and Pantropical species, but, also includes non-tropical Palaearctic species and East Asian endemics. For these species, Hainan Island is the southernmost record. The number of species is rather small, compared to adjacent areas. This may reflect a low intensity of sampling, but more likely a lack of natural lakes. Communities in reservoirs suffer from water level fluctuations, and the absence of permanent macrophyte stands, a preferred habitat of littoral cladocera. PMID- 26623783 TI - Mahseers genera Tor and Neolissochilus (Teleostei: Cyprinidae) from southern Vietnam. AB - Two new species and two new basin records of mahseers in the genera Tor and Neolissochilus are described from the upper Krong No and middle Dong Nai drainages of the Langbiang Plateau in southern Vietnam. These new species and new records are known from streams and rivers in montane mixed pine and evergreen forests between 140 and 1112 m. Their populations are isolated in the Sre Pok River of the Mekong basin, the middle of the Dong Nai basin, and the An Lao River. Both new species are differentiated from their congeners by a combination of the following characters: 23-24 lateral scales, 9-10 predorsal scales, 2/7 or 1/8 pelvic-fin rays, mouth position, median lobe of lower lip, rostral hood, colour in life and by divergent mitochondrial DNA. Tor mekongensis sp. nov. is differentiated from Tor dongnaiensis sp. nov. by the number of transverse scale rows (3/1/2 vs. 4/1/2), number of pelvic-fin rays (2/7 vs. 1/8), a blunt rostral hood vs. pointed, caudal-fin lobes that are equal vs. unequal, and by mitochondrial DNA (0.7% sequence divergence). Molecular evidence identifies both species as members of the genus Tor and distinct from all congeners sampled (uncorrected sequence divergences >1.9% for all Tor species for which homologous COI sequences are available). Tor sinensis is recorded in the Krong No and the Sre Pok rivers, further south of its known distribution. Polymorphism is described in Neolissochilus stracheyi with a Tor-like morph and a Neolissochilus like morph. PMID- 26623785 TI - A new lophopid genus as another piece in the biogeographical history puzzle of the family in the Sunda Shelf (Hemiptera: Fulgoromorpha: Lophopidae). AB - A new Lophopidae genus Binaluana gen. nov. and species B. emarginata sp. nov. from Palawan are described. Characters are given in order to distinguish this new genus from Bisma and Zeleja that share general figure with it. The morphological characters are coded for the genus and a new phylogenetic analysis using parsimony is performed. The Lophopidae remain monophyletic and Binaluana is placed as sister group of the genus Bisma. (Zeleja (Binaluana+Bisma)) is monophyletic and emerges at the base of the Zeleja+ group. The place of Binaluana within the Lophopidae is discussed along with its historical biogeographic origin. PMID- 26623786 TI - A review of Minilimosina Rohacek (Diptera: Sphaeroceridae) from China. AB - A review of the genus Minilimosina Rohacek, 1983 of China, comprising 16 species, is given, with data about types, published descriptions and figures, and distributions. A key to the Chinese species of the genus Minilimosina is provided and three new species are described and illustrated: M. gracilenta Su sp. nov., M. parafanta Su sp. nov. and M. tapiehella Su sp. nov.. The male of M. archboldi Marshall, 1985 is redescribed. Females of M. luteola Su, 2011 and M. cornigera Rohacek & Marshall, 1988 are described and illustrated for the first time. Phylogenetic relationships of M. cerciseta Su, 2011, M. luteola Su, 2011, M. obtusispina Su, 2013, M. quadrispinosa Su, 2011, M. gracilenta Su sp. nov., M. parafanta Su sp. nov. and M. tapiehella Su sp. nov. are discussed. PMID- 26623787 TI - Morphological and molecular characteristics of Milandanielia intermedia (Feider, 1950) (Trombidiformes: Microtrombidiidae) with data on its biology and ecology. AB - Milandanielia intermedia (Feider, 1950) is re-described. A female from which larvae were obtained by experimental rearing is designated as neotype. Verified diagnoses of active life instars are supplemented with data on habitat preferences, phenology and life cycle. Molecular identification of the species based on its COI sequence is provided. PMID- 26623788 TI - Endemic epigean Tenebrionids (Coleoptera: Tenebrionidae) from the Andean Region: exploring the patagonian-diversification hypothesis. AB - Tenebrionidae is a diverse insect family of Coleoptera that shows high levels of endemicity in epigean species. For the Andean region, which is divided into three subregions: Central Chilean, Subantarctic and Patagonian, it has been hypothesized that epigean tenebrionids have diversified in the Patagonian subregion and subsequently, they dispersed to Subantarctic and Central Chilean subregions. In this work, based on information obtained from museum collections and scientific studies, we presented the first list of endemic epigean tenebrionids from the Andean region with their taxonomic arrangement and geographic distribution. Moreover, we used these data to explore the veracity of the Patagonian-diversification hypothesis. A total of 416 species grouped into six subfamilies, 17 tribes and 41 genera were identified as endemic to the Andean region. Considering the spatial distribution it was observed that subfamilies, tribes, genera and species were unequally distributed across subregions. Results did not support the Patagonian-diversification hypothesis; to the contrary, they were more concordant with processes of isolation among subregions that have promoted speciation by interrupting gene flow among populations, resulting in endemism because species can not expand their range sizes. Finally, we discuss the implications of our findings to be considered in biodiversity conservation, because endemic species, by their high extinction risk, are primary targets in conservation strategies. PMID- 26623789 TI - Northernmost record of a poorly known tuskfish, Choerodon margaritiferus (Perciformes: Labridae), from southern Japan, and first description of a female. AB - We describe 5 specimens of Choerodon margaritiferus Fowler and Bean, 1928 (94.5 107.0 mm standard length, 1 male and 4 females) collected near Okinawa Island, southern Japan. This is the northernmost record of this species and the first record of it in Japanese waters; until now, C. margaritiferus was recorded only from the western central Pacific. This species was originally described on the basis of 1 male specimen, and all additional specimens described in the literature were also male. Morphological characters of both sexes are described, and new diagnostic characters of the female are presented. PMID- 26623790 TI - A review of the genus Abdosetae (Araneae: Phrurolithidae) from China. AB - Four species of the genus Abdosetae Fu, Zhang & MacDermott, 2010 from China are reviewed, and three of them are new to science: A. digitata sp. nov., A. falcata sp. nov. and A. hamata sp. nov. We re-examined the type material of A. hainan Fu, Zhang & MacDermott, 2010, re-delimited the generic characteristics and re described the type species. A key to all Abdosetae species and a distribution map of the Chinese species are provided. PMID- 26623791 TI - A new species of Tricorythopsis Traver, 1958 (Leptohyphidae) and occurrence of Pannota (Insecta: Ephemeroptera) species in Amapa state, Brazil. AB - The objectives of this study were to describe a new species of Tricorythopsis based on adults, and to report for the first time the following species and genera in Amapa state, Brazil: Amanahyphes saguassu Salles & Molineri, Macunahyphes australis (Banks), Macunahyphes pemonensis Molineri, Grillet, Nieto, Dominguez & Guerrero, Tricorythodes yapekuna Belmont, Salles & Hamada, Tricorythopsis faeculopsis Belmont, Salles & Hamada, Tricorythopsis pseudogibbus Dias & Salles, Tricorythopsis rondoniensis (Dias, Cruz & Ferreira), Tricorythopsis yucupe Dias, Salles & Ferreira (Leptohyphidae), Coryphorus aquilus Peters (Coryphoridae) and Brasilocaenis (Caenidae). Macunahyphes pemonensis is recorded for the first time in Brazil. Tricorythopsis yusuaia sp. nov., can be distinguished from congeners by the following combination of characteristics: abdomen with black and reddish marks, a strongly sclerotized spine present on the base of the median filament, and the base and lateral margins of penes being sclerotized. PMID- 26623792 TI - New species of Polycentropodidae (Trichoptera: Annulipalpia) from Northeast Region, Brazil. AB - Three new species of Polycentropodidae (Insecta: Trichoptera) from the Northeast Region of Brazil are diagnosed, described, and illustrated. Polycentropus brevicornutus n. sp. of the Polycentropus gertschi Group can be diagnosed mainly by its much reduced, almost vestigial intermediate appendages, and by the inferior appendages, which are deltoid and very linear in lateral aspect. The two new species of Polyplectropus are P. anchorus n. sp. and P. auriplicatus n. sp. in the P. annulicornis and P. bredini Groups, respectively. Polyplectropus anchorus n. sp. is very similar to P. annulicornis Ulmer 1905, but can be distinguished from its congener mainly by the endothecal spines without setae and with their apices directed dorsolaterad. Polyplectropus auriplicatus n. sp. resembles P. brasilensis but can be distinguished mainly by the shorter and deltoid intermediate appendages, the straighter dorsolateral processes of the preanal appendages, and the inferior appendages each with its mesoventral branch more developed and rounded. PMID- 26623793 TI - Two new species of the genus Xizicus (Orthoptera: Tettigoniidae: Meconematinae) in China. AB - Two new species of the genus Xizicus are described, namely Xizicus (Eoxizicus) uncicercus Mao & Shi sp. nov. and Xizicus (Eoxizicus) dischidus Di, Han & Shi sp. nov. from China, in addition, photographs of morphological structure of the species are provided. All type specimens are deposited in the Museum of Hebei University, Baoding, P. R. China. PMID- 26623794 TI - Redescription and a new synonym of the spider Pachygnatha amurensis Strand, 1907 (Araneae, Tetragnathidae, Tetragnathinae). PMID- 26623795 TI - Xestioplexia gen. n. with the description of a new species from China (Lepidoptera: Noctuidae). PMID- 26623796 TI - Theridion echinatum Gao & Li, 2014, a junior synonym of Theridion zonulatum Thorell, 1890 (Araneae, Theridiidae) with comments on its web architecture. PMID- 26623797 TI - Host plants of Empria sawflies (Hymenoptera, Tenthredinidae) in Japan include Rhododendron (Ericaceae). AB - New host plant records are given for six Empria species from Japan. They are Rosa multiflora [Rosaceae] for E. honshuana Prous & Heidemaa, 2011, Rubus sp. [Rosaceae] for E. japonica Heidemaa & Prous, 2011, Geum japonicum and G. calthifolium var. nipponicum [Rosaceae] for E. loktini Ermolenko, 1971, Rosa multiflora, Potentilla indica and probably Rubus parvifolius [Rosaceae] for E. quadrimaculata Takeuchi, 1952, Rhododendron molle subsp. japonicum [Ericaceae] for E. takeuchii Prous & Heidemaa, 2011, and Geum japonicum and Filipendula camtschatica [Rosaceae] for E. tridentis Lee & Ryu, 1996. This is the first record of Ericaceae as a host plant of Empria. The mode of host shifts in the evolution of Empria is inferred by using a phylogenetic hypothesis proposed by Prous et al. (2011a). PMID- 26623798 TI - Rectification of the position of the type locality of Brachycephalus tridactylus (Anura: Brachycephalidae), a recently described species from southern Brazil. PMID- 26623799 TI - Morphological and genetic variation in North Atlantic giant file clams, Acesta spp. (Bivalvia: Limidae), with description of a new cryptic species in the northwest Atlantic. AB - We analyze the morphological and genetic variability within and between seven species of Acesta and specimens recently collected in the northwest Atlantic using traditional morphological measurements, landmark-based geometric morphometrics, and the cytochrome oxidase subunit I (COI) gene sequences, with particular emphasis on North Atlantic species. Shell morphology and external shell appearance do not allow reliable distinction between the widely recognized northeastern Atlantic A. excavata and other northwest Atlantic species or populations of Acesta, with the exception of A. oophaga. Similarly, shape analysis reveals a wide variability within northeastern Atlantic A. excavata, and significant morphological overlap with A. bullisi from the Gulf of Mexico and A. rathbuni from the southwestern Pacific and South China Sea. Specimens from the northwestern and Mid-Atlantic display shell shapes marginally similar to that of A. excavata. These differences are at least partly related to anterior or posterior shifting of the shell body and to the opposite shifting of the hinge line/dorsal region and upper lunule. These morphological variations, along with the midline-width-ratio, explain much of the variability extracted by principal component analysis. Results from a mitochondrial DNA barcode approach (COI), however, suggest that the northwest Atlantic specimens belong to a new species for which we propose the name Acesta cryptadelphe sp. nov. Differences in larval shell sizes between northeastern and northwestern Atlantic specimens are consistent with this result. PMID- 26623800 TI - New Oppiidae (Acari, Oribatida) from New Zealand. AB - Three new species of oribatid mites of the family Oppiidae (Oribatida, Oppioidea), belonging to the genera/subgenera Tripiloppia Hammer, 1968 and Lanceoppia (Baioppia) Luxton, 1985, are described from Central Otago, South Island, New Zealand. Tripiloppia frigida sp. nov. is morphologically similar to T. dalenii Hammer, 1968, but differs from the latter by the lanceolate bothridial setae, five pairs of genital setae, and trapezoid anterior notogastral protrusion. Tripiloppia alpina sp. nov. is morphologically similar to T. frigida sp. nov., but differs from the latter by the short, diagonal costulae, strong teeth in humeral regions, barbed lamellar setae, and interlamellar setae shorter than rostral setae. Lanceoppia (Baioppia) trapezoides sp. nov. is morphologically similar to L. (B.) moritzi Hammer, 1968, but differs from the latter by the larger body length, presence of notogastral setae c, and long interlamellar setae. The taxonomic status of the genus Autoppia Golosova & Karppinen, 1983 and systematic placement of Autoppia algicola Golosova & Karppinen, 1983 are discussed, resulting in the following taxonomic proposals: Tripiloppia Hammer, 1968 (=Autoppia Golosova & Karppinen, 1983 syn. nov.); Tripiloppia algicola (Golosova & Karppinen, 1983) comb. nov. The identification keys to known species of Tripiloppia and Lanceoppia (Baioppia) are given. PMID- 26623801 TI - Amamiichthys, a new genus for the sparid fish Cheimerius matsubarai Akazaki 1962, and redescription of the species, with designation of a neotype. AB - A new genus, Amamiichthys, is proposed for the sparid fish Cheimerius matsubarai Akazaki 1962. This genus differs from all other genera in the family Sparidae by the following combination of characters: both jaws with an outer row of small molariform teeth and an inner row of similar, even smaller teeth; frontal bone flat, coarse and porous; strongly bifurcate protuberance of upper ethmoid just beneath mid-region of anteriormost portion of frontal bone; head and body pinkish, gradually becoming silvery toward abdomen, with many small blue spots, some pairs overlapping. The type species, Amamiichthys matsubarai, is redescribed and a neotype designated. PMID- 26623802 TI - Palearctic species of the genus Tephritis (Diptera, Tephritidae) associated with plants of the tribe Senecioneae (Asteraceae). AB - Tephritis arnicae (Linnaeus, 1758) from Europe was the hitherto only Palearctic species of the genus Tephritis known to infest flowerheads of asteraceous plants of the tribe Senecioneae. An additional species with similar biology, Tephritis arsenii, new species, recently discovered in Iran and Armenia is described. It is very similar to T. arnicae in the shape of the aculeus and spermathecae, as well as the wing with darkened anal lobe and abdominal tergites with black setulae, but differs from it by the white posterior orbital and notopleural setae, and also by details of the wing pattern. Larvae of T. arsenii feed in flowerheads of Doronicum dolichotrichum Cavill of the tribe Senecioneae (Asteraceae). PMID- 26623803 TI - Review of Oribotritia (Acari, Oribatida, Oribotritiidae) with a world checklist and description of a new species from China. AB - The oribatid mite genus Oribotritia Jacot, 1924 (Oribotritiidae) is reviewed. A new species of Oribotritia collected from litter in Hunchun, China, Oribotritia hunchunensis sp. nov., is described and figured. Four species, Oribotritia angusta Mahunka, 1982, Oribotritia asiatica Hammer, 1977, Oribotritia chichijimensis Aoki, 1980, Oribotritia gigas Bayoumi & Mahunka, 1979, are redescribed based on Chinese specimens. Oribotritia nepalensis Niedbala, 2000 is considered as a new junior subjective synonym of Oribotritia gigas Bayoumi & Mahunka, 1979. A comprehensive, fully annotated and referenced checklist of all known species and a key to known Chinese species of this genus are provided to facilitate to the further research. PMID- 26623804 TI - Oligoneuria (Yawari) anatina sp. nov. (Ephemeroptera: Oligoneuriidae) from the extreme north of Brazil. AB - Oligoneuria (Yawari) anatina sp. nov. is described and illustrated based on nymphs and imagoes collected in the municipality of Serra do Navio, state of Amapa, Brazil. The main characteristics that can be used to distinguish the new species from other species of the genus are, in imagoes: 1) forewing with spectral cross veins between IRS and MP2 (male) or between IRS and IMP (female), 2) posterior margin of styliger plate distally rounded and with paired rounded projections; in nymphs: 1) vertex of head with two pairs of tubercles, 2) lateral margin of anterior projection of head straight. Cytochrome Oxidase subunit I (COI) sequences were used to associate male imago and immature stages of the new species. PMID- 26623805 TI - Taxonomic changes in the treehopper genera Helonica Ball, Telamona Fitch, and Palonica Ball (Hemiptera: Membracidae: Smiliinae: Telamonini). AB - Nomenclatural changes within the treehopper tribe Telamonini are made as follows based on an examination of the type material of several species: the genus Helonica Ball is a junior synonym of Telamona Fitch, n. syn.; Telamona excelsa (Fairmaire), n. comb., with n. syn. T. unicolor Fitch; T. projecta Butler is reinstated from synonymy as a valid taxon for the North American taxa historically placed in Helonica; and Palonica albidorsata (Fowler) from Mexico, n. comb., is reinstated from synonymy based on morphological differences with T. excelsa and T. projecta. Lectotype designations are clarified for T. fasciata and T. unicolor based on specimens in the New York State Museum (NYSM). As a result of this work, the tribe Telamonini contains 68 species in 10 genera, the genus Palonica contains 7 species, and the genus Telamona contains 29 species. PMID- 26623806 TI - New species of Cryptophleps Lichtwardt (Diptera: Dolichopodidae) with a key to the Afrotropical and Palaearctic species of the genus. AB - Two new species, Cryptophleps namibica sp. nov., from Namibia and C. buttikeri sp. nov., from Saudi Arabia are described. The following new combinations are proposed: Cryptophleps izia (Negrobov, 1973) (Asyndetus), comb. nov. (Central Asia), Cryptophleps minuta (Negrobov & Shamshev, 1986) (Asyndetus), comb. nov. (Far Eastern Asia) and Cryptophleps vivida (Negrobov & Shamshev, 1986) (Asyndetus), comb. nov. (Far Eastern Asia). The systematic positions of species of Cryptophleps are discussed. An identification key to Afrotropical and Palaearctic species is provided. PMID- 26623807 TI - A new species of torrent catfish, Liobagrus hyeongsanensis (Teleostei: Siluriformes: Amblycipitidae), from Korea. AB - A new species of torrent catfish, Liobargus hyeongsanensis, is described from rivers and tributaries of the southeastern coast of Korea. The new species can be differentiated from its congeners by the following characteristics: a small size with a maximum standard length (SL) of 90 mm; body and fins entirely brownish yellow without distinct markings; a relatively short pectoral spine (3.7-6.5 % SL); a reduced body-width at pectoral-fin base (15.5-17.9 % SL); 50-54 caudal-fin rays; 6-8 gill rakers; 2-3 (mostly 3) serrations on pectoral fin; 60-110 eggs per gravid female. PMID- 26623808 TI - New species and additional records of Tetrabothrus Bernhauer from China (Coleoptera, Staphylinidae, Aleocharinae). AB - Material of the lomechusine genus Tetrabothrus Bernhauer, 1915 from China was studied. A new species is described and illustrated under the name T. xizangensis Z.-Q. Yan and L.-Z. Li, sp. nov. (Xizang). Tetrabothrus japonicus is reported in China for the first time, and the new locality for T. puezti and T. inflexus are given. All Chinese species are mapped, and an identification key is provided. PMID- 26623809 TI - A new species of the genus Tameothrips Bhatti (Thysanoptera: Thripidae) with four new records of thrips from India. AB - A new thrips species of the grass-inhabiting Anaphothrips genus-group, Tameothrips arundo sp. n., is described from specimens collected on Arundo donax (Poaceae) from high altitude in Himachal Pradesh State of India. Four species of thrips in two subfamilies of family Thripidae are also reported for the first time from India, all of them well outside their known range: Helionothrips aino Ishida and Panchaetothrips noxius Priesner in the Panchaetothripinae, and Parabaliothrips takahashii Priesner and Scirtothrips kenyensis Mound in the Thripinae. This is the first record of Parabaliothrips Priesner from India. Diagnostic features and data on material studied for these species are provided. PMID- 26623810 TI - Acinopus sabulosus and A. lepeletieri from north-west Africa are two distinct species (Coleoptera: Carabidae: Harpalini). PMID- 26623811 TI - A new species of Lilloiconcha Weyrauch, 1965 (Pulmonata: Charopidae) from central Chile. PMID- 26623812 TI - The advertisement call of three highland endemic species (Anura: Craugastoridae) from the Andean mountains of Colombia. PMID- 26623813 TI - A new species of death adder (Acanthophis: Serpentes: Elapidae) from north western Australia. AB - Australian death adders (genus Acanthophis) are highly venomous snakes with conservative morphology and sit-and-wait predatory habits, with only moderate taxonomic diversity that nevertheless remains incompletely understood. Analyses of mitochondrial and nuclear gene sequences and morphological characteristics of death adders in northern Australia reveal the existence of a new species from the Kimberley region of Western Australia and the Northern Territory, which we describe as Acanthophis cryptamydros sp. nov. Although populations from the Kimberley were previously considered conspecific with Northern Territory death adders of the A. rugosus complex, our mtDNA analysis indicates that its closest relatives are desert death adders, A. pyrrhus. We found that A. cryptamydros sp. nov. is distinct in both mtDNA and nDNA analysis, and possesses multiple morphological characteristics that allow it to be distinguished from all other Acanthophis species. This study further supports the Kimberley region as an area with high endemic biodiversity. PMID- 26623815 TI - Schuelkelia gen. n., a new eastern Palaearctic ant-like stone beetle, with synopsis of Eurasian genera of Cyrtoscydmini (Coleoptera: Staphylinidae: Scydmaeninae). AB - Schuelkelia unicornis gen. & sp. n. is described from Yunnan, China. The new taxon belongs to a group of genera characterized by the submentum lacking lateral sutures, and is most similar to Euconnus. Among the Eurasian genera Schuelkelia can be easily identified on the basis of the broad occipital constriction, pronotum lacking antebasal pits or grooves, elytra lacking externally visible basal foveae; mesoscutellum not visible between elytral bases; long and slender but weakly elevated mesoventral intercoxal process, and other features which are described and illustrated in detail. Morphological structures of Schuelkelia are compared with those of all other Palaearctic and Oriental Cyrtoscydmini, and keys to identification of all Eurasian and separately Chinese genera of Cyrtoscydmini are given. A brief illustrated synopsis of all genera of Cyrtoscydmini known to occur in the Oriental and Palaearctic regions is given, to facilitate identifications and future studies. PMID- 26623814 TI - A new genus of the mantispid-like Paraberothinae (Neuroptera: Berothidae) from Burmese amber, with special consideration of its probasitarsus spine-like setation. AB - Creagroparaberotha groehni gen. et sp. nov. (Neuroptera: Berothidae: Paraberothinae) is described from the earliest Cenomanian Burmese amber. The revised diagnosis of Paraberothinae is provided. The specialized probasitarsi in Paraberothinae, Rhachiberothinae (Berothidae) and Symphrasinae (Mantispidae) are considered as a homoiology (parallelism), i.e., convergent modifications of a homologous structure. The genus Berothone Khramov, 2015 is considered to belong to the subfamily Mesithoninae (Berothidae). PMID- 26623816 TI - Insights on the biology and ecology of the deep-water shrimp Parapontophilus occidentalis (Faxon, 1893) (Crustacea: Caridea: Crangonidae) in the eastern Pacific with notes on its morphology. AB - The deep-water crangonid Parapontophilus occidentalis (Faxon, 1893) is endemic to the eastern Pacific and has been reported from Mexico to Chile, in depths of 837 4082 m. Material collected off the west coast of the Baja California Peninsula (BCP) during the TALUD XV, XVI and XVI-B cruises consists of a series of 136 specimens (M:F = 1:3.6) with 30 % of ovigerous females. The material examined was captured in depths of 1296-2093 m. Size ranged from 8.4 to 16.1 mm CL, with females being significantly larger than males. Number of eggs carried by ovigerous females ranged from 7 to 998, without a significant relationship between female size and number of eggs. Using only data of females carrying at least 100 eggs, egg mass weight varied from 0.036 to 0.181 g. Size of oval-shaped eggs also varied considerably (0.515 to 0.922 mm). Larger densities of P. occidentalis were observed between 1700 and 2100 m, where larger individuals were collected, and sex proportions differed across all depth strata. At the northern BCP, P. occidentalis was collected at dissolved oxygen concentrations from 0.76 to 1.83 ml l(-1), at temperature from 2.1 to 3.4 degrees C, and salinity from 34.54 to 34.63 kg g(-1). Density of P. occidentalis was positively correlated with dissolved oxygen, salinity, and silt contribution to sediments, and negatively correlated with temperature and primary productivity five months before sampling. PMID- 26623817 TI - A new species of Buprestis subgenus Akiyamaia from South-Eastern Tibet, China (Coleoptera: Buprestidae: Buprestini). AB - Buprestis (Akiyamaia) intercostata sp. n. is described from Chayu, south-eastern Tibet. It is characterized by the presence of three additional longitudinal carinae inserted between the elevated suture and the three normal costae commonly found on each elytron of the previously known species of Akiyamaia. PMID- 26623818 TI - Two new dwarfgobies (Teleostei: Gobiidae) from the Ryukyu Islands, Japan: Eviota flavipinnata and Eviota rubrimaculata. AB - Two new species of Eviota from Yoron Island, the Ryukyu Islands, Japan, are described. Both species belong to the cephalic sensory-canal pore system pattern 2 (lacking only the H [IT] pore); have some pectoral-fin rays branched; have a dorsal/anal-fin formula of 9/8; no dark spot over the ural centrum; no prominent distinct dark spots on the pectoral-fin base; no postocular spots; and no strong dark spots on the caudal fin. The species share the most characters with E. afelei, E. bimaculata and E. punctulata, but differ from Eviota afelei and E. punctulata by having two versus three dark marks over the anal-fin base, and from Eviota bimaculata by lacking the two dark, prominent occipital spots present in that species. Both species differ from all other described species of Eviota in fresh coloration. Eviota flavipinnata has bright golden-yellow dorsal fins and an orange anal fin, and a fifth pelvic-fin ray that is 12% the length of the fourth ray. Eviota rubrimaculata has clear dorsal fins with red spots, large red spots on the body, and lacks the fifth pelvic-fin ray. PMID- 26623819 TI - Thermoarcturidae, a new crustacean family of three genera (Isopoda: Valvifera). AB - A new family Thermoarcturidae of valviferan isopod is erected for three genera, Califarcturus n. gen., Spinarcturus Kensley, 1978 and Thermoarcturus Paul & Menzies, 1971, each represented by one species. All share strong stiff setae on distal articles of pereopods 2-4, uropods with two rami, and a tomentum of fine setae over the cuticle. The members are distinguished from Antarcturidae, Arcturididae, Rectarcturidae and Arcturidae, similar arcturoid families that differ in having rows of filter setae on pereopods 2-4 and usually lack one or more uropodal rami. PMID- 26623820 TI - Skryjelites auritus gen. et sp. nov. and Quasimolites quasimodo gen. et sp. nov.- two new middle Cambrian hyolithids (?Mollusca) from the Czech Republic. AB - Two new endemic genera and species of extinct group of Hyolitha, Skryjelites auritus gen. et sp. nov. and Quasimolites quasimodo gen. et sp. nov. are described and illustrated from the Buchava Formation of the Barrandian area (Czech Republic). PMID- 26623821 TI - Description of a new species of Typhinellus (Gastropoda: Muricidae: Typhinae) from the Western Atlantic. PMID- 26623822 TI - A new genus and species of Orphninae (Coleoptera: Scarabaeidae) associated with epiphytes in an Andean cloud forest in Ecuador. PMID- 26623823 TI - A new species of Aegidium Arrow (Coleoptera: Scarabaeidae) from the Atlantic forest ecoregion in South America. PMID- 26623824 TI - Rediscovery of the enigmatic Stenosternus costatus Karsch (Coleoptera: Scarabaeidae: Orphninae) from Sao Tome Island. PMID- 26623825 TI - Terrathelphusa secula, a new species of semiterrestrial freshwater crab (Crustacea: Brachyura: Gecarcinucidae) from Sabah, East Malaysia, Borneo. AB - A new species of semiterrestrial gecarcinucid freshwater crab, Terrathelphusa secula, is described from Danum Valley in Sabah, East Malaysia, eastern Borneo. In the form of its carapace, third maxilliped, and male second gonopod, it most closely resembles T. ovis Ng, 1997, and T. telur Ng, 1997, from eastern Sarawak and Brunei, respectively. It differs markedly from these and other congeners in its proportionately much wider carapace, and a male first gonopod that is strongly curved and sickle-shaped. PMID- 26623827 TI - Status of Gobiosoma (Teleostei: Gobiidae) from Brazil: description of a new species, redescription of G. hemigymnum, molecular phylogeny of the genus, and key to Atlantic species. AB - It is unclear how many species of Gobiosoma occur in Brazil and what their geographic distributions are. Here we combine data from a comprehensive morphological survey and a molecular analysis to clarify this uncertain taxonomy and place Brazilian Gobiosoma within a phylogenetic framework. Recent collections in Brazil, from the states of Ceara to Santa Catarina, and in Uruguay yielded two allopatric species of Gobiosoma that are distinct in genetics, meristics, morphometrics, scale pattern and coloration. Comparisons were made with types and specimens of Gobiosoma hemigymnum, Garmannia mediocricula, Gobiosoma spilotum and Gobiosoma parri and all other known species of Gobiosoma. We place G. parri in synonomy with G. hemigymnum with a distribution of Rio de Janeiro to Uruguay and Argentina. The northern species, that extends from the states of Espirito Santo to Ceara, is described as a new species, Gobiosoma alfiei. A key to the Atlantic species of Gobiosoma is provided. PMID- 26623828 TI - Japanese species of the sawfly genus Nesodiprion (Hymenoptera, Diprionidae). AB - Nesodiprion flavipes sp. nov. associated with Tsuga diversifolia (Maxim.) Mast. and N. kojimai sp. nov. associated with Abies veitchii Lindl. are described from Honshu, Japan. Additional taxonomic and biological information is given for other Japanese congeners, N. japonicus (Marlatt, 1898), N. albiventris Togashi, 1998, N. shinoharai Togashi, 1998, N. nigerrimus Togashi, 1998, N. kagaensis Togashi, 1998, N. niger Togashi, 2001 and N. tsugae Togashi, 2001. The males of N. shinoharai, N. kagaensis and N. tsugae are described for the first time. The host plants of N. shinoharai are Pinus spp. Nesodiprion kagaensis is newly recorded from Hokkaido, Japan, and its host plants are Pinus spp. and Larix kaempferi (Lamb.) Carriere. Larvae of N. japonicus and N. kagaensis are briefly described. A division of Nesodiprion into the following five species groups is proposed: N. tsugae group, N. niger group, N. flavipes group, N. japonicus group and N. shinoharai group. Additions to the key to Nesodiprion species by Hara & Smith (2012) are given. PMID- 26623829 TI - Triomicrus Sharp of Eastern China (Coleoptera: Staphylinidae: Pselaphinae). AB - Twelve species of the genus Triomicrus Sharp are here recognized in eastern China, with eleven of them described as new: T. Inaequalis Shen & Yin, sp. n. and T. mirus Shen & Yin, sp. n. from Anhui, T. abhorridus Shen & Yin, sp. n., T. aculeus Shen & Yin, sp. n., T. damingensis Shen & Yin, sp. n., T. frondosus Shen & Yin, sp. n., T. gutianensis Shen & Yin, sp. n. and T. tibialis Shen & Yin, sp. n. from Zhejiang, T. anfractus Shen & Yin, sp. n. from Anhui and Zhejiang, T. Hamus Shen & Yin, sp. n. from Jiangxi, and T. contus Shen & Yin, sp. n. from Jiangxi and Zhejiang. New distributional data for T. rougemonti Lobl, Kurbatov &Nomura is given. A key for the identification of the Triomicrus species in eastern China is presented. PMID- 26623830 TI - Metazoan parasites of fishes from the Celestun coastal lagoon, Yucatan, Mexico. AB - The aims of this study were to produce a checklist of the metazoan parasites of fishes from the Celestun coastal lagoon and to determine the degree of faunal similarity among the fishes based on the metazoan parasites they share. A checklist was prepared including all available records (1996-2014) of parasites of marine, brackish water and freshwater fishes of the area. All of these data were included in a presence/absence database and used to determine similarity via Jaccard's index. The results indicate the presence of 62 metazoan parasite species infecting 22 fish species. The number of metazoan parasite species found in the fishes from the Celestun lagoon is apparently the highest reported worldwide for a tropical coastal lagoon. The parasites included 12 species of adult digeneans, 27 digeneans in the metacercarial stage, 6 monogeneans, 3 metacestodes, 9 nematodes, 2 acanthocephalans, 2 crustaceans and 1 annelid. Forty parasite species were autogenic and 23 were allogenic and 1 unknown. The overall similarity among all of the species of fish with respect to the metazoan parasites they share was low (0.08 +/- 0.12), with few similarity values above 0.4 being obtained. This low similarity was due primarily to the presence of suites of parasites exclusive to specific species of fish. The autogenic component of the parasite fauna (40 species) dominated the allogenic component (21 species). The most likely explanation for the large number of fish parasites found at Celestun is the good environmental condition of the lagoon, which allows the completion of parasite life cycles and free circulation of euryhaline fishes from the marine environment bringing marine parasites into the lagoon. PMID- 26623831 TI - Additional records of cicadas (Hemiptera: Cicadidae) to the fauna of Mindanao, Philippines, with the description of three new species and a key to the species of Champaka Distant. AB - This paper provides the revised checklist of the tribes, subtribes, genera, and species of the family Cicadidae from Mindanao, Philippines, comprising 22 species belonging to 16 genera. Three new species, Champaka solivenae sp. nov., Purana crassinotata sp. nov., and Ggomapsalta fragilis sp. nov., are described. Lembeja fatiloqua (Stal, 1870) is added to the list, which was omitted in the previous checklist. Neoncotympana leeseungmoi Lee, 2011 is added to the list, which was described after the previous checklist. Oncotympana averta Lee, 2011 is newly recorded from Mindanao, replacing Oncotympana sp. listed in the previous checklist. A key to the 12 species of Champaka Distant, 1905 is provided. PMID- 26623832 TI - New and little known species of Zorotypus Silvestri (Zoraptera: Zorotypidae) from China. AB - A new species of the insect order Zoraptera, Zorotypus hainanensis sp. n., is described from southern China based on apterous adults, which represents a fourth species of the genus in China. Additional collection data for Z. medoensis Hwang in Xizang (= Tibet) is provided. Illustrations of the major diagnostic features of both the new species and Z. medoensis are provided, and their taxonomic placements are briefly discussed. PMID- 26623833 TI - A revision of the South American genus Metecia Snellen (Lepidoptera, Noctuidae, Noctuinae). AB - The genus Metecia Snellen (Noctuidae. Noctuinae) from Southern Argentina and Chile is redescribed and three species are recognized: M. cornifrons Snellen, M. lacustris (Kohler) n. comb., and M. hypothetica (Kohler) n. comb. In addition, Euxoa pampeana Kohler is synonymized with Metecia cornifrons. Adults and male and female genitalia are described and illustrated for the first time, and a key to the species is provided. PMID- 26623834 TI - A review of the genus Deltote Reichenbah, Leipzig, 1817 with description of a new species from China (Lepidoptera, Noctuidae: Eustrotiinae). PMID- 26623835 TI - Notes on "A checklist of the Gyrinidae (Coleoptera: Adephaga) of Brazil" by Colpani et al. (2014). PMID- 26623836 TI - The genus Labania Hedqvist 1963 (Hymenoptera, Braconidae: Doryctinae) with description of a new species from Brazil. AB - In this paper a new species of doryctine wasp of the small and rarely collected genus Labania Hedqvist (Braconidae: Doryctinae) is described and illustrated from Brazil. Labania carolinae sp.n. is similar to Labania minuta Marsh, but it can be easily distinguished by the head yellow, with stemmaticum black, mesosoma and metasoma yellow, legs whitish yellow, propodeum with distinct areola, fore wing vein 1cu-a interstitial with 1M, and long ovipositor. PMID- 26623837 TI - First record of the jumping spider genus Bavia Simon, 1877 from India, with the description of a new species. PMID- 26623838 TI - OFER GON, YUN-CHIH LIAO & SHAO KWANG-TSAO (2015) A new species of the cardinalfish genus Jaydia (Teleostei: Apogonidae) from the Philippines. Zootaxa, 3980 (2): 286-292. AB - Table 1, catalogue number of holotype: replace ASIZP 68202 with PNM 15192. Table 1, catalogue number of 34.9 mm paratype: replace CAS 236506 with USNM 435707. Table 1, catalogue number of 46.5 mm paratype: replace CAS 236506 with SAIAB 200712 PMID- 26623839 TI - A study of the members of the tribe Phasmatini Gray, 1835, that occur within the boundaries of Wallacea (Phasmatodea: Phasmatidae: Phasmatinae: "Lanceocercata"). AB - The tribe Phasmatini Gray, 1835 predominantly includes very striking stick insects of remarkable size, most of which are characteristic for their large and often colourful wings. The tribe represents roughly half of the Giant Stick Insects of Wallacea, a subregion in Eastern Indonesia comprising thousands of islands that are separated by deep water straits from the continental islands to the west (Sundaland: Borneo, Java and Sumatra) and East (New Guinea). Within Wallacea the Phasmatini are represented by four genera, namely Anchiale Stal, 1875, Eurycnema Audinet-Serville, 1838, Paracyphocrania Redtenbacher, 1908 and Phasma Lichtenstein, 1796. Currently eight distinct species are known to occur in the Wallacea. Two of these are newly described in the present paper , this is Anchiale buruense sp. n. and Paracyphocrania major sp. n.. Keys are provided for the distinction of the Phasmatini taxa of Wallacea and information on the overall distribution of the four genera is presented, which reveals a derivation of the tribe from the Australian region. The tribe Phasmatini itself is briefly characterized and discussed. Brief characterizations of the four genera are provided along with complete lists of the species currently contained. Anchiale Stal, 1875 is represented in the Wallacea by two species. A. maculata (Olivier, 1792) is widely distributed throughout Wallacea except for Sulawesi and shows considerable intraspecific variability. Both sexes and the eggs are illustrated and the eggs formally described for the first time. The synonymies of A. maculata are clarified. A. stolli Sharp, 1898 and A. confusa Sharp, 1898 from New Britain and the Solomon Islands are shown to be errorneous synonyms of A. maculata and are here re-established as valid species (stat. rev.). A. caesarea Redtenbacher, 1908 is removed from the genus Acrophylla Gray, 1835 and transferred to Anchiale (comb. n.). The new species A. buruense sp. n. from the island of Buru (Maluku Islands) is described and illustrated based on both sexes and the egg. Eurycnema Audinet-Serville, 1838 has two species within the boundaries of Wallacea. E. nigrospinosa Redtenbacher, 1908 is only known from the Kei Islands in the southeastern portion of Wallacea and otherwise found on New Guinea. Both sexes and the eggs are illustrated. E. versirubra Audinet-Serville, 1838 is found on some of the Lesser Sunda Islands and otherwise distributed throughout Java, Sumatra and SE-Borneo. The records from Java, Sumatra and southeast Borneo are estimated to be artificial. Females of this species are dimorph and occur in two distinct colour morphs, which differ by the distinct colouration of the undersides of the tegmina and alae. E. versirubra colour morph versirubra has two forms, the insects either being bright green or dull yellow with the ventral surfaces of the tegmina and alae bright red. E. versirubra colour morph versifasciata, has the ventral surfaces of the tegmina and alae yellow, the insects themselves being pale bluish green to turquoise in colour. Only the bright green form appears to be natural with the other colour-forms caused by parthenogenetic reproduction in captivity. Both sexes, the eggs and the two aforementioned colour-morphs are illustrated. Paracyphocrania Redtenbacher, 1908 contains two known species and is endemic to Sulawesi and the nearby island of Peleng. The new species Paracyphocrania major sp. n. from Peleng is described and illustrated based on the female and egg. The male remains as yet unknown. The previously unknown male of P. lativentris Redtenbacher, 1908 is described for the first time. Both sexes and the eggs are illustrated. Vasilissa tecticollis Redtenbacher, 1908 is shown to have been misinterpreted previously, here removed from Paracyphocrania and shown to be a synonym of the Australian Tropidoderus rhodomus McCoy, 1882 (syn. n.). Hence, the type-locality of V. tecticollis originally given as "Philippines" is definitely wrong, which proves the tribe Phasmatini is not represented in the Philippines at all. Phasma Lichtenstein, 1796 is represented in Wallacea with two distinct species and has one further species on New Guinea. A key is provided to distinguish between the three known species of Phasma. Ph. gigas (Linnaeus, 1758) is widely distributed throughout Wallacea and found on almost all major islands, although the historic records from Sulawesi deserve evaluation. Ph. gigas is most certainly not present on New Guinea, with all New Guinean records actually referring to Ph. reinwardtii (de Haan, 1842). Ph. gigas exhibits remarkable intraspecific variability in the colouration and certain morphological features of the insects, with several of these variations appearing to be peculiar to certain localities and islands. The range of variation as well as both sexes and the eggs are illustrated. Papuanoidea straleni Werner, 1930 from New Guinea has erroneously been synonymised with Ph. gigas and is here shown to be a synonym of Ph. reinwardtii (de Haan, 1842) (syn. n.). The second Wallacean representative of the genus, Ph. marosense Hennemann, 1998, is endemic to Sulawesi. The previously unknown male is described for the first time and both sexes and the eggs are illustrated. Holotypes of the two newly described species, Anchiale buruense sp. n. and Paracyphocrania major sp. n., are deposited in the State Zoological Collections Munich, Germany (ZSMC). PMID- 26623840 TI - Revision of the genus Hydroides (Annelida: Serpulidae) from Australia. AB - Hydroides Gunnerus, 1768 is the largest and one of the economically most important genera of calcareous tubeworms (Serpulidae, Annelida) that includes a number of notorious fouling and bioinvading species. Although the representatives of the genus are typically found in shallow waters of tropical and subtropical areas worldwide, the species composition of the genus in Australia has never been revised. We conducted the first detailed regional taxonomic revision of Hydroides species based both on the historical collections from Australian museums (Australian Museum, Museum Victoria, South Australian Museum, Western Australian Museum, Queensland Museum, and Museum and Art Gallery of Northern Territory) and newly collected material from New South Wales, Victoria, Queensland, Northern Territory, and Western Australia. In total, 25 species are currently considered valid in Australia, including three new species: H. amri n. sp. from NSW, SA, and Vic (previously referred to as H. cf. brachyacantha), as well as H. glasbyi n. sp. and H. qiui n. sp., both from NT, and two new records of H. furcifera and H. multispinosa for Australia. We have synonymised H. spiratubus with H. albiceps, and H. spiculitubus with H. tambalagamensis in this study. The status of the taxon H. cf. recta remains undecided. An identification key and diagnoses accompanied by original high-quality photographs for all species recorded in Australia are provided. Application of molecular genetics is needed to resolve the status of some problematic species. PMID- 26623841 TI - Systematic revision and phylogeny of the genera Blakeius Ashmead, 1903 and Liomutilla Andre, 1907, with description of two new genera (Hymenoptera: Mutillidae, Myrmillinae). AB - Nine species of Palaearctic Myrmillinae with females bearing two round spots on the second metasomal tergite, currently assigned to two genera, Blakeius Ashmead, 1903 and Liomutilla Andre, 1907, are revised and their phylogenetic relationships are investigated. The cladistic analyses demonstrate that Blakeius is not strictly monophyletic but includes three distinct lineages: Blakeius s. str., containing three species, an additional two genera proposed as new (Bidecoloratilla Turrisi & Matteini Palmerini, gen. nov., with four species, type species Mutilla chiesi Spinola, 1839, and Bimaculatilla Turrisi & Matteini Palmerini, gen. nov., including only type species Myrmilla invreai Suarez, 1958), and the monotypic genus Liomutilla is nested within the former Blakeius. A new status is proposed for Bla. cobosi (Suarez, 1958), stat. nov., and the specific status of Bid. iberica (Suarez, 1958), is confirmed. New combinations are proposed for Bim. invreai (Suarez, 1958), comb. nov. (from Myrmilla), Bid. chiesi (Spinola, 1839), comb. nov., Bid. iberica (Suarez, 1958), comb. nov., Bid. leopoldina (Invrea, 1955), comb. nov. Bid. negrei (Suarez, 1958), comb. nov. (all from Blakeius). Lectotypes are designated for Myr. otini Giner Mari, 1959 (?) and Myr. leopoldina Invrea, 1955 (?). Redescriptions of all treated taxa, based also on material belonging to the type series, are provided, along with illustrations of both sexes. Based on extensive material of relevant museum collections and personal collections, the distributions of all treated taxa are revised and illustrated through distributional maps. A revised key to genera of the subfamily Myrmillinae of the Palaearctic Region is given. PMID- 26623842 TI - A review of the genus Dudaia Hedicke, 1923 (Diptera, Sphaeroceridae). AB - Species of the Afrotropical genus Dudaia Hedicke, 1923 of the subfamily Copromyzinae are revised. The status of Afroborborus Curran, 1931 as a junior synonym of Dudaia is corroborated. Twelve species have been described hitherto, two of them are proposed here to be junior synonyms: Copromyza (Dudaia) simulatilis Richards, 1980, and the name it replaced, Borborus (Dudaia) similis Vanschuytbroeck, 1948, are junior synonyms of Copromyza (Gymnometopina) jeanneli Richards, 1938; and Borborus (Dudaia) uelensis Vanschuytbroeck, 1959 is a junior synonym of Dudaia straeleni (Vanschuytbroeck, 1948). Ten species new to science are described: Dudaia abdita sp. nov. (Kenya), Dudaia aethiopica sp. nov. (Ethiopia), Dudaia albimana sp. nov. (Madagascar), Dudaia brevis sp. nov. (Madagascar), Dudaia communis sp. nov. (Democratic Republic of Congo, Republic of Congo, Ghana, Nigeria, and Tanzania), Dudaia malagasiensis sp. nov. (Madagascar), Dudaia microtuberculata sp. nov. (South Africa), Dudaia pseudohumeralis sp. nov. (Democratic Republic of Congo), Dudaia spangleri sp. nov. (Kenya), and Dudaia steineri sp. nov. (Madagascar). PMID- 26623843 TI - Little walking leaves from southeast Ecuador: biology and taxonomy of Typophyllum species (Orthoptera, Tettigoniidae, Pterochrozinae). AB - Eight katydid species of the leaf-mimicking specialist genus Typophyllum were found in the southeast of Ecuador in an area comprising part of the eastern Andean cordillera and foothills toward the Cordillera del Condor in elevations between 850 and 3000 m. They are described along with the peculiar calling songs and other interesting aspects of their biology. Three of these species are new: T. morrisi sp. nov., T. onkiosternum sp. nov. and T. vignoni sp. nov. A fourth species represented by a single male is possibly new as well. In males and females of a species considered as identical with T. egregium Hebard 1924, which was previously known from a unique female specimen, was found a remarkable variation of coloration, in addition to the striking sexual dimorphism typical for the genus, with the females being twice as large as the small males. The latter is related to the curious mating behaviour, which is documented for this species and T. erosifolium Walker 1870. The two other species found in the region are T. bolivari Vignon 1925 and T. mortuifolium Walker 1870. The calling songs of four species were recorded. In T. erosifolium and T. morrisi sp. nov. the sounds are almost pure sine waves at the lower boundary of ultrasound. In T. egregium and T. onkiosternum sp. nov. the spectrum of the carrier frequency is broader, which might be related to lower and denser vegetation at higher elevation. Based on the intraspecific variety found in T. egregium and T. erosifolium, which includes variation in tegmina shape and venation pattern, are established several syonymies among Typophyllum species from western South America. T. erosifolium is found to be identical with T. peruvianum Pictet 1888 syn. nov. Additionally are considered identical T. inflatum Vignon 1925 and T. gibbosusm Vignon 1925 syn. nov., T. trigonum Vignon 1925 and T. quadriincisum Vignon 1925 syn. nov., and finally T. lacinipenne Enderlein 1917 and T. acutum Vignon 1925 syn. nov. and T. undulatum Caudell 1918 syn. nov. The discussion treats the problematic taxonomy of the little walking leaves, bioacoustics, the pre-copulatory riding behaviour, the sophisticated mimesis, and very briefly the uncertain position within the katydid phylogeny. PMID- 26623844 TI - Taxonomic revision of the Neotropical Myrmicinae ant genus Blepharidatta Wheeler. AB - We revise the taxonomy of the exclusively Neotropical Myrmicinae ant genus Blepharidatta (Attini), redescribing the known species (B. brasiliensis and B. conops), and describing two new species, B. delabiei sp. n. (Brazil: Bahia) and B. fernandezi sp. n. (Colombia: Amazonas). We also describe worker sting apparatuses, larvae, males, and ergatoid gynes of all species, except for B. fernandezi, known only from few worker specimens; we provide a key for identifying workers, present distribution maps for all species and summarize the knowledge on the biology of Blepharidatta species. PMID- 26623845 TI - Check list and zoogeographic analysis of the scale insect fauna (Hemiptera: Coccomorpha) of Greece. AB - This paper presents an updated checklist of the Greek scale insect fauna and the results of the first zoogeographic analysis of the Greek scale insect fauna. According to the latest data, the scale insect fauna of the whole Greek territory includes 207 species; of which 187 species are recorded from mainland Greece and the minor islands, whereas only 87 species are known from Crete. The most rich families are the Diaspididae (with 86 species), followed by Coccidae (with 35 species) and Pseudococcidae (with 34 species). In this study the results of a zoogeographic analysis of scale insect fauna from mainland Greece and Crete are also presented. Five species, four from mainland Greece and one from Crete are considered to be endemic. Comparison with the scale insect fauna of other countries is provided. PMID- 26623846 TI - Taxonomic review of Drilus Olivier, 1790 (Elateridae: Agrypninae: Drilini) from Asia Minor, with descriptions of seven new species and comments on the female antennal morphology in Drilini. AB - The neotenic elaterid genus Drilus Olivier, 1790 in Asia Minor is reviewed. Twelve species are recognized, of which seven are described as new: Drilus badius sp. nov., D. huijbregtsi sp. nov., D. mertliki sp. nov., D. robustus sp. nov., D. sanliurfensis sp. nov., D. teunisseni sp. nov., and D. turcicus sp. nov. All known species are listed with diagnoses, data on variability and distribution. A key to the males of Drilus species in Asia Minor is provided and information on prey of known larvae is summarized. Antennal morphology of Drilini females is briefly discussed. PMID- 26623847 TI - Taxonomic revision of Chironius flavolineatus (Jan, 1863) with description of a new species (Serpentes: Colubridae). AB - We conducted a taxonomic review of Chironius flavolineatus on the basis of continuous and discrete morphological characters. We recognize a new species which is distinguished from all currently recognized congeners by the following unique combination of characters: first third of body black or dark gray; vertebral stripe yellowish or creamish white distinct from dorsals of nape and extending throughout almost whole body length; head dorsum tan to brown, distinct from background color of first third of body; posterior temporal scales ranging one to four; cloacal shield frequently divided; two to four rows of keeled dorsal scales at midbody; venter ground color gradually darkening towards cloaca; region of medial constriction of hemipenis slightly covered with spinules separating calyces of apex from spines below region of constriction; in lateral view, sulcus spermaticus positioned on convex face of hemipenis; ascending process of premaxilla oblique anteroposteriorly to longitudinal axis of skull; optic fenestrae not exceeding frontoparietal suture; posterior border of supratemporal exceeding braincase; dorsoventral axis of quadrate oblique mesolaterally, moving away from longitudinal axis of skull. Furthermore, we provide data on morphological variation, distribution, and an emended diagnosis for C. flavolineatus. PMID- 26623849 TI - Revision of the Neotropical genus Eschatocerus Mayr (Hymenoptera, Cynipidae, Eschatocerini) with biological notes and the first description of the terminal larva. AB - The gall wasp genus Eschatocerus (Hymenoptera, Cynipidae, Eschatocerini), a cynipid genus of gall inducers on Prosopis and Acacia species (Fabaceae), endemic to southern South America, is revised. Complete descriptions of the external morphology of the genus and its three known species, illustrated with scanning electron photographs, are given for the first time, and an updated key for the identification of the species is provided. The biology of the species of Eschatocerus and their galls is described. Host plant associations are given, and the terminal larva of Eschatocerus niger is described for the first time. Preliminary notes on the inquiline and parasitoid community associated with the galls of Eschatocerus species are also given. PMID- 26623848 TI - Three new species of freshwater Macrostomum (Platyhelminthes, Macrostomida) from southern China. AB - Macrostomum is a diverse genus of turbellarians with more than 180 species described from around the world. However, the Macrostomum fauna in China is poorly known. In this study, three new species of freshwater Macrostomum were described from southern China based on morphology of the penis stylet, an important character for species identification in this genus. In M. heyuanensis n. sp., the penis stylet bends 108 degrees leftwards at its 1/2 length then backwards besides the distal opening, and the terminal region is thicker than other parts of penis stylet. In M. dongyuanensis n. sp., the penis stylet is J shaped, with the opening at the tail end. In M. bicaudatum n. sp., the penis stylet is C-shaped, with the upper margin of the distal end longer but slimmer than the lower margin. In addition, molecular phylogenetic analyses were conducted to aid the classification of the novel species. Finally, their habitat and taxonomic status are compared and discussed. PMID- 26623851 TI - Synopsis of the genus Pharaonus (Coleoptera: Scarabaeidae: Rutelinae), with descriptions of new taxa. AB - An overview of the genus Pharaonus Blanchard, 1851 is presented. Pharaonus farsensis new species and P. adelphus new species are described from Iran, P. lederi turcmenius Ohaus, 1941 is recognized as new synonym of P. lederi (Reitter, 1888), and the subgenus Tamerlanius new subgenus is proposed for the two central Asian species. New distribution records and systematic notes are presented: P. caucasicus (Reitter, 1888) is removed from the fauna of Iran and P. varicoloreus (Burmeister, 1844) from that of Israel; P. fasciculatus (Burmeister, 1844) is reported for the first time from Israel, P. semenowi (Reitter, 1888) from Tajikistan. All known species are illustrated and a key to species is presented. PMID- 26623850 TI - Nereis alacranensis, a new species of polychaete (Annelida, Nereididae) from Alacranes Reef, southern Gulf of Mexico, with a key to Nereis from the Grand Caribbean. AB - A new species of polychaete, Nereis alacranensis n. sp., was found in dead coral rocks in the intertidal zone of Alacranes reef, southern Gulf of Mexico. N. alacranensis n. sp. can be included in a group of nereidids characterized by the absence of paragnaths in areas I and V of the pharynx, the presence of cones in a single row or absent in areas VII-VIII, and short blades in notopodial homogomph falcigers. The new species can be separated from the other species of the group by the presence of 3-7 cones in area VI and 7 cones arranged in a row in areas VII-VIII, finely dentate blades in notopodial homogomph falcigers, but most of all, by the presence of an unusual brown coarse arc shaped plate on the external ventral region of the peristomium. This structure has not yet been reported, at least in this genus. A taxonomic key of the species of Nereis recorded from the Grand Caribbean region is included. PMID- 26623852 TI - The jumping spider genus Thiodina Simon, 1900 reinterpreted, and revalidation of Colonus F.O.P-Cambridge, 1901 and Nilakantha Peckham & Peckham, 1901 (Araneae: Salticidae: Amycoida). AB - In this paper we call attention to the identity of the type species of Thiodina Simon, 1900, T. nicoleti Roewer, 1951. When Simon proposed the genus, he characterized it based on morphological features found in species he described, but not found in the type species he designated, and whose type specimens, apparently, he had not examined. Nicolet's original description makes it clear that the type species is not closely related to the more familiar species placed in the genus. This misinterpretation was followed by contemporary researchers and survives until today. Here we designate and describe a neotype for T. nicoleti. We revalidate Colonus F.O.P.-Cambridge, 1901 and Nilakantha Peckham & Peckham, 1901 to transfer most species formerly placed in Thiodina. The combinations Colonus puerperus (Hentz, 1846), Nilakantha cockerelli Peckham & Peckham, 1901 and N. peckhami Bryant, 1940 are restored. The following new combinations are established: Colonus branicki (Taczanowski, 1871) new comb., C. candidus (Mello Leitao, 1922) new comb., C. germaini (Simon, 1900) new comb., C. hesperus (Richman & Vetter, 2004) new comb., C. melanogaster (Mello-Leitao, 1917) new comb., C. pallidus (C.L. Koch, 1846) new comb., C. pseustes (Chamberlin & Ivie, 1936) new comb., C. punctulatus (Mello-Leitao, 1917) new comb., C. rishwani (Makhan, 2006) new comb., C. robustus (Mello-Leitao, 1945) new comb., C. sylvanus (Hentz, 1846) new comb., C. vaccula (Simon, 1900) new comb., C. vellardi (Soares & Camargo, 1948) new comb., Nilakantha beugelorum (Wolff, 1990) new comb., N. crucifera (F.O.P.-Cambridge, 1901) new comb., and N. inerma (Bryant, 1940) new comb. Thiodina setosa Mello-Leitao, 1947 is tentatively transferred to Cotinusa Simon, 1900. PMID- 26623853 TI - A new deep-sea species of the genus Urocaridella (Crustacea: Decapoda: Caridea: Palaemonidea) from Yap Seamount in the Western Pacific. AB - A new species of palaemonid shrimp, Urocaridella liui sp. nov., is discovered from deep waters on the Yap Seamount in the Western Pacific. The new species is unique in the genus by having a pronounced triangular protrusion on the third posterior part of the third pleonal tergite and the almost colorless body, as well as for its occurrence in waters deeper than 250 meters. Other distinct characteristics of this species are the arrangement of dorsal rostral teeth; shorter fingers of the first and second pereiopods and shorter dactyli of the posterior pereiopods; the ratio of the carpus/palm length of the first and second pereiopods; the slender, but not filiform third to fifth pereiopods; and rounded postero-ventrally margin of the fifth abdominal somite. A key to the species of Urocaridella is provided. PMID- 26623854 TI - Assembly of a Phragmites-associated Chloropidae (Diptera) fauna in North America: the Palearctic genus Cryptonevra Lioy in the Nearctic, and the genus Lipara Meigen in Canada. PMID- 26623855 TI - A review of the genera Cleigastra Macquart, Gonarcticus Becker, Gonatherus Rondani, Hexamitocera Becker, Nanna Strobl, Orthacheta Becker and Spathephilus Becker (Diptera, Scathophagidae) of Russia. AB - Flies of the genera Cleigastra Macquart, 1835, Gonarcticus Becker, 1894, Gonatherus Rondani, 1856, Hexamitocera Becker, 1894, Nanna Strobl, 1894, Orthacheta Becker, 1894 and Spathephilus Becker, 1894 (all Scathophagidae) of the fauna of Russia are reviewed. Key to genera, generic descriptions and keys for determination of species are given, and data on geographical distribution are summarized. One species, Nanna cryophila sp. nov., is described as new to science. One new synonymy is proposed: Nanna kamtschatkense (Hendel, 1930) = Nanna tibiella (Zetterstedt, 1838). Orthacheta cornuta (Loew, 1863) is recorded from Europe for the first time. Gonarcticus arcticus (Becker, 1907) is newly recorded from the Palaearctic Region and Russia. Additionally, Nanna flavipes (Fallen, 1819) is newly recorded from China, and Spathephilus nigriventris (Loew, 1864) is newly recorded from Kazakhstan. PMID- 26623856 TI - Muelleritermes: A new termite genus with two species from the Brazilian Atlantic Forest (Isoptera: Termitidae: Nasutitermitinae). AB - We present the description of Muelleritermes, new genus, and two new species: M. fritzi, sp. n. and M. globiceps, sp. n. Both species were found only in the Atlantic Forest of southern Brazil. All castes are described and illustrated, and a distribution map is provided. These species seem to be closely related to the genera Velocitermes and Diversitermes, sharing traits such as the presence of three types of soldiers and workers and a short mixed segment. This genus differs from Velocitermes and Diversitermes in the presence of a few ommatids on soldier's head, behind the antennae. It also differs from Velocitermes in the lack of a constriction on the head of major soldiers, and from Diversitermes in the presence of short hairs on top of the soldier's head, instead of microscopic ones. PMID- 26623857 TI - Checklist of helminths found in Patagonian wild mammals. AB - Using available reports, a checklist of the recorded helminth parasites of wild mammals from Patagonia was generated. Records of parasites found in Patagonia were included, together with records from mammals in areas outside of Patagonia but whose range extends into Patagonia. Information about the host, localities, and references were also included. A total of 1323 records (224 Cestoda, 167 Trematoda, 894 Nematoda, 34 Acanthocephala, and 4 Pentastomida) belonging to 452 helminth species (77 Cestoda, 76 Trematoda, 277 Nematoda, 21 Acanthocephala, and 1 Pentastomida) found in 57 native mammals (22 Rodentia, 4 Didelphimorphia 1 Microbiotheria, 7 Chiroptera, 5 Cingulata, and 13 Carnivora) were listed. However, only 10.6 % of the reports were conducted on samples from Patagonia and corresponded to 25% of mammals in the region. In addition, many studies were made on a few species and, for example, 52% corresponded to studies made on Lama guanicoe. This suggests the need to increase efforts to know the parasitic fauna in a peculiar region as is the Patagonia. This is the first compilation of the helminth parasites of mammals in Argentine Patagonia and is important for parasitological and paleoparasitological studies. PMID- 26623858 TI - New species of the genus Oligoneuriella Ulmer, 1924 (Ephemeroptera: Oligoneuriidae) from Turkey. AB - Three new species of the genus Oligoneuriella Ulmer, 1924 from Turkey are described, namely Oligoneuriella magna sp. nov., Oligoneuriella paulopilosa sp. nov. and Oligoneuriella pectinata sp. nov. Differential diagnostic characters are given with regard to the previously known Oligoneuriella species. Data on the affinities, biology, and distribution of the new species are also provided. New morphological characters (setation of mouthparts and gill plates) potentially useful for the taxonomy of the genus are introduced. PMID- 26623859 TI - First record of Microscapha LeConte from Baltic amber with description of a new species and list of fossil Melandryidae (Coleoptera: Tenebrionoidea). AB - Microscapha andrzeji sp. nov., the first fossil representative of the genus is described from Eocene Baltic amber. An updated list of fossil Melandryidae (Coleoptera: Tenebrionoidea) is provided. The presence of Microscapha within Baltic amber suggests some potential for palaeoenvironmental inferences based on the melandryid assemblage within the deposit. PMID- 26623860 TI - Third report of Allochaetophoridae Reck, 1959 (Acari: Trombidiformes) based on the description of a new species from Iran. AB - A new mite species Allochaetophora iranica sp. nov. (Tetranychoidea: Allochaetophoridae), is described and illustrated based on females and deutonymphs collected from Phragmites australis (Poaceae) in Iran (Kerman Province). This is the third report of the family Allochaetophoridae for the world and first report of it from Asia. PMID- 26623861 TI - Phylogenetic position of Electrostrymon picoloro, a new high elevation hairstreak from western Colombia (Lepidoptera: Lycaenidae: Eumaeini). AB - The phylogenetic position of a new high-elevation butterfly species, which we describe as Electrostrymon picoloro Prieto & Robbins, new species, is assessed. The ventral wing pattern and genitalic structures of this species are unique among Electrostrymon. This species is also unique among Electrostrymon in that it occurs, so far as is known, only in habitats above 2800 m elevation. A phylogenetic analysis places this species in Electrostrymon as the sister of a multi-species clade. The ancestors of E. picoloro appear to have colonized its high elevation habitat relatively early in the phylogenetic history of Electrostrymon, but the species then did not recolonize lower elevation habitats nor did it diversify into other extant species. PMID- 26623862 TI - Advertisement call of Rhinella major (Anura: Bufonidae) from the lower Amazonas River basin with comments on intraspecific variation. PMID- 26623863 TI - A new polymorphic Hemilophini Thomson, 1868 from the Tumuc Humac inselbergs, French Guiana (Coleoptera, Cerambycidae, Lamiinae). AB - A new Zeale Pascoe, 1866, Zeale granvillei sp. nov., is described from open areas at Mitaraka Mounts, French Guiana. The key to the species of Zeale is updated and the different forms of the new species are illustrated. A list of the material from Museum national d'Histoire naturelle (Paris) in this genus is provided. Some aspects of its behavior are given, including its possible host plant, Ichtyothere granvillei H. Robinson (Asteraceae). PMID- 26623864 TI - A new species of Parapharyngodon (Nematoda: Pharyngodonidae) infecting Dermatonotus muelleri (Anura: Microhylidae) from Caatinga, Northeastern Brazil. AB - Parapharyngodon silvoi n. sp. (Nematoda: Pharyngodonidae) is described from the large and small intestine of the Muller's termite frog Dermatonotus muelleri (Boettger, 1885) from the biome Caatinga, Exu municipality, Pernambuco State, Brazil, Dermatonotus muelleri is a fossorial species with a specialized termite diet, and feeding and reproductive behavior occurring only during the wet season. The new species is distinguished from other species of the genus Parapharyngodon by showing ovary not coiled around the esophagus, morphology of anterior cloacal lip, spicule size and number of caudal papillae. PMID- 26623865 TI - A new species of the genus Alienates Barber (Hemiptera: Heteroptera: Enicocephalidae: Alienatinae) from Venezuela. AB - New species Alienates thomasi sp. nov. Banar & Stys is described from Venezuela based on a single female. It is the first species recorded from South America, and is illustrated and compared with other Caribbean and Central American Alienates species. PMID- 26623866 TI - The genus Loxosceles Heineken & Lowe 1832 (Araneae: Sicariidae) in Colombia, with description of new cave-dwelling species. PMID- 26623867 TI - Curicaberis, a new genus of Sparassidae from North and Central America (Araneae, Sparassidae, Sparassinae). AB - The genus Curicaberis gen. nov. is described to include the type species, Curicaberis ferrugineus (C.L. Koch, 1836) comb. nov., and eight other species transferred from Olios Walckenaer, 1837: C. abnormis (Keyserling, 1884) comb. nov., C. annulatus (F.O. Pickard-Cambridge, 1900) comb. nov., C. bibranchiatus (Fox, 1937) comb. nov., C. ensiger (F.O. Pickard-Cambridge, 1900) comb. nov., C. ferrugineus (C.L. Koch, 1836) comb. nov., C. luctuosus (Banks, 1898) comb. nov., C. minax (O. Pickard-Cambridge,1896) comb. nov., C. manifestus (O. Pickard Cambridge, 1890) comb. nov., and C. peninsulanus (Banks, 1898) comb. nov.. All species are redescribed and illustrated. The males of C. ferrugineus comb. nov. and C. luctuosus comb. nov., and the female of C. annulatus comb. nov. are described and illustrated for the first time. Twenty-three new species are described: C. azul sp. nov. (?) from Veracruz, C. catarinas sp. nov. (?) from Chihuahua, C. chamela sp. nov. (? and ?), C. eberhardi sp. nov. (? and ?), C. jalisco sp. nov. (? and ?), and C. urquizai sp. nov. (? and ?) from Jalisco, C. culiacan sp. nov. (?) from Sinaloa, C. cuyutlan sp. nov. (?) from Colima, C. durango sp. nov. (?) from Durango, C. elpunto sp. nov. (? and ?), C. sanpedrito sp. nov. (? and ?), C. tortugero sp. nov. (?), C. yerba sp. nov. (?) and C. zapotec sp. nov. (?) from Oaxaca, C. huitiupan sp. nov. (?), from Chiapas, C. pedregal sp. nov. (?) from Distrito Federal, C. potosi sp. nov. (?) from San Luis Potosi, C. puebla sp. nov. (?) from Puebla, C. tepic sp. nov. (?) from Nayarit, and C. mitla sp. nov. (? and ?) from Veracruz and Oaxaca, C. chiapas sp. nov. (? and ?) from Chiapas and Tabasco, all in Mexico, C. granada sp. nov. (? and ?) from Granada and Managua in Nicaragua and Guanacaste in Costa Rica, and C. bagaces sp. nov. (?), from Guanacaste, Costa Rica. An identification key and distribution maps are provided for all known species. PMID- 26623868 TI - Diversity of spiders in Fanjing Mountain Nature Reserve, Guizhou, China, I: Six new species of Phrurolithidae (Araneae). AB - Male and female specimens of six new spider species of the family Phrurolithidae were collected from the Fanjing Mountain Nature Reserve: Otacilia microstoma sp. nov., O. songi sp. nov., O. subliupan sp. nov., Phrurolithus anticus sp. nov., P. fanjingshan sp. nov. and P. zhouyun sp. nov.. Photographs, line drawings and descriptions of all species are provided in the current study. Additionally, the assignment of each species has been discussed on the basis of the type species of Otacilia Thorell, 1897 and Phrurolithus C. L. Koch, 1839. PMID- 26623869 TI - New species and records of Otiothopinae from the Southern Atlantic Rainforest, with notes on the claw tufts in Fernandezina Biraben (Araneae: Palpimanidae). AB - Two new species of Otiothops MacLeay, 1839 (O. atalaia sp. n. and O. goytacaz sp. n.), a new species of Fernandezina Biraben, 1951 (F. jurubatiba sp. n.) as well as the female of F. tijuca Ramirez & Grismado, 1996 are described from the Atlantic Rainforest of southeastern Brazil, in the state of Rio de Janeiro. Scanning electron microscope images of the tarsi of F. jurubatiba sp. n. and F. dasilvai Platnick, Grismado & Ramirez, 1999 show that this genus has claw tufts on the posterior legs, composed of setae of variable structure. PMID- 26623870 TI - Stephanocampta Mathot (Hymenoptera: Mymaridae): descriptions of two new species and the female of S. indica Anwar & Zeya from India and a key to world taxa. AB - Two new species of Stephanocampta Mathot (Hymenoptera: Mymaridae), S. andamanensis sp. nov. and S. huberi sp. nov., are described from Andaman Islands (Andaman and Nicobar Islands Union Territory) and Manipur, India. The previously unknown female of S. indica Anwar & Zeya is described. A revised key to the world species of Stephanocampta is provided. Stephanocampta serenellae Viggiani stat. rev. is transferred back to Camptoptera Forster, based on examination of the holotype male from Sri Lanka. PMID- 26623871 TI - Five new species and two records of Triphorinae (Caenogastropoda, Triphoridae) from Brazil. AB - Triphoridae is one of the most speciose families of marine mollusks, being mainly represented by the subfamily Triphorinae. The present study aims to describe five new species of Triphorinae, and to report two species in Brazil previously known only from the Caribbean: Nanaphora verbernei (Moolenbeek & Faber) comb. nov. is herein disregarded as belonging to the genus Cheirodonta, owing to differences especially related to shell morphology; Triphora portoricensis Rolan & Redfern has its known geographic distribution greatly increased, despite its non planktotrophic development; Cheirodonta mizifio sp. nov. has a brown shell, with the median spiral cord emerging weakly in the beginning of sixth to eighth whorl of teleoconch; Eutriphora costai sp. nov. has a beige shell, with the median spiral cord emerging in the fifth whorl of teleoconch; Nanaphora leei sp. nov. has a large shell for the genus, with the median spiral cord emerging between the eighth and ninth whorl of teleoconch; Triphora charybdis sp. nov. has a white adapical spiral cord, brown median/abapical cords, with the median one usually emerging in the seventh whorl of teleoconch; Triphora scylla sp. nov. has a reticulated embryonic shell, with the median spiral cord of teleoconch emerging between the end of the sixth to the end of the tenth whorl. PMID- 26623872 TI - Biological, morphological and morphometric studies of Triatoma melanocephala Neiva & Pinto, 1923 (Hemiptera: Reduviidae: Triatominae). AB - Triatoma melanocephala Neiva & Pinto is found in the Brazilian states of Bahia, Paraiba, Pernambuco, Rio Grande do Norte, and Sergipe. In addition to the species' specific description, eight other articles on this insect were found in the literature. In this study, data was obtained on the morphology, morphometry, and life cycle of T. melanocephala, since this vector is of epidemiological and taxonomic importance. The specimens studied were obtained from a colony that has been kept at the Triatomine Insectarium of the College of Pharmaceutical Sciences of Sao Paulo State University's in Brazil. The morphological studies were performed using scanning electron microscopy. These studies characterized the eggs, the external adult female genitalia, and the ninth ventral abdominal segments of male and female nymphs. The morphometric studies characterized the five nymphal instars and the adult stage by measuring the head, thorax, abdomen, antennae, and mouthparts parameters. The life cycle of T. melanocephala was developed starting by 15 couples in the fifth instar. They were fed on Swiss mice every two weeks and observed daily. During daily observation, minimum temperature, maximum temperature, and relative humidity of the laboratory were measured. The results of the biological, morphometric, and morphological studies have increased the knowledge available on T. melanocephala. PMID- 26623873 TI - Description of a new genus for Euptychia hilara (C. Felder & R. Felder, 1867) (Lepidoptera: Nymphalidae: Satyrinae). AB - Based on external morphology, food plant records for caterpillars, and molecular analysis, Euptychia hilara (C. Felder & R. Felder, 1867) is removed from Euptychia Hubner 1818. A new genus, Inbio Nakahara & Espeland gen. nov., is proposed for this taxon. Inbio hilara comb. nov. is a member of a monophyletic clade containing Cyllopsis Felder, 1869, Paramacera Butler, 1868, and Atlanteuptychia Freitas, Barbosa & Mielke, 2013, although it can be morphologically distinguished from these genera. Lectotypes for Neonympha hilara C. Felder & R. Felder, 1867 and Euptychia anacleta Butler, 1877 (a synonym of E. hilara) are designated herein. PMID- 26623874 TI - A new species of the South East Asian genus Sarax Simon, 1892 (Arachnida: Amblypygi: Charinidae) and synonymization of Sarax mediterraneus Delle Cave, 1986. AB - A new species of the whip spider genus Sarax Simon, 1892 from Cebu Island in the Philippines is described: Sarax huberi sp. nov. With the description of this species, the diversity of the genus is increased to three species in the Philippines. Some additional data on their natural environment and their specific habitat are presented and compared with sibling species. The synonymization of Sarax mediterraneus Delle Cave, 1986 with Sarax buxtoni (Gravely, 1915) is carried out. PMID- 26623876 TI - Nargus (Eunargus) celli sp. nov. (Coleoptera: Leiodidae: Cholevinae: Cholevini), a new species from China. AB - Nargus (Eunargus) celli sp. nov. (Coleoptera: Leiodidae: Cholevinae: Cholevini) is described from Guangxi autonomous region, China. Important morphological characters of examined species of Eunargus Perreau are illustrated by color plates or line drawings. A key to three known species of the subgenus Eunargus Perreau is compiled, and known distribution is mapped. PMID- 26623875 TI - Taxonomic notes on the genus Baetiella Ueno from China, with the descriptions of three new species (Ephemeroptera: Baetidae). AB - Nine Baetiella species, including three new species, are reported from China. Baetiella lanpingensis n. sp. is diagnosed by the 2nd segment of labial palpus without inner-apical lobe, the posteromedian margin of terga I-VI each with a single protuberance, posterior margin of sterna V-IX each with a row of continuous long spatulate setae and median caudal filament with only one segment. Baetiella sexta n. sp. is characterized by the 2nd segment of labial palpus bearing an inner-apical lobe, the posteromedian margins of terga I-VI each with a single protuberance, posterior margins of sterna I-VII smooth and median caudal filament with 3-5 segments. Baetiella spathae n. sp. is distinguished from its congeners by the terminal segment of labial palpus asymmetric coniform, the posteromedian margin of terga I-IX each with a single protuberance and posterior margin of sterna V-IX each with a row of long spatulate setae. Additionally, B. macani (Muller-Liebenau, 1985) is removed from the synonymy with B. bispinosa (Gose, 1980) and considered as a valid species. B. marginata Braasch, 1983 is recorded for the first time from China. A key to fourteen species of Baetiella known from mature nymphal stages in the world is provided. PMID- 26623877 TI - New species of Nothybus Rondani, 1875 (Diptera: Nothybidae) from Vietnam with a key to Vietnamese species of the genus. AB - This study is part of an ongoing series of studies on the Vietnamese cyclorrhaphous fauna. One new species from Vietnam, Nothybus kuznetsovorum sp.nov., is described and figured. A key to species of Nothybus is provided. Genital structures are described and figured. PMID- 26623878 TI - Description of a new species and new country distribution records of Bactrocera (Diptera: Tephritidae: Dacinae) from Cambodia. AB - Bactrocera (Bactrocera) kohkongiae Leblanc (Diptera: Tephritidae: Dacinae), from the Koh Kong Province of Cambodia, is described as new. This species belongs to the Oriental fruit fly (B. dorsalis) complex. Genetic sequences (mitochondrial COI and nuclear EF1alpha and Period) are deposited in GenBank. A haplotype network, based on the COI sequences for 21 specimens, shows high genetic diversity. New country records from Cambodia are included for 22 species. PMID- 26623879 TI - Taxonomy of the Quedius mukuensis group (Coleoptera: Staphylinidae: Staphylinini: Quediina) with descriptions of four new species from China. AB - Four new species of the subgenus Microsaurus Dejean, 1833 of the genus Quedius Stephens, 1829 are described based on specimens collected from China: Q. (Microsaurus) indigestus sp. nov., Q. (Microsaurus) purus sp. nov. and Q. (Microsaurus) rectus sp. nov. from Sichuan, and Q. (Microsaurus) medius sp. nov. from Hubei. The new species all belong to the Quedius mukuensis group, which is now increased to a total of 16 species. Line drawings and color illustrations of the adults, and the genitalia of the new species and some other ones are given. A key to all the species of this group is provided. PMID- 26623880 TI - Additions of new species and records to the Tanaidomorpha (Crustacea: Tanaidacea) of Taiwan. AB - This study reports two new species and one new species record of tanaidomorphan tanaidaceans from Taiwan. The leptocheliid Leptochelia taitungensis sp. nov. can be separated from the most similar species, Leptochelia tarda, in the Leptochelia dubia/savignyi group by having long distal spines on the maxilliped endites and the male having two-articled uropod exopods. The tanaidid Zeuxo shitipingensis sp. nov. can be distinguished from Z. normani in the Zeuxo normani species complex by having a triangular left mandible lacinia mobilis, only one seta on the pleopod endopod inner margin, and the uropod endopod with five to six articles in most adult specimens. Morphological comparisons between Leptochelia taitungensis sp. nov. and its congeners within the dubia/savignyi group, as well as between Zeuxo shitipingensis sp. nov. and its congeners, are tabulated. PMID- 26623881 TI - Eriocaenus (Acari: Trombidiformes: Eriophyoidea), a new genus from Equisetum spp. (Equisetaceae): morphological and molecular delimitation of two morphologically similar species. AB - Surveys conducted on horsetails, Equisetum spp. (Equisetaceae), in Serbia led to the discovery of a new eriophyoid mite genus while searching for a classical biological control agent against these weeds in New Zealand. Eriocaenus gen. n. is described based on the type species Aceria equiseti Farkas, 1960 (transferred to Eriophyes by Farkas 1965; herein reassigned to the new genus) and Eriocaenus ramosissimi n. sp., a new species discovered on Equisetum ramosissimum Desf. in Serbia. Eriocaenus equiseti (Farkas, 1960), previously only known from Hungary, was found in Serbia for the first time on Equisetum arvense L. and Equisetum telmateia Ehrh., and is redescribed. Species descriptions include line drawings as well as phase contrast (PCLM), differential interference contrast (DIC) and scanning electron (SEM) micrographs. The differential diagnosis between the two Eriocaenus species is supplemented by molecular differentiation of 28S rDNA sequences including D2 fragments for both mites. PMID- 26623882 TI - Contribution to the genus Omalus Panzer, 1801 of China, with descriptions of two new species (Hymenoptera, Chrysididae). AB - In spite of that Chinese species of the genus Omalus Panzer, 1801 were recently revised by Wei et al. (2014), the study of more material has revealed the presence of other four species: two of them are new, O. corrugatus Rosa, Wei & Xu, sp. nov. (China, Guangdong) and O. hainanensis Rosa, Wei & Xu, sp. nov. (China, Hainan); the other two are newly recorded from China, O. stella (Semenov & Nikol'skaya, 1954) and O. timidus (Nurse, 1902), comb. nov. (from the genus Holophris Mocsary, 1890). An update key to Chinese species and illustrations are provided. PMID- 26623883 TI - Redefinition of the genus Bannapone and description of B. cryptica sp. nov. (Hymenoptera: Formicidae: Amblyoponinae). AB - The ant genus Bannapone was established by Xu in 2000 and has been recognized as one of the rarest ant genera in the world. In the course of our careful examination of Asian species of Stigmatomma, we have found that the following Stigmatomma species share a unique morphological characteristic in mandibular dentition with Bannapone mulanae and B. scrobiceps: Stigmatomma caliginosum (Onoyama, 1999), Stigmatomma fulvida (Terayama, 1987), S. pertinax (Baroni Urbani, 1978), S. zwaluwenburgi Williams, 1946 and an unnamed species "Stigmatomma sp. eg-3". In the present paper, we redefine Bannapone, describe "Stigmatomma sp. eg-3" as a new species of Bannapone, and transfer S. caliginosum, S. fulvida, S. pertinax and S. zwaluwenburgi Williams, 1946 to Bannapone. PMID- 26623884 TI - Two new species of Phyllodistomum Braun, 1899 (Digenea: Gorgoderidae), from freshwater fishes (Cyprinodontiformes: Goodeidae: Goodeinae) in central Mexico: An integrative taxonomy approach using morphology, ultrastructure and molecular phylogenetics. AB - An integrative taxonomy approach is used to characterise the diversity of gorgoderid trematodes that parasitize freshwater fishes of the subfamily Goodeinae in central Mexico. Records of Phyllodistomum sp. and Dendrorchis sp. from the urinary bladder of goodeines have been previously published, although the identification at species level was not achieved. A few specimens were collected and fixed to conduct a scanning electron microscopy study, and to obtain sequences of a mitochondrial (COI) and nuclear (28S rRNA) gene, to be analysed in the context of the molecular phylogeny of gorgoderid trematodes. Based on the new findings, two new species of Phyllodistomum Braun, 1899 are described. Phyllodistomum cribbi n. sp. was found in Zoogoneticus quitzeoensis (Bean), Allotoca zacapuensis Meyer, Radda & Dominguez-Dominguez, Hubbsina turneri de Buen and Z. purhepechus Dominguez-Dominguez, Perez-Rodriguez & Doadrio from Zacapu Lake, and La Luz Spring, in Michoacan, central Mexico. Phyllodistomum wallacei n. sp. parasitized Xenotaenia resolanae Turner, Ilyodon furcidens (Jordan & Gilbert), and Allodontichthys tamazulae Turner from the Cuzalapa, Ayuquila and Tamazula Rivers in Jalisco, western Mexico. These species are compared with several freshwater Phyllodistomum species from different areas of the world, especially a group of eight species that comprise a monophyletic clade in recent phylogenetic hypotheses of the Gorgoderidae Looss, 1899. The two new species are distinguished from other close relatives by the combination of morphological traits such as the body shape, sucker ratio, shape of the gonads, and extension of intestinal ceca. The new species are distinct in some ultrastructural characters of the body surface when compared with those species where scanning electron micrographs (SEM) and/or microphotographs are available. Data of two molecular markers (28S rRNA and COI genes) demonstrate that the two new species are distinct from each other and from those species of Phyllodistomum Braun, 1899 for which sequences are available. PMID- 26623885 TI - Redescription of the early larval stages of the pandalid shrimp Chlorotocus crassicornis (Decapoda: Caridea: Pandalidae). AB - The first four larval stages of the pandalid shrimp Chlorotocus crassicornis (A. Costa, 1871) are described and illustrated from laboratory-reared material obtained from ovigerous females collected in the southwestern Spain and south Taiwan. The second to fourth larval stages of this species are reported for the first time to science. Detailed examination of the first larval stages reveals that previous description misidentified some key larval characters which have prevented its identification in plankton samples. It is found that the zoeal morphology of Chlorotocus is not very different from other pandalid larvae, and in fact closely resembles Plesionika and Heterocarpus. PMID- 26623886 TI - Two new acoels (Acoelomorpha) of the genus Haplogonaria from the northwest Atlantic. AB - Two previously unknown species of Haplogonaria (Acoela), H. schillingi sp. nov. and H. baki sp. nov., are described from the coastline of Maine, USA. The two species are morphologically similar to each other but H. schillingi can be distinguished from H. baki by its red pigmentation, its possession of a large genital atrium that branches posteriorly to the seminal vesicle and anteriorly to the vagina, a seminal vesicle that is more ellipsoid-shaped than spherical, and a well-defined wall in the seminal bursa. We provide a description of the new species using live observation, light microscopy of serial sagittal sections, and confocal microscopy imaging of F-actin. We compare the morphology of the new species with other members of the genus and discuss the phylogenetic position of H. schillingi in light of conflicting morphological and molecular data. PMID- 26623887 TI - Bythaelurus tenuicephalus n. sp., a new deep-water catshark (Carcharhiniformes, Scyliorhinidae) from the western Indian Ocean. AB - A new dwarf deep-water catshark, Bythaelurus tenuicephalus, is described based on one adult and one juvenile male specimen from off Tanzania and Mozambique in the western Indian Ocean. The new species differs from its congeners by its slender head and snout, which is only slightly bell-shaped in dorsoventral view without distinct lateral indention. All other Bythaelurus species have distinctly bell shaped snouts with a strong lateral indention anterior to outer nostrils. Compared to its congeners in the western Indian Ocean, B. tenuicephalus n. sp. also has broader claspers in adult males (base width 2.1% TL vs. 1.5-1.8% TL). It further differs from B. clevai by attaining a smaller maximum size and having a color pattern of fewer and smaller blotches, larger oral papillae, a shorter snout, and broader claspers without knob-like apex and with a smaller envelope and a subtriangular (vs. subrectangular) exorhipidion. Compared to B. hispidus, the new species has a longer snout, a longer dorsal-caudal space, broader clasper without knob-like apex, and fewer vertebral centra. In contrast to B. lutarius, B. tenuicephalus attains a smaller maximum size and has a blotched (vs. largely plain) coloration, numerous (vs. lacking) oral papillae, shorter anterior nasal flaps, a longer caudal fin, a shorter pelvic anal space, and shorter and broader claspers. PMID- 26623888 TI - Nomenclatural changes in two families of asellote isopods (Acanthaspidiidae and Ischnomesidae). AB - Iolanthe Beddard, 1886a is shown to be a senior synonyn of Acanthaspidia Stebbing, 1893, the replacement name for the preoccupied Acanthoniscus Sars, 1879 (Isopoda: Asellota: Acanthaspidiidae). Ischnomesus kussakini nom. nov. is erected as a replacement name for Ischnomesus antarcticus (Kussakin, 1982), preoccupied in this combination (Isopoda: Asellota: Ischnomesidae). PMID- 26623889 TI - First record of the genus Lumahyphes Molineri, 2004 (Ephemeroptera: Leptohyphidae) from Brazil with description of a new species. AB - The genus Lumahyphes Molineri, 2004 (Ephemeroptera: Leptohyphidae) currently is comprised of three species. Lumahyphes cocal sp. nov. is described based on material from the state of Roraima in northern Brazil. The new species differs from the other described species by having the following combination of characteristics: greyish wing membrane; terga base color whitish and terga I-III & VIII-X washed completely with gray; dorsal structure of penes rounded; spines of penes S-shaped in lateral view; and apex of spines directed anteriorly. PMID- 26623890 TI - A new species of Camellocossus Yakovlev, 2011 (Lepidoptera: Cossidae) from Southern Oman. PMID- 26623891 TI - Morphology and distribution of pelagic ostracods of the genus Boroecia (Ostracoda: Halocyprididae) in the Central Arctic. AB - Morphologically similar Boroecia borealis and B. maxima are redescribed from the Central Arctic. Their morphological differences are minor but well defined. Their geographic and vertical distribution is studied based on an extensive body of materials collected by many expeditions in the Arctic Ocean during the period from 1929 to 1993 at the depth range of 0-4000 m. The comparison of the distribution of both species reveals that B. borealis prefers waters of subarctic structure in the Atlantic, and it inhabits waters in the relatively warm Atlantic layer in the Arctic. In contrast, B. maxima is a good indicator of cool Arctic waters. This species is also present in greater depths of the Northern Atlantic, where polar waters penetrate far towards the south. PMID- 26623892 TI - Aquatic Hemiptera (Heteroptera) of Kazakhstan, with notes on life history, ecology and distribution. AB - Based on extensive field collections (2000-2014) in Kazakhstan and a review of the material in the National Institute of Zoology of Kazakhstan, we identified 68 species of aquatic Hemiptera from 11 families. Most species have broad zoogeographic distribution, dominated by West Eurasian fauna (18 species) and West Palearctic fauna (10 species). Details of habitats, feeding types, and life history are included for the described species. PMID- 26623893 TI - An updated list of the plants associated with plant-parasitic Aphelenchoides (Nematoda: Aphelenchoididae) and its implications for plant-parasitism within this genus. AB - Few Aphelenchoides spp. are facultative plant-parasites (foliar and bulb nematodes); three of them are well known in agricultural systems, namely Aphelenchoides besseyi, A. fragariae and A. ritzemabosi. Ten other plant parasitic species, A. arachidis, A. bicaudatus, A. blastophthorus, A. dalianensis, A. ensete, A. nechaleos, A. paranechaleos, A. saprophilus, A. sphaerocephalus and A. subtenuis, have been reported from a limited number of plant species. We compiled a new database of the associated plants for these thirteen species, a comprehensive list that includes 1104 reports from 126 botanical families. A. besseyi, A. fragariae and A. ritzemabosi represent 94% of the reports, circa 83% and 16% of the total reports correspond to flowering plants and ferns, respectively, with three records on conifers and two from other botanical groups also listed. Most plant-parasitic Aphelenchoides show a remarkably broad diversity of associated plants. Most species appear to have no specific plant hosts (i.e. are generalists). The broad host ranges of these species and absence of more intimate interactions with the associated plants highlights the primitive mode of parasitism in Aphelenchoides species, making them potentially interesting in the study of the evolution of plant parasitism. Even though the compiled list of associated plants is long, it probably only represents a fraction of the potential range. The complete compilation has been uploaded to http://nematodes.myspecies.info/. PMID- 26623894 TI - Checklist of Recent thecideoid brachiopods from the Indian Ocean and Red Sea, with a description of a new species of Thecidellina from Europa Island and a re description of T. blochmanni Dall from Christmas Island. AB - Compilation of a checklist of Recent thecideoid brachiopods from the Indian Ocean and Red Sea indicates that members of this superfamily are represented by a small number of species. The subfamily Lacazellinae is represented by Ospreyella maldiviana from the Maldive Islands but the presence of Lacazella cannot yet be confirmed in the Indian Ocean as the holotype of Lacazella mauritiana from Mauritius is lost. The subfamily Thecidellininae is represented by Thecidellina blochmanni from Christmas Island in the eastern Indian Ocean and the Red Sea while a new species T. europa is here described from Europa Island in the Mozambique Channel. The subfamily Minutellinae is represented by Minutella minuta from Samper Bank and Walters Bank in the south-western Indian Ocean and in the Red Sea. Since the holotype of Thecidellina blochmanni from Flying Fish Cove, Christmas Island is also lost, this species is re-described and illustrated mainly from topotypes in the Museum fur Naturkunde, Berlin, from which a suggested neotype has been selected. PMID- 26623896 TI - Towards completion of the early Eocene aviary: A new bird group from the Messel oil shale (Aves, Eopachypterygidae, fam. nov.). AB - A new avian species is described from the early Eocene Messel fossil site in Germany. Eopachypteryx praeterita, gen. et sp. nov. is a small bird and exhibits a characteristic morphology with a short and robust beak, a distinctively shaped coracoid, stout humerus, robust pectoral girdle skeleton, and short hindlimbs. Although similarities to the Paleogene Eocuculus as well as to some extant telluravian and strisorine taxa are noted, the phylogenetic affinities of the new species are unresolved. To account for the fact that the new species is clearly distinguished from any of the known fossil or extant avian taxa, it is here assigned to the new taxon Eopachypterygidae, fam. nov.. Eopachypteryx praeterita is represented by three partial skeletons. A further partial skeleton from Messel belongs to a second, unnamed species, which is tentatively referred to Eopachypteryx. PMID- 26623895 TI - PLusiinae (Excl. Abrostolini) (Lepidoptera: Noctuidae) of Ethiopia. A faunistical survey with biogeographical comments. AB - The extensive survey in different regions of Ethiopia between 1987-1990 and 2005 2011 resulted in the recognition of 39 species of Plusiinae. The majority of the species belong to two large genera, Ctenoplusia (15 species) and Thysanoplusia (16 species). A new synonymy is established, Plusiotricha gorilla (Holland, 1894) is proved to represent the female sex of Plusiotricha livida Holland, 1894 (syn. nov.). The present paper does not include the records of the species of the tribe Abrostolini. Eighteen species are recorded for the first time from Ethiopia. Twenty species of the identified taxa are known only from tropical and subtropical Africa, while the areas of ten species extend from Africa to the Arabian Peninsula or even further to the north. Eight species are widespread not only in Africa but also in the Palearctic and Oriental regions. One species Autographa gamma, a well-known Palearctic pest of different vegetables-is found in the Afrotropical region only in Ethiopia, at medium and high mountain elevations but not in the tropical lowlands. PMID- 26623897 TI - Three new species of myrmecophilous scutacarid mites (Acari: Scutacaridae) from Western Siberia, Russia. AB - Three new species of myrmecophilous mites of the genus Scutacarus Gros, 1845 (Acariformes: Pygmephoroidea: Scutacaridae), S. lasiophilus sp. nov., S. myrmicinus sp. nov., and S. crinitus sp. nov. are described from ants and their nests in Tyumen Province, Western Siberia, Russia. PMID- 26623898 TI - Contribution to the study of Chinese Tersilochinae (Hymenoptera: Ichneumonidae). AB - New data on Chinese Tersilochinae are provided: one species, Tersilochus scutatus sp. n., is described from Liaoning province of China and the Russian Far East, and two species, Barycnemis bellator (Muller) and Tersilochus curvator Horstmann, are new records from China. Thus, this work raises the total number of known Chinese species to 31. Two close species, Diaparsis pulchra Khalaim and D. rara (Horstmann), are compared; specimens previously treated as D. rara, var. from the Russian Far East are found to belong to D. pulchra. Tersilochine faunas of China, South Korea and Primorskiy region of Russia are discussed. The fauna of Palaearctic China is still poorly known, being represented by an equal number of genera and somewhat fewer species than the fauna of South Korea, and it is half the size of the fauna of Primorskiy Region of Russia; the Oriental fauna of China, with only four described species, is virtually unknown. PMID- 26623899 TI - Clistopyga caramba sp. nov. (Hymenoptera: Ichneumonidae; Pimplinae), an astonishing example of mimicry in spider-attacking parasitoid wasps. AB - Clistopyga caramba sp. nov. Castillo & Saaksjarvi, collected from the tropical Andean-Amazonian interface in Peru, is described and illustrated. The new species is characterized by highly modified posterior metasomal tergites and a rare colour pattern of the metasoma. Two possible explanations for the bizarre metasomal morphology and colouration are proposed. PMID- 26623900 TI - The microlepidopterous natural enemy Brachymeria subrugosa Blanchard, 1942 (Hymenoptera, Chalcididae): identity, hosts and geographic distribution. AB - A lectotype is designated for Brachymeria subrugosa Blanchard 1942 (Hymenoptera: Chalcididae). The species is diagnosed, redescribed, and compared to B. subconica Boucek, both of which are illustrated by macrophotography. Taxonomic notes, new parasitoid/host associations and new geographical records are also given for B. subrugosa. Brachymeria annulipes (Costa Lima 1919), a junior secondary homonymy of Chalcis annulipes Walker 1834, is proposed as a junior synonym of B. subrugosa syn. nov. PMID- 26623901 TI - A systematic study of Ichneumonosoma de Meijere, Pelmatops Enderlein, Pseudopelmatops Shiraki and Soita Walker (Diptera: Tephritidae). AB - Four fruit fly genera, Ichneumonosoma de Meijere, Pelmatops Enderlein, Pseudopelmatops Shiraki and Soita Walker, were studied and 19 species are recognized. Three new species, Soita infuscata Chen & Norrbom, Ichneumonosoma quadripunctata Chen & Freidberg, and I. triangularis Chen & Norrbom are described and illustrated. Ichneumonosoma and Soita are revised, and keys to all the species are provided. Ichneumonosoma imitans (de Meijere) is newly recorded from Thailand. One new synonym is established: Soita Walker = Xaniosternum Enderlein, and Xaniosternum ophioneum Enderlein is moved from Xaniosternum to Soita (n. comb.). In addition, new morphological, geographic and biological information for two stalk-eyed fruit fly genera, Pelmatops and Pseudopelmatops, are provided. Pelmatops fukienensis Zia & Chen is newly recorded from Burma, Pelmetops ichneumoneus (Westwood) is newly recorded from Thailand and Burma, Pseudopelmatops angustifasciatus Zia & Chen is newly recorded from Vietnam, and the male of P. angustifasciatus is described and illustrated for the first time. The morphology of the compound eye and occipital protuberance of Pelmatops and Pseudopelmatops is described and illustrated for the first time. A cladistic analysis based on morphological characters of adults, a partial molecular analysis using the nuclear 28S rDNA (28S) and the mitochondrial cytochrome c oxidase I (COI) genes and a combined dataset were conducted to reconstruct the phylogeny of the four genera and their species. The results showed good support for monophyly of each of the four genera and the clade of the stalk-eyed fruit flies (Pelmatops + Pseudopelmatops). However, relationships of the stalk-eyed fruit flies with Soita and Ichneumonosoma are not clearly resolved, with the morphological analysis indicating that Ichneumonosoma is the sister group of the stalk-eyed fruit flies, but the 28S analysis and the combined analysis group Soita closer to the stalk-eyed fruit flies. Regarding relationships amongst congeners, Pelmatops was well resolved; Ichneumonosoma and Soita were partly resolved, and Pseudopelmatops was unresolved. In addition, a hypothesis about the biology of Pseudopelmatops and its relationship with Sesiidae (Lepidoptera) is discussed. PMID- 26623902 TI - Taxonomy of recent Adeonidae (Bryozoa, Cheilostomata) from Brazil, with the description of four new species. AB - Here we present the taxonomy of the cheilostome genera Adeonellopsis MacGillivray, 1886 and Reptadeonella Busk, 1884 in Brazil. Of the six species previously reported in Brazilian waters, we include redescriptions of Adeonellopsis subsulcata (Smitt, 1873), Reptadeonella bipartita (Canu & Bassler, 1928) and Reptadeonella costulata (Canu & Bassler, 1928). Four new species of Reptadeonella are described: Reptadeonella aspera n. sp., Reptadeonella brasiliensis n. sp. (previously misidentified as Reptadeonella violacea), Reptadeonella cucullata n. sp. and Reptadeonella leilae n. sp. Reptadeonella aspera n. sp., from Bahia State, is characterized by rugose frontal calcification, a tubular peristome, small suboral avicularium and elliptical spiramen. Reptadeonella brasiliensis n. sp. is the commonest intertidal species in NE Brazil; it is distinguished from other Brazilian Reptadeonella in having a nodular peristome, large subperistomial areolar pore and zooids with one or two frontal pores frequently replaced by a suboral avicularium and crescentic spiramen. Reptadeonella cucullata n. sp., from Espirito Santo and Bahia states, has a hood-like peristome, large subperistomial areolar pore, suboral avicularium with curved mandible and denticulate spiramen. Reptadeonella leilae n. sp., described from Bahia State, has a frontal shield with small granules, tubular peristome, semilunar to semicircular subperistomial areolar pore and circular spiramen. Diagnostic characters of Reptadeonella species are discussed. PMID- 26623903 TI - European Rhogogaster s. str., with notes on several Asian species (Hymenoptera: Tenthredinidae). AB - The European Rhogogaster s. str. species are revised, and several nominal taxa from Asia discussed. The taxonomic identity of the type species Tenthredo viridis Linnaeus, 1758 is different from that assumed in the past. Tenthredo dryas Benson, 1943 is syn. nov. of R. viridis. The name Rhogogaster scalaris (Klug, 1817), species revocata, is to be applied to Rhogogaster viridis auct. New subjective junior synonyms of R. scalaris (Klug, 1817) are R. chlorosoma podkumokensis Muche, 1973, syn. nov. and Tenthredo (Rhogogaster) carpatica Zhelochovtsev & Zinovjev, 1988, syn. nov. Rhogogaster magniserrula Viitasaari, spec. nov. is described from Finland and Russia. The former synonym of R. viridis auct., Tenthredo hebraica Geoffroy in Fourcroy, 1785, is treated as species incertae sedis within Rhogogaster. The Asian Rhogogaster viridis var. sibirica Enslin, 1912, is regarded as a valid species, Rhogogaster sibirica Enslin, 1912, stat. nov., and Rhogogaster kudiana Rohwer, 1925, is a subjective syn. nov. of R. sibirica. A key to the European Rhogogaster s. str. with special emphasis on Fennoscandia is given.The following nominal taxa are excluded from Rhogogaster: Rhogogaster viridis forma montana Betrem, 1933, is syn. nov. of Tenthredo olivacea Klug, 1817; Sciapteryx virescens Jakowlew, 1887, is Tenthredo (Eurogaster) virescens (Jakowlew, 1887), comb. nov.; Tenthredo interrupta Fabricius, 1804 (nomen oblitum) is syn. nov. of Tenthredopsis tessellata (Klug, 1817) (nomen protectum). Tenthredo viridis Poda, 1761, Tenthredo straminea Schrank, 1776, Tenthredo annalicornis [sic!] Gmelin, 1790, and Tenthredo chloros Rudow, 1871 are considered to be species incertae sedis within Tenthredinidae.Lectotypes are designated for Tenthredo interrupta Fabricius, 1804, Sciapteryx virescens Jakowlew, 1887, Sciopteryx gilva Konow, 1908, Rhogogaster viridis var. sibirica Enslin, 1912, R. viridis forma montana Betrem, 1933, R. chlorosoma podkumokensis Muche, 1973, R. genistae viridifrons Muche, 1973 and Tenthredo (Rhogogaster) carpatica "Bokotey" [= Zhelochovtsev & Zinovjev], 1988. PMID- 26623904 TI - New records of two species of the coral reef shrimp genus Thor Kingsley, 1878 (Crustacea: Decapoda: Thoridae) from the Ryukyu Islands, Japan. AB - The caridean shrimp genus Thor Kingsley, 1878 (Thoridae) is currently represented by 14 species distributed in shallow tropical to subtropical waters in the Indo Pacific, East Pacific and West Atlantic oceans. In this study, two species of the genus are reported on the basis of material from Okinawa and Kume islands in the Ryukyu Archipelago, southern Japan. Thor leptochelus (Xu & Li, 2015) n. comb., recently described from Xisha Islands, China and originally assigned to Thinora Bruce, 1997, is transferred to Thor. Relationship of the species to three congeneric species (T. cordelli Wicksten, 1996, T. spinipes Bruce, 1983 and T. spinosus Boone, 1935) is discussed. The second is T. marguitae Bruce, 1973, representing the rediscovery since the original description and new record for Japanese waters. The four specimens of T. leptochelus were all free-living, whereas the single specimen of T. marguitae was found to be associated with a solitary fungiid coral, as previously reported. PMID- 26623905 TI - A new leech species (Hirudinida: Erpobdellidae: Erpobdella) from a cave in the West Azerbaijan province of Iran. AB - Erpobdella borisi n. sp. is a predatory leech inhabiting cave waters in Iran. Probably, it is either a troglobiont or troglophile. The leech has no eyes, and the complete mid-body somite is divided unequally into five annuli. Results of phylogenetic analysis based on morphological characters and COI gene sequence indicate the species to be closely related to Erpobdella japonica, E. octoculata and E. testacea. PMID- 26623906 TI - Review of the Iranian Pteromalinae with spiculated antennae, and description of a new species of Norbanus Walker (Hymenoptera: Chalcidoidea, Pteromalidae). AB - Based on recently collected Pteromalidae (Hymenoptera: Chalcidoidea), 13 species were identified from genera of Pteromalinae that are characterized in part by the female clava being distinctly acuminate or apically bearing a narrow spicula. Included are two species of Callitula Spinola, three species of Homoporus Thomson, seven species of Norbanus Walker, and one species of Rhaphitelus Walker. One new species, Norbanus rasplusi n. sp., is described and six species are newly recorded from Iran: Homoporus subniger (Walker), Norbanus calabrus (Masi), N. cerasiops (Masi), N. meridionalis (Masi), N. obscurus (Masi) and N. scabriculus (Nees). PMID- 26623907 TI - A new species of Amusurgus (Usgmona) Furukawa from China (Orthoptera: Gryllidae: Trigonidiinae). AB - Amusurgus (Usgmona) excavatus Liu, Shi et Zhou, sp. nov. (China, Fujian) is described and illustrated with the male genitalia. Photos of habitus and ecological habitat are also included. PMID- 26623908 TI - Stenoloba ronkayi Sohn & Tzuoo 2012--a new homonym of S. ronkayi Behounek & Kononenko, 2010 and new synonym of S. glauca Kononenko & Ronkay 2001. A postscript to the revision of Chinese Stenoloba (Lepidoptera, Noctuidae). PMID- 26623909 TI - Scydmoraphes rothangensis Franz, a misplaced Himalayan species of Cyrtoscydmini (Coleoptera, Staphylinidae, Scydmaeninae). AB - Based on examination of the type series, Scydmoraphes rothangensis Franz is transferred to Stenichnus Thomson, resulting in Stenichnus (s. str.) rothangensis (Franz) comb. n. Structural details of this intriguing Himalayan species are illustrated in detail and compared with those of allied genera, and a redescription is given. PMID- 26623910 TI - Caurinus dectes Russell (Mecoptera: Boreidae: Caurininae) a range extension in Oregon and a new state record in Washington. PMID- 26623911 TI - Revision of Palearctic and Oriental Necrophila Kirby et Spence, part 3: subgenus Calosilpha Portevin (Coleoptera: Silphidae: Silphinae). AB - A taxonomic revision of the subgenus Calosilpha Portevin, 1920 (of the genus Necrophila Kirby & Spence, 1828) through Asia is presented. Four valid species are recognized: (1) Necrophila (C.) brunnicollis (Kraatz, 1877), widely distributed from Bhutan and China: Yunnan province to Far East of Russia and Japan (including Ryukyu Islands); (2) N. (C.) cyaneocephala (Portevin, 1914), endemic to Taiwan; (3) N. (C.) cyaniventris (Motschulsky, 1870), widely distributed from northern India to Vietnam and southern China (east to Hainan Island); and (4) N. (C.) ioptera (Kollar & Redtenbacher, 1844), comb. nov. (ex Calosilpha), widely distributed in Pakistan, India (Himachal Pradesh to Assam) and Nepal. Eusilpha (Calosilpha) bicolor imasakai Nishikawa, 1986 and Eusilpha (Calosilpha) kurosawai Nishikawa, 1986 are confirmed as junior subjective synonyms (sensu Cho & Lee 1995, Ji 2012) of Silpha brunnicollis Kraatz, 1877. Description of important adult taxonomic characters (including male genitalia) and a key to species is included. Georeferenced records for all four species are mapped. First reliable records of Necrophila (Calosilpha) brunnicollis from China: Hong Kong and Anhui, Fujian, Gansu, Hubei, Jiangxi, Jilin, Qinghai and Zheijiang provinces and Guangxi autonomous region; N. (C.) cyaniventris from India: Himachal Pradesh, Uttarakhand, Meghalaya, Arunachal Pradesh, Nagaland and Manipur; and N. (C.) ioptera from Pakistan, India: Uttarakhand, Uttar Pradesh, Bihar, Sikkim, West Bengal and Assam are given (only imprecise records from "Himalaya" had been published for the last two species). First records of N. (C.) brunnicollis from Bhutan, and of N. (C.) cyaniventris from China: Hainan and Yunnan provinces, Myanmar, Laos and Cambodia are given. Parsimony analysis supports the monophyly of Calosilpha, with two clades, one formed by N. (C.) brunnicollis and N. (C.) cyaneocephala and the other by N. (C.) cyaniventris and N. (C.) ioptera. Geometric morphometrics discriminated four taxa of Necrophila (Calosilpha). Results indicated a sexual dimorphism between sexes in all species. Shape variability was concluded between the taxa. Populations of N. (C.) brunnicollis from continental Asia and three regions of Japan (Honshu + Shikoku, Kyushu and Ryukyus) also were examined. MANOVA was significant and supported shape differences in male and female populations. When testing each pair of groups by discriminant analysis, only differences between male populations from Japan (Kyushu) and those from Japan (Honshu + Shikoku) showed insignificance. PMID- 26623912 TI - Four new species of Brueelia Keler, 1936 (Phthiraptera: Ischnocera: Philopteridae) from African songbirds (Passeriformes: Sturnidae and Laniidae). AB - Four new species in the louse genus Brueelia Keler, 1936 are described from African hosts of the families Sturnidae and Laniidae. They are: Brueelia rigbyi n. sp. ex Corvinella melanoleuca (Jardine, 1831), B. clara n. sp. ex Lamprotornis australis (A. Smith, 1836), B. tkachi n. sp. ex Spreo albicapillus albicapillus Blyth, 1856, and B. coryliventer n. sp. ex Creatophora cinerea (Meuschen, 1787). These four species are characterized by a unique abdominal chaetotaxy and a sinuous thickening of the distal margin of the male mesosome. These four species are very similar, and we consider them to form one species group. A key to the species of the group is provided. PMID- 26623913 TI - Two new Bdellidae (Trombidiformes: Bdelloidea) from Iran and the status of Neobiscirus Gomelauri, 1963. AB - Two new Bdellidae, Biscirus iranensis Paktinat-Saeej & Bagheri sp. nov. and Bdella farabii Paktinat-Saeej & Bagheri sp. nov., are described from northern Iran. The monotypic genus Neobiscirus considered a junior synonym of Biscirus, and its only species therefore considered Biscirus kobachidzei (Gomelauri, 1963) comb. nov. PMID- 26623915 TI - Review of the Australian wolf spider genus Venator (Araneae, Lycosidae). AB - Species of the Australian wolf spider genus Venator are reviewed including the type species, V. spenceri Hogg, 1900, from south-eastern Australia and V. immansuetus (Simon, 1909) comb. nov., a common species in south-west Western Australia. Venator marginatus Hogg, 1900 is only known from two female specimens and the genital morphology of this species does not conform to the diagnosis of genus as presented here. Therefore V. marginatus is considered incerta sedis. Venator includes medium-sized (9.0-22 mm body length) wolf spiders of overall brownish colouration, and with a black patch covering the anterior three quarters of the venter. They differ from all other wolf spiders in particular by genitalic characters, namely an elevated atrium of the female epigyne that forms a raised edged against the inverted T-shaped median septum. This edge often corresponds to a retrolateral incision on the tegular apophysis of the male pedipalp. The genus is mainly a representative of the Bassian fauna of the Australian continent where it occurs predominantly in dry sclerophyll forests. PMID- 26623914 TI - Litarcturus kexueiae sp. nov., a new deep-sea isopod from the Okinawa Trough (Crustacea, Isopoda, Valvifera, Antarcturidae). AB - A new species of the genus Litarcturus Brandt, 1990, L. kexueiae sp. nov., collected from deep sea of the Okinawa Trough, is described and illustrated. It is readily distinguished from the other seven species of the genus by bearing long supraocular spines about as long as the head and posterolateral pleotelsonic spines overreaching the pleotelson apex. PMID- 26623916 TI - First record of the genus Acropimpla Townes, 1960 (Hymenoptera: Ichneumonidae: Pimplinae) from Thailand, with descriptions of three new species. AB - Nine species of Acropimpla Townes, 1960 are recorded from Thailand with three species described as new: A. leoni sp.n., A. natae sp.n., A. patellalutea sp.n. Six species, A. aspera Gupta & Tikar, 1976, A. hapaliae (Rao, 1953), A. leucostoma (Cameron, 1907), A. nakula Gupta & Tikar, 1976, A. taishunensis Liu, He & Chen, 2010, and A. uchidai (Cushman, 1933) are recorded from Thailand for the first time. A key to the females of Acropimpla species in South East Asia is also provided. PMID- 26623917 TI - New species of the genus Phaonia R.-D., 1830 (Diptera, Muscidae) from Central Asia. AB - A list of species of Phaonia Robineau-Desvoidy, 1830 of Central Asia is given, and four new species of Phaonia are described from Tajikistan, Uzbekistan and Turkmenistan (P. babarabica sp. nov., P. juglans sp. nov., P. modesta sp. nov. and P. ninae sp. nov.). The male terminalia of all species and ovipositors of P. ninae sp. nov. and P. modesta sp. nov. are figured. Previous literature on the genus Phaonia in Central Asia is reviewed. PMID- 26623918 TI - A new species of Alopecosa Simon, 1885 (Araneae, Lycosidae) from the Altai Mountains (South Siberia, Russia). PMID- 26623919 TI - A new species of subgenus Eulandrevus Gorochov, 1988 (Orthoptera: Gryllidae: Landrevinae) from China. AB - Duolandrevus crickets are brown, smooth, shiny and bear reduced tegmina. They are forest species and have an equatorial distribution. Only the subgenus Eulandrevus of this genus, containing three species, has been recorded from China. Here, an additional species is described, recently discovered on Hainan Island, China. This species is similar to Duolandrevus (Eulandrevus) hongkongae Otte, 1988, but differs in body size and details of the elytra and genitalia. The description and illustrations of the new species Duolandrevus hainanensis are provided. PMID- 26623920 TI - ALBERT G. ORR & RORY A. DOW (2015) Description of two final stadium platystictid larvae from Borneo, including that of Drepanosticta ?attala Lieftinck, identified using DNA barcoding (Odonata: Zygoptera: Platystictidae). Zootaxa, 3985 (4): 565 574. PMID- 26623921 TI - Taxonomic status and morphological variation of Hydrodynastes bicinctus (Hermann, 1804) (Serpentes: Dipsadidae). AB - Hydrodynastes bicinctus was described with no type material or locality and it has two subspecies currently recognized that are not taxonomically well defined. We tested the validity of the two subspecies through meristic, morphometric, and color pattern characters. Two apparently distinct color patterns of H. bicinctus were noticed, one from the Cerrado open formations and the other from the Amazon rainforest. These aforementioned patterns, however, exhibited a high degree of geographic overlap and many specimens showed a blended pattern. Based on these results we propose synonymizing H. bicinctus schultzi with the nominal taxon. Furthermore, we designate a neotype for the species, present data on geographic distribution, and provide morphological descriptions of the hemipenis, cephalic glands, and skull. PMID- 26623923 TI - First-Principles Study of Phosphorene and Graphene Heterostructure as Anode Materials for Rechargeable Li Batteries. AB - There is a great desire to develop the high-efficient anodes materials for Li batteries, which require not only large capacity but also high stability and mobility. In this work, the phosphorene/graphene heterostructure (P/G) was carefully explored based on first-principles calculations. The binding energy of Li on the pristine phosphorene is relatively weak (within 1.9 eV), whereas the phosphorene/graphene heterostructure (P/G) can greatly improve the binding energy (2.6 eV) without affecting the high mobility of Li within the layers. The electronic structures show that the large Li adsorption energy and fast diffusion ability of the P/G origin from the interfacial synergy effect. Interestingly, the P/G also displays ultrahigh stiffness (Cac = 350 N/m, Czz = 464 N/m), which can effectively avoid the distortion of the pristine phosphorene after the insertion of lithium. Thus, P/G can greatly enhance the cycle life of the battery. Owing to the high capacity, good conductivity, excellent Li mobility, and ultrahigh stiffness, P/G is a very promising anode material in Li-ion batteries (LIBs). PMID- 26623924 TI - Assessment of Metal Toxicity in Marine Ecosystems: Comparative Toxicity Potentials for Nine Cationic Metals in Coastal Seawater. AB - This study is a first attempt to develop globally applicable and spatially differentiated marine comparative toxicity potentials (CTPs) or ecotoxicity characterization factors for metals in coastal seawater for use in life cycle assessment. The toxicity potentials are based exclusively on marine ecotoxicity data and take account of metal speciation and bioavailability. CTPs were developed for nine cationic metals (Cd, Cr(III), Co, Cu(II), Fe(III), Mn, Ni, Pb, and Zn) in 64 large marine ecosystems (LMEs) covering all coastal waters in the world. The results showed that the CTP of a specific metal varies 3-4 orders of magnitude across LMEs, largely due to different seawater residence times. Therefore, the highest toxicity potential for metals was found in the LMEs with the longest seawater residence times. Across metals, the highest CTPs were observed for Cd, Pb, and Zn. At the concentration levels occurring in coastal seawaters, Fe acts not as a toxic agent but as an essential nutrient and thus has CTPs of zero. PMID- 26623925 TI - Targeting the NLRP3 Inflammasome to Reduce Diet-Induced Metabolic Abnormalities in Mice. AB - Although the molecular links underlying the causative relationship between chronic low-grade inflammation and insulin resistance are not completely understood, compelling evidence suggests a pivotal role of the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Here we tested the hypothesis that either a selective pharmacological inhibition or a genetic downregulation of the NLRP3 inflammasome results in reduction of the diet-induced metabolic alterations. Male C57/BL6 wild type mice and NLRP3-/- littermates were fed control diet or high-fat, high fructose diet (HD). A subgroup of HD-fed wild-type mice was treated with the NLRP3 inflammasome inhibitor BAY 11-7082 (3 mg/kg intraperitoneally [IP]). HD feeding increased plasma and hepatic lipids and impaired glucose homeostasis and renal function. Renal and hepatic injury was associated with robust increases in profibrogenic markers, while only minimal fibrosis was recorded. None of these metabolic abnormalities were detected in HD-fed NLRP3-/- mice, and they were dramatically reduced in HD-mice treated with the NLRP3 inflammasome inhibitor. BAY 11-7082 also attenuated the diet-induced increase in NLRP3 inflammasome expression, resulting in inhibition of caspase-1 activation and interleukin (IL) 1beta and IL-18 production (in liver and kidney). Interestingly, BAY 11-7082, but not gene silencing, inhibited nuclear factor (NF)-kappaB nuclear translocation. Overall, these results demonstrate that the selective pharmacological modulation of the NLRP3 inflammasome attenuates the metabolic abnormalities and the related organ injury/dysfunction caused by chronic exposure to HD, with effects similar to those obtained by NLRP3 gene silencing. PMID- 26623926 TI - Early and Short-term Triiodothyronine Supplementation Prevents Adverse Postischemic Cardiac Remodeling: Role of Transforming Growth Factor-beta1 and Antifibrotic miRNA Signaling. AB - Activation of transforming growth factor (TGF)-beta1 signaling in the ischemia/reperfusion (I/R) injured myocardium leads to dysregulation of miR-29-30 133, favoring the profibrotic process that leads to adverse cardiac remodeling (CR). We have previously shown that timely correction of the postischemic low-T3 syndrome (Low-T3S) exerts antifibrotic effects, but the underlying molecular players are still unknown. Here we hypothesize that a prompt, short-term infusion of T3 in a rat model of post I/R Low-T3S could hamper the early activation of the TGFbeta1-dependent profibrotic cascade to confer long-lasting cardioprotection against adverse CR. Twenty-four hours after I/R, rats that developed the Low-T3S were randomly assigned to receive a 48-h infusion of 6 MUg/kg/d T3 (I/R-L+T3) or saline (I/R-L) and sacrificed at 3 or 14 d post-I/R. Three days post-I/R, Low-T3S correction favored functional cardiac recovery. This effect was paralleled by a drop in TGFbeta1 and increased miR-133a, miR-30c and miR-29c in the infarcted myocardium. Consistently, connective transforming growth factor (CTGF) and matrix metalloproteinase-2(MMP-2), validated targets of the above miRNAs, were significantly reduced. Fourteen days post-I/R, the I/R-L+T3 rats presented a significant reduction of scar size with a better preservation of cardiac performance and LV chamber geometry. At this time, TGFbeta1 and miR-29c levels were in the normal range in both groups, whereas miR-30c-133a, MMP-2 and CTGF remained significantly altered in the I/R group. In conclusion, the antifibrotic effect exerted by T3 in the early phase of postischemic wound healing triggers a persistent cardioprotective response that hampers the progression of heart dysfunction and adverse CR. PMID- 26623927 TI - Peroxisome Proliferator-Activated Receptor alpha Protects Renal Tubular Cells from Gentamicin-Induced Apoptosis via Upregulating Na+/H+ Exchanger NHE1. AB - Peroxisome proliferator-activated receptor (PPAR)-alpha is a transcription factor that has been reported to inhibit gentamicin-induced apoptosis in renal tubular cells. However, the antiapoptotic mechanism of PPARalpha is still unknown. In this study, we found that PPARalpha overexpression induced Na+/H+ exchanger-1 (NHE1) expression in the rat renal tubular cells NRK-52E. Beraprost, a PPARalpha ligand, also increased NHE1 expression in the renal tubules in normal mice, but not in PPARalpha knockout mice. Chromatin immunoprecipitation assays revealed that two PPARalpha binding elements were located in the rat NHE1 promoter region. Na+/H+ exchanger activity also increased in the PPARalpha-overexpressed cells. Flow cytometry showed that the PPARalpha-overexpressed cells were resistant to apoptosis-induced shrinkage. Cariporide, a selective NHE1 inhibitor, inhibited the antiapoptotic effect of PPARalpha in the gentamicin-treated cells. The interaction between NHE1 and ezrin/radixin/moesin (ERM) and between ERM and phosphatidylinositol 4,5-bisphosphate in the PPARalpha-overexpressed cells was more than in the control cells. ERM short interfering RNA (siRNA) transfection inhibited the PPARalpha-induced antiapoptotic effect. PPARalpha overexpression also increased the phosphoinositide 3-kinase (PI3K) expression, which is dependent on NHE1 activity. Increased PI3K further increased the phosphorylation of the prosurvival kinase Akt in the PPARalpha-overexpressed cells. Wortmannin, a PI3K inhibitor, inhibited PPARalpha-induced Akt activity and the antiapoptotic effect. We conclude that PPARalpha induces NHE1 expression and then recruits ERM to promote PI3K/Akt-mediated cell survival in renal tubular cells. The application of PPARalpha activation reduces the nephrotoxicity of gentamicin and may expand the clinical use of gentamicin. PMID- 26623928 TI - Efficiency transfer using the GEANT4 code of CERN for HPGe gamma spectrometry. AB - In this work we apply the GEANT4 code of CERN to calculate the peak efficiency in High Pure Germanium (HPGe) gamma spectrometry using three different procedures. The first is a direct calculation. The second corresponds to the usual case of efficiency transfer between two different configurations at constant emission energy assuming a reference point detection configuration and the third, a new procedure, consists on the transfer of the peak efficiency between two detection configurations emitting the gamma ray in different energies assuming a "virtual" reference point detection configuration. No pre-optimization of the detector geometrical characteristics was performed before the transfer to test the ability of the efficiency transfer to reduce the effect of the ignorance on their real magnitude on the quality of the transferred efficiency. The obtained and measured efficiencies were found in good agreement for the two investigated methods of efficiency transfer. The obtained agreement proves that Monte Carlo method and especially the GEANT4 code constitute an efficient tool to obtain accurate detection efficiency values. The second investigated efficiency transfer procedure is useful to calibrate the HPGe gamma detector for any emission energy value for a voluminous source using one point source detection efficiency emitting in a different energy as a reference efficiency. The calculations preformed in this work were applied to the measurement exercise of the EUROMET428 project. A measurement exercise where an evaluation of the full energy peak efficiencies in the energy range 60-2000 keV for a typical coaxial p-type HpGe detector and several types of source configuration: point sources located at various distances from the detector and a cylindrical box containing three matrices was performed. PMID- 26623929 TI - Determination of Kalpha,beta excitation factors in thin target for selected elements from Y to Te at 59.54 keV excitation energy. AB - The paper presents the first measurements of the Kalpha and Kbeta excitation factors for some selected elements from Y to Te. To determine the Kalpha and Kbeta excitation factors, the experimental values of K shell X-ray production cross sections and total absorption photoelectric cross sections were used. The measurements were performed using a Si(Li) detector coupled with 2048 multichannel analyzer and an Am-241 annular radioisotope source which is emitted 59.54 keV gamma-photons. It is observed that the Kalpha excitation factors are 5 6 times larger than the Kbeta excitation factors. The measured excitation factors were compared only with theoretical calculated ones since there are no other experimental reports for the present elements in the literature. The present experimental values of Kalpha and Kbeta excitation factors are in satisfactory agreement with the theoretical results. PMID- 26623930 TI - Fluence to local skin absorbed dose and dose equivalent conversion coefficients for monoenergetic positrons using Monte-Carlo code MCNP6. AB - Conversion coefficients fluence to local skin equivalent dose, as introduced in ICRP Publication 116, 2010, are calculated for positrons of energies ranging from 10 keV to 10 MeV using the code MCNP6. Fluence to dose equivalent conversion coefficients H'(0.07,0 degrees )/Phi are calculated for positrons of energy ranging between 20 keV and 10 MeV. A comparison between operational dose quantity H'(0.07,0 degrees ) and the Local-Skin equivalent Dose shows an overall good agreement between these two quantities, except between 60 keV and 100 keV. PMID- 26623931 TI - Dissolution of [226Ra]BaSO4 and partial separation of 226Ra from radium/barium sulfate: A new treatment method for NORM waste from petroleum industry. AB - Complete dissolution of [(226)Ra]BaSO4 precipitate was successfully performed using NaNO2 as a reducing agent in acidic solution at room temperature. Results showed a significant effect of acid and NaNO2 concentrations and temperature on the dissolution efficiency. The method was successfully used for separation of radium from NORM scale samples from the petroleum industry; sufficient volume reduction of NORM waste was achieved. The obtained (226)Ra solution was purified using two separation methods. The dissolution method can be of great interest in the development of radiochemical analysis of radium isotopes. PMID- 26623932 TI - Correction to The Semiquinone at the Q(i) Site of the bc1 Complex Explored Using HYSCORE Spectroscopy and Specific Isotopic Labeling of Ubiquinone in Rhodobacter sphaeroides via (13)C Methionine and Construction of a Methionine Auxotroph. PMID- 26623933 TI - Characterization of the novel dimethyl sulfide-degrading bacterium Alcaligenes sp. SY1 and its biochemical degradation pathway. AB - Recently, the biodegradation of volatile organic sulfur compounds (VOSCs) has become a burgeoning field, with a growing focus on the reduction of VOSCs. The reduction of VOSCs encompasses both organic emission control and odor control. Herein, Alcaligenes sp. SY1 was isolated from active sludge and found to utilize dimethyl sulfide (DMS) as a growth substrate in a mineral salt medium. Response surface methodology (RSM) analysis was applied to optimize the incubation conditions. The following conditions for optimal degradation were identified: temperature 27.03 degrees C; pH 7.80; inoculum salinity 0.84%; and initial DMS concentration 1585.39 MUM. Under these conditions, approximately 99% of the DMS was degraded within 30 h of incubation. Two metabolic compounds were detected and identified by gas chromatography-mass spectrometry (GC-MS): dimethyl disulfide (DMDS) and dimethyl trisulfide (DMTS). The DMS degradation kinetics for different concentrations were evaluated using the Haldane-Andrews model and the pseudo first-order model. The maximum specific growth rate and degradation rate of Alcaligenes sp. SY1 were 0.17 h(-1) and 0.63 gs gx(-1)h(-1). A possible degradation pathway is proposed, and the results suggest that Alcaligenes sp. SY1 has the potential to control odor emissions under aerobic conditions. PMID- 26623934 TI - Packaging Glass with a Hierarchically Nanostructured Surface: A Universal Method to Achieve Self-Cleaning Omnidirectional Solar Cells. AB - Fused-silica packaging glass fabricated with a hierarchical structure by integrating small (ultrathin nanorods) and large (honeycomb nanowalls) structures was demonstrated with exceptional light-harvesting solar performance, which is attributed to the subwavelength feature of the nanorods and an efficient scattering ability of the honeycomb nanowalls. Si solar cells covered with the hierarchically structured packaging glass exhibit enhanced conversion efficiency by 5.2% at normal incidence, and the enhancement went up to 46% at the incident angle of 60 degrees . The hierarchical structured packaging glass shows excellent self-cleaning characteristics: 98.8% of the efficiency is maintained after 6 weeks of outdoor exposure, indicating that the nanostructured surface effectively repels polluting dust/particles. The presented self-cleaning omnidirectional light-harvesting design using the hierarchical structured packaging glass is a potential universal scheme for practical solar applications. PMID- 26623935 TI - Volatile organic compounds and Photobacterium phosphoreum associated with spoilage of modified-atmosphere-packaged raw pork. AB - Accumulation of volatile organic compounds was monitored in association with sensory quality, bacterial concentrations and culture-independent microbial community analyses in raw pork loin and pork collar during storage under high oxygen modified atmosphere at +4 degrees C. Of the 48 volatile compounds detected in the pork samples, the levels of acetoin, diacetyl and 3-methyl-1 butanol had the highest correlations with the sensory scores and bacterial concentrations. These compounds accumulated in all of the four monitored lots of non-sterile pork but not in the sterilized pork during chilled storage. According to the culture-dependent and culture-independent characterization of bacterial communities, Brochothrix thermosphacta, lactic acid bacteria (Carnobacterium, Lactobacillus, Lactococcus, Leuconostoc, Weissella) and Photobacterium spp. predominated in pork samples. Photobacterium spp., typically not associated with spoilage of meat, were detected also in 8 of the 11 retail packages of pork investigated subsequently. Eleven isolates from the pork samples were shown to belong to Photobacterium phosphoreum by phenotypic tests and sequencing of the 16S rRNA and gyrB gene fragments. Off-odors in pork samples with high proportion of Photobacterium spp. were associated with accumulation of acetoin, diacetyl and 3-methyl-1-butanol in meat, but these compounds did not explain all the off-odors reported in sensory analyses. PMID- 26623936 TI - CD40 Generation 2.5 Antisense Oligonucleotide Treatment Attenuates Doxorubicin induced Nephropathy and Kidney Inflammation. AB - Preclinical and clinical data suggest CD40 activation contributes to renal inflammation and injury. We sought to test whether upregulation of CD40 in the kidney is a causative factor of renal pathology and if reduction of renal CD40 expression, using antisense oligonucleotides (ASOs) targeting CD40, would be beneficial in mouse models of glomerular injury and unilateral ureter obstruction. Administration of a Generation 2.5 CD40 ASO reduced CD40 mRNA and protein levels 75-90% in the kidney. CD40 ASO treatment mitigated functional, transcriptional, and pathological endpoints of doxorubicin-induced nephropathy. Experiments using an activating CD40 antibody revealed CD40 is primed in kidneys following doxorubicin injury or unilateral ureter obstruction and CD40 ASO treatment blunted CD40-dependent renal inflammation. Suborgan fractionation and imaging studies demonstrated CD40 in glomeruli before and after doxorubicin administration that becomes highly enriched within interstitial and glomerular foci following CD40 activation. Such foci were also sites of ASO distribution and activity and may be predominately comprised from myeloid cells as bone marrow CD40 deficiency sharply attenuated CD40 antibody responses. These studies suggest an important role of interstitial renal and/or glomerular CD40 to augment kidney injury and inflammation and demonstrate that ASO treatment could be an effective therapy in such disorders. PMID- 26623937 TI - Evaluation of 2'-Deoxy-2'-fluoro Antisense Oligonucleotides for Exon Skipping in Duchenne Muscular Dystrophy. AB - Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder typically caused by frame-shifting mutations in the DMD gene. Restoration of the reading frame would allow the production of a shorter but partly functional dystrophin protein as seen in Becker muscular dystrophy patients. This can be achieved with antisense oligonucleotides (AONs) that induce skipping of specific exons during pre-mRNA splicing. Different chemical modifications have been developed to improve AON properties. The 2'-deoxy-2'-fluoro (2F) RNA modification is attractive for exon skipping due to its ability to recruit ILF2/3 proteins to the 2F/pre-mRNA duplex, which resulted in enhanced exon skipping in spinal muscular atrophy models. In this study, we examined the effect of two different 2' substituted AONs (2'-F phosphorothioate (2FPS) and 2'-O-Me phosphorothioate (2OMePS)) on exon skipping in DMD cell and animal models. In human cell cultures, 2FPS AONs showed higher exon skipping levels than their isosequential 2OMePS counterparts. Interestingly, in the mdx mouse model, 2FPS was less efficient than 2OMePS and suggested safety issues as evidenced by increased spleen size and weight loss. Our results do not support a clinical application for 2FPS AON. PMID- 26623938 TI - Hydrophobically Modified siRNAs Silence Huntingtin mRNA in Primary Neurons and Mouse Brain. AB - Applications of RNA interference for neuroscience research have been limited by a lack of simple and efficient methods to deliver oligonucleotides to primary neurons in culture and to the brain. Here, we show that primary neurons rapidly internalize hydrophobically modified siRNAs (hsiRNAs) added directly to the culture medium without lipid formulation. We identify functional hsiRNAs targeting the mRNA of huntingtin, the mutation of which is responsible for Huntington's disease, and show that direct uptake in neurons induces potent and specific silencing in vitro. Moreover, a single injection of unformulated hsiRNA into mouse brain silences Htt mRNA with minimal neuronal toxicity. Thus, hsiRNAs embody a class of therapeutic oligonucleotides that enable simple and straightforward functional studies of genes involved in neuronal biology and neurodegenerative disorders in a native biological context. PMID- 26623939 TI - Electroporation Enhanced Effect of Dystrophin Splice Switching PNA Oligomers in Normal and Dystrophic Muscle. AB - Peptide nucleic acid (PNA) is a synthetic DNA mimic that has shown potential for discovery of novel splice switching antisense drugs. However, in vivo cellular delivery has been a limiting factor for development, and only few successful studies have been reported. As a possible modality for improvement of in vivo cellular availability, we have investigated the effect of electrotransfer upon intramuscular (i.m.) PNA administration in vivo. Antisense PNA targeting exon 23 of the murine dystrophin gene was administered by i.m. injection to the tibialis anterior (TA) muscle of normal NMRI and dystrophic mdx mice with or without electroporation. At low, single PNA doses (1.5, 3, or 10 ug/TA), electroporation augmented the antisense exon skipping induced by an unmodified PNA by twofold to fourfold in healthy mouse muscle with optimized electric parameters, measured after 7 days. The PNA splice switching was detected at the RNA level up to 4 weeks after a single-dose treatment. In dystrophic muscles of the MDX mouse, electroporation increased the number of dystrophin-positive fibers about 2.5-fold at 2 weeks after a single PNA administration compared to injection only. In conclusion, we find that electroporation can enhance PNA antisense effects in muscle tissue. PMID- 26623940 TI - Mitigating ammonia nitrogen deficiency in dairy wastewaters for algae cultivation. AB - This study demonstrated that the limiting factor to algae growth on dairy wastewater was the ammonia nitrogen deficiency. Dairy wastewaters were mixed with a slaughterhouse wastewater that has much higher ammonia nitrogen content. The results showed the mixing wastewaters improved the nutrient profiles and biomass yield at low cost. Algae grown on mixed wastewaters contained high protein (55.98 66.91%) and oil content (19.10-20.81%) and can be exploited to produce animal feed and biofuel. Furthermore, algae grown on mixed wastewater significantly reduced nutrient contents remained in the wastewater after treatment. By mitigating limiting factor to algae growth on dairy wastewaters, the key issue of low biomass yield of algae grown on dairy wastewaters was resolved and the wastewater nutrient removal efficiency was significantly improved by this study. PMID- 26623941 TI - Single-Point Mutation with a Rotamer Library Toolkit: Toward Protein Engineering. AB - Protein engineers have long been hard at work to harness biocatalysts as a natural source of regio-, stereo-, and chemoselectivity in order to carry out chemistry (reactions and/or substrates) not previously achieved with these enzymes. The extreme labor demands and exponential number of mutation combinations have induced computational advances in this domain. The first step in our virtual approach is to predict the correct conformations upon mutation of residues (i.e., rebuilding side chains). For this purpose, we opted for a combination of molecular mechanics and statistical data. In this work, we have developed automated computational tools to extract protein structural information and created conformational libraries for each amino acid dependent on a variable number of parameters (e.g., resolution, flexibility, secondary structure). We have also developed the necessary tool to apply the mutation and optimize the conformation accordingly. For side-chain conformation prediction, we obtained overall average root-mean-square deviations (RMSDs) of 0.91 and 1.01 A for the 18 flexible natural amino acids within two distinct sets of over 3000 and 1500 side chain residues, respectively. The commonly used dihedral angle differences were also evaluated and performed worse than the state of the art. These two metrics are also compared. Furthermore, we generated a family-specific library for kinases that produced an average 2% lower RMSD upon side-chain reconstruction and a residue-specific library that yielded a 17% improvement. Ultimately, since our protein engineering outlook involves using our docking software, Fitted/Impacts, we applied our mutation protocol to a benchmarked data set for self- and cross docking. Our side-chain reconstruction does not hinder our docking software, demonstrating differences in pose prediction accuracy of approximately 2% (RMSD cutoff metric) for a set of over 200 protein/ligand structures. Similarly, when docking to a set of over 100 kinases, side-chain reconstruction (using both general and biased conformation libraries) had minimal detriment to the docking accuracy. PMID- 26623942 TI - Trends in mental health inequalities in England during a period of recession, austerity and welfare reform 2004 to 2013. AB - Several indicators of population mental health in the UK have deteriorated since the financial crisis, during a period when a number of welfare reforms and austerity measures have been implemented. We do not know which groups have been most affected by these trends or the extent to which recent economic trends or recent policies have contributed to them. We use data from the Quarterly Labour Force Survey to investigate trends in self reported mental health problems by socioeconomic group and employment status in England between 2004 and 2013. We then use panel regression models to investigate the association between local trends in mental health problems and local trends in unemployment and wages to investigate the extent to which these explain increases in mental health problems during this time. We found that the trend in the prevalence of people reporting mental health problems increased significantly more between 2009 and 2013 compared to the previous trends. This increase was greatest amongst people with low levels of education and inequalities widened. The gap in prevalence between low and high educated groups widened by 1.29 percentage points for women (95% CI: 0.50 to 2.08) and 1.36 percentage points for men (95% CI: 0.31 to 2.42) between 2009 and 2013. Trends in unemployment and wages only partly explained these recent increases in mental health problems. The trend in reported mental health problems across England broadly mirrored the pattern of increases in suicides and antidepressant prescribing. Welfare policies and austerity measures implemented since 2010 may have contributed to recent increases in mental health problems and widening inequalities. This has led to rising numbers of people with low levels of education out of work with mental health problems. These trends are likely to increase social exclusion as well as demand for and reliance on social welfare systems. PMID- 26623943 TI - Feature description with SIFT, SURF, BRIEF, BRISK, or FREAK? A general question answered for bone age assessment. AB - Solving problems in medical image processing is either generic (being applicable to many problems) or specific (optimized for a certain task). For example, bone age assessment (BAA) on hand radiographs is a frequent but cumbersome task for radiologists. For this problem, many specific solutions have been proposed. However, general-purpose feature descriptors are used in many computer vision applications. Hence, the aim of this study is (i) to compare the five leading keypoint descriptors on BAA, and, in doing so, (ii) presenting a generic approach for a specific task. Two methods for keypoint selection were applied: sparse and dense feature points. For each type, SIFT, SURF, BRIEF, BRISK, and FREAK feature descriptors were extracted within the epiphyseal regions of interest (eROI). Classification was performed using a support vector machine. Reference data (1101 radiographs) of the University of Southern California was used for 5-fold cross validation. The data was grouped into 30 classes representing the bone age range of 0-18 years. With a mean error of 0.605 years, dense SIFT gave best results and outperforms all published methods. The accuracy was 98.36% within the range of 2 years. Dense SIFT represents a generic method for a specific question. PMID- 26623944 TI - Ischemia detection using Isoelectric Energy Function. AB - A novel method has been proposed for the detection of ischemia using an isoelectric energy function (IEEF) resulting from ST segment deviations in ECG signals. The method consists of five stages: pre-processing, delineation, measurement of isoelectric energy, a beat characterization algorithm and detection of ischemia. The isoelectric energy threshold is used to differentiate ischemic beats from normal beats for ischemic episode detection. Then, ischemic episodes are classified as transmural or subendocardial. The method is validated for recordings of the annotated European ST-T database (EDB). The results show 98.12% average sensitivity (SE) and 98.16% average specificity (SP). These results are significantly better than those of existing methods cited in the literature. The advantage of the proposed method includes simplicity, ruggedness and automatic discarding of noisy beats. PMID- 26623945 TI - In vitro evaluation of basal shapes and offset values of artificial teeth for CAD/CAM complete dentures. AB - STATEMENT OF PROBLEM: Artificial teeth are bonded onto the recesses of a milled denture base in a complete denture prepared using computer-aided design/computer aided manufacturing (CAD/CAM). Little is known, however, about the effects of basal shapes and offset values on the accuracy of positions of the bonded artificial teeth. PMID- 26623946 TI - Oxygen-Assisted Chemical Vapor Deposition Growth of Large Single-Crystal and High Quality Monolayer MoS2. AB - Monolayer molybdenum disulfide (MoS2) has attracted great interest due to its potential applications in electronics and optoelectronics. Ideally, single crystal growth over a large area is necessary to preserve its intrinsic figure of merit but is very challenging to achieve. Here, we report an oxygen-assisted chemical vapor deposition method for growth of single-crystal monolayer MoS2. We found that the growth of MoS2 domains can be greatly improved by introducing a small amount of oxygen into the growth environment. Triangular monolayer MoS2 domains can be achieved with sizes up to ~350 MUm and a room-temperature mobility up to ~90 cm(2)/(V.s) on SiO2. The role of oxygen is not only to effectively prevent the poisoning of precursors but also to eliminate defects during the growth. Our work provides an advanced method for high-quality single-crystal monolayer MoS2 growth. PMID- 26623947 TI - Lipophilic Prodrugs of SN38: Synthesis and in Vitro Characterization toward Oral Chemotherapy. AB - SN38 (7-ethyl-10-hydroxy camptothecin) is a potent anticancer agent belonging to the camptothecin family; however, its oral delivery is extensively restricted by poor solubility in pharmaceutically acceptable excipients and low transmucosal permeability. Lipid-based carriers are well-known for their ability to improve oral absorption and bioavailability of lipid soluble and highly permeable compounds. Thus, this study has focused on improving solubility in lipid excipients, controlling stability, and enhancing transmucosal permeability of SN38 by specific chemical modification. To achieve these aims, a series of lipophilic prodrugs were designed and synthesized by esterification at the C10 and/or C20 positon(s) of SN38 with dietary fatty acids of diverse hydrocarbon chain lengths. The solubility of these novel prodrugs in long-chain triglycerides was increased up to 444-fold, and cytotoxicity was significantly reduced in comparison to SN38. The prodrugs were stable in simulated gastric fluids but exhibited different rates of hydrolysis (t1/2 < 5 min to t1/2 > 2 h) in simulated intestinal fluids (in the presence of enzymes) depending on the alkyl chain length and the position modified. A predictable reconversion of prodrugs to SN38 in plasma was also confirmed. On the basis of these studies, SN38-undecanoate (C20) was identified as the optimal prodrug. Finally, in vitro permeability and uptake studies in rat intestinal mucosal membrane using an Ussing chamber showed significant improvement in transepithelial drug transport and cellular uptake. Together, these results indicate that well designed lipophilic prodrugs have potential for the efficacious and safe oral delivery of SN38. PMID- 26623948 TI - Skin Penetrating Peptide as a Tool to Enhance the Permeation of Heparin through Human Epidermis. AB - This study aimed to identify a new skin penetrating peptide (SPP) able to enhance unfractionated heparin (UFH) permeation through human epidermis by screening a phage display peptide library. The effects of the synthesized heptapeptide (DRTTLTN) on human stratum corneum organization were investigated by ATR-FTIR spectroscopy and molecular dynamics simulation. The DRTTLTN penetration within the human epidermis caused both a fluidization of the stratum corneum lipids and the extension of keratins due to the increase of the contribution of alpha helices. The coadministration of DRTTLTN with UFH resulted ineffective in increasing skin penetration due to UFH affinity for keratins. The conjugation of DRTTLTN to UFH by N-(3-(dimethylamino)propyl)-N'-ethylcarbodiimide hydrochloride and sodium N-hydroxysulfosuccinimide led to an increase of the flux of 24-36-fold with respect to raw UFH, depending on the adopted synthetic procedure. The new compounds showed a decrease of the antifactor Xa activity of about 4-5 times. DRTTLTN also permitted to increase the fluxes of small model molecules. In conclusion, these data support the use of SPP to enhance the skin penetration of poorly absorbed compounds even in the case of macromolecules as polysaccharides. PMID- 26623949 TI - Alternative synthesis and antibacterial evaluation of 1,5-dideoxy-1,5-imino-L rhamnitol. AB - A convenient synthesis is described of 5-azido-5-deoxy-2,3-O-isopropylidene-L rhamnofuranose from L-rhamnose in seven steps and 17% overall yield. A key feature of the synthesis is the selective oxidation of the secondary alcohol in 2,3-O-isopropylidene-L-rhamnofuranose in the presence of the hemiacetal to give the corresponding ketone in good yield using the Parikh-Doering reagent. 5-Azido 5-deoxy-2,3-O-isopropylidene-l-rhamnofuranose is then converted by a literature protocol to 1,5-dideoxy-1,5-imino-L-rhamnitol, which was found to have no significant antimicrobial activity against Pseudomonas aeruginosa, methicillin resistant Staphylococcus aureus, and Escherichia coli. PMID- 26623951 TI - Effects of a Mere-Presence Conspecific on Extinction of an Operant. AB - In a 2 * 2 factorial design, 32 hunger-motivated albino rats were trained to press a bar for food in a Skinner box. Animals practiced this operant, with or without a mere-presence conspecific, on a VR reinforcement schedule for 10 days and were extinguished with or without a conspecific in a nearby compartment. The results showed that the presence of a conspecific did not enhance this operant during practice sessions nor its resistance to extinction. During extinction the animals that experienced the presence or absence of a conspecific for the first time showed a reduced rate of responding. The findings cast doubt on a drive theory of social facilitation and support a generalization-decrement hypothesis. PMID- 26623952 TI - Primacy Effects and the Nature of the Communications: Movie Pictures. AB - "Primacy-recency" effects were studied when different information was received through two media: (a) written descriptions of a youth's extrovertive or introvertive behavior, which were read by S and (b) silent movie picture enactments of the behavior, which were viewed by S. College Ss (N = 180), in small groups, answered a questionnaire about their impressions of the person after the last communication. When successive communications were in the same medium, primary seemed to prevail, except that the filmed extrovertive behavior, whether first or last, was more influential than the filmed introvertive behavior. When two media were used, either film was more effective than the written description. Various group and individual scores gave somewhat different measures of what superficially appeared to be primary or recency. The results suggest that these terms may be inappropriate when communications are of uneven strength or in different media. PMID- 26623953 TI - A Comparison of Four Methods of Scaling for the Acquisition of Early Number Concept. AB - Four different methods of scaling for constructing a developmental scale of early number concept were compared: the Guttman scale analysis, the stochastic Mokken scale analysis, the ordering theoretic method, and the item tree analysis. Ss were 537 kindergarten and Grade 1 primary school children who were given three types of number comparison tasks, linear, linear-nonlinear, and nonlinear. The stochastic Mokken scale analysis was the most suitable one for constructing a developmental scale of these number comparison tasks. The final scale consisted of 12 equivalent number-comparison tasks, which together formed a strong Mokken scale. Implications for the development of early number concept are discussed. PMID- 26623950 TI - Disulfiram inhibition of cyanide formation after acetonitrile poisoning. AB - CONTEXT: Cyanide poisoning may be caused by acetonitrile, a common industrial organic solvent and laboratory agent. OBJECTIVE: To describe the potential use of disulfiram in treating acetonitrile poisoning in a human clinical case and to further study its effect in human liver microsomes in vitro. CASE DETAILS: A 30 year-old man initially presented with a cholinergic toxic syndrome following ingestion of aldicarb. Toxicological analysis revealed coingestion of ethanol. He subsequently developed severe metabolic acidosis caused by the cyanogenic compound acetonitrile which was erroneously interpreted as acetone in the chromatogram. After three treatments with hydroxocobalamin (5 g i.v.) and sodium thiosulfate (12.5 g i.v.) on days 2, 3, and 5, he had transient improvement but recurrent lactic acidosis. Treatment with disulfiram was associated on day 7 with resolution of metabolic acidosis and slowing of the decrease in acetonitrile concentration. He recovered from acetonitrile toxicity completely. The time course of acetonitrile, thiocyanate, and cyanide concentrations suggested that disulfiram inhibited cyanide formation. RESULTS: In vitro experiments with human liver microsomes showed the cyanide concentration was significantly lower after incubation with acetonitrile and disulfiram than acetonitrile alone (a mean 60% reduction in cyanide level). DISCUSSION: Although disulfiram was given late in the course of the poisoning it is possible that it contributed to the recovery. PMID- 26623954 TI - Individual Differences in Eyewitness Memory and Confidence Judgments. AB - The relationships between witness characteristics, event memory, and confidence judgments were investigated. A day after seeing two confederates (Cs) make an announcement, 170 Ss were given an unexpected memory test. They also completed the Group Embedded Figures Test (GEFT) and Rotter Scale. Neither of these test scores was related to memory accuracy, but female Ss were found to be more accurate than male Ss in their memory for the female C (but not for the male or for objects and actions). One significant correlation was obtained between the personality measures and confidence. Field-independents were better able to judge their own accuracy on an item by item basis, but this was true only for male Ss. In general, little support was found for the notion of predicting eyewitness performance on the basis of personality variables. PMID- 26623955 TI - Effects of Observational Learning, Overt Activity, and Class Placement on Children's Mediated Associative Learning. AB - The present study investigated the effects of instructional training on the generation and use of imaginal- or verbal-associative-learning mediators by third grade children. Instructional training was based on modeling (active practice) or observation of the generation of associative-learning mediators. Ss (N = 40) served both as models (active generators) and observers of mediated associative learning responses, alternating on successive trials of the task. Verbal mediation responding resulted in significantly more effective mediator use and recall performance than did imagery or control responding; this effect interacted with class placement. No difference was found between the modeling and observing conditions, indicating that both are effective in promoting mediated associative learning in young children. PMID- 26623956 TI - Effects of Free Recall of Grouping Pictures, Picture Names, and Complete Picture Descriptions. AB - The double-encoding hypothesis is one explanation for the superior free recall of picture stimuli compared to recall of the same stimuli in word form. This study attempted to describe fully in words the picture stimuli that were presented, because a picture's simple word label obviously is not equivalent in complexity to the picture itself. Pictures, their simple labels, and a series of words that completely described the pictures were presented to 90 Ss. Results indicated stimuli in the picture form were remembered better than both kinds of word stimuli. These results supported the double-encoding hypothesis. PMID- 26623957 TI - Developmental Effects on Free Recall of Grouping Pictures and Words. AB - The double-encoding hypothesis explains why superior free recall of picture stimuli compared to their equivalent word forms has been demonstrated to be valid with university level Ss. Two experiments compared the effects of grouping words and pictures to determine if there is a developmental factor involved in modifying the double-encoding hypothesis. Experiment 1 found that freshmen university students who grouped pictures or words remembered more pictures (p < .01), thus supporting the double-encoding hypothesis. Experiment 2 found no significant differences when sixth-grade students grouped pictures or words (p > .05), thus not supporting the double-encoding hypothesis. Recommendations for future studies were made. PMID- 26623958 TI - Semantic Memory Organization in Second Graders and Adults. AB - Adults (n = 20) and second-grade children (n = 20) named pictures while trying to ignore words printed inside the pictures. The words were either high or low associates of the pictures, and picture-word pairings either crossed or did not cross conceptual category boundaries. It was found that Ss at both ages experienced significantly more interference from within-category than cross category printed words. The pattern of associative and categorical interference effects were very similar for the two age groups. It was concluded that the semantic memory organization of second-grade children is based, at least in part, on conceptual category relationships. The results provided no evidence for an age related change in the relative strength of categorical and associative relationships in semantic memory. PMID- 26623959 TI - Disjunctive Concept Formation: S-R Hypothesis Versus Cognitive Theory. AB - The present study investigated the learning of disjunctive concepts under different postfeedback conditions in order to test opposing S-R associational and hypothesis-testing theories. A reception paradigm was employed which involved the use of three types of postfeedback intervals and four different postfeedback interval lengths, with 180 college men and women. The results, overall, supported predictions based upon S-R associational theory, as leaning processes occurred on all trials and not just on trials in which an error occurred. PMID- 26623960 TI - The Use of Generalization Gradients for the Study of Mediational Processes. AB - In Experiment I three groups (N = 60 college students) were presented with a 60 degrees training stimulus (TS) and subsequently tested for generalization along a line-tilt dimension with the use of an asymmetrical test series. During training, one group labeled the TS with a high-imagery word, another with a low imagery word, while a third served as a no-label control. While the control group showed an expected central tendency shift, the shift was completely inhibited for the high-imagery group. The low-imagery group's gradient appeared to show a partial inhibition effect, although statistical confirmation for a differential imagery effect was not obtained. In Experiment II (N = 180 college students) three words of high and three of low imagery were employed as labels. While the control condition resulted in a central tendency shift, both labeling conditions produced complete inhibition, indicating that verbal pretraining produces inhibitory effects regardless of the labels employed. The findings were discussed in terms of the acquired-distinctiveness-of-cues hypothesis. PMID- 26623962 TI - Corrigendum. PMID- 26623961 TI - Editorial: The Future of Our Basic Science and Scientists. PMID- 26623965 TI - Understanding and Reducing the Risk for Acne Scarring. AB - Scarring is a lifelong, physically disfiguring and often emotionally debilitating sequela resulting from acne vulgaris. Nearly 80% of patients have some scarring and 50% have clinically relevant scarring. Although the extent, duration, and intensity of inflammation are important risk factors, scarring also can develop in patients with relatively mild inflammation. Assessment of scarring should be part of the evaluation in all patients with acne and should be a consideration in determining treatment. Semin Cutan Med Surg 34(supp5):S89-S91 (c) 2015 published by Frontline Medical Communications. PMID- 26623966 TI - PSYCHIATRIC COMORBIDITY DOES NOT ONLY DEPEND ON DIAGNOSTIC THRESHOLDS: AN ILLUSTRATION WITH MAJOR DEPRESSIVE DISORDER AND GENERALIZED ANXIETY DISORDER. AB - BACKGROUND: High rates of psychiatric comorbidity are subject of debate: To what extent do they depend on classification choices such as diagnostic thresholds? This paper investigates the influence of different thresholds on rates of comorbidity between major depressive disorder (MDD) and generalized anxiety disorder (GAD). METHODS: Point prevalence of comorbidity between MDD and GAD was measured in 74,092 subjects from the general population (LifeLines) according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria. Comorbidity rates were compared for different thresholds by varying the number of necessary criteria from >= 1 to all nine symptoms for MDD, and from >= 1 to all seven symptoms for GAD. RESULTS: According to DSM thresholds, 0.86% had MDD only, 2.96% GAD only, and 1.14% both MDD and GAD (odds ratio (OR) 42.6). Lower thresholds for MDD led to higher rates of comorbidity (1.44% for >= 4 of nine MDD symptoms, OR 34.4), whereas lower thresholds for GAD hardly influenced comorbidity (1.16% for >= 3 of seven GAD symptoms, OR 38.8). Specific patterns in the distribution of symptoms within the population explained this finding: 37.3% of subjects with core criteria of MDD and GAD reported subthreshold MDD symptoms, whereas only 7.6% reported subthreshold GAD symptoms. CONCLUSIONS: Lower thresholds for MDD increased comorbidity with GAD, but not vice versa, owing to specific symptom patterns in the population. Generally, comorbidity rates result from both empirical symptom distributions and classification choices and cannot be reduced to either of these exclusively. This insight invites further research into the formation of disease concepts that allow for reliable predictions and targeted therapeutic interventions. PMID- 26623967 TI - Hepatitis E virus infection and acute-on-chronic liver failure in West Africa: a case-control study from The Gambia. AB - BACKGROUND: In sub-Saharan Africa, it is unknown whether hepatitis E virus (HEV) infection is a common precipitating event of acute-on-chronic liver failure (ACLF). AIMS: To estimate the prevalence of HEV infection in general population and assess whether HEV is a common trigger of ACLF in cirrhotic patients in The Gambia, West Africa. METHODS: We first conducted an HEV sero-survey in healthy volunteers. We then tested cirrhotic patients with ACLF (cases) and compensated cirrhosis (controls) for anti-HEV IgG as a marker of exposure to HEV, and anti HEV IgA and HEV RNA as a marker of recent infection. We also described the characteristics and survival of the ACLF cases and controls. RESULTS: In the healthy volunteers (n = 204), 13.7% (95% CI: 9.6-19.2) were positive for anti-HEV IgG, and none had positive HEV viraemia. After adjusting for age and sex, the following were associated with positive anti-HEV IgG: being a Christian, a farmer, drinking water from wells, handling pigs and eating pork. In 40 cases (median age: 45 years, 72.5% male) and 71 controls (39 years, 74.6% male), >=70% were infected with hepatitis B virus. Although hepatitis B flare and sepsis were important precipitating events of ACLF, none had marker of acute HEV. ACLF cases had high (70.0%) 28-day mortality. CONCLUSIONS: Hepatitis E virus infection is endemic in The Gambia, where both faecal-oral route (contaminated water) and zoonotic transmission (pigs/pork meat) may be important. However, acute HEV was not a common cause of acute-on-chronic liver failure in The Gambia. PMID- 26623968 TI - Endoscopic endonasal orbital cavernous hemangioma resection: global experience in techniques and outcomes. AB - BACKGROUND: Endoscopic orbital surgery represents the next frontier in endonasal surgery. The current literature is largely composed of small, heterogeneous, case series with little consensus regarding optimal techniques. The purpose of this study was to combine the experience of multiple international centers to create a composite of the global experience on the endoscopic management of a single type of tumor, the orbital cavernous hemangioma (OCH). METHODS: This was a retrospective study of techniques for endoscopic OCH resection from 6 centers on 3 continents. Only primary data from strictly endoscopic resection of OCHs were included. Responses were analyzed to qualitatively identify points of both consensus and variability among the different groups. RESULTS: Data for a total of 23 patients, 10 (43.5%) male and 13 (56.5%) female were collected. The majority of lesions were intraconal (60.9%). The mean +/- standard deviation (SD) surgical time was 150.7 +/- 75.0 minutes with a mean blood loss of 82.7 +/- 49.6 mL. Binarial approaches (26.1%) were used exclusively in the setting of intraconal lesions, which were associated with a higher rate of incomplete resection (31.3%), postoperative diplopia (25.0%), and the need for reconstruction (37.5%) than extraconal lesions. Orthotropia and symmetric orbital appearance were achieved in 60.9% and 78.3% of cases, respectively. CONCLUSION: Extraconal lesions were managed similarly; however, greater variability was evident for intraconal lesions. These included the laterality and number of hands in the approach, methods of medial rectus retraction, and the need for reconstruction. The increased technical complexity and disparity of techniques in addressing intraconal OCHs suggests that continued research into the optimal management of this subclass of lesions is of significant priority. PMID- 26623969 TI - Increased Cardiac Output and Preserved Gas Exchange Despite Decreased Alveolar Surface Area in Rats Exposed to Neonatal Hyperoxia and Adult Hypoxia. PMID- 26623971 TI - Synthesis of 5-Aminoimidazole-4-Carboxamide Riboside (AICAR) and Its Derivatives Using Inosine as Starting Material. AB - This unit contains four basic protocols describing the synthesis of 5 aminoimidazole-4-carboxamide riboside (AICAR), 5-aminoimidazole-4-carboxamide riboside (ZPM), their 4-N functionalized derivatives, and two sugar-modified analogs of AICAR. The first and second basic protocols reveal the importance of solid-phase synthesis to obtain novel AICAR and ZMP imidazole-modified analogs in a short time, whereas the third and fourth basic protocols allow for the rapid preparation of 5'-F-AICAR and D-ribityl AICA. PMID- 26623972 TI - Polymeric Cryogel-Based Boronate Affinity Chromatography for Separation of Ribonucleic Acid from Bacterial Extracts. AB - Three-dimensional monolithic columns are preferred stationary phase in column chromatography. Conventional columns based on silica or particles are efficient in bioseparation though associated with limitations of nonspecific interaction and uneven porosity that causes high mass transfer resistance for the movement of big molecules. Cryogels as a monolith column have shown promising application in bioseparation. Cryogels column can be synthesized in the form of a monolith at sub-zero temperature through gelation of pre-synthesized polymers or polymerization of monomers. Cryogels are macroporous and mechanically stable materials. They have open interconnected micron-sized pores with a wide range of porosity (10-200 MUm). Current protocol demonstrated the ability of poly(hydroxymethyl methacrylate)-co-vinylphenyl boronic acid p(HEMA-co-VPBA) cryogel matrix for selective separation of RNA from the bacterial crude extract. PMID- 26623973 TI - Highly Ordered Pyrene pi-Stacks on an RNA Duplex. AB - The syntheses of 2'-O-(pyren-1-ylmethyl)uridine phosphoramidite, 2'-O-(pyren-1 ylmethyl)adenosine phosphoramidite, and multiple pyrene-attached oligo-RNAs are described in this unit. The 2'-O-(pyren-1-ylmethyl)nucleosides are converted into the corresponding 2'-O-(pyren-1-ylmethyl)nucleoside 3'-phosphoramidites, which can be incorporated into the specific position of oligo-RNAs by solid-phase oligonucleotide synthesis. The multiple pyrene-attached oligo-RNA forms an A-form duplex with a complementary multiple pyrene-attached oligo-RNA; the pyrenes are associated with pi-stacking along the outside of the duplex. PMID- 26623974 TI - Calorimetry of Nucleic Acids. AB - This unit describes the application of calorimetry to characterize the thermodynamics of nucleic acids, specifically, the two major calorimetric methodologies that are currently employed: differential scanning (DSC) and isothermal titration calorimetry (ITC). DSC is used to study thermally induced order-disorder transitions in nucleic acids. A DSC instrument measures, as a function of temperature (T), the excess heat capacity (C(p)(ex)) of a nucleic acid solution relative to the same amount of buffer solution. From a single curve of C(p)(ex) versus T, one can derive the following information: the transition enthalpy (DeltaH), entropy (DeltaS), free energy (DeltaG), and heat capacity (DeltaCp); the state of the transition (two-state versus multistate); and the average size of the molecule that melts as a single thermodynamic entity (e.g., the duplex). ITC is used to study the hybridization of nucleic acid molecules at constant temperature. In an ITC experiment, small aliquots of a titrant nucleic acid solution (strand 1) are added to an analyte nucleic acid solution (strand 2), and the released heat is monitored. ITC yields the stoichiometry of the association reaction (n), the enthalpy of association (DeltaH), the equilibrium association constant (K), and thus the free energy of association (DeltaG). Once DeltaH and DeltaG are known, DeltaS can also be derived. Repetition of the ITC experiment at a number of different temperatures yields the DeltaCp for the association reaction from the temperature dependence of DeltaH. PMID- 26623975 TI - Pyrrole-Imidazole Polyamides: Manual Solid-Phase Synthesis. AB - Pyrrole-imidazole polyamides (PAs) are a family of DNA-binding peptides that bind in the minor groove of double-stranded DNA (dsDNA) in a sequence-selective, programmable fashion. This protocol describes a detailed manual procedure for the solid-phase synthesis of this family of compounds. The protocol entails solution phase synthesis of the Boc-protected pyrrole (Py) and imidazole (Im) carboxylic acid building blocks. This unit also describes the importance of choosing the appropriate condensing agent to form the amide linkages between each building block. Finally, a monomeric coupling protocol and a fragment-based approach are described that delivers PAs in 13% to 30% yield in 8 days. PMID- 26623976 TI - Pyrrole-Imidazole Polyamides: Automated Solid-Phase Synthesis. AB - In this unit, the fully automated solid-phase synthetic strategy of hairpin Py-Im polyamides is described using triphosgene (BTC) as a coupling agent. This automated methodology is compatible with all the typical building blocks, enabling the facile synthesis of polyamide libraries in 9% to 20% yield in 3 days. PMID- 26623980 TI - Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade. AB - Hypertension and type 2 diabetes mellitus (T2DM) are risk factors for cardiovascular disease. Dapagliflozin improves glycemic control and systolic blood pressure (SBP) in T2DM patients. This double-blind phase III study evaluated the effects of dapagliflozin on glycemic control and blood pressure in patients with inadequately controlled T2DM and hypertension, despite ongoing therapy with a renin-angiotensin system blocker. Patients were randomized to receive dapagliflozin 10 mg (n = 302) or placebo (n = 311) once daily for 12 weeks. Endpoints were change from baseline to week 12 in seated SBP and glycosylated hemoglobin (HbA1c); longitudinal repeated-measures analysis was performed. Additional endpoints included other hemodynamic measures, serum uric acid, fasting plasma glucose, body weight, blood lipids and heart rate. After 12 weeks, dapagliflozin-treated versus placebo-treated patients showed significant reductions in HbA1c (-0.6% vs -0.1%, p < 0.0001), mean seated SBP (-10.4 vs -7.3 mmHg, p = 0.0010) and mean 24 h ambulatory SBP (-9.6 vs -6.7 mmHg, p = 0.0043). Dapagliflozin also reduced body weight compared with placebo (-1.0 vs -0.3 kg). Dapagliflozin was well tolerated, with adverse events consistent with previous studies. Dapagliflozin improved glycemic control, and reduced SBP as well as body weight in patients with poorly controlled T2DM and hypertension. PMID- 26623993 TI - Chronic otitis media surgery and re-operation risk factor analysis: A nationwide retrospective cohort study of 18 895 patients. AB - CONCLUSION: Patients with risk factors including younger age, mastoiditis, external ear disease, treatment by older surgeons, and concomitant mastoidectomy should receive detailed management to minimize the probability of re-operation for chronic otitis media (COM). OBJECTIVES: Although COM remains a common ear disease requiring surgical intervention, its re-operation risks are less well documented. This study aimed to compare patients with COM who underwent re operation and those patients with no re-operation, and identify the risks of re operation. METHOD: This retrospective cohort study analyzed the trend of COM surgery from 1999-2009, and identified the re-operation risks of 18 895 patients with COM who underwent surgery from 2002-2006 using the National Health Insurance Research Database in Taiwan. RESULTS: Among the study population, 129 patients underwent revision surgery during a 5.5 +/- 1.5 year follow-up period. A univariate logistic regression analysis showed that the re-operation rate was significantly higher in patients under 18 years of age, those with mastoiditis, disorders of external ear, treatment by surgeons of 50-64 years of age, use of a very high volume surgeon, and combined surgery with mastoidectomy. A multivariate analysis further limited the re-operation risk factors to younger patients, those with mastoiditis, external ear disorders, treatment by older surgeons, and concomitant mastoidectomy. PMID- 26623994 TI - Germination of Fusarium graminearum Ascospores and Wheat Infection are Affected by Dry Periods and by Temperature and Humidity During Dry Periods. AB - The effects of temperature and relative humidity (RH) on germination of Fusarium graminearum ascospores, and of dry periods (DP) of different lengths and of temperature and RH during DP on ascospore survival were studied both in vitro and in planta. Optimal temperatures for ascospore germination at 100% RH were 20 and 25 degrees C; germination was <=5% when ascospores were incubated at 20 degrees C and RH <= 93.5%. Viable ascospores were found at all tested combinations of DP duration (0 to 48 h) * temperature (5 to 40 degrees C) or RH (32.5 to 100% RH). Germination declined as DP duration and temperature increased. Germination was lower for ascospores kept at 65.5% RH during the DP than at 76.0, 32.5, or 93.5% RH. Equations were developed describing the relationships between ascospore germination, DP duration and temperature or RH during DP. Durum wheat spikes were inoculated with ascospores and kept dry for 0 to 48 h at approximately 15 degrees C and 65% RH; plants were then kept in saturated atmosphere for 48 h to favor infection. Fungal biomass, measured as F. graminearum DNA by quantitative polymerase chain reaction, declined as DP increased to 24 and 48 h at 3 and 9 days postinfection but not in spikes at maturity. PMID- 26623995 TI - A Global Analysis of CYP51 Diversity and Azole Sensitivity in Rhynchosporium commune. AB - CYP51 encodes the target site of the azole class of fungicides widely used in plant protection. Some ascomycete pathogens carry two CYP51 paralogs called CYP51A and CYP51B. A recent analysis of CYP51 sequences in 14 European isolates of the barley scald pathogen Rhynchosporium commune revealed three CYP51 paralogs, CYP51A, CYP51B, and a pseudogene called CYP51A-p. The same analysis showed that CYP51A exhibits a presence/absence polymorphism, with lower sensitivity to azole fungicides associated with the presence of a functional CYP51A. We analyzed a global collection of nearly 400 R. commune isolates to determine if these findings could be extended beyond Europe. Our results strongly support the hypothesis that CYP51A played a key role in the emergence of azole resistance globally and provide new evidence that the CYP51A gene in R. commune has further evolved, presumably in response to azole exposure. We also present evidence for recent long-distance movement of evolved CYP51A alleles, highlighting the risk associated with movement of fungicide resistance alleles among international trading partners. PMID- 26623997 TI - Structure and Migration in U.S. Blumeria graminis f. sp. tritici Populations. AB - While wheat powdery mildew occurs throughout the south-central and eastern United States, epidemics are especially damaging in the Mid-Atlantic states. The structure of the U.S. Blumeria graminis f. sp. tritici population was assessed based on a sample of 238 single-spored isolates. The isolates were collected from 16 locations in 12 states (18 site-years) as chasmothecial samples in 2003 or 2005, or as conidial samples in 2007 or 2010. DNA was evaluated using nine single nucleotide polymorphism (SNP) markers in four housekeeping genes, and 10 simple sequence repeat (SSR) markers. The SSR markers were variably polymorphic, with allele numbers ranging from 3 to 39 per locus. Genotypic diversity was high (210 haplotypes) and in eight of the site-years, every isolate had a different SSR genotype. SNP haplotypic diversity was lower; although 15 haplotypes were identified, the majority of isolates possessed one of two haplotypes. The chasmothecial samples showed no evidence of linkage disequilibrium (P = 0.36), while the conidial samples did (P = 0.001), but the two groups had nearly identical mean levels of genetic diversity, which was moderate. There was a weakly positive relationship between genetic distance and geographic distance (R(2) = 0.25, P = 0.001), indicating modest isolation by distance. Most locations in the Mid-Atlantic and Great Lakes regions clustered together genetically, while Southeast locations formed a distinct but adjacent cluster; all of these were genetically separated from Southern Plains locations and an intermediate location in Kentucky. One-way migration was detected at a rate of approximately five individuals per generation from populations west of the Appalachian Mountains to those to the east, despite the fact that the Atlantic states experience more frequent and damaging wheat mildew epidemics. Overall, the evidence argues for a large-scale mosaic of overlapping populations that re-establish themselves from local sources, rather than continental-scale extinction and re-establishment, and a low rate of long-distance dispersal roughly from west to east, consistent with prevailing wind directions. PMID- 26623996 TI - Variables Associated with Severity of Bacterial Canker and Wilt Caused by Clavibacter michiganensis subsp. michiganensis in Tomato Greenhouses. AB - Clavibacter michiganensis subsp. michiganensis, the causal agent of bacterial canker and wilt of tomato, is considered to be one of the most important bacterial pathogens worldwide. In the year 2000 there was an increase in the number of infected greenhouses and in the severity of the disease in Israel. As part of the effort to cope with the disease, a comprehensive survey was conducted. Scouts recorded disease severity monthly in 681 production units. At the end of the season the scouts met with the growers and together recorded relevant details about the crop and cultural practices employed. The results suggested an absence of anisotropy pattern in the study region. Global Moran's I analysis showed that disease severity had significant spatial autocorrelation. The strongest spatial autocorrelation occurred within a 1,500 m neighborhood, which is comparable to the distance between production units maintained by one grower (Farm). Next, we tested three groups of variables including or excluding the Farm as a variable. When the Farm was included the explained variation increased in all the studied models. Overall, results of this study demonstrate that the most influential factor on bacterial canker severity was the Farm. This variable probably encompasses variation in experience, differences in agricultural practices between growers, and the quality of implementation of management practices. PMID- 26623998 TI - Identifying Potential Breast Carcinogens: A New Approach. PMID- 26623999 TI - Response to "Comment on 'In Vitro Effects of Bisphenol A beta-D-Glucuronide (BPA G) on Adipogenesis in Human and Murine Preadipocytes'". PMID- 26624001 TI - Cobalt Catalyzed C-H and N-H Bond Annulation of Sulfonamide with Terminal and Internal Alkynes. AB - Chelate assisted cobalt catalyzed C-H and N-H annulation of aryl sulfonamide with terminal and internal alkynes is reported. Very high regioselectivity and excellent functional group tolerance were achieved using oxygen as a co-oxidant. The reaction is scalable under mild conditions. PMID- 26624000 TI - Shear-wave sonoelastography for assessing masseter muscle hardness in comparison with strain sonoelastography: study with phantoms and healthy volunteers. AB - Objectives Shear-wave sonoelastography is expected to facilitate low operator dependency, high reproducibility and quantitative evaluation, whereas there are few reports on available normative values of in vivo tissue in head and neck fields. The purpose of this study was to examine the reliabilities on measuring hardness using shear-wave sonoelastography and to clarify normal values of masseter muscle hardness in healthy volunteers. Methods Phantoms with known hardness ranging from 20 to 140 kPa were scanned with shear-wave sonoelastography, and inter- and intraoperator reliabilities were examined compared with strain sonoelastography. The relationships between the actual and measured hardness were analyzed. The masseter muscle hardness in 30 healthy volunteers was measured using shear-wave sonoelastography. RESULTS: The inter- and intraoperator intraclass correlation coefficients were almost perfect. Strong correlations were seen between the actual and measured hardness. The mean hardness of the masseter muscles in healthy volunteers was 42.82 +/- 5.56 kPa at rest and 53.36 +/- 8.46 kPa during jaw clenching. CONCLUSIONS: The hardness measured with shear-wave sonoelastography showed high-level reliability. Shear wave sonoelastography may be suitable for evaluation of the masseter muscles. PMID- 26624002 TI - Stereoselective Tissue Distribution of Ketolorac in Rats - Differential Uptake of Ketolorac Enantiomers in Certain Tissues. PMID- 26624003 TI - Pharmacological Evaluation of Central Nervous System Effects of Ethanol Leaf Extract of Olax Subscorpioidea in Experimental Animals. AB - BACKGROUND: Olax subscorpioidea Oliv. (Olacaceae) is a medicinal plant used in folk medicine in the management of pain, mental illness, and convulsion. We evaluated neurosedative and anticonvulsant properties of the ethanol leaf extract of O. subscorpioidea (ELEOS). METHODS: Effects of ELEOS (3.125, 6.25, 12.5, 25 mg/kg) on novelty-induced behaviors were determined using open field test. Anxiolytic effect of ELEOS (3.125, 6.25, 12.5, 25 mg/kg) was assessed using hole board and elevated-plus maze paradigms. The effect of O. subscorpioidea on pentobarbitone sleeping time was also investigated. Anticonvulsant property of ELEOS (12.5-50 mg/kg) was evaluated using pentylenetetrazole, picrotoxin and strychnine-induced convulsions assays. The extract was administered once intraperitoneally. RESULTS: The LD50 of ELEOS was 300 mg/kg. ELEOS (3.125, 6.25, 12.5, 25 mg/kg) significantly reduced rearing (99.8+/-2.8, 76.2+/-2.9, 37.4+/ 1.2, 5.8+/-0.8) and grooming (48.0+/-3.6, 33.8+/-2.9, 25.4+/-1.6, 7.6+/-0.8) as compared with controls (185.8+/-5.1; 63.8+/-4.3). Treatment with ELEOS (3.125, 6.25, 12.5, 25 mg/kg) significantly reduced head-dipping on hole-board (10.6+/ 1.9, 8.8+/-1.2, 7.2+/-0.9, 6.0+/-1.1) as compared with control (27.8+/-1.5). However, there was no anxiolytic effect on EPM. ELEOS (12.5, 25, 50 mg/kg) significantly prolonged pentobarbitone-induced sleeping time (43.0+/-1.4, 51.0+/ 1.2, 61.0+/-1.8) as compared with control (31.0+/-0.7). At 50 mg/kg, ELEOS significantly prolonged onset of seizure (2.72+/-2.07) and latency to death (9.20+/-1.24) as compared with controls (0.54+/-0.02; 2.00+/-0.44) in pentylenetetrazole-induced convulsions with no effect on picrotoxin and strychnine-induced convulsions. CONCLUSION: The ELEOS is sedative and has mild anticonvulsant activity and this study supports pharmacological basis for its use in the management of mental illness and convulsion. PMID- 26624004 TI - Transcriptome Analysis of Plant Hormone-Related Tomato (Solanum lycopersicum) Genes in a Sunlight-Type Plant Factory. AB - In plant factories, measurements of plant conditions are necessary at an early stage of growth to predict harvest times of high value-added crops. Moreover, harvest qualities depend largely on environmental stresses that elicit plant hormone responses. However, the complexities of plant hormone networks have not been characterized under nonstress conditions. In the present study, we determined temporal expression profiles of all genes and then focused on plant hormone pathways using RNA-Seq analyses of gene expression in tomato leaves every 2 h for 48 h. In these experiments, temporally expressed genes were found in the hormone synthesis pathways for salicylic acid, abscisic acid, ethylene, and jasmonic acid. The timing of CAB expression 1 (TOC1) and abscisic acid insensitive 1 (ABA1) and open stomata 1 (OST1) control gating stomata. In this study, compare with tomato and Arabidopsis thaliana, expression patterns of TOC1 have similarity. In contrast, expression patterns of tomato ABI1 and OST1 had expression peak at different time. These findings suggest that the regulation of gating stomata does not depend predominantly on TOC1 and significantly reflects the extracellular environment. The present data provide new insights into relationships between temporally expressed plant hormone-related genes and clock genes under normal sunlight conditions. PMID- 26624005 TI - Evolving Healthcare Quality in Top Tertiary General Hospitals in China during the China Healthcare Reform (2010-2012) from the Perspective of Inpatient Mortality. AB - Healthcare reforms (HR) initiated by many countries impacts on healthcare systems worldwide. Being one of fast developing countries, China launched HR in 2009. Better understanding of its impact is helpful for China and others in further pursuit of HR. Here we evaluate inpatient mortality, a proxy to healthcare quality, in 43 top tertiary hospitals in China during this critical period. This is a hospital-based observational study with 8 million discharge summary reports (DSR) from 43 Chinese hospitals from 2010-2012. Using DSRs, we extract the vita status as the outcome, in addition to age, gender, diagnostic codes, and surgical codes. Nearly all hospitals have expanded their hospitalization capacities during this period. As of year 2010, inpatient mortality (IM) across hospitals varies widely from 20/00 to 200/00. Comparing IM of year 2011 and 2012 with 2010, the overall IM has been substantially reduced (OR = 0.883 and 0.766, p-values<0.001), showing steady improvements in healthcare quality. Surgical IM correlates with the overall IM (correlation = 0.60, p-value <0.001), but is less uniform. Over these years, surgical IM has also been steadily reduced (OR = 0.890 and 0.793, p values<0.001). Further analyses of treatments on five major diseases and six major surgeries revealed that treatments of myocardial infarction, cerebral hemorrhage and cerebral infarction have significant improvement. Observed temporal and spatial variations demonstrate that there is a substantial disparity in healthcare quality across tertiary hospitals, and that these hospitals are rapidly improving healthcare quality. Evidence-based assessment shed light on the reform impact. Lessons learnt here are relevant to further refining HR. PMID- 26624006 TI - Do Longer Intervals between Challenges Reduce the Risk of Adverse Reactions in Oral Wheat Challenges? AB - BACKGROUND: The use of oral food challenges (OFCs) in clinics is limited because they are complicated and associated with anaphylactic symptoms. To increase their use, it is necessary to develop novel, effective, and safe methods. However, the effectiveness of different OFCs has not been compared. OBJECTIVE: To investigate the effect of ingestion methods on wheat allergy symptoms and treatment during OFCs. METHOD: Without changing the total challenge dose, we changed the administration method from a 5-installment dose titration every 15 min (15-min interval method) to 3 installments every 30 min (30-min interval method). We retrospectively reviewed and compared the results of 65 positive 15-min interval wheat challenge tests conducted between July 2005 and February 2008 and 87 positive 30-min interval tests conducted between March 2008 and December 2009. RESULTS: A history of immediate symptoms was more common for the 30-min interval method; however, no difference between methods was observed in other background parameters. Switching from the 15-min to the 30-min interval method did not increase symptoms or require treatment. The rate of cardiovascular symptoms (p = 0.032), and adrenaline use (p = 0.017) was significantly lower with the 30-min interval method. The results did not change after adjusting for the effects of immediate symptom history in multivariate analysis. CONCLUSION: This study suggests that the 30-min interval method reduces the risk of adverse events, compared to the 15-min interval method. PMID- 26624007 TI - Can CD44 Be a Mediator of Cell Destruction? The Challenge of Type 1 Diabetes. AB - CD44 is a multi-functional receptor with multiple of isoforms engaged in modulation of cell trafficking and transmission of apoptotic signals. We have previously shown that injection of anti-CD44 antibody into NOD mice induced resistance to type 1 diabetes (T1D). In this communication we describe our efforts to understand the mechanism underlying this effect. We found that CD44 deficient NOD mice develop stronger resistance to T1D than wild-type littermates. This effect is not explained by the involvement of CD44 in cell migration, because CD44-deficient inflammatory cells surprisingly had greater invasive potential than the corresponding wild type cells, probably owing to molecular redundancy. We have previously reported and we show here again that CD44 expression and hyaluronic acid (HA, the principal ligand for CD44) accumulation are detected in pancreatic islets of diabetic NOD mice, but not of non-diabetic DBA/1 mice. Expression of CD44 on insulin-secreting beta cells renders them susceptible to the autoimmune attack, and is associated with a diminution in beta cells function (e.g., less insulin production and/or insulin secretion) and possibly also with an enhanced apoptosis rate. The diabetes-supportive effect of CD44 expression on beta cells was assessed by the TUNEL assay and further strengthened by functional assays exhibiting increased nitric oxide release, reduced insulin secretion after glucose stimulation and decreased insulin content in beta cells. All these parameters could not be detected in CD44-deficient islets. We further suggest that HA-binding to CD44-expressing beta cells is implicated in beta-cell demise. Altogether, these data agree with the concept that CD44 is a receptor capable of modulating cell fate. This finding is important for other pathologies (e.g., cancer, neurodegenerative diseases) in which CD44 and HA appear to be implicated. PMID- 26624008 TI - Socio-economic and Climate Factors Associated with Dengue Fever Spatial Heterogeneity: A Worked Example in New Caledonia. AB - BACKGROUND/OBJECTIVES: Understanding the factors underlying the spatio-temporal distribution of infectious diseases provides useful information regarding their prevention and control. Dengue fever spatio-temporal patterns result from complex interactions between the virus, the host, and the vector. These interactions can be influenced by environmental conditions. Our objectives were to analyse dengue fever spatial distribution over New Caledonia during epidemic years, to identify some of the main underlying factors, and to predict the spatial evolution of dengue fever under changing climatic conditions, at the 2100 horizon. METHODS: We used principal component analysis and support vector machines to analyse and model the influence of climate and socio-economic variables on the mean spatial distribution of 24,272 dengue cases reported from 1995 to 2012 in thirty-three communes of New Caledonia. We then modelled and estimated the future evolution of dengue incidence rates using a regional downscaling of future climate projections. RESULTS: The spatial distribution of dengue fever cases is highly heterogeneous. The variables most associated with this observed heterogeneity are the mean temperature, the mean number of people per premise, and the mean percentage of unemployed people, a variable highly correlated with people's way of life. Rainfall does not seem to play an important role in the spatial distribution of dengue cases during epidemics. By the end of the 21st century, if temperature increases by approximately 3 degrees C, mean incidence rates during epidemics could double. CONCLUSION: In New Caledonia, a subtropical insular environment, both temperature and socio-economic conditions are influencing the spatial spread of dengue fever. Extension of this study to other countries worldwide should improve the knowledge about climate influence on dengue burden and about the complex interplay between different factors. This study presents a methodology that can be used as a step by step guide to model dengue spatial heterogeneity in other countries. PMID- 26624010 TI - Structure-activity relationship of crustacean peptide hormones. AB - In crustaceans, various physiological events, such as molting, vitellogenesis, and sex differentiation, are regulated by peptide hormones. To understanding the functional sites of these hormones, many structure-activity relationship (SAR) studies have been published. In this review, the author focuses the SAR of crustacean hyperglycemic hormone-family peptides and androgenic gland hormone and describes the detailed results of our and other research groups. The future perspectives will be also discussed. PMID- 26624009 TI - Large Neutral Amino Acid Supplementation Exerts Its Effect through Three Synergistic Mechanisms: Proof of Principle in Phenylketonuria Mice. AB - BACKGROUND: Phenylketonuria (PKU) was the first disorder in which severe neurocognitive dysfunction could be prevented by dietary treatment. However, despite this effect, neuropsychological outcome in PKU still remains suboptimal and the phenylalanine-restricted diet is very demanding. To improve neuropsychological outcome and relieve the dietary restrictions for PKU patients, supplementation of large neutral amino acids (LNAA) is suggested as alternative treatment strategy that might correct all brain biochemical disturbances caused by high blood phenylalanine, and thereby improve neurocognitive functioning. OBJECTIVE: As a proof-of-principle, this study aimed to investigate all hypothesized biochemical treatment objectives of LNAA supplementation (normalizing brain phenylalanine, non-phenylalanine LNAA, and monoaminergic neurotransmitter concentrations) in PKU mice. METHODS: C57Bl/6 Pah-enu2 (PKU) mice and wild-type mice received a LNAA supplemented diet, an isonitrogenic/isocaloric high-protein control diet, or normal chow. After six weeks of dietary treatment, blood and brain amino acid and monoaminergic neurotransmitter concentrations were assessed. RESULTS: In PKU mice, the investigated LNAA supplementation regimen significantly reduced blood and brain phenylalanine concentrations by 33% and 26%, respectively, compared to normal chow (p<0.01), while alleviating brain deficiencies of some but not all supplemented LNAA. Moreover, LNAA supplementation in PKU mice significantly increased brain serotonin and norepinephrine concentrations from 35% to 71% and from 57% to 86% of wild-type concentrations (p<0.01), respectively, but not brain dopamine concentrations (p = 0.307). CONCLUSIONS: This study shows that LNAA supplementation without dietary phenylalanine restriction in PKU mice improves brain biochemistry through all three hypothesized biochemical mechanisms. Thereby, these data provide proof-of-concept for LNAA supplementation as a valuable alternative dietary treatment strategy in PKU. Based on these results, LNAA treatment should be further optimized for clinical application with regard to the composition and dose of the LNAA supplement, taking into account all three working mechanisms of LNAA treatment. PMID- 26624011 TI - Automated Learning of Subcellular Variation among Punctate Protein Patterns and a Generative Model of Their Relation to Microtubules. AB - Characterizing the spatial distribution of proteins directly from microscopy images is a difficult problem with numerous applications in cell biology (e.g. identifying motor-related proteins) and clinical research (e.g. identification of cancer biomarkers). Here we describe the design of a system that provides automated analysis of punctate protein patterns in microscope images, including quantification of their relationships to microtubules. We constructed the system using confocal immunofluorescence microscopy images from the Human Protein Atlas project for 11 punctate proteins in three cultured cell lines. These proteins have previously been characterized as being primarily located in punctate structures, but their images had all been annotated by visual examination as being simply "vesicular". We were able to show that these patterns could be distinguished from each other with high accuracy, and we were able to assign to one of these subclasses hundreds of proteins whose subcellular localization had not previously been well defined. In addition to providing these novel annotations, we built a generative approach to modeling of punctate distributions that captures the essential characteristics of the distinct patterns. Such models are expected to be valuable for representing and summarizing each pattern and for constructing systems biology simulations of cell behaviors. PMID- 26624012 TI - The Incubation Period of Primary Epstein-Barr Virus Infection: Viral Dynamics and Immunologic Events. AB - Epstein-Barr virus (EBV) is a human herpesvirus that causes acute infectious mononucleosis and is associated with cancer and autoimmune disease. While many studies have been performed examining acute disease in adults following primary infection, little is known about the virological and immunological events during EBV's lengthy 6 week incubation period owing to the challenge of collecting samples from this stage of infection. We conducted a prospective study in college students with special emphasis on frequent screening to capture blood and oral wash samples during the incubation period. Here we describe the viral dissemination and immune response in the 6 weeks prior to onset of acute infectious mononucleosis symptoms. While virus is presumed to be present in the oral cavity from time of transmission, we did not detect viral genomes in the oral wash until one week before symptom onset, at which time viral genomes were present in high copy numbers, suggesting loss of initial viral replication control. In contrast, using a sensitive nested PCR method, we detected viral genomes at low levels in blood about 3 weeks before symptoms. However, high levels of EBV in the blood were only observed close to symptom onset-coincident with or just after increased viral detection in the oral cavity. These data imply that B cells are the major reservoir of virus in the oral cavity prior to infectious mononucleosis. The early presence of viral genomes in the blood, even at low levels, correlated with a striking decrease in the number of circulating plasmacytoid dendritic cells well before symptom onset, which remained depressed throughout convalescence. On the other hand, natural killer cells expanded only after symptom onset. Likewise, CD4+ Foxp3+ regulatory T cells decreased two fold, but only after symptom onset. We observed no substantial virus specific CD8 T cell expansion during the incubation period, although polyclonal CD8 activation was detected in concert with viral genomes increasing in the blood and oral cavity, possibly due to a systemic type I interferon response. This study provides the first description of events during the incubation period of natural EBV infection in humans and definitive data upon which to formulate theories of viral control and disease pathogenesis. PMID- 26624013 TI - E2-2 Dependent Plasmacytoid Dendritic Cells Control Autoimmune Diabetes. AB - Autoimmune diabetes is a consequence of immune-cell infiltration and destruction of pancreatic beta-cells in the islets of Langerhans. We analyzed the cellular composition of the insulitic lesions in the autoimmune-prone non-obese diabetic (NOD) mouse and observed a peak in recruitment of plasmacytoid dendritic cells (pDCs) to NOD islets around 8-9 weeks of age. This peak coincides with increased spontaneous expression of type-1-IFN response genes and CpG1585 induced production of IFN-alpha from NOD islets. The transcription factor E2-2 is specifically required for the maturation of pDCs, and we show that knocking out E2-2 conditionally in CD11c+ cells leads to a reduced recruitment of pDCs to pancreatic islets and reduced CpG1585 induced production of IFN-alpha during insulitis. As a consequence, insulitis has a less aggressive expression profile of the Th1 cytokine IFN-gamma and a markedly reduced diabetes incidence. Collectively, these observations demonstrate a disease-promoting role of E2-2 dependent pDCs in the pancreas during autoimmune diabetes in the NOD mouse. PMID- 26624014 TI - Loss of Gadkin Affects Dendritic Cell Migration In Vitro. AB - Migration is crucial for the function of dendritic cells (DCs), which act as outposts of the immune system. Upon detection of pathogens, skin- and mucosa resident DCs migrate to secondary lymphoid organs where they activate T cells. DC motility relies critically on the actin cytoskeleton, which is regulated by the actin-related protein 2/3 (ARP2/3) complex, a nucleator of branched actin networks. Consequently, loss of ARP2/3 stimulators and upstream Rho family GTPases dramatically impairs DC migration. However, nothing is known yet about the relevance of ARP2/3 inhibitors for DC migration. We previously demonstrated that the AP-1-associated adaptor protein Gadkin inhibits ARP2/3 by sequestering it on intracellular vesicles. Consistent with a role of Gadkin in DC physiology, we here report Gadkin expression in bone marrow-derived DCs and show that its protein level and posttranslational modification are regulated upon LPS-induced DC maturation. DCs derived from Gadkin-deficient mice were normal with regards to differentiation and maturation, but displayed increased actin polymerization. While the actin-dependent processes of macropinocytosis and cell spreading were not affected, loss of Gadkin significantly impaired DC migration in vitro, however, in vivo DC migration was unperturbed suggesting the presence of compensatory mechanisms. PMID- 26624015 TI - CardioGenBase: A Literature Based Multi-Omics Database for Major Cardiovascular Diseases. AB - Cardiovascular diseases (CVDs) account for high morbidity and mortality worldwide. Both, genetic and epigenetic factors are involved in the enumeration of various cardiovascular diseases. In recent years, a vast amount of multi-omics data are accumulated in the field of cardiovascular research, yet the understanding of key mechanistic aspects of CVDs remain uncovered. Hence, a comprehensive online resource tool is required to comprehend previous research findings and to draw novel methodology for understanding disease pathophysiology. Here, we have developed a literature-based database, CardioGenBase, collecting gene-disease association from Pubmed and MEDLINE. The database covers major cardiovascular diseases such as cerebrovascular disease, coronary artery disease (CAD), hypertensive heart disease, inflammatory heart disease, ischemic heart disease and rheumatic heart disease. It contains ~1,500 cardiovascular disease genes from ~2,4000 research articles. For each gene, literature evidence, ontology, pathways, single nucleotide polymorphism, protein-protein interaction network, normal gene expression, protein expressions in various body fluids and tissues are provided. In addition, tools like gene-disease association finder and gene expression finder are made available for the users with figures, tables, maps and venn diagram to fit their needs. To our knowledge, CardioGenBase is the only database to provide gene-disease association for above mentioned major cardiovascular diseases in a single portal. CardioGenBase is a vital online resource to support genome-wide analysis, genetic, epigenetic and pharmacological studies. PMID- 26624016 TI - Improvements to a Markerless Allelic Exchange System for Bacillus anthracis. AB - A system was previously developed for conducting I-SceI-mediated allelic exchange in Bacillus anthracis. In this system, recombinational loss of a chromosomally integrated allelic exchange vector is stimulated by creation of a double-stranded break within the vector by the homing endonuclease I-SceI. Although this system is reasonably efficient and represents an improvement in the tools available for allelic exchange in B. anthracis, researchers are nonetheless required to "pick and patch" colonies in order to identify candidate "exchangeants." In the present study, a number of improvements have been made to this system: 1) an improved I SceI-producing plasmid includes oriT so that both plasmids can now be introduced by conjugation, thus avoiding the need for preparing electro-competent cells of each integration intermediate; 2) antibiotic markers have been changed to allow the use of the system in select agent strains; and 3) both plasmids have been marked with fluorescent proteins, allowing the visualization of plasmid segregation on a plate and obviating the need for "picking and patching." These modifications have made the process easier, faster, and more efficient, allowing for parallel construction of larger numbers of mutant strains. Using this improved system, the genes encoding the tripartite anthrax toxin were deleted singly and in combination from plasmid pXO1 of Sterne strain 34F2. In the course of this study, we determined that DNA transfer to B. anthracis could be accomplished by conjugation directly from a methylation-competent E. coli strain. PMID- 26624018 TI - Validation of the High-Risk Pregnancy Stress Scale in a sample of hospitalized Greek high-risk pregnant women. AB - The aim of the authors in this study was to determine the psychometric properties of the Greek adaptation of the High-Risk Pregnancy Stress Scale (HRPSS) in a sample of high-risk hospitalized pregnant women. The sample consisted of 133 high risk pregnant women with gestational age from 9 to 37 weeks. Data were collected between February and June of 2014. HRPSS was "forward-backward" translated from English to Greek. Principal axis factoring with promax rotation was used to test the factor structure of the HRPSS. Measures of state anxiety (STAI) and depressive symptoms (EPDS) were used to assess the convergent validity of the HRPSS. Exploratory factor analysis suggested three factors: concerns of pregnancy, movement restriction, and isolation and restriction of external activities. Construct validity was confirmed by computing correlations between the HRPSS and constructions of anxiety and depressive symptoms. Internal consistency reliability was satisfactory (alpha = 0.813). The original factor structure of the HRPSS was only partly replicated. The results of the exploratory factor analysis suggested that a three-factor solution instead of a two-factor solution would be the most adequate. The HRPSS is an appropriate measure for assessing the levels of concerns regarding pregnancy outcome, movement restriction, isolation, and external activity restrictions in Greek high-risk pregnant women. PMID- 26624017 TI - Anti-Apoptotic Protein Bcl-xL Expression in the Midbrain Raphe Region Is Sensitive to Stress and Glucocorticoids. AB - Anti-apoptotic proteins are suggested to be important for the normal health of neurons and synapses as well as for resilience to stress. In order to determine whether stressful events may influence the expression of anti-apoptotic protein Bcl-xL in the midbrain and specifically in the midbrain serotonergic (5-HT) neurons involved in neurobehavioral responses to adverse stimuli, adult male rats were subjected to short-term or chronic forced swim stress. A short-term stress rapidly increased the midbrain bcl-xl mRNA levels and significantly elevated Bcl xL immunoreactivity in the midbrain 5-HT cells. Stress-induced increase in glucocorticoid secretion was implicated in the observed effect. The levels of bcl xl mRNA were decreased after stress when glucocorticoid elevation was inhibited by metyrapone (MET, 150 mg/kg), and this decrease was attenuated by glucocorticoid replacement with dexamethasone (DEX; 0.2 mg/kg). Both short-term stress and acute DEX administration, in parallel with Bcl-xL, caused a significant increase in tph2 mRNA levels and slightly enhanced tryptophan hydroxylase immunoreactivity in the midbrain. The increasing effect on the bcl-xl expression was specific to the short-term stress. Forced swim repeated daily for 2 weeks led to a decrease in bcl-xl mRNA in the midbrain without any effects on the Bcl-xL protein expression in the 5-HT neurons. In chronically stressed animals, an increase in tph2 gene expression was not associated with any changes in tryptophan hydroxylase protein levels. Our findings are the first to demonstrate that both short-term stress and acute glucocorticoid exposures induce Bcl-xL protein expression in the midbrain 5-HT neurons concomitantly with the activation of the 5-HT synthesis pathway in these neurons. PMID- 26624019 TI - orthoFind Facilitates the Discovery of Homologous and Orthologous Proteins. AB - Finding homologous and orthologous protein sequences is often the first step in evolutionary studies, annotation projects, and experiments of functional complementation. Despite all currently available computational tools, there is a requirement for easy-to-use tools that provide functional information. Here, a new web application called orthoFind is presented, which allows a quick search for homologous and orthologous proteins given one or more query sequences, allowing a recurrent and exhaustive search against reference proteomes, and being able to include user databases. It addresses the protein multidomain problem, searching for homologs with the same domain architecture, and gives a simple functional analysis of the results to help in the annotation process. orthoFind is easy to use and has been proven to provide accurate results with different datasets. Availability: http://www.bioinfocabd.upo.es/orthofind/. PMID- 26624020 TI - Increased S100B Levels in Cannabis Use Disorder. AB - BACKGROUND: It has been determined that cannabis has adverse effects on brain tissue, and that increased S100 calcium binding protein B (S100B) blood levels are markers of neuronal damage. Therefore, the aim of this study was to evaluate the S100B levels in cannabis use disorder. METHOD: Thirty-two patients with cannabis use disorder and 31 matched healthy controls were enrolled in this study. Appropriate blood samples were taken from the enrolled subjects, and the serum S100B protein levels were measured with an electrochemiluminescence immunoassay for the quantification of the protein. FINDINGS: We found significantly increased S100B protein levels in patients with cannabis use disorder. The mean serum concentration of S100B was 0.081 +/- 0.018 MUg/l in patients with cannabis use disorder, and 0.069 +/- 0.018 MUg/l in the control group (p = 0.008). INTERPRETATION: Our data suggest that elevated S100B protein levels might indicate neuronal damage in the brains of people with cannabis use disorder. PMID- 26624021 TI - Subclinical Left Ventricular Dysfunction in Patients with Obstructive Sleep Apnea. PMID- 26624022 TI - The tryphosine genus Cheirimedon in Australian waters (Crustacea, Amphipoda, Lysianassidae, Tryphosinae). AB - The genus Cheirimedon is reviewed and the monotypic genus Tryphosoides placed in its synonymy. We describe fourteen new species of Cheirimedon, all from Australian waters, bringing the total number of species in the genus to 22. Full synonymies and distribution data are provided for all taxa. A key to the world species is provided. PMID- 26624023 TI - A taxonomic revision of the Phrynosoma douglasii species complex (Squamata: Phrynosomatidae). AB - Short-horned lizards (Phrynosoma douglasii species complex) occur throughout the inter-montane West and Great Plains of western North America. The comparative morphology and color pattern variation of short-horned lizards was studied in 3,174 specimens. Multivariate analyses of 20 morphological and color-pattern characters were applied to 977 specimens, and univariate statistics were summarized for 52 samples totaling 1,134 specimens. The results of the morphological data analyses support the recognition of P. douglasii (Bell 1828) as a distinct species, and the resurrection of P. brevirostris Girard 1858a and P. ornatissimum Girard 1858a as species distinct from P. hernandesi Girard 1858a. Two new species allied to P. brevirostris are described: P. bauri sp. nov. from the eastern plains of Colorado and northeastern New Mexico, southeastern Wyoming and southwestern Nebraska south of the North Platte River, and P. diminutum sp. nov. endemic to the San Luis Valley of southern Colorado and northern New Mexico. The Mexican taxon brachycercum Smith 1942 is reassigned as a subspecies of P. ornatissimum, based on non-discrete character differences and overall morphometric similarity. The ranges of P. hernandesi and P. ornatissimum broadly overlap in central New Mexico, the former taxon occupying the coniferous forests of disjunct mountain ranges, the latter occuring in the surrounding desert grasslands. Principal components analysis has revealed morphological evidence of hybridization where the two taxa meet, generally within ecotones between montane forest associations and grasslands. Principal components analysis has also revealed a high level of morphological variability in populations occurring in the Colorado Plateau region of northeastern Arizona, northwestern New Mexico, extreme southwestern Colorado and adjacent Utah. The evidence suggests that these populations arose through past hybridization between the two species. The taxon ornatum Girard 1858b, although sharing several traits with P. brevirostris, is morphologically close to P. hernandesi. It is regarded as a stabilized population of hybrid origin, but treated taxonomically as a subspecies of P. hernandesi. The taxonomic arrangement in this study, with the exception of P. douglasii, is largely discordant with the proposed taxonomy from a previously published study based on mitochondrial DNA sequence data. PMID- 26624024 TI - Tadpole diversity of Bolivia's lowland anuran communities: molecular identification, morphological characterisation, and ecological assignment. AB - The last decades have witnessed a rapid increase in our knowledge about amphibian diversity, and a growing number of studies have focused on anuran larval stages. Tadpoles can provide key information for conservation issues and the understanding of amphibian evolution. Moreover, research in tadpoles has the potential to advance species delimitation in the diverse and still understudied Neotropical amphibian fauna. In this study we present morphological tadpole characterisations of 41 lowland species illustrated by detailed imagery (mainly of live specimens). The larvae were identified via captive breeding and genetically using recently published DNA barcodes of adult Bolivian frogs. Tadpoles of three species (Rhinella mirandaribeiroi, Dendropsophus melanargyreus, and D. salli) are described for the first time. The descriptions of 38 tadpoles are at least new for Bolivia (due to the divergent status of many of the Bolivian lineages, further studies are needed to clarify their taxonomy). In addition, we provide information on tadpole habitats, which--combined with morphological data- reveal ecomorphological guilds that further illustrate Bolivia's lowlands tadpole diversity. PMID- 26624025 TI - Annotated Checklist of California Encyrtidae (Hymenoptera). AB - Based on examination of the literature and specimens, 208 described species in 90 genera of Encyrtidae are listed from California. Data on the original publication, deposition of types, geographic distribution and host records of these species are presented. Forty-three species were established in biocontrol programs, 157 are presumed native, 7 appear to be adventitious introductions, and the origin of one is undetermined. An additional 276 morphospecies are also listed as present in the state within an additional 21 described genera and potentially up to 20 undescribed genera. Altogether, 31 new genera and 36 new species are recorded for the state, as well as 70 new parasitoid-host records. Errors pertaining to California taxa in previously published papers are corrected. Metaphycus immaculatus (Howard) is reported as a new combination (from Aphycus Mayr). Three appendices are included: a host/parasitoid listing for the described species present in the state, a listing of taxa previously reported from California under invalid names, and a list of taxa either erroneously reported from the state, or unsuccessful biocontrol introductions. PMID- 26624026 TI - Endevouridae, a review with description of four new species (Crustacea, Amphipoda, Lysianassoidea). AB - The family Endevouridae is reviewed and four new species from the two genera, Endevoura and Ensayara, are described from Australian and Japanese waters. All species are diagnosed and the type species of Endevoura (End. mirabilis Chilton, 1921) and Ensayara (Ens. ramonella J.L. Barnard, 1964), respectively, are redescribed and illustrated. A key to the 19 known world species of Endevouridae is provided. PMID- 26624027 TI - A taxonomic study of the beetle cockroaches (Diploptera Saussure) from China, with notes on the genus and species worldwide (Blattodea: Blaberidae: Diplopterinae). AB - Four taxa of beetle cockroaches (Diploptera Saussure, 1864) from South China are described and illustrated, viz., two new species D. elliptica sp. n. and D. naevus sp. n., one new subspecies D. nigrescens guani subsp. n. and one widespread known species D. punctata (Eschscholtz, 1822). The genus and known species from around the world are discussed based on types and other specimens. D. pulchra Anisyutkin, 2007 is now regarded as a junior synonym of D. bicolor Hanitsch, 1925. Whether the populations of D. punctata represent or not different species needs to be studied in the future. A key, a distribution map, and photos of species are provided. PMID- 26624028 TI - Revision of the Bicyclus ignobilis species-group (Lepidoptera: Nymphalidae: Satyrinae) with descriptions of two new species. AB - The ignobilis-group of the genus Bicyclus Kirby 1871 is revised. The species group contains six species with a distinct wing pattern, but limited intraspecific variation, distributed across tropical African rainforest. We investigate a set of more than 1000 specimens from a range of museum collections, including some type material, and thoroughly update the biogeographical knowledge for the group. We also describe two new species as members of the group. The included species are: Bicyclus ignobilis (Butler 1870) stat. rev., B. rileyi Condamin 1961, B. maesseni Condamin 1971, B. brakefieldi Brattstrom 2012, B. ottossoni sp. nov. and B. vandeweghei sp. nov. Due to observing a gradual morphological cline within B. ignobilis without any sharp transitions we suppress the previously identified subspecies B. ignobilis eurini Condamin & Fox 1963 syn. nov. and B. ignobilis acutus Condamin 1965 syn. nov. PMID- 26624030 TI - Lamellibrachia sagami sp. nov., a new vestimentiferan tubeworm (Annelida: Siboglinidae) from Sagami Bay and several sites in the northwestern Pacific Ocean. AB - A new vestimentiferan tubeworm species of the genus Lamellibrachia Webb, 1969 is described. It was collected from cold seep areas off Hatsushima in Sagami Bay and at the Daini Tenryu Knoll in the Nankai Trough (606-1170 m depth). Lamellibrachia sagami sp. nov. differs from seven congeneric species in the following character states; showing a wider range of diameter of vestimental and trunk plaques than L. barhami, L. luymesi, L. satsuma and L. anaximandri; and having more numerous sheath lamellae (3-6 pairs) than L. juni (2-3 pairs) but fewer than L. victori (7 pairs) and L. columna (8-16 pairs). PMID- 26624029 TI - New genus and new species of Caprellidae (Crustacea: Peracarida: Amphipoda) from the mesophotic coral ecosystems of Puerto Rico and St. Croix, Caribbean Sea. AB - A new genus and two new species are described based on material collected from the mesophotic coral ecosystems of the U.S. Caribbean. The new genus Borikenella can be distinguished from other related genera such as Pseudaeginella, Paradeutella, Aciconula and Deutella by the combination of the following characters: pereopods 3 and 4 three-articulate, pereopods 5-7 six-articulate, mandible molar present, palp of the mandible with a setal formula 1-x-0, abdomen without appendages. The new species Liropus gurui, can be distinguished from the closely related L. japonicus mainly by the lack of anteroventral margin extended forward in pereonite 3, the lack of cleft and serration in the propodus of gnathopod 2, the longer pereopod 3 and the larger abdominal appendages. PMID- 26624031 TI - Two new species of the genus Prosopistoma (Ephemeroptera: Prosopistomatidae) from Iraq and Algeria. AB - In addition to the three so far known species of Prosopistoma Latreille, 1833 from West Palaearctic region, P. pennigerum (Muller, 1785), P. oronti Alouf, 1977 and P. orhanelicum Dalkiran, 2009, two new species are described based on larvae. Prosopistoma helenae sp. n. has been found in Iraq (Tigris River in Mosul) and Prosopistoma alaini sp. n. in Algeria (Oued Isser, Sidi Abdelli). Critical distinguishing characters of all West-Palaearctic species of Prosopistoma are discussed in detail. PMID- 26624032 TI - Establishment of a new genus for Eresiomera paradoxa (Schultze, 1917) and related taxa (Lepidoptera: Lycaenidae) with description of two new species. AB - Finding of two undescribed species, closely related to Eresiomera paradoxa (Schultze, 1917) in Liberia and the Democratic Repubic of Congo led the authors to revise the material available in the African Butterfly Reserarch Institute (ABRI), Nairobi. Examination of the material revealed that the placement of E. paradoxa and the related species neither in the genus Eresiomera Clench, 1965, nor in Pseuderesia Butler, 1874 in which the species was originally described, is satisfactory, based on characters offered by the wings and genitalia. Solving the problem a new genus, Parasiomera gen. nov. is erected for E. paradoxa and related taxa and two new species are described: P. alfa sp. nov., P. kivuensis sp. nov. The taxon orientalis Stempffer, 1962 orignally described as subspecies of Pseuderesia paradoxa is also elevated to species rank and placed in the new genus resulting the new combination and new status Parasiomera orientalis (Stempffer, 1962). To secure objectivity of the name usage of P. paradoxa, the only existing syntpe is designated as lectotype. PMID- 26624033 TI - A new species of Pseudoparaclius Grichanov (Diptera: Dolichopodidae) from Udzungwa Mountains National Park, Tanzania, and a key to Afrotropical species. AB - Pseudoparaclius udzungwa sp. nov. is described from Udzungwa Mountains National Park, Tanzania, and a key to all known Afrotropical species of Pseudoparaclius Grichanov is provided. Pseudoparaclius udzungwa is morphologically very similar to P. sanjensis (Grichanov) but has a modified male fore tarsus with laterally compressed tarsomeres 4-5, an epandrium with slightly shorter marginal teeth distiventrally, a blunt-tipped sclerotized part of the hypandrium, and an almost straight phallus. Males of P. udzungwa and P. sanjensis share a characteristic, oval, cup-shaped cercus not seen in any other known species of Pseudoparaclius. PMID- 26624034 TI - Taxonomic status of Tetragonopterus anomalus Steindachner, 1891, an inquirenda species in Characidae (Teleostei: Characiformes). PMID- 26624036 TI - First records of Ungla Navas (Neuroptera: Chrysopidae) from Venezuela, with descriptions of seven new species. AB - Ungla Navas is a small and relatively unstudied genus of Neotropical Chrysopini (Neuroptera: Chrysopidae: Chrysopinae) from Central and South America. Here, the genus is reported from Venezuela for the first time, and seven new species are described: Ungla demarmelsi sp. nov.; Ungla diazi sp. nov.; Ungla curimaguensis sp. nov.; Ungla martinsi sp. nov.; Ungla nigromaculifrons sp. nov.; Ungla rubricosa sp. nov.; and Ungla yutajensis sp. nov. PMID- 26624035 TI - Three new and two known free-living marine nematode species of the family Ironidae from the East China Sea. AB - Three new and two known species of free-living marine nematodes of the family Ironidae from the East China Sea are described and illustrated. Conilia sinensis sp. nov. is identified by the relatively large body size (1883-2399 um); the well developed lips; the number, shape and length of spicule (single and striated, length 87-100 um as arc); the shape of telamon; the number of supplements (1). Pheronous donghaiensis sp. nov. is characterized by its sharp tail point; caudal gland absent; buccal cavity armed with four big solid teeth and rows of minute denticles; spicules stout, with central septum at proximal end, male caudal region with two rows of small conical subventral papillae. Trissonchulus latispiculum sp. nov. can be distinguished by its head not set off from remaining body, tail short and blunt, buccal cavity with minute denticles, spinneret opening slightly ventrally, spicule broad and alate with central septum and head on proximal end. Trissonchulus benepapillosus (Schulz, 1935) and Trissonchulus oceanus Cobb 1920 which are first reported from China, are redescribed in detail with emphasis on new or hitherto poorly described morphological features. Types are deposited in the Institute of Oceanology, Chinese Academy of Sciences. PMID- 26624037 TI - Revision of Bondariella Hustache & Bondar (Coleoptera: Curculionidae), with descriptions of the first species from the Amazon and notes on natural history. AB - Bondariella Hustache & Bondar, 1942 is revised. In addition to the redescription of the genus and its four previously known species, we report and describe the first species from the Amazonian region: Bondariella rudicula sp. nov. and Bondariella crenata sp. nov. We also provide a key to the species, illustrations and notes on natural history. All six species of Bondariella have been collected on palm flowers from Brazil, with the previously known species having only been recorded from species of Syagrus Mart. from the Atlantic Forest and Caatinga biomes. The two new species have only been recorded from species of Euterpe Mart. from the Amazon biome. Future work may prove if the associations with Syagrus and Euterpe are specific to the biomes. PMID- 26624038 TI - New species of Eidmanacris Chopard, 1956 from Brazil (Orthoptera: Phalangopsidae: Luzarinae). AB - With 15 described species, Eidmanacris is one of the largest Luzarinae genera from South America. In Brazil, 12 species occur in two large biomes, the Atlantic Forest and Cerrado. Here, we describe four new species of Eidmanacris from Brazil: E. bernardii Nihei & de Mello, n. sp., E. papaveroi Nihei & de Mello, n. sp., E. simoesi Nihei & de Mello, n. sp., and E. eliethae Nihei & de Mello, n. sp., from Cerrado (E. bernardii n. sp.), and the other from Atlantic Forest. The type material is deposited in the Museu de Zoologia da Universidade de Sao Paulo (MZSP) and the Zoology Department Insect Colletion (Colecao de Insetos do Departamento de Zoologia), Botucatu campus of Sao Paulo State University, UNESP. PMID- 26624039 TI - Psammon rotifers in Central Vietnam, with the descriptions of three new species (Rotifera: Monogononta). AB - In order to address the dearth of information on Rotifera in Vietnam, and especially on rotifers inhabiting freshwater psammon in Southeast Asia, we collected and examined twenty-five hygropsammon samples from Bau Thiem Lake, Thua Thien Hue Province, central Vietnam. A total of eighty-nine species-level rotifer taxa were identified, belonging to 21 genera and 13 families. Of these, 48 taxa (54%) are new to Vietnam, including three species, Lecane climacois Harring & Myers, 1926, Notommata cerberus (Gosse, 1886) and Trichocerca intermedia (Stenroos, 1898) that are new to the Oriental region, and three species, Lecane phapi n. sp., Lecane dorysimilis n. sp. and Trichocerca bauthiemensis n. sp. that are new to science. These, and some additional rare species are commented upon and illustrated. We estimated that the alpha-diversity of psammon rotifers in Bau Thiem Lake may be as high as 99 (SD=8.4; Chao2) or 115 (Jacknife2) taxa. These results indicate a high potential of rotifer diversity in the hygropsammon at Bau Thiem Lake, central Vietnam. PMID- 26624040 TI - A new species of tree crickets Oecanthus (Orthoptera, Gryllidae, Oecanthinae) in tobacco plantation from Southern Brazil, with body color variation. AB - We provide herein a description of a new species of Oecanthus collected from the tobacco plantation in southern Brazil, municipality of Sao Lourenco do Sul, State of Rio Grande do Sul. Description focused metanotal gland features, phallic sclerites, and calling song. A large sampling of individuals was distributed into four groups according to body and appendages color and dotted. We also rank all kind of marks present in the scape and pedicel. We compare linear morphometric variables of the metanotal glands and tegmina, as well as calling song parameters between groups in order do define all of them as the same species. Photographs and measurements are provided. PMID- 26624041 TI - Review of the Ambrysus stali La Rivers species complex (Heteroptera: Nepomorpha: Naucoridae) with the description of a new species from Mesoamerica. AB - The Neotropical Ambrysus stali La Rivers species complex is reviewed and includes A. bifidus La Rivers & Nieser, A. scolius La Rivers, A. stali La Rivers, and A. tricuspis La Rivers. Ambrysus oblongulus Montandon is removed as a member of this complex. Features uniting these species are related to male genitalia and associated structures. Ambrysus maya n. sp. is the fifth species in the complex and is described from Belize, Guatemala, and Mexico based on specimens from recent collecting and museum collections. PMID- 26624042 TI - Linnaeomyia hortensis gen. et spec. nov. (Diptera: Cecidomyiidae, Porricondylinae) from a backyard site in Oland, Sweden. AB - A new genus containing a single new species of Porricondylinae (Diptera: Cecidomyiidae) is described and named Linnaeomyia hortensis gen. nov., spec. nov. The sole known specimen of L. hortensis, a male, was Malaise trapped in a backyard site on the Baltic island of Oland, southeast Sweden, in summer 2014. Morphological evidence supports our hypothesis that Linnaeomyia is most closely related to Neurepidosis Spungis, 1987. Several male genital characters, notably the spine-bearing gonostyli and the vestigial ejaculatory apodeme, substantiate the generic distinctiveness of L. hortensis. Although a backyard discovery, L. hortensis is unlikely to be a synanthropic species. PMID- 26624043 TI - A new species of Suwallia (Plecoptera: Chloroperlidae) from China. AB - A new species of the genus Suwallia, S. wolongshana sp. nov. is described and illustrated from specimens collected in Sichuan Province, China. The new species is characterized by the two sclerotized bands between the hemitergal processes. The new species is the fourth recorded species of Suwallia from China. PMID- 26624044 TI - Snailfishes of the Careproctus rastrinus complex (Liparidae): redescriptions of seven species in the North Pacific Ocean region, with the description of a new species from the Beaufort Sea. AB - Herein we review and recognize as valid all previously described species of the Careproctus rastrinus complex based on morphological evidence, provide diagnoses and descriptions of all species, describe a new species from the Beaufort Sea, and address the misapplication of several names throughout the area. In particular, the name C. rastrinus is restricted to populations of the western Pacific and is known conclusively only from the Sea of Okhotsk. Careproctus acanthodes, from the Sea of Japan and Sea of Okhotsk, and C. pellucidus, from the Pacific Ocean side of northern Japan, are resurrected from synonymy with C. rastrinus. Populations of the eastern Pacific previously routinely identified as C. rastrinus are recognized under two names: C. scottae, a name that is applied to deeper water Bering Sea, Aleutian Islands, and eastern Pacific populations having a postorbital pore, and Careproctus phasma, applied to shallow water populations of the Bering Sea and Gulf of Alaska lacking a postorbital pore. Although we consider Careproctus spectrum valid, the species has been routinely misidentified and is presently known only from the type series. Careproctus lerikimae is a new species described from the Beaufort Sea, diagnosed from other species of the C. rastrinus complex by the absence of the postorbital pore and higher median fin and vertebral counts. PMID- 26624045 TI - Taxonomic revision of the Andean leaf-eared mouse, Phyllotis andium Thomas 1912 (Rodentia: Cricetidae), with the description of a new species. AB - The Andean Leaf-eared mouse, Phyllotis andium Thomas 1912, has been considered a widespread medium-size sigmodontine rodent (230 mm of total length and 35 grams approximately) that occurs from Tungurahua, Ecuador, through the Andes, to Lima, Peru. Previous studies performed on Phyllotis noted evidence of morphological geographical variation within the species, which is likely because of the several potential geographical barriers that exist within the distribution range of P. andium. We carried out a taxonomic revision of this species based on qualitative and quantitative morphological analyses of 330 specimens from 92 localities. This included appropriate comparisons with other species of the andium/amicus group and performed molecular analysis based on cytochrome b sequences. As a result, morphologic qualitative analysis suggested the recognition of three different taxa, which are supported by morphologic quantitative and molecular analyses. The three taxa here identified have allopatric distributional ranges separated by important geographic barriers. Following these identification criteria, P. andium is now recognized for the samples from Tungurahua, Ecuador to Huanuco, Peru, and includes melanius and fruticicolus as synonymous; the southern populations from the Ancash and Lima departments, in the western Peruvian Andes, are proposed to represent a new species; and we recognize P. stenops as a valid species with tamborum as a synonym. Finally, we postulate that the diversification of these three species is related to key events in the Andean orogeny. PMID- 26624046 TI - A new species of the genus Stiphodon from Palawan, Philippines (Gobiidae: Sicydiinae). AB - Palawan is an island in the western Philippines, and the freshwater fish fauna of this island has received limited research attention. In the present study, a new goby species, Stiphodon palawanensis, is described on the basis of 57 specimens collected from freshwater streams on the island. This species can be distinguished from its congeners by having nine segmented rays in the second dorsal fin, 15 rays in the pectoral fin, a pointed first dorsal fin in males, premaxilla with 45-71 tricuspid teeth, the nape and posterior half of the occipital region covered by cycloid scales, 9-11 dusky transverse bars laterally on the trunk and tail, a line of black blotches (in male) or a black band (in female) on the distal part of the second dorsal fin, and the first dorsal and pectoral fins lacking distinctive markings. The new species has been found only on the Sulu Sea side of central Palawan. Three congeners, S. percnopterygionus, S. atropurpureus, and S. pulchellus have also been recorded from Palawan. PMID- 26624047 TI - The genus Macroocula Panfilov in Egypt, with two new species (Hymenoptera: Bradynobaenidae: Apterogyninae). AB - The genus Macroocula Panfilov in Egypt is reviewed. Seven species were previously recorded from Egypt: M. magna (Invrea, 1965), M. mahunkai Argaman, 1994, M. morawitzi (Radoszkowski, 1888), M. nigriventris (Invrea, 1960), M. nitida (Bischoff, 1920), M. savignyi (Klug, 1829) and M. sinaica (Invrea, 1963). Macroocula brothersi Gadallah & Soliman, sp. nov. (Egypt, Wadi Shab, Red Sea) and M. salehi Gadallah & Soliman, sp. nov. (Egypt, Wadi Shaghab, Aswan) are described and illustrated. The subspecies M. nitida nitida (Bischoff, 1920) and M. nitida patrizii (Invrea, 1932) are raised to species level. An illustrated key and a faunistic list of Macroocula species are given. PMID- 26624048 TI - Molecular phylogenetic analysis of Acridoidea (Orthoptera: Caelifera) based on mitochondrial cytochrome oxidase subunit sequences. AB - Phylogenetic relationships of Acridoidea were examined using mitochondrial cytochrome oxidase subunit sequences (COI, COII and COIII, total 2970bp). Fourteen grasshopper species of thirteen genera from seven families were sequenced to obtain mitochondrial genes data, along with twenty-two grasshopper species were obtained from the GenBank nucleotide database. The purpose of this study is to infer the phylogenetic relationships among families within Acridoidea and testing the monophyly of Acridoidea and each families of it. Phylogenic trees were reconstructed using Maximum Likelihood (ML) and Maximum Parsimony (MP) methods with Tettigonioidea and Gryllotalpoidea as outgroups. The putative initiation codon for COI is CCG in thirteen studied species and ATC in Bryodema luctuosum luctuosum. The 2970 bp concatenated sequences included 1431 conserved sites, 1539 variable sites, and 1216 parsimony-informative sites, the nucleotide compositions were significantly biased toward A and T (68.8%). The resulted phylogenetic trees supported the monophyly of Acridoidea, but did not entirely agree with the traditional morphology-based taxonomic system of grasshoppers within Acridoidea. The monophyly of three families of Acrididae, Catantopidae and Arcypteridae were not supported; Gomphoceridae and Arcypteridae were recovered together as a monophyletic group because of closer phylogenetic relationships; Pyrgomorphidae and Chrotogonidae have the same closer relationships; Pneumoridae, Pyrgomorphidae and Chrotogonidae were the most basal groups; while the taxonomic status of Pamphagidae, which was revealed as a monophyletic group, was not clear in this analysis. Moreover, the results indicate that a phylogeny inferred from the combination of several genes is more reliable than that from only a single gene sequence, and the third codon positions of protein coding genes can improve the topology and node supports of the phylogenetic trees. PMID- 26624049 TI - A new genus and family of copepods (Crustacea: Copepoda) parasitic on polychaetes of the genus Jasmineira Langerhans, 1880 (family Sabellidae) in the northeastern Atlantic. AB - A new genus and species of copepod, Jasmineiricola mackiei n. gen. et n. sp., parasitic on at least three species of the sabellid polychaete genus Jasmineira Langerhans, 1880 is described. The adult female is mesoparasitic, living with part of its body (the endosoma) embedded within the host and part (the ectosoma) protruding through the host's body wall. The endosoma consists of a well defined head region carried anteriorly on the trunk which has paired lateral lobes housing the ovaries. The head bears a rosette-like array of eight slender lobes, which are probably derived from the mouthparts. The only limbs present on the trunk are the subchelate maxillipeds positioned immediately posterior to the head. The ectosoma consists of a posterior genito-abdominal lobe bearing paired genital apertures. The male is unknown. The new genus cannot be placed in any of the five existing families of mesoparasitic copepods on polychaete hosts and is treated as the type of a new monotypic family, the Jasmineiricolidae. The new species occurs over a depth range from 19 to 279 m, and is widely distributed from UK coastal waters to Norwegian waters inside the Arctic Circle. PMID- 26624050 TI - A new species of Rhagovelia Mayr, 1865 (Hemiptera: Heteroptera: Veliidae) from Brazil. AB - Rhagovelia kararao sp. nov., collected in sandstone caves from northern Brazil, is described and compared with similar and related species. Rhagovelia pachymeri Nieser & Melo, 1997 is synonymized with Rhagovelia robusta Gould, 1931. An updated key to the species of the robusta group occurring in Brazil is presented. PMID- 26624051 TI - A new species of Neuraphes Thomson, 1859 (Coleoptera: Staphylinidae: Scydmaeninae) from Kazakhstan. AB - Neuraphes (s. str.) kazakhstanicus, new species of the tribe Cyrtoscydmini, is described from Kazakhstan. The genus is for the first time recorded from Central Asia. A detailed morphological study is presented. PMID- 26624052 TI - Revision of the Palaearctic genus Gonaporus Ashmead, 1902 of spider wasps (Hymenoptera: Pompilidae). AB - Twelve species (including six new ones) of the spider wasp genus Gonaporus Ashmead, 1902 are revised. The composition of the genus is discussed. Six new species of Gonaporus are described: G. simulator Wahis & I. Zonstein, sp. nov. (? ?, Egypt, Saudi Arabia, United Arab Emirates, Mauritania), G. emiratus I. Zonstein & Wahis, sp. nov. (? ?, United Arab Emirates), G. jaziratensis Wahis & I. Zonstein, sp. nov. (?, United Arab Emirates), G. mirabilis I. Zonstein & Wahis, sp. nov. (? ?, United Arab Emirates, Pakistan), G. setitarsus I. Zonstein & Wahis, sp. nov. (? ?, Pakistan), and G. spinosissimus Wahis & I. Zonstein, sp. nov. (? ?, Oman). A new synonymy is proposed for G. ecbatanus Wolf, 1990 = G. flamingo S. Zonstein, 2001, syn. nov. Gonaporus israelicus (Wolf, 1990), comb. nov. is transferred from Micraporus Priesner, 1955. An emended diagnosis to genus and a key to species are provided. The Gonaporus species inhabit open arid sandy biotopes of the Mediterranean Region, Africa, Near East and Central Asia. The subgenus Stigmaporus S. Zonstein, 2001 is elevated to full generic rank, stat. nov. A new combination is proposed for S. centralasiaticus (Wolf, 1990), comb. nov., S. lystracantha (Wolf, 1988), comb. nov. and S. wolfi (S. Zonstein, 2001), comb. nov. (all are from genus Gonaporus). PMID- 26624053 TI - The genus Notomicrus in Guadeloupe, with description of three new species (Coleoptera: Noteridae). AB - The genus Notomicrus Sharp, 1882 is recorded from Guadeloupe for the first time. Examination of recently collected material revealed the presence of four species, of which three are described as new species so far endemic to Guadeloupe. Notomicrus sabrouxi sp. n. is akin to the continental Neotropical species N. gracilipes Sharp, 1882 and N. traili Sharp, 1882. Notomicrus chailliei sp. n. and N. femineus sp. n. are sibling species which diverge from each other by 3.4% of observed distance in cytochrome oxidase 1 sequences. The latter species seems to be comprised of only females, and is suspected to reproduce by obligate parthenogenesis. The fourth species is N. sharpi Balfour-Browne, 1939. These species are morphologically described notably through scanning electron microscopy study, and data on their distribution in the Guadeloupe archipelago and habitat preferences are presented and discussed. PMID- 26624054 TI - Two new species of family Neotanaidae (Peracarida: Tanaidacea) from the Antarctic and Mid-Pacific Oceans. AB - Samples collected from the Antarctic (ANDEEP/2002) and Mid-Pacific (BIONOD/2012) Oceans allowed analyses of several specimens of the family Neotanaidae. From these surveys two new species are described: Neotanais bicornutus and Venusticrus thor. The new material led to a re-diagnosis of Venusticrus, and N. rotermundiae is now assigned to this genus. The male of N. bicornutus shares a number of characters with the "robustus" species group, but differs by having a pleotelson about 1.5 times as wide as long, cheliped carpus about 1.5 times as long as cephalothorax, cheliped propodus with two long dorsal projections, and uropod endopod article 1 with 8-10 fine setae proximal to mid-length on outer margin. The N. bicornutus preparatory female differs from all species by a combination of characters including the number of setae on dorsal margin of cheliped carpus (about 15 setae), the uropod attachment slightly posterior to mid-length, uropod basal article about 2.7 times as long as endopod article 1. The female of V. thor differs from those of V. insolitus, V. glandurus and V. rotermundiae by the body proportions, the pleon having three lateral setae on epimera, pleon with a blunt ventral keel, pereopodal setation, number of setae on maxilliped endite and basis as well as other characters. Total genomic DNA was extracted from two specimens of V. thor and sequences of two genes, i.e., cytochrome oxidase 1 (COI) and ribosomal (28S) were obtained. PMID- 26624055 TI - Three new species of the genus Xiphidiopsis Redtenbacher, 1891 (Orthoptera: Tettigoniidae: Meconematinae) in China. AB - The article reported three new species of the genus Xiphidiopsis Redtenbacher, 1891 in China: Xiphidiopsis (Xiphidiopsis) minorincisus Han, Chang & Shi sp. nov., Xiphidiopsis (Xiphidiopsis) protensus Han, Chang & Shi sp. nov. and Xiphidiopsis (Xiphidiopsis) anisolobulus Han, Di & Shi sp. nov. The type material is deposited in the Museum of Hebei University, Baoding, P. R. China. PMID- 26624056 TI - A new Asian genus of the tribe Elicini (Hemiptera: Fulgoromorpha: Tropiduchidae) with two new species from Vietnam. AB - A new genus Connelicita gen. nov. with 2 new species (C. backyensis sp. nov. and C. haiphongensis sp. nov.) of Tropiduchidae Elicini from Vietnam are described and illustrated. The Chinese species C. lungchowensis (Chou et Lu, 1977) comb. nov. is transferred into this new genus from the genus Sassula (Nogodinidae). A key to species of the new genus distributed in North Vietnam and China (Guangxi) is provided. PMID- 26624057 TI - Candeocoris bistillatus, new genus and new species of Ochlerini from Ecuador (Hemiptera: Heteroptera: Pentatomidae). AB - Recent examination of specimens from Ecuador revealed a series of males and females of an undescribed species clearly belonging to the Discocephalinae. The new species presents characteristics similar to genera of both Discocephalini and Ochlerini, preventing an undoubtful placement of the new species within any genus and tribe. We conducted a cladistic analysis to investigate the possible relationships of the new species within Discocephalinae. The new species was recovered as sister-group to the remaining Ochlerini, supporting the proposition of a new genus, so Candeocoris bistillatus Roell & Campos, gen. n. et sp. n. are described within Ochlerini. The new genus is recognized for its dark glossy aspect, tumid vertex of head, long and sinuous labrum, base of labium placed close to anterior limit of eyes, thick bristles on meso- and metatibiae, pygophore globose, and laterotergites 9 touching each other. The new species is recognized by a large yellow spot on each corium, yellow spots on each segment of the connexivum, bucculae with anterior tooth, laminar projections on superior layer of ventral rim of pygophore, vesica with a single median projection, and broad gonocoxites 8. PMID- 26624058 TI - On the specific status of Hedotettix cristatus Karny, 1915 (Tetrigidae: Tetriginae). AB - Hedotettix cristatus Karny, 1915 is a species described from a single male specimen from Taiwan. Wagan & Kevan in 1992 synonymised the species with Hedotettix punctatus Hancock, 1909. We re-evaluated the specific status of H. cristatus and made a detailed comparison between valuable diagnostic characters. Females of H. cristatus are reported and new localities for the species, found on amateur photos from Taiwan, are presented. H. cristatus stat.rev. is a valid species, endemic to Taiwan, while H. punctatus is a species with a disjunctive distribution, partly in India and partly in China (Hainan, Guangdong, Hubei). The main diagnostic differences between two species are: 1) antennal grooves position: in H. cristatus antennal grooves are situated at the level of the lower margin of the compound eyes or slightly below it, while in H. punctatus, however, antennal grooves are situated slightly above the lower margin of the compound eyes, never at its level or below, 2) scutellum morphology: in H. cristatus, frontal costa bifurcation starts in about upper 1/4 of the compound eye height, while in H. punctatus it starts at the level of upper margin of compound eyes or slightly below (with rare exceptions), 3) ratio of femora length/width: H. cristatus is species of robust femora, while H. punctatus has slender femora and 4) prozonal carinae: indistinguishable in H. cristatus, clear and elevated in H. punctatus. H. cristitergus Hancock, 1915 syn.nov. is synonymized with H. punctatus, as already proposed in some old papers. PMID- 26624059 TI - Sierolomorpha sogdiana spec. nov. from Central Asia, and a World catalogue of Sierolomorphidae (Hymenoptera). AB - Sierolomorpha sogdiana Lelej & Mokrousov, spec. nov. is described and illustrated from Central Asia (Uzbekistan). A key to the Palaearctic species of Sierolomorpha and a World catalogue of the family Sierolomorphidae (13 species in three genera) are given. PMID- 26624060 TI - CHI JIN, JIANYING FU & FENG ZHANG (2015) A review of the genus Abdosetae (Araneae: Phrurolithidae) from China. Zootaxa, 4007 (1): 091-103. PMID- 26624063 TI - Polychaetes and allies of Lizard Island. PMID- 26624064 TI - Lizard Island Polychaete Workshop: sampling sites and a checklist of polychaetes. AB - In August 2013, a two week polychaete workshop was held at Lizard Island, Great Barrier Reef. Twenty-one sites representing 121 collection events were sampled for polychetes around Lizard and on the Outer Barrier. Workshop participants sorted polychaetes to family and each participant received on loan selected families to work up. This Zootaxa monograph describes 91 new species, 67 new records for Lizard Island, and 19 for Australia. Details regarding the habitats and locations are provided in Table 2 together with two maps (Figs 1, 2) showing sampling locations. In this paper we also list previously collected polychaete material from the region together with any published records for families which are not included in this volume. PMID- 26624065 TI - Syllidae (Annelida: Phyllodocida) from Lizard Island, Great Barrier Reef, Australia. AB - Thirty species of the family Syllidae (Annelida, Phyllodocida) from Lizard Island have been identified. Three subfamilies (Eusyllinae, Exogoninae and Syllinae) are represented, as well as the currently unassigned genera Amblyosyllis and Westheidesyllis. The genus Trypanobia (Imajima & Hartman 1964), formerly considered a subgenus of Trypanosyllis, is elevated to genus rank. Seventeen species are new reports for Queensland and two are new species. Odontosyllis robustus n. sp. is characterized by a robust body and distinct colour pattern in live specimens consisting of lateral reddish-brown pigmentation on several segments, and bidentate, short and distally broad falcigers. Trypanobia cryptica n. sp. is found in association with sponges and characterized by a distinctive bright red colouration in live specimens, and one kind of simple chaeta with a short basal spur. PMID- 26624066 TI - Neosabellides lizae, a new species of Ampharetidae (Annelida) from Lizard Island, Great Barrier Reef, Australia. AB - Neosabellides lizae, a new species of Ampharetidae, is described from the intertidal zone off Lizard Island, Great Barrier Reef, Queensland, Australia. The new species is referred to the genus Neosabellides based on the shape of the prostomium, three pairs of branchiae, 14 thoracic segments with notopodia, 12 thoracic uncinigerous segments, and the first two pairs of abdominal uncinigers of thoracic type. The new species differs from all known species of Neosabellides in having 14 abdominal uncinigerous segments. PMID- 26624067 TI - Glyceriformia Fauchald, 1977 (Annelida: "Polychaeta") from Lizard Island, Great Barrier Reef, Australia. AB - Eight species of Glyceridae (Glycera brevicirris, Glycera cf. lapidum, Glycera onomichiensis, Glycera sagittariae, Glycera tesselata, Glycera tridactyla, Glycerella magellanica, Hemipodia cf. simplex) and six species of Goniadidae (Goniada antipoda, Goniada cf. brunnea, Goniada echinulata, Goniada emerita, Goniada grahami, Goniada paucidens) have been collected during several expeditions to the vicinity of Lizard Island (Australia, Queensland). An identification key to the Glyceriformia that inhabit the region is presented. Detailed and illustrated morphological descriptions are given for all investigated species. PMID- 26624068 TI - A taxonomic guide to the fanworms (Sabellidae, Annelida) of Lizard Island, Great Barrier Reef, Australia, including new species and new records. AB - This comprehensive taxonomic work is the result of the study of fan worms (Sabellidae, Annelida) collected over the last 40 years from around the Lizard Island Archipelago, Great Barrier Reef, Australia. Some species described herein are commonly found in Lizard Island waters but had not previously been formally reported in the literature. Most species appear to be not particularly abundant, and few specimens have been collected despite the sampling effort in the area over this time period. After this study, the overall sabellid diversity of the archipelago has been greatly increased (by more than 650%). Before this revision, only four sabellid species had been recorded for Lizard Island, and in this paper we report 31 species, 13 of which belong to nominal species, six are formally described as new species (Euchone danieloi n. sp., Euchone glennoi n. sp., Jasmineira gustavoi n. sp., Megalomma jubata n. sp., Myxicola nana n. sp., and Paradialychone ambigua n. sp.), and the identity of 12 species is still unknown (those referred as cf. or sp.). Two species are newly recorded in Australia and two in Queensland. The invasive species Branchiomma bairdi is reported for the first time at Lizard Island. The genus Paradialychone is reported for Australia for the first time. Standardised descriptions, general photographs of live and/or preserved specimens and distribution data are provided for all species. New species descriptions are accompanied by detailed illustrations and exhaustive morphological information. A dichotomous key for sabellid identification is also included. PMID- 26624069 TI - Sphaerodoridae (Annelida) from Lizard Island, Great Barrier Reef, Australia, including the description of two new species and reproductive notes. AB - Sphaerodorids are scarce at Lizard Island archipelago and other localities in the Great Barrier Reef, Australia. Intensive collections at a variety of habitats within the Lizard Island archipelago over the last four decades have resulted in a total of just 11 specimens. Nevertheless, they represent two new species and a new record for Lizard Island. Sphaerodoropsis aurantica n. sp. is characterised by nine longitudinal rows of sessile and spherical dorsal macrotubercles, arranged in a single transverse row per segment; parapodia with around 10 spherical papillae; and compound chaetae with thin shafts and long blades. Sphaerodoropsis plurituberculata n. sp. is characterised by more than 12 more or less clearly arranged longitudinal rows of sessile spherical dorsal tubercles (variable in size), in four transverse rows per segment; parapodia lacking papillae; and semi-compound chaetae with distally enlarged shaft and short blades. Ephesiella australiensis is reported for the first time in Lizard Island. Laboratory observations of live specimens of Sphaerodoropsis plurituberculata n. sp., revealed the use of spermatophores by males. These were found attached externally to the body surface of both sexes, indicating pseudo-copulation. PMID- 26624070 TI - Sabellariidae from Lizard Island, Great Barrier Reef, including a new species of Lygdamis and notes on external morphology of the median organ. AB - We document herein the occurrence of three species of Sabellariidae at Lizard Island, Great Barrier Reef, including a new Lygdamis species. Sabellaria lungalla, described from Northern Territory, is reported for Queensland for the first time. The genus Gesaia, represented by a planktonic larva collected in shallow waters of the Archipelago, is a new record for Australia. Lygdamis nasutus n. sp. is characterised by one of the most conspicuous median organ described in the family (cylindrical, distally pigmented and is provided with a flattened, teardrop corona), its paleae morphology (with straight paleae, outer ones with asymmetrical pointed tips and subtle thecal sculpture and inner paleae with blunt tips and smooth surface), three lateral lobes on chaetiger 2, abdominal chaetigers with two type of neurochaetae, and notopodial uncini with 1 4 longitudinal rows of teeth. Comparison of the external morphology of the medial organ and median ridge of several species has been undertaken. Even though its function remains uncertain, the median organ morphology seems species specific and may provide relevant information about the evolutionary history and adaptations of sabellariids. PMID- 26624071 TI - Nereididae (Annelida: Phyllodocida) of Lizard Island, Great Barrier Reef, Australia. AB - Nereididae is one of the most ubiquitous of polychaete families, yet knowledge of their diversity in the northern Great Barrier Reef is poor; few species have been previously reported from any of the atolls or islands including Lizard Island. In this study, the diversity of the family from Lizard Island and surrounding reefs is documented based on museum collections derived from surveys conducted mostly over the last seven years. The Lizard Island nereidid fauna was found to be represented by 14 genera and 38 species/species groups, including 11 putative new species. Twelve species are newly reported from Lizard Island; four of these are also first records for Australia. For each genus and species, diagnoses and/or taxonomic remarks are provided in addition to notes on their habitat on Lizard Island, and general distribution; the existence of tissue samples tied to vouchered museum specimens is indicated. Fluorescence photography is used to help distinguish closely similar species of Nereis and Platynereis. A key is provided to facilitate identification and encourage further taxonomic, molecular and ecological studies on the group. PMID- 26624072 TI - Telothelepodidae, Thelepodidae and Trichobranchidae (Annelida, Terebelliformia) from Lizard Island, Great Barrier Reef, Australia. AB - In a survey of the polychaetes of the Lizard Island region, six species of polychaetes belonging to the families Telothelepodidae Nogueira, Fitzhugh & Hutchings, 2013, Thelepodidae Hessle, 1917 and Trichobranchidae Malmgren, 1866 were found, from material collected during the Lizard Island Polychaete Taxonomic Workshop, and material collected by previous projects undertaken by the Australian Museum. This material includes one new species of Rhinothelepus Hutchings, 1974 (Telothelepodidae); one new species of each of the genera, Euthelepus McIntosh, 1885, Streblosoma Sars, 1872, and Thelepus Leuckart, 1849 (Thelepodidae); and one new species of Terebellides Sars, 1835 and another of Trichobranchus Malmgren, 1866 (Trichobranchidae). Keys for identification of these species are provided, together with full descriptions for all species, as well as comparisons with the morphologically most similar congeners. PMID- 26624073 TI - Serpulidae (Annelida) of Lizard Island, Great Barrier Reef, Australia. AB - Serpulidae are obligatory sedentary polychaetes inhabiting calcareous tubes that are most common in subtropical and tropical areas of the world. This paper describes serpulid polychaetes collected from Lizard Island, Great Barrier Reef, Australia in 1983-2013 and deposited in Australian museums and overseas. In total, 17 serpulid genera were recorded, but although the study deals with 44 nominal taxa, the exact number of species remains unclear because a number of genera (i.e., Salmacina, Protula, Serpula, Spirobranchus, and Vermiliopsis) need world-wide revisions. Some species described herein are commonly found in the waters around Lizard Island, but had not previously been formally reported. A new species of Hydroides (H. lirs) and two new species of Semivermilia (S. annehoggettae and S. lylevaili) are described. A taxonomic key to all taxa found at Lizard Island is provided. PMID- 26624074 TI - New records of Cotylea (Polycladida, Platyhelminthes) from Lizard Island, Great Barrier Reef, Australia, with remarks on the distribution of the Pseudoceros Lang, 1884 and Pseudobiceros Faubel, 1984 species of the Indo-Pacific Marine Region. AB - In the present work eleven polyclad species of Lizard Island are studied. Seven of them are new records for this locality of the Australian coral reef and one is new to science, Lurymare clavocapitata n. sp. (Family Prosthiostomidae). The remaining recorded species belong to the genera Pseudoceros (P. bimarginatus, P. jebborum, P. stimpsoni, P. zebra, P. paralaticlavus and P. prudhoei) and Pseudobiceros (Pb. hancockanus, Pb. hymanae, Pb. flowersi and Pb. uniarborensis). Regardless of the different distribution patterns, all pseudocerotid species show brilliant colours, but similar internal morphology. Furthermore, differences in the form and size of the stylet are characteristic, because it is a sclerotic structure that is not affected during fixation. In Pseudoceros, the distance between the sucker and the female pore also differs among species. These features do not vary enough to be considered as diagnostic, but they provide information that can help to disentangle similarly coloured species complexes. A key of the genera Pseudoceros and Pseudobiceros of the Indo-Pacific region is provided, in order to facilitate the identification of species from this area. PMID- 26624075 TI - Spionidae (Annelida: 'Polychaeta': Canalipalpata) from Lizard Island, Great Barrier Reef, Australia: the genera Malacoceros, Scolelepis, Spio, Microspio, and Spiophanes. AB - Seven species belonging to the spionid genera Malacoceros, Scolelepis, Spio, Microspio, and Spiophanes were found during the polychaete workshop on Lizard Island in August 2013. One species is new to science and named Scolelepis inversa n. sp., another Scolelepis species is probably also a new species but was represented in our samples by only a single specimen and not formally described. All other species have been reported previously from Australia. Species diagnoses of all species found during the workshop and of Scolelepis balihaiensis Hartmann Schroder, 1979, Microspio microcera (Dorsey, 1977) and M. minuta (Hartmann Schroder, 1962) have been critically reviewed and amended based on the study of type material. The potential synonymy of Microspio minuta (Hartmann-Schroder, 1962) and M. microcera (Dorsey, 1977) is discussed. The new combination Spio jirkovi (Sikorski, 1992) proposed by Sikorski (2013) is returned to Malacoceros. We added DNA barcodes for five species collected in the Lizard Island area to public databases which will be useful in future phylogenetic and phylogeographic studies. For Microspio we provide the first sequence data for this genus. PMID- 26624076 TI - Nephtyidae (Annelida: Phyllodocida) of Lizard Island, Great Barrier Reef, Australia. AB - Seven species of the family Nephtyidae are recorded from Lizard Island, none previously reported from the Great Barrier Reef. Two species of Aglaophamus, four species of Micronephthys, one new and one previously unreported from Australia, and one species of Nephtys, were identified from samples collected during the Lizard Island Polychaete Workshop 2013, as well as from ecological studies undertaken during the 1970s and deposited in the Australian Museum marine invertebrate Collections. A dichotomous key to aid identification of these species newly reported from Lizard Island is provided. PMID- 26624077 TI - Polycirridae (Annelida, Terebelliformia) from Lizard Island, Great Barrier Reef, Australia. AB - In a survey of the polychaetes of the Lizard Island Group, sixteen species of polycirrids were found, from material collected during the two weeks Lizard Island Taxonomic Workshop, together with material collected by previous projects of the Australian Museum based at Lizard Island, including CReefs (http://www. AIMS: gov.au/creefs/field-program.html). Those species are distributed as follows: two species of Amaeana Hartman, 1959, one new species of Hauchiella Levinsen, 1893, 2 species of Lysilla Malmgren, 1866, one of which is new to science, and 11 species of Polycirrus Grube, 1850, eight of which are new to science. Keys for identification of these genera and species are provided, together with full descriptions for all species, except for those with recent descriptions, and comparisons with the morphologically most similar congeners, in the case of the new species. PMID- 26624078 TI - Terebellidae (Annelida, Terebelliformia) from Lizard Island, Great Barrier Reef, Australia. AB - In a survey of the polychaetes of the Lizard Island region, sixteen new species of terebellids, plus one previously described species, were found from material collected during the two week long Lizard Island Taxonomic Workshop in 2013, along with material collected from previous projects carried out at Lizard Island. This included the CReefs Project (http://www. AIMS: gov.au/creefs/field program.html), of which Lizard was one of the nodes. Those species are distributed as follows: one species of each of the following genera Eupolymnia Verrill, 1900, Lanice Malmgren, 1866; Lanicides Hessle, 1917, Lanicola Hartmann Schroder, 1986, Pistella Hartmann-Schroder, 1996, Reteterebella Hartman, 1963, and Terebella Linnaeus, 1767; two species of Nicolea Malmgren, 1866; three species of Pista Malmgren, 1866 and four of Loimia Malmgren, 1866, together with another new species, belonging to the new genus Lizardia n. gen. Keys for identification of these genera and species are provided, together with generic diagnoses and full descriptions for all species; for each new species, comparisons with the morphologically most similar congeners are provided. A redescription of Reteterebella queenslandia Hartman, 1963 is also included. PMID- 26624079 TI - Six new species of the genus Armandia Filippi, 1861 (Polychaeta, Opheliidae) from Lizard Island (Great Barrier Reef, Australia). AB - From the study of the material collected during the Polychaete Workshop held in Lizard Island (Great Barrier Reef, Australia) in August 2013, six species belonging to the genus Armandia (Polychaeta, Opheliidae) are newly described. Armandia bifida n. sp. is characterised by the bifid shape of the prechaetal lobe in CH1-CH3, A. dolio n. sp. by the barrel-shaped anal (=pygidial) tube (=funnel), A. filibranchia n. sp. by the extremely long and thin branchiae, A. laminosa n. sp. by the foliose shape and large size of the prechaetal lobe in CH1-CH3, A. paraintermedia n. sp. by the squared-shaped anal tube and size and shape of anal cirri, and A. tubulata n. sp. by the tubular shape of the anal tube. All species are fully described and illustrated, and compared with similar species. Several body characters of taxonomic relevance (e.g., anal tube and parapodia shape) are studied based on SEM micrographs. A key of the Armandia species hitherto described or reported in South-East Asia and Australasia is provided based on features of the anal tube. PMID- 26624080 TI - The Oweniidae (Annelida; Polychaeta) from Lizard Island (Great Barrier Reef, Australia) with the description of two new species of Owenia Delle Chiaje, 1844. AB - Study of the Oweniidae specimens (Annelida; Polychaeta) from Lizard Island (Great Barrier Reef, Australia) stored at the Australian Museum, Sydney and newly collected in August 2013 revealed the presence of three species, namely Galathowenia quelis Capa et al., 2012 and two new species belonging to the genus Owenia Delle Chiaje, 1844. Owenia dichotoma n. sp. is characterised by a very short branchial crown of about 1/3 of thoracic length which bears short, dichotomously-branched tentacles provided with the major division close to the base of the crown. Owenia picta n. sp. is characterised by a long branchial crown of about 4/5 of thoracic length provided with no major divisions, ventral pigmentation on thorax and the presence of deep ventro-lateral groove on the first thoracic chaetiger. A key of Owenia species hitherto described or reported in South East Asia and Australasia regions is provided based on characters of the branchial crown. PMID- 26624081 TI - Minibrachium, a new subgenus of Rhamphobrachium (Annelida: Onuphidae) from Australia with the description of three new species. AB - This study describes a new subgenus of miniature, progenetic Rhamphobrachium species from eastern Australia. Minibrachium, n. subg. is characterised by such paedomorphic features as lack of peristomial cirri and branchiae, possession of only two pairs of modified parapodia with spiny recurved hooks and very early onset of subacicular hooks. Three new species are described, of which at least R. (Minibrachium) nutrix n. sp., the type species (from Lizard Island, Great Barrier Reef), is a fully grown adult, brooding several 16- to 20-chaetiger juveniles in the parental tubes. Rhamphobrachium (M.) talboti n. sp. (from off Sydney) and R. (M.) fractum n. sp. (from Bass Strait), although twice as large as the type species, have only partially developed frontal lips, indicating either incomplete growth or presenting an additional paedomorphic character. We discuss the position of the new subgenus in the Rhamphobrachium complex and present a key to the subgenera of Rhamphobrachium and species of R. (Minibrachium). PMID- 26624082 TI - Spionidae (Annelida) from Lizard Island, Great Barrier Reef, Australia: the genera Aonides, Dipolydora, Polydorella, Prionospio, Pseudopolydora, Rhynchospio, and Tripolydora. AB - Nineteen species in seven genera of spionid polychaetes are described and illustrated based on new material collected from the intertidal and shallow waters around the Lizard Island Group, northern Great Barrier Reef. Only one of these species had been previously reported from the Reef. Six species are described as new to science, and the taxonomy of seven species should be clarified in the future. Prionospio sensu lato is the most diverse group with 11 species identified in the present study. One species is identified in each of the genera Dipolydora, Polydorella, Rhynchospio and Tripolydora, and two species are identified in each of the genera Aonides and Pseudopolydora. The fauna of spionid polychaetes of the Great Barrier Reef seems to be more diverse than previously described and more species are expected to be found in the future. An identification key is provided to 16 genera of Spionidae reported from or likely to be found on the Great Barrier Reef. PMID- 26624083 TI - Six genetically distinct clades of Palola (Eunicidae, Annelida) from Lizard Island, Great Barrier Reef, Australia. AB - A total of 36 lots of Palola spp. (Eunicidae, Annelida) were collected during the Lizard Island Polychaete Workshop on Lizard Island, Great Barrier Reef, Queensland, Australia. Of these, 21 specimens were sequenced for a portion of the mitochondrial cytochrome c oxidase I gene. These sequences were analysed in conjunction with existing sequences of Palola spp. from other geographic regions. The samples from Lizard Island form six distinct clades, although none of them can clearly be assigned to any of the nominal species. Four of the six Lizard Island clades fall into species group A and the remaining two into species group B (which also includes the type species, Palola viridis). All sequenced specimens were characterized morphologically as far as possible and a dichotomous key was assembled. Based on this key, the remaining samples were identified as belonging to one of the clades. PMID- 26624084 TI - Seven new species of Paleanotus (Annelida: Chrysopetalidae) described from Lizard Island, Great Barrier Reef, and coral reefs of northern Australia and the Indo Pacific: two cryptic species pairs revealed between western Pacific Ocean and the eastern Indian Ocean. AB - Morphological investigation into the paleate genus Paleanotus Schmarda 1861 of the family Chrysopetalidae from northern Australian coral reefs, primarily Lizard Island and outlying reefs, included a complex of very small, slender individuals (length < 5 mm). This complex resolved into 7 new species, described herein: Paleanotus inornatus n. sp., P. adornatus n. sp., P. chrysos n. sp., P. aquifolia n. sp., P. latifolia n. sp., P. silus n. sp., and P. silopsis n. sp. A key is provided to the new species and Paleanotus distinguished from Treptopale and Hyalopale, two closely related genera. Diagnostic features of the apical structure and shape of the notochaetal main paleae plus median paleae shape and raised rib pattern, differentiates each species from the other. Gametous states are described. Two cryptic species pairs (Paleanotus silopsis n. sp. and P. silus n. sp.; Paleanotus aquifolia n. sp. and P. latifolia n. sp.) were identified. In each case one species is restricted to either the NE or NW Australian coast. In each pair the most eastern point for the NW Australian species range occurs at Darwin, western Arnhemland, Northern Territory. Additional material for each species pair extends their respective ranges northwards: NW Australia to Thailand, Andaman Sea, eastern Indian Ocean or NE Australia, Great Barrier Reef to the Philippines, western Pacific Ocean. Cryptic morphology and potential genetic diversity is discussed in Paleanotus inornatus n. sp. and P. adornatus n. sp. that possess overlapping widespread distribution patterns across northern Australia and Indo-Pacific reefs. The smallest bodied taxon, Paleanotus chrysos n. sp. is the only species with a Coral Sea range encompassing Lizard Island, Heron Island and New Caledonia. PMID- 26624085 TI - New records of Pectinariidae (Polychaeta) from Lizard Island, Great Barrier Reef, Australia and the description of two new species. AB - Five species of Pectinariidae have previously been reported from Australia. This study documents the first records of this family from the Lizard Island region: Pectinaria antipoda is recorded, in addition to its already currently wide Australian distribution; two new species, Amphictene lizardensis n. sp. and Pectinaria carnosus n. sp. were also discovered and described. A key to all Australian species of Pectinariidae is provided. PMID- 26624086 TI - New and previously known species of Oenonidae (Polychaeta: Annelida) from Lizard Island, Great Barrier Reef, Australia. AB - The family Oenonidae consists of Eunicida species with prionognath jaws. Its Australian fauna had been reported to comprise six species belonging to Arabella, Drilonereis, and Oenone. This study provides descriptions for four new species, redescriptions for three species (two previously recorded and a new record, Drilonereis cf. logani) and diagnoses for the genera recorded from Australia. Currently, eleven species of oenonids, distributed in three genera, are known for the Australian coast. On Lizard Island, this family shows low abundance (19 specimens collected) and high richness (seven species). Our results suggest that despite the increasing accumulation of information, the biodiversity of the family is still poorly estimated. PMID- 26624087 TI - Orbiniidae (Annelida: Errantia) from Lizard Island, Great Barrier Reef, Australia with notes on orbiniid phylogeny. AB - The fauna of Orbiniidae (Annelida: Errantia) from the Lizard Island has been studied. Five species were found and each was redescribed and illustrated using light microscopy and SEM. Scoloplos acutissimus Hartmann-Schroder, 1991 and Scoloplos dayi Hartmann-Schroder, 1980 collected for the first time since their original descriptions and confirmed through re-examination of their type materials. Molecular analyses were carried out using nuclear 18S rDNA and mitochondrial 16S rDNA and CO1 gene sequences with evolutionary distances and the Neighbor-Joining Method. The molecular analyses did not support the monophyly of the genera Scoloplos, Leitoscoloplos, Leodamas, and Naineris, and its results are incongruent with morphological data. PMID- 26624088 TI - Revealing the diversity of Cloeodes Traver, 1938 (Ephemeroptera: Baetidae) in the Neotropics: description of eleven new species from Brazilian mountain ranges. AB - In the present work, based on material from distinct mountain ranges in Brazil, 11 new species of Cloeodes with hind wings or hind wing pads are described, illustrated and discussed. Among the new species, in C. aiuruoca, C. amantykyra, C. atlanticus, C. boldrinii and C. ioachimi, the apex of the fore femora in the nymphs is extremely projected (a characteristic previously found only in two species of the genus). Cloeodes guara and C. tracheatus share the presence of unusual large and dark gills. Cloeodes melanotarsus is readily distinguished by conspicuous blackish tarsi, C. lucifer by the bright yellow coloration of tergum I, and C. xyrognathos by blade-like incisors. Cloeodes magnus, besides being the largest species of the genus, with a body size reaching 12 mm, possess short maxillary palp. Comments on the presence of C. irvingi and C. opacus in Brazil are also provided. An interactive online key is provided for the nymphs of all the species of Cloeodes in which hind wing pads are present. PMID- 26624089 TI - Taxonomic review of the major larval pests of bolete fungi (Boletaceae) in Europe: The Pegomya fulgens, furva and tabida species groups (Diptera: Anthomyiidae). AB - A taxonomic review of the European species of the Pegomya fulgens, furva and tabida species groups is given with emphasis on characters of importance for the identification of males and females. These Pegomya species groups are represented in Europe by two, two and nine species, respectively. Their mycophagous larvae may all feed exclusively on bolete sporocarps of Leccinum and Boletus aff. edulis. Their relationships and biology are summarized. Each species is given a selective list of references and synonymy, richly illustrated descriptions of males and females, a list or summary of the examined material, and a synopsis of the known distribution and biology. Pegomya ringdahli sp. nov., previously confused with P. scapularis (Zetterstedt, 1846), is described from Fennoscandia. Lectotypes are designated for Anthomyia fulgens Meigen, 1826 and Pegomyia (Pegomyia) furva Ringdahl, 1938. An identification key is given to all 17 species (males and females) of Pegomya that supposedly feed as larvae on sporocarps of Boletaceae and Suillaceae in Europe. PMID- 26624090 TI - Two new species of erect Bryozoa (Gymnolaemata: Cheilostomata) and the application of non-destructive imaging methods for quantitative taxonomy. AB - Two new species of cheilostome Bryozoa are described from continental-slope habitats off Mauritania, including canyon and cold-water coral (mound) habitats. Internal structures of both species were visualised and quantified using microcomputed tomographic (micro-CT) methods. Cellaria bafouri n. sp. is characterised by the arrangement of zooids in alternating longitudinal rows, a smooth cryptocyst, and the presence of an ooecial plate with denticles. Smittina imragueni n. sp. exhibits many similarities with Smittina cervicornis (Pallas, 1766), but differs especially in the shape and orientation of the suboral avicularium. Observations on Smittina imragueni and material labelled as Smittina cervicornis suggest that the latter represents a species group, members of which have not yet been discriminated, possibly because of high intracolony variation and marked astogenetic changes in surface morphology. Both new species are known only from the habitats where they were collected, probably reflecting the paucity of bryozoan sampling from this geographic area and depth range. Both species are able to tolerate low oxygen concentration, which is assumed to be compensated by the high nutrient supply off Mauritania. The application of micro-CT for the semiautomatic quantification of zooidal skeletal characters was successfully tested. We were able to automatically distinguish individual zooidal cavities and acquire corresponding morphological datasets. Comparing the obtained results with conventional SEM measurements allowed ascertaining the reliability of this new method. The employment of micro-CT allows the observation and quantification of previously unseen characters that can be used in describing and differentiating species that were previously indistinguishable. Furthermore, this method might help elucidate processes of colony growth and the function of individual zooids during this process. PMID- 26624091 TI - A checklist of the ants (Hymenoptera: Formicidae) of Peru. AB - The article presents a comprehensive list of the ants (Hymenoptera: Formicidae) of Peru. Distribution data for 592 valid names of species-group taxa in 76 genera and 12 subfamilies were collected through a bibliographical review. The most diverse subfamilies in terms of species richness are Myrmicinae (273 species/subspecies), Formicinae (86 species/subspecies) and Ponerinae (71 species/subspecies). The most diverse genera are Pheidole (86 species/subspecies), Camponotus (73 species/subspecies), and Pseudomyrmex (47 species/subspecies). With respect to geographic divisions, richness is highest in Madre de Dios (245 species/subspecies), followed by Huanuco (109 species/subspecies) and Cusco (104 species/subspecies). Regions in greatest need of additional survey work are Aycucho, Huancavelica, Moquegua and Tacna, from which virtually no information on the ant fauna is available. PMID- 26624092 TI - New genus, new species and new record of Neanurinae (Collembola, Neanuridae) for the Neotropics. AB - A new genus and a new species of Paleonurini (Collembola, Neanurinae) are described in this paper. The new species Ectonura snowdeni sp. nov., is the first record of the austral genus Ectonura for the Neotropics. A new genus from Southeast Brazil, Itanura gen. nov., is created based mainly on head tubercles arrangement. Its type species is Neanura brasiliensis Arle, 1959 comb. nov., which is redescribed with the designation of a lectotype. Its distribution range is expanded with two new records from high altitude mountains of Southeast Brazil. Specimens from these two localities exhibit small morphological differences with those of the type locality, which are discussed. PMID- 26624093 TI - Revision of Taiwanaenidea Kimoto, 1984 (Coleoptera: Chrysomelidae: Galerucinae). AB - The genus Taiwanaenidea Kimoto, 1984 is a little-known galerucine genus known only with original description, which lacks illustrations. A number of specimens belonging to this genus are now available for study with effective collection made by Taiwan Chrysomelid Research Team. Two new species, T. cheni Lee and Beenen sp. nov. and T. jungchangi Lee and Beenen sp. nov. are here described. The other two known species, T. collaris Kimoto, 1984 and T. strigosa Kimoto, 1984 are reviewed and illustrations of diagnostic characters are presented. A key to all species of this genus is provided. PMID- 26624094 TI - The Costa Rican Systenus Loew (Diptera: Dolichopodidae): rich local sympatry in an otherwise rare genus. AB - The Costa Rican Systenus Loew (Diptera: Dolichopodidae: Medeterinae) are described, illustrated and keyed, and comprise nine new species: Systenus divericatus sp. nov., S. eboritibia sp. nov., S. emusorum sp. nov., S. flavifemoratus sp. nov., S. maculipennis sp. nov., S. naranjensis sp. nov., S. parkeri sp. nov., S. tenorio sp. nov., and S. zurqui sp. nov. Eight species are known only from Malaise traps at a locale in Guanacaste Province, in contrast to a single species collected as part of the long running INBio survey of the Costa Rican insect fauna. On a global scale, Systenus is uncommon in collections, possibly the result of its known larval tree hole habitat and adult arboreal associations, making the genus less likely to be captured by ground-level trapping. This makes the high level of sympatry at one site even more remarkable and suggesting that more cryptic species-rich arboreal faunas await discovery. PMID- 26624095 TI - Diversity of spiders in Fanjing Mountain Nature Reserve, Guizhou, China,
III: A new species of Brommella (Dictynidae). AB - A new Chinese species of the dictynid genus Brommella Tullgren-Brommella digitata sp. nov.-from Fanjing Mountain Nature Reserve of Guizhou Province is photographed, illustrated and described. It can be distinguished from other Brommella species by the complex conductor and finger-like tegular apophysis of the male palp and anteriorly located copulatory openings of the female epigyne. This is the second species of Brommella from China. Additional photos, illustrations and material of B. punctosparsa (Oi 1957) are provided for comparison. The serrated embolus is firstly described for both species on the basis of SEM photos. PMID- 26624096 TI - Discovery of the first telemid spider (Araneae, Telemidae) from South America, and the first member of the family bearing a stridulatory organ. AB - The genus Kinku n. gen. is established for the first telemid spider found in South America. The new species, Kinku turumanya n. sp. is characterized by the unique conformation of the male palp and the presence of an abdominal anterioventral stridulatory organ. PMID- 26624097 TI - Redescription of Phrurolithus flavipes (Araneae: Phrurolithidae), with the first description of the male. AB - Phrurolithus C.L. Koch, 1839, with 71 named species, is the largest genus of the family Phrurolithidae, which contains 188 species belonging to 14 genera (Platnick 2014). It has an almost exclusively Holarctic distribution: 34 species are known from the Palaearctic, 35 are known from the Nearctic and two species are known from Hispaniola. The genus is rather poorly studied and has never been the subject of wide-scale revision. Almost half of its species are known from a single sex: 23 from females and nine from males. Additionally, 45 species are known from the original description only, and one species has never been illustrated (Platnick 2014). PMID- 26624098 TI - George James Allman (1812-1898): pioneer in research on Cnidaria and freshwater Bryozoa. AB - George James Allman (1812-1898), acclaimed for pioneering studies of Hydrozoa and Bryozoa, was born in Cork, Ireland. He earned B.A. (1839) and M.B. (1843) degrees at Trinity College, Dublin, and an M.D. (1847) from Trinity College and Oxford University. Choosing academia over medicine, he served as Professor of Botany, University of Dublin (1844-1855), and as Regius Professor of Natural History, University of Edinburgh (1855-1870). Allman initially undertook research on freshwater bryozoans, but his interests later turned to marine hydroids. His bibliography, with publication dates retraced herein, comprises more than 200 titles. Most important of these were monographs on limnic Bryozoa (1857) and "gymnoblastic" or anthoathecate Hydrozoa (1871, 1872). Other prime works were on hydroids from the Straits of Florida (1877) and from the Challenger Expedition (1883, 1888). He named 22 families, 64 genera and 283 species of Hydrozoa, along with three families and nine species of Bryozoa. Of these, names of some five families, 19 genera, and 146 species of hydrozoans, along with three families and three species of bryozoans, are currently recognized as valid. For distinguished academic service, Allman was awarded the Royal Medal (Royal Society of London, 1873), the Brisbane Prize (Royal Society of Edinburgh, 1873), the Cunningham Medal (Royal Irish Academy, 1878), the Gold Medal (Linnean Society of London, 1896), and an LL.D. from the University of Edinburgh (1873). He died 24 November 1898 in Parkstone, Dorset, England. Two genera and 22 species have been named in his honour. PMID- 26624099 TI - DNA-based association and description of the larval stage of Apatania helvetica Schmid 1954 (Trichoptera, Apataniidae) with notes on ecology and zoogeography. AB - This paper describes the hitherto unknown larva of Apatania helvetica Schmid 1954. Sequence data from the mitochondrial cytochrome c oxidase region were used to associate adult females and larvae. Genetic data confirmed the autochthonous status of this taxon within the parthenogenetic Apatania muliebris Complex ('sous groupe') sensu Schmid 1954. Information on the morphology of the larva is given, and the most important diagnostic features are illustrated. Apatania helvetica is morphologically close to Apatania muliebris McLachlan 1866 and A. fimbriata (Pictet 1834). In the context of Apataniidae, this trio of species can be separated by the presence of long tapering setae with flexible tips at the anterior border of the pronotum, by a central gap within the transverse setal band on the 1st abdominal dorsum, by biometry of the frontoclypeal setation and by their distribution in Europe. With respect to European ecoregions (Graf et al. 2008), Apatania muliebris has been recorded from the Alps, the central plains and highlands, the Baltic countries, Great Britain, Ireland and Scandinavia; A. fimbriata is known from the Alps, the western and central highlands, the western plains, the Hungarian lowlands and the Carpathians; and A. helvetica is restricted to the Alps and has been recorded only in Switzerland. PMID- 26624101 TI - Trachelostenini sensu novo: redescriptions of Trachelostenus Solier, Myrmecodema Gebien and Leaus Matthews & Lawrence, based on adults and larvae, and descriptions of three new species of Leaus (Coleoptera: Tenebrionidae). AB - The former family Trachelostenidae is returned to tribal status in Tenebrionidae Tenebrioninae and reconstituted to include Trachelostenus Solier, 1851 of southern Chile, currently in a separate family Trachelostenidae, Myrmecodema Gebien, 1943 of central Chile, currently in Stenochiinae-Cnodalonini, and Leaus Matthews & Lawrence, 1992 of eastern Australia, currently in Tenebrioninae Titaenini. The three genera are redescribed in both the adult and larval stages. Three new species: Leaus tropicalis sp.n. L. monteithi sp. n. and L. elusus sp. n. are described. Trachelostenine larval characters are compared with those of related tribes of Tenebrioninae: Titaenini, Heleini, Helopini, Helopinini, Ulomini and Toxicini. The Chilean genus Homocyrtus Dejean is briefly discussed and left incertae sedis in Tenebrionidae. Examination of Lagriola Kirsch (Lagriinae), originally associated with Trachelostenus, leads to the following name changes: Lagriola Kirsch, 1873 = Paratenetus Spinola, 1844, syn. n.; Paratenetus operosus (Kirsch, 1873) (Lagriola), comb. n.; Paratenetus championi, nom. n. for P. denticulatus Champion, 1886 nec P. denticulatus (Kirsch, 1873) (Lagriola) comb. n. PMID- 26624100 TI - A review of the South Pacific Manota Williston (Diptera, Mycetophilidae), with the description of thirteen new species. AB - The genus Manota is found to consist of 37 species in the South Pacific region. The following 13 species are described as new: M. acris sp. n. (Papua New Guinea (PNG)), M. alulata sp. n. (PNG), M. apentachaeta sp. n. (PNG), M. clivicola sp. n. (PNG), M. cordata sp. n. (PNG), M. feminea sp. n. (PNG), M. kaindiensis sp. n. (PNG), M. lunata sp. n. (PNG), M. nimia sp. n. (Solomon Is.), M. pentachaeta sp. n. (PNG), M. siciliculata sp. n. (PNG), M. sigma sp. n. (PNG) and M. unisetata sp. n. (Solomon Is.). New records of the following 11 species are presented: M. bicuspis Hippa, 2007 (PNG, Solomon Is.), M. biunculata Hippa, 2007 (PNG), M. evexa Hippa, 2007 (PNG), M. explicans Hippa, 2007 (PNG), M. hamulata Colless, 1966 (PNG), M. pacifica Edwards, 1928 (Samoa), M. parilis Hippa, 2007 (PNG, Vanuatu), M. perissochaeta Hippa, 2007 (PNG), M. serawei Hippa, 2007 (PNG), M. spathula Hippa, 2007 (PNG) and M. subspathula Hippa, 2007 (Australia). The latter is the first described species of Manota recorded from continental Australia. A redescription of M. pacifica Edwards, 1928 is given. PMID- 26624102 TI - New species and new records of Terebellidae (Annelida: Terebelliformia)
from off the Brazilian coast. AB - Three new species of Terebellidae Grube, 1850 were identified among material collected on hard substrates off the states of Paraiba and Pernambuco, northeastern Brazil. These species are Lanicola hutchingsae sp. nov., Eupolymnia corae sp. nov., and Neoleprea potiguara sp. nov., all herein described and compared with the morphologically most similar congeners. Lanicola hutchingsae sp. nov., is characterized by having lobes of segment 2-3 reaching beyond segment 1, with dorsal margin extending dorsally, covering bases of branchiae, and uncini with 3 rows of secondary teeth above main fang. Eupolymnia corae sp. nov., has lobes of segment 2 laterally higher, with dorsal margins rounded, and lobes of segments 3 and 4 progressively shorter, roughly triangular, with pointed tips, pairs of branchiae progressively shorter, all longitudinally aligned, and uncini throughout with 3 rows of secondary teeth above main fang. Neoleprea potiguara sp. nov., is characterized by having notopodia up to the segment 23, with nephridial papillae on segment 3 and genital papillae on segments 6-19. These are the first records for the genera Lanicola Hartmann-Schroder, 1986 and Neoleprea Hessle, 1917 in Brazilian waters. PMID- 26624103 TI - Descriptions of five new eriophyoid mite species of the Diptilomiopidae (Acari: Trombidiformes: Eriophyoidea) from Zhejiang Province, China. AB - Five new eriophyoid mite species from Zhejiang Province, China are described and illustrated: Diptacus coreanus sp. nov. from Litsea coreana H. Lev. (Lauraceae), Neorhynacus camphoratus sp. nov. from Cinnamomum camphora (L.) J. Presl (Lauraceae), Rhinotergum boehmerius sp. nov. from Boehmeria gracilis C.H. Wright (Urticaceae), Rhyncaphytoptus cathayensis sp. nov from Carya cathayensis Sarg. (Juglandaceae) and Rhyncaphytoptus lanceolatus sp. nov. from Cunnighamia lanceolata (Lamb.) Hook (Cupressaceae). All species were vagrant on their host plants with no visible damage observed. PMID- 26624104 TI - Redescription of the rare Philippine false gecko Pseudogekko brevipes (Reptilia: Squamata: Gekkonidae) and description of a new species. AB - Recent investigations into the species diversity of false geckos (genus Pseudogekko Taylor) have revealed several cryptic species, highlighting the need for a more thorough understanding of diversity within this enigmatic genus of endemic Philippine geckos. Newly available genetic data reveal that two of the four currently recognized species are complexes of multiple deeply divergent evolutionary lineages. In this paper we evaluate species diversity in one of these complexes, P. brevipes Boettger, and describe one additional new species. For nearly a century, P. brevipes has been recognized as a single, "widespread" species with a geographic range spanning two major faunal regions and several island groups. Poor understanding of this species has persisted due to both limited sampling and its apparent rarity. We evaluate both morphological and genetic data to define species limits in P. brevipes, and find character-based evidence to justify the recognition of two unique evolutionary lineages, one of which we describe as a new species (P. atiorum sp. nov.). The species included in this study have allopatric distributions and differ from congeners by numerous diagnostic characters of external morphology, and therefore should be recognized as full species in accordance with lineage-based species concepts. This newly described species increases the total number of species of Pseudogekko to seven. PMID- 26624105 TI - A new species of Ituglanis Costa & Bockmann, 1993 (Siluriformes: Trichomycteridae) endemic to the Tramandai-Mampituba ecoregion, southern Brazil. AB - Ituglanis boitata, new species, is described from the rio Tramandai system and rio Mampituba and Ararangua basins, southern Brazil. This new species is distinguished from congeners with the exception of I. bambui, I. boticario, I. paraguassuensis and I. proops by the supraorbital canal of the cephalic laterosensory system interrupted between nasal and frontal sections and the presence of pore s2 (vs. supraorbital canal uninterrupted and pore s2 absent). Ituglanis boitata differs from these species in osteological characters, measurements and body coloration. Ituglanis boitata presents a noticeable endemism in the Tramandai-Mampituba freshwater ecoregion, a recognized biogeographic unit for freshwater fishes including other 22 endemic species. A discussion about the intraspecific variation in the cephalic laterosensory system within Trichomycterinae is also provided. PMID- 26624107 TI - New species of Oideterus Thomson (Coleoptera, Cerambycidae, Prioninae, Anacolini) and notes on O. lobicollis. AB - Oideterus inaequalis sp. nov. is described from Ecuador and compared with the holotype of O. lobicollis. The latter is excluded from the fauna of Ecuador. A key to known females of Oideterus is provided. PMID- 26624106 TI - Valid or not? Yunnan mountain snake Plagiopholis unipostocularis (Serpentes: Colubridae: Pseudoxenodontinae). AB - Plagiopholis unipostocularis Zhao, Jiang & Huang, 1978 is a small snake endemic to Yunnan, southern China. Its validity is still controversial and unresolved. Based on extensive sampling in Yunnan, we conducted morphological comparison and molecular phylogenetics on the unidentified specimens of Plagiopholis from Yunnan. Based on a combination of morphological comparison and molecular phylogeny, the newly collected specimens could be identified as P. blakewayi. While some specimens exhibit one or more diagnostics of P. unipostocularis, and some characteristics are intermediate between that of Plagiopholis unipostocularis and P. blakewayi. Thus morphological continuities between two species uncovered P. unipostocularis is a synonymy of P. blakewayi, and the diagnostics of this species was revised accordingly. PMID- 26624108 TI - Making future taxonomy of Niphargus (Crustacea: Amphipoda: Niphargidae) in the Middle East easier: DELTA database of Middle East species with description of four new species from Iran. AB - Four new species from the amphipod genus Niphargus are described, namely N. borisi sp. nov., N. bisitunicus sp. nov., N. darvishi sp. nov. and N. sharifi sp. nov. All four species of this predominantly subterranean genus were collected from springs in the Western region of Iran (Zagros region), which is the eastern borderline of the genus range. The species are morphologically diagnosed, described and illustrated. With these newly described species, the total number of Niphargus species in the Middle East reaches twenty-three. In order to facilitate the identification of Niphargus species in the region and to make future taxonomy of the genus easier, we have compiled a database in DEscription Language for TAxonomy (DELTA) using 23 diagnostic traits for these 23 species and subspecies identified in the Middle East. The database is available on the web as supplementary material whereas the dichotomous identification key automatically generated from the database for routine use is provided as a part of the paper. PMID- 26624109 TI - Two new species of the genus Lepidophthalmus (Decapoda, Axiidea, Callianassidae) from coastal Pacific waters of Central America. AB - Two new species of intertidal ghost shrimp are described from coastal Central American habitats of the eastern Pacific Ocean, bringing the total known membership of the genus to 18 species. Lepidophthalmus natesi sp. nov. from Colombia and Nicaragua shares with Lepidophthalmus panamensis sp. nov. from Colombia and Panama the lack of extensive ventral pleomere armor, especially in lacking a median ventral sclerite on the second pleomere. The absence of this plate is also a character of the eastern Pacific species L. rafai Felder & Manning, 1998, but the two new species differ from it in telson shape. Ventral armor including this plate is present in Lepidophthalmus bocourti (A. Milne Edwards, 1870) and L. eiseni Holmes, 1904 which occur sympatrically with L. natesi sp. nov. in eastern Pacific tropical estuaries. As also known for at least L. bocourti, L. natesi sp. nov. invades and densely colonizes penaeid shrimp aquaculture ponds in regional estuarine settings. Individuals of L. panamensis sp. nov. are of smaller body size but also may be densely concentrated, especially in clayey substrates including those adjacent to intertidal rocks. Despite their similarities in the pleon and shape of the telson, the species can be readily separated by dentition of the cheliped fingers, relative length of the minor chela fingers, the second pleopod appendix of mature males, and egg size. The large eggs of L. panamensis sp. nov. suggest extremely abbreviated development. Characteristic coloration is described for both new species. PMID- 26624110 TI - Molecular phylogeny of the genus Lepidophthalmus (Decapoda, Callianassidae), with re-examination of its species composition. AB - Ghost shrimps (Decapoda: Callianassidae) are common estuarine and marine burrowing organisms of tropical to temperate waters, typically found in intertidal to shallow subtidal habitats. Except for an abbreviated planktonic larval phase, most callianassids live as obligate burrowers and appear to depend on the burrow for shelter, reproduction, and feeding. Recent studies have shown the genus Lepidophthalmus, a group largely restricted to estuaries and river mouths, to be surprisingly speciose, but relationships among these taxa and driving forces for their separation remain poorly understood. We include fifteen described species of Lepidophthalmus in a molecular phylogenetic analysis based upon sequence analyses of the 16S and 12S mitochondrial genes. Our findings clarify the monophyletic membership of the genus and confirm postulated species separations. We reconfirm validity of Lepidophthalmus eiseni, reject two recently proposed new genera for selected members of Lepidophthalmus, and define ecologically and morphologically informative clades among congeners. Limited capability for larval dispersal and regional biogeographic history could well account for high diversity and regional endemism observed within the genus. Biogeographic scenarios, including continental drift, closure of the Panamanian Isthmus, and post-glacial dispersals, are invoked to account for proposed reconstructions of historical relationships. PMID- 26624111 TI - Acanthosaura phuketensis (Squamata: Agamidae), a new long-horned tree agamid from southwestern Thailand. AB - We describe a new lowland forest-dwelling species of the genus Acanthosaura from Phuket Island and the Phuket mountain range in southwestern Thailand. Acanthosaura phuketensis sp. nov., the 11th species in the genus, seems most closely related to A. crucigera from Myanmar and western Thailand and A. cardamomensis from the Cardamom Mountains, but can be differentiated from them by a combination of morphological and coloration characteristics. This new discovery stresses the importance of preserving the last forest patches remaining on Phuket Island, home to three other squamate endemics. PMID- 26624112 TI - Two new species of Cyrtodactylus (Squamata: Gekkonidae) from the Southern Bukit Barisan Range of Sumatra and an estimation of their phylogeny. AB - We describe Cyrtodactylus psarops sp. nov. and C. semicinctus sp. nov., two new species of bent-toed geckos from montane forests in the southern Bukit Barisan Range of Sumatra, Indonesia. The new species are closely related to one another and to C. semenanjungensis, a lowland species currently known only from Peninsular Malaysia. Three characters of the new species immediately distinguish them from most congeners in the Sunda Region: they lack transversely enlarged subcaudals, have a precloacal depression, and have a greatly enlarged scale positioned at the apex of a continuous series of femoral and precloacal pore bearing scales. They differ from one another in cephalic pattern, tuberculation of the brachium, and in numbers of cloacal tubercles, dorsal bands, and ventrals in a transverse row. The greatly enlarged scale at the apex of the precloacal pores appears to be a rare apomorphy of these two species and C. agamensis. PMID- 26624113 TI - A new species of pencil smelt Nansenia boreacrassicauda (Microstomatidae, Argentiniformes) from the North Atlantic Ocean. AB - A new microstomatid oceanic species, Nansenia boreacrassicauda spec. nov., is described from the temperate and subarctic Atlantic Ocean. The new species is part of the "stubby caudal peduncle" group and includes the northernmost record of any Nansenia species close to the Arctic Circle. The new species is putatively most similar to the Mediterranean Nansenia iberica, distinguished by a smaller caudal peduncle length/depth ratio, a smaller predorsal distance, more gill rakers, a different lateral line scale type and distribution. Extended Nansenia species distributions and specimens that show extralimital characters in relation to previous works are presented, addressing the current problematic taxonomic issues prevalent in pencil smelts and closely related genera. The new species is described due to increased collecting and taxonomic efforts off Greenland and is not necessarily related to ocean temperature changes. PMID- 26624114 TI - Systematics and distribution of the giant fossil barn owls of the West Indies (Aves: Strigiformes: Tytonidae). AB - After reviewing the systematics and distribution of the extinct West Indian taxa of Tytonidae (Tyto) larger than the living barn owl Tyto alba (Scopoli), we reached the following conclusions: (1) the species T. ostologa Wetmore (1922) is the only giant barn owl known so far from Hispaniola; (2) T. pollens Wetmore (1937) was a somewhat larger and even more robust representative of T. ostologa known from the Great Bahama Bank and Cuba; (3) the very rare species T. riveroi Arredondo (1972b) is here synonymized with T. pollens; (4) the smallest taxon of these giant barn owls is T. noeli Arredondo (1972a), which is widespread and abundant in Quaternary deposits of Cuba and is here reported for the first time from two cave deposits in Jamaica; (5) the only large barn owl named so far from the Lesser Antilles is T. neddi Steadman & Hilgartner (1999), which is here synonymized with T. noeli; (6) a new taxon from Cuba, T. cravesae new species, which in size approached the linear dimensions of T. ostologa, is named and described herein. PMID- 26624115 TI - A new species of the rare Neotropical genus Auloceromyia Lindner, 1969
(Diptera: Stratiomyidae) and the first record of the male of A. pedunculata Pimentel & Pujol-Luz, 2000. AB - A new species of the Neotropical genus Auloceromyia Lindner-A. pachypoda nov. sp. is described and illustrated based on one male from Argentina and twelve females from Mato Grosso do Sul State, Brazil. The male of A. pedunculata Pimentel & Pujol-Luz is described and illustrated for the first time, together with the first description of the female terminalia. A key to the known species of the genus is provided. PMID- 26624116 TI - Additions to thalassinidean fauna (Crustacea: Decapoda) off Mauritania (NW Africa) with the description of a new genus and a new species. AB - The Maurit surveys along the Mauritanian coast revealed the small collection of thalassinideans examined in this work. A total of four species were identified, of which Ezaxius ferachevali n. gen., n. sp. is described and figured here. Calocaris macandreae Bell, 1853 is the most abundant species, while the presence of Calocarides coronatus (Trybom, 1904) is confirmed on the West African coast. Trypaea oblonga n. comb. is proposed for Callianassa oblonga Le Loeuff & Intes, 1974 and it has been recaptured for the first time since its original description, with the addition of a female specimen. We also include remarks on the current status of thalassinidean systematics. PMID- 26624117 TI - Review of the genus Taiwanomyrme Tsuneki, 1993 (Hymenoptera, Mutillidae, Mutillinae), with description of two new species from China. AB - Five species of Taiwanomyrme Tsuneki, 1993 are reviewed; two of them, T. latisquamula Tu, Lelej et Chen, sp. nov. (China: Guizhou) and T. impressoides Tu, Lelej et Chen, sp. nov. (China: Zhejiang, Fujian, Hunan), are described and illustrated. Smicromyrme taiwanus Tsuneki, 1993 is proposed as a new synonym for Taiwanomyrme friekae (Zavattari, 1913). A key to males and females of Taiwanomyrme and additions to the key of females of Oriental genera of the tribes Petersenidiini and Trogaspidiini are given. New ranges are given for T. basirufus (Chen, 1957) and T. impressus (Chen, 1957), specifically within China. PMID- 26624118 TI - Procambarus (Girardiella) holifieldi, a new species of crayfish (Decapoda: Cambaridae) from Alabama with a revision of the Hagenianus Group in the subgenus Girardiella. AB - Procambarus (Girardiella) holifieldi, new species, is a primary burrowing crayfish from a low-lying field in Perry County, Alabama. It belongs to the Hagenianus Group in the subgenus Girardiella. The new species is morphologically most similar to Procambarus (Girardiella) barbiger. They differ in the size and shape of the caudal processes. Procambarus barbiger has a beard along the mesial margin of the palm of the chela, while the new species lacks the beard. In addition to the description of the new species, the Hagenianus Group is reviewed and new synonymies are provided. We demonstrate that a cephalic process is indeed present in the Hagenianus Group. PMID- 26624119 TI - The potato pest Russelliana solanicola Tuthill (Hemiptera: Psylloidea): taxonomy and host-plant patterns. AB - The Neotropical jumping plant-louse Russelliana solanicola Tuthill is a potato pest and a probable vector of plant pathogens. Populations morphologically similar to those found on potatoes have been collected on plants of at least ten different families, four of which have been confirmed as hosts by the presence of immatures. This suggests that R. solanicola is either a single polyphagous species or a complex of closely related, monophagous species (host races/cryptic species). Results of our analyses of multiple morphometric characters show for both sexes a grouping of the populations of R. solanicola and a clear separation of the latter from other Russelliana species. On the other hand, within R. solanicola, there is an overlap of populations from different host-plants as well as from different geographical regions. The results of the present study strongly suggest that R. solanicola is a single, polyphagous species and the known distribution indicates that it is native to the Andes. It is likely that R. solanicola has been introduced into eastern Argentina, Brazil and Uruguay. The polyphagy together with the ability to disperse and transmit plant pathogens potentially make this species an economically important pest of potato and other crop species. PMID- 26624120 TI - Four new species of free-living marine nematodes of the family Desmodoridae (Nematoda: Desmodorida) and a redescription of Desmodora nini (Inglis, 1963) from the continental shelf off northeastern Brazil. AB - Four new species of marine nematodes were collected from the continental shelf of the Potiguar Basin in northeastern Brazil. Zalonema vicentei sp. n. and Zalonema mariae sp. n. are characterized by having multispiral fovea amphidialis, lateral alae and ventral ala. These features also are found in Pseudochromadora, Desmodorella and Psammonema. They differ in the cephalic arrangement, and shape of the cephalic capsule and the fovea amphidialis. Croconema fortis sp. n. resembles Desmodora in the shape of the fovea amphidialis and cephalic capsule, but differs in the number of subcephalic setae and ornamentation on the cuticule. Desmodora paraconica sp. n. is characterized by the loop-shaped fovea amphidialis and the long conical-cylindrical tail. This species is similar to the genus Bolbonema, but differs in having the cephalic setae anterior to the fovea amphidialis. Desmodora nini is redescribed, to record details lacking in the original description. PMID- 26624121 TI - Review of the last instar larvae and pupae of Hexatoma (Eriocera) and Hexatoma (Hexatoma) (Diptera, Limoniidae, Limnophilinae). AB - Description, illustrations and habitat characteristics are given for the previously unknown larvae and pupae of Nearctic species Hexatoma (Eriocera) californica, H. (E.) fuliginosa and East Palaearctic species H. (E.) sachalinensis, H. (E.) stackelbergi, H. (E.) ussuriensis and H. (s.str.) nubeculosa. Hexatoma (E.) sachalinensis, H. (E.) stackelbergi, and H. (s.str.) nubeculosa are reported new for Mongolia based on larval and reared adult collections. There are no distinguishing morphological characters to separate last instar larvae of the subgenera H. (Eriocera) and H. (Hexatoma), while pupae of these subgenera can be separated by the size and shape of the spines on the terminal segments. This study indicates that microscopic setae on the last abdominal segment, length of maxillary palpi, sclerotization of the spiracular field, length of spiracular lobes, length of setae on the apical part of the ventral lobes, the shape of the labrum and the arrangement of sensory structures on the labrum are the main larval characters to distinguish among species in this genus. The shape and length of the respiratory horns, size and number of the horns of the cephalic crest, length of the antennal sheaths, the lengths of the sheaths of the legs, size and shape of tubercles on the antennal scape are the main distinguishing pupal characters for the species of this genus. Nearly all known species of Hexatoma develop in sand or gravel in bottom of large and medium size rivers, smaller streams and creeks while last instar larvae and pupae can be found in the riparian zone, usually in gravel, sand or under stones. PMID- 26624122 TI - Sawflies of Ethiopia (Hymenoptera: Argidae, Tenthredinidae). AB - Sawflies were collected in Ethiopia during 2010-2013. Three species represent new records for the country: Arge deckerti Koch, 2005, Athalia excisa Koch, 2006 and Xenapates nigrifrons Koch, 2012. Arge flavifrons Mocsary, 1909, syn. n. and A. transvaalensis Cameron, 1911, syn. n. are subjective synonyms of A. micheli (Buysson, 1900) that is re-described here. Athalia fumosa Gribodo, 1879 sp. rev. is recognized as a valid species and is removed from synonymy with A. scioensis Gribodo, 1879. Distega braunsi Enslin, 1911 syn. n. and D. brunniventris Enslin, 1913 syn. n. are subjective synonyms of D. montium Konow, 1907. Pseudoneacidiophora Koch, 1998 is a new junior synonym of Kivua Forsius, 1934 (syn. n.), resulting in the new combination Kivua pleuritica (comb. n.) for Athalia pleuritica Forsius, 1927. Kivua camerunensis nom. n. is proposed for P. bicolor Koch, 1998 (preoccupied in Kivua by K. bicolor (Pasteels, 1949) (Bicrista bicolor Pasteels)), the second species formerly included in Pseudoneacidiophora. The female of Distega abyssinica Pasteels, 1955 is described for the first time. An annotated and illustrated list including six distribution maps is given for Ethiopian sawflies. It is composed of 34 species belonging to the genus Arge (Argidae), and seven genera of Tenthredinidae: Athalia (Athaliinae), Kivua, Neacidiophora, Xenapates (Allantinae), Distega, Trisodontophyes (Blennocampinae), and Dulophanes (Selandriinae). Some ecological aspects of Athalia species are discussed, especially for the most abundantly collected A. vollenhoveni Gribodo, 1879. PMID- 26624123 TI - A new species of Diadumene (Actiniaria: Diadumenidae) from the subtropical coast of Brazil. AB - Diadumene paranaensis n. sp., collected from the Yacht Club of Paranagua (Paranagua Bay, Parana State, southern Brazil), is described as a new species of sea anemone, based on external and internal morphology, cnidome, and molecular data for 16S/CO3 mitochondrial DNA. This species is partially similar to D. cincta due to the presence of macrobasic p-amastigophores in the tentacles, but is distinguished by the cinclides arranged in longitudinal rows and microbasic p amastigophores in the acontia. PMID- 26624124 TI - Rossella podagrosa Kirkpatrick, 1907-A valid species after all. AB - In this study we provide evidence that the species Rossella podagrosa Kirkpatrick, 1907, commonly considered a synonym of Rossella racovitzae Topsent, 1901, is truly a valid species. We show that it can be clearly distinguished from other species especially when taking into consideration the in situ habitus of the sponge in combination with the spicules. Furthermore we demonstrate the weaknesses in the so far published synonymy concept for the very complicated genus Rossella Carter, 1872. From this we conclude that the best strategy for further analysis of Rossella and establishment of acceptable synonymies will need to be based on detailed examination of the spicules, the holotypes, and in situ habitus. When possible it will be useful to analyze specimens from all Antarctic oceanographic regions. PMID- 26624125 TI - First crane fly from the Upper Jurassic of Australia (Diptera: Limoniidae). AB - The first crane fly (Diptera: Tipuloidea) fossil discovered in the Upper Jurassic Talbragar Fish Bed in Australia is described and illustrated. Eotipula grangeri sp. nov., described from a single specimen, is assigned to the family Limoniidae based primarily on the conformation of wing veins. It is the second and oldest record of Limoniidae from Australia, and the first of Jurassic age from the southern hemisphere. PMID- 26624126 TI - New species of Characidium (Characiformes: Crenuchidae) from the Rio Tapajos and Rio Xingu drainages, Para, Brazil. AB - Characidium nana is described from the Rio Xingu and Rio Tapajos drainages. The new species is distinguished from all its congeners by the absence of the inner series of dentary teeth, the absence of the parietal branch of the supraorbital laterosensory canal, the incomplete lateral line, the lack of an adipose fin, the presence of a conspicuous dark blotch on caudal peduncle as well as an evident dark, midlateral stripe, and the presence of 12 circumpeduncular scales. The relationships of the new species and its inclusion among the species of clade C4 are discussed. PMID- 26624127 TI - One new species of Ptomaphaminus Perreau, 2000 (Coleoptera: Leiodidae: Cholevinae: Ptomaphagini) from a granitic subterranean environment in Vietnam. AB - Ptomaphaminus granophilus n. sp. from Vietnam is described and illustrated. The special subterranean biotope of this species, deep interstices in a granitic blockfield, is emphasized. PMID- 26624128 TI - Taxonomic revision of Phygopoda Thomson, 1864 and Pseudophygopoda Tavakilian & Penaherrera-Leiva, 2007 (Insecta: Coleoptera: Cerambycidae: Cerambycinae). AB - A taxonomic revision based on the study of the external morphology and the terminalia of Phygopoda Thomson, 1864 and Pseudophygopoda Tavakilian & Penaherrera-Leiva, 2007 is presented. The genera and their species are redescribed. Five synonymies are proposed: Panamapoda Clarke, 2014 and Paraphygopoda Clarke, 2014 = Pseudophygopoda Tavakilian & Penaherrera-Leiva, 2007; Paraphygopoda viridimicans (Fisher, 1952); Paraphygopoda nappae Clarke, 2014; and Paraphygopoda longipennis (Zajciw, 1963) = Pseudophygopoda albitarsis (Klug, 1825). The genus Phygopoda is composed of five species: Phygopoda fugax Thomson, 1864; Phygopoda fulvitarsis Gounelle, 1911; Phygopoda ingae Penaherrera Leiva & Tavakilian, 2004; Phygopoda jacobi Fuchs, 1961; and Phygopoda nigritarsis Gounelle, 1911. Pseudophygopoda is now composed of three species: Pseudophygopoda subvestita (White, 1855), Pseudophygopoda panamensis (Giesbert, 1996) comb. nov., and Pseudophygopoda albitarsis (Klug, 1825) comb. nov. New geographical records are reported for six species. A key to the species of Phygopoda and Pseudophygopoda, photographs, plates of drawings, and maps of the geographical distribution of the species are provided. PMID- 26624129 TI - A review of Galaxiella pusilla (Mack) (Teleostei: Galaxiidae) in south-eastern Australia with a description of a new species. AB - The dwarf galaxias, Galaxiella pusilla (Mack), is a small, threatened freshwater fish from coastal south-eastern Australia. Recent genetic studies, using multiple nuclear and mitochondrial DNA markers, found substantial differences between populations in western Victoria and south Australia ('west region') compared to eastern Victoria, Flinders Island, and Tasmania ('east region') that suggest the presence of a cryptic species. Morphological measurements and meristic counts from multiple populations within each region were undertaken to investigate potential differences between regions. Several characters, found to discriminate between individuals in the regions and to be diagnostic for two taxa, were used to describe a new species, Galaxiella toourtkoourt, for the west region. This is only the second species in the Galaxiidae to exhibit sexual dimorphism. The original description of Galaxiella pusilla, based on five specimens, is revised following examination of a large number of individuals. Both species are considered nationally threatened and are categorised as 'endangered'; the revised distribution of G. pusilla s.s. is reduced by approximately 60%. A number of inconsistencies in the most recent revision of the genus Galaxiella are also corrected. PMID- 26624130 TI - A review of the Munidopsidae Ortmann, 1898 (Decapoda, Galatheoidea) in Chilean waters, including new records for the Southeastern Pacific. AB - The information about the family Munidopsidae in Chile is scarce and sparse, making identification of new material. difficult. Due to this we lack precise information about the number and accurate distribution of Chilean species. Recent expeditions to Chile have collected specimens of this group, allowing an exhaustive review of the registers and collections in four museums in the country. A total of 93 specimens from six expeditions were analyzed, belonging to twelve species, of which five represent first records for the Chilean waters. The family in Chile is now composed by 19 bathyal and abyssal species; three belong to the genus Galacantha and 16 to Munidopsis. Only three species have distributions restricted to southeastern Pacific waters (M. cochlearis, M. follirostris and M. opalescens). Three other species are widely distributed along the eastern Pacific from Alaska or from Oregon to Chile (M. aspera, M. quadrata and M. verrucosus). No relationships were observed between the extensive geographical distribution of species and the bathymetric distribution. PMID- 26624131 TI - Remarks of the genus Mirollia (Orthoptera: Tettigoniidae: Phaneropterinae) from China. AB - Mirollia species from China are discussed with six new species described. The male stridulatory structures and abdominal terminalia are used as the main taxonomic characters. The species are: M. maculosus sp. nov., M. terminalis sp. nov., M. petiolulata sp. nov., M. acutilobata sp. nov., M. amplecta sp. nov. and M. unispina sp. nov. Two species are reported as new records for China, namely M. caligata Ingrisch, 1998 and M. hexapinna Ingrisch, 1998, the female of M. deficientis Gorochov, 2005 is described for the first time. A key to species and a distribution map for the genus Mirollia in China are provided. All specimens are deposited in the Museum of Hebei University. PMID- 26624132 TI - A new rock dwelling Hemidactylus (Squamata: Gekkonidae) from Chhattisgarh, India. AB - A distinct new species of gecko of the genus Hemidactylus is described from the Kanker district of Chhattisgarh State, east-central India. This large-sized (SVL average 81.33+/-13.40 to at least 98.0 mm) Hemidactylus is characterized by a dorsum with small granules, intermixed with 10-12 rows of irregularly arranged, slightly larger, rounded, weakly-keeled tubercles at midbody; 10-12 and 13-15 subdigital lamellae on the first and fourth digits, respectively, of both manus and pes; a single enlarged postcloacal tubercle on either side of the tail; 10-12 femoral pores on each thigh separated by 5-8 poreless scales; 12-14 supralabials and 10-12 infralabials. PMID- 26624133 TI - Revision of the cirolanid isopod genus Odysseylana Malyutina, 1995 (Crustacea) with description of two new species from Singapore. AB - The genus Odysseylana Malyutina, 1995 is revised and a new diagnosis presented; two new species from Singapore are described: Odysseylana sakijang sp. nov. and Odysseylana temasek sp. nov. The monotypic genus Parilcirolana Yu & Li, 2001, is placed in synonymy, bringing total number of species in Odysseylana to four including the type species Odysseylana sirenkoi Malyutina, 1995 and Odysseylana setosa (Yu & Li, 2001) comb. nov. The genus is known only from coastal waters from Singapore to off Macau, western Pacific. The principal distinguishing character of Odysseylana are an elongate body shape (2.9-3.5 long as greatest width), head without a rostral point, pentagonal and flat frontal lamina; antenna peduncle articles 1-3 short, 4 and 5 subequal in length and longest; and pleopod 1 peduncle quadrate, and a slender pleopod 1 endopod. PMID- 26624134 TI - A new species of Characidium Reinhardt (Ostariophysi: Characiformes: Crenuchidae) from headwaters of Rio Pacaas Novos, Rio Madeira basin, Rondonia, Brazil. AB - Characidium summus, new species, is described from rio Pacaas Novos, rio Madeira basin, Rondonia, Brazil. The new species is the unique among congeners for completely lacking an adipose fin and having a complete lateral line. Characidium summus can be further distinguished from congeners, including C. vestigipinne that also has a complete lateral line and adipose fin absent, vestigial or reduced by the absence of dark bars or spots on head, body or fins, except for a dark blotch on the rear of the opercle, a narrow midlateral dark stripe, and a dark basicaudal spot. In addition, C. summus possess a vestigial supraorbital and a remarkably small pseutotympanum. The possible mimetic relationship between the new species with Erythrinus erythrinus is discussed. PMID- 26624135 TI - Five new species of genus Kisaura Ross (Trichoptera: Philopotamidae) from Himachal Pradesh (India). AB - Five new species of Kisaura Ross are described and illustrated from the Indian Himalaya. Newly described species are Kisaura trailaensis sp. n., K. barotensis sp. n., K. monospinata sp. n., K. sachensis sp. n. and K. curvata sp. n. In addition, K. madhyamika Schmid is recorded from Himachal Pradesh and a catalogue of Indian species of Kisaura is provided. PMID- 26624136 TI - Genera of the Scirtothrips genus-group (Thysanoptera, Thripidae) with a new species of Siamothrips from Malaysia. AB - The Scirtothrips genus-group is here considered to comprise 11 genera, and an identification key to these is presented. These genera are Ajothrips Bhatti, Anascirtothrips Bhatti, Biltothrips Bhatti, Cercyothrips Morgan, Drepanothrips Uzel, Ephedrothrips zur Strassen, Kenyattathrips Mound, Parascirtothrips Masumoto & Okajima, Scirtidothrips Hood, Scirtothrips Shull and Siamothrips Okajima. One genus, Sericopsothrips Hood, is considered a new synonym of Scirtothrips, with the only species now referred to as Scirtothrips palloris (Hood) comb.n. A second species in the genus Siamothrips is described from Malaysia as Siamothrips initium sp.n. PMID- 26624137 TI - On the taxonomy of the genus Acronicta Ochsenheimer, 1816 (Lepidoptera, Noctuidae). I. Redescription of Acronicta grumi (Alpheraky, 1897), with notes on synonymy and its subgeneric placement. PMID- 26624138 TI - On the diagnosis and conservation of the poorly known bromeligenous Scinax arduous Peixoto, 2002 (Amphibia; Anura; Hylidae). AB - Since Scinax arduous description, many other populations belonging to the Scinax perpusillus group have been recorded for the States of Espirito Santo and Minas Gerais, Southeastern Brazil. Both in collections and publications most of these new specimens are identified as S. arduous, Scinax cf. arduous, Scinax cf. perpusillus, Scinax gr. perpusillus, S. perpusillus and S. v-signatus. Such state of affairs may be due to the lack of information on the original description of S. arduous. Only two individuals [the holotype (female) and the paratype (male)] were used in the original description and diagnosis, therefore, information on variation and distribution were not available. Furthermore, in S. arduous description, the section on coloration in life was based only on two juveniles raised in laboratory. Herein we redefine Scinax arduous based on 44 males and 17 females from the type locality, the Municipality of Santa Teresa, in the State of Espirito Santo. In addition, we provide information on its conservation status, distribution, natural history, vocalization, tadpoles, and detailed photographs of both adults and larvae. PMID- 26624139 TI - A new species of Spelaeogammarus (Amphipoda: Bogidielloidea: Artesiidae) with an identification key for the genus. AB - There are five described species of the cave-dwelling amphipods of the genus Spelaeogammarus, all of them inhabiting caves on the Brazilian state of Bahia. A new species of this genus is here described, which is closely related to the already known species S. santanensis and S. titan. Spelaeogammarus sanctus sp. nov. differs from its congeneric species basically by the presence of more than 18 bifid setae on the dorsal margin of uropod 3 outer ramus and telson with one apical and two subapical stout setae, while the other species generally present less setae on the third uropod and more setae on telson. An identification key and an updated table of the Spelaeogammarus species diagnosis are provided, as well as a multivariate statistical approach of morphological variations among the species. PMID- 26624140 TI - Biology and morphology of immature stages of Adosomus roridus (Coleoptera: Curculionidae: Lixinae). AB - Mature larva and pupa of Adosomus (s. str.) roridus (Pallas, 1781) (Curculionidae: Lixinae: Cleonini) are described and compared with ten other taxa of Cleonini with known larvae. This weevil is an oligophagous species on the Asteraceae family. From our observations in Slovakia, we found active adults from April to September in dry sunny places within extensively used or fallow vineyards and in ruderal vegetation with host plants. The weevil is a root borer- larvae, pupae and fresh adults were collected from the root necks and roots of Common Tansy (Tanacetum vulgare L.) and rarely from Mugwort (Artemisia vulgaris L.). Each plant was usually occupied by one larva, or more rarely with two or three larvae. The new generation of adult individuals appeared from early summer to autumn. Both larvae and some of the adults overwinter, which is quite unique within Cleonini. PMID- 26624141 TI - An integrative taxonomic approach to characterize Trichogramma marandobai (Hymenoptera: Trichogrammatidae). PMID- 26624142 TI - Description of a new Betylobraconini-like parasitoid wasp genus and species (Hymenoptera: Braconidae: Rogadinae) from Chile. AB - Gondwanocentrus gen. nov. (type species Gondwanocentrus humphriesi sp. nov.) from Chile is described and illustrated. Morphological and weak molecular evidence indicate that the new genus may be a basal member of the Betylobraconini. The molecular data analysed to assess its placement additionally draw into question the relationship between Betylobraconini and Clinocentrini. Previously, the Betylobraconini were known only from the Australasian region, Oceania and Eocene Europe (Baltic amber), thus if Gondwanocentrus gen. nov. does belong to this group it confirms the groups present day Gondwanan distribution. PMID- 26624143 TI - Notes on three braconid wasps (Hymenoptera: Braconidae, Doryctinae) parasitizing oak long-horned beetle, Massicus raddei (Coleoptera: Cerambycidae), a severe pest of Quercus spp. in China, together with the description of a new species. AB - Three species of Doryctinae (Hymenoptera: Braconidae) parasitize larvae of oak longhorn beetle Massicus raddei Blessig (Coleoptera: Cerambycidae), a serious wood borer pest in North China. Rhoptrocentrus quercusi sp. nov., is described as a new species and Doryctes petiolatus Shestakov, as well as Zombrus bicolor (Enderlein). The three species are idiobiont ectoparasitoids, and may have potential for biological control of oak longhorn beetle. PMID- 26624144 TI - Redescription of the percoid fish Symphysanodon andersoni Kotthaus (Symphysanodontidae) from the northwestern Indian Ocean, based on the holotype and the second known specimen. AB - Symphysanodon andersoni was described in 1974 from a single specimen collected southwest of Socotra Island, near the entrance to the Gulf of Aden. A more recent report (2003) of its capture in the Gulf of Kutch, Arabian Sea, was based on a misidentification. The second known specimen of the Bucktoothed Slopefish, S. andersoni, (at 204 mm SL the largest known specimen of the genus Symphysanodon) was collected off the south coast of Oman, Arabian Sea, in April 2014. Symphysanodon andersoni is distinguishable from its congeners by number of tubed scales in the lateral line, 60 to 65 versus 42 to 59 in the other species of the genus. In view of the fact that S. andersoni is poorly known, we redescribe it based on the holotype and the new specimen collected off Oman and provide the first color photograph of the species. PMID- 26624145 TI - Two new species of the genus Aalatettix Zheng & Mao (Orthoptera, Tetrigoidea, Tetrigidae) from Taiwan, China. AB - Two new species of the genus Aalatettix Zheng & Mao, 2002, namely Aalatettix yangi sp. nov. and Aalatettix xiai sp. nov. are described and illustrated. The new species Aalatettix yangi sp. nov. is allied to Aalatettix gibbosa Zheng, Cao & Chen, 2011, but upper margin of pronotum waved in lateral view, width of frontal ridge narrower than width of basal joint of antennae, hind tibiae dark brown, base not pale. The new species Aalatettix xiai sp. nov. is allied to Aalatettix yangi sp. nov., but length of pronotum shorter, not reaching epiproct, width of vertex 1.5 times diameter of eye, lateral carinae of pronotum contracted backward distinctly, posterior apex of lower margin angular on lateral lobe of pronotum, lower margin of median femur waved, antennae placed under lower margin of eyes. The type specimens are deposited in the National Museum of Natural Science, Taichung, Taiwan, China. PMID- 26624146 TI - New records and synonymy in the genus Macropsidius (Hemiptera, Cicadellidae, Macropsinae) from China and description of a new Pediopsis species. AB - Leafhopper species Macropsidius duuschulus Dlabola and M. niger Matsumura are recorded for the first time from China. Macropsidius fukangensis (Li et Xu) comb. nov. (from Macropsis) is proposed. A new species, Pediopsis bannaensis sp. nov., is described and illustrated from China and Thailand. PMID- 26624147 TI - Notes on the systematic placement of Eutheia siamensis Franz (Coleoptera, Staphylinidae, Scydmaeninae). AB - Examination of the type series (holotype and single paratype) of Eutheia siamensis Franz (Thailand) revealed that it was composed of two different species, belonging not only in different genera, but also tribes. The holotype is a representative of Cephennomicrus Reitter (Cephenniini), while the paratype is a species of Paraneseuthia Franz (Eutheiini). Consequently, E. siamensis is redescribed as Cephennomicrus siamensis (Franz), comb. n.; and the paratype Paraneseuthia is illustrated, but the specimen is probably a female, and remains as an undescribed species. Cephennomicrus has already been recorded from Thailand, but Paraneseuthia is reported to occur in this country for the first time, filling a distributional gap between Far Eastern, Sundaland/Australian and recently discovered Himalayan and Turkish species of this interesting genus. PMID- 26624148 TI - Handschinurida nom. nov. (Collembola, Neanuridae), a substitute name for the homonym Handschinia Stach, 1949. PMID- 26624149 TI - The genus Visiana Swinhoe (Lepidoptera: Geometridae: Larentiinae) in Australia: resurrection of two species from synonymy. AB - Based on the study of morphological characters and DNA barcode (CO1) data, the present review revealed the existence of at least three species of Visiana Swinhoe (Lepidoptera: Geometridae: Larentiinae) in Australia. Visiana brujata (Guenee) is redescribed, and two species V. incertata (Walker), stat. rev. and V. repentinata (Walker), stat. rev. are resurrected from synonymy with V. brujata. Visiana breviaria (Walker), syn. rev., previously cited as a synonym of V. brujata, is now considered a synonym of V. incertata. Visiana brujata and V. incertata show close affinities with the sordidata group of species, whereas V. repentinata belongs to the vinosa species group. Images of adults and genitalia of all types are illustrated and the presence of the gnathos in the genus Visiana is discussed. PMID- 26624150 TI - Five new rotundabaloghiid mites (Acari: Uropodina) from South-East Asia. AB - Five new species of the family Rotundabaloghiidae are described from Indonesia and Malaysia. Angulobaloghia pedunculata sp. nov. differs from the other Angulobaloghia Hirschmann, 1979 species in the shape of the genital shield of the female. Rotundabaloghia (Rotundabaloghia) wangi sp. nov. has one pair of short and pilose setae (V8) on the ventral idiosoma, which is unique in the subgenus Rotundabaloghia (Rotundabaloghia) Hirschmann, 1975. Rotundabaloghia (Circobaloghia) javaensis sp. nov. has a small triangular anterior process on genital shield of female, which has not been detected previously in South-East Asian members of this subgenus. The long and thick ventral seta (V4) in Depressorotunda (Depressorotunda) robusta sp. nov. is a character state so far unknown in the subgenus Depressorotunda (Depressorotunda) Kontschan, 2010. Depressorotunda (Depressorotunda) hirca sp. nov. has two apically serrate anterior branches on the margin of the female genital shield. PMID- 26624151 TI - Redescription of the Indo-West Pacific scorpionfish (Scorpaenidae), Neomerinthe erostris (Alcock 1896), a senior synonym of Scorpaena gibbifrons Fowler 1938, N. rotunda Chen 1981, and N. bathyperimensis Zajonz & Klausewitz 2002. AB - The Indo-West Pacific species, Neomerinthe erostris (Alcock 1896), originally described as Scorpaena erostris, is redescribed as a senior synonym of Scorpaena gibbifrons Fowler 1938, N. rotunda Chen 1981, and N. bathyperimensis Zajonz & Klausewitz 2002. Although the latter three nominal species have been regarded as valid species and N. erostris has not been reported since 1898, examinations of type specimens of the four nominal species revealed that they represent a single species. A lectotype of Scorpaena erostris is herein designated. Neomerinthe erostris is characterized by having a distinct longitudinal ridge on the lateral surface of the maxilla and a strongly rounded dorsal profile of the head. PMID- 26624152 TI - Five new species in the idiocerine genus Busonia Distant (Hemiptera: Cicadellidae: Idiocerinae) from Thailand and Malaysia, with one new record from China. AB - Six species in the genus Busonia Distant are described and illustrated, including five new species from Thailand and Malaysia: Busonia curvata, B. fusca, B. lactata, B. micrata, B. serrata, spp. nov., and one newly recorded species from China: Busonia albilateralis Maldonado-Capriles. A redescription of this genus is provided together with a key to species for separation of males. PMID- 26624154 TI - Study of Gryllacridinae (Orthoptera: Stenopelmatidae) from Thailand and adjacent countries: the genera Ultragryllacris gen. nov. and Capnogryllacris. AB - A new material on the genera Ultragryllacris gen. nov. and Capnogryllacris Karny, 1937 from Thailand, Laos and Cambodia is considered. Five new species and subspecies are described: U. pulchra sp. nov.; U. p. alboclypeata subsp. nov.; C. thaica sp. nov.; C. sakaerat sp. nov.; C. phaeocephala cambodiensis subsp. nov. Capnogryllacris s. l. is divided into two possible subgenera (Capnogryllacris s. str. and Dictyogryllacris Karny, 1937, stat. nov.) as a minimum; the former genera Borneogryllacris Karny, 1937, syn. nov., Marthogryllacris Karny, 1937, syn. nov. and Erythrogryllacris Karny, 1937, syn. nov. are treated as synonyms of the subgenus Capnogryllacris. Previously unknown female for C. khmerica Gorochov, 2003 is described; neotype for C. martha (Griffini, 1914 ), type species of Marthogryllacris, is designated; C. erythrocephala Gorochov, 2003, sp. ressur. and C. e. borealis Gorochov, 2003, stat. ressur. are restored from synonyms of C. martha and from species status, respectively. PMID- 26624157 TI - Description of the female of Eutichurus ibiuna Bonaldo, 1994 (Araneae: Eutichuridae) with notes on natural history and sexual behavior. PMID- 26624155 TI - Heliothrips haemorrhoidalis and its relatives, with one new species and one new genus (Thysanoptera: Thripidae). AB - Heliothrips similis sp.n. is described as a close relative of the greenhouse thrips, Heliothrips haemorrhoidalis. This is the third species recognized here in the Neotropical genus Heliothrips. A pest species described from South Africa as Heliothrips sylvanus is transferred to a new genus, Neoheliothrips gen.n., as Neoheliothrips sylvanus (Faure) comb.n. PMID- 26624153 TI - Review of the Oriental genus Platysodes Westwood (Coleoptera: Scarabaeidae: Cetoniinae: Cremastocheilini) with a redescription of Platysodes madoni Bourgoin. AB - The genus Platysodes Westwood, 1873 (Coleoptera: Scarabaeidae: Cetoniinae: Cremastocheilini) is reviewed, with an identification key, images, and distributional map for all species. Platysodes madoni Bourgoin, 1923 is newly recorded from southern China, and a lectotype is designated for this species. The year of publication of Platysodes is corrected to 1873. PMID- 26624156 TI - New species and records of Pseudacteon Coquillett, 1907 (Diptera, Phoridae), parasitoids of the fire ant Solenopsis geminata group (Hymenoptera, Formicidae). AB - The genus Pseudacteon Coquillett (Diptera, Phoridae) has a worldwide distribution and comprises parasitic myrmecophilous species that decapitate host ants. Seventy one species are known in the genus, 41 of them occur in the Neotropical Region and are 25 from Brazil. In northeastern Brazil, there are only records for two species, Pseudacteon dentiger Borgmeier and Pseudacteon antiguensis Malloch. In this paper, two new species of the genus are described from female specimens, Pseudacteon pesqueroi new spec. and Pseudacteon plowesi new spec., and also, new records of three Pseudacteon species for the Brazilian Northeast are given. PMID- 26624160 TI - Taxonomic revision of the genus Benthana Budde-Lund, 1908 (Isopoda: Oniscidea: Philosciidae). AB - The neotropical genus Benthana (Philosciidae) is reviewed. Fourteen species are redescribed: Benthana picta, B. olfersii, B. longicornis, B. schubarti, B. albomarginata, B. werneri, B. santosi, B. longipenis, B. bocainensis, B. moreirai, B. dimorpha, B. iporangensis, B. sulcata, and B. longicaudata. Additional characters were proposed for B. convexa, B. taeniata, B. serrana, B. trinodulata, B. araucariana, and B. cairensis. New records are provided for 13 species, and four new species are described: Benthana aimores sp. nov., Benthana goitacas sp. nov., Benthana tupinamba sp. nov. and Benthana canastraensis sp. nov.. Two Chilean species are considered incertae sedis. A pictorial key and distribution maps for the species are provided. PMID- 26624158 TI - Eleven new replacement names in the genus Mesochorus Gravenhorst, 1829 (Ichneumonidae: Mesochorinae). AB - Eleven new replacement names in the genus Mesochorus Gravenhorst, 1829 are proposed due the synonymy with Plectochorus Uchida, 1933 and Stictopisthus Thomson, 1886 made by Wahl in his cladistic analysis of the genera of Mesochorinae. PMID- 26624163 TI - A taxonomic revision of the genus Oxyopomyrmex Andre, 1881 (Hymenoptera: Formicidae). AB - Oxyopomyrmex Andre, 1881 is a small genus of myrmicine ants found in arid grasslands of the Mediterranean region. Here we provide a new taxonomic revision of the genus. Twelve species are recognized, including five new to science: O. laevibus sp. nov. (Greece: Crete), O. magnus sp. nov. (Spain), O. negevensis sp. nov. (Israel) O. polybotesi sp. nov. (Greece: Nisyros, W Turkey) and O. pygmalioni sp. nov. (Cyprus). Oxyopomyrmex santschii var. nigripes Santschi, 1907 and O. santschii var. nitidior Santschi, 1910 are raised to species level. The following new synonymies are proposed: O. krueperi Forel, 1911 = O. lagoi Menozzi, 1936 syn. nov.; O. nigripes Santschi, 1907 = O. sabulonis var. rugocciput Santschi, 1923 syn. nov. = O. emeryi var. brunnescens Santschi, 1929 syn. nov.; O. nitidior Santschi, 1910 = O. emeryi var. laticeps Santschi, 1915 syn. nov. = O. emeryi st. sabulonis Santschi, 1915 syn. nov.; O. saulcyi Emery, 1889 = O. santschii Forel, 1904 syn. nov. = O. santschii var. siciliana Karavaiev, 1912 syn. nov. = O. gaetulus Santschi, 1929 syn. nov. = O. saulcyi var. latinodis Santschi, 1939 syn. nov. A neotype for O. oculatus Andre, 1881 is designated. An identification key based on the gyne, male and worker caste is provided. PMID- 26624164 TI - A checklist of longhorn beetles (Coleoptera: Cerambycidae) of Serbia. AB - A checklist of all taxa of the family Cerambycidae (longhorn beetles) from Serbia is presented. The checklist is based on compilation of data gathered both from authors and available literature published up to now. A total of 265 species and 92 subspecies belonging to 109 genera, 48 tribes, and six subfamilies are recorded for Serbia. However, the presence of 28 species listed in Serbia may be questionable. Known distribution and biology of Serbian taxa are provided. The diversity of the fauna of longhorn beetles in Serbia is compared with the surrounding areas in the Balkan Peninsula. PMID- 26624161 TI - A review of the mite subfamily Harpirhynchinae (Acariformes: Harpirhynchidae)- parasites of New World birds (Aves: Neognathae). AB - Mites of the subfamily Harpirhynchinae (Acariformes: Cheyletoidea: Harpirhynchidae) associated with neognathous birds (Aves: Neognathae) in the New World are revised. In all, 68 species in 8 genera are recorded. Among them, 27 new species and 1 new genus are described as new for science: Harpyrhynchoides gallowayi Bochkov, OConnor and Klompen sp. nov. from Columba livia (Columbiformes: Columbidae) from Canada (Manitoba), H. zenaida Bochkov, OConnor and Klompen sp. nov. from Zenaida macroura (Columbiformes: Columbidae) from USA (Michigan), H. calidris Bochkov, OConnor and Klompen sp. nov. from Calidris minutilla (Charadriiformes: Scolopacidae) from USA (Kansas), H. actitis Bochkov, OConnor and Klompen sp. nov. from Actitis macularius (Charadriiformes: Scolopacidae) from Canada (British Columbia), H. charadrius Bochkov, OConnor and Klompen sp. nov. from Charadrius vociferus (Charadriiformes: Charadriidae) from USA (Texas), H. pluvialis Bochkov, OConnor and Klompen sp. nov. from Pluvialis dominica (Charadriiformes: Charadriidae) from USA (Ohio), H. bubulcus Bochkov, OConnor and Klompen sp. nov. from Bubulcus ibis (Pelecaniformes: Ardeidae) from USA (Florida), H. ixobrychus Bochkov, OConnor and Klompen sp. nov. from Ixobrychus exilis (Pelecaniformes: Ardeidae) from USA (Michigan), H. puffinus Mertins sp. nov. from Puffinus gravis (Procellariformes: Procellariidae) from USA (Florida), H. megascops Bochkov, OConnor and Klompen sp. nov. from Megascops asio (Strigiformes: Strigidae) from USA (Michigan), H. athene Bochkov, OConnor and Klompen sp. nov. from Athene canicularia (Strigiformes: Strigidae) from USA (Texas), H. coccyzus Bochkov, OConnor and Klompen sp. nov. from Coccyzus americanus (Cuculiformes: Cuculidae) from USA (Michigan), H. crotophaga Bochkov, OConnor and Klompen sp. nov. from Crotophaga ani (Cuculiformes: Cuculidae) from Suriname; Crassacarus Bochkov, OConnor and Klompen, gen. nov.: Crassacarus alexfaini Bochkov, OConnor and Klompen sp. nov. (type of genus) from Cardinalis cardinalis (type host) from USA (Michigan), Passerina ciris (unknown locality in North America) (Passeriformes: Cardinalidae), and Setophaga petechia (Passeriformes: Parulidae) from USA (Michigan), C. tinae Bochkov, OConnor and Klompen sp. nov. from Carduelis tristis (Passeriformes: Fringillidae) from USA (Wyoming), C. fritschi Bochkov, OConnor and Klompen sp. nov. from Bombycilla cedrorum (Passeriformes: Bombycillidae) from USA (Michigan), C. sialia Bochkov, OConnor and Klompen sp. nov. from Sialia currucoides (Passeriformes: Turdidae) from USA (Wyoming), C. melanerpes Bochkov, OConnor and Klompen sp. nov. from Melanerpes formicivorus (Piciformes: Picidae) from USA (Kansas); Neharpyrhynchus turdus Bochkov, OConnor and Klompen sp. nov. from Turdus migratorius (Passeriformes: Turdidae) from USA (Michigan), N. campylorhynchus Bochkov, OConnor and Klompen sp. nov. from Campylorhynchus brunneicapillus (Passeriformes: Troglodytidae) from USA (unknown locality), N. spizella Bochkov, OConnor and Klompen sp. nov. from Spizella passerina (Passeriformes: Emberizidae) from USA (various localities), N. quiscalus Bochkov, OConnor and Klompen sp. nov. from Quiscalus quiscula (Passeriformes: Icteridae) from USA (Michigan), N. agelaius Bochkov, OConnor and Klompen sp. nov. from Agelaius phoeniceus (Passeriformes: Icteridae) from USA (Michigan), N. bombycilla Bochkov, OConnor and Klompen sp. nov. Bombycilla cedrorum (Passeriformes: Bombycillidae) from USA (Michigan), N. vireo Bochkov, OConnor and Klompen sp. nov. from Vireo olivaceus (Passeriformes: Vireonidae) from USA (Florida), N. picidarum Bochkov, OConnor and Klompen sp. nov. from Colaptes auratus (type host), Melanerpes formicivorus, Melanerpes uropygidialis, and Picoides pubescens (Piciformes: Picidae) from USA (various localities); Perharpyrhynchus charadrius Bochkov, OConnor and Klompen sp. nov. from Charadrius vociferus (Charadriiformes: Charadriidae) from USA (Michigan). Harpyrhynchoides oenae lamorali (Fain, 1972) syn. nov. is synonymized with Harpyrhynchoides oenae (Fain, 1972). Harpirhynchoides agapornis (Fain, 1972) comb. nov. and Crassacarus cylindripalpus (Fritsch, 1954) comb. nov. are transferred from the subgenus Pseudoharpirhynchus Fain, Bochkov and Mironov, 1999 (type species Harpirhynchus agapornis Fain, 1972) of the genus Harpirhynchus Megnin 1877. The subgenus Pseudoharpirhynchus syn. nov. is synonymized with the genus Harpyrhynchoides. Diagnoses for the subfamily and all genera recorded in the New Word (Anharpyrhynchus Fain, 1972, Crassacarus gen. nov., Harpirhynchus, Harpyrhynchoides Fain, 1972, Fainharpirhynchus Bochkov and Galloway, 2013, Neharpyrhynchus Fain, 1972, Perharpyrhynchus Fain, 1972, Trichorhynchiella Fain, 1995) are provided. Keys to all harpirhynchine genera and all their species occurring in the New World are also given. A list of all harpirhynchine species and their hosts is compiled. PMID- 26624162 TI - Checklist of the Iranian Ground Beetles (Coleoptera; Carabidae). AB - An up-to-date checklist of the ground beetles of Iran is presented. Altogether 955 species and subspecies in 155 genera belonging to 26 subfamilies of Carabidae are reported; 25 taxa are recorded for Iran for the fist time. New localities are listed and some previous distributional records are discussed. PMID- 26624165 TI - Entomobryoidea (Collembola) from Himachal Pradesh (India) in the Himalayas. AB - Collections made during March-April, 2010, October-November, 2010 and 2011 from different districts of Himachal Pradesh, India, by the Apterygota section of the Zoological Survey of India contained new species of Entomobryoidea. Localities sampled were Solan, Shimla, Kullu, Bilaspur, Kagra, Chamba and Sirmaur districts of Himachal Pradesh. Collections were mainly made using an aspirator from leaf litter, mosses, under stones, flowering garden plants and river embankments, wetlands and rotting logs. Sixteen species were found, belonging to genera: Entomobrya, Himalanura, Homidia, Sinella, Willowsia, Lepidocyrtus (Acrocyrtus), Lepidocyrtus (Cinctocyrtus), Seira, Drepanosira and Salina. Twelve of these have been described as new species. PMID- 26624167 TI - A survey of the praying mantises of Rwanda, including new records (Insecta, Mantodea). AB - We report the results of two surveys targeting praying mantises in four localities in Rwanda, specifically Akagera National Park, Nyungwe National Park, Volcanoes National Park, and the Arboretum de Ruhande at the National University of Rwanda. Using an assortment of collecting techniques, including metal halide light traps, sweep netting vegetation and general searching, we obtained 387 adult and 352 juvenile specimens, representing 41 species. A total of 28 novel species records for Rwanda are added to the 18 previously recorded species for the country, in addition to 20 novel species records for the broader region, including neighbouring Uganda and Burundi. This study provides high resolution images of the dorsal habitus of both sexes of representative species, both pinned and living. Species distribution records are presented and discussed. With a 155% increase in species recorded from Rwanda, this survey illustrates the need for further taxonomic work in the region. PMID- 26624166 TI - Zealandozetes southensis gen. nov., sp. nov. (Acari, Oribatida, Maudheimiidae) from alpine cushions plant in New Zealand. AB - A new oribatid mite genus, Zealandozetes gen. nov. (Oribatida, Maudheimiidae), with type species Zealandozetes southensis sp. nov., is proposed and described based on adult and juvenile instars. It inhabits the soil under and around cushion-forming plants in the high-altitude alpine zone of two mountain ranges (the Pisa Range and The Remarkables) in the South Island of New Zealand. It is distinguished from species of Maudheimia by having pteromorphs reduced to pleural carinae, notogastral saccules, small pedotecta I, and both postanal porose area and Ah expressed as complex saccules. Juveniles are similar to those of Maudheimia, except the humeral organ of Z. southensis is cupule-like and gastronotic microsclerites are lacking. We give a revised diagnosis for Maudheimiidae and discuss both supportive and contradictory evidence for inclusion of Zealandozetes. Finally, we discuss endemism of Zealandozetes with reference to the knowledge of New Zealand biogeography and its oribatid fauna. PMID- 26624168 TI - A checklist of comb-clawed beetles (Coleoptera: Tenebrionidae: Alleculinae) from Iran. AB - The fauna of Iranian Alleculinae is summarized in this paper. Seventy species from 12 genera are reported: the subtribe Alleculina Laporte with 4 genera and 18 species: Hymenalia Mulsant (7 species), Hymenophorus Mulsant (3 species), Mycetocharina Seidlitz (6 species), Prionychus Solier (2 species); the subtribe Gonoderina Seidlitz with 3 genera and 6 species: Gonodera Mulsant (1 species), Isomira Mulsant (4 species), Pseudocistela Crotch (1 species), the subtribe Mycetocharina Gistel with a single genus and 3 species: Mycetochara Berthold (3 species) and the tribe Cteniopodini Solier with 4 genera and 43 species: Cteniopus Solier (5 species), Omophlina Reitter (2 species), Omophlus Dejean (32 species) and Podonta Solier (4 species). Nine species are newly recorded for the fauna of Iran: Hymenalia atronitens (Fairmaire, 1892), Mycetocharina rufotestacea Reitter, 1898, Prionychus asiatica (Fairmaire, 1892), Isomira nitidula (Kiesenwetter, 1861), Mycetochara ocularis Reitter, 1884, Cteniopus impressicolis Fairmaire, 1892, Omophlus afghanus Muche, 1965, Omophlus schmidi Muche, 1965 and Podonta elongata Menetries, 1832. PMID- 26624169 TI - Description of a new species of Niphargus (Crustacea: Amphipoda: Niphargidae): the first record of a lake ecomorph in the Carpathian Mountains. AB - We describe and phylogenetically characterize a new species Niphargus mirocensis from Mt. Miroc, eastern Serbia. This species shows distinct morphology typical for a lake ecomorph of niphargid amphipod, i.e. large and stout body, elongated appendages and raptorial gnathopods and presents the first record of this ecomorph in Carpathian Mountains. Phylogenetic analyses based on Cytochrome Oxidase Subunit 1 gene (COI), Histone (H3) and 28S rRNA (28S) suggests that species is nested within a clade of lake ecomorphs spread in Italy and Central Dinaric Region. The new finding is geographic extension of clade's range, the species of which are generally narrow endemics. PMID- 26624170 TI - A new species of Shaanxiana (Lepidoptera: Lycaenidae) from southern China. AB - Shaanxiana australis sp. nov. (Theclinae: Theclini) is described from southern China, representing a new taxon of the genus and a remarkable known geographical range extension of the genus. The larval host plant of S. australis is unknown, but the most likely candidate is Fraxinus chinensis (Oleaceae), because congeneric Shaanxiana takashimai use Fraxinus spp. as larval hosts, and F. chinensis is known to grow at the type locality of S. australis. PMID- 26624171 TI - First record of Albunea occulta (Boyko) (Crustacea: Decapoda: Albuneidae) from the Andaman Islands, India. PMID- 26624172 TI - A new species of Short Brown Unpatterned Moray Eel of the Genus Gymnothorax (Anguilliformes: Muraenidae) from the Bay of Bengal. AB - A new species of short brown unpatterned moray eel of the genus Gymnothorax, Gymnothorax mishrai sp. nov. is described from a specimen of 324 mm total length, collected from the Bay of Bengal. The species is distinguished by having the dorsal-fin origin before gill opening, jaw pores with brown rim, two branchial pores, total vertebrae 134 (MVF: 9-59-134), three median intermaxillary teeth, uniserial maxillary and vomerine teeth. The new species is distinctly different from the other eight described species of this group. This species is also the first species of short brown unpatterned moray eel to be reported from India. PMID- 26624173 TI - An addition to the endemic Indian radiation of Eutropis: Phylogenetic position of Eutropis dissimilis Hallowell (Squamata: Scincidae). AB - Skinks of the genus Eutropis represent one of the most widespread and speciose lizard groups in tropical Asia. Numerous recent studies have utilized a variety of genes and methods to reconstruct the phylogeny of these lizards, however these studies have not resolved the placement of one of the widely distributed Eutropis Fitzinger, E. dissimilis. We have sequenced a specimen of E. dissimilis from the type locality and our result suggests that it is part of the Indian radiation of Eutropis and not related to African Trachylepis Fitzinger or Southeast Asian Dasia Gray as previously suggested. Furthermore, we report that the sequence of E. dissimilis used in an earlier study of the once cosmopolitan genus 'Mabuya' may have been erroneously identified and appears to be a sequence of E. novemcarinata. We also demonstrate that the evolution of a clear lower eyelid, which was considered a synapomorphy for the sister genus Trachylepis, has arisen multiple times in Eutropis. PMID- 26624174 TI - Nanohystricidae n. fam., an unusual, plesiomorphic enarthronote mite family endemic to New Zealand (Acari, Oribatida). AB - Nanohystrix hammerae n. gen., n. sp.--proposed on the basis of numerous adults and a few juveniles--is a new oribatid mite of the infraorder Enarthronota that appears to be phylogenetically relictual and endemic to northern New Zealand, in habitats ranging from native shrublands to native and semi-native forests. With an adult body length of 1-1.2 mm, the species is the largest known enarthronote mite outside Lohmanniidae, and it has an unusual combination of plesiomorphic and apomorphic traits. Plesiomorphies include: a well-formed median (naso) eye and pigmented lateral eyes; a bothridial seta with a simple, straight base; a vertically-oriented gnathosoma; a peranal segment; adanal sclerites partially incorporated in notogaster (uncertain polarity); three genu I solenidia and a famulus on tarsus II. Autapomorphies include: five pairs of pale cuticular disks on the notogaster, with unknown function; six pairs of long, erectile notogastral setae, including pair h2 incorporated in the second transverse scissure along with the f-row, and pair h1 in a third scissure; chelicerae that are unusually broad, creating a flat-faced appearance; legs I that are inferred to have an unusually wide range of motion. Further, it is the only enarthronote species known to have an elongated ovipositor, and one of few to have glassy, luminous notogastral setae. The gastronotum of juveniles lacks transverse scissures, but has isolated sclerites supporting setae, including erectile setae. The large character gaps between N. hammerae and other enarthronote taxa justifies proposal of a monotypic new family--Nanohystricidae n. fam.--which is tentatively grouped with several other relictual families in the paraphyletic Heterochthonioidea. Small muscles appear to be involved in the operation of all erectile setae, but seem to be only depressors, with erection effected by hysterosomal distension. Based on gut contents, its food is primarily fungal hyphae and spores, though ingestion of small arthropods also occurs (perhaps by necrophagy). Collections were made by Berlese-funnel samples of litter, by sweeping low vegetation, and (mainly) by pitfall traps; the latter two suggest that adults are surface-active. Tritonymphs were collected by pitfall traps, but earlier juveniles were collected only by Berlese-funnels. Adults are frequently infected with a eugregarine parasite, which can entirely fill the digestive caeca; immature trophozoites were also seen in tritonymphs. Adults also can serve as hosts for dispersal of secondary capilliconidia of the fungal genus Basidiobolus. PMID- 26624175 TI - A taxonomic review of the Neotropical genus Hansreia Halffter & Martinez, 1977 (Coleoptera: Scarabaeidae, Scarabaeinae). AB - The taxonomy of the genus Hansreia Halffter & Martinez is reviewed. The genus consists of six species, including three new species: H. peugeoti sp. nov., H. grossii sp. nov., H. krinskii sp. nov. Lectotypes are designated for Hansreia affinis (Fabricius 1801), H. oxygona (Perty 1830) [here considered a valid species] and H. coriacea (Schmidt 1922). The species status of H. coriacea is recognized. A detailed literature review, synonymies, description, illustration of key morphological characters as well as data of the studied material and geographic distribution is provided for each species. PMID- 26624176 TI - New species of Lepidocyrtus Bourlet and Entomobrya Rondani (Collembola: Entomobryoidea: Entomobryidae) from Brazil. AB - The taxonomic comprehension of Brazilian entomobryids had several contributions during the last decade, but the absence of detailed chaetotaxic schemes to most of endemic species difficult identifications and probably hides undescribed species in surveys across the country. Herein we describe two new species of the family and provide detailed dorsal chaetotaxy of them, in hope to guide future identifications and descriptions within the genera in Brazil and Neotropical Region. Lepidocyrtus sotoi sp. nov. is possibly more related to L. biphasis due to the lack of antennal and leg scales, but presents a unique dorsal head chaetotaxy among the Neotropical species of the genus. Entomobrya bahiana sp. nov. presents an uncommon color pattern and dorsal chaetotaxy in Th. II-III, Abd. II and IV when compared to other Entomobrya spp. from Neotropical Region. PMID- 26624177 TI - A new species of the genus Anthaxia (Anthaxia) (Coleoptera: Buprestidae) from Republic of South Africa. AB - Anthaxia (Anthaxia) kamieserrima sp. nov., a new endemic species from Republic of South Africa is described. New synonymy of Anthaxia (Anthaxia) aterrima Kerremams, 1903 (= Anthaxia (Anthaxia) braunsi Obenberger, 1922 syn. nov.) is proposed. Lectotypes and paralectotypes of A. aterrima and A. braunsi are designated. PMID- 26624178 TI - Revision of Neotropical species of ant-like stone beetles misplaced in Stenichnus and Scydmoraphes (Coleoptera, Staphylinidae, Scydmaeninae). AB - Genera Stenichnus and Scydmoraphes are distributed in the Northern Hemisphere, with a few rather peculiar species described from South America. Type series of Stenichnus andicola Franz, Scydmoraphes venezolanus Franz and Scydmoraphes peruanus Franz were examined and the first of these species is transferred to Sciacharis Broun, while two new generic names are established to accommodate the two latter species: Meridaphes gen. n. and Perumicrus gen. n. This results in three new combinations: Sciacharis (incertae sedis) andicola (Franz) comb. n., Meridaphes venezolanus (Franz) comb. n., and Perumicrus peruanus (Franz) comb. n. Morphological structures of all treated taxa are described and illustrated in detail. PMID- 26624179 TI - A checklist of ciliate parasites (Ciliophora) of fishes from Mexico. AB - A database with all available published accounts of the ciliate parasite species of Mexican fishes was assembled. This information, along with records derived from own recent research, allow generating a checklist containing all the records, which is a necessary first step to address future questions in the areas of ecology, evolutionary biology and biogeography of these host-parasite associations. The checklist is presented as a parasite-host list, and a host parasite list. The checklist contains 30 nominal species, from 9 genera and 8 families of ciliate parasites. Most of the primary records were done for exotic fish species, artificially introduced to Mexico for aquaculture purposes; however, recent works have been conducted in diverse species of native fishes. Excepting one, all the ciliate species listed here have been previously recorded for diverse fish species from different localities around the world. Based on the amount of information contained in this checklist, much more effort is necessary to accurately know the diversity of species of this type of parasites in fish fauna of Mexico. PMID- 26624180 TI - A new species of the Callophrys paulae Pfeiffer, 1932 species group from Afghanistan (Lepidoptera, Lycaenidae). AB - A new species from the Callophrys paulae Pfeiffer, 1932 species group--C. succuba sp. n.--is described from the mountains of Central Afghanistan, Bamyan Province. The new species differs from the geographically close C. p. jomuda Nekrutenko & Tshikolovets in morphology of the male and female genitalia along with the distinct wavy shape of the postdiscal white line on the hindwing underside. Discovery of the new species from C. paulae species group extends known distribution range of the group to the eastern part of the Iranian Plateau in Central Afghanistan. PMID- 26624181 TI - Three new species of Diplocirrus Haase, 1915 (Polychaeta: Flabelligeridae) from Campos Basin in SE Brazil. AB - Currently, 16 species of Flabelligeridae have been recorded in Brazil, four in the genus Diplocirrus: D. glaucus Malmgren, 1867 from Ubatuba, D. capensis Day, 1961 from Santos (Sao Paulo State) and Diplocirrus sp. from off north of Rio de Janeiro. Diplocirrus glaucus australis Nonato, 1981 is considered a nomen nudum. In the present study, three new species are described: Diplocirrus rugosus sp. nov., Diplocirrus salazarvallejoi sp. nov. and Diplocirrus acafi sp. nov., all collected from soft bottoms off southeast Brazil. A key to all Diplocirrus species is provided. PMID- 26624182 TI - Flaviata longa, a new species in Flaviata Lu & Qin and new synonymies in Empoasca (Matsumurasca) Anufriev (Hemiptera: Cicadellidae: Empoascini). AB - A new species of genus Flaviata Lu & Qin, Flaviata longa sp. nov. is described from Yunnan (southwest China). An identification key for males of all known species in this genus is provided. Photographs and illustrations of adults and male genitalia of the new species are also given. New synonymies for two species in the leafhopper subgenus Empoasca (Matsumurasca) Anufriev of Empoascini are proposed: E. (M.) southerni Zhang, 2014 = E. (M.) clypealata Qin & Zhang, 2011; E. (M.) qini Zhang, 2014 = E. (M.) quadrialata Qin & Zhang, 2011. PMID- 26624183 TI - Some common and less known Phaneropterinae (Orthoptera: Tettigoniidae; Phaneropterinae) with the description of a new species from India. AB - The present paper deals with the description of eleven katydids of the tettigonid subfamily Phaneropterinae (Tettigoniidae). The katydids of more common occurrence in different parts of India include: Phaneroptera gracilis Burmeister, Ducetia japonica (Thunberg), Himertula pallisignata Ingrisch and Shishodia, Isopsera peducnulata Brunner von Wattenwyl, and Trigonocorypha unicolor Stal; while those lesser known are Phaneroptera myllocerca Ragge, Himertula kinneari (Uvarov), Elimaea melanocantha (Walker), Elimaea carispina (Ingrisch and Shishodia), and Trigonocorypha angustata Uvarov. Record of a new species of the genus Ducetia, named as Ducetia serratus sp. nov., is mentioned. The key diagnostic morphological characters have been supported with photographs and illustrations of the body parts: head, pronotum, stridulatory file and the genitalia (supra anal plate and sub-genital plate). A key to identify the species of the reported katydids has been provided. PMID- 26624184 TI - A revision of the genus Belciana Walker, 1862 with description of three new species (Lepidoptera, Noctuidae: Pantheinae) from East and South East Asia. Revision of Pantheinae, contribution XII. AB - The Oriental Pantheinae genus Belciana Walker, 1862 is revised. Three new species, B. hreblayi sp. n., B. sulawesiana sp. n., B. pinratanai sp. n., from Taiwan, Indonesia and Thailand, are described. Five new combinations in the genus Diphteroides Bethune-Baker, 1906 are proposed: Diphteroides caerulea (Hampson, 1926) comb. n., D. habroscia (Prout, 1924) comb. n., D. patricolor (Prout, 1924) comb. n., D. serrata Bethune-Baker, 1906, D. subserrata (Prout, 1924) comb. n. and D. sophronia (Prout, 1924) comb. n. The extensive diagnoses of known species of Belciana are given. The imagines, male and female genitalia are illustrated. The checklist of the genus Belciana in East Asia is presented. PMID- 26624185 TI - A checklist of Branchiopoda (Anostraca and Cladocera) of Chilean continental waters. AB - The aim of the present study is to represent an annotated checklist of the Branchiopoda (Crustacea) reported from Chilean inland waters. Only Anostraca and Cladocera are found in Chile, while there are no reports on Notostraca and "Conchostraca". Our checklist contains 85 valid taxa, among which nine anostracans and 76 cladocerans. Such "low" biodiversity of the branchiopods in Chile is in reality an artifact of insufficient sampling. Our work indicates that more faunistic, taxonomic and biogeographical studies of Chilean branchiopods are necessary, especially in areas with subtropical climate, Atacama desert, Southern Patagonia, and central Chilean ephemeral pools. PMID- 26624186 TI - Redescription of Ateleopus japonicus Bleeker 1853, a senior synonym of Ateleopus schlegelii van der Hoeven 1855, Ateleopus purpureus Tanaka 1915, and Ateleopus tanabensis Tanaka 1918 with designation of a lectotype for A. japonicus and A. schlegelii (Ateleopodiformes: Ateleopodidae). AB - Three nominal species of Ateleopodidae; Ateleopus japonicus Bleeker 1853, A. purpureus Tanaka 1915, and A. tanabensis Tanaka 1918, were taxonomically reviewed. Examination of many specimens, including the holotype of A. tanabensis and the newly designated lectotype of A. japonicus and A. schlegelii, revealed that their morphological differences can be explained by intraspecific variation and ontogenetic change within one species. Mitochondrial DNA analyses supported the results of the morphological study. Thus, A. purpureus and A. tanabensis are considered junior synonyms of A. japonicus. We have concluded after an examination of the relevant publications that Ateleopus schlegelii van der Hoeven 1855 is also a junior synonym of A. japonicus. PMID- 26624187 TI - A new Glossocephalus (Crustacea: Amphipoda: Hyperiidea: Oxycephalidae) from deep water in the Monterey Bay region, California, USA, with an overview of the genus. AB - A new species of Glossocephalus, G. rebecae sp. nov., is described from deep water in the Monterey Bay region of California, Eastern Pacific Ocean. It seems to be associated exclusively with the mesopelagic ctenophore Bathocyroe fosteri. This association has been observed from 541-830 m depth. It is readily distinguished from G. milneedwardsi Bovallius, 1887 by the shape of the eye fields. The retina is organised into a crescent-shaped organ, occupying about one quarter of the back half of the head, with the crystalline cones projecting both anteriorly and laterally. An updated review of the genus is provided, taking into account the new species, together with an overview of G. milneedwardsi, and three new records of associations with ctenophores for G. milneedwardsi. New observations on the interaction of G. milneedwardsi with one of its ctenophore hosts, Mnemiopsis sp., are also documented. PMID- 26624188 TI - Taxonomic notes on Holcobunus Roewer, 1910, with descriptions of three new species, and new records for Holcobunus nigripalpis Roewer, 1910 (Opiliones: Eupnoi: Sclerosomatidae). AB - Three new Brazilian species of Holcobunus Roewer, 1910 are described, thus increasing the total number of species in the genus to five: Holcobunus bicornutus Mello-Leitao, 1940, H. nigripalpis Roewer, 1910, Holcobunus dissimilis sp. nov. (type locality: Espirito Santo, Santa Teresa, Reserva Biologia Augusto Ruschi), Holcobunus ibitirama sp. nov. (type locality: Espirito Santo, Ibitirama, Santa Marta, close to Parque Nacional Caparao), and Holcobunus uaisoh sp. nov. (type locality: Minas Gerais, Fervedouro, Parque Estadual Serra do Brigadeiro). A new record for Holcobunus nigripalpis Roewer, 1910 from Minas Gerais is also provided and the morphological variation in both penis and somatic morphology in the genus are presented and discussed. These observations enhance our understanding of both the diversity and distribution of Holcobunus. PMID- 26624189 TI - Microcenoscelis n. gen. (Coleoptera: Tenebrionidae: Ulomini) from tropical Africa, with description of a blind species from Zimbabwe. AB - Microcenoscelis n. gen. (Coleoptera: Tenebrionidae: Ulomini) caeca n. sp. is described from Zimbabwe, a small and completely blind species. A second known species, however with completely developed eyes, and originally described as Uloma minuscula Ardoin, 1969, was also placed in the new genus. Microcenoscelis n. gen. seems to be mostly related to the genera Cenoscelis Wollaston, 1867, and Cneocnemis Gebien, 1914. PMID- 26624190 TI - A redescription of Chaetonotus (Primochaetus) veronicae Kanneby, 2013 (Gastrotricha: Chaetonotidae). PMID- 26624191 TI - New combinations for six species belonging to Cryptotympanini Handlirsch (Hemiptera: Cicadidae), former members of the genus Tibicen Latreille, 1825. AB - The generic status of several species formerly placed in the genus Tibicen is reconsidered based on the recent erection of new genera as well as historical evidence. Subsolanus Moulds, 2015 syn. nov. is shown to be a junior synonym of Auritibicen Lee, 2015. Six species are reassigned from Tibicen to appropriate genera based on morphological characteristics. PMID- 26624192 TI - Leucosiid crabs from Papua New Guinea, with descriptions of eight new species (Crustacea: Decapoda: Brachyura). AB - Twenty-five species of leucosiid crabs are reported from Madang Province, Papua New Guinea. Of these, seven are new to science: two each are included in Alox Tan & Ng, 1995 and Tanaoa Galil, 2003, and one each in Ryphila Galil, 2009, Seulocia Galil, 2005, and Urnalana Galil, 2005. Fifteen additional species are new records for Papua New Guinea: Alox rugosum (Stimpson, 1858), Ancylodactyla nana (Zarenkov, 1990), Arcania heptacantha De Man, 1907, Heterolithadia fallax (Henderson, 1893), Hiplyra longimana (A. Milne Edwards, 1874), Myra curtimana Galil, 2001, M. digitata Galil 2004, Nursilia dentata Bell, 1855, Oreotlos etor Tan & Richer de Forges, 1993, Parilia major Sakai, 1961, Raylilia coniculifera Galil, 2001, R. uenoi (Takeda, 1995), Toru pilus (Tan, 1996), Urashima pustuloides (Sakai, 1961) and Leucosia rubripalma Galil, 2003. The new species are described and illustrated, and their affinities with allied taxa discussed. Colour photographs are provided for 20 species. PMID- 26624193 TI - Baltic Sea Gastrotricha--one new species and one new record of Chaetonotida from Poland. AB - Gastrotricha is a cosmopolitan phylum of aquatic and semi-aquatic invertebrates that comprise about 820 described species, which are divided into two orders: Chaetonotida Remane, 1925 [Rao & Clausen, 1970] and Macrodasyida Remane, 1925 [Rao & Clausen, 1970]. They inhabit natural as well as artificial habitats in diverse marine, freshwater, and semi-aquatic ecosystems (e.g. peatbogs, alder woods, riparian forests). Until now, 29 species of gastrotrichs from the Polish Baltic Sea region (including three freshwater species which were found in estuaries) were known. Sixteen species belong to Chaetonotida and thirteen to Macrodasyida. During this study we found two species, Heterolepidoderma sinus spec. nov., and Aspidiophorus lamellophorus Balsamo, Hummon, Todaro et Tongiorgi, 1997 which is new to the Baltic Sea fauna. H. sinus spec. nov. has distinct cuticular reinforcements in the anterior dilatation of the pharynx. Moreover, it is characterized by two kinds of lamellae: one type is represented by small triangular lamellae which aris from lateral scales, the second type is large and clearly visible and arises from ventral scales. None of the Heterolepidoderma species known so far has two types of lamellae. A. lamellophorus was previously known only from the Mediterranean Sea. The finding of two new gastrotrich species in the Baltic Sea shows that the knowledge of these small invertebrates in the area is still far from complete. PMID- 26624194 TI - A further contribution to the knowledge of two inadequately known species of geophilid centipedes from the Andes of South-Central Chile, currently assigned to the genus Plateurytion Attems, 1909 (Chilopoda: Geophilomorpha). AB - Two poorly known species of geophilid centipedes from the Andes of South-Central Chile, i.e., Plateurytion mundus (Chamberlin, 1955) and Plateurytion zapallar (Chamberlin, 1955) (Myriapoda: Chilopoda: Geophilomorpha), are herein redescribed and illustrated after type specimens of both taxa and new material of the latter, rectifying the condition of the coxosternites of the second maxillae, which are medially joined through a narrow, hyaline and non-areolate membranous isthmus only (instead of "broadly fused as in Pachymerium", as stated by Chamberlin), this being consistent with the current generic assignment of these species under Plateurytion Attems, 1909. New data on many morphological features of specific value, until now unknown, are also given for both taxa. Plateurytion zapallar is reported for the first time from Coquimbo region, 11 Km N of Los Vilos (Elqui province), Valparaiso region, Quebrada Huaquen, Pichicuy (Petorca province), La Campana National Park (Quillota province), and Quebrada el Tigre, Cachagua (Valpariso province). A key for identification of the South American species currently included in Plateurytion is given. PMID- 26624195 TI - Description of a new species of Trimma (Perciformes: Gobiidae) from the Red Sea, with a discussion of the generic separation of Trimma and Priolepis, with discussion of sensory papillae terminology. AB - A new species of Pygmygoby, Trimma quadrimaculatum, n. sp., is described from the Saudi Arabian coast of the Red Sea on the basis of 16 adult specimens. It is small-sized species, with the largest examined specimen reaching only 16.8 mm SL. The new species has characteristics of both Priolepis and Trimma, and easily may be confused with Priolepis randalli and Trimma mendelssohni; it can distinguish from other species by combination of characters: dorsal-fin rays D VI + I,8; anal fin rays I,7; longitudinal scale series 23-25; median predorsal scales 6-8 (usually 7 or 8); head naked; a pair of modified elongate papillae on nape; fifth pelvic-fin ray with 2 dichotomous branches; body with broad, irregular, brown bars, last bar posteriorly on caudal peduncle extending basally on to rays of caudal fin; head with three dark brown bars below eye; four subcutaneous dark brown spots ventrally on posterior half of body; and basal quarter of second and third membranes of first dorsal fin with diffuse dark blotch. Placement of the new species in Trimma is based on the presence of more characteristics currently associated with Trimma than with Priolepis. The generic separation of the two genera is discussed, suggesting that further work is needed to clarify the separation of these two genera. PMID- 26624196 TI - Two new species of Parasaveljevia Wieser, 1953 (Thoracostomopsidae, Nematoda) from Argentinean coasts (Chubut, Argentina). AB - Two new Parasavaljevia species are described, one from Puerto Madryn, and one from El Limite beach, San Jorge Gulf, Chubut Province, Argentina. The two species are characterised by a combination of characters. Parasavaljevia uncinoa n. sp. is characterised by having a long rectangular cirrus, positioned at the level of the inner labial setae, rectangular mandibles with prominent lateral hooks bearing denticles in three lines of nine each, and six cephalic setae of the same length, inserted at the anterior end of a small head capsule. Parasavaljevia limitense n. sp. is characterized by having a cirrus posterior positioned, between the labial and cephalic setae, rectangular-arched mandibles bearing denticles in five lines of ten each in a gradient of sizes; a small buccal cavity, small cephalic capsule and abundant cervical setae (4+10). An emendation of the genus diagnosis and a new key are given and discussed. PMID- 26624197 TI - Prodasineura hoffmanni sp. nov. (Odonata, Platycnemididae, Disparoneurinae) from eastern Cambodia. AB - Prodasineura hoffmanni sp. nov. is described from Annamense Mountains in eastern Cambodia (holotype: Cambodia, Mondulkiri Province, 4.2 km SE of Dak Dam village, 12 degrees 23'10-18'' N 107 degrees 19'22-30'' E, 877-878 m asl, 14. VI. 2014, RMNH). The species has a blue pattern, and the male is characterised by medium broad blue stripes on synthorax and blue colour at the end of the abdomen confined to a tiny spot on S9, dorsum of S10 and cerci. A female of P. doisuthepensis Hoess, 2007 is described. Based on original descriptions, the following synonymy is proposed: Prodasineura fujianensis Xu, 2006 = Prodasineura huai Zhou et Zhou, 2007, syn. n. PMID- 26624198 TI - Fossil carabids from Baltic amber--III--Tarsitachys bilobus Erwin, 1971 an interesting fossil ground beetle from Baltic amber (Coleoptera: Carabidae: Trechinae): Redescription and comments on its taxonomic placement. AB - Tarsitachys bilobus (Coleoptera, Carabidae) is a fossil species described by Erwin from Baltic amber. Its description was based on only one known specimen, and thus, part of its anatomical structures were unknown as they were poorly preserved in the Holotype. In this paper we complete the description with a second specimen. A new placement among Tachyina and a new status for the genus are proposed. PMID- 26624200 TI - A pictorial key to the species of the Aedes (Zavortinkius) in the Afrotropical Region (Diptera: Culicidae). AB - Six species of the subgenus Zavortinkius of Aedes Meigen in the Afrotropical Region are treated in a pictorial key based on diagnostic morphological features. Images of the diagnostic morphological structures of the adult thorax and leg are included. PMID- 26624199 TI - Description of the larva of Epigomphus crepidus Kennedy, 1936 (Odonata: Gomphidae). AB - The larva of Epigomphus crepidus Kennedy is described and figured and compared with other described congeners. It is characterized by 3rd antennomere spindle shaped, flattened dorso-ventrally, twice longer than its widest part; ventral pad of hypopharynx pentagonal; prementum subrectangular, with lateral margins slightly convex on apical 0.60; ligula very poorly developed, with a ventral row of nine short, truncate teeth on middle, and dorsal rows of short, stout piliform setae. Abdomen lacking dorsal protuberances, lateral spines on S7-9 divergent; sternites 3-8 divided into five plates, sternites 2 and 9 divided into three plates; male epiproct with a pair of dorsal tubercles rounded apically and divergent at basal 0.30. It differs from other species mainly in 3rd antennomere, sides of prementum and serrations on lateral margins of S7-9. PMID- 26624201 TI - Erratum: FERNANDO RUIZ-ESCOBAR, DIANA K. VALADEZ-VARGAS & OTTO M.P. OLIVEIRA (2015) CTENOPHORES FROM THE OAXACA COAST, INCLUDING A CHECKLIST OF SPECIES FROM THE PACIFIC COAST OF MEXICO. Zootaxa, 3936 (3): 435-445. PMID- 26624202 TI - Dynamical magnetoelectric phenomena of multiferroic skyrmions. AB - Magnetic skyrmions, vortex-like swirling spin textures characterized by a quantized topological invariant, realized in chiral-lattice magnets are currently attracting intense research interest. In particular, their dynamics under external fields is an issue of vital importance both for fundamental science and for technical application. Whereas observations of magnetic skyrmions has been limited to metallic magnets so far, their realization was also discovered in a chiral-lattice insulating magnet Cu2OSeO3 in 2012. Skyrmions in the insulator turned out to exhibit multiferroic nature with spin-induced ferroelectricity. Strong magnetoelectric coupling between noncollinear skyrmion spins and electric polarizations mediated by relativistic spin-orbit interaction enables us to drive motion and oscillation of magnetic skyrmions by application of electric fields instead of injection of electric currents. Insulating materials also provide an environment suitable for detection of pure spin dynamics through spectroscopic measurements owing to the absence of appreciable charge excitations. In this article, we review recent theoretical and experimental studies on multiferroic properties and dynamical magnetoelectric phenomena of magnetic skyrmions in insulators. We argue that multiferroic skyrmions show unique coupled oscillation modes of magnetizations and polarizations, so-called electromagnon excitations, which are both magnetically and electrically active, and interference between the electric and magnetic activation processes leads to peculiar magnetoelectric effects in a microwave frequency regime. PMID- 26624204 TI - Assessment of Hybrid Organic-Inorganic Antimony Sulfides for Earth-Abundant Photovoltaic Applications. AB - Hybrid organic-inorganic solar absorbers are currently the subject of intense interest; however, the highest-performing materials contain Pb. Here we assess the potential of three Sb-based semiconductors: (i) Sb2S3, (ii) Cs2Sb8S13, and (iii) (CH3NH3)2Sb8S13. While the crystal structure of Sb2S3 is composed of 1D chains, 2D layers are formed in the ternary cesium and hybrid methylammonium antimony sulfide compounds. In each case, a stereochemically active Sb 5s(2) lone pair is found, resulting in a distorted coordination environment for the Sb cations. The bandgap of the binary sulfide is found to increase, while the ionization potential also changes, upon transition to the more complex compounds. Based on the predicted electronic structure, device configurations are suggested to be suitable for photovoltaic applications. PMID- 26624205 TI - (11)B Solid-State NMR Interaction Tensors of Linear Two-Coordinate Boron: The Dimesitylborinium Cation. AB - Borinium cations (R2B(+)) are of particular fundamental and applied interest in part due to their pronounced Lewis acidity which enables unique chemical transformations. Solid-state NMR spectroscopy of magic-angle spinning and stationary powdered samples of the dicoordinate boron cation in the recently reported dimesitylborinium tetrakis(pentafluorophenyl)borate compound (Shoji et al. Nature Chem. 2014, 6, 498) is applied to characterize the (11)B electric field gradient (EFG) and chemical shift (CS) tensors. The experimental data are consistent with linear C-B(+)-C geometry. The (11)B quadrupolar coupling constant, 5.44 +/- 0.08 MHz, and the span of the CS tensor, 130 +/- 1 ppm, are both particularly large relative to literature data for a variety of boron functional groups, and represent the first such data for the linear C-B(+)-C borinium moiety. The NMR data are similar to those for the neutral tricoordinate analogue, trimesitylborane, but contrast with those of the Cp*2B(+) cation. Quantum chemical calculations are applied to provide additional insights into the relationship between the NMR observables and the molecular and electronic structure of the dimesitylborinium cation. PMID- 26624206 TI - Trend of Body Compositions with Aging among Chinese Adolescents, Adults and Elders. AB - INTRODUCTION: Rare reports can be found about sex- and age-specific body composition survey among Chinese population. The aim of this study is to explore the change of sex-specific body compositions with aging among Chinese adolescents, adults and elders. METHODS: In a large-scale population survey about physiological constants and health conditions, 75,714 subjects who aged from 8 to 80 completed body composition array. Body mass index (BMI), percentage body fat (PBF), water percentage of body weight (WPBW), water percentage of lean body mass (WPLBM), fat-free mass index (FFMI) and basic metabolic rate were examined with Biodynamics BI-310 body composition analyzer. General obesity is defined as BMI equal to or greater than 28 kg/m2. RESULTS: The prevalence rates of general obesity were 9.4% for males and 7.7% for females respectively. With aging, PBF and FMI showed a U-shape curvilinear trend and WPBW showed a parabolic trend for males. At same age group: 18-19 age groups, PBF and FMI declined to the valley and WPBW rose to the peak. For females, PBF, WPBW and FMI changed in a linear trend. The values of WPLBM and FFMI showed same curvilinear trend for two genders. WPLBM changed in a U-shape trend and touched the valley in twenties for males and in 18-19 age groups for females. The value of FFMI was larger for older age groups in the younger generation but smaller in the older generation. A parabolic trend peaking was seen in the thirties for males and in the forties for females. Regression models with age as independent variable showed that the larger rate of increase of PBF and smaller rates of increase for WPBM and WPLBM with aging for males. CONCLUSION: This study presents detailed data about sex specific body composition conditions. Different change trend with aging was found about body composition conditions. PMID- 26624207 TI - Prevalence and Association of Undernutrition with Quality of Life among Swedish People Aged 60 Years and Above: Results of the SNAC-B Study. AB - OBJECTIVES: This study aimed to assess the prevalence of undernutrition among elderly and to investigate the association of risk of undernutrition with health related quality of life and life satisfaction controlling for age, gender, marital status, economic status, housing arrangement, education level, functional ability, and diseases. DESIGN: A cross-sectional study design was used for this study. The baseline data (2001-2003) of "The Swedish National Study of Aging and Care-Blekinge (SNAC-B)" was used. SETTING: This population-based study focused on both home-living and special-housing residents. PARTICIPANTS: The participants (n=1402) were randomly selected and included both males and females 60-96 years of age residing in a municipality of south-east Sweden. MEASUREMENTS: The risk of undernutrition was estimated by the occurrence of at least one anthropometric measure (body mass index, mid-arm circumference, and calf circumference) below cut-off, in addition to the presence of at least one subjective measure (declined food intake, weight loss, and eating difficulty). The dependent variables, health related quality of life and life satisfaction, were measured by the validated short form health survey (SF-12) and Liang's life satisfactions index A (LSIA), respectively. RESULTS: According to the criterion, 8.5% of the participants were at risk of undernutrition, and subjects at nutritional risk were significantly older, female, unmarried/widowed/divorced, residing in special housing, and functionally impaired. The risk of undernutrition was significantly associated with poor health-related quality of life, both in the physical (OR 2.31, 95% CI 1.18-4.52) and mental (OR 2.34, 95% CI 1.22-4.47) dimensions. However, no significant association was observed between nutritional status and life satisfaction (OR 1.30, 95% CI 0.70-2.40). CONCLUSION: The risk of undernutrition significantly increases the risk of poor physical and mental health-related quality of life but has negligible impact on life satisfaction. This study also highlights the importance of functional ability both for the prevention of undernutrition and promotion of quality of life. However, more studies are needed to validate the tool used here for undernutrition risk assessment before it can be used in clinical or population settings. PMID- 26624208 TI - BMI and Body Fat Mass Is Inversely Associated with Vitamin D Levels in Older Individuals. AB - OBJECTIVE: To assess the association between obesity (measured by Body Mass Index (BMI) and fat percentage) and serum 25(OH)D levels in older persons. DESIGN: Cross-sectional analysis of data from 'the B-PROOF study' (B-vitamins for the Prevention Of Osteoporotic Fractures). PARTICIPANTS: 2842 participants aged 65 years and older. MEASUREMENTS: BMI and fat percentage, measured by Dual Energy X ray, and serum 25(OH)D levels. RESULTS: Mean age was 74 years (6.5 SD), with 50% women. Mean serum 25(OH)D levels were 55.8 nmol/L (25 SD). BMI and total body fat percentage were significant inversely associated with serum 25(OH)D levels after adjustment for confouders (beta-0.93; 95% CI [-1.15; -0.71], p<0.001 and beta 0.84; 95% CI [-1.04; -0.64], p<0.001). This association was most prominent in individuals with a BMI in the 'overweight' and 'obesity' range (beta -1.25 and 0.96 respectively) and fat percentage in the last two upper quartiles (beta-1.86 and -1.37 respectively). CONCLUSION: In this study, higher BMI and higher body fat percentage were significantly associated with lower serum 25(OH)D levels in older persons. This association was particularly present in individuals with overweight, and higher fat percentages, suggesting that these persons are at increased risk of vitamin D insufficiency. PMID- 26624210 TI - Validation of Nutrient Intake Estimates Derived Using a Semi-Quantitative FFQ against 3 Day Diet Records in the Baltimore Longitudinal Study of Aging. AB - OBJECTIVE: To examine the relative validity of a multicultural FFQ used to derive nutrient intake estimates in a community dwelling cohort of younger and older men and women compared with those derived from 3 day (3d) diet records during the same time-frame. DESIGN: Cross-sectional analyses. SETTING: The Baltimore Longitudinal Study of Aging (BLSA) conducted in the Baltimore, MD and District of Columbia areas. PARTICIPANTS: A subset (n=468, aged 26 to 95 years (y), 47% female, 65% non-Hispanic white) from the BLSA, with complete data for nutrient estimates from a FFQ and 3d diet records. MEASUREMENTS: Pearson's correlation coefficients (energy adjusted and de-attenuated) for intakes of energy and 26 nutrients estimated from the FFQ and the mean of 3d diet records were calculated in a cross-sectional analysis. Rankings of individuals based on FFQ for various nutrient intakes were compared to corresponding rankings based on the average of the 3d diet records. Bland Altman plots were examined for a visual representation of agreement between both assessment methods. All analyses were stratified by sex and age (above and below 65 y). RESULTS: Median nutrient intake estimates tended to be higher from the FFQ compared to average 3d diet records. Energy adjusted and de-attenuated correlations between FFQ intake estimates and records ranged from 0.23 (sodium intake in men) to 0.81 (alcohol intake in women). The FFQ classified more than 70 percent of participants in either the same or adjacent quartile categories for all nutrients examined. Bland Altman plots demonstrated good agreement between the assessment methods for most nutrients. CONCLUSIONS: This FFQ provides reasonably valid estimates of dietary intakes of younger and older participants of the BLSA. PMID- 26624209 TI - The Associations of Malnutrition and Aging with Fluid Volume Imbalance between Intra- and Extracellular Water in Patients with Chronic Kidney Disease. AB - OBJECTIVES: Fluid imbalance due to sodium retention and malnutrition can be characterized by the ratio of extracellular water (ECW) to intracellular water (ICW). We investigated whether the ECW/ICW ratio is a risk factor for adverse outcomes. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: 149 patients with chronic kidney disease from 2005 to 2009, who were followed until August 2013. MEASUREMENTS: Body fluid composition was measured by bioelectrical impedance analysis. Patients were categorized according to the ECW/ICW ratio tertile. Daily nutrient intake was estimated from 24-h dietary recall and analyzed using standard food composition tables. The main outcomes were adverse renal outcomes, as defined by a decline of 50% or more from the baseline glomerular filtration rate or initiation of renal replacement therapy, cardiovascular events, and all-cause mortality. RESULTS: The ECW/ICW ratio increased with downward ICW slope with age and renal dysfunction besides ECW excess with massive proteinuria. Sodium intake, protein intake, and calorie intake were negatively correlated with the ECW/ICW ratios due to the steeper decreasing ICW content with the decreased dietary intake than the decreasing ECW content. During a median 4.9-year follow up, patients in the highest tertile had the worst adverse renal outcomes (15.9 vs. 5.1 per 100 patient-years, P < 0.001), cardiovascular events (4.1 vs. 0.3 per 100 patient-years, P = 0.002), and mortality (11.2 vs. 1.3 per 100 patient-years, P < 0.001). The adjusted hazard ratio (95% confidence intervals) for adverse renal outcomes, cardiovascular events, and mortality were 1.15 (1.03 - 1.26), 1.12 (0.93 - 1.31), and 1.29 (1.11 - 1.50), respectively. CONCLUSIONS: Fluid imbalance between ICW and ECW occurring in malnourished and elderly patients with chronic kidney disease may explain the reserve capacity for volume overload and is associated with adverse renal outcomes and all-cause mortality. PMID- 26624211 TI - Examining the Association between Vitamin B12 Deficiency and Dementia in High Risk Hospitalized Patients. AB - OBJECTIVES: To explore the association between vitamin B12 deficiency and dementia in patients at high risk for vitamin B12 deficiency. DESIGN: Chart review. SETTING: Emergency, critical care/ trauma, neurology, medicine, and rehabilitation units of two hospitals in Southwestern Ontario, Canada. PARTICIPANTS: Adult patients (n = 666) admitted from 2010 to 2012. Data collection included: reason for admission, gender, age, clinical signs and symptoms of B12 deficiency, serum B12 concentration, and B12 supplementation. Patients with dementia were identified based on their medication profile and medical history. Vitamin B12 deficiency (pmol/L) was defined as serum B12 concentration <148; marginal deficiency: >=148-220 and adequate >220. Comparisons between B12-deficient patients with and without dementia were examined using parametric and non-parametric tests. RESULTS: Serum B12 values were available for 60% (399/666) of the patients, of whom 4% (16/399) were B12-deficient and 14% (57/399) were marginally deficient. Patients with dementia were not more likely to be B12-deficient or marginally deficient [21% (26/121)] compared to those with no dementia [17% (47/278), p=0.27)]. Based on documentation, 34% (25/73) of the B12-deficient and marginally-deficient patients did not receive B12 supplementation, of whom 40% (10/25) had dementia. CONCLUSION: In this sample of patients, there was no association between B12 deficiency and dementia. However, appropriate B12 screening protocols are necessary for high risk patient to identify deficiency and then receive B12 supplementation as needed. PMID- 26624212 TI - Analysing Time to Event Data in Dementia Prevention Trials: The Example of the GuidAge Study of EGb761. AB - Time-to-event analysis is frequently used in medical research to investigate potential disease-modifying treatments in neurodegenerative diseases. Potential treatment effects are generally evaluated using the logrank test, which has optimal power and sensitivity when the treatment effect (hazard ratio) is constant over time. However, there is generally no prior information as to how the hazard ratio for the event of interest actually evolves. In these cases, the logrank test is not necessarily the most appropriate to use. When the hazard ratio is expected to decrease or increase over time, alternative statistical tests such as the Fleming-Harrington test, provide a better sensitivity. An example of this comes from a large, five-year randomised, placebo-controlled prevention trial (GuidAge) in 2854 community-based subjects making spontaneous memory complaints to their family physicians, which evaluated whether treatment with EGb761 can modify the risk of developing AD. The primary outcome measure was the time to conversion from memory complaint to Alzheimer's type dementia. Although there was no significant difference in the hazard function of conversion between the two treatment groups according to the preplanned logrank test, a significant treatment-by-time interaction for the incidence of AD was observed in a protocol-specified subgroup analysis, suggesting that the hazard ratio is not constant over time. For this reason, additional post hoc analyses were performed using the Fleming-Harrington test to evaluate whether there was a signal of a late effect of EGb761. Applying the Fleming-Harrington test, the hazard function for conversion to dementia in the placebo group was significantly different from that in the EGb761 treatment group (p = 0.0054), suggesting a late effect of EGb761. Since this was a post hoc analysis, no definitive conclusions can be drawn as to the effectiveness of the treatment. This post hoc analysis illustrates the interest of performing another randomised clinical trial of EGb761 explicitly testing the hypothesis of a late treatment effect, as well as of using of better adapted statistical approaches for long term preventive trials when it is expected that prevention cannot have an immediate effect but rather a delayed effect that increases over time. PMID- 26624213 TI - Pro-Active Fall-Risk Management is Mandatory to Sustain in Hospital-Fall Prevention in Older Patients--Validation of the LUCAS Fall-Risk Screening in 2,337 Patients. AB - OBJECTIVES: Prevention of in-hospital falls contributes to improvement of patient safety. However, the identification of high-risk patients remains a challenge despite knowledge of fall-risk factors. Hence, objective was to prospectively validate the performance of the LUCAS (Longitudinal Urban Cohort Ageing Study) fall-risk screening, based on routine data (fall history, mobility, mental status) and applied by nurses. DESIGN: Observational study comparing two groups of patients who underwent different fall-risk screenings; the LUCAS screening (2010 - 2011) and the STRATIFY (St. Thomas's Risk Assessment Tool In Falling Elderly Inpatients) (2004 - 2006). SETTING: Urban teaching hospital. PARTICIPANTS: Consecutively hospitalized patients (>= 65 years old) were screened on admission; LUCAS n = 2,337, STRATIFY n = 4,735. MEASUREMENTS: The proportions of fallers were compared between the STRATIFY and the LUCAS time periods. The number of fallers expected was compared to that observed in the LUCAS time period. Standardized fall-incidence recording included case-note checks for unreported falls. Plausibility checks of fall-risk factors and logistic regression analysis for variable fall-risk factors were performed. RESULTS: The proportions of fallers during the two time periods were LUCAS n = 291/2,337 (12.5%) vs. STRATIFY n = 508/4,735 (10.7%). After adjustment for risk-factor prevalence, the proportion of fallers expected was 14.5% (334/2,337), the proportion observed was 12.5% (291/2,337) (p = 0.038). CONCLUSIONS: In-hospital fall prevention including systematic use of the LUCAS fall-risk screening reduced the proportion of fallers compared to that expected from the patients' fall-risk profile. Raw proportions of fallers are not suitable to evaluate fall prevention in hospital because of variable prevalence of patients' fall-risk factors over time. Continuous communication, education and training is needed to sustain in hospital falls prevention. PMID- 26624214 TI - Brief Report: Implementing a Mediterranean Diet Intervention into a RCT: Lessons Learned from a Non-Mediterranean Based Country. AB - OBJECTIVE: To examine the participant experiences regarding perceived barriers and facilitators which impact on consuming the Mediterranean diet in the East of England. DESIGN: Qualitative methodology with focus groups. SETTING: A healthy, middle-aged population situated in the East of England. INTERVENTION: An 8-week Mediterranean dietary intervention trial. PARTICIPANTS: Eleven participants (including three co-habiting partners) in three focus groups, ranging between 50 65 yrs with a mean age of 54.3 yrs (+/-4.0) RESULTS: Thematic analysis from the focus groups revealed that participants considered that the MD intervention had introduced a better quality of food, widening the food-horizon and allowed them to re-define cultural eating habits. They also reported several physical benefits from adapting to this diet and found the experience as positive. Whilst claiming that the MD was an enjoyable and pleasurable, the participants did express difficulty adapting to the eating pattern, finding difficulty in purchasing food items, an increase in food costs and found work, stress and time pressures undermining adherence. CONCLUSION: The participants' experiences suggested that the MD was an encouraging dietary change with a middle aged non-Mediterranean based population group. Future MD interventions should tailor interventions and support participants closely, particularly with the necessary planning, organisation and purchasing involved with implementing this diet in non Mediterranean countries. Secondly, researchers should also challenge any erroneous assumptions regarding the consumption of Mediterranean food, which may hinder implementation. PMID- 26624215 TI - Prevalence of Falls in an Urban Community-Dwelling Older Population of Cape Town, South Africa. AB - OBJECTIVE: Falls are a major cause of disability and mortality in older adults. Studies on falls in this population have mainly been conducted in high income countries, and scant attention has been given to the problem in low and middle income countries, including South Africa. The aim of the study was to establish a rate for falls in older adults in South Africa. DESIGN: A cross-sectional survey with a 12-month follow-up survey. SETTING: Three purposively selected suburbs of Cape Town: Plumstead, Wynberg Central and Gugulethu. PARTICIPANTS: Eight hundred and thirty seven randomly sampled ambulant community-dwelling subjects aged >= 65 years grouped according to ethnicity in three sub-samples: black Africans, coloureds (people of mixed ancestry) and whites. MEASUREMENTS: Data were collected on socio-demographic and health characteristics, and history of falls using a structured questionnaire and a protocol for physical assessments and measurements. RESULTS: Of the total baseline (n=837) and follow-up (n=632) survey participants, 76.5% and 77.2 % were females with a mean (S.D) age of 74 years (6.4) and 75 years (6.2), respectively. Rates of 26.4% and 21.9% for falls and of 11% and 6.3% for recurrent falls, respectively, were calculated at baseline and follow-up. Fall rates differed by ethnic sub-sample at baseline: whites 42 %, coloureds 34.4% and black Africans 6.4 % (p=0.0005). Rates of 236, 406 and 354 falls per 1000 person years were calculated for men, women and both genders, respectively. Recurrent falls were more common in women than in men. CONCLUSION: Falls are a significant problem in older adults in South Africa. Effective management of falls and falls prevention strategies for older people in South Africa, need to be developed and implemented. PMID- 26624216 TI - Can the Mini Nutritional Assessment (MNA) Be Used as a Nutrition Evaluation Tool for Subacute Inpatients over an Average Length of Stay? AB - OBJECTIVE: The prevalence of malnutrition in subacute inpatient settings has been reported to be 30-50%. While there are a number of nutrition evaluation tools which have been validated to diagnose malnutrition, the use of a validated nutrition evaluation tool to measure changes in nutritional status during an average length of stay for a subacute inpatient has not yet been tested. This study aims to determine the potential of the full MNA (full Mini Nutritional Assessment) and MNA (Mini Nutritional Assessment Short Form) scores to measure change in nutritional status over an average subacute inpatient stay (21 days). DESIGN: A prospective observational study. SETTING: The study was performed in three Rehabilitation and Geriatric Evaluation and Management (GEM) wards of the Kingston Centre, Monash Health, Melbourne, Australia. PARTICIPANTS: All patients >=65 years admitted to these wards with an expected length of stay of at least 14 days were considered for inclusion in this study. MEASUREMENTS: Nutritional status was assessed on admission using the full MNA as part of usual dietetic care and patients were provided with nutrition intervention/diet therapy based on full MNA classification. Full MNA score (0-30), MNA score (0-14), anthropometry (weight and height) and nutritional biochemistry (serum albumin, transthyretin and C-reactive protein) were compared between admission and day 20.5 +/- 2.4. RESULTS: Mean age (+/- SD) of 83 +/- 7 years, n=114. For those patients diagnosed at risk of malnutrition or malnourished (n=103), there were significant increases in full MNA score (1.8 +/- 2.4, p<0.001), MNA score (0.9 +/- 1.7, p<0.001), weight (0.6 +/- 2.5 kg, p=0.017) and serum albumin (1.4 +/- 4.4 g/L, p=0.003) over the study period. All four of the full MNA domain sub-scores, also increased significantly in those patients diagnosed at risk of malnutrition or malnourished (n=103): anthropometric assessment (p<0.001), dietary assessment (p<0.001), general status assessment (p=0.019) and self-perceived health and nutrition states (p=0.033). CONCLUSION: Both the MNA and full MNA can be used to evaluate nutrition progress within the subacute inpatient setting over a three week time period, thereby providing clinicians with feedback on a patient's nutrition progress and assisting with ongoing care planning. Due to its ease of use and shorter time required to complete, the MNA may be the preferred nutrition evaluation tool in this setting. PMID- 26624217 TI - The Relationship between Diet Quality and Falls Risk, Physical Function and Body Composition in Older Adults. AB - OBJECTIVES: We aimed to examine associations between diet quality, falls risk, physical function, physical activity and body composition. DESIGN: Cross sectional study. SETTING AND PARTICIPANTS: Data collected from 171 men and women, aged 60-88 years old, as part of the Falls Risk and Osteoporosis Longitudinal Study. MEASUREMENTS: Dietary Intake (Dietary Questionnaire for Epidemiological Studies Version 2 (DQES v2)), Falls Risk (FES-I, ABC, Berg Balance and Physiological Profile Assessment), Physical Function (SPPB), Physical Activity (PASE) and Body Composition (fat mass, lean mass, BMD, BMI, android/gynoid ratio) were ascertained. Diet quality was determined using two measures (Healthy Eating Index - HEI and Healthy Diet Indicator - HDI). One-way Analysis of Variance was used to compare mean scores between females and males and Pearson product-moment correlation coefficients were calculated to examine bivariate relationships. RESULTS: Although females and males were analysed separately, the HDI-total score showed more associations that the HEI in both genders. The HDI showed, in females weak negative associations with BMI (r =-.21, p=.04), gynoid fat (r = -.20, p=.01), total fat mass (r = -.20, p=.02), with a weak positive association between HDI and percentage lean mass (r =.20, p=.03). Males showed positive associations between HDI and age (r =.30 p=.02) physical function (SPPB)(r =.26, p=.04), and subjective falls-risk (ABC) (r =.26, p=.03). In addition, in males, a negative association was found between HDI and FES-I (r = -.25, p=.04). The only measure that was significantly associated with the HEI-total score was the android/gynoid ratio in males (r = -.29, p=.04). When controlling for age, females demonstrated weak positive associations between gynoid (r = .19 p = .02), android (r = .19, p = .02) and total fat mass (r = .20 p = .02) as well as weak negative correlation with lean mass (r = 1.19, p = .03). Age also impacts on the FES-I (r = .29 p <.01) and ABC (r = -.23 p <.01). CONCLUSIONS: The relationships between dietary quality and body composition, falls risk and physical function in older community dwelling, higher functioning adults appear to be gender specific. Better diet quality in females, is associated with lower BMI and fat mass, and higher lean mass, compared to males that are older and appear to have better physical function, are less likely to self-report falls risk, and have a better fat distribution i.e. a lower android/gynoid ratio have better diet quality. Furthermore, age is an important confounder and should be taken into consideration when assessing diet quality in older adults. In addition these gender and age differences may be clinically relevant and could aid in the delivery of targeted interventions. PMID- 26624218 TI - Analysis of Rockwood et Al's Clinical Frailty Scale and Fried et Al's Frailty Phenotype as Predictors of Mortality and Other Clinical Outcomes in Older Patients Who Were Admitted to a Geriatric Ward. AB - OBJECTIVES: There are few data regarding the accuracy of short frailty tools as predictors of mortality and other clinical outcomes of older patients admitted to a geriatric ward. We therefore analyzed the accuracy of Rockwood et al's Clinical Frailty Scale and an easy and quick to perform operationalization of Fried et al's frailty phenotype, as predictors of mortality and other clinical outcomes in our cohort of patients. DESIGN: Prospective analysis with a follow-up period of 6 months. SETTING AND PARTICIPANTS: 307 patients who were 65 years of age or older were included in the study. The patients were assessed in terms of the two frailty measures during their stay in a geriatric ward. RESULTS: The Clinical Frailty Scale and the frailty phenotype were both suitable for differentiating between patients who died due to any cause from those who survived during follow up (primary outcome) (area under the ROC curves (AUC) values 0.867 (95% CI 0.807 0.926), p<0.001 and 0.754 (95% CI 0.688-0.821), p<0.001, respectively). Regarding the secondary outcomes: 1. unplanned admission to hospital and 2. a fall during follow-up, the Clinical Frailty Scale discriminated or tended to discriminate between patients to whom these criteria applied and those to whom they did not (AUC=0.569 (95% CI 0.502-0.636), p=0.046 and AUC=0.574 (95% CI 0.501-0.647), p=0.071, respectively). The frailty phenotype did not show such a differentiation when applied to secondary outcomes (AUC=0.500 (95% CI 0.432-0.568), p=0.994 and AUC=0.518 (95% CI 0.439-0.598), p=0.658, respectively). CONCLUSIONS: Both short frailty instruments are suitable predictors of mortality in older patients who were admitted to a geriatric ward. The Clinical Frailty Scale, but not the frailty phenotype, predicted at least some of the secondary outcomes, i.e., the outcome unplanned admission to hospital during follow-up. PMID- 26624219 TI - The "Gln-Type" Thiol Dioxygenase from Azotobacter vinelandii is a 3 Mercaptopropionic Acid Dioxygenase. AB - Cysteine dioxygenase (CDO) is a non-heme iron enzyme that catalyzes the O2 dependent oxidation of l-cysteine to produce cysteinesulfinic acid. Bacterial CDOs have been subdivided as either "Arg-type" or "Gln-type" on the basis of the identity of conserved active site residues. To date, "Gln-type" enzymes remain largely uncharacterized. It was recently noted that the "Gln-type" enzymes are more homologous with another thiol dioxygenase [3-mercaptopropionate dioxygenase (MDO)] identified in Variovorax paradoxus, suggesting that enzymes of the "Gln type" subclass are in fact MDOs. In this work, a putative "Gln-type" thiol dioxygenase from Azotobacter vinelandii (Av) was purified to homogeneity and characterized. Steady-state assays were performed using three substrates [3 mercaptopropionic acid (3mpa), l-cysteine (cys), and cysteamine (ca)]. Despite comparable maximal velocities, the "Gln-type" Av enzyme exhibited a specificity for 3mpa (kcat/KM = 72000 M(-1) s(-1)) nearly 2 orders of magnitude greater than those for cys (110 M(-1) s(-1)) and ca (11 M(-1) s(-1)). Supporting X-band electron paramagnetic resonance (EPR) studies were performed using nitric oxide (NO) as a surrogate for O2 binding to confirm obligate-ordered addition of substrate prior to NO. Stoichimetric addition of NO to solutions of 3mpa-bound enzyme quantitatively yields an iron-nitrosyl species (Av ES-NO) with EPR features consistent with a mononuclear (S = (3)/2) {FeNO}(7) site. Conversely, two distinct substrate-bound conformations were observed in Av ES-NO samples prepared with cys and ca, suggesting heterogeneous binding within the enzymatic active site. Analytical EPR simulations are provided to establish the relative binding affinity for each substrate (3map > cys > ca). Both kinetic and spectroscopic results presented here are consistent with 3mpa being the preferred substrate for this enzyme. PMID- 26624220 TI - The Role of Dialysis Membranes on Intradialytic Selenium Removal and on Selenium Status in Patients Receiving Renal Replacement Therapy. AB - BACKGROUND/AIMS: Dialysis membrane has been implicated in selenium (Se) deficiency in hemodialysis (HD). Intradialytic Se removal into dialysate through different membranes was investigated. METHODS: We studied 19 patients on standard HD with low-flux polysulfone membrane (group A), 10 patients on standard HD with ethylene vinyl alcohol membrane (group B), 12 patients on hemodiafiltration (HDF; group C) and 16 healthy subjects (control group D). Se was measured in blood before and after dialysis session and in effluent dialysate every hour during session. RESULTS: In all patients together, pre-dialysis serum Se levels were lower than those in control group, but, in a separate analysis, only in standard HD. In all patient groups, there was a net Se removal into dialysate but it was greater in HDF patients who, however, had similar pre-dialysis serum Se levels to those in healthy controls. CONCLUSION: An intradialytic Se loss was found with all 3 membrane types, but it is not the principal factor for Se depletion in HD. PMID- 26624222 TI - On-Chip Isothermal Nucleic Acid Amplification on Flow-Based Chemiluminescence Microarray Analysis Platform for the Detection of Viruses and Bacteria. AB - This work presents an on-chip isothermal nucleic acid amplification test (iNAAT) for the multiplex amplification and detection of viral and bacterial DNA by a flow-based chemiluminescence microarray. In a principle study, on-chip recombinase polymerase amplification (RPA) on defined spots of a DNA microarray was used to spatially separate the amplification reaction of DNA from two viruses (Human adenovirus 41, Phi X 174) and the bacterium Enterococcus faecalis, which are relevant for water hygiene. By establishing the developed assay on the microarray analysis platform MCR 3, the automation of isothermal multiplex amplification (39 degrees C, 40 min) and subsequent detection by chemiluminescence imaging was realized. Within 48 min, the microbes could be identified by the spot position on the microarray while the generated chemiluminescence signal correlated with the amount of applied microbe DNA. The limit of detection (LOD) determined for HAdV 41, Phi X 174, and E. faecalis was 35 GU/MUL, 1 GU/MUL, and 5 * 10(3) GU/MUL (genomic units), which is comparable to the sensitivity reported for qPCR analysis, respectively. Moreover the simultaneous amplification and detection of DNA from all three microbes was possible. The presented assay shows that complex enzymatic reactions like an isothermal amplification can be performed in an easy-to-use experimental setup. Furthermore, iNAATs can be potent candidates for multipathogen detection in clinical, food, or environmental samples in routine or field monitoring approaches. PMID- 26624221 TI - Toddlers' dysregulated fear predicts delta-beta coupling during preschool. AB - Dysregulated fear, or the persistence of high levels of fear in low-threat contexts, is an early risk factor for the development of anxiety symptoms. Previous work has suggested both propensities for over-control and under-control of fearfulness as risk factors for anxiety problems, each of which may be relevant to observations of dysregulated fear. Given difficulty disentangling over-control and under-control through traditional behavioral measures, we used delta-beta coupling to begin to understand the degree to which dysregulated fear may reflect propensities for over- or under-control. We found that toddlers who showed high levels of dysregulated fear evidenced greater delta-beta coupling at frontal and central electrode sites as preschoolers relative to children who were low in dysregulated fear. Importantly, these differences were not observed when comparisons were made based on fear levels in high threat contexts. Results suggest dysregulated fear may involve tendencies toward over-control at the neural level. PMID- 26624223 TI - TWSVR: Regression via Twin Support Vector Machine. AB - Taking motivation from Twin Support Vector Machine (TWSVM) formulation, Peng (2010) attempted to propose Twin Support Vector Regression (TSVR) where the regressor is obtained via solving a pair of quadratic programming problems (QPPs). In this paper we argue that TSVR formulation is not in the true spirit of TWSVM. Further, taking motivation from Bi and Bennett (2003), we propose an alternative approach to find a formulation for Twin Support Vector Regression (TWSVR) which is in the true spirit of TWSVM. We show that our proposed TWSVR can be derived from TWSVM for an appropriately constructed classification problem. To check the efficacy of our proposed TWSVR we compare its performance with TSVR and classical Support Vector Regression(SVR) on various regression datasets. PMID- 26624224 TI - SIM-ELM: Connecting the ELM model with similarity-function learning. AB - This paper moves from the affinities between two well-known learning schemes that apply randomization in the training process, namely, Extreme Learning Machines (ELMs) and the learning framework using similarity functions. These paradigms share a common approach involving data remapping and linear separators, but differ in the role of randomization within the respective learning algorithms. The paper presents an integrated approach connecting the two models, which ultimately yields a new variant of the basic ELM. The resulting learning scheme is characterized by an analytical relationship between the dimensionality of the remapped space and the learning abilities of the eventual predictor. Experimental results confirm that the new learning scheme can improve over conventional ELM in terms of the trade-off between classification accuracy and predictor complexity (i.e., the dimensionality of the remapped space). PMID- 26624225 TI - Chemical and Phase Evolution of Amorphous Molybdenum Sulfide Catalysts for Electrochemical Hydrogen Production. AB - Amorphous MoSx is a highly active, earth-abundant catalyst for the electrochemical hydrogen evolution reaction. Previous studies have revealed that this material initially has a composition of MoS3, but after electrochemical activation, the surface is reduced to form an active phase resembling MoS2 in composition and chemical state. However, structural changes in the MoSx catalyst and the mechanism of the activation process remain poorly understood. In this study, we employ transmission electron microscopy (TEM) to image amorphous MoSx catalysts activated under two hydrogen-rich conditions: ex situ in an electrochemical cell and in situ in an environmental TEM. For the first time, we directly observe the formation of crystalline domains in the MoSx catalyst after both activation procedures as well as spatially localized changes in the chemical state detected via electron energy loss spectroscopy. Using density functional theory calculations, we investigate the mechanisms for this phase transformation and find that the presence of hydrogen is critical for enabling the restructuring process. Our results suggest that the surface of the amorphous MoSx catalyst is dynamic: while the initial catalyst activation forms the primary active surface of amorphous MoS2, continued transformation to the crystalline phase during electrochemical operation could contribute to catalyst deactivation. These results have important implications for the application of this highly active electrocatalyst for sustainable H2 generation. PMID- 26624226 TI - Drought tolerance strategies highlighted by two Sorghum bicolor races in a dry down experiment. AB - Drought stress is the major environmental stress that affects more and more frequently plant growth and productivity due to the current climate change scenario. Unravelling the physiological mechanism underlying the response of plants to water stress and discover traits related to drought tolerance provide new and powerful tools for the selection in breeding programmes. Four genotypes of Sorghum bicolor (L.) Moench were screened in a dry-down experiment using different approaches to discover physiological and molecular indicators of drought tolerance. Different strategies were identified in response to drought among the four genotypes and the two Sorghum race allowing to state the tolerance of durra race compared to the caudatum one and, within the durra race, the drought tolerance of the genotype IS22330. It retained high biomass production and high tolerance index, it had a low threshold of fraction of transpirable soil water and high capacity to recover leaf apparatus after drought stress. Furthermore in this study, the expression levels of four genes highlighted that they could be used as proxy for drought tolerance. Dehdrine (DHN) could be used for screening drought tolerance both in durra and in caudatum races. NADP-Malic Enzyme, Carbonic Anhydrase (CA) and Plasma membrane Intrinsic Protein (PIP2-5), being up-regulated by drought stress only in durra race, have a more limited, though nonetheless useful application. In the tolerant durra genotype IS22330 in particular, the regulation of stomatal openings was strongly related to NADP Malic Enzyme expression. PMID- 26624227 TI - ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy. AB - Diseases of ectopic calcification of the vascular wall range from lethal orphan diseases such as generalized arterial calcification of infancy (GACI), to common diseases such as hardening of the arteries associated with aging and calciphylaxis of chronic kidney disease (CKD). GACI is a lethal orphan disease in which infants calcify the internal elastic lamina of their medium and large arteries and expire of cardiac failure as neonates, while calciphylaxis of CKD is a ubiquitous vascular calcification in patients with renal failure. Both disorders are characterized by vascular Monckeburg's sclerosis accompanied by decreased concentrations of plasma inorganic pyrophosphate (PPi). Here we demonstrate that subcutaneous administration of an ENPP1-Fc fusion protein prevents the mortality, vascular calcifications and sequela of disease in animal models of GACI, and is accompanied by a complete clinical and biomarker response. Our findings have implications for the treatment of rare and common diseases of ectopic vascular calcification. PMID- 26624228 TI - Psoriasis and sleep disorders: A systematic review. AB - Psoriasis is an immune-mediated chronic inflammatory disorder which manifests as dermatologic lesions, and psoriatic arthritis (PsA) in about 30% of cases. Psoriasis is associated with multiple comorbidities including metabolic syndrome, hypertension, diabetes, cardiovascular events, obesity and psychiatric disorders, which can all affect the course of sleep disorders. A systematic review of the literature on the relationship between psoriasis, PsA, and formal sleep disorders identified 33 studies. There is an increased prevalence of obstructive sleep apnea (OSA) with 36%-81.8% prevalence in psoriasis versus 2%-4% in the general population. There was also an increase in the prevalence of restless legs syndrome of 15.1%-18% in psoriasis versus 5%-10% in European and North American samples. The wide variety of insomnia criteria used in studies resulted in an insomnia prevalence of 5.9%-44.8% in psoriasis, which is insufficient to show an elevated prevalence when the general population has a 10% prevalence of chronic insomnia and 30-35% prevalence of transient insomnia. There is evidence that symptoms of insomnia in psoriasis are directly mediated by pruritus and pain. Treatments that decrease the cutaneous symptoms in psoriasis were successful in mitigating insomnia, but did not show improvements in OSA where the relationship with psoriasis is multifactorial. PMID- 26624229 TI - Ozonation of piperidine, piperazine and morpholine: Kinetics, stoichiometry, product formation and mechanistic considerations. AB - Piperidine, piperazine and morpholine as archetypes for secondary heterocyclic amines, a structural unit that is often present in pharmaceuticals (e.g., ritalin, cetirizine, timolol, ciprofloxacin) were investigated in their reaction with ozone. In principle the investigated compounds can be degraded with ozone in a reasonable time, based on their high reaction rate constants with respect to ozone (1.9 * 10(4)-2.4 * 10(5) M(-1) s(-1)). However, transformation is insufficient (13-16%), most likely due to a chain reaction, which decomposes ozone. This conclusion is based on OH scavenging experiments, leading to increased compound transformation (18-27%). The investigated target compounds are similar in their kinetic and stoichiometric characteristics. However, the mechanistic considerations based on product formation indicate various reaction pathways. Piperidine reacts with ozone via a nonradical addition reaction to N hydroxypiperidine (yield: 92% with and 94% without scavenging, with respect to compound transformation). However, piperazine degradation with ozone does not lead to N-hydroxypiperazine. In the morpholine/ozone reaction, N hydroxymorpholine was identified. Additional oxidation pathways in all cases involved the formation of OH with high yields. One important pathway of piperazine and morpholine by ozonation could be the formation of C-centered radicals after ozone or OH radical attack. Subsequently, O2 addition forms unstable peroxyl radicals, which in one pathway loose superoxide radicals by generating a carbon-centered cation. Subsequent hydrolysis of the carbon-centered cation leads to formaldehyde, whereby ozonation of the N-hydroxy products can proceed in the same way and in addition give rise to hydroxylamine. A second pathway of the short-lived peroxyl radicals could be a dimerization to form short lived tetraoxides, which cleave by forming hydrogen peroxide. All three products have been found. PMID- 26624230 TI - When water saving limits recycling: Modelling economy-wide linkages of wastewater use. AB - The reclamation of wastewater is an increasingly important water source in parts of the world. It is claimed that wastewater recycling is a cheap and reliable form of water supply, which preserves water resources and is economically efficient. However, the quantity of reclaimed wastewater depends on water consumption by economic agents connected to a sewage system. This study uses a Computable General Equilibrium (CGE) model to analyse such a cascading water system. A case study of Israel shows that failing to include this linkage can lead to an overestimation of the potential of wastewater recycling, especially when economic agents engage in water saving. PMID- 26624231 TI - Enhanced DOC removal using anion and cation ion exchange resins. AB - Hardness and DOC removal in a single ion exchange unit operation allows for less infrastructure, is advantageous for process operation and depending on the water source, could enhance anion exchange resin removal of dissolved organic carbon (DOC). Simultaneous application of cationic (Plus) and anionic (MIEX) ion exchange resin in a single contact vessel was tested at pilot and bench scales, under multiple regeneration cycles. Hardness removal correlated with theoretical predictions; where measured hardness was between 88 and 98% of the predicted value. Comparing bench scale DOC removal of solely treating water with MIEX compared to Plus and MIEX treated water showed an enhanced DOC removal, where removal was increased from 0.5 to 1.25 mg/L for the simultaneous resin application compared to solely applying MIEX resin. A full scale MIEX treatment plant (14.5 MGD) reduced raw water DOC from 13.7 mg/L to 4.90 mg/L in the treated effluent at a bed volume (BV) treatment rate of 800, where a parallel operation of a simultaneous MIEX and Plus resin pilot (10 gpm) measured effluent DOC concentrations of no greater than 3.4 mg/L, even at bed volumes of treatment 37.5% greater than the full scale plant. MIEX effluent compared to simultaneous Plus and MIEX effluent resulted in differences in fluorescence intensity that correlated to decreases in DOC concentration. The simultaneous treatment of Plus and MIEX resin produced water with predominantly microbial character, indicating the enhanced DOC removal was principally due to increased removal of terrestrially derived organic matter. The addition of Plus resin to a process train with MIEX resin allows for one treatment process to remove both DOC and hardness, where a single brine waste stream can be sent to sewer at a full-scale plant, completely removing lime chemical addition and sludge waste disposal for precipitative softening processes. PMID- 26624232 TI - Evaluating Hydrogen Bonds and Base Stacking of Single, Tandem and Terminal GU Mismatches in RNA with a Mesoscopic Model. AB - Guanine-Uracil (GU) mismatches are crucial to the stability of the RNA double helix and need to be considered in RNA folding algorithms for numerous biotechnological applications. Yet despite its importance, many aspects of GU base pairs are still poorly understood. There is also a lack of parametrization which prevents it to be considered in mesoscopic models. Here, we adapted the mesoscopic Peyrard-Bishop model to deal with context-dependent hydrogen bonds of GU mismatches and calculated the model parameters related to hydrogen bonding and base stacking from available experimental melting temperatures. The context dependence causes a proliferation of parameters which made the problem computationally very demanding. We were able to overcome this problem by systematically regrouping the parameters during the minimization procedure. Our results not only provide the much needed parametrization but also answer several questions about the general properties of GU base pairs, as they can be associated straightforwardly to hydrogen bonding and base stacking. In particular, we found a very small Morse potential for tandem 5'-GU-3', which confirms a single hydrogen bond for this configuration, answering a long-standing question over conflicting experimental findings. Terminal GU base pairs are known to increase the duplex stability, but it is not clear why. Our results suggest that the increased terminal stability is mostly due to stronger hydrogen bonding. PMID- 26624235 TI - Sustained IGF-1 Secretion by Adipose-Derived Stem Cells Improves Infarcted Heart Function. AB - The mechanism by which stem cell-based therapy improves heart function is still unknown, but paracrine mechanisms seem to be involved. Adipose-derived stem cells (ADSCs) secrete several factors, including insulin-like growth factor-1 (IGF-1), which may contribute to myocardial regeneration. Our aim was to investigate whether the overexpression of IGF-1 in ADSCs (IGF-1-ADSCs) improves treatment of chronically infarcted rat hearts. ADSCs were transduced with a lentiviral vector to induce IGF-1 overexpression. IGF-1-ADSCs transcribe100- to 200-fold more IGF-1 mRNA levels compared to nontransduced ADSCs. IGF-1 transduction did not alter ADSC immunophenotypic characteristics even under hypoxic conditions. However, IGF 1-ADSCs proliferate at higher rates and release greater amounts of growth factors such as IGF-1, vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) under normoxic and hypoxic conditions. Importantly, IGF-1 secreted by IGF-1-ADSCs is functional given that Akt-1 phosphorylation was remarkably induced in neonatal cardiomyocytes cocultured with IGF-1-ADSCs, and this increase was prevented with phosphatidylinositol 3-kinase (PI3K) inhibitor treatment. Next, we tested IGF-1-ADSCs in a rat myocardial infarction (MI) model. MI was performed by coronary ligation, and 4 weeks after MI, animals received intramyocardial injections of either ADSCs (n = 7), IGF-1-ADSCs (n = 7), or vehicle (n = 7) into the infarcted border zone. Left ventricular function was evaluated by echocardiography before and after 6 weeks of treatment, and left ventricular hemodynamics were assessed 7 weeks after cell injection. Notably, IGF 1-ADSCs improved left ventricular ejection fraction and cardiac contractility index, but did not reduce scar size when compared to the ADSC-treated group. In summary, transplantation of ADSCs transduced with IGF-1 is a superior therapeutic approach to treat MI compared to nontransduced ADSCs, suggesting that gene and cell therapy may bring additional benefits to the treatment of MI. PMID- 26624234 TI - Computational Studies of Candida Antarctica Lipase B to Test Its Capability as a Starting Point To Redesign New Diels-Alderases. AB - The design of new biocatalysts is a target that is receiving increasing attention. One of the most popular reactions in this regard is the Diels-Alder cycloaddition because of its applications in organic synthesis and the absence of efficient natural enzymes that catalyze it. In this paper, the possibilities of using the highly promiscuous Candida Antarctica lipase B as a protein scaffold to redesign a Diels-Alderase has been explored by means of theoretical quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations. Free energy surfaces have been computed for two reactions in the wild-type and in several mutants with hybrid AM1/MM potentials with corrections at M06-2X/MM level. The study of the counterpart reactions in solution has allowed performing comparative analysis that render interesting conclusions. Since the dienophile anchors very well in the oxyanion hole of all tested protein variants, the slight electronic changes from reactant complex to the transition state suggest that mutations should be focused in favoring the formation of reactive conformations of a reactant complex that, in turn, would reduce the energy barrier. PMID- 26624237 TI - Varying Surface Chemistries for p-Doped and n-Doped Silicon Nanocrystals and Impact on Photovoltaic Devices. AB - Doping of quantum confined nanocrystals offers unique opportunities to control the bandgap and the Fermi energy level. In this contribution, boron-doped (p doped) and phosphorus-doped (n-doped) quantum confined silicon nanocrystals (SiNCs) are surface-engineered in ethanol by an atmospheric pressure radio frequency microplasma. We reveal that surface chemistries induced on the nanocrystals strongly depend on the type of dopants and result in considerable diverse optoelectronic properties (e.g., photoluminescence quantum yield is enhanced more than 6 times for n-type SiNCs). Changes in the position of the SiNCs Fermi levels are also studied and implications for photovoltaic application are discussed. PMID- 26624236 TI - Enantioselective Dehydrogenative Heck Arylations of Trisubstituted Alkenes with Indoles to Construct Quaternary Stereocenters. AB - An enantioselective, intermolecular dehydrogenative Heck arylation of trisubstituted alkenes to construct remote quaternary stereocenters has been developed. Using a new chiral pyridine oxazoline ligand, good to high enantioselectivity is achieved for various combinations of indole derivatives and trisubstituted alkenes. However, some combinations of substrates led to lower enantioselectivity, which provided the impetus to use structure enantioselectivity correlations to design a better performing ligand. PMID- 26624238 TI - A General Guidebook for the Theoretical Prediction of Physicochemical Properties of Chemicals for Regulatory Purposes. PMID- 26624239 TI - Urinary phthalate metabolites and depression in an elderly population: National Health and Nutrition Examination Survey 2005-2012. AB - Previous animal studies have demonstrated that phthalate exposure is associated with depression-like behaviors. However, no human study has explored this relationship. We explored the association between urinary phthalate metabolite concentrations and depression in a nationally representative sample of the U.S. elderly population. We analyzed 2030 participants aged 60 years or older with available data on phthalates and depression from the 2005 to 2012 National Health and Nutrition Examination Survey (NHANES). We selected 10 urinary phthalate metabolites with a weighted detection rate >60%. Depression was defined as a 9 item Patient Health Questionnaire score >=10. The models were adjusted for age, sex, race/ethnicity, education level, income-to-poverty ratio, health insurance coverage, marital status, smoking status, alcohol consumption, moderate physical activity, body mass index, comorbidity status, NHANEs cycle, and urinary creatinine levels. One-unit increases in log-transformed mono-(3-carboxypropyl) phthalate (MCPP) (odds ratio [OR]=1.24, 95% confidence interval [CI]=1.02-1.52) and mono(carboxynonyl) phthalate (MCNP) (OR=1.42, 95% CI=1.15-1.75) were positively associated with depression. When we stratified the urinary phthalate metabolites into quartiles, the highest quartiles (Q4) of MCNP (OR=2.57, 95% CI=1.25-5.27) and mono-n-butyl phthalate (MBP) (OR=2.40, 95% CI=1.10-5.22) were associated with depression compared with the lowest quartiles (Q1). Concentrations of urinary phthalate metabolites MCPP, MCNP, and MBP were positively associated with the risk of depression in a representative sample of the U.S. elderly population. However, the present cross-sectional study is hypothesis generating and the associations need to be investigated through further longitudinal studies. PMID- 26624241 TI - 2014 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 32nd Annual Report. AB - BACKGROUND: This is the 32nd Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 January 2014, 56 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 7.82 [7.02, 11.17] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system. METHODOLOGY: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure to the death. RESULTS: In 2014, 2,890,909 closed encounters were logged by NPDS: 2,165,142 human exposures, 56,265 animal exposures, 663,305 information calls, 6,085 human confirmed nonexposures, and 112 animal confirmed nonexposures. US poison centers (PCs) also made 2,617,346 follow-up calls in 2014. Total encounters showed a 5.5% decline from 2013, while health care facility human exposure cases increased by 3.3% from 2013. All information calls decreased by 17.7% and health care facility (HCF) information calls were essentially flat, decreasing by 0.04%, medication identification requests (Drug ID) decreased 29.8%, and human exposures reported to US PCs decreased 1.1%. Human exposures with less serious outcomes have decreased 3.40% per year since 2008 while those with more serious outcomes (moderate, major or death) have increased by 4.29% per year since 2000. The top 5 substance classes most frequently involved in all human exposures were analgesics (11.3%), cosmetics/personal care products (7.7%), household cleaning substances (7.7%), sedatives/hypnotics/antipsychotics (5.9%), and antidepressants (4.4%). Sedative/Hypnotics/Antipsychotics exposures as a class increased the most rapidly (2,368 calls (12.2%)/year) over the last 13 years for cases showing more serious outcomes. The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (14.0%), household cleaning substances (11.0%), analgesics (9.3%), foreign bodies/toys/miscellaneous (6.7%), and topical preparations (5.8%). Drug identification requests comprised 43.3% of all information calls. NPDS documented 1,835 human exposures resulting in death with 1,408 human fatalities judged related (RCF of 1-Undoubtedly responsible, 2 Probably responsible, or 3-Contributory). CONCLUSIONS: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures, despite a decrease in calls involving less serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national public health resource to collect and monitor US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, viral, bacterial, venomous, chemical agent, or commercial product), the identification of events of public health significance, resilience, response and situational awareness tracking. NPDS is a model system for the real-time surveillance of national and global public health.[Box: see text]. PMID- 26624243 TI - Applying Public Health Principles to the HIV Epidemic--How Are We Doing? PMID- 26624240 TI - Effects of particulate matter exposure on multiple sclerosis hospital admission in Lombardy region, Italy. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system, characterized by recurrent relapses of inflammation that cause mild to severe disability. Exposure to airborne particulate matter (PM) has been associated with acute increases in systemic inflammatory responses and neuroinflammation. In the present study, we hypothesize that exposure to PM<10MUm in diameter (PM10) might increase the occurrence of MS-related hospitalizations. METHODS: We obtained daily concentrations of PM10 from 53 monitoring sites covering the study area and we identified 8287 MS-related hospitalization through hospital admission-discharge records of the Lombardy region, Italy, between 2001 and 2009. We used a Poisson regression analysis to investigate the association between exposure to PM10 and risk of hospitalization. RESULTS: A higher RR of hospital admission for MS relapse was associated with exposure to PM10 at different time intervals. The maximum effect of PM10 on MS hospitalization was found for exposure between days 0 and 7: Hospital admission for MS increased 42% (95%CI 1.39-1.45) on the days preceded by one week with PM10 levels in the highest quartile. The p-value for trend across quartiles was<0.001. CONCLUSIONS: These data support the hypothesis that air pollution may have a role in determining MS occurrence and relapses. Our findings could open new avenues for determining the pathogenic mechanisms of MS and potentially be applied to other autoimmune diseases. PMID- 26624244 TI - Making Strides in Preventing Onychomycosis Recurrence. AB - Onychomycosis is a clinically important infection that is frequently progressive and may be associated with clinical sequelae. Accurate diagnosis, appropriate choice of antifungal agent-with consideration given to particular patient characteristics, including the presence of concomitant diseases and ability to comply with a given regimen-careful follow-up, and consideration of long-term management and reinfection prevention strategies are crucial to successful treatment. Semin Cutan Med Surg 34(supp3):S56-S58 (c) 2015 published by Frontline Medical Communications. PMID- 26624245 TI - Nonresponders to Prostaglandin Analogs Among Normal-Tension Glaucoma Patients. AB - PURPOSE: To investigate patients whose intraocular pressure (IOP) did not decrease after treatment using a prostaglandin analog (nonresponders). METHODS: This was an open-label, retrospective, case series study from a single institution. We retrospectively investigated the mean IOP reduction rates, and the proportions of nonresponders, among normal tension glaucoma (NTG) patients (209 cases, 209 eyes) treated using 1 of 4 prostaglandin analogs: latanoprost (40 patients), travoprost (64 patients), tafluprost (52 patients), or bimatoprost (53 patients). Absolute IOP was compared with pretreatment values for all 4 groups at the first and second visits after commencement of prostaglandin analog monotherapy. The IOP reduction rate was compared between groups. The proportion of nonresponders, defined as patients with IOP reduction rate <10% at both visits, was calculated in each group. RESULTS: The average IOP had significantly decreased from the pretreatment value at the first visit after treatment; the average IOP reduction rate ranged from 15.3% to 22.6%. The IOP reduction rate in the bimatoprost group was significantly higher than those in the travoprost and tafluprost groups (P < 0.001). We identified 6 nonresponders (15.0%) in the latanoprost group, 9 (14.1%) in the travoprost group, 4 (7.7%) in the tafluprost group, and none (0.0%) in the bimatoprost group; nonresponse rates were significantly lower in the bimatoprost group than in the other groups (P <= 0.05). CONCLUSION: Among NTG patients treated using prostaglandin analogs, from 0% to 15% were classified as nonresponders, depending on the prostaglandin analog used. The proportion of nonresponders was significantly lower in the bimatoprost group. PMID- 26624246 TI - Differential regulation of angiotensin II-induced extracellular signal regulated kinase-1/2 and -5 in progressive glomerulonephritis. AB - AIM: Extracellular signal regulated kinase (ERK)1/2 and ERK5 are key kinases of the signalling pathways involved in various cellular responses to kidney injury; however, the mechanistic links between those kinase and renin-angiotensin system (RAS) activations in glomerulonephritis (GN) have not been fully elucidated. In this study, we sought to clarify the potential roles of ERK1/2 and ERK5 via RAS activation in the pathogenesis of GN. METHODS: A rat model of progressive GN was induced by anti-glomerular basement membrane (GBM) injection and the signal transduction pathway in angiotensin II (Ang II)-induced glomerular pathologic alterations were investigated in primary cultured mesangial cells (MCs). RESULTS: Rats developed typical cellular crescents in glomeruli on day 7 that progressed to severe fibrocellular crescents and glomerulosclerosis on day 28. Strong expression of phospho-ERK1/2 was observed on day 7 and phospho-ERK5 expression was markedly increased on day 28 of GN. An angiotensin II type 1 receptor blocker (ARB) suppressed those augmentations. Moreover, ARB treatment attenuated the increases in macrophage infiltration and PCNA-positive cells observed on day 7 in GN rats, as well as the increase in collagen type 1 expression on day 28. Consistently, MCs stimulated by Ang II showed significant increases in proliferation and the expression of MCP-1 and collagen type 1. Interestingly, while the ERK1/2 inhibitor PD98059 abolished the elevations in MCP-1 expression and cell proliferation, the ERK5 inhibitor BIX02189 abrogated the elevation in collagen type 1 expression. CONCLUSION: Altogether, these data suggest that ERK1/2 regulates acute inflammatory reactions, while ERK5 promotes the development of RAS-induced chronic glomerular fibrosis activation in GN. PMID- 26624247 TI - The Event: An Underexamined Risk Concept. AB - Some of the terms used in risk assessment and management are poorly and even contradictorily defined. One such term is "event," which arguably describes the most basic of all risk-related concepts. The author cites two contemporary textbook interpretations of "event" that he contends are incorrect and misleading. He then examines the concept of an event in A. N. Kolmogorov's probability axioms and in several more-current textbooks. Those concepts are found to be too narrow for risk assessments and inconsistent with the actual usage of "event" by risk analysts. The author goes on to define and advocate linguistic definitions of events (as opposed to mathematical definitions) definitions constructed from natural language. He argues that they should be recognized for what they are: the de facto primary method of defining events. PMID- 26624248 TI - The Empirical Evidence for Telemedicine Interventions in Mental Disorders. AB - PROBLEM AND OBJECTIVE: This research derives from the confluence of several factors, namely, the prevalence of a complex array of mental health issues across age, social, ethnic, and economic groups, an increasingly critical shortage of mental health professionals and the associated disability and productivity loss in the population, and the potential of telemental health (TMH) to ameliorate these problems. Definitive information regarding the true merit of telemedicine applications and intervention is now of paramount importance among policymakers, providers of care, researchers, payers, program developers, and the public at large. This is necessary for rational policymaking, prudent resource allocation decisions, and informed strategic planning. This article is aimed at assessing the state of scientific knowledge regarding the merit of telemedicine interventions in the treatment of mental disorders (TMH) in terms of feasibility/acceptance, effects on medication compliance, health outcomes, and cost. MATERIALS AND METHODS: We started by casting a wide net to identify the relevant studies and to examine in detail the content of studies that met the eligibility criteria for inclusion. Only studies that met rigorous methodological criteria were included. Necessary details include the specific nature and content of the intervention, the research methodology, clinical focus, technological configuration, and the modality of the intervention. RESULTS: The published scientific literature on TMH reveals strong and consistent evidence of the feasibility of this modality of care and its acceptance by its intended users, as well as uniform indication of improvement in symptomology and quality of life among patients across a broad range of demographic and diagnostic groups. Similarly, positive trends are shown in terms of cost savings. CONCLUSION: There is substantial empirical evidence for supporting the use of telemedicine interventions in patients with mental disorders. PMID- 26624250 TI - Effect of low-intensity pulsed ultrasound on orthodontically induced root resorption caused by torque: A prospective, double-blind, controlled clinical trial. AB - OBJECTIVES: To evaluate the effects of low-intensity pulsed ultrasound (LIPUS) on orthodontically induced tooth root resorption caused by torque in human subjects. MATERIALS AND METHODS: Ten healthy patients (12-35 years of age) who required extraction of all first premolars as a part of their routine orthodontic treatment were recruited. A 15 degrees twist was applied in the arch wire using 0.019 * 0.025-inch TMA in a 0.022-inch bracket system (Synergy R) that produced a buccal root torque of approximately 5 N/mm at the bracket level. Using a split mouth design, randomization, and blinding, one side of the arch received LIPUS for 20 minutes per day for 4 weeks at an incident intensity of 30 mW/cm(2) of the transducers' surface area. The other side served as a self-control, which received a sham transducer. After 4 weeks, all first premolars were extracted and micro-computed tomographic analysis was performed on these extracted teeth. A linear mixed-model statistical analysis was used. RESULTS: LIPUS-treated teeth showed significantly less total volume of resorption lacunae compared to control teeth by a mean difference of (0.54 +/- 0.09 mm(3)) (P < .001) and percentage of root resorption by a mean difference of (0.33 +/- 0.05 mm(3)) (P < .001). In addition, significantly fewer resorption lacunae were found on all root surfaces in the LIPUS group compared to the control except in the instance of the distal surface. LIMITATIONS: This study was performed on limited number of cases during a 4-week period. CONCLUSIONS: LIPUS minimizes root resorption when applied during torque tooth movement over a 4-week period. PMID- 26624249 TI - Bactericidal antibiotics promote reactive oxygen species formation and inflammation in human sinonasal epithelial cells. AB - BACKGROUND: Bactericidal antibiotics have been shown to stimulate reactive oxygen species (ROS) formation in mammalian cells through mitochondrial dysfunction. This results in oxidative tissue damage that may have negative consequences for long-term antibiotic use. Antibiotics are widely and heavily used in the treatment of acute and chronic sinusitis; however, the relationship between antibiotics and ROS formation in sinonasal epithelial cells (SNECs) has not yet been demonstrated. METHODS: Human SNECs were collected from patients during endoscopic sinus surgery and grown in culture at the air-liquid interface. Differentiated SNECs were stimulated with the bactericidal antibiotics amoxicillin and levofloxacin and the bacteriostatic antibiotic clarithromycin for 24 hours. ROS were quantified via fluorescence. Cell death was quantified by lactate dehydrogenase (LDH) secretion. Expression of inflammatory markers such as tumor necrosis factor alpha (TNF-alpha) and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant genes were measured by real-time polymerase chain reaction (RT-PCR). RESULTS: Cultured SNECs treated with the bactericidal antibiotics amoxicillin and levofloxacin resulted in a significant increase in production of ROS (p < 0.05) and secretion of LDH (p < 0.05). The increase in ROS formation correlated with an increase in expression of Nrf2-mediated antioxidant genes as well as the expression and production of proinflammatory cytokine TNF alpha, and interleukin 1 beta (IL-1beta) (p < 0.05). SNECs treated with clarithromycin did not demonstrate statistically significant increases in ROS or proinflammatory cytokine production. CONCLUSION: In this study, we show that treatment of cultured human SNECs with bactericidal antibiotics leads to formation of ROS with an associated increase in inflammatory and antioxidant gene expression and cell death. This suggests that long-term or inappropriate antibiotic use in the treatment of sinusitis may result in oxidative tissue damage to the sinonasal epithelium. Future studies will explore the clinical implications of such damage to the sinonasal epithelium. PMID- 26624251 TI - Morphologic evaluation of the incisive canal and its proximity to the maxillary central incisors using computed tomography images. AB - OBJECTIVE: To evaluate the morphologic features and the relative position of the incisive canal with regard to the maxillary incisor roots using computed tomography (CT). MATERIALS AND METHODS: Morphologic evaluation of the incisive canal and its proximity to the maxillary central incisors were measured using CT images of 38 adults with skeletal and dental class I normal occlusion. Linear measurements were performed on the axial cross-sectional images corresponding to three vertical levels, the palatal opening of the incisive canal (L1), midlevel between the opening level and the root apex of the maxillary central incisors (L2), and the root apex of the maxillary central incisors (L3). RESULTS: The percentage of subjects with an incisive canal width greater than the interroot distance of the central incisors was 86.8% and 63.2% at levels L1 and L2, respectively. The anteroposterior distance between the maxillary incisor roots and the boarder of the incisive canal was approximately 5-6 mm at levels L1 and L2. CONCLUSION: The anteroposterior distance between the maxillary central incisor roots and the incisive canal was approximately 5-6 mm. More than 60% of the subjects had an incisive canal width greater than the interroot distance. Evaluation of the proximity of the incisive canal to the maxillary incisors, along with its dimensional characteristics, may be helpful when a considerable amount of maxillary retraction is planned. PMID- 26624257 TI - Neural correlates of altered sensorimotor gating in boys with Tourette Syndrome: A combined EMG/fMRI study. AB - OBJECTIVES: It has been hypothesised that altered sensorimotor gating might be a core problem in Tourette Syndrome (TS). However, the underlying neurophysiological mechanisms are elusive. METHODS: We applied functional magnetic resonance imaging (fMRI) to investigate the neural correlates of altered sensorimotor gating by means of prepulse inhibition (PPI) in 22 boys with TS and 22 healthy boys using tactile PPI. The electromyography of the startle response was recorded simultaneously to the acquisition of the fMRI images. RESULTS: As expected, PPI of the startle response was reduced in boys with TS compared to the healthy boys. We found decreased PPI-related blood oxygen level-dependent (BOLD) activity in boys with TS in the middle frontal gyrus, postcentral gyrus, superior parietal cortex, cingulate gyrus and caudate body. In boys with TS PPI of the startle response was positively correlated to PPI-related BOLD activity in the superior parietal cortex. CONCLUSIONS: Our findings indicate that deficient sensorimotor gating in boys with TS is associated with reduced recruitment of brain regions responsible for the higher-order integration of somatosensory stimuli. Due to our strict sample selection we were able to reduce confounding by neural adaptation processes, long-term medication, gender or comorbidities. PMID- 26624252 TI - Integrating the GPCR transactivation-dependent and biased signalling paradigms in the context of PAR1 signalling. AB - Classically, receptor-mediated signalling was conceived as a linear process involving one agonist, a variety of potential targets within a receptor family (e.g. alpha- and beta-adrenoceptors) and a second messenger (e.g. cAMP)-triggered response. If distinct responses were stimulated by the same receptor in different tissues (e.g. lipolysis in adipocytes vs. increased beating rate in the heart caused by adrenaline), the differences were attributed to different second messenger targets in the different tissues. It is now realized that an individual receptor can couple to multiple effectors (different G proteins and different beta-arrestins), even in the same cell, to drive very distinct responses. Furthermore, tailored agonists can mould the receptor conformation to activate one signal pathway versus another by a process termed 'biased signalling'. Complicating issues further, we now know that activating one receptor can rapidly trigger the local release of agonists for a second receptor via a process termed 'transactivation'. Thus, the end response can represent a cooperative signalling process involving two or more receptors linked by transactivation. This overview, with a focus on the GPCR, protease-activated receptor-1, integrates both of these processes to predict the complex array of responses that can arise when biased receptor signalling also involves the receptor transactivation process. The therapeutic implications of this signalling matrix are also briefly discussed. Linked Articles This article is part of a themed section on Molecular Pharmacology of G Protein-Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc. PMID- 26624271 TI - MRI scanning in patients implanted with a round window or stapes coupled floating mass transducer of the Vibrant Soundbridge. AB - Conclusion MRI examinations in patients with an alternatively coupled VSB can lead to unpleasant side-effects. However, the residual hearing was not impaired, whereas the hearing performance with the VSB was decreased in one patient which could be fixed by a surgical revision. Different experiences for the VSB 503 can be expected. Objective To investigate the in vivo effects of MRI scanning on the Vibrant Soundbridge system (VSB) with an alternatively coupled Floating Mass Transducer (FMT). Method Sixty-five VSB (502) implantees were included in this study. Of them, 42 questionnaires could be evaluated with the patients' statements about their medical, otological, and general condition before, during, and after an MRI scan which was indicated for different medical reasons, despite the previous implantation of an alternatively coupled Vibrant Soundbridge System. Results In four patients (9.5%), five MRI examinations were performed. These were done for different indications (e.g. knee and shoulder joint diagnostics). During the scanning, noise and subjectively perceived distortion of the implant were described. A deterioration of the hearing gain with the VSB in place was found in one patient. A decrease of the hearing threshold was not observed. PMID- 26624272 TI - Causal judgments about empirical information in an interrupted time series design. AB - Empirical information available for causal judgment in everyday life tends to take the form of quasi-experimental designs, lacking control groups, more than the form of contingency information that is usually presented in experiments. Stimuli were presented in which values of an outcome variable for a single individual were recorded over six time periods, and an intervention was introduced between the fifth and sixth time periods. Participants judged whether and how much the intervention affected the outcome. With numerical stimulus information, judgments were higher for a pre-intervention profile in which all values were the same than for pre-intervention profiles with any other kind of trend. With graphical stimulus information, judgments were more sensitive to trends, tending to be higher when an increase after the intervention was preceded by a decreasing series than when it was preceded by an increasing series ending on the same value at the fifth time period. It is suggested that a feature analytic model, in which the salience of different features of information varies between presentation formats, may provide the best prospect of explaining the results. PMID- 26624273 TI - A Preventive Approach to Arsenic Toxicity: Testing Folic Acid in Bangladesh. PMID- 26624276 TI - sigma-Aromatic cyclic M3(+) (M = Cu, Ag, Au) clusters and their complexation with dimethyl imidazol-2-ylidene, pyridine, isoxazole, furan, noble gases and carbon monoxide. AB - The sigma-aromaticity of M3(+) (M = Cu, Ag, Au) is analyzed and compared with that of Li3(+) and a prototype sigma-aromatic system, H3(+). Ligands (L) like dimethyl imidazol-2-ylidene, pyridine, isoxazole and furan are employed to stabilize these monocationic M3(+) clusters. They all bind M3(+) with favorable interaction energy. Dimethyl imidazol-2-ylidene forms the strongest bond with M3(+) followed by pyridine, isoxazole and furan. Electrostatic contribution is considerably more than that of orbital contribution in these M-L bonds. The orbital interaction arises from both L -> M sigma donation and L <- M back donation. M3(+) clusters also bind noble gas atoms and carbon monoxide effectively. In general, among the studied systems Au3(+) binds a given L most strongly followed by Cu3(+) and Ag3(+). Computation of the nucleus-independent chemical shift (NICS) and its different extensions like the NICS-rate and NICS in plane component vs. NICS out-of-plane component shows that the sigma-aromaticity in L bound M3(+) increases compared to that of bare clusters. The aromaticity in pyridine, isoxazole and furan bound Au3(+) complexes is quite comparable with that in the recently synthesized Zn3(C5(CH3)5)3(+). The energy gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital also increases upon binding with L. The blue-shift and red-shift in the C-O stretching frequency of M3(CO)3(+) and M3(OC)3(+), respectively, are analyzed through reverse polarization of the sigma- and pi-orbitals of CO as well as the relative amount of OC -> M sigma donation and M -> CO pi back donation. The electron density analysis is also performed to gain further insight into the nature of interaction. PMID- 26624275 TI - Menthols as Chiral Auxiliaries for Asymmetric Cycloadditive Oligomerization: Syntheses and Studies of beta-Proline Hexamers. AB - To produce a novel class of structurally ordered poly-beta-prolines, an emergent method for synthesizing chiral beta-peptide molecular frameworks was developed based on 1,3-dipolar cycloaddition chemistry of azomethine ylides. Functionalized short beta-peptides with up to six monomeric residues were efficiently synthesized in homochiral forms using a cycloadditive oligomerization approach. X ray, NMR, and CD structural analyses of the novel beta-peptides revealed secondary structure features that were generated primarily by Z/E-beta-peptide bond isomerism. Anticancer in cellulo activity of the new beta-peptides toward hormone-refractory prostate cancer cells was observed and was dependent on the absolute configuration of the stereogenic centers and the chain length of the beta-proline oligomers. PMID- 26624274 TI - Detection of Novel Genomic Markers for Predicting Prognosis in Hepatocellular Carcinoma Patients by Integrative Analysis of Copy Number Aberrations and Gene Expression Profiles: Results from a Long-Term Follow-Up. AB - The aim of this study was to explore novel genomic biomarkers predicting hepatocellular carcinoma (HCC) prognosis by integrative analysis of DNA copy number aberrations (CNAs) and gene expression profiles. Array comparative genomic hybridization and expression array were performed on 45 and 31 HCC samples, respectively. To identify functionally important genes, concordant results of DNA copy number and gene expression were retrieved by integrative analysis. Cox regression analysis indicated that the CNAs in 192 genomic regions were significantly associated with overall survival (OS; p < 0.05). Integrative analysis capturing concordant results demonstrated that the low expression of TLE4 (p = 0.041) and XPA (p = 0.006) was associated with poor OS. In the analysis of tumor recurrence, 514 genomic regions with CNAs were associated with recurrence. Integrative analysis revealed that the overexpression of 16 genes, including FGR (p = 0.003), RELA (p = 0.049), LTBP3 (p = 0.050), and RIN1 (p = 0.023), was significantly associated with shorter time to tumor recurrence. On multivariate analysis, FGR and XPA were independent risk factors of early recurrence and poor OS, respectively. Integrated analysis of CNAs and gene expression profiles correlated with long-term follow-up data successfully identified potential prognostic markers predicting survival and tumor recurrence in patients with HCC who underwent surgical resection. PMID- 26624277 TI - Sources of variability of speech, spatial, and qualities of hearing scale (SSQ) scores in normal-hearing and hearing-impaired populations. AB - OBJECTIVE: To identify and quantify sources of variability in scores on the speech, spatial, and qualities of hearing scale (SSQ) and its short forms among normal-hearing and hearing-impaired subjects using a French-language version of the SSQ. DESIGN: Multi-regression analyses of SSQ scores were performed using age, gender, years of education, hearing loss, and hearing-loss asymmetry as predictors. Similar analyses were performed for each subscale (Speech, Spatial, and Qualities), for several SSQ short forms, and for differences in subscale scores. STUDY SAMPLE: One hundred normal-hearing subjects (NHS) and 230 hearing impaired subjects (HIS). RESULTS: Hearing loss in the better ear and hearing-loss asymmetry were the two main predictors of scores on the overall SSQ, the three main subscales, and the SSQ short forms. The greatest difference between the NHS and HIS was observed for the Speech subscale, and the NHS showed scores well below the maximum of 10. An age effect was observed mostly on the Speech subscale items, and the number of years of education had a significant influence on several Spatial and Qualities subscale items. CONCLUSION: Strong similarities between SSQ scores obtained across different populations and languages, and between SSQ and short forms, underline their potential international use. PMID- 26624278 TI - Role of an endothelin type A receptor antagonist in regulating torsion-induced testicular apoptosis in rats. AB - Testicular torsion is a well-known medical emergency that can lead to pathological changes in the testicular tissues and male infertility. This investigation was undertaken to gain insight into the effects of an endothelin type A receptor antagonist (BQ123) on torsion-induced germ cell loss. Twenty eight male Wistar albino rats were divided into four groups. In group I (control group), a sham operation to the left testis was performed. In group II (I/R injury), I/R injury was created by rotating the left testis 720 degrees in a clockwise direction for 2 h and detorsing the testis after 2 h. In group III (I/R injury+BQ123), the rats were subjected to I/R injury and BQ123 injection (1 mg/kg, intravenous). In group IV (control+BQ123), the sham operated rats were subjected to BQ123. The testes of the rats were removed in all groups. Torsion induced apoptosis and the effects of BQ123 were examined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL) technique, immunohistochemistry and western blotting. In group II, the number of TUNEL-positive cells increased after testicular torsion. Immunohistochemistry and western blotting showed that apoptotic proteins (active caspase 3 and Bax) were upregulated, and the anti-apoptotic protein Bcl2 was downregulated in I/R injury. The administration of BQ123 caused a significant decrease in the number of apoptotic cells and the expression of apoptotic proteins (p<0.05) when compared with the I/R injury group. No significant effect of BQ123 was observed in the testicular cells of group IV. This animal study provides evidence of the regulatory effects of BQ123 on torsion-induced testicular apoptosis. PMID- 26624280 TI - Estimating HIV Prevalence in Zimbabwe Using Population-Based Survey Data. AB - Estimates of HIV prevalence computed using data obtained from sampling a subgroup of the national population may lack the representativeness of all the relevant domains of the population. These estimates are often computed on the assumption that HIV prevalence is uniform across all domains of the population. Use of appropriate statistical methods together with population-based survey data can enhance better estimation of national and subgroup level HIV prevalence and can provide improved explanations of the variation in HIV prevalence across different domains of the population. In this study we computed design-consistent estimates of HIV prevalence, and their respective 95% confidence intervals at both the national and subgroup levels. In addition, we provided a multivariable survey logistic regression model from a generalized linear modelling perspective for explaining the variation in HIV prevalence using demographic, socio-economic, socio-cultural and behavioural factors. Essentially, this study borrows from the proximate determinants conceptual framework which provides guiding principles upon which socio-economic and socio-cultural variables affect HIV prevalence through biological behavioural factors. We utilize the 2010-11 Zimbabwe Demographic and Health Survey (2010-11 ZDHS) data (which are population based) to estimate HIV prevalence in different categories of the population and for constructing the logistic regression model. It was established that HIV prevalence varies greatly with age, gender, marital status, place of residence, literacy level, belief on whether condom use can reduce the risk of contracting HIV and level of recent sexual activity whereas there was no marked variation in HIV prevalence with social status (measured using a wealth index), method of contraceptive and an individual's level of education. PMID- 26624279 TI - Banking or Bankrupting: Strategies for Sustaining the Economic Future of Public Cord Blood Banks. AB - BACKGROUND: Cord blood is an important source of stem cells. However, nearly 90% of public cord blood banks have declared that they are struggling to maintain their financial sustainability and avoid bankruptcy. The objective of this study is to evaluate how characteristics of cord blood units influence their utilization, then use this information to model the economic viability and therapeutic value of different banking strategies. METHODS: Retrospective analysis of cord blood data registered between January 1st, 2009 and December 31st, 2011 in Bone Marrow Donor Worldwide. Data were collected from four public banks in France, Germany and the USA. Samples were eligible for inclusion in the analysis if data on cord blood and maternal HLA typing and biological characteristics after processing were available (total nucleated and CD34+ cell counts). 9,396 banked cord blood units were analyzed, of which 5,815 were Caucasian in origin. A multivariate logistic regression model assessed the influence of three parameters on the CBU utilization rate: ethnic background, total nucleated and CD34+ cell counts. From this model, we elaborated a Utilization Score reflecting the probability of transplantation for each cord blood unit. We stratified three Utilization Score thresholds representing four different banking strategies, from the least selective (scenario A) to the most selective (scenario D). We measured the cost-effectiveness ratio for each strategy by comparing performance in terms of number of transplanted cord blood units and level of financial deficit. RESULTS: When comparing inputs and outputs over three years, Scenario A represented the most extreme case as it delivered the highest therapeutic value for patients (284 CBUs transplanted) along with the highest financial deficit (USD 5.89 million). We found that scenario C resulted in 219 CBUs transplanted with a limited deficit (USD 0.98 million) that charities and public health could realistically finance over the long term. We also found that using a pre-freezing level of 18 x 10(8) TNC would be the most cost effective strategy for a public bank. CONCLUSION: Our study shows that a swift transition from strategy A to C can play a vital role in preventing public cord blood banks worldwide from collapsing. PMID- 26624281 TI - Curriculum Mapping with Academic Analytics in Medical and Healthcare Education. AB - BACKGROUND: No universal solution, based on an approved pedagogical approach, exists to parametrically describe, effectively manage, and clearly visualize a higher education institution's curriculum, including tools for unveiling relationships inside curricular datasets. OBJECTIVE: We aim to solve the issue of medical curriculum mapping to improve understanding of the complex structure and content of medical education programs. Our effort is based on the long-term development and implementation of an original web-based platform, which supports an outcomes-based approach to medical and healthcare education and is suitable for repeated updates and adoption to curriculum innovations. METHODS: We adopted data exploration and visualization approaches in the context of medical curriculum innovations in higher education institutions domain. We have developed a robust platform, covering detailed formal metadata specifications down to the level of learning units, interconnections, and learning outcomes, in accordance with Bloom's taxonomy and direct links to a particular biomedical nomenclature. Furthermore, we used selected modeling techniques and data mining methods to generate academic analytics reports from medical curriculum mapping datasets. RESULTS: We present a solution that allows users to effectively optimize a curriculum structure that is described with appropriate metadata, such as course attributes, learning units and outcomes, a standardized vocabulary nomenclature, and a tree structure of essential terms. We present a case study implementation that includes effective support for curriculum reengineering efforts of academics through a comprehensive overview of the General Medicine study program. Moreover, we introduce deep content analysis of a dataset that was captured with the use of the curriculum mapping platform; this may assist in detecting any potentially problematic areas, and hence it may help to construct a comprehensive overview for the subsequent global in-depth medical curriculum inspection. CONCLUSIONS: We have proposed, developed, and implemented an original framework for medical and healthcare curriculum innovations and harmonization, including: planning model, mapping model, and selected academic analytics extracted with the use of data mining. PMID- 26624282 TI - Detecting Positioning Errors and Estimating Correct Positions by Moving Window. AB - In recent times, improvements in smart mobile devices have led to new functionalities related to their embedded positioning abilities. Many related applications that use positioning data have been introduced and are widely being used. However, the positioning data acquired by such devices are prone to erroneous values caused by environmental factors. In this research, a detection algorithm is implemented to detect erroneous data over a continuous positioning data set with several options. Our algorithm is based on a moving window for speed values derived by consecutive positioning data. Both the moving average of the speed and standard deviation in a moving window compose a moving significant interval at a given time, which is utilized to detect erroneous positioning data along with other parameters by checking the newly obtained speed value. In order to fulfill the designated operation, we need to examine the physical parameters and also determine the parameters for the moving windows. Along with the detection of erroneous speed data, estimations of correct positioning are presented. The proposed algorithm first estimates the speed, and then the correct positions. In addition, it removes the effect of errors on the moving window statistics in order to maintain accuracy. Experimental verifications based on our algorithm are presented in various ways. We hope that our approach can help other researchers with regard to positioning applications and human mobility research. PMID- 26624283 TI - Health Seeking Behaviour and Treatment Intentions of Dengue and Fever: A Household Survey of Children and Adults in Venezuela. AB - BACKGROUND: Dengue in Venezuela is a major public health problem with an increasing incidence of severe cases. Early diagnosis and timely treatment influences the outcome of dengue illness, as delay in care-seeking is significantly associated with complications leading to severe dengue. We aimed to understand patterns of health seeking behaviour (HSB) in individuals exposed to high dengue incidence in order to improve early attendance to health centres. METHODS: Between September 2013 and February 2014 a cross-sectional household survey was performed in Maracay, Venezuela. Intended HSB of adults and children's parents/guardians was assessed with respect to fever or suspected dengue. Data was collected through structured questionnaires from 105 individuals. RESULTS: Most individuals felt at risk of dengue and believed it could be a deadly disease. In the case of suspected dengue, the majority (60%) would choose to first seek medical help versus first treating at home, in contrast to 11% in the case of fever. Amongst those who decided to visit a doctor, a suspected dengue infection would prompt them to search medical help earlier than if having only fever (p<0.001). Multivariate analysis modelling showed that the independent factors associated with the intention to firstly visit a doctor versus treating at home in the case of dengue were feeling at risk (OR = 3.29; p = 0.042) and being an adult (as opposed to caring for a child as a parent/guardian; OR = 3.33, p = 0.021), while having had a previous dengue infection (OR = 0.29; p = 0.031) and living in the neighbourhood Cana de Azucar (OR = 0.28, p = 0.038) were negatively associated with seeking medical care as their first action. CONCLUSION: Knowledge of HSB related to dengue is scarce in the Americas, our study attempts to contribute to a better understanding of HSB in this region. Improving early dengue disease recognition and awareness may enhance prompt attendance to medical care in affected populations and thereby reduce mortality and severity of dengue. Especially for those with a previous dengue infection, efforts have to be made to promote prompt health centre attendance. PMID- 26624284 TI - The Health Literacy of Hong Kong Chinese Parents with Preschool Children in Seasonal Influenza Prevention: A Multiple Case Study at Household Level. AB - BACKGROUND: Health literacy influences individual and family health behaviour, health services use, and ultimately health outcomes and health care costs. In Hong Kong, people are at risk of seasonal influenza infection twice a year for three-month periods. Seasonal influenza is significantly associated with an increased number of hospitalized children. There is no research that provides an understanding of parents' health knowledge and their access to health information concerning seasonal influenza, nor their capacity to effectively manage influenza episodes in household. Such knowledge provides valuable insight into enhancing parents' health literacy to effectively communicate health messages to their children and support healthy behaviour development through role modelling. METHODS: A multiple case study was employed to gain a multifaceted understanding of parents' health literacy regarding seasonal influenza prevention. Purposive intensity sampling was adopted to recruit twenty Hong Kong Chinese parents with a healthy three-to-five year old preschool child from three kindergartens. A content analysis was employed to categorize, tabulate and combine data to address the propositions of the study. Comprehensive comparisons were made across cases to reveal the commonalities and differences. RESULTS: Four major themes were identified: inadequate parents' knowledge and reported skills and practices related to seasonal influenza prevention; parental knowledge seeking and exchange practices through social connection; parents' approaches to health information and limited enabling environments including shortage of health resources and uneven resource allocation for health promotion. CONCLUSIONS: The findings recommend that community health professionals can play a critical role in increasing parents' functional, interactive and critical health literacy; important elements when planning and implementing seasonal influenza health promotion. PMID- 26624286 TI - Specific Interaction between eEF1A and HIV RT Is Critical for HIV-1 Reverse Transcription and a Potential Anti-HIV Target. AB - Reverse transcription is the central defining feature of HIV-1 replication. We previously reported that the cellular eukaryotic elongation factor 1 (eEF1) complex associates with the HIV-1 reverse transcription complex (RTC) and the association is important for late steps of reverse transcription. Here we show that association between the eEF1 and RTC complexes occurs by a strong and direct interaction between the subunit eEF1A and reverse transcriptase (RT). Using biolayer interferometry and co-immunoprecipitation (co-IP) assays, we show that association between the eEF1 and RTC complexes occurs by a strong (KD ~3-4 nM) and direct interaction between eEF1A and reverse transcriptase (RT). Biolayer interferometry analysis of cell lysates with titrated levels of eEF1A indicates it is a predominant cellular RT binding protein. Both the RT thumb and connection domains are required for interaction with eEF1A. A single amino acid mutation, W252A, within the thumb domain impaired co-IP between eEF1A and RT, and also significantly reduced the efficiency of late reverse transcription and virus replication when incorporated into infectious HIV-1. Molecular modeling analysis indicated that interaction between W252 and L303 are important for RT structure, and their mutation to alanine did not impair heterodimerisation, but negatively impacted interaction with eEF1A. Didemnin B, which specifically binds eEF1A, potently inhibited HIV-1 reverse transcription by greater than 2 logs at subnanomolar concentrations, especially affecting reverse transcription late DNA synthesis. Analysis showed reduced levels of RTCs from HIV-1-infected HEK293T treated with didemnin B compared to untreated cells. Interestingly, HIV-1 with a W252A RT mutation was resistant to didemnin B negative effects showing that didemnin B affects HIV-1 by targeting the RT-eEF1A interaction. The combined evidence indicates a direct interaction between eEF1A and RT is crucial for HIV reverse transcription and replication, and the RT-eEF1A interaction is a potential drug target. PMID- 26624287 TI - Are Early Somatic Embryos of the Norway Spruce (Picea abies (L.) Karst.) Organised? AB - BACKGROUND: Somatic embryogenesis in conifer species has great potential for the forestry industry. Hence, a number of methods have been developed for their efficient and rapid propagation through somatic embryogenesis. Although information is available regarding the previous process-mediated generation of embryogenic cells to form somatic embryos, there is a dearth of information in the literature on the detailed structure of these clusters. METHODOLOGY/PRINCIPAL FINDINGS: The main aim of this study was to provide a more detailed structure of the embryogenic tissue clusters obtained through the in vitro propagation of the Norway spruce (Picea abies (L.) Karst.). We primarily focused on the growth of early somatic embryos (ESEs). The data on ESE growth suggested that there may be clear distinctions between their inner and outer regions. Therefore, we selected ESEs collected on the 56th day after sub-cultivation to dissect the homogeneity of the ESE clusters. Two colourimetric assays (acetocarmine and fluorescein diacetate/propidium iodide staining) and one metabolic assay based on the use of 2,3,5-triphenyltetrazolium chloride uncovered large differences in the metabolic activity inside the cluster. Next, we performed nuclear magnetic resonance measurements. The ESE cluster seemed to be compactly aggregated during the first four weeks of cultivation; thereafter, the difference between the 1H nuclei concentration in the inner and outer clusters was more evident. There were clear differences in the visual appearance of embryos from the outer and inner regions. Finally, a cluster was divided into six parts (three each from the inner and the outer regions of the embryo) to determine their growth and viability. The innermost embryos (centripetally towards the cluster centre) could grow after sub cultivation but exhibited the slowest rate and required the longest time to reach the common growth rate. To confirm our hypothesis on the organisation of the ESE cluster, we investigated the effect of cluster orientation on the cultivation medium and the influence of the change of the cluster's three-dimensional orientation on its development. Maintaining the same position when transferring ESEs into new cultivation medium seemed to be necessary because changes in the orientation significantly affected ESE growth. CONCLUSIONS AND SIGNIFICANCE: This work illustrated the possible inner organisation of ESEs. The outer layer of ESEs is formed by individual somatic embryos with high metabolic activity (and with high demands for nutrients, oxygen and water), while an embryonal group is directed outside of the ESE cluster. Somatic embryos with depressed metabolic activity were localised in the inner regions, where these embryonic tissues probably have a very important transport function. PMID- 26624288 TI - The relationship between dysfunctional family patterns and symptom severity among adolescent patients with eating disorders: A gender-specific approach. AB - The objective of the authors in this study was to identify factors related to dysfunctional family functioning that may be associated with the severity of symptoms among adolescent patients with an eating disorder (ED) at first-contact care. A total of forty-eight mothers and forty-five fathers of fifty patients with EDs were recruited from an ED unit in Madrid, Spain, between October 2011 and July 2012. Parents completed self-report assessments related to family functioning and psychological wellbeing. Patients went through clinical interviews and completed a self-report questionnaire assessing symptom severity. Compared to fathers, mothers showed higher levels of anxiety and emotional over involvement and perceived to a greater degree the positive and negative aspects of their experience as caregivers. Regarding the relationship between family functioning and symptom severity, mothers' perceptions of their family relationships as enmeshed and less adaptive, along with anxiety, accounted for 39% of variance in the severity of ED symptoms. Anxiety and symptom accommodation by the fathers accounted for 27% of variance in the symptom severity. Interventions that help parents to cope with their caregiving role should target behavioral, cognitive, and emotional aspects of their functioning and be gender specific, to improve the outcome of ED in patients. PMID- 26624285 TI - The Ribosome Biogenesis Protein Nol9 Is Essential for Definitive Hematopoiesis and Pancreas Morphogenesis in Zebrafish. AB - Ribosome biogenesis is a ubiquitous and essential process in cells. Defects in ribosome biogenesis and function result in a group of human disorders, collectively known as ribosomopathies. In this study, we describe a zebrafish mutant with a loss-of-function mutation in nol9, a gene that encodes a non ribosomal protein involved in rRNA processing. nol9sa1022/sa1022 mutants have a defect in 28S rRNA processing. The nol9sa1022/sa1022 larvae display hypoplastic pancreas, liver and intestine and have decreased numbers of hematopoietic stem and progenitor cells (HSPCs), as well as definitive erythrocytes and lymphocytes. In addition, ultrastructural analysis revealed signs of pathological processes occurring in endothelial cells of the caudal vein, emphasizing the complexity of the phenotype observed in nol9sa1022/sa1022 larvae. We further show that both the pancreatic and hematopoietic deficiencies in nol9sa1022/sa1022 embryos were due to impaired cell proliferation of respective progenitor cells. Interestingly, genetic loss of Tp53 rescued the HSPCs but not the pancreatic defects. In contrast, activation of mRNA translation via the mTOR pathway by L-Leucine treatment did not revert the erythroid or pancreatic defects. Together, we present the nol9sa1022/sa1022 mutant, a novel zebrafish ribosomopathy model, which recapitulates key human disease characteristics. The use of this genetically tractable model will enhance our understanding of the tissue-specific mechanisms following impaired ribosome biogenesis in the context of an intact vertebrate. PMID- 26624289 TI - Enhanced p122RhoGAP/DLC-1 Expression Can Be a Cause of Coronary Spasm. AB - BACKGROUND: We previously showed that phospholipase C (PLC)-delta1 activity was enhanced by 3-fold in patients with coronary spastic angina (CSA). We also reported that p122Rho GTPase-activating protein/deleted in liver cancer-1 (p122RhoGAP/DLC-1) protein, which was discovered as a PLC-delta1 stimulator, was upregulated in CSA patients. We tested the hypothesis that p122RhoGAP/DLC-1 overexpression causes coronary spasm. METHODS AND RESULTS: We generated transgenic (TG) mice with vascular smooth muscle (VSM)-specific overexpression of p122RhoGAP/DLC-1. The gene and protein expressions of p122RhoGAP/DLC-1 were markedly increased in the aorta of homozygous TG mice. Stronger staining with anti-p122RhoGAP/DLC-1 in the coronary artery was found in TG than in WT mice. PLC activities in the plasma membrane fraction and the whole cell were enhanced by 1.43 and 2.38 times, respectively, in cultured aortic vascular smooth muscle cells from homozygous TG compared with those from WT mice. Immediately after ergometrine injection, ST-segment elevation was observed in 1 of 7 WT (14%), 6 of 7 heterozygous TG (84%), and 7 of 7 homozygous TG mice (100%) (p<0.05, WT versus TGs). In the isolated Langendorff hearts, coronary perfusion pressure was increased after ergometrine in TG, but not in WT mice, despite of the similar response to prostaglandin F2alpha between TG and WT mice (n = 5). Focal narrowing of the coronary artery after ergometrine was documented only in TG mice. CONCLUSIONS: VSM-specific overexpression of p122RhoGAP/DLC-1 enhanced coronary vasomotility after ergometrine injection in mice, which is relevant to human CSA. PMID- 26624290 TI - Altered Lipid Composition of Surfactant and Lung Tissue in Murine Experimental Malaria-Associated Acute Respiratory Distress Syndrome. AB - Malaria-associated acute lung injury (MA-ALI) and its more severe form malaria associated acute respiratory distress syndrome (MA-ARDS) are common, often fatal complications of severe malaria infections. However, little is known about their pathogenesis. In this study, biochemical alterations of the lipid composition of the lungs were investigated as possible contributing factors to the severity of murine MA-ALI/ARDS. C57BL/6J mice were infected with Plasmodium berghei NK65 to induce lethal MA-ARDS, or with Plasmodium chabaudi AS, a parasite strain that does not induce lung pathology. The lipid profile of the lung tissue from mice infected with Plasmodium berghei NK65 developing MA-ALI/ARDS, but not that from mice without lung pathology or controls, was characterized by high levels of phospholipids -mainly phosphatidylcholine- and esterified cholesterol. The high levels of polyunsaturated fatty acids and the linoleic/oleic fatty acid ratio of the latter reflect the fatty acid composition of plasma cholesterol esters. In spite of the increased total polyunsaturated fatty acid pool, which augments the relative oxidability of the lung membranes, and the presence of hemozoin, a known pro-oxidant, no excess oxidative stress was detected in the lungs of Plasmodium berghei NK65 infected mice. The bronchoalveolar lavage (BAL) fluid of Plasmodium berghei NK65 infected mice was characterized by high levels of plasma proteins. The phospholipid profile of BAL large and small aggregate fractions was also different from uninfected controls, with a significant increase in the amounts of sphingomyelin and lysophosphatidylcholine and the decrease in phosphatidylglycerol. Both the increase of proteins and lysophosphatidylcholine are known to decrease the intrinsic surface activity of surfactant. Together, these data indicate that an altered lipid composition of lung tissue and BAL fluid, partially ascribed to oedema and lipoprotein infiltration, is a characteristic feature of murine MA-ALI/ARDS and possibly contribute to lung dysfunction. PMID- 26624291 TI - Disruption of Skin Stem Cell Homeostasis following Transplacental Arsenicosis; Alleviation by Combined Intake of Selenium and Curcumin. AB - Of late, a consirable interest has grown in literature on early development of arsenicosis and untimely death in humans after exposure to iAs in drinking water in utero or during the childhood. The mechanism of this kind of intrauterine arsenic poisoning is not known; however it is often suggested to involve stem cells. We looked into this possibility by investigating in mice the influence of chronic in utero exposure to arsenical drinking water preliminarily on multipotent adult stem cell and progenitor cell counts at the beginning of neonatal age. We found that repeated intake of 42.5 or 85 ppm iAs in drinking water by pregnant BALB/c mice substantially changed the counts of EpASCs, the progenitor cells, and the differentiated cells in epidermis of their zero day old neonates. EpASCs counts decreased considerably and the differentiated/apoptosed cell counts increased extensively whereas the counts of progenitor cell displayed a biphasic effect. The observed trend of response was dose-dependent and statistically significant. These observations signified a disruption in stem cell homeostasis. The disorder was in parallel with changes in expression of biomarkers of stem cell and progenitor (TA) cell besides changes in expression of pro-inflammatory and antioxidant molecules namely Nrf2, NFkB, TNF-alpha, and GSH. The biological monitoring of exposure to iAs and the ensuing transplacental toxicity was verifiable correspondingly by the increase in iAs burden in hair, kidney, skin, liver of nulliparous female mice and the onset of chromosomal aberrations in neonate bone marrow cells. The combined intake of selenite and curcumin in utero was found to prevent the disruption of homeostasis and associated biochemical changes to a great extent. The mechanism of prevention seemed possibly to involve (a) curcumin and Keap-1 interaction, (b) consequent escalated de novo GSH biosynthesis, and (c) the resultant toxicant disposition. These observations are important with respect to the development of vulnerability to arsenicosis and other morbidities later in life after repeated in utero or postnatal exposure to iAs in drinking water that may occur speculatively through impairment of adult stem cell dependent innate tissue repair mechanism. PMID- 26624292 TI - Development of the First Cisgenic Apple with Increased Resistance to Fire Blight. AB - The generation and selection of novel fire blight resistant apple genotypes would greatly improve the management of this devastating disease, caused by Erwinia amylovora. Such resistant genotypes are currently developed by conventional breeding, but novel breeding technologies including cisgenesis could be an alternative approach. A cisgenic apple line C44.4.146 was regenerated using the cisgene FB_MR5 from wild apple Malus *robusta 5 (Mr5), and the previously established method involving A. tumefaciens-mediated transformation of the fire blight susceptible cultivar 'Gala Galaxy' using the binary vector p9-Dao-FLPi. The line C44.4.146 was shown to carry only the cisgene FB_MR5, controlled by its native regulatory sequences and no transgenes were detected by PCR or Southern blot following heat induced recombinase-mediated elimination of the selectable markers. Although this line contains up to 452 bp of vector sequences, it still matches the original definition of cisgenesis. A single insertion of T-DNA into the genome of 'Gala Galaxy' in chromosome 16 was identified. Transcription of FB_MR5 in line C44.4.146 was similar to the transcription in classically bred descendants of Mr5. Three independent shoot inoculation experiments with a Mr5 avirulent strain of Erwinia amylovora were performed using scissors or syringe. Significantly lower disease symptoms were detected on shoots of the cisgenic line compared to those of untransformed 'Gala Galaxy'. Despite the fact that the pathogen can overcome this resistance by a single nucleotide mutation, this is, to our knowledge, the first prototype of a cisgenic apple with increased resistance to fire blight. PMID- 26624294 TI - Monte Carlo simulation of diffusion and ionic conductivity in a simple cubic random alloy via the interstitialcy mechanism. AB - This Monte Carlo study deals with mass and charge transport in binary ionic alloys governed by interstitialcy defects acting as diffusion vehicles. In particular, we calculate tracer correlation factors f(A) and f(B) in a simple cubic random alloy AB for diffusion via the collinear interstitialcy mechanism as a function of composition and jump frequency ratio wA/wB. [corrected]. Interstitialcy correlation factors f(I), which play a crucial role in the interpretation of ion-conductivity data, are also determined. The evaluation of partial correlation factors provides insight into the types of jumps that mostly contribute to the different transport processes under consideration. Examination of the percolation behaviour yields the site-percolation threshold of the mobile component B for w(A) = 0. Surprisingly, a unique second-order threshold composition is found, which relates to the abundance of different interstitialcy jump types when wA << wB [corrected]. Both numerically obtained threshold values are accurately reproduced by estimated analytical expressions based on simple arguments. Practical implications of the simulation results are explored by calculating tracer diffusivity ratios D*(A)/D*(B) and by comparing self-diffusion with ionic conductivity using the Nernst-Einstein equation. PMID- 26624295 TI - Catalog of the subgenus Melanoconion of Culex (Diptera: Culicidae) for South America. AB - Species of Culex (Melanoconion) Theobald are recognized as vectors of arboviruses. The species of this subgenus pose a real taxonomic challenge. The current classification of the subgenus recognizes a total of 160 species divided in two major sections, Melanoconion and Spissipes; and several non-formal groupings within each section. We gathered bibliographic records of the subgenus in South America, with particular focus on the period of time after the publication of the Catalog by Pecor et al. (1992) until present time. This compilation included 139 species occurring in South American countries with all the relevant bibliographic sources, including the corresponding information for those medically important species. PMID- 26624293 TI - The Burkholderia pseudomallei Proteins BapA and BapC Are Secreted TTSS3 Effectors and BapB Levels Modulate Expression of BopE. AB - Many Gram-negative pathogens use a type III secretion system (TTSS) for the injection of bacterial effector proteins into host cells. The injected effector proteins play direct roles in modulation of host cell pathways for bacterial benefit. Burkholderia pseudomallei, the causative agent of melioidosis, expresses three different TTSSs. One of these systems, the TTSS3, is essential for escape from host endosomes and therefore intracellular survival and replication. Here we have characterized three putative TTSS3 proteins; namely BapA, BapB and BapC. By employing a tetracysteine (TC)-FlAsHTM labelling technique to monitor the secretion of TC-tagged fusion proteins, BapA and BapC were shown to be secreted during in vitro growth in a TTSS3-dependant manner, suggesting a role as TTSS3 effectors. Furthermore, we constructed B. pseudomallei bapA, bapB and bapC mutants and used the well-characterized TTSS3 effector BopE as a marker of secretion to show that BapA, BapB and BapC are not essential for the secretion process. However, BopE transcription and secretion were significantly increased in the bapB mutant, suggesting that BapB levels modulate BopE expression. In a BALB/c mouse model of acute melioidosis, the bapA, bapB and bapC mutants showed a minor reduction of in vivo fitness. Thus, this study defines BapA and BapC as novel TTSS3 effectors, BapB as a regulator of BopE production, and all three as necessary for full B. pseudomallei in vivo fitness. PMID- 26624296 TI - Five new species of Jaspis (Porifera: Demospongiae: Tetractinellida:
Astrophorina) from Brazil with redescription of the type species Jaspis johnstonii (Schmidt, 1862). AB - The genus Jaspis comprises 32 valid species, six of which were previously recorded from the Atlantic Ocean. Two species have already been recorded from the Brazilian coast: J. johnstonii and J. salvadori (Rio Grande do Sul and Espirito Santo States respectively). Their respective type specimens, deposited at Museum National d'Historie Naturelle, Paris (Jaspis salvadori, holotype) and at Universalmuseum Joanneum, Zoology Center of Natural History, Austria (Jaspis johnstonii, syntype) were reexamined, but due to differences in spicule composition these records are considered to be invalid. The present paper describes five new species of Jaspis collected on the Brazilian coast (Jaspis atolensis sp. nov., J. iacuitaster sp. nov., J. corticomicroxea sp. nov., J. variaster sp. nov. and J. gigoxea sp. nov.) bringing the total number of species worldwide to 36, all of which were compared in tabular format. The type species, Jaspis johnstonii, was also redescribed. PMID- 26624297 TI - New and remarkable Asian and North African species of Colletes Latreille (Hymenoptera: Colletidae). AB - In addition to previous studies on Asian and North African species of Colletes Latreille, we here further report records of 25 rarely collected and little known species. Six new species are described: Colletes comaticus Kuhlmann, sp. nov. (?, Iran), C. uzbekus Kuhlmann & Proshchalykin, sp. nov. (?, Uzbekistan), C. kazakhus Kuhlmann & Proshchalykin, sp. nov. (?, Kazakhstan), C. tibestensis Kuhlmann, sp. nov. (?, Chad, Sudan), C. packeri Kuhlmann, sp. nov. (?, ?, Thailand, Laos) and C. jemeniticus Kuhlmann, sp. nov. (?, Yemen). The female of C. issykkuli Kuhlmann 2003 and the male of C. kaline Kuhlmann & Proshchalykin 2013 are here described for the first time. New synonymies are established for Colletes uralensis Noskiewicz 1936 (=C. kipyatkovi Kuhlmann & Proshchalykin 2013, syn. nov.) and C. salsolae Cockerell 1934 (=C. omanus Kuhlmann 2003, syn. nov.). PMID- 26624298 TI - Genetic differentiation among species of the genus Thermophis Malnate (Serpentes, Colubridae) and comments on T. shangrila. AB - The genus Thermophis includes the two species, T. baileyi and T. zhaoermii, which differ morphologically, geographically and molecularly. Recently, a third Thermophis species was described from Shangri-La, northern Yunnan Province, China, and named T. shangrila. The new species was based on morphological and genetic data derived from three specimens. However, the morphological features used to delimit this species seem vague, because they may fall within the range of intraspecific variation of T. zhaoermii. Furthermore, the reported genetic differences in nuclear data are questionable. They likely resulted from a misinterpretation probably due to alignment/analytical flaws or sample/sequence mix-up. Here, we used partial sequences of three mitochondrial (CO1, ND4, cytb) genes and one nuclear (c-mos) gene to analyse the genetic variation between and within species of Thermophis. We inferred the phylogeny using Bayesian Inference and Maximum Likelihood approaches and present additional morphological data that contribute to the knowledge on intraspecific variation in the genus. Our results indicate lacking robustness in the distinguishing morphological features and in the genetic differentiation of T. shangrila and highlight the need for more detailed morphological and molecular studies from a substantially larger sample. PMID- 26624299 TI - Phlaeopterus Motschulsky, 1853 (Coleoptera: Staphylinidae: Omaliinae: Anthophagini)--a new genus for the Palaearctic: new combination. AB - The genus Phlaeopterus Motschulsky, 1853, which was previously known only from North America, is recorded for the Palaearctic fauna for the first time: P. czerskyi (Shavrin, 2001) comb. nov. (East Siberia: Khamar-Daban Mts.) is transferred from the genus Lesteva Latreille, 1797, redescribed, and illustrated. PMID- 26624300 TI - Nukuhiva Berland, 1935 is a troglobitic wolf spider (Araneae: Lycosidae), not a nursery-web spider (Pisauridae). AB - The monotypic genus Nukuhiva Berland, 1935 with N. adamsoni (Berland, 1933) as type species, is re-described and transferred from the Pisauridae Simon, 1890 (fishing or nursery-web spiders) to the Lycosidae Sundevall, 1833 (wolf spiders) based on genitalic and somatic characters. Nukuhiva adamsoni, originally described from French Polynesia, appears to inhabit mountainous habitats of volcanic origin. Its troglobitic morphology--comparatively small eyes and pale, uniform coloration--suggest it to be associated with subterranean habitats such as caves or lava tubes, similar to the Hawaiian troglobitic species Lycosa howarthi Gertsch, 1973 and Adelocosa anops Gertsch, 1973. PMID- 26624301 TI - New species and additional records of the subgenus Termidonia Motschulsky of the genus Zyras Stephens in China (Coleoptera, Staphylinidae, Aleocharinae). AB - Two new species are described from Yunnan: Zyras (Termidonia) baihuamontis sp. nov., and Z. (T.) nabanensis sp. nov. Additional records of two species of subgenus Termidonia Motschulsky, 1860 are reported. Adults of the four species are illustrated, and identification key is provided for Chinese species. PMID- 26624302 TI - Fennerosquilla heptacantha (Crustacea: Stomatopoda: Squillidae) in South Atlantic Ocean. AB - Fennerosquilla is a monotypic genus that belongs to the family Squillidae, which has the highest generic diversity within Stomatopoda. This genus has been recorded in the north Atlantic Ocean, the Gulf of Mexico and Caribbean Sea, between 105 and 458 m depth. The present specimen was collected during the project "Avaliacao da Biota Bentonica e Planctonica na porcao offshore das Bacias Potiguar e Ceara", in 2011, from the continental slope region of Brazil. In this expedition Fennerosquilla heptacantha was found at 178-193 m depth, and represents the first record of the species in the south Atlantic Ocean (Rio Grande do Norte State, northeastern Brazil), expanding the southern limit distribution. The specimen is the largest recorded, measuring 149 mm total length. The pigmentation zone on median region of telson and all diagnostic characters are still preserved and agree with the original description. Fennerosquilla heptacantha has a disjunct deep water distribution (more than 100 m) in the tropical western Atlantic, mostly along the continental slope. PMID- 26624303 TI - Remarkable sexually dimorphic Aroidothrips longistylus newly recorded from China (Thysanoptera: Thripidae). AB - Sexual dimorphism is a phenotypic differentiation between males and females of the same species. Thrips display a wide variety of sexual dimorphism between taxa including size, ornamentation and coloration (Crespi 1986, Mound 2005, Tyagi et al. 2008). During recent surveys on the thrips fauna in subtropical China, Aroidothrips longistylus Ananthakrishnan, an interesting and little known sexually dimorphic species, was found. This discovery greatly extends the geographic distribution of this species that has been known only from South India (Tyagi et al. 2008). PMID- 26624304 TI - Rotifera from the Mediterranean Sea, with description of ten new species. AB - A total of 43 rotifer taxa, belonging to 14 genera, was identified in 47 psammon and periphyton samples collected in the northern part of the western basin of the Mediterranean Sea. Of these, 10 previously described species are new to the Mediterranean, 10 species are new to science and could be described, and 5 others are potential new ones of which insufficient material was available to warrant a full description. Rotifers formed a constant component of meiofauna, from the eulittoral to at least 8 km off shore and a depth of 66 m. A clear zonation was apparent with one to two species only found in the eulittoral zone and sublittoral fringe, and 42 taxa occurring in the sublittoral zone. The trophi of seven previously known species are redescribed based on scanning electron microscopy. Dicranophorus bulgaricus Althaus, 1957 is redirected to Allodicranophorus gen. nov. and Lepadella pontica Althaus, 1957 to Halolepadella gen. nov. PMID- 26624305 TI - Neotropical Hemerodromia Meigen (Diptera: Empididae), a world of discovery II: New species from Atlantic forest, Brazil. AB - Eight new species of Hemerodromia Meigen are described from the Brazilian Atlantic forest, H. brevicercata sp. nov., H. carioca sp. nov., H. cornuhypandrialis sp. nov., H. megalamellata sp. nov., H. membranosa sp. nov., H. mourai sp. nov., H. cummingi sp. nov., and H. ubajaraensis sp. nov. are described and illustrated. This is the first record of the genus from the Brazilian southeast and northeast. PMID- 26624306 TI - Zoeal stages of Labidochirus anomalus (Balss, 1913) (Decapoda: Anomura: Paguridae) obtained under laboratory conditions. AB - Zoeal stages of the hermit crab Labidochirus anomalus (Balss, 1913) (Decapoda: Anomura: Paguridae) are described and illustrated from the larvae reared in the laboratory. The development included four zoeal stages following the typical pattern in the Paguridae. Morphological features of the larvae of L. anomalus are compared with those described for the related species L. splendescens (Owen, 1839). The larvae of both species share numerous zoeal characters and are similar as the species of one genus. At the same time, zoeae of L. anomalus have no dorsal carina on the carapace and long posterolateral carapace spines-key features of the larvae of L. splendescens. These zoeal characters considered as generic are not characteristic of only the genus Labidochirus but sporadically occur among Pagurus species. Main characters of zoeal stages allow assignment of both Labidochirus species to the Group A of Pagurus (the typical representative P. bernhardus). PMID- 26624307 TI - Argyrogrammana Strand (Lepidoptera: Riodinidae) from Parque Nacional da Serra do Divisor, Acre, Brazil, with the description of four new species. AB - The species of Argyrogrammana Strand, 1932 collected at the Parque Nacional da Serra do Divisor, Acre, Brazil (PNSD) are listed and detailed with behavioral notes. In total, 17 species were recorded, including 13 new records for Brazil (marked with an asterisk): A. alstonii (Smart, 1979)*, A. nurtia ludibunda Brevignon & Gallard, 1995*, A. pulchra (Talbot, 1929)*, A. bonita Hall & Willmott, 1995*, A. amalfreda (Staudinger, [1877])*, A. physis phyton (Stichel, 1911), A. halli Dolibaina & Dias, sp. nov.*, A. celata Hall & Willmott, 1995*, A. gallardi Dolibaina & Dias, sp. nov.*, A. aparamilla Hall & Willmott, 1995*, A. praestigiosa (Stichel, 1929), A. johannismarci Brevignon, 1995*, A. brevignoni Dolibaina & Dias, sp. nov.*, A. rameli (Stichel, 1930), A. willmotti Dolibaina & Dias, sp. nov.*, A. iracyi P. Jauffret & J. Jauffret, 2007 and A. saulensis tunari Gallard, 2008, comb. nov.*. Four new species are described, two from "amalfreda complex": A. halli Dolibaina & Dias, sp. nov. and A. gallardi Dolibaina & Dias, sp. nov.; one from "trochilia complex": A. brevignoni Dolibaina & Dias, sp. nov.; and one from "stilbe complex": A. willmotti Dolibaina & Dias, sp. nov. Argyrogrammana iracyi saulensis Gallard, 2008 is recognized as a valid species, A. saulensis saulensis, stat. nov., and a new combination is proposed to A. saulensis tunari Gallard, 2008, comb. nov. The females of A. iracyi P. Jauffret & J. Jauffret, 2007 and A. saulensis tunari are recognized and figured for the first time. The taxonomy of the species found at the PNSD is discussed and adults are figured, including illustrations of the genitalia. PMID- 26624308 TI - On the species of the genus Anthaxia Eschscholtz, 1829 described by A. Thery from Angola in 1947 (Coleoptera: Buprestidae: Anthaxiini). AB - The type specimens of the genus Anthaxia Eschscholtz, 1829 described from Angola by A. Thery (1947) were studied, critically evaluated and some of them synonymised: Anthaxia (Cratomerus) reticollis Quedenfeldt, 1886 = A. (C.) coelestis Thery, 1947, syn. nov., A. (Haplanthaxia) egena Kerremans, 1913 = A. (H.) decimata Thery, 1947, syn. nov., A. (H.) duvivieri Kerremans, 1898 = A. (H.) eumede Thery, 1947, syn. nov., A. (H.) mashuna Obenberger, 1931 = A. (H.) morula Thery, 1947, syn. nov. and A. (H.) sjoestedti Kerremans, 1908 = A. (H.) recisa Thery, 1947, syn. nov. The male of A. (H.) monardi Thery, 1947 is briefly described and A. (H.) puchneri Bily, 2014 is shortly discussed. All mentioned species and the relevant types of the newly synonymised species are illustrated. PMID- 26624309 TI - Description of three new species and new distributional data for four species of Anagyrus (Hymenoptera: Encyrtidae) from China. AB - Anagyrus brevifuniculus Zu & Li, sp. nov., A. maculistigmus Zu & Li, sp. nov. and A. pseudobicolor Zu & Li, sp. nov. are described; A. tricolor (Girault) is newly recorded from the Palaearctic region and A. matritensis (Mercet) from China. New distributional data for A. fusciventris (Girault) and A. jenniferae Noyes & Hayat are also provided. PMID- 26624310 TI - The leafhopper genus Atkinsoniella Distant (Hemiptera: Cicadellidae: Cicadellinae) with descriptions of two new species from China. AB - Two new species in the genus Atkinsoniella from China, Atkinsoniella longiuscula, and A. valida spp. nov. are described and illustrated. A checklist of the known species worldwide is provided. PMID- 26624311 TI - Contribution to the knowledge of the mayfly genus Teloganella Ulmer, 1939 (Ephemeroptera: Ephemerelloidea). AB - We consider the genus Janohyphella Selvakumar, Sivaramakrishnan & Jacobus, 2014 (Ephemeroptera:Teloganodidae) to be a new junior synonym of Teloganella Ulmer, 1939 [=Janohyphella, syn. n.] based on comparative examination of new and previously studied materials from Malaysia and India. Thus, we propose the following new combination, Teloganella indica, comb. n., and provide new or modified diagnoses for this species, T. umbrata Ulmer, 1939 and the genus Teloganella Ulmer, 1939. PMID- 26624312 TI - A new species of Parakari (Ephemeroptera: Baetidae) from Guiana Highlands. AB - The genus Parakari was described from Guiana Highlands in southeastern Venezuela by Nieto & Derka in 2011 for two species inhabiting streams draining isolated, flat-topped table mountains called tepuis. A description of a third representative, Parakari roraimensis sp. n., is given here based on material collected from a coldwater stream at the foothills of Roraima-tepui (SE Venezuela). Detailed morphological descriptions of mature nymph and female adult are given. A differential diagnosis and a key to nymphs of the three Parakari species are provided. PMID- 26624313 TI - Checklist and type designations of New Zealand Aleocharinae (Coleoptera: Staphylinidae). AB - A checklist of all identified species of the staphylinid subfamily Aleocharinae known to occur in New Zealand and associated outer islands (including the Kermadec, Chatham and Auckland Islands) is presented. Included for each species, and for synonyms known from New Zealand, is a reference to the original description, type locality and type depository, and for each species the known distribution within and outside New Zealand. Type material was sought and is summarized for all indigenous New Zealand species, with lectotypes designated for 55 names and confirmation of holotypes and prior designation of lectotypes when necessary. One nomenclatural change is implemented: the preoccupied generic name Gyronotus Cameron is replaced by Marecon Blackwelder. Other taxonomic changes are not made, pending further study and revision that is badly needed. Of the 169 currently known species of Aleocharinae reported from New Zealand, at least 26 are believed to be adventive from elsewhere, two may occur naturally elsewhere, and 141 (83%) are evidently endemic to this region. Of the 65 genera represented by these described species, 27 (42%) are also endemic to the New Zealand region; an additional five genera represented in New Zealand only by unidentified or undescribed species are also noted. Ten genera are adventive. However, the actual aleocharine fauna of New Zealand will undoubtedly be much larger, and the generic composition highly modified, when the fauna is fully explored and studied in a world context. PMID- 26624314 TI - New Eocene damselflies and first Cenozoic damsel-dragonfly of the isophlebiopteran lineage (Insecta: Odonata). AB - The study of a new specimen of Petrolestes hendersoni from the Eocene Green Formation allows a more precise description of the enigmatic damselfly and the diagnosis of the Petrolestini. Petrolestes messelensis sp. nov. is described from the Eocene Messel Formation in Germany, extending the distribution of the Petrolestini to the European Eocene. The new damsel-dragonfly family Pseudostenolestidae is described for the new genus and species Pseudostenolestes bechlyi, from the Eocene Messel Formation. It is the first Cenozoic representative of the Mesozoic clade Isophlebioptera. PMID- 26624315 TI - Contribution to the faunistics of shore bugs (Hemiptera: Heteroptera: Leptopodomorpha) in the Palaearctic Region and the Himalayas. AB - New distributional data on 33 species of the infraorder Leptopodomorpha (3 species of the family Leptopodidae and 30 species and subspecies of Saldidae) from the Palaearctic Region and Himalayas are provided. The following new or confirmed records are listed: Chartoscirta cocksii (Curtis, 1835) from Kosovo; Halosalda halophila (Jakovlev, 1876), Saldula amplicollis (Reuter, 1891) and Saldula xanthochila (Fieber, 1859) from Iran; Macrosaldula jakowleffi (Reuter, 1891) from Nepal and Pakistan; Macrosaldula scotica (Curtis, 1835) from Uzbekistan; Macrosaldula variabilis (Herrich-Schaeffer, 1835), Saldula lindskogi Vinokurov, 2004, Saldula opacula (Zetterstedt, 1838) from Afghanistan; Micracanthia ornatula (Reuter, 1881) from Oman; Saldula fucicola (J. Sahlberg, 1870) from Bosnia and Herzegovina and Bulgaria; Saldula lindbergi Lindskog, 1975 from Lebanon; Saldula melanoscela (Fieber, 1859) from Iran and Montenegro; Saldula palustris (Douglas, 1874) and Saldula pilosella hirsuta (Reuter, 1888) from Montenegro; Saldula orthochila (Fieber, 1859) from Afghanistan and Pakistan; Saldula pallipes (Fabricius, 1794) from Montenegro and Nepal; Saldula pilosella pilosella (Thomson, 1871) from Libya; and Saldula saltatoria (Linnaeus, 1758) from Iran and Nepal. A tabular checklist of Leptopodomorpha of Afghanistan, Iran and Pakistan is also provided. PMID- 26624316 TI - Rhodochlanis suaedicola sp. nov. (Hemiptera: Sternorrhyncha: Psylloidea: Aphalaridae) associated with Suaeda japonica (Amaranthaceae) from Korea. AB - A new psyllid species, Rhodochlanis suaedicola sp. nov., is described and illustrated from Korea based on adults and fifth instar immatures. Rhodochlanis is reported for the first time from Korea. The new species is associated with Suaeda japonica (Amaranthaceae) growing in saline habitats. Salt marshes in Korea are threatened by sea side developments. It is suggested that these habitats should be protected to ensure the survival of R. suaedicola. PMID- 26624317 TI - Annotated checklist of the decapod crustaceans of the Gulf of Oman, northwestern Indian Ocean. AB - The decapod crustaceans of the Gulf of Oman have been documented based on the published literature and new sampling along the Iranian coast between 2005 and 2015. A total of 121 species were collected along the Iranian coast, of which 43 are new records for the Gulf of Oman. The Decapoda of the Gulf is currently represented by 258 species belonging to five infraorders: Axiidea, Achelata, Anomura, Brachyura, and Caridea. Brachyura, with 176 species, are the best represented group, followed by Anomura and Caridea with 42 and 17 species, respectively. The least diverse groups are Achelata, with five species, and Axiidea, with three. On the basis of the available information, the northern (Iranian) coast with 189 species is more diverse than the southern (United Arab Emirates and Oman) coast with 134 species. PMID- 26624318 TI - A new cave-dwelling species of the alpheid shrimp genus Salmoneus Holthuis, 1955 (Crustacea: Decapoda: Caridea) from the Ryukyu Islands, southern Japan. AB - A new species of the alpheid shrimp genus Salmoneus Holthuis, 1955, S. antricola n. sp., is described and illustrated on the basis of a single ovigerous specimen from an aphotic marine cave at a depth of 12 m, off Ie Island, Okinawa Islands, the Ryukyu Archipelago. It is morphologically similar to five species presently referred to the S. jarli (Holthuis, 1951) species group: S. erasimorum Dworschak, Anker & Abed-Navandi, 2000, S. komaii Anker, 2011, S. paulayi Anker, 2011, S. poupini Anker, 2011, and S. sketi Fransen, 1991. However, the minor cheliped with an elongate carpus being subequal to the chela, the lack of teeth on the cutting edges of the minor cheliped fingers, and the very slender third to fifth pereopods are obvious characters that distinguish S. antricola n. sp. from all of its presumed close relatives. Among the 50 species of Salmoneus, only S. sketi and the present new species are known from marine caves. PMID- 26624319 TI - A new species of Hemerobiella Kimmins (Neuroptera, Hemerobiidae) from Venezuela with notes on the genus. AB - Hemerobiella periotoi Sosa & Lara sp. nov. is described from Venezuela. The new species was collected at the edges of a mature cloud forest in Lara state. This is the third species known in Hemerobiella Kimmins, and the second recorded from Venezuela. Additionally, new Venezuelan records and illustrations of H. oswaldi Monserrat, as well as, a key to Hemerobiella species are provided. PMID- 26624320 TI - Amphimela raydahensis sp. nov. from the Kingdom of Saudi Arabia (Coleoptera: Chrysomelidae: Galerucinae: Alticini). AB - Amphimela raydahensis sp. nov. is described from Garf Raydah Nature Reserve (Abha, Asir Province), southwestern Kingdom of Saudi Arabia. This species was collected using black light traps at different elevations dominated by cacti and wild olive trees. This is the first confirmed species of Amphimela known from the Arabian Peninsula. PMID- 26624321 TI - Molecular phylogeny of Caribbean dipsadid (Xenodontinae: Alsophiini) snakes, including identification of the first record from the Cay Sal Bank, The Bahamas. AB - We document the first specimen of a dipsadid snake from the Anguilla Cays, Cay Sal Bank, The Bahamas. We analyze 3,426 base pairs (bp) of sequence data derived from five mitochondrial loci and one nuclear locus using Maximum Likelihood (ML) and Bayesian Inference (BI) methods. Our molecular data agree with some aspects of morphology (e.g., scale counts, dentition, and color pattern) supporting identification of this specimen as the Cuban Racer, Cubophis cantherigerus cantherigerus (Bibron 1840), a species previously regarded as endemic to Cuba. This discovery provides another example of the strong Cuban affinities of the terrestrial vertebrate fauna of Bahamian islands. PMID- 26624322 TI - Description of a new genus and thirteen new species of Ctenidae (Araneae, Ctenidae) from the Choco region of Ecuador. AB - The genus Chococtenus n. gen. is established for a group of Ctenidae with a unique ventral and spine-like retrolateral tibial apophysis, primarily found in the Choco-Tumbes-Magdalena corridor. Thirteen new species are described: Chococtenus otonga n. sp., C. neblina n. sp., C. cuchilla n. sp., C. fantasma n. sp., C. waitti n. sp., C. cappuccino n. sp., C. lasdamas n. sp., C. suffuscus n. sp., C. otongachi n. sp., C. kashakara n. sp., C. piemontana n. sp., C. luchoi n. sp. and C. duendecito n. sp. Ctenus acanthoctenoides Schmidt and Enoploctenus miserabilis (Strand) are transferred to Chococtenus. PMID- 26624323 TI - A new species of the genus Obolopteryx Cohn et al. 2014 and a conspecific
gynandromorph (Ensifera: Tettigoniidae: Phaneropterinae). AB - Obolopteryx truncoangulata n. sp., Barrientos-Lozano & Rocha-Sanchez, and a field collected conspecific gynandromorph are described, both from the northern Mexico's Highland. O. truncoangulata n. sp., may be separated from congeneric O. brevihastata based on morphological characters. The male's pronotum is more constricted mesally, and the tegmina are shorter. The disto-dorsal abdominal tergites sub-triangular projection broadly bilobated. Cerci broader proximally, and thumb and shaft more robust and shorter; subgenital plate deep "U" shape emarginated distally, lateral angles excised about mid portion. In females, tegmina, ovipositor, subgenital plate and basal sclerites are of different shape than analogous structures in O. brevihastata. Information on geographic distribution and ecology is provided. PMID- 26624324 TI - Three new genera and three new species of Lasiopteridi (Diptera: Cecidomyiidae) on Rubiaceae from Guadeloupe, French West Indies, and a key to genera of Neotropical Lasiopteridi unplaced to tribe. AB - Three new genera of Lasiopteridi (Diptera: Cecidomyiidae), Faramitella Gagne, new genus, Anapeza Gagne, new genus, and Pellacara Gagne, new genus, each with one new species, are described. The new species are from leaf galls on Rubiaceae collected in Guadeloupe, F.W.I.: Faramitella planicauda Gagne, new species, was reared from Faramea occidentalis (L.) A. Rich.; Anapeza tumida Gagne, new species, and Pellacara postica, new species, were both reared from Psychotria mapourioides DC. The three new genera belong to Lasiopteridi but are unassigned to tribe. A key to the adult stage of these and 23 other Neotropical genera of unplaced Lasiopteridi whose adults are known is provided. PMID- 26624325 TI - Spratelloides atrofasciatus Schultz, 1943, a valid species of round herring (Clupeiformes: Clupeidae). AB - The western Pacific marine clupeoid fish, Spratelloides atrofasciatus Schultz, 1943, previously regarded as a synonym of S. gracilis (Temminck and Schlegel, 1846), is redescribed here as a valid species on the basis of the holotype and 115 non-type specimens collected from the Ryukyu Islands. Both S. atrofasciatus and S. gracilis are similar chiefly in having a midlateral band that does not fade anteriorly. S. atrofasciatus differs from Spratelloides gracilis in having fewer anal fin rays, pectoral fin rays, vertebrae and gillrakers. Spratelloides atrofasciatus also has a shorter head length, a shorter upper jaw length, a shorter snout length, a wider lateral band equal to the eye diameter; numerous black pigment spots on the inner side of the gill opening that are visible from the outside in preserved specimens (vs not visible in S. gracilis). The two species are sympatrically distributed in the Ryukyu Islands. Spratelloides atrofasciatus matures from 32 mm SL and grows to a known maximum size of 45mm SL, while S. gracilis matures from about 50 mm SL and grows to over 100 mm SL. PMID- 26624326 TI - Confirmation of occurrence of Trechus Clairville, 1806 in the Baltic amber forests, with description of a flightless edaphic species, and remarks on Trechoides Motschulsky, 1856 (Coleoptera: Carabidae: Trechini). AB - The first reliably identified Trechini beetle species from Baltic amber, Trechus balticus sp. n., is described. This new fossil species is most similar to extant species of the Palaearctic Trechus sensu stricto, as well as to the Nearctic Microtrechus Jeannel, 1927. Since the fossil specimen is a female and some important character states cannot be investigated, its true systematic position within the genus Trechus sensu lato remains open. Trechoides fasciatus Motschulsky, 1856 is another fossil species that perhaps belongs to the Trechini clade. However, since the original description does not present any character of systematic value and, because the type is very probably lost, the true systematic position of this taxon remains unknown. PMID- 26624327 TI - Review of the aphid genus Aspidophorodon Verma, 1967 with descriptions of three new species from China (Hemiptera: Aphididae: Aphidinae). AB - The aphid genus Aspidophorodon Verma, 1967 is reviewed, with descriptions of three new species from China, namely Aspidophorodon (Aspidophorodon) cornuatus Qiao sp. nov., Aspidophorodon (Aspidophorodon) musaicus Qiao sp. nov., and Aspidophorodon (Aspidophorodon) obtusus Qiao sp. nov.. Aspidophorodon sinisalicis Zhang, 1980 and Trichosiphonaphis lijiangensis Zhang, Zhong & Zhang, 1992 are considered as junior synonyms of Aspidophorodon (Aspidophorodon) salicis Miyazaki, 1971, syn. nov.. The Chinese endemic genus Margituberculatus Zhang, Zhong & Zhang, 1992 is proposed as a junior synonym of Aspidophorodon (Eoessigia) David, Rajasingh & Narayanan, 1972, syn. nov., this subgenus is thereby recorded from China for the first time and Margituberculatus longituberculatus Zhang, Zhong & Zhang, 1992 is referred to as Aspidophorodon (Eoessigia) longituberculatus (Zhang, Zhong & Zhang, 1992) comb. nov.. A generic diagnosis and keys to Aspidophorodon species are given. Molecular evidence to support the validity of new species and their subgeneric affiliation is also provided. PMID- 26624328 TI - Kassinasma, a new generic replacement name for Kassinella Keller 1970 (Anthozoa: Streptelasmatida) non Borissiak 1956 (Brachiopoda: Strophomenacea). PMID- 26624329 TI - Reinstatement and redescription of Forsterinaria inornata magdalena (Hayward) (Nymphalidae: Satyrinae) from Cochabamba, Bolivia. PMID- 26624330 TI - A new genus and species of Micropterous Blissidae (Hemiptera: Heteroptera: Lygaeoidea) from Ecuador. AB - The new genus Barrerablissus and the new species B. strigosus are described from Napo Province, Ecuador. A key to the known genera of the Western Hemisphere Blissidae with apterous or micropterous condition is included. Dorsal and ventral view and digital photographs of head, pronotum, scutellum, metathoracic scent gland auricle and male genital capsule are added. PMID- 26624331 TI - A new species of Libellula Linnaeus, 1758, from the Cuatro Cienegas basin, Coahuila, Mexico (Anisoptera: Libellulidae). AB - A new species of Libellula is described from specimens collected in the most interesting area of Cuatro Cienegas, Coahuila, Mexico. Libellula coahuiltecana sp. nov. is similar in color and morphology to L. needhami Westfall with which it co-occurs locally. It differs from the latter by having conspicuous orange spots on base of wings and nodal area, and costal, subcostal, and wing tip areas slightly infumated with the same color. Other differences exist in the morphology of the secondary genitalia of males and the shape of the vulvar plate of female. PMID- 26624332 TI - A new species of Modisimus Simon (Araneae: Pholcidae) in Baja California Sur, Mexico. PMID- 26624333 TI - Erratum: HERNAN ARISTIZABAL-GARCIA, CARLA FERNANDA BURGUEZ FLORIANO, FELIPE FERRAZ FIGUEIREDO MOREIRA & PITAGORAS DA CONCEICAO BISPO (2015) New species and notes on Microveliinae from northern South America (Hemiptera: Heteroptera: Veliidae). Zootaxa, 3980 (4): 591-596. PMID- 26624334 TI - A taxonomic revision of South American species of the seed-harvester ant genus Pogonomyrmex (Hymenoptera: Formicidae). Part I. AB - South American species in the seed-harvester ant genus Pogonomyrmex (subfamily Myrmicinae) are interesting biologically because of their numerous queen phenotypes and life histories. This paper provides a taxonomic revision and reviews the natural history for 21 South American species of Pogonomyrmex so that we can better study their rich and interesting ecology, life history, and evolution. Species treated herein comprise all South American species-groups except for the brevibarbis and rastratus-groups. The following taxa are raised to species: pencosensis Forel 1914 and serpens Santschi 1922. The following new synonomies are proposed: bruchi Forel 1913 is synonomized under coarctatus Mayr 1868 and cunicularius carnivora Santschi 1925 under serpens Santschi 1922. The following new species is described: tinogasta. This paper redescribes workers of all species, and I describe queens and diagnose males for the following species: bispinosus (ergatoid queen, male), inermis (queen, male), laticeps (male), lobatus (queen, male), micans (queen), naegelii (ergatoid queen), pencosensis (ergatoid queen), serpens (ergatoid queen), tinogasta (brachypterous queen), and uruguayensis (queen, male). A neotype was designated for the untraceable or possibly lost type of P. bispinosus, and a holotype or lectotype was designated from syntypes for all other previously described taxa in order to provide a single name-bearing specimen and to facilitate future taxonomic studies. Of the 21 species treated herein, five species have ergatoid (wingless) queens (bispinosus, cunicularius, pencosensis, serpens, mayri), two have brachypterous (short-winged) queens (mendozanus, tinogasta), and two have dimorphic queens (winged and ergatoid in naegelii, brachypterous and ergatoid in laticeps). I also provide keys for workers and queens (in English and Spanish), photographs of all castes, distribution maps, and a summary of known biology. PMID- 26624335 TI - THE MELOIDAE (COLEOPTERA) OF WISCONSIN. AB - There are recent faunistic surveys of selected insect taxa (e.g. Mutillidae, Scarabaeoidea, and Tenebrionidae) in Wisconsin but a formal investigation of the Meloidae (blister beetles) is lacking. The blister beetle fauna of several states has been published, but this study represents the first in the Midwestern United States. We provide a comprehensive list of all meloid species documented from Wisconsin. Also included are taxonomic keys as well as summaries for each species (species pages) which includes taxonomy, description, and natural history. Specimens were obtained from public and private collections, and field sampling. This survey advances our knowledge of meloids in Wisconsin as well as provides a contribution beyond this geographic area. During this survey, 28 meloid species in seven genera were documented in Wisconsin from 2605 specimens. Of these taxa, 10 species are considered new state records. While Epicauta pensylvanica represented nearly half of the specimens reviewed, and likely inhabits all counties within the state, other species were rarely encountered. This includes 10 species which were represented by seven specimens or fewer in this study. It is unclear if the rarity of these specimens is correlated with the rarity of the species or if it is due to other factors. Regardless, these rarely collected meloids in Wisconsin warrant further attention. PMID- 26624336 TI - New Zealand Diastylidae and Gynodiastylidae (Crustacea: Cumacea). AB - Recent work in the collections at the New Zealand National Institute of Water and Atmospheric Research collections in Wellington has yielded 14 new diastylid species in five genera, Colurostylis whitireia n. sp., Diastylis acanthoelachys n. sp., D. adaioacanthus n. sp., D. curtain n. sp., D. dasys n. sp., D. enodis n. sp., D. homoacanthus n. sp., D. implanus n. sp., D. spinacellulosus n. sp., Diastylopsis aspratilis n. sp., D. bicarina n. sp., Leptostylis wisniewskiae n. sp., L. zealandiensis n. sp., Makrokylindrus semiechinata n. sp. and a single new gynodiastylid species, Gynodiastylis chathamensis n. sp. Makrokylindrus is recorded from New Zealand waters for the first time. Keys to all diastylid and gynodiastylid species from New Zealand waters are included, as well as an updated global key to Diastylopsis. PMID- 26624337 TI - The dorsal chaetotaxy of first instar Trogolaphysa jataca, with description of twelve new species of Neotropical Trogolaphysa (Hexapoda: Collembola: Paronellidae). AB - Adult members of tribe Paronellini are characterized by a substantially reduced idiochaetotaxy and as a result chaeta homology determination is often ambiguous. To evaluate previous hypotheses of chaetae homology in adult Trogolaphysa, a complete description of the dorsal chaetotaxy of first instar Trogolaphysa jataca (Wray, 1953b), supplemented with observations on first instar Trogolaphysa paracarpenteri sp. nov., is presented. It is showed that first instar Trogolaphysa carries an almost complete set of dorsal chaetae and that the reduction in adult idiochaetotaxy is secondary. In addition, the organization of primary chaetae in T. jataca points to a closer relationship with genera in subfamily Entomobryinae than to Orchesellinae. Based on chaetae correspondence between first instar and adult T. jataca it is established that the inner median chaetae on adult head corresponds to M1 instead of S1, the mesothorax p3 complex includes chaetae p1-p4, and on the fourth abdominal segment, anterior macrochaeta on column A corresponds to A3, and the secondary bothriotrix corresponds to D3p. In addition, T. relicta (Palacios-Vargas, Ojeda & Christiansen, 1985) is re described based on a paratype, and 12 new species are described: from Mexico, T. stannardi sp. nov., T. dimorphica sp. nov., T. laterolineata sp. nov., T. marieloiseae sp. nov., T. clarencei sp. nov., T. ocellata sp. nov., T. paracarpenteri sp. nov., T. palaciosi sp. nov., T. octosetosa sp. nov., and T. trioculata sp. nov.; from Jamaica, T. balteata sp. nov.; and from Argentina, T. entreriosensis sp. nov. PMID- 26624338 TI - Description of larval instars of Dryinus tarraconensis Marshall, 1868 and
Gonatopus baeticus (Ceballos, 1927) (Hymenoptera: Chrysidoidea: Dryinidae), parasitoids of the genus Dictyophara Germar (Hemiptera: Auchenorrhyncha: Dictyopharidae). AB - The last immature stage and the mature larva of Dryinus tarraconensis Marshall, 1868 and Gonatopus baeticus (Ceballos, 1927) are described for the first time. Features of immature and mature larvae of both species are discussed in the context of their implications for characterizing the subfamilies Dryininae and Gonatopodinae. PMID- 26624339 TI - Two new Phrynobatrachus species (Amphibia: Anura: Phrynobatrachidae) from the Republic of the Congo. AB - We describe two new species of puddle frogs, genus Phrynobatrachus, from the south-western Republic of the Congo. One of them, P. horsti sp. nov., occurs also in neighbouring Gabon and is morphologically most similar to the Cameroonian P. ruthbeateae. It differs from the latter species by smaller males with longer thighs and shanks. The new species comprises various colour morphs but always has less conspicuous black borders between flanks and belly than P. ruthbeateae. The distinct and large black axillary blotch of P. ruthbeateae is either much smaller in P. horsti sp. nov., or broken into numerous irregularly shaped smaller dots. Similarly, a black transversal line at the anterior ventral border of thighs and the black face mask is less distinct and irregularly delimitated in P. horsti sp. nov. when compared to P. ruthbeateae. The mean genetic difference in the sampled region of the 16S rRNA gene between P. horsti sp. nov. and 40 other western African congeners range from 3.66-18.10%. The second new species, P. mayokoensis sp. nov., differs from all other known congeners by the combination of a compact and warty body, the absence of a spiny eyelid tubercle and pedal webbing, a conspicuous black triangle on throat and anterior part of the belly, and a distinct large red blotch on the anterior-proximal surface of the thighs. It exhibited a mean genetic difference in the 16S rRNA to 40 other western African congeners ranging from 1.34-16.98%. The genetically most similar sequence stems from a GenBank entry of a Gabonese frog, determined as P. ogoensis. A comparison of the new species with P. ogoensis syntypes confirmed their specific distinctiveness, most convincingly underlined by the absence of pedal webbing in the new species and the pronounced pedal webbing in P. ogoensis. The GenBank entry thus most likely is based on a misidentification and P. mayokoensis sp. nov. may also occur in neighbouring Gabon. The discovery of the two new frog species is further evidence of the huge gap in our knowledge concerning the species richness in the Guineo-Congolian rainforests. PMID- 26624341 TI - A checklist of millipede genus Hyleoglomeris Verhoeff, 1910 in mainland China, with descriptions of seven new species (Diplopoda, Glomerida, Glomeridae). AB - Seven new cavernicolous species of the millipede genus Hyleoglomeris Verhoeff, 1910 are described and illustrated from karsts in southern China: H. grandis sp. n., H. baxian sp. n. from Guangxi Zhuang Autonomous Region; H. rhinoceros sp. n., H. getuhensis sp. n., H. generalis sp. n., H. variabilis sp. n. and H. multistriata sp. n., from Guizhou Province. All of them are presumed troglobites except for H. multistriata sp. n. which is likely to be a troglophile because of its well pigmented body. A distribution map of Hyleoglomeris in Guizhou and Guangxi is also provided. PMID- 26624340 TI - A long-lasting taxonomic problem in European Sympycnus resolved, with the description of a new species and data on habitat preferences. AB - Type specimens of Sympycnus pulicarius, S. annulipes, S. cinerellus and S. desoutteri were examined to clear up a long-lasting taxonomic confusion. Our study revealed that they represent, together with S. pygmaeus and S. annulipes var. brunnitibialis, a single species, with S. pulicarius as the senior subjective synonym, which is redescribed in this paper. Lectotypes were designated for Dolichopus pulicarius, Porphyrops annulipes, Chrysotus cinerellus and Sympycnus desoutteri. The postpedicel in this species shows substantial variation in shape and size, but the presence of a posteroventral bristle on the mid tibia is more reliable and the particular chaetotaxy and relative lengths of the tarsomeres of the male hind tarsus are entirely consistent. Both latter features separate S. pulicarius from another species, S. septentrionalis sp. nov., that is described here. Ecological data on both species were examined. An analysis of Malaise trap and white pan trap samples collected in Belgium revealed that S. pulicarius is most common in the western part of Flanders, and most abundant in open grassy habitats. In contrast to S. pulicarius, which is widespread over Europe, S. septentrionalis sp. nov. seems confined to northern Europe, where it exhibits a similar habitat preference. PMID- 26624342 TI - A new species of Woodcock (Aves: Scolopacidae: Scolopax) from Hispaniola, West Indies. AB - Several hundred late Holocene fossils from Trouing Jean Paul, a cave in Massif de la Selle, Haiti, represent an extinct species of woodcock (Scolopax brachycarpa, new species). Scolopax brachycarpa is known from most major skeletal elements; although volant, its carpometacarpus was very short relative to its humerus. The only other species of Scolopax from the West Indies is the extinct and presumably closely related S. anthonyi of Puerto Rico, which also had a relatively short carpometacarpus compared to continental congeners. Both Scolopax brachycarpa and S. anthonyi share more osteological characters with the Eurasian S. rusticola than with the North American S. minor. PMID- 26624343 TI - Apparent sympatry of Stiphrornis pyrrholaemus Schmidt & Angehr, 2008 and S. xanthogaster Sharpe, 1903 (Passeriformes: Muscicapidae) in Gabon, and taxonomic implications. AB - We report the occurrence of the recently-described Stiphrornis pyrrholaemus in the Makokou area, northeastern Gabon, more than 600 kilometers NE from its type locality, in areas covered by dense primary to secondary forest. The previous records of Stiphrornis from the same area were referred to S. xanthogaster. We confirm this attribution on the basis of museum specimens. Although several recent sources treat all Stiphrornis as a single species, our findings strongly suggest the sympatric coexistence of two Stiphrornis species and thus that they should be treated as separate species under the Biological Species Concept. PMID- 26624344 TI - Two new species and key to four species of the genus Humphaplotropis from China (Orthoptera: Pamphagidae, Pamphaginae). AB - Two new species i.e.: Humphaplotropis xiai sp. nov. and Humphaplotropis hebeiensis sp. nov. of the genus Humphaplotropis Xiao, Yin et Yin, 2013, are described from Hebei and Jiangsu, China in this paper. The new species Humphaplotropis xiai sp. nov. differs all known species of the genus by the abdomen like sawtooth in lateral view. The new species Humphaplotropis hebeiensis sp. nov. is similar to Humphaplotropis culaishanensis Lin, Cao et Yin, 2014, but differs from the latter by: lateral carinae of frontal ridge parallel; anterior margin of pronotum with acute angular in the middle, the apex reaching the hind margin of eyes; tegmina wider, cover 4/5 tympanum. Hind tibia yellow brown on upper side; epiphallus with 44 spikes, ancorae oblique inward distinctly, both posterior projections shorter than median projection. Type specimens are deposited in the Shanghai Entomological Museum, C.A.S., Shanghai and Natural Museum of Hebei University, Baoding, Hebei China respectively. PMID- 26624345 TI - Two new species of the genus Eotmethis (Orthoptera, Acridoidea, Pamphagidae) from China. AB - Two new species of the genus Eotmethis Bey-Bienko, 1948, namely Eotmethis xiai sp. nov., and Eotmethis platyverticus sp. nov. from the Ningxia Hui Autonomous Region and Gansu province are described in this paper. The new species Eotmethis xiai sp. nov. is allied to E. recipennis Xi & Zheng, 1986, but differs from latter by the vertical diameter of eye about 1.2 times as long as horizontal diameter, prozona of pronotum equal to metazona, tegmina of female shorter, reaching 2nd abdominal tergite only. The new species Eotmethis platyverticus sp. nov. is allied to E. holanennis Zheng & Gow, 1981, but differs from latter by width of vertex between eyes 2 times diameter of eye and prozona of pronotum longer than metazoan in female. The type specimens are deposited in College of Life Sciences, Hebei University, Baoding, China. PMID- 26624346 TI - Clarification of type material for Bornean species of the genus Osteochilus (Cyprinidae). AB - Two species and one subspecies of the genus Osteochilus (Cypriniformes: Cyprinidae) were described from Borneo in a revision of the group by Karnasuta in 1993. Examination of type material has illuminated points of conflict regarding some of the type specimens listed in original descriptions. Based on archived correspondence and the author's original thesis, we were able to determine the disposition of specimens and revise collection information for type material accordingly. PMID- 26624347 TI - Three new species of tiger beetles and new data on Cicindelina species from Angola (Coleoptera: Carabidae: Cicindelinae). AB - Three new species of tiger beetles, two of the genus Trichotaenia Rivalier, 1957 and one of the genus Cylindera Westwood, 1831, subgenus Ifasina Jeannel, 1946 are described from Angola. An annotated list of species of Cicindelina sampled in this country is provided also. Records for three species previously unknow from Angola are given: Ophryodera smrzi Werner, 2005, Lophyra clatharta (Dejean, 1825) and Lophyra sumlini Cassola, 1976. Some considerations on the distribution and general ecology of these beetles in Angola are also presented. Further, two dichotomic keys are made available for the identification of Trichotaenia species with marked shoulders and Cylindera (Ifasina) species of western and southwestern Africa, respectively. PMID- 26624348 TI - Ischnura foylei sp. nov. (Odonata, Coenagrionidae) from the highlands of Sumatra. AB - Ischnura foylei sp. nov. is described from Indonesia, Sumatra, Jambi Province, Danau Gunung Tujuh (or Danau Sakti), a lake situated in an extinct volcanic crater, 1 degrees 41'15"S, 101 degrees 25'28"S, 1995 m a.s.l. Structurally it is close to I. senegalensis but larger and with differently shaped cerci in males and a more trilobate posterior lobe of the prothorax; males and androchromatic females have a unique colour pattern. PMID- 26624349 TI - A new species of Charinus Simon, 1892 (Amblypygi, Charinidae) from termite nests in French Guiana. AB - The genus Charinus is represented by 51 species, distributed in all tropical regions. Their small size allows them to use a wide range of micro-habitats, from caves, litter to insect nests. The new species C. sillami sp. nov. was found into termite nests of three different species: Neocapritermes taracua, Spinitermes sp. and Embiratermes neotenicus. Only Paracharon caecus (Paleoamblypygi: Paracharontidae) was previously known to be associated with Isoptera. Eleven species of Charinus were previously known from Northern South America. Charinus sillami sp. nov. is the second species of the genus occurring in French Guiana. An updated key of Northern South-American species is provided. PMID- 26624350 TI - Platybracon Yang et al. (2008) (Hymenoptera: Braconidae), junior homonymy and subjective synonymy--a systematic and nomenclatural note. PMID- 26624351 TI - The tadpole of Hylodes meridionalis (Mertens, 1927), a lotic stream anura from the Atlantic Rainforest of Brazil. PMID- 26624353 TI - Redescription of males of the aphid species Cinara (Cupressobium) tujafilina and Cinara (Cupressobium) cupressi (Hemiptera, Lachninae). AB - This paper presents the first comprehensive description of the winged males of Cinara tujafilina and Cinara cupressi (Hemiptera, Lachninae) and establishes the morphological characters enabling differentiation between them. We show that some populations of C. tujafilina, a species considered to be anholocyclic, may not have lost the genetic ability to produce males and under favourable conditions can develop in a holocyclic manner. PMID- 26624352 TI - A new species of Tropidopedia from the Amazon rainforest, Brazil (Hymenoptera: Apidae), with a revised phylogenetic overview of the genus. AB - We describe a new species of the bee tribe Tapinotaspidini, Tropidopedia guaranae Mahlmann & Oliveira sp. n. from the Amazon rainforest, Amazonas, Brazil. We emend the phylogenetic tree of Aguiar & Melo (2007) to include the new species and comment upon some characters presented by those authors. PMID- 26624354 TI - Pseudacteon notocaudatus and Pseudacteon obtusitus (Diptera: Phoridae), two new species of fire ant parasitoids from South America. AB - Ongoing studies in South America of phorid flies of the genus Pseudacteon Coquillett 1907 have revealed two further new species in this genus that are described here: P. obtusitus and P. notocaudatus. Both species are parasitoids of Solenopsis (F.) fire ants. PMID- 26624355 TI - Freshwater and brackish bryozoan species of Croatia (Bryozoa: Gymnolaemata, Phylactolaemata) and their genetic identification. AB - Freshwater and brackish species of bryozoans belong to the Phylactolaemata and Gymnolaemata class. Twelve species of bryozoans were recorded and morphologically determined at eight locations in the Black Sea and the Adriatic basin in Croatia. Twelve species of Bryozoa have been listed in the taxonomic index for Croatia (Conopeum seurati, Lophopus crystallinus Paludicella articulata, Cristatella mucedo, Fredericella sultana, Hyalinella punctata, Plumatella casmiana, Plumatella emarginata, Plumatella fruticosa, Plumatella fungosa, Plumatella geimermassardi and Plumatella repens). For the purposes of gene identification of recorded species, molecular markers for nuclear 18S and 28S genes, ITS2 region and mitochondrial COI gene were amplified. Genetic identifications of morphologically determined bryozoan species were confirmed using highly similar sequences local alignment analysis. Proliferation of freshwater bryozoan species over long distances with the help of the vector animals was confirmed by defining haplotypes on the base of 18S, 28S and ITS2 sequences associated with the Black Sea-Mediterranean waterfowl flyway. PMID- 26624356 TI - Three new species, two newly recorded species and one newly recorded genus of Lithocolletinae (Lepidoptera: Gracillariidae) from China. AB - The Chinese representatives of the genera Chrysaster Kumata and Cameraria Chapman (Gracillariidae: Lithocolletinae) were studied. Chrysaster is recorded for the first time in China. Three species belonging to Cameraria, C. diplodura Bai, sp. nov., C. rhynchophysa Bai, sp. nov. and C. jiulianshanica Bai, sp. nov., are described as new. Chrysaster hagicola Kumata and Cameraria magnisignata Kumata are new records for China. Adults and genitalia of the five species are illustrated. A key to the Chinese species of Cameraria is provided. PMID- 26624357 TI - A new species of Deinodryinus Perkins, 1907 (Hymenoptera, Dryinidae) from Minas Gerais, Brazil. AB - Deinodryinus pratapolensis sp. nov. is described and illustrated. This species was collected by yellow pan trap, in a gallery forest at Pratapolis (Minas Gerais, Brazil). PMID- 26624358 TI - Life among crevices: osteology of Nannophrys marmorata (Anura: Dicroglossidae). PMID- 26624359 TI - A new species of Amalothrips Ananthakhrishnan from Malaysia, with first description of male. AB - Amalothrips noorazlani sp. n. is described from Malaysia based on both sexes, and a key is provided to the species of this genus. This is the first record of Amalothrips species outside India, and the first description of a male Amalothrips. The male has a pair of drepanae, the tergal posteromargin bears a toothed craspedum, but there are no sternal pore plates. PMID- 26624360 TI - Cryptic speciation in the Lesser Elaenia Elaenia chiriquensis (Aves: Passeriformes: Tyrannidae). AB - Tyrant-flycatchers (Tyrannidae) are a taxonomically confusing bird group containing a large degree of cryptic diversity that has only recently begun to be unraveled through the application of acoustic and molecular methods. We investigated all three subspecies of the Lesser Elaenia, Elaenia chiriquensis Lawrence, across their range using sound recordings as well as nuclear and mitochondrial markers. We show that two of the three subspecies, the nominate race from southern Central America and the widespread South American subspecies E. c. albivertex Pelzeln, have undergone very low levels of vocal and molecular differentiation across their fragmented range. In contrast, the isolated taxon E. c. brachyptera Berlepsch, endemic to the western and also, as recently shown, eastern slopes of the northern Andes, is phylogenetically and vocally distinct from other Lesser Elaenias, indicating that it constitutes a separate biological species. PMID- 26624361 TI - Tydeus shabestariensis sp. nov. and description of the male of Neopronematus sepasgosariani (Acari: Tydeoidea), with a key to the Iranian species of Tydeus. AB - A new species of the family Tydeidae from Iran, Tydeus shabestariensis sp. nov., is described from adult males and females collected from soil in apple orchards. A key to species of Tydeus of Iran, based on females, is provided. The male of Neopronematus sepasgosariani (Tydeoidea: Iolinidae) is also described and illustrated for the first time. PMID- 26624362 TI - Description of new species of Phanodermopsis (Enoplida, Phanodermatidae) with key to genera of family Phanodermatidae and pictorial key to Phanodermopsis species. AB - A new representative of the family Phanodermatidae, Phanodermopsis nana sp. n., is described. The new species is found in the Sea of Japan and characterized by its small body size, long anterior sensilla and short tail. The new species differs from P. ingrami in body length (~ 7000 um in P. ingrami vs ~ 3000 um in P. nana sp. n.). The De Man's ratios (a, b, c) are smaller in P. nana sp. n. and the outer labial setae are longer (1 corresponding body diameter) than in P. ingrami (1/2 corresponding body diameter). The vulva is more posterior in P. ingrami (V% = 58-61%) than in P. nana sp. n. (V% = 51-58%). A dichotomous key to the 9 valid genera of Phanodermatidae and a pictorial key to species of Phanodermopsis are provided. The length of the spicules is proposed as the main differentiating feature for distinguishing Phanodermopsis and Crenopharynx species. Phanodermopsis longisetae Chitwood, 1936 which has extremely long spicules (5.2 anal body diameters) is transferred to the genus Crenopharynx. PMID- 26624363 TI - A new libelluloid family from the Eocene Green River Formation (Colorado, USA) (Odonata, Anisoptera). AB - The new family Urolibellulidae is proposed for the new genus and species Urolibellula eocenica, based on a fossil dragonfly from the Eocene Green River Formation (USA). This new taxon is considered as the sister group of the extant Libellulidae. As the oldest libellulid dragonfly is dated from the Turonian, the Urolibellulidae should also be at least Late Cretaceous. PMID- 26624364 TI - Endecous peruassuensis n. sp. (Orthoptera: Grylloidea: Phalangopsidae) from caves of Eastern Brazil: evidence of isolation in the subterranean realm and discussion about troglomorphisms. AB - We describe a new species of the genus Endecous Saussure (1878), recorded at the Lapa do Cipo and Olhos d'Agua caves, which are located in the Itacarambi municipality, Minas Gerais state, Eastern Brazil. Another species, E. aguassay Mews, 2008 was recordedin the surroundings of the caves. The genus Endecous corresponds to the most common cricket in Brazilian hypogean environments. In general, these crickets inhabit the areas around cave entrances up to the aphotic zones of caves. The genus Endecous is the only cave cricket to present troglobiomorphosis, i.e., an apterous condition. The distribution of the new species is limited to these two caves, which suggests an endemism in this karst system similar to the distribution of other endemic animals, such as harvestmen and amblypygid arachnids. This species is the sixth troglobitic one described for Olhos d'Agua cave, which sets this cave as a spot of subterranean fauna in Brazil. PMID- 26624365 TI - A new species of the caridean shrimp genus Lebbeus White, 1847 (Crustacea: Decapoda: Thoridae) from the southwestern Sea of Okhotsk, Hokkaido, Japan. AB - A new species of the caridean shrimp genus Lebbeus White, 1847 (Thoridae), L. fujimotoi n. sp. is described and illustrated on the basis of material from the Nemuro Strait, southwestern part of the Sea of Okhotsk, Hokkaido, Japan, at depths of 500-800 m. The new species belongs in the informal species group characterized by the possession of an epipod only on the third maxilliped, containing only L. elegans Komai, Kohtsuka & Hayashi, 2004 among the 65 previously described specific taxa. The elongate and strongly upturned rostrum with more numerous ventral teeth (seven or eight versus one to four) and the presence of a posteroventral tooth on the fourth pleonal pleuron immediately distinguish the new species from L. elegans. Species of Lebbeus reported from the Sea of Okhotsk are briefly overviewed. PMID- 26624366 TI - Meharia ganslmeieri sp. nov.--a new Cossidae species from Zambia (Lepidoptera). PMID- 26624367 TI - A new species of Zaglyptogastra Ashmead, 1900 (Hymenoptera: Braconidae: Braconinae) from Vietnam. AB - The moderately large genus Zaglyptogastra Ashmead, 1900 is newly recorded for Vietnam and one new species, Z. vietnamica Long sp. n., is described and illustrated. Differences between the new species and two described species, Z. aswada El-Heneidy & Quicke, 2007, from Indonesia (Sumatra) and Z. vitalisi (Turner, 1919), from Laos, are given. PMID- 26624368 TI - Paraclausastrea vorarlbergensis sp. nov.; a new coral from the Lower Cretaceous of western Austria (Scleractinia; upper Barremian-lower Aptian; Schrattenkalk Fm.; Vorarlberg). AB - The new taxon Paraclausastrea vorarlbergensis sp. nov. is described from the upper Barremian-lower Aptian (Schrattenkalk Fm.) of western Austria (Vorarlberg). It belongs to the montlivaltiids and is characterized by thamnasterioid to submeandroid corallite integration, diameters of corallites ranging between 3 and 6.5 mm, and septa that are generally developed in 4 incomplete cycles in 6 generally irregular systems. In a small number corallites that are around 6 mm in diameter, 4 complete cycles are present. In corallites that are around 2 mm in diameter, usually between 12 and 18 septa are present. The new species differs from all other forms of Paraclausastrea in having the largest number of septa. This is the first report of this genus for the Schrattenkalk Formation. PMID- 26624369 TI - New species and subspecies of the genus Lesteva Latreille, 1797 (Coleoptera: Staphylinidae: Omaliinae) from Taiwan. AB - Two new taxa of the genus Lesteva Latreille, 1797 from Taiwan (Hualien County) are described and illustrated: L. smetanai sp. n. and L. rufopunctata taiwanica subsp. n. A key to species known from Taiwan is provided. PMID- 26624370 TI - A new Batillipedidae (Tardigrada, Arthrotardigrada) from Argentina. AB - A new species of marine tardigrade, Batillipes acuticauda sp. n., has been found in midlittoral sand sediments collected at Monte Hermoso beach (Buenos Aires province, Argentina). The new species differs from all other members of Batillipedidae by its combination of caudal apparatus, lateral processes and toe patterns. It is the first description of an arthrotardigrade from Argentina. PMID- 26624371 TI - Two new species of the genus Loxopamea Hreblay & Plante 1995 (Lepidoptera: Noctuidae) from China. PMID- 26624372 TI - New data on the genus Wiedemannia Zetterstedt (Diptera: Empididae) from the Caucasus with description of four new species. AB - Currently, 17 species of aquatic dance flies of the genus Wiedemannia are known from the Caucasus including four new species: W. ivkovicae sp. nov. (South Ossetia), W. nartshukae sp. nov. (South Ossetia), W. ossetiana sp. nov. (South Ossetia) and W. pseguashae sp. nov. (Georgia, South Ossetia). Wiedemannia (Chamaedipsia) lota Walker 1851 (Russia; Georgia) is recorded from the Caucasus for the first time. The inaccuracies in species records from the different countries of the Caucasus have been eliminated. Nine species are recorded for the first time from the territory of Georgia, five species for Abkhazia and one for Russia. The new species are described, all species illustrated and distribution listed. A key to species of Wiedemannia from the Caucasus is provided. PMID- 26624373 TI - A new species of Neoathripsodes Holzenthal, 1989 (Trichoptera: Leptoceridae) with new generic and species records in Bahia State, Brazil. AB - Trichoptera is the most species-rich clade of exclusively aquatic insects. In Brazil, 645 species have been recorded, distributed in 70 genera and 16 families. In the Northeast Region of Brazil, 85 species have been recorded, including 56 in Bahia State. Sixteen of the Northeast Region species belong to the family Leptoceridae. Among these, the long-horned caddisfly genus Neoathripsodes Holzenthal has been a monotypic genus since its erection more than 26 years ago. It is an endemic genus in the states of Minas Gerais, Rio de Janeiro and Sao Paulo and only the male stage has been described for its only known species, Neoathripsodes anomalus. In this paper, we describe a new species of Neoathripsodes, with the first description of a female in this genus. Additionally, we present new records for the family Leptoceridae in Bahia, especially from the Serra Bonita Mountains, in order to help solve a long-term problem in Brazilian caddisfly research: An uneven proportion of studies in some regions of the country due to historical reasons. The Northeast Region of Brazil still remains a neglected area in which efforts to unearth its biodiversity should be focused. In this work, four species are recorded for the first time for Bahia State and its Serra Bonita Mountains: Grumichella rostrata Thienemann 1905, Neoathripsodes holzenthali n. sp., Nectopsyche fuscomaculata Flint 1983, and Notalina cipo Holzenthal 1986. Neoathripsodes and Notalina are new generic records for Bahia State. The following four species are new records for Serra Bonita: Atanatolica bonita Costa & Calor 2014, Oecetis martinae Quinteiro & Calor 2015, O. furcata Quinteiro & Calor 2015, and Triplectides gracilis (Burmeister 1839). Additional new distributional records for Bahia State are included in this study. PMID- 26624374 TI - Contribution to the taxonomy of scaly crickets (Orthoptera: Mogoplistidae: Mogoplistinae) from Southeast Asia. AB - Three new species of scaly crickets are described: Ornebius xinyao sp. n. from Singapore; Ornebius dowwiangkanae sp. n. and Terraplistes ingrischi sp. n. from Thailand. Ornebius insculptus Tan & Ingrisch, 2013 from Singapore is also corrected for nomenclatural error from the original name Ornebius insculpta. PMID- 26624375 TI - Two new species of the genus Taphioporus Moseyko & Kirejtshuk (Chrysomelidae: Eumolpinae) from Baltic amber. AB - Two new species of Taphioporus Moseyko & Kirejtshuk are described and illustrated from Baltic amber: T. rufous sp. nov. and T. carsteni sp. nov. Members of this fossil genus are known from Baltic and Rovno amber. A key to species of Taphioporus is provided. PMID- 26624376 TI - First report of a parthenogenetic Grylloidea and new genus of Neoaclini (Insecta: Orthoptera: Grylloidea: Phalangopsidae: Phalangopsinae). AB - This study describes a new genus and species of Neoaclini cricket based on specimens collected in the Brazilian Atlantic forest. In addition to the morphological description, we also report karyotype. Ubiquepuella telytokous n. sp. represents the first recorded occurrence of parthenogenesis in Grylloidea. Although the exclusively parthenogenetic reproduction is rare in Orthoptera, we acknowledge this phenomenon in this species based on successful reproduction in the laboratory setting (i.e., approximately ten generations) despite the absence of males, indicating thelytokous parthenogenesis. PMID- 26624377 TI - A new species of Moenkhausia Eigenmann (Characiformes: Characidae) from the upper rio Juruena basin, Central Brazil. AB - Moenkhausia lineomaculata, new species, is described herein from the upper rio Juruena, upper rio Tapajos basin. The new species seems to be part of a monophyletic group formed by M. cosmops, M. cotinho, M. diktyota, M. forestii, M. oligolepis, M. sanctaefilomenae, and M. pyrophthalma, the Moenkhausia oligolepis/M. sanctaefilomenae complex, by sharing a reticulated color pattern on body and the presence of a light area preceding a wide, dark caudal-peduncle blotch. The new species is distinguished from these species, except M. cotinho, by the presence of longitudinal series of dark dots on body, and from M. cotinho by the humeral blotch evenly pigmented along its length and by having the dark line along horizontal septum starting approximately at the vertical through dorsal-fin origin. The new species presents intraspecific variation in lateral line scales perforation, a feature often present in species of the aforementioned group. PMID- 26624378 TI - A new species of clearwing moth (Lepidoptera: Sesiidae: Osminiini) from Peninsular Malaysia, exhibiting bee-like morphology and behaviour. AB - A new species of Sesiidae, tribe Osminiini from Peninsular Malaysia, Heterosphecia pahangensis Skowron, displaying numerous bee-mimicking features, is described. DNA barcodes showed significant differences with related taxa. However, the paucity of Sesiidae barcodes from Southeast Asia prevents meaningful taxonomic comparisons. The closest match out of published data on Sesiidae barcodes is Heterosphecia bantanakai, Arita & Gorbunov (2000a) from the tribe Osminiini, which has 9.98% sequence divergence from Heterosphecia pahangensis. Photographs of the moth in its natural habitat are shown. Behavioural aspects, such as mud-puddling and mode of flight, are described and presented in a video. PMID- 26624380 TI - A new species of freshwater crab of the genus Kingsleya Ortmann, 1897 (Crustacea: Brachyura: Pseudothelphusidae) from Amazonia, Brazil. AB - A new species of freshwater crab, Kingsleya celioi, from the Brazilian Amazon (Para State) is described and illustrated. The new species can be easily separated from their congeners by a suite of morphological characters, including the apical plate of the first gonopod large, widest medially in abdominal view, with single large spine-like outgrowth in midlength of mesial margin; distal, proximal lobes of apical plate unequal in size, distal lobe largest, tapering distally in lateral view. PMID- 26624379 TI - Libanasa kilomeni, a new species of East African Lutosinae (Orthoptera: Anostostomatidae). AB - A new species of Libanasa, L. kilomeni, is described. In contrast to L. brachyura, an inhabitant of lowland wet to submontane forest along the Tanzanian coast and part of the Eastern Arc Mountains of Tanzania, this new species is found in montane forest in the North Pare Mountains. L. kilomeni n. sp. is restricted to a small forest reserve and due to forest clearing at lower elevations probably driven to its upper ecological border. Therefore this species is considered endangered and should be included in the IUCN red list. PMID- 26624381 TI - A taxonomic revision of the neotropical termite genus Ruptitermes (Isoptera, Termitidae, Apicotermitinae). AB - The taxonomy of Ruptitermes Mathews 1977 is revised. Nine new species are described: R. araujoi, sp. n. (from Brazil), R. atyra, sp. n. (from Brazil, Peru, and Panama), R. bandeirai, sp. n. (from Brazil), R. cangua, sp. n. (from Brazil), R. kaapora, sp. n. (from Paraguay and Brazil), R. krishnai, sp. n. (from Trinidad), R. maraca, sp. n. (from Brazil), R. piliceps, sp. n. (from Brazil), and R. pitan, sp. n. (from Brazil). Ruptitermes franciscoi (Snyder 1959), new combination, is transferred from Anoplotermes Fr. Muller to Ruptitermes. Ruptitermes proratus Emerson 1949 is placed under the synonymy of R. reconditus (Silvestri, 1901). The genus is redescribed to accommodate all the species included. Ruptitermes arboreus, R. reconditus and R. xanthochiton are redescribed based on the examination of large series. A key to the 13 species of the genus based on the external morphology of workers is provided. The enteric valve armature is described and illustrated for all species except R. kaapora. Distribution maps are presented for all species. PMID- 26624382 TI - A redescription of Lithornis vulturinus (Aves, Palaeognathae) from the Early Eocene Fur Formation of Denmark. AB - The extinct Lithornithidae include several genera and species of flying palaeognathous birds of controversial affinities known from the Early Paleogene of North America and Europe. An almost complete, articulated skeleton from the Early Eocene marine deposits of the Fur Formation (Denmark) was recently assigned to Lithornis vulturinus Owen, 1840. This study provides a detailed redescription and comparison of this three-dimensionally preserved specimen (MGUH 26770), which is one of the best preserved representatives of the Lithornithidae yet known. We suggest that some new features might be diagnostic of Lithornis vulturinus, including a pterygoid fossa shallower than in other species of Lithornis and the presence of a small caudal process on the os palatinum. We propose that Lithornis nasi (Harrison, 1984) is a junior synonym of Lithornis vulturinus and we interpret minor differences in size and shape among the specimens as intraspecific variation. To date, Lithornis vulturinus is known with certainty from the latest Paleocene-earliest Eocene to Early Eocene of the North Sea Basin (Olst, Fur and London Clay Formations). Among the four species of the genus Lithornis, the possibility that Lithornis plebius Houde, 1988 (Early Eocene of Wyoming) is conspecific with either Lithornis vulturinus or Lithornis promiscuus Houde, 1988 (Early Eocene of Wyoming) is discussed. The presence of closely related species of Lithornis on either side of the North Atlantic in the Early Eocene reflects the existence of a high-latitude land connection between Europe and North America at that time. PMID- 26624383 TI - A review of the Silba admirabilis McAlpine species group (Diptera: Lonchaeidae) with descriptions of thirteen new species from the Afrotropical region. AB - The Silba admirabilis species group is diagnosed within the genus Silba Macquart by the combination of partly yellow tarsomeres and the distinctive features of the male genitalia. Thirteen new species within this species group are described from the Afrotropical region; namely Silba bakongo MacGowan sp. nov., Silba boulangi MacGowan sp. nov., Silba bredoi MacGowan sp. nov., Silba garamba MacGowan sp. nov., Silba hambai MacGowan sp. nov., Silba inimvua MacGowan sp. nov., Silba lubumbashi MacGowan sp. nov., Silba mbuti MacGowan sp. nov., Silba saegeri MacGowan sp. nov., Silba spiculata MacGowan sp. nov., Silba tekei MacGowan sp. nov., Silba upemba MacGowan sp. nov., and Silba wittei MacGowan sp. nov. Ten previously described species within the genus Silba are also identified as belonging to the S. admirabilis species group. One species of the genus Lonchaea also belonging to this group is re-assigned to Silba. The synonymies Silba displata McAlpine, 1964 = Silba hilli (Malloch, 1928) and Silba fragranti MacGowan, 2007 = Silba chalkei McAlpine, 1956 are established. A key and illustrations of male genitalia are provided to all species. Further information is presented relating to the taxonomy and distribution of previously described members of this species group whose range extends from the Afrotropical to Australasian regions. PMID- 26624384 TI - Silversides of the genus Labidesthes (Atheriniformes: Atherinopsidae). AB - The two species of Labidesthes, L. sicculus and L. vanhyningi, are herein redescribed. Labidesthes sicculus is separated from L. vanhyningi by the presence of an anterolateral process of the post temporal that is longer than it is wide (versus wider than long), a ratio of thoracic length to abdominal length greater than two (versus less than two), and a midlateral stripe that is narrows in front of first dorsal fin (versus expanding in front of first dorsal fin). Labidesthes sicculus is found in Gulf of Mexico drainages from the Brazos River East to the Pascagoula River, Mississippi River (absent in middle and upper Missouri River), and Great Lakes-St. Lawrence River (absent in Lake Superior). Labidesthes vanhyningi is found in Gulf Mexico drainages from the Neches River East around peninsular Florida North on the Atlantic Coast to the Pee Dee River, in the Mississippi River it is confined to lowland areas of the Lower Mississippi River. PMID- 26624386 TI - Phytoseiid mites (Acari: Mesostigmata) from Araucaria Forest of the State of Rio Grande do Sul, Brazil, with new records and descriptions of four new species. AB - This paper reports on the Phytoseiidae from an Araucaria forest in the State of Rio Grande do Sul, describing four new species, namely Transeius kroeffis n. sp., Typhlodromalus araucariae n. sp., Typhlodromips pompeui n. sp. and Typhlodromips salvadorii n. sp.. Iphiseiodes moraesi Ferla & Silva, Neoseiulus tunus (DeLeon), Typhlodromips japi Lofego, Demite & Feres, Typhlodromips pallinii Goncalves, Silva & Ferla, Typhloseiopsis dorsoreticulatus Lofego, Demite & Feres are reported for the first time from this type of habitat in Rio Grande do Sul state, Brazil. PMID- 26624387 TI - Redescription of late-instar larva of Scydmoraphes sparshalli (Denny) Coleoptera: Staphylinidae, Scydmaeninae). AB - The larva of Scydmoraphes sparshalli is redescribed. This is the first complete description of an immature Scydmoraphes with special focus on the chaetotaxic characters. The larva is unique among Cyrtoscydmini in having three pairs of stemmata, a very long sensory appendage of the antennomere II, mandibles with mesal row of microserrations interrupted by smooth portion of mandibular margin; maxillary mala with asetose apex and a row of very long, modified setae on mesal margin, and extremely elongate maxillary palpomere III and labium. A comparative study of previous descriptions resulted in recognizing a misidentification of a Scydmoraphes larva (the "Typ 2-Larve" of Schmid) as a putative Neuraphes (Pararaphes). The serial homology of chaetotaxic structures in the larva of Scydmoraphes sparshalli is discussed, and comparative notes on the larvae of Scydmoraphes, Neuraphes and Stenichnus are given, with an identification key. PMID- 26624385 TI - New records for the Kosovo caddisfly fauna with the description of a new species, Drusus dardanicus sp. nov. (Trichoptera: Limnephilidae). AB - The Balkan Peninsula is one of the most important European hotspots of freshwater biodiversity. The region is, however, to a large extent insufficiently investigated. Here we present data on distribution of caddisflies in one particularly understudied area, the Republic of Kosovo. Our data include the first records of Adicella altandroconia Botosaneanu & Novak and Halesus tessellatus (Rambur) for the Kosovo caddisfly fauna, and a new locality for the recently described Ecclisopteryx keroveci Previsic, Graf, & Vitecek. Further, we describe the new caddisfly species Drusus dardanicus sp. nov. from the Kopaonik Mountains. The new species belongs to the D. discophorus Species Group and differs morphologically from its most similar congeners (D. discophorus Radovanovic, D. balcanicus Kumanski, and D. bureschi Kumanski) mainly in exhibiting (1) subtrianglar superior appendages; (2) a narrow, dorsal spinate area of tergite VIII; and (3) evenly rounded tips of intermediate appendages in caudal view. In phylogenetic analysis, D. dardanicus sp. nov. is well delineated and recovered as a sister taxon to D. osogovicus Kumanski, a species recorded from Bulgaria. The recent discovery of a new species and other rare or microendemic species presents important contributions to the knowledge on the rich freshwater biodiversity in Kosovo. These species face increasing anthropogenic pressure and threats to their conservation. PMID- 26624388 TI - First record of the Nephropid genus Acanthacaris Bate, 1888 (Crustacea: Decapoda: Nephropidae) from Taiwan. AB - The giant deep-sea lobster genus Acanthacaris Bate, 1888 is reported for the first time from Taiwan. The single specimen with a total length of 36 cm was collected near a cold seep off southwestern Taiwan at about 1300 m deep and identified as A. tenuimana Bate, 1888. PMID- 26624389 TI - JULIANA CHAMORRO-RENGIFO, HOLGER BRAUN & CRISTIANO LOPES-ANDRADE (2015) REASSESSMENT AND DIVISION OF THE GENUS AGRAECIA AUDINET-SERVILLE (ORTHOPTERA: TETTIGONIIDAE: CONOCEPHALINAE: AGRAECIINI). Zootaxa, 3993 (1): 001-076. PMID- 26624390 TI - Review of North European species of the genus Lathrolestes (Hymenoptera, Ichneumonidae) with description of one new species from Oland (Sweden). AB - The genus Lathrolestes Forster (Hymenoptera: Ichneumonidae) from Northern Europe is reviewed. A new species, L. oelandinus sp. n. from Oland (Southern Sweden) is described. Illustrated diagnoses for 23 Northern European species are provided. Lathrolestes soperi Reshchikov, 2010 is recorded for the first time in the Palaearctic region (from the UK) and L. bipunctatus (Bridgman, 1886), L. citreus (Brischke, 1878), L. clypeatus (Zetterstedt, 1838) are new records for Denmark, and L. moravicus Habermehl, 1923 is a new record for Finland, France and Russia. Additionally L. ensator recorded newly from Belorus, L. erythrocephalus from Azerbaijan, L. macropygus and L. pictilis from Austria. Trophic interactions of the genus are discussed. PMID- 26624391 TI - Ten species of Culicoides Latreille (Diptera: Ceratopogonidae) newly recorded from Thailand. AB - A survey of biting midges in animal sheds, mangroves and beaches along the Andaman coastal region in southern Thailand between April 2012 and May 2013 collected 10 species of Culicoides which were not previously known from Thailand. These new records are C. arenicola, C. flavipunctatus, C. hui, C. kinari, C. kusaiensis, C. parabubalus, C. quatei, C. spiculae, C. pseudocordiger and C. tamada. An updated checklist of species of Culicoides reported from Thailand is provided. PMID- 26624392 TI - New species of Scalibregmatidae (Annelida, Polychaeta) from the East Antarctic Peninsula including a description of the ecology and post-larval development of species of Scalibregma and Oligobregma. AB - A large collection of scalibregmatid polychaetes from the east Antarctic Peninsula in May 2000 has yielded specimens of three new species of Scalibregma, Pseudoscalibregma, and Oligobregma. The new species of Scalibregma is represented by more than 400 specimens that include post-larval and juvenile forms which, for the first time, provide data on the sequence of development of key characters of a scalibregmatid. These data demonstrate that taxonomic characters including the form of the prostomium and presence of branchiae develop late in ontogeny and that small specimens cannot be reliably referred to a species or genus without a growth sequence. Juvenile morphology is also presented for the new species of Oligobregma. The new species of Scalibregma is compared with five northern hemisphere species and differs in details of the peristomium, upper and lower lips of the mouth, dorsal and ventral cirri, and nature of the short spinous setae of setiger 1. The new species of Pseudoscalibregma is unique in the nature of asymmetrical ventral cirri of posterior setigers. The new species of Oligobregma has large acicular spines in both noto- and neuropodia and these are present in juveniles. However, the final adult configuration of the prostomium is not evident until late in development. The taxonomic significance of the timing of development of post-larval and juvenile morphology elucidated in this study is discussed in relation to the validity of certain taxa and the current system of genera used in the family. PMID- 26624393 TI - A new species of Niganda Moore, 1879 from Thailand, with descriptions of variation in male genitalia and female facies of N. radialis Moore (Lepidoptera: Notodontidae, Ceirinae). AB - Niganda phichai Pellinen, sp. n., is described from northern Thailand. The new species is diagnosed and illustrated, including details of the genitalia and DNA sequencing. Variability in the male genitalia of Niganda radialis Gaede is reviewed, and notes are presented on the facies of female N. radialis. PMID- 26624394 TI - A new species of Anilios (Scolecophidia: Typhlopidae) from Central Australia. AB - Anilios fossor sp. nov. is described from a single specimen collected in 1989 from Ruby Gap Nature Park, Northern Territory. The species differs from all other Anilios species in the combination of 20 midbody scales, 514 dorsal scales, a rounded, non-angulate snout in lateral and dorsal profile, a nasal cleft contacting the second supralabial and not extending to the head dorsum, and a large round rostral shield in dorsal view. It is unclear whether the paucity of material of this species represents a limited distribution, or poor sampling in a remote, sparsely settled part of the continent. Evidence for the recognition of the Australian typhlopid fauna as a distinct genus Anilios is critically reviewed, and the genus is found to be recognizable only on genetic evidence. Some other recent nomenclatural and taxonomic changes in the Australian typhlopid fauna are considered and rejected. PMID- 26624395 TI - A new species of Pseudophoxinus (Teleostei: Cyprinidae) from Southwestern Anatolia, Turkey. AB - Pseudophoxinus mehmeti, new cyprinid species from the Alankoy basin in south western Turkey, is distinguished from all species of Pseudophoxinus in adjacent regions by the combination of the following characters: body slender, its length 1.3-1.5 times its depth; caudal peduncle length 1.6-2.0 times its depth; mouth almost superior, with the tip of the mouth-cleft approximately level with the middle of the pupil; snout with a pointed tip, its length markedly greater than eye diameter; lateral line not complete, with 30-50 perforated scales and 48-60+2 scale rows in lateral series; 111/2-131/2 scale rows between lateral line and dorsal-fin origin, 31/2-51/2 scale rows between lateral line and anal-fin origin; dorsal-fin with 61/2-71/2 branched rays; anal-fin with 61/2-71/2 branched rays; a distinct black epidermal stripe from eye to caudal-fin base in preserved individuals. PMID- 26624396 TI - A novel species of Euspondylus (Squamata: Gymnophthalmidae) from the Andes Mountains of central Peru. AB - The South American gymnophthalmid genus Euspondylus is distributed from Venezuela through Peru, with its highest diversity occurring in Peru. Euspondylus paxcorpus sp. nov. is a new species from Junin, Peru possessing prefrontal scales and represented by 60 specimens. The new species differs from all other species by the combination of four supraoculars with supraocular/supraciliary fusion, 5-7 occipitals, a single palpebral scale, five supralabials and infralabials, quadrangular dorsal scales with low keels arranged in transverse series only, 40 45 in a longitudinal count and 22-28 in a transverse count, 12 rows of ventrals in a transverse count and 23-25 in a longitudinal count, and no sexual dimorphism in coloration. The discovery of E. paxcorpus increases the known number of Euspondylus species to 13. Because the coloration patterns of the specimens were greatly different after preservation in alcohol, caution should be used when identifying Euspondylus species from museum specimens. PMID- 26624397 TI - A new species of the genus Euricania Melichar, 1898 (Hemiptera: Fulgoromorpha: Ricaniidae) from China, with a world checklist and a key to all species recorded for the country. AB - One new species of the planthopper genus Euricania Melichar, 1898 - E. paraclara sp. nov. is described from Guizhou (southwest China). A checklist of all Euricania species and an identification key to the species of the Chinese fauna are provided. Photographs of the adult and illustrations of male and female genitalia of the new species are also given. PMID- 26624398 TI - Probathylepadidae, a new family of Scalpelliformes (Thoracica: Cirripedia: Crustacea), for Probathylepas faxian gen. nov., sp. nov., from a hydrothermal vent in the Okinawa Trough. AB - A new pedunculate barnacle, Probathylepas faxian gen. and sp. nov., is described from a hydrothermal vent in the Okinawa Trough. A new scalpelliform family, Probathylepadidae, is also proposed for the new genus and species. Probathylepadidae differs from all other five families of the order Scalpelliformes by the capitulum bearing eight primal plates and two whorls of imbricating supplementary plates, and the peduncle being without scales. The relationships between the species of the new family and sessile barnacles are also discussed. PMID- 26624399 TI - Shallow and deep-sea chitons of the genus Leptochiton Gray, 1847 (Mollusca: Polyplacophora: Lepidopleurida) from Peruvian and Chilean waters. AB - The Southeast region off Chile and Peru has yielded a very rich diverse fauna of basal chitons of the genus Leptochiton. The present contribution is based on the study of 1055 specimens of chitons. Thirteen leptochitonid species are reported of which seven species are new, namely Leptochiton lascrusesi n. sp., L. linseae n. sp., L. longibranchiae n. sp., L. peruvianus n. sp., L. macleani n. sp., L. sigwartae n. sp., and L. mutschkeae n. sp. Five species were found on the shelf, but only one of those is limited to this zone. The other eight species live in bathyal or abyssal depths. Thus, 12 of 13 species were found deeper than 200 m. The genus Leptochiton originated in the late Palaeozoic in shallow waters. It probably shifted to deep-waters because of competition by more advanced genera of chitons. The leptochitonid fauna of the Peru-Chile Trench turned out to be rich. Five species were studied from this trench system. Two of them-L. longibranchiae n. sp. and L. peruvianus n. sp.-are characterized by an unusually high number of gills and an accordingly wider distribution in the mantle cavity, reaching in an anterior direction to valves V and III. This morphological peculiarity is unusual for Lepidopleurida and resembles the conditions found in the order Chitonida. PMID- 26624400 TI - Diversity of Paranura Axelson, 1902 (Collembola: Neanuridae: Neanurinae) in Pacific Region of Russia and United States. AB - Eight new species of the genus Paranura are described from temperate zone of Holarctic. Five of them: Paranura reticulata sp. nov., Paranura oregonensis sp. nov., Paranura reducta sp. nov., Paranura cassagnaui sp. nov. and Paranura microchaetosa sp. nov. were found in coniferous forests of Oregon state, USA. Three others: Paranura kedrovayensis sp. nov., Paranura setosa sp. nov. and Paranura conjuncta sp. nov. were collected in mixed woods of Russian Far East. All new species are illustrated in detail and compared with existing taxa. P. reticulata sp. nov. is characterised by having three ocular chaetae, relatively short chaeta F on head, four ordinary chaetae De on th. III and three chaetae Di in abd. V (in s-uenoi two chaetae). The presence of only one ordinary chaeta De on abdomen IV is the most characteristic and recognizable character of P. oregonensis sp. nov. P. reducta sp. nov. is most diagnostically recognized by labral chaetotaxy, with only 4 chaetae. The species is true saproxylic form living inside decayed logs of coniferous trees only. P. cassagnaui sp. nov. is easy to distinguish by the presence of complete chaetotaxy of central area of head, presence of microchaetae on furcal remnant and the fusion of tubercles Di on abd. V. P. microchaetosa sp. nov. and P. kedrovayensis sp. nov. are superficially very similar to each other in dorsal chaetotaxy, and differ in number of ordinary chaetae De on abd. IV, trochanter and labium, and in the presence/absence of microchaetae on furcal remnant. P. setosa sp. nov. can be easily identified by one or two additional chaetae on central area of head, a character unknown in other species of the genus. P. conjuncta sp. nov. is characterised by the fusion of tubercles Di on abdomen V, the presence of microchaetae on furcal remnant and developed tubercle on central area of head. In addition, P. mjohjangensis Deharveng & Weiner, 1984 is newly recorded from Russia. An updated key to all world species of Paranura is also provided. PMID- 26624401 TI - The acanthocephalan fauna of Iran, a check list. AB - The acanthocephalan fauna of Iran is reported for the first time since the report of Pomphorhynchus perforator (von Linstow, 1908) Meyer, 1932 in 1964. The knowledge of the acanthocephalan biodiversity of Iran, with parasite-host and host-parasite checklists, is presented. The species of Acanthocephala are presented in alphabetical order, followed by the species of hosts, localities and references. A total of 30 known species of Acanthocephala from 21 genera, 12 families and 7 orders are reported from 80 species of different vertebrates of Iran. One species, Moniliformis moniliformis (Bremser, 1811) Travassos, 1915 was recorded from humans. The group of hosts with the largest number of reported species of acanthocephalan is Actinopterygii (ray-finned fishes). PMID- 26624402 TI - A new genus for a new species of Podoscirtini from southeast Tibet (Orthoptera: Gryllidae; Podoscirtinae; Podoscirtini). PMID- 26624403 TI - First description of the male of Alopecosa azsheganovae Esyunin, 1996 (Araneae: Lycosidae). PMID- 26624404 TI - Description of the last instar larva of Anacroneuria tucuman Stark (Plecoptera: Perlidae) from northern Argentina. AB - The last instar larva of Anacroneuria tucuman Stark is described based on material from the Yungas Forest in Jujuy Province, Argentina. This is the first record of the species for the Province. PMID- 26624405 TI - First record of Aleiodes (Hemigyroneuron) (Hymenoptera: Braconidae: Rogadinae) from the Arabian Peninsula: description of new species with remarkable wing venation convergence to Gyroneuron and Gyroneuronella. AB - A new species of Aleiodes (Hemigyroneuron) from Saudi Arabia is described and illustrated. It represents the first species known from outside of sub-Saharan Africa, Madagascar, South East Asia and the East Palaearctic. It belongs to a species group comprising A. (H.) plurivena, glandularis and sharkeyi, but displays even more derived wing venation which is remarkably convergent with that of two distantly related rogadine genera, Gyroneuron and Gyroneuronella. PMID- 26624406 TI - A new species of Branchinecta (Crustacea: Anostraca) from Uruguay. AB - Branchinecta uruguayensis, a new species of fairy shrimp, is described from a single seasonally astatic aquatic habitat in coastal Uruguay. This is the first record of an anostracan from the nation of Uruguay. Male B. uruguayensis n. sp. are separated from other Branchinecta species by the form of the second antennae. Branchinecta uruguayensis n. sp. share the distal antennomere lobiform projection with B. papillata Rogers, De los Rios, & Zuniga, 2008 and B. achalensis Cesar, 1985. Branchinecta uruguayensis n. sp. females are readily separated from all other Branchinecta by the presence of posteriolateral thoracic spines and lateral crenulations on the first abdomen segment margins. A key is provided to the Branchinectidae of South America. PMID- 26624407 TI - Strongylovelia lillyae sp. nov. (Hemiptera: Gerromorpha: Veliidae) from Tamil Nadu, India: the first species of the genus described from the Indian subcontinent. AB - Strongylovelia lillyae sp. nov. is described from Kanyakumari district, Tamil Nadu, India and constitutes the first species of the genus from Indian subcontinent. The new species is closely related to Strongylovelia setosa Zettel & Tran and S. vasarhelyii Zettel & Tran from Vietnam. A distribution map and photographs of S. lillyae sp. nov. are presented here. PMID- 26624408 TI - A new species of Geodiscelis Michener & Rozen (Hymenoptera: Colletidae: Xeromelissinae) from Peru. AB - A new species of the bee genus Geodiscelis Michener & Rozen, 1999, G. antiminera sp. nov., is here described and illustrated. This is the sixth species of the genus, and the second recorded from Peru. The combination of malar area ~1.5x longer than wide, wing veins dark-brown, metepisternum nearly glabrous, and medioventral process on gonocoxa conical and well-developed, separates G. antiminera sp. nov. from all other Geodiscelis species. An updated identification key for all known species is provided. Phylogenetic analyses show that G. antiminera sp. nov. belongs to the subgenus Nazcoediscelis Packer & Dumesh, 2014 and is sister to the other three species in the subgenus. PMID- 26624409 TI - Revision of the genus Devadatta Kirby, 1890 in Borneo based on molecular and morphological methods, with descriptions of four new species (Odonata: Zygoptera: Devadattidae). AB - Species of Devadatta from Borneo are studied using both morphological and molecular methods. As well as D. podolestoides Laidlaw, four new species are recognised from the island: D. aran spec. nov. (holotype ?, from Pulong Tau National Park, Miri division, Sarawak, Malaysia, deposited in RMNH), D. clavicauda spec. nov. (holotype ?, from Bukit Mina, Bukit Mina Wildlife Corridor, Sarawak Planted Forest Project, Bintulu division, Sarawak, Malaysia, deposited in RMNH), D. somoh spec. nov. (holotype ?, from the Sungai Kahei area, Ulu Balui, Kapit division, Sarawak, Malaysia, deposited in RMNH) and D. tanduk spec. nov. (holotype ?, from Poring Hot Springs, Kinabalu National Park, West Coast division, Sabah, Malaysia, deposited in RMNH). The Philippine taxon D. basilanensis Laidlaw is considered a good species rather than a subspecies of D. podolestoides. The Bornean species plus D. basilanensis are provisionally considered to form a species group, the podolestoides-group, within Devadatta. The species of the podolestoides-group are so similar in morphology and colouration that they are close to truly cryptic species. Two species appear to exhibit character displacement where their ranges overlap with other Devadatta species. A molecular analysis using four markers (COI, 16S, ITS and 28S) is presented. This analysis includes specimens of all species from the podolestoides group and two Devadatta species from mainland Asia. PMID- 26624410 TI - Biology and morphology of immature stages of Lixus canescens (Coleoptera: Curculionidae: Lixinae). AB - Mature larvae and pupae of Lixus (Eulixus) canescens Steven, 1829 (Curculionidae: Lixinae: Lixini) are described and compared with known larvae and pupae of other Lixus species. The biology of the species was studied in Ukraine. A species of Crambe (Brassicaceae) was identified as host plant of both larvae and adults of this weevil. The weevil is very likely oligophagous. Lixus canescens prefers dry, sunny places, such as open areas of sand close to sea shores with growing host plants. Overwintering beetles emerge in the late spring (mid-May), and then feed and mate on the host plants. The highest level of activity of the adults was observed at the end of May. Larvae are endophagous in the host plant stem. At the end of July, the larvae pupate within the stem inside a pupation cell. Adults leave the cells at the end of summer and do not hibernate on the host plants. They then, most likely, spend some time feeding on the host plants and looking for suitable shelter in which to overwinter. PMID- 26624411 TI - Why so scarce? Dictyopharidae from Madagascar (Hemiptera: Fulgoromorpha). AB - A new genus and species of Dictyopharidae from Madagascar-Tupala occulta gen. et sp. nov. is described and illustrated. It is the third known dictyopharid and the second representing tribe Dictyopharini. Two other taxa with taxonomic problems ascribed to Dictyopharidae are discussed. The question of paucity of Dictyopharidae of Madagascar is raised and several possible explanations are presented. PMID- 26624413 TI - The Cephenniini of China. VII. New species and new records of Cephennodes Reitter of Shaanxi, Gansu and Sichuan (Coleoptera: Staphylinidae: Scydmaeninae). AB - Nine new Chinese species of Cephennodes are described: C. (s. str.) intricatus sp. n. (Gansu), C. (s. str.) cryptointricatus sp. n. (Gansu), C. (s. str.) monofoveatus sp. n. (Shaanxi), C. (s. str.) pinnapes sp. n. (Sichuan), C. (s. str.) elegantissimus sp. n. (Sichuan), C. (s. str.) palpalis sp. n. (Gansu), C. (Fusionodes) corpulentus sp. n. (Sichuan), C. (Fusionodes) gutta sp. n. (Shaanxi) and C. (Fusionodes) medusa sp. n. (Sichuan). Cephennodes elegantissimus and C. palpalis are not placed in any species group within Cephennodes, while the remaining new taxa belong to the excavatus group (C. intricatus and C. cryptointricatus), the taurus group (C. monofoveatus), the inflatipes group (C. pinnapes), the graeseri group (C. gutta and C. medusa) and the newly established serratus group (C. corpulentus). Additionally, new records of previously described species are given: C. (s. str.) subcaudatus Jaloszynski (Shaanxi), C. (s. str.) parabdominalis Jaloszynski (Shaanxi) and C. (s. str.) pteroscapus Jaloszynski (Sichuan). PMID- 26624412 TI - Phylogeny of the genus Rhynchocalamus (Reptilia; Colubridae) with a first record from the Sultanate of Oman. AB - The genus Rhynchocalamus comprises three species distributed in Southwest Asia. Little is known about them, most probably because of their secretive fossorial lifestyle. The poor knowledge of the genus is even underscored by the fact that its phylogenetic affinities remained unclear until very recently. The least known of the species, Rhynchocalamus arabicus, is known only from the holotype collected in Aden, Yemen, and it has not been observed since its description in 1933. Here we provide a second record for this species, which represents the first record of this genus for Oman. This extends its range in southern Arabia by more than 1000 km. The observed specimen was determined as R. arabicus on the basis of its similarity in size, color, and scalation with the holotype. Furthermore, we sequenced three mitochondrial (12S, 16S, cytb) and one nuclear (cmos) genes for R. arabicus and for two individuals of R. melanocephalus and one R. satunini and inferred the phylogenetic relationships of all currently recognized species of the genus for the first time. The results of our phylogenetic analyses indicate that Rhynchocalamus is a member of the Western Palearctic clade of Colubrinae and is sister to Lytorhynchus, with which it forms a very well supported clade and shares some morphological characters. As our results show, R. satunini is the basal lineage of the genus and R. melanocephalus is sister to R. arabicus. PMID- 26624414 TI - The Tribe Anisoscelini (Hemiptera: Heteroptera, Coreidae) in Argentina. AB - Eight genera and 21 species of the tribe Anisoscelini (Coreidae, Coreinae) are recorded in Argentina: Anisoscelis foliaceus (Fabricius); Coribergia declivicollis (Berg); Dalmatomammurius vandoesburgi (Brailovsky); Holymenia hystrio (Fabricius); Leptoglossus chilensis (Spinola); L. cinctus (Herrich Schaeffer); L. concolor Walker; L. crassicornis (Dallas); L. dentatus Berg; L. fasciatus (Westwood); L. gonagra (Fabricius); L. impictus (Stal); L. ingens (Mayr); L. neovexillatus Allen; L. quadricollis (Westwood); L. stigma (Herbst); L. vexillatus (Stal); L. zonatus (Dallas); Phthia lunata (Fabricius); Phthiacnemia picta (Drury) and Ugnius kermesinus (Linnaeus). A key to genera belonging to the tribe is provided. L. stigma is recorded for the first time in Argentina with new locality records for La Rioja, Salta and San Juan. PMID- 26624415 TI - New taxa of Cryphocricinae (Heteroptera: Naucoridae) from the Guiana Shield: Hygropetrocoris Sites, n. gen. and two new species of Ambrysus Stal. AB - A new genus and species of Naucoridae are described from two male specimens that inhabited an algae-covered granite rock seep in Guyana. Hygropetrocoris Sites NEW GENUS is diagnosed by a nearly vertical and apparently freely movable head, bulbous eyes, hair lines and hair patches on the hemelytra, profemur with anterior excavation that can receive a prominent tooth on the opposable protibia, and stout marginal tufts of setae on the pronotum, embolium, and connexiva. H. guyana Sites NEW SPECIES is further diagnosed by pseudoparameres that are wide, black, directed posterolaterally, and bluntly produced laterally. Character states of this genus are compared with those of the other genera of Cryphocricinae. Two new species of Ambrysus Stal from the region also are described. Ambrysus brunneus Sites NEW SPECIES is described from a single female specimen and diagnosed by a digitate lobe on laterosternite VI, shape of the subgenital plate, and concolorous dark brown dorsal coloration; Ambrysus shorti Sites NEW SPECIES is described from a single male specimen and diagnosed by its small size, narrow body form, and tentacular setae of the parameres. PMID- 26624416 TI - First record of the plant bug genus Euchilofulvius from Myanmar (Hemiptera: Heteroptera: Miridae: Cylapinae), with description of a new species. PMID- 26624417 TI - A new notoaturine genus from New Zealand (Acari: Hydrachnidia: Aturidae: Notoaturinae). PMID- 26624418 TI - Notes on the systematic placement of Sciacharis (Anthicimimus) (Coleoptera: Staphylinidae: Scydmaeninae). PMID- 26624420 TI - Areas of endemism in the Southwestern Atlantic Ocean based on the distribution of benthic hydroids (Cnidaria: Hydrozoa). AB - Geographic distributions of 130 species of benthic hydroids were used to infer areas of endemism in the Southwestern Atlantic Ocean (SWAO, between 22 degrees S and 55 degrees S). Endemicity Analysis (EA) was carried out with the software NDM VNDM, using a 2 degrees x 2 degrees grid with different values of F (F = 0.5 and F = 1.0) for inferred presence. Hypothesized areas of endemism (16 with F = 0.5 and 13 with F = 1.0) formed three generalized patterns: (1) Tropical, (2) Subtropical, and (3) disjunctions along Tropical and Subtropical areas. Areas of endemism estimated here were compared with provinces, ecoregions and areas of endemism previously defined (but not based on algorithmic analysis) in the literature. Ecological and historical aspects that are potentially relevant for the SWAO realm were contrasted, related and discussed to areas of endemism. This is the first study to apply NDM VNDM to the marine realm and one of the few that focuses on the SWAO. PMID- 26624419 TI - New species of sponges (Porifera, Demospongiae) from the Aleutian Islands and Gulf of Alaska. AB - Ten new species of demosponges, assigned to the orders Poecilosclerida, Axinellida and Dictyoceratida, discovered in the Gulf of Alaska and along the Aleutian Island Archipelago are described and compared to relevant congeners. Poecilosclerida include Cornulum globosum n. sp., Megaciella lobata n. sp., M. triangulata n. sp., Artemisina clavata n. sp., A. flabellata n. sp., Coelosphaera (Histodermion) kigushimkada n. sp., Stelodoryx mucosa n. sp. and S. siphofuscus n. sp. Axinellida is represented by Raspailia (Hymeraphiopsis) fruticosa n. sp. and Dictyoceratida is represented by Dysidea kenkriegeri n. sp. The genus Cornulum is modified to allow for smooth tylotes. We report several noteworthy biogeographical observations. We describe only the third species within the subgenus Histodermion and the first from the Indo-Pacific Region. Additionally, the subgenus Hymerhaphiopsis was previously represented by only a single species from Antarctica. We also report the first record of a dictyoceratid species from Alaska. The new collections further highlight the richness of the sponge fauna from the region, particularly for the Poecilosclerida. PMID- 26624421 TI - New species of Euplocania Enderlein (Psocodea: 'Psocoptera': Psocomorpha: Ptiloneuridae) from Colombia. AB - Seven species of Colombian Euplocania, are here described and illustrated, they increase to 16 the number of species in the genus, eight of which are endemic to Colombia. A new species group is also described. PMID- 26624422 TI - Aguapanela, a new tarantula genus from the Colombian Andes (Araneae, Theraphosidae). AB - A new monotypic genus of Theraphosidae is described from Colombia: Aguapanela Perafan & Cifuentes gen. nov. with only the type species Aguapanela arvi Perafan, Cifuentes & Estrada sp. nov., from Caldas and Medellin, Antioquia, Colombian Andes. The new genus differs from other theraphosid spiders mainly in the presence of stridulatory setae on the palps and legs I and II, together with the presence of type III and IV urticating setae. Males lack a tibial apophysis on leg I and have a simple palpal bulb with the subtegulum less extended than usual in Theraphosinae, elongated curved embolus, ventrally concave, and with two prolateral keels very flat and developed on the dorsal edge. The female spermathecae have two digitiform elongated and granulated seminal receptacles attached to a semicircular wide membranous base. We describe, diagnose and illustrate the new genus and give some biological remarks. Morphological, systematic and biogeographic aspects are discussed. Chromatographic and electrophoretic profiles of its venom are analyzed. PMID- 26624423 TI - Contributions to the study of the Ethiopian Lepidoptera. I. The genus Melittia Hubner, 1819 ["1816"] (Lepidoptera: Sesiidae) with description of a new species. AB - The genus Melittia Hubner, 1819 ["1816"] (Sesiidae) is reviewed for the country of Ethiopia. Melittia ambo sp. nov. is described from vicinities of Ambo, West Shewa zone, Oromia. Adults, including male and female genitalia, and the larval host plant, Citrullus colocynthis (L.) Schrad. (Cucurbitaceae), are illustrated. Additional, Melittia pyropis Hampson, 1919 is recorded for Ethiopia for the first time, and the holotype of M. abyssiniensis Hampson, 1919 is illustrated. PMID- 26624424 TI - New species of plume moths of the genus Agdistis Hubner, 1825 (Lepidoptera: Pterophoridae: Agdistinae) from southern Africa. 7. AB - Four new species of Agdistis (Pterophoridae) are described from Southern Africa: Agdistis sergeii Kovtunovich & Ustjuzhanin sp. nov., Agdistis wolframi Kovtunovich & Ustjuzhanin sp. nov., Agdistis pseudomeyi Kovtunovich & Ustjuzhanin sp. nov. and Agdistis ruhanga Kovtunovich & Ustjuzhanin sp. nov. In addition, descriptions and images of the previously unknown female genitalia of three species are given: A. insolitus Kovtunovich & Ustjuzhanin, 2010, A. meyi Arenberger, 2008 and A. toliarensis Bigot, 1987. The male is described to a species possibly A. piccolo Gielis, 1990, of which only female was previously known. PMID- 26624425 TI - The water mite family Hygrobatidae Koch in Australia. The genera Aspidiobatella Cook, Australorivacarus Viets, Gondwanabates Imamura and Rhynchaustrobates Cook (Acari: Hydrachnidia). AB - The following eight new species are described from Australia: Gondwanabates crassipalpis, G. flavus, G. spatulifer, Rhynchaustrobates bipartitus, R. sclerosus, R. truusae, R. uniscutatus and R. victorianus. Numerous new records are given of the following hygrobatid genera in Australia: Aspidiobatella Cook, 1986, Australoricacarus K.O. Viets, 1978, Gondwanabates Imamura, 1984 and Rhynchaustrobates Cook, 1986. The males of Aspidiobatella smola Cook and Gondwanabates hopkinsi Imamura and the female of Gondwanabates crassipes Cook are described for the first time. PMID- 26624426 TI - Description and phylogeny of a new prostomatid, Metacystis similis nov. spec. (Protista, Ciliophora) from the East China Sea. AB - The living morphology and infraciliature of a new marine prostomatid, Metacystis similis nov. spec., have been observed and investigated. Based on both morphological and molecular biological data, several closely-related and easily confused taxa were compared. The diagnosis for this new taxon: cylindrical marine Metacystis with a slightly blunt anterior end, in vivo 50-70 x 18-23 MUm; body not loricate, uniformly cinctured by 16-18 transverse rings of cilia, which are also arranged in 32-36 longitudinal kineties; oral apparatus consisting of one circumoral dikinety and six girdles of densely packed monokinetids; single spherical macronucleus located in the center of the body; caudal region possessing one transparent, protruding hemicycle terminal vacuole. Information concerning the small-subunit rRNA gene sequence of the new species was also provided. PMID- 26624427 TI - Sialis primitivus sp. nov. (Megaloptera: Sialidae), a remarkable new alderfly species from China. AB - A new species of the alderfly, Sialis primitivus sp. nov. from China is described. Remarkably, the general habitus of the new species resembles the New World genera Protosialis van der Weele, 1909 and Ilyobius Enderlein, 1910 as well as the Madagascan endemic genus Haplosialis Navas, 1927 by having similar wing venation. However, the characteristics of mouthparts and genitalia indicate the new species belongs to Sialis and probably represents the basalmost species among all known extant Sialis species. PMID- 26624428 TI - K.P. DINESH, S.P. VIJAYAKUMAR, B.H. CHANNAKESHAVAMURTHY, VARUN R. TORSEKAR, NIRMAL U. KULKARNI & KARTIK SHANKER (2015) SYSTEMATIC STATUS OF FEJERVARYA (AMPHIBIA, ANURA, DICROGLOSSIDAE) FROM SOUTH AND SE ASIA WITH THE DESCRIPTION OF A NEW SPECIES FROM THE WESTERN GHATS OF PENINSULAR INDIA. Zootaxa, 3999(1): 079 094. PMID- 26624429 TI - Swedish Plectida (Nematoda). Part 10. The genus Deontolaimus de Man, 1880. AB - The genus Deontolaimus de Man, 1880 is revised and the genus Camacolaimus de Man, 1889 is considered a junior synonym of Deontolaimus based on re-examination of type material of Camacolaimus tardus de Man, 1889 and C. barbatus Warwick, 1970. Two known and three new species of Deontolaimus are described from bottom sediments collected in marine habitats of Sweden: Deontolaimus uniformis (Cobb, 1920) comb. n., D. longicauda (de Man, 1922) comb. n., Deontolaimus catalinae sp. n., D. paraguillei sp. n. and Deontolaimus timmi sp. n. Deontolaimus catalinae sp. n. is characterized by body length of 1.3-1.7 mm; anterior-most somatic sensilla located short distance posterior to amphid; cephalic sensilla equal to 0.2 labial region diameter in length; amphidial fovea ventrally-unispiral with one turn, located in front of cephalic sensilla bases; excretory pore located short distance posterior to onchiostyle base; onchiostyle with bluntly rounded tip and subcylindrical body; male with alveolar supplements extending from anterior end to middle of body, tubular supplements absent; spicules 36-40 um long; and didelphic female reproductive system. Deontolaimus paraguillei sp. n. is characterized by body length of 1.4-1.8 mm; anterior-most somatic sensilla located at level with onchiostyle; cephalic sensilla equal to 0.2-0.3 labial region diameter in length; amphidial fovea ventrally-unispiral with one turn, located at level with cephalic sensilla bases; excretory pore located just posterior to nerve ring level; onchiostyle with bluntly rounded tip and subcylindrical body; male with alveolar supplements extending from anterior end to about three body diameters in front of cloaca, tubular supplements absent; spicules 42-46 um long; and didelphic female reproductive system. Deontolaimus timmi sp. n. is characterized by body length of 0.7-0.9 mm; anterior-most somatic sensilla located at level with onchiostyle; cephalic sensilla equal to 0.2-0.3 labial region diameter in length; amphidial fovea ventrally-unispiral with one turn, located just in front of cephalic sensilla bases; excretory pore located just posterior to nerve ring level; onchiostyle with triangular tip with bluntly rounded apex and strongly sclerotized dorsal edge, and subcylindrical body; male with alveolar supplements extending from anterior end to anterior part of intestine, tubular supplements absent; spicules 28 um long; and didelphic female reproductive system. The following nomenclatorial changes are proposed: genera Acontiolaimus Filipjev, 1918, Camacolaimoides De Coninck & Schuurmans Stekhoven, 1933, Camacolaimus de Man, 1889, Digitonchus Cobb, 1920 and Ypsilon Cobb, 1920 are synonimized with the genus Deontolaimus de Man, 1880; Camacolaimus reykjanesi De Coninck, 1943 and Camacolaimus glauxicola Allgen, 1951a are considered junior synonyms of Deontolaimus papillatus de Man, 1880; Camacolaimus barbatus apud Pastor de Ward, 1984 is described as the separate species Deontolaimus catalinae sp. n.; Camacolaimus tardus apud Lorenzen, 1969 is considered to be the separate species Deontolaimus lorenzeni nom. n.; Camacolaimus tardus apud Timm, 1963 is described as the separate species Deontolaimus timmi sp. n.; Camacolaimus barbatus Warwick, 1970 is considered a junior synonym of Deontolaimus tardus (de Man, 1889) comb. n.; Camacolaimus parvus Timm, 1961 is transferred to the genus Deontolaimus as D. parvus (Timm, 1961) comb. n.; Digitonchus cylindricaudatus Chitwood, 1951 is transferred to the genus Deontolaimus as D. cylindricaudatus (Chitwood, 1951) comb. n.; Ypsilon exile Cobb, 1920 is transferred to the genus Deontolaimus as D. exilis (Cobb, 1920) comb. n.; Camacolaimus guillei de Bovee, 1977 is transferred to the genus Deontolaimus as D. guillei (de Bovee, 1977) comb. n.; Camacolaimus longicauda de Man, 1922 is transferred to the genus Deontolaimus as D. longicauda (de Man, 1922) comb. n.; Camacolaimus monhystera Gerlach, 1967 is transferred to the genus Deontolaimus as D. monhystera (Gerlach, 1967) comb. n.; Camacolaimus pontollittoralis Uzunov, 1977 is transferred to the genus Deontolaimus as D. pontollittoralis (Uzunov, 1977) comb. n.; Camacolaimus praedator de Man, 1922 is transferred to the genus Deontolaimus as D. praedator (de Man, 1922) comb. n.; Camacolaimus prytherchi Chitwood, 1935 is transferred to the genus Deontolaimus as D. prytherchi (Chitwood, 1935) comb. n.; Camacolaimus tardus de Man, 1889 is transferred to the genus Deontolaimus as D. tardus (de Man, 1889) comb. n.; Camacolaimus trituberculatus Blome, 1982 is transferred to the genus Deontolaimus as D. trituberculatus (Blome, 1982) comb. n.; and Digitonchus uniformis Cobb, 1920 is transferred to the genus Deontolaimus as D. uniformis (Cobb, 1920) comb. n. A taxonomic review and identification key for species of the genus Deontolaimus are also given. PMID- 26624430 TI - Zulma Ageitos de Castellanos: Publications and status of described taxa. AB - Zulma Ageitos de Castellanos was an Argentinian malacologist working in the "Facultad de Ciencias Naturales y Museo" at La Plata University where she taught invertebrate zoology between 1947 and 1990. Her scientific publications are listed in chronological order. Described genus-group and species-group taxa are listed. Information about the type locality and type material, and taxonomic remarks are also provided. Finally, type material of all described taxa was requested and, when located, illustrated. PMID- 26624431 TI - A taxonomic review of the genus Goffartia Hirschmann, 1952 (Rhabditida: Diplogastridae) with a note on the relationship of congeners. AB - This paper deals with the descriptions and diagnoses of the species of the relatively rare and poorly-understood genus Goffartia Hirschmann, 1952. A comparative account of the salient morphological characters including stoma, amphids, pharynx, and the male accessory sex organs of the six species viz., G. africana (Micoletzky, 1915) Hirschmann, 1952; G. filicaudata (Andrassy, 1968) Sudhaus & Furst von Lieven, 2003; G. heteroceri Hirschmann, 1952; G. praepilata Shoshin, 1989 and G. variabilis (Micoletzky, 1922) Hirschmann, 1952 and the recently described G. phalacra Singh, Yousuf, Kumar & Ahmad, 2014, has been given. This paper also discusses the variations among and the relationships between these congeners, and provides an identification key. PMID- 26624432 TI - Keys to genera of the spider wasps (Hymenoptera: Pompilidae) of Russia and neighbouring countries, with check-list of genera. AB - Keys to 55 genera of spider wasps of Russia and neighbouring countries in females and males are given. Of them 34 genera are distributed in Russia. An annotated list of genera with type species and distribution data within Russia and biogeographical regions is given. The genus Xenaporus Ashmead, 1902 and X. eremocanus Wolf, 1990 are newly recorded from Russia. According to ICZN 1995 (Opinion 1820) new synonymy (valid name first) is proposed for the type species of genus Cryptocheilus Panzer, 1806: Sphex annulata Fabricius, 1798 (=Pompilus alternatus Lepeletier de Saint Fargeau, 1845, syn. nov.; =Pompilus comparatus Smith, 1855, syn. nov.; =Priocnemis culpabilis Costa, 1893, syn. nov.; Salius annulatilis Richards, 1935, syn. nov.). PMID- 26624433 TI - Undetected for a century: Palaearctic Agrilus ribesi Schaefer (Coleoptera: Buprestidae) on currant in North America, with adult morphology, larval biology and DNA barcode. AB - We report the Eurasian species Agrilus ribesi Schaefer, 1946, for the first time from North America and propose that the damage to currants (Ribes spp.) in Ontario prior to 1940 and ascribed to A. cuprescens were caused by this species. We provide morphological diagnostic characters for A. ribesi and closely related A. cuprescens and we complement this information with DNA barcodes from four alien Agrilus species established in North America (i.e., A. ribesi Schaefer, A. cuprescens (Menetries), A. planipennis Fairmaire and A. sulcicollis Lacordaire) to enable DNA-based identification of these invasive species. Additionally, published information on A. ribesi is summarized and new data are provided on the host plants and biology of larva in North America. The distribution of A. ribesi is mapped, both in its native Palaearctic region and in Canada and the USA, together with the range of its potential host plants in North America. A. ribesi was recovered as a sister-species of A. cuprescens on the neighbor joining DNA barcoding tree and low genetic variability of North American populations may indicate a single introduction to North America for each of these species. PMID- 26624434 TI - Six new species of Microdon Meigen from Madagascar (Diptera: Syrphidae). AB - Six new species of the myrmecophilous hoverfly genus Microdon Meigen (Diptera: Syrphidae) are described from Madagascar. Redescriptions are given for the three other Madagascan species of this genus. Keys are presented to the Madagascan genera of the subfamily Microdontinae and to the Madagascan species of Microdon. PMID- 26624435 TI - Revalidation of genus Chrysellampus Semenov, 1932, with description of two new species from China (Hymenoptera, Chrysididae). AB - The genus Chrysellampus Semenov, 1932 is revalidated. Chinese species are revised and keyed for the first time. Five species are recorded, two of them are new for science: Chrysellampus obtusidentibus Rosa, Wei & Xu, sp. nov. (Yunnan), and C. proximocellis Rosa, Wei & Xu, sp. nov. (Gansu and Yunnan). New synonymy for Chrysellampus Semenov, 1932 (=Parellampus Semenov, 1932, syn. nov.) and new combination for C. praeteritorum (Semenov, 1932), comb. nov. are proposed. PMID- 26624436 TI - Two new species of Timea from the Southwest Atlantic (Timeidae, Demospongiae, Porifera). AB - Comprising 56 species, Timea Gray, 1867 belongs to the monotypic family Timeidae Gray, 1867, with both family and genus characterized by the presence of (sub)tylostyles as megascleres, and euasters as microscleres. Two new species are described from the coast of Rio de Janeiro state, Timea berlincki sp. nov. and Timea clandestina sp. nov., the first of which also from Sao Paulo state (southeastern Brazil). Both are compared to other species based on their morphological and skeletal characters. Records of all species of the genus worldwide are tabulated and discussed, and an identification key for Tropical western Atlantic species of Timea is offered. PMID- 26624437 TI - Two new species of Hexactinellida (Porifera) from the South China Sea. AB - In this paper, two new sponge species, Semperella jiaolongae sp. nov. (Amphidiscosida, Pheronematidae) and Saccocalyx microhexactin sp. nov. (Lyssacinosida, Euplectellidae) are described based on materials from the South China Sea. Semperella jiaolongae sp. nov. is diagnosed mainly by the dermal areas present on both sides of the body, occurring together with atrial areas randomly distributed on one side, and the distinctive shape of micropentactins. Saccocalyx microhexactin sp. nov. is characterized by possession of two types of drepanocomes and one of microhexactins. An analysis based on partial sequence of the 16S rRNA gene was undertaken to show the congruence between morphological identification and phylogenetic classification of the two new species. PMID- 26624438 TI - A new species of Isospora Schneider, 1881 (Apicomplexa: Eimeiriidae) from the grey-hooded attila Attila rufus Vieillot, 1819 (Passeriformes: Tyrannidae) on the Marambaia island, Brazil. AB - The New World tyrant-flycatcher (Tyrannidae) Attila rufus (Vieillot, 1819) is commonly known as grey-hooded attila or 'capitao-de-saira' in Brazil (Sick 1997; CBRO 2014). This species has a wide distribution and their population trends appear to be stable; therefore, it is least concern according to IUCN (2015) criteria. PMID- 26624439 TI - Two new high-altitude subspecies of Tapinopterus (Tapinopterus) cognatus (Dejean, 1831) (Coleoptera: Carabidae: Pterostichinae) from Serbia. AB - The genus Tapinopterus Schaum, 1858 currently comprises around 60 species belonging to eight subgenera, inhabiting mostly the Balkan Peninsula and Asia Minor (Schatzmayr 1942, 1943; Bousquet 2003; Curcic et al. 2008; Arndt et al. 2011; Lohaj et al. 2012). The taxa live in limited geographic areas and are mostly montane (Trautner & Geigenmuller 1987; Gueorguiev & Gueorguiev 1998). The territory of Serbia is inhabited by two species of Tapinopterus, T. (T.) cognatus (Dejean, 1831) (recorded in Bulgaria and Romania as well) and T. (T.) miridita (Apfelbeck, 1904) (recorded in Albania and the Republic of Macedonia as well), as well as by the three subspecies, T. (T.) cognatus cognatus (Dejean, 1831) (known from Mt. Suva Planina in Serbia and from Bulgaria), T. (T.) cognatus winkleri Mandl, 1936 (known from the Svrljiske Planine Mts. and Mt. Stara Planina in both Serbia and Bulgaria), and T. (T.) miridita miridita (Apfelbeck, 1904) (known from Mt. Sar Planina in both Serbia and the Republic of Macedonia), respectively (Mandl 1936; Schatzmayr 1942, 1943; Gueorguiev & Gueorguiev 1995; Drovenik & Peks 1999; Bousquet 2003; Curcic et al. 2007; Gueorguiev & Giachino 2008). In our opinion, T. (T.) cognatus cognatus does not live in Bulgaria (as was previously reported) (Bousquet 2003), while the older Schatzmayr's (1943) record "Klisura" should refer to the Iron Gate Gorge in SW Romania and NE Serbia, not to any Bulgarian place. The other mentioned locality, i.e., Mt. Suva Planina in Serbia, is situated far from the type locality (Iron Gate). Since nearly all Tapinopterus taxa are regional or local endemics, this southernmost record in SE Serbia for T. cognatus cognatus seems unlikely. In view of the high diversity of Tapinopterus on the Balkan Peninsula, it is expected that new taxa exist in border areas of the distribution in Serbia. During the last years, the first (SC), second (NI) and fourth author (DA) of the paper investigated a number of epigean montane habitats in SE and C Serbia in order to confirm such an assumption, by collecting a series of ground beetles at high altitude sites. After careful examination of the samples, we identified two Tapinopterus subspecies new to science. PMID- 26624440 TI - The opisthobranch gastropods (Mollusca: Heterobranchia) from Venezuela: an annotated and illustrated inventory of species. AB - The Caribbean waters of Venezuela are composed by a large variety of habitats, with over 2800 km of coastline, islands, and islets. This area is a transitional zone between two main biogeographic provinces, the Caribbean and the Brazilian, separated by the fresh water outflows of the Orinoco and Amazon rivers, and is therefore expected to be an area of high species diversity. However, concerning the study of molluscs, Venezuela is probably the poorest known region in the Caribbean. The best compilation of opisthobranch species known in Venezuela was produced almost a decade ago, mentioning the occurrence of 57 species, plus seven determined only to genus level. In this work, 134 species are reported for Venezuela (71 are illustrated), representing about 40 % of the entire diversity of opisthobranchs known in the Caribbean. Among the species occurring in Venezuela, 49 have here the southern limit of their distribution range and only one the northern limit. Forty-six species are recorded for the first time to the country and one is a new record for the Caribbean Sea, namely Placida cremoniana. In addition, the distribution and ecology of the species are given based in literature and new data. PMID- 26624441 TI - DNA barcoding and male genital morphology reveal five new cryptic species in the West Palearctic bee Seladonia smaragdula (Vachal, 1895) (Hymenoptera: Apoidea: Halictidae). AB - Several forms or variants have long been recognized in the West Palearctic sweat bee Seladonia smaragdula (Vachal, 1895). Using DNA barcoding and morphological characters, primarily of the male genitalia, these variants are here recognized and described as five new species: S. gemmella Pauly sp. nov., S. submediterranea Pauly sp. nov., S. orientana Pauly & Devalez sp. nov., S. phryganica Pauly & Devalez sp. nov., and S. cretella Pauly & Devalez sp. nov. Also, we designate a lectotype for Halictus smaragdulus Vachal, consider Seladonia butea (Warncke, 1975) and S. morinella (Warncke, 1975) as nomina dubia, and discuss the identity of the Seladonia specimens from Australia currently determined as S. smaragdula. PMID- 26624442 TI - A taxonomic review, new species and a key to species of Platycoelus Blanchard, 1843 (Coleoptera: Carabidae: Pterostichini). AB - Based on the study of type material for species of Platycoelus Blanchard, 1843 significant changes to the current taxonomy of species included in this genus is required. Psegmatopterus politissimus (White 1846) from New Zealand is found to be congeneric with Platycoelus species and so is a new combination. Platycoelus irideomicans (Tschitscherine 1890) status novum; P. caledonicus (Tschitscherine 1901) status novum; P. sulcatulus (MacLeay 1888) status novum; and P. planipennis (MacLeay 1871) status novum; each previously considered synonyms of P. poeciloides are each recognized as a distinct species. Five new species are described, four from Queensland, Australia: P. chongheeae sp. nov., type locality Iron Range National Park; P. orion sp. nov., type locality Normanton; P. brigalowphilus sp. nov., type locality Southwood National Park; and P. politus sp. nov., type locality Cooloola National Park. The fifth species described is P. hermes sp. nov., type locality Aitape, Papua New Guinea. These changes and additions bring the total number of species in the genus to 19. A key and habitus images for all species is provided as are illustrations of the male genitalia for species where male specimens were available. PMID- 26624443 TI - A new species of Leposternon Wagler, 1824 (Squamata, Amphisbaenia) from northeastern Argentina. AB - A new species of Leposternon is described from the Humid Chaco biome in Argentina. The species is known only from its type locality, at El Bagual Ecological Reserve, a conservation unit located in the province of Formosa. The new species can be distinguished from all its congeners by the presence of rostral processes in the maxillae and nasals that contact each other on the facial portion of the skull. Additionally, we present a key for the species of Leposternon. PMID- 26624444 TI - Fungus-feeding Thysanoptera: Phlaeothripinae of the Idiothrips genus-group in Australia, with nine new species. AB - In a group of fungus-feeding Phlaeothripinae characterized by complex body sculpture, identification keys are provided to three genera and 15 species from Australia, including nine new species. In the genus Azaleothrips one new species is described, and one Asian species is newly recorded from Australia. The genus Stictothrips is recorded from Australia for the first time, with two new species. Within the genus Strepterothrips considerable structural diversity is recorded including three new species in which antennal segment III is greatly reduced and bears no sense cones. Some species in this genus exhibit the unusual condition of having several setae on the pelta, the first abdominal tergite. Problems in the production of generic diagnoses within the Phlaeothripinae are discussed. PMID- 26624446 TI - A new species of freshwater sponge, Heteromeyenia barlettai sp. nov. from an aquarium in Sao Paulo, Brazil (Spongillida: Spongillidae). AB - A new species of freshwater sponge, Heteromeyenia barlettai sp. nov., is proposed here based on specimens discovered in a private aquarium in Sao Paulo, Brazil, and most likely inadvertently collected from the Parana Basin. The present study also presents a redescription of H. insignis on the basis of the specimen reported upon by Volkmer (1963), collected from the Atlantico Sul Hydrographic Basin. Spicule measurements (n=30) were made for comparison with other Heteromeyenia species. This is the first time that H. insignis has its complete set of spicules studied under SEM. After comparison with the redescription of the type of H. baileyi, we also find characteristics that justify the maintenance of H. insignis as a valid species. A key to species of Heteromeyenia is provided. PMID- 26624445 TI - Trypanosoma naviformis sp. nov. (Kinetoplastidae: Trypanosomatidae) from widespread African songbirds, the Olive sunbird (Cyanomitra olivacea) and Yellow whiskered greenbul (Andropadus latirostris). AB - Trypanosoma naviformis n. sp. is described from the African olive sunbird Cyanomitra olivacea in Ghana based on the morphology of its hematozoic trypomastigotes and partial sequences of the small subunit ribosomal RNA gene. This parasite belongs to the group of small non-striated avian trypanosomes (< 30 um in length in average) with the kinetoplast situated close to the posterior end of the body. Trypanosoma naviformis can be distinguished from other small avian trypanosomes due to its poorly visible flagellum, central position of its nucleus, and the symmetrically (in relation to the nucleus) narrowing of both ends of the hematozoic trypomastigotes, which are boat-like in shape. Illustrations of trypomastigotes of the new species are given, and SSU rDNA lineages associated with this parasite are documented. This parasite has been reported in Ghana and Cameroon and was also found in the yellow-whiskered greenbul, Andropadus latirostris in these countries. It appears to be widespread in its range given the distribution of these bird species in Africa. PMID- 26624447 TI - Desmacella Schmidt, 1870 from Brazil: Description of two new species and a review of records (Desmacellida: Demospongiae: Porifera). AB - Three species of Desmacella Schmidt, 1870 are described from the Brazilian coast: Desmacella microsigmata sp. nov., Desmacella tylovariabilis sp. nov. and Desmacella annexa Schmidt, 1870. The new species were compared with Desmacella species from the Atlantic Ocean, which differ by the size of their spicules and by the presence of microspined sigmas. Desmacella annexa was found to have microspined toxiform microxeas and sigmas. Desmacella now contains 31 species distributed worldwide. PMID- 26624448 TI - Description of three new species related to Themus (Haplothemus) coriaceipennis (Fairmaire, 1889) (Coleoptera: Cantharidae). AB - The male of Themus (Haplothemus) coriaceipennis (Fairmaire, 1889) is discovered and described for the first time. Three new species related to this species are described from China: T. (H.) rectus sp. nov., T. (H.) bimaculaticollis sp. nov. and T. (H.) licentimimus sp. nov., which are provided with the illustrations of habitus and genitalia of both sexes and abdominal sternites VIII of female. A key to the species related to T. (H.) coriaceipennis is also provided. PMID- 26624449 TI - Description of a new species of Ameroseius Berlese (Acari: Ameroseiidae) from Norway, with a key to related species. AB - Ameroseius is the largest genus of the mite family Ameroseiidae (Mesostigmata), with a worldwide distribution. Ameroseius norvegicus Narita, Abduch & Moraes n. sp. is described based on the morphology of adult females collected from litter in a strawberry field, in Norway. The new species is most similar to Ameroseius ulmi Hirschmann. A key is provided to separate them as well as other similar species constituting what is here referred to as the sculptilis group. PMID- 26624450 TI - Chekhovichia, a new generic replacement name for Rotalites Leleshus 1970 (Anthozoa: Heliolitoidea) non Lamarck 1801 (Protista: Foraminifera). AB - The genus Rotalites was established by Leleshus (1970: 97) for fossil Upper Silurian heliolitoids (Anthozoa) from Southern Tien Shan. However, the name is preoccupied by Rotalites Lamarck (1801: 401) of Foraminifera (Protista) (cf. Loeblich & Tappan, 1987). In accordance with the International Code of Zoological Nomenclature, Chekhovichia nom. nov. is proposed here as a replacement name for Rotalites Leleshus non Lamarck. PMID- 26624451 TI - The feather mites of the hoatzin Opisthocomus hoazin (Muller) (Aves: Opisthocomiformes), with the description of two new genera and six new species (Acari: Analgoidea, Pterolichoidea). AB - Six new species and two new genera of feather mites are described from the hoatzin Opisthocomus hoazin (Muller) (Opisthocomiformes: Opisthocomidae) in Brazil: Gymnolichus lacrimosus sp. n., G. latihumeralis sp. n. (Xolalgidae), Temnalges hoazin sp. n., T. atelodiscus sp. n. (Psoroptoididae), Ciganalichus boasfilhoi gen. n., sp. n., and Hoazinacarus anisosetus gen. n., sp. n. (Pterolichidae). Illustrations of two previously known species, Opisthocomacarus umbellifer (Trouessart, 1899) and Stakyonemus hystrix (Trouessart, 1899) are provided. We show that the hoatzin bears a much richer feather mite fauna than previously thought and presently includes eight mite species from three families: Xolalgidae, Psoroptoididae (Analgoidea) and Pterolichidae (Pterolichoidea). They represent two morpho-ecological groups: (1) mites inhabiting the wing and tail feathers, and (2) mites living in downy and body contour feathers. We hypothesize that these mites represent a native feather mite fauna of the hoatzin, inherited from its ancestors and existing on this bird for a long time. The controversial and unresolved relationships of this bird with other bird taxa are briefly discussed in the light of the new acarofauna discovered. PMID- 26624452 TI - Revision of Ascra with proposition of the bifida species group and description of two new species (Hemiptera: Pentatomidae: Edessinae). AB - Edessa is comprised of six subgenera, Aceratodes, Ascra, Dorypleura, Edessa, Hypoxys and Pygoda. Ascra is here elevated to genus status based on characteristics of the male and female genitalia and the gibbous pronotum. This genus is comprised of eight species previously placed in Edessa-E. bifida, E. cordifera, E. petersii, E. abdita, E. championi, E. privata, E. conspersa and E. morbosa, as well as six new species. The genus Ascra was further divided into two groups of species bifida and privata separated by a different pattern of punctuation on body and pygophore. Here we present only the bifida species group formed by A. bifida, A. cordifera, A. petersii, A. abdita, and A. championi, as well as two new species-A. vluteum and A. flavoscutellata. Lectotypes of Aceratodes sigillatus, Edessa abdita, E. championi, E. cornuta, E. densata and E. petersii are designated. Aceratodes sigillatus, Edessa cornuta, E. densata, E. picata, and E. florida are considered junior synonyms of A. bifida. Interestingly, some species of this genus are considered edible in Mexico. PMID- 26624453 TI - Uca (Petruca), a new subgenus for the rock fiddler crab Uca panamensis (Stimpson, 1859) from Central America, with comments on some species of the American broad fronted subgenera. AB - Among the fiddler crabs from the Americas, Uca panamensis (Stimpson, 1859) (Crustacea: Decapoda: Ocypodidae) is unusual in its behavior and ecology, living in stony habitats rather than sandy or muddy substrates. This species also has several unusual morphological characters of the carapace and major and minor chelae, and had been placed in either the subgenera Minuca Bott, 1954, or Leptuca Bott, 1973. The armature at the inner corner of the orbital floor, as well as the morphology of the urocardiac ossicles of the gastric mill of U. panamensis, are, however, plesiomorphic characters, and are closer to the condition in species belonging the subgenera Uca and Afruca. Phylogenetic relationships, based on mitochondrial 16S rDNA and cytochrome oxidase subunit I, and nuclear 28S rDNA, supported by its unusual morphological features indicate that this species belongs to its own subgenus. A new subgenus Uca (Petruca) subgen. nov. is herein established for U. panamensis. In addition, the status of Uca thayeri Rathbun, 1900, U. umbratila Crane, 1941, U. virens Salmon & Atsaides, 1968, and U. longisignalis Salmon & Atsaides, 1968, are revised and discussed based on a reappraisal of their phylogenetic relationships. PMID- 26624454 TI - Genetic differentiation in the Mexican endemic Rufous-backed Robin, Turdus rufopalliatus (Passeriformes: Turdidae). AB - The Rufous-backed Robin (Turdus rufopalliatus) is endemic to deciduous and semideciduous tropical forests of western Mexico. Of the currently recognized subspecies, T. r. graysoni, from the Tres Marias Islands and nearby coastal Nayarit, has been considered a separate species; however, this treatment has been challenged due to an apparent contact zone on the mainland, although no hybrids have ever been recorded. Here, we use mitochondrial DNA sequences from individuals sampled across the species' range to assess their phylogeographic relationships. We found reciprocal monophyly between Tres Marias Islands and mainland populations, which share no haplotypes between them. Evolutionary divergence detected within T. rufopalliatus suggests that mainland and island populations have been isolated from each other, and divergence decreases if insular populations are excluded. Demographic parameters suggest that populations are in the process of a rapid expansion from ancestral populations with a lower population size. These results are consistent with morphometric and plumage differences that have been used to recognize the Tres Marias Islands populations from the mainland ones, thus suggesting species status of the island form. PMID- 26624455 TI - Two new species of Homidia (Collembola, Entomobryidae) and a key to species in the genus from Zhejiang Province, China. AB - Two new species of Homidia are described from Yandang Mountain, China: H. yandangensis sp. nov. and H. quadrimaculata sp. nov. The new species are diagnosed by their unique colour patterns, the number of macrochaetae on areas A8 10 of abdominal segment IV, the relative position of specialised microchaetae/specialised ordinary chaetae on abdominal segment I and specialised ordinary chaetae/macrochaeta m3 on abdominal segment V. Specimens from two localities of H. yandangensis sp. nov. differ in the macrochaeta a5 on area A9 of abdominal segment IV. Descriptions of the subadult dorsal thoracic and abdominal chaetotaxy of H. yandangensis sp. nov. and a key to species of Homidia from Zhejiang Province are provided here. PMID- 26624456 TI - A new species of bright-eyed treefrog (Mantellidae) from Madagascar, with comments on call evolution and patterns of syntopy in the Boophis ankaratra complex. AB - We describe a new species of Boophis treefrog from Ranomafana National Park in the southern central east of Madagascar. This region has remarkably high anuran diversity, and along with neighbouring sites, hosts more than 35 Boophis species. Boophis boppa sp. nov. is part of the B. ankaratra sub-clade (herein named the B. ankaratra complex), previously identified within the monophyletic B. albipunctatus species group. It occurs sympatrically with two other species of the complex (B. ankaratra and B. schuboeae). Morphological differentiation of species within the B. ankaratra clade remains elusive, but species are well characterized by distinct advertisement calls, with B. boppa having the longest note duration and inter-note intervals when compared to closely related species. Furthermore, it has moderate differentiation in mitochondrial DNA, with pairwise distances of 1.9-3.7% to all other species in sequences of the mitochondrial 16S rRNA marker. Additional evidence is given by the lack of haplotype sharing with related species for the nuclear exon DNAH-3. All examples of syntopic occurrence in this complex involve species with strongly different advertisement calls, while allopatric species have more similar calls. Such a pattern might result from adaptive call co-evolution but could also be the result of non-adaptive processes. Thorough clarification of the systematics of the B. ankaratra sub clade is required, and we outline future directions for both bioacoustic and genetic research. PMID- 26624457 TI - A new species of Pareiorhaphis (Siluriformes: Loricariidae) from the headwaters of the Arroio Garapia, coastal drainage of Rio Grande do Sul state, Brazil. AB - Pareiorhaphis garapia, new species, is described based on specimens collected in the headwaters of the Arroio Garapia, Rio Maquine basin, a coastal drainage of Rio Grande do Sul State, southern Brazil. The new species is distinguished from all other Pareiorhaphis species in having the nuchal plate covered by thick skin, the exposed posterior process of the cleithrum comparatively narrow, and the last segment of the preopercular ramus of the latero-sensory canal reduced to an ossified tubule. The absence of a dorsal-fin spinelet, the reduced number of plates in the dorsal and mid-dorsal series of lateral plates, and morphometric traits also distinguish the new species from its congeners. The restricted geographic distribution of P. garapia, endemic to a headwater stream of the Rio Maquine basin, and the syntopic occurrence of P. nudulus are discussed. PMID- 26624458 TI - Taxonomic notes on the crab spider genus Tobias Simon, 1895 (Araneae, Thomisidae, Stephanopinae). AB - The males of Tobias caudatus Mello-Leitao, 1929 and Tobias pustulosus Simon, 1929 are described for the first time, females are redescribed and both sexes are illustrated. New distribution records are presented for both species. Tobias monstruosus Mello-Leitao, 1929 is considered a junior synonym of T. pustulosus. The types of Tobias albovittatus Caporiacco, 1954, and Tobias gradiens Mello Leitao, 1929 are lost, and Tobias albicans Mello-Leitao, 1929 and Tobias corticatus Mello-Leitao, 1917 are known only from poorly preserved specimens, thus they all are considered nomina dubia. PMID- 26624459 TI - List of unavailable infrasubspecific names originally published in Oberea Dejean, 1835, with nomenclatural notes on the genus (Coleoptera: Cerambycidae). AB - A list of 153 infrasubspecific and therefore unavailable names originally introduced in Oberea Dejean, 1935, is given. All were so far considered by previous authors to have been made available by Breuning in his 1960's global key of the genus. Two of them (Oberea maculithorax v. pulla Matsushita, 1933 and Oberea suturalis v. flaveola Breuning 1960) refer to taxa in Obereopsis Chevrolat, 1855; and Leuconitocris Breuning, 1950, respectively. PMID- 26624460 TI - Second highly modified hypogean species of the genus Morimotoidius Habu from western Jiangxi Province, China, with a new locality for M. zhushandong (Coleoptera: Carabidae: Platynini). AB - Morimotoidius cavicola sp. n. is described and illustrated from a limestone cave called Guanfeng Dong in Yichun City of western Jiangxi Province, China. It is the second hypogean and highly morphologically modified species of the genus Morimotoidius recorded in China. M. cavicola sp. n. is easily recognized by its shorter pronotum which is less expanded medially than that in M. zhushandong Pang & Tian, 2014. M. zhushandong is also recorded from the cave Zhuangxi Dong. A distribution map, together with a modified key to Chinese species of the genus are also provided. PMID- 26624461 TI - A new species and two new combinations in the genus Strotihypera Kononenko & Han, 2011 (Lepidoptera, Noctuidae, Noctuinae: Elaphriini). A postscript to the description of the genus Strotihypera. AB - Elaphriini is a small tribe of the subfamily Noctuinae with predominantly New World distribution. Only three genera, Elaphria Hubner, 1818 with four species, Galgula Guenee, 1852 with one species (Fibiger & Hacker 2010) and Strotihypera Kononenko & Han, 2011 with one species are known from the Eurasia. The majority of species occurs in tropical and subtropical regions. The review of Eurasian Elaphriini with description of the new genus Strotihypera has recently been published by Kononenko & Han (2011). In the subsequent years in the result of intensive collecting in South West China we found a new species allied to Strotihypera flavipuncta (Leech, 1889) and two related species Strotihypera ochreipuncta (Wileman, 1914), comb. n. and "Hyperstrotia" macroplaga (Hampson, 1907), comb. n. The description of a new species and the review of two of its allies are presented here as a postscript to the description of the genus Strotihypera (Kononenko & Han 2011). PMID- 26624462 TI - Revision of the New World Species of the Millipede-Parasitic Genus Myriophora Brown (Diptera: Phoridae). AB - The New World species of the millipede-parasitic genus Myriophora Brown are revised. Sixty-five species based on the female sex are treated, mostly from the Neotropical Region. Of these, fifty-seven are new to science: Myriophora alexandrae sp. nov., Myriophora alienipennis sp. nov., Myriophora angustifascia sp. nov., Myriophora annetteae sp. nov., Myriophora annulata sp. nov., Myriophora bicuspidis sp. nov., Myriophora bilsae sp. nov., Myriophora bimaculata sp. nov., Myriophora borealis sp. nov., Myriophora brevitarsus sp. nov., Myriophora browni sp. nov. Hash, Myriophora brunneipleuron sp. nov., Myriophora communis sp. nov., Myriophora curvata sp. nov., Myriophora curvicacumen sp. nov., Myriophora dennisoni sp. nov., Myriophora discalis sp. nov., Myriophora diversa sp. nov., Myriophora dividida sp. nov., Myriophora dolionatis sp. nov., Myriophora flavicosta sp. nov., Myriophora fuscidorsum sp. nov., Myriophora gigantea sp. nov., Myriophora gobaleti sp. nov., Myriophora harwoodi sp. nov., Myriophora hebes sp. nov., Myriophora heratyi sp. nov., Myriophora inaequalisetarum sp. nov., Myriophora infirmata sp. nov., Myriophora jeffersoni sp. nov., Myriophora kerri sp. nov., Myriophora kungae sp. nov., Myriophora longisetarum sp. nov., Myriophora luteitergum sp. nov., Myriophora magnilabellum sp. nov., Myriophora misionesensis sp. nov., Myriophora nigra sp. nov., Myriophora nigralinea sp. nov., Myriophora obscuritergum sp. nov., Myriophora pallida sp. nov., Myriophora parva sp. nov., Myriophora pectinata sp. nov., Myriophora perpendicularis sp. nov., Myriophora plana sp. nov., Myriophora porrasae sp. nov., Myriophora porrecta sp. nov., Myriophora reminatis sp. nov., Myriophora scopulata sp. nov., Myriophora simplex sp. nov., Myriophora sinesplendida sp. nov., Myriophora smithi sp. nov., Myriophora spicaphora sp. nov., Myriophora spicaticonus sp. nov., Myriophora tenuis sp. nov., Myriophora uruguaiensis sp. nov., Myriophora vancouverensis sp. nov., Myriophora wellsorum sp. nov. The first key to the species of Myriophora is provided. PMID- 26624463 TI - Freyinae, a major new subfamily of Neotropical jumping spiders (Araneae: Salticidae). AB - Freyinae, new subfamily, is described for a group of genera of Neotropical jumping spiders that can be distinguished from other non-ant mimic salticoid Neotropical salticids by having the following three morphological features: a slightly more elongate carapace, a distinctive prolateral tibial macrosetae arrangement (medially placed subdistal and subproximal macrosetae, with a subdorsal medial macroseta in some males), and an unusual dorsoventrally thick tegulum basal division (although one or two of these features are sometimes lost). It includes 20 genera previously considered valid, of which 19 are retained: Akela Peckham & Peckham, 1896, Aphirape C.L. Koch, 1850, Asaracus C.L. Koch, 1846, Capidava Simon, 1902, Chira Peckham & Peckham, 1896, Edilemma Ruiz & Brescovit, 2006, Eustiromastix Simon, 1902, Freya C.L. Koch, 1850, Frigga C.L. Koch, 1850, Kalcerrytus Galiano, 2000, Nycerella Galiano, 1982, Onofre Ruiz & Brescovit, 2007, Pachomius Peckham & Peckham, 1896, Phiale C.L. Koch, 1846, Rishaschia Makhan, 2006, Sumampattus Galiano, 1983, Trydarssus Galiano, 1995, Tullgrenella Mello-Leitao, 1941, and Wedoquella Galiano, 1984. Romitia Caporiacco, 1947 (and its synonym Uspachus Galiano, 1995) is synonymized with Pachomius, new synonymy. New genera described in the subfamily are: Drizztius, Leptofreya, Megafreya, Philira, Tarkas, Triggella, and Xanthofreya. The following nomenclatorial changes are made: New synonyms: Freya demarcata Chamberlin & Ivie, 1936 = Freya (sub Cyrene) albosignata (F.O.P.-Cambridge, 1901); Freya (sub Cyrene) grisea (F.O.P.-Cambridge, 1901) = Freya (sub Cyrene) infuscata (F.O.P. Cambridge, 1901); Freya (sub Cyrene) emarginata (F.O.P.-Cambridge, 1901) and Nycerella (sub Heraclea) sanguinea paradoxa (Peckham & Peckham, 1896) = Nycerella (sub Heraclea) sanguinea (Peckham & Peckham, 1896); Pachomius (sub Phiale) maculosus (Chickering, 1946) = Phiale (sub Cyrene) bilobata (F.O.P.-Cambridge, 1901); Phiale (sub Cyrene) mediocava (F.O.P.-Cambridge, 1901) = Freya (sub Cyrene) maculatipes (F.O.P.-Cambridge, 1901); Phiale (sub Cyrene) simplicicava (F.O.P.-Cambridge, 1901) = Freya (sub Cyrene) bifurcata (F.O.P.-Cambridge, 1901). New combinations: Capidava rufithorax Simon, 1902 = Drizztius rufithorax; Freya frontalis Banks, 1929 = Eustiromastix frontalis; Chira (sub Attus) spinipes (Taczanowski, 1872) = Eustiromastix spinipes; Freya (sub Euophrys) ambigua (C.L. Koch, 1846) = Leptofreya ambigua; Freya (sub Cyrene) bifurcata (F.O.P.-Cambridge, 1901) = Leptofreya bifurcata; Freya (sub Cyrene) laticava (F.O.P.-Cambridge, 1901) = Leptofreya laticava; Freya (sub Cyrene) longispina (F.O.P.-Cambridge, 1901) = Leptofreya longispina; Phiale (sub Cyrene) bilobata (F.O.P.-Cambridge, 1901) = Pachomius bilo-batus; Phiale (sub Cyrene) hieroglyphica (F.O.P. Cambridge, 1901) = Pachomius hieroglyphicus; Phiale (sub Cyrene) niveoguttata (F.O.P.-Cambridge, 1901) = Pachomius niveoguttatus; Romitia (sub Euophrys) albipalpis (Taczanowski, 1878) = Pachomius albipalpis; Romitia (sub Euophrys) andina (Taczanowski, 1878) = Pachomius andinus; Romitia (sub Uspachus) bahiensis (Galiano, 1995) = Pachomius bahiensis; Romitia (sub Uspachus) columbiana (Galiano, 1995) = Pachomius columbianus; Romitia (sub Uspachus) juquiaensis (Galiano, 1995) = Pachomius juquiaensis; Romitia (sub Phiale) ministerialis (C.L. Koch, 1846) = Pachomius ministerialis; Romitia (sub Uspachus) misionensis (Galiano, 1995) = Pachomius misionensis; Romitia nigra Caporiacco, 1947 = Pachomius nigrus; Romitia (sub Uspachus) patellaris (Galiano, 1995) = Pachomius patellaris; Chira (sub Diagondas) micans (Simon, 1902) = Philira micans; Chira superba Caporiacco, 1947 = Philira superba; Freya (sub Cyrene) maculatipes (F.O.P.-Cambridge, 1901) = Tarkas maculatipes; Freya (sub Cyrene) bifida (F.O.P. Cambridge, 1901) = Triggella bifida; Freya infuscata (F.O.P.-Cambridge, 1901) = Triggella infuscata; Freya (sub Cyrene) minuta (F.O.P.-Cambridge, 1901) = Triggella minuta; Freya (sub Cyrene) albosignata (F.O.P.-Cambridge, 1901) = Xanthofreya albosignata; Freya arraijanica Chickering, 1946 = Xanthofreya arraijanica; Phiale (sub Cyrene) bicuspidata (F.O.P.-Cambridge, 1901) = Xantho freya bicuspidata; Freya chionopogon Simon, 1902 = Xanthofreya chionopogon; Freya (sub Heraclea) rustica (Peckham & Peckham, 1896) = Xanthofreya rustica. Combinations restored: Phiale (sub Pachomius) flavescens (Peckham & Peckham, 1896) = Pachomius flavescens; Phiale (sub Pachomius) similis (Peckham & Peckham, 1896) = Pachomius similis. Invalid name: Freya dyali Roewer 1951 is an invalid replacement name for Euophrys trifasciata "Dyal 1935", which was a redescription of Euophrys trifasciata C.L. Koch, 1846, not a homonym. New species: Drizztius geminensis. First female descriptions and transfers of mismatched females: First descriptions for Asaracus megacephalus C.L. Koch, 1846, Capidava biuncata Simon, 1902, and Phiale formosa (Banks, 1909); the true female of Eustiromastix spinipes is described, and its mismatched female is identified as the female of Eustiromastix falcatus Galiano, 1981; the mismatched female of Freya (sub Cyrene) prominens (F.O.P.-Cambridge, 1901) is identified as the female of Xanthofreya rustica; the misidentified female of X. rustica is identified as the female of Leptofreya bifurcata. Lectotypes: designated for Cyrene bifida F.O.P.-Cambridge, 1901 and Cyrene formosa Banks, 1909. New synapomorphy: a constricted proximal end of the cymbium of the male palp is an apparent new synapomorphy for Salticoida. PMID- 26624464 TI - The Zoogeography of Marine Tardigrada. AB - This monograph describes the global records of marine water bears (Phylum Tardigrada). We provide a comprehensive list of marine tardigrades recorded from around the world, providing an up-to-date taxonomy and a complete bibliography accompanied by geographic co-ordinates, habitat, substrate and biogeographic comments. A link is provided to an on-line interactive map where all occurrences for each species are shown. In total we list 197 taxa and their 2240 records from 39 oceans and seas and 18 Major Fishing Areas (FAO). It is hoped this work will serve as a reference point and background for further zoogeographic and taxonomic studies on marine tardigrades. PMID- 26624465 TI - Revision of the genus Thyreocephalus and description of Afrus gen. nov. of Africa south of the Sahara (Coleoptera: Staphylinidae: Staphylininae). AB - A revision of the genus Thyreocephalus Guerin-Meneville, 1844 of Africa south of the Sahara is presented. A new genus Afrus gen. nov. was described with the type species Thyreocephalus spegazzinii Bernhauer, 1915, which resulted in following new combination: Afrus spegazzinii (Bernhauer, 1915), comb. nov. Eulissus collarti (Cameron, 1932) was transferred to Afrus. Based on a revision of types and of additional material, 32 species of the genus Thyreocephalus and two species of the genus Afrus are recognized in Africa south of the Sahara. All species are described or redescribed and illustrated, seven of them for the first time: Thyreocephalus camerunensis sp. nov., T. manfredi sp. nov., T. marginipennis sp. nov., T. meridioafricanus sp. nov., T. pseudoafricanus sp. nov., T. subcorticalis sp. nov. and T. tsingidianus sp. nov. Neotypes are designated for Eulissus ater Laporte, 1835, Xantholinus coeruleipennis Quedenfeldt, 1881, and X. interocularis Eppelsheim, 1895. Lectotypes are designated for Eulissus atlanticus Bernhauer, 1915, E. burgeoni Bernhauer, 1929, E. mokaensis Bernhauer, 1915, E. secretus Bernhauer, 1935, E. turneri Bernhauer, 1937, Xantholinus alluaudi Fauvel, 1907, X. mocquerysi Fauvel, 1903, X. pilosus Roth, 1851, Thyreocephalus diversiceps Bernhauer, 1936, and T. spegazzinii Bernhauer, 1915. Eulissus africanus Bernhauer, 1913, E. alluaudi (Fauvel, 1907) (originally described in Xantholinus Dejean, 1821), E. atlanticus Bernhauer, 1915, E. brunneiventris Tottenham, 1956, E. burgeoni Bernhauer, 1929, E. guineensis Bernhauer, 1912, E. mokaensis Bernhauer, 1915, E. secretus Bernhauer, 1935, E. strinatii Scheerpeltz, 1958, and Xantholinus nairobiensis Fauvel, 1907 were transferred to Thyreocephalus. Following synonymies are proposed: Thyreocephalus nairobiensis (Fauvel, 1907) = Eulissus turneri Bernhauer, 1937, syn. nov., Thyreocephalus interocularis (Eppelsheim, 1895) = Thyreocephalus diversiceps Bernhauer, 1936, syn. nov., Thyreocephalus mokaensis (Bernhauer, 1915) = Eulissus flaviventris Bernhauer, 1939, syn. nov. = Thyreocephalus semirufus Coiffait, 1968, syn. nov., Thyreocephalus mocquerysi (Fauvel, 1903) = Eulissus milliaui Bernhauer, 1932, syn. nov. The distribution of both genera in Africa south of Sahara is mapped and a key to species is presented. PMID- 26624466 TI - Diversity of Hemerodromia Meigen, 1822 (Diptera: Empididae) in Thailand, the tip of a tropical iceberg? AB - The genus Hemerodromia in Thailand is revised and full descriptions and keys are provided for all 25 species. Twenty new species are recognised: H. alphalutea sp. nov., H. anisoserrata sp. nov., H. anomala sp. nov., H. attenuata sp. nov., H betalutea sp. nov., H. conspecta sp. nov., H. deltalutea sp. nov., H. deminuta sp. nov., H. demissa sp. nov., H. epsilutea sp. nov., H. etalutea sp. nov., H. gammalutea sp. nov., H. isochita sp. nov., H. namtokhinpoon sp. nov., H. ocellata sp. nov., H. oriens sp. nov., H. phahompokensis sp. nov., H. songsee sp. nov., H. systoechon sp. nov. and H. zetalutea sp. nov. Five species known previously from China are recognised: H. acutata Grootaert, Yang & Saigusa, H. flaviventris Yang & Yang, H. furcata Grootaert, Yang & Saigusa, H. fusca Yang & Yang and H. yunnanensis Yang & Yang. Hemerodromia songsee sp. nov. and H. fusca Yang & Yang are also recorded from Vietnam. Distribution maps of all species are presented. Four categories of distribution patterns of apparently endemic species were identified in (1) the northern mountains (2) the northern lowlands (3) the south, and (4) east of Thailand. Some lowland species with wide distributions in eastern Asia were interpreted as 'old Oriental elements'. Other montane species have wide distributions extending between the Himalayas and southeast China. Three lowland species have an apparently obligate association with alkaline, mineralised water courses where tufa deposition was evident. Tufa-linked assemblages of Hemerodromia may indicate a previously unrecognised and potentially diverse habitat for aquatic Empididae in Southeast Asia. Major historical factors determining contemporary distribution patterns were analysed in reference to a Climate History Model (Plant et al. 2012) and included (i) latitudinal migrations in response to climatically induced changes in the distribution of habitat (ii) radiation of high-elevation endemics from more widespread lowland forms (iii) historical connectivity and fragmentation of hydrological networks with possible marooning of taxa in stable tufa spring systems (iv) persistence of lowland forms in climatically 'buffered' stream environments during progressive aridification. Analysis of sampling methodology concluded that hand collecting was 2,000X more efficient at collecting numbers of Hemerodromia with a species discovery rate 775X greater than that with passive trapping methods (Malaise, flight interception and pan traps etc.) although both approaches are needed for full assessment of species richness. Consideration of the climatic, ecological and biogeographic complexity of tropical Southeast Asia suggests that an extremely rich Hemerodromia fauna awaits discovery in the region. PMID- 26624467 TI - A new species of Dactyloa from eastern Panama, with comments on other Dactyloa species present in the region. AB - Giant anoles of the genus Dactyloa have been considered to be represented in eastern Panama by six species. In this contribution, we describe a seventh species that is restricted to the Maje, San Blas, Darien, and Piedras-Pacora mountain ranges. The new species resembles D. ibanezi, D. limon, and D. purpurescens in external morphology but differs from these species in dewlap coloration, dorsal color pattern, morphometrics, and scalation. The recognition of the new species is further supported by DNA barcoding (genetic distances >2.7% in 16S and >7.8% in COI between the new species and all other species of Dactyloa). We discuss the taxonomic identity of D. purpurescens, and, based on morphological evidence, we place D. chocorum in the synonymy of the former species. An identification key for all 11 Dactyloa species occurring in Panama is provided. PMID- 26624468 TI - Revision of the Western Australian pebble-mimic dragon species-group (Tympanocryptis cephalus: Reptilia: Agamidae). AB - Recent work on species complexes of the pebble-mimic dragons of the Australian genus Tympanocryptis has greatly clarified evolutionary relationships among taxa and also indicated that species diversity has been severely underestimated. Here we provide a morphological and molecular appraisal of variation in the T. cephalus species-group and find evidence for recognizing five species-level lineages from Western Australia. Four species-level lineages are strongly supported with a combined mitochondrial and nuclear DNA Bayesian analysis (a fifth population from the Gascoyne region lacked tissue samples). Morphologically, we found subtle, yet consistent, differences among the populations in scalation, color and pattern. True T. cephalus Gunther is restricted to the coastal Pilbara region and characterized by five dark blotches on the dorsum, keeled ventrals, and other characters. Two other lineages within the Pilbara, from the Hamersley range and Fortescue/northern Pilbara region, differed from T. cephalus senso stricto by possessing a more elongate body and a plain dorsum. Furthermore, the Hamersley lineage differed from the Fortescue lineage by possessing slightly more reddish coloration and feeble keeling on the snout. Although there are few specimens and no tissue samples available for the Gascoyne population, these individuals are larger, have rugose scales on the snout, and possess scattered enlarged tubercles with three large blotches on the dorsum. The name T. cephalus gigas Mitchell is available for this population. The most widespread lineage, and the one best represented in collections and in field guides, occurs throughout central Western Australia. These Goldfield populations are characterized by a protruding snout, narrow rostral, and uniform reddish brown coloration, often with a dark wash. Based on the genetic and morphological differences, we redescribe T. cephalus, resurrect and elevate T. gigas to a full species and designate a neotype for this taxon, and describe three lineages as new species (T. diabolicus sp. nov., T. fortescuensis sp. nov., T. pseudopsephos sp. nov.). PMID- 26624469 TI - Aletheiana tenella, a new genus and new species of freshwater hymenosomatid crab (Crustacea: Decapoda: Brachyura) from Central Sulawesi, Indonesia. AB - A new genus and new species of free-living hymenosomatid crab, Aletheiana tenella, is described from Central Sulawesi, Indonesia. The two known Sulawesi hymenosomatid species, Cancrocaeca xenomorpha Ng, 1991, and Sulaplax ensifer Naruse, Ng & Guinot, 2008, are both from cave habitats. Aletheiana gen. nov. is most similar to Neorhynchoplax Sakai, 1938 (from freshwater and intertidal habitats in the Indo-West Pacific), and Sulaplax, but can be distinguished by its front possessing only one subventral rostral lobe, the base of the antenna is positioned between the base of the ocular peduncle and antennular fossa, the posterior margin of the epistome has two low, rounded median lobes, the merus of the third maxilliped is elongated, the ambulatory dactylus has a prominent subdistal spine, the cutting edges of the chela are armed with distinct teeth proximally, and the male abdomen is slender and elongate with the telson linguiform. PMID- 26624471 TI - Fecal Ciliate Composition of Domestic Horses (Equus caballus Linnaeus, 1758) Living in Kyrgyzstan. AB - Species composition and distribution of intestinal ciliates were investigated in the feces from 15 domestic horses living in Bishkek, Kyrgyzstan. Twenty-three species belonging to 14 genera were identified. This is the first study on intestinal ciliates in domestic horses living in Kyrgyzstan. The mean number of ciliates was 14.1 +/- 6.8 x10(4) cells ml(-1) of feces and the mean number of ciliate species per host was 6.0 +/- 3.2. No endemic or new species were detected. Blepharocorys was the major genus as these ciliates were detected in high proportions. In contrast Holophryoides, Allantosoma were only observed at low frequencies. Recorded ciliate species in this investigation had almost the same characteristics as those described in previous studies. There was no important geographic variation in the intestinal ciliate fauna of equids. PMID- 26624470 TI - The systematic status of Gonocephalus robinsonii Boulenger, 1908 (Squamata: Agamidae: Draconinae). AB - The generic assignment of the draconine lizard Gonocephalus robinsonii from the highlands of West-Malaysia has been uncertain since the original description. Here we present a study based on morphology, previously published karyotype data and molecular phylogenetics using 16S rRNA sequences to evaluate the systematic status of G. robinsonii. As a result we describe Malayodracon gen. nov. to accommodate the species. PMID- 26624472 TI - New Acotylea (Polycladida, Platyhelminthes) from the east coast of the North Atlantic Ocean with special mention of the Iberian littoral. AB - Polyclad species diversity, although generally well known for European North Atlantic waters, is nearly unknown for the Iberian Peninsula. The "Ria de Arousa", located on the Atlantic coast of Galicia (Spain), is a place where many positive biological factors for species biodiversity converge. Therefore, it is an ideal location to study polyclad diversity. This research, which describes new records and new species, contributes to the knowledge of the distribution of Polycladida (Platyhelminthes), particularly of the suborder Acotylea, in the Atlantic waters of the Iberian Peninsula. The new records include the re descriptions of Cryptocelis compacta Lang, 1884, Stylochus neapolitanus (Delle Chiaje, 1841-1844) and Discocelis tigrina (Blanchard, 1847), while the two newly described species are Hoploplana elisabelloi n. sp. and Armatoplana celta n. sp. PMID- 26624473 TI - A study on the genus Agrilaxia Kerremans, 1903 from Venezuela (Coleoptera: Buprestidae: Buprestinae: Anthaxiini). AB - Study on the genus Agrilaxia Kerremans, 1903 from Venezuela. Altogether eight species were recorded from this country, four of them are described in this paper: Agrilaxia (Agrilaxia) biformis sp. nov., A. (A.) michaeli sp. nov., A. (A.) stephani sp. nov. and A. (A.) venezuelana sp. nov. All species are illustrated and new species are compared with the most similar/related species. A male of Agrilaxia (A.) balloui Fisher, 1942 is described and the male genitalia are illustrated. New country records are given for Agrilaxia (A.) balloui, A. (A.) costaricensis Obenberger, 1922, A. (A.) glabra Bily & Brule 2013 and A. (A.) simillima Cobos, 1972. PMID- 26624474 TI - Three new species of the genus Pseudovelia Hoberlandt, 1950 (Hemiptera: Heteroptera: Veliidae) from China. AB - Three species of the genus Pseudovelia Hoberlandt, 1950 from China are described as new: Pseudovelia recava sp. nov. from Guizhou, P. sichuanensis sp. nov. from Sichuan and P. spiculata sp. nov. from Taiwan. Photographs of the male dorsal habitus, male forelegs, male middle legs, male hind legs, details of the fore tibia and hind tarsus, and genitalic structures are provided, accompanied by line drawings of male genitalic structures, habitat photos and a geographic distribution map. PMID- 26624475 TI - Descriptions of two new Species of Goniozus Forster, 1856 (Hymenoptera: Bethylidae) associated with insect induced plant galls from India. AB - Two new species of the genus Goniozus viz., Goniozus inauditus Santhosh sp. nov. and G. kuriani Santhosh sp. nov. associated with insect induced plant galls from South India are described. The parasitic relationship of Goniozus with the nonlepidopteran hosts living in the concealed habitats and their association with insect induced plant galls and its inhabitants are reviewed. The possible host range extension of Goniozus is commented. PMID- 26624476 TI - Description of two ubiquitous species of Desmosomatidae (Isopoda: Asellota) from the Northwest Pacific Basin east of the Kuril-Kamchatka Trench. AB - Two new species of Desmosomatidae, Eugerdella kurabyssalis sp. nov. and Parvochelus serricaudis sp. nov., are described from the Northwest Pacific open abyssal plain to the east of the Kuril-Kamchatka Trench. These species constituted about one fourth of all collected desmosomatid specimens of the KuramBio expedition (2012), indicating it may be the most abundant species of the family in this area. E. kurabyssalis sp. nov. is rather similar to E. minutula Mezhov, 1986 and E. theodori Brix, 2007, resembling them in the shape of its body segments and appendages, including the absence of the mandibular palp and morphology of the pereopod I. The new species can be distinguished from the mentioned species by the number of cusps of the mandibular incisor process and lacinia mobilis, the relatively stouter pereopods and different setation of the pereopod I ischium. P. serricaudis sp. nov. is the second species of the genus Parvochelus Brix & Kihara, 2015 (see Brix et al. 2015) and the first record of the genus from the Pacific Ocean and from the Northern Hemisphere. P. serricaudis sp. nov. can be distinguished from P. russus Brix & Kihara, 2015 by its relatively stouter pereopod I, presence of the mandibular palp and the shape of the maxilliped palp articles and female operculum. A discussion of the taxonomic characters and the modified diagnosis of the genus Parvochelus are presented. PMID- 26624477 TI - On Verhoeff's Otostigmus subgenus Malaccopleurus, the nudus group of Otostigmus subgenus Otostigmus Porat, 1876, and Digitipes Attems, 1930, with a description of the foetus stadium larva in O. sulcipes Verhoeff, 1937, (Chilopoda: Scolopendromorpha: Scolopendridae). AB - The species of Verhoeff's Southeast Asian subgenus Malaccopleurus (an unavailable name) are here assigned to subgenus Otostigmus. His Otostigmus (M.) trisulcatus Verhoeff, 1937 is a junior subjective synonym of O. (M.) sulcipes Verhoeff, 1937. The foetus stadium of O. sulcipes is described. Otostigmus (M.) sutteri Wurmli, 1972, is also assigned to the subgenus Otostigmus and may be conspecific with O. geophilinus Haase, 1887, the specimens of which show some variation. The specimen from Teinzo, Myanmar with labels O. politus Karsch, 1881, and O. geophilinus is of uncertain identity. Otostigmus sulcipes closely resembles O. nudus Pocock, 1890, and O. taeniatus Pocock, 1896, of Lewis's (2010) nudus group. Otostigmus lawrencei Dobroruka, 1968, resembles a Cormocephalus species and is of uncertain identity. The genus Digitipes is characterised by the process on the femur of the ultimate legs in males. Three African species have been recognised. The males of Digitipes verdascens Attems, 1930, D. reichardti (Kraepelin, 1903) are known but D. krausi Dobroruka, 1968, lacks the femoral process and was described as a female. In these three species, only the tergite of the ultimate leg-bearing segment is marginate but in other characters D. krausi resembles Otostigmus species and is assigned to Otostigmus as O. krausi (Dobroruka, 1968) comb. nov. The Indian Digitipes periyarensis Joshi & Edgecombe, 2013, which differs markedly from other Digitipes species is a junior subjective synonym of Otostigmus nudus. It is possible that future molecular studies may show that some species currently assigned to Otostigmus are, in fact, Digitipes. PMID- 26624478 TI - The puzzling distribution of Heteromurus (Verhoeffiella) absoloni Kseneman, 1938 (Collembola: Entomobryidae: Heteromurinae) resolved: detailed redescription of the nominal species and description of a new species from Catalonia (Spain). AB - The species Heteromurus (Verhoeffiella) absoloni Kseneman, 1938 is redescribed in detail and characterized by its barcode, based on specimens from its type locality in Montenegro. A neotype is designated. Dorsal S-chaetotaxy is given for the first time in the subgenus Verhoeffiella. Chaeta morphology and distribution are thoroughly analyzed, in particular on antennae where 12 chaetal types are recognized. Several morphological features are newly described for the genus and for Heteromurinae. The widely disjunct distribution of the species is approached through morphological and molecular comparison of specimens from the type locality in Montenegro and from the Catalan population. We established that this last record is a new species described here as Heteromurus (Verhoeffiella) gamae sp. nov. New combination is proposed Heteromurus (Verhoeffiella) constantinellus (Curcic & Lucic in Lucic, Curcic & Mitic 2007) comb. nov. A table of all species of the subgenus is provided. The taxonomic status of Verhoeffiella and the problems of species discriminations in the subgenus are discussed. PMID- 26624479 TI - A new species of Dolicholana Bruce, 1986 (Isopoda, Cymothoidea, Cirolanidae), the first record of the genus from the Atlantic Ocean. AB - The isopod genus Dolicholana Bruce, 1986, previously known only from the Indo West Pacific, is recorded for the first time from the Atlantic Ocean. A new species, Dolicholana brucei sp. nov., is described from the northeastern Brazilian coast, and is the first record of the genus Dolicholana Bruce, 1986 for the Atlantic Ocean. The material was collected from the upper part of the continental slope off Rio Grande do Norte (150 m depth). The new species is characterized by pereopod 1 propodal palm being crenulate, ischium of pereopod 1 and 2 with a plumose seta on the anterior margin, peduncle of pleopods 3-5 bearing an accessory lobe acute on the distolateral angle, pleotelson posterior margin being rounded, and the uropodal endopod and the exopod apices distally being rounded. A revised key to the genus is provided. PMID- 26624480 TI - A survey of nematodes of the genus Cucullanus Muller, 1777 (Nematoda, Seuratoidea) parasitic in marine fishes off Brazil, including description of three new species. AB - A taxonomic survey of six nematode species (including three new taxa) from the genus Cucullanus Muller, 1777, parasites of marine fishes off the Brazilian coast, is provided. Nematodes were studied using light and scanning electron microscopy (SEM). Cucullanus gastrophysi n. sp. parasitic in Lophius gastrophysus Miranda Ribeiro differs from its congeners by the combination of the following features: shape and number of sclerotized structures in the oesophastome (a pair of lateral elongate structures and a single small reniform one), position of deirids and excretory pore (both anterior to oesophagus base), spicule length and spicule/body length ratio (0.97-1.29 mm and 6.5-10.5%, respectively), morphology and length of gubernaculum (V-shaped, 107-135 um long). Cucullanus protrudens n. sp. from Pagrus pagrus (Linnaeus) has the cloacal lips broadly protruded, which differentiates it from several species of Cucullanus; other features, e.g., the length of spicules and gubernaculum (400-415 um and 91-103 um, respectively), arrangement of caudal papillae and position of excretory pore (slightly posterior to oesophagus-intestine junction) also characterize this species. Cucullanus pseudopercis n. sp. from Pseudopercis semifasciata (Cuvier) has deirids and excretory pore posterior to the oesophagus-intestine junction, which distinguishes the species from most of the congeners; furthermore, the arrangement of caudal papillae in combination with the length of spicules and gubernaculum (1.0-1.5 mm and 178-196 um, respectively) separate this species from other taxa. Newly collected specimens of C. cirratus Muller, 1777 (type species of the genus) from Urophycis brasiliensis (Kaup), C. pedroi from Conger orbignianus Valenciennes (type host of the species) and C. genypteri Sardella, Navone & Timi, 1997 from Genypterus brasiliensis Regan, were studied as well. Comparisons between newly collected samples and the taxonomic data available for each respective species revealed features that were not previously mentioned (e.g. presence of unpaired cloacal papilla, detailed morphology of cloacal lips), as well as negligible differences in morphometry and caudal papillae arrangement. Observations on the type material of C. carioca suggested affinities with the genus Dichelyne Jagerskiold, 1902; however, the poor preservation of these specimens does not allow further conclusions. Cucullanus rougetae is considered to be a species inquirenda. PMID- 26624482 TI - Revision of the aphyonid genus Aphyonus (Teleostei, Ophidiiformes) with a new genus and two new species. AB - The cosmopolitan, deep sea, aphyonid genus Aphyonus is known from less than 100 specimens. The type species A. gelatinosus Gunther, 1878 and three additional valid species, A. brevidorsalis Nielsen, 1969, A. bolini Nielsen, 1974, and A. rassi Nielsen, 1975 were all based on single specimens. Since then several specimens have been caught of which 52 are examined for the present revision. Most of the specimens are referred to A. gelatinosus but also to A. bolini and A. rassi. A result of the enlarged material is that the type species, A. gelatinosus, is found to differ so much from the remaining species that a new genus, Paraphyonus, is established for these species. Furthermore two new species of Paraphyonus are here described, P. iselini based on six specimens from the tropical northwestern Atlantic Ocean and P. merretti based on three specimens from the northeastern Atlantic Ocean. The present knowledge of the variation of the Paraphyonus species makes it relevant to transfer Barathronus solomonensis Nielsen & Moller, 2008 to this genus. PMID- 26624481 TI - Orolaelaps (Acari: Mesostigmata: Melicharidae): description of two new species, redescription of Orolaelaps quisqualis and new characterisation of the genus. AB - Until now, the genus Orolaelaps De Leon was known only from the USA. Two new species of this genus, namely Orolaelaps piracicabensis n. sp. and Orolaelaps tupiniquim n. sp., are described from specimens collected in the State of Sao Paulo, Brazil. Orolaelaps quisqualis De Leon, the type species of the genus, is redescribed and an updated diagnosis of Orolaelaps is provided. PMID- 26624483 TI - Two new species of predatory biting midges of the genus Alluaudomyia from Europe and the Canary Islands (Diptera: Ceratopogonidae). AB - Alluaudomyia canariensis Szadziewski & Dominiak sp. nov. from the Canary Islands and A. wyskokensis Szadziewski & Dominiak sp. nov. from Poland and Ukraine are described and illustrated. The genus Alluaudomyia is reported from the Canary Islands for the first time. The article is supplemented with a checklist and an identification key for the species so far recorded from Europe and the Canary Islands. PMID- 26624485 TI - Description of two new species of Pisione (Polychaeta: Sigalionidae) and first record of Pisione galapagoensis Westheide in the Southern Mexican Pacific. AB - The genus Pisione Grube 1857 was composed up to now of 40 species and 4 subspecies. Although distributed worldwide, in the Mexican Pacific little is known about its taxonomy and distribution, and only two species of this genus have been recorded: Pisione longispinulata Aguado & San Martin, 2004 and Pisione remota (Southern, 1914), but the records of the latter remain questionable. For this study, 406 pisionids from soft sediments of Acapulco Bay, Southern Mexican Pacific, were examined. Two new species are described: Pisione hippocampus n. sp. characterized by having protruding notoaciculae in posterior chaetigers, the second dorsal cirrus elongated and copulatory organs resembling the body shape of a seahorse and Pisione sanmartini n. sp. characterized by having protruding notoaciculae from the first chaetiger, buccal aciculae with a distal crenulate plate resembling the edge of a shell, and prechaetal bifurcated lobes along the body. Pisione galapagoensis Westheide, 1974 is newly recorded for the Mexican Pacific, its known distribution being extended northward from the Galapagos Islands and Panama. A comparative table with the main diagnostic characters and the distribution of all the species so far described in the genus Pisione is included, as well as a key to the species of the Eastern Pacific. PMID- 26624484 TI - Morphological diversity of the labial sensilla of phytophagous and predatory Pentatomidae (Hemiptera: Heteroptera), with reference to their possible functions. AB - Sensory structure on the labial surface of five genera of Pentatomidae (Hemiptera: Heteroptera) belonging to two subfamilies i.e. Asopinae and Pentatominae have been studied using Scanning Electron Microscopy. Three representatives of the subfamily Pentatominae (phytophagous)-Dolycoris indicus (Stal), Plautia crossota (Dallas) and Piezodorus hybneri (Gmelin) and two of Asopinae (predatory)-Perillus bioculatus (Fabricius) and Eocanthecona furcellata (Wolff) were studied to morphologically characterize and compare the sensory structures present on the labium. Six types of labial sensilla were found on their labial tip and surface. The labial sensilla identified were sensilla peg (SP), basiconica (SB), campaniformia (SCa), chaetica (SCh), styloconica (SStc) and trichodea (ST). Their possible functions were discussed relating to morphology and location. A new form of sensilla basiconica was also observed in D. indicus. Sensilla styloconica were restricted only to the predatory pentatomid bugs. Cuticular projections (Cpr) on the sensorial region of the studied pentatomids were also observed along with labial cuticular pores. PMID- 26624486 TI - Integrative redescription of a forgotten Italian pill millipede endemic to the Apuan Alps-Glomeris apuana Verhoeff, 1911 (Diplopoda, Glomerida, Glomeridae). AB - The Italian pill millipede species Glomeris apuana Verhoeff, 1911, is redescribed from fresh material and its COI barcoding fragment is sequenced. The new specimens were compared to the original type series, of which a lectotype was selected. G. apuana was apparently still viewed as a subspecies of G. ligurica, as its name cannot be found in 'Fauna Europaea', or any faunal lists or catalogues in the last 85 years. We show that the species is both genetically and morphologically unique. G. apuana is easy to identify based on its entirely black coloration in combination with the absence of any main striae on the thoracic shield. Genetically, G. apuana shows large p-distances of >10% to four different populations of G. ligurica Latzel, 1884. G. apuana also differs from other sequenced Glomeris species, G. marginata Latreille, 1803, G. connexa Koch, 1847, and G. klugii Brandt, 1833 by p-distances of >10%. Specimens of G. klugii from a population occurring in sympatry with G. apuana were newly sequenced. All records of G. apuana, a large, easy to identify and conspicuous species, are from a narrow coastal zone of the Apuan Alps, an area in which the species might be microendemic. PMID- 26624487 TI - Head Lift Exercise Improves Swallowing Dysfunction in Spinal and Bulbar Muscular Atrophy. AB - BACKGROUND: Dysphagia due to bulbar involvement is a major symptom of patients with spinal and bulbar muscular atrophy (SBMA). The aim of this pilot study was to test the efficacy and safety of the head lift exercise for swallowing dysfunction in SBMA. METHODS: We enrolled 6 subjects with genetically confirmed SBMA and instructed them to perform the head lift exercise for 6 weeks. The efficacy outcome measures were the changes from baseline in tongue pressure, the scores of swallowing functional questionnaires, and the motor functional scales and parameters of videofluorography (VF). RESULTS: All subjects completed the study and no major adverse effects were recorded. Tongue pressure significantly increased by 19.2 +/- 0.15% (p < 0.05) after the 6-week head lift exercise. The scores for oral dysphagia also improved, although there was no significant change in VF parameters or other variables examined pre- and post-exercise. CONCLUSION: Our findings suggested that the head lift exercise may improve swallowing dysfunction, particularly tongue pressure, in SBMA. PMID- 26624488 TI - Prophylactic Probiotics for Preterm Infants: A Systematic Review and Meta Analysis of Observational Studies. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a major morbidity and cause of mortality in preterm neonates. Probiotics seem to have a beneficial role in preventing NEC, which is confirmed in meta-analyses of randomized controlled trials (RCTs). We therefore aimed to review and confirm the efficacy of probiotics in preterm neonates obtained in observational studies. OBJECTIVE: To assess the effects of prophylactic probiotics in preterm infants. METHODS: A meta analysis was performed searching PubMed, EMBASE, CENTRAL (the Cochrane Library) and www.clinicaltrials.gov. Reference lists of reviews of RCTs were also searched. Included studies were observational studies that enrolled preterm infants <37 weeks of gestational age. Trials were included if they administered any probiotics and measured at least one clinical outcome (e.g. NEC, all-cause mortality, sepsis or long-term development scores). Two authors extracted characteristics and outcomes from included studies. The Newcastle-Ottawa Scale was used for quality assessment. A random-effects meta-analysis model was used, and heterogeneity was assessed by the I2 test. RESULTS: We included 12 studies with 10,800 premature neonates (5,144 receiving prophylactic probiotics and 5,656 controls). The meta-analysis showed a significantly decreased incidence of NEC (risk ratio, RR = 0.55, 95% confidence interval, 95% CI, 0.39-0.78; p = 0.0006) and mortality (RR = 0.72, 95% CI, 0.61-0.85; p < 0.0001). Sepsis did not differ significantly between the two groups (RR = 0.86, 95% CI, 0.74-1.00; p = 0.05). CONCLUSIONS: Probiotic supplementation reduces the risk of NEC and mortality in preterm infants. The effect sizes are similar to findings in meta-analyses of RCTs. However, the optimal strain, dose and timing need further investigation. PMID- 26624490 TI - Air-Stable Surface-Passivated Perovskite Quantum Dots for Ultra-Robust, Single- and Two-Photon-Induced Amplified Spontaneous Emission. AB - We demonstrate ultra-air- and photostable CsPbBr3 quantum dots (QDs) by using an inorganic-organic hybrid ion pair as the capping ligand. This passivation approach to perovskite QDs yields high photoluminescence quantum yield with unprecedented operational stability in ambient conditions (60 +/- 5% lab humidity) and high pump fluences, thus overcoming one of the greatest challenges impeding the development of perovskite-based applications. Due to the robustness of passivated perovskite QDs, we were able to induce ultrastable amplified spontaneous emission (ASE) in solution processed QD films not only through one photon but also through two-photon absorption processes. The latter has not been observed before in the family of perovskite materials. More importantly, passivated perovskite QD films showed remarkable photostability under continuous pulsed laser excitation in ambient conditions for at least 34 h (corresponds to 1.2 * 10(8) laser shots), substantially exceeding the stability of other colloidal QD systems in which ASE has been observed. PMID- 26624491 TI - Polyannulated Bis(N-heterocyclic carbene)palladium Pincer Complexes for Electrocatalytic CO2 Reduction. AB - Phenanthro- and pyreno-annulated N-heterocyclic carbenes (NHCs) have been incorporated into lutidine-linked bis-NHC Pd pincer complexes to investigate the effect of these polyannulated NHCs on the ability of the complexes to electrochemically reduce CO2 to CO in the presence of 2,2,2-trifluoroacetic acid and 2,2,2-trifluoroethanol as proton sources. These complexes are screened for their ability to reduce CO2 and modeled using density functional theory calculations, where the annulated phenanthrene and pyrene moieties are shown to be additional sites for redox activity in the pincer ligand, enabling increased electron donation. Electrochemical and computational studies are used to gain an understanding of the chemical significance of redox events for complexes of this type, highlighting the importance of anion binding and dissociation. PMID- 26624492 TI - Comparison of Anterior Segment-Optical Coherence Tomography Parameters in Phacomorphic Angle Closure and Acute Angle Closure Eyes. AB - PURPOSE: The purpose of this study is to compare anterior segment-optical coherence tomography (AS-OCT) parameters in phacomorphic angle closure and acute primary angle closure (APAC) eyes. METHODS: In this cross-sectional case series, a total of 134 patients with phacomorphic angle closure (28 eyes) or APAC (54 eyes), as well as normal control subjects (52 eyes), were enrolled. Patients underwent AS-OCT imaging and A-scan biometry of both eyes. Anterior chamber depth (ACD), anterior chamber area (ACA), iris thickness (IT), iris curvature, lens vault (LV), anterior vault (AV), and angle parameters including angle opening distance (AOD 500 and AOD750) and trabecular iris space area (TISA500 and TISA750) were measured in qualified images using the Zhongshan Angle Assessment Program and compared among eyes with phacomorphic angle closure, APAC, and normal control subjects. RESULTS: Phacomorphic angle closure and APAC eyes had smaller AOD, ACD, ACA, ACW, AV, and posterior corneal arc length and greater LV than normal controls (P < 0.001 for all comparisons). After adjustment for age, sex, and pupil diameter, phacomorphic angle closure had greater AOD500 (P = 0.02), TISA500 (P = 0.003), TISA750 (P = 0.05), axial length (P = 0.03), and LV (P = 0.001) and less ACD (P = 0.001), ACA (P = 0.003), IT750 (P = 0.01), and IT2000 (P = 0.04) than APAC eyes: ACD < 1.59 mm (odds ratio [OR], 29.57; P < 0.01) and LV > 1042 MUm (OR,12.12; P < 0.01) were the two biometric parameters that could highly discriminate phacomorphic angle closure from the APAC eyes. In multivariate analysis, ACD, LV, AOD500, and axial length could significantly distinguish the two entities. CONCLUSIONS: Ocular biometric parameters can differentiate phacomorphic angle closure from APAC eyes. Shallower ACD and greater LV, axial length, and ACA are the main parameters that distinguish phacomorphic angle closure from APAC. PMID- 26624494 TI - Electrophysiological ON and OFF Responses in Autosomal Dominant Optic Atrophy. AB - PURPOSE: To assess the effect of autosomal dominant optic atrophy (ADOA) on ON and OFF retinal ganglion cell (RGC) function by evaluating the ON and OFF components of the photopic negative response (PhNR). METHODS: Twelve participants from six families with OPA1 ADOA and 16 age-matched controls were recruited. Electrophysiological assessment involved pattern ERGs (PERGs), focal (20 degrees ) and full-field long-duration (250 ms) flash ERGs using a red light-emitting diode flash on a rod-saturating blue background, and full-field brief (300 MUs) xenon flash ERGs using a red filter over a continuous rod saturating blue background. Amplitudes and implicit times of the ERG components were analyzed and the diagnostic potential of each electrophysiological technique was determined by generating receiver operating characteristic (ROC) curves. RESULTS: Mean amplitudes of the N95 and all PhNRs, except the full-field PhNRON, were significantly reduced in participants with ADOA (P < 0.01). Subtraction of the group-averaged focal ERG of ADOA participants from that of controls showed an equal loss in the focal PhNRON and PhNROFF components, whereas in the full-field ERG the loss in the PhNROFF was greater than that in the PhNRON component. The areas under the ROC curve (AUC) for the focal PhNRON (0.92), focal PhNROFF (0.95), and full-field PhNROFF (0.83), were not significantly different from that of the PERG N95 (0.99). CONCLUSIONS: In patients with ADOA, the PhNRON and PhNROFF components are nearly symmetrically reduced in the long-duration ERG, suggesting that ON- and OFF-RGC pathways may be equally affected. PMID- 26624493 TI - Arrestin 1 and Cone Arrestin 4 Have Unique Roles in Visual Function in an All Cone Mouse Retina. AB - PURPOSE: Previous studies discovered cone phototransduction shutoff occurs normally for Arr1-/- and Arr4-/-; however, it is defective when both visual arrestins are simultaneously not expressed (Arr1-/-Arr4-/-). We investigated the roles of visual arrestins in an all-cone retina (Nrl-/-) since each arrestin has differential effects on visual function, including ARR1 for normal light adaptation, and ARR4 for normal contrast sensitivity and visual acuity. METHODS: We examined Nrl-/-, Nrl-/-Arr1-/-, Nrl-/-Arr4-/-, and Nrl-/-Arr1-/-Arr4-/- mice with photopic electroretinography (ERG) to assess light adaptation and retinal responses, immunoblot and immunohistochemical localization analysis to measure retinal expression levels of M- and S-opsin, and optokinetic tracking (OKT) to measure the visual acuity and contrast sensitivity. RESULTS: Study results indicated that Nrl-/- and Nrl-/-Arr4-/- mice light adapted normally, while Nrl-/ Arr1-/- and Nrl-/-Arr1-/-Arr4-/- mice did not. Photopic ERG a-wave, b-wave, and flicker amplitudes followed a general pattern in which Nrl-/-Arr4-/- amplitudes were higher than the amplitudes of Nrl-/-, while the amplitudes of Nrl-/-Arr1-/- and Nrl-/-Arr1-/-Arr4-/- were lower. All three visual arrestin knockouts had faster implicit times than Nrl-/- mice. M-opsin expression is lower when ARR1 is not expressed, while S-opsin expression is lower when ARR4 is not expressed. Although M-opsin expression is mislocalized throughout the photoreceptor cells, S opsin is confined to the outer segments in all genotypes. Contrast sensitivity is decreased when ARR4 is not expressed, while visual acuity was normal except in Nrl-/-Arr1-/-Arr4-/-. CONCLUSIONS: Based on the opposite visual phenotypes in an all-cone retina in the Nrl-/-Arr1-/- and Nrl-/-Arr4-/- mice, we conclude that ARR1 and ARR4 perform unique modulatory roles in cone photoreceptors. PMID- 26624495 TI - Optical Coherence Tomography Angiography of a Choroidal Neovascularization in Adult Onset Foveomacular Vitelliform Dystrophy: Pearls and Pitfalls. AB - PURPOSE: The purpose of this study was to determine the sensitivity and specificity of optical coherence tomography angiography (OCT-A) in detecting choroidal neovascularization (CNV)-complicating adult onset foveomacular vitelliform dystrophy (AOFVD) and to highlight the possible pitfalls related to the heterogeneous spectrum of acquired vitelliform maculopathies. METHODS: Twenty five eyes of 22 consecutive AOFVD patients with suspected CNV were enrolled. Conventional multimodal imaging findings, based on fluorescein angiography (FA), indocyanine green angiography (ICGA) and B-Scan OCT, were used as a basis and were compared with those obtained from OCT-A to define its sensitivity and specificity for detecting CNV in the case of AOFVD. A qualitative and quantitative analysis of the CNV appearance and of the associated OCT-A findings were also performed with the aim of defining features and elucidating possible diagnostic pitfalls. RESULTS: Conventional multimodal imaging allowed diagnosis of a CNV in 5 of 25 eyes (20%), whereas a CNV lesion was clearly observed on OCT A in 4 of 25 cases (16%). The sensitivity and specificity of CNV detection by OCT A in cases of AOFVD was 4 of 5 cases (80%) and 20 of 20 cases (100%), respectively. Optical coherence tomography angiography in 10 cases (40%) showed a focal hyperintense signal, without vascular aspects, at the level of the outer nuclear layer or immediately above the subretinal material accumulation. CONCLUSIONS: Our study demonstrates the capability of OCT-A to allow diagnosis of the presence of a CNV in AOFVD patients. Although FA remains the gold standard for determining the presence of a neovascular network, OCT-A offers noninvasive monitoring of the retinal and choroidal microvasculature, aiding in diagnosis and treatment decisions during follow-up. PMID- 26624496 TI - Macular Choroidal Thickness in Children: The Shandong Children Eye Study. AB - PURPOSE: To examine the thickness of the macular choroid and its associations in school children aged 6 to 18 years. METHODS: The school-based cross-sectional Shandong Children Eye Study included 6026 (94.7%) of 6364 eligible children fulfilling the inclusion criterion of an age from 4 to 18 years. Spectral-domain optical coherence tomography (SD-OCT) was performed for a subgroup of 972 school children aged 6+ years. All participants underwent ocular examinations, including measurement of visual acuity, cycloplegic refractometry, biometry, and SD-OCT (enhanced depth imaging mode) for measurement of choroidal thickness. RESULTS: The study included 972 children (501 girls) with a mean age of 11.3 +/- 3.3 years (range, 6-18 years) and mean axial length of 24.10 +/- 1.56 mm (range, 16.57 28.82 mm). Mean choroidal thickness was thicker (P < 0.001) at 500 MUm temporal to the foveola (290 +/- 67 MUm) than in the subfoveal region (283 +/- 67 MUm; range, 113-507 MUm) and the region 500 MUm superior to the fovea (283 +/- 66 MUm), where it was thicker (P < 0.001) than at 500 MUm inferior of the foveola (281 +/- 66 MUm), and it was thinnest (P < 0.001) at 500 MUm nasal of the foveola (268 +/- 67 MUm). In multivariate analysis, thicker SFCT was (overall correlation coefficient r: 0.51) associated with shorter axial length (P < 0.001; standardized correlation coefficient beta: -0.48; B: -23.7; 95% confidence interval [CI]: -27.2 to -20.3), male sex (P = 0.006; beta: -0.08; B: -10.7; 95% CI: -18.3 to -3.11), and younger age (P = 0.04; beta: -0.07; B: -1.46; 95% CI: 2.85 to -0.07). CONCLUSIONS: As in adults, thicker SFCT in children and teenagers was markedly associated with shorter axial length, and to a lesser degree with male sex and older age. As in adults, increasing axial myopia in teenagers is associated with choroidal thinning and development of a leptochoroid. PMID- 26624497 TI - Elevated S100A8/A9 and S100A12 Serum Levels Reflect Intraocular Inflammation in Juvenile Idiopathic Arthritis-Associated Uveitis: Results From a Pilot Study. AB - PURPOSE: Juvenile idiopathic arthritis-associated uveitis (JIAU) is the most common uveitis entity in childhood. As S100A8/A9 and S100A12 proteins are valuable biomarkers in childhood arthritis, we investigated the occurrence of these proteins in childhood uveitis. METHODS: Serum samples from patients with JIAU (n = 79) or idiopathic anterior uveitis (IAU, n = 24), as well as from nonuveitic controls (n = 24), were collected. Furthermore, aqueous humor samples (JIAU n = 17, nonuveitic controls n = 16, IAU n = 12) were obtained. Samples were analyzed for S100A8/A9 and S100A12 protein levels by ELISA. Intergroup comparisons were performed, involving patient data, clinical data, and S100 levels. RESULTS: S100A8/A9 and S100A12 serum levels were elevated in IAU and JIAU patients as compared to nonuveitic controls (all P < 0.05). S100 serum levels in JIAU patients were higher in active arthritis (not significant; P = 0.289 for S100A8/A9 and P = 0.196 for S100A12) and active uveitis (P = 0.010 for S100A8/A9 and P = 0.026 for S100A12) than in controls. No significant differences in S100 levels were found in a subgroup analysis for sex, antinuclear antibody (ANA) status, disease duration, or presence of uveitis complications. In JIAU patients, S100 serum levels correlated with age and age at onset of uveitis. A longitudinal analysis in JIAU patients showed a correlation of serum S100A8/A9 and S100A12 levels with uveitis activity (both P = 0.03). S100A8/A9 levels in aqueous humor of patients with JIAU (P = 0.001) and IAU (P = 0.0002) were increased as compared to nonuveitic controls. CONCLUSIONS: Increased S100A8/A9 and S100A12 levels are found in the serum and aqueous humor of patients with autoimmune uveitis. Serum levels reflect activity of joint and eye disease. PMID- 26624498 TI - A Single Intravitreal Injection of Ranibizumab Provides No Neuroprotection in a Nonhuman Primate Model of Moderate-to-Severe Nonarteritic Anterior Ischemic Optic Neuropathy. AB - PURPOSE: Ranibizumab, a vascular endothelial growth factor-antagonist, is said to be neuroprotective when injected intravitreally in patients with nonarteritic anterior ischemic optic neuropathy (NAION). We evaluated the efficacy of a single intravitreal (IVT) injection of ranibizumab in a nonhuman primate model of NAION (pNAION). METHODS: We induced pNAION in one eye of four adult male rhesus monkeys using a laser-activated rose Bengal induction method. We then immediately injected the eye with either ranibizumab or normal saline (NS) intravitreally. We performed a clinical assessment, optical coherence tomography, electrophysiological testing, fundus photography, and fluorescein angiography in three of the animals (one animal developed significant retinal hemorrhages and, therefore, could not be analyzed completely) prior to induction, 1 day and 1, 2, and 4 weeks thereafter. Following the 4-week analysis of the first eye, we induced pNAION in the contralateral eye and then injected either ranibizumab or NS, whichever substance had not been injected in the first eye. We euthanized all animals 5 to 12 weeks after the final assessment of the second eye and performed both immunohistochemical and light and electron microscopic analyses of the retina and optic nerves of both eyes. RESULTS: A single IVT dose of ranibizumab administered immediately after induction of pNAION resulted in no significant reduction of clinical, electrophysiological, or histologic damage compared with vehicle-injected eyes. CONCLUSIONS: A single IVT dose of ranibizumab is not neuroprotective when administered immediately after induction of pNAION. PMID- 26624499 TI - Impact of CB1 Receptor Deletion on Visual Responses and Organization of Primary Visual Cortex in Adult Mice. AB - PURPOSE: The endocannabinoids (eCBs) and their receptors are expressed in the cortex of developing animals where they act as a neuromodulating system during critical stages of brain development such as cell proliferation and migration, and axon guidance. Little is known on the impact of the cannabinoid system on cortical map formation and receptive field properties of cortical sensory neurons. The present study evaluates in vivo the functional organization of the primary visual cortex (V1) of mice lacking cannabinoid CB1R receptor (cnr1-/-). METHODS: Using optical imaging of intrinsic signals, azimuth, and elevation maps of cnr1-/- mice were compared with their wild-type littermates (cnr1+/+). RESULTS: Topographic maps were affected in mutant mice as they exhibited narrower visual field and changes in the shape of V1. CB1R exerted its action in an axis dependent manner as all changes were observed in the azimuth axis. Spatial frequency and contrast sensitivity were also compared between the two groups. Both properties were affected by the chronic lacking of CB1R as mutant mice exhibited a significantly lower contrast sensitivity as well as lower spatial frequency selectivity. CONCLUSIONS: Taken together, these results suggest an important role for CB1R in cortical map formation. Our results also clearly demonstrate the impact of CB1R in the development of visual properties of primary visual cortex neurons. Because psychoactive effects of cannabis consumption on visual experience are mediated mainly through CB1R, our results could possibly explain neuronal mechanisms involved in those perceptual changes. PMID- 26624500 TI - Backbone Flexibility Influences Nucleotide Incorporation by Human Translesion DNA Polymerase eta opposite Intrastrand Cross-Linked DNA. AB - Intrastrand cross-links (IaCL) connecting two purine nucleobases in DNA pose a challenge to high-fidelity replication in the cell. Various repair pathways or polymerase bypass can cope with these lesions. The influence of the phosphodiester linkage between two neighboring 2'-deoxyguanosine (dG) residues attached through the O(6) atoms by an alkylene linker on bypass with human DNA polymerase eta (hPol eta) was explored in vitro. Steady-state kinetics and mass spectrometric analysis of products from nucleotide incorporation revealed that although hPol eta is capable of bypassing the 3'-dG in a mostly error-free fashion, significant misinsertion was observed for the 5'-dG of the IaCL containing a butylene or heptylene linker. The lack of the phosphodiester linkage triggered an important increase in frameshift adduct formation across the 5'-dG by hPol eta, in comparison to the 5'-dG of IaCL DNA containing the phosphodiester group. PMID- 26624501 TI - Endocrine activities and cellular stress responses in the marsh frog Pelophylax ridibundus exposed to cobalt, zinc and their organic nanocomplexes. AB - Metal-containing materials are extensively used in industry, personal care products and medicine, and their release in the environment causes concern for the potential impacts on aquatic organisms. We assessed endocrine disrupting potential of N-vinyl-2-pyrrolidone-based nanoparticles (Me-PSs) containing cobalt (Co(2+)) or zinc (Zn(2+)), using the marsh frog Pelophylax ridibundus as a model. Adult males were exposed for 14 days to waterborne Co(2+) (50MUg/L), Zn(2+) (100MUg/L) or corresponding concentrations of Co-PS, Zn-PS, or parental polymeric compound (PS). The indices of thyroid activity, vitellogenesis, cytochrome P450 dependent monooxygenases activity (EROD) and cytotoxicity markers were evaluated. Exposure to Co(2+) led to the elevation of serum thyrotropin (TSH) and hepatic deiodinase activities accompanied by the up-regulation of EROD activity. In contrast, the action of the polymer-containing substances (Co-PS, Zn-PS and PS) as well as free Zn(2+) caused a prominent decrease of EROD activity and a decrease in serum cortisol and TSH concentrations. Exposures to Zn(2+), Zn-PS and PS upregulated vitellogenesis in males. All exposures except Co(2+) caused neurotoxicity as indicated by the depletion of cholinesterase. These results demonstrate toxicity of Co- and Zn-containing Me-PSs and their parental compounds (Zn(2+) and PS) in frogs and indicate distinct mechanisms of Co(2+) action. Broad disruption of the hormonal pathways and reduced capacity for organic xenobiotic detoxification may have deleterious impacts on amphibian populations from habitats exposed to metallorganic pollution. PMID- 26624502 TI - Focal anatomic resurfacing implantation for bilateral humeral and femoral heads' avascular necrosis in a patient with Hodgkin's lymphoma and literature review. AB - INTRODUCTION: The femoral and humeral heads are among the most common sites of osteonecrosis. The aims of this case report was to report three years' results for sequential treatment of bilateral, concomitant involvement of humeral and femoral heads with focal anatomic resurfacing implantation in a single patient with Hodgkin's lymphoma and to review the relevant literature, which is relatively scarce. PRESENTATION OF CASE: We present a 48-year-old male patient with concomitant, bilateral femoral and humeral head avascular necrosis. He was diagnosed as Hodgkin's lymphoma in 1984. He had bilateral groin and shoulder pain, lasting for three years and aggravated by joint motions. Radiological evaluations demonstrated bilateral focal osteonecrosis of femoral heads and humeral heads, respectively. Despite conservative treatment, he did not obtain any symptomatic relief. Following the common decision, he was treated with sequential implantations with the HemiCAP((r)) device for both bilateral pathologies, by a single surgeon and standard surgical approaches. Neither intraoperative nor postoperative complication was encountered. After the follow up period of 36 months after the last surgery, he was symptomless and with normal range of motion for all four joints. DISCUSSION: The bilateral, concomitant involvement of humeral and femoral head in the setting of avascular necrosis is relatively rare. Moreover, the optimal treatment method at earlier stages, in young patients has not been established yet. CONCLUSION: This study is the first report to present the three-years' clinical result of a single, relevant case, who was treated with sequential focal anatomic resurfacing implantations (HemiCAP((r))) in four aforementioned joints. PMID- 26624503 TI - Retroperitoneal non-functioning paraganglioma: A difficult tumour to diagnose and treat. AB - Paragangliomas are rare neoplasms arising from cells of the primitive neural crest. These tumours are often difficult to diagnose and treat. We report a case of a 42 year old female presenting with abdominal pain who had a retroperitoneal tumour situated at the aortic bifurcation. Serum catecholamine levels were normal. Complete resection of the tumour was performed. The histological examination and immunohistochemical analyses concluded the diagnosis of an organ of Zuckerkandl paraganglioma. PMID- 26624504 TI - Penetrating trauma to the kidney and Meckel's Diverticulum in a patient with unilateral renal agenesis. AB - INTRODUCTION: Emergency laparotomy for abdominal gunshot wounds is frequently performed in South Africa and remains associated with significant morbidity and mortality. The occurrence of congenital anomalies during surgery is an unexpected finding and presents a major challenge. PRESENTATION OF CASE: The successful management of a haemodynamically unstable 26-year-old man with unilateral renal agenesis, concomitant right renal and hepatic injuries, and a transected Meckel's Diverticulum following an abdominal gunshot wound is presented. DISCUSSION: Intraoperative decision-making is difficult when congenital visceral anomalies form part of the injury complex in trauma. Basic principles of damage control surgery that include initial exploration, secondary resuscitation and definite operation must be adhered to. Repair of complex injuries are delayed until the definitive laparotomy. The presence of one congenital anomaly should alert the surgeon to the possibility of further anomalies. CONCLUSION: Although congenital visceral anomalies are spectacular findings at laparotomy, they should not distract the trauma surgeon. Adhering to damage control surgery principles and careful inspection of the peritoneal cavity for further abnormalities remain the mainstay of successful management. PMID- 26624505 TI - Temperature Spatially Offset Raman Spectroscopy (T-SORS): Subsurface Chemically Specific Measurement of Temperature in Turbid Media Using Anti-Stokes Spatially Offset Raman Spectroscopy. AB - Here we propose and demonstrate a new analytical method for the noninvasive measurement of subsurface temperatures within diffusely scattering (turbid) media in combination with high chemical selectivity. The method is based upon the first combination of Stokes/anti-Stokes light scattering measurements and the recently developed spatially offset Raman spectroscopy (SORS). This approach has been conceptually demonstrated by measuring material-specific temperatures within a turbid sublayer of poly(tetrafluoroethylene) (PTFE) through a highly diffusely scattering overlayer of poly(oxymethylene) POM (3 mm thick). Root-mean-square errors (RMSEs) of 0.16-0.71 degrees C were achieved when measuring temperatures over ranges between 24 and 45 degrees C. This unique capability complements the array of existing, predominantly surface-based, temperature measurement techniques. It paves the way for a wide range of topical applications including subsurface, chemically specific, noninvasive temperature measurements within translucent media including the human body, subsurface monitoring of chemical or catalytic processes in manufacture quality and process control, and research. PMID- 26624506 TI - Therapeutic potential of low-dose IL-2 in a chronic GVHD patient by in vivo expansion of regulatory T cells. AB - Chronic graft-versus-host disease (cGVHD) is a common complication following allogeneic hematopoietic stem cell transplantation (HSCT), which is characterized by autoimmune like inflammatory responses and reduced levels of regulatory T cells (Tregs). Recently, the use of low-dose IL-2 has been reported to selectively increase Tregs and therefore facilitate immune regulation and promote clinical improvements in cGVHD patients. In this report, we describe the case of a cGVHD patient who was treated with daily low-dose IL-2 therapy. Our observations demonstrate that low-dose IL-2 could induce significant expansion of Tregs in vivo leading to improved Treg/Th17 ratios. The patient showed moderate clinical benefits suggesting that multiple factors may be involved in the immunological responses. Therefore, while the therapeutic potential of low-dose IL-2 is promising, strategic approaches may be needed to induce a clinically significant and sustained Treg effect. PMID- 26624507 TI - Prolyl-4-Hydroxylase 2 Potentially Contributes to Hepatocellular Carcinoma Associated Erythrocytosis by Maintaining Hepatocyte Nuclear Factor-4alpha Expression. AB - BACKGROUND: Increased red blood cell count (Erythrocytosis) is an important paraneoplastic syndrome of hepatocellular carcinoma (HCC) and is a significant risk factor for lethal lung artery thromboembolism. HCC-associated erythrocytosis is partially caused by the ability of several HCC cells to produce erythropoietin (EPO). Prolyl-4-hydroxylase 2 (PHD2) is an enzyme encoded by the gene EGLN1. The best-known function of PHD2 is to mediate the oxygen-dependent degradation of the labile alpha-subunit of hypoxia-inducible factor (HIF). However, there is increasing evidence that PHD2 also regulates HIF-independent pathways by interacting with other substrates. METHODS: In the EPO-producing human HCC cell line HepG2, the expression of PHD2 gene was silenced with siRNA. EPO production was estimated using quantitative PCR and ELISA. RESULTS: In HepG2 cells, PHD2 suppresses the activity of TGF-beta1 pathway and consequently maintains the expression of hepatocyte nuclear factor-4alpha (HNF-4alpha), an important transcription factor promoting the EPO expression in hepatocytes. PHD2 knockdown caused a marked reduction of EPO production. HIF seemed not to be involved in this biology. CONCLUSION: Our findings show that PHD2 represents a potential contributing factor for HCC-associated erythrocytosis. Selective inhibition of PHD2 in HCC cells might be considered as a new way to manage erythrocytosis in HCC patients. PMID- 26624508 TI - Direct Pen Writing of Adhesive Particle-Free Ultrahigh Silver Salt-Loaded Composite Ink for Stretchable Circuits. AB - In this article, we describe a writable particle-free ink for fast fabrication of highly conductive stretchable circuits. The composite ink mainly consists of soluble silver salt and adhesive rubber. Low toxic ketone was employed as the main solvent. Attributed to ultrahigh solubility of silver salt in short-chain ketone and salt-assisted dissolution of rubber, the ink can be prepared into particle-free transparent solution. As-prepared ink has a good chemical stability and can be directly filled into ballpoint pens and use to write on different substrates to form well adhesive silver salt-based composite written traces as needed. As a result of high silver salt loading, the trace can be converted into highly conductive silver nanoparticle-based composites after in situ reduction. Because of the introduction of adhesive elastomeric rubber, the as-formed conductive composite written trace can not only maintain good adhesion to various substrates but also show good conductivity under various deformations. The conductivity of written traces can be enhanced by repeated writing-reduction cycles. Different patterns can be fabricated by either direct handwriting or hand copying. As proof-of-concept demonstrations, a typical handwriting heart-like circuit was fabricated to show its capability to work under different deformations, and a pressure-sensitive switch was also manufactured to present pressure-dependent change of resistance. PMID- 26624509 TI - Reply to L.M. Brown et al. "Brief history of the Cambridge STEM aberration correction project and its progeny" in Ultramicroscopy 157, 88 (2015). AB - We comment on a Short Communication recently published in Ultramicroscopy in which Brown et al. criticize our description of the time sequence of events in the development of aberration correction systems in electron optics during the 1990s put forward in the introduction to the Ultramicroscopy April 2015 Special Issue. We present an analysis of the published literature furnishing evidence that our description is correct. PMID- 26624510 TI - Characterizing the response of a scintillator-based detector to single electrons. AB - Here we report the response of a high angle annular dark field scintillator-based detector to single electrons. We demonstrate that care must be taken when determining the single electron intensity as significant discrepancies can occur when quantifying STEM images with different methods. To account for the detector response, we first image the detector using very low beam currents (~8fA), and subsequently model the interval between consecutive single electrons events. We find that single electrons striking the detector present a wide distribution of intensities, which we show is not described by a simple function. Further, we present a method to accurately account for the electrons within the incident probe when conducting quantitative imaging. The role detector settings play on determining the single electron intensity is also explored. Finally, we extend our analysis to describe the response of the detector to multiple electron events within the dwell interval of each pixel. PMID- 26624511 TI - Direct in situ thermometry: Variations in reciprocal-lattice vectors and challenges with the Debye-Waller effect. AB - Conventional in situ transmission electron microscopy (TEM) enables the atomic scale study of dynamic materials processes on millisecond time scales. Specimen holders capable of being heated to over 1000 degrees C have provided insight into myriad processes, including nanoscale thermal transport, structural phase transitions, and catalytic reactions. In order for such studies to be accurate and precise, direct determination of the specimen temperature - rather than the heating-element temperature - is critical. Further, such methods should be versatile in that any temperature across a wide range may be measured, irrespective of single-indicator properties specific to the specimen (e.g., first order phase transition, melting point, etc.). Here, we describe a rigorous approach to direct, in situ thermometry of TEM specimens that exploits lattice thermal expansion and the resultant decrease in diffraction-vector magnitude in reciprocal space. Via sub-pixel measurement of reciprocal-lattice-vector magnitudes, picometer increases in lattice parameters are measured over a continuous temperature range and compared to those expected from the coefficient of thermal expansion. Statistical treatment of several experimental trials conducted on nanostructured aluminum thin films shows excellent agreement with both theory and (indirect) measurement of the in situ heating holder. Additionally, we illustrate how uncontrolled, thermally-induced variation in single-crystal orientation leads to modulation of the excitation error and, therefore, the Bragg-spot intensities resulting in a convolution of heating and tilting effects, thus complicating temperature determination via the Debye-Waller effect. PMID- 26624512 TI - Orientation mapping by transmission-SEM with an on-axis detector. AB - Conventional orientation mapping in a scanning electron microscope (SEM) is a valuable technique for characterizing crystalline materials, but its application to ultrafine or nano-grain materials is limited by its spatial resolution. The resolution can be increased by collecting transmission diffraction patterns in SEM. In previous works, such patterns were collected using off-axis detectors in nearly vertical position. To avoid some drawbacks of such arrangement, a new configuration was devised in which the scintillator is located underneath the thin foil on the optical axis of the microscope, and the light is reflected towards the camera by a mirror. This simple configuration gives intense patterns even at very low probe currents, and can be potentially used for collecting maps of relatively high spatial resolution. Example maps reveal details with dimensions of about 5nm. Because of its resolution and geometric simplicity, the proposed configuration will open new opportunities in SEM-based characterization of nanocrystalline materials. PMID- 26624513 TI - Realization of a tilted reference wave for electron holography by means of a condenser biprism. AB - As proposed recently, a tilted reference wave in off-axis electron holography is expected to be useful for aberration measurement and correction. Furthermore, in dark-field electron holography, it is considered to replace the reference wave, which is conventionally diffracted in an unstrained object area, by a well defined object-independent reference wave. Here, we first realize a tilted reference wave by employing a biprism placed in the condenser system above three condenser lenses producing a relative tilt magnitude up to 20/nm at the object plane (300kV). Paraxial ray-tracing predicts condenser settings for a parallel illumination at the object plane, where only one half of the round illumination disc is tilted relative to the optical axis without displacement. Holographic measurements verify the kink-like phase modulation of the incident beam and return the interference fringe contrast as a function of the relative tilt between both parts of the illumination. Contrast transfer theory including condenser aberrations and biprism instabilities was applied to explain the fringe contrast measurement. A first dark-field hologram with a tilted - object-free - reference wave was acquired and reconstructed. A new application for bright/dark field imaging is presented. PMID- 26624514 TI - Quantitative assessment of contact and non-contact lateral force calibration methods for atomic force microscopy. AB - Atomic Force Microscopy (AFM) has been widely used for measuring friction force at the nano-scale. However, one of the key challenges faced by AFM researchers is to calibrate an AFM system to interpret a lateral force signal as a quantifiable force. In this study, five rectangular cantilevers were used to quantitatively compare three different lateral force calibration methods to demonstrate the legitimacy and to establish confidence in the quantitative integrity of the proposed methods. The Flat-Wedge method is based on a variation of the lateral output on a surface with flat and changing slopes, the Multi-Load Pivot method is based on taking pivot measurements at several locations along the cantilever length, and the Lateral AFM Thermal-Sader method is based on determining the optical lever sensitivity from the thermal noise spectrum of the first torsional mode with a known torsional spring constant from the Sader method. The results of the calibration using the Flat-Wedge and Multi-Load Pivot methods were found to be consistent within experimental uncertainties, and the experimental uncertainties of the two methods were found to be less than 15%. However, the lateral force sensitivity determined by the Lateral AFM Thermal-Sader method was found to be 8-29% smaller than those obtained from the other two methods. This discrepancy decreased to 3-19% when the torsional mode correction factor for an ideal cantilever was used, which suggests that the torsional mode correction should be taken into account to establish confidence in Lateral AFM Thermal-Sader method. PMID- 26624515 TI - Dopant profiling based on scanning electron and helium ion microscopy. AB - In this paper, we evaluate and compare doping contrast generated inside the scanning electron microscope (SEM) and scanning helium ion microscope (SHIM). Specialised energy-filtering techniques are often required to produce strong doping contrast to map donor distributions using the secondary electron (SE) signal in the SEM. However, strong doping contrast can be obtained from n-type regions in the SHIM, even without energy-filtering. This SHIM technique is more sensitive than the SEM to donor density changes above its sensitivity threshold, i.e. of the order of 10(16) or 10(17)donorscm(-3) respectively on specimens with or without a p-n junction; its sensitivity limit is well above 2*10(17)acceptorscm(-3) on specimens with or without a p-n junction. Good correlation is found between the widths and slopes of experimentally measured doping contrast profiles of thin p-layers and the calculated widths and slopes of the potential energy distributions across these layers, at a depth of 1 to 3nm and 5 to 10nm below the surface in the SHIM and the SEM respectively. This is consistent with the mean escape depth of SEs in silicon being about 1.8nm and 7nm in the SHIM and SEM respectively, and we conclude that short escape depth, low energy SE signals are most suitable for donor profiling. PMID- 26624516 TI - Outwitting the series resistance in scanning spreading resistance microscopy. AB - The performance of nanoelectronics devices critically depends on the distribution of active dopants inside these structures. For this reason, dopant profiling has been defined as one of the major metrology challenges by the international technology roadmap of semiconductors. Scanning spreading resistance microscopy (SSRM) has evolved as one of the most viable approaches over the last decade due to its excellent spatial resolution, sensitivity and quantification accuracy. However, in case of advanced device architectures like fins and nanowires a proper measurement of the spreading resistance is often hampered by the increasing impact of parasitic series resistances (e.g. bulk series resistance) arising from the confined nature of the aforementioned structures. In order to overcome this limitation we report in this paper the development and implementation of a novel SSRM mode (fast Fourier transform-SSRM: FFT-SSRM) which essentially decouples the spreading resistance from parasitic series resistance components. We show that this can be achieved by a force modulation (leading to a modulated spreading resistance signal) in combination with a lock-in deconvolution concept. In this paper we first introduce the principle of operation of the technique. We discuss in detail the underlying physical mechanisms as well as the technical implementation on a state-of-the-art atomic force microscope (AFM). We demonstrate the performance of FFT-SSRM and its ability to remove substantial series resistance components in practice. Eventually, the possibility of decoupling the spreading resistance from the intrinsic probe resistance will be demonstrated and discussed. PMID- 26624517 TI - Past experience shapes ongoing neural patterns for language. AB - Early experiences may establish a foundation for later learning, however, influences of early language experience on later neural processing are unknown. We investigated whether maintenance of neural templates from early language experience influences subsequent language processing. Using fMRI, we scanned the following three groups performing a French phonological working memory (PWM) task: (1) monolingual French children; (2) children adopted from China before age 3 who discontinued Chinese and spoke only French; (3) Chinese-speaking children who learned French as a second language but maintained Chinese. Although all groups perform this task equally well, brain activation differs. French monolinguals activate typical PWM brain regions, while both Chinese-exposed groups also activate regions implicated in cognitive control, even the adoptees who were monolingual French speakers at testing. Early exposure to a language, and/or delayed exposure to a subsequent language, continues to influence the neural processing of subsequently learned language sounds years later even in highly proficient, early-exposed users. PMID- 26624518 TI - Inactivation mechanism of chlorination in Escherichia coli internalized in Limnoithona sinensis and Daphnia magna. AB - Zooplankton may harbor microorganisms in the aquatic environment, thus protecting them from disinfection during drinking water treatment. However, few studies have evaluated the protective effect of internalization by zooplankton against bacterial disinfection. In this study, we investigated the role of zooplankton (Limnoithona sinensis and Daphnia magna) as a refuge for ingested bacteria against inactivation by chlorination. Only 30% of chlorine reached the internalized bacteria inside the digestive tract of zooplankton. However, this was sufficient to achieve 1.4 log inactivation of internalized Escherichia coli in L. sinensis and 1.2 log inactivation in D. magna at Ct values of 80 mg min/L. Inactivation of internalized bacteria was achieved through the active transfer of free chlorine in the bulk water into the zooplankton digestive tract during grazing activity. D. magna was more sensitive to hypochlorous acid than L. sinensis, and its grazing behavior was inhibited during the inactivation experiment. PMID- 26624519 TI - Evaluation of the potentials of humic acid removal in water by gas phase surface discharge plasma. AB - Degradation of humic acid (HA), a predominant type of natural organic matter in ground water and surface waters, was conducted using a gas phase surface discharge plasma system. HA standard and two surface waters (Wetland, and Weihe River) were selected as the targets. The experimental results showed that about 90.9% of standard HA was smoothly removed within 40 min's discharge plasma treatment at discharge voltage 23.0 kV, and the removal process fitted the first order kinetic model. Roles of some active species in HA removal were studied by evaluating the effects of solution pH and OH radical scavenger; and the results presented that O3 and OH radical played significant roles in HA removal. Scanning electron microscope (SEM) and FTIR analysis showed that HA surface topography and molecular structure were changed during discharge plasma process. The mineralization of HA was analyzed by UV-Vis spectrum, dissolved organic carbon (DOC), specific UV absorbance (SUVA), UV absorption ratios, and excitation emission matrix (EEM) fluorescence. The formation of disinfection by-products during HA sample chlorination was also identified, and CHCl3 was detected as the main disinfection by-product, but discharge plasma treatment could suppress its formation to a certain extent. In addition, approximately 82.3% and 67.9% of UV254 were removed for the Weihe River water and the Wetland water after 40 min of discharge plasma treatment. PMID- 26624520 TI - Assessing the Protective Activity of a Recently Discovered Phenolic Compound against Oxidative Stress Using Computational Chemistry. AB - The protection exerted by 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA), a phenolic compound recently isolated from the Pacific oyster, against oxidative stress (OS) is investigated using the density functional theory. Our results indicate that DHMBA is an outstanding peroxyl radical scavenger, being about 15 times and 4 orders of magnitude better than Trolox for that purpose in lipid and aqueous media, respectively. It was also found to react faster with HOO(*) than other known antioxidants such as resveratrol and ascorbic acid. DHMBA is also predicted to be able to sequester Cu(II) ions, consequently inhibiting the OS induced by Cu(II)-ascorbate mixtures and downgrading the (*)OH production via the Haber-Weiss reaction. However, it is proposed that DHMBA is more efficient as a primary antioxidant (free radical scavenger), than as a secondary antioxidant (metal ion chelator). In addition, it was found that DHMBA can be efficiently regenerated in aqueous solution, at physiological pH. Such regeneration is expected to contribute to increase the antioxidant protection exerted by DHMBA. These results suggest that probably synthetic routes for this compound should be pursued, because albeit its abundance in nature is rather low, its antioxidant activity is exceptional. PMID- 26624521 TI - Temperature Dependent Solvation and Partitioning of Coumarin 152 in Phospholipid Membranes. AB - Time resolved fluorescence emission was used to quantify coumarin 152 (C152) partitioning into a model lipid vesicle membrane. For these studies, the lipid vesicles were composed of the symmetric, saturated phosphocholine, 1,2 dimyristoyl-sn-glycero-3-phosphocholine (14:0 DMPC). C152 fluorescence lifetimes were measured as a function of sample temperature, and changes in the relative contributions of these lifetimes (corrected for quantum yield) to the overall emission decay data were attributed to changes in the distribution of C152 solutes between the aqueous buffer, the polar vesicle headgroup region, and the hydrophobic interior of the vesicle bilayer. When the bilayer was in its more rigid, gel state, C152 remained predominantly in the aqueous buffer. Upon melting to its liquid crystalline state, each bilayer showed evidence of accommodating more C152 into a polar region associated with the lipid headgroups. At no temperature did C152 show strong affinity for the bilayer's hydrophobic interior. Above 50 degrees C, this behavior reversed itself with C152 moving back out of the vesicle membrane and into the buffer. All observed changes in partitioning behavior were reversible. The interesting temperature dependence of C152 partitioning suggests that C152 solvation within the lipid headgroup region represents a sensitive balance between enthalpic and entropic contributions with C152 accommodation by the bilayer being exothermic but entropically unfavorable. PMID- 26624522 TI - Characteristics and degradation of carbon and phosphorus from aquatic macrophytes in lakes: Insights from solid-state (13)C NMR and solution (31)P NMR spectroscopy. AB - Water extractable organic matter (WEOM) derived from macrophytes plays an important role in biogeochemical cycling of nutrients, including carbon (C), nitrogen (N) and phosphorus (P) in lakes. However, reports of their composition and degradation in natural waters are scarce. Therefore, compositions and degradation of WEOM derived from six aquatic macrophytes species of Tai Lake, China, were investigated by use of solid-state (13)C NMR and solution (31)P NMR spectroscopy. Carbohydrates were the predominant constituents of WEOM fractions, followed by carboxylic acid. Orthophosphate (ortho-P) was the dominant form of P (78.7% of total dissolved P) in the water extracts, followed by monoester P (mono P) (20.6%) and little diester P (0.65%). The proportion of mono-P in total P species increased with the percentage of O-alkyl and O-C-O increasing in the WEOM, which is likely due to degradation and dissolution of biological membranes and RNA from aquatic plants. Whereas the proportion of mono-P decreased with alkyl-C, NCH/OCH3 and COO/N-C=O increasing, which may be owing to the insoluble compounds including C functional groups of alkyl-C, NCH/OCH3 and COO/N-C=O, such as aliphatic biopolymers, lignin and peptides. Based on the results of this study and information in the literature about water column and sediment, we propose that WEOM, dominated by polysaccharides, are the most labile and bioavailable component in debris of macrophytes. Additionally, these WEOMs would also be a potential source for bioavailable organic P (e.g., RNA, DNA and phytate) for lakes. PMID- 26624523 TI - Facial emotion processing in patients with social anxiety disorder and Williams Beuren syndrome: an fMRI study. AB - BACKGROUND: Social anxiety disorder (SAD) and Williams-Beuren syndrome (WBS) are 2 conditions with major differences in terms of genetics, development and cognitive profiles. Both conditions are associated with compromised abilities in overlapping areas, including social approach, processing of social emotional cues and gaze behaviour, and to some extent they are associated with opposite behaviours in these domains. We examined common and distinct patterns of brain activation during a facial emotion processing paradigm in patients with SAD and WBS. METHODS: We examined patients with SAD and WBS and healthy controls matched by age and laterality using functional MRI during the processing of happy, fearful and angry faces. RESULTS: We included 20 patients with SAD and 20 with WBS as well as 20 matched controls in our study. Patients with SAD and WBS did not differ in the pattern of limbic activation. We observed differences in early visual areas of the face processing network in patients with WBS and differences in the cortical prefrontal regions involved in the top-down regulation of anxiety and in the fusiform gyrus for patients with SAD. Compared with those in the SAD and control groups, participants in the WBS group did not activate the right lateral inferior occipital cortex. In addition, compared with controls, patients with WBS hypoactivated the posterior primary visual cortex and showed significantly less deactivation in the right temporal operculum. Participants in the SAD group showed decreased prefrontal activation compared with those in the WBS and control groups. In addition, compared with controls, participants with SAD showed decreased fusiform activation. Participants with SAD and WBS also differed in the pattern of activation in the superior temporal gyrus, a region that has been linked to gaze processing. LIMITATIONS: The results observed in the WBS group are limited by the IQ of the WBS sample; however, the specificity of findings suggests that the pattern of brain activation observed for WBS is more likely to reflect a neurobiological substrate rather than intellectual impairment per se. CONCLUSION: Patients with SAD and WBS showed common and specific patterns of brain activation. Our results highlight the role of cortical regions during facial emotion processing in individuals with SAD and WBS. PMID- 26624525 TI - Biobased Fat Mimicking Molecular Structuring Agents for Medium-Chain Triglycerides (MCTs) and Other Edible Oils. AB - To develop sustainable value-added materials from biomass, novel small-molecule sugar ester gelators were synthesized using biocatalysis. The facile one-step regiospecific coupling of the pro-antioxidant raspberry ketone glucoside and unsaturated or saturated long- and medium-chain fatty acids provides a simple approach to tailor the structure and self-assembly of the amphiphilic product. These low molecular weight molecules demonstrated the ability to self-assemble in a variety of solvents and exhibited supergelation, with a minimum gelation concentration of 0.25 wt %, in numerous organic solvents, as well as in a range of natural edible oils, specifically a relatively unstudied group of liquids: natural medium-chain triglyceride oils, notably coconut oil. Spectroscopic analysis details the gelator structure as well as the intermolecular noncovalent interactions, which allow for gelation. X-ray diffraction studies indicate fatty acid chain packing of gelators is similar to that of natural fats, signifying the crystalline nature may lead to desirable textural properties and mouthfeel. PMID- 26624526 TI - Key Roles of Lewis Acid-Base Pairs on ZnxZryOz in Direct Ethanol/Acetone to Isobutene Conversion. AB - The effects of surface acidity on the cascade ethanol-to-isobutene conversion were studied using ZnxZryOz catalysts. The ethanol-to-isobutene reaction was found to be limited by the secondary reaction of the key intermediate, acetone, namely the acetone-to-isobutene reaction. Although the catalysts with coexisting Bronsted acidity could catalyze the rate-limiting acetone-to-isobutene reaction, the presence of Bronsted acidity is also detrimental. First, secondary isobutene isomerization is favored, producing a mixture of butene isomers. Second, undesired polymerization and coke formation prevail, leading to rapid catalyst deactivation. Most importantly, both steady-state and kinetic reaction studies as well as FTIR analysis of adsorbed acetone-d6 and D2O unambiguously showed that a highly active and selective nature of balanced Lewis acid-base pairs was masked by the coexisting Bronsted acidity in the aldolization and self-deoxygenation of acetone to isobutene. As a result, ZnxZryOz catalysts with only Lewis acid-base pairs were discovered, on which nearly a theoretical selectivity to isobutene (~ 88.9%) was successfully achieved, which has never been reported before. Moreover, the absence of Bronsted acidity in such ZnxZryOz catalysts also eliminates the side isobutene isomerization and undesired polymerization/coke reactions, resulting in the production of high purity isobutene with significantly improved catalyst stability (<2% activity loss after 200 h time-on-stream). This work not only demonstrates a balanced Lewis acid-base pair for the highly active and selective cascade ethanol-to-isobutene reaction but also sheds light on the rational design of selective and robust acid-base catalyst for C-C coupling via aldolization reaction. PMID- 26624524 TI - Progranulin deficiency induces overactivation of WNT5A expression via TNF alpha/NF-kappaB pathway in peripheral cells from frontotemporal dementia-linked granulin mutation carriers. AB - BACKGROUND: Loss-of-function progranulin gene (GRN) mutations have been identified as the major cause of frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein 43 (TDP-43) pathology (frontotemporal lobar degeneration [FTLD]-TDP); however, little is known about the association between progranulin (PGRN) deficiency and neuronal loss in individuals with FTLD-TDP. Previously we reported enhanced proliferative activity associated with the activation of WNT5A/CDK6/pRb signalling in PGRN-deficient cells. The objective of this work was to elucidate the association between PGRN deficiency, WNT5A signalling and cell proliferation in immortalized lymphoblasts from carriers of the c.709-1G > A GRN mutation (asymptomatic and FTLD-TDP). METHODS: We assessed cell proliferation in carriers of the c.709-1G > A GRN gene mutation and controls without GRN mutation and without sign of neurologic degeneration by cell counting or using an MTT assay. We used a luciferase assay to measure the nuclear factor-kappa (NF-kappa) activity. We evaluated messenger RNA levels using quantitative real-time polymerase chain reaction and protein levels by immunoblotting. Co-immunoprecipitation was used to analyze the interaction between PGRN and its receptors. RESULTS: We enrolled 19 carriers of the GRN gene mutation and 10 controls in this study. The PGRN-deficient cells showed increased expression of WNT5A due to NF-kappaB signalling overactivation. We observed a competition between PGRN and tumour necrosis factor-alpha (TNF alpha) for binding both TNF receptors (TNFR) I and II. Blocking NF-kappaB signalling using wedelolactone or specific antibodies against TNFRs inhibited WNT5A overexpression and proliferation of PGRN-deficient cells. Conversely, the activation of NF-kappaB signalling by TNF-alpha increased WNT5A-dependent proliferation of control cells. LIMITATIONS: All cell lines were derived from individuals harboring the same splicing GRN mutation. Nevertheless, most of the known GRN mutations lead to haploinsufficiency of the protein. CONCLUSION: Our results revealed an important role of NF-kappaB signalling in PGRN-associated FTLD-TDP and confirm that PGRN can bind to TNF-alpha receptors regulating the expression of WNT5A, suggesting novel targets for treatment of FTLD-TDP linked to GRN mutations. PMID- 26624527 TI - Novel Ruthenium Sensitizers with a Phenothiazine Conjugated Bipyridyl Ligand for High-Efficiency Dye-Sensitized Solar Cells. AB - Two efficient ruthenium sensitizers with a phenothiazine-modified bipyridine as an ancillary ligand, coded SCZ-1 and SCZ-2, have been developed as dyes in dye sensitized solar cells (DSSCs). Both sensitizers exhibit low-energy metal-to ligand charge transfer (MLCT) bands centered at 539 nm with high molar extinction coefficients of 1.77 * 10(4) M(-1) cm(-1) for SCZ-1 and 1.66 * 10(4) M(-1) cm(-1) for SCZ-2, which are significantly higher than the corresponding value for the reference N719 (1.27 * 10(4) M(-1) cm(-1)), indicating that the light-harvesting capacity of ruthenium sensitizers can be reinforced by introducing phenothiazine moieties into the bipyridine ligand. Under AM 1.5G irradiation (100 mW cm(-2)), SCZ-1 and SCZ-2 sensitized DSSC devices show impressive power conversion efficiencies (PCE) up to 10.4% by using of iodide-based electrolytes, which exceeds that of N719 (9.9%) under the same conditions. Both of the open circuit voltage (VOC) and fill factor (FF) of SCZ-sensitized solar cells approximate to those of N719-sensitized cell. The relatively higher efficiencies of the SCZ sensitized cells than that of N719-sensitized cell come from their higher short circuit photocurrent density (JSC), which may be mainly attributed to the high absorption coefficient. The absorption spectrum and device efficiency of SCZ-1 are both quite close to those of SCZ-2, suggesting that the difference in alkyl chains on the N atom of phenothiazine is not a decisive factor in affecting the photovoltaic performance of dyes. PMID- 26624528 TI - Structure of Neat Liquids Consisting of (Perfect and Nearly) Tetrahedral Molecules. PMID- 26624529 TI - High efficient removal of fluoride from aqueous solution by a novel hydroxyl aluminum oxalate adsorbent. AB - A novel adsorbent, hydroxyl aluminum oxalate (HAO), for the high efficient removal of fluoride from aqueous solution was successfully synthesized. The adsorbent was characterized and its performance in fluoride (F(-)) removal was evaluated for the first time. Kinetic data reveal that the F(-) adsorption is rapid in the beginning followed by a slower adsorption process; 75.9% adsorption can be achieved within 1min and only 16% additional removal occurred in the following 239min. The F(-) adsorption kinetics was well described by the pseudo second-order kinetic model. The calculated adsorption capacity of this adsorbent for F(-) by Langmuir model was 400mgg(-1) at pH 6.5, which is one of the highest capabilities of today's materials. The thermodynamic parameters calculated from the temperature-dependent isotherms indicate that the adsorption reaction of F(-) on the HAO is a spontaneous process. The FT-IR spectra of HAO before and after adsorbing F(-) show adsorption mechanism should be hydroxyl and oxalate interchange with F(-). PMID- 26624530 TI - Microfluidic preparation of a highly active and stable catalyst by high performance of encapsulation of polyvinylpyrrolidone (PVP)-Pt nanoparticles in microcapsules. AB - The encapsulation of active metals in microcapsules would be highly advantageous in maintaining or improving the reaction performance of an array of widely used chemical reactions. However, conventional methods suffer from low uniformity, complicated fabrication steps, sintering, leaching, decline of catalytic activity, and/or poor reusability. Here, we report an efficient microfluidic approach to encapsulate Pt nanoparticle stabilized by polyvinylpyrrolidone (PVP) in photocurable double-emulsion droplets with semipermeable thin shells. The encapsulated catalysts are prepared by the in situ photopolymerization of a double emulsion. The rapid and exquisite microfluidics-based fabrication process successfully generates monodisperse microcapsules without loss of the PVP-Pt nanoparticles, which is the first demonstration of the microfluidic encapsulation of active metal with promising catalytic activity. Specifically, compared to quasi-homogeneous catalysis of PVP-Pt nanoparticles for 4-nitrophenol hydrogenation, the encapsulated PVP-Pt nanoparticles demonstrate excellent catalytic activity, a leaching-proof nature, and high reusability under the same reaction conditions. We envision that the approach described here may be an example of elegant catalyst design to efficiently overcome difficult problems in active-metal encapsulation and to dramatically enhance catalytic activity by taking advantage of the unique aspects of microfluidic methods. PMID- 26624531 TI - Role of coating agent in iron oxide nanoparticle formation in an aqueous dispersion: Experiments and simulation. AB - Iron oxide (Fe3O4) nanoparticle was synthesized by coprecipitation and was modeled and solved using a hybrid (discrete-continuous) model, based on a kinetic Monte Carlo (kMC) simulation scheme. The latter was combined with the constant number MC method, to improve both speed and accuracy of the simulation. Complete particle size distribution (PSD) from simulation matches very well with PSD of both uncoated and coated (with either polyacrylic acid or dextran) Fe3O4 nanoparticles, obtained from our experiments. The model is general, as the time scales of various processes (nucleation, diffusion-growth and coagulation-growth) are incorporated in rate equations, while, input simulation parameters are experimentally measured quantities. With the help of the validated model, effect of coating agent on coagulation-growth was estimated by a single, fitted, coagulation-efficiency parameter. Our simulation shows that, logarithm of coagulation-efficiency scales linearly with logarithm of inverse of the molecular weight of the coating agent. With this scaling law, our model is able to a priori predict the experimental PSD of Fe3O4 nanoparticles, synthesized with an even higher molecular weight of dextran. PMID- 26624532 TI - Surface interactions, thermodynamics and topography of binary monolayers of Insulin with dipalmitoylphosphatidylcholine and 1-palmitoyl-2 oleoylphosphatidylcholine at the air/water interface. AB - The molecular packing, thermodynamics and surface topography of binary Langmuir monolayers of Insulin and DPPC (dipalmitoylphosphatidylcholine) or POCP (1 palmitoyl-2-oleoylphosphatidylcholine) at the air/water interface on Zn(2+) containing solutions were studied. Miscibility and interactions were ascertained by the variation of surface pressure-mean molecular area isotherms, surface compressional modulus and surface (dipole) potential with the film composition. Brewster Angle Microscopy was used to visualize the surface topography of the monolayers. Below 20mN/m Insulin forms stable homogenous films with DPPC and POPC at all mole fractions studied (except for films with XINS=0.05 at 10mN/m where domain coexistence was observed). Above 20mN/m, a segregation process between mixed phases occurred in all monolayers without squeezing out of individual components. Under compression the films exhibit formation of a viscoelastic or kinetically trapped organization leading to considerable composition-dependent hysteresis under expansion that occurs with entropic-enthalpic compensation. The spontaneously unfavorable interactions of Insulin with DPPC are driven by favorable enthalpy that is overcome by unfavorable entropic ordering; in films with POPC both the enthalpic and entropic effects are unfavorable. The surface topography reveals domain coexistence at relatively high pressure showing a striped appearance. The interactions of Insulin with two major membrane phospholipids induces composition-dependent and long-range changes of the surface organization that ought to be considered in the context of the information transducing capabilities of the hormone for cell functioning. PMID- 26624533 TI - Investigation on the adsorption of phosphorus by Fe-loaded ceramic adsorbent. AB - This aim of this study was to remove phosphorus from aqueous solution using a Fe loaded ceramic (Fe-LC) adsorbent prepared by mixing dolomite, montmorillonite, FeSO4.7H2O and starch. Simplex-centroid mixture design method was used to determine the optimum mixture proportions by evaluating both phosphorus adsorption efficiency and adsorbent hardness. The study found that the optimum adsorption capacity and the strength can be achieved with the composition of 3.87g dolomite, 3.00g starch, 2.13g montmorillonite and 1.00g FeSO4.7H2O (10g in total). The optimized Fe-LC was evaluated in the batch and the fixed bed experiments. The point of zero charge, pHpzc was found to be 6.0. The adsorption kinetic and isotherm data well agreed with the pseudo-second-order kinetic and the Langmuir isotherm models, respectively. The breakthrough time increased with increasing in the bed depth, whereas inverse relationship was observed with the initial phosphorus concentration in the fixed bed studies. The co-existing anions (SO4(2-), NO3(-) and Cl(-)) had negligible influence on phosphorus removal. The BDST and Thomas model explained the breakthrough behavior for phosphorus removal with a high degree of correlation. PMID- 26624534 TI - Functional protein micropatterning for drug design and discovery. AB - INTRODUCTION: The past decade has witnessed tremendous progress in surface micropatterning techniques for generating arrays of various types of biomolecules. Multiplexed protein micropatterning has tremendous potential for drug discovery providing versatile means for high throughput assays required for target and lead identification as well as diagnostics and functional screening for personalized medicine. However, ensuring the functional integrity of proteins on surfaces has remained challenging, in particular in the case of membrane proteins, the most important class of drug targets. Yet, generic strategies to control functional organization of proteins into micropatterns are emerging. AREAS COVERED: This review includes an overview introducing the most common approaches for surface modification and functional protein immobilization. The authors present the key photo and soft lithography techniques with respect to compatibility with functional protein micropatterning and multiplexing capabilities. In the second part, the authors present the key applications of protein micropatterning techniques in drug discovery with a focus on membrane protein interactions and cellular signaling. EXPERT OPINION: With the growing importance of target discovery as well as protein-based therapeutics and personalized medicine, the application of protein arrays can play a fundamental role in drug discovery. Yet, important technical breakthroughs are still required for broad application of these approaches, which will include in vitro "copying" of proteins from cDNA arrays into micropatterns, direct protein capturing from single cells as well as protein microarrays in living cells. PMID- 26624554 TI - Ending the HIV-AIDS Pandemic--Follow the Science. PMID- 26624555 TI - Psychosocial Issues in Acne Management: Disease Burden, Treatment Adherence, and Patient Support. AB - Physical and emotional scarring are equally important burdens of acne vulgaris in patients of any age. Effective therapeutic regimens are readily available, and the consistent and correct use of these medications results in effective disease management, reduced risk for scarring, as well as improvement in various factors that affect quality of life. Nevertheless, adherence to treatment recommendations generally is poor. Clinicians can help improve adherence with a variety of strategies, including counseling, education, and choosing treatment options that are most consistent with a patient's lifestyle. Semin Cutan Med Surg 34(supp5):S92-S94 (c) 2015 published by Frontline Medical Communications. PMID- 26624556 TI - Brimonidine Can Prevent In Vitro Hydroquinone Damage on Retinal Pigment Epithelium Cells and Retinal Muller Cells. AB - PURPOSE: Brimonidine is a selective alpha-2 adrenergic agonist used to reduce intraocular pressure and it has been shown to have some neuroprotective effects. Hydroquinone (HQ) is a toxicant present in cigarette smoke, and other sources. In this study, we investigated the cyto-protective effects in vitro of Brimonidine on human retinal pigment epithelium cells (ARPE-19) and human retinal Muller cells (MIO-M1) that had been treated with HQ. METHODS: Cells were pretreated for 6 h with different doses of Brimonidine tartrate 0.1% (1/2*, 1*, 5*, 10*), followed by a 24-h exposure to 100 MUM of HQ, while the Brimonidine was still present. Assays were used to measure cell viability, mitochondrial membrane potential (DeltaPsim), reactive oxygen species (ROS) production, and lactate dehydrogenase (LDH) release. RESULTS: Brimonidine increased the cell viability at all concentrations studied in both cell lines studied. DeltaPsim also improved at all Brimonidine doses in ARPE-19 cells and in the 5* and 10* dosages MIO-M1 cells. The ROS levels decreased at 1*, 5*, and 10* doses of Brimonidine in ARPE 19 but only at 10* on MIO-M1 cells. The 10*-Brimonidine ARPE-19 cells had decreased LDH release, but no LDH changes were observed on MIO-M1 cells. CONCLUSION: HQ-induced toxicity is mediated through mitochondrial damaging, oxidative stress-related and necrosis-related pathways; Brimonidine significantly prevented the mitochondrial damaging and oxidative stress-related effects but had little effect on blocking the necrosis component of HQ-toxicity. Brimonidine protective effects differ between the different retinal cell types and high concentrations of Brimonidine (10*) have minimal damaging effects on human retinal cells. PMID- 26624557 TI - Reappraisal of adhesive strapping as treatment for infantile umbilical hernia. AB - BACKGROUND: Most umbilical hernias spontaneously close by 3-5 years of age; therefore, surgical repair is considered only in children whose hernias have not closed by this point. At present, adhesive strapping is not the preferred treatment for umbilical hernias because of the lack of supporting evidence regarding its efficacy, and its association with skin complications. This aim of this study was to examine umbilical hernia closure on ultrasonography, and reassess the merits of adhesive strapping. METHODS: Between January 2013 and December 2014, 89 infants underwent adhesive strapping for umbilical hernia. The strapping was changed once a week. The diameter of the hernia orifice was measured on ultrasonography every 2 weeks until closure. The closure speed (CS) of the hernia orifice was compared between the infants treated with adhesive strapping and those undergoing observation alone. The association between CS and birthweight, gestational age, diameter of the hernia orifice, and timing of treatment (before 12 weeks of age vs between 12 and 26 weeks of age) was also analyzed. RESULTS: Closure was achieved after 2-13 weeks of strapping in 81 infants (91%), and the likelihood of closure was not affected by the diameter of the hernia orifice, gestational age, or the timing of treatment. The mean CS of the infants treated with adhesive strapping was significantly faster than that of the infants undergoing observation alone (2.59 vs 0.37 mm/week, P < 0.05). Adhesive strapping was discontinued in five of the 89 infants (5.6%) due to severe skin complications. CONCLUSION: Adhesive strapping promoted early spontaneous umbilical hernia closure compared with observation alone, regardless of the diameter of the hernia orifice. Adhesive strapping is an effective alternative to surgery and observation. PMID- 26624559 TI - Similar Microcirculatory Alterations in Patients with Normodynamic and Hyperdynamic Septic Shock. AB - RATIONALE: In normodynamic septic shock, the quantitative assessment of sublingual microcirculation has shown decreases in perfused vascular density and red blood cell velocity. However, no studies have been performed in hyperdynamic septic shock. OBJECTIVES: To characterize the microcirculatory patterns and rule out the presence of fast red blood cell velocity in patients with hyperdynamic septic shock. METHODS: We prospectively evaluated the sublingual microcirculation in healthy volunteers (n = 20) and in patients with hyperdynamic (n = 20) and normodynamic (n = 20) septic shock. Hyperdynamic septic shock was defined by a cardiac index >4.0 L/min/m(2). The microcirculation was assessed with sidestream dark field imaging and AVA 3.0 software. MEASUREMENTS AND MAIN RESULTS: There were no differences in perfused vascular density, proportion of perfused vessels, or microvascular flow index between patients with hyperdynamic and normodynamic septic shock, but these variables were reduced compared with those of healthy volunteers, A similar pattern was observed in red blood cell velocity (912 +/- 291, 968 +/- 204, and 1303 +/- 120 MUm/s, respectively; P < 0.0001) and its coefficient of variation. In both types of septic shock, no microvessel had a red blood cell velocity higher than the 100th percentile value for healthy volunteers. CONCLUSIONS: Patients with hyperdynamic septic shock showed microcirculatory alterations similar to those of patients with normal cardiac output. Both groups of patients had reduced perfused vascular density and red blood cell velocity and increased flow heterogeneity compared with that of healthy subjects. Fast red blood cell velocity was not found, even in patients with high cardiac output. These results support the conclusion that microcirculatory function is frequently dissociated from systemic hemodynamic derangements in septic shock. PMID- 26624560 TI - Assessment of skills using a spacer device for a metered-dose inhaler and related independent predictive factors in caregivers of asthmatic preschool children. AB - BACKGROUND: The correct use of inhalation devices is essential for successful therapy. We aimed to evaluate the skills in the use of a spacer device with an metered-dose inhaler (MDI) and factors that influence this skill in asthmatic preschool children's caregivers. METHODS: The caregivers of 12-month-old to 72 month-old children were interviewed face-to-face and filled out questionnaires. To assess use of the spacer device, we asked the caregivers to verbally describe and demonstrate how they used the device. RESULTS: A total of 244 patients were included in the study, and 142 (58.2%) of the caregivers demonstrated every step for using the spacer device. The most frequently mistaken step was waiting for 30 seconds for the second puff after the first puff. When statistically significant and clinically important parameters were analyzed in a logistic regression model, the parameters satisfaction with the spacer device (odds ratio [OR] 29.9; 95% confidence interval [CI], 7.64 to 117.39; p < 0.001), a university graduate (OR 13.5; 95% CI, 3.36 to 54.8; p < 0.001), family monthly income of more than US$1500 (OR 5.3; 95% CI, 2.16 to 13.39; p < 0.001), device training provided by a clinical trainer (OR 12.3; 95% CI, 4.82 to 31.73; p < 0.001), regular follow-ups (OR 3.6; 95% CI, 1.57 to 8.47; p = 0.003), and the absence of a severe attack during the last year (OR 6.5; 95% CI, 2.64 to 16.43; p < 0.001) were found to be independent factors that affected the correct demonstration of the device. CONCLUSION: The factors most effective in the correct use of the MDI spacer device were satisfaction with the device, training having been given by a clinical trainer on this subject, and the caregiver being a university graduate. PMID- 26624561 TI - House passes 21st Century Cures Act: Legislation would boost NIH funding, speed drug development. PMID- 26624562 TI - Regular coffee consumption may improve survival in patients with colon cancer. PMID- 26624563 TI - Younger patients with breast cancer may decline tamoxifen due to fertility concerns. PMID- 26624565 TI - Moreira DM, Nickel JC, Gerber L, Muller RL, Andriole GL, Castro-Santamaria R and Freedland SJ. Baseline prostate inflammation is associated with a reduced risk of prostate cancer in men undergoing repeat prostate biopsy: Results from the REDUCE study. Cancer. 2014;120:190-196. PMID- 26624564 TI - Diet quality of cancer survivors and noncancer individuals: Results from a national survey. AB - BACKGROUND: Patterns of poor nutritional intake may exacerbate the elevated morbidity experienced by cancer survivors. It remains unclear whether cancer survivors adhere to existing dietary guidelines and whether survivors' diets differ from those of individuals without cancer over the long term. METHODS: The authors evaluated dietary intake and quality in 1533 adult cancer survivors who participated in the National Health and Nutrition Examination Survey from 1999 to 2010 compared with dietary intake and quality in 3075 individuals who had no history of cancer and were matched to the cancer survivors by age, sex, and race/ethnicity. Dietary intake was assessed using 24-hour dietary recalls. The 2010 Healthy Eating Index (HEI-2010) was used to evaluate diet quality. RESULTS: The mean +/- standard deviation HEI-2010 total score was 47.2 +/- 0.5 in the cancer survivors and 48.3 +/- 0.4 in the noncancer group (P = .03). Compared with the noncancer group, cancer survivors had a significantly lower score for empty calories (13.6 vs 14.4; P = .001), which corresponded to worse adherence to dietary intake of calories from solid fats, alcohol, and added sugars. Cancer survivors also had significantly lower dietary intake of fiber than the noncancer group (15.0 vs 15.9 g per day; P = .02). In relation to recommended intake, survivors' mean dietary intake of vitamin D, vitamin E, potassium, fiber, and calcium was 31%, 47%, 55%, 60%, and 73%, respectively; whereas their mean dietary intake of saturated fat and sodium was 112% and 133%, respectively, of the recommended intake. CONCLUSIONS: Cancer survivors had poor adherence to the US Department of Agriculture 2010 Dietary Guidelines for Americans, and their intake patterns were worse than those in the general population for empty calories and fiber. PMID- 26624566 TI - Moreira DM, Aronson WJ, Terris MK, Kane CJ, Amling CL, Cooperberg MR, Boffetta P and Freedland SJ. Cigarette smoking is associated with an increased risk of biochemical disease recurrence, metastasis, castration-resistant prostate cancer, and mortality after radical prostatectomy. Cancer. 2014;120:197-204. PMID- 26624567 TI - Polycystic ovary syndrome and metabolic syndrome: the worrisome twosome? AB - By virtue of insulin resistance being the common etiology for polycystic ovary syndrome (PCOS) and metabolic syndrome, the cardiometabolic risks of these two syndromes are shared. The usual concerns of a PCOS patient are cosmetic or reproductive. However, there are more serious concerns past the reproductive age. Early treatment of insulin resistance, hypertension and hyperlipidemia reduces the long-term risk. This review highlights the unhealthy association of metabolic syndrome with PCOS and emphasizes the importance of early diagnosis, patient education and long-term follow-up beyond the reproductive age into menopause to prevent the long-term serious co-morbidities. PMID- 26624568 TI - Nickel-Catalyzed Formal Homocoupling of Methoxyarenes for the Synthesis of Symmetrical Biaryls via C-O Bond Cleavage. AB - A new method has been developed for the nickel-catalyzed homocoupling of methoxyarenes via C-O bond cleavage using a diboron reagent. The use of 1,3 dicyclohexylimidazol-2-ylidene as a ligand was found to be critical to the success of the reaction. This new method allows the synthesis of a wide range of biaryl compounds. PMID- 26624573 TI - Directed forgetting of negative performed actions is difficult: A behavioural study. AB - Strong evidence suggests that both performing actions and emotional stimuli can enhance memory by capturing attention. However, the synergetic effect of the two factors on directed forgetting has not been assessed. In this study, we used an item-method directed forgetting paradigm to examine the forgetting of emotional materials depending on whether actions were performed. The results showed that action performance influenced the directed forgetting of emotional words. Specifically, when actions were performed there was a directed forgetting effect for neutral and positive words but not for negative words. In comparison, for verbal tasks, directed forgetting was observed for all words. The elaborative encoding prior to the remember/forget instructions and the influence of negative emotion on attentional inhibition after the presentation of the instructions together suggest that it is more difficult to intentionally forget negative performed actions. PMID- 26624574 TI - The role of tensor veli palatini muscle (TVP) and levetor veli palatini [corrected] muscle (LVP) in the opening and closing of pharyngeal orifice of Eustachian tube. AB - CONCLUSION: This study developed an easy way to induce otitis media in an animal model and find the relation between tensor veli palatini muscle (TVP) and levetor veli palatini [corrected] muscle (LVP) in the opening and closing of the pharyngeal orifice of Eustachian tube. It was proved that otitis media is caused due to the dysfunction of Eustachian tube and the only muscle responsible for opening and closing of ETPO (Eustachian tube pharyngeal orifice) is TVP and LVP has no role in the opening and closing of the Eustachian tube pharyngeal orifice. OBJECTIVE: To develop valid animal model for otitis media of effusion and to study the relation of paratubular muscles in the functioning of Eustachian tube. METHODS: Two different methods were used to induce middle ear disease: (1) Excision of tensor veli palatini and levetor veli palatini [corrected] muscles (TVP and LVP); and (2) Injection of botulinum toxin type A on TVP and LVP. RESULT: Otomiscroscopic, tympanograph, and pathological examination showed the presence of middle ear disease in those animals whose TVP was excised and paralyzed, but on those groups of animals whose LVP was excised and paralyzed, abnormalities were seen. PMID- 26624575 TI - Motion sickness and sopite syndrome associated with parabolic flights: a case report. AB - OBJECTIVE: The purpose of this paper was to provide an extensive description of a case of sopite syndrome, a manifestation of motion sickness scarcely described in the literature. DESIGN: The following questionnaires were used to assess sopite syndrome symptoms pre, during and post parabolic flight; Misery Scale rate, Positive and Negative Affect Scale, the Motion Sickness Assessment Questionnaire and the Epworth Sleepiness Scale. STUDY SAMPLE: Case report of a 35-year old female compared to a control group (n = 26). RESULTS: We describe of sopite syndrome during parabolic flight. The subject reported drowsiness and she noted mood changes such as irritation and annoyance. Furthermore, she was not able to perform her assigned task. Her symptoms escalated into extreme fatigue and the inability to stay awake. Nauseogenic symptoms improved, but soporific symptoms persisted for several hours after the motion stimulus (i.e. parabolic flight). CONCLUSIONS: This case points towards the need for controlled studies to assess the prevalence of this syndrome among the general population and select groups. Future research should focus on developing tests for personnel screening and explore treatment options. PMID- 26624576 TI - Correction: The importance of hydration and DNA conformation in interpreting infrared spectra of cells and tissues. AB - Correction for 'The importance of hydration and DNA conformation in interpreting infrared spectra of cells and tissues' by Bayden R. Wood et al., Chem. Soc. Rev., 2015, DOI: . PMID- 26624577 TI - Effects of Essential Oil from Hinoki Cypress, Chamaecyparis obtusa, on Physiology and Behavior of Flies. AB - Phytoncides, which are volatile substances emitted from plants for protection against plant pathogens and insects, are known to have insecticidal, antimicrobial, and antifungal activities. In contrast to their negative effects on microorganisms and insects, phytoncides have been shown to have beneficial effects on human health. Essential oil from Hinoki cypress (Chamaecyparis obtusa) is mostly used in commercial products such as air purifiers. However, the physiological/behavioral impact of essential oil from C. obtusa on insects is not established. In this study, we tested the effects of essential oil extracted from C. obtusa on the physiologies and behaviors of Drosophila melanogaster and Musca domestica. Exposure to essential oil from C. obtusa decreased the lifespan, fecundity, locomotive activity, and developmental success rate of D. melanogaster. In addition, both fruit flies and house flies showed strong repellent behavioral responses to the essential oil, with duration times of about 5 hours at 70 MUg/ml. These results suggest that essential oil from C. obtusa can be used as a 'human-friendly' alternative insect repellent. PMID- 26624578 TI - Ultrasonographic Measurement of the Achilles and Supraspinatus Tendon Thicknesses in Patients with Chronic Lead Exposure. AB - OBJECTIVE: The study aimed to assess tendon thickness in patients with chronic occupational lead exposure by using ultrasonography. METHODS: Twenty-seven male workers (mean age 32.9 +/- 6.2 years, range 25-44 years) with occupational lead exposure and 27 age- and body mass index (BMI)-matched healthy male subjects (mean age 33.1 +/- 5.6 years, range 25-44 years) were enrolled. Ultrasonographic measurements were obtained from the supraspinatus and Achilles tendons by using a linear probe (5-10 MHz). RESULTS: Mean Achilles tendon values at long axis (p = 0.034) and tendon cross-sectional area (p = 0.013) were significantly smaller in the lead-exposed group than the control group. On the other hand, no significant difference was found regarding the thickness of the supraspinatus tendon (p > 0.05). CONCLUSION: Our preliminary results imply that subjects with occupational lead exposure have smaller Achilles tendons than healthy subjects. Chronic lead exposure may affect the tendons due to reduction of collagen synthesis. Further studies are definitely needed to confirm our initial findings. PMID- 26624579 TI - Primary Cardiac Angiosarcoma with Adrenal Metastasis. PMID- 26624580 TI - Investigation of the Blood Glucose Lowering Potential of the Jamaican Momordica charantia (Cerasee) Fruit in Sprague-Dawley Rats. AB - The Momordica charantia (MC) fruit has been documented to possess antidiabetic properties. However, these studies were not without controversy surrounding the blood glucose-lowering ability and the mechanism of action in diabetes therapy. In an effort to evaluate such claims in the Jamaican MC species known as cerasee, aqueous extracts of the unripe fruit were studied in normal and diabetic rats. Normal male Sprague-Dawley rats were divided into groups (n = 6) orally administered distilled water, 10% dimethyl sulfoxide (DMSO) solution, the aqueous extract (400 mg/kg body weight) and glibenclamide (15 mg/kg body weight), respectively prior to assessment of fasting blood glucose (FBG) concentration. The oral glucose tolerance test (OGTT) was conducted in normoglycaemic rats orally administered distilled water, 10% DMSO solution, glibenclamide (15 mg/kg body weight) or aqueous extracts of the fruit (200 and 400 mg/kg body weight). Blood glucose concentration was also monitored in streptozotocin-induced diabetic rats administered the aqueous extract (250 mg/kg body weight) or water vehicle after an overnight fast. The aqueous extracts showed no hypoglycaemic or antidiabetic activity. However, the administration of the aqueous extracts (200 and 400 mg/kg body weight) resulted in significant improvement in glucose tolerance of glucose-primed normoglycaemic rats during the OGTT. These data suggest that the glucose-lowering mechanism of the Jamaican MC fruit species likely involves altered glucose absorption across the gastrointestinal tract. PMID- 26624581 TI - Preliminary Investigations of the Anti-asthmatic Properties of the Aqueous Extract of Justicia pectoralis (Fresh Cut). AB - BACKGROUND: Justicia pectoralis (fresh cut plant), family Acantheceae, is a herb that is native to central America and the Caribbean. A crude extract prepared from the leaves of Justicia pectoralis is commonly used in Jamaican ethnotraditional medicine to reduce difficulty in breathing and suppress wheezing in asthmatic individuals. OBJECTIVES: To investigate the anti-inflammatory and antihistamine activity of an aqueous extract of Justicia pectoralis. METHOD: In in vivo experiments, guinea pigs were sensitized by the method of Weinrich and Undem (1987). The effect of water on the wheals was assessed in the control group, n = 4. The effect of 3.3 mg of the crude extract was noted in histamine induced wheals over a period of three hours. The extract was injected via intraperitoneal injections. In in vitro experiments, 3.3 mg of crude sample was tested for its effectiveness against histamine-induced tracheal contraction caused by cumulative dosing of histamine. RESULTS: The crude extract was efficacious in reducing the formation of histamine-induced wheals (p < 0.05). Results obtained from in vitro studies indicated that the crude extract (3.3 mg) caused significant reduction in tracheal smooth muscle contraction resulting from cumulative doses of histamine (p < 0.05). However, as the histamine doses increased, fresh cut extract was not able to maintain inhibition of histamine induced tracheal smooth muscle contraction. This is an indication that the extract showed competitive reversible antagonism, possibly at histamine receptors. CONCLUSION: A crude extract of the leaves Justicia pectoralis reduced the formation of histamine-induced wheals in sensitized guinea pigs (p < 0.05) and also reduced histamine-induced tracheal smooth muscle contractions (p < 0.05). It blocked the effect of contraction produced by histamine in the airways; this property supports folklore claims for its use as an antihistamine. PMID- 26624582 TI - Performance Assessment of the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism Method for Rapid Detection of Susceptibility to Ethambutol and Molecular Prediction of Extensively Drug-resistant Tuberculosis in Clinical Isolates of Mycobacterium tuberculosis. AB - INTRODUCTION: The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was employed for rapid detection of ethambutol (EMB) resistant clinical isolates of Mycobacterium tuberculosis. MATERIALS AND METHODS: From 182 clinical isolates of M tuberculosis collected from different regions, 103 strains were entered in the investigation. DNA was extracted by Chelex 100 method and PCR was performed using specific primers for embB gene. Polymerase chain reaction products were digested with HaeIII and NlaII restriction endonucleases and the patterns of restriction fragments were analysed. Some randomly selected samples were sequenced. RESULTS: Out of 103 studied strains, 52 were resistant to EMB. The cases of secondary tuberculosis were 53 (51.50 +/- 1.77%), and primary cases 50 (48.50 +/- 1.77%; p > 0.05). From 63 extensively drug-resistant (XDR), pre-XDR and multidrug-resistant (MDR) isolates, 27 (87%), 18 (81.8%) and 7 (70%) strains were resistant to EMB, respectively. Results of PCR-RFLP method showed that from 27R EMB XDR isolates, 13 (sensitivity 48% with CI: 0.307, 0.66 and specificity 100%), from 18R EMB pre XDR strains, 4 (sensitivity 22% with CI: 0.09, 0.45 and specificity 100%) and of 7R EMB MDR, 2 (sensitivity 28% with CI: 0.082, 0.64 and specificity 100%) had mutation in ATG-Met codon 306. Results of sequencing were concordant with RFLP method. Overall, sensitivity of the molecular method was 36.5% (CI: 0.09, 0.45) and specificity 100%. None of the 40 pansusceptible strains was embB306 mutants. Extensively drug-resistant strains had a higher proportion of embB306 mutants (43%) than pre-XDR and MDR isolates (odds ratio 6.78; p < 0.001). CONCLUSION: Fast detection of susceptibility to EMB drug is possible by PCR-RFLP. The embB306 locus is a candidate marker for rapid prediction of high resistance consisting of MDR and XDR forms to anti-tuberculosis drugs using this method. PMID- 26624583 TI - Atherosclerosis and Liver Function Tests in Coronary Angiography Patients. AB - OBJECTIVE: Elevated aminotransferase levels indicating liver function, even in the normal range, have attracted great concern as potential novel markers of cardiovascular risk assessment. We hypothesized the possibility that liver function test variations in the normal range might be meaningfully associated to coronary artery disease (CAD). METHOD: Eighty-eight patients were randomly selected from those who underwent coronary angiography from June 2010 to June 2011 after applying to the outpatient cardiology clinic in Gulhane Military Medical Academy. According to the results of angiographies, patients were classified into three groups as normal, non-critical (< 50% involvement in coronaries), and critical (>= 50% involvement in coronaries). In addition to angiographic intervention, measurements of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations, albumin and the other serum parameters were performed in all patients. RESULTS: The patient groups of CAD were balanced (28 critical cases, 30 non-critical cases and 30 normal cases). Mean age was 51.93 +/- 9.3 (range 32-65) years and 19.3 per cent (n = 17) were females. Multiple linear regression analysis of all three liver function tests explained a significant portion of the variance, but adjusted r-squares were small (AST = 0.174, ALT = 0.242, albumin = 0.124). Albumin was significantly higher for patients with critical CAD than for patients with no CAD (beta = 3.205, p = 0.002). Non-critical CAD was not significantly different from no CAD for any of the dependent variables. Mean AST was significantly higher for patients taking aspirin (beta = 0.218, p = 0.049), as was mean ALT (beta = 0.264, p = 0.015). CONCLUSION: Alanine aminotransferase and AST may not be associated with angiographically determined coronary atherosclerosis. Albumin may be more sensitive to demonstrate the burden of atherosclerosis. These results indicate that the association between the liver function tests and coronary atherosclerosis may be more complex than generally appreciated. PMID- 26624584 TI - Study of Sex Hormone-binding Globulin Gene Polymorphism and Risk of Type 2 Diabetes Mellitus in Egyptian Men. AB - OBJECTIVES: Conditions of hypoandrogenism in men have been linked to insulin resistance, suggesting that alterations in normal sex steroid physiology could play a role in the pathogenesis of Type 2 diabetes mellitus (T2DM). Sex hormone binding globulin (SHBG) gene polymorphisms may be the cause of sex steroid alteration. The aim of this work is to study the effect of SHBG gene polymorphisms on the risk of T2DM through its impact on testosterone and oestradiol level in Egyptian men. SUBJECTS AND METHODS: A case control study was performed in the diabetes clinic at Zagazig University Hospital on 185 males with Type 2 diabetes and their matched healthy controls. Two polymorphisms (rs6257 and rs6259) of the gene encoding SHBG were genotyped and serum levels of SHBG, testosterone and oestradiol were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Carriers of rs6257 variant allele (CC or CT) and carriers of rs6259 wild allele (GG) appear to have a high risk of diabetes than carriers of other alleles (OR 2.241, 1.585 and 2.391, respectively). They also showed a significant decrease in plasma level of both SHBG and testosterone and a significant increase in oestradiol blood level compared with carriers of other alleles. CONCLUSIONS: Sex hormone-binding globulin gene polymorphisms at position rs6257 and rs6259 are associated with higher risk of T2DM in Egyptian men, through lowering circulating levels of SHBG and consequently, lowering testosterone and elevating oestradiol level. PMID- 26624585 TI - Spatial Distribution of Epidemiological Cases of Dengue Fever in Suriname, 2001 2012. AB - OBJECTIVE: To characterize the frequency, incidence and severity of dengue fever in Suriname and to detect historic clusters of disease by integrating epidemiological data into a spatial visualization platform. METHODS: The frequency, incidence and severity of all reported dengue fever (DF) and dengue haemorrhagic fever (DHF) cases in Suriname from 2001 to 2012 were calculated and stratified by demographic factors. Using a geographic information systems (GIS) platform, we visualized the distribution of DF cases and used Moran's I to detect autocorrelation. Furthermore, a retrospective spatial Poisson probability model was used to identify local clusters of DF within Suriname. Local clusters were divided into neighborhoods and individual DF cases were mapped to the street level. RESULTS: In Suriname, cases of DF emerge in cyclical patterns (three to five years) with seasonal peaks following the short and the long rainy season. Chi-square analysis indicated a statistically significant (p < 0.05) difference between age group, ethnicity and district and the onset of DHF. The spatial analysis detected spatial autocorrelation and four statistically significant (p < 0.05) clusters were identified in the two most populated districts of Paramaribo and Wanica. CONCLUSION: In Suriname, identification of demographic and environmental risk factors that contribute to the development of DHF is essential to determine how preventive action can be more effectively allocated. The integration of epidemiological data into a GIS platform allowed for the identification of historic epidemiological clusters of dengue which will be used to guide environmental health studies in Suriname. PMID- 26624586 TI - Early Sexual Debut and Associated Factors among In-school Adolescents in Six Caribbean Countries. AB - OBJECTIVE: This report examines early sexual debut (< age 15 years) among 15-year old in-school adolescents in six Caribbean countries. SUBJECTS AND METHODS: The total sample included 9948 school children aged primarily 13-16 years from nationally representative samples from six Caribbean countries. Univariate and multivariate analyses were conducted to assess the relationship between early sexual debut and substance use, unintentional injuries and violence, mental distress, physical activity, protective factors and socio-economic status variables. RESULTS: Approximately one-fourth of the sample (26.9%) had experienced sexual debut before age 15 years, 37.2% among boys and 16.9% among girls. In multivariate logistic regression analysis, it was found that male gender, substance use (smoking and alcohol use), having been in a physical fight in the past 12 months, sedentary behaviour, truancy and lack of parental or guardian attachment were associated with early sexual debut. CONCLUSION: This study found a high prevalence of early sexual debut. The risk factors identified were consistent with the Problem Behaviour Theory, which can be incorporated into broader sexual health promotion programmes. PMID- 26624587 TI - Analysis of the Clinical Characteristics of Patients with Acute Coronary Syndrome in Different States of Renal Function. AB - This study aimed to investigate the effect of chronic kidney dysfunction (CKD) on the clinical characteristics of patients with acute coronary syndrome (ACS) and the degree of coronary arterial stenosis. The study enrolled 368 patients with ACS who underwent coronary angiography. Blood glucose, glycated haemoglobin (HbA1c), total cholesterol, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), uric acid (UA), and serum creatinine were examined randomly, and the severity of coronary artery lesions was assessed using the Gensini score. Patients were divided into three groups according to estimated glomerular filtration rate: normal renal function (n = 102), mild renal insufficiency (n = 198), and moderate to severe renal dysfunction (n = 68). The characteristics of patients with coronary artery lesions in the three groups were analysed. Of all patients, 27.7% had normal renal function. In the moderate to severe renal dysfunction group, the majority of patients were women whose average age was older. The ratio of patients with history of hypertension and diabetes mellitus was higher, random blood glucose, HbA1c, TG, UA and Gensini score were obviously increased, while HDL-C was significantly decreased; all differences had statistical significance (p < 0.05). Different degrees of CKD occur in patients with ACS. In patients with ACS and CKD, metabolism of glucose and fat are significantly abnormal, and coronary arterial lesions are more serious. PMID- 26624588 TI - Effect of Repeated Recruitment Manoeuvres on Patients with Severe Acute Respiratory Distress Syndrome. AB - OBJECTIVE: The study aimed to evaluate the influence of repeated recruitment manoeuvres (RRMs) on lung injury in patients with acute respiratory distress syndrome (ARDS). METHODS: Forty-one ventilated patients with severe ARDS were selected for this study. Recruitment manoeuvres (RMs) were conducted with continuous positive airway pressure (CPAP; 30 cm H2O for 40 seconds). Recruitment manoeuvres were repeated every two hours for all three groups. Changes in haemodynamics, pulmonary compliance, gas exchange and extravascular lung water index (EVLWI) were monitored before RM (pre-RM), 10 minutes after each RM, and four hours after RM3 (4 hours post-RRM). Pulmonary inflammatory factors (tumour necrosis factor-alpha [TNF-alpha] and interleukin [IL]-6 and -10) were also analysed. RESULTS: Compared with those in pre-RM, pulmonary compliance, oxygenation index (ratio of partial pressure of arterial oxygen to fraction of inspired oxygen [PaO2/FiO2]) and EVLWI remarkably improved in RM1, RM2, RM3 and 4 hours post-RRM (p < 0.05). The PaO2/FiO2 ratio increased significantly in RM1 and RM3 (p < 0.05). Extravascular lung water index decreased significantly in RM1 compared with that in RM3 and 4 hours post-RRM (p < 0.05). There was no significant difference in cytokines. CONCLUSION: Repeated recruitment manoeuvres during lung-protected ventilation can improve pulmonary compliance and oxygenation and significantly decrease extravascular lung water in ARDS patients. Lung injury was not worsened by RRMs in patients with severe ARDS. PMID- 26624589 TI - Utility of the Tono-Pen in Measuring Intraocular Pressure in Trinidad: A Cross sectional Study. AB - AIM: To determine the sensitivity and specificity of the ReichertTM Tono-Pen AVIA(r) when used by novice medical students in an ethnically diverse population in Trinidad. SUBJECTS AND METHOD: Participants were residents of Trinidad between the ages of 20 and 90 years attending the Ophthalmology Clinic at the Eric Williams Medical Sciences Complex (EWMSC). Intraocular pressure (IOP) was measured using the Goldmann applanation tonometer (the gold standard) for ophthalmology clinic patients as part of their routine care. Intraocular pressure measurements were then taken using the Tono-Pen. RESULTS: One hundred persons participated, consisting of Indo-Trinidadians (55%), Afro-Trinidadians (36%), Mixed (8%) and 1% of Caucasian descent. Fourteen per cent reported a diagnosis of glaucoma, with 70.6% of these being of African descent. One hundred and ninety eight readings of IOP were taken. At a cut-off point of 21 mmHg, there were nine true positives, four false positives, seven false negatives and 178 true negatives. The sensitivity and specificity were found to be 56.3% (95% CI 33.2, 76.9) and 97.8% (95% CI 94.5, 99.1), respectively. The positive predictive value was calculated as 69.2% (95% CI 42.4, 87.3) while the negative predictive value was 96.2% (95% CI 92.4, 98.2). The prevalence of elevated IOP in this population was 8.1% (95% CI 4.8, 13.0). The likelihood ratio of a positive result was calculated to be 25.6 (95% CI 8.6, 73.9). CONCLUSION: The high specificity and negative predictive value suggests that the Tono-Pen can be used with minimal training, and can prove beneficial at the primary care level in the exclusion of increased IOP in an ethnically diverse high-risk Caribbean population. PMID- 26624590 TI - Profile of a Malignant Brain Tumour in Jamaica: An Eight-year Review, 2005 to 2012. AB - OBJECTIVE: Glioblastoma multiforme (GBM) is the most malignant and most common primary brain tumour worldwide. This study was undertaken to investigate the demographics of this tumour in Jamaica as there is to date no such published data. Data from the recently started Intracranial Tumour Registry (ITR) at the University Hospital of the West Indies was used. METHODS: All cases of GBM entered into the ITR between 2005 and 2012 were gathered. Of these, only patients with pathologically proven diagnoses were entered into the study. Demographic data, including age and gender, were recorded. The distribution of the tumours by anatomic location was also documented. RESULTS: Of the 602 patients entered into the ITR up to that time, 42 were found to have histologically proven GBM with a male to female ratio of 2.2:1. There was an age range of 8-92 years with a mean age of diagnosis of 48 years. The majority of the tumours (66.7%) occurred in the left cerebral hemisphere with the most common lobe being the temporal lobe. Two patients (4.8%) had lesions spanning both hemispheres. CONCLUSIONS: This preliminary study reveals that there is a similar gender distribution of GBM within our population compared with the rest of the world. It, however, revealed that the mean age of diagnosis in our population (48 years) is lower than that quoted in the worldwide literature (53 to 64 years). One possible explanation for this is the possibility that many of our GBMs are actually secondary tumours which are thought to arise from less malignant, undiagnosed precursors. The percentage of GBMs occurring in the paediatric population was similar to the rest of the world. PMID- 26624591 TI - Denoising of Ultrasound Cervix Image Using Improved Anisotropic Diffusion Filter. AB - OBJECTIVE: The purpose of this study was to evaluate an improved oriented speckle reducing anisotropic diffusion (IADF) filter that suppress the speckle noise from ultrasound B-mode images and shows better result than previous filters such as anisotropic diffusion, wavelet denoising and local statistics. METHODS: The clinical ultrasound images of the cervix were obtained by ATL HDI 5000 ultrasound machine from the Regional Cancer Centre, Medical College campus, Thiruvananthapuram. The standardized ways of organizing and storing the image were in the format of bmp and the dimensions of 256 x 256 with the help of an improved oriented speckle reducing anisotropic diffusion filter. For analysis, 24 ultrasound cervix images were tested and the performance measured. RESULTS: This provides the quality metrics in case of maximum peak signal-to-noise ratio (PSNR) of 31 dB, structural similarity index map (SSIM) of 0.88 and edge preservation accuracy of 88%. CONCLUSIONS: The IADF filter is the optimal method and it is capable of strong speckle suppression with less computational complexity. PMID- 26624592 TI - Should Delayed Cholecystectomy Following Acute Calculous Cholecystitis Be Discouraged in a Resource-restricted Setting? AB - BACKGROUND: Early cholecystectomy for acute calculous cholecystitis (ACC) reduces hospital stay and complications during the waiting period. The purpose of this study is to establish the patterns of management of ACC at the University Hospital of the West Indies (UHWI) and to evaluate the advantages of early versus delayed cholecystectomy. METHODS: This was a retrospective chart review of patients admitted with a diagnosis of ACC. Data collection included demographics, management strategy, timing to cholecystectomy, significant events while awaiting cholecystectomy and duration of hospital stay. Mann-Whitney U and Chi-squared tests were used for analysis. P-value of < 0.05 was considered significant. RESULTS: A total of 102 patient charts were extracted, 59 of which were managed conservatively and 43 managed with early cholecystectomy. The mean time to surgery after conservative management was 173 days. About 30% of persons managed conservatively had significant attacks while awaiting surgery, which included need for re-admission and earlier intervention. There was a trend toward longer mean total hospital stay in the conservative group (xsx = 5.03, xCons = 6.12; p = 0.054). CONCLUSION: Conservative management of ACC results in significant delays in definitive management and risks of complications during the waiting period. Early cholecystectomy should be encouraged even in a resource-restricted setting. PMID- 26624593 TI - Does Nasal Septal Deviation Affect the Success of Tympanoplasty Surgery? AB - OBJECTIVE: This paper deals with the investigation of the effects of nasal septal deviation evaluated by acoustic rhinometry (ARM) in the success of tympanoplasty surgery. SUBJECT AND METHODS: All patients who underwent tympanoplasty surgery by the same surgeon were reviewed. The patients with nasopharyngeal or nasal masses, polyps, symptoms of allergic rhinitis or rhinosinusitis, or concha bullosa were excluded from the study. Forty patients who underwent tympanoplasty at least one year ago were included in the study. The patients were divided into two groups according to the graft success results. Acoustic rhinometry evaluations of the patients were performed. RESULTS: There were 25 and 15 cases in the intact graft (group A) and re-perforated group (group B), respectively. For the same side of the operated ear, ARM values of group A were 0.47 cm2, at the first narrowest cross-sectional area (MCA 1), 0.43 cm2 at the second narrowest cross-sectional area (MCA 2), 1.51 cm3 volume at the first 2 cm of the nasal cavity (Vol 1) and 3.33 cm3 volume between the second and fifth cm of the nasal cavity (Vol 2). Acoustic rhinometry values of group B were 0.50 cm2, 0.47 cm2, 1.60 cm3 and 3.19 cm3 for MCA 1, MCA 2, Vol 1 and Vol 2, respectively. CONCLUSION: The results of this study showed that nasal septal deviation may not affect the success of tympanoplasty surgery, and septoplasty may not be necessary before ear surgery. PMID- 26624594 TI - Retrocaval Ureter in Children: A Report of Eight Cases. AB - OBJECTIVE: The aim of this study is to report on our last nine years' experience in the diagnosis and treatment of retrocaval ureter. METHODS: Eight patients with retrocaval ureter were reviewed. Intravenous urography and retrograde pyelography were used for confirming the diagnosis. All of the patients had undergone surgery, one case being done laparoscopically. The mean age of the patients was 9.2 years (range 2 to 13 years). RESULTS: Five patients were boys and three were girls. The clinical manifestations were right flank pain in three (37.5%), gross haematuria in one (12.5%) and urinary tract infection in one (12.5%). Three asymptomatic patients were diagnosed by routine physical examination. All of the patients had Type 2 and right-sided retrocaval ureter. Associated anomalies were seen in none of the patients. Retrocaval ureter is a rare anomaly in the paediatric age group. CONCLUSION: Laparoscopy is a promising method to repair the retrocaval ureter. PMID- 26624595 TI - The Impact of Turmeric Cream on Healing of Caesarean Scar. AB - OBJECTIVE: The aim of this study was to assess the impact of turmeric cream on the healing of Caesarean wound. METHODS: This study was done as a randomized double blind trial in three groups on women who had a Caesarean operation. The redness, oedema, ecchymosis, drainage, approximation (REEDA) scale was used to evaluate the wound healing process. The chi2, analysis of variance (ANOVA) and Tukey tests were used for statistical analysis. RESULTS: Seven days after the surgery, the averages of REEDA score in the intervention, placebo and control groups were respectively, 0.46, 0.88, and 1.17 (p < 0.001), while on day 14, it was 0.03, 0.22 and 0.36 (p < 0.001), showing a significant statistical difference. Similarly, there was a difference between the intervention and placebo groups in the amount of oedema on the 7th and 14th days after the surgery (respectively, p = 0.066 and p < 0.001). The observed difference between the intervention and control groups in the amount of oedema was statistically significant on the 7th and 14th days after the surgery (p < 0.001). CONCLUSION: Turmeric was effective in faster healing of wounds of Caesarean operation. The use of turmeric is suggested to reduce the complications of the wounds from Caesarean section. PMID- 26624596 TI - Confidence in Prescription Writing among Junior Physicians in Trinidad and Tobago. AB - BACKGROUND: A fundamental skill in the practice of medicine is the ability to safely and rationally prescribe drugs. This research aims to estimate the percentage of newly registered medical officers who reported confidence in writing prescriptions. METHODS: A questionnaire was distributed to 200 medical officers employed at public health tertiary institutions throughout Trinidad and Tobago. These comprised medical interns (provisionally registered) and house officers (fully registered). Participants indicated their confidence or reluctance to prescribe with or without supervision. Estimates and comparisons between the two groups were obtained using Fisher's exact and Chi-squared tests. RESULTS: The response rate was 73.5%. More medical interns (68%; n = 41) than house officers (56%; n = 42) stated that they were 'Confident' or 'Very Confident' (p = 0.126) to prescribe. Approximately eighty-four per cent (83.6%; n = 51) of medical interns and 89.2% (n = 66) of house officers felt confident to prescribe antibiotics (p = 0.465). A greater percentage of medical interns (84.2%; n = 50) than house officers (66.7%; n = 49) agreed that undergraduate training equipped them to write prescriptions safely and rationally (c2 = 6.17, df = 1; p = 0.012). CONCLUSIONS: While most recent medical graduates felt confident about their prescription writing, there is a need to objectively measure this ability. PMID- 26624597 TI - A Review of Clostridium difficile Infection at the University Hospital of the West Indies, Jamaica. AB - OBJECTIVES: This study examined the frequency of Clostridium difficile infection (CDI) among hospital admission and diarrhoeal stool samples over a six-year period. METHODS: A review of all suspected cases of C difficile positive patients from 2007 to 2012 at the University Hospital of the West Indies (UHWI), Jamaica, was performed. Clostridium difficile infection was confirmed by clinical features and a positive enzyme-linked immunosorbent assay (ELISA) stool test for Clostridium Toxins A and B. The demographics, clinical features, risk factors, treatment and outcomes were also examined. RESULTS: There were 56 patients reviewed. The most commonly affected age group was 40-59 years of age. The proportion of CDI cases per total stool samples increased from 0.5% in 2007 to 5.9% in 2010 then fell to 2.2% in 2011 but increased again to 4.3% in 2012. The proportion of cases per total UHWI admissions also increased from 0.12 cases per 1000 admissions in 2007 to 1.16 in 2010 and 1.36 in 2012 (p < 0.001). Most CDI cases were nosocomial (76% males, 48.6% females). Co-morbidities included hypertension and end-stage renal disease. Ceftazidime was the most common antibiotic associated with the development of CDI. Resolution occurred in 62.5% of patients. Duration of hospital stay was longer in males than females (>= 21 versus < 7 days) and males had more adverse outcomes, with death in 23.8% versus 11.4%. CONCLUSION: There has been an increase in the frequency of CDI at UHWI with a greater than expected frequency of community acquired CDI. Increased awareness is needed of the increasing risk for CDI and measures must be taken to prevent the disease, especially in hospitalized patients. PMID- 26624598 TI - Role of Reactive Oxygen Species and Advanced Glycation End Products in the Malfunctioning of Dental Implants. AB - OBJECTIVE: In the last decade, dental implants have emerged as a crucial modality and serve as an individual form of therapy for dental failure. However, disparities in host responses have led to peri-implantitis and implant failure. The pathological mechanisms driving peri-implantitis remain largely unknown. In this study, we evaluated the role of oxidative stress and advanced glycation end products (AGE) in the progression of peri-implantitis and dental implants failure, compared with chronic periodontal disease. SUBJECTS AND METHODS: Three patient groups (peri-implantitis, chronic periodontal disease and control), each with 10 subjects (7M/3F) and average age ranging from 40-60 years were selected for analysis. Salivary oxidative stress and tissue AGE levels were analysed by probing for reactive oxygen species (ROS) and Maillard reaction-related fluorescence, respectively. RESULTS: We observed significant increase (> 2-fold) in oxidative stress and AGE levels in patients with peri-implantitis and chronic periodontal disease compared to controls, with chronic periodontal disease having the highest levels. In addition, we observed a strong positive correlation (r = 0.94) between oxidative stress and AGE levels in the patients. CONCLUSION: We propose that increased AGE levels and oxidative stress, although not the only pathway, are significant mediators in the pathogenesis of peri-implantitis. Altering them may potentially be used in combination with other modalities to manage peri-implantitis. PMID- 26624600 TI - Substance Use and Abuse and Its Effects on Mental Disorders in Trinidad and Tobago - The Available Prevention and Management Strategies. AB - This paper deals with the relationship between substance abuse and mental illness in Trinidad and Tobago, its implications and management strategies. Dealing with mental health issues is an uphill battle and an attempt will be made in this paper to address the major issues at hand. PMID- 26624599 TI - Human Evolution: The Real Cause for Birth Palsy. AB - OBJECTIVE: Birth palsy, otherwise known as obstetric brachial plexus paralysis (OBPP), is a closed stretch injury to the brachial plexus of nerves during the birth process resulting in varying degree of paralysis and contractures of the upper limb. The study aimed to find out the susceptibility of humans and small bodied primates to birth palsy. METHOD: A comparative study on parturition in modern humans, hominoids, hominids, small-bodied primates and great apes was done to determine if the changes in female pelvis and neonatal head and shoulder during human evolution is the real cause for OBPP. RESULTS: During evolution, the morphology of the female pelvis and birth canal changed into a narrow and twisted one and also the size of the fetal head increased. Thus, the narrow and twisted pelvis of the mother, and the relatively large head and broad shoulders of the newborn has made the birthing process of modern human and small bodied primates a precarious fine-tuned act with a very narrow margin for error. This has necessitated proper obstetric care to reduce or even at times obviate the incidence of birth injuries like OBPP. CONCLUSION: Human evolution has made human babies susceptible to birth palsy and thus is the real cause of birth palsy. PMID- 26624601 TI - Fluoroscopy-guided Sacroiliac Joint Steroid Injection for Low Back Pain in a Patient with Osteogenesis Imperfecta. AB - BACKGROUND: Osteogenesis imperfecta, also known as 'brittle bone disease', is a genetic connective tissue disease. It is characterized by bone fragility and osteopenia (low bone density). In this case, a 57-year old female presented to the University Hospital of the West Indies (UHWI), Physical Medicine and Rehabilitation Clinic with left low back pain rated 6/10 on the numeric rating scale (NRS). Clinically, the patient had sacroiliac joint mediated pain although X-rays did not show the sacroiliac joint changes. Fluoroscopy-guided left sacroiliac joint steroid injection was done. METHODS: Numeric rating scale and Oswestry Disability Index (ODI) questionnaire were used to evaluate outcome. This was completed at baseline, one week follow-up and at eight weeks post fluoroscopy guided sacroiliac joint steroid injection. RESULTS: Numeric rating scale improved from 6/10 before the procedure to 0/10 post procedure, and ODI questionnaire score improved from a moderate disability score of 40% to a minimal disability score of 13%. Up to eight weeks, the NRS was 0/10 and ODI remained at minimal disability of 15%. CONCLUSION: Fluoroscopy-guided sacroiliac joint injection is a known diagnostic and treatment method for sacroiliac joint mediated pain. To our knowledge, this is the first case published on the use of fluoroscopy-guided sacroiliac joint steroid injection in the treatment of sacroiliac joint mediated low back pain in a patient with osteogenesis imperfecta. PMID- 26624602 TI - Follow-up of Pseudomembranous Colitis in Children Using Colonoscopy: A Case Report. AB - Pseudomembranous colitis (PMC) occurs mainly in adults and is believed to be caused almost exclusively by toxins produced by Clostridium difficile. Colonoscopy found that PMC occurs mainly in the colon, sigmoid colon and rectum in up to 80% ~ 100% of cases. Colonoscopy is simple and fast. It has the significance of making a definite diagnosis and can be used as the main examination method of diagnosis. Reports of children suffering from PMC are rare. Herein, we report a case of PMC in a child. This report has some clinical value for the study of the spectrum of PMC in patients. PMID- 26624603 TI - Giant Cornu Cutaneum Superimposed on Basal Cell Carcinoma. AB - Cornu cutaneum (CC) is a clinical term that describes the horn-like keratotic lesions extending vertically from the skin. Benign, premalignant or malignant lesions may be present at the base of CC. Seborrhoeic keratosis and squamous cell carcinoma (SCC) are the most commonly reported benign and malignant forms, respectively. Basal cell carcinoma (BCC) at the base is rare. Here, we report on an 85-year old female patient having multiple CC lesions, one being giant on her face and two of the lesions diagnosed with BCC at the base. This case is of significance due to the presence of giant and multiple CC and detection of BCC at the base of more than one lesion. This present case indicates the need for the treatment of possible malignant lesions underlying CC in the elderly by total surgical excision. PMID- 26624604 TI - Ewing's Sarcoma Localized in the Mandible: A Case Report. AB - Ewing's sarcoma is one of the most aggressive primary bone tumours. Ewing's sarcoma arising from the bones of the head and neck region is extremely rare; only 4-9% of all Ewing's sarcoma originate in this region. We report a case of Ewing's sarcoma localized in the mandible because of its unusual presentation. PMID- 26624605 TI - Treatment with Doxycycline of Generalized Annular Elastolytic Giant Cell Granuloma Associated with Borrelia burgdorferi Infection. AB - This is a case of generalized annular elastolytic giant cell granuloma (AEGCG) associated with borrelia infection and genes of p-30, p-31, p-39. A possible cross-mediated reaction from the T-cell type which might have induced the AEGCG is discussed from the concept of "heat-shock proteins (HSPs) and molecular mimicry". PMID- 26624607 TI - Radiolucent Foreign Body: A Diagnostic Dilemma. PMID- 26624606 TI - Transjugular Intrahepatic Portosystemic Shunt Combined with Haemoperfusion in an End-stage Renal Disease Patient with Liver Cirrhosis-related Refractory Portal Hypertensive Variceal Bleeding: A Case Report. AB - Transjugular intrahepatic portosystemic shunt (TIPS) is recommended as the second line option for variceal bleeding in liver cirrhosis patients when the bleeding is not well controlled by medical and/or endoscopic therapy. However, due to a high incidence of post-TIPS hepatic encephalopathy, particularly in patients with end-stage renal disease (ESRD), TIPS is rarely used in such cases. We report a case involving the successful and safe use of TIPS combined with haemoperfusion to treat an ESRD patient with liver cirrhosis-related refractory portal hypertensive variceal bleeding. Our case suggests the possibility of inserting TIPS to stop recurrent variceal bleeding in ESRD patients with liver cirrhosis. Haemoperfusion may be used to reduce the risk of post-TIPS hepatic encephalopathy. PMID- 26624608 TI - Treatment of Attention Deficit Hyperactivity Disorder Accompanied by Epilepsy in a Child. PMID- 26624609 TI - Intracranial Haemorrhage in a Patient Diagnosed with Idiopathic Thrombocytopaenic Purpura and Diabetic Ketoacidosis. PMID- 26624610 TI - Ultrasound Imaging for Prompt Monitorization of the Treatment Response in Patients with Multi-joint Involvement. PMID- 26624611 TI - Preface. PMID- 26624612 TI - Unique Dental Morphology of Homo floresiensis and Its Evolutionary Implications. AB - Homo floresiensis is an extinct, diminutive hominin species discovered in the Late Pleistocene deposits of Liang Bua cave, Flores, eastern Indonesia. The nature and evolutionary origins of H. floresiensis' unique physical characters have been intensively debated. Based on extensive comparisons using linear metric analyses, crown contour analyses, and other trait-by-trait morphological comparisons, we report here that the dental remains from multiple individuals indicate that H. floresiensis had primitive canine-premolar and advanced molar morphologies, a combination of dental traits unknown in any other hominin species. The primitive aspects are comparable to H. erectus from the Early Pleistocene, whereas some of the molar morphologies are more progressive even compared to those of modern humans. This evidence contradicts the earlier claim of an entirely modern human-like dental morphology of H. floresiensis, while at the same time does not support the hypothesis that H. floresiensis originated from a much older H. habilis or Australopithecus-like small-brained hominin species currently unknown in the Asian fossil record. These results are however consistent with the alternative hypothesis that H. floresiensis derived from an earlier Asian Homo erectus population and experienced substantial body and brain size dwarfism in an isolated insular setting. The dentition of H. floresiensis is not a simple, scaled-down version of earlier hominins. PMID- 26624613 TI - Artificial Neural Networks-Based Software for Measuring Heat Collection Rate and Heat Loss Coefficient of Water-in-Glass Evacuated Tube Solar Water Heaters. AB - Measurements of heat collection rate and heat loss coefficient are crucial for the evaluation of in service water-in-glass evacuated tube solar water heaters. However, conventional measurement requires expensive detection devices and undergoes a series of complicated procedures. To simplify the measurement and reduce the cost, software based on artificial neural networks for measuring heat collection rate and heat loss coefficient of water-in-glass evacuated tube solar water heaters was developed. Using multilayer feed-forward neural networks with back-propagation algorithm, we developed and tested our program on the basis of 915 measured samples of water-in-glass evacuated tube solar water heaters. This artificial neural networks-based software program automatically obtained accurate heat collection rate and heat loss coefficient using simply "portable test instruments" acquired parameters, including tube length, number of tubes, tube center distance, heat water mass in tank, collector area, angle between tubes and ground and final temperature. Our results show that this software (on both personal computer and Android platforms) is efficient and convenient to predict the heat collection rate and heat loss coefficient due to it slow root mean square errors in prediction. The software now can be downloaded from http://t.cn/RLPKF08. PMID- 26624615 TI - How to measure the impact of premenstrual symptoms? Development and validation of the German PMS-Impact Questionnaire. AB - With 75% of women of reproductive age affected, premenstrual symptoms are very common, ranging from emotional and cognitive to physical symptoms. Premenstrual Syndrome and Premenstrual Dysphoric Disorder can lead to substantial functional interference and psychological distress comparable to that of dysthymic disorders. The assessment of this impact is required as a part of the diagnostic procedure in the DSM-5. In the absence of a specific measure, the authors developed the PMS-Impact Questionnaire. A sample of 101 women reporting severe premenstrual complaints was assessed with the twenty-two items in the questionnaire during their premenstrual phase in an ongoing intervention study at the Philipps-University Marburg from August 2013 until January 2015. An exploratory factor analysis revealed a two-factor solution (labeled Psychological Impact and Functional Impact) with 18 items. A Cronbach's alpha of 0.90 for Psychological Impact and of 0.90 for Functional Impact indicated good reliability. Convergent construct validity was demonstrated by moderate to high correlations with the Pain Disability Index. Low correlations with the Big Five Inventory-10 indicated good divergent validity. The PMS-Impact Questionnaire was found to be a valid, reliable, and an economic measure to assess the impact of premenstrual symptoms. In future research, cross validations and confirmatory factor analyses should be conducted. PMID- 26624614 TI - Simple Elastic Network Models for Exhaustive Analysis of Long Double-Stranded DNA Dynamics with Sequence Geometry Dependence. AB - Simple elastic network models of DNA were developed to reveal the structure dynamics relationships for several nucleotide sequences. First, we propose a simple all-atom elastic network model of DNA that can explain the profiles of temperature factors for several crystal structures of DNA. Second, we propose a coarse-grained elastic network model of DNA, where each nucleotide is described only by one node. This model could effectively reproduce the detailed dynamics obtained with the all-atom elastic network model according to the sequence dependent geometry. Through normal-mode analysis for the coarse-grained elastic network model, we exhaustively analyzed the dynamic features of a large number of long DNA sequences, approximately ~150 bp in length. These analyses revealed positive correlations between the nucleosome-forming abilities and the inter strand fluctuation strength of double-stranded DNA for several DNA sequences. PMID- 26624616 TI - Long Term Control of Scabies Fifteen Years after an Intensive Treatment Programme. AB - INTRODUCTION: Scabies is a major public health problem in the Pacific and is associated with an increased risk of bacterial skin infections, glomerulonephritis and rheumatic fever. Mass drug administration with ivermectin is a promising strategy for the control of scabies. Mass treatment with ivermectin followed by active case finding was conducted in five communities in the Solomon Islands between 1997 and 2000 and resulted in a significant reduction in the prevalence of both scabies and bacterial skin infections. METHODS: We conducted a prospective follow-up study of the communities where the original scabies control programme had been undertaken. All residents underwent a standardised examination for the detection of scabies and impetigo. RESULTS: Three hundred and thirty eight residents were examined, representing 69% of the total population of the five communities. Only 1 case of scabies was found, in an adult who had recently returned from the mainland. The prevalence of active impetigo was 8.8% overall and 12.4% in children aged 12 years or less. DISCUSSION: We found an extremely low prevalence of scabies 15 years after the cessation of a scabies control programme. The prevalence of impetigo had also declined further since the end of the control programme. Our results suggest that a combination of mass treatment with ivermectin and intensive active case finding may result in long term control of scabies. Larger scale studies and integration with other neglected tropical disease control programmes should be priorities for scabies control efforts. PMID- 26624617 TI - Low Left Atrial Compliance Contributes to the Clinical Recurrence of Atrial Fibrillation after Catheter Ablation in Patients with Structurally and Functionally Normal Heart. AB - Stiff left atrial (LA) syndrome was initially reported in post-cardiac surgery patients and known to be associated with low LA compliance. We investigated the physiological and clinical implications of LA compliance by estimating LA pulse pressure (LApp) among patients with atrial fibrillation (AF) and structurally and functionally normal heart. Among 1038 consecutive patients with LA pressure measurements before AF ablation, we included 334 patients with structurally and functionally normal heart (81.7% male, 54.1+/-10.6 years, 77.0% paroxysmal AF) after excluding those with hypertension, diabetes, and previous ablation or cardiac surgery. We measured LApp (peak-nadir LA pressure) at the beginning of the ablation procedure and compared the values with clinical parameters and the AF recurrence rate. AF patients with normal heart were younger and more frequently male and had paroxysmal AF, a lower body mass index, and a lower LApp compared to others (all p<0.05). Based on the median value, the low LA compliance group (LApp>=13 mmHg) had a smaller LA volume index and lower LA voltage (all p<0.05) compared to the high LA compliance group. During a mean follow-up of 16.7+/-11.8 months, low LA compliance was independently associated with two fold higher risk of clinical AF recurrence (HR:2.202; 95%CI:1.077-4.503; p = 0.031). Low LA compliance, as determined by an elevated LApp, was associated with a smaller LA volume index and lower LA voltage and independently associated with higher clinical recurrence after catheter ablation in AF patients with structurally and functionally normal heart. PMID- 26624620 TI - Consistent picture of the octet-nodal gap and its evolution with doping in heavily overdoped Ba(1-x)KxFe2As2. AB - We investigate the pairing symmetry in heavily overdoped Ba(1-x)KxFe2As2 based on the spin-fluctuation mechanism. We propose a Fermi-patch mechanism that is different from the conventional Fermi-surface-nesting picture. The exotic octet nodes of the superconducting gap and the unusual evolution of the gap with doping observed by the recent experiments are well explained in a unified manner. We demonstrate that the scattering of electrons on the Fermi patches is mainly responsible for the incommensurate spin fluctuations and consequently the Fermi surface-dependent multi-gap structure, since the Fermi level is close to the flat band. In addition, we find that a d-wave pairing state will prevail over the s wave pairing state around the Lifshitz transition point. PMID- 26624618 TI - Trim33 Binds and Silences a Class of Young Endogenous Retroviruses in the Mouse Testis; a Novel Component of the Arms Race between Retrotransposons and the Host Genome. AB - Transposable elements (TEs) have been active in the mammalian genome for millions of years and the silencing of these elements in the germline is important for the survival of the host. Mice carrying reporter transgenes can be used to model transcriptional silencing. A mutagenesis screen for modifiers of epigenetic gene silencing produced a line with a mutation in Trim33; the mutants displayed increased expression of the reporter transgene. ChIP-seq of Trim33 in testis revealed 9,109 peaks, mostly at promoters. This is the first report of ChIP-seq for Trim33 in any tissue. Comparison with ENCODE datasets showed that regions of high read density for Trim33 had high read density for histone marks associated with transcriptional activity and mapping to TE consensus sequences revealed Trim33 enrichment at RLTR10B, the LTR of one of the youngest retrotransposons in the mouse genome, MMERVK10C. We identified consensus sequences from the 266 regions at which Trim33 ChIP-seq peaks overlapped RLTR10B elements and found a match to the A-Myb DNA-binding site. We found that TRIM33 has E3 ubiquitin ligase activity for A-MYB and regulates its abundance. RNA-seq revealed that mice haploinsufficient for Trim33 had altered expression of a small group of genes in the testis and the gene with the most significant increase was found to be transcribed from an upstream RLTR10B. These studies provide the first evidence that A-Myb has a role in the actions of Trim33 and suggest a role for both A-Myb and Trim33 in the arms race between the transposon and the host. This the first report of any factor specifically regulating RLTR10B and adds to the current literature on the silencing of MMERVK10C retrotransposons. This is also the first report that A-Myb has a role in the transcription of any retrotransposon. PMID- 26624619 TI - Nest Predation Deviates from Nest Predator Abundance in an Ecologically Trapped Bird. AB - In human-modified environments, ecological traps may result from a preference for low-quality habitat where survival or reproductive success is lower than in high quality habitat. It has often been shown that low reproductive success for birds in preferred habitat types was due to higher nest predator abundance. However, between-habitat differences in nest predation may only weakly correlate with differences in nest predator abundance. An ecological trap is at work in a farmland bird (Lanius collurio) that recently expanded its breeding habitat into open areas in plantation forests. This passerine bird shows a strong preference for forest habitat, but it has a higher nest success in farmland. We tested whether higher abundance of nest predators in the preferred habitat or, alternatively, a decoupling of nest predator abundance and nest predation explained this observed pattern of maladaptive habitat selection. More than 90% of brood failures were attributed to nest predation. Nest predator abundance was more than 50% higher in farmland, but nest predation was 17% higher in forest. Differences between nest predation on actual shrike nests and on artificial nests suggested that parent shrikes may facilitate nest disclosure for predators in forest more than they do in farmland. The level of caution by parent shrikes when visiting their nest during a simulated nest predator intrusion was the same in the two habitats, but nest concealment was considerably lower in forest, which contributes to explaining the higher nest predation in this habitat. We conclude that a decoupling of nest predator abundance and nest predation may create ecological traps in human-modified environments. PMID- 26624621 TI - Nano-TiO2 Is Not Phytotoxic As Revealed by the Oilseed Rape Growth and Photosynthetic Apparatus Ultra-Structural Response. AB - Recently nano-materials are widely used but they have shown contrasting effects on human and plant life. Keeping in view the contrasting results, the present study has evaluated plant growth response, antioxidant system activity and photosynthetic apparatus physiological and ultrastructural changes in Brassica napus L. plants grown under a wide range (0, 500, 2500, 4000 mg/l) of nano-TiO2 in a pot experiment. Nano-TiO2 has significantly improved the morphological and physiological indices of oilseed rape plants under our experimental conditions. All the parameters i-e morphological (root length, plant height, fresh biomass), physiological (photosynthetic gas exchange, chlorophyll content, nitrate reductase activity) and antioxidant system (Superoxide dismutase, SOD; Guaiacol peroxidase, POD; Catalase, CAT) recorded have shown improvement in their performance by following nano-TiO2 dose-dependent manner. No significant chloroplast ultra-structural changes were observed. Transmission electron microscopic images have shown that intact & typical grana and stroma thylakoid membranes were in the chloroplast, which suggest that nano-TiO2 has not induced the stressful environment within chloroplast. Finally, it is suggested that, nano TiO2 have growth promoting effect on oilseed rape plants. PMID- 26624622 TI - Direct, Specific and Rapid Detection of Staphylococcal Proteins and Exotoxins Using a Multiplex Antibody Microarray. AB - BACKGROUND: S. aureus is a pathogen in humans and animals that harbors a wide variety of virulence factors and resistance genes. This bacterium can cause a wide range of mild to life-threatening diseases. In the latter case, fast diagnostic procedures are important. In routine diagnostic laboratories, several genotypic and phenotypic methods are available to identify S. aureus strains and determine their resistances. However, there is a demand for multiplex routine diagnostic tests to directly detect staphylococcal toxins and proteins. METHODS: In this study, an antibody microarray based assay was established and validated for the rapid detection of staphylococcal markers and exotoxins. The following targets were included: staphylococcal protein A, penicillin binding protein 2a, alpha- and beta-hemolysins, Panton Valentine leukocidin, toxic shock syndrome toxin, enterotoxins A and B as well as staphylokinase. All were detected simultaneously within a single experiment, starting from a clonal culture on standard media. The detection of bound proteins was performed using a new fluorescence reading device for microarrays. RESULTS: 110 reference strains and clinical isolates were analyzed using this assay, with a DNA microarray for genotypic characterization performed in parallel. The results showed a general high concordance of genotypic and phenotypic data. However, genotypic analysis found the hla gene present in all S. aureus isolates but its expression under given conditions depended on the clonal complex affiliation of the actual isolate. CONCLUSIONS: The multiplex antibody assay described herein allowed a rapid and reliable detection of clinically relevant staphylococcal toxins as well as resistance- and species-specific markers. PMID- 26624623 TI - Development and Validation of a Gene-Based Model for Outcome Prediction in Germ Cell Tumors Using a Combined Genomic and Expression Profiling Approach. AB - Germ Cell Tumors (GCT) have a high cure rate, but we currently lack the ability to accurately identify the small subset of patients who will die from their disease. We used a combined genomic and expression profiling approach to identify genomic regions and underlying genes that are predictive of outcome in GCT patients. We performed array-based comparative genomic hybridization (CGH) on 53 non-seminomatous GCTs (NSGCTs) treated with cisplatin based chemotherapy and defined altered genomic regions using Circular Binary Segmentation. We identified 14 regions associated with two year disease-free survival (2yDFS) and 16 regions associated with five year disease-specific survival (5yDSS). From corresponding expression data, we identified 101 probe sets that showed significant changes in expression. We built several models based on these differentially expressed genes, then tested them in an independent validation set of 54 NSGCTs. These predictive models correctly classified outcome in 64-79.6% of patients in the validation set, depending on the endpoint utilized. Survival analysis demonstrated a significant separation of patients with good versus poor predicted outcome when using a combined gene set model. Multivariate analysis using clinical risk classification with the combined gene model indicated that they were independent prognostic markers. This novel set of predictive genes from altered genomic regions is almost entirely independent of our previously identified set of predictive genes for patients with NSGCTs. These genes may aid in the identification of the small subset of patients who are at high risk of poor outcome. PMID- 26624624 TI - Cytotaxonomy of Eurypyga helias (Gruiformes, Eurypygidae): First Karyotypic Description and Phylogenetic Proximity with Rynochetidae. AB - The sunbittern (Eurypyga helias) is a South American Gruiformes, the only member of Family Eurypigidae. In most phylogenetic proposals, it is placed in a more distant position than other families of the so-called "core Gruiformes". Different studies based on molecular, morphological and biogeographical data suggest that the Eurypigidae is closely related to the kagu (Rhynochetos jubatus), the only species in Rynochetidae, another family not included in the core Gruiformes. Here, the karyotype of the sunbittern is described for the first time, by classical and molecular cytogenetics, using whole chromosome probes derived from Gallus gallus and Leucopternis albicollis. We found a diploid number of 80, with only one pair of biarmed autosomal macrochromosomes, similar to that observed in the kagu. Chromosome painting revealed that most syntenies found in the avian putative ancestral karyotype (PAK) were conserved in the sunbittern. However, PAK1, PAK2, and PAK5 corresponded to two chromosome pairs each. Probes derived from L. albicollis confirm that fissions in PAK1 and PAK2 were centric, whereas in PAK5 the fission is interstitial. In addition, there is fusion of segments homologous to PAK2q and PAK5. From a phylogenetic point of view, comparisons of our results with two other Gruiformes belonging to family Rallidae suggest that the PAK5q fission might be a synapomorphy for Gruiformes. Fissions in PAK1 and PAK2 are found only in Eurypigidae, and might also occur in Rynochetidae, in view of the similar chromosomal morphology between the sunbittern and the kagu. This suggests a close phylogenetic relationship between Eurypigidae and Rynochetidae, whose common ancestor was separated by the Gondwana vicariancy in South America and New Caledonia, respectively. PMID- 26624625 TI - Similar Intracellular Location and Stimulus Reactivity, but Differential Mobility of Tailless (Vicia faba) and Tailed Forisomes (Phaseolus vulgaris) in Intact Sieve Tubes. AB - Sieve elements of legumes contain forisomes-fusiform protein bodies that are responsible for sieve-tube occlusion in response to damage or wound signals. Earlier work described the existence of tailless and tailed forisomes. This study intended to quantify and compare location and position of tailless (in Vicia faba) and tailed (in Phaseolus vulgaris) forisomes inside sieve elements and to assess their reactivity and potential mobility in response to a remote stimulus. Location (distribution within sieve elements) and position (forisome tip contacts) of more than altogether 2000 forisomes were screened in 500 intact plants by laser scanning confocal microscopy in the transmission mode. Furthermore, we studied the dispersion of forisomes at different locations in different positions and their positional behaviour in response to distant heat shocks. Forisome distribution turned out to be species-specific, whereas forisome positions at various locations were largely similar in bushbean (Phaseolus) and broadbean (Vicia). In general, the tailless forisomes had higher dispersion rates in response to heat shocks than the tailed forisomes and forisomes at the downstream (basal) end dispersed more frequently than those at the upstream end (apical). In contrast to the tailless forisomes that only oscillate in response to heat shocks, downstream-located tailed forisomes can cover considerable distances within sieve elements. This displacement was prevented by gentle rubbing of the leaf (priming) before the heat shock. Movement of these forisomes was also prohibited by Latrunculin A, an inhibitor of actin polymerization. The apparently active mobility of tailed forisomes gives credence to the idea that at least the latter forisomes are not free-floating, but connected to other sieve element structures. PMID- 26624626 TI - A new species of Leptolalax (Anura: Megophryidae) from Vietnam and Cambodia. AB - We describe a new, medium-sized Leptolalax species from the Kon Tum Plateau of Vietnam and adjacent Cambodia. Leptolalax isos sp. nov. is distinguished from its congeners by a combination of an absence of distinct dark brown/black dorsolateral markings; toes with rudimentary webbing, wide lateral dermal fringes in males and weak or absent lateral dermal fringes in females; most males with wide lateral dermal fringes on Finger II, a body size of 23.7-27.9 mm in 38 adult males and 28.6-31.5 mm in 9 adult females, near immaculate white chest and belly; absence of white speckling on the dorsum; and a call consisting of 2-3 notes with a dominant frequency of 5.9-6.2 kHz (at 22.4-22.8o C). Uncorrected sequence divergences between L. isos sp. nov. and all homologous 16S rRNA sequences available are >10%. At present, the new species is known from montane evergreen forest between ~650-1100 m elevation in northeastern Cambodia and central Vietnam. Habitat within the range of the new species is threatened by deforestation and upstream hydroelectric dams. PMID- 26624627 TI - A taxonomic study on the species of the genus Furcilarnaca (Orthoptera, Gryllacrididae, Gryllacridinae). AB - A taxonomic study of the genus Furcilarnaca Gorochov, 2004 is presented. Four new species are described: F. affinis sp. nov., F. hirta sp. nov., F. fractiflexa sp. nov., F. brachyptera sp. nov.. Two new combinations F. fallax (Liu et al., 2010) comb. nov. and F. pulex (Karny, 1928) comb. nov. are given. A key to the species and the distributional data of Furcilarnaca are provided. PMID- 26624628 TI - Four new species of the genus Thoracophorus Motschulsky, 1857 for the Neotropical region (Coleoptera: Staphylinidae: Osoriinae). AB - Four new species of the genus Thoracophorus Motschulsky, 1857 of the Neotropical region are described: T. verhaaghi n. sp., T. zicsii n. sp., T. struyvei n. sp., and T. perplexus n. sp. The new species originate from French Guiana, Peru, and Ecuador. Similar species T. filum Sharp, 1887, T. proximus Irmler, 1985, T. exilis (Erichson, 1840) and T. aequalis Sharp, 1887 are compared to discuss differences between them and the newly described species and their known distribution. PMID- 26624629 TI - Revision of Tarodes Pocock, 1899 and Udvardya Proszynski, 1992 (Araneae: Salticidae), with descriptions of two new species of Udvardya from New Guinea. AB - Tarodes Pocock, 1899 and Udvardya Proszynski, 1992 are redefined and redescribed. The male of T. lineatus Pocock, 1899 and the female of U. elegans Proszynski, 1992 are redescribed for comparisons. Additionally, two species of Udvardya from New Guinea, U. bellatrix sp. nov. and U. fortis sp. nov., are diagnosed, described and illustrated. Geographical distribution of the species is given. PMID- 26624630 TI - Astrotischeria neotropicana sp. nov.-a leaf-miner on Sida, Malvaceae, currently with the broadest distribution range in the Neotropics (Lepidoptera, Tischeriidae). AB - This paper describes Astrotischeria neotropicana Diskus & Stonis, sp. nov. (Lepidoptera: Tischeriidae), a new leaf-miner on Sida (Malvaceae) with a broad distribution range in tropical Central & South America. The new species is currently recorded from the Amazon Basin in Peru and Ecuador to tropical lowlands in Guatemala and Belize (including the Caribbean Archipelago). The new species is illustrated with photographs of the adults, male and female genitalia, and the leaf-mines; distribution map is also provided. PMID- 26624631 TI - Paragnomoxyala gen. nov. (Xyalidae, Monhysterida, Nematoda) from the East China Sea. AB - A new genus, Paragnomoxyala gen. nov., and a new species, Paragnomoxyala breviseta sp. nov. are described from the East China Sea. Paragnomoxyala gen. nov. is characterized by having large funnel-shaped buccal cavity with cuticularized walls and extended anteriorly; lips very high; striated cuticle; four cephalic setae, absence of outer labial setae; circular amphidial fovea; straight spicules and absence of gubernaculum; tail conico-cylindrical with three terminal setae; female monodelphic with an anterior outstretched ovary. It differs from similar genera by having a large buccal cavity unique in Xyalidae, straight spicules, lacking gubernaculum, and conico-cylindrical tail with terminal setae. Paragnomoxyala breviseta sp. nov. is characterized by having a large funnel-shaped buccal cavity, with cuticularized walls and extended anteriorly, 1.6-1.8 hd long and 63-79% cbd wide; four cephalic setae 3-4 um long; circular amphids 6-9 um in diameter; spicules straight but slightly bent at both ends; absence of gubernaculum and precloacal supplement. PMID- 26624633 TI - Cyrtarachne keralensis Jose, 2011 is a junior synonym of Anepsion maritatum (O. Pickard-Cambridge, 1877) (Araneae, Araneidae). AB - The Indo-pacific araneid genus Anepsion, with A. rhomboides (L. Koch, 1867) as the type species, was erected by Strand in 1929. He proposed the name Anepsion as a replacement name for Anepsia L. Koch, 1871, preoccupied by Anepsia Gistl, 1848, a dipteran genus (OBIS Australia, 2015). The genus was revised by Chrysanthus (1961, 1969) and currently has 16 described species and 1 subspecies (World Spider Catalog 2015). In the present paper, we are reporting the genus from India for the first time and synonymising Cyrtarachne keralensis Jose, 2011 with Anepsion maritatum O. Pickard-Cambridge, 1877. A redescription and illustrations of both male and female of A. maritatum are provided. PMID- 26624632 TI - A new brachypterous scarab species, Orphnus longicornis (Coleoptera: Scarabaeidae: Orphninae), from the East African Rift. AB - The Afrotropical Region is the center of the diversity of the scarab beetle genus Orphnus MacLeay, 1819 (Coleoptera: Scarabaeidae: Orphninae), with 94 species occurring from Sahel in the north to Little Karoo in the south (Paulian, 1948; Petrovitz, 1971; Frolov, 2008). The East African Rift is one of the richest regions of the Afrotropics housing more than 20 species of Orphnus (Paulian, 1948; Frolov, 2013), most of which are endemic to this region. Yet the scarab beetle fauna of the East African Rift, and especially the Eastern Arc Mountains, is still inadequately studied. Examination of the material housed in the Museum of Natural History of Humboldt-Universitat, Berlin, Germany (ZMHUB), revealed a series of brachypterous Orphnus beetles belonging to an undescribed species. The new species is described and illustrated below. PMID- 26624634 TI - Thaumaleidae (Diptera) collected by the late Dr. W. Joost in the Caucasus Mountains. AB - The aquatic insect collection of the late Dr. W. Joost contained two new species of Thaumaleidae (Diptera) from the Caucasus Mountains: Thaumalea monikae sp. n. and Thaumalea biacuminata sp. n. These two new species are herein described, and the most abundant species in Dr. Joost's collection, Thaumalea martinovskyi Joost, 1979, is redescribed based on the type material. Figures of male and female genitalia for all species are provided. All three species show morphological similarities to taxa from the Eastern Mediterranean area. Thaumalea monikae is related to the European T. bezzii-species group, T. biacuminata to the T. serrata-group, and T. martinovskyi to T. kyladica Wagner, 1981 and T. malickyi Theischinger, 1979 from the Eastern Mediterranean area. PMID- 26624635 TI - A new genus and species of Cicadellini (Hemiptera: Cicadellidae) from China. AB - The leafhopper genus Atkinsoniella was originally established by Distant (1908) for two species with A. decisa as type species. So far, 75 valid species are known worldwide and of these, 63 are from China (Yang et al. 2011). Because Atkinsoniella is a very large and morphologically heterogeneous genus it is desirable to recognize smaller groups of species with distinctive characteristics. PMID- 26624636 TI - Two new species of Prochas Walkley from Brazil (Hymenoptera, Ichneumonidae, Campopleginae). AB - Two new species of the monotypic genus Prochas Walkley from Brazil, P. brasiliensis sp. nov. and P. shimborii sp. nov., are described and illustrated. A key to species is also provided. PMID- 26624637 TI - Redescription of Tharyx killariensis (Southern) from Ireland and description of two new species of Tharyx from the Kattegat, Sweden (Polychaeta, Cirratulidae). AB - Two new species of the cirratulid genus Tharyx are reported from shallow waters in the Kattegat inshore Sweden. In addition, the lectotype of Tharyx killariensis (Southern, 1914) is redescribed resulting in a revised concept of the noto- and neuropodial acicular spines of posterior parapodia for that species. These spines were originally reported as bidentate crotchets with sharply pointed teeth; in reality the spines have blunt, knob-shaped tips, typical of several other species of Tharyx. Both of the new species are atypical for the genus Tharyx. T. maryae n. sp. has an expanded posterior end more typical of the genus Aphelochaeta, but otherwise shares characters of Tharyx. T. robustus n. sp. has a body shape that is consistently broad and dorsoventrally flattened throughout, rather than elongate and narrow as in other species of the genus. Both of the new species, however, have short, blunt-tipped spines in far posterior parapodia. With the addition of the two new species, the genus Tharyx now includes 11 species that are compared and contrasted. Morphology that defines and characterizes species of Tharyx is reviewed. PMID- 26624638 TI - A new species of Acroperus Baird, 1843 (Cladocera: Chydoridae) from Africa. AB - A new species of Acroperus Baird, 1843 (Cladocera: Chydoridae) is described based on the material from Lake Tana, Ethiopia and two water bodies in Eastern Cape, Republic of South Africa. In Africa, Acroperus africanus sp. nov. had a chance to be confused by previous authors with Palearctic A. harpae (Baird, 1834) and A. angustatus Sars, 1863, but it could be easily distinguished from the latter by: (1) smaller seta on the proximal segment of antenna II endopod; (2) larger values of seta 3/seta 2 length ratio on the limb I, as well as some additional features. Diversity of the genus in Africa is underestimated yet, and further investigations of taxon distribution and ecology are necessary. PMID- 26624639 TI - A revision of the genus Protomicroplitis Ashmead (Hymenoptera, Braconidae, Microgastrinae), with the description of a new species. AB - The New World genus Protomicroplitis is revised. One new species is described from Central America, a dichotomous key and extensive illustrations for the three known species are provided. The genus has a restricted distribution, from Canada (45 degrees N) to Costa Rica (10 degrees N). Two species of Condica (Lepidoptera: Noctuidae) are the only known hosts. The following new taxonomic and nomenclatural acts are made. New species: Protomicroplitis centroamericanus Fernandez-Triana. New combinations: Diolcogaster alce (Nixon, 1965), Diolcogaster breviterebrus Rao & Chalikwar, 1970, Diolcogaster coenonymphae (Watanabe, 1937), Diolcogaster erro (Nixon, 1965), Diolcogaster glaphyra (de Saeger, 1944), Diolcogaster integra (Wilkinson, 1929), Diolcogaster medon (Nixon, 1965), Diolcogaster melleus (Nixon, 1965), Diolcogaster nephele (Nixon, 1965), Diolcogaster orientalis (Rao & Chalikwar, 1970), Diolcogaster pyrene (Nixon, 1965), Diolcogaster rugulosus (Rao & Chalikwar, 1970), Diolcogaster urios (Nixon, 1965). Revised combinations: Choeras tegularis (Szepligeti, 1905), Diolcogaster seriphus (Nixon, 1965). PMID- 26624640 TI - Cleptes pallipes Lepeletier synonym of Cleptes semiauratus (Linnaeus) and description of Cleptes striatipleuris sp. nov. (Hymenoptera: Chrysididae, Cleptinae). AB - The interpretation of Linnaeus' name Sphex semiaurata Linnaeus, 1761 has been controversial. After type examinations, we conclude that it is identical with the common Cleptes pallipes Lepeletier, 1806 and thus re-establish the old synonymy: Cleptes semiauratus (Linnaeus, 1761) (=Cleptes pallipes Lepeletier, 1806, syn. reinst.). We have been unable to find an available name for the species with which it has been confused. In order to be able to designate a suitable type specimen, we prefer to describe it as a new species rather than suggest a replacement name: Cleptes striatipleuris Rosa, Forshage, Paukkunen & Soon sp. nov. (=Cleptes semiauratus sensu Lepeletier, 1806, nec Linnaeus, 1761; =C. splendens sensu Linsenmaier 1959, nec Fabricius, 1798). PMID- 26624641 TI - Notes on the genus Echinoaesalus Zelenka, 1993 (Coleoptera: Lucanidae), with the description of a new species from the Malay Peninsula. AB - Echinoaesalus cechovskyi new species is described from the Malay Peninsula. Echinoaesalus hidakai borneoensis Huang & Imura, 2011 is elevated to the species level as E. borneoensis new status. The male or female genitalia of Echinoaesalus timidus (Krikken, 1975), E. hidakai (Araya, Kon, & Johki, 1993), E. borneoensis, and E. sabahensis Zelenka, 1994 are described and illustrated for the first time. The intraspecific variation of E. timidus is discussed. PMID- 26624642 TI - The first fossil record of the Emesinae genus Emesopsis Uhler (Hemiptera: Heteroptera, Reduviidae) from Eocene Baltic amber. AB - Two new fossil representatives of the assassin bug family Reduviidae are described as new from Baltic amber (Upper Eocene), belonging to the genus Emesopsis of the tribe Ploiariolini (Emesinae): Emesopsis putshkovi sp. nov. and E. similis sp. nov. These representatives of the Emesinae are the oldest fossil bugs of the genus Emesopsis known so far, and reported for the first time. This genus is also briefly diagnosed. PMID- 26624643 TI - Three new species of the genus Conophyma Zubovsky, 1898 (Orthoptera, Acridoidea, Catantopidae, Conophyminae) from Xinjiang, China. AB - Three new species of the genus Conophyma Zobovsky, 1898 from Xinjiang, West China are described in this paper. The Conophyma xiai sp. nov. is similar to C. olive Huang, 2006, but differs from latter by: vertical diameter of eyes 1.7 times subocular furrow, minimum width of interspace of mesosternum 1.6 times length, hind tibia yellow and furculae smaller. The new species Conophyma nigrifemora sp. nov. is similar to C. xiai sp. nov., but differs from latter by: vertex of head longer, apex narrower; posterior margin of pronotum straight; minimum width 1.6 times its length in interspace of mesosternum; posterior margin of epiproct with curve projection in the middle; epiphallus almost straight on the lower margin, The new species Conophyma hejinensis sp. nov. is similar to C. rufitibia Li & Ti, 1995, but differs from latter by: anterior and posterior margin of pronotum excised in the middle, minimum width of interspace of mesosternum 1.2 times length, hind tibia yellow and posterior margin of epiproct straight, with acute projection in the middle. Type specimens are deposited in the Natural Museum of Hebei University, Baoding, Hebei, China. PMID- 26624644 TI - Description of a new species of Oligosita Walker (Chalcidoidea: Trichogrammatidae), egg parasitoid of Balclutha brevis Lindberg (Homoptera: Cicadellidae) living on Pennisetum setaceum, from Italy. AB - A new species of Oligosita Walker (Chalcidoidea: Trichogrammatidae), O. balcluthae Viggiani et Laudonia n. sp., is described as a parasitoid of the eggs of Balclutha brevis Lindberg (Homoptera: Cicadellidae) associated with crimson fountain grass, Pennisetum setaceum (Poaceae) in Italy. Morphological features and biology of the new species are discussed and illustrated. The 28S-D2 and ITS2 regions were successfully amplified and sequenced. PMID- 26624645 TI - A new strikingly-colored species of the genus Galathea Fabricius, 1793 (Crustacea: Decapoda: Anomura: Galatheidae) from the Ryukyu Islands, Japan. AB - A new shallow-water squat lobster, Galathea ryuguu, is described on the basis of material obtained from a colony of unidentified sea fan of the genus Muricella Verrill, 1868. The new species is most closely allied to G. squamea Baba, 1979, but is distinguished by the ornamentation and armature of the carapace, third maxilliped, and ambulatory legs. PMID- 26624646 TI - Erratum: MARIANNA ISABELLA ROSA RODRIGUES DE OLIVEIR, LUIZ NORBERTO WEBER & MARCELO FELGUEIRAS NAPOLI (2013) Internal oral morphology in larvae of the genus Rhinella Fitzinger, 1826 (Amphibia, Anura, Bufonidae). Zootaxa, 3745 (5): 501 523. PMID- 26624647 TI - A new genus of Trachelipodidae Strouhal, 1953 (Crustacea, Isopoda, Oniscidea) from the eastern Mediterranean. AB - Levantoniscus n. gen. is erected for two new species from Cyprus: Levantoniscus bicostulatus n. sp. and Levantoniscus makrisi n. sp. Levantoniscus wahrmani (Strouhal, 1968) n. comb. from Israel and southern Turkey is transferred from the genus Bathytropa Budde-Lund, 1885 and family Bathytropidae. The new genus is included in the family Trachelipodidae and is characterized by distinct dorsal ornamentation, interlocking pleopods and uncovered pleopodal lungs which are located in invaginations on pleopod 3-5 exopodites. PMID- 26624648 TI - Characterization of an isolate of Heterorhabditis bacteriophora (Nematoda: Heterorhabditidae) from the Northern Territory, Australia, using morphology and molecular data. AB - An entomopathogenic nematode, Heterorhabditis H39, was found in Darwin, Australia. Based on morphological and morphometric similarities, and molecular characterisation, it is an isolate of Heterorhabditis bacteriophora. Males, hermaphrodites, females and juveniles showed important similarities on most characters that define H. bacteriophora. The morphometrics of the infective juvenile of Heterorhabditis H39 are similar to those of H. bacteriophora, including average body length (562 (537-587) vs 570 (520-600) um), maximum body width (21 (19-22) vs 24 (21-31) um), distance from the anterior end to the EP (96 (87-104) vs 104 (94-109) um) and tail length (101 (94-111) vs 91 (83-99) um). The morphology of the spicules and gubernaculum of male Heterorhabditis H39 are indistinguishable from those of H. bacteriophora. The biology and life cycle of Heterorhabditis H39 are similar to those of other Heterorhabditis species. The Neighbour-Joining Tree based on 475 nucleotides of the SSU rRNA gene showed that Heterorhabditis H39 formed a monophyletic group with other H. bacteriophora isolates with a bootstrap value of 100. Thus, phylogenetic study of SSU sequence data provided strong evidence that Heterorhabditis H39 is an isolate of H. bacteriophora. This is the first record of H. bacteriophora in northern Australia. PMID- 26624649 TI - Molecular systematics and undescribed diversity of Madagascan scolecophidian snakes (Squamata: Serpentes). AB - We provide an updated molecular phylogenetic analysis of global diversity of typhlopid and xenotyphlopid blindsnakes, adding a set of Madagascan samples and sequences of an additional mitochondrial gene to an existing supermatrix of nuclear and mitochondrial gene segments. Our data suggest monophyly of Madagascan typhlopids, exclusive of introduced Indotyphlops braminus. The Madagascar-endemic typhlopid clade includes two species previously assigned to the genus Lemuriatyphlops (in the subfamily Asiatyphlopinae), which were not each others closest relatives. This contradicts a previous study that described Lemuriatyphlops based on a sequence of the cytochrome oxidase subunit 1 gene from a single species and found this species not forming a clade with the other Malagasy species included. Based on our novel phylogenetic assessment we include all species in this endemic typhlopid clade in the genus Madatyphlops and in the subfamily Madatyphlopinae and consider Lemuriatyphlops as junior synonym. Within Madatyphlops, we identify several candidate species. For some of these (those in the M. arenarius complex), our preliminary data suggest sympatric occurrence and morphological differentiation, thus the existence of undescribed species. We also comment on the genus-level classification of several non-Madagascan typhlopids. We suggest that African species included in Madatyphlops (Afrotyphlops calabresii, A. cuneirostris, A. platyrhynchus, and Rhinotyphlops leucocephalus) should not be included in this genus. We furthermore argue that recent claims of Sundatyphlops, Antillotyphlops, and Cubatyphlops being "undiagnosable" or "not monophyletic" were based on errors in tree reconstruction and failure to notice diagnostic characters, and thus regard these three genera as valid. PMID- 26624650 TI - A new species of Dixonius (Squamata: Gekkonidae) from Phu Quy Island, Vietnam. AB - We describe a new species of Dixonius on the basis of five specimens from Phu Quy Island, Binh Thuan Province, in southern Vietnam. The new species can be distinguished from congeners based on molecular and morphological differences. Diagnostic features are: small size (SVL up to 44 mm); 7 or 8 supralabials; 11 or 12 rows of keeled tubercles on dorsum; 21-23 ventral scale rows; 5 or 6 precloacal pores in males; a canthal stripe running from rostrum through the eye and terminating behind the head; second pair of postmentals about one third to one half size of first pair; ground color of dorsum brown, with one or two rows of light yellow or orange spots in one or two rows along flanks, and irregular bands or a reticulated network of dark marks on dorsum. This is the fifth species of Dixonius known to occur in Vietnam. PMID- 26624651 TI - Taxonomic notes on Wahydra Steinhauser (Hesperiidae, Hesperiinae, Anthoptini) with description of four new species. AB - The genus Wahydra Steinhauser, 1991 was classified as Anthoptini together with other eight genera, based on the shape of the brand, hind tibial spurs and male genitalia, the species of Wahydra are scarcely represented in collections, therefore the taxonomic knowledge of the genus remains poorly explored. Aiming to contribute to the recognition and organization of the diversity of Wahydra, in the present study, four new species: Wahydra trinitas Henao, Mielke, Carneiro & Casagrande sp. nov., Wahydra curtis Mielke, Henao, Carneiro & Casagrande sp. nov., Wahydra shueyi Carneiro, Henao, Mielke & Casagrande sp. nov., and Wahydra mapiriensis Casagrande, Henao, Carneiro & Mielke sp. nov.; are describe. In addition Dalla curia Evans, 1955 is considered a syn. nov. of Wahydra tassa Evans, 1955, and Wahydra obscura is treated as a syn. nov. of Wahydra ekka Evans, 1955 comb. nov. Male genitalia is illustrated for all species, except for Wahydra dores (Bell, 1959) and Wahydra thisbe (Hayward, 1942). The female and genitalia of Wahydra vola (Evans, 1955) are described and illustrated here for the first time. PMID- 26624652 TI - Morphological and molecular characterization of Tylencholaimellus persicus sp. n. (Dorylaimida: Tylencholaimellidae) from Iran. AB - Tylencholaimellus persicus sp. n. is described and illustrated based on morphological and molecular characters. The new species is characterized by its 613-885 MUm long body, expanded lip region separated from body contour by a sharp constriction, forming a large disk-like structure, odontostyle and odontophore respectively 12-14 and 6.5-8.0 MUm long, female genital system mono opisthodelphic with relatively long anterior uterine sac (AUS; 50-80 MUm in length), position of vulva relative to the body length (V = 36.5-41.5), broadly rounded tail, abundant males in population with 22-25 MUm long spicules and one ventromedian copulatory supplement. The new species is compared with five known species of the genus that have a perioral disc, rounded tail and AUS: T. coronatus, T. incertus, T. montanus, T. ozarkensis and T. projectus. Compared to these five species, the new species has an expanded lip region separated from body contour by a sharp constriction, but can further be separated by a combination of morphological and morphometric characters such as odontostyle length, tail shape, differences in ratios c' and V and male characters. Because of having similar general morphology, the new species was also compared with a species of genus Margollus, M. bokanicus, and the differences between the two species are discussed. In addition to morphological and morphometric data, molecular phylogenetic analyses were performed using partial sequences of the 18S SSU and 28S LSU D2/D3 rDNA segments, in which the new species forms a clade with four species/isolates of Tylencholaimellus in the SSU tree and one isolate of Tylencholaimus in the LSU tree using Bayesian inference (BI). PMID- 26624653 TI - Notes on some enigmatic taxa of limnoterrestrial rhabdocoels, with the description of two new species. AB - Six taxa of limnoterrestrial rhabdocoels are discussed, two of them, both belonging to Typhloplanidae Graff, 1905, are new to science. Adenoplea reisingeri n. sp. can be distinguished from its congeners by the absence of a separate seminal receptacle, the presence of a copulatory bursa and the fact that it has an unarmed copulatory organ. Carcharodopharynx schlitzensis n. sp. can be distinguished from C. arcanus (Reisinger, 1924) Poche, 1926, the only other species within the genus, by the fact that the cirrus bears spines. For four other taxa: Adenoplea perigraptopera Reisinger, 1924, A. meridionalis Kolasa, 1981, C. arcanus (Reisinger, 1924) Poche, 1926 and Archivortex silvestris Reisinger, 1924, new data on morphology and distribution are provided. Neotypes are designated for A. perigraptopera and C. arcanus. PMID- 26624654 TI - A new species of Blattisocius (Acari: Mesostigmata: Blattisociidae), with a new characterisation of the genus. AB - A new species of Blattisocius Keegan, Blattisocius thaicocofloris n. sp., is described from Thailand from adult females and males, raising to 18 the number of species known in this genus. This is the first species of this genus described from flowers (of Cocos nucifera L.; Arecaceae), although two species, Blattisocius apis Basha & Yousef and Blattisocius apisassociae Chinniah & Mohanasundaram, were reported in association with honeybees, which could suggest an association with flowers. The new species requires updates to the diagnostic characteristics of the genus and recently published keys for generic identification of blattisociid subfamilies, blattisociine genera and Blattisocius species. PMID- 26624655 TI - A new species of the rodent genus Hylomyscus from Angola, with a distributional summary of the H. anselli species group (Muridae: Murinae: Praomyini). AB - A new species of Hylomyscus, H. heinrichorum, is described from mountains in western Angola. Based on morphological traits and cranial morphometry, the new species is assigned to the H. anselli species group and is hypothesized to be most closely related to H. anselli Bishop proper, a species named from Zambia. Members of both the H. anselli and H. denniae species groups occupy the Afromontane Biotic Zone, found in various mountain systems to the south and east of the Congo Basin. Evidence is reviewed that supports the independent radiation of these two species groups within montane forest from different Guineo-Congolian ancestral stocks. PMID- 26624656 TI - Review of the Hemyda Robineau-Desvoidy of China (Diptera: Tachinidae). AB - The Chinese species of Hemyda Robineau-Desvoidy (Phasiinae, Cylindromyiini) are revised. Five species are recognized, consisting of the previously recorded species H. hertingi Ziegler & Shima, H. obscuripennis (Meigen) and H. vittata (Meigen), one new species from NW Yunnan, Hemyda deqinensis sp. nov., and one new record for China, H. dominikae Draber-Monko. A generic diagnosis of Hemyda is provided, each of the previously described species is diagnosed, the new species is described, and a key is given to the five Chinese species. PMID- 26624657 TI - Paradiopatra Ehlers, 1887 (Annelida: Onuphidae) from southwestern Europe with the description of a new species and new ultramorphological data for the genus. AB - This work recognises five species of Paradiopatra from southwestern Europe, represented in the Bay of Biscay, the Atlantic coasts of Iberia and the western Mediterranean Sea. One species, Paradiopatra florencioi sp. nov., is newly described from the Cantabrian slope, northern Spain. We are presenting detailed diagnoses of all species and report ontogenetic changes of P. bihanica and P. hispanica. Scanning electron microscopy elucidated previously known Methylene Blue or Green staining patterns of the ventral glandular pads as cuticular pores. A dichotomous key to all species is included. PMID- 26624658 TI - Morphology and phylogenetic position of three species of genus Camptocercus Baird, 1843 (Cladocera: Anomopoda: Chydoridae). AB - Morphology of three species of the cladoceran genus Camptocercus Baird, 1843 (Anomopoda: Chydoridae), North Asian C. streletskayae Smirnov, 1998, Australian C. australis Sars, 1896 and Neotropical C. dadayi Stingelin, 1913, is investigated. Revealed data confirm a high level of morphological diversity within the genus. C. australis and C. dadayi belong to the uncinatus-clade of the genus, while C. streletsakayae is an advanced species with unclear phylogenetic position within the genus. PMID- 26624659 TI - The classification and phylogenetic status of Jekelius (Reitterius) punctulatus (Jekel, 1866) and Jekelius (Jekelius) brullei (Jekel, 1866) (Coleoptera: Geotrupidae) using molecular data. AB - The phylogenetic placement of Jekelius brullei (Jekel, 1866) and J. punctulatus (Jekel, 1866) (Coleoptera: Geotrupidae) was assessed using mitochondrial and nuclear molecular data to discern contrasting nomenclatural views provided by Lopez-Colon (1996) and the Catalogue of Palaearctic Coleoptera (Lobl et al. 2006). Our results support both the monophyletic and classification status of the genus Jekelius Lopez-Colon, 1989; and the splitting of the genus into the subgenera Jekelius Lopez-Colon, 1989 and Reitterius Lopez-Colon, 1996. The basal phylogenetic placement of these two species also suggests an oriental origin for Jekelius within the western Palaearctic region. Finally, we include a potential distributional map of Jekelius (Reitterius) punctulatus (Jekel, 1866) based on an exhaustive search of occurrence data. PMID- 26624660 TI - The occurrence of Pandalopsis spinosior Hanamura, Kohno & Sakaji, 2000 (Crustacea: Decapoda: Caridea: Pandalidae) in Hokkaido, northern Japan, and reassessment of its diagnostic characters. AB - Pandalopsis spinosior Hanamura, Kohno & Sakaji, 2000 (Decapoda: Caridea: Pandalidae) was originally described on the basis of material collected in the Urup Strait, South Kurile Islands, but there have been no subsequent records of the species since the original description. The Marine Science Museum, Fukushima Prefecture (Aquamarine Fukushima) has carried out investigations on deep-water animals in the Nemuro Strait, off Shiretoko Peninsula, Hokkaido, Japan, amongst the collections a large, commercially important pandalid shrimp routinely identified with P. coccinata Urita, 1941. Examination of the specimens from the collections, however, resulted in an unexpected identification with P. spinosior, instead of P. coccinata. In this short article, diagnostic characters of P. spinosior are reassessed, and comparison with P. coccinata is made. The validity of P. zarenkovi Ivanov & Sokolov, 2001, for which possible synonymy with P. spinosior was suggested, is maintained for the time being. PMID- 26624661 TI - Cheramus iranicus, a new species of ghost shrimp (Decapoda: Axiidea: Callianassidae) from the Persian Gulf, Iran. AB - A new species of callianassid ghost shrimp is described from the Persian Gulf, Iran. Cheramus iranicus sp. nov. is the first member of Cheramus described from Iranian subtidal waters and can be differentiated by a large cheliped with a ventroproximal spine on the merus and 7 spines on the ventral margin of the ischium, the endopod of the uropod has 4 movable spines on the distal margin and the posterior margin of the telson is strongly bilobed with a prominent medial tooth and two pairs of lateral movable spines. It is compared to other described Cheramus-like species showing a high degree of morphological similarity. PMID- 26624662 TI - Additions to the checklist of the ants (Hymenoptera: Formicidae) of Peru. AB - A recent species checklist of the ants of Peru recorded 592 nominal species and 79 genera on the basis of a literature review. Here we complement the previously published checklist with the addition of 83 nominal species and six genera, including three genera recorded only from morphospecies. This increases the list of ants reported from Peru to at least 679 species and subspecies and 85 genera. We also modify the list of species known as endemic from Peru, discuss the historical importance of the Peruvian ant fauna in myrmecology, and highlight potential research for future studies. PMID- 26624663 TI - Tanzawana flavomaculata (Hymenoptera, Ichneumonidae, Ctenopelmatinae), a new genus and species of parasitoid of Fagineura crenativora (Tenthredinidae, Nematinae), a serious pest of beech tree. AB - We describe a new genus, and a new species, of parasitoid--Tanzawana flavomaculata Watanabe & Kasparyan (Hymenoptera: Ichneumonidae: Ctenopelmatinae)- based on material collected in Honshu, Japan. As T. flavomaculata is found on Fagineura crenativora Vikberg & Zinovjev, 2000 (Hymenoptera: Tenthredinidae), a serious pest of beech tree, this parasitoid is an important natural enemy of F. crenativora that can be used for the biological control of this pest. PMID- 26624664 TI - A new species of Platydecticus (Orthoptera: Tettigoniidae: Tettigoniinae; Nedubini) from the Andes of Chile. AB - A new species of the genus Platydecticus is described based on adult male and female specimens and the egg. The new species, Platydecticus diaguita, inhabits the Andes Range at 27o S latitude, above 3000 m elevation. Both sexes are easily identifiable by genital morphology characters and by the external characters of the fastigium of the vertex and the reduced number of spines in the hind tibia. It is also the smallest species described for the genus. PMID- 26624666 TI - Taxonomy of 'Euconnus complex'. Part V. Review of type species of Euconnus subgenera Tetramelus, Paratetramelus and Heteroconnus (Coleoptera, Staphylinidae, Scydmaeninae). AB - Morphological structures of the type species of Tetramelus, Paratetramelus and Heteroconnus, subgenera of Euconnus, are described and illustrated in detail. These three taxa, showing many similarities, are retained as separate subgenera within Euconnus. They probably form a natural group characterized by gradually thickened antennae, head and pronotum with thick bristles, pronotum bell-shaped, broadest in anterior half, and prosternum about as long as half length of prothorax. Tetramelus shows adaptations to edaphic life, such as lack of wings and associated structures, reduced eyes and often lightly pigmented body; these are also possible pre-adaptations that have enabled several highly specialized species to inhabit caves. Paratetramelus differs from Tetramelus primarily in the 'anthiciform' head with large eyes, and developed hind wings; Heteroconnus is unique in narrowly separated metacoxae and modified pronotum in males, bearing presumably glandular structures. These three subgenera show a broad distribution (Tetramelus worldwide; Paratetramelus in Africa, Madagascar and Nepal; Heteroconnus in Africa and New Caledonia) and therefore further study is required to verify the placement of species inhabiting locations remote from those where the type species of each subgenus occur. PMID- 26624665 TI - The new Andean jumping spider genus Urupuyu and its placement within a revised classification of the Amycoida (Araneae: Salticidae). AB - Urupuyu gen. nov. is described for three new species of small black jumping spiders from the cloud forests of Ecuador: Urupuyu antisana sp. nov. (type species), U. edwardsi sp. nov., and U. occidentale sp. nov. Phylogenetic analyses with DNA sequences (28S, actin 5C, wingless, 16SND1 and CO1) indicate Urupuyu is closely related to the huriine amycoids Hurius and Scoturius, a placement also supported by morphological traits. Our phylogenetic analysis serves to clarify the relationships within the Amycoida in general, leading to our proposing a revised classification for the group, with subfamilies Gophoinae, Sitticinae, Bredinae subfam. nov., Scopocirinae, Thiodininae, Sarindinae, Huriinae, Simonellinae, and Amycinae. We confirm the marpissine-like Breda belongs within the Amycoida. The phylogeny implies that ant mimicry has evolved at least twice (simonellines and sarindines) and probably a third time (Atomosphyrus in the thiodinines) within the Amycoida. The following new synonymies are proposed for suprageneric names: Hyetusseae Simon, 1903 and Arachnomureae Mello-Leitao, 1917 = Thiodininae Simon, 1901; Zunigeae Simon, 1901 = Sarindinae Simon, 1901; Synemosynae Banks, 1892 = Simonellinae Peckham, Peckham & Wheeler, 1888; Magoninae Petrunkevitch, 1928 = Amycinae F.O.P.-Cambridge, 1900. PMID- 26624667 TI - Reprising the taxonomy of Cyprus Scops Owl Otus (scops) cyprius, a neglected island endemic. AB - The endemic Cyprus Scops Owl Otus (scops) cyprius has been treated as a subspecies of the widespread Eurasian Scops Owl O. scops since at least the 1940s. However, its song is distinct from that of all other subspecies of O. scops in being double-noted, rather than single-noted. Its plumage also differs, most obviously in being consistently darker than other subspecies and in lacking a rufous morph. However, it shows no biometric differences from O. s. cycladum and southern populations of O. s. scops. It is also unusual among scops (s. l.) populations in being at least partially resident, although two specimens showing characters of this taxon were collected in Israel in early spring, and the numbers of birds that are resident on Cyprus appear to vary, with few recent winter records. It differs from O. s. scops by one synapomorphic nucleotide exchange in the analysed mitochondrial marker, indicating a recent separation. Given that large numbers of O. s. scops and O. s. cycladum pass through Cyprus on spring migration, and that the latter breeds in adjacent countries, it seems probable that cycladum would colonize the island, but for the presence of cyprius. That it does not do so, and that cyprius retains its distinctive song and plumage, suggests that isolating mechanisms exist. We recommend that cyprius be considered specifically distinct, as are other distinctively voiced insular Otus populations. PMID- 26624668 TI - Unveiling the Rosetta Stone of syllids: redescription and neotype designation of Syllis monilaris Savigny in Lamarck, 1818, type species of type genus of family Syllidae Grube, 1850 (Annelida). AB - Syllis monilaris Savigny in Lamarck, 1818, the type species of the genus Syllis Savigny in Lamarck, 1818, is redescribed based on two specimens deposited in the Museum fur Naturkunde Berlin (Germany). One specimen is designated as neotype, since the original type material is considered to be lost, and there is a necessity to stabilize the nomenclature of the group. The species is large sized, with long dorsal cirri on anterior segments, becoming short and fusiform from midbody, it has thick compound chaetae with short, unidentate blades, not fused to shafts. The lack of chaetae with fused shafts and blades contradicts the division of the genus Syllis into subgenera as proposed by Langerhans (1879), who considered the subgenus Syllis as having thick fused chaetae on midbody, in addition to compound chaetae, and the subgenus Typosyllis with only compound chaetae. A discussion about the systematics of the genus is included, and according to this new data, Typosyllis is a junior synonymy of Syllis. PMID- 26624669 TI - Review of some species in the genera Pselaphodes Westwood and Labomimus Sharp (Coleoptera: Staphylinidae: Pselaphinae). AB - Eight species of the genera Pselaphodes Westwood and Labomimus Sharp described from 1870 to 1925 are reviewed, six of them are redescribed, with their major diagnostic characters illustrated. Lectotypes are designated for the following names: Pselaphodes antennatus Bryant, 1915, Pselaphodes simplicicornis Champion, 1925, Pselaphodes spinosus Champion, 1925, and Pselaphodes villosus Westwood, 1870. Three new combinations and a new synonymy are proposed: Labomimus foveolatus (Raffray, 1882) comb. n. (transferred from Pselaphodes), Labomimus torticornis (Champion, 1925) comb. n. (transferred from Pselaphodes), and Pselaphodes championi (Jeannel, 1960) comb. n. (transferred from Labomimus), syn. n. (= Pselaphodes spinosus Champion, 1925). PMID- 26624670 TI - Four new Entiminae from the Mediterranean region (Coleoptera: Curculionidae: Entiminae: Phyllobiini, Trachyphloeini), with additional data on the distribution of some poorly known species. AB - Argoptochus sappho sp. n. and Pelletierellus bryophilus sp. n. from Lesbos island, Greece, Cathormiocerus kostali sp. n. from Morocco, and C. meyeri sp. n. from Portugal are described. New faunistic data are presented for Argoptochus moraveci Borovec, 2006, Cathormiocerus inflatiscapus Escalera, 1918, C. jeani (Borovec, 1989), C. longiscapus Pic, 1912, C. tenuiscapus Fairmaire, 1884, Pelletierellus bosnicus (Apfelbeck, 1898) and P. neglectus (Borovec, 1992). Males of Cathormiocerus inflatiscapus Escalera, 1918 and C. tenuiscapus Fairmaire, 1884 are described for the first time and the penises of these species are illustrated. PMID- 26624671 TI - Three new species of Dysponetus Levinsen, 1879 (Polychaeta: Chrysopetalidae) from the South Atlantic and Southern Ocean, with a re-description of Dysponetus bulbosus Hartmann-Schroder, 1982. AB - Three new species of Dysponetus (Polychaeta: Chrysopetalidae) are described from the South Atlantic and Southern Ocean: Dysponetus ovalisetosus n. sp. from the Falkland Islands, Dysponetus bricklei n. sp. from South Georgia and Dysponetus antarcticus n. sp. from Antarctica are all characterized by having notochaetae that are oval in cross-section in contrast to the D-shape described for seven of the other species of Dysponetus. Dysponetus antarcticus n. sp. is the most distinct due to the combination of both a ventral cirrus on segment 3 and four eyes. Formerly mis-identified as Dysponetus bulbosus Hartmann-Schroder, 1982, it was discovered while clarifying the contradictory descriptions of that species published by Hartmann-Schroder in 1982 and 1986. Dysponetus bulbosus is re described and newly figured. Dysponetus bricklei n. sp. and Dysponetus ovalisetosus n. sp. can be determined by comparing several characters including position of the median antenna, shape of the palps and cirri, and the number and shape of both the noto- and neurochaetae. PMID- 26624672 TI - A new species of Characidium Reinhardt (Ostariophysi: Characiformes: Crenuchidae) from coastal rivers in the extreme south of Bahia, Brazil. AB - Characidium helmeri, a species of the family Crenuchidae apparently endemic to rivers draining the extreme south of Bahia, Brazil, is described. The new species is easily distinguished from congeners by having dark, vertically elongated, irregular spots or dashes on flanks, usually more evident over midlateral stripe and/or ventral half of body, where it may present a somewhat curved or zigzag shape. Characidium helmeri can be further distinguished from most congeners by having lateral line reduced to 13-22 pored scales, adipose fin absent, isthmus naked on its anteriormost portion, 14 scales around caudal peduncle, 4 scales above lateral line and 4 below, two series of dentary teeth, supraorbital absent or extremely reduced, and basicaudal black spot well defined. The occurrence of reductive characters in Characidium is briefly discussed. PMID- 26624673 TI - Description of the final stadium larvae of Onychargia atrocyana Selys, 1865 from Sarawak, identified using DNA barcoding (Odonata: Zygoptera: Platycnemididae), with an overview of larval characters in the Platycnemididae. AB - The final stadium larva of Onychargia atrocyana Selys, 1865, is described and illustrated based on two female specimens collected at Gunung Mulu National Park, Sarawak, East Malaysia. The larvae were identified by matching the mitochondrial marker COI with that of known adult specimens from Gunung Mulu, Bintulu and Kuching in Sarawak and from Pahang state in West Malaysia. The specimens presented close matches with all adults in this gene. As O. atrocyana is a taxonomically isolated species with no close congeners in Borneo the determination is beyond doubt. O. atrocyana is the only member of the Onychargiinae for which the larva is known. It is compared with the known larvae of other platycnemidid subfamilies, and the possible significance of larval morphology in higher classification of the group is discussed. PMID- 26624674 TI - Inocellia indica sp. nov. (Raphidioptera: Inocelliidae): a new snakefly species from northeastern India. AB - A new species of the snakefly genus Inocellia Schneider, 1843 from northeastern India is described: Inocellia indica sp. nov. The new taxon represents the second species of Raphidioptera from the northeastern part of the Indian Subcontinent and appears to be closely related to I. bhutana Aspock, Aspock & Rausch, 1991 from neighboring Bhutan. PMID- 26624675 TI - Contributions to the tribe Leptocorisini, with descriptions of Planusocoris schaeferi gen. & sp. nov. (Hemiptera: Alydidae). AB - In this paper, the genus Grypocephalus Hsiao, 1963 is taxonomically reviewed worldwide. Bloeteocoris Ahmad, 1965 is proposed as a new junior synonym for Grypocephalus Hsiao, 1963. All the species of Bloeteocoris Ahmad, 1965 are herein transferred to Grypocephalus Hsiao, 1963, in which, Bloeteocoris minutus Ahmad, 1965 is synonymized with Grypocephalus pallipectus Hsiao, 1963. Planusocoris schaeferi gen. & sp. nov. of Leptocorisini is described as new to science. Photographs of adults, and illustrations of male and female genitalia of the involved species are provided. The genera of the world Leptocorisini are keyed. The type specimens of P. schaeferi sp. nov. are deposited in the Insect Collection, Institute of Entomology, Nankai University, Tianjin, China. PMID- 26624676 TI - New species of Plectropsyche Ross 1947 (Trichoptera: Hydropsychidae: Hydropsychinae). AB - Two new species from Mexico and Central America of the genus Plectropsyche Ross are described and the male and female genitalia are figured. The only extant previous described species, Plectropsyche hoogstraali Ross and its synonym Plectropsyche pitella (Denning) from Mexico are studied. A map with the distribution of all known Plectropsyche species is presented and an illustrated key for the males of the extant species are included. PMID- 26624677 TI - The genus Philoctetes Abeille de Perrin, 1879 from China, with description of two new species (Hymenoptera, Chrysididae). AB - The Chinese species of the genus Philoctetes Abeille de Perrin, 1879 are revised and keyed for the first time. Six species are recorded, of which two are new for science: Philoctetes longiflagellis Rosa, Wei & Xu, sp. nov. (Inner Mongolia and Shanxi) and P. simulator Rosa, Notton & Xu, sp. nov. (Tianjin). The new synonym, Philoctetes cupratus (Mocsary, 1914), syn. nov. of Philoctetes mongolicus (du Buysson, 1901), is proposed. Philoctetes mongolicus (du Buysson, 1901) is newly recorded from Pakistan. PMID- 26624678 TI - Description of a new species of the costata-group (Cladocera, Chydoridae, Aloninae) from Brazil. AB - The aim of this study is to describe a new species of the costata-group from Brazil. Alona margipluma sp. nov. shares morphological traits with A. costata Sars, 1862, A. natalensis Sinev, 2008, and A. cheni Sinev, 1999, but differs from them in: (i) thin setulae between the marginal setae on the valves, (ii) setae 4 5 on the exopodite of limb III long and different in length, (iii) bottle-shaped sensillum on the basal endite of limb IV. For identification of Alona margipluma sp. nov. it is necessary to check carefully the main head pores and postabdomen characters since the former superficially resemble A. iheringula, A. setigera and Alona guttata. PMID- 26624679 TI - Taxonomic notes on the genus Gribodia Zavattari, 1912 (Hymenoptera: Vespidae: Eumeninae) from Vietnam and China, with description of a new species. AB - The genus Gribodia Zavattari, 1912, is newly recorded from Vietnam and China. Gribodia nigra sp. nov. (China, Hainan) is described and figured and G. cupreipennis (Bingham) is redescribed. A key to six known species of the genus is provided. PMID- 26624680 TI - Contribution to the genus Chrysidea Bischoff, 1913 from China, with description of a new species (Hymenoptera, Chrysididae). AB - The genus Chrysidea Bischoff, 1913 belongs to the tribe Chrysidini (Hymenoptera, Chrysididae). Bohart (1988) revalidated the genus after it was considered as subgenus of Chrysis Linnaeus, 1761 (Linsenmaier 1959) or Trichrysis Lichtenstein, 1876 (Kimsey & Bohart 1981) and synonymised it with Chrysis (Trichrysis) (Linsenmaier 1984). Kimsey & Bohart (1991) gave a checklist of 19 known species of Chrysidea, of which three are known from the Oriental Region, C. bidenticulata (Mocsary, 1913), C. furiosa (Cameron, 1897) and C. monticellii (du Buysson, 1906). Only one species, C. pumila (Klug, 1845), has been recorded for the Palaearctic part of China (Hammer 1936; Rosa et al. 2014). PMID- 26624681 TI - Microdytes huangyongensis sp. n. and new records of Allopachria Zimmermann, 1924 from Zhejiang Province, China (Coleoptera: Dytiscidae). AB - An excursion to Zhejiang, China was made in August 2014, and two species of Microdytes J. Balfour-Browne, 1946 (M. uenoi Sato, 1972 and M. huangyongensis sp. n.) and two species of Allopachria Zimmermann, 1924 (A. miaowangi Wewalka, 2010, and A. schoenmanni Wewalka, 2000) were collected. Only one species of Microdytes (M. uenoi Sato, 1972) was recorded from Zhejiang before. The genus Allopachria is reported from Zhejiang for the first time. The genus Microdytes occurs throughout southern and south-eastern Asia. Since the revision of Microdytes by Wewalka (1997), sixteen new species and one new synonymy have been reported (Wewalka 1998; Wewalka & Wang 1998; Wewalka et al. 2007; Bian & Ji 2009; Miller & Wewalka 2010; Wewalka 2011). Including the new species the genus Microdytes comprises 46 species. Specimens were examined with a Leica M205c stereomicroscope. Further details were studied under an Olympus BX51 compound microscope. The photograph of the holotype (Fig 1) was made with a KEYENCE VHX-2000 C digital microscope. All specimens studied were deposited in the Institute of Applied Ecology, Shenyang, Chinese Academy of Sciences (IAECAS). PMID- 26624682 TI - A new species of Apteranabropsis Gorochov, 1988 from Guangxi, China (Orthoptera: Anostostomatidae: Anabropsinae: Anabropsini) with key to known species. AB - This paper describes and illustrates a new species of the genus Apteranabropsis (Anostostomatidae: Anabropsinae) from Guangxi, China, namely Apteranabropsis guangxiensis Bian & Shi sp. nov. A key to all known species of Apteranabropsis is provided. PMID- 26624684 TI - Epistylis smalli (Ciliophora: Peritrichia) a new peritrich from Guaiba Lake, Southern Brazil. AB - Epistylis smalli n. sp., a freshwater colonial peritrich, was collected in Guaiba Lake, Southern Brazil. Its morphology was investigated using in vivo observations and protargol stained specimens. E. smalli possess an elongate zooid that measures in vivo, on average, 173 MUm in length and 50 MUm in width. A C-shaped macronucleus that surrounds the infundibulum and a single contractile vacuole could be easily observed in the living cell. The oral infraciliature observed in silver-stained specimens was typical of peritrich ciliates, with three infundibular polykinetids bearing three rows of kinetosomes. A detailed description of the live and stained zooids is given. PMID- 26624683 TI - New Acosmetura species (Orthoptera: Tettigoniidae: Meconematinae) from China, with notes on their distribution. AB - One new species of Acosmetura (Orthoptera: Tettigoniidae: Meconematinae) is described from China, namely Acosmetura listrica Bian & Shi, sp. nov. and distinctive characters are illustrated. In addition, a key to the known species with morphological photographs of Acosmetura longicercata Liu, Zhou & Bi, 2008 from Tianmushan, Zhejiang is provided in this paper. Based on the comprehensive physical geographical regionalization, Acosmetura listrica sp. nov. is distributed in Huinan and the middle and lower reaches of Changjiang River, which belongs to the Northern Subtropical Humid Climate Zone. PMID- 26624685 TI - Two new species of the genus Cordilura Fallen, 1810 (Diptera, Scathophagidae) from the Russian Far East. PMID- 26624686 TI - A new species and a key to 19 species of the genus Traulia Stal, 1873 (Orthoptera: Catantopidae) from China. AB - A new species of the genus Traulia Stal, 1873 namely Traulia xiai sp. nov. is described from China in this paper. The new species is similar to Traulia brachypeza Bi, 1986, but differs from the latter by the short tegmina, reaching the middle of third abdominal tergite only. The new species is also similar to Traulia ornate Shiraki, 1910, but differs from the latter by hind tibia all orange red and furculae of male absent. We think that Traulia yifengensis Wang, Xiangyu & Liu, 1997 is a valid species, not a synonym of Traulia brachypeza Bi, 1985 by Wei & Huang (2012), because the tegmina of Traulia yifengensis is very long, extending over the end of abdomen distinctly. A key to 19 species of this genus from China is also given in this paper. The type specimens are deposited in the National Museum of Natural Science, Taichung, Taiwan, China. PMID- 26624687 TI - A review of the genus Potemnemus Thomson, 1864 (Coleoptera: Cerambycidae) with description of a new species from Papua New Guinea. AB - All preserved type specimens and type series of the genus Potemnemus Thomson, 1864 from museum collections have been examined. The presented taxonomic study is based on examination of morphological characters as well as studies of the genitalia. The genitalia are described for the first time. The type of P. scabrosus Olivier, 1790 is lost, and the original drawing has been designated as a lectotype. The monospecific genus Parapotemnemus Breuning, 1971 nov. syn. is considered to be a junior synonym of Potemnemus Thomson, 1864 based on similarities in both external and male genitalia characters. Potemnemus wheatcrofti (Breuning, 1971) nov. comb. thus becomes a new combination. The holotype of P. wheatcrofti nov. comb. is lost, and a paratype ? has been designated as a neotype. Potemnemus nylanderi nov. sp. is described from the eastern parts of Papua New Guinea. The following new synonyms within the genus Potemnemus have been introduced: P. hispidus Gressitt, 1952 nov. syn. is a junior synonym of P. sepicanus Kriesche, 1923, P. detzneri Kriesche, 1923 nov. syn. is a junior synonym of P. trimaculatus Lea, 1918, and P. loriai Breuning, 1956 nov. syn. and P. triturberculatus Breuning, 1942 nov. syn. are both junior synonyms of P. scabrosus (Olivier, 1790). As a result of the present study the following species have been resurrected to species level: Potemnemus trimaculatus Lea, 1918 sp. res., P. wolfi Berchmans, 1925 sp. res., and P. thomsoni Lansberge, 1880 sp. res. The genus Periaptodes Pascoe, 1866 gen. res. has been resurrected as a valid genus based on differences in both external and male genitalia characters, and re descriptions of the genera Potemnemus and Periaptodes are presented. Consequently, the following species have been transferred back to Periaptodes from Potemnemus: Periaptodes frater (Van de Poll, 1887), P. lictor Pascoe, 1866, P. olivieri (Thomson, 1864), P. potemnemoides Kriesche, 1936. P. testator Pascoe, 1866, P. paratestator Breuning, 1980. P. testator has priority as the type species of the genus Periaptodes (designation by Breuning, 1944). McKeown's designation in 1947 of Periaptodes lictor Pascoe, 1866 as type species of the genus is therefore invalid. A key to the species of Potemnemus is provided. PMID- 26624688 TI - The genus Hylcalosia Fischer, 1967 (Hymenoptera: Braconidae: Alysiinae) of the Russian Far East. AB - The braconid genus Hylcalosia Fischer, 1967 of the fauna of Russia are reviewed. A new species, Hylcalosia livadiae sp. nov., from Primorskiy Territory is described. Based on new material, illustrated redescriptions of H. hymaenei Belokobylskij, 1992 and H. sutchanica Belokobylskij, 1992 are provided. Hylcalosia adsimilis Papp, 1994 is synonymised with H. sutchanica Belokobylskij, 1992 (syn. nov.). The most northern records in the Palaearctic Region, Amur Province of Russia, of the genus Hylcalosia and the species H. hymaenei and H. sutchanica are documented. A new key to all known species of this genus is provided. PMID- 26624689 TI - A taxonomic revision of order Pilisuctorida (Ciliophora, Apostomatia) with keys to the subordinate taxa. AB - The article is to present a review of the taxonomic literature of pilisuctorid ciliates and new data from samples taken in Ukraine and Mexico. In order to contribute to the knowledge of this specialised ciliate group, the present article contains the general characteristics of order Pilisuctorida members, information on morphology and life cycles of all its representatives and some own data on distribution of three species of genus Conidophrys in Ukraine and Mexico. The taxonomic composition of this order, and diagnoses of all taxa are also included, as well the keys to the taxa. PMID- 26624690 TI - A new species of deepwater wrasse (Labridae: Terelabrus) from the western Pacific Ocean. AB - A new labrid fish Terelabrus dewapyle sp. nov. is described as the second species of the genus, on the basis of five specimens collected from southern Japan, Papua New Guinea, and Fiji in depths of 72-92 m. The sole paratype of T. rubrovittatus Randall & Fourmanoir 1998 is herein identified as T. dewapyle and designated as a paratype of the latter. The new species can be distinguished from T. rubrovittatus by the following characters: lower number of scale rows in the longitudinal series (41 or 42 vs. 45-48 in the latter), fewer pored lateral-line scales (39 or 40 vs. 43-45), and fewer gill rakers (12 or 13 vs. 14 or 15); a broader space between the anteroventral margin of the orbit and the maxilla [least distance 1.2-3.7% (mean 2.5%) SL vs. 0.5-2.3% (1.6%)]; no red blotches on the midlateral red stripe in adults and young (vs. 8-10 red blotches superimposed on midlateral red stripe in adults); no yellow band on the dorsal fin (vs. broad vivid yellow band submarginally on the dorsal fin in adults, pale yellow band in young); a vivid yellow (vs. white) space between the upper and midlateral red stripes; and a black blotch superimposed on the midlateral red stripe on the opercle in young, the black blotch fading with growth (vs. black blotch absent or indistinct). PMID- 26624691 TI - The second genus and species of the extinct neuropteroid family Corydasialidae, from early Eocene McAbee, British Columbia, Canada: do they belong to Megaloptera? AB - Ypresioneura obscura gen. et sp. nov. from the early Eocene (Ypresian) McAbee locality (Canada, British Columbia) is described. It is assigned to the extinct neuropteroid family Corydasialidae, as the second known genus and species. The Corydasialidae was previously known only from late Eocene (Priabonian) Baltic amber. It was originally assigned to the Megaloptera, but the character states that support this conclusion are not strongly diagnostic. There is still doubt as to whether this family belongs to Megaloptera or to the Neuroptera. If this is a megalopteran (which we favor), it is the first specimen of the order from the insect-rich Okanagan Highlands series of Ypresian localities, which occur sporadically across the southern interior of British Columbia, Canada into north central Washington, USA. PMID- 26624692 TI - The first description of the leaf-mining Nepticulidae (Lepidoptera) feeding on the South American plant genus Liabum, Asteraceae. AB - First Liabum Adans. (Asteraceae) feeding Nepticulidae are reported. Two new new species from the Andes (Ecuador) are described: Stigmella serpantina Diskus & Stonis, sp. nov. and S. pangorica Diskus & Stonis, sp. nov. The male genitalia of both species and the female genitalia, as well the leaf-mines of S. serpantina sp. nov. are illustrated. PMID- 26624693 TI - Parambassis serrata, a new species of glassperch (Teleostei: Ambassidae) from the Kaladan drainage, India. AB - Parambassis serrata, a new species of glassperch from the Kolo River, Kaladan drainage, Mizoram, India is described. It is distinguished from its congeners by the combination of characters that includes: presence of a faint, vertically elongated brown humeral blotch; posterior margin of most spines of first dorsal fin proximally blackish; 14-16 dorsal and anal-fin branched rays; a black longitudinal stripe on ventral surface of caudal peduncle; absence of predorsal scales; a serrated preopercular ridge; 51-56 scales in lateral series; and 11 pectoral-fin rays. PMID- 26624694 TI - Hypocaccus (s.l.) hirsutus sp. nov., an atypical new species of the genus Hypocaccus C. Thomson, 1867 from India (Coleoptera: Histeridae: Saprininae). AB - An atypical new species of Hypocaccus C. Thomson, H. hirsutus sp. nov. from south India is described and figured, but left unassigned to a subgenus. Current problems of taxonomy, morphological characters and inter-relationships of Hypocaccus subgenera are discussed and notes on the distribution of Hypocaccus C. Thomson, 1867 in India are given. PMID- 26624695 TI - A new species of Bryoleuca Hampson, 1908 from Afghanistan (Lepidoptera, Noctuidae, Bryophilinae). AB - A new species of the raptricula species-group, Bryoleuca pljushtchi sp. n. is described. A diagnostic comparison is made with Bryoleuca raptricula ([Denis & Schiffermuller], 1775), Bryoleuca felina (Eversmann, 1852), Bryoleuca orthogramma (Boursin, 1954), Bryoleuca volodia An, Choi & Ronkay, 2013 and Bryoleuca nahnybidai Pekarsky, 2014. Adults and female genitalia of the new species and its closest relatives are illustrated. Modern taxonomic studies of the raptricula group started by Fibiger et al. (2009) and got progress by the clarification of the taxonomic status of B. felina (Pekarsky & Ronkay 2010). Subsequently, further two newly recognised species were described in the last two years, B. volodia and B. nahnybidai. The first attempt to prepare the checklist of the subfamily was made by Hacker (1990) and, later, European check list was given in the Noctuidae Europaeae, Vol. 11 (Fibiger et al. 2009). As for the fauna of Afghanistan, Kocak and Kemal (2012) listed twelve Bryophilinae species one of which, B. raptricula, belongs to the genus Bryoleuca. The taxonomic situation of the raptricula species complex is far not completely known yet. Present paper contains the description of a new Bryoleuca species from Afghanistan. The single female of this new species was collected by Ukrainian entomologists Igor Pljushtch and Oleg Pak in Central Afghanistan in 2013. PMID- 26624696 TI - ALBANE VILARINO & ADOLFO R. CALOR (2015) NEW SPECIES OF POLYCENTROPODIDAE (TRICHOPTERA: ANNULIPALPIA) FROM NORTHEAST REGION, BRAZIL. Zootaxa, 4007(1): 113 120. PMID- 26624697 TI - New species and host plants of Anastrepha (Diptera: Tephritidae) primarily from Peru and Bolivia. AB - Twenty-eight new species of Anastrepha are described and illustrated: A. acca (Bolivia, Peru), A. adami (Peru), A. amplidentata (Bolivia, Peru), A. annonae (Peru), A. breviapex (Peru), A. caballeroi (Peru), A. camba (Bolivia, Peru), A. cicra (Bolivia, Peru), A. disjuncta (Peru), A. durantae (Peru), A. echaratiensis (Peru), A. eminens (Peru), A. ericki (Peru), A. gonzalezi (Bolivia, Peru), A. guevarai (Peru), A. gusi (Peru), A. kimi (Colombia, Peru), A. korytkowskii (Bolivia, Peru), A. latilanceola (Bolivia, Peru), A. melanoptera (Peru), A. mollyae (Bolivia, Peru), A. perezi (Peru), A. psidivora (Peru), A. robynae (Peru), A. rondoniensis (Brazil, Peru), A. tunariensis (Bolivia, Peru), A. villosa (Bolivia), and A. zacharyi (Peru). The following host plant records are reported: A. amplidentata from Spondias mombin L. (Anacardiaceae); A. caballeroi from Quararibea malacocalyx A. Robyns & S. Nilsson (Malvaceae); A. annonae from Annona mucosa Jacq. and Annona sp. (Annonaceae); A. durantae from Duranta peruviana Moldenke (Verbenaceae); and A. psidivora from Psidium guajava L. (Myrtaceae). PMID- 26624699 TI - Catalogue of the Iranian Microgastrinae (Hymenoptera: Braconidae). AB - In the present study, the Iranian Microgastrinae (Hymenoptera: Braconidae) fauna is summarized. It is based on a detailed study of all available published data and new material collected. In total 99 species belonging to 8 genera are from Iran: Apanteles Forster, 1862 (36 species), Cotesia Cameron, 1891 (34 species), Deuterixys Mason, 1981 (1 species), Diolcogaster Ashmead, 1900 (4 species), Microgaster Latreille, 1804 (4 species), Microplitis Forster, 1862 (11 species), Pholesetor Mason, 1981 (4 species) and Protapanteles Ashmead, 1898 (5 species) in 4 tribes (Apantilini, Cotesiini, Microgastrini and Microplitini). A faunistic list with distribution data, and host records are given. Four species are new records for the fauna of Iran: Apanteles brunnistigma Abdinbekova, 1969, A. ingenuoides Papp, 1971, Microplitis decipiens Prell, 1925 and M. marshallii Kokujev, 1898. PMID- 26624698 TI - Damselflies of the genus Argia of the Guiana Shield (Odonata: Coenagrionidae). AB - This revision of all 21 species of Argia known to occur within the Guiana Shield includes descriptions of new species, synonymies, keys to both sexes based primarily on morphology of caudal appendages and genital ligula in males and of the mesostigmal plates in females, diagnoses accompanied by illustrations and distribution maps for all species. Twelve new species are described: A. appendiculata (Holotype ?: Venezuela, Amazonas State, Cerro de la Neblina, Base Camp, 0 degrees 50' N, 66 degrees 10' W, 18 ii 1985, P.J. & P.M. Spangler, R.A. Faitoute leg., in USNM), A. azurea (Holotype ?: Guyana, Potaro-Siparuni Region, Kaieteur Ravine, about 5 degrees 10' N, 59 degrees 28' W, 11 iv 1912, J.M. Geddes leg., in UMMZ), A. cuneifera (Holotype ?: Venezuela, Amazonas State, Cerro de la Neblina, Base Camp, 0 degrees 50' N, 66 degrees 10' W, 20-24 iii 1984, O.S. Flint, Jr. & J.A. Louton leg., in USNM), A. deceptor (Holotype ?: French Guiana, Cayenne Department, Regina Commune, Saut Athanase, 4 degrees 10'59" N, 52 degrees 20'6" W, 9 x 2001, L. Juillerat leg, in MHNN), A. donnellyi (Holotype ?: Venezuela, Bolivar State, small marsh and creek on plateau surface above Conac River, 10 km E of El Pauji; about 4 degrees 31' N, 61 degrees 31' W, 5 viii 1990, RWG leg., in CSCA), A. gemella (Holotype ?: Brazil, Amazonas State, Reserva Ducke, 26 km E Manaus (3 degrees 0'15'' S, 59 degrees 56'23'' W, 120 m), 2-4 ii 1979, O.S. Flint Jr. leg., in USNM), A. guyanica (Holotype ?: Venezuela, Amazonas State, Cerro de la Neblina, Camp IV, 0 degrees 58' N, 65 degrees 57' W, 15-18 iii 1984, O.S. Flint, Jr. leg., in USNM), A. joallynae (Holotype ?: Venezuela, Bolivar State, Canaima, palm marsh, 6 degrees 14'30" N, 62 degrees 50'53" W, 22 25 ix 1980, R.W. & J.A. Garrison. leg., in CSCA), A. loutoni (Holotype ?: Brazil, Amazonas State, Purus River, Nova Olinda, about 3 degrees 30' S, 57 degrees 56' W, 6 ii 1979, O.S. Flint, Jr. leg., in FSCA), A. meioura (Holotype ?: Brazil, Amazonas State, Manaus, about 2 degrees 55' S, 59 degrees 59' W, 26 vi 1922, J.H. Williamson & J.W. Strohm leg., in UMMZ), A. palmata (Holotype ?: Brazil, Amazonas State, Manaus, about 5 miles N of Flores on route to Campos Sales, small creek in virgin forest, about 3 degrees 0'S, 60 degrees 1' W, 15 vi 1922, J.H. Williamson & J.W. Strohm leg., in UMMZ), and A. recurvata (Holotype ?: Venezuela, Amazonas State, San Carlos de Rio Negro, 1 degrees 55' N, 67 degrees 4' W, 97 m, 14-21 iii 1984, J. De Marmels leg., in MIZA). The status of Argia impura Rambur, 1842, is discussed and the following nomenclatural changes are proposed: Argia stigmatica Navas, 1934 and A. umbriaca Fraser, 1946 are considered junior synonyms of Argia indicatrix Calvert, 1902, and Argia eliptica Selys, 1865 and A. icterica Navas, 1934 are considered junior synonyms of A. oculata Hagen in Selys, 1865. PMID- 26624700 TI - Contributions to the aphid fauna (Hemiptera, Aphidoidea) of Chukotka Autonomous Okrug with descriptions of five new species. AB - The first study of the aphid fauna from Chukotka Autonomous Okrug has been made; 18 species are reported from this territory, the most north-eastern of Russia and of the Palaeartic Region. Five new species are described: Aphis aquilonalis sp. nov. on Rumex arcticus Trautv.; Aphis beringiensis sp. nov. were collected by yellow trap; Macrosiphoniella (Asterobium) jaroslavi sp. nov. on Artemisia arctica Less. and Artemisia tilesii Ledeb.; Macrosiphum chukotense sp. nov., a polyphagous species found on plants in nine different families; and Pleotrichophorus tuberculatus sp. nov. on Artemisia tilesii Ledeb. In addition, the male and oviparous female of Acyrthosiphon boreale Hille Ris Lambers, 1952 and the fundatrix and male of Pleotrichophorus knowltoni Corpuz-Raros and Cook, 1974 are described for the first time. PMID- 26624702 TI - A redescription of the endemic Madagascan genus Tricompastes (Hemiptera: Heteroptera: Pentatomidae). AB - The endemic Madagascan genus Tricompastes Cachan, 1952 (Hemiptera: Heteroptera: Pentatomidae: Pentatominae: Triplatygini), containing a single species Tricompastes gigas Cachan, 1952, is redescribed and illustrated, including first descriptions of male and female genitalia. First exact localities of the species are provided. Lectotype of T. gigas is designated. PMID- 26624701 TI - Two new species of African suckermouth catfishes, genus Chiloglanis (Siluriformes: Mochokidae), from Kenya with remarks on other taxa from the area. AB - Recent expeditions in Kenya and examination of existing collections confirmed the presence of two undescribed Chiloglanis species and revealed previously unknown diversity within the Athi River system. The two new species are easily distinguished from described congeners in the area by external morphology, allopatric distributions, and genetic markers. Chiloglanis kerioensis sp. nov., is restricted to the Kerio River system and is the only known suckermouth catfish from the Lake Turkana basin. Chiloglanis devosi sp. nov., is known only from the type locality, the Northern Ewaso Nyiro (Ng'iro) below Chanler's Falls. In addition to these two new species, this study confirmed the presence of an undescribed Chiloglanis sp. occurring sympatrically with Chiloglanis brevibarbis in the Tsavo River. A dichotomous key for identifying all described Chiloglanis species found within Kenya is presented along with comments. PMID- 26624703 TI - A new species of Ptychochromis from southeastern Madagascar (Teleostei: Cichlidae). AB - We describe a new species in the endemic Malagasy cichlid genus Ptychochromis. Ptychochromis mainty, new species, is known from four individuals, all collected in the Fort Dauphin region of southeastern Madagascar, and shares a palatine morphology (eastern-type palatine) with other eastern congeners. Ptychochromis mainty is distinguished from all congeners by a nearly uniform dark brown to black pigmentation pattern in preservation and by the presence of a relatively continuous and expansive black longitudinal midlateral blotch in life, extending from the posterior margin of the opercle to the caudal peduncle. The new species is further distinguished from other eastern Ptychochromis species by having minimal or no overlap of the first supraneural with the dorsoposterior region of the supraoccipital crest (vs. marked overlap). We present a molecular-based phylogeny for all available Ptychochromis species, which supports the hypothesis that P. mainty is a distinct taxon. The new species is recovered as the sister taxon to P. grandidieri within a clade comprising species with an eastern-type palatine morphology. We present a geometric morphometric analysis that provides additional evidence to distinguish P. mainty from congeners. PMID- 26624704 TI - Egg morphology, laying behavior and record of the host plants of Ricania speculum (Walker, 1851), a new alien species for Europe (Hemiptera: Ricaniidae). AB - The exotic planthopper, Ricania speculum (Ricaniidae) was recently detected in Liguria, in northern Italy, and recorded as a first alert for Europe. The first morphological description of eggs and laying behavior are given. Eggs are inserted into the woody tissue of a wide range of different host plants in such a unique manner among native and alien planthoppers of Italy that it can be used to describe the prevalence and diffusion of the species in new environments, though in the absence of juveniles and/or adults. In addition, the paper lists the host plants utilized for egg laying and describes the eggs. PMID- 26624705 TI - Towards understanding Lepidocyrtus Bourlet, 1839 (Collembola, Entomobryidae) I: diagnosis of the subgenus Setogaster,
new records and redescriptions of species. AB - The taxonomic status of the subgenera of Lepidocyrtus Bourlet is confused. Currently ten subgenera are recognised but their separation, using the existing set of diagnostic characters, is not clear. Collections over the last forty years have shown that species of Setogaster Salmon, originally described as a genus (Trichogaster Handschin) and currently considered a subgenus of Lepidocyrtus, are common and widespread in Australia. The diagnostic characters of Setogaster, as given by Handschin, are: 1) the basal mucronal spine with spinelet; 2) lack of scales on antennae, legs, ventral tube and dorsal region of manubrium; and, for some species, 3) tufts of long filaments laterally on abdomen III. These three diagnostic characters for Setogaster are shared with some other subgenera, making their delimitation unclear. We provide here an array of new characters that are associated with Handschin's characters which separate Setogaster from all European species of the subgenera Lanocyrtus and Lepidocyrtus s. str. On this basis we define subgenus Setogaster more in detail, redescribe some species in the subgenus, corroborate the presence of the subgenus in many Australian localities, and confirm three records of exotic, introduced species in Australia. Lepidocyrtus nigrofasciatus Womersley, Lepidocyrtus praecisus Schott, and the Hawaiian Lepidocyrtus kuakea Christiansen & Bellinger, are placed in Setogaster subgenus; Lepidocyrtus (Trichogaster) pallida Salmon from Singapore is placed in the subgenus Acrocyrtus; Merapicyrtus Yoshii & Suhardjono is considered a synonym of Setogaster. PMID- 26624706 TI - Three new species of the pill millipede genus Hyleoglomeris Verhoeff, 1910, from northern Thailand (Diplopoda, Glomerida, Glomeridae). AB - Seven species of the basically warm temperate to tropical Eurasian genus Hyleoglomeris are currently known from Thailand, including three new ones: H. hongkhraiensis sp. n. and H. aurea sp. n. from Chiang Mai Province, and H. cavicola sp. n. from Sukhothai Province. A new distribution map and a key to all Hyleoglomeris species presently known to occur in Thailand are given. PMID- 26624707 TI - New isolate of Mononchoides composticola Steel, Moens, Scholaert, Boshoff, Houthoofd & Bert, 2011 (Nematoda: Neodiplogasteridae) from Iran. AB - Mononchoides composticola was isolated during a survey on free living nematodes from vermicompost in Iran. This population of M. composticola is characterised by a dorsal claw-like tooth; 7-9 um long and 3-5 um wide, 14-15 finely visible longitudinal ridges on the cuticle, in which each ridge comprises two lines, long spicules (39-45 MUm long), a short gubernaculum (15-17 um or less than half of the spicule length), two pairs of precloacal papillae, five pairs of postcloacal papillae, papillae (v3) comprising three small papillae, and a long filiform tail (418-654 MUm in females, 382-455 MUm in males). Molecular analysis of M. composticola based on sequence of the 18S rDNA placed it close to M. composticola (GU943511; GU943512; from Belgium) and M. striatus (AY593924; from The Netherlands) in a well supported clade (1.00 posterior probability). Measurements, illustrations, LM and SEM pictures, and the phylogenetic position of M. composticola are given. PMID- 26624708 TI - Deep-sea serpulids (Annelida: Polychaeta) in tetragonal tubes: on a tube convergence path from the Mesozoic to Recent. AB - Serpulids typically build cylindrical calcareous tubes attached to hard substrates. Until now, only three serpulid species inhabiting free-lying polygonal tubes were reported from the deep sea: Spirodiscus grimaldii Fauvel, 1909 with quadrangular spirally coiled tubes, Bathyditrupa hovei Kupriyanova, 1993a with quadrangular tusk-shaped tubes, and Ditrupa groenlandica McIntosh, 1877 with octagonal tusk-shaped tubes. Similar free-lying tubes with tetragonal cross-section, both coiled and tusk-shaped, are described from shallow-water Mesozoic deposits as Nogrobs de Montfort, 1808, Tetraserpula Parsch, 1956, Tetraditrupa Regenhardt, 1961, Glandifera Regenhardt, 1961 and Tubulostium Stoliczka, 1868. We have revised deep-sea serpulids with tetragonal (and secondary octagonal) tubes and compared their tube ultrastructures and mineralogies with those of morphologically similar fossils. Revision of the Recent material has revealed six species in five genera: Spirodiscus grimaldii, S. groenlandicus comb. nov., Bathyditrupa hovei, Bathyvermilia gregrousei sp. nov., Hyalopomatus dieteri sp. nov. and Zibrovermilia zibrowii gen. et sp. nov. Comparisons showed significant ultrastructural and mineralogical differences between Recent and Mesozoic species. Similar tetragonal tube morphology of the Recent forms appears to be a result of convergence due to adaptation to similar soft-sediment habitats of the deep sea. None of Recent genera should be synonymised with any fossil genus, and the genus Spirodiscus Fauvel, 1909, previously synonymised with fossil Nogrobs, should be re-instated. However, a huge stratigraphic gap (66 Myr) between the earliest known fossil tetragonal tubes and their Recent counterparts still allows the possibility that such essentially different structures is a result of ultrastructural evolution, a hypothesis that could be verified by discovery and further study of Caenozoic material. PMID- 26624709 TI - Eight new species, a new record, and redescription of the genus Discoxenus Wasmann, 1904: The first record of termitophilous rove beetles in Cambodia (Coleoptera: Staphylinidae: Aleocharinae). AB - As the first record of the Cambodian termitophilous rove beetles, eight new species of the genus Discoxenus Wasmann, 1904 (Aleocharini: Compactopediina) are described, along with a redescription of the genus. Discoxenus katayamai Kanao & Maruyama, 2010, which was originally known from Thailand, is newly recorded from Cambodia and redescribed. Discoxenus species are morphologically divided into two species groups, namely the latiabdominalis and the assmuthi. The latiabdominalis species group includes D. latiabdominalis n. sp. and D. cambodiensis n. sp., and both species are associated with Odontotermes maesodensis Ahmad, 1965. The assmuthi species group comprises 11 species: D. assmuthi Wasmann, 1904, D. lepisma Wasmann, 1904, D. indicus Kistner, 1982, D. malaysiensis Kistner, 1982, D. phourini n. sp., D. kohkongensis n. sp., D. hirsutus n. sp., D. minutus n. sp., D. lucidus n. sp., D. kakizoei n. sp., and D. katayamai. The members in the assmuthi species group are associated with Odontotermes or Hypotermes termites. One of the unique morphological features of the assmuthi species group is the strongly developed distal crest of the male aedeagal median lobe while that observed in the latiabdominalis species group is not produced, which is general character state in the tribe Aleocharini. The character state of distal crest and several other morphological features such as mouthparts are considered to support the monophyly of respective species groups in Discoxenus. PMID- 26624710 TI - New records of Anthalona acuta Van Damme, Sinev & Dumont 2011 and Anthalona brandorffi (Sinev & Hollwedel, 2002) in Brazil, with description of a new species of the simplex-branch (Crustacea: Cladocera: Chydoridae). AB - The range of geographical distribution of Anthalona acuta Van Damme, Sinev & Dumont 2011 and Anthalona brandorffi (Sinev & Hollwedel, 2002) in Brazil has increased by almost 2000 km to the south. New records of Anthalona verrucosa verrucosa (Sars, 1901) were also added. Populations of Anthalona brandorffi from Central Brazil showed a peculiar morphological variation, with some individuals having only a single denticle on the labral keel. A new species of the simplex branch, Anthalona neotropica sp. nov., was described based on Brazilian material, and this is the first taxon of this branch registered in the Neotropics. It differs from Anthalona simplex Van Damme, Sinev & Dumont 2011, a Central African species, in the morphology of underneath sack of the lateral head pores, length of IDL setae and armature of first flaming-torch seta of limb IV. It could be distinguished from Anthalona sanoamuangae Sinev & Kotov, 2012 (distributed through the South- East Asia) by the morphology of the main head pores, length of IDL setae and armature of the pecten of postabdominal claw. Anthalona neotropica sp. nov. seems to have a benthic/hyporheic habit. All studied species have a wide geographical distribution and could be confused with Anthalona verrucosa Sars, 1901, thus at least some if not all previous records of this species on the continent must be revised. PMID- 26624711 TI - Annotated Checklist of Chinese Cladocera (Crustacea: Branchiopoda). Part II. Order Anomopoda (families Macrotrichidae, Eurycercidae and Chydoridae). AB - About 114 "species" of Macrothrichidae, Eurycercidae, and Chydoridae (Cladocera, Anomopoda), belonging to 39 genera, have been reported from China, with 14 species in 6 genera in Macrothrichidae, 2 species in one genus in Eurycercidae, and 98 species in 31 genera in Chydoridae. In total, 203 species in 62 genera, 13 families and 4 orders have so far been reported from the country. Of these, 187 are tentatively considered as valid, while 16 are incertae sedis. In reality, many records hide taxonomic problems that remain to be settled. Up to 10 percent of this fauna might be endemic at the species level, but we expect this number to increase pending new, comprehensive studies. No endemic genera fall to be recorded. Most of the several hundreds of taxonomic or biogeeographic papers from which this information was extracted suffer from poor or outdated taxonomy, such that up to half of all species are up for re-evaluation. Detailed morphological examination, but also provoked male production, especially in chydorids, are ways to improve identifications and should be stimulated. On the other hand, the inventory is certainly still incomplete with several tropical-subtropical taxa still to be expected in China. The extreme south and islands are among promising sites that remain to be explored, as well as extreme habitats all over the country. Molecular studies in China started around the beginning or the present decade, and should be multiplied. PMID- 26624712 TI - Cossidae (Lepidoptera) of the Russian Caucasus with the description of a new species. AB - An annotated list of the Cossidae of the Russian portion of the Caucasus including 20 species from 11 genera and two subfamilies is presented for the first time. A new species Cryptoholcocerus daghestanica sp. nov. is also described. PMID- 26624713 TI - Revision of the genus Procoryphaeus Mazur, 1984 (Coleoptera: Histeridae: Histerinae: Exosternini). AB - The genus Procoryphaeus Mazur, 1984 is revised herein. It contains three species: Procoryphaeus violaceus (Lewis, 1905) from Thailand: Tenasserim Mountains; Malaysia: Borneo: Sabah; Indonesia: Java, Sumatra and Papua, Procoryphaeus pilosus (Lewis, 1893) from Tanimbar Island, Indonesia and Procoryphaeus wallacei (Marseul, 1864) from Indonesia: Papua. All type specimens are figured, and male genitalia of P. violaceus are drawn. Lectotypes of Pachycraerus (Coryphaeus) wallacei Marseul, 1864, Coryphaeus violaceus Lewis, 1905 and Coryphaeus pilosus Lewis, 1893 are designated. The exact identities of P. violaceus and P. wallacei species remain unclear since they are morphologically very similar and both respective type specimens are females. A key to species is given. PMID- 26624714 TI - Stenopodidean shrimps (Crustacea: Decapoda) from New Caledonian waters. AB - A small collection of 159 specimens of stenopodidean shrimps from New Caledonian waters has been studied and found to represent 13 species in 6 genera, adding 8 new species of stenopodideans to the Southwest Pacific fauna. Two new species are recognized, Richardina crosnieri n. sp. and Spongiocaris neocaledonensis n. sp. Two species of Odontozona are redescribed. Illustrations are provided for all 13 species. Association with host hexactinellid sponges is verified for some of the commensal spongicoloids, and the first association of a stenopodidean shrimp with a gorgonian is reported. Bathymetric ranges are extended for the infraorder, as well as at the generic and specific levels. PMID- 26624715 TI - Myrmecophilous pygmephoroid mites (Acari: Pygmephoroidea) associated with Lasius flavus (Hymenoptera: Formicidae) in Russia. AB - Twenty four species of pygmephoroid mites (Acari: Pygmephoroidea: Neopygmephoridae, Scutacaridae, Microdispidae) are recorded from the ant Lasius flavus (Fabricius) or from its nests from Western Siberia and Crimea. Four of them of the genus Scutacarus Gros, 1845 (Acari: Scutacaridae), S. insolitus sp. nov., S. heterotrichus sp. nov., S. moseri sp. nov. and S. sibiriensis sp. nov. are described as new for science. Four species of scutacarid mites are recorded for the first time in Russia. The comparison of pygmephoroid mite communities associated with Lasius flavus from Crimean and West Siberian populations and notes on phoresy of pygmephoroid mites on ants are provided. PMID- 26624716 TI - Three new species of the Indo-Pacific fish genus Hime (Aulopidae, Aulopiformes), all resembling the type species H. japonica (Gunther 1877). AB - Descriptions of three new species of the aulopid genus Hime from the central and western Pacific and presumably the easternmost Indian Ocean are presented. Hime surrubea sp. nov., confined to the Hawaiian Island region, has been misidentified in species accounts and faunal lists as H. japonica and although resembling it is separable from that species by its shorter caudal peduncle, slightly larger head, larger eye, especially relative to head size, and slightly smaller pectoral and pelvic fins. Hime capitonis sp. nov. is known conclusively only from seamounts off the southern tip of New Caledonia and Vanuatu, and is distinguishable by its distinctively large head (32.3-35.6% SL) and eyes (orbital diameter 10.8-13.0% SL) and relatively few scales between the anus and anal fin origin (7-9). The Indonesian H. caudizoma sp. nov. is so far known from only 8 specimens, acquired in markets in southeastern Lombok and presumably caught nearby in what would be regarded the eastern reaches of the Indian Ocean. The species is recognisable by its dorsal fin of rather uniform moderate height with nearly straight distal margin and 17 rather than 16 rays, none of which is filamentous in either sex, the second penultimate ray rather than anterior rays the longest in males. Like the other two described here, H. caudizoma has among the largest head and eyes of the family. Observations on the dorsal fin form and other features of H. microps Parin & Kotlyar, 1989 are provided based on a large male specimen collected at Rapa Iti, Austral Islands and a re-evaluation of the original description. PMID- 26624717 TI - Sierra Nevada (Granada, Spain): a high-altitude biogeographical crossroads for millipedes (Diplopoda), with first data on its MSS fauna and description of a new species of the genus Ceratosphys Ribaut, 1920 (Chordeumatida: Opisthocheiridae). AB - Millipedes (Diplopoda), with a few notable exceptions, are poor dispersers, showing a very high degree of endemicity, not the least in mountains. The first samplings of the Mesovoid Shallow Substratum (MSS) of the higher altitudes of the Sierra Nevada Mountains (Baetic System, Southern Spain) have led to the discovery of a high number of millipedes, each of the species present showing a different degree of establishment in this subterranean environment. An update of the knowledge on the millipedes of this region, the first data of the millipede communities in the MSS and the description of Ceratosphys cryodeserti Gilgado, Mauries & Enghoff n. sp. are here provided, as well as the first data on the humidity and temperature fluctuations in the MSS of this high mountain. The new species is similar to other Baetico-Riffan species, while the only previously known congener from the region, C. soutadei Mauries, 1969, has more similarities to certain Pyrenean species. Biogeographical relationships of all the captured species are also discussed. PMID- 26624718 TI - A new species of Laelaspis Berlese (Acari: Mesostigmata: Laelapidae) from Iran, with a revised generic concept and notes on significant morphological attributes in the genus. AB - A short diagnosis and a more detailed diagnosis of the genus Laelaspis are presented. Until now, a total of 40 described species belong to the genus, including a new species described here, and excluding the four following species previously described as Laelaspis or Hypoaspis (Laelaspis): L. badrii Nasr & Nawar [considered as Cosmolaelaps badrii comb. nov.], L. zuluensis Tragardh, Hypoaspis (L.) lawrencei Van Aswegen & Loots, and Hypoaspis (L.) latodentis Karg. In addition, L. morazae sp. nov., is described on the basis of adult female and male specimens associated with Lepisiota semenovi (Ruzsky) (Formicidae) in Mashad County, northeastern Iran, and in the nest of an unknown ant in Shahreza County, central Iran. Laelaspis persicus is redescribed based on the holotype, paratype and additional specimens collected in north, southeastern and southwestern Iran. PMID- 26624719 TI - Occurrence of a new species of Letana (Orthoptera: Tettigoniidae: Phaneropterinae) in India. AB - A new species of the Oriental genus Letana, Walker (Orthoptera: Tettigoniidae: Phaneropterinae), proposed as Letana dentata sp. nov., collected from the North eastern province, Meghalaya, India (Ri bhoi 90 degrees 55'15 to 91 degrees 16' latitude and 25 degrees 40' to 25 degrees 21' longitude, 993 MSL), is described together with the morphological characterization of eight reported species. Of these, Letana rubescens (Stal, 1861) collected from Shalimar, Srinagar, Jammu and Kashmir (India) is being reported for the first time from India. The other species of Letana include: L. atomifera, L. bulbosa, L. inflata, L. infurcata, L. pyrifera and L. rufonatata. Taxonomic and diagnostic characters with illustrations of the head, pronotum, ventral view of left tegmina to show stridulatory file teeth and the genitalia (supra-anal plate and subgenital plate) including the phallus sclerite has been given. PMID- 26624720 TI - On the systematic position of Electrocrania Kusnezov, 1941 with the description of a new species from Baltic amber (Lepidoptera: Micropterigidae). AB - A new fossil species of Electrocrania Kusnezov is described, i.e. Electrocrania michalskii sp. nov. The male moth in Baltic amber is in a sufficiently good condition to allow its assignment to the family Micropterigidae on the basis of four re-cognized autapomorphies of this family (Kristensen 1998). The unique venation of the specimen places it in the genus Electrocrania stat. rev. and allows a redescription of that genus that has recently been treated as synonym of Micropterix Hubner. It is argued that Electrocrania is a distinct genus within Micropterigidae that is not associated with Micropterix, but probably can be assigned to the "Northern Hemisphere genera"-lineage of Micropterigidae. PMID- 26624721 TI - Revision of the pulchella-group of Alona s. lato leads to its translocation to Ovalona Van Damme et Dumont, 2008 (Branchiopoda: Anomopoda: Chydoridae). AB - The pulchella-group of Alona s.l. (Cladocera: Anomopoda: Chydoridae) is transferred to Ovalona Van Damme et Dumont, 2008, and an emended diagnosis is provided. Ovalona meridionalis (Sinev, 2006) is removed from Ovalona due to differences in thoracic limb morphology. At the moment, Ovalona consists of 17 species, and is the largest natural genus of Aloninae. A key for the world fauna and diagnosis for all species is provided. The morphology of O. nuragica (Margaritora, 1971) is studied for the first time. The position of Ovalona within subfamily Aloninae and the distribution of the genus are discussed. PMID- 26624722 TI - An annotated checklist of the Cladocera (Crustacea: Branchiopoda) of Colombia. AB - Based on the revision of available literature on the Colombian Cladocera (Crustacea: Branchiopoda), we present an annotated checklist, with taxonomical comments for all taxa recorded since the start of research on this group in the country in 1913. We have listed 101 valid taxa, of which most records belong to the Caribbean region of Colombia. The situation in Colombian Cladocera taxonomy is, at present, unfavorable for any realistic conclusions on biodiversity, ecology and biogeography. PMID- 26624723 TI - Bees of the Lasioglossum series (Hymenoptera: Halictidae) in South Korea, with an illustrated keys to species. AB - The South Korean fauna of the bee genus Lasioglossum Curtis (Halictidae: Halictini) belonging to the Lasioglossum series (i.e., those with the second submarginal crossvein strong) are reviewed. A total of 12 species are recognized for the country. Lasioglossum circularum Fan & Ebmer is recorded for the first time from the Korean Peninsula and the following species are newly recorded from South Korea: L. denticolle (Morawitz), L. formosae (Strand), L. kansuense (Bluthgen), L. occidens (Smith), L. sutshanicum Pesenko, and L. upinense (Morawitz). Bionomical data as well as illustrated keys to females and males of South Korean species are provided. DNA sequences including a part of barcode region are given for L. kansuense and L. occidens. PMID- 26624724 TI - A review of clearwing moths in the tribe Synanthedonini, with descriptions of six new species from Taiwan (Lepidoptera: Sesiidae). AB - The Synanthedonini fauna of Taiwan is reviewed, and a checklist of 9 species for this region is provided. Six new species are described: Paranthrenella dortmundi Liang & Hsu sp. nov., Paranthrenella weiyui Liang & Hsu sp. nov., Ichneumenoptera gryphus Liang & Hsu sp. nov., Kantipuria glansvorax Liang & Hsu sp. nov., Synanthedon ceraunus Liang & Hsu sp. nov., and Synanthedon phoenix Liang & Hsu sp. nov. New records of relationships between host plants and the immatures of Synanthedonini in Taiwan are also provided, with three species feeding on callus tissue of stems of Fagaceae, two on Lauraceae, and one on Rosaceae. One species is an obligatory borer into acorns of Fagaceae, and such kind of feeding strategy is rare among clearwing moths. PMID- 26624725 TI - A new species of Alhajarmyia Stuckenberg (Diptera: Vermileonidae), the first wormlion fly described from East Africa and its biogeographical implications. AB - A second species of the genus Alhajarmyia Stuckenberg (A. stuckenbergi Swart, Kirk-Spriggs & Copeland, sp. n.), is described and figured, from the Eastern Arc Mountains of Kenya (Kasigau Mountain and Taita Hills), being the first vermileonid recorded from East Africa. The species is shown to differ from its congener, A. umbraticola (Stuckenberg & Fisher), described from Oman in the Arabian Peninsula, based on external characters including male and female terminalia. An identification key is provided together with distribution maps for the two species, and biogeographical aspects are discussed. PMID- 26624726 TI - A second New World hoverfly, Toxomerus floralis (Fabricius) (Diptera: Syrphidae), recorded from the Old World, with description of larval pollen-feeding ecology. AB - Recently (2013-2014), several hoverfly specimens from two localities in Benin and Cameroon (West and Central Africa) were caught from a species that we could not identify using existing identification keys for Afrotropical Syrphidae. Specific identification as Toxomerus floralis (Fabricius) was accomplished using morphology and various Neotropical identification keys. Corroboration of this identification was made by sequencing of the standard COI barcode region and a subsequent BLAST-IDS in BOLD that revealed a 100% sequence similarity with Toxomerus floralis from Suriname (South America). Species identification was further supported by sequencing parts of the nuclear 18S and 28S rRNA genes. The species is widespread in Togo, Benin, Nigeria and Cameroon, and eggs, larvae and adults are abundant at several localities. Yet, the full extent of its geographic distribution within tropical Africa remains to be determined. This is only the second known established introduction of a non-African hoverfly species in the Afrotropics. Interestingly, the larvae of the species have been reported as predators of Aphididae and Delphacidae but we found them to be pollenivorous, which is a rare feeding mode within the subfamily Syrphinae. Moreover, it is the only known Syrphinae species of which the larvae feed on pollen from two plant species from different families (Cyperaceae and Orobranchaceae). This example illustrates how DNA barcoding may allow a fast and accurate identification of introduced species. PMID- 26624727 TI - Eonandeva gen. nov., a new distinctive genus from Eocene Baltic amber (Diptera: Chironomidae). AB - A new fossil genus, Eonandeva gen. nov., with two new species: E. helva sp. nov. (type for the genus) and E. latistyla sp. nov., is described from Eocene Baltic amber (~45-40 Ma). Adult males of both new species show the wing venation pattern, shape and chaetotaxy typical for the tribe Tanytarsini. The characters defined as prior apomorphies for the new genus--the gonostylus with a subapical flattened lobe and the stout, strongly elongated superior volsella--separate Eonandeva from the closely related extant genus Nandeva Wiedenbrug, Reiss et Fittkau, 1998. PMID- 26624728 TI - Six new species of Triomicrus Sharp from southern China (Coleoptera: Staphylinidae: Pselaphinae). AB - Seven species of the genus Triomicrus Sharp are recognized in southern China, six of them are described as new: T. acutus and T. nanlingensis Shen & Yin, sp. n. (Guangdong), T. pinnatus Shen & Yin, sp. n. (Guangdong and Hunan), T. cochlis Shen & Yin, sp. n. (Guangdong, Hunan and Guangxi), and T. cavus Shen & Yin, sp. n. and T. longus Shen & Yin, sp. n. (Guangxi). A key for the identification of Triomicrus in southern China is presented. PMID- 26624729 TI - Erection of a new genus Biura gen. nov., of the subtribe Aolina (Hemiptera: Cicadidae: Cicadinae: Dundubiini). AB - A new genus, Biura gen. nov., is erected within the subtribe Aolina Boulard, 2012, designating Haphsa bicolora Sanborn, 2009 as the type species. This new genus is distinguished from all other genera in Aolina by the light-colored body lacking prominent markings, non-infuscated wings, very small and short male operculum, thin and long uncal lobes, and distinctly prominent basal lobes of the pygofer. PMID- 26624730 TI - Erratum: PATRICIO DE LOS RIOS ESCALANTE & ALEXEY A. KOTOV (2015) A checklist of Branchiopoda (Anostraca and Cladocera) of Chilean continental waters. Zootaxa, 4027 (3): 366-388. PMID- 26624731 TI - Taxonomic review of the New World spider genus Elaver O. Pickard-Cambridge, 1898 (Araneae, Clubionidae). AB - Elaver O. Pickard-Cambridge, 1898 is characterized and redescribed, including 49 species occurring from the United States to Argentina. Thirty seven previously known species are redescribed: Elaver achuca (Roddy, 1966) revalidated, E. balboae (Chickering, 1937), E. barroana (Chickering, 1937), E. calcarata (Kraus, 1955), E. carlota (Bryant, 1940), E. chisosa (Roddy, 1966), E. crinophora (Franganillo, 1934), E. crocota (O. Pickard-Cambridge, 1896), E. albicans (Franganillo, 1930) name restored, E. depuncta O. Pickard-Cambridge, 1898, E. elaver (Bryant, 1940), E. excepta (L. Koch, 1866), E. grandivulva (Mello-Leitao, 1930), E. hortoni (Chickering, 1937), E. implicata (Gertsch, 1941), E. juana (Bryant, 1940), E. kohlsi (Gertsch & Jellison, 1939), E. linguata (F.O. Pickard Cambridge, 1900), E. madera (Roddy, 1966), E. mirabilis (O. Pickard-Cambridge, 1896) new. comb., E. mulaiki (Gertsch, 1935), E. multinotata (Chickering, 1937), E. orvillei (Chickering, 1937), E. placida O. Pickard-Cambridge, 1898, E. portoricensis (Petrunkevitch, 1930), E. quadrata (Kraus, 1955), E. richardi (Gertsch, 1941), E. sericea O. Pickard-Cambridge, 1898, E. sigillata (Petrunkevitch, 1925), E. simplex (O. Pickard-Cambridge, 1896), E. texana (Gertsch, 1933), E. tigrina O. Pickard-Cambridge, 1898 name restored, E. tricuspis (F.O. Pickard-Cambridge, 1900), E. tristani (Banks, 1909), E. tumivulva (Banks, 1909), E. valvula (F.O. Pickard-Cambridge, 1900) and E. wheeleri (Roewer, 1933). Ten new species are described: E. candelaria n. sp. and E. helenae n. sp. from Mexico; E. arawakan n. sp. from Haiti; E. lizae n. sp. from Costa Rica; E. darwichi n. sp. from Ecuador; E. juruti n. sp., E. tourinhoae n. sp. and E. vieirae n. sp. from Brazil; E. shinguito n. sp. from Peru and E. beni n. sp. from Bolivia. The female of E. hortoni is described for the first time. Lectotypes are designated for E. sigillata and its actual female is described for the first time. Four new synonyms are proposed: E. languida (Gertsch, 1941) is synonimized with E. multinotata; E. dorothea (Gertsch, 1935) with E. wheeleri; E. exempta (Gertsch & Davis, 1940) with E. placida and E. vulnerata (Kraus, 1955) with E. calcarata. The drawings in the original descriptions of E. kawitpaaia (Barrion & Litsinger, 1995) and E. turongdaliriana (Barrion & Litsinger, 1995) are sufficiently informative to exclude these species from Elaver but not to accurately establish its generic affiliation. Thus, until the types become available for examination, these species must remain as Clubionidae incertae sedis. Heterochemmis (F.O. Pickard-Cambridge, 1900) is synonymized with Elaver and Heterochemmis mutatus Gertsch & Davis,1940 is recognized as a junior synonym of Elaver mirabilis n. comb., the type species of Heterochemmis. New records are presented for E. valvula, E. balboae, E. brevipes (Keyserling, 1891), E. grandivulva and E. lutescens (Schmidt, 1971). Two species described by Franganillo, E. tenera (Franganillo, 1935) and E. tenuis (Franganillo, 1935), are considered species inquirendae. PMID- 26624732 TI - A revision of the Axylus group of Agraeciini (Orthoptera: Tettigoniidae: Conocephalinae) and of some other species formerly included in Nicsara or Anthracites Revision of the Indo-Australian Conocephalinae, Part 3. AB - Axylus group is used to include the five genera Axylus Stal, 1877, Anthracites Redtenbacher, 1891 sensu stricto, Eucoptaspis Willemse, 1966, Eulobaspis gen. nov., and Heminicsara Karny, 1912. It is mainly based on a combination of the characters shape of pronotum, spiniform meso- and metasternal lobes, and similar basic ground plans of the male cerci, titillators and female subgenital plates. The five genera together with two superficially similar genera Euanthracites gen. nov. and Sulasara gen. nov. are fully revised. Papuacites gen. nov. is proposed for two New Guinean species formerly included in Anthracites. Nicsara Walker, 1869 is restricted to Australian species; Spinisternum Willemse, 1942 is synonymised with Heminicsara Karny, 1912; Odontocoryphus Karny, 1907 based on two nymphs is synonymised with Macroxiphus Pictet, 1888; Pseudoliara Karny, 1907 described after one nymph is regarded incertae sedis. 40 new combination of species are proposed: Axylus bimaculatus (Redtenbacher, 1891) comb. nov., A. inferior (Brunner, 1898) comb. nov., A. inflatus (Brunner, 1898) comb. nov., A. loboensis (De Haan, 1842) comb. nov., A. minutus (Dohrn, 1905) comb. nov., A. nigrifrons (Brunner, 1898) comb. nov., A. philippinus (Hebard, 1922) comb. nov., A, taylori (Hebard, 1922) comb. nov., and A. thoracicus (Dohrn, 1905) comb. nov. (all from Nicsara); Euanthracites apoensis (Hebard, 1922) comb. nov., E. femoralis (Dohrn, 1905) comb. nov., E. rufus (Ingrisch, 1998) comb. nov., and E. tibialis (Karny, 1931) comb. nov. (from Anthracites); Eucoptaspis inexpectatus (Willemse, 1953) comb. nov. (from Gonatacanthus Karny, 1907); Eulobaspis dehaani (Karny, 1920) comb. nov., E. emarginata (Karny, 1926) comb. nov., E. moluccana (Redtenbacher, 1891) comb. nov., E. personata (Karny, 1926) comb. nov., E. quadrimaculata (Karny, 1926) comb. nov., E. rotundata (Karny, 1926) comb. nov., and E. strigatipes (Bolivar, 1898) comb. nov. (from Nicsara); Eulobaspis lobaspoides (Karny, 1907) comb. nov. and E. ornata (Brunner, 1898) comb. nov. (from Axylus); Heminicsara excisa (Karny, 1926) comb. nov., H. insulana (Willemse, 1966) comb. nov., H. schlaginhaufeni (Karny, 1912) comb. nov., and H. viridipes (Karny, 1912) comb. nov. (from Nicsara); Heminicsara castaneipictus (Willemse, 1966) comb. nov., H. insularis (Willemse, 1942) comb. nov., and H. palauensis (Vickery & Kevan, 1999) comb. nov. (from Spinisternum); Heminicsara decipiens (Karny, 1926) comb. nov. and H. griffinii (Karny, 1911) comb. nov. (from Gonatacanthus); Heminicsara novaeguineae (Willemse, 1966) comb. nov. (from Eucoptaspis); Sulasara aethiops (Karny, 1931) comb. nov., S. karnyi (Willemse, 1932) comb. nov., and Sulasara sarasini (Karny, 1931) comb. nov. (from Nicsara); Papuacites nigrifrons (Karny, 1912) comb. nov. and P. nakanaiensis (Naskrecki & Rentz, 2010) comb. nov. (from Anthracites); Paramacroxiphus multispinosa (Bolivar, 1898) comb. nov. (from Nicsara); Palaeoagraecia globiceratus Vickery & Kevan, 1999 comb. nov. (from Macroxiphus). Odontocoryphus pullus Karny, 1907 becomes a new synonym of Macroxiphus sumatranus sumatranus (Haan, 1842). 87 species are described as new: nine species in Axylus: A. brachypterus sp. nov., A. dulang sp. nov., A. furcatus sp. nov., A. mengkoka sp. nov., A. montanus sp. nov., A. negros sp. nov. , A. superior sp. nov., A. totop sp. nov. , A. unicolor sp. nov.; six species in Anthracites: A. bilineatus sp. nov., A. flagellatus sp. nov., A. pyramidalis sp. nov., A. romblon sp. nov., A. sinuatus sp. nov., A. unispinus sp. nov.; four species in Euanthracites: E. bispinus sp. nov., E. eboreus sp. nov., E. ile sp. nov., E. uru sp. nov.; six species in Eucoptaspis: E. adonara sp. nov., E. hexamaculatus sp. nov., E. remotus sp. nov., E. stylatus sp. nov., E. trapezoides sp. nov., E. wawo sp. nov.; eight species in Eulobaspis: E. bacan C.Willemse & Ingrisch sp. nov., E. baduri sp. nov., E. buruensis sp. nov., E. ceramica C.Willemse & Ingrisch sp. nov., E. morotai sp. nov., E. sudirman sp. nov., E. ternate sp. nov., E. variata sp. nov.; 51 species in Heminicsara: H. albatros sp. nov., H. albipuncta sp. nov., H. albogeniculata Naskrecki & Ingrisch sp. nov., H. alticola sp. nov., H. ammea sp. nov., H. anggi sp. nov., H. bilobata sp. nov., H. cingima sp. nov., H. comprima sp. nov., H. coriformis sp. nov., H. corneli sp. nov., H. cyclops sp. nov., H. despecta Naskrecki & Ingrisch sp. nov., H. dilatata sp. nov., H. dividata sp. nov., H. dobo sp. nov., H. elongata Naskrecki & Ingrisch sp. nov., H. furcata sp. nov., H. gibba sp. nov., H. gugusu Naskrecki & Ingrisch sp. nov., H. illugi sp. nov., H. jacobii Karny, 1912, H. jayawijaya sp. nov., H. kelila sp. nov., H. kolombangara sp. nov., H. lamas Naskrecki & Ingrisch sp. nov., H. longiloba sp. nov., H. lord sp. nov., H. malu sp. nov., H. mamberamo sp. nov., H. manus sp. nov., H. montana sp. nov., H. nigra sp. nov., H. nomoensis sp. nov., H. obiensis sp. nov., H. ohu sp. nov., H. pak sp. nov., H. parallela Naskrecki & Ingrisch sp. nov., H. pinniger sp. nov., H. popoman sp. nov., H. rugosa sp. nov., H. scutula sp. nov., H. sica sp. nov., H. sinewit sp. nov., H. siwi sp. nov., H. stylata sp. nov., H. tabtab sp. nov., H. truncata Naskrecki & Ingrisch sp. nov., H. tumulus sp. nov., H. umasani sp. nov., H. wanuma sp. nov., H. zugi sp. nov.; and three species in Sulasara: S. armata sp. nov., S. renschi sp. nov., S. tambu sp. nov. PMID- 26624733 TI - Australian and New Guinean Stingless Bees of the Genus Austroplebeia Moure (Hymenoptera: Apidae)--a revision. AB - The stingless bee genus Austroplebeia Moure occurring in Australia and New Guinea is revised, based on a morphological analysis of samples from 177 colonies. Five species are recognised: A. cincta (Mocsary), A. essingtoni (Cockerell), A. australis (Friese), A. cassiae (Cockerell) and A. magna, sp. nov. Three different colour morphs of A. australis are described. Five new synonymies are proposed: A. cockerelli (Rayment), A. ornata (Rayment), A. percincta (Cockerell) and A. websteri (Rayment) = A. australis; A. symei (Rayment) = A. cassiae. Workers, males and queens are described for all species. Populations of A. cincta, recently found in Queensland, Australia, are compared with A. cincta from the type locality and other areas in New Guinea. A lectotype is designated for A. percincta (Cockerell). Provenance of type material is discussed. A key to the species, distributions and nest descriptions are provided. PMID- 26624734 TI - The trap-jaw ant genus Odontomachus Latreille (Hymenoptera: Formicidae) from Sumatra, with a new species description. AB - The ant genus Odontomachus Latreille is reviewed for Sumatra, the sixth largest island in the world and located in western Indonesia. Previously three species were recorded from the island: O. simillimus F. Smith, O. rixosus F. Smith, and O. latidens Mayr. We add two species to the fauna, O. procerus Emery stat. nov and Odontomachus minangkabau sp. nov. The new species belongs to O. rixosus species group, and it is morphologically most similar to O. rixosus and O. pararixosus Terayama & Ito. However, it can be separated from the latter two by its large body (HL 3.13-3.55 mm, WL 4.15-4.65 mm), the masticatory margin with 11 14 denticles, and dark-colored body. Odontomachus latidens subsp. sumatranus Emery is newly synonymized with O. procerus. The castes and sexes of the known species are also described, including the first descriptions of the male for O. latidens, O. procerus, and O. rixosus. A key to the Sumatran species based on the worker caste is provided, and the bionomics of each species is summarized. PMID- 26624735 TI - Semiterrestrial crabs of the genus Geosesarma De Man, 1892 (Crustacea, Brachyura, Sesarmidae) from western Borneo, Indonesia, with descriptions of three new species. AB - The poorly known semiterrestrial sesarmid crab, Geosesarma amphinome (De Man, 1899), from Kalimantan Barat in western Borneo, is redescribed and figured. Three other species from areas surrounding the town of Pontianak, are here described as new. Geosesarma ambawang sp. nov., G. pontianak sp. nov., and G. pylaemenes sp. nov. can be distinguished from congeners on Borneo and adjacent areas by their colours in life, form of the carapaces and ambulatory legs, and the structures of the male abdomens and first gonopods. PMID- 26624736 TI - Two new species of Chiropterotriton (Caudata: Plethodontidae) from northern Mexico. AB - Species of the genus Chiropterotriton are distributed through much of northern and eastern Mexico. The genus has presented taxonomic difficulties, with a number of species waiting to be described. We describe two new species, Chiropterotriton cieloensis sp. nov. and Chiropterotriton infernalis sp. nov., from the Mexican state of Tamaulipas based on both molecular and morphological data. We present a phylogenetic hypothesis for the group, with emphasis on the taxa from northern Mexico, based on mitochondrial DNA, and discuss the other species of northern Mexico, especially the wider-ranging C. multidentatus, to which the new species were formerly assigned. PMID- 26624737 TI - Garra mondica, a new species from the Mond River drainage with remarks on the genus Garra from the Persian Gulf basin in Iran (Teleostei: Cyprinidae). AB - Garra mondica, new species, from the Mond River drainage in Iran is distinguished from its congeners by having 71/2 branched dorsal-fin rays; the breast, belly and back in front of the dorsal-fin origin naked and 9+8 branched caudal-fin rays. Garra mondica is also distinguished from all other congeners in the Persian Gulf basin, except an unidentified species from the Kol River, by having two fixed, diagnostic nucleotide substitutions in the mtDNA COI barcode region. The identity of G. gymnothorax, a nominal species from the Karun River drainage, and G. crenulata, a nominal species from Central Iran, are discussed. Garra populations examined from the Karun have a unique mtDNA COI barcode sequence, but their diagnostic characters are not consistent with the description and syntypes of G. gymnothorax. G. crenulata is considered as a synonym of G. rufa. Two populations of Garra from the Kol River have a sequence of the COI barcode region very similar to G. mondica, but cannot be identified as G. mondica and their identity cannot be resolved here. PMID- 26624738 TI - A reappraisal of the rhacophorid bush frog Raorchestes flaviventris (Boulenger, 1882), with an evaluation of the taxonomic status of R. emeraldi Vijayakumar, Dinesh, Prabhu and Shankar, 2014. AB - Raorchestes flaviventris, a species of rhacophorid bush frog described from the Western Ghats by George Albert Boulenger in 1882, has never been reported from the region since its description. However, we herewith report a record of the species after almost 132 years and redescribe the species and also clarify confusions that prevailed over the taxonomic status of the species and its closely-related congeners, along with shedding light on literature regarding its distribution. Also, the recently described R. emeraldi Vijayakumar et al., 2014, which we suggest to be the same species, becomes a junior subjective synonym of R. flaviventris. PMID- 26624739 TI - A novel third species of the Western Ghats endemic genus Ghatixalus (Anura: Rhacophoridae), with description of its tadpole. AB - The Western Ghats biodiversity hotspot is a recognized center of rhacophorid diversity as demonstrated by several recent studies. The endemic genus Ghatixalus is represented by two species from two separate high-elevation regions within the Ghats. Here, we describe a third species that can be distinguished by morphological and larval characters, as well as by its phylogenetic placement. PMID- 26624740 TI - Redescription of Aposycorax chilensis (Tonnoir) (Diptera, Psychodidae, Sycoracinae) with the first identification of a blood meal host for the species. AB - Adults of Aposycorax chilensis were collected from several sites during fieldwork in Chilean Patagonia, December 2013. Specimens were swept or aspirated from roadside seeps and found in greatest numbers during the morning hours. DNA was extracted from a recently blood-fed female and was subjected to the polymerase chain reaction using vertebrate-specific 16S primers. An amplicon was obtained and the resulting sequence was found to have over 99% identity with two frogs in the genus Batrachyla, thus establishing this species' preference for amphibian hosts. The diagnosis and description of adult A. chilensis are revised, including the first description of the complete male genital tract. Habitat characteristics for this species and rotation of the male genitalia are discussed. PMID- 26624741 TI - Labrorostratus caribensis, a new oenonid polychaete from the Grand Caribbean living in the body cavity of a nereidid, with emendation of the genus. AB - Endoparasitic relationships among polychaetes are uncommon and mostly restricted to about 20 species of the family Oenonidae. We herein describe Labrorostratus caribensis, a new oenonid species living in the body cavity of a nereidid polychaete in Chinchorro Bank (Mexican Caribbean). This is the first report of a parasitic relationship between oenonids and nereidids in the Grand Caribbean region. The new species is diagnosed by the jaw apparatus reduced to only maxillary carriers fused, one simple modified ventral chaeta from midbody and lack of acicular spines. The generic diagnosis is emended to include species without maxillary plates. A synopsis of parasitism among polychaetes worldwide is presented. PMID- 26624742 TI - Mexican species of the genus Exenterus Hartig (Hymenoptera: Ichneumonidae: Tryphoninae) reared from diprionid hosts. AB - Two new species of the tryphonine genus Exenterus from Mexico, E. durangensis Khalaim & Ruiz-Cancino, sp. nov. and E. sehuerachicus Khalaim & Ruiz-Cancino, sp. nov., are described. Both species belong to the group of Exenterus species characterized by the unusually short, depressed tarsi. Exenterus durangensis was reared from the sawfly Zadiprion falsus Smith and E. sehuerachicus from Neodiprion autumnalis Smith (Hymenoptera: Diprionidae). This is the first record of the genus Exenterus as a parasitoid of these hosts. An identification key to separate the two Mexican species of Exenterus is provided. PMID- 26624743 TI - The tadpoles of two species of the Bokermannohyla circumdata group (Hylidae, Cophomantini). AB - We describe the external morphology and oral cavity of the tadpoles of Bokermannohyla caramaschii and B. diamantina respectively from the states of Espirito Santo and Bahia, Brazil. Larvae of both species are distinguished from each other by external characters such as body shape, labial tooth-row formula, number of marginal papillae, coloration and internal oral anatomy features. Some of the character states of the tadpoles of B. caramaschii and B. diamantina that are shared with all other described tadpoles of the Bokermannohyla circumdata group, such as the absence/reduction of small flaps with accessory labial teeth laterally in the oral disc, and the absence/reduction of submarginal papillae, may represent morphological synapomorphies of this species group, or at least of some internal clade. The general pattern of brownish coloration with longitudinal stripes on the caudal muscle is also common to most species of the group. We did not find character states of the oral cavity that are exclusively shared by species of the B. circumdata group, or by other groups of Bokermannohyla. PMID- 26624744 TI - Definition of the concordis species group of the genus Euseius (Acari: Phytoseiidae), with a morphological reassessment of the species included. AB - Phytoseiidae (Acari) is the best known family of predatory mites. Within this family, Euseius Wainstein is one of the largest genera. The species of this genus have generalist feeding behavior, including in their diet mites and pollen. Some studies have demonstrated the potential of certain Euseius species to control pest mites. Euseius concordis (Chant) has been mentioned in the literature as potentially useful for the control of the tomato russet mite, Aculops lycopersici (Tryon) (Eriophyidae). Several other American species are morphologically similar to E. concordis; the morphological variation of these species is poorly understood. The objective of this study was a taxonomic re-evaluation of E. concordis and of the world species most similar to it. Measurements of species collected in this study and a taxonomic key to separate the species of this group are provided. Morphological evaluations confirmed that Euseius flechtmanni Denmark & Muma is a junior synonym of E. concordis, and determined that Euseius caseariae De Leon is also a junior synonym of E. concordis, that Euseius ho (De Leon) and Euseius brazilli (El-Banhawy) are junior synonyms of Euseius mesembrinus (Dean) and that Euseius vivax (Chant & Baker) is not a junior synonym of Euseius fructicolus (Gonzalez & Schuster), as previously thought. PMID- 26624745 TI - A new species of limestone karst inhabiting forest frog, genus Platymantis (Amphibia: Anura: Ceratobatrachidae: subgenus Lupacolus) from southern Luzon Island, Philippines. AB - We describe a new species of limestone karst dwelling forest frog of the genus Platymantis from the Quezon Protected Landscape in southeastern Luzon Island, Philippines. We assign Platymantis quezoni, sp. nov., to the diverse assemblage of terrestrial species in the Platymantis dorsalis Group, subgenus Lupacolus on the basis of its body size and proportions, only slightly expanded terminal discs of the fingers and toes, and its terrestrial microhabitat. The new species is distinguished from these and all other Philippine congeners by features of its external morphology, its restriction to a distinctive limestone karst microhabitat, and its advertisement call, which is unique among frogs of the family Ceratobatrachidae. Several distinguishing morphological characters include its moderate body size (22.1-33.9 mm SVL for 16 adult males and 32.4-39.7 mm SVL for five adult females), slightly expanded terminal discs of the fingers and toes, smooth skin with limited dermal tuberculation, and a dorsal color pattern of mottled tan to dark brown with black blotches. The new species is the sixth Philippine Platymantis known to occur exclusively on limestone karst substrates (previously known karst-obligate species include: P. bayani, P. biak, P. insulatus, P. paengi, and P. speleaus). Recently accelerated discovery of limestone karst anurans across the Philippines suggests that numerous additional species may await discovery on the hundreds of scattered karst formations throughout the archipelago. This possibility suggests that a major conservation priority in coming years will be to study, characterize, describe, and preserve the endemic species supported by this patchy, unique and imperiled type of forest ecosystem in the Philippines. PMID- 26624746 TI - Systematic revision of the Malagasy chameleons Calumma boettgeri and C. linotum (Squamata: Chamaeleonidae). AB - We revise the taxonomic status of two species of Madagascan chameleons in light of a recent molecular phylogenetic study on the Calumma nasutum group. The investigation of morphological and osteological characters led to a clear delineation between two species within the C. boettgeri complex, C. boettgeri and C. linotum. Calumma linotum has been considered either a synonym of C. boettgeri or a dubious, poorly defined taxon. So far it has only been known from the male holotype with the imprecise locality 'Madagascar'. Based on pholidosis, morphological measurements and characters of the skull that were analyzed using micro-X-ray computed tomography (micro-CT) scans, we ascribe the population of chameleons from Montagne d'Ambre, formerly assigned to C. boettgeri, to C. linotum. Calumma linotum differs from C. boettgeri in the larger size of tubercle scales on the extremities and rostral appendage, the larger diameter of the extremities relative to the body size, the presence of a parietal crest as well as the form of the nasal bones and the anterior tip of the frontal. The life colouration of the males is also characteristic, with a blue rostral appendage and greenish turquoise extremities. The body and rostral appendage of C. boettgeri in contrast are inconspicuously yellowish brown coloured. All confirmed distribution records of C. boettgeri are confined to the biogeographic Sambirano region whereas C. linotum is only known from Montagne d'Ambre and a locality at the base of the Tsaratanana massif. Additional literature records of C. boettgeri and C. linotum from northeastern Madagascar are in need of confirmation. We also confirm the synonymy of Chamaeleo macrorhinus (described from a female holotype with an unknown locality) with Calumma boettgeri. The use of micro-CT exposed further characteristics for species delimitation in an integrative taxonomic approach. In addition to the skull, we also micro-CT scanned the hemipenes of C. boettgeri and C. linotum, using an iodine-based tissue stain, and provide 3D PDF models of these organs. This method enables detailed illustration and the detection of variation in particular characters, and might be an important tool in further taxonomic studies on the C. nasutum group and other squamate reptiles. PMID- 26624747 TI - On the taxonomy of the genera Proneca Swinhoe, 1890, Ctenane Swinhoe, 1905 and Selca Walker, 1866 (Lepidoptera, Nolidae, Nolinae), with the description of two new species from Sumatra. AB - Present paper contains the characterisation of the genera Proneca Swinhoe, 1890, Ctenane Swinhoe, 1905, and Selca Walker, 1866, and their species, with the description of two new species, Proneca brunneostriata sp. n. and Ctenane michaeli sp. n., from Sumatra. Two new combinations and a new synonymy are established. With 32 colour photos and 24 genitalia figures. PMID- 26624748 TI - Neocaeculus orientalis sp. nov. (Acari, Trombidiformes, Caeculidae) from Thailand. AB - A new species of the predatory mite family Caeculidae, N. orientalis sp. nov., is described and illustrated, based on adult and all active immature instars from moss and forest litter of various localities in Thailand. Neocaeculus orientalis sp. nov. differs from its congeners in uniquely having the adult femur I divided but femora II-IV entire, adult coxal setation of 5-1-2-1 (4a excluded), and heterogeneous coxal setae. It is the first Neocaeculus species known to have no seta vi (= po) in all stages. A comparison of the diagnostic characters of known Neocaeculus species is given. PMID- 26624749 TI - Chromosomal and morphological taxonomy of a new species of black fly in the genus Metacnephia (Diptera: Simuliidae) from Western Anatolia, Turkey. AB - A new species of black fly collected in April from streams 950-1000 m above sea level in Western Anatolia, Turkey, is described on the basis of females, males, pupae, larvae, and polytene chromosomes. Metacnephia phrygiensis new species is structurally and chromosomally distinct from all other known species of the genus, particularly in having unique fixed inversions in chromosomal arms IL and IIIL and a fenestrated cocoon. PMID- 26624750 TI - A new species of the endemic genus Hemicyrthus Reiche (Coleoptera: Scarabaeidae: Dynastinae) from New Caledonia, with a revised key. AB - Hemicyrthus blaffarti new species (Coleoptera: Scarabaeidae: Dynastinae) from the Parc Provincial de la Riviere Bleue in southern New Caledonia is described. It differs from the most similar species, H. elongatus, by the completely and sharply margined pronotal base, the presence of elytral micropunctures, shorter apical setae of the mesotibiae and meta-tibiae, and a different shape of the parameres. For the first time, a sexually dimorphic character is described in this genus: the median emargination of the last sternite has a developed margin in males, but not in females. A revised key for all Hemicyrthus species is given. Hemicyrthus as a genus of short-range endemics, and its biogeographical relationships are briefly discussed. PMID- 26624751 TI - The identity and distribution of Fiorinia phantasma (Cockerell & Robinson) (Hemiptera: Coccomorpha: Diaspididae), with a new synonym. AB - The morphologies of Fiorinia phantasma (Cockerell & Robinson) (Hemiptera: Coccomorpha: Diaspididae) and F. coronata Williams & Watson are reviewed, and the name F. coronata is placed as a junior synonym of the name F. phantasma syn. n. The known geographical distribution and host range of F. phantasma is documented and discussed. An identification key to 12 of the 16 species of Fiorinia known from the Australasian, Nearctic and Neotropical Regions is provided. PMID- 26624752 TI - A revision of the genus Tambana Moore, 1882 with description of eight new species and one subspecies (Lepidoptera, Noctuidae: Pantheinae). Revision of Pantheinae, contribution XIII. AB - The oriental Pantheinae genus Tambana Moore, 1882 (type-species Tambana variegata Moore, 1882) with 16 previously described species is revised. Eight new species and one subspecies (T. tibetica sp. n., T. xilinga sp. n., T. mekonga sp. n., T. helmuti sp. n., T. fansipana sp. n., T. laura sp. n., T. indeterminata sp. n., T. annamica sp. n., T. annamica stumpfi ssp. n.) are described from China, Vietnam and Myanmar. One unrecognized taxon is included to the revision. Three new synonyms and one new combination are introduced (Trisuloides klapperichii Mell 1958, syn. n. of Tambana entoxantha (Hampson, 1894); Tambana behouneki Speidel & Kononenko, 1998, syn. n. of Tambana glauca (Hampson, 1898); Trichosea gerryi Thony, 1996, syn. n. of Tambana funebris (Berio, 1973), comb. n. (Trichosea). The updated checklist of 26 taxa of Tambana is presented. Short diagnoses are given for the described species. In addition the related genus Xanthomantis Warren, 1909 with two species X. cornelia (Staudinger, 1888) and X. contaminata (Draudt, 1937) is reviewed. PMID- 26624753 TI - Revision of the Nearctic species of the genus Iphthiminus Spilman (Coleoptera: Tenebrionidae). AB - Nearctic species of Iphthiminus Spilman (Coleoptera: Tenebrionidae) are revised by examining external morphological structures and genital characters. Of the six Nearctic species, only three are considered valid: Iphthiminus serratus (Mannerheim 1843), I. opacus (Leconte 1866), and I. lewisii (Horn 1870). Photographs are taken to highlight structures and a key is created to identify the species. Three names are synonymized: (senior synonym in brackets) I. sublaevis (Bland 1865) [=Nyctobates sublaevis (Bland 1865)], I. salebrosus (Casey 1924) [=Iphthimus salebrosus (Casey 1924)] are synonymized under I. serratus (Mannerheim 1843) [=Nyctobates serratus (Mannerheim 1843)], and I. laevissimus (Casey 1890 [=Iphthimus laevissimus (Casey 1890)] is synonymized under Iphthiminus lewisii (Horn 1870) [=Iphthimus lewisii (Horn 1870)]. Lectotypes are designated for Iphthimus serratus lewisii Horn 1870 and Iphthimus opacus LeConte 1866. PMID- 26624754 TI - Review of the Gauromydas giant flies (Insecta, Diptera, Mydidae), with descriptions of two new species from Central and South America. AB - Gauromydas Wilcox, Papavero & Pimentel, 1989 are giant flies, and include the largest fly known, G. heros (Perty, 1833). This genus was originally erected to group four Neotropical species, namely G. apicalis (Wiedemann, 1830), G. autuorii (d'Andretta, 1951), G. heros, and G. mystaceus (Wiedemann, 1830). As with most of the remaining Mydidae, adults of Gauromydas are very rarely collected. We here describe two new species of Gauromydas (G. mateus sp. nov. and G. papaveroi sp. nov.) discovered in entomological collections, including specimens unstudied for up to eight decades. We also provide revised diagnoses for the remaining four species of Gauromydas, along with a new key and new distribution records for the genus. PMID- 26624755 TI - New species of Histiotus (Chiroptera: Vespertilionidae) from northeastern Brazil. AB - Histiotus are vespertilionid bats endemic to South America, easily recognized by its very long ears. During a twelve-month bat inventory in northeastern Brazil, eleven specimens of Histiotus were collected with a unique combination of characters that did not match those of any known species. In this paper, we describe these specimens as a new species. Histiotus sp. nov is distinguished from its congeners by its pale transparent wings and translucent ears, a triangular-shaped ear with a prominent lobe in the inner border connected by a band (~4 mm) across the forehead; its general golden-brownish body color and well marked bicolor dorsal hairs. Its geographic distribution is unique among vespertilionids, arranged in a northeast-southwest diagonal across South America, includes the Caatinga and Cerrado of Brazil and Chaco of Bolivia. The available data suggest a seasonal reproductive pattern, with births occurring in the mid to late rainy season. PMID- 26624756 TI - A probable non-annelid origin of pods attached to Amaeana ellobophora (Annelida: Polycirridae). PMID- 26624757 TI - On the taxonomy of the genus Acronicta (Lepidoptera, Noctuidae). II. A replacement name for Acronicta geminata (Draudt, 1950). PMID- 26624758 TI - The potential of type species to destabilise the taxonomy of zooxanthellate Scleractinia. PMID- 26624759 TI - Nossidium katyae, a new species of Bolivian Ptiliidae (Coleoptera), described and figured. AB - This is the third report on a collection of Ptiliidae from Bolivian forest leaf litter made by Dr Petr Banar of the Brno Museum (Czech Republic) in 2013. A new species Nossidium katyae, is described and figured on the basis of a single specimen collected in the Amboro National Park. Comparative figures of Nossidium pilosellum Marsham are provided together with a brief synopsis of views on the desirability of establishing a new subfamily within the Ptiliidae to include Nossidium group species. PMID- 26624760 TI - Exostoma tenuicaudata, a new species of glyptosternine catfish (Siluriformes: Sisoridae) from the upper Brahmaputra drainage, northeastern India. PMID- 26624761 TI - A new species of Pseudophanias Raffray from a cave in central Nepal (Coleoptera: Staphylinidae: Pselaphinae). PMID- 26624762 TI - The scarab beetle tribe Pentodontini (Coleoptera: Scarabaeidae: Dynastinae) of Colombia: taxonomy, natural history, and distribution. AB - Pentodontini is the most diverse tribe of Dynastinae (Coleoptera: Scarabaeidae), and most of the genera are restricted to a single biogeographic region. In this work, the taxonomic composition of the Pentodontini in Colombia was determined, and genera and species were diagnosed based on external morphology and male genitalia. Records of 1,580 specimens from 31 departments and 398 localities in Colombia were obtained from 24 species in the genera Bothynus Hope, Denhezia Dechambre, Euetheola Bates, Hylobothynus Ohaus, Oxyligyrus Arrow, Parapucaya Prell, Pucaya Ohaus, and Tomarus Erichson. Oxyligyrus cayennensis Endrodi, Tomarus cicatricosus (Prell), and T. pullus (Prell) are reported for the first time from Colombia. Pucaya punctata Endrodi is reduced to synonymy with Pucaya pulchra Arrow. Possible changes in the classification of Denhezia Dechambre are discussed. Dichotomous keys are provided for Colombian genera and species. Taxonomic descriptions and distribution maps are included for all species. PMID- 26624763 TI - Confused identity: subgenera of Pseudoeudesis Binaghi belong in two tribes (Coleoptera: Staphylinidae: Scydmaeninae). AB - Afroeudesis Franz and Oreoeudesis Franz, Afrotropical subgenera of Pseudoeudesis Binaghi (Scydmaenini), are elevated to the genus rank and transferred to Cyrtoscydmini. The East Palaearctic genus Nanoscydmus Jaloszynski is reduced to a subgenus of Afroeudesis stat. n., resulting in Afroeudesis (Nanoscydmus) baoshanus (Jaloszynski), comb. n. and Afroeudesis (Nanoscydmus) nepalensis (Jaloszynski), comb. n. Morphological structures of the type species of Afroeudesis and Oreoeudesis are illustrated and described in detail, and the following species are redescribed: Afroeudesis (s. str.) basilewskyi Franz (Tanzania), Oreoeudesis lindneri Franz (Tanzania), Oreoeudesis aberdarensis Franz (Kenya) and Oreoeudesis camerunensis Franz (Cameroon). PMID- 26624764 TI - Benthic Ostracods of Skogsbergiella (Myodocopina: Cylindroleberididae) from the Southern Ocean. AB - Skogsbergiella tetrathrix sp. nov. and S. species A, species of the family Cylindroleberididae are described from the Drake Passage (59 degrees 21.97'S - 60 degrees 4.27'W to 59 degrees 22.55'S - 60 degrees 4.01'W, depth 2372-2380 m) and Weddell Sea (75 degrees 49.9'S-27 degrees 31.7'W to 74 degrees 51.55'S-27 degrees 40.3'W, depth 467-475m) respectively. Skogsbergiella tetrathrix sp.nov. is very close to S. macrothrix Kornicker, 1975 but differs by greater size of carapace, 2-jointed rod-shaped organ, lesser number of setae on comb of fifth limb and teeth on combs of seventh limb, and absence of lateral eyes. S. species A is similar to S. skogsbergi Kornicker, 1971 and S. senex Kornicker, 1996 but differs in size and number of setae on the dorsal margin of mandibular basale and seventh limb. PMID- 26624765 TI - Antocha crane flies from Taiwan (Diptera: Limoniidae: Limoniinae). AB - Taiwanese species of the crane fly subgenus Antocha (Antocha) Osten Sacken, 1860, are reviewed. Antocha (Antocha) taiwanensis, new species, is described and figured. Previously known species, Antocha (A.) bifida Alexander, 1924a and Antocha (A.) styx Alexander, 1930 are redescribed and illustrated. Antocha (A.) javanensis Alexander, 1915 is removed from the list of Taiwanese crane flies. Antocha (A.) gracillima Alexander, 1924b and species close to Antocha (A.) streptocera Alexander, 1949 are listed for the first time in Taiwan. Identification key for all Taiwanese Antocha species is given. PMID- 26624766 TI - An Inventory of Tortricidae (Lepidoptera) from the Rostov-on-Don province of Russia. AB - Records of leafroller moths (Tortricidae) from the Rostov-on-Don province of southern Russia are presented based on 10 years of field work (2005-2014). The list includes 91 species from 43 collecting sites; 80 species are recorded from the region for the first time. Compared to other well-surveyed, adjacent areas, the tortricid fauna is considerably more depauperate, and this may be explained in part by the predominance of steppe vegetation. PMID- 26624767 TI - New World species of Asymphyloptera Collin (Diptera: Empididae: Clinocerinae). AB - Eight species are recognized among New World species of Asymphyloptera Collin, including seven new species (A. cajanuma sp. nov. (Ecuador), A. chilensis sp. nov. (Chile), A. chiricahua sp. nov. (USA: Arizona), A. dominica sp. nov. (Dominica), A. havasu sp. nov. (USA: Arizona), A. lutea sp. nov. (Costa Rica) and A. mexicana sp. nov. (Mexico)). The new species are described, male terminalia illustrated, distributions mapped and a key to species is presented. Two additional undescribed species based on single females, are known from Ecuador and Venezuela. PMID- 26624768 TI - New species of Euschistus (Euschistus) from Jamaica, Euschistus (Mitripus) and Ladeaschistus from southern South America (Hemiptera: Heteroptera: Pentatomidae: Pentatominae). AB - Three new species of the Carpocorini are described: Euschistus (Euschistus) baranowskii Eger & Bianchi sp. nov. from Jamaica, Euschistus (Mitripus) saramagoi Bianchi, Cioato & Grazia sp. nov. from Brazil, and Ladeaschistus borgesi Bianchi, Cioato & Grazia sp. nov. from Argentina, Bolivia and Brazil. Comparative illustrations of external and internal genitalia of the species are provided. PMID- 26624769 TI - Lethe gregoryi Watkins (Lepidoptera, Nymphalidae, Satyrinae), a distinct species. AB - In this paper, Lethe helle gregoryi Watkins, 1927 is raised to specific status, viz. L. gregoryi stat. nov., and L. moelleri bitaensis Yoshino, 1999 syn. nov. is found to be a junior synonym of gregoryi. Lethe gesangdawai Huang, 2001 is sunk to a subspecies of L. gregoryi, viz. L. gregoryi gesangdawai stat. nov. PMID- 26624770 TI - Review of Platyplastinx Enderlein, 1937 (Diptera, Psychodidae) with descriptions of four new species. AB - Platyplastinx Enderlein, with eight previously described species, is currently known to occur in the southeastern United States, Costa Rica, Ecuador and Brazil. Four new species from Brazil are described: Platyplastinx amazonensis sp. nov., P. duckhousei sp. nov., P. exiguus sp. nov. and P. hirsutus sp. nov. Platyplastinx obscurus (Bravo, Lago & Castro, 2004) comb. n. is transferred from Alepia. The generic diagnosis is updated, global species are listed, and an identification key for males of all species is provided. Thirteen species are now known, eight of which are described from Brazil. PMID- 26624771 TI - A new species of genus Leluthia Cameron (Hymenoptera: Braconidae) parasitizing Agrilus sp. (Coleoptera: Buprestidae) from China with a key to the East Palaearctic species. AB - A new species of genus Leluthia Cameron (Hymenoptera: Braconidae), L. chinensis Li & van Achterberg, sp. nov. is described and illustrated. It was reared from Agrilus sp. (Coleoptera: Buprestidae), a twig-boring pest of Caragana korshinskii Kom. (Leguminosae) in Inner Mongolia Autonomous Region, NW China. A key to the East Palaearctic species of the genus Leluthia is provided. PMID- 26624772 TI - An annotated catalogue and bibliography of the taxonomy, synonymy and distribution of the Recent Vetigastropoda of South Africa (Mollusca). AB - A complete inventory of the known Recent vetigastropod fauna of South Africa is provided. Bibliographic citations to works discussing the taxonomy, synonymy and distribution of the species in a southern African or south-western Indian Ocean context are provided. Additional explanatory notes are given where pertinent. New genus records for South Africa: Acremodontina B.A. Marshall, 1995; Choristella Bush, 1879; Cocculinella Thiele, 1909; Conjectura Finlay, 1926; Crosseola Iredale, 1924; Falsimargarita Powell, 1951; Lepetella Verrill, 1880; Profundisepta McLean & Geiger, 1998; Stomatella Lamarck, 1816; Stomatia Helbling, 1779; Stomatolina Iredale, 1937; Synaptocochlea Pilsbry, 1890; Tibatrochus Nomura, 1940; Visayaseguenzia Poppe, Tagaro & Dekker, 2006; Zetela Finlay, 1926. New species records for South Africa: Acremodontina aff. carinata Powell, 1940; Anatoma finlayi (Powell, 1937); Anatoma munieri (P. Fischer, 1862); Calliotropis acherontis B.A. Marshall, 1979; Calliotropis bucina Vilvens, 2006; Cocculinella minutissima (E.A. Smith, 1904); Diodora ruppellii (G.B. Sowerby (I), 1835); Emarginula costulata Deshayes, 1863; Emarginula decorata Deshayes, 1863; Jujubinus hubrechti Poppe, Tagaro & Dekker, 2006; Lepetella sp.; Seguenzia orientalis Thiele, 1925; Stomatella auricula Lamarck, 1816; Stomatia phymotis Helbling, 1779; Stomatolina angulata (A. Adams, 1850); Stomatolina cf. calliostoma (A. Adams, 1850); Stomatolina aff. danblumi Singer & Mienis, 1999; Stomatolina cf. rubra (Lamarck, 1822); Stomatolina sp.; Synaptocochlea concinna (Gould, 1845); Tectus mauritianus (Gmelin, 1791); Tibatrochus cf. incertus (Schepman, 1908); Turbo imperialis Gmelin, 1791; Turbo tursicus Reeve, 1848; Visayaseguenzia compsa (Melvill, 1904).New species: Spectamen martensi, replacement name for Spectamen semisculptum sensu Herbert (1987) (non Martens, 1904). New name: Oxystele antoni is proposed as a new name for Trochus (Turbo) variegatus (non Gmelin, 1791 =Heliacus) Anton, 1838. Revised taxonomy: Cyclostrema semisculptum Martens, 1904 is an earlier name for Solariella intermissa Thiele, 1925, and is referable to the genus Zetela Finlay, 1926; Margarita bicarinata A. Adams & Reeve, 1850 is considered to be a senior synonym of Solariella undata G.B. Sowerby (II), 1870, and is referable to the genus Ilanga Herbert, 1987. Validation of the name Trochus tigrinus Chemnitz, 1781 is credited to Dillwyn (1817) rather than Anton (1838). New synonyms: Clanculus exquisita Turton, 1932 =Calliostoma africanum Bartsch, 1915; Cyclostrema alfredensis Bartsch, 1915 =Parviturbo alfredensis (Bartsch, 1915); Cynisca gloriosa Bartsch, 1915 =Cinysca spuria (Gould, 1861); Herbertina hayesi Herbert, 1995 =Bruceina chenoderma (Barnard, 1963); Ilanga millardi Herbert, 1987 =Ilanga humillima (Thiele, 1925); Leptothyra africana Bartsch, 1915 =Cinysca spuria (Gould, 1861); Leptothyra albocincta Turton, 1932 =Tricolia striolata (Turton, 1932); Solariella undata G.B. Sowerby (II), 1870, S. gratiosa Thiele, 1925 and S. valdiviae Thiele, 1925 =Ilanga bicarinata bicarinata (A. Adams & Reeve, 1850); Solariella chuni Thiele, 1925, S. intermissa Thiele, 1925, S. gilchristi Barnard, 1963 and S. macleari Barnard, 1963 =Zetela semisculpta (Martens, 1904); Turbo (Collonia) armillatus G.B. Sowerby (III), 1886 =Cinysca spuria (Gould, 1861). New combinations: Basilissa (Ancistrobasis) compsa Melvill, 1904 is transferred to Visayaseguenzia; Calcar rhysopoma Barnard, 1964 is transferred to Bothropoma; Calliostoma glaucophaos Barnard, 1963 is transferred to Falsimargarita; Calliotropis chenoderma Barnard, 1963 is transferred to Bruceina; Collonia bicarinata Martens, 1902 is transferred to Cinysca; Crossea agulhasensis Thiele, 1925 is transferred to Conjectura; Cyclostrema semisculptum Martens, 1904 is transferred to Zetela; Cyclostremella farica Bartsch, 1915 is transferred to Dikoleps; Cynisca africana Bartsch, 1915 is transferred to Homalopoma; Leptogyra africana: Bartsch, 1915 is transferred to Cirsonella; Leptothyra agulhasensis Thiele, 1925 is transferred to Homalopoma; Leptothyra alfredensis Bartsch, 1915 is transferred to Parviturbo; Leptothyra sola Barnard, 1963 is transferred to a Parviturbo; Liotia (Cynisca) semiclausa Thiele, 1925 is transferred to Cinysca; Monilea spuria Gould, 1861 is transferred to Cinysca; Monodonta gibbula Thiele, 1925 is transferred to Cantrainea; Puncturella voraginosa Herbert & Kilburn, 1986 is transferred to Profundisepta; Solariella fuscomaculata G.B. Sowerby (III), 1892 is transferred to Skenea; Solariella turbynei Barnard, 1963 is transferred to Zetela; Turbo boswellae Barnard, 1969 is transferred to Cantrainea; Turbo foveolatus Barnard, 1963 is transferred to Crosseola; Turbo ponsonbyi G.B. Sowerby (III), 1897 is transferred to Bothropoma; Vitrinella agulhasensis Thiele, 1925 is transferred to Parviturbo; Vitrinella (Docomphala) arifca Bartsch, 1915 is transferred to Lodderena; Vitrinella inclinans Barnard, 1963 is transferred to Skenea. PMID- 26624773 TI - Taxonomic revision and cladistic analysis of the Neotropical genus Acrochaeta Wiedemann, 1830 (Diptera: Stratiomyidae: Sarginae). AB - The Neotropical genus Acrochaeta Wiedemann is revised and a cladistics analysis of the genus based on morphological characters is presented. This paper raises the total number of extant Acrochaeta species from 10 to 14 with the description of nine new species, the synonymy of one species, the transfer of five species to other genera and the transfer of one species of Merosargus to Acrochaeta. The new species described (of which eight are from Brazil and one from Bolivia and Peru) are Acrochaeta asapha nov. sp., A. balbii nov. sp., A. dichrostyla nov. sp., A. polychaeta nov. sp., A. pseudofasciata nov. sp., A. pseudopolychaeta nov. sp., A. rhombostyla nov. sp. A. ruschii nov. sp. and A. stigmata nov. sp. The primary types of all Acrochaeta species were studied at least from photos, when possible with the study of dissected male or female terminalia. A. mexicana Lindner is proposed as a junior synonym of A. flaveola Bigot. M. chalconota (Brauer) comb. nov., M. degenerata (Lindner) comb. nov., M. longiventris (Enderlein) comb. nov. and M. picta (Brauer) comb. nov. are herein transferred from Acrochaeta to Merosargus Loew, and Chrysochlorina elegans (Perty) comb. nov. is transferred from Acrochaeta to Chrysochlorina James. A. convexifrons (McFadden) comb. nov. is transferred from Merosargus to Acrochaeta. The limits of the genus and its insertion in the Sarginae are considered, and an updated generic diagnosis is provided. All species of the genus are redescribed and diagnosed, and illustrated with photos of the habitus, thorax, wing, and drawings of the antenna and male and female terminalia. Distribution maps are provided for the species, along with an identification key for adults of all species. Parsimony analyses were carried out under equal and implied weight. Our matrix includes 43 terminal taxa--of which 26 are outgroup species from four different sargine genera--and 59 adult morphological characters. The phylogenetic analysis supports the monophyly of Acrochaeta based on features of the head, thorax and abdomen. An inner clade (Acrochaeta flaveola species group) within the genus was clearly recovered based on characters of male and female terminalia. There is good evidence for the paraphyly of Merosargus with Acrochaeta as a subclade, demanding a wider study of the subfamily for a sound solution for the genus Merosargus. PMID- 26624774 TI - THE TYPES OF PALAEARCTIC HIPPORHININI (Coleoptera, Curculionidae, Cyclominae) CONSERVED AT THE MUSEUM NATIONAL D'HISTOIRE NATURELLE, PARIS. AB - The Palaearctic species of Curculionidae: Cyclominae: Hipporhinini conserved at the Museum national d'Histoire Naturelle, Paris were critically revised in order to recognise the type specimens, select lectotypes or, where necessary, designate neotypes. Out of 135 species whose types were presumably preserved in the MNHN, original type specimens of 116 could be found. The holotypes of 21 species were available, either because originally designated as such, or because the species was unequivocally based on a single specimen; a paratype of another taxon, whose holotype is preserved in another collection, was also examined. The lectotypes of 93 species were designated, and a syntype of another species was also seen. Neotypes of 10 more species were designated, thus leading to a total number of species whose type is conserved at the MNHN to 126. Type specimens of five more species described by French authors, not present in the MNHN but conserved in other museums, were found as well and were included in the paper, with the further designation of three lectotypes. All types treated herein were labelled and photographed. PMID- 26624775 TI - Taxonomy of the genus Osorius Guerin-Meneville (Coleoptera: Staphylinidae, Osoriinae) from China. AB - This paper studies the taxonomy of the genus Osorius Guerin-Meneville, 1829 (Coleoptera: Staphylinidae, Osoriinae) and reports 10 new species and three new records from China: Osorius depressicapitatus sp. nov. (Yunnan and Xizang), O. guizhouensis sp. nov. (Guizhou), O. huangi sp. nov. (Hunan), O. limatidepressus sp. nov. (Sichuan), O. micromidas sp. nov. (Yunnan), O. minutoserratus sp. nov. (Yunnan), O. rectomarginatus sp. nov. (Yunnan, Guangxi, Hainan, Fujian, Guangdong and Xizang), O. striolatus sp. nov. (Hunan and Guangdong), O. trichinosis sp. nov. (Guizhou and Zhejiang), O. tuberocapitatus sp. nov. (Hubei), O. aspericeps Fauvel, 1905, new record of China (Yunnan, Sichuan, Xizang and Zhejiang), O. frontalis Fauvel, 1905, new record of China (Sichuan), and O. punctulatus Motschulsky, 1857, new record of China (Yunnan and Fujian). The number of the Chinese Osorius species is thus increased to 21 in total. The paper provides line drawings for 21 species and redescriptions for the species recorded for the first time in China. A key to Chinese species is also included. PMID- 26624776 TI - A new Dendropsophus Fitzinger, 1843 (Anura: Hylidae) of the parviceps group from the lowlands of the Guiana Shield. AB - Many Amazonian frog species that are considered widely distributed may actually represent polyspecific complexes.. A minute tree frog from the Guiana Shield originally assigned to the allegedly widely distributed Dendropsophus brevifrons proved to be a yet undescribed species within the D. parviceps group. We herein describe this new species and present a phylogeny for the D. parviceps group. The new species is diagnosed from other Dendropsophus of the parviceps group by its small body size (19.6-21.7 mm in males, 22.1-24.5 mm in females), thighs dorsally dark grey with cream blotches without bright yellow patch, absence of dorsolateral and canthal stripe, and an advertisement call comprising trills (length 0.30-0.35 s) composed of notes emitted at a rate of 131-144 notes/s, generally followed by click series of 2-3 notes. Its tadpole is also singular by having fused lateral marginal papillae and absence of both labial teeth and submarginal papillae. Genetic distances (p-distance) are >5.3% on the 12S and >9.3% on the 16S from D. brevifrons, its closest relative. This species occurs from the Brazilian state of Amapa, across French Guiana and Suriname to central Guyana and is likely to also occur in adjacent Brazilian states and eastern Venezuela. This species is not rare but is difficult to collect because of its arboreal habits and seasonal activity peaks. PMID- 26624777 TI - Bees of the genus Sphecodes Latreille 1804 of Siberia, with a key to species (Hymenoptera: Apoidea: Halictidae). AB - Twenty-one species of the bee genus Sphecodes Latreille are recorded from Siberia. Sphecodes schwarzi Astafurova & Proshchalykin, sp. nov. is described from Tyva Republic and Mongolia (Dornod Aimag). Five species: Sphecodes alternatus Smith, 1853, S. reticulatus Thomson, 1870, S. rufiventris (Panzer, 1798), S. pinguiculus Perez, 1903, and S. spinulosus Hagens, 1875 are newly recorded from the Asian part of Russia and seven species: S. ferruginatus Hagens, 1882, S. hyalinatus Hagens,1882, S. longulus Hagens, 1882, S. miniatus Hagens, 1882, S. nippon Meyer, 1922, S. puncticeps Thomson, 1870, and S. scabricollis Wesmael, 1835 are recorded for the first time from Siberia. Sphecodes angarensis Cockerell, 1937 is newly synonymized under S. gibbus (Linnaeus, 1758). Illustrated keys for males and females of all species from Siberia and neighbouring Mongolia are provided. PMID- 26624778 TI - Phytotelmatrichis, a new genus of Acrotrichinae (Coleoptera: Ptiliidae) associated with the phytotelmata of Zingiberales plants in Peru. AB - Phytotelmatrichis, gen. n. a new genus of Ptiliidae: Acrotrichinae with two species Phytotelmatrichis peruviensis sp. n. and Phytotelmatrichis osopaddington sp. n. is described and illustrated. The new species were found during a survey of insects in the aquatic environments that form in the hollows (phytotelmata) in the leaves and floral bracts of Zingiberales plants. The new taxa were found in the the Zingiberales genera Calathea (Marantaceae), Heliconia (Heliconiaceae), and Alpinia and Renealmia (Zingiberaceae) in southern Peru. Sampling of other habitats in the same areas over five years and using a range of different techniques did not yield more specimens of this new genus. This suggests that the new species are restricted to phytotelmata. PMID- 26624779 TI - A new genus and species of net-winged midge from Madagascar (Diptera: Blephariceridae: Blepharicerinae). AB - Larvae of a species from the subfamily Blepharicerinae were first discovered in the 1950's, but the lack of additional records prevented description of the species. A recent study of important additional specimens from the late Brian Stuckenberg has provided the basis for describing this unusual fly. This paper provides a description of larvae, pupae, and adults of Aphromyia stuckenbergi gen. et sp. nov., and a brief discussion of its phylogenetic position within the family. The latter is confounded by marked adult colocephaly (reduction of the head) and concomitant reduction in mouthparts, and by lack of recent collections that would permit molecular analyses and further morphological study. Known from only two collections, the most recent nearly 60 years ago, this highly endemic and rare fly is arguably one the most endangered species in Madagascar. PMID- 26624780 TI - Binhthuanomon vinhtan, a new genus and new species of semi-terrestrial freshwater crab (Crustacea: Decapoda: Brachyura: Potamidae) from south central Vietnam. AB - A new genus and new species of semi-terrestrial crab of the family Potamidae, Binhthuanomon vinhtan n. sp., is described from south central Vietnam. The new genus is morphologically closest to Villopotamon Dang & Ho, 2003, and Balssipotamon Dang & Ho, 2008, in the shapes of the carapace and first gonopod but is easily distinguished by distinct carapace characteristics and gonopod 1 structures, and the habitat occupied. PMID- 26624781 TI - Leucosiid crabs (Crustacea: Decapoda: Brachyura) from Taiwan, with three new records. AB - Four leucosiid species from Taiwan are presented. Ebalia nudipes Sakai, 1963, with its male first gonopod figured for the first time. Galilia petricola Komai & Tsuchida, 2014, is recorded on the basis of a larger specimen, and distinguishing features with its only congener, G. narusei Ng & Richer de Forges, 2007, reappraised. Nursia rhomboidalis (Miers, 1879), previously known only from Japan, Korea, and mainland China, is also recorded from Taiwan. Myra fugax (Fabricius, 1798) is now formally recorded from Taiwan, and female characters identified to help separate the three known Taiwanese species of Myra. PMID- 26624782 TI - New species and records of ptyctimous mites (Acari, Oribatida) from Cuba. AB - An annotated checklist of identified oribatid mites from Cuba, including 16 species, 9 genera and 4 families, is provided. Three new species, Prototritia triangularibus Niedbala sp. nov. (Protoplophoridae), Hoplophthiracarus vinalesensis Niedbala sp. nov. and Protophthiracarus paratripartitus Niedbala sp. nov. (both Steganacaridae), are described from leaf litter. Three species of the subgenus Atropacarus (Hoplophorella)-A. (H.) andrei (Balogh, 1958), A. (H.) brachys Niedbala, 2004 and A. (H.) stilifer (Hammer, 1961)-are recorded in the Cuban mite fauna for the first time. PMID- 26624783 TI - The first longhorned beetle record for the Prepuna in the Bolivian Andes and Potosi Department in Bolivia: a new species of Dirocoremia (Coleoptera: Cerambycidae: Rhopalophorini). AB - Compared to other Bolivian ecoregions, the Prepuna and Puna in the Bolivian highlands are distinguished by low precipitation and low biological diversity. These factors have likely contributed to the perception that the Prepuna and Puna are less interesting for entomological studies, and reports of longhorned beetles from these regions remain scarce. Here, the first longhorned beetle record for the Bolivian Prepuna and Potosi Department is reported, an unknown species of Dirocoremia Marques, 1994. Dirocoremia tupizai sp. n. can be distinguished from congeners by its dark-brown to black metatibiae with short and sparse subapical brushes of hairs. PMID- 26624784 TI - Erratum: ANATOLY V. KRUPITSKY, IGOR G. PLJUSHTCH & OLEG V. PAK (2015) A new species of the Callophrys paulae Pfeiffer, 1932 species group from Afghanistan (Lepidoptera, Lycaenidae). Zootaxa, 4027 (2): 281-286. PMID- 26624786 TI - Radiographic Assessment and Surgical Implications of Arcuate Eminence Pneumatization. AB - BACKGROUND: The middle cranial fossa (MCF) approach is a valuable yet technically challenging technique. Identification of the superior semicircular canal (SCC) using the arcuate eminence (AE) was proposed as a surface landmark. However, the AE is sometimes absent, with inconsistent relationship to the SCC. Air cells in the AE area facilitate safer identification of the SCC. The aim of this study is to determine the radiographic prevalence of AE pneumatization. METHODS: Two hundred consecutive fine-cut temporal bone CT scans were retrospectively reviewed. The region of the petrosal bone at and above the level of the SCC dome was assessed for the presence of air cells, and graded 0 (no pneumatization) to 2 (well pneumatized). RESULTS: Four hundred temporal bones were studied. The average age was 49 years (range 18-89). Of all AE assessments, 47 (12%) were nonpneumatized, 62 (15%) partially pneumatized, and 291 (73%) well pneumatized. There was no significant correlation between patient age and pneumatization grade (p = 0.72). CONCLUSION: The SCC is a valuable landmark in MCF surgery as it holds consistent relationships to adjacent critical structures. Surrounding air cells should facilitate safer initial identification of the SCC, as the AE region is well pneumatized in 73% of patients. PMID- 26624787 TI - Open circuit potential build-up in perovskite solar cells from dark conditions to 1 sun. AB - The high open-circuit potential (Voc) achieved by perovskite solar cells (PSCs) is one of the keys to their success. The Voc analysis is essential to understand their working mechanisms. A large number of CH3NH3PbI3-xClx PSCs were fabricated on single large-area substrates and their Voc dependencies on illumination intensity, I0, were measured showing three distinctive regions. Similar results obtained in Al2O3 based PSCs relate the effect to the compact TiO2 rather than the mesoporous oxide. We propose that two working mechanisms control the Voc in PSCs. The rise of Voc at low I0 is determined by the employed semiconductor n type contact (TiO2 or MgO coated TiO2). In contrast, at I0 close to AM1.5G, the employed oxide does not affect the achieved voltage. Thus, a change of regime from an oxide-dominated EFn (as in the dye sensitized solar cells) to an EFn, directly determined by the CH3NH3PbI3-xClx absorber is suggested. PMID- 26624788 TI - Macrocyclic Dizinc(II) Alkyl and Alkoxide Complexes: Reversible CO2 Uptake and Polymerization Catalysis Testing. AB - The synthesis of three new dizinc(II) complexes bearing a macrocyclic [2 + 2] Schiff base ligand is reported. The bis(anilido)tetraimine macrocycle reacts with diethylzinc to form a bis(ethyl)dizinc(II) complex, [L(Et)Zn2Et2] (1). The reaction of complex 1 with isopropyl alcohol is reported, forming a bis(isopropyl alkoxide)dizinc complex, [L(Et)Zn2((i)PrO)2] (2). Furthermore, complex 1, with 2 equiv of alcohol, is applied as an initiator for racemic lactide ring-opening polymerization. It shows moderately high activity, resulting in a pseudo-first order rate coefficient of 9.8 * 10(-3) min(-1), with [LA] = 1 M and [initiator] = 5 mM at 25 degrees C and in a tetrahydrofuran solvent. Polymerization occurs with good control, as evidenced by the linear fit to a plot of molecular weight versus conversion, the narrow dispersities, and the limited transesterification. The same initiating system is inactive for the ring-opening copolymerization of carbon dioxide (CO2) and cyclohexene oxide at 80 degrees C and 1 bar of CO2 pressure. However, stoichiometric reactions between complex 2 and CO2, at 1 bar pressure, result in the reversible formation of new dizinc carbonate species, [L(Et)Zn2((i)PrO)((i)PrOCO2)] (3a) and [L(Et)Zn2((i)PrOCO2)2] (3b), and the reaction was studied using density functional theory calculations. All of the new complexes, 1-3b, are fully characterized, including NMR spectroscopy, elemental analysis, and single-crystal X-ray diffraction. PMID- 26624789 TI - Using Pseudocontact Shifts and Residual Dipolar Couplings as Exact NMR Restraints for the Determination of Protein Structural Ensembles. AB - Nuclear magnetic resonance (NMR) spectroscopy provides detailed information about the structure and dynamics of proteins by exploiting the conformational dependence of the magnetic properties of certain atomic nuclei. The mapping between NMR measurements and molecular structures, however, often requires approximated descriptions based on the fitting of a number of parameters, thus reducing the quality of the information available from the experiments. To improve on this limitation, we show here that it is possible to use pseudocontact shifts and residual dipolar couplings as "exact" NMR restraints. We implement this strategy by using a replica-averaging method and illustrate its application by calculating an ensemble of structures representing the dynamics of the two domain protein calmodulin. PMID- 26624790 TI - SpinCouple: Development of a Web Tool for Analyzing Metabolite Mixtures via Two Dimensional J-Resolved NMR Database. AB - A new Web-based tool, SpinCouple, which is based on the accumulation of a two dimensional (2D) (1)H-(1)H J-resolved NMR database from 598 metabolite standards, has been developed. The spectra include both J-coupling and (1)H chemical shift information; those are applicable to a wide array of spectral annotation, especially for metabolic mixture samples that are difficult to label through the attachment of (13)C isotopes. In addition, the user-friendly application includes an absolute-quantitative analysis tool. Good agreement was obtained between known concentrations of 20-metabolite mixtures versus the calibration curve-based quantification results obtained from 2D-Jres spectra. We have examined the web tool availability using nine series of biological extracts, obtained from animal gut and waste treatment microbiota, fish, and plant tissues. This web-based tool is publicly available via http://emar.riken.jp/spincpl. PMID- 26624791 TI - Unconventional Charge-Density-Wave Transition in Monolayer 1T-TiSe2. AB - Reducing the dimension in materials sometimes leads to unexpected discovery of exotic and/or pronounced physical properties such as quantum Hall effect in graphene and high-temperature superconductivity in iron-chalcogenide atomically thin films. Transition-metal dichalcogenides (TMDs) provide a fertile ground for studying the interplay between dimensionality and electronic properties, since they exhibit a variety of electronic phases like semiconducting, superconducting, and charge-density-wave (CDW) states. Among TMDs, bulk 1T-TiSe2 has been a target of intensive studies due to its unusual CDW properties with the periodic lattice distortions characterized by the three-dimensional (3D) commensurate wave vector. Clarifying the ground states of its two-dimensional (2D) counterpart is of great importance not only to pin down the origin of CDW, but also to find unconventional physical properties characteristic of atomic-layer materials. Here, we show the first experimental evidence for the realization of 2D CDW phase without Fermi-surface nesting in monolayer 1T-TiSe2. Our angle-resolved photoemission spectroscopy (ARPES) signifies an electron pocket at the Brillouin zone corner above the CDW-transition temperature (TCDW ~ 200 K), while, below TCDW, an additional electron pocket and replica bands appear at the Brillouin zone center and corner, respectively, due to the back-folding of bands by the 2 * 2 superstructure potential. Similarity in the spectral signatures to bulk 1T TiSe2 implies a common driving force of CDW, i.e., exciton condensation, whereas the larger energy gap below TCDW in monolayer 1T-TiSe2 suggests enhancement of electron-hole coupling upon reducing dimensionality. The present result lays the foundation for the electronic-structure engineering based with atomic-layer TMDs. PMID- 26624792 TI - The effect of electrical stimulation on post mortem myofibrillar protein degradation and small heat shock protein kinetics in bull beef. AB - This study aimed to determine the effect of electrical stimulation and ultimate pH (pHu) on shear force, myofibrillar protein degradation and small heat shock protein (sHSP) concentrations in M. longissimus lumborum (LL). The LL from both sides of carcasses (n=15) was excised with low voltage electrical stimulation (ES) applied to an LL muscle from one side, while the opposing LL muscle was not stimulated (NS). Muscles were categorised into low (pHu<5.8), intermediate (5.8<=pHu<6.2) and high pHu (pHu>=6.2) and aged for up to 28days post mortem at 1.5 degrees C. High pHu meat tenderised faster which corresponded with the faster degradation of titin and desmin in this group compared with low and intermediate pHu meat. Electrical stimulation significantly affected the variable levels of alphabeta-crystallin and HSP20 with higher concentrations of these sHSP in ES muscles at later ageing timepoints compared with NS muscles. PMID- 26624793 TI - Developing food-grade coatings for dry-cured hams to protect against ham mite infestation. AB - Dry-cured hams may become infested with ham mites, Tyrophagus putrescentiae, during the aging process. Methyl bromide is the only known available fumigant pesticide that is effective at controlling ham mite infestations in dry cured ham plants. However, methyl bromide will be phased out of all industries as early as 2015 due to its status as an ozone-depleting substance. Research was conducted to develop and evaluate the potential of using food-grade film coatings to control mite infestations, without affecting the aging process and sensory properties of the dry-cured hams. Cubes coated with xanthan gum+20% propylene glycol and carrageenan/propylene glycol alginate+10% propylene glycol were effective at controlling mite infestations under laboratory conditions. Water vapor permeability was measured to estimate the impact of coatings during the aging process. It was evident that carrageenan/propylene glycol alginate coatings were permeable to moisture, which potentially makes them usable during aging. PMID- 26624794 TI - Characterization of volatile metabolites associated with confinement odour during the shelf-life of vacuum packed lamb meat under different storage conditions. AB - Confinement odour was investigated. Volatiles were extracted directly from the pack, using solid phase microextraction and analysed by gas chromatography-mass spectrometry. Sensory evaluation and microbiological analysis of the meat surface were also performed. Commercial samples of vacuum packed lamb legs (n=85), from two meat processing plants, were kept for 7weeks at -1.5 degrees C then at different regimes of temperature (-1.5 to +4 degrees C) until 11, 12 or 13weeks. Persistent odour was observed in 66% of samples, confinement odour in 24% and no odour in 11%. Volatiles associated with confinement odour (3-methyl-butanal, 3 hydroxy-2-butanone and sulphur dioxide) corresponded with end/sub products of glucose fermentation and catabolism of amino acids by bacteria (all bacteria naturally found in meat and do not represent a risk to health). Confinement odour could indicate a stage at which the environment for bacteria growth is becoming favourable for the production of volatiles with strong odours that are noticed by the consumer. PMID- 26624795 TI - ANOVA and the analysis of drug combination experiments. PMID- 26624796 TI - Autophagy: eat thyself, sustain thyself. PMID- 26624797 TI - Hitting the target. PMID- 26624798 TI - Homocysteine Exposure Impairs Myocardial Resistance to Ischaemia Reperfusion and Oxidative Stress. AB - BACKGROUND/AIMS: Hyperhomocysteinaemia is recognised as a strong independent risk factor for developing cardiovascular disease. This study investigated how an acute homocysteine dose affected cardiac performance during ischaemia reperfusion and cardiomyocyte contractility and morphology under normal conditions and during oxidative stress. METHODS: Cardiac function was measured in isolated and perfused rat hearts before and after 40 minutes' global normothermic ischaemia. Where used, 0.1 mM L-homocysteine was present prior to, and throughout ischaemia, before wash out after 10 minutes' reperfusion. Calcium transients under normal conditions and changes in contractile synchronicity during oxidative stress (exposure to 0.2 mM H2O2) were measured in freshly isolated rat cardiomyocytes incubated for 60 minutes +/- 0.1 mM L-homocysteine. RESULTS: During ischaemia reperfusion 0.1 mM L-homocysteine significantly reduced the rate pressure product during reperfusion (10,038 +/- 749 vs. 5955 +/- 567 mmHg bpm, p < 0.001), but did not affect time to ischaemic contracture. Incubation of freshly isolated cardiomyocytes with 0.1 mM L-homocysteine significantly decreased the amplitude of the calcium transient and slowed the time to half relaxation. CONCLUSIONS: These findings suggest that homocysteine exposure affected myocardial recovery from ischaemia and contractile homeostasis although the exact mechanisms for these changes remain to be determined. PMID- 26624799 TI - Large-Scale Prediction of Beneficial Drug Combinations Using Drug Efficacy and Target Profiles. AB - The identification of beneficial drug combinations is a challenging issue in pharmaceutical and clinical research toward combinatorial drug therapy. In the present study, we developed a novel computational method for large-scale prediction of beneficial drug combinations using drug efficacy and target profiles. We designed an informative descriptor for each drug-drug pair based on multiple drug profiles representing drug-targeted proteins and Anatomical Therapeutic Chemical Classification System codes. Then, we constructed a predictive model by learning a sparsity-induced classifier based on known drug combinations from the Orange Book and KEGG DRUG databases. Our results show that the proposed method outperforms the previous methods in terms of the accuracy of high-confidence predictions, and the extracted features are biologically meaningful. Finally, we performed a comprehensive prediction of novel drug combinations for 2,639 approved drugs, which predicted 142,988 new potentially beneficial drug-drug pairs. We showed several examples of successfully predicted drug combinations for a variety of diseases. PMID- 26624801 TI - Asymmetric Copper-Catalyzed Carbozincation of Cyclopropenes en Route to the Formation of Diastereo- and Enantiomerically Enriched Polysubstituted Cyclopropanes. AB - The enantioselective synthesis of cyclopropylzinc reagents has been achieved via a copper-catalyzed carbozincation of 3,3-disubstituted cyclopropenes with diorganozinc reagents. The obtained organozinc compounds can be easily functionalized with a broad range of electrophiles, including palladium-catalyzed cross-couplings, affording highly substituted cyclopropanes. The operationally simple procedure using very low quantities of a commercially available and inexpensive copper catalyst provides a new tool for the synthesis of highly enantioenriched cyclopropanes as single diastereoisomers. PMID- 26624800 TI - HMGB1 induced inflammatory effect is blocked by CRISPLD2 via MiR155 in hepatic fibrogenesis. AB - A number of studies have showed that High mobility group box-1 (HMGB1), which played key role in inflammation activation by triggering the toll like receptor 4 (TLR4) signaling axis in hepatic fibrogenesis, may share similar inflammation stimulating mechanism with LPS. Herein, we introduced a recently established anti LPS protein cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2) to investigate endogenous protection mechanism of HMGB1 induced inflammatory response. Our results shows that stromal cells and monocytes showed an evaluated pattern for CRISPLD2 expression after HMGB1 treatment, which was dependent on the integrity of TLR4 function. Pro-inflammatory Cytokines levels were significantly elevated after CRISPLD2 silencing despite the HMGB1 status. Soluble CRISPLD2 administration relieve the HMGB1 dependent pro-inflammatory cytokines release. Interestingly, we found that miRNA 155 play a key role in the process. Our data suggest that CRISPLD2 may have a unique anti-HMGB1 effect via miRNA and play an important role in immune balance. PMID- 26624802 TI - Intrapartum fetal heart rate patterns of trisomy 21 fetuses: A case-control study. AB - BACKGROUND/AIM: To determine whether there are specific characteristic intrapartum heart rate patterns for fetuses with trisomy 21(T21). BACKGROUND STUDY DESIGN/PATIENTS: Intrapartum fetal heart rate (FHR) tracings of T21 fetuses were compared to those of euploid fetuses in a retrospective, observational, matched, case-control study. The study group consisted of 42 fetuses with T21 and 42 matched euploid controls. Matching was designed to accommodate possible confounders. The sign test and McNemar's test were used for categorical variables. The paired t test was used for comparison between quantitative variables. RESULTS: Intrapartum baseline FHR of fetuses with T21 was found to be slightly decreased compared to controls (122.5 vs 129.05 beats per minute, p=0.028). No differences were detected in the presence of periodic changes, or FHR variability between the groups. CONCLUSION: When evaluating intrapartum FHR of fetuses with T21, decreased baseline FHR can be expected. PMID- 26624803 TI - Evaluation of the relationship between opioid exposure in extremely low birth weight infants in the neonatal intensive care unit and neurodevelopmental outcome at 2 years. AB - BACKGROUND: Extremely low birth weight (ELBW) infants are exposed to many painful procedures while in the neonatal intensive care unit (NICU), such as catheter insertion and endotracheal intubation. Exposure of ELBW infants to repetitive pain and stress in the NICU can lead to cardiovascular instability and may alter neuronal and synaptic organization. Opioid analgesics are administered to reduce pain, stress and to potentially reduce poor neurologic outcomes. They may also be utilized as sedation for mechanically ventilated ELBW infants. There is limited data in regards to neurodevelopmental outcomes of preterm infants exposed to opioids, and available studies have conflicting results. OBJECTIVE: To examine the relationship between cumulative opioid dose in ELBW infants in the NICU and neurodevelopmental outcomes at 20 months corrected age (CA). STUDY DESIGN: 100 ELBW infants who had complete neurodevelopmental assessments at 20 months CA were categorized by cumulative opioid exposure during the NICU stay (high vs. low/no opioid). Outcome measures included cognitive, motor and language scores from the Bayley Scales of Infant and Toddler Development-III (BSITD-III). Multiple regression analyses adjusted for the impact of social and neonatal risk factors on outcome. RESULTS: There were 60 patients with high and 40 with low/no opioid exposure. Infants in the high dose group had a higher number of median ventilator days (53.5 vs. 45.6 days, p=0.046) and a higher incidence of necrotizing enterocolitis (5% vs. 21.7%, p=0.022). There were no significant differences in BSITD-III scores between the two opiate groups. In multivariate analysis cumulative opioid dose was associated with lower cognitive scores on the BSITD III even after adjusting for social and neonatal risk factors (beta=-0.247, p=0.012). CONCLUSION: Cumulative opioid dose is associated with worse cognitive scores at 20 months CA even after adjusting for social and neonatal risk factors. PMID- 26624804 TI - Copper Oxidation/Reduction in Water and Protein: Studies with DFTB3/MM and VALBOND Molecular Dynamics Simulations. AB - We apply two recently developed computational methods, DFTB3 and VALBOND, to study copper oxidation/reduction processes in solution and protein. The properties of interest include the coordination structure of copper in different oxidation states in water or in a protein (plastocyanin) active site, the reduction potential of the copper ion in different environments, and the environmental response to copper oxidation. The DFTB3/MM and VALBOND simulation results are compared to DFT/MM simulations and experimental results whenever possible. For a copper ion in aqueous solution, DFTB3/MM results are generally close to B3LYP/MM with a medium basis, including both solvation structure and reduction potential for Cu(II); for Cu(I), however, DFTB3/MM finds a two-water coordination, similar to previous Born-Oppenheimer molecular dynamics simulations using BLYP and HSE, whereas B3LYP/MM leads to a tetrahedron coordination. For a tetraammonia copper complex in aqueous solution, VALBOND and DFTB3/MM are consistent in terms of both structural and dynamical properties of solvent near copper for both oxidation states. For copper reduction in plastocyanin, DFTB3/MM simulations capture the key properties of the active site, and the computed reduction potential and reorganization energy are in fair agreement with experiment, especially when the periodic boundary condition is used. Overall, the study supports the value of VALBOND and DFTB3(/MM) for the analysis of fundamental copper redox chemistry in water and protein, and the results also help highlight areas where further improvements in these methods are desirable. PMID- 26624806 TI - Intramolecular sp(3) Functionalization of Cyclopropyl alpha-Amino Acid-Derived Benzamides. AB - Intramolecular Pd-catalyzed functionalization of cyclopropyl alpha-amino acid derived benzamides proceeds without silver or pivalate additives. Both electronically and sterically diverse ethyl 1,2,3,4-tetrahydroisoquinolone-3 carboxylates were accessible in good to excellent yields. PMID- 26624805 TI - Controlled and targeted release of antigens by intelligent shell for improving applicability of oral vaccines. AB - Conventional oral vaccines with simple architecture face barriers with regard to stimulating effective immunity. Here we describe oral vaccines with an intelligent phase-transitional shielding layer, poly[(methyl methacrylate)-co (methyl acrylate)-co-(methacrylic acid)]-poly(D,L-lactide-co-glycolide) (PMMMA PLGA), which can protect antigens in the gastro-intestinal tract and achieve targeted vaccination in the large intestine. With the surface immunogenic protein (SIP) from group B Streptococcus (GBS) entrapped as the antigen, oral administration with PMMMA-PLGA (PTRBL)/Trx-SIP nanoparticles stimulated robust immunity in tilapia, an animal with a relatively simple immune system. The vaccine succeeded in protecting against Streptococcus agalactiae, a pathogen of worldwide importance that threatens human health and is transmitted in water with infected fish. After oral vaccination with PTRBL/Trx-SIP, tilapia produced enhanced levels of SIP specific antibodies and displayed durability of immune protection. 100% of the vaccinated tilapia were protected from GBS infection, whereas the control groups without vaccines or vaccinated with Trx-SIP only exhibited respective infection rates of 100% or >60% within the initial 5 months after primary vaccination. Experiments in vivo demonstrated that the recombinant antigen Trx-SIP labeled with FITC was localized in colon, spleen and kidney, which are critical sites for mounting an immune response. Our results revealed that, rather than the size of the nanoparticles, it is more likely that the negative charge repulsion produced by ionization of the carboxyl groups in PMMMA shielded the nanoparticles from uptake by small intestinal epithelial cells. This system resolves challenges arising from gastrointestinal damage to antigens, and more importantly, offers a new approach applicable for oral vaccination. PMID- 26624807 TI - Erratum for Euro Surveill. 2015;20(46). PMID- 26624808 TI - What if the Electrical Conductivity of Graphene Is Significantly Deteriorated for the Graphene-Semiconductor Composite-Based Photocatalysis? AB - The extraordinary electrical conductivity of graphene has been widely regarded as the bible in literature to explain the activity enhancement of graphene semiconductor composite photocatalysts. However, from the viewpoint of an entire composite-based artificial photosynthetic system, the significant matter of photocatalytic performance of graphene-semiconductor composite system is not just a simple and only issue of excellent electrical conductivity of graphene. Herein, the intentional design of melamine resin monomers functionalized three dimensional (3D) graphene (donated as MRGO) with significantly deteriorated electrical conductivity enables us to independently focus on studying the geometry effect of MRGO on the photocatalytic performance of graphene semiconductor composite. By coupling semiconductor CdS with graphene, including MRGO and reduced graphene oxide (RGO), it was found that the CdS-MRGO composites exhibit much higher visible light photoactivity than CdS-RGO composites although the electrical conductivity of MRGO is remarkably much lower than that of RGO. The comparison characterizations evidence that such photoactivity enhancement is predominantly attributed to the restacking-inhibited 3D architectural morphology of MRGO, by which the synergistic effects of boosted separation and transportation of photogenerated charge carriers and increased adsorption capacity can be achieved. Our work highlights that the significant matter of photocatalytic performance of graphene-semiconductor composite is not a simple issue on how to harness the electrical conductivity of graphene but the rational ensemble design of graphene-semiconductor composite, which includes the integrative optimization of geometrical and electrical factors of individual component and the interface composition. PMID- 26624809 TI - S-Shaped Conformation of the Quaterthiophene Molecular Backbone in Two Dimensional Bisterpyridine-Derivative Self-Assembled Nanoarchitecture. AB - The conformation and the two-dimensional self-assembly of 4'-(3',4"-dihexyloxy 5,2':5',2":5",2'''-quaterthien-2,5'''-diyl)-bis(2,2':6',2"-terpyridine) molecules are theoretically and experimentally investigated. This molecular building block forms a hydrogen-bonded chiral supramolecular nanoarchitecture on graphite at the solid/liquid interface. Scanning tunneling microscopy (STM) shows that the molecule adopts an S-shaped conformation in this structure. DFTB+ calculations reveal that this conformation is not the lowest-energy conformation. The molecular nanoarchitecture appears to be stabilized by hydrogen bonding as well as van der Waals interactions. I-, L-, and D-shaped molecular conformations are, however, locally observed at the domain boundary, but these conformations do not self-assemble into organized 2D structures. PMID- 26624812 TI - Boy and the Candle: Gerard Sekoto. PMID- 26624813 TI - AAMC Report Examines How to Increase the Pipeline of Black Men Entering Medical School. PMID- 26624814 TI - A Healthy Living Wage. PMID- 26624821 TI - Harnessing the Right Combination of Extrinsic and Intrinsic Motivation to Change Physician Behavior. PMID- 26624822 TI - A PIECE OF MY MIND. Every Little Anniversary. PMID- 26624823 TI - Cesarean Delivery Rates: Revisiting a 3-Decades-Old Dogma. PMID- 26624825 TI - Relationship Between Cesarean Delivery Rate and Maternal and Neonatal Mortality. AB - IMPORTANCE: Based on older analyses, the World Health Organization (WHO) recommends that cesarean delivery rates should not exceed 10 to 15 per 100 live births to optimize maternal and neonatal outcomes. OBJECTIVES: To estimate the contemporary relationship between national levels of cesarean delivery and maternal and neonatal mortality. DESIGN, SETTING, AND PARTICIPANTS: Cross sectional, ecological study estimating annual cesarean delivery rates from data collected during 2005 to 2012 for all 194 WHO member states. The year of analysis was 2012. Cesarean delivery rates were available for 54 countries for 2012. For the 118 countries for which 2012 data were not available, the 2012 cesarean delivery rate was imputed from other years. For the 22 countries for which no cesarean rate data were available, the rate was imputed from total health expenditure per capita, fertility rate, life expectancy, percent of urban population, and geographic region. EXPOSURES: Cesarean delivery rate. MAIN OUTCOMES AND MEASURES: The relationship between population-level cesarean delivery rate and maternal mortality ratios (maternal death from pregnancy related causes during pregnancy or up to 42 days postpartum per 100,000 live births) or neonatal mortality rates (neonatal mortality before age 28 days per 1000 live births). RESULTS: The estimated number of cesarean deliveries in 2012 was 22.9 million (95% CI, 22.5 million to 23.2 million). At a country-level, cesarean delivery rate estimates up to 19.1 per 100 live births (95% CI, 16.3 to 21.9) and 19.4 per 100 live births (95% CI, 18.6 to 20.3) were inversely correlated with maternal mortality ratio (adjusted slope coefficient, -10.1; 95% CI, -16.8 to -3.4; P = .003) and neonatal mortality rate (adjusted slope coefficient, -0.8; 95% CI, -1.1 to -0.5; P < .001), respectively (adjusted for total health expenditure per capita, population, percent of urban population, fertility rate, and region). Higher cesarean delivery rates were not correlated with maternal or neonatal mortality at a country level. A sensitivity analysis including only 76 countries with the highest-quality cesarean delivery rate information had a similar result: cesarean delivery rates greater than 6.9 to 20.1 per 100 live births were inversely correlated with the maternal mortality ratio (slope coefficient, -21.3; 95% CI, -32.2 to -10.5, P < .001). Cesarean delivery rates of 12.6 to 24.0 per 100 live births were inversely correlated with neonatal mortality (slope coefficient, -1.4; 95% CI, -2.3 to -0.4; P = .004). CONCLUSIONS AND RELEVANCE: National cesarean delivery rates of up to approximately 19 per 100 live births were associated with lower maternal or neonatal mortality among WHO member states. Previously recommended national target rates for cesarean deliveries may be too low. PMID- 26624827 TI - CPAP vs Mandibular Advancement Devices and Blood Pressure in Patients With Obstructive Sleep Apnea: A Systematic Review and Meta-analysis. AB - IMPORTANCE: Obstructive sleep apnea is associated with higher levels of blood pressure (BP), which can lead to increased cardiovascular risk. OBJECTIVE: To compare the association of continuous positive airway pressure (CPAP), mandibular advancement devices (MADs), and inactive control groups (placebo or no treatment) with changes in systolic BP (SBP) and diastolic BP (DBP) in patients with obstructive sleep apnea. DATA SOURCES: The databases of MEDLINE, EMBASE, and the Cochrane Library were searched up to the end of August 2015 and study bibliographies were reviewed. STUDY SELECTION: Randomized clinical trials comparing the effect of CPAP or MADs (vs each other or an inactive control) on BP in patients with obstructive sleep apnea were selected by consensus. Of 872 studies initially identified, 51 were selected for analysis. DATA EXTRACTION AND SYNTHESIS: Data were extracted by one reviewer and checked by another reviewer. A network meta-analysis using multivariate random-effects meta-regression was used to estimate pooled differences between each intervention. Meta-regression was used to assess the association between trial characteristics and the reported effects of CPAP vs inactive control. MAIN OUTCOMES AND MEASURES: Absolute change in SBP and DBP from baseline to follow-up. RESULTS: Of the 51 studies included in the analysis (4888 patients), 44 compared CPAP with an inactive control, 3 compared MADs with an inactive control, 1 compared CPAP with an MAD, and 3 compared CPAP, MADs, and an inactive control. Compared with an inactive control, CPAP was associated with a reduction in SBP of 2.5 mm Hg (95% CI, 1.5 to 3.5 mm Hg; P < .001) and in DBP of 2.0 mm Hg (95% CI, 1.3 to 2.7 mm Hg; P < .001). A 1 hour-per-night increase in mean CPAP use was associated with an additional reduction in SBP of 1.5 mm Hg (95% CI, 0.8 to 2.3 mm Hg; P < .001) and an additional reduction in DBP of 0.9 mm Hg (95% CI, 0.3 to 1.4 mm Hg; P = .001). Compared with an inactive control, MADs were associated with a reduction in SBP of 2.1 mm Hg (95% CI, 0.8 to 3.4 mm Hg; P = .002) and in DBP of 1.9 mm Hg (95% CI, 0.5 to 3.2 mm Hg; P = .008). There was no significant difference between CPAP and MADs in their association with change in SBP (-0.5 mm Hg [95% CI, -2.0 to 1.0 mm Hg]; P = .55) or in DBP (-0.2 mm Hg [95% CI, -1.6 to 1.3 mm Hg]; P = .82). CONCLUSIONS AND RELEVANCE: Among patients with obstructive sleep apnea, both CPAP and MADs were associated with reductions in BP. Network meta-analysis did not identify a statistically significant difference between the BP outcomes associated with these therapies. PMID- 26624824 TI - Effect of Metformin Added to Insulin on Glycemic Control Among Overweight/Obese Adolescents With Type 1 Diabetes: A Randomized Clinical Trial. AB - IMPORTANCE: Previous studies assessing the effect of metformin on glycemic control in adolescents with type 1 diabetes have produced inconclusive results. OBJECTIVE: To assess the efficacy and safety of metformin as an adjunct to insulin in treating overweight adolescents with type 1 diabetes. DESIGN, SETTING, AND PARTICIPANTS: Multicenter (26 pediatric endocrinology clinics), double-blind, placebo-controlled randomized clinical trial involving 140 adolescents aged 12.1 to 19.6 years (mean [SD] 15.3 [1.7] years) with mean type 1 diabetes duration 7.0 (3.3) years, mean body mass index (BMI) 94th (4) percentile, mean total daily insulin 1.1 (0.2) U/kg, and mean HbA1c 8.8% (0.7%). INTERVENTIONS: Randomization to receive metformin (n = 71) (<=2000 mg/d) or placebo (n = 69). MAIN OUTCOMES AND MEASURES: Primary outcome was change in HbA1c from baseline to 26 weeks adjusted for baseline HbA1c. Secondary outcomes included change in blinded continuous glucose monitor indices, total daily insulin, BMI, waist circumference, body composition, blood pressure, and lipids. RESULTS: Between October 2013 and February 2014, 140 participants were enrolled. Baseline HbA1c was 8.8% in each group. At 13-week follow-up, reduction in HbA1c was greater with metformin (-0.2%) than placebo (0.1%; mean difference, -0.3% [95% CI, -0.6% to 0.0%]; P = .02). However, this differential effect was not sustained at 26-week follow up when mean change in HbA1c from baseline was 0.2% in each group (mean difference, 0% [95% CI, -0.3% to 0.3%]; P = .92). At 26-week follow-up, total daily insulin per kg of body weight was reduced by at least 25% from baseline among 23% (16) of participants in the metformin group vs 1% (1) of participants in the placebo group (mean difference, 21% [95% CI, 11% to 32%]; P = .003), and 24% (17) of participants in the metformin group and 7% (5) of participants in the placebo group had a reduction in BMI z score of 10% or greater from baseline to 26 weeks (mean difference, 17% [95% CI, 5% to 29%]; P = .01). Gastrointestinal adverse events were reported by more participants in the metformin group than in the placebo group (mean difference, 36% [95% CI, 19% to 51%]; P < .001). CONCLUSIONS AND RELEVANCE: Among overweight adolescents with type 1 diabetes, the addition of metformin to insulin did not improve glycemic control after 6 months. Of multiple secondary end points, findings favored metformin only for insulin dose and measures of adiposity; conversely, use of metformin resulted in an increased risk for gastrointestinal adverse events. These results do not support prescribing metformin to overweight adolescents with type 1 diabetes to improve glycemic control. TRIAL REGISTRATION: clinicaltrials.org Identifier: NCT01881828. PMID- 26624828 TI - Dose-Finding Trials: Optimizing Phase 2 Data in the Drug Development Process. PMID- 26624826 TI - Planned Cesarean Delivery at Term and Adverse Outcomes in Childhood Health. AB - IMPORTANCE: Planned cesarean delivery comprises a significant proportion of births globally, with combined rates of planned and unscheduled cesarean delivery in a number of regions approaching 50%. Observational studies have shown that offspring born by cesarean delivery are at increased risk of ill health in childhood, but these studies have been unable to adjust for some key confounding variables. Additionally, risk of death beyond the neonatal period has not yet been reported for offspring born by planned cesarean delivery. OBJECTIVE: To investigate the relationship between planned cesarean delivery and offspring health problems or death in childhood. DESIGN, SETTING, AND PARTICIPANTS: Population-based data-linkage study of 321,287 term singleton first-born offspring born in Scotland, United Kingdom, between 1993 and 2007, with follow-up until February 2015. EXPOSURES: Offspring born by planned cesarean delivery in a first pregnancy were compared with offspring born by unscheduled cesarean delivery and with offspring delivered vaginally. MAIN OUTCOMES AND MEASURES: The primary outcome was asthma requiring hospital admission; secondary outcomes were salbutamol inhaler prescription at age 5 years, obesity at age 5 years, inflammatory bowel disease, type 1 diabetes, cancer, and death. RESULTS: Compared with offspring born by unscheduled cesarean delivery (n = 56,015 [17.4%]), those born by planned cesarean delivery (12,355 [3.8%]) were at no significantly different risk of asthma requiring hospital admission, salbutamol inhaler prescription at age 5 years, obesity at age 5 years, inflammatory bowel disease, cancer, or death but were at increased risk of type 1 diabetes (0.66% vs 0.44%; difference, 0.22% [95% CI, 0.13%-0.31%]; adjusted hazard ratio [HR], 1.35 [95% CI, 1.05-1.75]). In comparison with children born vaginally (n = 252,917 [78.7%]), offspring born by planned cesarean delivery were at increased risk of asthma requiring hospital admission (3.73% vs 3.41%; difference, 0.32% [95% CI, 0.21%-0.42%]; adjusted HR, 1.22 [95% CI, 1.11-1.34]), salbutamol inhaler prescription at age 5 years (10.34% vs 9.62%; difference, 0.72% [95% CI, 0.36% 1.07%]; adjusted HR, 1.13 [95% CI, 1.01-1.26]), and death (0.40% vs 0.32%; difference, 0.08% [95% CI, 0.02%-1.00%]; adjusted HR, 1.41 [95% CI, 1.05-1.90]), whereas there were no significant differences in risk of obesity at age 5 years, inflammatory bowel disease, type 1 diabetes, or cancer. CONCLUSIONS AND RELEVANCE: Among offspring of women with first births in Scotland between 1993 and 2007, planned cesarean delivery compared with vaginal delivery (but not compared with unscheduled cesarean delivery) was associated with a small absolute increased risk of asthma requiring hospital admission, salbutamol inhaler prescription at age 5 years, and all-cause death by age 21 years. Further investigation is needed to understand whether the observed associations are causal. PMID- 26624829 TI - Stomatitis, Cutaneous Bullae, and Renal Failure. PMID- 26624830 TI - Evolocumab (Repatha)--A Second PCSK9 Inhibitor to Lower LDL-Cholesterol. PMID- 26624831 TI - Chronic Conditions in Adults With Cerebral Palsy. PMID- 26624832 TI - The Art of JAMA Article. PMID- 26624833 TI - The Art of JAMA Article--Reply. PMID- 26624834 TI - Approaches to Prevention of Cardiovascular Disease. PMID- 26624835 TI - Approaches to Prevention of Cardiovascular Disease--Reply. PMID- 26624836 TI - Regulation of Powdered Alcohol. PMID- 26624837 TI - Regulation of Powdered Alcohol--Reply. PMID- 26624838 TI - Incorrect Date of Narrative. PMID- 26624841 TI - The Writer as Critic. PMID- 26624839 TI - Incorrect Nonproprietary Drug Name and Approved Use. PMID- 26624842 TI - JAMA PATIENT PAGE. PCSK9 Inhibitors for Treating High Cholesterol. PMID- 26624843 TI - Organic Covalent Patterning of Nanostructured Graphene with Selectivity at the Atomic Level. AB - Organic covalent functionalization of graphene with long-range periodicity is highly desirable-it is anticipated to provide control over its electronic, optical, or magnetic properties-and remarkably challenging. In this work we describe a method for the covalent modification of graphene with strict spatial periodicity at the nanometer scale. The periodic landscape is provided by a single monolayer of graphene grown on Ru(0001) that presents a moire pattern due to the mismatch between the carbon and ruthenium hexagonal lattices. The moire contains periodically arranged areas where the graphene-ruthenium interaction is enhanced and shows higher chemical reactivity. This phenomenon is demonstrated by the attachment of cyanomethyl radicals (CH2CN(*)) produced by homolytic breaking of acetonitrile (CH3CN), which is shown to present a nearly complete selectivity (>98%) binding covalently to graphene on specific atomic sites. This method can be extended to other organic nitriles, paving the way for the attachment of functional molecules. PMID- 26624844 TI - 4-Phenylpyridin-2-one Derivatives: A Novel Class of Positive Allosteric Modulator of the M1 Muscarinic Acetylcholine Receptor. AB - Positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (M1 mAChR) are a promising strategy for the treatment of the cognitive deficits associated with diseases including Alzheimer's and schizophrenia. Herein, we report the design, synthesis, and characterization of a novel family of M1 mAChR PAMs. The most active compounds of the 4-phenylpyridin-2-one series exhibited comparable binding affinity to the reference compound, 1-(4-methoxybenzyl)-4-oxo 1,4-dihydroquinoline-3-carboxylic acid (BQCA) (1), but markedly improved positive cooperativity with acetylcholine, and retained exquisite selectivity for the M1 mAChR. Furthermore, our pharmacological characterization revealed ligands with a diverse range of activities, including modulators that displayed both high intrinsic efficacy and PAM activity, those that showed no detectable agonism but robust PAM activity and ligands that displayed robust allosteric agonism but little modulatory activity. Thus, the 4-phenylpyridin-2-one scaffold offers an attractive starting point for further lead optimization. PMID- 26624849 TI - Treatment of hepatitis C virus infection for adults and children: Updated Swedish consensus recommendations. AB - In a recent expert meeting, Swedish recommendations for the treatment of HCV infection were updated. An interferon-free combination of direct-acting antiviral agents was recommended as the first line standard-of-care treatment for chronic HCV infection. Interferon-based therapy should be considered as a second line option after an individual benefit-risk assessment. Treatment is strongly recommended for HCV infected patients with bridging fibrosis or cirrhosis (Metavir stages F3-4), before and after liver transplantation, and in the presence of extra-hepatic manifestations. Additionally, patients with moderate liver fibrosis (stage F2) as well as women in need of in vitro fertilisation should be prioritised for therapeutic intervention. Treatment indications for people who inject drugs, children, chronic kidney disease and HIV co-infection are also discussed. PMID- 26624852 TI - Association of the Polymorphism in Nucleobindin 2 Gene and the Risk of Metabolic Syndrome. AB - OBJECTIVE: Nesfatin-1, originates from the precursor protein nucleobindin 2 (NUCB2) and plays an important role in the development of metabolic syndrome (MetS), including obesity and hypertension. This study aimed to determine whether the 1012C>G polymorphism of NUCB2 gene is correlated with the development of MetS in the Chinese Han population. MATERIALS AND METHODS: The 1012C>G polymorphism of NUCB2 gene was detected in a population of 326 patients with MetS and 165 healthy subjects. RESULTS: MetS patients showed lower CG and GG genotypes, as well as lower G allele frequencies, compared with healthy subjects. Unconditional logistic regression analysis showed that the GG genotype as well as the G allele were both significantly associated with the decreased risk of developing MetS. In addition, the GG genotype of NUCB2 was significantly correlated with lower levels of waist circumference, body mass index, and fasting plasma glucose in patients with MetS. CONCLUSIONS: 1012C>G polymorphism of NUCB2 is correlated with a reduced risk of developing MetS in a Chinese Han population. PMID- 26624851 TI - CARE Track for Advanced Cancer: Impact and Timing of an Outpatient Palliative Care Clinic. AB - BACKGROUND: Studies suggest that outpatient palliative care can reduce hospitalization and increase hospice utilization for patients with cancer, however there are insufficient resources to provide palliative care to all patients from time of diagnosis. It is also unclear whether inpatient consultation alone provides similar benefits. A better understanding of the timing, setting, and impact of palliative care for patients with cancer is needed. OBJECTIVES: The purpose of this study was to measure timing of referral to outpatient palliative care and impact on end-of-life (EOL) care. DESIGN: The Comprehensive Assessment with Rapid Evaluation and Treatment (CARE Track) program is a phased intervention integrating outpatient palliative care into cancer care. In Year 1 patients were referred at the discretion of their oncologist. SETTING: Academic medical center. MEASUREMENTS: We compared EOL hospitalization, hospice utilization, and costs of care for CARE Track patients compared to those never seen by palliative care or seen only in hospital. RESULTS: Patients were referred a median of 72.5 days prior to death. CARE Track patients had few hospitalizations at end of life, were less likely to die in hospital, had increased hospice utilization, and decreased costs of care; these results were significant even after controlling for differences between groups. Inpatient consultation alone did not impact these variables. However, only approximately half of patients with incurable cancers were referred to this program. CONCLUSION: Referral outpatient palliative care within 3 months of death improved EOL care and reduced costs, benefits not seen with inpatient care only. However, many patients were never referred, and methods of systematically identifying appropriate patients are needed. PMID- 26624853 TI - Introduction. PMID- 26624850 TI - On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection. AB - BACKGROUND: Antiretroviral preexposure prophylaxis has been shown to reduce the risk of human immunodeficiency virus type 1 (HIV-1) infection in some studies, but conflicting results have been reported among studies, probably due to challenges of adherence to a daily regimen. METHODS: We conducted a double-blind, randomized trial of antiretroviral therapy for preexposure HIV-1 prophylaxis among men who have unprotected anal sex with men. Participants were randomly assigned to take a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) or placebo before and after sexual activity. All participants received risk-reduction counseling and condoms and were regularly tested for HIV 1 and HIV-2 and other sexually transmitted infections. RESULTS: Of the 414 participants who underwent randomization, 400 who did not have HIV infection were enrolled (199 in the TDF-FTC group and 201 in the placebo group). All participants were followed for a median of 9.3 months (interquartile range, 4.9 to 20.6). A total of 16 HIV-1 infections occurred during follow-up, 2 in the TDF FTC group (incidence, 0.91 per 100 person-years) and 14 in the placebo group (incidence, 6.60 per 100 person-years), a relative reduction in the TDF-FTC group of 86% (95% confidence interval, 40 to 98; P=0.002). Participants took a median of 15 pills of TDF-FTC or placebo per month (P=0.57). The rates of serious adverse events were similar in the two study groups. In the TDF-FTC group, as compared with the placebo group, there were higher rates of gastrointestinal adverse events (14% vs. 5%, P=0.002) and renal adverse events (18% vs. 10%, P=0.03). CONCLUSIONS: The use of TDF-FTC before and after sexual activity provided protection against HIV-1 infection in men who have sex with men. The treatment was associated with increased rates of gastrointestinal and renal adverse events. (Funded by the National Agency of Research on AIDS and Viral Hepatitis [ANRS] and others; ClinicalTrials.gov number, NCT01473472.). PMID- 26624854 TI - Prediction of 1-year mortality and impact of bivalirudin therapy according to level of baseline risk: A patient-level pooled analysis from three randomized trials. AB - OBJECTIVES: We aimed to construct a predictive model for one-year mortality in patients undergoing invasive coronary evaluation and to examine the impact of bivalirudin on survival according to the level of baseline risk. BACKGROUND: Compared to heparin plus GP IIb/IIIa inhibitors (HEP/GPI), bivalirudin decreases bleeding complications in a range of clinical presentations. The impact of preprocedural risk assessment on survival and whether this is modified by bivalirudin, has not been investigated in detail. METHODS: We examined patient level data from the REPLACE-2, ACUITY, and HORIZONS-AMI trials (n = 18,819) to construct a risk-adjusted mortality model using baseline clinical variables. RESULTS: One-year mortality occurred in 287 patients (3.1%) assigned to bivalirudin and 336 patients (3.6%) assigned to HEP/GPI (HR 0.85; 95% CI, 0.73 1.00; P = 0.048). Using 11 highly significant predictors of mortality, we developed an integer-risk score to classify patients into risk tertiles. High risk patients had a rate of 1-year mortality over 9-fold greater than low-risk patients. Consequently, the absolute mortality reduction attributed to bivalirudin was more marked in high-risk patients: 3.1% (-0.8% to 7.0%) in the overall cohort, 4.8% (0.5% to 9.2%) in the PCI cohort (P-interaction versus intermediate and low risk categories, 0.09 and P = 0.02, respectively). CONCLUSIONS: In patients undergoing invasive coronary evaluation, 1-year mortality can be predicted using baseline variables. Bivalirudin treatment (versus HEP/GPI) conferred a survival benefit. PMID- 26624856 TI - Impact of medically recalcitrant chronic rhinosinusitis on incidence of asthma. AB - BACKGROUND: The long-term impact of chronic rhinosinusitis (CRS) with or without allergic rhinitis (AR) on asthma is poorly documented. This study analyzed potential associations of ongoing CRS and AR on asthma. METHODS: Using the MarketScanTM claims database, patients with CRS and endoscopic sinus surgery (ESS) in 2010 were identified. The date of first sinusitis was determined for all. Patients with asthma at time of first sinusitis diagnosis were excluded. The remaining patients were grouped based on duration of sinusitis, from first diagnosis to surgery-group 1: 1 to <2 years (n = 181); group 2: 2 to <3 years (n = 195); group 3: 3 to <4 years (n = 292); and group 4: 4 to <5 years (n = 536). Yearly incidence and prevalence of newly diagnosed asthmatics was analyzed for all groups. A secondary analysis evaluated the association between AR and asthma. RESULTS: Preoperatively, yearly incidence of patients with new asthma diagnoses averaged 4.48% (95% confidence interval [CI], 3.93% to 5.11%) and was significantly greater for patients with AR (5.93%; 95% CI, 4.56% to 7.66%) vs non AR (4.15%; 95% CI, 3.56% to 4.82%); p = 0.03. Postoperatively, yearly incidence of asthma was 0.42% (95% CI, 0.18% to 0.88%). No patient had asthma at time of first diagnosis; however, by time of surgery, 9.4%, 12.8%, 18.2%, and 22.40% of patients had been diagnosed with asthma, in groups 1 through 4, respectively. CONCLUSION: AR was a significant risk factor for asthma in patients with CRS. Medically recalcitrant CRS was associated with high incidence rates of asthma, which declined post-operatively. Patients operated earlier in the disease continuum were therefore at decreased risk of developing asthma. PMID- 26624855 TI - Statin therapy and plasma free fatty acids: a systematic review and meta-analysis of controlled clinical trials. AB - AIM: The aim of this meta-analysis was to evaluate the effect of statin therapy on plasma FFA concentrations in a systematic review and meta-analysis of controlled clinical trials. METHODS: PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched (from inception to February 16 2015) to identify controlled trials evaluating the impact of statins on plasma FFA concentrations. A systematic assessment of bias in the included studies was performed using the Cochrane criteria. A random effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. Random effects meta-regression was performed using unrestricted maximum likelihood method to evaluate the impact of potential moderators. RESULTS: Meta-analysis of data from 14 treatment arms indicated a significant reduction in plasma FFA concentrations following treatment with statins (weighted mean difference (WMD) -19.42%, 95% CI -23.19, - 15.64, P < 0.001). Subgroup analysis confirmed the significance of the effect with both atorvastatin (WMD -20.56%, 95% CI -24.51, -16.61, P < 0.01) and simvastatin (WMD -18.05%, 95% CI -28.12, -7.99, P < 0.001). Changes in plasma FFA concentrations were independent of treatment duration (slope -0.10, 95% CI -0.30, 0.11, P = 0.354) and magnitude of reduction in plasma low density lipoprotein cholesterol concentrations (slope 0.55, 95% CI -0.17, 1.27, P = 0.133) by statins. CONCLUSIONS: The results of the present study suggest that statin therapy may lower plasma FFA concentrations. The cardiovascular and metabolic significance of this finding requires further investigation. PMID- 26624862 TI - Polymorphisms in period genes and bone response to hormone therapy in postmenopausal Korean women. AB - OBJECTIVE: In this study, we aimed to explore the association between polymorphisms in the period (PER) gene and bone response to hormone therapy (HT) in postmenopausal Korean women. METHODS: The PER1 c.2284C > G, c.2247C > T, PER2 c.3731G > A, PER3 c.2592G > A, c.3083T > C polymorphisms, and PER3 54bp variable number of tandem repeats (VNTR) were analyzed in 509 postmenopausal Korean women who received HT. Bone mineral density (BMD) at the lumbar spine and femoral neck before and after 1 year of HT and serum levels of osteoprotegerin (OPG), soluble receptor activator of the nuclear factor-kappaB ligand (sRANKL) and bone turnover markers were measured after 6 months of HT. RESULTS: The PER1 c.2884 C > G polymorphism and PER3 54bp VNTR were associated with annual percent changes in BMD of the femoral neck after 1 year of HT (p < 0.05). Changes in BMD at the femoral neck in the non-CC genotype of the PER1 c.2884C > G polymorphism and in the 4-repeat homozygote of PER3 54bp VNTR were significantly lower than those in CC genotype and non-4-repeat homozygote, respectively. The PER1 c.2884C > G polymorphism was associated with the non-response (>3% BMD loss/year after HT) of HT. The non-CC genotype of the PER1 c.2884C > G polymorphism showed a 1.92-times higher risk of non-response at the lumbar spine and/or femoral neck (p = 0.01) compared with the CC genotype. No significant changes in bone markers after 6 months of HT were noted according to the PER1 c.2884C > G polymorphism. CONCLUSIONS: The PER1 c.2884C > G polymorphism may be associated with risk of non response to HT in postmenopausal Korean women. PMID- 26624867 TI - Response to Letter to the Editor: Pulmonary Delivery of Dry Powders During Invasive Mechanical Ventilation: Innovations Are Required. PMID- 26624861 TI - Copper(II)-Promoted Cyclization/Difunctionalization of Allenols and Allenylsulfonamides: Synthesis of Heterocycle-Functionalized Vinyl Carboxylate Esters. AB - A unique method to affect intramolecular aminooxygenation and dioxygenation of allenols and allenylsulfonamides is described. These operationally simple reactions occur under neutral or basic conditions where copper(II) carboxylates serve as reaction promoter, oxidant, and carboxylate source. Moderate to high yields of heterocycle-functionalized vinyl carboxylate esters are formed with moderate to high levels of diastereoselectivity. Such vinyl carboxylate esters could serve as precursors to alpha-amino and alpha-oxy ketones and derivatives thereof. PMID- 26624868 TI - Enhanced encoding of the co-actor's target stimuli during a shared non-motor task. AB - Task co-representation has been proposed to rely on the motor brain areas' capacity to represent others' action plans similarly to one's own. The joint memory (JM) effect suggests that working in parallel with others influences the depth of incidental encoding: Other-relevant items are better encoded than non task-relevant items. Using this paradigm, we investigated whether task co representation could also emerge for non-motor tasks. In Experiment 1, we found enhanced recall performance to stimuli relevant to the co-actor also when the participants' task required non-motor responses (counting the target words) instead of key-presses. This suggests that the JM effect did not depend on simulating the co-actor's motor responses. In Experiment 2, direct visual access to the co-actor and his actions was found to be unnecessary to evoke the JM effect in case of the non-motor, but not in case of the motor task. Prior knowledge of the co-actor's target category is sufficient to evoke deeper incidental encoding. Overall, these findings indicate that the capacity of task co-representation extends beyond the realm of motor tasks: Simulating the other's motor actions is not necessary in this process. PMID- 26624881 TI - Pharmacotherapy for chronic cognitive impairment in traumatic brain injury. AB - BACKGROUND: Traumatic brain injury (TBI) is a major cause of chronic disability. Worldwide, it is the leading cause of disability in the under 40s, resulting in severe disability in some 150 to 200 million people per annum. In addition to mood and behavioural problems, cognition-particularly memory, attention and executive function-are commonly impaired by TBI. Cognitive problems following TBI are one of the most important factors in determining people's subjective well being and their quality of life. Drugs are widely used in an attempt to improve cognitive functions. Whilst cholinergic agents in TBI have been reviewed, there has not yet been a systematic review or meta-analysis of the effect on chronic cognitive problems of all centrally acting pharmacological agents. OBJECTIVES: To assess the effects of centrally acting pharmacological agents for treatment of chronic cognitive impairment subsequent to traumatic brain injury in adults. SEARCH METHODS: We searched ALOIS-the Cochrane Dementia and Cognitive Improvement Group's Specialised Register-on 16 November 2013, 23 February 2013, 20 January 2014, and 30 December 2014 using the terms: traumatic OR TBI OR "brain injury" OR "brain injuries" OR TBIs OR "axonal injury" OR "axonal injuries". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. Supplementary searches were also performed in MEDLINE, EMBASE, PsycINFO, The Cochrane Library, CINAHL, LILACs, ClinicalTrials.gov, the World Health Organization (WHO) Portal (ICTRP) and Web of Science with conference proceedings. SELECTION CRITERIA: We included randomised controlled trials (RCTs) assessing the effectiveness of any one centrally acting pharmacological agent that affects one or more of the main neurotransmitter systems in people with chronic traumatic brain injury; and there had to be a minimum of 12 months between the injury and entry into the trial. DATA COLLECTION AND ANALYSIS: Two review authors examined titles and abstracts of citations obtained from the search. Relevant articles were retrieved for further assessment. A bibliographic search of relevant papers was conducted. We extracted data using a standardised tool, which included data on the incidence of adverse effects. Where necessary we requested additional unpublished data from study authors. Risk of bias was assessed by a single author. MAIN RESULTS: Only four studies met the criteria for inclusion, with a total of 274 participants. Four pharmacological agents were investigated: modafinil (51 participants); (-)-OSU6162, a monoamine stabiliser (12 participants of which six had a TBI); atomoxetine (60 participants); and rivastigmine (157 participants). A meta-analysis could not be performed due to the small number and heterogeneity of the studies.All studies examined cognitive performance, with the majority of the psychometric sub-tests showing no difference between treatment and placebo (n = 274, very low quality evidence). For (-)-OSU6162 modest superiority over placebo was demonstrated on three measures, but markedly inferior performance on another. Rivastigmine was better than placebo on one primary measure, and a single cognitive outcome in a secondary analysis of a subgroup with more severe memory impairment at baseline. The study of modafinil assessed clinical global improvement (n = 51, low quality evidence), and did not find any difference between treatment and placebo. Safety, as measured by adverse events, was reported by all studies (n = 274, very low quality evidence), with significantly more nausea reported by participants who received rivastigmine compared to placebo. There were no other differences in safety between treatment and placebo. No studies reported any deaths. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether pharmacological treatment is effective in chronic cognitive impairment in TBI. Whilst there is a positive finding for rivastigmine on one primary measure, all other primary measures were not better than placebo. The positive findings for (-)-OSU6162 are interpreted cautiously as the study was small (n = 6). For modafinil and atomoxetine no positive effects were found. All four drugs appear to be relatively well tolerated, although evidence is sparse. PMID- 26624882 TI - Bisphosphonates enhance EGFR-TKIs efficacy in advanced NSCLC patients with EGFR activating mutation: A retrospective study. AB - BACKGROUND: Bisphosphonates have exhibited anti-tumor activity in non-small cell lung cancer (NSCLC). We aimed to evaluate whether the combination of bisphosphonates with tyrosine kinase inhibitors of EGFR (EGFR-TKIs) could obtain a synergistic effect on advanced NSCLC patients with EGFR mutations. METHODS: Between January 2008 and October 2013, 114 advanced EGFR mutations NSCLC patients who received EGFR-TKIs as first-line therapy were recruited from two cancer centers. Patients were separated into EGFR-TKIs alone or EGFR-TKIs plus bisphosphonates (combination) group. Median progression free survival (mPFS), median overall survival (mOS) distributions and survival curves were analyzed. RESULTS: Among the 114 patients, 62 had bone metastases (19 patients treated with EGFR-TKIs, 43 patients treated with EGFR-TKIs + bisphosphonates). Median PFS and OS were significantly improved in combination group compared with EGFR-TKIs group (mPFS: 15.0 vs 7.3 months, P = 0.0017; mOS: 25.2 vs 10.4 months, P = 0.0015) in patients with bone metastases. Among the 71 patients (19 patients with bone metastases) treated with EGFR-TKIs alone, patients with bone metastases had poor survival prognosis (mPFS:7.3 vs 12.1 months, P = 0.0434; mOS:10.4 vs 22.0 months, P = 0.0036). The survival of patients with bone metastases who received EGFR-TKIs plus bisphosphonates therapy was non-inferior to patients without bone metastases treated with EGFR-TKIs alone (mPFS: 15.0 vs 12.1 months, p = 0.1871; mOS: 25.2 vs 22.0 months, p = 0.9798). CONCLUSIONS: Concomitant use of bisphosphonates and EGFR-TKIs improves therapeutic efficacy and brings survival benefits to NSCLC patients with EGFR mutation and bone metastases. PMID- 26624884 TI - Perceived success/failure and attributions associated with self-regulatory efficacy to meet physical activity recommendations for women with arthritis. AB - The relationship between attributional dimensions women assign to the cause of their perceived success or failure at meeting the recommended physical activity dose and self-regulatory efficacy for future physical activity was examined among women with arthritis. Women (N = 117) aged 18-84 years, with self-reported medically-diagnosed arthritis, completed on-line questions in the fall of 2013 assessing endurance physical activity, perceived outcome for meeting the recommended levels of endurance activity, attributions for one's success or failure in meeting the recommendations, and self-regulatory efficacy to schedule/plan endurance activity over the next month. The main theoretically driven finding revealed that the interaction of the stability dimension with perceived success/failure was significantly related to self-regulatory efficacy for scheduling and planning future physical activity (beta = 0.35, p = .002). Outcomes attributed to more versus less stable factors accentuated differences in self-regulatory efficacy beliefs following perceived success and failure at being active. It appears that attributional dimensions were associated with self regulatory efficacy in women with arthritis. This suggests that rather than objectively observed past mastery experience, women's subjective perceptions and explanations of their past experiences were related to efficacy beliefs, especially following a failure experience. PMID- 26624883 TI - Immortalization of Fetal Bovine Colon Epithelial Cells by Expression of Human Cyclin D1, Mutant Cyclin Dependent Kinase 4, and Telomerase Reverse Transcriptase: An In Vitro Model for Bacterial Infection. AB - Cattle are the economically important animals in human society. They are essential for the production of livestock products such as milk and meats. The production efficiency of livestock products is negatively impacted by infection with zoonotic pathogens. To prevent and control infectious diseases, it is important to understand the interaction between cattle tissue and pathogenic bacteria. In this study, we established an in vitro infection model of an immortalized bovine colon-derived epithelial cell line by transducing the cells with lentiviral vectors containing genes encoding cell cycle regulators cyclin D1, mutant cyclin dependent kinase 4 (CDK4), and human telomerase reverse transcriptase (TERT). The established cell line showed continuous cell proliferation, expression of epithelial markers, and an intact karyotype, indicating that the cells maintained their original nature as colon-derived epithelium. Furthermore, we exposed the established cell line to two strains of Salmonella enterica and EHEC. Interestingly, S. Typhimurium showed higher affinity for the established cell line and invaded the cytoplasm than S. Enteritidis. Quantitative RT-PCR revealed that gene expression of Toll-like receptor 1 (TLR1), TLR 2 and TLR 3, whereas TLR 4, 5 and 6 were not detectable in established cells. Our established immortalized colon-derived epithelial cell should be a useful tool for studies evaluating the molecular mechanisms underlying bacterial infection. PMID- 26624885 TI - Introduction. PMID- 26624887 TI - Non-rigid dual respiratory and cardiac motion correction methods after, during, and before image reconstruction for 4D cardiac PET. AB - Respiratory motion (RM) and cardiac motion (CM) degrade the quality and resolution in cardiac PET scans. We have developed non-rigid motion estimation methods to estimate both RM and CM based on 4D cardiac gated PET data alone, and compensate the dual respiratory and cardiac (R&C) motions after (MCAR), during (MCDR), and before (MCBR) image reconstruction. In all three R&C motion correction methods, attenuation-activity mismatch effect was modeled by using transformed attenuation maps using the estimated RM. The difference of using activity preserving and non-activity preserving models in R&C correction was also studied. Realistic Monte Carlo simulated 4D cardiac PET data using the 4D XCAT phantom and accurate models of the scanner design parameters and performance characteristics at different noise levels were employed as the known truth and for method development and evaluation. Results from the simulation study suggested that all three dual R&C motion correction methods provide substantial improvement in the quality of 4D cardiac gated PET images as compared with no motion correction. Specifically, the MCDR method yields the best performance for all different noise levels compared with the MCAR and MCBR methods. While MCBR reduces computational time dramatically but the resultant 4D cardiac gated PET images has overall inferior image quality when compared to that from the MCAR and MCDR approaches in the 'almost' noise free case. Also, the MCBR method has better noise handling properties when compared with MCAR and provides better quantitative results in high noise cases. When the goal is to reduce scan time or patient radiation dose, MCDR and MCBR provide a good compromise between image quality and computational times. PMID- 26624886 TI - Reduced Cardiovascular Mortality 10 Years after Supplementation with Selenium and Coenzyme Q10 for Four Years: Follow-Up Results of a Prospective Randomized Double Blind Placebo-Controlled Trial in Elderly Citizens. AB - BACKGROUND: Selenium and coenzyme Q10 are important antioxidants in the body. As the intake of selenium is low in Europe, and the endogenous production of coenzyme Q10 decreases as age increases, an intervention trial using selenium and coenzyme Q10 for four years was performed. As previously reported, the intervention was accompanied by reduced cardiovascular mortality. The objective of the present study was to analyze cardiovascular mortality for up to 10 years after intervention, to evaluate if mortality differed in subgroups differentiated by gender, diabetes, ischemic heart disease (IHD), and functional class. METHODS: Four-hundred forty-three healthy elderly individuals were included from a rural municipality in Sweden. All cardiovascular mortality was registered, and no participant was lost to the follow-up. Based on death certificates and autopsy results mortality was registered. FINDINGS: Significantly reduced cardiovascular mortality could be seen in those on selenium and coenzyme Q10 intervention. A multivariate Cox regression analysis demonstrated a reduced cardiovascular mortality risk in the active treatment group (HR: 0.51; 95%CI 0.36-0.74; P = 0.0003). The reduced mortality could be seen to persist during the 10-year period. Subgroup analysis showed positive effects in both genders. An equally positive risk reduction could be seen in those with ischemic heart disease (HR: 0.51; 95%CI 0.27-0.97; P = 0.04), but also in the different functional classes. CONCLUSIONS: In a 10-year follow-up of a group of healthy elderly participants given four years of intervention with selenium and coenzyme Q10, significantly reduced cardiovascular mortality was observed. The protective action was not confined to the intervention period, but persisted during the follow-up period. The mechanism explaining the persistency remains to be elucidated. Since this was a small study, the observations should be regarded as hypothesis-generating. PMID- 26624889 TI - Flexible Sheet-Type Sensor for Noninvasive Measurement of Cellular Oxygen Metabolism on a Culture Dish. AB - A novel flexible sensor was developed for the noninvasive oxygen metabolism measurement of cultivated cells and tissues. This device is composed of a transparent double-layered polymer sheet of ethylene-vinyl alcohol (EVOH) and poly(dimethylsiloxane) (PDMS) having an array of microhole structures of 90 MUm diameter and 50 MUm depth on its surface. All the microhole structures were equipped with a 1-MUm-thick optical chemical sensing layer of platinum porphyrin fluoropolymer on their bottom. The three-dimensional microstructures of the sensor were fabricated by a newly developed simple and low-cost production method named self-aligned hot embossing. The device was designed to be attached slightly above the cells cultivated on a dish to form a temporarily closed microspace over the target cells during measurement. Since the change in oxygen concentration is relatively fast in the microcompartmentalized culture medium, a rapid evaluation of the oxygen consumption rate is possible by measuring the phosphorescence lifetime of the platinum porphyrin-fluoropolymer. The combined use of the device and an automated optical measurement system enabled the high-throughput sensing of cellular oxygen consumption (100 points/min). We monitored the oxygen metabolism of the human breast cancer cell line MCF7 on a Petri dish and evaluated the oxygen consumption rate to be 0.72 +/- 0.12 fmol/min/cell. Furthermore, to demonstrate the utility of the developed sensing system, we demonstrated the mapping of the oxygen consumption rate of rat brain slices and succeeded in visualizing a clear difference among the layer structures of the hippocampus, i.e., the cornu ammonis (CA1 and CA3) and dentate gyrus (DG). PMID- 26624888 TI - Biophysical Characterization of Nucleophosmin Interactions with Human Immunodeficiency Virus Rev and Herpes Simplex Virus US11. AB - Nucleophosmin (NPM1, also known as B23, numatrin or NO38) is a pentameric RNA binding protein with RNA and protein chaperon functions. NPM1 has increasingly emerged as a potential cellular factor that directly associates with viral proteins; however, the significance of these interactions in each case is still not clear. In this study, we have investigated the physical interaction of NPM1 with both human immunodeficiency virus type 1 (HIV-1) Rev and Herpes Simplex virus type 1 (HSV-1) US11, two functionally homologous proteins. Both viral proteins show, in mechanistically different modes, high affinity for a binding site on the N-terminal oligomerization domain of NPM1. Rev, additionally, exhibits low-affinity for the central histone-binding domain of NPM1. We also showed that the proapoptotic cyclic peptide CIGB-300 specifically binds to NPM1 oligomerization domain and blocks its association with Rev and US11. Moreover, HIV-1 virus production was significantly reduced in the cells treated with CIGB 300. Results of this study suggest that targeting NPM1 may represent a useful approach for antiviral intervention. PMID- 26624890 TI - Leptospira Serovars for Diagnosis of Leptospirosis in Humans and Animals in Africa: Common Leptospira Isolates and Reservoir Hosts. AB - The burden of leptospirosis in humans and animals in Africa is higher than that reported from other parts of the world. However, the disease is not routinely diagnosed in the continent. One of major factors limiting diagnosis is the poor availability of live isolates of locally circulating Leptospira serovars for inclusion in the antigen panel of the gold standard microscopic agglutination test (MAT) for detecting antibodies against leptospirosis. To gain insight in Leptospira serovars and their natural hosts occurring in Tanzania, concomitantly enabling the improvement of the MAT by inclusion of fresh local isolates, a total of 52 Leptospira isolates were obtained from fresh urine and kidney homogenates, collected between 1996 and 2006 from small mammals, cattle and pigs. Isolates were identified by serogrouping, cross agglutination absorption test (CAAT), and molecular typing. Common Leptospira serovars with their respective animal hosts were: Sokoine (cattle and rodents); Kenya (rodents and shrews); Mwogolo (rodents); Lora (rodents); Qunjian (rodent); serogroup Grippotyphosa (cattle); and an unknown serogroup from pigs. Inclusion of local serovars particularly serovar Sokoine in MAT revealed a 10-fold increase in leptospirosis prevalence in Tanzania from 1.9% to 16.9% in rodents and 0.26% to 10.75% in humans. This indicates that local serovars are useful for diagnosis of human and animal leptospirosis in Tanzania and other African countries. PMID- 26624891 TI - Comparison of the Levels of Pro-Inflammatory Cytokines Released in the Vastus Lateralis Muscle of Patients with Fibromyalgia and Healthy Controls during Contractions of the Quadriceps Muscle--A Microdialysis Study. AB - OBJECTIVE: Fibromyalgia is associated with central hyperexcitability, but it is suggested that peripheral input is important to maintain central hyperexcitability. The primary aim was to investigate the levels of pro inflammatory cytokines released in the vastus lateralis muscle during repetitive dynamic contractions of the quadriceps muscle in patients with fibromyalgia and healthy controls. Secondarily, to investigate if the levels of pro-inflammatory cytokines were correlated with pain or fatigue during these repetitive dynamic contractions. MATERIAL AND METHODS: 32 women with fibromyalgia and 32 healthy women (controls) participated in a 4 hour microdialysis session, to sample IL 1beta, IL-6, IL-8, and TNF from the most painful point of the vastus lateralis muscle before, during and after 20 minutes of repeated dynamic contractions. Pain (visual analogue scale; 0-100) and fatigue Borg's Rating of Perceived Exertion Scale; 6-20) were assessed before and during the entire microdialysis session. RESULTS: The repetitive dynamic contractions increased pain in the patients with fibromyalgia (P < .001) and induced fatigue in both groups (P < .001). Perceived fatigue was significantly higher among patients with fibromyalgia than controls (P < .001). The levels of IL-1beta did not change during contractions in either group. The levels of TNF did not change during contractions in patients with fibromyalgia, but increased in controls (P < .001) and were significantly higher compared to patients with fibromyalgia (P = .033). The levels of IL-6 and IL-8 increased in both groups alike during and after contractions (P's < .001). There were no correlations between pain or fatigue and cytokine levels after contractions. CONCLUSION: There were no differences between patients with fibromyalgia and controls in release of pro-inflammatory cytokines, and no correlations between levels of pro-inflammatory cytokines and pain or fatigue. Thus, this study indicates that IL-1beta, IL-6, IL-8, and TNF do not seem to play an important role in maintenance of muscle pain in fibromyalgia. PMID- 26624892 TI - Transcript Expression Data from Human Islets Links Regulatory Signals from Genome Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream Effectors. AB - The intersection of genome-wide association analyses with physiological and functional data indicates that variants regulating islet gene transcription influence type 2 diabetes (T2D) predisposition and glucose homeostasis. However, the specific genes through which these regulatory variants act remain poorly characterized. We generated expression quantitative trait locus (eQTL) data in 118 human islet samples using RNA-sequencing and high-density genotyping. We identified fourteen loci at which cis-exon-eQTL signals overlapped active islet chromatin signatures and were coincident with established T2D and/or glycemic trait associations. At some, these data provide an experimental link between GWAS signals and biological candidates, such as DGKB and ADCY5. At others, the cis signals implicate genes with no prior connection to islet biology, including WARS and ZMIZ1. At the ZMIZ1 locus, we show that perturbation of ZMIZ1 expression in human islets and beta-cells influences exocytosis and insulin secretion, highlighting a novel role for ZMIZ1 in the maintenance of glucose homeostasis. Together, these findings provide a significant advance in the mechanistic insights of T2D and glycemic trait association loci. PMID- 26624893 TI - Effect of Monochromatic Light on Expression of Estrogen Receptor (ER) and Progesterone Receptor (PR) in Ovarian Follicles of Chicken. AB - Artificial illumination is widely used in modern poultry houses and different wavelengths of light affect poultry production and behaviour. In this study, we measure mRNA and protein abundance of estrogen receptors (ERs) and progesterone receptors (PRs) in order to investigate the effect of monochromatic light on egg production traits and gonadal hormone function in chicken ovarian follicles. Five hundred and fifty-two 19-wk-old laying hens were exposed to three monochromatic lights: red (RL; 660 nm), green (GL; 560 nm), blue (BL; 480 nm) and control cool white (400-760 nm) light with an LED (light-emitting diode). There were 4 identical light-controlled rooms (n = 138) each containing 3 replicate pens (46 birds per pen). Water was supplied ad libitum and daily rations were determined according to the nutrient suggestions for poultry. Results showed that under BL conditions there was an increase in the total number of eggs at 300 days of age and egg-laying rate during the peak laying period. The BL and GL extended the duration of the peak laying period. Plasma melatonin was lowest in birds reared under BL. Plasma estradiol was elevated in the GL-exposed laying hens, and GL and BL increased progesterone at 28 wk of age. In the granulosa layers of the fifth largest preovulatory follicle (F5), the third largest preovulatory follicle (F3) and the largest preovulatory follicle (F1), ERalpha mRNA was increased by BL and GL. Treatment with BL increased ERbeta mRNA in granulosa layers of F5, F3 and F1, while GL increased ERbeta mRNA in F5 and F3. There was a corresponding increase in abundance of the proteins in the granulosa layers of F5, with an increase in PR-B, generated via an alternative splice site, relative to PR-A. Treatment with BL also increased expression of PR mRNA in all of the granulosa layers of follicles, while treatment with GL increased expression of PR mRNA in granulosa layers of SYF(small yellow follicle), F5 and F1. These results indicate that blue and green monochromatic lights promote egg production traits via stimulating gonadal hormone secretion and up-regulating expression of ERs and PRs. Changes in PR-B protein suggest that this form of the progesterone receptor is predominant for progesterone action in the granulosa layers of preovulatory follicles in chickens during light stimulation. PMID- 26624894 TI - Argon Mediates Anti-Apoptotic Signaling and Neuroprotection via Inhibition of Toll-Like Receptor 2 and 4. AB - PURPOSE: Recently, the noble gas argon attracted significant attention due to its neuroprotective properties. However, the underlying molecular mechanism is still poorly understood. There is growing evidence that the extracellular regulated kinase 1/2 (ERK1/2) is involved in Argon's protective effect. We hypothesized that argon mediates its protective effects via the upstream located toll-like receptors (TLRs) 2 and 4. METHODS: Apoptosis in a human neuroblastoma cell line (SH-SY5Y) was induced using rotenone. Argon treatment was performed after induction of apoptosis with different concentrations (25, 50 and 75 Vol% in oxygen 21 Vol%, carbon dioxide and nitrogen) for 2 or 4 hours respectively. Apoptosis was analyzed using flow cytometry (annexin-V (AV)/propidiumiodide (PI)) staining, caspase-3 activity and caspase cleavage. TLR density on the cells' surface was analyzed using FACS and immunohistochemistry. Inhibition of TLR signaling and extracellular regulated kinase 1/2 (ERK1/2) were assessed by western blot, activity assays and FACS analysis. RESULTS: Argon 75 Vol% treatment abolished rotenone-induced apoptosis. This effect was attenuated dose- and time dependently. Argon treatment was accompanied with a significant reduction of TLR2 and TLR4 receptor density and protein expression. Moreover, argon mediated increase in ERK1/2 phosphorylation was attenuated after inhibition of TLR signaling. ERK1/2 and TLR signaling inhibitors abolished the anti-apoptotic and cytoprotective effects of argon. Immunohistochemistry results strengthened these findings. CONCLUSION: These findings suggest that argon-mediated anti-apoptotic and neuroprotective effects are mediated via inhibition of TLR2 and TLR4. PMID- 26624895 TI - Learning Predictive Interactions Using Information Gain and Bayesian Network Scoring. AB - BACKGROUND: The problems of correlation and classification are long-standing in the fields of statistics and machine learning, and techniques have been developed to address these problems. We are now in the era of high-dimensional data, which is data that can concern billions of variables. These data present new challenges. In particular, it is difficult to discover predictive variables, when each variable has little marginal effect. An example concerns Genome-wide Association Studies (GWAS) datasets, which involve millions of single nucleotide polymorphism (SNPs), where some of the SNPs interact epistatically to affect disease status. Towards determining these interacting SNPs, researchers developed techniques that addressed this specific problem. However, the problem is more general, and so these techniques are applicable to other problems concerning interactions. A difficulty with many of these techniques is that they do not distinguish whether a learned interaction is actually an interaction or whether it involves several variables with strong marginal effects. METHODOLOGY/FINDINGS: We address this problem using information gain and Bayesian network scoring. First, we identify candidate interactions by determining whether together variables provide more information than they do separately. Then we use Bayesian network scoring to see if a candidate interaction really is a likely model. Our strategy is called MBS-IGain. Using 100 simulated datasets and a real GWAS Alzheimer's dataset, we investigated the performance of MBS-IGain. CONCLUSIONS/SIGNIFICANCE: When analyzing the simulated datasets, MBS-IGain substantially out-performed nine previous methods at locating interacting predictors, and at identifying interactions exactly. When analyzing the real Alzheimer's dataset, we obtained new results and results that substantiated previous findings. We conclude that MBS-IGain is highly effective at finding interactions in high-dimensional datasets. This result is significant because we have increasingly abundant high-dimensional data in many domains, and to learn causes and perform prediction/classification using these data, we often must first identify interactions. PMID- 26624896 TI - Positive Surgical Margin, HPV Persistence, and Expression of Both TPX2 and PD-L1 Are Associated with Persistence/Recurrence of Cervical Intraepithelial Neoplasia after Cervical Conization. AB - OBJECTIVE: To determine the clinicopathologic and immunohistochemical predictors of the persistence/recurrence of cervical intraepithelial neoplasia (CIN) after cervical conization. METHODS: Medical records of 502 patients who received cervical conization treatment of CIN between 2005 and 2012 were reviewed. The clinicopathologic parameters were analyzed using Cox hazard regression. Fifty patients with CIN persistence/recurrence were matched to 50 cases without CIN persistence/recurrence. These 100 cervical specimens were assessed for expression of insulin-like growth factor II messenger RNA (mRNA)-binding protein 3 (IMP3), targeting protein for xenopus kinesin-like protein 2 (TPX2), and programmed cell death-1 ligand-1 (PD-L1) using immunohistochemical staining. RESULTS: Multivariate analysis found that the independent predictors of CIN persistence/recurrence were positive surgical margin (hazard ratio 5.777, 95% confidence interval 2.334-14.301, p < 0.001) and human papilloma virus persistence for 6 months (hazard ratio 20.685, 95% confidence interval 7.350 57.657, p < 0.001). Co-expression of TPX2 and PD-L1 was significantly higher in CIN persistence/recurrence group than the group without CIN persistence/recurrence (p = 0.013). The depth of glandular involvement (GI) was less than 3mm in about 86.8% (59/68) CIN2-3 lesions, However, No statistically significant associations between GI and persistence/recurrence were observed (P = 0.58). CONCLUSION: Positive surgical margin, HPV persistence, and expression of both TPX2 and PD-L1 are associated with persistence/recurrence of cervical intraepithelial neoplasia after cervical conization. PMID- 26624897 TI - Winged Fruits of Deviacer in the Oligocene from the Ningming Basin in Guangxi, South China. AB - Deviacer guangxiensis Chen & Manchester sp. nov. is described based on asymmetric samaras from the Oligocene Ningming Formation in Guangxi, South China, representing the first documentation of Deviacer fossils in Asia. The Oligocene species, with relatively large fruits, represents the youngest record of the genus so far known; all other records are from the Paleocene and Eocene, or late Eocene-early Oligocene in western North America and Europe. It indicates that the extinct genus, Deviacer, was widely distributed in the northern hemisphere during the Paleogene. PMID- 26624899 TI - Verbal Fluencies and Fampridine Treatment in Multiple Sclerosis. AB - BACKGROUND/AIMS: Fampridine is sometimes reported to improve cognition and especially the information-processing speed. Motor improvement might be a confounding factor. The aim of this study was to evaluate the effects of fampridine on verbal fluencies in patients with multiple sclerosis (MS). METHODS: Fifty MS patients were included in a prospective monocentric open label trial with a mean Expanded Disability Status Scale of 5.3 +/- 1.1. Assessments of verbal phonological and semantic fluencies were repeated twice (within 1 week) before fampridine treatment and twice after fampridine treatment in order to have the maximal practice effect. Gait velocity and fatigue (visual analogical scale) were also assessed. Distribution into gait responders, gait non-responders, fluency responders and fluency non-responders, was described. RESULTS: Verbal fluencies were significantly higher after fampridine treatment. No correlation was observed between phonological fluency improvement and semantic fluency improvement. Gait responders and gait non-responders did not present significant differences in verbal fluency performance and fatigue score. No correlation between gait velocity improvement and fatigue improvement compared with verbal fluency improvement was observed. CONCLUSION: Our results suggest that fampridine could have a selective procognitive effect on phonological fluency in MS, even in the gait non-responder patients. PMID- 26624900 TI - Correction: Reusable manganese compounds containing pyrazole-based ligands for olefin epoxidation reactions. AB - Correction for 'Reusable manganese compounds containing pyrazole-based ligands for olefin epoxidation reactions' by Ester Manrique et al., Dalton Trans., 2015, 44, 17529-17543. PMID- 26624901 TI - Comparison of the Rate of Renal Function Decline in NonProteinuric Patients With and Without Diabetes. AB - BACKGROUND: Patients with diabetes and chronic kidney disease (CKD) without proteinuria are often believed to have a cause of CKD other than diabetes. It was hypothesized that if this is true, the rate of renal function decline should be similar among nonproteinuric patients with and without diabetes. METHODS: Patients seen in the nephrology, endocrinology and general internal medicine clinics at the Medical University of South Carolina (MUSC) between 2008 and 2012 with hypertension and diabetes were identified by ICD9 diagnosis codes. Patients with less than 2 measures of serum creatinine, without urine studies over the study period and with proteinuria were excluded. Four hundred seventy-two patients met the inclusion and exclusion criteria and had an initial estimated glomerular filtration rate (eGFR) between 35 and 80 mL/min per 1.73 m2. The annual rate of decline in eGFR was estimated for each patient from the lowest eGFR in each year by fitting a regression model with random intercept and slope. RESULTS: In unadjusted analyses, the rate of eGFR decline was greater in patients with diabetes than without diabetes (-0.71 versus -0.30 mL . min(-1) . yr(-1), P = 0.03). After adjusting for age, race, sex, baseline eGFR and use of renin angiotensin-aldosterone system blockade, the rate of decline was still greater among patients with diabetes than among those without diabetes (-0.68 versus 0.36 mL . min(-1) . yr(-1), P = 0.03). CONCLUSIONS: Patients with diabetes had more rapid decline in kidney function compared with individuals without diabetes, despite the absence of proteinuria. These results suggest that even in the absence of proteinuria, diabetes may be associated with CKD. PMID- 26624902 TI - Time is the Present. PMID- 26624898 TI - Effect of High-Density Lipoprotein Metabolic Pathway Gene Variations and Risk Factors on Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in China. AB - PURPOSE: To investigate the effect of genetic variants in the high-density lipoprotein (HDL) metabolic pathway and risk factors on neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) in China. METHODS: A total of 742 Chinese subjects, including 221 controls, 230 cases with nAMD, and 291 cases with PCV, were included in the present study. Five single nucleotide polymorphisms (SNPs) from three genes in the HDL metabolic pathway (HDLMP) including cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC) and lipoprotein lipase (LPL) were genotyped in all study subjects with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Risk factors including gender, hypertension, hyperlipidemia, diabetes mellitus, and coronary artery disease were identified. Chi-square tests or Fisher's exact tests were applied to discover associations between SNPs and risk factors for PCV and nAMD. Gene-gene interactions and gene-environment interactions were evaluated by the multifactor-dimensionality reduction (MDR) method. RESULTS: CETP rs3764261 were significantly associated with an increased risk for PCV (odds ratio (OR) = 1.444, P = 0.0247). LIPC rs1532085 conferred an increased risk for PCV (OR = 1.393, P = 0.0094). We found no association between PCV and LPL rs12678919, LIPC rs10468017 or CETP rs173539. No association was found between five SNPs with nAMD. Regarding risk factors, females were found to have significantly decreased risks for both PCV and nAMD (P = 0.006 and 0.001, respectively). Coronary artery disease (CAD) was a risk factor in PCV patients but played a protective role in nAMD patients. Hyperlipidemia was associated with PCV but not with nAMD. Neither hypertension nor diabetes mellitus was associated with PCV or nAMD. The MDR analysis revealed that a three-locus model with rs12678919, rs1532085, and gender was the best model for nAMD, while a five-locus model consisting of rs10468017, rs3764261, rs1532085, gender, and hyperlipidemia was best for PCV. CONCLUSION: Our large-sample study suggested that CETP rs3764261 conferred an increased risk for PCV. We also first found the association between rs1532085 and PCV. The result of present study also showed that gender and CAD are associated with PCV and nAMD. Significant association was found between hyperlipidemia and PCV but not nAMD. PMID- 26624904 TI - Update From the Advisory Committee on Immunization Practices. PMID- 26624903 TI - Association Between COX-2 Polymorphisms and Lung Cancer Risk. AB - BACKGROUND Multiple relevant risk factors for lung cancer have been reported in different populations, but results of previous studies were not consistent. Therefore, a meta-analysis is necessary to summarize these outcomes and reach a relatively comprehensive conclusion. MATERIAL AND METHODS STATA 12.0 software was used for all statistical of the relationship between COX-2 polymorphisms and lung cancer risk. Inter-study heterogeneity was examined with the Q statistic (significance level at P<0.1). The publication bias among studies in the meta analysis was analyzed with Begg's funnel plot and Egger's test. Hardy-Weinberg equilibrium was tested in all controls of the studies. RESULTS COX-2 rs20417 polymorphism had a significant association with reduced risk of lung cancer under homozygous and recessive models, and similar results were observed in white and population-based subgroups under 2 and 3 contrasts, respectively. Additionally, rs2066826 polymorphism manifested a strong correlation with increased risk of lung cancer under 5 genetic models. CONCLUSIONS In COX-2 gene, rs20417 may have a certain relationship with reduced risk of lung cancer, while rs2066826 may increase the risk of lung cancer. PMID- 26624905 TI - Hospital Epidemiology and Infection Control for Children: Report From the Society for Healthcare Epidemiology of America Pediatric Leadership Council. PMID- 26624906 TI - Diagnosis and Management of Clostridium difficile Infection by Pediatric Infectious Diseases Physicians. AB - BACKGROUND: The incidence of C difficile infection (CDI) has risen among children; however, optimal management of CDI within a diverse pediatric population remains unclear. Although adult guidelines recommend oral vancomycin for treatment of second recurrence or severe CDI, dedicated pediatric data to support pediatric specific management guidelines are lacking. Our objective was to describe current CDI management practices by pediatric infectious diseases (ID) physicians. METHODS: We surveyed pediatric members of the Emerging Infections Network, a network of infectious diseases (ID) physicians across North America, in October 2012. Clinical vignettes were used to determine how physicians modify CDI management based on clinical presentation or presence of comorbidities, including solid organ transplantation, inflammatory bowel disease, and neutropenia. RESULTS: Of the 285 physicians surveyed, 167 (59%) responded. There were no significant differences in geography, level of experience, or hospital type between respondents and non-respondents. All respondents (100%) used oral metronidazole for the initial occurrence of mild CDI in a normal host. Management varied substantially for mild CDI in patients with a variety of comorbidities, in whom metronidazole therapy was less frequently preferred (41 79%). For management of severe CDI, 65% preferred oral vancomycin alone or in combination with at least one other agent. For a second recurrence, oral vancomycin alone or in combination was preferred by 92%. Among 125 respondents who reported using alternative therapies for recurrent or severe CDI, 23 (18%) recommend fecal microbiota transplantation, while 20 (16%) reported using fidaxomicin. CONCLUSIONS: Pediatric ID physicians prefer metronidazole for treatment of mild CDI in healthy children, but management strategies vary for patients with comorbidities or recurrent or severe disease. These findings highlight the need for pediatric comparative effectiveness studies aimed at determining the optimal treatment for pediatric CDI. PMID- 26624907 TI - Risk Factors for Invasive Fungal Infection in Premature Infants: Enhancing a Targeted Prevention Approach. AB - BACKGROUND: Premature infants are at high risk of developing invasive candidal infections (ICI). We investigated maternal and perinatal risk factors for ICI that may help in defining at-risk infants, allowing more targeted antifungal prophylaxis to prevent morbidity and mortality. METHODS: Maternal and neonatal data from infants with a birthweight between 500 and 1250 g admitted across 95 neonatal intenisve care units were analyzed for risk factors for ICI. RESULTS: Data from 1890 infants were analyzed, 78 of whom had ICI. Overall mortality was 20.5% for all cases of ICI, 18.8% with candidemia, 17.2% with candiduria, and 75% when Candida was isolated in both the blood and urine. Birthweight, gestational age, male sex, and vaginal delivery were predictors of infection on univariate analysis. After logistic regression, gestational age (P < .01) and male sex (P < .01) remained significant. Vaginal birth and receiving antibiotics during the first week of life increased the risk for ICI in the 22-25 weeks' and 26-28 weeks' gestation subgroups. CONCLUSIONS: Gestational age and male gender are risk factors for the development of ICI, whereas vaginal delivery and antibiotics during the first week further increase the incidence in the more premature infants. Knowing maternal and perinatal risk factors for ICI allows more targeted antifungal prophylaxis in at-risk infants. PMID- 26624908 TI - Successful Use of Temocillin as Salvage Therapy for Cervical Osteomyelitis Secondary to Multidrug-Resistant Burkholderia cepacia. AB - Infection with multidrug resistant Burkholderia cepacia presents a therapeutic challenge in patients with cystic fibrosis. In this study, we present a case of progressive cervical osteomyelitis secondary to B cepacia that failed surgical drainage and extended therapy with meropenem, piperacillin-tazobactam, doxycycline, and aminoglycosides. Temocillin (Negaban) was successfully used to clear the infection. PMID- 26624909 TI - Healthcare-Associated Pertussis Outbreak in Arizona: Challenges and Economic Impact, 2011. AB - An outbreak investigation identified 15 pertussis cases among 5 infants and 10 healthcare professionals at 1 hospital's neonatal intensive care unit (NICU). The cost of the outbreak to this hospital was $97 745. Heightened awareness of pertussis in NICUs is key to preventing healthcare-associated spread and minimizing outbreak-control-related costs. Bordetella pertussis is a highly communicable bacterial pathogen that causes a prolonged cough illness and is spread by respiratory droplet transmission. Infants aged <=6 months are most susceptible to B pertussis infection and pertussis-associated complications, including pneumonia, encephalopathy, and death, and are commonly hospitalized for treatment [ 1]. Despite a universal pertussis vaccination program, 27 550 pertussis cases were reported in the United States during 2010 [ 2]. Pertussis outbreaks in healthcare settings can be challenging and costly to control [3]. On September 13, 2011 and September 15, 2011, 3 pertussis cases, including 2 confirmed by B pertussis isolation, among preterm infants discharged <=30 days previously from a 71-bed NICU of a general hospital (NICU A) were reported by Hospital B, a large pediatric facility, to Maricopa County Department of Public Health. This report describes the outbreak, examines outbreak-associated costs and risk factors that might have contributed to healthcare-associated transmission, and provides guidance to prevent outbreaks in healthcare settings. PMID- 26624910 TI - Outpatient Parenteral Antimicrobial Therapy Practices Among Pediatric Infectious Diseases Consultants: Results of an Emerging Infections Network Survey. AB - We conducted a survey of pediatric members of the Emerging Infections Network regarding outpatient parenteral antimicrobial therapy (OPAT) practices and clinical decision making about OPAT initiation. We identified substantial variation in characteristics and resources of pediatric OPAT practices. Opportunities to improve oversight of OPAT in children should be explored. PMID- 26624911 TI - Kingella kingae Corneal Infections in Children. PMID- 26624912 TI - Leclercia adecarboxylata Sepsis and Cerebral Herniation. AB - Leclercia adecarboxylata, a gram-negative bacillus of the Enterobacteriaceae family, is rarely identified as a pathogen in humans. We describe a fatal case of L adecarboxylata sepsis in a child. This is the first reported pediatric death associated with infection due to L adecarboxylata. PMID- 26624913 TI - Balamuthia mandrillaris Encephalitis: Survival of a Child With Severe Meningoencephalitis and Review of the Literature. AB - Balamuthia mandrillaris causes granulomatous amoebic encephalitis, which is frequently fatal. There are few reports of survival in children. A 4-year-old child developed severe meningoencephalitis with multiple intracranial ring enhancing lesions. Empiric therapy was commenced after a biopsy was performed, and the patient had a good clinical response. Molecular testing and indirect immunofluorescence later confirmed the diagnosis of Balamuthia encephalitis. Diagnosis of Balamuthia encephalitis is often delayed. The literature is reviewed with particular reference to reported survival. Prompt tissue diagnosis and initiation of therapy are common features among survivors. In previous reports, miltefosine was not used to treat children, but it was well tolerated in this case and should be considered as a therapeutic option. PMID- 26624918 TI - Abrupt versus Gradual Spin-Crossover in Fe(II)(phen)2(NCS)2 and Fe(III)(dedtc)3 Compared by X-ray Absorption and Emission Spectroscopy and Quantum-Chemical Calculations. AB - Molecular spin-crossover (SCO) compounds are attractive for information storage and photovoltaic technologies. We compared two prototypic SCO compounds with Fe(II)N6 (1, [Fe(phen)2(NCS)2], with phen = 1,10-phenanthroline) or Fe(III)S6 (2, [Fe(dedtc)3], with dedtc = N,N'-diethyldithiocarbamate) centers, which show abrupt (1) or gradual (2) thermally induced SCO, using K-edge X-ray absorption and Kbeta emission spectroscopy (XAS/XES) in a 8-315 K temperature range, single crystal X-ray diffraction (XRD), and density functional theory (DFT). Core-to valence and valence-to-core electronic transitions in the XAS/XES spectra and bond lengths change from XRD provided benchmark data, verifying the adequacy of the TPSSh/TZVP DFT approach for the description of low-spin (LS) and high-spin (HS) species. Determination of the spin densities, charge distributions, bonding descriptors, and valence-level configurations, as well as similar experimental and calculated enthalpy changes (DeltaH), suggested that the varying metal-ligand bonding properties and deviating electronic structures converge to similar enthalpic contributions to the free-energy change (DeltaG) and thus presumably are not decisive for the differing SCO behavior of 1 and 2. Rather, SCO seems to be governed by vibrational contributions to the entropy changes (DeltaS) in both complexes. Intra- and intermolecular interactions in crystals of 1 and 2 were identified by atoms-in-molecules analysis. Thermal excitation of individual dedtc ligand vibrations accompanies the gradual SCO in 2. In contrast, extensive inter- and intramolecular phen/NCS vibrational mode coupling may be an important factor in the cooperative SCO behavior of 1. PMID- 26624919 TI - Identification and characterization of epitopes on Plasmodium knowlesi merozoite surface protein-142 (MSP-142) using synthetic peptide library and phage display library. AB - Plasmodium knowlesi can cause potentially life threatening human malaria. The Plasmodium merozoite surface protein-142 (MSP-142) is a potential target for malaria blood stage vaccine, and for diagnosis of malaria. Two epitope mapping techniques were used to identify the potential epitopes within P. knowlesi MSP 142. Nine and 14 potential epitopes were identified using overlapping synthetic peptide library and phage display library, respectively. Two regions on P. knowlesi MSP-142 (amino acid residues 37-95 and residues 240-289) were identified to be the potential dominant epitope regions. Two of the prominent epitopes, P10 (TAKDGMEYYNKMGELYKQ) and P31 (RCLLGFKEVGGKCVPASI), were evaluated using mouse model. P10- and P31-immunized mouse sera reacted with recombinant P. knowlesi MSP 142, with the IgG isotype distribution of IgG2b>IgG1>IgG2a>IgG3. Significant higher level of cytokines interferon-gamma and interleukin-2 was detected in P31 immunized mice. Both P10 and P31 could be the suitable epitope candidates to be used in malaria vaccine designs and immunodiagnostic assays, provided further evaluation is needed to validate the potential uses of these epitopes. PMID- 26624920 TI - Subarachnoideal blood spread following epidural blood patch given to treat spontaneous intracranial hypotension: Can it cause neurological complications? AB - OBJECTIVE: (1) To determine the frequency of subarachnoid blood spread following epidural blood patch (EBP) in a cohort of subjects with spontaneous intracranial hypotension (SIH). (2) To describe the outcome of these patients. PATIENTS AND METHODS: In a cohort of 106 patients exhibiting SIH, spiral spinal CT scans were obtained post-lumbar EBP and neuroradiological data was reviewed for evidence of subarachnoideal bleeding. RESULTS: Subarachnoideal blood spread was detected on spinal CT scans following EBP in 9 of 106 patients with SIH. All patients exhibited a complete recovery and no neurological complications were observed. CONCLUSIONS: A low incidence of subarachnoideal blood spread was observed following EBP given to treat SIH. Instances of subarachnoideal blood spread were not associated with neurological complications or altered efficacy of the EBP procedure. PMID- 26624921 TI - Imperceptible and Ultraflexible p-Type Transistors and Macroelectronics Based on Carbon Nanotubes. AB - Flexible thin-film transistors based on semiconducting single-wall carbon nanotubes are promising for flexible digital circuits, artificial skins, radio frequency devices, active-matrix-based displays, and sensors due to the outstanding electrical properties and intrinsic mechanical strength of carbon nanotubes. Nevertheless, previous research effort only led to nanotube thin-film transistors with the smallest bending radius down to 1 mm. In this paper, we have realized the full potential of carbon nanotubes by making ultraflexible and imperceptible p-type transistors and circuits with a bending radius down to 40 MUm. In addition, the resulted transistors show mobility up to 12.04 cm(2) V(-1) S(-1), high on-off ratio (~10(6)), ultralight weight (<3 g/m(2)), and good mechanical robustness (accommodating severe crumpling and 67% compressive strain). Furthermore, the nanotube circuits can operate properly with 33% compressive strain. On the basis of the aforementioned features, our ultraflexible p-type nanotube transistors and circuits have great potential to work as indispensable components for ultraflexible complementary electronics. PMID- 26624922 TI - Surface-Enhanced Spectroscopy for Higher-Order Light Scattering: A Combined Experimental and Theoretical Study of Second Hyper-Raman Scattering. AB - Motivated to explore the ultimate limits of surface-enhanced nonlinear spectroscopies, we report on the first observation of molecular second hyper Raman scattering with the aid of surface enhancement and provide a new theoretical framework for first-principles calculations of the second hyper-Raman effect. Second hyper-Raman enhancement factors, determined to be a minimum of 10(5) times stronger than those in Raman scattering, demonstrate a clear trend toward larger enhancements for nonlinear phenomena, and the nearly quantitative agreement between simulation and experiment provides a unique spectroscopic window into higher-order molecular responses. PMID- 26624923 TI - Colloidal Confinement of Polyphosphate on Gold Nanoparticles Robustly Activates the Contact Pathway of Blood Coagulation. AB - Platelet-sized polyphosphate (polyP) was functionalized on the surface of gold nanoparticles (GNPs) via a facile conjugation scheme entailing EDAC (N-(3 (dimethylamino)propyl)-N'-ethylcarbodiimide hydrochloride)-catalyzed phosphoramidation of the terminal phosphate of polyP to cystamine. Subsequent reduction of the disulfide moiety allowed for anchoring to the colloidal surface. The ability of the synthesized polyP-GNPs to initiate the contact pathway of clotting in human pooled normal plasma (PNP) was then assayed by quantifying changes in viscous, mechanical, and optical properties upon coagulation. It is revealed that the polyP-GNPs are markedly superior contact activators compared to molecularly dissolved, platelet-sized polyP (of equivalent polymer chain length). Moreover, the particles' capacity to mobilize Factor XII (FXII) and its coactivating proteins appear to be identical to very-long-chain polyP typically found in bacteria. These data imply that nanolocalization of anionic procoagulants on colloidal surfaces, achieved through covalent anchoring, may yield a robust contact surface with the ability to sufficiently cluster active clotting factors together above their threshold concentrations to cease bleeding. The polyP-GNPs therefore serve as a promising foundation in the development of a nanoparticle hemostat to treat a range of hemorrhagic scenarios. PMID- 26624924 TI - Electrostatic Assembly of Sandwich-like Ag-C@ZnO-C@Ag-C Hybrid Hollow Microspheres with Excellent High-Rate Lithium Storage Properties. AB - Herein, we introduce a facile electrostatic attraction approach to produce zinc silver citrate hollow microspheres, followed by thermal heating treatment in argon to ingeniously synthesize sandwich-like Ag-C@ZnO-C@Ag-C hybrid hollow microspheres. The 3D carbon conductive framework in the hybrids derives from the in situ carbonation of carboxylate acid groups in zinc-silver citrate hollow microspheres during heating treatment, and the continuous and homogeneous Ag nanoparticles on the outer and inner surfaces of hybrid hollow microspheres endow the shells with the sandwiched configuration (Ag-C@ZnO-C@Ag-C). When applied as the anode materials for lithium ion batteries, the fabricated hybrid hollow microspheres with sandwich-like shells reveal a very large reversible capacity of 1670 mAh g(-1) after 200 cycles at a current density of 0.2 A g(-1). Even at the very large current densities of 1.6 and 10.0 A g(-1), the high specific capacities of about 1063 and 526 mAh g(-1) can be retained, respectively. The greatly enhanced electrochemical properties of Ag-C@ZnO-C@Ag-C hybrid microspheres are attributed to their special structural features such as the hollow structures, the sandwich-like shells, and the nanometer-sized building blocks. PMID- 26624925 TI - The significant association of Taq1A genotypes in DRD2/ANKK1 with smoking cessation in a large-scale meta-analysis of Caucasian populations. AB - Although a number of studies have analyzed the relation between the DRD2/ANKK1 gene Taq1A polymorphism and smoking cessation, the results remain controversial. The primary objective of the present study was to determine whether this variant indeed has any effect on smoking cessation. The A1-dominant model that considers A1/* (*=A1 or A2) and A2/A2 as two genotypes and compares their frequencies in current and former smokers was applied. A total of 22 studies with 11,075 subjects were included in the meta-analyses. Considering the potential influence of between-study heterogeneity, we conducted stratified meta-analyses with the Comprehensive Meta-Analysis statistical software (version 2.0). Results based on either cross-sectional or longitudinal studies consistently showed a statistically significant association between Taq1A A1/* genotypes and smoking cessation. Further, a more significant association of the variant with smoking cessation was detected when both types of studies were combined. However, there was marginal evidence of heterogeneity among studies (I(2)=33.9%; P=0.06). By excluding other ethnicities and subjects with cancer, the meta-analysis on the basis of 9487 Caucasians demonstrated that Taq1A A1/* genotypes indeed were significantly associated with smoking cessation under both the fixed- and random effects models (pooled OR 1.22; 95% CI 1.11-1.34; P=3.9 * 10(-5) for both models). No evidence of between-study heterogeneity or publication bias was observed. Thus, we conclude that the polymorphism of Taq1A has an important role in the process of abstaining from smoking, and smokers carrying A2/A2 genotype have a higher likelihood of smoking cessation than those who carry A1/A1 or A1/A2. PMID- 26624926 TI - Proteasome system dysregulation and treatment resistance mechanisms in major depressive disorder. AB - Several studies have demonstrated that allelic variants related to inflammation and the immune system may increase the risk for major depressive disorder (MDD) and reduce patient responsiveness to antidepressant treatment. Proteasomes are fundamental complexes that contribute to the regulation of T-cell function. Only one study has shown a putative role of proteasomal PSMA7, PSMD9 and PSMD13 genes in the susceptibility to an antidepressant response, and sparse data are available regarding the potential alterations in proteasome expression in psychiatric disorders such as MDD. The aim of this study was to clarify the role of these genes in the mechanisms underlying the response/resistance to MDD treatment. We performed a case-control association study on 621 MDD patients, of whom 390 were classified as treatment-resistant depression (TRD), and we collected peripheral blood cells and fibroblasts for mRNA expression analyses. The analyses showed that subjects carrying the homozygous GG genotype of PSMD13 rs3817629 had a twofold greater risk of developing TRD and exhibited a lower PSMD13 mRNA level in fibroblasts than subjects carrying the A allele. In addition, we found a positive association between PSMD9 rs1043307 and the presence of anxiety disorders in comorbidity with MDD, although this result was not significant following correction for multiple comparisons. In conclusion, by confirming the involvement of PSMD13 in the MDD treatment response, our data corroborate the hypothesis that the dysregulation of the complex responsible for the degradation of intracellular proteins and potentially controlling autoimmunity- and immune tolerance-related processes may be involved in several phenotypes, including the TRD. PMID- 26624928 TI - Lapatinib Induced Suicidal Death of Human Erythrocytes. AB - BACKGROUND/AIMS: The human epidermal growth factor receptors tyrosine kinase inhibitor lapatinib has been shown to trigger suicidal death or apoptosis of tumor cells and is thus used for the treatment of malignancy. Side effects of lapatinib include anemia, which could, at least in theory, result from stimulation of eryptosis, the suicidal death of erythrocytes which is characterized by cell shrinkage and phospholipid scrambling of the cell membrane leading to phosphatidylserine translocation to the erythrocyte surface. Mechanisms involved in the triggering of eryptosis include oxidative stress, increase of cytosolic Ca2+ activity ([Ca2+]i), and ceramide. The present study explored, whether lapatinib induces eryptosis. METHODS: Phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, abundance of reactive oxygen species (ROS) from DCFDA dependent fluorescence, and ceramide abundance utilizing labelled specific antibodies. RESULTS: A 48 hours exposure of human erythrocytes to lapatinib (>= 1 ug/ml) significantly increased the percentage of annexin-V-binding cells, and significantly decreased forward scatter. Lapatinib (7.5 ug/ml) did not significantly modify DCFDA fluorescence and ceramide abundance. Lapatinib slightly, but significantly decreased Fluo3-fluorescence (>= 5 ug/ml). Lapatinib (7.5 ug/ml) enhanced the annexin-V-binding in the presence of the Ca2+ ionophore ionomycin (1 uM) without significantly modifying Fluo3 fluorescence in the presence of ionomycin. The effect of lapatinib on forward scatter but not on annexin-V-binding was significantly blunted by removal of extracellular Ca2+. CONCLUSION: Lapatinib triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect occurring despite decrease of cytosolic Ca2+ activity. PMID- 26624927 TI - Role of emotional processing in depressive responses to sex-hormone manipulation: a pharmacological fMRI study. AB - Sex-hormone fluctuations may increase risk for developing depressive symptoms and alter emotional processing as supported by observations in menopausal and pre- to postpartum transition. In this double-blinded, placebo-controlled study, we used blood-oxygen level dependent functional magnetic resonance imaging (fMRI) to investigate if sex-steroid hormone manipulation with a gonadotropin-releasing hormone agonist (GnRHa) influences emotional processing. Fifty-six healthy women were investigated twice: at baseline (follicular phase of menstrual cycle) and 16 +/- 3 days post intervention. At both sessions, fMRI-scans during exposure to faces expressing fear, anger, happiness or no emotion, depressive symptom scores and estradiol levels were acquired. The fMRI analyses focused on regions of interest for emotional processing. As expected, GnRHa initially increased and subsequently reduced estradiol to menopausal levels, which was accompanied by an increase in subclinical depressive symptoms relative to placebo. Women who displayed larger GnRHa-induced increase in depressive symptoms had a larger increase in both negative and positive emotion-elicited activity in the anterior insula. When considering the post-GnRHa scan only, depressive responses were associated with emotion-elicited activity in the anterior insula and amygdala. The effect on regional activity in anterior insula was not associated with the estradiol net decline, only by the GnRHa-induced changes in mood. Our data implicate enhanced insula recruitment during emotional processing in the emergence of depressive symptoms following sex-hormone fluctuations. This may correspond to the emotional hypersensitivity frequently experienced by women postpartum. PMID- 26624929 TI - Pathways through Equilibrated States with Coexisting Phases for Gas Hydrate Formation. AB - Under ambient conditions, water freezes to either hexagonal ice or a hexagonal/cubic composite ice. The presence of hydrophobic guest molecules introduces a competing pathway: gas hydrate formation, with the guests in clathrate cages. Here, the pathways of the phase transitions are sought as sequences of states with coexisting phases, using a generalized replica exchange algorithm designed to sample them in equilibrium, avoiding nonequilibrium processes. For a dilute solution of methane in water under 200 atm, initializing the simulation with the full set of replicas leads to methane trapped in hexagonal/cubic ice, while gradually adding replicas with decreasing enthalpy produces the initial steps of hydrate growth. Once a small amount of hydrate is formed, water rearranges to form empty cages, eventually transforming the remainder of the system to metastable beta ice, a scaffolding for hydrates. It is suggested that configurations with empty cages are reaction intermediates in hydrate formation when more guest molecules are available. Free energy profiles show that methane acts as a catalyst reducing the barrier for beta ice versus hexagonal/cubic ice formation. PMID- 26624930 TI - Copper-Mediated Aerobic Oxidative Synthesis of 3-Bromo-imidazo[1,2-a]pyridines with Pyridines and Enamides. AB - A conversion of pyridines and enamides for the synthesis of 3-bromo-imidazo[1,2 a]pyridines was developed by copper-mediated aerobic oxidative coupling in a one pot manner. This procedure tolerates various functional groups and affords a series of 3-bromo-imidazo[1,2-a]pyridines under mild conditions. PMID- 26624931 TI - The potential of organic substrates based on mushroom substrate and straw to dissipate fungicides contained in effluents from the fruit-packaging industry - Is there a role for Pleurotus ostreatus? AB - Citrus fruit-packaging plants (FPP) produce large wastewater volumes with high loads of fungicides like ortho-phenylphenol (OPP) and imazalil (IMZ). No methods are in place for the treatment of those effluents and biobeds appear as a viable alternative. We employed a column study to investigate the potential of spent mushroom substrate (SMS) of Pleurotus ostreatus, either alone or in mixture with straw and soil plus a mixture of straw /soil to retain and dissipate IMZ and OPP. The role of P. ostreatus on fungicides dissipation was also investigated by studying in parallel the performance of fresh mushroom substrate of P. ostreatus (FMS) and measuring lignolytic enzymatic activity in the leachates. All substrates effectively reduced the leaching of OPP and IMZ which corresponded to 0.014-1.1% and 0.120-0.420% of their initial amounts respectively. Mass balance analysis revealed that FMS and SMS/Straw/Soil (50/25/25 by vol) offered the most efficient removal of OPP and IMZ from wastewaters respectively. Regardless of the substrate, OPP was restricted in the top 0-20cm of the columns and was bioavailable (extractable with water), compared to IMZ which was less bioavailable (extractable with acetonitrile) but diffused at deeper layers (20 50, 50-80cm) in the SMS- and Straw/Soil-columns. PLFAs showed that fungal abundance was significantly lower in the top layer of all substrates from where the highest pesticide amounts were recovered suggesting an inhibitory effect of fungicides on total fungi in the substrates tested. Our data suggest that biobeds packed with SMS-rich substrates could ensure the efficient removal of IMZ and OPP from wastewaters of citrus FPP. PMID- 26624932 TI - The fate of fusion Cry1Ab/1Ac proteins from Bt-transgenic rice in soil and water. AB - Toxin proteins form transgenic crops entering into the environment are likely affect non-target organisms. To investigate the entry route and fate of fusion Cry1Ab/1Ac proteins from transgenic rice expressing insecticide toxins from Bacillus thuringiensis (Bt) in soil and water, we conducted greenhouse and field experiments in 2013 and 2014. Cry1Ab/1Ac proteins from Bt-transgenic rice in soil was found within a horizontal range of 25cm, where most of plant roots distributed. Concentration of Cry1Ab/1Ac proteins was lower in water than in soil in the greenhouse experiment, and no Cry1Ab/1Ac protein was detected in field water. Cry1Ab/1Ac concentration from rice straws was higher in ditch water than in distilled water due to the existence of aquatic organisms in ditch water. Bt proteins from transgenic crops enter into soil ecosystems mainly through root exudates and into aquatic ecosystems through plant residues, which determines Bt fate in the environment. PMID- 26624934 TI - FeS@C on Carbon Cloth as Flexible Electrode for Both Lithium and Sodium Storage. AB - Flexible and self-supported carbon-coated FeS on carbon cloth films (denoted as FeS@C/carbon cloth) is prepared by a facial hydrothermal method combined with a carbonization treatment. The FeS@C/carbon cloth could be directly used as electrodes for Li-ion batteries (LIBs) and sodium-ion batteries (NIBs). The synthetic effects of the structure, highly electron-conductive of carbon cloth, porous structure for electrolyte access, and uniform carbon shell on FeS surface to accommodate the volume change lead to improved cyclability and rate capability. For lithium storage, the FeS@C/carbon cloth electrode delivers a high discharge capacity of 420 mAh g(-1) even after 100 cycles at a current density of 0.15 C and 370 mAh g(-1)at a high current density of 7.5 C (1 C = 609 mA g(-1). When used for sodium storage, it keeps a reversible capacity of 365 mAh g( 1)after 100 cycles at 0.15 C. Similar process can be utilized for the formation of various cathode and anode composites on carbon cloth for flexible energy storage devices. PMID- 26624935 TI - Accelerating the "On Water" Reaction: By Organic-Water Interface or By Hydrodynamic Effects? AB - A series of organic reactions proceed dramatically faster in a heterogeneous mixture of the reactants and water than in a homogeneous mixture. Currently it is unclear whether the rate acceleration is due to the free OH groups at the organic water interface, or due to the hydrodynamic effects caused by vigorous stirring, vortexing, or ultrasonication. Herein we produced static droplets in microfluidic devices to answer this question. In the work, a series of organic droplets containing diethyl azodicarboxylate (DEAD) and quadricyclane surrounded by water were produced, which were transferred to and confined in glass capillaries to minimize the hydrodynamic effects. The cycloaddition process of DEAD with quadricyclane was recorded by a CCD camera. The results showed the reaction proceeded in three steps, and the organic-water interface alone was catalytically efficient enough to enhance the reaction rate to the same level as in the bulk emulsion reaction, indicating that the hydrodynamic effects were negligible. PMID- 26624936 TI - Trans-saccadic integration of peripheral and foveal feature information is close to optimal. AB - Due to the inhomogenous visual representation across the visual field, humans use peripheral vision to select objects of interest and foveate them by saccadic eye movements for further scrutiny. Thus, there is usually peripheral information available before and foveal information after a saccade. In this study we investigated the integration of information across saccades. We measured reliabilities--i.e., the inverse of variance-separately in a presaccadic peripheral and a postsaccadic foveal orientation--discrimination task. From this, we predicted trans-saccadic performance and compared it to observed values. We show that the integration of incongruent peripheral and foveal information is biased according to their relative reliabilities and that the reliability of the trans-saccadic information equals the sum of the peripheral and foveal reliabilities. Both results are consistent with and indistinguishable from statistically optimal integration according to the maximum-likelihood principle. Additionally, we tracked the gathering of information around the time of the saccade with high temporal precision by using a reverse correlation method. Information gathering starts to decline between 100 and 50 ms before saccade onset and recovers immediately after saccade offset. Altogether, these findings show that the human visual system can effectively use peripheral and foveal information about object features and that visual perception does not simply correspond to disconnected snapshots during each fixation. PMID- 26624938 TI - A Two-Dimensional Liquid Structure Explains the Elevated Melting Temperatures of Gallium Nanoclusters. AB - Melting in finite-sized materials differs in two ways from the solid-liquid phase transition in bulk systems. First, there is an inherent scaling of the melting temperature below that of the bulk, known as melting point depression. Second, at small sizes changes in melting temperature become nonmonotonic and show a size dependence that is sensitive to the structure of the particle. Melting temperatures that exceed those of the bulk material have been shown to occur for a very limited range of nanoclusters, including gallium, but have still never been ascribed a convincing physical explanation. Here, we analyze the structure of the liquid phase in gallium clusters based on molecular dynamics simulations that reproduce the greater-than-bulk melting behavior observed in experiments. We observe persistent nonspherical shape distortion indicating a stabilization of the surface, which invalidates the paradigm of melting point depression. This shape distortion suggests that the surface acts as a constraint on the liquid state that lowers its entropy relative to that of the bulk liquid and thus raises the melting temperature. PMID- 26624937 TI - Age-related changes in auditory and visual interactions in temporal rate perception. AB - We investigated how aging affects the integration of temporal rate for auditory flutter (amplitude modulation) presented with visual flicker. Since older adults were poorer at detecting auditory amplitude modulation, modulation depth was individually adjusted so that temporal rate was equally discriminable for 10 Hz flutter and flicker, thereby balancing the reliability of rate information available to each sensory modality. With age-related sensory differences normalized in this way, rate asynchrony skewed both auditory and visual rate judgments to the same extent in younger and older adults. Therefore, reliability based weighting of temporal rate is preserved in older adults. Concurrent presentation of synchronous 10 Hz flicker and flutter improved temporal rate discrimination consistent with statistically optimal integration in younger but not older adults. In a control experiment, younger adults were presented with the same physical auditory stimulus as older adults. This time, rate asynchrony skewed perceived rate with greater auditory weighting rather than balanced integration. Taken together, our results indicate that integration of discrepant auditory and visual rates is not altered due to the healthy aging process once sensory deficits are accounted for, but that aging does abolish the minor improvement in discrimination performance seen in younger observers when concordant rates are integrated. PMID- 26624933 TI - Late presentation for HIV care across Europe: update from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study, 2010 to 2013. AB - Late presentation (LP) for HIV care across Europe remains a significant issue. We provide a cross-European update from 34 countries on the prevalence and risk factors of LP for 2010-2013. People aged >= 16 presenting for HIV care (earliest of HIV-diagnosis, first clinic visit or cohort enrollment) after 1 January 2010 with available CD4 count within six months of presentation were included. LP was defined as presentation with a CD4 count < 350/mm(3) or an AIDS defining event (at any CD4), in the six months following HIV diagnosis. Logistic regression investigated changes in LP over time. A total of 30,454 people were included. The median CD4 count at presentation was 368/mm(3) (interquartile range (IQR) 193 555/mm(3)), with no change over time (p = 0.70). In 2010, 4,775/10,766 (47.5%) were LP whereas in 2013, 1,642/3,375 (48.7%) were LP (p = 0.63). LP was most common in central Europe (4,791/9,625, 49.8%), followed by northern (5,704/11,692; 48.8%), southern (3,550/7,760; 45.8%) and eastern Europe (541/1,377; 38.3%; p < 0.0001). There was a significant increase in LP in male and female people who inject drugs (PWID) (adjusted odds ratio (aOR)/year later 1.16; 95% confidence interval (CI): 1.02-1.32), and a significant decline in LP in northern Europe (aOR/year later 0.89; 95% CI: 0.85-0.94). Further improvements in effective HIV testing strategies, with a focus on vulnerable groups, are required across the European continent. PMID- 26624939 TI - Niizalactams A-C, Multicyclic Macrolactams Isolated from Combined Culture of Streptomyces with Mycolic Acid-Containing Bacterium. AB - A terrestrial bacterium, Streptomyces sp. NZ-6, produced niizalactams A-C (1-3), unprecedented di- and tricyclic macrolactams, by coculturing with the mycolic acid-containing bacterium Tsukamurella pulmonis TP-B0596. Their complete structures, including absolute configurations, were elucidated on the basis of spectroscopic data and chemical derivatization. Their unique skeletons are proposed to be biosynthesized from a common 26-membered macrolactam intermediate by SN2 cyclization or an intramolecular Diels-Alder reaction. PMID- 26624955 TI - Aerobic biodegradation of toluene-2,4-di(8:2 fluorotelomer urethane) and hexamethylene-1,6-di(8:2 fluorotelomer urethane) monomers in soils. AB - Aerobic soil biodegradation of toluene-2,4-di(8:2 fluorotelomer urethane) (FTU) and hexamethylene-1,6-di(8:2 fluorotelomer urethane) (HMU) in a forest soil and FTU in an agricultural silty clay loam soil was monitored for up to 6 months. Fluorotelomer alcohols were measured in headspace and parent monomers and all metabolites in soil extracts. Negligible degradation of FTU biodegradation occurred in the agricultural soil with 94 +/- 15% recovered at day 180. However, in the forest soil, both FTU and HMU degradation was evident with significant losses of 24% (117 d) and 27% (180 day), respectively, and concomitant increases in the terminal metabolite, perfluorooctanoic acid (PFOA) concentrations were well above what could result from residual 8:2 FTOH. Kinetic modeling estimated half-lives for FTU (aromatic backbone) and HMU (aliphatic backbone) in the forest soil to be 3-5 months and 15.9-22.2 months, respectively. The addition of a structurally similar non-fluorinated FTU analog, toluene-2,4-dicarbamic acid diethyl ester (TDAEE) enhanced production of terminal end products from 8:2 FTOH degradation. However, there was no clear evidence that TDAEE enhanced cleavage of the urethane bond, thus TDAEE appeared to just serve as an additional carbon source. TDAEE's half-life was ~ one week. A second addition of TDAEE appeared to retard subsequent degradation of FTU exemplifying the microbial dynamics and diversity impacting degradation of polyfluoroalkyl substances. Enhanced degradation of HMU was observed upon re-aeration indicating oxygen may have been limiting during some periods although degradation of intermediate metabolites to terminal metabolites was still occurring, albeit at slower rates. PMID- 26624956 TI - Occurrence and removal of butyltin compounds in a waste stabilisation pond of a domestic waste water treatment plant of a rural French town. AB - The aim of this study was to investigate the fate and behaviour of butyltin pollutants, including monobutyltin (MBT), dibutylin (DBT), and tributyltin (TBT), in waste stabilisation ponds (WSP). The study was conducted as part of a baseline survey and included five sampling campaigns comprising bottom sludge and the water column from each pond from a typical WSP in France. Butyltins were detected in all raw wastewater and effluents, reflecting their widespread use. Our results revealed high affinity between butyltins and particulate matter and high accumulation of butyltins in the sludge taken from anaerobic ponds. The dissolved butyltins in the influent ranged from 21.5 to 28.1 ng(Sn).L(-1) and in the effluent, from 8.8 to 29.3 ng(Sn).L(-1). The butyltin concentrations in the sludge ranged from 45.1 to 164 and 3.6-8.1 ng(Sn).g(-1) respectively in the first and last ponds. Our results showed an average treatment efficiency of 71% for MBT, 47% for DBT, 55% for TBT. Laboratory sorption experiments enabled the calculation of a distribution coefficient (Kd = 75,000 L.kg-1) between TBT and particulate matter from the WSPs. The Kd explained the accumulation and persistence of the TBT in the sludge after settling of particulate matter. The continuous supply of contaminated raw wastewater and the sorption-desorption processes in the ponds led to incomplete bio- and photolytic degradation and to the persistence of butyltins in dissolved and particulate matrices throughout the survey period. It is thus recommended to use shallow ponds and to pay particular attention when sludge is used for soil amendment. PMID- 26624957 TI - Assessing environmental risk of pharmaceuticals in Portugal: An approach for the selection of the Portuguese monitoring stations in line with Directive 2013/39/EU. AB - In line with the Directive 2013/39/EU the most representative surface waters, regarding pharmaceuticals contamination, were selected based on a Portuguese nationwide monitoring exercise. To meet this purpose, and given that wastewater treatment plants (WWTPs) are regarded as the major point sources of pharmaceuticals environmental contamination, the occurrence, fate and environmental risk assessment (ERA) of eleven of the most consumed pharmaceuticals, belonging to several therapeutic classes were assessed in 15 WWTPs (influents (WWIs) and effluents (WWEs)), from five different regions during one year (4 sampling campaigns). Results showed that all samples were contaminated with at least 1, and up to 8 from the 11 targeted pharmaceuticals. The highest concentrations observed were 150 and 33 MUg L(-1) for WWI and WWE, respectively. Regarding temporal and spacial influence, winter, Alentejo, Algarve and Center regions presented higher mass loads. The ERA posed by 7 of the selected pharmaceuticals presented a risk quotient higher than 1 to the three trophic levels. Our findings highlighted that the rivers Mondego, Tagus, Ave, Trancao, Fervenca and Xarrama should be selected as surface water monitoring stations. This study gives a good overview on pharmaceuticals contamination in WWTPs and its impact on surface waters in Portugal. Thus, a more integrative approach to rank and prioritize pharmaceuticals, based on an integrated assessment of ERA and exposure of surface water, was provided to support the future selection of the 6 most representative monitoring stations in Portugal, as required by the above mentioned directive. PMID- 26624958 TI - ADDENDUM. PMID- 26624959 TI - Similarities between N-Acetylcysteine and Glutathione in Binding to Lead(II) Ions. AB - N-Acetylcysteine is a natural thiol-containing antioxidant, a precursor for cysteine and glutathione, and a potential detoxifying agent for heavy metal ions. However, previous accounts of the efficiency of N-acetylcysteine (H2NAC) in excretion of lead are few and contradicting. Here, we report results on the nature of lead(II) complexes formed with N-acetylcysteine in aqueous solution, which were obtained by combining information from several spectroscopic methods, including (207)Pb, (13)C, and (1)H NMR, Pb LIII-edge X-ray absorption, ultraviolet-visible (UV-vis) spectroscopy, and electro-spray ionization mass spectrometry (ESI-MS). Two series of solutions were used containing CPb(II) = 10 and 100 mM, respectively, varying the H2NAC/Pb(II) mole ratios from 2.1 to 10.0 at pH 9.1-9.4. The coordination environments obtained resemble those previously found for the Pb(II) glutathione system: at a ligand-to-lead mole ratio of 2.1, dimeric or oligomeric Pb(II) N-acetylcysteine complexes are formed, while a trithiolate [Pb(NAC)3](4-) complex dominates in solutions with H2NAC/Pb(II) mole ratios >3.0. PMID- 26624960 TI - Clinical usefulness of serum 2'-5'-oligoadenylate synthetase for early diagnosis of viral infections among febrile adult patients. AB - BACKGROUND: This study aimed to evaluate the clinical usefulness of serum 2'-5' oligoadenylate synthetase (2-5AS) levels in diagnosing viral infection. METHODS: 2-5AS, procalcitonin (PCT) and C-reactive protein (CRP) serum levels and leukocyte counts were evaluated in 104 febrile patients (26 viral and 55 bacterial infections, 23 non-infectious diseases). RESULTS: Assessment of areas under the receiver-operator characteristic curves revealed that 2-5AS and CRP levels and the age of the patient differentiated between viral and bacterial infections, 2-5AS levels differentiated between viral infection and non infectious disease and PCT levels differentiated between bacterial infection and non-infectious disease. The decision tree constructed according to the results correctly classified the origin of fever in 88 of 104 patients (85%). CONCLUSIONS: 2-5AS is a useful diagnostic biomarker for viral infections and combining it with the PCT and CRP levels and leukocyte counts improves determination of causes of fever. PMID- 26624961 TI - Identifying and Managing Complications and Comorbidities in Patients With Psoriasis. AB - The common comorbidities of cutaneous psoriasis include psoriatic arthritis (PsA), Crohn's disease, uveitis, and depression. In addition, cardiovascular disease risk factors (including metabolic syndrome) are seen more frequently among patients with psoriasis, and strong epidemiologic evidence has demonstrated that psoriasis is independently associated with myocardial infarction. Because these comorbid conditions and other medical complications adversely affect morbidity and mortality in patients with psoriasis, dermatologists can play an important role in promptly identifying and, when necessary, referring patients for further workup and treatment when signs or symptoms of these comorbidities or complications are observed. Semin Cutan Med Surg 34(supp2):S30-S33 (c) 2015 published by Frontline Medical Communications. PMID- 26624962 TI - Allelic Frequency of a 24-bp Duplication in Exon 10 of the CHIT1 Gene in the General Iranian Population. AB - BACKGROUND: The human chitinase chitotriosidase enzyme, which is encoded by the CHIT1 gene, is produced by macrophages, and may be important in immune responses to chitin-containing organisms, such as fungi. Plasma chitotriosidase activity is used to diagnose and monitor some forms of lysosomal storage disorders, such as Gaucher's and Niemann-Pick disease. However, homozygous duplication of a 24-bp region in exon 10 of the CHIT1 gene eliminates enzyme activity and may complicate disease monitoring. The high prevalence of this mutation highlights the need to determine its frequency in different populations and screen patients for this mutation to verify whether chitotriosidase activity is a reliable marker of lysosomal storage disease. This study investigated the allele frequency of the 24 bp duplication in the general Iranian population. METHODS: To identify the 24-bp duplication in exon 10 of the CHIT1 gene (H allele), genotyping of DNA extracted from peripheral blood leukocytes of 577 healthy Iranians was performed using polymerase chain reaction (PCR) amplification and high resolution melting (HRM) PCR techniques. RESULTS: In this study, heterozygous and homozygous duplications were detected in 183 (31.7%) and 35 (6.1%) subjects, respectively. In addition, the allelic frequency was 21.9% (95% confidence interval). CONCLUSION: Our study indicates that genotype analysis by HRM-PCR is a fast, reliable, and highly accurate screening approach for identifying the 24-bp duplication in CHIT1 exon 10. Due to the wide range of duplication frequencies among different ethnic groups, new biomarkers are necessary for assessing genetic characteristics of lysosomal storage disorders in different populations. PMID- 26624963 TI - Successes and Challenges of Interprofessional Physiologic Birth and Obstetric Emergency Simulations in a Nurse-Midwifery Education Program. AB - This article describes childbirth simulation design and implementation within the nurse-midwifery education program at the University of California, San Francisco. Nurse-midwife and obstetrician faculty coordinators were supported by faculty from multiple professions and specialties in curriculum review and simulation development and implementation. The primary goal of the resulting technology enhanced simulations of normal physiologic birth and obstetric emergencies was to assist learners' development of interprofessional competencies related to communication, teamwork, and patient-centered care. Trainees included nurse midwifery students; residents in obstetrics, pediatrics, and family medicine; medical students; and advanced practice nursing students in pediatrics. The diversity of participant types and learning levels provided benefits and presented challenges to effective scenario-based simulation design among numerous other theoretical and logistical considerations. This project revealed practical solutions informed by emerging health sciences and education research literature, faculty experience, and formal course evaluations by learners. Best practices in simulation development and implementation were incorporated, including curriculum revision grounded in needs assessment, case- and event-based clinical scenarios, optimization of fidelity, and ample time for participant debriefing. Adequate preparation and attention to detail increased the immersive experience and benefits of simulation. Suggestions for fidelity enhancement are provided with examples of simulation scenarios, a timeline for preparations, and discussion topics to facilitate meaningful learning by maternity and newborn care providers and trainees in clinical and academic settings. Pre- and postsimulation measurements of knowledge, skills, and attitudes are ongoing and not reported. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health. PMID- 26624965 TI - Effect of jumping interval training on neuromuscular and physiological parameters: a randomized controlled study. AB - This study analyzed the effect of 4 weeks of jumping interval training (JIT), included in endurance training, on neuromuscular and physiological parameters. Eighteen recreational runners, randomized in control and experimental groups, performed 40 min of running at 70% of velocity at peak oxygen uptake, for 3 times per week. Additionally, the experimental group performed the JIT twice per week, which consisted of 4 to 6 bouts of continuous vertical jumps (30 s) with 5-min intervals. Three days before and after the training period, the countermovement (CMJ) and continuous jump (CJ30), isokinetic and isometric evaluation of knee extensors/flexors, progressive maximal exercise, and submaximal constant-load exercise were performed. The JIT provoked improvement in neuromuscular performance, indicated by (i) increased jump height (4.7%; effect size (ES) = 0.99) and power output (~ 3.7%; ES ~ 0.82) of CMJ and rate of torque development of knee extensors in isometric contraction (29.5%; ES = 1.02); (ii) anaerobic power and capacity, represented by the mean of jump height (7.4%; ES = 0.8), and peak power output (PPO) (5.6%; ES = 0.73) of the first jumps of CJ30 and the mean of jump height (10.2%, ES = 1.04) and PPO (9.5%, ES = 1.1), considering all jumps of CJ30; and (iii) aerobic power and capacity, represented by peak oxygen uptake (9.1%, ES = 1.28), velocity at peak oxygen uptake (2.7%, ES = 1.11), and velocity corresponding to the onset of blood lactate accumulation (9.7%, ES = 1.23). These results suggest that the JIT included in traditional endurance training induces moderate to large effects on neuromuscular and physiological parameters. PMID- 26624964 TI - Early initiation of low-level parenteral dextrose induces an accelerated diabetic phenotype in septic C57BL/6J mice. AB - Development of hyperglycemia during sepsis is associated with increased morbidity and mortality. Nutritional support is common practice in the intensive care unit, but the metabolic effects are not well understood. The purpose of this study is to determine the effect of early low-level calorie provision on the development of hyperglycemia in a clinically relevant murine model of sepsis. C57BL/6J mice underwent femoral arterial and venous catheterization followed by cecal ligation and puncture (CLP) or sham surgery and low-dose intravenous dextrose or saline infusion. Blood glucose, plasma insulin, and cytokines were measured after 24 h. Additional septic mice underwent hyperinsulinemic-euglycemic clamps or received intravenous insulin concurrent with dextrose to determine whole-body insulin sensitivity and test the efficacy of insulin to reverse hyperglycemia. Neither dextrose infusion nor CLP alone induced hyperglycemia. Early initiation of low level dextrose in septic mice produced a variable glycemic response: 49% maintained euglycemia (blood glucose < 200) and 27% developed severe hyperglycemia (blood glucose >= 600). Hyperglycemia was associated with increased inflammation and reduced insulin secretion and sensitivity compared with control mice or CLP mice maintaining euglycemia. Insulin prevented the progression to severe hyperglycemia but was ineffective in reestablishing glycemic control once hyperglycemia had developed. In conclusion, early initiation of clinically relevant low-level dextrose (~ 20% daily caloric requirements) precipitated hyperglycemia akin to an acute diabetic phenotype in septic mice characterized by decreased insulin sensitivity, decreased insulin secretion, and an increased inflammatory response. PMID- 26624966 TI - Efficacy of olfactory training in patients with olfactory loss: a systematic review and meta-analysis. AB - BACKGROUND: Olfactory loss is a challenging clinical problem with few proven therapeutic options. Early experimental results with olfactory training suggest that this novel therapy may be an effective intervention for olfactory dysfunction of multiple etiologies. The aim of this study was to systematically review currently available studies that assess the efficacy and outcomes of olfactory training in patients with olfactory loss. METHODS: A comprehensive systematic literature review was performed with the assistance of a reference librarian using the PubMed, PsycInfo, Google Scholar, EMBASE, and Proquest databases. Eligible studies were extracted based on defined inclusion criteria and the effect of olfactory training on objective olfactory function was evaluated qualitatively and by meta-analysis. RESULTS: A total of 10 studies with 639 patients were identified and systematically reviewed. Sufficient data for meta-analysis was available for 3 studies. Patients receiving olfactory training experienced a statistically significant improvement in the Threshold, Discrimination, Identification (TDI) score compared to control patients (mean difference [MD] 3.77; 95% confidence interval [CI], 2.28 to 5.26). Improvement in olfactory function was observed in discrimination (MD 1.92; 95% CI, 1.13 to 2.71) and identification (MD 1.61; 95% CI, 0.55 to 2.68), but not in olfactory thresholds (MD -0.01; 95% CI, -0.42 to 0.39). CONCLUSION: Olfactory training is a promising modality for the treatment of olfactory dysfunction. Results of this systematic review and meta-analysis suggest that it may be an effective treatment for olfactory dysfunction due to multiple etiologies. Additional high-quality studies are needed to define indications, outcomes, and duration of therapy for this novel therapy. PMID- 26624970 TI - Sarcoidosis of the vagina treated with methotrexate. AB - We describe the first case of mediolateral episiotomic sarcoidosis of the deep vaginal tissue, without involvement of the pulmonary parenchyma or pulmonary symptoms. A 68-year-old female was admitted with a vaginal mass that had developed about 1 month prior. On bimanual examination, we found a painful solid mass approximately 4 cm in diameter on the episiotomy line of the deep vaginal tissue. The patient underwent pelvic magnetic resonance imaging on suspicion of a malignancy, and a vaginal true-cut biopsy was performed. The biopsy specimen exhibited non-caseating, granulomatous inflammation and many multinucleated giant cells, strongly suggesting sarcoidosis. We had excluded other granulomatous diseases; a final diagnosis was made of stage-1 sarcoidosis in the deep vaginal mass. A 3-month course of methotrexate (2.5 mg/week) was commenced to treat a flare-up of rheumatoid arthritis. The vaginal mass resolved. To the best of our knowledge, this is the first case of sarcoidosis in a deep vaginal mass without pulmonary parenchymal or other solid-organ involvement. PMID- 26624972 TI - Comparison of Standard and Quadruple-Phase Contrast Material Injection for Artifacts, Image Quality, and Radiation Dose in the Evaluation of Head and Neck Cancer Metastases. AB - PURPOSE: To investigate opacification of head and neck vasculature during computed tomography (CT) of supraclavicular lymph nodes with a quadruple-phase contrast media and saline dual-injection protocol. MATERIALS AND METHODS: This retrospective study was institutional review board approved. In 180 consecutive patients, routine head and neck CT was performed with one of two protocols: protocol A, craniocaudal scan direction with 100 mL of contrast material injected intravenously as a single bolus; or protocol B, 100 mL of contrast material injected in four phases (phases 1-2, 60 mL of contrast material and saline injected at 2.5 mL/sec; phases 3-4, 40 mL of contrast material and saline injected at 2.5 mL/sec); both protocols had a fixed scan delay of 70 seconds. Attenuation of supraclavicular arteries and veins was measured with arteriovenous contrast ratio (AVCR) and contrast-to-noise ratio (CNR). Effective dose was calculated. Data were compared with the two-sample t test. Receiver operating characteristic (ROC) and visual grading characteristic analyses were performed. RESULTS: Arterial attenuation was up to 20% higher (P < .05) after protocol B (mean +/- standard deviation, 234.5 HU +/- 33.2) than protocol A (160.0 HU +/- 29.5). Venous system attenuation was significantly lower in protocol B (164.0 HU +/- 17.0) than in protocol A (664.0 HU +/- 12.0), with up to a 75% reduction (P < .0001). Protocol B generated significant (P < .0001) improvements in AVCR at multiple anatomic sites. At all anatomic levels, mean CNR with protocol B (34.4 HU +/- 9.0) was significantly higher than that with protocol A (14.5 HU +/- 14.0) (P < .0313). Effective dose was significantly reduced with protocol B (2.6 mSv +/ 0.4 vs 3.2 mSv +/- 0.8 with protocol A; P < .0041). ROC analysis demonstrated significantly higher area under the ROC curve for protocol B (P < .0022), with interreader agreement increasing from poor to excellent in lymph node visualization. CONCLUSION: Significant improvement in lymph node visualization at the cervicothoracic junction is achieved with a quadruple-phase contrast media injection protocol. PMID- 26624971 TI - Neoadjuvant Chemotherapy for Breast Cancer: Functional Tumor Volume by MR Imaging Predicts Recurrence-free Survival-Results from the ACRIN 6657/CALGB 150007 I-SPY 1 TRIAL. AB - PURPOSE: To evaluate volumetric magnetic resonance (MR) imaging for predicting recurrence-free survival (RFS) after neoadjuvant chemotherapy (NACT) of breast cancer and to consider its predictive performance relative to pathologic complete response (PCR). MATERIALS AND METHODS: This HIPAA-compliant prospective multicenter study was approved by institutional review boards with written informed consent. Women with breast tumors 3 cm or larger scheduled for NACT underwent dynamic contrast-enhanced MR imaging before treatment (examination 1), after one cycle (examination 2), midtherapy (examination 3), and before surgery (examination 4). Functional tumor volume (FTV), computed from MR images by using enhancement thresholds, and change from baseline (DeltaFTV) were measured after one cycle and before surgery. Association of RFS with FTV was assessed by Cox regression and compared with association of RFS with PCR and residual cancer burden (RCB), while controlling for age, race, and hormone receptor (HR)/ human epidermal growth factor receptor type 2 (HER2) status. Predictive performance of models was evaluated by C statistics. RESULTS: Female patients (n = 162) with FTV and RFS were included. At univariate analysis, FTV2, FTV4, and DeltaFTV4 had significant association with RFS, as did HR/HER2 status and RCB class. PCR approached significance at univariate analysis and was not significant at multivariate analysis. At univariate analysis, FTV2 and RCB class had the strongest predictive performance (C statistic = 0.67; 95% confidence interval [CI]: 0.58, 0.76), greater than for FTV4 (0.64; 95% CI: 0.53, 0.74) and PCR (0.57; 95% CI: 0.39, 0.74). At multivariate analysis, a model with FTV2, DeltaFTV2, RCB class, HR/HER2 status, age, and race had the highest C statistic (0.72; 95% CI: 0.60, 0.84). CONCLUSION: Breast tumor FTV measured by MR imaging is a strong predictor of RFS, even in the presence of PCR and RCB class. Models combining MR imaging, histopathology, and breast cancer subtype demonstrated the strongest predictive performance in this study. PMID- 26624973 TI - Quantitative Features of Liver Lesions, Lung Nodules, and Renal Stones at Multi Detector Row CT Examinations: Dependency on Radiation Dose and Reconstruction Algorithm. AB - PURPOSE: To determine if radiation dose and reconstruction algorithm affect the computer-based extraction and analysis of quantitative imaging features in lung nodules, liver lesions, and renal stones at multi-detector row computed tomography (CT). MATERIALS AND METHODS: Retrospective analysis of data from a prospective, multicenter, HIPAA-compliant, institutional review board-approved clinical trial was performed by extracting 23 quantitative imaging features (size, shape, attenuation, edge sharpness, pixel value distribution, and texture) of lesions on multi-detector row CT images of 20 adult patients (14 men, six women; mean age, 63 years; range, 38-72 years) referred for known or suspected focal liver lesions, lung nodules, or kidney stones. Data were acquired between September 2011 and April 2012. All multi-detector row CT scans were performed at two different radiation dose levels; images were reconstructed with filtered back projection, adaptive statistical iterative reconstruction, and model-based iterative reconstruction (MBIR) algorithms. A linear mixed-effects model was used to assess the effect of radiation dose and reconstruction algorithm on extracted features. RESULTS: Among the 23 imaging features assessed, radiation dose had a significant effect on five, three, and four of the features for liver lesions, lung nodules, and renal stones, respectively (P < .002 for all comparisons). Adaptive statistical iterative reconstruction had a significant effect on three, one, and one of the features for liver lesions, lung nodules, and renal stones, respectively (P < .002 for all comparisons). MBIR reconstruction had a significant effect on nine, 11, and 15 of the features for liver lesions, lung nodules, and renal stones, respectively (P < .002 for all comparisons). Of note, the measured size of lung nodules and renal stones with MBIR was significantly different than those for the other two algorithms (P < .002 for all comparisons). Although lesion texture was significantly affected by the reconstruction algorithm used (average of 3.33 features affected by MBIR throughout lesion types; P < .002, for all comparisons), no significant effect of the radiation dose setting was observed for all but one of the texture features (P = .002 .998). CONCLUSION: Radiation dose settings and reconstruction algorithms affect the extraction and analysis of quantitative imaging features in lesions at multi detector row CT. PMID- 26624974 TI - Potential Heating Effect in the Gravid Uterus by Using 3-T MR Imaging Protocols: Experimental Study in Miniature Pigs. AB - Purpose To determine the changes in temperature within the gravid miniature pig uterus during magnetic resonance (MR) imaging at 3 T. Materials and Methods The study received ethics committee approval for animal experimentation. Fiber-optic temperature sensors were inserted into the fetal brain, abdomen, bladder, and amniotic fluid of miniature pigs (second trimester, n = 2; third trimester, n = 2). In the first trimester (n = 2), the sensors were inserted only into the amniotic fluid (three sacs per miniature pig, for a total of six sacs). Imaging was performed with a 3-T MR imager by using different imaging protocols in a random order for animal, each lasting approximately 15 minutes. The first regimen consisted of common sequences used for human fetal MR examination, including normal specific absorption rate (SAR). The second regimen consisted of five low SAR sequences, for which three gradient-echo sequences were interspersed with two diffusion-weighted imaging series. Finally, a high-SAR regimen maximized the radiofrequency energy deposition (constrained by the 2-W per kilogram of body weight SAR limitations) by using five single-shot turbo spin-echo sequences. Differences in temperature increases between the three regimens and between the three trimesters were evaluated by using one-way analysis of variance. The maximum cumulative temperature increase over 1 hour was also evaluated. Results Low-SAR regimens resulted in the lowest temperature increase (mean +/- standard deviation, -0.03 degrees C +/- 0.20), normal regimens resulted in an intermediate increase (0.31 degrees C +/- 0.21), and high-SAR regimens resulted in the highest increase (0.56 degrees C +/- 0.20) (P < .0001). Mean temperature increase in the third trimester was 0.38 degrees C +/- 0.27, with no significant differences compared with the first (0.23 degrees C +/- 0.27) and second (0.25 degrees C +/- 0.32) trimesters (P = .07). The cumulative temperature increase over 1-hour imaging time with high SAR can reach 2.5 degrees C. Conclusion In pregnant miniature pigs, the use of 3-T magnets for diagnostic MR imaging with normal SAR regimens does not lead to temperature increases above 1 degrees C if imaging time is kept below 30 minutes. Longer imaging time, especially with high-SAR regimens, can lead to an increase of 2.5 degrees C. ((c)) RSNA, 2015 Online supplemental material is available for this article. PMID- 26624976 TI - Pharmacokinetics, Safety, and Tolerability of a New Fluticasone Propionate Multidose Dry Powder Inhaler Compared With Fluticasone Propionate Diskus((r)) in Healthy Adults. AB - BACKGROUND: Fluticasone propionate (Fp) is an inhaled corticosteroid with well established safety and efficacy profiles. This study evaluated the systemic pharmacokinetics of Fp inhaled from a novel, inhalation-driven multidose dry powder inhaler (MDPI) that does not require coordination of actuation with inhalation. METHODS: This was a single-center, open-label, randomized, 3-period crossover, single-dose study in healthy Japanese and Caucasian subjects aged 20 45 years, inclusive. Subjects were randomized to one of six treatment sequences including combinations of four inhalations of Fp MDPI 100 MUg (400 MUg total dose), Fp MDPI 200 MUg (800 MUg total dose), and Fp Diskus((r)) 100 MUg (400 MUg total dose). The primary objective was to assess pharmacokinetics (maximum plasma concentration [Cmax] and area under concentration-vs.-time curve [AUC]) for each treatment. Safety and tolerability were also assessed. RESULTS: Thirty subjects (15 Caucasian, 15 Japanese) met entry criteria and were randomized; all 30 subjects completed the study. At the inhaled Fp total doses evaluated (400 and 800 MUg), the shapes of plasma concentration-vs.-time curves and systemic exposure (AUC0-t and Cmax) were similar in Japanese and Caucasian subjects. Geometric mean ratios (Japanese/Caucasian) for AUC0-t ranged from 1.11 to 1.15, and for Cmax ranged from 0.90 to 1.05, with no substantial differences between ethnic groups. In both ethnic groups, and in the combined population, systemic exposure (AUC0-t and Cmax) was highest for Fp MDPI 800 MUg, followed by Fp MDPI 400 MUg, and last by Fp Diskus 400 MUg. No clinical laboratory, vital signs, or physical examination findings were considered clinically significant. CONCLUSIONS: Systemic exposure following inhaled single doses of Fp was comparable in healthy adult Japanese and Caucasian subjects for each total dose and inhaler. The new MDPI provided more efficient drug delivery than Diskus, suggesting that Fp MDPI may provide similar clinical efficacy at a lower inhaled dose compared with Diskus. Single-dose inhaled Fp (400-800 MUg) was generally well tolerated in healthy adults. PMID- 26624978 TI - Validation of the parent version of the World Health Organization Adult ADHD Self Report Scale for adolescents. AB - OBJECTIVE: To investigate the validity of a parent version of the World Health Organization Adult Attention-Deficit/Hyperactivity Disorder (ADHD) Self-Report Scale for adolescents (ASRS-AP) and the 6-question screening version (ASRS-AP-S). METHODS: Adolescent psychiatric outpatients (N = 112, mean age 15 years, 40% boys) and their parents were interviewed with the Kiddie Schedule of Affective Disorders and Schizophrenia (K-SADS), and the parents reported on the ASRS AP/ASRS-AP-S. RESULTS: Internal consistency (Cronbach's alpha) was 0.93 for ASRS AP and 0.85 for ASRS-AP-S, 0.91 and 0.87 for the inattention subscale, and 0.91 and 0.72 for the hyperactivity subscale, respectively. The concurrent validity (Spearman's correlation coefficient) between the total K-SADS ADHD symptom severity score and the sum of the score on the ASRS-AP/ASRS-AP-S was 0.75 and 0.66, respectively. Diagnostic accuracy measures for the ASRS-AP and ASRS-AP-S were 78% and 80% sensitivity, 75% and 74% specificity, 73% and 71% positive predictive value (PPV), and 81% and 82% negative predictive value (NPV), respectively. CONCLUSIONS: The ASRS-AP and ASRS-AP-S showed high internal consistency and concurrent validity in relation to total K-SADS ADHD symptom severity score. Both scales showed favourable diagnostic accuracy measures. PMID- 26624979 TI - Molecular pathway activation features linked with transition from normal skin to primary and metastatic melanomas in human. AB - Melanoma is the most aggressive and dangerous type of skin cancer, but its molecular mechanisms remain largely unclear. For transcriptomic data of 478 primary and metastatic melanoma, nevi and normal skin samples, we performed high throughput analysis of intracellular molecular networks including 592 signaling and metabolic pathways. We showed that at the molecular pathway level, the formation of nevi largely resembles transition from normal skin to primary melanoma. Using a combination of bioinformatic machine learning algorithms, we identified 44 characteristic signaling and metabolic pathways connected with the formation of nevi, development of primary melanoma, and its metastases. We created a model describing formation and progression of melanoma at the level of molecular pathway activation. We discovered six novel associations between activation of metabolic molecular pathways and progression of melanoma: for allopregnanolone biosynthesis, L-carnitine biosynthesis, zymosterol biosynthesis (inhibited in melanoma), fructose 2, 6-bisphosphate synthesis and dephosphorylation, resolvin D biosynthesis (activated in melanoma), D-myo inositol hexakisphosphate biosynthesis (activated in primary, inhibited in metastatic melanoma). Finally, we discovered fourteen tightly coordinated functional clusters of molecular pathways. This study helps to decode molecular mechanisms underlying the development of melanoma. PMID- 26624980 TI - SRC family kinase FYN promotes the neuroendocrine phenotype and visceral metastasis in advanced prostate cancer. AB - FYN is a SRC family kinase (SFK) that has been shown to be up-regulated in human prostate cancer (PCa) tissues and cell lines. In this study, we observed that FYN is strongly up-regulated in human neuroendocrine PCa (NEPC) tissues and xenografts, as well as cells derived from a NEPC transgenic mouse model. In silico analysis of FYN expression in prostate cancer cell line databases revealed an association with the expression of neuroendocrine (NE) markers such as CHGA, CD44, CD56, and SYP. The loss of FYN abrogated the invasion of PC3 and ARCaPM cells in response to MET receptor ligand HGF. FYN also contributed to the metastatic potential of NEPC cells in two mouse models of visceral metastasis with two different cell lines (PC3 and TRAMPC2-RANKL). The activation of MET appeared to regulate neuroendocrine (NE) features as evidenced by increased expression of NE markers in PC3 cells with HGF. Importantly, the overexpression of FYN protein in DU145 cells was directly correlated with the increase of CHGA. Thus, our data demonstrated that the neuroendocrine differentiation that occurs in PCa cells is, at least in part, regulated by FYN kinase. Understanding the role of FYN in the regulation of NE markers will provide further support for ongoing clinical trials of SFK and MET inhibitors in castration-resistant PCa patients. PMID- 26624981 TI - Mitochondrial retrograde signaling inhibits the survival during prolong S/G2 arrest in Saccharomyces cerevisiae. AB - Cell senescence is dependent on the arrest in cell cycle. Here we studied the role of mitochondrial retrograde response signaling in yeast cell survival under a prolonged arrest. We have found that, unlike G1, long-term arrest in mitosis or S phase results in a loss of colony-forming abilities. Consistent with previous observations, loss of mitochondrial DNA significantly increased the survival of arrested cells. We found that this was because the loss increases the duration of G1 phase. Unexpectedly, retrograde signaling, which is typically triggered by a variety of mitochondrial dysfunctions, was found to be a negative regulator of the survival after the release from S-phase arrest induced by the telomere replication defect. Deletion of retrograde response genes decreased the arrest induced death in such cells, whereas deletion of negative regulator of retrograde signaling MKS1 had the opposite effect. We provide evidence that these effects are due to alleviation of the strength of the S-phase arrest. PMID- 26624982 TI - Targeting heparanase overcomes chemoresistance and diminishes relapse in myeloma. AB - In most myeloma patients, even after several rounds of intensive therapy, drug resistant tumor cells survive and proliferate aggressively leading to relapse. In the present study, gene expression profiling of tumor cells isolated from myeloma patients after sequential rounds of chemotherapy, revealed for the first time that heparanase, a potent promoter of myeloma growth and progression, was elevated in myeloma cells that survived therapy. Based on this clinical data, we hypothesized that heparanase was involved in myeloma resistance to drug therapy. In several survival and viability assays, elevated heparanase expression promoted resistance of myeloma tumor cells to chemotherapy. Mechanistically, this enhanced survival was due to heparanase-mediated ERK signaling. Importantly, use of the heparanase inhibitor Roneparstat in combination with chemotherapy clearly diminished the growth of disseminated myeloma tumors in vivo. Moreover, use of Roneparstat either during or after chemotherapy diminished regrowth of myeloma tumors in vivo following therapy. These results provide compelling evidence that heparanase is a promising, novel target for overcoming myeloma resistance to therapy and that targeting heparanase has the potential to prevent relapse in myeloma and possibly other cancers. PMID- 26624985 TI - Predictors of high healthcare resource utilization and liver disease progression among patients with chronic hepatitis C. AB - BACKGROUND: Since hepatitis C virus therapy is typically prioritized for patients with more advanced disease, predicting which patients will progress could help direct scarce resources to those likely to benefit most. This study aims to identify demographics and clinical characteristics associated with high healthcare resource utilization (HRU) and liver disease progression among CHC patients. METHODS: Using health insurance claims (January 2001-March 2013), adult patients with >=2 CHC claims (ICD-9-CM: 070.44 or 070.54), and >=6 months of continuous insurance coverage before and >=36 months after the first CHC diagnosis were included. Patients with human immunodeficiency virus were excluded. Generalized estimating equations were used to identify the demographic and clinical characteristics of being in the 20% of patients with the highest HRU. Factors predicting liver disease progression were also identified. RESULTS: In the study population (n = 4898), liver disease severity and both CHC- and non CHC-related comorbidities and conditions were strong predictors of high healthcare costs, with odds ratios (ORs; 95% confidence interval [CI]) for >=2 CHC-related and >=2 non-CHC-related comorbidities/conditions of 2.78 (2.48-3.12) and 2.19 (1.76-2.72), respectively. CHC- and non-CHC-related comorbidities and conditions were also strong predictors of liver disease progression with ORs (95% CI) for >=2 CHC-related and >=2 non-CHC-related comorbidities and conditions of 2.18 (1.83-2.60) and 1.50 (1.14-1.97), respectively. LIMITATIONS: Potential inaccuracies in claims data, information or classification bias, and findings based on a privately insured population. CONCLUSION: This study suggests that CHC patients with high healthcare resource utilization have a high level of comorbidity at baseline and also that non-CHC comorbidities and conditions are strong predictors of high HRU. Non-cirrhotic CHC patients with one or more comorbidities are at high risk of progressing to cirrhosis or end-stage liver disease. PMID- 26624983 TI - Ibrutinib synergizes with poly(ADP-ribose) glycohydrolase inhibitors to induce cell death in AML cells via a BTK-independent mechanism. AB - Targeting Bruton's tyrosine kinase (BTK) with the small molecule BTK inhibitor ibrutinib has significantly improved patient outcomes in several B-cell malignancies, with minimal toxicity. Given the reported expression and constitutive activation of BTK in acute myeloid leukemia (AML) cells, there has been recent interest in investigating the anti-AML activity of ibrutinib. We noted that ibrutinib had limited single-agent toxicity in a panel of AML cell lines and primary AML samples, and therefore sought to identify ibrutinib sensitizing drugs. Using a high-throughput combination chemical screen, we identified that the poly(ADP-ribose) glycohydrolase (PARG) inhibitor ethacridine lactate synergized with ibrutinib in TEX and OCI-AML2 leukemia cell lines. The combination of ibrutinib and ethacridine induced a synergistic increase in reactive oxygen species that was functionally important to explain the observed cell death. Interestingly, synergistic cytotoxicity of ibrutinib and ethacridine was independent of the inhibitory effect of ibrutinib against BTK, as knockdown of BTK did not sensitize TEX and OCI-AML2 cells to ethacridine treatment. Thus, our findings indicate that ibrutinib may have a BTK-independent role in AML and that PARG inhibitors may have utility as part of a combination therapy for this disease. PMID- 26624986 TI - Beyond widowhood: Do prior discovered themes that describe the experiences of older Australian widowed women persist over time? AB - In previous cross-sectional studies researchers have explored the experiences of widowed women in the 1921-1926 cohort of the Australian Longitudinal Study on Women's Health and identified three major themes: health, social relationships and support, and financial and structural issues. In the current study the authors examine longitudinal data collected over 15 years to assess whether these themes persisted and/or evolved over time. The sample included 162 widowed women aged 70-90 years. Thematic analysis was used with a constant comparison method. Many women reported good health despite managing comorbidities. Social relationships frequently shifted from friends to family to more formal support. Most financial and structural issues related to managing increasing health costs as women aged. These results confirmed that the three major themes previously reported persisted over time, and underscore the importance of continuing to support women, and their changing needs, well beyond the initial period of bereavement. PMID- 26624987 TI - Zuclopenthixol versus placebo for schizophrenia. AB - BACKGROUND: Zuclopenthixol is an older antipsychotic that has three distinct formulations (zuclopenthixol dihydrochloride, zuclopenthixol acetate or Acuphase and zuclopenthixol decanoate). Although it has been in common use for many years no previous systematic review of its efficacy compared to placebo in schizophrenia has been undertaken. OBJECTIVES: To evaluate the effectiveness of all formulations of zuclopenthixol when compared with a placebo in schizophrenia. SEARCH METHODS: On 6 November 2013 and 20 October 2015, we searched the Cochrane Schizophrenia Group Trials Register, which is based on regular searches of MEDLINE, EMBASE, CINAHL, BIOSIS, AMED, PubMed, PsycINFO, and registries of clinical trials. We also checked the references of all included studies and contacted authors of included studies for relevant studies and data. SELECTION CRITERIA: We included all randomised controlled trials comparing zuclopenthixol of any form with placebo for treatment of schizophrenia or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We extracted and cross-checked data independently. We identified only a small number of studies so we cross checked all studies. We calculated fixed-effect relative risks (RR) and 95% confidence intervals (CI) for dichotomous data. We analysed by intention-to-treat. Where possible we converted continuous outcomes into dichotomous outcomes. When this was not possible we used mean differences (MD) for continuous variables. We assessed risk of bias for included studies and used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to create a 'Summary of findings' table. MAIN RESULTS: Only two studies, with a total of 65 participants, were eligible for inclusion in the review. Overall the quality of the two studies was low, with small study populations and significant sources of bias, so we were not able to use all the data in our comparisons. . The studies were old from 1968 and 1972, and would be unlikely to pass modern peer review standard. We were only able to find short-term data and only trials randomising zuclopenthixol dihydrochloride. We also hoped to identify data for zuclopenthixol acetate versus placebo and zuclopenthixol decanoate versus placebo comparisons. We were unable to identify any studies that included data on these two fairly widely used drugs.For our primary outcome of interest, clinically significant improvement, we found one study that provided useable data. Global state measured by clinical global impression scale (CGI) improvement showed different ratings when assessed by a psychiatrist or a nurse.The psychiatrist scores failed to achieve statistical significance, however when assessed by nursing staff, the difference favouring zuclopenthixol did reach statistical significance (1 RCT n = 29, RR 2.57 95% CI 1.06 to 6.20, very low quality data). There was also evidence of increased sedation with those treated with zuclopenthixol when compared with placebo (1 RCT n = 29, RR 4.67 95% CI 1.23 to 17.68, very low quality data). 'Leaving the study early' data were equivocal. No useable data were available for outcomes such as relapse, mental state, death, quality of life, service use or economic costs. AUTHORS' CONCLUSIONS: For people with schizophrenia this review shows that zuclopenthixol dihydrochloride may help with the symptoms of schizophrenia. The review provides some trial evidence that, if taking zuclopenthixol dihydrochloride, people may experience some adverse effects and sedation compared with placebo. However this evidence is of very low quality and with some significant sources of bias. There are no data for zuclopenthixol decanoate or zuclopenthixol acetate.For clinicians, the available trial data on the absolute effectiveness of zuclopenthixol dihydrochloride do support its use but the limited nature of the data and significant sources of bias make conclusions hard to draw. Zuclopenthixol in all three forms is a commonly used antipsychotic and it is disappointing that there are so few data regarding its use. PMID- 26624988 TI - Efficacy and Safety of Onychomycosis Treatments: An Evidence-Based Overview. AB - Three systemic agents commonly are used for the treatment of onychomycosis. Until the introduction of ciclopirox in 1999, these were the only FDA-approved therapeutic options for managing these infections. With the recent approval of two new topical antifungal agents-efinaconazole in the azole class, and tavaborole, a unique boron-containing medication- clinicians and patients have an improved roster of medications for managing onychomycosis. Semin Cutan Med Surg 34(supp3):S46-S50 (c) 2015 published by Frontline Medical Communications. PMID- 26624989 TI - A female pelvic bone shape model for air/bone separation in support of synthetic CT generation for radiation therapy. AB - Separating bone from air in MR data is one of the major challenges in using MR images to derive synthetic CT. The problem is further complicated when the anatomic regions filled with air are altered across scans due to air mobility, for instance, in pelvic regions, thereby the air regions estimated using an ultrashort echo time (UTE) sequence are invalid in other image series acquired for multispectral classification. This study aims to develop and investigate a female pelvic bone shape model to identify low intensity regions in MRI where air is unlikely to be present in support of synthetic CT generation without UTE imaging. CT scans of 30 patients were collected for the study, 17 of them also have corresponding MR scans. The shape model was built from the CT dataset, where the reference image was aligned to each of the training images using B-spline deformable registration. Principal component analysis was performed on B-spline coefficients for a compact model where shape variance was described by linear combination of principal modes. The model was applied to identify pelvic bone in MR images by deforming the corresponding MR data of the reference image to target MR images, where the search space of the deformation process was constrained within the subspace spanned by principal modes. The local minima in the search space were removed effectively by the shape model, thus supporting an efficient binary search for the optimal solution. We evaluated the model by its efficacy in identifying bone voxels and excluding air regions. The model was tested across the 17 patients that have corresponding MR scans using a leave-one-out cross validation. A simple model using the first leading principal mode only was found to achieve reasonable accuracy, where an averaged 87% of bone voxels were correctly identified. Finally dilation of the optimally fit bone mask by 5 mm was found to cover 96% of bone voxels while minimally impacting the overlap with air (below 0.4%). PMID- 26624990 TI - Effectiveness and Complications of Percutaneous Needle Tenotomy with a Large Needle for Muscle Contractures: A Cadaver Study. AB - BACKGROUND: Twenty-two percent of institutionalised elderly persons have muscle contractures. Contractures have important functional consequences, rendering hygiene and positioning in bed or in a chair difficult. Medical treatment (such as botulinum toxin injections, physiotherapy or positioning) is not very effective and surgery may be required. Surgery is carried out in the operating theatre, under local or general anaesthesia but is often not possible in fragile patients. Mini-invasive tenotomy could be a useful alternative as it can be carried out in ambulatory care, under local anaesthesia. OBJECTIVE: To evaluate the effectiveness of percutaneous needle tenotomy and the risks of damage to adjacent structures in cadavers. METHOD: Thirty two doctors who had never practiced the technique (physical medicine and rehabilitation specialists, geriatricians and orthopaedic surgeons) carried out 401 tenotomies on the upper and lower limbs of 8 fresh cadavers. A 16G needle was used percutaneous following location of the tendons. After each tenotomy, a neuro-orthopaedic surgeon and an anatomist dissected the area in order to evaluate the success of the tenotomy and any adjacent lesions which had occurred. RESULTS: Of the 401 tenotomies, 72% were complete, 24.9% partial and 2.7% failed. Eight adjacent lesions occurred (2%): 4 (1%) in tendons or muscles, 3 (0.7%) in nerves and 1 (0.2%) in a vessel. CONCLUSION: This percutaneous needle technique effectively ruptured the desired tendons, with few injuries to adjacent structures. Although this study was carried out on cadavers, the results suggest it is safe to carry out on patients. PMID- 26624991 TI - Correction: Are High-Severity Fires Burning at Much Higher Rates Recently than Historically in Dry-Forest Landscapes of the Western USA? PMID- 26624993 TI - Determination of a Central Avascular Triangle within the Obturator Foramen: A Radioanatomic Study. AB - PURPOSE: To map the vascular anatomy of the obturator foramen using fixed anatomic landmarks. METHOD: Twenty obturator regions were dissected in 10 fresh female cadavers after vascular blue dye injection in five cadavers (50%). Furthermore, 104 obturator regions were reconstructed by angiotomodensitometry from 52 women under investigation for suspected arterial disease. The anatomy of the obturator region was mapped by measuring the distance of vascular structures from the middle of the two branches of the ischiopubic bone, which were used as fixed landmarks. RESULTS: The bifurcation of the obturator artery was at a mean (SD) distance of 30.0 mm (4.5) from the middle of the ischiopubic branch (MISP). The anterior branch of the obturator vessels was 15.2 mm (10.1) from the MISP. The posterior branch of the obturator vessels was 5.5 mm (4.0) and 23.6 mm (8.7) from the middle of the outer edge of the obturator foramen (MOE) and the MISP, respectively. Using 5 degrees and 95 degrees percentiles of these measurements we defined a central avascular triangle. CONCLUSIONS: Our data show that, beyond inter-individual variations, a central triangular avascular area can be identified in the obturator foramen between the posterior and anterior obturator artery using fixed landmarks. PMID- 26624992 TI - Metabolic Profiling of Chicken Embryos Exposed to Perfluorooctanoic Acid (PFOA) and Agonists to Peroxisome Proliferator-Activated Receptors. AB - Untargeted metabolic profiling of body fluids in experimental animals and humans exposed to chemicals may reveal early signs of toxicity and indicate toxicity pathways. Avian embryos develop separately from their mothers, which gives unique possibilities to study effects of chemicals during embryo development with minimal confounding factors from the mother. In this study we explored blood plasma and allantoic fluid from chicken embryos as matrices for revealing metabolic changes caused by exposure to chemicals during embryonic development. Embryos were exposed via egg injection on day 7 to the environmental pollutant perfluorooctanoic acid (PFOA), and effects on the metabolic profile on day 12 were compared with those caused by GW7647 and rosiglitazone, which are selective agonists to peroxisome-proliferator activated receptor alpha (PPARalpha) and PPARgamma, respectively. Analysis of the metabolite concentrations from allantoic fluid by Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) showed clear separation between the embryos exposed to GW7647, rosiglitazone, and vehicle control, respectively. In blood plasma only GW7647 caused a significant effect on the metabolic profile. PFOA induced embryo mortality and increased relative liver weight at the highest dose. Sublethal doses of PFOA did not significantly affect the metabolic profile in either matrix, although single metabolites appeared to be altered. Neonatal mortality by PFOA in the mouse has been suggested to be mediated via activation of PPARalpha. However, we found no similarity in the metabolite profile of chicken embryos exposed to PFOA with those of embryos exposed to PPAR agonists. This indicates that PFOA does not activate PPAR pathways in our model at concentrations in eggs and embryos well above those found in wild birds. The present study suggests that allantoic fluid and plasma from chicken embryos are useful and complementary matrices for exploring effects on the metabolic profile resulting from chemical exposure during embryonic development. PMID- 26624994 TI - The Interaction of Deworming, Improved Sanitation, and Household Flooring with Soil-Transmitted Helminth Infection in Rural Bangladesh. AB - BACKGROUND: The combination of deworming and improved sanitation or hygiene may result in greater reductions in soil-transmitted helminth (STH) infection than any single intervention on its own. We measured STH prevalence in rural Bangladesh and assessed potential interactions among deworming, hygienic latrines, and household finished floors. METHODOLOGY: We conducted a cross sectional survey (n = 1,630) in 100 villages in rural Bangladesh to measure three exposures: self-reported deworming consumption in the past 6 months, access to a hygienic latrine, and household flooring material. We collected stool samples from children 1-4 years, 5-12 years, and women 15-49 years. We performed mini FLOTAC on preserved stool samples to detect Ascaris lumbricoides, Enterobius vermicularis, hookworm, and Trichuris trichiura ova. Approximately one-third (32%) of all individuals and 40% of school-aged children had an STH infection. Less than 2% of the sample had moderate/heavy intensity infections. Deworming was associated with lower Ascaris prevalence (adjusted prevalence ratio (PR) = 0.53; 95% CI 0.40, 0.71), but there was no significant association with hookworm (PR = 0.93, 95% CI 0.60, 1.44) or Trichuris (PR = 0.90, 95% CI 0.74, 1.08). PRs for hygienic latrine access were 0.91 (95% CI 0.67,1.24), 0.73 (95% CI 0.43,1.24), and 1.03 (95% CI 0.84,1.27) for Ascaris, hookworm, and Trichuris, respectively. Finished floors were associated with lower Ascaris prevalence (PR = 0.56, 95% CI 0.32, 0.97) but not associated with hookworm (PR = 0.48 95% CI 0.16,1.45) or Trichuris (PR = 0.98, 95% CI 0.72,1.33). Across helminths and combinations of exposures, adjusted prevalence ratios for joint exposures were consistently more protective than those for individual exposures. CONCLUSIONS: We found moderate STH prevalence in rural Bangladesh among children and women of childbearing age. This study is one of the first to examine independent and combined associations with deworming, sanitation, and hygiene. Our results suggest that coupling deworming with sanitation and flooring interventions may yield more sustained reductions in STH prevalence. PMID- 26624995 TI - A PCR-Based Method to Construct Lentiviral Vector Expressing Double Tough Decoy for miRNA Inhibition. AB - DNA vector-encoded Tough Decoy (TuD) miRNA inhibitor is attracting increased attention due to its high efficiency in miRNA suppression. The current methods used to construct TuD vectors are based on synthesizing long oligonucleotides (~90 mer), which have been costly and problematic because of mutations during synthesis. In this study, we report a PCR-based method for the generation of double Tough Decoy (dTuD) vector in which only two sets of shorter oligonucleotides (< 60 mer) were used. Different approaches were employed to test the inhibitory potency of dTuDs. We demonstrated that dTuD is the most efficient method in miRNA inhibition in vitro and in vivo. Using this method, a mini dTuD library against 88 human miRNAs was constructed and used for a high-throughput screening (HTS) of AP-1 pathway-related miRNAs. Seven miRNAs (miR-18b-5p, -101 3p, -148b-3p, -130b-3p, -186-3p, -187-3p and -1324) were identified as candidates involved in AP-1 pathway regulation. This novel method allows for an accurate and cost-effective generation of dTuD miRNA inhibitor, providing a powerful tool for efficient miRNA suppression in vitro and in vivo. PMID- 26624997 TI - Correction: Health Behaviours As a Mechanism in the Prospective Relation between Workplace Reciprocity and Absenteeism: A Bridge too Far? PMID- 26624996 TI - Recruitment of Mediator Complex by Cell Type and Stage-Specific Factors Required for Tissue-Specific TAF Dependent Gene Activation in an Adult Stem Cell Lineage. AB - Onset of terminal differentiation in adult stem cell lineages is commonly marked by robust activation of new transcriptional programs required to make the appropriate differentiated cell type(s). In the Drosophila male germ line stem cell lineage, the switch from proliferating spermatogonia to spermatocyte is accompanied by one of the most dramatic transcriptional changes in the fly, as over 1000 new transcripts turn on in preparation for meiosis and spermatid differentiation. Here we show that function of the coactivator complex Mediator is required for activation of hundreds of new transcripts in the spermatocyte program. Mediator appears to act in a sequential hierarchy, with the testis activating Complex (tMAC), a cell type specific form of the Mip/dREAM general repressor, required to recruit Mediator subunits to the chromatin, and Mediator function required to recruit the testis TAFs (tTAFs), spermatocyte specific homologs of subunits of TFIID. Mediator, tMAC and the tTAFs co-regulate expression of a major set of spermatid differentiation genes. The Mediator subunit Med22 binds the tMAC component Topi when the two are coexpressed in S2 cells, suggesting direct recruitment. Loss of Med22 function in spermatocytes causes meiosis I maturation arrest male infertility, similar to loss of function of the tMAC subunits or the tTAFs. Our results illuminate how cell type specific versions of the Mip/dREAM complex and the general transcription machinery cooperate to drive selective gene activation during differentiation in stem cell lineages. PMID- 26624998 TI - Schizosaccharomyces pombe Homologs of Human DJ-1 Are Stationary Phase-Associated Proteins That Are Involved in Autophagy and Oxidative Stress Resistance. AB - The Parkinson's disease protein DJ-1 is involved in various cellular functions including detoxification of dicarbonyl compounds, autophagy and oxidative stress response. DJ-1 homologs are widely found in both prokaryotes and eukaryotes, constituting a superfamily of proteins that appear to be involved in stress response. Schizosaccharomyces pombe contains six DJ-1 homologs, designated Hsp3101-Hsp3105 and Sdj1 (previously named SpDJ-1). Here we show that deletion of any one of these six genes somehow affects autophagy during prolonged stationary phase. Furthermore, deletions of each of these DJ-1 homologs result in reduced stationary phase survival. Deletion of sdj1 also increases the sensitivity of stationary-phase cells to oxidative stress induced by hydrogen peroxide (H2O2) whereas overexpression of sdj1 has the opposite effect. Consistent with their role in stationary phase, expression of hsp3101, hsp3102, hsp3105 and sdj1, and to a lesser extent hsp3103 and hsp3104, is increased in stationary phase. The induction of hsp3101, hsp3102, hsp3105 and sdj1 involves the Sty1-regulated transcription factor Atf1 but not the transcription factor Pap1. Our results firmly establish that S. pombe homologs of DJ-1 are stationary-phase associated proteins and are likely involved in autophagy and antioxidant defense in stationary phase of S. pombe cells. PMID- 26624999 TI - Transcriptional Up-Regulation of APE1/Ref-1 in Hepatic Tumor: Role in Hepatocytes Resistance to Oxidative Stress and Apoptosis. AB - OBJECTIVE: Human Hepatocellular Carcinoma (HCC) is the fifth most frequent neoplasm worldwide and the most serious complication of long-standing chronic liver diseases (CLD). Its development is associated with chronic inflammation and sustained oxidative stress. Deregulation of apurinic apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1), a master regulator of cellular response to oxidative stress, has been associated with poor prognosis in several cancers including HCC. DESIGN: In the present study we investigated the APE1/Ref-1 mRNA levels in cirrhotic and HCC tissues obtained during HCC resection. The possible protective role of APE1/Ref-1 against oxidative stress and apoptosis was evaluated in vitro in immortalized human hepatocytes (IHH) over-expressing APE1/Ref-1. RESULTS: APE1/Ref-1 was up-regulated in HCC, regulation occurring at the transcriptional level. APE1/Ref-1 mRNA content increased with the progression of liver disease with the transcriptional up-regulation present in cirrhosis significantly increased in HCC. The up-regulation was higher in the less differentiated cancers. In vitro, over-expression of APE1/Ref-1 in normal hepatocytes conferred cell protection against oxidative stress and it was associated with BAX inhibition and escape from apoptosis. CONCLUSION: APE1/Ref-1 is up-regulated in HCC and this over-expression correlates with cancer aggressiveness. The up-regulation occurs at the transcriptional level and it is present in the earliest phases of hepatocarcinogenesis. The APE-1/Ref-1 over expression is associated with hepatocyte survival and inhibits BAX activation and apoptosis. These data suggest a possible role of APE1/Ref-1 over-expression both in hepatocyte survival and HCC development calling attention to this molecule as a promising marker for HCC diagnosis and treatment. PMID- 26625000 TI - Representation and Processing of Lexical Tone and Tonal Variants: Evidence from the Mismatch Negativity. AB - Pronunciation variation is ubiquitous in the speech signal. Different models of lexical representation have been put forward to deal with speech variability, which differ in the level as well as the nature of mental representation. We present the first mismatch negativity (MMN) study investigating the effect of allophonic variation on the mental representation and neural processing of lexical tones. Native speakers of Standard Chinese (SC) participated in an oddball electroencephalography (EEG) experiment. All stimuli have the same segments (ma) but different lexical tones: level [T1], rising [T2], and dipping [T3]. In connected speech with a T3T3 sequence, the first T3 may undergo allophonic change and is produced with a rising pitch contour (T3V), similar to the lexical T2 pitch contour. Four oddball conditions were constructed (T1/T3, T3/T1, T2/T3, T3/T2; standard/deviant). All four conditions elicited MMN effects, with the T1-T3 pair eliciting comparable MMNs, but the T2-T3 pair asymmetrical MMN effects. There were significantly greater and earlier MMN effects in the T2/T3 condition than that in the reversed T3/T2 condition. Furthermore, the T3/T2 condition showed more rightward MMN effects than the T2/T3 condition and the T1 T3 pair. Such asymmetries suggest co-activation of long-term memory representations of both T3 and T3V when T3 serves as the standard. The acoustic similarity between the activated T3V (by the standard T3) and the incoming deviant stimulus T2 induces acoustic processing of the tonal contrast in the T3/T2 condition, similar to that of within-category lexical tone processing, which is in contrast to the processing of between-category lexical tones observed in the T2/T3, T1/T3, and T3/T1 conditions. PMID- 26625001 TI - Disability and Living with HIV: Baseline from a Cohort of People on Long Term ART in South Africa. AB - BACKGROUND: Through access to life saving antiretroviral treatment (ART) in southern Africa, HIV has been reconceptualised as a chronic disease. This comes with new challenges of HIV-related co-morbidities and disabilities. We still lack an understanding of the types and scope of disabilities experienced by people on long term ART and how this impacts health, adherence, and livelihood. This paper describes the results of a cohort study examining the new health- and disability related needs of the millions of people on ART in the region. METHODS: Data was collected from a cohort of people who had been on ART for six months or longer in a semi-urban public health care setting in South Africa. 1042 adults (18 and older) participated in the cross-sectional study which investigated disabilities/activity limitations, health, ART adherence, depression symptoms, and livelihood. We analysed the associations between these constructs using descriptive statistics, and bivariate and multivariate analyses. RESULTS: A large number of participants (35.5%) obtained a weighted score of two or more on the WHODAS 2.0 indicating possible activity limitations. A positive relationship was found between activity limitations and depression symptoms, adherence, and worse health outcomes, while none was found for BMI or CD4 count. These associations varied by type of activity limitations and, in some cases, by gender. CONCLUSION: Activity limitations are potentially experienced by a large portion of people on ART in southern Africa which impacts health and ART adherence negatively. These results highlight the importance of better understanding the new health-related needs of people who are on long term ART, as well as the nuances of the disability they experience. This is urgently needed in order to enable HIV endemic countries to better prepare for the new health-related needs of the millions of people on ART in southern Africa. PMID- 26625002 TI - Predicting Perinatal Outcome from Prenatal Ultrasound Characteristics in Pregnancies Complicated by Gastroschisis. AB - INTRODUCTION: The objective of the study was to establish the predictive value of prenatal ultrasound markers for complex gastroschisis (GS) in the first 10 days of life. MATERIAL AND METHODS: In this retrospective cohort study over 11 years (2000-2011) of 117 GS cases, the following prenatal ultrasound signs were analyzed at the last second- and third-trimester ultrasounds: intrauterine growth restriction, intra-abdominal bowel dilatation (IABD) adjusted for gestational age, extra-abdominal bowel dilatation (EABD) >=25 mm, stomach dilatation, stomach herniation, perturbed mesenteric circulation, absence of bowel lumen and echogenic dilated bowel loops (EDBL). RESULTS: Among 114 live births, 16 newborns had complex GS (14.0%). Death was seen in 16 cases (13.7%): 3 intrauterine fetal deaths, 9 complex GS and 4 simple GS. Second-trimester markers had limited predictive value. Third-trimester IABD, EABD, EDBL, absence of intestinal lumen and perturbed mesenteric circulation were statistically associated with complex GS and death. IABD was able to predict complex GS with a sensitivity of 50%, a specificity of 91%, a positive predictive value of 47% and a negative predictive value of 92%. DISCUSSION: Third-trimester IABD adjusted for gestational age appears to be the prenatal ultrasound marker most strongly associated with adverse outcome in GS. PMID- 26625003 TI - Can Fasting Glucose Levels or Post-Breakfast Glucose Fluctuations Predict the Occurrence of Nocturnal Asymptomatic Hypoglycemia in Type 1 Diabetic Patients Receiving Basal-Bolus Insulin Therapy with Long-Acting Insulin? AB - OBJECTIVE: To investigate whether the occurrence of nocturnal asymptomatic hypoglycemia may be predicted based on fasting glucose levels and post-breakfast glucose fluctuations. PATIENTS AND METHODS: The study subjects comprised type 1 diabetic patients who underwent CGM assessments and received basal-bolus insulin therapy with long-acting insulin. The subjects were evaluated for I) fasting glucose levels and II) the range of post-breakfast glucose elevation (from fasting glucose levels to postprandial 1- and 2-hour glucose levels). The patients were divided into those with asymptomatic hypoglycemia during nighttime and those without for comparison. Optimal cut-off values were also determined for relevant parameters that could predict nighttime hypoglycemia by using ROC analysis. RESULTS: 64 patients (mean HbA1c 8.7 +/- 1.8%) were available for analysis. Nocturnal asymptomatic hypoglycemia occurred in 23 patients (35.9%). Fasting glucose levels (I) were significantly lower in those with hypoglycemia than those without (118 +/- 35 mg/dL vs. 179 +/- 65 mg/dL; P < 0.001). The range of post-breakfast glucose elevation (II) was significantly greater in those with hypoglycemia than in those without (postprandial 1-h, P = 0.003; postprandial 2 h, P = 0.005). The cut-off values determined for relevant factors were as follows: (I) fasting glucose level < 135 mg/dL (sensitivity 0.73/specificity 0.83/AUC 0.79, P < 0.001); and (II) 1-h postprandial elevation > 54 mg/dL (0.65/0.61/0.71, P = 0.006), 2-h postprandial elevation > 78 mg/dL (0.65/0.73/0.71, P = 0.005). CONCLUSIONS: Nocturnal asymptomatic hypoglycemia was associated with increases in post-breakfast glucose levels in type 1 diabetes. Study findings also suggest that fasting glucose levels and the range of post breakfast glucose elevation could help predict the occurrence of nocturnal asymptomatic hypoglycemia. PMID- 26625004 TI - Pilot trial of paclitaxel-trastuzumab adjuvant therapy for early stage breast cancer: a trial of the ECOG-ACRIN cancer research group (E2198). AB - BACKGROUND: Blockade of human epidermal growth factor receptor type 2 (HER2) has dramatically improved outcome for patients with HER2-positive breast cancer. Trastuzumab, an anti-HER2 monoclonal antibody, has previously demonstrated improvement in overall survival (OS) in patients with metastatic and early stage HER2-positive breast cancer. However, trastuzumab can cause congestive heart failure (CHF) with an increased frequency for patients who have also received an anthracycline. The current trial was designed to evaluate the impact of the duration of trastuzumab on CHF. METHODS: E2198 included 227 eligible women with histologically confirmed stage II or IIIA HER2-positive breast cancer. The patients were randomised to receive 12 weeks of paclitaxel and trastuzumab followed by four cycles of doxorubicin and cyclophosphamide (abbreviated Arm) or the aforementioned treatment with additional 1 year of trastuzumab (conventional Arm). The primary end point was to evaluate the safety of this variable duration of trastuzumab therapy, particularly cardiac toxicity defined as CHF or left ventricular ejection fraction decrease >10%. Secondary end points included disease-free survival (DFS) and OS. RESULTS: Compared with 12-week treatment with trastuzumab, 1 year of trastuzumab-based therapy did not increase the frequency or severity of cardiac toxicity: three patients on the abbreviated Arm and four on the conventional Arm experienced CHF. The 5-year DFS was 76% and 73% for the abbreviated and conventional Arms, respectively, with a hazard ratio (HR) of 1.3 (95% CI: 0.8-2.1; P=0.3). There was also no statistically significance difference in OS (HR, 1.4; P=0.3). CONCLUSIONS: Compared with 12 weeks of treatment, 1 year of treatment with trastuzumab did not significantly increase the risk of cardiac toxicity. Although not powered for efficacy comparisons, the longer duration of trastuzumab therapy did not demonstrate a signal for marked superiority. PMID- 26625005 TI - Colorectal cancer, comorbidity, and risk of venous thromboembolism: assessment of biological interactions in a Danish nationwide cohort. AB - BACKGROUND: Venous thromboembolism (VTE) is a major source of morbidity and mortality in cancer patients. Incident colorectal cancer (CRC) and comorbidity both predict VTE, but potential synergy between these factors has not been explored. METHODS: Danish nationwide cohort study of CRC cases diagnosed in 1995 2010 and a matched general population reference cohort of subjects without CRC who matched cases on age, sex, and comorbidities. We calculated the Charlson Comorbidity Index using diagnoses recorded in the Danish National Patient Registry. We calculated standardised incidence rates (SIRs) and interaction contrasts (IC) to measure additive interaction between comorbidity and CRC status with respect to 5-year VTE incidence. RESULTS: Among 56 189 CRC patients, 1372 VTE cases were diagnosed over 145 211 person-years (SIR=9.5 cases per 1000 person years). Among 271 670 reference subjects, 2867 VTE cases were diagnosed over 1 068 860 person-years (SIR=2.8 cases per 1000 person-years). CRC and comorbidity were positively and independently associated with VTE, but there was no evidence for biological interaction between these factors (e.g., comparing the 'severe comorbidity' stratum with the 'no comorbidity' stratum, IC=0.8, 95% CI: -3.3, 4.8). CONCLUSIONS: There is neither a deficit nor a surplus of VTE cases among patients with both comorbidity and CRC, compared with rates expected from these risk factors in isolation. PMID- 26625007 TI - Systematic Protein Level Regulation via Degradation Machinery Induced by Genotoxic Drugs. AB - In this study we monitored protein dynamics in response to cisplatin, 5 fluorouracil, and irinotecan with different concentrations and administration modes using "reverse-phase" protein arrays (RPPAs) in order to gain comprehensive insight into the protein dynamics induced by genotoxic drugs. Among 666 protein time-courses, 38% exhibited an increasing trend, 32% exhibited a steady decrease, and 30% fluctuated within 24 h after drug exposure. We analyzed almost 12,000 time-course pairs of protein levels based on the geometrical similarity by correlation distance (dCor). Twenty-two percent of the pairs showed dCor > 0.8, which indicates that each protein of the pair had similar dynamics. These trends were disrupted by a proteasome inhibitor, MG132, suggesting that the protein degradation system was activated in response to the drugs. Among the pairs with high dCor, the average dCor of pairs with apoptosis-related protein was significantly higher than those without, indicating that regulation of protein levels was induced by the drugs. These results suggest that the levels of numerous functionally distinct proteins may be regulated by common degradation machinery induced by genotoxic drugs. PMID- 26625008 TI - Influence of Antipodally Coupled Iodine and Carbon Atoms on the Cage Structure of 9,12-I2-closo-1,2-C2B10H10: An Electron Diffraction and Computational Study. AB - Because of the comparable electron scattering abilities of carbon and boron, the electron diffraction structure of the C2v-symmetric molecule closo-1,2-C2B10H12 (1), one of the building blocks of boron cluster chemistry, is not as accurate as it could be. On that basis, we have prepared the known diiodo derivative of 1, 9,12-I2-closo-1,2-C2B10H10 (2), which has the same point-group symmetry as 1 but in which the presence of iodine atoms, with their much stronger ability to scatter electrons, ensures much better structural characterization of the C2B10 icosahedral core. Furthermore, the influence on the C2B10 geometry in 2 of the antipodally positioned iodine substituents with respect to both carbon atoms has been examined using the concerted application of gas electron diffraction and quantum chemical calculations at the MP2 and density functional theory (DFT) levels. The experimental and computed molecular geometries are in good overall agreement. Molecular dynamics simulations used to obtain vibrational parameters, which are needed for analyzing the electron diffraction data, have been performed for the first time for this class of compound. According to DFT calculations at the ZORA-SO/BP86 level, the (11)B chemical shifts of the boron atoms to which the iodine substituents are bonded are dominated by spin-orbit coupling. Magnetically induced currents within 2 have been calculated and compared to those for [B12H12](2-), the latter adopting a regular icosahedral structure with Ih point group symmetry. Similar total current strengths are found but with a certain anisotropy, suggesting that spherical aromaticity is present; electron delocalization in the plane of the hetero atoms in 2 is slightly hindered compared to that for [B12H12](2-), presumably because of the departure from ideal icosahedral symmetry. PMID- 26625006 TI - Hypermethylation of genes in testicular embryonal carcinomas. AB - BACKGROUND: Testicular embryonal carcinoma (EC) is a major subtype of non seminomatous germ cell tumours in males. Embryonal carcinomas are pluripotent, undifferentiated germ cell tumours believed to originate from primordial germ cells. Epigenetic changes during testicular EC tumorigenesis require better elucidation. METHODS: To identify epigenetic changes during testicular neoplastic transformation, we profiled DNA methylation of six ECs. These samples represent different stages (stage I and stage III) of divergent invasiveness. Non-cancerous testicular tissues were included. Expression of a number of hypermethylated genes were examined by quantitative RT-PCR and immunohistochemistry (IHC). RESULTS: A total of 1167 tumour-hypermethylated differentially methylated regions (DMRs) were identified across the genome. Among them, 40 genes/ncRNAs were found to have hypermethylated promoters. Quantitative RT-PCR confirmed downregulation of 8 out of 9 of the genes. Among the confirmed genes, five were sex-linked genes, including X-linked genes STAG2, SPANXD/E and MIR1184, and Y-linked genes RBMY1A1/1B/1D and FAM197Y2P. RBMY1A is a testis-specific gene for spermatogenesis. RNF168 and USP13 are potential tumour suppressors. Expression of RBMY1A was lost in EC and seminoma as documented in the Protein Atlas. We confirmed downregulation of USP13 in EC by IHC. CONCLUSIONS: Our genome-wide analysis of testicular EC identified methylation changes in several previously unknown genes. This may provide insight of crosstalk between normal germ cell development and carcinogenesis. PMID- 26625009 TI - Anxiety and oppositional behavior profiles among youth with selective mutism. AB - Selective mutism (SM) is a debilitating condition in which a child does not speak in social situations where speech is expected. The clinical conceptualization of SM has been debated historically, with evidence pointing partly to anxious and oppositional behavior profiles. Behavioral characteristics were examined in a clinical sample of 57 youth formally diagnosed with selective mutism. Parents rated children across internalizing and externalizing behaviors on the Child Behavior Checklist. Eighteen highly rated items were subjected to exploratory and then confirmatory factor analysis. Anxiety and oppositional behavior factors were derived. The anxious behavior profile was associated with social anxiety disorder symptoms, social problems, and aggressive behaviors but not oppositional defiant disorder symptoms. The oppositional behavior profile was associated with aggressive behaviors, oppositional defiant disorder symptoms, social problems, and inversely to social anxiety disorder symptoms. Results are consistent with emerging research regarding subgroups of children with SM. Behavior profiles are discussed as well with respect to assessment and treatment implications. LEARNING OUTCOMES: Readers will learn about the nature of children with selective mutism as well as behaviors that differentiate anxious and oppositional behavior profiles. Items that comprise anxious and oppositional behavior profiles are presented. These item profiles may have ramifications for assessment and treatment. PMID- 26625010 TI - Water-Mediated Dimerization of Ubiquitin Ions Captured by Cryogenic Ion Mobility Mass Spectrometry. AB - The dynamics, structures, and functions of most biological molecules are strongly influenced by the nature of the peptide's or protein's interaction with water. Here, cryogenic ion mobility-mass spectrometry studies of ubiquitin have directly captured a water-mediated protein-protein binding event involving hydrated, noncovalently bound dimer ions in solution, and this interaction has potential relevance to one of the most important protein-protein interactions in nature. As solvent is removed, dimer ions, viz. [2 M + 14H](14+), can be stabilized by only a few attached water molecules prior to dissociation into individual monomeric ions. The hydrophobic patch of ubiquitin formed by the side chains of Leu-8, Ile 44, and Val-70 meet all the necessary conditions for a protein-protein binding "hot spot," including the requirement for occlusion of water to nearby hydrophilic sites, and it is suggested that this interaction is responsible for formation of the hydrated noncovalent ubiquitin dimer. PMID- 26625012 TI - Lift-Off Free Fabrication Approach for Periodic Structures with Tunable Nano Gaps for Interdigitated Electrode Arrays. AB - We report a simple, low-cost and lift-off free fabrication approach for periodic structures with adjustable nanometer gaps for interdigitated electrode arrays (IDAs). It combines an initial structure and two deposition process steps; first a dielectric layer is deposited, followed by a metal evaporation. The initial structure can be realized by lithography or any other structuring technique (e.g., nano imprint, hot embossing or injection molding). This method allows the fabrication of nanometer sized gaps and completely eliminates the need for a lift off process. Different substrate materials like silicon, Pyrex or polymers can be used. The electrode gap is controlled primarily by sputter deposition of the initial structure, and thus, adjustable gaps in the nanometer range can be realized independently of the mask or stamp pattern. Electrochemical characterizations using redox cycling in ferrocenemethanol (FcMeOH) demonstrate signal amplification factors of more than 110 together with collection factors higher than 99%. Furthermore, the correlation between the gap width and the amplification factor was studied to obtain an electrochemical performance assessment of the nano gap electrodes. The results demonstrate an exponential relationship between amplification factor and gap width. PMID- 26625011 TI - Supramolecular Au(I)-Cu(I) Complexes as New Luminescent Labels for Covalent Bioconjugation. AB - Two new supramolecular organometallic complexes, namely, [Au6Cu2(C2C6H4CHO)6(PPh2C6H4PPh2)3](PF6)2 and [Au6Cu2(C2C6H4NCS)6(PPh2C6H4PPh2)3](PF6)2, with highly reactive aldehyde and isothiocyanate groups have been synthesized and characterized using X-ray crystallography, ESI mass spectrometry, and NMR spectroscopy. The compounds obtained demonstrated bright emission in solution with the excited-state lifetime in microsecond domain both under single- and two-photon excitation. The luminescent complexes were found to be suitable for bioconjugation in aqueous media. In particular, they are able to form the covalent conjugates with proteins of different molecular size (soybean trypsin inhibitor, human serum albumin, rabbit anti-HSA antibodies). The conjugates demonstrated a high level of the phosphorescent emission from the covalently bound label, excellent solubility, and high stability in physiological media. The highest quantum yield, storage stability, and luminance were detected for bioconjugates formed by covalent attachment of the aldehyde-bearing supramolecular Au(I)-Cu(I) complex. The measured biological activity of one of the labeled model proteins clearly showed that introduced label did not prevent the biorecognition and specific protein protein complex formation that was extremely important for the application of the conjugates in biomolecular detection and imaging. PMID- 26625013 TI - Chemoproteomic profiling of protein modifications by lipid-derived electrophiles. AB - Lipid-derived electrophiles (LDEs) are a group of endogenous reactive metabolites generated as products of lipid peroxidation when cells are under oxidative stress. LDEs are able to covalently modify nucleophilic residues in proteins to alter their structures and activities, either resulting in irreversible functional damage or triggering aberrant signaling pathways. Traditional biochemical methods have revealed individual protein targets modified by LDEs, however, deciphering the toxicity and/or signaling roles of LDEs requires systematic studies of these modifications in a high-throughput fashion. Here we survey recent progress in developing chemical proteomic strategies to globally profile protein-LDE interactions directly from complex proteomes. These powerful chemoproteomic methods have yielded a rich inventory of proteins and residue sites that are sensitive to LDE modification, serving as valuable resources to investigate mechanisms of their cellular toxicity at the molecular level. PMID- 26625015 TI - Multilayer recording holographic data storage using a varifocal lens generated with a kinoform. AB - A multilayer recording method using a varifocal lens generated with a kinoform is presented. In this recording method, a focus position is axially displaced by adding a defocus phase to a phase modulation pattern, which consists of a random phase mask and a computer-generated reference pattern. Shift selectivity and multiplexed recording are experimentally investigated in coaxial holographic data storage. Experimental results show that the proposed method allows the recording of holograms along an optical axis without any mechanical movement. PMID- 26625016 TI - Experimental demonstration of sub-picosecond optical pulse shaping in silicon based on discrete space-to-time mapping. AB - We experimentally demonstrate on-chip optical pulse shaping based on discrete space-to-time mapping in cascaded co-directional couplers. The demonstrated shapers validate a recent design methodology that exploits the direct relationship between the discrete complex spatial apodization profile of a structure of cascaded couplers and the time-domain impulse response of the device. In this design, the amplitude and phase of the apodization profile can be controlled through the coupling strength of each coupler and the relative time delay between the waveguides connecting consecutive couplers, respectively. This design methodology has been successfully used to demonstrate direct synthesis of high-quality flat-top and phase-coded pulse trains with resolutions down to the sub-picosecond range using passive devices in a silicon-on-insulator platform. PMID- 26625014 TI - RNA epigenetics--chemical messages for posttranscriptional gene regulation. AB - Chemical modifications in cellular RNA are diverse and abundant. Commonly found in ribosomal RNA (rRNA), transfer RNA (tRNA), long-noncoding RNA (lncRNA), and small nuclear (snRNA), these components play various structural and functional roles. Until recently, the roles of chemical modifications within messenger RNA (mRNA) have been understudied. Recent maps of several mRNA modifications have suggested regulatory functions for these marks. This review summarizes recent advances in identifying and understanding biological roles of posttranscriptional mRNA modification, or 'RNA epigenetics', with an emphasis on the most common internal modification of eukaryotic mRNA, N(6)-methyladenosine (m(6)A). We also discuss YTH proteins as direct mediators of m(6)A function and the emerging role of this mark in a new layer of gene expression regulation. PMID- 26625017 TI - Overcoming bifurcation instability in high-repetition-rate Ho:YLF regenerative amplifiers. AB - We demonstrate a Ho:YLF regenerative amplifier (RA) overcoming bifurcation instability and consequently achieving high extraction energies of 6.9 mJ at a repetition rate of 1 kHz with pulse-to-pulse fluctuations of 1.1%. Measurements of the output pulse energy, corroborated by numerical simulations, identify an operation point (OP) that allows high-energy pulse extraction at a minimum noise level. Complete suppression of the onset of bifurcation was achieved by gain saturation after each pumping cycle in the Ho:YLF crystal via lowering the repetition rate and cooling the crystal. Even for moderate cooling, a significant temperature dependence of the Ho:YLF RA performance was observed. PMID- 26625018 TI - Mode-interactions and polarization conversion in a crystalline microresonator. AB - We observe couplings between orthogonally polarized modes in a birefringent whispering-gallery-mode resonator. The modes show strong interactions leading to polarization conversion and avoid mode crossings. We show that a phenomenological model, based on the coupled-mode theory, is in good agreement with the experiments. The device provides an excellent laboratory to perform controllable and tunable mode interactions. PMID- 26625020 TI - Schrodinger plasmon-solitons in Kerr nonlinear heterostructures with magnetic manipulation. AB - We investigate surface plasmon-soliton (SPS) propagation in transverse magnetic field in heterostructures with Kerr nonlinearity. The nonlinear Schrodinger equation in the framework of perturbation theory has been derived for three cases: a single-interface metal/nonlinear-dielectric structure and double interface structures of nonlinear-dielectric/metal/dielectric with either ferromagnetic or nonmagnetic dielectric. The effect of the magneto-optical nonreciprocity in the Schrodinger equation is found. The estimations show that the effect is the strongest for the double-interface structure with a magnetic substrate in the vicinity of the resonant plasmonic frequency. We have also shown that the external magnetic field modifies SPS amplitude and width. PMID- 26625019 TI - Spectrally reconfigurable integrated multi-spot particle trap. AB - Optical manipulation of small particles in the form of trapping, pushing, or sorting has developed into a vast field with applications in the life sciences, biophysics, and atomic physics. Recently, there has been increasing effort toward integration of particle manipulation techniques with integrated photonic structures on self-contained optofluidic chips. Here, we use the wavelength dependence of multi-spot pattern formation in multimode interference (MMI) waveguides to create a new type of reconfigurable, integrated optical particle trap. Interfering lateral MMI modes create multiple trapping spots in an intersecting fluidic channel. The number of trapping spots can be dynamically controlled by altering the trapping wavelength. This novel, spectral reconfigurability is utilized to deterministically move single and multiple particles between different trapping locations along the channel. This fully integrated multi-particle trap can form the basis of high throughput biophotonic assays on a chip. PMID- 26625021 TI - Observation of localized flat-band modes in a quasi-one-dimensional photonic rhombic lattice. AB - We experimentally demonstrate the photonic realization of a dispersionless flat band in a quasi-one-dimensional photonic lattice fabricated by ultrafast laser inscription. In the nearest neighbor tight binding approximation, the lattice supports two dispersive and one nondispersive (flat) band. We experimentally excite superpositions of flat-band eigenmodes at the input of the photonic lattice and show the diffractionless propagation of the input states due to their infinite effective mass. In the future, the use of photonic rhombic lattices, together with the successful implementation of a synthetic gauge field, will enable the observation of Aharonov-Bohm photonic caging. PMID- 26625022 TI - Light source for narrow and broadband coherent Raman scattering microspectroscopy. AB - We present a light source that is well adapted to both narrow- and broadband coherent Raman scattering (CRS) methods. Based on a single oscillator, the light source delivers synchronized broadband pulses via supercontinuum generation and narrowband, frequency-tunable pulses via four-wave mixing in a photonic crystal fiber. Seeding the four-wave mixing with a spectrally filtered part of the supercontinuum yields high-pulse energies up to 8 nJ and the possibility of scanning a bandwidth of 2000 cm(-1) in 25 ms. All pulses are emitted with a repetition frequency of 1 MHz, which ensures efficient generation of CRS signals while avoiding significant damage of the samples. Consequently, the light source combines the performance of individual narrow- and broadband CRS light sources in one setup, thus enabling hyperspectral imaging and rapid single-resonance imaging in parallel. PMID- 26625023 TI - Nondiffracting Bessel beams with polarization state that varies with propagation distance. AB - We generate nondiffracting Bessel beams whose polarization state varies with propagation distance. We use a reflective geometry where a single parallel aligned spatial light modulator device is used to spatially modulate two orthogonal linear polarizations with two axicon phase profiles. Then, by adding an extra phase retardation radial profile between these linear states, we are able to modulate the state of polarization along the line focus of the axicon. We provide experimental results that demonstrate the polarization axial control with zero-order and higher order Bessel beams. PMID- 26625024 TI - Ar plasma irradiation improved optical and electrical properties of TiO2/Ag/TiO2 multilayer thin film. AB - Embedding a thin metal layer between two thin dielectric or semiconductor layers [dielectric/metal/dielectric (DMD)] leads to a kind of transparent electrode that is promising as a substitute for the currently widely applied indium tin oxide electrode. However, the optical and electrical properties of DMD still wait for further improvement. In this study, Ar plasma irradiation (API) was, for the first time to our knowledge, applied to improve the optical and electrical properties of a TiO2/Ag/TiO2 electrode that was fabricated by electron-beam evaporation of TiO2 and electric-resistance heating of high purity Ag under vacuum. Ar plasma was produced by radio frequency glow discharge. The Ag layer was bombarded before the second layer of TiO2 was deposited. The electrode with configuration of TiO2 (24 nm)/Ag(14 nm)/TiO2 (24 nm) after API for 10 s shows excellent performance. The mean transmittance between 370 and 800 nm reaches 94% and the sheet resistance is as low as 6 Omega/sq, while Haacke's figure of merit is as high as 112*10(-3) Omega(-1). The improvement mechanism is discussed based on field emission scanning electron microscope images and absorption spectra. The improvement is attributed to the fact that API reduces the localized surface plasmon resonance of Ag nanoparticles and makes the Ag film thinner and denser. PMID- 26625025 TI - In situ probing of mode-locked vertical-external-cavity-surface-emitting lasers. AB - We utilize an asynchronous optical sampling technique to study the gain dynamics of vertical-external-cavity-surface-emitting lasers (VECSELs) under mode-locked operation. This allows for an in situ characterization of the gain depletion and recovery over nanoseconds with femtosecond-scale resolution. Our method allows for a more direct study of intracavity gain dynamics than traditional pump/probe measurements. We observe a rapid depletion of the gain on the timescale of the intracavity pulse. Afterward, a rapid recovery over a few picoseconds due to intraband scattering and carrier heating takes place, followed by a long recovery attributed to the continuous supply of carriers by the pump laser. PMID- 26625026 TI - Demonstration of obstruction-free data-carrying N-fold Bessel modes multicasting from a single Gaussian mode. AB - By designing and optimizing complex phase pattern combining with axicon phase distribution, we report data multicasting from a single Gaussian mode to multiple Bessel modes using a single phase-only spatial light modulator. Under the obstructed path conditions, obstruction-free data-carrying N-fold Bessel modes multicasting is demonstrated in the experiment. We also experimentally study N fold multicasting of a 20 Gbit/s quadrature phase-shift keying signal from a single Gaussian mode to multiple Bessel modes and measure the link performance. All the multicasted Bessel modes show relatively low crosstalk from their neighboring modes and achieve a bit-error rate of less than 1e-3. PMID- 26625027 TI - Sub-Doppler resolution mid-infrared spectroscopy using a difference-frequency generation source spectrally narrowed by laser linewidth transfer. AB - The spectral linewidth of a 3.28 MUm difference-frequency-generation source has been reduced to 3.5 kHz using a laser linewidth transfer technique [Opt. Express21, 7891 (2013)]. We use an optical frequency comb with a broad servo bandwidth to transfer a narrow linewidth of a pump laser, a 1.06 MUm Nd:YAG laser, to a signal laser, a 1.57 MUm external-cavity laser diode. This source enables us to record the Lamb dip of the nu3 band R(2) E transition of methane with a molecular spectral linewidth of 21 kHz while the frequency axis is absolutely calibrated. PMID- 26625028 TI - Widely bandwidth-tunable silicon filter with an unlimited free-spectral range. AB - Next-generation high-capacity optical networks require flexible allocation of spectrum resources, for which low-cost optical filters with an ultra-wide bandwidth tunability beyond 100 GHz are desired. We demonstrate an integrated band-pass filter with the bandwidth continuously tuned across 670 GHz (117-788 GHz) which, to the best of our knowledge, is the widest tuning span ever demonstrated on a silicon chip. The filter also features simultaneous wavelength tuning and an unlimited free spectral range. We measured an out-of-band contrast of up to 55 dB, low in-band ripples of less than 0.3 dB, and in-band group delay variation of less than 8 ps. This result was achieved using cascaded Bragg grating-assisted contra-directional couplers and micro-heaters on the 220 nm silicon-on-insulator platform with a very compact footprint of less than 7000 MUm2. Another design with the bandwidth continuously tunable from 50 GHz to 1 THz is also presented. PMID- 26625029 TI - All-optical multi-channel wavelength conversion of Nyquist 16 QAM signal using a silicon waveguide. AB - We experimentally demonstrate on-chip all-optical multi-channel wavelength conversion of Nyquist 16 ary quadrature amplitude modulation (16 QAM) signal in a silicon waveguide. The measured optical signal-to-noise ratio (OSNR) penalties of wavelength conversion are ~2 dB. The observed constellations of converted idlers indicate favorable performance of silicon-waveguide-based multi-channel wavelength conversion. We also experimentally study and compare the phase conjugated wavelength conversion by degenerate four-wave mixing (FWM) and transparent wavelength conversion by non-degenerate FWM in the silicon waveguide. PMID- 26625030 TI - Microstructure optimization of the composite phase ceramic phosphor for white LEDs with excellent luminous efficacy. AB - The two-phase MgAl2O4-Ce:YAG ceramic phosphor was fabricated by the solid-state reaction in vacuum, and it presented a better luminous efficacy than the single phase transparent ceramic phosphor when directly combined with the blue light emitting diodes. The addition of MgAl2O4 implemented the control of the grain sizes and the variation of microstructure, and the microstructure optimization further improved the luminous efficacy of the composite phase ceramic phosphor. A maximum luminous efficacy attaining 99 lm/W at the correlated color temperature 5000 K was obtained. The composite phase ceramic phosphor is expected to be a promising candidate for use in the high-power light source. PMID- 26625031 TI - Adaptive holographic interferometer at 1.55 MUm based on optically addressed spatial light modulator. AB - We report the realization of an adaptive holographic interferometer based on two beam coupling in an optically addressed liquid crystal spatial light modulator operating at 1.55-MUm. The system allows efficient phase demodulation in noisy environment and behaves as an optical high-pass filter, with a cut-off frequency of approximately 10 Hz, thus filtering slow phase disturbances (due to, for example, temperature variations or low frequency fluctuations) and keeping the detection linear without the need of heterodyne or active stabilization. PMID- 26625032 TI - A simple method for generating unidirectional surface plasmon polariton beams with arbitrary profiles. AB - The efficient steering of surface plasmon polariton (SPP) fields is a vital issue in various plasmonic applications, such as plasmonic circuitry. We present a straightforward and efficient method for generating unidirectionally propagating SPP beams with arbitrary amplitude and phase profiles by manipulating Delta shaped nanoantennas. As an example, a second-order Hermite-Gauss SPP beam is generated with this method. The near-field distribution of the generated SPP beam is experimentally characterized to validate the effectiveness of the method. PMID- 26625033 TI - 0.4 MUJ, 7 kW ultrabroadband noise-like pulse direct generation from an all-fiber dumbbell-shaped laser. AB - We report the direct generation of 0.4 MUJ, 7 kW ultrabroadband picosecond noise like pulses from an Yb-doped all-fiber oscillator based on dual nonlinear optical loop mirrors (NOLMs). Under the highest pump power, the average power of the main output port reached 1.4 W, and the 3 dB spectral bandwidths reached 76 nm and 165 nm from the two output ports, respectively. The design of dual-NOLMs shows both exceptional compactness in construction and distinct flexibility on the engineering of the mode-locking behaviors. To the best of our knowledge, this is the first demonstration of a watt-level dual-NOLM-based fiber laser. Based on this laser, the pulse energy and peak power of picosecond noise-like pulse from an all-fiber oscillator have been elevated by an order of magnitude. PMID- 26625034 TI - Interferometric technique for investigation of nonradiative transition kinetics in silica-fiber laser media. AB - A novel tool for investigation of nonradiative processes in active solid-state laser media is proposed. The technique is based on using an interferometer for population-kinetics detection by means of resonantly enhanced nonlinearity. The advantages of this method in comparison with traditional luminescence-kinetics techniques are verified on the example of decay time measurements for nonradiative 4I(11/2)->4I(13/2) transition in an Er3+-doped active optical fiber. PMID- 26625035 TI - Near-infrared autofluorescence spectroscopy of in vivo soft tissue sarcomas. AB - Soft tissue sarcomas (STS) are a rare and heterogeneous group of malignant tumors that are often treated via surgical resection. Inadequate resection can lead to local recurrence and decreased survival rates. In this study, we investigate the hypothesis that near-infrared (NIR) autofluorescence can be utilized for tumor margin analysis by differentiating STS from the surrounding normal tissue. Intraoperative in vivo measurements were acquired from 30 patients undergoing STS resection and were characterized to differentiate between normal tissue and STS. Overall, normal muscle and fat were observed to have the highest and lowest autofluorescence intensities, respectively, with STS falling in between. With the exclusion of well-differentiated liposarcomas, the algorithm's accuracy for classifying muscle, fat, and STS was 93%, 92%, and 88%, respectively. These findings suggest that NIR autofluorescence spectroscopy has potential as a rapid and nondestructive surgical guidance tool that can inform surgeons of suspicious margins in need of immediate re-excision. PMID- 26625036 TI - High-resolution subsurface microscopy of CMOS integrated circuits using radially polarized light. AB - Under high numerical aperture (NA) conditions, a linearly polarized plane wave focuses to a spot that is extended along the E-field vector, but radially polarized light is predicted to form a circular spot whose diameter equals the narrower dimension obtained with linear polarization. This effect provides an opportunity for improved resolution in high-NA microscopy, and here we present a performance study of subsurface two-photon optical-beam-induced current solid immersion-lens microscopy of a complementary metal-oxide semiconductor integrated circuit, showing a resolution improvement by using radially polarized illumination. By comparing images of the same structural features we show that radial polarization achieves a resolution of 126 nm, while linear polarization achieves resolutions of 122 and 165 nm, depending on the E-field orientation. These results are consistent with the theoretically expected behavior and are supported by high-resolution images which show superior feature definition using radial polarization. PMID- 26625037 TI - Higher-order laser mode converters with dielectric metasurfaces. AB - A simple and compact converter based on the dielectric metasurface is proposed for the transformation of Gaussian mode to Hermite-Gaussian and Laguerre-Gaussian modes. We establish the relationship between the phase of a desired mode and the local orientation of the optical axis based on the evolution of Pancharatnam Berry phase on Poincare sphere. By controlling the local orientation of the optical axis in the dielectric metasurface, we can achieve any desired higher order laser mode. PMID- 26625038 TI - Quasi-phase matching for efficient long-range plasmonic third-harmonic generation via graphene. AB - We propose and numerically investigate an efficient method for long-range third harmonic generation (THG) of propagating surface plasmon polaritons (SPP) waves on graphene sheets for nonlinear plasmonic purposes in the terahertz (THZ) gap region of the electromagnetic spectrum via a developed nonlinear finite difference time-domain technique. We reveal that although extended and unmodulated graphene sheets with low Fermi levels can offer high-conversion efficiency (CE) for SPP THG at short distances, suitable for miniaturized plasmonic circuits, they suffer from inherent absorption loss induced by graphene that noticeably reduces the CE of the THG at long ranges. We suggest a structure benefiting from low Fermi-level graphene regions of strong nonlinear response as oscillators and high Fermi-level ones of low loss as a propagating medium in a periodic manner, which satisfies the quasi-phase matching condition and shows considerable efficiency improvement at long propagation distances. We predict that such a configuration can find valuable potential applications in the realm of nonlinear THz plasmonics for generating new frequencies and also in spectroscopy, signal processing, and so on. PMID- 26625039 TI - Optical fiber random grating-based multiparameter sensor. AB - A novel multiparameter fiber-optic sensor based on a femtosecond laser micromachined random grating is proposed and demonstrated to realize simultaneous measurement of temperature, axial strain, and surrounding refractive index. A wavelength-division spectral cross-correlation algorithm is adopted to extract the phase variation induced spectral shift responding to different external disturbances. Sensitivities of 10.32 pm/ degrees C, 1.24 pm/MUepsilon, and 1520.6 pm/RIU were achieved for temperature, axial strain, and surrounding refractive index, respectively. The fiber random grating without phase mask fabrication and high physical strength is an excellent alternative aiming at simple and compact multifunctional fiber sensors. PMID- 26625041 TI - Characterizing the carrier-envelope offset in an optical frequency comb without traditional f-to-2f interferometry. AB - We present a new method to measure the frequency noise and modulation response of the carrier-envelope offset (CEO) beat of an optical frequency comb that does not make use of the traditional f-to-2f interferometry. Instead, we use an appropriate combination of different signals to extract the contribution of the CEO frequency without directly detecting it. We present a proof-of-principle validation realized with a commercial Er:fiber frequency comb and show an excellent agreement with the results obtained using a standard f-to-2f interferometer. This approach is attractive for the characterization of novel frequency comb technologies for which self-referencing is challenging, such as semiconductor mode-locked lasers, microresonator-based systems, or GHz repetition rate lasers. PMID- 26625040 TI - Rotational distortion correction in endoscopic optical coherence tomography based on speckle decorrelation. AB - We present a new technique for the correction of nonuniform rotation distortion in catheter-based optical coherence tomography (OCT), based on the statistics of speckle between A-lines using intensity-based dynamic light scattering. This technique does not rely on tissue features and can be performed on single frames of data, thereby enabling real-time image correction. We demonstrate its suitability in a gastrointestinal (GI) balloon-catheter OCT system, determining the actual rotational speed with high temporal resolution, and present corrected cross-sectional and en face views showing significant enhancement of image quality. PMID- 26625042 TI - Highly efficient single-pass sum frequency generation by cascaded nonlinear crystals. AB - The cascading of nonlinear crystals has been established as a simple method to greatly increase the conversion efficiency of single-pass second-harmonic generation compared to a single-crystal scheme. Here, we show for the first time that the technique can be extended to sum frequency generation, despite differences in the phase relations of the involved fields. An unprecedented 5.5 W of continuous-wave diffraction-limited green light is generated from the single pass sum frequency mixing of two diode lasers in two periodically poled nonlinear crystals (conversion efficiency 50%). The technique is generally applicable and can be applied to any combination of fundamental wavelengths and nonlinear crystals. PMID- 26625043 TI - Lateral optical force on paired chiral nanoparticles in linearly polarized plane waves. AB - We demonstrate that a lateral optical force (LOF) can be induced on paired chiral nanoparticles with opposite handedness under the illumination of a linearly polarized plane wave. The LOFs on both chiral particles are equal and thus can move the pair sideways, with the direction depending on the separation between two particles, as well as the handedness of particle chirality. Analytical theory reveals that the LOF comes largely from the optical potential gradient established by the multiple scattering of light between the paired particles with asymmetric chirality. In addition, it is weakly dependent on the material loss of a particle, a feature of gradient force, while heavily dependent on the magnitude and handedness of particle chirality. The effect is expected to find applications in sorting and separating chiral dimers of different handedness. PMID- 26625044 TI - Random electromagnetic model beams with correlations described by two families of functions. AB - The electromagnetic Schell-model beams whose cross-spectral matrices have elements belonging to different families of functions are considered for the first time. The spatial distributions of polarization properties of such beams are shown to be made completely or partially different from that of the average intensity. PMID- 26625045 TI - High-speed gate-tunable terahertz coherent perfect absorption using a split-ring graphene. AB - We exploit split-ring graphene to realize coherent perfect absorption (CPA) in the terahertz (THz) regime. By controlling the relative phase of two counter propagating coherent beams, the coherent absorption at resonant frequency of 2.91 THz can be tuned continuously from 99.7% to less than 2.1*10(-4)%, which gives a modulation contrast of 56.7 dB. Moreover, the coherent absorption also can be tuned by varying the gate-controlled Fermi energy based on the electro-absorption effect of graphene, giving a modulation contrast of 19 dB. Center frequency tunable CPA is also achieved using gate-tunable split-ring graphene. We discuss the tolerance of the geometric parameters (radii of the inner and outer circles, gap aperture) and study the device performance dependence on the relative intensities of two input beams and the angle between two input beams. Additionally, the response time of the device is analyzed to be ~36 ps, which indicates possible high-speed gate-tunable THz CPA operations. PMID- 26625046 TI - In-line digital holographic imaging in volume holographic microscopy. AB - A dual-plane in-line digital holographic imaging method incorporating volume holographic microscopy (VHM) is presented to reconstruct objects in a single shot while eliminating zero-order and twin-image diffracted waves. The proposed imaging method is configured such that information from different axial planes is acquired simultaneously using multiplexed volume holographic imaging gratings, as used in VHM, and recorded as in-line holograms where the corresponding reference beams are generated in the fashion of Gabor's in-line holography. Unlike conventional VHM, which can take axial intensity information only at focal depths, the proposed method digitally reconstructs objects at any axial position. Further, we demonstrate the proposed imaging technique's ability to effectively eliminate zero-order and twin images for single-shot three-dimensional object reconstruction. PMID- 26625047 TI - High-average-power 2 MUm few-cycle optical parametric chirped pulse amplifier at 100 kHz repetition rate. AB - Sources of long wavelengths few-cycle high repetition rate pulses are becoming increasingly important for a plethora of applications, e.g., in high-field physics. Here, we report on the realization of a tunable optical parametric chirped pulse amplifier at 100 kHz repetition rate. At a central wavelength of 2 MUm, the system delivered 33 fs pulses and a 6 W average power corresponding to 60 MUJ pulse energy with gigawatt-level peak powers. Idler absorption and its crystal heating is experimentally investigated for a BBO. Strategies for further power scaling to several tens of watts of average power are discussed. PMID- 26625048 TI - Analytical model for coherent perfect absorption in one-dimensional photonic structures. AB - Coherent perfect absorption (CPA) is the phenomenon where a linear system with low intrinsic loss strongly absorbs two incident beams but only weakly absorbs either beam when incident separately. We present an analytical model that captures the relevant physics of CPA in one-dimensional photonic structures. This model elucidates an absorption-mediated interference effect that underlies CPA-an effect that is normally forbidden in Hermitian systems but is allowed when conservation of energy is violated due to the inclusion of loss. By studying a planar cavity model, we identify the optimal mirror reflectivity to guarantee CPA in the cavity at resonances extending in principle over any desired bandwidth. As a concrete example, we design a resonator that produces CPA in a 1-MUm-thick layer of silicon over a 200-nm bandwidth in the near-infrared. PMID- 26625049 TI - Interaction of high-order solitons with external dispersive waves. AB - The effect of mutual interaction between second-order soliton and dispersive waves (DWs) is investigated. It is predicted analytically and confirmed numerically that DWs (both transmitted and reflected components) become polychromatic after interaction with the soliton. Collision with DWs of considerable intensity can lead to acceleration/deceleration and central frequency shift of the soliton, while still preserving the soliton's oscillating structure. Two second-order solitons with resonant DWs trapped between them can form an effective solitonic cavity with "flat" or "concave mirrors," depending on the intensity of the input. PMID- 26625050 TI - Refractive-index measurement and inverse correction using optical coherence tomography. AB - We describe a novel technique for determination of the refractive index of hard biological tissue as well as nonopaque technical samples based on optical coherence tomography (OCT). Our method relies on an inverse refractive-index correction (I-RIC), which matches a measured feature geometry distorted due to refractive-index boundaries to its real geometry. For known feature geometry, the refractive index can be determined with high precision from the best match between the distorted and corrected images. We provide experimental data for refractive-index measurements on a polymethylmethacrylate (PMMA) and on an ex vivo porcine cranial-bone, which are compared to reference measurements and previously published data. Our method is potentially capable of in vivo measurements on rigid biological tissue such as bone as, for example, is required to improve guidance in robot-aided surgical interventions and also for retrieving complex refractive-index profiles of compound materials. PMID- 26625051 TI - Power enhancement of burst-mode ultraviolet pulses using a doubly resonant optical cavity. AB - We report a doubly resonant enhancement cavity (DREC) that can realize a simultaneous enhancement of two incoming laser beams at different wavelengths and different temporal structures. The double-resonance condition is theoretically analyzed, and different DREC locking methods are experimentally investigated. Simultaneous locking of a Fabry-Perot cavity to both an infrared (1064 nm) and its frequency-tripled ultraviolet (355 nm) pulses has been demonstrated by controlling the frequency difference between the two beams with a fiber-optic frequency shifter. The DREC technique enables novel applications of optical cavities to power enhancement of burst-mode lasers with arbitrary macropulse width and repetition rate. PMID- 26625052 TI - Analysis of silicon-on-insulator slot waveguide ring resonators targeting high Q factors. AB - Vertical slot waveguide micro-ring resonators in silicon photonics have already been demonstrated in previous works and applied to several schemes, including sensing and hybrid nonlinear optics. Their performances, first quantified by the reachable Q-factors, are still perceived to be restrained by larger intrinsic propagation losses than those suffered by simple Si wire waveguides. In this Letter, the optical loss mechanisms of slot waveguide micro-ring resonators are thoroughly investigated with a special focus on the coupler loss contribution that turns out to be the key obstacle to achieving high Q-factors. By engineering the coupler design, slotted ring resonators with a 50 MUm radius are experienced with a loaded Q-factor up to 10 times improvement from Q=3,000 to Q=30,600. The intrinsic losses due to the light propagation in the bent slot ring itself are proved to be as low as 1.32+/-0.87 dB/cm at lambda=1,550 nm. These investigations of slot ring resonators open high performance potentials for on chip nonlinear optical processing or sensing in hybrid silicon photonics. PMID- 26625053 TI - Observation of interference effects via four-photon excitation of highly excited Rydberg states in thermal cesium vapor. AB - We report on the observation of electromagnetically induced transparency (EIT) and absorption (EIA) of highly excited Rydberg states in thermal Cs vapor using a four-step excitation scheme. The advantage of this four-step scheme is that the final transition to the Rydberg state has a large dipole moment and one can achieve similar Rabi frequencies to two- or three-step excitation schemes using two orders of magnitude less laser power. This scheme enables new applications such as dephasing free Rydberg excitation. The observed lineshapes are in good agreement with simulations based on multilevel optical Bloch equations. PMID- 26625054 TI - Ptychographic imaging with a compact gas-discharge plasma extreme ultraviolet light source. AB - We report the demonstration of a scanning probe coherent diffractive imaging method (also known as ptychographic CDI) using a compact and partially coherent gas-discharge plasma source of extreme ultraviolet (EUV) radiation at a 17.3 nm wavelength. Until now, CDI has been mainly carried out with coherent, high brightness light sources, such as third generation synchrotrons, x-ray free electron lasers, and high harmonic generation. Here we performed ptychographic lensless imaging of an extended sample using a compact, lab-scale source. The CDI reconstructions were achieved by applying constraint relaxation to the CDI algorithm. Experimental results indicate that our method can handle the low spatial coherence and broadband nature of the EUV illumination, as well as the residual background due to visible light emitted by the gas-discharge source. The ability to conduct ptychographic imaging with lab-scale and partially coherent EUV sources is expected to significantly expand the applications of this powerful CDI method. PMID- 26625055 TI - Polarization-rotating, Bragg-grating filters on silicon-on-insulator strip waveguides using asymmetric periodic corner corrugations. AB - We report on a wavelength-selective, polarization-rotating filter using a partially etched asymmetric Bragg grating on a compact single-mode, silicon-on insulator (SOI) strip waveguide. The asymmetric Bragg grating rotates and reflects the fundamental transverse electric (TE) and transverse magnetic (TM) modes at selected wavelengths. Our device offers wavelength-selective, polarization-rotating reflection at its reflection port and wavelength-selective, polarization-independent notch filtering at its through port. The device is fabricated using a CMOS-compatible process with 193 nm-deep ultraviolet lithography on an SOI platform. We present results for a 294.4 MUm long device that has a 3 dB bandwidth of 2.63 nm and a low-excess loss of less than 1 dB. This device also has a maximum polarization-extinction-ratio of greater than 27 dB. PMID- 26625056 TI - Ultrahigh and persistent optical depths of cesium in Kagome-type hollow-core photonic crystal fibers. AB - Alkali-filled hollow-core fibers are a promising medium for investigating light matter interactions, especially at the single-photon level, due to the tight confinement of light and high optical depths achievable by light-induced atomic desorption (LIAD). However, until now these large optical depths could only be generated for seconds, at most once per day, severely limiting the practicality of the technology. Here we report the generation of the highest observed transient (>10(5) for up to a minute) and highest observed persistent (>2000 for hours) optical depths of alkali vapors in a light-guiding geometry to date, using a cesium-filled Kagome-type hollow-core photonic crystal fiber (HC-PCF). Our results pave the way to light-matter interaction experiments in confined geometries requiring long operation times and large atomic number densities, such as generation of single-photon-level nonlinearities and development of single photon quantum memories. PMID- 26625057 TI - Aberration-free short focal length x-ray lenses. AB - We treat the problem of defining the ideal x-ray refractive lens design for point focusing of low emittance x-ray beams at third- and fourth-generation synchrotron sources. The task is accomplished by using Fermat's principle to define a lens shape that is completely free from geometrical aberrations. Current microfabrication resolution limits are identified, and a design that tolerates the inherent fabrication imperfections is proposed. The refractive lens design delivers nanometer-sized focused x-ray beams and is compatible with current microfabrication techniques. PMID- 26625058 TI - Continuous-wave 193.4 nm laser with 120 mW output power. AB - This Letter describes an all-solid-state continuous-wave, deep-ultraviolet coherent source that generates more than 100 mW of output power at 193.4 nm. The source is based on nonlinear frequency conversion of three single-frequency infrared fiber laser master-oscillator power-amplifier (MOPA) light sources. PMID- 26625059 TI - Broadband and high-brightness light source: glass-clad Ti:sapphire crystal fiber. AB - High-brightness near-infrared broadband amplified spontaneous emission (ASE) was generated by glass-clad Ti:sapphire crystal fibers, which were developed using the co-drawing laser-heated pedestal growth method. As much as 29.2 mW of ASE power was generated using 520 nm laser diodes as the excitation source on an a cut, 18 MUm core-diameter Ti:sapphire crystal fiber (CF). The 3 dB bandwidth was 163.8 nm, and the radiance was 53.94 W.mm(-2) sr(-1). The propagation loss of the glass-clad sapphire CF measured using the cutback method was 0.017 cm(-1) at 780 nm. For single-mode applications, more than 100 MUW of power was coupled into a SM600 single-mode fiber. PMID- 26625060 TI - 60 W power-over-fiber feed using double-clad fibers for radio-over-fiber systems with optically powered remote antenna units. AB - We experimentally demonstrated the ability to feed 60 W of optical power into a power-over-fiber link using a double-clad fiber for radio-over-fiber systems with optically powered remote antenna units. In order to improve the available optical feed power and the power transmission efficiency of the power-over-fiber link, we have designed a specially customized tapered fiber bundle divider for the remote antenna unit. We demonstrated, for the first time, bidirectional radio-over-fiber transmission over a 300 m double-clad fiber with an improved power transmission efficiency and optical power feeding up to 60 W input. PMID- 26625061 TI - Efficient transfer of an arbitrary qutrit state in circuit quantum electrodynamics. AB - Compared with a qubit, a qutrit (i.e., three-level quantum system) has a larger Hilbert space and thus can be used to encode more information in quantum information processing and communication. Here, we propose a method to transfer an arbitrary quantum state between two flux qutrits coupled to two resonators. This scheme is simple because it only requires two basic operations. The state transfer operation can be performed fast because only resonant interactions are used. Numerical simulations show that the high-fidelity transfer of quantum states between the two qutrits is feasible with current circuit-QED technology. This scheme is quite general and can be applied to accomplish the same task for other solid-state qutrits coupled to resonators. PMID- 26625062 TI - Compressive Fresnel holography approach for high-resolution viewpoint inference. AB - Holography provides a means for indirect acquirement and reconstruction of 3-D object features. Here, we demonstrate high-resolution viewpoint object inference by formulating the object's reconstruction in the framework of compressive sensing. Further, when the object is dominated by speckle noise and cannot be considered to be sparse, we propose a digital resampling diversity compressive sensing approach to reconstruct a high-quality viewpoint inferred object. The results can be used in all types of holography for display and research purposes. PMID- 26625063 TI - Generation of picosecond laser pulses at 1030 nm with gigahertz range continuously tunable repetition rate. AB - We report on a watt range laser system generating picosecond pulses using electro optical modulation of a 1030 nm single frequency low noise laser diode. Its repetition rate is continuously tunable between 11 and 18 GHz. Over this range, output spectra and pulse characteristics are measured and compared with a numerical simulation. Finally, amplitude and residual phase noise measurements of the source are also presented. PMID- 26625064 TI - Terahertz-bandwidth photonic temporal differentiator based on a silicon-on isolator directional coupler. AB - We experimentally demonstrate a terahertz-bandwidth photonic differentiator employing a silicon-on-insulator directional coupler. The integrated waveguide coupler with two identical paralleled strip waveguides achieves a first-order differentiator when full energy coupling is met from one waveguide to another. The integrated waveguide coupler can offer different operation bandwidths by changing the length and gap of the strip waveguides. Due to the large 3 dB bandwidth of the directional coupler, we implement the first differentiator with an operation bandwidth of 1.25 THz. The performance of this photonic differentiator is tested using Gaussian-like pulses with a pulsewidth of 2.8 ps, 4 ps, 6 ps, 8 ps, and 10 ps, respectively. The differentiation processing errors and relative energy efficiency are also discussed. This silicon chip may have potential applications in integrated photonic computing circuits with sub picosecond pulses. PMID- 26625065 TI - Integrated microwave photonic splitter with reconfigurable amplitude, phase, and delay offsets. AB - This work presents an integrated microwave photonics splitter with reconfigurable amplitude, phase, and delay offsets. The core components for this function are a dual-parallel Mach-Zehnder modulator, a deinterleaver, and tunable delay lines, all implemented using photonic integrated circuits. Using a demonstrator with an optical free spectral range of 25 GHz, we show experimentally the RF splitting function over two continuous bands, i.e., 0.9-11.6 GHz and 13.4-20 GHz. This result promises a deployable solution for creating wideband, reconfigurable RF splitters in integrated forms. PMID- 26625066 TI - Stable integrated hyper-parametric oscillator based on coupled optical microcavities. AB - We propose a flexible scheme based on three coupled optical microcavities that permits us to achieve stable oscillations in the microwave range, the frequency of which depends only on the cavity coupling rates. We find that the different dynamical regimes (soft and hard excitation) affect the oscillation intensity, but not their periods. This configuration may permit us to implement compact hyper-parametric sources on an integrated optical circuit with interesting applications in communications, sensing, and metrology. PMID- 26625067 TI - Single-pass and omniangle light extraction from light-emitting diodes using transformation optics. AB - We present a light-extraction approach allowing for single-pass and omniangle outcoupling of light from light-emitting diodes (LED). By using transformation optics, we perceive a feasible graded-index structure that is a transition from the LED exit facet to a low refractive index region with expanded space that represents air. Apart from the material dispersion of the constituents, our approach is wavelength independent. The suggested extractor is geometrically compact with size parameters comparable to the width of an LED and therefore well adapted for pixelated LEDs. A beam-expanding functionality is possible while fully preserving the outcoupling efficiency by applying index and geometry truncation. PMID- 26625068 TI - Topological nanocolloids with facile electric switching of plasmonic properties. AB - Combining topology and plasmonics paradigms in nanocolloidal systems may enable new means of pre-engineering desired composite material properties. Here we design and realize orientationally ordered assemblies of noble metal nanoparticles with genus-one topology and unusual long-range ordering mediated by their interactions with the surrounding nematic fluid host. Facile electric switching of these composites is reminiscent of that of pristine liquid crystals (LCs), but provides a means of reconfiguring the nanoparticle assembly and thus also the ensuing composite medium's optical properties. Our findings may lead to formation of new molecular-colloidal soft matter phases with unusual optical properties, as well as optical metamaterials. PMID- 26625069 TI - Spatial evolution of depolarization in homogeneous turbid media within the differential Mueller matrix formalism. AB - We show, through visible-range Mueller polarimetry, as well as numerical simulations, that the depolarization in a homogeneous turbid medium consisting of submicron spherical particles follows a parabolic law with the path-length traveled by light through the medium. This result is in full agreement with the phenomenological theory of the fluctuating medium within the framework of the differential Mueller matrix formalism. We further found that the standard deviations of the fluctuating elementary polarization properties of the medium depend linearly on the concentration of particles. These findings are believed to be useful for the phenomenological interpretation of polarimetric experiments, with special emphasis on biomedical applications. PMID- 26625070 TI - Optical bistability with film-coupled metasurfaces. AB - Metasurfaces comprising arrays of film-coupled, nanopatch antennas are a promising platform for low-energy, all-optical switches. The large field enhancements that can be achieved in the dielectric spacer region between the nanopatch and the metallic substrate can substantially enhance optical nonlinear processes. Here we consider a dielectric material that exhibits an optical Kerr effect as the spacer layer and numerically calculate the optical bistability of a metasurface using the finite element method (FEM). We expect the proposed method to be highly accurate compared with other numerical approaches, such as those based on graphical post-processing techniques, because it self-consistently solves for both the spatial field distribution and the intensity-dependent refractive index distribution of the spacer layer. This method offers an alternative approach to finite-difference time-domain (FDTD) modeling. We use this numerical tool to design a metasurface optical switch and our optimized design exhibits exceptionally low switching intensity of 33 kW/cm2, corresponding to switching energy on the order of tens of attojoules per resonator, a value much smaller than those found for most devices reported in the literature. We propose our method as a tool for designing all-optical switches and modulators. PMID- 26625071 TI - Estimation of Cn2 based on scintillation of fixed targets imaged through atmospheric turbulence. AB - We define a pixel-based scintillation index for dynamic incoherent imaging of fixed high-contrast targets through atmospheric turbulence. We propose a simple setup to study this parameter varying the Cn(2) constant in controlled laboratory conditions (weak fluctuation regime). We find the semi-empirical relationship between the pixel-based scintillation index and the index of refraction structure constant, which we then employ to estimate Cn(2) successfully in an independent case in which this value was not known beforehand. PMID- 26625072 TI - Miniature all-silica fiber-optic sensor for simultaneous measurement of relative humidity and temperature. AB - This Letter presents a miniature fiber-optic sensor created at the tip of an optical fiber suitable for simultaneous measurement of relative humidity and temperature. The proposed sensor is based on two cascaded Fabry-Perot interferometers, the first configured as a relative humidity sensing element made from silica micro-wire coated with thin porous SiO2 layer, and the second as a temperature sensing element made from a segment of a standard single-mode fiber. The sensor has linear characteristics for both measurement parameters and a sensitivity of 0.48 deg/%RH and 3.7 deg/ degrees C. PMID- 26625073 TI - All-fiber amplifier similariton laser based on a fiber Bragg grating filter. AB - This article presents, for the first time to our knowledge, an all-fiber amplifier similariton laser based on a fiber Bragg grating filter. The laser emits 2.9 nJ pulses at a wavelength of 1554 nm with a repetition rate of 31 MHz. The dechirped pulses have a duration of 89 fs. The characteristic features of the pulse profile and spectrum along with the dynamics of the laser are highlighted in representative simulations. These simulations also address the effect of the filter shape and detuning with respect to the gain spectral peak. PMID- 26625074 TI - Toward the integration of optical sensors in smartphone screens using femtosecond laser writing. AB - We demonstrate a new type of sensor incorporated directly into Corning Gorilla glass, an ultraresistant glass widely used in the screen of popular devices such as smartphones, tablets, and smart watches. Although physical space is limited in portable devices, the screens have been so far neglected in regard to functionalization. Our proof-of-concept shows a new niche for photonics device development, in which the screen becomes an active component integrated into the device. The sensor itself is a near-surface waveguide, sensitive to refractive index changes, enabling the analysis of liquids directly on the screen of a smartphone, without the need for any add-ons, thus opening this part of the device to advanced functionalization. The primary function of the screen is unaffected, since the sensor and waveguide are effectively invisible to the naked eye. We fabricated a waveguide just below the glass surface, directly written without any surface preparation, in which the change in refractive index on the surface-air interface changes the light guidance, thus the transmission of light. This work reports on sensor fabrication, using a femtosecond pulsed laser, and the light-interaction model of the beam propagating at the surface is discussed and compared with experimental measurement for refractive indexes in the range 1.3-1.7. A new and improved model, including input and output reflections due to the effective mode index change, is also proposed and yields a better match with our experimental measurements and also with previous measurements reported in the literature. PMID- 26625075 TI - Fiber Fabry-Perot interferometer with controllable temperature sensitivity. AB - We proposed a fiber taper based on the Fabry-Perot (FP) interferometer structure with controllable temperature sensitivity. The FP interferometer is formed by inserting a segment of tapered fiber tip into the capillary and subsequently splicing the other end of the capillary to a single-mode fiber (SMF), the tapered fiber endface, and the spliced face form the FP cavity. Through controlling the inserted tapered fiber length, a series of FP interferometers were made. Because the inserted taper tip has the degree of freedom along the fiber axial, when the FP interferometer is subjected to temperature variation, the thermal expansion of the fiber taper tip will resist the FP cavity length change caused by the evolution of capillary length, and we can control the temperature sensitivity by adjusting the inserted taper length. In this structure, the equivalent thermal expansion coefficient of the FP interferometer can be defined; it was used to evaluate the temperature sensitivity of the FP interferometer, which provides an effective method to eliminate the temperature effect and to enhance other measurement accuracy. We fabricated the FP interferometers and calibrated their temperature characters by measuring the wavelength shift of the resonance dips in the reflection spectrum. In a temperature range of 50 degrees C to 150 degrees C, the corresponding temperature sensitivities can be controlled between 0 and 1.97 pm/ degrees C when the inserted taper is between 75 and 160 MUm. Because of its controllable temperature sensitivity, ease of fabrication, and low cost, this FP interferometer can meet different temperature sensitivity requirements in various application areas, especially in the fields which need temperature insensitivity. PMID- 26625076 TI - Gaussian Schell-model arrays. AB - We introduce a novel class of planar, quasi-homogeneous Schell-model source for producing far fields with optical lattice average intensity patterns and derive the corresponding beam conditions. The array dimension, lobes intensity profile, and periodicity of the optical lattice can be flexibly tuned by changing the correlation parameters of the source field. It is also found that, with an appropriate choice of the source parameters, the radiant intensity may possess flat-topped intensity patterns. PMID- 26625077 TI - Analysis of the multi-spectral inhomogeneous metasurfaces consisting of different arrays of components. AB - The analytical method to study the multi-spectral inhomogeneous metasurfaces with various components is presented. Because of symmetrical distribution of different components, we can find the effective polarizability of the inhomogeneous metasurfaces. This polarizability provides equivalent conductivity of each metasurface with two and three different nanodisk arrays. Full-wave simulations confirm the analysis of inhomogeneous metasurfaces. In a metasurface, symmetrical distribution of components with a unique periodicity is limited to three types in a hexagonal combination. Then we extend the proposed approach to partly symmetric inhomogeneous metasurfaces in subwavelength scale for four different nanodisks. Also, monolayer and multi-layer absorbers consisting of inhomogeneous metasurfaces with graphene nanodisks are designed as the examples of wideband applications of this method in infrared regime. PMID- 26625078 TI - Plasmon modes of a silver thin film taper probed with STEM-EELS. AB - By focusing propagating surface plasmons, electromagnetic energy can be delivered to nanoscale volumes. In this context, we employ electron energy loss spectroscopy in a scanning transmission electron microscope to characterize the full plasmonic mode spectrum of a silver thin film tapered to a sharp tip. We show that the plasmon modes can be ordered in film and edge modes and corroborate our assignment through supplementary numerical simulations. In particular, we find that the focused plasmon field at the taper tip is fueled by edge modes. PMID- 26625079 TI - Frequency characteristics of far-detuned parametric four-wave mixing in Rb. AB - We have investigated the frequency characteristics of the coherent 420 nm beam generated via parametric four-wave mixing (FWM). A single, high-power 778 nm laser is directed through a high-density rubidium cell with a detuning of 1 THz from the intermediate state, generating fields at 420 nm and 5.23 MUm through FWM. The frequency of the 420 nm light has been found to shift as the excitation laser is tuned. The measured frequency shift ratio of 1.87+/-0.04 corresponds with the selection of a different velocity class at each excitation frequency, implying that the 5.23 MUm beam frequency is correspondingly shifted. The 420 nm light has been tuned over a range of 1 GHz. This parametric FWM process has potential application as a tunable photon source at novel wavelengths. PMID- 26625080 TI - Multifunctional nanoparticles based on the Nd3+/Yb3+ codoped NaYF4. AB - Broadband near-infrared luminescence (NIR) from 720 to 950 nm, which is located in the biological window, has been successfully achieved from Nd3+/Yb3+ codoped hexagonal NaYF4 nanoparticles when excited by 980 nm diode laser. Using the fluorescence intensity ratio technique, the temperature sensing behavior of Nd3+ NIR emissions exhibits various advantages over other rare earth ion based nanothermometers. The light-induced thermal loading for the 980 nm excited NaYF4:Nd3+/Yb3+ was also investigated. The results illustrate the multifunctionality of such fluoride nanoparticles, which could simultaneously act as the luminescent nanothermometers and nanoheaters and find potential application in photothermal therapy. PMID- 26625081 TI - Optical finite representation of the Lorentz group. AB - We implement a finite-dimensional representation of the 2+1D Lorentz group with a PT-symmetric waveguide array. Our device can be engineered to behave like a multi port oscillator or directional coupler with amplification. We show that the two waveguide coupler with linear losses, the Vernier effect in coupled asymmetric micro-cavity lasers, and the so-called linear PT-symmetric dimer belong to this symmetry class of optical systems. PMID- 26625082 TI - Image signal transmission with Airy beams. AB - We propose and demonstrate an approach for image signal transmission based on self-accelerating Airy beams. The spatial information is encoded in the Fourier space through a 4-f telescope system, which can circumvent obstacles to realize a self-bending signal transmission. Furthermore, the information can be retrieved from the Airy beams after propagation through a disordered scattering medium. Our experimental results agree well with theoretical predictions. PMID- 26625083 TI - Temporal summation in a neuromimetic micropillar laser. AB - Neuromimetic systems are systems mimicking the functionalities or architecture of biological neurons and may present an alternative path for efficient computing and information processing. We demonstrate here experimentally temporal summation in a neuromimetic micropillar laser with an integrated saturable absorber. Temporal summation is the property of neurons to integrate delayed input stimuli and to respond by an all-or-none kind of response if the inputs arrive in a sufficiently small time window. Our system alone may act as a fast optical coincidence detector and paves the way to fast photonic spike-processing networks. PMID- 26625084 TI - Half-spectral unidirectional invisibility in non-Hermitian periodic optical structures. AB - The phenomenon of half-spectral unidirectional invisibility is introduced for one dimensional periodic optical structures with tailored real and imaginary refractive index distributions in a non PT-symmetric configuration. The effect refers to the property in which the optical medium appears to be invisible, both in reflection and transmission, below the Bragg frequency when probed from one side and above the Bragg frequency when probed from the opposite side. Half spectral invisibility is obtained by a combination of in-phase index and gain gratings whose spatial envelopes are related to each other by a Hilbert transform. PMID- 26625085 TI - Reduction of image discontinuity in coarse integral volumetric imaging. AB - The authors describe two methods to reduce the discontinuity of the image in coarse integral volumetric imaging. The discontinuity of elemental images from neighboring elemental lenses is smoothed by introducing Fresnel elemental lenses with interleaved grooves. The discontinuity of volumetric layers with long intervals is made indistinct by introducing a smoothing filter and an edge filter to connect the layered images smoothly. The effectiveness of the proposed methods is confirmed by the prototype systems. PMID- 26625086 TI - Homology modelling and molecular docking studies of human placental cadherin protein for its role in teratogenic effects of anti-epileptic drugs. AB - Anti-epileptic drugs (AEDs) have high risk of teratogenic side effects, including neural tube defects while mother is on AEDs for her own prevention of convulsions during pregnancy. The present study investigated the interaction of major marketed AEDs and human placental (hp)-cadherin protein, in-silico, to establish the role of hp-cadherin protein in teratogenicity and also to evaluate the importance of Ca(2+) ion in functioning of the protein. A set of 21 major marketed AEDs were selected for the study and 3D-structure of hp-cadherin was constructed using homology modelling and energy minimized using MD simulations. Molecular docking studies were carried out using selected AEDs as ligand with hp cadherin (free and bound Ca(2+) ion) to study the behavioural changes in hp cadherin due to presence of Ca(2+) ion. The study reflected that four AEDs (Gabapentin, Pregabalin, Remacimide and Vigabatrine) had very high affinity towards hp-cadherin and thus the later may have prominent role in the teratogenic effects of these AEDs. From docking simulation analysis it was observed that Ca(2+) ion is required to make hp-cadherin energetically favourable and sterically functional. PMID- 26625088 TI - Risk factors associated with human papillomavirus prevalence and cervical neoplasia among Cameroonian women. AB - BACKGROUND: This study used community-based cervical cancer screening for high risk human-papillomavirus (HPV) to determine demographic and lifestyle factors associated with HPV prevalence and cervical intraepithelial neoplasia grade 2 or worse (CIN2+). METHODS: Women (n=838) aged 25-65 years were recruited in two sequential studies in Cameroon. Demographic and historical data were obtained from participants and specimens were self-collected for HPV-testing using real time PCR. HPV-positive women underwent biopsy and endocervical curettage. Associations were determined using bivariate analysis and logistic regression. RESULTS: HPV and self-reported HIV prevalence were 39.0% and 9.2%, respectively. Eighteen (9.3%) CIN2+ lesions were found among HPV-positive women. Housewives had a higher risk of being HPV infected (OR=1.60, p=0.010). HIV co-infection (aOR=3.44, p<0.001) and hormonal contraception (aOR=1.97, p=0.007) were associated with increased HPV prevalence. HPV-positive women who used condoms during sexual intercourse were at lower risk of CIN2+ (aOR=0.15, p=0.029). CIN2-3 lesions were found in women younger than 50 years, with a median age of 36 years (31-44). HPV-16/18-positive women had a 4.65-fold increased risk of CIN2+ (p=0.015). CONCLUSIONS: Young, single women and housewives were at higher risk of HPV infection. Preventive strategies for cervical cancer in low-resource settings should target women aged 30-50 years for HPV screening, and should focus treatment and follow-up on HPV-16/18-positive women. Further studies are needed to clarify if other risk factors require attention. PMID- 26625087 TI - A multinational case-control study on childhood brain tumours, anthropogenic factors, birth characteristics and prenatal exposures: A validation of interview data. AB - Little is known about the aetiology of childhood brain tumours. We investigated anthropometric factors (birth weight, length, maternal age), birth characteristics (e.g. vacuum extraction, preterm delivery, birth order) and exposures during pregnancy (e.g. maternal: smoking, working, dietary supplement intake) in relation to risk of brain tumour diagnosis among 7-19 year olds. The multinational case-control study in Denmark, Sweden, Norway and Switzerland (CEFALO) included interviews with 352 (participation rate=83.2%) eligible cases and 646 (71.1%) population-based controls. Interview data were complemented with data from birth registries and validated by assessing agreement (Cohen's Kappa). We used conditional logistic regression models matched on age, sex and geographical region (adjusted for maternal age and parental education) to explore associations between birth factors and childhood brain tumour risk. Agreement between interview and birth registry data ranged from moderate (Kappa=0.54; worked during pregnancy) to almost perfect (Kappa=0.98; birth weight). Neither anthropogenic factors nor birth characteristics were associated with childhood brain tumour risk. Maternal vitamin intake during pregnancy was indicative of a protective effect (OR 0.75, 95%-CI: 0.56-1.01). No association was seen for maternal smoking during pregnancy or working during pregnancy. We found little evidence that the considered birth factors were related to brain tumour risk among children and adolescents. PMID- 26625089 TI - Associations between marital and educational status and risk of completed suicide in Hungary. AB - BACKGROUND: Suicide rates in Hungary are notoriously high. According to the literature, marital and educational status are associated with suicidal behaviour and these associations are somewhat influenced by gender. Since in Hungary these associations have not yet been investigated by means of large-scale multivariate epidemiological studies we aimed to investigate these in the current paper. METHOD: Census data on marital and educational status, age and gender from 1980, 1990, 2001 and 2011 were used for the general population. Corresponding data from the same years for suicide victims derived from the Hungarian Demographic Register. Suicide victims younger than 20 years were excluded. Negative binomial regression analyses were used to reveal the effects of the above variables on suicide. All statistical procedures were conducted using Stata 12 software (StataCorp. 2011). RESULTS: Female gender, young age, higher educational attainment and marriage were significantly associated with decreased risks of suicide. Intriguingly, effects of educational and marital status on suicide were stronger in males. LIMITATIONS: Data on the length of the periods between changes in marital status and suicides were unavailable. Our four categories are not suitable to cover the whole gamut of marital statuses in a modern society (e.g. we did not have a specific category for people living in cohabitation). Ecological study design. CONCLUSION: We found that in Hungary between 1980 and 2011 the effects of some frequently investigated societal factors (e.g. educational and marital status) on suicide risk were very similar to those found in the majority of other countries. The effects of studied determinants of suicide have not changed dramatically over the past three decades in Hungary. PMID- 26625090 TI - The relationship between challenging parenting behaviour and childhood anxiety disorders. AB - BACKGROUND: This research investigates the relationship between challenging parenting behaviour and childhood anxiety disorders proposed by Bogels and Phares (2008). Challenging parenting behaviour involves the playful encouragement of children to go beyond their own limits, and may decrease children's risk for anxiety (Bogels and Phares, 2008). METHOD: Parents (n=164 mothers and 144 fathers) of 164 children aged between 3.4 and 4.8 years participated in the current study. A multi-method, multi-informant assessment of anxiety was used, incorporating data from diagnostic interviews as well as questionnaire measures. Parents completed self-report measures of their parenting behaviour (n=147 mothers and 138 fathers) and anxiety (n=154 mothers and 143 fathers). Mothers reported on their child's anxiety via questionnaire as well as diagnostic interview (n=156 and 164 respectively). Of these children, 74 met criteria for an anxiety disorder and 90 did not. RESULTS: Fathers engaged in challenging parenting behaviour more often than mothers. Both mothers' and fathers' challenging parenting behaviour was associated with lower report of child anxiety symptoms. However, only mothers' challenging parenting behaviour was found to predict child clinical anxiety diagnosis. LIMITATIONS: Shared method variance from mothers confined the interpretation of these results. Moreover, due to study design, it is not possible to delineate cause and effect. CONCLUSIONS: The finding with respect to maternal challenging parenting behaviour was not anticipated, prompting replication of these results. Future research should investigate the role of challenging parenting behaviour by both caregivers as this may have implications for parenting interventions for anxious children. PMID- 26625091 TI - Cognitive distortions mediate depression and affective response to social acceptance and rejection. AB - BACKGROUND: The emotional context insensitivity (ECI) hypothesis suggests individuals with depression have blunted affective responses to both positive and negative events. We tested ECI in a social context to examine how depression relates to affective responses to social acceptance and rejection outcomes. Furthermore, we aimed to identify cognitive mechanisms linking depression with affective response to social feedback. Finally, we tested whether these processes are similar for social anxiety. METHOD: 90 participants (age 18-26 years; 53 women) completed the two-visit Chatroom task. At Visit 1 they rated their expectations about being liked by 60 peers. At Visit 2 they completed self reports of depressive and social anxiety symptoms, and of cognitive flexibility, then received acceptance or rejection feedback from each peer and rated their affective response. RESULTS: Greater depressive symptoms related to negative expectancy bias, lower cognitive flexibility, and less positive affective response to acceptance, but did not relate to rejection. Negative expectations and cognitive flexibility mediated the relationship between depressive symptoms and affective response for acceptance; only negative expectations mediated rejection responses. These cognitive mechanisms were not related to social anxiety. LIMITATIONS: A community sample was used to assess depression. Rumination and current mood state were omitted as potential predictors of affective response. CONCLUSIONS: Findings support the ECI framework. Depression but not social anxiety interferes with positive and negative affect through cognitively mediated dampening of emotional response to social acceptance and rejection. Emotion regulation strategies in depression therapy can target social flexibility to improve alignment of affective reactions to social outcomes. PMID- 26625092 TI - Differentiation between major depressive disorder and bipolar disorder by auditory steady-state responses. AB - BACKGROUND: The auditory steady-state response (ASSR) elicited by gamma band neural oscillations has received considerable interest as a biomarker of psychiatric disorders. Although recent ASSR studies have reported that patients with bipolar disorder (BD) show altered ASSRs, little is known about ASSRs in patients with major depressive disorder (MDD). The aim of this study was to evaluate whether ASSRs in MDD subjects differed from those in BD subjects or normal controls (NC). METHOD: We analyzed ASSRs in 14 MDD patients, 19 BD patients, and 29 normal control subjects. We used whole-head 306-channel magnetoencephalography to evaluate ASSR power and phase-locking factors (PLF) elicited by 20-, 30-, 40-, and 80-Hz click trains. We determined optimal sensitivity and specificity of ASSR power and PLF for the diagnosis of MDD or BD via receiver operating characteristic (ROC) curve analysis using a nonparametric approach. RESULTS: MDD patients exhibited no significant differences in ASSR power or PLF compared with NC subjects, while BD patients showed deficits on the ASSR measures. MDD patients showed significantly larger ASSR power and PLF for 30 , 40-, and 80-Hz stimuli compared with BD patients. The area under the curve (AUC) for the ROC analysis (MDD vs. BD) was 0.81 [95% CI=0.66-0.96, p=0.003] concerning 40-Hz ASSR power. LIMITATIONS: We could not exclude the effect of medication and the sample size of the current study is relatively small. CONCLUSIONS: We could differentiate between MDD and BD subjects in terms of gamma band ASSR. Our data suggest that the 40-Hz ASSR may be a potential biomarker for differentiation between MDD and BD patients. PMID- 26625093 TI - Tracing the associations between sex, the atypical and the combined atypical melancholic depression subtypes: A path analysis. AB - BACKGROUND: Numerous studies have examined determinants leading to preponderance of women in major depressive disorder (MDD), which is particularly accentuated for the atypical depression subtype. It is thus of interest to explore the specific indirect effects influencing the association between sex and established depression subtypes. METHODS: The data of 1624 subjects with a lifetime diagnosis of MDD derived from the population-based PsyCoLaus data were used. An atypical (n=256), a melancholic (n=422), a combined atypical and melancholic features subtype (n=198), and an unspecified MDD group (n=748) were constructed according to the DSM-IV specifiers. Path models with direct and indirect effects were applied to the data. RESULTS: Partial mediation of the female-related atypical and combined atypical-melancholic depression subtypes was found. Early anxiety disorders and high emotion-orientated coping acted as mediating variables between sex and the atypical depression subtype. In contrast, high Body Mass Index (BMI) served as a suppression variable, also concerning the association between sex and the combined atypical-melancholic subtype. The latter association was additionally mediated by an early age of MDD onset and early/late anxiety disorders. LIMITATIONS: The use of cross-sectional data does not allow causal conclusions. CONCLUSIONS: This is the first study that provides evidence for a differentiation of the general mechanisms explaining sex differences of overall MDD by depression subtypes. Determinants affecting the pathways begin early in life. Since some of them are primarily of behavioral nature, the present findings could be a valuable target in mental health care. PMID- 26625094 TI - NMDA receptor antagonist enhances antidepressant efficacy and alleviates learning memory function impairment induced by electroconvulsive shock with regulating glutamate receptors expression in hippocampus. PMID- 26625096 TI - Angular Scattering Dynamics of the CH4 + Cl -> CH3 + HCl Reaction Using Nearside Farside, Local Angular Momentum, and Resummation Theories. AB - The differential cross section (DCS) for the CH4 + Cl -> CH3 + HCl reaction is studied at six total energies where all of the species are in their ground states. The scattering (S) matrix elements have been calculated by the rotating line umbrella method for a dual-level ab initio analytic potential energy surface. We make the first application to this reaction of nearside-farside (NF) and local angular momentum (LAM) techniques, including resummation orders (r) of 0, 1, 2, and 3 for the partial-wave series representation of the full scattering amplitude. We find that resummation usually cleans the NF r = 0 DCSs of unphysical oscillations, especially at small angles. This cleaning effect is typically most pronounced when changing from no resummation (r = 0) to r = 1; further resummations from r = 1 to r = 2 and from r = 2 to r = 3 have smaller effects. The NF DCS analyses show that the reaction is N-dominated at sideward and large angles, whereas at small angles there are oscillations caused by NF interference. The NF LAM analysis provides consistent and complementary information, in particular for the total angular momenta that contribute to the reaction at different scattering angles. The NF analyses also provide justification for simpler N-dominant dynamical theories such as the semiclassical optical model, which provides an explanation for the distorted mirror image effect for the moduli of the S matrix elements and the DCSs, as well as the use of a hard-sphere DCS over limited angular ranges. PMID- 26625097 TI - The Role of PGC-1alpha in the Development of Insulin Resistance in Skeletal Muscle - Revisited. AB - Currently, obesity is a predominant medical condition and an important risk factor for the development of several diseases, including type 2 diabetes mellitus. Importantly, most research has indicated lipid-induced insulin resistance in skeletal muscles is a key link between the aforementioned pathological conditions. PGC-1alpha is a prominent regulator of myocellular energy metabolism orchestrating gene transcription programming in response to numerous environmental stimuli. Moreover, it is widely acknowledged that mitochondrial metabolism (primary metabolic target of PGC-1alpha) disturbances are widely acknowledged contributors to type 2 diabetes development. Therefore, it seems surprising that the exact physiological contribution of PGC-1alpha in the development of insulin resistance in skeletal muscle remains poorly understood. This review aims to reconcile these allegedly different findings by looking for a common denominator in the role(s) of PGC-1alpha in respect to lipid induced insulin resistance in skeletal muscle. Our scrutiny of the literature indicates that interventions at the level of PGC-1alpha may exert beneficial effects on myocytes in respect to lipid-induced insulin resistance. The latter takes place as a result of a positive net energy balance (fatty acids oxidation surpassing their accumulation rate). Moreover, the aforementioned effects may not necessarily be limited to physically active states. They seem to occur, however, only within a physiologically observed range in muscle cells (approximately 1 fold changes in PGC-1alpha protein expression). PMID- 26625095 TI - Daily minority stress and affect among gay and bisexual men: A 30-day diary study. AB - BACKGROUND: This study examined the time-variant association between daily minority stress and daily affect among gay and bisexual men. Tests of time-lagged associations allow for a stronger causal examination of minority stress-affect associations compared with static assessments. Multilevel modeling allows for comparison of associations between minority stress and daily affect when minority stress is modeled as a between-person factor and a within-person time-fluctuating state. METHODS: 371 gay and bisexual men in New York City completed a 30-day daily diary, recording daily experiences of minority stress and positive affect (PA), negative affect (NA), and anxious affect (AA). Multilevel analyses examined associations between minority stress and affect in both same-day and time-lagged analyses, with minority stress assessed as both a between-person factor and a within-person state. RESULTS: Daily minority stress, modeled as both a between person and within-person construct, significantly predicted lower PA and higher NA and AA. Daily minority stress also predicted lower subsequent-day PA and higher subsequent-day NA and AA. LIMITATIONS: Self-report assessments and the unique sample may limit generalizability of this study. CONCLUSIONS: The time variant association between sexual minority stress and affect found here substantiates the basic tenet of minority stress theory with a fine-grained analysis of gay and bisexual men's daily experience. Time-lagged effects suggest a potentially causal pathway between minority stress as a social determinant of mood and anxiety disorder symptoms among gay and bisexual men. When modeled as both a between-person factor and within-person state, minority stress demonstrated expected patterns with affect. PMID- 26625099 TI - Aromaticity of Diazaborines and Their Protonated Forms. AB - Substitution of a CH group in benzene with nitrogen has a little effect on its aromaticity (Wang et al., Org. Lett. 2010, 12, 4824). How does the same type of substitution affect aromatic character of the three isomeric azaborines? Does further protonation change aromaticity of diazaborines? This work is aimed at answering these questions. Such a knowledge should be of interest for further exploration and application of BN/CC isosterism. Aromaticity of diazaborines and their protonated forms is studied with the aid of four aromaticity indices, HOMA, NICS(0)pizz, PDI and ECRE. Generally, NICS(0)pizz and PDI point to similar aromaticity of diazaborines and their parent azaborines, while HOMA and ECRE indicate some changes. Thus, aromaticity of 1,2-azaborine slightly decreases/increases when CH meta/ortho,para to B is substituted with nitrogen. Aromaticity of the most aromatic 1,3-azaborine remains almost unchanged when CH meta to B and N is replaced with nitrogen, and becomes slightly weaker when any other CH group is substituted with nitrogen. Replacement of the CH ortho to N in 1,4-azaborine does not change much its cyclic delocalization, while replacement of the CH ortho to B leads to smaller cyclic delocalization. Protonated forms are either of similar or decreased aromaticity compared with neutral molecules. PMID- 26625098 TI - Salivary alpha-amylase response following repeated psychosocial stress in patients with panic disorder. AB - BACKGROUND: This study examined autonomic responses (salivary alpha-amylase, sAA; heart rate, HR) to repeated psychosocial stress as a candidate mechanism linking autonomic hyper-arousal and sensitization to the occurrence of panic disorder (PD). METHODS: Thirty-three patients with PD and 34 healthy controls were exposed to the Trier Social Stress Test (TSST) twice on consecutive days. RESULTS: sAA changes were comparable between PD and controls on both testing days with overall decreasing sAA responses (delta) on day two. In contrast, HR delta increased on day two in both groups. This sensitization was driven by female controls while male PD showed most pronounced HR changes to the first TSST. CONCLUSIONS: Overall, a general autonomic hyper-arousal in PD could not be confirmed. In contrast, sAA responses slightly habituated to repeated stress. Whether sAA findings mirror assumed habituation effects of repeated stress exposure on normalizing autonomic reactivity remains to be investigated in longitudinal studies. PMID- 26625100 TI - Benchmarking Ground-State Geometries and Vertical Excitation Energies of a Selection of P-Type Semiconducting Molecules with Different Polarity. AB - A benchmark of TD-DFT, wave function-based and semiempiric methods was performed for the geometries and excitation energies of diverse molecular organic semiconductors with varying polarity. Geometries were benchmarked by means of RMSD (root-mean-square deviation) values and MAE (maximum absolute error) values of geometric parameters specific for the electronic structure of the respective molecule. MS-CASPT2 calculations were used to benchmark excitation energies with respect to a confidence interval around the values obtained with CASPT2. The effect of spin-component scaling (SCS) on several wave function-based methods was thoroughly evaluated. PMID- 26625101 TI - [Serious silicosis still exits in Sweden]. AB - Many measures have been taken in Sweden to eliminate the occurrence of serious silicosis. However, between 1997 and 2013 there were 111 deaths with silicosis as underlying cause, 110 men and 1 woman. In most cases the deceased was rather old; only fourteen persons were below 74 years of age. We have studied the exposure between 2007 and 2012 in the 71 persons who died of silicosis as underlying or contributing cause through medical records. We could find information regarding 48 of them. Ten persons worked in mines, 10 in stone industry, 14 with crushing or blasting of rock, 4 in foundries, 3 were concrete workers and 7 suffered exposure in other industries. The study shows that the measures taken in Sweden have not been sufficient to totally eliminate serious silicosis. PMID- 26625102 TI - [Primary aldosteronism is an underdiagnosed cause of hypertension. Important to find undiagnosed patients--effective treatment available]. AB - Primary aldosteronism is the most common cause of secondary hypertension with an estimated prevalence of 5-13 % among patients with hypertension. The most common causes are aldosterone producing adrenal adenoma and idiopathic adrenal hyperplasia. Patients with primary aldosteronism have a higher prevalence of cardiovascular morbidity and mortality compared to patients with essential hypertension. An effective treatment is available for patients with primary aldosteronism, with mineralocorticoid receptor antagonists in bilateral, and minimal invasive adrenal surgery in unilateral disease, which emphasizes the importance of early detection, adequate diagnostic work-up and treatment. In this paper we give a short review of the etiology, pathophysiology, co-morbidities, screening, diagnostic work-up, treatment, and treatment outcomes of primary aldosteronism. PMID- 26625103 TI - [Spontaneous coronary artery dissection can cause acute coronary syndrome. Unusual condition that requires thoughtful management and more research]. AB - Spontaneous coronary artery dissection (SCAD) is a non-traumatic and non iatrogenic injury occurring in the vessel wall caused by either a primary intimal dissection or a primary hematoma in the medial layer. SCAD is more common among women than men and accounts for a small minority of acute coronary syndromes. The causes of SCAD are multifactorial. Peripartum SCAD is most common. Fibromuscular dysplasia has a strong association with SCAD. As spontaneous healing is common in SCAD and PCI is associated with complications an initial conservative approach should always be considered. Medical treatment is based on the underlying cause. Beta blockers are recommended to all patients. The prognosis varies; the highest mortality is reported among women suffering peripartum SCAD. Quality of life is often affected in SCAD patients and accompanied by a high rate of rehospitalizations. More research which focuses on the underlying causes, optimal treatment and rehabilitation is needed. PMID- 26625104 TI - [Endovascular treatment good in acute ischemic stroke]. AB - Systemic thrombolysis is an established treatment in acute ischemic stroke. Endovascular treatment to reperfuse occluded vessels has been in clinical practice the last decade. The role of neurointervention in acute ischemic stroke has been questioned. Within the last year, several randomized controlled trials have been published, comparing endovascular treatment and systemic thrombolysis with systemic thrombolysis alone. A meta-analysis, using data from six trials treating 1569 patients, was recently published. In this meta-analysis, patients treated with endovascular therapy in addition to IV thrombolysis had a more favourable clinical outcome compared to patients receiving IV thrombolysis alone, after 3 months. Compared to the individual studies, a decreased mortality in the intervention group was shown. Assessing the safety of endovascular treatment, there was no increased risk of intracranial bleed-ing, compared to IV thrombolysis alone. This meta-analysis highlights and summarizes the scientific evidence for endovascular treatment in acute ischemic stroke. PMID- 26625105 TI - [Our experience of proven experience. Some concepts profiles, and a tool for clarification]. PMID- 26625106 TI - [HPV screening for cervical cancer--the calculation of the Swedish National Board of Health and Welfare is too pessimistic]. PMID- 26625107 TI - [Group therapy is a good complementary treatment after bariatric surgery]. PMID- 26625108 TI - [Guidelines for HPV screening should be reconsidered]. PMID- 26625109 TI - [Not Available]. PMID- 26625110 TI - [Not Available]. PMID- 26625111 TI - [The tale of the entomological abduction of a woman]. PMID- 26625112 TI - ["Swedish young people do not need flavored snuff"]. PMID- 26625113 TI - [Not Available]. PMID- 26625114 TI - [Country profiles important tool at COP21 in Paris]. PMID- 26625116 TI - Fast Calcium Imaging with Optical Sectioning via HiLo Microscopy. AB - Imaging intracellular calcium concentration via reporters that change their fluorescence properties upon binding of calcium, referred to as calcium imaging, has revolutionized our way to probe neuronal activity non-invasively. To reach neurons densely located deep in the tissue, optical sectioning at high rate of acquisition is necessary but difficult to achieve in a cost effective manner. Here we implement an accessible solution relying on HiLo microscopy to provide robust optical sectioning with a high frame rate in vivo. We show that large calcium signals can be recorded from dense neuronal populations at high acquisition rates. We quantify the optical sectioning capabilities and demonstrate the benefits of HiLo microscopy compared to wide-field microscopy for calcium imaging and 3D reconstruction. We apply HiLo microscopy to functional calcium imaging at 100 frames per second deep in biological tissues. This approach enables us to discriminate neuronal activity of motor neurons from different depths in the spinal cord of zebrafish embryos. We observe distinct time courses of calcium signals in somata and axons. We show that our method enables to remove large fluctuations of the background fluorescence. All together our setup can be implemented to provide efficient optical sectioning in vivo at low cost on a wide range of existing microscopes. PMID- 26625115 TI - Can Genetic Analysis of Putative Blood Alzheimer's Disease Biomarkers Lead to Identification of Susceptibility Loci? AB - Although 24 Alzheimer's disease (AD) risk loci have been reliably identified, a large portion of the predicted heritability for AD remains unexplained. It is expected that additional loci of small effect will be identified with an increased sample size. However, the cost of a significant increase in Case Control sample size is prohibitive. The current study tests whether exploring the genetic basis of endophenotypes, in this case based on putative blood biomarkers for AD, can accelerate the identification of susceptibility loci using modest sample sizes. Each endophenotype was used as the outcome variable in an independent GWAS. Endophenotypes were based on circulating concentrations of proteins that contributed significantly to a published blood-based predictive algorithm for AD. Endophenotypes included Monocyte Chemoattractant Protein 1 (MCP1), Vascular Cell Adhesion Molecule 1 (VCAM1), Pancreatic Polypeptide (PP), Beta2 Microglobulin (B2M), Factor VII (F7), Adiponectin (ADN) and Tenascin C (TN C). Across the seven endophenotypes, 47 SNPs were associated with outcome with a p-value <=1x10(-7). Each signal was further characterized with respect to known genetic loci associated with AD. Signals for several endophenotypes were observed in the vicinity of CR1, MS4A6A/MS4A4E, PICALM, CLU, and PTK2B. The strongest signal was observed in association with Factor VII levels and was located within the F7 gene. Additional signals were observed in MAP3K13, ZNF320, ATP9B and TREM1. Conditional regression analyses suggested that the SNPs contributed to variation in protein concentration independent of AD status. The identification of two putatively novel AD loci (in the Factor VII and ATP9B genes), which have not been located in previous studies despite massive sample sizes, highlights the benefits of an endophenotypic approach for resolving the genetic basis for complex diseases. The coincidence of several of the endophenotypic signals with known AD loci may point to novel genetic interactions and should be further investigated. PMID- 26625117 TI - Historical Epidemics Cartography Generated by Spatial Analysis: Mapping the Heterogeneity of Three Medieval "Plagues" in Dijon. AB - OBJECTIVES: This work was designed to adapt Geographical Information System-based spatial analysis to the study of historical epidemics. We mapped "plague" deaths during three epidemics of the early 15th century, analyzed spatial distributions by applying the Kulldorff's method, and determined their relationships with the distribution of socio-professional categories in the city of Dijon. MATERIALS AND METHODS: Our study was based on a database including 50 annual tax registers (established from 1376 to 1447) indicating deaths and survivors among the heads of households, their home location, tax level and profession. The households of the deceased and survivors during 6 years with excess mortality were individually located on a georeferenced medieval map, established by taking advantage of the preserved geography of the historical center of Dijon. We searched for clusters of heads of households characterized by shared tax levels (high-tax payers, the upper decile; low-tax payers, the half charged at the minimum level) or professional activities and for clusters of differential mortality. RESULTS: High tax payers were preferentially in the northern intramural part, as well as most wealthy or specialized professionals, whereas low-tax payers were preferentially in the southern part. During two epidemics, in 1400-1401 and 1428, areas of higher mortality were found in the northern part whereas areas of lower mortality were in the southern one. A high concentration of housing and the proximity to food stocks were common features of the most affected areas, creating suitable conditions for rats to pullulate. A third epidemic, lasting from 1438 to 1440 had a different and evolving geography: cases were initially concentrated around the southern gate, at the confluence of three rivers, they were then diffuse, and ended with residual foci of deaths in the northern suburb. CONCLUSION: Using a selected historical source, we designed an approach allowing spatial analysis of urban medieval epidemics. Our results fit with the view that the 1400-1401 epidemic was a Black Death recurrence. They suggest that this was also the case in 1428, whereas in 1438-1440 a different, possibly waterborne, disease was involved. PMID- 26625118 TI - Use of Viremia to Evaluate the Baseline Case Fatality Ratio of Ebola Virus Disease and Inform Treatment Studies: A Retrospective Cohort Study. AB - BACKGROUND: The case fatality ratio (CFR) of Ebola virus disease (EVD) can vary over time and space for reasons that are not fully understood. This makes it difficult to define the baseline CFRs needed to evaluate treatments in the absence of randomized controls. Here, we investigate whether viremia in EVD patients may be used to evaluate baseline EVD CFRs. METHODS AND FINDINGS: We analyzed the laboratory and epidemiological records of patients with EVD confirmed by reverse transcription PCR hospitalized in the Conakry area, Guinea, between 1 March 2014 and 28 February 2015. We used viremia and other variables to model the CFR. Data for 699 EVD patients were analyzed. In the week following symptom onset, mean viremia remained stable, and the CFR increased with viremia, V, from 21% (95% CI 16%-27%) for low viremia (V < 104.4 copies/ml) to 53% (95% CI 44%-61%) for intermediate viremia (104.4 <= V < 105.2 copies/ml) and 81% (95% CI 75%-87%) for high viremia (V >= 105.2 copies/ml). Compared to adults (15-44 y old [y.o.]), the CFR was larger in young children (0-4 y.o.) (odds ratio [OR]: 2.44; 95% CI 1.02-5.86) and older adults (>= 45 y.o.) (OR: 2.84; 95% CI 1.81-4.46) but lower in children (5-14 y.o.) (OR: 0.46; 95% CI 0.24-0.86). An order of magnitude increase in mean viremia in cases after July 2014 compared to those before coincided with a 14% increase in the CFR. Our findings come from a large hospital based study in Conakry and may not be generalizable to settings with different case profiles, such as with individuals who never sought care. CONCLUSIONS: Viremia in EVD patients was a strong predictor of death that partly explained variations in CFR in the study population. This study provides baseline CFRs by viremia group, which allow appropriate adjustment when estimating efficacy in treatment studies. In randomized controlled trials, stratifying analysis on viremia groups could reduce sample size requirements by 25%. We hypothesize that monitoring the viremia of hospitalized patients may inform the ability of surveillance systems to detect EVD patients from the different severity strata. PMID- 26625119 TI - Creating Cycling-Friendly Environments for Children: Which Micro-Scale Factors Are Most Important? An Experimental Study Using Manipulated Photographs. AB - BACKGROUND: Increasing participation in transportation cycling represents a useful strategy for increasing children's physical activity levels. Knowledge on how to design environments to encourage adoption and maintenance of transportation cycling is limited and relies mainly on observational studies. The current study experimentally investigates the relative importance of micro-scale environmental factors for children's transportation cycling, as these micro-scale factors are easier to change within an existing neighborhood compared to macro scale environmental factors (i.e. connectivity, land-use mix, ...). METHODS: Researchers recruited children and their parents (n = 1232) via 45 randomly selected schools across Flanders and completed an online questionnaire which consisted of 1) demographic questions; and 2) a choice-based conjoint (CBC) task. During this task, participants chose between two photographs which we had experimentally manipulated in seven micro-scale environmental factors: type of cycle path; evenness of cycle path; traffic speed; traffic density; presence of speed bumps; environmental maintenance; and vegetation. Participants indicated which route they preferred to (let their child) cycle along. To find the relative importance of these micro-scale environmental factors, we conducted Hierarchical Bayes analyses. RESULTS: Type of cycle path emerged as the most important factor by far among both children and their parents, followed by traffic density and maintenance, and evenness of the cycle path among children. Among parents, speed limits and maintenance emerged as second most important, followed by evenness of the cycle path, and traffic density. CONCLUSION: Findings indicate that improvements in micro-scale environmental factors might be effective for increasing children's transportation cycling, since they increase the perceived supportiveness of the physical environment for transportation cycling. Investments in creating a clearly designated space for the young cyclist, separated from motorized traffic, appears to be the most effective way to increase perceived supportiveness. Future research should confirm our laboratory findings with experimental on-site research. PMID- 26625121 TI - Clinical and Hormonal Features of a Male Adolescent with Congenital Isolated Follicle-Stimulating Hormone Deficiency. AB - AIM: Our aim was to describe the clinical and genetic findings in an adolescent male with isolated follicle-stimulating hormone (FSH) deficiency and demonstrate the efficacy of recombinant human FSH (rhFSH) replacement in this case. METHODS: A 14.5-year-old adolescent male was referred with normal pubertal development and small testes. Serum testosterone, FSH, and luteinising hormone (LH) were measured at baseline and after gonadotropin-releasing hormone (GnRH) stimulation. Testicular biopsy was performed, and rhFSH replacement was administered for 6 months. The patient's FSHbeta gene was amplified and sequenced. RESULTS: Basal and GnRH-stimulated FSH levels were undetectable, in contrast with increased LH levels under both conditions. Histopathological investigation of a testicular biopsy specimen revealed a reduced number of Sertoli cells, the absence of germ cells, Leydig cell hyperplasia, and a thickened basement membrane in seminiferous tubules. The testicular size changed from 1 ml at baseline to 6 ml after 6 months of rhFSH replacement. Sequencing of the FSHbeta gene exon 3 revealed a new missense mutation (c.364T>C, resulting in p.Cys122Arg) in a homozygous state in the patient; both parents and a sister carried the same mutation in a heterozygous state. We also compared our case with all similar cases published previously. CONCLUSION: We herein described an adolescent male with isolated FSH deficiency due to a novel FSHbeta gene mutation associated with a prepubertal testes size and normal virilisation. PMID- 26625120 TI - Factors Affecting Gender Differences in the Association between Health-Related Quality of Life and Metabolic Syndrome Components: Tehran Lipid and Glucose Study. AB - OBJECTIVE: Using structural equation modeling, this study is one of the first efforts aimed at assessing influential factors causing gender differences in the association between health-related quality of life (HRQoL) and metabolic syndrome. METHODS: A sample of 950 adults, from Tehran Lipid and Glucose Study were recruited for this cross sectional study in 2005-2007. Health-related quality of life was assessed using the Iranian version of SF-36. Metabolic syndrome components (MetSCs) and physical and mental HRQoL were considered as continuous latent constructs explaining the variances of their observed components. Structural equation modeling was performed to examine the association between the constructs of MetSCs and the physical and mental HRQoL within the two gender groups. RESULTS: Based on the primary hypothesis, MetSCs and HRQoL were fitted in a model. The negative effect of MetSCs on HRQoL was found to be significant only in the physical domain and only in women. The proportion of all the cardio-metabolic risk factors as well as subscales of physical HRQoL that have been explained via the two constructs of MetSCs and HRQoL, respectively, were significantly higher in women. Physical activity in both men (beta = 3.19, p<0.05) and women (beta = 3.94, p<0.05), age (beta = -3.28, p<0.05), education (beta = 2.63, p<0.05) only in women and smoking (beta = 2.28, p<0.05) just in men, directly affected physical HRQoL. Regarding the mental domain, physical activity (beta = 3.37, p<0.05) and marital status (beta = 3.44, p<0.05) in women and age (beta = 2.01, p<0.05) in men were direct effective factors. Age and education in women as well as smoking in men indirectly affected physical HRQoL via MetSCs. CONCLUSION: Gender differences in the association between MetSCs and physical HRQoL could mostly be attributed to the different structures of both MetSCs and physical HRQoL constructs in men and women. Age and smoking are the most important socio-behavioral factors which could affect this gender-specific association in the mental domain. PMID- 26625122 TI - Effects of Tannic Acid, Green Tea and Red Wine on hERG Channels Expressed in HEK293 Cells. AB - Tannic acid presents in varying concentrations in plant foods, and in relatively high concentrations in green teas and red wines. Human ether-a-go-go-related gene (hERG) channels expressed in multiple tissues (e.g. heart, neurons, smooth muscle and cancer cells), and play important roles in modulating cardiac action potential repolarization and tumor cell biology. The present study investigated the effects of tannic acid, green teas and red wines on hERG currents. The effects of tannic acid, teas and red wines on hERG currents stably transfected in HEK293 cells were studied with a perforated patch clamp technique. In this study, we demonstrated that tannic acid inhibited hERG currents with an IC50 of 3.4 MUM and ~100% inhibition at higher concentrations, and significantly shifted the voltage dependent activation to more positive potentials (Delta23.2 mV). Remarkably, a 100-fold dilution of multiple types of tea (green tea, oolong tea and black tea) or red wine inhibited hERG currents by ~90%, and significantly shifted the voltage dependent activation to more positive potentials (Delta30.8 mV and Delta26.0 mV, respectively). Green tea Lung Ching and red wine inhibited hERG currents, with IC50 of 0.04% and 0.19%, respectively. The effects of tannic acid, teas and red wine on hERG currents were irreversible. These results suggest tannic acid is a novel hERG channel blocker and consequently provide a new mechanistic evidence for understanding the effects of tannic acid. They also revealed the potential pharmacological basis of tea- and red wine-induced biology activities. PMID- 26625123 TI - The Structure of the RNA-Dependent RNA Polymerase of a Permutotetravirus Suggests a Link between Primer-Dependent and Primer-Independent Polymerases. AB - Thosea asigna virus (TaV), an insect virus belonging to the Permutatetraviridae family, has a positive-sense single-stranded RNA (ssRNA) genome with two overlapping open reading frames, encoding for the replicase and capsid proteins. The particular TaV replicase includes a structurally unique RNA-dependent RNA polymerase (RdRP) with a sequence permutation in the palm sub-domain, where the active site is anchored. This non-canonical arrangement of the RdRP palm is also found in double-stranded RNA viruses of the Birnaviridae family. Both virus families also share a conserved VPg sequence motif at the polymerase N-terminus which in birnaviruses appears to be used to covalently link a fraction of the replicase molecules to the 5'-end of the genomic segments. Birnavirus VPgs are presumed to be used as primers for replication initiation. Here we have solved the crystal structure of the TaV RdRP, the first non-canonical RdRP of a ssRNA virus, in its apo- form and bound to different substrates. The enzyme arranges as a stable dimer maintained by mutual interactions between the active site cleft of one molecule and the flexible N-terminal tail of the symmetrically related RdRP. The latter, partially mimicking the RNA template backbone, is involved in regulating the polymerization activity. As expected from previous sequence-based bioinformatics predictions, the overall architecture of the TaV enzyme shows important resemblances with birnavirus polymerases. In addition, structural comparisons and biochemical analyses reveal unexpected similarities between the TaV RdRP and those of Flaviviruses. In particular, a long loop protruding from the thumb domain towards the central enzyme cavity appears to act as a platform for de novo initiation of RNA replication. Our findings strongly suggest an unexpected evolutionary relationship between the RdRPs encoded by these distant ssRNA virus groups. PMID- 26625125 TI - Pharmacologic Treatment Options in Mild, Moderate, and Severe Acne Vulgaris. AB - Most patients with acne have a disease that responds to acute treatment and can be controlled long term with a maintenance regimen of topical therapy. It is the minority of patients-generally, but not exclusively-the most severely affected, who respond poorly to acute therapy and require continued systemic therapy. The goals of therapy are resolution of visible lesions, prevention of new lesions, avoidance of scarring, and improvement of patient quality of life. Treatment choices are made on the basis of lesion type, number, and size, with consideration given to the presence of physical and psychological scarring. Semin Cutan Med Surg 34(supp5):S82-S85. PMID- 26625124 TI - Trends in HIV surveillance data in the EU/EEA, 2005 to 2014: new HIV diagnoses still increasing in men who have sex with men. AB - Human immunodeficiency virus (HIV) transmission remains significant in Europe. Rates of acquired immunodeficiency syndrome (AIDS) have declined, but not in all countries. New HIV diagnoses have increased among native and foreign-born men who have sex with men. Median CD4(+) T-cell count at diagnosis has increased, but not in all groups, and late diagnosis remains common. HIV infection and AIDS can be eliminated in Europe with resolute prevention measures, early diagnosis and access to effective treatment. PMID- 26625126 TI - Revised Morning Loops of the Arabidopsis Circadian Clock Based on Analyses of Direct Regulatory Interactions. AB - The network structure of the plant circadian clock is complex and direct regulatory interactions between individual components have proven particularly difficult to predict from genetic analyses. Here, we systematically investigate in vivo binding interactions between the morning-specific transcription factor, LATE ELONGATED HYPOCOTYL (LHY) and the promoters of other components of the network. We then demonstrate the functionality of these interactions by testing the responsiveness of the target gene to an ethanol-induced change in expression level of the LHY protein. We uncover novel, negative autoregulatory feedback loops from LHY and the closely related CIRCADIAN CLOCK ASSOCIATED-1 (CCA1) onto their own and each other's expression. Furthermore we show that LHY acts as a repressor of all other clock components, including PSEUDO-RESPONSE REGULATORs (PRRs) 9 and 7, which were previously thought to be positive regulatory targets. These experimental results lead to a substantial revision of the morning loops of the clock. PMID- 26625129 TI - Association of Irisin and CRP Levels with the Radiographic Severity of Knee Osteoarthritis. AB - OBJECTIVE: Irisin, a recently identified myokine, is implicated in protecting mice from obesity. This study was designed to examine the relation of irisin levels in serum and synovial fluid (SF) with the radiographic severity of osteoarthritis (OA). METHODS: Our study included 215 patients with knee OA. Irisin levels in serum and SF were evaluated using an enzyme-linked immunosorbent assay. The progression of OA was assessed using Kellgren-Lawrence grading system. RESULTS: Knee OA patients had lower serum irisin concentrations and increased serum C-reactive protein (CRP) levels compared with healthy controls. There were markedly decreased irisin levels in both the serum and the SF, as well as increased serum CRP levels of knee OA patients with Kellgren and Lawrence (KL) grade 4 compared with patients classified as KL grade 2 and 3. Furthermore, patients with KL grade 3 showed markedly reduced serum and SF levels of irisin, as well as increased serum CRP levels compared with patients classified as KL grade 2. Irisin levels in serum and SF of knee OA patients were negatively correlated with disease severity evaluated by KL grading criteria. CONCLUSION: Irisin levels in the serum and SF of knee OA patients were negatively correlated with disease severity evaluated by the radiographic KL grading criteria. PMID- 26625127 TI - Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial Dependent Biosynthesis. AB - Metformin is a biguanide widely prescribed to treat Type II diabetes that has gained interest as an antineoplastic agent. Recent work suggests that metformin directly antagonizes cancer cell growth through its actions on complex I of the mitochondrial electron transport chain (ETC). However, the mechanisms by which metformin arrests cancer cell proliferation remain poorly defined. Here we demonstrate that the metabolic checkpoint kinases AMP-activated protein kinase (AMPK) and LKB1 are not required for the antiproliferative effects of metformin. Rather, metformin inhibits cancer cell proliferation by suppressing mitochondrial dependent biosynthetic activity. We show that in vitro metformin decreases the flow of glucose- and glutamine-derived metabolic intermediates into the Tricarboxylic Acid (TCA) cycle, leading to reduced citrate production and de novo lipid biosynthesis. Tumor cells lacking functional mitochondria maintain lipid biosynthesis in the presence of metformin via glutamine-dependent reductive carboxylation, and display reduced sensitivity to metformin-induced proliferative arrest. Our data indicate that metformin inhibits cancer cell proliferation by suppressing the production of mitochondrial-dependent metabolic intermediates required for cell growth, and that metabolic adaptations that bypass mitochondrial-dependent biosynthesis may provide a mechanism of tumor cell resistance to biguanide activity. PMID- 26625128 TI - Spatiotemporal Aspects of Hendra Virus Infection in Pteropid Bats (Flying-Foxes) in Eastern Australia. AB - Hendra virus (HeV) causes highly lethal disease in horses and humans in the eastern Australian states of Queensland (QLD) and New South Wales (NSW), with multiple equine cases now reported on an annual basis. Infection and excretion dynamics in pteropid bats (flying-foxes), the recognised natural reservoir, are incompletely understood. We sought to identify key spatial and temporal factors associated with excretion in flying-foxes over a 2300 km latitudinal gradient from northern QLD to southern NSW which encompassed all known equine case locations. The aim was to strengthen knowledge of Hendra virus ecology in flying foxes to improve spillover risk prediction and exposure risk mitigation strategies, and thus better protect horses and humans. Monthly pooled urine samples were collected from under roosting flying-foxes over a three-year period and screened for HeV RNA by quantitative RT-PCR. A generalised linear model was employed to investigate spatiotemporal associations with HeV detection in 13,968 samples from 27 roosts. There was a non-linear relationship between mean HeV excretion prevalence and five latitudinal regions, with excretion moderate in northern and central QLD, highest in southern QLD/northern NSW, moderate in central NSW, and negligible in southern NSW. Highest HeV positivity occurred where black or spectacled flying-foxes were present; nil or very low positivity rates occurred in exclusive grey-headed flying-fox roosts. Similarly, little red flying-foxes are evidently not a significant source of virus, as their periodic extreme increase in numbers at some roosts was not associated with any concurrent increase in HeV detection. There was a consistent, strong winter seasonality to excretion in the southern QLD/northern NSW and central NSW regions. This new information allows risk management strategies to be refined and targeted, mindful of the potential for spatial risk profiles to shift over time with changes in flying-fox species distribution. PMID- 26625130 TI - Power-Frequency Magnetic Field Inhibits Adipogenic Differentiation in Human ADSC. AB - BACKGROUND/AIMS: Semicircular lipoatrophy (SL) is an idiopathic condition characterized by atrophy of subcutaneous fatty tissue. Although several studies have suggested a possible association between SL and occupational exposure to power frequency magnetic fields (MF), no mechanism has been proposed so far that explains an influence of these fields on adipogenesis. METHODS: The study investigates the effects of a 50 Hz, 100 uT MF on the adipogenesis of stem cells isolated from human adipose tissue (ADSC). Cells were plated in Petri dishes and either exposed intermittently to the field for 42 hours or sham-exposed. RESULTS: Field exposure significantly reduced lipid accumulation within the cells, revealed in Oil Red O stained samples by spectrophotometry and colorimetry. Early cell passages were particularly sensitive to the effect: 30.40 +/- 5.77% and 47.96 +/- 12.47% below controls in the spectrophotometric and colorimetric assays, respectively. Such antiadipogenic effect was accompanied by significant changes in the expression of key effectors/regulators of early adipogenesis: PPARx03B3;, p-ERK1/2 and Sox9, indicating that at least the ERK/PPARx03B3; signaling pathway could be involved in the effect. CONCLUSIONS: These results constitute an experimental support to the hypothesis that power frequency MF can be one of the factors involved in the etiology of SL. PMID- 26625131 TI - Impact of Patient Navigation Interventions on Timely Diagnostic Follow Up for Abnormal Cervical Screening. AB - OBJECTIVE: As part of the Patient Navigation Research Program, we examined the effect of patient navigation versus usual care on timely diagnostic follow-up, defined as clinical management for women with cervical abnormalities within accepted time frames. METHODS: Participants from four Patient Navigation Research Program centers were divided into low- and high-risk abnormality groups and analyzed separately. Low-risk participants (n = 2088) were those who enrolled with an initial Pap test finding of atypical squamous cells of undetermined significance (ASCUS) with a positive high-risk human papillomavirus (HPV) serotype, atypical glandular cells, or low-grade squamous intraepithelial lesion (LGSIL). High-risk participants were those with an initial finding of high-grade squamous intraepithelial lesion (HGSIL) (n = 229). A dichotomous outcome of timely diagnostic follow-up within 180 days was used for the low-risk abnormality group and timely diagnostic follow-up within 60 days for the high-risk group, consistent with treatment guidelines. A logistic mixed-effects regression model was used to evaluate the intervention effect using a random effect for study arm within an institution. A backward selection process was used for multivariable model building, considering the impact of each predictor on the intervention effect. RESULTS: Low-risk women in the patient navigation arm showed an improvement in the odds of timely diagnostic follow-up across all racial groups, but statistically significant effects were only observed in non-English-speaking Hispanics (OR 5.88, 95% CI 2.81-12.29). No effect was observed among high-risk women. CONCLUSION: These results suggest that patient navigation can improve timely diagnostic follow-up among women with low-risk cervical abnormalities, particularly in non-English-speaking Hispanic women. PMID- 26625132 TI - Antenatal Risk Factors of Postpartum Depression at 20 Weeks Gestation in a Japanese Sample: Psychosocial Perspectives from a Cohort Study in Tokyo. AB - BACKGROUND: Prevalence of postnatal depression (PND) is high (Western countries, 10-15%; Japan, 17%). PND can cause parenting impairment and affect family health (e.g. child behaviors, cognitive development and physical health). This study aimed to reveal the risk factors of PND during the pregnancy period in a Japanese sample, and to identify the psychosocial risk factors of PND that should be appended to existing obstetric interview sheets. A cohort study with a Japanese sample was conducted. METHODS: All 14 obstetrics hospitals in the Setagaya ward, Tokyo, Japan, participated in this study. Pregnant women who booked their delivery between December 2012 and May 2013 were enrolled. Data used for this study were collected at 20 weeks gestation, a few days and one month postnatal. The questionnaires consisted of psychosocial factors and the Edinburgh Postnatal Depression Scale (EPDS). To identify PND risk factors, multivariate analyses were performed. RESULTS: A total of 1,775 women participated in this study. Eventually, the data of 1,133 women were used for the multivariate analyses. The demonstrated significant risk factors include EPDS score, primipara, "a perceived lack of family cohesion", "current physical illness treatment" and "current psychiatric illness treatment". CONCLUSION: This study highlights the importance of mental health screening using psychological measures during the pregnancy period. In addition, family environment, parity, physical and psychiatric illness should be paid attention by professionals in maternal and child health. The results also suggest that mothers' feelings of developing their families should be supported. PMID- 26625133 TI - Ranking of Reactions Based on Sensitivity of Protein Noise Depends on the Choice of Noise Measure. AB - Gene expression is a stochastic process. Identification of the step maximally affecting noise in the protein level is an important aspect of investigation of gene product distribution. There are numerous experimental and theoretical studies that seek to identify this important step. However, these studies have used two different measures of noise, viz. coefficient of variation and Fano factor, and have compared different processes leading to contradictory observations regarding the important step. In this study, we performed systematic global and local sensitivity analysis on two models of gene expression to investigate relative contribution of reaction rate parameters to steady state noise in the protein level using both the measures of noise. We analytically and computationally showed that the ranking of parameters based on the sensitivity of the noise to variation in a given parameter is a strong function of the choice of the noise measure. If the Fano factor is used as the noise measure, translation is the important step whereas for coefficient of variation, transcription is the important step. We derived an analytical expression for local sensitivity and used it to explain the distinct contributions of each reaction parameter to the two measures of noise. We extended the analysis to a generic linear catalysis reaction system and observed that the reaction network topology was an important factor influencing the local sensitivity of the two measures of noise. Our study suggested that, for the analysis of contributions of reactions to the noise, consideration of both the measures of noise is important. PMID- 26625135 TI - Correction to Role of the Flavan-3-ol and Galloyl Moieties in the Interaction of (-)-Epigallocatechin Gallate with Serum Albumin. PMID- 26625136 TI - Outcome of Adult Respiratory Failure Patients Receiving Prolonged (>=14 Days) ECMO. AB - OBJECTIVE: To examine the outcomes of prolonged (>=14 days) extracorporeal membrane oxygenation (P-ECMO) for adult severe respiratory failure and to assess characteristics associated with survival. BACKGROUND: The use of ECMO for treatment of severe respiratory adult patients is associated with overall survival rates of 50% to 70% with median ECMO duration of 10 days. No prior multi institutional studies have examined outcomes of P-ECMO for severe respiratory failure. METHODS: Data on all adult (>=18 years) patients who required P-ECMO for severe respiratory failure from 1989 to 2013 were extracted from the Extracorporeal Life Support Organization international multi-institutional registry. We examined outcomes over 23 years and compared the 2 more recent time periods of 1989 to 2006 versus 2007 to 2013. RESULTS: Up to 974 patients, mean age 40.2 (18-83) years, had ECMO duration of mean 25.2 days/median 21.0 days (range: 14-208 days). Venovenous ECMO support was most common (venovenous: 79.5%, venoarterial: 9.9%). Reason for ECMO discontinuation included native lung recovery (54%), organ failure (23.7%), family request (6.7%), hemorrhage (2.7%), and diagnosis incompatible with life (5.6%). Forty patients (4.1%) underwent lung transplant with 50% postoperative in-hospital mortality. Increased prevalence of P-ECMO was noted with 72% (701/974) of all cases reported since 2008. Survival to hospital discharge was 45.4% (443/974) and did not vary with ECMO duration. Multivariate logistic regression analysis confirmed that P-ECMO patients 2007 to 2013 had a lower risk of death [odds ratio (OR): 0.650; 95% confidence interval (CI), 0.454-0.929; P = 0.010] compared with 1989 to 2006. Factors independently associated with survival were younger age (OR: 0.983; 95% CI, 0.974-0.993; P < 0.001) and lower PaCO2 (OR, 0.991; 95% CI, 0.986-0.996; P < 0.001). CONCLUSIONS: Prolonged ECMO use for adult respiratory failure was associated with a lower (45.4%) hospital survival rate, compared with prior reported survival rates of short duration ECMO. Prolonged ECMO survival significantly increased in recent years, and increasing ECMO duration did not alter the survival fraction in the 1989 to 2013 study cohort. Although P-ECMO survival rates are less than short ECMO runs, P-ECMO support is justified. PMID- 26625137 TI - Correlation of Dynamic Surface Tension with Sedimentation of PTFE Particles and Water Penetration in Powders. AB - The dynamic surface tension of aqueous poly(ethylene oxide)-poly(propylene oxide) poly(ethylene oxide) [(PEO-PPO-PEO)]-type polymeric surfactant (P103, P105, F108, P123, and F127) solutions were correlated with water penetration in packed Teflon powders, the sedimentation of Teflon suspensions in these solutions, foamability, and contact angle measurements on a Teflon surface. The DST trend with bubble lifetime indicated that the overall slowdown in the diffusion process in aqueous solutions is a function of a higher poly(ethylene oxide) (PEO) molecular weight for a given series of block copolymers containing equal PPO molecular weights, favoring slower diffusion kinetics to the air-water interface caused by preferential partitioning in bulk water. The wettability of poly(tetrafluoroethylene) (PTFE) powder illustrates better water penetration for polymers with low molecular weight and lower HLB values. The wettability of F127 solutions decreases with corresponding increases in concentration resulting from higher viscosity, which restrains the diffusion kinetics at the PTFE-water interface. The foamability decreases drastically with higher PEO molecular weight as attributed by slower diffusion kinetics, leading to a decrease in the effective concentration of molecules at the foam interface. The contact angle on glass and the PTFE surface are in good agreement with assumptions made by other analytical techniques showing a lower value of the contact angle with a lower HLB of the Pluronic, which relates to the higher adsorption of molecules at the interface. It is concluded that the adsorption of molecules at the PTFE-water interface decreases in aqueous Pluronic solutions with corresponding increases in the hydrophilic lipophilic balance (HLB), which is consistent with foaming, water penetration in a packed powder of PTFE, the rate of sedimentation, and DST data. A PTFE dispersion containing P123 showed the maximum wettability and lowest sedimentation among the series of block copolymers introduced, which is attributed to faster diffusion kinetics and a higher PPO contribution fostering faster adsorption at the PTFE surface. The dynamic surface tension of aqueous Pluronic solutions seems to correlate well with the adsorption characteristics at the air-water and PTFE-water interfaces. PMID- 26625134 TI - Inequalities in Alcohol-Related Mortality in 17 European Countries: A Retrospective Analysis of Mortality Registers. AB - BACKGROUND: Socioeconomic inequalities in alcohol-related mortality have been documented in several European countries, but it is unknown whether the magnitude of these inequalities differs between countries and whether these inequalities increase or decrease over time. METHODS AND FINDINGS: We collected and harmonized data on mortality from four alcohol-related causes (alcoholic psychosis, dependence, and abuse; alcoholic cardiomyopathy; alcoholic liver cirrhosis; and accidental poisoning by alcohol) by age, sex, education level, and occupational class in 20 European populations from 17 different countries, both for a recent period and for previous points in time, using data from mortality registers. Mortality was age-standardized using the European Standard Population, and measures for both relative and absolute inequality between low and high socioeconomic groups (as measured by educational level and occupational class) were calculated. Rates of alcohol-related mortality are higher in lower educational and occupational groups in all countries. Both relative and absolute inequalities are largest in Eastern Europe, and Finland and Denmark also have very large absolute inequalities in alcohol-related mortality. For example, for educational inequality among Finnish men, the relative index of inequality is 3.6 (95% CI 3.3-4.0) and the slope index of inequality is 112.5 (95% CI 106.2-118.8) deaths per 100,000 person-years. Over time, the relative inequality in alcohol related mortality has increased in many countries, but the main change is a strong rise of absolute inequality in several countries in Eastern Europe (Hungary, Lithuania, Estonia) and Northern Europe (Finland, Denmark) because of a rapid rise in alcohol-related mortality in lower socioeconomic groups. In some of these countries, alcohol-related causes now account for 10% or more of the socioeconomic inequality in total mortality. Because our study relies on routinely collected underlying causes of death, it is likely that our results underestimate the true extent of the problem. CONCLUSIONS: Alcohol-related conditions play an important role in generating inequalities in total mortality in many European countries. Countering increases in alcohol-related mortality in lower socioeconomic groups is essential for reducing inequalities in mortality. Studies of why such increases have not occurred in countries like France, Switzerland, Spain, and Italy can help in developing evidence-based policies in other European countries. PMID- 26625138 TI - IL-25 Receptor Expression on Airway Dendritic Cells after Allergen Challenge in Subjects with Asthma. AB - RATIONALE: IL-25 is an epithelial-derived cytokine, whose effects are mediated by the IL-25 receptor (IL-17RB), and that has been implicated in the pathogenesis of allergic disease and airway viral responses. Airway myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) are professional antigen presenting cells. pDCs may play a protective role in asthma and are key players in the innate immune response through recognition of microbial products via Toll like receptors (TLRs). The effects of inhaled allergens on the expression of IL 17RB by mDCs and pDCs, and the effects of IL-25 on pDCs, are unknown. OBJECTIVES: To evaluate allergen-induced changes in IL-17RB expression by mDCs and pDCs and to investigate the effects of IL-25 on pDCs. METHODS: Patients with mild atopic asthma (n = 13) were challenged with inhaled allergen. Blood and sputum DCs were enumerated and IL-17RB expression was determined by flow cytometry before and 7 and 24 hours after allergen challenge. The effects of IL-25 on pDCs in vitro were also assessed. MEASUREMENTS AND MAIN RESULTS: Inhaled allergen significantly increased mDC and pDC numbers in sputum but not in blood. The percentage of IL 17RB(+) mDCs and pDCs was significantly increased in blood and sputum 24 hours after challenge. IL-25 up-regulated TLR9 expression by pDCs and orchestrated the responses to TLR9 ligation. CONCLUSIONS: IL-17RB is up-regulated on blood and sputum mDCs and pDCs after allergen inhalation. IL-25 modulates pDC function through an effect on TLR9 expression. PMID- 26625139 TI - Functional Analysis of the Unique Cytochrome P450 of the Liver Fluke Opisthorchis felineus. AB - The basic metabolic cytochrome P450 (CYP) system is essential for biotransformation of sterols and xenobiotics including drugs, for synthesis and degradation of signaling molecules in all living organisms. Most eukaryotes including free-living flatworms have numerous paralogues of the CYP gene encoding heme monooxygenases with specific substrate range. Notably, by contrast, the parasitic flatworms have only one CYP gene. The role of this enzyme in the physiology and biochemistry of helminths is not known. The flukes and tapeworms are the etiologic agents of major neglected tropical diseases of humanity. Three helminth infections (Opisthorchis viverrini, Clonorchis sinensis and Schistosoma haematobium) are considered by the International Agency for Research on Cancer (IARC) as definite causes of cancer. We focused our research on the human liver fluke Opisthorchis felineus, an emerging source of biliary tract disease including bile duct cancer in Russia and central Europe. The aims of this study were (i) to determine the significance of the CYP activity for the morphology and survival of the liver fluke, (ii) to assess CYP ability to metabolize xenobiotics, and (iii) to localize the CYP activity in O. felineus tissues. We observed high constitutive expression of CYP mRNA (Real-time PCR) in O. felineus. This enzyme metabolized xenobiotics selective for mammalian CYP2E1, CYP2B, CYP3A, but not CYP1A, as determined by liquid chromatography and imaging analyses. Tissue localization studies revealed the CYP activity in excretory channels, while suppression of CYP mRNA by RNA interference was accompanied by morphological changes of the excretory system and increased mortality rates of the worms. These results suggest that the CYP function is linked to worm metabolism and detoxification. The findings also suggest that the CYP enzyme is involved in vitally important processes in the organism of parasites and is a potential drug target. PMID- 26625140 TI - The structure and continuous stoichiometry change of 1DTbBrx@SWCNTs. AB - HRTEM and HAADF STEM of 1DTbBrx@SWCNT meta-nanotubes reveal three structural modifications of 1D nanocrystals within single wall carbon nanotube channels attributed to a different stoichiometry of the guest crystal. For SWCNTs with diameters Dm > 1.4 nm a most complete tetragonal unit cell is observed. When crystallization occurs inside SWCNT with Dm < 1.4 nm 1D TbBrx crystal deforms a nanotube to elliptical shape in cross section. In this case the 1D crystal unit cell becomes monoclinic, with possible loss of a part of bromine atoms. Two modifications of a monoclinic unit cell appear. One of them is characterized by single or pair vacancies in the structure of the 1D crystal. Another structure is explained by peripheral and central bromine atoms loss. An appearance of such modifications can be stimulated by electron irradiation. The loss of bromine atoms is in agreement with chemical analysis data. Electronic properties of obtained meta-nanotubes are investigated using optical absorption and Raman spectroscopy. It is shown that intercalation of terbium bromide into SWCNTs leads to acceptor doping of SWCNTs. According to local EDX analysis and elemental mapping this doping can arise from significant stoichiometry change in 1D nanocrystal indicating an average Tb:Br atomic ratio of 1:2.8 +/- 0.1. PMID- 26625141 TI - Fn14, a Downstream Target of the TGF-beta Signaling Pathway, Regulates Fibroblast Activation. AB - Fibrosis, the hallmark of human injuries and diseases such as serious burns, is characterized by excessive collagen synthesis and myofibroblast accumulation. Transforming growth factor-beta (TGF-beta), a potent inducer of collagen synthesis, has been implicated in fibrosis in animals. In addition to TGF-beta, fibroblast growth factor-inducible molecule 14 (Fn14) has been reported to play an important role in fibrotic diseases, such as cardiac fibrosis. However, the function and detailed regulatory mechanism of Fn14 in fibrosis are unclear. Here, we investigated the effect of Fn14 on the activation of human dermal fibroblasts. In normal dermal fibroblasts, TGF-beta signaling increased collagen production and Fn14 expression. Furthermore, Fn14 siRNA blocked extracellular matrix gene expression; even when TGF-beta signaling was activated by TGF-beta1, fibroblast activation remained blocked in the presence of Fn14 siRNA. Overexpressing Fn14 increased extracellular matrix gene expression. In determining the molecular regulatory mechanism, we discovered that SMAD4, an important TGF-beta signaling co-mediator, bound to the Fn14 promoter and activated Fn14 transcription. Taken together, these results indicate that the TGF-beta signaling pathway activates Fn14 expression through the transcription factor SMAD4 and that activated Fn14 expression increases extracellular matrix synthesis and fibroblast activation. Therefore, Fn14 may represent a promising approach to preventing the excessive accumulation of collagen or ECM in skin fibrosis. PMID- 26625142 TI - Functional Characterization of a Novel Class of Morantel-Sensitive Acetylcholine Receptors in Nematodes. AB - Acetylcholine receptors are pentameric ligand-gated channels involved in excitatory neuro-transmission in both vertebrates and invertebrates. In nematodes, they represent major targets for cholinergic agonist or antagonist anthelmintic drugs. Despite the large diversity of acetylcholine-receptor subunit genes present in nematodes, only a few receptor subtypes have been characterized so far. Interestingly, parasitic nematodes affecting human or animal health possess two closely related members of this gene family, acr-26 and acr-27 that are essentially absent in free-living or plant parasitic species. Using the pathogenic parasitic nematode of ruminants, Haemonchus contortus, as a model, we found that Hco-ACR-26 and Hco-ACR-27 are co-expressed in body muscle cells. We demonstrated that co-expression of Hco-ACR-26 and Hco-ACR-27 in Xenopus laevis oocytes led to the functional expression of an acetylcholine-receptor highly sensitive to the anthelmintics morantel and pyrantel. Importantly we also reported that ACR-26 and ACR-27, from the distantly related parasitic nematode of horses, Parascaris equorum, also formed a functional acetylcholine-receptor highly sensitive to these two drugs. In Caenorhabditis elegans, a free-living model nematode, we demonstrated that heterologous expression of the H. contortus and P. equorum receptors drastically increased its sensitivity to morantel and pyrantel, mirroring the pharmacological properties observed in Xenopus oocytes. Our results are the first to describe significant molecular determinants of a novel class of nematode body wall muscle AChR. PMID- 26625144 TI - Asymmetry analysis of the arm segments during forward handspring on floor. AB - Asymmetry in gymnastics underpins successful performance and may also have implications as an injury mechanism; therefore, understanding of this concept could be useful for coaches and clinicians. The aim of this study was to examine kinematic and external kinetic asymmetry of the arm segments during the contact phase of a fundamental skill, the forward handspring on floor. Using a repeated single subject design six female National elite gymnasts (age: 19 +/- 1.5 years, mass: 58.64 +/- 3.72 kg, height: 1.62 +/- 0.41 m), each performed 15 forward handsprings, synchronised 3D kinematic and kinetic data were collected. Asymmetry between the lead and non-lead side arms was quantified during each trial. Significant kinetic asymmetry was observed for all gymnasts (p < 0.005) with the direction of the asymmetry being related to the lead leg. All gymnasts displayed kinetic asymmetry for ground reaction force. Kinematic asymmetry was present for more gymnasts at the shoulder than the distal joints. These findings provide useful information for coaching gymnastics skills, which may subjectively appear to be symmetrical. The observed asymmetry has both performance and injury implications. PMID- 26625143 TI - Simvastatin Attenuates Oxidative Stress, NF-kappaB Activation, and Artery Calcification in LDLR-/- Mice Fed with High Fat Diet via Down-regulation of Tumor Necrosis Factor-alpha and TNF Receptor 1. AB - Simvastatin (SIM) is anti-inflammatory. We used low density lipoprotein receptor knockout (LDLR-/-) mice and human aortic smooth muscle cells (HASMCs) as model systems to study the effect of SIM on arterial calcification and to explore the potential mechanisms contributing to this protective effect. High-fat diet (HFD) caused the LRLR -/- to develop dyslipidemia, diabetics, atherosclerosis and aortic smooth muscle calcification. SIM, N-acetyl cysteine (NAC, a ROS scavenger) and apocynin (APO, a NADPH oxidase inhibitor) did not significantly retard the development of dyslipidemia or diabetic. However, those treatments were still effective in attenuating the HFD-induced atherosclerosis and aortic smooth muscle calcification. These findings suggest that the protective effect of SIM against aortic calcification is not contributed by the cholesterol lowering effect. SIM, NAC and APO were found to attenuate the HFD induced elevation of serum TNF-alpha, soluble TNFR1 (sTNFR1), 3-nitro-tyrosine. We hypothesized that the pro inflammatory cytokine, oxidative stress and TNFR1 played a role in inducing aortic calcification. We used HASMC to investigate the role of TNF-alpha, oxidative stress and TNFR1 in inducing aortic calcification and to elucidate the mechanism contributes the protective effect of SIM against aortic calcification. We demonstrated that treating HASMC with TNF-alpha induced cell Ca deposit and result in an increase in ALP, NADPH oxidase activity, NF-kB subunit p65, BMP2, MSX2, and RUNX2 expression. SIM suppressed the TNF-alpha induced activation of NADPH oxidase subunit p47, the above-mentioned bone markers and TNFR1 expression. Furthermore, p65, p47 and TNFR1 siRNAs inhibited the TNF-alpha-mediated stimulation of BMP-2, MSX2, RUNX2 expression. SIM, APO, and NAC either partially inhibit or completely block the TNF-alpha induced H2O2 or superoxide production. These results suggest that SIM may, independent of its cholesterol-lowering effect, suppresses the progression of vascular diseases through the inhibition of the inflammation mediators TNF-alpha and TNFR1. PMID- 26625145 TI - Screening and Monitoring Before and During Systemic Therapy: Recommendations for Patients With Psoriasis. AB - When patients with psoriasis are candidates for systemic therapy, the list of appropriate agents for each patient should be derived from careful patient and family history and selected laboratory screening protocols so that the potential risks associated with treatment can be minimized. Once a therapeutic choice is made, monitoring strategies also are necessary for early identification and intervention of adverse events that may arise. In addition to appropriate screening and monitoring protocols, communication between patient and clinician is essential to enhance the benefits of therapy and minimize the risks. Semin Cutan Med Surg 34(supp2):S40-S42 (c) 2015 published by Frontline Medical Communications. PMID- 26625153 TI - Alpha-Oxo Acids Assisted Transformation of FeS to Fe3S4 at Low Temperature: Implications for Abiotic, Biotic, and Prebiotic Mineralization. AB - The mineral greigite (Fe3S4) distributes widely in anoxic marine and lake sedimentary systems, with important implications for magnetostratigraphy and paleomagnetism. In living organisms, magnetotactic bacteria can synthesize greigite grains with regular sizes and morphologies. The cubic Fe3S4 structure also occurs as an integral constituent and active center in a family of iron sulfur proteins in all life-forms on Earth. This basic biochemistry shared by all organisms implies that the Fe3S4 structure might have evolved in the first protocell. Therefore, greigite is of general interest in geochemistry, geophysics, biomineralogy, and origin-of-life sciences. However, the growth of thermodynamically metastable Fe3S4 crystals often requires strictly defined conditions because both Fe and S show variable valences and it is hard to tune their valence fluctuation. Here, we show that freshly precipitated FeS can be selectively oxidized to form greigite in the presence of alpha-oxo acids, even at room temperature. Based on a brief overview of the experimental findings, a metal organic complex intermediate model has been put forward and discussed for the discriminative chemical transformation. The results not only provide a possible pathway for the abiotic formation of greigite in nature but also may help explain the biotic mineralization of greigite in magnetotactic bacteria. Moreover, in the context of prebiotic evolution, along with the synergic evolution between greigite and alpha-oxo acids, Fe3S4 might have been sequestered by primordial peptides, and the whole finally evolved into the first iron-sulfur protein. KEY WORDS: Greigite-Mineralization-alpha-Oxo acid-Magnetosome-Iron-sulfur protein Prebiotic evolution. PMID- 26625154 TI - A Mixed-Method Approach for Quantifying Illegal Fishing and Its Impact on an Endangered Fish Species. AB - Illegal harvest is recognized as a widespread problem in natural resource management. The use of multiple methods for quantifying illegal harvest has been widely recommended yet infrequently applied. We used a mixed-method approach to evaluate the extent, character, and motivations of illegal gillnet fishing in Lake Hovsgol National Park, Mongolia and its impact on the lake's fish populations, especially that of the endangered endemic Hovsgol grayling (Thymallus nigrescens). Surveys for derelict fishing gear indicate that gillnet fishing is widespread and increasing and that fishers generally use 3-4 cm mesh gillnet. Interviews with resident herders and park rangers suggest that many residents fish for subsistence during the spring grayling spawning migration and that some residents fish commercially year-round. Interviewed herders and rangers generally agree that fish population sizes are decreasing but are divided on the causes and solutions. Biological monitoring indicates that the gillnet mesh sizes used by fishers efficiently target Hovsgol grayling. Of the five species sampled in the monitoring program, only burbot (Lota lota) showed a significant decrease in population abundance from 2009-2013. However, grayling, burbot, and roach (Rutilus rutilus) all showed significant declines in average body size, suggesting a negative fishing impact. Data-poor stock assessment methods suggest that the fishing effort equivalent to each resident family fishing 50-m of gillnet 11-15 nights per year would be sufficient to overexploit the grayling population. Results from the derelict fishing gear survey and interviews suggest that this level of effort is not implausible. Overall, we demonstrate the ability for a mixed-method approach to effectively describe an illegal fishery and suggest that these methods be used to assess illegal fishing and its impacts in other protected areas. PMID- 26625155 TI - Nerve Sheath Tumors in Neurofibromatosis Type 1: Assessment of Whole-Body Metabolic Tumor Burden Using F-18-FDG PET/CT. AB - PURPOSE: To determine the metabolically active whole-body tumor volume (WB-MTV) on F-18-fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) in individuals with neurofibromatosis type 1 (NF1) using a three dimensional (3D) segmentation and computerized volumetry technique, and to compare PET WB-MTV between patients with benign and malignant peripheral nerve sheath tumors (PNSTs). PATIENTS AND METHODS: Thirty-six NF1 patients (18 patients with malignant PNSTs and 18 age- and sex-matched controls with benign PNSTs) were examined by F-18-FDG PET/CT. WB-MTV, whole-body total lesion glycolysis (WB-TLG) and a set of semi-quantitative imaging-based parameters were analyzed both on a per-patient and a per-lesion basis. RESULTS: On a per-lesion basis, malignant PNSTs demonstrated both a significantly higher MTV and TLG than benign PNSTs (p < 0.0001). On a per-patient basis, WB-MTV and WB-TLG were significantly higher in patients with malignant PNSTs compared to patients with benign PNSTs (p < 0.001). ROC analysis showed that MTV and TLG could be used to differentiate between benign and malignant tumors. CONCLUSIONS: WB-MTV and WB-TLG may identify malignant change and may have the potential to provide a basis for investigating molecular biomarkers that correlate with metabolically active disease manifestations. Further evaluation will determine the potential clinical impact of these PET-based parameters in NF1. PMID- 26625156 TI - Grass-Shrub Associations over a Precipitation Gradient and Their Implications for Restoration in the Great Basin, USA. AB - As environmental stress increases positive (facilitative) plant interactions often predominate. Plant-plant associations (or lack thereof) can indicate whether certain plant species favor particular types of microsites (e.g., shrub canopies or plant-free interspaces) and can provide valuable insights into whether "nurse plants" will contribute to seeding or planting success during ecological restoration. It can be difficult, however, to anticipate how relationships between nurse plants and plants used for restoration may change over large-ranging, regional stress gradients. We investigated associations between the shrub, Wyoming big sagebrush (Artemisia tridentata ssp. wyomingensis), and three common native grasses (Poa secunda, Elymus elymoides, and Pseudoroegneria spicata), representing short-, medium-, and deep-rooted growth forms, respectively, across an annual rainfall gradient (220-350 mm) in the Great Basin, USA. We hypothesized that positive shrub-grass relationships would become more frequent at lower rainfall levels, as indicated by greater cover of grasses in shrub canopies than vegetation-free interspaces. We sampled aerial cover, density, height, basal width, grazing status, and reproductive status of perennial grasses in canopies and interspaces of 25-33 sagebrush individuals at 32 sites along a rainfall gradient. We found that aerial cover of the shallow rooted grass, P. secunda, was higher in sagebrush canopy than interspace microsites at lower levels of rainfall. Cover and density of the medium-rooted grass, E. elymoides were higher in sagebrush canopies than interspaces at all but the highest rainfall levels. Neither annual rainfall nor sagebrush canopy microsite significantly affected P. spicata cover. E. elymoides and P. spicata plants were taller, narrower, and less likely to be grazed in shrub canopy microsites than interspaces. Our results suggest that exploring sagebrush canopy microsites for restoration of native perennial grasses might improve plant establishment, growth, or survival (or some combination thereof), particularly in drier areas. We suggest that land managers consider the nurse plant approach as a way to increase perennial grass abundance in the Great Basin. Controlled experimentation will provide further insights into the life stage specific effectiveness and practicality of a nurse plant approach for ecological restoration in this region. PMID- 26625157 TI - Hepatitis E Virus Seroprevalence Rate in HIV-Infected Patients in Germany: A Comparison of Two Commercial Assays. AB - OBJECTIVES: Cases of chronic hepatitis E virus (HEV) infection have been described in HIV-infected patients. There are several commercial anti-HEV assays, but anti-HEV seroprevalence rates differ largely depending on the assay used. The aim of this study was to (1) compare two commercial anti-HEV assays in a German cohort of HIV-positive individuals, and (2) determine whether HEV takes chronic courses in controlled HIV infection. METHODS: 246 HIV patients were tested for both HEV RNA and HEV antibodies. All patients received antiretroviral therapy, if this was indicated, according to European guidelines. All but 19 individuals had CD4+ counts above 200/ul. Anti-HEV IgG was determined by two independent commercial assays (Wantai and MP). RESULTS: None of the patients tested HEV RNA positive. Anti-HEV IgG was detected more frequently by the Wantai assay (26%) than the MP assay (1.6%, p < 0.001). Patients born in Europe tested more frequently positive for anti-HEV (p = 0.047) than individuals from other regions. Increasing age but not CD4 count correlated with a higher likelihood of anti-HEV positivity (R = 0.313, p < 0.001). CONCLUSIONS: About one quarter of HIV-infected patients show evidence of previous HEV contact. The risk of developing chronic HEV infection is very low in individuals receiving appropriate antiretroviral therapy. The large variability in HEV seroprevalence rates determined by different assays requires consideration for the diagnostic workup of HIV patients. PMID- 26625159 TI - Relationship of Hippocampal Volume to Amyloid Burden across Diagnostic Stages of Alzheimer's Disease. AB - AIMS: To assess how hippocampal volume (HV) from volumetric magnetic resonance imaging (vMRI) is related to the amyloid status at different stages of Alzheimer's disease (AD) and its relevance to patient care. METHODS: We evaluated the ability of HV to predict the florbetapir positron emission tomography (PET) amyloid positive/negative status by group in healthy controls (HC, n = 170) and early/late mild cognitive impairment (EMCI, n = 252; LMCI, n = 136), and AD dementia (n = 75) subjects from the Alzheimer's Disease Neuroimaging Initiative Grand Opportunity (ADNI-GO) and ADNI2. Logistic regression analyses, including elastic net classification modeling with 10-fold cross-validation, were used with age and education as covariates. RESULTS: HV predicted amyloid status only in LMCI using either logistic regression [area under the curve (AUC) = 0.71, p < 0.001] or elastic net classification modeling [positive predictive value (PPV) = 72.7%]. In EMCI, age (AUC = 0.70, p < 0.0001) and age and/or education (PPV = 63.1%), but not HV, predicted amyloid status. CONCLUSION: Using clinical neuroimaging, HV predicted amyloid status only in LMCI, suggesting that HV is not a biomarker surrogate for amyloid PET in clinical applications across the full diagnostic spectrum. PMID- 26625160 TI - Housing for ageing LGBTQ people in Sweden: a descriptive study of needs, preferences, and concerns. AB - BACKGROUND/AIM: With an increasing number of ageing people who identify themselves as lesbian, gay, bisexual, transgender, or queer (LGBTQ), there is a risk that traditional housing for older people fails to meet the needs of these people. The aim of this study was to describe LGBTQ people's needs, preferences, and concerns according to ageing and housing. MATERIALS AND METHODS: Based on a survey (n = 487), and six focus-group discussions (n = 30), with LGBTQ persons, quantitative and qualitative approaches were used to analyse the findings. RESULTS: When comparing the ranking of preferences (in terms of activity options, environmental features, and staff competence) in a senior housing setting between the LGBTQ people (n = 200) and heterosexual matched controls (n = 198), only minor differences were detected. The findings from the focus groups included: (1) a dilemma between segregation and openness, (2) the importance of safety associated with ageing together with persons with similar experiences, and (3) networks of persons at different ages connected through close friendship supported participation in activities in LGBTQ-profiled senior housing. CONCLUSION AND SIGNIFICANCE: The findings provide knowledge to improve awareness of sexual orientation when it comes to needs and preferences in relation to ageing and housing in a Swedish context. PMID- 26625158 TI - Wham: Identifying Structural Variants of Biological Consequence. AB - Existing methods for identifying structural variants (SVs) from short read datasets are inaccurate. This complicates disease-gene identification and efforts to understand the consequences of genetic variation. In response, we have created Wham (Whole-genome Alignment Metrics) to provide a single, integrated framework for both structural variant calling and association testing, thereby bypassing many of the difficulties that currently frustrate attempts to employ SVs in association testing. Here we describe Wham, benchmark it against three other widely used SV identification tools-Lumpy, Delly and SoftSearch-and demonstrate Wham's ability to identify and associate SVs with phenotypes using data from humans, domestic pigeons, and vaccinia virus. Wham and all associated software are covered under the MIT License and can be freely downloaded from github (https://github.com/zeeev/wham), with documentation on a wiki (http://zeeev.github.io/wham/). For community support please post questions to https://www.biostars.org/. PMID- 26625161 TI - Automatic Detection of Attention Shifts in Infancy: Eye Tracking in the Fixation Shift Paradigm. AB - This study measured changes in switches of attention between 1 and 9 months of age in 67 typically developing infants. Remote eye-tracking (Tobii X120) was used to measure saccadic latencies, related to switches of fixation, as a measure of shifts of attention, from a central stimulus to a peripheral visual target, measured in the Fixation Shift Paradigm. Fixation shifts occur later if the central fixation stimulus stays visible when the peripheral target appears (competition condition), than if the central stimulus disappears as the peripheral target appears (non-competition condition). This difference decreases with age. Our results show significantly faster disengagement in infants over 4 months than in the younger group, and provide more precise measures of fixation shifts, than behavioural observation with the same paradigm. Reduced saccadic latencies in the course of a test session indicate a novel learning effect. The Fixation Shift Paradigm combined with remote eye-tracking measures showed improved temporal and spatial accuracy compared to direct observation by a trained observer, and allowed an increased number of trials in a short testing time. This makes it an infant-friendly non-invasive procedure, involving minimal observational training, suitable for use in future studies of clinical populations to detect early attentional abnormalities in the first few months of life. PMID- 26625163 TI - The Ebola Vaccine, Iatrogenic Injuries, and Legal Liability. AB - Amir Attaran and Kumanan Wilson propose a compensation system for vaccine injuries, based on no-fault principles, to ensure that recipients of Ebola vaccines are fairly compensated in cases of iatrogenic harm. PMID- 26625162 TI - The First Extracellular Domain Plays an Important Role in Unitary Channel Conductance of Cx50 Gap Junction Channels. AB - Gap junction (GJ) channels provide direct passage for ions and small molecules to be exchanged between neighbouring cells and are crucial for many physiological processes. GJ channels can be gated by transjunctional voltage (known as Vj gating) and display a wide range of unitary channel conductance (gammaj), yet the domains responsible for Vj-gating and gammaj are not fully clear. The first extracellular domain (E1) of several connexins has been shown to line part of their GJ channel pore and play important roles in Vj-gating properties and/or ion permeation selectivity. To test roles of the E1 of Cx50 GJ channels, we generated a chimera, Cx50Cx36E1, where the E1 domain of Cx50 was replaced with that of Cx36, a connexin showing quite distinct Vj-gating and gammaj from those of Cx50. Detailed characterizations of the chimera and three point mutants in E1 revealed that, although the E1 domain is important in determining gammaj, the E1 domain of Cx36 is able to effectively function within the context of the Cx50 channel with minor changes in Vj-gating properties, indicating that sequence differences between the E1 domains in Cx36 and Cx50 cannot account for their drastic differences in Vj-gating and gammaj. Our homology models of the chimera and the E1 mutants revealed that electrostatic properties of the pore-lining residues and their contribution to the electric field in the pore are important factors for the rate of ion permeation of Cx50 and possibly other GJ channels. PMID- 26625164 TI - With a Little Help from My Friends: Group Orientation by Larvae of a Coral Reef Fish. AB - Theory and some empirical evidence suggest that groups of animals orient better than isolated individuals. We present the first test of this hypothesis for pelagic marine larvae, at the stage of settlement, when orientation is critical to find a habitat. We compare the in situ behaviour of individuals and groups of 10-12 Chromis atripectoralis (reef fish of the family Pomacentridae), off Lizard Island, Great Barrier Reef. Larvae are observed by divers or with a drifting image recording device. With both methods, groups orient cardinally while isolated individuals do not display significant orientation. Groups also swim on a 15% straighter course (i.e. are better at keeping a bearing) and 7% faster than individuals. A body of observations collected in this study suggest that enhanced group orientation emerges from simple group dynamics rather than from the presence of more skilful leaders. PMID- 26625165 TI - Understanding the Potential of Digital Intraoral and Benchtop Scanning Workflows. AB - Although the overwhelming majority of dental offices now use digital radiography and patient records, relatively few yet use either stand-alone intraoral scanning systems (6%) or complete systems that combine intraoral scanning with computer aided design and computer-aided manufacturing (12%). This should change as dentists become more aware of the numerous advantages scanning systems offer in terms of patient care and communication of patient information, particularly with the dental laboratory. This article reviews the various types of scanner architecture as well as potential workflow models. PMID- 26625166 TI - Dental Cone-Beam Scans: Important Anatomic Views for the Contemporary Implant Surgeon. AB - Intraoral cone-beam computed tomography (CBCT), otherwise known as volume imaging CT scan, provides 3-dimensional images of mandibular and maxillary structures. These images offer highly accurate and valuable diagnostic information to facilitate treatment planning for implant cases. This article serves as a primer on how to read and interpret CBCT cross sectional views. It identifies anatomic structures of interest and discusses their clinical relevance. PMID- 26625167 TI - CAD/CAM Fabrication of Definitive Implant Prostheses: A Digital Workflow From Planning to Implant Placement to Final Restoration. AB - Traditional methods of performing dental implant surgery and fabricating a definitive implant-supported prosthesis are being supplanted by digital techniques that provide greater precision and a more durable and esthetic restoration. In the present case, a 68-year-old woman presented a severely compromised dentition. She had received extensive restorative dentistry in the past and, due to recurrent caries and chronic periodontitis, was facing the loss of her maxillary teeth, as well as teeth in the lower left quadrant. This case report illustrates the use of a number of digital techniques for both treatment planning and fabrication of the final restoration. PMID- 26625168 TI - Salvaging Implants With an Nd:YAG Laser: A Novel Approach to a Growing Problem. AB - As the incidence of implant placement expands, so too does the occurrence of implant-related pathological conditions such as peri-implant mucositis and peri implantitis. This article will discuss implementation of a laser protocol that serves as a treatment modality designed specifically to help save ailing and failing implants. This multi-stage approach incorporates application of laser energy from a particular Nd:YAG laser with variable pulse width. This laser wavelength has demonstrated a variety of capabilities that may contribute to its clinical effectiveness. Representative long-term results of this treatment method are described, and a case depicting the protocol is presented. PMID- 26625169 TI - Sensitivity analysis and diagnostic accuracy of the Brief Smell Identification Test in patients with chronic rhinosinusitis. AB - BACKGROUND: The Brief Smell Identification Test (BSIT) is an abbreviated version of the Smell Identification Test (SIT) used to assess olfactory function. Although the BSIT can be efficiently administered in under 5 minutes, the accuracy of the BSIT in relation to the SIT in patients with chronic rhinosinusitis (CRS) is unknown. METHODS: Patients with CRS were recruited as part of an ongoing multi-institutional observational cohort study. A total of 183 participants provided both BSIT and SIT olfactory function scores during initial enrollment. Linear associations between BSIT and SIT scores were evaluated using Pearson's correlation coefficients (rp ). The sensitivity, specificity, and accuracy of BSIT scores were determined using SIT scores as the "gold standard." RESULTS: A strong bivariate linear association was found between BSIT and SIT scores (rp = 0.893; p < 0.001) for all participants. A significantly lower proportion of patients were identified as having abnormal olfaction using the BSIT compared to the SIT (47% vs 68%, respectively; p < 0.001). Using the currently defined score of <=8 as a cut-point for abnormal olfactory function, the BSIT demonstrated a sensitivity of 63% and specificity of 88% with an overall accuracy of 71%. Increasing the cut-point to <=9 resulted in an increased sensitivity of 86%, a specificity of 76%, and an improved overall accuracy of 83%. CONCLUSION: In patients with CRS, BSIT scores strongly correlate with SIT scores; however, the BSIT underestimates olfactory dysfunction as defined by the suggested cut-point of <=8. Increasing the cut-point to <=9 increased the sensitivity and accuracy of the BSIT. PMID- 26625170 TI - Forging Our Future as a Diverse and Inclusive Midwifery Profession. PMID- 26625171 TI - Polytheonamide biosynthesis showcasing the metabolic potential of sponge associated uncultivated 'Entotheonella' bacteria. AB - The vast majority of microorganisms on the planet have not been grown under laboratory conditions due to unknown metabolic and environmental constraints. This uncultivated majority has enormous potential as a reservoir of unique enzymology and biosynthetic pathways. The following review offers a glimpse into this unexplored enzymatic stockpile through recent progress made on the biosynthesis of the potent polytheonamide cytotoxins. These structurally highly complex pore-forming peptides, isolated from the marine sponge Theonella swinhoei, are synthesized by the ribosome and then modified through numerous unusual transformations including iterative epimerase and N-methyltransferase activities. The bacterial source of these metabolites was identified as the taxonomically remote, uncultivated sponge symbiont 'Entotheonella factor' with a biosynthetic prowess that rivals those of industrially exploited microorganisms. PMID- 26625173 TI - Traffic accidents involving fatigue driving and their extent of casualties. AB - The rapid progress of motorization has increased the number of traffic-related casualties. Although fatigue driving is a major cause of traffic accidents, the public remains not rather aware of its potential harmfulness. Fatigue driving has been termed as a "silent killer." Thus, a thorough study of traffic accidents and the risk factors associated with fatigue-related casualties is of utmost importance. In this study, we analyze traffic accident data for the period 2006 2010 in Guangdong Province, China. The study data were extracted from the traffic accident database of China's Public Security Department. A logistic regression model is used to assess the effect of driver characteristics, type of vehicles, road conditions, and environmental factors on fatigue-related traffic accident occurrence and severity. On the one hand, male drivers, trucks, driving during midnight to dawn, and morning rush hours are identified as risk factors of fatigue-related crashes but do not necessarily result in severe casualties. Driving at night without street-lights contributes to fatigue-related crashes and severe casualties. On the other hand, while factors such as less experienced drivers, unsafe vehicle status, slippery roads, driving at night with street lights, and weekends do not have significant effect on fatigue-related crashes, yet accidents associated with these factors are likely to have severe casualties. The empirical results of the present study have important policy implications on the reduction of fatigue-related crashes as well as their severity. PMID- 26625172 TI - Gay Acres: Sexual Orientation Differences in Health Indicators Among Rural and Nonrural Individuals. AB - PURPOSE: Geographic location is a significant factor that influences health status and health disparities. Yet, little is known about the relationship between geographic location and health and health disparities among lesbian, gay, and bisexual (LGB) persons. This study used a US population-based sample to evaluate the associations of sexual orientation with health indicators by rural/nonrural residence. METHODS: Data were pooled from the 10 states that collected sexual orientation in the 2010 Behavioral Risk Factor Surveillance System surveys. Rural status was defined using metropolitan statistical area, and group differences by sexual orientation were stratified by gender and rural/nonrural status. Chi-square tests for categorical variables were used to assess bivariate relationships. Multivariable logistic regression models stratified by gender and rural/nonrural status were used to assess the association of sexual orientation to health indicators, while adjusting for age, race/ethnicity, education, and partnership status. All analyses were weighted to adjust for the complex sampling design. FINDINGS: Significant differences between LGB and heterosexual participants emerged for several health indicators, with bisexuals having a greater number of differences than gay men/lesbians. There were fewer differences in health indicators for rural LGB participants compared to heterosexuals than nonrural participants. CONCLUSIONS: Rural residence appears to influence the pattern of LGB health disparities. Future work is needed to confirm and identify the exact etiology or rural/nonrural differences in LGB health. PMID- 26625176 TI - Emergency contraception: Sources of information and perceptions of access among young adults. AB - Emergency contraception (EC) can prevent pregnancy for up to 5 days after unprotected sex. Although EC has become increasingly available, little is known about perceptions of young adults regarding access to EC or whether information sources about EC relate to perceived access among young adults. Over a 1-week period in November 2013, a self-report survey was administered to 352 college students (67% women) at the student union of a large, public university in the southeastern United States. The survey assessed three aspects of EC: perceived access, information sources, and prior use. Twenty-one percent of participants had used EC. Participants reported relatively high perceptions of access to EC, with females reporting higher perceptions of access than males. Prior to the study, 7.4% of students had never heard of EC; the remaining students had heard of EC from an average of four sources. Among women, hearing of EC from media, interpersonal, or health education sources was significantly associated with greater perceived access (ps < .05). Among men, no specific information sources were associated with perceived access (ps > .10). Future EC awareness efforts for women should leverage all three of these sources, while future research should examine specific sources to focus on the content, quality, and frequency of messages. PMID- 26625177 TI - Dose rate dependence of the PTW 60019 microDiamond detector in high dose-per pulse pulsed beams. AB - Recombination effects can affect the detectors used for the dosimetry of radiotherapy fields. They are important when using ionization chambers, especially in liquid-filled ionization chambers, and should be corrected for. The introduction of flattening-filter-free accelerators increases the typical dose per-pulse used in radiotherapy beams, which leads to more important recombination effects. Diamond detectors provide a good solution for the dosimetry and quality assurance of small radiotherapy fields, due to their low energy dependence and small volume. The group of Universita di Roma Tor Vergata has developed a synthetic diamond detector, which is commercialized by PTW as microDiamond detector type 60019. In this work we present an experimental characterization of the collection efficiency of the microDiamond detector, focusing on high dose-per pulse FFF beams. The collection efficiency decreases with dose-per-pulse, down to 0.978 at 2.2 mGy/pulse, following a Fowler-Attix-like curve. On the other hand, we have found no significant dependence of the collection efficiency on the pulse repetition frequency (or pulse period). PMID- 26625178 TI - A population-based study on the association between educational length, prostate specific antigen testing and use of prostate biopsies. AB - OBJECTIVE: The aim of this study was to determine whether educational length affects prostate-specific antigen (PSA) testing and the time to prostate biopsy for men with raised PSA values. MATERIALS AND METHODS: Using register data on all men in Stockholm County in 2013 (n = 1,052,841), the limited-duration point prevalence of PSA testing and time between test and prostate biopsy or repeat testing were analysed. Patterns of follow-up were assessed using Kaplan-Meier product limit estimators and Cox proportional hazard models. Educational length was categorized as short (<= 9 years), intermediate (10-12 years) or long (>= 13 years). RESULTS: PSA testing increased with educational length in all age groups. Among men aged 50-69 years, 61% with long and 54% with short education had had a PSA test within the preceding 10 years (p < 0.001). In men with PSA 4-10 ng/ml, 40% [95% confidence interval (CI) 38-41] with long and 27% (95% CI 26-29) with short education underwent a prostate biopsy within 12 months. After adjusting for PSA level and age, educational length was still associated with the chance of having a prostate biopsy in men with PSA 4-10 ng/ml (hazard ratio 1.22, 95% CI 1.12-1.31), but not in men with higher PSA values. CONCLUSION: PSA testing increased with educational length. Men with long education were more likely to have a prostate biopsy after an increased PSA value below 10 ng/ml than men with short education. These differences may contribute to the worse prostate cancer outcomes observed among men with lower socioeconomic status. PMID- 26625179 TI - Study Design and Interim Outcomes of Guangzhou Institute of Respiratory Disease COPD Biobank. AB - BACKGROUND: GIRD COPD Biobank is a multicenter observational study blood-based database with local characteristics, in order to investigate the causes, risk factors, pathogenesis, prevalence patterns and trends of COPD and promote new pathogenic insights in China. METHODS: We enrolled 855 clinically COPD patients and 660 controls with normal lung function. Extensive data collection has been undertaken with questionnaires, clinical measurements, and collection and storage of blood specimens, following Standard Operating Procedures (SOP). All surveys had similar quality controls, supervisions, and training of the investigator team. RESULTS: Since September 2010, a total of 1515 subjects (1116 [73.7%] males; 855 [56.4%] diagnosed with COPD) were enrolled. Analyses of the design and interim results of the GIRD COPD Biobank Study identified patients with COPD were older, lower educational level, a longer history of pack-year smoking, less in kitchen fan usage, X-ray exposure, and history of disease (P < 0.01 for all); Most of the COPD subjects belonged to moderately severe or worse, stratified according to Global Lung Function Initiative (GLI); COPD patients had relatively more co-morbidities than controls; Environmental hazard exposures might be the main contributors to the reported respiratory symptoms; Cold air, haze, and influenza acted the top three factors to induce respiratory symptoms in both COPD cases and controls. CONCLUSION: The GIRD COPD Biobank Study has the potential to provide substantial novel insights into the genetics, biomarkers, environmental and lifestyle aspects of COPD. It is expected to provide new insights for pathogenesis and the long-term progression of COPD. PMID- 26625180 TI - Gaussia Luciferase as a Genetic Fusion Partner with Antibody Fragments for Sensitive Immunoassay Monitoring of Clinical Biomarkers. AB - In this study, we show the utility of Gaussia luciferase (GLuc), which is much smaller than previously found luciferases, as the fusion partner with artificial antibody species for developing sensitive immunoassay systems. As an example, we constructed a bioluminescent enzyme-linked immunosorbent assay (BL-ELISA) system determining the major glucocorticoid cortisol. A monoclonal antibody was newly elicited against a cortisol-albumin conjugate, and the genes encoding its variable domains (VH and VL) were cloned and combined to encode a single-chain Fv fragment (scFv). scFv was then linked to the wild-type GLuc gene or that encoding GLuc mutants reported to show improved emission kinetics and expressed in the periplasmic space of several Escherichia coli strains. Notably, the wild-type GLuc fusion protein (scFv-wtGLuc) showed the most suitable luminescent properties for BL-ELISAs. In our system, scFv-wtGLuc was reacted competitively with the analyte and immobilized cortisol moieties, and the bound GLuc activity was monitored with coelenterazine as the substrate. Successful batch-type luminescence detection was achieved using a plate reader without built-in injectors. The midpoint and limit of detection in a typical dose-response curve were 4.1 and 0.26 pg/assay, respectively, thus exhibiting much more sensitivity than conventional cortisol immunoassays. Serum cortisol levels (as the sum with cortisone) for healthy subjects, determined without any pretreatment, were compatible with reported reference ranges. The scFv-wtGLuc probe was stable over a year under storage as periplasmic extracts at -30 degrees C or with repeated freeze-thawing. These results suggest that GLuc fusions with antibody fragments might serve as useful and highly sensitive immunoassay probes in various clinical settings. PMID- 26625181 TI - Identification and Characterization of Kukoamine Metabolites by Multiple Ion Monitoring Triggered Enhanced Product Ion Scan Method with a Triple-Quadruple Linear Ion Trap Mass Spectrometer. AB - Kukoamines are a series of bioactive phytochemicals conjugated by a polyamine backbone and phenolic moieties. Understanding the structural diversity of kukoamine metabolites in plants is meaningful for drug discovery. In this study, an LC-MS/MS method was established for kukoamine profiling and characterization from lycii cortex (LyC) via a triple-quadrupole linear ion trap mass spectrometry (Q-TRAP). On the basis of the typical fragmentation of kukoamine, a diagnostic ion, which represents the features of the backbone and phenolic substitute, was chosen as the product ion for precursor ion scan, and then the screened precursor ions were applied to a successive multiple ion monitoring triggered enhanced product ion scan (MIM-EPI) to simultaneously present the profile survey and MS/MS acquisition. Because the MIM narrowed the ion scan range in Q1 and the ion trap enhanced the ion fragments passing through Q2, the qualitative capability of quadrupole MS can be greatly improved, especially for capture of the uncommon metabolites. There are 12 kukoamine metabolites identified from LyC, with either spermine or spermidine backbone and with conjugation of one to three dihydrocaffeoyls or other kinds of phenolic moieties. Except for kukoamines A and B, other metabolites were identified in LyC for the first time. This approach can be utilized for metabolite identification in other substrates. PMID- 26625183 TI - How far does it get?--The effect of shooting distance and type of firearm on the simultaneous analysis of DNA and RNA from backspatter recovered from inside and outside surfaces of firearms. AB - When a firearm projectile hits a biological target a spray of biological material (e.g. blood and tissue) is ejected from the entrance wound and propelled back into the direction of the firearm. This phenomenon has been termed 'backspatter' and if backspattered biological material reaches the firearm on its backward trajectory it may persist on and be recovered from the firearm's inside surfaces. Molecular genetic analysis of backspatter generated by contact shots and shots from very short distances has already been demonstrated to critically contribute to victim identification and the reconstruction of firearm-related crimes. It is not known, however, up to what shooting distance can backspatter be found on firearms' inside surfaces and what influence the weapon's type and caliber has on backspatter attributes (e.g. reach, amount and distribution). Therefore, the present pilot study investigated the effect of serval combinations of shooting distances and types of firearms and ammunitions on the analyzability of co extracted DNA and micro-RNA in samples of backspatter collected from interior and exterior surfaces of the firearms after experimental shootings employing standardized ballistic models. We demonstrate the limiting effect of shooting distance and the type of firearm on the yield of nucleic acids recovered from backspatter and the success rates of forensic DNA profiling and RNA based body fluid and organ tissue identification in experimental shootings. PMID- 26625182 TI - Assessment of Inhibitors of Pathogenic Crimean-Congo Hemorrhagic Fever Virus Strains Using Virus-Like Particles. AB - Crimean-Congo hemorrhagic fever (CCHF) is an often lethal, acute inflammatory illness that affects a large geographic area. The disease is caused by infection with CCHF virus (CCHFV), a nairovirus from the Bunyaviridae family. Basic research on CCHFV has been severely hampered by biosafety requirements and lack of available strains and molecular tools. We report the development of a CCHF transcription- and entry-competent virus-like particle (tecVLP) system that can be used to study cell entry and viral transcription/replication over a broad dynamic range (~4 orders of magnitude). The tecVLPs are morphologically similar to authentic CCHFV. Incubation of immortalized and primary human cells with tecVLPs results in a strong reporter signal that is sensitive to treatment with neutralizing monoclonal antibodies and by small molecule inhibitors of CCHFV. We used glycoproteins and minigenomes from divergent CCHFV strains to generate tecVLPs, and in doing so, we identified a monoclonal antibody that can prevent cell entry of tecVLPs containing glycoproteins from 3 pathogenic CCHFV strains. In addition, our data suggest that different glycoprotein moieties confer different cellular entry efficiencies, and that glycoproteins from the commonly used strain IbAr10200 have up to 100-fold lower ability to enter primary human cells compared to glycoproteins from pathogenic CCHFV strains. PMID- 26625184 TI - Quantifying the Nucleation and Growth Kinetics of Microwave Nanochemistry Enabled by in Situ High-Energy X-ray Scattering. AB - The fast reaction kinetics presented in the microwave synthesis of colloidal silver nanoparticles was quantitatively studied, for the first time, by integrating a microwave reactor with in situ X-ray diffraction at a high-energy synchrotron beamline. Comprehensive data analysis reveals two different types of reaction kinetics corresponding to the nucleation and growth of the Ag nanoparticles. The formation of seeds (nucleation) follows typical first-order reaction kinetics with activation energy of 20.34 kJ/mol, while the growth of seeds (growth) follows typical self-catalytic reaction kinetics. Varying the synthesis conditions indicates that the microwave colloidal chemistry is independent of concentration of surfactant. These discoveries reveal that the microwave synthesis of Ag nanoparticles proceeds with reaction kinetics significantly different from the synthesis present in conventional oil bath heating. The in situ X-ray diffraction technique reported in this work is promising to enable further understanding of crystalline nanomaterials formed through microwave synthesis. PMID- 26625185 TI - Electromechanical delay of the knee flexor muscles after anterior cruciate ligament reconstruction using semitendinosus tendon. AB - The purpose of the study was to evaluate whether using only the semitendinosus as a tripled short graft would affect the electromechanical delay (EMD) of the knee flexors. EMD was evaluated in volunteers (N = 15) after they had undergone surgery for anterior cruciate ligament (ACL) reconstruction where the semitendinosus tendon alone was used as a graft. The results were compared with the intact leg and healthy controls (N = 15). After warming up, each subject performed four maximally explosive isometric contractions on an isokinetic dynamometer. Torques were measured by the dynamometer, while the electrical activity of the semitendinosus and biceps femoris muscles was detected using surface electromyography. EMD was found to be significantly increased (p = 0.001) in patients who had undergone ACL reconstruction compared to the controls. On the contrary, no significant differences (p = 0.235) were found for the biceps femoris muscle between the two groups. Similar results were found when the study group was compared with the intact leg group (p = 0.027 for semitendinosus and p = 0.859 for biceps femoris). Harvesting the semitendinosus tendon increases the EMD for the semitendinosus muscle but does not influence the EMD outcomes for the biceps femoris muscle. PMID- 26625186 TI - Safety Lead Optimization and Candidate Identification: Integrating New Technologies into Decision-Making. AB - Discovery toxicology focuses on the identification of the most promising drug candidates through the development and implementation of lead optimization strategies and hypothesis-driven investigation of issues that enable rational and informed decision-making. The major goals are to [a] identify and progress the drug candidate with the best overall drug safety profile for a therapeutic area, [b] remove the most toxic drugs from the portfolio prior to entry into humans to reduce clinical attrition due to toxicity, and [c] establish a well-characterized hazard and translational risk profile to enable clinical trial designs. This is accomplished through a framework that balances the multiple considerations to identify a drug candidate with the overall best drug characteristics and provides a cogent understanding of mechanisms of toxicity. The framework components include establishing a target candidate profile for each program that defines the qualities of a successful candidate based on the intended therapeutic area, including the risk tolerance for liabilities; evaluating potential liabilities that may result from engaging the therapeutic target (pharmacology-mediated or on target) and that are chemical structure-mediated (off-target); and characterizing identified liabilities. Lead optimization and investigation relies upon the integrated use of a variety of technologies and models (in silico, in vitro, and in vivo) that have achieved a sufficient level of qualification or validation to provide confidence in their use. We describe the strategic applications of various nonclinical models (established and new) for a holistic and integrated risk assessment that is used for rational decision-making. While this review focuses on strategies for small molecules, the overall concepts, approaches, and technologies are generally applicable to biotherapeutics. PMID- 26625187 TI - The utility of multiple molecular methods including whole genome sequencing as tools to differentiate Escherichia coli O157:H7 outbreaks. AB - A standardised method for determining Escherichia coli O157:H7 strain relatedness using whole genome sequencing or virulence gene profiling is not yet established. We sought to assess the capacity of either high-throughput polymerase chain reaction (PCR) of 49 virulence genes, core-genome single nt variants (SNVs) or k mer clustering to discriminate between outbreak-associated and sporadic E. coli O157:H7 isolates. Three outbreaks and multiple sporadic isolates from the province of Alberta, Canada were included in the study. Two of the outbreaks occurred concurrently in 2014 and one occurred in 2012. Pulsed-field gel electrophoresis (PFGE) and multilocus variable-number tandem repeat analysis (MLVA) were employed as comparator typing methods. The virulence gene profiles of isolates from the 2012 and 2014 Alberta outbreak events and contemporary sporadic isolates were mostly identical; therefore the set of virulence genes chosen in this study were not discriminatory enough to distinguish between outbreak clusters. Concordant with PFGE and MLVA results, core genome SNV and k-mer phylogenies clustered isolates from the 2012 and 2014 outbreaks as distinct events. k-mer phylogenies demonstrated increased discriminatory power compared with core SNV phylogenies. Prior to the widespread implementation of whole genome sequencing for routine public health use, issues surrounding cost, technical expertise, software standardisation, and data sharing/comparisons must be addressed. PMID- 26625188 TI - A Closer Look into the Traditional Purification Process of CdSe Semiconductor Quantum Dots. AB - This paper describes how the postprocessing procedure for wurtzite CdSe quantum dots (QDs) 4.8 and 6.7 nm in diameter is affected by both the choice of nonsolvent and the number of processing steps. Using a host of analytical techniques (ultraviolet-visible, photoluminescence, nuclear magnetic, X-ray photoelectron, and infrared spectroscopy, as well as thermogravimetric analysis), we find that control over the ligand type and surface density can be achieved simply by the number of washing steps used during the postprocessing procedure. Using multiple washing steps we can achieve colloidally stable solutions of QDs with organic mass fractions as low as 13% by mass. For CdSe QDs passivated with trioctylphosphine oxide (TOPO) and stearic acid (SA), essentially no TOPO is bound to the particle surface after three or four washing steps, with a plateau in the amount of SA being removed. The results can be explained using the L- and X-type ligand classification system for QDs, with L-type ligands (TOPO) removed in the early processing steps but the removal of X-type (SA) ligand stalling at a large number of washing steps due to charging of the QDs. Importantly, very little change is observed in the photoluminescence (PL) properties, suggesting that the choice of nonsolvent during postprocessing will allow the production of QD materials with very low organic content by mass but with good PL quantum yields. PMID- 26625190 TI - Eliciting Help Without Pity: The Effect of Changing Media Images on Perceptions of Disability. AB - This study investigated whether newer, more positive disability charity images can elicit helping behavior without producing pity. One hundred sixty-one university undergraduate students were presented with 35 older (1960-1990) and newer (1991-2010) disability charity images and completed a questionnaire about each image. Results indicate that overall, identification with depicted individuals was low; positive attitudes and perceptions of capabilities were moderate to high. Newer images led to more positive responses, but no significant difference in willingness to help. Eliciting pity through negative depictions of disability appears not to be a necessary precondition for eliciting helping behavior toward people with disabilities. PMID- 26625191 TI - Roll over Weismann: extracellular vesicles in the transgenerational transmission of environmental effects. AB - The ability of environmental exposures to induce phenotypic change across multiple generations of offspring has gathered an enormous amount of interest in recent years. There are by now many examples of nongenetic transgenerational effects of environmental exposures, covering a broad range of stressors. Available evidence indicates that epigenetic inheritance may mediate at least some of these transgenerational effects, but how environmental exposures induce changes to the epigenome of the germline is unknown. One possibility is that exposed somatic cells can communicate their exposures to the germline to induce a stable change. In this Perspective, we propose that extracellular vesicles shed by somatic cells represent a credible means by which environmental experience could effect a transmissible epigenetic change in the germline, leading to the inheritance of acquired traits. PMID- 26625192 TI - Cardiorespiratory Fitness, Body Fatness, and Submaximal Systolic Blood Pressure Among Young Adult Women. AB - OBJECTIVES: We examined the independent and combined associations of cardiorespiratory fitness (CRF), body fat (BF) percentage (BF%), and body mass index (BMI) with submaximal systolic blood pressure (SSBP) among young adult women. MATERIALS AND METHODS: Analyses included a sample of 211 normotensive women with a BMI between 20 and 35 kg/m(2); BF% was calculated using total BF measured from dual X-ray absorptiometry, CRF was assessed using a graded exercise test, and SSBP was measured at each stage. RESULTS: There was a significant direct association of SSBP with BF% and BMI, whereas an inverse association between SSBP and CRF when adjusted for the covariates. There was no significant association between SSBP and BF% across the stages 1-3 with a borderline significant association at stage 4 when further adjusted for CRF, whereas no association at any of the stages when adjusted for BMI. A borderline significant association between SSBP and BMI was found at stage 1 and significant association at stages 2-4 when additionally adjusted for CRF, whereas the association disappeared at stages 1-2 when adjusted for BF%. The inverse association between SSBP and CRF was eliminated at stages 3-4 when further adjusted for BF% with borderline significant association at stages 1-2. The associations remained significant at the stages 1-2 but not at stages 3-4 after adjusting for BMI. CONCLUSION: CRF, BF%, and BMI seem to have critical roles in determining SSBP with CRF and BF% being more potent at lower intensity exercise, whereas BMI was more strongly associated at higher intensity exercise. PMID- 26625193 TI - Terahertz and Infrared Spectroscopy of Room-Temperature Imidazolium-Based Ionic Liquids. AB - The terahertz- and infrared-frequency vibrational modes of various room temperature imidazolium-based ionic liquids with molecular anions were examined extensively. We found that the molar-concentration-normalized absorption coefficient spectra in the low-wavenumber range for imidazolium cations with different alkyl-chain lengths were nearly identical for the same anion. Regarding the overall view of a wide range of imidazolium-based ionic liquids, we found that the reduced mass of the combination of an imidazolium-ring cation and the anion and the force constant play significant roles in determining the central frequency of the broad absorption band. In addition to these findings, we also discuss the correlation between the (+)C-H stretching vibrational modes in the 3000-3300 cm(-1) range of the infrared spectra and the intermolecular vibrational band in the low-wavenumber range. Finally, we describe some interesting characteristics of the intermolecular vibrational band observed in a wide range of imidazolium-based ionic liquids. PMID- 26625194 TI - Novel combined strategy of obstetric haemorrhage management during caesarean section using intrauterine balloon tamponade. AB - OBJECTIVE: The aim of this trial was to evaluate the performance of a combined strategy of postpartum haemorrhage management, based upon thromboelastographic (TEG) assessment of coagulation, early surgical haemostasis and mechanical compression of the uterine wall combined with uterine cavity draining, via intrauterine balloon tamponade (BT). METHODS: We carried out an open controlled trial, which included 119 women with obstetric haemorrhage (main group - combined strategy: n = 90, control group - conventional strategy: n = 29). The combined strategy included three essential components: (1) early surgical haemostasis, (2) mechanical pressure upon the uterine wall and draining of the uterine cavity via BT and (3) treatment of blood coagulation disorders identified via TEG. RESULTS: The combined haemorrhage management strategy resulted in significantly lower number of peripartum hysterectomies compared with standard management (4.44% versus 31.03%, respectively, p = 0.02). Blood loss of >2000 ml occurred significantly less common in the main group compared with the control group (16.2% versus 27.6%, respectively, p = 0.03). Mean total blood loss after combined management was significantly lower than after the standard approach (2502 +/- 203 ml versus 1836 +/- 108 ml, p = 0.04). CONCLUSIONS: The proposed combined strategy of obstetric haemorrhage management represents a powerful tool for fertility-sparing treatment of this life-threatening condition. PMID- 26625195 TI - Kinetics of the OH Radical Reaction with Fulvenallene from 298 to 450 K. AB - Self-recombination and cross-reactions of large resonant stabilized hydrocarbon radicals such as fulvenallenyl (C7H5) are predicted to form polycyclic aromatic hydrocarbons in combustion and the interstellar medium. Although fulvenallenyl is likely to be present in these environments, large uncertainties remain about its formation mechanisms. We have investigated the formation of fulvenallenyl by reacting the OH radical with fulvenallene (C7H6) over the 298 to 450 K temperature range and at a pressure of 5 Torr (667 Pa). The reaction rate coefficient is found to be 8.8(+/-1.7) * 10(-12) cm(3) s(-1) at room temperature with a negative temperature dependence that can be fit from 298 to 450 K to k(T) = 8.8(+/-1.7) * 10(-12) (T/298 K)(-6.6(+/-1.1)) exp[-(8.72(+/-3.03) kJ mol( 1))/(R((1/T) - (1/298 K)))] cm(3) s(-1). The comparison of the experimental data with calculated abstraction rate coefficients suggests that over the experimental temperature range, association of the OH radical to fulvenallene plays a significant role likely leading to a low fulvenallenyl branching fraction. PMID- 26625196 TI - Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast. AB - Malignant phyllodes tumor is a rare breast malignancy with sarcomatous overgrowth and with limited effective treatment options for recurrent and metastatic cases. Recent clinical trials indicated a potential for anti-angiogenic, anti-EGFR and immunotherapeutic approaches for patients with sarcomas, which led us to investigate these and other targetable pathways in malignant phyllodes tumor of the breast. Thirty-six malignant phyllodes tumors (including 8 metastatic tumors with two cases having matched primary and metastatic tumors) were profiled using gene sequencing, gene copy number analysis, whole genome expression, and protein expression. Whole genome expression analysis demonstrated consistent over expression of genes involved in angiogenesis including VEGFA, Angiopoietin-2, VCAM1, PDGFRA, and PTTG1. EGFR protein overexpression was observed in 26/27 (96%) of cases with amplification of the EGFR gene in 8/24 (33%) cases. Two EGFR mutations were identified including EGFRvIII and a presumed pathogenic V774M mutation, respectively. The most common pathogenic mutations included TP53 (50%) and PIK3CA (15%). Cases with matched primary and metastatic tumors harbored identical mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively). Tumor expression of PD-L1 immunoregulatory protein was observed in 3/22 (14%) of cases. Overexpression of molecular biomarkers of increased angiogenesis, EGFR and immune checkpoints provides novel targeted therapy options in malignant phyllodes tumors of the breast. PMID- 26625197 TI - Forkhead transcription factor FoxF1 interacts with Fanconi anemia protein complexes to promote DNA damage response. AB - Forkhead box F1 (Foxf1) transcription factor is an important regulator of embryonic development but its role in tumor cells remains incompletely understood. While 16 proteins were characterized in Fanconi anemia (FA) core complex, its interactions with cellular transcriptional machinery remain poorly characterized. Here, we identified FoxF1 protein as a novel interacting partner of the FA complex proteins. Using multiple human and mouse tumor cell lines and Foxf1+/- mice we demonstrated that FoxF1 physically binds to and increases stability of FA proteins. FoxF1 co-localizes with FANCD2 in DNA repair foci in cultured cells and tumor tissues obtained from cisplatin-treated mice. In response to DNA damage, FoxF1-deficient tumor cells showed significantly reduced FANCD2 monoubiquitination and FANCM phosphorylation, resulting in impaired formation of DNA repair foci. FoxF1 knockdown caused chromosomal instability, nuclear abnormalities, and increased tumor cell death in response to DNA-damaging agents. Overexpression of FoxF1 in DNA-damaged cells improved stability of FA proteins, decreased chromosomal and nuclear aberrations, restored formation of DNA repair foci and prevented cell death after DNA damage. These findings demonstrate that FoxF1 is a key component of FA complexes and a critical mediator of DNA damage response in tumor cells. PMID- 26625198 TI - Apoptosis induced by a HIPK2 full-length-specific siRNA is due to off-target effects rather than prevalence of HIPK2-Deltae8 isoform. AB - Small interfering RNAs (siRNAs) are widely used to study gene function and extensively exploited for their potential therapeutic applications. HIPK2 is an evolutionary conserved kinase that binds and phosphorylates several proteins directly or indirectly related to apoptosis. Recently, an alternatively spliced isoform skipping 81 nucleotides of exon 8 (Hipk2-Deltae8) has been described. Selective depletion of Hipk2 full-length (Hipk2-FL) with a specific siRNA that spares the Hipk2-Deltae8 isoform has been shown to strongly induce apoptosis, suggesting an unpredicted dominant-negative effect of Hipk2-FL over the Deltae8 isoform. From this observation, we sought to take advantage and assessed the therapeutic potential of generating Hipk2 isoform unbalance in tumor-initiating cells derived from colorectal cancer patients. Strong reduction of cell viability was induced in vitro and in vivo by the originally described exon 8-specific siRNA, supporting a potential therapeutic application. However, validation analyses performed with additional exon8-specific siRNAs with different stabilities showed that all exon8-targeting siRNAs can induce comparable Hipk2 isoform unbalance but only the originally reported e8-siRNA promotes cell death. These data show that loss of viability does not depend on the prevalence of Hipk2 Deltae8 isoform but it is rather due to microRNA-like off-target effects. PMID- 26625199 TI - Human T-cell leukemia virus type-1-encoded protein HBZ represses p53 function by inhibiting the acetyltransferase activity of p300/CBP and HBO1. AB - Adult T-cell leukemia (ATL) is an often fatal malignancy caused by infection with the complex retrovirus, human T-cell Leukemia Virus, type 1 (HTLV-1). In ATL patient samples, the tumor suppressor, p53, is infrequently mutated; however, it has been shown to be inactivated by the viral protein, Tax. Here, we show that another HTLV-1 protein, HBZ, represses p53 activity. In HCT116 p53+/+ cells treated with the DNA-damaging agent, etoposide, HBZ reduced p53-mediated activation of p21/CDKN1A and GADD45A expression, which was associated with a delay in G2 phase-arrest. These effects were attributed to direct inhibition of the histone acetyltransferase (HAT) activity of p300/CBP by HBZ, causing a reduction in p53 acetylation, which has be linked to decreased p53 activity. In addition, HBZ bound to, and inhibited the HAT activity of HBO1. Although HBO1 did not acetylate p53, it acted as a coactivator for p53 at the p21/CDKN1A promoter. Therefore, through interactions with two separate HAT proteins, HBZ impairs the ability of p53 to activate transcription. This mechanism may explain how p53 activity is restricted in ATL cells that do not express Tax due to modifications of the HTLV-1 provirus, which accounts for a majority of patient samples. PMID- 26625200 TI - Two clinical drugs deubiquitinase inhibitor auranofin and aldehyde dehydrogenase inhibitor disulfiram trigger synergistic anti-tumor effects in vitro and in vivo. AB - Inhibition of proteasome-associated deubiquitinases (DUBs) is emerging as a novel strategy for cancer therapy. It was recently reported that auranofin (Aur), a gold (I)-containing compound used clinically to treat rheumatoid arthritis, is a proteasome-associated DUB inhibitor. Disulfiram (DSF), an inhibitor of aldehyde dehydrogenase, is currently in clinical use for treating alcoholism. Recent studies have indicated that DSF can also act as an antitumor agent. We investigated the effect of combining DSF and Aur on apoptosis induction and tumor growth in hepatoma cancer cells. Here we report that (i) the combined treatment of Aur and DSF results in synergistic cytotoxicity to hepatoma cells in vitro and in vivo; (ii) Aur and DSF in combination induces caspase activation, endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS) production; (iii) pan caspase inhibitor z-VAD-FMK could efficiently block apoptosis but not proteasome inhibition induced by Aur and DSF combined treatment, and ROS is not required for Aur+DSF to induce apoptosis. Collectively, we demonstrate a model of synergism between DSF and proteasome-associated DUB inhibitor Aur in the induction of apoptosis in hepatoma cancer cells, identifying a potential novel anticancer strategy for clinical use in the future. PMID- 26625201 TI - Reducing the serine availability complements the inhibition of the glutamine metabolism to block leukemia cell growth. AB - Leukemia cells are described as a prototype of glucose-consuming cells with a high turnover rate. The role of glutamine in fueling the tricarboxylic acid cycle of leukemia cells was however recently identified confirming its status of major anaplerotic precursor in solid tumors. Here we examined whether glutamine metabolism could represent a therapeutic target in leukemia cells and whether resistance to this strategy could arise. We found that glutamine deprivation inhibited leukemia cell growth but also led to a glucose-independent adaptation maintaining cell survival. A proteomic study revealed that glutamine withdrawal induced the upregulation of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT), two enzymes of the serine pathway. We further documented that both exogenous and endogenous serine were critical for leukemia cell growth and contributed to cell regrowth following glutamine deprivation. Increase in oxidative stress upon inhibition of glutamine metabolism was identified as the trigger of the upregulation of PHGDH. Finally, we showed that PHGDH silencing in vitro and the use of serine-free diet in vivo inhibited leukemia cell growth, an effect further increased when glutamine metabolism was blocked. In conclusion, this study identified serine as a key pro-survival actor that needs to be handled to sensitize leukemia cells to glutamine-targeting modalities. PMID- 26625202 TI - Non-epigenetic function of HDAC8 in regulating breast cancer stem cells by maintaining Notch1 protein stability. AB - Here, we report a novel non-epigenetic function of histone deacetylase (HDAC) 8 in activating cancer stem cell (CSC)-like properties in breast cancer cells by enhancing the stability of Notch1 protein. The pan-HDAC inhibitors AR-42 and SAHA, and the class I HDAC inhibitor depsipeptide, suppressed mammosphere formation and other CSC markers by reducing Notch1 expression in MDA-MB-231 and SUM-159 cells. Interrogation of individual class I isoforms (HDAC1-3 and 8) using si/shRNA-mediated knockdown, ectopic expression and/or pharmacological inhibition revealed HDAC8 to be the primary mediator of this drug effect. This suppression of Notch1 in response to HDAC8 inhibition was abrogated by the proteasome inhibitor MG132 and siRNA-induced silencing of Fbwx7, indicating Notch1 suppression occurred through proteasomal degradation. However, co immunoprecipitation analysis indicated that HDAC8 did not form complexes with Notch1 and HDAC inhibition had no effect on Notch1 acetylation. In a xenograft tumor model, the tumorigenicity of breast cancer cells was decreased by HDAC8 knockdown. These findings suggest the therapeutic potential of HDAC8 inhibition to suppress Notch1 signaling in breast cancer. PMID- 26625203 TI - Biocompatible and colloidally stabilized mPEG-PE/calcium phosphate hybrid nanoparticles loaded with siRNAs targeting tumors. AB - Calcium phosphate nanoparticles are safe and effective delivery vehicles for small interfering RNA (siRNA), as a result of their excellent biocompatibility. In this work, mPEG-PE (polyethylene glycol-L-alpha-phosphatidylethanolamine) was synthesized and used to prepare nanoparticles composed of mPEG-PE and calcium phosphate for siRNA delivery. Calcium phosphate and mPEG-PE formed the stable hybrid nanoparticles through self-assembly resulting from electrostatic interaction in water. The average size of the hybrid nanoparticles was approximately 53.2 nm with a negative charge of approximately -16.7 mV, which was confirmed by dynamic light scattering (DLS) measurements. The nanoparticles exhibited excellent stability in serum and could protect siRNA from ribonuclease (RNase) degradation. The cellular internalization of siRNA-loaded nanoparticles was evaluated in SMMC-7721 cells using a laser scanning confocal microscope (CLSM) and flow cytometry. The hybrid nanoparticles could efficiently deliver siRNA to cells compared with free siRNA. Moreover, the in vivo distribution of Cy5-siRNA-loaded hybrid nanoparticles was observed after being injected into tumor-bearing nude mice. The nanoparticles concentrated in the tumor regions through an enhanced permeability and retention (EPR) effect based on the fluorescence intensities of tissue distribution. A safety evaluation of the nanoparticles was performed both in vitro and in vivo demonstrating that the hybrid nanoparticle delivery system had almost no toxicity. These results indicated that the mPEG-PE/CaP hybrid nanoparticles could be a stable, safe and promising siRNA nanocarrier for anticancer therapy. PMID- 26625204 TI - Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma. AB - AIMS: Antibodies targeting the checkpoint molecules programmed cell death 1 (PD 1) and its ligand PD-L1 are emerging cancer therapeutics. We systematically investigated PD-1 and PD-L1 expression patterns in the poor-prognosis tumor entity high-grade serous ovarian carcinoma. METHODS: PD-1 and PD-L1 protein expression was determined by immunohistochemistry on tissue microarrays from 215 primary cancers both in cancer cells and in tumor-infiltrating lymphocytes (TILs). mRNA expression was measured by quantitative reverse transcription PCR. An in silico validation of mRNA data was performed in The Cancer Genome Atlas (TCGA) dataset. RESULTS: PD-1 and PD-L1 expression in cancer cells, CD3+, PD-1+, and PD-L1+ TILs densities as well as PD-1 and PD-L1 mRNA levels were positive prognostic factors for progression-free (PFS) and overall survival (OS), with all factors being significant for PFS (p < 0.035 each), and most being significant for OS. Most factors also had prognostic value that was independent from age, stage, and residual tumor. Moreover, high PD-1+ TILs as well as PD-L1+ TILs densities added prognostic value to CD3+TILs (PD-1+: p = 0.002,; PD-L1+: p = 0.002). The significant positive prognostic impact of PD-1 and PD-L1 mRNA expression could be reproduced in the TCGA gene expression datasets (p = 0.02 and p < 0.0001, respectively). CONCLUSIONS: Despite their reported immune-modulatory function, high PD-1 and PD-L1 levels are indicators of a favorable prognosis in ovarian cancer. Our data indicate that PD-1 and PD-L1 molecules are biologically relevant regulators of the immune response in high-grade serous ovarian carcinoma, which is an argument for the evaluation of immune checkpoint inhibiting drugs in this tumor entity. PMID- 26625206 TI - Paralinguistic abilities of adults with intellectual disability. AB - The aim of this research was to determine the ability level of paralinguistic production and comprehension in adults with intellectual disability (ID) with regard to the level of their intellectual functioning and presence of co-morbid psychiatric conditions or dual diagnosis (DD). The sample consisted of 120 participants of both genders, ranging in age between 20 and 56 years (M=31.82, SD=8.702). Approximately 50% of the sample comprised participants with a co existing psychiatric condition. Each of these two sub-samples (those with ID only and those with DD) consisted of 25 participants with mild ID and 35 participants with moderate ID. The paralinguistic scale from The Assessment Battery for Communication (ABaCo; Sacco et al., 2008) was used to assess the abilities of comprehension and production of paralinguistic elements. The results showed that the participants with mild ID are more successful than the participants with moderate ID both in paralinguistic comprehension tasks (p=.000) and in paralinguistic production tasks (p=.001). Additionally, the results indicated the presence of separate influences of both ID levels on all of the paralinguistic abilities (F [116]=42.549, p=.000) and the existence of DD (F [116]=18.215, p=.000). PMID- 26625205 TI - The oncolytic virus dl922-947 reduces IL-8/CXCL8 and MCP-1/CCL2 expression and impairs angiogenesis and macrophage infiltration in anaplastic thyroid carcinoma. AB - Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human solid tumor and current treatments are ineffective in increasing patients' survival. Thus, the development of new therapeutic approaches for ATC is needed. We have previously shown that the oncolytic adenovirus dl922-947 induces ATC cell death in vitro and tumor regression in vivo. However, the impact of dl922-947 on the pro-tumorigenic ATC microenvironment is still unknown. Since viruses are able to regulate cytokine and chemokine production from infected cells, we sought to investigate whether dl922-947 virotherapy has such effect on ATC cells, thereby modulating ATC microenvironment. dl922-947 decreased IL-8/CXCL8 and MCP-1/CCL2 production by the ATC cell lines 8505-c and BHT101-5. These results correlated with dl922-947-mediated reduction of NF-kappaB p65 binding to IL8 promoter in 8505-c and BHT101-5 cells and CCL2 promoter in 8505-c cells. IL-8 stimulates cancer cell proliferation, survival and invasion, and also angiogenesis. dl922 947-mediated reduction of IL-8 impaired ATC cell motility in vitro and ATC induced angiogenesis in vitro and in vivo. We also show that dl922-947-mediated reduction of the monocyte-attracting chemokine CCL2 decreased monocyte chemotaxis in vitro and tumor macrophage density in vivo. Interestingly, dl922-947 treatment induced the switch of tumor macrophages toward a pro-inflammatory M1 phenotype, likely by increasing the expression of the pro-inflammatory cytokine interferon gamma. Altogether, we demonstrate that dl922-947 treatment re-shape the pro tumorigenic ATC microenvironment by modulating cancer-cell intrinsic factors and the immune response. An in-depth knowledge of dl922-947-mediated effects on ATC microenvironment may help to refine ATC virotherapy in the context of cancer immunotherapy. PMID- 26625207 TI - Neuropsychological evaluation and parental assessment of behavioral and motor difficulties in children with neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem disorder, with large inter and intrafamilial clinical variability and uncertain prognosis. In children with NF1 cognitive disorders, learning difficulties and behavioral problems are common. The present study aims to establish the neuropsychological and behavioral profiles of 78 patients with NF1, aged between 5 and 18 years, and to examine the relationship between these profiles and the transmission of NF1 (sporadic vs. familial), clinical manifestations, and environmental factors. We used several questionnaires completed by parents and neuropsychological tests. The results confirmed specific neuropsychological disabilities in children with NF1, especially involving visuospatial and fine motor skills, learning difficulties and behavioral problems. Cognitive difficulties were significantly more frequent in patients with familial than in those with sporadic NF1. All parental questionnaires were correlated with each other, but parental reports were not associated with FSIQ, SES, school status, and clinical manifestations of the disease. Neuropsychological tests were poorly related to parental reports of cognitive and behavioral difficulties. PMID- 26625208 TI - Therapeutic effect of TMZ-POH on human nasopharyngeal carcinoma depends on reactive oxygen species accumulation. AB - Nasopharyngeal carcinoma (NPC) is a common head and neck malignancy without efficient chemotherapeutic agents for it. In our current study, we demonstrated the cytotoxicity effects of a newly patented compound temozolomide-perillyl alcohol (TMZ-POH) on NPC in vitro and in vivo, and the possible mechanisms involved. Human NPC cell lines CNE1, CNE2, HNE2, and SUME-alpha were treated with control (DMSO), TMZ, POH, TMZ plus POH, and TMZ-POH. Our data indicated that TMZ POH could inhibit NPC cell proliferation, cause G2/M arrest and DNA damage. TMZ POH triggered apoptosis in NPC cells via significant activation of caspase-3 and poly(ADP-ribose) polymerase (PARP). Importantly, TMZ-POH-induced cell death was found to be associated with (i) the loss of inner mitochondrial membrane potential (DeltaPsim) and release of mitochondrial Cytochrome c, (ii) the increase in ROS generation, and (iii) the activation of stress-activated protein kinases (SAPK)/c-Jun N-terminal kinases (JNK) signaling pathway. The generation of ROS in response to TMZ-POH seems to play a crucial role in the cell death process since the blockage of ROS production using the antioxidant N-acetyl-L cysteine or catalase reversed the TMZ-POH-induced JNK activation, DNA damage, and cancer cell apoptosis. These results provide the rationale for further research and preclinical investigation of the antitumor effect of TMZ-POH against human NPC. PMID- 26625209 TI - The matricellular protein CYR61 interferes with normal pancreatic islets architecture and promotes pancreatic neuroendocrine tumor progression. AB - The significance of matricellular proteins during development and cancer progression is widely recognized. However, how these proteins actively contribute to physiological development and pathological cancer progression is only partially elucidated. In this study, we investigated the role of the matricellular protein Cysteine-rich 61 (CYR61) in pancreatic islet development and carcinogenesis. Transgenic expression of CYR61 in beta cells (Rip1CYR mice) caused irregular islets morphology and distorted sorting of alpha cells, but did not alter islets size, number or vascularization. To investigate the function of CYR61 during carcinogenesis, we crossed Rip1CYR mice with Rip1Tag2 mice, a well established model of beta cell carcinogenesis. Beta tumors in Rip1Tag2CYR mice were larger, more invasive and more vascularized compared to tumors in Rip1Tag2 mice. The effect of CYR61 on angiogenesis was fully abrogated by treating mice with the anti-VEGFR2 mAb DC101. Results from in vitro assays demonstrated that CYR61 modulated integrin alpha6beta1-dependent invasion and adhesion without altering its expression. Taken together, these results show that CYR61 expression in pancreatic beta cells interferes with normal islet architecture, promotes islet tumor growth, invasion and VEGF/VERGFR-2-dependent tumor angiogenesis. Taken together, these observations demonstrate that CYR61 acts as a tumor promoting gene in pancreatic neuroendocrine tumors. PMID- 26625210 TI - Peritoneal and hematogenous metastases of ovarian cancer cells are both controlled by the p90RSK through a self-reinforcing cell autonomous mechanism. AB - The molecular mechanisms orchestrating peritoneal and hematogenous metastases of ovarian cancer cells are assumed to be distinct. We studied the p90RSK family of serine/threonine kinases that lie downstream the RAS-ERK/MAPK pathway and modulate a variety of cellular processes including cell proliferation, survival, motility and invasiveness. We found the RSK1 and RSK2 isoforms expressed in a number of human ovarian cancer cell lines, where they played redundant roles in sustaining in vitro motility and invasiveness. In vivo, silencing of both RSK1 and RSK2 almost abrogated short-term and long-term metastatic engraftment of ovarian cancer cells in the peritoneum. In addition, RSK1/RSK2 silenced cells failed to colonize the lungs after intravenous injection and to form hematogenous metastasis from subcutaneous xenografts. RSK1/RSK2 suppression resulted in lessened ovarian cancer cell spreading on endogenous fibronectin (FN). Mechanistically, RSK1/RSK2 knockdown diminished FN transcription, alpha5beta1 integrin activation and TGF-beta1 translation. Reduced endogenous FN deposition and TGF-beta1 secretion depended on the lack of activating phosphorylation of the transcription/translation factor YB-1 by p90RSK. Altogether data show how p90RSK activates a self-reinforcing cell autonomous pro-adhesive circuit necessary for metastatic seeding of ovarian cancer cells. Thus, p90RSK inhibitors might hinder both the hematogenous and the peritoneal metastatic spread of human ovarian cancer. PMID- 26625213 TI - Incorporation of a Doubly Functionalized Synthetic Amino Acid into Proteins for Creating Chemical and Light-Induced Conjugates. AB - Z-Lysine (ZLys) is a lysine derivative with a benzyloxycarbonyl group linked to the epsilon-nitrogen. It has been genetically encoded with the UAG stop codon, using the pair of an engineered variant of pyrrolysyl-tRNA synthetase (PylRS) and tRNA(Pyl). In the present study, we designed a novel Z-lysine derivative (AmAzZLys), which is doubly functionalized with amino and azido substituents at the meta positions of the benzyl moiety, and demonstrated its applicability for creating protein conjugates. AmAzZLys was incorporated into proteins in Escherichia coli, by using the ZLys-specific PylRS variant. AmAzZLys was then site-specifically incorporated into a camelid single-domain antibody specific to the epidermal growth factor receptor (EGFR). A one-pot reaction demonstrated that the phenyl amine and azide were efficiently linked to the 5 kDa polyethylene glycol and a fluorescent probe, respectively, through specific bio-orthogonal chemistry. The antibody was then tested for the ability to form a photo-cross link between its phenylazide moiety and the antigen, while the amino group on the same ring was used for chemical labeling. When incorporated at a selected position in the antibody and exposed to 365 nm light, AmAzZLys formed a covalent bond with the EGFR ectodomain, with the phenylamine moiety labeled fluorescently prior to the reaction. The present results illuminated the versatility of the ZLys scaffold, which can accommodate multiple reactive groups useful for protein conjugation. PMID- 26625212 TI - Device-modified trabeculectomy for glaucoma. AB - BACKGROUND: Glaucoma is an optic neuropathy that leads to vision loss and blindness. It is the second most common cause of irreversible blindness worldwide. The main treatment for glaucoma aims to reduce intraocular pressure (IOP) in order to slow or prevent further vision loss. IOP can be lowered with medications, and laser or incisional surgeries. Trabeculectomy is the most common incisional surgical procedure to treat glaucoma. Device-modified trabeculectomy is intended to improve drainage of the aqueous humor to lower IOP. Trabeculectomy modifying devices include Ex-PRESS, Ologen, amniotic membrane, expanded polytetrafluoroethylene (E-PTFE) membrane, Gelfilm and others. However, the effectiveness and safety of these devices are uncertain. OBJECTIVES: To assess the relative effectiveness, primarily with respect to IOP control and safety, of the use of different devices as adjuncts to trabeculectomy compared with standard trabeculectomy in eyes with glaucoma. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2014, Issue 12), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to December 2014), EMBASE (January 1980 to December 2014), PubMed (1948 to December 2014), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to December 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 22 December 2014. SELECTION CRITERIA: We included randomized controlled trials comparing devices used during trabeculectomy with trabeculectomy alone. We also included studies where antimetabolites were used in either or both treatment groups. DATA COLLECTION AND ANALYSIS: We used standard procedures expected by Cochrane. MAIN RESULTS: We found 33 studies that met our inclusion criteria, of which 30 were published as full-length journal articles and three as conference abstracts. Only five studies have been registered. The 33 studies included a total of 1542 participants with glaucoma, and compared five types of devices implanted during trabeculectomy versus trabeculectomy alone. Five studies reported the use of Ex-PRESS (386 participants), eight studies reported the use of Ologen (327 participants), 18 studies reported the use of amniotic membrane (726 participants), one study reported the use of E-PTFE (60 participants), and one study reported the use of Gelfilm (43 participants). These studies were conducted in North America, South America, Europe, Asia, and the Middle East. Planned participant follow-up periods ranged from three months to five years. The studies were reported poorly which limited our ability to judge risk of bias for many domains. Only two studies explicitly masked outcome assessment so, we rated 31 studies at high risk of detection bias.Low-quality evidence from three studies showed that use of Ex-PRESS compared with trabeculectomy alone may be associated with a slightly lower IOP at one year (mean difference (MD) -1.58 mm Hg, 95% confidence interval (CI) -2.74 to -0.42; 165 eyes). Cataract surgery and hyphema may be less frequent in the Ex-PRESS group than in the trabeculectomy-alone group (cataract surgery: risk ratio (RR) 0.32, 95% CI 0.14 to 0.74, 3 studies, low quality evidence; hyphema: RR 0.33, 95% CI 0.12 to 0.94, 4 studies, low-quality evidence). The effect of whether Ex-PRESS prevents hypotony was uncertain (RR 0.92, 95% CI 0.63 to 1.33, 2 studies, very low-quality evidence). All these studies received funding from the device manufacturer.Very low-quality evidence from five studies suggests that use of Ologen compared with trabeculectomy alone is associated with slightly higher IOP at one year (MD 1.40 mm Hg, 95% CI -0.57 to 3.38; 177 eyes). The effect of Ologen on preventing hypotony was uncertain (RR 0.75, 95% CI 0.47 to 1.19, 5 studies, very low-quality evidence). Differences between the two treatment groups for other reported complications also were inconclusive.Low-quality evidence from nine studies suggests that use of amniotic membrane with trabeculectomy may be associated with lower IOP at one year compared with trabeculectomy alone (MD -3.92 mm Hg, 95% CI -5.41 to -2.42; 356 eyes). Low-quality evidence showed that use of amniotic membrane may prevent adverse events and complications, such as hypotony (RR 0.40, 95% CI 0.17 to 0.94, 5 studies, low-quality evidence).The report from the only E-PTFE study (60 eyes) showed no important differences for postoperative IOP at one year (MD -0.44 mm Hg, 95% CI -1.76 to 0.88) between the trabeculectomy + E-PTFE versus the trabeculectomy-alone groups. Hypotony was the only postoperative complication observed less frequently in the E-PTFE group compared to the trabeculectomy-alone group (RR 0.29, 95% CI 0.11 to 0.77).The one Gelfilm study reported uncertainty in the difference in IOP and complication rates between the two groups at one year; no further data were provided in the study report. AUTHORS' CONCLUSIONS: Overall, the use of devices with standard trabeculectomy may help with greater IOP reduction at one-year follow-up than trabeculectomy alone; however, due to potential biases and imprecision in effect estimates, the quality of evidence is low. When we examined outcomes within subgroups based on the type of device used, our findings suggested that the use of an Ex-PRESS device or an amniotic membrane as an adjunct to trabeculectomy may be slightly more effective in reducing IOP at one year after surgery compared with trabeculectomy alone. The evidence that these devices are as safe as trabeculectomy alone is unclear. Due to various limitations in the design and conduct of the included studies, the applicability of this evidence synthesis to other populations or settings is uncertain. Further research is needed to determine the effectiveness and safety of other devices and in subgroup populations, such as people with different types of glaucoma, of various races and ethnicity, and with different lens types (e.g. phakic, pseudophakic). PMID- 26625211 TI - Epigenetic inactivation of the putative DNA/RNA helicase SLFN11 in human cancer confers resistance to platinum drugs. AB - Platinum-derived drugs such as cisplatin and carboplatin are among the most commonly used cancer chemotherapy drugs, but very few specific molecular and cellular markers predicting differential sensitivity to these agents in a given tumor type have been clearly identified. Epigenetic gene silencing is increasingly being recognized as a factor conferring distinct tumoral drug sensitivity, so we have used a comprehensive DNA methylation microarray platform to interrogate the widely characterized NCI60 panel of human cancer cell lines with respect to CpG methylation status and cisplatin/carboplatin sensitivity. Using this approach, we have found promoter CpG island hypermethylation associated silencing of the putative DNA/RNA helicase Schlafen-11 (SLFN11) to be associated with increased resistance to platinum compounds. We have also experimentally validated these findings in vitro. In this setting, we also identified the BRCA1 interacting DHX9 RNA helicase (also known as RHA) as a protein partner for SLFN11, suggesting a mechanistic pathway for the observed chemoresistance effect. Most importantly, we have been able to extend these findings clinically, following the observation that those patients with ovarian and non-small cell lung cancer carrying SLFN11 hypermethylation had a poor response to both cisplatin and carboplatin treatments. Overall, these results identify SLFN11 epigenetic inactivation as a predictor of resistance to platinum drugs in human cancer. PMID- 26625215 TI - HLA class I is most tightly linked to levels of tapasin compared with other antigen-processing proteins in glioblastoma. PMID- 26625214 TI - Histopathological features of papillary thyroid carcinomas detected during four screening examinations of a Ukrainian-American cohort. AB - BACKGROUND: There are limited data on the histopathology of papillary thyroid carcinomas (PTCs) diagnosed in irradiated populations. We evaluated the associations between iodine-131 dose and the histopathological characteristics of post-Chernobyl PTCs, the changes in these characteristics over time, and their associations with selected somatic mutations. METHODS: This study included 115 PTCs diagnosed in a Ukrainian-American cohort (n=13,243) during prescreening and four successive thyroid screenings. Of these PTCs, 65 were subjected to somatic mutation profiling. All individuals were <18 years at the time of the Chernobyl accident and had direct thyroid radioactivity measurements. Statistical analyses included multivariate linear and logistic regression. RESULTS: We identified a borderline significant linear-quadratic association (P=0.063) between iodine-131 dose and overall tumour invasiveness (presence of extrathyroidal extension, lymphatic/vascular invasion, and regional or distant metastases). Irrespective of dose, tumours with chromosomal rearrangements were more likely to have lymphatic/vascular invasion than tumours without chromosomal rearrangements (P=0.020) or tumours with BRAF or RAS point mutations (P=0.008). Controlling for age, there were significant time trends in decreasing tumour size (P<0.001), the extent of lymphatic/vascular invasion (P=0.005), and overall invasiveness (P=0.026). CONCLUSIONS: We determined that the invasive properties of PTCs that develop in iodine-131-exposed children may be associated with radiation dose. In addition, based on a subset of cases, tumours with chromosomal rearrangements appear to have a more invasive phenotype. The increase in small, less invasive PTCs over time is a consequence of repeated screening examinations. PMID- 26625216 TI - Exogenous administration of protease-resistant, non-matrix-binding IGFBP-2 inhibits tumour growth in a murine model of breast cancer. PMID- 26625217 TI - Hypermethylation of the 5' CpG island of the gene encoding the serine protease Testisin promotes its loss in testicular tumorigenesis. PMID- 26625218 TI - Ethnicity, deprivation and screening: survival from breast cancer among screening eligible women in the West Midlands diagnosed from 1989 to 2011. PMID- 26625219 TI - PIK3CA oncogenic mutations represent a major mechanism of resistance to trastuzumab in HER2/neu overexpressing uterine serous carcinomas. PMID- 26625220 TI - Benzene exposure and risk of lymphohaematopoietic cancers in 25,000 offshore oil industry workers. PMID- 26625221 TI - Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas. PMID- 26625222 TI - Comment on 'Are the studies on cancer risk from CT scans biased by indication? Elements of answer from a large-scale cohort study in France'--Evidence of confounding by predisposing factors unclear. PMID- 26625223 TI - Granulocyte colony-stimulating factor receptor signalling via Janus kinase 2/signal transducer and activator of transcription 3 in ovarian cancer. PMID- 26625224 TI - Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma. PMID- 26625225 TI - [Which evidence is adequate in geriatric patients?]. PMID- 26625226 TI - [Update PAVK: Epidemiology, comorbidity and prognosis of peripheral arterial obstructive disease]. AB - The number of patients suffering from PAD is increasing worlwide and the rate of hospitalized patients in Germany is continously increasing. The diagnosis can be made reliably by ankle- and toe-pressure measurements with calculating the ABI and TBI. Clinical relevant comorbidities are CAD, heart insuffiency , chronic renal failure and diabetes. The prognosis of asymptomatic and symptomatic patients is characterized by an increased cardiovascular morbidity and mortality. PMID- 26625227 TI - [The diversity of leptin]. AB - The role of leptin in regulation of energy homeostasis is well established, yet both the diagnostic as well as the therapeutic relevance of leptin in diet induced obesity remains unresolved. Nevertheless, in the last few years, the substantial impact of leptin substitution in selected forms of monogenic obesity has advanced our knowledge about the neuroendocrine network of body weight regulation. Moreover, leptin seems to play a crucial role in intestinal nutrient reabsorption, regulation of blood pressure, fertility, inflammation and autoimmune diseases. A better understanding of these processes could possibly provide novel diagnostic and therapeutic options in the future. PMID- 26625228 TI - [Use of direct oral anticoagulants in the elderly]. AB - Equal safety and efficacy of direct oral anticoagulants as compared to vitamin K antagonists have been shown in elderly and very old patients. The use of these seem to have certain advantages in this special patient cohort: higher drug safety, no need for lab monitoring, less drug-drug interactions and a lower rate of intracranial hemorrhages. However, more data is needed to quantify the exact bleeding risk for geriatric patients. Elderly patients suffer quite frequently from significant comorbidities, such as renal failure, dementia, vision loss etc., which might put them at higher risk to suffer from medication side effects, especially bleeding complications. Routine clinical examinations combined with monitoring of renal function are therefore of paramount importance. Regarding these precautions the use of the new oral anticoagulants in the elderly is hence quite justified and rising. PMID- 26625229 TI - [Current standards in the treatment of pancreatic cancer]. AB - The poor prognosis of pancreatic adenocarcinoma on the one hand side is due to the fact that early symptoms are nonspecific, often misdiagnosed and the disease is on the other hand side rapidly progressive, so that at diagnosis in about 80 % of cases already locally advanced inoperable, or metastatic cancer stages are present. In these cases the 1 year survival rate ranged from 20 % to 50 % depending of performance status and the used regimen. Thus, symptomatic supportive treatment is as important as palliative chemotherapy. Today several evidence-based chemotherapies are available - and others are expected soon - resulting in a highly significant overall survival benefit. Individual patient characteristics have to be considered for the selection of treatment. Even after successful surgery with curative intention, the 5-year survival rate is about 10 %. By adjuvant chemotherapy the survival probability as well as cure rate can be more than doubled. Since the preparation of the S3 guidelines for pancreatic cancer additional options in the care of patients with pancreatic cancer have become available to be incorporated in clinical practice. PMID- 26625230 TI - [Endocarditis - an update]. AB - Infective endocarditis remains a diagnostic and therapeutic challenge. This update focuses on recent developments in the diagnostic workup, therapeutic management and prophylaxis of infective endocarditis. Recommendations of the new guidelines of the European Society of Cardiology and the updated statement of the American Heart Association are compared and discussed. The new entity transcatheter aortic valve implantation (TAVI)-associated endocarditis is also highlighted. PMID- 26625231 TI - [Nasal Highflow - Treatment option in severe hypoxaemia?]. AB - Nasal High Flow (NHF) provides a warmed and humidified air stream. In pediatrics, this method is already in widespread use and is increasingly replacing the CPAP. New studies show success in treating adults. Currently the acute hypoxemic insufficiency cause of pneumoniae is a secured area of use. NHF is not inferior in comparison to other oxygen delivery systems. At this juncture effectiveness of this easy to use method is not clear. Preliminary reports describe an improvement in ventilation by the NHF. Here, a wash-out of the airways and improved alveolar ventilation seem to be the main operating principles. PMID- 26625232 TI - [Aortic regurgitation: update 2015]. AB - Aortic regurgitation is the consequence of a heterogenous alterations to the aortic valve and ascending aorta, respectively. Due to the widespread use of transcatheter aortic valve implantation, paravalvular leakage has gained interest as a special subtype of aortic regurgitation. The present article summarizes the current state and recent developments in the diagnostics and therapy of the different forms of aortic regurgitation. PMID- 26625233 TI - [Dialysis and renal transplantation: update 2015]. PMID- 26625234 TI - [Immunotherapy in lung cancer: checkpoint inhibitors]. AB - Monoclonal antibodies against the PD-1 receptor or its ligands result in a recovery of T cell responses against tumor antigens. Nivolumab is the first antibody that has been approved in lung cancer. This mode of action is very intersting, especially because of long term responses and the moderate toxicity. PMID- 26625235 TI - [Conservative Therapy of Osteoarthritis]. AB - The therapy of osteoarthritis is based on conservative therapeutic approaches, depending on the disease's severity. In this context, physical therapy and the use of sufficient analgesic regimes are of decisive importance. This article will discuss the current evidence based therapeutic concepts as well as promising new therapeutic approaches. PMID- 26625236 TI - [Short bowel syndrome and intestinal failure - new developments]. AB - Intestinal failure is characterized by intestinal water and electrolyte losses as well as malabsorption of macronutrients. It often requires individually composed parenteral support (so call compounding). Teduglutide, a DPP-IV resistant GLP2 analogue, is available a pharmacologic treatment, which stimulates intestinal absorption and can facilitate infusion free days. Catheter infections are the most common complication of home parenteral support. The incidence can be minimized using Taurolidin as a catheter block solution. PMID- 26625237 TI - [Non-alcoholic fatty liver diseases]. PMID- 26625238 TI - [58-year old woman with primary biliary cirrhosis and crepitations]. PMID- 26625239 TI - [Undulant fever and autoimmune hemolytic anemia in a 20-year-old exchange student from Jordan - the human brucellosis as an important differential diagnosis in migrants]. AB - HISTORY AND CLINICAL FINDINGS: A 20-year-old Jordanian exchange student presents with recurrent fever, night sweats, cough, and swelling and redness around the ankle. Physical examination further reveals bilateral ankle arthritis and painful cervical lymphadenopathy. INVESTIGATIONS AND DIAGNOSIS: Laboratory tests show signs of autoimmune hemolytic anemia, elevated liver function tests, and moderate laboratory signs of inflammation. All blood cultures reveal growth of gram negative coccoid rods which are initially identified by mass spectrometry as Moraxella lacunata and Ochrobactrum anthropi. However, antimicrobial therapy with imipenem / cilastatin does not improve the patient's clinical condition. Based on the travel history including consumption of yogurt from unpasteurized sheep's milk, we perform serological tests with a strongly positive result for Brucella species, and additional work-up of blood culture isolates confirm the definitive diagnosis of brucellosis (Malta fever, infection by Brucella melitensis). TREATMENT AND COURSE: After initiation of antimicrobial therapy with doxycycline and rifampin the patient shows complete resolution of fever. Arthritis, autoimmune hemolytic anemia and accompanying hepatitis improve in the course. CONCLUSIONS: Thus, since brucellosis is endemic to countries like Jordan, it should be considered as a possible agent of fever of unknown origin especially in migrants unresponsive to empiric therapy and appropriate diagnostic tests including meticulous validation of blood cultures should be performed. Standard therapy is a combination of doxycycline with rifampin for at least 6 weeks. PMID- 26625251 TI - Therapeutic Effect of a Synthetic RORalpha/gamma Agonist in an Animal Model of Autism. AB - Autism is a developmental disorder of the nervous system associated with impaired social communication and interactions as well excessive repetitive behaviors. There are no drug therapies that directly target the pathology of this disease. The retinoic acid receptor-related orphan receptor alpha (RORalpha) is a nuclear receptor that has been demonstrated to have reduced expression in many individuals with autism spectrum disorder (ASD). Several genes that have been shown to be downregulated in individuals with ASD have also been identified as putative RORalpha target genes. Utilizing a synthetic RORalpha/gamma agonist, SR1078, that we identified previously, we demonstrate that treatment of BTBR mice (a model of autism) with SR1078 results in reduced repetitive behavior. Furthermore, these mice display increased expression of ASD-associated RORalpha target genes in both the brains of the BTBR mice and in a human neuroblastoma cell line treated with SR1078. These data suggest that pharmacological activation of RORalpha may be a method for treatment of autism. PMID- 26625253 TI - Isotretinoin: Mechanism of Action and Patient Selection. AB - Oral isotretinoin is a highly effective treatment for appropriately selected patients with acne. This medication is the only treatment that targets all four of the identified factors underlying acne pathogenesis. In addition to the approved indication of resistant nodular scarring acne, clinical studies and experience have shown that other categories of patients benefit from isotretinoin therapy, including those with resistant scarring papular acne, those with resistant acne that interferes with normal living, those who have severe acne related psychological sequelae, and those with acne who have a skin picking habit or compulsion. Semin Cutan Med Surg 34(supp5):S86-S88(c) 2015 published by Frontline Medical Communications. PMID- 26625254 TI - TNF Inhibitors in Psoriasis: A Review. AB - Adalimumab, etanercept, and infliximab are tumor necrosis factor (TNF) inhibitors that are currently approved by the US Food and Drug Administration for the treatment of moderate to severe psoriasis. The availability of these biologic agents established a new benchmark in the treatment of psoriasis that requires systemic therapy to control psoriasis signs and symptoms. Although a number of other biologic agents and small molecules have been approved recently, TNF inhibitors remain a cornerstone of psoriasis therapy. Semin Cutan Med Surg 34(supp2):S37-S39 (c) 2015 published by Frontline Medical Communications. PMID- 26625252 TI - The Local HIF-2alpha/EPO Pathway in the Bone Marrow is Associated with Excessive Erythrocytosis and the Increase in Bone Marrow Microvessel Density in Chronic Mountain Sickness. AB - AIM: Chronic mountain sickness (CMS) is characterized by excessive erythrocytosis, and angiogenesis may be involved in the pathogenesis of this disease. The bone marrow niche is the primary site of erythropoiesis and angiogenesis. This study was aimed at investigating the associations of the levels of hypoxia-inducible factors (HIFs), erythropoietin (EPO), and erythropoietin receptor (EPOR), as well as microvessel density (MVD) in the bone marrow with CMS. RESULTS: A total of 34 patients with CMS and 30 control subjects residing in areas at altitudes of 3000-4500 m were recruited for this study. The mRNA and protein expression of HIF-2alpha and EPO in the bone marrow cells was significantly higher in the CMS patients than in the controls. Moreover, changes in HIF-2alpha expression in CMS patients were significantly correlated with EPO and hemoglobin levels. In contrast, the expression of mRNA and protein expression of HIF-1alpha and EPOR did not differ significantly between the CMS and control patients. Increased MVD was observed in the bone marrow of the patients with CMS and it was significantly correlated with hemoglobin. CONCLUSIONS: Bone marrow cells of CMS patients may show enhanced activity of the HIF-2alpha/EPO pathway, and EPO may regulate the erythropoiesis and vasculogenesis through autocrine or/and paracrine mechanisms in the bone marrow niche. The increased MVD in the bone marrow of CMS patients appears to be involved in the pathogenesis of this disease. PMID- 26625255 TI - Mapping Electrochemical Heterogeneity at Iron Oxide Surfaces: A Local Electrochemical Impedance Study. AB - Alternating current scanning electrochemical microscopy (AC-SECM) was used for the first time to map key electrochemical attributes of oriented hematite (alpha Fe2O3) single crystal surfaces at the micron-scale. Localized electrochemical impedance spectra (LEIS) of the (001) and (012) faces provided insight into the spatial variations of local double layer capacitance (C(dl)) and charge transfer resistance (R(ad)). These parameters were extracted by LEIS measurements in the 0.4-8000 Hz range to probe the impedance response generated by the redistribution of water molecules and charge carriers (ions) under an applied AC. These were attributed to local variations in the local conductivity of the sample surfaces. Comparison with global EIS measurements on the same samples uncovered highly comparable frequency-resolved processes, that were broken down into contributions from the bulk hematite, the interface as well as the microelectrode/tip assembly. This work paves the way for new studies aimed at mapping electrochemical processes at the mesoscale on this environmentally and technologically important material. PMID- 26625256 TI - Erratum. PMID- 26625257 TI - Development of (177)Lu-DOTA-Dendrimer and Determination of Its Effect on Metal and Ion Levels in Tumor Tissue. AB - Dendrimers are synthetic nanomolecules with well-defined chemical structures. Different strategies have been used for radiolabeling dendrimers with different radioisotopes. In this study, the aim was to conjugate dendrimers with (177)Lu, to observe the in vivo behavior of the labeled compound and to measure the elementary changes in tumor tissue that could be caused by ionizing radiation. PAMAM G4 dendrimers conjugated with DOTA were labeled with (177)Lu. The radiolabeled compound was characterized and its stability was evaluated by reverse phase high performance liquid chromatography. Radiolabeling yield was >98% and stable for 24 hours. Biodistribution studies of (177)Lu-DOTA-dendrimers in C57BL/6 melanoma-bearing mice showed blood clearance with hepatic and renal depuration and tumor uptake. The concentrations of Br, Ca, Cl, Fe, K, Mg, Na, Rb, S, and Zn were determined in tumor tissues of C57BL/6 mice treated with (177)Lu DOTA-dendrimers and in untreated mice. The results showed decreased concentrations of Br (62%), Ca (24%), Cl (51%), K (12%) and Na (60%) and increased concentrations of Fe (8%), Mg (28%), Rb (100%), S (6%) and Zn (4%) in tumor tissues of mice treated with (177)Lu-DOTA-dendrimers. These data may be useful to evaluate changes in tumor tissues as indicators of damage that could be caused by ionizing radiation. PMID- 26625258 TI - Discovery of a Good Responder Subtype of Esophageal Squamous Cell Carcinoma with Cytotoxic T-Lymphocyte Signatures Activated by Chemoradiotherapy. AB - Definitive chemoradiotherapy (CRT) is a less invasive therapy for esophageal squamous cell carcinoma (ESCC). Five-year survival rate of locally advanced ESCC patients by definitive CRT were 37%. We previously reported that tumor-specific cytotoxic T-lymphocyte (CTL) activation signatures were preferentially found in long-term survivors. However, it is unknown whether the CTL activation is actually driven by CRT. We compared gene expression profiles among pre- and post treatment biopsy specimens of 30 ESCC patients and 121 pre-treatment ESCC biopsy specimens. In the complete response (CR) cases, 999 overexpressed genes including at least 234 tumor-specific CTL-activation associated genes such as IFNG, PRF1, and GZMB, were found in post-treatment biopsy specimens. Clustering analysis using expression profiles of these 234 genes allowed us to distinguish the immune activated cases, designating them as I-type, from other cases. However, despite the better CR rate in the I-type, overall survival was not significantly better in both these 30 cases and another 121 cases. Further comparative study identified a series of epithelial to mesenchymal transition-related genes overexpressed in the early relapse cases. Importantly, the clinical outcome of CDH2-negative cases in the I-type was significantly better than that of the CDH2 positive cases in the I-type. Furthermore, NK cells, which were activated by neutrophils-producing S100A8/S100A9, and CTLs were suggested to cooperatively enhance the effect of CRT in the CDH2-negative I-type. These results suggested that CTL gene activation may provide a prognostic advantage in ESCCs with epithelial characteristics. PMID- 26625259 TI - The SUMOylation Pathway Restricts Gene Transduction by Adeno-Associated Viruses. AB - Adeno-associated viruses are members of the genus dependoviruses of the parvoviridae family. AAV vectors are considered promising vectors for gene therapy and genetic vaccination as they can be easily produced, are highly stable and non-pathogenic. Nevertheless, transduction of cells in vitro and in vivo by AAV in the absence of a helper virus is comparatively inefficient requiring high multiplicity of infection. Several bottlenecks for AAV transduction have previously been described, including release from endosomes, nuclear transport and conversion of the single stranded DNA into a double stranded molecule. We hypothesized that the bottlenecks in AAV transduction are, in part, due to the presence of host cell restriction factors acting directly or indirectly on the AAV-mediated gene transduction. In order to identify such factors we performed a whole genome siRNA screen which identified a number of putative genes interfering with AAV gene transduction. A number of factors, yielding the highest scores, were identified as members of the SUMOylation pathway. We identified Ubc9, the E2 conjugating enzyme as well as Sae1 and Sae2, enzymes responsible for activating E1, as factors involved in restricting AAV. The restriction effect, mediated by these factors, was validated and reproduced independently. Our data indicate that SUMOylation targets entry of AAV capsids and not downstream processes of uncoating, including DNA single strand conversion or DNA damage signaling. We suggest that transiently targeting SUMOylation will enhance application of AAV in vitro and in vivo. PMID- 26625261 TI - Predicting Mental Imagery-Based BCI Performance from Personality, Cognitive Profile and Neurophysiological Patterns. AB - Mental-Imagery based Brain-Computer Interfaces (MI-BCIs) allow their users to send commands to a computer using their brain-activity alone (typically measured by ElectroEncephaloGraphy-EEG), which is processed while they perform specific mental tasks. While very promising, MI-BCIs remain barely used outside laboratories because of the difficulty encountered by users to control them. Indeed, although some users obtain good control performances after training, a substantial proportion remains unable to reliably control an MI-BCI. This huge variability in user-performance led the community to look for predictors of MI BCI control ability. However, these predictors were only explored for motor imagery based BCIs, and mostly for a single training session per subject. In this study, 18 participants were instructed to learn to control an EEG-based MI-BCI by performing 3 MI-tasks, 2 of which were non-motor tasks, across 6 training sessions, on 6 different days. Relationships between the participants' BCI control performances and their personality, cognitive profile and neurophysiological markers were explored. While no relevant relationships with neurophysiological markers were found, strong correlations between MI-BCI performances and mental-rotation scores (reflecting spatial abilities) were revealed. Also, a predictive model of MI-BCI performance based on psychometric questionnaire scores was proposed. A leave-one-subject-out cross validation process revealed the stability and reliability of this model: it enabled to predict participants' performance with a mean error of less than 3 points. This study determined how users' profiles impact their MI-BCI control ability and thus clears the way for designing novel MI-BCI training protocols, adapted to the profile of each user. PMID- 26625262 TI - Yttrium-90 radioembolization for the treatment of chemorefractory colorectal liver metastases: Technical results, clinical outcome and factors potentially influencing survival. AB - BACKGROUND: The purpose of this study was to retrospectively assess the technical and clinical outcomes, overall survival and prognostic factors for prolonged survival after yttrium-90 ((90)Y) radioembolization as a salvage therapy for patients with chemorefractory liver-only or liver-dominant colorectal metastases. MATERIAL AND METHODS: From January 2005 to January 2014, all the patients selected for (90)Y radioembolization to treat chemorefractory colorectal liver metastases were identified. Demographic, laboratory, imaging and dosimetry data were collected. Post-treatment technical and clinical outcomes were analyzed as well as overall survival; finally several factors potentially influencing survival were analyzed. RESULTS: In total 88 patients were selected for angiographic workup; 71 patients (81%) finally underwent catheter-directed (90)Y microsphere infusion into the hepatic artery 25 days (standard deviation 13 days) after angiographic workup. Median infused activity was 1809 MBq; 30-day toxicity included: fatigue (n = 39; 55%), abdominal discomfort (n = 33; 47%), nausea (n = 5; 7%), fever (n = 14; 20%), diarrhea (n = 6; 9%), liver function abnormalities and elevated bilirubin (transient) (n = 3; 4%). Gastric ulcer was found in five patients (7%). A late complication was radioembolization-induced portal hypertension (REIPH) in three patients (4%). Median time to progression in the liver was 4.4 months. Estimated survival at six and 12 months was 65% and 30%, respectively, with a 50% estimated survival after 8.0 months in this group of chemorefractory patients. Prognostic factors for worse survival were high preprocedural bilirubin, alkaline phosphatase and tumor volume levels. CONCLUSION: (90)Y microsphere radioembolization for chemorefractory colorectal liver metastases has an acceptable safety profile with a 50% estimated survival after 8.0 months. Pretreatment high bilirubin, alkaline phosphatase and tumor volume levels were associated with early death. PMID- 26625260 TI - BRAFV600E-Associated Gene Expression Profile: Early Changes in the Transcriptome, Based on a Transgenic Mouse Model of Papillary Thyroid Carcinoma. AB - BACKGROUND: The molecular mechanisms driving the papillary thyroid carcinoma (PTC) are still poorly understood. The most frequent genetic alteration in PTC is the BRAFV600E mutation--its impact may extend even beyond PTC genomic profile and influence the tumor characteristics and even clinical behavior. METHODS: In order to identify BRAF-dependent signature of early carcinogenesis in PTC, a transgenic mouse model with BRAFV600E-induced PTC was developed. Mice thyroid samples were used in microarray analysis and the data were referred to a human thyroid dataset. RESULTS: Most of BRAF(+) mice developed malignant lesions. Nevertheless, 16% of BRAF(+) mice displayed only benign hyperplastic lesions or apparently asymptomatic thyroids. After comparison of non-malignant BRAF(+) thyroids to BRAF(-) ones, we selected 862 significantly deregulated genes. When the mouse BRAF-dependent signature was transposed to the human HG-U133A microarray, we identified 532 genes, potentially indicating the BRAF signature (representing early changes, not related to developed malignant tumor). Comparing BRAF(+) PTCs to healthy human thyroids, PTCs without BRAF and RET alterations and RET(+), RAS(+) PTCs, 18 of these 532 genes displayed significantly deregulated expression in all subgroups. All 18 genes, among them 7 novel and previously not reported, were validated as BRAFV600E-specific in the dataset of independent PTC samples, made available by The Cancer Genome Atlas Project. CONCLUSION: The study identified 7 BRAF-induced genes that are specific for BRAF V600E-driven PTC and not previously reported as related to BRAF mutation or thyroid carcinoma: MMD, ITPR3, AACS, LAD1, PVRL3, ALDH3B1, and RASA1. The full signature of BRAF-related 532 genes may encompass other BRAF-related important transcripts and require further study. PMID- 26625263 TI - Connectivity and Dispersal Patterns of Protected Biogenic Reefs: Implications for the Conservation of Modiolus modiolus (L.) in the Irish Sea. AB - Biogenic reefs created by Modiolus modiolus (Linnaeus, 1758) (horse mussel reefs) are marine habitats which support high levels of species biodiversity and provide valuable ecosystem services. Currently, M. modiolus reefs are listed as a threatened and/or declining species and habitat in all OSPAR regions and thus are highlighted as a conservation priority under the EU Marine Strategy Framework Directive (MSFD). Determining patterns of larval dispersal and genetic connectivity of remaining horse mussel populations can inform management efforts and is a critical component of effective marine spatial planning (MSP). Larval dispersal patterns and genetic structure were determined for several M. modiolus bed populations in the Irish Sea including those in Wales (North Pen Llyn), Isle of Man (Point of Ayre) and Northern Ireland (Ards Peninsula and Strangford Lough). Simulations of larval dispersal suggested extant connectivity between populations within the Irish Sea. Results from the genetic analysis carried out using newly developed microsatellite DNA markers were consistent with those of the biophysical model. Results indicated moderately significant differentiation between the Northern Ireland populations and those in the Isle of Man and Wales. Simulations of larval dispersal over a 30 day pelagic larval duration (PLD) suggest that connectivity over a spatial scale of 150km is possible between some source and sink populations. However, it appears unlikely that larvae from Northern Ireland will connect directly with sites on the Llyn or Isle of Man. It also appears unlikely that larvae from the Llyn connect directly to any of the other sites. Taken together the data establishes a baseline for underpinning management and conservation of these important and threatened marine habitats in the southern part of the known range. PMID- 26625264 TI - A Rotational Cylindrical fMRI Phantom for Image Quality Control. AB - PURPOSE: A novel phantom for image quality testing for functional magnetic resonance imaging (fMRI) scans is described. METHODS: The cylindrical, rotatable, ~4.5L phantom, with eight wedge-shaped compartments, is used to simulate rest and activated states. The compartments contain NiCl2 doped agar gel with alternating concentrations of agar (1.4%, 1.6%) to produce T1 and T2 values approximating brain grey matter. The Jacard index was used to compare the image distortions for echo planar imaging (EPI) and gradient recalled echo (GRE) scans. Contrast to noise ratio (CNR) was compared across the imaging volume for GRE and EPI. RESULTS: The mean T2 for the two agar concentrations were found to be 106.5+/ 4.8, 94.5+/-4.7 ms, and T1 of 1500+/-40 and 1485+/-30 ms, respectively. The Jacard index for GRE was generally found to be higher than for EPI (0.95 versus 0.8). The CNR varied from 20 to 50 across the slices and echo times used for EPI scans, and from 20 to 40 across the slices for the GRE scans. The phantom provided a reproducible CNR over 25 days. CONCLUSIONS: The phantom provides a quantifiable signal change over a head-size imaging volume with EPI and GRE sequences, which was used for image quality assessment. PMID- 26625266 TI - Synthesis of Alocasin A. AB - Herein is reported a synthesis of alocasin A (1), an alkaloid component of Alocasia macrorrhiza, a herbaceous plant used in folk medicine throughout southern Asia. A double Suzuki-Miyaura cross-coupling reaction between a 3 borylindole and 2,5-dibromopyrazine was used to assemble the heteroaromatic framework of the natural product. Removal of the protecting groups gave a synthetic sample of 1, the spectroscopic data of which matched those in the isolation report of this compound. PMID- 26625265 TI - The Influence of the 1-(3-Trifluoromethyl-Benzyl)-1H-Pyrazole-4-yl Moiety on the Adenosine Receptors Affinity Profile of Pyrazolo[4,3-e][1,2,4]Triazolo[1,5 c]Pyrimidine Derivatives. AB - A new series of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) derivatives has been developed in order to explore their affinity and selectivity profile at the four adenosine receptor subtypes. In particular, the PTP scaffold was conjugated at the C2 position with the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole, a group believed to confer potency and selectivity toward the human (h) A2B adenosine receptor (AR) to the xanthine ligand 8-(1-(3-(trifluoromethyl)benzyl) 1H-pyrazol-4-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (CVT 6975). Interestingly, the synthesized compounds turned out to be inactive at the hA2B AR but they displayed affinity at the hA3 AR in the nanomolar range. The best compound of the series (6) shows both high affinity (hA3 AR Ki = 11 nM) and selectivity (A1/A3 and A2A/A3 > 9090; A2B/A3 > 909) at the hA3 AR. To better rationalize these results, a molecular docking study on the four AR subtypes was performed for all the synthesized compounds. In addition, CTV 6975 and two close analogues have been subjected to the same molecular docking protocol to investigate the role of the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole on the binding at the four ARs. PMID- 26625267 TI - Assessment of pneumatization of the paranasal sinuses: a comprehensive and validated metric. AB - BACKGROUND: The purpose of this study was to develop and validate a radiographic metric for characterizing the degree of paranasal sinus pneumatization. A validated metric for the extent of sinus pneumatization that comprehensively includes the maxillary, ethmoid, frontal, and sphenoid cavities is not currently available. METHODS: A validation study was performed in which 5 independent reviewers evaluated 49 sinus computed tomography (CT) scans in coronal, sagittal, and axial orientations. Reviewers evaluated each scan, bilaterally, for 18 proposed dichotomous items as part of the Assessment of Pneumatization of the Paranasal Sinuses (APPS) metric. Evaluation of APPS items was independent of sinus opacification, which was simultaneously evaluated using the standard and validated Lund-Mackay scoring system. Interrater and intrarater reliability was assessed for each proposed APPS parameter and Lund-Mackay item using Fleiss kappa statistic. RESULTS: Nine parameters were included in the final APPS metric due to substantial interrater reliability (kappa(mean) = 0.61, kappa(range) = 0.41-0.81) and intrarater consistency (kappa(mean) = 0.64, kappa(range) = 0.53-0.77), variable radiographic presence, and unique contribution to the characterization of sinus pneumatization. Kappa values were also calculated for Lund-Mackay interrater reliability (kappa(mean) = 0.58, kappa(range) = 0.45-0.66) and intrarater consistency (kappa(mean) = 0.71, kappa(range) = 0.65-0.75). The final APPS metric has comparable interrater and intrarater reliability to Lund-Mackay scoring. APPS scores were normally distributed within the study group by Anderson Darling normality test (p < 0.005). CONCLUSION: The APPS score is the first comprehensive and validated metric for quantifying the degree of paranasal sinus pneumatization and anatomic variation. This has important potential utility in standardizing evaluation of sinus CT and researching the relationship of sinus pneumatization with clinical parameters. PMID- 26625270 TI - A randomized clinical trial evaluating the safety and efficacy of sitagliptin added to the combination of sulfonylurea and metformin in patients with type 2 diabetes mellitus and inadequate glycemic control. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) treatment generally requires multiple antihyperglycemic agents. When diet, exercise, and treatment with sulfonylurea and metformin do not achieve glycemic goals, several options are available. The present study evaluated the efficacy and tolerability of sitagliptin 100 mg/day added to therapy with sulfonylurea and metformin. METHODS: Patients with HbA1c >=7.5% and <=10.5% while on a sulfonylurea and metformin were randomized 1: 1 to sitagliptin 100 mg/day or placebo for 24 weeks. At Week 24, patients in the placebo group switched to pioglitazone 30 mg/day and both groups continued treatment for another 30 weeks. RESULTS: Of 427 patients randomized, 339 (79.4%) completed the study. At Week 24, significantly greater (P < 0.001) mean reductions from baseline were seen in the sitagliptin versus placebo group for HbA1c (-0.84% vs -0.16%, respectively), 2-h post-meal glucose (-2.0 vs -0.2 mmol/L, respectively) and fasting plasma glucose (-0.7 vs 0.3 mmol/L, respectively). At Week 54, improvements in glycemic control continued. At Week 24, the incidence of adverse events (AEs) was numerically greater with sitagliptin than placebo, primarily because of a higher incidence of hypoglycemia. At Week 54, the incidence of AEs was similar in both groups, primarily because of a higher incidence of hypoglycemia and edema in the placebo/pioglitazone group after Week 24. The only meaningful change in body weight was an increase in the placebo/pioglitazone group at Week 54. CONCLUSIONS: In this study, sitagliptin 100 mg/day was generally well tolerated and provided improvement in glycemic control when added to the combination of sulfonylurea and metformin in patients with T2DM. PMID- 26625272 TI - Mediatorless solar energy conversion by covalently bonded thylakoid monolayer on the glassy carbon electrode. AB - Light reactions of photosynthesis that take place in thylakoid membranes found in plants or cyanobacteria are among the most effective ways of utilizing light. Unlike most researches that use photosystem I or photosystem II as conversion units for converting light to electricity, we have developed a simple method in which the thylakoid monolayer was covalently immobilized on the glassy carbon electrode surface. The activity of isolated thylakoid membrane was confirmed by measuring evolving oxygen under illumination. Glassy carbon surfaces were first modified with partial or full monolayers of carboxyphenyl groups by reductive C-C coupling using 4-aminobenzoic acid and aniline and then thylakoid membrane was bioconjugated through the peptide bond between amine residues of thylakoid and carboxyl groups on the surface. Surface properties of modified surfaces were characterized by cyclic voltammetry, contact angle measurements, and electrochemical impedance spectroscopy. Photocurrent of 230 nA cm(-2) was observed when the thylakoid monolayer was formed on the mixed monolayer of 4 carboxylpheny and benzene at applied potential of 0.4V vs. Ag/AgCl. A small photocurrent resulted when the 4-carboxyphenyl full monolayer was used. This work shows the possibility of solar energy conversion by directly employing the whole thylakoid membrane through simple surface modification. PMID- 26625271 TI - Using Next Generation Sequencing for Multiplexed Trait-Linked Markers in Wheat. AB - With the advent of next generation sequencing (NGS) technologies, single nucleotide polymorphisms (SNPs) have become the major type of marker for genotyping in many crops. However, the availability of SNP markers for important traits of bread wheat (Triticum aestivum L.) that can be effectively used in marker-assisted selection (MAS) is still limited and SNP assays for MAS are usually uniplex. A shift from uniplex to multiplex assays will allow the simultaneous analysis of multiple markers and increase MAS efficiency. We designed 33 locus-specific markers from SNP or indel-based marker sequences that linked to 20 different quantitative trait loci (QTL) or genes of agronomic importance in wheat and analyzed the amplicon sequences using an Ion Torrent Proton Sequencer and a custom allele detection pipeline to determine the genotypes of 24 selected germplasm accessions. Among the 33 markers, 27 were successfully multiplexed and 23 had 100% SNP call rates. Results from analysis of "kompetitive allele-specific PCR" (KASP) and sequence tagged site (STS) markers developed from the same loci fully verified the genotype calls of 23 markers. The NGS-based multiplexed assay developed in this study is suitable for rapid and high-throughput screening of SNPs and some indel-based markers in wheat. PMID- 26625273 TI - Decoding the Structural Bases of D76N beta2-Microglobulin High Amyloidogenicity through Crystallography and Asn-Scan Mutagenesis. AB - D76N is the first natural variant of human beta-2 microglobulin (beta2m) so far identified. Contrary to the wt protein, this mutant readily forms amyloid fibres in physiological conditions, leading to a systemic and severe amyloidosis. Although the Asp76Asn mutant has been extensively characterized, the molecular bases of its instability and aggregation propensity remain elusive. In this work all Asp residues of human beta2m were individually substituted to Asn; D-to-N mutants (D34N, D38N, D53N, D59N, D96N and D98N) were characterised in terms of thermodynamic stability and aggregation propensity. Moreover, crystal structures of the D38N, D53N, D59N and D98N variants were solved at high-resolution (1.24 1.70 A). Despite showing some significant variations in their thermal stabilities, none showed the dramatic drop in melting temperature (relative to the wt protein) as observed for the pathogenic mutant. Consistently, none of the variants here described displayed any increase in aggregation propensity under the experimental conditions tested. The crystal structures confirmed that D-to-N mutations are generally well tolerated, and lead only to minor reorganization of the side chains in close proximity of the mutated residue. D38N is the only exception, where backbone readjustments and a redistribution of the surface electrostatic charges are observed. Overall, our results suggest that neither removing negative charges at sites 34, 38, 53, 59, 96 and 98, nor the difference in beta2m pI, are the cause of the aggressive phenotype observed in D76N. We propose that the dramatic effects of the D76N natural mutation must be linked to effects related to the crucial location of this residue within the beta2m fold. PMID- 26625274 TI - Rural Bypass for Elective Surgeries. AB - PURPOSE: Rural bypass of Critical Access Hospitals (CAHs) for elective inpatient and outpatient surgical procedures has not been studied. Residents choosing to have their elective surgeries elsewhere, when the local CAH provides those surgical services, erode their rural hospital's financial base. The purpose of this research is to describe the elective surgical bypass rate, the procedures most commonly bypassed by rural residents, the distribution of volume among CAHs that offer elective surgical services, and factors predictive of bypass. METHODS: A sample of elective surgery discharges was created from the 2011 Healthcare Cost and Utilization Project State Inpatient Databases and State Ambulatory Surgery Databases for Colorado, North Carolina, Vermont, and Wisconsin. Frequencies of procedures bypassed and CAH volume distribution were performed. Logistic regression was used to model factors associated with rural bypass for elective surgical care. FINDINGS: The rural bypass rate for elective surgical procedures is 48.4%. Procedures bypassed most are operations on the musculoskeletal system, eye, and digestive system. Annual volume distribution for elective surgical procedures among CAHs varied widely. Patients who are younger, medically complex, at higher surgical risk, and have private insurance are at higher odds of bypass. Patients are also more likely to bypass low-volume hospitals. CONCLUSION: Rural hospitals should consider developing surgical services that are performed electively and on an outpatient basis that are attractive to a broader rural population. CAHs that already offer elective surgical procedures and yet who are still bypassed must examine the mutable factors that drive bypass behavior. PMID- 26625282 TI - Chromosome Analyses of Apareiodon argenteus and Apareiodon davisi (Characiformes, Parodontidae): An Extensive Chromosomal Polymorphism of 45S and 5S Ribosomal DNAs. AB - This study analyzed two Apareiodon species without available chromosome data: Apareiodon argenteus and Apareiodon davisi. Both species have 54 metacentric/submetacentric chromosomes, with centromeric blocks of heterochromatin. Nucleolus organizer regions were active in chromosome pair 2 in A. argenteus and pairs 4 and 9 in A. davisi. In A. argenteus, 45S and 5S ribosomal genes were located in chromosome pairs 2 and 18, respectively. Polymorphisms were observed in these ribosomal sequences in A. davisi, with variations in the number/position of sites, and colocalization of these genes in some chromosome pairs. The WAp repetitive fraction was dispersed along the chromosomes of the two species. The satellite DNA pPh2004 was identified in chromosome pairs 7, 8, 10, 11, and 18 in A. argenteus and in pair 24 in A. davisi. The present study describes the first case of chromosomal polymorphisms involving two ribosomal sequences in Parodontidae and discusses the role of repetitive DNAs in the genome and karyotype diversity of this family. PMID- 26625281 TI - Quantitation of the enantiomers of tramadol and its three main metabolites in human whole blood using LC-MS/MS. AB - The analgesic drug tramadol and its metabolites are chiral compounds, with the (+)- and (-)-enantiomers showing different pharmacological and toxicological effects. This novel enantioselective method, based on LC-MS/MS in reversed phase mode, enabled measurement of the parent compound and its three main metabolites O desmethyltramadol, N-desmethyltramadol and N,O-didesmethyltramadol simultaneously. Whole blood samples of 0.5g were fortified with internal standards (tramadol-(13)C-D3 and O-desmethyl-cis-tramadol-D6) and extracted under basic conditions (pH 11) by liquid-liquid extraction. Chromatography was performed on a chiral alpha-1-acid glycoprotein (AGP) column preceded by an AGP guard column. The mobile phase consisted of 0.8% acetonitrile and 99.2% ammonium acetate (20mM, pH 7.2). A post-column infusion with 0.05% formic acid in acetonitrile was used to enhance sensitivity. Quantitation as well as enantiomeric ratio measurements were covered by quality controls. Validation parameters for all eight enantiomers included selectivity (high), matrix effects (no ion suppression/enhancement), calibration model (linear, weight 1/X(2), in the range of 0.25-250ng/g), limit of quantitation (0.125-0.50ng/g), repeatability (2-6%) and intermediate precision (2-7%), accuracy (83-114%), dilution integrity (98-115%), carry over (not exceeding 0.07%) and stability (stable in blood and extract). The method was applied to blood samples from a healthy volunteer administrated a single 100mg dose and to a case sample concerning an impaired driver, which confirmed its applicability in human pharmacokinetic studies as well as in toxicological and forensic investigations. PMID- 26625283 TI - Neurocognitive Profiles of Methamphetamine Users: Comparison of Those With or Without Concomitant Ketamine Use. AB - OBJECTIVE: Methamphetamine (MAMP) and ketamine are neurotoxic drugs whose chronic use has been linked with a cognitive decline in some users. This paper aims to assess the possible effect of concomitant ketamine use on the neurocognitive performance of MAMP users. METHODS: This study divides 42 MAMP users into MAMP users who use ketamine (MAMP+K, n = 16) and MAMP users who do not use ketamine (MAMP-K, n = 26). The performance of these two groups was compared using the Brief Assessment of Cognition in Schizophrenia (BACS), Conners' Continuous Performance Tests (CPT), the Wisconsin Card Sorting Test (WCST), the Iowa Gambling Task (IGT), and the Barratt Impulsiveness Scale (BIS). RESULTS: In comparison to the MAMP-K group, the MAMP+K group showed worse performances in verbal fluency, executive function and composite score in BACS; worse performances in total errors, perseverative errors, nonperseverative errors and conceptual level response in WCST; and greater levels of total scores and novelty seeking in BIS. Neither the attention function evaluated with CPT nor the decision-making behavior evaluated with IGT was associated with previous ketamine use. CONCLUSION: This study detected worse executive function and higher impulsivity level among MAMP users with additional ketamine use versus their counterparts without ketamine use. Further studies with a longitudinal design and a large sample size are necessary to clarify the connection between cognitive deficits and concomitant use of MAMP and ketamine. PMID- 26625284 TI - The power of three. PMID- 26625285 TI - Production, crystallization and X-ray diffraction analysis of the protease CT441 from Chlamydia trachomatis. AB - The prokaryotic obligate intracellular pathogen Chlamydia trachomatis is the most prevalent cause of preventable blindness, affecting approximately six million people worldwide. In addition, C. trachomatis is the most commonly reported sexually transmitted pathogen in Europe and the US, causing pelvic inflammation, ectopic pregnancy and infertility. As in other intracellular pathogens, proteases play crucial roles during most stages of the complex life cycle of Chlamydia. CT441 is a chlamydial protease that has been reported to interfere with oestrogen signalling of the host cell. Here, the recombinant production, purification and crystallization of an inactive variant of CT441, designated CT441 degrees (active-site Ser455 replaced by Ala), are described. CT441 degrees was crystallized in space group P22121, with unit-cell parameters a = 86.7, b = 184.0, c = 209.6 A. A complete diffraction data set was collected to a resolution of 2.95 A. PMID- 26625286 TI - Heterogeneous nucleation is required for crystallization of the ZnuA domain of pneumococcal AdcA. AB - Zn(2+) is an essential nutrient for all known forms of life. In the major human pathogen Streptococcus pneumoniae, the acquisition of Zn(2+) is facilitated by two Zn(2+)-specific solute-binding proteins: AdcA and AdcAII. To date, there has been a paucity of structural information on AdcA, which has hindered a deeper understanding of the mechanism underlying pneumococcal Zn(2+) acquisition. Native AdcA consists of two domains: an N-terminal ZnuA domain and a C-terminal ZinT domain. In this study, the ZnuA domain of AdcA was crystallized. The initial crystals of the ZnuA-domain protein were obtained using dried seaweed as a heterogeneous nucleating agent. No crystals were obtained in the absence of the heterogeneous nucleating agent. These initial crystals were subsequently used as seeds to produce diffraction-quality crystals. The crystals diffracted to 2.03 A resolution and had the symmetry of space group P1. This study demonstrates the utility of heterogeneous nucleation. The solution of the crystal structures will lead to further understanding of Zn(2+) acquisition by S. pneumoniae. PMID- 26625287 TI - Incorporation of copper ions into crystals of T2 copper-depleted laccase from Botrytis aclada. AB - Laccases belong to the class of multicopper oxidases catalyzing the oxidation of phenols accompanied by the reduction of molecular oxygen to water without the formation of hydrogen peroxide. The activity of laccases depends on the number of Cu atoms per enzyme molecule. The structure of type 2 copper-depleted laccase from Botrytis aclada has been solved previously. With the aim of obtaining the structure of the native form of the enzyme, crystals of the depleted laccase were soaked in Cu(+)- and Cu(2+)-containing solutions. Copper ions were found to be incorporated into the active site only when Cu(+) was used. A comparative analysis of the native and depleted forms of the enzymes was performed. PMID- 26625288 TI - Expression, purification and crystallization of a plant polyketide cyclase from Cannabis sativa. AB - Plant polyketides are a structurally diverse family of natural products. In the biosynthesis of plant polyketides, the construction of the carbocyclic scaffold is a key step in diversifying the polyketide structure. Olivetolic acid cyclase (OAC) from Cannabis sativa L. is the only known plant polyketide cyclase that catalyzes the C2-C7 intramolecular aldol cyclization of linear pentyl tetra-beta ketide-CoA to generate olivetolic acid in the biosynthesis of cannabinoids. The enzyme is also thought to belong to the dimeric alpha+beta barrel (DABB) protein family. However, because of a lack of functional analysis of other plant DABB proteins and low sequence identity with the functionally distinct bacterial DABB proteins, the catalytic mechanism of OAC has remained unclear. To clarify the intimate catalytic mechanism of OAC, the enzyme was overexpressed in Escherichia coli and crystallized using the vapour-diffusion method. The crystals diffracted X-rays to 1.40 A resolution and belonged to space group P3121 or P3221, with unit cell parameters a = b = 47.3, c = 176.0 A. Further crystallographic analysis will provide valuable insights into the structure-function relationship and catalytic mechanism of OAC. PMID- 26625289 TI - Crystallization behaviour of glyceraldehyde dehydrogenase from Thermoplasma acidophilum. AB - The glyceraldehyde dehydrogenase from Thermoplasma acidophilum (TaAlDH) is a microbial enzyme that catalyzes the oxidation of D-glyceraldehyde to D-glycerate in the artificial enzyme cascade designed for the conversion of glucose to the organic solvents isobutanol and ethanol. Various mutants of TaAlDH were constructed by a random approach followed by site-directed and saturation mutagenesis in order to improve the properties of the enzyme that are essential for its functioning within the cascade. Two enzyme variants, wild-type TaAlDH (TaAlDHwt) and an F34M+S405N variant (TaAlDH F34M+S405N), were successfully crystallized. Crystals of TaAlDHwt belonged to the monoclinic space group P1211 with eight molecules per asymmetric unit and diffracted to a resolution of 1.95 A. TaAlDH F34M+S405N crystallized in two different space groups: triclinic P1 with 16 molecules per asymmetric unit and monoclinic C121 with four molecules per asymmetric unit. These crystals diffracted to resolutions of 2.14 and 2.10 A for the P1 and C121 crystals, respectively. PMID- 26625290 TI - Combining dehydration, construct optimization and improved data collection to solve the crystal structure of a CRM1-RanGTP-SPN1-Nup214 quaternary nuclear export complex. AB - High conformational flexibility is an intrinsic and indispensable property of nuclear transport receptors, which makes crystallization and structure determination of macromolecular complexes containing exportins or importins particularly challenging. Here, the crystallization and structure determination of a quaternary nuclear export complex consisting of the exportin CRM1, the small GTPase Ran in its GTP-bound form, the export cargo SPN1 and an FG repeat containing fragment of the nuclear pore complex component nucleoporin Nup214 fused to maltose-binding protein is reported. Optimization of constructs, seeding and the development of a sophisticated protocol including successive PEG-mediated crystal dehydration as well as additional post-mounting steps were essential to obtain well diffracting crystals. PMID- 26625291 TI - Structure of Spo0M, a sporulation-control protein from Bacillus subtilis. AB - Spo0M is a sporulation-control protein that is thought to play an essential role in the early stage of endospore formation. While little is known about the functions of Spo0M, a recent phylogenetic study suggests that, based on its amino acid sequence, Spo0M might belong to the arrestin clan. The crystal structure of the Spo0M protein was determined at a resolution of 2.3 A. Ten amino acids at the end of the N-terminus were removed to improve the thermal stability of the purified Spo0M protein and the crystal structure of Spo0M was determined by SAD. Spo0M has a well conserved N-terminal domain with an arrestin-like fold, which consists of a beta-strand sandwich structure. Surprisingly, the C-terminal domain of Spo0M, which has no structural homology to arrestin-clan proteins, bears significant structural similarity to the FP domain of the human PI31 protein. In addition, Spo0M harbours a potential polar-core structure connecting the N- and C terminal domains with several salt bridges, as seen in the crystal structures of arrestin and VPS26. The structure reported here constitutes the first structural information on a bacterial protein that shares significant structural homology to members of the arrestin clan and the FP domain. PMID- 26625293 TI - Crystallographic analysis of a cupin superfamily enzyme from Microcystis aeruginosa involved in aeruginosin biosynthesis. AB - Aeruginosins are a class of cyanobacteria-derived bioactive linear tetrapeptides composed of nonproteinogenic amino-acid residues, such as the 2-carboxy-6 hydroxyoctahydroindole (Choi) moiety, which is the hallmark of aeruginosin. The biosynthetic pathway of the Choi moiety remains elusive. Previous studies have suggested that AerE, a protein that possesses two cupin domains, participates in the biosynthesis of the Choi moiety. In this study, recombinant AerE from Microcystis aeruginosa, which was overexpressed in Escherichia coli and purified by Ni(2+)-chelating affinity and gel-filtration chromatography, was successfully crystallized and X-ray diffraction analysis was performed. The crystal belonged to the orthorhombic space group P212121, with unit-cell parameters a = 34.770, b = 62.133, c = 87.401 A. The diffraction data from the crystal were scaled to a maximum resolution of 1.60 A. The calculated Matthews coefficient of the crystal is 1.93 A(3) Da(-1), suggesting that there is one molecule in the asymmetric unit. PMID- 26625292 TI - Seeding for sirtuins: microseed matrix seeding to obtain crystals of human Sirt3 and Sirt2 suitable for soaking. AB - Sirtuins constitute a family of NAD(+)-dependent enzymes that catalyse the cleavage of various acyl groups from the E-amino group of lysines. They regulate a series of cellular processes and their misregulation has been implicated in various diseases, making sirtuins attractive drug targets. To date, only a few sirtuin modulators have been reported that are suitable for cellular research and their development has been hampered by a lack of structural information. In this work, microseed matrix seeding (MMS) was used to obtain crystals of human Sirt3 in its apo form and of human Sirt2 in complex with ADP ribose (ADPR). Crystal formation using MMS was predictable, less error-prone and yielded a higher number of crystals per drop than using conventional crystallization screening methods. The crystals were used to solve the crystal structures of apo Sirt3 and of Sirt2 in complex with ADPR at an improved resolution, as well as the crystal structures of Sirt2 in complex with ADPR and the indoles EX527 and CHIC35. These Sirt2-ADPR indole complexes unexpectedly contain two indole molecules and provide novel insights into selective Sirt2 inhibition. The MMS approach for Sirt2 and Sirt3 may be used as the basis for structure-based optimization of Sirt2/3 inhibitors in the future. PMID- 26625294 TI - Expression, purification, crystallization and X-ray diffraction analysis of ChiL, a chitinase from Chitiniphilus shinanonensis. AB - Chitin, a linear polysaccharide consisting of beta-1,4-linked N-acetyl-D glucosamine (GlcNAc), is widely used because of its biochemical properties. GlcNAc oligomers prepared from chitin have useful biological activities, such as immunostimulation and the induction of plant defence responses. Microbial chitinolytic enzymes have been investigated extensively for their potential use in the eco-friendly enzymatic production of GlcNAc and its oligomers. Chitiniphilus shinanonensis SAY3(T) is a recently found bacterium with a strong chitinolytic activity. The chitinolytic enzymes from this strain are potentially useful for the efficient production of GlcNAc and its oligomers from chitin. ChiL from C. shinanonensis is an endo-type chitinase belonging to the family 18 glycoside hydrolases (GH18). To understand the enzymatic reaction mechanism of ChiL and utilize it for further enzyme engineering, the catalytic domain (41-406) of ChiL, the construct for which was carefully designed, was expressed, purified and crystallized by the vapour-diffusion method. The crystal belonged to the orthorhombic space group P212121, with unit-cell parameters a = 69.19, b = 81.55, c = 130.01 A, and diffracted to 1.25 A resolution. The Matthews coefficient (VM = 2.2 A(3) Da(-1)) suggested the presence of two monomers per asymmetric unit with a solvent content of 45%. PMID- 26625295 TI - Crystallographic insights into the structure-activity relationships of diazaborine enoyl-ACP reductase inhibitors. AB - Enoyl-ACP reductase, the last enzyme of the fatty-acid biosynthetic pathway, is the molecular target for several successful antibiotics such as the tuberculosis therapeutic isoniazid. It is currently under investigation as a narrow-spectrum antibiotic target for the treatment of several types of bacterial infections. The diazaborine family is a group of boron heterocycle-based synthetic antibacterial inhibitors known to target enoyl-ACP reductase. Development of this class of molecules has thus far focused solely on the sulfonyl-containing versions. Here, the requirement for the sulfonyl group in the diazaborine scaffold was investigated by examining several recently characterized enoyl-ACP reductase inhibitors that lack the sulfonyl group and exhibit additional variability in substitutions, size and flexibility. Biochemical studies are reported showing the inhibition of Escherichia coli enoyl-ACP reductase by four diazaborines, and the crystal structures of two of the inhibitors bound to E. coli enoyl-ACP reductase solved to 2.07 and 2.11 A resolution are reported. The results show that the sulfonyl group can be replaced with an amide or thioamide without disruption of the mode of inhibition of the molecule. PMID- 26625297 TI - Crystallographic analysis of RsmA, a ribosomal RNA small subunit methyltransferase A from Staphylococcus aureus. Corrigendum. AB - The paper by Liu et al. [(2015), Acta Cryst. F71, 1063-1066] is corrected. PMID- 26625296 TI - Structures of plasmepsin II from Plasmodium falciparum in complex with two hydroxyethylamine-based inhibitors. AB - Plasmepsin II (PMII) is one of the ten plasmepsins (PMs) identified in the genome of Plasmodium falciparum, the causative agent of the most severe and deadliest form of malaria. Owing to the emergence of P. falciparum strains that are resistant to current antimalarial agents such as chloroquine and sulfadoxine/pyrimethamine, there is a constant pressure to find new and lasting chemotherapeutic drug therapies. Previously, the crystal structure of PMII in complex with NU655, a potent antimalarial hydroxyethylamine-based inhibitor, and the design of new compounds based on it have been reported. In the current study, two of these newly designed hydroxyethylamine-based inhibitors, PG418 and PG394, were cocrystallized with PMII and their structures were solved, analyzed and compared with that of the PMII-NU655 complex. Structural analysis of the PMII PG418 complex revealed that the flap loop can adopt a fully closed conformation, stabilized by interactions with the inhibitor, and a fully open conformation, causing an overall expansion in the active-site cavity, which in turn causes unstable binding of the inhibitor. PG418 also stabilizes the flexible loop Gln275 Met286 of another monomer in the asymmetric unit of PMII, which is disordered in the PMII-NU655 complex structure. The crystal structure of PMII in complex with the inhibitor PG418 demonstrates the conformational flexibility of the active site cavity of the plasmepsins. The interactions of the different moieties in the P1' position of PG418 and PG394 with Thr217 have to be taken into account in the design of new potent plasmepsin inhibitors. PMID- 26625298 TI - Nocturnal Oxygen Desaturation Index is Inversely Correlated with Airflow Limitation in Patients with Chronic Obstructive Pulmonary Disease. AB - The concurrent diagnosis of chronic obstructive pulmonary disease (COPD) and sleep apnoea-hypopnoea syndrome (SAHS) (overlap syndrome), can contribute to worsening respiratory symptoms, but whether the severity of COPD is associated with co-morbid SAHS is unknown. We investigated whether the severity of COPD is associated with the complication of SAHS by examination of nocturnal oximetry as an alternative to polysomnography. Patients with COPD concurrently completed nocturnal oximetry, pulmonary function tests, a COPD assessment test, an Epworth sleepiness scale and a hospital anxiety and depression scale to evaluate the severity of COPD and possible concurrent presence of SAHS. We retrospectively analysed the data to assess correlation between the oxygen desaturation index (ODI) and each clinical variables and evaluated the predictors of ODI >= 15. This study included 103 patients (91 males, 88%) with a mean age of 72 +/- 8 years and body mass index of 22 +/- 3 kg/m(2). ODI was positively correlated with FEV1, FEV1/FVC and FEV1% predicted, which meant that ODI was inversely correlated with airflow limitation. Univariate logistic regression analysis revealed that FEV1% predicted and FEV1/FVC were predictors of ODI >= 15. ODI is inversely correlated with airflow limitation and milder COPD patients may have co-morbid SAHS. PMID- 26625299 TI - Directional Light Extinction and Emission in a Metasurface of Tilted Plasmonic Nanopillars. AB - Plasmonic optical antennas and metamaterials with an ability to boost light matter interactions for particular incidence or emission angles could find widespread use in solar harvesting, biophotonics, and in improving photon source performance at optical frequencies. However, directional plasmonic structures have generally large footprints or require complicated geometries and costly nanofabrication technologies. Here, we present a directional metasurface realized by breaking the out-of-plane symmetry of its individual elements: tilted subwavelength plasmonic gold nanopillars. Directionality is caused by the complex charge oscillation induced in each individual nanopillar, which essentially acts as a tilted dipole above a dielectric interface. The metasurface is homogeneous over a macroscopic area and it is fabricated by a combination of facile colloidal lithography and off-normal metal deposition. Fluorescence excitation and emission from dye molecules deposited on the metasurface is enhanced in specific directions determined by the tilt angle of the nanopillars. We envisage that these directional metasurfaces can be used as cost-effective substrates for surface-enhanced spectroscopies and a variety of nanophotonic applications. PMID- 26625300 TI - Is passive drag dependent on the interaction of kayak design and paddler weight in flat-water kayaking? AB - Drag is one of the major factors that influences kayaking performance. To focus on the drag of the kayak's hull shape and the paddlers' weight per se, the passive drag (Dp) was measured on a flat-water sprint course for one paddler with added weights. Dp was measured by an electromechanical towing device using a load cell, at incremental and constant velocities from 2.78 to 5.56 m/s. Three kayaks of different sizes and shapes (Nelo(r) K1 Quattro-M, ML, and L) were used and the paddlers' body weight was adjusted with weights so the total paddler weight in the kayak was 65, 75, and 85 kg. The mean Dp increased by the power function of D = kv(n) (mean R(2) = .990; SD .006). The Dp went from 21.37 +/- 1.29 N at 2.78 m/s to 89.32 +/- 6.43 N at 5.56 m/s. For the two lighter weighted kayaks (65 and 75 kg), the lowest Dp was observed with different kayak sizes (M, ML, or L) depending on the target velocity. The manufacturers suggest that paddlers should select a kayak size according to their body weight to minimise drag; however, the results of this study suggest that target velocities, and thus competition distance should also be factored into kayak selection. PMID- 26625301 TI - International travel and acquisition of multidrug-resistant Enterobacteriaceae: a systematic review. AB - International travel is considered to be an important risk factor for acquisition of multidrug-resistant Enterobacteriaceae (MRE). The aim of this systematic review was to determine the effect of international travel on the risk of post travel faecal carriage of MRE. Secondary outcomes were risk factors for acquisition of MRE. A systematic search for relevant literature in seven international databases was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles needed to report on (i) foreign travel, (ii) screening of asymptomatic participants, (iii) antimicrobial susceptibility data and (iv) faecal Enterobacteriaceae carriage. Two researchers independently screened the abstracts, assessed the full article texts for eligibility and selected or rejected them for inclusion in the systematic review. In case of disagreement, a third researcher decided on inclusion. Eleven studies were identified. In all studies, a high prevalence (>20%) of carriage of MRE after international travel was found. The highest prevalence was observed in travellers returning from southern Asia. Foreign travel was associated with an increased risk of carriage of MRE. Further research is needed to assess if this leads to an increase in the number of infections with MRE. Systematic review registration number: PROSPERO CRD42015024973. PMID- 26625302 TI - Spontaneous Healing of Mycobacterium ulcerans Lesions in the Guinea Pig Model. AB - Buruli Ulcer (BU) is a necrotizing skin disease caused by Mycobacterium ulcerans infection. BU is characterized by a wide range of clinical forms, including non ulcerative cutaneous lesions that can evolve into severe ulcers if left untreated. Nevertheless, spontaneous healing has been reported to occur, although knowledge on this process is scarce both in naturally infected humans and experimental models of infection. Animal models are useful since they mimic different spectrums of human BU disease and have the potential to elucidate the pathogenic/protective pathway(s) involved in disease/healing. In this time-lapsed study, we characterized the guinea pig, an animal model of resistance to M. ulcerans, focusing on the macroscopic, microbiological and histological evolution throughout the entire experimental infectious process. Subcutaneous infection of guinea pigs with a virulent strain of M. ulcerans led to early localized swelling, which evolved into small well defined ulcers. These macroscopic observations correlated with the presence of necrosis, acute inflammatory infiltrate and an abundant bacterial load. By the end of the infectious process when ulcerative lesions healed, M. ulcerans viability decreased and the subcutaneous tissue organization returned to its normal state after a process of continuous healing characterized by tissue granulation and reepethelialization. In conclusion, we show that the experimental M. ulcerans infection of the guinea pig mimics the process of spontaneous healing described in BU patients, displaying the potential to uncover correlates of protection against BU, which can ultimately contribute to the development of new prophylactic and therapeutic strategies. PMID- 26625304 TI - Difficult Discharge in Pediatric Rehabilitation Medicine Causing Moral Distress. AB - An ethical dimension exists in nearly all decisions made. Yet, there are clinical decisions in which the ethical dilemma is so difficult for the clinician that it results in moral distress. We present one example of a morally distressing situation in which care was provided for a child who had altered physical abilities after a trauma and was being discharged to a suboptimal family environment. Caring for a child with an acquired spinal cord injury requires significant resources. When a family is able to physically care for the child, but has demonstrated incomplete follow-through, the team is at risk for experiencing significant moral distress. PMID- 26625305 TI - Pulmonary Delivery of Dry Powders During Invasive Mechanical Ventilation: Innovations Are Required. PMID- 26625306 TI - Assessing the Physiological Cost of Active Videogames (Xbox Kinect) Versus Sedentary Videogames in Young Healthy Males. AB - OBJECTIVES: The aims of this study were twofold: (1) to compare the physiological costs of active videogames (AVGs) and sedentary videogames (SVGs) and (2) to compare the exercise intensities attained during AVGs with the exercise intensity criteria for moderate and vigorous physical activity, as stated in current physical activity recommendations for improving public health. MATERIALS AND METHODS: Nineteen young males participated in the study (age, 23 +/- 3 years; height, 178 +/- 6 cm; weight, 78 +/- 15 kg). Participants completed a maximum oxygen uptake ([Formula: see text]) test and a gaming session, including AVGs ("Reflex Ridge," "River Rush," and "Boxing" for the Microsoft [Redmond, WA] KinectTM) and SVGs ("FIFA 14" [Electronic Arts, Burnaby, BC, Canada] and "Call of Duty" [Activision, Santa Monica, CA]). Heart rate (HR) and oxygen uptake [Formula: see text]) were recorded continuously during all videogames. Rating of perceived exertion (RPE) was taken every 3 minutes during AVGs and SVGs. Energy expenditure (EE), expressed as metabolic equivalents (METs), was calculated. One MET was defined as the volume of oxygen consumed at rest in a seated position and is equal to 3.5 mL of O2/kg of body mass/minute. The exercise intensity for each game was expressed as a percentage of [Formula: see text] and percentage of age predicted maximum HR (HRmax). RESULTS: Exercise intensity (percentage HRmax, percentage [Formula: see text], and RPE) and EE (METs) were significantly higher during active gaming compared with sedentary gameplay (P < 0.01). AVGs elicited moderate levels of exercise intensity (64-72 percent HRmax) in line with current recommended physical activity guidelines. CONCLUSIONS: Our results indicate AVGs provoke physiological responses equivalent to a moderate-intensity physical activity. PMID- 26625307 TI - Preterm at birth is not associated with greater cardiovascular risk in adolescence. AB - OBJECTIVE: To determine the effects of preterm birth and gender on subsequent cardiovascular risk factors among urban adolescents in a capital in the Brazilian northeast and to compare them with a group of adolescents term at birth. METHODS: In a retrospective double cohort, data of birth weight were extracted from hospital registers of children born in a same day of birth, between 1992 and 2002. We classified the preterm as a unique group born before 37 weeks of gestation. A total of 134 adolescents, aged 10-20 years were found and investigated. We measured anthropometric and clinical data, blood lipid profile and glucose after overnight fasting. RESULTS: Preterm subjects had less years of scholar education, especially between females (p = 0.01). Preterm females also had lower height (p = 0.00) and waist-hip circumference ratio (p = 0.01). Preterm males had lower cesarean delivery (p = 0.05) and greater family history of cardiovascular disease (p = 0.05). Although the differences on clinical or laboratorial measurements were small and non-significant for cardiovascular risk factors, systolic blood pressure (SBP) and diastolic blood pressure (DBP) tended to be higher in preterm groups, especially for females (SBP = 4.1 mmHg and DBP = 1.6 mmHg, p = 0.12 and p = 0.38, respectively). CONCLUSION: Premature did not increase cardiovascular risk adolescents in this sample. The lower association between premature and poor health outcomes among adolescents in a low average socioeconomic status population from a capital in the Brazilian northeast corroborates previous findings in other countries. PMID- 26625308 TI - Src and STAT3 inhibitors synergize to promote tumor inhibition in renal cell carcinoma. AB - The intracytoplasmic tyrosine kinase Src serves both as a conduit and a regulator for multiple processes required for the proliferation and survival cancer cells. In some cancers, Src engages with receptor tyrosine kinases to mediate downstream signaling and in other cancers, it regulates gene expression. Src therefore represents a viable oncologic target. However, clinical responses to Src inhibitors, such as dasatinib have been disappointing to date. We identified Stat3 signaling as a potential bypass mechanism that enables renal cell carcinoma (RCC) cells to escape dasatinib treatment. Combined Src-Stat3 inhibition using dasatinib and CYT387 (a JAK/STAT inhibitor) synergistically reduced cell proliferation and increased apoptosis in RCC cells. Moreover, dasatinib and CYT387 combine to suppress YAP1, a transcriptional co-activator that promotes cell proliferation, survival and organ size. Importantly, this combination was well tolerated, and caused marked tumor inhibition in RCC xenografts. These results suggest that combination therapy with inhibitors of Stat3 signaling may be a useful therapeutic approach to increase the efficacy of Src inhibitors. PMID- 26625309 TI - Stimulation of dendritic cells by DAMPs in ALA-PDT treated SCC tumor cells. AB - Photodynamic therapy (PDT) not only kills tumor cells directly but also rapidly recruits and activates immune cells favoring the development of antitumor adaptive immunity. It is believed that Topical 5-aminolevulinic acid mediated photodynamic therapy (ALA-PDT) can induce anti-tumor immune responses through dangerous signals damage-associated molecular patterns (DAMPs). In this study, we investigated the effect of ALA-PDT induced DAMPs on immune cells. We focused on the stimulation of dendritic cells by major DAMPs, enhanced the expression of calreticulin (CRT), heat shock proteins 70 (HSP70), and high mobility group box 1 (HMGB1), either individually or in combination. We evaluated in vitro and in vivo expressions of DAMPs induced by ALA-PDT using immunohistochemistry, western blot, and ELISA in a squamous cell carcinoma (SCC) mouse model. The role of DAMPs in the maturation of DCs potentiated by ALA-PDT-treated tumor cells was detected by FACS and ELISA. Our results showed that ALA-PDT enhanced the expression of CRT, HSP70, and HMGB1. These induced DAMPs played an important part in activating DCs by PDT-treated tumor cells, including phenotypic maturation (increase of surface expression of MHC-II, CD80, and CD86) and functional maturation (enhanced capability to secrete IFN-gamma and IL-12). Furthermore, injecting ALA-PDT treated tumor cells into naive mice resulted in complete protection against cancer cells of the same origin. Our findings indicate that ALA-PDT can increase DAMPs and enhance tumor immunogenicity, providing a promising strategy for inducing a systemic anticancer immune response. PMID- 26625310 TI - Infiltrating mast cells increase prostate cancer chemotherapy and radiotherapy resistances via modulation of p38/p53/p21 and ATM signals. AB - Early studies indicated that mast cells in prostate tumor microenvironment might influence prostate cancer (PCa) progression. Their impacts to PCa therapy, however, remained unclear. Here we found PCa could recruit more mast cells than normal prostate epithelial cells then alter PCa chemotherapy and radiotherapy sensitivity, leading to PCa more resistant to these therapies. Mechanism dissection revealed that infiltrated mast cells could increase p21 expression via modulation of p38/p53 signals, and interrupting p38-p53 signals via siRNAs of p53 or p21 could reverse mast cell-induced docetaxel chemotherapy resistance of PCa. Furthermore, recruited mast cells could also increase the phosphorylation of ATM at ser-1981 site, and inhibition of ATM activity could reverse mast cell-induced radiotherapy resistance. The in vivo mouse model with xenografted PCa C4-2 cells co-cultured with mast cells also confirmed that mast cells could increase PCa chemotherapy resistance via activating p38/p53/p21 signaling. Together, our results provide a new mechanism showing infiltrated mast cells could alter PCa chemotherapy and radiotherapy sensitivity via modulating the p38/p53/p21 signaling and phosphorylation of ATM. Targeting this newly identified signaling may help us better suppress PCa chemotherapy and radiotherapy resistance. PMID- 26625312 TI - Different prognostic impact of STK11 mutations in non-squamous non-small-cell lung cancer. AB - STK11 is commonly mutated in lung cancer. In light of recent experimental data showing that specific STK11 mutants could acquire oncogenic activities due to the synthesis of a short STK11 isoform, we investigated whether this new classification of STK11 mutants could help refine its role as a prognostic marker. We conducted a retrospective high-throughput genotyping study in 567 resected non-squamous non-small-cell lung cancer (NSCLC) patients. STK11 exons 1 or 2 mutations (STK11ex1-2) with potential oncogenic activity were analyzed separately from exons 3 to 9 (STK11ex3-9). STK11ex1-2 and STK11ex3-9 mutations occurred in 5% and 14% of NSCLC. STK11 mutated patients were younger (P = .01) and smokers (P< .0001). STK11 mutations were significantly associated with KRAS and inversely with EGFR mutations. After a median follow-up of 7.2 years (95%CI 6.8-.4), patients with STK11ex1-2 mutation had a median OS of 24 months (95%CI 15 57) as compared to 69 months (95%CI 56-93) for wild-type (log-rank, P = .005) and to 91 months (95%CI 57-unreached) for STK11ex3-9 mutations (P = .003). In multivariate analysis, STK11ex1-2 mutations remained associated with a poor prognosis (P = .002). Results were validated in two public datasets. Western blots showed that STK11ex1-2 mutatedtumors expressed short STK11 isoforms. Finally using mRNAseq data from the TCGA cohort, we showed that a stroma-derived poor prognosis signature was enriched in STK11ex1-2 mutated tumors. All together our results show that STK11ex1-2 mutations delineate an aggressive subtype of lung cancer for which a targeted treatment through STK11 inhibition might offer new opportunities. PMID- 26625311 TI - Suppression of tumor angiogenesis by metformin treatment via a mechanism linked to targeting of HER2/HIF-1alpha/VEGF secretion axis. AB - Anti-angiogenesis is currently considered as one of the major antitumor strategies for its protective effects against tumor emergency and later progression. The anti-diabetic drug metformin has been demonstrated to significantly inhibit tumor angiogenesis based on recent studies. However, the mechanism underlying this anti-angiogenic effect still remains an enigma. In this study, we investigated metformin-induced inhibitory effect on tumor angiogenesis in vitro and in vivo. Metformin pretreatment significantly suppressed tumor paracrine signaling-induced angiogenic promotion even in the presence of heregulin (HRG)-beta1 (a co-activator of HER2) pretreatment of HER2+ tumor cells. Similar to that of AG825, a specific inhibitor of HER2 phosphorylation, metformin treatment decreased both total and phosphorylation (Tyr 1221/1222) levels of HER2 protein and significantly reduced microvessel density and the amount of Fitc conjugated Dextran leaking outside the vessel. Furthermore, our results of VEGF neutralizing and -rescuing tests showed that metformin markedly abrogated HER2 signaling-induced tumor angiogenesis by inhibiting VEGF secretion. Inhibition of HIF-1alpha signaling by using RNAi or YC-1, a specific inhibitor of HIF-1alpha synthesis, both completely diminished mRNA level of VEGF and greatly inhibited endothelial cell proliferation promoted by HER2+ tumor cell-conditioned medium in both the absence and presence of HRG-beta1 pretreatment. Importantly, metformin treatment decreased the number of HIF-1alpha nucleus positive cells in 4T1 tumors, accompanied by decreased microvessel density. Our data thus provides novel insight into the mechanism underlying the metformin-induced inhibition of tumor angiogenesis and indicates possibilities of HIF-1alpha-VEGF signaling axis in mediating HER2-induced tumor angiogenesis. PMID- 26625314 TI - Critical role of PPARgamma in myeloid-derived suppressor cell-stimulated cancer cell proliferation and metastasis. AB - Lysosomal acid lipase (LAL) is a key enzyme controlling neutral lipid metabolic signaling in myeloid-derived suppressor cells (MDSCs). MDSCs from LAL-deficient (lal-/-) mice directly stimulate cancer cell proliferation. PPARgamma ligand treatment inhibited lal-/- MDSCs stimulation of tumor cell growth and metastasis in vivo, and tumor cell proliferation and migration in vitro. In addition, PPARgamma ligand treatment impaired lal-/- MDSCs transendothelial migration, and differentiation from lineage-negative cells. The corrective effects of PPARgamma ligand on lal-/- MDSCs functions were mediated by regulating the mammalian target of rapamycin (mTOR) pathway, and subsequently blocking MDSCs ROS overproduction. Furthermore, in the myeloid-specific dominant-negative PPARgamma (dnPPARgamma) overexpression bitransgenic mouse model, tumor growth and metastasis were enhanced, and MDSCs from these mice stimulated tumor cell proliferation and migration. MDSCs with dnPPARgamma overexpression showed increased transendothelial migration, overactivation of the mTOR pathway, and ROS overproduction. These results indicate that PPARgamma plays a critical role in neutral lipid metabolic signaling controlled by LAL, which provides a mechanistic basis for clinically targeting MDSCs to reduce the risk of cancer proliferation, growth and metastasis. PMID- 26625313 TI - Novel variants in MLL confer to bladder cancer recurrence identified by whole exome sequencing. AB - Bladder cancer (BC) is distinguished by high rate of recurrence after surgery, but the underlying mechanisms remain poorly understood. Here we performed the whole-exome sequencing of 37 BC individuals including 20 primary and 17 recurrent samples in which the primary and recurrent samples were not from the same patient. We uncovered that MLL, EP400, PRDM2, ANK3 and CHD5 exclusively altered in recurrent BCs. Specifically, the recurrent BCs and bladder cancer cells with MLL mutation displayed increased histone H3 tri-methyl K4 (H3K4me3) modification in tissue and cell levels and showed enhanced expression of GATA4 and ETS1 downstream. What's more, MLL mutated bladder cancer cells obtained with CRISPR/Cas9 showed increased ability of drug-resistance to epirubicin (a chemotherapy drug for bladder cancer) than wild type cells. Additionally, the BC patients with high expression of GATA4 and ETS1 significantly displayed shorter lifespan than patients with low expression. Our study provided an overview of the genetic basis of recrudescent bladder cancer and discovered that genetic alterations of MLL were involved in BC relapse. The increased modification of H3K4me3 and expression of GATA4 and ETS1 would be the promising targets for the diagnosis and therapy of relapsed bladder cancer. PMID- 26625315 TI - The pepper's natural ingredient capsaicin induces autophagy blockage in prostate cancer cells. AB - Capsaicin, the pungent ingredient of red hot chili peepers, has been shown to have anti-cancer activities in several cancer cells, including prostate cancer. Several molecular mechanisms have been proposed on its chemopreventive action, including ceramide accumulation, endoplasmic reticulum stress induction and NFkappaB inhibition. However, the precise mechanisms by which capsaicin exerts its anti-proliferative effect in prostate cancer cells remain questionable. Herein, we have tested the involvement of autophagy on the capsaicin mechanism of action on prostate cancer LNCaP and PC-3 cells.The results showed that capsaicin induced prostate cancer cell death in a time- and concentration-dependent manner, increased the levels of microtubule-associated protein light chain 3-II (LC3-II, a marker of autophagy) and the accumulation of the cargo protein p62 suggesting an autophagy blockage. Moreover, confocal microscopy revealed that capsaicin treatment increased lysosomes which co-localized with LC3 positive vesicles in a similar extent to that produced by the lysosomal protease inhibitors E64 and pepstatin pointing to an autophagolysosomes breakdown inhibition. Furthermore, we found that capsaicin triggered ROS generation in cells, while the levels of ROS decreased with N-acetyl-cysteine (NAC), a ROS scavenger. Co-treatment of cells with NAC and capsaicin abrogated the effects of capsaicin on autophagy and cell death. Normal prostate PNT2 and RWPE-1 cells were more resistant to capsaicin induced cytotoxicity and did not accumulate p62 protein.Taken together, these results suggest that ROS-mediated capsaicin-induced autophagy blockage contributes to antiproliferation in prostate cancer cells, which provides new insights into the anticancer molecular mechanism of capsaicin. PMID- 26625316 TI - Cooperative therapeutic anti-tumor effect of IL-15 agonist ALT-803 and co targeting soluble NKG2D ligand sMIC. AB - Shedding of the human NKG2D ligand MIC (MHC class I-chain-related molecule) from tumor cell surfaces correlates with progression of many epithelial cancers. Shedding-derived soluble MIC (sMIC) enables tumor immune escape through multiple immune suppressive mechanisms, such as disturbing natural killer (NK) cell homeostatic maintenance, impairing NKG2D expression on NK cells and effector T cells, and facilitating the expansion of arginase I+ myeloid suppressor cells. Our recent study has demonstrated that sMIC is an effective cancer therapeutic target. Whether targeting tumor-derived sMIC would enhance current active immunotherapy is not known. Here, we determined the in vivo therapeutic effect of an antibody co-targeting sMIC with the immunostimulatory IL-15 superagonist complex, ALT-803, using genetically engineered transplantable syngeneic sMIC+ tumor models. We demonstrate that combined therapy of a nonblocking antibody neutralizing sMIC and ALT-803 improved the survival of animals bearing sMIC+ tumors in comparison to monotherapy. We further demonstrate that the enhanced therapeutic effect with combined therapy is through concurrent augmentation of NK and CD8 T cell anti-tumor responses. In particular, expression of activation induced surface molecules and increased functional potential by cytokine secretion are improved greatly by the administration of combined therapy. Depletion of NK cells abolished the cooperative therapeutic effect. Our findings suggest that administration of the sMIC-neutralizing antibody can enhance the anti-tumor effects of ALT-803. With ALT-803 currently in clinical trials to treat progressive solid tumors, the majority of which are sMIC+, our findings provide a rationale for co-targeting sMIC to enhance the therapeutic efficacy of ALT-803 or other IL-15 agonists. PMID- 26625318 TI - A new method to estimate left ventricular circumferential midwall systolic function by standard echocardiography: Concordance between models and validation by speckle tracking. AB - BACKGROUND: Assessment of left ventricular circumferential (LVcirc) systolic function by standard echocardiography can be performed by estimating midwall fractional shortening (mFS) and stress-corrected mFS (ScmFS). Their determination is based on spherical or cylindrical LV geometric models, which often yield discrepant values. We developed a new model based on a more realistic truncated ellipsoid (TE) LV shape, and explored the concordance between models among hypertensive patients. We also compared the relationships of different mFS and ScmFS estimates with indexes of LVcirc systolic strain. METHODS: In 364 hypertensive subjects, mFS was determined using the spherical (mFSspher), cylindrical (mFScyl), and TE model (mFSTE). Corresponding values of ScmFSspher, ScmFScyl, and ScmFSTE were obtained. Global circumferential strain (GCS) and systolic strain rate (GCSR) were also measured by speckle tracking. RESULTS: The three models showed poor concordance for the estimation of mFS, with average differences ranging between 11% and 30% and wide limits of agreement. Similar results were found for ScmFS, where reclassification rates for the identification of abnormal LVcirc systolic function ranged between 18% and 29%. When tested against strain indexes, mFSTE and ScmFSTE showed the best correlations (R=0.81 and R=0.51, p<0.0001 for both) with GCS and GCSR. Multivariable analysis confirmed that mFSTE and ScmFSTE showed the strongest independent associations with LVcirc strain measures. CONCLUSIONS: Substantial discrepancies in LVcirc midwall systolic indexes exist between different models, supporting the need of model-specific normative data. The use of the TE model might provide indexes that show the best associations with established strain measures of LVcirc systolic function. PMID- 26625317 TI - Synergistic cooperation between ABT-263 and MEK1/2 inhibitor: effect on apoptosis and proliferation of acute myeloid leukemia cells. AB - In spite of intensive research to improve treatment of acute myeloid leukemia (AML) more than half of all patients continue to develop a refractory disease. Therefore there is need to improve AML treatment. The overexpression of the BCL-2 family anti-apoptotic members, like BCL-2 or BCL-xL has been largely reported in lymphoid tumors but also in AML and other tumors. To counteract the anti apoptotic effect of BCL-2, BH3 mimetics have been developed to target cancer cells. An increase in activity of ERK1/2 mitogen activated protein (MAP) kinase has also been reported in AML and might be targeted by MEK1/2 inhibitors. Hence, in the current work, we investigated whether the association of a BH3 mimetic such ABT-263 and the MEK1/2 inhibitor pimasertib (MEKI), was efficient to target AML cells. A synergistic increasing of apoptosis was observed in AML cell lines and in primary cells without affecting normal bone marrow cells. Such cooperation was confirmed on tumor growth in a mouse xenograft model of AML. In addition we demonstrated that MEKI sensitized the cells to apoptosis through its ability to promote a G1 cell cycle arrest. So, this combination of a MAP Kinase pathway inhibitor and a BH3 mimetic could be a promising strategy to improve the treatment of AML. PMID- 26625319 TI - Occupational exposure to hand-arm vibration. PMID- 26625320 TI - Attack the ATAK : "omicron?sigma ? thetaepsilon?sigma sigmaupsilonnuepsilonzetaepsilonupsilonxiepsilon, ?nuthetarhoomegapiomicronsigma MU? chiomegarhoiotazetaepsilontauomega" (ous o theos synezeuxe anthropos me horizeto) "what therefore God hath joined together, let not man put asunder". PMID- 26625321 TI - Importance of P-wave indices in stroke. PMID- 26625322 TI - Efficient attenuation of Friedreich's ataxia (FRDA) cardiomyopathy by modulation of iron homeostasis-human induced pluripotent stem cell (hiPSC) as a drug screening platform for FRDA. AB - BACKGROUND: Friedreich's ataxia (FRDA), a recessive neurodegenerative disorder commonly associated with hypertrophic cardiomyopathy, is caused by silencing of the frataxin (FXN) gene encoding the mitochondrial protein involved in iron sulfur cluster biosynthesis. METHODS: Application of our previously established FRDA human induced pluripotent stem cell (hiPSC) derived cardiomyocytes model as a platform to assess the efficacy of treatment with either the antioxidant coenzyme Q10 analog, idebenone (IDE) or the iron chelator, deferiprone (DFP), which are both under clinical trial. RESULTS: DFP was able to more significantly suppress synthesis of reactive oxygen species (ROS) than IDE at the dosages of 25 MUM and 10nM respectively which agreed with the reduced rate of intracellular accumulation of iron by DFP treatment from 25 to 50 MUM. With regard to cardiac electrical-contraction (EC) coupling function, decay velocity of calcium handling kinetics in FRDA-hiPSC-cardiomyocytes was significantly improved by DFP treatment but not by IDE. Further mechanistic studies revealed that DFP also modulated iron induced mitochondrial stress as reflected by mitochondria network disorganization and decline level of respiratory chain protein, succinate dehydrogenase (CxII) and cytochrome c oxidase (COXIV). In addition, iron-response protein (IRP-1) regulatory loop was overridden by DFP as reflected by resumed level of ferritin (FTH) back to basal level and the attenuated transferrin receptor (TSFR) mRNA level suppression thereby reducing further iron uptake. CONCLUSIONS: DFP modulated iron homeostasis in FRDA-hiPSC-cardiomyocytes and effectively relieved stress-stimulation related to cardiomyopathy. The resuming of redox condition led to the significantly improved cardiac prime events, cardiac electrical-coupling during contraction. PMID- 26625323 TI - Aortic prosthetic graft infection detected by (18)F-fluorodeoxyglucose positron emission tomography/computed tomography. PMID- 26625324 TI - Comparison of hybrid endovascular and open surgical repair for proximal aortic arch diseases. AB - BACKGROUND: To compare the outcomes of hybrid endovascular and open surgical repair for proximal aortic arch diseases. METHODS: A total of 55 consecutive patients with aortic arch aneurysm or aortic dissection involving any of zone 0 to 1 (39 male, age 63.4 +/- 14.3 years) underwent a hybrid endovascular repair (n=35) or open surgical repair (n=20) from 2006 to 2014 were analyzed retrospectively. Perioperative and late outcomes were compared. RESULTS: Baseline characteristics were similar between the two groups, except age and EuroSCORE II, which were higher in the hybrid group. Perioperative mortality or stroke was not significantly different between the two groups, however, tended to be lower in the hybrid repair group than in the open repair group (11.4% vs. 30.0%, p=0.144). Incidences of other morbidities did not differ. During follow-up, over-all survival was similar between the hybrid and the open repair was similar (87.3% vs. 79.7% at 1 year and 83.8% vs. 72.4% at 3 years; p=0.319). However, reintervention-free survival was significantly lower for hybrid repair compared with open repair (83.8% vs. 100% at 1 year and 65.7% vs. 100% at 3 years; p=0.022). CONCLUSIONS: Hybrid repair of proximal aortic disease showed comparable perioperative and late outcomes compared with open surgical repair despite a higher reintervention rate during follow-up. Therefore, hybrid repair may be considered as an acceptable treatment alternative to surgery especially in patients at high surgical risk. PMID- 26625325 TI - Exercise-induced pulmonary oedema in endurance triathletes. PMID- 26625326 TI - Metabolic syndrome in the non-pregnant state is associated with the development of preeclampsia. AB - BACKGROUND: The aim of this study was to investigate the association between metabolic syndrome in the non-pregnant state and the development of preeclampsia. METHODS: We enrolled 212,463 Korean women who had their first delivery between January, 2011 and December, 2012 and had undergone a national health screening examination through the National Health Insurance during the 1-2 years before their first delivery. Women who had hypertension in the non-pregnant state were excluded. The presence of metabolic syndrome was defined using the modified criteria published in National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS: The prevalence of metabolic syndrome in non-pregnant state was 1.2%. Preeclampsia developed in 3.1% and its prevalence among women with and without metabolic syndrome was 7.3% and 3.0%, respectively. The pre pregnancy prevalence of metabolic syndrome was higher in women who developed preeclampsia compared to that in those who had a normal pregnancy (1.1% vs. 2.8%; p<0.001). On multivariate regression analysis, women with metabolic syndrome had an increased risk of developing preeclampsia (odds ratio: 1.48; 95% CI: 1.26 to 1.74) compared to that in those without metabolic syndrome, after adjusting for age, family history of hypertension, smoking status, and pre-pregnancy body mass index. The risk of preeclampsia increased with a rise in the number of components of metabolic syndrome. CONCLUSION: Metabolic syndrome in the non-pregnant state was associated with the development of preeclampsia. Further studies are needed to evaluate whether early intervention for metabolic syndrome before pregnancy can decrease the risk of developing preeclampsia. PMID- 26625327 TI - Antithrombotic management in patients with atrial fibrillation undergoing coronary stent implantation: What is the impact of guideline adherence? AB - AIMS: Patients with atrial fibrillation (AF) who undergo percutaneous coronary intervention (PCI) and stenting require triple antithrombotic therapy according to current ESC guidelines. The purpose of this study was to assess guideline implementation and predictive factors of the prognosis related to ESC guideline adherence. METHODS AND RESULTS: We enrolled consecutive AF patients referred for PCI with stent from 2011 to 2014. Among 371 patients (72% male; mean age 76 +/- 11) followed up for 505 +/- 372 days (median 391, interquartile range 550 days), 118 (45%) undergoing elective coronary stenting and 41 (31%) among those with acute coronary syndrome were guideline adherent. Oral anticoagulation (OAC) before hospitalization was the only factor independently associated with guideline adherence (OR, 0.45; 95% CI 0.26-0.77; p=0.003). OAC underuse and antiplatelet therapy (APT) underuse were independently associated with increased risks of death (OR 5.55; 95% CI 2.42-13.47; p<0.0001 and OR 5.56; 95% CI, 2.17 14.65; p=0.0004, respectively) and major adverse cardiac events (MACE) (OR 4.18; 95% CI 2.05-8.79; p<0.0001 and OR 4.81; 95% CI, 2.09-11.18; p=0.0002, respectively). CONCLUSION: Guidelines for antithrombotic therapy in patients with AF who undergo PCI and stent implantation are still poorly followed in clinical practice. OAC and APT underuse were both associated with an increased risk of death and MACE in this population. PMID- 26625328 TI - Subacute recoil in bioresorbable vascular scaffold in a complex coronary lesion: A lesson from daily clinical practice. PMID- 26625329 TI - The heart after idarubicin overdose. Cardiac death in a patient with acute promyelocitic leukaemia. PMID- 26625330 TI - Echocardiography-based screening for rheumatic heart disease : What does borderline mean? PMID- 26625331 TI - Electrocardiographic differences in desmosomal and non-desmosomal arrhythmogenic cardiomyopathy. PMID- 26625332 TI - Interventions for the treatment of oral and oropharyngeal cancers: targeted therapy and immunotherapy. AB - BACKGROUND: Oral cancers are the sixth most common cancer worldwide, yet the prognosis following a diagnosis of oral cavity or oropharyngeal cancers remains poor, with approximately 50% survival at five years. Despite a sharp increase in research into molecularly targeted therapies and a rapid expansion in the number of clinical trials assessing new targeted therapies, their value for treating oral cancers is unclear. Therefore, it is important to summarise the evidence to determine the efficacy and toxicity of targeted therapies and immunotherapies for the treatment of these cancers. OBJECTIVES: To assess the effects of molecularly targeted therapies and immunotherapies, in addition to standard therapies, for the treatment of oral cavity or oropharyngeal cancers. SEARCH METHODS: We searched the following electronic databases: Cochrane Oral Health Group Trials Register (to 3 February 2015), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2015, Issue 1), MEDLINE via Ovid (1946 to 3 February 2015) and EMBASE via Ovid (1980 to 3 February 2015). We searched the US National Institutes of Health Trials Register (clinicaltrials.gov), the World Health Organization Clinical Trials Registry Platform, the American Society of Clinical Oncology conference abstracts and the Radiation Therapy Oncology Group clinical trials protocols for ongoing trials. We placed no restrictions on the language or date of publication. SELECTION CRITERIA: We included randomised controlled trials where more than 50% of participants had primary tumours of the oral cavity or oropharynx, and which compared targeted therapy or immunotherapy, plus standard therapy, with standard therapy alone. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the results of the electronic searches, extracted data and assessed the risk of bias of the included studies. We attempted to contact study authors for missing data or clarification where necessary. We combined sufficiently similar studies in meta-analyses using random effects models when there were at least four studies and fixed-effect models when fewer than four studies. We obtained or calculated a hazard ratio (HR) and 95% confidence interval (CI) for the primary outcomes where possible. For dichotomous outcomes, we reported risk ratios (RR) and 95% CIs. MAIN RESULTS: Twelve trials (2488 participants) satisfied the inclusion criteria. In the included trials, 12% of participants (298 participants) had tumours of the oral cavity and 59% (1468 participants) had oropharyngeal tumours. The remaining 29% had tumours of the larynx or hypopharynx and less than 1% had tumours at other sites.No included trial was at low risk of bias; seven had an unclear risk of bias, and five had a high risk of bias. We grouped trials by intervention type into three main comparisons: standard therapy plus epidermal growth factor receptor monoclonal antibody (EGFR mAb) therapy (follow-up period 24 to 70 months); standard therapy plus tyrosine kinase inhibitors (TKIs) (follow-up period 40 to 60 months) and standard therapy plus immunotherapy (follow-up period 24 to 70 months), all versus standard therapy alone.Moderate quality evidence showed that EGFR mAb therapy may result in 18% fewer deaths when added to standard therapy (HR of mortality 0.82; 95% CI 0.69 to 0.97; 1421 participants, three studies, 67% oropharyngeal tumours, 2% oral cavity tumours).There was also moderate quality evidence that EGFR mAb may result in 32% fewer locoregional failures when added to radiotherapy (RT) (HR 0.68; 95% CI 0.52 to 0.89; 424 participants, one study, 60% oropharyngeal tumours).A subgroup analysis separating studies by type of standard therapy (radiotherapy (RT) or chemoradiotherapy (CRT)) showed some evidence that adding EGFR mAb therapy to RT may result in a 30% reduction in the number of people whose disease progresses (HR 0.70; 95% CI 0.54 to 0.91; 424 participants, one study, 60% oropharyngeal tumours, unclear risk of bias). For the subgroup comparing EGFR mAb plus CRT with CRT alone there was insufficient evidence to determine whether adding EGFR mAb therapy to CRT impacts on progression-free survival (HR 1.08; 95% CI 0.89 to 1.32; 891 participants, one study, 70% oropharyngeal tumours, high risk of bias). The high subgroup heterogeneity meant that we were unable to pool these subgroups.There was evidence that adding cetuximab to standard therapy may result in increased skin toxicity and rash (RR 6.56; 95% CI 5.35 to 8.03; 1311 participants, two studies), but insufficient evidence to determine any difference in skin toxicity and rash in the case of nimotuzumab (RR 1.06; 95% CI 0.85 to 1.31; 92 participants, one study).There was insufficient evidence to determine whether TKIs added to standard therapy impacts on overall survival (HR 0.99; 95% CI 0.62 to 1.57; 271 participants, two studies; very low quality evidence), locoregional control (HR 0.89; 95% CI 0.53 to 1.49; 271 participants, two studies; very low quality evidence), disease-free survival (HR 1.51; 95% CI 0.61 to 3.71; 60 participants, one study; very low quality evidence) or progression-free survival (HR 0.80; 95% CI 0.51 to 1.28; 271 participants, two studies; very low quality evidence). We did find evidence of an increase in skin rash (erlotinib: RR 6.57; 95% CI 3.60 to 12.00; 191 participants, one study; lapatinib: RR 2.02; 95% CI 1.23 to 3.32; 67 participants, one study) and gastrointestinal complaints (lapatinib: RR 15.53; 95% CI 2.18 to 110.55; 67 participants, one study).We found very low quality evidence from one small trial that adding recombinant interleukin (rIL-2) to surgery may increase overall survival (HR 0.52; 95% CI 0.31 to 0.87; 201 participants, 62% oral cavity tumours, 38% oropharyngeal tumours) and there was insufficient evidence to determine whether rIL-2 impacts on adverse effects. AUTHORS' CONCLUSIONS: We found some evidence that adding EGFR mAb to standard therapy may increase overall survival, progression-free survival and locoregional control, while resulting in an increase in skin toxicity for some mAb (cetuximab).There is insufficient evidence to determine whether adding TKIs to standard therapies changes any of our primary outcomes.Very low quality evidence from a single study suggests that rIL-2 combined with surgery may increase overall survival compared with surgery alone. PMID- 26625333 TI - Is Stress Hyperglycemia a Predicting Factor of Developing Diabetes in Future? AB - OBJECTIVE: Stress hyperglycemia is a transient increase in blood glucose during an acute physiological stress in the absence of diabetes. Stress hyperglycemia can be occurred in certain clinical conditions such as trauma, burns, sepsis and strokes in adults. In this study we aimed to evaluate the incidence of stress hyperglycemia among patients admitted to the Firouzgar hospital. METHOD: In this analytical cross sectional study, all patients who referred to emergency department of Firouzgar hospital due to one of the causes of trauma, myocardial infarction (MI), subarachnoid hemorrhage (SAH), head trauma, sepsis, CVA, and abdominal surgery and had stress hyperglycemia during 2012-2014 were evaluated. Blood glucose test including random blood sugar (BS) and glycosylated hemoglobin (HbA1C) was performed for patients at admission. Patients with BS>180 mgmg/dl and no previous history of diabetes were enrolled in this study. Patients were referred to endocrinology clinic after 3 months of the first test and were re evaluated for diabetes mellitus. Fasting Blood Sugar (FBS), HbA1C and 2 h post glucose load test blood sugar were measured. Diabetes was confirmed if FBS was above 126 mg/dl or 2 h post glucose load BS was over 200 mg/dl. RESULT: A total of 98 (67 males & 31 women) patients enrolled in the study. No significant statistical relation found between mean of HBA1C at 3 months after admission and the background event (P=0.138). No statistical relation found between BMI and developing diabetes (P=0.352). 26 and 8 percent of the participants developed diabetes, and 25.8% were in pre-diabetic state. There was a statistical relation between gender and developing diabetes (P=0.027) and men developed diabetes more than women. Based on logistic regression the Odds Ratio (OR) was 1.017. CONCLUSION: Our study demonstrates a significant relationship between stress hyperglycemia and development of diabetes. Stress hyperglycemia could be a predicting factor of development of diabetes. PMID- 26625334 TI - Combinatorial Treatment of Bone Marrow Transplantation and Regulatory T Cells Improves Glycemia in Streptozotocin-diabetic Mice. AB - Autologous hematopoietic stem cell transplantation (HSCT) has limited benefits in patients with a long-duration of diabetes. To test whether a T regulatory cells (Tregs) and syngeneic bone marrow transplantation (syn-BMT) co-transplantation regimen will be effective, BMT+/-Tregs infusion was performed in streptozotocin diabetic mice with a long-duaration of diabetes. Diabetic status, pancreata morphometry and Tregs/Th17 balancing were tested on day 100 after transplantation. While hyperglycemia relapsed in mice receiving BMT monotherapy about 6 weeks after transplantation, combined therapy with BMT+Tregs improved hyperglycemia and C-peptides, preserved islet cell mass within 100 days after BMT. Although both groups BMT and BMT+Tregs induced Tregs/Th17 rebalancing, combined treatment of BMT+Tregs synergistically elevated TGF-beta1 and FoxP3 expression compared with BMT monotherapy. The sustained rebalance of Tregs/Th17 may be one possible explanation for the longer benefits of the combined treatment of BMT+Tregs over BMT monotherapy to mice with a long-duaration of diabetes. This observation of the therapeutic potential of BMCs+Tregs treatment may have important implications for clinical therapy for patients with a long-duration of diabetes. PMID- 26625335 TI - Phenotypic changes associated with the fitness cost in antibiotic resistant Escherichia coli strains. AB - BACKGROUND: the acquisition of antibiotic resistance in bacterial cells is often accompanied with a reduction of fitness in the absence of antibiotics, known as the "fitness cost". The magnitude of this fitness cost is an important biological parameter that influences the degree to which antibiotic resistant strains become widespread. However, the relationship between the fitness cost and comprehensive phenotypic and genotypic changes remains unclear. Here, we quantified the fitness cost of resistant strains obtained by experimental evolution in the presence of various antibiotics, and analyzed how the cost correlated to phenotypic and genotypic changes in the resistant strains. RESULTS: we measured the specific growth rate of the resistant strains in the presence of various concentrations of drugs or in their absence. In the absence of drugs, the resistant strains showed reductions of approximately 20% to 50% in growth rate compared with the parent strain, which corresponded to the fitness cost. We found that the decrease of the specific growth rate was correlated with overall expression changes between the parent and resistant strains, measured by the Euclid distance between expression profiles. We also found that there are a number of genes whose changes in expression levels were significantly correlated with the growth rate, which may account for the observed correlation between the fitness cost and overall expression changes. CONCLUSIONS: our analysis provides a basis for quantitative understanding of the mechanism of the fitness cost. This understanding may provide clues on how to influence the fitness cost that accompanies resistance acquisition and consequently how to limit the spread of antibiotic resistant strains. PMID- 26625336 TI - Screening of lignan patterns in Schisandra species using ultrasonic assisted temperature switch ionic liquid microextraction followed by UPLC-MS/MS analysis. AB - The ultrasonic assisted temperature-switch ionic liquid microextraction (UATS ILME) has been successfully applied in extracting of seven lignans from Schisandra. 1-Butyl-3-methylimidazolium tetrafluoroborate ([C4MIM][BF4]) aqueous solution was selected for extracting the target analytes in raw material at 80 degrees C. The lignans were deposited into a single drop by in situ forming 1 butyl-3-methylimidazolium hexafluorophosphate ([C4MIM][PF6]) by cooling down to 0 degrees C and centrifuging for 10min. The extracts were analyzed by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) in a robust multiple-reaction monitoring (MRM) mode in five minutes. Meanwhile, the proposed method was validated and successfully applied to the determination of seven lignans in twelve Schisandra species. The results indicated that UATS-ILME combined with UPLC-MS/MS is a powerful and practical tool, which has great potential for comprehensive quality control of herbal medicines. PMID- 26625337 TI - Combination of GC/FID/Mass spectrometry fingerprints and multivariate calibration techniques for recognition of antimicrobial constituents of Myrtus communis L. essential oil. AB - Myrtus communis L. is an aromatic evergreen shrub and its essential oil possesses known powerful antimicrobial activity. However, the contribution of each component of the plant essential oil in observed antimicrobial ability is unclear. In this study, chemical components of the essential oil samples of the plant were identified qualitatively and quantitatively using GC/FID/Mass spectrometry system, antimicrobial activity of these samples against three microbial strains were evaluated and, these two set of data were correlated using chemometrics methods. Three chemometric methods including principal component regression (PCR), partial least squares (PLS) and orthogonal projections to latent structures (OPLS) were applied for the study. These methods showed similar results, but, OPLS was selected as preferred method due to its predictive and interpretational ability, facility, repeatability and low time-consuming. The results showed that alpha-pinene, 1,8 cineole, beta-pinene and limonene are the highest contributors in antimicrobial properties of M. communis essential oil. Other researches have reported high antimicrobial activities for the plant essential oils rich in these compounds confirming our findings. PMID- 26625338 TI - Enrichment and separation of chlorogenic acid from the extract of Eupatorium adenophorum Spreng by macroporous resin. AB - A simple and efficient chromatographic method for separation of chlorogenic acid from Eupatorium adenophorum Spreng extract was developed. The adsorption properties of nine macroporous resins were evaluated. NKA-II resin showed much better adsorption/desorption properties. The adsorption of chlorogenic acid on NKA-II resin at 25 degrees C was well fitted to Langmuir isotherm model and pseudo-second-order kinetic model. The dynamic adsorption and desorption experiments were carried out on columns packed with NKA-II resin to optimize the separation process. The content of chlorogenic acid in the product increased to 22.17%, with a recovery yield of 82.41%. PMID- 26625339 TI - LC-MS/MS determination and comparative pharmacokinetics of strychnine, brucine and their metabolites in rat plasma after intragastric administration of each monomer and the total alkaloids from Semen Strychni. AB - A rapid, specific and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the simultaneous determination of strychnine, brucine, strychnine N-oxide and brucine N-oxide in rat plasma. Plasma samples were pretreated via simple protein precipitation with methanol and ephedrine hydrochloride was used as internal standard. Chromatographic separation was carried out on an ZORBAX Eclipse XDB-C18 column (2.1*150mm, 3.5MUm) by gradient elution with methanol and 10mM ammonium acetate (adjusted to pH 4.0 with formic acid). The quantification of the analytes was performed by mass spectrometry with TurboIonSpray ionization (ESI) inlet in the positive ion multiple reaction monitoring (MRM) mode. The results showed that the calibration curve was linear in the concentration range of 0.510~306.3ngmL(-1) for strychnine, brucine and 0.102~306.0ngmL(-1) for strychnine N-oxide and brucine N oxide, respectively. The intra- and inter-day precisions were less than 14.9%, and the accuracy ranged from 89.4 to 113% at three QC levels for the 4 analytes. The validated method was successfully applied to the pharmacokinetic study of strychnine, brucine, strychnine N-oxide and brucine N-oxide in rat plasma after oral administration of each monomer and the total alkaloids from Semen Strychni. After single oral administration of the total alkaloids from Semen Strychni at 4 dose levels, Cmax, AUC0-t of strychnine and brucine increased and were proportional to the oral doses. In comparative pharmacokinetics studies, no significant difference was found between each monomer and the total strychnos alkaloids on the pharmacokinetic parameters such as Cmax and AUC. Mean Cmax and AUC of strychnine and brucine were slight increased in the monomer groups in comparison to the total strychnos alkaloids groups, which suggested that some other alkaloids in the Semen Strychni may decrease the absorption of strychnine and brucine in body. PMID- 26625340 TI - Detecting Surgical Tools by Modelling Local Appearance and Global Shape. AB - Detecting tools in surgical videos is an important ingredient for context-aware computer-assisted surgical systems. To this end, we present a new surgical tool detection dataset and a method for joint tool detection and pose estimation in 2d images. Our two-stage pipeline is data-driven and relaxes strong assumptions made by previous works regarding the geometry, number, and position of tools in the image. The first stage classifies each pixel based on local appearance only, while the second stage evaluates a tool-specific shape template to enforce global shape. Both local appearance and global shape are learned from training data. Our method is validated on a new surgical tool dataset of 2 476 images from neurosurgical microscopes, which is made freely available. It improves over existing datasets in size, diversity and detail of annotation. We show that our method significantly improves over competitive baselines from the computer vision field. We achieve 15% detection miss-rate at 10(-1) false positives per image (for the suction tube) over our surgical tool dataset. Results indicate that performing semantic labelling as an intermediate task is key for high quality detection. PMID- 26625341 TI - Noninvasive Vascular Elastography With Plane Strain Incompressibility Assumption Using Ultrafast Coherent Compound Plane Wave Imaging. AB - Plane strain tensor estimation using non-invasive vascular ultrasound elastography (NIVE) can be difficult to achieve using conventional focus beamforming due to limited lateral resolution and frame rate. Recent developments in compound plane wave (CPW) imaging have led to high speed and high resolution imaging. In this study, we present the performance of NIVE using coherent CPW. We show the impact of CPW beamforming on strain estimates compared to conventional focus sequences. To overcome the inherent variability of lateral strains, associated with the low lateral resolution of linear array transducers, we use the plane strain incompressibility to constrain the estimator. Taking advantage of the approximate tenfold increase in frame rate of CPW compared with conventional focus imaging, we introduce a time-ensemble estimation approach to further improve the elastogram quality. By combining CPW imaging with the constrained Lagrangian speckle model estimator, we observe an increase in elastography quality (~ 10 dB both in signal-to-noise and contrast-to-noise ratios) over a wide range of applied strains (0.02 to 3.2%). PMID- 26625342 TI - Invasive plant species and litter decomposition: time to challenge assumptions. PMID- 26625343 TI - Finding support for theoretical tradeoffs in xylem structure and function. PMID- 26625345 TI - Current plant speciation research: unravelling the processes and mechanisms behind the evolution of reproductive isolation barriers. PMID- 26625344 TI - Minding (and bridging) the gap between evolutionary ecology and atmospheric biogeochemistry in a study of plant pollinator behaviour. PMID- 26625346 TI - The apoplast as battleground for plant-microbe interactions. PMID- 26625347 TI - Flooding stress signaling through perturbations in oxygen, ethylene, nitric oxide and light. PMID- 26625348 TI - Various shrug exercises can change scapular kinematics and scapular rotator muscle activities in subjects with scapular downward rotation syndrome. AB - Scapular dyskinesis, characterized by scapular downward rotation syndrome (SDRS) affects scapula-humeral rhythm and results in shoulder dysfunction. Previous study has led to the recommendation of standard shrug exercise to contend with SDRS and strengthen the upper trapezius (UT) muscle. However, few researchers have examined which shrug exercise is most effective. The aim of this research was to compare scapular kinematic changes and scapular rotator muscles activity across three different shrug exercises in SDRS. The amounts of scapular downward rotation were measured by a caliper and the scapular upward rotation angle was measured using two digital inclinometers. Surface electromyography was used to measure EMG amplitude from the UT, lower trapezius (LT), serratus anterior (SA), and levator scapula (LS). Seventeen subjects with SDRS were recruited for this study. The subjects performed three shrug exercises with 30 degrees shoulder abduction (preferred shrug, frontal shrug, and stabilization shrug). The stabilization shrug showed a significantly greater scapular upward rotation angle compared with the preferred shrug (P=0.004) and frontal shrug (P=0.006). The UT activity was significantly greater in the frontal shrug than in the preferred shrug (P=0.002). The UT/LS muscle activity ratio was also significantly greater in the frontal shrug than in the preferred shrug (P=0.004). The stabilization shrug should be preferred to enhance the upward rotation angle. In addition, the frontal shrug can be used as an effective method to increase UT activity and to decrease LS activity in SDRS. PMID- 26625349 TI - Prevalence of sinusitis and efficacy of intranasal corticosteroid treatment on asthmatic symptoms in asthmatic patients with rhinosinusitis: a pilot study. AB - BACKGROUND: Prevalence of sinusitis on sinus computed tomography (CT) in asthmatic patients and efficacy of intranasal corticosteroid treatment on asthmatic symptoms in asthmatic patients with rhinosinusitis on sinus CT is unclear. METHODS: Sinus CT of asthmatic patients were evaluated using the Lund Mackay system (LMS). Intranasal corticosteroid treatment (mometasone furoate) was newly added to symptomatic asthmatic patients with rhinosinusitis treated without intranasal corticosteroids, and the findings of the Asthma Control Test (ACT), Asthma Control Questionnaire in 5 items (ACQ5), spirometry, and sinus CT were evaluated before and 3 months after additional intranasal corticosteroid treatment. RESULTS: In a total of 160 asthmatic patients, rhinosinusitis and maxillary, ethmoidal, sphenoidal, and frontal sinusitis were observed in 75.0%, 70.0%, 53.1%, 33.1%, and 28.8%, respectively. Nasal symptoms and rhinophonia were observed in 81.9% and 72.5%, respectively, and patients with nasal symptoms and those with rhinophonia both showed significantly higher LMS scores in each sinus. Chronic rhinosinusitis (CRS) was observed in 66.9%, and these patients had significantly more severe asthma than the patients without CRS. In patients with CRS, patients with rhinophonia showed significantly higher LMS scores than those without rhinophonia. ACT, ACQ5, and the value of the forced expiratory volume in 1 second (FEV1) all significantly improved 3 months after the additive intranasal corticosteroid treatment in 24 patients, despite the fact that their LMS scores remained unchanged. CONCLUSION: Additive intranasal corticosteroid treatment may be an effective treatment option for symptomatic asthmatic patients with rhinosinusitis. PMID- 26625350 TI - Is Allelopathic Activity of Ipomoea murucoides Induced by Xylophage Damage? AB - Herbivory activates the synthesis of allelochemicals that can mediate plant-plant interactions. There is an inverse relationship between the activity of xylophages and the abundance of epiphytes on Ipomoea murucoides. Xylophagy may modify the branch chemical constitution, which also affects the liberation of allelochemicals with defense and allelopathic properties. We evaluated the bark chemical content and the effect of extracts from branches subjected to treatments of exclusion, mechanical damage and the presence/absence of epiphytes, on the seed germination of the epiphyte Tillandsia recurvata. Principal component analysis showed that branches without any treatment separate from branches subjected to treatments; damaged and excluded branches had similar chemical content but we found no evidence to relate intentional damage with allelopathy; however 1-hexadecanol, a defense volatile compound correlated positively with principal component (PC) 1. The chemical constitution of branches subject to exclusion plus damage or plus epiphytes was similar among them. PC2 indicated that palmitic acid (allelopathic compound) and squalene, a triterpene that attracts herbivore enemies, correlated positively with the inhibition of seed germination of T. recurvata. Inhibition of seed germination of T. recurvata was mainly correlated with the increment of palmitic acid and this compound reached higher concentrations in excluded branches treatments. Then, it is likely that the allelopathic response of I. murucoides would increase to the damage (shade, load) that may be caused by a high load of epiphytes than to damage caused by the xylophages. PMID- 26625351 TI - P-glycoprotein regulates Staphylococcus aureus enterotoxin B-stimulated interleukin-5 and thymic stromal lymphopoietin secretion in organotypic mucosal explants. AB - BACKGROUND: T-helper 2 (Th2) inflammation is a hallmark of chronic rhinosinusitis with nasal polyps (CRSwNP) although the pathogenesis is poorly understood. P glycoprotein (permeability glycoprotein, P-gp) is an efflux pump that is capable of regulating cytokine transport and is expressed within sinonasal mucosa. The purpose of this study was to examine if the oversecretion of interleukin 5 (IL-5) and thymic stromal lymphopoietin (TSLP) in CRSwNP could be explained through P-gp mediated secretory pathways. METHODS: Fifteen ethmoid mucosal explants were harvested from patients with CRS (n = 10) and CRSwNP (n = 10) and stimulated with Staphylococcus aureus enterotoxin B (SEB). P-gp was inhibited using zosuquidar trihydrochloride (herein Zosuquidar). P-gp expression was measured using real time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). IL-5, IL-8, and TSLP secretion were quantified using ELISA. RESULTS: P gp protein was overexpressed in CRSwNP (28.32 +/- 25.94 ng/mL per mg explant) as compared to CRS (10.74 +/- 8.61; p = 0.01, 2-tailed Mann-Whitney U test). There was no difference in messenger RNA (mRNA) expression. SEB induced a significant increase in IL-5 and TSLP but not IL-8 secretion relative to control in the CRSwNP explants only. Subsequent P-gp inhibition significantly reduced IL-5 and TSLP secretion (p = 0.04 for both, 2-tailed Student t test) to control levels. The concentration of IL-5 and TSLP secretion were strongly and significantly correlated to the concentration of P-gp within the same explant (IL-5: r = 0.791, p = 0.001; TSLP: r = 0.687, p = 0.003; 2-tailed Spearman's rank-order correlation). CONCLUSION: P-gp protein is expressed at higher concentrations in CRSwNP as compared to CRS. This overexpression directly contributes to the relative hypersecretion of IL-5 and TSLP. These findings suggest a novel mechanism for Th2 skewing in CRSwNP. PMID- 26625352 TI - Non-Invasive Monitoring of Temporal and Spatial Blood Flow during Bone Graft Healing Using Diffuse Correlation Spectroscopy. AB - Vascular infiltration and associated alterations in microvascular blood flow are critical for complete bone graft healing. Therefore, real-time, longitudinal measurement of blood flow has the potential to successfully predict graft healing outcomes. Herein, we non-invasively measure longitudinal blood flow changes in bone autografts and allografts using diffuse correlation spectroscopy in a murine femoral segmental defect model. Blood flow was measured at several positions proximal and distal to the graft site before implantation and every week post implantation for a total of 9 weeks (autograft n = 7 and allograft n = 10). Measurements of the ipsilateral leg with the graft were compared with those of the intact contralateral control leg. Both autografts and allografts exhibited an initial increase in blood flow followed by a gradual return to baseline levels. Blood flow elevation lasted up to 2 weeks in autografts, but this duration varied from 2 to 6 weeks in allografts depending on the spatial location of the measurement. Intact contralateral control leg blood flow remained at baseline levels throughout the 9 weeks in the autograft group; however, in the allograft group, blood flow followed a similar trend to the graft leg. Blood flow difference between the graft and contralateral legs (DeltarBF), a parameter defined to estimate graft-specific changes, was elevated at 1-2 weeks for the autograft group, and at 2-4 weeks for the allograft group at the proximal and the central locations. However, distal to the graft, the allograft group exhibited significantly greater DeltarBF than the autograft group at 3 weeks post-surgery (p < 0.05). These spatial and temporal differences in blood flow supports established trends of delayed healing in allografts versus autografts. PMID- 26625354 TI - PTSD and Trauma-Related Difficulties in Sexual Minority Women: The Impact of Perceived Social Support. AB - This study examined posttraumatic stress disorder (PTSD) and related symptoms among sexual minority (SM) and heterosexual women and the influence of social support on the relationship between SM status and symptoms. We hypothesized that SM women would endorse higher symptoms of PTSD and related difficulties and that social support would moderate the relationship between SM status and symptoms. The sample, women seeking treatment for PTSD related to interpersonal violence (n = 477; mean age = 36.07 years; 22.9% SM) completed clinician-administered measures of PTSD and self-report measures of trauma-related difficulties and social support. The rate of PTSD diagnosis was higher for SM women. Social support and SM status were significantly associated with suicidality, self perceptions, depression, somatic complaints, and functional impairment. The interaction between social support and SM status was significant for both functional impairment (beta = -.26) and somatic complaints (beta = -.39). High social support had an equal, positive effect among SM and nonminority women, whereas low social support had a greater negative impact among SM women. Results suggested the particular salience of social support on functioning and symptom severity among SM women and the potential importance of including interventions addressing social support into PTSD treatments for SM women. PMID- 26625353 TI - Mental Health Over Time in a Military Sample: The Impact of Alcohol Use Disorder on Trajectories of Psychopathology After Deployment. AB - To identify trajectories of depression and posttraumatic stress (PTS) symptom groups after deployment and determine the effect of alcohol use disorder on these trajectories, depression symptoms were modeled using the 9-item Patient Health Questionnaire in 727 Ohio National Guard members, and PTS symptoms were modeled using the PTSD Checklist in 472 Ohio National Guard members. There were 55.8% who were resistant to depression symptoms across the 4 years of study, and 41.5% who were resistant to PTS symptoms. There were 18.7% and 42.2% of participants who showed resilience (experiencing slightly elevated symptoms followed by a decline, according to Bonanno et al., 2002) to depression and PTS symptoms, respectively. Mild and chronic dysfunction constituted the smallest trajectory groups across disorders. Marital status, deployment to an area of conflict, and number of lifetime stressors were associated with membership into different latent groups for depression (unstandardized beta estimates range = 0.69 to 1.37). Deployment to an area of conflict, number of lifetime traumatic events and education predicted membership into different latent groups for PTS (significant unstandardized beta estimate range = 0.83 to 3.17). AUD was associated with an increase in both symptom outcomes (significant unstandardized beta estimate range = 0.20 to 9.45). These results suggested that alcohol use disorder may have contributed substantially to trajectories of psychopathology in this population. PMID- 26625356 TI - Erratum for "A Systematic Review of Dropout from Psychotherapy for Posttraumatic Stress Disorder among Iraq and Afghanistan Combat Veterans". PMID- 26625355 TI - Predictors of Initiation and Engagement of Cognitive Processing Therapy Among Veterans With PTSD Enrolled in Collaborative Care. AB - Collaborative care (CC) increases access to evidence-based pharmacotherapy and psychotherapy. The study aim was to identify the characteristics of rural veterans receiving a telemedicine-based CC intervention for posttraumatic stress disorder (PTSD) who initiated and engaged in cognitive processing therapy (CPT) delivered via interactive video. Veterans diagnosed with PTSD were recruited from 11 community-based outpatient clinics (N = 133). Chart abstraction identified all mental health encounters received during the 12-month study. General linear mixed models were used to identify characteristics that predicted CPT initiation and engagement (attendance at 8 or more sessions). For initiation, higher PTSD severity according to the Clinician Administered PTSD Scale (d = -0.39, p = .038) and opt-out recruitment (vs. self-referral; d = -0.49, p = .010) were negative predictors. For engagement, major depression (d = -1.32, p = .006) was a negative predictor whereas a pending claim for military service connected disability (d = 2.02, p = .008) was a positive predictor. In general, veterans enrolled in CC initiated and engaged in CPT at higher rates than usual care. Those with more severe symptoms and comorbidity, however, were at risk of not starting or completing CPT. PMID- 26625357 TI - Hidden Perils of the "Wild Blue Yonder" after Traumatic Brain Injury. PMID- 26625358 TI - Improved Classification of Lung Cancer Using Radial Basis Function Neural Network with Affine Transforms of Voss Representation. AB - Lung cancer is one of the diseases responsible for a large number of cancer related death cases worldwide. The recommended standard for screening and early detection of lung cancer is the low dose computed tomography. However, many patients diagnosed die within one year, which makes it essential to find alternative approaches for screening and early detection of lung cancer. We present computational methods that can be implemented in a functional multi genomic system for classification, screening and early detection of lung cancer victims. Samples of top ten biomarker genes previously reported to have the highest frequency of lung cancer mutations and sequences of normal biomarker genes were respectively collected from the COSMIC and NCBI databases to validate the computational methods. Experiments were performed based on the combinations of Z-curve and tetrahedron affine transforms, Histogram of Oriented Gradient (HOG), Multilayer perceptron and Gaussian Radial Basis Function (RBF) neural networks to obtain an appropriate combination of computational methods to achieve improved classification of lung cancer biomarker genes. Results show that a combination of affine transforms of Voss representation, HOG genomic features and Gaussian RBF neural network perceptibly improves classification accuracy, specificity and sensitivity of lung cancer biomarker genes as well as achieving low mean square error. PMID- 26625360 TI - Meningococcal Disease: Epidemiology and Early Effects of Immunization Programs. PMID- 26625361 TI - Update From the Advisory Committee on Immunization Practices. PMID- 26625359 TI - Identification of New Regions in HIV-1 gp120 Variable 2 and 3 Loops that Bind to alpha4beta7 Integrin Receptor. AB - BACKGROUND: The gut mucosal homing integrin receptor alpha4beta7 present on activated CD4+ T cells interacts with the HIV-1 gp120 second variable loop (V2). Case control analysis of the RV144 phase III vaccine trial demonstrated that plasma IgG binding antibodies specific to scaffolded proteins expressing the first and second variable regions (V1V2) of HIV envelope protein gp120 containing the alpha4beta7 binding motif correlated inversely with risk of infection. Subsequently antibodies to the V3 region were also shown to correlate with protection. The integrin receptor alpha4beta7 was shown to interact with the LDI/V motif on V2 loop but recent studies suggest that additional regions of V2 loop could interact with the alpha4beta7. Thus, there may be several regions on the V2 and possibly V3 loops that may be involved in this binding. Using a cell line, that constitutively expressed alpha4beta7 receptors but lacked CD4, we examined the contribution of V2 and V3 loops and the ability of V2 peptide-, V2 integrin-, V3-specific monoclonal antibodies (mAbs), and purified IgG from RV144 vaccinees to block the V2/V3-alpha4beta7 interaction. RESULTS: We demonstrate that alpha4beta7 on RPMI8866 cells bound specifically to its natural ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1) as well as to cyclic-V2 and cyclic-V3 peptides. This binding was inhibited by anti-alpha4beta7-specific monoclonal antibody (mAb) ACT-1, mAbs specific to either V2 or V3 loops, and by purified primary virions or infectious molecular clones expressing envelopes from acute or chronic subtypes A, C, and CRF01_AE viruses. Plasma from HIV-1 infected Thai individuals as well as purified IgG from uninfected RV144 vaccinees inhibited (0-50%) the binding of V2 and V3 peptides to alpha4beta7. CONCLUSION: Our results indicate that in addition to the tripeptide LDI/V motif, other regions of the V2 and V3 loops of gp120 were involved in binding to alpha4beta7 receptors and this interaction was blocked by anti-V2 peptide, anti-V2 integrin, and anti-V3 antibodies. The ability of purified IgG from some of the uninfected RV144 vaccinees to inhibit alpha4beta7 raises the hypothesis that anti-V2 and anti-V3 antibodies may play a role in blocking the gp120-alpha4beta7 interaction after vaccination and thus prevent HIV-1 acquisition. PMID- 26625362 TI - Role of Human Bocavirus in Upper Respiratory Tract Infections and Acute Otitis Media. AB - BACKGROUND: Human bocavirus (HBoV) is a newly described parvovirus. HBoV1 has been associated with respiratory infections, including acute otitis media (AOM), but the knowledge on the significance of HBoV1 in upper respiratory tract infections (URI) and AOM in relation to other respiratory viruses is limited. The objective of this study was to compare the rate of detection of HBoV1 to that of other respiratory viruses in specimens from children with URI, with and without AOM complication. METHODS: Nasopharyngeal secretions (NPS) were collected during URI from healthy children (6-35 months) followed prospectively for 1 year; specimens have been previously analyzed for broad spectrum of respiratory viruses. Archived NPS were analyzed for HBoV1 using a high-throughput, quantitative polymerase chain reaction method. RESULTS: Seven hundred and seven NPS samples collected during URI episodes from 201 children were studied for HBoV1. A total of 94 (47%) children tested positive for HBoV1 DNA during 172 (24%) URI episodes; HBoV1 was present as the only virus in 44 (6%) URI episodes. Overall, 37% of URI episodes were complicated by AOM. Of URI associated with single virus (n = 303), the rate of AOM complicating URI associated with HBoV1 only was 52% (23 of 44); this was a higher AOM rate, compared to that of other respiratory viruses. CONCLUSIONS: Among URI associated with single respiratory virus, HBoV1-URI was commonly associated with AOM complication. The important role of HBoV1 on AOM pathogenesis needs to be studied further. PMID- 26625363 TI - Risk Factors for Pneumococcal Colonization of the Nasopharynx in Alaska Native Adults and Children. AB - BACKGROUND: Alaska Native children have high invasive pneumococcal disease (IPD) rates, and lack of in-home running water has been shown to have a significant association with infection. Pneumococcal conjugate vaccines reduced IPD; however, this population saw substantial replacement disease and colonization with nonvaccine serotypes. We evaluated risk factors for nasopharyngeal pneumococcal colonization in Alaska Native adults and children. METHODS: We conducted annual surveys from 2008 through 2011 of residents of all ages in 8 rural Alaskan villages. Interviews were conducted, medical charts were reviewed, and nasopharyngeal swabs were cultured for Streptococcus pneumoniae. Multivariate logistic regression models were developed for 3 age groups (under 10 years, 10-17 years, and 18 years and older) to determine risk factors for colonization. RESULTS: We obtained 12 535 nasopharyngeal swabs from 4980 participants. Our population lived in severely crowded conditions, and 48% of households lacked in home running water. In children <10 years, colonization was associated with lack of in-home running water, household crowding, and more children in the home. Pneumococcal vaccination status was not associated with colonization. In older children and adults, increased number of persons in the household was associated with pneumococcal colonization. CONCLUSIONS: Higher colonization prevalence may partially explain increased IPD rates seen in those lacking in-home water services. Improving availability of sanitation services and reducing household crowding may reduce the burden of IPD in this population. PMID- 26625364 TI - Pediatric Pleural Empyema in the Province of Quebec: Analysis of a 10-Fold Increase Between 1990 and 2007. AB - BACKGROUND: Although the frequency of pneumonia has decreased over time, an increase in pleural empyema has been observed in different settings worldwide. This study assessed the epidemiology of community-acquired pediatric pleural empyema in the province of Quebec through validation of cases found in a hospitalization discharge database. METHODS: We used the national administrative database of hospitalization to identify children (6 months-14 years) hospitalized for pleural empyema or pleural effusion with drainage from January 1990 until December 2007 and reviewed their medical charts. Patients with pleural effusion secondary to chest trauma, thoracic surgery, malignancies, cardiac failure, or metabolic disorders were excluded. RESULTS: Predictive positive value (PPV) of empyema code in any position among discharge diagnostics in the administrative database was 86.5% (95% confidence interval: 81.9%-90.3%). After chart revision, 292 met the inclusion criteria. Age-adjusted incidence of pleural empyema in the pediatric population increased from 0.23 in 1990 to 4.01/100,000 person-years in 2007. A bacterial pathogen was identified in 46.5%; Streptococcus pneumoniae (Sp) (42%) and S pyogenes (30%) were most frequent. There was no obvious change in the PPV and proportions of children with chronic disease or asthma and in identified pathogens over time, but an increase in pre-admission respiratory symptoms duration (from 3.8 days to 5.7) and nonsteroidal anti-inflammatory drug use (from 0% to 19%) was observed. CONCLUSIONS: From 1990 to 2007, we observed a 10-fold increase in the incidence of pediatric hospitalizations associated with pleural empyema. This increase preceded the introduction of a pneumococcal conjugated vaccine program in Quebec. Sp remained the major pathogen identified. PMID- 26625365 TI - Are Elevated Vancomycin Serum Trough Concentrations Achieved Within the First 7 Days of Therapy Associated With Acute Kidney Injury in Children? AB - BACKGROUND: In 2008, the empiric vancomycin dosing recommendation in children at our institution was changed from 40 to 60 mg/kg per day. Subsequently, an increased incidence of acute kidney injury (AKI) in patients receiving vancomycin was suspected. The objective of this study was to evaluate AKI in children receiving vancomycin and to determine risk factors for AKI development. METHODS: Medical records of patients aged 30 days through 17 years who received vancomycin for at least 72 hours between January and December 2007 (40 mg/kg per day) and January and December 2010 (60 mg/kg per day) were reviewed. Patients with cystic fibrosis, an elevated baseline serum creatinine, or without a serum creatinine concentration obtained after receipt of vancomycin were excluded. Acute kidney injury was defined using adapted pediatric RIFLE criteria as an increase in serum creatinine from baseline of 50% or more. RESULTS: Acute kidney injury occurred in 19.4% of the 859 children included, with no difference between the 2007 and 2010 periods (18.8% vs 20%, respectively; P = .636). Intensive care unit admission (odds ratio [OR], 1.86; 95% confidence interval [CI], 1.20-2.94) and an initial vancomycin trough concentration >=15 mg/L (OR, 2.18; 95% CI, 1.21-3.92) were determined to be significantly associated with AKI. CONCLUSIONS: These results suggest an initial vancomycin serum trough concentration of >=15 mg/L and intensive care unit admission are predictors of AKI in this pediatric population. PMID- 26625366 TI - Rifapentine Pharmacokinetics and Tolerability in Children and Adults Treated Once Weekly With Rifapentine and Isoniazid for Latent Tuberculosis Infection. AB - BACKGROUND: In a phase 3, randomized clinical trial (PREVENT TB) of 8053 people with latent tuberculosis infection, 12 once-weekly doses of rifapentine and isoniazid had good efficacy and tolerability. Children received higher rifapentine milligram per kilogram doses than adults. In the present pharmacokinetic study (a component of the PREVENT TB trial), rifapentine exposure was compared between children and adults. METHODS: Rifapentine doses in children ranged from 300 to 900 mg, and adults received 900 mg. Children who could not swallow tablets received crushed tablets. Sparse pharmacokinetic sampling was performed with 1 rifapentine concentration at 24 hours after drug administration (C24). Rifapentine area under concentration-time curve (AUC) was estimated from a nonlinear, mixed effects regression model (NLME). RESULTS: There were 80 children (age: median, 4.5 years; range, 2-11 years) and 77 adults (age: median, 40 years; all >=18 years) in the study. The geometric mean rifapentine milligram per kilogram dose was greater in children than in adults (children, 23 mg/kg; adults, 11 mg/kg). Rifapentine geometric mean AUC and C24 were 1.3-fold greater in children (all children combined) than in adults. Children who swallowed whole tablets had 1.3-fold higher geometric mean AUC than children who received crushed tablets, and children who swallowed whole tablets had a 1.6-fold higher geometric mean AUC than adults. The higher rifapentine doses in children were well tolerated. To obtain rifapentine exposures comparable in children to adults, dosing algorithms modeled by NLME were developed. CONCLUSIONS: A 2-fold greater rifapentine dose for all children resulted in a 1.3-fold higher AUC compared to adults administered a standard dose. Use of higher weight-adjusted rifapentine doses for young children are warranted to achieve systemic exposures that are associated with successful treatment of latent tuberculosis infection in adults. PMID- 26625367 TI - Potential Utility of Multiplex Amplification Respiratory Viral Panel Testing in the Management of Acute Respiratory Infection in Children: A Retrospective Analysis. AB - BACKGROUND: Multiplex real-time polymerase chain reaction respiratory viral panel (RVP) testing offers enhanced test performance characteristics compared with older testing methods. However, the impact of RVP testing on physician antimicrobial prescription practices remains unclear. Our objective was to assess the potential relationship of RVP testing to physician treatment practices for children hospitalized with acute respiratory illness (ARI). METHODS: We performed a retrospective chart review of children hospitalized for ARI during peak prevalence of respiratory viral infections in 2009-2011. Demographics, diagnostic testing, antimicrobial use, and clinical outcomes were abstracted from the electronic medical record. Antimicrobial use was compared with RVP testing data. RESULTS: A total of 1727 patients met inclusion criteria. Of these patients, 254 (14.7%) children who were hospitalized for ARI received oseltamivir and 856 (49.6%) children received antibiotics. More children who received oseltamivir were positive for influenza by RVP (76.9% vs 18.0%; P < .0001). Children who underwent RVP testing received antibiotics more often than those who were not tested (53.7% vs 46.0%; P = .001), but children with a positive RVP test result received antibiotics less often (51.6% vs 67.0%; P = .003). A total of 5.8% of children who were positive for a viral pathogen by RVP had antibiotics discontinued. Antibiotics were started in fewer children when RVP results were positive (10.9% vs 100.0%; P < .0001). CONCLUSIONS: Respiratory viral panel testing was associated with more appropriate oseltamivir use in children hospitalized with ARI. Physicians started antibiotics more often in children with a negative RVP test result and occasionally discontinued antibiotics in children diagnosed with a viral pathogen. These results suggest that RVP testing may enhance physician decision-making when prescribing antimicrobials in children hospitalized with ARI. PMID- 26625368 TI - Toxocariasis: A Review for Pediatricians. AB - Toxocariasis is a parasitic disease caused by roundworms of cats and dogs. The disease is endemic throughout the United States and causes significant morbidity in children, including damage to the lungs, liver, or central nervous system, especially the eyes. Two well established clinical syndromes of disease include visceral and ocular toxocariasis. Symptoms of visceral toxocariasis include abdominal pain, cough, or wheezing. Vision loss or strabismus are common symptoms of ocular toxocariasis. Serologic testing for presence of Toxocara antibody is available, although a positive test result does not necessarily correlate with active clinical infection. Albendazole or mebendazole is the recommended treatment for visceral toxocariasis. Treatment options for ocular toxocariasis include corticosteroids or ophthalmic surgery; anthelminthic medications also may be used. Risk for toxocariasis can be reduced by handwashing after soil contact, routine pets deworming, discouraging geophagia, and appropriate disposal of pet feces. PMID- 26625369 TI - Age-Dependent Carriage of Kingella kingae in Young Children and Turnover of Colonizing Strains. AB - In a longitudinal study, Kingella kingae carriage rate was nil below 6 months of age, 1.5% at 6 months, 9.6% at 12 months, remained stable between 10.4% and 12.0% during the second year of life, and decreased significantly to 5.3% at 30 months. Replacement of carried strains occurred over time. PMID- 26625370 TI - Azithromycin Inhibits Macrophage Tumor Necrosis Factor Secretion in Response to Both Azithromycin-Susceptible and Azithromycin-Resistant Pneumococci. AB - We studied the effect of azithromycin (AZM) on macrophage responses to pneumococci. We found that exposure of pneumococci to AZM led to reduced tumor necrosis factor (TNF) secretion by macrophages; this effect was observed in response to both AZM-susceptible and AZM-resistant (AZM-R) pneumococci. PMID- 26625371 TI - Literature Review. PMID- 26625372 TI - A Systematic Approach to the Differential Diagnosis of Encephalitis in Children. PMID- 26625373 TI - Pediatric Cervicofacial Actinomycosis: An Unusual Cause of Head and Neck Masses. AB - Cervicofacial actinomycosis is an unusual cause of head and neck masses in children. This low prevalence of disease in children inevitably leads to delay in clinical recognition and often requires invasive intervention for diagnosis and curative therapy. We present an illustrative case and review cases of cervicofacial actinomycosis in the pediatric literature with particular attention to clinical presentation, course, and outcome. PMID- 26625374 TI - A Teenager Patient With Recurrent Pulmonary Abscesses. PMID- 26625375 TI - Antiviral Drug-Resistance Typing Reveals Compartmentalization and Dynamics of Acyclovir-Resistant Herpes Simplex Virus Type-2 (HSV-2) in a Case of Neonatal Herpes. AB - A neonate suffering from herpes simplex virus type 2 disease with central nervous system involvement developed an early recurrence under acyclovir therapy. Isolates from the cerebrospinal fluid and skin lesions were acyclovir resistant, while viruses from blood and trachea were not. Acyclovir combined with foscavir followed by long-term suppressive acyclovir therapy supported normal neurological development. PMID- 26625380 TI - Epidemiology of Dengue in Latin America. PMID- 26625381 TI - Clostridium difficile in the Pediatric Population of Monroe County, New York. AB - BACKGROUND: Clostridium difficile infection (CDI) incidence in hospitalized children has increased over the past decade and disease has been reported in the community. Therefore, population surveillance that includes nonhospitalized cases is important to accurately estimate the burden of CDI in children. We describe the epidemiology of CDI in the pediatric population of Monroe County, New York. METHODS: Active, laboratory, and population-based surveillance for CDI has been ongoing in Monroe County through the Emerging Infections Program of the Centers for Disease Control and Prevention since 2010. Infants less than 12 months of age are excluded. RESULTS: In 2010, the incidence of CDI in the pediatric population was 33.8 per 100 000 population, which increased to 45.8 in 2011and remained stable in 2012. Seventy-one percent of the CDI cases were community-associated, 60% had an underlying medical condition, and 71% received antibiotics before their illness. The North American pulsed-field gel electrophoresis type 1 (NAP1) epidemic strain was identified in 27% of cultured stool specimens. CONCLUSIONS: Clostridium difficile infection has emerged as a disease affecting children in both the community and hospital settings, with a higher proportion of community illness in our population. The majority of children with CDI had chronic underlying conditions and prior antibiotic exposure. To prevent CDI in this population, the judicious use of antibiotics, especially in the outpatient setting, may be the best strategy. Further population-based studies are warranted to determine preventable risk factors for CDI in the pediatric population. PMID- 26625382 TI - Characterization of the Acute Inflammatory Response in Measles Infection. AB - Among 167 hospitalized children with measles, circulating concentrations of interleukin (IL)-6, IL-1beta, IL-1Ra, IL-4, interferon (IFN)-alpha, IFN-beta, and T helper-17 cytokines were low, whereas leukopenia, increased lactate dehydrogenase, IL-18, and IFN-gamma concentrations characterized the inflammatory response. In addition to understanding measles-induced immunologic responses, this profile may assist in differential diagnosis. PMID- 26625383 TI - The Economics of Strategies to Reduce Respiratory Syncytial Virus Hospitalizations in Alaska. AB - BACKGROUND: Alaska Native infants experience high rates of respiratory syncytial virus (RSV) hospitalizations. Through 2008, Alaska administered a 7-dose (maximum) palivizumab regime to high-risk infants from October to May. In 2009, the maximum was reduced to 3 doses for 32- to 34-week preterm babies and 6 doses for other groups. METHODS: We used 11 years of data and regional Medicaid reimbursement rates to model the cost effectiveness of 4 palivizumab intervention strategies to reduce RSV hospitalizations among Alaskan infants including: current strategy, old strategy (1998-2008), and 2 hypothetical strategies using the current strategy plus 1 or 3 doses to all newborn infants during the RSV season. RESULTS: The current strategy represents 5 hospitalizations averted per year for the palivizumab cohort (~50-56 children) at ~$52 846 per hospitalization averted, compared with no intervention. Compared with the old strategy, the mean cost per hospitalization prevented for the current strategy was 63% lower, net program costs were 85% lower, and the mean hospitalizations prevented were 27% lower. Compared with current strategy only, the addition of 1 dose to all newborns during the RSV season could decrease the mean cost per hospitalization prevented by 23%, increase the number of hospitalizations prevented by 2.5-fold, and increase the net programmatic costs by 3.3-fold; administering up to 3 doses to infants further reduced hospitalizations and increased costs. CONCLUSIONS: The current palivizumab strategy improved the cost-effectiveness ratio compared with the old strategy. Further improvement could be obtained by adding doses for Alaskan Native newborns during the RSV season; however, programmatic costs would increase. PMID- 26625384 TI - Expressed Breast Milk as a Predictor of Neonatal Yeast Colonization in an Intensive Care Setting. AB - BACKGROUND: Yeast colonization is a predictor for invasive infection in neonates. Candida albicans and Candida parapsilosis are leading causes of invasive fungal infection (IFI) in this population. This study examines maternal breast milk as a predictor of colonization of infants with yeast. METHODS: Inclusion criteria were admission longer than 72 hours to the neonatal intensive care unit and parental consent. Cultures of expressed breast milk, when available, and swabs from oral, rectal, and inguinal sites were obtained weekly for 12 weeks, or until discharge, transfer, or death. Cultures were analyzed using standard laboratory methods. Clinical information was extracted from medical records. RESULTS: One hundred thirty infants were enrolled from February 2011 to November 2012. Cultures were obtained in 129 patients. The median (interquartile range [IQR]) gestational age was 34.4 weeks (33.1-37.1 weeks). The median (IQR) birth weight was 2157.5 g (1740-3060 g). No infants developed IFIs. Twenty-nine (22%) infants were colonized with yeast. Potential correlates for colonization in univariate analysis included exposure to antenatal steroids, postnatal antibiotics, and receipt of breast milk containing yeast. Potential correlates that remained after multivariable logistic regression included exposure to antenatal steroids and receipt of breast milk containing yeast. In cases in which yeast was recovered from an individual infant and from the breast milk received by that infant, there was only 30% concordance between yeast species. DISCUSSION: Recovery of yeast from breast milk is associated with colonization with yeast in the neonate. Because Candida transmission via breast milk had a 30% concordance, breast milk is only one of several ways colonization occurs. Further study is needed on mechanisms of colonization. PMID- 26625385 TI - Hepatotoxicity in Children Receiving Isoniazid Therapy for Latent Tuberculosis Infection. AB - BACKGROUND: The frequency of isoniazid hepatotoxicity is low in children receiving isoniazid therapy for latent tuberculosis infection. However, isoniazid hepatotoxicity may cause liver failure and death. We evaluated children who developed isoniazid hepatotoxicity to determine demographic and clinical characteristics. METHODS: A retrospective review was performed of medical records of 1582 patients aged <18 years who were evaluated for isoniazid therapy at a public health department and clinic in California. RESULTS: There were 13 patients who had latent tuberculosis infection and who developed isoniazid hepatotoxicity (0.8% of all 1582 patients who started isoniazid; 1.1% of 1235 patients who completed the 9-month isoniazid therapy). There were 8 girls (62%) and 9 Hispanic children (69%) who had hepatotoxicity. Sex, age, and race were not independently associated with the development of isoniazid hepatotoxicity. Symptoms and signs of hepatotoxicity were present in 11 of the 13 patients, and 2 other patients had alanine aminotransferase >5 times the upper limit of normal and no signs of hepatotoxicity. The most common symptoms included abdominal pain, anorexia, vomiting, and nausea. Most patients developed hepatotoxicity within 6 months of starting isoniazid, but 3 patients developed hepatotoxicity >=6 months after starting isoniazid. After stopping isoniazid, the alanine aminotransferase levels decreased to normal in all patients. CONCLUSIONS: In children who have latent tuberculosis infection, isoniazid hepatotoxicity has low frequency and typically is reversible when isoniazid is stopped. Evidence of late drug-induced liver injury indicates the importance of monitoring symptoms and serum transaminases throughout isoniazid therapy. PMID- 26625386 TI - Second Bacteremia During Antibiotic Treatment in Children With Acute Myeloid Leukemia: A Report From the Canadian Infections in Acute Myeloid Leukemia Research Group. AB - BACKGROUND: The risk of second bacteremia during antibiotic treatment for initial bacteremia is unknown in high-risk populations. Our objectives were to describe the prevalence of second bacteremia during treatment and identify risk factors in children with acute myeloid leukemia (AML). METHODS: We conducted a retrospective, population-based cohort study that included children and adolescents with de novo, non-M3 AML who were diagnosed and treated between January 1, 1995 and December 31, 2004 at 15 Canadian centers. Patients were monitored for bacteremia during chemotherapy until completion of treatment, hematopoietic stem cell transplantation, relapse, refractory disease, or death. RESULTS: There were 290 episodes of bacteremia occurring in 185 (54.3%) of 341 children. Eighteen (6.2%) had a second bacteremia while receiving antibiotic treatment. Two episodes of second bacteremia were complicated by sepsis; there were no infection-related deaths. Eleven episodes (61.1%) had either an initial Gram-positive and subsequent Gram-negative bacteremia or initial Gram-negative followed by Gram-positive bacteremia. Days receiving corticosteroids (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.07-1.12; P < .0001), cumulative dose of corticosteroids (OR, 1.04; 95% CI, 1.00-1.08; P = .035), and days of neutropenia from start of course to initial bacteremia (OR, 1.07; 95% CI, 1.02 1.12; P = .007) were significantly associated with second bacteremia. CONCLUSIONS: In pediatric AML, 6% of patients will experience a second bacteremia during antibiotic treatment; duration of corticosteroid exposure and neutropenia are risk factors. These patients remain at high risk for second bacteremia after identification of the initial bacteremia and warrant continued broad-spectrum treatment during profound neutropenia. PMID- 26625387 TI - Effective Biomarkers for Diagnosis of Neonatal Sepsis. AB - Infection in neonates continues to be a global problem with significant morbidity and mortality. The diagnosis of neonatal sepsis is complicated by nonspecific clinical symptomatology, a high-false negative rate, and a delay in obtaining blood culture results. An ideal biomarker needs to have a high degree of accuracy in recognizing the presence or absence of definite infection at an early stage, to guide the initiation and duration of antibiotic therapy. The diagnostic utility of the following biomarkers seems to be most practical in the early (interleukin [IL]-6, IL-8, tumor necrosis factor-alpha, neutrophil CD64), mid (procalcitonin) and late (C-reactive protein) phases of neonatal sepsis. Future research studies to assess reliability of these biomarkers should be (1) adequately powered for sample size and (2) use the gold-standard definition of blood-culture proven pathogen-specific sepsis. Significant advances in diagnostic accuracy of novel biomarkers to allow early, accurate, and cost-effective identification of pathogens responsible for neonatal sepsis is anticipated in the next 5 years. PMID- 26625388 TI - Non-Toxigenic Penicillin and Cephalosporin-Resistant Corynebacterium diphtheriae Endocarditis in a Child: A Case Report and Review of the Literature. AB - Reports of invasive disease caused by non-toxigenic Corynebacterium diphtheriae are increasing; however, medical management has not been extensively studied. We describe what we believe is the first documented case of penicillin and cephalosporin-resistant C diphtheriae endocarditis in a child successfully treated with vancomycin, meropenem, and valvular replacement surgery. PMID- 26625389 TI - How Accurate Are International Classification of Diseases-10 Diagnosis Codes in Detecting Influenza and Pertussis Hospitalizations in Children? AB - Influenza and pertussis are major causes of pediatric morbidity. We measured the accuracy of their International Classification of Diseases (ICD-10-AM) diagnosis codes using linked population-based laboratory and hospital data in 245,249 children. Influenza diagnosis codes had high specificity (98.6%) and modest positive predictive value (PPV; 84.1%) and sensitivity (86.1%, 95% CI: 83.4% 88.6%) for a laboratory-confirmed episode. For pertussis diagnosis codes, PPV (86.8%) and specificity (98.9%) were high, but sensitivity was poor (27.8%, 95% CI: 23.5%-32.4%). Measures varied according to age, remoteness, Aboriginality, severity, and detection method. Both laboratory and hospitalization data are needed to accurately determine the burden of pediatric influenza and pertussis. PMID- 26625390 TI - A 14-Year-Old Boy With Nodules on His Feet. PMID- 26625391 TI - Literature Review. PMID- 26625392 TI - Voriconazole Therapeutic Drug Monitoring. PMID- 26625393 TI - West Nile Virus Meningoencephalitis in an Infant With Seizures and Abnormal Neuroimaging. PMID- 26625394 TI - Pulmonary Protothecosis in a Pediatric Liver Transplant Patient. AB - Immunocompromised patients are susceptible to infections from common and unusual microorganisms. Protothecosis is seldom suspected on clinical grounds, yet it is readily diagnosed once detected in the laboratory. We report the first pediatric liver transplant recipient with pulmonary protothecosis, detected during an episode of Pneumocystis jirovecii pneumonia, and we conducted a review of the available literature. PMID- 26625395 TI - Recurrent Nocardia Sepsis in a Patient With Sickle Cell Anemia Receiving Continuous Deferoxamine. AB - Nocardia species are ubiquitous soil-borne organisms that most commonly cause invasive disease in patients with defective cell-mediated immunity. We report a case of recurrent Nocardia sepsis in a patient with sickle cell disease and chronic iron overload, who was undergoing high-dose infusions of deferoxamine through a central venous catheter. PMID- 26625400 TI - Patch-Based Nonlinear Image Registration for Gigapixel Whole Slide Images. AB - OBJECTIVE: Image registration of whole slide histology images allows the fusion of fine-grained information-like different immunohistochemical stains-from neighboring tissue slides. Traditionally, pathologists fuse this information by looking subsequently at one slide at a time. If the slides are digitized and accurately aligned at cell level, automatic analysis can be used to ease the pathologist's work. However, the size of those images exceeds the memory capacity of regular computers. METHODS: We address the challenge to combine a global motion model that takes the physical cutting process of the tissue into account with image data that is not simultaneously globally available. Typical approaches either reduce the amount of data to be processed or partition the data into smaller chunks to be processed separately. Our novel method first registers the complete images on a low resolution with a nonlinear deformation model and later refines this result on patches by using a second nonlinear registration on each patch. Finally, the deformations computed on all patches are combined by interpolation to form one globally smooth nonlinear deformation. The NGF distance measure is used to handle multistain images. RESULTS: The method is applied to ten whole slide image pairs of human lung cancer data. The alignment of 85 corresponding structures is measured by comparing manual segmentations from neighboring slides. Their offset improves significantly, by at least 15%, compared to the low-resolution nonlinear registration. CONCLUSION/SIGNIFICANCE: The proposed method significantly improves the accuracy of multistain registration which allows us to compare different antibodies at cell level. PMID- 26625401 TI - A Spiking Neural Network Methodology and System for Learning and Comparative Analysis of EEG Data From Healthy Versus Addiction Treated Versus Addiction Not Treated Subjects. AB - : This paper introduces a method utilizing spiking neural networks (SNN) for learning, classification, and comparative analysis of brain data. As a case study, the method was applied to electroencephalography (EEG) data collected during a GO/NOGO cognitive task performed by untreated opiate addicts, those undergoing methadone maintenance treatment (MMT) for opiate dependence and a healthy control group. METHODS: the method is based on an SNN architecture called NeuCube, trained on spatiotemporal EEG data. OBJECTIVE: NeuCube was used to classify EEG data across subject groups and across GO versus NOGO trials, but also facilitated a deeper comparative analysis of the dynamic brain processes. RESULTS: This analysis results in a better understanding of human brain functioning across subject groups when performing a cognitive task. In terms of the EEG data classification, a NeuCube model obtained better results (the maximum obtained accuracy: 90.91%) when compared with traditional statistical and artificial intelligence methods (the maximum obtained accuracy: 50.55%). SIGNIFICANCE: more importantly, new information about the effects of MMT on cognitive brain functions is revealed through the analysis of the SNN model connectivity and its dynamics. CONCLUSION: this paper presented a new method for EEG data modeling and revealed new knowledge on brain functions associated with mental activity which is different from the brain activity observed in a resting state of the same subjects. PMID- 26625403 TI - A Statistical Atrioventricular Node Model Accounting for Pathway Switching During Atrial Fibrillation. AB - OBJECTIVE: The atrioventricular (AV) node plays a central role in atrial fibrillation (AF), as it influences the conduction of impulses from the atria into the ventricles. In this paper, the statistical dual pathway AV node model, previously introduced by us, is modified so that it accounts for atrial impulse pathway switching even if the preceding impulse did not cause a ventricular activation. METHODS: The proposed change in model structure implies that the number of model parameters subjected to maximum likelihood estimation is reduced from five to four. The model is evaluated using the data acquired in the RATe control in atrial fibrillation (RATAF) study, involving 24-h ECG recordings from 60 patients with permanent AF. RESULTS: When fitting the models to the RATAF database, similar results were obtained for both the present and the previous model, with a median fit of 86%. The results show that the parameter estimates characterizing refractory period prolongation exhibit considerably lower variation when using the present model, a finding that may be ascribed to fewer model parameters. CONCLUSION: The new model maintains the capability to model RR intervals, while providing more reliable parameters estimates. SIGNIFICANCE: The model parameters are expected to convey novel clinical information, and may be useful for predicting the effect of rate control drugs. PMID- 26625402 TI - Automatic Craniomaxillofacial Landmark Digitization via Segmentation-Guided Partially-Joint Regression Forest Model and Multiscale Statistical Features. AB - OBJECTIVE: The goal of this paper is to automatically digitize craniomaxillofacial (CMF) landmarks efficiently and accurately from cone-beam computed tomography (CBCT) images, by addressing the challenge caused by large morphological variations across patients and image artifacts of CBCT images. METHODS: We propose a segmentation-guided partially-joint regression forest (S PRF) model to automatically digitize CMF landmarks. In this model, a regression voting strategy is first adopted to localize each landmark by aggregating evidences from context locations, thus potentially relieving the problem caused by image artifacts near the landmark. Second, CBCT image segmentation is utilized to remove uninformative voxels caused by morphological variations across patients. Third, a partially-joint model is further proposed to separately localize landmarks based on the coherence of landmark positions to improve the digitization reliability. In addition, we propose a fast vector quantization method to extract high-level multiscale statistical features to describe a voxel's appearance, which has low dimensionality, high efficiency, and is also invariant to the local inhomogeneity caused by artifacts. RESULTS: Mean digitization errors for 15 landmarks, in comparison to the ground truth, are all less than 2 mm. CONCLUSION: Our model has addressed challenges of both interpatient morphological variations and imaging artifacts. Experiments on a CBCT dataset show that our approach achieves clinically acceptable accuracy for landmark digitalization. SIGNIFICANCE: Our automatic landmark digitization method can be used clinically to reduce the labor cost and also improve digitalization consistency. PMID- 26625404 TI - Fast Multiclass Dictionaries Learning With Geometrical Directions in MRI Reconstruction. AB - OBJECTIVE: Improve the reconstructed image with fast and multiclass dictionaries learning when magnetic resonance imaging is accelerated by undersampling the k space data. METHODS: A fast orthogonal dictionary learning method is introduced into magnetic resonance image reconstruction to provide adaptive sparse representation of images. To enhance the sparsity, image is divided into classified patches according to the same geometrical direction and dictionary is trained within each class. A new sparse reconstruction model with the multiclass dictionaries is proposed and solved using a fast alternating direction method of multipliers. RESULTS: Experiments on phantom and brain imaging data with acceleration factor up to 10 and various undersampling patterns are conducted. The proposed method is compared with state-of-the-art magnetic resonance image reconstruction methods. CONCLUSION: Artifacts are better suppressed and image edges are better preserved than the compared methods. Besides, the computation of the proposed approach is much faster than the typical K-SVD dictionary learning method in magnetic resonance image reconstruction. SIGNIFICANCE: The proposed method can be exploited in undersampled magnetic resonance imaging to reduce data acquisition time and reconstruct images with better image quality. PMID- 26625405 TI - Interoperative Biopsy Site Relocalization in Endoluminal Surgery. AB - Barrett's oesophagus, a premalignant condition of the oesophagus has been on a rise in the recent years. The standard diagnostic protocol for Barrett's involves obtaining biopsies at suspicious regions along the oesophagus. The localization and tracking of these biopsy sites "interoperatively" poses a significant challenge for providing targeted treatments and tracking disease progression. This paper proposes an approach to provide guided navigation and relocalization of the biopsy sites using an electromagnetic tracking system. The characteristic of our approach over existing ones is the integration of an electromagnetic sensor at the flexible endoscope tip, so that the endoscopic camera depth inside the oesophagus can be computed in real time, allowing to retrieve and display an image from a previous exploration at the same depth. We first describe our system setup and methodology for interoperative registration. We then propose three incremental experiments of our approach. First, on synthetic data with realistic noise model to analyze the error bounds of our system. The second on in vivo pig data using an optical tracking system to provide a pseudo ground truth. Accuracy results obtained were consistent with the synthetic experiments despite uncertainty introduced due to breathing motion, and remain inside acceptable error margin according to medical experts. Finally, a third experiment designed using data from pigs to simulate a real task of biopsy site relocalization, and evaluated by ten gastro-intestinal experts. It clearly demonstrated the benefit of our system toward assisted guidance by improving the biopsy site retrieval rate from 47.5% to 94%. PMID- 26625406 TI - Parallel Solver for Diffuse Optical Tomography on Realistic Head Models With Scattering and Clear Regions. AB - Diffuse optical tomography is an imaging technique, based on evaluation of how light propagates within the human head to obtain the functional information about the brain. Precision in reconstructing such an optical properties map is highly affected by the accuracy of the light propagation model implemented, which needs to take into account the presence of clear and scattering tissues. We present a numerical solver based on the radiosity-diffusion model, integrating the anatomical information provided by a structural MRI. The solver is designed to run on parallel heterogeneous platforms based on multiple GPUs and CPUs. We demonstrate how the solver provides a 7 times speed-up over an isotropic scattered parallel Monte Carlo engine based on a radiative transport equation for a domain composed of 2 million voxels, along with a significant improvement in accuracy. The speed-up greatly increases for larger domains, allowing us to compute the light distribution of a full human head ( ~ 3 million voxels) in 116 s for the platform used. PMID- 26625408 TI - PDE Based Algorithms for Smooth Watersheds. AB - Watershed segmentation is useful for a number of image segmentation problems with a wide range of practical applications. Traditionally, the tracking of the immersion front is done by applying a fast sorting algorithm. In this work, we explore a continuous approach based on a geometric description of the immersion front which gives rise to a partial differential equation. The main advantage of using a partial differential equation to track the immersion front is that the method becomes versatile and may easily be stabilized by introducing regularization terms. Coupling the geometric approach with a proper "merging strategy" creates a robust algorithm which minimizes over- and under-segmentation even without predefined markers. Since reliable markers defined prior to segmentation can be difficult to construct automatically for various reasons, being able to treat marker-free situations is a major advantage of the proposed method over earlier watershed formulations. The motivation for the methods developed in this paper is taken from high-throughput screening of cells. A fully automated segmentation of single cells enables the extraction of cell properties from large data sets, which can provide substantial insight into a biological model system. Applying smoothing to the boundaries can improve the accuracy in many image analysis tasks requiring a precise delineation of the plasma membrane of the cell. The proposed segmentation method is applied to real images containing fluorescently labeled cells, and the experimental results show that our implementation is robust and reliable for a variety of challenging segmentation tasks. PMID- 26625407 TI - Theoretical Analysis of Penalized Maximum-Likelihood Patlak Parametric Image Reconstruction in Dynamic PET for Lesion Detection. AB - Detecting cancerous lesions is a major clinical application of emission tomography. In a previous work, we studied penalized maximum-likelihood (PML) image reconstruction for lesion detection in static PET. Here we extend our theoretical analysis of static PET reconstruction to dynamic PET. We study both the conventional indirect reconstruction and direct reconstruction for Patlak parametric image estimation. In indirect reconstruction, Patlak parametric images are generated by first reconstructing a sequence of dynamic PET images, and then performing Patlak analysis on the time activity curves (TACs) pixel-by-pixel. In direct reconstruction, Patlak parametric images are estimated directly from raw sinogram data by incorporating the Patlak model into the image reconstruction procedure. PML reconstruction is used in both the indirect and direct reconstruction methods. We use a channelized Hotelling observer (CHO) to assess lesion detectability in Patlak parametric images. Simplified expressions for evaluating the lesion detectability have been derived and applied to the selection of the regularization parameter value to maximize detection performance. The proposed method is validated using computer-based Monte Carlo simulations. Good agreements between the theoretical predictions and the Monte Carlo results are observed. Both theoretical predictions and Monte Carlo simulation results show the benefit of the indirect and direct methods under optimized regularization parameters in dynamic PET reconstruction for lesion detection, when compared with the conventional static PET reconstruction. PMID- 26625409 TI - Standardized Evaluation System for Left Ventricular Segmentation Algorithms in 3D Echocardiography. AB - Real-time 3D Echocardiography (RT3DE) has been proven to be an accurate tool for left ventricular (LV) volume assessment. However, identification of the LV endocardium remains a challenging task, mainly because of the low tissue/blood contrast of the images combined with typical artifacts. Several semi and fully automatic algorithms have been proposed for segmenting the endocardium in RT3DE data in order to extract relevant clinical indices, but a systematic and fair comparison between such methods has so far been impossible due to the lack of a publicly available common database. Here, we introduce a standardized evaluation framework to reliably evaluate and compare the performance of the algorithms developed to segment the LV border in RT3DE. A database consisting of 45 multivendor cardiac ultrasound recordings acquired at different centers with corresponding reference measurements from three experts are made available. The algorithms from nine research groups were quantitatively evaluated and compared using the proposed online platform. The results showed that the best methods produce promising results with respect to the experts' measurements for the extraction of clinical indices, and that they offer good segmentation precision in terms of mean distance error in the context of the experts' variability range. The platform remains open for new submissions. PMID- 26625410 TI - Compressed Sensing Doppler Ultrasound Reconstruction Using Block Sparse Bayesian Learning. AB - In this paper we propose a framework for using duplex Doppler ultrasound systems. These type of systems need to interleave the acquisition and display of a B-mode image and of the pulsed Doppler spectrogram. In a recent study (Richy , 2013), we have shown that compressed sensing-based reconstruction of Doppler signal allowed reducing the number of Doppler emissions and yielded better results than traditional interpolation and at least equivalent or even better depending on the configuration than the study estimating the signal from sparse data sets given in Jensen, 2006. We propose here to improve over this study by using a novel framework for randomly interleaving Doppler and US emissions. The proposed method reconstructs the Doppler signal segment by segment using a block sparse Bayesian learning (BSBL) algorithm based CS reconstruction. The interest of using such framework in the context of duplex Doppler is linked to the unique ability of BSBL to exploit block-correlated signals and to recover non-sparse signals. The performance of the technique is evaluated from simulated data as well as experimental in vivo data and compared to the recent results in Richy , 2013. PMID- 26625411 TI - Safety Assessment of Advanced Imaging Sequences I: Measurements. AB - A method for rapid measurement of intensities (I(spta)), mechanical index (MI), and probe surface temperature for any ultrasound scanning sequence is presented. It uses the scanner's sampling capability to give an accurate measurement of the whole imaging sequence for all emissions to yield the true distributions. The method is several orders of magnitude faster than approaches using an oscilloscope, and it also facilitates validating the emitted pressure field and the scanner's emission sequence software. It has been implemented using the experimental synthetic aperture real-time ultrasound system (SARUS) scanner and the Onda AIMS III intensity measurement system (Onda Corporation, Sunnyvale, CA, USA). Four different sequences have been measured: a fixed focus emission, a duplex sequence containing B-mode and flow emissions, a vector flow sequence with B-mode and flow emissions in 17 directions, and finally a SA duplex flow sequence. A BK8820e (BK Medical, Herlev, Denmark) convex array probe is used for the first three sequences and a BK8670 linear array probe for the SA sequence. The method is shown to give the same intensity values within 0.24% of the AIMS III Soniq 5.0 (Onda Corporation, Sunnyvale, CA, USA) commercial intensity measurement program. The approach can measure and store data for a full imaging sequence in 3.8-8.2 s per spatial position. Based on I(spta), MI, and probe surface temperature, the method gives the ability to determine whether a sequence is within U.S. FDA limits, or alternatively indicate how to scale it to be within limits. PMID- 26625412 TI - In Vivo Quantification of the Nonlinear Shear Modulus in Breast Lesions: Feasibility Study. AB - Breast cancer detection in the early stages is of great importance since the prognosis, and the treatment depends more on this. Multiple techniques relying on the mechanical properties of soft tissues have been developed to help in early detection. In this study, we implemented a technique that measures the nonlinear shear modulus (NLSM) (MU(NL)) in vivo and showed its utility to detect breast lesions from healthy tissue. The technique relies on the acoustoelasticity theory in quasi-incompressible media. In order to recover MU(NL), static elastography and supersonic shear imaging are combined to subsequently register strain maps and shear modulus maps while the medium is compressed. Then, MU(NL) can be recovered from the relationship between the stress, deduced from strain maps, and the shear modulus. For this study, a series of five nonlinear phantoms were built using biological tissue (pork liver) inclusions immersed in an agar-gelatin gel. Furthermore, 11 in vivo acquisitions were performed to characterize the NLSM of breast tissue. The phantom results showed a very good differentiation of the liver inclusions when measuring MU(NL) with a mean value of -114.1 kPa compared to -34.7 kPa for the gelatin. Meanwhile, values for the shear modulus for the liver and the gelatin were very similar, 3.7 and 3.4 kPa, respectively. In vivo NLSM mean value for the healthy breast tissue was of -95 kPa, while mean values of the benign and the malignant lesions were -619 and -806 kPa with a strong v ariability, respectively. This study shows the potential of the acoustoelasticity theory in quasi-incompressible medium to bring a new parameter for breast cancer diagnosis. PMID- 26625413 TI - The Dynamic Allan Variance V: Recent Advances in Dynamic Stability Analysis. AB - The dynamic Allan variance (DAVAR) measures the stability variations of precise clocks and oscillators. When an anomaly occurs, the DAVAR changes with time, its shape depending on the anomaly. In this work, we first discuss our current knowledge about the DAVAR, by focusing on the meaning of dynamic stability. Then, we extend our knowledge by obtaining additional properties of the DAVAR. Furthermore, we visually investigate the DAVAR for the main anomalies of precise clocks and oscillators. Finally, we review a variety of applications based on the DAVAR. PMID- 26625414 TI - A Truncated Nuclear Norm Regularization Method Based on Weighted Residual Error for Matrix Completion. AB - Low-rank matrix completion aims to recover a matrix from a small subset of its entries and has received much attention in the field of computer vision. Most existing methods formulate the task as a low-rank matrix approximation problem. A truncated nuclear norm has recently been proposed as a better approximation to the rank of matrix than a nuclear norm. The corresponding optimization method, truncated nuclear norm regularization (TNNR), converges better than the nuclear norm minimization-based methods. However, it is not robust to the number of subtracted singular values and requires a large number of iterations to converge. In this paper, a TNNR method based on weighted residual error (TNNR-WRE) for matrix completion and its extension model (ETNNR-WRE) are proposed. TNNR-WRE assigns different weights to the rows of the residual error matrix in an augmented Lagrange function to accelerate the convergence of the TNNR method. The ETNNR-WRE is much more robust to the number of subtracted singular values than the TNNR-WRE, TNNR alternating direction method of multipliers, and TNNR accelerated proximal gradient with Line search methods. Experimental results using both synthetic and real visual data sets show that the proposed TNNR-WRE and ETNNR-WRE methods perform better than TNNR and Iteratively Reweighted Nuclear Norm (IRNN) methods. PMID- 26625415 TI - Edge-Aware BMA Filters. AB - There has been continuous research in edge-aware filters which have found many applications in computer vision and image processing. In this paper, we propose a principled-approach for the development of edge-aware filters. The proposed approach is based on two well-established principles: 1) optimal parameter estimation and 2) Bayesian model averaging (BMA). Using this approach, we formulate the problem of filtering a pixel in a local pixel patch as an optimal estimation problem. Since a pixel belongs to multiple local patches, there are multiple estimates of the same pixel. We combine these estimates into a final estimate using BMA. We demonstrate the versatility of this approach by developing a family of BMA filters based on different settings of cost functions and log likelihood and log-prior functions. We also present a new interpretation of the guided filter and develop a BMA guided filter which includes the guided filter as a special case. We show that BMA filters can produce similar smoothing results as those of the state-of-the-art edge-aware filters. Two BMA filters are computationally as efficient as the guided filter which is one of the fastest edge-aware filters. We also demonstrate that the BMA guided filter is better than the guided filter in preserving sharp edges. A new feature of the BMA guided filter is that the filtered image is similar to that produced by a clustering process. PMID- 26625416 TI - Joint Multilabel Classification With Community-Aware Label Graph Learning. AB - As an important and challenging problem in machine learning and computer vision, multilabel classification is typically implemented in a max-margin multilabel learning framework, where the inter-label separability is characterized by the sample-specific classification margins between labels. However, the conventional multilabel classification approaches are usually incapable of effectively exploring the intrinsic inter-label correlations as well as jointly modeling the interactions between inter-label correlations and multilabel classification. To address this issue, we propose a multilabel classification framework based on a joint learning approach called label graph learning (LGL) driven weighted Support Vector Machine (SVM). In principle, the joint learning approach explicitly models the inter-label correlations by LGL, which is jointly optimized with multilabel classification in a unified learning scheme. As a result, the learned label correlation graph well fits the multilabel classification task while effectively reflecting the underlying topological structures among labels. Moreover, the inter-label interactions are also influenced by label-specific sample communities (each community for the samples sharing a common label). Namely, if two labels have similar label-specific sample communities, they are likely to be correlated. Based on this observation, LGL is further regularized by the label Hypergraph Laplacian. Experimental results have demonstrated the effectiveness of our approach over several benchmark data sets. PMID- 26625418 TI - Direction-Dependent Adaptation of Dynamic Gait Stability Following Waist-Pull Perturbations. AB - Balance recovery during an unexpected disturbance is a complex motor task, where part of the variability depends on the type of the perturbation itself. Despite of this, little is known to what extent adaptation mechanisms to repeated perturbations are dependent on the direction and the amplitude of the applied disturbances. Here, we used a modified version of the Active Tethered Pelvic Assist Device (A-TPAD) to apply unexpected force-controlled multidirectional waist-pull perturbations while subjects were walking. Healthy young subjects were divided into two groups and were exposed to a single training session. Each group received perturbations of different amplitudes along the Medio-Lateral (ML) or the Antero-Posterior (AP) direction. Dynamic stability was determined in both the AP and ML directions in terms of base of support (BoS) and margin of stability (MoS). Results showed: 1) an adaptation of the balance recovery reactions only for perturbations delivered along the AP directions; 2) aftereffects able to modify the control of stability during the post-training session of which type and extent depends on the direction of the perturbations previously applied; and 3) a directional and amplitude effect on the dynamic stability at the end of the balance recovery reactions. PMID- 26625417 TI - Evaluate the Feasibility of Using Frontal SSVEP to Implement an SSVEP-Based BCI in Young, Elderly and ALS Groups. AB - This paper studies the amplitude-frequency characteristic of frontal steady-state visual evoked potential (SSVEP) and its feasibility as a control signal for brain computer interface (BCI). SSVEPs induced by different stimulation frequencies, from 13 ~ 31 Hz in 2 Hz steps, were measured in eight young subjects, eight elders and seven ALS patients. Each subject was requested to participate in a calibration study and an application study. The calibration study was designed to find the amplitude-frequency characteristics of SSVEPs recorded from Oz and Fpz positions, while the application study was designed to test the feasibility of using frontal SSVEP to control a two-command SSVEP-based BCI. The SSVEP amplitude was detected by an epoch-average process which enables artifact-contaminated epochs can be removed. The seven ALS patients were severely impaired, and four patients, who were incapable of completing our BCI task, were excluded from calculation of BCI performance. The averaged accuracies, command transfer intervals and information transfer rates in operating frontal SSVEP-based BCI were 96.1%, 3.43 s/command, and 14.42 bits/min in young subjects; 91.8%, 6.22 s/command, and 6.16 bits/min in elders; 81.2%, 12.14 s/command, and 1.51 bits/min in ALS patients, respectively. The frontal SSVEP could be an alternative choice to design SSVEP-based BCI. PMID- 26625420 TI - On the Universality and Non-Universality of Spiking Neural P Systems With Rules on Synapses. AB - Spiking neural P systems with rules on synapses are a new variant of spiking neural P systems. In the systems, the neuron contains only spikes, while the spiking/forgetting rules are moved on the synapses. It was obtained that such system with 30 neurons (using extended spiking rules) or with 39 neurons (using standard spiking rules) is Turing universal. In this work, this number is improved to 6. Specifically, we construct a Turing universal spiking neural P system with rules on synapses having 6 neurons, which can generate any set of Turing computable natural numbers. As well, it is obtained that spiking neural P system with rules on synapses having less than two neurons are not Turing universal: i) such systems having one neuron can characterize the family of finite sets of natural numbers; ii) the family of sets of numbers generated by the systems having two neurons is included in the family of semi-linear sets of natural numbers. PMID- 26625419 TI - Task-Oriented Gaming for Transfer to Prosthesis Use. AB - The aim of this study is to establish the effect of task-oriented video gaming on using a myoelectric prosthesis in a basic activity of daily life (ADL). Forty-one able-bodied right-handed participants were randomly assigned to one of four groups. In three of these groups the participants trained to control a video game using the myosignals of the flexors and extensors of the wrist: in the Adaptive Catching group participants needed to catch falling objects by opening and closing a grabber and received ADL-relevant feedback during performance. The Free Catching group used the same game, but without augmented feedback. The Interceptive Catching group trained a game where the goal was to intercept a falling object by moving a grabber to the left and right. They received no additional feedback. The control group played a regular Mario computer game. All groups trained 20 minutes a day for four consecutive days. Two tests were conducted before and after training: one level of the training game was performed, and participants grasped objects with a prosthesis simulator. Results showed all groups improved their game performance over controls. In the prosthesis-simulator task, after training the Adaptive Catching group outperformed the other groups in their ability to adjust the hand aperture to the size of the objects and the degree of compression of compressible objects. This study is the first to demonstrate transfer effects from a serious game to a myoelectric prosthesis task. The specificity of the learning effects suggests that research into serious gaming will benefit from placing ADL-specific constraints on game development. PMID- 26625421 TI - Warning Drivers about Impending Collisions Using Vibrotactile Flow. AB - Vibrotactile collision warning signals that create a sensation of motion across a driver's body result in faster brake reaction times (BRTs) to potential collision events. To date, however, such warnings have only simulated linear motion. We extended this research by exploring the effectiveness of collision warnings that incorporate vibrotactile patterns or "vibrotactile flow". In Experiment 1, expanding and contracting vibrotactile flow warnings were compared with a static warning (all tactors activated simultaneously) and a no warning condition in a car following scenario. Both vibrotactile flow warnings produced significantly faster BRTs than the static and no warning conditions. However, there was no directional effect. That is, there was no significant difference between contracting and expanding signals. Warnings that utilize vibrotactile flow therefore appear to provide an effective means of informing drivers about potential collision events. However, unlike comparable warnings utilizing linear motion, their effectiveness does not seem to depend on the precise relationship between the warning and collision events. Experiment 2 demonstrated that a tactile warning incorporating linear motion produced significantly faster BRTs than an expanding vibrotactile flow warning. Taken together, these results suggest that vibrotactile warnings that simulate linear motion may be more effective than vibrotactile flow warnings. PMID- 26625422 TI - Image Categorization by Learning a Propagated Graphlet Path. AB - Spatial pyramid matching is a standard architecture for categorical image retrieval. However, its performance is largely limited by the prespecified rectangular spatial regions when pooling local descriptors. In this paper, we propose to learn object-shaped and directional receptive fields for image categorization. In particular, different objects in an image are seamlessly constructed by superpixels, while the direction captures human gaze shifting path. By generating a number of superpixels in each image, we construct graphlets to describe different objects. They function as the object-shaped receptive fields for image comparison. Due to the huge number of graphlets in an image, a saliency-guided graphlet selection algorithm is proposed. A manifold embedding algorithm encodes graphlets with the semantics of training image tags. Then, we derive a manifold propagation to calculate the postembedding graphlets by leveraging visual saliency maps. The sequentially propagated graphlets constitute a path that mimics human gaze shifting. Finally, we use the learned graphlet path as receptive fields for local image descriptor pooling. The local descriptors from similar receptive fields of pairwise images more significantly contribute to the final image kernel. Thorough experiments demonstrate the advantage of our approach. PMID- 26625423 TI - Quantized Attention-Gated Kernel Reinforcement Learning for Brain-Machine Interface Decoding. AB - Reinforcement learning (RL)-based decoders in brain-machine interfaces (BMIs) interpret dynamic neural activity without patients' real limb movements. In conventional RL, the goal state is selected by the user or defined by the physics of the problem, and the decoder finds an optimal policy essentially by assigning credit over time, which is normally very time-consuming. However, BMI tasks require finding a good policy in very few trials, which impose a limit on the complexity of the tasks that can be learned before the animal quits. Therefore, this paper explores the possibility of letting the agent infer potential goals through actions over space with multiple objects, using the instantaneous reward to assign credit spatially. A previous method, attention-gated RL employs a multilayer perceptron trained with backpropagation, but it is prone to local minima entrapment. We propose a quantized attention-gated kernel RL (QAGKRL) to avoid the local minima adaptation in spatial credit assignment and sparsify the network topology. The experimental results show that the QAGKRL achieves higher successful rates and more stable performance, indicating its powerful decoding ability for more sophisticated BMI tasks as required in clinical applications. PMID- 26625424 TI - Training Radial Basis Function Neural Networks for Classification via Class Specific Clustering. AB - In training radial basis function neural networks (RBFNNs), the locations of Gaussian neurons are commonly determined by clustering. Training inputs can be clustered on a fully unsupervised manner (input clustering), or some supervision can be introduced, for example, by concatenating the input vectors with weighted output vectors (input-output clustering). In this paper, we propose to apply clustering separately for each class (class-specific clustering). The idea has been used in some previous works, but without evaluating the benefits of the approach. We compare the class-specific, input, and input-output clustering approaches in terms of classification performance and computational efficiency when training RBFNNs. To accomplish this objective, we apply three different clustering algorithms and conduct experiments on 25 benchmark data sets. We show that the class-specific approach significantly reduces the overall complexity of the clustering, and our experimental results demonstrate that it can also lead to a significant gain in the classification performance, especially for the networks with a relatively few Gaussian neurons. Among other applied clustering algorithms, we combine, for the first time, a dynamic evolutionary optimization method, multidimensional particle swarm optimization, and the class-specific clustering to optimize the number of cluster centroids and their locations. PMID- 26625425 TI - Synchronization of Arbitrarily Switched Boolean Networks. AB - This paper investigates the complete synchronization problem for the drive response switched Boolean networks (SBNs) under arbitrary switching signals, where the switching signals of the response SBN follow those generated by the drive SBN at each time instant. First, the definition of complete synchronization is introduced for the drive-response SBNs under arbitrary switching signals. Second, the concept of switching reachable set starting from a given initial state set is put forward. Based on it, a necessary and sufficient condition is derived for the complete synchronization of the drive-response SBNs. Last, we give a simple algebraic expression for the switching reachable set in a given number of time steps, and two computable algebraic criteria are obtained for the complete synchronization of the SBNs. A biological example is given to demonstrate the effectiveness of the obtained main results. PMID- 26625426 TI - Integration-Enhanced Zhang Neural Network for Real-Time-Varying Matrix Inversion in the Presence of Various Kinds of Noises. AB - Matrix inversion often arises in the fields of science and engineering. Many models for matrix inversion usually assume that the solving process is free of noises or that the denoising has been conducted before the computation. However, time is precious for the real-time-varying matrix inversion in practice, and any preprocessing for noise reduction may consume extra time, possibly violating the requirement of real-time computation. Therefore, a new model for time-varying matrix inversion that is able to handle simultaneously the noises is urgently needed. In this paper, an integration-enhanced Zhang neural network (IEZNN) model is first proposed and investigated for real-time-varying matrix inversion. Then, the conventional ZNN model and the gradient neural network model are presented and employed for comparison. In addition, theoretical analyses show that the proposed IEZNN model has the global exponential convergence property. Moreover, in the presence of various kinds of noises, the proposed IEZNN model is proven to have an improved performance. That is, the proposed IEZNN model converges to the theoretical solution of the time-varying matrix inversion problem no matter how large the matrix-form constant noise is, and the residual errors of the proposed IEZNN model can be arbitrarily small for time-varying noises and random noises. Finally, three illustrative simulation examples, including an application to the inverse kinematic motion planning of a robot manipulator, are provided and analyzed to substantiate the efficacy and superiority of the proposed IEZNN model for real-time-varying matrix inversion. PMID- 26625427 TI - Semisupervised Multiclass Classification Problems With Scarcity of Labeled Data: A Theoretical Study. AB - In recent years, the performance of semisupervised learning (SSL) has been theoretically investigated. However, most of this theoretical development has focused on binary classification problems. In this paper, we take it a step further by extending the work of Castelli and Cover to the multiclass paradigm. In particular, we consider the key problem in SSL of classifying an unseen instance x into one of K different classes, using a training data set sampled from a mixture density distribution and composed of l labeled records and u unlabeled examples. Even under the assumption of identifiability of the mixture and having infinite unlabeled examples, labeled records are needed to determine the K decision regions. Therefore, in this paper, we first investigate the minimum number of labeled examples needed to accomplish that task. Then, we propose an optimal multiclass learning algorithm, which is a generalization of the optimal procedure proposed in the literature for binary problems. Finally, we make use of this generalization to study the probability of error when the binary class constraint is relaxed. PMID- 26625428 TI - Using Digital Masks to Enhance the Bandwidth Tolerance and Improve the Performance of On-Chip Reservoir Computing Systems. AB - Reservoir computing (RC) is a computing scheme related to recurrent neural network theory. As a model for neural activity in the brain, it attracts a lot of attention, especially because of its very simple training method. However, building a functional, on-chip, photonic implementation of RC remains a challenge. Scaling delay lines down from optical fiber scale to chip scale results in RC systems that compute faster, but at the same time requires that the input signals be scaled up in speed, which might be impractical or expensive. In this brief, we show that this problem can be alleviated by a masked RC system in which the amplitude of the input signal is modulated by a binary-valued mask. For a speech recognition task, we demonstrate that the necessary input sample rate can be a factor of 40 smaller than in a conventional RC system. In addition, we also show that linear discriminant analysis and input matrix optimization is a well-performing alternative to linear regression for reservoir training. PMID- 26625429 TI - Scalable Linear Visual Feature Learning via Online Parallel Nonnegative Matrix Factorization. AB - Visual feature learning, which aims to construct an effective feature representation for visual data, has a wide range of applications in computer vision. It is often posed as a problem of nonnegative matrix factorization (NMF), which constructs a linear representation for the data. Although NMF is typically parallelized for efficiency, traditional parallelization methods suffer from either an expensive computation or a high runtime memory usage. To alleviate this problem, we propose a parallel NMF method called alternating least square block decomposition (ALSD), which efficiently solves a set of conditionally independent optimization subproblems based on a highly parallelized fine-grained grid-based blockwise matrix decomposition. By assigning each block optimization subproblem to an individual computing node, ALSD can be effectively implemented in a MapReduce-based Hadoop framework. In order to cope with dynamically varying visual data, we further present an incremental version of ALSD, which is able to incrementally update the NMF solution with a low computational cost. Experimental results demonstrate the efficiency and scalability of the proposed methods as well as their applications to image clustering and image retrieval. PMID- 26625430 TI - Bayesian Recurrent Neural Network for Language Modeling. AB - A language model (LM) is calculated as the probability of a word sequence that provides the solution to word prediction for a variety of information systems. A recurrent neural network (RNN) is powerful to learn the large-span dynamics of a word sequence in the continuous space. However, the training of the RNN-LM is an ill-posed problem because of too many parameters from a large dictionary size and a high-dimensional hidden layer. This paper presents a Bayesian approach to regularize the RNN-LM and apply it for continuous speech recognition. We aim to penalize the too complicated RNN-LM by compensating for the uncertainty of the estimated model parameters, which is represented by a Gaussian prior. The objective function in a Bayesian classification network is formed as the regularized cross-entropy error function. The regularized model is constructed not only by calculating the regularized parameters according to the maximum a posteriori criterion but also by estimating the Gaussian hyperparameter by maximizing the marginal likelihood. A rapid approximation to a Hessian matrix is developed to implement the Bayesian RNN-LM (BRNN-LM) by selecting a small set of salient outer-products. The proposed BRNN-LM achieves a sparser model than the RNN-LM. Experiments on different corpora show the robustness of system performance by applying the rapid BRNN-LM under different conditions. PMID- 26625431 TI - Can the Virtual Labels Obtained by Traditional LP Approaches Be Well Encoded in WLR? AB - Semisupervised dimension reduction via virtual label regression first derives the virtual labels of unlabeled data by employing a newly designed label propagation (LP) approach (called Special random walk (SRW)) and then encodes them in a weighted linear regression model. Nie et al. (2011) highlighted two important characteristics of SRW nonexistent in the previous LP approaches: outlier detection and probability value output, which guarantee the elegant encoding of the resultant virtual labels in the weighted label regression. However, in this brief, we show that the relationship between the SRW and the previous work on LP is very close. Naturally, a problem deserving investigation is whether traditional LP approaches are indeed unable to share the above two characteristics of SRW. We aim to address this problem. PMID- 26625432 TI - Synchronization Analysis and Design of Coupled Boolean Networks Based on Periodic Switching Sequences. AB - A novel synchronization analysis method is developed to solve the complete synchronization problem of many Boolean networks (BNs) coupled in the leader follower configuration. First, an error system is constructed in terms of the algebraic representation using the semitensor product of matrices. Then, the synchronization problem of coupled BNs is converted into a problem whether all the trajectories of the error system are convergent to the zero vector. Second, according to the structure analysis of this error system, which is in the form of a switched system with leader BN states as the switching signal, a necessary and sufficient synchronization condition is derived. An algorithm is developed, which helps to determine as soon as possible whether complete synchronization among coupled BNs is achieved. Finally, a constructive design approach to follower BNs is provided. All of these follower BNs designed by our approach can completely synchronize with a given leader BN from the (Tt+1) th step at most, where Tt is the transient period of the leader BN. PMID- 26625433 TI - Optimal Output Regulation for Heterogeneous Multiagent Systems via Adaptive Dynamic Programming. AB - In this paper, the optimal output regulation problem for partially model-free heterogeneous linear multiagent systems with disturbance generated by an exosystem is addressed by using adaptive dynamic programming and double compensator method. The topology graph for the information exchange of the agents has a spanning tree. The dynamic of individual agent is assumed to be nonidentical and of different dimensions. One distributed compensator is designed to deal with the nonidentical agents, and the other compensator is used to handle the optimal performance index. By constructing the double compensator, the distributed feedback control laws are designed to make the output of each agent synchronize with the reference output and minimize the energy of the output error simultaneously. To overcome the lack of the dynamics knowledge of each agent, a novel online policy iteration algorithm is developed to obtain the optimal feedback gain matrix. Finally, two examples are presented to illustrate the effectiveness of our results. PMID- 26625434 TI - Circular Mixture Modeling of Color Distribution for Blind Stain Separation in Pathology Images. AB - In digital pathology, to address color variation and histological component colocalization in pathology images, stain decomposition is usually performed preceding spectral normalization and tissue component segmentation. This paper examines the problem of stain decomposition, which is a naturally nonnegative matrix factorization (NMF) problem in algebra, and introduces a systematical and analytical solution consisting of a circular color analysis module and an NMF based computation module. Unlike the paradigm of existing stain decomposition algorithms where stain proportions are computed from estimated stain spectra using a matrix inverse operation directly, the introduced solution estimates stain spectra and stain depths via probabilistic reasoning individually. Since the proposed method pays extra attentions to achromatic pixels in color analysis and stain co-occurrence in pixel clustering, it achieves consistent and reliable stain decomposition with minimum decomposition residue. Particularly, aware of the periodic and angular nature of hue, we propose the use of a circular von Mises mixture model to analyze the hue distribution, and provide a complete color based pixel soft-clustering solution to address color mixing introduced by stain overlap. This innovation combined with saturation-weighted computation makes our study effective for weak stains and broad-spectrum stains. Extensive experimentation on multiple public pathology datasets suggests that our approach outperforms state-of-the-art blind stain separation methods in terms of decomposition effectiveness. PMID- 26625435 TI - Graphical Tasks to Measure Upper Limb Function in Patients With Parkinson's Disease: Validity and Response to Dopaminergic Medication. AB - The most widely used method to assess motor functioning in Parkinson's disease (PD) patients is the unified Parkinson's disease rating scale-III (UPDRS-III). The UPDRS-III has limited ability to detect subtle changes in motor symptoms. Alternatively, graphical tasks can be used to provide objective measures of upper limb motor dysfunction. This study investigated the validity of such graphical tasks to assess upper limb function in PD patients and their ability to detect subtle changes in performance. Fourteen PD patients performed graphical tasks before and after taking dopaminergic medication. Graphical tasks included figure tracing, writing, and a modified Fitts' task. The Purdue pegboard test was performed to validate these graphical tasks. Movement time (MT), writing size, and the presence of tremor were assessed. MT on the graphical tasks correlated significantly with performance on the Purdue pegboard test (Spearman's rho > 0.65; p < 0.05). MT decreased significantly after the intake of dopaminergic medication. Tremor power decreased after taking dopaminergic medication in most PD patients who suffered from tremor. Writing size did not correlate with performance on the Purdue pegboard test, nor did it change after taking medication. Our set of graphical tasks is valid to assess upper limb function in PD patients. MT proved to be the most useful measure for this purpose. The response on dopaminergic medication was optimally reflected by an improved MT on the graphical tasks in combination with a decreased tremor power, whereas writing size did not respond to dopaminergic treatment. PMID- 26625436 TI - Age Dependence of Arterial Pulse Wave Parameters Extracted From Dynamic Blood Pressure and Blood Volume Pulse Waves. AB - Atherosclerosis is a significant cause of mortality in the aged population, and it affects arterial wall properties causing differences in measured arterial pulse wave (PW). In this study, both dynamic arterial blood pressure PWs and blood volume PWs are analyzed. The PWs are recorded noninvasively from multiple measurement points from the upper and lower limbs from 52 healthy (22-90-year old) volunteers without known cardiovascular diseases. For each signal, various parameters earlier proposed in the literature are computed, and 25 different novel parameters are formed by combining these parameters. The results are evaluated in terms of age and heart rate (HR) dependence of the parameters. In general, the results show that 14 out of 25 tested combined parameters have stronger age dependence than any of the individual parameters. The highest obtained linear correlation coefficients between the age and combined parameter and individual parameter equal to 0.85 ( ) and 0.79 ( ), respectively. Most of the combined parameters have also improved discrimination capability when classifying the test subjects into different age groups. This is a promising result for further studies, but indicate that the age dependence of the parameters must be taken into account in further studies with atherosclerotic patients. PMID- 26625437 TI - Content Coding of Psychotherapy Transcripts Using Labeled Topic Models. AB - Psychotherapy represents a broad class of medical interventions received by millions of patients each year. Unlike most medical treatments, its primary mechanisms are linguistic; i.e., the treatment relies directly on a conversation between a patient and provider. However, the evaluation of patient-provider conversation suffers from critical shortcomings, including intensive labor requirements, coder error, nonstandardized coding systems, and inability to scale up to larger data sets. To overcome these shortcomings, psychotherapy analysis needs a reliable and scalable method for summarizing the content of treatment encounters. We used a publicly available psychotherapy corpus from Alexander Street press comprising a large collection of transcripts of patient-provider conversations to compare coding performance for two machine learning methods. We used the labeled latent Dirichlet allocation (L-LDA) model to learn associations between text and codes, to predict codes in psychotherapy sessions, and to localize specific passages of within-session text representative of a session code. We compared the L-LDA model to a baseline lasso regression model using predictive accuracy and model generalizability (measured by calculating the area under the curve (AUC) from the receiver operating characteristic curve). The L LDA model outperforms the lasso logistic regression model at predicting session level codes with average AUC scores of 0.79, and 0.70, respectively. For fine grained level coding, L-LDA and logistic regression are able to identify specific talk-turns representative of symptom codes. However, model performance for talk turn identification is not yet as reliable as human coders. We conclude that the L-LDA model has the potential to be an objective, scalable method for accurate automated coding of psychotherapy sessions that perform better than comparable discriminative methods at session-level coding and can also predict fine-grained codes. PMID- 26625438 TI - A Penalized Semialgebraic Deflation ICA Algorithm for the Efficient Extraction of Interictal Epileptic Signals. AB - As a noninvasive technique, electroencephalography (EEG) is commonly used to monitor the brain signals of patients with epilepsy such as the interictal epileptic spikes. However, the recorded data are often corrupted by artifacts originating, for example, from muscle activities, which may have much higher amplitudes than the interictal epileptic signals of interest. To remove these artifacts, a number of independent component analysis (ICA) techniques were successfully applied. In this paper, we propose a new deflation ICA algorithm, called penalized semialgebraic unitary deflation (P-SAUD) algorithm, that improves upon classical ICA methods by leading to a considerably reduced computational complexity at equivalent performance. This is achieved by employing a penalized semialgebraic extraction scheme, which permits us to identify the epileptic components of interest (interictal spikes) first and obviates the need of extracting subsequent components. The proposed method is evaluated on physiologically plausible simulated EEG data and actual measurements of three patients. The results are compared to those of several popular ICA algorithms as well as second-order blind source separation methods, demonstrating that P-SAUD extracts the epileptic spikes with the same accuracy as the best ICA methods, but reduces the computational complexity by a factor of 10 for 32-channel recordings. This superior computational efficiency is of particular interest considering the increasing use of high-resolution EEG recordings, whose analysis requires algorithms with low computational cost. PMID- 26625439 TI - A Switched System Approach to Exponential Stabilization of Sampled-Data T-S Fuzzy Systems With Packet Dropouts. AB - This paper investigates the problem of exponential stabilization for sampled-data Takagi-Sugeno (T-S) fuzzy control systems with packet dropouts. An input delay approach is adopted to model the sample-and-hold behavior with a time-varying delayed control input, and a switched system approach is proposed to model the data-missing phenomenon. On this basis, the sampled-data T-S fuzzy control system with packet dropouts is modeled as a switched T-S fuzzy system with time-varying delay. The objective is to design a sampled-data fuzzy controller to guarantee the exponential stability of the resulting closed-loop system. Based on a new piecewise time-dependent Lyapunov functional, a novel sufficient condition is derived for the existence of exponentially stabilizing sampled-data fuzzy controllers. All the solutions to the problem are formulated in the form of linear matrix inequalities. Finally, two simulation examples are provided to illustrate the effectiveness of the proposed methods. PMID- 26625440 TI - A Classification Algorithm for Electroencephalography Signals by Self-Induced Emotional Stimuli. AB - The aim of this paper is to propose a real-time classification algorithm for the low-amplitude electroencephalography (EEG) signals, such as those produced by remembering an unpleasant odor, to drive a brain-computer interface. The peculiarity of these EEG signals is that they require ad hoc signals preprocessing by wavelet decomposition, and the definition of a set of features able to characterize the signals and to discriminate among different conditions. The proposed method is completely parameterized, aiming at a multiclass classification and it might be considered in the framework of machine learning. It is a two stages algorithm. The first stage is offline and it is devoted to the determination of a suitable set of features and to the training of a classifier. The second stage, the real-time one, is to test the proposed method on new data. In order to avoid redundancy in the set of features, the principal components analysis is adapted to the specific EEG signal characteristics and it is applied; the classification is performed through the support vector machine. Experimental tests on ten subjects, demonstrating the good performance of the algorithm in terms of both accuracy and efficiency, are also reported and discussed. PMID- 26625441 TI - Ordered Subspace Clustering With Block-Diagonal Priors. AB - Many application scenarios involve sequential data, but most existing clustering methods do not well utilize the order information embedded in sequential data. In this paper, we study the subspace clustering problem for sequential data and propose a new clustering method, namely ordered sparse clustering with block diagonal prior (BD-OSC). Instead of using the sparse normalizer in existing sparse subspace clustering methods, a quadratic normalizer for the data sparse representation is adopted to model the correlation among the data sparse coefficients. Additionally, a block-diagonal prior for the spectral clustering affinity matrix is integrated with the model to improve clustering accuracy. To solve the proposed BD-OSC model, which is a complex optimization problem with quadratic normalizer and block-diagonal prior constraint, an efficient algorithm is proposed. We test the proposed clustering method on several types of databases, such as synthetic subspace data set, human face database, video scene clips, motion tracks, and dynamic 3-D face expression sequences. The experiments show that the proposed method outperforms state-of-the-art subspace clustering methods. PMID- 26625442 TI - Coupled Deep Autoencoder for Single Image Super-Resolution. AB - Sparse coding has been widely applied to learning-based single image super resolution (SR) and has obtained promising performance by jointly learning effective representations for low-resolution (LR) and high-resolution (HR) image patch pairs. However, the resulting HR images often suffer from ringing, jaggy, and blurring artifacts due to the strong yet ad hoc assumptions that the LR image patch representation is equal to, is linear with, lies on a manifold similar to, or has the same support set as the corresponding HR image patch representation. Motivated by the success of deep learning, we develop a data-driven model coupled deep autoencoder (CDA) for single image SR. CDA is based on a new deep architecture and has high representational capability. CDA simultaneously learns the intrinsic representations of LR and HR image patches and a big-data-driven function that precisely maps these LR representations to their corresponding HR representations. Extensive experimentation demonstrates the superior effectiveness and efficiency of CDA for single image SR compared to other state of-the-art methods on Set5 and Set14 datasets. PMID- 26625443 TI - Africa's Indigenous Fruit Trees: A Blessing in Decline. PMID- 26625444 TI - Racial and Ethnic Disparities in Research Studies: The Challenge of Creating More Diverse Cohorts. PMID- 26625446 TI - Case-Control Studies to Assess the Effectiveness of Vaccines. PMID- 26625447 TI - Kawasaki Disease in Latin American Children: Past, Current, and Future Challenges. AB - Kawasaki disease (KD) is the leading cause of acquired cardiac disease in children in developed countries and Asia. However, there is a paucity of data available from Latin America. In response to the gap in knowledge about KD in Latin America, a group of pediatric infectious disease researchers from the Kawasaki Disease Research Center at the University of California San Diego and the Sociedad Latinoamericana de Infectologia Pediatrica joined efforts during the last decade to address this problem. The Red de Enfermedad de Kawasaki en America Latina (Latin American Kawasaki Disease Network) was launched in 2013 to study the epidemiology of KD among children from the major pediatric tertiary referral hospitals in Latin America. This multinational multicenter network is primarily composed of pediatric infectious diseases, cardiology, rheumatology, and immunology subspecialists and pediatricians from 20 countries, and it is one of the world's largest networks to study the general epidemiology of KD. The first 2 prospective and retrospective multinational multicenter studies looking at the epidemiology of KD in the region were initiated in 2014. Future plans for the network include establishing collaborative research alliances and projects with other centers around the world. To date [ 1], there have been no published studies describing the overall incidence and prevalence of KD in Latin American children. The most important and recent epidemiological study addressing this issue, related to Chile, was published in 2012 [ 2]. Of these, the most recent relevant study addressed the seasonality of KD in different parts of the globe, including some Latin American and Caribbean countries [ 4]. In this document, we briefly summarize relevant available information from Latin America. Although there have been other publications from individual countries that are outside the scope of this communication, the majority of these reports are single case reports, or case series that have been published predominantly in local journals that are not indexed in PubMed and instead are in regional Spanish, Portuguese, and English databases. PMID- 26625448 TI - Update From the Advisory Committee on Immunization Practices. PMID- 26625450 TI - Invasive Staphylococcus aureus Infections in Children in Tropical Northern Australia. AB - BACKGROUND: Despite a high burden of staphylococcal skin disease in children and high incidence of Staphylococcus aureus bacteremia in adult Indigenous populations in northern Australia, there are few studies describing incidence or clinical information of invasive S aureus (ISA) infections in children. METHODS: We conducted a retrospective review for all cases of S aureus bacteremia and sterile site infections, for children under 15 years, in northern Australia over a 4-year period (2007-2010). Cases were categorized as neonatal (<28 days) and pediatric (>=28 days). RESULTS: Forty-four cases (9 neonatal, 35 pediatric) were identified. The annual incidence of ISA was 27.9 cases per 100 000 population. Among pediatric cases, the annual incidence was significantly higher in the Indigenous (46.6) compared with the non-Indigenous (4.4) population (IRR: 10.6 [95% confidence interval, 3.8-41.4]). Pediatric infections were predominantly community-associated (86%). Clinical infection sites included osteoarticular (66%), pleuropulmonary (29%), and endocarditis (9%), and multifocal disease was common (20%). Eighty-three percent of pediatric cases presented with sepsis; 34% resulted in intensive care admission. Neonatal cases were all born prematurely; 89% were late-onset infections. Overall, 27% of infections were due to methicillin-resistant S aureus (MRSA). Compared with methicillin-sensitive S aureus (MSSA), there was no difference in severity or presentation in pediatric MRSA cases, but a higher proportion of MRSA cases were readmitted. CONCLUSIONS: The annual incidence of ISA infection in this study is among the highest described, largely due to a disproportionate burden in Indigenous children. Infections are frequently severe and infection with MRSA is common. Children presenting with suspected ISA in this region should be treated empirically for MRSA. PMID- 26625449 TI - Safety and Efficacy of High-Dose Daily Vitamin D3 Supplementation in Children and Young Adults Infected With Human Immunodeficiency Virus. AB - BACKGROUND: Suboptimal vitamin D (vitD) status is common in children and young adults infected with human immunodeficiency virus (HIV). The vitD supplemental dose needed to normalize vitD status in this population is unknown. METHODS: In this double-blind trial, subjects infected with HIV ages 8.3 to 24.9 years were randomized to vitD3 supplementation of 4000 IU/day or 7000 IU/day and evaluated at 6 and 12 week for changes in vitD status and HIV indicators. A dose was considered unsafe if serum calcium was elevated (above age and sex-specific range) associated with elevated serum 25 hydroxyvitamin D (25(OH)D); >160 ng/mL). RESULTS: At baseline, 95% of subjects (n = 44; 43% with perinatally acquired HIV, 57% with behaviorally acquired HIV) had a suboptimal serum 25(OH)D concentration of <32 ng/mL (mean +/- standard deviation, 19.3 +/- 7.4; range, 4.4-33.6 ng/mL). After 12 weeks (main outcome) of D3 supplementation, both D3 doses were safe and well tolerated, with no evidence of elevation of serum calcium concentrations or deterioration in HIV immunologic or virologic status. Sufficient vitD status, defined as serum 25(OH)D >=32 ng/mL, was achieved in 81% of all subjects, and only the 7000 IU/day group (86%) achieved this a priori efficacy criterion in >80% of subjects. Change in serum 25(OH)D did not differ between HIV acquisition groups. CONCLUSIONS: A 7000 IU/day D3 supplementation was safe and effective in children and young adults infected with HIV. PMID- 26625452 TI - Extended-Spectrum beta-Lactamase-Producing and Third-Generation Cephalosporin Resistant Enterobacteriaceae in Children: Trends in the United States, 1999-2011. AB - BACKGROUND: Enterobacteriaceae infections resistant to extended-spectrum beta lactams are an emerging problem in children. We used a large database of clinical isolates to describe the national epidemiology of extended-spectrum beta lactamase (ESBL)-producing and third-generation cephalosporin-resistant (G3CR) Enterobacteriaceae. METHODS: Antimicrobial susceptibilities of Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis reported to ~300 laboratories participating in The Surveillance Network (TSN) between January 1999 and December 2011 were used to phenotypically identify G3CR and ESBL isolates cultured from patients <18 years. Bi-annual trends in the prevalence of each phenotype were stratified by species, patient location, culture site, age, and region. Children of age 0-1 years were excluded from analysis as data were only available from 2010 onwards. RESULTS: Out of 368,398 pediatric isolates, 1.97% (7255) were identified as G3CR, and 0.47% (1734) as ESBL producers. The prevalence of both phenotypes increased, respectively, from 1.39% and 0.28% in 1999-2001 to 3% and 0.92% in 2010-2011. Trends were significant across all demographic and age groups, including outpatients, with the highest proportion of isolates in the 1-5 year-old age group. The majority of G3CR and ESBL isolates were E. coli (67.8% and 65.2%, respectively). Among ESBLs, resistance to >=3 antibiotic classes was 74%. The lower regional prevalence of ESBL-producing bacteria in the upper Midwest relative to the rest of the country is consistent with recent local data. CONCLUSIONS: Rates of G3CR and ESBL infections in children are increasing in both inpatient and ambulatory settings nationally. The identification of host factors and exposures leading to infection in children is essential. PMID- 26625451 TI - Extended-Spectrum beta-Lactamase-Producing Enterobacteriaceae Infections in Children: A Two-Center Case-Case-Control Study of Risk Factors and Outcomes in Chicago, Illinois. AB - BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae infections are an emerging problem in children. We sought to identify risk factors and describe outcomes associated with pediatric ESBL-producing bacterial infections at 2 hospitals in Chicago, IL from 2008 to 2011. METHODS: A case-case control study of children aged 0-17 years was conducted. Cases of Escherichia coli, Klebsiella, and Proteus spp. ESBL-producing bacterial infections (n = 30) were compared to uninfected controls and in parallel, cases of non-ESBL-producing bacterial infections (n = 30) were compared to uninfected controls (n = 60). We then qualitatively compared these results. RESULTS: Median age of cases was 1.06 years; 62% of isolates were from urine, and 60% were E. coli. By multivariable analysis, ESBL cases were 5.7 and 3.3 times more likely to have gastrointestinal (P = .001; 95% confidence interval [CI] 1.9-17.0) and neurologic (P = .001; 95% CI 1.1-3.7) comorbidities, respectively, than controls; non-ESBL cases were also more likely to have gastrointestinal comorbidities than controls (P = .014; odds ratio 3.6; 95% CI 1.2-10.1). Study period prevalence remained stable (1.7%). Most (60%) infections occurred in the intensive care unit; however, 30% of children presented in the outpatient setting. Seventy-seven percent of isolates were multidrug resistant (ie, resistant to >=3 antibiotic classes). Recurrence of infection occurred in 17% of ESBL cases. Crude mortality rates (7%) did not differ between cases and controls. CONCLUSIONS: The incidence of pediatric infection due to ESBL-positive Enterobacteriaceae was stable at 2 large tertiary care medical centers over a 4-year period. Multidrug resistance in pediatric ESBL isolates is common. Risk factors for infection due to ESBL-producing bacteria include neurologic medical conditions. PMID- 26625454 TI - The Group A Streptococcal Carrier State Reviewed: Still an Enigma. AB - Despite the common nature of group A streptococcal (GAS) infections, the carrier state of this organism is not well understood. In this article, we review the historical and recent research on the definition, epidemiology, and pathogenesis of the GAS carrier state. In addition, we outline trials of antimicrobial agents in the eradication of the carrier state and discuss indications for providing treatment to patients in the clinical setting. PMID- 26625453 TI - Variation in Risk of Hospital-Onset Clostridium difficile Infection Across beta Lactam Antibiotics in Children With New-Onset Acute Lymphoblastic Leukemia. AB - BACKGROUND: Antibiotic exposure is common among children with leukemia. However, limited data exist regarding the risk of Clostridium difficile infection (CDI) across anti-pseudomonal beta-lactam antibiotics commonly used for fever and neutropenia. METHODS: A multicenter cohort of children with newly diagnosed acute lymphoblastic leukemia (ALL) was established from 43 freestanding children's hospitals from 1999 to 2009. Patients were followed until their index CDI event, defined by the CDI ICD-9 code plus a C difficile test charge, or until 180 days from ALL diagnosis. Cox proportional hazards models were performed to identify the hazards of CDI after exposure to anti-pseudomonal beta-lactams, adjusting for demographics, other antibiotic exposures, severity of illness, antacids, gastrointestinal manipulation, and confounding by hospital. RESULTS: A cohort of 8268 ALL patients was assembled; median age was 5.5 years (interquartile range, 3.26-10.58). Two-hundred sixty-eight (3.2%) patients developed CDI within 180 days of ALL diagnosis. Each 1-day increase in exposure to an anti-pseudomonal beta-lactam within the prior 30 days was associated with a significantly increased risk for CDI (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.01, 1.09). Ceftazidime (HR, 1.05; 95% CI, 1.02, 1.08) and cefepime (HR, 1.07; 95% CI, 1.02, 1.12) were each independently associated with CDI. CONCLUSIONS: Efforts to reduce total exposure to anti-pseudomonal beta-lactam agents may help to reduce the risk of CDI in children with newly diagnosed ALL. Cefepime and ceftazidime were independently associated with CDI, whereas anti-pseudomonal penicillins and carbapenems were not. These findings, if confirmed, have potential implications for antibiotic choice during periods of fever and neutropenia. PMID- 26625455 TI - Long-Term Predictors of Recurrent Laboratory-Confirmed Giardiasis: A 10-Year National Surveillance Study. AB - During 2002 to 2011, 275 of 6828 children with giardiasis in Israel were reported with recurrent, over 6 months apart, episodes. The only significant multivariable adjusted risk predictor of a recurrent episode was non-Jewish ethnicity (hazard ratio, 4.61 [95% confidence interval, 3.32-6.40]; P < .001), also accompanied by significant interaction with lower maternal education. PMID- 26625456 TI - Duration of Bordetella pertussis Polymerase Chain Reaction Positivity in Confirmed Pertussis Illness. AB - Pertussis cases have been increasing in the United States for the past 40 years. Polymerase chain reaction (PCR) testing is now the preferred method of diagnosis, but little is known about duration of PCR positivity. We conducted a pilot study using serial B pertussis PCR testing to determine duration of PCR positivity. Kaplan-Meier survival analysis suggested a median duration of 58 days (interquartile range, 40-110 days). PMID- 26625457 TI - Vaccination Rates for Measles, Mumps, Rubella, and Influenza Among Children Presenting to a Pediatric Emergency Department in New York City. AB - We compared measles, mumps, rubella (MMR), and influenza vaccination rates of children presenting to a Pediatric Emergency Department (PED) in New York City with rates from national assessments. MMR and influenza vaccination rates in this PED population were generally comparable to community rates, but lower than Healthy People 2020 targets. PMID- 26625458 TI - Early Onset Neonatal Sepsis and Meningitis. PMID- 26625459 TI - Fatal Case of Norovirus Gastroenteritis Due to Severe Dehydration. PMID- 26625460 TI - Sorting Out a Sore Spot. PMID- 26625461 TI - Plague in a Pediatric Patient: Case Report and Use of Polymerase Chain Reaction as a Diagnostic Aid. AB - We report a case of bubonic plaque in a 7-year-old patient who presented with a core temperature of 107 degrees F, seizures, vomiting, altered mental status, and septic shock. This case highlights the utility of polymerase chain reaction (PCR) as a diagnostic aid for rapid presumptive identification of Yersinia pestis as well as the importance of correlating PCR results with clinical data. We discuss the various manifestations of plague as they relate to infection control, postexposure prophylaxis, antimicrobial therapy, and treatment duration. PMID- 26625462 TI - Pneumonia With Chest Wall Invasion in a School-Aged Child. PMID- 26625463 TI - Congenital Tuberculosis: A Missed Opportunity. PMID- 26625468 TI - Introduction. PMID- 26625469 TI - Prehension Combined With Gait in Individuals With Chronic Low Back Pain. AB - Low back pain (LBP) can affect performance in the combined task (CT) of gait and prehension, since it increases muscle activity amplitude during voluntary movements, impairs the anticipatory postural adjustments and reduces gait speed. We analyzed and compared the effect of adding the prehension movement toward a dowel located at three different heights (80, 100 and 120% of the lower limb length) on gait of individuals with and without LBP. The CT caused anticipatory adjustments, showing that gait changes started during the approach phase and continued on the step corresponding to grasping, especially for the lowest dowel height. Furthermore, individuals with LBP reduced walking speed, increased the width of the base of support, increased electromyography activity of low back trunk muscles, and increased the margin of dynamic stability compared with control group. These results suggest that individuals with LBP used a strategy to reduce threat to body stability due to addition of the manual task. PMID- 26625470 TI - [Toward establishment of certificated educators for kidney disease]. PMID- 26625471 TI - [A case of ANCA-associated vasculitis with esophageal stenosis and pseudodiverticulosis]. AB - A previously healthy 67-year-old woman visited our institution because of cough that had persisted for 3 months, fever at night, left tinnitus, and hearing loss from 1 month prior. She lost 2 kg in weight over the last 6 months, and her C reactive protein level and leukocyte count were increased. Computed tomography revealed multiple small nodules in both lung fields. She was admitted to our hospital for further examination to determine the optimal medical treatment. Because the myeloperoxidase antineutrophil cytoplasmic antibody (ANCA) titer was 132.5 U/mL and microscopic hematuria was observed, vasculitis was considered. A percutaneous kidney biopsy was performed and revealed microscopic polyangiitis. For this reason, the case was diagnosed as ANCA-associated vasculitis. Esophageal stenosis and pseudodiverticulosis were observed on upper gastrointestinal endoscopy. Pathological changes due to inflammation were observed in the biopsy and esophagography. Pulse therapy with methylprednisolone at 1,000 mg/day was administered to the patient as the first-line treatment, followed by prednisolone at 40 mg/day as remission induction treatment. Bloody urine and lung shadows disappeared, and the steroid dose was tapered at hospital discharge. The patient's hearing ability and the esophageal pathological change that was considered to be ANCA-associated vasculitis were improved. Although a few studies have reported that esophageal stenosis and pseudodiverticulosis accompany ANCA associated vasculitis, we think that examination for the possible presence of gastrointestinal tract lesions is important. PMID- 26625472 TI - David Renfrew White (28 December 1914-3 August 2015) MB ChB, D.D.R., F.R.A.C.R. PMID- 26625473 TI - Effective Treatment for a Complicated Lower Limb Ulcer. PMID- 26625474 TI - Reply. PMID- 26625475 TI - A simple approximation for calculating sample sizes for comparing independent proportions. AB - A simple approximation is provided to the formula for the sample sizes needed to detect a difference between two binomial probabilities with specified significance level and power. The formula for equal sample sizes was derived by Casagrande, Pike and Smith (1978, Biometrics 34 , 483-486) and can be easily generalized to the case of unequal sample sizes. It is shown that over fairly wide ranges of parameter values and ratios of sample sizes, the percentage error which results from using the approximation is no greater than 1%. The approximation is especially useful for the inverse problem of estimating power when the sample sizes are given. PMID- 26625476 TI - Edits Updates. PMID- 26625477 TI - Registrars in Action: How Cancer Registry Data Are Used to Improve Public Health. PMID- 26625478 TI - Arizona Cancer Registry: Identifying Barriers and Developing Strategies to Improve Melanoma Reporting by Physicians in Arizona. PMID- 26625479 TI - Cancer Data Registry of Idaho: Using Area-Based Measures to Target Disparities and Guide Policy Initiatives. PMID- 26625480 TI - Nebraska Cancer Registry: Using a Linked Cancer Registry-Hospital Discharge Database for Treatment-Related Research. PMID- 26625481 TI - New Jersey State Cancer Registry: Implementing CDC's Registry PlusTM Web Plus for Ambulatory Centers and Physicians' Offices. PMID- 26625482 TI - [Becoming a psychiatrist in 2015]. PMID- 26625483 TI - Washington State Cancer Registry: Using Cancer Registry Data to Identify Disparities in Late-Stage Female Breast Cancers. PMID- 26625484 TI - [Observations and reflexions on 10 therapeutic factors in ambulatory care]. PMID- 26625485 TI - [Thank you, Haiti]. PMID- 26625486 TI - [Epilogue]. PMID- 26625487 TI - The root of cattle fatigue. PMID- 26625488 TI - Financial return on veterinary degrees, then versus now. PMID- 26625489 TI - Human lung lysozyme: sources and properties. AB - Lysozyme in human airway secretions is thought to defend the lung against airborne bacteria. Although lysozyme has been purified and characterized from human tears, milk, saliva, and other sources (1-5), human lung lysozyme has received little attention except for measurements of concentrations in sputum (6, 7), immunocytochemical and histochemical localization (8-12),and studies of secretion by alveolar macrophages (13). This study was designed to identify the sources of secreted lung lysozyme, to quantitate the secretory activities of the various sources,and to compare the properties of lysozyme from lung cells with those from other tissues. PMID- 26625490 TI - Auburn dean emeritus receives AVMA Award. PMID- 26625491 TI - House votes down restructuring of college accreditor. PMID- 26625492 TI - AVMA encourages alternatives to certain dog and cat suppliers. PMID- 26625493 TI - Grant aims to give minorities a boost in whitest profession. PMID- 26625494 TI - NIH grant expands after-school science program nationwide. PMID- 26625495 TI - Spate of construction happening at CSU. PMID- 26625496 TI - AVMA applauds walking horse legislation. PMID- 26625497 TI - $16 million bolsters NC State endowments. PMID- 26625498 TI - Past and future perfect. PMID- 26625499 TI - Orofacial pain and the prospects of precision medicine. PMID- 26625500 TI - Response to Letter Regarding Article, "Cardiac Structure and Function Across the Glycemic Spectrum in Elderly Men and Women Free of Prevalent Heart Disease: The Atherosclerosis Risk In the Community Study". PMID- 26625501 TI - Addressing the primary care workforce crisis. AB - Our nation's primary care system is in crisis. As medical homes and accountable care organizations increasingly rely on a strong primary care workforce, the shortage of primary care physicians now calls for more policy attention and urgency. In the spirit of the 2014 Institute of Medicine recommendations on graduate medical education (GME) funding, we propose that CMS explicitly reward teaching hospitals if a certain share of their graduates (we propose 30%) remain in primary care 3 years after residency, either through additional payments or release of a withhold. Such a policy could allow hospitals to retain GME funding at a time when continued federal subsidization of GME is being called into question. Moreover, hospitals stand to benefit from producing primary care physicians, both under traditional fee-for-service contracts that reward volume through referrals and, especially, under risk contracts that reward for greater numbers of covered lives. PMID- 26625502 TI - The association among medical home readiness, quality, and care of vulnerable patients. AB - OBJECTIVES: Despite broad support for the patient-centered medical home (PCMH), the implications of PCMH implementation efforts that require that participants have some degree of PCMH readiness at baseline are unclear. Therefore, we sought to examine the association among PCMH readiness, quality, and the care of vulnerable patients. STUDY DESIGN: We conducted a cross-sectional study of adult visits to a nationally representative sample of US office-based primary care physicians in 2007 and 2008. METHODS: Using National Committee for Quality Assurance criteria, we determined whether or not a visit occurred at a PCMH-ready practice. We used t tests and multiple linear regression to measure the association between PCMH readiness and performance on 9 validated outpatient quality indicators. RESULTS: Among 12,235 visits to general practitioners and 5123 visits to general internists, 73% occurred at practices that were PCMH ready. Visits by patients with 3 or more chronic medical conditions were more likely to occur at ready practices (P = .001). Visits by patients that were poor or minority were equally likely to occur at ready and unready practices. Performance at ready practices was higher for 3 of 9 quality indicators related to chronic disease management and preventive counseling (P = .031 [beta-blocker or diuretic prescribed for hypertension]; P = .018 [diet counseling]; and P <.001 [exercise counseling]). CONCLUSIONS: Implementation efforts that encourage the enrollment of practices most ready for the PCMH could improve the quality of care for complex patients without exacerbating socioeconomic disparities in access to care. PMID- 26625503 TI - Trends in public perceptions of electronic health records during early years of meaningful use. AB - OBJECTIVES: The proportion of US doctors using electronic health records (EHRs) has risen sharply in response to the federal Meaningful Use (MU) program, which incentivizes EHR adoption. To track consumer perceptions of EHRs during this period, we conducted a national telephone survey annually for 3 consecutive years, from 2011 to 2013, corresponding with the early years of MU. STUDY DESIGN: Nationwide random digit-dial survey. METHODS: The survey used random digit-dial sampling on a dual frame of landline and cell phone numbers in the continental United States, but was not otherwise stratified by geographic region, race, or other variables. Because our primary goal was to identify relationships between variables and EHR attitudes, we constructed post hoc survey weights to align all 3 samples with each other. Relationships between sociodemographics and EHR questions were assessed with logistic regression models using the survey weights. Cross-year comparisons were conducted with chi2 tests and Cochran-Armitage tests for linear trend. RESULTS: Between 2011 and 2013, the proportion of respondents with a doctor who used an EHR rose from 64% to 71%. In 2011, 64% endorsed the belief that EHRs would improve healthcare quality, dropping to 62% by 2013. Simultaneously, the proportion concerned about the effects of EHRs on privacy dropped from 48% to 41%. Consumers whose doctors used EHRs were generally more likely to believe EHRs would improve healthcare quality and less concerned about privacy risks than those whose doctors did not use EHRs. CONCLUSIONS: Overall, we conclude that during the early years of the MU program, exposure to EHRs increased while confidence in the benefits of EHRs and concerns about privacy risks became less marked. The subset of people exposed to EHRs via their physicians continued to have more positive attitudes toward them than those without that exposure. These attitudinal trends may be linked to increased familiarity with health information technology. PMID- 26625504 TI - Feasibility of integrating standardized patient-reported outcomes in orthopedic care. AB - OBJECTIVES: Osteoarthritis of the knee is a chronic disease associated with pain and reduced quality of life. The ability to reliably measure patient-reported symptoms is important for clinical decision making and evaluation of outcomes. Electronic and web-based tools can eliminate much of the labor-intensive aspects of questionnaire administration and enables both real-time evaluation of responses by physicians and integration of data from multiple sites. This article describes the results of implementing a single integrated electronic questionnaire system into routine orthopedic practice at 2 diverse institutions. STUDY DESIGN: Case study. METHODS: A web-based version of a general quality-of life questionnaire (EuroQol 5-dimension [EQ-5D]) and the pain domain of a disease specific questionnaire (Knee Osteoarthritis Outcome Score [KOOS]) were administered in the office waiting room to (n = 666) patients at 2 centers over a 9-month period using touchscreen devices. Data were analyzed and descriptive statistics were calculated to assess feasibility of integration into the distinct work flows and to assess the agreement of the results. RESULTS: The electronic questionnaire had a completion rate of 93% to 95%. Average questionnaire completion times were 3 to 5 minutes at each institution. Mean EQ-5D and KOOS scores for patients pre- and postsurgery were also consistent with prior literature studies. CONCLUSIONS: Lessons learned for future adoption of questionnaire systems elsewhere include the need for baseline assessment of clinic work flows to identify the optimal point of administration and the need for IT support. This study demonstrates the feasibility of routinely collecting patient-reported data as part of standard care, which will become increasingly important as the nationwide emphasis on tracking quality and cost-effectiveness of treatments in orthopedics grows. PMID- 26625505 TI - A randomized controlled trial of co-payment elimination: the CHORD trial. AB - OBJECTIVES: Efforts to improve adherence by reducing co-payments through value based insurance design are become more prevalent despite limited evidence of improved health outcomes. The objective of this study was to determine whether eliminating patient co-payments for blood pressure medications improves blood pressure control. STUDY DESIGN: Randomized controlled trial. METHODS: The Collaboration to Reduce Disparities in Hypertension (CHORD) was a randomized controlled trial with 12 months' follow-up conducted among patients from the Philadelphia and Pittsburgh Veterans Administration Medical Centers. We enrolled 479 patients with poorly controlled systolic blood pressure. Participants were randomly assigned to: a) receive reductions in co-payments from $8 to $0 per medication per month for each antihypertensive prescription filled, b) a computerized behavioral intervention (CBI), c) both co-pay reduction and CBI, or d) usual care. Our main outcome measure was change in systolic blood pressure from enrollment to 12 months post enrollment. We also measured adherence using the medication possession ratio in a subset of participants. RESULTS: There were no significant interactions between the co-payment interventions and the CBI interventions. There was no relative difference in the change in medication possession ratio between baseline and 12 months (0.05% and -.90% in control and incentive groups, respectively; P = .74) or in continuous medication gaps of 30, 60, or 90 days. Blood pressure decreased among all participants, but to a similar degree between the financial incentive and control groups. Systolic pressure within the incentive group dropped 13.2 mm Hg versus 15.2 mm Hg for the control group (difference = 2.0; 95% CI, -2.3 to 6.3; P = .36). The proportion of patients with blood pressure under control at 12 months was 29.5% in the incentive group versus 33.9 in the control group (odds ratio, 0.8; 95% CI, 0.5 1.3; P = .36). CONCLUSIONS: Among patients with poorly controlled blood pressure, financial incentives--as implemented in this trial--that reduced patient cost sharing for blood pressure medications did not improve medication adherence or blood pressure control. PMID- 26625506 TI - A randomized controlled trial of negative co-payments: the CHORD trial. AB - OBJECTIVES: Value-based insurance designs are being widely used. We undertook this study to examine whether a financial incentive that lowered co-payments for blood pressure medications below $0 improved blood pressure control among patients with poorly controlled hypertension. STUDY DESIGN: Randomized controlled trial. METHODS: Participants from 3 Pennsylvania hospitals (n = 337) were randomly assigned to: a) be paid $8 per medication per month for filling blood pressure prescriptions, b) a computerized behavioral intervention (CBI), c) both payment and CBI, or d) usual care. The primary outcome was change in blood pressure between baseline and 12 months post enrollment. We also measured adherence using the medication possession ratio in a subset of participants. RESULTS: There were no significant interactions between the incentive and the CBI interventions. There were no significant changes in medication possession ratio in the treatment group. Blood pressure decreased among all participants, but to a similar degree between the financial incentive and control groups. Systolic blood pressure (SBP) dropped 13.7 mm Hg for the incentive group versus 10.0 mm Hg for the control group (difference = -3.7; 95% CI, -9.0 to 1.6; P = .17). The proportion of patients with blood pressure under control 12 months post enrollment was 35.6% of the incentive group versus 27.7% of the control group (odds ratio, 1.4; 95% CI, 0.8-2.5; P = .19). Diabetics in the incentive group had an average drop in SBP of 12.7 mm Hg between baseline and 12 months compared with 4.0 mm Hg in the control group (P = .02). Patients in the incentive group without diabetes experienced average SBP reductions of 15.0 mm Hg, compared with 16.3 mm Hg for control group nondiabetics (P = .71). CONCLUSIONS: Among patients with poorly controlled blood pressure, financial incentives-as implemented in this trial-did not improve blood pressure control or adherence except among patients with diabetes. PMID- 26625507 TI - Global payment contract attitudes and comprehension among internal medicine physicians. AB - OBJECTIVES: Global payment contracts (GPCs) are increasingly common agreements between insurance payers and healthcare providers that incorporate aspects of risk adjustment, capitation, and pay-for-performance. Physicians are often viewed as potential barriers to implementation of organizational change, but little is known about internist opinion on GPC involvement or specific internist attributes that might predict GPC support. We aimed to investigate internist and internal medicine subspecialist support of GPC involvement, and to identify associations among physician attributes, GPC knowledge, and GPC support. STUDY DESIGN: Cross sectional. METHODS: General medicine and internal medicine subspecialist physicians within the Beth Israel Deaconess Department of Medicine in Boston, Massachusetts, were surveyed 4 years after care organization entry into a GPC. Measurements collected included reported support for GPC involvement, reason for support, and demonstrated comprehension of key GPC details. RESULTS: Of the 281 respondents (49% response rate), 85% reported supporting involvement in a GPC. In a multivariate ordinal logistic regression model, exposure to prior information about GPCs, demonstrated comprehension of key GPC details, longer time since completion of residency, and lower clinical time commitment were all independently associated with higher levels of GPC involvement support. CONCLUSIONS: Four years since first engaging in a global payment contract, a majority of internal medicine physician respondents support this decision. Understanding predictors of physician support for GPC involvement within our care organization may help other health systems to approach organizational change. Health system leaders debating GPC involvement should consider engaging physicians via educational interventions geared toward improving GPC support. PMID- 26625508 TI - Between Two Worlds: Liminality and Late-Stage Cancer-Directed Therapy. AB - Disease-directed therapy near death is a growing trend among persons living with late-stage cancer. As a sociocultural phenomenon, cancer-directed therapy (e.g., chemotherapy) when given for very advanced disease is a process that offers questionable benefits and portends further suffering, but also suggests potential for growth and transcendence. Theories and concepts drawn from cultural anthropology, sociology, and existentialism illustrate how contextual factors contribute to the creation of a "liminal space"; the latter part of the cancer trajectory where living and dying can overlap. When applied to clinical practice, this theoretical framework gives the patient, family, and health care provider a way of "unmasking" a period of transition during terminal illness when aggressive disease-directed care continues to be provided. The liminal space may function as an existential plane; a gateway or threshold with inherent potential for psychospiritual development during the final stage of life. PMID- 26625509 TI - Maladaptive Perfectionism: Understanding the Psychological Vulnerability to Suicide in Terms of Developmental History. AB - This study aimed to explore how the life history of suicide victims with no history of treatment in mental health care or of attempted suicide seemed to presdispose them to maladaptive perfectionism. The study is part of an ongoing psychological autopsy study. It aimed to produce a phenomenological understanding of the vulnerability to suicide related to perfectionism, based on the life history of six male suicide victims aged 22 to 58. Interpretative Phenomenological Analysis was used to analyze the interview data of 41 key informants. Three main themes emerged: (a) exposure to high expectations combined with little recognition and warmth; (b) reduced ability to cope with failures and weaknesses; and (c) fear of emotional rejection. Together these themes illustrate that feelings of shame, mainly resulting from an unfulfilled need for attachment, a desire for love and recognition may relate to maladaptive perfectionism, which influences the suicidal process. The results may have important implications for suicide prevention programs. PMID- 26625510 TI - Development of a Scale to Measure Death Perspectives: Overcoming and Participating. AB - Kastenbaum and Aisenberg have suggested that persons can cope with the impact of death and dying by altering their understanding of what each means to them as well as by changing their behavioral responses to such experiences. The present study's purpose was to develop a reliable and valid measure to assess an individual's particular death perspective based on Kastenbaum and Aisenberg's distinctions between overcomers and participators. The Death Perspective Scale developed here assessed the extent to which individuals utilize either an overcoming or participating approach to (a) assigning meaning to dying and death and (b) behaviorally responding to death-related experiences. Based upon the data collected from 168 adults varying by age and gender, findings suggested that both overcoming and participating could be reliably assessed, correlated with measures of death anxiety and death attitudes, and varied reliably (p < .05) by age and gender, wherein such differences were for the most part consistent with predictions by Kastenbaum and Aisenberg espoused over 30 years ago. Findings here suggested that overcomers reported more fear of death and dying and were less accepting in this respect, while participators reported fewer death-related fears and were more accepting. Women and older adults were more participating, while men and younger adults were more overcoming, though such effects varied depending upon whether meaning versus response to death was considered. The consistency between the present findings and the predictions Kastenbaum and Aisenberg suggests that while person's orientations to death and dying seem to transcend sociocultural change, empirically based efforts to better understand how our death system impacts persons need to move forward. PMID- 26625511 TI - Miss B Pursues Death and Miss P Life in the Light of V. E. Frankl's Existential Analysis/Logotherapy. AB - Ms B's in United Kingdom and Ms P's in Finland choices in life when dealing with acute ventilator-assisted tetraplegia were analyzed by means of Viktor E. Frankl's existential analysis/logotherapy. The freedom of will to existential meaning and to worth in one's suffering realizes in the attitudinal change the person chooses or is forced to adopt when subject to severe circumstances. Life becomes existentially meaningful relative to inescapable suffering by the completion of three values: creative, experiential, and attitudinal values. If the search for meaning on these paths is frustrated or obstructed, a person's will to meaning transforms into existential frustration along with an existential vacuum and feelings of despair emerge and harm the person's will to survive. However, a person's frustrated meaning in life, when subject to unavoidable severe conditions, can be averted and redirected by applying the basic tenets in an existential analytic/logotherapeutic approach to the extreme situation. PMID- 26625512 TI - Evalution of Femicide Cases Committed Between the Years 1996-2005 in Antalya. AB - Criminal death incidence of women varies between developed and developing countries, and it has become a common public problem in almost every country. We do not have any data about femicide cases published in Turkey until today. In our study, we tried to call attention to femicide cases. In our study, we evaluated 141 cases of female homicides with an interval of 10 years between January 1996 and May 2005, retrospectively. Data retrieved were statistically evaluated using chi-square test. Most of the cases were between 21 and 35 years of age. Spouse murders are usually witnessed during the process of divorce. Establishment of institutions which will ensure the security of women during this period is of paramount importance. If we protect women during divorce and separation proceedings, we can prevent femicide cases. We also think that laws may be strengthened for protecting women who are vulnerable at such times. PMID- 26625513 TI - [Noninvasive Electrophysiological Predictors and Biomarkers of Malignant Arrhythmias in Patients With Ischemic Heart Disease: a 2-Year Prospective Follow up]. AB - AIM: to assess prognostic value of clinical and instrumental parameters, results of noninvasive electrophysiological tests and biomarkers as predictors of malignant ventricular arrhythmias in patients with ischemic heart disease (IHD) during long-term follow-up as well as during myocardial revascularization surgery and early postoperative period. MATERIAL: We prospectively enrolled 97 patients (mean age 61 +/- 10 years) with angiographically confirmed coronary artery disease. Most patients (68%) had heart failure NYHA functional class II-III. Mean left ventricular ejection fraction (LVEF) was 50 +/- 13%; 20% of patients had LVEF <= 35%. Sixty two patients had revascularization procedures during follow up. METHODS: We used 24-hour Holter monitoring and signal-averaged electrocardiography to obtain the following parameters: microvolt T-wave alternans, QT-interval duration and dynamics, heart rate turbulence (HRT) and variability. Laboratory tests included serum creatinine and creatinine clearance, brain natriuretic peptide (BNP), NT-proBNP, C-reactive protein and troponin T levels. RESULTS. During mean follow-up period of 25 +/- 11 months life threatening ventricular arrhythmias were observed in 11 patients (11%). On univariate analysis, history of percutaneous coronary intervention (p < 0.05), history of malignant arrhythmias or syncope (p < 0.05), LVEF <= 47% (p < 0.01), left atrium size 24.7 cm (p < 0.05), left atrium index (p = 0.01), filtered QRS duration (p < 0.05), abnormal heart rate turbulence (HRT) (chi-square test = 6.2, p = 0.01), abnormal turbulence slope (chi-square test = 9.5, p < 0.01), BNP >= 158 picogram/ml (p < 0.01), NT-proBNP >= 787 rg/ml (chi-square test = 4.4, p < 0.05) were significantly associated with malignant arrhythmias in long-term follow-up. History of malignant arrhythmias or syncope (OR 11.1, 95% Cl 2.8-44.4; p < 0.01), abnormal HRT (OR 13.6, 95% Cl 2.8-66.1; p < 0.01), and plasma BNP >= 158 picogram/ml (OR 14.3, 95% CI 3.2-65.0; p < 0.01) were independent predictors of malignant arrhythmias on multivariate Cox regression analysis. CONCLUSION: History of malignant arrhythmias, pathological HRT and plasma brain natriuretic peptide level >= 158 picogram/ml were independent predictors of malignant ventricular arrhythmias during 2 years follow-up of patients with IHD. PMID- 26625514 TI - [Predictors of Efficacy of Radiofrequency Ablation of Pulmonary Veins Performed During Coronary Bypass Surgery in Patients With Ischemic Heart Disease and Paroxysmal Atrial Fibrillation]. AB - We performed simultaneous coronary artery bypass grafting (CABG) and radiofrequency ablation (RFA) ostia of pulmonary veins in 254 patients (147 men and 107 women) with ischemic heart disease and paroxysmal atrial fibrillation (AF). In-hospital mortality in patients with early recurrence of AF was 8.4%, in patients without recurrence of AF 1.9% (chi2 = 4.65; p = 0.03). The patients were followed-up during 12 months after operation. During follow-up 166 patients (69.5%) had no recurrence of AF without receiving antiarrhythmic drugs (AAP), 33 patients (13.8%) had recurrences of AF, and 40 patients (16.7%) receiving AAD had repeated rare paroxysms of AF. Main predictors of late AF recurrence were age > 65 years, AF duration > 5 years, preoperative atrial effective refractory period < 240 ms, frequency threshold of AF induction < 400 counts/min, anteroposterior left atrial size > 50 mm, glomerular filtration rate < 60 ml/min/1.73 m2. Reverse dynamics of structural, functional and electrophysiological parameters of the heart due to CABG and RFA, use of beta-blockers, angiotensin converting enzyme inhibitors and aldosterone antagonists were associated with the preservation of a stable sinus rhythm. The cardiovascular mortality during 12 months follow-up accounted for 2.1% and 1.2% in groups of patients with and without late recurrences of AF respectively (p > 0.05) to coronary artery bypass grafting surgery and RFA, taking drugs--beta-blockers, angiotensin converting enzyme inhibitors and aldosterone antagonists--were associated with the preservation of a stable sinus rhythm. PMID- 26625515 TI - [Therapy of Arterial Hypertension in Patients With Chronic Heart Failure and Signs of Chronic Kidney Disease With Fixed Perindopril/Amlodipine Combination]. AB - PURPOSE: to assess efficacy of a fixed combination of perindopril arginine and amlodipine besylate in the treatment of hypertensive patients with chronic heart failure (CHF) and signs of chronic kidney disease (CKD). MATERIAL AND METHODS: Persons with CKD (n = 53, age 64.5 +/- 8.2 years) were selected from 118 patients with grade 2-3 essential hypertension with CHF. Presence of CKD was confirmed by elevated blood levels of cystatin C and lowered glomerular filtration rate (GFR). Used doses of fixed perindopril/amlodipine combination were 5/5, 5/10, 10/10 mg. Efficacy was assessed after 2 months of therapy on the basis of results of the examination which included clinical blood pressure (BP), BP monitoring, 6-min walk test. Blood levels of creatinine, urea, cystatin C and GFR were also measured. RESULTS: Target BP was achieved in 92.6% of patients. Clinical BP was significantly decreased. Daily average systolic BP decreased by 14.7%, diastolic BP--by 14.4%. Systolic and diastolic BP load also decreased. Clinical condition improved. Tolerance to physical work increased. Level of cystatin C significantly decreased while GFR increased. CONCLUSION: Fixed perindopril/amlodipine combination produced good therapeutic effect in hypertensive patients with CHF and CKD. PMID- 26625516 TI - [The Antihypertensive Effect of the Fixed Combination of Lisinopril and Amlodipine in Patients With Coronary Heart Disease After Coronary Artery Bypass Grafting]. AB - Literature data and results of our own register have indicate that hypertension is one of the most common risk factor in patients with ischemic heart disease (IHD) who have undergone coronary artery bypass grafting (CABG). But despite proven benefits of control of hypertension after CABG adherence of patients to corresponding recommendations remains low. Fixed combinations of antihypertensive drugs are associated with better compliance. In 30 IHD patients after CABG we studied effects of fixed lisinoprillamlodipine combination. This combination was safe and had high antihypertensive activity. Practically all patients responded to therapy and achieved target level of arterial pressure. PMID- 26625517 TI - [What Are the Realities of Prescription and Control of Antithrombotic Therapy in Atrial Fibrillation in Outpatient Practice?]. AB - We analyzed documentation of 648 outpatients with nonvalvular atrial fibrillation receiving ambulatory care in 3 cities in Russia (Moscow, Krasnodar, and Bryansk). Frequency of use of any anticoagulant in patients with AF and high risk of stroke and systemic embolism was low (30.9% overall, novel oral anticoagulants--5.7%). But portions of patients who according to documents received antiaggregants or no antithrombotic drugs at all were high (53.6 and 13.4%, respectively). Among patients receiving warfarin only 19.6% checked international normalized ratio (INR) every month while 75% did it once in 3 months or rarer or did not control this parameter at all. Among patients in whom INR control was sufficiently regular only in 44% percentage of time in the therapeutic range exceeded 60%. Thus persistent effective anticoagulation was achieved only in 12.6% of warfarin treated outpatients. PMID- 26625518 TI - [Changes in Cerebral Blood Flow and Cognitive Function in Patients Undergoing Coronary Bypass Surgery With Cardiopulmonary Bypass]. AB - PURPOSE: to study effect of coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB) on regional cerebral blood flow and cognitive function in patients with ischemic heart disease (IHD). MATERIAL AND METHODS: We included into this study 22 patients with IHD subjected to CABG surgery with CPB. All patients underwent brain SPECT scanning and comprehensive neuropsychological testing 1 day before, 10-14 days and 6 months after surgery. RESULTS: Overall CABG with CPB was followed by reduction of regional cerebral blood flow relative to baseline in frontal and parietal cortex (p < 0.01). Substantial reduction (> 5%) of cerebral perfusion in early postoperative period was observed in 15 patients (68%) while seven patients (32%) had no significant changes of regional cerebral blood flow. Changes of cerebral perfusion correlated with dynamics of cognitive status. Mean measures of immediate verbal memory, delayed memory, and learning decreased after surgery by 25.6 (p = 0.002), 43.3 (p = 0.000003), and 23.1% (p = 0.00000), respectively. Moreover after CABG with CPB patients demonstrated slowing of psychomotor speed by 13.6% (p = 0.03). CONCLUSION: CABG with CPB was associated with reduction of cerebral perfusion leading to cognitive dysfunction. Immediate and delayed verbal and visual memory, learning and psychomotor speed were most sensitive to the negative effects of surgery. PMID- 26625519 TI - [An Association Between T455C Polymorphism of Apolipoprotein C-III Gene, Insulin Resistance and Metabolic Syndrome Components]. AB - AIM: to study an association between T455C apolipoprotein C-III (apo C-III) gene polymorphism, insulin resistance (IR), metabolic syndrome (MS) and its components in a Kyrgyz ethnic group. MATERIAL AND METHODS: 259 persons: 162 patients with MS and 97 sex and age matched controls without MS, diabetes mellitus and cardiovascular diseases were included in the study. Clinical examination with arterial blood pressure, anthropometric data measurement and laboratory tests for blood glucose and lipid parameters were performed in all included persons. In 140 patients test for immunoreactive serum insulin was done. DNA was extracted from blood cells and T455C polymorphism of apo C-III gene was determined by PCR method. RESULTS: In examined persons the most frequent was TC genotype as in group with MS as in controls. The difference on genotype's frequency between group was close to significant level (chi2 =5.48; p = 0.06) and odd ratio (OR) for MS between CC and TT carriers was 2.57 (95% CI 1.15-5.72); p = 0.019). Frequency of 455C allele in control group was--0.44 and in group with MS--0.54 (chi2 = 4.55; p = 0.036). In carriers of CC genotype there was noted that the frequency of IR (61.8% vs 23.1% vs 36.3%; p < 0.005), insulin level (11.9 [7.04 16.3] vs 5.73 [3.34-10.3] vs 7.54 [4.59-12.2] uIU/ml; p < 0.01) and HOMA index (3.14 [1.66-4.79] vs 1.46 [0.8-2.6] vs 2.05 [1.12-3.6]; p < 0.01) were significantly higher compared with TT and TC genotypes groups respectively. OR for IR between CC and TT carriers was 5.39 (95% CI 1.7-16.9; p = 0.0028). There also was an association between CC genotype and other MS components such as abdominal obesity (chi2--6.24; p--0.044, OR (95% CI--2.21 [1.03-4.82]) and high level of blood triglycerides (chi2--7.57; p--0.022, OR (95% CI) 2.5 [1.14-5.5]). CONCLUSION: In examined Kyrgyz ethnic population the most frequent was heterozygous TC genotype of T455C polymorphism of apo C-III. An association of 455C allele and CC genotype with MS, IR, abdominal obesity and high level of triglycerides was revealed. Key words: apolipoprotein C-III; T455C gene polymorphism; metabolic syndrome, insulin resistance. PMID- 26625521 TI - [The Relationship Between Level of End-Products of Tissue Glycation and Pulse Wave Velocity in Non-diabetic Patients With Cardiovascular Disease]. AB - AIM: of the study was to assess the relationship between advanced glycation end products measured by skin autofluorescence (AGEs) and pulse wave velocity (PWV) in non-diabetic patients with cardiovascular disease (CVD). MATERIAL AND METHODS: Skin autofluorescence (AGE--reader, DiagnOptic) and PWV in humero-malleolar segment (PWVhm) were measured in 93 non-diabetic CVD patients (mean age 63.5 years): 28 with ischemic heart disease (IHD) and 65 without IHD from the group with moderate/high risk of development of cardiovascular complications. RESULTS: Significant positive association was observed between AGEs and PWVhm (r = 0.31, p = 0.003). This correlation was found only in patients without IHD (r = 0.44, p < 0.0003). Positive association AGEs with of age (r = 0.52, p = 0.006) was observed irrespective of IHD. AGEs was not the significant determinant of PWVhm in multiple regression analysis. CONCLUSION: Relationship between AGEs and PWVhm was found in non-diabetic moderate/high-risk patients. In contrast to age and systolic blood pressure AGEs was not the significant determinant of PWVhm. PMID- 26625520 TI - [The Action of Apelin-12 and Its Analog on Hemodynamics and Cardiac Contractile Function of Rats With Isoproterenol-Induced Myocardial Lesion]. AB - Introduction of isoproterenol (beta-adrenoreceptor agonist) into rats is one of the widespread experimental models of heart failure. It is caused by diffuse ischemic damage of cardiomyocytes, followed by development of substitutive fibrosis. Apelin is a natural regulator of the myocardial contractility. The effects of apelin molecule fragment, apelin-12 and its more stable synthetic analogue, apelin-12-2 on cardiac contractile function of rats with isoproterenol induced myocardial lesion (IML) and control animals has been studied in this work using invasive (catheterization of the left ventricle) and non-invasive (echocardiography and impedansometry) methods. Infusion of both peptides was made by sequentially increasing rate from 0.5 to 50 ug/kg/min. In the control group, efficacy of apelin-12 was low while apelin-12-2 moderately but significantly increased indices of myocardial contractility and relaxability. These changes were more pronounced in rats with IML and, in addition, the heart rate and LV systolic pressure increased in this group. These results correlate well with echocardiographic studies which showed increases of LV end diastolic volume, stroke volume and ejection fraction by 17-38%. These alterations are probably due to improved Ca2+ transport in cardiomyocytes, as in experiments on isolated cardiomyocytes both apelins have facilitated and improved Ca2+ removal from myoplasma. The results allow to conclude that apelin-12-2 seems to be a promising candidate for further development as a therapeutic agent in heart failure. PMID- 26625522 TI - [Analysis of Efficiency of the Standard of Sanatorium Care of Patients With Arterial Hypertension]. AB - Analysis of efficiency of the standard of sanatorium care of patients with arterial hypertension is presented. Rates of arbitrary use of methods of care and their use in accordance with requirements of the standard were compared in patients with diferent results of treatment. It was found that existing standard was insufficiently adequate for application in the work of attending physician. Observance of requirements of the standard was associated with 93 +/- 0.8% achievement of positive results. Rates of use of methods of care in groups of patients with positive and negative result of sanatorium stay were significantly different. PMID- 26625524 TI - [Opportunities Provided by Stress Echocardiography and Stress Speckle tracking for the Evaluation of Myocardial Reserve Among Patients With Heart Defects]. AB - Heart failure risk factors research as well as studies of myocardial dysfunction to identify subclinical heart disease are important problems that can be solved with stress echocardiography and new methods of myocardial function analysis. Key factors defining the prognosis of patients with valvular diseases are heart remodeling and myocardial contractility. Heart remodeling types have been studied in detail by the present time. Elucidation of capability of stress echocardiography to detect asymptomatic dysfunction and assess prognosis of the results of surgery is continuing. Most important technological achievements of the last ten years gave us the opportunity to quantitatively assess myocardial function and movement. Tissue Doppler and Speckle Tracking enabled us to find alternative to invasive methods way to determination of parameters of global and regional myocardial function. Nowadays the first research results on the use of Speckle Tracking to estimate the contractile reserve are appearing. A high prognostic significance of global longitudinal deformation has been revealed. The aim of this article is to summarize available data on assessment of severity of valvular heart disease and the state of myocardial contractile reserve using stress echocardiography, Tissue Doppler and Speckle tracking data. PMID- 26625523 TI - [Perspectives for the Blockade of the Renin-angiotensin-aldesteron System and Modulation of Natriuretic Peptides System in the Treatment of Arterial Hypertension and Heart Failure]. PMID- 26625525 TI - [Effect of Antihypertensive Drugs on Regression of Left Ventricular Hypertrophy]. AB - In this review we show that combination treatment with blockers of renin angiotensin-aldosterone system and dihydropyridine calcium antagonists plays the leading role in lowering of left ventricular myocardial mass. We also demonstrate benefits of the use of fixed combinations of drugs for the treatment of patients with arterial hypertension including those with left ventricular hypertrophy, and stress advantages of angiotensin II receptor blockers characterized by low risk of unfavorable effects and high compliance to treatment over other classes of antihypertensive drugs. PMID- 26625526 TI - [New Anticoagulants in the Treatment of Patients With Recent Acute Coronary Syndrome. Place of Rivaroxaban]. PMID- 26625527 TI - [The New Fixed Combination of Antihypertensive Drugs in Clinical Practice]. PMID- 26625528 TI - [Catheter Isolation of Pulmonary Veins in a Patient With Paroxysmal Atrial Fibrillation After Repair of Interventricular Septum With a Xeno-Pericardial Patch]. AB - Catheter radiofrequency ablation of focal atrial fibrillation was successfully performed in a patient after closure of interventricular septal defect with a xeno-pericardial patch and plastic of tricuspid valve. The case demonstrates feasibility of carrying out such interventions under intracardiac echocardiographic guidance in patients with disturbed anatomy and complicated access to the left atrium. PMID- 26625529 TI - [The Case of the Rapid Progression of Coronary Heart Disease: From the Debut Before Transplantation]. PMID- 26625530 TI - ON THE NEW CQC INSPECTION REGIME. Flaws in ratings leave trusts with a raw deal. PMID- 26625531 TI - LABOUR'S 10 YEAR PLAN WON'T WIN THE KEYS TO DOWNING STREET. PMID- 26625532 TI - PATIENT SAFETY NEEDS TO BE IMPROVED. PMID- 26625533 TI - CHANGE CHALLENGE CAMPAIGN. Put frontline staff in the driving seat for change. PMID- 26625534 TI - OLDER PEOPLE'S SERVICES. Turnaround starts with a system-wide approach. PMID- 26625535 TI - [Results of a post-marketing surveillance of meropenem for febrile neutropenia]. AB - The post-marketing surveillance of meropenem (Meropen) for febrile neutropenia (FN) was conducted between July 2010 and June 2012 to evaluate safety and efficacy under actual clinical use. There were 1191 and 1124 evaluable cases for safety and efficacy respectively, of 1207 case cards collected from 180 institutions. In safety analysis, the incidence of adverse drug reactions (ADRs) associated with use of meropenem (including abnormal laboratory findings) was 15.7% (187/1191 cases), and the main ADRs were alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, hepatic function abnormal, and liver disorder, which were similar to these observed in the clinical study for FN or post marketing surveillances of meropenem conducted before. In efficacy analysis, the overall efficacy was 81.8% (919/1124 cases). Also, it was 79.2% (708/894 cases) for hematological malignancy and 91.8% (213/232 cases) for solid cancer. These results confirmed meropenem (Meropen) is one of the well-tolerated and potent antimicrobial agents for febrile neutropenia. PMID- 26625536 TI - [Sensitivity surveillance of Streptococcus pneumoniae isolates for several antibacterial agents in Gifu and Aichi prefectures (2011-2012)]. AB - We investigated the susceptibility to antibacterial agents, genotype of penicillin-binding protein (PBP) genes and macrolide resistant genes, and the serotypes against 270 strains of Streptococcus pneumoniae isolated from medical facilities in Gifu and Aichi prefectures between October 2011 and April 2012. These results were compared with those against S. pneumoniae isolated in 2008 2009 and 2010-2011. The number of gPSSP with 3 normal PBP genes, gPISP with 1 or 2 normal PBP genes and gPRSP with 3 abnormal genes isolated in 2011-2012 was 15 (5.6%), 162 (60.0%) and 93 (34.4%) strains, respectively. Compared with those isolated in 2008-2009 and 2010-2011, the numbers of gPRSP were decreasing. On the other hand, the isolates with no macrolide-resistant gene, only mefA, only ermB, and both mefA and ermB were 16 (5.9%), 75 (27.8%), 153 (56.7%) and 26 (9.6%). Compared with those isolated in 2008-2009 and 2010-2011, the numbers of isolates with ermB, which was usually associated with high-level resistance, were increasing. The prevalent pneumococcal serotypes in children were type 3 (14.4%), following by type 15 and 19F (9.3%). The coverages of 7-valent pneumococcal conjugate vaccine (PCV7) and 13-valent pneumococcal conjugate vaccine (PCV13) were calculated as 22.9% and 49.2%, respectively. The coverages of PCV7 and PCV13 in gPRSP isolated from children were 47.7% (21/44 strains) and 72.7% (32/44 strains). The MIC90 of each antibacterial agent was as follows; 0.125pg/mL for imipenem, panipenem and garenoxacin, 0.25 MUg/mL for meropenem and doripenem, 0.5 MUg/mL for cefditoren, moxifloxacin and tosufloxacin, 1 MUg/mL for amoxicillin, clavulanic acid/amoxicillin, cefteram, cefcapene and ceftriaxone, 2 MUg/mL for benzylpenicillin, ampicillin, sulbactam/ampicillin, piperacillin, tazobactam/piperacillin and levofloxacin, 4 MUg/mL for cefdinir, flomoxef and pazufloxacin, 16 MUg/mL for minocycline, > 64 MUg/mL for clarithromycin and azithromycin, and these MIC90s were about the same as those in 2010-2011. PMID- 26625537 TI - [Voriconazole dosage optimization in adult patients based on different CYP2C19 genotypes]. PMID- 26625539 TI - [Reports of JARA]. PMID- 26625538 TI - [The 5th Chiba Symposium on Mycosis]. PMID- 26625540 TI - Assessing the Need for Hospitalization in Order to Conduct a Psychiatric Evaluation as part of Criminal Law Procedure. AB - BACKGROUND: In criminal law, psychiatrists are consulted regarding the "insanity defense" and the defendant's competency to stand trial. Court-ordered hospital admissions for such evaluations are on the increase, creating a major burden on the health system. OBJECTIVES: To assess, in a hospital setting, whether hospitalization of the defendant is necessary for conducting a psychiatric evaluation. METHODS: A 6 month prospective observational study exploring the phenomenon was conducted at the Beer Yaakov Mental Health Center. The psychiatrist was asked both at the initiation and at the end of the assessment process whether the subject was competent to stand trial and responsible for his/her actions and if hospitalization was necessary in order to conduct the evaluation. RESULTS: During the study period there were 112 admissions with a court request for a psychiatric evaluation. In 73 of the cases (65.2%) the evaluating psychiatrist believed there was no need for hospitalization. This assessment did not change by the end of the hospitalization in all cases. Employment and alcohol use were the only factors associated with a lower need for hospitalization (OR 0.24, 95% CI 0.07-0.77, and OR 0.34, 95% CI 0.13-0.90, respectively). CONCLUSIONS: In the majority of cases, based on the evaluating psychiatrist's responses, the evaluation could have been conducted without need for hospitalization. The findings indicate that an outpatient unit designated to write court-requested psychiatric evaluations could significantly reduce the rates of hospital admissions for this purpose. PMID- 26625541 TI - Left Cardiac Sympathetic Denervation in Patients with CASQ2-Associated Catecholaminergic Polymorphic Ventricular Tachycardia. AB - BACKGROUND: Left cardiac sympathetic denervation (LCSD) was reported to be effective in patients with intractable ryanodine receptor mutation-associated catecholaminergic polymorphic ventricular tachycardia (CPVT). OBJECTIVES: To report our experience with LCSD in calsequestrin (CASQ2) mutation-associated CPVT. METHODS: LCSD was performed in three patients with CASQ2 mutation associated CPVT with symptoms and exercise-induced ventricular arrhythmia despite high dose beta-blocker RESULTS: None of them experienced symptoms or exercise induced ventricular arrhythmia after LCSD. However, all had recurrence of symptoms and/or exercise-induced ventricular arrhythmia after 6 months (6-18 months). CONCLUSIONS: LCSD conferred short-term suppression but less than optimal long-term suppression of exercise-induced ventricular arrhythmia among CASQ2 associated CPVT patients. PMID- 26625542 TI - Management of Complicated Gastric Bezoars in Children and Adolescents. AB - BACKGROUND: Gastric bezoars in children are infrequent. Most are trichobezoars. Surgical intervention is sometimes necessary. OBJECTIVES: To describe the clinical findings and radiological workup, as well as treatment and outcome of patients with complicated gastric bezoars who underwent surgery in our institution. METHODS: We conducted a retrospective review of all cases of surgery for gastric bezoars performed in our institution between 2000 and 2010. Data collected included gender and age of the patients, composition and extent of the bezoar, presenting signs and symptoms, imaging studies used, performance of endoscopy, and surgical approach. Outcome was measured by the presence of postoperative complications. RESULTS: We identified seven patients with gastric bezoars who underwent surgery. All were females aged 4-19 years. Six had trichobezoars and one had a mass composed of latex gloves. Presenting symptoms included abdominal pain, vomiting, weight loss, and halitosis. All patients had a palpable epigastric mass. A large variety of imaging modalities was used. Endoscopic removal was attempted in three patients and the laparoscopic approach in one patient, but both routes failed. All patients eventually underwent laparotomy with gastrotomy and recovered without complications. CONCLUSIONS: The presence of gastric bezoars should be suspected in any child with unexplained abdominal pain, vomiting, weight loss, or halitosis, or with a palpable abdominal mass, especially in girls. A variety of imaging modalities can aid in diagnosis. Endoscopic removal might be attempted, although failure of this approach is frequent, necessitating surgical intervention, preferably laparotomy and gastrotomy, which has an excellent outcome. PMID- 26625543 TI - Should Intravenous Contrast be Administered in MRI Evaluation of Pediatric Outpatients with Chronic Headache? AB - BACKGROUND: The practice of administering intravenous contrast to children varies by institution depending on their routine. OBJECTIVES: To assess the necessity of routine contrast administration in brain magnetic resonance imaging (MRI) of pediatric outpatients referred for chronic headache workups. METHODS: We conducted a retrospective review of consecutive pediatric brain MRI examinations performed during January and February 2014 in 30 pediatric outpatients referred for evaluation of chronic headache. Independent review was performed by two board certified neuroradiologists. The raters reviewed each MRI first as a non-contrast examination (without seeing the post-contrast images) and then with post-contrast images. RESULTS: No abnormalities were found in six patients. One patient had an indeterminate finding of a tubular cerebellar lesion requiring follow-up. In the remaining patients (n = 23), the findings were subclinical and included: mucosal thickening in the paranasal sinuses in 9 patients, cystic changes of the pineal gland in 8 (size 2-9 mm), small developmental venous anomalies in 6, non-specific FLAIR hyperintensities in 4, opacification of the mastoids in 2, and telangiectasia in 1 patient. The subclinical cases that were missed on pre contrast images were: one small developmental venous anomaly, one telangiectasia and one small pineal cyst, none of which hold clinical significance. All kappa inter-rater and intra-rater agreement scores resulted in values above 0.75, excellent agreement according to Fleiss guidelines. CONCLUSIONS: There seems to be little reason to medically justify large-scale use of routine IV contrast administration to evaluate a brain MRI of pediatric patients referred for chronic headache. PMID- 26625544 TI - Periodontal Conditions and Tumor Necrosis Factor-Alpha Level in Gingival Crevicular Fluid of Scleroderma Patients. AB - BACKGROUND: Systemic sclerosis (SSc) is a chronic disease with prominent vasculopathy, inflammation, production of autoantibodies, and tissue fibrosis. Periodontitis is a chronic inflammatory oral condition manifesting as microbial infection, inflammation and destruction of the alveolar bone. In both conditions tumor necrosis factor-alpha (TNFalpha) and other proinflammatory cytokines play an important role in pathogenesis. OBJECTIVES: To assess the periodontal status in SSc patients and compare these parameters to TNFalpha level in gingival crevicular fluid (GCF) of SSc patients and healthy controls. METHODS: Twenty SSc patients and 20 controls underwent periodontal examination, including probing depth (PD), plaque index (PI), gingival-index (GI), bleeding on probing (BOP), and measurement of TNFalpha levels in collected GCF. RESULTS: SSc patients had a greater PD (3.74 +/- 0.32 mm vs. 3.35 +/- 0.31 mm, P > 0.003), GI (1.53 +/- 0.34 vs. 1.12 +/- 0.54, P > 0.049), and non-significantly higher BOP than controls. TNFalpha levels in GCF were higher in SSc patients (1.63 +/- 0.36 vs. 1.15 +/- 0.34 pg/ml, P = 0.001). Periodontitis parameters correlated with several SSc variables; PI in particular was higher in patients with longer disease duration, sclerodactyly, more severe skin involvement, and SSc activity score. CONCLUSIONS: Patients with SSc have higher indices of periodontal inflammation and higher TNFalpha level in GCF than did healthy individuals. These changes probably reflect the complexity of factors that influence oral health in SSc. Common pathologic pathways may be responsible for the association between SSc and periodontitis, which requires further study. PMID- 26625545 TI - Atypical Femoral Fractures: Radiological Evaluation and Bisphosphonate Exposure. AB - BACKGROUND: Evidence suggests that prolonged bisphosphonate (BP) treatment predisposes to atypical fractures (AF), but the etiology has yet to be determined. Addressing causality begins with case identification, which requires radiological adjudication. However, many trials based their case findings on coded diagnoses. OBJECTIVES: To investigate the feasibility of case findings by the coding system and the reproducibility of radiological evaluations in two hospitals in Israel, and to compare BP exposure of AF patients to a control group with typical (intertrochanteric of femoral neck) fractures. METHODS: Diagnostic databases from 2007 to 2010 were reviewed and admission X-rays of patients were examined in two steps by two radiologists. Fractures were classified as atypical or not atypical according to published criteria. A 2:1 control group was created. Ambulatory drug acquisition was reviewed. RESULTS: Of the 198 patients who fulfilled the search criteria, 38 were classified by initial radiological opinion as AF. Subsequent radiological opinion judged 16 as not atypical. Of the AF patients, 80% were exposed to BP. Of those, 81% continued to receive BP treatment for 2.4 years after AF. Only one AF patient was discharged with suspected AF diagnosis. In the control group, 27% were exposed to BP prior to fracture (P < 0.001). CONCLUSIONS: Thorough radiological revision is mandatory for proper classification of AF, and even when performed there is significant inconsistency in interpretation. Conclusions drawn from trials based solely on coded diagnoses lead to significant bias. BP exposure was significantly higher in the AF group. Caregiver unawareness of AF leads to improper management. PMID- 26625546 TI - Prevalence of Classic and Non-Classic Antiphospholipid Antibodies in Multiple Sclerosis. AB - BACKGROUND: The association between antiphospholipid antibodies (aPL) and multiple sclerosis (MS) has been suggested previously, but prior studies provided contradicting findings. OBJECTIVES: To characterize the expression profile of eight classic and non-classic aPL in patients diagnosed with MS. METHODS: Using the BioPlex 2200 immunoassay, we measured the levels of serum immunoglobulin (Ig)M and IgG isotypes of three classic aPL and five non-classic aPL in 98 subjects with MS and 237 healthy controls. RESULTS: Three non-classic aPL were significantly more prevalent among MS patients in comparison to the control group. These antibodies included IgM and IgG against phosphatidylserine-beta2GPI (PS-B2), IgG prothrombin complex (PT-PT) and IgM prothrombin (PT). The positive results according to Bonferroni correction are PS-B2 IgG and PT-PT IgG. The remaining aPL profiles did not differ significantly between the two groups. CONCLUSIONS: An association between certain non-classic aPL and MS has been established. The specific role of these autoantibodies in the pathogenesis of the condition remains uncertain. PMID- 26625547 TI - The Implementation of Robotic Surgery in Israel. AB - BACKGROUND: In the last decade the number of robotic devices and the medical procedures utilizing them increased significantly around the world. OBJECTIVE: To evaluate the implementation of robotic surgeries in Israel in various surgical disciplines. METHODS: We conducted a retrospective study accessing information about the annual purchases of robots, the number of physicians trained for their use, and the number of robotic surgeries performed each year, according to indications of surgery and the disciplines of the operating medical staff. The data were taken from the database of Intuitive Surgical Inc. RESULTS: Six robots were purchased by six medical centers in Israel during the years 2008-2013. There are currently 150 physicians trained to use the robot in one of the simulators of Intuitive Surgical Inc. Of them, 104 are listed as active robotic surgeons. Most of these physicians are urologists, gynecologists, or general surgeons. The number of robotic surgeries increased each year in all fields in which it was implemented. In 2013, 975 robotic surgeries were performed in Israel. Of them, 52% were performed by urologists; 89% of them were radical prostatectomy. CONCLUSIONS: The use of robotic surgery increased considerably in Israel over recent years, in urology, gynecology, general surgery, and otolaryngology. Despite the lack of conclusive evidence of the advantages of robotic surgery over the laparoscopic approach, the market power and the desire to be at the technological forefront drive many medical centers to purchase the robot and to train physicians in its use. PMID- 26625548 TI - Canine Scent Detection of Volatile Elements, Characteristic of Malignant Cells, in Cell Cultures. AB - BACKGROUND: In recent years several reports have been published describing dogs' ability to detect, by scent, patients with cancer. This ability is based on the sniffing of volatile organic elements that are secreted by malignant cells or react to them. OBJECTIVES: To evaluate the ability of trained dogs to detect breast cancer cell cultures (MCF7) compared to the control pseudo-normal keratinocyte cell line (HaCaT), and to detect melanoma (BG) and type 2 epithelial lung carcinoma (A549) malignant cell cultures to which they were not previously exposed in the course of their training. METHODS: Cell cultures were prepared in a standard manner. Two Belgian Shepherd dogs were trained and then tested in a single-blind test (for dogs and trainers) on their ability to detect the "target specimen," a MCF7 breast cancer cell culture. Following this, the ability of the dogs to detect cancer cell cultures that they were not previously exposed to (i.e., A549, BG) was tested. In each test round, four specimens placed in identical blocks were arranged in a line with one meter between them: one target specimen (MCF7, A549, BG), two control specimens (HaCaT), and a sample containing cell culture medium only. RESULTS: The two dogs picked out all the target specimens of MCF7 breast cancer cell cultures that they were trained to detect (10/10) as well as all the target specimens that they were not previously exposed to [A549 (5/5) and BG (5/5)], but did not pick out the control specimens or the cell culture medium. Thus, the sensitivity, specificity, and positive and negative predictive values for both dogs were 100%. CONCLUSIONS: The results of this study support the assumption that cancer cells have a unique odor pattern, and that this odor pattern is common to different types of cancer. PMID- 26625549 TI - Thymus Activity, Vitamin D, and Respiratory Infections in Adolescent Swimmers. AB - BACKGROUND: Several studies have identified associations between low vitamin D concentrations and risk of upper respiratory infections (URI). T lymphocytes have a major anti-viral role, are affected by vitamin D metabolism, and may mediate the link between vitamin D and URIs. Competitive swimmers have a relatively high rate of URIs, alongside a high prevalence of low vitamin D concentration. OBJECTIVES: To examine the associations linking T cell receptor excision circles (TREC, markers of thymus activity), circulating 25(OH)D concentrations and the effect of vitamin D supplementation, and URI symptoms in young competitive swimmers. METHODS: We tested 82 adolescent swimmers for serum 25(OH)D and TREC concentrations and found that 55 had vitamin D insufficiency. Randomized supplementation of either vitamin D3 or placebo was given for 12 winter weeks. URI symptoms were recorded weekly. The associations between TREC copy numbers, vitamin D and URI burden were examined. RESULTS: TREC concentrations decreased with the participants' age (r = -0.346, P = 0.003), with no significant between gender difference. TREC concentrations did not materially differ among subjects with normal, insufficient or deficient vitamin D status, and were not affected by vitamin D supplementation. No significant correlations were found between TREC levels or their changes during the study period, and mean URI severity or duration. CONCLUSIONS: Thymus activity, represented by higher TREC levels, was not related to vitamin D concentrations or status, and was not affected by vitamin D supplementation in adolescent swimmers. TREC concentrations were not associated with URI severity or duration in this population. PMID- 26625550 TI - Are all CPVT Patients Equal?? PMID- 26625551 TI - Endoethelial Progenitor Cells are Affected by Medications and Estrogen. AB - EPCs constitute an essential cornerstone in the building and maintenance of the endothelial blood vessels, as well as the functioning of most of the systems of our body, including the endocrine, neurological, hematological, immune and inflammatory systems as well as organs such as kidney, heart, lungs and brain. Moreover, they serve as gatekeepers, preventing degenerative processes that affect every organ and tissue. It is important to know and understand that medications and hormones have an effect on these cells. This knowledge may help us to stimulate and maintain EPCs as well as plan future pharmacological interventions. PMID- 26625552 TI - Karyomegalic Interstitial Nephritis with Chronic Kidney Disease. PMID- 26625554 TI - Recurrent Unilateral Orchitis as a Presenting Symptom of Polyarteritis Nodosa. PMID- 26625553 TI - Ribavirin Desensitization in Chronic Hepatitis C. PMID- 26625555 TI - Cutaneous Polyarteritis Nodosa Associated with Destructive Arthritis. PMID- 26625556 TI - Resolution of Roth Spots during Treatment of Chronic Myelogenous Leukemia. PMID- 26625557 TI - The 13th Medinterna International Meeting: New Avenues in Autoimmunity. PMID- 26625558 TI - PRE-EXISTING IMMUNITY: A FITNESS INDEX FOR INFLUENZA VACCINATION. PMID- 26625559 TI - INTERFERON-GAMMA-RELEASE ASSAY PREVENTS UNNECESSARY TUBERCULOSIS THERAPY. PMID- 26625560 TI - To the Editor. PMID- 26625561 TI - Potpourri of Opinions... From Many... AB - I'm sure I have missed some of the topics that have been mentioned and discussed over recent years, but one thing is clear, "we must all work for positive, realistic changes in pharmacy with the emphasis on helping pharmacists do their jobs better and to make the necessary modifications for a better future for pharmacy." PMID- 26625562 TI - SAFER STERILE COMPOUNDING: Choosing and Using Disinfectants for the Cleanroom. AB - Compounders worldwide are responsible for ensuring that the sterile preparations they dispense are pure, potent, and safe. To achieve that result, proper cleaning and disinfection of International Organization for Standardization controlled environments must occur. Because those tasks must be performed according to established standards, the compounding pharmacist must research regulatory requirements and appropriate products for use. In this report, we focus on U.S. regulations, guiding entities, and effective products that enable compliance with the increasingly stringent procedures required for pharmaceutical compounding. We also review cleaning and disinfecting processes, discuss the importance of correctly choosing and using disinfectants and/ or sporicidal disinfectants with surface claims in the cleanroom, and provide answers to questions frequently asked by staff who use those agents. In addition, we profile specific disinfectants that are compliant with UnitedStates Pharmacopeia Chapter <797> and current good manufacturing practice standards. Biological safety cabinets and compounding aseptic containment isolators must undergo an additional process that deactivates hazardous drug residues and removes them from the interior surfaces of those devices before they are cleaned and disinfected, but that discussion is beyond the scope of this article. PMID- 26625563 TI - BIOTECHNOLOGY, NANOTECHNOLOGY, AND PHARMACOGENOMICS AND PHARMACEUTICAL COMPOUNDING, PART 2. AB - This article, which represents part 2 of a two part article, completes the discussion on the rapidly changing world of pharmaceuticals as biotechnology continues to grow and nanotechnology appears on the horizon. PMID- 26625564 TI - Estradiol: THE EMERGING EVIDENCE FOR A PROTECTIVE ROLE AGAINST INSULIN RESISTANCE AND OBESITY. AB - Estrogen therapy is a well-known and commonly used symptomatic treatment of hot flashes, night sweats and vaginal dryness associated with menopause. The most active estrogen, estradiol, is also understood to have a protective effect against osteoporosis. Like many hormones, though, estradiol has many roles in the body, both in males and females, and studies of these roles continue to emerge. A major function of estradiol involves obesity, insulin resistance, and cardiovascular disease; studies have shown the beneficial effects of estradiol in these areas, and this is somewhat at variance with traditional belief. In recent years, many researchers have studied its protective, beneficial effect, and have arrived at convincing evidence. In females, and, to some extent in males, estradiol is very important in protecting against obesity and lessening the likelihood of insulin resistance and cardiovascular disease. For both menopausal women and hypogonadal men, estradiol levels should be monitored and considered for long-term healthcare benefits. PMID- 26625566 TI - U.S. FOOD AND DRUG ADMINISTRATION PROPOSED GUIDANCE DOCUMENT: Compounding Animal Drugs from Bulk Substances. PMID- 26625565 TI - Efficacy and Clinical Value of Commonly Used Ingredients in Pain Management Compounds: A LITERATURE REVIEW. AB - The need for continued improvement in pain management is growing. This review is aimed towards identifying the literature regarding clinical and therapeutic value of the commonly used ingredients in pain management compounds: lidocaine, tetracaine, ketoprofen, ketamine, and gabapentin. Prospectively, future studies should be conducted to identify the exact benefits and side effects of compounded pain management therapies, such that these compounds can be effectively utilized when deemed appropriate. PMID- 26625567 TI - Physical Quantitative Verification of Nonsterile Compounded Preparations: Individualized Dosage Units. AB - United States Pharmacopeia <795> states that to ensure accuracy and completeness, the compounder shall observe the finished preparation. One such verification method described in United States Pharmacopeia <1163> is weight assessment of final nonsterile compounded preparations. This article will focus on this weight assessment technique and discuss common pitfalls and tools which can be used to better comply with current industry quality- control guidelines. PMID- 26625568 TI - The "Negative" List. AB - H.R. 3204 requires the formation of a Pharmacy Compounding Advisory Committee to address the following: The "Negative List"; The "Positive List of Active Pharmaceutical Ingredients"; and "Demonstrable Difficulties in Compounding." At the first meeting of the Pharmacy Compounding Advisory Committee, the Committee addressed the drug products that have been withdrawn or removed from the market and cannot be compounded because they have been found to be unsafe or not effective. This article provides a current list of drugs which cannot be used in compounding, as well as a "kit" where the combination of ingredients/products cannot be compounded. PMID- 26625569 TI - BASICS OF STERILE COMPOUNDING: Barrier Isolator Technologies in Aseptic Processing. AB - Barrier isolator technologies have made significant contributions to the advancement of aseptic processing and the increased level of sterility assurance. This article discusses why this is so and provides brief information about types of isolators, isolator attributes, isolator challenges, and considerations in isolator design, implementation, and validation. PMID- 26625570 TI - Use of 8.4% Sodium Bicarbonate in Buffering Commonly Administered Vancomycin Hydrochloride Solutions for Use with Midline or Peripheral Line Catheters. AB - The primary objective of this study was to evaluate the use of 8.4% sodium bicarbonate in the buffering of commonly administered vancomycin hydrochloride solutions for use with midline or peripheral line catheters. Nine admixtures of vancomycin hydrochloride were aseptically prepared for this study. Vancomycin hydrochloride solutions were prepared in triplicates in the following strengths, 1 gram, 2 grams, and 3 grams, which were added to 250-mL bags of sodium chloride 0.9% injection (with overfill). To each prepared solution of vancomycin hydrochloride, 0.5 mL of 8.4% sodium bicarbonate was added. The pH was measured to obtain a baseline level. At day 9, the pH of each sample was measured and compared to those at baseline. The osmolality of each sample was also measured. There was no statistical difference in the pH at baseline and at day 9 (alpha = 0.05, P = 0.347). A solution of vancomycin hydrochloride that is compounded in 250 mL of sodium chloride 0.9% injection (including overfill) and buffered with 0.5 mL of 8.4% sodium bicarbonate maintained a pH in the range of 5 to 9 and an osmolality in the range of 150 mOsm/kg to 500 mOsm/kg. PMID- 26625571 TI - Stability of Prednisone in Oral Mix Suspending Vehicle. AB - The stability of prednisone (5 mg/mL) formulated as a suspension in Oral Mix vehicle was evaluated. Oral Mix is a novel oral, dye-free suspending vehicle developed by Medisca Pharmaceutique Inc. for preparation of extemporaneous dosage forms. This drug was chosen based on its high frequency of prescription among the pediatric population. Suspensions were prepared from both pure active and commercial tablets utilizing two different container closures: amber glass bottles and polypropylene syringes (PreciseDose Dispenser Medisca Pharmaceutique Inc.). Formulations were stored at 5 degrees C or 25 degrees C and organoleptic properties, pH, and concentration were evaluated at predetermined time points up to 90 days. Validated stability-indicating high-performance liquid chromatography methods were developed. Beyond-use date was evaluated by statistical analysis of the overall degradation trend. Prednisone was stable for at least 90 days at 25 degrees C. No changes in organoleptic properties or pH were observed for either of the formulations, and the global stability was roughly equivalent and sometimes superior to the stability of the same drugs in other previously used vehicles. Thus, Oral Mix was found to be a suitable dye-free vehicle for extemporaneous formulations. PMID- 26625572 TI - Development and Validation of an Inexpensive, Simple, and Rapid Technique for Measuring the Accuracy of Extemporaneously Compounded Pharmaceuticals. AB - Use of ultraviolet detection to quantitate analytes is a basic concept of analytical chemistry. The basis of this application is well defined by Beer Lambert's law. To this end, the authors applied Beer-Lambert's law as a simple and rapid tool to measure the accuracy of extemporaneously compounded pharmaceuticals. Using two commonly extemporaneously compounded formulations, the authors demonstrated the application of this tool. Advantages and limitations of the ultraviolet-visible technique are discussed. The authors speculate that more advanced spectral techniques for quality control will be adopted in the future. These techniques will be more accurate and will be associated with fewer limitations. However, costs associated with use will be greater. PMID- 26625573 TI - Stability of Diphenhydramine Hydrochloride, Lorazepam, and Dexamethasone Sodium Phosphate in 0.9% Sodium Chloride Stored in Polypropylene Syringes. AB - Chemotherapy induced nausea and vomiting is problematic for many patients undergoing chemotherapy. Multiple-drug treatments have been developed to mitigate chemotherapy induced nausea and vomiting. A patient-controlled infusion of diphenhydramine hydrochloride, lorazepam, and dexamethasone sodium phosphate has been studied in patients who are refractory to first-line therapy. Unfortunately, the physical and chemical compatibility of this three-drug combination is not available in the published literature. Chemical compatibility was evaluated using high-performance liquid chromatography with ultraviolet detection. Visual observation was employed to detect change in color, clarity, or gas evolution. Turbidity and pH measurements were performed in conjunction with visual observation at hours 0, 24, and 48. Results showed that diphenhydramine hydrochloride 4 mg/mL, lorazepam 0.16 mg/mL, and dexamethasone sodium phosphate 0.27 mg/mL in 0.9% sodium chloride stored in polypropylene syringes were compatible, and components retained greater than 95% of their original concentration over 48 hours when stored at room temperature. PMID- 26625574 TI - Why it's tough to survive a year in space. PMID- 26625575 TI - The last choice. PMID- 26625576 TI - Staffing That Is Evidence Based: A Consensus Model. PMID- 26625577 TI - Strategic Planning and Doctor Of Nursing Practice Education: Developing Today's and Tomorrow's Leaders. AB - Strategic planning and thinking skills are essential for today's nurse leaders. Doctor of nursing practice (DNP) programs provide an opportunity for developing effective nurse strategists. A well-designed strategy course can stimulate intellectual growth at all levels of Bloom's Taxonomy. Discussion forums in online education provide new opportunities for rich interaction among peers en route to development of well-informed strategic plans. An interprofessional perspective adds a rich and vital aspect to doctoral nursing education and it serves to inform strategic plan development. A roadmap for teaching strategic planning to current and future nursing leaders will guide the integration of essential content into DNP programs. PMID- 26625578 TI - Improving Congestive Heart Failure Care with a Clinical Decision Unit. AB - Evidence supporting the development of Clinical Decision Units (CDUs) to impact congestive heart failure readmission rates comes from several categories of the literature. In this study, a pre-post design with comparison group was used to evaluate the impact of the CDU. Early changes in clinical and financial outcome indicators are encouraging. Nurse leaders seek ways to improve clinical outcomes while managing the current financially challenging environment. Implementation of a CDU provides many opportunities for nurse leaders to positively impact clinical care and financial performance within their institutions. PMID- 26625579 TI - Geographical Imbalance of Anesthesia Providers and its Impact On the Uninsured and Vulnerable Populations. AB - The purpose of this study was to determine if there is a relationship between socioeconomic factors related to geography and insurance type and the distribution of anesthesia provider type. Using the 2012 Area Resource File, the correlation analyses illustrates county median income is a key factor in distinguishing anesthesia provider distribution. Certified registered nurse anesthetists (CRNAs) correlated with lower-income populations where anesthesiologists correlated with higher-income populations. Furthermore, CRNAs correlated more with vulnerable populations such as the Medicaid-eligible population, uninsured population, and the unemployed. Access to health care is multifactorial; however, assuring the population has adequate insurance is one of the hallmark achievements of the Affordable Care Act. Removing barriers to CRNA scope of practice to maximize CRNA services will facilitate meeting the demand by vulnerable populations after full implementation of the Affordable Care Act. PMID- 26625580 TI - Evaluation of an Innovative Program To Improve Outcomes among Military Beneficiaries with Diabetes. AB - Patients with Type 2 Diabetes Mellitus (T2DM) are a challenging population and the goals of maintaining a HgA1c of 7 or less, and limiting emergency department (ED) visits and hospitalizations, are not new. The Patient-Centered Medical Home (PCMH) is a practice model mandated by the U.S. Air Force. The primary objective of this study was to quantify and evaluate the effects of PCMH implementation on one group of chronic disease patients, those with T2DM, using the outcomes of HgA1c, ED visits, and hospitalized days. A secondary objective was to use PCMH evaluations to explain outcome variations and then help clinic sites recognize areas of strength and weaknesses so they could continue care improvement efforts. Support was found for the effect of PCMH implementation on HgA1c of patients with T2DM seen in military clinics. Support was mixed for PCMH and its positive effect on hospitalized days and ED visits of patients with T2DM. PMID- 26625581 TI - Joint Statement: The Role of the Nurse Leader in Care Coordination and Transition Management Across the Health Care Continuum. PMID- 26625582 TI - High Reliability and Excellence in Staffing. AB - Nurse staffing is a complex issue, with many facets and no one right answer. High reliability organizations (HROs) strive and succeed in achieving a high degree of safety or reliability despite operating in hazardous conditions. HROs have systems in place that make them extremely consistent in accomplishing their goals and avoiding potential errors. However, the inability to resolve quality issues may very well be related to the lack of adoption of high-reliability principles throughout our organizations. PMID- 26625583 TI - Intuition: A Powerful Self-Care Tool for a Life that Thrives. AB - Most nurses have the capability to be highly intuitive beings. There are many techniques for nurturing and feeding our intuition. Listening to our inner voice, creating moments of real silence, disconnecting from devices, and getting adequate sleep can all help open the channels of intuition and inner knowing. As we search for ways of thriving in our lives, make a dedicated effort to stay connected and honor your inner voice that serves as a beacon, reflecting your heart's song and purpose. Nourishing and tending to our intuitive inner selves will allow our sixth sense of knowing to flourish! PMID- 26625584 TI - Transforming Mental Health Care: Starting with Change Around the Edges. AB - It is essential for those of us who work in health professions to recognize the good work individuals and organizations are doing to improve the delivery of mental health services in communities across the country. Despite their allure, new practices and radical innovations are hard to come by and resisted by many organizations. Programs like Mental Health First Aid and Make It Ok are examples of how a program can alter a person's understanding of mental illness. Without knowing about successes and new models of care, nurses cannot be as strategic in their efforts to influence meaningful social and systemic change. Changes at the edges of the health care system are happening in the care of mental illness. Changes must continue to be made that will eventually make their way into the center. PMID- 26625585 TI - Challenges of Preceptorship. PMID- 26625586 TI - Evidence the outcomes. PMID- 26625587 TI - New vaccine recommendations. PMID- 26625589 TI - Poor beginnings: a postcode lottery for child health? PMID- 26625588 TI - Review to assess the care of newborn babies. PMID- 26625590 TI - Easing the big itch. PMID- 26625591 TI - Quick evaluation of a limping child. PMID- 26625592 TI - Working together to tackle child sexual exploitation. PMID- 26625593 TI - Taking a fresh approach to school readiness. PMID- 26625594 TI - 'Your time is now'. PMID- 26625595 TI - Building a picture of health from data. PMID- 26625596 TI - Great minds think alike. PMID- 26625597 TI - Childhood flu--more than just a spray! PMID- 26625598 TI - Grief encounters. PMID- 26625599 TI - PRIOR AUTHORIZATIONS. PMID- 26625600 TI - Good Afternoon, Dr. Johnson. PMID- 26625601 TI - C. Lowry Barnes, MD. One Physician's Work to Advance Orthopaedic Care in Arkansas. PMID- 26625602 TI - The Journey Through Patient-Centered Medical Home Transformation: Case Studies From The Field. PMID- 26625603 TI - Screening for Lung Cancer in Arkansas. PMID- 26625604 TI - Fifty-six-year-old man with anaphylaxis: A novel delayed food hypersensitivity reaction. AB - Anaphylaxis and urticaria are commonly seen in both primary care and allergy clinics. Foods, drugs, and insects are frequent culprits for immediate reactions; however, the trigger for recurring and/or chronic episodes is often unclear. We present a 56-year-old male with recurrent symptoms of urticaria, angioedema, and anaphylaxis found to be triggered by sensitization to galactose-alpha 1, 3 galactose (alpha-gal), a novel food allergen. PMID- 26625605 TI - Do Not Miss This Diagnosis: Slipped Capital Femoral Epiphysis (SCFE). PMID- 26625606 TI - [HYGIENIC JUSTIFICATION OF OPTIMIZATION OF THE INTEGRATED ASSESSMENT OF DRINKING WATER ACCORDING TO THE WATER QUALITY INDEX]. AB - The present study is devoted to theoretical questions of optimization of integrated assessment of the composition and properties of drinking water with the use of the Water Quality Index (WQI) and considering in it all 4 criteria for its hygienic quality-sanitary-toxicological, microbiological, radiation and organoleptic. There is presented a sequence of the analysis of benchmark data of the laboratory study of drinking water, including the selection of priority indices, their distribution into 4 groups according to hygienic criteria, calculations the ratios of real values (C) of indices to their hygiene MPC and the final calculation of the WQI. There is emphasized the importance of classes of hazard of substances, and the need for the special attention to the substances carcinogens in the integrated assessment of water quality. To overcome the non equivalence of contributions to the assessment of water quality factors, measured in different units, often disparated in their effect on human health, there are used the principles of combined action at levels below the MCL:C/MPC indices of performance of the unidirectional action are summed (e.g. carcinogenic substances), from indices of the independent action there are selected the most significant ones with the highest values of C/MPC, besides that there are also used counterbalancing factors K determined accordingly to Delphi method, with a maximum values of 5 for carcinogens and the minimum value of 1 for the substances affecting the organoleptic properties ofwater. There is presented the scheme of the final calculation of the value of WQI. PMID- 26625607 TI - [RADIATION SAFETY DURING REMEDIATION OF THE "SEVRAO" FACILITIES]. AB - Within a framework of national program on elimination of nuclear legacy, State Corporation "Rosatom" is working on rehabilitation at the temporary waste storage facility at Andreeva Bay (Northwest Center for radioactive waste "SEVRAO"--the branch of "RosRAO"), located in the North-West of Russia. In the article there is presented an analysis of the current state of supervision for radiation safety of personnel and population in the context of readiness of the regulator to the implementation of an effective oversight of radiation safety in the process of radiation-hazardous work. Presented in the article results of radiation-hygienic monitoring are an informative indicator of the effectiveness of realized rehabilitation measures and characterize the radiation environment in the surveillance zone as a normal, without the tendency to its deterioration. PMID- 26625608 TI - [ECOLOGICAL AND TOXICOLOGICAL ASSESSMENT OF DISPOSAL OF SEWAGE SLUDGE AS FERTILIZER]. AB - In the article there is considered the question of the accumulation of heavy metals in soil and their uptake by plants as a result of prolonged use of sewage sludge as fertilizer. There have been calculated coefficients of concentrations of elements and the total pollution index. There was performed the comparison of the data obtained with accepted sanitary-hygienic standards. PMID- 26625609 TI - [SANITARY SIGNIFICANCE OF SOIL SEA COASTS]. AB - There was investigated the dynamics of growth of Listeria monocytogenes and Yersinia pseudotuberculosis in soils of sea coast (mid-flight and maritime soils). These bacteria were shown to reproduced well in all researched soils, preferring nevertheless maritime soils. The content of the humus was determined to be the one of the limiting factors restricting the multiplication of pathogenic bacteria in studied soils. Abiotic characteristic of soils of sea coast were established to render the direct positive influence on the preservation and reproduction of pathogenic microflora in them. This is promoted by a degree of a saturation by the bases, cation-exchange capacity, quantity of humus. In the formation of environmental policy it should be taken into account and the human-induced load on the soil should be limited PMID- 26625610 TI - [MEDICAL AND SOCIAL STATE OF HEALTH IN FAMILIES WITH THE FOCUS OF RESPIRATORY CHLAMYDIA]. AB - Medical and social state of health in family persons was assessed on the basis of a questionnaire. Developed by the author's questionnaire included two sections, reflecting the state of health, health risk factors and social characteristics of the family members of ENT patients. In the article there is presented an analysis of the medical and social state of 44 families of patients with diseases of the upper respiratory tract associated with chlamydial infection. The comparison was performed with 43 families of ENT patients with unconfirmed respiratory chlamydia. Diagnosis of Chlamydia infection complex was carried out with the use of laboratory methods (direct immunofluorescence and enzyme-linked immunosorbent assays, polymerase chain reaction). The health and social status of families with hearth respiratory chlamydia were shown to be significantly worse compared with families with the lack of the latter PMID- 26625611 TI - [HALOTOLERANCE OF ENTEROBACTERIA ISOLATED FROM WATER AND FISH IN THE VOLGA RIVER DELTA]. AB - In the article there are presented the results of a study of halotolerance of enterobacteria isolated from water and fish in the Volga River delta, which were dominant in the microbial landscape of these biotopes. Their halotolerance was studied by means of inoculation of daily pure cultures of meat--peptone broth with 3, 7 and 10% of sodium chloride and incubation at 37 degrees C. At that all studied microflora was found to have significant indices of halotolerance with a predominance of aquatic isolates. At that in 3,0 and 7,0 % NaCl concentrations were very similar, but in 10% NaCl broth the halotolerance of water strain was almost 2.0 times higher than the in fish ones. Among isolated Enterobacteriaceae most halophilic bacteria were from the Proteus group, Citrobacteria and Enterobacteria. The halotolerance of isolated enterobacteria in hydroecosystem of the Volga River delta had seasonal specificity and dynamics. There was established the dynamic growth of this sign in the water and fish strains from spring to autumn. Thus, the analysis of the obtained results of the long-term conducted study has shown the wide dissemination of conditionally pathogenic enterobacteria in water and fish, and their high halotolerance and the ability of some of them to remain viable up to salt production. It gives grounds to recommend the necessity of the introduction of them into the normative documentation in the implementation ofthe sanitary-microbiological control of not only raw materials but also ready salted fish production. PMID- 26625612 TI - [MONITORING OF THE CONTENT OF HEAVY METALS AND ELEMENTS IN THE SNOW COVER IN AGRICULTURAL SOILS AT THE TERRITORY OF THE MOSCOW REGION]. AB - The monitoring of snow cover pollution by heavy metals and elements (zinc, copper, lead, cadmium, arsenic, nickel, chromium, strontium, manganese, fluorine, lithium) was performed in 20 districts of the Moscow region in 2009, 2012 and 2013. The assessment of the levels of contamination by heavy metals and elements was given by means of comparison of them with the average values in the snow cover near Moscow in the end of the last century and in some areas of the world, that no exposed to technological environmental impact. 7 districts of Moscow region were characterized by a high content of lead and cadmium in the snow water. It requires the control of water, soil and agricultural products pollution. PMID- 26625613 TI - [STATE OF THE SOIL IN THE TERRITORY OF THE CITY WITH THE DEVELOPED PETROLEUM REFINING INDUSTRY]. AB - In 2013-2014, there was performed the study of the soil in the territory of the city of Novokuibyshevsk. The concentrations of heavy metals and petroleum products on the territory of the industrial zone of the city of Novokuibyshevsk were determined. The evaluation of concentrations ofanthropogenic toxicants was carried out in Novokuibyshevsk by means of laboratory monitoring of environmental pollution. The obtained values were compared with the MPC or in the absence of MPC--with tentatively permissible concentrations (TPC) of chemicals in soil background concentrations in the Volga region of Samara region, as well as with previous studies of the soil of the city of Novokuibyshevsk in 2005. The studies revealed that in 2014, if compared with 2005, concentrations of heavy metals in soil on the territory of the industrial zone of the city of Novokuibyshevsk and within the city border decreased. There were obtained significant differences in the soil content ofcadmium, copper, lead, Nickel and zinc in 2005 and 2013-2014. Unlike the content of salts of heavy metals, the content of petroleum products in the soil over the past 9 years had tended to increase. The maximum concentration of petroleum products was detected in the industrial zone of CHP-1. The number of samples with extremely high pollution rised from 4% to 8%, with high pollution- from 10% to 12%. Also, an increase in the number of samples with the level of 2 20 background values accounted from 56% to 66%. The gain in concentrations of petroleum in the soil on the territory of the city of Novokuibyshevsk was associated not only with the activity of the enterprises of oil refining and petrochemical industry, but also with the elevating number of road transport. PMID- 26625614 TI - [THE HEALTH OF CHILDREN IN THE INDUSTRIALIZED REGION]. AB - There was performed an assessment of the quality of the environment and the state of health of the child population of the one out of industrialized regions of the Moscow region. There were determined priority risk factors for diseases of the respiratory system and skin. The indices and the structure of morbidity rate were analyzed according to the incidence of outpatient visits. There was developed a comprehensive hygienic model for the preventive and therapeutic activities aimed at the improvement of the environment and reduction of the morbidity rate in children's population. PMID- 26625615 TI - [LED LIGHTING AS A FACTOR FOR THE STIMULATION OF THE HORMONE SYSTEM]. AB - There are considered questions of non-visual effects of blue LED light sources on hormonal systems (cortisol, glucose, insulin) providing the high human performance. In modern conditions hygiene strategy for child and adolescent health strategy was shown to be replaced by a strategy of light stimulation of the hormonal profile. There was performed a systematic analysis of the axis "light stimulus-hypothalamus-pituitary-adrenals-cortisol-glucose-insulin". The elevation of the content of cortisol leads to the increase of the glucose level in the blood and the stimulation of the production of insulin, which can, like excessive consumption of food, give rise to irreversible decline in the number of insulin receptors on the cell surface, and thus--to a steady reduction in the ability of cells to utilize glucose, i.e. to type 2 diabetes or its aggravation. PMID- 26625616 TI - [RADIATION HYGIENIC MONITORING AT THE AREA OF THE LOCATION OF THE FAR EASTERN CENTER FOR RADIOACTIVE WASTE MANAGEMENT (FEC "DALRAO"--BRANCH OF FSUE "ROSRAO")]. AB - Intensification ofactivities in the field of spent nuclear fuel (SNF) and radioactive waste (RW) management in the Far East region of Russia assumes an increase of the environmental load on the territories adjacent to the enterprise and settlements. To ensure radiation safety during works on SNF and radioactive waste management in the standard mode of operation and during the rehabilitation works in the contaminated territories, there is need for the optimization of the existing system of radiation-hygienic monitoring, aimed at the implementation of complex dynamic observation of parameters of radiation-hygienic situation and radiation amount of the population living in the vicinity of the Far Eastern Center for Radioactive Waste Management (FEC "DALRAO"). To solve this problem there is required a significant amount of total and enough structured information on the character of the formation of the radiation situation, the potential ways of the spread of man-made pollution to the surrounding area, determining the radiation load on the population living in the vicinity of the object. In this paper there are presented the results of field studies of the radiation situation at the plant FEC "DALRAO", which were obtained during the course of expedition trips in 2009-2012. PMID- 26625617 TI - [THE CONTENT OF MERCURY IN SEDIMENTS AND THE CLAMS UNIO PICTORUM FROM THE URAL RIVER]. AB - There was investigated the mercury total content in bottom sediments and some bodies of clams from the area of the middle reach of the Ural river near the Orenburg city. In bottom sediments there was revealed an excess of the ecological standard for mercury. There was noted the uneven distribution of toxicant in bodies of clams: the maximal contents was detected in hepatopancreas, minimal--in "foot", that apparently is determined by the unequal metabolitic activity of these tissues. The highest concentration of mercury in the tissues of clams was noted at the station "Ural river above the camp" Dubki". PMID- 26625618 TI - [APPROACHES TO URBAN AREA RANKING ACCORDINGLY TO THE LEVEL OF HEAVY METAL POLLUTION]. AB - Urban area ranking was performed according to the level of the heavy metal pollution based on the data of the snow and soil chemical characteristics. With reference to cumulative rates of the snow cover and soil pollution by heavy metals in the territory of the city of Kazan there were selected four areas: I- Derbyshki; II--Teplocontrol; III--Gorki; IV--Kirovsky district. The pollution level of snow cover in the territory of the city was determined by pollution level indices calculated with the application of Maximum Permissible Concentration (MPC) of chemical substances in ambient waters for household and recreational and service facilities use. The assessment of the pollution level in soils in the city showed the total territory of Kazan to be mildly polluted by manganese, concerning other heavy metals the categories of the soil pollution vary on areas. Results of hair biological monitoring in children are an informative auxiliary tool for the evaluation of the present ecological situation concerning heavy metals in certain territories of the city. PMID- 26625619 TI - [CALCULATION OF THE PROBABILITY OF METALS INPUT INTO AN ORGANISM WITH DRINKING POTABLE WATERS]. AB - The work was performed in framework of the State program for the improvement of the competitiveness of Kazan (Volga) Federal University among the world's leading research and education centers and subsidies unveiled to Kazan Federal University to perform public tasks in the field of scientific research. In the current methodological recommendations "Guide for assessing the risk to public health under the influence of chemicals that pollute the environment," P 2.1.10.1920-04 there is regulated the determination of quantitative and/or qualitative characteristics of the harmful effects to human health from exposure to environmental factors. We proposed to complement the methodological approaches presented in P 2.1.10.1920-04, with the estimation of the probability of pollutants input in the body with drinking water which is the greater, the higher the order of the excess of the actual concentrations of the substances in comparison with background concentrations. In the paper there is proposed a method of calculation of the probability of exceeding the actual concentrations of metal cations above the background in samples of drinking water consumed by the population, which were selected at the end points of consumption in houses and apartments, to accommodate the passage of secondary pollution ofwater pipelines and distributing paths. Research was performed on the example of Kazan, divided into zones. The calculation of probabilities was made with the use of Bayes' theorem. PMID- 26625620 TI - [HYGIENIC AND FUNCTIONAL AND PHYSIOLOGICAL APPROACHES IN THE IDENTIFICATION OF PRENOSOLOGICAL STATES IN STUDENTS]. AB - The study of the risk for adverse changes assumes and is considered in the study in terms of the revealing of exertion of systems, particularly due to lengthiness of the process of formation of the "state" of health in young people. METHODS: sanitatary--hygienic practice, medical statistical with in-depth study of individual health. RESULTS: There were obtained results in the field of physiology and hygiene. There were established with assigning the class working conditions actually affecting the levels of sanitation and hygiene, factors reflecting the factor load in educational institutions. There was revealed the general direction of the functional changes according to nosological forms, including in the comparison on different training profiles. The study of the morbidity rate, including the dynamics of individual health was supplemented with features of mechanisms of adaptation in students at different stages of the education. For students of radio engineering profile of training adaptation mechanisms were established at the level of exertion. The data of the paper are aimed at the improvement of the correction of the health status of students. PMID- 26625622 TI - [FEATURES OF CHANGES IN THE IMMUNE REACTIVITY IN EMPLOYEES IN MODERN PRODUCTION OF SULPHATE CELLULOSE]. AB - There are reported changes in the indices of the immunoreactivity of the body in employees in modern productions of sulphate cellulose in dependence on the specificity of exposing factors of the production environment. At that the main adverse factor affecting the state of the immune reactivity of workers was found to be is air pollution of the working area with methyl-sulfur compounds in the pulping process, with chlorine and chlorine dioxide--in the process of bleaching, lime and limestone dust--in the process of caustic regeneration. There were shown differences in the character and severity of the immune response to the impact of different chemical compounds. The exertion of protective immune mechanisms is most pronounced in workers employed in the process of boiling and bleaching, in whom there were revealed significant changes in humoral compartment of immunity (pronounced inhibition of the IgA synthesis, which plays an important role in the state of broncho-pulmonary immunity). At the same time, the inhibition of the functional activity of phagocytic neutrophils was the most significant in workers who was experienced to the exposure to lime and limestone dust, testifying about the depression of nonspecific mechanisms of anti-infectious protection. The revealed changes in the immune system are the basis for the formation in workers certain health disorders, mainly with broncho-pulmonary pathology. PMID- 26625621 TI - [ASSESSMENT OF THE CYTOKINE STATUS IN EMPLOYEES IN CONDITIONS OF CHRONIC EXPOSURE TO VINYL CHLORIDE]. AB - In the article there are presented the results of the evaluation of cytokine profile in males working in the production of vinyl chloride (trained workers without signs of disorders of the neuropsychic status and persons with early signs of neurointoxication with vinyl chloride, characterized by asthenic (emotional lability) disorder with the autonomic dysfunction). There are established differences of pro- and anti-inflammatory responses in workers in dependence on the severity of disorders of the neuropsychic status. The most pronounced imbalance of cytokines was in workers with initial manifestations of neurointoxication with vinyl chloride. The increase in the concentration of pro inflammatory cytokines (IL-1beta, IL-8, TNF-alpha) in trained employees without signs of disorders of the neuropsychic status is the one of the early and sensitive indices characterizing the formation ofthe body's resistance to exposure of adverse factors of production. PMID- 26625623 TI - [EVALUATION OF THE CARCINOGENIC RISK OF LEAD IN THE COHORT STUDY OF MALE WORKERS OCCUPATIONALLY EXPOSED TO INORGANIC LEAD IN 27 MOSCOW PRINTING-HOUSES]. AB - As millions of people worldwide are expoed to inorganic lead, both in the workplace and in general environment, its potential carcinogenicity is an important health problem. Although lead has been shown to be carcinogenic in laboratory animals, epidemiological studies have been inconclusive, and the relationship between lead and human cancer is still unclear. There were several limitations that complicated the analysis and evaluation of the carcinogenic potential of lead compounds. In particular, many of the cohort studies of lead and cancer, mostly among heavily lead-exposed workers, have been limited by a failure to identify and control for covariates, especially co-exposures to other metals such as arsenic, cadmium, and chromium, which have been shown to be carcinogenic. Most of the epidemiological studies unfortunately do not have data on dose-response. The scientific merit of our study is the virtual absence of confounding by other known carcinogens. Another advantage of our study is the presence of three occupational sub-cohorts with different levels and routes of lead exposure. Most previous studies have data on dose-response provided only by comparisons of exposed to unexposed persons. In summary, the results of this cohort study suggest that occupational exposure to lead may increase the risk of cancers of the pancreas, kidney and rectum. In conclusion, despite several limitations, the results of our study add to the evidence that carcinogenicity to humans may be an additional adverse health effect of lead. PMID- 26625624 TI - [THE RISK OF DEVELOPING DISEASE IN FEMALE WORKERS INVOLVED IN MODERN SECTOR EMPLOYMENT AND THE HEALTH OF THEIR CHILDREN]. AB - There was studied the state of health of females in modern sector employment: office workers (group 1) and managers (group 2), and the health of their newborns. There was established the increase of the risk for the development of extragenital disorders in groups 1 and 2 compared with the control. For adreno genital syndrome OR = 3.83; (CI: 1.15-12.74) in group 1 and OR = 4,50 (CI: 1.24 16.28) Group 2; for respiratory diseases OR = 2.77-2.98 (CI: 1.82- 4.85) in groups 1 and 2; for digestive diseases OR = 2.45 (CI: 1.39-4.32) in group 1 and 2.77 (CI: 1.46-5.26)--in Group 2. The risk of infertility in the history of the group 2 was OR = 2.56 (CI: 1.33-4.92). The frequency of reproductive loss in the history is signficantly higher in group 1 (12,9 ? 1.28), is increasing in group 2 (20.19 +/- 2.75) with 9.74 +/- 2.12 in 100 females in the control. In complications of pregnancy the frequency of the threat of its interruption increases from 16.99 +/- 2.31 cases per 100 females in the group 1 to 21.60 +/- 2.82 in Group 2, with 11.79 +/- 2.31 in the control (p < 0.01). In newborn of these female workers there was revealed an increase in the frequency of the congenital defects of development (CDD) of the circulatory system in group 1 by 1.5 times in the group 2-2.5 times if compared to the control (16.38 +/- 1.41 and 24.88 +/- 2.96, with 9.74 +/- 2.12 cases per 100 infants (p < 0.01; p < 0.001), respectively, the frequency of congenital malformations of the urinary system in groups 1 and 2 (10.00 +/- 1.14 and 10.80 +/- 2.13), was significantly higher than in control--3.08 +/- 1.24 per 100 births (p < 0.01); CDD of genitalia was significantly higher in group 1 (11.01 +/- 1.19) with 5.13 +/- 1.58 per 100 infants in the control (p < 0.01). Thus, disorders of reproductive health in females involved in modern sector employment depend on the degree of occupational hazard factors; can lead to congenital disease in their newborn, which requires the development of preventive measures. PMID- 26625625 TI - [NIGHT SHIFT WORK AND HEALTH DISORDER RISK IN FEMALE WORKERS]. AB - There was evaluated the risk to health in females employed in shift work, including night shifts. According to the data of periodical medical examinations health indices of 403 females employed in shift work, including night shifts, were compared with indices of 205 females--workers of administrative units of the same enterprise. Overall relative risk (RR) for the health disorder associated with the night shift was 1.2 (95%; confidence interval (CI): 1.09-1.28). A statistically significant increase in risk was observed in relation to uterine fibroids (OR 1.3; 95% CI: 1.06-1.54), mastopathy (OR 1.4; 95% CI: 1.2-1.6), inorganic sleep disorders (OR 8.8; 95% CI 2.6-29.8). At the boundary of the statistical significance there was the increase in the risk for obesity (OR 1.2; 95% C: 0.97-1.39), hypertension (OR 1.2; 95% CI, 0.9-1.5) and endometriosis (OR 1.5; 95% CI: 0.98-2.16). There was revealed an adverse effect of night shifts on the gestation course: ectopic pregnancy in the experimental group occurred 6.6 times more frequently than in the control group (95% CI: 0.87-50.2), and spontaneous abortion--1.7 times (95% CI: 0.95-3.22). The performed study has once again confirmed the negative impact of smoking on women's reproductive health: smoking women in the experimental group compared with the control group smokers had 2.7 times increased risk of uterine fibroids (within 1.06-7.0), the risk in non-smokers was significantly lower--1.2 (0.98-1.4). The findings suggest about a wide range of health problems related to employment on shift work, including night shifts, which indicates to the need for adoption of regulatory and preventive measures aimed to this professional group. PMID- 26625626 TI - [CHRONIC FLUORIDE INTOXICATION AS A RISK FACTOR FOR THE DEVELOPMENT OF ATHEROSCLEROSIS]. AB - In workers employed in the aluminum industry, the main harmful production factor is exposure to fluoride salts, which can cause chronic fluoride intoxication. For the assessment of the impact of chronic fluoride intoxication on the development of atherosclerosis, we conducted a comprehensive survey of 87 aluminum-metal makers with chronic fluoride intoxication and 43 aluminum-metal makers without occupational diseases, mean age--52.1 +/- 0.4 years. There were considered the presence and severity of atherosclerosis of brachiocephalic arteries, and the arteries of the lower extremities in the studied group, there was evaluated the effect of other risk factors for atherosclerosis (smoking, presence of hypertension, diabetes, dyslipidemia). With the use of Doppler ultrasound of the arteries it was revealed that in metallurgists with chronic fluoride intoxication atherosclerosis was detected in 73.6% versus 55.8% in persons of the comparison group. The performed analysis of the prevalence of main risk factors for atherosclerosis showed that in metal makers with chronic fluoride intoxication in combination with atherosclerosis hypertension is more common (in 54.7%) than in metallurgists with chronic fluoride intoxication without atherosclerosis--only 26.1%. According to the frequency of occurrence of smoking, diabetes mellitus, hypercholesterolemia, and hypertriglyceridemia, there were no significant differences between the metallurgists with chronic fluoride intoxication, with and without atherosclerosis, and the control group, the increase in LDL cholesterol occurs significantly more often in metal-makers with chronic fluoride intoxication in combination with atherosclerosis if compared to workers without occupational diseases. Thus, chronic fluoride intoxication acts as a risk factor in the development of atherosclerosis: atherosclerosis in metal-makers with chronic fluoride intoxication occurs more frequently than in workers who do not have professional pathology. Hypertension and elevated levels of LDL cholesterol were established to increase the relative risk of developing atherosclerosis in metallurgists with chronic fluoride intoxication. At that there are no significant differences in the prevalence of common risk factors for atherosclerosis (smoking, diabetes, hypercholesterolemia, hypertriglyceridemia). PMID- 26625627 TI - [SOCIOHYGIENIC FACTORS FOR THE LIFESTYLE IN STUDENTS]. AB - In the paper there are presented the studies of the social status and lifestyle in students of Tuvan and Russian nationality according to self-assessment by students of the material and domestic living conditions, health status, physical development, nutrition, socio-demographic characteristics. Students of the Tuvan University were shown to differ according to a low level of material provision, predominance ofrural students over urban ones, low educational qualifications of parents of students, due to the general socio-economic characteristics of the republic with a low level of urbanization, economic development, features of indigenous way of life. 43.8% of students believe that they have "good health." Students of 1-2 courses rated their health status as worst. Assessment of health largely depends on gender--young men assess their health higher than young women. In the self-assessment of the lifestyle, health and physical development in the students there are ethnic differences related to the peculiarities of mentality of the indigenous and non-indigenous population. PMID- 26625628 TI - [THE USE OF SMALL FORM OF PHYSICAL TRAINING IN PREVENTION OF VIOLATIONS AND DISEASES OF THE EYE IN SCHOOLCHILDREN]. AB - INTRODUCTION: One of the actual healthcare problems of children is the problem of prevention of the violations of their vision. Out of the complex of factors that affect this function, it is necessary to consider motor activity. AIM: The study of the main types of motor activity of schoolchildren needed to preserve and improve the vision. Patients and methods. There was performed a survey of 384 parents of schoolchildren in Moscow. Specially developed by the authors questionnaire contained questions relating to the main types of motor activity of pupils that affect the state of their vision. RESULTS: The main type of motor activity in the majority of schoolchildren (96.9%) are the only physical exercise classes at school. Among schoolchildren: every day 7.8% do morning exercises, 13.5% regularly use "physical exercise minutes" between training sessions at home, 7.3% constantly do special exercises for eyes during working on the computer and watching television; 94.3% and 88.5% do not include special exercises for eyes in the morning exercises complexes and "physical exercise minutes" correspondingly. Among students with refractive disorders and diseases of the eye, 95.3% are not engaged in the correction of these states in the classroom for physical therapy, 88% on the recommendation of a doctor on their own. 3-5% of the parents are not informed about the existence of special exercises for the eyes. CONCLUSION: Motor activity of schoolchildren of a number of secondary schools in the city of Moscow has significant shortcomings that negatively affect the state of their vision and needs to be optimized, which from the point of view of the authors, should include increasing motor activity through the use of small forms of physical training in the mode of the day. To do this, the authors as a modern information technology suggested the creation of film library of physical exercises and "physical exercise minutes" for daily use in the classroom, through the translation in the classroom on the screen using the video equipment. PMID- 26625629 TI - [MODERN VIEW ON CHILDREN'S BIOLOGICAL DEVELOPMENT]. AB - The present review is devoted to the modern analysis of understanding of biological development, as a health index. There are considered works about tendencies of biological development of the child's organism in the conditions of environment, training and education. There are presented results of the study of indices of biological age of children's and teenagers' residing in various regions of the Russian Federation, and also in the near-abroad and far-abroad countries. The scientific materials devoted to the study of the biological development of the children's population were analyzed in the context of epochal variability. Modern approaches to the identification of the causes and risk factors for the formation of deviations in biological development of children and teenagers are presented. PMID- 26625630 TI - [MODELING OF AGGREGATION AND SEDIMENTATION OF NANOPARTICLES AND MICROPARTICLES INA GASEOUS MEDIUM]. AB - There are suggested new mathematical models allowing to describe in a given spatial--time coordinates the processes of aggregation and sedimentation of nanoparticles and microparticles of different sizes, owing to their concentration, dispersion composition, and other physical properties of matter particles and air. PMID- 26625631 TI - [VOLATILE FATTY ACIDS IN SALIVA--BIOLOGICAL MARKERS FOR ASSESSMENT OF DRINKING WATER POLLUTANTS ON CHILDREN]. AB - The use of modern methods of analysis is aimed to the search of ultimately novel biological markers. Volatile fatty acids in saliva were not used previously for the assessment of the effects of contaminating substances in the drinking water on the body of children. The aim of the study is to investigate the informative value of volatile fatty acids in saliva as biological markers of the impact for the assessment of the exposure to contaminating substances in the drinking water on the body of children. Hygienic assessment of drinking water quality was made according to data of the own research of drinking water from centralized supply system of the city of Ivanovo. For the comparison of indices there was investigated the drinking water from wells at the village Podvyaznovsky of the Ivanovo region. In the Ivanovo water from the distributing network of centralized drinking water supply system of the city of Ivanovo, there were identified indices of the permanganate oxidation and the total concentration of residual chlorine exceeding norms, and also chloroform and carbon tetrachloride were in concentrations not exceeding the norms. Studied by us the samples of drinking water from Podvyaznovsky village wells, the water met the standards for all investigated parameters. The was studied the informative value of volatile fatty acids in the saliva of children aged 9-14 years from the city of Ivanovo and the Podvyaznovsky village, Ivanovo region. There was established the fall in acetic, butyric, isovaleric acids and the total amount of volatile fatty acids in the saliva in children of the city of Ivanovo, consuming water treated with chlorine of Ivanovo centralized drinking water supply system. Indices of volatile fatty acids in saliva are informative for the assessment of the impact of organic pollutants, residual chlorine and organic chlorine compounds of drinking water on the body of children. PMID- 26625633 TI - Miles to go: New Orleans' mental health services still on the mend. PMID- 26625634 TI - Some Advantage plans lose members. PMID- 26625632 TI - [The 90th anniversary year of the All-Russian Research Institute of Railway Hygiene]. PMID- 26625635 TI - Primary-care docs reaping the most from shared-savings ACOs. PMID- 26625636 TI - Medical-debt collectors frustrated by FCC's cellphone ruling. PMID- 26625637 TI - BILLIING SQUEEZE. Hospitals in the middle as insurers and doctors battle over out of-network charges. PMID- 26625638 TI - HELP WANTED In HIRING RNs. Hospitals outsource recruitment of permanent nurses with hard-to-find skills. PMID- 26625639 TI - Hospital admission policy in Dismaland. PMID- 26625641 TI - Insurer tells public how much it pays providers. PMID- 26625640 TI - 10 years after Katrina, New Orleans has transformed primary care, behavioral health. PMID- 26625642 TI - Hospitals will continue to be the delivery system's cornerstone'. PMID- 26625643 TI - By the numbers. Largest biotechnology companies. Ranked by 12-month revenue as of June 30, 2015. PMID- 26625644 TI - Assaults on Medical, Nursing and Paramedical Staff. PMID- 26625645 TI - What can Doctors Expect from the new Medical Council Guidelines? PMID- 26625646 TI - Irish Trainees Continuing to Emigrate. PMID- 26625647 TI - Testicular Sperm Extraction and Intracytoplasmic Sperm Injection: Outcomes in a specialist fertility centre. AB - Assisted reproduction with testicular sperm extraction (TESE) and intra cytoplasmic sperm injection (ICSI) are fertility treatment options for couples with severe oligospermia or azoospermia. A retrospective review was performed of 146 TESE procedures in a specialist fertility centre in Ireland. The indication for TESE was obstructive azoospermia (OA) in 59% (n = 80) and non-obstructive azoospermia (NOA) in 41% (n = 56). Sperm retrieval rates after TESE were determined and the pregnancy rates per ICSI cycle number were evaluated. Sperm retrieval rates were 99% (n = 79/80) and 32% (n = 18/56) for OA and NOA men respectively. Fifty-eight couples proceeded to ICSI. Overall 114 ICSI cycles were performed and 33 cycles resulted in fertilisation (29%). Our sperm retrieval and pregnancy rates are consistent with international studies and support the ongoing role for TESE and ICSI as successful assisted reproductive techniques for male factor infertility in Ireland. PMID- 26625648 TI - Review of Time to Surgical Decompression in Traumatic Spinal Cord Injured Patients. AB - Interventions which may improve neurological outcomes, including time to surgical decompression, in traumatic spinal cord injury (TSCI) evoke much interest. The majority of TSCI patients in Ireland are managed acutely at the National Spinal Injuries Unit (NSIU). A retrospective review of healthcare records of TSCI patients, who had surgical management there, in 2010, 2011, 2012, was performed. From the information gathered, the duration of each stage of the patient pathway was calculated. Median duration between onset of injury and time of arrival at local hospital was 1 hour 25 minutes, between arrival at local hospital and referral to NSIU was 4 hours 17 minutes, between referral to and arrival at NSIU was 6 hours 25 minutes, between onset of injury and arrival at NSIU was 13 hours 7 minutes, between onset of injury and surgical decompression was 27 hours. A number of factors have been identified which could influence these time durations. PMID- 26625649 TI - In-hospital Paging Systems: An Effective Method of Communication between Hospital Staff in 2015? AB - Policies in relation to paging are designed to achieve effective in-hospital communication. This study recorded data in relation to pages received by interns over a two-week period. A survey was conducted assessing perceptions on paging and existing hospital policy. Four interns collected data in relation to 20 regular-day, 4 extended-day and 4 on-call (two weekday and two weekend) shifts (n = 423 pages). Sixty-nine pages (16%) were made during pager-free periods. On average 3 minutes per hour were spent dealing with pages. Compliance with ISBAR ranged from 50.1% to 83.4%. Of the episodes where pages were made during protected times (n = 85), 67% did not meet urgent criteria. While the majority of these pages were from nurses, they were less likely to violate the policy than other staff (relative risk 0.648, p = 0.016). Efforts need to be made to ensure pager-free periods are respected in the interest of effective communication, staff morale and protected training time. PMID- 26625650 TI - Evaluation of Presenting Symptoms and Long-Term Outcomes of Patients Requiring Excision of a Transobturator Tape (TOT). AB - The transobturator tape (TOT) is an effective treatment for stress urinary incontinence (SUI). Erosion of TOT mesh is a recognised complication requiring excision. A retrospective analysis of 228 females undergoing a TOT procedure over 4 years identified 16 patients (7%) that underwent excision of eroded mesh. Mean age of patients requiring excision was 48.8 years and mean weight was 72.7kg. Mean time to re-presentation was 14.5 months. Presenting symptoms included dyspareunia in 9 patients (56.2%), dysuria in 3 (18.7%), persistent incontinence in 3 (18.7%) and groin pain in one patient. Ten patients (62.5%) had a prior urogynecological procedure. After excision of eroded tape-mesh, 7 (43.7%) required a rectus fascial sling and 4 (25%) underwent repeat TOT for recurrence of SUI. Five patients (31.2%) required no further surgery. At present 10 patients (62.5%) report resolution of SUI, 4 (25%) report mild SUI and 2 (12.5%) patients have moderate/severe SUI. Resolution of symptoms occurred in the majority of patients after excision of eroded mesh and an additional anti-incontinence procedure. PMID- 26625651 TI - Patients Hospitalised with an Acute Exacerbation of COPD: Is There a Need for a Discharge Bundle of Care? AB - Acute Exacerbations of COPD (AECOPD) are the commonest cause of hospitalisation for patients with COPD. A number of interventions are known to improve care for such patients. Internationally and in Ireland, there is significant variation in care delivered to such patients. We reviewed admissions with AECOPD (n = 174) to an Irish teaching hospital during one year, to determine if recommended interventions had been delivered to patients prior to discharge. The most frequently delivered of such interventions were: assessment of oxygen requirements 151 (87%) and arrangements for follow-up 135 (78%). The least frequently delivered were: referral for pulmonary rehabilitation 19 (11%) and advice given regarding influenza vaccination 27 (17%). Patients who received care from a respiratory physician or respiratory clinical nurse specialist (RCNS) received more interventions than those cared for by other specialties. This study demonstrates poor compliance with internationally agreed interventions. The introduction of a discharge bundle of care for use in Irish hospitals should be considered. PMID- 26625652 TI - The Use of Inhaled Nitric Oxide in a Tertiary Neonatal Intensive Care Unit. AB - There is currently insufficient evidence to create a standardised protocol for the use and weaning of inhaled nitric oxide (iNO). We aimed to determine our application of iNO in this patient cohort. We performed a retrospective chart review on patients receiving iNO therapy for persistent pulmonary hypertension of the newborn (PPHN) from a single tertiary neonatal centre in 2014. The data was entered into the European Inhaled Nitric Oxide Registry. Thirty two babies were treated with iNO during this period, 9 of which were less than 32 weeks gestation. The median time to initiation of iNO treatment was 4-5 hours and the median duration of treatment was 74 hours for term and 66 hours for preterm infants. We recommend that further use of the European Inhaled Nitric Oxide Registry across more neonatal units in the Republic of Ireland could lead to the development of national guidelines on iNO use and weaning in this cohort. PMID- 26625653 TI - The Establishment of a Pilot Paediatric Obesity Clinic at the University Hospital, Limerick. AB - This study describes the establishment of a pilot Paediatric Obesity Clinic (POC) in the University Hospital Limerick (UHL). Referrals were received from consultant paediatricians in the catchment areas of UHL for paediatric patients with high levels of excess adiposity. Fifteen patients and their families were invited to the POC in 2012. An initial medical assessment was conducted by 2 consultant paediatricians. Patients were also reviewed by a dietitian, a physiotherapist and physical activity experts from local Sports Partnerships. Twelve children and their families attended the POC (mean age = 8.08 years; Range = 3.6-13.6): 11/12 were overweight and 9/12 were obese. Abnormalities in blood work were detected as follows: 1/7 had elevated LDL-cholesterol; 2/8 had elevated triglyceride levels; 4/8 had elevated fasting insulin; 2/8 had elevated fasting glucose. With the current prevalence of obesity in paediatric populations, initiatives such as UHL's POC need to be established, funded and supported, to try to meet complex, multidisciplinary patient needs and to prevent future complex and expensive health complications. PMID- 26625654 TI - Insights and Concerns of Patients and GPs Regarding Introduction of Universal Health Insurance in Ireland. AB - The implementation of a universal health insurance (UHI) model is a key political policy in Ireland. The objective here was to determine the understanding of general practitioners (GPs) and patients regarding UHI, its implementation and impact on both sets of stakeholders. Postal questionnaire to GPs, and opportunistic survey sampling of patients in two different GP practices were carried out. Response rates were 92.5% (patients) and 78% (GPs). 79.4% of patients (n = 418) and 96.7% of GPs (n = 149) have a 'poor' understanding of how UHI will be implemented. 89% (n = 493) of patients and 98.7% (n = 153) of GPs feel government communication about UHI has been 'poor'. 98.1% of GPs (n = 152) and 77.3% of patients (n = 383) are not confident that 'UHI will be ready for implementation by 2015'. Neither stakeholder group is confident in the government's ability to deliver UHI within the given timeframe. There is a lack of knowledge and consultation on proposals for its implementation. PMID- 26625655 TI - A Paediatric Hernia with a Twist: The Presentation, Imaging Findings and Management of a Strangulated Ovarian Hernia. AB - Indirect inguinal hernias are the most commonly encountered congenital abnormality in infants. They may be complicated by herniation of abdominal or pelvic viscus. In girls, a herniated ovary is a relatively common finding, however torsion of the ovary is infrequent. A tender irreducible inguinal hernia in an infant girl should raise the possibility of a strangulated herniated ovary as it requires urgent surgical attention. When in doubt, ultrasound with colour Doppler easily confirms the diagnosis. Here we present the case of an ovarian inguinal hernia which had undergone torsion and review the presentation, imaging findings and management. PMID- 26625656 TI - Deep Full Thickness Burn to a Finger from a Topical Wart Treatment. AB - We present a case of a deep full thickness burn from topical formic acid. Our patient developed a burn over her proximal interphalangeal joint (PIPJ) of her finger, secondary to inappropriate application of an anti-wart treatment. The burn required extensive deridement, and the resultant defect was reconstructed using a subcutaneous flap from the adjacent finger (a reverse cross finger flap). She was reviewed six months post-surgery, and overall she has a sub-optimal result. This incident was referred to the Irish Medicine's Board who have since reviewed the case and ordered the manufacturer to alter their usage instructions. PMID- 26625657 TI - An Assessment of Surgical Experience among Obstetric and Gynaecology SpR Trainees. AB - Changes in gynaecological practice have resulted in a significant reduction in surgical exposure for trainees. We have attempted to assess surgical experience among obstetric and gynaecology SpR's in Ireland using an anonymous on-line questionnaire. Trainees were asked to assess their own ability to perform a variety of general gynaecological procedures. There was a 97% response rate (29/33 trainees). There were 11 trainees who were in the final or penultimate year of the scheme. This group were analysed separately to assess competency rates in those approaching the end of the scheme. They were subdivided in to those who have completed one year in a general hospital doing pure gynaecology and those who have not. Approximately half of this group (6/11) had completed a pure gynaecology year. All of these trainees deemed themselves competent to perform all general gynaecological procedures listed, with the exception of trans urethral tape procedures, for which 3/6 reported the requirement of direct supervision. Only 2/6 deemed themselves competent to perform a total laparoscopic hysterectomy. Year 4/5 trainees who had not completed a pure gynaecology year displayed significantly lower competency rates for most of the procedures. With the current changes in gynaecological practice, these results highlight the importance of dedicated gynaecological surgical training. PMID- 26625658 TI - Gynaecology Training for Higher Specialist Trainees in Obstetrics and Gynaecology, a Personal View. PMID- 26625659 TI - ASSOCIATED NON DIAPHRAGMATIC ANOMALIES AMONG CASES WITH CONGENITAL DIAPHRAGMATIC HERNIA. AB - Cases with congenital diaphragmatic hernia (CDH) often have other associated anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in CDH in a defined population. The anomalies associated with CDH were collected in all live births, stillbirths and terminations of pregnancy during 29 years in 386,088 consecutive pregnancies of known outcome in the area covered by our population based registry of congenital anomalies. Of the 139 cases with CDH born during this period (total prevalence of 3.60 per 10,000), 85 (61.2%) had associated major anomalies. There were 25 (18.0%) cases with chromosomal abnormalities including 12 trisomies 18, and 24 (17.3%) nonchromosomal recognized dysmorphic conditions. There were no predominant recognized dysmorphic conditions, but Fryns syndrome. However, other recognized dysmorphic conditions were registered including fetal alcohol syndrome, de Lange syndrome, sequences (laterality sequence and ectopia cordis), and complexes (limb body wall complex). Thirty six (25.9%) of the cases had non syndromic multiple congenital anomalies (MCA). Anomalies of the cardiovascular system (n = 53, 27.5%), the urogenital system (n = 34, 17.6%), the musculoskeletal system (n = 29, 15.0%), and the central nervous system (n = 19, 9.8%) were the most common other congenital anomalies. We observed specific patterns of anomalies associated with CDH which emphasizes the need to evaluate all patients with CDH for possible associated malformations. In conclusion the overall prevalence of associated anomalies, which was close to two in three infants, emphasizes the need for a thorough investigation of cases with CDH. A routine screening for other anomalies may be considered in infants and in fetuses with CDH. One should be aware that the anomalies associated with CDH can be classified into a recognizable anomaly, syndrome or pattern in more than one out of two cases with CDH. PMID- 26625660 TI - PRENATAL DIAGNOSIS OF DE NOVO SUPERNUMERARY MARKER CHROMOSOME ORIGINATED FROM CHROMOSOME 16 BY ARRAY-CGH. AB - A 33 years-old pregnant woman was referred for amniocentesis at 19 weeks of gestation due to abnormal serum biochemistry. A non-satellited, monocentric marker chromosome was observed with a frequency of 50% in cultured amniocytes. Parental karyotypes were normal. The marker chromosome was found to be derived from chromosome 16 by FISH and array-CGH analysis. Genetic counseling was given to parents and the family decided to terminate the pregnancy. Dysmorphic findings including; low set ears, exophtalmos depressed nasal bridge, large mouth and lips, posture anomalies at the extremities were detected at autopsy. PMID- 26625661 TI - CEREBRAL VENOUS THROMBOSIS AND TURNER SYNDROME: A RARE REPORTED ASSOCIATION. AB - Turner Syndrome is the only known viable chromosomal monosomy, characterised by the complete or partial absence of an X chromosome. It's the most common chromosomal abnormality in females. Apart from the well known dysmorphic features of the syndrome, it has been associated with a number of vascular pathologies; mainly involving the cardiovascular, renovascular, peripheral vascular and cerebrovascular system. It seems striking that thromboembolism is not considered as a feature of the syndrome. Most of the thromboembolism cases are related to the arterial vascular system; except for some rare reported portal venous thrombosis cases, peripheral venous thrombosis cases and to the best of our knowledge a single case of cerebral venous thrombosis with Dandy Walker malformation and polymicrogyria. We herein report a cerebral venous thrombosis case with Turner Syndrome. With no other found underlying etiology, we want to highlight that Turner Syndrome, itself, may have a relationship not only with the cerebral arterial vascular system pathologies but also with the cerebral venous thrombosis. PMID- 26625662 TI - ESOPHAGEAL ATRESIA WITH RECURRENT TRACHEOESOPHAGEAL FISTULAS AND MICRODUPLICATION 22q11.23. AB - The microduplication 22q11.2 syndrome has a wide range of clinical manifestations. The phenotype ranges from normal to mental retardation and congenital anomalies. Esophageal atresia/tracheoesophageal fistula (EA/TEF) has recently been linked with the Tbx1 gene mutation located on the long arm of chromosome 22(22q11.21). We report a case with 1.4 Mb 22q11.23 duplication detected by array-CGH. The father of this infant has the same interstitial microduplication but with a normal phenotype. The phenotype seen in our case is type C (3B) esophageal atresia, tracheoesophageal fistula, and ventricular septal defect. Our patient underwent primary repair of OA/TEF malformations, which was later complicated by pneumonia and a recurrent TEF. PMID- 26625663 TI - ALOBAR HOLOPROSENCEPHALY, CLEFT LIP/PALATE, URORECTAL SEPTUM MALFORMATION SEQUENCE AND CONGENITAL PERINEAL HERNIA IN A FETUS. AB - We report on a fetus with alobar holoprosencephaly, complete cleft lip and palate, urorectal septum malformation sequence and perineal hernia. To our knowledge this appears to be a novel fetal malformation syndrome. PMID- 26625664 TI - MYOCLONIC ASTATIC EPILEPSY IN A PATIENT WITH A DE NOVO 4q21.22q21.23 MICRODUPLICATION. AB - Myoclonicastatic epilepsy (MAE) is a rare form of symptomatic generalized epilepsy of uncertain etiology. To search the possible genetic basis of the disorder, here we investigate a 15 year-old patient with MAE, who is the only person presenting epilepsy in the family. High resolution array-CGH analysis was conducted on DNA extracted from peripheral blood of the patient and the parents. The copy number variant(s) (CNVs) identified were further confirmed by Fluorescent In Situ Hybridization (FISH). The array-CGH identified a de novo microduplication of about 778 Kb in the chromosome region 4q21.22-q21.23, involving 11 genes. This is the first report of a de novo CNV in MAE. The genes involved in the duplication are potential candidates that can be investigated in the future to determine their exact role in the etiopathogenesis of the disorder. However, we suggest performing microarray chromosomal analysis in patients with MAE, since rare de novo CNVs could be identified, and this is known to affect the diagnostic process and recurrence risk assessment. PMID- 26625665 TI - A CASE OF MACROCEPHALY-CAPILLARY MALFORMATION SYNDROME PRESENTING WITH HOT WATER EPILEPSY. PMID- 26625666 TI - SPINAL MUSCULAR ATROPHY TYPE 1 AND POLAND SYNDROME: A NOVEL ASSOCIATION IN A MEXICAN FEMALE INFANT. PMID- 26625667 TI - BIRT-HOGG-DUBE SYNDROME: A CASE REPORT. PMID- 26625668 TI - A PATIENT WITH AZOOSPERMIA AND 45,X/46,X,r(Y) (p11.2q11.2) MOSAICISM WITHOUT AZF DELETIONS. PMID- 26625669 TI - CONGENITAL ABSENCE OF THE PORTAL VEIN IN A CHILD WITH TURNER SYNDROME. PMID- 26625670 TI - CYCLOPIA AND OTHER DEFECTS IN A FETUS WITH UNIQUE CHROMOSOMAL REARRANGEMENT. PMID- 26625671 TI - FOUR CASES OF SIRENOMELIA WITH DIFFERENT MANIFESTATION. PMID- 26625672 TI - CLINICAL FEATURES OF A CASE WITH 46,XX,del(18)(p11.1p11.3). PMID- 26625673 TI - AGENESIS OF THE DUCTUS VENOSUS--A CASE WITH NOONAN SYNDROME. PMID- 26625674 TI - A NOVEL MUTATION ASSOCIATED WITH NEPHROLITIHASIS IN ELLIS-VAN CREVELD SYNDROME. PMID- 26625675 TI - ON THE LEADERSHIP CHALLENGE. Give new and upcoming NHS leaders a leg up. PMID- 26625676 TI - RESILIENCE BUILDING HAS A HIDDEN COST. PMID- 26625677 TI - CANCER SPENDING CUTS EXPOSE A CHALLENGE. PMID- 26625678 TI - PROCUREMENT. THE BEST PRICES. PMID- 26625679 TI - TECHNOLOGY. A NEW TAKE ON LETTERS. PMID- 26625680 TI - SELF-CARE BY SMARTPHONE. PMID- 26625681 TI - "Nurses key to success of new care models". PMID- 26625683 TI - Standards aim to help prepare district nursing for a 'new era'. PMID- 26625682 TI - Nurse prescribing facing raft of new challenges. PMID- 26625684 TI - Education ringfence loss 'would hit frontline care'. PMID- 26625685 TI - RCN calls on Wales to put staffing first. PMID- 26625687 TI - Call for primary care services in A&E departments. PMID- 26625686 TI - Critical inspection reports draw attention to nursing shortages. PMID- 26625688 TI - Taking hypertension medication at night 'lowers risk of diabetes'. PMID- 26625689 TI - Probe launched into first rise in C. difficile cases for eight years. PMID- 26625690 TI - Latest vaccine data shows dip in MMR uptake. PMID- 26625691 TI - Paediatric nurse outreach service saves bed days and ups continuity. PMID- 26625692 TI - "Talking therapies will help our staff more than dance classes". PMID- 26625694 TI - Drug trolley alarms improve patient safety. PMID- 26625693 TI - "Caring nurses inspired me to pass their gift of kindness on". PMID- 26625695 TI - Providing better asthma care for children in school. AB - Assessing the needs of children, young people and families is a fundamental part of the school nurse's role. This article describes a project in Doncaster that has enabled a partnership working with children, young people, families, school nurses and school staff aimed at providing improved services throughout the primary and secondary school day. PMID- 26625696 TI - The assistant practitioner role in healthcare. AB - The assistant practitioner role is intended to free up nurses to make better use of their professional skills and improve patient outcomes. However, it can be perceived as a threat to nurses because it involves handing over clinical aspects of their work to unregistered and unregulated support workers. This article looks at how the role is developing, and the implications for nursing and quality of patient care. PMID- 26625697 TI - Using an alarm to improve drug trolley safety. AB - Leaving drug trolleys unlocked and unattended during drug rounds creates opportunities for drug theft and tampering. A new device was developed by our trust to detect when an open drug trolley is left unattended; it then sounds an alarm to remind staff to return to the trolley. This article describes use of the alarm on general hospital wards in one trust in the east of England. When the alarm was installed into drug trolleys on ahospital ward, it reduced the number of times unlocked trolleys were left unattended. The drug trolley alarm successfully changed the behaviour of staff on drug rounds and, in so doing, improved patient safety. PMID- 26625698 TI - PART 2 of 3: PAIN MANAGEMENT. Transmission of pain signals to the brain. AB - Pain is the body's way of telling us something is wrong, and has a sensory and emotional component. This three-part series focuses on acute pain, describing the physiology of a normal and well-behaved pain pathway and how this relates to commonly used pain management strategies. The first article introduced the pain system and how the body detects a threatening (noxious) stimulus. This article describes how that "pain message" is transmitted to the spinal cord and the brain and how the brain responds to the stimulus, while identifying pain relief strategies linked to the physiological process. Part 3, to be published next week, discusses pain assessment. PMID- 26625699 TI - 60 SECOND WITH Jo Sutton. PMID- 26625700 TI - Making change happen. PMID- 26625701 TI - pH-Independent Charge Resonance Mechanism for UV Protective Functions of Shinorine and Related Mycosporine-like Amino Acids. AB - The UV-protective ability of mycosporine-like amino acids (MAAs) has been well documented and is believed to serve as a protecting agent for marine organisms from solar radiation. However, the effective UV absorption by MAAs has not been well correlated to MAA (neutral) structures. In this study, the origin of UV protecting ability of MAAs was elucidated by experimental and theoretical spectroscopic investigations. The absorption maxima of mycosporine-glycine and shinorine in the UVA region were practically unaffected over a wide range of pH 4 10 and only slightly blue-shifted at pH 1-2. It was revealed that the zwitterionic nature of the amino acid residue facilitates the protonation to the chromophoric 3-aminocyclohexenone and 1-amino-3-iminocyclohexene moieties and the operation of the charge resonance in the protonated species well accounts for their allowed low-energy transitions in the UVA region. The RI-CC2/TZVP calculations on model systems in their protonated forms well reproduced the observed transition energies and oscillator strengths of MAAs, only with insignificant systematic overestimations of the both values. The slight hypsochromic shifts at pH 1-2 were explained by (partial) protonation to a carboxylate anion in the amino acid residue, as confirmed by theory. Fluorescence spectral investigations of shinorine were also performed for the first time in water to confirm the effective nonradiative deactivation. Consequently, this study unequivocally demonstrated that the 3-aminocyclohexenone as well as 1-amino 3-iminocyclohexene moieties, which are readily protonated at a wide range of pH, are responsible for the UV-protective ability of aqueous solution of MAAs. PMID- 26625702 TI - Endoplasmic reticulum stress intolerance in EIF2B3 mutant oligodendrocytes is modulated by depressed autophagy. AB - OBJECTIVE: Eukaryotic translation initiation factor 2B (eIF2B) is an essential factor for the initiation of protein synthesis. Mutations in eIF2B encoded by EIF2B1-5 cause a lethal leukoencephalopathy--vanishing white matter disease (VWM). Previous studies have suggested that an improper activated unfolded protein response (UPR) after endoplasmic reticulum stress (ERS) contributed to the pathogenesis of the disease. Autophagy, an important compensatory pathway after ERS, was analyzed in this study. METHODS: To determine the tolerance differences to ERS, cell viability and apoptosis rates were detected in oligodendrocyte cell lines transfected with EIF2B3-c.1037T>C or the wild type. Autophagy flux was measured between groups. Autophagy inducers and inhibitors were used to identify the role of autophagy in the mutant oligodendrocytes. RESULTS: We confirmed that oligodendrocytes with mutant EIF2B3 was less tolerant to ERS than the wild type, with decreased cell viability and increased apoptosis rates. Autophagy flux was depressed in mutant oligodendrocytes under baseline condition and after ERS stimulation. Reduced expression of autophagy related gene (Atg) 3 and Atg 7 were involved in the depression of autophagy flux. The mutant oligodendrocytes pretreated with autophagy inducers showed stable cell viability and decreased apoptosis despite ERS induction, whereas the autophagy inhibitors aggravated cell apoptosis and viability declination. CONCLUSIONS: Oligodendrocytes transfected with mutant EIF2B3 was less tolerant to ERS than the wild type. Depressed autophagy flux was observed in the mutant cells at baseline and after ERS stimulation. Improperly depressed autophagy played a role in the susceptibility to ERS in EIF2B3 mutant oligodendrocytes. PMID- 26625703 TI - Limiting the Number of Potential Binding Modes by Introducing Symmetry into Ligands: Structure-Based Design of Inhibitors for Trypsin-Like Serine Proteases. AB - In the absence of X-ray data, the exploration of compound binding modes continues to be a challenging task. For structure-based design, specific features of active sites in different targets play a major role in rationalizing ligand binding characteristics. For example, dibasic compounds have been reported as potent inhibitors of various trypsin-like serine proteases, the active sites of which contain several binding pockets that can be targeted by cationic moieties. This results in several possible orientations within the active site, complicating the binding mode prediction of such compounds by docking tools. Therefore, we introduced symmetry in bi- and tribasic compounds to reduce conformational space in docking calculations and to simplify binding mode selection by limiting the number of possible pocket occupations. Asymmetric bisbenzamidines were used as starting points for a multistage and structure-guided optimization. A series of 24 final compounds with either two or three benzamidine substructures was ultimately synthesized and evaluated as inhibitors of five serine proteases, leading to potent symmetric inhibitors for the pharmaceutical drug targets matriptase, matriptase-2, thrombin and factor Xa. This study underlines the relevance of ligand symmetry for chemical biology. PMID- 26625704 TI - Impact of an Infant Transport Mattress on CT Dose and Image Quality. AB - RATIONALE AND OBJECTIVES: Neonates are at increased risk for cold stress and hypothermia in cool environments. An infant transport mattress (ITM) is commonly used to increase neonate temperature during transport and has been used during CT scanning. This study determined the impact of an ITM on radiation dose and image artifacts during CT scanning. MATERIALS AND METHODS: CT images from a single clinical patient scanned with an ITM were reviewed, and observations of image artifacts were recorded. A phantom was scanned with and without the ITM while varying tube-current modulation, reconstruction method, slice thickness, metal reduction algorithm, tube voltage, and tube current. The effects of the ITM on computed tomography dose index (CTDIvol), mean Hounsfield unit (HU), and HU standard deviation were recorded. RESULTS: The clinical patient scan demonstrated significantly decreased mean HU and increased HU standard deviation. In the phantom, the ITM increased CTDIvol 27% and induced an artifact that decreased the mean HU by 3.5 HU and increased HU standard deviation by 4.6 HU. Angular tube current modulation, strong iterative reconstruction, thick slices, metal artifact reduction, and high mA reduced the artifact. CONCLUSIONS: Using ITM during CT scanning is not recommended given the relatively brief scanning time, increased dose, and induced image artifacts. Based on our results, several acquisition parameters may be altered to mitigate the image artifact if an ITM is required during scanning. PMID- 26625705 TI - Orbital Indeterminate Lesions in Adults: Combined Magnetic Resonance Morphometry and Histogram Analysis of Apparent Diffusion Coefficient Maps for Predicting Malignancy. AB - RATIONALE AND OBJECTIVES: The aim of this study was to evaluate the added value of histogram analysis of apparent diffusion coefficient (ADC) maps in differentiating indeterminate orbital malignant tumors from benign tumors, compared to using magnetic resonance (MR) morphological features alone. MATERIALS AND METHODS: We retrospectively evaluated 54 patients with orbital tumors from March 2013 to February 2015. All the patients were assessed by both routine MR and diffusion-weighted imaging, and divided into benign group and malignant group. Routine MR imaging features and histogram parameters derived from ADC maps, including mean ADC (ADCmean), median ADC (ADCmedian), standard deviation, skewness, kurtosis, and 10th and 90th percentiles of ADC (ADC10 and ADC90), were compared between two groups. Univariate and multivariate logistic regression analyses were used to identify the most valuable variables in predicting malignancy. Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic value of significant variables. RESULTS: Multivariate logistic regression analysis indicated that two or more quadrants involved, iso intense on T2-weighted imaging (T2WI), and ADC10 were significant predictors for orbital malignancy. By using model 2 (iso-intense on T2WI + two or more quadrants involved + ADC10 < 0.990) as the criterion, higher AUC and specificity could be achieved than by using model 1 (iso-intense on T2WI + two or more quadrants involved) alone, (model 2 vs model 1; area under curve (AUC), 0.827 vs 0.793; sensitivity, 65.4% vs 69.2%; specificity, 100% vs 89.3%). CONCLUSIONS: Iso intense on T2WI, two or more quadrants involved, and ADC10 are risk factors for orbital malignancy. Histogram analysis of ADC map might provide added value in predicting orbital malignancy. PMID- 26625706 TI - Patient-directed Internet-based Medical Image Exchange: Experience from an Initial Multicenter Implementation. AB - RATIONALE AND OBJECTIVES: Inefficient transfer of personal health records among providers negatively impacts quality of health care and increases cost. This multicenter study evaluates the implementation of the first Internet-based image sharing system that gives patients ownership and control of their imaging exams, including assessment of patient satisfaction. MATERIALS AND METHODS: Patients receiving any medical imaging exams in four academic centers were eligible to have images uploaded into an online, Internet-based personal health record. Satisfaction surveys were provided during recruitment with questions on ease of use, privacy and security, and timeliness of access to images. Responses were rated on a five-point scale and compared using logistic regression and McNemar's test. RESULTS: A total of 2562 patients enrolled from July 2012 to August 2013. The median number of imaging exams uploaded per patient was 5. Most commonly, exams were plain X-rays (34.7%), computed tomography (25.7%), and magnetic resonance imaging (16.1%). Of 502 (19.6%) patient surveys returned, 448 indicated the method of image sharing (Internet, compact discs [CDs], both, other). Nearly all patients (96.5%) responded favorably to having direct access to images, and 78% reported viewing their medical images independently. There was no difference between Internet and CD users in satisfaction with privacy and security and timeliness of access to medical images. A greater percentage of Internet users compared to CD users reported access without difficulty (88.3% vs. 77.5%, P < 0.0001). CONCLUSION: A patient-directed, interoperable, Internet-based image sharing system is feasible and surpasses the use of CDs with respect to accessibility of imaging exams while generating similar satisfaction with respect to privacy. PMID- 26625707 TI - Evidence of Resting-state Activity in Propofol-anesthetized Patients with Intracranial Tumors. AB - RATIONALE AND OBJECTIVES: Resting-state (RS) networks, revealed by functional magnetic resonance imaging (fMRI) studies in healthy volunteers, have never been evaluated in anesthetized patients with brain tumors. Our purpose was to examine the presence of residual brain activity on the auditory network during propofol induced loss of consciousness in patients with brain tumors. MATERIALS AND METHODS: Twenty subjects with intracranial masses were prospectively studied by means of intraoperative RS-fMRI acquisitions before any craniectomy. After performing single-subject independent component analysis, spatial maps and time courses were assigned to an auditory RS network template from the literature and compared via spatial regression coefficients. RESULTS: All fMRI data were of sufficient quality for further postprocessing. In all but two patients, the RS functional activity of the auditory network could be successfully mapped. In almost all patients, contralateral activation of the auditory network was present. No significant difference was found between the mean distance of the RS activity clusters and the lesion periphery for tumors located in the temporal gyri vs. those in other brain regions. The spatial deviation between the activated cluster in our experiment and the template was significantly (P = 0.04) higher in patients with tumors located in the temporal gyri than in patients with tumors located in other regions. CONCLUSIONS: Propofol-induced anesthesia in patients with intracranial lesions does not alter the blood-oxygenation level depended signal, and independent component analysis of intraoperative RS-fMRI may allow assessment of the auditory network in a clinical setting. PMID- 26625708 TI - Metagenomic sequencing of bile from gallstone patients to identify different microbial community patterns and novel biliary bacteria. AB - Despite the high worldwide prevalence of gallstone disease, the role of the biliary microbiota in gallstone pathogenesis remains obscure. Next-generation sequencing offers advantages for systematically understanding the human microbiota; however, there have been few such investigations of the biliary microbiome. Here, we performed whole-metagenome shotgun (WMS) sequencing and 16S rRNA sequencing on bile samples from 15 Chinese patients with gallstone disease. Microbial communities of most individuals were clustered into two types, according to the relative enrichment of different intestinal bacterial species. In the bile samples, oral cavity/respiratory tract inhabitants were more prevalent than intestinal inhabitants and existed in both community types. Unexpectedly, the two types were not associated with fever status or surgical history, and many bacteria were patient-specific. We identified 13 novel biliary bacteria based on WMS sequencing, as well as genes encoding putative proteins related to gallstone formation and bile resistance (e.g., beta-glucuronidase and multidrug efflux pumps). Bile samples from gallstone patients had reduced microbial diversity compared to healthy faecal samples. Patient samples were enriched in pathways related to oxidative stress and flagellar assembly, whereas carbohydrate metabolic pathways showed varying behaviours. As the first biliary WMS survey, our study reveals the complexity and specificity of biliary microecology. PMID- 26625709 TI - Consumption of a calcium and vitamin D-fortified food product does not affect iron status during initial military training: a randomised, double-blind, placebo controlled trial. AB - Ca/vitamin D supplementation maintains bone health and decreases stress fracture risk during initial military training (IMT); however, there is evidence that Ca may negatively affect the absorption of other critical micronutrients, particularly Fe. The objective of this randomised, double-blind, placebo controlled trial was to determine whether providing 2000 mg/d Ca and 25 ug/d vitamin D in a fortified food product during 9 weeks of military training affects Fe status in young adults. Male (n 98) and female (n 54) volunteers enrolled in US Army basic combat training (BCT) were randomised to receive a snack bar with Ca/vitamin D (n 75) or placebo (snack bar without Ca/vitamin D; n 77) and were instructed to consume 2 snack bars/d between meals throughout the training course. Circulating ionised Ca was higher (P0.05) in markers of Fe status between placebo and Ca/vitamin D groups. Collectively, these data indicate that Ca/vitamin D supplementation through the use of a fortified food product consumed between meals does not affect Fe status during IMT. PMID- 26625710 TI - Impact of Adapted Sports Activities on the Progression of Carotid Atherosclerosis in Subjects With Spinal Cord Injury. AB - OBJECTIVE: To determine whether regular performance of adapted sports is associated with long-term changes in carotid atherosclerosis in subjects with spinal cord injury (SCI). DESIGN: Prospective observational study. SETTING: Academic medical center. PARTICIPANTS: Men with chronic (>1y) SCI and no preserved motor function below the injury level were evaluated in 2007 and 2012 (N=17). Nine subjects did not perform physical activity between the studied time points (control group), whereas 8 subjects entered competitive upper-body sports programs (rugby: n=5, basketball: n=1, jiu-jitsu: n=1, and tennis: n=1) after baseline and were regularly training at the time of the second evaluation (sports group). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Clinical, laboratory, hemodynamic, and carotid ultrasonography analysis. RESULTS: The studied groups showed no differences in all studied variables at baseline. After 5 years of follow-up, the control group showed increases in heart rate (87.0+/ 3.1 vs 74.7+/-3.8 beats per minute; P=.004), but the participants had no significant changes in carotid intima-media thickness (IMT) (.65+/-.05 vs .67+/ .03mm; P=.73) or IMT/diameter (.118+/-.007 vs .136+/-.013; P=.24). In contrast, the sports group showed long-term decreases in carotid IMT (.56+/-.05 vs .74+/ .05mm; P=.001) and IMT/diameter (.097+/-.006 vs .141+/-.009; P<.001), but the participants did not show any variation in the other studied variables at follow up. CONCLUSIONS: Regular upper-body sports activities are associated with long term reductions in carotid atherosclerosis in subjects with SCI and might be a potential prevention strategy aiming to reduce cardiovascular risk in this population. PMID- 26625711 TI - The Norwegian preeclampsia family cohort study: a new resource for investigating genetic aspects and heritability of preeclampsia and related phenotypes. AB - BACKGROUND: Preeclampsia is a major pregnancy complication without curative treatment available. A Norwegian Preeclampsia Family Cohort was established to provide a new resource for genetic and molecular studies aiming to improve the understanding of the complex pathophysiology of preeclampsia. METHODS: Participants were recruited from five Norwegian hospitals after diagnoses of preeclampsia registered in the Medical birth registry of Norway were verified according to the study's inclusion criteria. Detailed obstetric information and information on personal and family disease history focusing on cardiovascular health was collected. At attendance anthropometric measurements were registered and blood samples were drawn. The software package SPSS 19.0 for Windows was used to compute descriptive statistics such as mean and SD. P-values were computed based on t-test statistics for normally distributed variables. Nonparametrical methods (chi square) were used for categorical variables. RESULTS: A cohort consisting of 496 participants (355 females and 141 males) representing 137 families with increased occurrence of preeclampsia has been established, and blood samples are available for 477 participants. Descriptive analyses showed that about 60% of the index women's pregnancies with birth data registered were preeclamptic according to modern diagnosis criteria. We also found that about 41% of the index women experienced more than one preeclamptic pregnancy. In addition, the descriptive analyses confirmed that preeclamptic pregnancies are more often accompanied with delivery complications. CONCLUSION: The data and biological samples collected in this Norwegian Preeclampsia Family Cohort will provide an important basis for future research. Identification of preeclampsia susceptibility genes and new biomarkers may contribute to more efficient strategies to identify mothers "at risk" and contribute to development of novel preventative therapies. PMID- 26625713 TI - Engineered Cx40 variants increased docking and function of heterotypic Cx40/Cx43 gap junction channels. AB - Gap junction (GJ) channels provide low resistance passages for rapid action potential propagation in the heart. Both connexin40 (Cx40) and Cx43 are abundantly expressed in and frequently co-localized between atrial myocytes, possibly forming heterotypic GJ channels. However, conflicting results have been obtained on the functional status of heterotypic Cx40/Cx43 GJs. Here we provide experimental evidence that the docking and formation of heterotypic Cx40/Cx43 GJs can be substantially increased by designed Cx40 variants on the extracellular domains (E1 and E2). Specifically, Cx40 D55N and P193Q, substantially increased the probability to form GJ plaque-like structures at the cell-cell interfaces with Cx43 in model cells. More importantly the coupling conductance (Gj) of D55N/Cx43 and P193Q/Cx43 GJ channels are significantly increased from the Gj of Cx40/Cx43 in N2A cells. Our homology models indicate the electrostatic interactions and surface structures at the docking interface are key factors preventing Cx40 from docking to Cx43. Improving heterotypic Gj of these atrial connexins might be potentially useful in improving the coupling and synchronization of atrial myocardium. PMID- 26625712 TI - Rapid emergence and predominance of a broadly recognizing and fast-evolving norovirus GII.17 variant in late 2014. AB - Norovirus genogroup II genotype 4 (GII.4) has been the predominant cause of viral gastroenteritis since 1996. Here we show that during the winter of 2014-2015, an emergent variant of a previously rare norovirus GII.17 genotype, Kawasaki 2014, predominated in Hong Kong and outcompeted contemporary GII.4 Sydney 2012 in hospitalized cases. GII.17 cases were significantly older than GII.4 cases. Root to-tip and Bayesian BEAST analyses estimate GII.17 viral protein 1 (VP1) evolves one order of magnitude faster than GII.4 VP1. Residue substitutions and insertion occur in four of five inferred antigenic epitopes, suggesting immune evasion. Sequential GII.4-GII.17 infections are noted, implicating a lack of cross protection. Virus bound to saliva of secretor histo-blood groups A, B and O, indicating broad susceptibility. This fast-evolving, broadly recognizing and probably immune-escaped emergent GII.17 variant causes severe gastroenteritis and hospitalization across all age groups, including populations who were previously less vulnerable to GII.4 variants; therefore, the global spread of GII.17 Kawasaki 2014 needs to be monitored. PMID- 26625715 TI - Serodiagnostic potential of immuno-PCR using a cocktail of mycobacterial antigen 85B, ESAT-6 and cord factor in tuberculosis patients. AB - A novel indirect immuno-polymerase chain reaction (I-PCR) assay was developed for the detection of circulating anti-Ag85B (antigen 85B, Rv1886c), anti-ESAT-6 (early secretory antigenic target-6, Rv3875) and anti-cord factor (trehalose 6,6' dimycolate) antibodies from the sera samples of pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) patients and the results were compared with an analogous enzyme-linked immunosorbent assay (ELISA). We covalently attached the amino-modified reporter DNA to the dithiothreitol (DTT)-reduced anti-human IgG antibody through a chemical linker succinimidyl 4-[N-maleimidomethyl]-cyclohexane 1-carboxylate (SMCC). The detection of cocktail of anti-Ag85B, anti-ESAT-6 and anti-cord factor antibodies was found to be superior to the detection of individual antibodies. The sensitivities of 89.5% and 77.5% with I-PCR and 70.8% and 65% with ELISA were observed in smear-positive and smear-negative PTB cases, respectively with high specificity (90.9%). On the other hand, a sensitivity of 77.5% with I-PCR and 65% with ELISA was observed in EBTB cases. The detection of cocktail of antibodies by I-PCR is likely to improve the utility of existing algorithms for TB diagnosis. PMID- 26625714 TI - The Hippo pathway mediates inhibition of vascular smooth muscle cell proliferation by cAMP. AB - AIMS: Inhibition of vascular smooth muscle cell (VSMC) proliferation by intracellular cAMP prevents excessive neointima formation and hence angioplasty restenosis and vein-graft failure. These protective effects are mediated via actin-cytoskeleton remodelling and subsequent regulation of gene expression by mechanisms that are incompletely understood. Here we investigated the role of components of the growth-regulatory Hippo pathway, specifically the transcription factor TEAD and its co-factors YAP and TAZ in VSMC. METHODS AND RESULTS: Elevation of cAMP using forskolin, dibutyryl-cAMP or the physiological agonists, Cicaprost or adenosine, significantly increased phosphorylation and nuclear export YAP and TAZ and inhibited TEAD-luciferase report gene activity. Similar effects were obtained by inhibiting RhoA activity with C3-transferase, its downstream kinase, ROCK, with Y27632, or actin-polymerisation with Latrunculin-B. Conversely, expression of constitutively-active RhoA reversed the inhibitory effects of forskolin on TEAD-luciferase. Forskolin significantly inhibited the mRNA expression of the pro-mitogenic genes, CCN1, CTGF, c-MYC and TGFB2 and this was reversed by expression of constitutively-active YAP or TAZ phospho-mutants. Inhibition of YAP and TAZ function with RNAi or Verteporfin significantly reduced VSMC proliferation. Furthermore, the anti-mitogenic effects of forskolin were reversed by overexpression of constitutively-active YAP or TAZ. CONCLUSION: Taken together, these data demonstrate that cAMP-induced actin-cytoskeleton remodelling inhibits YAP/TAZ-TEAD dependent expression of pro-mitogenic genes in VSMC. This mechanism contributes novel insight into the anti-mitogenic effects of cAMP in VSMC and suggests a new target for intervention. PMID- 26625716 TI - Dual strategies to improve oral bioavailability of oleanolic acid: Enhancing water-solubility, permeability and inhibiting cytochrome P450 isozymes. AB - Oleanolic acid (OA) is a typical BCS IV drug with low water-solubility and poor permeability, metabolized by cytochrome P450 (CYP) isozymes in the intestinal tract, such as CYP3A. These are the reasons for the low oral bioavailability of OA which have restricted its wide application. In this study, a solidified phospholipid complex (OPCH) composed of OA-phospholipid complex (OPC) and hydroxyapatite (HA) was prepared by simple solvent evaporation. OPC was used to improve the liposolubility of OA, and HA was used to improve the flowability of OPC. Ketoconazole (KCZ, inhibitor of CYP3A) was co-administrated with OPCH to inhibit the metabolism of OA by CYP3A in the intestine. DSC, PXRD, SEM and IR analysis confirmed the formation of OPC and OPCH. Compared with the water solubility and n-octanol solubility of OA, that of OPCH was increased nearly 15.3 fold and 3.19-fold, respectively. An in vitro dissolution study showed that the cumulative dissolution rate of OPCH was nearly 2.23-fold and 4.57-fold higher than that of OA and OPC at 2h. Single-pass intestinal perfusion studies showed that the absorption of OA from OPCH was increased nearly 1.6-2.6-fold compared with that of pure OA and this was mainly due to the improved permeability and was further increased by OPCH with KCZ 1.2-2.4-fold compared with that of OPCH because KCZ inhibited metabolism of OA by CYP3A. A pharmacokinetic study of OPCH in rats following co-administration of KCZ was investigated. The Cmax was increased markedly from 59.5 to 78.7 and 131.3ng/mL in case of OA alone, OPCH alone and OPCH with KCZ. In parallel with the Cmax, the AUC0-24h was increased from 259.6 to 306.6 and 707.7ngh/mL, respectively. All the results obtained demonstrated that formulation of OPCH and co-administration of KCZ significantly improved the bioavailability of OA by increasing the solubility and permeability in combination with inhibiting the metabolism of OA. PMID- 26625717 TI - PEGylated siRNA lipoplexes for silencing of BLIMP-1 in Primary Effusion Lymphoma: In vitro evidences of antitumoral activity. AB - Silencing of the B lymphocyte-induced maturation protein 1 (Blimp-1), a pivotal transcriptional regulator during terminal differentiation of B cells into plasma cells with siRNAs is under investigation as novel therapeutic approach in Primary Effusion Lymphoma (PEL), a HHV-8 related and aggressive B cell Lymphoma currently lacking of an efficacious therapeutic approach. The clinical application of small interfering RNA (siRNA) in cancer therapy is limited by the lack of an efficient systemic siRNA delivery system. In this study we aim to develop pegylated siRNA lipoplexes formed using the cationic lipid DOTAP and DSPE-PEG2000, capable to effectively stabilize anti-Blimp-1 siRNA and suitable for systemic administration. Two types of pegylated lipoplexes using a classic (C-PEG Lipoplexes) or a post-pegylation method (P-PEG-Lipoplexes) were formulated and compared in their physicochemical properties (size, zeta potential, morphology and structure) and efficiency on PEL cell lines. A stable siRNAs protection was obtained with post pegylation approach (2% molar of DSPE-PEG2000 with respect to lipid) resulting in structures with diameters of 300 nm and a complexation efficiency higher that 80% (0.08 nmol/10 nmol of lipid). In vitro studies on PEL cell lines suggested that empty liposomes were characterized by a low cell toxicity also after PEG modification (cell viability and cell density over 85% after treatment with 10 MUM of lipid). We demonstrated that P-PEG-Lipoplexes were able to significantly reduce the levels of BLIMP-1 protein leading to reduction of viability (less that 15% after transfection with 100 nM of complexed siRNAs) and activation of apoptosis. In vitro efficiency encourages us to further test the in vivo potential of P-PEG-Lipoplexes in PEL therapy. PMID- 26625718 TI - Robotic pilot study for analysing spasticity: clinical data versus healthy controls. AB - BACKGROUND: Spasticity is a motor disorder that causes significant disability and impairs function. There are no definitive parameters that assess spasticity and there is no universally accepted definition. Spasticity evaluation is important in determining stages of recovery. It can determine treatment effectiveness as well as how treatment should proceed. This paper presents a novel cross sectional robotic pilot study for the primary purpose of assessment. The system collects force and position data to quantify spasticity through similar motions of the Modified Ashworth Scale (MAS) assessment in the Sagittal plane. Validity of the system is determined based on its ability to measure velocity dependent resistance. METHODS: Forty individuals with Acquired Brain Injury (ABI) and 45 healthy individuals participated in a robotic pilot study. A linear regression model was applied to determine the effect an ABI has on force data obtained through the robotic system in an effort to validate it. Parameters from the model were compared for both groups. Two techniques were performed in an attempt to classify between healthy and patients. Dynamic Time Warping (DTW) with k-nearest neighbour (KNN) classification is compared to a time-series algorithm using position and force data in a linear discriminant analysis (LDA). RESULTS: The system is capable of detecting a velocity dependent resistance (p<0.05). Differences were found between healthy individuals and those with MAS 0 who are considered to be healthy. DTW with KNN is shown to improve classification between healthy and patients by approximately 20 % compared to that of an LDA. CONCLUSIONS: Quantitative methods of spasticity evaluation demonstrate that differences can be observed between healthy individuals and those with MAS of 0 who are often clinically considered to be healthy. Exploiting the time-series nature of the collected data demonstrates that position and force together are an accurate predictor of patient health. PMID- 26625720 TI - Altered circulating mitochondrial DNA and increased inflammation in patients with diabetic retinopathy. AB - AIMS: We previously showed that circulating mitochondrial DNA (MtDNA) levels are altered in diabetic nephropathy. The aim of the current study was to determine if circulating MtDNA levels are altered in patients with diabetic retinopathy. METHODS: Patients with diabetes (n=220) were studied in a clinical setting using a cross-sectional study design as the following groups: DR-0 (no retinopathy, n=53), DR-m (mild non-proliferative diabetic retinopathy NPDR, n=98) and DR-s (severe proliferative diabetic retinopathy, n=69). MtDNA content in peripheral blood DNA was measured as the mitochondrial to nuclear genome ratio using real time qPCR. Circulating cytokines were measured using the luminex assay and MtDNA damage was assessed using PCR. Differences were considered significant at P<0.05. RESULTS: Circulating MtDNA values were higher in DR-m compared to DR-0 (P=0.02) and decreased in DR-s compared to DR-m (P=0.001). These changes remained significant after adjusting for associated parameters. In parallel there were increased levels of circulating cytokines IL-4 (P=0.005) and TNF-alpha (P=0.02) in the DR-s group and increased MtDNA damage in DR-m patients compared to DR-0 (P=0.03). CONCLUSIONS: Our data show that circulating MtDNA levels are independently associated with diabetic retinopathy, showing an increase in DR-m and decrease in DR-s with a parallel increase in MtDNA damage and inflammation. Hyperglycemia-induced changes in MtDNA in early diabetes may contribute to inflammation and progression of diabetic retinopathy. Longitudinal studies should be carried out to determine a potential causality of MtDNA in diabetic retinopathy. PMID- 26625722 TI - Alkaloid synthesis using chiral secondary amine organocatalysts. AB - Over the last decade, several excellent enantioselective total syntheses of important alkaloids using asymmetric reactions mediated by chiral secondary amine organocatalysts as a key step have been accomplished. This perspective article examines the full strategies of these alkaloid syntheses, especially the application of the organocatalytic reaction to construct the alkaloid scaffolds. PMID- 26625721 TI - Use of prospective hospital surveillance data to define spatiotemporal heterogeneity of malaria risk in coastal Kenya. AB - BACKGROUND: Malaria in coastal Kenya shows spatial heterogeneity and seasonality, which are important factors to account for when planning an effective control system. Routinely collected data at health facilities can be used as a cost effective method to acquire information on malaria risk for large areas. Here, data collected at one specific hospital in coastal Kenya were used to assess the ability of such passive surveillance to capture spatiotemporal heterogeneity of malaria and effectiveness of an augmented control system. METHODS: Fever cases were tested for malaria at Msambweni sub-County Referral Hospital, Kwale County, Kenya, from October 2012 to March 2015. Remote sensing data were used to classify the development level of each monitored community and to identify the presence of rice fields nearby. An entomological study was performed to acquire data on the seasonality of malaria vectors in the study area. Rainfall data were obtained from a weather station located in proximity of the study area. Spatial analysis was applied to investigate spatial patterns of malarial and non-malarial fever cases. A space-time Bayesian model was performed to evaluate risk factors and identify locations at high malaria risk. Vector seasonality was analysed using a generalized additive mixed model (GAMM). RESULTS: Among the 25,779 tested febrile cases, 28.7 % were positive for Plasmodium infection. Malarial and non-malarial fever cases showed a marked spatial heterogeneity. High risk of malaria was linked to patient age, community development level and presence of rice fields. The peak of malaria prevalence was recorded close to rainy seasons, which correspond to periods of high vector abundance. Results from the Bayesian model identified areas with significantly high malaria risk. The model also showed that the low prevalence of malaria recorded during late 2012 and early 2013 was associated with a large-scale bed net distribution initiative in the study area during mid-2012. CONCLUSIONS: The results indicate that the use of passive surveillance was an effective method to detect spatiotemporal patterns of malaria risk in coastal Kenya. Furthermore, it was possible to estimate the impact of extensive bed net distribution on malaria prevalence among local fever cases over time. Passive surveillance based on georeferenced malaria testing is an important tool that control agencies can use to improve the effectiveness of interventions targeting malaria (and other causes of fever) in such high-risk locations. PMID- 26625723 TI - Qualitative insights into promotion of pharmaceutical products in Bangladesh: how ethical are the practices? AB - BACKGROUND: The pharmaceutical market in Bangladesh is highly concentrated (top ten control around 70 % of the market). Due to high competition aggressive marketing strategies are adopted for greater market share, which sometimes cross limit. There is lack of data on this aspect in Bangladesh. This exploratory study aimed to fill this gap by investigating current promotional practices of the pharmaceutical companies including the role of their medical representatives (MR). METHODS: This qualitative study was conducted as part of a larger study to explore the status of governance in health sector in 2009. Data were collected from Dhaka, Chittagong and Bogra districts through in-depth interview (healthcare providers and MRs), observation (physician-MR interaction), and round table discussion (chief executives and top management of the pharmaceutical companies). RESULTS: Findings reveal a highly structured system geared to generate prescriptions and ensure market share instituted by the pharmaceuticals. A comprehensive training curriculum for the MRs prepares the newly recruited science graduates for generating enough prescriptions by catering to the identified needs and demands of the physicians expressed or otherwise, and thus grab higher market-share for the companies they represent. Approaches such as inducements, persuasion, emotional blackmail, serving family members, etc. are used. The type, quantity and quality of inducements offered to the physicians depend upon his/her capacity to produce prescriptions. The popular physicians are cultivated meticulously by the MRs to establish brand loyalty and fulfill individual and company targets. The physicians, willingly or unwillingly, become part of the system with few exceptions. Neither the regulatory authority nor the professional or consumer rights bodies has any role to control or ractify the process. CONCLUSIONS: The aggressive marketing of the pharmaceutical companies compel their MRs, programmed to maximize market share, to adopt unethical means if and when necessary. When medicines are prescribed and dispensed more for financial interests than for needs of the patients, it reflects system's failed ability to hold individuals and entities accountable for adhering to basic professional ethics, code of conduct, and statutory laws. PMID- 26625725 TI - Calibration and efficiency curve of SANAEM ionization chamber for activity measurements. AB - A commercially available Fidelis ionization chamber was calibrated and assessed in PTB with activity standard solutions. The long-term stability and linearity of the system was checked. Energy-dependent efficiency curves for photons and beta particles were determined, using an iterative method in ExcelTM, to enable calibration factors to be calculated for radionuclides which were not used in the calibration. Relative deviations between experimental and calculated radionuclide efficiencies are of the order of 1% for most photon emitters and below 5% for pure beta emitters. The system will enable TAEK-SANAEM to provide traceable activity measurements. PMID- 26625726 TI - Calculation of the decision threshold in gamma-ray spectrometry using sum peaks. AB - In the presence of radon daughters, gamma rays from (88)Y with energies at 898.0keV or 1836.1keV appear on a high, continuous background or overlap with other peaks. Therefore a calculation of the decision threshold from the sum peak at 2734.1keV represents a useful alternative, because here the continuous background is low. The decision threshold calculated from this peak can attain a value being comparable to the decision threshold calculated from the gamma-ray peak at 898.0keV. PMID- 26625724 TI - Difference in expression between AQP1 and AQP5 in porcine endometrium and myometrium in response to steroid hormones, oxytocin, arachidonic acid, forskolin and cAMP during the mid-luteal phase of the estrous cycle and luteolysis. AB - BACKGROUND: Recently, we demonstrated in vitro that AQP1 and AQP5 in the porcine uterus are regulated by steroid hormones (P4, E2), arachidonic acid (AA), forskolin (FSK) and cAMP during the estrous cycle. However, the potential of the porcine separated uterine tissues, the endometrium and myometrium, to express these AQPs remains unknown. Thus, in this study, the responses of AQP1 and AQP5 to P4, E2 oxytocin (OT), AA, FSK and cAMP in the porcine endometrium and myometrium were examined during the mid-luteal phase of the estrous cycle and luteolysis. METHODS: Real-time PCR and western blot analysis. RESULTS: Progesterone up-regulated the expression of AQP1/AQP5 mRNAs and proteins in the endometrium and myometrium, especially during luteolysis. Similarly, E2 also stimulated the expression of both AQPs, but only in the endometrium. AA led to the upregulation of AQP1/AQP5 in the endometrium during luteolysis. In turn, OT increased the expression of AQP1/AQP5 mRNAs and proteins in the myometrium during mid-luteal phase. Moreover, a stimulatory effect of forskolin and cAMP on the expression of AQP1/AQP5 mRNAs and proteins in the endometrium and myometrium dominated during luteolysis, but during the mid-luteal phase their influence on the expression of these AQPs was differentiated depending on the type of tissue and the incubation duration. CONCLUSIONS: These results seem to indicate that uterine tissues; endometrium and myometrium, exhibit their own AQP expression profiles in response to examined factors. Moreover, the responses of AQP1/AQP5 at mRNA and protein levels to the studied factors in the endometrium and myometrium are more pronounced during luteolysis. This suggests that the above effects of the studied factors are connected with morphological and physiological changes taking place in the pig uterus during the estrous cycle. PMID- 26625727 TI - Comparison of LabSOCS and GESPECOR codes used in gamma-ray spectrometry. AB - Two dedicated software packages -LabSOCS and GESPECOR- for efficiency evaluation in gamma-ray spectrometry, were compared for equivalence. The detection efficiency and the coincidence-summing corrections coefficients were calculated for a specific HPGe detector, for different sample parameters and energies typically encountered in environmental radioactivity measurements. The discrepancy between the results obtained with the two codes were acceptable for most of the applications. Furthermore, the deviations between the values of the standard sources/ reference materials activities from the certificate and the values obtained after Monte Carlo simulation were less than 8% for LabSOCS and 9% for GESPECOR. PMID- 26625728 TI - Tumor thickness and risk of lymph node metastasis in patients with squamous cell carcinoma of the tongue. AB - OBJECTIVES: Oral squamous cell carcinomas, and tongue malignancies in particular, are among the most common tumors of the oral cavity. Classification for therapeutic and prognostic purposes is routinely made using the tumor, node, metastasis (TNM) system; however, current definitions do not include tumor thickness. We therefore aimed to identify variables associated with survival, and to evaluate the correlation between tumor thickness and the occurrence of lymph node metastasis. PATIENTS AND METHODS: All patients undergoing radical tumor resection for squamous cell carcinomas of the tongue between 2000 and 2012 were included. Specimens were analyzed histopathologically and co-variables were interpreted. Follow-up was performed clinically and radiologically for at least 3years according to current guidelines. RESULTS: We included 492 patients who had a median follow-up of 70months. Variables associated with survival (p<0.05) were age, tumor stage, N stage, UICC (Union for International Cancer Control) stage, tumor grade, and recurrence. In the receiver operating characteristic curve and Youden-Index analyses, the optimal tumor thickness cut-off was 8mm to detect significant differences in overall survival. CONCLUSION: We highlight the importance of tumor thickness as a predictive variable in tongue cancer. Specifically, a cut-off point of 8mm allowed for a more accurate and statistically precise prediction of lymph node metastasis. These findings could supplement the current classification of tongue cancers and form the basis for treatment. PMID- 26625729 TI - Bucket-handle meniscal tear in a 9-year-old girl: a case report and review of the literature. AB - Bucket-handle meniscal tears used to be rare in children younger than 10 years of age. However, nowadays, we encounter more cases because of increased sport and recreational activities. In this paper, we report on a 9-year-old girl who presented with an isolated medial meniscal bucket-handle tear of the right knee and review the literature for similar cases. Bucket-handle meniscal tears are rare in young children. However, it should be ruled out in patients with knee pain and mechanical symptoms following knee injury. PMID- 26625730 TI - A core outcome set for all types of cardiac surgery effectiveness trials: a study protocol for an international eDelphi survey to achieve consensus on what to measure and the subsequent selection of measurement instruments. AB - BACKGROUND: Cardiovascular disease (CVD) is a major contributor to the burden of disease and the number one cause of death worldwide. From 1990 until today, more people died from coronary heart disease than from any other cause. CVD is regularly treated with minimally or non-minimally invasive off- or on-pump cardiothoracic surgery and several interventions related to the outcome of the surgical procedures have been evaluated in clinical trials, but heterogeneity in outcome reporting hinders comparison of interventions across trials and limits the ability of research synthesis. This problem is encountered with the introduction of core outcome sets (COSs), which should be measured and reported, as a minimum, in all clinical trials for a specific clinical field. METHODS/DESIGN: This study protocol describes the methods used to develop a COS for all types of cardiac surgery effectiveness trials. We aim to reach consensus on what to measure in an international three-round eDelphi exercise involving adult patients in need or after cardiothoracic surgery, cardiothoracic surgeons, cardiologists, anaesthesiologists, nursing staff and researchers with expertise in this particular field of medical research. Subsequently, outcome measurement instruments (how to measure) will be determined. Recommendations on COS development given by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative and the Outcome Measures in Rheumatology (OMERACT) Initiative were followed. DISCUSSION: The proposed COS aims to provide methodological guidance for future cardiothoracic surgical trials to ensure the comparability of effects of interventions across studies and enable research synthesis. This does not imply that primary outcomes should always and exclusively be those of the COS. However, to ensure the comparability of results across trials, the outcomes included in this COS should be considered for inclusion besides measuring trial specific clinical endpoints. PMID- 26625731 TI - Ultrasound of wrist and hand masses. AB - Ultrasound is a useful tool to investigate soft tissue masses in the wrist and hand. In most situations ultrasound helps distinguish between a cyst and a tissue mass. This article provides a simple clinical approach to the use of ultrasound imaging for the diagnosis and preoperative assessment of wrist and hand masses. PMID- 26625732 TI - Healthy living according to adults with intellectual disabilities: towards tailoring health promotion initiatives. AB - BACKGROUND: A healthy lifestyle can prevent several health problems experienced by adults with intellectual disabilities (ID). For the development of effective and usable health promoting interventions for people with ID, the perspective of the intended audience should be taken into account. The aim of this qualitative study was to gain insight into the perspectives of people with mild to moderate ID on healthy living. METHOD: Qualitative study. Five semi-structured focus groups were conducted with a total of 21 adults with mild to moderate ID in the Netherlands. Discussions focused on three main themes: (1) perceptions of own health, (2) what participants consider as healthy living and (3) factors experienced to be related to the ability to live healthily. Interviews were analysed thematically resulting in two main domains: (1) perceptions of what is healthy and unhealthy and (2) factors that participants experience to be related to their ability to live healthily. RESULTS: For participants, healthy living entails more than healthy food and exercising: feeling healthy, happiness and level of independence are perceived as important as well. Factors experienced to relate to their ability to live healthily were (a lack of) motivation, support from others and environmental factors such as available health education, (a lack of) facilities and a(n) (dis)advantageous location of work or residence. CONCLUSIONS: This qualitative study shows that adults with mild to moderate ID have a good understanding of what being healthy and living healthily constitute. As they face several difficulties in their attempts to live healthily, existing health promotion programmes for people with ID must be tailored to individual preferences and motivations and adapted for individual physical disabilities. Moreover, because of their dependency on others, tailoring should also be focused on the resources and hindering factors in their physical and social environment. PMID- 26625733 TI - Prevalence of hepatitis B and C viruses infection among military personnel at Bahir Dar Armed Forces General Hospital, Ethiopia. AB - BACKGROUND: Military personnel are high-risk people for parenteral and sexually transmitted diseases such as hepatitis B virus (HBV) and hepatitis C virus (HCV). Data regarding HBV and HCV prevalence among military personnel in Ethiopia is limited. Hence, the study aimed to determine sero-prevalence and associated risk factors of HBV and HCV among military personnel at Bahir Dar Armed Forces General Hospital, Ethiopia. METHODS: A cross-sectional study was conducted in a total of 403 military personnel from February to May 2015. Socio-demographic characteristics and risk factors were collected through face to face interview using structured questionnaire. HBV and HCV infection was determined using HBsAg and anti-HCV antibody rapid tests. Logistic regression analysis was employed to assess possible risk factors for HBV and HCV infections. RESULTS: The sero prevalence of HBV and HCV infection were 4.2 and 0.2%, respectively. None of the study subjects were co-infected with HBV and HCV. Higher prevalence of HBV infection (11.3%) was observed in the age group of 40 and above. Being at the age of 40 years and above (COR 7.6; 95% CI 2.0-29.0, p = 0.003), history of nose piercing (COA 5.9; 95% CI 1.2-29.9, p = 0.033) and sexually transmitted infection (COR 4.3; 95% CI 1.1-16.4, p = 0.03) were significantly associated with these viral hepatitis infections. CONCLUSION: Intermediate prevalence of HBV and low prevalence of HCV were observed among military personnel. Strengthening HBV screening strategies among military personal may further reduce these viral diseases. PMID- 26625734 TI - An Overview of Matrix Metalloproteinase 9 Polymorphism and Gastric Cancer Risk. AB - Matrix metalloproteinase (MMP) 9, a key member of multifunctional family of zinc dependent endopeptidases has been found to be upregulated during inflammation and in some cancers. MMPs cleave extracellular matrix (ECM) proteins and play critical roles in cellular apoptosis, angiogenesis, tumor growth and metastasis. Several genetic polymorphisms have been identified that show allele specific effects on MMP9 regulation and are associated with gastric cancer, the fourth most common malignancy in the world. Besides Helicobacter pylori infection, genetic predisposition is another documented risk factor for gastric carcinoma. The single nucleotide polymorphism (SNP) at position -1562C/T of MMP9 results in the modulation for binding of transcription factors to the MMP9 gene promoter and thereby causes differences in protein expression and enzymatic activity. MMP9 transcriptional regulation during gastric cancer development remains poorly known although several studies have demonstrated associations between MMP9 -1562 C/T polymorphism with different diseases. Knowledge on mechanisms of MMP9 upregulation during gastric cancer may provide new paradigm in diagnostics and therapeutics. PMID- 26625735 TI - Review of the Cervical Cancer Burden and Population-Based Cervical Cancer Screening in China. AB - Cervical cancer continues to be a serious public health problem in the developing world, including China. Because of its large population with geographical and socioeconomic inequities, China has a high burden of cervical cancer and important disparities among different regions. In this review, we first present an overview of the cervical cancer incidence and mortality over time, and focus on diversity and disparity in access to care for various subpopulations across geographical regions and socioeconomic strata in China. Then, we describe population-based cervical cancer screening in China, and in particular implementation of the National Cervical Cancer Screening Program in Rural Areas (NACCSPRA) and the challenges that this program faces. These include low screening coverage, shortage of qualified health care personnel and limited funds. To improve prevention of cervical cancer and obtain better cancer outcomes, the Chinese government needs to urgently consider the following key factors: reducing disparities in health care access, collecting accurate and broadly representative data in cancer registries, expanding target population size and increasing allocation of government funding for training of personnel, improving health education for women, enhancing quality control of screening services and improving a system to increase follow up for women with positive results. PMID- 26625736 TI - Techniques for Evaluation of LAMP Amplicons and their Applications in Molecular Biology. AB - Loop-mediated isothermal amplification (LAMP) developed by Notomi et al. (2000) has made it possible to amplify DNA with high specificity, efficiency and rapidity under isothermal conditions. The ultimate products of LAMP are stem-loop structures with several inverted repeats of the target sequence and cauliflower like patterns with multiple loops shaped by annealing between every other inverted repeats of the amplified target in the similar strand. Because the amplification process in LAMP is achieved by using four to six distinct primers, it is expected to amplify the target region with high selectivity. However, evaluation of reaction accuracy or quantitative inspection make it necessary to append other procedures to scrutinize the amplified products. Hitherto, various techniques such as turbidity assessment in the reaction vessel, post-reaction agarose gel electrophoresis, use of intercalating fluorescent dyes, real-time turbidimetry, addition of cationic polymers to the reaction mixture, polyacrylamide gel-based microchambers, lateral flow dipsticks, fluorescence resonance energy transfer (FRET), enzyme-linked immunosorbent assays and nanoparticle-based colorimetric tests have been utilized for this purpose. In this paper, we reviewed the best-known techniques for evaluation of LAMP amplicons and their applications in molecular biology beside their advantages and deficiencies. Regarding the properties of each technique, the development of innovative prompt, cost-effective and precise molecular detection methods for application in the broad field of cancer research may be feasible. PMID- 26625737 TI - Chronic Myeloid Leukemia--Prognostic Value of Mutations. AB - Chronic myeloid leukemia (CML) is a stem cell disorder characterized by unrestricted proliferation of the myeloid series that occurs due to the BCR-ABL fusion oncogene as a result of reciprocal translocation t(9;22) (q34;q11). This discovery has made this particular domain a target for future efforts to cure CML. Imatinib revolutionized the treatment options for CML and gave encouraging results both in case of safety as well as tolerability profile as compared to agents such as hydroxyurea or busulfan given before Imatinib. However, about 2-4% of patients show resistance and mutations have been found to be one of the reasons for its development. European Leukemianet gives recommendations for BCR ABL mutational analysis along with other tyrosine kinase inhibitors (TKIs) that should be administered according to the mutations harbored in a patient. The following overview gives recommendations for monitoring patients on the basis of their mutational status. PMID- 26625738 TI - Colorectal Cancer in the Arab World--Screening Practices and Future Prospects. AB - Colorectal cancer (CRC) incidence and mortality rates have dropped 30% in the US in the last 10 years among adults ages 50 and older due to the widespread uptake of colonoscopy, yet incidences in the Arab countries have been increasing in the past ten years, albeit with lower figures when compared with developed countries. Lifestyle changes, food consumption patterns and obesity have been observed during the past years where the regular consumption of traditional foods is being replaced with more Western-style and ready-made foods. Most high income countries have implemented population based colorectal cancer screening programs, which aid in decreasing the incidence and mortality of cancer, while these are lacking in most of the Arab world countries due to many cultural and religious barriers to CRC screening as well as lack of high education or familiarity. What is needed is health education to modify risky lifestyle, and to increase motives and enhance positive attitudes towards early screening especially amongst high risk groups in addition to policy designed to encourage healthier living. PMID- 26625739 TI - Progression of NETs Correlating with Tumor-Related Diseases. AB - As an important component of innate immune system, the neutrophil is involved in many physiological processes, including tumor-related diseases. In 2004, the phenomenon of NETs, network structures of extracellular decondensed chromatin released from activated neutrophils, was reported for the first time. This review focuses on the function of NETs in tumor cell proliferation, metastasis, and tumor-associated thrombosis; it also explores the application of NET specific markers in the diagnosis of pre-thrombotic state and tumor associated diseases; the potential of NET inhibitor for the treatment of tumor-related diseases is also covered. In view of the rapid development of NETs, it may provide new therapeutic targets for tumor-associated thrombosis, and even tumors themselves. PMID- 26625740 TI - Can Cancer Therapy be Achieved by Bridging Apoptosis and Autophagy: a Method Based on microRNA-Dependent Gene Therapy and Phytochemical Targets. AB - A failure of a cell to self destruct has long been associated with cancer progression and development. The fact that tumour cells may not instigate cell arrest or activate cell death mechanisms upon cancer drug delivery is a major concern. Autophagy is a mechanism whereby cell material can be engulfed and digested while apoptosis is a self-killing mechanism, both capable of hindering multiplication after cell injury. In particular situations, autophagy and apoptosis seem to co-exist simultaneously or interdependently with the aid of mutual proteins. This review covers roles of microRNAs and chemopreventive agents and makes an attempt at outlining possible partnerships in maximizing cancer cell death with minimal normal cell damage. PMID- 26625741 TI - 131I-Labeled-Metuximab Plus Transarterial Chemoembolization in Combination Therapy for Unresectable Hepatocellular Carcinoma: Results from a Multicenter Phase IV Clinical Study. AB - OBJECTIVE: This study evaluated the safety and objective response of combining 131I-labeled-metuximab (Licartin) with transarterial chemoembolization (TACE) in the treatment of unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: In a multicenter open-label clinical trial, 341 enrolled patients with stage III/IV HCC according to TNM criteria were nonrandomly assigned to a trial group (n=167) and a control group (n=174), undergoing TACE following hepatic intra-arterial injection of licartin or TACE alone from July 2007 to July 2009. Radiopharmaceutical distribution was evaluated. The primary endpoint was overall survival; secondary endpoints included time-to-progression (TTP), toxicity and adverse events (AEs). RESULTS: The radiobiological distribution demonstrated better localization of licartin in liver tumors than other tissues (P<0.01). The organ absorbed doses to liver and red marrow were 3.19 +/- 1.01 Gy and 0.55 +/- 0.22 Gy, respectively. The 1-year survival rate was significantly higher [79.47% vs. 65.59%, hazard ratio (HR), 0.598, P=0.041] and TTP significantly improved (6.82 +/- 1.28 vs. 4.7 +/- 1.14 months, P=0.037) compared with the control group. Patients at stage III achieved more benefit of one year survival than stage IV in the trial group (86.9% vs. 53.8%, P<0.001). There were significant different toxicities in leukocytopenia, thrombocytopenia and increased total bilirubin level [P<0.001, P=0.013, P<0.01, relative risk (RR) 1.63, 1.33, 1.43], but no differences in severe AEs of upper GI hemorrhage and severe liver dysfunction between the groups (5.39% vs. 2.3%, P=0.136). CONCLUSIONS: Owing to excellent tumor-targeting, promised efficacy and favourable toxicity profile, the novel combination therapy of licartin and TACE could be applied in patients with unresectable HCC. PMID- 26625742 TI - C-kit Mutations in Endometrial Cancer: Correlation with Tumor Histologic Type. AB - OBJECTIVE: Endometrial cancer is the fourth most common cancer among women in developed countries. Affected patients may benefit from systemic chemotherapy, alone or in combination with targeted therapies if the disease is clinically diagnosed prior to expansion and metastasis to other organs.The aim of this study was to evaluate the prognostic role of c-kit mutations and comparision with tumor type and grade in human uterine endometrial carcinomas. MATERIALS AND METHODS: Seventy five patients with endometrial carcinoma and seventy five normal controls were studied for possible mutations in exon 17 of the c-kit gene using single strand conformational polymorphisms and sequencing. RESULTS: c-kit mutation in exon 17 appeared to be significantly different between endometrial carcinoma and normal endometrium. The pattern and frequency of the mutations was also shown to be different between tumors from different stages. PMID- 26625743 TI - Attitudes of Medical Students Regarding Cancer Pain Management: Comparison Between Pre- and Post-Lecture Test Findings. AB - BACKGROUND: Medical practitioners' attitudes have a significant impact on quality of care for cancer pain patients. This study was conducted to determine if being given a lecture concerning cancer pain and its management could improve the attitudes of medical students. MATERIALS AND METHODS: A comparative study was conducted in 126 fifth-year medical students. Each student completed a pretest consisting of 3 questions about attitudes toward the optimal use of analgesics and 5 questions about attitudes toward prescribing opioids. Then they were given a 1.5-hour lecture, immediately following which they completed a post-test with the same questions. RESULTS: Analysis with either comparison between groups or by matching, the post-test showed significantly more positive attitudes (p<0.05) of the medical students in all 3 questions about optimal use of analgesics and 4 out of 5 questions about prescription of opioids. The post-test results showed significantly more negative attitudes concerning the most appropriate stage for patients with severe pain to receive maximal doses of analgesics. CONCLUSIONS: Conservative attitudes, especially concerns about addiction, have been associated with a reluctance in many physicians to prescribe opioids. This study found that cancer pain education can help to improve medical student attitudes. However, fear of addiction and tolerance was still evident so emphasis of this particular issue during a lecture is essential. Providing appropriate information by means of a lecture can improve the attitudes of medical students regarding cancer pain management. However, more information should be given to lessen fear of addiction and tolerance. PMID- 26625744 TI - Protection and Dissection of Recurrent Laryngeal Nerve in Salvage Thyroid Cancer Surgery to Patients with Insufficient Primary Operation Extent and Suspicious Residual Tumor. AB - Some thyroid cancer patients undergone insufficient tumor removal in the primary surgery in China . our aim is to evaluate the impact of dissection of the recurrent laryngeal nerve during a salvage thyroid cancer operation in these patients to prevent nerve injury. Clinical data of 49 enrolled patients who received a salvage thyroid operation were retrospectively reviewed. Primary pathology was thyroid papillary cancer. The initial procedure performed included nodulectomy (20 patients), partial thyroidectomy (19 patients) and subtotal thyroidectomy (10 patients). The effect of dissection and protection of the recurrent laryngeal nerve and the mechanism of nerve injury were studied. The cervical courses of the recurrent laryngeal nerves were successfully dissected in all cases. Nerves were adherent to or involved by scars in 22 cases. Three were ligated near the place where the nerve entered the larynx, while another three were cut near the intersection of inferior thyroid artery with the recurrent laryngeal nerve. Light hoarseness occurred to four patients without a preoperative voice change. In conclusion, accurate primary diagnosis allows for a sufficient primary operation to be performed, avoiding insufficient tumor removal that requires a secondary surgery. The most important cause of nerve damage resulted from not identifying the recurrent laryngeal nerve during first surgery , and meticulous dissection during salvage surgery was the most efficient method to avoid nerve damage. PMID- 26625745 TI - Tumor Diameter for Prediction of Recurrence, Disease Free and Overall Survival in Endometrial Cancer Cases. AB - AIMS: To analyse the predictors of recurrence, disease free survival and overall survival in cases with endometrial cancer. MATERIALS AND METHODS: A total of 152 women diagnosed with endometrial cancer were screened using a prospectively collected database including age, smoking history, menopausal status, body mass index, CA125, systemic disorders, tumor histology, tumor grade, lymphovascular space invasion, tumor diameter, cervical involvement, myometrial invasion, adnexal metastases, positive cytology, serosal involvement, other pelvic metastases, type of surgery, fertility sparing approach to assess their ability to predict recurrence, disease free survival and overall survival. RESULTS: In ROC analyses tumor diameter was a significant predictor of recurrence (AUC:0.771, P<0.001). The optimal cut off value was 3.75 with 82% sensitivity and 63% specificity. In correlation analyses tumor grade (r=0.267, p=0.001), tumor diameter (r=0.297, p<0.001) and the serosal involvement (r=0.464, p<0.001) were found to significantly correlate with the recurrence. In Cox regression analyses when some different combinations of variables included in the model which are found to be significantly associated with the presence of recurrence, tumor diameter was found to be a significant confounder for disease free survival (OR=1.2(95 CI,1.016-1.394, P=0.031). On Cox regression for overall survival only serosal involvement was found to be a significant predictor (OR=20.8 (95 % CI 2.4 179.2, P=0.006). In univariate analysis of tumor diameter > 3.75 cm and the recurrence, there was 14 (21.9 %) cases with recurrence in group with high tumor diameter where as only 3 (3.4 %) cases group with smaller tumor size (Odds ratio:7.9 (95 %CI 2.2-28.9, p<0.001). CONCLUSIONS: Although most of the significantly correlated variables are part of the FIGO staging, tumor diameter was also found to be predictor for recurrence with higher values than generally accepted. PMID- 26625746 TI - Clinical Presentation and Frequency of Risk Factors in Patients with Breast Carcinoma in Pakistan. AB - BACKGROUND: Breast cancer is known to be one of the most prevalent cancers among women in both developing and developed countries .The incidence of breast cancer in Pakistan has increased dramatically within the last few years and is the second country after Israel in Asia to have highest proportional cases of breast cancer. However, there are limited data for breast cancer available in the literature from Pakistan. OBJECTIVES: The study was conducted to bring to light the common clinical presentation of breast cancer and to evaluate the frequency of established risk factors in breast carcinoma patients and furthermore to compare the findings between premenopausal and postmenopausal women in Pakistan. MATERIALS AND METHODS: A 6 months (from July 2012 to Dec 2012) cross sectional survey was conducted in Surgical and Oncology Units of Civil Hospital, Karachi. Data were collected though a well developed questionnaire from 105 female patients diagnosed with carcinoma of breast and analyzed using SPSS version 17. Institutional ethical approval was obtained prior to data collection. RESULTS: Out of 105 patients, 43 were premenopausal and 62 were postmenopausal, 99 being married. Mean age at diagnosis was 47.8 +/- 12.4 years. A painless lump was the most frequent symptom, notived by 77.1%(n=81). Some 55.2% (n=58) patients had a lump in the right breast and 44.8%(n=47) in the left breast. In the majority of cases, the lump was present in upper outer quadrant 41.9% (n=44). Mean period of delay from appearance of symptoms to consulting a doctor was 5.13 +/- 4.8 months, from the shortest 1 month to the longest 36 months. Long delay (> 3 months) was the most frequent figure 41.9%. Considering overall risk factors most frequent were first pregnancy after 20 years of age (41%), physical breast trauma (28.6%), lack of breast feeding(21.9%), and early menarche <11 years (19%), followed by null parity (16.2%), consumption of high fat diet (15.2%), family history of breast cancer or any other cancer in first degree relatives (9.5% and 13.3%, respectively). Some of the less common factors were late menopause >54 years (8.6%), use of oral contraceptive pills (10.5%), use of hormone replacement therapy (4.7%),smoking (4.7%) and radiation (0.96%). Significant differences (p<0.005) were observed between pre and post menopausal women regarding history of physical breast trauma, practice of breast feeding and parity. CONCLUSIONS: A painless lump was the most frequent clinical presentation noted. Overall age at first child > 20 years, physical breast trauma, lack of breast feeding ,early menarche <11 were the most frequent risk factors. Physical breast trauma, lower parity, a trend for less breast feeding had more significant associations with pre-menopausal than post-menopausal onset. Increase opportunity of disease prevention can be obtained through better understanding of clinical presentation and risk factors important in the etiology of breast cancer. PMID- 26625747 TI - Roles of Kermanshahi Oil, Animal Fat, Dietary and Non- Dietary Vitamin D and other Nutrients in Increased Risk of Premenopausal Breast Cancer: A Case Control Study in Kermanshah, Iran. AB - BACKGROUND: Kermanshahi oil is one the most favorable oils in Iran especially in Kermanshah province. We aimed to evaluate the role of usual intake of Kermanshahi oil and other kinds of dietary fats as well as different meats, vegetables and fruits, carbohydrates, cereals, grains, sweets, candy and lifestyle habits in risk of breast cancer. MATERIALS AND METHODS: A case-control study with 47 consecutive, newly diagnosed premenopausal breast- cancer patients and 105 age and socioeconomic matched healthy women was conducted from 2013-2014 in Imam Reza hospital of Kermanshah using a standardized, validated questionnaire assessing various anthropometric, socio-demographic, lifestyle and dietary characteristics. RESULTS: Kermanshahi oil intake was associated with a 2.1-fold (OR= 2.123, 95% CI 1.332- 3.38) (p= 0.002) higher likelihood of having breast cancer, while daily intake of other solid animal fats also increased the likelihood by 2.8-fold (OR = 2.754, 95% CI 1.43- 5.273) (p < 0.001), after various adjustments made. Lack of fish oil, white meat, vegetables, soy products, nuts and dairy products (especially during adolescence) in daily regimens and lack of sun exposure were significantly associated with premenopausal breast cancer risk in this region. CONCLUSIONS: This study suggested that animal fat increases the risk of premenopausal breast cancer but many other dietary and non-dietary factors including calcium and vitamin D deficiency are consistently associated with increased odds of breast cancer in this region. PMID- 26625748 TI - Mutagenicity Assessment of Drinking Water in Combination with Flavored Black Tea Bags: a Cross Sectional Study in Tehran. AB - Diseases related to water impurities may present as major public health burdens. The present study aimed to assess the mutagenicity of drinking water from different zones of Tehran, and evaluate possible health risks through making tea with tea bags, by Ames mutagenicity test using TA 100, TA 98 and YG1029 strains. For this purpose, 450 water samples were collected over the period of July to December 2014 from 5 different zones of Tehran. Except for one sample, no mutagenic potential was detected during these two seasons and the MI scores were almost normal (<= 1-1.6) in TA 100, TA 98 and YG1029 strains. Although no mutagenic effects were considered in TA 98 and TA 100 in the test samples of our three evaluated tea bag brands, one sample from a local company showed mutagenic effects in the YG1029 strain (MI=1.7-1.9 and 2) after prolonged (10-15 min.) steeping. Despite the mild mutagenic effect discovered for one of the brand, this cross sectional study showed relative safety of water samples and black tea bags in Tehran. According to the sensitivity of YG1029 to the mutagenic potential of water and black tea, even without metabolic activation by s9 fraction, this metabolizer strain could be considered as sensitive and applicable to food samples for quantitative analysis of mutagens. PMID- 26625749 TI - Risk of Breast Cancer among Young Women and Importance of Early Screening. AB - BACKGROUND: Breast cancer is the most common type of cancer in women throughout the world. However, in comparison with Western women, it presents relatively early in women of Asian ethnicity. Early menarche, late menopause, use of OCP's, family history of benign or malignant breast disease, exposure to radiation and BMI in the under-weight range are well known risk factors for the development of breast cancer in premenopausal women. Early detection with the use of breast self examination (BSE) and breast cancer screening programs can lead to a reduction in the mortality rates due to breast cancer. The aim of our study was to assess the risk factors for breast cancer among young women and to emphasize the importance of early screening among them. MATERIALS AND METHODS: We conducted a cross sectional study among women aged 18 to 25 using a self- administered questionnaire. Data was collected over a period of 6 months from June to December, 2014. A total of 300 young women selected randomly from Dow Medical College and various departments of Karachi University successfully completed the survey. RESULTS: Respondents were 18-25 years of age (mean age=21.5). Out of the 300 young females, 90 (30%) had at least one risk factor, 90 (30%) had two, 40 (13%) had three, 8 (2.7%) had four, 2 (0.7%) had five while one female was found to have six positive risk factors for breast cancer. Some 66 women (22%) experienced symptoms of breast cancer such as non-cyclical pain and lumps. While 222 women (74%) had never performed breast self-examination, 22 (7.3%) had had a breast examination done by a health professional while 32 (10.7%) had participated in breast screening programs. A total of 223 (74.3%) women considered breast cancer screening important for young women. CONCLUSIONS: The percentage of young women with risk factors for breast cancer was found to be alarmingly high. Therefore, screening for breast cancer should start at an early age especially in high risk groups. Awareness about breast self-examination should be emphasized. Moreover, screening programs should be started to ensure early detection and reduction of mortality rates caused by breast cancer also in young Pakistani females. PMID- 26625750 TI - Clinicopathological Significance of CD133 and ALDH1 Cancer Stem Cell Marker Expression in Invasive Ductal Breast Carcinoma. AB - BACKGROUND: Biomarkers in breast neoplasms provide invaluable information regarding prognosis and help determining the optimal treatment. We investigated the possible correlation between cancer stem cell (CSC) markers (CD133, and ALDH1) in invasive ductal breast carcinomas with some clinicopathological parameters. AIM: To assess the correlation between expression of cancer stem cell (CSC) markers (CD133, and ALDH1) and clinicopathological parameters of invasive ductal breast carcinomas. MATERIALS AND METHODS: Immunohistochemical analysis of CD133 and ALDH1 was performed on a series of 120 modified radical mastectomy (MRM) specimens diagnosed as invasive ductal breast carcinoma. RESULTS: Expression of both CD133 and ALDH1 was significantly changed and related to tumor size, tumor stage (TNM), and lymph node metastasis. A negative correlation between CD133 and ALDH1 was found. CONCLUSIONS: Detecting the expression of CD133 and ALDH1 in invasive ductal breast carcinomas may be of help in more accurately predicting the aggressive properties and determining the optimal treatment. PMID- 26625751 TI - Comparison of Serum Fucose Levels in Leukoplakia and Oral Cancer Patients. AB - BACKGROUND: Tumor markers, designated as a broad group of substances produced by malignancies, could be in the form of biochemical substances, immunological substances, cell surface changes and genetic alterations. Cancer, a disorder of cellular behavior is characterized by alteration of serum glycoproteins. L fucose, a hexose, which is the terminal sugar in most of the plasma glycoproteins, may be useful as a tumor marker for the detection, monitoring and prognostic assessment of malignancies. The aim of the study was to ascertain the role of serum fucose as a biomarker for early detection of oral cancer and to compare serum fucose levels in healthy controls, leukoplakia and oral cancer patients. MATERIALS AND METHODS: The study included 60 (100.0%) subjects, who were grouped as 20 (33.3%) control subjects, 20 (33.3%) squamous cell carcinoma patients and 20 (33.3%) leukoplakia patients. Fucose estimation was done using UV visible spectrophotometry based on the method as adopted by Winzler using cysteine reagent. The results were analyzed statistically using ANOVA with Bonferroni post hoc tests. RESULTS: Results showed a high significance in serum fucose in oral squamous cell carcinoma (OSCC) and leukoplakia subjects compared to normal controls. There was a gradual increase in the values noted from control to leukoplakia and to squamous cell carcinoma. CONCLUSIONS: Estimation of serum fucose may be a reliable marker and can be used as an effective diagnostic biomarker in oral squamous cell carcinoma patients. PMID- 26625752 TI - Oncology Nurses Knowledge and Attitudes Regarding Cancer Pain Management. AB - BACKGROUND: Oncology nurses play a crucial role in cancer pain management and must be highly informed to ensure their effective practice in the cancer setting. The aim of this study was to determine the baseline level of knowledge and attitudes of oncology nurses regarding cancer pain management. MATERIALS AND METHODS: A cross-sectional survey research design was employed. The sample comprised 58 cancer nurses working in Shahid Sadoughi hospital, Yazd, Iran. The ''Nurses Knowledge and Attitudes Survey Regarding Pain'' (NKAS) tool and a demographic form were utilized to ascertain the knowledge and attitudes of oncology nurses working in oncology settings. RESULTS: The average correct response rate for oncology nurses was 66.6%, ranging from 12.1% to 94.8%. The nurses mean score on the knowledge and attitudes survey regarding pain management was 28.5%. Results revealed that the mean percentage score overall was 65.7%. Only 8.6% of nurse participants obtained a passing score of 75% or greater. Widespread knowledge deficits and poor attitudes were noted in this study, particularly regard pharmacological management of pain. CONCLUSIONS: The present study provides important information about knowledge deficits in pain management among oncology nurses and limited training regarding pain management. Our results support the universal concern of inadequate knowledge and attitudes of nurses regarding cancer pain. It is suggested educational and quality improvement initiatives in pain management could enhance nurses knowledge in the area of pain and possibly improve practice. PMID- 26625753 TI - Association Assessment among Risk Factors and Breast Cancer in a Low Income Country: Bangladesh. AB - BACKGROUND: In the low incoming country Bangladesh, breast cancer is second most common neoplasm and is increasing at an alarming rate among females. Lack of awareness and illiteracy are contributory factors for late presentation and therefore mortality. PURPOSE: To examine associations of different factors with breast cancer mortality and to raise awareness among the women of society in Bangladesh. MATERIALS AND METHODS: This descriptive case-control study was conducted on 160 participants from April 2011 till July 2014. Through a valid questionnaire covering personal and family history, data were collected by face to face interview. For analyzing correlations among factors with breast cancer data, binary logistic regression, Pearson's chi2- value, odd ratios and p-value tests were conducted with SPSS version 20. RESULTS: The mean age of the patients was 43.0 (SD= +/- 11.12). In ascending order the leading significant factors were hormone therapy (p<0.0000, OR=4.897), abortion (p<0.0001, OR=3.452), early start menarche (p<0.0002, OR=3.500), family history (p<0.0022, OR=3.235), and late menopause (p<0.0093, OR=3.674) with both chi2 test and logistic regression analyses. Non-significant factors were cancer experience, fatty food habits, marital status and taking alcohol. CONCLUSIONS: Regarding the investigation of this study, significant and insignificant factor's correlation visualization with breast cancer will be helpful to increase awareness among Bangladeshi women as well as all over the world. PMID- 26625754 TI - Immunohistochemical Evaluation of Angiogenesis Related Markers in Pyogenic Granuloma of Gingiva. AB - BACKGROUND: Pyogenic granuloma is a common non-neoplastic connective tissue proliferation. ICAM-1 and VCAM-1 are vascular adhesion molecules and CD34 is a marker for evaluation of angiogenesis. The purpose of this study was to compare the immunohistochemical expression of ICAM-1, VCAM-1 and CD34 in oral pyogenic granuloma and normal gingiva. MATERIALS AND METHODS: This study was performed on thirty five formalin-fixed, paraffin embedded samples of gingival pyogenic granuloma. Also we used thirty five paraffined blocks of normal gingiva as control group which were taken from crown lengthening surgery. We employed immunohistochemistry staining for our prepared microscopic slides using monoclonal mouse anti-human antibodies against ICAM-1 (CD54), VCAM-1 (CD106) and CD34. Slides were examined under light microscope and then the mean amount of stained vessels also known as microvascular density (MVD) in highly vascularized areas (hot spots) was measured. Paired t-test and repeated measures ANOVA were used to compare the difference between quantitative variables and Chi-square test for qualitative variables in different groups. Pearson correlation coefficient was used to compare relations between quantitative variables. P<0.05 was considered significant. RESULTS: The mean of MVD for ICAM-1, VCAM-1 and CD34 was significantly higher in pyogenic granuloma than normal gingiva (p<0.001 and p<0.001 and p<0.001, respectively). Expression of CD34 in pyogenic granuloma was significantly higher than ICAM-1 and VCAM-1 (P<0.001). Besides, expression of ICAM-1 in normal gingiva, was significantly lower than two other markers (p<0.001). CONCLUSIONS: Regarding the results, it seems that ICAM-1, VCAM-1 and CD34 are useful biomarkers in evaluation of vascular and inflammatory lesions such as gingival pyogenic granuloma and the results indicate the role of these biomarkers in pathogenesis of oral pyogenic granuloma. PMID- 26625755 TI - Effects of Fresh Yellow Onion Consumption on CEA, CA125 and Hepatic Enzymes in Breast Cancer Patients: A Double- Blind Randomized Controlled Clinical Trial. AB - Onion (Allium cepa) consumption has been remarked in folk medicine which has not been noted to be administered so far as an adjunct to conventional doxorubicin based chemotherapy in breast cancer patients. To our knowledge, this is the first study aimed to investigate the effects of consuming fresh yellow onions on hepatic enzymes and cancer specific antigens compared with a low-onion containing diet among breast cancer (BC) participants treated with doxorubicin. This parallel design randomized controlled clinical trial was conducted on 56 BC patients whose malignancy was confirmed with histopathological examination. Subjects were assigned in a stratified-random allocation into either group received body mass index dependent 100-160 g/d of onion as high onion group (HO; n=28) or 30-40 g/d small onion in low onion group (LO; n=28) for eight weeks intervention. Participants, care givers and laboratory assessor were blinded to the assignments (IRCT registry no: IRCT2012103111335N1). The compliance of participants in the analysis was appropriate (87.9%). Comparing changes throughout pre- and post-dose treatments indicated significant controls on carcinoembryonic antigen, cancer antigen-125 and alkaline phosphatase levels in the HO group (P<0.05). Our findings for the first time showed that regular onion administration could be effective for hepatic enzyme conveying adjuvant chemotherapy relevant toxicity and reducing the tumor markers in BC during doxorubicin-based chemotherapy. PMID- 26625756 TI - Low Frequency of ETV6-RUNX1 (t 12; 21) in Saudi Arabian Pediatric Acute Lymphoblastic Leukemia Patients: Association with Clinical Parameters and Early Remission. AB - BACKGROUND: Pediatric acute lymphoblastic leukemia (pALL) patients at King Abdulaziz Medical City represent a pure Saudi Arabian population. ETV6-RUNX1 positive pALL patients have good prognosis as compared to ETV6-RUNX1 negative counterparts. Therefore, frequencies of these two patient groups have a huge consideration in treatment strategies of pALL in a given population. Different geographical locations have been reported to have different frequencies of ETV6 RUNX1 ranging from 10% in Southeast Asia to 30% in Australia. AIM: Therefore, the objective of this study was to establish the ETV6-RUNX1 status of Saudi Arabian pALL patients and its association with clinical parameters and early remission. MATERIALS AND METHODS: Clinical parameters and ETV6-RUNX1 status (using FISH technique) of pALL patients attending the Pediatric Oncology Clinic, King Abdulaziz Medical City, Riyadh from 2006 to 2011 were studied. Comparisons between ETV6-RUNX1 positive and negative groups were accomplished using chi square test or Fisher's exact test. All statistical analyses were performed using SAS version 9.2 (SAS Institute, Inc., Cary, NC). RESULTS: Out of 54 patients, 33 were male and 21 were females (ratio 1.57:1). B- and T-cell lineages were found in 47 (87%) and 7 (13%) patients respectively. Only 5 (9.3%) patients were ETV6 RUNX1 positive while 49(80.7%) were ETV6-RUNX1 negative. All ETV6-RUNX1 patients (100%) were of B-cell lineage and 80% (4/5) were in the 3-7 year age group. None of the ETV6-RUNX11 patients had >= 5% blasts (no remission) at day 14 as compared with 9% in the ETV6-RUNX1 negative group (Figure 1). CONCLUSIONS: Frequency of ETV6-RUNX1 positive patients (less than 10%) in our pALL patients is much lower than reported for most European countries, North America, Australia and Japan while it is in accordance with ETV6-RUNX1 frequencies from Egypt (11.6%), Pakistan (10%), Spain (2%) and India (5-7%). This shows ethnic differences in genetics of pALL as well as higher frequencies of ETV6-RUNX1 positive pALL mostly in more industrialized countries, probably due to some industrial pollutants or westernized lifestyle. PMID- 26625757 TI - Clinical Implication of EGF A61G Polymorphism in the Risk of Non Small Cell Lung Adenocarcinoma Patients: A Case Control Study. AB - BACKGROUND: The epidermal growth factor (EGF) plays important roles in non-small cell lung cancer (NSCLC) susceptibility and functional polymorphism in the EGF (+61A/G) gene has been linked to increased risk of NSCLC. This study aimed to evaluate the role of the EGF +61A/G polymorphism in risk of NSCLC adenocarcinoma (ADC) occurrence and survival in an Indian population. MATERIALS AND METHODS: This case- control study included 100 histopathologically confirmed NSCLC (ADC) patients and 100 healthy controls. EGF (A61G) was genotyped by AS-PCR to elucidate putative associations with clinical outcomes. The association of the polymorphism with the survival of NSCLC patients was estimated by Kaplan-Meier curves. RESULTS: It was found that EGF 61AG heterozygous and GG homozygous genotype is significantly associated with increased risk of NSCLC (ADC) occurrence compared to AA genotype, [OR 2.61 (1.31-5.18) and 3.25 (1.31-8.06), RR 1.51(1.15-2.0) and 1.72 (1.08-2.73) and RD 23.2 (6.90-39.5) and 28.53(7.0-50.1) for heterozygous AG (p=0.005) and homozygous GG (p=0.009)]. Patients homozygous for the G allele exhibited a significantly poor overall survival. The median survival time for patients with EGF 61 AA, AG, and GG genotypes was 10.5, 7.4, and 7.1 months (p=0.02), respectively. NSCLC (ADC) patients with GG + AG exhibited 7.3 months median survival compared to the AA genotype (p=0.009). CONCLUSIONS: The present study revealed that the EGF A61G genotype may be a novel independent prognostic marker to identify patients at higher risk of occurrence and an unfavourable clinical outcome. PMID- 26625758 TI - Predictors of Tobacco Use among Youth in India: GATS 2009-2010 Survey. AB - BACKGROUND: Tobacco use among youth in India is an increasingly rising burden. It is affected by various socio-demographic factors, which form predictors of use. Focus on these predictors can help policy makers in curbing the major morbidity and mortality due to tobacco among youth. OBJECTIVE: To study the various socio- demographic variables associated with tobacco use among youth in India. MATERIALS AND METHODS: The study was a secondary analysis of data from the Global Adult Tobacco Survey, India 2009-10, in the age group of 15-24 years. Predictors of smoking and smokeless tobacco were analysed using data on occupation, education, and other sociodemographic factors place of living. Epi Info used for conducting the analysis. RESULTS: The total population interviewed in GATS India -2010 was 69,926. Of these the youth population between 15- 24. The total number of tobacco users (smokers and smokeless) was 2,969 (22.%). There were 11 (3.05%) dual users. Smokeless form of tobacco (15.1%) was used more than smoked form among youth. Males and urban youth preferred smoked form of tobacco over smokeless form. Smoking among youth had an inverse relation with increasing education level. Majority of smokeless form of tobacco users and dual users belonged to poor economic classes. CONCLUSIONS: This productive age group is more susceptible to tobacco addiction, especially smokeless tobacco. Rural youth, students, female sex and poor socio-economic strata prefer smokeless whereas urban, male and lesser educated youth preferred smoked form of tobacco. Efforts should be directed towards discouraging tobacco use initiation among the young population in India. PMID- 26625759 TI - Epidemiologic Data, Tumor Size, Histologic Tumor Type and Grade, Pathologic Staging and Follow Up in Cancers of the Ampullary Region and Head of Pancreas in 311 Whipple Resection Specimens of Pakistani Patients. AB - AIM: To report the histologic findings on Whipple resection specimens and thus determine the extent and spread of carcinomas of ampullary region and head of pancreas in our population. SETTING: Section of Histopathology, Department of Pathology, Aga Khan University Hospital (AKUH), Karachi, Pakistan. MATERIALS AND METHODS: A case series of 311 consecutive Whipple resection specimens received between January 1,2003 and December 31, 2014. Specimens processed for histologic sections and representative sections submitted and histologically examined as per established and standard protocols. All relevant tumor parameters including histologic type, histologic grade, pathologic T and N stage and tumor size were assessed. Epidemiologic data were also recorded. All findings were analysed using SPSS 19.0 software. RESULTS: Ampullary (periampullary) carcinomas were much more common than carcinomas of the head of the pancreas, especially in males, with an average age of 53 years. Mean tumor size was 2.5 cms, over 54% were well differentiated. A large majority were pT2 or pT3 and N0. Carcinomas of pancreatic head were also more common in males, mean age was 55 years, mean tumor size was 3.5 cms, and over 65% were moderately differentiated. The majority were T2 or T3 and pN1. Prognostically, significant statistical correlation was seen with tumor grade and pathologic T and N stage (p values statistically significant). However, tumor size was not statistically significant. CONCLUSIONS: Ampullary carcinomas are more common compared to pancreatic carcinomas. Majority of ampullary carcinomas were well differentiated while majority of pancreatic carcinomas were moderately differentiated. Large majority of both types of cases were pT2 or T3. Histologic tumor grade and pathologic T and N stage are significantly related to prognosis in Pakistani patients with ampullary and pancreatic cancers. PMID- 26625760 TI - Initiating Smokeless Tobacco Use across Reproductive Stages. AB - BACKGROUND: The use of smokeless tobacco (SLT) among women is increasing in India, especially among those with limited education and resources. Preventing the initiation of SLT among women is critical since it has known negative consequences for oral and reproductive health. Most research on tobacco initiation in India focuses on adolescents. This paper addresses the unrecognized issues of post marital initiation among women of reproductive age, highlighting the importance of reproductive stages in women's tobacco initiation. The objective is to examine the correlates of SLT initiation among low income women in Mumbai from pre-marriage through early marriage, first pregnancy and beyond, using case examples to illustrate initiation during each of these stages. MATERIALS AND METHODS: In 2011-2012, cross-sectional community level survey data were collected from a representative sample of 409 daily SLT-using married women aged 18-40 years in a low income community in Mumbai. Information on socio demographics, initiation by reproductive stage, types of tobacco use, childhood exposure to tobacco, learning to use, and initiation influences and reasons were collected through a researcher-administered survey. Univariate and bivariate analysis assessed factors influencing initiation of SLT use by reproductive stage. In addition 42 narratives of tobacco use were collected from a purposive sample of pregnant and non-pregnant married women addressing the same questions in detail. Narratives were transcribed, translated, and coded for key concepts including initiation of tobacco use. RESULTS: Thirty-two percent of women initiated SLT use before marriage, 44% initiated after marriage but before pregnancy, 18.1% initiated during their first pregnancy and the remainder started after their first pregnancy. Mean age of marriage among women in this study was 16 years. Younger women (i.e. age at time of the interview of less than 30 years) were 0.47 [95% CI (0.32, 0.87)] percent less likely to initiate after marriage than women aged more than 30 years. Women who got married before 18 years of age were 2.34 [95% CI (1.40, 3.93)] times more likely to initiate after marriage than their counterparts. Childhood exposure was a predictor for initiating SLT use prior to marriage but not after. Women reporting tooth and gum pain were 1.85 times more likely to initiate after marriage than their counterparts. Husband and neighbours were the most significant influences on post-marital initiation. Narratives highlighted differences in processes of initiation pre and post marriage and during pregnancy. CONCLUSIONS: Most tobacco prevention interventions are directed to adolescents in school. This study suggests that especially for low literate or illiterate women, school based interventions are ineffective. To be effective strategies to prevent SLT initiation must reach women in urban areas at or immediately after marriage and during their first pregnancy. Messages must negate culturally rooted beliefs about the health benefits of SLT in order to prevent initiation and onset of daily use. PMID- 26625761 TI - Treatment and Survival in Patients with Chronic Myeloid Leukemia in a Chronic Phase in West Iran. AB - BACKGROUND: CML includes 30% of all leukemias, and occurs from childhood to old age. The present study was a retrospective analysis of chronic phase CML patients registered to a Hematology Clinic in Kermanshah, Iran, with checking of treatment options. MATERIALS AND METHODS: Between 2002 and 2014, 85 CML patients referred to our hematology clinic were enrolled in our study. We surveyed age, sex, B symptoms, splenomegaly, Sokal score, Hasford score, treatment and survival in all patients. Philadelphia chromosome analysis was conducted for each patient by conventional cytogenetics. We compared treatment in the patients with three drugs, imatinib, hydroxyurea (HU) and interferon alpha (IFN-alpha). RESULTS: The mean age of the patients at diagnosis was 47.5 +/- 14.5 years (range, 23-82 years), with 43 (50.6%) being male. Some 13 (15.3%) were referred to our clinic for the first time with B-symptoms and 44 patients (51.8%) had splenomegaly. The Sokal score for 77 (90.6%) was low, 4 (4.7%) was intermediate and 4(4.7%) was high, but Hasford (Euro) scores for all patients were low. The 5-year survival rate for treated patients with imatinib, imatinib plus HU and imatinib plus HU plus IFN-alpha was 90.5%, 81.1% and 55.6%, respectively CONCLUSIONS: The results show that imatinib therapy alone provides better survival in CML patients compared to HU or IFN-alpha. Combinations of IFN-alpha and/or HU with imatinib probably reduce survival. PMID- 26625762 TI - Dietary Ziziphus jujuba Fruit Influence on Aberrant Crypt Formation and Blood Cells in Colitis-Associated Colorectal Cancer in Mice. AB - Ziziphus jujuba (ZJ) fruit is rich in bioactive functional components such as polysaccharides, triterpenoid acid, flavonoids and oleamide. It has been commonly used in the treatment of various diseases including diabetes, digestive disorders, diarrhea, skin infections, liver and urinary complaints. However, dietary effects with regard to chemoprevention of colon cancer have not been studied. The present study was performed to evaluate the protective effects of dietary ZJ against colitis-associated colon carcinogenesis in azoxymethane (AOM) dextran sodium sulphate (DSS)-treated mice. AOM was injected (10 mg/kg b.wt., i.p.) and three cycles of 2% DSS in drinking water for 7 days with 14 days of normal drinking water in-between were administered to induce colitis-associated colon cancer. ZJ fruit was supplemented into feed at levels of 5 and 10%. Dietary ZJ significantly attenuated aberrant crypt foci (ACF) formation and also decreased the progression of hyperplasia to dysplasia. In addition, it significantly reduced circulating white blood cells, lymphocytes, neutrophils, monocytes, eosinophils, basophils and platelets compared to colon cancer mice. We conclude that ZJ supplementation may delay the progression of colon cancer from hyperplasia to dysplasia and ultimately adenocarcinoma and cancer. In addition, it decreased circulating tumor-related leukocytes, main regulators of cancer inflammation. Dietary consumption of ZJ fruit attenuated the formation of ACF and delayed the progression of colon cancer. PMID- 26625763 TI - Complications and Carcinogenic Effects of Mustard Gas--a Systematic Review and Meta-Analysis in Iran. AB - BACKGROUND: Catastrophic effects of mustard gas as a chemical warfare agent have always been a major problem for those exposed to this agent. In this meta analysis it was tried to evaluate carcinogenesis, ocular, cutaneous and respiratory complications of mustard gas exposure among Iranians who had been exposed to this agent during the Iran-Iraq war. MATERIALS AND METHODS: In this meta-analysis, the required data were collected using keywords "mustard gas", "sulfur mustard", "cancer", "neoplasm", "respiratory complications", "ocular complications" , "lung disease", "chronic complication", "eye", "skin", "cutaneous complication", "carcinogenesis" and their combination with keywords "Iran", "Iranian", "prevalence", "mortality" and their Farsi equivalent terms from the databases of SID, Iranmedex, Magiran, Pubmed, Science Direct, Google Search engine, Gray Literature and Reference of References. To determine the prevalence of each complication and perform meta-analysis, CMA: 2 (Comprehensive Meta-Analysis) software with a randomized model was used. RESULTS: Of the 542 articles found, 7 national articles, consistent with the aims of this study were selected. Meta- analysis of seven papers revealed that cancer risk, especially cancer of the respiratory system was elevated, so that the relative risk (RR) of cancer role of mustard gas was inconsistent from 2/1 to 4 in this survey. Also prevalence of delayed skin disorders due to sulfur mustard was 94.6%, pulmonary complications 94.5% and ocular complications 89.9%. The incidence of various cancers in victims exposed to mustard gas was 1.7% worldwide where the rate was 2.2% in Iranian victims of the Iraq-Iran war. CONCLUSIONS: Based on present study the prevalence of delayed mustard gas related cutaneous, pulmonary and ocular complications is above 90% and risk of carcinogenesis is higher in comparison to worldwide statistics. This may suggest need for long-term and persistent follow up and rehabilitation procedures for populations exposed to this agent. PMID- 26625764 TI - Overexpression of Cyclin E and its Low Molecular Weight Isoforms Cooperate with Loss of p53 in Promoting Oncogenic Properties of MCF-7 Breast Cancer Cells. AB - Cyclin E, a key coordinator of the G1 to S transition in the cell cycle, may be deregulated in several malignancies, including breast cancer. The most significant aberration in cyclin E is its elastase mediated proteolytic cleavage into tumor specific low molecular weight isoforms (LMW-Es). LMW-Es are biochemically hyperactive and biologically drive tumorigenesis in transgenic mouse models. Additionally, expression of LMW-Es has been correlated with poor survival in breast cancer cases. Here we determine whether expression of LMW-Es in a breast cancer cell line that is naturally devoid of these deregulated forms would alter their progression through each phase of the cell cycle. The results revealed that LMW-Es expression resulted in an increased doubling time, concomitant with a predominant increase in the population in the S phase of the cell cycle. Moreover, downregulation of p53 in LMW-Es cells resulted in additional shortening of the doubling time and enrichment of cells in the S and G2/M phases of the cell cycle. Furthermore, expression of LMW-Es sensitized cells to beta-estradiol (E2) mediated growth and changed expression patterns of estrogen receptor and Bcl-2. Intriguingly, expression of LMW-Es could surpass anti-apoptotic effects raised by p53 upregulation. Taken together these studies suggest that overexpression of LMW-Es in collaboration with p53 loss results in altered growth properties of MCF-7 cells, enhancing the oncogenic activity of these ER positive breast cancer cells. PMID- 26625765 TI - Seroprevalence of Anti-EBV IgG among Various Age Groups from Khon Kaen Province, Thailand. AB - Epstein-Barr virus (EBV) is an extremely common herpesvirus that may cause asymptomatic infection or various diseases, including infectious mononucleosis, certain lymphoproliferative diseases and several types of neoplasms. Vaccine development is an important strategy to reduce the burden of EBV-associated diseases and the timing of vaccinations should be before primary infection occurs. In the past, more than 90% of Thai children were infected with EBV in early childhood. Now, due to the improved healthcare system in Thailand, we aim to determine current prevalence of EBV infection among people in different age groups. A total of 538 sera were collected from residents of Khon Kaen province in northeastern Thailand for detecting anti-EBV IgG. Sera of infants under 2 years-old were also tested for anti-EBV IgM and EBV-DNA. The prevalence of anti EBV IgG was 47.1% (95% CI: 23.3-70.8) in infants aged 0-6 months, 34.9% (95% CI: 23.1-46.7) in those aged 6-24 months, 87.9% (95% CI: 79.5-96.3) in children aged 3-5 years and then maintained at above 95% through adulthood. These seropositivity rates among Thai children remain similar to those found in a previous study conducted 20 years ago. Thai children are still exposed to EBV from an early age. Therefore, a prophylactic vaccine should be given within the first two years of life. PMID- 26625766 TI - Genetic Variation in MicroRNAs and Risk of Oral Squamous Cell Carcinoma in South Indian Population. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules, implicated in several activities like initiation, progression and prognosis of various cancers. Single nucleotide polymorphisms (SNPs) in miRNA genes can lead to alteration in mRNA expression, resulting in diverse functional consequences. The aim of our study was to investigate the association of miR-149C>T and miR-196a2C>T SNPs with susceptibility to development of oral squamous cell carcinoma (OSCC) in South Indian subjects. MATERIALS AND METHODS: 100 OSCC patients and 102 healthy controls from the general population were recruited for the study. Genetic analysis was performed by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) as per a standard protocol. RESULTS: The genotype frequencies in miR-196a2 polymorphism, of TT, CT and CC in the OSCC patients were 69%,10% and 22% respectively while for control group it was 80%, 15% and 5% respectively. The CC genotype of miR196a2 polymorphism was significantly associated with oral squamous cell carcinoma. The genotype frequencies in miR-149 polymorphisms of CC, CT and TT in the oral squamous cell carcinoma (OSCC) patients were 72%, 22% and 6% respectively and for control group 88%, 12% and 0% respectively. CT and TT genotypes of miR149 polymorphism were found to be significantly associated with OSCC (p = 0.05 and 0.07). CONCLUSIONS: Our study suggests that miR-196a2C>T and miR-149C>T polymorphisms may play crucial roles in the development of OSCC in South Indian subjects. PMID- 26625767 TI - Whole Brain Radiotherapy Combined with Stereotactic Radiosurgery versus Stereotactic Radiosurgery Alone for Brain Metastases. AB - BACKGROUND: The aim of this study was to evaluate the effect of whole brain radiotherapy (WBRT) combined with streotactic radiosurgery versus stereotactic radiosurgery (SRS) alone for patients with brain metastases. MATERIALS AND METHODS: This was a retrospective study that evaluated the results of 46 patients treated for brain metastases at Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Radiation Oncology Department, between January 2012 and January 2015. Twenty-four patients were treated with WBRT+SRS while 22 patients were treated with only SRS. RESULTS: Time to local recurrence was 9.7 months in the WBRT+SRS arm and 8.3 months in SRS arm, the difference not being statistically significant (p= 0.7). Local recurrence rate was higher in the SRS alone arm but again without significance (p=0,06). CONCLUSIONS: In selected patient group with limited number (one to four) of brain metastases SRS alone can be considered as a treatment option and WBRT may be omitted in the initial treatment. PMID- 26625768 TI - Evaluation of Platelet Indices in Lung Cancer Patients. AB - BACKGROUND: In this study, we aimed to determine platelet indices such as platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), Plateletcrit (PCT) platelet count (PLT) in lung cancer cases, and evaluate any relationships between these parameters and stage or histologic types. MATERIALS AND METHODS: This retrospective study covered 44 lung cancer patients and 47 healthy subjects. Platelet indices including PLT, PCT, MPV, PDW were estimated and compared with normal subjects. The results were evaluated statistically. RESULTS: The PDW value was significantly higher in the cancer group compared to the control group; however, the values for PCT and MPV were lower. CONCLUSIONS: We suggest potential use of platelet indices in diagnosis of lung cancer. PMID- 26625769 TI - Prevalence of Oxaliplatin-induced Chronic Neuropathy and Influencing Factors in Patients with Colorectal Cancer in Iran. AB - BACKGROUND: The chemotherapeutic agent oxaliplatin can cause acute and chronic forms of peripheral neuropathy. The aim of this study was to evaluate the incidence of chronic neuropathy and its risk factors in colorectal cancer (CRC) patients treated with FOLFOX or XELOX regimens in the Oncology Ward of Hazrat-e Rasoul Hospital in Tehran. MATERIALS AND METHODS: A total of 130 patients with CRC were entered into our study, aged over 18 years, without history of receiving other neurotoxic agents or other predisposing factors such as diabetes or neurologic diseases and kidney and liver dysfunction. For the FOLFOX regimen, patients received oxaliplatin, 85 mg/m2, every 2 weeks for 12 courses and with the XELOX regimen, oxaliplatin was 130 mg/m(2), every 3 weeks for 8 courses. Based on Common Toxicity Criteria (CTC or NCI-CTC v.3), the patients were divided into 5 groups (grades) based on the severity of their symptoms. RESULTS: Fifty seven patients (43.8%) were male and 73(56.2%) female. Some 19 patients (14.7%) had BMI<20, 97(74.6%) were between 20-25 and 14 (10.8%) >= 25. In 105 patients (80.7%) neuropathy was found. There was significant correlation between BMI, hypomagnesaemia and especially, severity of anemia in patients with neuropathy compared to those without. CONCLUSIONS: Oxaliplatin regimens can induce chronic neuropathy in CRC patients, with anemia, high BMI and hypomagnesaemia as risk factors that can predispose to this kind of neurotoxicity. PMID- 26625770 TI - Diagnostic Performance of Breast MRI in the Evaluation of Contralateral Breast in Patients with Diagnosed Breast Cancer. AB - AIMS: The purpose of our study was to evaluate the diagnostic performance of breast magnetic resonance imaging (MRI) in the evaluation of contralateral breast in patients with diagnosed breast cancer. A secondary objective was to determine accuracy of breast MRI in diagnosing multi-focal and multicentric lesions in the ipsilateral breast. MATERIALS AND METHODS: Using a non-probability convenience sampling technique, patients with histopathologically diagnosed breast cancer with MRI of breast performed to exclude additional lesions were included. MRI findings were correlated with histopathology. In addition, follow-up imaging with mammography and ultrasound was also assessed for establishing stability of negative findings and for the detected of benign lesions. RESULTS: Out of 157 MRI breast conducted during the period of 2008 to 2013, 49 were performed for patients with diagnosed breast cancer. The sample comprised of all females with mean age 50.7 +/- 11.0 years. The patient follow-up imaging was available for a period of 2-5 years. The sensitivity, specificity, and positive and negative predictive values of MRI in the detection of multifocal/multicenteric lesions was 85.7%, 88.8%, 60% and 96.6% respectively and for the detection of lesions in the contralateral breast were 100%, 97%, 83.3% and 100% respectively. CONCLUSIONS: Our study highlights the diagnostic performance and the added value of MRI in the detection of multifocal /multicenteric and contralateral malignant lesions. In patients with diagnosed breast cancer having dense breast parenchyma and with infiltrating lobular carcinoma as the index lesion MRI is particularly useful with excellent negative predictive value in the exclusion of additional malignant foci in the ipsilateral and contralateral breasts. PMID- 26625771 TI - Role of Electromagnetic Field Exposure in Childhood Acute Lymphoblastic Leukemia and No Impact of Urinary Alpha- Amylase--a Case Control Study in Tehran, Iran. AB - Childhood acute lymphoblastic leukemia (ALL) is one of the most common hematologic malignancies which accounts for one fourth of all childhood cancer cases. Exposure to environmental factors around the time of conception or pregnancy can increase the risk of ALL in the offspring. This study aimed to evaluate the influence of prenatal and postnatal exposure to high voltage power lines on the incidence of childhood ALL. It also examines the role of various factors such as environmental factors and alpha-amylase as a marker in the development of leukemia. This cross-sectional case control study was carried out on 22 cases and 100 controls who born and lived in low socioeconomic families in Tehran and were hospitalized for therapeutic purposes in different hospitals of rom 2013-2014. With regard to the underlying risk factors; familial history and parental factors were detected as risk factors of ALL but in this age, socioeconomic and zonal matched case control study, prenatal and childhood exposure to high voltage power lines was considered as the most important environmental risk factor (p=0.006, OR=3.651, CI 95% 1.692-7.878). As the population study was from low socioeconomic state, use of mobiles, computers and microwaves was negligible. Moreover prenatal and postnatal exposure to all indoor electrically charged objects were not detected as significant environmental factors in the present study. This work defined the risk of environmental especially continuous pre and postnatal exposure to high voltage power lines and living in pollutant regions through the parents or children as well as the previously described risk factors of ALL for the first time in low socioeconomic status Iranian population. PMID- 26625772 TI - Down Regulation of miR-34a and miR-143 May Indirectly Inhibit p53 in Oral Squamous Cell Carcinoma: a Pilot Study. AB - BACKGROUND: Aberrant microRNA expression has been associated with the pathogenesis of a variety of human malignancies including oral squamous cell carcinoma (SCC). In this study, we examined primary oral SCCs for the expression of 6 candidate miRNAs, of which five (miR-34a, miR-143, miR-373, miR-380-5p, and miR- 504) regulate the tumor suppressor TP53 and one (miR-99a) is involved in AKT/mTOR signaling. MATERIALS AND METHODS: Tumor tissues (punch biopsies) were collected from 52 oral cancer patients and as a control, 8 independent adjacent normal tissue samples were also obtained. After RNA isolation, we assessed the mature miRNA levels of the 6 selected candidates against RNU44 and RNU48 as endogenous controls, using specific TaqMan miRNA assays. RESULTS: miR-34a, miR 99a, miR-143 and miR-380-5p were significantly down-regulated in tumors compared to controls. Moreover, high levels of miR-34a were associated with alcohol consumption while those of miR-99a and miR-143 were associated with advanced tumor size. No significant difference was observed in the levels of miR-504 between the tumors and controls whereas miR-373 was below the detection level in all but two tumor samples. CONCLUSIONS: Low levels of miR-380-5p and miR-504 that directly target the 3'UTR of TP53 suggest that p53 may not be repressed by these two miRNAs in OSCC. On the other hand, low levels of miR-34a or miR-143 may relieve MDM4 and SIRT1 or MDM2 respectively, which will sequester p53 indicating an indirect mode of p53 suppression in oral tumors. PMID- 26625773 TI - Salvage Transoral Robotic Surgery for Recurrent or Residual Head and Neck Squamous Cell Carcinoma: A Single Institution Experience. AB - BACKGROUND: The present study was conducted to evaluate the technical feasibility, safety and adequacy of surgical margins with salvage transoral robotic surgery (TORS) for recurrent or residual head and neck squamous cell carcinoma patients. MATERIALS AND METHODS: Thirty patients who underwent salvage TORS using the 'DaVinci' robot were enrolled in the study and data related to their surgical time, complications and functional outcome were recorded. RESULTS: The feasibility of salvage TORS in our study was observed to be 100%. Positive margins were encountered in only 6.7% of patients. Mean blood loss was 23.3 ml with no patient requiring blood transfusion. Postoperative complications in the form of primary haemorrhage requiring active surgical intervention occurred in 13.3%. Oral feeding could be started as early as the 3rd postoperative day in a few patients, with nasogastric tubes being removed on the 12th postoperative day. Long term gastrostomy tube dependency was seen in 10% cases. Median survival of patients was 19 months. CONCLUSIONS: Salvage TORS is a safe, effective and feasible option in the management of treatment failure cases. It offers an alternative surgical approach with unexpected benefits in terms of tracheostomy tube use, Ryle's tube and gastrostomy dependence. PMID- 26625774 TI - Diagnostic Performance of HPV E6/E7 mRNA and HPV DNA Assays for the Detection and Screening of Oncogenic Human Papillomavirus Infection among Woman with Cervical Lesions in China. AB - BACKGROUND: Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide and it is responsible for most cases of cervical uterine cancer. Although HPV infections of the cervix do not always progress to cancer, 90% of cervical cancer cases have been found to be associated with high risk HPV (HR- HPV) infection. HPV DNA testing is widely used, along with Papanicolaou (Pap) testing, to screen for cervical abnormalities. However, there are no data on the prevalence of genotype-specific HPV infections assessed by measuring HPV E6/E7 mRNA in women representative of the Chinese population across a broad age range. MATERIALS AND METHODS: In the present study, we compared the results with the CervicGen HPV RT-qDx assay, which detects 16 HR-HPV genotypes (Alpha-9: HPV 16, 31, 33, 35, 52, and 58; Alpha-7: HPV 18, 39, 45, 51, 59, and 68; and Alpha-5, 6: HPV 53, 56, 66, and 69), and the REBA HPV-ID assay, which detects 32 HPV genotypes based on the reverse blot hybridization assay (REBA) for the detection of oncogenic HPV infection according to cytological diagnosis. We also investigated the prevalence and genotype distribution of HPV infection with a total of 324 liquid-based cytology samples collected in western Shandong province, East China. RESULTS: The overall HPV prevalences determined by HPV DNA and HPV E6/E7 mRNA assays in this study were 79.9% (259/324) and 55.6% (180/324), respectively. Although the positivity of HPV E6/E7 mRNA expression was significantly lower than HPV DNA positivity, the HPV E6/E7 mRNA assay showed greater specificity than the HPV DNA assay (88.6% vs. 48.1%) in normal cytology samples. The prevalence of Alpha-9 (HPV 16, 31, 33, 35, 52, and 58) HPV infection among these women accounted for up to 80.3% and 76.1% of the high-grade lesions detected in the HPV mRNA and DNA tests, respectively. The HR-HPV genotype distribution, based on HPV DNA and E6/E7 mRNA expression by age group in patients with cytologically confirmed lesions, was highest in women aged 40 to 49 years (35.9% for cytologically confirmed cases, Pearson correlation r value=0.993, p<0.001) for high-grade lesions. Among the oncogenic HR-HPV genotypes for all age groups, there was little difference in the distribution of HPV genotypes between the HPV DNA (HPV -16, 53, 18, 58, and 33) and HPV E6/E7 mRNA (HPV -16, 53, 33, 58, and 18) assays. HPV 16 was the most common HPV genotype among women with high grade lesions. CONCLUSIONS: Our results suggest that the HPV E6/E7 mRNA assay can be a sensitive and specific tool for the screening and investigation of cervical cancer. Furthermore, it may provide useful information regarding the necessity for early cervical cancer screenings and the development of additional effective HPV vaccines, such as one for HPV 53 and 58. Additionally, gaining knowledge of HPV distribution may also inform us about ecological changes in HPV after the vaccination. PMID- 26625775 TI - Antitumoral and Antioxidant Potential of Egyptian Propolis Against the PC3 Prostate Cancer Cell Line. AB - It has been shown previously that nutritional supplements rich in polyphenolic compounds play a significant role in prostate cancer chemoprevention. Propolis is a natural, resinous hive product that has several pharmacological activities including antimicrobial, antioxidant, anti-inflammatory, and antitumoral activities. The aim of this study was to compare the cytotoxic, antioxidant and antitumoral activities of an ethanolic extract of Egyptian propolis (EEP) in vitro with an established chemotherapeutic drug such as doxorubicin (DOX), and the effects of their combination against the PC3 human prostate cancer cell line. Cellular viability and IC50 levels with EEP, DOX and their (v/v) combination were detected by sulphorhodamine-B (SRB) assay after incubation of PC3 cells for 72 h with different doses (0, 0.01, 0.1, 1, 10 and 100 MUg/ml). Two selected doses of IC50 and IC25 were applied to cells for 24h for antitumor evaluation assay of treatment compounds. EEP and its (v/v) combination with DOX showed significant antitumor potential besides high antioxidant properties of superoxide dismutase (SOD), total antioxidant capacity (TAC), catalase (CAT), nitric oxide (NO) and reduced glutathione (GSH) levels when compared with the control untreated cells. DNA fragmentation assay and semi quantitative RT-PCR analyses for p53 and Bax genes showed that EEP activated cellular apoptosis and increased the mRNA expression levels more than other treatment. In conclusion, EEP alone or in combination with DOX at both doses used here showed greater antioxidant, antiproliferative and apoptotic effects against the PC3 cell lines as compared to treatment with DOX alone. Therefore, EEP could be considered as a promising candidate for prostate cancer chemotherapy. PMID- 26625776 TI - Clinical Significance of the NQO1 C609T Polymorphism in Non Small Cell Lung Adenocarcinoma Patients. AB - BACKGROUND: NAD(P)H: quinone oxidoreductase 1 (NQO1) is part of the antioxidant defence system involved in detoxification. This study aimed to analyze the influence of NQO1 (C609T) genetic polymorphism in non small cell lung cancer (NSCLC)as a putative risk factor. MATERIALS AND METHODS: Present study included 100 cases of NSCLC (adenocarcinoma) patients and 100 age and sex matched healthy controls. NQO1 (C609T) genotyping was performed by allele specific PCR for assessment of putative associations with clinical outcome and genotypes of. The association of the polymorphism with the survival of NSCLC patients' was analyzed by Kaplan-Meier method. RESULTS: In Indian NSCLC (adenocarcinoma) patients increased risk of developing NSCLC was found to be associated with NQO1 609TT genotype [OR 3.68(0.90-14.98), RR 2.04(0.78-5.31)] for CT [OR 2.91(1.58- 5.34), RR 1.74(1.23-2.44) p= 0.0005 for CT], for CT+TT [ OR 3.26(1.82-5.82), RR 1.87(1.34-2.61) p<0.0001 for CT+TT]. A significant difference (p=0.0009) was observed in genotype distribution among cases and healthy controls. Patients with CT+TT genotype exhibited a significant poor overall survival compared with patients displaying homozygous CC genotype (p=0.03) and when survival independently compared with CC, TT and CT genotype was also found to be significantly associated (p=0.02). Overall median survival times were CT 6.0 months, TT 8.2 months, and CT + TT (6.4 months)]. CONCLUSIONS: The present study revealed that NQO1 CT, TT and CT+TT genotypes may be associated with clinical outcome and risk of developing NSCLC in the Indian population. PMID- 26625777 TI - Clinico-Hematological Profile and Risk Stratification in Patients with Essential Thrombocythemia: Experience from Pakistan. AB - BACKGROUND: Essential thrombocythemia (ET) is a Philadelphia chromosome-negative myeloproliferative neoplasm characterized by sustained thrombocytosis and megakaryocytic hyperplasia. It is an uncommon hematological malignancy which primarily affects elderly individuals. The rational of this study was to determine its clinico-hematological profile along with risk stratification in Pakistan patients. MATERIALS AND METHODS: In this retrospective cross sectional study, 21 patients with ET were enrolled from January 2011 to December 2014. Data was analyzed with SPSS version 21. RESULTS: The mean age was 56.7 +/- 19.0 years (range 18-87) and the male to female ratio was 1:1.1. Of the total, 62% of patients were above 50 years of age. Overall 61.9% were diagnosed incidentally and were asymptomatic. In symptomatic patients, major complaints were weakness (19%); erythromelalgia (14.2%), transit ischemic attack (9.5%) and gastrointestinal bleed (4.7%). The mean hemoglobin count was 11.7 +/- 2.4 g/dl with a total leukocyte count of 13.3 +/- 8.1 x 10(9)/l and platelets count of 1188.8 +/- 522.2 x 10(9)/l. Serum lactate dehydrogenase, serum creatinine and uric acid were 454.3 +/- 127.8, 1.2 +/- 0.5 and 7.4 +/- 3.4 respectively. According to risk stratification, 57.1% were in high risk; 23.8% in intermediate risk while 19.1% in low risk group. CONCLUSIONS: ET in our patients in Pakistan, unlike in the West, is seen in a relatively young population. Primarily patients were asymptomatic and risk stratification revealed predominance of high risk disease in our setting. PMID- 26625778 TI - In silico docking of methyl isocyanate (MIC) and its hydrolytic product (1, 3 dimethylurea) shows significant interaction with DNA Methyltransferase 1 suggests cancer risk in Bhopal-Gas- Tragedy survivors. AB - DNA methyltransferase 1 (DNMT1) is a relatively large protein family responsible for maintenance of normal methylation, cell growth and survival in mammals. Toxic industrial chemical exposure associated methylation misregulation has been shown to have epigenetic influence. Such misregulation could effectively contribute to cancer development and progression. Methyl isocyanate (MIC) is a noxious industrial chemical used extensively in the production of carbamate pesticides. We here applied an in silico molecular docking approach to study the interaction of MIC with diverse domains of DNMT1, to predict cancer risk in the Bhopal population exposed to MIC during 1984. For the first time, we investigated the interaction of MIC and its hydrolytic product (1,3-dimethylurea) with DNMT1 interacting (such as DMAP1, RFTS, and CXXC) and catalytic (SAM, SAH, and Sinefungin) domains using computer simulations. The results of the present study showed a potential interaction of MIC and 1,3-dimethylurea with these domains. Obviously, strong binding of MIC with DNMT1 interrupting normal methylation will lead to epigenetic alterations in the exposed humans. We suggest therefore that the MIC- exposed individuals surviving after 1984 disaster have excess risk of cancer, which can be attributed to alterations in their epigenome. Our findings will help in better understanding the underlying epigenetic mechanisms in humans exposed to MIC. PMID- 26625779 TI - Survey of HER2-neu Expression in Colonic Adenocarcinoma in the West of Iran. AB - BACKGROUND: Overexpression of HER2-neu has been reported in many epithelial malignancies, including cancers of the breast, ovaries, lungs, prostate, bladder, pancreas, colorectum and stomach as well as osteosarcomas. The aim of this study was evaluation of expression of HER2-neu immunohistochemistry (IHC) status and clinicopathologic features in a series of colonic adenocarcinomas. MATERIALS AND METHODS: In this descriptive and analytical study, we surveyed 211 samples of colon adenocarcinoma from 182 patients (86.3%) undergoing total or partial colectomy and 29 (7.13%) with biopsies by colonoscopy. A sufficient sample size was obtained from all cases and the slides were stained with hematoxylin and eosin and also by IHC (HER2) staining. RESULTS: The mean age for the patients at diagnosis was 57.9 years (range, 15-88 years). One hundred and twenty one patients (57.3%) were male. Of all patients, 201 samples (95.3%) were conventional adenocarcinomas (159, 29 and 13 cases were well, moderately and poorly differentiated, respectively) and 10 (4.7%) were mucinous type. Out of 211 cases, 171 were checked for lymph nodes metastasis and 64 were positive. There is a correlation between HER2 scores and differentiation, most score 3 cases being well differentiated (P<0.05). CONCLUSIONS: In patients with advanced colon cancer, surgery alone is not curative and other forms of therapy may be required to prolong patient survival. HER2 overexpression was found in some cases and this could be a guideline to new adjuvant therapy for these patients. PMID- 26625780 TI - Hazardous Health Behaviour among Medical Students: a Study from Turkey. AB - BACKGROUND: Hazardous health behaviour in young people is an important factor that affects the individual risk for non-communicable diseases and other disorders later in life. This study aimed to determine the hazardous health behaviour of first and last class medical students of Erciyes University. MATERIALS AND METHODS: This descriptive study was carried out with 240 medical students from the first and 130 students from the last (sixth) class. Data were obtained by questionnaire between March-April 2012. In total, 339 students were included with a response rate of 91.6%. Socio-demographic characteristics, school success, self-reported economic difficulties, health perceptions, hazardous health behaviour related to chronic disease, tobacco, alcohol, substance use, body weight, height, traffic, violence and nutrition were assessed in line with the literature. RESULTS: Of the participants; 64.0% were from first and 36.0% were from the last class. Mean ages for the first and last classes were 19.4 +/- 1.5 and 24.0 +/- 1.5 years, respectively. In the current study, males exhibited more hazardous behaviour than females. Sime 19.8% of the students in the study group used alcohol, 35.4% used a waterpipe, and 24.8% used tobacco at least once. These rates increased in both genders in the last class and the increase in males was significant. Some 3.8% of the students in the current study used pleasure inducing illegal substances at least once. All the students participating in the current study were single, the number of males reported not using condoms (8.6%) was 4.56 times higher compared to females. Some 64.0% of the students did not perform physical activity lasting at least 30 minutes for five times a week, 13.0% did not sleep for mean 7-8 hours daily, males having a 2.9 times higher risk. More than 1/3 of the students did not consume cooked vegetable dishes and 1/4 did not consume fresh fruits and salads, the rates were higher among males. CONCLUSIONS: In the current study, hazardous health behaviour was prevalent among medical students, with higher risks among males and last class students. According to these results, medical curriculum may be focused on decreasing hazardous health behaviour. In addition, in order to prevent unhealthy behaviour, the number of youth-friendly health facilities should be increased. PMID- 26625781 TI - Lifestyle and Sporadic Colorectal Cancer in India. AB - BACKGROUND: The study evaluated the patient, lifestyle and tumor profile in patients undergoing upfront surgery for sporadic colorectal cancer (CRC) in Indian population. MATERIALS AND METHODS: One hundred consecutive patients were included. Details related to their demographic profile, habits, signs and symptoms, tumor profile, further treatment and follow up were recorded. RESULTS: The majority of the patients had colonic cancer (68%), advanced tumor stage 3 and 4 (46%), moderately differentiated tumors (70%) with absence of lymphatic invasion (60%) and metastasis (90%). Correlations between tumor location and abdominal pain (p-value 0.002), bleeding per rectum (p-value <0.001), difficulty in micturition (p-value 0.012) and constipation (p-value 0.007) were found to be statistically significant. Abdominal pain was more frequently reported in patients with metastasis (p-value 0.031). Loss of weight statistically correlated with absence of lymphatic invasion (p-value 0.047). Associations between tumor stage and alcohol intake (p-value 0.050) and non vegetarian diet (p-value 0.006); lymphatic invasion and intake of spicy food (p-value 0.040) and non vegetarian diet (p-value 0.001) and metastasis and alcohol intake (p-value 0.041) were also observed. Age and tumor grade were also correlated (p-value 0.020). CONCLUSIONS: Minimizing the adverse lifestyle factors can help in reducing the overall incidence of CRC in the Indian population. PMID- 26625782 TI - Association of Metastasis with Clinicopathological Data in Mexican Patients with Osteosarcoma, Giant Cell Tumor of Bone and Chondrosarcoma. AB - BACKGROUND: Bone tumors are neoplasias with a high overall mortality; one of the main factors that reduce survival is their high capacity to develop metastases. It has been reported that finding lung metastases at diagnosis of osteosarcoma (OS), chondrosarcoma (CS) and giant cell tumor of bone (GCTb) is quite common. In this study, we inquire the relationship of metastases caused by these tumors with different clinical and pathological aspects, in order to guide medical personnel in the diagnosis and opportune treatment of metastases or micro metastases. MATERIALS AND METHODS: We collected data of 384 patients with clinical, radiological and histopathological diagnosis of OS, GCTb and CS that attended the National Rehabilitation Institute (INR) during 2006 to 2014. Chi-square and Fisher's exact tests were performed for data analysis. RESULTS: In the three tumor types, the presence of metastases at diagnosis was variable (p=0.0001). Frequency of metastases was 36.7%, 31.7% and 13.2% for OS, CS and GCTb respectively. The average age had no significant difference (p>0.05) in relation to metastases, even so, patients with OS and GCTb and metastases, were older while patients with CS and metastases were younger, in comparison to patients without metastases. Males had a higher frequency of metastases (68.2%, p = 0.09) in contrast to CS and GCTb, in which the metastases was more frequent in women with 51.9% (p = 0.44) and 57.9% (p = 0.56) respectively. Broadly, metastasis was associated with primary tumors located in the femur (44.4%), followed by the tibia (15.6%); metastases was more frequent when primary tumor of GCTb and OS were in the same bones, but were located in the hip (26.3%) for CS. CONCLUSIONS: The frequency of metastases in OS, GCTb and CS is high in our population and is determined by different clinicopathological variables related to the kind of tumor. Further studies are needed in order to evaluate metastases subsequent to diagnosis and associations with survival and clinicopathological factors , as well as to determine the sensitivity and specificity of current methods of detection. PMID- 26625783 TI - Chromogenic In Situ Hybridisation Test for Breast Cancer Patients with Equivocal IHC Results--a Study from Iran. AB - BACKGROUND: HER2/neu overexpression on cell membranes of breast cancer cells is due to HER2/neu gene amplification and it is important to identify potential candidates for anti HER2 therapy with trastuzumab. IHC, FISH and CISH are standard FDA approved assays currently used to determine HER2 status in routine practice. The aim of this study was to determine HER2 gene amplification, using the CISH method in breast carcinoma samples which had IHC +2 reactions. MATERIALS AND METHODS: This study was conducted from 2008- 2010 using 334 consecutive breast carcinoma samples referred from local laboratories to Mehr Hospital. CISH assays were performed for all cases, and IHC tests were also done for determining efficacy and accuracy of local labs. HER2 status in local IHC tests was compared with central IHC and CISH results. RESULTS: Of 334 breast cancer patients, 16 were negative for HER2 IHC (0, +1), 201 cases were equivocal (+2), and 31 positive (+3). Of 334 referral cases, 88 were CISH positive (26.3%) and 246 were CISH negative (73.7%). Of 201 IHC +2 cases, HER2 gene amplification was observed in 42 cases (kappa: 0.42). A 29.9% concordance was found between local IHC and central IHC. Sensitivity and specificity of local IHC were 90% and 53.8%, respectively. CONCLUSIONS: Low accuracy of IHC results in local labs was associated with the following factors: using former FDA-approved criteria for HER2 interpretation, utilizing non-validated kits, and lack of any quality assurance program. Therefore, following the new 2014 ASCO/CAP guideline and comprehensive quality assurance should be implemented to ensure accuracy of HER2 testing. PMID- 26625784 TI - Alteration of Thyroid Function in Indian HER 2-Negative Breast Cancer Patients Undergoing Chemotherapy. AB - BACKGROUND: Thyroid hormones (TH) are regulated by the hypothalamic-pituitary axis, which plays an important role in cell growth, differentiation, development and other aspects of metabolism. It is believed that an active hypothalamic pituitary axis increases the susceptibility of thyroid dysfunction during systemic chemotherapy. In order to investigate the relation between thyroid function and chemotherapy the present study was designed to investigate TH in breast cancer patients receiving at least three cycles of chemotherapy. The levels of TH were measured at the baseline and before each cycle of chemotherapy. MATERIALS AND METHODS: Blood samples for estimation of TH levels were collected from 80 (pre-menopausal-40; post-menopausal-40) breast cancer patients just before they were undergoing--1st, 2nd, 3rd and 4th cycle of chemotherapy. The serum was separated and T3, T4 and TSH levels were determined by chemiluminescence method. RESULTS: T3 and T4 were found significantly decreased and TSH was found significantly increased after 1st (p<0.001), 2nd (p<0.0001) and 3rd cycle of chemotherapy (p<0.0001). The variation of T3 levels (decreased) and TSH levels (increased) was found more in post-menopausal (p<0.0001) women then in pre-menopausal women after 3rd cycle of chemotherapy as compared to baseline (p<0.001). CONCLUSIONS: TH were remarkably altered after each cycle of chemotherapy leading to decline in thyroid function of breast cancer patients. Further, the results also indicated that post- menopausal women were more prone towards decline in thyroid function then pre-menopausal women. The present study proposes the monitoring of TH after each cycle of chemotherapy in breast cancer patients. PMID- 26625785 TI - Breast Cancer Knowledge and Screening Behavior among Female School Teachers in Gaza City. AB - A cross-sectional survey of 370 female teachers working at Governmental schools in Gaza city was conducted. Twenty four schools were selected randomly of all female schools of the city that included primary, preparatory and secondary. In each school all-female teachers aged 35-45 year were invited to fill out a self- administered questionnaire to investigate knowledge and behavior toward breast cancer screening. The survey revealed that more than 75% of women had never undergone clinical breast examination and 60% had never undergone mammography, whereas 62% performed breast self-examination (BSE). Women who performed BSE had significantly higher knowledge about breast cancer screening (P=0.001). Women attending CBE and mammography screening also had significantly higher knowledge (P=0.001). There were significant associations between the practices and presence of positive breast cancer family history (P= 0.002) and the level of education of husbands (P=0.024). The oldest women demonstrated higher performance rates of screening methods than the youngest (P = 0.001). Lack of breast screening knowledge was identified among more than one third of the women, and 24.6% of women did not know any screening method. About a half of women harboured misconceptions about breast cancer screening, including the belief that breast cancer not treatable. Women residing in Gaza city (P=0.00) and with husbands less educated were more likely to have a high level of misconceptions (P=0.01). PMID- 26625786 TI - Comparison Study of Uptake of Colorectal Cancer Testing between Ethnic Minorities and the General Population in Hong Kong. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers. This study aimed to compare the uptake of CRC testing in the general public and in ethnic minorities in Hong Kong. MATERIALS AND METHODS: This cross-sectional survey covered 2,327 South Asian and Chinese adults aged over 50, recruited from two separate studies. A structured questionnaires were administered by research staff over the telephone or in face- to-face interviews. RESULTS: The uptake rate of CRC testing among South Asians was significantly lower than that of the general population in Hong Kong. Factors associated with the uptake rate were health professional's recommendation, perception of regular visits to doctor, use of complementary therapy, ethnicity, perceived susceptibility to cancer, presence of chronic illness, and education level. In addition, a significant interaction (p<0.05) between ethnicity and health professionals' recommendations was found, after adjustment for the main independent factors identified. CONCLUSIONS: Older people with lower educational attainment, without chronic illness and those have lower perceived susceptibility to cancer may be targeted for CRC testing promotion in the society. In addition, health professionals can play a highly influential role in promoting such testing, particularly among ethnic minorities. PMID- 26625787 TI - Religious Coping and Quality of Life in Women with Breast Cancer. AB - BACKGROUND: The aim of this study was to assess the predictive role of religious coping in quality of life of breast cancer patients. MATERIALS AND METHODS: This multi-center cross-sectional study was conducted in Tehran, Iran, from October 2014 to May 2015. A total of 224 women with breast cancer completed measures of socio-demographic information, religious coping (brief RCOPE), and quality of life (FACT-B). Data were analyzed using descriptive statistics and the t-test, ANOVA, and linear regression analysis. RESULTS: The mean age was 47.1 (SD=9.07) years and the majority were married (81.3%). The mean score for positive religious coping was 22.98 (SD=4.09) while it was 10.13 (SD=3.90) for negative religious coping. Multiple linear regression showed positive and negative religious coping as predictor variables explained a significant amount of variance in overall QOL score (R(2)=.22, P=.001) after controlling for socio demographic, and clinical variables. Positive religious coping was associated with improved QOL (beta=0.29; p=0.001). In contrast, negative religious coping was significantly associated with worse QOL (beta=-0.26; p=0.005). CONCLUSIONS: The results indicated the used types of religious coping strategies are related to better or poorer QOL and highlight the importance of religious support in breast cancer care. PMID- 26625788 TI - Oral Cancer Early Detection--a Pressing Need for Continuing Education in Jordan. AB - AIMS: To identify deficiencies in the knowledge of general medical (GMPs) and dental practitioners (GDPs) regarding early detection of oral cancer, to compare differences between subgroups, and to identify educational needs for continuing education courses on this subject. MATERIALS AND METHODS: 165 GDPs and 165 GMPs were directly interviewed to assess their knowledge about oral cancer using a pre tested survey. Knowledge scores were generated from correct responses of participants to factual questions about oral cancer. RESULTS: Few participants (15.2% of GDPs and 12.8% of GMPs) reported that they attended any continuing education courses on oral cancer during their professional career. Most participants (81.6% of GDPs and 86.3% of GMPs) admitted that their knowledge about oral cancer was not up to date and that they would need to attend continuing education courses on oral cancer if available. A few significant differences were identified between groups regarding knowledge about risk factors, clinical presentations and diagnostic techniques but the overall knowledge scores showed no significant difference between GMPs and GDPs. CONCLUSIONS: The present study identified several deficiencies in the knowledge of GMPs and GDPs regarding risk factors, clinical presentations, and diagnostic techniques of oral cancer. Interventions to correct these defects through properly designed continuing education courses are required. PMID- 26625789 TI - Health Beliefs of Nursing Faculty Students about Breast Cancer and Self Breast Examination. AB - BACKGROUND: Breast cancer usually shows a slow development rate and when it is recognized in early stages very successful treatment results can be achieved. This research was planned to research the health beliefs of nursing faculty students about breast cancer and breast self-examination (BSE). MATERIALS AND METHODS: The first class students of nursing faculty formed the basis for this descriptive research (N=347). Sample selection was not made and all female students who wanted to participate voluntarily in the research during March-May of 2014 were included (n=331). RESULTS: It was determined that 85.5% of students had knowledge about cancer, 79.5 % knew of breast cancer, and 65.3% were aware of how BSE is performed. According to the responses of students to the scale of the health belief model that is used to determine the health beliefs of students, item-point averages of trust and obstacle sub-dimensions were high. CONCLUSIONS: It is determined that more than half of students had knowledge about breast cancer and breast self-examination. Their health beliefs were affected by trust and obstacle perceptions, knowledge level about cancer, and awareness about how BSE is done. These factors should be considered in planning trainings that will be given to students. Social responsibility projects should have designed to create the awareness that cancer is a treatable disease. PMID- 26625790 TI - Spatiotemporal Distribution of Gastrointestinal Tract Cancer through GIS over 2007-2012 in Kermanshah-Iran. AB - BACKGROUND: Cancer is one of the common causes of disability and mortality in the world. The present study aimed to define the spatiotemporal distribution of gastrointestinal tract cancers using a geographic information system (GIS) over the time period of 2007-2012 in Kermanshah-Iran. MATERIALS AND METHODS: The method of studying was descriptive-analytical as well as comparative with gastrointestinal tract cancer patients based in the City of Kermanshah over the time period covered. For data analysis, the GIS and SPSS 16.0 were applied. RESULTS: According to the pathological reports within the space of 5 years, 283 cases of gastrointestinal tract cancer (157 in males, 156 in females) were reported. The performed tests in terms of spatial distribution in the environment of GIS indicated that the disease demonstrated a clustered pattern in the City of Kermanshah. More to the point, some loci of this disease have emerged in the City of Kermanshah that in the first level, 6 neighborhoods with 29-59 cases of this disease per square kilometer and in the second level, 15-29 cases. CONCLUSIONS: Gastrointestinal tract cancer demonstrated an ascending trend within the space of 5 years of research and the spatiotemporal distribution of cancer featured a concentrated and clustered pattern in the City of Kermanshah. PMID- 26625791 TI - Burden Assessment of Thyroid cancer in Iran from 1990 to 2010: Lessons Obtained from Global Burden of Disease Report 2010. AB - BACKGROUND: Thyroid tumors are generally regarded as rare malignancies. Nowadays, however, their global incidence is growing continuously partially due to western life style and utilization of more sensitive methods of early detection. It is approximately three times more prevalent in females than in males. Most cases of thyroid cancer are asymptomatic nodules or just have local cervical symptoms or adenopathy in early stages. MATERIALS AND METHODS: The Global Burden of Diseases report 2010 study (released 3/2013) profited from 100 collaborators worldwide and used a vast network of data on health outcomes, vital registries, and population surveys. It shared many of the Global Burden of Diseases 1990 principal databases such as all available data on injuries, diseases, risk factors, as well as comparable metrics, and used different scientific approved methods to estimate important health status data like: death rate, life expectancy, healthy adjusted life expectancy, disability-adjusted life years (DALY), years of living lost due to premature death and years of life with disabilities. RESULTS: DALY as thyroid cancer burden per 100,000 Iranian populations had increased by about 14% during 1990 to 2010 in all ages; from 6.1 (95% UI 4.2-9.74) years in 1990 to 6.95 (95% UI 5.06-9.18) years in 2010 in both sex. The 2010 peak age-group was estimated at 45-49 years in males and 40-45 years in females. PMID- 26625792 TI - Optomizing Transfection Efficiency of Cervical Cancer Cells Transfected by Cationic Liposomes LipofectamineTM2000. AB - BACKGROUND: Currently, cationic liposome has become the commonly used vehicles for gene transfection. Furthermore, one of the most significant steps in microRNAs expression studies is transferring microRNAs into cell cultures successfully. In this study we aim to approach the feasibility of transfection of cervical cancer cell lines mediated by liposome and to obtain the optimized transfection condition for cervical cancer cell lines. MATERIALS AND METHODS: Lipofectamine(TM)2000 as the carrier, miR-101 mimic was transfected into Hela cells and Siha cells. Using green fluorescent protein as reporter gene, to set different groups according to cell seeding density, the amount of miRNA , miRNA and the proportion of Liposomes, Whether to add serum into medium to study their impact on the liposomal transfection efficiency. Finally, MTT assay was used to analyze the relative minimal cell toxicity of liposome reagents. RESULTS: The seeding density of Hela cell line and Siha are 1.5 x 10(4) (per well of 24 well plates), miRNA amount is 1ul of both, the ratio of miRNA and liposome is 1:0.5 of Hela cell line; 1:0.7 of Siha cell line respectively, after 24 hours we can get the highest transfection efficiency. Compared with serum medium, only Siha cells cultured with serum-free medium obtained higher transfection efficiency before transfection (P<0.01).MTT assay showed that according to the above conditions which has the lowest cytotoxicity. CONCLUSIONS: The method of Liposome to transfected is a suitable way and it can be an efficient reagent for miRNA delivery for Hela cells and Siha cells in vitro. It may serve as a reference for the further research or application. PMID- 26625793 TI - Survey of Her2-neu Expression and its Correlation with Histology of Gastric Carcinoma and Gastroesophageal Junction Adenocarcinoma. AB - BACKGROUND: There is increasing evidence that HER2-neu is an important biomarker in gastric carcinomas (GC) and gastroesophageal junction (GEJ) adenocarcinomas. The aim of this study was to evaluate HER2-neu expression and also some clinicopathological features of these neoplasms. MATERIALS AND METHODS: We selected 211 paraffin-embedded blocks, 193 GC and 18 GEJ. Then 4 micron sections were prepared for staining with hematoxylin and eosin and also for IHC (Her2 neu). The Chi-square test was used for significance between expression of HER2 neu and clinicopathological parameters. RESULTS: In patients with advanced cancer of GC and GEJ, HER2-neu overexpression was more associated with the intestinal cancer subtype. CONCLUSIONS: This could be a guide to new complementary therapy for affected patients. PMID- 26625794 TI - Leukemia in Iran: Epidemiology and Morphology Trends. AB - BACKGROUND: Leukemia accounts for 8% of total cancer cases and involves all age groups with different prevalence and incidence rates in Iran and the entire world and causes a significant death toll and heavy expenses for diagnosis and treatment processes. This study was done to evaluate epidemiology and morphology of blood cancer during 2003-2008. MATERIALS AND METHODS: This cross- sectional study was carried out based on re- analysis of the Cancer Registry Center report of the Health Deputy in Iran during a 6-year period (2003 - 2008). Statistical analysis for incidence time trends and morphology change percentage was performed with joinpoint regression analysis using the software Joinpoint Regression Program. RESULTS: During the studied years a total of 18,353 hematopoietic and reticuloendothelial system cancers were recorded. Chi square test showed significant difference between sex and morphological types of blood cancer (P value<0.001). Joinpoint analysis showed a significant increasing trend for the adjusted standard incidence rate (ASIR) for both sexes (P-value<0.05). Annual percent changes (APC) for women and men were 18.7 and 19.9, respectively. The most common morphological blood cancers were ALL, ALM, MM and CLL which accounted for 60% of total hematopoietic system cancers. Joinpoint analyze showed a significant decreasing trend for ALM in both sexes (P-value<0.05). CONCLUSIONS: Hematopoietic system cancers in Iran demonstrate an increasing trend for incidence rate and decreasing trend for ALL, ALM and CLL morphology. PMID- 26625795 TI - Wound Complications after Laparotomy for Endometrial Cancer. AB - This study was conducted to determine the incidence of wound complications after laparotomy for endometrial cancer and significant predictors of risks. Medical records of patients with endometrial cancer undergoing laparotomy for surgical staging at Srinagarind Hospital, Khon Kaen University between January 2007 and December 2013 were reviewed. Intravenous antibiotic prophylaxis was routinely given 30 minutes before surgery. The primary endpoint was wound complications (including seroma, hematoma, separation, or infection) requiring additional medical and/or surgical management within 4 weeks of laparotomy. During the study period, 357 patients with complete medical records were reviewed. The mean age was 56.9 years. Wound complications were observed in 28 patients (7.84%, 95% CI, 5.27% to 11.14%). Body mass index (BMI) >= 30 kg/m2, diabetes mellitus (DM), and prior abdominal surgery were observed as significant independent factors predicting an increased risk of wound complications with adjusted odds ratios (95% CIs) of 2.96 (1.23-7.16), 2.43 (1.06-5.54), and 3.05 (1.03-8.98), respectively. In conclusion, the incidence of wound complications after laparotomy for endometrial cancer was 7.8%. Significant independent predictors of risk included BMI, DM and prior abdominal surgery. PMID- 26625796 TI - Effect of Skin Cancer Training Provided to Maritime High School Students on Their Knowledge and Behaviour. AB - BACKGROUND: This study was conducted with the purpose of evaluating the effect of skin cancer training provided to maritime high school students on their knowledge and behaviour. MATERIALS AND METHODS: The study had a quasi-experimental design with pre-test and post-test intervention and control groups. Two maritime high schools located in the city of Antalya were included within the scope of the study between March and June 2013, covering a total of 567 students. RESULTS: While the knowledge mean scores of students regarding skin cancer and sun protection did not vary in the pre-test (6.2 +/- 1.9) and post-test (6.8 +/- 1.9) control group, the knowledge mean scores of students in the experimental group increased from 6.0 +/- 2.3 to 10.6 +/- 1.2 after the provided training. Some 25.4% of students in the experimental group had low knowledge level and 62.2% had medium knowledge level in the pre-test; whereas no students had low knowledge level and 94.3% had high knowledge level in the post-test. It was determined that tenth grade students, those who had previous knowledge on the subject, who considered themselves to be protecting from the sun better, had higher knowledge levels and their knowledge levels increased as the risk level increased. It was found that the provided training was effective and increased positively the knowledge, attitude and behaviour levels of students in the experimental group in terms of skin cancer and sun protection. CONCLUSIONS: Along with the provided training which started to form a lifestyle, appropriate attitudes and behaviours concerning skin cancer and sun protection could be brought to students who will work in outdoor spaces and are members of the maritime profession within the risk group. PMID- 26625797 TI - Correlation between Patterns of Mdm2 SNIP 309 and Histopathological Severity of Helicobacter pylori Associated Gastritis in Thailand. AB - BACKGROUND: The commonly held view of the tumor suppressor p53 is as a regulator of cell proliferation, apoptosis and many other biological processes as well as external and internal stress responses. Mdm2 SNIP309 is a negative regulator of p 53. Therefore, this study aimed to determine the correlation between the patterns of Mdm2 SNIP 309 and the inflammation grading of Helicobacter pylori associated gastritis in a Thai population. MATERIALS AND METHODS: A cross-sectional study was carried out from November 2014 through June 2015. Biopsy specimens were obtained from infected patients and infection was proved by positive histology. The gastric mucosa specimens were sent to the Molecular Genetic Unit, Institute of Medicine, Suranaree University of Technology where they were tested by molecular methods to detect the patterns of Mdm2 SNIP 309 using the real-time PCR hybridization probe method. The results were analyzed and compared with the Updated Sydney classification. RESULTS: A total of 100 infected patients were interviewed and gastric mucosa specimens were collected. In this study the percentage of Mdm2 SNIP 309 T/T homozygous and Mdm2 SNIP309 G/T heterozygous was 78% and 19 % respectively whereas Mdm2 SNIP309 G/G homozygous was 3%. Mdm2 SNIP 309 T/T homozygous and Mdm2 SNIP309 G/T heterozygous correlated with mild to moderate inflammation (P<0.01) whereas Mdm2 SNIP309 G/G homozygous correlated with severe inflammation (P<0.01). CONCLUSIONS: Our study found the frequency of Mdm2 SNP309 G/G in our Thai population to be very low, and suggests that this can explain to some extent the low incidence of severe inflammation and gastric cancer changes in the Thai population. Mild to moderate inflammation are the most common pathologic gradings due to the unique genetic polymorphism of Mdm2 SNIP 309 in the Thai population. PMID- 26625798 TI - Breast Radiotherapy with Mixed Energy Photons; a Model for Optimal Beam Weighting. AB - Utilization of high energy photons (>10 MV) with an optimal weight using a mixed energy technique is a practical way to generate a homogenous dose distribution while maintaining adequate target coverage in intact breast radiotherapy. This study represents a model for estimation of this optimal weight for day to day clinical usage. For this purpose, treatment planning computed tomography scans of thirty-three consecutive early stage breast cancer patients following breast conservation surgery were analyzed. After delineation of the breast clinical target volume (CTV) and placing opposed wedge paired isocenteric tangential portals, dosimeteric calculations were conducted and dose volume histograms (DVHs) were generated, first with pure 6 MV photons and then these calculations were repeated ten times with incorporating 18 MV photons (ten percent increase in weight per step) in each individual patient. For each calculation two indexes including maximum dose in the breast CTV (Dmax) and the volume of CTV which covered with 95% Isodose line (VCTV, 95%IDL) were measured according to the DVH data and then normalized values were plotted in a graph. The optimal weight of 18 MV photons was defined as the intersection point of Dmax and VCTV, 95%IDL graphs. For creating a model to predict this optimal weight multiple linear regression analysis was used based on some of the breast and tangential field parameters. The best fitting model for prediction of 18 MV photons optimal weight in breast radiotherapy using mixed energy technique, incorporated chest wall separation plus central lung distance (Adjusted R2=0.776). In conclusion, this study represents a model for the estimation of optimal beam weighting in breast radiotherapy using mixed photon energy technique for routine day to day clinical usage. PMID- 26625799 TI - Community-Based Health Education and Communication Model Development for Opisthorchiasis Prevention in a High Risk Area, Khon Kaen Province, Thailand. AB - BACKGROUND: This study aimed to evaluate the impact of a community-based health education and communication programme on reducing liver fluke infections caused by the consumption of uncooked fish among people in a high-risk area of Thailand. MATERIALS AND METHODS: The study was quasi-experimental in nature, with three stages. Stage 1 involved a situational and capacity analysis of designated communities in Khon Kaen province. This was followed by the development of a model for community-based health education and communication to prevent liver fluke infections among high-risk people, and, lastly, implementation and evaluation of the model were performed. Data were collected using both qualitative and quantitative methods. In total, 390 people were surveyed, and quasi-experimental and comparison groups, each with 90 people, were assessed between May 2011 and April 2012. Analysis was using statistical OR, 95 % CI, the Willcoxon matched pairs signed ranks test, the chi-square test, and the Mann Whitney U test. RESULTS: The findings showed that most respondents had a high level of knowledge and understanding of liver fluke disease (89.5%, 95% CI:86.0 92.4), and positive attitudes toward the prevention of the disease (94.4%, 95% CI:91.6-96.4). However, with regard to changes in consumption of uncooked fish, most respondents were still in the pre-contemplation phase (55.1%, 95% CI:50.0 60.1), followed by the contemplation phase, 22.6%. Furthermore, four factors were found to be associated with the consumption of uncooked fish--the consumption of alcohol (OR 4.16, 95% CI:1.79-9.65), gender (OR 3.17 , 95% CI:1.53-6.54), smoking (OR 3.03, 95% CI:1.31-7.05), and age 40 years and above (OR 2.68, 95% CI:1.02 7.05). After nine months of the health education and communication programme using local media based on local wisdom, culture and persons, the results showed that, compared to the control group, members of the experimental group had a higher level of knowledge, a better attitude and lower levels of ill- advised consumption behaviour. Also, it was found that consumption of uncooked fish, by an assessment of the level of stage of change, was reduced. (p-value 0.002). CONCLUSIONS: The health education and communication programme developed as part of the study was effective in changing the consumption of uncooked fish. Therefore, this approach should be promoted in other high-risk areas in Thailand in the future. PMID- 26625800 TI - Determination of Initial Beam Parameters of Varian 2100 CD Linac for Various Therapeutic Electrons Using PRIMO. AB - The aim of the present research was to establish primary characteristics of electron beams for a Varian 2100C/D linear accelerator with recently developed PRIMO Monte Carlo software and to verify relations between electron energy and dose distribution. To maintain conformity of simulated and measured dose curves within 1%/1mm, mean energy, Full Width at Half Maximum (FWHM) of energy and focal spot FWHM of initial beam were changed iteratively. Mean and most probable energies were extracted from validated phase spaces and compared with related empirical equation results. To explain the importance of correct estimation of primary energy on a clinical case, computed tomography images of a thorax phantom were imported in PRIMO. Dose distributions and dose volume histogram (DVH) curves were compared between validated and artificial cases with overestimated energy. Initial mean energies were obtained of 6.68, 9.73, 13.2 and 16.4 MeV for 6, 9, 12 and 15 nominal energies, respectively. Energy FWHM reduced with increase in energy. Three mm focal spot FWHM for 9 MeV and 4 mm for other energies made proper matches of simulated and measured profiles. In addition, the maximum difference of calculated mean electrons energy at the phantom surface with empirical equation was 2.2 percent. Finally, clear differences in DVH curves of validated and artificial energy were observed as heterogeneity indexes were 0.15 for 7.21 MeV and 0.25 for 6.68 MeV. The Monte Carlo model presented in PRIMO for Varian 2100 CD was precisely validated. IAEA polynomial equations estimated mean energy more accurately than a known linear one. Small displacement of R50 changed DVH curves and homogeneity indexes. PRIMO is a user-friendly software which has suitable capabilities to calculate dose distribution in water phantoms or computerized tomographic volumes accurately. PMID- 26625801 TI - The Carcinogenic Liver Fluke Opisthorchis viverrini among Rural Community People in Northeast Thailand: a Cross- Sectional Descriptive Study using Multistage Sampling Technique. AB - Opisthorchis viverrini infection is a serious public health problem in Southeast Asia especially in the northeast and north of Thailand. Therefore, a cross sectional survey using multistage sampling was conducted from the rural communities of Surin province, Thailand, during September 2013 to July 2014. O. viverrini infection was determined using Kato's thick smear technique. Socio demographic, information resources, and history data were collected using predesigned semi-structured questionnaires. A total of 510 participants completed interviews and had stools collected. Some 32 (6.47%) participants were infected with O. viverrini. The rate was slightly higher in males (6.61%) than females (6.32%). High frequencies were found in the age groups 61-70 (19.4%) and 71-80 years (19.4%), those involved in agriculture (10.5%), and in primary school (10.3%). The distribution of high infection was found in Tha Tum (16.7%) and Sankha district (16.7%), followed by Samrong Thap (13.3%), Si Narong (13.33%), and Buachet district (13.33%). Chi-square testing indicated that age (61-70 and 71-80 year old), education (primary school) and occupation (agriculture), were significantly associated with O. viverrini infection (p-value<0.05). Of 72.6% participants who had past histories with stool examination, 17.0% of them had been infected with O. viverrini and 43.2% treated with praziquantel. This finding confirmed that O. viverrini is still a problem in Surin province, Thailand, and therefore, interventions are urgently required for mass treatment and health education implementation. PMID- 26625802 TI - Postoperative Serum CEA Level is a More Significant Prognostic Factor than Post/Preoperative Serum CEA Ratio in Non-small Cell Cancer Patients. AB - BACKGROUND: In non-small cell lung cancer (NSCLC) patients with preoperative high serum carcinoembryonic antigen (CEA) level, patients with a persistently high serum CEA level after surgery have been reported to have a poor prognosis. In addition, in other cancers, the post/preoperative serum CEA ratio has been reported as a useful parameter. MATERIALS AND METHODS: We enrolled 123 NSCLC patients with preoperative high CEA levels (>= 5 ng/mL) who underwent curative surgery between 2004 and 2011. Prognostic significance of postoperative serum CEA level and the CEA ratio was examined. RESULTS: The 5-year survival of patients with persistently high serum CEA level after surgery was poor. On the other hand, patients with normal postoperative serum CEA levels had significant favorable prognosis. The patients with CEA ratio>1 had poor prognosis, however the number was only 7 (5.7%). The 5-year survival rates of patients with other subgroup based on the CEA ratio (0.5 >= CEA ratio and 0.5 <= CEA ratio <= 1) was similar. Multivariate analysis revealed prognostic significance for the postoperative serum CEA level but not the CEA ratio. CONCLUSIONS: For NSCLC patients with preoperative high serum CEA level, their postoperative serum CEA levels is a more significant prognostic factor than the post/preoperative serum CEA ratio. PMID- 26625803 TI - Lack of Prognostic Impact of Adjuvant Radiation on Oncologic Outcomes in Elderly Women with Breast Cancer. AB - BACKGROUND: Radiotherapy plays an important role as adjuvant treatment in locally advanced breast cancer and in those patients who have undergone breast-conserving surgery. This study aimed to investigate the prognostic impact of adjuvant radiation on oncologic outcomes in elderly women with breast cancer. MATERIALS AND METHODS: In this retrospective study, we reviewed and analyzed the characteristics, treatment outcome and survival of elderly women (aged >= 60 years) with breast cancer who were treated and followed-up between 1993 and 2014. The median follow up for the surviving patients was 38 (range 3-207) months. RESULTS: One hundred and seventy-eight patients with a median age of 74 (range 60 95) years were enrolled in the study. Of the total, 60 patients received postoperative adjuvant radiation (radiation group) and the remaining 118 did not (control group). Patients in the radiation group were significantly younger than those in the control group (P value=0.004). In addition, patients in radiation group had higher node stage (P value<0.001) and disease stage (P=0.003) and tended to have higher tumor grade (P=0.031) and received more frequent (P value <0.001) adjuvant and neoadjuvant chemotherapy compared to those in the control group. There was no statistically significant difference between two groups regarding the local control, disease-free survival and overall survival rates. CONCLUSIONS: In this study, we did not find a prognostic impact for adjuvant radiation on oncologic outcomes in elderly women with breast cancer. PMID- 26625804 TI - Molecular Profiling of Breast Carcinoma in Almadinah, KSA: Immunophenotyping and Clinicopathological Correlation. AB - PURPOSE: To subtype breast cancer (BC) in Saudi women according to the recent molecular classification and to correlate these subtypes with available clinicopathological parameters. MATERIALS AND METHODS: Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (Her2/neu) immunostaining was semi-quantitatively assessed to define molecular subtypes of luminal A and B, HER-2 and triple negative (basal- like) in BC paraffin embedded sections from 115 Saudi female patients diagnosed between 2005 to 2015 at the Department of Pathology, King Fahd Hospital, Almadinah, Saudi Arabia. RESULTS: The most common subtypes were luminal A (47%), followed by luminal B (27.8%) and basal like subtypes (18.3%), whereas HER-2 was the least common subtype (6.9%). Luminal A was predominantly found in the old age group, with low tumor grade (p< 0.001) and small tumor size, whereas HER-2 and basal-like subtypes were significantly associated with young age, high tumor grade, lymph node metastasis and lymphovascular invasion (p< 0.03, 0.004, 0.05 and 0.04 respectively). All subtypes showed advanced clinical stage at the time of presentation. CONCLUSIONS: Molecular subtypes of Saudi BC patients in Almadinah region are consistent with most of the worldwide subtyping. The biological behaviour of each molecular subtype could be expected based on its characteristic clinicopathological features. Along with other prognostic indicators, molecular subtyping would be helpful in predicting prognosis and management of our BC patients. We recommend screening and early diagnosis of BC in our population. PMID- 26625805 TI - Serum Beta-2 Microglobulin: a Possible Marker for Disease Progression in Egyptian Patients with Chronic HCV Related Liver Diseases. AB - BACKGROUND: Egypt has the highest prevalence of HCV infection in the world (~14.7%). Around 10-15% of HCV-infected persons will advance to cirrhosis within the first 20 years. The incidence of HCC is expected to grow in the next two decades, largely due to HCV related cirrhosis, and detection of HCC at an early stage is critical for a favorable clinical outcome. No simple reliable non invasive marker has been available till now. B2M, a non-glycosylated polypeptide composed of 99 amino acids, is one of the components of HLA class I molecules on the surfaces of all nucleated cells. It has been reported that the level of serum B2M is elevated in patients with chronic hepatitis C and HCV-related HCC when compared to HCV-negative patients or healthy donors. Determining the clinical utility of serum beta2M as a marker for disease progression in Egyptian patients with HCV related chronic hepatitis, cirrhosis and hepatocellular carcinoma was the aim of the present study. MATERIALS AND METHODS: In this analytical cross sectional study 92 participants were included in 4 equal groups: Group (1) non cirrhotic chronic HCV; Group (2) HCV related liver cirrhosis; Group (3) HCC on top of HCV,; and Group (4) healthy controls. History taking, clinical examination, routine labs and abdominal ultrasound were conducted for all patients, PCR and Metavir scores for group (1) patients, and triphasic CT abdomen and AFP for Group (3) patients. beta2M levels were measured in serum with a fully automated IMX system. RESULTS: The mean serum B2M level of Group (1) was 4.25 +/- 1.48 MUg/ml., Group (2) was 7.48 +/- 3.04, Group (3) was 6.62 +/- 2.49 and Group (4) was 1.62 +/- 0.63. Serum B2M levels were significantly higher in diseased than control group (p<0.01) being significantly higher in cirrhosis (7.48 +/- 3.04) and HCC groups (6.62 +/- 2.49) than the HCV group (4.25 +/- 1.48) (p<0.01). There was a significant correlation between B2M Level and ALK, total and direct bilirubin and INR (p<0.05), and a significant inverse correlation between B2M level and albumin, total proteins, HB and WBCS values (p<0.05). There was no significant correlation between B2M level and viral load or Metavir score, largest tumour size or AFP (p>0.05). The best B2M cut-off for HCV diagnosis was 2.6 with a sensitivity of 100%, a specificity of 92%, a positive predictive value (PPV) of 97% and a negative predictive value (NPV) of 100%. The best B2M cut-off for HCC diagnosis was 4.55 which yielded sensitivity, specificity, positive predictive value, negative predictive values of 74%, 62%, 39.5, 87.8% respectively (p-value <0.01) while best cut-off for cirrhosis was 4.9, with sensitivity 74 % and specificity 74%. The sensitivity for HCC diagnosis increased upon B2M and AFP combined estimation to 91%, specificity to 79%, NPV to 95% and accuracy to 83%. CONCLUSIONS: Serum B2M level is elevated in HCV related chronic liver diseases and may be used as a marker for HCV disease progression towards cirrhosis and carcinoma. PMID- 26625806 TI - Knowledge about Colorectal Cancer in Northern Iran: a Population-Based Telephone Survey. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies of the gastrointestinal tract. The aim of this study was to assess the general knowledge of CRC in individuals living in Rasht, Iran, using a population-based cross sectional telephone survey. MATERIALS AND METHODS: A total of 1557 participants between 18 and 80 years of age were interviewed using random sampling from the telephone directory. Knowledge of risk factors, symptoms, diagnosis, and prevention of CRC was assessed using a validated questionnaire. RESULTS: The mean knowledge level of the 1,557 respondents (average age 46 y) was 13.5 +/- 4.29 (maximum possible score = 26), and 46.4% (722/1,557) of the subjects achieved grades lower than the mean score. The mean scores for knowledge of symptoms and risk factors were 3.97 +/- 1.83 (range: 0-7) and 5.17 +/- 1.65 (range: 0-9), respectively. Older age, higher education, and employment were significantly associated with better scores for recognition of risk factors and warning symptoms. The majority of subjects correctly identified weight loss (70.2%; 1,093/1,557) and rectal bleeding (63.3%; 986/1,557) as symptoms of CRC, and that smoking (85.9%; 1,337/1,557) and a low- fiber diet (73.4%; 1,143/1,557) were risk factors. Approximately half of the subjects noted increasing age, genetic background and fried food as other risk factors. A considerable number (54.8%; 853/1,557) identified colonoscopy as a screening method for detecting CRC in asymptomatic patients. However, a third of the subjects in the target group for screening (>= 50 y) were not interested in undergoing screening, primarily due to a lack of symptoms. CONCLUSIONS: Our results suggest that the knowledge of CRC is poor among the public, and therefore greater attempts should be made to increase awareness. Public education emphasizing the risk factors and symptoms of CRC, as well as the importance of regular screening regardless of the presence of symptoms, may help to reduce CRC morbidity and mortality. PMID- 26625807 TI - Safety of Lienal Polypeptide Injection Combined with Chemotherapy in Treating Patients with Advanced Cancer. AB - OBJECTIVE: To assess the safety of Liena polypeptide injection (produced by JILIN FSENS PHARMACEUTICAL CO.,LTD) combined with chemotherapy in treating patients with advanced cancers. METHOD: A consecutive cohort of patients with advanced cancers were treated with Liena polypeptide injection combined with chemotherapy. And chemotherapy for patients with advanced cancers were adopted from regimens suggested by NCCN guideline. Liena polypeptide injection was intravenously injected at a dosage of 2 ml plus 100ml normal saline for continuous 7 days during chemotherapy as one course. After at least two courses of treatment, safety and side effects were evaluated. RESULTS: There were 20 female and 14 male patients with advanced cancer recruited into this study, including 10 patients with breast, 8 patients with colorectal, 8 patients with lung, 4 patients with gastric, and 1 patient with esophageal cancer, as well as 1 patient with non Hodgkin's lymphoma, 1 patient with low pharyngeal and 1 patient with urethral cancer. The median age of patients was 59 (40-82) years. Incidences of Grade 1 to 2 myelosuppression was observed in 5/34 patients, and Grade 1 to 2 elevation of hepatic enzyme was recorded in 3/34 patients. Adverse effects on the gastrointestinal tract were documented in 5/34 patients, and were Grade 1. No Grade 3-4 toxicities were diagnosed. No treatment related death was found. CONCLUSIONS: Liena polypeptide injection combined with chemotherapy was safe in treating several sites of tumors, that mainly included lung, colorectal and breast cancer. However, further study should be conducted to clarify the effectiveness of this treatment. PMID- 26625808 TI - Protein Expression of Stromelysin-2 in Head and Neck Squamous Cell Carcinomas. AB - BACKGROUND: Some matrix metalloproteinases (MMPs) are involved in invasion and metastasis of head and neck squamous cell carcinoma (HNSCC). However, there are few studies on association between stromelysin-2 (ST-2) and invasive behavior of HNSCC. The purpose of this study was to investigate Stromelysin-2 expression by immunohistochemistry. MATERIALS AND METHODS: This study was conducted on 81 specimens, including 61 HNSCC and 20 non neoplastic epithelium. Sections with 5 micron thickness were prepared and stained with immunohistochemistry technique. Then expression of ST-2 was evaluated according to percentage of stained cells and intensity of staining. Data were analyzed by SPSS (V.21) using Kruskal-Wallis and Tukey tests (P<0.05). RESULTS: The 61 HNSCC specimens were grades I 36.1%, II 34.4% and III 29.5%. The level of ST-2 expressions were moderate (++) and intensive (+++) in 21.3% and 78.7% of tumors, respectively. The ST-2 expression level was only significant between the tumors with grade I and grade III (P=0.016). Tumors presented ST-2 expression with staining intensity of mild 6.6%, moderate 26.2% and strong 67.2%. Staining intensity of ST-2 in grade I tumors was significantly lower than grade II and grade III (P<0.05), and there was no significant difference between grades II and III (P=0.99). CONCLUSIONS: According to this study, the expression of ST-2 is associated with histopathological grade and tumor differentiation in HNSCCs. PMID- 26625809 TI - Use of Complementary and Alternative Medicine in Patients with Gynecologic Cancer: a Systematic Review. AB - PURPOSE: Research carried out with gynecologic cancer patients using CAM was reviewed to provide a source for discussing which CAM method is used for which purpose, patients' perceptions on the effects/side effects occurred during/after using CAM and their sources of information regarding CAM. MATERIALS AND METHODS: This literature review was carried out for the period between January 2000 and March 2015 using Scopus, Dynamed, Med-Line, Science Direct, Ulakbim, Research Starters, Ebscohost, Cinahl Complete, Academic Onefile, Directory of Open Access Journals, BMJ Online Journals (2007-2009), Ovid, Oxford Journal, Proquest Hospital Collection, Springer-Kluwer Link, Taylor and Francis, Up To Date, Web Of Science (Citation Index), Wiley Cochrane-Evidence Base, Wiley Online Library, and Pub-Med search databases with "complementary and alternative medicine, gynecologic cancer" as keywords. After searching through these results, a total of 12 full length papers in English were included. RESULTS: CAM use in gynecologic cancer patients was discussed in 8 studies and CAM use in breast and gynecologic cancer patients in 4. It was determined that the frequency of CAM use varies between 40.3% and 94.7%. As the CAM method, herbal medicines, vitamins/minerals were used most frequently in 8 of the studies. When the reasons why gynecologic cancer patients use CAM are examined, it is determined that they generally use to strengthen the immune system, reduce the side effects of cancer treatment and for physical and psychological relaxation. In this review, most of the gynecologic cancer patients perceived use of CAM as beneficial. CONCLUSIONS: In order that the patients obtain adequate reliable information about CAM and avoid practices which may harm the efficiency of medical treatment, it is recommended that "Healthcare Professionals" develop a common language. PMID- 26625810 TI - Feasibility Study of Case-Finding for Breast Cancer by Community Health Workers in Rural Bangladesh. AB - BACKGROUND: Mortality from breast cancer is high in low- and middle-income countries, in part because most patients have advanced stage disease when first diagnosed. Case-finding may be one approach to changing this situation. MATERIALS AND METHODS: We conducted a pilot study to explore the feasibility of population based case finding for breast cancer by community health workers (CHWs) using different data collection methods and approaches to management of women found to have breast abnormalities. After training 8 CHWs in breast problem recognition, manual paper data collection and operation of a cell-phone software platform for reporting demographic, history and physical finding information, these CHWs visited 3150 women >age 18 and over they could find--from 2356 households in 8 villages in rural Bangladesh. By 4 random assignments of villages, data were collected manually (Group 1), or with the cell-phone program alone (Group 2) or with management algorithms (Groups 3 and 4), and women adjudged to have a serious breast problem were shown a motivational video (Group 3), or navigated/accompanied to a breast problem center for evaluation (Group 4). RESULTS: Only three visited women refused evaluation. The manual data acquisition group (1) had missing data in 80% of cases, and took an average of 5 minutes longer to acquire, versus no missing data in the cell phone-reporting groups (2,3 and 4). One woman was identified with stage III breast cancer, and was appropriately treated. CONCLUSIONS: Among very poor rural Bangladeshi women, there was very limited reluctance to undergo breast evaluation. The estimated rarity of clinical breast cancer is supported by these population-based findings. The feasibility and efficient use of mobile technology in this setting is supported. Successor studies may most appropriately be trials focusing on improving the suggested benefits of motivation and navigation, on increasing the numbers of cases found, and on stage of disease at diagnosis as the primary endpoint. PMID- 26625811 TI - Comparison of Single Agent Gemcitabine and Docetaxel in Second-Line Therapy for Advanced Stage Non-Small Cell Lung Cancer in a University Hospital in Turkey. AB - PURPOSE: To compare the efficacy and toxicity of gemcitabine versus docetaxel in a second-line setting of nonsmall cell lung cancer (NSCLC) patients previously treated with platin-based combination chemotherapy. MATERIALS AND METHODS: We retrospectively evaluated the medical records of 57 patients treated with single agent gemcitabine or docetaxel in second-line setting of advanced NSCLC who received one prior platinum-based therapy. RESULTS: The mean age was 56.7 +/- 8.39 years with 55 ( 96.5%) males and two (3.5%) females. Forty of them received docetaxel and 17 gemcitabine. The mean number of chemotherapy cycles was 6.8 +/- 4.0 in the gemcitabine group, while it was 4.6 +/- 3.0 in the docetaxel group. Overall response rates were 8% and 12% (P=0.02) for gemcitabine and docetaxel, respectively. The median survival time was 22 versus 21 months for gemcitabine and docetaxel, respectively. The median times to progression were 8 and 5 months. There was no difference between the two groups in terms of incidence of adverse affects (40% vs 47.1%). All of the hematological side effects were grade 1/2. No major toxicity was encountered necessitating stopping the drug for either group. CONCLUSIONS: Treatment with gemcitabine demonstrated clinically equivalent efficacy with a significantly improved safety profile compared with those receiving docetaxel in the second-line setting for advanced NSCLC in this study. Based on these results, treatment with gemcitabine should be considered a standard treatment option for second-line NSCLC. PMID- 26625812 TI - Thalidomide Combined with Chemotherapy in Treating Patients with Advanced Colorectal Cancer. AB - OBJECTIVE: To assess the safety and effectiveness of thalidomide (produced by CHANGZHOU PHARMACEUTICAL FACTORY CO.LTD) combined with chemotherapy in treating patients with advanced colorectal cancer. METHOD: A consecutive cohort of pretreated patients with advanced colorectal cancer were treated with thalidomide combined with chemotherapy. And chemotherapy for patients with advanced colorectal cancer were administered according to the condition of patients. Thalidomide was orally administered at a dosage of 50mg/day to 150 mg/day before sleeping for at least 14 days. After at least 14 days of treatment, safety and side effects were evaluated. RESULTS: There were 12 female and 3 male patients with advanced cancer recruited into this study, including 9 patients with colon, 6 patients with rectal cancer. The median age of patients was 57(41- 82) years. Partial response was observed in 2 patients (2/15), and stable disease in 3 patients(3/15). Incidences of Grade 1 to 2 myelosuppression was observed in 1/15 patients, and Grade 1 to 2 elevation of hepatic enzyme was recorded in 1/15 patients. Adverse effects on the gastrointestinal tract were documented in 1/15 patients, and were Grade 1. No Grade 3-4 toxicities were diagnosed. No treatment related death was found. CONCLUSIONS: Thalidomide combined with chemotherapy was safe and mildly effective in treating patients with advanced colorectal cancer. However, further study should be conducted to clarify the effectiveness of this combination. PMID- 26625813 TI - Hepatic Resection after Initial Transarterial Chemoembolization Versus Transarterial Chemoembolization Alone for the Treatment of Hepatocellular Carcinoma: A Meta-analysis of Observational Studies. AB - BACKGROUND: There is no consensus regarding the selection of treatment options for hepatocellular carcinoma (HCC) after initial transarterial chemoembolization (TACE). This meta-analysis aimed to explore the survival benefit of hepatic resection after initial TACE for the treatment of HCC. MATERIALS AND METHODS: We searched three major databases to identify all relevant papers comparing the outcomes of hepatic resection after initial TACE versus TACE alone for the treatment of HCC. Hazard ratios (HRs) with 95% confidence intervals (95%CIs) were calculated to evaluate the survival benefit of hepatic resection after initial TACE over TACE alone. RESULTS: Three of 2,037 initially identified papers were included. All of them were cohort studies from Asia. There was a significantly better overall survival (OS) in patients undergoing hepatic resection after initial TACE than in those undergoing TACE alone (HR=0.63, 95%CI=0.52-0.76, P<0.00001). The heterogeneity among studies was not statistically significant (P=0.96; I2=0%). CONCLUSIONS: Hepatic resection could improve the OS of HCC patients treated initial TACE. Further randomized controlled trials are now necessary to identify the target populations for the sequential use of hepatic resection after initial TACE and to compare the outcomes between patients undergoing hepatic resection after initial TACE session versus those undergoing TACE alone. PMID- 26625814 TI - Relation of BAALC and ERG Gene Expression with Overall Survival in Acute Myeloid Leukemia Cases. AB - BACKGROUND: The objectives of this study were to evaluate the expression of brain and acute leukemia, cytoplasmic (BAALC) gene and erythroblast transformation specific related gene (ERG) in de novo cases of acute myeloid leukemia (AML) and identify roles in disease progression and outcome. MATERIALS AND METHODS: This study included 50 newly diagnosed AML patients, along with 10 apparently healthy normal controls. BAALC and ERG expression was detected in the bone marrow of both patients and controls using real-time RT-PCR. RESULTS: BAALC and ERG expression was detected in 52% of cases but not in any controls. There was a statistically significant correlation between BAALC and ERG gene expression and age (p- value=0.004 and 0.019, respectively). No statistical significance was noted for sex, lymphadenopathy, hepatomegaly, splenomegaly, other hematological findings, immunophenotyping and FAB sub-classification except for ERG gene and FAB (p value=0.058). A statistical significant correlation was found between response to treatment with ERG expression (p-value=0.028) and age (p-value=0.014). A statistically significant variation in overall survival was evident with patient age, BM blast cells, FAB subgroups, BAALC and ERG expression (p-value= <0.001, 0.045, 0.041, <0.008 and 0.025 respectively). CONCLUSIONS: Our results suggest that BAALC and ERG genes are specific significant molecular markers in AML disease progression, response to treatment and survival. PMID- 26625815 TI - Presence of Human Papillomavirus DNA in Colorectal Cancer Tissues in Shiraz, Southwest Iran. AB - BACKGROUND: Colorectal cancer is one of the most common cancers worldwide. Viruses including human papillomavirus (HPV) have been reported to be associated with different cancers but any association with colorectal cancers remains controversial. AIM: To evaluate any association between HPV infection and adenocarcinoma of the colon and adenomatous polyps. MATERIALS AND METHODS: Paraffin-embedded tissue specimens of 70 colorectal adenocarcinomas, 70 colorectal adenomatous polyps, and 70 colorectal normal tissues were subjected to DNA extraction. The quality of the extracted DNA was confirmed by amplification of a beta-globin fragment using polymerase chain reaction (PCR). PCR using specific primers were performed to detect HPV DNA. Specific primers targeting the E6 region of the HPVs 16 and 18 were used for genotyping. RESULTS: HPV DNA was detected in 2 (2.85%) out of 70 adenocarcinoma colorectal tissues and 4 (5.71%) out of 70 adenomatous colorectal tissues. All normal colorectal tissues were negative for HPV DNA. HPV-16 was the most predominant genotype (5 sample) followed by HPV-18 (4 sample). Despite the above observations, statistical analyses indicated no significant differences in the frequencies of HPV positive subjects between the cancerous and normal samples. CONCLUSIONS: Although the differences observed in the frequencies of HPV positive cases in our study was not significant relative to those of control subjects, the fact of 6 positive samples among cancerous tissues, may still suggest a role of HPV in colorectal carcinogenesis. The study collectively indicated that some colorectal cancerous tissues are infected with high risk HPV genotype. The findings merit more investigation. PMID- 26625816 TI - JAK-2 V617F Mutational Analysis in Primary Idiopathic Myelofibrosis: Experience from Southern Pakistan. AB - BACKGROUND: Primary idiopathic myelofibrosis (PMF) is a clonal Ph-chromosome negative myeloproliferative neoplasm characterized by dysregulated kinase signaling and release of abnormal cytokines. In the recent past, following JAK2 V617F mutation invention, important revolution has been made in the molecular diagnostic biology of this disease. The rational of this study was to determine the mutational status of JAK2 V617F in Pakistan patients with PMF. MATERIALS AND METHODS: In this cross sectional study, 20 patients with PMF were enrolled from January 2011 to December 2014. Diagnosis was based on WHO criteria for PMF. All patients were screened for G-T point mutation (V617F) in the JAK2 gene on chromosome 9 by allele specific PCR. RESULTS: The mean age was 57.9 +/- 16.5 years. The male to female ratio was 3:1. The frequency of JAK2 V617F positivity in our PMF patients was found to be 55%. Positive correlations of JAK2 V617F mutation were established with high TLC count, raised LDH and marked splenomegaly (P<0.05). No correlation of JAK2 V617F could be established with age and gender (P>0.05). CONCLUSIONS: The JAK2 V617F mutation frequency in our PMF patients was similar to those reported previously. In our hands JAK2 V617F mutated patients expressed an aggressive disease phenotype. Screening for the mutation in all suspected PMF cases could be beneficial in differentiating patients with reactive and clonal marrow fibrosis. PMID- 26625817 TI - Acute Promyelocytic Leukemia: a Single Center Study from Southern Pakistan. AB - BACKGROUND: Acute promyelocytic leukemia (APL) is a distinctive clinical, biological and molecular subtype of acute myeloid leukemia. However, data from Pakistan are scarce. Therefore we reviewed the demographic and clinical profile along with risk stratification of APL patients at our center. MATERIALS AND METHODS: In this descriptive cross sectional study, 26 patients with acute promyelocytic leukemia were enrolled from January 2011 to June 2015. Data were analyzed with SPSS version 22. RESULTS: The mean age was 31.8 +/- 1.68 years with a median of 32 years. The female to male ratio was 2:1.2. The majority of our patients had hypergranular variant (65.4%) rather than the microgranular type. The major complaints were bleeding (80.7%), fever (76.9%), generalized weakness (30.7%) and dyspnea (15.38%). Physical examination revealed petechial rashes as a predominant finding detected in 61.5% followed by pallor in 30.8%. The mean hemoglobin was 8.04 +/- 2.29 g/dl with the mean MCV of 84.7 +/- 7.72 fl. The mean total leukocyte count of 5.44 +/- 7.62 x 10(9)/l; ANC of 1.08 +/- 2.98 x 10(9)/l and mean platelets count were 38.84 +/- 5.38 x 10(9)/l. According to risk stratification, 15.3% were in high, 65.4% in intermediate and 19.2% in low risk groups. CONCLUSIONS: Clinico-epidemiological features of APL in Pakistani patients appear comparable to published data. Haemorrhagic diathesis is the commonest presentation. Risk stratification revealed predominance of intermediate risk disease. PMID- 26625818 TI - 3D CACT-assisted Radiofrequency Ablation Following Transarterial Chemoembolization for Hepatocellular Carcinoma: Early Experience. AB - BACKGROUND: To explored the value of 3D C-arm CT (CACT) guidance system in performing radiofrequency ablation (RFA) following transarterial chemoembolizationon (TACE) for hepatocellular carcinomas. MATERIALS AND METHODS: RFA of hepatocellular carcinomas (HCC) were performed on 15 patients (21 lesions) with the assistance of CACT guidance system. Technical success, procedure time, complications and patient radiation exposure were investigated. The puncture performance level was evaluated on a five-point scale (5-1: excellent- poor). Complete ablation rate was evaluated after two months follow-up using enhanced CT scans. RESULTS: The technical success rate of RFA procedure under CACT navigation system was 100%. Mean total procedure time was 24.24 +/- 6.53 min, resulting in a mean effective exposure dose of 15.4 +/- 5.1 mSv. The mean puncture performance level rated for CACT guided RFA procedure was 4.87 +/- 0.35. Complete ablation (CA) was achieved in 20 (95.2%) of the treated 21 tumors after the first RFA session. None of patients developed intra-procedural complications. CONCLUSIONS: 3D CACT guidance system enables reliable and efficient needle positioning by providing real-time intraoperative guidance for performing RFA on HCCs. PMID- 26625819 TI - MicroRNA-124 rs531564 Polymorphism and Cancer Risk: A Meta-analysis. AB - Several studies reported there was a polymorphism (rs531564 C > G) in miR-124 gene. To investigate the MiR-124 rs531564 polymorphism and cancer risk. We conducted a literature search of the Medline, Embase and Wangfang Medicine databases to identify all relevant studies for this meta-analysis. We determined that the miR-124 rs531564 polymorphism was significantly associated with decreased risks of cancers in the allelic model (G vs C, OR=0.71, 95% CI=0.53 0.94, P=0.02), homozygote model (GG vs CC, OR=0.42, 95% CI=0.26-0.66, P=0.0002), dominant model (GG/GC vs CC, OR=0.71, 95% CI=0.51-0.98, P=0.04) and recessive model (GG vs GC/CC, OR=0.43, 95% CI=0.27-0.69, P=0.0004). In an analysis stratified by cervical cancer group, significant associations were observed in the allelic model (G vs C, OR=0.46, 95% CI=0.32-0.66, P<0.0001), and dominant model (GG/GC vs CC, OR=0.45, 95% CI=0.3-0.66, P<0.0001). Subgroup analysis also revealed a decreased risk for esophageal squamous cell carcinoma in the homozygote model (GG vs CC, OR=0.45, 95% CI=0.27-0.75, P=0.002) and recessive model (GG vs GC/CC, OR=0.46, 95% CI=0.28-0.75, P=0.002). This meta-analysis suggests that the miR-124 rs531564 C > G polymorphism is an important risk factor for cancers among the Chinese population. PMID- 26625820 TI - Helicobacter pylori Infection and Gastric Mucosal Atrophy in Two Ethnic Groups in Nepal. AB - Serum anti-Helicobacter pylori antibodies and pepsinogens (PGs) have been used as gastric cancer screening and gastric mucosal status markers. Nepal is a low risk country for gastric cancer. However, the mountainous populace in the northern region culturally linked to Tibet as well as Bhutan, a neighboring country, have a high risk of GC. We collected gastric biopsy specimens and sera from 146 dyspeptic patients living in Kathmandu, Nepal. We also examined the sera of 80 volunteers living in the mountainous regions of the Himalayas. The optimal cut off was calculated for serum biomarkers against the histology. Kathmandu patients (43.8%) were serologically positive for H. pylori infection, which was significantly lower than that for the mountainous (61.3%, P = 0.01). The same results also found in the prevalence of PG-positivity, PG I levels and PG I/II ratios (P = 0.001, P <0.0001 and P = 0.03, respectively). Moreover, the PG I/II ratios were significantly, and inversely correlated with the OLGA score (r = 0.33, P <0.009). The low incidence of gastric cancer in Nepal can be attributed to low gastric mucosal atrophy. However, the mountainous subjects have high-risk gastric mucosal status, which could be considered a high-risk population in Nepal. PMID- 26625821 TI - DNA Ploidy and S-phase Fraction Analysis in Paediatric B-cell Acute Lymphoblastic Leukemia Cases: a Tertiary Care Centre Experience. AB - DNA ploidy is an important prognostic parameter in paediatric B-ALL, but the significance of the S-phase fraction is unclear. In present study, DNA ploidy was assessed in 40 pediatric B-ALL cases by flow cytometry. The DI (DNA index) and percentage of cells in S-phase were calculated using Modfit software. Aneuploidy was noted in 26/40 (65%) cases. A DI of 1.10-1.6 (hyperdiploidy B) was noted in 20/40 (50%) and 6/40 (15%) had a DI>1.60 (triploid and tetraploid range). Some 14/40 (35%) cases had a diploid DI between 0.90-1.05. None of the cases had a DI <0.90 (hypodiploid) or in the 1.06-1.09 (hyperdiploid A) range. The mean S-phase fraction was 2.6%, with 24/40 (60%) having low and 16/40 (40%) high S-phase fractions. No correlation was noted with standard ALL risk and treatment response factors with DI values or S-phase data, except for a positive correlation of low S-phase with high NCI risk category (p=0.032). Overall frequency of hyperdiploidy in our cohort of B-ALL patients was very high (65%). No correlation between hyperdiploidy B and low TLC or common B-phenotype was observed in our study as 42% cases with DI 1.10-1.6 had TLC> 50 x 109 and 57.1% CD 10 negativity. The study also highlighted that S-phase fraction analysis does not add any prognostic information and is not a useful parameter for assessment in ALL cases. However, larger studies with long term outcome analysis are needed to derive definitive conclusions. PMID- 26625822 TI - Fitting Cure Rate Model to Breast Cancer Data of Cancer Research Center. AB - BACKGROUND: The Cox PH model is one of the most significant statistical models in studying survival of patients. But, in the case of patients with long-term survival, it may not be the most appropriate. In such cases, a cure rate model seems more suitable. The purpose of this study was to determine clinical factors associated with cure rate of patients with breast cancer. MATERIALS AND METHODS: In order to find factors affecting cure rate (response), a non-mixed cure rate model with negative binomial distribution for latent variable was used. Variables selected were recurrence cancer, status for HER2, estrogen receptor (ER) and progesterone receptor (PR), size of tumor, grade of cancer, stage of cancer, type of surgery, age at the diagnosis time and number of removed positive lymph nodes. All analyses were performed using PROC MCMC processes in the SAS 9.2 program. RESULTS: The mean (SD) age of patients was equal to 48.9 (11.1) months. For these patients, 1, 5 and 10-year survival rates were 95, 79 and 50 percent respectively. All of the mentioned variables were effective in cure fraction. Kaplan-Meier curve showed cure model's use competence. CONCLUSIONS: Unlike other variables, existence of ER and PR positivity will increase probability of cure in patients. In the present study, Weibull distribution was used for the purpose of analysing survival times. Model fitness with other distributions such as log-N and log-logistic and other distributions for latent variable is recommended. PMID- 26625823 TI - Absence of 185delAG and 6174delT Mutations among Breast Cancer Patients of Eastern India. AB - BACKGROUND: The incidence of breast cancer in India is on the rise and is rapidly becoming the number one cancer in females, pushing the cervical cancer to the second position. Most of the predisposition to hereditary breast and ovarian cancer has been attributed to inherited defects in two tumor suppressor genes BRCA1 and BRCA2. Alterations in these genes have been reported in different populations, some of which are population- specific mutations showing founder effects. Two specific mutations in the BRCA1 (185delAG) and BRCA2 (6174delT) genes have been reported to be of high prevalence in different populations. The aim of this study was to estimate the carrier frequency of 185delAG and 6174delT mutations in eastern Indian breast cancer patients. MATERIALS AND METHODS: We selected 231 histologically confirmed breast cancer patients from our tertiary cancer care center in eastern India. Family history was obtained by interview or a self-reported questionnaire. The presence of the mutation was investigated by allele specific duplex/multiplex-PCR on genomic DNA extracted from peripheral blood. RESULTS: A total of 231 patients (age range: 26-77 years), 130 with a family history and 101 without were screened. The two founder mutations 185delAG in BRCA1 and 6174delT in BRCA2 were not found in any of the subjects. This was confirmed by molecular analysis. CONCLUSIONS: Our findings suggest that these BRCA mutations may not have a strong recurrent effect on breast cancer among the eastern Indian population. The contribution of these founder mutations to breast cancer incidence is probably low and could be limited to specific subgroups. This may be particularly useful in establishing further pre-screening strategies. PMID- 26625824 TI - Massive Parallel Sequencing for Diagnostic Genetic Testing of BRCA Genes--a Single Center Experience. AB - The aim of this study was to implement massive parallel sequencing (MPS) technology in clinical genetics testing. We developed and tested an amplicon based method for resequencing the BRCA1 and BRCA2 genes on an Illumina MiSeq to identify disease-causing mutations in patients with hereditary breast or ovarian cancer (HBOC). The coding regions of BRCA1 and BRCA2 were resequenced in 96 HBOC patient DNA samples obtained from different sample types: peripheral blood leukocytes, whole blood drops dried on paper, and buccal wash epithelia. A total of 16 random DNA samples were characterized using standard Sanger sequencing and applied to optimize the variant calling process and evaluate the accuracy of the MPS-method. The best bioinformatics workflow included the filtration of variants using GATK with the following cut-offs: variant frequency >14%, coverage (>25x) and presence in both the forward and reverse reads. The MPS method had 100% sensitivity and 94.4% specificity. Similar accuracy levels were achieved for DNA obtained from the different sample types. The workflow presented herein requires low amounts of DNA samples (170 ng) and is cost-effective due to the elimination of DNA and PCR product normalization steps. PMID- 26625825 TI - Mechanism of Action of Nigella sativa on Human Colon Cancer Cells: the Suppression of AP-1 and NF-kappaB Transcription Factors and the Induction of Cytoprotective Genes. AB - BACKGROUND AND AIMS: Colorectal cancer is one of the leading causes of death in the world. The aim of this study was to investigate the growth-suppression potentiality of a crude saponin extract (CSENS) prepared from medicinal herb, Nigella sativa, on human colon cancer cells, HCT116. MATERIALS AND METHODS: HCT116 cells were subjected to increasing doses of CSENS for 24, 48 and 72 h, and then harvested and assayed for cell viability by WST-1. Flow cytometry analyses, cell death detection ELISA, fluorescent stains (Hoechst 33342 and acridine orange/ethidium bromide), DNA laddering and comet assays were carried out to confirm the apoptogenic effects of CSENS. Luciferase reporter gene assays, quantitative reverse transcription-polymerase chain reaction and Western blot analyses were performed to assess the impact of CAERS and CFEZO on the expression levels of key regulatory proteins in HCT116 cells. RESULTS: The results demonstrated that CSENS inhibited proliferation and induced apoptosis. Apoptosis was confirmed by flow cytometry analyses, while CSENS-treated cells exhibited morphological hallmarks of apoptosis including cell shrinkage, irregularity in cellular shape, cellular detachment and chromatin condensation. Biochemical signs of apoptosis, such as DNA degradation, were observed by comet assay and gel electrophoresis. The pro-apoptotic effect of CSENS was caspase-3-independent and associated with increase of the Bax/Bcl-2 ratio. CSENS treatment down-regulated transcriptional and DNA-binding activities of NF-kappaB and AP-1 proteins, associated with down-regulation of their target oncogenes, c-Myc, cyclin D1 and survivin. On the other hand, CSENS up-regulated transcriptional and DNA-binding activities of Nrf2 and expression of cytoprotective genes. In addition, CSENS modulated the expression levels of ERK1/2 MAPK, p53 and p21. CONCLUSIONS: These findings suggest that CSENS may be a valuable agent for treatment of colon cancer. PMID- 26625826 TI - Serum Anti-Gal-3 Autoantibody is a Predictive Marker of the Efficacy of Platinum Based Chemotherapy against Pulmonary Adenocarcinoma. AB - BACKGROUND: Identification of predictive markers for the efficacy of platinum based chemotherapy is necessary to improve the quality of the life of cancer patients. MATERIALS AND METHODS: We detected proteins recognized by autoantibodies in pretreated sera from patients with lung adenocarcinoma (AC) evaluated as showing progressive disease (PD) or a partial response (PR) after cisplatin-based chemotherapy by proteomic analysis. Then, the levels of the candidate autoantibodies in the pretreated serum were validated by dot-blot analysis for 22 AC patients who received platinum-based chemotherapy, and the expression of identified proteins was immunohistochemically analyzed in 40 AC biopsy specimens. RESULTS: An autoantibody against galectin-3 (Gal-3) was detected in pretreated sera from an AC patient with PD. Serum IgG levels of anti Gal-3 autoantibody were significantly higher in patients evaluated with PD than in those with PR and stable disease (SD) (p = 0.0084). Furthermore, pretreated biopsy specimens taken from patients evaluated as showing PD following platinum- based chemotherapy showed a tendency to have a higher positive rate of Gal-3 than those with PR and SD (p = 0.0601). CONCLUSIONS: These results suggest that serum IgG levels of anti-Gal-3 autoantibody may be useful to predict the efficacy of platinum-based chemotherapy for patients with lung AC. PMID- 26625827 TI - Dietary Practices, Addictive Behavior and Bowel Habits and Risk of Early Onset Colorectal Cancer: a Case Control Study. AB - BACKGROUND: The abrupt rise of colorectal cancer in developing countries is raising concern in healthcare settings. Studies on assessing relationships with modifiable and non-modifiable risk factors in the Pakistani population have been limited. The present investigation was designed to examine associations of dietary practices, addictive behavior and bowel habits in developing colorectal cancer (CRC) among patients in a low-resource setup. MATERIALS AND METHODS: An age-gender matched case control study was conducted from October 2011 to July 2015 in Karachi, Pakistan. Cases were from the surgical oncology department of a public sector tertiary care hospital, while their two pair-matched controls were recruited from the general population. A structured questionnaire was used which included questions related to demographic characteristics, family history, dietary patterns, addictive behavior and bowel habits. RESULTS: A family history of cancer was associated with a 2.2 fold higher chance of developing CRC. Weight loss reduced the likelihood 7.6 times. Refraining from a high fat diet and consuming more vegetables showed protective effects for CRC. The risk of CRC was more than twice among smokers and those who consumed Asian specific addictive products as compared to those who avoid using these addictions (ORsmoking: 2.12, 95% CI: 1.08 - 4.17, ORpan: 2.92, 95% CI: 1.6 - 5.33, ORgutka: 2.13, 95% CI: 1.14 - 3.97). Use of NSAID attenuated risk of CRC up to 86% (OR: 0.14, 95% CI: 0.07 - 0.31). CONCLUSIONS: Most of the findings showed concordance with the literature elucidating protective effects of consuming vegetables and low fat diet while documenting adverse associations with family history, weight loss, constipation and hematochezia. Moreover, this study highlighted Asian specific indigenous addictive products as important factors. Further studies are needed to validate the findings produced by this research. PMID- 26625828 TI - Predictive Value of IHC4 Score for Pathological Response to Neoadjuvant Chemotherapy in Hormone Receptor-Positive Breast Cancer. AB - PURPOSE: This study aimed to explore the value of IHC4 in predicting pathological response after neoadjuvant chemotherapy in patients with hormonal receptor (HR) positive breast cancer (BC). MATERIALS AND METHODS: In this retrospective exploratory study, data for 68 HR-positive BC patients who received neoadjuvant chemotherapy were recorded. IHC4 scores were calculated based on estrogen receptors/progesterone receptors, Ki-67 and HER2 status. Logistic and ordinal regression analyses in addition to likelihood ratio test were used to explore associations of IHC4 scores and other clinico-pathological parameters with pathological complete response (pCR) and pathological stage. RESULTS: Taking the 25th percentile as the cut-off, a lower IHC4 score was associated with an increased probability of pCR (low; 52.9% vs. High; 21.6%, OR=4.1, 95% CI= 1.28 13.16, p=0.018) and a lower pathological stage (OR =3.9, 95% CI=1.34-11.33, p=0.012). When the IHC4 score was treated as a continuous variable, a lower score was again associated with an increased probability of pCR (OR=1.010, 95% CI=1.001 1.018, p=0.025) and lower pathological stage (OR=1.009, 95% CI= 1.002-1.017, P=0.008). Lower clinical stage was associated with a better pCR rate that was of borderline significance (P=0.056). When clinical stage and IHC4 score were incorporated together in a logistic model, the likelihood ratio test gave a P value of 0.004 after removal of the IHC4 score and 0.011 after removal of the stage, indicating a more significant predictive value of the IHC4 score for pCR. CONCLUSIONS: This study suggests that the IHC4 score can predict pathological response to neoadjuvant chemotherapy in HR-positive BC patients. This finding now needs to be validated in a larger cohort of patients. PMID- 26625829 TI - Having Private Cancer Insurance in Korea: Gender Differences. AB - BACKGROUND: As coverage of public insurance is not sufficient to cover diagnosis or treatment of cancer, having private health insurance is important to prepare for unexpected expenses of cancer. The purpose of this study was to assess factors associated with having private cancer insurance, considering gender among the socio- demographic factors and health behavior. MATERIALS AND METHODS: We used data from the 2011 Korea Health Panel, which included 10,871 participants aged 20 years and older. Socio-demographics, health behavior, and perceived cancer risk were the independent variables and having private cancer insurance was the dependent variable. Multivariable logistic regression analysis was used to identify factors associated with having private cancer insurance. RESULTS: The variables relating to middle age, higher education, higher household income, married men, and the perceived cancer risk groups of 1-10% and 11-30% were significantly associated with having private cancer insurance. Additionally, females who had private non-cancer health insurance were positively associated with the dependent variables (OR=1.36; 95% CI=1.17-1.57). Education, smoking status, exercise, and perceived cancer risk possibility were significantly associated with having private cancer insurance only among women. The men lowered the overall percentages of those having private cancer insurance (OR=0.53, 95% CI=0.45-0.63). CONCLUSIONS: We found that there were significant differences between men and women who had private cancer insurance. Women with private cancer insurance are more likely to follow precautionary health behavior than men. This could be interpreted as resulting from masculine ideologies. It is important to make males recognize the seriousness of the cancer risk. In general, household income was highly associated with private cancer insurance. These results reveal an inequity among the buyers of private cancer insurance in terms of economic status level, education level, and health condition. PMID- 26625830 TI - Survival and Clinical Aspects for Patients with Chronic Lymphocytic Leukemia in Kermanshah, Iran. AB - Chronic lymphocytic leukemia (CLL)is the most common leukemia in adults in Western countries but is relatively rare in Asia. Immune hemolytic anemia, Evan's syndrome, lymphadenopathy, organomegaly and B symptoms are the main complaints of patients in CLL. The present retrospective analysis evaluated a group of 109 patients with CLL over a 9-year period, studying correlations between sex, age and overall survival. The patients were hospitalized in the Clinic of Hematology and Oncology, Kermanshah, Iran, between 2006 and 2014. Data analysis for sex and age was performed using IBM SPSS19 and overall survival was plotted by Kaplan- Meier plot, Log-rank test in Graph Pad prism 5 Software for five-year periods. The mean age of diagnosis for CLL patients was 60.73 years, 59.6% male. Survival rate patients was 64% and mean overall survival was 38.5 months. In the Rai system, fourteen patients (12.8%) had stage III and twenty eight patients (25.7%) had stage IV. Most frequent clinical features in patients with CLL were lymphadenopathy (38.7%) and organomegaly (34%), respectively. There is not relationship between sex and age in patients but overall survival rate in females was higher than in males. In Asian countries, CLL is more in male and in age above 60 years. Complaints about lymphadenopathy and virus infection are prevalent. PMID- 26625831 TI - Colorectal Cancer Mortality Characteristics and Predictions in China, 1991-2011. AB - BACKGROUND: To identify the epidemiological characteristics of colorectal cancer mortality in China during the period of 1991-2011, and forecast the future five year trend. MATERIALS AND METHODS: Mortality data for colorectal cancer in China from 1991 to 2011 was used to describe epidemiological characteristics in terms of age group, gender, and rural/urban residence. Trend surface analysis was performed to analyze the geographical distribution of colorectal cancer. Four models including curve estimation, time series modeling, gray modeling and joinpoint regression were applied to forecast the trends for the future five years. RESULTS: Since 1991 the colorectal cancer mortality rate increased yearly, and our results showed that the trend would continue to increase in the ensuing 5 years. The mortality rate in males was higher than that of females and the rate in urban areas was higher than in rural areas. The mortality rate was relatively low for individuals less than 60 years of age, but increased dramatically afterwards. People living in the northeastern China provinces or in eastern China had a higher mortality rate for colorectal cancer than those living in middle or western China provinces. CONCLUSIONS: The steadily increasing mortality of colorectal cancer in China will become a substantial public health burden in the foreseeable future. For this increasing trend to be controlled, further efforts should concentrate on educating the general public to increase prevention and early detection by screening. More effective prevention and management strategies are needed in higher mortality areas (Eastern parts of China) and high-risk populations (60+ years old). PMID- 26625832 TI - Detection of Gene Amplification by Multiplex Ligation-Dependent Probe Amplification in Comparison with In Situ Hybridization and Immunohistochemistry. AB - Gene amplification is an important mechanism in the development and progression of cancer. Currently, gene amplification status is generally determined by in situ hybridization (ISH). Multiplex ligation-dependent probe amplification (MLPA) is a PCR-based method that allows copy number detection of up to 50 nucleic acid sequences in one reaction. The aim of the present study was to compare results for HER2, CCND1, MYC and ESR1 gene amplification detected by MLPA with fluorescent in situ hybridization (FISH) and chromogenic in situ hybridization (CISH) as clinically approved methods. Tissue samples of 170 invasive breast cancers were collected. All were ER positive. Tissue samples had previously been tested for HER2 using immunohistochemistry. Amplification of the selected genes were assessed using MLPA, FISH and CISH and results were compared. HER2 MLPA and ISH results were also compared with HER2 immunohistochemistry (IHC) which detects protein overexpression. Amplification of HER2, CCND1, MYC and ESR1 by MLPA were found in 9%, 19%, 20% and 2% of samples, respectively. Amplification of HER2, CCND1, MYC and ESR1 by FISH was noted in 7%, 16%, 16% and 1% of samples, respectively. A high level of concordance was found between MLPA/ FISH (HER2: 88%, CCND1: 88%, MYC: 86%, ESR1: 92%) and MLPA/ CISH (HER2: 84%). Of all IHC 3+ cases, 91% were amplified by MLPA. In IHC 2+ group, 31% were MLPA amplified. In IHC 1+ group, 2% were MLPA amplified. None of the IHC 0 cases were amplified by MLPA. Our results indicate that there is a good correlation between MLPA, IHC and ISH results. Therefore, MLPA can serve as an alternative to ISH for detection of gene amplification. PMID- 26625833 TI - Family History of Cancer and Head and Neck Cancer Risk in a Chinese Population. AB - BACKGROUND: The aim of this study was to investigate whether family history of cancer is associated with head and neck cancer risk in a Chinese population. MATERIALS AND METHODS: This case-control study included 921 cases and 806 controls. Recruitment was from December 2010 to January 2015 in eight centers in East Asia. Controls were matched to cases with reference to sex, 5-year age group, ethnicity, and residence area at each of the centers. RESULTS: We observed an increased risk of head and neck cancer due to first degree family history of head and neck cancer, but after adjustment for tobacco smoking, alcohol drinking and betel quid chewing the association was no longer apparent. The adjusted OR were 1.10 (95% CI=0.80-1.50) for family history of tobacco-related cancer and 0.96 (95%CI=0.75-1.24) for family history of any cancer with adjustment for tobacco, betel quid and alcohol habits. The ORs for having a first-degree relative with HNC were higher in all tobacco/ alcohol subgroups. CONCLUSIONS: We did not observe a strong association between family history of head and neck cancer and head and neck cancer risk after taking into account lifestyle factors. Our study suggests that an increased risk due to family history of head and neck cancer may be due to shared risk factors. Further studies may be needed to assess the lifestyle factors of the relatives. PMID- 26625834 TI - Clinical Practice of Blood Transfusion in Orthotopic Organ Transplantation: A Single Institution Experience. AB - BACKGROUND: Orthotopic organ transplantation, a treatment option for irreversible organ dysfunction according to organ failure, severe damaged organ or malignancy in situ, was usually accompanied with massive blood loss thus transfusion was required. We aimed to evaluate the adverse impact of blood transfusion on solid organ transplantation. MATERIALS AND METHODS: From January, 2009 to December, 2014, patients who received orthotopic organ transplantation at Far Eastern Memorial Hospital medical center were enrolled. Clinical data regarding anemia status and red blood cell (RBC) transfusion before, during and after operation, as well as patient outcomes were collected for further univariate analysis. RESULTS: A total of 105 patients who underwent orthotopic transplantation, including liver, kidney and small intestine were registered. The mean hemoglobin (Hb) level upon admission and before operation were 11.6 +/- 1.8 g/dL and 11.7 +/ 1.7 g/dL, respectively; and the nadir Hb level post operation and the final Hb level before discharge were 8.3 +/- 1.6 g/dL and 10.2 +/- 1.6 g/dL, respectively. The median units (interquartile range) of RBC transfusion in pre-operative, peri operative and post-operative periods were 0 (0-0), 2 (0-12), and 2 (0-6) units, respectively. Furthermore, the median (interquartile range) length of hospital stay (LHS) from admission to discharge and from operation to discharge were 28 (17-44) and 24 (16-37) days, respectively. Both peri-operative and post-operative RBC transfusion were associated with longer LHS from admission to discharge and from operation to discharge. Furthermore, it increased the risk of post-operative septicemia. While peri-operative RBC transfusion elevated the risk of acute graft rejection in patients who received orthotopic transplantation. CONCLUSIONS: Worse outcome could be anticipated in those who had received massive RBC transfusion in transplantation operation. Hence, peri-operative RBC transfusion should be avoided as much as possible. PMID- 26625835 TI - Regulating Mitochondrial Biogenesis: from Herbal Remedies to Phytomedicine for Cancer Prevention. PMID- 26625836 TI - Association of ATP6AP2 Gene Polymorphisms with Essential Hypertension in a South Chinese Han Population. PMID- 26625837 TI - A new bisbenzylisoquinoline alkaloid isolated from Thalictrum foliolosum, as a potent inhibitor of DNA topoisomerase IB of Leishmania donovani. AB - Chemical investigation of the stem of Thalictrum foliolosum resulted in the isolation of two new bisbenzylisoquinoline alkaloids (1 and 2) along with known protoberberine group of isoquinoline alkaloids thalifendine (3) and berberine (4). The structures of the new compounds were established by detailed 2D NMR spectral analysis with their configurations determined from their optical rotation values and confirmed using circular dichroism. Inhibitory activities of these four compounds against DNA topoisomerase IB of Leishmania donovani were evaluated. Compound 2 exhibited almost complete inhibition of the enzyme activity at 50 MUM concentration and it was found to be effective in killing both wild type as well as SAG resistant promastigotes of the parasite. PMID- 26625839 TI - Chemical modification of arglabin and biological activity of its new derivatives. AB - This review summarizes the results of own research on chemical modification of the molecule of sesquiterpene lactone arglabin from Artemisia glabella Kar. et Kir. Over 70 new arglabin derivatives were obtained which are polyfunctional compounds with oxy functions, atoms of haloids, phosphorus, nitrogen, and cyclopropane fragments. For the first time the results of bioscreening of new arglabin derivatives are reported. PMID- 26625838 TI - Diterpene alkaloids and diterpenes from Spiraea japonica and their anti-tobacco mosaic virus activity. AB - Five new naturally occurring natural products, including two atisine-type diterpene alkaloids (1 and 2), two atisane-type diterpenes (3 and 4), and a new natural product spiramine C2 (5), along with nine known ones (6-14), were isolated from the ethanolic extracts of the whole plant of Spiraea japonica var. acuminata Franch. Their structures were elucidated by extensive spectroscopic analysis. The anti-tobacco mosaic virus (TMV) activities of all the compounds were evaluated by the conventional half-leaf method. Six compounds (2, 3, 6, 7, 11, and 12) exhibited moderate activities at 100 MUg/mL with inhibition rates in the range of 69.4-92.9%, which were higher than that of the positive control, ningnanmycin. Their preliminary structure-activity relationships were also discussed. PMID- 26625840 TI - Lignans from the rhizomes of Iris tectorum. AB - Chemical examination of the ethanol extract of rhizomes of Iris tectorum led to the isolation and characterization of three new lignans, (7R,7'R,8S,8'S)-5' methoxy-neo-olivil (1a), (7S,7'S,8R,8'R) -5'-methoxy-neo-olivil (1b), (7S,7'R,8S,8'S)-neo-olivil (2a), (7R,7'S,8R,8'R)-neo-olivil (2b), (7R,7'R,8S,8'S,7''S,8''S)-threo-neo-olivil-4'-O-8-guaiacylglycerol ether (3), together with six known ones (4-9). Among them, compounds 1 and 2 were found to be racemic mixtures, respectively, which were verified by chiral HPLC analysis, compound 3 was a new sesquineolignan. The structures were elucidated on the basis of extensive spectroscopic analysis. To our knowledge, this is the first report of lignan constituents isolated from I. tectorum. All compounds were evaluated for their cytotoxicity against five human tumor cell lines and none of them displayed significant toxicity in tested cell lines at a concentration of 10 MUM. PMID- 26625846 TI - Characterizing the structure and content of nurse handoffs: A Sequential Conversational Analysis approach. AB - Effective communication during nurse handoffs is instrumental in ensuring safe and quality patient care. Much of the prior research on nurse handoffs has utilized retrospective methods such as interviews, surveys and questionnaires. While extremely useful, an in-depth understanding of the structure and content of conversations, and the inherent relationships within the content is paramount to designing effective nurse handoff interventions. In this paper, we present a methodological framework-Sequential Conversational Analysis (SCA)-a mixed-method approach that integrates qualitative conversational analysis with quantitative sequential pattern analysis. We describe the SCA approach and provide a detailed example as a proof of concept of its use for the analysis of nurse handoff communication in a medical intensive care unit. This novel approach allows us to characterize the conversational structure, clinical content, disruptions in the conversation, and the inherently phasic nature of nurse handoff communication. The characterization of communication patterns highlights the relationships underlying the verbal content of nurse handoffs with specific emphasis on: the interactive nature of conversation, relevance of role-based (incoming, outgoing) communication requirements, clinical content focus on critical patient-related events, and discussion of pending patient management tasks. We also discuss the applicability of the SCA approach as a method for providing in-depth understanding of the dynamics of communication in other settings and domains. PMID- 26625847 TI - 2015 International Conference on Human Health and Medical Engineering (HHME 2015). PMID- 26625841 TI - Graphene oxide inhibits hIAPP amyloid fibrillation and toxicity in insulin producing NIT-1 cells. AB - Human islet amyloid polypeptide (hIAPP or amylin) aggregation is directly associated with pancreatic beta-cell death and subsequent insulin deficiency in type 2 diabetes (T2D). Since no cure is currently available for T2D, it is of great benefit to devise new anti-aggregation molecules, which protect beta-cells against hIAPP aggregation-induced toxicity. Engineered nanoparticles have been recently exploited as anti-aggregation nanomedicines. In this work, we studied graphene oxide (GO) nanosheets for their potential for hIAPP aggregation inhibition by combining computational modeling, biophysical characterization and cell toxicity measurements. Using discrete molecular dynamics (DMD) simulations and in vitro studies, we showed that GO exhibited an inhibitory effect on hIAPP aggregation. DMD simulations indicated that the strong binding of hIAPP to GO nanosheets was driven by hydrogen bonding and aromatic stacking and that the strong peptide-GO binding efficiently inhibited hIAPP self-association and aggregation on the nanosheet surface. Secondary structural changes of hIAPP upon GO binding derived from DMD simulations were consistent with circular dichroism (CD) spectroscopy measurements. Transmission electron microscopy (TEM) images confirmed the reduction of hIAPP aggregation in the presence of GO. Furthermore, we carried out a cell toxicity assay and found that these nanosheets protected insulin-secreting NIT-1 pancreatic beta-cells against hIAPP-induced toxicity. Our multidisciplinary study suggests that GO nanosheets have the potential to be utilized as an anti-aggregation nanomedicine itself in addition to a biosensor or delivery vehicle for the mitigation of T2D progression. PMID- 26625848 TI - [Temporal ambivalences of aging: Individual patterns of time use in conflict between time wealth and time poverty]. AB - Throughout their lives people are confronted with different time resources and demands that change continuously up into old age. With the help of a qualitative interview study the narrative constructions of subjective time experiences as well as individual ways of dealing with time in retirement were investigated. In particular the influences of older persons' experience of time within the dimensions of everyday time and life time were analyzed. In addition, the study focused on potential time conflicts between these two dimensions and the question of how older people deal with the ambivalence between everyday time wealth and biographical time poverty in older age. The results of the interviews with 50 retired men and women (aged 56-91 years) in Germany, which were analyzed with "grounded theory" techniques, indicated that time in retirement does not indeed always run smoothly. In particular, the individual perception of increasing biographical time poverty exerts pressure on the arrangement of activities and daily routine in retirement. The resulting time conflicts are reflected in differential patterns of time use through which older persons try to cope with their ambivalent time experiences. PMID- 26625849 TI - Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from nonacademic institutions 1-31 July 2015. PMID- 26625851 TI - Multifocal Intraocular Lens Results in Correcting Presbyopia in Eyes After Radial Keratotomy. AB - OBJECTIVES: To report results of multifocal intraocular lens (IOL) implantation in 2 patients with refractive error and presbyopia after previous radial keratotomy (RK). METHODS: A refractive multifocal IOL with rotational asymmetry (LS313-MF30; Oculentis, Berlin, Germany) was implanted. RESULTS: The first patient was a 60-year-old man with myopia who underwent unilateral RK 20 years before. His uncorrected distance visual acuity (UDVA) was 20/400, and his distance corrected near vision was J9 in both eyes. Six months after bilateral surgery, his binocular UDVA and uncorrected near visual acuity (UNVA) improved to 20/20 and J1, respectively, although he experienced diurnal fluctuation. The second patient was a 55-year-old woman with hyperopia who underwent bilateral RK 18 years before. Uncorrected distance visual acuity was 20/25 in both eyes, but UNVA was between J9 and J10. Three months after unilateral surgery, UDVA and UNVA of the postsurgical eye improved to 20/20 and J1, respectively. Neither patient reported any significant photic phenomena, and both were satisfied with the results of treatment. CONCLUSIONS: The desirable clinical outcomes and levels of satisfaction expressed by these patients indicate that surgery using this particular multifocal IOL may benefit presbyopic patients with previous RK. PMID- 26625852 TI - Risk factors for chronic undernutrition among children in India: Estimating relative importance, population attributable risk and fractions. AB - Nearly 40% of the world's stunted children live in India and the prevalence of undernutrition has been persistently high in recent decades. Given numerous available interventions for reducing undernutrition in children, it is not clear of the relative importance of each within a multifactorial framework. We assess the simultaneous contribution of 15 known risk factors for child chronic undernutrition in India. Data are from the 3rd Indian National Family Health Survey (NFHS-3), a nationally representative cross-sectional survey undertaken in 2005-2006. The study population consisted of children aged 6-59 months [n = 26,842 (stunting/low height-for-age), n = 27,483 (underweight/low weight-for age)]. Risk factors examined for their association with undernutrition were: vitamin A supplementation, vaccination, use of iodized salt, household air quality, improved sanitary facilities, safe disposal of stools, improved drinking water, prevalence of infectious disease, initiation of breastfeeding, dietary diversity, age at marriage, maternal BMI, height, education, and household wealth. Age/sex-adjusted and multivariable adjusted effect sizes (odds ratios) were calculated for risk factors along with Population Attributable Risks (PAR) and Fractions (PAF) using logistic regression. In the mutually adjusted models, the five most important predictors of childhood stunting/underweight were short maternal stature, mother having no education, households in lowest wealth quintile, poor dietary diversity, and maternal underweight. These five factors had a combined PAR of 67.2% (95% CI: 63.3-70.7) and 69.7% (95% CI: 66.3-72.8) for stunting and underweight, respectively. The remaining factors were associated with a combined PAR of 11.7% (95% CI: 6.0-17.4) and 15.1% (95% CI: 8.9-21.3) for stunting and underweight, respectively. Implementing strategies focused on broader progress on social circumstances and infrastructural domains as well as investments in nutrition specific programs to promote dietary adequacy and diversity are required to ensure a long term trajectory of optimal child growth and development in India. PMID- 26625850 TI - Orthopedic tissue regeneration: cells, scaffolds, and small molecules. AB - Orthopedic tissue regeneration would benefit the aging population or patients with degenerative bone and cartilage diseases, especially osteoporosis and osteoarthritis. Despite progress in surgical and pharmacological interventions, new regenerative approaches are needed to meet the challenge of creating bone and articular cartilage tissues that are not only structurally sound but also functional, primarily to maintain mechanical integrity in their high load-bearing environments. In this review, we discuss new advances made in exploiting the three classes of materials in bone and cartilage regenerative medicine--cells, biomaterial-based scaffolds, and small molecules--and their successes and challenges reported in the clinic. In particular, the focus will be on the development of tissue-engineered bone and cartilage ex vivo by combining stem cells with biomaterials, providing appropriate structural, compositional, and mechanical cues to restore damaged tissue function. In addition, using small molecules to locally promote regeneration will be discussed, with potential approaches that combine bone and cartilage targeted therapeutics for the orthopedic-related disease, especially osteoporosis and osteoarthritis. PMID- 26625853 TI - Response to Pickett and Wilkinson (2015). PMID- 26625854 TI - Revealing ultralarge and localized elastic lattice strains in Nb nanowires embedded in NiTi matrix. AB - Freestanding nanowires have been found to exhibit ultra-large elastic strains (4 to 7%) and ultra-high strengths, but exploiting their intrinsic superior mechanical properties in bulk forms has proven to be difficult. A recent study has demonstrated that ultra-large elastic strains of ~6% can be achieved in Nb nanowires embedded in a NiTi matrix, on the principle of lattice strain matching. To verify this hypothesis, this study investigated the elastic deformation behavior of a Nb nanowire embedded in NiTi matrix by means of in situ transmission electron microscopic measurement during tensile deformation. The experimental work revealed that ultra-large local elastic lattice strains of up to 8% are induced in the Nb nanowire in regions adjacent to stress-induced martensite domains in the NiTi matrix, whilst other parts of the nanowires exhibit much reduced lattice strains when adjacent to the untransformed austenite in the NiTi matrix. These observations provide a direct evidence of the proposed mechanism of lattice strain matching, thus a novel approach to designing nanocomposites of superior mechanical properties. PMID- 26625855 TI - Causal Genetic Inference Using Haplotypes as Instrumental Variables. AB - In genomic studies with both genotypes and gene or protein expression profile available, causal effects of gene or protein on clinical outcomes can be inferred through using genetic variants as instrumental variables (IVs). The goal of introducing IV is to remove the effects of unobserved factors that may confound the relationship between the biomarkers and the outcome. A valid inference under the IV framework requires pairwise associations and pathway exclusivity. Among these assumptions, the IV expression association needs to be strong for the casual effect estimates to be unbiased. However, a small number of single nucleotide polymorphisms (SNPs) often provide limited explanation of the variability in the gene or protein expression and can only serve as weak IVs. In this study, we propose to replace SNPs with haplotypes as IVs to increase the variant-expression association and thus improve the casual effect inference of the expression. In the classical two-stage procedure, we developed a haplotype regression model combined with a model selection procedure to identify optimal instruments. The performance of the new method was evaluated through simulations and compared with the IV approaches using observed multiple SNPs. Our results showed the gain of power to detect a causal effect of gene or protein on the outcome using haplotypes compared with using only observed SNPs, under either complete or missing genotype scenarios. We applied our proposed method to a study of the effect of interleukin-1 beta (IL-1beta) protein expression on the 90-day survival following sepsis and found that overly expressed IL-1beta is likely to increase mortality. PMID- 26625856 TI - Enrichment of Desulfitobacterium spp. from forest and grassland soil using the O demethylation of phenyl methyl ethers as a growth-selective process. AB - The O-demethylation of phenyl methyl ethers under anaerobic conditions is a metabolic feature of acetogens and Desulfitobacterium spp. Desulfitobacteria as well as most acetogens are Gram-positive bacteria with a low GC content and belong to the phylum Firmicutes. The consumption of the phenyl methyl ether syringate was studied in enrichment cultures originating from five different topsoils. Desulfitobacterium spp. were detected in all topsoils via quantitative PCR. Desulfitobacteria could be enriched using the O-demethylation of syringate as a growth-selective process. The enrichment was significantly favoured by an external electron acceptor such as 3-chloro-4-hydroxyphenylacetate or thiosulfate. Upon cultivation in the presence of syringate and thiosulfate, which naturally occur in soil, a maximum number of 16S rRNA gene copies of Desulfitobacterium spp. was reached within the first three subcultivation steps and accounted for 3-10% of the total microbial community depending on the soil type. Afterwards, a loss of Desulfitobacterium gene copies was observed. Community analyses revealed that Proteobacteria, Acidobacteria, Actinobacteria and Bacteroidetes were the main phyla in the initial soil samples. Upon addition of syringate and thiosulfate as growth substrates, these phyla were rapidly outcompeted by Firmicutes, which were under-represented in soil. The main Firmicutes genera identified were Alkalibaculum, Clostridium, Sporobacterium, Sporomusa and Tissierella, which might be responsible for outcompeting the desulfitobacteria. Most of these organisms belong to the acetogens, which have previously been described to demethylate phenyl methyl ethers. The shift of the native community structure to almost exclusively Firmicutes supports the participation of members of this phylum in environmental demethylation processes. PMID- 26625857 TI - Novel avian single-chain fragment variable (scFv) targets dietary gluten and related natural grain prolamins, toxic entities of celiac disease. AB - BACKGROUND: Celiac disease (CD) is a chronic, small intestinal inflammatory disease mediated by dietary gluten and related prolamins. The only current therapeutic option is maintenance of a strict life-long gluten-free diet, which implies substantial burden for CD patients. Different treatment regimes might be feasible, including masking of toxic celiac peptides with blocking antibodies or fragments thereof. The objective of this study was therefore to select and produce a recombinant avian single-chain fragment variable (scFv) directed against peptic-tryptic digested gliadin (PT-Gliadin) and related celiac toxic entities. RESULTS: Gluten-free raised chicken of same age were immunized with PT Gliadin. Chicken splenic lymphocytes, selected with antigen-coated magnetic beads, served as RNA source for the generation of cDNA. Chicken VH and VL genes were amplified from the cDNA by PCR to generate full-length scFv constructs consisting of VH and VL fragments joined by a linker sequence. ScFv constructs were ligated in a prokaryotic expression vector, which provides a C-terminal hexahistidine tag. ScFvs from several bacterial clones were expressed in soluble form and crude cell lysates screened for binding to PT-Gliadin by ELISA. We identified an enriched scFv motif, which showed reactivity to PT-Gliadin. One selected scFv candidate was expressed and purified to homogeneity. Polyclonal anti-PT-Gliadin IgY, purified from egg yolk of immunized chicken, served as control. ScFv binds in a dose-dependent manner to PT-Gliadin, comparable to IgY. Furthermore, IgY competitively displaces scFv from PT-Gliadin and natural wheat flour digest, indicating a common epitope of scFv and IgY. ScFv was tested for reactivity to different gastric digested dietary grain flours. ScFv detects common and khorasan wheat comparably with binding affinities in the high nanomolar range, while rye is detected to a lesser extent. Notably, barley and cereals which are part of the gluten-free diet, like corn and rice, are not detected by scFv. Similarly, the pseudo-grain amaranth, used as gluten-free alternative, is not targeted by scFv. This data indicate that scFv specifically recognizes toxic cereal peptides relevant in CD. CONCLUSION: ScFv can be of benefit for future CD treatment regimes. PMID- 26625858 TI - Innate biology versus lifestyle behaviour in the aetiology of obesity and type 2 diabetes: the GLACIER Study. AB - AIMS/HYPOTHESIS: We compared the ability of genetic (established type 2 diabetes, fasting glucose, 2 h glucose and obesity variants) and modifiable lifestyle (diet, physical activity, smoking, alcohol and education) risk factors to predict incident type 2 diabetes and obesity in a population-based prospective cohort of 3,444 Swedish adults studied sequentially at baseline and 10 years later. METHODS: Multivariable logistic regression analyses were used to assess the predictive ability of genetic and lifestyle risk factors on incident obesity and type 2 diabetes by calculating the AUC. RESULTS: The predictive accuracy of lifestyle risk factors was similar to that yielded by genetic information for incident type 2 diabetes (AUC 75% and 74%, respectively) and obesity (AUC 68% and 73%, respectively) in models adjusted for age, age(2) and sex. The addition of genetic information to the lifestyle model significantly improved the prediction of type 2 diabetes (AUC 80%; p = 0.0003) and obesity (AUC 79%; p < 0.0001) and resulted in a net reclassification improvement of 58% for type 2 diabetes and 64% for obesity. CONCLUSIONS/INTERPRETATION: These findings illustrate that lifestyle and genetic information separately provide a similarly high degree of long-range predictive accuracy for obesity and type 2 diabetes. PMID- 26625859 TI - Invasive pleural malignant mesothelioma with rib destruction and concurrent osteosarcoma in a dog. AB - A 7-year-old Dachshund was clinically examined because of a 10-day history of lameness in the left hind limb. On the basis of radiological and cytological findings, an osteosarcoma of the left acetabular region was suspected. The dog underwent a hemipelvectomy and osteosarcoma was diagnosed by subsequent histopathological examination. An immovable subcutaneous mass was noted on the left chest wall during the physical examination and non-septic neutrophilic inflammation was diagnosed by cytology. Forty days later, the dog showed signs of respiratory distress with an in-diameter increase of the subcutaneous mass up to 4 cm. Thoracic radiography and ultrasonography revealed pleural effusion and a lytic process in the fourth left rib. Furthermore, ultrasound examination revealed a mixed echogenic mobile structure with a diameter of around 2 cm floating within the pleural fluid of the left hemithorax close to the pericardium. The dog underwent surgery for an en bloc resection of the subcutaneous mass together with the fourth rib and the parietal pleura. Moreover, the left altered lung lobe, corresponding to the mobile structure detected by ultrasound, was removed. Based on cytological, histopathological, and immunohistochemical examinations, an invasive epithelioid pleural malignant mesothelioma was diagnosed. PMID- 26625860 TI - Audio-visual aid in teaching "fatty liver". AB - Use of audio visual tools to aid in medical education is ever on a rise. Our study intends to find the efficacy of a video prepared on "fatty liver," a topic that is often a challenge for pre-clinical teachers, in enhancing cognitive processing and ultimately learning. We prepared a video presentation of 11:36 min, incorporating various concepts of the topic, while keeping in view Mayer's and Ellaway guidelines for multimedia presentation. A pre-post test study on subject knowledge was conducted for 100 students with the video shown as intervention. A retrospective pre study was conducted as a survey which inquired about students understanding of the key concepts of the topic and a feedback on our video was taken. Students performed significantly better in the post test (mean score 8.52 vs. 5.45 in pre-test), positively responded in the retrospective pre-test and gave a positive feedback for our video presentation. Well-designed multimedia tools can aid in cognitive processing and enhance working memory capacity as shown in our study. In times when "smart" device penetration is high, information and communication tools in medical education, which can act as essential aid and not as replacement for traditional curriculums, can be beneficial to the students. (c) 2015 by The International Union of Biochemistry and Molecular Biology, 44:241-245, 2016. PMID- 26625862 TI - Monocyte chemoattractant protein-1 and the kidney. AB - PURPOSE OF REVIEW: Recently, initial studies have been carried out in patients using monocyte chemoattractant protein-1 (MCP-1) inhibitors. This review summarizes the known function of MCP-1 in regulating monocytes during inflammation and its role in inflammatory disease of the kidney. RECENT FINDINGS: MCP-1 is one of the first chemokines described and plays an important role in renal inflammatory disease. The function of MCP-1 has been investigated and analyzed in both animal models of renal disease and renal patients. MCP-1 mediates firstly the release of monocytes from the bone marrow, and then generates a gradient in the endothelial glycocalyx to direct monocytes to sites of inflammation, thereby alleviating the migration of blood leukocytes into the inflamed tissue. In addition, MCP-1 has direct signaling effects in monocytes and influences migration, proliferation, and differentiation of leukocytes. Blockade of MCP-1 in several models of renal disease has ameliorated the disease, suggesting that inhibition of MCP-1 is a promising and valid strategy to treat patients with renal inflammatory disease. SUMMARY: Understanding the role of MCP 1 in monocyte homeostasis and the implications of MCP-1 inhibition in renal disease will help in designing better diagnostic and therapeutic strategies in patients with inflammatory renal disease. PMID- 26625861 TI - Variation is function: Are single cell differences functionally important?: Testing the hypothesis that single cell variation is required for aggregate function. AB - There is a growing appreciation of the extent of transcriptome variation across individual cells of the same cell type. While expression variation may be a byproduct of, for example, dynamic or homeostatic processes, here we consider whether single-cell molecular variation per se might be crucial for population level function. Under this hypothesis, molecular variation indicates a diversity of hidden functional capacities within an ensemble of identical cells, and this functional diversity facilitates collective behavior that would be inaccessible to a homogenous population. In reviewing this topic, we explore possible functions that might be carried by a heterogeneous ensemble of cells; however, this question has proven difficult to test, both because methods to manipulate molecular variation are limited and because it is complicated to define, and measure, population-level function. We consider several possible methods to further pursue the hypothesis that variation is function through the use of comparative analysis and novel experimental techniques. PMID- 26625863 TI - The role of mechanistic target of rapamycin in maintenance of glomerular epithelial cells. AB - PURPOSE OF REVIEW: Recent studies have emerged to reveal the pivotal roles of mechanistic target of rapamycin (mTOR) signaling not only in the maintenance of the physiological functions of renal cells but also in the pathogenesis of renal cell dysfunctions and kidney diseases. We introduce the current understanding of mTOR signaling, and its crucial roles in glomerular epithelial cell biology and the pathophysiology related to kidney diseases. RECENT FINDINGS: mTOR, a Ser/Thr kinase, forms two distinct functional complexes, mTORC1 and mTORC2. Recent studies revealed that physiologic levels of mTORC1 and mTORC2 activity play key roles in maintaining podocyte and glomerular functions. However, aberrant activation of mTORC1 or loss of mTORC2 activity in podocytes may underlie the pathogenesis of glomerular disorders, including diabetic kidney disease. SUMMARY: An effective treatment for mTORC1-associated podocyte and glomerular dysfunction may require the attenuation of mTORC1 activity in the setting of both an intact mTORC2 pathway and normal basal mTORC1 activity in order to preserve physiologic podocyte functions. PMID- 26625864 TI - Endothelin-1 and the kidney: new perspectives and recent findings. AB - PURPOSE OF REVIEW: The role of endothelin-1 (ET-1) in the kidney has been under study for many years; however, the complex mechanisms by which endothelin controls the physiology/pathophysiology of this organ are not fully resolved. This review aims to summarize recent findings in the field, especially regarding glomerular and tubular damage, Na/water homeostasis and sex differences in ET-1 function. RECENT FINDINGS: Podocytes have been recently identified as a target of ET-1 in the glomerular filtration barrier via ETA receptor activation. Activation of the ETA receptor by ET-1 leads to renal tubular damage by promoting endoplasmic reticulum stress and apoptosis in these cells. In addition, high flow rates in the nephron in response to high salt intake induce ET-1 production by the collecting ducts and promote nitric oxide-dependent natriuresis through epithelial sodium channel inhibition. Recent evidence also indicates that sex hormones regulate the renal ET-1 system differently in men and women, with estrogen suppressing renal ET-1 production and testosterone upregulating that production. SUMMARY: Based on the reports reviewed in here, targeting of the renal endothelin system is a possible therapeutic approach against the development of glomerular injury. More animal and clinical studies are needed to better understand the dimorphic control of this system by sex hormones. PMID- 26625865 TI - Cutaneous control of blood pressure. AB - PURPOSE OF REVIEW: Textbook theory holds that blood pressure (BP) is regulated by the brain, by blood vessels, or by the kidney. Recent evidence suggests that BP could be regulated in the skin. RECENT FINDINGS: The skin holds a complex capillary counter current system, which controls body temperature, skin perfusion, and apparently systemic BP. Epidemiological data suggest that sunlight exposure plays a role in controlling BP. Ultraviolet A radiation produces vasodilation and a fall in BP. Keratinocytes and immune cells control blood flow in the extensive countercurrent loop system of the skin by producing nitric oxide, a key regulator of vascular tone. The balance between hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha activity in keratinocytes controls skin perfusion, systemic thermoregulation, and systemic BP by nitric oxide-dependent mechanisms. Furthermore, the skin accumulates Na which generates a barrier to promote immunological host defense. Immune cells control skin Na metabolism and the clearance of Na via the lymphatic system. Reduced lymphatic clearance increases BP. SUMMARY: Apart from the well-known role of the brain, blood vessels, and the kidney, the skin is important for systemic BP control in humans and in experimental animals. PMID- 26625866 TI - Ischemia as a factor affecting innate immune responses in kidney transplantation. AB - PURPOSE OF REVIEW: Ischemic injury inevitably occurs during the procurement of organs for transplantation, and the injury is worsened by inflammation following reperfusion. The purpose of this review is to describe the role of the innate immune system in ischemia-induced renal injury in kidneys procured for transplantation. The key role of pattern recognition receptors in immune responses to ischemia is described. Innate immune receptors are emerging novel targets for the amelioration of ischemic injury of donor kidneys. RECENT FINDINGS: Several families of pattern recognition receptors are direct mediators of early injurious events during kidney procurement, and also innate and adaptive immune responses after transplantation. The deleterious events associated with the activation of the innate immune system in donor kidneys significantly contribute to short and long-term allograft outcomes. SUMMARY: Although a number of therapies have been proposed to decrease ischemic donor kidney injury, targeting the innate immune system is an exciting new area that is gaining significant interest in transplantation. As we learn more about how these important receptors are regulated by ischemia, strategies will likely evolve to allow their modulation in ischemic renal injury. PMID- 26625867 TI - Towards An Advanced Graphene-Based Magnetic Resonance Imaging Contrast Agent: Sub acute Toxicity and Efficacy Studies in Small Animals. AB - Current clinical Gd(3+)-based T1 magnetic resonance imaging (MRI) contrast agents (CAs) are suboptimal or unsuitable, especially at higher magnetic fields (>1.5 Tesla) for advanced MRI applications such as blood pool, cellular and molecular imaging. Herein, towards the goal of developing a safe and more efficacious high field T1 MRI CA for these applications, we report the sub-acute toxicity and contrast enhancing capabilities of a novel nanoparticle MRI CA comprising of manganese (Mn(2+)) intercalated graphene nanoparticles functionalized with dextran (hereafter, Mangradex) in rodents. Sub-acute toxicology performed on rats intravenously injected with Mangradex at 1, 50 or 100 mg/kg dosages 3 times per week for three weeks indicated that dosages <=50 mg/kg could serve as potential diagnostic doses. Whole body 7 Tesla MRI performed on mice injected with Mangradex at a potential diagnostic dose (25 mg/kg or 455 nanomoles Mn(2+)/kg; ~2 orders of magnitude lower than the paramagnetic ion concentration in a typical clinical dose) showed persistent (up to at least 2 hours) contrast enhancement in the vascular branches (Mn(2+) concentration in blood at steady state = 300 ppb, per voxel = 45 femtomoles). The results lay the foundations for further development of Mangradex as a vascular and cellular/ molecular MRI probe. PMID- 26625868 TI - An ABA down-regulated bHLH transcription repressor gene, bHLH129 regulates root elongation and ABA response when overexpressed in Arabidopsis. AB - Plant hormone abscisic acid (ABA) plays a crucial role in modulating plant responses to environmental stresses. Basic helix-loop-helix (bHLH) transcription factors are one of the largest transcription factor families that regulate multiple aspects of plant growth and development, as well as of plant metabolism in Arabidopsis. Several bHLH transcription factors have been shown to be involved in the regulation of ABA signaling. We report here the characterization of bHLH129, a bHLH transcription factor in Arabidopsis. We found that the expression level of bHLH129 was reduced in response to exogenously applied ABA, and elevated in the ABA biosynthesis mutant aba1-5. Florescence observation of transgenic plants expressing bHLH129-GFP showed that bHLH129 was localized in the nucleus, and transient expression of bHLH129 in protoplasts inhibited reporter gene expression. When expressed in Arabidopsis under the control of the 35S promoter, bHLH129 promoted root elongation, and the transgenic plants were less sensitivity to ABA in root elongation assays. Quantitative RT-PCR results showed that ABA response of several genes involved in ABA signaling, including ABI1, SnRK2.2, SnRK2.3 and SnRK2.6 were altered in the transgenic plants overexpressing bHLH129. Taken together, our study suggests that bHLH129 is a transcription repressor that negatively regulates ABA response in Arabidopsis. PMID- 26625869 TI - Tolerability and performance of BIP endotracheal tubes with noble metal alloy coating--a randomized clinical evaluation study. AB - BACKGROUND: Hospital acquired infections worsen the outcome of patients treated in intensive care units and are costly. Coatings with silver or metal alloys may reduce or alter the formation of biofilm on invasive medical devices. An endotracheal tube (ETT) is used to connect the patient to a ventilator and coated tubes have been tested in relation to bacterial colonization and respiratory infection. In the present study, we aimed to evaluate and compare a coated and uncoated ETT for patient symptoms and local tracheal tolerability during short term clinical use. Degree of bacterial colonization was also described. METHODS: A silver-palladium-gold alloy coating ('Bactiguard(r)'Infection Protection, BIP) has been extensively used on urinary tract catheters and lately also on central venous catheters. We performed a randomised, single-blinded, controlled, first in man, post Conformite Europeenne (EC) certification and CE marking study, focused on Bactiguard(r) coated ETTs (BIP ETT). Thirty patients at a tertiary university hospital scheduled for upper abdominal elective surgery with an expected duration of anaesthesia of at least 3 h were randomised; BIP ETT (n = 20) or standard ETT (n = 10). The tolerability was assessed with a modified version of Quality of Life Head and Neck Module, QLQ-H&N35 and by inspection of the tracheal mucosa with a fibre-optic bronchoscope before intubation and at extubation. Adverse Events (AE) and bacterial adherence were also studied. Statistical evaluations were carried out with the Fisher's Exact Test, the Clopper-Pearson method, as well as a Proportional Odds Model. RESULTS: Differences between groups were identified in 2 of 8 patient related symptoms with regard to tolerability by QLQ H&N35 (cough, p = 0.022 and dry mouth, p = 0.014 in the treatment group.). No mucosal damage was identified with bronchoscopy. A low level of bacterial colonization with normal flora, equal between groups, was seen after short-term of intubation (median 5 h). No serious Adverse Events related to the use of an ETT were observed. The results should be treated with caution due to statistical confounders, a small study size and large inter-individual variability in bacterial adhesion. CONCLUSIONS: The new device BIP ETT is well tolerated and has good clinical performance during short-term intubation. Studies with larger sample sizes and longer intubation periods (>24 h) in the ICU-setting are needed and can now be planned in order to identify possible differences in clinical outcomes. TRIAL REGISTRATION: Registered in ClinicalTrials.gov, REGISTRATION NUMBER: NCT01682486 , Date of Registration: August, 30, 2012. PMID- 26625871 TI - Rapid accumulation and low degradation: key parameters of Tomato yellow leaf curl virus persistence in its insect vector Bemisia tabaci. AB - Of worldwide economic importance, Tomato yellow leaf curl virus (TYLCV, Begomovirus) is responsible for one of the most devastating plant diseases in warm and temperate regions. The DNA begomoviruses (Geminiviridae) are transmitted by the whitefly species complex Bemisia tabaci. Although geminiviruses have long been described as circulative non-propagative viruses, observations such as long persistence of TYLCV in B. tabaci raised the question of their possible replication in the vector. We monitored two major TYLCV strains, Mild (Mld) and Israel (IL), in the invasive B. tabaci Middle East-Asia Minor 1 cryptic species, during and after the viral acquisition, within two timeframes (0-144 hours or 0 20 days). TYLCV DNA was quantified using real-time PCR, and the complementary DNA strand of TYLCV involved in viral replication was specifically quantified using anchored real-time PCR. The DNA of both TYLCV strains accumulated exponentially during acquisition but remained stable after viral acquisition had stopped. Neither replication nor vertical transmission were observed. In conclusion, our quantification of the viral loads and complementary strands of both Mld and IL strains of TYLCV in B. tabaci point to an efficient accumulation and preservation mechanism, rather than to a dynamic equilibrium between replication and degradation. PMID- 26625870 TI - PLK2 phosphorylates and inhibits enriched TAp73 in human osteosarcoma cells. AB - TAp73, a member of the p53 tumor suppressor family, can substitute for p53 function, especially in p53-null and p53-mutant cells. However, TAp73 enrichment and phosphorylation change its transcriptional activity. Previously, we found that the antitumor function of TAp73 was reactivated by dephosphorylation. Polo like kinase 2 (PLK2) plays an important role in bone development. Using a biological information database and phosphorylation prediction software, we hypothesized that PLK2 phosphorylates TAp73 and inhibits TAp73 function in osteosarcomas. Actually,we determined that PLK2 physically binds to and phosphorylates TAp73 when TAp73 protein abundance is up-regulated by cisplatin. PLK2-phosphorylated TAp73 at residue Ser48 within the TA domain; phosphorylation of TAp73 was abolished by mutating this residue. Moreover, PLK2 inhibition combined with cisplatin treatment in osteosarcoma Saos2 cells up-regulated p21 and puma mRNA expression to a greater extent than cisplatin treatment alone. Inhibiting PLK2 in TAp73-enriched Saos2 cells resulted in inhibited cell proliferation, increased apoptosis, G1 phase arrest, and decreased cell invasion. However, these changes did not occur in TAp73 knockdown Saos2 cells. In conclusion, these findings reveal a novel PLK2 function in the phosphorylation of TAp73, which prevents TAp73 activity in osteosarcoma cells. Thereby, this research provides an insight into the clinical treatment of malignant tumors overexpressing TAp73. PMID- 26625872 TI - Neuroinflammation. PMID- 26625874 TI - Dual role of fatty acid-binding protein 5 on endothelial cell fate: a potential link between lipid metabolism and angiogenic responses. AB - Fatty acid-binding proteins (FABP) are small molecular mass intracellular lipid chaperones that are expressed in a tissue-specific manner with some overlaps. FABP4 and FABP5 share ~55 % amino acid sequence homology and demonstrate synergistic effects in regulation of metabolic and inflammatory responses in adipocytes and macrophages. Recent studies have shown that FABP4 and FABP5 are also co-expressed in a subset of endothelial cells (EC). FABP4, which has a primarily microvascular distribution, enhances angiogenic responses of ECs, including proliferation, migration, and survival. However, the vascular expression of FABP5 has not been well characterized, and the role of FABP5 in regulation of angiogenic responses in ECs has not been studied to date. Herein we report that while FABP4 and FABP5 are co-expressed in microvascular ECs in several tissues, FABP5 expression is also detected in ECs of larger blood vessels. In contrast to FABP4, EC-FABP5 levels are not induced by VEGF-A or bFGF. FABP5 deficiency leads to a profound impairment in EC proliferation and chemotactic migration. These effects are recapitulated in an ex vivo assay of angiogenesis, the aortic ring assay. Interestingly, in contrast to FABP4 deficient ECs, FABP5-deficient ECs are significantly more resistant to apoptotic cell death. The effect of FABP5 on EC proliferation and survival is mediated, only in part, by PPARdelta-dependent pathways. Collectively, these findings demonstrate that EC-FABP5, similar to EC-FABP4, promotes angiogenic responses under certain conditions, but it can also exert opposing effects on EC survival as compared to EC-FABP4. Thus, the balance between FABP4 and FABP5 in ECs may be important in regulation of angiogenic versus quiescent phenotypes in blood vessels. PMID- 26625876 TI - Spectrum bias, a common unrecognised issue in orthopaedic agreement studies: do CT scans really influence the agreement on treatment plans in fractures of the distal radius? AB - OBJECTIVES: Current studies on the additional benefit of using computed tomography (CT) in order to evaluate the surgeons' agreement on treatment plans for fracture are inconsistent. This inconsistency can be explained by a methodological phenomenon called 'spectrum bias', defined as the bias inherent when investigators choose a population lacking therapeutic uncertainty for evaluation. The aim of the study is to determine the influence of spectrum bias on the intra-observer agreement of treatment plans for fractures of the distal radius. METHODS: Four surgeons evaluated 51 patients with displaced fractures of the distal radius at four time points: T1 and T2: conventional radiographs; T3 and T4: radiographs and additional CT scan (radiograph and CT). Choice of treatment plan (operative or non-operative) and therapeutic certainty (five-point scale: very uncertain to very certain) were rated. To determine the influence of spectrum bias, the intra-observer agreement was analysed, using Kappa statistics, for each degree of therapeutic certainty. RESULTS: In cases with high therapeutic certainty, intra-observer agreement based on radiograph was almost perfect (0.86 to 0.90), but decreased to moderate based on a radiograph and CT (0.47 to 0.60). In cases with high therapeutic uncertainty, intra-observer agreement was slight at best (-0.12 to 0.19), but increased to moderate based on the radiograph and CT (0.56 to 0.57). CONCLUSION: Spectrum bias influenced the outcome of this agreement study on treatment plans. An additional CT scan improves the intra observer agreement on treatment plans for a fracture of the distal radius only when there is therapeutic uncertainty. Reporting and analysing intra-observer agreement based on the surgeon's level of certainty is an appropriate method to minimise spectrum bias. Cite this article: Bone Joint Res 2015;4:190-194. PMID- 26625875 TI - Pheromone Blend Analysis and Cross-Attraction among Populations of Maruca vitrata from Asia and West Africa. AB - The legume pod borer, Maruca vitrata, is a pantropical pest on leguminous crops. (E,E)-10,12-Hexadecadienal, (E,E)-10,12-hexadecadienol, and (E)-10-hexadecenal were described previously as sex pheromone components for this nocturnal moth. A blend of these components in a ratio of 100:5:5 attracted males in field trapping experiments in Benin, but not in Taiwan, Thailand, or Vietnam. This finding suggests geographic variation in the pheromone blend between Asian and West African populations of M. vitrata. We, therefore, determined the pheromone compositions of single pheromone glands of females from the three Asian regions and from Benin by gas chromatography-mass spectrometry. Additionally, we compared the responses of males from Taiwan and Benin to calling females and to gland extracts of females from both regions in laboratory no-choice and two-choice assays. Chemical analysis revealed the presence of (E,E)-10,12-hexadecadienal and (E,E)-10,12-hexadecadienol, as well as the absence of (E)-10-hexadecenal in all four populations. The relative amounts of the detected compounds did not vary significantly among the insect populations. The behavioral bioassays showed that Taiwanese and Beninese males were similarly attracted to females from both regions, as well as to their gland extracts. As a result, we did not find geographic variation in the sexual communication system of M. vitrata between West African and Asian insect populations. PMID- 26625877 TI - How I manage Evans Syndrome and AIHA cases in children. AB - The management of Evans Syndrome in children is challenging due to the lack of evidence-based data on treatment. Steroids, the first-choice therapy, are successful in about 80% of cases. For children who are resistant, relapse or become steroid-dependent, rituximab is considered a valid second-line treatment, with the exception of those with an underlying diagnosis of autoimmune lymphoproliferative syndrome who may benefit from other options such as mycophenolate mofetil and sirolimus. Better knowledge of the immunological mechanisms underlying cytopenias and the availability of new immunosuppressive drugs can be helpful in the choice of more targeted therapies that would enable the reduction of the use of long-term steroid administration or other more aggressive options, such as splenectomy or stem cell transplantation. This manuscript provides an overview of the pathogenic background of the disease, and suggests a clinical approach to diagnosis and treatment with a particular focus on the management of relapsing/resistant disease. PMID- 26625878 TI - Dosing strategies and optimization of targeted therapy in advanced renal cell carcinoma. AB - Within the past decade, treatment options for metastatic renal cell carcinoma have expanded dramatically. Currently, seven targeted agents are approved for use in metastatic renal cell carcinoma and have superseded the use of parenteral cytokine therapy with interleukin-2 or interferon, the former standards of care for metastatic renal cell carcinoma. Targeted agents include inhibitors of the vascular endothelial growth factor pathway (i.e. sorafenib, sunitinib, pazopanib, axitinib, and bevacizumab) and inhibitors of the mammalian target of rapamycin pathway (i.e. temsirolimus and everolimus). These newer therapies have been shown to improve progression-free survival compared with previous approaches. Because most of these targeted agents are taken orally, responsibility for dose administration has shifted to patients, which might result in variable adherence. Additionally, with new treatments for metastatic renal cell carcinoma comes the challenge of selecting dosing schemes that maximize therapeutic benefit and minimize adverse events. Much of the information related to the effectiveness of dose modifications for targeted therapies in metastatic renal cell carcinoma has been gathered from clinical studies that have strict inclusion and exclusion criteria, which might not translate directly to real-world patient populations. This review discusses the impact of dose adherence on the effectiveness of targeted agents to treat metastatic renal cell carcinoma, assesses the literature regarding the effectiveness of approved dosing strategies, and provides a summary of alternative dosing strategies. PMID- 26625873 TI - Experimental animal models and inflammatory cellular changes in cerebral ischemic and hemorrhagic stroke. AB - Stroke, including cerebral ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage, is the leading cause of long-term disability and death worldwide. Animal models have greatly contributed to our understanding of the risk factors and the pathophysiology of stroke, as well as the development of therapeutic strategies for its treatment. Further development and investigation of experimental models, however, are needed to elucidate the pathogenesis of stroke and to enhance and expand novel therapeutic targets. In this article, we provide an overview of the characteristics of commonly-used animal models of stroke and focus on the inflammatory responses to cerebral stroke, which may provide insights into a framework for developing effective therapies for stroke in humans. PMID- 26625879 TI - The role of preoperative breast magnetic resonance (MR) imaging for surgical decision in patients with triple-negative breast cancer. AB - BACKGROUND: Several reliable randomized studies do not recommend routine preoperative breast MR imaging for patients with breast cancer. However, because the principle of MR imaging is based on the dynamics of contrast enhancement, a specific biologic subgroup of tumors should sensitively respond to the imaging process. METHODS: From 2008 to 2013, 918 eligible patients with breast cancer underwent breast surgery and were divided into two groups based on preoperative breast MR findings: patients in whom the surgical plan was changed and those in whom the surgical plan remained unchanged. We investigated the changing patterns of breast surgery based on routine mammography, ultrasound, and preoperative breast magnetic resonance (MR) findings and analyzed the association between additional suspicious lesions on breast MR imaging and clinicopathologic factors. RESULTS: Additional suspicious breast lesions were detected on preoperative MR imaging in 104 cases (11.3%), and the surgical strategy was changed as the final decision in 97 cases (10.6%). There was no difference between oncologic results between two groups. However, the triple-negative breast cancer (TNBC) was significantly associated with changing of the surgical strategy based on breast MR findings (P = 0.048). CONCLUSIONS: Additional preoperative breast MR imaging may be helpful in surgical decision for patients with TNBC. PMID- 26625882 TI - Neurochemical modulation of repetition suppression and novelty signals in the human brain. AB - The repeated processing of a sensory stimulus, such as a picture or sound, leads to a decrement in response in neurons that fired to the initial presentation. These effects are well known from single cell recordings in the inferior temporal cortex in monkeys, and functional neuroimaging in humans on large-scale neural activity could show similar effects in extrastriate, frontal and medial temporal lobe (MTL) regions. The role of specific neurotransmitters in repeated processing of information is, however, less clear. In the first part of this article, we will introduce the two concepts of repetition suppression and novelty signals, which is followed by a brief overview of pharmacological neuroimaging in humans. We will then summarize human studies suggesting that gamma-aminobutyric-acid (GABA) and acetylcholine (ACh) play an important role in modulating behavioral priming and associated repetition suppression in extrastriate and frontal brain regions. Finally, we review studies on neural novelty signals in the dopaminergic mesolimbic system, and conclude that dopamine (DA) regulates the temporal aspects of novelty processing and closely relates to long-term memory encoding rather than behavioral priming. As such, this review describes differential roles of GABA, ACh and DA in repeated stimulus processing, and further suggests that repetition suppression and neural novelty signals may not be two sides of the same coin but rather independent processes. PMID- 26625880 TI - Improvement in Renal Function and Reduction in Serum Uric Acid with Intensive Statin Therapy in Older Patients: A Post Hoc Analysis of the SAGE Trial. AB - BACKGROUND: Improvement in renal function and decreases in serum uric acid (SUA) have been reported following prolonged high-intensity statin (HMG-CoA reductase inhibitor) therapy. This post hoc analysis of the SAGE trial examined the effect of intensive versus less intensive statin therapy on renal function, safety, and laboratory parameters, including SUA, in elderly coronary artery disease (CAD) patients (65-85 years) with or without chronic kidney disease (CKD). METHODS: Patients were randomized to atorvastatin 80 mg/day or pravastatin 40 mg/day and treated for 12 months. Patients were stratified using Modification of Diet in Renal Disease (MDRD) estimated glomerular filtration rates (eGFRs) in CKD (eGFR <60 mL/min/1.73 m(2)) and non-CKD populations. RESULTS: Of the 893 patients randomized, 858 had complete renal data and 418 of 858 (49%) had CKD (99% Stage 3). Over 12 months, eGFR increased with atorvastatin and remained stable with pravastatin (+2.38 vs. +0.18 mL/min/1.73 m(2), respectively; p < 0.0001). MDRD eGFR improved significantly in both CKD treatment arms; however, the increased eGFR in patients without CKD was significantly greater with atorvastatin (+2.08 mL/min/1.73 m(2)) than with pravastatin (-1.04 mL/min/1.73 m(2)). Modest reductions in SUA were observed in both treatment arms, but a greater fall occurred with atorvastatin than with pravastatin (-0.52 vs. -0.09 mg/dL, p < 0.0001). Change in SUA correlated negatively with changes in eGFR and positively with changes in low-density lipoprotein cholesterol. Reports of myalgia were rare (3.6% CKD; 5.7% non-CKD), and there were no episodes of rhabdomyolysis. Elevated serum alanine and aspartate transaminase to >3 times the upper limit of normal occurred in 4.4% of atorvastatin- and 0.2% of pravastatin-treated patients. CONCLUSION: Intensive management of dyslipidemia in older patients with stable coronary heart disease may have beneficial effects on renal function and SUA. PMID- 26625883 TI - Enhanced Light Emission due to Formation of Semi-polar InGaN/GaN Multi-quantum Wells. AB - InGaN/GaN multi-quantum wells (MQWs) are grown on (0001) sapphire substrates by metal organic chemical vapor deposition (MOCVD) with special growth parameters to form V-shaped pits simultaneously. Measurements by atomic force microscopy (AFM) and transmission electron microscopy (TEM) demonstrate the formation of MQWs on both (0001) and ([Formula: see text]) side surface of the V-shaped pits. The latter is known to be a semi-polar surface. Optical characterizations together with theoretical calculation enable us to identify the optical transitions from these MQWs. The layer thickness on ([Formula: see text]) surface is smaller than that on (0001) surface, and the energy level in the ([Formula: see text]) semi polar quantum well (QW) is higher than in the (0001) QW. As the sample temperature is increased from 15 K, the integrated cathodoluminescence (CL) intensity of (0001) MQWs increases first and then decreases while that of the ([Formula: see text]) MQWs decreases monotonically. The integrated photoluminescence (PL) intensity of (0001) MQWs increases significantly from 15 to 70 K. These results are explained by carrier injection from ([Formula: see text]) to (0001) MQWs due to thermal excitation. It is therefore concluded that the emission efficiency of (0001) MQWs at high temperatures can be greatly improved due to the formation of semi-polar MQWs. PMID- 26625884 TI - AlN Nanowall Structures Grown on Si (111) Substrate by Molecular Beam Epitaxy. AB - AlN nanowall structures were grown on Si (111) substrate using molecular beam epitaxy at substrate temperature of 700 degrees C with N/Al flux ratios ranging from 50 to 660. A few types of other AlN nanostructures were also grown under the nitrogen-rich conditions. The AlN nanowalls were ranged typically 60-120 nm in width and from 190 to 470 nm in length by changing N/Al flux ratio. The AlN nanowall structures grown along the c-plane consisted of AlN (0002) crystal with full-width at half maximum of the rocking curve about 5000 arcsec. PMID- 26625885 TI - Gas-Sensing Devices Based on Zn-Doped NiO Two-Dimensional Grainy Films with Fast Response and Recovery for Ammonia Molecule Detection. AB - Zn-doped NiO two-dimensional grainy films on glass substrates are shown to be an ammonia-sensing material with excellent comprehensive performance, which could real-time detect and monitor ammonia (NH3) in the surrounding environment. The morphology and structure analysis indicated that the as-fabricated semiconductor films were composed of particles with diameters ranging from 80 to 160 nm, and each particle was composed of small crystalline grain with a narrow size about 20 nm, which was the face-centered cubic single crystal structure. X-ray diffraction peaks shifted toward lower angle, and the size of the lattice increased compared with undoped NiO, which demonstrated that zinc ions have been successfully doped into the NiO host structure. Simultaneously, we systematically investigated the gas-sensing properties of the Zn-doped NiO sensors for NH3 detection at room temperature. The sensor based on doped NiO sensing films gave four to nine times faster response and four to six times faster recovery speeds than those of sensor with undoped NiO films, which is important for the NiO sensor practical applications. Moreover, we found that the doped NiO sensors owned outstanding selectivity toward ammonia. PMID- 26625886 TI - Ultrasonic Substrate Vibration-Assisted Drop Casting (SVADC) for the Fabrication of Photovoltaic Solar Cell Arrays and Thin-Film Devices. AB - A simple, low-cost, versatile, and potentially scalable casting method is proposed for the fabrication of micro- and nano-thin films, herein termed as ultrasonic "substrate vibration-assisted drop casting" (SVADC). The impingement of a solution drop onto a substrate in a simple process called drop casting, usually results in spreading of the liquid solution and the formation of a non uniform thin solid film after solvent evaporation. Our previous and current supporting results, as well as few similar reports by others, confirm that imposing ultrasonic vibration on the substrate can simply convert the uncontrollable drop casting method into a controllable coating technique. Therefore, the SVADC may be used to fabricate an array of emerging thin-film solar cells, such as polymer, perovskite, and quantum-dot solar cells, as well as other small thin-film devices, in a roll-to-roll and automated fabrication process. The preliminary results demonstrate a ten-fold increase in electrical conductivity of PEDOT: PSS made by SVADC compared with the film made by conventional drop casting. Also, simple planar perovskite solar cells made here using SVADC show promising performance with an efficiency of over 3 % for a simple structure without performing process optimization or using expensive materials and treatments. PMID- 26625887 TI - Nanotribological and Nanomechanical Properties Changes of Tooth After Bleaching and Remineralization in Wet Environment. AB - Teeth bleaching cases had increased with people's desire for oral aesthetic; however, bleached teeth would still undertake chewing actions and remineralizing process in saliva. Nanotribological and nanomechanical properties are proper displays for dental performance of bleached teeth. The purpose of the research was to reveal the effect of bleaching and remineralization on the nanotribological and nanomechanical properties of teeth in wet environment. The specimens were divided into four groups according to the bleaching products used: 12 % hydrogen peroxide (HP) (12HP group); 15 % carbamide peroxide (CP) (15CP group); 35 % CP (35CP group); and artificial saliva (control group). The nanotribological and nanomechanical property changes of tooth enamel after bleaching and remineralization were evaluated respectively by nanoscratch and nanoindentation tests in wet environment, imitating the wet oral environment. The morphology changes were evaluated by statistical parametric mapping (SPM) and scanning electron microscopy (SEM). After bleaching, 12HP group and 15CP group showed increased scratch depth with more pile ups on the scratch edges, decreased nanohardness, and corroded surface appearance. While the 35CP group showed an increase in nanoscratch depth, no change in nanohardness and surface appearance was observed. The control group showed no change in these measurements. After remineralization, the three bleaching groups showed decreased nanoscratch depth and no change of nanohardness compared with the bleached teeth. And the control group showed no changes in nanotribological and nanomechanical properties. The nanotribological and nanomechanical properties of the 12HP group and 15CP group were affected by bleaching, but the nanotribological properties recovered partly and the nanomechanical properties got no change after 1 week of remineralization. As for the 35CP group, the nanotribological properties were influenced and the nanomechanical properties were not affected. These results remind us of taking actions to protect our teeth during bleaching. PMID- 26625888 TI - Structure of Biocompatible Coatings Produced from Hydroxyapatite Nanoparticles by Detonation Spraying. AB - Detonation-produced hydroxyapatite coatings were studied by scanning electron microscopy (SEM), X-ray powder diffraction (XRD), Raman spectroscopy, and electron paramagnetic resonance (EPR) spectroscopy. The source material for detonation spraying was a B-type carbonated hydroxyapatite powder. The coatings consisted of tetracalcium phosphate and apatite. The ratio depended slightly on the degree of crystallinity of the initial powder and processing parameters of the coating preparation. The tetracalcium phosphate phase was homogeneous; the apatite phase contained defects localized on the sixfold axis and consisted of hydroxyapatite and oxyapatite. Technological factors contributing to the transformation of hydroxyapatite powder structure during coating formation by detonation spraying are discussed. PMID- 26625889 TI - Inorganic Solar Cells Based on Electrospun ZnO Nanofibrous Networks and Electrodeposited Cu2O. AB - The nanostructured ZnO/copper oxide (Cu2O) photovoltaic devices based on electrospun ZnO nanofibrous network and electrodeposited Cu2O layer have been fabricated. The effects of the pH value of electrodeposition solution and the Cu2O layer thickness on the photovoltaic performances have been investigated. It is revealed that the pH value influences the morphology and structure of the Cu2O layer and thus the device performances. The Cu2O layer with an appropriate thickness benefits to charge transfer and light absorption. The device prepared at the optimal conditions shows the lowest recombination rate and exhibits a power conversion efficiency of ~0.77 %. PMID- 26625890 TI - Design of FLT3 Inhibitor - Gold Nanoparticle Conjugates as Potential Therapeutic Agents for the Treatment of Acute Myeloid Leukemia. AB - BACKGROUND: Releasing drug molecules at the targeted location could increase the clinical outcome of a large number of anti-tumor treatments which require low systemic damage and low side effects. Nano-carriers of drugs show great potential for such task due to their capability of accumulating and releasing their payload specifically, at the tumor site. RESULTS: FLT3 inhibitor - gold nanoparticle conjugates were fabricated to serve as vehicles for the delivery of anti-tumor drugs. Lestaurtinib, midostaurin, sorafenib, and quizartinib were selected among the FLT3 inhibitor drugs that are currently used in clinics for the treatment of acute myeloid leukemia. The drugs were loaded onto nanoparticle surface using a conjugation strategy based on hydrophobic-hydrophobic interactions with the Pluronic co-polymer used as nanoparticle surface coating. Optical absorption characterization of the particles in solution showed that FLT3 inhibitor incorporated gold nanoparticles were uniformly distributed and chemically stable regardless of the drug content. Drug loading study revealed a high drug content in the case of midostaurin drug which also showed increased stability. Drug release test in simulated cancer cell conditions demonstrated more than 56 % release of the entrapped drug, a result that correlates well with the superior cytotoxicity of the nano-conjugates comparatively with the free drug. CONCLUSIONS: This is a pioneering study regarding the efficient loading of gold nanoparticles with selected FLT3 inhibitors. In vitro cytotoxicity assessment shows that FLT3-incorporated gold nanoparticles are promising candidates as vehicles for anti-tumor drugs and demonstrate superior therapeutic effect comparatively with the bare drugs. PMID- 26625891 TI - Enhanced Electrochemical Catalytic Efficiencies of Electrochemically Deposited Platinum Nanocubes as a Counter Electrode for Dye-Sensitized Solar Cells. AB - Platinum nanocubes (PtNCs) were deposited onto a fluorine-doped tin oxide glass by electrochemical deposition (ECD) method and utilized as a counter electrode (CE) for dye-sensitized solar cells (DSSCs). In this study, we controlled the growth of the crystalline plane to synthesize the single-crystal PtNCs at room temperature. The morphologies and crystalline nanostructure of the ECD PtNCs were examined by field emission scanning electron microscopy and high-resolution transmission electron microscopy. The surface roughness of the ECD PtNCs was examined by atomic force microscopy. The electrochemical properties of the ECD PtNCs were analyzed by cyclic voltammetry, Tafel polarization, and electrochemical impedance spectra. The Pt loading was examined by inductively coupled plasma mass spectrometry. The DSSCs were assembled via an N719 dye sensitized titanium dioxide working electrode, an iodine-based electrolyte, and a CE. The photoelectric conversion efficiency (PCE) of the DSSCs with the ECD PtNC CE was examined under the illumination of AM 1.5 (100 mWcm(-2)). The PtNCs in this study presented a single-crystal nanostructure that can raise the electron mobility to let up the charge-transfer impedance and promote the charge-transfer rate. In this work, the electrocatalytic mass activity (MA) of the Pt film and PtNCs was 1.508 and 4.088 mAmg(-1), respectively, and the MA of PtNCs was 2.71 times than that of the Pt film. The DSSCs with the pulse-ECD PtNC CE showed a PCE of 6.48 %, which is higher than the cell using the conventional Pt film CE (a PCE of 6.18 %). In contrast to the conventional Pt film CE which is fabricated by electron beam evaporation method, our pulse-ECD PtNCs maximized the Pt catalytic properties as a CE in DSSCs. The results demonstrated that the PtNCs played a good catalyst for iodide/triiodide redox couple reactions in the DSSCs and provided a potential strategy for electrochemical catalytic applications. PMID- 26625892 TI - Diversity analysis of sulfite- and sulfate-reducing microorganisms by multiplex dsrA and dsrB amplicon sequencing using new primers and mock community-optimized bioinformatics. AB - Genes encoding dissimilatory sulfite reductase (DsrAB) are commonly used as diagnostic markers in ecological studies of sulfite- and sulfate-reducing microorganisms. Here, we developed new high-coverage primer sets for generation of reductive bacterial-type dsrA and dsrB polymerase chain reaction (PCR) products for highly parallel amplicon sequencing and a bioinformatics workflow for processing and taxonomic classification of short dsrA and dsrB reads. We employed two diverse mock communities that consisted of 45 or 90 known dsrAB sequences derived from environmental clones to precisely evaluate the performance of individual steps of our amplicon sequencing approach on the Illumina MiSeq platform. Although PCR cycle number, gene-specific primer mismatches and stringent filtering for high-quality sequences had notable effects on the observed dsrA and dsrB community structures, recovery of most mock community sequences was generally proportional to their relative input abundances. Successful dsrA and dsrB diversity analysis in selected environmental samples further proved that the multiplex amplicon sequencing approach is adequate for monitoring spatial distribution and temporal abundance dynamics of dsrAB containing microorganisms. Although tested for reductive bacterial-type dsrAB, this method is readily applicable for oxidative-type dsrAB of sulfur-oxidizing bacteria and also provides guidance for processing short amplicon reads of other functional genes. PMID- 26625893 TI - Supersensitive Kappa Opioid Receptors Promotes Ethanol Withdrawal-Related Behaviors and Reduce Dopamine Signaling in the Nucleus Accumbens. AB - BACKGROUND: Chronic ethanol exposure reduces dopamine transmission in the nucleus accumbens, which may contribute to the negative affective symptoms associated with ethanol withdrawal. Kappa opioid receptors have been implicated in withdrawal-induced excessive drinking and anxiety-like behaviors and are known to inhibit dopamine release in the nucleus accumbens. The effects of chronic ethanol exposure on kappa opioid receptor-mediated changes in dopamine transmission at the level of the dopamine terminal and withdrawal-related behaviors were examined. METHODS: Five weeks of chronic intermittent ethanol exposure in male C57BL/6 mice were used to examine the role of kappa opioid receptors in chronic ethanol-induced increases in ethanol intake and marble burying, a measure of anxiety/compulsive-like behavior. Drinking and marble burying were evaluated before and after chronic intermittent ethanol exposure, with and without kappa opioid receptor blockade by nor-binaltorphimine (10mg/kg i.p.). Functional alterations in kappa opioid receptors were assessed using fast scan cyclic voltammetry in brain slices containing the nucleus accumbens. RESULTS: Chronic intermittent ethanol-exposed mice showed increased ethanol drinking and marble burying compared with controls, which was attenuated with kappa opioid receptor blockade. Chronic intermittent ethanol-induced increases in behavior were replicated with kappa opioid receptor activation in naive mice. Fast scan cyclic voltammetry revealed that chronic intermittent ethanol reduced accumbal dopamine release and increased uptake rates, promoting a hypodopaminergic state of this region. Kappa opioid receptor activation with U50,488H concentration-dependently decreased dopamine release in both groups; however, this effect was greater in chronic intermittent ethanol-treated mice, indicating kappa opioid receptor supersensitivity in this group. CONCLUSIONS: These data suggest that the chronic intermittent ethanol-induced increase in ethanol intake and anxiety/compulsive like behaviors may be driven by greater kappa opioid receptor sensitivity and a hypodopaminergic state of the nucleus accumbens. PMID- 26625895 TI - Mutated Pathways as a Guide to Adjuvant Therapy Treatments for Breast Cancer. AB - Adjuvant therapy following breast cancer surgery generally consists of either a course of chemotherapy, if the cancer lacks hormone receptors, or a course of hormonal therapy, otherwise. Here, we report a correlation between adjuvant strategy and mutated pathway patterns. In particular, we find that for breast cancer patients, pathways enriched in nonsynonymous mutations in the chemotherapy group are distinct from those of the hormonal therapy group. We apply a recently developed method that identifies collaborative pathway groups for hormone and chemotherapy patients. A collaborative group of pathways is one in which each member is altered in the same-generally large-number of samples. In particular, we find the following: (i) a chemotherapy group consisting of three pathways and a hormone therapy group consisting of 20, the members of the two groups being mutually exclusive; (ii) each group is highly enriched in breast cancer drivers; and (iii) the pathway groups are correlates of subtype-based therapeutic recommendations. These results suggest that patient profiling using these pathway groups can potentially enable the development of personalized treatment plans that may be more accurate and specific than those currently available. PMID- 26625894 TI - Combined Neuropeptide S and D-Cycloserine Augmentation Prevents the Return of Fear in Extinction-Impaired Rodents: Advantage of Dual versus Single Drug Approaches. AB - BACKGROUND: Despite its success in treating specific anxiety disorders, the effect of exposure therapy is limited by problems with tolerability, treatment resistance, and fear relapse after initial response. The identification of novel drug targets facilitating fear extinction in clinically relevant animal models may guide improved treatment strategies for these disorders in terms of efficacy, acceleration of fear extinction, and return of fear. METHODS: The extinction facilitating potential of neuropeptide S, D-cycloserine, and a benzodiazepine was investigated in extinction-impaired high anxiety HAB rats and 129S1/SvImJ mice using a classical cued fear conditioning paradigm followed by extinction training and several extinction test sessions to study fear relapse. RESULTS: Administration of D-cycloserine improved fear extinction in extinction-limited, but not in extinction-deficient, rodents compared with controls. Preextinction neuropeptide S caused attenuated fear responses in extinction-deficient 129S1/SvImJ mice at extinction training onset and further reduced freezing during this session. While the positive effects of either D-cycloserine or neuropeptide S were not persistent in 129S1/SvImJ mice after 10 days, the combination of preextinction neuropeptide S with postextinction D-cycloserine rendered the extinction memory persistent and context independent up to 5 weeks after extinction training. This dual pharmacological adjunct to extinction learning also protected against fear reinstatement in 129S1/SvImJ mice. CONCLUSIONS: By using the potentially nonsedative anxiolytic neuropeptide S and the cognitive enhancer D-cycloserine to facilitate deficient fear extinction, we provide here the first evidence of a purported efficacy of a dual over a single drug approach. This approach may render exposure sessions less aversive and more efficacious for patients, leading to enhanced protection from fear relapse in the long term. PMID- 26625897 TI - Using Organizational Science to Improve the Resident Selection Process: An Outsider's Perspective. PMID- 26625896 TI - Targeted Photodynamic Virotherapy Armed with a Genetically Encoded Photosensitizer. AB - Photodynamic therapy (PDT) is a minimally invasive antitumor therapy that eradicates tumor cells through a photosensitizer-mediated cytotoxic effect upon light irradiation. However, systemic administration of photosensitizer often makes it difficult to avoid a photosensitive adverse effect. The red fluorescent protein KillerRed generates reactive oxygen species (ROS) upon green light irradiation. Here, we show the therapeutic potential of a novel tumor-specific replicating photodynamic viral agent (TelomeKiller) constructed using the human telomerase reverse transcriptase (hTERT) promoter. We investigated the light induced antitumor effect of TelomeKiller in several types of human cancer cell lines. Relative cell viability was investigated using an XTT assay. The in vivo antitumor effect was assessed using subcutaneous xenografted tumor and lymph node metastasis models. KillerRed accumulation resulted in ROS generation and apoptosis in light-irradiated cancer cells. Intratumoral injection of TelomeKiller efficiently delivered the KillerRed protein throughout the tumors and exhibited a long-lasting antitumor effect with repeated administration and light irradiation in mice. Moreover, intratumorally injected TelomeKiller could spread into the regional lymph node area and eliminate micrometastasis with limited-field laser irradiation. Our results suggest that KillerRed has great potential as a novel photosensitizer if delivered with a tumor-specific virus mediated delivery system. TelomeKiller-based PDT is a promising antitumor strategy to efficiently eradicate tumor cells. PMID- 26625898 TI - Systematic Review of Ambulatory Transitional Care Management (TCM) Visits on Hospital 30-Day Readmission Rates. AB - To reduce readmission rates and prevent adverse outcomes after discharge, hospitals have begun implementing "transitional care" initiatives. This systematic review identifies research on the particular set of services now reimbursable by Medicare (transitional care management [TCM]) and evaluates the studies for program effectiveness. Results of 3 databases were screened for peer reviewed journal articles published between January 2004 and 2015 that report on readmissions of adults in the US health care system under the Medicare TCM bundle. ClinicalTrials.gov was queried for funded studies. Of 969 identified studies, 77 met inclusion criteria for relevance to transitional care and appropriateness of population and setting. Of these, only 3 articles incorporated all required elements for TCM service. Although 2 were program improvement designs and none were randomized controlled studies, each report reduced readmission rates. Evidence for TCM effectiveness is limited. Additional study of TCM implementation and programmatic support for TCM is warranted. PMID- 26625900 TI - MRI Screening in Women With a Personal History of Breast cancer. PMID- 26625899 TI - Performance of the Breast Cancer Risk Assessment Tool Among Women Age 75 Years and Older. AB - BACKGROUND: The Breast Cancer Risk Assessment Tool (BCRAT, "Gail model") is commonly used for breast cancer prediction; however, it has not been validated for women age 75 years and older. METHODS: We used Nurses' Health Study (NHS) data beginning in 2004 and Women's Health Initiative (WHI) data beginning in 2005 to compare BCRAT's performance among women age 75 years and older with that in women age 55 to 74 years in predicting five-year breast cancer incidence. BCRAT risk factors include: age, race/ethnicity, age at menarche, age at first birth, family history, history of benign breast biopsy, and atypia. We examined BCRAT's calibration by age by comparing expected/observed (E/O) ratios of breast cancer incidence. We examined discrimination by computing c-statistics for the model by age. All statistical tests were two-sided. RESULTS: Seventy-three thousand seventy-two NHS and 97 081 WHI women participated. NHS participants were more likely to be non-Hispanic white (96.2% vs 84.7% in WHI, P < .001) and were less likely to develop breast cancer (1.8% vs 2.0%, P = .02). E/O ratios by age in NHS were 1.16 (95% confidence interval [CI] = 1.09 to 1.23, age 57-74 years) and 1.31 (95% CI = 1.18 to 1.45, age >= 75 years, P = .02), and in WHI 1.03 (95% CI = 0.97 to 1.09, age 55-74 years) and 1.10 (95% CI = 1.00 to 1.21, age >= 75 years, P = .21). E/O ratio 95% confidence intervals crossed one among women age 75 years and older when samples were limited to women who underwent mammography and were without significant illness. C-statistics ranged between 0.56 and 0.58 in both cohorts regardless of age. CONCLUSIONS: BCRAT accurately predicted breast cancer for women age 75 years and older who underwent mammography and were without significant illness but had modest discrimination. Models that consider individual competing risks of non-breast cancer death may improve breast cancer risk prediction for older women. PMID- 26625901 TI - CFTR silencing in pancreatic beta-cells reveals a functional impact on glucose stimulated insulin secretion and oxidative stress response. AB - Cystic fibrosis (CF)-related diabetes (CFRD) has become a critical complication that seriously affects the clinical outcomes of CF patients. Although CFRD has emerged as the most common nonpulmonary complication of CF, little is known about its etiopathogenesis. Additionally, whether oxidative stress (OxS), a common feature of CF and diabetes, influences CFRD pathophysiology requires clarification. The main objective of this study was to shed light on the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in combination with OxS in insulin secretion from pancreatic beta-cells. CFTR silencing was accomplished in MIN6 cells by stable expression of small hairpin RNAs (shRNA), and glucose-induced insulin secretion was evaluated in the presence and absence of the valuable prooxidant system iron/ascorbate (Fe/Asc; 0.075/0.75 mM) along with or without the antioxidant Trolox (1 mM). Insulin output from CFTR-silenced MIN6 cells was significantly reduced (~ 70%) at basal and at different glucose concentrations compared with control Mock cells. Furthermore, CFTR silencing rendered MIN6 cells more sensitive to OxS as evidenced by both increased lipid peroxides and weakened antioxidant defense, especially following incubation with Fe/Asc. The decreased insulin secretion in CFTR-silenced MIN6 cells was associated with high levels of NF-kappaB (the major participant in inflammatory responses), raised apoptosis, and diminished ATP production in response to the Fe/Asc challenge. However, these defects were alleviated by the addition of Trolox, thereby pointing out the role of OxS in aggravating the effects of CFTR deficiency. Our findings indicate that CFTR deficiency in combination with OxS may contribute to endocrine cell dysfunction and insulin secretion, which at least in part may explain the development of CFRD. PMID- 26625903 TI - Size and characteristics of the biomedical research workforce associated with U.S. National Institutes of Health extramural grants. AB - The U.S. National Institutes of Health (NIH) annually invests approximately $22 billion in biomedical research through its extramural grant programs. Since fiscal year (FY) 2010, all persons involved in research during the previous project year have been required to be listed on the annual grant progress report. These new data have enabled the production of the first-ever census of the NIH funded extramural research workforce. Data were extracted from All Personnel Reports submitted for NIH grants funded in FY 2009, including position title, months of effort, academic degrees obtained, and personal identifiers. Data were de-duplicated to determine a unique person count. Person-years of effort (PYE) on NIH grants were computed. In FY 2009, NIH funded 50,885 grant projects, which created 313,049 full- and part-time positions spanning all job functions involved in biomedical research. These positions were staffed by 247,457 people at 2,604 institutions. These persons devoted 121,465 PYE to NIH grant-supported research. Research project grants each supported 6 full- or part-time positions, on average. Over 20% of positions were occupied by postdoctoral researchers and graduate and undergraduate students. These baseline data were used to project workforce estimates for FYs 2010-2014 and will serve as a foundation for future research. PMID- 26625902 TI - Rab GAPs AS160 and Tbc1d1 play nonredundant roles in the regulation of glucose and energy homeostasis in mice. AB - The related Rab GTPase-activating proteins (Rab GAPs) AS160 and Tbc1d1 regulate the trafficking of the glucose transporter GLUT4 that controls glucose uptake in muscle and fat cells and glucose homeostasis. AS160- and Tbc1d1-deficient mice exhibit different adipocyte- and skeletal muscle-specific defects in glucose uptake, GLUT4 expression and trafficking, and glucose homeostasis. A recent study analyzed male mice with simultaneous deletion of AS160 and Tbc1d1 (AS160(-/ )/Tbc1d1(-/-) mice). Herein, we describe abnormalities in male and female AS160( /-)/Tbc1d1(-/-) mice on another strain background. We confirm the earlier observation that GLUT4 expression and glucose uptake defects of single-knockout mice join in AS160(-/-)/Tbc1d1(-/-) mice to affect all skeletal muscle and adipose tissues. In large mixed fiber-type skeletal muscles, changes in relative basal GLUT4 plasma membrane association in AS160(-/-) and Tbc1d1(-/-) mice also combine in AS160(-/-)/Tbc1d1(-/-) mice. However, we found different glucose uptake abnormalities in isolated skeletal muscles and adipocytes than reported previously, resulting in different interpretations of how AS160 and Tbc1d1 regulate GLUT4 translocation to the cell surface. In support of a larger role for AS160 in glucose homeostasis, in contrast with the previous study, we find similarly impaired glucose and insulin tolerance in AS160(-/-)/Tbc1d1(-/-) and AS160(-/-) mice. However, in vivo glucose uptake abnormalities in AS160(-/ )/Tbc1d1(-/-) skeletal muscles differ from those observed previously in AS160(-/ ) mice, indicating additional defects due to Tbc1d1 deletion. Similar to AS160- and Tbc1d1-deficient mice, AS160(-/-)/Tbc1d1(-/-) mice show sex-specific abnormalities in glucose and energy homeostasis. In conclusion, our study supports nonredundant functions for AS160 and Tbc1d1. PMID- 26625904 TI - Combination of small RNAs for skeletal muscle regeneration. AB - Selectively controlling the expression of the target genes through RNA interference (RNAi) has significant therapeutic potential for injuries or diseases of tissues. We used this strategy to accelerate and enhance skeletal muscle regeneration for the treatment of muscular atrophy. In this study, we used myostatin small interfering (si)RNA (siGDF-8), a major inhibitory factor in the development and postnatal regeneration of skeletal muscle and muscle-specific microRNAs (miR-1 and -206) to further accelerate muscle regeneration. This combination of 3 small RNAs significantly improved the gene expression of myogenic regulatory factors in vitro, suggesting myogenic activation. Moreover, cell proliferation and myotube formation improved without compromising each other, which indicates the myogenic potential of this combination of small RNAs. The recovery of chemically injured tibialis anterior muscles in rats was significantly accelerated, both functionally and structurally. This novel combination of siRNA and miRNAs has promising therapeutic potential to improve in situ skeletal muscle regeneration. PMID- 26625905 TI - Neonatal near miss: a systematic review. AB - BACKGROUND: The concept of neonatal near miss has been proposed as a tool for assessment of quality of care in neonates who suffered any life-threatening condition. However, there are no internationally agreed concepts or criteria for defining or identifying neonatal near miss. The purpose of this study was to perform a systematic review of studies and markers that are able to identify neonatal near miss cases and predict neonatal mortality. METHODS: Electronic searches were performed in the Medline, Embase and Scielo databases, with no time or language restriction, until December 2014. The term "neonatal near miss" was used alone or in combination with terms related to neonatal morbidity/mortality and neonatal severity scores. Study selection criteria involved three steps: title, abstract and full text of the articles. Two researchers performed study selection and data extraction independently. Heterogeneity of study results did not permit the performance of meta-analysis. RESULTS: Following the inclusion and exclusion criteria adopted, only four articles were selected. Preterm and perinatal asphyxia were used as near miss markers in all studies. Health indicators on neonatal morbidity and mortality were extracted or estimated. The neonatal near miss rate was 2.6 to 8 times higher than the neonatal mortality rate. CONCLUSIONS: Pragmatic and management criteria are used to help develop the neonatal near miss concept. The most severe cases are identified and mortality is predicted with these criteria. Furthermore, the near miss concept can be used as a tool for evaluating neonatal care. It is the first step in building management strategies to reduce mortality and long-term sequelae. PMID- 26625906 TI - Specific effects of EEG based neurofeedback training on memory functions in post stroke victims. AB - BACKGROUND: Using EEG based neurofeedback (NF), the activity of the brain is modulated directly and, therefore, the cortical substrates of cognitive functions themselves. In the present study, we investigated the ability of stroke patients to control their own brain activity via NF and evaluated specific effects of different NF protocols on cognition, in particular recovery of memory. METHODS: N = 17 stroke patients received up to ten sessions of either SMR (N = 11, 12-15 Hz) or Upper Alpha (N = 6, e.g. 10-12 Hz) NF training. N = 7 stroke patients received treatment as usual as control condition. Furthermore, N = 40 healthy controls performed NF training as well. To evaluate the NF training outcome, a test battery assessing different cognitive functions was performed before and after NF training. RESULTS: About 70 % of both patients and controls achieved distinct gains in NF performance leading to improvements in verbal short- and long-term memory, independent of the used NF protocol. The SMR patient group showed specific improvements in visuo-spatial short-term memory performance, whereas the Upper Alpha patient group specifically improved their working memory performance. NF training effects were even stronger than effects of traditional cognitive training methods in stroke patients. NF training showed no effects on other cognitive functions than memory. CONCLUSIONS: Post-stroke victims with memory deficits could benefit from NF training as much as healthy controls. The used NF training protocols (SMR, Upper Alpha) had specific as well as unspecific effects on memory. Hence, NF might offer an effective cognitive rehabilitation tool improving memory deficits of stroke survivors. PMID- 26625907 TI - An improved SYBR Green-1-based fluorescence method for the routine monitoring of Plasmodium falciparum resistance to anti-malarial drugs. AB - BACKGROUND: The recently introduced SYBR Green1 (SG) assay for testing parasites susceptibility to anti-malarial drugs needs further improvement. This has been necessitated by various setbacks, the major one being the low fluorescence intensity associated with it use. This shortcoming diminishes the anticipated hope that this novel method was going to replace the more traditional ones, such as the isotopic and microscopy. In order to restore confidence in its use, series of experiments to determine conditions that give the best fluorescence intensity were conducted. METHODS: Conditions that yield the maximum fluorescent signal were ascertained by measuring the fluorescence after incubation of Plasmodium falciparum culture at different parasites concentration with lysis buffer containing SYBR Green (LBS) at different time period. In order to ascertain the effect of freeze-thaw on fluorescence intensity, P. falciparum culture was frozen for 1 h, thawed, incubated with LBS and the fluorescence measured. The optimized conditions determined in this study were then used to assess the susceptibility of clinical isolates of P. falciparum to artesunate, chloroquine and mefloquine. The concentration of anti-malarial drug inhibiting parasite growth by 50 % (IC50) for each drug was estimated using the online ICEstimator. The IC50 generated using the optimized SG method determined in this study was compared with that obtained using microscopic method and the previously reported standard SG method. RESULTS: Over all, the SG method was found to be easy to perform and sensitive. Freeze-thaw of parasite culture followed by incubation with lysis buffer containing the dye for 3 h was consistently observed to give the highest fluorescence signal. The IC50 values for chloroquine, mefloquine and artesunate determined were consistent and comparable with that determined with the previously reported standard SG method and the microscopic method. CONCLUSION: The authors conclude that freezing and thawing of parasite culture, followed by incubation with LBS in the dark for 3 h provided a significant improvement in fluorescence signal. The IC50 generated using the improved SG method is comparable with that from microscopy and the standard method. PMID- 26625908 TI - Determinants of acceptance of end-of-life interventions: a comparison between withdrawing life-prolonging treatment and euthanasia in Austria. AB - BACKGROUND: End-of-life decisions remain a hotly debated issue in many European countries and the acceptance in the general population can act as an important anchor point in these discussions. Previous studies on determinants of the acceptance of end-of-life interventions in the general population have not systematically assessed whether determinants differ between withdrawal of life prolonging treatment (WLPT) and euthanasia (EUT). METHODS: A large, representative survey of the Austrian adult population conducted in 2014 (n = 1,971) included items on WLPT and EUT. We constructed the following categorical outcome: (1) rejection of both WLPT and EUT, (2) approval of WLPT but rejection of EUT, and (3) approval of both WLPT and EUT. The influence of socio demographics, personal experiences, and religious and socio-cultural orientations on the three levels of approval were assessed via multinomial logistic regression analysis. RESULTS: Higher education and stronger socio-cultural liberal orientations increased the likelihood of approving both WLPT and EUT; personal experience with end-of-life care increased only the likelihood of approval of WLPT; and religiosity decreased approval of EUT only. CONCLUSION: This study found evidence for both shared (education, liberalism) and different (religiosity, care experiences) determinants for the acceptance of WLPT and EUT. PMID- 26625910 TI - Quasiclassical Trajectory Study on the Role of CH-Stretching Vibrational Excitation in the F((2)P) + CHD3(v(1)=0,1) Reactions. AB - To analyze the role of CH-stretching vibrational excitation on the reactivity and dynamics of the F((2)P) + CHD3(v1=0,1) reactions, quasiclassical trajectory calculations using a full-dimensional analytical potential energy surface at different collision energies were performed. The extra energy of the CH excitation had almost no effect on the reactivity for the DF + CHD2 channel, although it increased the reactivity for the HF + CD3 channel, with the net effect being that CH excitation barely modified overall reactivity. In addition, the DF/HF branching ratio was not far from the statistical value for the ground state reaction, whereas CH excitation decreased this ratio. These results, intimately related to the topology of the entrance channel, agree with recent theoretical results obtained using different surfaces (although some differences even persist among them) but strongly contradict recent experiments. This controversy will doubtless guarantee more accurate experiments and theoretical calculations in the future. However, properties related to the exit channel show reasonable theoretical/experimental agreement. Thus, the extra energy of CH excitation is mainly channelled into the HF and DF products for the HF + CD3 and DF + CHD 2 channels, respectively, and the product scattering distributions are forward in both channels, where CH excitation has almost no effect on them. PMID- 26625909 TI - Factors behind job preferences of Peruvian medical, nursing and midwifery students: a qualitative study focused on rural deployment. AB - BACKGROUND: Deployment of health workforce in rural areas is critical to reach universal health coverage. Students' perceptions towards practice in rural areas likely influence their later choice of a rural post. We aimed at exploring perceptions of students from health professions about career choice, job expectations, motivations and potential incentives to work in a rural area. METHODS: In-depth interviews and focus groups were conducted among medical, nursing and midwifery students from universities of two Peruvian cities (Ica and Ayacucho). Themes for assessment and analysis included career choice, job expectations, motivations and incentives, according to a background theory a priori built for the study purpose. RESULTS: Preference for urban jobs was already established at this undergraduate level. Solidarity, better income expectations, professional and personal recognition, early life experience and family models influenced career choice. Students also expressed altruism, willingness to choose a rural job after graduation and potential responsiveness to incentives for practising in rural areas, which emerged more frequent from the discourse of nursing and midwifery students and from all students of rural origin. Medical students expressed expectations to work in large urban hospitals offering higher salaries. They showed higher personal, professional and family welfare expectations. Participants consistently favoured both financial and non financial incentives. CONCLUSIONS: Nursing and midwifery students showed a higher disposition to work in rural areas than medical doctors, which was more evident in students of rural origin. Our results may be useful to improve targeting and selection of undergraduate students, to stimulate the inclination of students to choose a rural job upon graduation and to reorient school programmes towards the production of socially committed health professionals. Policymakers may also consider using our results when planning and implementing interventions to improve rural deployment of health professionals. PMID- 26625911 TI - Are urgent care centers a viable venue for recruitment in clinical trials? AB - Clinical trials are extremely difficult to undertake and recruiting patients for these trials is one of the most significant challenges. This brief report sought to determine the suitability of an urgent care center as a research recruitment site by assessing its patients' views on participating in clinical trials. One thousand and two subjects were surveyed over a 45-day period; 9.0 % had previously participated in clinical trials while 46.6 % indicated they would be interested in participating in future clinical trials if given the opportunity. This research suggests that the urgent care venue is a viable recruitment source for clinical trials. PMID- 26625913 TI - On the emergence and consolidation of bioethics as a discipline, as seen from a sociological perspective. AB - This article examines the emergence and consolidation of bioethics as a discipline from a sociological perspective. This reconstruction helps us to understand on the one hand what is meant by bioethics and what its practices and areas of inquiry are, and on the other to identify various concepts and expert opinions about what the field of study for bioethics should be, opinions which lead in practice to different applications of the discipline in health sciences. This becomes relevant for epistemological discussions about the discipline and for consolidating a sociology of bioethics in the context of Ibero-America. PMID- 26625912 TI - Editors' note. PMID- 26625914 TI - Hansen's disease in the state of Amazonas: policy and institutional treatment of a disease. AB - This article discusses the historical aspects of the policies for controlling Hansen's disease in the state of Amazonas from the second half of the nineteenth century until the dismantling of this model in 1978. We present the historical changes in the local institutions and policies, and their relationship with national policies. The history and policies related to Hansen's disease in the state of Amazonas are analyzed through the following institutions: Umirisal, the Oswaldo Cruz Dispensary, the Paricatuba Leprosarium, the Antonio Aleixo Colony, and the Gustavo Capanema Preventorium. We seek to show that these institutions cared for the people who suffered from Hansen's disease and those related to them, and were also responsible for carrying out the policies for fighting and controlling the disease. PMID- 26625915 TI - [For a society without secure psychiatric hospitals]. AB - The article explores the possibility of defending a society without secure psychiatric hospitals in Brazil. These hospitals have been sustained by persistent legal and psychiatric paradigms, including the notions "safety measure" and "dangerousness," in conjunction with particular social and historical circumstances. The open repression of so-called dangerous individuals is still practiced in the name of the principle of social defense, outdated concepts notwithstanding. Together, law and psychiatry constructed spaces of power/knowledge within these workings of social control. Addressing this topic from the transdisciplinary field of social memory means identifying the struggles within particular power/knowledge arrangements, which play out in a state of ongoing tension. PMID- 26625916 TI - [Therapeutic communities: "new" outlooks and public health proposals]. AB - Problems related to alcohol and other substance abuse are on a steady rise. Certain controversial measures currently aim at immediate solutions, such as the public funding of therapeutic communities. The article draws comparisons between the legacy of early twentieth-century public health practices in psychoactive substance abuse and current proposals for intervention through therapeutic communities. The study researched primary sources from the perspective of historical materialism. Historically produced by society as a whole, problems stemming from substance abuse continue to place the greatest burden on users, the people around them, and public health. PMID- 26625917 TI - [Pediatric psychosomatic medicine and the medicalization of childhood in Buenos Aires, 1940-1970]. AB - This article analyzes how the dominance of pediatric psychosomatic medicine in the Argentine medical field caused a transformation in treatments. It shows how, beginning in the 1950s, psy-experts and interdisciplinary approaches found a space at the Hospital de Ninos (Children's Hospital) in Buenos Aires; and how the growth of attachment theory made it possible for mothers to stay with their children in hospital. It explains the construction of certain conditions as "family diseases" in a context of declining birthrates. It focuses on the speeches of a key figure, Florencio Escardo, not only because he was hegemonic in the scientific field but because he also played an important role dispensing advice in the media. PMID- 26625918 TI - [Senior years, subjectivation, and biopolitics]. AB - The article explores the historical emergence of "senior years" as a contemporary signifier and concept that has left behind the previous interpretation of the aging process in modernity. It addresses this vital shift that occurred in the history of the West from an interdisciplinary perspective that encompasses social, economic, political, and familial interpretations. Emphasizing forms of subjectivation found during the senior years, it offers a critical interpretation of theoretical writings in psychopathology and neurology and highlights the process of social exclusion suffered by the elderly in the historical context of modernity. PMID- 26625919 TI - [The Hospital Real de Todos-os-Santos and its healing agents]. AB - The article explores the actions of king Dom Joao II (1481-1495), who spearheaded a major assistance reform in Portugal during the late fifteenth century, when charitable institutions were grappling with a serious crisis. The king and his queen, Dona Leonor, ordered two large, modern hospitals to be built, centralizing assistance work and cementing a new assistance model. Relying on chronicles and royal decrees from the period, the article focuses on the main hospital that was built then: Hospital Real de Todos-os-Santos, located in Lisbon. The king and queen also intervened heavily in the practice of health agents by regulating, overseeing, and inspecting the work of doctors and apothecaries. PMID- 26625920 TI - [Philanthropy, privatization, and reform: psychiatric assistance scenarios in the state of Parana]. AB - The article discusses different psychiatric assistance arrangements in Parana from the earliest years through today, taking into account the state's unique features and relations with national policies. This assistance was first provided in 1903, when the Hospicio Nossa Senhora da Luz philanthropic asylum was founded. It was only in 1954 that Hospital Colonia Adauto Botelho, the state's first public hospital, began operations. In the 1960s, the Parana government signed agreements with private hospitals for more beds in the interior, accelerating the provision of psychiatric assistance and fostering a privatization approach. This strategy led to the current situation in Parana, where specialized hospitals are the rule, despite the existence of other facilities foreseen under the psychiatric reform legislation. PMID- 26625921 TI - [The invention of animals: a history of Mexican veterinary medicine in the nineteenth century]. AB - This article analyzes a phenomenon I call "the invention of animals," that is, the way in which veterinary medicine and the practices of physiology, microbiology and zootechnics produced new and different ways of thinking about, studying, understanding, regulating, legislating, commercializing, exploiting and experiencing "the animal." In particular, the text focuses on the evolution of this phenomenon in Mexico during the nineteenth century, since during this period the impact of these disciplines on animal bodies led to significant changes in the fields of human medicine, public health, and livestock production. PMID- 26625922 TI - [Preserving the cultural heritage of health in Brazil: an emerging question]. AB - In a discussion that applies the category "heritage" to goods within the realm of health, the article problematizes the recent recognition and incipient protection of the cultural heritage of health in Brazil. It presents a roster of assets that receive federal protection through Brazil's Instituto do Patrimonio Historico e Artistico Nacional (IPHAN), including hospitals and health-related buildings as well as inventories conducted in a number of state capitals by the Brazilian Network for Cultural Heritage in Health. This approach suggests that preserving this valuable heritage is a matter of importance for the history of health in Brazil. PMID- 26625923 TI - ["Doliarina and iron powder": an important medicine at Peckolt Pharmacy]. AB - The pharmacist Theodoro Peckolt was one of the most important figures in the history of the chemistry of natural Brazilian products. Like other nineteenth century pharmacists in Brazil, he developed formulations and sold them at his pharmacy in Rio de Janeiro, and these enjoyed great prestige in the eyes both of the public and the medical community. The article discusses the relation between the illness originally called "opilacao" (ancylostomiasis, or hookworm) and nineteenth-century treatment. It focuses especially on Peckolt Pharmacy's "Doliarina and iron powder," a formulation extracted from the Ficus gomelleira rubber plant. One of the article's goals is to use modern methods to analyze Ficus gomelleira and identify the chemical composition of the drug. PMID- 26625924 TI - [The press, gender, and scientific culture in the 1960s: an interview with Eulina Cavalcante, journalist for the newspaper News Seller]. AB - The article offers an interview with journalist Eulina Cavalcante de Almeida, editor of the woman's section of the ABC Paulista newspaper News Seller in the 1960s. Almeida was responsible for introducing women's and scientific issues to the paper's female readers. Science formed one of the foundations of her writing as she offered her women readers scientific information, especially in the area of health. In the 1960s, the level of scientific literacy in Brazil rose and Almeida's work dovetailed with this trend. The woman's section of News Seller played a valuable role in science communication in the ABC Paulista. PMID- 26625925 TI - [Correspondence from Julio Porto-Carrero to Arthur Ramos: the Brazilian Psychoanalytic Society and concern over the translation of psychoanalytic terms in the 1920s and 1930s]. AB - The article presents the correspondence that psychiatrist Julio Porto-Carrero sent to psychiatrist Arthur Ramos in 1932 to inform him about the activities of the Brazilian Psychoanalytic Society and about a concern over systematizing the translation of certain psychoanalytic concepts into Portuguese. This correspondence is used in conjunction with the analysis of other sources to suggest that psychiatrists and psychoanalysts in Rio de Janeiro were then endeavoring to make a place for psychoanalysis in the day's medical and scientific circles and encourage ever more specialists in Brazil to take an interest in Freud's theory. PMID- 26625926 TI - [From educational and health tourism for children to social tourism: vacation camps in the Province of Buenos Aires, Argentina]. AB - The early twentieth century saw the rise of vacation camps for frail children as educational and health-giving experiences provided by medical and philanthropic organizations. This article analyzes some of these early experiences, seen here as the predecessors of social tourism, in the Province of Buenos Aires. A combination of written sources are examined, mainly institutional reports, periodicals such as the Monitor de la Educacion Comun - published by the Consejo Nacional de Educacion (National Board of Education) - or laws, with photographs and plans for different examples. I argue that these buildings were both physical and cultural "brands" in the places where they were located, and that their architectural structure encapsulated ideas about leisure space and cures in unique natural environments. PMID- 26625931 TI - Factors affecting willingness to practice medicine in underserved areas: a survey of Argentine medical students. AB - INTRODUCTION: Previous research has explored the effect of motivations, incentives and working conditions on willingness to accept jobs in rural and remote areas. These studies demonstrated that difficult working conditions, low job satisfaction and remuneration, and poor security, predisposed new medical graduates to select cities instead of rural districts. Since Argentina has a critical shortage of health staff in rural and low-income marginal suburban settings, and limited qualitative and quantitative local research has been done to address this issue, the present study was developed to assess the factors associated with the willingness of medical students to work in low-resource underprivileged areas of the country after graduation. METHODS: A cross-sectional descriptive design was used with data collected from a self-administered questionnaire and using quantitative analysis methods. A total of 400 eligible second-year medical students were invited to participate in a survey focused on sociodemographic characteristics, incentives and working conditions expected in deprived areas, extrinsic and intrinsic motivations, university medical education and government promotion policies. RESULTS: Twenty-one per cent of medical students showed a strong willingness to work in a deprived area, 57.3% manifested weak willingness and 21.5% unwillingness to work in a low-resource setting. Being female, of older age, not having a university-trained professional parent, previous exposure or service in a poor area, choice of pediatrics as a specialty and strong altruistic motivations were highly associated with the willingness to practice medicine in rural or underprivileged areas. Only 21.5% of respondents considered that medical schools encourage the practice of medicine in poor deprived regions. Likewise, only 6.2% of students considered that national public health authorities suitably stimulate physician distribution in poorer districts. CONCLUSIONS: One-third of students expressed high altruistic motivations and should therefore be encouraged during their careers. Better remuneration and the assurance of a position at an urban hospital in the future may tip the choice in favor of underprivileged regions. Since most respondents said that neither government nor medical schools sufficiently encourage the practice of medicine in poor deprived regions, government policy-makers should recommend changes in resource allocation to better promote official proposals and opportunities to work. PMID- 26625932 TI - Characteristics of users of a tailored, interactive website for parents and its impact on adolescent vaccination attitudes and uptake. AB - BACKGROUND: We examined the characteristics of parents using an iPad-based intervention about vaccines, and its impact on vaccination attitudes and behavior. METHODS: Interventions were implemented in three primary care clinics from June 2012-September 2013. Baseline and follow up surveys assessed vaccination attitudes and intentions. Medical records were used to examine adolescent vaccine uptake. RESULTS: During the study, 42 parents viewed tailored educational content. Users were generally positive about vaccines, though one out of five worried that vaccines caused more harm than good. Among the 16 parents completing the post-intervention survey, there was a slightly higher, non statistically significant, mean vaccination intention after viewing the website than prior to viewing it for three of the four adolescent vaccines (all except tetanus-diphtheria-acellular pertussis). Using the intervention did not increase the likelihood of adolescent vaccination. CONCLUSIONS: Providing educational material via iPads in clinic waiting rooms does not appear to be an effective strategy for engaging parents about vaccines. Overall, parents' interaction with TeenVaxScene was low, and had little impact on their vaccination attitudes and beliefs. However, use of TeenVaxScene did not appear to worsen parents' attitudes about vaccines. New and creative ideas for engaging parents to use such educational materials are needed. PMID- 26625933 TI - Validation of the modified agglutination test for the detection of Toxoplasma gondii in free-range chickens by using cat and mouse bioassay. AB - The modified agglutination test (MAT) is one of the most commonly used tests for the detection of antibodies to Toxoplasma gondii in animal and human sera. The objective of the present study was to evaluate the diagnostic accuracy of the MAT and bioassay in free-range/backyard (FR) chickens (Gallus domesticus). Previously published T. gondii test results from 2066 chickens from 19 countries were compiled for the present study. The frequency of isolation of T. gondii increased for MAT titres between 1:5 and 1:160, and ranged from 61 to 75% for antibody titres of 1:160, 1:320, and ?1:640. Twenty-three cats fed pooled hearts from a total of 802 FR seronegative (MAT, <1:5) chickens from several countries did not excrete oocysts, indicating a high negative predictive value of MAT because FR chickens would have been exposed to many microbes; cats are the most sensitive indicators of T. gondii infection in tissues and can excrete millions of oocysts after ingesting even a few bradyzoites. Of the 29 cats in this study, six cats, fed hearts pooled from 15-122 FR chickens, excreted oocysts; but these identifications were likely related to misidentification or prozone. Results of the present study support the validity of MAT for the detection of T. gondii infection in chickens. PMID- 26625934 TI - Plant expression and characterization of the transmission-blocking vaccine candidate PfGAP50. AB - BACKGROUND: Despite the limited success after decades of intensive research and development efforts, vaccination still represents the most promising strategy to significantly reduce the disease burden in malaria endemic regions. Besides the ultimate goal of inducing sterile protection in vaccinated individuals, the prevention of transmission by so-called transmission blocking vaccines (TBVs) is being regarded as an important feature of an efficient malaria eradication strategy. Recently, Plasmodium falciparum GAP50 (PfGAP50), a 44.6 kDa transmembrane protein that forms an essential part of the invasion machinery (glideosome) multi-protein complex, has been proposed as novel potential transmission-blocking candidate. Plant-based expression systems combine the advantages of eukaryotic expression with a up-scaling potential and a good product safety profile suitable for vaccine production. In this study we investigated the feasibility to use the transient plant expression to produce PfGAP50 suitable for the induction of parasite specific inhibitory antibodies. RESULTS: We performed the transient expression of recombinant PfGAP50 in Nicotiana benthamiana leaves using endoplasmatic reticulum (ER) and plastid targeting. After IMAC-purification the protein yield and integrity was investigated by SDS-PAGE and Western Blot. Rabbit immune IgG derived by the immunization with the plastid-targeted variant of PfGAP50 was analyzed by immune fluorescence assay (IFA) and zygote inhibition assay (ZIA). PfGAP50 could be produced in both subcellular compartments at different yields IMAC (Immobilized Metal Affinity Chromatography) purification from extract yielded up to 4.1 MUg/g recombinant protein per fresh leaf material for ER-retarded and16.2 MUg/g recombinant protein per fresh leave material for plasmid targeted PfGAP50, respectively. IgG from rabbit sera generated by immunization with the recombinant protein specifically recognized different parasite stages in immunofluorescence assay. Furthermore up to 55 % inhibition in an in vitro zygote inhibition assay could be achieved using PfGAP50-specific rabbit immune IgG. CONCLUSIONS: The results of this study demonstrate that the plant-produced PfGAP50 is functional regarding the presentation of inhibitory epitopes and could be considered as component of a transmission-blocking malaria vaccine formulation. PMID- 26625937 TI - Semi-quantitative myocardial perfusion measured by computed tomography in patients with refractory angina: a head-to-head comparison with quantitative rubidium-82 positron emission tomography as reference. AB - INTRODUCTION: Computed tomography (CT) is a novel method for assessment of myocardial perfusion and has not yet been compared to rubidium-82 positron emission tomography (PET). We aimed to compare CT measured semi-quantitative myocardial perfusion with absolute quantified myocardial perfusion using PET and to detect stenotic territories in patients with severe coronary artery disease. MATERIALS AND METHODS: Eighteen patients with stenosis narrowing coronary arteries >=70% demonstrated on invasive coronary angiography underwent rest and adenosine stress imaging obtained by 320-multidetector CT scanner and CT/PET 64 slice scanner. CT measured myocardial attenuation density (AD) and perfusion index (PI) were correlated to absolute PET myocardial perfusion values. RESULTS: Rest AD, rest and stress PI did not correlate to PET findings (r = 0.412, P = 0.113; r = 0.300, P = 0.259; and r = 0.508, P = 0.064, respectively). However, there was a significant correlation between stress AD and stress PET values (r = 0.670, P = 0.009) and between stress and rest differences for AD and PI with PET differences (r = 0.620, P = 0.006; and r = 0.639, P = 0.004, respectively). Furthermore, significant differences were observed between remote and stenotic territories for rest and stress AD (48 +/- 14HU and 37 +/- 16HU, P = 0.002; 76 +/ 19HU and 58 +/- 13HU, P<0.001, respectively), PI (9.6 +/- 2.9 and 7.5 +/- 3.1, P = 0.002; 21.6 +/- 4.1 and 16.9 +/- 3.9, P<0.001, respectively) and PET (0.96 +/- 0.37 ml g-1 min-1 and 0.86 +/- 0.26 ml g-1 min-1 , P = 0.036; 2.07 +/- 0.76 ml g-1 min-1 and 1.61 +/- 0.76 ml g-1 min-1 , P = 0.006, respectively). CONCLUSIONS: Semi-quantitative CT parameters may be useful in the detection of myocardium subtended by stenotic coronary arteries. PMID- 26625935 TI - The novel protein kinase C epsilon isoform modulates acetylcholine release in the rat neuromuscular junction. AB - BACKGROUND: Various protein kinase C (PKC) isoforms contribute to the phosphorylating activity that modulates neurotransmitter release. In previous studies we showed that nPKCepsilon is confined in the presynaptic site of the neuromuscular junction and its presynaptic function is activity-dependent. Furthermore, nPKCepsilon regulates phorbol ester-induced acetylcholine release potentiation, which further indicates that nPKCepsilon is involved in neurotransmission. The present study is designed to examine the nPKCepsilon involvement in transmitter release at the neuromuscular junction. RESULTS: We use the specific nPKCepsilon translocation inhibitor peptide epsilonV1-2 and electrophysiological experiments to investigate the involvement of this isoform in acetylcholine release. We observed that nPKCepsilon membrane translocation is key to the synaptic potentiation of NMJ, being involved in several conditions that upregulate PKC isoforms coupling to acetylcholine (ACh) release (incubation with high Ca(2+), stimulation with phorbol esters and protein kinase A, stimulation with adenosine 3',5'-cyclic monophosphorothioate, 8-Bromo-, Rp isomer, sodium salt -Sp-8-BrcAMP-). In all these conditions, preincubation with the nPKCepsilon translocation inhibitor peptide (epsilonV1-2) impairs PKC coupling to acetylcholine release potentiation. In addition, the inhibition of nPKCepsilon translocation and therefore its activity impedes that presynaptic muscarinic autoreceptors and adenosine autoreceptors modulate transmitter secretion. CONCLUSIONS: Together, these results point to the importance of nPKCepsilon isoform in the control of acetylcholine release in the neuromuscular junction. PMID- 26625938 TI - Beta emitters rhenium-188 and lutetium-177 are equally effective in radioimmunotherapy of HPV-positive experimental cervical cancer. AB - Cervical cancer caused by the infection with the human papillomavirus (HPV) remains the fourth leading killer of women worldwide. Therefore, more efficacious treatments are needed. We are developing radioimmunotherapy (RIT) of HPV-positive cervical cancers by targeting E6 and E7 viral oncoproteins expressed by the cancer cells with the radiolabeled monoclonal antibodies (mAbs). To investigate the influence of different radionuclides on the RIT efficacy-we performed RIT of experimental cervical cancer with Rhenium-188 ((188) Re) and Lutetium-177 ((177) Lu)-labeled mAb C1P5 to E6. The biodistribution of (188) Re- and (177) Lu-labeled C1P5 was performed in nude female mice bearing CasKi cervical cancer xenografts and the radiation dosimetry calculations for the tumors and organs were carried out. For RIT the mice were treated with 7.4 MBq of either (188) Re-C1P5 or (177) Lu-C1P5 or left untreated, and observed for their tumor size for 28 days. The levels of (188) Re- and (177) Lu-C1P5 mAbs-induced double-strand breaks in CasKi tumors were compared on days 5 and 10 post treatment by staining with anti-gamma H2AX antibody. The radiation doses to the heart and lungs were similar for both (177) Lu-C1P5 and (188) Re-C1P5. The dose to the liver was five times higher for (177) Lu-C1P5. The doses to the tumor were 259 and 181 cGy for (177) Lu-C1P5 and (188) Re-C1P5, respectively. RIT with either (177) Lu-C1P5 or (188) Re-C1P5 was equally effective in inhibiting tumor growth when each was compared to the untreated controls (P = 0.001). On day 5 there was a pronounced staining for gamma H2AX foci in (177) Lu-C1P5 group only and on day 10 it was observed in both (177) Lu-C1P5 and (188) Re-C1P5 groups. (188) Re- and (177) Lu-labeled mAbs were equally effective in arresting the growth of CasKi cervical tumors. Thus, both of these radionuclides are candidates for the clinical trials of this approach in patients with advanced, recurrent or metastatic cervical cancer. PMID- 26625939 TI - The Effectiveness of Occupational Therapy Supervised Usage of Adaptive Devices on Functional Outcomes and Independence after Total Hip Replacement in Iranian Elderly: A Randomized Controlled Trial. AB - The aim of this randomized controlled trial was to assess the effect of an occupational therapy protocol of teaching the usage of adaptive devices to older individuals in Iran who have had a total hip replacement as compared with conventional occupational therapy on functional outcomes and independence. Forty individuals diagnosed with osteoarthritis and a total hip replacement aged >60 years were randomly allocated to either control group (n = 20) or experimental (n = 20) group. Pain, disability, independence and hip muscle strength were assessed with visual analogue scale, Western Ontario and McMaster Universities Osteoarthritis and Barthel Index and dynamometer, 2 days before and 6 weeks after the hip operation. Both groups received conventional occupational therapy, but the experimental group was additionally supervised on the use of adaptive devices. Correct use of the devices was instructed during the training session. Both groups significantly improved on all variables post-operatively. However, the experimental group showed significantly more improvement in all dependent variables post-operatively. No data were available on the use of the devices by the control group patients. Supervision of the utilization of the adaptive devices during regular home visits by the occupational therapist is recommended. Further research is needed to clarify which aspects of this supervision were most beneficial for the patients. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26625940 TI - Frailty predicts short-term incidence of future falls among British community dwelling older people: a prospective cohort study nested within a randomised controlled trial. AB - BACKGROUND: Although population-based studies have shown frailty predicted future falls, their follow-up periods were one year or longer and short-term fall risks associated with frailty are unknown. METHODS: A prospective cohort study nested within a randomised controlled trial was conducted to examine associations between frailty and short-term incident future falls among community-dwelling older people. Two hundred forty eight community-dwelling people > =65 years without history of > =three falls and allocated to a usual care arm of exercise intervention trial were prospectively monitored for falls over 24 weeks. Frailty index (FI) was constructed from 40 deficits at baseline. The future fall risks according to frailty status was examined using logistic regression models. RESULTS: Of 248 participants, 46 were classified as frail and 57 had one or more falls during follow-up. Both each 0.01 increase in FI and frailty defined as FI > =0.25 were significantly associated with higher risks of future falls in multivariate logistic regression models adjusted for age, gender and history of two falls in the previous year (odds ratio (OR) = 1.05, 95 % confidence interval (95 % CI) = 1.02-1.07, p < 0.001; OR = 3.04, 95 % CI = 1.53-6.02, p = 0.001, respectively). Receiver operating characteristic (ROC) curve analysis showed FI predicted future falls with fair accuracy with area under ROC curve of 0.62 (95 % CI = 0.53-0.71, p < 0.01). CONCLUSIONS: Frailty was a significant and independent predictor of short-term future falls among community-dwelling older people who had volunteered for a physical activity study. It is important for healthcare practitioners to recognise frailty as a risk factor of imminent future falling even in older people who appear to be ageing well. PMID- 26625941 TI - Oral surgery in a patient with cirrhosis and thrombocytopenia: a case report. AB - PURPOSE: While most oral surgical procedures can be safely performed in an outpatient setting, certain medical conditions may present a higher chance of postoperative complications. In particular, those predisposing the patient to bleeding abnormalities pose a potential risk when performing such treatments. The authors report a case involving full-mouth extractions in a patient with cirrhosis and thrombocytopenia after obtaining a platelet transfusion. METHODS/CASE: A 62-year-old Caucasian female presented to a university special care dental clinic requiring extractions. Her pertinent medical history was remarkable for cirrhosis and thrombocytopenia, with a platelet count of 32,000/uL. Upon medical consultation, the patient was appointed for a prophylactic platelet transfusion. The surgery was rendered uneventfully, and the patient achieved adequate hemostasis without hospitalization. CONCLUSION/CLINICAL RELEVANCE: Patients with cirrhosis pose a potential bleeding risk with dental surgical procedures. Pre-operative medical consultation, review of pertinent laboratory values, and prophylactic platelet transfusion allow these patients to be managed safely in an outpatient setting. PMID- 26625942 TI - Atomic-Level Quality Assessment of Enzymes Encapsulated in Bioinspired Silica. AB - Among protein immobilization strategies, encapsulation in bioinspired silica is increasingly popular. Encapsulation offers high yields and the solid support is created through a protein-catalyzed polycondensation reaction that occurs under mild conditions. An integrated strategy is reported for the characterization of both the protein and bioinspired silica scaffold generated by the encapsulation of enzymes with an external silica-forming promoter or with the promoter expressed as a fusion to the enzyme. This strategy is applied to the catalytic domain of matrix metalloproteinase 12. Analysis reveals that the structure of the protein encapsulated by either method is not significantly altered with respect to the native form. The structural features of silica obtained by either strategy are also similar, but differ from those obtained by other approaches. In case of the covalently linked R5-enzyme construct, immobilization yields are higher. Encapsulation through a fusion protein, therefore, appears to be the method of choice. PMID- 26625943 TI - Three Approaches to Modeling Gene-Environment Interactions in Longitudinal Family Data: Gene-Smoking Interactions in Blood Pressure. AB - Blood pressure (BP) has been shown to be substantially heritable, yet identified genetic variants explain only a small fraction of the heritability. Gene-smoking interactions have detected novel BP loci in cross-sectional family data. Longitudinal family data are available and have additional promise to identify BP loci. However, this type of data presents unique analysis challenges. Although several methods for analyzing longitudinal family data are available, which method is the most appropriate and under what conditions has not been fully studied. Using data from three clinic visits from the Framingham Heart Study, we performed association analysis accounting for gene-smoking interactions in BP at 31,203 markers on chromosome 22. We evaluated three different modeling frameworks: generalized estimating equations (GEE), hierarchical linear modeling, and pedigree-based mixed modeling. The three models performed somewhat comparably, with multiple overlaps in the most strongly associated loci from each model. Loci with the greatest significance were more strongly supported in the longitudinal analyses than in any of the component single-visit analyses. The pedigree-based mixed model was more conservative, with less inflation in the variant main effect and greater deflation in the gene-smoking interactions. The GEE, but not the other two models, resulted in substantial inflation in the tail of the distribution when variants with minor allele frequency <1% were included in the analysis. The choice of analysis method should depend on the model and the structure and complexity of the familial and longitudinal data. PMID- 26625944 TI - Transformable liquid-metal nanomedicine. AB - To date, numerous inorganic nanocarriers have been explored for drug delivery systems (DDSs). However, the clinical application of inorganic formulations has often been hindered by their toxicity and failure to biodegrade. We describe here a transformable liquid-metal nanomedicine, based on a core-shell nanosphere composed of a liquid-phase eutectic gallium-indium core and a thiolated polymeric shell. This formulation can be simply produced through a sonication-mediated method with bioconjugation flexibility. The resulting nanoparticles loaded with doxorubicin (Dox) have an average diameter of 107 nm and demonstrate the capability to fuse and subsequently degrade under a mildly acidic condition, which facilitates release of Dox in acidic endosomes after cellular internalization. Equipped with hyaluronic acid, a tumour-targeting ligand, this formulation displays enhanced chemotherapeutic inhibition towards the xenograft tumour-bearing mice. This liquid metal-based DDS with fusible and degradable behaviour under physiological conditions provides a new strategy for engineering theranostic agents with low toxicity. PMID- 26625946 TI - Simulation in undergraduate paediatrics: a cluster-randomised trial. AB - BACKGROUND: Medical students lack confidence in recognising, assessing and managing unwell patients, particularly children. Our aim was to evaluate the impact of a 1-day novel paediatric simulation course on medical students' ability to recognise and assess sick children, and to evaluate medical students' views on the use of simulation in child health teaching. METHODS: We conducted a cluster randomised trial with a mixed-methods design. Students were cluster randomised into the intervention (simulation) group or control group (standard paediatric attachment). Students in the intervention group attended a 1-day simulation course during the last week of their attachment. The primary outcome measure was students' self-reported ability and confidence in recognising, assessing and managing sick children. RESULTS: There were 61 students in the study: 32 in the intervention group and 29 in the control group. Self-assessed confidence in recognising, assessing and managing a sick child was higher after the simulation course, compared with controls (p < 0.001). Six key themes were identified, including: increased confidence in emergency situations; the value of learning through participation in 'real-life' realistic scenarios in a safe environment; and an appreciation of the importance of human factors. Students found the simulation useful and wanted it offered to all undergraduates during child health attachments. DISCUSSION: A 1-day simulation course improves medical students' confidence in assessing and managing unwell children, and is highly valued by students. It could be used to complement undergraduate teaching on the management of sick children. Further studies are needed to evaluate its impact on real-life clinical performance and confidence over time. Students lack confidence in managing unwell patients, particularly children. PMID- 26625945 TI - Comparative miRNAs analysis of Two contrasting broccoli inbred lines with divergent head-forming capacity under temperature stress. AB - BACKGROUND: MicroRNAs (miRNAs) play a vital role in growth, development, and stress response at the post-transcriptional level. Broccoli (Brassica oleracea L. var italic) is an important vegetable crop, and the yield and quality of broccoli are decreased by heat stress. The broccoli inbred lines that are capable of producing head at high temperature in summer are unique varieties in Taiwan. However, knowledge of miRNAomes during the broccoli head formation under heat stress is limited. METHODS: In this study, molecular characterization of two nearly isogenic lines with contrasting head-forming capacity was investigated. Head-forming capacity was better for heat-tolerant (HT) than heat-sensitive (HS) broccoli under heat stress. RESULTS: By deep sequencing and computational analysis, 20 known miRNAs showed significant differential expression between HT and HS genotypes. According to the criteria for annotation of new miRNAs, 24 novel miRNA sequences with differential expression between the two genotypes were identified. To gain insight into functional significance, 213 unique potential targets of these 44 differentially expressed miRNAs were predicted. These targets were implicated in shoot apical development, phase change, response to temperature stimulus, hormone and energy metabolism. The head-forming capacity of the unique HT line was related to autonomous regulation of Bo-FT genes and less expression level of heat shock protein genes as compared to HS. For the genotypic comparison, a set of miRNAs and their targets had consistent expression patterns in various HT genotypes. CONCLUSIONS: This large-scale characterization of broccoli miRNAs and their potential targets is to unravel the regulatory roles of miRNAs underlying heat-tolerant head-forming capacity. PMID- 26625947 TI - High level of inbreeding in final phase of 1000 Genomes Project. AB - The 1000 Genomes Project provides a unique source of whole genome sequencing data for studies of human population genetics and human diseases. The last release of this project includes more than 2,500 sequenced individuals from 26 populations. Although relationships among individuals have been investigated in some of the populations, inbreeding has never been studied. In this article, we estimated the genomic inbreeding coefficient of each individual and found an unexpected high level of inbreeding in 1000 Genomes data: nearly a quarter of the individuals were inbred and around 4% of them had inbreeding coefficients similar or greater than the ones expected for first-cousin offspring. Inbred individuals were found in each of the 26 populations, with some populations showing proportions of inbred individuals above 50%. We also detected 227 previously unreported pairs of close relatives (up to and including first-cousins). Thus, we propose subsets of unrelated and outbred individuals, for use by the scientific community. In addition, because admixed populations are present in the 1000 Genomes Project, we performed simulations to study the robustness of inbreeding coefficient estimates in the presence of admixture. We found that our multi-point approach (FSuite) was quite robust to admixture, unlike single-point methods (PLINK). PMID- 26625948 TI - Ginseng alleviates cyclophosphamide-induced hepatotoxicity via reversing disordered homeostasis of glutathione and bile acid. AB - Cyclophosphamide (CP), a chemotherapeutic agent, is restricted due to its side effects, especially hepatotoxicity. Ginseng has often been clinically used with CP in China, but whether and how ginseng reduces the hepatotoxicity is unknown. In this study, the hepatoprotective effects and mechanisms under the combined usage were investigated. It was found that ginseng could ameliorate CP-induced elevations of ALP, ALT, ALS, MDA and hepatic deterioration, enhance antioxidant enzymes' activities and GSH's level. Metabolomics study revealed that 33 endogenous metabolites were changed by CP, 19 of which were reversed when ginseng was co-administrated via two main pathways, i.e., GSH metabolism and primary bile acids synthesis. Furthermore, ginseng could induce expression of GCLC, GCLM, GS and GST, which associate with the disposition of GSH, and expression of FXR, CYP7A1, NTCP and MRP 3, which play important roles in the synthesis and transport of bile acids. In addition, NRF 2, one of regulatory elements on the expression of GCLC, GCLM, GS, GST, NTCP and MRP3, was up-regulated when ginseng was co administrated. In conclusion, ginseng could alleviate CP-induced hepatotoxicity via modulating the disordered homeostasis of GSH and bile acid, which might be mediated by inducing the expression of NRF 2 in liver. PMID- 26625950 TI - Massive gene loss in mistletoe (Viscum, Viscaceae) mitochondria. AB - Parasitism is a successful survival strategy across all kingdoms and has evolved repeatedly in angiosperms. Parasitic plants obtain nutrients from other plants and some are agricultural pests. Obligate parasites, which cannot complete their lifecycle without a host, may lack functional photosystems (holoparasites), or have retained photosynthesis (hemiparasites). Plastid genomes are often reduced in parasites, but complete mitochondrial genomes have not been sequenced and their mitochondrial respiratory capacities are largely unknown. The hemiparasitic European mistletoe (Viscum album), known from folklore and postulated therapeutic properties, is a pest in plantations and forestry. We compare the mitochondrial genomes of three Viscum species based on the complete mitochondrial genome of V. album, the first from a parasitic plant. We show that mitochondrial genes encoding proteins of all respiratory complexes are lacking or pseudogenized raising several questions relevant to all parasitic plants: Are any mitochondrial gene functions essential? Do any genes need to be located in the mitochondrial genome or can they all be transferred to the nucleus? Can parasitic plants survive without oxidative phosphorylation by using alternative respiratory pathways? More generally, our study is a step towards understanding how host- and self-perception, host integration and nucleic acid transfer has modified ancestral mitochondrial genomes. PMID- 26625949 TI - Quantifying the heritability of glioma using genome-wide complex trait analysis. AB - Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) influencing glioma risk. While these SNPs only explain a small proportion of the genetic risk it is unclear how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we applied Genome-Wide Complex Trait Analysis (GCTA) to three GWAS datasets totalling 3,373 cases and 4,571 controls and performed a meta-analysis to estimate the heritability of glioma. Our results identify heritability estimates of 25% (95% CI: 20-31%, P = 1.15 * 10(-17)) for all forms of glioma - 26% (95% CI: 17-35%, P = 1.05 * 10(-8)) for glioblastoma multiforme (GBM) and 25% (95% CI: 17-32%, P = 1.26 * 10(-10)) for non-GBM tumors. This is a substantial increase from the genetic variance identified by the currently identified GWAS risk loci (~6% of common heritability), indicating that most of the heritable risk attributable to common genetic variants remains to be identified. PMID- 26625951 TI - Sexually antagonistic selection during parental care is not generated by a testosterone-related intralocus sexual conflict-insights from full-sib comparisons. AB - The evolution of shared male and female traits can be hampered if selection favours sex-specific optima. However, such genomic conflicts can be resolved when independent male and female mechanisms evolve. The existence, extent and consequences of conflict and/or conflict resolution are currently debated. Endocrinological traits like plasma testosterone (T) are suitable test cases, given their important role in mediating correlated traits, plus their opposing sex-specific fitness effects. We compared full-sibling (brother/sister) captive canaries to test for (1) sexually antagonistic selection characterized by contrasting fitness patterns within pairs of relatives, (2) intersexual genetic correlation of plasma T (h(2) = 0.41 +/- 0.31) and (3) intralocus sexual conflict over T levels featured by distinct sex-specific fitness optima. We found potential for sexually antagonistic selection, since high fledgling mass was reached by either brothers or sisters, but not by both. We report a positive intersexual correlation for T, as a requirement for intralocus sexual conflict. However, high levels of T were associated with increased female and decreased male fitness (fledgling mass), which contrasts our expectations and challenges the hypothesis of intralocus sexual conflict driven by T. We hypothesize that behavioural and physiological trade-offs differ between sexes when raising offspring, driving T levels towards a state of monomorphism. PMID- 26625952 TI - Total antioxidant status and oxidative stress in recurrent aphthous stomatitis. AB - BACKGROUND: Recurrent aphthous stomatitis is an idiopathic, chronic, recurrent inflammatory disease of the oral mucosa. It is thought that oxidative stress caused by systemic inflammation plays a basic role in the etiopathogenesis of recurrent aphthous stomatitis. The aim of this study is to review oxidative status and DNA damage in recurrent aphthous stomatitis. METHOD: The study included 42 patients with an active recurrent aphthous stomatitis lesion and 39 healthy volunteers with similar demographic characteristics. DNA damage was analyzed using alkaline single cell gel electrophoresis (comet assay). Plasma levels of total antioxidant status and total oxidative status were determined by using an automated measurement method. Oxidative stress index was calculated as total oxidative status/total antioxidant status and * 100. RESULTS: The total oxidative status and oxidative stress index values were significantly higher in the recurrent aphthous stomatitis group compared to the control group, while total antioxidant status values were significantly lower. In the recurrent aphthous stomatitis group, DNA damage was observed to be significantly higher than the control group. In correlation analysis, significant correlation was found between DNA damage and the oxidative stress index and total oxidative status values in the recurrent aphthous stomatitis group. CONCLUSION: This is the first report in the literature that demonstrates association of recurrent aphthous stomatitis with increased oxidative status. PMID- 26625953 TI - Occupational performance: a case for self-determination. AB - The term, 'self-determination', implies that individuals have choice and control over aspects of their lives. Individual/family preferences and choices are now core aspects of Australia's National Disability Insurance Scheme, underpinning the importance attributed to these concepts in relation to the fostering of wellbeing. As occupational therapists, in collaboration with our clients, we facilitate and enable occupational performance goals which are personally meaningful and self-endorsed. As such, our professional practice provides us with a powerful motivational tool by which we can harness individuals' energies in the pursuit of their goals - occupation. Self-Determination Theory (SDT) is an influential theory of human motivation and is presented as a way of understanding the elements of our occupational therapy transactions, and the way in which we enact them so as to enhance client outcomes. In SDT, it is proposed that individuals engage in, pursue and persist with certain behaviours when three psychological needs are being met. These needs are for autonomy (engaging in behaviour that is self-endorsed), relatedness (feeling cared for and connected to others) and competence (feeling effective in one's environment). A focus on supporting satisfaction of these basic psychological needs, it will be argued, engenders therapeutic alliance and internalisation of goal pursuits, thus optimising therapy engagement and outcomes. Examples of practice approaches that attend to the psychological needs for autonomy, relatedness and competence will be presented. A case will be made for embedding SDT into our models of practice as a sound way of articulating how we practise. PMID- 26625955 TI - Contrast-enhanced tomosynthesis: The best of both worlds or more of the same? PMID- 26625954 TI - Voluntary ethanol consumption reduces GABAergic neuroactive steroid (3alpha,5alpha)3-hydroxypregnan-20-one (3alpha,5alpha-THP) in the amygdala of the cynomolgus monkey. AB - Neuroactive steroids such as (3alpha,5alpha)3-hydroxypregnan-20-one (3alpha,5alpha-THP, allopregnanolone) enhance the gamma-aminobutyric acid (GABA) ergic effects of ethanol and modulate excessive drinking in rodents. Moreover, chronic ethanol consumption reduces 3alpha,5alpha-THP levels in human plasma, rat hippocampus and mouse limbic regions. We explored the relationship between 3alpha,5alpha-THP levels in limbic brain areas and voluntary ethanol consumption in the cynomolgus monkey following daily self-administration of ethanol for 12 months and further examined the relationship to hypothalamic-pituitary-adrenal (HPA) axis function prior to ethanol exposure. Monkeys were subjected to scheduled induction of ethanol consumption followed by free access to ethanol or water for 22 h/day over 12 months. Immunohistochemistry was performed using an anti-3alpha,5alpha-THP antibody. Prolonged voluntary drinking resulted in individual differences in ethanol consumption that ranged from 1.2 to 4.2 g/kg/day over 12 months. Prolonged ethanol consumption reduced cellular 3alpha,5alpha-THP immunoreactivity by 13 +/- 2 percent (P < 0.05) in the lateral amygdala and 17 +/- 2 percent (P < 0.05) in the basolateral amygdala. The effect of ethanol was most pronounced in heavy drinkers that consumed >=3 g/kg >= 20 percent of days. Consequently, 3alpha,5alpha-THP immunoreactivity in both the lateral and basolateral amygdala was inversely correlated with average daily ethanol intake (Spearman r = -0.87 and -0.72, respectively, P < 0.05). However, no effect of ethanol and no correlation between drinking and 3alpha,5alpha-THP immunoreactivity were observed in the basomedial amygdala. 3alpha,5alpha-THP immunoreactivity following ethanol exposure was also correlated with HPA axis function prior to ethanol exposure. These data indicate that voluntary ethanol drinking reduces amygdala levels of 3alpha,5alpha-THP in non-human primates and that amygdala 3alpha,5alpha-THP levels may be linked to HPA axis function. PMID- 26625956 TI - Nascent Integrin Adhesions Form on All Matrix Rigidities after Integrin Activation. AB - Integrin adhesions assemble and mature in response to ligand binding and mechanical factors, but the molecular-level organization is not known. We report that ~100-nm clusters of ~50 beta3-activated integrins form very early adhesions under a wide variety of conditions on RGD surfaces. These adhesions form similarly on fluid and rigid substrates, but most adhesions are transient on rigid substrates. Without talin or actin polymerization, few early adhesions form, but expression of either the talin head or rod domain in talin-depleted cells restores early adhesion formation. Mutation of the integrin binding site in the talin rod decreases cluster size. We suggest that the integrin clusters constitute universal early adhesions and that they are the modular units of cell matrix adhesions. They require the association of activated integrins with cytoplasmic proteins, in particular talin and actin, and cytoskeletal contraction on them causes adhesion maturation for cell motility and growth. PMID- 26625957 TI - Translational Control of Autophagy by Orb in the Drosophila Germline. AB - Drosophila Orb, the homolog of vertebrate CPEB, is a key translational regulator involved in oocyte polarity and maturation through poly(A) tail elongation of specific mRNAs. orb also has an essential function during early oogenesis that has not been addressed at the molecular level. Here, we show that orb prevents cell death during early oogenesis, thus allowing oogenesis to progress. It does so through the repression of autophagy by directly repressing, together with the CCR4 deadenylase, the translation of Autophagy-specific gene 12 (Atg12) mRNA. Autophagy and cell death observed in orb mutant ovaries are reduced by decreasing Atg12 or other Atg mRNA levels. These results reveal a role of Orb in translational repression and identify autophagy as an essential pathway regulated by Orb during early oogenesis. Importantly, they also establish translational regulation as a major mode of control of autophagy, a key process in cell homeostasis in response to environmental cues. PMID- 26625959 TI - Current topics on inhibitors of respiratory complex I. AB - There are a variety of chemicals which regulate the functions of bacterial and mitochondrial complex I. Some of them, such as rotenone and piericidin A, have been indispensable molecular tools in mechanistic studies on complex I. A large amount of experimental data characterizing the actions of complex I inhibitors has been accumulated so far. Recent X-ray crystallographic structural models of entire complex I may be helpful to carefully interpret this data. We herein focused on recent hot topics on complex I inhibitors and the subjects closely connected to these inhibitors, which may provide useful information not only on the structural and functional aspects of complex I, but also on drug design targeting this enzyme. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt. PMID- 26625958 TI - Jmjd3-Mediated H3K27me3 Dynamics Orchestrate Brown Fat Development and Regulate White Fat Plasticity. AB - Progression from brown preadipocytes to adipocytes engages two transcriptional programs: the expression of adipogenic genes common to both brown fat (BAT) and white fat (WAT), and the expression of BAT-selective genes. However, the dynamics of chromatin states and epigenetic enzymes involved remain poorly understood. Here we show that BAT development is selectively marked and guided by repressive H3K27me3 and is executed by its demethylase Jmjd3. We find that a significant subset of BAT-selective genes, but not common fat genes or WAT-selective genes, are demarcated by H3K27me3 in both brown and white preadipocytes. Jmjd3-catalyzed removal of H3K27me3, in part through Rreb1-mediated recruitment, is required for expression of BAT-selective genes and for development of beige adipocytes both in vitro and in vivo. Moreover, gain- and loss-of-function Jmjd3 transgenic mice show age-dependent body weight reduction and cold intolerance, respectively. Together, we identify an epigenetic mechanism governing BAT fate determination and WAT plasticity. PMID- 26625960 TI - Complete Response after Chemoradiotherapy in Rectal Cancer (Watch-and-Wait): Have we Cracked the Code? AB - Patients with locally advanced rectal cancer receive preoperative chemoradiation as the standard of care, producing a pathological complete response in 10-20% and a complete clinical response (CCR) in 20-30%. Small observational studies suggest a selective non-operative management with rigorous surveillance is an option and is increasingly being advocated in many parts of the world for patients who achieve a CCR or near CCR. The assumption is that oncological outcomes for good responders, who are observed, compare favourably with patients subjected to radical surgery. Late regrowth of the primary is rare, almost invariably endoluminal and, hence, can be salvaged. However, concerns remain among some surgeons and oncologists regarding the reproducibility of published results in routine practice. We have previously reviewed this topic. The aim of this brief overview was to re-assess the feasibility and safety of a non-operative approach based on the currently available literature. We make recommendations as to the quality of care required to undertake this management. Significant heterogeneity remains in the initial inclusion criteria, staging and restaging methods, study design, timing of assessment, duration and rigour of follow-up of the trials reviewed - all of which obscure the validity of the results. PMID- 26625961 TI - An Ex vivo culture model for placental cytomegalovirus infection using slices of Guinea pig placental tissue. AB - Congenital infection with human cytomegalovirus (CMV) through the placenta is one of the major causes of birth and developmental abnormalities. Guinea pig CMV (GPCMV) causes in utero infection, which makes its animal models useful for studies on congenital diseases. Here, we established an ex vivo culture method for tissue slices prepared from guinea pig placentas and demonstrated that viral spread in the model resembles those in the placenta of GPCMV-infected animals and that the infection is independent of the pentameric glycoprotein complex for endothelial/epithelial cell tropism. Thus, this model affords a useful tool for pathobiological studies on CMV placental infection. PMID- 26625962 TI - Mechanical loading and the synthesis of 1,25(OH)2D in primary human osteoblasts. AB - The metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D) is synthesized from its precursor 25-hydroxyvitamin D (25(OH)D) by human osteoblasts leading to stimulation of osteoblast differentiation in an autocrine or paracrine way. Osteoblast differentiation is also stimulated by mechanical loading through activation of various responses in bone cells such as nitric oxide signaling. Whether mechanical loading affects osteoblast differentiation through an enhanced synthesis of 1,25(OH)2D by human osteoblasts is still unknown. We hypothesized that mechanical loading stimulates the synthesis of 1,25(OH)2D from 25(OH)D in primary human osteoblasts. Since the responsiveness of bone to mechanical stimuli can be altered by various endocrine factors, we also investigated whether 1,25(OH)2D or 25(OH)D affect the response of primary human osteoblasts to mechanical loading. Primary human osteoblasts were pre-incubated in medium with/without 25(OH)D3 (400 nM) or 1,25(OH)2D3 (100 nM) for 24h and subjected to mechanical loading by pulsatile fluid flow (PFF). The response of osteoblasts to PFF was quantified by measuring nitric oxide, and by PCR analysis. The effect of PFF on the synthesis of 1,25(OH)2D3 was determined by subjecting osteoblasts to PFF followed by 24h post-incubation in medium with/without 25(OH)D3 (400 nM). We showed that 1,25(OH)2D3 reduced the PFF-induced NO response in primary human osteoblasts. 25(OH)D3 did not significantly alter the NO response of primary human osteoblasts to PFF, but 25(OH)D3 increased osteocalcin and RANKL mRNA levels, similar to 1,25(OH)2D3. PFF did not increase 1,25(OH)2D3 amounts in our model, even though PFF did increase CYP27B1 mRNA levels and reduced VDR mRNA levels. CYP24 mRNA levels were not affected by PFF, but were strongly increased by both 25(OH)D3 and 1,25(OH)2D3. In conclusion, 1,25(OH)2D3 may affect the response of primary human osteoblasts to mechanical stimuli, at least with respect to NO production. Mechanical stimuli may affect local vitamin D metabolism in primary human osteoblasts. Our results suggest that 1,25(OH)2D3 and mechanical loading, both stimuli of the differentiation of osteoblasts, interact at the cellular level. PMID- 26625963 TI - Re: 'Editor's Choice - The Impact of Early Pelvic and Lower Limb Reperfusion and Attentive Peri-operative Management on the Incidence of Spinal Cord Ischemia During Thoracoabdominal Aortic Aneurysm Endovascular Repair'. PMID- 26625964 TI - [Congenital depressed skull fracture: The steps to follow?]. PMID- 26625965 TI - [Prenatal maltreatment]. PMID- 26625966 TI - [Stridor in neonates with hypoxic-ischaemic encephalopathy subject to selective cerebral or whole body hypothermia]. AB - INTRODUCTION: Hypothermia treatment has improved the prognosis of asphyxiated neonates. Widely used, it has demonstrated to be safe without severe side effects. The aim of this article is to review the incidence of stridor amongst asphyxiated newborns treated with hypothermia in our unit. METHODS: Retrospective chart review of our patients. RESULTS: Stridor was presented in 7/75 (9.3%) of patients during hypothermia. Three received whole body hypothermia, 3 selective cerebral, and in one case both techniques were used. All cases required increased respiratory support. CONCLUSIONS: Different mechanisms may be responsible for the appearance of stridor in patients with hypoxic-ischaemic encephalopathy (HIE). In our series the incidence of stridor was similar for the two hypothermia devices. To better understand these possible side effects of hypothermia, further prospective studies (which should include laryngoscopy) are needed. PMID- 26625967 TI - [Pulmonary hypoplasia: An analysis of cases over a 20-year period]. AB - INTRODUCTION: Pulmonary hypoplasia is the most frequent congenital anomaly associated with perinatal mortality. MATERIAL AND METHODS: A retrospective and descriptive review was conducted on cases of patients diagnosed with pulmonary hypoplasia between 1995 and 2014 in a tertiary university hospital. An analysis was made of the prenatal imaging, clinical manifestations, post-natal diagnostic tests, treatment and management, long-term follow up, and survival data. RESULTS: A total of 60 cases were identified, all of them with prenatal imaging. Sixteen patients required foetal surgery. Congenital diaphragmatic hernia was the most frequent diagnosis. Main clinical presentation was respiratory distress with severe hypoxemia and high requirements of mechanical ventilation. Mortality rate was 47% within first 60 days of life, and 75% for the first day of life. Pneumonia and recurrent bronchitis episodes were observed during follow-up. They had a lung function obstructive pattern, and their quality of life and exercise tolerance was good. CONCLUSIONS: High neonatal mortality and significant long term morbidity associated with pulmonary hypoplasia requires an early diagnosis and a specialised multidisciplinary team management. PMID- 26625968 TI - [Evaluation of coordination and balance in preterm children]. AB - INTRODUCTION: Recent studies show that many preterm children without apparent neurological sequelae present some difficulties in different areas, such as coordination or balance during their school years. The Movement Assessment Battery for Children-2 (MABC-2) has demonstrated to be a useful tool to validate the coordination, while the stabilometric platform was the reference standard test for validating the balance. PATIENTS AND METHOD: Case-control study carried out on preterm children from 7 to 10 years old and healthy term infant controls of the same ages. The same age band of MABC-2 was applied and the static balance by the stabilometric platform was analysed. RESULTS: A total of 89 subjects were included, 30 preterm children<=1,500g birthweight, 29 preterm children>1,500g birthweight, and 30 controls. Preterm children obtained the lowest scores on an overall basis in hand dexterity and balance tests in MABC-2, regardless of their birthweight. Lower gestational age was associated with poorer outcomes in hand dexterity and total scores in MABC-2. Balance results were similar using the stabilometric platform, regardless of prematurity. CONCLUSIONS: A little more than 10% preterm and term children could have coordination disorders or be at risk of developing them using the MABC-2. Despite the visual-motor coordination being similar, preterm children could face greater difficulties in hand dexterity while, in the absence of neurological comorbidity, preterm and term children balance could be comparable. PMID- 26625969 TI - Atypical valuation of monetary and cigarette rewards in substance dependent smokers. AB - OBJECTIVE: Substance dependent (SD) relative to non-dependent (ND) individuals exhibit an attenuated reward positivity, an electrophysiological signal believed to index sensitivity of anterior cingulate cortex (ACC) to rewards. Here we asked whether this altered neural response reflects a specific devaluation of monetary rewards relative to drug-related rewards by ACC. METHODS: We recorded the reward positivity from SD and ND individuals who currently smoke, following an overnight period of abstinence, while they engaged in two feedback tasks. In a money condition the feedback indicated either a monetary reward or no reward, and in a cigarette condition the feedback indicated either a drug-related reward or no reward. RESULTS: Overall, cigarette relative to monetary rewards elicited a larger reward positivity. Further, for the subjects who engaged in the money condition first, the reward positivity was smaller for the SD compared to the ND participants, but for the subjects who engaged in the cigarette condition first, the reward positivity was larger for the SD compared to the ND participants. CONCLUSIONS: Our results suggest that the initial category of feedback "primed" the response of the ACC to the alternative feedback type on subsequent trials, and that SD and ND individuals responded differently to this priming effect. SIGNIFICANCE: We propose that for people who misuse addictive substances, the prospect of obtaining drug-related rewards engages the ACC to exert control over extended behaviors. PMID- 26625970 TI - Location of School Lunch Salad Bars and Fruit and Vegetable Consumption in Middle Schools: A Cross-Sectional Plate Waste Study. AB - BACKGROUND: The school lunch environment is a prime target for increasing a child's consumption of fresh fruits and vegetables (F/V). Salad bars are heavily encouraged in schools; however, more research is needed to examine the contexts in which salad bars promote consumption of F/V among students. OBJECTIVE: To compare the amount of fresh F/V self-served, consumed, and wasted by students during lunch at schools with differing salad bar placement: inside or outside of the serving line. DESIGN: Cross-sectional plate waste study in which salad bar placement differed between schools. PARTICIPANTS/SETTING: A random sample of middle school students (N=533) from six schools (three schools per district). MAIN OUTCOME MEASURES: Amount of fresh F/V taken, consumed, and wasted. STATISTICAL ANALYSES: Negative binomial multivariable regression examined placement of salad bars, adjusting for sex, grade, race/ethnicity, free/reduced status, day of the week, and nesting of students within schools. RESULTS: Almost all students (98.6%) in the schools with salad bars inside serving lines self served F/V compared with only 22.6% of students in the schools with salad bars outside lines (adjusted prevalence ratio=5.38; 95% CI 4.04 to 7.17). Similarly, students at schools with salad bars inside the line had greater prevalence of consuming any F/V compared with students in schools with salad bars outside the line (adjusted prevalence ratio=4.83; 95% CI 3.40 to 6.81). On average, students with the salad bar outside the line wasted less F/V compared with those with salad bars inside the line (30% vs 48%, respectively). CONCLUSIONS: Few students visited salad bars located outside the lunch line. Salad bars inside the lunch line resulted in significantly greater fresh F/V taken, consumed, and wasted. When possible, schools should try to include salad bars inside the line to increase students' exposure to F/V. PMID- 26625971 TI - Novel and reported APC germline mutations in Chinese patients with familial adenomatous polyposis. AB - OBJECTIVE: Familial adenomatous polyposis (FAP) is mainly caused by germline mutations in the adenomatous polyposis coli (APC) gene. This study aimed to detect pathogenic variants in five Chinese FAP families and review all previously reported pathogenic variants of APC gene in Chinese population. METHODS: Five non consanguineous FAP families and 100 unrelated ethnicity-matched controls were included in the study. Sanger sequencing was performed to screen for APC coding and splicing variants. Chinese and English literature on APC germline mutations were reviewed to compile the mutation spectrum of APC gene in Chinese FAP patients. RESULTS: One pathogenic variant was detected in each family for the five pedigrees we tested. Three variants (c.3183_3187delACAAA, c.2626C>T and c.1312+1G>A) were previously reported as pathogenic. The other two variants were novel: c.794_795insG/p.Val266SerfsTer11 and c.2142_2143insG/p.His715AlafsTer19. They are absent from public databases (1000 Genomes, dbSNP, ESP and ExAC) and 100 normal controls, and are classified as pathogenic based on the new ACMG/AMP variant classification guidelines. Literature review and current study revealed a total of 82 different pathogenic variants from 127 Chinese FAP families. Among these families, 83 families had frameshift variants (65.35%), 26 with nonsense variants (20.47%), six with splice site variants (4.72%), three with missense variants (2.36%) and nine with large deletion or duplication variants (7.09%). Apart from the two previously reported mutation hotspots c.3927_3931delAAAGA (20.47%) and c.3183_3187delACAAA (7.09%), c.847C>T/p.Arg283Ter variant occurred with a frequency of 3.15% (4 out of 127) in Chinese FAP patients. CONCLUSIONS: We reported two novel pathogenic variants. The comprehensive compilation of variants and comparison revealed largely similar mutation spectrum between Chinese and Western patient populations. Some unique features noticed in Chinese patient population may help to better understand the pathogenesis of FAP. PMID- 26625972 TI - The pri-let-7a-2 rs1143770C>T is associated with prognosis of surgically resected non-small cell lung cancer. AB - BACKGROUND: Evidence indicates that let-7 of microRNA may be a prognostic factor in lung cancer. Genetic variation in microRNA precursors could influence the processing and expression of microRNAs, which could affect the prognosis of lung cancer. We aimed to investigate the impact of single nucleotide polymorphisms (SNPs) of pri-let-7 on the prognosis of non-small cell lung cancer (NSCLC). METHOD: A total of 761 patients with surgically resected NSCLC were included. Four SNPs (pri-let-7a-2 rs1143770 and rs629367, pri-let-7a-1 rs10739971, and pri let-7f-2 rs17276588) were genotyped using sequenom mass spectrometry-based genotyping assay. Overall survival (OS) and disease-free survival (DFS) were evaluated using Kaplan-Meier method and Cox proportional hazards model. RESULTS: Of the 4 SNPs evaluated, the rs1143770C>T was found to be significantly associated with OS and DFS. The rs1143770 CT or TT genotype exhibited a significantly better OS and DFS compared with the rs1143770 CC genotype (adjusted hazard ratio for OS=0.67, confidence interval, 0.49-0.91, P=0.01 and adjusted hazard ratio for DFS=0.74, confidence interval, 0.58-0.95, P=0.02). CONCLUSION: This observation indicates that pri-let-7a-2 rs1143770C>T may have a prognostic impact on surgically resected NSCLC. PMID- 26625973 TI - BmRobo2/3 is required for axon guidance in the silkworm Bombyx mori. AB - Axon guidance is critical for proper wiring of the nervous system. During the neural development, the axon guidance molecules play a key role and direct axons to choose the correct way to reach the target. Robo, as the receptor of axon guidance molecule Slit, is evolutionarily conserved from planarians to humans. However, the function of Robo in the silkworm, Bombyx mori, remained unknown. In this study, we cloned robo2/3 from B. mori (Bmrobo2/3), a homologue of robo2/3 in Tribolium castaneum. Moreover, BmRobo2/3 was localized in the neuropil, and RNAi mediated knockdown of Bmrobo2/3 resulted in the longitudinal connectives forming closer to the midline. These data demonstrate that BmRobo2/3 is required for axon guidance in the silkworm. PMID- 26625974 TI - Polymorphisms and haplotypes of insulin-like factor 3 gene are associated with risk of polycystic ovary syndrome in Indian women. AB - BACKGROUND: Insulin-like factor 3 (INSL3), secreted by the ovarian theca cells is involved in androgen production, follicular growth and oocyte maturation. Both androgens and INSL3 levels are reported to be elevated in women with polycystic ovary syndrome (PCOS), indicating that INSL3 could contribute to PCOS etiology. This case-control association study explored the impact of INSL3 polymorphisms on PCOS susceptibility and its related traits. METHODS: Genotyping of exonic polymorphisms of INSL3 was performed in controls (n=333) and PCOS (n=405) women. Phenotyping (clinical, biochemical and hormonal parameters) was carried out in 205 controls and 301 PCOS women. Genotype, haplotype and genotype-phenotype associations were determined using statistical tests. RESULTS: Three polymorphisms in exon 1-rs2286663 (G/A), rs1047233 (A/G), and rs6523 (A/G), and one in exon 3-rs1003887 (G/A), were present in our study subjects. The frequencies of rs6523 and AGAG haplotype were significantly increased in PCOS women. The rs6523 polymorphism showed significant association with increased cholesterol and HDL-C levels in PCOS women while in controls with decreased FBS, Bio-T and FAI, and increased SHBG levels. Significant association of, rs1047233 polymorphism with improved androgen related parameters in controls, rs2286663 polymorphism with decreased QUICKI in PCOS and rs1003887 polymorphism with increased insulin levels and HOMA-IR in controls were observed. CONCLUSIONS: The rs6523 polymorphism and AGAG haplotype of INSL3 showed significant association with increased risk of PCOS. Additionally, INSL3 polymorphisms influenced metabolic and hyperandrogenemia related parameters in both controls and PCOS women. This is the first study to suggest that INSL3 may be a genetic predisposition factor in PCOS pathophysiology. PMID- 26625975 TI - Structural analysis and knock-out of a Burkholderia pseudomallei homolog of the eukaryotic transcription coactivator PC4. AB - Homologs of the eukaryotic transcription coactivator PC4, which also functions in DNA repair and oxidative stress, were recently identified in prokaryotes. Crystallographic analysis of BPSL1147, a putative homolog from the pathogen Burkholderia pseudomallei K96243, reveals a highly conserved core structure and suggests a nucleic acid binding mode similar to that of PC4. Knock-out and complementation experiments do not reveal distinguishing phenotypes under normal growth conditions or in the presence of H2O2, arguing against a critical role in repair or the oxidative stress response of Burkholderia. These results may reflect redundancy or point at a bacteriophage origin of Burkholderia PC4 homologs. PMID- 26625976 TI - Comparison of planar bone scintigraphy and single photon emission computed tomography for diagnosis of active condylar hyperplasia. AB - PURPOSE: The aim of this study was to compare the reliability and correlations with age and gender of two nuclear medicine tests used for diagnosis of active condylar hyperplasia, namely, planar bone scintigraphy versus single photon emission computed tomography (SPECT). MATERIAL AND METHOD: This was a descriptive observational study carried out in 61 patients (38 women and 23 men) clinically diagnosed as having facial asymmetry and suspected unilateral condylar hyperplasia. The patients had both planar bone scintigraphy and SPECT diagnostic imaging as well as reference data of the percentage of (99)Tc(m) MDP (methylenediphosphonate) uptake in the condyle, clivus, and fourth lumbar vertebra (L4), respectively, for SPECT and planar scintigraphy calculations. Radioactive counts were measured per region of interest and the respective ratios were calculated. The age range of the patients was 13-50 years (mean +/- standard deviation = 21.16 +/- 8.75). The two groups were compared by a nonparametric (Mann-Whitney U test. Uptake percentage and delta values had normal distribution and consequently were compared by a Student t test. RESULTS: A total of 61 anterior planar images and 61 SPECT images were compared. Eight patients presented high uptake in planar bone scintigraphy images (13.11%), while 32 patients (52.46%) had high uptake with SPECT. The prevalence of condylar hyperactivity was higher in women than in men both for right condyle (ratio 4:3) and for left condyle (10:1) and the prevalence was significantly higher for the right condyle. CONCLUSION: The study indicates that SPECT is more sensitive to identify condylar hyperactivity as compared to planar bone scintigraphy in patients with clinical presumptive diagnostic of condylar hyperplasia. PMID- 26625978 TI - Dysfunctional feedback processing in adolescent males with conduct disorder. AB - Abnormalities in neural feedback-processing systems may play a role in the development of dysfunctional behavior in individuals diagnosed with conduct disorder (CD). The present study investigated the relation between CD adolescents and feedback processing by measuring event-related potentials (ERPs) in a single outcome gambling task, which included reward valence (loss and gain) and reward magnitude (10 and 50cents) as outcomes. N2 and P3 components have been established as effective indicators in studies of behavioral disinhibition, reward processing, and decision-making. Eighteen adolescent males (age: 13 17years) diagnosed with CD and 19 healthy age-matched male controls were recruited. Compared to healthy controls, CD individuals exhibited reduced N2 amplitudes in response to loss condition. There was also a significant decreased P3 amplitude in all conditions. The amplitudes of P3 were negatively correlated with impulsivity scores across both groups, and the amplitudes of N2 were positively correlated with impulsivity scores across both groups. Our findings suggest that adolescents with CD may be impaired in neural sensitivity feedback and the processing of environmental cues compared to healthy controls. Moreover, N2 and P3 may be reliable indices to detect different sensitivity in reward and punishment feedback processing. PMID- 26625979 TI - Maintenance of algal endosymbionts in Paramecium bursaria: a simple model based on population dynamics. AB - Algal endosymbiosis is widely distributed in eukaryotes including many protists and metazoans, and plays important roles in aquatic ecosystems, combining phagotrophy and phototrophy. To maintain a stable symbiotic relationship, endosymbiont population size in the host must be properly regulated and maintained at a constant level; however, the mechanisms underlying the maintenance of algal endosymbionts are still largely unknown. Here we investigate the population dynamics of the unicellular ciliate Paramecium bursaria and its Chlorella-like algal endosymbiont under various experimental conditions in a simple culture system. Our results suggest that endosymbiont population size in P. bursaria was not regulated by active processes such as cell division coupling between the two organisms, or partitioning of the endosymbionts at host cell division. Regardless, endosymbiont population size was eventually adjusted to a nearly constant level once cells were grown with light and nutrients. To explain this apparent regulation of population size, we propose a simple mechanism based on the different growth properties (specifically the nutrient requirements) of the two organisms, and based from this develop a mathematical model to describe the population dynamics of host and endosymbiont. The proposed mechanism and model may provide a basis for understanding the maintenance of algal endosymbionts. PMID- 26625977 TI - Patching Broken DNA: Nucleosome Dynamics and the Repair of DNA Breaks. AB - The ability of cells to detect and repair DNA double-strand breaks (DSBs) is dependent on reorganization of the surrounding chromatin structure by chromatin remodeling complexes. These complexes promote access to the site of DNA damage, facilitate processing of the damaged DNA and, importantly, are essential to repackage the repaired DNA. Here, we will review the chromatin remodeling steps that occur immediately after DSB production and that prepare the damaged chromatin template for processing by the DSB repair machinery. DSBs promote rapid accumulation of repressive complexes, including HP1, the NuRD complex, H2A.Z and histone methyltransferases at the DSB. This shift to a repressive chromatin organization may be important to inhibit local transcription and limit mobility of the break and to maintain the DNA ends in close contact. Subsequently, the repressive chromatin is rapidly dismantled through a mechanism involving dynamic exchange of the histone variant H2A.Z. H2A.Z removal at DSBs alters the acidic patch on the nucleosome surface, promoting acetylation of the H4 tail (by the NuA4-Tip60 complex) and shifting the chromatin to a more open structure. Further, H2A.Z removal promotes chromatin ubiquitination and recruitment of additional DSB repair proteins to the break. Modulation of the nucleosome surface and nucleosome function during DSB repair therefore plays a vital role in processing of DNA breaks. Further, the nucleosome surface may function as a central hub during DSB repair, directing specific patterns of histone modification, recruiting DNA repair proteins and modulating chromatin packing during processing of the damaged DNA template. PMID- 26625980 TI - Pregnancy, exercise and nutrition research study with smart phone app support (Pears): Study protocol of a randomized controlled trial. AB - OBJECTIVE: Maternal adiposity confers an increased risk of GDM in pregnancy. A low glycemic index (GI) dietary intervention has been found to improve glucose homeostasis and reduce gestational weight gain. Mobile Health (mHealth) Technology-assisted interventions are becoming commonplace as an aid to treating many chronic diseases. The aim of this study is to assess the impact of a 'healthy lifestyle package' with mHealth smart phone technology as support compared with usual care on the incidence of GDM in an overweight and obese pregnant population. METHODS: We propose a randomized controlled trial of an mHealth assisted healthy lifestyle intervention package versus standard obstetric care in pregnant women with a BMI >=25kg/m(2)-39.9kg/m(2). Patients are randomized to control or intervention group in a 1:1 ratio. The intervention arm healthy lifestyle package includes a motivational counseling session to encourage behavior change, involving targeted, low GI nutritional advice and daily physical activity prescription delivered before 18weeks gestation, as well as a smart phone app to provide ongoing healthy lifestyle advice and support throughout pregnancy. The primary outcome is the incidence of GDM at 29weeks' gestation and power analysis indicates that 253 women are required in each group to detect a difference. CONCLUSION: This will be the first clinical trial to evaluate the effectiveness of a smart phone technology-assisted targeted healthy lifestyle intervention, which is grounded in behavior change theories and techniques, to support antenatal management of an overweight and obese pregnant population in preventing GDM. PMID- 26625981 TI - A combined computational and experimental investigation of Mg doped alpha-Fe2O3. AB - In the current work, pristine alpha-Fe2O3 metal oxide was doped with Mg in an attempt to modulate its electronic properties. To this end, we employed an experimental high throughput strategy, including scanning XRD and optical spectroscopy, which were complimented by atomistic density functional theory (DFT) calculations. The combined study reveals that at Mg/Fe atomic ratios up to ~1/3, the bandgaps of the hematite-Mg composite materials are similar to that of the pure material. The observed bandgaps are rationalized by electronic band structure and density of states calculations. Additional rationale for the similar bandgaps in pure and doped hematite is provided by topological Bader charge analyses, which indicate that the Mg and Fe ions in the hematite matrix have similar partial atomic charges. Nonetheless, the small charge density difference between the Mg and Fe ions induces a slight spin polarization on both oxygen and Fe ions, resulting in changes in the band edges. Further charge density analyses, using charge density maps and chemical-bonding analyses with the crystal orbital Hamiltonian population scheme, indicate that Mg forms ionic bonds with the neighboring oxygen atoms. This change from iron-oxygen covalent bonds to a more ionic nature for magnesium-oxygen bonds is probably responsible for the reduction observed in the computed bulk modulus of alpha Mg(0.17)Fe(1.83)O3 (193 GPa) compared to alpha-Fe2O3 (202 GPa). PMID- 26625982 TI - Diastereoselective synthesis of substituted hexahydrobenzo[de]isochromanes and evaluation of their antileishmanial activity. AB - Hexahydrobenzo[de]isochromanes and hexahydropyrano[3,4,5-ij]isoquinolines can be efficiently synthesized via Friedel Crafts and oxa Pictet-Spengler reaction of acrylyl enol ethers mediated by triflic acid in good yields. The reaction is highly stereoselective. Two of the hexahydrobenzo[de]isochromanes are found to have moderate antileishmanial activity. PMID- 26625983 TI - Difficulty of predicting the presence of lymph node metastases in patients with clinical early stage gastric cancer: a case control study. AB - BACKGROUND: The relationship between pathological factors and lymph node metastasis of pathological stage early gastric cancer has been extensively investigated. By contrast, the relationship between preoperative factors and lymph node metastasis of clinical stage early gastric cancer has not been investigated. The present study was to investigate discrepancies between preoperative and postoperative values. METHODS: From January 2011 to December 2013, 1042 patients with clinical stage early gastric cancer who underwent gastrectomy with lymphadenectomy were enrolled. Preoperative and postoperative values were collected for subsequent analysis. Receiver operating characteristics curves were computed using independent predictive factors. RESULTS: Several discrepancies were observed between preoperative and postoperative values, including existence of ulcer, gross type, and histology (all McNemar p-values were <0.001). Multivariate analyses identified the following independent predictive factors for lymph node metastasis: postoperative values including age (p = 0.002), tumor size (p < 0.001), and tumor depth (p < 0.001); preoperative values including age (p = 0.017), existence of ulcer (p = 0.037), tumor size (p = 0.009), and prediction of the presence of lymph node metastasis in computed tomography scans (p = 0.002). These postoperative and preoperative independent predictive factors produced areas under the receiver operating characteristics curves of 0.824 and 0.660, respectively. CONCLUSIONS: Surgeons need to be aware of limitations in preoperative predictions of the presence of lymph node metastasis for clinical stage early gastric cancer. PMID- 26625985 TI - Corrigendum. PMID- 26625984 TI - Herpes simplex virus 1 UL41 protein abrogates the antiviral activity of hZAP by degrading its mRNA. AB - BACKGROUND: The zinc finger antiviral protein (ZAP) is a host restriction factor that inhibits the replication of various viruses by degradation of certain viral mRNA. However, previous study demonstrated that ectopic expression of rat ZAP did not suppress the replication of herpes simplex virus type 1 (HSV-1), an archetypal member of the alphaherpesvirus subfamily, and the molecular mechanism underneath is still illusive. RESULTS: Human ZAP (hZAP) does not suppress the replication of herpes simplex virus 1, and HSV-1 UL41 protein was identified as an antagonist of hZAP by degrading its mRNA. Infection of wild-type (WT), but not UL41-null mutant (R2621) virus, diminished the accumulation of hZAP to abrogate its antiviral activity. Moreover, ectopic expression of hZAP inhibited the replication of R2621 but not WT HSV-1. CONCLUSION: HSV-1 UL41 was shown for the first time to evade the antiviral function of hZAP via its RNase activity. PMID- 26625986 TI - 3D Printing technologies for drug delivery: a review. AB - With the FDA approval of the first 3D printed tablet, Spritam(r), there is now precedence set for the utilization of 3D printing for the preparation of drug delivery systems. The capabilities for dispensing low volumes with accuracy, precise spatial control and layer-by-layer assembly allow for the preparation of complex compositions and geometries. The high degree of flexibility and control with 3D printing enables the preparation of dosage forms with multiple active pharmaceutical ingredients with complex and tailored release profiles. A unique opportunity for this technology for the preparation of personalized doses to address individual patient needs. This review will highlight the 3D printing technologies being utilized for the fabrication of drug delivery systems, as well as the formulation and processing parameters for consideration. This article will also summarize the range of dosage forms that have been prepared using these technologies, specifically over the last 10 years. PMID- 26625987 TI - Clinical Economics and Nursing. PMID- 26625988 TI - Pain, health perception and sleep: impact on the quality of life of firefighters/rescue professionals. AB - OBJECTIVE: To evaluate the quality of life of firefighters and rescue professionals, and characterize their socio-demographic, health, work and lifestyle profile. METHODS: Cross-sectional study that used a socio-demographic, lifestyle, health, work data questionnaire and the WHOQOL-BREF quality of life aspects, in Fire Department bases, Civil Air Patrol Group of the Military Police and Rescue Group of Emergency Services. RESULTS: Ninety professionals participated in this study - 71 firefighters, 9 nurses, 7 doctors and 3 flight crew members. The average age of the group was 36.4 +/- 7.8 years; they worked about 63.7 hours per week; 20.2% reported pain in the last week and 72.7% had body mass index above 25 kg/m2. The average of the WHOQOL-BREF domains was: physical (74.6), psychological (75.2), social (76.5) and environmental (58.7). Significant association was found (Mann-Whitney test and Spearman correlation) between the WHOQOL-BREF domains and pain in the past six months, in the last week, health perception, job satisfaction, hours of sleep, domestic tasks and study. CONCLUSION: The main factors related to quality of life were presence of pain, health perception, sleep and domestic activity. PMID- 26625989 TI - Analgesic efficacy of lidocaine and multimodal analgesia for chest tube removal: A randomized trial study. AB - OBJECTIVE: To assess the analgesic efficacy of subcutaneous lidocaine and multimodal analgesia for chest tube removal following heart surgery. METHODS: Sixty volunteers were randomly allocated in two groups; 30 participants in the experimental group were given 1% subcutaneous lidocaine, and 30 controls were given a multimodal analgesia regime comprising systemic anti-inflammatory agents and opioids. The intensity and quality of pain and trait and state anxiety were assessed. The association between independent variables and final outcome was assessed by means of the Chi-squared test with Yates' correction and Fisher's exact test. RESULTS: The groups did not exhibit significant difference with respect to the intensity of pain upon chest tube removal (p= 0.47). The most frequent descriptors of pain reported by the participants were pressing, sharp, pricking, burning and unbearable. CONCLUSION: The present study suggests that the analgesic effect of the subcutaneous administration of 1% lidocaine combined with multimodal analgesia is most efficacious. PMID- 26625990 TI - Validation to Portuguese of the Scale of Student Satisfaction and Self-Confidence in Learning. AB - OBJECTIVE: Translate and validate to Portuguese the Scale of Student Satisfaction and Self-Confidence in Learning. MATERIAL AND METHODS: Methodological translation and validation study of a research tool. After following all steps of the translation process, for the validation process, the event III Workshop Brazil - Portugal: Care Delivery to Critical Patients was created, promoted by one Brazilian and another Portuguese teaching institution. RESULTS: 103 nurses participated. As to the validity and reliability of the scale, the correlation pattern between the variables, the sampling adequacy test (Kaiser-Meyer-Olkin) and the sphericity test (Bartlett) showed good results. In the exploratory factorial analysis (Varimax), item 9 behaved better in factor 1 (Satisfaction) than in factor 2 (Self-confidence in learning). The internal consistency (Cronbach's alpha) showed coefficients of 0.86 in factor 1 with six items and 0.77 for factor 2 with 07 items. CONCLUSION: In Portuguese this tool was called: Escala de Satisfacao de Estudantes e Autoconfianca na Aprendizagem. The results found good psychometric properties and a good potential use. The sampling size and specificity are limitations of this study, but future studies will contribute to consolidate the validity of the scale and strengthen its potential use. PMID- 26625991 TI - A content validity study of signs, symptoms and diseases/health problems expressed in LIBRAS. AB - OBJECTIVES: To validate the content of signs, symptoms and diseases/health problems expressed in LIBRAS for people with deafness. Method: Methodological development study, which involved 36 people with deafness and three LIBRAS specialists. The study was conducted in three stages: investigation of the signs, symptoms and diseases/health problems, referred to by people with deafness, reported in a questionnaire; video recordings of how people with deafness express, through LIBRA, the signs, symptoms and diseases/health problems; and validation of the contents of the recordings of the expressions by LIBRAS specialists. Data were processed in a spreadsheet and analyzed using univariate tables, with absolute frequencies and percentages. The validation results were analyzed using the Content Validity Index (CVI). RESULTS: 33 expressions in LIBRAS, of signs, symptoms and diseases/health problems were evaluated, and 28 expressions obtained a satisfactory CVI (1.00). CONCLUSIONS: The signs, symptoms and diseases/health problems expressed in LIBRAS presented validity, in the study region, for health professionals, especially nurses, for use in the clinical anamnesis of the nursing consultation for people with deafness. PMID- 26625992 TI - Governance of professional nursing practice in a hospital setting: a mixed methods study. AB - OBJECTIVE: To elaborate an interpretative model for the governance of professional nursing practice in a hospital setting. METHOD: A mixed methods study with concurrent triangulation strategy, using data from a cross-sectional study with 106 nurses and a Grounded Theory study with 63 participants. The quantitative data were collected through the Brazilian Nursing Work Index - Revised and underwent descriptive statistical analysis. Qualitative data were obtained from interviews and analyzed through initial, selective and focused coding. RESULTS: Based on the results obtained with the Brazilian Nursing Work Index - Revised, it is possible to state that nurses perceived that they had autonomy, control over the environment, good relationships with physicians and organizational support for nursing governance. The governance of the professional nursing practice is based on the management of nursing care and services carried out by the nurses. To perform these tasks, nurses aim to get around the constraints of the organizational support and develop management knowledge and skills. CONCLUSION: It is important to reorganize the structures and processes of nursing governance, especially the support provided by the organization for the management practices of nurses. PMID- 26625993 TI - Levels of career commitment and career entrenchment of nurses from public and private hospitals. AB - OBJECTIVE: To determine the prevalence of the types of relations to career - commitment and entrenchment - of nurses from public and private hospitals. METHODS: Field survey with a quantitative approach. A total of 237 nurses participated in the survey through a questionnaire with 43 questions about sociodemographic data, occupation, and relation to career. Descriptive statistics, frequency analysis, and Mann-Whitney U test were used for data analysis. RESULTS: Nurses from public and private hospitals have a high level of career commitment and a median level of career entrenchment. CONCLUSIONS: Nurses have a stronger relation of affection and identification to career than a relation of stagnation, maintained primarily due to investments, followed by emotional costs and lack of alternatives. This fact is associated with individuals continuing in nursing and having a strong commitment to activities. PMID- 26625994 TI - Safety culture in the operating room of a public hospital in the perception of healthcare professionals. AB - OBJECTIVE: To evaluate the perception of healthcare professionals about the safety culture in the operating room of a public hospital, large-sized, according to the domains of the Safety Attitudes Questionnaire (SAQ). METHOD: Descriptive, cross-sectional and quantitative research, with the application of the SAQ to 226 professionals. Descriptive data analysis, instrument consistency and exploratory factor analysis. RESULTS: Participants were distributed homogeneously between females (49.6%) and males (50.4%); mean age of 39.6 (SD+/-9.9) years and length of professional experience of 9.9 (SD +/- 9.2) years. And Cronbach's alpha of 0.84. It was identified six domains proposed in the questionnaire: stress perception (74.5) and job satisfaction (70.7) showed satisfactory results; teamwork environment (59.1) and climate of security (48.9) presented scores below the minimum recommended (75); unit's management perceptions (44.5), hospital management perceptions (34.9) and working conditions (41.9) presented the lowest averages. CONCLUSIONS: The results showed that, from the perspective of the professionals, there is weakness in the values, attitudes, skills and behaviors that determine the safety culture in a healthcare organization. PMID- 26625995 TI - Use of Balanced Indicators as a Management Tool in Nursing. AB - OBJECTIVE: To develop a proposal for a nursing panel of indicators based on the guiding principles of Balanced Scorecard. METHOD: A single case study that ranked 200 medical records of patients, management reports and protocols, which are capable of generating indicators. RESULTS: We identified 163 variables that resulted in 72 indicators; of these, 32 nursing-related: two financial indicators (patient's average revenue per day and patient's revenue per day by product used); two client indicators (overall satisfaction rate of patient with nursing care and adherence rate to the patient satisfaction survey); 23 process indicators, and five learning and growth indicators (average total hours of training, total of approved nursing professionals in the internal selection process, absenteeism rate, turnover rate and index of performance evaluation). CONCLUSION: Although there is a limit related to the amount of data generated, the methodology of Balanced Scorecard has proved to be flexible and adaptable to incorporate nursing services. It was possible to identify indicators with adherence to more than one area. Internal processes was the area with the higher number of indicators. PMID- 26625996 TI - Diagnostic accuracy of the defining characteristics of the excessive fluid volume diagnosis in hemodialysis patients. AB - OBJECTIVE: To evaluate the accuracy of the defining characteristics of the excess fluid volume nursing diagnosis of NANDA International, in patients undergoing hemodialysis. METHOD: This was a study of diagnostic accuracy, with a cross sectional design, performed in two stages. The first, involving 100 patients from a dialysis clinic and a university hospital in northeastern Brazil, investigated the presence and absence of the defining characteristics of excess fluid volume. In the second step, these characteristics were evaluated by diagnostic nurses, who judged the presence or absence of the diagnosis. To analyze the measures of accuracy, sensitivity, specificity, and positive and negative predictive values were calculated. Approval was given by the Research Ethics Committee under authorization No. 148.428. RESULTS: The most sensitive indicator was edema and most specific were pulmonary congestion, adventitious breath sounds and restlessness. CONCLUSION: The more accurate defining characteristics, considered valid for the diagnostic inference of excess fluid volume in patients undergoing hemodialysis were edema, pulmonary congestion, adventitious breath sounds and restlessness. Thus, in the presence of these, the nurse may safely assume the presence of the diagnosis studied. PMID- 26625997 TI - Prescriptive Authority and Nursing: a comparative analysis of Brazil and Canada. AB - OBJECTIVE: To analyse the differences between medication prescriptions by nurses in Brazil and Ontario, Canada. METHODS: A comparative study between two different scenarios; this comparison was not performed between the two countries because Canada does not standardize this practice, which is legally established and is considered as an advanced professional knowledge area in Brazil. RESULTS: Prescription is a professional position to be occupied by nurses. However, there is tension surrounding this practice because it is perceived as a threat to privileges or traditions of other health professionals. Prescibing medication by nurses in Brazil and Ontario follows current legislation and training proccess in each context. CONCLUSIONS: There are some challenges to be overcome in ensuring the visibility and consolidation of the practice by nurses in these realities: guarantee of professional competence, credibility, acceptability, and the respectability of clientele in your professional scope by other health professionals. PMID- 26625998 TI - Human error in daily intensive nursing care. AB - OBJECTIVES: To identify the errors in daily intensive nursing care and analyze them according to the theory of human error. METHOD: Quantitative, descriptive and exploratory study, undertaken at the Intensive Care Center of a hospital in the Brazilian Sentinel Hospital Network. The participants were 36 professionals from the nursing team. The data were collected through semistructured interviews, observation and lexical analysis in the software ALCESTE(r). RESULTS: Human error in nursing care can be related to the approach of the system, through active faults and latent conditions. The active faults are represented by the errors in medication administration and not raising the bedside rails. The latent conditions can be related to the communication difficulties in the multiprofessional team, lack of standards and institutional routines and absence of material resources. CONCLUSION: The errors identified interfere in nursing care and the clients' recovery and can cause damage. Nevertheless, they are treated as common events inherent in daily practice. The need to acknowledge these events is emphasized, stimulating the safety culture at the institution. PMID- 26625999 TI - Evaluation of self-esteem in cancer patients undergoing chemotherapy treatment. AB - OBJECTIVE: To evaluate the self-esteem of cancer patients undergoing chemotherapy. METHOD: Descriptive analytical cross-sectional study with a quantitative approach. Around 156 patients that attended an oncology unit of a mid-sized hospital participated in the study. RESULTS: We found a higher frequency of patients with high self-esteem, but some of them showed average or low self-esteem. The scale showed a Cronbach's alpha value of 0.746, by considering its acceptable internal consistency for the evaluated items. No independent variables showed significant associations with self-esteem. CONCLUSION: The cancer patients evaluated have presented high self-esteem; thus, it becomes crucial for nursing to plan the assistance of patients undergoing chemotherapy treatments, which enables actions and strategies that meet their physical and psychosocial conditions, aiming to maintain and rehabilitate these people's emotional aspects. PMID- 26626000 TI - Adolescents with attention deficit hyperactivity disorder and exposure to violence: parents' opinion. AB - OBJECTIVE: To identify the opinion of parents or guardians of adolescents diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) about their children's exposure as perpetrators or victims of violence situations in family life or outside. METHOD: Qualitative study with use of thematic oral history. Nine parents of 07 adolescents with ADHD participated. Data were collected from April to September of 2013 using thematic interview. The interviews were recorded at scheduled times at the participants' home, with an average duration of 30 minutes. The findings were submitted to inductive thematic analysis. RESULTS: Data analysis allowed the identification of the occurrence of "Conflicts in family life" and "Conflicts in the context of school and community". Parents reported the involvement of their children as victims, perpetrators and witnesses of physical and psychological violence, and the difficulty of them and the school to understand and handle these situations. CONCLUSION: Violence occurs in ADHD adolescents' interpersonal relationships. Communication between health professionals, school and families is precarious. Through the systematization of nursing care, nurses can plan strategies that articulate support networks and interpersonal relationships of adolescents with the disorder (family and school). PMID- 26626001 TI - Child development: analysis of a new concept. AB - OBJECTIVES: To perform concept analysis of the term child development (CD) and submit it to review by experts. METHOD: Analysis of concept according to the hybrid model, in three phases: theoretical phase, with literature review; field phase of qualitative research with professionals who care for children; and analytical phase, of articulation of data from previous steps, based on the bioecological theory of development. The new definition was analyzed by experts in a focus group. Project approved by the Research Ethics Committee. RESULTS: We reviewed 256 articles, from 12 databases and books, and interviewed 10 professionals, identifying that: The CD concept has as antecedents aspects of pregnancy, factors of the child, factors of context, highlighting the relationships and child care, and social aspects; its consequences can be positive or negative, impacting on society; its attributes are behaviors and abilities of the child; its definitions are based on maturation, contextual perspectives or both. The new definition elaborated in concept analysis was validated by nine experts in focus group. It expresses the magnitude of the phenomenon and factors not presented in other definitions. CONCLUSION: The research produced a new definition of CD that can improve nursing classifications for the comprehensive care of the child. PMID- 26626002 TI - Surgical Safety in Pediatrics: practical application of the Pediatric Surgical Safety Checklist. AB - OBJECTIVES: To assess the practical application of the Pediatric Surgical Safety Checklist on the preoperative period and to verify family satisfaction regarding the use of the material. METHOD: Exploratory study that aimed to analyze the use of the checklist by children who underwent surgical interventions. The sample was constituted by 60 children (from preschoolers to teens) and 60 family members. The variables related to demographic characterization, filling out the checklist, and family satisfaction, being evaluated through inferential and descriptive statistical analysis. RESULTS: Most children (71.7%) were male, with a median age of 7.5 years. We identified the achievement of 65.3% of the checklist items, 30.0% were not filled due to non-performance of the team and 4.7% for children and family reasons. In the association analysis, we found that the removal of accessories item (p = 0.008) was the most checked by older children. Regarding satisfaction, the family members evaluated the material as great (63.3%) and good (36.7%) and believed that there was a reduction of the child's anxiety (83.3%). CONCLUSION: The use of the checklist in clinical practice can change health services regarding safety culture and promote customer satisfaction. PMID- 26626003 TI - The illness of women and men with sickle cell disease: a Grounded Theory study. AB - OBJECTIVE: To understand the meanings given by women and men with sickle cell disease on the illness experience. METHOD: Analytical study with a qualitative approach, conducted with 17 adults with sickle cell disease using the Theory Based on Data, or Grounded Theory, as theoretical-methodological referential. Data were collected between the years of 2012 and 2013, in an individual in-depth interview. All the interviews were recorded and analyzed according to the Grounded Theory comparative analysis technique. RESULTS: Data show four categories which group the experience of illness, the feelings experienced and the path to living with sickle cell disease. CONCLUSIONS: It was possible to understand that the experience was built by a process in which these people redefined the meaning of their lives, applying new directions to life and to care regarding the experience of the illness. In the context of chronic disease, the nurse's care is also seen in this study as a foundation, providing attention, directions, and guidance through the required confrontations. Understanding the experience lived by these people, it is possible to enlarge the dimensions and the essence of nursing care required throughout life. PMID- 26626004 TI - Association of socioeconomic and clinical variables with the state of frailty among older inpatients. AB - OBJECTIVES: To identify the prevalence of frailty among inpatient older adults in a clinical hospital and check the association of the socioeconomic and clinical characteristics with the state of frailty. METHOD: Observational, cross-sectional and analytical study, conducted with 255 hospitalized patients. Materials used: structured instrument for the economical and clinical data and frailty phenotype of Fried. Descriptive and bivariate statistical analysis was carried out and, by means of chi-square tests and ANOVA One-way (p<0.05). RESULTS: The prevalence of frailty corresponded to 26.3%, while pre-frailty represented 53.3%. The highest proportion of frail seniors was identified for 80 years or older (p = 0.004), widowed (p = 0.035) and with the highest average length of stay (p = 0.006). CONCLUSION: Inpatient older adults presented high percentages of frail states associated with socioeconomic variables and hospitalization period. The identification of the health conditions related to pre-frailty and frailty can foster the planning and implementation of the assistance to older adults in this context. PMID- 26626005 TI - Cohort study of institutionalized elderly people: fall risk factors from the nursing diagnosis. AB - OBJECTIVE: To determine the incidence of falls in elderly residents of long-stay institutions of the Federal District, to identify the aspects involved in the falls, in terms of risk factors, from the application of scales and the Taxonomy II of NANDA-I, and to define the level of accuracy with its sensitivity and specificity for application in the clinical nursing practice. METHOD: This was a cohort study with the evaluation of 271 elderly people. Cognition, functionality, mobility and other intrinsic factors were evaluated. After six months, the elderly people who fell were identified, with significance analysis then performed to define the risk factors. RESULTS: The results showed an incidence of 41%. Of the 271 patients included, 69 suffered 111 episodes of falls during the monitoring period. Risk factors were the presence of stroke with its sequelae (OR: 1.82, 95% CI 1.01 - 3.28, p=.045), presenting more than five chronic diseases (OR: 2.82, 95% CI 1.43 - 5.56, p=.0028), foot problem (OR: 2.45, 95% CI 1.35 - 4.44, p=.0033) and motion (OR: 2.04, 95% CI 1.15 - 3.61, p=.0145). CONCLUSION: The taxonomy has high validity regarding the detection of elderly people at risk of falling and should be applied consistently in the clinical nursing practice. PMID- 26626006 TI - Connection between competence, usability, environment and risk of falls in elderly adults. AB - OBJECTIVE: To determine connections between competence, usability, environment and risk of falls in elderly adults. METHOD: Correlational descriptive study, 123 elderly adults, both male and female, aged 70 years and older were included. Data was collected via the Tinetti Scale, CESD-7 Scale, Montreal Cognitive Assessment, Usability Questionnaire on Housing and Housing Enabler; and sociodemographic and health background certificate data. For data analysis, descriptive and inferential statistics were used, multivariate linear and logistic regression models were adjusted. RESULTS: 42.0% of the elderly adults had presented with falls, with a higher prevalence in women, and in the group of 70-75 years. The physical environment of the house, gait, and usability were set as risk factors for falls. A negative relationship between usability and depressive symptoms, cognitive health, balance, gait, the social and physical environment was found, p <0.05; and a strong positive correlation between walking and balance, p <0.05. CONCLUSION: This study helps to better understand the phenomenon of falling, to find a connection between usability with the risk of falls, and other variables. PMID- 26626007 TI - Systemic Arterial Hypertension in the Emergency Service: medication adherence and understanding of this disease. AB - OBJECTIVE: To identify the epidemiological profile of hypertension patients, how much they understand about the disease and the rate of adherence to treatment by these patients who had been hospitalized in the Brazilian emergency service. METHODS: This cross-sectional study was performed with 116 patients, both male and female and aged over 18 years, who had been hospitalized in the Emergency Service of a University Hospital between March and June, 2013. The studied variables were data referring to socio-demographics, comorbidities, physical activity and knowledge regarding the disease. Patient adherence to treatment and the identification of the barriers were respectively evaluated using the Morisky test and the Brief Medication Questionnaire. RESULTS: Most of the patients involved in this study were women (55%), with white skin color (55%), married (51%), retirees or pensioners (64%) and with a low educational level (58%). Adherence to treatment, in most cases (55%), was moderate and the most prevalent adherence barrier was recall (67%). When medication was acquired at no cost to the patient, there was greater adherence to treatment. CONCLUSION: This study's patients had a moderate understanding about the disease. The high correlation between the number of drugs used and the recall barrier suggests that monotherapy is an option that can facilitate treatment adherence and reduce how often the patients forget to take their medication. PMID- 26626008 TI - Hypertension and diabetes-related morbidity and mortality trends in a municipality in the countryside of Sao Paulo. AB - OBJECTIVES: To identify the main causes for hospital admissions and deaths related to systemic arterial hypertension and diabetes mellitus (DM), and to analyze morbidity and mortality trends, in a municipality in Sao Paulo's countryside, by comparing two three-years periods, 2002 to 2004 and 2010 to 2012. METHODS: Cross-sectional study which used secondary data regarding deaths from the Information System on Mortality and concerning hospital admissions from the DataSus Hospital Information System. Univariate and multivariate statistical analyses were conducted. RESULTS: From 2002 to 2012, 325,439 people were admitted to hospitals, 14.7% of them due to circulatory system diseases (CSD) and 0.7% due to DM. The deaths distributed as the following: 29,027 deaths (31.5%) were due to CSD; 8.06% due to cerebrovascular diseases (CVD); and 2.75% due to DM. There was a significant association between admittance and death causes and patients' gender and age in the three-year periods (p<0.001). The highest lethality in hospital admissions was found to be due to CVD (10%). That trend showed that mortality rates dropped, younger patients were admitted due to DM, and older patients were admitted due to CVD - they were more often females. CONCLUSION: The main causes for hospital admissions were the CSDs; main mortality causes were the CVDs in hypertensive and diabetic women. Those findings can back public policies which prioritize the promotion of health. PMID- 26626009 TI - Alcoholic patients' response to their disease: perspective of patients and family. AB - OBJECTIVE: To know the perspective of alcoholic patients and their families about the behavioral characteristics of the disease, identifying the issues to modify the addictive behavior and seek rehabilitation. METHOD: Ethnographic research using interpretative anthropology, via participant observation and a detailed interview with alcoholic patients and their families, members of Alcoholics Anonymous (AA) and Alanon in Spain. RESULTS: Development of disease behavior in alcoholism is complex due to the issues of interpreting the consumption model as a disease sign. Patients often remain long periods in the pre-contemplation stage, delaying the search for assistance, which often arrives without them accepting the role of patient. This constrains the recovery and is related to the social thought on alcoholism and self-stigma on alcoholics and their families, leading them to deny the disease, condition of the patient, and help. The efforts of self-help groups and the involvement of health professionals is essential for recovery. CONCLUSION: Understanding how disease behavior develops, and the change process of addictive behavior, it may be useful for patients, families and health professionals, enabling them to act in a specific way at each stage. PMID- 26626010 TI - Drug use, mental health and problems related to crime and violence: cross sectional study. AB - OBJECTIVE: To investigate the correlation between disorders related to the use of alcohol and other drugs and symptoms of mental disorders, problems related to crime and violence and to age and gender. METHODS: Cross-sectional descriptive study carried out with 128 users of a Psychosocial Care Center for Alcohol and other Drugs, in the city of Sao Paulo, interviewed by means of the instrument entitled Global Appraisal of Individual Needs - Short Screener. Univariate and multiple linear regression models were used to verify the correlation between the variables. RESULTS: Using univariate regression models, internalizing and externalizing symptoms and problems related to crime/violence proved significant and were included in the multiple model, in which only the internalizing symptoms and problems related to crime and violence remained significant. CONCLUSIONS: There is a correlation between the severity of problems related to alcohol use and severity of mental health symptoms and crime and violence in the study sample. The results emphasize the need for an interdisciplinary and intersectional character of attention to users of alcohol and other drugs, since they live in a socially vulnerable environment. PMID- 26626011 TI - Lights, camera and action in the implementation of central venous catheter dressing. AB - OBJECTIVE: To develop and validate an educational digital video on changing the dressing of short-term, non-cuffed, non-tunneled central venous catheters in hospitalized adult patients. METHOD: This is a descriptive, methodological study based on Paulo Freire's assumptions. The development of the script and video storyboard were based on scientific evidence, on the researchers' experience, and that of nurse experts, as well as on a virtual learning environment. RESULTS: The items related to the script were approved by 97.2% of the nurses and the video was approved by 96.1%. CONCLUSION: The educational instrument was considered to be appropriate and we believe it will contribute to professional training in the nursing field, the updating of human resources, focusing on the educational process, including distance education. We believe it will consequently improve the quality of care provided to patients with central venous catheters. PMID- 26626012 TI - Ethical problems experienced by oncology nurses. AB - OBJECTIVE: To know the ethical problems experienced by oncology nurses. METHOD: Descriptive and exploratory study with a qualitative approach, performed in inpatient units and in chemotherapy out-patients units that provide assistance to oncological patients in two capitals in the South region of Brazil. Eighteen nurses participated in this study, selected by snowball sampling type. For data collection, semi-structured interviews were carried out, which were recorded and transcribed, and then analyzed by thematic analysis. RESULTS: Two categories were established: when informing or not becomes a dilemma - showing the main difficulties related to oncological treatment information regarding health staff, health system, and infrastructure; to invest or not - dilemmas related to finitude - showing situations of dilemmas related to pain and confrontation with finitude. CONCLUSION: For the effective confrontation of the ethical problems experienced by oncology nurses to occur, it is important to invest in the training of these professionals, preparing them in an ethical and human way to act as lawyers of the patient with cancer, in a context of dilemmas related mainly to the possibility of finitude. PMID- 26626013 TI - Early hyperreactive malarial splenomegaly and risk factors for evolution into the full-blown syndrome: a single-centre, retrospective, longitudinal study. AB - BACKGROUND: The hyperreactive malarial splenomegaly (HMS) represents a chronic, potentially fatal complication of malaria. Case definition includes: gross splenomegaly, high level of anti-malarial antibody and IgM, response to long-term anti-malarial prophylaxis. In this study, a large series of patients not fully meeting the case definition was tentatively classified as early hyperreactive malarial splenomegaly (e-HMS). The main research questions was: does "e-HMS" tend to evolve to the full-blown syndrome? And if so, what are the main factors influencing this evolution? METHODS: Retrospective, longitudinal study. The patient database was searched to retrieve all potentially eligible patients. e HMS was defined by splenomegaly of any size (with or without raised IgM), high anti-malarial antibody titre and exclusion of other causes of splenomegaly. The clinical outcome at following visits was analysed in relation to re-exposure to malaria, and to treatment (only part of the patients with e-HMS were treated with a single anti-malarial treatment and advised to follow an effective anti-malarial prophylaxis, if re-exposed). The association of the outcome with the main independent variables was first assessed with univariate analysis. A stepwise logistic regression model was then performed to study the association of the outcome with the main independent variables. RESULTS: One hundred and twenty-six subjects with e-HMS were retrieved. Eighty-one had at least one follow-up visit. Of 46 re-exposed to malaria for a variable period, 21 (46 %) had progressed, including 10/46 (22 %) evolving to full-blown HMS, while of 29 patients not re exposed, 24 (93 %) had improved or cured and five (7 %) progressed (p < 0.001). At logistic regression re-exposure was confirmed as a major risk factor of progression (OR 9.458, CI 1.767-50.616) while treatment at initial visit was protective (OR 0.187, CI 0.054-0.650). CONCLUSION: e-HMS should be regarded as a clinical condition predisposing to HMS. Although the case definition may include false positives, e-HMS should be treated just as the full-blown syndrome. A single anti-malarial treatment is probably adequate, followed by effective prophylaxis for patients exposed again to malaria transmission. PMID- 26626014 TI - An exploration of undergraduate medical students' satisfaction with faculty support supervision during community placements in Uganda. AB - INTRODUCTION: To produce health professionals who are oriented towards addressing community priority health needs, the training in medical schools has been transformed to include a component of community-based training. During this period, students spend a part of their training in the communities they are likely to serve upon graduation. They engage and empower local people in the communities to address their health needs during their placements, and at the same time learn from the people. During the community-based component, students are constantly supervised by faculty from the university to ensure that the intended objectives are achieved. The purpose of the present study was to explore student experiences of support supervision from university faculty during their community-based education, research and service (COBERS placements) and to identify ways in which the student learning can be improved through improved faculty supervision. METHODS: This was a cross-sectional study involving students at the College of Health Sciences, Makerere University, Uganda, who had a community-based component during their training. Data were collected using both questionnaires and focus group discussions. Quantitative data were analyzed using statistical software and thematic approaches were used for the analysis of qualitative data. RESULTS: Most students reported satisfaction with the COBERS supervision; however, junior students were less satisfied with the supervision than the more senior students with more experience of community-based training. Although many supervisors assisted students before departure to COBERS sites, a significant number of supervisors made little follow-up while students were in the community. Incorporating the use of information technology avenues such as emails and skype sessions was suggested as a potential way of enhancing supervision amidst resource constraints without faculty physically visiting the sites. CONCLUSIONS: Although many students were satisfied with COBERS supervision, there are still some challenges, mostly seen with the more junior students. Using information technology could be a solution to some of these challenges. PMID- 26626015 TI - Motivation or demotivation of health workers providing maternal health services in rural areas in Vietnam: findings from a mixed-methods study. AB - BACKGROUND: Motivation is an important driver for health professionals to maintain their professional competencies, continue in the workforce and make a positive contribution to their workplace. While there is some research about the motivation of health workers in low- to middle-income countries, maternal morbidity and mortality remains high and this can be lowered by improving the quality of maternal health services and the training and maintenance of the skills of maternal health workers. This study examines the impact of motivation on maintenance of professional competence among maternal health workers in Vietnam using mixed methods. METHODS: The study consisted of a survey using a self-administered questionnaire of 240 health workers in five districts across two Vietnamese provinces and in-depth interviews with 43 health workers and health managers at the commune, district and provincial level to explore external factors that influenced motivation. The questionnaire includes a 23-item motivation instrument based on the Kenyan health context, modified for Vietnamese language and culture. RESULTS: The 240 responses represented an estimated 95% of the target sample. Multivariate analysis showed that three factors contributed to the motivation of health workers: access to training (beta = -0.14, P = 0.03), ability to perform key tasks (beta = 0.22, P = 0.001) and shift schedule (beta = 0.13, P = 0.05). Motivation was higher in health workers self-identifying as competent or who were enabled to provide more maternal care services. Motivation was lower in those who worked more frequent night shifts and those who had received training in the last 12 months. The interviews identified that the latter was because they felt the training was irrelevant to them, and in some cases, they do not have the opportunity to practice their learnt skills. The qualitative data also showed other factors relating to service context and organisational management practices contributed to motivation. CONCLUSIONS: The study demonstrates the importance of understanding the motivations of health workers and the factors that contribute to this and may contribute to more effective management of the health workforce in low- and middle-income countries. PMID- 26626016 TI - Is it ethical to prevent secondary use of stored biological samples and data derived from consenting research participants? The case of Malawi. AB - BACKGROUND: This paper discusses the contentious issue of reuse of stored biological samples and data obtained from research participants in past clinical research to answer future ethical and scientifically valid research questions. Many countries have regulations and guidelines that guide the use and exportation of stored biological samples and data. However, there are variations in regulations and guidelines governing the reuse of stored biological samples and data in Sub-Saharan Africa including Malawi. DISCUSSION: The current research ethics regulations and guidelines in Malawi do not allow indefinite storage and reuse of biological samples and data for future unspecified research. This comes even though the country has managed to answer pertinent research questions using stored biological samples and data. We acknowledge the limited technical expertise and equipment unavailable in Malawi that necessitates exportation of biological samples and data and the genuine concern raised by the regulatory authorities about the possible exploitation of biological samples and data by researchers. We also acknowledge that Malawi does not have bio-banks for storing biological samples and data for future research purposes. This creates room for possible exploitation of biological samples and data collected from research participants in primary research projects in Malawi. However, research ethics committees require completion and approval of material transfer agreements and data transfer agreements for biological samples and data collected for research purposes respectively and this requirement may partly address the concern raised by the regulatory authorities. Our concern though is that there is no such requirement for biological samples and data collected from patients for clinical or diagnostic purposes. In conclusion, we propose developing a medical data and material transfer agreement for biological samples and data collected from patients for clinical or diagnostic purposes in both public and private health facilities that may end up in research centers outside Malawi. We also propose revision of the current research ethics regulations and guidelines in Malawi in order to allow secondary use of biological samples and data collected from primary research projects as a way of maximizing the use of collected samples and data. Finally, we call for consultation of all stakeholders within the Malawi research community when regulatory authorities are developing policies that govern research in Malawi. PMID- 26626017 TI - Cellular immune response in intraventricular experimental neurocysticercosis. AB - Neurocysticercosis (NCC) is considered a neglected parasitic infection of the human central nervous system. Its pathogenesis is due to the host immune response, stage of evolution and location of the parasite. The aim of this study was to evaluate the in situ and systemic immune response through cytokines dosage (IL-4, IL-10, IL-17 and IFN-gamma) as well as the local inflammatory response of the experimental NCC with Taenia crassiceps. The in situ and systemic cellular and inflammatory immune response were evaluated through the cytokines quantification at 7, 30, 60 and 90 days after inoculation and histopathological analysis. All cysticerci were found within the cerebral ventricles. There was a discrete intensity of inflammatory cells of mixed immune profile, polymorphonuclear and mononuclear cells, at the beginning of the infection and predominance of mononuclear cells at the end. The systemic immune response showed a significant increase in all the analysed cytokines and predominance of the Th2 immune profile cytokines at the end of the infection. These results indicate that the location of the cysticerci may lead to ventriculomegaly. The acute phase of the infection showed a mixed Th1/Th17 profile accompanied by high levels of IL-10 while the late phase showed a Th2 immune profile. PMID- 26626018 TI - Olfaction in Parkin single and compound heterozygotes in a cohort of young onset Parkinson's disease patients. AB - BACKGROUND: Parkin related Parkinson's disease (PD) is differentiated from idiopathic PD by absent or sparse Lewy bodies, and preserved olfaction. The significance of single Parkin mutations in the pathogenesis of PD is debated. OBJECTIVES: To assess olfaction results according to Parkin mutation status. To compare the prevalence of Parkin single heterozygous mutations in patients diagnosed with PD to the rate in healthy controls in order to establish whether these single mutations could be a risk factor for developing PD. METHODS: Parkin gene mutation testing was performed in young onset PD (diagnosed <50 years old) to identify three groups: Parkin homozygous or compound heterozygote mutation carriers, Parkin single heterozygote mutation carriers, and non-carriers of Parkin mutations. Olfaction was tested using the 40-item British version of the University of Pennsylvania smell identification test (UPSIT). RESULTS: Of 344 young onset PD cases tested, 8 (2.3%) were Parkin compound heterozygotes and 13 (3.8%) were Parkin single heterozygotes. Olfaction results were available in 282 cases (eight compound heterozygotes, nine single heterozygotes, and 265 non carriers). In Parkin compound heterozygotes, the median UPSIT score was 33, interquartile range (IQR) 28.5-36.5, which was significantly better than in single Parkin heterozygotes (median 19, IQR 18-28) and non-carriers (median score 22, IQR 16-28) (ANOVA P < 0.001). These differences persisted after adjusting for age, disease duration, gender, and smoking (P < 0.001). There was no significant difference in UPSIT scores between single heterozygotes and non-carriers (P = 0.90). CONCLUSIONS: Patients with Parkin compound heterozygous mutations have relatively preserved olfaction compared to Parkin single heterozygotes and non carriers. The prevalence of Parkin single heterozygosity is similar to the 3.7% rate reported in healthy controls. PMID- 26626019 TI - Current distribution of the invasive mosquito species, Aedes koreicus [Hulecoeteomyia koreica] in northern Italy. AB - BACKGROUND: The invasive species Aedes (Finlaya) koreicus was first identified in north-eastern Italy in 2011, during the ongoing surveillance activity of Aedes albopictus. Following this finding, a more intensive monitoring was carried out to assess the distribution of the species and to collect biological data. Herein, we report the new records obtained by four years of surveillance. FINDINGS: The presence of Ae. koreicus was checked using ovitraps, adults traps and by larval collections in all possible breeding sites from May 2011 to July 2015. The monitoring started in the site of the first detection (Province of Belluno) and was then extended in the neighbouring Provinces belonging to four Regions. Aedes koreicus was found in 73 municipalities out of 155 monitored (47.1 %), including 23 municipalities (14.8 %) previously not infested. The area of first detection of Ae. koreicus (Province of Belluno) was also the most infested (68 %). However the mosquito has also been found to the west (Province of Trento) and to the south and south-west (Provinces of Vicenza and Treviso) of the initially infested area. CONCLUSIONS: The spread of Ae. koreicus is directed towards south and west from the original infested area, likely due to the dense road connections and the habitat suitability of the new areas. According to these records, northern Italy has a high probability to be invaded by Ae. koreicus in the next decade. These data can be useful to validate predictive models of potential distribution and dispersal of this species in Italy or in Europe. PMID- 26626020 TI - Specific interactions of alcohols and non-alcohols with a biologically active boronic acid derivative: a spectroscopic study. AB - The photophysical properties of 4-fluoro-2-methoxyphenyl boronic acid (4FMPBA) are characterized using absorption and fluorescence techniques in series of non alcohols and alcohols. The results are analyzed using different solvent polarity functions and Kamlet and Catalan's multiple regression approaches. The excited state dipole moment and change in dipole moment are calculated using both the solvatochromic shift method and Reichardt's microscopic solvent polarity parameter ETN. The ground state dipole moment is evaluated using quantum chemical calculations. It is found that general solute-solvent and hydrogen bond interactions are operative in this system. A red shift of ~ 9 nm in the emission spectra is observed with an increase in the solvent polarity, which depicts pi >pi(*) transitions, as well as the possibility of an intramolecular charge transfer (ICT) character in the emitting singlet state of 4FMPBA. The relative quantum yield, radiative and non-radiative decay constants are calculated in alkanes and alcohols using the single point method. It is found that the quantum yield of the molecule varies from 16.81% to 50.79% with the change in solvent polarity, indicating the dependence of fluorescence on the solvent environment. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26626021 TI - Impact of body fat distribution on neoadjuvant chemotherapy outcomes in advanced breast cancer patients. AB - Obesity is known to decrease the efficacy of neoadjuvant chemotherapy (NAC) against breast cancer; however, the relationship between actual body composition and NAC outcomes remains unknown. Therefore, we determined the effect of body composition on NAC outcomes. A total of 172 advanced breast cancer patients who underwent surgery after NAC were retrospectively analyzed. Body composition parameters including abdominal circumference (AC), subcutaneous fat area (SFA), visceral fat area (VFA), and skeletal muscle area (SMA) were calculated using computed tomography volume-analyzing software. VFA/SFA ratio was used to evaluate visceral obesity. The associations of body composition parameters with pathological complete remission (pCR) and survival were analyzed. AC, SFA, and VFA were significantly correlated with body mass index (BMI) (all P < 0.05; r = 0.82, r = 0.71, and r = 0.78, respectively). AC, SFA, and VFA increased significantly and SMA decreased significantly after menopause (all P < 0.05). VFA/SFA ratio increased significantly after menopause, even though BMI remained unchanged. Body composition parameters were not associated with pCR. Distant disease-free survival (DDFS) was significantly worse in the high VFA group than in the low VFA group (P < 0.05). Furthermore, in the high VFA group, postmenopausal patients had significantly shorter DDFS than premenopausal patients (P < 0.05). VFA was independently associated with DDFS in the multivariate analysis (P < 0.05). High visceral fat is associated with worse NAC outcomes in breast cancer patients, especially postmenopausal patients. Interventions targeting visceral fat accumulation will likely improve NAC outcomes. PMID- 26626022 TI - Does human ejaculate quality relate to phenotypic traits? AB - A given man's phenotype embodies cues of his ancestral ability to effectively defend himself and his kin from harm, to survive adverse conditions, and to acquire status and mating opportunities. In this review, we explore the hypothesis that a man's phenotype also embodies cues to fertility or the probability that an ejaculate will fertilize ova. Female mate choice depends on the ability to discern the quality of a male reproductive partner through his phenotype, and male fertility may be among the traits that females have evolved to detect. A female who selects as mates males that deliver higher quality ejaculates will, on average, be more fecund than her competitors. Data on several non-human species demonstrate correlations between ejaculate quality and secondary sexual characteristics that inform female mate choice, suggesting that females may select mates in part on the basis of fertility. While the non-human literature on this topic has advanced, the human literature remains limited in scope and there is no clear consensus on appropriate methodologies or theoretical positions. We provide a comprehensive review and meta-analysis of this literature, and conclude by proposing solutions to the many issues that impede progress in the field. In the process, we hope to encourage interest and insight from investigators in other areas of human mating and reproductive biology. Am. J. Hum. Biol. 28:318-329, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26626023 TI - Learning from Primary Health Care Centers in Nepal: reflective writings on experiential learning of third year Nepalese medical students. AB - BACKGROUND: Medical education can play important role in cultivating the willingness among the medical students to work in underprivileged areas after their graduation. Experiential learning through early exposure to primary health care centers could help students better understand the opportunities and challenges of such settings. However, the information on the real experiences and reflections of medical students on the rural primary health care settings from low-income countries like Nepal are still limited. The aim of this study is to demonstrate the learning process of the medical students through their reflective writings based on Kolb's theory of experiential learning. METHODS: The students wrote their experiences, observations and reflections on the experiential learning from the primary health care centers on individual logbook as part of their community posting assignments. We analyzed the data of 50 logbooks through content analysis using Kolb's experiential learning cycle as a theoretical framework. RESULTS: The students' reflections are structured around the four main learning stages of Kolb's experiential learning theory. Each learning stage consisted of different categories. The first stage consisted of concrete experiences on rural health and learning by doing. The second stage included their reflective observations on primary versus tertiary care, application of theoretical knowledge and role of supervisors. In the third stage, the students developed and refined their concepts on self-development, understanding reality, compassion and sense of responsibility. The final stage, active experimentation, included their immediate future plans, suggestions to improve curriculum, plans after becoming a doctor and suggestions to improve policies. CONCLUSION: This study provided important insights on different stages of experiential learning of medical students on primary health care in low resource rural settings. Reflective writing of experiential learning could be an important step to address the gaps in medical education for resource constraint settings like that of Nepal and other low-income countries. PMID- 26626024 TI - Large-scale production and antiviral efficacy of multi-target double-stranded RNA for the prevention of white spot syndrome virus (WSSV) in shrimp. AB - BACKGROUND: RNA interference (RNAi) is a specific and effective approach for inhibiting viral replication by introducing double-stranded (ds)RNA targeting the viral gene. In this study, we employed a combinatorial approach to interfere multiple gene functions of white spot syndrome virus (WSSV), the most lethal shrimp virus, using a single-batch of dsRNA, so-called "multi-WSSV dsRNA." A co cultivation of RNase-deficient E. coli was developed to produce dsRNA targeting a major structural protein (VP28) and a hub protein (WSSV051) with high number of interacting protein partners. RESULTS: For a co-cultivation of transformed E. coli, use of Terrific broth (TB) medium was shown to improve the growth of the E. coli and multi-WSSV dsRNA yields as compared to the use of Luria Bertani (LB) broth. Co-culture expression was conducted under glycerol feeding fed-batch fermentation. Estimated yield of multi-WSSV dsRNA (MUg/mL culture) from the fed batch process was 30 times higher than that obtained under a lab-scale culture with LB broth. Oral delivery of the resulting multi-WSSV dsRNA reduced % cumulative mortality and delayed average time to death compared to the non treated group after WSSV challenge. CONCLUSION: The present study suggests a co cultivation technique for production of antiviral dsRNA with multiple viral targets. The optimal multi-WSSV dsRNA production was achieved by the use of glycerol feeding fed-batch cultivation with controlled pH and dissolved oxygen. The cultivation technique developed herein should be feasible for industrial scale RNAi applications in shrimp aquaculture. Interference of multiple viral protein functions by a single-batch dsRNA should also be an ideal approach for RNAi-mediated fighting against viruses, especially the large and complicated WSSV. PMID- 26626026 TI - Direct Assembly of Mesoporous Silica Functionalized with Polypeptides for Efficient Dye Adsorption. AB - Herein, we introduce a new polypeptide-functionalized mesoporous silica template fabricated from a biodegradable poly(ethylene oxide-b-E-caprolactone) (PEO-b-PCL) diblock copolymer and a poly(tyrosine) (PTyr) biopolymer. The crystallization behavior of the PEO-b-PCL diblock copolymer changes after blending, but the secondary structure of PTry remains stable. After selective solvent extraction in THF, the PEO-b-PCL is removed, but PTyr remains within the silica matrix due to its different solubility. Fourier-transform IR spectroscopic analysis (FTIR), thermal gravitometry analysis (TGA), small-angle X-ray scattering (SAXS), and X ray diffraction (XRD) studies confirm the retention of PTyr to form a polypeptide functionalized mesoporous material. The adsorption of methylene blue hydrate (MB) from aqueous solution into the polypeptide-functionalized mesoporous silica is investigated, thus revealing that the nanocomposite exhibits a high adsorption capacity relative to pure silica due to hydrogen-bonding interactions between the hydroxy phenolic group of PTyr and the N-containing aromatic ring from MB. PMID- 26626025 TI - Rapid, efficient, and simple motor neuron differentiation from human pluripotent stem cells. AB - BACKGROUND: Human pluripotent stem cells (hPSCs) are being applied in regenerative medicine and for the in vitro modeling of human intractable disorders. In particular, neural cells derived from disease-specific human induced pluripotent stem cells (hiPSCs) established from patients with neurological disorders have been used as in vitro disease models to recapitulate in vivo pathogenesis because neural cells cannot be usually obtained from patients themselves. RESULTS: In this study, we established a rapid, efficient, and simple method for efficiently deriving motor neurons from hPSCs that is useful for pathophysiological analysis and the development of drugs to treat motor neuron diseases. Treatment with GSK3beta inhibitors during the initial phase of differentiation in combination with dual SMAD inhibition was sufficient to induce PAX6 (+) and SOX1 (+) neural progenitors within 1 week, and subsequent treatment with retinoic acid (RA) and purmorphamine, which activates sonic hedgehog (SHH) signaling, resulted in the highly efficient induction of HB9(+) and ISL-1(+) motor neurons within 2 weeks. After 4 weeks of monolayer differentiation in motor neuron maturation medium, hPSC-derived motor neurons were shown to mature, displaying larger somas and clearer staining for the mature motor neuron marker choline acetyltransferase (ChAT). Moreover, hPSC-derived motor neurons were able to form neuromuscular junctions with human myotubes in vitro and induced acetylcholine receptor (AChR) clustering, as detected by Alexa 555-conjugated alpha-Bungarotoxin (alpha-BTX), suggesting that these hPSC-derived motor neurons formed functional contacts with skeletal muscles. This differentiation system is simple and is reproducible in several hiPSC clones, thereby minimizing clonal variation among hPSC clones. We also established a system for visualizing motor neurons with a lentiviral reporter for HB9 (HB9 (e438) ::Venus). The specificity of this reporter was confirmed through immunocytochemistry and quantitative RT-PCR analysis of high-positive fractions obtained via fluorescence-activated cell sorting (FACS), suggesting its applicability for motor neuron-specific analysis. CONCLUSIONS: Our motor neuron differentiation system and lentivirus-based reporter system for motor neurons facilitate the analysis of disease-specific hiPSCs for motor neuron diseases. PMID- 26626027 TI - Immunometabolic Responses to Concurrent Training: The Effects of Exercise Order in Recreational Weightlifters. AB - Inoue, DS, Panissa, VLG, Monteiro, PA, Gerosa-Neto, J, Rossi, FE, Antunes, BMM, Franchini, E, Cholewa, JM, Gobbo, LA, and Lira, FS. Immunometabolic responses to concurrent training: the effects of exercise order in recreational weightlifters. J Strength Cond Res 30(7): 1960-1967, 2016-The relationship between immunometabolic response and performance is not well understood. This study evaluated the influence of concurrent strength and high-intensity aerobic sequence of exercise order between sessions on strength performance, metabolic, and inflammatory response. Eleven recreational weightlifters underwent the following 2 randomized sessions: (a) strength-aerobic exercise order (SA) and (b) aerobic-strength exercise order (AS). Blood samples were collected before (Pre) and immediately after the first exercise (Post-1) and the second exercise (Post 2) of each session. The SA condition presented a higher number of repetitions (SA: 54 +/- 15 vs. AS: 43 +/- 12) and total volume (SA: 7,265 +/- 2,323 vs. AS: 5,794 +/- 1846 kg) than the AS condition (both p = 0.001). Glucose was higher in Pre when compared with post-1 in both orders (p <= 0.05); changes in lactate were time-dependent in the different orders (p <= 0.05); however, AS post-2 lactate was lower when compared with SA post-2 (p <= 0.05). Interleukin-6 levels showed time-dependent changes for both exercise orders (p <= 0.05). Tumor necrosis factor alpha (TNF-alpha) level was increased only in AS post-1 (AS: pre = 21.91 +/- 35.47, post-1 = 26.99 +/- 47.69 pg.ml vs. SA: pre = 25.74 +/- 43.64, post-1 = 29.74 +/- 46.05 pg.ml, p <= 0.05). These results suggest that concurrent training order exhibits different immunometabolic responses and, at least in part, can be associated with the acute decline in strength performance induced by concurrent exercise. Our results point to a possible role of TNF-alpha (post-1 AS condition) as a trigger to restore the energy demand by providing substrates to help maintain contractile activity in skeletal muscle. PMID- 26626028 TI - The Effects of Caffeine on Vertical Jump Height and Execution in Collegiate Athletes. AB - Bloms, LP, Fitzgerald, JS, Short, MW, and Whitehead, JR. The effects of caffeine on vertical jump height and execution in collegiate athletes. J Strength Cond Res 30(7): 1855-1861, 2016-Caffeine ingestion elicits a variety of physiological effects that may be beneficial to maximal-intensity exercise performance, although its effectiveness and physical mechanism of action enhancing ballistic task performance are unclear. The purpose of this study was to examine the effects of caffeine ingestion on vertical jump height and jump execution in Division I collegiate athletes. The study used a single-blind, randomized, crossover design. Athletes (n = 25) consumed either caffeine (5 mg.kg) or placebo. After a 60-minute waiting period, athletes performed 3 squat jumps (SJ) and 3 countermovement jumps (CMJ) while standing on a force platform. Jump height and execution variables were calculated from mechanography data. In comparison with placebo, caffeine increased SJ height (32.8 +/- 6.2 vs. 34.5 +/- 6.7 cm; p = 0.001) and CMJ height (36.4 +/- 6.9 vs. 37.9 +/- 7.4 cm; p = 0.001). Peak force (p = 0.032) and average rate of force development (p = 0.037) were increased during the CMJ in the caffeine trail compared with the control. Time to half peak force was the only execution variable improved with caffeine (p = 0.019) during the SJ. It seems that caffeine affects both height and execution of jumping. Our data indicate that the physical mechanism of jump enhancement is increased peak force production or rate of force development during jumping depending on technique. The physical mechanism of jump enhancement suggests that the ergogenic effects of caffeine may transfer to other ballistic tasks involving the lower body musculature in collegiate athletes. PMID- 26626029 TI - WHY DO WE DO WHAT WE DO? PMID- 26626030 TI - Improving Adherence to Screening Colonoscopy Preparation and Appointments: A Multicomponent Quality Improvement Program. AB - Colorectal screening for cancer by colonoscopy is recommended for adults 50 years and older. Scheduling patients for sedated endoscopic procedures involves balancing physician schedules, room availability and equipment, proper patient preparedness, and necessary personnel. Both nonattendance and poor preparations contribute to inefficiency, wasted resources, and increased costs. We noted nonattendance rates ranging from 21% to 29%. As a first step, we examined patient factors associated with nonattendance using a retrospective case control study. Younger patients (<60 years), screening appointment, and insurance type were associated with nonattendance. On the basis of these findings, initial efforts focused on additional nurse strategies of follow-up contact and education for screening colonoscopies. As we improved attendance rate, concomitantly we discovered cancellation rates increasing. Subsequently, an interdisciplinary and interdepartmental quality improvement program has been ongoing to target a number of system-, nurse-, and patient-specific factors contributing to nonattendance and cancellations due to poor preparations. Rates have improved but require ongoing monitoring and surveillance. We describe the ongoing efforts and challenges aimed at both nonattendance and cancellations. PMID- 26626031 TI - Predictors of Early Discontinuation of Pegylated Interferon for Reasons Other Than Lack of Efficacy in United States Veterans With Chronic Hepatitis C. AB - During the dual-therapy era, many patients with chronic hepatitis C discontinued therapy for reasons other than lack of efficacy (non-LOE). We determined whether selected patient characteristics predicted non-LOE discontinuation using national databases of U.S. veterans with Genotypes 1-4. We identified U.S. veterans in the Veterans Health Administration system in 2004-2009 who had hepatitis C-confirming RNA laboratory results and initiated therapy with pegylated interferon and ribavirin. We used a rule to classify patients who discontinued pegylated interferon early, based on pharmacy refill and viral response data. Multivariate Cox regression was used to identify predictors of non-LOE discontinuation. Of 321,238 patients with a hepatitis C International Classification of Diseases, Ninth Revision, code, 15,297 (4.8%) met all inclusion criteria. Non-LOE discontinuers comprised 30.3% of patients. For Genotypes 1-4, the predictors (adjusted hazard ratio) of greatest magnitude were comorbidities of myocardial infarction/congestive heart failure (1.36), renal disease (1.34), and platelets 100/mm or more (1.38). For Genotypes 2 and 3, predictors of greatest magnitude were Black race (1.30), myocardial infarction/congestive heart failure (1.84), albumin 3.5 mg/dl or more (1.65), sleep aid use (1.32), and poor persistence with antidepressants (1.31) and antihypertensive agents (1.37). Our study suggests that many host factors may have contributed to non-LOE dual-therapy discontinuation in veterans and may possibly predict non-LOE discontinuation in triple therapy. PMID- 26626032 TI - Electrosurgery in the Gastrointestinal Suite: Knowledge Is Power. AB - Electrosurgery allows both cutting and coagulation of tissue and is an essential tool for therapeutic endoscopy. Electrosurgery is also the most commonly used and misunderstood technology by all surgical and medical disciplines. In other words, everyone uses it, but few understand it! The aims of this article are to (1) present a useful review of the fundamentals of electrosurgery technology; (2) relate the fundamentals to commonly performed flexible endoscopy procedures; and (3) provide a review of the safe application of grounding pads, careful management of accessories, and special patient safety considerations. PMID- 26626033 TI - Implementation of the High-Risk Alcoholism Relapse Scale in a Liver Transplant Clinic. AB - Because of the high prevalence of alcohol relapse after liver transplantation, transplant programs are challenged to evaluate alcoholism among liver transplant patients. Relapse after liver transplantation can have detrimental outcomes such as organ rejection, medical and social resource exhaustion, financial burden to the family and society, and negative public perception of organ transplantation. The purpose of this project was to improve post-liver transplant assessment for the risk of relapse to heavy alcohol use by implementing a protocol using the High-Risk Alcoholism Relapse (HRAR) scale (DiMartini et al., 2000; Yates et al., 1993). The project was conducted in an urban organ transplant center's outpatient post liver transplant clinic. Chart reviews assessed the process of patients identified as being at high risk and the transplant providers' completion of the HRAR scale. Eleven percent of patients assessed were identified as being at high risk for relapse of heavy alcohol use and 85% of providers used the HRAR scale in their clinic interviews. This project demonstrates that further refinements in techniques of predicting the risks of relapse are necessary, and nurses are in ideal positions to screen patients for alcohol use. PMID- 26626034 TI - Challenges With Acute Care and Response to Treatment Among Adult Patients With Cyclic Vomiting Syndrome. AB - Cyclic vomiting syndrome is a chronic gastrointestinal tract disorder. The symptoms include cycles of extreme nausea, vomiting, and abdominal pain separated by periods of wellness. Previous research suggests a quality gap in early recognition and appropriate management of adults with cyclic vomiting syndrome. The purpose of this study was to explore and describe adult patients' experiences with cyclic vomiting syndrome, including challenges receiving a diagnosis and responses to treatment. This study was conducted using a phenomenological research design. A purposeful sample included 16 adult patients with cyclic vomiting syndrome. All data were collected electronically via Survey Monkey and analyzed using content analysis and constant comparison techniques. Two global themes emerged from the data. These were perceived lack of knowledge among healthcare providers and responses to cyclic vomiting syndrome-related treatments. Perceived lack of healthcare provider knowledge contributed to diagnostic delay, inappropriate treatment, and avoidance of care. A combination of medications aimed at managing symptoms and inducing sleep was the most effective abortive medical regimen described. Marijuana use was common. Hot-water bathing was practiced by users and nonusers of marijuana. PMID- 26626035 TI - RAPIDLY RECURRING GASTRIC POLYP AFTER ENDOSCOPIC POLYPECTOMY. PMID- 26626036 TI - 80% BY 2018: How Are Your Team and Community Doing on This Endeavor? PMID- 26626038 TI - Hormone replacement therapy after treatment for a gynaecological malignancy. AB - PURPOSE OF REVIEW: Provision of hormone replacement therapy (HRT) to women following a diagnosis of a gynaecological malignancy is a complex and controversial area associated with a lack of published guidance. As the average age of women affected by gynaecological cancer decreases and survival following provision of effective therapies increases, clinicians face new considerations for longer-term health concerns of patients. Additionally, there is a growing understanding of the influence of tumour biology upon response to cytotoxic therapies and it is essential that we use this knowledge to guide provision of HRT. RECENT FINDINGS: Available evidence for ovarian, vulval, cervical, and endometrial cancers demonstrates no excess risk of recurrence in patients taking HRT with the exception of some subtypes of cancer (uterine sarcomas, granulosa cell, and low-grade serous ovarian cancer). Evidence for the incidence of hormone receptor status is suggestive that HRT may be ill-advised in an additional proportion of patients and we recommend characterization of all tumours in patients who may require HRT. SUMMARY: The risk and benefits of HRT should be evaluated for all women who undergo a premature menopause as a result of gynaecological malignancy to reduce menopausal symptoms and protect against cardiovascular and skeletal morbidity. There is no evidence to suggest a higher rate of disease recurrence in women using HRT in comparison to nonusers in the majority of gynaecological malignancies. Routine histological testing of tumours for hormone receptor status is an achievable goal and may help to stratify patients further into low and high-risk groups for hormone therapy. PMID- 26626037 TI - Many Phenotypes Without Many False Discoveries: Error Controlling Strategies for Multitrait Association Studies. AB - The genetic basis of multiple phenotypes such as gene expression, metabolite levels, or imaging features is often investigated by testing a large collection of hypotheses, probing the existence of association between each of the traits and hundreds of thousands of genotyped variants. Appropriate multiplicity adjustment is crucial to guarantee replicability of findings, and the false discovery rate (FDR) is frequently adopted as a measure of global error. In the interest of interpretability, results are often summarized so that reporting focuses on variants discovered to be associated to some phenotypes. We show that applying FDR-controlling procedures on the entire collection of hypotheses fails to control the rate of false discovery of associated variants as well as the expected value of the average proportion of false discovery of phenotypes influenced by such variants. We propose a simple hierarchical testing procedure that allows control of both these error rates and provides a more reliable basis for the identification of variants with functional effects. We demonstrate the utility of this approach through simulation studies comparing various error rates and measures of power for genetic association studies of multiple traits. Finally, we apply the proposed method to identify genetic variants that impact flowering phenotypes in Arabidopsis thaliana, expanding the set of discoveries. PMID- 26626039 TI - Global strategies for the treatment of early-stage and advanced cervical cancer. AB - PURPOSE OF REVIEW: Recent peer-reviewed publications on the treatment of early, locally advanced and advanced cervical cancer patients are reviewed to gain insight into the main research done in the field. RECENT FINDINGS: In early-stage patients where cure is offered to most patients, research focuses on more conservative or less morbid approaches to increase quality of life and reduce the treatment-related sexual dysfunction. No major advances have occurred for treating locally advanced disease since the introduction of concurrent chemoradiation, but efforts are directed to increase efficacy while reducing toxicity with the use of combination chemoradiation and modern radiation technologies. Molecular-targeted therapy and identification of targetable gene alterations as well as immunotherapy are actively pursued in patients with advanced disease. SUMMARY: Although global statistics indicate a trend for decreased age-standardized incidence rates, social and economical factors impede the uptake of therapeutic advances achieved as many patients have no access even to basic resources for treating cancer. The adherence to quality indicators in delivery of optimized standard concurrent chemoradiation and adherence to guidelines in cervical cancer surgery must not be underestimated. Major efforts are needed in both the scientific and social aspects of cervical cancer treatment to reduce mortality. PMID- 26626040 TI - Acquired factor inhibitor in a patient with monoclonal gammopathy of undetermined significance responding to rituximab. AB - Bleeding diathesis is a rare manifestation of monoclonal gammopathies that is often attributed to a dysfunction of the coagulation pathway. Patients usually present with a severe bleeding disorder attributed to an acquired factor inhibitor, most commonly factor VIII inhibitor. Data are sparse concerning this disease, and subsequently the best course of action is not yet defined in such clinical instances. In this article, we report the case of a patient, known to have a monoclonal gammopathy of unknown significance, who was followed for over two decades for a bleeding disorder attributed to an acquired thrombin inhibitor. We describe also the different modalities used as maintenance and event treatments as the patient presented repetitive cataclysmic bleedings. PMID- 26626041 TI - Dilute Russell's viper venom and activated partial thromboplastin time in lupus anticoagulant diagnosis: is mixing essential? AB - Dilute Russell's viper venom (DRVV) testing and activated partial thromboplastin time (APTT) have been effectively used in combination for lupus anticoagulant testing. The purpose of our study was to evaluate the role of mixing in activated partial thromboplastin and dilute Russell's viper venom testing for evaluation of lupus anticoagulants. Citrated blood from patients who were not on oral anticoagulant therapy was studied. Mixing study with 1 : 1 normal plasma for elevated APTT and also few samples with elevated screen time was carried out. Elevated APTT was seen in only 48.1% of patients with lupus anticoagulant. Correction of APTT was seen in 27.8% of lupus anticoagulant-positive patients. DRVV test on mixing resulted in 83.8% false-negative values. Integrated DRVV test could be a standalone test for testing lupus anticoagulant. Mixing study may be restricted for patients on oral anticoagulants or patients with strong lupus anticoagulant. PMID- 26626042 TI - High-efficiency polymer solar cells with small photon energy loss. AB - A crucial issue facing polymer-based solar cells is how to manage the energetics of the polymer/fullerene blends to maximize short-circuit current density and open-circuit voltage at the same time and thus the power conversion efficiency. Here we demonstrate that the use of a naphthobisoxadiazole-based polymer with a narrow bandgap of 1.52 eV leads to high open-circuit voltages of approximately 1 V and high-power conversion efficiencies of ~9% in solar cells, resulting in photon energy loss as small as ~0.5 eV, which is much smaller than that of typical polymer systems (0.7-1.0 eV). This is ascribed to the high external quantum efficiency for the systems with a very small energy offset for charge separation. These unconventional features of the present polymer system will inspire the field of polymer-based solar cells towards further improvement of power conversion efficiencies with both high short-circuit current density and open-circuit voltage. PMID- 26626044 TI - A Thought on Possible Pathogenesis of Ebola Viral Hemorrhagic Disease and Potential Treatments: Could it Be Thrombotic Thrombocytopenic Purpura-Like Syndrome? PMID- 26626043 TI - Risk of hip fracture among older people using antihypertensive drugs: a nationwide cohort study. AB - BACKGROUND: Many people with a high risk of hip fracture have coexisting cardiovascular diseases. We aimed to examine associations between exposure to antihypertensive drugs and the risk of hip fracture among older people. METHODS: We conducted a cohort study of the 906,422 people born before 1945 and living in Norway in 2005. We obtained information on all prescriptions of antihypertensive drugs dispensed (the Norwegian Prescription Database) in 2004-2010 and the dates of primary hip fractures (the Norwegian Hip Fracture Registry) in 2005-2010. We compared the incidence rates of hip fracture during the time people were exposed and unexposed to antihypertensive drugs by calculating the standardized incidence ratio (SIR). RESULTS: Altogether, 39,938 people experienced a primary hip fracture (4.4 %). The risk of hip fracture was decreased among people exposed to thiazides (SIR 0.7, 95 % confidence interval (CI) 0.6-0.7), beta-blockers (SIR 0.7, 95 % CI 0.7-0.8), calcium channel blockers (SIR 0.8, 95 % CI 0.8-0.8), angiotensin II receptor blockers (SIR 0.8, 95 % CI 0.7-0.8), ACE inhibitor/thiazide combination products (SIR 0.7, 95 % CI 0.6-0.7) and angiotensin II receptor blocker/thiazide combination products (SIR 0.6, 95 % CI 0.6-0.6). Use of loop diuretics and ACE inhibitors (plain products) was associated with increased fracture risk in people born after 1924, and with decreased risk in those born before 1925. The protective associations were stronger among exposed men than among exposed women for all drugs except loop diuretics. The SIRs decreased with increasing age among exposed people, except for thiazides and angiotensin II receptor blockers. CONCLUSIONS: We found a reduced risk of hip fracture associated with overall use of most antihypertensive drugs, but an increased risk with loop diuretics and ACE inhibitors among people younger than 80 years and in new users of loop diuretics. This may have great impact at the population level, because the use of antihypertensive drugs is widespread in people at risk of hip fracture. Clinical studies are needed to further explore these associations. PMID- 26626045 TI - Enhancing speed of pinning synchronizability: low-degree nodes with high feedback gains. AB - Controlling complex networks is of paramount importance in science and engineering. Despite recent efforts to improve controllability and synchronous strength, little attention has been paid to the speed of pinning synchronizability (rate of convergence in pinning control) and the corresponding pinning node selection. To address this issue, we propose a hypothesis to restrict the control cost, then build a linear matrix inequality related to the speed of pinning controllability. By solving the inequality, we obtain both the speed of pinning controllability and optimal control strength (feedback gains in pinning control) for all nodes. Interestingly, some low-degree nodes are able to achieve large feedback gains, which suggests that they have high influence on controlling system. In addition, when choosing nodes with high feedback gains as pinning nodes, the controlling speed of real systems is remarkably enhanced compared to that of traditional large-degree and large-betweenness selections. Thus, the proposed approach provides a novel way to investigate the speed of pinning controllability and can evoke other effective heuristic pinning node selections for large-scale systems. PMID- 26626046 TI - Resonant Andreev Spectroscopy in normal-Metal/thin-Ferromagnet/Superconductor Device: Theory and Application. AB - We develop a theoretical model to describe the transport properties of normal metal/thin-ferromagnet/superconductor device. We perform experimental test of the model using a gold tip on PdNi/Nb bilayer. The resonant proximity effect causes conductance features very sensitive to the local ferromagnetic properties, enabling accurate measurement of polarization and thickness of the ferromagnet by point contact spectroscopy. PMID- 26626047 TI - Using complex networks towards information retrieval and diagnostics in multidimensional imaging. AB - We present a fresh and broad yet simple approach towards information retrieval in general and diagnostics in particular by applying the theory of complex networks on multidimensional, dynamic images. We demonstrate a successful use of our method with the time series generated from high content thermal imaging videos of patients suffering from the aqueous deficient dry eye (ADDE) disease. Remarkably, network analyses of thermal imaging time series of contact lens users and patients upon whom Laser-Assisted in situ Keratomileusis (Lasik) surgery has been conducted, exhibit pronounced similarity with results obtained from ADDE patients. We also propose a general framework for the transformation of multidimensional images to networks for futuristic biometry. Our approach is general and scalable to other fluctuation-based devices where network parameters derived from fluctuations, act as effective discriminators and diagnostic markers. PMID- 26626048 TI - Multiple melt bodies fed the AD 2011 eruption of Puyehue-Cordon Caulle, Chile. AB - Within the volcanological community there is a growing awareness that many large- to small-scale, point-source eruptive events can be fed by multiple melt bodies rather than from a single magma reservoir. In this study, glass shard major- and trace-element compositions were determined from tephra systematically sampled from the outset of the Puyehue-Cordon Caulle (PCC) eruption (~1 km(3)) in southern Chile which commenced on June 4(th), 2011. Three distinct but cogenetic magma bodies were simultaneously tapped during the paroxysmal phase of this eruption. These are readily identified by clear compositional gaps in CaO, and by Sr/Zr and Sr/Y ratios, resulting from dominantly plagioclase extraction at slightly different pressures, with incompatible elements controlled by zircon crystallisation. Our results clearly demonstrate the utility of glass shard major and trace-element data in defining the contribution of multiple magma bodies to an explosive eruption. The complex spatial association of the PCC fissure zone with the Liquine-Ofqui Fault zone was likely an influential factor that impeded the ascent of the parent magma and allowed the formation of discrete melt bodies within the sub-volcanic system that continued to independently fractionate. PMID- 26626049 TI - The prevalence of anemia and iron deficiency is more common in breastfed infants than their mothers in Bhaktapur, Nepal. AB - BACKGROUND/OBJECTIVES: Iron deficiency anemia is a widespread public health problem, particularly in low- and middle-income countries. Maternal iron status around and during pregnancy may influence infant iron status. We examined multiple biomarkers to determine the prevalence of iron deficiency and anemia among breastfed infants and explored its relationship with maternal and infant characteristics in Bhaktapur, Nepal. SUBJECTS/METHODS: In a cross-sectional survey, we randomly selected 500 mother-infant pairs from Bhaktapur municipality. Blood was analyzed for hemoglobin, ferritin, total iron-binding capacity, transferrin receptors and C-reactive protein. RESULTS: The altitude-adjusted prevalence of anemia was 49% among infants 2-6-month-old (hemaglobin (Hb) <10.8 g/dl) and 72% among infants 7-12-month-old (Hb <11.3 g/dl). Iron deficiency anemia, defined as anemia and serum ferritin <20 or <12 MUg/l, affected 9 and 26% of infants of these same age groups. Twenty percent of mothers had anemia (Hb <12.3 g/dl), but only one-fifth was explained by depletion of iron stores. Significant predictors of infant iron status and anemia were infant age, sex and duration of exclusive breastfeeding and maternal ferritin concentrations. CONCLUSIONS: Our findings suggest that iron supplementation in pregnancy is likely to have resulted in a low prevalence of postpartum anemia. The higher prevalence of anemia and iron deficiency among breastfed infants compared with their mothers suggests calls for intervention targeting newborns and infants. PMID- 26626051 TI - Object size can influence perceived weight independent of visual estimates of the volume of material. AB - The size-weight illusion is the phenomenon that the smaller of two equally heavy objects is perceived to be heavier than the larger object when lifted. One explanation for this illusion is that heaviness perception is influenced by our expectations, and larger objects are expected to be heavier than smaller ones because they contain more material. If this would be the entire explanation, the illusion should disappear if we make objects larger while keeping the volume of visible material the same (i.e. objects with visible holes). Here we tested this prediction. Our results show that perceived heaviness decreased with object size regardless of whether objects visibly contained the same volume of material or not. This indicates that object size can influence perceived heaviness, even when it can be seen that differently sized objects contain the same volume of material. PMID- 26626050 TI - Identification of Nicotiana benthamiana microRNAs and their targets using high throughput sequencing and degradome analysis. AB - BACKGROUND: Nicotiana benthamiana is a widely used model plant species for research on plant-pathogen interactions as well as other areas of plant science. It can be easily transformed or agroinfiltrated, therefore it is commonly used in studies requiring protein localization, interaction, or plant-based systems for protein expression and purification. To discover and characterize the miRNAs and their cleaved target mRNAs in N. benthamiana, we sequenced small RNA transcriptomes and degradomes of two N. benthamiana accessions and validated them by Northern blots. RESULTS: We used a comprehensive molecular approach to detect and to experimentally validate N. benthamiana miRNAs and their target mRNAs from various tissues. We identified 40 conserved miRNA families and 18 novel microRNA candidates and validated their target mRNAs with a genomic scale approach. The accumulation of thirteen novel miRNAs was confirmed by Northern blot analysis. The conserved and novel miRNA targets were found to be involved in various biological processes including transcription, RNA binding, DNA modification, signal transduction, stress response and metabolic process. Among the novel miRNA targets we found the mRNA of REPRESSOR OF SILENCING (ROS1). Regulation of ROS1 by a miRNA provides a new regulatory layer to reinforce transcriptional gene silencing by a post-transcriptional repression of ROS1 activity. CONCLUSIONS: The identified conserved and novel miRNAs along with their target mRNAs also provides a tissue specific atlas of known and new miRNA expression and their cleaved target mRNAs of N. benthamiana. Thus this study will serve as a valuable resource to the plant research community that will be beneficial well into the future. PMID- 26626052 TI - FSAP-mediated nucleosome release from late apoptotic cells is inhibited by autoantibodies present in SLE. AB - Inefficient clearance of apoptotic cells and the subsequent exposure of the immune system to nuclear contents are crucially involved in the pathogenesis of systemic lupus erythematosus (SLE). Factor VII-activating protease (FSAP) is activated in serum upon contact with dead cells, and releases nucleosomes from late apoptotic cells into the extracellular environment. We investigated whether FSAP-mediated nucleosome release from late apoptotic cells is affected in SLE patients. Nucleosome release in sera of 27 SLE patients and 30 healthy controls was investigated by incubating late apoptotic Jurkat cells with serum and analyzing the remaining DNA content by flow cytometry. We found that nucleosome release in sera of SLE patients with high disease activity was significantly decreased when compared with that in SLE sera obtained during low disease activity or from healthy individuals. Upon removal of IgG/IgM antibodies from SLE sera, nucleosome release was restored. Similarly, monoclonal antinuclear antibodies inhibited nucleosome release in healthy donor serum or by plasma purified FSAP. This inhibition was lost when Fab fragments were used, suggesting that antigen cross-linking is involved. In conclusion, FSAP-mediated nucleosome release from late apoptotic cells is greatly impaired in SLE patient sera, possibly hampering the clearance of these cells and thereby propagating inflammation. PMID- 26626053 TI - A Case-Based Approach to Integrating Opioid Pharmacokinetic and Pharmacodynamic Concepts in Cancer Pain Management. AB - Opioids are prescribed for cancer pain. Over the past decade, the annual increase in opioid prescriptions has been accompanied by an increase in opioid-associated deaths. Health care professionals must be proficient in proper dosing, titrating, and monitoring of opioid medications. With the numerous opioid medications and formulations available, an understanding of pharmacokinetic (PK) and pharmacodynamic (PD) concepts is necessary to appropriately individualize opioid based cancer pain regimens. The purpose of this review is to highlight PK/PD concepts that are clinically relevant to the use of opioids. By way of a cancer pain patient case scenario, PK/PD concepts that are relevant in the initiation, titration, and rotation of an opioid regimen are discussed. PMID- 26626054 TI - Development of quality indicators for physiotherapy for patients with PAOD in the Netherlands: a Delphi study. AB - OBJECTIVES: The aim of the study was to develop quality indicators (QIs) for physiotherapy management of patients with intermittent claudication (IC) in the Netherlands. DESIGN: As part of an international six-step method to develop QIs, an online survey Delphi-procedure was completed. After two Delphi-rounds a validation round was performed. PARTICIPANTS: Twenty-six experts were recruited to participate in this study. Twenty-four experts completed two Delphi-rounds. A third round was conducted inviting 1200 qualified and registered physiotherapists of the Dutch integrated care network 'Claudicationet' to validate a draft set of quality indicators. RESULTS: Out of 83 potential QIs in the Dutch physiotherapy guideline on 'Intermittent claudication', consensus among the experts selected nine indicators. All nine quality indicators were validated by 300 physiotherapists. CONCLUSION: A final set of nine indicators was derived from (1) a Dutch evidence-based physiotherapy guideline, (2) an expert Delphi procedure and (3) a validation by 300 physiotherapists. This set of indicators should be validated in clinical practice. PMID- 26626055 TI - Extended nicotine self-administration increases sensitivity to nicotine, motivation to seek nicotine and the reinforcing properties of nicotine-paired cues. AB - An array of pharmacological and environmental factors influence the development and maintenance of tobacco addiction. The nature of these influences likely changes across the course of an extended smoking history, during which time drug seeking can become involuntary and uncontrolled. The present study used an animal model to examine the factors that drive nicotine-seeking behavior after either brief (10 days) or extended (40 days) self-administration training. In Experiment 1, extended training increased rats' sensitivity to nicotine, indicated by a leftward shift in the dose-response curve, and their motivation to work for nicotine, indicated by an increase in the break point achieved under a progressive ratio schedule. In Experiment 2, extended training imbued the nicotine-paired cue with the capacity to maintain responding to the same high level as nicotine itself. However, Experiment 3 showed that the mechanisms involved in responding for nicotine or a nicotine-paired cue are dissociable, as treatment with the partial nicotine receptor agonist, varenicline, suppressed responding for nicotine but potentiated responding for the nicotine-paired cue. Hence, across extended nicotine self-administration, pharmacological and environmental influences over nicotine seeking increase such that nicotine seeking is controlled by multiple sources, and therefore highly resistant to change. PMID- 26626056 TI - The effect of local bone density on mechanical failure after internal fixation of pertrochanteric fractures. AB - INTRODUCTION: The aim of this prospective study was to investigate the effect of local hip bone density on mechanical failure after fixation of pertrochanteric fractures and to establish possible risk factors for the failures. MATERIALS AND METHODS: A total of 136 consecutive patients presenting a closed unilateral pertrochanteric fracture were enrolled. The patients were treated with a sliding hip screw or an intramedullary nail. Dual energy X-ray absorptiometry measurements for bone density of the contralateral hip were made within 4 weeks postoperatively. Follow-up evaluations on the standard radiographs were documented for any mechanical failure including loss of reduction, screw or blade cut-out, lateral migration of the screw or blade, and implant breakage. Secondary outcomes were also recorded including patient characteristics and fixation construct variables as possible predictors for mechanical failure. RESULTS: At a minimum of 2 years of follow-up, 38 patients were reported with mechanical failure at an estimated risk of 27.9 %. The local bone density measurements for the study population showed no difference between patients with (0.710 g/cm(2)) and without (0.726 g/cm(2)) mechanical failure (P = 0.180). We also observed no significant correlation between local bone density and failure in patients with good fracture reduction (P = 0.862). The multivariate regression analysis identified fracture type (P < 0.001) and quality of fracture reduction (P < 0.001) as being independent predictors for mechanical failure, whereas local bone density was not (P = 0.658). CONCLUSIONS: Local hip bone density does not appear to have a significant influence on mechanical failure after internal fixation of pertrochanteric fractures. Stable fractures and fractures with good reduction are expected to obtain satisfactory outcomes. PMID- 26626057 TI - Differential distribution patterns of ammonia-oxidizing archaea and bacteria in acidic soils of Nanling National Nature Reserve forests in subtropical China. AB - In addition to ammonia-oxidizing bacteria (AOB) the more recently discovered ammonia-oxidizing archaea (AOA) can also oxidize ammonia, but little is known about AOA community structure and abundance in subtropical forest soils. In this study, both AOA and AOB were investigated with molecular techniques in eight types of forests at surface soils (0-2 cm) and deep layers (18-20 cm) in Nanling National Nature Reserve in subtropical China. The results showed that the forest soils, all acidic (pH 4.24-5.10), harbored a wide range of AOA phylotypes, including the genera Nitrosotalea, Nitrososphaera, and another 6 clusters, one of which was reported for the first time. For AOB, only members of Nitrosospira were retrieved. Moreover, the abundance of the ammonia monooxygenase gene (amoA) from AOA dominated over AOB in most soil samples (13/16). Soil depth, rather than forest type, was an important factor shaping the community structure of AOA and AOB. The distribution patterns of AOA and AOB in soil layers were reversed: AOA diversity and abundances in the deep layers were higher than those in the surface layers; on the contrary, AOB diversity and abundances in the deep layers were lower than those in the surface layers. Interestingly, the diversity of AOA was positively correlated with pH, but negatively correlated with organic carbon, total nitrogen and total phosphorus, and the abundance of AOA was negatively correlated with available phosphorus. Our results demonstrated that AOA and AOB were differentially distributed in acidic soils in subtropical forests and affected differently by soil characteristics. PMID- 26626058 TI - The role of formate in combatting oxidative stress. AB - The interaction of keto-acids with reactive oxygen species (ROS) is known to produce the corresponding carboxylic acid with the concomitant formation of CO2. Formate is liberated when the keto-acid glyoxylate neutralizes ROS. Here we report on how formate is involved in combating oxidative stress in the nutritionally-versatile Pseudomonas fluorescens. When the microbe was subjected to hydrogen peroxide (H2O2), the levels of formate were 8 and two-fold higher in the spent fluid and the soluble cell-free extracts obtained in the stressed cultures compared to the controls respectively. Formate was subsequently utilized as a reducing force to generate NADPH and succinate. The former is mediated by formate dehydrogenase (FDH-NADP), whose activity was enhanced in the stressed cells. Fumarate reductase that catalyzes the conversion of fumarate into succinate was also markedly increased in the stressed cells. These enzymes were modulated by H2O2. While the stressed whole cells produced copious amounts of formate in the presence of glycine, the cell-free extracts synthesized ATP and succinate from formate. Although the exact role of formate in anti-oxidative defence has to await further investigation, the data in this report suggest that this carboxylic acid may be a potent reductive force against oxidative stress. PMID- 26626059 TI - A Middle Ground? Residential Mobility and Attainment of Mixed-Race Couples. AB - Marriage and cohabitation between members of different racial and ethnic groups has increased in the United States over recent decades. Despite this demographic shift, we know relatively little about how the growing numbers of mixed-race couples are faring in systems of residential stratification. Previous research indicates that mixed-race couples tend to be located in diverse neighborhoods, but because this past research has used cross-sectional data and has not focused on actual residential mobility, it is not clear whether mixed-race couples choose diverse neighborhoods or are just more likely to develop in diverse neighborhoods. To provide a more complete picture of this topic, I conduct a prospective analysis of the residential location and mobility patterns of mixed race couples, focusing on the extent to which these couples are more likely than monoracial couples to move into, and/or remain in, diverse neighborhoods. The use of longitudinal data between 1985 and 2009 from the Panel Study of Income Dynamics (PSID) linked to neighborhood- and metropolitan-level data from multiple population censuses reveals that in comparison with monoracial couples, mixed race couples tend to be located in neighborhoods with higher levels of racial and ethnic diversity and tend to enter more diverse residential destinations when they move. However, these outcomes vary substantially across types of mixed-race couples. Moreover, the outcomes associated with individual- and metropolitan level conditions provide limited support for the common contention that the residential patterns of mixed-race couples reflect differences in residential preferences, and point to the role of broader patterns of racial stratification in shaping their residential outcomes. PMID- 26626060 TI - What's new in cell therapies in ARDS? PMID- 26626061 TI - Transportation of children on extracorporeal membrane oxygenation: one-year experience of the first neonatal and paediatric mobile ECMO team in the north of France. PMID- 26626062 TI - Health-related quality-of-life among survivors of acute kidney injury in the intensive care unit: a systematic review. AB - PURPOSE: To summarize evidence on long-term health-related quality-of-life (HRQL) among survivors of acute kidney injury (AKI) in the intensive care unit (ICU). METHODS: We performed a comprehensive search of the literature for studies reporting original data describing HRQL utilizing validated instruments. Search, study selection and data abstraction were performed in duplicate. Study quality was appraised. Due to study heterogeneity, data are primarily summarized qualitatively. RESULTS: Our search yielded 2193 articles of which 18 were selected for detailed analysis. The quality of these 18 studies was generally good. Numerous HRQL instruments were utilized, and assessment occurred at variable follow-up duration (range 2 months to 14.5 years). HRQL among AKI survivors was reduced when compared to age/sex-matched populations. HRQL among survivors with and without AKI was generally described as similar beyond 6 months. Physical component domains were consistently more impaired than mental component domains. Survivors had considerable limitations in activities of daily living, implying newly acquired disability, with few returning to work. Despite diminished HRQL, patients' HRQL was generally perceived as satisfactory, and the majority would receive similar treatment again, including renal replacement therapy in the ICU, if necessary. CONCLUSIONS: Among survivors of critical illness complicated by AKI, HRQL was impaired when referenced to population norms, but it was not significantly different from that of survivors without AKI. Physical limitations and disabilities were more commonly exhibited by AKI patients. Importantly, the impaired HRQL was generally perceived as acceptable to patients, most of whom expressed willingness to undergo similar treatment in the future. PMID- 26626063 TI - A case report with hypersensitivity to ferrous but tolerance of ferric iron salts. PMID- 26626064 TI - Using Twitter to expand the reach and engagement of allergists. PMID- 26626065 TI - Vaccine Refusal and Trust: The Trouble With Coercion and Education and Suggestions for a Cure. AB - There can be little doubt about the ethical imperative to ensure adequate vaccination uptake against certain infectious diseases. In the face of vaccine refusal, health authorities and providers instinctively appeal to coercive approaches or increased education as methods to ensure adequate vaccine uptake. Recently, some have argued that public fear around Ebola should be used as an opportunity for such approaches, should an Ebola vaccine become available. In this article, the author describes the difficulties associated with coercion and education when addressing vaccine opposition. Both coercion and education can cause opposite effects than intended in certain circumstances. The correct area of focus is to address the breakdown in trust within clinical relationships. The author presents suggestions for an approach towards vaccine refusal that may be more promising. PMID- 26626066 TI - Ethics, Foreseeability, and Tragedy in Australian Immigration Detention. PMID- 26626067 TI - Revisiting the Persisting Tension Between Expert and Lay Views About Brain Death and Death Determination: A Proposal Inspired by Pragmatism. AB - Brain death or determination of death based on the neurological criterion has been an enduring source of controversy in academic and clinical circles. The controversy chiefly concerns how death is defined, and it also bears on the justification of the proposed criteria for death determination and their interpretation. Part of the controversy on brain death and death determination stems from disputed crucial medical facts, but in this paper I formulate another hypothesis about the nature of ongoing controversies. At stake is a misunderstood relationship between, on the one hand, the nature of our lay (or our "manifest image") views about death and, on the other hand, the nature of scientific insights (and related conceptual refinements) into death and its determination (the "scientific image"). The misunderstanding of this relationship has partly anchored the controversy and continues to fuel it. Based on a perspective inspired by pragmatism, which stresses the positive contribution of science to ethical and policy debates but also challenges different forms of scientism in science and philosophy found in foundationalist interpretations, I scrutinize three different stances regarding the relationship between lay and scientific perspectives about the definition of death: (1) foundational lay views, (2) foundational expert views, and (3) co-evolving views. I argue that only the latter is sustainable given recent challenges to foundationalist interpretations. PMID- 26626068 TI - Exploring perceived control and self-rated health in re-admissions among younger adults: A retrospective study. AB - OBJECTIVE: Although health promotion calls for patient empowerment, it is not integrated in reducing re-admissions. This study examines the link among patient perceived control, self-rated health and fewer hospital re-admissions. METHODS: An empirical explorative retrospective cross-sectional study with 208 respondents aged 40-65 with poor health and identical health plans. All measures hold good psychometric properties. RESULTS: Self-rated health was strongly related to fewer re-admissions. Perceived control moderated the relationship between self-rated health and fewer re-admissions. Perceived control and self-rated health, together, contributed 5.2% to the variance in re-admissions. CONCLUSION: Perceived control and perceived health status each explained a different share of the variance of re-admissions. Together, these perceptions reduced re-admissions by .40. Patient-clinician communication upon discharge may be a new direction to reduce re-admissions, improve delivery of care and promote health. PRACTICE IMPLICATIONS: To reduce re-admissions, managements need to invest in restructuring the patient discharge process. A physician-patient dialogue shaping patient perceptions about their health status, perceived room for health improvement, and available internal and external resources may make a difference. Findings stress the need to allocate more time and resources for discharge communication processes and for physician training on psycho-social skills that may empower patients upon discharge. PMID- 26626069 TI - Do Interventions to Increase Walking Work? A Systematic Review of Interventions in Children and Adolescents. AB - BACKGROUND: Physical activity (PA) levels decline as children move into adolescence, with this decline more notable in girls. As a consequence, many young people are failing to meet current PA guidelines. Walking has been a cornerstone of PA promotion in adults and may provide an effective means of increasing PA levels among younger people. OBJECTIVE: Our objective was to conduct a systematic review of interventions aimed at promoting increased levels of walking among children and adolescents. METHODS: Eight electronic databases CINAHL, Cochrane Library CENTRAL database, EMBASE, Medline OVID, PsycINFO, Scopus, SPORTDiscus and Web of Knowledge-were searched from their inception up to January 2015 using predefined text terms: walking terms AND intervention terms AND population terms AND (physical activity OR exercise). Reference lists of published systematic reviews and original articles included in the review were also screened. Included studies were randomised and non-randomised controlled trials reporting a specific measure of walking levels (self-reported or objective) to assess the effectiveness of interventions aimed at promoting walking in children and adolescents (aged 5-18 years). Only full articles published in English in peer-reviewed journals were included. Risk of bias and behaviour change techniques of included studies were assessed. RESULTS: Twelve studies were included in this review. The majority of studies assessed interventions delivered within an educational setting, with one study conducted within the family setting. Nine of the included studies reported significant increases in walking in intervention groups versus controls. Commonly employed behaviour change techniques within successful interventions included goals and planning, feedback and monitoring, social support and repetition and substitution. CONCLUSIONS: Walking interventions, particularly those conducted in the school environment, have the potential to increase PA in children and adolescents. Conclusions on which interventions most effectively increased walking behaviours in this population were hindered by the limited number of identified interventions and the short duration of interventions evaluated. The short-term effectiveness of the majority of included studies on levels of walking in this population is promising and further research, particularly within non educational settings and targeted at sub-groups (e.g. adolescent girls and overweight/obese children and adolescents), is warranted. PMID- 26626070 TI - A Systematic Evaluation of Field-Based Screening Methods for the Assessment of Anterior Cruciate Ligament (ACL) Injury Risk. AB - BACKGROUND: Laboratory-based measures provide an accurate method to identify risk factors for anterior cruciate ligament (ACL) injury; however, these methods are generally prohibitive to the wider community. Screening methods that can be completed in a field or clinical setting may be more applicable for wider community use. Examination of field-based screening methods for ACL injury risk can aid in identifying the most applicable method(s) for use in these settings. OBJECTIVE: The objective of this systematic review was to evaluate and compare field-based screening methods for ACL injury risk to determine their efficacy of use in wider community settings. DATA SOURCES: An electronic database search was conducted on the SPORTDiscusTM, MEDLINE, AMED and CINAHL databases (January 1990 July 2015) using a combination of relevant keywords. A secondary search of the same databases, using relevant keywords from identified screening methods, was also undertaken. STUDY SELECTION: Studies identified as potentially relevant were independently examined by two reviewers for inclusion. Where consensus could not be reached, a third reviewer was consulted. Original research articles that examined screening methods for ACL injury risk that could be undertaken outside of a laboratory setting were included for review. STUDY APPRAISAL AND SYNTHESIS METHODS: Two reviewers independently assessed the quality of included studies. Included studies were categorized according to the screening method they examined. A description of each screening method, and data pertaining to the ability to prospectively identify ACL injuries, validity and reliability, recommendations for identifying 'at-risk' athletes, equipment and training required to complete screening, time taken to screen athletes, and applicability of the screening method across sports and athletes were extracted from relevant studies. RESULTS: Of 1077 citations from the initial search, a total of 25 articles were identified as potentially relevant, with 12 meeting all inclusion/exclusion criteria. From the secondary search, eight further studies met all criteria, resulting in 20 studies being included for review. Five ACL screening methods-the Landing Error Scoring System (LESS), Clinic-Based Algorithm, Observational Screening of Dynamic Knee Valgus (OSDKV), 2D-Cam Method, and Tuck Jump Assessment-were identified. There was limited evidence supporting the use of field-based screening methods in predicting ACL injuries across a range of populations. Differences relating to the equipment and time required to complete screening methods were identified. LIMITATIONS: Only screening methods for ACL injury risk were included for review. Field-based screening methods developed for lower-limb injury risk in general may also incorporate, and be useful in, screening for ACL injury risk. CONCLUSIONS: Limited studies were available relating to the OSDKV and 2D-Cam Method. The LESS showed predictive validity in identifying ACL injuries, however only in a youth athlete population. The LESS also appears practical for community-wide use due to the minimal equipment and set-up/analysis time required. The Clinic-Based Algorithm may have predictive value for ACL injury risk as it identifies athletes who exhibit high frontal plane knee loads during a landing task, but requires extensive additional equipment and time, which may limit its application to wider community settings. PMID- 26626071 TI - Standing Classrooms: Research and Lessons Learned from Around the World. AB - Children spend between 50 and 70 % of their time sitting while at school. Independent of physical activity levels, prolonged sitting is associated with poor health outcomes in adulthood. While there is mixed evidence of health associations among children and adolescents, public health guidelines in the USA, UK, Australia and Canada now recommend young people should break up long periods of sitting as frequently as possible. A potentially effective approach for reducing and breaking up sitting throughout the day is changing the classroom environment. This paper presents an overview of a relatively new area of research designed to reduce youth sitting time while at school by changing the classroom environment (n = 13 studies). Environmental changes included placement of height adjustable or stand-biased standing desks/workstations with stools, chairs, exercise balls, bean bags or mats in the classroom. These 13 published studies suggest that irrespective of the approach, youth sitting time was reduced by between ~44 and 60 min/day and standing time was increased by between 18 and 55 min/day during classroom time at school. Other benefits include increased energy expenditure and the potential for improved management of students' behaviour in the classroom. However, few large trials have been conducted, and there remains little evidence regarding the impact on children's learning and academic achievement. Nevertheless, with an increasing demand placed on schools and teachers regarding students' learning outcomes, strategies that integrate moving throughout the school day and that potentially enhance the learning experience and future health outcomes for young people warrant further exploration. PMID- 26626072 TI - At What Age Do Children and Adolescents Develop Lower Limb Tendon Pathology or Tendinopathy? A Systematic Review and Meta-analysis. AB - BACKGROUND: Tendon pathology and tendinopathy have been reported in children and adolescents; however, the age at onset and prevalence of the conditions have not been examined systematically. OBJECTIVE: To examine the prevalence of lower limb tendon pathology and tendinopathy in children and adolescents, and the factors associated with these conditions in this population. METHODS: Six databases were searched (MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, Scopus, the Web of Science and the Allied and Complementary Medicine Database). Studies were included if the prevalence of lower limb tendon pathology and/or tendinopathy were reported in humans under the age of 18 years. Studies were divided according to the method of diagnosis (physical examination, ultrasound or a questionnaire) and further divided into studies that reported prevalence data by tendon [reported two data points (right and left) for each participant] and those that reported prevalence data for each participant [reporting one data point (right or left) per participant]. RESULTS: Seventeen studies met the inclusion criteria. Lower limb tendinopathy prevalence (presence of pain and dysfunction) ranged between 8.2 and 33.3%, and increased in prevalence as age increased up to 18 years. The odds ratio for studies reporting tendinopathy by tendon was 0.37 (95% confidence interval 0.20-0.69) in favour of boys presenting with tendinopathy. Study aims and reporting methods were heterogeneous. CONCLUSIONS: The age at onset of lower limb tendinopathy in children and adolescents has not been widely studied. This systematic review found that tendinopathy is present in children and adolescents, and increases in prevalence with age up to 18 years. Male sex is significantly associated with tendinopathy in studies that report tendinopathy by tendon. PMID- 26626073 TI - Identification of amino acid residues responsible for high initial luminescence intensity in a calcium-binding photoprotein, clytin-II. AB - Clytin-II (CL-II) is an isotype of the calcium-binding photoprotein clytin-I (CL I) from Clytia gregaria. CL-II shows approximately 4.5-fold higher initial luminescence intensity than CL-I with the same luminescence capacity, and is a potential candidate for a G-protein-coupled receptor assay among photoproteins. To investigate the high initial luminescence intensity of CL-II, the chimeric proteins between CL-I and CL-II were prepared and the responsible amino acid residues in CL-II were identified by site-specific mutagenesis of CL-I. The luminescence properties of CL-I were converted to those of CL-II by the replacement of only four amino acids in CL-I, and these amino acids did not interact with 2-peroxycolenterazine. PMID- 26626074 TI - Silencing of angiotensin II type-1 receptor inhibits high glucose-induced epithelial-mesenchymal transition in human renal proximal tubular epithelial cells via inactivation of mTOR/p70S6K signaling pathway. AB - The epithelial-mesenchymal transition (EMT) plays a significant role in renal tubulointerstitial fibrosis (TIF), which is one of hallmark pathological feature of diabetic nephropathy (DN). Angiotensin II via its type-1 receptor AT1R is involved in the development of TIF. The purpose of our study was aimed to investigate the effect of silencing of AT1R on EMT and elucidate the possible mechanism underling these effects. EMT was induced by high glucose (HG) in human proximal tubular epithelial cell line HK-2 cells. The mRNA levels of AT1R were determined. The expression of AT1R was silenced by small interfering RNA (siRNA) technology and confirmed by quantitative real time PCR (qRT-PCR). After transfection with siAT1R, cell viability and expression levels of epithelial cell marker (epithelial (E)-cadherin), mesenchymal cell marker (alpha-smooth muscle actin (alpha-SMA)), four transcriptional factors (snail, slug, twist, and ZEB-1) were determined, as well as the roles of mechanistic target of rapamycin (mTOR)/p70S6K signaling pathway. The levels of AT1R were significantly higher after exposure to HG (P < 0.05). Transfection with siAT1R had no effect on cell viability, but reversed HG-induced EMT by up-regulation of E-cadherin expression and decrease of alpha-SMA, snail, and twist levels. MTOR/p70S6K signaling pathway was highly activated in HK-2 cells cultured under HG, but was inhibited by transfection with siAT1R. Our results suggest that silencing of AT1R inhibits EMT induced by HG in HK-2 cells via inactivation of mTOR/p70S6K signaling pathway. Silencing of AT1R might be a new strategy to treat DN. PMID- 26626075 TI - Lin28a protects against diabetic cardiomyopathy via the PKA/ROCK2 pathway. AB - BACKGROUND: Lin28a enhances glucose uptake and insulin-sensitivity. However, the role of Lin28a on experimental diabetic cardiomyopathy (DCM) is not well understood. We investigated the potential role and mechanism ofLin28a in diabetes induced myocardial dysfunction in mice. METHODS: Diabetes was induced by intraperitoneal (i.p.) injections of Streptozocin (STZ) in mice. Animals were randomized to be treated with lentivirus carrying Lin28a siRNA or Lin28a cDNA. Cardiac function, cardiomyocyte autophagy, apoptosis and mitochondria morphology in diabetic mice were compared between groups. The target proteins of Lin28a were examined by western blot analysis. RESULTS: Lin28a levels were markedly reduced in the cardiac tissue compared to the control mice. Lin28a overexpression significantly improved left ventricular ejection fraction (LVEF), promoted autophagy, decreased myocardial apoptotic index and alleviated mitochondria cristae destruction in diabetic mice. Lin28a knockdown exacerbated diabetic injury as evidenced by decreased LVEF, increased apoptotic index and aggravated mitochondria cristae destruction. Interestingly, pretreatment with a PKA inhibitor, N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide], di-HCl Salt (H89) abolished the beneficial effects of Lin28a overexpression. RhoA expression and ROCK2-expression were decreased in vivo after Lin28a overexpression, while Lin28a knockdown increased the expression of RhoA and ROCK2 in diabetic mice. CONCLUSIONS: Lin28a protects against DCM through PKA/ROCK2 dependent pathway. Lin28a might serve as a potential therapeutic target for the treatment of the patients with DCM. PMID- 26626077 TI - Predicting unintended effects of drugs based on off-target tissue effects. AB - Unintended effects of drugs can be caused by various mechanisms. Conventional analysis of unintended effects has focused on the target proteins of drugs. However, an interaction with off-target tissues of a drug might be one of the unintended effect-related mechanisms. We propose two processes to predict a drug's unintended effects by off-target tissue effects: 1) identification of a drug's off-target tissue and; 2) tissue protein - symptom relation identification (tissue protein - symptom matrix). Using this method, we predicted that 1,177 (10.7%) side-effects were related to off-target tissue effects in 11,041 known side-effects. Off-target tissues and unintended effects of successful repositioning drugs were also predicted. The effectiveness of relations of the proposed tissue protein - symptom matrix were evaluated by using the literature mining method. We predicted unintended effects of drugs as well as those effect related off-target tissues. By using our prediction, we are able to reduce drug side-effects on off-target tissues and provide a chance to identify new indications of drugs of interest. PMID- 26626078 TI - Erratum to: Genetic Counselors' Experiences Regarding Communication of Reproductive Risks with Autosomal Recessive Conditions found on Cancer Panels. PMID- 26626076 TI - The role of Wnt regulation in heart development, cardiac repair and disease: A tissue engineering perspective. AB - Wingless-related integration site (Wnt) signaling has proven to be a fundamental mechanism in cardiovascular development as well as disease. Understanding its particular role in heart formation has helped to develop pluripotent stem cell differentiation protocols that produce relatively pure cardiomyocyte populations. The resultant cardiomyocytes have been used to generate heart tissue for pharmaceutical testing, and to study physiological and disease states. Such protocols in combination with induced pluripotent stem cell technology have yielded patient-derived cardiomyocytes that exhibit some of the hallmarks of cardiovascular disease and are therefore being used to model disease states. While FDA approval of new treatments typically requires animal experiments, the burgeoning field of tissue engineering could act as a replacement. This would necessitate the generation of reproducible three-dimensional cardiac tissues in a well-controlled environment, which exhibit native heart properties, such as cellular density, composition, extracellular matrix composition, and structure function. Such tissues could also enable the further study of Wnt signaling. Furthermore, as Wnt signaling has been found to have a mechanistic role in cardiac pathophysiology, e.g. heart attack, hypertrophy, atherosclerosis, and aortic stenosis, its strategic manipulation could provide a means of generating reproducible and specific, physiological and pathological cardiac models. PMID- 26626079 TI - Wnt signaling pathway improves central inhibitory synaptic transmission in a mouse model of Duchenne muscular dystrophy. AB - The dystrophin-associated glycoprotein complex (DGC) that connects the cytoskeleton, plasma membrane and the extracellular matrix has been related to the maintenance and stabilization of channels and synaptic receptors, which are both essential for synaptogenesis and synaptic transmission. The dystrophin deficient (mdx) mouse model of Duchenne muscular dystrophy (DMD) exhibits a significant reduction in hippocampal GABA efficacy, which may underlie the altered synaptic function and abnormal hippocampal long-term plasticity exhibited by mdx mice. Emerging studies have implicated Wnt signaling in the modulation of synaptic efficacy, neuronal plasticity and cognitive function. We report here that the activation of the non-canonical Wnt-5a pathway and Andrographolide, improves hippocampal mdx GABAergic efficacy by increasing the number of inhibitory synapses and GABA(A) receptors or GABA release. These results indicate that Wnt signaling modulates GABA synaptic efficacy and could be a promising novel target for DMD cognitive therapy. PMID- 26626080 TI - Recombinant Adeno Associated Viral (AAV) vector type 9 delivery of Ex1-Q138 mutant huntingtin in the rat striatum as a short-time model for in vivo studies in drug discovery. AB - Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by dyskinesia, cognitive impairment and emotional disturbances, presenting progressive neurodegeneration in the striatum and intracellular mutant Huntingtin (mHTT) aggregates in various areas of the brain. Recombinant Adeno Associated Viral (rAAV) vectors have been successfully used to transfer foreign genes to the brain of adult animals. In the present study we report a novel in vivo rat HD model obtained by stereotaxic injection of rAAV serotype2/9 containing Exon1-Q138 mHTT (Q138) and Exon1-Q17 wild type HTT (Q17; control), respectively in the right and in the left striatum, and expressed as C-terminal GFP fusions to facilitate detection of infected cells and aggregate production. Immunohistochemical analysis of brain slices from animals sacrificed twenty-one days after viral infection showed that Q138 injection resulted in robust formation of GFP-positive aggregates in the striatum, increased GFAP and microglial activation and neurodegeneration, with little evidence of any of these events in contralateral tissue infected with wild type (Q17) expressing construct. Differences in the relative metabolite concentrations (N-Acetyl Aspartate/Creatine and Myo-Inositol/Creatine) were observed by H1 MR Spectroscopy. By quantitative RT-PCR we also demonstrated that mHTT induced changes in the expression of genes previously shown to be altered in other rodent HD models. Importantly, administration of reference compounds previously shown to ameliorate the aggregation and neurodegeneration phenotypes in preclinical HD models was demonstrated to revert the mutant HTT-dependent effects in our model. In conclusion, the AAV2/9-Q138/Q17 exon 1 HTT stereotaxic injection represents a useful first-line in vivo preclinical model for studying the biology of mutant HTT exon 1 in the striatum and to provide early evidence of efficacy of therapeutic approaches. PMID- 26626081 TI - Synaptic scaling up in medium spiny neurons of aged BACHD mice: A slow progression model of Huntington's disease. AB - Huntington's disease (HD) is an autosomal dominant disease that develops in midlife (~ 40 years-old at onset) and then progresses slowly. It is still unclear how striatal medium spiny neurons (MSNs), the most vulnerable neurons in HD, maintain their function for decades despite the chronic expression of mutant huntingtin (mHTT). In this study, we used aged BACHD mice, a HD model expressing the full-length human mHTT gene, to investigate the molecular, morphological and functional properties of striatal MSNs. We report that the density of dendritic spines in MSNs is substantially lower in aged BACHD mice than in wild-type (WT) mice, in the absence of major dendritic changes and neuronal loss. This spine loss is accompanied by changes in transcription, resulting in a low expression of the striatum-specific G protein-coupled receptor 88 (Gpr88) as well as a reorganization of the composition of AMPAR subunits (high Gria1/Gria2 mRNA ratio). We also detected functional changes in BACHD MSNs. Notably, BACHD MSNs were hyperexcitable and the amplitude of AMPAR-mediated synaptic currents was higher than in WT MSNs. Altogether, these data show that both the intrinsic properties and the strength of the remaining synapses are modified in MSNs with low dendritic spine density in aged BACHD mice. These homeostatic mechanisms may compensate for the substantial loss of synaptic inputs and thus alleviate the deleterious effects of mHTT expression on the activity of MSNs and also possibly on the motor phenotype in aged BACHD. PMID- 26626082 TI - The Tokuhashi score: effectiveness and pitfalls. AB - PURPOSE: Accurate survival estimation is prerequisite to determine the most appropriate treatment for patients with metastatic spine disease. Several authors have proposed classification systems analyzing clinical and radiological parameters, such as, performance status, metastasis localization, and primary tumor histotype, but the modified Tokuhashi score (mTS) is the most widely used. Although it is regarded as one of the most complete and accurate systems, it does not take the effectiveness of new therapeutic strategies into consideration, contributing to a progressive loss of accuracy. The purpose of this review is to verify the ability of the mTS to accurately estimate metastatic spine patient survival, nearly 10 years after it was introduced. METHODS: A literature review was conducted to evaluate mTS accuracy to predict metastatic spine patient survival. RESULTS: Ten studies were selected, representing 1686 patients. The total predictive accuracy of the mTS was 63.00%; for patients expected to survive less than 6 months (group I), it was 64.10%; 6-12 months (group II), 55.32%; and more than 12 months (group III), 77.21%. A progressive decrease in accuracy over time was statistically significant in groups I and II. CONCLUSIONS: The mTS is suggestive of actual survival for patients with a good prognosis. It is less accurate for patients with an estimated survival of less than 12 months. The decreasing trend in mTS accuracy over time will likely further reduce mTS utility. An important opportunity exists to develop new instruments to assist spine surgeons and oncologists to choose appropriate surgical or non-surgical treatment modalities for patients with metastatic spine disease. PMID- 26626083 TI - Correction of sagittal plane deformity and predictive factors for a favourable radiological outcome following multilevel posterior lumbar interbody fusion for mild degenerative scoliosis. AB - PURPOSE: Limited data is available in the literature on the radiographic results of multilevel posterior lumbar interbody fusion (MPLIF) in the treatment of degenerative scoliosis. The objective of our study was to evaluate the segmental and global correction achieved with MPLIF in the treatment of degenerative scoliosis. METHODS: Between 2009 and 2014, 42 patients underwent correction of degenerative scoliosis with MPLIF. Several radiological parameters were measured pre- and post-operatively by two independent observers. A statistical analysis was performed to assess the inter-observer reliability of the measurements and to determine the degree of segmental correction achieved at each intervertebral disc. Using sagittal vertical axis (SVA) less than 47 mm; lumbar lordosis (LL) within 11 degrees of pelvic incidence (PI); and pelvic tilt (PT) no more than 22 degrees as radiological criteria for procedural acceptability, we determined predictive factors for a favourable radiological outcome. RESULTS: Forty-two patients (34 female) were included in our study. The average amount of correction per segment was 6.2 degrees . The overall correction achieved with MPLIF was 16.6 degrees . Twenty-six of the 42 patients (61.9 %) had post-operative SVA values less than 47 mm. Nineteen of the 42 patients (45.2 %) had average post-operative LL within 11 degrees of the PI. Sixteen of the 42 patients (38.1 %) had PT less than 22 degrees . Younger age, female gender and a low pre-operative PT were significantly associated with the attainment of a satisfactory sagittal alignment. CONCLUSION: Our results demonstrate that a satisfactory correction can be achieved in degenerative scoliosis with MPLIF. In addition, our results show that it is significantly more likely to achieve a satisfactory radiological outcome in younger, female patients with low pre-operative PT. PMID- 26626084 TI - Saturated fatty acids are not off the hook. AB - A recent meta-analysis by Chowdhury et al. (2014) has disclaimed the association between coronary artery diseases and either circulating blood levels or the intake of total saturated fatty acids (SFA). Scrutiny revealed that two of the eight studies included in the meta-analysis focused on the proportion of pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0) and their impact on cardiovascular disease (CVD) risk. These odd-chain fatty acids are markers for milk or ruminant fat intake. Both studies indicated inverse associations between milk-fat intake and first-ever myocardial infarction. Neither of the two studies described the association between total circulating blood SFA on coronary outcomes. In contrast to the cardioprotective effects of dairy consumption, we expected that an elevated intake of palmitic acid (C16:0) and stearic acid (C18:0) de novo may raise CVD risk. Thus, it is of particular importance to differentiate the effects of individual circulating SFA on cardiovascular outcomes. Excluding the studies that evaluated the association of fatty acids from milk fat and cardiovascular outcomes revealed a positive association of total SFA blood levels and coronary outcome (RR 1.21, CI 1.04-1.40). Therefore, results obtained from studies of C15:0 and C17:0 cannot be mixed with results from studies of other SFA because of the opposite physiological effects of regular consumption of foods rich in C16:0 and C18:0 compared to high intake of milk or ruminant fat. In our opinion, it is vital to analyze the impact of individual SFA on CVD incidence in order to draw prudent conclusions. PMID- 26626086 TI - Development of a wireless blood pressure measuring device with smart mobile device. AB - Today, smart mobile devices (telephones and tablets) are very commonly used due to their powerful hardware and useful features. According to an eMarketer report, in 2014 there were 1.76 billion smartphone users (excluding users of tablets) in the world; it is predicted that this number will rise by 15.9% to 2.04 billion in 2015. It is thought that these devices can be used successfully in biomedical applications. A wireless blood pressure measuring device used together with a smart mobile device was developed in this study. By means of an interface developed for smart mobile devices with Android and iOS operating systems, a smart mobile device was used both as an indicator and as a control device. The cuff communicating with this device through Bluetooth was designed to measure blood pressure via the arm. A digital filter was used on the cuff instead of the traditional analog signal processing and filtering circuit. The newly developed blood pressure measuring device was tested on 18 patients and 20 healthy individuals of different ages under a physician's supervision. When the test results were compared with the measurements made using a sphygmomanometer, it was shown that an average 93.52% accuracy in sick individuals and 94.53% accuracy in healthy individuals could be achieved with the new device. PMID- 26626085 TI - MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin. AB - Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM. PMID- 26626087 TI - Mct8 and trh co-expression throughout the hypothalamic paraventricular nucleus is modified by dehydration-induced anorexia in rats. AB - Thyrotropin-releasing hormone (TRH) is a neuropeptide with endocrine and neuromodulatory effects. TRH from the paraventricular hypothalamic nucleus (PVN) participates in the control of energy homeostasis; as a neuromodulator TRH has anorexigenic effects. Negative energy balance decreases PVN TRH expression and TSH concentration; in contrast, a particular model of anorexia (dehydration) induces in rats a paradoxical increase in TRH expression in hypophysiotropic cells from caudal PVN and high TSH serum levels, despite their apparent hypothalamic hyperthyroidism and low body weight. We compared here the mRNA co expression pattern of one of the brain thyroid hormones' transporters, the monocarboxylate transporter-8 (MCT8) with that of TRH in PVN subdivisions of dehydration-induced anorexic (DIA) and control rats. Our aim was to identify whether a low MCT8 expression in anorexic rats could contribute to their high TRH mRNA content.We registered daily food intake and body weight of 7-day DIA and control rats and analyzed TRH and MCT8 mRNA co-expression throughout the PVN by double in situ hybridization assays. We found that DIA rats showed increased number of TRHergic cells in caudal PVN, as well as a decreased percentage of TRH expressing neurons that co-expressed MCT8 mRNA signal. Results suggest that the reduced proportion of double TRH/MCT8 expressing cells may be limiting the entry of hypothalamic triiodothyronine to the greater number of TRH-expressing neurons from caudal PVN and be in part responsible for the high TRH expression in anorexia rats and for the lack of adaptation of their hypothalamic-pituitary thyroid axis to their low food intake. PMID- 26626088 TI - The overshoot and phenotypic equilibrium in characterizing cancer dynamics of reversible phenotypic plasticity. AB - The paradigm of phenotypic plasticity indicates reversible relations of different cancer cell phenotypes, which extends the cellular hierarchy proposed by the classical cancer stem cell (CSC) theory. Since it is still questionable if the phenotypic plasticity is a crucial improvement to the hierarchical model or just a minor extension to it, it is worthwhile to explore the dynamic behavior characterizing the reversible phenotypic plasticity. In this study we compare the hierarchical model and the reversible model in predicting the cell-state dynamics observed in biological experiments. Our results show that the hierarchical model shows significant disadvantages over the reversible model in describing both long term stability (phenotypic equilibrium) and short-term transient dynamics (overshoot) in cancer cell populations. In a very specific case in which the total growth of population due to each cell type is identical, the hierarchical model predicts neither phenotypic equilibrium nor overshoot, whereas the reversible model succeeds in predicting both of them. Even though the performance of the hierarchical model can be improved by relaxing the specific assumption, its prediction to the phenotypic equilibrium strongly depends on a precondition that may be unrealistic in biological experiments. Moreover, it still does not show as rich dynamics as the reversible model in capturing the overshoots of both CSCs and non-CSCs. By comparison, it is more likely for the reversible model to correctly predict the stability of the phenotypic mixture and various types of overshoot behavior. PMID- 26626089 TI - Surgical implantation and functional assessment of an invasive telemetric system to measure autonomic responses in domestic pigs. AB - The first aim of this study was to establish a surgical procedure to implant a new telemetric device for the continuous recording of electrocardiogram (ECG) and blood pressure (BP) in freely moving pigs. A second aim was the functional assessment of cardiovascular parameters, including heart rate variability (HRV) and blood pressure variability (BPV), so that these data could be used as the basis for the objective evaluation of autonomic activity and balance in different behavioural contexts. Eleven domestic pigs (German Landrace) underwent surgery for the placement of a telemetric device. At day 15 after surgery, 512 consecutive inter-beat intervals and pressure waves were analysed using different detection methods (automatic and manually corrected) while the animals were resting or feeding, respectively. HRV and BPV were calculated. Incomplete datasets were found in four pigs due to missing ECG or BP signals. Technical and surgical issues concerning catheterisation and detachment of the negative ECG lead were continuously improved. In the remaining pigs, excellent signal quality (manually corrected data of 1%) was obtained during resting and acceptable signal quality (<10%) was obtained during feeding. Automatic triggering was sufficiently reliable to eliminate errors in BP recordings during active behaviour, but this was not the case for ECG recordings. Sympathetic arousal with accompanying vagal withdrawal during feeding was documented. The established surgical implantation and functional assessment of the telemetric system with the reliable registration of cardiovascular parameters in freely moving pigs could serve as a basis for future studies of autonomic regulation in context of stress and animal welfare. PMID- 26626090 TI - An overview of Mycoplasma bovis mastitis in Israel (2004-2014). AB - The prevalence of Mycoplasma bovis in milk samples submitted to the Israeli National Service for Udder Health and Milk Quality was determined during the period 2004-2014 and the genetic pattern of the obtained isolates was assessed by multilocus sequence typing (MLST). Mycoplasma spp. were identified in 66 herds including M. bovis (n = 60), M. cottewii (n = 3), M. bovigenitalium (n = 2), M. alkalescens (n = 2) and M. yeatsii (n = 1). The proportion of M. bovis infected herds was relatively low (0-0.68%) in 2004-2007, increased to 3.77% during the 2008 outbreak, and ranged from 0.77 to 2.77% during the 2009-2014 period. Since 2008, about eight M. bovis positive dairy herds have been identified in Israel annually, with six of which on average being newly infected. MLST of 57 M. bovis isolates revealed that sequence type 10 was the dominant genotype identified in 60% of the herds. In conclusion, these data show that M. bovis is the main mycoplasmal mastitic pathogen in Israel. PMID- 26626091 TI - Frequency of tail lesions and risk factors for tail biting in heavy pig production from weaning to 170 kg live weight. AB - Tail biting lesions have a negative effect on both the welfare of pigs and on the revenue of the pig farm. Due to the multifactorial nature of this abnormal behaviour and its sporadic onset, an epidemiological approach was adopted to identify the management and housing factors influencing the occurrence of tail biting and the frequency of bitten pigs in the weaning and fattening phases up to 170 kg live weight in heavy pig production. Data were collected from a sample of 67 commercial pig farms via an on-farm visit and a questionnaire to the farmer. Data collected included general farm information, hygiene and herd health, prevention, management, climate control, feeding and production traits. In the weaning phase, the occurrence of tail biting was increased by a factor of 16.64 for tipped vs. short-docked tails, by a factor of 68.09 when the observer detected poor air quality, and by a factor of 14.44 when the feeding time was variable. In fattening pigs, a high stocking density increased the risk of tail biting by a factor of 18.00. The frequency of lesions in weaners was greater in pigs with tipped tails (0.29 vs. 0.03%; P = 0.034), whereas in fatteners the frequency of lesions was greater when drinkers were not present in the lying area (0.71 vs. 0.05%; P = 0.009) and when air turnover was not detected in the barn (0.70 vs. 0.07%; P = 0.005). There was also a trend for increased tail biting when the stocking density was high (1.06 vs. 0.33%; P = 0.057). Many of the risk factors that emerged for heavy pigs in the present study could be easily managed to reduce the risk of tail biting and the frequency of tail lesions through the systematic evaluation and control of stocking density, climate, and feed and water management. PMID- 26626092 TI - Heritability of hemivertebrae in the French bulldog using an animal threshold model. AB - Ordinal regression and animal threshold analyses were used to estimate the influence of fixed effects and heritabilities on the number and grade of hemivertebrae, as well as the number of coccygeal vertebrae, in 105 French bulldogs. The fixed effects of sex, year and month of birth were not significant (P > 0.05). The prevalence of hemivertebrae was 0.85 with a slightly higher prevalence in females compared with males. Heritability estimates for the number and grade of hemivertebrae were 0.58 and 0.53, respectively. The number of coccygeal vertebrae showed a heritability estimate of 0.35. In addition, the number of coccygeal vertebrae was negatively correlated with the number and grade of hemivertebrae. The prevalence of hemivertebrae could increase if dogs with shorter tails are preferentially selected for breeding purposes. PMID- 26626093 TI - Detection and characterisation of Yersinia enterocolitica strains in cold-stored carcasses of large game animals in Poland. AB - Yersinia enterocolitica is an important foodborne pathogen. The aim of the present study was to identify the bioserotypes and virulence markers of Y.enterocolitica strains isolated from three different anatomical regions of cold stored carcasses of large game animals intended for human consumption. Y.enterocolitica strains were found in 12/20 (60%) of the roe deer carcasses examined, 7/16 (43.8%) of red deer carcasses and 11/20 (55%) of wild boar carcasses. Of the 52 Y.enterocolitica strains, 19 were isolated from the perineum, followed by 17 strains from the peritoneum of the longissimus dorsi muscle and 16 from the tonsils. Only one strain was isolated from warm culture. Bioserotype 1A/NI was the most commonly found and was detected in 29/52 isolates. All isolates contained amplicons corresponding to ystB gene fragments. The relatively high degree of carcass contamination with Y.enterocolitica is of concern due to the growing popularity of game meat with consumers. PMID- 26626094 TI - A preliminary investigation of the role of the transcription co-activators YAP/TAZ of the Hippo signalling pathway in canine and feline mammary tumours. AB - Breast cancer is the most common cancer in women worldwide. Cancer metastases are responsible for the high mortality rate. A small but distinct subset of cells, cancer stem cells (CSCs), have the capacity to self-renew, initiate tumour formation, and develop metastases. The CSC content in human breast cancer correlates with the Hippo tumour suppressor signalling pathway. Specifically, the activity of YAP/TAZ, transcription co-activators of the Hippo pathway, sustains the self-renewal and tumour-initiation capacities of CSCs. Little is known about YAP/TAZ in canine and feline mammary tumours, which are very common tumours. The preliminary aim of the study was to investigate the expression of YAP/TAZ in canine and feline mammary tumours by Western blot and immunohistochemistry. Increased cytoplasmic and nuclear expression of YAP/TAZ was observed in all carcinomas compared to normal tissues, indicating neoplastic deregulation of the Hippo pathway. Nuclear expression significantly increased in grade III (high grade carcinomas) compared to grade I (low grade carcinomas) tumours, suggesting that YAP/TAZ play a role in the increased aggressiveness of these tumours. Moreover, different scoring systems for immunohistochemical analyses were compared and the H index and the Allred scores were the most significant. In conclusion, YAP/TAZ are expressed in aggressive canine and feline mammary tumours as reported in some human cancers. Further studies might better elucidate the role of the Hippo pathway in prognosis and as a target for new therapies. In addition, tumours in dogs and cats may be a useful model to study this pathway. PMID- 26626095 TI - DNA testing man's best friend: Roles and responsibilities. PMID- 26626096 TI - Canine portosystemic shunts: Single or multiple tests to make the correct diagnosis? PMID- 26626097 TI - Modulation of acute transient exercise-induced hypertension after oral administration of four angiotensin-converting enzyme inhibitors in normotensive horses. AB - Changes in blood pressure (BP) during acute hypertension in response to angiotensin-converting enzyme inhibitors (ACEIs) have not been investigated in normotensive horses. In this study, six healthy horses were subjected to five trials, consisting in a treadmill exercise workload of 8 m/s for 1 min, 2 h after oral administration (PO) of placebo (0 mg/kg), enalapril (2.0 mg/kg), quinapril (1.0 mg/kg), ramipril (0.2 mg/kg) or benazepril (0.5 mg/kg). Serum angiotensin converting enzyme (ACE) activity was measured and systolic (SBP) and diastolic (DBP) blood pressures were recorded at rest (R), 2 h after placebo or ACEI administration (pre-E) and within the first 20 s after exercise (post-E). Mean maximum serum ACE inhibition 2 h after PO administration was 4.8% (placebo), 39.4% (enalapril), 46.4% (quinapril), 55.0% (ramipril) and 71.68% (benazepril). There were no significant differences in serum ACE inhibition between enalapril and quinapril. SBP and DBP at times R and pre-E were not different in any of the five trials. In response to exercise, SBP increased by 67.6% (placebo), 52.7% (enalapril), 43.1% (quinapril), 26.6% (ramipril) and 4.2% (benazepril). In response to exercise, DBP increased by 20.6, 13.2, 11.7, 16.6 and 3.7% after placebo, enalapril, quinapril, ramipril and benazepril administration, respectively. Serum ACE activity changed during exercise, but statistical significance was not achieved. In conclusion, administration of PO benazepril at a dose of 0.5 mg/kg modulated physiological hypertension induced by exercise in horses that were otherwise normotensive. PMID- 26626098 TI - Quality of life after great saphenous vein ablation in Thai patients with great saphenous vein reflux. AB - BACKGROUND/OBJECTIVE: To determine the quality of life (QoL) in Thais after intervention for great saphenous vein (GSV) reflux. METHODS: Patients with Clinical Etiologic Anatomic Pathophysiologic classes 2 and 3 were enrolled in this study. QoL was measured using the EuroQol descriptive system (EQ-5D) questionnaire, and patients chose to receive either endovenous treatment or surgery after consulting with their surgeons. The QoL before the intervention, at 1 week, and at 1 month after the intervention were evaluated. Patients who reported "no problem" in each domain of the EQ-5D questionnaire before and 1 month after the intervention were compared. Utility gain was estimated from the questionnaire and compared between clinical classes. The proportion of worsening QoL at 1 week after the intervention was compared between patients receiving endovenous procedures and surgery. RESULTS: A total of 83 patients-56 received endovenous procedures [23 received ultrasound-guided foam sclerotherapy (UGFS) and 33 received radiofrequency ablation (RFA)] and 27 received surgery-were enrolled. QoLs were significantly better in all domains after the intervention: pain/discomfort (58%), mobility (42%), anxiety/depression (38%), usual activities (19%), and self-care (9%). Utility gain was 0.255 (95% confidence interval: 0.197 0.313) and higher in class 3. At 1 week after the intervention, surgery had significantly higher patients with worse mobility scores. Among endovenous procedures, UGFS had higher patients with worse pain/discomfort scores than RFA at 1 week after the intervention (16% vs. 0%, p = 0.025). CONCLUSION: GSV ablation for GSV reflux in Thai patients with CEAP C2 and C3 categories significantly improves both physical and mental QoL; patients who received endovenous procedures were found to have better early physical QoL. PMID- 26626099 TI - Laparoendoscopic single-site adrenalectomy in patients with primary hyperaldosteronism: A prospective study with long-term follow up. AB - OBJECTIVE: Laparoendoscopic single-site (LESS) adrenalectomy is a promising minimally invasive technique, however, the current evidence has not confirmed its long-term effectiveness in primary aldosteronism (PA). We conducted a study to analyze the long-term efficacy of LESS adrenalectomy in patients with PA. METHODS: A total of 49 patients who had been clinically confirmed with PA who had an indication for unilateral adrenalectomy were included in this study. Perioperative data were obtained for all patients. Blood pressure and the levels of serum aldosterone, renin, and potassium were checked periodically. The median follow-up was 16.5 months. RESULTS: No intra- or early post-operative complication occurred. All LESS adrenalectomies were completed successfully, except one with laparoscopic conversion. Hypokalemia was resolved in all cases and no patient required potassium supplements after surgery. Post-operative cure of hypertension was achieved in 63% of our patients. Overall, 84% of our PA patients had clinical improvement in blood pressure control after surgery. CONCLUSIONS: Our long-term experience revealed that LESS adrenalectomy is a safe and effective approach, which demonstrated comparable long-term cure and improvement of hypertension to a conventional laparoscopic series in treating PA. PMID- 26626100 TI - Evaluation of the antigenicity of hydrolyzed cow's milk protein formulas using the mouse basophil activation test. AB - Hypoallergenic infant formulas are widely used for infants with cow's milk allergy. The aim of this study was to assess the utility of the mouse basophil activation test (BAT) in the evaluation of residual antigenicity in these formulas. Whole blood samples derived from beta-lactoglobulin- or casein immunized mice were incubated with one of the following formulas: conventional, partially hydrolyzed, or extensively hydrolyzed. Basophilic activation was analyzed by flow cytometry using an IgE-dependent activation marker CD200R1 and an IgG-dependent activation marker CD200R3. Systemic anaphylaxis was induced by i.v. injection of milk formula and results were compared. Conventional formula induced pronounced changes in CD200R1 and CD200R3 expression on basophils, whereas extensively hydrolyzed formulas did not elicit any changes in these markers. Similarly, challenge with conventional formula induced anaphylaxis, whereas extensively hydrolyzed formulas did not induce anaphylaxis. Although the partially hydrolyzed formula also induced basophilic activation and systemic anaphylaxis, the magnitude of these effects was smaller than that observed with the conventional formula. Compared to CD200R1, the observed trend in CD200R3 expression resembled the results obtained from systemic anaphylaxis test more closely. These findings show that mouse BAT, in particular using CD200R3, is highly useful for the evaluation of antigenicity of milk formulas. PMID- 26626102 TI - Location, location, location: priority effects in wood decay communities may vary between sites. AB - Priority effects are known to have a major influence on fungal community development in decomposing wood, but it has not yet been established whether these effects are consistent between different geographical locations. Here, beech (Fagus sylvatica) wood disks that had been pre-colonized with three wood decay basidiomycetes were placed in seven woodland sites with similar characteristics for 12-24 months, and the successor communities profiled using culture-based techniques coupled with amplicon sequencing. On the majority of sites, assembly history differed as a result of primary versus secondary resource capture only (i.e. different communities developed in uncolonized control disks compared with those that had been pre-colonized), but on certain sites distinct successor communities followed each pre-colonizer species. This study provides preliminary evidence that differences in abiotic factors and species pools between sites can cause spatial variation in how priority effects influence wood decay communities. PMID- 26626101 TI - The role of gut microbiota in fetal methylmercury exposure: Insights from a pilot study. AB - PURPOSE: The mechanisms by which gut microbiota contribute to methylmercury metabolism remain unclear. Among a cohort of pregnant mothers, the objectives of our pilot study were to determine (1) associations between gut microbiota and mercury concentrations in biomarkers (stool, hair and cord blood) and (2) the contributions of gut microbial mercury methylation/demethylation to stool methylmercury. METHODS: Pregnant women (36-39 weeks gestation, n=17) donated hair and stool specimens, and cord blood was collected for a subset (n=7). The diversity of gut microbiota was determined using 16S rRNA gene profiling (n=17). For 6 stool samples with highest/lowest methylmercury concentrations, metagenomic whole genome shotgun sequencing was employed to search for the mercury methylation gene (hgcA), and two mer operon genes involved in methylmercury detoxification (merA and merB). RESULTS: Seventeen bacterial genera were significantly correlated (increasing or decreasing) with stool methylmercury, stool inorganic mercury, or hair total mercury; however, aside from one genus, there was no overlap between biomarkers. There were no definitive matches for hgcA or merB, while merA was detected at low concentrations in all six samples. MAJOR CONCLUSIONS: Proportional differences in stool methylmercury were not likely attributed to gut microbiota through methylation/demethylation. Gut microbiota potentially altered methylmercury metabolism using indirect pathways. PMID- 26626103 TI - In silico multiple-targets identification for heme detoxification in the human malaria parasite Plasmodium falciparum. AB - Detoxification of hemoglobin byproducts or free heme is an essential step and considered potential targets for anti-malaria drug development. However, most of anti-malaria drugs are no longer effective due to the emergence and spread of the drug resistant malaria parasites. Therefore, it is an urgent need to identify potential new targets and even for target combinations for effective malaria drug design. In this work, we reconstructed the metabolic networks of Plasmodium falciparum and human red blood cells for the simulation of steady mass and flux flows of the parasite's metabolites under the blood environment by flux balance analysis (FBA). The integrated model, namely iPF-RBC-713, was then adjusted into two stage-specific metabolic models, which first was for the pathological stage metabolic model of the parasite when invaded the red blood cell without any treatment and second was for the treatment stage of the parasite when a drug acted by inhibiting the hemozoin formation and caused high production rate of heme toxicity. The process of identifying target combinations consisted of two main steps. Firstly, the optimal fluxes of reactions in both the pathological and treatment stages were computed and compared to determine the change of fluxes. Corresponding enzymes of the reactions with zero fluxes in the treatment stage but non-zero fluxes in the pathological stage were predicted as a preliminary list of potential targets in inhibiting heme detoxification. Secondly, the combinations of all possible targets listed in the first step were examined to search for the best promising target combinations resulting in more effective inhibition of the detoxification to kill the malaria parasites. Finally, twenty three enzymes were identified as a preliminary list of candidate targets which mostly were in pyruvate metabolism and citrate cycle. The optimal set of multiple targets for blocking the detoxification was a set of heme ligase, adenosine transporter, myo-inositol 1-phosphate synthase, ferrodoxim reductase-like protein and guanine transporter. In conclusion, the method has shown an effective and efficient way to identify target combinations which are obviously useful in the development of novel antimalarial drug combinations. PMID- 26626104 TI - Indicator displacement assay for cholesterol electrochemical sensing using a calix[6]arene functionalized graphene-modified electrode. AB - A novel electrochemical method has been developed towards cholesterol detection based on competitive host-guest interaction by selecting methylene blue (MB) and calix[6]arene functionalized graphene (CX6-Gra) as the "reporter pair". In the presence of cholesterol, the MB molecules are displaced by cholesterol in the CX6 Gra.MB complex, leading to a "switch off" electrochemical response. A linear response range of 0.50 to 50.00 MUM for cholesterol with a low detection limit of 0.20 MUM (S/N = 3) was obtained by using the proposed method. This method could be successfully utilized to detect cholesterol in serum samples, and may be expanded to the analysis of other non-electroactive species. Besides, the host guest interaction between cholesterol and CX6 was studied by molecular modeling calculations, which revealed that the complexation could reduce the energy of the system and the complex of a 1 : 1 host-guest stoichiometry had the lowest binding free energy of -8.01 kcal mol(-1). In addition, the constructed electrochemical sensing platform is important as it does not use any enzyme or antibody for the detection of cholesterol efficiently and selectively over common interfering species. PMID- 26626105 TI - Real-Time Propagation via Time-Dependent Density Functional Theory Plus the Hubbard U Potential for Electron-Atom Coupled Dynamics Involving Charge Transfer. AB - We present methods for combining time-dependent density functional theory and the Hubbard U potential in the framework of the real-time propagation of Kohn-Sham orbitals to describe electron-atom coupled dynamics beyond the Born-Oppenheimer approximation. The time evolution of the noncommuting nonlocal operators were realized through Crank-Nicolson's inversion method and Suzuki-Trotter's split exponentiation. The electron dynamics related to the high speed motion of an alkali atom on a conjugated carbon plane is presented. The nonequilibrium charge oscillation between a metal surface and a localized atomic orbital, as modeled with graphene and Ca, is discussed. PMID- 26626108 TI - Interactions of hydrogen with the iron and iron carbide interfaces: a ReaxFF molecular dynamics study. AB - Hydrogen embrittlement (HE) is a well-known material phenomenon that causes significant loss in the mechanical strength of structural iron and often leads to catastrophic failures. In order to provide a detailed atomistic description of HE we have used a reactive bond order potential to adequately describe the diffusion of hydrogen as well as its chemical interaction with other hydrogen atoms, defects, and the host metal. The currently published ReaxFF force field for Fe/C/H systems was originally developed to describe Fischer-Tropsch (FT) catalysis [C. Zou, A. C. T. van Duin and D. C. Sorescu, Top. Catal., 2012, 55, 391-401], and especially had been trained for surface formation energies, binding energies of small hydrocarbon radicals on different surfaces of iron and the barrier heights of surface reactions. We merged this force field with the latest ReaxFF carbon parameters [S. Goverapet Srinivasan, A. C. T. van Duin and P. Ganesh, J. Phys. Chem. A, 2015, 119, 1089-5639] and used the same training data set to refit the Fe/C interaction parameters. The present work is focused on evaluating the applicability of this reactive force field to describe material characteristics and study the role of defects and impurities in the bulk and at the precipitator interfaces. We study the interactions of hydrogen with pure and defective alpha-iron (ferrite), Fe3C (cementite), and ferrite-cementite interfaces with a vacancy cluster. We also investigate the growth of nanovoids in alpha-iron using a grand canonical Monte Carlo (GCMC) scheme. The calculated hydrogen diffusion coefficients for both ferrite and cementite phases predict a decrease in the work of separation with increasing hydrogen concentration at the ferrite-cementite interface, suggesting a hydrogen-induced decohesion behavior. Hydrogen accumulation at the interface was observed during molecular dynamics (MD) simulations, which is consistent with experimental findings. These results demonstrate the ability of the ReaxFF potential to elucidate various aspects of hydrogen embrittlement in alpha-iron and hydrogen interactions at a more complex metal/metal carbide interface. PMID- 26626107 TI - Serum Potassium Levels and Short-Term Outcomes in Patients With ST-Segment Elevation Myocardial Infarction. AB - Current guidelines recommend maintaining serum potassium levels between 4.0 and 5.0 mEq/L (1 mEq/L = mmol/L) in patients with acute myocardial infarction. However, these guidelines are based on studies conducted before the beta blocker and reperfusion era. We retrospectively analyzed 6613 patients diagnosed with ST segment elevation myocardial infarction (STEMI) who presented without renal insufficiency. Patients were categorized into 5 groups according to mean serum potassium levels: <3.5, 3.5 to <4.0, 4.0 to <4.5, 4.5 to <5.0, and >=5.0 mEq/L. Patients with potassium levels of 4.0 to <4.5 mEq/L had the lowest predefined event rates, which were 6.4% for 7-day malignant arrhythmia, 3.7% for 7-day mortality, and 5.3% for 30-day mortality. Compared with the reference group (4.0 to <4.5 mEq/L), multivariate regression analysis revealed significantly higher 30 day mortality risk in patients with potassium level of 4.5 to <5.0 (hazard ratio [HR]: 1.52, 95% confidence interval [CI]: 1.17-1.98; P = .002) and even higher risk in patients with potassium level of >=5.0 mEq/L (HR: 1.80, 95% CI: 1.22 2.66; P = .002). The lowest 30-day mortality was observed in patients with STEMI having potassium levels between 4.0 and 4.5 mEq/L, and a level >4.5 mEq/L significantly increased mortality risk. PMID- 26626106 TI - Hepatitis-Associated Liver Cancer: Gaps and Opportunities to Improve Care. AB - The global burden of hepatocellular carcinoma (HCC; primary liver cancer) is increasing. HCC is often unaccompanied by clear symptomatology, causing patients to be unaware of their disease. Moreover, effective treatment for those with advanced disease is lacking. As such, effective surveillance and early detection of HCC are essential. However, current screening and surveillance guidelines are not being fully implemented. Some at-risk populations fall outside of the guidelines, and patients who are screened are often not diagnosed at an early enough stage for treatment to be effective. From March 17 to 19, 2015, the Hepatitis B Foundation sponsored a workshop to identify gaps and limitations in current approaches to the detection and treatment of HCC and to define research priorities and opportunities for advocacy. In this Commentary, we summarize areas for further research and action that were discussed throughout the workshop to improve the recognition of liver disease generally, improve the recognition of liver cancer risk, and improve the recognition that screening for HCC makes a life-saving difference. Participants agreed that primary prevention of HCC relies on prevention and treatment of viral hepatitis and other underlying etiologies. Earlier diagnosis (secondary prevention) needs to be substantially improved. Areas for attention include increasing practitioner awareness, better definition of at-risk populations, and improved performance of screening approaches (ultrasound, biomarkers for detection, risk stratification, targeted therapies). The heterogeneous nature of HCC makes it unlikely that a single therapeutic agent will be universally effective. Medical management will benefit from the development of new, targeted treatment approaches. PMID- 26626109 TI - Examining the attitudes of hospital pharmacists to reporting medication safety incidents using the theory of planned behavior: reply. PMID- 26626110 TI - Efficient access to conjugated 4,4'-bipyridinium oligomers using the Zincke reaction: synthesis, spectroscopic and electrochemical properties. AB - The cyclocondensation reaction between rigid, electron-rich aromatic diamines and 1,1'-bis(2,4-dinitrophenyl)-4,4'-bipyridinium (Zincke) salts has been harnessed to produce a series of conjugated oligomers containing up to twelve aromatic/heterocyclic residues. These oligomers exhibit discrete, multiple redox processes accompanied by dramatic changes in electronic absorption spectra. PMID- 26626111 TI - How Big is Our System. PMID- 26626112 TI - Caring for Caregivers: Challenging the Assumptions. AB - Informal and mostly unpaid caregivers - spouses, family, friends and neighbours - play a crucial role in supporting the health, well-being, functional independence and quality of life of growing numbers of persons of all ages who cannot manage on their own. Yet, informal caregiving is in decline; falling rates of engagement in caregiving are compounded by a shrinking caregiver pool. How should policymakers respond? In this paper, we draw on a growing international literature, along with findings from community-based studies conducted by our team across Ontario, to highlight six common assumptions about informal caregivers and what can be done to support them. These include the assumption that caregivers will be there to take on an increasing responsibility; that caregiving is only about an aging population; that money alone can do the job; that policymakers can simply wait and see; that front-line care professionals should be left to fill the policy void; and that caregivers should be addressed apart from cared-for persons and formal care systems. While each assumption has a different focus, all challenge policymakers to view caregivers as key players in massive social and political change, and to respond accordingly. PMID- 26626113 TI - A More Nuanced Discussion Required. AB - Williams and colleagues make a valuable contribution to the home care policy literature, however, their arguments are not always convincing. Missing is a more nuanced discussion of research showing that even when governments provide more supportive services for older adults, families continue to provide care, and a discussion of alternative forms of caring that may arise in the future such as care from siblings and non-married older adults helping one another. Drawing on research pointing to several countries that offer caregivers a range of services would also have been helpful. Furthermore, it is not clear, as the authors argue, that the reason policy makers have moved toward providing for higher needs patients with fewer and fewer services for lower needs patients is a 'wait and see' attitude. Alternative reasoning is just as plausible. The benefits of providing supports to caregivers of children are well articulated but this does not negate the need among caregivers to older adults where some of the issues differ from caring for sick and disabled minors. Finally, action items for government are not offered but could have been helpful. Examples are provided. PMID- 26626114 TI - Caregiving as a Public Health Issue: Framing Policy Discussions. AB - Industrialized nations, Canada included, face potential care crises brought about by decreasing fertility rates, increasing longevity and changing patterns of work, family life and migration. Predicted shortages of caregivers alongside the challenges of caregiving call for the identification of ways to support caregivers and facilitate and reward care work. This article identifies and expands on several key barriers to developing meaningful care policies aimed at supporting informal caregivers. Where appropriate, relevant research, practice and policy implications are discussed. To develop effective policies, it is essential to: recognize heterogeneity among informal caregivers; conceptualize informal care as part of the formal system; and use a proactive, multi-faceted and multi-level approach to supporting care work. Caregiving policies aimed at promoting and protecting the well-being of individuals, families and communities and effectively stewarding individual and collective resources are needed now and in the future. PMID- 26626115 TI - Taking Caregivers Seriously: An Elaboration on Research Practice. AB - It's time to take the needs of caregivers seriously; doing so will benefit both those providing and receiving care. This is the thrust of the argument by Williams et al. and we couldn't agree more. Our commentary offers elaboration on the sixth and final assumption - that caregivers' needs should be considered apart from cared-for persons and formal system capacity. In helping policymakers come to grips with this, we extend on Williams et al.'s argument by offering both research practices that can improve understanding of care relations and a discussion of the assessment tools that can be adopted to address the needs of the caregiver. PMID- 26626116 TI - Caring for the Family Caregiver: Lessons Learned in Child Health. AB - Policy to support informal caregivers is a critical health policy issue in Canada. Lessons may be learned from the perspectives and experience in the child health field with applicability for all cared-for persons and their informal caregivers. Familycentred care addresses the centrality of the family caregiver in the design and delivery of health services. A life course approach focuses on key periods of transition and downstream effects facing caregivers over their lifetime. The medical home model where care delivery is more coordinated offers potential direct cost savings for both family caregivers and the healthcare system. Models of pediatric home care that focus on promoting caregiver capacity and integration of unregulated providers show the promise of being acceptable and sustainable solutions to increasing demands for caregiver respite. Finally, a number of assumptions that are somewhat unique to the pediatric caregiver experience are explored and/or challenged. These lessons and assumptions may provide insight for policymakers in the development of systems and supports for all cared-for persons and their caregivers in Canada. PMID- 26626117 TI - Diversity Within Family Caregiving: Extending Definitions of "Who Counts" to Include Marginalized Communities. AB - As researchers in the field of diversity and aging, we share Williams et al.'s call for policymakers to pay attention to the experiences of family caregivers across a wider spectrum than that which currently operates in health and social care. This paper addresses the particular issues at play in interactions between caregivers from marginalized 1communities and mainstream service providers. Using case studies from our work with ethnocultural minority (2) and LGBT (3) older adults, this commentary describes the unique realities faced by marginalized communities in their efforts to both provide care and gain access to a broad range of health and social care services. The assumptions addressed provide a basis for reconsidering how caregivers are perceived, experience services and demonstrate resilience in developing alternative forms of support. PMID- 26626118 TI - Considerations on Caring for Caregivers in an Aging Society. AB - While it is anticipated that healthcare systems around the world will continue to rely heavily on family members and friends to provide unpaid care especially to meet the needs of our aging population, current assumptions and issues around caregivers need to be challenged and addressed if we are to expect their future support. This paper builds on Williams et al's assertion that many current assumptions and issues around caregivers need to be challenged and addressed if we are to expect their future support. Indeed, with the pool of available caregivers expected to actually shrink in the future, this paper therefore examines four key policy issues in greater depth that we can address to enable individuals to age in place and others to maintain and take on caregiving roles. Through the establishment of policies that support robust and longterm capacity planning; make clear what care recipients and caregivers can expect to receive in the form of government supports; appreciate the increasing diversity that is occurring among those taking on caregiving roles and those requiring care; and recognize the need to invest in strategies that combat social isolation, we may not only improve our future health and well-being but ensure we are also enabled to care for ourselves as we age. PMID- 26626119 TI - Erratum. PMID- 26626120 TI - Novel insights into immunotherapy for hepatitis B patients. AB - The possible use of immunotherapy for hepatitis B has emerged for two major reasons: (1) chronic hepatitis B (CHB) is an immune-mediated pathological condition, and (2) commercially available antiviral drugs are of limited efficacy. Although various immunomodulatory agents have been used to treat patients with CHB during the last three decades, there is currently no consensus among physicians and hepatologists regarding the suitability of immunotherapy for patients with CHB. However, new insights into immunotherapy for CHB have emerged; these may facilitate design of effective and tolerable immunotherapy regimens for these patients. This review provides a comprehensive overview of immunotherapy for CHB. PMID- 26626121 TI - Immunohistochemical evaluation of ROCK activation in invasive breast cancer. AB - BACKGROUND: Two isoforms of Rho-associated coiled-coil kinase (ROCK), ROCKI and ROCKII, play an important role in many cellular processes. Despite the accumulating evidence showing that ROCK could be a potential cancer therapeutic target, the relevant tumor types to ROCK activation are not well clarified. The aim of this study was to evaluate the ROCK activation status in different tumor types of breast cancer. RESULTS: We evaluated the immunoreactivities of phosphorylation-specific antibodies of ROCKI and ROCKII to inform their kinase activation in 275 of breast carcinoma tissues, including 56 of carcinoma in situ, 116 of invasive carcinoma, and 103 of invasive carcinoma with metastasis. ROCKII activation signal detected in nucleus was significantly correlated with tumor metastasis, while ROCKI and cytosolic ROCKII activation signals made no significant difference in that metastasis. Furthermore, nuclear ROCKII activation signal was associated with poor clinical outcome and correlated with late tumor stage, low expression of estrogen receptor (ER) and progesterone receptor (PR), overexpression of human epidermal growth factor receptor 2 (HER2) and high Ki67 labeling index. CONCLUSIONS: Nuclear ROCKII activation signal might contribute to the tumor metastasis in breast cancer. Differences in ROCK activation that underlie the phenotypes of breast cancer could enhance our understanding for the use of ROCK inhibitors in cancer therapy. PMID- 26626123 TI - Indonesian medical students' preferences associated with the intention toward rural practice. AB - INTRODUCTION: The aim of this study was to identify the preference of Indonesian medical students to work in rural areas, to enroll in the (PTT; which means 'temporary employment') program, and to identify factors that influence their choice of a preferred future practice area. Under the PTT program, doctors are obliged to work as temporary staff on a contract basis for a certain period in a rural area of Indonesia. METHODS: The study design was cross-sectional and a total sampling method was used. The subjects were year 4 and 5 medical students from the Faculty of Medicine at Universitas Indonesia and had already been exposed to clinical practice rotations within their education program. Students rated the importance of 21 factors influencing their future workplace preference using a questionnaire with a five-point Likert scale. RESULTS: A total of 310 students (83.3%) responded to the questionnaire. The authors found that 27 out of 310 (8.71%) subjects wanted to work in rural areas, while 128 out of 264 (48.5%) students who chose other than rural areas wanted to enroll in the PTT program. A previous experience of living in rural areas seemed to be the only factor favouring students' choice to have future practice in rural areas (adjusted odds ratio (OR) 3.20, 95% confidence interval (CI) 1.27-8.08, =0.01). Factors that influenced respondents to say they didn't intend to practice rurally were the influence of spouse (adjusted OR 0.38, 95%CI 0.16-0.89, =0.03), and the opportunities for career advancement (adjusted OR 0.28, 95%CI 0.11-0.73, =0.009). The choice of enrollment in the PTT program was positively associated with opportunity for an academic career (adjusted OR 2.39, 95%CI 1.27-4.50, =0.007) and negatively associated with proximity to family/friends (adjusted OR 0.38, 95%CI 0.22-0.65, 0.001). CONCLUSIONS: Only 8.7% of the students were interested in rural areas for their future practice location. Multiple factors were associated with students' interest to choose a career in rural areas later, after graduation from medical school. PMID- 26626124 TI - Approaches for the vaccination and treatment of Neospora caninum infections in mice and ruminant models. AB - Neospora caninum is a leading cause of abortion in cattle, and is thus an important veterinary health problem of high economic significance. Vaccination has been considered a viable strategy to prevent bovine neosporosis. Different approaches have been investigated, and to date the most promising results have been achieved with live-attenuated vaccines. Subunit vaccines have also been studied, and most of them represented components that are functionally involved in (i) the physical interaction between the parasite and its host cell during invasion or (ii) tachyzoite-to-bradyzoite stage conversion. Drugs have been considered as an option to limit the effects of vertical transmission of N. caninum. Promising results with a small panel of compounds in small laboratory animal models indicate the potential value of a chemotherapeutical approach for the prevention of neosporosis in ruminants. For both, vaccines and drugs, the key for success in preventing vertical transmission lies in the application of bioactive compounds that limit parasite proliferation and dissemination, without endangering the developing fetus not only during an exogenous acute infection but also during recrudescence of a chronic infection. In this review, the current status of vaccine and drug development is presented and novel strategies against neosporosis are discussed. PMID- 26626122 TI - Engineering and expression of a human rotavirus candidate vaccine in Nicotiana benthamiana. AB - BACKGROUND: Human rotaviruses are the main cause of severe gastroenteritis in children and are responsible for over 500 000 deaths annually. There are two live rotavirus vaccines currently available, one based on human rotavirus serotype G1P[8], and the other a G1-G4 P[8] pentavalent vaccine. However, the recent emergence of the G9 and other novel rotavirus serotypes in Africa and Asia has prompted fears that current vaccines might not be fully effective against these new varieties. RESULTS: We report an effort to develop an affordable candidate rotavirus vaccine against the new emerging G9P[6] (RVA/Human wt/ZAF/GR10924/1999/G9P[6]) strain. The vaccine is based on virus-like particles which are both highly immunogenic and safe. The vaccine candidate was produced in Nicotiana benthamiana by transient expression, as plants allow rapid production of antigens at lower costs, without the risk of contamination by animal pathogens. Western blot analysis of plant extracts confirmed the successful expression of two rotavirus capsid proteins, VP2 and VP6. These proteins assembled into VLPs resembling native rotavirus particles when analysed by transmission electron microscopy (TEM). Expression of the rotavirus glycoprotein VP7 and the spike protein VP4 was also tried. However, VP7 expression caused plant wilting during the course of the time trial and expression could never be detected for either protein. We therefore created three fusion proteins adding the antigenic part of VP4 (VP8*) to VP6 in an attempt to produce more appropriately immunogenic particles. Fusion protein expression in tobacco plants was detected by western blot using anti-VP6 and anti-VP4 antibodies, but no regular particles were observed by TEM, even when co-expressed with VP2. CONCLUSION: Our results suggest that the rotavirus proteins produced in N. benthamiana are candidates for a subunit vaccine specifically for the G9P[6] rotavirus strain. This could be more effective in developing countries, thereby possibly providing a higher overall efficacy for the existing vaccines. The production of rotavirus proteins in plants would probably result in lower manufacturing costs, making it more affordable for developing countries. Further investigation is required to evaluate the immunogenic potential of the VLPs and fusion proteins created in this study. PMID- 26626125 TI - Alternative methods for the replacement of eye irritation testing. AB - In the last decades significant regulatory attempts were made to replace, refine and reduce animal testing to assess the risk of consumer products for the human eye. As the original in vivo Draize eye test has been criticized for limited predictivity, costs and ethical issues, several animal-free test methods have been developed to categorize substances according to the global harmonized system (GHS) for eye irritation.This review summarizes the progress of alternative test methods for the assessment of eye irritation. Based on the corneal anatomy and the current knowledge of the mechanisms causing eye irritation, different ex vivo and in vitro methods will be presented and discussed in regard of possible limitations and their status of regulatory acceptance. In addition to established in vitro models, this review will also highlight emerging, full thickness cornea models that might be applicable to predict all GHS categories. PMID- 26626126 TI - Single-item migraine screening tests, self-reported bothersome headache or stripe pattern hypersensitivity? AB - BACKGROUND: A simple screening tool may potentially help the migraine diagnosis in a primary care setting. The use of single-item tests, such as stripe pattern hypersensitivity test and self-reported bothersome headache (HA) question, as migraine screening tools have not been fully explored. METHODS: Two hundred and fifty-four subjects (patients and companions) were randomly enrolled from an OB/GYN clinic (men 82, women 172; age 38 +/- 14). They were instructed to rate the stripe sensitivity level (0-4) and to report any bothersome HA (yes/no). A brief structured HA interview was conducted to describe the HA characteristics and for migraine diagnosis based on the ICHD-IIIbeta criteria. RESULTS: In a multivariate model, bothersome HA question and stripe pattern hypersensitivity test were both significantly associated with EM+PM+CM (odds ratio: 24.0, P < 0.01 vs 2.6, P = 0.01) or EM (odds ratio: 16.2, P < 0.01 vs 3.0, P < 0.01). Bothersome HA question had a greater screening power than stripe pattern hypersensitivity for screening EM+PM+CM (area under the ROC curve: 0.84 [95% CI 0.78-0.89] vs 0.62 [95% CI 0.55-0.69]) or EM (area under the ROC curve: 0.80 [95% CI 0.73-0.86] vs 0.64 [95% CI 0.56-0.72]). CONCLUSION: When performed in an OB/GYN clinic, self reported bothersome HA question seemed more powerful than visual stripe pattern test in screening migraine thus could potentially be used as a single-item screening test. PMID- 26626127 TI - Attenuation of Plasmodium falciparum in vitro drug resistance phenotype following culture adaptation compared to fresh clinical isolates in Cambodia. AB - BACKGROUND: There is currently no standardized approach for assessing in vitro anti-malarial drug susceptibility. Potential alterations in drug susceptibility results between fresh immediate ex vivo (IEV) and cryopreserved culture-adapted (CCA) Plasmodium falciparum isolates, as well as changes in parasite genotype during culture adaptation were investigated. METHODS: The 50 % inhibitory concentration (IC50) of 12 P. falciparum isolates from Cambodia against a panel of commonly used drugs were compared using both IEV and CCA. Results were compared using both histidine-rich protein-2 ELISA (HRP-2) and SYBR-Green I fluorescence methods. Molecular genotyping and amplicon deep sequencing were also used to compare multiplicity of infection and genetic polymophisms in fresh versus culture-adapted isolates. RESULTS: IC50 for culture-adapted specimens were significantly lower compared to the original fresh isolates for both HRP-2 and SYBR-Green I assays, with greater than a 50 % decline for the majority of drug assay combinations. There were correlations between IC50s from IEV and CCA for most drugs assays. Infections were nearly all monoclonal, with little or no change in merozoite surface protein 1 (MSP1), MSP2, glutamate-rich protein (GLURP) or apical membrane antigen 1 (AMA1) polymorphisms, nor differences in P. falciparum multidrug resistance 1 gene (PfMDR1) copy number or single nucleotide polymorphisms following culture adaptation. CONCLUSIONS: The overall IC50 reduction combined with the correlation between fresh isolates and culture adapted drug susceptibility assays suggests the utility of both approaches, as long as there is consistency of method, and remaining mindful of possible attenuation of resistance phenotype occurring in culture. Further study should be done in higher transmission settings where polyclonal infections are prevalent. PMID- 26626128 TI - Early Vaginal Opening in Juvenile Female Rats Given BRAF-Inhibitor Dabrafenib Is Not Associated with Early Physiologic Sexual Maturation. AB - Dabrafenib (DAB), an inhibitor of BRAF kinase activity, is approved for metastatic melanoma with a BRAF V600E mutation. In support of pediatric cancer development, a nonclinical juvenile rat toxicity study was conducted in which females had early vaginal opening (VO). It was hypothesized that the early VO was not indicative of sexual maturation, but a result of a local effect on the vagina. An investigative study was conducted that mimicked the definitive study design, with rats given DAB or vehicle orally from Postnatal Day (PND) 7 to 35 and with necropsy subsets just before VO, at the first and second estrus, along with age-matched controls. Histopathology was performed on reproductive tissues, including immunohistochemistry for BRAF expression. VO occurred earlier in DAB females than in controls (PND 27.2 vs. 31.5); however, the timing of the first estrus was unaffected (PND 34.0 vs. 33.0). DAB-treated females evaluated just before VO (PND 22.0) had mostly immature reproductive tracts with no evidence of ovulation, similar to age-matched controls; however, DAB-treated females had keratinized and histologically open vaginas. Also, there was raised skin around the urogenital area, which correlated with hyperplasia/keratosis of the vulvar skin and keratinization of the distal vagina. BRAF expression (evaluated in controls) was localized to these tissues. Thus, early VO in rats given DAB likely represents a local effect accelerating vaginal keratinization to become open and not accelerated sexual maturation. PMID- 26626129 TI - Molecular insights into the enzymatic diversity of flavin-trafficking protein (Ftp; formerly ApbE) in flavoprotein biogenesis in the bacterial periplasm. AB - We recently reported a flavin-trafficking protein (Ftp) in the syphilis spirochete Treponema pallidum (Ftp_Tp) as the first bacterial metal-dependent FAD pyrophosphatase that hydrolyzes FAD into AMP and FMN in the periplasm. Orthologs of Ftp_Tp in other bacteria (formerly ApbE) appear to lack this hydrolytic activity; rather, they flavinylate the redox subunit, NqrC, via their metal dependent FMN transferase activity. However, nothing has been known about the nature or mechanism of metal-dependent Ftp catalysis in either Nqr- or Rnf-redox containing bacteria. In the current study, we identified a bimetal center in the crystal structure of Escherichia coli Ftp (Ftp_Ec) and show via mutagenesis that a single amino acid substitution converts it from an FAD-binding protein to a Mg(2+)-dependent FAD pyrophosphatase (Ftp_Tp-like). Furthermore, in the presence of protein substrates, both types of Ftps are capable of flavinylating periplasmic redox-carrying proteins (e.g., RnfG_Ec) via the metal-dependent covalent attachment of FMN. A high-resolution structure of the Ftp-mediated flavinylated protein of Shewanella oneidensis NqrC identified an essential lysine in phosphoester-threonyl-FMN bond formation in the posttranslationally modified flavoproteins. Together, these discoveries broaden our understanding of the physiological capabilities of the bacterial periplasm, and they also clarify a possible mechanism by which flavoproteins are generated. PMID- 26626131 TI - Readiness of ethics review systems for a changing public health landscape in the WHO African Region. AB - BACKGROUND: The increasing emphasis on research, development and innovation for health in providing solutions to the high burden of diseases in the African Region has warranted a proliferation of studies including clinical trials. This changing public health landscape requires that countries develop adequate ethics review capacities to protect and minimize risks to study participants. Therefore, this study assessed the readiness of national ethics committees to respond to challenges posed by a globalized biomedical research system which is constantly challenged by new public health threats, rapid scientific and technological advancements affecting biomedical research and development, delivery and manufacture of vaccines and therapies, and health technology transfer. METHODS: This is a descriptive study, which used a questionnaire structured to elicit information on the existence of relevant national legal frameworks, mechanisms for ethical review; as well as capacity requirements for national ethics committees. The questionnaire was available in English and French and was sent to 41 of the then 46 Member States of the WHO African Region, excluding the five Lusophone Member States. Information was gathered from senior officials in ministries of health, who by virtue of their offices were considered to have expert knowledge of research ethics review systems in their respective countries. RESULTS: Thirty three of the 41 countries (80.5 %) responded. Thirty (90.9 %) of respondent countries had a national ethics review committee (NEC); 79 % of which were established by law. Twenty-five (83.3 %) NECs had secretarial and administrative support. Over 50 % of countries with NECs indicated a need for capacity strengthening through periodic training on international guidelines for health research (including clinical trials) ethics; and allocation of funds for administrative and secretariat support. CONCLUSIONS: Despite the existing training initiatives, the Region still experiences a shortage of professionals trained in health research ethics/ethicists. Committees continue to face various capacity needs especially for evaluating clinical trials, for monitoring ongoing research, database management and for accrediting institutional ethics committees. Given the growing number of clinical trials involving human participants in the African Region, there is urgent need for supporting countries without NECs to establish them; capacity strengthening where they exist; and creation of a regional network and joint ethical review mechanisms, whose membership would be open to all NECs of the Region. PMID- 26626132 TI - Eustachian Tube Function in 6-Year-Old Children with and without a History of Middle Ear Disease. AB - OBJECTIVE: To test the hypothesis that eustachian tube opening efficiency, measured as the fractional gradient equilibrated (FGE), is lower in 6-year-old children with no middle ear disease but a well-documented history of recurrent acute otitis media, as compared with children with a negative disease history (control). STUDY DESIGN: Cross-sectional study. SETTING: Tertiary care pediatric hospital. SUBJECTS AND METHODS: Bilateral eustachian tube function was evaluated in 44 healthy 6-year-old children (19 boys, 29 white). None had middle ear disease at the time of testing, but 23 had a history of recurrent acute otitis media. Twenty-one had no significant past otitis media. Eustachian tube function was measured with a pressure chamber protocol that established negative middle ear gauge pressures (referenced to the chamber pressure) and recorded that pressure before and after a swallow. FGE was calculated as the change in middle ear gauge pressure with swallowing divided by the preswallow pressure. Between group comparisons of the preswallow pressures and FGEs were made with a 2-tailed Student's t test. RESULTS: FGE was independent of the preswallow middle ear gauge pressure. For the 39 and 44 evaluable ears in the control and recurrent acute otitis media groups, the mean preswallow pressures were -194 daPa (95% confidence interval [95% CI] = -211 to -177) versus -203 (95% CI = -216 to -190; P > .40), and FGEs were 0.32 (95% CI = 0.21-0.43) vs 0.16 (95% CI = 0.08-0.24; P = .016), respectively. CONCLUSION: In children with past recurrent acute otitis media, residual eustachian tube opening inefficiency is maintained after they have "outgrown" their middle ear disease. PMID- 26626133 TI - Grant-Writing Pearls and Pitfalls: Maximizing Funding Opportunities. AB - This invited article reviews the grant process to include the following objectives: (1) to provide an understanding of otolaryngology funding mechanisms in the context of career progression; (2) to outline key components of a well written grant; (3) to highlight vital members of a successful research team, with emphasis on the mentor-mentee relationship; and (4) to clarify grant scoring with emphasis on common pitfalls to avoid. Current otolaryngology funding mechanisms and up-to-date resources are provided. The review is aimed to assist otolaryngology residents, faculty new to the grant process, as well as experienced researchers striving to improve their grant review scores. PMID- 26626134 TI - Acoustic Reflex Screening of Conductive Hearing Loss for Third Window Disorders. AB - OBJECTIVE: This study examines the effectiveness of acoustic reflexes in screening for third window disorders (eg, superior semicircular canal dehiscence) prior to middle ear exploration for conductive hearing loss. STUDY DESIGN: Case series with chart review. SETTING: Outpatient tertiary otology center. SUBJECTS AND METHODS: A review was performed of 212 ears with acoustic reflexes, performed as part of the evaluation of conductive hearing loss in patients without evidence of chronic otitis media. The etiology of hearing loss was determined from intraoperative findings and computed tomography imaging. The relationship between acoustic reflexes and conductive hearing loss etiology was assessed. RESULTS: Eighty-eight percent of ears (166 of 189) demonstrating absence of all acoustic reflexes had an ossicular etiology of conductive hearing loss. Fifty-two percent of ears (12 of 23) with at least 1 detectable acoustic reflex had a nonossicular etiology. The positive and negative predictive values for an ossicular etiology were 89% and 57% when acoustic reflexes were used alone for screening, 89% and 39% when third window symptoms were used alone, and 94% and 71% when reflexes and symptoms were used together, respectively. CONCLUSION: Acoustic reflex testing is an effective means of screening for third window disorders in patients with a conductive hearing loss. Questioning for third window symptoms should complement screening. The detection of even 1 acoustic reflex or third window symptom (regardless of reflex status) should prompt further workup prior to middle ear exploration. PMID- 26626135 TI - Deletion diagnostics for the generalised linear mixed model with independent random effects. AB - The Generalised linear mixed model (GLMM) is widely used for modelling environmental data. However, such data are prone to influential observations, which can distort the estimated exposure-response curve particularly in regions of high exposure. Deletion diagnostics for iterative estimation schemes commonly derive the deleted estimates based on a single iteration of the full system holding certain pivotal quantities such as the information matrix to be constant. In this paper, we present an approximate formula for the deleted estimates and Cook's distance for the GLMM, which does not assume that the estimates of variance parameters are unaffected by deletion. The procedure allows the user to calculate standardised DFBETAs for mean as well as variance parameters. In certain cases such as when using the GLMM as a device for smoothing, such residuals for the variance parameters are interesting in their own right. In general, the procedure leads to deleted estimates of mean parameters, which are corrected for the effect of deletion on variance components as estimation of the two sets of parameters is interdependent. The probabilistic behaviour of these residuals is investigated and a simulation based procedure suggested for their standardisation. The method is used to identify influential individuals in an occupational cohort exposed to silica. The results show that failure to conduct post model fitting diagnostics for variance components can lead to erroneous conclusions about the fitted curve and unstable confidence intervals. PMID- 26626130 TI - Motif co-regulation and co-operativity are common mechanisms in transcriptional, post-transcriptional and post-translational regulation. AB - A substantial portion of the regulatory interactions in the higher eukaryotic cell are mediated by simple sequence motifs in the regulatory segments of genes and (pre-)mRNAs, and in the intrinsically disordered regions of proteins. Although these regulatory modules are physicochemically distinct, they share an evolutionary plasticity that has facilitated a rapid growth of their use and resulted in their ubiquity in complex organisms. The ease of motif acquisition simplifies access to basal housekeeping functions, facilitates the co-regulation of multiple biomolecules allowing them to respond in a coordinated manner to changes in the cell state, and supports the integration of multiple signals for combinatorial decision-making. Consequently, motifs are indispensable for temporal, spatial, conditional and basal regulation at the transcriptional, post transcriptional and post-translational level. In this review, we highlight that many of the key regulatory pathways of the cell are recruited by motifs and that the ease of motif acquisition has resulted in large networks of co-regulated biomolecules. We discuss how co-operativity allows simple static motifs to perform the conditional regulation that underlies decision-making in higher eukaryotic biological systems. We observe that each gene and its products have a unique set of DNA, RNA or protein motifs that encode a regulatory program to define the logical circuitry that guides the life cycle of these biomolecules, from transcription to degradation. Finally, we contrast the regulatory properties of protein motifs and the regulatory elements of DNA and (pre-)mRNAs, advocating that co-regulation, co-operativity, and motif-driven regulatory programs are common mechanisms that emerge from the use of simple, evolutionarily plastic regulatory modules. PMID- 26626136 TI - Expression, tissue localization and serodiagnostic potential of Taenia multiceps acidic ribosomal protein P2. AB - BACKGROUND: The larval stage of Taenia multiceps, also known as coenurus, is the causative agent of coenurosis, which results in severe health problems in sheep, goats, cattle and other animals that negatively impact on animal husbandry. There is no reliable method to identify coenurus infected goats in the early period of infection. METHODS: We identified a full-length cDNA that encodes acidic ribosomal protein P2 from the transcriptome of T. multiceps (TmP2). Following cloning, sequencing and structural analyses were performed using bioinformatics tools. Recombinant TmP2 (rTmP2) was prokaryotically expressed and then used to test immunoreactivity and immunogenicity in immunoblotting assays. The native proteins in adult stage and coenurus were located via immunofluorescence assays, while the potential of rTmP2 for indirect ELISA-based serodiagnostics was assessed using native goat sera. In addition, 20 goats were randomly divided into a drug treatment group and a control group. Each goat was orally given mature, viable T. multiceps eggs. The drug treatment group was given 10% praziquantel by intramuscular injection 45 days post-infection (p.i), and all goats were screened for anti-TmP2 antibodies with the indirect ELISA method established here, once a week for 17 weeks p.i. RESULTS: The open reading frame (366 bp) of the target gene encodes a 12.62 kDa protein, which showed high homology to that from Taenia solium (93% identity) and lacked a signal peptide. Immunofluorescence staining showed that TmP2 was highly localized to the parenchymatous zone of both the adult parasite and the coenurus; besides, it was widely distributed in cystic wall of coenurus. Building on good immunogenic properties, rTmP2-based ELISA exhibited a sensitivity of 95.0% (19/20) and a specificity of 96.3% (26/27) in detecting anti-P2 antibodies in the sera of naturally infected goats and sheep. In goats experimentally infected with T. multiceps, anti-TmP2 antibody was detectable in the control group from 3 to 10 weeks and 15 to 17 weeks p.i. In the drug-treated group, the anti-TmP2 antibody dropped below the cut-off value about 2 weeks after treatment with praziquantel and remained below this critical value until the end of the experiment. CONCLUSION: The indirect ELISA method developed in this study has the potential for detection of T. multiceps infections in hosts. PMID- 26626137 TI - Design and Sensing Properties of a Self-Assembled Supramolecular Oligomer. AB - Supramolecular polymers are a class of macromolecules stabilized by weak non covalent interactions. These self-assembled aggregates typically undergo stimuli induced reversible assembly and disassembly. They thus hold great promise as so called functional materials. In this work, we present the design, synthesis, and responsive behavior of a short supramolecular oligomeric system based on two hetero-complementary subunits. These "monomers" consist of a tetrathiafulvalene functionalized calix[4]pyrrole (TTF-C[4]P) and a glycol diester-linked bis-2,5,7 trinitrodicyanomethylenefluorene-4-carboxylate (TNDCF), respectively. We show that when mixed in organic solvents, such as CHCl3 , CH2 ClCH2 Cl, and methylcyclohexane, supramolecular aggregation takes place to produce short oligomers stabilized by hydrogen bonding and donor-acceptor charge-transfer (CT) interactions. The self-associated materials were characterized by 1 H NMR and UV/Vis/NIR absorption spectroscopy, as well as by concentration- and temperature dependent absorption spectroscopy and dynamic light scattering (DLS) analyses of both the monomeric and oligomerized species. The self-associated system produced from TTF-C[4]P and TNDCF exhibits a concentration-dependent aggregation behavior typical of supramolecular polymers. Further support for the proposed self assembly came from theoretical calculations. The fluorescence emitting properties of TNDCF are quenched under conditions that promote the formation of supramolecular aggregates containing TTF-C[4]P and TNDCF. This quenching effect has been utilized as a probe for the detection of substrates in the form of anions (i.e., chloride) and nitroaromatic explosives (i.e., 1,3,5 trinitrobenzene). Specifically, the addition of these substrates to mixtures of TTF-C[4]P and TNDCF produced a fluorescence "turn-on" response. PMID- 26626138 TI - Development of microsatellite markers for Hyacinth macaw (Anodorhynchus hyacinthinus) and their cross-amplification in other parrot species. AB - BACKGROUND: Hyacinth macaw Anodorhynchus hyacinthinus is the largest parrot of the world and is considered vulnerable to extinction due to its habitat loss and illegal trade associated to the international pet market demand. Genetic studies on this species are still incipient to generate a consistent characterization of the population dynamics and to develop appropriate conservation strategies. In this sense, microsatellite markers may support the detection of a population genetic structure for this bird species. However, at this time, none Hyacinth macaw species-specific primers for microsatellite loci have been so far established. This study aimed to develop and characterize polymorphic microsatellite markers for A. hyacinthinus and to check for their cross amplification in other parrot species. FINDINGS: Sequences containing repeated dinucleotide motifs were prospected and optimized from a genomic library that was enriched for microsatellites using magnetic beads. The analyses of 43-57 samples from wild individuals of three distinct Brazilian subpopulations led to the characterization of five polymorphic microsatellite loci. Allele richness per locus ranged from two to 12. Three loci exhibited observed heterozygosity values higher than 50%, but the overall average value among all loci was close to 45%. In addition, successful primer cross-amplification was verified in seven other investigated species of Neotropical parrots. CONCLUSIONS: The newly developed markers have shown to be potentially useful for in situ and ex situ population studies to support future conservation actions of Hyacinth macaw and other parrots. PMID- 26626140 TI - Research that makes a difference. PMID- 26626139 TI - Association of osteoprotegerin with impaired glucose regulation and microalbuminuria: the REACTION study. AB - BACKGROUND: High osteoprotegerin (OPG) has been reported in association with insulin resistance and type 2 diabetes. We aimed to evaluate the association of serum OPG with impaired glucose regulation (IGR) and microalbuminuria among middle-aged and older Chinese. METHODS: Serum OPG was measured in 599 individuals with normal glucose regulation, 730 with impaired glucose regulation and 327 newly diagnosed patients with diabetes. Serum OPG was measured using ELISA methods and urine albumin/creatinine ratio was used to determine the urinary albumin excretion. RESULTS: Serum OPG levels were significantly higher in subjects with isolated impaired fasting glucose, isolated impaired glucose tolerance, combined impaired fasting glucose/impaired glucose tolerance and diabetes than in those with normal glucose regulation, whereas serum OPG levels were not different in the four groups with dysregulation of glucose metabolism. OPG was associated with a higher risk for IGR (OR 1.108 for each 0.1 MUg/l increase in OPG, 95% CI 1.009-1.117, p = 0.01) after adjustment for gender, age, BMI, current smoking and alcohol intake, family history of diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), lipid profile; the corresponding OR of combined impaired glucose regulation and type 2 diabetes was 1.121 (95% CI 1.101-1.141, p = 0.0005). OPG was associated with the risk of microalbuminuria (OR 1.025, 95% CI 1.006-1.044, p = 0.02) after adjustment for gender, age, current smoking, current alcohol intake, family history of diabetes, BMI, waist/hip ratio, HOMA-IR, eGFR and lipid profile. CONCLUSIONS: Serum OPG level is closely and independently associated with IGR and is an independent risk factor for microalbuminuria. PMID- 26626141 TI - Monitoring oil displacement processes with k-t accelerated spin echo SPI. AB - Magnetic resonance imaging (MRI) is a robust tool to monitor oil displacement processes in porous media. Conventional MRI measurement times can be lengthy, which hinders monitoring time-dependent displacements. Knowledge of the oil and water microscopic distribution is important because their pore scale behavior reflects the oil trapping mechanisms. The oil and water pore scale distribution is reflected in the magnetic resonance T2 signal lifetime distribution. In this work, a pure phase-encoding MRI technique, spin echo SPI (SE-SPI), was employed to monitor oil displacement during water flooding and polymer flooding. A k-t acceleration method, with low-rank matrix completion, was employed to improve the temporal resolution of the SE-SPI MRI measurements. Comparison to conventional SE SPI T2 mapping measurements revealed that the k-t accelerated measurement was more sensitive and provided higher-quality results. It was demonstrated that the k-t acceleration decreased the average measurement time from 66.7 to 20.3 min in this work. A perfluorinated oil, containing no (1) H, and H2 O brine were employed to distinguish oil and water phases in model flooding experiments. High quality 1D water saturation profiles were acquired from the k-t accelerated SE SPI measurements. Spatially and temporally resolved T2 distributions were extracted from the profile data. The shift in the (1) H T2 distribution of water in the pore space to longer lifetimes during water flooding and polymer flooding is consistent with increased water content in the pore space. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26626142 TI - Hemostasis in sinus surgery. AB - PURPOSE OF REVIEW: Optimization of the surgical field involves a complex interplay of many factors. Although it is agreed that hemostasis is critical to safe, efficient, and successful sinus surgery, a lack of consensus exists as to the best way to achieve it. This review examines the current body of evidence supporting many of the practices surgeons believe to influence hemostasis. RECENT FINDINGS: Although many of the practices discussed in this article have long been considered to influence hemostasis, it is not until recently that high-level evidence supporting their use has been available. Well designed studies now exist supporting the preoperative use of oral steroids in polyp patients, the importance of adequate reverse trendelenburg positioning, the use of flexible laryngeal mask ventilation during general anesthesia, and the increased safety and comparable efficacy of topical epinephrine over other topical and injectable agents. Controversy still exists as to the ideal method of achieving controlled hypotensive anesthesia, although new evidence has emerged as to what hemodynamic parameters should be adhered to, to reduce the risk of cerebral hypoperfusion. SUMMARY: Numerous factors influence hemostasis and so it is important that ENT surgeons have a sound understanding of the evidence supporting their everyday surgical practice. Improved standardization of scoring and reporting of bleeding may increase the power of research studies to draw more definitive conclusions about the role that certain factors have on hemostasis. PMID- 26626143 TI - Prognostic importance of mitral regurgitation complicated by acute myocardial infarction during a 5-year follow-up period in the drug-eluting stent era. AB - BACKGROUND: Mitral regurgitation (MR) is a frequent complication of left ventricular dysfunction, with an incidence ranging from 13 to 59% after acute myocardial infarction (AMI), which is associated with poor clinical outcome. The aim of this study was to assess the clinical and angiographic characteristics associated with MR, the incidence and predictors of MR, and the outcomes of MR after AMI in those who were successfully treated with primary percutaneous coronary intervention (PCI) using a drug-eluting stent. METHODS: We analyzed a multicenter all-comer AMI registry and identified 4748 patients between January 2004 and December 2009. Of these, 1894 patients were treated with PCI using a drug-eluting stent and had MR. The association between MR and the composite of major adverse cardiac and cerebrovascular events (MACCE; all-cause death, recurrent nonfatal myocardial infarction, stroke, and any revascularization) was examined. RESULTS: Patients with MR after the index PCI showed significantly higher cumulative incidence of MACCE compared with no-MR patients over the 5-year survival period (P=0.002). When the MR groups were compared on the basis of the severity of MR, ranging from mild to severe grades, a higher grade of MR was found to be associated with a higher incidence of MACCE (P<0.001). Multivariate Cox proportional hazard analysis revealed that no reflow, left-ventricular ejection fraction less than 50%, and anemia, in addition to MR, were consistently associated with increased all-cause death during the 5-year period (adjusted hazard ratio 1.408, 95% confidence interval 1.052-1.884, P=0.021). CONCLUSION: MR after AMI in patients successfully treated with primary PCI was associated with poor long-term outcome regardless of ST-segment elevation at diagnosis during the drug-eluting stent era. PMID- 26626144 TI - Structured line illumination Raman microscopy. AB - In the last couple of decades, the spatial resolution in optical microscopy has increased to unprecedented levels by exploiting the fluorescence properties of the probe. At about the same time, Raman imaging techniques have emerged as a way to image inherent chemical information in a sample without using fluorescent probes. However, in many applications, the achievable resolution is limited to about half the wavelength of excitation light. Here we report the use of structured illumination to increase the spatial resolution of label-free spontaneous Raman microscopy, generating highly detailed spatial contrast from the ensemble of molecular information in the sample. Using structured line illumination in slit-scanning Raman microscopy, we demonstrate a marked improvement in spatial resolution and show the applicability to a range of samples, including both biological and inorganic chemical component mapping. This technique is expected to contribute towards greater understanding of chemical component distributions in organic and inorganic materials. PMID- 26626145 TI - Karyopherin alpha 2 is a novel prognostic marker and a potential therapeutic target for colon cancer. AB - BACKGROUND: Karyopherin alpha 2 (KPNA2), a member of the karyopherin family, plays a vital role in carcinogenesis. Yet its role in colon cancer is poorly characterized. We sought to clarify the clinical significance of its dysregulated expression in human colon tumor specimens. METHODS: We evaluated KPNA2 mRNA and protein expression by real-time polymerase chain reaction and Western blotting in 40 primary colon cancer tissues and paired adjacent normal colon mucosa specimens. KPNA2 protein expression in colon tissue microarray of tumor and normal tissue specimens and lymph node metastasis specimens obtained from 195 colon cancer patients were analyzed immunohistochemically. The effect of KPNA2 knockdown on carcinogenesis potential of human colon cancer cells was determined using Cell Counting Kit-8 (CCK8), colony formation, cell migration, and tumorigenesis in nude mice. RESULTS: KPNA2 was expressed at higher levels in colon tumors and lymph node metastasis specimens than in normal tissues. Patients with KPNA2-positive tumors were significantly correlated with the American Joint Committee on Cancer (AJCC) stage (p = 0.01), T-classification (p = 0.018), regional lymph node metastasis (p = 0.025), distant metastasis (p = 0.014), and differentiated degree (p = 0.001). KPNA2 was shown to be an independent prognostic indicator of disease-free survival (HR 1.681; 95 % CI: 1.170-2.416; p = 0.005) and overall survival (HR 2.770; 95 % CI: 1.314-5.837; p = 0.007) for patients with colon cancer. Knockdown of KPNA2 expression inhibited colon cancer cell proliferation, colony formation, and migration. CONCLUSION: KPNA2 might play an important role in colorectal carcinogenesis and functions as a novel prognostic indicator and a potential therapeutic target for colorectal cancer. PMID- 26626146 TI - Eosinophilic Peritonitis Caused by Echinococcus granulosus in a Patient Receiving Maintenance Peritoneal Dialysis. PMID- 26626147 TI - Activation of CO and CO2 on homonuclear boron bonds of fullerene-like BN cages: first principles study. AB - Using density functional theory we investigate the electronic and atomic structure of fullerene-like boron nitride cage structures. The pentagonal ring leads to the formation of homonuclear bonds. The homonuclear bonds are also found in other BN structures having pentagon line defect. The calculated thermodynamics and vibrational spectra indicated that, among various stable configurations of BN 60 cages, the higher number of homonuclear N-N bonds and lower B:N ratio can result in the more stable structure. The homonuclear bonds bestow the system with salient catalytic properties that can be tuned by modifying the B atom bonding environment. We show that homonuclear B-B (B2) bonds can anchor both oxygen and CO molecules making the cage to be potential candidates as catalyst for CO oxidation via Langmuir-Hinshelwood (LH) mechanism. Moreover, the B-B-B (B3) bonds are reactive enough to capture, activate and hydrogenate CO2 molecules to formic acid. The observed trend in reactivity, viz B3 > B2 > B1 is explained in terms of the position of the boron defect state relative to the Fermi level. PMID- 26626148 TI - Mitigation of Fumonisin Biomarkers by Green Tea Polyphenols in a High-Risk Population of Hepatocellular Carcinoma. AB - Green tea polyphenols (GTP) are highly effective in inhibiting a variety of tumorigenic effects induced by carcinogens. In this study we assessed GTP mitigation on biomarkers of fumonisin B1 (FB1), a class 2B carcinogen, in blood and urine samples collected from an intervention trial. A total of 124 exposed people were recruited and randomly assigned to low-dose (GTP 500 mg, n = 42), high-dose (GTP 1,000 mg, n = 41) or placebo (n = 41) for 3 months. After one month of intervention, urinary FB1 was significantly decreased in high-dose group compared to that of placebo group (p = 0.045), with reduction rates of 18.95% in the low-dose group and 33.62% in the high-dose group. After three-month intervention, urinary FB1 showed significant decrease in both low-dose (p = 0.016) and the high-dose (p = 0.0005) groups compared to that of both placebo group and baseline levels, with reduction rates of 40.18% in the low-dose group and 52.6% in the high-dose group. GTP treatment also significantly reduced urinary excretion of sphinganine (Sa), sphingosine (So), and Sa/So ratio, but had no effect on serum Sa, So, and Sa/So ratio. Analysis with mixed-effect model revealed significant interactions between time and treatment effects of GTP on both urinary free FB1 levels and Sa/So ratios. PMID- 26626149 TI - Bivalent interaction of the PZP domain of BRPF1 with the nucleosome impacts chromatin dynamics and acetylation. AB - BRPF1 (bromodomain PHD finger 1) is a core subunit of the MOZ histone acetyltransferase (HAT) complex, critical for normal developmental programs and implicated in acute leukemias. BRPF1 contains a unique assembly of zinc fingers, termed a PZP domain, the physiological role of which remains unclear. Here, we elucidate the structure-function relationship of this novel epigenetic reader and detail the biological and mechanistic consequences of its interaction with nucleosomes. PZP has a globular architecture and forms a 2:1 stoichiometry complex with the nucleosome, bivalently interacting with histone H3 and DNA. This binding impacts the nucleosome dynamics, shifting the DNA unwrapping/rewrapping equilibrium toward the unwrapped state and increasing DNA accessibility. We demonstrate that the DNA-binding function of the BRPF1 PZP domain is required for the MOZ-BRPF1-ING5-hEaf6 HAT complex to be recruited to chromatin and to acetylate nucleosomal histones. Our findings reveal a novel link between chromatin dynamics and MOZ-mediated acetylation. PMID- 26626150 TI - MERAV: a tool for comparing gene expression across human tissues and cell types. AB - The oncogenic transformation of normal cells into malignant, rapidly proliferating cells requires major alterations in cell physiology. For example, the transformed cells remodel their metabolic processes to supply the additional demand for cellular building blocks. We have recently demonstrated essential metabolic processes in tumor progression through the development of a methodological analysis of gene expression. Here, we present the Metabolic gEne RApid Visualizer (MERAV, http://merav.wi.mit.edu), a web-based tool that can query a database comprising ~4300 microarrays, representing human gene expression in normal tissues, cancer cell lines and primary tumors. MERAV has been designed as a powerful tool for whole genome analysis which offers multiple advantages: one can search many genes in parallel; compare gene expression among different tissue types as well as between normal and cancer cells; download raw data; and generate heatmaps; and finally, use its internal statistical tool. Most importantly, MERAV has been designed as a unique tool for analyzing metabolic processes as it includes matrixes specifically focused on metabolic genes and is linked to the Kyoto Encyclopedia of Genes and Genomes pathway search. PMID- 26626151 TI - Exploded view of higher order G-quadruplex structures through click-chemistry assisted single-molecule mechanical unfolding. AB - Due to the long-range nature of high-order interactions between distal components in a biomolecule, transition dynamics of tertiary structures is often too complex to profile using conventional methods. Inspired by the exploded view in mechanical drawing, here, we used laser tweezers to mechanically dissect high order DNA structures into two constituting G-quadruplexes in the promoter of the human telomerase reverse transcriptase (hTERT) gene. Assisted with click chemistry coupling, we sandwiched one G-quadruplex with two dsDNA handles while leaving the other unit free. Mechanical unfolding through these handles revealed transition dynamics of the targeted quadruplex in a native environment, which is named as native mechanical segmentation (NMS). Comparison between unfolding of an NMS construct and that of truncated G-quadruplex constructs revealed a quadruplex quadruplex interaction with 2 kcal/mol stabilization energy. After mechanically targeting the two G-quadruplexes together, the same interaction was observed during the first unfolding step. The unfolding then proceeded through disrupting the weaker G-quadruplex at the 5'-end, followed by the stronger G-quadruplex at the 3'-end via various intermediates. Such a pecking order in unfolding well reflects the hierarchical nature of nucleic acid structures. With surgery-like precisions, we anticipate this NMS approach offers unprecedented perspective to decipher dynamic transitions in complex biomacromolecules. PMID- 26626153 TI - High Frequency of Imprinted Methylation Errors in Human Preimplantation Embryos. AB - Assisted reproductive technologies (ARTs) represent the best chance for infertile couples to conceive, although increased risks for morbidities exist, including imprinting disorders. This increased risk could arise from ARTs disrupting genomic imprints during gametogenesis or preimplantation. The few studies examining ART effects on genomic imprinting primarily assessed poor quality human embryos. Here, we examined day 3 and blastocyst stage, good to high quality, donated human embryos for imprinted SNRPN, KCNQ1OT1 and H19 methylation. Seventy six percent day 3 embryos and 50% blastocysts exhibited perturbed imprinted methylation, demonstrating that extended culture did not pose greater risk for imprinting errors than short culture. Comparison of embryos with normal and abnormal methylation didn't reveal any confounding factors. Notably, two embryos from male factor infertility patients using donor sperm harboured aberrant methylation, suggesting errors in these embryos cannot be explained by infertility alone. Overall, these results indicate that ART human preimplantation embryos possess a high frequency of imprinted methylation errors. PMID- 26626155 TI - Dietary vitamin A intake and bone health in the elderly: the Rotterdam Study. PMID- 26626152 TI - LOOP IIId of the HCV IRES is essential for the structural rearrangement of the 40S-HCV IRES complex. AB - As obligatory intracellular parasites, viruses rely on cellular machines to complete their life cycle, and most importantly they recruit the host ribosomes to translate their mRNA. The Hepatitis C viral mRNA initiates translation by directly binding the 40S ribosomal subunit in such a way that the initiation codon is correctly positioned in the P site of the ribosome. Such a property is likely to be central for many viruses, therefore the description of host-pathogen interaction at the molecular level is instrumental to provide new therapeutic targets. In this study, we monitored the 40S ribosomal subunit and the viral RNA structural rearrangement induced upon the formation of the binary complex. We further took advantage of an IRES viral mutant mRNA deficient for translation to identify the interactions necessary to promote translation. Using a combination of structure probing in solution and molecular modeling we establish a whole atom model which appears to be very similar to the one obtained recently by cryoEM. Our model brings new information on the complex, and most importantly reveals some structural rearrangement within the ribosome. This study suggests that the formation of a 'kissing complex' between the viral RNA and the 18S ribosomal RNA locks the 40S ribosomal subunit in a conformation proficient for translation. PMID- 26626154 TI - Screening cell mechanotype by parallel microfiltration. AB - Cell mechanical phenotype or 'mechanotype' is emerging as a valuable label-free biomarker. For example, marked changes in the viscoelastic characteristics of cells occur during malignant transformation and cancer progression. Here we describe a simple and scalable technique to measure cell mechanotype: this parallel microfiltration assay enables multiple samples to be simultaneously measured by driving cell suspensions through porous membranes. To validate the method, we compare the filtration of untransformed and HRas(V12)-transformed murine ovary cells and find significantly increased deformability of the transformed cells. Inducing epithelial-to-mesenchymal transition (EMT) in human ovarian cancer cells by overexpression of key transcription factors (Snail, Slug, Zeb1) or by acquiring drug resistance produces a similar increase in deformability. Mechanistically, we show that EMT-mediated changes in epithelial (loss of E-Cadherin) and mesenchymal markers (vimentin induction) correlate with altered mechanotype. Our results demonstrate a method to screen cell mechanotype that has potential for broader clinical application. PMID- 26626156 TI - Metabolic and physiologic improvements from consuming a paleolithic, hunter gatherer type diet. PMID- 26626157 TI - Effects of physical exercise interventions in frail older adults: a systematic review of randomized controlled trials. AB - BACKGROUND: Low physical activity has been shown to be one of the most common components of frailty, and interventions have been considered to prevent or reverse this syndrome. The purpose of this systematic review of randomized, controlled trials is to examine the exercise interventions to manage frailty in older people. METHODS: The PubMed, Web of Science, and Cochrane Central Register of Controlled Trials databases were searched using specific keywords and Medical Subject Headings for randomized, controlled trials published during the period of 2003-2015, which enrolled frail older adults in an exercise intervention program. Studies where frailty had been defined were included in the review. A narrative synthesis approach was performed to examine the results. The Physiotherapy Evidence Database (PEDro scale) was used to assess the methodological quality of the selected studies. RESULTS: Of 507 articles, nine papers met the inclusion criteria. Of these, six included multi-component exercise interventions (aerobic and resistance training not coexisting in the intervention), one included physical comprehensive training, and two included exercises based on strength training. All nine of these trials included a control group receiving no treatment, maintaining their habitual lifestyle or using a home-based low level exercise program. Five investigated the effects of exercise on falls, and among them, three found a positive impact of exercise interventions on this parameter. Six trials reported the effects of exercise training on several aspects of mobility, and among them, four showed enhancements in several measurements of this outcome. Three trials focused on the effects of exercise intervention on balance performance, and one demonstrated enhanced balance. Four trials investigated functional ability, and two showed positive results after the intervention. Seven trials investigated the effects of exercise intervention on muscle strength, and five of them reported increases; three trials investigated the effects of exercise training on body composition, finding improvements in this parameter in two of them; finally, one trial investigated the effects of exercise on frailty using Fried's criteria and found an improvement in this measurement. Exercise interventions have demonstrated improvement in different outcome measurements in frail older adults, however, there were large differences between studies with regard to effect sizes. CONCLUSIONS: This systematic review suggested that frail older adults seemed to benefit from exercise interventions, although the optimal program remains unclear. More studies of this topic and with frail populations are needed to select the most favorable exercise program. PMID- 26626158 TI - Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug. AB - Taxanes are highly effective chemotherapeutic drugs against proliferating cancer and an established option in the standard treatment of ovarian and breast cancer. However, treatment with paclitaxel is associated with severe side effects, including sensory axonal neuropathy, and its poor solubility in water complicates its formulation. In this paper we report the in vitro and in vivo activity of a new form of paclitaxel, modified for conjugation with a tumor-selective tetrabranched peptide carrier (NT4). NT4 selectively targets tumor cells by binding to membrane sulfated glycosaminoglycans (GAG) and to endocytic receptors, like LRP1 and LRP6, which are established tumor markers. Biological activity of NT4-paclitaxel was tested in vitro on MDA-MB 231 and SKOV-3 cell lines, representing breast and ovarian cancer, respectively, and in vivo in an orthotopic mouse model of human breast cancer. Using in vivo bioluminescence imaging, we found that conjugation of paclitaxel with the NT4 peptide led to increased therapeutic activity of the drug in vivo. NT4-paclitaxel induced tumor regression, whereas treatment with unconjugated paclitaxel only produced a reduction in tumor growth. Moreover, unlike paclitaxel, NT4-paclitaxel is very hydrophilic, which may improve its pharmacokinetic profile and allow the use of less toxic dilution buffers, further decreasing its general chemotherapic toxicity. PMID- 26626161 TI - Terezine derivatives from the fungus Phoma herbarum PSU-H256. AB - Investigation of the fungus Phoma herbarum PSU-H256 isolated from a leaf of Hevea brasiliensis resulted in the isolation of eight terezine derivatives (E-L) together with four known compounds. Their structures were established by analysis of spectroscopic evidence. For terezines E and H, their structures were confirmed by single-crystal X-ray diffraction crystallography. In addition, the absolute configuration at C-7 in terezine E was established by Mosher's method. Terezines K and L were tested for antibacterial, antimalarial, antimycobacterial and cytotoxic activities, but were inactive. PMID- 26626159 TI - AIM2 inflammasome in infection, cancer, and autoimmunity: Role in DNA sensing, inflammation, and innate immunity. AB - Recognition of DNA by the cell is an important immunological signature that marks the initiation of an innate immune response. AIM2 is a cytoplasmic sensor that recognizes dsDNA of microbial or host origin. Upon binding to DNA, AIM2 assembles a multiprotein complex called the inflammasome, which drives pyroptosis and proteolytic cleavage of the proinflammatory cytokines pro-IL-1beta and pro-IL-18. Release of microbial DNA into the cytoplasm during infection by Francisella, Listeria, Mycobacterium, mouse cytomegalovirus, vaccinia virus, Aspergillus, and Plasmodium species leads to activation of the AIM2 inflammasome. In contrast, inappropriate recognition of cytoplasmic self-DNA by AIM2 contributes to the development of psoriasis, dermatitis, arthritis, and other autoimmune and inflammatory diseases. Inflammasome-independent functions of AIM2 have also been described, including the regulation of the intestinal stem cell proliferation and the gut microbiota ecology in the control of colorectal cancer. In this review we provide an overview of the latest research on AIM2 inflammasome and its role in infection, cancer, and autoimmunity. PMID- 26626160 TI - Characterization of an epoxide hydrolase from the Florida red tide dinoflagellate, Karenia brevis. AB - Epoxide hydrolases (EH, EC 3.3.2.3) have been proposed to be key enzymes in the biosynthesis of polyether (PE) ladder compounds such as the brevetoxins which are produced by the dinoflagellate Karenia brevis. These enzymes have the potential to catalyze kinetically disfavored endo-tet cyclization reactions. Data mining of K. brevis transcriptome libraries revealed two classes of epoxide hydrolases: microsomal and leukotriene A4 (LTA4) hydrolases. A microsomal EH was cloned and expressed for characterization. The enzyme is a monomeric protein with molecular weight 44kDa. Kinetic parameters were evaluated using a variety of epoxide substrates to assess substrate selectivity and enantioselectivity, as well as its potential to catalyze the critical endo-tet cyclization of epoxy alcohols. Monitoring of EH activity in high and low toxin producing cultures of K. brevis over a three week period showed consistently higher activity in the high toxin producing culture implicating the involvement of one or more EH in brevetoxin biosynthesis. PMID- 26626162 TI - A Review of New Pharmacologic Treatments for Patients With Chronic Heart Failure With Reduced Ejection Fraction. AB - Heart failure (HF) impacts an estimated 5.7 million Americans, and its prevalence is projected to increase to more than 8 million Americans in the next 15 years. Key clinical trials have established an evidence-based foundation for treatment of heart failure with reduced ejection fraction (HFrEF). Ivabradine and sacubitril/valsartan, which inhibit the f-channel and the angiotensin receptor and neprilysin, respectively, were recently approved by the Food and Drug Administration for HFrEF. In systolic heart failure, treatment with the If inhibitor ivabradine significantly reduced the combined endpoint of cardiovascular mortality or heart failure hospital admission vs placebo (P < .05). In the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with angiotensin-converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure trial, sacubitril/valsartan significantly reduced the combined endpoint of cardiovascular death or heart failure hospitalization vs enalapril (P < .001). The place of therapy with ivabradine and sacubitril/valsartan is defined by these trials and their interplay with guideline-directed medical therapy. Ivabradine and sacubitril/valsartan increase pharmacotherapy options for the treatment of HFrEF but are not yet first-line agents. Clinical application will be better defined in the coming years as practitioners increase their familiarity with ivabradine and sacubitril/valsartan. PMID- 26626163 TI - NB-UVB phototherapy for generalized granuloma annulare. AB - Granuloma annulare (GA) is a benign, usually self-limited, granulomatous skin disease of unknown etiology. The generalized form of the disease shows a more chronic, relapsing course, rare spontaneous resolution, and poorer response to therapy. Psoralen plus UVA phototherapy has been reported to be effective for GA. However, little is known regarding the efficacy of narrowband UVB phototherapy. Our goal was to determine the efficacy of NB-UVB phototherapy in generalized GA. We carried out a retrospective study of patients with generalized GA treated with NB-UVB phototherapy over a period of 3 years. On completion of treatment, outcome was assessed as complete response (complete clearance of the lesions), partial response (>50% clearance of the lesions), and poor response (<50% clinical response). Therapy was stopped if no improvement was seen after 20 treatments. Thirteen patients were included in the study. 54% of patients treated with NB-UVB had a complete/partial response by the end of the treatment period. NB-UVB phototherapy was well-tolerated, with no serious adverse effects. NB-UVB phototherapy is effective in a substantial portion of patients with generalized GA. To determine the true efficacy of this therapeutic modality, a prospective study comparing it to PUVA is warranted. PMID- 26626165 TI - Human immunodeficiency virus infection and its association with sarcopenia. AB - Presarcopenia and sarcopenia were evaluated in HIV-infected individuals and in healthy elderly controls according to the consensus definitions of the European Working Group on Sarcopenia in Older People. Bioelectrical impedance, a hydraulic hand dynamometer, and gait speed were used to evaluate muscle mass, muscle strength, and physical performance, respectively. Adjusted and unadjusted binary logistic regression predicted the risk of sarcopenia. Predictor contribution was assessed by the Wald test. Significance was established at p<=0.05. The HIV infected group consisted of 33 patients on treatment (42.4% women; mean age 59+/ 7 years; mean BMI 25+/-6kg/m(2); viral load undetectable in 30 cases). The HIV uninfected group consisted of 60 individuals (71.7% women; mean age 70+/-7 years; mean BMI 28+/-6kg/m(2)). Of the controls, 4 (6.7%) individuals had presarcopenia and 4 (6.7%) sarcopenia compared to 4 (12.1%) and 8 (24.2%), respectively, in the HIV-infected group. The HIV-infected patients had a 4.95 higher risk (95% CI: 1.34-18.23) for sarcopenia compared to the controls. It should be pointed out that the control group was on average 10 years older. This risk increased further (RR=5.20; 95% CI: 1.40-19.20) after adjusting for age and BMI. HIV-infected patients were shown to be at a greater risk of sarcopenia, an indicator of frailty, even following adjustment for age and BMI. PMID- 26626164 TI - Resistance patterns, prevalence, and predictors of fluoroquinolones resistance in multidrug resistant tuberculosis patients. AB - BACKGROUND: Fluoroquinolones are the backbone of multidrug resistant tuberculosis treatment regimens. Despite the high burden of multidrug resistant tuberculosis in the country, little is known about drug resistance patterns, prevalence, and predictors of fluoroquinolones resistance among multidrug resistant tuberculosis patients from Pakistan. OBJECTIVE: To evaluate drug resistance patterns, prevalence, and predictors of fluoroquinolones resistance in multidrug resistant tuberculosis patients. METHODS: This was a cross-sectional study conducted at a programmatic management unit of drug resistant tuberculosis, Lady Reading Hospital Peshawar, Pakistan. Two hundred and forty-three newly diagnosed multidrug resistant tuberculosis patients consecutively enrolled for treatment at study site from January 1, 2012 to July 28, 2013 were included in the study. A standardized data collection form was used to collect patients' socio demographic, microbiological, and clinical data. SPSS 16 was used for data analysis. RESULTS: High degree of drug resistance (median 5 drugs, range 2-8) was observed. High proportion of patients was resistant to all five first-line anti tuberculosis drugs (62.6%), and more than half were resistant to second line drugs (55.1%). The majority of the patients were ofloxacin resistant (52.7%). Upon multivariate analysis previous tuberculosis treatment at private (OR=1.953, p=0.034) and public private mix (OR=2.824, p=0.046) sectors were predictors of ofloxacin resistance. CONCLUSION: The high degree of drug resistance observed, particularly to fluoroquinolones, is alarming. We recommend the adoption of more restrictive policies to control non-prescription sale of fluoroquinolones, its rational use by physicians, and training doctors in both private and public private mix sectors to prevent further increase in fluoroquinolones resistant Mycobacterium tuberculosis strains. PMID- 26626166 TI - Patterns of influenza B circulation in Brazil and its relevance to seasonal vaccine composition. AB - Data on the burden of disease and circulation patterns of influenza B lineages for Brazil are limited. This review aims to describe the pattern of influenza B occurrence in Brazil to have a better understanding of its epidemiology and its relevance when considering seasonal influenza vaccine composition. A review of the data including analysis of international and local surveillance data as well as information from online search of databases using Medical Subject Headings terms in conjunction with screening of abstracts from scientific events was performed. Based on international epidemiologic surveillance data, moderate levels of influenza B disease (19%; 2006-2014) were observed. Of these nine years, it was possible to compare data from three years (2007, 2008 and 2013) which have information on the circulating influenza B lineage. Co-circulation of influenza B lineages was observed in all these three influenza seasons, of which, during one season, a high degree of mismatch between the vaccine lineage and the predominant circulating lineage (91.4% [2013]) was observed. Local surveillance data reveal a distinct and dynamic distribution of respiratory viruses over the years. Data from published literature and abstracts show that influenza B is a significant cause of disease with an unpredictable circulation pattern and showing trends indicating reemergence of the B/Victoria lineage. The abstracts report notable levels of co-circulation of both influenza B lineages (2000-2013). Mismatch between the Southern hemisphere vaccine and the most prevalent circulating viruses in Brazil were observed in five influenza seasons. The evidence on co-circulation of two influenza B lineages and mismatched seasons in Brazil indicates the benefit of quadrivalent influenza vaccines in conferring broader seasonal influenza protection. Additionally, improving influenza surveillance platforms in Brazil is important for monitoring disease trends and the impact of introducing seasonal influenza vaccination. PMID- 26626167 TI - Oral paracoccidiodomycosis mimicking lip carcinoma. PMID- 26626168 TI - New patterns of HCV subtypes distribution in the Khyber Pakhtunkhwa province of Pakistan. PMID- 26626169 TI - How we can utilize the Xpert MTB/RIF assay to decide on airborne infection isolation of inpatients with tuberculosis suspicion in Brazil: a brief review of the current data. PMID- 26626170 TI - Accuracy of genomic selection for alfalfa biomass yield in different reference populations. AB - BACKGROUND: Genomic selection based on genotyping-by-sequencing (GBS) data could accelerate alfalfa yield gains, if it displayed moderate ability to predict parent breeding values. Its interest would be enhanced by predicting ability also for germplasm/reference populations other than those for which it was defined. Predicting accuracy may be influenced by statistical models, SNP calling procedures and missing data imputation strategies. RESULTS: Landrace and variety material from two genetically-contrasting reference populations, i.e., 124 elite genotypes adapted to the Po Valley (sub-continental climate; PV population) and 154 genotypes adapted to Mediterranean-climate environments (Me population), were genotyped by GBS and phenotyped in separate environments for dry matter yield of their dense-planted half-sib progenies. Both populations showed no sub-population genetic structure. Predictive accuracy was higher by joint rather than separate SNP calling for the two data sets, and using random forest imputation of missing data. Highest accuracy was obtained using Support Vector Regression (SVR) for PV, and Ridge Regression BLUP and SVR for Me germplasm. Bayesian methods (Bayes A, Bayes B and Bayesian Lasso) tended to be less accurate. Random Forest Regression was the least accurate model. Accuracy attained about 0.35 for Me in the range of 0.30-0.50 missing data, and 0.32 for PV at 0.50 missing data, using at least 10,000 SNP markers. Cross-population predictions based on a smaller subset of common SNPs implied a relative loss of accuracy of about 25% for Me and 30% for PV. Genome-wide association analyses based on large subsets of M. truncatula aligned markers revealed many SNPs with modest association with yield, and some genome areas hosting putative QTLs. A comparison of genomic vs. conventional selection for parent breeding value assuming 1-year vs. 5-year selection cycles, respectively, indicated over three-fold greater predicted yield gain per unit time for genomic selection. CONCLUSIONS: Genomic selection for alfalfa yield is promising, based on its moderate prediction accuracy, moderate value of cross population predictions, and lack of sub-population structure. There is limited scope for searching individual QTLs with overwhelming effect on yield. Some of our results can contribute to better design of genomic selection experiments for alfalfa and other crops with similar mating systems. PMID- 26626172 TI - Service user and patient and public involvement in palliative and supportive care research. PMID- 26626177 TI - Fibroblast Growth Factors and Vascular Endothelial Growth Factor Promote Cardiac Reprogramming under Defined Conditions. AB - Fibroblasts can be directly reprogrammed into cardiomyocyte-like cells (iCMs) by overexpression of cardiac transcription factors, including Gata4, Mef2c, and Tbx5; however, this process is inefficient under serum-based culture conditions, in which conversion of partially reprogrammed cells into fully reprogrammed functional iCMs has been a major hurdle. Here, we report that a combination of fibroblast growth factor (FGF) 2, FGF10, and vascular endothelial growth factor (VEGF), termed FFV, promoted cardiac reprogramming under defined serum-free conditions, increasing spontaneously beating iCMs by 100-fold compared with those under conventional serum-based conditions. Mechanistically, FFV activated multiple cardiac transcriptional regulators and converted partially reprogrammed cells into functional iCMs through the p38 mitogen-activated protein kinase and phosphoinositol 3-kinase/AKT pathways. Moreover, FFV enabled cardiac reprogramming with only Mef2c and Tbx5 through the induction of cardiac reprogramming factors, including Gata4. Thus, defined culture conditions promoted the quality of cardiac reprogramming, and this finding provides new insight into the mechanism of cardiac reprogramming. PMID- 26626176 TI - Lumen Formation Is an Intrinsic Property of Isolated Human Pluripotent Stem Cells. AB - We demonstrate that dissociated human pluripotent stem cells (PSCs) are intrinsically programmed to form lumens. PSCs form two-cell cysts with a shared apical domain within 20 hr of plating; these cysts collapse to form monolayers after 5 days. Expression of pluripotency markers is maintained throughout this time. In two-cell cysts, an apical domain, marked by EZRIN and atypical PKCzeta, is surrounded by apically targeted organelles (early endosomes and Golgi). Molecularly, actin polymerization, regulated by ARP2/3 and mammalian diaphanous related formin 1 (MDIA), promotes lumen formation, whereas actin contraction, mediated by MYOSIN-II, inhibits this process. Finally, we show that lumenal shape can be manipulated in bioengineered micro-wells. Since lumen formation is an indispensable step in early mammalian development, this system can provide a powerful model for investigation of this process in a controlled environment. Overall, our data establish that lumenogenesis is a fundamental cell biological property of human PSCs. PMID- 26626178 TI - Integrated Analysis of Contractile Kinetics, Force Generation, and Electrical Activity in Single Human Stem Cell-Derived Cardiomyocytes. AB - The quantitative analysis of cardiomyocyte function is essential for stem cell based approaches for the in vitro study of human cardiac physiology and pathophysiology. We present a method to comprehensively assess the function of single human pluripotent stem cell-derived cardiomyocyte (hPSC-CMs) through simultaneous quantitative analysis of contraction kinetics, force generation, and electrical activity. We demonstrate that statistical analysis of movies of contracting hPSC-CMs can be used to quantify changes in cellular morphology over time and compute contractile kinetics. Using a biomechanical model that incorporates substrate stiffness, we calculate cardiomyocyte force generation at single-cell resolution and validate this approach with conventional traction force microscopy. The addition of fluorescent calcium indicators or membrane potential dyes allows the simultaneous analysis of contractility and calcium handling or action potential morphology. Accordingly, our approach has the potential for broad application in the study of cardiac disease, drug discovery, and cardiotoxicity screening. PMID- 26626179 TI - Sodium Iodide Symporter PET and BLI Noninvasively Reveal Mesoangioblast Survival in Dystrophic Mice. AB - Muscular dystrophies are a heterogeneous group of myopathies, characterized by muscle weakness and degeneration, without curative treatment. Mesoangioblasts (MABs) have been proposed as a potential regenerative therapy. To improve our understanding of the in vivo behavior of MABs and the effect of different immunosuppressive therapies, like cyclosporine A or co-stimulation-adhesion blockade therapy, on cell survival noninvasive cell monitoring is required. Therefore, cells were transduced with a lentiviral vector encoding firefly luciferase (Fluc) and the human sodium iodide transporter (hNIS) to allow cell monitoring via bioluminescence imaging (BLI) and small-animal positron emission tomography (PET). Non-H2 matched mMABs were injected in the femoral artery of dystrophic mice and were clearly visible via small-animal PET and BLI. Based on noninvasive imaging data, we were able to show that co-stim was clearly superior to CsA in reducing cell rejection and this was mediated via a reduction in cytotoxic T cells and upregulation of regulatory T cells. PMID- 26626180 TI - Recombinant Laminins Drive the Differentiation and Self-Organization of hESC Derived Hepatocytes. AB - Stem cell-derived somatic cells represent an unlimited resource for basic and translational science. Although promising, there are significant hurdles that must be overcome. Our focus is on the generation of the major cell type of the human liver, the hepatocyte. Current protocols produce variable populations of hepatocytes that are the product of using undefined components in the differentiation process. This serves as a significant barrier to scale-up and application. To tackle this issue, we designed a defined differentiation process using recombinant laminin substrates to provide instruction. We demonstrate efficient hepatocyte specification, cell organization, and significant improvements in cell function and phenotype. This is driven in part by the suppression of unfavorable gene regulatory networks that control cell proliferation and migration, pluripotent stem cell self-renewal, and fibroblast and colon specification. We believe that this represents a significant advance, moving stem cell-based hepatocytes closer toward biomedical application. PMID- 26626181 TI - Induced Pluripotent Stem Cells to Model Human Fibrodysplasia Ossificans Progressiva. AB - Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by progressive ossification of soft tissues, for which there is no effective treatment. Mutations in the bone morphogenetic protein (BMP) type I receptor activin receptor-like kinase 2 (ACVR1/ALK2) are the main cause of FOP. We generated human induced pluripotent stem cells (hiPSCs) from FOP patients with the ALK2 R206H mutation. The mutant ALK2 gene changed differentiation efficiencies of hiPSCs into FOP bone-forming progenitors: endothelial cells (ECs) and pericytes. ECs from FOP hiPSCs showed reduced expression of vascular endothelial growth factor receptor 2 and could transform into mesenchymal cells through endothelial-mesenchymal transition. Increased mineralization of pericytes from FOP hiPSCs could be partly inhibited by the ALK2 kinase inhibitor LDN 212854. Thus, differentiated FOP hiPSCs recapitulate some aspects of the disease phenotype in vitro, and they could be instrumental in further elucidating underlying mechanisms of FOP and development of therapeutic drug candidates. PMID- 26626182 TI - Prevention of perioperative vascular prosthetic infection with a novel triple antimicrobial-bonded arterial graft. AB - OBJECTIVE: Previously, we investigated a locally developed technique of bonding arterial grafts with three antimicrobials to protect against early (within 2 weeks) perioperative bacterial contamination encountered occasionally during aortic graft prosthetic reconstruction. Vascular graft infections are classified by their appearance time (early [<4 months] vs late [>4 months] after graft implantation), degree of incorporation into the surrounding vessel wall, connectivity to the postoperative wound, and extent of graft involvement. In the current phase of testing, we evaluated the ability of our novel triple antimicrobial-bonded graft to prevent infection in the first 8 weeks after implantation. METHODS: In nine Sinclair miniature pigs, we surgically implanted a 6-mm vascular Dacron patch graft in the infrarenal abdominal aorta. Five pigs received grafts chemically bonded with a 60-mg/mL solution of rifampin, minocycline, and chlorhexidine, and four pigs received unbonded grafts. Before implantation, the five bonded grafts and three of the unbonded grafts were immersed for 15 minutes in a 2-mL solution containing 1-2 * 107 colony-forming units (CFUs)/mL of Staphylococcus aureus (ATCC 29213); the fourth unbonded graft served as a control. RESULTS: At week 9, all of the grafts were explanted. All S aureus-inoculated bonded grafts (n = 5) showed no bacterial growth. The unbonded, uninoculated graft (n = 1) showed low-level bacterial growth (<1.2 * 103 CFUs); S cohnii spp urealyticus, but not S aureus, was isolated, which suggested accidental direct perioperative contamination. Two pigs that received S aureus inoculated, unbonded grafts were euthanized because of severe S aureus infection (<6.56 * 108 CFUs per graft). Results of histopathologic analysis were concordant with the microbiologic findings. Most intergroup differences were observed in the inflammatory infiltrate in the aortic wall at the site of graft implantation. In all pigs that received bonded grafts, Gram staining showed no bacteria. CONCLUSIONS: Our triple-bonded aortic graft prevented perioperative aortic graft infection for at least 8 weeks in a porcine model. The synergistic antimicrobial activity of this graft was sufficient to prevent and/or eradicate infection during that period. Further studies are needed to assess the graft's ability to combat early-onset vascular graft infection for up to 4 months. PMID- 26626183 TI - Adjuvant therapy of uterine clear cell carcinoma: a review. AB - PURPOSE: Uterine clear-cell carcinoma (UCCC) is a rare subset of type II endometrial carcinoma with a poor prognosis relative to the most common type of endometrioid carcinoma. Due to its rarity, there has been limited direct evidence of the efficacy of specific adjuvant therapy posthysterectomy in women with UCCC. We present a review of current literature regarding adjuvant therapy of uterine clear cell carcinoma. METHODS: We searched for English-language publications through Pubmed using a combination of the following key words: endometrial carcinoma, clear cell carcinoma, recurrence, prognosis, adjuvant therapy, radiation treatment and chemotherapy. Due to the rarity of UCCC, studies were not limited by design or number of patients. RESULTS: There is a paucity of randomized prospective controlled studies focusing on UCCC adjuvant therapy. Findings have largely been derived from retrospective studies of type II endometrial carcinomas or all endometrial cancers as a group. Very few retrospective studies were found to focus on UCCC adjuvant therapy, although certain larger studies did have subset analyses of UCCC patients. CONCLUSIONS: For early stage disease, locoregional radiotherapy, especially vaginal brachytherapy, has evidence of efficacy. The therapeutic gain of radiotherapy may be further improved with the addition of systemic chemotherapy. Evidence for combined radiation therapy with systemic chemotherapy in women with advanced stage UCCC has remained debatable. UCCC-specific studies are needed to determine the best adjuvant therapy for UCCC without the confounding effects of USC and other endometrial cancers. PMID- 26626184 TI - Management of women with epilepsy: from preconception to post-partum. AB - PURPOSE: The physiological changes during pregnancy can significantly alter antiepileptic drug (AED)'s absorption, distribution, metabolism and elimination, thus influencing their plasma concentration. Considering that the risks of using old and new AEDs during pregnancy are still debated, our aim is to review the available evidence on this topic. METHODS: Narrative overview, synthesizing the findings of literature retrieved from searches of computerized databases. RESULTS: The old AEDs generation (benzodiazepines, phenytoin, carbamazepine, phenobarbital and valproic acid) is teratogenic: minor congenital malformations, such as facial dysmorphism and other anomalies, occur in 6-20% of infants exposed to AEDs in utero; this value is two times greater than the value reported in the general population. Major congenital malformations (MCM) such as cleft lip and cleft palate, heart defects (atrial septal defect, Fallot's tetralogy, ventricular septal defect, aortic coarctation, patent ductus arteriosus, and pulmonary stenosis) and urogenital anomalies were estimated to be 4-6% of infants born from mothers treated with AEDs, compared to 2-3% of the general population. CONCLUSION: It is essential to inform women treated with AED that planning pregnancy is necessary, when possible. The problems related to antiepileptic therapy and the possibilities of prenatal diagnosis should be accurately discussed with the patient, when possible before pregnancy: individual circumstances, desire to have children, severity of epilepsy, risks of seizures, family history of congenital malformations and all other potential risk factors must be considered, involving the patient in shared clinical decision-making. PMID- 26626185 TI - Women Like Being Valued for Sex, as Long as it is by a Committed Partner. AB - How do women respond to being valued for sex by their partners? Although research supporting objectification theory suggests that women's reactions to sexual valuation are primarily negative, a separate body of research indicates that women expend significant effort to enhance their sexual appeal. Evolutionary perspectives suggest that whether women are more or less satisfied with partners who value them for sex may depend on how committed those partners are. Being sexually valued by a relatively uncommitted partner may violate women's desire to avoid short-term sexual relationships and thus may be negatively associated with relationship satisfaction. In contrast, being sexually valued by a highly committed partner may positively influence women's relationship satisfaction because it signals to them that they have successfully attracted a long-term relationship partner. Two studies of newly married couples supported these predictions. In Study 1 (N = 109), husbands' sexual valuation was positively associated with marital satisfaction among wives who perceived that those husbands were highly committed, but negatively associated with marital satisfaction among wives who perceived that those husbands were relatively less committed. Study 2 (N = 99) revealed the same pattern for wives (but not husbands) using a likely manifestation of sexual valuation-engaging in frequent sex. These findings join others to demonstrate that interpersonal processes do not have universally positive or negative implications for relationships; rather, their implications depend on the context in which they occur, including contexts that were reproductively beneficial or costly throughout evolutionary history. PMID- 26626186 TI - Food environment and childhood obesity: the effect of dollar stores. AB - In this paper we examine the effect of dollar stores on children's Body Mass Index (BMI). We use a dataset compiled by the Arkansas Center for Health Improvement that reflects a BMI screening program for public school children in the state of Arkansas. We combine propensity score matching with difference-in differences methods to deal with time-invariant as well time-varying unobserved factors. We find no evidence that the presence of dollar stores within a reasonably close proximity of the child's residence increases BMI. In fact, we see an increase in BMI when dollar stores leave a child's neighborhood. Given the proliferation of dollar stores in rural and low-income urban areas, the question of whether dollar stores are contributing to high rates of childhood obesity is policy relevant. However, our results provide some evidence that exposure to dollar stores is not a causal factor. PMID- 26626188 TI - Micro-RNAs in cognition and cognitive disorders: Potential for novel biomarkers and therapeutics. AB - Micro-RNAs (miRNAs) are small regulatory non-coding RNAs involved in the regulation of many biological functions. In the brain, they have distinct expression patterns depending on region, cell-type and developmental stage. Their expression profile is altered by neuronal activation in response to behavioral training or chemical/electrical stimulation. The dynamic changes in miRNA level regulate the expression of genes required for cognitive processes such as learning and memory. In addition, in cognitive dysfunctions such as dementias, expression levels of many miRNAs are perturbed, not only in brain areas affected by the pathology, but also in peripheral body fluids such as serum and cerebrospinal fluid. This presents an opportunity to utilize miRNAs as biomarkers for early detection and assessment of cognitive dysfunctions. Further, since miRNAs target many genes and pathways, they may represent key molecular signatures that can help understand the mechanisms of cognitive disorders and the development of potential therapeutic agents. PMID- 26626187 TI - Association of osteoporosis and bone medication with the periodontal condition in elderly women. AB - This study investigated whether osteoporosis and its treatment may affect periodontal condition in elderly women. The findings highlighted that women with osteoporosis had a higher chance to present severe periodontitis than women with normal bone mineral density (BMD), particularly those who were not treated for osteoporosis. INTRODUCTION: This study investigated whether osteoporosis increases the frequency and severity of chronic periodontitis in elderly women and evaluated the influence of vitamin D and osteoporosis treatment in the periodontal condition. METHODS: In this cross-sectional study, elderly women were selected among 1266 subjects evaluated for lumbar spine and proximal femur bone mineral density (BMD) using dual energy X-ray absorptiometry. Sociodemographic, clinical characteristics, and complete periodontal examination were recorded. Serum 25-hydroxyvitamin D levels were measured by chemiluminescence. RESULTS: Forty-eight elderly women with normal BMD and 86 with osteoporosis were selected. Women with osteoporosis presented higher frequency of sites with clinical attachment level >=6 mm (p = 0.003) and gingival recession >=3 mm (p = 0.002) than those with normal BMD and were more than twice as likely to present severe periodontitis (odds ratio (OR) = 2.49, 95 % CI [1.14 to 5.43]). Osteoporotic women who were not treated for the condition had more chance to present severe periodontitis (OR = 3.16, 95 % CI [1.28 to 7.82]) than those who did use bisphosphonates (OR = 2.04, 95 % CI [0.85 to 4.89]). Among the participants who presented low levels of vitamin D, those with osteoporosis exhibited a higher chance to present severe periodontitis than those with normal BMD (p = 0.027), but the association between vitamin D levels and osteoporosis was not statistically significant after adjustment (p = 0.198). CONCLUSIONS: Elderly women with osteoporosis have a greater chance to present periodontitis, with higher severity than those with normal BMD. Osteoporosis treatment provides protection for periodontitis. PMID- 26626189 TI - Modulation of mitochondrial dysfunction in neurodegenerative diseases via activation of nuclear factor erythroid-2-related factor 2 by food-derived compounds. AB - Oxidative stress and mitochondrial dysfunction are early events in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Mitochondria are important key players in cellular function based on mitochondrial energy production and their major role in cell physiology. Since neurons are highly depending on mitochondrial energy production due to their high energy demand and their reduced glycolytic capacity mitochondrial dysfunction has fatal consequences for neuronal function and survival. The transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2) is the major regulator of cellular response to oxidative stress. Activation of Nrf2 induces the transcriptional regulation of antioxidant response element (ARE) dependent expression of a battery of cytoprotective and antioxidant enzymes and proteins. Moreover, activation of Nrf2 protects mitochondria from dysfunction and promotes mitochondrial biogenesis. Therefore, the Nrf2/ARE pathway has become an attractive target for the prevention and treatment of oxidative stress-related neurodegenerative diseases. Small food-derived inducers of the Nrf2/ARE pathway including l-sulforaphane from broccoli and isoliquiritigenin from licorice displayed promising protection of mitochondrial function in models of oxidative stress and neurodegenerative diseases and represent a novel approach to prevent and treat aging-associated neurodegenerative diseases. PMID- 26626191 TI - Glycyrrhizic acid attenuates stem cell-like phenotypes of human dermal papilla cells. AB - BACKGROUND: Although the growth of unwanted hair or hirsutism is a harmless condition, many people find it bothersome and embarrassing. Maintaining stem cell features of dermal papilla cells is a critical biological process that keeps the high rate of hair growth. Glycyrrhizic acid has been reported to impair hair growth in some studies; however, its underlying mechanism has not yet been investigated. PURPOSE: This study aimed to explore the effect and underlying mechanism of glycyrrhizic acid on stemness of human dermal papilla cells. STUDY DESIGN/METHODS: The stem cell molecular markers, epithelial to mesenchymal markers and Wnt/beta-catenin-associated proteins of human dermal papilla cell line and primary human dermal papilla cells were analysed by western blot analysis and immunocytochemistry. RESULTS: The present study demonstrated that glycyrrhizic acid significantly depressed the stemness of dermal papilla cells in dose- and time-dependent manners. Clonogenicity and stem cell markers in the glycyrrhizic acid-treated cells were found to gradually decrease in the culture in a time-dependent manner. Our results demonstrated that glycyrrhizic acid exerted the stem cell suppressing effects through the interruption of ATP dependent tyrosine kinase/glycogen synthase kinase3beta-dependent mechanism which in turn down-regulated the beta-catenin signalling pathway, coupled with decreased its down-stream epithelial-mesenchymal transition and self-renewal transcription factors, namely, Oct-4, Nanog, Sox2, ZEB1 and Snail. The effect of glycyrrhizic acid on the reduction of stem cell features was also observed in the primary dermal papilla cells directly obtained from human hair follicles. CONCLUSION: These results revealed a novel molecular mechanism of glycyrrhizic acid in regulation of dermal papilla cells and provided the evidence supporting the use of this compound in suppressing the growth of unwanted hair. PMID- 26626192 TI - The authenticity and quality of Rhodiola rosea products. AB - BACKGROUND: Rhodiola rosea L. Crassulaceae, root (Golden Root, Arctic Root) is a high-value herbal medicinal product, registered in the UK for the treatment of stress-induced fatigue, exhaustion and anxiety based on traditional use and used throughout Europe as a herbal medicinal product for similar indications. Numerous unregistered supplements are also available. There are several Chinese species used in traditional Chinese medicine (TCM), including Rhodiola crenulata (Hook.f. & Thomoson) that is believed to be a common adulterant in the R. rosea value chain. AIMS: The project is embedded in a larger study aiming to investigate the diverse value chains that lead to the production of R. rosea as an herbal medicinal product or supplement. Here we focus on a comparison of the quality of the finished products and assess any phytochemical variation between products registered under the Traditional Herbal Medicine Products Directive (THMPD) and products obtained from the market without any registration (i.e. generally unlicensed supplements). Our key aim is to establish the extent of the problem in terms of adulteration of consumer products claiming to contain R. rosea (or R. crenulata). METHODS: Approximately 40 commercial products (granulated powders and extracts) were sourced from different suppliers. We analysed these samples using high performance thin layer chromatography (HPTLC), mass spectrometry (MS) and (1)H NMR spectroscopy coupled with multi-variate analysis software following a method previously developed by our group for the analysis of turmeric products. RESULTS: We investigate the phytochemistry of the different species and assess the potential of R. crenulata as an adulterant at the end of the R. rosea value chains. The consistency of the products varies significantly. Approximately one fifth of commercial products that claimed to be R. rosea did not contain rosavin (the key reference markers used to distinguish R. rosea from related species). Moreover some products appeared not to contain salidroside, another marker compound found in other Rhodiola species. Approximately 80% of the remaining commercial products were lower in rosavin content than the registered products and appeared to be adulterated with other Rhodiola species. CONCLUSIONS: The variation in phytochemical constituents present in Rhodiola products available to European buyers via the internet and other sources is a major cause for concern. Adulteration with different species, and other sometimes unknown adulterants, appears to be commonplace. Good quality systems and manufacturing practices, including those required under the THMPD, enable consumers to have confidence that products are authentic and meet a high specification for quality and safety. PMID- 26626190 TI - Acetyl salicylic acid attenuates cardiac hypertrophy through Wnt signaling. AB - Ventricular hypertrophy is a powerful and independent predictor of cardiovascular morbid events. The vascular properties of low-dose acetyl salicylic acid (aspirin) provide cardiovascular benefits through the irreversible inhibition of platelet cyclooxygenase 1; however, the possible anti-hypertrophic properties and potential mechanism of aspirin have not been investigated in detail. In this study, healthy wild-type male mice were randomly divided into three groups and subjected to transverse aortic constriction (TAC) or sham operation. The TAC operated mice were treated with the human equivalent of low-dose aspirin (10 mg.kg(-1).d(-1)); the remaining mice received an equal amount of phosphate buffered saline with 0.65% ethanol, which was used as a vehicle. A cardiomyocyte hypertrophy model induced by angiotensin II (10 nmol.L(-1)) was treated with the human equivalent of low (10 or 100 MUmol.L(-1)) and high (1000 MUmol.L(-1)) aspirin concentrations in plasma. Changes in the cardiac structure and function were assessed through echocardiography and transmission electron microscopy. Gene expression was determined through RT-PCR and western blot analysis. Results indicated that aspirin treatment abrogated the increased thickness of the left ventricular anterior and posterior walls, the swelling of mitochondria, and the increased surface area in in vivo and in vitro hypertrophy models. Aspirin also normalized the upregulated hypertrophic biomarkers, beta-myosin heavy chain (beta MHC), atrial natriuretic peptide (ANP), and b-type natriuretic peptide (BNP). Aspirin efficiently reversed the upregulation of beta-catenin and P-Akt expression and the TAC- or ANG II-induced downregulation of GSK-3beta. Therefore, low-dose aspirin possesses significant anti-hypertrophic properties at clinically relevant concentrations for anti-thrombotic therapy. The downregulation of beta catenin and Akt may be the underlying signaling mechanism of the effects of aspirin. PMID- 26626194 TI - Reflections on Caring: Watching a Mother. PMID- 26626195 TI - Eugenic World Building and Disability: The Strange World of Kazuo Ishiguro's Never Let Me Go. AB - A crucial challenge for critical disability studies is developing an argument for why disabled people should inhabit our democratic, shared public sphere. The ideological and material separation of citizens into worthy and unworthy based on physiological variations imagined as immutable differences is what I call eugenic world building. It is justified by the idea that social improvement and freedom of choice require eliminating devalued human traits in the interest of reducing human suffering, increasing life quality, and building a more desirable citizenry. In this essay, I outline the logic of inclusive and eugenic world building, define and explain the role of the "normate" in eugenic logic, and provide a critical disability studies reading of the 2005 novel Never Let Me Go by Kazuo Ishiguro and its 2010 film adaptation. I argue that the ways of being in the world we think of as disabilities must be understood as the natural variations, abilities, and limitations inherent in human embodiment. When this happens, disability will be understood not as a problem to be eliminated but, rather, as a valid way of being in the world that must be accommodated through a sustaining and sustainable environment designed to afford access for a wide range of human variations. PMID- 26626193 TI - In vitro and in vivo investigations on the antitumour activity of Chelidonium majus. AB - BACKGROUND: Chelidonium majus L. (Papaveraceae) (greater celandine) is a medicinal herb that is widely spread in Europe. Antitumoural activity has been reported for C. majus extracts. HYPOTHESIS/PURPOSE: To investigate the antitumour activity of a C. majus extract in vitro and in vivo. STUDY DESIGN: Cytotoxic effects of C. majus extracts were evaluated on human cancer cell lines, i.e. PANC 1 (pancreas cancer), HT-29 (colon cancer), MDA-MB-231 (breast cancer), PC-EM005 and PC-EM002 (primary endometrium cancer cells), and PANC02 (murine pancreatic adenocarcinoma cells). A preliminary in vivo study was performed to evaluate the effect of a defatted C. majus extract and Ukrain(TM) in a highly metastatic murine pancreatic model. METHODS: Chelidonium majus L. herb containing 1.26% (dry weight) of total alkaloids expressed as chelidonine was used to prepare an 80% ethanolic extract (CM2). This crude extract was then defatted with n-hexane, resulting in a defatted C. majus extract (CM2B). Cytotoxic effects of the two extracts (CM2 and CM2B) were evaluated on human and murine cell lines in vitro. CM2B and Ukrain(TM) were evaluated in a highly metastatic murine pancreatic model. RESULTS: Four main benzylisoquinoline alkaloids were identified in CM2B, i.e. chelidonine, sanguinarine, chelerythrine and protopine, using HPLC-UV. CM2 showed a high cytotoxic activity against PANC-1 (IC50, 20.7 ug/ml) and HT-29 (IC50, 20.6 ug/ml), and a moderate cytotoxic activity against MDA-MB-231 (IC50, 73.9 ug/ml). CM2 as well as CM2B showed a moderate to high cytotoxic activity against the PANC02 cell line (IC50, 34.4 and 36.0 ug/ml). Low to almost no cytotoxic effect was observed on primary endometrium cancer cells PC-EM005, PC EM002 and on normal fibroblast cells 3T3, when treated with CM2B. Significantly less metastases were counted in mice treated with 1.2 mg/kg CM2B, but not with 3.6 mg/kg Ukrain(TM), compared to the control group. The extract, however, did not affect the weight of the primary tumours. PMID- 26626196 TI - The first perforating branch of the deep femoral artery: A reliable recipient vessel for vascularized fibular grafts: An anatomical study. AB - INTRODUCTION: Although the perforating branches of the deep femoral artery have been introduced as recipient vessels for vascularized fibular grafts in the treatment of osteonecrosis of the femoral head, comprehensive knowledge of the related anatomy is deficient. The aims of this study were to provide detailed anatomical data for the perforating branches of the deep femoral artery and validate their usefulness as recipient vessels for vascularized fibular grafts. MATERIALS AND METHODS: Anatomical dissection was performed on 11 fresh human cadaveric lower extremities. The number, locations, and diameters of the perforating branches were documented. The topographic relationships with the vastus ridge and the tendinous insertion of the gluteus maximus were clarified. The diameters of the perforating branches were compared with those of the ascending branch of the lateral circumflex femoral and the peroneal arteries. RESULTS: The mean number of perforating branches was 3.5. The mean distances from the vastus ridge to the first, second, and third perforating branches were 8.1, 13.7, and 20.4 cm, respectively. The first perforating branch was always located medial to the tendinous insertion of the gluteus maximus, whereas the second perforating branch was always located distal to the gluteus maximus. The mean diameters of the first, second, third, and fourth perforating branches were 3.1, 2.3, 1.6, and 1.2 mm, respectively. The mean diameters of the ascending branch of the lateral circumflex femoral and the peroneal arteries were 2.0 and 3.6 mm, respectively. CONCLUSION: The first perforating branch of the deep femoral artery is an appropriate alternative recipient vessel for vascularized fibular grafts in the treatment of osteonecrosis of the femoral head. It has a very consistent anatomy with a suitable location and diameter for anastomosis of the peroneal artery. PMID- 26626199 TI - Transfer of the radial branch of the superficial radial nerve to the sensory branch of the ulnar nerve for sensory restoration after C7-T1 brachial plexus injury. AB - Previously, we have reconstructed the motor function of patients with C7-T1 brachial plexus palsies through combined nerve and tendon transfers. However, these patients lose not only the motor function of the hand but also the sensation on the ulnar side of the hand. Without sensory recovery, the injured hand may be further damaged, particularly by burns in this contact zone. Therefore, we described a technique to restore the sensation at the ulnar aspect of the hand by performing a transfer of the radial branch of the superficial radial nerve to the sensory branch of the ulnar nerve. PMID- 26626197 TI - Thin melanomas (<1 mm) and new NICE guidance for sentinel lymph node biopsy. PMID- 26626198 TI - The marginal branch triangle: Anatomic reference for its location and preservation during cosmetic surgery. AB - BACKGROUND: Many studies have been dedicated toward bettering the understanding of the anatomy of this branch and the relative danger zone. However, most of these articles have focused on identifying the location of this branch based on its trajectory and associations with deep structures, causing some difficulties for aesthetic surgeons to identify its location during facial aesthetic surgery. Here, we present the concept of the marginal nerve triangle; its contents, relations and clinical applications in cosmetic surgery are discussed. METHODS: This is an anatomical study performed using 64 hemifaces from 32 Peruvian fresh cadavers (25 men and 7 women). They were dissected manually and observed macroscopically by the authors. The marginal nerve and the related structures were dissected from its origin to the terminal branches and associated with the described triangular area. RESULTS: The marginal branch of the facial nerve was found to lie in the described triangle in all cases. This is a triangular area formed by the intersection of three points located at the lateral commissure of the mouth, the mastoid apophysis and a point located over the anterior border of the extracellular matrix (ECM) muscle with a line which intersects the lateral commissure of the mouth and the mandibular groove. CONCLUSIONS: The trajectory of the marginal and cervical branches of the facial nerve can be reliably and easily found at the described triangle following the reference points. This study will help guide surgeons to these branches of the facial nerve as it applies to aesthetic surgery. PMID- 26626200 TI - DNA studies of newly synthesized heteroleptic platinum(II) complexes [Pt(bpy)(iip)](2+) and [Pt(bpy)(miip)](2.). AB - Two new mono-nuclear heteroleptic platinum(II) complexes, [Pt(bpy)(iip)](PF6)2 (1) and [Pt(bpy)(miip)](PF6)2.2H2O (2) (bpy is 2,2'-bipyridine; iip is 2-(imidazo 4-yl)-1H-imidazo[4,5-f] [1,10] phenanthroline; miip is 2-(1-methylimidazo-2-yl) 1H-imidazo[4,5-f] [1, 10] phenanthroline), have been synthesized and fully characterized by CHN analysis, electrospray ionization and MALDI-TOF mass spectrometry, (1)H NMR, FT-IR (ATR), and UV-Vis spectrophotometer. Cytotoxicity, ability to inhibit DNA transcription and DNAse activity of the complexes were studied. The DNA-binding behaviors of both complexes have also been studied by spectroscopic methods, cyclic voltammetry and viscosity measurements. Both complexes showed cytotoxic properties and 2 was more cytotoxic than 1. DNA transcription was inhibited upon increasing concentrations of both complexes. The complex 2 was found to be a better inhibitor than 1. The same pattern can be seen in the DNAse profile of the complexes. In addition, 2 was found to promote cleavage of pBR322 DNA at a lower concentration than 1. The spectroscopic, electrochemical and viscometric results indicate that both complexes show some degree of binding to DNA in an intercalative mode, resulting in intrinsic binding constants K b = 3.55 +/- 0.6 * 10(4) M(-1) and 7.01 +/- 0.9 * 10(4) M(-1) for 1 and 2, respectively. The difference in the DNA-binding affinities of 1 and 2 may presumably be explained by the methylated imidazole nitrogen atom that makes the compound more hydrophobic and gives better intercalative binding ability to DNA's hydrophobic environment. PMID- 26626202 TI - Functional polymorphisms of Monocyte Chemoattractant Protein-1 gene and Pott's disease risk. AB - OBJECTIVE: Monocyte Chemoattractant Protein-1 (MCP-1/CCL2), a key player in immune-mediated responses against Mycobacterium tuberculosis, is encoded by a polymorphic gene. Functionally relevant polymorphic variations in the MCP-1 gene have been associated with both susceptibility to and protection against tuberculosis-related disorders. Here, we investigated the potential impact of some of these polymorphisms on Pott's disease risk in a patient cohort from Algeria. METHODS: DNA from 132 Algerian patients with exclusive Pott's disease and 204 healthy controls, included under a case-control design, were analyzed for the MCP1 -2518A/G (rs1024611), -362G/C (rs2857656) and int1del554-567 (rs3917887) polymorphisms. PHASE software was used for haplotype reconstruction. Genetic associations were examined using chi-square tests. RESULTS: We found that the rs1024611 -2518 GG, rs2857656 -362 CC and rs3917887 int1del554-567 del/del homozygous genotypes each were significantly more prevalent in patients than in controls (respective corrected p value [Pc]=0.01, 0.04 and 0.04) Haplotype distribution profile further confirmed this, as the homozygous combination of GCdel haplotype was also found with raised susceptibility to Pott's disease (Pc=0.03). CONCLUSION: Our findings confirm and replicate the recent data from China (which dealt essentially with rs1024611 and rs2857656) and also reinforce them by providing trans-ethnic evidence and extending the genetic association to the rs3917887. PMID- 26626203 TI - Clinical outcomes of combined necrotizing pancreatitis versus extrapancreatic necrosis alone. AB - INTRODUCTION: Extrapancreatic necrosis (EPN) alone, i.e., in the absence of pancreatic parenchyma necrosis has gradually come to be regarded as a separate entity of acute necrotizing pancreatitis (ANP). However, data regarding the prognostic significance of EPN are quite limited, and the outcomes of interventions for patients with EPN alone are not well elucidated. The aim of this study was to explore the differences in the outcomes of patients with EPN alone and patients with both the pancreatic parenchyma and extrapancreatic necrosis (combined necrosis). METHODS: From January 2009 to December 2013, a total of 334 patients with ANP who had received interventions in the West China Hospital in China were included. Based on the extent of necrosis as assessed with contrast-enhanced CT, the patients were divided into Group 1 (n = 285) in which the necrosis involved both the pancreatic parenchyma and extrapancreatic tissues (combined necrosis) and Group 2 (n = 49) in which the necrosis involved only the extrapancreatic tissues. Additionally, Group 3 included 443 patients with interstitial pancreatitis who were also included in the analyses. The demographic characteristics, support treatment information, organ failure information, infection necrosis, persistent systemic inflammatory response syndrome (SIRS) in the first week of onset, CT severity index, and intervention types, as well as the postoperative stay lengths, ICU utility, and complications were collected and compared. RESULTS: Compared with the patients in Group 1, the patients in Group 2 suffered less persistent SIRS in the first week of onset (12/24.5% vs. 145/50.9%; P < 0.05), less persistent organ failure (6/12.2% vs. 95/33.3%; P < 0.05), less persistent multiple organ failure (3/6.1% vs. 67/23.5%; P < 0.05), and less bacteremia (5/10.2% vs. 107/37.5%; P < 0.001). The intervention types were significantly different between the two groups (P < 0.001); initial open necrosectomy was performed in 174/61.6% and 8/16.3% of the patients in Groups 1 and 2, respectively, and initial percutaneous catheter drainage (PCD) was performed in 73/25.6% and 29/59.2% of the patients in the two respective groups. Second open necrosectomies following PCD were required in 61/83.5% and 9/31.0% of the patients in Groups 1 and 2, respectively (P < 0.001). A greater number of patients in Group 1 were diagnosed with infected necrosis (204/71.6% vs. 10/20.4%; P < 0.001) and had to be sent to the ICU for further postoperative care (221/77.5% vs. 23/46.9%; P < 0.001). The postoperative stay was longer for Group 1 (median: 43.0 vs. 26.5 days; P < 0.001). Residual necrotic tissue or abscess was the most common postoperative complication in both groups. The mortality was higher in Group 1 (52/18.2% vs. 1/2.1%; P < 0.05). Compared with the patients in Group 2, the patients with interstitial pancreatitis exhibited milder courses and better outcomes. Subgroup comparisons with Group 1 indicated that early multiple organ failure was significantly associated with higher mortality. CONCLUSION: The patients with EPN alone exhibited significantly better prognoses than those with combined necrosis, and EPN alone should be regarded as a separate group of acute necrotizing pancreatitis. Open necrosectomy can be avoided in the majority of patients with EPN alone, who receive PCD as the initial first intervention. PMID- 26626201 TI - Mast cells and histamine alter intestinal permeability during malaria parasite infection. AB - Co-infections with malaria and non-typhoidal Salmonella serotypes (NTS) can present as life-threatening bacteremia, in contrast to self-resolving NTS diarrhea in healthy individuals. In previous work with our mouse model of malaria/NTS co-infection, we showed increased gut mastocytosis and increased ileal and plasma histamine levels that were temporally associated with increased gut permeability and bacterial translocation. Here, we report that gut mastocytosis and elevated plasma histamine are also associated with malaria in an animal model of falciparum malaria, suggesting a broader host distribution of this biology. In support of mast cell function in this phenotype, malaria/NTS co infection in mast cell-deficient mice was associated with a reduction in gut permeability and bacteremia. Further, antihistamine treatment reduced bacterial translocation and gut permeability in mice with malaria, suggesting a contribution of mast cell-derived histamine to GI pathology and enhanced risk of bacteremia during malaria/NTS co-infection. PMID- 26626204 TI - Endoscopic retrograde cholangiopancreatography-related adverse events in patients with type 1 autoimmune pancreatitis. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is frequently performed for the diagnosis and treatment of type 1 autoimmune pancreatitis (AIP). However, the prevalence of ERCP-related adverse events in patients with type 1 AIP has not been evaluated. We aimed to clarify the feasibility of ERCP in patients with type 1 AIP. METHODS: We retrospectively reviewed 82 consecutive ERCP procedures performed in patients with type 1 AIP from 2004 to 2014 in one university hospital and three tertiary-care referral centers. One hundred four ERCP procedures in chronic pancreatitis and 1123 in non-AIP cohort were enrolled as control groups. We compared the incidence of post-ERCP pancreatitis (PEP) between type 1 AIP and control groups. We evaluated the incidence of ERCP-related adverse events and various predictive factors for hyperamylasemia after ERCP. RESULTS: Pancreatography and cholangiography by ERCP were obtained in 78 (95.1%) and 76 (92.7%) patients, respectively. The incidence of PEP, cholangitis, and bleeding was 1.2% (1/82), 0%, and 1.2%, respectively. PEP occurred in type 1 AIP patient with diffuse parenchymal imaging, and the severity was mild. The incidences of PEP were 2.9% (3/104) and 5.4% (61/1123) in chronic pancreatitis and normal cohort, respectively. The incidence of PEP was slightly lower in type 1 AIP than non-AIP cohort (1.2% vs 5.8%, p = 0.119). There were no significant predictive factors for hyperamylasemia after ERCP in type 1 AIP. CONCLUSIONS: The incidence of ERCP-related adverse events is low in patients with type 1 AIP. ERCP related procedures are feasible in the diagnosis and treatment of AIP. PMID- 26626205 TI - Response to pomalidomide plus fixed low-dose dexamethasone in a case of secondary plasma cell leukaemia. AB - This is, to our knowledge, the first reported case of secondary Plasma Cell Leukemia that was successfully by pomalidomide plus fixed low-dose dexamethasone. Pomalidomide at a dosage of 4 mg orally on days 1-21 of repeated 28-day cycles associated with fixed low-dose dexamethasone (40 mg on days 1, 8, 15 and 22 of each 28-day cycle), outside of the clinical trials, was started as a final attempt. After the fourth course, the patient achieved an interesting response that included a significant reduction of circulating plasma cells from the peripheral blood, a very important decrease of the M-component, and normalization of haematological value. The toxicities were acceptable. The time to best response was 4 months. PMID- 26626206 TI - Small interfering RNA silencing of interleukin-6 in mesenchymal stromal cells inhibits multiple myeloma cell growth. AB - Studies demonstrated that mesenchymal stromal cells (MSC) from bone marrow stroma produced high concentration of interleukin-6 (IL-6) that promoted multiple myeloma cell growth. In view of the failure of IL-6 monoclonal antibody therapy to demonstrate substantial clinical responses in early clinical trials, more effective methods are needed in order to disrupt the favourable microenvironment provided by the bone marrow stroma. In this study, we evaluated the short interfering RNA (siRNA)-mediated silencing of IL-6 in MSC and the efficacy of these genetically modified MSC, with IL-6 suppression, on inhibition of U266 multiple myeloma cell growth. IL-6 mRNA and protein were significantly suppressed by 72h post IL-6 siRNA transfection without affecting the biological properties of MSC. Here we show significant inhibition of cell growth and IL-6 production in U266 cells co-cultured with MSC transfected with IL-6 siRNA when compared to U266 cells co-cultured with control MSC. We also show that the tumour volume and mitotic index of tumours in nude mice co-injected with U266 and MSC transfected with IL-6 siRNA were significantly reduced compared to tumours of mice co injected with control MSC. Our results suggest potential use of RNA interference mediated therapy for multiple myeloma. PMID- 26626208 TI - Schwannomas with pseudoglandular elements: clinicopathologic study of 61 cases. AB - Schwannomas are benign neoplasms of peripheral nerve sheath. A number of morphologic variants of schwannoma have been described. The pseudoglandular variant is very rare. We retrieved and reviewed hematoxylin and eosin slides of all cases of schwannoma reported between 2007 and 2014 to look for pseudoglandular elements. Pseudoglandular cystic spaces were seen in 61 (6.3%) of 971 schwannomas diagnosed during the study period. Of these 61 cases, 56 (91.8%) were located in the spinal nerve roots. The majority (60.6%) were male. Mean age in these 61 cases was 41 years. Mean tumor size was 3.5 cm. All 61 cases showed typical Antoni A and Antoni B areas with multiple pseudoglandular cystic spaces scattered throughout. These areas were lined by flat to cuboidal cells which showed positivity for immunohistochemical stain S-100 and were negative for epithelial membrane antigen. An average of 7 pseudoglandular cystic spaces was noted per case. In conclusion, pseudoglandular cystic spaces are lined by Schwann cells and most likely represent degenerative changes in schwannoma probably degenerated Verocay bodies. They are rare albeit well-defined features seen in a significant though small number of schwannomas. It is important not to mistake them for other neoplasms. Larger studies are required to determine predilection of these changes in spinal nerve root schwannomas as seen in our series. PMID- 26626207 TI - Efficacy and safety of lenalidomide treatment in multiple myeloma (MM) patients- Report of the Polish Myeloma Group. AB - The aim of the multi-centre retrospective study was to evaluate the efficacy and safety of lenalidomide (LEN) therapy in patients with resistant or relapsed multiple myeloma (MM) as well as in patients with stable disease (LEN used due to neurological complications). The primary endpoint of this study was an overall response rate (ORR). The secondary endpoints were as follows: time to progression (TTP), overall survival (OS) and the safety of drug use. Data were collected in 19 centres of the Polish Multiple Myeloma Study Group. The study group consisted of 306 subjects: 153 females and 153 males. In 115 patients (38.8%, group A), a resistant myeloma was diagnosed; in 135 (44.1%, group B) a relapse, and in 56 (18.3%, group C) a stable disease were stated. In 92.8% of patients, LEN+DEX combination was used; in remaining group, LEN monotherapy or a combination therapy LEN+bortezomib or LEN+bendamustine and other were used. In the entire study group, ORR was 75.5% (including 12.4% patients achieving complete remission [CR] or stringent CR [sCR]). Median time to progression (TTP) was 20 months. Median overall survival (OS) was 33.3 months. The regression model for "treatment response" was on the borderline of statistical significance (p=0.07), however the number of LEN treatment cycles >= 6 (R(2)=17.2%), baseline LDH level (R(2)=1.1%) and no ASCT use (R(2)=1.7%) where the factors most affecting treatment response achievement. The regression model for dependant variable--"overall survival"--was statistically significant (p=0.0000004). Factors with the most impact on OS were as follows: number of LEN cycles treatment >= 6 (R(2)=16.7%), treatment response achievement (R(2)=6.9%), beta-2-microglobulin (beta-2-M) level (R(2)=4.8%), renal function (R(2)=3.0%) and lack of 3/4 grade adverse events (R(2)=1.4%). SUMMARY: LEN is an effective and safe therapeutic option, even in intensively treated resistant and relapsed MM patients, as well as in patients with stable disease and previous treatment-induced neurological complications. In particular, the number of LEN treatment cycles >= 6 was the factor which affected treatment response achievement the most, together with an important impact on OS. PMID- 26626209 TI - Pleomorphic hyalinizing angiectatic tumor revisited: all tumors manifest typical morphologic features of myxoinflammatory fibroblastic sarcoma, further suggesting 2 morphologic variants of a single entity. AB - We describe 9 cases of pleomorphic hyalinizing angiectatic tumor (PHAT). Recently described TGFBR3 and MGEA5 gene rearrangements in these tumors have confirmed the long-hypothesized link between PHAT and another soft tissue entity, the myxoinflammatory fibroblastic sarcoma (MIFS). Myxoinflammatory fibroblastic sarcoma and PHAT share the same translocation and in addition have a very similar clinical presentation. However, to our best knowledge, no study has ever addressed the striking morphologic similarities between MIFS and PHAT. Our findings based on histological criteria suggest that most, if not all, tumors diagnosed as PHAT might, in fact, represent examples of MIFS that, in addition to a conventional MIFS morphology, manifest aberrant angiectatic hyalinized vessels. PMID- 26626210 TI - Global Vaccine and Immunization Research Forum: Opportunities and challenges in vaccine discovery, development, and delivery. AB - The World Health Organization, the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and the Bill & Melinda Gates Foundation convened the first Global Vaccine and Immunization Research Forum (GVIRF) in March 2014. This first GVIRF aimed to track recent progress of the Global Vaccine Action Plan research and development agenda, identify opportunities and challenges, promote partnerships in vaccine research, and facilitate the inclusion of all stakeholders in vaccine research and development. Leading scientists, vaccine developers, and public health officials from around the world discussed scientific and technical challenges in vaccine development, research to improve the impact of immunization, and regulatory issues. This report summarizes the discussions and conclusions from the forum participants. PMID- 26626211 TI - Worldwide rabies deaths prevention--A focus on the current inadequacies in postexposure prophylaxis of animal bite victims. AB - The World Health Organization reports that over 60,000 humans die of rabies annually, worldwide. Most occur in remote regions of developing countries. Almost all victims received no postexposure rabies prophylaxis (PEP). There are no facilities or health personnel able to provide it in many areas where the disease is prevalent. A first approach to correct this problem would be by extending provision of modern PEP to areas where human rabies is most prevalent. PMID- 26626212 TI - Efficacy of a new bivalent vaccine of porcine circovirus type 2 and Mycoplasma hyopneumoniae (FosteraTM PCV MH) under experimental conditions. AB - The objective of this study was to evaluate the efficacy of a new bivalent vaccine (FosteraTM PCV MH, Zoetis) of porcine circovirus type 2 (PCV2) and Mycoplasma hyopneumoniae in growing pigs under experimental conditions. A total of 80 pigs were randomly divided into 8 groups (10 pigs per group). The pigs were administered the bivalent vaccine intramuscularly as a 2.0 mL dose at 21 days of age based on the manufacturer's instructions. Three weeks after vaccination, the pigs were inoculated with either PCV2 (intranasal route) or M. hyopneumoniae (intratracheal route) or both. Regardless of the type of inoculation, vaccinated pigs after challenge exhibited effective reduction of clinical signs, PCV2 viremia levels and mycoplasma nasal shedding, and lung and lymphoid lesion when compared to unvaccinated challenged pigs. Vaccinated challenged pigs had significantly higher (P<0.05) levels of PCV2-specific neutralizing antibodies, and numbers of PCV2-and M. hyopneumoniae-specific interferon-gamma secreting cells compared to unvaccinated challenged pigs. This study demonstrates that the bivalent vaccine is able to protect pigs against either PCV2 or M. hyopneumoniae infection or both based on clinical, microbiological, immunological, and pathological evaluation. PMID- 26626213 TI - Brucella suis strain 2 vaccine is safe and protective against heterologous Brucella spp. infections. AB - Brucellosis is a wide spread zoonotic disease that causes abortion and infertility in mammals and leads to debilitating, febrile illness in humans. Brucella abortus, Brucella melitensis and Brucella suis are the major pathogenic species to humans. Vaccination with live attenuated B. suis strain 2 (S2) vaccine is an essential and critical component in the control of brucellosis in China. The S2 vaccine is very effective in preventing brucellosis in goats, sheep, cattle and swine. However, there are still debates outside of China whether the S2 vaccine is able to provide protection against heterologous virulent Brucella species. We investigated the residual virulence, immunogenicity and protective efficacy of the S2 vaccine in BALB/c mice by determining bacteria persistence in spleen, serum antibody response, cellular immune response and protection against a heterologous virulent challenge. The S2 vaccine was of low virulence as there were no bacteria recovered in spleen four weeks post vaccination. The vaccinated mice developed Brucella-specific IgG in 2-3 weeks, and a burst production of IFN gamma at one week as well as a two-fold increase in TNF-alpha production. The S2 vaccine protected mice from a virulent challenge by B. melitensis M28, B. abortus 2308 and B. suis S1330, and the S2 vaccinated mice did not develop any clinical signs or tissue damage. Our study demonstrated that the S2 vaccine is of low virulence, stimulates good humoral and cellular immunity and protects animals against infection by heterologous, virulent Brucella species. PMID- 26626214 TI - Intraoperative Optical Biopsy during Robotic Assisted Radical Prostatectomy Using Confocal Endomicroscopy. AB - PURPOSE: Intraoperative optical biopsy technologies may aid in the identification of important anatomical landmarks and improve surgical outcomes of robotic assisted radical prostatectomy. We evaluate the feasibility of confocal laser endomicroscopy during robotic assisted radical prostatectomy. MATERIALS AND METHODS: A total of 21 patients with biopsy proven prostate cancer scheduled for robotic assisted radical prostatectomy were recruited. After intravenous administration of fluorescein 15 patients underwent in vivo intraoperative confocal laser endomicroscopy of prostatic and periprostatic structures using a 2.6 or 0.85 mm imaging probe. Standard robotic instruments were used to grasp and maneuver the confocal laser endomicroscopy probes for image acquisition. Confocal laser endomicroscopy imaging was performed ex vivo on fresh prostate specimens from 20 patients. Confocal video sequences acquired in vivo and ex vivo were reviewed and analyzed, with additional image processing using a mosaicing algorithm. Processed confocal images were compared with standard hematoxylin and eosin analysis of imaged regions. RESULTS: Confocal laser endomicroscopy was successfully integrated with robotic surgery, including co-registration of confocal video sequences with white light and probe handling with standard robotic instrumentation. Intraoperative confocal laser endomicroscopy imaging of the neurovascular bundle before and after nerve sparing dissection revealed characteristic features including dynamic vascular flow and intact axon fibers. Ex vivo confocal imaging of the prostatic parenchyma demonstrated normal prostate glands, stroma and prostatic carcinoma. CONCLUSIONS: We report the initial feasibility of optical biopsy of prostatic and periprostatic tissue during robotic assisted radical prostatectomy. Image guidance and tissue interrogation using confocal laser endomicroscopy offer a new intraoperative imaging method that has the potential to improve the functional and oncologic outcomes of prostate cancer surgery. PMID- 26626215 TI - Perioperative and Short-Term Outcomes of Robotic vs Open Bladder Neck Procedures for Neurogenic Incontinence. AB - PURPOSE: Complex urological reconstruction may be facilitated by the improved magnification and dexterity provided by a robotic approach. Minimally invasive surgery also has the potential advantages of decreased length of stay and improved convalescence. We reviewed perioperative and short-term outcomes between robot-assisted and open bladder neck sling/repair with catheterizable channel in patients with neurogenic bladder. MATERIALS AND METHODS: We performed an institutional review board approved retrospective chart review of all patients who underwent open or robotic bladder neck reconstruction without augmentation cystoplasty for refractory urinary incontinence between 2010 and 2014. Age at surgery, operative time, length of stay, complications within 30 days of surgery and future continence procedures (injection of bladder neck/catheterizable channel, additional bladder neck surgery, botulinum toxin A injection) were compared between the groups. RESULTS: A total of 45 patients underwent bladder neck reconstruction (open in 26, robotic in 19) with a mean follow up of 2.8 years. There was no difference in preoperative urodynamics, age at surgery or length of stay (median 4 days in each group, p >0.9). Operative time was significantly longer in the robotic group (8.2 vs 4.5 hours, p <0.001). Three patients (16%) undergoing robotic and 3 (12%) undergoing open surgery had a complication within 30 days (p >0.9). Of patients undergoing open repair 14 (56%) underwent 23 subsequent surgeries for incontinence. By comparison, 8 patients undergoing robotic repair (42%) underwent 12 additional procedures (p = 0.5). CONCLUSIONS: Although a robotic approach may take longer to perform, it does not result in increased complications or length of stay, or worsened continence outcomes. PMID- 26626216 TI - Validation of a Genomic Classifier for Predicting Post-Prostatectomy Recurrence in a Community Based Health Care Setting. AB - PURPOSE: We determined the value of Decipher(r), a genomic classifier, to predict prostate cancer outcomes among patients after prostatectomy in a community health care setting. MATERIALS AND METHODS: We examined the experience of 224 men treated with radical prostatectomy from 1997 to 2009 at Kaiser Permanente Northwest, a large prepaid health plan in Portland, Oregon. Study subjects had aggressive prostate cancer with at least 1 of several criteria such as preoperative prostate specific antigen 20 ng/ml or greater, pathological Gleason score 8 or greater, stage pT3 disease or positive surgical margins at prostatectomy. The primary end point was clinical recurrence or metastasis after surgery evaluated using a time dependent c-index. Secondary end points were biochemical recurrence and salvage treatment failure. We compared the performance of Decipher alone to the widely used CAPRA-S (Cancer of the Prostate Risk Assessment Post-Surgical) score, and assessed the independent contributions of Decipher, CAPRA-S and their combination for the prediction of recurrence and treatment failure. RESULTS: Of the 224 patients treated 12 experienced clinical recurrence, 68 had biochemical recurrence and 34 experienced salvage treatment failure. At 10 years after prostatectomy the recurrence rate was 2.6% among patients with low Decipher scores but 13.6% among those with high Decipher scores (p=0.02). When CAPRA-S and Decipher scores were considered together, the discrimination accuracy of the ROC curve was increased by 0.11 compared to the CAPRA-S score alone (combined c-index 0.84 at 10 years after radical prostatectomy) for clinical recurrence. CONCLUSIONS: Decipher improves our ability to predict clinical recurrence in prostate cancer and adds precision to conventional pathological prognostic measures. PMID- 26626217 TI - Calcium Oxalate Stone Fragment and Crystal Phagocytosis by Human Macrophages. AB - PURPOSE: In murine and human hyperoxaluric conditions macrophages can be seen surrounding renal calcium oxalate crystal deposits. We hypothesized that macrophages have a role in degrading and destroying these deposits. We investigated the inflammatory response and phagocytic mechanisms when macrophages were exposed to human kidney stones and inorganic crystals. MATERIALS AND METHODS: Human monocytes were differentiated into resting, fully differentiated macrophages by treatment with recombinant human macrophage colony-stimulating factor (M-CSF) or GM-CSF (granulocyte M-CSF) for 6 days. After confirming phenotype by flow cytometry the macrophages were exposed for 20 hours to fragments of sterile human calcium oxalate stones or calcium oxalate crystals. Crystal uptake was determined, and supernatant cytokine and chemokine profiles were analyzed using antibody arrays. Quantitative reverse transcriptase polymerase chain reaction was done to validate mRNA profile expression. RESULTS: Under direct vision fluorescence microscopy activated human macrophages were noted to surround stone fragments and synthesized crystals, and destroy them in a step-by-step process that involved clathrin mediated endocytosis and phagocytosis. An inflammatory cascade was released by macrophages, including the chemokines chemokine ligand (CCL)2, CCL3, interleukin (IL)-1 receptor antagonist (IL-1ra), complement component C5/C5a and IL-8. Response patterns to stone and crystal material depended on macrophage phenotype and activation status. CONCLUSIONS: In our in vitro study macrophages differentiated with M-CSF showed greater ability to phagocytize crystal deposits than those treated with GM-CSF. Following clathrin mediated endocytosis macrophages released a number of cytokines that are crucial for the inflammatory immune response. This suggests that tissue macrophages have an important role in preventing kidney stone disease by removing and digesting interstitial renal crystal deposits. PMID- 26626218 TI - Noctural Enuresis as a Risk Factor for Falls in Older Community Dwelling Women with Urinary Incontinence. AB - PURPOSE: We determined the association of urinary symptoms with fall risk and physical limitations in older community dwelling women with urinary incontinence. MATERIALS AND METHODS: We performed an in-depth assessment of daytime and nighttime urinary symptoms, fall risk, physical function, physical performance tests and mental function in older community dwelling women with urinary incontinence who had not sought care for urinary symptoms. All assessments were performed in participant homes. We used univariable and multivariable linear regression to examine the relationship of urinary symptoms to fall risk, physical function and physical performance. RESULTS: Of 37 women with a mean +/- SD age of 74 +/- 8.4 years who had urinary incontinence 48% were at high risk for falls. Nocturnal enuresis was reported by 50% of the women. Increased fall risk was associated with increasing frequency of nocturnal enuresis (p = 0.04), worse lower limb function (p <0.001), worse upper limb function (p <0.0001) and worse performance on a composite physical performance test of strength, gait and balance (p = 0.02). Women with nocturnal enuresis had significantly lower physical performance test scores than women without nocturnal enuresis (median 7, range 0 to 11 vs 9, range 1 to 12, p = 0.04). In a multivariable regression model including age, nocturnal enuresis episodes and physical function only physical function was associated with an increased fall risk (p <0.0001). CONCLUSIONS: Nocturnal enuresis is common in older community dwelling women with urinary incontinence. It may serve as a marker of fall risk even in women who do not seek care for urinary symptoms. Interventions targeting upper and lower body physical function could potentially decrease the risk of falls in older women with urinary incontinence. PMID- 26626219 TI - Microsurgical Anatomy of the Spermatic Cord and Spermatic Fascia: Distribution of Lymphatics, and Sensory and Autonomic Nerves. AB - PURPOSE: An understanding of the microsurgical anatomy of the spermatic cord and spermatic fascia is important for surgeons during microsurgical varicocelectomy and denervation. We examined the distribution of the lymphatics, and the sensory and autonomic nerves of the spermatic cord. MATERIALS AND METHODS: We collected spermatic cords from 11 men undergoing orchiectomy for localized testicular tumors and we biopsied a third of the spermatic fascia from 36 men undergoing microsurgical varicocelectomy. Immunohistochemical staining of the pan-neuronal marker PGP 9.5 (protein gene product 9.5), the sensory nociceptor marker CPRP (calcitonin gene-related peptide), the sympathetic marker TH (tyrosine hydroxylase), the parasympathetic marker VIP (vasoactive intestinal polypeptide) and the lymphatic marker D2-40 was performed. We counted the number of nerves and lymphatics. RESULTS: PGP 9.5 staining revealed dense nerve distributions in the spermatic cord and fascia. Sensory and autonomic nerve fibers were basically co localized in the same nerve. Of the nerves 50% were identified near the vas deferens and 20% were identified in the spermatic fascia. Sensory and sympathetic nerve fibers represented most of the nerves but a few parasympathetic nerve fibers were observed. Of the lymphatics 36 per patient were identified in the spermatic cord but only a few were identified in the spermatic fascia. CONCLUSIONS: Sensory and sympathetic nerves accounted for the majority of the nerves. Although the functional aspects of the nerves remain undetermined, information on the distribution of nerves and lymphatics is useful when dealing with nerves and preserving lymphatics during microsurgical varicocelectomy or denervation. PMID- 26626220 TI - Evidence of Need to Use Self-Report Measures of Psychosocial Functioning in Older Children and Adolescents with Voiding Dysfunction. AB - PURPOSE: Previous reports have revealed significantly higher rates of psychosocial difficulties in children and adolescents with voiding dysfunction compared to their healthy peers. However, these findings are based solely on parental reporting and do not include self-reporting of psychosocial problems in older pediatric patients. MATERIALS AND METHODS: We collected data from 200 consecutive patients 11 to 16 years old during outpatient clinic visits. Patients completed the Pediatric Symptom Checklist-Youth Report, parents completed the parental report of the same measure, and patients and parents collaboratively completed the Dysfunctional Voiding Scoring System. RESULTS: Of the patients 25.5% met the cutoff score for clinically significant levels of psychosocial difficulties. However, only a fourth of those patients met the cutoff on the parent and self-report measures. Additionally patient self-reports of internalizing and externalizing problems were significantly related to severity of voiding dysfunction. CONCLUSIONS: Screening for psychosocial problems in older children and adolescents with voiding dysfunction should include reports from the parent and the child. In our sample 37.3% of patients needing a mental health followup would have been missed if only 1 version of the measure had been administered. PMID- 26626221 TI - The Prevalence of Clinically Significant Prostate Cancer According to Commonly Used Histological Thresholds in Men Undergoing Template Prostate Mapping Biopsies. AB - PURPOSE: Transrectal prostate biopsies are inaccurate and, thus, the prevalence of clinically significant prostate cancer in men undergoing biopsy is unknown. We determined the ability of different histological thresholds to denote clinically significant cancer in men undergoing a more accurate biopsy, that of transperineal template prostate mapping. MATERIALS AND METHODS: In this multicenter, cross-sectional cohort of men who underwent template prostate mapping biopsies between May 2006 and January 2012, 4 different thresholds of significance combining tumor grade and burden were used to measure the consequent variation with respect to the prevalence of clinically significant disease. RESULTS: Of 1,203 men 17% (199) had no previous biopsy, 38% (455) had a prior negative transrectal ultrasound biopsy, 24% (289) were on active surveillance and 21% (260) were seeking risk stratification. Mean patient age was 63.5 years (SD 7.6) and median prostate specific antigen was 7.4 ng/ml (IQR 5.3-10.5). Overall 35% of the patients (424) had no cancer detected. The prevalence of clinically significant cancer varied between 14% and 83% according to the histological threshold used, in particular between 30% and 51% among men who had no previous biopsy, between 14% and 27% among men who had a prior negative biopsy, between 36% and 74% among men on active surveillance, and between 47% and 83% among men seeking risk stratification. CONCLUSIONS: According to template prostate mapping biopsy between 1 in 2 and 1 in 3 men have prostate cancer that is histologically defined as clinically significant. This suggests that the commonly used thresholds may be set too low. PMID- 26626222 TI - Risks and Benefits of Pharmacological Prophylaxis for Venous Thromboembolism Prevention in Patients Undergoing Robotic Partial Nephrectomy. AB - PURPOSE: We investigate the safety and efficacy of pharmacological venous thromboembolism prophylaxis in patients treated with robotic partial nephrectomy at our center. MATERIALS AND METHODS: We retrospectively examined our robotic partial nephrectomy database for cases performed between 2006 and 2014. Clinical venous thromboembolism episodes within 6 months from surgery were documented. Patients were stratified according to the administration of pharmacological venous thromboembolism prophylaxis into pharmacological prophylaxis (222) and no pharmacological prophylaxis (762) groups. The groups were compared in terms of perioperative outcomes, complications and adverse hemorrhagic events defined as the administration of 2 or more units of red blood cells, the need for vascular embolization or any procedures related to blood loss. RESULTS: There were no differences between the pharmacological prophylaxis and no pharmacological prophylaxis groups regarding mean operation time, median warm ischemia time and estimated blood loss. The rates of venous thromboembolism events were comparable between the groups (pharmacological prophylaxis 1.8% vs no pharmacological prophylaxis 2.1%, p=0.75). Overall 90% of venous thromboembolism events occurred within the first postoperative month. In the multivariable regression analysis encompassing pharmacological prophylaxis, perioperative aspirin intake, body mass index, operation time, Charlson comorbidity index, fellowship training and tumor complexity, operation time (OR 1.06, p=0.009) and Charlson comorbidity index (OR 1.28, p <0.0001) were associated with adverse hemorrhagic events. CONCLUSIONS: The administration of pharmacological prophylaxis did not increase the rate of adverse hemorrhagic events. Isolated inpatient administration of pharmacological prophylaxis after robotic partial nephrectomy does not appear to protect against venous thromboembolism postoperatively in that the majority of venous thromboembolism events occurred within the first 30 days after surgery. Longer duration of pharmacological prophylaxis for the prevention of venous thromboembolism after robotic partial nephrectomy should be considered. PMID- 26626223 TI - Role of the Anterior Cingulate Cortex in the Control of Micturition Reflex in a Rat Model of Parkinson's Disease. AB - PURPOSE: In the current study we examined dynamic changes in neural activity of the anterior cingulate cortex and the midbrain periaqueductal gray during the micturition reflex in a Parkinson's disease model as well as the effects of direct stimulation of the anterior cingulate cortex on the micturition reflex. MATERIALS AND METHODS: Electrodes were inserted in the anterior cingulate cortex or the periaqueductal gray. The effects of intravenous administration of the adenosine A2A receptor antagonist ZM24138 on pelvic nerve evoked field potentials were examined. The effect of electrical stimulation of the anterior cingulate cortex was also examined. RESULTS: Rats with Parkinson's disease showed bladder overactivity as evidenced by a significant decrease in the intercontraction interval compared with sham operated rats. Intravenous administration of ZM24138 increased the intercontraction interval in both groups with the inhibitory effects greater in rats with Parkinson's disease. It dose dependently increased the amplitude of evoked potentials in the anterior cingulate cortex of rats with Parkinson's disease but not in sham operated rats. Intravenous administration of ZM24138 decreased evoked potential amplitude in the periaqueductal gray of both groups with the inhibitory effects greater in Parkinson's disease vs sham operated rats. Electrical stimulation of the anterior cingulate cortex significantly increased the intercontraction interval. CONCLUSIONS: These results suggest that anterior cingulate cortex neurons have an inhibitory role in bladder control. Neural activity in the anterior cingulate cortex was significantly increased along with suppression of bladder overactivity after ZM241385 administration in the Parkinson's disease model and the stimulation of the anterior cingulate cortex inhibited the micturition reflex. Understanding the roles of the anterior cingulate cortex in the modulation of micturition could provide further insights into the pathophysiology of overactive bladder. PMID- 26626224 TI - Nanoparticles of perfluorocarbon emulsion contribute to the reduction of methemoglobin to oxyhemoglobin. AB - Here we show that methemoglobin is converted to oxyhemoglobin in the presence of perfluorocarbon (PFS) emulsion. Methemoglobin in blood at the level of above 30% can cause severe complications and lethal outcome. Some pharm chemicals in blood in vivo and in vitro can lead to oxidation of iron, Fe(2+)->Fe(3+), and to increased level of methemoglobin. The oxidized heme is not able to carry oxygen, hypoxia arises and irreversible changes are developing in vital organs. We added NaNO2 solution in different concentrations to blood in vitro in order to yield methemoglobin. Then the suspension of PFC nanoparticles was added. As methemoglobin interacted with PFC nanoparticles the optical density of peaks typical for oxyhemoglobin increased and spectral peak of methemoglobin decreased. The greater the concentration of PFC and the more was the incubation time, the more efficient was the process of reduction of methemoglobin to oxyhemoglobin. We proved experimentally that with an initial concentration of methemoglobin in average 95% the addition of nanoparticles of PFC decreases its concentration to 9% in average. At the same time the concentration of oxyhemoglobin increased in average from 5% to 81%. PMID- 26626225 TI - Extended release of vitamins from magnetite loaded polyanionic polymeric beads. AB - Here we explore a novel approach of increasing the release duration of folic and ascorbic acid from magnetite entrapped into calcium-alginate beads. Synthesis and characterization of magnetite-vitamins complexes are reported. The magnetite vitamins complexes were characterized by FT-IR, XRD, SEM, BET and DTA-TG. Also calcium-alginate magnetic beads were prepared by dripping a mixture of sodium alginate with magnetite-vitamins complexes into calcium chloride solution. Extended release profile of the two experimental models was evaluated and quantified by UV-vis. PMID- 26626226 TI - Guidelines, "minimal requirements" and standard of care in glioblastoma around the Mediterranean Area: A report from the AROME (Association of Radiotherapy and Oncology of the Mediterranean arEa) Neuro-Oncology working party. AB - Glioblastoma is the most common and the most lethal primary brain tumor in adults. Although studies are ongoing, the epidemiology of glioblastoma in North Africa (i.e. Morocco, Algeria and Tunisia) remains imperfectly settled and needs to be specified for a better optimization of the neuro-oncology healthcare across the Mediterranean area and in North Africa countries. Over the last years significant therapeutic advances have been accomplished improving survival and quality of life of glioblastoma patients. Indeed, concurrent temozolomide radiotherapy (temoradiation) and adjuvant temozolomide has been established as the standard of care associated with a survival benefit and a better outcome. Therefore, considering this validated strategy and regarding the means and some other North Africa countries specificities, we decided, under the auspices of AROME (association of radiotherapy and oncology of the Mediterranean area; www.aromecancer.org), a non-profit organization, to organize a dedicated meeting to discuss the standards and elaborate a consensus on the "minimal requirements" adapted to the local resources. Thus, panels of physicians involved in daily multidisciplinary brain tumors management in the two borders of the Mediterranean area have been invited to the AROME neuro-oncology working party. We report here the consensus, established for minimal human and material resources for glioblastoma diagnosis and treatment faced to the standard of care, which should be reached. If the minimal requirements are not reached, the patients should be referred to the closest specialized medical center where at least minimal requirements, or, ideally, the standard of care should be guaranteed to the patients. PMID- 26626227 TI - Enhancement of soluble expression of codon-optimized Thermomicrobium roseum sarcosine oxidase in Escherichia coli via chaperone co-expression. AB - The codon-optimized sarcosine oxidase from Thermomicrobium roseum (TrSOX) was successfully expressed in Escherichia coli and its soluble expression was significantly enhanced via the co-expression of chaperones. With the assistance of whole-genome analysis of T. roseum DSM 5159, the sox gene was predicated and its sequence was optimized based on the codon bias of E. coli. The TrSOX gene was successfully constructed in the pET28a plasmid. After induction with IPTG for 8h, SDS-PAGE analysis of crude enzyme solutions showed a significant 43 kDa protein band, indicating SOX was successfully expressed in E. coli. However, the dark band corresponding to the intracellular insoluble fraction indicated that most of TrSOX enzyme existed in the inactive form in "inclusion bodies" owing to the "hot spots" of TrSOX. Furthermore, the co-expression of five different combinations of chaperones indicated that the soluble expression of TrSOX was greatly improved by the co-expression of molecular chaperones GroES-GroEL and DnaK-DnaJ-GrpE-GroES GroEL. Additionally, the analysis of intramolecular forces indicated that the hydrophobic amino acids, hydrogen bonds, and ionic bonds were favorable for enhancing the interaction and stability of TrSOX secondary structure. This study provides a novel strategy for enhancing the soluble expression of TrSOX in E. coli. PMID- 26626228 TI - Genomic evidence for distinct carbon substrate preferences and ecological niches of Bathyarchaeota in estuarine sediments. AB - Investigations of the biogeochemical roles of benthic Archaea in marine sediments are hampered by the scarcity of cultured representatives. In order to determine their metabolic capacity, we reconstructed the genomic content of four widespread uncultured benthic Archaea recovered from estuary sediments at 48% to 95% completeness. Four genomic bins were found to belong to different subgroups of the former Miscellaneous Crenarcheota Group (MCG) now called Bathyarchaeota: MCG 6, MCG-1, MCG-7/17 and MCG-15. Metabolic predictions based on gene content of the different genome bins indicate that subgroup 6 has the ability to hydrolyse extracellular plant-derived carbohydrates, and that all four subgroups can degrade detrital proteins. Genes encoding enzymes involved in acetate production as well as in the reductive acetyl-CoA pathway were detected in all four genomes inferring that these Archaea are organo-heterotrophic and autotrophic acetogens. Genes involved in nitrite reduction were detected in all Bathyarchaeota subgroups and indicate a potential for dissimilatory nitrite reduction to ammonium. Comparing the genome content of the different Bathyarchaeota subgroups indicated preferences for distinct types of carbohydrate substrates and implicitly, for different niches within the sedimentary environment. PMID- 26626229 TI - Autoimmune epilepsy. AB - Despite the fact that epilepsy is the third most common chronic brain disorder, relatively little is known about the processes leading to the generation of seizures. Accumulating data support an autoimmune basis in patients with antiepileptic drug-resistant seizures. Besides, recent studies show that epilepsy and autoimmune disease frequently co-occur. Autoimmune epilepsy is increasingly recognized in the spectrum of neurological disorders characterized by detection of neural autoantibodies in serum or spinal fluid and responsiveness to immunotherapy. An autoimmune cause is suspected based on frequent or medically intractable seizures and the presence of at least one neural antibody, inflammatory changes indicated in serum or spinal fluid or on MRI, or a personal or family history of autoimmunity. It is essential that an autoimmune etiology be considered in the initial differential diagnosis of new onset epilepsy, because early immunotherapy assures an optimal outcome for the patient. PMID- 26626230 TI - A Comparison of Three Approaches to the Reduced-Scaling Coupled Cluster Treatment of Non-Resonant Molecular Response Properties. AB - We have investigated the performance of the reduced-scaling coupled cluster method based on projected atomic orbitals (PAOs), pair natural orbitals (PNOs), and orbital specific virtuals (OSVs) for the prediction of linear response properties. These methods introduce different degrees of controllable sparsity in the ground-state and perturbed coupled cluster wave functions, leading to localization errors in properties such as dynamic polarizabilities and specific optical rotations. Using a series of chiral test compounds, we find that the inherent costs associated with computing response properties are significantly greater than those for determining the ground-state energy. As the dimensionality of the molecular system increases-from (pseudo)linear structures, such as fluoroalkanes, to cagelike structures, such as beta-pinene-the crossover point between canonical-orbital and localized-orbital algorithms increases substantially. Furthermore, both the OSV and PNO methods provide greater reduction in cost (as measured by the size of the double-excitation space) than do PAOs, and PNOs provide the greatest level of sparsity for the systems examined here. Single-excitation truncation induces much larger errors than corresponding doubles truncation due to the fact that the first-order contribution to the one electron perturbed wave function appears in the singles amplitudes. Both the PNO and OSV methods perform reasonably well for frequency-dependent polarizabilities provided appropriate thresholds are used for the occupation-number and weak-pair cutoffs on which each method depends. Specific rotations, however, are very sensitive to wave function truncation, to the extent that aggressive thresholds can yield the incorrect sign of the rotation, due to the delicate balance of positive and negative wave function contributions to the mixed electric-/magnetic field response. PMID- 26626231 TI - Size-dependent strain and surface energies of gold nanoclusters. AB - Gold nanocluster properties exhibit unique size-dependence. In this contribution, we employ reactive molecular dynamics simulations to calculate the size- and temperature-dependent surface energies, strain energies and atomic displacements for icosahedral, cuboctahedral, truncated octahedral and decahedral Au nanoclusters. The calculations demonstrate that the surface energy decreases with increasing cluster size at 0 K but increases with size at higher temperatures. The calculated melting curves as a function of cluster size demonstrate the Gibbs Thomson effect. Atomic displacements and strain are found to strongly depend on the cluster size and both are found to increase with increasing cluster size. These results are of importance for understanding the size- and temperature dependent surface processes on gold nanoclusters. PMID- 26626232 TI - Chemical constituents of the soft corals Sinularia vanderlandi and Sinularia gravis from the coast of Madagascar. AB - The crude extracts of the Madagascan soft corals Sinularia vanderlandi and Sinularia gravis (Alcyoniidae) showed activity against Plasmodium falciparum which led us to study their chemical constituents. The new cadinane-type sesquiterpenoid vanderlandin (1) has been obtained from S. vanderlandi along with 24-methylenecholesterol (2). Four new compounds, the spatane-type diterpenoid gravilin (3), the monoalkylmonoacylglycerol 4, the dihomoditerpenoid ketone 5, and isodecaryiol (9), along with the three known compounds (+)-(S) geranyllinalool (6), (-)-(R)-nephthenol (7), and 11,12-epoxysarcophytol A (8) have been isolated from the methanol extract of S. gravis. The structures were elucidated based on extensive spectroscopic methods, in particular various 2D NMR techniques. The structure of isodecaryiol (9) including its absolute configuration could be confirmed by X-ray diffraction. PMID- 26626233 TI - Dual-Wavelength Electrochemiluminescence Ratiometry Based on Resonance Energy Transfer between Au Nanoparticles Functionalized g-C3N4 Nanosheet and Ru(bpy)3(2+) for microRNA Detection. AB - Here, a dual-wavelength ratiometric electrochemiluminescence (ECL) approach is reported based on resonance energy transfer (RET) from graphite-like carbon nitride nanosheet (g-C3N4 NS) to Ru(bpy)3(2+) for sensitive detection of microRNA (miRNA). In this approach, Au nanoparticles (Au NPs) functionalized g-C3N4 NS nanohybrid (Au-g-C3N4 NH) coated on glassy carbon electrode (GCE) could exhibit strong and stable ECL emissions with emission peak centered at 460 nm. The ECL emission at such wavelength matched well with the absorption peak of Ru(bpy)3(2+) as well as impeccably stimulating the emission of Ru(bpy)3(2+) at the wavelength of 620 nm, producing ECL-RET with high efficiency. Thus, based on the ECL signals quenching at 460 nm and increasing at 620 nm, a dual-wavelength ratiometric ECL RET system was achieved. This system was then utilized for determination of target miRNA. With the attachment of thiol-modified molecular beacon on Au-g-C3N4 NH, target miRNA hybridized with the molecular beacon to form a DNA-RNA duplex. The obtained DNA-RNA duplex could be cleaved by duplex-specific nuclease to release target miRNA which would take part in the next cycle for further hybridization. Finally, the introducing of Ru(bpy)3(2+) was through the probe DNA Ru(bpy)3(2+) complementary with the rest single-strand DNA on electrode. By measuring the ratio of ECL(460 nm)/ECL(620 nm), we could accurately quantify the concentration of miRNA-21 in a wide range from 1.0 fM to 1.0 nM. This work provides an important reference for the study of dual-wavelength ECL ratiometry and also exhibits potential capability in the detection of nucleic acids. PMID- 26626234 TI - Treatment strategies for the infertile polycystic ovary syndrome patient. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Infertility is a prevalent presenting feature of PCOS, and approximately 75% of these women suffer infertility due to anovulation. Lifestyle modification is considered the first-line treatment and is associated with improved endocrine profile. Clomiphene citrate (CC) should be considered as the first line pharmacologic therapy for ovulation induction. In women who are CC resistant, second-line treatment should be considered, as adding metformin, laparoscopic ovarian drilling or treatment with gonadotropins. In CC treatment failure, Letrozole could be an alternative or treatment with gonadotropins. IVF is considered the third-line treatment; the 'short', antagonist-based protocol is the preferred option for PCOS patients, as it is associated with lower risk of developing ovarian hyperstimulation syndrome (specifically by using a gonadotropin--releasing hormone agonist as ovulation trigger), but with comparable outcomes as the long protocol. PMID- 26626235 TI - Evaluation of obstructive sleep apnea symptoms in pregnant women with chronic disease. AB - OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) is a disease which is estimated to be undiagnosed to a large extent. Hence, the prevalence of OSAS in pregnant women is unknown. We aimed to evaluate the symptoms of obstructive sleep apnea in pregnant women with chronic diseases. METHODS: In the study, 97 pregnant women with chronic diseases and 160 healthy pregnant women were included. A form questioning socio-demographic characteristics and pregnancy characteristics, Epworth scale and the Berlin questionnaire to evaluate the risk of OSAS were applied to participants. RESULTS: It has been determined that 10-12.5% of healthy pregnant women, 34-45.4% of pregnants with chronic diseases and 20.6-23.3% of all pregnant women had a high risk of OSAS, the pregnants with chronic disease compared to healthy pregnant women had statistically significant higher risk of OSAS. The risk of OSAS was found to be significantly higher especially in pregnant women with hypertension and diabetes. CONCLUSIONS: OSAS can lead to the adverse consequences in pregnancy, should be questioned for all pregnants especially those with chronic diseases. Pregnant women with OSAS should be monitored more carefully in terms of diabetes and hypertension in antenatal care. PMID- 26626236 TI - A standardized kit for automated quantitative assessment of candidate protein biomarkers in human plasma. AB - BACKGROUND: An increasingly popular mass spectrometry-based quantitative approach for health-related research in the biomedical field involves the use of stable isotope-labeled standards (SIS) and multiple/selected reaction monitoring (MRM/SRM). To improve inter-laboratory precision and enable more widespread use of this 'absolute' quantitative technique in disease-biomarker assessment studies, methods must be standardized. Results/methodology: Using this MRM-with SIS-peptide approach, we developed an automated method (encompassing sample preparation, processing and analysis) for quantifying 76 candidate protein markers (spanning >4 orders of magnitude in concentration) in neat human plasma. DISCUSSION/CONCLUSION: The assembled biomarker assessment kit - the 'BAK-76' - contains the essential materials (SIS mixes), methods (for acquisition and analysis), and tools (Qualis-SIS software) for performing biomarker discovery or verification studies in a rapid and standardized manner. PMID- 26626237 TI - High burden of RSV hospitalization in very young children: a data linkage study. AB - Linked administrative population data were used to estimate the burden of childhood respiratory syncytial virus (RSV) hospitalization in an Australian cohort aged <5 years. RSV-coded hospitalizations data were extracted for all children aged <5 years born in New South Wales (NSW), Australia between 2001 and 2010. Incidence was calculated as the total number of new episodes of RSV hospitalization divided by the child-years at risk. Mean cost per episode of RSV hospitalization was estimated using public hospital cost weights. The cohort comprised of 870 314 children. The population-based incidence/1000 child-years of RSV hospitalization for children aged <5 years was 4.9 with a rate of 25.6 in children aged <3 months. The incidence of RSV hospitalization (per 1000 child years) was 11.0 for Indigenous children, 81.5 for children with bronchopulmonary dysplasia (BPD), 10.2 for preterm children with gestational age (GA) 32-36 weeks, 27.0 for children with GA 28-31 weeks, 39.0 for children with GA <28 weeks and 6.7 for term children with low birthweight. RSV hospitalization was associated with an average annual cost of more than AUD 9 million in NSW. RSV was associated with a substantial burden of childhood hospitalization specifically in children aged <3 months and in Indigenous children and children born preterm or with BPD. PMID- 26626238 TI - Development of a highly reproducible system to evaluate inhibition of cytochrome P450 3A4 activity by natural medicines. AB - PURPOSE: In recent years, a number of natural medicines have been reported to have inductive or inhibitive effects on the activity of drug metabolizing enzymes, upon co-administration with prescribed medicines. However, information regarding natural medicine-drug interactions that influence drug metabolism is limited owing to the lack of efficient screening method for such interactions. Therefore, to understand whether P450 activity is affected by natural medicine in small intestines, we have established frozen recombinant P450-expressing cells infected with human CYP3A4 expressing adenovirus (Ad-CYP3A4) to evaluate the effect of natural medicines on CYP3A4 activity. METHODS: Ad-CYP3A4 cells were created by infecting HepG2 cells with Ad-CYP3A4 at 10 multiplicity of infection (MOI) and these cells were stored using cryopreservation medium (fAd-CYP3A4 cells) to obtain long-term consistent data and stable supplies of cells expressing a constant level of CYP3A4 activity. RESULTS: The CYP3A4 activity in fAd-CYP3A4 cells remained unaffected at the end of each frozen period (0, 1, 2, and 6 months). Inhibitory effect on CYP3A4 activity by typical inhibitors (ketoconazole, hyperforin) and natural medicines (Cat's Claw, Devil's Claw, Feverfew, Peppermint Oil, Red Clover, and Siberian Eleuthero) were evaluated. The inhibitors had nearly equal IC50 values in fAd-CYP3A4 cells, Ad-CYP3A4 cells and recombinant CYP3A4 microsomes. Cat's Claw, Peppermint Oil and Siberian Eleuthero inhibited CYP3A4 activity more potently than 0.1 MUM ketoconazole in fAd-CYP3A4 cells. CONCLUSIONS: In the present study, we have successfully developed a highly reproducible system to evaluate CYP3A4 inhibition in small intestines by natural medicines. PMID- 26626239 TI - The Differential Effects of Resveratrol and trans-epsilon-Viniferin on the GABA Induced Current in GABAA Receptor Subtypes Expressed in Xenopus Laevis Oocytes. AB - PURPOSE: The natural products resveratrol and trans-epsilon-viniferin have been reported to have many beneficial effects, which include the enhancement of cognition and memory. There have been no studies which have reported the effects of these compounds on the different GABAA receptor subtypes and this study aimed to address this. METHODS: The effects of both resveratrol, and its dimer, trans epsilon-viniferin, have been investigated on different GABAA receptor subtypes expressed in Xenopus laevis oocytes, using the two-electrode voltage clamp technique. RESULTS: Resveratrol induced a current of 22 +/- 3.53 nA in the alpha1beta2gamma2L subtype of the GABAA receptor (but not in the alpha5beta3gamma2L and alpha2beta2gamma2L subtypes) when applied alone. It also positively modulated the GABA-induced current (IGABA) in alpha1beta2gamma2L receptors, in adose-dependent manner (EC50 58.24 MUM). The effects of resveratrol were not sensitive to the benzodiazepine antagonist flumazenil. trans-epsilon Viniferin exhibited a different pattern of activity to resveratrol; it alone had no effect on any of the subtypes, but it did negatively modulate the GABA-induced current (IGABA) in all three subtypes. The greatest inhibition was found in the alpha1beta2gamma2L subtype (IC50 5.79 MUM), with the inhibition in the alpha2beta2gamma2L (IC50 of 19.08 MUM) and alpha5beta3gamma2L (IC50 of 21.05 MUM) subtypes being similar. The effects of trans-epsilon-viniferin in alpha1beta2gamma2L and alpha2beta2gamma2L receptors werealso not sensitive to the benzodiazepine antagonist flumazenil while, in the alpha5beta3gamma2L subtype the effect was not sensitive to the inverse agonist L-655,708, indicating different binding sites for this molecule. CONCLUSIONS: The results of the present study indicate that both resveratrol and trans-epsilon-viniferin modulate the GABA induced current in different ways, and that trans-epsilon-viniferin may be a lead compound for the discovery of agents which selectively inhibit the GABA-induced current in alpha1-containing subtypes.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626240 TI - Interactions Between Nutraceutical Supplements and Standard Acute Myeloid Leukemia Chemotherapeutics. AB - PURPOSE: Concomitant use of nutraceuticals with chemotherapy is very common. Cancer patients self-medicate to relieve the side effects associated with chemotherapy, improve disease outcome and to regain control of their medical care. However, there is limited empirical evidence on potential drug nutraceutical interactions and their resulting effect on chemotherapy efficacy. METHOD: To investigate drug-nutraceutical interactions we created and screened a library of commonly used nutraceuticals for their modulatory effects on the activity of cytarabine and daunorubicin, two primary chemotherapeutics used to treat acute myeloid leukemia (AML). Combination screening was performed in 3 AML cell lines (OCI-AML2, KG1a and U937) using the MTS viability assay. Lead compounds were validated using with the Annexin V/ Propidium iodide assay and CalcuSyn drug combination software. RESULTS: We identified zinc as a nutraceutical that enhanced AML chemotherapy efficacy with combination index (CI) values of 0.649, 0.632 and 0.615 at EC 25, 50 and 75, respectively; CI values <0.9, >1.1 or between 0.9-1.1 denote statistical synergy, antagonism or additivity, respectively. In contrast, we show that echinacea hindered AML chemotherapy efficacy by significantly reducing the ability of cytarabine to induce cell death. CONCLUSION: Given the positive and negative effects of nutraceuticals, patients undergoing chemotherapy must consult with their oncologist before consuming over-the-counter supplements. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626241 TI - Lipid-lowering Activity of Natural and Semi-Synthetic Sterols and Stanols. AB - Consumption of plant sterols/ stanols has long been demonstrated to reduce plasma cholesterol levels. The objective of this review is to demonstrate the lipid lowering activity and anti-atherogenic effects of natural and semi-synthetic plant sterols/ stanols based on evidence from cell-culture studies, animal studies and clinical trials. Additionally, this review highlights certain molecular mechanisms by which plant sterols/ stanols lower plasma cholesterol levels with a special emphasis on factors that affect the cholesterol-lowering activity of plant sterols/stanols. The crystalline nature and the poor oil solubility of these natural products could be important factors that limit their cholesterol-lowering efficiency. Several attempts have been made to improve the cholesterol-lowering activity by enhancing the bioavailability of crystalline sterols and stanols. Approaches involved reduction of the crystal size and/or esterification with fatty acids from vegetable or fish oils. However, the most promising approach in this context is the chemical modification of plant sterols /stanols into water soluble disodium ascorbyl phytostanyl phosphates analogue by esterification with ascorbic acid. This novel semi-synthetic stanol derivative has improved efficacy over natural plant sterols/ stanols and can provide additional benefits by combining the cholesterol-lowering properties of plant stanols with the antioxidant potential of ascorbic acid. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626242 TI - Pre-Clinical Pharmacokinetic and Pharmacodynamic Characterization of Selected Chiral Flavonoids: Pinocembrin and Pinostrobin. AB - PURPOSE: Delineate the stereospecific pharmacokinetics and pharmacodynamics of the chiral flavonoids pinocembrin and pinostrobin. OBJECTIVE: Characterize for the first time the stereoselective pharmacokinetics of two flavonoids, pinocembrin and pinostrobin and their bioactivity in several in vitro assays with relevant roles in heart disease, colon cancer, and diabetes etiology and pathophysiology. METHODS: Chiral flavonoids were intravenously and orally administered to male Sprague-Dawley rats. Concentrations in serum and urine were characterized via stereospecific HPLC or LC/MS. Pure enantiomeric forms of each flavonoid were tested, where possible, to identify the stereospecific contribution to bioactivity in comparison to their racemates. RESULTS: Short half lives (0.2-6 h) in serum were observed, while a better estimation of half-life (3 26 h) and other pharmacokinetic parameters were observed using urinary data. The flavonoids are predominantly excreted via non-renal routes (fe values of 0.3-4.6 %), and undergo rapid and extensive phase II metabolism. Chiral differences in the chemical structure of these compounds result in significant pharmacodynamic differences. CONCLUSION: The importance of understanding the stereospecific pharmacokinetics and pharmacodynamics of two chiral flavonoids were delineated.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626243 TI - Medicinal use of Sceletium: Characterization of Phytochemical Components of Sceletium Plant Species using HPLC with UV and Electrospray Ionization--Tandem Mass Spectroscopy. AB - PURPOSE: Sceletium plants have been used for its medicinal properties for centuries. However, there is a wide range of Sceletium plant species in which various alkaloidal components such as ?7mesembrenone, mesembrenol, mesembranol, mesembrenone, mesembrine hydrochloride, epimesembranol and, sceletium A4 differ between species. Hence, to ensure the quality of Sceletium products used as a medicine, it is imperative to identify the appropriate species using both botanical and chemical methods. The chemical approach to identify and characterize the phytochemical composition of a particular species facilitates the choice of species that will provide the purported therapeutic outcome. Hence, specific analytical methods to identify relevant constituents from complex matrices are necessary. Although HPLC-UV detection is commonly used to identify and estimate phytochemical content of medicinal plants, use of mass spectroscopy (MS) and tandem mass spectroscopy (MS/MS) can unequivocally confirm their presence/absence based on characteristic ions and fragmentation patterns. METHODS: The various alkaloidal components were characterized by electrospray ionization (ESI) MS and MS/MS using an ionizing medium of 0.1% ammonium hydroxide in water mixed with acetonitrile. Compounds were purified and characterized for use as reference standards to identify the relevant alkaloidal constituents of several Sceletium plant species using HPLC with on-line UV-MS detection. RESULTS: ESI-MS provided the [M+H](+) ions with respective m/z values that related to the respective molecular weights 287, 289, 291, 287, 289, 324 and 291 for the above mentioned alkaloids, whereas, ESI MS/MS provided the characteristic fragment ions to confirm the structural identity of the individual alkaloids and subsequently used to confirm the presence and/or absence of specific alkaloids in various Sceletium plant samples. CONCLUSIONS: Whilst HPLC-UV detection has been a widely used conventional analytical technique for both qualitative and quantitative analyses, the results highlight the necessity of ESI-MS detection to avoid erroneous identification of phytochemical components, particularly with mesembrine-type compounds which have closely related chemical structures. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626244 TI - Curcumin Reduces Tumour Necrosis Factor-Enhanced Annexin V-Positive Microparticle Release in Human Vascular Endothelial Cells. AB - PURPOSE: Circulating microparticles have been highlighted as biomarkers of cardiovascular disease state and progression. The aim of this study was to evaluate the effects of curcumin on microparticle release from endothelial cells undergoing TNF-induced cell activation and apoptosis. METHODS: This study evaluated the effects of curcumin on microparticle release, cytotoxicity, apoptosis, cell adhesion molecule expression and monocyte adhesion in EAhy926 human endothelial cells. RESULTS: The results showed that the numbers of microparticles were increased by tumour necrosis factor (TNF) or the combination of TNF and cycloheximide (CHX). Curcumin attenuated microparticle release caused by TNF or TNF plus CHX treatments. The pretreatment by curcumin not only negated the accelerated cell death and apoptosis caused by TNF and CHX, but also diminished TNF-induced cell activation, as assessed by reduced surface expression of intercellular adhesion molecule 1, and adhesion of monocytes to endothelial monolayers. CONCLUSION: Curcumin reduced microparticle release from endothelial cells undergoing cell activation and apoptosis, which supports its protective role in TNF-associated endothelial dysfunction, and highlights its potential use as a nutraceutical agent for vascular inflammatory diseases. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626245 TI - Antidepressant, Anxiolytic and Antinociceptive Activities of Constituents from Rosmarinus Officinalis. AB - PURPOSE: Rosmarinus officinalis, traditionally known as rosemary, has been widely used in traditional medicines and has long been known as the herb of remembrance. However, few studies have investigated the effects of non-volatile components of rosemary on central nervous system function. METHODS: Fractionation of R. officinalis led to the isolation of salvigenin, rosmanol and cirsimaritin, which were investigated in mouse models of acute toxicity, antinociception (tail immersion and hot plate tests), depression (tail suspension and forced swim tests) and anxiety (elevated plus maze and light/dark box paradigms). RESULTS: Rosmanol, cirsimaritin and salvigenin were not found to exhibit any signs of acute toxicity (50-200 mg/kg), but elicited antinociceptive, antidepressant and anxiolytic activities. CONCLUSION: Rosmanol, cirsimaritin and salvigenin, all previously shown to have biphasic modulation of GABAA receptors, demonstrated CNS activity in mouse models of antinociception, antidepressant and anxiolysis. The anxiolytic activity of all three compounds was not ameliorated by flumazenil, but was inhibited by pentylenetetrazol, suggesting a mode of action via GABAA receptors at a site other than the high affinity benzodiazepine binding site. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626246 TI - Phytochemical Comparison of the Water and Ethanol Leaf Extracts of the Cree medicinal plant, Sarracenia purpurea L. (Sarraceniaceae). AB - PURPOSE: The Cree of Eeyou Istchee in Northern Quebec identified Sarracenia purpurea L. as an important plant for the treatment of Type 2 diabetes. Traditionally the plant is used as a decoction (boiling water extract) of the leaf, however, in order to study the extract in a laboratory setting, an 80% ethanol extract was used. In this study, the phytochemistry of both extracts of the leaves was compared and quantified. METHODS: Two S. purpurea leaf extracts were prepared, one a traditional hot water extract and the other an 80% ethanol extract. Using UPLC-ESI-MS, the extracts were phytochemically compared for 2 triterpenes, betulinic acid and ursolic acid, using one gradient method and for 10 additional substances, including the actives quercetin-3-O-galactoside and morroniside, using a different method. RESULTS: The concentrations of the nine phenolic substances present, as well as an active principle, the iridoid glycoside morroniside, were very similar between the two extracts, with generally slightly higher concentrations of phenolics in the ethanol extract as expected. However, two triterpenes, betulinic acid and ursolic acid, were 107 and 93 times more concentrated, respectively, in the ethanol extract compared to the water extract. CONCLUSION: The main phytochemical markers and most importantly the antidiabetic active principles, quercetin-3-O-galactoside and morroniside, were present in similar amounts in the two extracts, which predicts similar bioactivity.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626247 TI - Calebin A: Analytical Development for Pharmacokinetics Study, Elucidation of Pharmacological Activities and Content Analysis of Natural Health Products. AB - PURPOSE: To develop a bioanalytical assay using RP-HPLC to quantify the curcuminoid calebin A, to characterize its pharmacokinetics in rats after intravenous (IV) and oral (PO) administration, to identify its pharmacological activities and to evaluate its content in natural health products. METHODS: An RP HPLC method was developed for the detection of calebin A. Separation was carried out using a Phenomenex(r) Kinetex(r) C18 column with UV detection at 339 nm. An isocratic mobile phase consisting of acetonitrile and water with 10 mM ammonium formate (pH 7.0) (40:60, v/v) at a flow rate of 0.8 mL/min was employed. Linear standard curves were established and applied in the pharmacokinetic study. Calebin A was administered to male Sprague-Dawley (CD) rats IV (20 mg/kg) or PO (500 mg/kg) (n=4/route of administration). Serum and urine samples were collected for 72 h post dose. In vitro antioxidant activity, anti-inflammatory activity (cyclooxygenase and lipoxygenase inhibition), dipeptidyl peptidase-4 (DPP-4) inhibition and cytochrome P450 inhibitory activties of calebin A were examined using commercial assay kits. Content analysis of calebin A in 14 natural health products advertised to contain turmeric were carried out using methanolic extraction. RESULTS: The HPLC method was successfully applied to a pharmacokinetic study of calebin A in rats. After IV and PO administration of calebin A, the compound was detected as the aglycone and a glucuronidated metabolite. Oral bioavailabitily was found to be ~0.5%, serum half-life was ~1-3 h. Calebin A appears to be primarily excreted via non-renal routes. Calebin A possessed concentration-dependent antioxidant activity and DPP-4 inhibition. Calebin A appears to be a non-selective cyclooxygenase inhibitor and also a poor lipoxygenase inhibitor. The curcuminoid displayed in vitro interactions with CYP2D6 and CYP1A2. Content analysis of 14 natural health products that claimed to contain turmeric showed that concentration of calebin A was inconsistent among the products. CONCLUSION: A successful assay was developed for the detection of calebin A using RP-HPLC. Preliminary pharmacokinetic studies indicate that an unoptimised formulation of calebin A has poor oral bioavailability. Calebin A exhibits various pharmacological activities. This article is open to POST PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626248 TI - Potential Complementary Therapy for Adverse Drug Reactions to Sulfonamides: Chemoprotection Against Oxidative and Nitrosative Stress by TCM Constituents and Defined Mixtures. AB - PURPOSE: Our working hypothesis is that bioactive phytochemicals that are important constituents of Traditional Chinese Medicine and their defined mixtures have potential as complementary therapy for chemoprotection against adverse drug reactions whose toxicity is not related to the pharmacological action of the drug but where oxidative and nitrosative stress are causative factors. METHODS: In this investigation we measured cytotoxicity, lipid peroxidation, protein carbonylation and ROS/NOS-mediated changes in the disulfide proteome of Jurkat E6.1 cells resulting from exposure to sulfamethoxazole N-hydroxylamine with or without pre-treatment with low uM concentrations of baicalein, crocetin, resveratrol and schisanhenol alone and in defined mixtures to compare the ability of these treatment regimens to protect against ROS/RNS toxicity to Jurkat E6.1 cells in culture. RESULTS: Each of the Traditional Chinese Medicine constituents and defined mixtures tested had significant chemoprotective effects against the toxicity of ROS/RNS formed by exposure of Jurkat E6.1 cells to reactive metabolites of sulfamethoxazole implicated as the causative factors in adverse drug reactions to sulfa drugs used for therapy. At equimolar concentrations, the defined mixtures tended to be more effective chemoprotectants overall than any of the single constituents against ROS/RNs toxicity in this context. CONCLUSIONS: At low uM concentrations, defined mixtures of TCM constituents that contain ingredients with varied structures and multiple mechanisms for chemoprotection have excellent potential for complementary therapy with sulfa drugs to attenuate adverse effects caused by oxidative/nitrosative stress. Typically, such mixtures will have a combination of immediate activity due to short in vivo half-lives of some ingredients cleared rapidly following metabolism by phase 2 conjugation enzymes; and some ingredients with more prolonged half-lives and activity reliant on phase 1 oxidation enzymes for their metabolic clearance. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626249 TI - Evaluation by microarray of the potential safety of Sarracenia purpurea L. (Sarraceniaceae) a traditional medicine used by the Cree of Eeyou Istchee. AB - PURPOSE: The purpose of this study was to assess safety of the traditional antidiabetic extracts of either S. purpurea or its lead active principle, morroniside at the transcriptional level. The overarching objective was to profile and validate transcriptional changes in the cytochrome P450 family of genes, in response to treatment with S. purpurea ethanolic extract or its lead active, morroniside. METHODS: Transcriptional activity was profiled using a 19K human cDNA microarray in C2BBe1 cells, clone of Caco-2 intestinal cells, which are a model of first-pass metabolism (1, 2). Cells were treated with S. purpurea extract for 4 and 24 hrs, as well as the pure compound morroniside for 4 hrs, to determine their effects. RESULTS: No evidence of cytochrome P450 transcriptome regulation or of transcriptional activation of other diabetes relevant mRNA was detected after rigorous quantitative-PCR validation of microarray results. CONCLUSION: Our data do not support a transcriptional mechanism of action for either S. purpurea extract or its lead active, morroniside. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626250 TI - Development and Evaluation of a Topical Anti-Inflammatory Preparation Containing Dodonaea polyandra Extract. AB - PURPOSE: We have previously reported that the Australian Northern Kaanju (Kuuku I'yu) medicinal plant Dodonaea polyandra has anti-inflammatory activity. This is attributed largely to the presence of clerodane diterpenoids contained within the leaf resin. We envisaged developing a topical preparation to treat indications relating to skin inflammation. However, it was unknown whether the resin could be incorporated into a suitable dosage form while retaining the therapeutic value demonstrated in previous work. Therefore, the following study was undertaken to assess parameters of safety and efficacy for a prototype formulation containing the leaf resin extracted from D. polyandra. METHODS: Using the assessment criteria of optimum appearance, tactile feeling, spreadability and odour, 78 different formulations were developed. Formulation stability was assessed using a centrifugal test with preparations displaying phase separation further modified or re-formulated. A prototype formulation containing 5% w/w plant resin was selected and subjected to in vitro release studies. This was quantified through HPLC analysis using two major bioactive diterpenoids as reference. The prototype formulation was tested for efficacy in a TPA-induced acute murine skin inflammation model as well as a 3D human skin model for irritancy/toxicity (EpidermTM). RESULTS: The prototype resin cream was a chartreuse-coloured homogenous semisolid preparation that was readily spreadable upon contact with skin with no sensation of tackiness, residual greasiness, or irritation. The optimized cream showed no phase separation after 30 min centrifugation at 825 g. In the TPA-induced inflammation model, the resin formulation significantly reduced ear thickness and interleukin-1 beta levels in mouse ear tissue. The 5% w/w resin cream formulation showed no irritancy in a 3D human skin model. CONCLUSIONS: Our results demonstrate that bioactive resin from D. polyandra can be formulated into a stable and non-irritant semi-solid dosage form and reduce parameters of acute skin inflammation in vivo. This article is open to POST PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626251 TI - Flavonols Protect Against UV Radiation-Induced Thymine Dimer Formation in an Artificial Skin Mimic. AB - PURPOSE: Exposure of skin to ultraviolet light has been shown to have a number of deleterious effects including photoaging, photoimmunosuppression and photoinduced DNA damage which can lead to the development of skin cancer. In this paper we present a study on the ability of three flavonols to protect EpiDermTM, an artificial skin mimic, against UV-induced damage. METHODS: EpiDermTM samples were treated with flavonol in acetone and exposed to UVA (100 kJ/m(2) at 365 nm) and UVB (9000 J/m(2) at 310 nm) radiation. Secretion of matrix metalloproteinase-1 (MMP-1) and tumor necrosis factor-alpha (TNF-a) were determined by ELISA, cyclobutane pyrimidine dimers were quantified using LC-APCI-MS. RESULTS: EpiDermTM treated topically with quercetin significantly decreased MMP-1 secretion induced by UVA (100 uM) or UVB (200 uM) and TNF-a secretion was significantly reduced at 100 uM quercetin for both UVA and UVB radiation. In addition, topically applied quercetin was found to be photostable over the duration of the experiment. EpiDermTM samples were treated topically with quercetin, kaempferol or galangin (52 uM) immediately prior to UVA or UVB exposure, and the cyclobutane thymine dimers (T-T (CPD)) were quantified using an HPLC-APCI MS/MS method. All three flavonols significantly decreased T-T (CPD) formation in UVB irradiated EpiDermTM, however no effect could be observed for the UVA irradiation experiments as thymine dimer formation was below the limit of quantitation. CONCLUSIONS: Our results suggest that flavonols can provide protection against UV radiation-induced skin damage through both antioxidant activity and direct photo-absorption. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626252 TI - A New Cytotoxic Steroidal Glycoalkaloid from the Methanol Extract of Blumea lacera Leaves. AB - PURPOSE: Blumea lacera (B. lacera) (Asteraceae) is a well-known Bangladeshi medicinal plant. This study aimed to identify and characterize constituents associated with the significant cytotoxic activity of this plant that we reported previously. Here, we describe the isolation and characterization of a new steroidal glycoalkaloid (SGA) 1, the evaluation of its cytotoxic activity, apoptotic potential, and effect on cell cycle in comparison to analogous steroidal glycoalkaloids (SGAs). METHODS: SGA 1 was isolated using C18 SPE and HPLC, and subsequently structurally characterized using 1D and 2D NMR, MS and other spectroscopic methods, along with a comparative inspection of the literature. Cytotoxic activity of 1 and seven SGA analogues and steroidal alkaloids (SAs), (beta-solamarine, alpha-solanine, beta-solamargine, alpha solasonine, khasianine, solasodine, tomatidine HCl) were evaluated for their cytotoxicity against two healthy (NIH3T3 and VERO) and four human cancer (AGS, HT 29, MCF-7 and MDA-MB-231) cell lines using the MTT assay. Cytotoxic SGAs were further evaluated for apoptosis-inducing potential and cell cycle arresting ability against breast cancer cells (MCF-7) using the FITC Annexin V and propidium iodide (PI) assay. RESULTS: Bioactivity guided fractionation of the methanol extract of B. lacera led to isolation of compound 1: (25R)-3beta-{O-beta D-glucopyranosyl-(1 -> 4)-O-alpha-L-rhamnopyranosyl-(1 -> 4)-[O-alpha-L rhamnopyranosyl-(1 -> 2)]-alpha-L-rhamnopyranosyl}-22alphaN-spirosol-5-ene. SGA 1 was the most cytotoxic compound against a number of human cancer cell lines with an IC50 of 2.62 uM against MCF-7 cells. It displayed the highest apoptotic potential (32% AV+/PI-) on MCF-7 cells compared to other cytotoxic SGA analogues and a slight, but significant cell cycle arresting effect. CONCLUSIONS: A new SGA 1 was isolated from B. lacera and its cytotoxic activity, as well as that of other SAGs, was evaluated. SAR investigations on SGA 1, in relation to SGA analogues, show that the number and nature of sugar moieties along with the linkages of the sugar to the aglycone are crucial for cytotoxic and apoptotic activity. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626253 TI - Effects of Ginkgo biloba Extract EGb 761, Donepezil and their Combination on Central Cholinergic Function in Aged Rats. AB - PURPOSE: Ginkgo extract EGb 761 and cholinesterase inhibitors have been shown to be effective in the treatment of dementia patients. In addition to neuroprotective effects, Ginkgo extract EGb 761 has been reported to elevate brain levels of certain neurotransmitters such as dopamine, noradrenaline, and acetylcholine. In the present study, we investigated the impact of EGb 761, donepezil and the combination of both drugs on the central cholinergic system in aged rats. METHODS: 24 month old rats received EGb 761 (100 mg/kg/day), donepezil (1.5 mg/kg/day), the combination of both drugs or vehicle control by oral gavage for 14 days. We used microdialysis in rat hippocampus to monitor extracellular concentrations of acetylcholine (ACh), choline, glucose and lactate. Brain homogenates were prepared to measure activities of acetylcholinesterase (AChE), choline acetyltransferase (ChAT) and high affinity choline uptake (HACU). RESULTS: While EGb 761 alone had no effect, donepezil and the combination of donepezil and EGb 761 increased basal ACh levels by 2- to 3-fold. Concomitantly, significant reductions of AChE and HACU were measured in both groups. No differences were seen between donepezil and the combination in these parameters. Treatment with EGb 761 decreased extracellular choline release and showed a tendency to moderately elevate ChAT activity. CONCLUSIONS: We found that donepezil and EGb 761 do not display a pharmacological interaction when given together. Adding EGb 761 did not modify the effects of donepezil on the hippocampal cholinergic system. Reduced choline levels indicate neuroprotective properties of EGb 761. Therefore, the combination of EGb 761 and donepezil may be beneficial in the treatment of Alzheimer's disease (AD). This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626254 TI - Attenuation of Oxidative Stress in HEK 293 Cells by the TCM Constituents Schisanhenol, Baicalein, Resveratrol or Crocetin and Two Defined Mixtures. AB - PURPOSE: Our working hypothesis is that single bioactive phytochemicals with antioxidant properties that are important constituents of Traditional Chinese Medicine (TCM) and their defined mixtures have potential as chemoprotective agents for chronic conditions characterized by oxidative and nitrosative stress, including Alzheimer's. Here we evaluate the ability of baicalein, crocetin, trans resveratrol or schisanhenol and two defined mixtures of these TCM phytochemicals to attenuate the toxicity resulting from exposure to cell permeant t-butyl hydroperoxide (tBPH) in wild-type and bioengineered (to express choline acetyltransferase) HEK 293 cells. METHODS: Endpoints of tBHP-initiated oxidative and nitrosative stress in both types of HEK 293 cells and its attenuation by TCM constituents and mixtures included cytotoxicity (LDH release); depletion of intracellular glutathione (GSH); formation of S-glutathionylated proteins; oxidative changes to the disulfide proteome; and real-time changes in intracellular redox status. RESULTS: At low uM concentrations, each of the TCM constituents and mixtures effectively attenuated intracellular toxicity due to exposure of HEK 293 cells to 50 or 250 uM tBHP for 30 min to 3 h. Confocal microscopy of HEK 293 cells transfected with mutated green fluorescent protein (roGFP2) showed effective attenuation of tBHP oxidation by baicalein in real time. Three redox-regulated proteins prominent in the disulfide proteome of HEK 293 cells were identified by MALDI-TOF mass spectrometry. CONCLUSIONS: We conclude that single TCM chemicals and their simple mixtures have potential for use in adjunct chemoprotective therapy. Advantages of mixtures compared to single TCM constituents include the ability to combine compounds with varying molecular mechanisms of cytoprotection for enhanced biological activity; and to combine chemicals with complementary pharmacokinetic properties to increase half-life and prolong activity in vivo. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626255 TI - Pharmacologic Activities of 3'-Hydroxypterostilbene: Cytotoxic, Anti-Oxidant, Anti-Adipogenic, Anti-Inflammatory, Histone Deacetylase and Sirtuin 1 Inhibitory Activity. AB - PURPOSE: Delineate the selected pharmacodynamics of a naturally occurring stilbene 3'-Hydroxypterostilbene. OBJECTIVE: Characterize for the first time the pharmacodynamics bioactivity in several in-vitro assays with relevant roles in heart disease, inflammation, cancer, and diabetes etiology and pathophysiology. METHODS: 3'-Hydroxypterostilbene was studied in in-vitro assays to identify possible bioactivity. RESULTS: 3'-Hydroxypterostilbene demonstrated anti-oxidant, anti-inflammatory, cytotoxic, anti-adipogenic, histone deacetylase, and sirtuin-1 inhibitory activity. CONCLUSIONS: The importance of understanding individual stilbene pharmacologic activities were delineated. Small changes in chemical structure of stilbene compounds result in significant pharmacodynamic differences. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626256 TI - Selective Induction of Apoptosis by Azadarichta indica Leaf Extract by Targeting Oxidative Vulnerabilities in Human Cancer Cells. AB - PURPOSE: Natural products have been a great source of medications used in conventional medicines for the treatment of various diseases; more importantly, they have played a significant role in the development of anti-cancer drugs for a number of decades. The benefits to employing whole extracts of natural health products, rather than a single ingredient, for cancer treatment remains unexplored. Our research group has previously demonstrated the potential anti cancer benefits of several natural health products (NHPs), prompting further studies into other NHPs, such as Neem (Azadarichta indica), a tree native to India and has been used in Ayurvedic medicine for over 4000 years. The objective of this study is to determine the possible anti-cancer potential of aqueous and ethanolic Neem leaf extracts (NLEs) and to identify the specific mode(s) of action. METHODS: Cells were treated with NLE and cell viability was then assessed using a water-soluble tetrazolium salt. Cell death was confirmed using the fluorescent dye propidium iodide and apoptosis was identified using the Annexin-V binding assay. Mitochondrial membrane permeabilization was visualized using JC-1 staining and the production of whole cell and mitochondrial ROS was measured with 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) and Amplex Red, respectively. In vivo efficacy of aqueous NLE was assessed in human tumour xenografts in CD-1 nu/nu immunocompromised mice. RESULTS: Results indicate that both ethanolic and aqueous extracts of Neem leaf were effective in inducing apoptosis in leukemia and colon cancer cells, following destabilization of the mitochondrial membrane. Furthermore, an increase in the production of reactive oxygen species (ROS) was observed in cancer cells treated with NLEs, indicating that oxidative stress may play a role in the mechanism of cell death. Additionally, in vivo results showed that aqueous NLE (delivered orally) was well tolerated and inhibited tumour growth of human xenografts in mice. CONCLUSIONS: These findings suggest the potential of NLEs as safer and effective alternatives to conventional chemotherapy. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626257 TI - Structure and Potential Cellular Targets of HAMLET-like Anti-Cancer Compounds made from Milk Components. AB - The HAMLET family of compounds (Human Alpha-lactalbumin Made Lethal to Tumours) was discovered during studies on the properties of human milk, and is a class of protein-lipid complexes having broad spectrum anti-cancer, and some specific anti bacterial properties. The structure of HAMLET-like compounds consists of an aggregation of partially unfolded protein making up the majority of the compound's mass, with fatty acid molecules bound in the hydrophobic core. This is a novel protein-lipid structure and has only recently been derived by small-angle X-ray scattering analysis. The structure is the basis of a novel cytotoxicity mechanism responsible for anti-cancer activity to all of the around 50 different cancer cell types for which the HAMLET family has been trialled. Multiple cytotoxic mechanisms have been hypothesised for the HAMLET-like compounds, but it is not yet clear which of those are the initiating cytotoxic mechanism(s) and which are subsequent activities triggered by the initiating mechanism(s). In addition to the studies into the structure of these compounds, this review presents the state of knowledge of the anti-cancer aspects of HAMLET-like compounds, the HAMLET-induced cytotoxic activities to cancer and non-cancer cells, and the several prospective cell membrane and intracellular targets of the HAMLET family. The emerging picture is that HAMLET-like compounds initiate their cytotoxic effects on what may be a cancer-specific target in the cell membrane that has yet to be identified. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626258 TI - Hepatotoxicity of Pyrrolizidine Alkaloids. AB - PURPOSE: This article aimed 1) to review herbal medicine containing pyrrolizidine alkaloids (PA)-induced toxicities of the liver; 2) to encourage the recognition and prevention of common problems encountered when using complementary and alternative medicine and 3) to review the toxic effects of herbal remedies containing PAs. DESIGN AND METHODS: We performed a systematic literature search using the PubMed and Google Scholar engines. The search was not restricted to languages. We also provide an interpretation of the data. CONCLUSIONS: Herbal remedies containing PAs can induce liver damage, including hepato- sinusoidal obstruction syndrome or veno-occlusive disease. Preventing overdose and monitoring long-term use of such remedies may avoid glutathione depletion leading to mitochondrial injury, and therefore avoid liver cell damage. Moreover, immediately stopping the herbal medication prevents further harm to the liver. Chronic consumption of hepatotoxicants can lead to cancer formation and promotion. The role of active metabolites in PA-induced liver toxicity and their mechanism of action require further investigation. This article is open to POST PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 26626259 TI - Natural Products: Biochemical-Chemical Characterization, and Evidence for Therapeutic Potential. PMID- 26626261 TI - Considerations in the Diagnosis and Management of Pediatric Patients With Favorable Histology Wilms Tumor Who Present With Only Pulmonary Nodules. AB - More than 70% of children with stage IV, favorable histology (FH) Wilms tumor will be relapse-free survivors 16 years after diagnosis. Successful treatment generally includes whole lung radiation therapy and doxorubicin. Such therapy is associated with adverse, long-term effects, including impaired pulmonary function, congestive heart failure, and second malignant neoplasms, especially breast cancer. Cooperative groups have adopted a risk-based approach to the treatment of these patients. It is important to recall the good overall prognosis for this group before recommendations for intensification are made based on preliminary data and in the absence of histological confirmation of persistent malignant disease. PMID- 26626260 TI - CYP1B1 promotes tumorigenesis via altered expression of CDC20 and DAPK1 genes in renal cell carcinoma. AB - BACKGROUND: Cytochrome P450 1B1 (CYP1B1) has been shown to be up-regulated in many types of cancer including renal cell carcinoma (RCC). Several reports have shown that CYP1B1 can influence the regulation of tumor development; however, its role in RCC has not been well investigated. The aim of the present study was to determine the functional effects of CYP1B1 gene on tumorigenesis in RCC. METHODS: Expression of CYP1B1 was determined in RCC cell lines, and tissue microarrays of 96 RCC and 25 normal tissues. To determine the biological significance of CYP1B1 in RCC progression, we silenced the gene in Caki-1 and 769-P cells by RNA interference and performed various functional analyses. RESULTS: First, we confirmed that CYP1B1 protein expression was significantly higher in RCC cell lines compared to normal kidney tissue. This trend was also observed in RCC samples (p < 0.01). Interestingly, CYP1B1 expression was associated with tumor grade and stage. Next, we silenced the gene in Caki-1 and 769-P cells by RNA interference and performed various functional analyses to determine the biological significance of CYP1B1 in RCC progression. Inhibition of CYP1B1 expression resulted in decreased cell proliferation, migration and invasion of RCC cells. In addition, reduction of CYP1B1 induced cellular apoptosis in Caki-1. We also found that these anti-tumor effects on RCC cells caused by CYP1B1 depletion may be due to alteration of CDC20 and DAPK1 expression based on gene microarray and confirmed by real-time PCR. Interestingly, CYP1B1 expression was associated with CDC20 and DAPK1 expression in clinical samples. CONCLUSIONS: CYP1B1 may promote RCC development by inducing CDC20 expression and inhibiting apoptosis through the down-regulation of DAPK1. Our results demonstrate that CYP1B1 can be a potential tumor biomarker and a target for anticancer therapy in RCC. PMID- 26626262 TI - Person-Centered Care: A Definition and Essential Elements. AB - Improving healthcare safety, quality, and coordination, as well as quality of life, are important aims of caring for older adults with multiple chronic conditions and/or functional limitations. Person-centered care is an approach to meeting these aims, but there are no standardized, agreed-upon parameters for delivering such care. The SCAN Foundation charged a team from the American Geriatrics Society (AGS) in collaboration with a research and clinical team from the Keck School of Medicine of the University of Southern California to provide the evidence base to support a definition of person-centered care and its essential elements. An interprofessional panel of experts in person-centered care principles and practices that the AGS convened developed this statement. PMID- 26626264 TI - "No way Jose!" Clinicians must have authority over patient care: the manager's scope of practice does not cover medical decisions. PMID- 26626263 TI - Seroprevalence of hepatitis B surface antigen and anti HCV antibody and its associated risk factors among pregnant women attending maternity ward of Felege Hiwot Referral Hospital, northwest Ethiopia: a cross-sectional study. AB - BACKGROUND: Viral hepatitis is a life-threatening liver disease that has become important public health issue in developing countries including Ethiopia. This study was undertaken to determine the seroprevalence of HBsAgs and anti-HCV antibodies and what socio-demographic factors are associated with sero-positivity of Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infections among pregnant women attending maternity ward of Felege Hiwot Referral Hospital, northwest, Ethiopia. METHODS: Hospital based cross-sectional study was conducted from November 2013 to January 2014. Blood samples were randomly collected from 384 pregnant women. Data on socio-demographic characteristics, obstetric and potential risk factors were collected using semi-structured questionnaire. Chromatographic kits were used to detect the presence of HBsAg and antibodies against HCV in serum samples of the studied subjects. Chi-square test was used for assessing the association between socio-demographic variables and HBV and HCV status. Logistic regression analysis was done to determine the strength of association between risk factors and HBV or HCV infection. P-values less than 0.05 were considered as significant. RESULTS: Seroprevalnce of hepatitis B and C virus infections were found to be 4.4 and 0.26 %, respectively. None of the pregnant women were co-infected by these two viruses. Amongst the potential risk factors, previous history of dental procedure (AOR = 4.104, CI = 1.276-13.201, P = 0.018), house hold contact (AOR = 5.475, CI = 1.472-20.368, P = 0.011), multiple sexual exposure (AOR = 5.041, CI = 1.580-16.076, P = 0.006), and delivery at traditional birth attendants (AOR = 4.100, CI = 0.195-86.129, P = 0.024) were significantly associated with and important predictors of hepatitis B infection. CONCLUSIONS: This study found an intermediate endemicity (4.4 %) of HBV infection in pregnant women whereas seroprevalence of anti-HCV antibody was very small, but this needs to be confirmed by other similar studies with larger sample size. Thus, scaling up of the screening of pregnant women for HBV and HCV infections and provision of health education about the risk factors, the mode of transmissions and prevention is recommended. PMID- 26626265 TI - Sudden cardiac arrest on the football field of play--highlights for sports medicine from the European Resuscitation Council 2015 Consensus Guidelines. AB - The European Resuscitation Council (ERC) 2015 Guidelines for Resuscitation were published recently. For the first time, these guidelines included a subsection on 'cardiac arrest during sports activities' in the section dealing with cardiac arrest in special circumstances, endorsing both the importance and unique nature of this form of cardiac arrest. This paper reviews four critical areas in the management of sudden cardiac arrest in a football player: recognition, response, resuscitation and removal from the field of play. Expeditious response with initiation of immediate resuscitation at the side of a collapsed player remains crucial for survival, and chest compressions should be continued until the automated external defibrillator (AED) has been fully activated, so that the sideline medical team response to the side of a non-contact collapsed player on the field of play, with AED and defibrillation, occurs within a maximum of 2 min from collapse. PMID- 26626267 TI - Great Britain Rowing Team Guideline for diagnosis and management of rib stress injury: Part 1. AB - BACKGROUND: Rib stress injury (RSI) is the development of pain due to bone oedema caused by overload along the rib shaft and is commonly seen in rowers. Often clinicians who manage this injury are experienced with the condition at the elite level. There may, however, be a lack of confidence in diagnosing and managing this condition by clinicians who are not regularly exposed to this injury. As a result, an evidence-based guideline has been developed to aid diagnosis and management of RSI. METHODS: A detailed literature search was conducted reviewing the diagnosis and management of RSI. Detailed discussions were held by the Great Britain Rowing Medical Team to identify key issues in diagnosis and management of RSI. An up-to-date, evidence-based approach to managing RSI was created using both expert knowledge and current literature to formulate a functional guideline outlining best practice in management of RSI in rowers. RESULTS: A clinical guideline has been created incorporating 5 key areas: diagnosis, severity grading, investigation, management and associated risk factors for RSI. Important indicators for each key area are incorporated within the guideline using relevant literature where possible alongside expert opinion. The guideline has deliberately been kept concise and tailored for use in the clinical setting. CONCLUSIONS: A new clinical guideline for management of RSIs has been developed to facilitate clinicians in identifying RSI, aiding accurate diagnosis and providing effective management. This guideline is to be disseminated to clinicians, rowing coaches and clubs throughout the UK. PMID- 26626266 TI - Professional Rugby Union players have a 60% greater risk of time loss injury after concussion: a 2-season prospective study of clinical outcomes. AB - AIM: To investigate incidence of concussion, clinical outcomes and subsequent injury risk following concussion. METHODS: In a two-season (2012/2013, 2013/2014) prospective cohort study, incidence of diagnosed match concussions (injuries/1000 h), median time interval to subsequent injury of any type (survival time) and time spent at each stage of the graduated return to play pathway were determined in 810 professional Rugby Union players (1176 player seasons). RESULTS: Match concussion incidence was 8.9/1000 h with over 50% occurring in the tackle. Subsequent incidence of any injury for players who returned to play in the same season following a diagnosed concussion (122/1000 h, 95% CI 106 to 141) was 60% higher (IRR 1.6, 95% CI 1.4 to 1.8) than for those who did not sustain a concussion (76/1000 h, 95% CI 72 to 80). Median time to next injury following return to play was shorter following concussion (53 days, 95% CI 41 to 64) than following non-concussive injuries (114 days, 95% CI 85 to 143). 38% of players reported recurrence of symptoms or failed to match their baseline neurocognitive test during the graduated return to play protocol. SUMMARY AND CONCLUSIONS: Players who returned to play in the same season after a diagnosed concussion had a 60% greater risk of time-loss injury than players without concussion. A substantial proportion of players reported recurrence of symptoms or failed to match baseline neurocognitive test scores during graduated return to play. These data pave the way for trials of more conservative and comprehensive graduated return to play protocols, with a greater focus on active rehabilitation. PMID- 26626268 TI - Olympic weightlifting training improves vertical jump height in sportspeople: a systematic review with meta-analysis. AB - PURPOSE: This systematic review was conducted to evaluate the effect of Olympic weightlifting (OW) on vertical jump (VJ) height compared to a control condition, traditional resistance training and plyometric training. METHODS: Five electronic databases were searched using terms related to OW and VJ. Studies needed to include at least one OW exercise, an intervention lasting >=6 weeks; a comparison group of control, traditional resistance training or plyometric training; and to have measured VJ height. The methodological quality of studies was assessed using the Downs and Black Checklist. Random and fixed effects meta-analyses were performed to pool the results of the included studies and generate a weighted mean effect size (ES). RESULTS: Six studies (seven articles) were included in the meta-analyses and described a total of 232 participants (175 athletes and 57 physical education students) with resistance training experience, aged 19.5+/-2.2 years. Three studies compared OW versus control; four studies compared OW versus traditional resistance training; and three studies compared OW versus plyometric training. Meta-analyses indicated OW improved VJ height by 7.7% (95% CI 3.4 to 5.4 cm) compared to control (ES=0.62, p=0.03) and by 5.1% (95% CI 2.2 to 3.0 cm) compared to traditional resistance training (ES=0.64 p=0.00004). Change in VJ height was not different for OW versus plyometric training. CONCLUSIONS: OW is an effective training method to improve VJ height. The similar effects observed for OW and plyometric training on VJ height suggests that either of these methods would be beneficial when devising training programmes to improve VJ height. PMID- 26626269 TI - Risk factors for musculoskeletal injury in preprofessional dancers: a systematic review. AB - BACKGROUND: Preprofessional dancers partake in rigorous training and have high injury prevalence. Attempts to identify risk factors for dance injuries have focused on a diversity of intrinsic and extrinsic factors. OBJECTIVE: To identify and evaluate the evidence examining risk factors for musculoskeletal injury in preprofessional ballet and modern dancers. METHODS: Fifteen electronic databases were systematically searched to October 2015. Studies selected met a priori inclusion criteria and investigated musculoskeletal injury risk factors in preprofessional (elite adolescent, student, young adult) ballet and modern dancers. Two reviewers independently assessed the quality and level of evidence using the Downs and Black (DB) criteria and a modified Oxford Centre of Evidence Based Medicine 2009 model, respectively. RESULTS: Of 1364 potentially relevant studies, 47 were included and scored. Inconsistent injury definition and methodology precluded meta-analysis. The most common modifiable risk factors investigated were anthropometrics (ie, body mass index, adiposity), joint range of motion (ie, lower extremity), dance exposure (ie, years training, exposure hours) and age. The median DB score across studies was 8/33 (range 2-16). The majority of studies were classified as level 3 evidence and few considered risk factor inter-relationships. There is some level 2 evidence that previous injury and poor psychological coping skills are associated with increased injury risk. CONCLUSIONS: Because of the lack of high-quality studies, consensus regarding risk factors for musculoskeletal injury in preprofessional dancers remains difficult. There is a need for injury definition consensus and high-quality prospective studies examining the multifactorial relationship between risk factors and injury in preprofessional dance. PMID- 26626270 TI - The stigma of mental health in athletes: are mental toughness and mental health seen as contradictory in elite sport? PMID- 26626271 TI - The incidence of concussion in youth sports: a systematic review and meta analysis. AB - OBJECTIVE: To conduct a comprehensive systematic review and meta-analysis of studies assessing the incidence of concussion in youth athletes. Specifically, we estimate the overall risk of concussion in youth sports and compare sport specific estimates of concussion risk. DESIGN: Systemic review and meta-analysis. DATA SOURCES: A search of Medline, Embase (1980 through September 2014), and SportDiscus (1985 through September 2014) supplemented by manual searches of bibliographies and conference proceedings. INCLUSION CRITERIA: We included studies if they met the inclusion criteria of study design (prospective cohort study), relevant sports identified from the literature (eg, American football, rugby, hockey, lacrosse, soccer/football, basketball, baseball, softball, wrestling, field hockey, track, taekwondo, volleyball and cheerleading), population (males and females <=18 years old), and outcome (concussion). RESULTS: Of the 698 studies reviewed for eligibility, 23 articles were accepted for systematic review and 13 of which were included in a meta-analysis. Random effects models were used to pool overall and sport-specific concussion incidence rates per 1000 athlete exposures (AEs). The overall risk of concussion was estimated at 0.23 (95% CI 0.19 to 0.28). The three sports with the highest incidence rates were rugby, hockey and American football at 4.18, 1.20 and 0.53, respectively. Lowest incidence rates per 1000 AEs occurred in volleyball, baseball and cheerleading at 0.03, 0.06 and 0.07, respectively. Quality of the included studies varied, with the majority of studies not reporting age and gender-specific incidence rates or an operational definition for concussion. CONCLUSIONS: There are striking differences in the rates of incident youth concussion across 12 sports. This systematic review and meta-analysis can serve as the current sport-specific baseline risk of concussion among youth athletes. PMID- 26626273 TI - The effects of attachment and outness on illness adjustment among gay men with prostate cancer. AB - OBJECTIVE: Previous research has suggested that gay men facing prostate cancer may be particularly vulnerable to poor illness adjustment. Moreover, although attachment and greater disclosure of sexual orientation have been associated with health outcomes, their associations in this population have been largely unexamined. The purpose of the present study was to investigate whether greater outness about one's sexual orientation significantly mediated the associations between anxious and avoidant attachment and illness intrusiveness among gay men with prostate cancer. METHODS: Ninety-two gay and bisexual men who had received a diagnosis of prostate cancer in the past 4 years were recruited for the present study. Self-report questionnaires assessed demographic and medical variables, attachment, outness level and comfort, and illness intrusiveness. Bootstrapping procedures were used to assess for mediation. RESULTS: Results suggested significant associations between anxious attachment, outness comfort, and illness intrusiveness. Less comfort with outness significantly mediated the association between greater anxious attachment and more illness intrusiveness. Avoidant attachment was not significantly associated with illness intrusiveness. CONCLUSIONS: Findings support the mediating role of the subjective experience of being an out gay man in the association between anxious attachment and illness intrusiveness. These results suggest that facilitating greater comfort with outness would be beneficial for illness adjustment among gay men with prostate cancer whom have more anxious attachment styles. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26626272 TI - Athletic groin pain (part 1): a prospective anatomical diagnosis of 382 patients- clinical findings, MRI findings and patient-reported outcome measures at baseline. AB - BACKGROUND: Athletic groin pain remains a common field-based team sports time loss injury. There are few reports of non-surgically managed cohorts with athletic groin pain. AIM: To describe clinical presentation/examination, MRI findings and patient-reported outcome (PRO) scores for an athletic groin pain cohort. METHODS: All patients had a history including demographics, injury duration, sport played and standardised clinical examination. All patients underwent MRI and PRO score to assess recovery. A clinical diagnosis of the injured anatomical structure was made based on these findings. Statistical assessment of the reliability of accepted standard investigations undertaken in making an anatomical diagnosis was performed. RESULT: 382 consecutive athletic groin pain patients, all male, enrolled. Median time in pain at presentation was (IQR) 36 (16-75) weeks. Most (91%) played field-based ball-sports. Injury to the pubic aponeurosis (PA) 240 (62.8%) was the most common diagnosis. This was followed by injuries to the hip in 81 (21.2%) and adductors in 56 (14.7%) cases. The adductor squeeze test (90 degrees hip flexion) was sensitive (85.4%) but not specific for the pubic aponeurosis and adductor pathology (negative likelihood ratio 1.95). Analysed in series, positive MRI findings and tenderness of the pubic aponeurosis had a 92.8% post-test probability. CONCLUSIONS: In this largest cohort of patients with athletic groin pain combining clinical and MRI diagnostics there was a 63% prevalence of PA injury. The adductor squeeze test was sensitive for athletic groin pain, but not specific individual pathologies. MRI improved diagnostic post-test probability. No hernia or incipient hernia was diagnosed. CLINICAL TRIAL REGISTRATION NUMBER: NCT02437942. PMID- 26626274 TI - Limitations of the rabbit pyrogen test for assessing meningococcal OMV based vaccines. AB - The rabbit pyrogen test was developed in the early 1900's to detect contaminating pyrogens in parenteral medicines. Since its conception alternative methods with improved sensitivity, relevancy and which are ethically more acceptable have been developed. However, the test is a current Pharmacopeial method and is used to evaluate the pyrogen content of some vaccines. In this article the limitations and pitfalls of using the test to measure pyrogenicity of vaccines containing outer membrane vesicles are described. The method is unsuitable as a safety test for these products due to the high levels of endotoxin present in the vaccine which generate a pyrogenic response in rabbits when delivered intravenously without any dilution. Its use as a consistency test is also ambiguous as the test gives a qualitative rather than quantitative response and the rabbit models are highly variable. In addition there is evidence that measuring the temperature rise of the animals over three hours does not capture the maximum fever response. Finally the article considers the use of alternative methods and the validity of animal models when applying a consistency based approach for assessing the quality of licensed products. PMID- 26626276 TI - A determinant-based criterion for working correlation structure selection in generalized estimating equations. AB - In generalized estimating equations (GEE), the correlation between the repeated observations on a subject is specified with a working correlation matrix. Correct specification of the working correlation structure ensures efficient estimators of the regression coefficients. Among the criteria used, in practice, for selecting working correlation structure, Rotnitzky-Jewell, Quasi Information Criterion (QIC) and Correlation Information Criterion (CIC) are based on the fact that if the assumed working correlation structure is correct then the model-based (naive) and the sandwich (robust) covariance estimators of the regression coefficient estimators should be close to each other. The sandwich covariance estimator, used in defining the Rotnitzky-Jewell, QIC and CIC criteria, is biased downward and has a larger variability than the corresponding model-based covariance estimator. Motivated by this fact, a new criterion is proposed in this paper based on the bias-corrected sandwich covariance estimator for selecting an appropriate working correlation structure in GEE. A comparison of the proposed and the competing criteria is shown using simulation studies with correlated binary responses. The results revealed that the proposed criterion generally performs better than the competing criteria. An example of selecting the appropriate working correlation structure has also been shown using the data from Madras Schizophrenia Study. PMID- 26626275 TI - Comparison of the specificity of antibodies to VAR2CSA in Cameroonian multigravidae with and without placental malaria: a retrospective case-control study. AB - BACKGROUND: Antibodies (Ab) to VAR2CSA prevent Plasmodium falciparum-infected erythrocytes from sequestrating in the placenta, i.e., prevent placental malaria (PM). The specificity of Ab to VAR2CSA associated with absence of PM is unknown. Accordingly, differences in the specificity of Ab to VAR2CSA were compared between multigravidae with and without PM who had Ab to VAR2CSA. METHODS: In a retrospective case-control study, plasma collected from Cameroonian multigravidae with (n = 96) and without (n = 324) PM were screened in 21 assays that measured antibody levels to full length VAR2CSA (FV2), individual VAR2CSA DBL domains, VAR2CSA domains from different genetic backgrounds (variants), as well as proportion of high avidity Ab to FV2. RESULTS: Multigravidae with and without PM had similar levels of Ab to FV2, the six VAR2CSA DBL domains and different variants, while the proportion of high avidity Ab to FV2 was significantly higher in women without PM at delivery (p = 0.0030) compared to women with PM. In a logistic regression model adjusted for gravidity and age, the percentage of high avidity Ab to FV2 was associated with reduced likelihood of PM in multigravidae. A 5 % increase in proportion of high avidity Ab to FV2 was associated with a nearly 15 % lower likelihood of PM. CONCLUSION: Ab avidity to FV2 may be an important indicator of immunity to PM. PMID- 26626277 TI - Lack of integrase inhibitors associated resistance mutations among HIV-1C isolates. AB - BACKGROUND: Although biochemical analysis of HIV-1 integrase enzyme suggested the use of integrase inhibitors (INIs) against HIV-1C, different viral subtypes may favor different mutational pathways potentially leading to varying levels of drug resistance. Thus, the aim of this study was to search for the occurrence and natural evolution of integrase polymorphisms and/or resistance mutations in HIV 1C Ethiopian clinical isolates prior to the introduction of INIs. METHODS: Plasma samples from chronically infected drug naive patients (N = 45), of whom the PR and RT sequence was determined previously, were used to generate population based sequences of HIV-1 integrase. HIV-1 subtype was determined using the REGA HIV-1 subtyping tool. Resistance mutations were interpreted according to the Stanford HIV drug resistance database ( http://hivdb.stanford.edu ) and the updated International Antiviral Society (IAS)-USA mutation lists. Moreover, rates of polymorphisms in the current isolates were compared with South African and global HIV-1C isolates. RESULTS: All subjects were infected with HIV-1C concordant to the protease (PR) and reverse transcriptase (RT) regions. Neither major resistance-associated IN mutations (T66I/A/K, E92Q/G, T97A, Y143HCR, S147G, Q148H/R/K, and N155H) nor silent mutations known to change the genetic barrier were observed. Moreover, the DDE-catalytic motif (D64G/D116G/E152 K) and signature HHCC zinc-binding motifs at codon 12, 16, 40 and 43 were found to be highly conserved. However, compared to other South African subtype C isolates, the rate of polymorphism was variable at various positions. CONCLUSION: Although the sample size is small, the findings suggest that this drug class could be effective in Ethiopia and other southern African countries where HIV-1C is predominantly circulating. The data will contribute to define the importance of integrase polymorphism and to improve resistance interpretation algorithms in HIV 1C isolates. PMID- 26626278 TI - Solid-Phase Enrichment and Analysis of Azide-Labeled Natural Products: Fishing Downstream of Biochemical Pathways. AB - Many methods have been devised over the decades to trace precursors of specific molecules in cellular environments as, for example, in biosynthesis studies. The advent of click chemistry has facilitated the powerful combination of tracing and at the same time sieving the highly complex metabolome for compounds derived from simple or complex starting materials, especially when the click reaction takes place on a solid support. While the principle of solid-phase click reactions has already been successfully applied for selective protein and peptide enrichment, the successful enrichment of much smaller primary and secondary metabolites, showing great structural diversity and undergoing many different biosynthetic steps, has seen only little development. For bacterial secondary metabolism, a far broader tolerance for "clickable" precursors was observed than in ribosomal proteinogenesis, thus making this method a surprisingly valuable tool for the tracking and discovery of compounds within the cellular biochemical network. The implementation of this method has led to the identification of several new compounds from the bacterial genera Photorhabdus and Xenorhabdus, clearly proving its power. PMID- 26626279 TI - Estimating the value of medical treatments to patients using probabilistic multi criteria decision analysis. AB - BACKGROUND: Estimating the value of medical treatments to patients is an essential part of healthcare decision making, but is mostly done implicitly and without consulting patients. Multi criteria decision analysis (MCDA) has been proposed for the valuation task, while stated preference studies are increasingly used to measure patient preferences. In this study we propose a methodology for using stated preferences to weigh clinical evidence in an MCDA model that includes uncertainty in both patient preferences and clinical evidence explicitly. METHODS: A probabilistic MCDA model with an additive value function was developed and illustrated using a case on hypothetical treatments for depression. The patient-weighted values were approximated with Monte Carlo simulations and compared to expert-weighted results. Decision uncertainty was calculated as the probability of rank reversal for the first rank. Furthermore, scenario analyses were done to assess the relative impact of uncertainty in preferences and clinical evidence, and of assuming uniform preference distributions. RESULTS: The patient-weighted values for drug A, drug B, drug C, and placebo were 0.51 (95% CI: 0.48 to 0.54), 0.51 (95% CI: 0.48 to 0.54), 0.54 (0.49 to 0.58), and 0.15 (95% CI: 0.13 to 0.17), respectively. Drug C was the most preferred treatment and the rank reversal probability for first rank was 27%. This probability decreased to 18% when uncertainty in performances was not included and increased to 41% when uncertainty in criterion weights was not included. With uniform preference distributions, the first rank reversal probability increased to 61%. The expert-weighted values for drug A, drug B, drug C, and placebo were 0.67 (95% CI: 0.65 to 0.68), 0.57 (95% CI: 0.56 to 0.59), 0.67 (95% CI: 0.61 to 0.71), and 0.19 (95% CI: 0.17 to 0.21). The rank reversal probability for the first rank according to experts was 49%. CONCLUSIONS: Preferences elicited from patients can be used to weigh clinical evidence in a probabilistic MCDA model. The resulting treatment values can be contrasted to results from experts, and the impact of uncertainty can be quantified using rank probabilities. Future research should focus on integrating the model with regulatory decision frameworks and on including other types of uncertainty. PMID- 26626280 TI - A Different New Year's Resolution: Honor Your Military Students. PMID- 26626281 TI - Supporting Students With Disabilities. PMID- 26626282 TI - Psychosocial interventions for supporting women to stop smoking in pregnancy. PMID- 26626283 TI - Attitude and confidence of undergraduate medical programme educators to practice and teach evidence-based healthcare: a cross-sectional survey. AB - AIM: Medical student educators play critical roles in evidence-based healthcare (EBHC) teaching and learning and as role models practicing EBHC. This study assessed their confidence to practice and teach EBHC, their attitude to EBHC and barriers to practicing and teaching EBHC. METHODS: We conducted a cross-sectional online survey of educators of undergraduate medical students at a South African academic institution. STATA 12 was used for quantitative data analysis. Responses to open-ended questions were coded, and further interpretation done using thematic content analysis. RESULTS: Forty two (19%) educators from various departments responded to the invitation sent to everyone formally involved in teaching undergraduate medical students. They had high levels of knowledge and understanding of EBHC. Many had received training in teaching and learning approaches, although EBHC training received was mainly on enabling competencies. Limitations to practicing EBHC included lack of time, clinical workload, limited access to Internet and resources, knowledge and skills. One quarter of the respondents indicated that they teach EBHC. Perceived barriers to teaching EBHC reported related to students (e.g. lack of interest), context (e.g. access to databases) and educators (e.g. competing priorities). Respondents' suggestions for support included reliable Internet access, easy point-of-care access to databases and resources, increasing awareness of EBHC, building capacity to practice and facilitate learning of EBHC and a supportive community of practice. CONCLUSION: Educators play a critical role in facilitating EBHC learning not just in the classroom, but also in practice. Without adequate support, training and development, they are ill equipped to be the role models future healthcare professionals need. PMID- 26626284 TI - The future of ICRP: towards a centenary and beyond. AB - The International Commission on Radiological Protection (ICRP) has been in existence for 87 y, since its establishment in 1928. It remains a leading authority in radiological protection, and its role is to provide recommendations and guidance on all aspects of protection against ionising radiation. The published recommendations of ICRP form the basis of radiation safety standards worldwide. Modernisation of the organisation in recent years has led to new initiatives and changes. These have included writing a strategic plan and code of ethics for the first time. Elections for committee membership have been through open nominations, a process which will shortly be repeated for the membership in the next term, commencing on 1 July 2017. Biennial symposia started in 2011, and the success of the first two symposia has secured this venture as a regular part of the ICRP calendar. ICRP has also revised its method of working with other organisations by establishing 'special liaison organisation' status. This has improved collaboration with the ever-expanding number of organisations working in radiological protection, with whom it is important that ICRP has essential links. ICRP is also looking to review its legal basis and governing documents in the future, in order to ensure that best practices are being followed as ICRP evolves. In addition, the strategic plan will be reviewed and updated regularly. Other ways of working with organisations will be considered to further strengthen engagement with the wider radiological protection community. ICRP aims to make its publications available at low or no cost, and to produce both a plain language overview of the system of radiological protection and a summary of the recommendations. These activities will require additional financial resources, and ICRP has embarked on a fundraising campaign to support such efforts. ICRP can be proud of its history of maintaining its independence and preserving the wide respect earned over many years. Despite long traditions, ICRP has evolved and will continue to do so to perform as a more modern organisation as it heads towards a centenary and beyond. PMID- 26626286 TI - Overview of ICRP Committee 4: application of the Commission's recommendations. AB - Committee 4 develops principles and recommendations on radiological protection of people in all exposure situations. The committee meeting in 2014 was hosted by GE Healthcare in Arlington Heights, IL, USA on 27 July-1 August 2014. The programme of work of Committee 4 encompasses several broad areas, including a series of reports covering various aspects of existing exposure situations, leading the efforts of the International Commission on Radiological Protection (ICRP) to update and elaborate recommendations in light of the accident at Fukushima Daiichi nuclear power plant for emergencies and living in contaminated areas, elaborating the underpinnings of the system of radiological protection, and developing focussed reports on specific topic areas in consultation with ICRP's special liaison organisations. Committee 4 has six active Task Groups working on naturally occurring radioactive material; cosmic radiation in aviation; updates of ICRP Publications 109 and 111; ethics of radiological protection; surface and near-surface disposal of solid radioactive waste; and exposures resulting from contaminated sites from past industrial, military, and nuclear activities. In addition, there is a Working Party on tolerability of risk, and ongoing work with the various special liaison organisations of ICRP. PMID- 26626288 TI - Size effects in the conduction electron spin resonance of anthracite and higher anthraxolite. AB - Electron paramagnetic resonance spectroscopy of conduction electrons, i.e. Conduction Electron Spin Resonance (CESR), is a powerful tool for studies of carbon samples. Conductive samples cause additional effects in CESR spectra that influence the shape and intensity of the signals. In cases where conduction electrons play a dominant role, whilst the influence of localized paramagnetic centres is small or negligible, the effects because of the spins on conduction electrons will dominate the spectra. It has been shown that for some ratios of the bulk sample sizes (d) to the skin depth (delta), which depend on the electrical conductivity, additional size effects become visible in the line asymmetry parameter A/|B|, which is the ratio of the maximum to the absolute, minimum value of the resonance signal. To study these effects the electrical direct current-conductivity and CESR measurements are carried out for two amorphous bulk coal samples of anthracite and a higher anthraxolite. The observed effects are described and discussed in terms of the Dyson theory. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26626287 TI - Surveillance of potential hosts and vectors of scrub typhus in Taiwan. AB - BACKGROUND: Scrub typhus is a lethal infectious disease vectored by larval trombiculid mites (i.e. chiggers) infected with Orientia tsutsugamushi (OT) and recent decades have witnessed an emergence of scrub typhus in several countries. Identification of chigger species and their vertebrate hosts is fundamental for the assessment of human risks to scrub typhus under environmental changes, but intensive and extensive survey of chiggers and their hosts is still lacking in Taiwan. METHODS: Chiggers were collected from shrews and rodents in nine counties of Taiwan and were assayed for OT infections with nested polymerase chain reaction (PCR). PCR products were further sequenced to reveal probable OT strains. Rodents were assessed for OT exposure by immunofluorescent antibody assay. Lastly, incidence rate of scrub typhus in each county was associated with loads and prevalence of chigger infestations, seropositivity rate in rodents, and OT positivity rate in chiggers. RESULTS: Rattus losea was the most abundant (48.7% of 1,285 individuals) and widespread (occurred in nine counties) small mammal species and hosted the majority of chiggers (76.4% of 128,520 chiggers). Leptotrombidium deliense was the most common (64.9% of all identified chiggers) and widespread (occurred in seven counties) chigger species but was replaced by Leptotrombidium pallidum or Leptotrombidium scutellare during the cold seasons in two counties (Matsu and Kinmen) where winter temperatures were lower than other study sites. Seropositivity rate for OT exposure in 876 assayed rodents was 43.0% and OT positivity rate in 347 pools of chiggers was 55.9%, with 15 OT strains identified in the 107 successfully sequenced samples. Incidence rate of scrub typhus was positively correlated with chigger loads, prevalence of chigger infestations, seropositivity rate but not OT positivity rate in chiggers. CONCLUSIONS: Our study reveals R. losea as the primary host for chiggers and there exists a geographical and seasonal variation in chigger species in Taiwan. It also emphasizes the importance of recognition of chigger vectors and their vertebrate hosts for a better prediction of human risks to scrub typhus under rapid environmental changes. PMID- 26626290 TI - Opening of the Adenosine Triphosphate-sensitive Potassium Channel Attenuates Morphine Tolerance by Inhibiting JNK and Astrocyte Activation in the Spinal Cord. AB - OBJECTIVES: In the present study, we investigated the role of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in chronic morphine tolerance. MATERIALS AND METHODS: Male mice were injected intrathecally with morphine or saline, respectively (each in 10 MUL). Different doses of the KATP opener cromakalim (0.3, 1, or 3 MUg/10 MUL/mouse) were administered 15 minutes before the morphine (10 MUg/10 MUL/mouse) challenge daily for 7 consecutive days. Half an hour after morphine injection, the tail-flick latency was measured to evaluate the antinociceptive effect of morphine. On the seventh day, mice were euthanized with sodium pentobarbital (100 mg/kg) at 1 hour after morphine injection, and their spinal cords were removed for the assays of Western blot, immunofluorescence, and quantitative real-time polymerase chain reaction. RESULTS: Opening of the KATP channel attenuates chronic morphine tolerance, suppresses astrocyte activation inhibits the increase in interleukin-1beta at the transcriptional and the translational levels, and reduces the upregulation of phosphorylated c-Jun N-terminal kinase mitogen-activated protein kinase in the spinal cord after chronic morphine treatment. Moreover, transcriptional levels of spinal cord astrocyte KATP channel subunits, named the inwardly rectifying potassium (Kir) 6.1 and sulfonylurea receptor 1, are decreased in morphine tolerant mice. DISCUSSION: Cromakalim suppresses morphine-induced astrocyte activation significantly by suppressing the c-Jun N-terminal kinase pathway, resulting in a reduced release of interleukin-1beta and the attenuation of morphine chronic antinociceptive tolerance. PMID- 26626293 TI - Clinically Important Change in Insomnia Severity After Chronic Pain Rehabilitation. AB - OBJECTIVES: Insomnia is a common problem for people with chronic pain. It is unclear, however, whether interdisciplinary treatment centered on pain management, rather than sleep, confers a benefit in reducing insomnia symptoms. In this study, we examined clinically important change in insomnia severity following participation in an interdisciplinary chronic pain rehabilitation program. METHODS: A total of 140 patients (43 men and 97 women) completed a 4 week outpatient day program for interdisciplinary rehabilitation that incorporated psychoeducation about pain, physical fitness, and group psychotherapy. The Insomnia Severity Index (ISI) was included as an outcome, along with measures of pain, mood, and function. RESULTS: On the ISI before treatment, 20 patients (14.3%) reported no insomnia, 36 (25.7%) had a mild or subthreshold problem, and 84 (60%) had moderate (31.4%) or severe (28.6%) clinical insomnia. After treatment, ISI scores showed a statistically significant improvement overall (P<0.001). Six indices of individual change were examined among those with moderate-severe insomnia at baseline. Depending on the index used, rates of clinically important improvement ranged from 2.4% to 47.6%; however, only 2 patients with insomnia met criteria for full remission. Among patients with no or subthreshold symptoms at baseline, from 0% to 14.3% were worse after treatment, depending on the criterion. DISCUSSION: Insomnia improves overall following interdisciplinary rehabilitation for chronic pain, but most patients with clinical insomnia continue to have a significant sleep problem after treatment, and some patients may get worse. Interventions to alleviate persistent insomnia comorbid with chronic pain are likely to require a more intensive focus on sleep itself. PMID- 26626292 TI - Assessing the Impact of Renal Function on Trajectory of Intravenous Patient controlled Analgesic Demands Over Time After Open and Laparoscopic Colorectal Surgery Using Latent Curve Analysis. AB - OBJECTIVES: Intravenous patient-controlled analgesia (IVPCA) is often used to relieve pain after colorectal surgery. This study aimed to model the trajectory of analgesic demand over time after colorectal cancer surgery and explore potentially relevant influential factors using latent curve analysis, focusing on laparoscopic-assisted surgery and renal function. MATERIALS AND METHODS: Patients receiving colorectal surgery with postoperative IVPCA were randomly divided into 2 equal parts to enable model construction and cross validation. Archived data were retrieved from the IVPCA pump. Latent curve modeling with 2 latent variables that reflected the baseline and slope of IVPCA demand trajectory over time was used and the effects of potentially influential factors on the 2 latent variables were evaluated. Goodness-of-fit indices were used to assess the model fit to both the model construction and validation data sets. RESULTS: Data were collected from 834 patients, of whom 112 had laparoscopic-assisted surgery. Latent curve analysis revealed that body weight increased the baseline analgesic demand over time, whereas increasing age, female sex, poor renal function, and laparoscopic assisted surgery decrease it. By contrast, only age and weight exerted significant effects on the slope parameter to modify the trajectory of IVPCA demand. Patients with higher age or less weight tended to have a smoother decreasing trajectory of analgesic demands over time. There was good cross validation, as the parameter estimates derived from the model construction data set fitted well to the validation data set (root mean square error of approximation: 0.05). CONCLUSION: Laparoscopic-assisted surgery and renal function affected the baseline trajectory of IVPCA demand over time, but had no significant effect on its shape. PMID- 26626289 TI - Perceptions of pre-clerkship medical students and academic advisors about sleep deprivation and its relationship to academic performance: a cross-sectional perspective from Saudi Arabia. AB - BACKGROUND: The medical student population is believed to be at an increased risk for sleep deprivation. Little is known about students' perceptions towards sleep deprivation and its relationship to academic performance. The aim of study is to explore the perceptions of medical students and their academic advisors about sleep deprivation and its relationship to academic performance. METHODS: The study took place at Alfaisal University, College of Medicine, Riyadh, Saudi Arabia. An online, anonymous, cross-sectional, self-rating survey was administered to first-, third-year students and their academic advisors. Two tailed Mann-Whitney U test was used to compare the mean 5-point Likert scale responses between students according to gender, academic year and cumulative grade point average (cGPA). RESULTS: A total of 259 students and 21 academic advisors participated in the survey (response rates: 70.6 and 84%, respectively). The vast majority of students agreed that sleep deprivation negatively affects academic performance (78.8%) and mood (78.4%). Around 62.2 and 73.7% of students agreed that the demanding medical curriculum and stress of final exams lead to sleep deprivation, respectively. While 36.7% of students voiced the need for incorporation of curricular separate courses about healthy sleep patterns into medical curriculum, a much greater proportion of students (45.9%) expressed interest in extracurricular activities about healthy sleep patterns. Interestingly, only 13.5% of students affirmed that they were counselled about sleep patterns and academic performance by their academic advisors. There were several statistically significant differences of means of students' perceptions according to gender, academic year and cGPA. Despite almost all academic advisors (95.5%) asserted the importance of sleep patterns to academic performance, none (0%) inquired about sleep patterns when counselling students. Nineteen academic advisors (90.5%) recommended incorporation of sleep patterns related learning into medical curricula; among those, only 1 (n = 1/19; 5.3%) recommended learning as a separate course whereas the majority (n = 18/19; 94.7%) recommended learning in forms of extracurricular activities and integration into relevant ongoing courses. CONCLUSIONS: Our results showed that students had correct conceptions about the negative impact of sleep deprivation on academic performance and mood. Also, our results highlighted the need for curricular/extracurricular education and counseling about healthy sleep patterns. PMID- 26626298 TI - Health Care Costs and Utilization in Patients Receiving Prescriptions for Long acting Opioids for Acute Postsurgical Pain. AB - OBJECTIVES: Severe pain after joint replacement surgeries is common and is usually managed by opioid analgesics. We described joint replacement surgery patients who received prescriptions for long-acting opioids (LAOs) and compared their health care utilization and costs with postsurgical patients who did not receive LAO prescriptions. MATERIALS AND METHODS: Patients undergoing hip, knee, or shoulder replacement surgery between January 1, 2008 and December 31, 2011were included in the study and were classified by their exposure to LAOs. We estimated multivariate models to compare the groups' health care utilization and costs in the first 7 days and in the 1, 3, 6, and 12 months after surgery. RESULTS: Of 118,816 patients who met our inclusion criteria, 15,094 (13%) received LAO prescriptions in 30 days following surgery. LAO recipients were slightly younger and more likely than nonrecipients to have taken antibiotics, antidepressants, benzodiazepines, antihypertensives, sedatives, muscle relaxants, and short-acting opioids in the 60 days before surgery. LAO recipients were more likely to have had a hospitalization and an emergency department visit in the subsequent 1 week and in the next 1, 3, 6, and 12 months. Patients receiving LAO prescriptions incurred greater costs in the 1 week and in the 1, 3, 6, and 12 months following their surgeries compared with patients who did not receive LAO prescriptions. DISCUSSION: We found associations between patients who received prescriptions for LAOs and increased costs and utilization. Future studies should elucidate causal relationships between LAOs and increased resource use. Providers should consider alternative pain management strategies. PMID- 26626294 TI - Everyday Executive Functioning in Chronic Pain: Specific Deficits in Working Memory and Emotion Control, Predicted by Mood, Medications, and Pain Interference. AB - OBJECTIVES: People with chronic pain may experience impairments in high-level cognitive skills, particularly executive functions. Such impairments are not adequately measured in most clinical pain management settings yet could be a key influence on everyday functioning. We administered a well-validated, well-normed self-report measure to determine which aspects of executive functioning are compromised in the daily experience of patients with chronic pain, and whether these are associated with pain severity, medications, and mood. MATERIALS AND METHODS: Sixty-three patients attending a multidisciplinary pain management clinic, and 66 pain-free age-matched and sex-matched controls, completed the Behavior Rating Inventory of Executive Function, Adult version (BRIEF-A). The BRIEF-A measures 9 aspects of executive function: Inhibit, Shift, Emotional Control, Initiate, Self-Monitor, Working Memory, Plan/Organize, Task Monitor, and Organization of Materials. Patients completed a battery of mood and pain-related measures. RESULTS: Profile analysis revealed that patients with chronic pain reported significantly greater overall executive function impairments than controls. The patients showed greatest impairments on Working Memory and Emotional Control subscales, with more than half scoring in the clinically elevated range. A significant proportion of the variance in these scores was explained by total medication detriment (but not opioids alone), negative emotional states, and pain interference. Pain intensity and duration were not strong predictors of reported executive dysfunction. DISCUSSION: Multiple factors impact on self-reported executive problems in this population. Specific deficits in Working Memory and Emotional Control have implications for patient engagement with treatment, and retention of information provided in therapy. A screening tool like the BRIEF-A may be useful in pain management settings. PMID- 26626296 TI - Is Intraoperative Remifentanil Associated With Acute or Chronic Postoperative Pain After Prolonged Surgery? An Update of the Literature. AB - OBJECTIVE: Remifentanil is an ultra-short-acting opioid that is used commonly during both short-term and prolonged surgery. This review investigated associations of intraoperative remifentanil administration with acute postoperative pain, hyperalgesia, and chronic postoperative pain, with emphasis on the perioperative coanesthetic drug regimen used. METHODS: Medline and Embase databases were searched for randomized studies, evaluating the intraoperative use of remifentanil (>2 h) versus another analgesic or a different dosage of remifentanil, and reporting acute postoperative pain parameters such as postoperative pain scores, hyperalgesia, acute opioid tolerance, or analgesics requirements. Furthermore, all studies in which remifentanil was used intraoperatively and parameters for chronic postoperative pain were measured were included (pain levels after a prolonged period of time after surgery). RESULTS: From the 21 studies that were identified, less than half of the studies found higher acute postoperative pain, higher postoperative analgesic requirements after intraoperative remifentanil use, or both. Coanesthetics to some extent determined this incidence, with mainly studies using volatile agents reporting increased pain levels. There was less evidence when remifentanil was combined with total intravenous anesthesia or a combination of anesthetics. The limited number of studies (n=4) evaluating chronic pain suggested a potential association with the intraoperative use of remifentanil. DISCUSSION: Although studies are diverse and sample sizes small, coanesthetics used in combination with remifentanil may influence the occurrence of postoperative hyperalgesia. No firm conclusions could be made regarding acute and chronic pain, indicating that further research with the goal to investigate the effect of volatile or intravenous anesthetics along with simultaneous remifentanil infusion on acute and chronic postoperative pain is needed. PMID- 26626297 TI - Pain Catastrophizing and Anxiety are Associated With Heat Pain Perception in a Community Sample of Adults With Chronic Pain. AB - BACKGROUND: The principle aim of this study was to investigate the associations between heat pain (HP) perception, pain catastrophizing, and pain-related anxiety in a heterogenous cohort of community-dwelling adults with chronic pain admitted to a 3-week outpatient pain rehabilitation program. METHODS: All adults consecutively admitted to an outpatient pain rehabilitation program from July 2009 through January 2011 were eligible for study recruitment (n=574). Upon admission, patients completed the Pain Catastrophizing Scale (PCS), the short version of the Pain Anxiety Symptoms Scale (PASS-20), and HP perception was assessed using a standardized quantitative sensory testing (QST) method of levels. RESULTS: Greater PCS scores were significantly correlated with lower standardized values of HP threshold (HP 0.5) (P=0.006) and tolerance (HP 5) (P=0.003). In a multiple variable model adjusted for demographic and clinical factors known to influence HP perception, every 10-point increase in the PCS was associated with a -0.124 point change in HP 0.5 (P=0.014) and a -0.142 change in HP 5 (P=0.014) indicating that participants with higher PCS scores had lower HP thresholds and tolerances, respectively. Similarly, greater PASS-20 scores significantly correlated with lower standardized values of HP 0.5 and HP 5. In a multiple variable model, every 10-point increase in the PASS-20 was associated with a -0.084 point change in HP 0.5 (P=0.005) and a -0.116 point change in HP 5 (P=0.001) indicating that participants with higher PASS-20 scores had lower HP thresholds and tolerances, respectively. CONCLUSIONS: The findings of this study extend the use of a standardized method for assessing HP in a heterogenous sample of adults with chronic pain. Although pain catastrophizing shares significant variance with pain-related anxiety, our findings suggest that either measure would be appropriate for use in future studies that incorporate the QST method of levels. PMID- 26626299 TI - Chronic Opioid Therapy After Lumbar Fusion Surgery for Degenerative Disk Disease in a Workers' Compensation Patients. PMID- 26626291 TI - Somatosensory and Biomechanical Abnormalities in Females With Patellofemoral Pain. AB - OBJECTIVES: Chronic patellofemoral pain (PFP) is a common orthopedic condition for which little is understood of the alterations in pain processing such as hyperalgesia, hypoesthesia, and the relationship of altered knee mechanics to hyperalgesia. We assessed pain, pressure pain thresholds (PPT), detection to light touch, and the relationship of pain and PPTs to knee abduction angle during a stair step down task between females with and without PFP. MATERIALS AND METHODS: Twenty females diagnosed with PFP and 20 age-matched pain-free females participated in this study. Individuals underwent an instrumented assessment of knee mechanics during a stair step down task, PPT and detection of light touch over the center of the patella and lateral retinaculum, and PPT outside painful area over the right elbow. RESULTS: The PFP group had significantly lower PPT values at the patella (P=0.02), lateral retinaculum (P=0.001), and at the elbow (P=0.03). There was an elevated threshold to detect light touch over the center of their patella (P=0.04). A significant relationship between both pain (r=-0.49, P=0.03) and PPT values (r=0.65, P=0.004) to the frontal plane knee angle existed in the PFP group which was not present in the control group (r=-0.17, P=0.49) or in the elbow (r=-0.009, P=0.972). DISCUSSION: These results suggest that PFP is characterized by an increase in both localized and centralized pain sensitivity that is related to movement mechanics. Thus, PFP has both biomechanical, nociceptive components as well as inferred aspects of altered central sensitization. PMID- 26626285 TI - Measuring, discussing, and living together: lessons from 4 years in Suetsugi. AB - Cooperating with radiological protection experts and taking radiation measurements, the residents of Suetsugi, Iwaki City, Fukushima have been striving to reshape their lives since the accident at Fukushima Daiichi nuclear power plant. Suetsugi lies within 30 km of the power plant, so the residents have had serious reservations about continuing their lives there since the accident. Today, radiation remains a 'line' dividing their lives, with any dose measurements directly affecting their daily decision making. Assisted by medical and scientific specialists, the residents faced this challenging situation by measuring exposures individually and then discussing the results among themselves. Since 2012, the residents of Suetsugi have been using personal dosimeters, made village-wide trips for whole-body counter tests, and measured food contamination throughout the village. The results have been shared openly between the residents. Obtaining and discussing their own data were crucial to gain understanding of various results and to practice radiological protection in their daily routine. These 4 y of experience in Suetsugi demonstrate cooperation between various stakeholders, which should be a lesson for the future. PMID- 26626300 TI - Emergency Visits for Prescription Opioid Overdose. PMID- 26626295 TI - The Fibromyalgia Survey Score Correlates With Preoperative Pain Phenotypes But Does Not Predict Pain Outcomes After Shoulder Arthroscopy. AB - OBJECTIVES: Fibromyalgia (FM) characteristics can be evaluated using a simple, self-reported measure that correlates with postoperative opioid consumption after lower-extremity joint arthroplasty. The purpose of this study was to determine whether preoperative pain history and the FM survey score can predict postoperative outcomes after shoulder arthroscopy, which may cause moderate to severe pain. MATERIALS AND METHODS: In this prospective study, 100 shoulder arthroscopy patients completed preoperative validated self-report measures to assess baseline quality of recovery score, physical functioning, depression, anxiety, and neuropathic pain. FM characteristics were evaluated using a validated measure of widespread pain and comorbid symptoms on a 0 to 31 scale. Outcomes were assessed on postoperative day 2 (opioid consumption [primary], pain, physical functioning, quality of recovery score), and day 14 (opioid consumption, pain). RESULTS: FM survey scores ranged from 0 to 13. The cohort was divided into tertiles for univariate analyses. Preoperative depression and anxiety (P<0.001) and neuropathic pain (P=0.008) were higher, and physical functioning was lower (P<0.001), in higher FM survey score groups. The fibromyalgia survey score was not associated with postoperative pain or opioid consumption; however, it was independently associated with poorer quality of recovery scores (P=0.001). The only independent predictor of postoperative opioid use was preoperative opioid use (P=0.038). DISCUSSION: FM survey scores were lower than those in a previous study of joint arthroplasty. Although they distinguished a negative preoperative pain phenotype, FM scores were not independently associated with postoperative opioid consumption. Further research is needed to elucidate the impact of a FM-like phenotype on postoperative analgesic outcomes. PMID- 26626304 TI - Effectiveness of Plasma Exchange for Acute Pancreatitis Induced by Hypertriglyceridemia During Pregnancy. PMID- 26626301 TI - The efficacy and safety of probiotics intervention in preventing conversion of impaired glucose tolerance to diabetes: study protocol for a randomized, double blinded, placebo controlled trial of the Probiotics Prevention Diabetes Programme (PPDP). AB - BACKGROUND: Alterations in intestinal microbiota correlate with risk of development of obesity and type 2 diabetes. Probiotics have been suggested to play an important role in the management of dysglycemia, although the evidence is limited. In this study, we aim to explore the efficacy and safety of probiotics intervention in preventing type 2 diabetes in Chinese patients with impaired glucose tolerance. METHODS/DESIGN: A 24-month randomized intervention is conducted from January 2014 to December 2016. The target sample size for intervention is 200 middle-aged men and women aged 30-65 year-old with impaired glucose tolerance. Participants with persistent impaired glucose tolerance were assigned to group A (tablet A) and B (tablet B) in sequential order. The participants and investigators were blinded to the assignment. The primary outcome is development of diabetes. The secondary outcome measures include body composition, biochemical variables and the safety of the probiotics. DISCUSSION: The results from this trial will provide the evidence on the efficacy and safety of probiotics administration in preventing conversion of impaired glucose tolerance to diabetes in a Chinese context. TRIAL REGISTRATION: ChiCTRTRC13004024. PMID- 26626306 TI - Response to the letter: Litigation for VTE in the NHS; the denominator matters. PMID- 26626307 TI - Litigation for VTE in the NHS; the denominator matters. PMID- 26626309 TI - Erratum to: microRNA 490-3P enhances the drug-resistance of human ovarian cancer cells. PMID- 26626305 TI - Heterochromatin components in germline stem cell maintenance. AB - Stem cell maintenance requires expression of genes essential for stemness and repression of differentiation genes. How this is achieved remains incompletely understood. Here we investigate the requirement for central components of heterochromatin, Heterochromatin Protein 1 (HP1) and the histone H3 lys9 methyltransferase Su(var)3-9, in the Drosophila male germline stem cell (GSC) self-renewal, a paradigm for studying adult stem cell behavior. We found that mutations or RNAi knock down of HP1 or Su(var)3-9 cause loss of GSCs, accompanied by defects in cell division or survival and premature expression of the differentiation gene bag of marbles (bam). Conversely, over-expressing HP1 increases GSC number in wildtype flies and, strikingly, restores fertility to the sterile hopscotch (hop) mutant flies that lack niche signals. These results suggest that the central components of heterochromatin play roles including repressing differentiation genes in Drosophila male GSC maintenance. PMID- 26626310 TI - Mapping divided households and residency changes: the effect of couple separation on sexual behavior and risk of HIV infection. AB - Using census data we identify geographic patterns in residency changes in Lesotho over a decade. Using kriging to spatially interpolate data from 8,510 households we identify regions where households have members temporarily living away from home (divided households). Further, using a multivariate analysis and data from 2,026 couples we determine whether a partners' absence increases the likelihood of having extramarital partners and/or risk of HIV infection. Approximately 40% of individuals moved between 2001 and 2011; mainly to, and within, urbanized regions. Many households are divided: ~40% have members elsewhere in Lesotho, ~30% in South Africa (SA). Geographic patterns are apparent; they differ based on where the household member is living. Many couples were temporarily separated: ~50% of wives, ~20% of husbands. Separation was not a risk factor for HIV. Only men were more likely to have extramarital partners if their spouse was away: ~1.5 times if in Lesotho, ~3 times if in SA. The high degree of geographic mixing necessitates synchronizing interventions within Lesotho, and with SA, to successfully reduce transmission. It will be challenging to reduce concurrency in men with wives away from home. Our results are generalizable to other sub-Saharan countries where residency changes are common. PMID- 26626302 TI - Phase diagram for the transition from photonic crystals to dielectric metamaterials. AB - Photonic crystals and dielectric metamaterials represent two different classes of artificial media but are often composed of similar structural elements. The question is how to distinguish these two types of periodic structures when their parameters, such as permittivity and lattice constant, vary continuously. Here we discuss transition between photonic crystals and dielectric metamaterials and introduce the concept of a phase diagram, based on the physics of Mie and Bragg resonances. We show that a periodic photonic structure transforms into a metamaterial when the Mie gap opens up below the lowest Bragg bandgap where the homogenization approach can be justified and the effective permeability becomes negative. Our theoretical approach is confirmed by microwave experiments for a metacrystal composed of tubes filled with heated water. This analysis yields deep insight into the properties of periodic structures, and provides a useful tool for designing different classes of electromagnetic materials with variable parameters. PMID- 26626303 TI - CD11c(hi) Dendritic Cells Regulate Ly-6C(hi) Monocyte Differentiation to Preserve Immune-privileged CNS in Lethal Neuroinflammation. AB - Although the roles of dendritic cells (DCs) in adaptive defense have been defined well, the contribution of DCs to T cell-independent innate defense and subsequent neuroimmunopathology in immune-privileged CNS upon infection with neurotropic viruses has not been completely defined. Notably, DC roles in regulating innate CD11b(+)Ly-6C(hi) monocyte functions during neuroinflammation have not yet been addressed. Using selective ablation of CD11c(hi)PDCA-1(int/lo) DCs without alteration in CD11c(int)PDCA-1(hi) plasmacytoid DC number, we found that CD11c(hi) DCs are essential to control neuroinflammation caused by infection with neurotropic Japanese encephalitis virus, through early and increased infiltration of CD11b(+)Ly-6C(hi) monocytes and higher expression of CC chemokines. More interestingly, selective CD11c(hi) DC ablation provided altered differentiation and function of infiltrated CD11b(+)Ly-6C(hi) monocytes in the CNS through Flt3-L and GM-CSF, which was closely associated with severely enhanced neuroinflammation. Furthermore, CD11b(+)Ly-6C(hi) monocytes generated in CD11c(hi) DC-ablated environment had a deleterious rather than protective role during neuroinflammation, and were more quickly recruited into inflamed CNS, depending on CCR2, thereby exacerbating neuroinflammation via enhanced supply of virus from the periphery. Therefore, our data demonstrate that CD11c(hi) DCs provide a critical and unexpected role to preserve the immune-privileged CNS in lethal neuroinflammation via regulating the differentiation, function, and trafficking of CD11b(+)Ly-6C(hi) monocytes. PMID- 26626308 TI - Collaborative regulation of CO2 transport and fixation during succinate production in Escherichia coli. AB - In Escherichia coli, succinic acid is synthesized by CO2 fixation-based carboxylation of C3 metabolites. A two-step process is involved in CO2 integration: CO2 uptake into the cell and CO2 fixation by carboxylation enzymes. The phosphoenolpyruvate (PEP) carboxylase (PPC) and carboxykinase (PCK) are two important carboxylation enzymes within the succinate synthetic pathway, while SbtA and BicA are two important bicarbonate transporters. In this study, we employed a dual expression system, in which genes regulating both CO2 uptake and fixation were co-overexpressed, or overexpressed individually to improve succinate biosynthesis. Active CO2 uptake was observed by the expression of SbtA or/and BicA, but the succinate biosynthesis was decreased. The succinate production was significantly increased only when a CO2 fixation gene (ppc or pck) and a CO2 transport gene (sbtA or bicA) were co-expressed. Co-expression of pck and sbtA provided the best succinate production among all the strains. The highest succinate production of 73.4 g L(-1) was 13.3%, 66.4% or 15.0% higher than that obtained with the expression of PCK, SbtA alone, or with empty plasmids, respectively. We believe that combined regulation of CO2 transport and fixation is critical for succinate production. Imbalanced gene expression may disturb the cellular metabolism and succinate production. PMID- 26626313 TI - Genome-wide gene-environment interactions on quantitative traits using family data. AB - Gene-environment interactions may provide a mechanism for targeting interventions to those individuals who would gain the most benefit from them. Searching for interactions agnostically on a genome-wide scale requires large sample sizes, often achieved through collaboration among multiple studies in a consortium. Family studies can contribute to consortia, but to do so they must account for correlation within families by using specialized analytic methods. In this paper, we investigate the performance of methods that account for within-family correlation, in the context of gene-environment interactions with binary exposures and quantitative outcomes. We simulate both cross-sectional and longitudinal measurements, and analyze the simulated data taking family structure into account, via generalized estimating equations (GEE) and linear mixed-effects models. With sufficient exposure prevalence and correct model specification, all methods perform well. However, when models are misspecified, mixed modeling approaches have seriously inflated type I error rates. GEE methods with robust variance estimates are less sensitive to model misspecification; however, when exposures are infrequent, GEE methods require modifications to preserve type I error rate. We illustrate the practical use of these methods by evaluating gene drug interactions on fasting glucose levels in data from the Framingham Heart Study, a cohort that includes related individuals. PMID- 26626312 TI - Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark. AB - Leber congenital amaurosis (LCA) represents the most severe form of inherited retinal dystrophies with an onset during the first year of life. Currently, 21 genes are known to be associated with LCA and recurrent mutations have been observed in AIPL1, CEP290, CRB1 and GUCY2D. In addition, sequence analysis of LRAT and RPE65 may be important in view of treatments that are emerging for patients carrying variants in these genes. Screening of the aforementioned variants and genes was performed in 64 Danish LCA probands. Upon the identification of heterozygous variants, Sanger sequencing was performed of the relevant genes to identify the second allele. In combination with prior arrayed primer extension analysis, this led to the identification of two variants in 42 of 86 cases (49%). Remarkably, biallelic RPE65 variants were identified in 16% of the cases, and one novel variant, p.(D110G), was found in seven RPE65 alleles. We also collected all previously published RPE65 variants, identified in 914 alleles of 539 patients with LCA or early-onset retinitis pigmentosa, and deposited them in the RPE65 Leiden Open Variation Database (LOVD). The in silico pathogenicity assessment of the missense and noncanonical splice site variants, as well as an analysis of their frequency in ~60 000 control individuals, rendered 864 of the alleles to affect function or probably affect function. This comprehensive database can now be used to select patients eligible for gene augmentation or retinoid supplementation therapies. PMID- 26626314 TI - SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases. AB - Hereditary cerebellar ataxias and hereditary spastic paraplegias are clinically and genetically heterogeneous and often overlapping neurological disorders. Mutations in SPG7 cause the autosomal recessive spastic paraplegia type 7 (SPG7), but recent studies indicate that they are also one of the most common causes of recessive cerebellar ataxia. In Quebec, a significant number of patients affected with cerebellar ataxia and spasticity remain without a molecular diagnosis. We performed whole-exome sequencing in three French Canadian (FC) patients affected with spastic ataxia and uncovered compound heterozygous variants in SPG7 in all three. Sanger sequencing of SPG7 exons and exon/intron boundaries was used to screen additional patients. In total, we identified recessive variants in SPG7 in 22 FC patients belonging to 12 families (38.7% of the families screened), including two novel variants. The p.(Ala510Val) variant was the most common in our cohort. Cerebellar features, including ataxia, were more pronounced than spasticity in this cohort. These results strongly suggest that variants affecting the function of SPG7 are the fourth most common form of recessive ataxia in FC patients. Thus, we propose that SPG7 mutations explain a significant proportion of FC spastic ataxia cases and that this gene should be considered in unresolved patients. PMID- 26626311 TI - The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype. AB - Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach. PMID- 26626315 TI - Mitochondria-related miR-151a-5p reduces cellular ATP production by targeting CYTB in asthenozoospermia. AB - Mitochondria, acting as the energy metabolism factory, participate in many key biological processes, including the maintenance of sperm viability. Mitochondria related microRNA (miRNA), encoded by nuclear genome or mitochondrial genome, may play an important regulatory role in the control of mitochondrial function. To investigate the potential role of mitochondria-related miRNAs in asthenozoospermia, we adopted a strategy consisting of initial screening by TaqMan Low Density Array (TLDA) and further validation with quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Validation of the profiling results was conducted in two independent phases. Eventually, two seminal plasma miRNAs (sp-miRs) (miR-101-3p, let-7b-5p) were found to be significantly decreased, while sp-miR-151a-5p was significantly increased in severe asthenozoospermia cases compared with healthy controls. To further study their potential roles in asthenozoospermia, we then evaluated mitochondrial function of GC-2 cells transfected with these potentially functional miRNAs. Our results demonstrated that transfection with miR-151a-5p mimics decreased the mitochondrial respiratory activity. Besides, Adenosine Triphosphate (ATP) level was decreased when transfected with miR-151a-5p mimics. In addition, Cytochrome b (Cytb) mRNA and protein levels were also decreased when miR-151a-5p was overexpressed. These results indicate that miR-151a-5p may participate in the regulation of cellular respiration and ATP production through targeting Cytb. PMID- 26626316 TI - The site of tumor development determines immunogenicity via temporal mobilization of antigen-laden dendritic cells in draining lymph nodes. AB - The elimination of solid tumors largely depends on effective T-cell priming by dendritic cells (DCs). For decades, studies focusing on antitumoral immune responses have been performed with tumors transplanted subcutaneously (s.c.). These studies however do not take into account the heterogeneous tissue distribution and functionality of the different DC subsets. Given the crucial role of DCs in inducing protective immune response, we postulated that the anatomic location of tumor development may greatly impact tumor immunogenicity. We therefore implanted tumor cells either in the DC-rich dermis environment or in the s.c. tissue that mainly contains macrophages and monocytes. We showed that intradermal (i.d.), but not s.c. tumors are rapidly rejected in a T-cell dependent manner and induce protective T-cell responses. The rejection of i.d. tumors correlates with rapid recruitment of dermal DCs presenting the tumor antigen to both CD4 and CD8 T cells in the draining lymph nodes (dLNs). The same DC subsets were mobilized upon s.c. tumor transplantation but with delayed kinetics. Altogether, our results show that the anatomical site of tumor development influences tumor immunogenicity, notably by controlling the kinetics of DC mobilization in the draining LNs. PMID- 26626317 TI - [Oxytocin in cesarean-sections. What's new?]. AB - Oxytocin is the uterotonic agent of choice in the prevention and treatment of postpartum uterine atony. Nevertheless, there is no consensus on the optimal dose and rate for use in cesarean sections. The use of high bolus doses (e.g., 10 IU of oxytocin) can determine deleterious cardiovascular changes for the patient, especially in situations of hypovolemia or low cardiac reserve. Furthermore, high doses of oxytocin for prolonged periods may lead to desensitization of oxytocin receptors in myometrium, resulting in clinical inefficiency. PMID- 26626318 TI - [Tropical spastic paraparesis - anesthetic approach]. AB - INTRODUCTION: HTLV-1 infection is endemic in Japan, Caribbean, Africa, and South America. It is transmitted from mother to child, sexual contact, blood transfusions, or sharing needles. Tropical Spastic paraparesis (TSP) is a chronic degenerative neurological disease associated with this infection. It results from a spinal cord symmetrical degeneration at the thoracic level and is characterized by progressive motor weakness in the lower limbs, hyperreflexia, sensitivity changes, urinary incontinence, and bladder dysfunction. CLINICAL CASE: Female, 53 years old, HTLV-1 infection and TSP. She had decreased strength in the lower limbs and hyperreflexia, paretic gait, spasticity, and neurogenic bladder symptoms, with recurrent urinary infections. She was scheduled for cystectomy. The patient was monitored according to standard ASA. Due to severe coagulopathy and the possibility of neurological worsening, epidural catheter was not placed. The induction of general anesthesia was performed with midazolam and fentanyl, followed by etomidate and cisatracurium. She was intubated with a tube size seven and maintained with desflurane and oxygen. Anesthesia was uneventful; the surgery lasted 1 hour and 50minutes. There were no complications in the immediate postoperative period, during hospitalization, nor deterioration of the neurological examination. The patient was discharged 20 days later. DISCUSSION/CONCLUSION: There are reports of decreased electromyographic response and neurological deterioration associated with propofol in these patients, etomidate was used. The hepatic metabolism of rocuronium posed a risk, we chose to use cistracurium. It was concluded that the anesthesia chosen did not affect the course of the disease. PMID- 26626319 TI - Perioperative bridging anticoagulation in patients with atrial fibrillation ongoing an elective surgical dermatologic therapy. PMID- 26626320 TI - A Randomized Controlled Exploratory Pilot Study to Evaluate the Effect of Rotigotine Transdermal Patch on Parkinson's Disease-Associated Chronic Pain. AB - Pain is a troublesome nonmotor symptom of Parkinson's disease (PD). This double blind exploratory pilot study (NCT01744496) was the first to specifically investigate the effect of a dopamine agonist on PD-associated pain as primary outcome. Patients with advanced PD (ie, receiving levodopa) and at least moderate PD-associated chronic pain (>=3 months, >=4 points on 11-point Likert pain scale) were randomized to rotigotine (optimal/maximum dose <=16 mg/24h) or placebo and maintained for 12 weeks. Primary efficacy variable was change in pain severity (Likert pain scale) from baseline to end of maintenance. Secondary variables included percentage of responders (>=2-point Likert pain scale reduction), King's PD Pain Scale (KPPS) domains, and PD Questionnaire (PDQ-8). Statistical analyses were exploratory. Of 68 randomized patients, 60 (rotigotine, 30; placebo, 30) were evaluable for efficacy. A numerical improvement in pain was observed in favor of rotigotine (Likert pain scale: least-squares mean [95%CI] treatment difference, -0.76 [-1.87 to 0.34]; P = .172), and proportion of responders was 18/30 (60%) rotigotine vs 14/30 (47%) placebo. An ~2-fold numerical improvement in KPPS domain "fluctuation-related pain" was observed with rotigotine vs placebo. Rotigotine improved PDQ-8 vs placebo (-8.01 [-15.56 to -0.46]; P = .038). These results suggest rotigotine may improve PD-associated pain; a large scale confirmatory study is needed. PMID- 26626321 TI - Invasive meningococcal disease in England: assessing disease burden through linkage of multiple national data sources. AB - BACKGROUND: In England, Public Health England conducts enhanced surveillance of invasive meningococcal disease (IMD). The continuing decline in reported IMD cases has raised concerns that the MRU may be underestimating true IMD incidence. METHODS: We linked five national datasets to estimate disease burden over five years, including PHE Meningococcal Reference Unit (MRU) confirmations, hospital episode statistics (HES), electronic reports of significant infections by National Health Service (NHS) Hospitals, death registrations and private laboratory reports. RESULTS: During 2007-11, MRU confirmed 5115 IMD cases and 4275 (84%) matched to HES, including 3935 (92%) with A39* (meningococcal disease) and 340 (8%) with G00* (bacterial meningo-encephalitis) ICD-10 codes. An additional 2792 hospitalised cases with an A39* code were identified in HES. Of these, 1465 (52%) matched to one of 53,806 samples tested PCR-negative for IMD by MRU and only 73 of the remaining 1327 hospitalised A39* cases were confirmed locally or by a private laboratory. The characteristics of hospitalised cases without laboratory confirmation were similar to PCR-negative than PCR-positive IMD cases. CONCLUSIONS: Interrogation of multiple national data sources identified very few laboratory confirmations in addition to the MRU-confirmed cases. The large number of unconfirmed and PCR-negative cases in HES suggests increased awareness among clinicians with low thresholds for hospitalising patients with suspected IMD. PMID- 26626323 TI - The effects of acute ethanol administration on ethanol withdrawal-induced anxiety like syndrome in rats: A biochemical study. AB - Withdrawal from long-term ethanol consumption results in overexcitation of glutamatergic neurotransmission in the amygdala, which induces an anxiety-like syndrome. Most alcoholics that suffer from such symptoms frequently depend on habitual drinking as self-medication to alleviate their symptoms. Metabotropic glutamate receptor subtype 5 (mGlu5) and protein kinase C (PKC) epsilon have been reported to mediate acute and chronic effects of ethanol. This study explores the changes in mGlu5 and PKC epsilon in the amygdala following acute administration of ethanol during ethanol withdrawal (EW) induced anxiety. Male Wistar rats were fed a modified liquid diet containing low-fat cow milk, sucrose, and maltodextrin, with a gradual introduction of 2.4%, 4.8% and 7.2% ethanol for 20 days. Six hours into EW, the rats were intraperitoneally injected with normal saline and ethanol (2.5 g/kg, 20% v/v), and exposed to open-field and elevated plus maze tests. Then, amygdala tissue was dissected from the rat brain for Western blot and gene expression studies. EW-induced anxiety was accompanied by a significant increase in mGlu5, total PKC epsilon, and phosphorylated PKC epsilon protein levels, and also of mRNA of mGlu5 (GRM5) in the amygdala. Acute administration of ethanol significantly attenuated EW-induced anxiety as well as an EW-induced increase in GRM5. The acute challenge of ethanol to EW rats had little effect on the phosphorylated and total protein levels of PKC epsilon in the amygdala. Our results demonstrate that amygdala PKC epsilon may not be directly involved in the development of anxiety following EW. PMID- 26626322 TI - The pan-genome of Lactobacillus reuteri strains originating from the pig gastrointestinal tract. AB - BACKGROUND: Lactobacillus reuteri is a gut symbiont of a wide variety of vertebrate species that has diversified into distinct phylogenetic clades which are to a large degree host-specific. Previous work demonstrated host specificity in mice and begun to determine the mechanisms by which gut colonisation and host restriction is achieved. However, how L. reuteri strains colonise the gastrointestinal (GI) tract of pigs is unknown. RESULTS: To gain insight into the ecology of L. reuteri in the pig gut, the genome sequence of the porcine small intestinal isolate L. reuteri ATCC 53608 was completed and consisted of a chromosome of 1.94 Mbp and two plasmids of 138.5 kbp and 9.09 kbp, respectively. Furthermore, we generated draft genomes of four additional L. reuteri strains isolated from pig faeces or lower GI tract, lp167-67, pg-3b, 20-2 and 3c6, and subjected all five genomes to a comparative genomic analysis together with the previously completed genome of strain I5007. A phylogenetic analysis based on whole genomes showed that porcine L. reuteri strains fall into two distinct clades, as previously suggested by multi-locus sequence analysis. These six pig L. reuteri genomes contained a core set of 1364 orthologous gene clusters, as determined by OrthoMCL analysis, that contributed to a pan-genome totalling 3373 gene clusters. Genome comparisons of the six pig L. reuteri strains with 14 L. reuteri strains from other host origins gave a total pan-genome of 5225 gene clusters that included a core genome of 851 gene clusters but revealed that there were no pig-specific genes per se. However, genes specific for and conserved among strains of the two pig phylogenetic lineages were detected, some of which encoded cell surface proteins that could contribute to the diversification of the two lineages and their observed host specificity. CONCLUSIONS: This study extends the phylogenetic analysis of L. reuteri strains at a genome-wide level, pointing to distinct evolutionary trajectories of porcine L. reuteri lineages, and providing new insights into the genomic events in L. reuteri that occurred during specialisation to their hosts. The occurrence of two distinct pig-derived clades may reflect differences in host genotype, environmental factors such as dietary components or to evolution from ancestral strains of human and rodent origin following contact with pig populations. PMID- 26626324 TI - Cervical necrotizing fasciitis: management challenges in poor resource environment. AB - Necrotizing fasciitis of the head and neck is a rare and potentially fatal disease. It is a bacterial infection characterized by spreading along fascia planes and subcutaneous tissue resulting in tissue necrosis and likely death. It is commonly of dental or pharyngeal origin. Factors affecting the success of the treatment are early diagnosis, appropriate antibiotics and surgical debridement. Our study showed eight patients, five males and three females with mean age of 49.25 years (range 20-71 years). Clinical presentations were a rapidly progressing painful neck swelling, fever, dysphagia and trismus. The aetiology varied from idiopathic, pharyngeal/tonsillar infection, trauma and nasal malignancy. There were associated variable comorbidities (diabetes mellitus, HIV infection, hypertension and congestive cardiac failure). All the patients received early and aggressive medical treatment. The earliest time of surgery was 12 h after admission because of the poor financial status of patients. Three cases came in with complications of the disease and were not fit for extensive debridement under general anaesthesia. For them limited and reasonable bed side debridement was done. Mortality was 50 % from multiple organ failure, HIV encephalopathy, aspiration pneumonitis and septicemia. The duration of hospital stay for the patients that died ranged from 1 to 16 days and 4 to 34 days for the survivor. Our study heightens awareness and outlines the management challenges of necrotizing fasciitis of the head and neck in a poor resource setting. PMID- 26626325 TI - Efficiency of Measurements of Hepatitis C Virus RNA. AB - Hepatitis C virus loading was evaluated using modifications of PCR product detection: terminal point fluorescent detection, real time assay, and agarose gel electrophoresis. The advantages and flaws of the real time PCR and electrophoretic detection of amplification products for evaluation of the quantity of virus particle copies are evaluated. PMID- 26626326 TI - Rapid Ngn2-induction of excitatory neurons from hiPSC-derived neural progenitor cells. AB - Since the discovery of somatic reprogramming, human induced pluripotent stem cells (hiPSCs) have been exploited to model a variety of neurological and psychiatric disorders. Because hiPSCs represent an almost limitless source of patient-derived neurons that retain the genetic variations thought to contribute to disease etiology, they have been heralded as a patient-specific platform for high throughput drug screening. However, the utility of current protocols for generating neurons from hiPSCs remains limited by protracted differentiation timelines and heterogeneity of the neuronal phenotypes produced. Neuronal induction via the forced expression of exogenous transcription factors rapidly induces defined populations of functional neurons from fibroblasts and hiPSCs. Here, we describe an adapted protocol that accelerates maturation of functional excitatory neurons from hiPSC-derived neural progenitor cells (NPCs) via lentiviral transduction of Neurogenin 2 (using both mNgn2 and hNGN2). This methodology, relying upon a robust and scalable starting population of hiPSC NPCs, should be readily amenable to scaling for hiPSC-based high-throughput drug screening. PMID- 26626327 TI - The clinical potentials of adjunctive fluvoxamine to clozapine treatment: a systematic review. AB - RATIONALE: New clozapine optimization strategies are warranted, as some patients do not achieve sufficient response and experience various adverse effects. Fluvoxamine is a potent CYP1A2 inhibitor and may increase the ratio of clozapine to its primary metabolite N-desmethylclozapine (NDMC). OBJECTIVES: This study aims to review all pharmacodynamic effects and the adverse effect profile of changing the clozapine/NDMC ratio with adjunctive fluvoxamine. METHODS: MEDLINE, Embase, and the Cochrane Library were searched with the search terms "clozapine" and "fluvoxamine" without any time limit. Language was restricted to English, Scandinavian, Polish, and German. Studies were sorted for relevance based on title and abstract. Clinical recommendations of potential indications/effects were graded as level A, B, C, or D depending on studies of high, moderate, low, or very low quality, respectively. RESULTS: Based on data from 24 case reports/series, seven cohort studies, and two randomized controlled trials, 241 patients were studied. Evidence (A) supported that adjunctive fluvoxamine increased clozapine plasma levels. This may increase the probability of response in patients, where sufficient clozapine plasma levels cannot be achieved. Adjunctive fluvoxamine reduced metabolic adverse effects of clozapine (B) but not agranulocytosis risk (B). Although depressive or obsessive-compulsive symptoms may improve, a SSRI with no CYP1A2 inhibition should rather be used (C). No studies investigated the effect of adjunctive fluvoxamine to minimize clozapine rebound psychosis (D) or to reduce the effects of smoking on clozapine plasma levels (D). CONCLUSIONS: Adjunctive fluvoxamine may have clinical potentials for optimizing clozapine treatment but further clinical studies are warranted to explore the clinical implications. PMID- 26626328 TI - Lithium ions attenuate serum-deprivation-induced apoptosis in PC12 cells through regulation of the Akt/FoxO1 signaling pathways. AB - RATIONALE: Lithium is currently used in the treatment of mental illness. We have previously reported that lithium stimulated the protein kinase B/Forkhead box O1 (Akt/FoxO1) pathway in rats. However, little information is available regarding its neuroprotective role of this pathway and underlying mechanisms. OBJECTIVES: PC12 cells treated with serum deprivation were used as a toxicity model to study the protective effect of lithium and its underlying mechanisms. METHODS: Cell viability was determined by methyl thiazolyl tetrazolium assay and Hoechst staining. FoxO1 subcellular location and its overexpression were used to study the underlying mechanisms. Various pathway inhibitors were used to investigate the possible pathways, while the phosphorylation of Akt and FoxO1 was analyzed by Western blot. RESULTS: Lithium pretreatment dose-dependently reduced PC12 cell apoptosis induced by serum starvation. The protective effect of lithium was abolished by LY294002, a PI3K-specific inhibitor, and Akt inhibitor Akt inhibitor VIII, whereas mitogen-activated protein kinase kinase (MEK kinase) inhibitor U0126 had no effect. Lithium induced the phosphorylation of Akt and FoxO1 in a time- and concentration-dependent manner. Lithium-induced phosphorylation of Akt and FoxO1 is mediated by the PI3K/Akt pathway. Serum deprivation caused nuclear translocation of FoxO1 while application of lithium reversed the effect of serum deprivation. Moreover, overexpression of FoxO1 enhanced cell apoptosis induced by serum withdrawal. Finally, lithium was found to reduce the exogenous and endogenous FoxO1 protein levels in PC12 cells in a concentration-dependent fashion. CONCLUSIONS: The protective effect of lithium against serum starvation cell death is mediated by the PI3K/Akt/FoxO1 pathway. PMID- 26626329 TI - Comprehensive studies on the nature of interaction between carboxylated multi walled carbon nanotubes and bovine serum albumin. AB - Herein, the interaction between carboxylated multi-walled carbon nanotubes (MWCNTs-COOH) and bovine serum albumin has been investigated by using circular dichroism, UV-vis, and fluorescence spectroscopic methods and molecular modeling in order to better understand the basic behavior of carbon nanotubes in biological systems. The spectral results showed that MWCNTs-COOH bound to BSA and induced the relatively large changes in secondary structure of protein by mainly hydrophobic forces and pi-pi stacking interactions. Thermal denaturation of BSA in the presence of MWCNTs-COOH indicated that carbon nanotubes acted as a structure destabilizer for BSA. In addition, the putative binding site of MWCNTs COOH on BSA was near to domain II. With regard to human health, the present study could provide a better understanding of the biological properties, cytotocicity of surface modified carbon nanotubes. PMID- 26626333 TI - Henry Buchwald, M.D., Ph.D. PMID- 26626332 TI - Farewell, 2015 ... Hello, 2016! PMID- 26626331 TI - The binding of cellulase variants to dislocations: a semi-quantitative analysis based on CLSM (confocal laser scanning microscopy) images. AB - Binding of enzymes to the substrate is the first step in enzymatic hydrolysis of lignocellulose, a key process within biorefining. During this process elongated plant cells such as fibers and tracheids have been found to break into segments at irregular cell wall regions known as dislocations or slip planes. Here we study whether cellulases bind to dislocations to a higher extent than to the surrounding cell wall. The binding of fluorescently labelled cellobiohydrolases and endoglucanases to filter paper fibers was investigated using confocal laser scanning microscopy and a ratiometric method was developed to assess and quantify the abundance of the binding of cellulases to dislocations as compared to the surrounding cell wall. Only Humicola insolens EGV was found to have stronger binding preference to dislocations than to the surrounding cell wall, while no difference in binding affinity was seen for any of the other cellulose variants included in the study (H. insolens EGV variants, Trichoderma reesei CBHI, CBHII and EGII). This result favours the hypothesis that fibers break at dislocations during the initial phase of hydrolysis mostly due to mechanical failure rather than as a result of faster degradation at these locations. PMID- 26626330 TI - Transcriptional profiling suggests that Nevirapine and Ritonavir cause drug induced liver injury through distinct mechanisms in primary human hepatocytes. AB - Drug induced liver injury (DILI), a major cause of pre- and post-approval failure, is challenging to predict pre-clinically due to varied underlying direct and indirect mechanisms. Nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) and Ritonavir, a protease inhibitor, are antiviral drugs that cause clinical DILI with different phenotypes via different mechanisms. Assessing DILI in vitro in hepatocyte cultures typically requires drug exposures significantly higher than clinical plasma Cmax concentrations, making clinical interpretations of mechanistic pathway changes challenging. We previously described a system that uses liver-derived hemodynamic blood flow and transport parameters to restore primary human hepatocyte biology, and drug responses at concentrations relevant to in vivo or clinical exposure levels. Using this system, primary hepatocytes from 5 human donors were exposed to concentrations approximating clinical therapeutic and supra-therapeutic levels of Nevirapine (11.3 and 175.0 MUM) and Ritonavir (3.5 and 62.4 MUM) for 48 h. Whole genome transcriptomics was performed by RNAseq along with functional assays for metabolic activity and function. We observed effects at both doses, but a greater number of genes were differentially expressed with higher probability at the toxic concentrations. At the toxic doses, both drugs showed direct cholestatic potential with Nevirapine increasing bile synthesis and Ritonavir inhibiting bile acid transport. Clear differences in antigen presentation were noted, with marked activation of MHC Class I by Nevirapine and suppression by Ritonavir. This suggests CD8+ T cell involvement for Nevirapine and possibly NK Killer cells for Ritonavir. Both compounds induced several drug metabolizing genes (including CYP2B6, CYP3A4 and UGT1A1), mediated by CAR activation in Nevirapine and PXR in Ritonavir. Unlike Ritonavir, Nevirapine did not increase fatty acid synthesis or activate the respiratory electron chain with simultaneous mitochondrial uncoupling supporting clinical reports of a lower propensity for steatosis. This in vitro study offers insights into the disparate direct and immune-mediated toxicity mechanisms underlying Nevirapine and Ritonavir toxicity in the clinic. PMID- 26626334 TI - Measurement of urinary advanced glycation end-products (AGEs) using a fluorescence assay for metabolic syndrome-related screening tests. AB - AIMS: The simple screening test of advanced glycation end-products (AGEs) has not been established yet. We aimed to clarify the usefulness of simple measurement of AGEs for screening tests. METHODS: The subjects were healthy participants and patients with metabolic syndrome. Urine samples were diluted from 1:10 to 1:200 using phosphate-buffered saline, and the fluorescence intensity was measured at 440nm after excitation at 370nm in a 96-well microplate spectrophotometer. The obtained intensities were adjusted according to the urinary creatinine levels. RESULTS: In patients with metabolic syndrome, urinary AGE levels were significantly higher than in healthy individuals (median [range], 168.25 [82.51 1276.15] AU/g creatinine [n=37] versus 134.67 [37.86-776.31] AU/g creatinine [n=350], respectively; p=0.0066). We found significant positive correlations between urinary AGEs and systolic and diastolic blood pressures (Spearman's correlation r=0.119 [p=0.019] and r=0.128 [p=0.012], respectively). There was no significant correlation between estimated glomerular filtration rate and urinary AGEs (r=0.018 [p=0.744]), confirming that renal dysfunction did not influence results of urinary AGE measurements. When all of the participants in the study were classified into four groups according to the numbers of components of metabolic syndrome, we found a significant tendency (p=0.0127) for urinary AGE levels to be higher with the increasing number of metabolic syndrome components. CONCLUSION: These results suggested that measurement of urinary AGE levels may be useful for evaluating the risk of metabolic syndrome. PMID- 26626336 TI - Muscle group specific changes in the electromechanical delay following short-term resistance training. AB - OBJECTIVES: The time delay between the onset of a muscle's electrical activity and force is believed to have important functional implications, and has been shown to decrease following resistance training in males. The purpose of this investigation was to examine changes in the voluntary electromechanical delay (EMD) for the leg extensors and flexors following a short-term resistance training intervention in females. DESIGN: Pretest/posttest control group experiment. METHODS: Twenty-two previously untrained females (mean+/-SD age=21+/ 2 years; mass=65.4+/-13.3kg) were randomly assigned to training (n=10) and control (n=12) groups. The training group performed barbell back squats and deadlifts twice per week for four weeks. EMD for the vastus lateralis (extensors) and biceps femoris (flexors) was examined during maximal voluntary contractions at pre- and posttesting. Data were examined using analyses of covariance (ANCOVAs) with the pretest and posttest scores serving as the covariate and dependent variable, respectively, and by evaluating the number of participants that exceeded the minimal difference statistic. RESULTS: For the leg extensors, the adjusted EMD posttest mean for the training group was significantly lower than that for the control group (74.3 vs. 91.8ms; p=0.015; eta(2)=0.275), and five training participants displayed decreases that exceeded the minimal difference. The ANCOVA for the leg flexors was not significant (adjusted means=98.0 vs. 90.0ms; p=0.487; eta(2)=.026). CONCLUSIONS: Four weeks of multi joint resistance training resulted in decreased EMD for the leg extensors, but not the flexors. PMID- 26626337 TI - Antivenom shortage is not circumstantial but structural. PMID- 26626335 TI - Lesson From the New York City Out-of-Hospital Uncontrolled Donation After Circulatory Determination of Death Program. AB - STUDY OBJECTIVE: In 2006, the Institute of Medicine emphasized substantial potential to expand organ donation opportunities through uncontrolled donation after circulatory determination of death (uDCDD). We pilot an out-of-hospital uDCDD kidney program for New York City in partnership with communities that it was intended to benefit. We evaluate protocol process and outcomes while identifying barriers to success and means for improvement. METHODS: We conducted a prospective, participatory action research study in Manhattan from December 2010 to May 2011. Daily from 4 to 12 pm, our organ preservation unit monitored emergency medical services (EMS) frequencies for cardiac arrests occurring in private locations. After EMS providers independently ordered termination of resuscitation, organ preservation unit staff determined clinical eligibility and donor status. Authorized parties, persons authorized to make organ donation decisions, were approached about in vivo preservation. The study population included organ preservation unit staff, authorized parties, passersby, and other New York City agency personnel. Organ preservation unit staff independently documented shift activities with daily operations notes and teleconference summaries that we analyzed with mixed qualitative and quantitative methods. RESULTS: The organ preservation unit entered 9 private locations; all the deceased lacked previous registration, although 4 met clinical screening eligibility. No kidneys were recovered. We collected 837 notes from 35 organ preservation unit staff. Despite frequently recounting protocol breaches, most responses from passersby including New York City agencies were favorable. No authorized parties were offended by preservation requests, yielding a Bayesian posterior median 98% (95% credible interval 76% to 100%). CONCLUSION: In summary, the New York City out-of-hospital uDCDD program was not feasible. There were frequent protocol breaches and confusion in determining clinical eligibility. In the small sample of authorized persons we encountered during the immediate grieving period, negative reactions were infrequent. PMID- 26626338 TI - Cytokines in human leptospirosis. AB - BACKGROUND: Leptospirosis is a zoonotic disease with increased public health concern. Cytokines produced in response to the infection with pathogenic leptospires have been proposed to be involved in the pathogenesis of the disease. The aim of the study was to measure and evaluate the levels of 27 cytokines in patients with acute leptospirosis. METHODS: The levels of 27 cytokines were measured from 42 acute leptospirosis cases; 47 samples were obtained from severe cases. Statistical analysis was performed using SPSS. RESULTS: IL-6, IL-8, GM CSF, IP-10, MCP-1, and VEGF levels differed significantly between the severe cases and the control group, while GM-CSF levels differed significantly between the mild cases and the control group (p<0.05). IL-6, IP-10 and MCP-1 were elevated in most cases. IP-10 was significantly higher in severe than in non severe cases (p<0.05). The high IP-10 levels suggest a cellular immune response, despite the fact that leptospires are not intracellular organisms. IL-1ra, MCP-1, MIP-1b and TNF-alpha peaked 1-5 days post onset of illness (p.o.i.), IL-1b, IL-6, IL-8, IL-9, GM-CSF, IP-10 and MIP-1a peaked 6-10 days p.o.i., while VEGF peaked later (11-15 days p.o.i.). TNF-alpha was significantly lower in the severe cases with pulmonary involvement (p<0.05). CONCLUSIONS: Having a better insight into the host immune response in leptospirosis could be the basis for immunotherapeutic targets, especially for the severe cases in which antibiotic treatment is not enough. PMID- 26626339 TI - Malaria control at a gold mine in Sadiola District, Mali, and impact on transmission over 10 years. AB - BACKGROUND: The SEMOS gold mine's malaria vector control programme forms part of the company's community responsibilities with the programme being managed by the mine's health department since 2005. METHODS: Data from approximately 10 years of malaria vector control for the Sadiola District are given: namely malaria vector control methods used by the control programme, positive malaria case data and entomological surveys from 2006, 2011 and 2014. RESULTS: Distribution of pyrethroid-treated bed nets and indoor residual spraying (IRS) with deltamethrin were implemented by the programme from 2005-2011. No IRS was done in 2012. Spraying with the organophosphate, pirimiphos-methyl resumed in 2013 and 2014 and was followed by a 70% drop in malaria cases in 2014. Anopheles arabiensis was the major vector present in 2006 and was susceptible to deltamethrin. In 2011 and 2014, An. gambiae s.s. was the most abundant vector with deltamethrin 24 h mortality of 68% and 19%, respectively. CONCLUSIONS: Resistance to the pyrethroid deltamethrin has increased in An. gambiae s.s. since 2011, possibly due to the scale-up in distribution of long-lasting insecticide-treated bed nets. Resistance management strategies are recommended using different classes of insecticides for IRS, and including the distribution of new-generation bed nets. PMID- 26626341 TI - A randomized controlled study comparing community based with health facility based direct observation of treatment models on patients' satisfaction and TB treatment outcome in Nigeria. AB - BACKGROUND: Directly observed treatment short-course (DOTS) strategy is an effective mode of treating TB. We aimed to study the cost effectiveness and patients' satisfaction with home based direct observation of treatment (DOT), an innovative approach to community-based DOT (CBDOT) and hospital based DOT (HBDOT). METHODS: A randomized controlled trial involving 150 newly diagnosed pulmonary TB patients in four TB clinics in Ile Ife , Nigeria, was done. They were randomly assigned to receive treatment with anti TB drugs for the intensive phase administered at home by a TB worker (CBDOT) or at the hospital (HBDOT). Outcome measures were treatment completion/default rates, cost effectiveness and patients' satisfaction with care using a 13 item patients satisfaction questionnaire (PS-13) at 2 months. This trial was registered with pactr.org: number PACTR 201503001058381. RESULTS: At the end of intensive phase, 15/75 (20%) and 2/75 (3%) of patients in the HBDOT and CBDOT, respectively had defaulted from treatment, p= 0.01. Of those with pretreatment positive sputum smear, 97% (68/70) on CBDOT and 54/67 (81%) on HBDOT were sputum negative for AFB at the end of 2 months of treatment, p=0.01. The CBDOT method was associated with a higher patient satisfaction score compared with HBDOT (OR 3.1; 95% CI 1.25-7.70), p=0.001.The total cost for patients was higher in HBDOT (US$159.38) compared with the CBDOT (US$89.52). The incremental cost effectiveness ratio was US$410 per patient who completed the intensive phase treatment with CBDOT. CONCLUSIONS: CBDOT is a cost effective approach associated with better compliance to treatment and better patient satisfaction compared to HBDOT. PMID- 26626342 TI - Estimating the burden of disease and the economic cost attributable to chikungunya, Colombia, 2014. AB - BACKGROUND: Chikungunya (CHIK) virus disease is expected to be a considerable cause of disability and economic burden in Latin America given its chronic sequelae, particularly its chronic inflammatory rheumatism. There have been no previous studies assessing CHIK costs and disability in Latin America. METHODS: We calculated incidence rates for CHIK during the 2014 outbreak in Colombia using epidemiological data provided by the Colombian National Institute of Health, using demographic data from the National Administrative Department of Statistics. The burden of disease was estimated through disability adjusted life years (DALYs) lost and the costs were estimated based on the national recommendations for CHIK acute and chronic phase attention. RESULTS: There were a total of 106 592 cases, with incidence rates ranging from 0 to 1837.3 cases/100 000 population in different departments. An estimate was made of total DALYs lost of 40.44 to 45.14 lost/100 000 population. The 2014 outbreak estimated costs were at least US$73.6 million. CONCLUSIONS: Our estimates raise concerns about the effects of continued CHIK spread in Colombia and other Latin-American countries. The lack of transmission control for this disease and potential for spread means that there will be significant acute and chronic disability and related costs in the short and long term for Latin American health care systems. PMID- 26626340 TI - Prevalence of drug resistant TB among outpatients at an HIV/TB clinic in Lilongwe, Malawi. AB - BACKGROUND: We sought to determine the prevalence of drug resistant TB among outpatients initiating TB treatment in Lilongwe, Malawi. METHODS: This was a prospective cohort study of patients 18 years and older initiating TB treatment at Martin Preuss Centre, the primary integrated HIV/TB clinic in Lilongwe, Malawi, from April 2011 to July 2012. Procedures included questionnaires, physical exam, chest x-ray, full blood count and sputum collection. Sputum samples underwent acid-fast bacilli (AFB) smear testing and culture by Lowenstein Jensen (LJ) and liquid Mycobacteria Growth Indicator Tube (MGIT) methods. Drug sensitivity was investigated using the Hain GenoType MTBDRplus line probe assay. RESULTS: Of the 702 patients, 219 (31.2%) were female and 653 (93.0%) were presenting for first-time TB treatment. HIV co-infection was present in 420 (59.8%) cases, with 137 (32.6%) of those patients receiving antiretroviral therapy at presentation. TB was culture-confirmed in 375 (53.4%) patients, 349 of which were first time treatment and 26 retreatment. Ten cases of isoniazid resistant TB (2.9% of culture confirmed cases of newly treated TB), one of rifampin-resistant TB (0.3% culture confirmed cases of newly treated TB) and one of multi-drug resistant TB (MDR-TB) (3.8% of culture confirmed cases of retreatment TB) were detected. CONCLUSIONS: MDR-TB prevalence is low among outpatients initiating TB treatment in Lilongwe. PMID- 26626343 TI - Cost-effectiveness analysis of parenteral antimicrobials for acute melioidosis in Thailand. PMID- 26626345 TI - Pre-existing adversity, level of child protection involvement, and school attendance predict educational outcomes in a longitudinal study. AB - Maltreatment largely occurs in a multiple-risk context. The few large studies adjusting for confounding factors have raised doubts about whether low educational achievement results from maltreatment or co-occurring risk factors. This study examined prevalence, risk and protective factors for low educational achievement among children involved with the child protection system compared to other children. We conducted a population-based record-linkage study of children born in Western Australia who sat national Year 3 reading achievement tests between 2008 and 2010 (N=46,838). The longitudinal study linked data from the Western Australian Department of Education, Department of Child Protection and Family Support, Department of Health, and the Disability Services Commission. Children with histories of child protection involvement (unsubstantiated maltreatment reports, substantiations or out-of-home care placement) were at three-fold increased risk of low reading scores. Adjusting for socio-demographic adversity partially attenuated the increased risk, however risk remained elevated overall and for substantiated (OR=1.68) and unsubstantiated maltreatment (OR=1.55). Risk of low reading scores in the out-of-home care group was fully attenuated after adjusting for socio-demographic adversity (OR=1.16). Attendance was significantly higher in the out-of-home care group and served a protective role. Neglect, sexual abuse, and physical abuse were associated with low reading scores. Pre-existing adversity was also significantly associated with achievement. Results support policies and practices to engage children and families in regular school attendance, and highlight a need for further strategies to prevent maltreatment and disadvantage from restricting children's opportunities for success. PMID- 26626347 TI - Special issue Lipids: From (bio)synthesis to function. PMID- 26626346 TI - GM-CSF and the role of myeloid regulatory cells in the pathogenesis and treatment of Crohn's disease. AB - BACKGROUND: Intestinal monocytes/macrophages sustain the intestinal immune homeostasis and might be an attractive therapeutic target for the management of inflammatory bowel disease (IBD). Granulocyte macrophage colony-stimulating factor (GM-CSF) exerts beneficial effects on intestinal inflammation and promotes signal transducer and activator of transcription 3 (STAT3)-mediated expansion of myeloid-derived suppressor cells (MDSCs). However, the full action mechanism of GM-CSF, and especially whether monocytes mediate its therapeutic effects in vivo, had not been previously elucidated. CONCLUSIONS: This review article summarizes recent developments in the immunology of mucosal diseases and describes new aspects of the role of myeloid regulatory cells in IBD and the function of GM-CSF in maintaining the intestinal immune homeostasis in Crohn's disease (CD). This review article highlights the exploration of stimulating in addition to suppressive therapies for patients with IBD and underpins that myeloid regulatory cells might become a promising novel cell-based therapeutic option. PMID- 26626348 TI - Absorption and retention of free and milk protein-bound cyano- and hydroxocobalamins. An experimental study in rats. AB - INTRODUCTION: Cobalamin/Vitamin B12 (Cbl) is an essential vitamin, supplied mainly as hydroxocobalamin (OHCbl) by animal products, including cows' milk. Cyanocobalamin (CNCbl) is the usual form in vitamin pills. The aim was to explore absorption and tissue accumulation of two Cbl forms, administered alone or bound to milk protein. MATERIALS AND METHODS: We synthesized labeled OH[(57)Co]Cbl from commercially available CN[(57)Co]Cbl. Recombinant bovine transcobalamin (rbTC) was produced in yeast and skimmed milk obtained off the shelf. Male Wistar rats (250-300 g) received labeled Cbl by gastric gavage. First, we administered CN[(57)Co]Cbl, free or rbTC-bound (n = 15 in each group). Rats were sacrificed after two, 24, and 48 h. In the following studies, rats were sacrificed after 24 h. We compared absorption of free or rbTC-bound CN[(57)Co]Cbl added to cows' milk and analogous absorption of OH[(57)Co]Cbl, free or rbTC-bound, to absorption of free CN[(57)Co]Cbl, (n = 10 in each group). Blood, tissues, 24-h urine and feces were collected. Labeled Cbl was measured using a gamma counter. Results are expressed as percentage of administered dose. RESULTS: Absorptions of CNCbl and OHCbl were neither influenced by rbTC-binding nor administration in milk. Absorption increased in the first 24 h with no further tissue accumulation during the subsequent 24 h. Accumulation of free CNCbl and (OHCbl) was 1.4, (4.1) (liver); 20.2, (16.4) (kidney); and 0.05, (0.02) (plasma)% 24 h after administration. Total organ accumulations were 21.6, (20.5)%. While total accumulations of CNCbl and OHCbl were equal, distributions between liver, kidney, and plasma showed significant differences (p < 0.0001; p = 0.01; p < 0.0001). CONCLUSIONS: Cbl added to milk (spiked with rbTC) has high bioavailability matching that of free Cbl. OHCbl and CNCbl are absorbed equally well, but much more OHCbl accumulated in the liver. Benefits of oral supplementation with OHCbl compared to CNCbl should be investigated. PMID- 26626349 TI - Isolation, Purification and Characterization of Two Laccases from Carrot (Daucus carota L.) and Their Response to Abiotic and Metal Ions Stresses. AB - Laccases, which belong to the blue copper oxidase enzyme family, oxidize many organic and inorganic compounds. The laccase-encoding genes DcLac1 and DcLac2 were isolated from the economically important tuberous root carrot, and their proteins were successfully expressed and purified using the Escherichia coli expression system BL21(DE3). DcLac1 and DcLac2 had molecular masses of approximately 64 and 61.9 kDa, respectively. With 2,2'-azinobis-(3 ethylbenzthiazoline-6-sulfonate acid) as the substrate, DcLac1 and DcLac2 had K m values of 3.9043 and 1.255 mM, respectively, and V max values of 54.0832 and 81.7996 MUM mg(-1) min(-1), respectively. Moreover, DcLac1 and DcLac2 had optimal pH values of 2.8 and 2.6, respectively, and optimal temperatures of 45 and 40 degrees C, respectively. The activities of the two enzymes were promoted by Ca(2+), Mg(2+), Cu(2+), and Na(+) but inhibited by Fe(2+), Zn(2+), Mn(2+), K(+), SDS, and EDTA. Expression profiles showed that the two DcLac genes had almost identical responses to high and low temperature stresses but different responses to salt, drought, and metal stresses. This study provided insights into the characteristics and tolerance response mechanisms of laccase in carrot. PMID- 26626350 TI - Histone deacetylase-mediated morphological transition in Candida albicans. AB - Candida albicans is the most common opportunistic fungal pathogen, which switches its morphology from single-cell yeast to filament through the various signaling pathways responding to diverse environmental cues. Various transcriptional factors such as Nrg1, Efg1, Brg1, Ssn6, and Tup1 are the key components of these signaling pathways. Since C. albicans can regulate its transcriptional gene expressions using common eukaryotic regulatory systems, its morphological transition by these signaling pathways could be linked to the epigenetic regulation by chromatin structure modifiers. Histone proteins, which are critical components of eukaryotic chromatin structure, can regulate the eukaryotic chromatin structure through their own modifications such as acetylation, methylation, phosphorylation and ubiquitylation. Recent studies revealed that various histone modifications, especially histone acetylation and deacetylation, participate in morphological transition of C. albicans collaborating with well known transcription factors in the signaling pathways. Here, we review recent studies about chromatin-mediated morphological transition of C. albicans focusing on the interaction between transcription factors in the signaling pathways and histone deacetylases. PMID- 26626351 TI - Pyrosequencing reveals bacterial diversity in Korean traditional wheat-based nuruk. AB - The emerging global importance of Korea's alcoholic beverages emphasizes the need for quality enhancement of nuruk, a traditional Korean cereal starter that is used extensively in traditional brewing. Apart from fungi and yeasts, bacteria known to be ubiquitously present are also a part of the nuruk ecosystem and are known to influence fermentation activity by influencing fermentation favorable factors. In the current study, bacterial diversity and temporal variations in the traditional wheat-based nuruk, fermented at two representative temperature conditions for 30 days, along with two commercial wheat-based nuruk samples for comparison analysis were evaluated using libraries of PCR amplicons and 454 pyrosequencing targeting of the hypervariable regions V1 to V3 of the 16S rRNA gene. A total of 90,836 16S reads were analyzed and assigned to a total of 314, 321, and 141 Operational Taxonomic Units (OTUs) for nuruk A, B, and C, respectively. Diversity parameters clearly indicated nuruk B to be more diverse in terms of bacterial composition than nuruk A. Taxonomic assignments indicated that nuruk A was dominated by phylum Cyanobacteria, whereas nuruk B was dominated by phylum Actinobacteria. For both nuruk A and B, members of the phylum Firmicutes mostly converged into the family Bacillaceae; these microorganisms might be present in negligible numbers at the beginning but became significant as the fermentation progressed. The commercial samples were predominated by phylum Firmicutes, which is composed of Lactobacillaceae and Leoconostocaceae. The findings of this study provide new insights into understanding the changes in bacterial community structure during traditional nuruk starter production. PMID- 26626352 TI - Characterization of cell death in Escherichia coli mediated by XseA, a large subunit of exonuclease VII. AB - Exonuclease VII (ExoVII) of Escherichia coli is a single strandspecific DNA nuclease composed of two different subunits: the large subunit, XseA, and the small subunit, XseB. In this study, we found that multicopy single-stranded DNAs (msDNAs), Ec83 and Ec78, are the in vivo substrates of ExoVII; the enzyme cuts the phosphodiester bond between the fourth and fifth nucleotides from the 5'end. We used this msDNA cleavage to assess ExoVII activity in vivo. Both subunits were required for enzyme activity. Expression of XseA without XseB caused cell death, even though no ExoVII activity was detected. The lethality caused by XseA was rescued by surplus XseB. In XseA-induced death, cells were elongated and multinucleated, and their chromosomes were fragmented and condensed; these are the morphological hallmarks of apoptotic cell death in bacteria. A putative caspase recognition sequence (FVAD) was found in XseA, and its hypothetical caspase product with 257 amino acids was as active as the intact protein in inducing cell death. We propose that under ordinary conditions, XseA protects chromosome as a component of the ExoVII enzyme, but in some conditions, the protein causes cell death; the destruction of cell is probably carried out by the amino terminal fragment derived from the cleavage of XseA by caspase-like enzyme. PMID- 26626353 TI - Inhibition of quorum sensing, biofilm, and spoilage potential in Shewanella baltica by green tea polyphenols. AB - We investigated the quorum sensing (QS) system of Shewanella baltica and the anti QS related activities of green tea polyphenols (TP) against spoilage bacteria in refrigerated large yellow croaker. Autoinducer-2 (AI-2) and the diketopiperazines (DKPs) cyclo-(L-Pro-L-Leu) and cyclo-(L-Pro-L-Phe) were detected in the culture extract of S. baltica XH2, however, no N-acylhomoserine lactones (AHLs) activity was observed. Green TP at sub-inhibitory concentrations interfered with AI-2 and DKPs activities of S. baltica without inhibiting cell growth and promoted degradation of AI-2. The green TP treatment inhibited biofilm development, exopolysaccharide production and swimming motility of S. baltica in a concentration- dependent manner. In addition, green TP decreased extracellular protease activities and trimethylamine production in S. baltica. A transcriptional analysis showed that green TP repressed the luxS and torA genes in S. baltica, which agreed with the observed reductions in QS activity and the spoilage phenotype. Epigallocatechin gallate (EGCG)-enriched in green TP significantly inhibited AI-2 activity of S. baltica. These findings strongly suggest that green TP could be developed as a new QS inhibitor for seafood preservation to enhance shelf life. PMID- 26626354 TI - In silico analysis and experimental validation of lipoprotein and novel Tat signal peptides processing in Anabaena sp. PCC7120. AB - Signal peptide (SP) plays a pivotal role in protein translocation. Lipoprotein- and twin arginine translocase (Tat) dependent signal peptides were studied in All3087, a homolog of competence protein of Synechocystis PCC6803 and in two putative alkaline phosphatases (ALPs, Alr2234 and Alr4976), respectively. In silico analysis of All3087 is shown to possess the characteristics feature of competence proteins such as helix-hairpin-helix, N and C-terminal HKD endonuclease domain, calcium binding domain and N-terminal lipoprotein signal peptide. The SP recognition-cleavage site in All3087 was predicted (AIA-AC) using SignalP while further in-depth analysis using Pred-Lipo and WebLogo analysis for consensus sequence showed it as IAA-C. Activities of putative ALPs were confirmed by heterologous overexpression, activity assessment and zymogram analysis. ALP activity in Anabaena remains cell bound in log-phase, but during late log/stationary phase, an enhanced ALP activity was detected in extracellular milieu. The enhancement of ALP activity during stationary phase was not only due to inorganic phosphate limitation but also contributed by the presence of novel bipartite Tat-SP. The Tat signal transported the folded active ALPs to the membrane, followed by anchoring into the membrane and successive cleavage enabling transportation of the ALPs to the extracellular milieu, because of bipartite architecture and processing of transit Tat-SP. PMID- 26626355 TI - In vivo antimalarial activity of the endophytic actinobacteria, Streptomyces SUK 10. AB - Endophytic bacteria, such as Streptomyces, have the potential to act as a source for novel bioactive molecules with medicinal properties. The present study was aimed at assessing the antimalarial activity of crude extract isolated from various strains of actinobacteria living endophytically in some Malaysian medicinal plants. Using the four day suppression test method on male ICR strain mice, compounds produced from three strains of Streptomyces (SUK8, SUK10, and SUK27) were tested in vivo against Plasmodium berghei PZZ1/100 in an antimalarial screen using crude extracts at four different concentrations. One of these extracts, isolated from Streptomyces SUK10 obtained from the bark of Shorea ovalis tree, showed inhibition of the test organism and was further tested against P. berghei-infected mice for antimalarial activity at different concentrations. There was a positive relationship between the survival of the infected mouse group treated with 50 ug/kg body weight (bw) of ethyl acetate SUK10 crude extract and the ability to inhibit the parasites growth. The parasite inhibition percentage for this group showed that 50% of the mice survived for more than 90 days after infection with the parasite. The nucleotide sequence and phylogenetic tree suggested that Streptomyces SUK10 may constitute a new species within the Streptomyces genus. As part of the drug discovery process, these promising finding may contribute to the medicinal and pharmaceutical field for malarial treatment. PMID- 26626358 TI - Erratum to: The Mycobacterium tuberculosis relBE toxin: antitoxin genes are stress-responsive modules that regulate growth through translation inhibition. PMID- 26626356 TI - Lactobacillus rhamnosus CCFM1107 treatment ameliorates alcohol-induced liver injury in a mouse model of chronic alcohol feeding. AB - Lactobacillus rhamnosus CCFM1107 was screened for high antioxidative activity from 55 lactobacilli. The present study attempted to explore the protective properties of L. rhamnosus CCFM1107 in alcoholic liver injury. A mouse model was induced by orally feeding alcohol when simultaneously treated with L. rhamnosus CCFM1107, the drug Hu-Gan- Pian (HGP), L. rhamnosus GG (LGG), and L. plantarum CCFM1112 for 3 months. Biochemical analysis was performed for both serum and liver homogenate. Detailed intestinal flora and histological analyses were also carried out. Our results indicated that the administration of L. rhamnosus CCFM1107 significantly inhibited the increase in the levels of serum aminotransferase and endotoxin, as well as the levels of triglyceride (TG) and cholesterol (CHO) in the serum and in the liver. Glutathione (GSH), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were elevated while the levels of malondialdehyde (MDA) were decreased. The enteric dysbiosis caused by alcohol was restored by increasing the numbers of both lactobacilli and bifidobacteria and decreasing the numbers of both enterococci and enterobacter. Histological analysis confirmed the protective effect of L. rhamnosus CCFM1107. Compared with the other lactobacilli and to the drug Hu-Gan-Pian, there is a high chance that L. rhamnosus CCFM1107 provides protective effects on alcoholic liver injury by reducing oxidative stress and restoring the intestinal flora. PMID- 26626359 TI - Modelling the emergence of coordinated collective motion by minimizing dissatisfaction. AB - Coordinated collective motion (CCM) has been recently studied using agent-based simulations by applying three behavioural rules: repulsion, attraction and alignment. But these rules are so similar to the expected group behaviour that it can hardly be labelled emergent. We developed an agent-based model that produces CCM using a set of low-level dyadic interaction rules. The agents change their positions with regard to other agents in order to minimize their own dissatisfaction with their inter-individual distances. To test the emergence of CCM, several simulation experiments were performed. The results show that the agents were able to achieve CCM after a few thousand time steps, and that the bigger the area perceived by them, the more coordinated and cohesive the group motion became. An increased memory span and capacity to remember other agents' identities improved cohesion and coordination. The relationship with biological referents is discussed. PMID- 26626357 TI - Innate signaling mechanisms controlling Mycobacterium chelonae-mediated CCL2 and CCL5 expression in macrophages. AB - Mycobacterium chelonae (Mch) is an atypical rapidly growing mycobacterium (RGM) that belongs to the M. chelonae complex, which can cause a variety of human infections. During this type of mycobacterial infection, macrophage-derived chemokines play an important role in the mediation of intracellular communication and immune surveillance by which they orchestrate cellular immunity. However, the intracellular signaling pathways involved in the macrophage-induced chemokine production during Mch infections remain unknown. Thus, the present study aimed to determine the molecular mechanisms by which Mch activates the gene expressions of chemokine (C-C motif) ligand 2 (CCL2) and CCL5 in murine bone marrow-derived macrophages (BMDMs) and in vivo mouse model. Toll-like receptor 2 (TLR2) deficient mice showed increased bacterial burden in spleen and lung and decreased protein expression of CCL2 and CCL5 in serum. Additionally, Mch infection triggered the mRNA and protein expression of CCL2 and CCL5 in BMDMs via TLR2 and myeloid differentiation primary response gene 88 (MyD88) signaling and that it rapidly activated nuclear factor (NF)-kappaB signaling, which is required for the Mch-induced expressions of CCL2 and CCL5 in BMDMs. Moreover, while the innate receptor Dectin-1 was only partly involved in the Mch-induced expression of the CCL2 and CCL5 chemokines in BMDMs, the generation of intracellular reactive oxygen species (ROS) was an important contributor to these processes. Taken together, the present data indicate that the TLR2, MyD88, and NF-kappaB pathways, Dectin-1 signaling, and intracellular ROS generation contribute to the Mch mediated expression of chemokine genes in BMDMs. PMID- 26626360 TI - The response of guinea pig primary utricular and saccular irregular neurons to bone-conducted vibration (BCV) and air-conducted sound (ACS). AB - This study sought to characterize the response of mammalian primary otolithic neurons to sound and vibration by measuring the resting discharge rates, thresholds for increases in firing rate and supra-threshold sensitivity functions of guinea pig single primary utricular and saccular afferents. Neurons with irregular resting discharge were activated in response to bone conducted vibration (BCV) and air conducted sound (ACS) for frequencies between 100 Hz and 3000 Hz. The location of neurons was verified by labelling with neurobiotin. Many afferents from both maculae have very low or zero resting discharge, with saccular afferents having on average, higher resting rates than utricular afferents. Most irregular utricular and saccular afferents can be evoked by both BCV and ACS. For BCV stimulation: utricular and saccular neurons show similar low thresholds for increased firing rate (around 0.02 g on average) for frequencies from 100 Hz to 750 Hz. There is a steep increase in rate change threshold for BCV frequencies above 750 Hz. The suprathreshold sensitivity functions for BCV were similar for both utricular and saccular neurons, with, at low frequencies, very steep increases in firing rate as intensity increased. For ACS stimulation: utricular and saccular neurons can be activated by high intensity stimuli for frequencies from 250 Hz to 3000 Hz with similar flattened U-shaped tuning curves with lowest thresholds for frequencies around 1000-2000 Hz. The average ACS thresholds for saccular afferents across these frequencies is about 15-20 dB lower than for utricular neurons. The suprathreshold sensitivity functions for ACS were similar for both utricular and saccular neurons. Both utricular and saccular afferents showed phase-locking to BCV and ACS, extending up to frequencies of at least around 1500 Hz for BCV and 3000 Hz for ACS. Phase-locking at low frequencies (e.g. 100 Hz) imposes a limit on the neural firing rate evoked by the stimulus since the neurons usually fire one spike per cycle of the stimulus. CONCLUSION: These results are in accord with the hypothesis put forward by Young et al. (1977) that each individual cycle of the waveform, either BCV or ACS, is the effective stimulus to the receptor hair cells on either macula. We suggest that each cycle of the BCV or ACS stimulus causes fluid displacement which deflects the short, stiff, hair bundles of type I receptors at the striola and so triggers the phase-locked neural response of primary otolithic afferents. PMID- 26626361 TI - Quantitative PCR analysis and protein distribution of drug transporter genes in the rat cochlea. AB - Membrane transporters can be major determinants in the targeting and effectiveness of pharmaceutical agents. A large number of biologically important membrane transporters have been identified and localized to a variety of tissues, organs and cell types. However, little is known about the expression of key membrane transporters in the inner ear, a promising site for targeted therapeutics, as well as a region vulnerable to adverse drug reactions and environmental factors. In this study, we examined the levels of endogenous membrane transporters in rat cochlea by targeted PCR array analysis of 84 transporter genes, followed by validation and localization in tissues by immunohistochemistry. Our studies indicate that several members of the SLC, VDAC and ABC membrane transporter families show high levels of expression, both at the RNA and protein levels in the rat cochlea. Identification and characterization of these membrane transporters in the inner ear have clinical implications for both therapeutic and cytotoxic mechanisms that may aid in the preservation of auditory function. PMID- 26626362 TI - A method to measure sound transmission via the malleus-incus complex. AB - BACKGROUND: The malleus-incus complex (MIC) plays a crucial role in the hearing process as it transforms and transmits acoustically-induced motion of the tympanic membrane, through the stapes, into the inner-ear. However, the transfer function of the MIC under physiologically-relevant acoustic stimulation is still under debate, especially due to insufficient quantitative data of the vibrational behavior of the MIC. This study focuses on the investigation of the sound transformation through the MIC, based on measurements of three-dimensional motions of the malleus and incus with a full six degrees of freedom (6 DOF). METHODS: The motion of the MIC was measured in two cadaveric human temporal bones with intact middle-ear structures excited via a loudspeaker embedded in an artificial ear canal, in the frequency range of 0.5-5 kHz. Three-dimensional (3D) shapes of the middle-ear ossicles were obtained by sequent micro-CT imaging, and an intrinsic frame based on the middle-ear anatomy was defined. All data were registered into the intrinsic frame, and rigid body motions of the malleus and incus were calculated with full six degrees of freedom. Then, the transfer function of the MIC, defined as velocity of the incus lenticular process relative to velocity of the malleus umbo, was obtained and analyzed. RESULTS: Based on the transfer function of the MIC, the motion of the lenticularis relative to the umbo reduces with frequency, particularly in the 2-5 kHz range. Analysis of the individual motion components of the transfer function indicates a predominant medial-lateral component at frequencies below 1 kHz, with low but considerable anterior-posterior and superior-inferior components that become prominent in the 2-5 kHz range. CONCLUSION: The transfer function of the human MIC, based on motion of the umbo and lenticularis, has been visualized and analyzed. While the magnitude of the transfer function decreases with frequency, its spatio-temporal complexity increases significantly. PMID- 26626363 TI - A novel Halomonas ventosae-specific virulent halovirus isolated from the Qiaohou salt mine in Yunnan, Southwest China. AB - Although Halomonas phages belonging to the families Myoviridae and Siphoviridae have been reported, no virulent Halomonas siphoviruses are known. In this study, a virulent bacteriophage, QHHSV-1, of the family Siphoviridae that specifically infects H. ventosae QH52-2 was isolated from the Qiaohou salt mine. Restriction analysis indicated that QHHSV-1 is a dsDNA virus with a genome size of 33.5-39.5 kb. Transmission electron microscopy showed that QHHSV-1 is a typical representative of the Siphoviridae, with an icosahedral head (47 nm in diameter) and a non-contractile tail (75 nm in length). We also assessed the adsorption rate of QHHSV-1 for the host bacterium and found significant inhibition after the addition of 10 mM CaCl2. Based on a one-step growth curve, we determined a latent period of 30 min and a burst size of 73 PFU/infected cell. At the optimal pH of 8.0, 25.9 and 15.2 % of the phages survived after a 60-min incubation at 50 and 60 degrees C, respectively. Phage replication was possible at a wide range of salt concentrations, from 2.0 to 20 % (w/v), with an optimum concentration of 5 %. The survival of QHHSV-1 at different salt concentrations decreased with time and 25 % survival after 25 days at 30 % salt concentration. PMID- 26626366 TI - Benefit of rectal washout for anterior resection and left sided resections. AB - PURPOSE: To assess the effectiveness of rectal wash out in preventing local recurrence for patients who undergo anterior resection for recto-sigmoid cancer. MATERIALS AND METHODS: A best evidence topic was constructed according to a structured protocol. Medline 1948-2015 and EMBASE 1980 to 2015 using the OVID interface: ( Rectal) AND (Washout) AND (Anterior Resection). In addition, the reference lists of the relevant papers were searched. OUTCOMES: Eight papers among the 17 relevant articles were identified as representing the best evidence including 3 prospective non-randomized studies, 1 retrospective non randomized study and 4 meta-analyses. CONCLUSIONS: On the basis of current evidence, rectal washout does not stop local recurrence of cancer after anterior resection or left sided colonic resection, but it may reduce the rate of local recurrence. A randomised controlled trial to address this issue would formally answer this question. PMID- 26626367 TI - Thyroid carcinoma in Graves' disease: A meta-analysis. AB - BACKGROUND: The incidence of thyroid carcinoma is increasing worldwide. Graves' disease is the most common hyperthyroid disease. Studies have suggested an increased risk of thyroid malignancy in Graves' disease: there has not yet been a meta-analysis to allow quantitative comparison. The purpose of this study was to determine the risk of thyroid carcinoma in Graves' disease, and to gather information on the histological subtypes of carcinoma and the co-existence of thyroid nodules. METHODS: Several databases and article reference lists were searched. Inclusion criteria included appropriate diagnostic criteria for thyroid conditions and a diagnoses of carcinoma based on histology. RESULTS: 33 studies were selected, all reporting on surgically-resected specimens. The event rate of thyroid carcinoma in Graves' disease was 0.07 (95% CI 0.04 to 0.12). There was no data to allow comparison with patients without hyperthyroid diseases. There was no increase in the odds of developing carcinoma in Graves' disease compared to toxic multinodular goitre and toxic uninodular goitre. 88% of thyroid carcinomas in Graves' disease were papillary, with solitary papillary micro-carcinoma (diameter 10 mm or less) comprising 23% of all detected thyroid carcinomas. Patients with Graves' disease and co-existing thyroid nodules were almost 5 times more likely to be diagnosed with thyroid carcinoma than those without nodules. CONCLUSION: Thyroid malignancy in Graves' disease requiring surgical treatment should be considered as likely as in other hyperthyroid diseases needing surgical treatment. Clinicians should consider screening selected patients with Graves' disease for nodules whilst being aware of potentially over-diagnosing papillary micro-carcinoma. PMID- 26626365 TI - Gut microbiota analysis reveals a marked shift to bifidobacteria by a starter infant formula containing a synbiotic of bovine milk-derived oligosaccharides and Bifidobacterium animalis subsp. lactis CNCM I-3446. AB - Non-digestible milk oligosaccharides were proposed as receptor decoys for pathogens and as nutrients for beneficial gut commensals like bifidobacteria. Bovine milk contains oligosaccharides, some of which are structurally identical or similar to those found in human milk. In a controlled, randomized double blinded clinical trial we tested the effect of feeding a formula supplemented with a mixture of bovine milk-derived oligosaccharides (BMOS) generated from whey permeate, containing galacto-oligosaccharides and 3'- and 6'-sialyllactose, and the probiotic Bifidobacterium animalis subsp. lactis (B. lactis) strain CNCM I 3446. Breastfed infants served as reference group. Compared with a non supplemented control formula, the test formula showed a similar tolerability and supported a similar growth in healthy newborns followed for 12 weeks. The control, but not the test group, differed from the breast-fed reference group by a higher faecal pH and a significantly higher diversity of the faecal microbiota. In the test group the probiotic B. lactis increased by 100-fold in the stool and was detected in all supplemented infants. BMOS stimulated a marked shift to a bifidobacterium-dominated faecal microbiota via increases in endogenous bifidobacteria (B. longum, B. breve, B. bifidum, B. pseudocatenulatum). PMID- 26626364 TI - Movements of HIV-1 genomic RNA-APOBEC3F complexes and PKR reveal cytoplasmic and nuclear PKR defenses and HIV-1 evasion strategies. AB - APOBEC3 cytidine deaminases and viral genomic RNA (gRNA) occur in virions, polysomes, and cytoplasmic granules, but have not been tracked together. Moreover, gRNA traffic is important, but the factors that move it into granules are unknown. Using in situ hybridization of transfected cells and protein synthesis inhibitors that drive mRNAs between locales, we observed APOBEC3F cotrafficking with gRNA without altering its movements. Whereas cells with little cytoplasmic gRNA were translationally active and accumulated Gag, suprathreshold amounts induced autophosphorylation of the cytoplasmic double-stranded RNA (dsRNA)-dependent protein kinase (PKR), causing eIF2alpha phosphorylation, protein synthesis suppression, and gRNA sequestration in stress granules. Additionally, we confirmed recent evidence that PKR is activated by chromosome associated cellular dsRNAs after nuclear membranes disperse in prophase. By arresting cells in G2, HIV-1 blocks this mechanism for PKR activation and eIF2alpha phosphorylation. However, cytopathic membrane damage in CD4- and coreceptor-positive cultures infected with laboratory-adapted fusogenic HIV-1LAI eventually enabled PKR entry and activation in interphase nuclei. These results reveal multiple stages in the PKR-HIV-1 battleground that culminate in cell death. We discuss evidence suggesting that HIV-1s evolve in vivo to prevent or delay PKR activation by all these mechanisms. PMID- 26626372 TI - The Origin of Layer Structure Artifacts in Simulations of Liquid Water. AB - A recent paper (Yonetani, Chem. Phys. Lett. 2005, 406, 49-53) shows that in computer simulations of TIP3P water (Jorgensen et al. J. Chem. Phys. 1983, 79, 926-935) a strange layer formation can occur when a long cutoff is used. This result is counterintuitive because, in principle, increasing the cutoff should give more accurate results. Here we test this finding for different water models and try to explain why layer formation occurs. In doing so we find that under certain conditions, layer formation coincides with a sharp density increase to 1050 g/L, while simultaneously a pressure of 600 bar develops and water diffusion becomes anisotropic. This leads us to conclude that a group-based cutoff (of at least 1.4 nm) stabilizes an anomalous phase with most water models. In some cases the ordering is strengthened further by periodicity in the simulation cell, but periodicity effects can even be observed with a short cutoff (0.9 nm) and a relatively large box of 4 nm. Water models that have a relatively large quadrupole moment, more in accord with the experimental gas-phase values, in particular TIP4P (Jorgensen et al. J. Chem. Phys. 1983, 79, 926-935), are much less affected by the problem, because the dipole-dipole interaction is quenched at long distance. A comparison of different cutoff treatments, namely truncation, reaction field, particle mesh Ewald (PME), and switch and shift functions, for the simulation of water shows that only PME and shift functions yield realistic dipole-dipole interactions at long distance. The impact for biomolecular simulations is discussed. PMID- 26626374 TI - 2D Entropy of Discrete Molecular Ensembles. AB - A method is presented for the estimation of the conformational entropy of discrete macromolecular ensembles associated with multiple rotameric dihedral angle states. A covariance matrix is constructed of all mobile dihedral angles, which are represented as complex numbers on the unit circle, and subjected to a principal component analysis. The total entropy is decomposed into additive contributions from each eigenmode, for which a 2D entropy is computed after convolution of the projection coefficients of the conformer ensemble for that mode with a 2D Gaussian function. The method is tested for ensembles of linear polymer chains for which the exact conformational entropies are known. These include chains with up to 15 dihedral angles exhibiting two or three rotamers per dihedral angle. The performance of the method is tested for molecular ensembles that exhibit various forms of correlation effects, such as ensembles with mutually exclusive combinations of rotamers, ensembles with conformer populations biased toward compact conformers, ensembles with Gaussian distributed pairwise rotamer energies, and ensembles with electrostatic intramolecular interactions. For all these ensembles, the method generally provides good estimates for the exact conformational entropy. The method is applied to a protein molecular dynamics simulation to assess the effect of side-chain-backbone and side-chain side-chain correlations on the conformational entropy. PMID- 26626376 TI - Quantifying Aromaticity at the Molecular and Supramolecular Limits: Comparing Homonuclear, Heteronuclear, and H-Bonded Systems. AB - The aromatic/antiaromatic characteristics of B-N and P-N analogues of benzene and cyclobutadiene have been studied using quantum chemical methods. We use established parameters such as nucleus-independent chemical shifts, charge density at the ring critical point, and stabilization energies to quantify the nature of interactions in these molecular systems. B3N3H6 and N3P3F6 resemble benzene in being aromatic, albeit to a lesser extent, while B2N2H4 and N2P2F4 are found to be aromatic, opposite to that for cyclobutadiene. A sigma-pi separation analysis has been performed to critically examine the contributions from the pi electrons compared to that from the sigma backbone. The structural aspects in the weak interaction limits such as the H-bonded cyclic trimers of HX (X = F, Cl, and Br) have also been investigated. Even in such weak interaction limits, these cyclic systems are found to be substantially stable. These H-bonded systems exhibit nonlocal polarizations across the full-perimeter of the ring that lead to aromaticity. We propose the term "H-bonded aromaticity" for such closed-loop weakly delocalized systems. This new formalism of aromaticity has the potential to explain structures and properties in supramolecular systems. PMID- 26626375 TI - Stability of Carbon-Nitrogen Cages in 3-Fold Symmetry. AB - Molecules consisting entirely of nitrogen have been studied extensively for their potential as high energy density materials (HEDM). One class of potential high energy nitrogen molecules is the cage of three-coordinate nitrogen. Previous theoretical studies of cages Nx have shown that the most stable isomers are cylindrical molecules with 3-fold symmetry and triangular endcaps, but such molecules are not stable with respect to dissociation. In the current study, nitrogen cages are modified to include carbon atom substituents. Carbon atoms are studied for their potential to stabilize the nitrogen structures while maintaining significant levels of energy release from the molecules. Theoretical calculations are carried out on a sequence of high-energy cages with carbon and nitrogen. Density functional theory (B3LYP), perturbation theory (MP2 and MP4), and coupled-cluster theory (CCSD(T)) are used in conjunction with the correlation consistent basis sets of Dunning. Stability trends as a function of molecule size are calculated and discussed. PMID- 26626373 TI - Preaveraged Hydrodynamic Interaction Revisited via Boundary Element Computations. AB - The effect of preaveraging the Oseen tensor to yield a scalar approximation is examined for transport problems of rigid objects with stick boundary conditions using new very high accuracy computational codes. Nearly exact computations are compared to analytical results and preaveraged results for spheroids and, similarly, for a set of three globular proteins. In agreement with previous work, we find that the error in translational diffusion is less than 1%. However, in the case of rotational diffusion and intrinsic viscosity, the error is sensitively dependent on shape. In the case of the axial component of the rotational diffusion, the error is about -34% independent of shape, but for the perpendicular component, the error starts at -30% (sphere) and decreases as the axial ratio increases and then yields a similar but positive error. For the instrinsic viscosity, the errors are around 10% near spherical and decrease toward the needle or disk shape. For the globular proteins, the errors are similar to those found for the ellipsoids near the spherical shape. The calculations show that preaveraging is acceptable only for translational diffusion of rigid objects. PMID- 26626368 TI - Effective reinforcement learning following cerebellar damage requires a balance between exploration and motor noise. AB - Reinforcement and error-based processes are essential for motor learning, with the cerebellum thought to be required only for the error-based mechanism. Here we examined learning and retention of a reaching skill under both processes. Control subjects learned similarly from reinforcement and error-based feedback, but showed much better retention under reinforcement. To apply reinforcement to cerebellar patients, we developed a closed-loop reinforcement schedule in which task difficulty was controlled based on recent performance. This schedule produced substantial learning in cerebellar patients and controls. Cerebellar patients varied in their learning under reinforcement but fully retained what was learned. In contrast, they showed complete lack of retention in error-based learning. We developed a mechanistic model of the reinforcement task and found that learning depended on a balance between exploration variability and motor noise. While the cerebellar and control groups had similar exploration variability, the patients had greater motor noise and hence learned less. Our results suggest that cerebellar damage indirectly impairs reinforcement learning by increasing motor noise, but does not interfere with the reinforcement mechanism itself. Therefore, reinforcement can be used to learn and retain novel skills, but optimal reinforcement learning requires a balance between exploration variability and motor noise. PMID- 26626370 TI - Correction: Biophysical separation of Staphylococcus epidermidis strains based on antibiotic resistance. AB - Correction for 'Biophysical separation of Staphylococcus epidermidis strains based on antibiotic resistance' by Paul V. Jones et al., Analyst, 2015, 140, 5152 5161. PMID- 26626377 TI - Relativistic DFT Calculation of (119)Sn Chemical Shifts and Coupling Constants in Tin Compounds. AB - The nuclear shielding and spin-spin coupling constants of (119)Sn in stannane, tetramethylstannane, methyltin halides Me4-nSnXn (X = Cl, Br, I; n = 1-3), tin halides, and some stannyl cations have been investigated computationally by DFT methods and Slater all-electron basis sets, including relativistic effects by means of the zeroth order regular approximation (ZORA) method up to spin-orbit coupling. Calculated (119)Sn chemical shifts generally correlate well with experimental values, except when several heavy halogen atoms, especially iodine, are bound to tin. In such cases, calculated chemical shifts are almost constant at the scalar (spin-free) ZORA level; only at the spin-orbit level is a good correlation, which holds for all compounds examined, attained. A remarkable "heavy-atom effect", analogous to that observed for analogous alkyl halides, is evident. The chemical shift of the putative stannyl cation (SnH3(+)) has also been examined, and it is concluded that the spectrum of the species obtained in superacids is inconsistent with a simple SnH3(+) structure; strong coordination to even weak nucleophiles such as FSO3H leads to a very satisfactory agreement. On the contrary, the calculated (119)Sn chemical shift of the trimesitylstannyl cation is in very good agreement with the experimental value. Coupling constants between (119)Sn and halogen nuclei are also well-modeled in general (taking into account the large uncertainties in the experimental values); relativistic spin orbit effects are again quite evident. Couplings to (13)C and (1)H also fall, on the average, on the same correlation line, but individual values show a significant deviation from the expected unit slope. PMID- 26626378 TI - The IMOMM (Integrated Molecular Orbitals/Molecular Mechanics) Approach for Ligand Stabilized Metal Clusters. Comparison to Full Density Functional Calculations for the Model Thiolate Cluster Cu13(SCH2CH3)8. AB - To validate the IMOMM (integrated molecular orbitals/molecular mechanics) method for ligand-stabilized transition metal clusters, we compare results of this combined quantum mechanical and molecular mechanical (QM/MM) approach, as implemented in the program ParaGauss (Kerdcharoen, T.; Birkenheuer, U.; Kruger, S.; Woiterski, A.; Rosch, N. Theor. Chem. Acc. 2003, 109, 285), to a full density functional (DF) treatment. For this purpose, we have chosen a model copper ethylthiolate cluster, Cu13(SCH2CH3)8 in D4h symmetry. The evaluation is based on 16 conformers of the cluster which exhibit single and bridging coordination of the ligands at the Cu13 cluster as well as various ligand orientations. For corresponding isomers, we obtained moderate deviations between QM and QM/MM results: 0.01-0.06 A for pertinent bond lengths and up to ~15 degrees for bond angles. Ligand binding energies of the two approaches deviated less than 6 kcal/mol. The largest discrepancies between full DF and IMOMM results were found for isomers exhibiting short Cu-H and H-H contacts. We traced this back to the localization of different minima, reflecting the unequal performance of the DF and the force-field methods for nonbonding interactions. Thus, QM/MM results can be considered as more reliable because of the well-known limitations of standard exchange-correlation functionals for the description of nonbonding interactions for this class of systems. PMID- 26626380 TI - Sparkle/AM1 Parameters for the Modeling of Samarium(III) and Promethium(III) Complexes. AB - The Sparkle/AM1 model is extended to samarium(III) and promethium(III) complexes. A set of 15 structures of high crystallographic quality (R factor < 0.05 A), with ligands chosen to be representative of all samarium complexes in the Cambridge Crystallographic Database 2004, CSD, with nitrogen or oxygen directly bonded to the samarium ion, was used as a training set. In the validation procedure, we used a set of 42 other complexes, also of high crystallographic quality. The results show that this parametrization for the Sm(III) ion is similar in accuracy to the previous parametrizations for Eu(III), Gd(III), and Tb(III). On the other hand, promethium is an artificial radioactive element with no stable isotope. So far, there are no promethium complex crystallographic structures in CSD. To circumvent this, we confirmed our previous result that RHF/STO-3G/ECP, with the MWB effective core potential (ECP), appears to be the most efficient ab initio model chemistry in terms of coordination polyhedron crystallographic geometry predictions from isolated lanthanide complex ion calculations. We thus generated a set of 15 RHF/STO-3G/ECP promethium complex structures with ligands chosen to be representative of complexes available in the CSD for all other trivalent lanthanide cations, with nitrogen or oxygen directly bonded to the lanthanide ion. For the 42 samarium(III) complexes and 15 promethium(III) complexes considered, the Sparkle/AM1 unsigned mean error, for all interatomic distances between the Ln(III) ion and the ligand atoms of the first sphere of coordination, is 0.07 and 0.06 A, respectively, a level of accuracy comparable to present day ab initio/ECP geometries, while being hundreds of times faster. PMID- 26626379 TI - Time-Dependent Quantum Wave Packet Calculations of Three-Dimensional He - O2 Inelastic Scattering. AB - We have studied a three-dimensional time-dependent quantum dynamics of He - O2 inelastic scattering by using a recently published ab initio potential energy surface. The state-to-state transition probabilities at zero total angular momentum have been calculated in the energy range of 0.12-0.59 eV, and the product rotational distributions are extracted. J-shifting approximation is used to estimate the probabilities for J > 0. The integral cross sections and thermal rate constants are then calculated. PMID- 26626371 TI - Quantitative Tissue Proteomics Analysis Reveals Versican as Potential Biomarker for Early-Stage Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most aggressive tumors, and the treatment outcome of this disease is improved when the cancer is diagnosed at an early stage. This requires biomarkers allowing an accurate and early tumor diagnosis. To identify potential markers for such applications, we analyzed a patient cohort consisting of 50 patients (50 HCC and 50 adjacent nontumorous tissue samples as controls) using two independent proteomics approaches. We performed label-free discovery analysis on 19 HCC and corresponding tissue samples. The data were analyzed considering events known to take place in early events of HCC development, such as abnormal regulation of Wnt/b-catenin and activation of receptor tyrosine kinases (RTKs). 31 proteins were selected for verification experiments. For this analysis, the second set of the patient cohort (31 HCC and corresponding tissue samples) was analyzed using selected (multiple) reaction monitoring (SRM/MRM). We present the overexpression of ATP-dependent RNA helicase (DDX39), Fibulin-5 (FBLN5), myristoylated alanine-rich C-kinase substrate (MARCKS), and Serpin H1 (SERPINH1) in HCC for the first time. We demonstrate Versican core protein (VCAN) to be significantly associated with well differentiated and low-stage HCC. We revealed for the first time the evidence of VCAN as a potential biomarker for early-HCC diagnosis. PMID- 26626369 TI - Human thioredoxin 2 deficiency impairs mitochondrial redox homeostasis and causes early-onset neurodegeneration. AB - Thioredoxin 2 (TXN2; also known as Trx2) is a small mitochondrial redox protein essential for the control of mitochondrial reactive oxygen species homeostasis, apoptosis regulation and cell viability. Exome sequencing in a 16-year-old adolescent suffering from an infantile-onset neurodegenerative disorder with severe cerebellar atrophy, epilepsy, dystonia, optic atrophy, and peripheral neuropathy, uncovered a homozygous stop mutation in TXN2. Analysis of patient derived fibroblasts demonstrated absence of TXN2 protein, increased reactive oxygen species levels, impaired oxidative stress defence and oxidative phosphorylation dysfunction. Reconstitution of TXN2 expression restored all these parameters, indicating the causal role of TXN2 mutation in disease development. Supplementation with antioxidants effectively suppressed cellular reactive oxygen species production, improved cell viability and mitigated clinical symptoms during short-term follow-up. In conclusion, our report on a patient with TXN2 deficiency suggests an important role of reactive oxygen species homeostasis for human neuronal maintenance and energy metabolism. PMID- 26626381 TI - A QTAIM and Electron Delocalization Computational Study of tert-Butylmethylene, Trimethylsilylmethylene, and Trimethylgermylmethylene. A New Method for Unambiguously Characterizing the Bonding between Pairs of Atoms in Reaction Intermediates. AB - While studies on the experimental photolytic and thermolytic extrusion of nitrogen from tert-butyldiazomethane and tert-butyldiazirine and the decomposition of other precursors have shown a mixture of C-H and C-C insertion products depending on conditions, the analogous trimethylsilyldiazomethane undergoes solely Si-C insertion. Description of the singlet tert-butylmethylene intermediates potentially involved in the C-H and C-C insertion reactions and were addressed through computational means by Armstrong et al. (J. Am. Chem. Soc. 1995, 117, 3685-3689). In addition to re-examining singlet tert-butylmethylene at a higher level of theory [CCSD/6-311+G(d,p)], we have studied the silicon and germanium analogues trimethylsilylmethylene and trimethylgermylmethylene. A computational atoms-in-molecules and atomic-basin-delocalization-indices analysis established that the singlet carbenes, while exhibiting varying degrees of delocalization, are not bridged species based on the fact that none possess a pentacoordinate methyl group. In addition, from the results, we are able to make a prediction of solely a Ge-C insertion product for the extrusion of nitrogen from trimethylgermyldiazomethane. Most importantly, we demonstrated that a combination of quantum theory of atoms in molecules (QTAIM) molecular graphs, the evaluation of delocalization indices, and a visualization of the closeness of atomic basins [Formula: see text] a QTAIM-DI-VISAB analysis [Formula: see text] should be considered as the method of choice for unambiguously characterizing the bonding between pairs of atoms not only of carbenes but of other reaction intermediates such as carbocations, carbanions, and radicals. PMID- 26626384 TI - Hydrolysis of the Anticancer Drug Cisplatin: Pitfalls in the Interpretation of Quantum Chemical Calculations. AB - All three hydrolysis reactions of the anticancer drug cisplatin, cis [Pt(NH3)2Cl2], including the acidity constants (pKa) of the aqua complexes have been compared using a combined density functional theory (DFT) and continuum dielectric model (CDM) approach. The calculations predict very similar activation barriers (25-27 kcal/mol) and reaction free energies (0-2 kcal/mol) for each of the three hydrolysis reactions. The predicted relative free energies of both Pt(II) and Ru(II) anticancer complexes agree well with available experimental values. However, our calculated data strongly disagree with several recent computational studies that predicted the second and third hydrolysis to be thermodynamically highly unfavorable and thus would have ruled out the involvement of cis-[Pt(NH3)2(OH2)2](2+) and cis-[Pt(NH3)2(OH2)(OH)](+) in the mode of action of the drug. This controversy can be resolved by the fact that former computational predictions of activation and reaction free energies in solution were based on second-shell reactant adducts and product adducts, which are the correct endpoints of the intrinsic reaction coordinate in vacuo but artifacts in aqueous solution. PMID- 26626383 TI - A Molecular Energy Decomposition Scheme for Atoms in Molecules. AB - An exact energy partition method based on a physically sound decomposition of the nondiagonal first-order and diagonal second-order density matrices put forward by Li and Parr (J. Chem. Phys. 1986, 84, 1704) is presented. The method splits the total energy into intra- and interatomic components and is applicable on quite general wave functions. To explore it numerically, the energy components of three test molecules (H2, N2, and LiH) have been computed using four different partitions of the charge density rho(r) into atomic densities. Several aspects on the chemical bond and the relative importance of different components of the binding energy are analyzed. The merits of different partitions of rho(r) are also discussed. PMID- 26626382 TI - Dependence of the Intermolecular Electrostatic Interaction Energy on the Level of Theory and the Basis Set. AB - As electrostatic forces play a prominent role in the process of folding and binding of biological macromolecules, an examination of the method dependence of the electrostatic interaction energy is of great importance. An extensive analysis of the basis set and method dependence of electrostatic interaction energies (Ees) in molecular systems using six test dimers of alpha-glycine is presented. A number of Hartree-Fock, Kohn-Sham, Moller-Plesset, configuration interaction (CI), quadratic CI, and coupled cluster calculations were performed using several double-, triple-, and quadruple-zeta-quality Gaussian- and Slater type (Kohn-Sham calculations only) basis sets. The main factor affecting Ees was found to be the inclusion of diffuse functions in the basis set expansions. Moller-Plesset (even at second order), quadratic CI, and coupled cluster calculations produce the most consistent results. Hartree-Fock and CI methods usually overestimate the Ees, while the Kohn-Sham approach tends to underestimate the magnitude of the electrostatic interaction. The combination of the transferable-pseudoatom databank and the exact potential and multipole moment method reproduces Kohn-Sham B3LYP/6-31G** results on which it is based, confirming the excellent transferability of the pseudoatom densities within the systems studied. However, because Kohn-Sham calculations with double-zeta-quality basis sets show considerable deviations from advanced correlated methods, further development of the databank using electron densities from such methods is highly desirable. PMID- 26626385 TI - Exploring the Mechanisms of Reactions in Solution from Transition Path Sampling Molecular Dynamics Simulations. AB - Recent advances in molecular dynamics simulations of rare reaction events and aggregation processes are reviewed. Therein the central focus is dedicated to employing the transition path sampling method to study reactions in solution. We describe systematic approaches for generating initial transition pathways and efficient strategies for computationally feasible exploration of further transition routes. The unprejudiced study of reaction mechanisms is illustrated for reactions in aqueous solution and other complex systems. Transition path sampling allows very detailed investigation of solvent effects. Apart from stabilization of reactant, transition, or product state ensembles, this also includes the role of the solvent as a heat bath and as a putative reaction partner. The latter issue is of particular importance for reactions in aqueous solutions, which involve proton-transfer steps that may be assisted by water molecules via the Grotthuss mechanism. PMID- 26626386 TI - Investigation of Salt Bridge Stability in a Generalized Born Solvent Model. AB - Potentials of mean force (PMFs) of salt bridge formation between oppositely charged amino acid side chains were calculated both in explicit solvent and in a Generalized Born (GB) continuum solvent model to quantify the potential overstabilization of side chain ion pairs in GB relative to explicit solvation. These show that salt bridges are too stable by as much as 3-4 kcal/mol in the GB solvent models that we tested, consistent with previously reported observations of significantly different structural ensembles in GB models and explicit solvent for proteins containing ionizable groups. We thus investigated a simple empirical correction, wherein the intrinsic GB radii of hydrogen atoms bound to charged nitrogen atoms are reduced, effectively increasing the desolvation penalty of the positively charged groups. The thermodynamics of salt bridge formation were considerably improved, as exemplified by the close match of the corrected GB PMF to the reference explicit solvent PMF, and more significantly by our ability to closely reproduce the experimental temperature melting profile of the TC5b Trp cage miniprotein, which is otherwise highly distorted by prevalent non-native salt bridges when using standard GB parameters. PMID- 26626387 TI - Estimation of Absolute Free Energies of Hydration Using Continuum Methods: Accuracy of Partial Charge Models and Optimization of Nonpolar Contributions. AB - Absolute free energies of hydration (DeltaGhyd) for more than 500 neutral and charged compounds have been computed, using Poisson-Boltzmann (PB) and Generalized Born (GB) continuum methods plus a solvent-accessible surface area (SA) term, to evaluate the accuracy of eight simple point-charge models used in molecular modeling. The goal is to develop improved procedures and protocols for protein-ligand binding calculations and virtual screening (docking). The best overall PBSA and GBSA results, in comparison with experimental DeltaGhyd values for small molecules, were obtained using MSK, RESP, or ChelpG charges obtained from ab initio calculations using 6-31G* wave functions. Correlations using semiempirical (AM1BCC, AM1CM2, and PM3CM2) or empirical (Gasteiger-Marsili and MMFF94) methods yielded mixed results, particularly for charged compounds. For neutral compounds, the AM1BCC method yielded the best agreement with experimental results. In all cases, the PBSA and GBSA results are highly correlated (overall r(2) = 0.94), which highlights the fact that various partial charge models influence the final results much more than which continuum method is used to compute hydration free energies. Overall improved agreement with experimental results was demonstrated using atom-based constants in place of a single surface area term. Sets of optimized SA constants, suitable for use with a given charge model, were derived by fitting to the difference in experimental free energies and polar continuum results. The use of optimized atom-based SA constants for the computation of DeltaGhyd can fine-tune already reasonable agreement with experimental results, ameliorate gross deficiencies in any particular charge model, account for nonoptimal radii, or correct for systematic errors. PMID- 26626388 TI - Force Field Effects on a beta-Sheet Protein Domain Structure in Thermal Unfolding Simulations. AB - The secondary structure propensities observed in protein simulations depend heavily on the force field parameters used. The existing empirical force fields often have difficulty in balancing the relative stabilities of helical and extended conformations. The resultant secondary structure bias may not be apparent in short simulations at room temperature starting from the native folded states. However, it can manifest itself dramatically at high temperatures and lead to large deviations from experimentally observed secondary structure propensities. Motivated by thermal unfolding simulations of several WW domains, which have a three-stranded beta-sheet structure, we chose the FBP28 WW domain as a well-characterized system to investigate several AMBER force fields as well as parametrization of the NPSA (Neutralized, Polarized ionizable side chains with a solvent-accessible Surface Area-dependent term) implicit solvent model. The ff94 force field and two variants with altered parameters for the backbone torsion term were found to convert the native beta-sheet structure directly to a single helix at high temperatures, whereas the ff96 force field produced significant non native beta-sheet content at high temperatures. The ff03 force field was able to reproduce the beta-sheet-coil transition and experimentally observed unfolding pathways with both an explicit water solvent and the NPSA implicit solvent model at relatively low temperatures. However, the protein domain became predominantly helical after unfolding. Modification of the solvation parameter in the NPSA implicit solvent model was not sufficient to remedy this problem. The results imply that the intrinsic secondary structure bias in a force field cannot easily be solved by modifying a single parameter such as backbone torsion potential or a solvation parameter of a solvent model. Nevertheless, the results show that the AMBER ff03 force field together with an explicit solvent model or the NPSA implicit solvent model is a useful tool for studying the unfolding of both alpha- and beta-sheet structure protein domains, and an integrative consideration of all force field parameters is likely to be necessary for a complete solution. PMID- 26626389 TI - Predicting Lattice Energy of Organic Crystals by Density Functional Theory with Empirically Corrected Dispersion Energy. AB - Calculation of the lattice energy of organic crystals is needed for predicting important structural and physicochemical properties such as polymorphism and growth morphology. Quantum mechanical methods that can be used for calculating typical organic crystals are unable to fully estimate van der Waals energies in a crystal. A method by augmenting the density functional theory with an analytical, nonelectronic approach for accounting for the dispersion energy was tested for selected organic crystals. The results illustrate the feasibility of this method for the prediction of the lattice energy of organic crystals. It is also shown that the dispersion energy is a dominant component of the lattice energy, particularly for those organic crystals that have no hydrogen bonds. PMID- 26626390 TI - Molecular Dynamics Simulation of Iminosugar Inhibitor-Glycosidase Complex: Insight into the Binding Mechanism of 1-Deoxynojirimycin and Isofagomine toward beta-Glucosidase. AB - The binding mechanism of iminosugar inhibitor 1-deoxynojirimycin and isofagomine toward beta-glucosidase was studied with nanosecond time scale molecular dynamics. Four different systems were analyzed according to the different protonated states of inhibitor and enzyme (acid/base carboxyl group, Glu166). The simulations gained quite a reasonable result according to the thermodynamic experimental fact. Further conclusions were made including the following: (1) 1 deoxynojirimycin binds with the beta-glucosidase as conjugate acid forms; (2) the slow onset inhibition of isofagomine aims to slow deprotonation of the acid/base carboxyl group which is caused by a nearly zero hydrogen bond interaction between the hydroxyls of the acid/base carboxyl group; and (3) the nucleophile carboxyl group plays an important role when the inhibitor binds with glucosidase. PMID- 26626391 TI - All-Atom Calculation of the Normal Modes of Bacteriorhodopsin Using a Sliding Block Iterative Diagonalization Method. AB - Conventional normal-mode analysis of molecular vibrations requires computation and storage of the Hessian matrix. For a typical biological system such storage can reach several gigabytes posing difficulties for straightforward implementation. In this work we discuss an iterative block method to carry out full diagonalization of the Hessian while only storing a few vectors in memory. The iterative approach is based on the conjugate gradient formulation of the Davidson algorithm for simultaneous optimization of L roots, where in our case 10 < L < 300. The procedure is modified further by automatically adding a new vector into the search space for each locked (converged) root and keeping the new vector orthogonal to the eigenvectors previously determined. The higher excited states are then converged with the orthonormality constraint to the locked roots by applying a projector which is carried out using a read-rewind step done once per iteration. This allows for convergence of as many roots as desired without increasing the computer memory. The required Hessian-vector products are calculated on the fly as follows, Kp = dgp/dt, where K is the mass weighted Hessian, and gp is the gradient along p. The method has been implemented into the TINKER suite of molecular design codes. Preliminary results are presented for the normal modes of bacteriorhodopsin (bR) up to 300 cm(-)(1) and for the high frequency range between 2840 and 3680 cm(-)(1). There is evidence of a highly localized, noncollective mode at ~1.4 cm(-)(1), caused by long-range interactions acting between the cytoplasmic and extracellular domains of bR. PMID- 26626392 TI - A Self-Consistent Space-Domain Decomposition Method for QM/MM Computations of Protein Electrostatic Potentials. AB - This paper introduces a self-consistent computational protocol for modeling protein electrostatic potentials according to static point-charge model distributions. The protocol involves a simple space-domain decomposition scheme where individual molecular domains are modeled as Quantum-Mechanical (QM) layers embedded in the otherwise classical Molecular-Mechanics (MM) protein environment. ElectroStatic-Potential (ESP) atomic charges of the constituent molecular domains are computed, to account for mutual polarization effects, and iterated until obtaining a self-consistent point-charge model of the protein electrostatic potential. The novel protocol achieves quantitative agreement with full QM calculations in the description of electrostatic potentials of small polypeptides where polarization effects are significant, showing a remarkable improvement relative to the corresponding electrostatic potentials obtained with popular MM force fields. The capabilities of the method are demonstrated in several applications, including calculations of the electrostatic potential in the potassium channel protein and the description of protein-protein electrostatic interactions. PMID- 26626393 TI - Base Flipping in a GCGC Containing DNA Dodecamer: A Comparative Study of the Performance of the Nucleic Acid Force Fields, CHARMM, AMBER, and BMS. AB - The improving quality of empirical force field parameters along with other methodological improvements and ever increasing computational resources have lead to more reliable computations on biological macromolecules. In the case of oligonucleotides, three force fields, namely CHARMM27, AMBER4.1, and BMS, have been developed and are widely used by the simulation community. Testing of these force fields to date has primarily focused on their treatment of the canonical forms of DNA and RNA. However, many biological functions of oligonucleotides involve significant variation of their structures from the canonical forms. In the present work, the three force fields are evaluated via computation of potentials of mean force (PMF) of the base flipping process in a DNA dodecamer, 5'-GTCAGCGCATGG-3'. Results are compared with available experimental data on the equilibrium between the opened and closed (i.e. Watson-Crick base paired) state of the underlined C and its WC partner G. Quantitative analysis shows CHARMM to be in the best agreement with experiment, closely followed by AMBER with BMS in the poorest agreement. Various components contributing to the change in the free energy such as base pair interactions, stacking interactions, solvation effects, and intrinsic potential energy changes were evaluated and compared. The results indicate that while all three force fields reasonably represent the canonical structures, the balance of forces contributing to their structural and dynamic properties differ significantly. PMID- 26626394 TI - Comparison of Protocols for Calculation of Peptide Structures from Experimental NMR Data. AB - In a comparison of structure calculation protocols we clearly demonstrate the need for generating independent starting structures, which is for peptides most efficiently achieved by distance geometry (DG) methods. Our test set consisted of 20 peptides with 7-9 amino acid residues additionally constrained by backbone cyclization and/or the presence of a disulfide bridge. Small peptides usually adopt defined conformational properties only upon introduction of additional constraints, such as cyclization. Therefore, we believe the results of our comparison to be applicable to a large and important class of molecules. The problems associated with the use of restrained molecular dynamics (MD) for conformational searching in the context of structure calculation consist in energy barriers that derive mainly but not exclusively from the experimental NOE constraints. A valid alternative to the DG approach, although for peptides computationally less efficient, is MD simulated annealing starting from random structures as commonly performed in the protein structure calculation from NMR data. As a consequence of our study it must be expected that a considerable fraction of published peptide structures are artificially well-defined or even wrong. Given the relevance of peptide studies for both drug development and protein folding we regard it highly important that structure calculations of peptides are performed with more consideration. PMID- 26626395 TI - A Fast QM/MM (Quantum Mechanical/Molecular Mechanical) Approach to Calculate Nuclear Magnetic Resonance Chemical Shifts for Macromolecules. AB - A fast approach to calculate nuclear magnetic resonance (NMR) chemical shifts within the quantum mechanical/molecular mechanical (QM/MM) framework has been developed. The QM treatment is based on our recently implemented MNDO/NMR method (Wang et al. J. Chem. Phys. 2004, 120, 11392). The effect of the QM/MM partitioning on chemical shifts has been investigated by test calculations on the water dimer and on the protein crambin. It has been shown that the quantum mechanical treatment of the hydrogen bond and nearby groups with significant magnetic susceptibilities is necessary in order to reproduce the full QM results. The method is also applied to a protein-ligand complex FKBP-GPI, and excellent agreement for proton chemical shifts of the ligand is obtained by including the side-chain atoms of the binding site residues into the QM region. The NMR chemical shift calculations using QM/MM-minimized structures still yield satisfactory results. Our results demonstrate that this QM/MM NMR method is able to treat critical regions of very large macromolecules without compromising accuracy if a relatively large QM region is used. PMID- 26626396 TI - Improving the QM/MM Description of Chemical Processes: A Dual Level Strategy To Explore the Potential Energy Surface in Very Large Systems. [J. Chem. Theory Comput. 1, 1008-1016 (2005)]. PMID- 26626397 TI - The effect of the metal fragment on the aromaticity and synchronicity of the gold(i)-catalysed divinylcyclopropane-cycloheptadiene rearrangement. AB - The gold(i)-catalysed divinylcyclopropane-cycloheptadiene rearrangement has been studied computationally within the Density Functional Theory framework. Regardless of the ligand directly attached to the transition metal (L = phosphine, phosphite and N-heterocyclic carbene), the process is found to occur concertedly via endo-boatlike transition structures. The influence of the transition metal fragment on the transformation is analysed and compared to the corresponding uncatalysed process in terms of the computed activation barriers, synchronicity and aromaticity of the associated transition states. PMID- 26626398 TI - Let's talk about sex (again): advancing the conversation around long-acting reversible contraception for teenagers. AB - Long-acting reversible contraception (LARC) has incredible potential for decreasing teenage pregnancy rates in the USA, but use among adolescents remains low. LARC methods, including intrauterine devices and implants, are recommended as first-line choices for teenagers by multiple medical professional associations. Barriers at the system, provider and patient level persist, but new demonstration projects, in addition to provisions of the Affordable Care Act, show great promise in facilitating LARC use. A renewed national discourse should acknowledge the reality that many US teenagers have sex, that LARC is safe and effective and that LARC offers an opportunity to prevent teenage pregnancy. By encouraging widespread access and use, a large, positive impact across multiple health and economic sectors can be achieved. PMID- 26626399 TI - Cheers: cracking open the bottleneck of extraction in bioanalysis. PMID- 26626400 TI - Electrophilic Cyanate As a Recognition Motif for Reactive Sulfur Species: Selective Fluorescence Detection of H2S. AB - An ESIPT-based fluorescent dye, 3-hydroxyflavone, is chemically masked with an electrophilic cyanate motif in order to construct a fluorescent probe for cellular sulfur species. This novel probe structure, displays an extremely fast, highly sensitive and selective "turn-on" type fluorescent response toward H2S. We have also documented its utility for imaging of H2S in the living cells. PMID- 26626401 TI - Synthesis of functionalized 5-substituted thiazolidine-2-thiones via adscititious xanthate-promoted radical cyclization of allyl(alkyl/aryl)dithiocarbamates. AB - Functionalized 5-substituted thiazolidine-2-thiones were synthesized efficiently from alkyl allyl(alkyl/aryl)-dithiocarbamates via radical cyclization with the corresponding S-alkyl O-ethyl xanthates as the adscititious radical precursors. The application of the adscititious radical precursors improves not only the yields, but also the efficiency in the radical cyclization reaction significantly. The current adscititious radical precursor method provides a new strategy for the achievement and improvement of some radical reactions which are hardly or difficultly realized by the traditional direct methods. PMID- 26626402 TI - Encapsulation of low lipophilic and slightly water-soluble dihydroartemisinin in PLGA nanoparticles with phospholipid to enhance encapsulation efficiency and in vitro bioactivity. AB - CONTEXT: PLGA nanoparticles have been widely utilised to encapsulate lipophilic drugs for sustained release. OBJECTIVE: This study was to enhance encapsulation efficiency and drug loading for the poorly lipophilic drug dihydroartemisinin (DHA) in PLGA nanoparticles, where amphiphilic phospholipid was employed as the intermediate. MATERIALS AND METHODS: DHA-phospholipid complex formulation was optimised using the response surface method. DHA-phospholipid complex nanoparticles (DHA-PLC-NPs) were prepared using the solvent evaporation method. RESULTS: The particle size, zeta potential, entrapment efficiency and drug loading of the nanoparticles were 265.3 +/- 7.9 nm, -21.4 +/- 6.3 mV, 74.2 +/- 6.5% and 2.80 +/- 0.35%, respectively. Compared with the rapidly released free form, DHA underwent sustained release from the nanoparticles. DHA-PLC-NPs presented stronger cell proliferative inhibition than DHA treatment alone and apoptosis was obviously induced after DHA-PLC-NPs treatment. CONCLUSION: Phospholipid complexes are useful intermediate to improve the lipophilicity of drugs, the interaction with the hydrophobic core of PLGA and the encapsulation efficiency of poorly lipophilic drugs in polymeric nanoparticles. PMID- 26626403 TI - Influence of silicone oil tamponade on self-sealing sclerotomy using 25-gauge transconjunctival sutureless vitrectomy: a retrospective comparative study. AB - BACKGROUND: Characteristic complications have been reported for transconjunctival sutureless vitrectomy, such as postoperative sclerotomy leakage and postoperative hypotony. Particular attention to sclerotomy closure is required in cases of silicone oil tamponade, because postoperative supplementation of silicone oil implies reoperation, whereas postoperative supplement of gas is comparatively easy. This study investigated sclerotomy closure in cases of silicone oil tamponade using 25-gauge transconjunctival sutureless vitrectomy. METHODS: We enrolled 19 consecutive eyes with silicone oil injection (Group A, self-sealing sclerotomies, n = 10) (Group B, sutured sclerotomies, n = 9) and 10 eyes with silicone oil removal (Group C, self-sealing sclerotomies) using 25-gauge TSV. Postoperative intraocular pressure was compared between Groups A and B, and between Groups A and C using repeated-measures analysis of variance (ANOVA), one way factorial ANOVA, and the Tukey-Kramer test. RESULTS: No significant differences in age or axial length were seen among groups, but surgical time differed significantly between Group C and the other groups. Mean duration of silicone oil tamponade was 3.2 +/- 1.4 months in Group C, and no sclerotomies in Group A or C required suture placement. Postoperative silicone oil leakage to the subconjunctival space was not encountered in Group A. No cases showed postoperative hypotony (defined as intraocular pressure <5 mmHg). Significant differences in intraocular pressure within the same postoperative period were not identified between Groups A and B. Conversely, significant differences in intraocular pressure within the same postoperative period were identified at postoperative days 1 and 2, although not at postoperative week 1 or postoperative month 1 between Groups A and C. CONCLUSIONS: The procedure for sclerotomy closure seems to have little influence on postoperative intraocular pressure in eyes with silicone oil tamponade using 25-gauge transconjunctival sutureless vitrectomy, because silicone oil tamponade may avoid postoperative hypotony by decreasing sclerotomy leakage in the early postoperative period. PMID- 26626405 TI - Falling for her psychiatrist: an unusual cause of falls in the elderly. AB - We describe the case of an elderly woman with auditory hallucinations of her psychiatrist commanding her to fall. The case highlights an unusual cause of falls in the elderly, not previously described in the falls literature. PMID- 26626404 TI - Short-term pre- and post-operative stress prolongs incision-induced pain hypersensitivity without changing basal pain perception. AB - BACKGROUND: Chronic stress has been reported to increase basal pain sensitivity and/or exacerbate existing persistent pain. However, most surgical patients have normal physiological and psychological health status such as normal pain perception before surgery although they do experience short-term stress during pre- and post-operative periods. Whether or not this short-term stress affects persistent postsurgical pain is unclear. RESULTS: In this study, we showed that pre- or post-surgical exposure to immobilization 6 h daily for three consecutive days did not change basal responses to mechanical, thermal, or cold stimuli or peak levels of incision-induced hypersensitivity to these stimuli; however, immobilization did prolong the duration of incision-induced hypersensitivity in both male and female rats. These phenomena were also observed in post-surgical exposure to forced swimming 25 min daily for 3 consecutive days. Short-term stress induced by immobilization was demonstrated by an elevation in the level of serum corticosterone, an increase in swim immobility, and a decrease in sucrose consumption. Blocking this short-term stress via intrathecal administration of a selective glucocorticoid receptor antagonist, RU38486, or bilateral adrenalectomy significantly attenuated the prolongation of incision-induced hypersensitivity to mechanical, thermal, and cold stimuli. CONCLUSION: Our results indicate that short-term stress during the pre- or post-operative period delays postoperative pain recovery although it does not affect basal pain perception. Prevention of short-term stress may facilitate patients' recovery from postoperative pain. PMID- 26626406 TI - Metastatic Group 3 Medulloblastoma in a Patient With Tuberous Sclerosis Complex: Case Description and Molecular Characterization of the Tumor. AB - Medulloblastoma is the most common pediatric brain tumor. We describe a child with tuberous sclerosis complex that developed a Group 3, myc overexpressed, metastatic medulloblastoma (MB). Considering the high risk of treatment-induced malignancies, a tailored therapy, omitting radiation, was given. Based on the evidence of mammalian target of rapamycin mTORC, mTOR Complex; RAS, Rat sarcoma; RAF, rapidly accelerated fibrosarcoma (mTOR) pathway activation in the tumor, targeted therapy was applied resulting in complete remission of disease. Although the PI3K/AKT/mTOR signaling pathway plays a role in MB, we did not find TSC1/TSC2 (TSC, tuberous sclerosis complex) mutation in our patient. We speculate that a different pathway resulting in mTOR activation is the basis of both TSC and MB in this child; H&E, haematoxilin and eosin; Gd, gadolinium. PMID- 26626408 TI - Person-Centered Care for Older Adults with Chronic Conditions and Functional Impairment: A Systematic Literature Review. AB - Person-centered care (PCC) shifts focus away from the traditional biomedical model in favor of embracing personal choice and autonomy for people receiving health services. It has become an important avenue for improving primary care, and older adults remain a priority target for PCC because they are more likely to have complex care needs than younger individuals. Nevertheless, despite a growing body of evidence regarding its use, PCC still lacks an agreed-upon definition. A literature review was conducted to explore extant scholarship on PCC for older adults, assess corresponding definitions of PCC, and identify important elements of quality PCC. Nearly 3,000 articles published between 1990 and 2014 were identified. Excluding search results outside the parameters of this study, the final review comprised 132 nonduplicate sources focused on patient-centered care or PCC in older adults. Fifteen descriptions of PCC were identified, addressing 17 central principles or values. The six most-prominent domains of PCC were holistic or whole-person care, respect and value, choice, dignity, self determination, and purposeful living. The body of evidence reviewed suggests that PCC is an important area of growing interest. Although multiple definitions and elements of PCC abound-with many commonalities and some overlap-the field would benefit from a consensus definition and list of essential elements to clarify how to operationalize a PCC approach to health care and services for older adults. This work guided the development of a separate American Geriatrics Society expert panel statement presenting a standardized definition and a list of PCC elements for older adults with chronic conditions or functional impairment. PMID- 26626407 TI - Identification of regions within the Legionella pneumophila VipA effector protein involved in actin binding and polymerization and in interference with eukaryotic organelle trafficking. AB - The Legionella pneumophila effector protein VipA is an actin nucleator that co localizes with actin filaments and early endosomes in infected macrophages and which interferes with organelle trafficking when expressed in yeast. To identify the regions of VipA involved in its subcellular localization and functions, we ectopically expressed specific VipA mutant proteins in eukaryotic cells. This indicated that the characteristic punctate distribution of VipA depends on its NH2 -terminal (amino acid residues 1-133) and central coiled-coil (amino acid residues 133-206) regions, and suggested a role for the COOH-terminal (amino acid residues 206-339) region in association with actin filaments and for the NH2 terminal in co-localization with early endosomes. Co-immunoprecipitation and in vitro assays showed that the COOH-terminal region of VipA is necessary and sufficient to mediate actin binding, and is essential but insufficient to induce microfilament formation. Assays in yeast revealed that the NH2 and the COOH terminal regions, and possibly an NPY motif within the NH2 region of VipA, are necessary for interference with organelle trafficking. Overall, this suggests that subversion of eukaryotic vesicular trafficking by VipA involves both its ability to associate with early endosomes via its NH2 -terminal region and its capacity to bind and polymerize actin through its COOH-terminal region. PMID- 26626409 TI - DISTRIBUTION AND SHORT- AND LONG-TERM EFFECTS OF INJECTED GELIFIED ETHANOL INTO THE LUMBOSACRAL INTERVERTEBRAL DISC IN HEALTHY DOGS. AB - Radiopaque gelified ethanol preparation has been described as a useful agent for treatment of humans with intervertebral disc protrusion. The material is injected into the nucleus pulposus under image guidance with intention to cause the protruded disc material to recede. Because treatment options for dogs with chronic protrusions are limited, new and minimally invasive treatments are desirable. The aim of this experimental, descriptive, prospective study was to assess the feasibility and safety of percutaneous injection of gelified ethanol into the lumbosacral intervertebral disc of dogs. Lumbosacral intervertebral discs of normal dogs (n = 9) were imaged with magnetic resonance imaging and then injected with gelified ethanol using image guidance. The accuracy of gelified ethanol placement in the nucleus pulposus and presence of leakage of the injected material were documented. Postinjection computed tomography (CT) findings (n = 9), short-term (n = 9) and long-term (n = 4) follow-up magnetic resonance imaging and CT findings were compared to document the distribution of the injected preparation and identify effects on adjacent tissues. Percutaneous injection of the intervertebral disc was successful in delivering radiopaque gelified ethanol to the nucleus pulposus in all dogs. Leakage of the injected material into the vertebral canal was present in three dogs immediately following injection and in another additional dog at 1 year following injection. All dogs tolerated the injection well and had no clinical adverse reactions within the study period. Findings indicated that injection of the nucleus pulposus of healthy dogs was well tolerated, even in the presence of mild leakage of material from the intervertebral disc. PMID- 26626410 TI - Zinc bioavailability in rats fed a plant-based diet: a study of fermentation and zinc supplementation. AB - BACKGROUND: Zinc deficiency is a significant problem, in developing countries and in vegetarians, which can be caused by plant-based diets. Thus, dietary strategies, such as fermentation, to improve zinc bioavailability of diets should be investigated. OBJECTIVE: To improve zinc bioavailability in a plant-based diet by the inclusion of fermented food. DESIGN: Cassava tubers were fermented and made to replace the unfermented cassava in a basal plant-based diet, and compared with plant-based diets with and without zinc supplement. The zinc bioavailability of the diets was evaluated in Wistar rats that were fed these diets for 28 days. The evaluation was for zinc apparent absorption (ZnAA), serum zinc levels, and zinc deposits in liver and femur; in addition, the feed efficiency ratio (FER) of the diets and femur weight (FW) of the rats were evaluated. RESULTS: During the cassava fermentation, lactic acid increased and pH decreased (from 6.8 to 3.9), which is favorable for native phytase activity, resulting in a 90.2% reduction of phytate content in cassava. The diet containing fermented cassava showed significantly higher levels of ZnAA, FER, and FW (p<0.001). Moreover, the zinc levels in serum and femur were significantly higher (p<0.001) compared with the results of the diet with unfermented cassava. The results clearly show a higher zinc bioavailability in the diet containing fermented cassava and are comparable with the results obtained with the plant-based diet with zinc supplement. CONCLUSIONS: In conclusion, the fermentation of cassava reduces the phytate content. The diet containing the fermented cassava represents a better nutritional alternative than the diet with unfermented cassava and is comparable with the zinc-supplemented diets. PMID- 26626412 TI - Erratum to: 'Reduced ratio of eicosapentaenoic acid and docosahexaenoic acid to arachidonic acid is associated with early onset of acute coronary syndrome'. PMID- 26626413 TI - Giant Volume Change and Topological Gaps in Temperature- and Pressure-Induced Phase Transitions: Experimental and Computational Study of ThMo2 O8. AB - By applying high temperature (1270 K) and high pressure (3.5 GPa), significant changes occur in the structural volume and crystal topology of ThMo2 O8 , allowing the formation of an unexpected new ThMo2 O8 polymorph (high temperature/high-pressure (HT/HP) orthorhombic ThMo2 O8 ). Compared with the other three ThMo2 O8 polymorphs prepared at the ambient pressure (monoclinic, orthorhombic, and hexagonal phases), the molar volume for the quenched HT/HP orthorhombic ThMo2 O8 is decreased by almost 20 %. As a result of such a dramatic structural transformation, a permanent high-pressure quenchable state is able to be sustained when the pressure is released. The crystal structures of the three ambient ThMo2 O8 phases are based on three-dimensional (3D) frameworks constructed from corner-sharing ThOx (x=6, 8, or 9) polyhedra and MoO4 tetrahedra. The HT/HP-orthorhombic ThMo2 O8 , however, crystallizes in a novel structural topology, exhibiting very dense arrangements of ThO11 and MoO4+1 polyhedra connecting along the crystallographic c axis. The phase transitions among all four of these ThMo2 O8 polymorphs are unveiled and fully characterized with regard to the structural transformation, thermal stability, and vibrational properties. The complementary first principles calculations of Gibbs free energies reveal the underlying energetics of the phase transition, which support the experimental findings. PMID- 26626414 TI - Stimulus-preceding negativity represents a conservative response tendency. AB - Humans tend to be conservative and typically will retain their initial decision even if an option to change is provided. We investigated whether the stimulus preceding negativity (SPN), an event-related potential associated with the affective-motivational anticipation of feedback in gambling tasks, represents the strong response tendency to retain an initial decision. We compared SPNs in three different card-gambling tasks wherein the participants were given the opportunity to change their initial decision after they chose one of three cards. In two of these tasks, the winning probability was equiprobable (1/3 and 1/2, respectively) whether or not the participants changed their initial decision. However, in the Monty Hall dilemma task, changing the initial decision stochastically doubled the probability of winning (2/3) compared with retaining (1/3). In this counterintuitive probabilistic dilemma task, after the participant chose an option among three cards, a nonreward (losing) option is revealed. Then, the participants are offered a chance to change their mind and asked to make their final decision: to retain their initial choice or change to the alternate option. In all tasks, maintenance of previous behaviors was observed, although the rate of retaining earlier choices tended to be lower in the Monty Hall dilemma task than in the other two tasks. The SPNs were larger on retain trials than on change trials irrespective of task. These results suggest that underlying brain activities associated with the strong tendency to retain the initial decision can be observed by the SPN and thus it reflects expectancy of outcomes in terms of self-chosen behaviors. PMID- 26626415 TI - Effects of theta burst stimulation on referred phantom sensations in patients with spinal cord injury. AB - To further explore the mechanisms underlying cortical reorganization in patients with phantom sensations after deafferentation, a repetitive transcranial magnetic stimulation study was carried out in two patients with referred phantom sensations (RPS) after incomplete spinal cord injury at the thoracic level. We delivered continuous (inhibitory), intermittent (excitatory), and placebo theta burst stimulation to the contralateral primary motor cortex (M1), primary somatosensory cortex (S1), and secondary somatosensory cortex (S2). Perception of RPS was significantly and transiently disrupted by inhibitory theta burst stimulation applied over S1 and, to a lesser extent, S2. This study supports the hypothesis that RPS depend on remapping in the somatosensory cortex and provides further electrophysiological evidence in vivo that cortical reorganizational processes are critically modulated by GABAergic mechanisms. Enhancement of GABAergic activity may block cortical reorganization, leading to RPS in spinal cord injury patients. PMID- 26626411 TI - Metabolic changes associated with tumor metastasis, part 1: tumor pH, glycolysis and the pentose phosphate pathway. AB - Metabolic adaptations are intimately associated with changes in cell behavior. Cancers are characterized by a high metabolic plasticity resulting from mutations and the selection of metabolic phenotypes conferring growth and invasive advantages. While metabolic plasticity allows cancer cells to cope with various microenvironmental situations that can be encountered in a primary tumor, there is increasing evidence that metabolism is also a major driver of cancer metastasis. Rather than a general switch promoting metastasis as a whole, a succession of metabolic adaptations is more likely needed to promote different steps of the metastatic process. This review addresses the contribution of pH, glycolysis and the pentose phosphate pathway, and a companion paper summarizes current knowledge regarding the contribution of mitochondria, lipids and amino acid metabolism. Extracellular acidification, intracellular alkalinization, the glycolytic enzyme phosphoglucose isomerase acting as an autocrine cytokine, lactate and the pentose phosphate pathway are emerging as important factors controlling cancer metastasis. PMID- 26626416 TI - Interactions of tumour-derived micro(nano)vesicles with human gastric cancer cells. AB - BACKGROUND: Tumour cells release membrane micro(nano)fragments called tumour derived microvesicles (TMV) that are believed to play an important role in cancer progression. TMV suppress/modify antitumour response of the host, but there is also some evidence for their direct interaction with cancer cells. In cancer patients TMV are present in body fluid and tumour microenvironment. The present study aimed at characterization of whole types/subpopulations, but not only exosomes, of TMV from newly established gastric cancer cell line (called GC1415) and to define their interactions with autologous cells. METHODS: TMV were isolated from cell cultures supernatants by centrifugation at 50,000*g and their phenotype was determined by flow cytometry. The size of TMV was analysed by dynamic light scattering and nanoparticle tracking analysis, while morphology by transmission electron microscopy and atomic force microscopy. Interactions of TMV with cancer cells were visualized using fluorescence-activated cell sorter, confocal and atomic force microscopy, biological effects by xenografts in NOD SCID mice. RESULTS: Isolated TMV showed expression of CD44H, CD44v6 (hyaluronian receptors), CCR6 (chemokine receptor) and HER-2/neu molecules, exhibited different shapes and sizes (range 60-900 nm, highest frequency of particles with size range of 80-120 nm). TMV attached to autologous cancer cells within 2 h and then were internalized by them at 24 h. CD44H, CD44v6 and CCR6 molecules may play a role in attachment of TMV to cancer cells, while HER-2 associated with CD24 be involved in promoting cancer cells growth. Pre-exposure of cancer cells to TMV resulted in enhancement of tumour growth and cancer cell-induced angiogenesis in NOD SCID mice model. CONCLUSIONS: TMV interact directly with cancer cells serving as macro-messengers and molecular cargo transfer between gastric cancer cells resulting in enhancement of tumour growth. TMV should be considered in future as target of anticancer therapy. PMID- 26626417 TI - Ageing of people with Down's syndrome: a systematic literature review from 2000 to 2014. AB - Life expectancy of people with Down's syndrome (DS) has increased considerably, now exceeding 60 years. People with DS start to get old around the age of 45. By referring to the WHO's International Classification of Functioning, Disability and Health (ICF) biopsychosocial perspective, this study aimed to present an up to-date review of the past 14 years of literature concerning the ageing of people with DS. PUBMED, PsycInfo and the Social Sciences Citation Index were searched for studies published between 2000 and 2014. Studies were selected if they were written in English, focused on people more than 45 years of age with DS, and if terms related to DS and ageing appeared in either the title or the abstract. A total of 30 studies were retrieved and their meaningful concepts were linked to the ICF. In total, 38 ICF categories were identified that were mainly related to intellectual functions (b117) (19%), general metabolic functions (b540) (7.4%), mobility of joint functions (b710), muscle power functions (b730) (4.2%), gait pattern functions (b770) (4.2%) and structure of the brain (s110) (4.3%). Only two studies considered environmental factors, and only one considered the joint analysis of health condition and environmental factors. Data about the ageing of people with DS are predominantly based on medical evaluations and descriptions of their physical impairments. Few attempts have been made towards a comprehensive assessment of elderly people with DS with a joint analysis of their health condition and its interaction with environmental factors. PMID- 26626418 TI - (1) H and (13) C NMR data on natural and synthetic capsaicinoids. AB - Capsaicinoids are the compounds responsible for the pungency of chili peppers. These substances have attracted the attention of many research groups in recent decades because of their antinociceptive, analgesic, anti-inflammatory, and anti obesity properties, among others. There are nearly 160 capsaicinoids reported in the literature. Approximately 25 of them are natural products, while the rest are synthetic or semi-synthetic products. A large amount of NMR data for the capsaicinoids is dispersed throughout literature. Therefore, there is a need to organize all this NMR data in a systematic and orderly way. This review summarizes the (1) H and (13) C NMR data on 159 natural and synthetic capsaicinoids, with a brief discussion of some typical and relevant aspects of these NMR data. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26626419 TI - Beyond NIMBYs and NOOMBYs: what can wind farm controversies teach us about public involvement in hospital closures? AB - BACKGROUND: Many policymakers, researchers and commentators argue that hospital closures are necessary as health systems adapt to new technological and financial contexts, and as population health needs in developed countries shift. However closures are often unpopular with local communities. Previous research has characterised public opposition as an obstacle to change. Public opposition to the siting of wind farms, often described as NIMBYism (Not In My Back Yard), is a useful comparator issue to the perceived NOOMBYism (Not Out Of My Back Yard) of hospital closure protestors. DISCUSSION: The analysis of public attitudes to wind farms has moved from a fairly crude characterisation of the 'attitude-behaviour gap' between publics who support the idea of wind energy, but oppose local wind farms, to empirical, often qualitative, studies of public perspectives. These have emphasised the complexity of public attitudes, and revealed some of the 'rational' concerns which lie beneath protests. Research has also explored processes of community engagement within the wind farm decision-making process, and the crucial role of trust between communities, authorities, and developers. Drawing on what has been learnt from studies of opposition to wind farms, we suggest a range of questions and approaches to explore public perspectives on hospital closure more thoroughly. Understanding the range of public responses to service change is an important first step in resolving the practical dilemma of effecting health system transformation in a democratic fashion. PMID- 26626420 TI - Notch and its ligands in alloimmunity and rejection. AB - PURPOSE OF REVIEW: The Notch signaling pathway is known to play a pivotal role in T- and B-cell development and fate, presenting it as an attractive therapeutic target in alloimmunity. This review provides an overview of the mechanisms of Notch signaling, focusing on new insights into its diverse functions in T-cell activation, differentiation and memory subset formation, and the consequences thereof in transplantation. RECENT FINDINGS: Recent evidence has shown that while not critical for early antigen-specific CD4 T-cell activation, Notch signaling regulates the survival of memory CD4 T cells via control of glycolytic metabolism; in contrast, Notch signaling is critical for the generation of short lived CD8 effector T cells, but not memory CD8 cells. Transient, selective inhibition of various Notch receptors and ligands in models of solid organ transplantation has been shown to successfully modulate the alloimmune response, affecting the balance between effector and regulatory cells, with particular influence on the natural regulatory T-cell population. SUMMARY: These studies reveal diverse roles for individual Notch receptors and ligands in peripheral immunity and indicate that selective targeting of the Notch pathway is a promising, novel approach for immune modulation in transplantation; the advent of therapeutic human antibodies to neutralize both the Notch ligands and the individual Notch receptors suggests that this approach could be efficiently developed. PMID- 26626422 TI - Neonatal tolerance: applicability to solid organ transplantation. AB - PURPOSE OF REVIEW: The phenomenon of tolerance induced during immunologic immaturity has been explored for more than 60 years. Although direct application of neonatal tolerance to organ transplantation in human newborns is limited, exploiting discrete components of neonatal immaturity is proving fruitful. RECENT FINDINGS: Two reviews comprehensively considered features and impact of neonatal tolerance as described in the 1950s. Recent imaging studies in mice demonstrated complex functional interactions especially of donor regulatory T cells with emerging neonatal immune components. The propensity of the developing immune system toward tolerance rather than immunity to non-self carbohydrates in ABO incompatible transplantation was shown using glyconanotechnology tools to have exquisite specificity, and is associated with age-related changes in the B-cell compartment and complement components. Discarded infant thymus was found to be a source of abundant therapeutic regulatory T cells. Erythroid precursors transiently present in newborn mice and humans were shown to have immunosuppressive properties that may contribute to a tolerogenic environment. SUMMARY: Neonatal tolerance has profound impact on immunology well beyond transplantation. Continued exploration of mechanisms underlying the malleability of the developing immune system and exploitation of particular components are leading to tools for immune manipulation beyond infancy. PMID- 26626421 TI - Novel technologies to engineer graft for tolerance induction. AB - PURPOSE OF REVIEW: Conquering allograft rejection remains an elusive goal in spite of recent breakthroughs in the field of immunosuppression. Much of the problem lies in the toxicity and side-effects of long-term use of systemic immunosuppressant drugs, which are sometimes ineffective in controlling rejection, but also hinder establishment of transplant tolerance. In this review, we discuss novel technologies that use grafts engineered with immunomodulatory molecules as a means of inducing tolerance. RECENT FINDINGS: Several recent studies have demonstrated the feasibility of engineering cells, tissues, or solid organ grafts with immunoregulatory biologics to achieve long termgraft survival without the use of chronic immunosuppression. This approach was shown to primarily change the ratio of T effector versus CD4+CD25+FoxP3+ T regulatory cells within the graft microenvironment in favor of attaining localized tolerance induction and maintenance. SUMMARY: Localized immunomodulation using biologic engineered allografts represent a new paradigm for achieving long-term graft survival in the absence of chronic use of immunosuppression. The manipulation of the graft, rather than the recipient, not only ensures short- and long-term safety by minimizing the adverse effects of immunosuppression, but also allows retention of immune competency critical for the ability of the recipient to fight infections and cancer. PMID- 26626423 TI - LSD1 is essential for oocyte meiotic progression by regulating CDC25B expression in mice. AB - Mammalian oocytes are arrested at prophase I until puberty when hormonal signals induce the resumption of meiosis I and progression to meiosis II. Meiotic progression is controlled by CDK1 activity and is accompanied by dynamic epigenetic changes. Although the signalling pathways regulating CDK1 activity are well defined, the functional significance of epigenetic changes remains largely unknown. Here we show that LSD1, a lysine demethylase, regulates histone H3 lysine 4 di-methylation (H3K4me2) in mouse oocytes and is essential for meiotic progression. Conditional deletion of Lsd1 in growing oocytes results in precocious resumption of meiosis and spindle and chromosomal abnormalities. Consequently, most Lsd1-null oocytes fail to complete meiosis I and undergo apoptosis. Mechanistically, upregulation of CDC25B, a phosphatase that activates CDK1, is responsible for precocious meiotic resumption and also contributes to subsequent spindle and chromosomal defects. Our findings uncover a functional link between LSD1 and the major signalling pathway governing meiotic progression. PMID- 26626424 TI - Presence of the knockdown resistance mutation, Vgsc-1014F in Anopheles gambiae and An. arabiensis in western Kenya. AB - INTRODUCTION: The voltage gated sodium channel mutation Vgsc-1014S (kdr-east) was first reported in Kenya in 2000 and has since been observed to occur at high frequencies in the local Anopheles gambiae s.s. POPULATION: The mutation Vgsc 1014F has never been reported from An. gambiae Complex complex mosquitoes in Kenya. FINDINGS: Molecularly confirmed An. gambiae s.s. (hereafter An. gambiae) and An. arabiensis collected from 4 different parts of western Kenya were genotyped for kdr from 2011 to 2013. Vgsc-1014F was observed to have emerged, apparently, simultaneously in both An. gambiae and An. arabiensis in 2012. A portion of the samples were submitted for sequencing in order to confirm the Vgsc 1014F genotyping results. The resulting sequence data were deposited in GenBank (Accession numbers: KR867642-KR867651, KT758295-KT758303). A single Vgsc-1014F haplotype was observed suggesting, a common origin in both species. CONCLUSION: This is the first report of Vgsc-1014F in Kenya. Based on our samples, the mutation is present in low frequencies in both An. gambiae and An. arabiensis. It is important that we start monitoring relative frequencies of the two kdr genes so that we can determine their relative importance in an area of high insecticide treated net ownership. PMID- 26626426 TI - Clinical symptoms predict concurrent social and global functioning in an early psychosis sample. AB - AIM: Although well established in chronic schizophrenia, the key determinants of functioning remain unknown during the early phase of a psychotic disorder. The aim of this study was to comprehensively examine the social cognitive, basic neurocognitive and clinical predictors of concurrent social functioning and global functioning in an early psychosis sample. METHODS: This study examined the relationship between social cognition, basic neurocognition and clinical symptoms with concurrent functioning in 51 early psychosis individuals. Assessments included a range of self-report, observational and clinician-rated measures of cognitive, symptom severity and functioning domains. RESULTS: Results revealed a significant association between self-reported social function and lower levels of both social interaction anxiety and negative psychotic symptoms. A significant association was also observed between lower levels of negative psychotic symptoms and observed social functioning. Lastly, results demonstrated a significant association between reduced negative psychotic symptoms and clinician-rated global functioning. CONCLUSIONS: Clinical domains such as negative symptoms and social interaction anxiety significantly contribute to an optimal model predicting outcome during the early phase of a psychotic disorder. These clinical features may also provide useful markers of an individual's capacity for social participation. Clinical implications include the need for early targeted intervention to address social anxiety and negative psychotic symptoms to facilitate optimum patient outcome. PMID- 26626425 TI - M1 and M3 muscarinic receptors may play a role in the neurotoxicity of anhydroecgonine methyl ester, a cocaine pyrolysis product. AB - The smoke of crack cocaine contains cocaine and its pyrolysis product, anhydroecgonine methyl ester (AEME). AEME possesses greater neurotoxic potential than cocaine and an additive effect when they are combined. Since atropine prevented AEME-induced neurotoxicity, it has been suggested that its toxic effects may involve the muscarinic cholinergic receptors (mAChRs). Our aim is to understand the interaction between AEME and mAChRs and how it can lead to neuronal death. Using a rat primary hippocampal cell culture, AEME was shown to cause a concentration-dependent increase on both total [(3)H]inositol phosphate and intracellular calcium, and to induce DNA fragmentation after 24 hours of exposure, in line with the activation of caspase-3 previously shown. Additionally, we assessed AEME activity at rat mAChR subtypes 1-5 heterologously expressed in Chinese Hamster Ovary cells. l-[N-methyl-(3)H]scopolamine competition binding showed a preference of AEME for the M2 subtype; calcium mobilization tests revealed partial agonist effects at M1 and M3 and antagonist activity at the remaining subtypes. The selective M1 and M3 antagonists and the phospholipase C inhibitor, were able to prevent AEME-induced neurotoxicity, suggesting that the toxicity is due to the partial agonist effect at M1 and M3 mAChRs, leading to DNA fragmentation and neuronal death by apoptosis. PMID- 26626427 TI - Positive expression of NANOG, mutant p53, and CD44 is directly associated with clinicopathological features and poor prognosis of oral squamous cell carcinoma. AB - BACKGROUND: In order to predict long-term prognosis and define individual treatment modalities for patients with oral squamous cell carcinoma (OSCC), more reliable tumor biomarkers are needed during the pretreatment workup period. The present study aimed to identify more reliable immunohistochemical tumor prognostic markers in the pretreatment biopsy specimens of patients with OSCC. METHODS: We selected 57 patients who were diagnosed with primary OSCC through histopathological analysis. Pretreatment biopsy specimens were immunohistochemically analyzed for the transcription factor NANOG, cancer stem cell marker CD44, and mutant tumor protein 53 (mutant p53). The immunostaining patterns were assessed for their association with the clinicopathological features of OSCC and overall survival rates. RESULTS: Late tumor stage, positive neck node metastasis, and high-grade differentiation were associated with significantly poorer survival rates. Enhanced expression of NANOG and mutant p53 positivity were significantly associated with clinically late-stage tumors, positive neck node metastasis, histologically high-grade tumors, and poor overall survival rates. OSCCs with strong co-detection of NANOG and mutant p53 were linked to significantly lower survival rates than those with both weak NANOG expression and p53 negativity. Increased expression of CD44 had a limited correlation with unfavorable clinicopathological features. CONCLUSION: High expression of NANOG and positive expression of mutant p53 in the pretreatment biopsy specimens of patients with OSCC were associated with poor survival rates and unfavorable clinicopathological features. These results demonstrate that NANOG, mutant p53, and CD44 could be used as immunohistochemical markers in the pretreatment specimens of OSCC. In particular, analysis for co-expression of NANOG and mutant p53 should be made highly available as a tool for prognosis and selecting individual treatment modalities. PMID- 26626428 TI - Alzheimer therapy with an antibody against N-terminal Abeta 4-X and pyroglutamate Abeta 3-X. AB - Full-length Abeta1-42 and Abeta1-40, N-truncated pyroglutamate Abeta3-42 and Abeta4-42 are major variants in the Alzheimer brain. Abeta4-42 has not been considered as a therapeutic target yet. We demonstrate that the antibody NT4X and its Fab fragment reacting with both the free N-terminus of Abeta4-x and pyroglutamate Abeta3-X mitigated neuron loss in Tg4-42 mice expressing Abeta4-42 and completely rescued spatial reference memory deficits after passive immunization. NT4X and its Fab fragment also rescued working memory deficits in wild type mice induced by intraventricular injection of Abeta4-42. NT4X reduced pyroglutamate Abeta3-x, Abetax-40 and Thioflavin-S positive plaque load after passive immunization of 5XFAD mice. Abeta1-x and Abetax-42 plaque deposits were unchanged. Importantly, for the first time, we demonstrate that passive immunization using the antibody NT4X is therapeutically beneficial in Alzheimer mouse models showing that N-truncated Abeta starting with position four in addition to pyroglutamate Abeta3-x is a relevant target to fight Alzheimer's disease. PMID- 26626429 TI - Reversible Fluoxetine-Induced Hyperthyroidism: A Case Report. AB - BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are typically used as antidepressants. Clinically significant SSRI-induced thyroid dysfunction is rare. CASE: We report a case of hyperthyroidism induced by fluoxetine in a female patient with major depressive disorder. Her thyroid profiles indicated hyperthyroidism after a 10-week treatment with fluoxetine and were restored after discontinuation of fluoxetine and administration with venlafaxine. In the first year of follow-up, her thyroid functions as well as her depressive symptoms remained perfectly normal. CONCLUSIONS: This case highlights the necessity of monitoring thyroid profiles during SSRI treatment. PMID- 26626430 TI - Clinical Pharmacokinetics of IPX066: Evaluation of Dose Proportionality and Effect of Food in Healthy Volunteers. AB - OBJECTIVES: IPX066 is an oral, extended-release capsule formulation of carbidopa levodopa (CD-LD) available in 4 strengths. The goals of this investigation were to assess the dose proportionality of IPX066 and to study the effects of a high fat, high-calorie meal and of sprinkling the capsule contents on applesauce on the pharmacokinetics of IPX066 in healthy volunteers. METHODS: Three open-label studies were conducted. In the first study, subjects received 1 capsule of each IPX066 strength (23.75-95, 36.25-145, 48.75-195, and 61.25-245 mg of CD-LD). In the second study, subjects received 1 and 2 capsules of IPX066 245-mg LD under fasting conditions. In the third study, subjects received 2 capsules of IPX066 245-mg LD under 3 conditions: fasting; following a high-fat, high-calorie breakfast; and with the capsule contents sprinkled on applesauce under fasting conditions. RESULTS: Peak plasma concentrations (Cmax) and systemic exposure (AUCt, AUCinf) for LD and CD increased dose-proportionally over the range of the IPX066 capsule strengths. Comparison of 1 and 2 IPX066 245-mg LD capsules showed dose-proportional pharmacokinetics for Cmax and AUCt. Sprinkling the capsule contents on applesauce did not affect the pharmacokinetics. A high-fat, high calorie meal delayed the initial increase in LD concentration by approximately 1 to 2 hours, reduced Cmax by 21%, and increased AUCinf by 13% compared with the fasted state. CONCLUSIONS: IPX066 shows dose-proportional pharmacokinetics. Sprinkling the capsule contents on applesauce does not affect the pharmacokinetics; a high-fat, high-calorie meal delayed absorption by 1 to 2 hours, slightly reduced Cmax, and slightly increased extent of absorption. PMID- 26626432 TI - Revealing the characteristics of a novel bioflocculant and its flocculation performance in Microcystis aeruginosa removal. AB - In the present work, a novel bioflocculant, EPS-1, was prepared and used to flocculate the kaolin suspension and Microcystis aeruginosa. We focused on the characteristics and flocculation performance of EPS-1, especially with regard to its protein components. An important attribute of EPS-1 was its protein content, with 18 protein types identified that occupied a total content of 31.70% in the EPS-1. Moreover, the flocculating activity of these protein components was estimated to be no less than 33.93%. Additionally, polysaccharides that occupied 57.12% of the total EPS-1 content consisted of four monosaccharides: maltose, D xylose, mannose, and D-fructose. In addition, carbonyl, amino, and hydroxyl groups were identified as the main functional groups. Three main elements, namely C1s, N1s, and O1s, were present in EPS-1 with relative atomic percentages of 62.63%, 24.91%, and 10.5%, respectively. Zeta potential analysis indicated that charge neutralization contributed to kaolin flocculation, but was not involved in M. aeruginosa flocculation. The flocculation conditions of EPS-1 were optimized, and the maximum flocculating efficiencies were 93.34% within 2 min for kaolin suspension and 87.98% within 10 min for M. aeruginosa. These results suggest that EPS-1 could be an alternative to chemical flocculants for treating wastewaters and cyanobacterium-polluted freshwater. PMID- 26626431 TI - Crossover from a heavy fermion to intermediate valence state in noncentrosymmetric Yb2Ni12(P,As)7. AB - We report measurements of the physical properties and electronic structure of the hexagonal compounds Yb2Ni12Pn7 (Pn = P, As) by measuring the electrical resistivity, magnetization, specific heat and partial fluorescence yield x-ray absorption spectroscopy (PFY-XAS). These demonstrate a crossover upon reducing the unit cell volume, from an intermediate valence state in Yb2Ni12As7 to a heavy fermion paramagnetic state in Yb2Ni12P7, where the Yb is nearly trivalent. Application of pressure to Yb2Ni12P7 suppresses TFL, the temperature below which Fermi liquid behavior is recovered, suggesting the presence of a quantum critical point (QCP) under pressure. However, while there is little change in the Yb valence of Yb2Ni12P7 up to 30 GPa, there is a strong increase for Yb2Ni12As7 under pressure, before a near constant value is reached. These results indicate that any magnetic QCP in this system is well separated from strong valence fluctuations. The pressure dependence of the valence and lattice parameters of Yb2Ni12As7 are compared and at 1 GPa, there is an anomaly in the unit cell volume as well as a change in the slope of the Yb valence, indicating a correlation between structural and electronic changes. PMID- 26626434 TI - [Transfusion according to haemoglobin levels or therapeutic objectives]. PMID- 26626433 TI - Pneumomediastinum and pneumothorax during emergency tracheotomy under spontaneous ventilation: Macklin meets Mueller? AB - Potentially serious complications associated to emergency tracheotomy continue being a matter of concern. We review the pathogenesis of gas leakage in this setting and discuss about the possible mechanisms involved in its cause. We present two cases of pneumomediastinum, subcutaneous emphysema and pneumothorax in the context of emergency tracheotomy under spontaneous ventilation, finally resolved by chest drainage. The combination of overly negative pleural pressures due to extreme inspiratory efforts in the context of an almost completely obstructed airway together with over-pressurized alveoli because of gaseous entrapment secondary to serious expiratory obstruction appears to be the most plausible primary cause of air leaks in our patients. Understanding the underlying mechanisms evolved in its production will help clinicians to suspect and diagnose this phenomenon. PMID- 26626435 TI - Changes in haemostasis and thrombosis associated with thyroid disease: Presentation of 2 cases. AB - There is a relationship between thyroid diseases and primary and secondary changes in haemostasis. The most frequent association between them are hypocoagulability states with clinical hypothyroidism and vascular thrombophilia (hypercoagulability and/or hypofibrinolysis) with hyperparathyroidism. However, there are recent studies that have detected changes in haemostasis -primary and secondary- associated with thyroid diseases with normal hormone levels, suggesting other pathogenic mechanisms not yet known. The cases are presented of 2 patients with thyroid disease that required surgery: one multinodular goitre and one papillary carcinoma of the thyroid, both with normal hormone levels. They were shown to have haemostasis disorders during the preoperative work up. These showed a Factor VII deficiency and a Factor XI deficiency along with a thrombotic disease of unknown origin, respectively. PMID- 26626436 TI - One hundred and fifty five years from the first Spanish inhaled anesthesia in battlefield. PMID- 26626437 TI - Emergency anaesthesia in adult patients with Sanfilippo syndrome. PMID- 26626438 TI - Keeping your options open: Maintenance of thermal plasticity during adaptation to a stable environment. AB - Phenotypic plasticity may allow species to cope with environmental variation. The study of thermal plasticity and its evolution helps understanding how populations respond to variation in temperature. In the context of climate change, it is essential to realize the impact of historical differences in the ability of populations to exhibit a plastic response to thermal variation and how it evolves during colonization of new environments. We have analyzed the real-time evolution of thermal reaction norms of adult and juvenile traits in Drosophila subobscura populations from three locations of Europe in the laboratory. These populations were kept at a constant temperature of 18oC, and were periodically assayed at three experimental temperatures (13oC, 18oC, and 23oC). We found initial differentiation between populations in thermal plasticity as well as evolutionary convergence in the shape of reaction norms for some adult traits, but not for any of the juvenile traits. Contrary to theoretical expectations, an overall better performance of high latitude populations across temperatures in early generations was observed. Our study shows that the evolution of thermal plasticity is trait specific, and that a new stable environment did not limit the ability of populations to cope with environmental challenges. PMID- 26626439 TI - Flexion bonding transfer of multilayered graphene as a top electrode in transparent organic light-emitting diodes. AB - Graphene has attracted considerable attention as a next-generation transparent conducting electrode, because of its high electrical conductivity and optical transparency. Various optoelectronic devices comprising graphene as a bottom electrode, such as organic light-emitting diodes (OLEDs), organic photovoltaics, quantum-dot LEDs, and light-emitting electrochemical cells, have recently been reported. However, performance of optoelectronic devices using graphene as top electrodes is limited, because the lamination process through which graphene is positioned as the top layer of these conventional OLEDs is a lack of control in the surface roughness, the gapless contact, and the flexion bonding between graphene and organic layer of the device. Here, a multilayered graphene (MLG) as a top electrode is successfully implanted, via dry bonding, onto the top organic layer of transparent OLED (TOLED) with flexion patterns. The performance of the TOLED with MLG electrode is comparable to that of a conventional TOLED with a semi-transparent thin-Ag top electrode, because the MLG electrode makes a contact with the TOLED with no residue. In addition, we successfully fabricate a large size transparent segment panel using the developed MLG electrode. Therefore, we believe that the flexion bonding technology presented in this work is applicable to various optoelectronic devices. PMID- 26626440 TI - MicroRNA-186 induces sensitivity of ovarian cancer cells to paclitaxel and cisplatin by targeting ABCB1. AB - BACKGROUND: Recent studies have shown that microRNAs may regulate the ABCB1 gene (ATP-binding cassette, sub-family B [MDR/TAP], member 1). Computational programs have predicted that the 3'-untranslated region (3'-UTR) of ABCB1 contains a potential miRNA-binding site for miR-186. Here, we investigated the role of miR 186 in sensitizing ovarian cancer cells to paclitaxel and cisplatin. RESULTS: Human ovarian carcinoma cell lines OVCAR3, A2780, A2780/DDP, and A2780/Taxol were exposed to paclitaxel or cisplatin with or without miR-186 transfection, and cell viability was determined by MTT assay. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis were used to assess the MDR1, GST-pi, and MRP1 expression levels. Dual-luciferase reporter assay was used to reveal the correlation between miR-186 and ABCB1. Lower miR-186 while higher MDR1 and GST-pi mRNA expression levels were found in the A2780/Taxol and A2780/DDP cells than in the A2780 cells. After miR-186 transfection, all the cell lines showed increased sensitivity to paclitaxel and cisplatin. MiR-186 transfection induced apoptosis while anti-miR-186 transfection reduced apoptosis. The dual-luciferase reporter assay verified that that miR-186 combined with the 3'-untranslated region (UTR) of ABCB1. MDR1 and GST-pi mRNA and protein expression levels were downregulated after transfection with miR-186 but upregulated following anti-miR-186 transfection compared to the mock and negative control cancer cells; however, the MRP1 expression levels did not significantly differ among the groups. CONCLUSION: Our results are the first to demonstrate that miR-186 may sensitize ovarian cancer cell to paclitaxel and cisplatin by targeting ABCB1 and modulating the expression of GST-pi. PMID- 26626442 TI - Comparing efficacy of topical tea and zinc sulfate in the treatment of acne rosacea. PMID- 26626441 TI - Interest in Babies Negatively Predicts Testosterone Responses to Sexual Visual Stimuli Among Heterosexual Young Men. AB - Men's testosterone may be an important physiological mechanism mediating motivational and behavioral aspects of the mating/parenting trade-off not only over time but also in terms of stable differences between mating-oriented and parenting-oriented individuals. In this study, we tested the hypothesis that self reported interest in babies is inversely related to testosterone reactivity to cues of short-term mating among heterosexual young men. Among 100 participants, interest in babies was related to a slow life-history strategy, as assessed by the Mini-K questionnaire, and negatively related to testosterone responses to an erotic video. Interest in babies was not associated with baseline testosterone levels or with testosterone reactivity to nonsexual social stimuli. These results provide the first evidence that differential testosterone reactivity to sexual stimuli may be an important aspect of individual differences in life-history strategies among human males. PMID- 26626443 TI - Arrhythmias Seen in Baseline 24-Hour Holter ECG Recordings in Healthy Normal Volunteers During Phase 1 Clinical Trials. AB - Regulatory agencies encourage sponsors to submit 24-hour ambulatory ECG data for assessing cardiac safety of new drugs, and some arrhythmias, hitherto considered rare, have been observed in some early-phase studies. Interpretation of these observations is difficult given the dearth of published data on the prevalence of cardiac arrhythmias seen during 24-hour continuous ECG monitoring in healthy volunteers (HV) from clinical trials. We analyzed drug-free ambulatory ECG recordings from 1273 HV (1000 males, 273 females; age 18-65 years) from 22 phase 1 studies that were analyzed in a core ECG laboratory; all subjects had normal screening ECGs. Supraventricular arrhythmias such as supraventricular premature complexes were observed in 60.8% of healthy volunteers, supraventricular tachycardia in 2.2%, and atrial fibrillation in 0.1%. Ventricular arrhythmias included premature ventricular complexes (PVCs) in 43.4%, >200 PVCs per 24 hours in 3.3%, multifocal PVCs in 5.3%, nonsustained ventricular tachycardia in 0.7%, and accelerated idioventricular rhythm in 0.3%. Bradyarrhythmias included sinus pause >3 seconds in 0.3%, and second-degree AV block in 2.4%. Complete heart block and torsades de pointes were not seen in any subject. Based on the observed incidence, we estimated the maximum number of healthy subjects in whom these arrhythmias may be seen as a matter of chance in studies with smaller sample sizes if the study drug has no arrhythmogenic effect. Our results and these estimates could help interpret whether cardiac arrhythmias observed in early phase studies are due to chance or possibly are a drug effect. PMID- 26626444 TI - Left ventricular calcification in a patient with endomyocardial fibrosis. PMID- 26626445 TI - Complications of myocardial infarction: Echocardiography for differential diagnosis of heart murmur. PMID- 26626446 TI - Hanging by a thread: Major detachment of an aortic prosthetic valve. PMID- 26626447 TI - Body mass index may be an influential factor in heart rate variability. PMID- 26626448 TI - Meibomian Gland Absence Related Dry Eye in Ectodysplasin A Mutant Mice. AB - Meibomian gland dysfunction is the most frequent cause of evaporative dry eye, yet its underlying pathophysiology is unknown. To gain insight into this pathophysiology, we characterized the time-dependent tear film and ocular surface changes occurring in X-linked anhidrotic-hypohidrotic ectodermal dysplasia mice (Tabby), which lack the meibomian gland. These mice sequentially developed corneal epithelial defects, central corneal stromal edema, neovascularization, and pannus 8 to 16 weeks after birth. Aqueous tear secretion was normal, whereas tear break-up time and ex vivo tear evaporation times were all shortened. Corneal epithelial microvilli were less numerous, conjunctival goblet cell density was unaffected, and MUC5AC and MUC5B gene expression was increased. Markers of squamous metaplasia (cytokeratin 10 and small proline-rich protein 1B) were noticed in the corneal epithelium of Tabby mice as early as the fourth week. Taken together, the Tabby mouse is a relevant meibomian gland dysfunction-related dry eye model that may lead to a better understanding of how meibomian glands are related to ocular surface health. This model may also help with discovering novel drug options for treating evaporative dry eye. PMID- 26626449 TI - A Birth-cohort testing intervention identified hepatitis c virus infection among patients with few identified risks: a cross-sectional study. AB - BACKGROUND: International guidelines and U.S. guidelines prior to 2012 only recommended testing for hepatitis C virus (HCV) infection among patients at risk, but adherence to guidelines is poor, and the majority of those infected remain undiagnosed. A strategy to perform one-time testing of all patients born during 1945-1965, birth cohort testing, may diagnose HCV infection among patients whose risk remains unknown. We sought to determine if a birth-cohort testing intervention for HCV antibody positivity helped identify patients with fewer documented risk factors or medical indications than a pre-intervention, risk based testing strategy. METHODS: We used a cross-sectional design with retrospective electronic medical record review to examine patients identified with HCV antibody positivity (Ab+) during a pre-intervention (risk-based) phase, the standard of care at the time, vs. a birth-cohort testing intervention phase. We compared demographic and clinical characteristics and HCV risk-associated factors among patients whose HCV Ab + was identified during the pre-intervention (risk-based testing) vs. post birth-cohort intervention phases. Study subjects were patients identified as HCV-Ab + in the baseline (risk-based) and birth cohort testing phases of the Hepatitis C Assessment and Testing (HepCAT) Project. RESULTS: Compared to the risk-based phase, patients newly diagnosed with HCV Ab + after the birth-cohort intervention were significantly less likely to have a history of any substance abuse (30.5% vs. 49.5%, p = 0.02), elevated alanine transaminase levels of > 40 U/L (22.0% vs. 46.7%, p = 0.002), or the composite any risk-associated factor (55.9% vs. 79.0%, p = 0.002). CONCLUSIONS: Birth cohort testing is an useful strategy for identifying previously undiagnosed HCV Ab + because it does not require providers ask risk-based questions, or patients to disclose risk behaviors, and appears to identify HCV Ab + in patients who would not have been identified using a risk-based testing strategy. PMID- 26626451 TI - A retrospective pilot study examining the use of Acthar gel in sarcoidosis patients. AB - INTRODUCTION: Acthar was reported as effective for the treatment of pulmonary sarcoidosis in the 1950s. Use of drug waned due to cost and toxicity compared to prednisone. Recent interest has reemerged as an alternative to high dose oral glucocorticoids. METHODS: Chart review was performed on all advanced sarcoidosis patients seen at two centers who received at least one dose of Acthar gel therapy with at least six months of posttreatment follow up. In all cases prior sarcoidosis therapy and indications for use along with clinical outcome were noted. All patients initially received 80 IU intramuscular or subcutaneous administration twice a week. RESULTS: A total of 47 patients were treated with Acthar gel therapy during the study period, and 18 (37%) discontinued drug within six months due to cost (four patients), death (two patients), or drug toxicity (eleven patients), or noncompliance (1 patient). Of the remaining 29 patients, eleven experienced objective improvement in one or more affected organs. All but two patients noted disease improvement or oral glucocorticoid reduction. Twenty one patients were treated for more than six months (Median 274 days). Nineteen patients were on prednisone at time of starting Acthar gel: seventeen had their prednisone dosage reduced by more than fifty percent and one patient discontinued cyclophosphamide therapy. CONCLUSION: In this group of advanced sarcoidosis patients, Acthar gel treatment for at least three months was associated with objective improvement in a third of patients. A third of patients were unable to take at least a three months of treatment. PMID- 26626450 TI - Cloning, expression and functional characterization of two sesquiterpene synthase genes from moso bamboo (Phyllostachys edulis). AB - The purpose of this work was to characterize the functions of two sesquiterpene synthase genes from moso bamboo (Phyllostachys edulis). Two novel sesquiterpene synthase genes, belonging to the Tpsa subfamily, were isolated from moso bamboo. MoTPS2 was 1641 bp in length and encoded a protein of 63 kDa, whereas MoTPS6 was 1626 bp in length, encoded protein 62.4 kDa. Both genes were expressed in Pichia pastoris for heterologous expression, and protein contents reached 0.243 MUg MUL( 1) for MoTPS2 and 0.088 MUg MUL(-1) for MoTPS6. The soluble enzymes were catalytically active, and capable of converting farnesyl pyrophosphate to two distinct sesquiterpene compounds. The MoTPS2 gene encoded a farnesol synthase which was responsible for the production of (E, E)-farnesol. MoTPS6 showed nerolidol synthase activity, catalyzing the formation of (E)-nerolidol. Functional characterization of both MoTPSs should prove beneficial for future research into large-scale fermentation of sesquiterpenes. PMID- 26626452 TI - Association of polycyclic aromatic hydrocarbons and asthma among children 6-19 years: NHANES 2001-2008 and NHANES 2011-2012. AB - BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are a group of chemicals that can induce oxidative stress and related cytotoxicity. Whether environmental exposure of PAHs has effects on asthma in the general population is still unclear. This study investigated the association of urinary PAHs with asthma in U.S. children. METHODS: 15 447 children who participated in the US National Health and Nutrition Examination Survey 2001-2008 and 2011-2012 were studied. Ten urinary PAHs were analyzed for their association with asthma or asthma related symptoms. Multivariate logistic regression was applied to assess associations between urinary PAHs and asthma adjusted for age, gender, ethnicity, body mass index and the poverty income ratio. RESULTS: When stratified by age and sex, we found a remarkable association between urinary 2-phenanthrene and diagnosed asthma in boys (OR: 2.353, 95% CI: 1.156-4.792; P = 0.021) aged 13-19 years old. Positive association was observed between ever wheeze and 4-phenanthrene among girls aged 13-19 years (OR: 4.086, 95% CI: 1.326-12.584, P = 0.043). Moreover, an overall positive association between 1-pyrene and diagnosed asthma was observed. However, no association existed between levels of 1-napthol, 2-napthol, 3 fluorene, 2-fluorene, 3-phenanthrene, 1-phenanthrene or 9-fluorene with asthma or asthma symptom in this population. CONCLUSIONS: This data provide epidemiological evidences that urinary PAHs are positively associated with asthma in children aged 6-19 years. However, the underlying mechanisms still need further exploration. PMID- 26626454 TI - Value of plasma neutrophil gelatinase-associated lipocalin in predicting the mortality of patients with sepsis at the emergency department. AB - BACKGROUND: Sepsis is a major cause of morbidity and mortality in the emergency department. This study aimed to evaluate the assessment of severity of sepsis by and prognostic value of plasma neutrophil gelatinase-associated lipocalin (NGAL) compared with other widely used biological markers of inflammation in patients with sepsis. METHODS: NGAL, procalcitonin, and C-reactive protein values were measured in 470 patients with suspected sepsis, and the Mortality in Emergency Department Sepsis (MEDS) score was obtained for all enrolled subjects, who were followed for up to 28days. RESULTS: The median plasma NGAL value was increased with sepsis severity according to the MEDS score. The plasma NGAL value was higher in nonsurvivors than in survivors. The area under the receiver operating characteristic curve of NGAL (0.797) was greater than that of procalcitonin (0.599) and MEDS score (0.774) in predicting 28-day hospital mortality. Multivariable logistic regression found that the plasma NGAL value was an independent predictor for hospital mortality in patients with sepsis. The plasma NGAL values were positively correlated with C-reactive protein and procalcitonin levels, and MEDS scores. CONCLUSIONS: Plasma NGAL is a valuable biological marker in the assessment of severity and prediction of prognosis of patients with sepsis in the emergency department. PMID- 26626453 TI - Fast dimension reduction and integrative clustering of multi-omics data using low rank approximation: application to cancer molecular classification. AB - BACKGROUND: One major goal of large-scale cancer omics study is to identify molecular subtypes for more accurate cancer diagnoses and treatments. To deal with high-dimensional cancer multi-omics data, a promising strategy is to find an effective low-dimensional subspace of the original data and then cluster cancer samples in the reduced subspace. However, due to data-type diversity and big data volume, few methods can integrative and efficiently find the principal low dimensional manifold of the high-dimensional cancer multi-omics data. RESULTS: In this study, we proposed a novel low-rank approximation based integrative probabilistic model to fast find the shared principal subspace across multiple data types: the convexity of the low-rank regularized likelihood function of the probabilistic model ensures efficient and stable model fitting. Candidate molecular subtypes can be identified by unsupervised clustering hundreds of cancer samples in the reduced low-dimensional subspace. On testing datasets, our method LRAcluster (low-rank approximation based multi-omics data clustering) runs much faster with better clustering performances than the existing method. Then, we applied LRAcluster on large-scale cancer multi-omics data from TCGA. The pan cancer analysis results show that the cancers of different tissue origins are generally grouped as independent clusters, except squamous-like carcinomas. While the single cancer type analysis suggests that the omics data have different subtyping abilities for different cancer types. CONCLUSIONS: LRAcluster is a very useful method for fast dimension reduction and unsupervised clustering of large scale multi-omics data. LRAcluster is implemented in R and freely available via http://bioinfo.au.tsinghua.edu.cn/software/lracluster/ . PMID- 26626455 TI - Association of MMP-9 to TIMP-1 ratio with long-term body weight and waist circumference after dietary weight reduction in men with metabolic syndrome. PMID- 26626457 TI - Factors affecting computed tomography image quality for assessment of mechanical aortic valves. AB - Evaluating mechanical valves with computed tomography (CT) can be problematic because artifacts from the metallic components of valves can hamper image quality. The purpose of this study was to determine factors affecting the image quality of cardiac CT to improve assessment of mechanical aortic valves. A total of 144 patients who underwent aortic valve replacement with mechanical valves (ten different types) and who underwent cardiac CT were included. Using a four point grading system, the image quality of the CT scans was assessed for visibility of the valve leaflets and the subvalvular regions. Data regarding the type of mechanical valve, tube voltage, average heart rate (HR), and HR variability during CT scanning were compared between the non-diagnostic (overall image quality score <=2) and diagnostic (overall image quality score >2) image quality groups. Logistic regression analyses were performed to identify predictors of non-diagnostic image quality. The percentage of valve types that incorporated a cobalt-chrome component (two types in total) and HR variability were significantly higher in the non-diagnostic image group than in the diagnostic group (P < 0.001 and P = 0.013, respectively). The average HR and tube voltage were not significantly different between the two groups (P > 0.05). Valve type was the only independent predictor of non-diagnostic quality. The CT image quality for patients with mechanical aortic valves differed significantly depending on the type of mechanical valve used and on the degree of HR variability. PMID- 26626456 TI - Clinical and genetic factors associated with suicide in mood disorder patients. AB - Suicidality is a continuum ranging from ideation to attempted and completed suicide, with a complex etiology involving both genetic heritability and environmental factors. The majority of suicide events occur in the context of psychiatric conditions, preeminently major depression and bipolar disorder. The present study investigates clinical factors associated with suicide in a sample of 553 mood disorder patients, recruited within the 'Psy Pluriel' center, Centre Europeen de Psychologie Medicale, and the Department of Psychiatry of Erasme Hospital (Brussels). Furthermore, genetic association analyses examining polymorphisms within COMT, BDNF, MAPK1 and CREB1 genes were performed in a subsample of 259 bipolar patients. The presence or absence of a previous suicide attempt and of current suicide risk were assessed. A positive association with suicide attempt was reported for younger patients, females, lower educated, smokers, those with higher scores on depressive symptoms and higher functional disability and those with anxiety comorbidity and familial history of suicidality in first- and second-degree relatives. Anxiety disorder comorbidity was the stronger predictor of current suicide risk. No associations were found with polymorphisms within COMT and BDNF genes, whereas significant associations were found with variations in rs13515 (MAPK1) and rs6740584 (CREB1) polymorphisms. From a clinical perspective, our study proposes several clinical characteristics, such as increased depressive symptomatology, anxiety comorbidity, functional disability and family history of suicidality, as correlates associated with suicide. Genetic risk variants in MAPK1 and CREB1 genes might be involved in a dysregulation of inflammatory and neuroplasticity pathways and are worthy of future investigation. PMID- 26626458 TI - Artificial neural network modeling enhances risk stratification and can reduce downstream testing for patients with suspected acute coronary syndromes, negative cardiac biomarkers, and normal ECGs. AB - Despite uncertain yield, guidelines endorse routine stress myocardial perfusion imaging (MPI) for patients with suspected acute coronary syndromes, unremarkable serial electrocardiograms, and negative troponin measurements. In these patients, outcome prediction and risk stratification models could spare unnecessary testing. This study therefore investigated the use of artificial neural networks (ANN) to improve risk stratification and prediction of MPI and angiographic results. We retrospectively identified 5354 consecutive patients referred from the emergency department for rest-stress MPI after serial negative troponins and normal ECGs. Patients were risk stratified according to thrombolysis in myocardial infarction (TIMI) scores, ischemia was defined as >5 % reversible perfusion defect, and obstructive coronary artery disease was defined as >50 % angiographic obstruction. For ANN, the network architecture employed a systematic method where the number of neurons is changed incrementally, and bootstrapping was performed to evaluate the accuracy of the models. Compared to TIMI scores, ANN models provided improved discriminatory power. With regards to MPI, an ANN model could reduce testing by 59 % and maintain a 96 % negative predictive value (NPV) for ruling out ischemia. Application of an ANN model could also avoid 73 % of invasive coronary angiograms while maintaining a 98 % NPV for detecting obstructive CAD. An online calculator for clinical use was created using these models. The ANN models improved risk stratification when compared to the TIMI score. Our calculator could also reduce downstream testing while maintaining an excellent NPV, though further study is needed before the calculator can be used clinically. PMID- 26626459 TI - Peripheral Circadian Clocks Mediate Dietary Restriction-Dependent Changes in Lifespan and Fat Metabolism in Drosophila. AB - Endogenous circadian clocks orchestrate several metabolic and signaling pathways that are known to modulate lifespan, suggesting clocks as potential targets for manipulation of metabolism and lifespan. We report here that the core circadian clock genes, timeless (tim) and period (per), are required for the metabolic and lifespan responses to DR in Drosophila. Consistent with the involvement of a circadian mechanism, DR enhances the amplitude of cycling of most circadian clock genes, including tim, in peripheral tissues. Mass-spectrometry-based lipidomic analysis suggests a role of tim in cycling of specific medium chain triglycerides under DR. Furthermore, overexpression of tim in peripheral tissues improves its oscillatory amplitude and extends lifespan under ad libitum conditions. Importantly, effects of tim on lifespan appear to be mediated through enhanced fat turnover. These findings identify a critical role for specific clock genes in modulating the effects of nutrient manipulation on fat metabolism and aging. PMID- 26626460 TI - Leptin, BMI, and a Metabolic Gene Expression Signature Associated with Clinical Outcome to VEGF Inhibition in Colorectal Cancer. AB - VEGF (vascular endothelial growth factor) signaling inhibitors are widely used in different cancer types; however, patient selection remains a challenge. Analyses of samples from a phase III clinical trial in metastatic colorectal cancer testing chemotherapy versus chemotherapy with the small molecule VEGF receptors inhibitor cediranib identified circulating leptin levels, BMI, and a tumor metabolic and angiogenic gene expression signature associated with improved clinical outcome in patients treated with cediranib. Patients with a glycolytic and hypoxic/angiogenic profile were associated with increased benefit from cediranib, whereas patients with a high lipogenic, oxidative phosphorylation and serine biosynthesis signature did not gain benefit. These findings translated to pre-clinical tumor xenograft models where the same metabolic gene expression profiles were associated with in vivo sensitivity to cediranib as monotherapy. These findings suggest a link between patient physiology, tumor biology, and response to antiangiogenics, which may guide patient selection for VEGF therapy in the future. PMID- 26626461 TI - Reduced Insulin Production Relieves Endoplasmic Reticulum Stress and Induces beta Cell Proliferation. AB - Pancreatic beta cells are mostly post-mitotic, but it is unclear what locks them in this state. Perturbations including uncontrolled hyperglycemia can drive beta cells into more pliable states with reduced cellular insulin levels, increased beta cell proliferation, and hormone mis-expression, but it is unknown whether reduced insulin production itself plays a role. Here, we define the effects of ~50% reduced insulin production in Ins1(-/-):Ins2(f/f):Pdx1Cre(ERT):mTmG mice prior to robust hyperglycemia. Transcriptome, proteome, and network analysis revealed alleviation of chronic endoplasmic reticulum (ER) stress, indicated by reduced Ddit3, Trib3, and Atf4 expression; reduced Xbp1 splicing; and reduced phospho-eIF2alpha. This state was associated with hyper-phosphorylation of Akt, which is negatively regulated by Trib3, and with cyclinD1 upregulation. Remarkably, beta cell proliferation was increased 2-fold after reduced insulin production independently of hyperglycemia. Eventually, recombined cells mis expressed glucagon in the hyperglycemic state. We conclude that the normally high rate of insulin production suppresses beta cell proliferation in a cell autonomous manner. PMID- 26626463 TI - Is the experience of meaningful activities understood in nursing homes? A qualitative study. AB - Lack of occupation can lead to boredom, apathy, social exclusion and solitude. Occupation should incorporate meaningful activities. The aim of this study is to describe how Spanish Nursing Home residents experienced and made sense of meaningful activities. A qualitative phenomenological approach was followed. Data were collected over an 18-month period between 2012 and 2014. Purposeful sampling was conducted with Spanish residents in nursing homes in Madrid. Data were collected using unstructured and semi-structured interviews. The data were analyzed using the Giorgi proposal. Thirty-eight residents (20 female and 18 male) participated. Three main themes describing the significance of meaningful activity in nursing homes emerged from the data: Feeling the passage of time, Seeking an occupation, and Living with restrictions. Nursing homes should strive to develop diverse and meaningful activity programs for residents in order to occupy their time and provide them with a greater sense of purpose. PMID- 26626462 TI - Pdgfrbeta+ Mural Preadipocytes Contribute to Adipocyte Hyperplasia Induced by High-Fat-Diet Feeding and Prolonged Cold Exposure in Adult Mice. AB - The expansion of white adipose tissue (WAT) in obesity involves de novo differentiation of new adipocytes; however, the cellular origin of these cells remains unclear. Here, we utilize Zfp423(GFP) reporter mice to characterize adipose mural (Pdgfrbeta(+)) cells with varying levels of the preadipocyte commitment factor Zfp423. We find that adipose tissue contains distinct mural populations, with levels of Zfp423 distinguishing adipogenic from inflammatory like mural cells. Using our "MuralChaser" lineage tracking system, we uncover adipose perivascular cells as developmental precursors of adipocytes formed in obesity, with adipogenesis and precursor abundance regulated in a depot-dependent manner. Interestingly, Pdgfrbeta(+) cells do not significantly contribute to the initial cold-induced recruitment of beige adipocytes in WAT; it is only after prolonged cold exposure that these cells differentiate into beige adipocytes. These results provide genetic evidence for a mural cell origin of white adipocytes in obesity and suggest that beige adipogenesis may originate from multiple sources. PMID- 26626464 TI - Respiratory muscle endurance after training in athletes and non-athletes: A systematic review and meta-analysis. AB - The objectives of this systematic review was to evaluate the effects of respiratory muscle training (RMT) on respiratory muscle endurance (RME) and to determine the RME test that demonstrates the most consistent changes after RMT. Electronic searches were conducted in EMBASE, MEDLINE, COCHRANE CENTRAL, CINHAL and SPORTDiscus. The PEDro scale was used for quality assessment and meta analysis were performed to compare effect sizes of different RME tests. Twenty studies met the inclusion criteria. Isocapnic hyperpnea training was performed in 40% of the studies. Meta-analysis showed that RMT improves RME in athletes (P = 0.0007) and non-athletes (P = 0.001). Subgroup analysis showed differences among tests; maximal sustainable ventilatory capacity (MSVC) and maximal sustainable threshold loading tests demonstrated significant improvement after RMT (P = 0.007; P = 0.003 respectively) compared to the maximal voluntary ventilation (MVV) (P = 0.11) in athletes whereas significant improvement after RMT was only shown by MSVC in non-athletes. The effect size of MSVC was greater compared to MVV in studies that performed both tests. The meta-analysis results provide evidence that RMT improves RME in athletes and non-athletes and MSVC test that examine endurance over several minutes are more sensitive to improvement after RMT. PMID- 26626466 TI - Etiology of Obesity Over the Life Span: Ecologic and Genetic Highlights from New Zealand Cohorts. AB - The origins of the New Zealand population are highly diverse. New Zealand Maori are the indigenous peoples with a population of approximately half a million (~12 %), with the remainder comprising predominantly European/Caucasian (~50 %), Pacific Island Polynesian (~28 %) and Asian (~10 %) peoples. With a prevalence of overweight and obesity of 65 % for adults >15 years of age, of which 28 % have a BMI > 30 kg/m(2), New Zealand has been ranked third highest in a global OECD obesity review, behind only the US and Mexico. Levels of childhood obesity are also significant, with 31 % of New Zealand's children either overweight or obese. Few gender differences exist, but there are significant differences between ethnicities (Asian > European Caucasian > Maori > Pacific) with disproportionate representation by those poorer and with less formal education. A high 62 % of Pacifika are obese and virtually the entire adult population has a BMI >25 kg/m(2). Public health measures to limit progressive increases in weight are unsuccessful, and clearly should be priority for government focused on disease prevention. PMID- 26626467 TI - Weight Gain, Overweight, and Obesity: Determinants and Health Outcomes from the Australian Longitudinal Study on Women's Health. AB - Recent estimates suggest that 35.3 % of adult Australians are overweight and a further 27.5 % are obese. The Australian Longitudinal Study on Women's Health (ALSWH) is a prospective study of women's health that commenced in Australia in 1996. The study recruited approximately 40,000 women in three birth cohorts, 1973 1978, 1946-1951 and 1921-1926, who have since been followed up approximately every three years using self-report surveys. Six surveys have been completed to date. This review aims to describe the changes in weight and weight status over time in the three ALSWH cohorts, and to review and summarise the published findings to date relating to the determinants and health consequences of weight gain, overweight and obesity. Future plans for the ALSWH include on-going surveys for all cohorts, with a seventh survey in 2013-2015, and establishment of a new cohort of women born in 1990-1995, which is currently being recruited. PMID- 26626465 TI - Etiology of Obesity Over the Life Span: Ecological and Genetic Highlights from Asian Countries. AB - Obesity is a worldwide pandemic, and the prevalence rate has doubled since the 1980s. Asian countries are also experiencing the global epidemic of obesity with its related health consequences. The prevalence of overweight and obesity are increasing at an alarming rate across all age groups in Asia. These increases are mainly attributed to rapid economic growth, which leads to socio-economic, nutrition and lifestyle transitions, resulting in a positive energy balance. In addition, fat mass and obesity-associated gene variants, copy number variants in chromosomes and epigenetic modifications have shown positive associations with the risk of obesity among Asians. In this review highlights of prevalence and related ecological and genetic factors that could influence the rapid rise in obesity among Asian populations are discussed. PMID- 26626468 TI - The Association Between Diet and Obesity in Specific European Cohorts: DiOGenes and EPIC-PANACEA. AB - This review summarizes evidence from two projects embedded within the European Prospective Investigation into Cancer and Nutrition (EPIC) on the association between dietary factors and obesity risk, in particular change in weight and waist circumference. A total of 12 publications from DiOGenes and six from EPIC PANACEA were reviewed. The results show that dietary fiber, especially cereal fiber, was inversely associated with weight or waist change, as well as fruit/vegetable intake and the Mediterranean dietary pattern. Energy density and meat consumption were positively associated with the anthropometric changes, as was glycemic index with waist change. Clear associations with macronutrient composition were not observed. In additional studies, interactions with genetic polymorphism were investigated and shown to be present for protein intake and GI, although effect estimates were small. These interactions require replication. These results show that in European populations dietary factors are independently associated with weight/waist change. The findings provide further clues for the prevention of obesity. PMID- 26626469 TI - Using the Neuroscience of Obesity, Eating Behavior, and Sleep to Inform the Neural Mechanisms of Night Eating Syndrome. AB - The development and maintenance of night eating syndrome (NES) is likely influenced by physiological, psychological, and social factors. Within the physiological domain, neural mechanisms (e.g., neurotransmitters and specific brain region functioning) remain understudied in contrast to other eating disorders and obesity. The serotonin system has been hypothesized to contribute to NES based on one single photon emission computed tomography (SPECT) study and supportive pharmacologic treatment outcome findings, but additional neural models are plausible. Functional magnetic resonance imaging (fMRI) is a brain imaging tool that is increasingly being used to study obesity, eating behavior, and sleep. Converging data from these literatures using food motivation and decision making fMRI paradigms suggest that the prefrontal and limbic brain systems might also play a role in the development and/or maintenance of NES. We use these data to support a new neural model of NES for future testing and validation. PMID- 26626470 TI - Delayed Timing of Eating: Impact on Weight and Metabolism. AB - Animal studies of delayed eating have provided useful information regarding the potential relationship between nighttime eating and increased weight and metabolic dysregulation, which occur in the absence of increased locomotion or increased caloric intake. We first review recent studies detailing these relationships and possible mechanisms in rodents. We then examine human data showing that sleep restriction leads to increased energy intake and weight gain, followed by a review of the human phenotype of delayed eating, night eating syndrome, and its relation to weight and metabolism. Finally, we examine human experimental studies of delayed eating and discuss preliminary data that show slight weight gain, dysfunction in energy expenditure, and abnormalities in the circadian rhythms of appetitive, stress, and sleep hormones. Well-controlled, longer-term experimental studies in humans are warranted to test the effect of delayed eating without sleep restriction to clarify whether limiting or eliminating nighttime eating could lead to weight loss and significantly improve related disorders, such as diabetes and heart disease, over time. PMID- 26626471 TI - Nutritional Aspects of Late Eating and Night Eating. AB - The timing of food intake has been investigated as a novel factor in the etiology, maintenance, and treatment of obesity. Indeed, consuming a large proportion of food later in the day and into the night has been associated with higher body weight and may even impair weight loss. The diet quality of late eaters may be a factor involved in these relationships. Moreover, the nutritional characteristics of the foods consumed during the night may negatively affect metabolic and circadian rhythms that are required for optimal health. This review will first examine the diet quality of late-eaters and describe common foods consumed as nocturnal snacks. Second, this review will briefly acknowledge the potential adverse metabolic and circadian effects of consuming certain foods very late in the evening or during the night. PMID- 26626472 TI - Restless Eating, Restless Legs, and Sleep Related Eating Disorder. AB - Restless legs syndrome (RLS) often presents with a primary complaint of sleep initiation difficulty with only ambiguous allusions to motor symptoms. This may result in the condition being misdiagnosed as a psychophysiological insomnia. Further, nocturnal eating is common in RLS and like the classic motor symptoms, patients will describe an inability to initiate sleep until their urge (to eat) is addressed. Restless nocturnal eating arises, intensifies, and subsides in parallel to motor symptoms. Once misdiagnosed as psychophysiological insomnia, RLS patients are frequently treated with benzodiazepine receptor agonists. The CNS actions of these sedating agents, suppression of memory and executive function, unleash predisposed amnestic behaviors. In the case of RLS this would be expected to include the inappropriate ambulatory and eating behaviors of sleep related eating disorder (SRED). The evidence and implications of a link between the restless eating of RLS and SRED is presented here. PMID- 26626473 TI - Neuroendocrine Profile in the Night Eating Syndrome. AB - Night eating syndrome (NES) has recently been getting more attention as a recognized eating disorder. NES is characterized by a delay in the circadian pattern of food intake, associated with morning anorexia, evening hyperphagia, awakenings from sleep with ingestion of food, depressed mood, and obesity. Although the behavioral characteristics of NES were first described in 1955, the neuroendocrine characteristics have only been described recently. Researchers have examined several hormones that appear to differ in night eaters compared to controls, including melatonin, leptin, and cortisol. Researchers have more recently examined the hypothalamic-pituitary-adrenal axis in more detail, with emphasis on corticotrophin releasing hormone. Further studies have examined ghrelin, growth hormone, prolactin, and IGF-1, with differences observed in the circadian pattern of these hormones in those with NES compared to controls. Despite increasing interest in the neuroendocrine profile of night eating behavior, the biological basis of NES is still not well understood. PMID- 26626474 TI - Personality Traits in Obesity Associated with Binge Eating and/or Night Eating. AB - Specific personality traits, as assessed by the Temperament and Character Inventory (TCI), have been identified in individuals with obesity, but their association with binge and/or night eating has scarcely been reported. Indeed, our systematic search of Medline (1987 to 2013) yielded only five studies on the issue. Taken together, they suggest that personality traits do not have any significant role in determining body mass index, and therefore obesity class. However, obese individuals, in comparison with normal weight individuals, do seem to have a distinctive personality profile, characterized by low self-directedness and cooperativeness, and obese individuals with binge eating show lower self directedness than those without. Moreover obese individuals with binge eating and/or night eating share a temperament profile characterized by high novelty seeking and harm-avoidance, two traits also observed in other eating disorder categories and in clinical depression. Future longitudinal studies are needed to investigate the role of personality traits in the onset of binge eating and night eating in obese individuals, and to clarify their influence, if any, on treatment outcomes. Such information will enable us to determine whether the evaluation of personality traits should be included in the comprehensive assessment of obese individuals. PMID- 26626475 TI - The Treatment of Night Eating Syndrome: A Review and Theoretical Model. AB - The treatment of night eating syndrome, a disorder characterized by evening hyperphagia, morning anorexia, and insomnia, continues to gain attention with its inclusion in the DSM-V. Known treatments for NES include pharmacological, phototherapy, weight loss and dietary, and psychological interventions, which, together with the syndrome's clinical characteristics, support a treatment guiding biobehavioral model. The biobehavioral model proposes that a genetic predisposition, coupled with stress, enhances midbrain serotonin transporter (SERT) binding, which results in lower post-synaptic serotonin, dysregulating circadian rhythms and decreasing satiety. Selective serotonin reuptake inhibitors should therefore decrease SERT binding, increase postsynaptic serotonin, and restore circadian function and satiety regulation. Psychological interventions may be used to decrease stress as well as address insomnia and circadian rhythm disruptions. Dietary and behavioral interventions may produce beneficial changes in satiety as well as dysregulated eating. Avenues for future treatment outcome studies, including alternative pharmacological and combination therapies, are discussed. PMID- 26626476 TI - Erratum to: The Treatment of Night Eating Syndrome: A Review and Theoretical Model. PMID- 26626477 TI - Reduced Maternal Erythrocyte Long Chain Polyunsaturated Fatty Acids Exist in Early Pregnancy in Preeclampsia. AB - The present prospective study examines proportions of maternal erythrocyte fatty acids across gestation and their association with cord erythrocyte fatty acids in normotensive control (NC) and preeclamptic pregnancies. We hypothesize that maternal fatty acid status in early pregnancy influences fetal fatty acid stores in preeclampsia. 137 NC women and 58 women with preeclampsia were included in this study. Maternal blood was collected at 3 time points during pregnancy (16 20th weeks, 26-30th weeks and at delivery). Cord blood was collected at delivery. Fatty acids were analyzed using gas chromatography. The proportions of maternal erythrocyte alpha-linolenic acid, docosahexaenoic acid, nervonic acid, and monounsaturated fatty acids (MUFA) (p < 0.05 for all) were lower while total n-6 fatty acids were higher (p < 0.05) at 16-20th weeks of gestation in preeclampsia as compared with NC. Cord 18:3n-3, 22:6n-3, 24:1n-9, MUFA, and total n-3 fatty acids (p < 0.05 for all) were also lower in preeclampsia as compared with NC. A positive association was observed between maternal erythrocyte 22:6n-3 and 24:1n 9 at 16-20th weeks with the same fatty acids in cord erythrocytes (p < 0.05 for both) in preeclampsia. Our study for the first time indicates alteration in maternal erythrocyte fatty acids at 16th weeks of gestation which is further reflected in cord erythrocytes at delivery in preeclampsia. PMID- 26626478 TI - Soy Protein Alleviates Hypertension and Fish Oil Improves Diastolic Heart Function in the Han:SPRD-Cy Rat Model of Cystic Kidney Disease. AB - Abnormalities in cardiac structure and function are very common among people with chronic kidney disease, in whom cardiovascular disease is the major cause of death. Dietary soy protein and fish oil reduce kidney disease progression in the Han:SPRD-Cy model of cystic renal disease. However, the effects of these dietary interventions in preventing alterations in cardiac structure and function due to kidney disease (reno-cardiac syndrome) in a cystic kidney disease model are not known. Therefore, weanling Han:SPRD-Cy diseased (Cy/+) and normal (+/+) rats were given diets containing either casein or soy protein, and either soy or fish oil in a three-way design for 8 weeks. Diseased rats had larger hearts, augmented left ventricular mass, and higher systolic and mean arterial blood pressure compared to the normal rats. Assessment of cardiac function using two-dimensional guided M-mode and pulse-wave Doppler echocardiography revealed that isovolumic relaxation time was prolonged in the diseased compared to normal rats, reflecting a diastolic heart dysfunction, and fish oil prevented this elevation. Soy protein resulted in a small improvement in systolic and mean arterial pressure but did not improve diastolic heart function, while fish oil prevented diastolic heart dysfunction in this model of cystic kidney disease. PMID- 26626479 TI - Structural Basis of Detection and Signaling of DNA Single-Strand Breaks by Human PARP-1. AB - Poly(ADP-ribose)polymerase 1 (PARP-1) is a key eukaryotic stress sensor that responds in seconds to DNA single-strand breaks (SSBs), the most frequent genomic damage. A burst of poly(ADP-ribose) synthesis initiates DNA damage response, whereas PARP-1 inhibition kills BRCA-deficient tumor cells selectively, providing the first anti-cancer therapy based on synthetic lethality. However, the mechanism underlying PARP-1's function remained obscure; inherent dynamics of SSBs and PARP-1's multi-domain architecture hindered structural studies. Here we reveal the structural basis of SSB detection and how multi-domain folding underlies the allosteric switch that determines PARP-1's signaling response. Two flexibly linked N-terminal zinc fingers recognize the extreme deformability of SSBs and drive co-operative, stepwise self-assembly of remaining PARP-1 domains to control the activity of the C-terminal catalytic domain. Automodification in cis explains the subsequent release of monomeric PARP-1 from DNA, allowing repair and replication to proceed. Our results provide a molecular framework for understanding PARP inhibitor action and, more generally, allosteric control of dynamic, multi-domain proteins. PMID- 26626480 TI - PARP-1 Activation Requires Local Unfolding of an Autoinhibitory Domain. AB - Poly(ADP-ribose) polymerase-1 (PARP-1) creates the posttranslational modification PAR from substrate NAD(+) to regulate multiple cellular processes. DNA breaks sharply elevate PARP-1 catalytic activity to mount a cell survival repair response, whereas persistent PARP-1 hyperactivation during severe genotoxic stress is associated with cell death. The mechanism for tight control of the robust catalytic potential of PARP-1 remains unclear. By monitoring PARP-1 dynamics using hydrogen/deuterium exchange-mass spectrometry (HXMS), we unexpectedly find that a specific portion of the helical subdomain (HD) of the catalytic domain rapidly unfolds when PARP-1 encounters a DNA break. Together with biochemical and crystallographic analysis of HD deletion mutants, we show that the HD is an autoinhibitory domain that blocks productive NAD(+) binding. Our molecular model explains how PARP-1 DNA damage detection leads to local unfolding of the HD that relieves autoinhibition, and has important implications for the design of PARP inhibitors. PMID- 26626481 TI - NSD3-Short Is an Adaptor Protein that Couples BRD4 to the CHD8 Chromatin Remodeler. AB - The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3 short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by using a PWWP chromatin reader module, and by employing an acidic transactivation domain. Genetic targeting of NSD3 or CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome, and each is released from super enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4-NSD3-CHD8 complexes from chromatin to suppress transcription. PMID- 26626482 TI - PrimPol Is Required for Replicative Tolerance of G Quadruplexes in Vertebrate Cells. AB - G quadruplexes (G4s) can present potent blocks to DNA replication. Accurate and timely replication of G4s in vertebrates requires multiple specialized DNA helicases and polymerases to prevent genetic and epigenetic instability. Here we report that PrimPol, a recently described primase-polymerase (PrimPol), plays a crucial role in the bypass of leading strand G4 structures. While PrimPol is unable to directly replicate G4s, it can bind and reprime downstream of these structures. Disruption of either the catalytic activity or zinc-finger of PrimPol results in extreme G4-dependent epigenetic instability at the BU-1 locus in avian DT40 cells, indicative of extensive uncoupling of the replicative helicase and polymerase. Together, these observations implicate PrimPol in promoting restart of DNA synthesis downstream of, but closely coupled to, G4 replication impediments. PMID- 26626483 TI - AMPK-Dependent Phosphorylation of GAPDH Triggers Sirt1 Activation and Is Necessary for Autophagy upon Glucose Starvation. AB - Eukaryotes initiate autophagy to cope with the lack of external nutrients, which requires the activation of the nicotinamide adenine dinucleotide (NAD(+)) dependent deacetylase Sirtuin 1 (Sirt1). However, the mechanisms underlying the starvation-induced Sirt1 activation for autophagy initiation remain unclear. Here, we demonstrate that glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a conventional glycolytic enzyme, is a critical mediator of AMP-activated protein kinase (AMPK)-driven Sirt1 activation. Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated. Preventing this shift of GAPDH abolishes Sirt1 activation and autophagy, while enhancing it, through overexpression of nuclear-localized GAPDH, increases Sirt1 activation and autophagy. GAPDH is thus a pivotal and central regulator of autophagy under glucose deficiency, undergoing AMPK-dependent phosphorylation and nuclear translocation to activate Sirt1 deacetylase activity. PMID- 26626484 TI - Massively Systematic Transcript End Readout, "MASTER": Transcription Start Site Selection, Transcriptional Slippage, and Transcript Yields. AB - We report the development of a next-generation sequencing-based technology that entails construction of a DNA library comprising up to at least 4(7) (~ 16,000) barcoded sequences, production of RNA transcripts, and analysis of transcript ends and transcript yields (massively systematic transcript end readout, "MASTER"). Using MASTER, we define full inventories of transcription start sites ("TSSomes") of Escherichia coli RNA polymerase for initiation at a consensus core promoter in vitro and in vivo; we define the TSS-region DNA sequence determinants for TSS selection, reiterative initiation ("slippage synthesis"), and transcript yield; and we define effects of DNA topology and NTP concentration. The results reveal that slippage synthesis occurs from the majority of TSS-region DNA sequences and that TSS-region DNA sequences have profound, up to 100-fold, effects on transcript yield. The results further reveal that TSSomes depend on DNA topology, consistent with the proposal that TSS selection involves transcription-bubble expansion ("scrunching") and transcription-bubble contraction ("anti-scrunching"). PMID- 26626485 TI - During postnatal development endogenous neurosteroids influence GABA-ergic neurotransmission of mouse cortical neurons. AB - As neuronal development progresses, GABAergic synaptic transmission undergoes a defined program of reconfiguration. For example, GABAA receptor (GABAAR)-mediated synaptic currents, (miniature inhibitory postsynaptic currents; mIPSCs), which initially exhibit a relatively slow decay phase, become progressively reduced in duration, thereby supporting the temporal resolution required for mature network activity. Here we report that during postnatal development of cortical layer 2/3 pyramidal neurons, GABAAR-mediated phasic inhibition is influenced by a resident neurosteroid tone, which wanes in the second postnatal week, resulting in the brief phasic events characteristic of mature neuronal signalling. Treatment of cortical slices with the immediate precursor of 5alpha-pregnan-3alpha-ol-20-one (5alpha3alpha), the GABAAR-inactive 5alpha-dihydroprogesterone, (5alpha-DHP), greatly prolonged the mIPSCs of P20 pyramidal neurons, demonstrating these more mature neurons retain the capacity to synthesize GABAAR-active neurosteroids, but now lack the endogenous steroid substrate. Previously, such developmental plasticity of phasic inhibition was ascribed to the expression of synaptic GABAARs incorporating the alpha1 subunit. However, the duration of mIPSCs recorded from L2/3 cortical neurons derived from alpha1 subunit deleted mice, were similarly under the developmental influence of a neurosteroid tone. In addition to principal cells, synaptic GABAARs of L2/3 interneurons were modulated by native neurosteroids in a development-dependent manner. In summary, local neurosteroids influence synaptic transmission during a crucial period of cortical neurodevelopment, findings which may be of importance for establishing normal network connectivity. PMID- 26626487 TI - Beneficial effects of Glycyrrhizae radix extract in preventing oxidative damage and extending the lifespan of Caenorhabditis elegans. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Glycyrrhizae radix (GR) is a medicinal herb extensively used in traditional Chinese medicine. This study aimed to evaluate the pharmacological effect of GR and the possible mechanisms of GR, to provide a pharmacological basis in traditional medicine. MATERIALS AND METHODS: In the present study, C. elegans (L1-larvae to young adults) was exposed to 0.12-0.24 g/mL of GR in 12-well sterile tissue culture plates at 20 degrees C in the presence of food. Lethality, growth, lifespan, reproduction, locomotion, metabolism, intestinal autofluorescence, and reactive oxygen species (ROS) production assays were performed to investigate the possible safety profile and beneficial effects of GR in these nematodes. We found that the lifespan of nematodes exposed to 0.18-0.24 g/mL of GR was extended. We then determined the mechanism of the longevity effect of GR using quantitative reverse transcription PCR and oxidative stress resistance assays induced by heat and paraquat. RESULTS: Prolonged exposure to 0.12-0.24 g/mL of GR did not induce lethality, alter body length, morphology or metabolism, affect brood size, locomotion, the development of D-type GABAergic motor neurons, or induce significant induction of intestinal autofluorescence and intestinal ROS production. In C. elegans, pretreatment with GR suppressed the damage due to heat-stress or oxidative stress induced by paraquat, a ROS generator, on lifespan, and inhibited the induction of intestinal ROS production induced by paraquat. Moreover, prolonged exposure to GR extended lifespan, increased locomotion and decreased intestinal ROS production in adult day-12 nematodes. Furthermore, prolonged exposure to GR significantly altered the expression patterns of genes encoding the insulin-like signaling pathway which had a key role in longevity control. Mutation of daf-16 gene encoding the FOXO transcription factor significantly decreased lifespan, suppressed locomotion, and increased intestinal ROS production in GR exposed adult nematodes. CONCLUSIONS: GR is relatively safe and has protective effects against the damage caused by both heat-stress and oxidative stress at the examined concentrations. Furthermore, GR is capable of extending the lifespan of nematodes, and the insulin-like signaling pathway may play a crucial role in regulating the lifespan extending effects of GR. PMID- 26626486 TI - Protein phosphatase role in adenosine A1 receptor-induced AMPA receptor trafficking and rat hippocampal neuronal damage in hypoxia/reperfusion injury. AB - Adenosine signaling via A1 receptor (A1R) and A2A receptor (A2AR) has shown promise in revealing potential targets for neuroprotection in cerebral ischemia. We recently showed a novel mechanism by which A1R activation with N(6) cyclopentyl adenosine (CPA) induced GluA1 and GluA2 AMPA receptor (AMPAR) endocytosis and adenosine-induced persistent synaptic depression (APSD) in rat hippocampus. This study further investigates the mechanism of A1R-mediated AMPAR internalization and hippocampal slice neuronal damage through activation of protein phosphatase 1 (PP1), 2A (PP2A), and 2B (PP2B) using electrophysiological, biochemical and imaging techniques. Following prolonged A1R activation, GluA2 internalization was selectively blocked by PP2A inhibitors (okadaic acid and fostriecin), whereas inhibitors of PP2A, PP1 (tautomycetin), and PP2B (FK506) all prevented GluA1 internalization. Additionally, GluA1 phosphorylation at Ser831 and Ser845 was reduced after prolonged A1R activation in hippocampal slices. PP2A inhibitors nullified A1R-mediated downregulation of pSer845-GluA1, while PP1 and PP2B inhibitors prevented pSer831-GluA1 downregulation. Each protein phosphatase inhibitor also blunted CPA-induced synaptic depression and APSD. We then tested whether A1R-mediated changes in AMPAR trafficking and APSD contribute to hypoxia induced neuronal injury. Hypoxia (20 min) induced A1R-mediated internalization of both AMPAR subunits, and subsequent normoxic reperfusion (45 min) increased GluA1 but persistently reduced GluA2 surface expression. Neuronal damage after hypoxia reperfusion injury was significantly blunted by pre-incubation with the above protein phosphatase inhibitors. Together, these data suggest that A1R-mediated protein phosphatase activation causes persistent synaptic depression by downregulating GluA2-containing AMPARs; this previously undefined role of A1R stimulation in hippocampal neuronal damage represents a novel therapeutic target in cerebral ischemic damage. PMID- 26626488 TI - The phytoecdysteroid beta-ecdysone is genotoxic in Rodent Bone Marrow Micronuclei and Allium cepa L. Assays. AB - ETHNAOPHARMACOLOGIAL RELEVANCE: In South America, the beta-ecdysone ecdysteroid has been found in species of the genus Pfaffia Mart. Due to the similar morphology of its roots to the Panax ginseng C. A. Mey. (Korean ginseng), some species of this genus has been known as Brazilian ginseng and have been used as tonic and aphrodisiac, as well as for the treatment of diabetes and rheumatism. AIM OF THE STUDY: Here we report a cytogenotoxic evaluation of beta-ecdysone (a natural ecdysteroid found in plants) in Rodent Bone Marrow Micronuclei and Allium cepa Assays. MATERIALS AND METHODS: Three beta-ecdysone (pure) concentrations (based in human therapeutic dosage) were used in the Micronucleus Assay. The animals were treated during two consecutive days. Micronucleated cells were counted in 2000 polychromatic erythrocytes per animal. For A. cepa L. Assay, one beta-ecdysone concentration was analyzed. The onions bulbs were exposed for 24h. RESULTS: The Micronucleus Assay showed genotoxic effects for all treatments, expressed by an increase of micronucleated cells. In A. cepa L. Assay, cell abnormalities associated to the malfunction/non-formation of mitotic spindle (aneugenic effect) and chromosomal bridges (clastogenic effect) were observed. CONCLUSIONS: The results indicate a cytogenotoxic activity of beta-ecdysone. Therefore, the popular use of Pfaffia and others species containing beta-ecdysone should be considered with caution. PMID- 26626489 TI - The effect of regadenoson-induced transient disruption of the blood-brain barrier on temozolomide delivery to normal rat brain. AB - The blood-brain barrier (BBB) significantly reduces the delivery of many systemically administered agents to the central nervous system. Although temozolomide is the only chemotherapy to improve survival in patients with glioblastoma, its concentration in brain is only 20 % of that in blood. Regadenoson, an FDA approved adenosine receptor agonist used for cardiac stress testing, transiently disrupts rodent BBB allowing high molecular weight dextran (70 kD) to enter the brain. This study was conducted to determine if regadenoson could facilitate entry of temozolomide into normal rodent brain. Temozolomide (50 mg/kg) was administered by oral gavage to non-tumor bearing F344 rats. Two-thirds of the animals received a single dose of intravenous regadenoson 60-90 min later. All animals were sacrificed 120 or 360 min after temozolomide administration. Brain and plasma temozolomide concentrations were determined using HPLC/MS/MS. Brain temozolomide concentrations were significantly higher at 120 min when it was given with regadenoson versus alone (8.1 +/- 2.7 and 5.1 +/- 3.5 ug/g, P < 0.05). A similar trend was noted in brain:plasma ratios (0.45 +/- 0.08 and 0.29 +/- 0.09, P < 0.05). Brain concentrations and brain:plasma ratios were not significantly different 360 min after temozolomide administration. No differences were seen in plasma temozolomide concentrations with or without regadenoson. These results suggest co-administration of regadenoson with temozolomide results in 60% higher temozolomide levels in normal brain without affecting plasma concentrations. This novel approach to increasing intracranial concentrations of systemically administered agents has potential to improve the efficacy of chemotherapy in neuro-oncologic disorders. PMID- 26626492 TI - Comparison of Thermal Safety Practice Guidelines for Diagnostic Ultrasound Exposures. AB - This article examines the historical evolution of various practice guidelines designed to minimize the possibility of thermal injury during a diagnostic ultrasound examination, including those published by the American Institute of Ultrasound in Medicine, British Medical Ultrasound Society and Health Canada. The guidelines for prenatal/neonatal examinations are in general agreement, but significant differences were found for postnatal exposures. We propose sets of thermal index versus exposure time for these examination categories below which there is reasonable assurance that an examination can be conducted without risk of producing an adverse thermal effect under any scanning conditions. If it is necessary to exceed these guidelines, the occurrence of an adverse thermal event is still unlikely in most situations because of mitigating factors such as transducer movement and perfusion, but the general principle of "as low as reasonably achievable" should be followed. Some limitations of the biological effects studies underpinning the guidelines also are discussed briefly. PMID- 26626491 TI - Preclinical Assessment of the Efficacy of Anti-Angiogenic Therapies in Hepatocellular Carcinoma. AB - Diffuse hepatocellular carcinoma (HCC) is a complex affliction in which comorbidities can bias global outcome of cancer therapy. Better methods are thus warranted to directly assess effects of therapy on tumor angiogenesis and growth. As tumor angiogenesis is invariably associated with changes in local blood flow, we assessed the utility of ultrasound imaging in evaluation of the efficacy of anti-angiogenic therapy in a spontaneous transgenic mouse model of HCC. Blood flow velocities were measured monthly in the celiac trunk before and after administration of sorafenib or bevacizumab at doses corresponding to those currently used in clinical practice. Concordant with clinical experience, sorafenib, but not bevacizumab, reduced microvascular density and suppressed tumor growth relative to controls. Evolution of blood flow velocities correlated with microvascular density and with the evolution of tumor size. Ultrasound imaging thus provides a useful non-invasive tool for preclinical evaluation of new anti-angiogenic therapies for HCC. PMID- 26626490 TI - A pilot study of bevacizumab-based therapy in patients with newly diagnosed high grade gliomas and diffuse intrinsic pontine gliomas. AB - Although bevacizumab has not proven effective in adults with newly diagnosed high grade gliomas (HGG), feasibility in newly diagnosed children with diffuse intrinsic pontine gliomas (DIPG) or HGG has not been reported in a prospective study. In a safety and feasibility study, children and young adults with newly diagnosed HGG received radiotherapy (RT) with bevacizumab (10 mg/kg: days 22, 36) and temozolomide (75-90 mg/m(2)/day for 42 days) followed by bevacizumab (10 mg/kg, days 1, 15), irinotecan (125 mg/m(2), days 1, 15) and temozolomide (150 mg/m(2)/day days 1-5). DIPG patients did not receive temozolomide. Telomerase activity, quality of life (QOL), and functional outcomes were assessed. Among 27 eligible patients (15 DIPG, 12 HGG), median age 10 years (range 3-29 years), 6 discontinued therapy for toxicity: 2 during RT (grade 4 thrombocytopenia, grade 3 hepatotoxicity) and 4 during maintenance therapy (grade 3: thrombosis, hypertension, skin ulceration, and wound dehiscence). Commonest >=grade 3 toxicities included lymphopenia, neutropenia and leukopenia. Grade 3 hypertension occurred in 2 patients. No intracranial hemorrhages occurred. For DIPG patients, median overall survival (OS) was 10.4 months. For HGG patients, 3-year progression free survival and OS were 33 % (SE +/- 14 %) and 50 % (SE +/- 14 %), respectively. All 3 tested tumor samples, demonstrated histone H3.3K27M (n = 2 DIPG) or G34R (n = 1 HGG) mutations. QOL scores improved over the course of therapy. A bevacizumab-based regimen is feasible and tolerable in newly diagnosed children and young adults with HGG and DIPG. PMID- 26626493 TI - Assessing the genetic diversity of rice originating from Bangladesh, Assam and West Bengal. AB - BACKGROUND: Genetic diversity among rice cultivars from Bangladesh and North East India was assessed using a custom 384-SNP microarray assay. A total of 511 cultivars were obtained from several sources, choosing landraces likely to be from the aus subpopulation and modern improved cultivars from Bangladesh. Cultivars from the OryzaSNP set and Rice Diversity Panel 1 (RDP1) were also included for reference. RESULTS: The population analysis program STRUCTURE was used to infer putative population groups in the panel, revealing four groups: indica (76 cultivars), japonica (55) and two distinct groups within the aus subpopulation (aus-1 = 99, aus-2 = 151). Principal Component Analysis was used to confirm the four population groups identified by STRUCTURE. The analysis revealed cultivars that belonged to neither aus-1 nor aus-2 but which are clearly aus based on the combined probabilities of their membership of the two aus groups which have been termed aus-admix (96). Information obtained from the panel of 511 cultivars was used to assign rice groups to 74 additional landraces obtained from Assam and West Bengal. While both the aus-1 and aus-2 groups were represented approximately equally in India, aus-2 (which includes cultivar N 22) was more common in Bangladesh, but was not found at all in West Bengal. CONCLUSIONS: Examining the distribution of landrace names within theaus-1 and aus-2 groups suggests that aus-1 is associated with the term "boro", a word used to describe a winter growing season in Bangladesh and Assam. The information described here has been used to select a population of 300 cultivars for Genome Wide Association studies of the aus rice subpopulation. PMID- 26626494 TI - Stem cell-derived hepatocytes: A novel model for hepatitis E virus replication. AB - BACKGROUND & AIMS: Yearly, approximately 20million people become infected with the hepatitis E virus (HEV) resulting in over 3million cases of acute hepatitis. Although HEV-mediated hepatitis is usually self-limiting, severe cases of fulminant hepatitis as well as chronic infections have been reported, resulting annually in an estimated 60,000 deaths. We studied whether pluripotent stem cell (PSC)-derived hepatocytes, mesodermal and/or neuroprogenitor cells support HEV replication. METHODS: Human PSC were differentiated towards hepatocyte-like cells, mesodermal cells and neuroprogenitors and subsequently infected with HEV. Infection and replication of HEV was analyzed by qRT-PCR, RNA in situ hybridization, negative strand RT-PCR, production of infectious virions and transfection with a transient HEV reporter replicon. RESULTS: PSC-derived hepatocytes supported the complete replication cycle of HEV, as demonstrated by the intracellular presence of positive and negative strand HEV RNA and the production of infectious virions. The replication of the virus in these cells was inhibited by the antiviral drugs ribavirin and interferon-alpha2b. In contrast to PSC-derived hepatocytes, PSC-derived mesodermal cells and neuroprogenitors only supported HEV replication upon transfection with a HEV subgenomic replicon. CONCLUSION: We demonstrate that PSC can be used to study the hepatotropism of HEV infection. The complete replication cycle of HEV can be recapitulated in infected PSC-derived hepatocytes. By contrast other germ layer cells support intracellular replication but are not infectable with HEV. Thus the early steps in the viral cycle are the main determinant governing HEV tissue tropism. PSC-hepatocytes offer a physiological relevant tool to study the biology of HEV infection and replication and may aid in the design of therapeutic strategies. PMID- 26626495 TI - Liver transplant center variability in accepting organ offers and its impact on patient survival. AB - BACKGROUND & AIMS: Despite an allocation system designed to give deceased-donor livers to the sickest patients, many transplantable livers are declined by U.S. transplant centers. It is unknown whether centers vary in their propensities to decline organs for the highest priority patients, and how these decisions directly impact patient outcomes. METHODS: We analyzed Organ Procurement and Transplantation Network (OPTN) data from 5/1/07-6/17/13, and included all adult liver-alone waitlist candidates offered an organ that was ultimately transplanted. We evaluated acceptance rates of liver offers for the highest ranked patients and their subsequent waitlist mortality. RESULTS: Of the 23,740 unique organ offers, 8882 (37.4%) were accepted for the first-ranked patient. Despite adjusting for organ quality and recipient severity of illness, transplant centers within and across geographic regions varied strikingly (p<0.001) in the percentage of organ offers they accepted for the highest priority patients. Among all patients ranked first on waitlists, the adjusted center-specific organ acceptance rates ranged from 15.7% to 58.1%. In multivariable models, there was a 27% increased odds of waitlist mortality for every 5% absolute decrease in a center's adjusted organ offer acceptance rate (adjusted OR: 1.27, 95% CI: 1.20 1.32). However, the absolute difference in median 5-year adjusted graft survival was 4% between livers accepted for the first-ranked patient, compared to those declined and transplanted at a lower position. CONCLUSION: There is marked variability in center practices regarding accepting livers allocated to the highest priority patients. Center-level decisions to decline organs substantially increased patients' odds of dying on the waitlist without a transplant. PMID- 26626496 TI - Effects of glucagon-like peptide-1 on glucagon secretion in patients with non alcoholic fatty liver disease. AB - BACKGROUND & AIMS: We evaluated the glucagon-suppressive effect of glucagon-like peptide-1 (GLP-1) and its potential effects on endogenous glucose production and whole body lipolysis in non-diabetic patients with non-alcoholic fatty liver disease (NAFLD). METHODS: On two separate days, 10 non-diabetic patients with liver biopsy-verified NAFLD (NAFLD activity score 2.5+/-1.0) and 10 matched controls underwent 2h intravenous infusions of GLP-1 (0.8 pmol*kg(-1)*min(-1)) and placebo. Since GLP-1-mediated glucagon suppression has been shown to be glucose-dependent, plasma glucose was clamped at fasting level during the first hour, and then raised and clamped at 'postprandial level' (fasting plasma glucose level plus 3 mmol/L) for the remaining hour. We evaluated relative plasma levels of glucagon, endogenous glucose production and whole body lipolysis rates with stable isotopes and respiratory quotient using indirect calorimetry. RESULTS: Compared to controls, patients with NAFLD were insulin resistant (homeostasis model assessment (HOMA(IR)): 3.8+/-2.2 vs. 1.6+/-1.5, p=0.003) and had fasting hyperglucagonaemia (7.5+/-5.3 vs. 5.8+/-1.5 mmol/L, p=0.045). Similar relative glucagon suppression was seen in both groups during GLP-1 infusion at fasting ( 97+/-75 vs. -93+/-41 pmol/L*min(-1)p=0.566) and 'postprandial' plasma glucose levels (-108+/-101 vs. -97+/-53 pmol/L*min(-1), p=0.196). Increased insulinotropic effect of GLP-1 was observed in NAFLD patients. No effect of GLP-1 on endogenous glucose production was observed in any of the groups. CONCLUSIONS: Patients with NAFLD exhibited fasting hyperglucagonaemia, but intact GLP-1 mediated glucagon suppression independently of plasma glucose concentrations. Preserved glucagonostatic effect and increased insulinotropic effects of GLP-1 in NAFLD may be important to maintain normo-glycaemia in these patients. PMID- 26626497 TI - Evaluation of APRI and FIB-4 scoring systems for non-invasive assessment of hepatic fibrosis in chronic hepatitis B patients. AB - BACKGROUND & AIMS: While the gold standard in the assessment of liver fibrosis remains liver biopsy, non-invasive methods have been increasingly used for chronic hepatitis B (CHB). This study aimed to evaluate the performance of two commonly used non-invasive scoring systems (aspartate aminotransferase-to platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4)) to predict fibrosis stage in CHB patients. METHODS: Demographic, histologic and clinical laboratory data from two trials investigating tenofovir disoproxil fumarate in CHB were analyzed. Predicted fibrosis stage, based on established scales and cut-off values for APRI and FIB-4 scores, was compared with Ishak scores obtained from liver biopsy at baseline and at 240 week follow-up. RESULTS: In the 575 patients with a baseline liver biopsy, APRI and FIB-4 scores correlated with Ishak stage (p<0.01); however extensive overlap in the distribution of both scores across Ishak stages prevented accurate determination of fibrosis. The majority (81-89%) of patients with advanced fibrosis or cirrhosis were missed by the scores. Similarly, 71% patients without fibrosis were misclassified as having clinically significant fibrosis. APRI and FIB-4 scores at week 240 tended to be low and underestimate fibrosis stage in the patients with liver biopsies after 240 weeks of therapy. APRI or FIB-4 reduction did not correlate with fibrosis regression after 240 weeks of antiviral therapy. CONCLUSIONS: APRI and FIB-4 scores are not suitable for use in clinical practice in CHB patients for assessment of hepatic fibrosis according to Ishak stage, especially in gauging improvements in liver fibrosis following therapy. PMID- 26626499 TI - Axillary Silicone Granulomas in Patients With Melanoma. AB - Subcutaneous lesions may be detected during follow-up of patients with melanoma. The main entities that should be contemplated in the differential diagnosis in such cases are in-transit and regional lymph node metastases. We describe 2 cases of women with breast implants who developed palpable subcutaneous lesions in the axillary region during follow-up of melanoma. In both cases, the ultrasound study showed diffuse hyperechoic signals forming the characteristic snowstorm sign in the subcutaneous tissue. Ultrasound proved to be a key diagnostic tool for ruling out melanoma-related disease, such as in-transit metastases and regional lymph node metastases. PMID- 26626498 TI - Refining the phenotype associated with CASC5 mutation. AB - Autosomal recessive primary microcephaly is a neurodevelopmental disorder characterized by congenitally reduced head circumference by at least two standard deviations (SD) below the mean for age and gender. It is associated with nonprogressive mental retardation of variable degree, minimal neurological deficit with no evidence of architectural anomalies of the brain. So far, 12 genetic loci (MCPH1-12) and corresponding genes have been identified. Most of these encode centrosomal proteins. CASC5 is one the most recently unravelled genes responsible for MCPH with mutations reported in three consanguineous families of Moroccan origin, all of whom harboured the same CASC5 homozygous mutation (c.6125G>A; p.Met2041Ile). Here, we report the identification, by whole exome sequencing, of the same missense mutation in a consanguineous Algerian family. All patients exhibited a similar clinical phenotype, including congenital microcephaly with head circumferences ranging from -3 to -4 standard deviations (SD) after age 5 years, moderate to severe cognitive impairment, short stature (adult height -3 SD), dysmorphic features included a sloping forehead, thick eyebrows, synophris and a low columella. Severe vermis hypoplasia and a large cyst of the posterior fossa were observed in one patient. Close microsatellite markers showed identical alleles in the Algerian the previously and Moroccan patients. This study confirms the involvement of CASC5 in autosomal recessive microcephaly and supports the hypothesis of a founder effect of the c.6125G>A mutation. In addition, this report refines the phenotype of this newly recognized form of primary microcephaly. PMID- 26626500 TI - Review of Cutaneous Graft-vs-Host Disease. AB - Graft-vs-host disease (GVHD) is a multisystem disease that arises as a complication of allogeneic hematopoietic stem cell transplant. It is due to recognition of the recipient's tissues by immune cells from the donor. The skin and mucous membranes are the organs most commonly affected. GVHD is classified as acute or chronic depending on the pathophysiology and clinical presentation. Acute GVHD typically presents with the triad of rash, diarrhea, and hyperbilirubinemia, and treatment is based on systemic corticosteroid and immunosuppressant therapy. The cutaneous manifestations of chronic GVHD are divided into sclerodermiform and nonsclerodermiform, and the mucous membranes and skin appendages may also be affected. The diagnosis is mainly clinical, but skin biopsy can help in doubtful cases. Treatment can be topical, systemic, or physical, depending on the size, site, and depth of the lesions and the involvement of other organs. PMID- 26626501 TI - A Case Series of 4 Patients With Peristomal Pyoderma Gangrenosum: Review of Risk Factors and Treatment Response. AB - The literature on peristomal pyoderma gangrenosum (PPD) is scarce, and studies to date have included few patients. It is therefore difficult to determine the incidence of PPD, investigate risk factors, or evaluate the effectiveness of the different treatments available. We report on a series of 4 patients diagnosed with PPD at our hospital in 2013 and 2014, and review the clinical characteristics and responses to treatment. Three of the patients had inflammatory bowel disease and 1 had rectal cancer. Three patients responded favorably to initial treatment with 0.1% tacrolimus ointment (administered as monotherapy in 2 cases and combined with immunosuppressants in the other). However, on withdrawal of tacrolimus, the disease recurred in all 3 patients, requiring treatment reintroduction or modification. PMID- 26626503 TI - GEMMs addressing Pax5 loss-of-function in childhood pB-ALL. AB - Germline mutations in transcription factors, which are implicated in hematopoiesis in general or specifically in B-cell differentiation have recently been described to confer an inherited risk to pB-ALL with often reduced penetrance. Predicting leukemia development, therapy response and long term follow up of mutation carriers is challenging because experience from large patient cohorts and their long term follow up are not available. Genetically Engineered Murine Models (GEMMs) represent a promising approach to create individualized and precise models reproducing the molecular makeup of the human disease. This review focuses on PAX5 loss-of-function and summarizes techniques of murine model generation, available GEMMs, which mimic Pax5 loss-of-function in leukemia development and discusses the challenges and drawbacks of these models. These aspects are discussed in the context of creating a robust model, which serves not only for validation of the relevance of a genomic alteration in pB-ALL but at the same time as a valid preclinical model. PMID- 26626504 TI - Physiological and biochemical variables in captive tigers (Panthera tigris) immobilised with dexmedetomidine and ketamine or dexmedetomidine, midazolam and ketamine. AB - Physiological and biochemical variables in captive tigers (Panthera tigris) immobilised with dexmedetomidine and ketamine or dexmedetomidine, midazolam and ketamine were evaluated. Thirty tigers received either dexmedetomidine (0.025 mg/kg) and ketamine (3 mg/kg) (group DK) or dexmedetomidine (0.0125 mg/kg), midazolam (0.1 mg/kg) and ketamine (3 mg/kg) (group DMK). Heart rate, SPO2 and blood pressure were measured at five-minute intervals. Arterial pH, PO2, PCO2, glucose, K+ and arterial and venous lactate were measured at 15 and 45 minutes after immobilisation. A generalised linear mixed model was used for statistical comparison. There was no difference within or between groups at any time point for any measured variable. Measured PO2 was 73.2+/-17.5 mm Hg and SPO2 was 88.9+/ 10.8 per cent. Systolic, mean and diastolic blood pressures were 170.5+/-48.4, 138.9+/-41.8 and 121.8+/-37.2 mm Hg, respectively. Venous lactate was higher than arterial lactate within groups at each time point. Seizure-like behaviour was observed in 25 per cent of tigers in group DK but not in group DMK. The addition of midazolam into a protocol for immobilisation of tigers did not result in a difference in any of the measured variables but may have prevented the development of seizure-like behaviour. PMID- 26626505 TI - Urinary excretion of calcium and phosphate in dogs with pituitary-dependent hypercortisolism: case control study in 499 dogs. AB - Pituitary-dependent hypercortisolism (PDH) in dogs is frequently associated with high serum phosphate and parathormone concentrations which are in turn associated with prognosis and clinical presentation. The pathogenesis of such abnormalities remains unknown. The aim of the present study was to evaluate the serum and urinary concentrations and the urinary fractional excretion of phosphate and calcium in dogs with PDH. Medical records of newly diagnosed PDH dogs before treatment from one referral centre were retrospectively evaluated. One clinically normal and one sick dog for each dog with PDH were included as controls. One hundred and sixty-seven dogs with PDH were included. The serum phosphate concentration in PDH dogs was significantly (P<0.0001) higher compared with clinically normal control dogs (CNDs) and sick control dogs (SCDs). The serum calcium concentration in PDH dogs was significantly higher compared with SCDs but not different compared with CNDs. Urinary fractional excretion of phosphate in PDH dogs was significantly lower compared with CNDs and SCDs. Urinary fractional excretion of calcium in PDH dogs was significantly higher compared with CNDs and SCDs. In conclusion, PDH dogs have lower phosphaturia and higher calciuria compared with control dogs. These findings suggest that, at least in part, high serum phosphate concentrations are related to the renal retention of phosphate. PMID- 26626507 TI - Analyses of the Molecular Mechanisms Associated with Silk Production in Silkworm by iTRAQ-Based Proteomics and RNA-Sequencing-Based Transcriptomics. AB - Silkworm is used as a model organism to analyze two standard complex traits, which are high and low silk yields. To understand the molecular mechanisms of silk production, the posterior silk glands aged to the third day of the fifth instar were analyzed from the ZB strain with low silk production and from the control strain Lan10. Using isobaric tags for relative and absolute quantification (iTRAQ) quantitative shotgun proteomics and RNA-sequencing-based transcriptomics, 139 proteins and 630 transcripts were identified as novel in the ZB strain compared with the Lan10 strain, indicating that these results significantly expand the coverage of proteins and transcripts of the posterior silk glands in the silkworm. Of the 89 differently changed proteins, 23 were increased, and 66 were decreased. Of the 788 transcripts, 779 were upregulated, and 9 were downregulated. These results confirm that decreased energy utilization/protein translation and enhanced protein degradation are the key factors in lower silk production. Moreover, this study provides novel insight into the molecular changes that may result in lower silk production, namely, a combination of impaired transcription activity, missed protein folding/transport, and lowered yields of the main components of fibroin, along with weakened growth/development of the posterior silk gland. PMID- 26626508 TI - A Novel Hamiltonian Replica Exchange MD Protocol to Enhance Protein Conformational Space Sampling. AB - Limited searching in the conformational space is one of the major obstacles for investigating protein dynamics by numerical approaches. For this reason, classical all-atom molecular dynamics (MD) simulations of proteins tend to be confined to local energy minima, particularly when the bulk solvent is treated explicitly. To overcome this problem, we have developed a novel replica exchange protocol that uses modified force-field parameters to treat interparticle nonbonded potentials within the protein and between protein and solvent atoms, leaving unperturbed those relative to solvent-solvent interactions. We have tested the new protocol on the 18-residue-long tip of the P domain of calreticulin in an explicit solvent. With only eight replicas, we have been able to considerably enhance the conformational space sampled during a 100 ns simulation, compared to as many parallel classical molecular dynamics simulations of the same length or to a single one lasting 450 ns. A direct comparison between the various simulations has been possible thanks to the implementation of the weighted histogram analysis method, by which conformations simulated with modified force-field parameters can be assigned different weights. Interatom, inter-residue distances in the structural ensembles obtained with our novel replica exchange approach and by classical MD simulations compare equally well with those derived from NMR data. Rare events, such as unfolding and refolding, occur with reasonable statistical frequency. Visiting of conformations characterized by very small Boltzmann weights is also possible. Despite their low probability, such regions of the conformational space may play an important role in the search for local potential-energy minima and in dynamically controlled functions. PMID- 26626509 TI - Detailed Balance in Ehrenfest Mixed Quantum-Classical Dynamics. AB - We examine the equilibrium limits of self-consistent field (Ehrenfest) mixed quantum-classical dynamics. We derive an analytical expression for the equilibrium mean energy of a multistate quantum oscillator coupled to a classical bath. We show that, at long times, for an ergodic system, the mean energy of the quantum subsystem always exceeds the temperature of the classical bath that drives it. Furthermore, the energy becomes larger as the number of states increases and diverges as the number of quantum levels approaches infinity. We verify these results by simulations. PMID- 26626506 TI - Supra-molecular assembly of a lumican-derived peptide amphiphile enhances its collagen-stimulating activity. AB - C16-YEALRVANEVTLN, a peptide amphiphile (PA) incorporating a biologically active amino acid sequence found in lumican, has been examined for its influence upon collagen synthesis by human corneal fibroblasts in vitro, and the roles of supra molecular assembly and activin receptor-like kinase ALK receptor signaling in this effect were assessed. Cell viability was monitored using the Alamar blue assay, and collagen synthesis was assessed using Sirius red. The role of ALK signaling was studied by receptor inhibition. Cultured human corneal fibroblasts synthesized significantly greater amounts of collagen in the presence of the PA over both 7-day and 21-day periods. The aggregation of the PA to form nanotapes resulted in a notable enhancement in this activity, with an approximately two fold increase in collagen production per cell. This increase was reduced by the addition of an ALK inhibitor. The data presented reveal a stimulatory effect upon collagen synthesis by the primary cells of the corneal stroma, and demonstrate a direct influence of supra-molecular assembly of the PA upon the cellular response observed. The effects of PA upon fibroblasts were dependent upon ALK receptor function. These findings elucidate the role of self-assembled nanostructures in the biological activity of peptide amphiphiles, and support the potential use of a self-assembling lumican derived PA as a novel biomaterial, intended to promote collagen deposition for wound repair and tissue engineering purposes. PMID- 26626510 TI - Path Integral Simulations of Proton Transfer Reactions in Aqueous Solution Using Combined QM/MM Potentials. AB - A bisection sampling method was implemented in path integral simulations of chemical reactions in solution in the framework of the quantized classical path approach. In the present study, we employ a combined quantum mechanical and molecular mechanical (QM/MM) potential to describe the potential energy surface and the path integral method to incorporate nuclear quantum effects. We examine the convergence of the bisection method for two proton-transfer reactions in aqueous solution at room temperature. The first reaction involves the symmetrical proton transfer between an ammonium ion and an ammonia molecule. The second reaction is the ionization of nitroethane by an acetate ion. To account for nuclear quantum mechanical corrections, it is sufficient to quantize the transferring light atom in the ammonium ion-ammonia reaction, while it is necessary to also quantize the donor and acceptor atoms in the nitroethane acetate ion reaction. Kinetic isotope effects have been computed for isotopic substitution of the transferring proton by a deuteron in the nitroethane-acetate reaction. In all computations, it is important to employ a sufficient number of polymer beads along with a large number of configurations to achieve convergence in these simulations. PMID- 26626511 TI - Influence of Long-Range Electrostatic Treatments on the Folding of the N-Terminal H4 Histone Tail Peptide. AB - A series of ca. 20-ns molecular dynamics simulation runs of the N-terminal H4 histone tail in its un- and tetraacetylated forms were performed using three different long-range electrostatic treatments namely, spherical-cutoff, reaction field, and particle mesh Ewald. Comparison of the dynamical properties of the peptide reveals that internal flexibility and sampling of the conformational space are heavily dependent on the chosen method. Among the three tested methods, the particle mesh Ewald treatment yields the least conformational variation and a structural stabilization tendency around the initially defined topological framework. PMID- 26626512 TI - Essential Dynamics: A Tool for Efficient Trajectory Compression and Management. AB - We present a simple method for compression and management of very large molecular dynamics trajectories. The approach is based on the projection of the Cartesian snapshots collected along the trajectory into an orthogonal space defined by the eigenvectors obtained by diagonalization of the covariance matrix. The transformation is mathematically exact when the number of eigenvectors equals 3N 6 (N being the number of atoms), and in practice very accurate even when the number of eigenvectors is much smaller, permitting a dramatic reduction in the size of trajectory files. In addition, we have examined the ability of the method, when combined with interpolation, to recover dense samplings (snapshots collected at a high frequency) from more sparse (lower frequency) data as a method for further data compression. Finally, we have investigated the possibility of using the approach when extrapolating the behavior of the system to times longer than the original simulation period. Overall our results suggest that the method is an attractive alternative to current approaches for including dynamic information in static structure files such as those deposited in the Protein Data Bank. PMID- 26626513 TI - Sensitivity Analysis and Charge-Optimization for Flexible Ligands: Applicability to Lead Optimization. AB - Sensitivity analysis and charge-optimization have been suggested as methods to guide the optimization of lead compounds in early-stage drug discovery. However, applications to date have been restricted by the simplifying assumption of a rigid ligand. The present study applies both formalisms to the case of a flexible ligand in a model application to an HIV-protease inhibitor. The results suggest that sensitivity analysis is a fast and robust method for guiding charge changes in both a rigid and a flexible ligand, although its accuracy is limited by the fact that it represents a linear approximation. The more complete quadratic analysis provided by charge-optimization produces unexpected results when the ligand is considered to be flexible. For example, it can yield atomic charges which powerfully stabilize the bound conformation of the ligand relative to the conformation assumed for the free state, thus markedly destabilizing the assumed free conformation. Such results are traceable to the fact that the energy matrix possesses negative eigenvalues. However, optimizing charges under the assumption that the ligand does not change conformation upon binding leads to a set of charges that robustly improve affinity, even when the free conformation is later allowed to vary. Thus, both sensitivity analysis and charge-optimization appear to be useful techniques. PMID- 26626514 TI - An Atoms in Molecules Study of the Halogen Resonance Effect. AB - We report a detailed study by means of the theory of atoms in molecules (AIM) of the resonance effect exhibited in systems where a halogen is adjacent to a carbon carbon double bond. Moreover, we have carried out a comparable study of the respective saturated halohydrocarbons and hydrocarbons, as well as the related unsaturated hydrocarbons. The valence shell charge concentration (VSCC) of the atoms in systems that exhibit the halogen resonance effect is considerably different from that of the systems where only the electron withdrawing inductive effect is present. Our analysis of the bonded maximum charge concentration and the electronic properties at the bond critical points clearly indicate that the carbon-carbon double bond is strongly distorted as a result of the halogen resonance effect. Population analyses show that the halogen resonance effect is a donor effect, but the opposing electron-withdrawing inductive effect is stronger. Moreover, the analysis in terms of link points of the VSCCs of the carbons accounts for the observed position-dependence of electrophilic aromatic substitution in alpha- and beta-halonaphthalenes. PMID- 26626515 TI - Proton Affinities of Anionic Bases: Trends Across the Periodic Table, Structural Effects, and DFT Validation. AB - We have carried out an extensive exploration of the gas-phase basicity of archetypal anionic bases across the periodic system using the generalized gradient approximation of density functional theory (DFT) at BP86/QZ4P//BP86/TZ2P. First, we validate DFT as a reliable tool for computing proton affinities and related thermochemical quantities: BP86/QZ4P//BP86/TZ2P is shown to yield a mean absolute deviation of 1.6 kcal/mol for the proton affinity at 0 K with respect to high-level ab initio benchmark data. The main purpose of this work is to provide the proton affinities (and corresponding entropies) at 298 K of the anionic conjugate bases of all main-group-element hydrides of groups 14-17 and periods 2-6. We have also studied the effect of stepwise methylation of the protophilic center of the second- and third-period bases. PMID- 26626516 TI - Quantum Mechanical Calculations for Benzene Dimer Energies: Present Problems and Future Challenges. AB - Factors influencing quantum mechanical calculations of nonbonded interactions between organic molecules are still imperfectly understood. Much effort has gone into efforts to calculate the structures and binding energies of stable benzene dimers. However, little experimental evidence is available for comparison with theoretical results. As a benchmark for assessing the reliability and accuracy of such calculations, the benzene crystal structure seems a more suitable target than the elusive dimer structures. PMID- 26626517 TI - Electronic Excitations of the Chromophore from the Fluorescent Protein asFP595 in Solutions. AB - We present the results of modeling spectral properties of the chromophore, 2 acetyl-4-(p-hydroxybenzylidene)-1-methyl-5-imidazolone (AHBMI), from the newly discovered fluorescent protein asFP595 in different solvents and compare computational and recent experimental data. The time-dependent density functional theory (TDDFT) method is used to estimate positions of spectral bands with large oscillator strengths for vertical transitions to excited states following geometry optimizations of chromophore coordinates in vacuo and in solutions. The performance of different TDDFT functionals in computing excitations for a simpler chromophore from the green fluorescent protein was tested at the preliminary stage. Properties of various protonation states (neutral, anionic, zwitterionic) for the cis and trans conformations of AHBMI are compared. By using the polarizable continuum model, the following solvents have been considered for AHBMI: water, ethanol, acetonitrile, and dimethyl sulfoxide. It is shown that the bands found experimentally in aqueous solution refer to the cis neutral and cis anionic (or trans zwitterionic) conformations. The computed band positions deviate from experimental ones in water by no more than 35 nm (0.23 eV). In accord with experimental studies, the band shifts in different solvents do not show correlation with the dielectric constant or dipole moment; however, the computed values of the shifts are much smaller than those measured experimentally for the ionic species. PMID- 26626518 TI - A Fast Implementation of Perfect Pairing and Imperfect Pairing Using the Resolution of the Identity Approximation. AB - We present an efficient implementation of the perfect pairing and imperfect pairing coupled-cluster methods, as well as their nuclear gradients, using the resolution of the identity approximation to calculate two-electron integrals. The perfect pairing and imperfect pairing equations may be solved rapidly, making integral evaluation the bottleneck step. The method's efficiency is demonstrated for a series of linear alkanes, for which we show significant speed-ups (of approximately a factor of 10) with negligible error. We also apply the imperfect pairing method to a model of a recently synthesized stable singlet biradicaloid based on a planar Ge-N-Ge-N ring, confirming its biradical character, which appears to be remarkably high. PMID- 26626519 TI - Evaluation of Two-Center, Two-Electron Integrals. AB - We present a new analytic treatment of two-electron integrals over two-center integrals including correlation (interelectronic distance) explicitly in the wave function. All the integrals needed for the evaluation of the matrix elements of any diatomic two-electron molecule are obtained as analytic recursion expressions. As an application of this method in molecular physics, we calculate the value of the ground-state energy and equilibrium internuclear distance of the hydrogen molecule in the Born-Oppenheimer approximation. PMID- 26626520 TI - The omega, phi, and psi Space of N-Hydroxy-N-methylacetamide and N-Acetyl-N ' hydroxy-N '-methylamide of Alanine and Their Boron Isosteres. AB - The conformational space of N-hydroxy-N-methylacetamide [CH3-CO-N(OH)CH3, NMAOH] and its boron isostere [CH3-CO-B(OH)CH3, BMAOH] has been studied by quantum chemical methods. The potential energy surface of NMAOH and BMAOH has been built at the HF, B3LYP, and MP2 levels of theory with the 6-31+G* basis set. The minima and transition states for rotations about various torsional angles have been located, and the energy barriers have been estimated. The global minimum energy structure of both peptides exhibits an intramolecular hydrogen bond between the carbonyl oxygen and the hydroxyl group, imparting a conformational rigidity to the peptides. The omega rotation barrier is lower in the boron isostere than in NMAOH. The difference in the rotation barrier has been attributed to second-order orbital interactions, like negative hyperconjugation, as revealed by NBO calculations. In contrast, the rotation barrier around the torsion angle tau (torsion governing rotation about the N-O and B-O bonds) is relatively higher in the boron analogue. This difference is due to the double bond character in the B O bond as opposed to the N-O bond which has the character of a single bond. As an extension, N-acetyl-N'-hydroxy-N'-methylamide of alanine (Ala-NOH) and its boron isostere (Ala-BOH) have been adopted as model peptides to study the conformational preferences about the phi and psi torsion angles. The study reveals a strong preference for a Type I beta turn as well as inclinations for a left-handed alpha helix, for positive phi torsions, and for extended psi conformations for Ala-NOH; Ala-BOH, on the other hand, shows a leaning toward positive phi and extended psi, with no preference for any regular secondary structure motifs. The replacement of nitrogen by boron changes the electronic and conformational properties of the peptide, extending greater flexibility around the omega angle, a strong preference for positive phi values, and a shift in the site of nucleophilic attack from the carbonyl group to boron. PMID- 26626521 TI - Oxidative Addition of the Chloromethane C-Cl Bond to Pd, an ab Initio Benchmark and DFT Validation Study. AB - We have computed a state-of-the-art benchmark potential energy surface (PES) for the archetypal oxidative addition of the chloromethane C-Cl bond to the palladium atom and have used this to evaluate the performance of 26 popular density functionals, covering LDA, GGA, meta-GGA, and hybrid density functionals, for describing this reaction. The ab initio benchmark is obtained by exploring the PES using a hierarchical series of ab initio methods [HF, MP2, CCSD, and CCSD(T)] in combination with a hierarchical series of seven Gaussian-type basis sets, up to g polarization. Relativistic effects are taken into account through a full four-component all-electron approach. Our best estimate of kinetic and thermodynamic parameters is -11.2 (-10.8) kcal/mol for the formation of the most stable reactant complex, 3.8 (2.7) kcal/mol for the activation energy of direct oxidative insertion (OxIn), and -28.0 (-28.8) kcal/mol for the reaction energy (all energies relative to separate reactants, zero-point vibra-tional energy corrected values in parentheses). Our work highlights the importance of sufficient higher angular momentum polarization functions for correctly describing metal-d-electron correlation. The best overall agreement with our ab initio benchmark is obtained by functionals from all three categories, GGA, meta GGA, and hybrid DFT, with mean absolute errors of 0.8-3.0 kcal/mol and errors in activation energies for OxIn ranging from 0.0 to 1.2 kcal/mol. For example, three well-known functionals, BLYP, OLYP, and B3LYP, compare very reasonably with, respectively, an underestimation of the barrier for OxIn of -4.2 kcal/mol and overestimations of 4.2 and 1.6 kcal/mol. Interestingly, all important features of the CCSD(T) benchmark potential energy surfaces for the Pd-induced activation of C-H, C-C, C-F, and C-Cl bonds are reproduced correctly within a few kcal/mol by BLYP, OLYP, and B3LYP, while at the same time, none of these functionals is the "best one" in each individual case. This follows from an overall comparison of the results of the present as well as previous studies. PMID- 26626522 TI - Theoretical Study of the Structure and Properties of [(eta(5) C5Me4H)2Zr]2(MU(2),eta(2),eta(2)-N2). AB - Recently Pool et al. [Pool, J. A.; Lobkovsky, E.; Chirik, P. J. Nature 2004, 427, 527.] showed that the [(eta(5)-Cp')2Zr]2(MU(2),eta(2),eta(2)-N2), Cp' = eta(5) C5Me4H, complex is promising for dinitrogen hydrogenation. In the present study we examine computationally the structure and relative energies of different possible positional isomers of this dimer complex as well as different isomers of the monomer complex (Cp'2Zr)(eta(2)-N2). The relative stability of isomers of the monomer is determined by the electrostatic repulsion between the negatively charged N atoms of the N2 molecule and the negatively charged C atoms of the Cp' ring that are bound to H. Substitution of H atoms by methyl groups significantly changes the charge distribution in Cp rings, increases the negative charge of CH atom, and affects the relative stability of the isomers. On the other hand, competition between the electrostatic effects and the steric repulsion determines the relative energy of the positional isomers of the dimer (Cp'2Zr)2(MU(2),eta(2),eta(2)-N2). PMID- 26626523 TI - Conformational Studies of Polyprolines. AB - Proline rich peptide sequences are very important recognition elements that have a significant bias toward the all-trans-polyproline type II (PII) conformation. Our gas-phase quantum mechanics calculations at the B3LYP/6-31G* level of theory are in good agreement with previous experimental and theoretical studies. They show that all-trans-proline conformations are energetically more favorable than all-cis-polyprolines (PI, polyproline type I). Estimates of the solvent effects show that the condensed phase can make the PI form more populated in the correct environment. Our survey of proline oligomers in the Protein Data Bank confirmed that the predominant conformations from our calculations are seen experimentally. More importantly, we propose two new secondary structures for polyprolines, namely polyproline type III and type IV (PIII and PIV). PIII is a right-handed, "square helix" from trans-proline oligomers. PIV is a beta-sheet form of cis prolines. As suggested by its calculated IR spectra, the PIII form shares characteristics of both the PI and PII forms: it has trans-amide rotamers similar to PII and forms a right-handed helix like PI. We propose that the high energy PIII form could exist as a conformational intermediate between PI and PII. These new forms also show that the handedness of polyproline helices depends not only on the peptide rotamers (cis or trans) but also on the values of the psi torsions. Changing the psi torsion from approximately 140 degrees to approximately -30 degrees causes the trans oligomers to flip from a typical left handed PII to a right-handed helix. Likewise, as the psi torsion of the cis proline oligomers changes from roughly 165 degrees to -30 degrees , the conformation changes from a characteristic right-handed PI to a beta-sheet. PMID- 26626524 TI - Quantum-Chemical Design of Cryptand-like Ditopic Salt Binders. AB - Hartree-Fock, density functional, and MP2 methods are applied to the problem of designing neutral, bicyclic C3-symmetric cages incorporating interacting anion- and cation-binding sites which strongly bind NaCl as an ion contact pair. A large number of trial ligands L and their complexes L:NaCl are tested, with the focus on maximizing binding by (i) optimizing the cavity size and shape and (ii) varying the nature of the anion- and cation-binding functionalities. The corresponding complexes L:Cl(-) and L:Na(+) are also studied in some detail. An analysis of their structures and charge distributions helps to build a consistent picture of the requirements for a successful NaCl binding. The 'best' candidate ligand utilizes a tripodal triether-substituted amine N(CH2CH2OR-)3 to bind the sodium cation; three thiourea groups in a tripodal arrangement with a 1,3,5 trisubstituted benzyl spacer group {C6H3(CH2NHC [Formula: see text] XNH-)3 X=O,S} to bind chloride; and a -CH2CH2- spacer linking the two binding sites. A simple Quantitative Structure-Property analysis suggests that the binding cavity shape and size is near to the optimal one for this system. PMID- 26626525 TI - Design of Density Functionals by Combining the Method of Constraint Satisfaction with Parametrization for Thermochemistry, Thermochemical Kinetics, and Noncovalent Interactions. AB - We present a new hybrid meta exchange-correlation functional, called M05-2X, for thermochemistry, thermochemical kinetics, and noncovalent interactions. We also provide a full discussion of the new M05 functional, previously presented in a short communication. The M05 functional was parametrized including both metals and nonmetals, whereas M05-2X is a high-nonlocality functional with double the amount of nonlocal exchange (2X) that is parametrized only for nonmetals. In particular, M05 was parametrized against 35 data values, and M05-2X is parametrized against 34 data values. Both functionals, along with 28 other functionals, have been comparatively assessed against 234 data values: the MGAE109/3 main-group atomization energy database, the IP13/3 ionization potential database, the EA13/3 electron affinity database, the HTBH38/4 database of barrier height for hydrogen-transfer reactions, five noncovalent databases, two databases involving metal-metal and metal-ligand bond energies, a dipole moment database, a database of four alkyl bond dissociation energies of alkanes and ethers, and three total energies of one-electron systems. We also tested the new functionals and 12 others for eight hydrogen-bonding and stacking interaction energies in nucleobase pairs, and we tested M05 and M05-2X and 19 other functionals for the geometry, dipole moment, and binding energy of HCN-BF3, which has recently been shown to be a very difficult case for density functional theory. We tested eight functionals for four more alkyl bond dissociation energies, and we tested 12 functionals for several additional bond energies with varying amounts of multireference character. On the basis of all the results for 256 data values in 18 databases in the present study, we recommend M05-2X, M05, PW6B95, PWB6K, and MPWB1K for general-purpose applications in thermochemistry, kinetics, and noncovalent interactions involving nonmetals and we recommend M05 for studies involving both metallic and nonmetallic elements. The M05 functional, essentially uniquely among the functionals with broad applicability to chemistry, also performs well not only for main-group thermochemistry and radical reaction barrier heights but also for transition-metal-transition-metal interactions. The M05-2X functional has the best performance for thermochemical kinetics, noncovalent interactions (especially weak interaction, hydrogen bonding, pi...pi stacking, and interactions energies of nucleobases), and alkyl bond dissociation energies and the best composite results for energetics, excluding metals. PMID- 26626526 TI - Semiempirical Comparative Binding Energy Analysis (SE-COMBINE) of a Series of Trypsin Inhibitors. AB - A scheme to decompose the intermolecular interaction energy of a series of complexes at the semiempirical (SE) level has been developed and validated. The comparative binding energy analysis (COMBINE) (Ortiz, A. R.; Pisabarro, M. T.; Gago, F.; Wade, R. C. J. Med. Chem. 1995, 38, 2681-2691) and the semiempirical quantum mechanical method pairwise energy decomposition (PWD) (Raha, K.; van der Vaart, A. J.; Riley, K. E.; Peters, M. B.; Westerhoff, L. M. Kim, H.; Merz, K. M., Jr. J. Am. Chem. Soc. 2005, 127, 6583-6594) were coupled together to form SE COMBINE. This approach calculates the residue pairwise electrostatic interaction energies, and QSAR models were built with the energies as descriptors using partial least squares (PLS). The application of SE-COMBINE was used as an investigation of the intermolecular interactions between 88 benzamidine inhibitors and trypsin and to test the ability of this new method to predict binding free energies. The predictive capability of SE-COMBINE is shown to be comparable to those of other QSAR methods, and using graphical intermolecular interaction maps (IMMs) enhances the interpretability of receptor-based QSARs. PMID- 26626527 TI - Density-Fitting Method in Symmetry-Adapted Perturbation Theory Based on Kohn-Sham Description of Monomers. AB - We present a new implementation of symmetry-adapted perturbation theory of intermolecular interactions based on Kohn-Sham description of monomers. With density-fitting of molecular integrals, the scaling of the computational cost of the method is reduced from the sixth to the fifth power of the system size. Computational requirements of some operations scaling as the fifth power have also been significantly reduced. The new method allows an accurate treatment of molecules consisting of as many as a few dozen of atoms, using both nonhybrid and hybrid density functionals. PMID- 26626528 TI - NO-MNDO: Reintroduction of the Overlap Matrix into MNDO. AB - The effect of reintroducing the overlap matrix into the secular equations for an NDDO (neglect of diatomic differential overlap)-based semiempirical molecular orbital method has been investigated. The modification is expected to improve the description of interactions between electron pairs. The idea has been tested by implementation and evaluation of a nonorthogonal version of the MNDO method (NO MNDO) with parametrization for hydrogen, carbon, nitrogen, and oxygen. Overall, the accuracy of NO-MNDO for heats of formation is nearly identical to that for the more highly parametrized AM1 method. The mean absolute error (MAE) for heats of formation of a comprehensive set of 622 neutral, closed-shell molecules is reduced from 8.4 kcal/mol with MNDO to 6.8 kcal/mol with NO-MNDO. In addition, the performance for conformational equilibria and torsional barriers is significantly improved with NO-MNDO, presumably owing to the improved description of closed-shell interactions. For molecular geometries, the usual training and test sets have been expanded through use of MP2/6-31G(d) results for consistent comparisons. The performance of NO-MNDO for bond lengths, bond angles, and dihedral angles remains good with MAEs of 0.017 A, 2.5 degrees , and 4.5 degrees . Additionally, NO-MNDO corrects severe errors by MNDO for R(*) + H-R' hydrogen atom transfers, while testing for activation barriers for nine pericyclic reactions reveals only modest improvement. PMID- 26626529 TI - Improved Efficiency of Replica Exchange Simulations through Use of a Hybrid Explicit/Implicit Solvation Model. AB - The use of parallel tempering or replica exchange molecular dynamics (REMD) simulations has facilitated the exploration of free energy landscapes for complex molecular systems, but application to large systems is hampered by the scaling of the number of required replicas with increasing system size. Use of continuum solvent models reduces system size and replica requirements, but these have been shown to provide poor results in many cases, including overstabilization of ion pairs and secondary structure bias. Hybrid explicit/continuum solvent models can overcome some of these problems through an explicit representation of water molecules in the first solvation shells, but these methods typically require restraints on the solvent molecules and show artifacts in water properties due to the solvation interface. We propose an REMD variant in which the simulations are performed with a fully explicit solvent, but the calculation of exchange probability is carried out using a hybrid model, with the solvation shells calculated on the fly during the fully solvated simulation. The resulting reduction in the perceived system size in the REMD exchange calculation provides a dramatic decrease in the computational cost of REMD, while maintaining a very good agreement with results obtained from the standard explicit solvent REMD. We applied several standard and hybrid REMD methods with different solvent models to alanine polymers of 1, 3, and 10 residues, obtaining ensembles that were essentially independent of the initial conformation, even with explicit solvation. Use of only a continuum model without a shell of explicit water provided poor results for Ala3 and Ala10, with a significant bias in favor of the alpha-helix. Likewise, using only the solvation shells and no continuum model resulted in ensembles that differed significantly from the standard explicit solvent data. Ensembles obtained from hybrid REMD are in very close agreement with explicit solvent data, predominantly populating polyproline II conformations. Inclusion of a second shell of explicit solvent was found to be unnecessary for these peptides. PMID- 26626530 TI - Toward a Theoretical Quantitative Estimation of the lambdamax of Anthraquinones Based Dyes. AB - We have computed the absorption spectra of a large series of anthraquinone dyes by using the time-dependent density functional theory (TD-DFT) for the excited state calculations and the polarizable continuum model (PCM) for evaluating bulk solvent effects. On one hand, we compare the results obtained with the B3LYP and the PBE0 hybrid functionals, combined with different atomic basis sets. On the other hand, using multiple linear regression, we take advantage of the lambdamax predicted by these two functionals in order to reach the best agreement between theoretical estimates and experimental measurements. It turns out that 1. PBE0 provides more accurate results than B3LYP; in addition the average errors provided by the former are less basis set dependent. 2. Multiple linear regression provides excited state spectra in better agreement with experiment than any simple linear fit that could be performed. 3. Using our best fitting procedure, we obtained a mean absolute error of 6 nm for a set of 66 anthraquinones, with no deviations exceeding 25 nm. The related standard deviation, useful for predictions, is only 8 nm, i.e.,[Formula: see text] =[Formula: see text] +/- 8 nm (or +/-0.05 eV) for unknown anthraquinone compounds. PMID- 26626531 TI - Quantum Chemical Calculations of the Influence of Anchor-Cum-Spacer Groups on Femtosecond Electron Transfer Times in Dye-Sensitized Semiconductor Nanocrystals. AB - Electronic properties of dye-sensitized semiconductor nanocrystals, consisting of perylene (Pe) chromophores attached to 2 nm TiO2 nanocrystals via different anchor-cum-spacer groups, have been studied theoretically using density functional theory (DFT) cluster calculations. Approximate effective electronic coupling strengths for the heterogeneous electron-transfer interaction have been extracted from the calculated electronic structures and are used to estimate femtosecond electron-transfer times theoretically. Results are presented for perylenes attached to the TiO2 via formic acid (Pe-COOH), propionic acid (Pe-CH2 CH2-COOH), and acrylic acid (Pe-CH [Formula: see text] CH-COOH). The calculated electron transfer times are between 5 and 10 fs with the formic acid and the conjugated acrylic acid bridges and about 35 fs with the saturated propionic acid bridge. The calculated electron injection times are of the same order of magnitude as the corresponding experimental values and qualitatively follow the experimental trend with respect to the influence of the different substitutions on the injection times. PMID- 26626532 TI - QM/MM Free-Energy Perturbation Compared to Thermodynamic Integration and Umbrella Sampling: Application to an Enzymatic Reaction. AB - We used the free-energy perturbation (FEP) method in quantum mechanics/molecular mechanics (QM/MM) calculations to compute the free-energy profile of the hydroxylation reaction in the enzyme p-hydroxybenzoate hydroxylase (PHBH). k statistics were employed to analyze the FEP sampling including estimation of the sampling error. Various approximations of the free-energy perturbation method were tested. We find that it is adequate not only to freeze the density of the QM part during the dynamics at frozen QM geometry but also to approximate this density by electrostatic-potential-fitted point charges. It is advisable to include all atoms of a QM/MM link in the perturbation. The results of QM/MM-FEP for PHBH are in good agreement with those of thermodynamic integration and umbrella sampling. PMID- 26626533 TI - S-doped mesoporous nanocomposite of HTiNbO5 nanosheets and TiO2 nanoparticles with enhanced visible light photocatalytic activity. AB - The S-doped mesoporous nanocomposite (S-TNT) of HTiNbO5 nanosheets (NSs) and anatase TiO2 nanoparticles (NPs) with exposed {101} facets has been successfully synthesized by first mixing freeze-dried HTiNbO5 NSs with titanium isopropoxide and then calcination with thiourea in air. The exposed anatase {101} facets can act as a possible reservoir of the photogenerated electrons, yielding a highly reactive surface for the reduction of O2 to O2(-). The partial substitution of Ti(4+) by S(6+) in the lattice of TiO2 NPs leads to a charge imbalance in S-TNT and the formation of Ti-O-S bonds. As a result, the formed cationic S-TNT favours adsorption of hydroxide ions (OH(-)(ads)) and thus captures the photo-induced holes to form hydroxyl radicals (OH). Moreover, with the formation of Ti-O-S bonds, partial electrons can be transferred from S to O atoms and hence the electron-deficient S atoms might capture photo-induced electrons. The surface adsorbed SO4(2-) could also act as an efficient electron trapping center to promote the separation of charge carriers. In addition, the Ti(3+) species due to the removal of oxygen atoms during calcination and the associated oxygen vacancy defects on the surface of S-TNT could act as hole and electron scavengers, respectively. Besides, the closely contacted interface is formed between HTiNbO5 NSs and anatase TiO2 NPs due to the common features of TiO6 octahedra in two components, resulting in a nanoscale heterojunction structure to speed up the separation rate of photogenerated charge carriers. The formation of a nano heterojunction and the incorporation of Ti(3+) and S dopants give rise to the visible and near-infrared light response of S-TNT. The combined effects greatly retard the charge recombination and improve the photocatalytic activity for the degradation of rhodamine B (RhB) and phenol solution under visible light irradiation. The corresponding photocatalytic mechanism was investigated via the active species capture experiments. The present work may provide an insight into the fabrication of delicate composite photocatalysts with excellent performance. PMID- 26626534 TI - Long-acting hormonal contraception. AB - Today, a new category of fertility-regulating agents has been created: long acting, reversible hormonal contraceptives; they minimize compliance, while maximize effectiveness. They comprise subdermal implants and intrauterine devices. Other long-acting agents exist, such as Depo Provera and Noristerat. Use of Depo Provera and Noristerat carries great effectiveness, good clinical safety and usefulness in developing countries. They cause no significant increase in breast cancer risk, but they may carry an increased risk of HIV. Subcutaneous delivery systems have two common features: prolongation of effect is obtained by a drug reservoir and for most of their duration of action they provide a continuous, sustained release of the active hormone. Finally, the intrauterine system Mirena represents both a very effective contraceptive and a specific treatment for menorrhagia. PMID- 26626535 TI - T Cells Target Pancreatic Tumors. AB - Researchers have generated engineered T cells that home in on mesothelin, a protein produced in large amounts by pancreatic tumors. In mice, the T cells entered pancreatic tumors and destroyed cancer cells. Repeated infusions of the T cells nearly doubled survival times in the animals. PMID- 26626536 TI - Assay development for determination of tenofovir in human plasma by solid phase analytical derivatization and LC-MS/MS. AB - BACKGROUND: A novel method was developed and validated to measure tenofovir in human plasma. RESULTS/METHODOLOGY: This method employed solid phase analytical derivatization and analysis by LC-MS/MS. Stable-labeled internal standard was added to plasma samples followed by solid phase extraction. Retained analytes were derivatized on the solid phase extraction cartridges with a diazomethane solution to yield methyl-ester derivatives. Samples were analyzed using LC-MS/MS incorporating the use of a strong cation exchange column. The method was validated over a range of 5.00-750 ng/ml. The approach developed in this report for tenofovir could be applied to other analytes that share similar structural similarities. CONCLUSION: The tenofovir LC-MS/MS method was used to support a clinical study of over 400 samples with a 100% success rate. PMID- 26626538 TI - Synthesis of 1,4-amino alcohols by Grignard reagent addition to THF and N tosyliminobenzyliodinane. AB - The synthesis of 1,4-amino alcohols from THF treated with N tosyliminobenzyliodinane (PhINTs) followed by a Grignard reagent under mild reaction conditions at room temperature is described herein. Various Grignard reagents were shown to be compatible, furnishing the corresponding 4-substituted N-1,4-tosylamino alcohols in good to excellent yields. A partial or full detosylation of the N-tosyl-1,4-amino alcohol was observed in instances involving a sterically bulky Grignard reagent, leading to the deprotected 1,4-amino alcohol product in moderate to good yields. The synthetic utility of this protocol was demonstrated by the synthesis of a 5-substituted-N-tosyl-1,5-amino alcohol from THP and the conversion of two examples to their corresponding gamma-lactam and pyrrolidine adducts. PMID- 26626537 TI - Mutagenic Bypass of an Oxidized Abasic Lesion-Induced DNA Interstrand Cross-Link Analogue by Human Translesion Synthesis DNA Polymerases. AB - 5'-(2-Phosphoryl-1,4-dioxobutane) (DOB) is an oxidized abasic site that is produced by several antitumor agents and gamma-radiolysis. DOB reacts reversibly with a dA opposite the 3'-adjacent nucleotide to form DNA interstrand cross-links (ICLs), genotoxic DNA lesions that can block DNA replication and transcription. Translesion synthesis (TLS) is an important step in several ICL repair pathways to bypass unhooked intermediates generated by endonucleolytic incision. The instability of DOB-ICLs has made it difficult to learn about their TLS-mediated repair capability and mutagenic potential. We recently developed a method for chemically synthesizing oligonucleotides containing a modified DOB-ICL analogue. Herein, we examined the capabilities of several highly relevant eukaryotic TLS DNA polymerases (pols), including human pol eta, pol kappa, pol iota, pol nu, REV1, and yeast pol zeta, to bypass this DOB-ICL analogue. The prelesion, translesion, and postlesion replication efficiency and fidelity were examined. Pol eta showed moderate bypass activity when encountering the DOB-ICL, giving major products one or two nucleotides beyond the cross-linked template nucleotide. In contrast, DNA synthesis by the other pols was stalled at the position before the cross-linked nucleotide. Steady-state kinetic data and liquid chromatography-mass spectrometry sequencing of primer extension products by pol eta unambiguously revealed that pol eta-mediated bypass is highly error-prone. Together, our study provides the first set of in vitro evidence that the DOB-ICL is a replication-blocking and highly miscoding lesion. Compared to several other TLS pols examined, pol eta is likely to contribute to the TLS-mediated repair of the DOB-ICL in vivo. PMID- 26626539 TI - The effects of Nintendo Wii(TM)-based balance and upper extremity training on activities of daily living and quality of life in patients with sub-acute stroke: a randomized controlled study. AB - OBJECTIVE: The aim of this study was to investigate the effects of Nintendo Wii(TM)-based balance and upper extremity training on activities of daily living and quality of life in patients with subacute stroke. METHODS: 42 adults with stroke (mean age (SD) = 58.04 (16.56) years and mean time since stroke (SD) = (55.2 +/- 22.02 days (~8 weeks)) were included in the study. Participants were enrolled from the rehabilitation department of a medical center (a single inpatient rehabilitation facility). Participants were randomly assigned to Nintendo Wii group (n = 20) or Bobath neurodevelopmental treatment (NDT) (n = 22). The treatments were applied for 10 weeks (45-60 minutes/day, 3 days/week) for both of two groups. Nintendo Wii group used five games selected from the Wii sports and Wii Fit packages for upper limb and balance training, respectively. The patients in Bobath NDT group were applied a therapy program included upper extremity activites, strength, balance gait and functional training. The functional independence in daily life activities and health-related quality of life was assessed with Functional Independence Measure (FIM) and Nottingham Health Profile (NHP), respectively. Participant's treatment satisfaction was recorded by using Visual Analogue Scale. A second evaluation (FIM and NHP) occurred after 10 weeks at the end of rehabilitative treatment (post-training). Treatment satisfaction was measured after 10 sessions. RESULTS: There were significant difference between FIM and NHP values in NDT and Nintendo Wii group (p < 0.05). However, a significant difference was not found between the groups with regard to FIM and NHP (p > 0.05). The patients in Nintendo Wii group were detected to be better satisfied from the therapy (p < 0.05). A significant difference was found between subparameters and total FIM score, all subparameters and total NHP score in both groups (p < 0.05). CONCLUSION: These findings suggested that the Nintendo Wii training was as effective as Bobath NDT on daily living functions and quality of life in subacute stroke patients. PMID- 26626540 TI - Assessing the effect of estimation error on risk-adjusted CUSUM chart performance. AB - Mark A. Jones, Stefan H. Steiner. Assessing the effect of estimation error on risk-adjusted CUSUM chart performance. Int J Qual Health Care (2012) 24(2): 176 181 doi: 10.1093/intqhc/mzr082. The authors would like to correct an error identified in the above paper. Table 5 included incorrect information. The correct table has been reprinted below. Furthermore, in the discussion on p. 180 of this paper, one of the incorrect numbers in Table 5 was quoted. This section is reproduced below with the correct numbers. In the case of homogeneous patients where adverse event risk was assumed to be constant at 6.6% the estimated level of estimation error: SD (ARL0) = 85.9 was less than the equivalent risk-adjusted scenario where SD (ARL0) = 89.2 but only by around 4%. PMID- 26626541 TI - Executive Function Deficits in Patients after Cerebellar Neurosurgery. AB - The cerebellum has long been perceived as a structure responsible for the human motor function. According to the contemporary approach, however, it plays a significant role in complex behavior regulatory processes. The aim of this study was to describe executive functions in patients after cerebellar surgery. The study involved 30 patients with cerebellar pathology. The control group comprised 30 neurologically and mentally healthy individuals, matched for sex, age, and number of years of education. Executive functions were measured by the Wisconsin Card Sorting Test (WCST), Stroop Color Word Test (SCWT), Trail Making Test (TMT), and working memory by the Digit Span. Compared to healthy controls, patients made more Errors and Perseverative errors in the WCST, gave more Perseverative responses, and had a lower Number of categories completed. The patients exhibited higher response times in all three parts of the SCWT and TMT A and B. No significant differences between the two groups were reported in their performance of the SCWT and TMT with regard to the measures of absolute or relative interference. The patients had lower score on the backward Digit Span. Patients with cerebellar pathology may exhibit some impairment within problem solving and working memory. Their worse performance on the SCWT and TMT could, in turn, stem from their poor motor-somatosensory control, and not necessarily executive deficits. Our results thus support the hypothesis of the cerebellum's mediating role in the regulation of the activity of the superordinate cognitive control network in the brain. (JINS, 2016, 22, 47-57). PMID- 26626542 TI - Where is the Evo in Evo-Devo (evolutionary developmental biology)? AB - I provide a brief discussion of the present/future of Evo-Devo, reviewing opinions expressed by colleagues with different opinions/backgrounds about what Evo-Devo should be and the potential of this flourishing field and combining them with an analysis of the recent, and excellent inaugural meeting of the Pan American Society for Evo-Devo. As an advocate of Evo-Devo and its enormous future potential, I feel that despite our different views and fields of research, we Evo Devoists are all in the same boat and should try our best to make sure this potential is fully expressed. Therefore, I call attention to some concerns raised by other colleagues, which in my opinion are demonstrated by a quantitative analysis of the titles/abstracts of the 56 talks at this meeting. This analysis is very simple, in order to maintain the needed objectivity and minimize bias. Yet, it is profound in its implications, precisely because of its simplicity and because this meeting is clearly a major landmark for the development/future directions of Evo-Devo. The analysis shows that terms associated with development at the more molecular/genetic level were vastly overrepresented compared to terms related to evolution or to development at the whole organism level. That is, it provides support for the idea that current Evo-Devo is mainly focused on Devo, and that Devo itself is largely focused on "Geno," that is, on molecular/genetic developmental studies. This trend seems to be leading towards a loss of focus on the whole organism and on the major microevolutionary and macroevolutionary questions/theories that remain to be solved/tested. PMID- 26626543 TI - Development of Electrically Conductive Double-Network Hydrogels via One-Step Facile Strategy for Cardiac Tissue Engineering. AB - Cardiac tissue engineering is an effective method to treat the myocardial infarction. However, the lack of electrical conductivity of biomaterials limits their applications. In this work, a homogeneous electronically conductive double network (HEDN) hydrogel via one-step facile strategy is developed, consisting of a rigid/hydrophobic/conductive network of chemical crosslinked poly(thiophene-3 acetic acid) (PTAA) and a flexible/hydrophilic/biocompatible network of photo crosslinking methacrylated aminated gelatin (MAAG). Results suggest that the swelling, mechanical, and conductive properties of HEDN hydrogel can be modulated via adjusting the ratio of PTAA network to MAAG network. HEDN hydrogel has Young's moduli ranging from 22.7 to 493.1 kPa, and its conductivity (~10(-4) S cm(-1)) falls in the range of reported conductivities for native myocardium tissue. To assess their biological activity, the brown adipose-derived stem cells (BADSCs) are seeded on the surface of HEDN hydrogel with or without electrical stimulation. Our data show that the HEDN hydrogel can support the survival and proliferation of BADSCs, and that it can improve the cardiac differentiation efficiency of BADSCs and upregulate the expression of connexin 43. Moreover, electrical stimulation can further improve this effect. Overall, it is concluded that the HEDN hydrogel may represent an ideal scaffold for cardiac tissue engineering. PMID- 26626544 TI - Moving Toward Implementation of Person-Centered Care for Older Adults in Community-Based Medical and Social Service Settings: "You Only Get Things Done When Working in Concert with Clients". AB - Specialized, fragmented acute care is not aligned optimally to serve older adults. Person-centered care (PCC) has emerged as an evidence-based solution that involves enlisting patients as partners in treatment planning. Although several efforts have captured person-centered voices in outpatient care, more information is needed at the organizational and provider level to better understand the feasibility, challenges, and effect of PCC in community-based and social services settings. To assess themes and emerging trends, researchers conducted telephone interviews with leaders at nine organizations providing PCC for older adults. Questions were focused on the legacy of PCC services, whether and how PCC was connected to better quality care, and what tools were used for measuring PCC. Three themes on PCC for older adults emerged. (1) Each organization ascribed to a unique definition and operational structure for PCC. (2) Despite these differences, all organizations specified a strong commitment to PCC. Most noted financial resources and staffing as challenges and opportunities affecting feasibility. (3) Terms such as "patient-centered" care and other PCC synonyms may warrant greater clarification, because ideological differences set these classifications apart. Results from this analysis indicate the lack of a single, established definition for PCC. As interest in and support for PCC mounts, organizations in outpatient medical and community-based settings clearly have undertaken individual efforts to interpret what PCC is and how to provide it. Interview responses reflect this inconsistency, highlighting how staff and financing in particular can bolster or burden the PCC paradigm and what a consensus definition could do for the field. PMID- 26626545 TI - Bioactive Sheath/Core nanofibers containing olive leaf extract. AB - This study aimed at producing silk fibroin (SF)/hyaluronic acid (HA) and olive leaf extract (OLE) nanofibers with sheath/core morphology by coaxial electrospinning method, determining their antimicrobial properties, and examining release profiles of OLE from these coaxial nanofibers. Optimum electrospinning process and solution parameters were determined to obtain uniform and bead-free coaxial nanofibers. Scanning electron microscopy and transmission electron microscopy (TEM) were used to characterize the morphology of the nanofibers. The antimicrobial activities of nanofibers were tested according to AATCC test method 100. Total phenolic content and total antioxidant activity were tested using in vitro batch release system. The quality and quantity of released components of OLE were determined by high-performance liquid chromatography. The changes in nanofibers were examined by Fourier-transform infrared spectroscopy. Uniform and bead-free nanofibers were produced successfully. TEM images confirmed the coaxial structure. OLE-loaded nanofibers demonstrated almost perfect antibacterial activities against both of gram-negative and gram-positive bacteria. Antifungal activity against C. albicans was rather poor. After a release period of 1 month, it was observed that ~70-95% of the OLE was released from nanofibers and it was still bioactive. Overall results indicate that the resultant shell/core nanofibers have a great potential to be used as biomaterials. PMID- 26626546 TI - Protective role of methylprednisolone and heparin in ischaemic-reperfusion injury of the rat testicle. AB - This study evaluated the therapeutic efficacy of heparin and methylprednisolone in the treatment of ischaemic reperfusion (IR) injury of the testis. Twenty-four male Sprague-Dawley rats were allocated equally into three groups of eight animals each. The left testes were rotated 720 degrees for 2 h in the rats in the torsion-detorsion group. Rats in the treatment groups underwent the same surgical procedure as the torsion-detorsion group but were also given methylprednisolone (group II) or heparin (group III) by an intraperitoneal route 30 min prior to detorsion. Left orchiectomy was performed in all rats from each experimental animal at 2 h after detorsion, and the tissue was harvested for the measurement of malondialdehyde (MDA), protein carbonyl (PC) and nitric oxide (NO) and the endogenous antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase. Additional tissue was evaluated using histopathological and immunohistochemical changes. PC and MDA levels were significantly reduced in the treated groups compared to the control group. There was no statistically significant difference in NO level or SOD, GSH-Px and catalase activity among the treatment groups. Histopathological and immunohistochemical findings supported biochemical changes. It is concluded that pre-treatment with methylprednisolone or heparin protects the testis in ischaemic reperfusion injury caused by testicular torsion-detorsion. PMID- 26626549 TI - Attractive Dispersion Interactions Versus Steric Repulsion of tert-Butyl groups in the Crystal Packing of a D3h -Symmetric Tris(quinoxalinophenanthrophenazine). AB - The crystalline packing of a pi-extended D3h -symmetric triptycene reveals a particular pi stacking motif with an almost-eclipsed arrangement of adjacent pi planes despite the steric repulsion of tert-butyl substituents. Four model compounds were analyzed by using single-crystal X-ray diffraction and theoretical calculations to study the influence of dispersion interactions of molecular parts and understand the relationship between the molecular structure and this unique packing motif. PMID- 26626547 TI - What is the effectiveness of printed educational materials on primary care physician knowledge, behaviour, and patient outcomes: a systematic review and meta-analyses. AB - BACKGROUND: Printed educational materials (PEMs) are commonly used simple interventions that can be used alone or with other interventions to disseminate clinical evidence. They have been shown to have a small effect on health professional behaviour. However, we do not know whether they are effective in primary care. We investigated whether PEMs improve primary care physician (PCP) knowledge, behaviour, and patient outcomes. METHODS: We conducted a systematic review of PEMs developed for PCPs. Electronic databases were searched for randomized controlled trials, quasi randomized controlled trials, controlled before and after studies, and interrupted time series. We combined studies using meta-analyses when possible. Statistical heterogeneity was examined, and meta analysis was performed using a random effects model when significant statistical heterogeneity was present and a fixed effects model otherwise. The template for intervention description and replication (TIDieR) checklist was used to assess the quality of intervention description. RESULTS: Our search identified 12,439 studies and 40 studies met our inclusion criteria. We combined outcomes from 26 studies in eight meta-analyses. No significant effect was found on clinically important patient outcomes, physician behaviour, or physician cognition when PEMs were compared to usual care. In the 14 studies that could not be included in the meta-analyses, 14 of 71 outcomes were significantly improved following receipt of PEMs compared to usual care. Most studies lacked details needed to replicate the intervention. CONCLUSIONS: PEMs were not effective at improving patient outcomes, knowledge, or behaviour of PCPs. Further trials should explore ways to optimize the intervention and provide detailed information on the design of the materials. PROTOCOL REGISTRATION: PROSPERO, CRD42013004356. PMID- 26626550 TI - Tc-99m imaging in thyroidectomized differentiated thyroid cancer patients immediately before I-131 treatment. AB - PURPOSE: The aim of this study was to evaluate the clinical role of technetium 99m pertechnetate (Tc-99m) imaging in thyroidectomized differentiated thyroid cancer patients immediately before radioiodine-131 (I-131) treatment (Tx). PATIENT AND METHODS: Eighty-six consecutive post-total-thyroidectomy patients (15 men, 71 women; mean age: 46.8 years) with pathologically diagnosed differentiated thyroid cancer were retrospectively studied. Tc-99m imaging immediately before I 131 Tx using both patient-based and lesion-based measurements were analyzed and were further compared with those of post-Tx I-131 whole-body scans. RESULTS: For patients with unequivocally positive Tc-99m uptake, the sensitivity was 77% (patient-based) and 59% (site-based). The positive predictive value (PPV) was 100% for both patient-based and site-based measurements. If equivocal Tc-99m uptake was counted as positive, the sensitivity was 83 and 67%, and the PPV was 100 and 99% for patient-based and site-based measurements, respectively. CONCLUSION: (a) To increase sensitivity yet maintaining high PPV, equivocal Tc 99m uptake should be considered a positive finding. (b) The nearly 100% PPV of Tc 99m imaging immediately before I-131 Tx for remnant detection suggests that Tc 99m imaging not only serves as an alternative to low-dose I-131 scanning in the low-risk post-thyroidectomy patients but also provides a clue for the subsequent I-131 therapeutic dosage and even for the outcome prediction. PMID- 26626551 TI - A systematic review of single-sample glomerular filtration rate measurement techniques and demonstration of equal accuracy to slope-intercept methods. AB - PURPOSE: We aimed to identify the most accurate single-sample glomerular filtration rate (SS-GFR) technique for all patient ages. MATERIALS AND METHODS: We performed a systematic review of all published SS-GFR measurement techniques and compared the results from each test with a gold-standard nine-point 'area under-curve' measurement of GFR as well as slope-intercept (SI-GFR) methods for 412 GFR tests. RESULTS: We have shown that for patients of all ages the SS-GFR technique developed by Fleming and colleagues delivers the best accuracy and precision, with results equivalent to those calculated by SI-GFR. The median percentage difference from the gold-standard GFR for the Fleming technique is 4.8% (95% confidence interval 3.9-5.7%) and that for the three-point SI-GFR is 5.6% (95% confidence interval 4.9-6.3%). The interquartile range of the distribution of percentage difference from the gold standard is -0.23 to 11% for the Fleming method and 1.6-11% for the three-point SI-GFR. CONCLUSION: The Fleming technique outperforms the method currently recommended by the international guidelines, and is simpler as only one equation is required for all patients instead of separate equations for adults and children. We propose that the SS-GFR technique of Fleming replace the methods currently recommended by the international and BNMS guidelines for routine measurement of GFR for expected results greater than 30 ml/min/1.73 m. A thorough system of measurement checks should be implemented for all methods of GFR assessment; the perceived lack of opportunity for quality control checks to be performed on the result of a single sample measurement is addressed in the companion paper of this study. PMID- 26626552 TI - [ESC guidelines 2015 for ventricular arrhythmias and prevention of sudden cardiac death. What is new?]. AB - The new European Society of Cardiology (ESC) guidelines for the management of patients with ventricular arrhythmia and the prevention of sudden cardiac death, recently published at the annual ESC meeting in London, contain an extensive update of the recommendations for the diagnostics, drug therapy, interventional and device therapy of ventricular arrhythmia. The new recommendations for implantable cardioverter defibrillator (ICD) treatment for primary and secondary prophylaxis of sudden cardiac death can be seen as a focused update of the previously published guidelines. Pre-existing recommendations for catheter ablation of ventricular arrhythmias have been partly extensively expanded with respect to the results of recent clinical trials. The guideline committee also adapted their recommendations regarding the hereditary arrhythmia syndromes to the 2013 consensus report of the American Heart Association (AHA), the European Heart Rhythm Association (EHRA) and the Asia Pacific Heart Rhythm Society (APHRS). PMID- 26626554 TI - [ESC guidelines 2015 on pulmonary hypertension]. AB - The European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines published in 2015 include the most important recommendations for the diagnosis and treatment of pulmonary hypertension (PH). The classification of PH into five groups remained unchanged as compared to the previous recommendations; however, there are minor shifts within the groups. Accordingly, a distinction is made between pulmonary arterial hypertension (PAH), PH due to left heart disease, PH due to chronic hypoxia or lung disease, chronic thromboembolic PH and PH due to unclear or multifactorial mechanisms. The diagnosis of PH is based on right heart catheterization where PH is defined as a mean pulmonary arterial pressure >= 25 mmHg at rest. For the definition of PAH, in addition to a pulmonary capillary wedge pressure <= 15 mmHg, a pulmonary vascular resistance > 3 Wood units is obligatory. Echocardiography is considered to be the most important non invasive procedure within the diagnostic algorithm and for patients with collagen vascular disease. This is recommended during initial diagnostic work-up and should be followed-up annually. Several novel drugs which were approved since publication of the previous guidelines, were included in the new recommendations. For the first time there is a recommendation for a targeted drug for inoperable chronic thromboembolic PH. An important part of the guidelines is the discussion on PAH upfront combination therapy. PMID- 26626553 TI - [Diagnosis and management of acute pulmonary embolism. ESC guidelines 2014]. AB - Acute pulmonary embolism (PE) still represents a challenge regarding a rapid diagnosis and a risk-adapted therapy. In the 2014 guidelines of the European Society of Cardiology (ESC) on the diagnosis and management of acute PE, several new recommendations have been issued based on new study data. Some established scores for risk stratification were developed further and there is now good evidence for the use of age-adjusted D-dimer cut-off levels. For the risk stratification in patients without clinical features of shock, the utilization of the pulmonary embolism severity index (PESI) and simplified PESI (sPESI) scores is recommended. In patients with intermediate risk, right ventricular morphology and function can be evaluated by computer tomography or echocardiography and biomarkers facilitate further risk stratification. For the treatment of patients with venous thromboembolism with or without PE, the non-vitamin K-dependent oral anticoagulants (NOACs) are a safe alternative to the standard anticoagulation regimen with heparin and vitamin K antagonists. Systemic thrombolytic therapy should be restricted to patients with high risk or intermediate high risk with hemodynamic instability. Finally, new recommendations for the diagnosis and therapy of patients with chronic thromboembolic pulmonary hypertension (CTEPH), with cancer or during pregnancy are given. PMID- 26626555 TI - Automated extraction and validation of children's gait parameters with the Kinect. AB - BACKGROUND: Gait analysis for therapy regimen prescription and monitoring requires patients to physically access clinics with specialized equipment. The timely availability of such infrastructure at the right frequency is especially important for small children. Besides being very costly, this is a challenge for many children living in rural areas. This is why this work develops a low-cost, portable, and automated approach for in-home gait analysis, based on the Microsoft Kinect. METHODS: A robust and efficient method for extracting gait parameters is introduced, which copes with the high variability of noisy Kinect skeleton tracking data experienced across the population of young children. This is achieved by temporally segmenting the data with an approach based on coupling a probabilistic matching of stride template models, learned offline, with the estimation of their global and local temporal scaling. A preliminary study conducted on healthy children between 2 and 4 years of age is performed to analyze the accuracy, precision, repeatability, and concurrent validity of the proposed method against the GAITRite when measuring several spatial and temporal children's gait parameters. RESULTS: The method has excellent accuracy and good precision, with segmenting temporal sequences of body joint locations into stride and step cycles. Also, the spatial and temporal gait parameters, estimated automatically, exhibit good concurrent validity with those provided by the GAITRite, as well as very good repeatability. In particular, on a range of nine gait parameters, the relative and absolute agreements were found to be good and excellent, and the overall agreements were found to be good and moderate. CONCLUSION: This work enables and validates the automated use of the Kinect for children's gait analysis in healthy subjects. In particular, the approach makes a step forward towards developing a low-cost, portable, parent-operated in-home tool for clinicians assisting young children. PMID- 26626556 TI - Minor head injury: limiting patient exposure to ionizing radiation, risk stratification, and concussion management. AB - PURPOSE OF REVIEW: We review recommendations from recent publications on the evaluation of minor head trauma. We focus on the risks of radiation from computed tomographies (CTs), the establishment of patient risk stratifications to help guide the necessity of emergent neuroimaging, and current thoughts regarding concussions. RECENT FINDINGS: Pediatric minor head injury is a common complaint in ambulatory settings. There is a significant amount of parental and practitioner anxiety regarding prognosis and whether or not to obtain CT imaging. New evidence has demonstrated the significant harmful effects of ionizing radiation. Recent studies have risk-stratified patients to identify those at risk of clinically important traumatic brain injury, to minimize the exposure to ionizing radiation for those who are at a low risk of any significant disorder. SUMMARY: Pediatric minor head injury is a common complaint, but the vast majority of those injured will suffer no significant consequences. The Pediatric Emergency Care Applied Research Network has created an algorithm to identify minor head trauma patients who require emergent head CTs versus those at low risk who do not require neuroimaging. Additionally, in recent years there has been an increase in the occurrence of concussions. We describe the characteristics of concussions, appropriate management, and the return-to-play guidelines. PMID- 26626557 TI - Evolving hematopoietic stem cell transplantation strategies in severe aplastic anemia. AB - PURPOSE OF REVIEW: Significant improvements in unrelated donor hematopoietic stem cell transplantation (HSCT) in recent years have solidified its therapeutic role in severe aplastic anemia (SAA) and led to the evolution of treatment algorithms, particularly for children. RECENT FINDINGS: Advances in understanding the genetics of inherited bone marrow failure syndromes (IBMFS) have allowed more confidence in accurately diagnosing SAA and avoiding treatments that could be dangerous and ineffective in individuals with IBMFS, which can be diagnosed in 10 20% of children presenting with a picture of SAA. Additionally long-term survival after matched sibling donor and matched unrelated donor HSCT now exceed 90% in children. Late effects after HSCT for SAA are minimal with current strategies, and compare favorably to late effects after upfront immunosuppressive therapy, except for patients with chronic graft versus host disease. SUMMARY: Careful assessment for signs or symptoms of IBMFS, along with genetic screening for these disorders, is of major importance. Matched sibling donor HSCT is already considered the standard of care for upfront therapy and some groups are evaluating matched unrelated donor HSCT as primary therapy. Ongoing studies will continue to challenge treatment algorithms and may lead to an even more expanded role for HSCT in SAA. PMID- 26626558 TI - Future directions in the treatment of osteosarcoma. AB - PURPOSE OF REVIEW: Overall survival rates for osteosarcoma have remained essentially unchanged over the past 3 decades despite attempts to improve outcome via dose intensification and modification based on response. This review describes recent findings from contemporary clinical trials, advances in the comprehension of osteosarcoma biology and genomic complexity, and potential opportunities using targeted and immune-mediated therapies. RECENT FINDINGS: Recent results from international collaborative trials have failed to demonstrate an ability to improve outcomes using a design in which the randomized question is dictated based on histologic response to preoperative chemotherapy. Novel prognostic markers assessable at diagnosis are vital to identifying subsets of osteosarcoma. Clinical trials focus has now shifted to serial phase II studies of novel agents to evaluate for activity in recurrent and refractory disease. In depth analyses have revealed profound genomic instability and heterogeneity across patients, with nearly universal TP53 aberration. Although driver mutational events have not clearly been established, frequent derangements in specific pathways may suggest opportunities for therapeutic exploitation. Genomic complexity may lend support to a role for immune-mediated therapies. SUMMARY: Rigorous preclinical investigations are potentially generating novel strategies for the treatment of osteosarcoma that will inform the next generation of clinical trials, with the opportunity to identify agents that will improve survival outcomes. PMID- 26626559 TI - Ankyrin-mediated self-protection during cell invasion by the bacterial predator Bdellovibrio bacteriovorus. AB - Predatory Bdellovibrio bacteriovorus are natural antimicrobial organisms, killing other bacteria by whole-cell invasion. Self-protection against prey-metabolizing enzymes is important for the evolution of predation. Initial prey entry involves the predator's peptidoglycan DD-endopeptidases, which decrosslink cell walls and prevent wasteful entry by a second predator. Here we identify and characterize a self-protection protein from B. bacteriovorus, Bd3460, which displays an ankyrin based fold common to intracellular pathogens of eukaryotes. Co-crystal structures reveal Bd3460 complexation of dual targets, binding a conserved epitope of each of the Bd3459 and Bd0816 endopeptidases. Complexation inhibits endopeptidase activity and cell wall decrosslinking in vitro. Self-protection is vital - DeltaBd3460 Bdellovibrio deleteriously decrosslink self-peptidoglycan upon invasion, adopt a round morphology, and lose predatory capacity and cellular integrity. Our analysis provides the first mechanistic examination of self protection in Bdellovibrio, documents protection-multiplicity for products of two different genomic loci, and reveals an important evolutionary adaptation to an invasive predatory bacterial lifestyle. PMID- 26626560 TI - Interictal cytokine levels were correlated to seizure severity of epileptic patients: a retrospective study on 1218 epileptic patients. AB - BACKGROUND: Many aspects on the correlation between epilepsy and cytokine levels were unclear. This study aims to investigate the correlations between cytokine levels and severe epilepsy. METHODS: Totally 1218 epileptic patients were grouped by types of epilepsy: TLE (temporal lobe epilepsy, n = 409), XLE (extra-temporal lobe epilepsy, n = 290) and IGE (idiopathic generalized epilepsy, n = 519). Two hundred healthy volunteers were as controls. Clinical findings and levels of 14 serum and CSF cytokines and 6 STAT members were collected, measured and analyzed. RESULTS: Analysis showed no differences in interictal cytokine levels among patients from TLE, XLE and IGE groups. Interictal serum levels of IL-1b, IL-1Ra, IL-6, IL-8, IFNgamma, IFNlambda3 and IL-17a were associated with seizure severity of epileptic patients, measured by seizure frequency, VA score or NHS3. Multivariate regression analysis indicated that interictal concentrations of serum IL-6, IFNgamma, IL-17a, IFNlambda3, and CSF IL-6, IL-17a, IFNlambda3 were significant biomarkers for patients with severe epilepsy. mRNA levels of IL-6, IFNgamma, IL-17a, and IFNlambda3 were elevated in different types of epilepsy. Activation of all STATs was elevated in epilepsy, and STAT3 was activated 9-fold in average, which was the highest among all STATs. CONCLUSIONS: Interictal serum IL-6, IFNgamma, IL-17a, IFNlambda3, and CSF IL-6, IL-17a, IFNlambda3 could be used as potential biomarkers for severe epilepsy. Activation of STATs, especially STAT3, was important in epilepsy. Our findings pointed out crucial roles of cytokine levels in epilepsy. PMID- 26626561 TI - Characteristics of the shark fisheries of Fiji. AB - Limited information is available on artisanal and subsistence shark fisheries across the Pacific. The aim of this study was to investigate Fiji's inshore fisheries which catch sharks. In January and February 2013, 253 semi-directive interviews were conducted in 117 villages and at local harbours on Viti Levu, Vanua Levu, Taveuni, Ovalau and a number of islands of the Mamanuca and Yasawa archipelagos. Of the 253 interviewees, 81.4% reported to presently catch sharks, and 17.4% declared that they did not presently catch any sharks. Of the 206 fishers that reported to catch sharks, 18.4% targeted sharks and 81.6% caught sharks as bycatch. When targeted, primary use of sharks was for consumption or for sale. Sharks caught as bycatch were frequently released (69.6%), consumed (64.9%) or shared amongst the community (26.8%). Fishers' identification based on an identification poster and DNA barcoding revealed that at least 12 species of elasmobranchs, 11 shark and one ray species (Rhynchobatus australiae) were caught. This study, which is the first focused exploration of the shark catch in Fiji's inshore fisheries, suggests that the country's artisanal shark fisheries are small but have the potential to develop into larger and possibly more targeted fisheries. PMID- 26626562 TI - Sequential biases in accumulating evidence. AB - Whilst it is common in clinical trials to use the results of tests at one phase to decide whether to continue to the next phase and to subsequently design the next phase, we show that this can lead to biased results in evidence synthesis. Two new kinds of bias associated with accumulating evidence, termed 'sequential decision bias' and 'sequential design bias', are identified. Both kinds of bias are the result of making decisions on the usefulness of a new study, or its design, based on the previous studies. Sequential decision bias is determined by the correlation between the value of the current estimated effect and the probability of conducting an additional study. Sequential design bias arises from using the estimated value instead of the clinically relevant value of an effect in sample size calculations. We considered both the fixed-effect and the random effects models of meta-analysis and demonstrated analytically and by simulations that in both settings the problems due to sequential biases are apparent. According to our simulations, the sequential biases increase with increased heterogeneity. Minimisation of sequential biases arises as a new and important research area necessary for successful evidence-based approaches to the development of science. (c) 2015 The Authors. Research Synthesis Methods Published by John Wiley & Sons Ltd. PMID- 26626563 TI - Coronary Stenosis Associated with a Giant Coronary Aneurysm. PMID- 26626564 TI - Implementing solutions to improve and expand telehealth adoption: participatory action research in four community healthcare settings. AB - BACKGROUND: Adoption of telehealth has been slower than anticipated, and little is known about the service improvements that help to embed telehealth into routine practice or the role of frontline staff in improving adoption. This paper reports on participatory action research carried out in four community health settings using telehealth for patients with Chronic Obstructive Pulmonary Disease and Chronic Heart Failure. METHODS: To inform the action research, in-depth case studies of each telehealth service were conducted (May 2012-June 2013). Each service was then supported by researchers through two cycles of action research to implement changes to increase adoption of telehealth, completed over a seven month period (July 2013-April 2014). The action research was studied via observation of multi-stakeholder workshops, analysis of implementation plans, and focus groups. RESULTS: Action research participants included 57 staff and one patient, with between eight and 20 participants per site. The case study findings were identified as a key source of information for planning change, with sites addressing common challenges identified through this work. For example, refining referral criteria; standardizing how and when patients are monitored; improving data sharing; and establishing evaluation processes. Sites also focused on raising awareness of telehealth to increase adoption in other clinical teams and to help secure future financial investment for telehealth, which was required because of short-term funding arrangements. Specific solutions varied due to local infrastructures, resources, and opinion, as well as previous service developments. Local telehealth champions played an important role in engaging multiple stakeholders in the study. CONCLUSIONS: Action research enabled services to make planned changes to telehealth and share learning across multiple stakeholders about how and when to use telehealth. However, adoption was impeded by continual changes affecting telehealth and wider service provision, which also hindered implementation efforts and affected motivation of staff to engage with the action research, particularly where local decision-makers were not engaged in the study. Wider technological barriers also limited the potential for change, as did uncertainties about goals for telehealth investment, thereby making it difficult to identify outcomes for demonstrating the added value over existing practice. PMID- 26626565 TI - Tunable-Porosity Membranes From Discrete Nanoparticles. AB - Thin film composite membranes were prepared through a facile single-step wire wound rod coating procedure in which internally crosslinked poly(styrene-co butadiene) polymer nanoparticles self-assembled to form a thin film on a hydrophilic ultrafiltration support. This nanoparticle film provided a defect free separation layer 130-150 nm thick, which was highly permeable and able to withstand aggressive pH conditions beyond the range of available commercial membranes. The nanoparticles were found to coalesce to form a rubbery film when heated above their glass transition temperature (Tg). The retention properties of the novel membrane were strongly affected by charge repulsion, due to the negative charge of the hydroxyl functionalized nanoparticles. Porosity was tuned by annealing the membranes at different temperatures, below and above the nanoparticle Tg. This enabled fabrication of membranes with varying performance. Nanofiltration properties were achieved with a molecular weight cut-off below 500 g mol(-1) and a low fouling tendency. Interestingly, after annealing above Tg, memory of the interstitial spaces between the nanoparticles persisted. This memory led to significant water permeance, in marked contrast to the almost impermeable films cast from a solution of the same polymer. PMID- 26626566 TI - Comparative study of in situ hybridization, immunohistochemistry and parasitological culture for the diagnosis of canine leishmaniosis. AB - BACKGROUND: The establishment of an accurate diagnostic protocol for canine visceral leishmaniosis (CanL) is a significant laboratory challenge and the lack of a reliable reference standard is one of the major problems. The aim of this study was to compare in situ hybridization (ISH), immunohistochemistry (IHC) and parasitological culture (PC) for detection of L. infantum in skin, spleen, lymph node and bone marrow of clinically healthy and sick seropositive dogs. FINDINGS: The study included 65 dogs positive with both DPP(r) and ELISA for anti Leishmania antibodies. In situ hybridization of spleen or lymph node had the highest positivity rates of L. infantum detection. The total positivity rates for IHC, ISH and PC were 70%, 68.1% and 65.8%, respectively. When combining techniques, the positivity rates were 81.5% in the spleen, 79.0% in lymph nodes, 59.0% in bone marrow and 52.3% in the skin. The highest percentage of infected dogs (87.7%) was detected by using lymph node samples. When examining only skin, positivity was significantly higher in sick dogs than in the clinically healthy dogs. Infection with L. infantum was confirmed in 95.8% of sick dogs and in 82.4% of healthy dogs. CONCLUSIONS: Considering the advantages of accurately diagnosing different Leishmania species and of being more sensitive than PC, ISH should be considered as reference standard test for the diagnosis of CanL. Spleen and lymph node are the most suitable tissues to confirm infection with L. infantum in seropositive dogs. The testing of only skin from clinically healthy dogs may result in a high percentage of false negative results. PMID- 26626570 TI - CCR 20th Anniversary Commentary: Molecular Pathology of ALK-Rearranged Lung Tumors. AB - The article by Rodig and colleagues, which was published in the August 15, 2009, issue of Clinical Cancer Research, helped detail the clinicopathologic profile of ALK-positive tumors and initiated the development of ALK diagnostics. Subsequent clinical trials utilized these findings, resulting in the approval of effective targeted therapies. The ALK story is a model for the development of therapies in the genomic era. PMID- 26626567 TI - Circadian and light-driven regulation of rod dark adaptation. AB - Continuous visual perception and the dark adaptation of vertebrate photoreceptors after bright light exposure require recycling of their visual chromophore through a series of reactions in the retinal pigmented epithelium (RPE visual cycle). Light-driven chromophore consumption by photoreceptors is greater in daytime vs. nighttime, suggesting that correspondingly higher activity of the visual cycle may be required. However, as rod photoreceptors are saturated in bright light, the continuous turnover of their chromophore by the visual cycle throughout the day would not contribute to vision. Whether the recycling of chromophore that drives rod dark adaptation is regulated by the circadian clock and light exposure is unknown. Here, we demonstrate that mouse rod dark adaptation is slower during the day or after light pre-exposure. This surprising daytime suppression of the RPE visual cycle was accompanied by light-driven reduction in expression of Rpe65, a key enzyme of the RPE visual cycle. Notably, only rods in melatonin proficient mice were affected by this daily visual cycle modulation. Our results demonstrate that the circadian clock and light exposure regulate the recycling of chromophore in the RPE visual cycle. This daily melatonin-driven modulation of rod dark adaptation could potentially protect the retina from light-induced damage during the day. PMID- 26626568 TI - Hypoxic preconditioning potentiates the trophic effects of mesenchymal stem cells on co-cultured human primary hepatocytes. AB - INTRODUCTION: Mesenchymal stem/stromal cells (MSCs) improve the metabolic function of co-cultured hepatocytes. The present study aimed to further enhance the trophic effects of co-culture with hepatocytes using hypoxic preconditioning (HPc) of the MSCs and also to investigate the underlying molecular mechanisms involved. METHODS: Human adipose tissue-derived MSCs were subjected to hypoxia (2 % O2; HPc) or normoxia (20 % O2) for 24 h and then co-cultured with isolated human hepatocytes. Assays of metabolic function and apoptosis were performed to investigate the hepatotrophic and anti-apoptotic effects of co-culture. Indirect co-cultures and co-culture with MSC-conditioned medium investigated the role of paracrine factors in the hepatotrophic effects of co-culture. Reactive oxygen species (ROS) activity was antagonised with N-acetylcysteine to investigate whether HPc potentiated the effects of MSCs by intracellular ROS-dependent mechanisms. Tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF) beta1, and extracellular collagen production was determined and CASP9 and BAX/BCL 2 signalling pathways analysed to investigate the role of soluble factors, extracellular matrix deposition, and apoptosis-associated gene signalling in the effects of co-culture. RESULTS: HPc potentiated the hepatotrophic and anti apoptotic effects of co-culture by ROS-dependent mechanisms. There was increased MSC TGF-beta1 production, and enhanced MSC deposition of extracellular collagen, with reduced synthesis of TNF-alpha, as well as a downregulation of the expression of pro-apoptotic CASP9, BAX, BID and BLK genes and upregulated expression of anti-apoptotic BCL-2 in hepatocytes. CONCLUSIONS: HPc potentiated the trophic and anti-apoptotic effects of MSCs on hepatocytes via mechanisms including intracellular ROS, autocrine TGF-beta, extracellular collagen and caspase and BAX/BCL-2 signalling pathways. PMID- 26626571 TI - New Strategies in Stereotactic Radiotherapy for Oligometastases. AB - Patients with metastatic solid tumors are usually treated with palliative intent. Systemic therapy and palliative radiation are often used, with the goals of prolonging survival or maintaining quality of life, but not of cure. In contrast to this paradigm, the theory of oligometastasis suggests that some patients who have a small number of metastases may be amenable to cure if all lesions can be eradicated. Aggressive treatment of patients with oligometastases, using either surgery or radiotherapy, has become more common in the past decade, yet in most situations, no randomized evidence is available to support such an approach. Stereotactic ablative radiotherapy (SABR) is a novel treatment for oligometastases, delivering large doses of radiotherapy in only a few treatments, with excellent rates of local control, and appears to be an excellent noninvasive alternative to surgical resection of metastases. This article reviews recent biologic and clinical data that support the existence of the oligometastatic state and discusses gaps in this evidence base. The emerging role for SABR in the management of this challenging patient population is discussed with a focus on ongoing clinical trials in an attempt to improve overall survival, delay progression, or induce immunologic anticancer effects through the abscopal effect. PMID- 26626572 TI - Counseling for personal care options at neonatal end of life: a quantitative and qualitative parent survey. AB - BACKGROUND: The death of a newborn is a traumatic life changing event in the lives of parents. We hypothesized that bereaved parents of newborn infants want to have choices in the personal care of their infant at the end of life. METHODS: Parents who had suffered a perinatal or neonatal loss between 1 and 6 years before the survey in a regional level IV neonatal intensive care unit (NICU) and associated labor and delivery room were invited to participate. Parents chose between an online survey, paper survey or telephone interview. The survey included multiple choice and open ended questions. RESULTS: Parents prefer multiple options for the personal care of their infant at the end of life. Emergent themes were need for guidance by the medical team, memory making, feeling cared for and respected by staff, and regrets related to missed opportunities. CONCLUSION: While parents differ in their preferences in utilizing specific personal care options for their infant's end of life, they share a common preference for being presented with multiple options to choose from and in being guided and supported by healthcare providers, while being afforded the opportunity to make memories with their infant by bonding with and parenting them. PMID- 26626574 TI - Bucking the trend: genetic analysis reveals high diversity, large population size and low differentiation in a deep ocean cetacean. AB - Understanding the genetic structure of a population is essential to its conservation and management. We report the level of genetic diversity and determine the population structure of a cryptic deep ocean cetacean, the Gray's beaked whale (Mesoplodon grayi). We analysed 530 bp of mitochondrial control region and 12 microsatellite loci from 94 individuals stranded around New Zealand and Australia. The samples cover a large area of the species distribution (~6000 km) and were collected over a 22-year period. We show high genetic diversity (h=0.933-0.987, pi=0.763-0.996% and Rs=4.22-4.37, He=0.624-0.675), and, in contrast to other cetaceans, we found a complete lack of genetic structure in both maternally and biparentally inherited markers. The oceanic habitats around New Zealand are diverse with extremely deep waters, seamounts and submarine canyons that are suitable for Gray's beaked whales and their prey. We propose that the abundance of this rich habitat has promoted genetic homogeneity in this species. Furthermore, it has been suggested that the lack of beaked whale sightings is the result of their low abundance, but this is in contrast to our estimates of female effective population size based on mitochondrial data. In conclusion, the high diversity and lack of genetic structure can be explained by a historically large population size, in combination with no known exploitation, few apparent behavioural barriers and abundant habitat. PMID- 26626573 TI - Novel fusion antigen displayed-bacterial ghosts vaccine candidate against infection of Escherichia coli O157:H7. AB - Infection with Escherichia coli O157:H7 may develop into hemorrhagic colitis, or hemolytic uremic syndrome (HUS), which usually causes kidney failure or even death. The adhesion and toxins are the important virulent factors. In this study, a novel vaccine candidate rSOBGs was constructed based on the bacterial ghost (BG). rSOBGs maintained the integrity of cellular morphology and displayed the linear Stx2Am-Stx1B antigen on the surface of outer membrane. rSOBGs induced Stxs specific IgA/IgG antibodies and stronger intimin-specific IgA/IgG antibodies effectively in sera in this study. In vivo, the rSOBGs provided the higher protection rate (52%) than native bacterial ghost-OBGs (12%) when challenged intragastricly with high dose (500 LD50) viable E. coli O157:H7. Meanwhile, the rSOBGs provided higher protection rate (73.33%) than OBGs when challenged with 2 LD50 even to 5 LD50 lysed E. coli O157:H7. In vitro, the rSOBGs-immunized sera possessed neutralizing activity to lysed pathogenic bacteria. Furthermore, the results of histopathology also displayed that the administration of rSOBGs have the ability to reduce or inhibit the adhesion lesions and toxins damages of organs. The novel vaccine candidate rSOBGs induced both anti-toxin and anti adhesion immune protection, suggesting the possibility to prevent the infectious diseases caused by Escherichia coli O157:H7. PMID- 26626575 TI - Early replication dynamics of sex-linked mitochondrial DNAs in the doubly uniparental inheritance species Ruditapes philippinarum (Bivalvia Veneridae). AB - Mitochondrial homoplasmy, which is maintained by strictly maternal inheritance and a series of bottlenecks, is thought to be an adaptive condition for metazoans. Doubly uniparental inheritance (DUI) is a unique mode of mitochondrial transmission found in bivalve species, in which two distinct mitochondrial genome (mtDNA) lines are present, one inherited through eggs (F) and one through sperm (M). During development, the two lines segregate in a sex- and tissue-specific manner: females lose M during embryogenesis, whereas males actively segregate it in the germ line. These two pivotal events are still poorly characterized. Here we investigated mtDNA replication dynamics during embryogenesis and pre-adulthood of the venerid Ruditapes philippinarum using real-time quantitative PCR. We found that both mtDNAs do not detectably replicate during early embryogenesis, and that the M line might be lost from females around 24 h of age. A rise in mtDNA copy number was observed before the first reproductive season in both sexes, with the M mitochondrial genome replicating more than the F in males, and we associate these boosts to the early phase of gonad production. As evidence indicates that DUI relies on the same molecular machine of mitochondrial maternal inheritance that is common in most animals, our data are relevant not only to DUI but also to shed light on how differential segregations of mtDNA variants, in the same nuclear background, may be controlled during development. PMID- 26626576 TI - Contact zone dynamics during early stages of speciation in a chorus frog (Pseudacris crucifer). AB - Characterizing the genetic and behavioural consequences of contact between previously geographically isolated lineages provides insights into the mechanisms underlying diversification and ultimately speciation. The spring peeper (Pseudacris crucifer) is a widespread Nearctic chorus frog with six divergent mitochondrial DNA (mtDNA) lineages, many of which came into secondary contact during the Holocene. We examined genetics, morphology, advertisement calls and female preference for two lineages that began diverging in allopatry in the Pliocene and now overlap in southwestern Ontario, Canada. We found non-coincident clines in mtDNA and nuclear DNA, mirroring directionality of premating isolation barriers. We also found divergence in a range of traits between these two lineages, displacement in male call attributes and female preference for calls of their natal lineage in sympatry. Hybrids were morphologically distinct from both parental lineages, but hybrid male calls were acoustically intermediate. Female hybrids showed asymmetrical preference for Eastern male calls. These results considered together provide evidence of either unidirectional hybridization or selection against hybrids, potentially implying reproductive character displacement. Our work demonstrates the utility of integrated, multi-character approaches to understanding the processes of divergence and the nature of speciation. PMID- 26626577 TI - The story of an exceptional serine protease, tissue-type plasminogen activator (tPA). AB - The only acute treatment of ischemic stroke approved by the health authorities is tissue recombinant plasminogen activator (tPA)-induced thrombolysis. Under physiological conditions, tPA, belonging to the serine protease family, is secreted by endothelial and brain cells (neurons, astrocytes, microglia, oligodendrocytes). Although revascularisation induced by tPA is beneficial during a stroke, research over the past 20 years shows that tPA can also be deleterious for the brain parenchyma. Thus, in this review of the literature, after a brief history on the discovery of tPA, we reviewed current knowledge of mechanisms by which tPA can influence brain function in physiological and pathological conditions. PMID- 26626578 TI - Polyandrous females provide sons with more competitive sperm: Support for the sexy-sperm hypothesis in the rattlebox moth (Utetheisa ornatrix). AB - Given the costs of multiple mating, why has female polyandry evolved? Utetheisa ornatrix moths are well suited for studying multiple mating in females because females are highly polyandrous over their life span, with each male mate transferring a substantial spermatophore with both genetic and nongenetic material. The accumulation of resources might explain the prevalence of polyandry in this species, but another, not mutually exclusive, possibility is that females mate multiply to increase the probability that their sons will inherit more competitive sperm. This latter "sexy-sperm" hypothesis posits that female multiple mating and male sperm competitiveness coevolve via a Fisherian runaway process. We tested the sexy-sperm hypothesis by using competitive double matings to compare the sperm competition success of sons of polyandrous versus monandrous females. In accordance with sexy-sperm theory, we found that in 511 offspring across 17 families, the male whose polyandrous mother mated once with each of three different males sired significantly more of all total offspring (81%) than did the male whose monandrous mother was mated thrice to a single male. Interestingly, sons of polyandrous mothers had a significantly biased sex ratio of their brood toward sons, also in support of the hypothesis. PMID- 26626579 TI - Pressure-driven formation and stabilization of superconductive chromium hydrides. AB - Chromium hydride is a prototype stoichiometric transition metal hydride. The phase diagram of Cr-H system at high pressures remains largely unexplored due to the challenges in dealing with the high activation barriers and complications in handing hydrogen under pressure. We have performed an extensive structural study on Cr-H system at pressure range 0 ~ 300 GPa using an unbiased structure prediction method based on evolutionary algorithm. Upon compression, a number of hydrides are predicted to become stable in the excess hydrogen environment and these have compositions of Cr2Hn (n = 2-4, 6, 8, 16). Cr2H3, CrH2 and Cr2H5 structures are versions of the perfect anti-NiAs-type CrH with ordered tetrahedral interstitial sites filled by H atoms. CrH3 and CrH4 exhibit host guest structural characteristics. In CrH8, H2 units are also identified. Our study unravels that CrH is a superconductor at atmospheric pressure with an estimated transition temperature (T c) of 10.6 K, and superconductivity in CrH3 is enhanced by the metallic hydrogen sublattice with T c of 37.1 K at 81 GPa, very similar to the extensively studied MgB2. PMID- 26626580 TI - Systemic treatments in psoriatic patients: is the occurrence of melanoma uncommon? PMID- 26626581 TI - Population Pharmacokinetic and Pharmacodynamic Modeling of AZD4901 and Simulation to Support Dose Selection for the Phase 2a Study. AB - Significant and reversible reductions in testosterone levels were observed with AZD4901 in both preclinical and clinical testing. A comprehensive population pharmacokinetic/pharmacodynamic (PK/PD) modeling of AZD4901 concentration and testosterone relationship from 3 phase 1 studies was performed using NONMEM to support dose selection for phase 2a development. A 2-compartment model with first order absorption and first-order elimination best described AZD4901 PK. Circadian rhythm of baseline testosterone concentrations was well described by a cosine function. An indirect response model with inhibition of testosterone production was used to link the AZD4901 concentration to testosterone response. The AZD4901 concentration to yield 50% maximum testosterone suppression (IC50) was estimated to be 230 ng/mL. Based on simulations, following 40 mg twice daily (BID) treatment, the AZD4901 steady-state trough concentration will be much higher compared to 80 mg once daily (QD). The AZD4901 concentration time above IC50 after 40 mg BID is 84% of the time of the dosing interval compared to only 49% after 80 mg QD. The mean predicted testosterone concentrations at steady state are lower and overall less variable over 24 hours for 40 mg BID dosing compared to 80 mg QD dosing. Population PK and PK/PD analyses demonstrated that AZD4901 40 mg BID is a better dosing strategy to more consistently suppress testosterone during the entire dosing interval. Consequently, 40 mg BID dosing was suggested in a phase 2a trial in females with polycystic ovary syndrome, and the trial resulted in a positive outcome as shown by significant testosterone decrease compared to placebo. PMID- 26626583 TI - Grass carp Ctenopharyngodon idella Fibulin-4 as a potential interacting partner for grass carp reovirus outer capsid proteins. AB - Mammalian EGF containing fibulin-like extracellular matrix protein 2 (Fibulin 4/EFEMP2), an extracellular matrix(ECM) protein and a member of the fibulin family, is involved in elastic fiber formation, connective tissue development and some human diseases. In a yeast-two hybrid screening of host proteins interacting with outer capsid protein of grass carp reovirus (GCRV), a grass carp homologue of Fibulin-4 (designated as GcFibulin-4) is suggested to hold the potential to bind VP7, VP56 and VP55, the outer capsid protein encoded by type I, II, III GCRV, respectively. GcFibulin-4 gene of grass carp was cloned and sequenced from the cDNA library constructed for the yeast two-hybrid screening. Full-length cDNA of GcFibulin-4 contains an open reading frame (ORF) of 1323 bp encoding a putative protein of 440 amino acids. Phylogenetic analysis of GcFibulin-4 indicated that it shared a high homology with zebra fish Fibulin-4 protein. Transcriptional distribution analysis of GcFibulin-4 in various tissues of healthy grass carp showed that GcFibulin-4 was highly expressed in muscle, moderately expressed in the intestine and brain, and slightly expressed in other examined tissues; the expression pattern is consistent with tissue tropism of GCRV resulting in hemorrhage symptom in the corresponding tissues. Our results suggested that Fibulin-4 might enable free GCRV particles, the pathogen for grass carp hemorrhagic disease, to target fish tissues more efficiently by interacting with viral outer capsid proteins. PMID- 26626582 TI - Pediatric Nurse Performance on a Medication Dosage Calculation Assessment Tool. AB - Nurses who care for children must be competent to perform medication dosage calculations because most pediatric doses are weight based and obtained from adult formulations. PURPOSE: The purpose of the study was to describe and compare nurse performance on a medication dosage calculation assessment tool, considering work unit, years experience, and certification status. DESIGN: A secondary analysis of data from 851 Registered Nurses (RN) was completed. Multiple regression was used to model the effect of work unit, certification, and experience on score. FINDINGS: The mean assessment tool score was 92.4 (47-100). The work unit and the interaction between certification status and experience were significant in relation to score on the calculation assessment. PMID- 26626584 TI - Expression profile analysis of two cathepsin S in channel catfish (Ictalurus punctatus) mucosal tissues following bacterial challenge. AB - Cathepsin S belongs to the papain family of cysteine protease, and is considered to play key roles in immune responses after bacterial challenge. However, despite the recognized importance of Cathepsin S in immunity, no studies have systematically characterized Cathepsin S in catfish. In this regard, here, we characterized the Cathepsin S gene family in channel catfish, and investigated their expression patterns following two different Gram-negative bacterial challenge. In the present study, two Cathepsin S genes (ctss and ctssa) were captured in channel catfish. In comparison to other species, the catfish Cathepsin S genes are highly conserved in their structural features. Phylogenetic analysis indicated the strongest phylogenetic relationship with zebrafish, which is consistent with their evolutional relationships. Tissue distribution analysis revealed that Cathepsin S genes were ubiquitously expressed in catfish tissues. Following bacterial infection, the Cathepsin S genes were significantly up regulated at most time-points in mucosal surfaces, with an acute response post Edwardsiella ictaluri infection. Obviously, the expression profiles were quite distinct between two Cathepsin S genes, across the tissues and between pathogens, suggesting that Cathepsin S genes may exert disparate roles in mucosal immune responses. Our findings here, provide early insight into the immune functions of Cathepsin S in catfish; however, further studies are needed to determine the mechanisms of Cathepsin S for antigen presentation during inflammatory processes and innate host defense. PMID- 26626586 TI - Editorial overview: Differentiation and disease. PMID- 26626585 TI - Coagulation factor II from rock bream (Oplegnathus fasciatus): First report on the molecular biological function and expression analysis in the teleost. AB - The rapid haemostasis of fish prevents bleeding or infection that could be caused by physical properties of the aquatic environment. Additionally, the innate immune system is the first line of defence against infection and is responsible for the recognition of pathogen-associated molecular patterns, which are important for the activation of acquired immune responses. Coagulation factor II (CFII) is an important factor in the coagulation system and is involved in recognition and interaction with various bacterial and extracellular proteins. In this study, we identified and characterised the gene encoding CFII in rock bream (Oplegnathus fasciatus) (RbCFII) and analysed its expression in various tissues after a pathogen challenge. The full-length RbCFII cDNA (2079 bp) contained an open reading frame of 1854 bp encoding 617 amino acids. Alignment analysis revealed that a gamma-carboxyglutamic acid-rich domain, two kringle domains, and a trypsin-like serine protease domain of the deduced protein were well conserved. RbCFII was ubiquitously expressed in all tissues examined but, predominantly detected in the liver and skin. RbCFII expression was dramatically up-regulated in the kidney, spleen and liver after infection with Edwardsiella tarda, Streptococcus iniae, or red seabream iridovirus. The recombinant protein RbCFII (rRbCFII) produced using an Escherichia coli expression system was able to bind all examined bacteria. Interestingly, rRbCFII has agglutination activities towards E. coli and E. tarda, while no agglutination was shown toward Vibrio ordalii and S. iniae. These findings indicate that rRbCFII performs an immunological function in the immune response, and might be involved in innate immunity as well as blood coagulation. PMID- 26626587 TI - Emodin improves lipid and glucose metabolism in high fat diet-induced obese mice through regulating SREBP pathway. AB - Currently, obesity has become a worldwide epidemic associated with Type 2 diabetes, dyslipidemia, cardiovascular disease and chronic metabolic diseases. Emodin is one of the active anthraquinone derivatives from Rheum palmatum and some other Chinese herbs with anti-inflammatory, anticancer and hepatoprotective properties. In the present study, we investigated the anti-obesity effects of emodin in obese mice and explore its potential pharmacological mechanisms. Male C57BL/6 mice were fed with high-fat diet for 12 weeks to induce obesity. Then the obese mice were divided into four groups randomly, HFD or emodin (40mg/kg/day and 80mg/kg/day) or lovastatin (30mg/kg/ day) for another 6 weeks. Body weight and food intake were recorded every week. At the end of the treatment, the fasting blood glucose, glucose and insulin tolerance test, serum and hepatic lipid levels were assayed. The gene expressions of liver and adipose tissues were analyzed with a quantitative PCR assay. Here, we found that emodin inhibited sterol regulatory element-binding proteins (SREBPs) transactivity in huh7 cell line. Furthermore, emodin (80mg/kg/day) treatment blocked body weight gain, decreased blood lipids, hepatic cholesterol and triglyceride content, ameliorated insulin sensitivity, and reduced the size of white and brown adipocytes. Consistently, SREBP-1 and SREBP-2 mRNA levels were significantly reduced in the liver and adipose tissue after emodin treatment. These data demonstrated that emodin could improve high-fat diet-induced obesity and associated metabolic disturbances. The underlying mechanism is probably associated with regulating SREBP pathway. PMID- 26626590 TI - Examining hospital pharmacists' goals for medication counseling within the communication accommodation theoretical framework. AB - BACKGROUND: Medication counseling opportunities are key times for pharmacists to speak to patients about their medications and any changes made during their hospital stay. Communication Accommodation Theory (CAT) posits that an individual's goals drive their communication behavior. The way in which pharmacists communicate with patients may be determined by the goals they set for these medication counseling sessions. OBJECTIVES: To examine hospital pharmacists' goals in patient medication counseling within the CAT framework. METHODS: Hospital pharmacist focus groups were held in two teaching hospitals. Interested pharmacists attended a focus group designed to elicit their goals in patient medication counseling. Focus groups were audio recorded and transcribed verbatim. NVivo((r)) software was used to assist in coding and organization. The codes were reviewed for reliability by pharmacists independent of the focus groups. An inductive thematic analysis was applied to the data. RESULTS: Six 1 h focus groups were conducted with a total of 24 pharmacists participating. Saturation of information was achieved after four focus groups. Greater than 80% consensus was achieved for reliability of the identified codes. Patient-centered themes constructed from these codes were to build rapport, to empower patients and to improve patients' experience, health and safety. Exemplars provided by pharmacists for the goals of building rapport and empowering patients were aligned with five CAT communication behaviors (approximation, interpretability, discourse management, emotional expression and interpersonal control). CONCLUSIONS: Patient-centered goals described by hospital pharmacists for medication counseling aligned well with CAT behaviors necessary for effective communication. Further research using the CAT framework to examine the effectiveness of hospital pharmacist-patient exchanges that include both participants' perspectives is required to better understand how well pharmacists communicate with patients. PMID- 26626588 TI - The formation and design of the TRIAGE study--baseline data on 6005 consecutive patients admitted to hospital from the emergency department. AB - BACKGROUND: Patient crowding in emergency departments (ED) is a common challenge and associated with worsened outcome for the patients. Previous studies on biomarkers in the ED setting has focused on identification of high risk patients, and and the ability to use biomarkers to identify low-risk patients has only been sparsely examined. The broader aims of the TRIAGE study are to develop methods to identify low-risk patients appropriate for early ED discharge by combining information from a wide range of new inflammatory biomarkers and vital signs, the present baseline article aims to describe the formation of the TRIAGE database and characteristize the included patients. METHODS: We included consecutive patients >= 17 years admitted to hospital after triage staging in the ED. Blood samples for a biobank were collected and plasma stored in a freezer (-80 degrees C). Triage was done by a trained nurse using the Danish Emergency Proces Triage (DEPT) which categorizes patients as green (not urgent), yellow (urgent), orange (emergent) or red (rescusitation). Presenting complaints, admission diagnoses, comorbidities, length of stay, and 'events' during admission (any of 20 predefined definitive treatments that necessitates in-hospital care), vital signs and routine laboratory tests taken in the ED were aslo included in the database. RESULTS: Between September 5(th) 2013 and December 6(th) 2013, 6005 patients were included in the database and the biobank (94.1 % of all admissions). Of these, 1978 (32.9 %) were categorized as green, 2386 (39.7 %) yellow, 1616 (26.9 %) orange and 25 (0.4 %) red. Median age was 62 years (IQR 46-76), 49.8 % were male and median length of stay was 1 day (IQR 0-4). No events were found in 2658 (44.2 %) and 158 (2.6 %) were admitted to intensive or intermediate-intensive care unit and 219 (3.6 %) died within 30 days. A higher triage acuity level was associated with numerous events, including acute surgery, endovascular intervention, i.v. treatment, cardiac arrest, stroke, admission to intensive care, hospital transfer, and mortality within 30 days (p < 0.001). CONCLUSION: The TRIAGE database has been completed and includes data and blood samples from 6005 unselected consecutive hospitalized patients. More than 40 % experienced no events and were therefore potentially unnecessary hospital admissions. PMID- 26626591 TI - Hospital pharmacists' perceptions of medication counseling: A focus group study. AB - BACKGROUND: Medication counseling sessions are key times for a pharmacist to speak to patients about their medications and the changes made to their therapies during their hospital stay. OBJECTIVES: To explore hospital pharmacists' perceptions of their roles and goals in patient medication counseling, and perceived barriers and facilitators to achieving their goals. METHODS: Hospital pharmacist focus groups were held in two tertiary referral hospitals. Eligible pharmacists had provided medication counseling within the previous six months in inpatient and/or outpatient settings. Interested pharmacists attended a focus group designed to elicit their opinions and perceptions of patient medication counseling. Focus groups were audio recorded and transcribed verbatim. Inductive thematic analysis was applied to the data to identify initial patterns (codes) which were then organized into common overarching themes using NVivo((r)) software. The codes were reviewed for reliability by pharmacists independent of the focus groups. RESULTS: Six, 1-h focus groups were conducted with a total of 24 pharmacists participating. Saturation of information was determined after four focus groups. Greater than 80% consensus was achieved for reliability of the identified codes. A number of themes emerged from these codes around the goals, roles, and the barriers and facilitators to meeting these goals. Pharmacists' patient-centered goals in medication counseling were to build rapport, to empower patients and to improve patients' experience, health and safety. These goals would be accomplished through specific roles such as being an assessor, educator and problem-solver. Pharmacists frequently cited time pressures caused by systemic (hospital), and pharmacy specific processes as key challenges to achieving their goals. Factors that enabled pharmacists to meet their goals were those related to effective interprofessional collaboration and the quality of professional practice (such as training, expanded roles and advanced planning for discharge). CONCLUSIONS: Hospital pharmacists emphasized patient-centered goals in medication counseling and outlined the challenges to meet those goals. The findings from this study will be used to develop strategies for effective communication and inform pharmacy practice changes to improve patient care. PMID- 26626589 TI - The variations of IL-23R are associated with susceptibility and severe clinical forms of pulmonary tuberculosis in Chinese Uygurs. AB - BACKGROUND: The incidence of tuberculosis (TB) remains high among Chinese Uygurs (a long-dwelling ethnic minority in Xinjiang) in China and the variants in IL-23R likely contribute to individual's diversity in host response during infection. METHODS: A hospital based one to one matched case-control study was performed to assess the role of single nucleotide polymorphisms (SNPs) and copy number variation (CNV) of IL-23R in susceptibility and clinical features of pulmonary TB in Chinese Uygurs. Thirteen SNPs in IL-23R were genotyped by multiplex SNaPshot and a CNV was analyzed using Taqman real-time PCR in 250 pairs of pulmonary TB patients and controls. RESULTS: The SNP rs7518660 (OR = 4.78, 95% CI 3.14-8.52) and the CNV in IL23R (OR = 2.75, 95% CI 1.51-4.98) were significantly associated with susceptibility to pulmonary TB. The SNP rs11465802 (OR = 3.23, 95% CI 1.85 5.62) was significantly associated with drug-resistance and the SNP rs1884444 (OR = 3.61, 95% CI 1.90-6.85) was significantly related to cavitary lesion in Chinese Uygurs. CONCLUSIONS: Our study shows for the first time that SNP and CNV in IL23R were associated with susceptibility, drug resistance and cavity formation of pulmonary TB. Our findings indicate that these IL-23R polymorphisms may be considered as risk factors for active pulmonary TB and its severe clinical forms. PMID- 26626592 TI - Beyond the 'teachable moment' - A conceptual analysis of women's perinatal behaviour change. AB - BACKGROUND: Midwives are increasingly expected to promote healthy behaviour to women and pregnancy is often regarded as a 'teachable moment' for health behaviour change. This view focuses on motivational aspects, when a richer analysis of behaviour change may be achieved by viewing the perinatal period through the lens of the Capability-Opportunity-Motivation Behaviour framework. This framework proposes that behaviour has three necessary determinants: capability, opportunity, and motivation. AIM: To outline a broader analysis of perinatal behaviour change than is afforded by the existing conceptualisation of the 'teachable moment' by using the Capability-Opportunity-Motivation Behaviour framework. FINDINGS: Research suggests that the perinatal period can be viewed as a time in which capability, opportunity or motivation naturally change such that unhealthy behaviours are disrupted, and healthy behaviours may be adopted. Moving away from a sole focus on motivation, an analysis utilising the Capability Opportunity-Motivation Behaviour framework suggests that changes in capability and opportunity may also offer opportune points for intervention, and that lack of capability or opportunity may act as barriers to behaviour change that might be expected based solely on changes in motivation. Moreover, the period spanning pregnancy and the postpartum could be seen as a series of opportune intervention moments, that is, personally meaningful episodes initiated by changes in capability, opportunity or motivation. DISCUSSION: This analysis offers new avenues for research and practice, including identifying discrete events that may trigger shifts in capability, opportunity or motivation, and whether and how interventions might promote initiation and maintenance of perinatal health behaviours. PMID- 26626594 TI - Acute aneurysmal rupture in a severe SAH patient seen on head CT angiography scan. PMID- 26626593 TI - mRNA-seq reveals skeletal muscle atrophy in response to handling stress in a marine teleost, the red cusk-eel (Genypterus chilensis). AB - BACKGROUND: Fish reared under intensive conditions are repeatedly exposed to stress, which negatively impacts growth. Although most fish follow a conserved pattern of stress response, with increased concentrations of cortisol, each species presents specificities in the cell response and stress tolerance. Therefore, culturing new species requires a detailed knowledge of these specific responses. The red cusk-eel (Genypterus chilensis) is a new economically important marine species for the Chilean aquaculture industry. However, there is no information on the stress- and cortisol-induced mechanisms that decrease skeletal muscle growth in this teleost. RESULTS: Using Illumina RNA-seq technology, skeletal muscle sequence reads for G. chilensis were generated under control and handling stress conditions. Reads were mapped onto a reference transcriptome, resulting in the in silico identification of 785 up-regulated and 167 down-regulated transcripts. Gene ontology enrichment analysis revealed a significant up-regulation of catabolic genes associated with skeletal muscle atrophy. These results were validated by RT-qPCR analysis for ten candidates genes involved in ubiquitin-mediated proteolysis, autophagy and skeletal muscle growth. Additionally, using a primary culture of fish skeletal muscle cells, the effect of cortisol was evaluated in relation to red cusk-eel skeletal muscle atrophy. CONCLUSIONS: The present data demonstrated that handling stress promotes skeletal muscle atrophy in the marine teleost G. chilensis through the expression of components of the ubiquitin-proteasome and autophagy-lysosome systems. Furthermore, cortisol was a powerful inductor of skeletal muscle atrophy in fish myotubes. This study is an important step towards understanding the atrophy system in non-model teleost species and provides novel insights on the cellular and molecular mechanisms that control skeletal muscle growth in early vertebrates. PMID- 26626595 TI - Partial Protection of PC12 Cells from Cellular Stress by Low-Dose Sodium Nitroprusside Pre-treatment. AB - The PC12 rat pheochromocytoma cell line is an in vitro model system widely used for the investigation of intracellular signaling events contributing to neuronal differentiation and cell death. We found earlier that the nitric oxide donor compound sodium nitroprusside (SNP) induced apoptosis of PC12 cells if it was applied in high concentration (400 uM). Yoshioka et al. (J Pharmacol Sci 101:126 134, 2006) reported that cell death evoked by cytotoxic concentrations of SNP could be prevented by a 100 uM SNP pre-treatment in a murine macrophage cell line. The apoptosis caused by toxic-dose SNP treatment (400 uM) could be partially overcome in PC12 cells as well by the low-dose SNP pre-treatment. The partial inhibition of apoptosis was accompanied by reduced phosphorylation of certain proteins (such as stress-activated protein kinases, the p53, and the eIF2alpha proteins), decreased caspase activation, and less intense internucleosomal DNA fragmentation. The 100 uM SNP pre-treatment reduced the pro apoptotic potential of certain other stress stimuli (serum withdrawal, cisplatin and tunicamycin treatments) as well, although the underlying biochemical changes were not entirely uniform. On the contrary, the 100 uM SNP pre-treatment was unable to prevent cell death caused by the protein synthesis inhibitor anisomycin. Further clarification of the above-mentioned processes may be important in understanding the mechanisms by which mild nitrosative stress protects cells against certain forms of cellular stress conditions. PMID- 26626597 TI - Parasites, Power, and Photography. PMID- 26626598 TI - Human Health Risks Associated with Metals from Urban Soil and Road Dust in an Oilfield Area of Southeastern Algeria. AB - Hassi Messaoud town is a recent city that is situated inside the oil field, which hosts an important petroleum extraction field and refinery. Large-scale and long term oil refinery and corresponding industrial activities may contaminate the surrounding soil/dust and could lead to pollution levels that can affect human health. The soil and road dust samples were analysed for different trace elements: copper (Cu), manganese (Mn), nickel (Ni), lead (Pb), and zinc (Zn). Geo accumulation index (I(geo)), pollution index (PI), and integrated pollution index (IPI) were calculated to evaluate the heavy metal contamination level of urban soil and road dust. The I(geo) values indicate unpolluted to moderate polluted of investigated metals in the soil samples. The assessment results of PI support the results of I(geo), and IPI indicates heavy metals in road dust polluted seriously. The noncarcinogenic health risk assessment shows that ingestion of soil/dust particles is the route for exposure to heavy metals, followed by dermal adsorption. The human exposure risk assessment based on different exposure pathways showed that the hazard index (HI) was <1.0 for all of the elements. The relative exposure risk (noncarcinogenic) was greater for toddlers. Although the overall risk was within the acceptable limit of 1.00, the HI of Pb from the soil (0.103) and road dust (0.132) was close to the threshold limits, which over the long-term may pose a health risk. PMID- 26626599 TI - The Association Between Urinary Benzophenone Concentrations and Personal Care Product Use in Korean Adults. AB - Benzophenone (BP) derivatives are widely used in personal care products (PCPs) for protection from ultraviolet radiation. Because of their broad applications, BP derivatives have been found in various human bodily fluids. In the present study, we investigated the relationship between urinary concentrations of BP derivatives and PCP use in Korean adults. A urinary BP biomonitoring survey was conducted in Korea by the Ministry of Food and Drug Safety in 2014. BP derivatives (BP-1, BP-3, and 4-OH-BP) were measured in urine samples from 168 Korean adults (mean age, 43.2 +/- 15.4 years) by high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry. Information about the use of PCPs in the past 7 days was obtained by direct interviews. The mean levels of BP-1, BP-3, and 4-OH-BP were 0.87, 5.87, and 0.13 ng/g creatinine, respectively. The geometric mean levels of BP-1, BP-3, and 4-OH BP were significantly higher in female than those in male. The medians of the urinary concentration of BP derivatives were significantly higher among users of the following PCPs than those in non-users; the PCPs included sunscreen, skin care products, functional cosmetics, makeup base, makeup, lip cosmetics, eye cosmetics, color cosmetics, perfume products, and nail products. A regression analysis revealed a significant linear association between urinary BP-3 concentrations and the number of additional cosmetic products used. These findings provide evidence of a positive association between exposure to PCPs and urinary BP derivative concentrations in Korean adults. PMID- 26626600 TI - What's New About the New US Obesity Guidelines? PMID- 26626596 TI - Mosquito Defense Strategies against Viral Infection. AB - Mosquito-borne viral diseases are a major concern of global health and result in significant economic losses in many countries. As natural vectors, mosquitoes are very permissive to and allow systemic and persistent arbovirus infection. Intriguingly, persistent viral propagation in mosquito tissues neither results in dramatic pathological sequelae nor impairs the vectorial behavior or lifespan, indicating that mosquitoes have evolved mechanisms to tolerate persistent infection and developed efficient antiviral strategies to restrict viral replication to nonpathogenic levels. Here we provide an overview of recent progress in understanding mosquito antiviral immunity and advances in the strategies by which mosquitoes control viral infection in specific tissues. PMID- 26626601 TI - Obesity Prevention in Latin America. AB - In Latin American countries, obesity prevalence has increased significantly as a result of rapid urbanization and an improvement in socioeconomic conditions. We report the prevalence of overweight and/or obesity and prevention efforts in five countries: Mexico, Colombia, Brazil, Peru, and Chile. In children, the highest and lowest rates of obesity are found in Chile (23 % in 6-year-olds) and Peru (1.8 % in those <5 years), respectively. In adults, Mexico and Chile present similar high rates of obesity (around 35 %), whereas in Brazil and Colombia, the rates are around 20 % and 16.5 %, respectively. In general, the highest prevalence occurs in low-income women. Every country has developed initiatives to target obesity, from the government to the private sector and academia, mainly at the health sector and school settings. Food labeling is being addressed, but has not been implemented yet. Two interventions are described, a community-based in Mexico and a school-based in Chile. Because the increase in chronic diseases, especially diabetes, has paralleled that of obesity, effective prevention efforts are urgently needed. PMID- 26626603 TI - Obesity Interventions in the Community : Engaged and Participatory Approaches. AB - Obesity is a pervasive global public health concern of utmost priority. Effective and efficient interventions are urgently needed to reverse current trends, especially among children. The past decade has witnessed increasing adoption and implementation of community-engaged and -participatory interventions that employ a bottom-up approach to identifying and realizing sustainable solutions within communities. It is argued herein that community-based approaches are most effective when implemented via a systems perspective that integrates across societal sectors. This approach seizes upon the synergistic effects that result from simultaneously mobilizing community assets at multiple levels. This paper provides an overview of the evolution and theory behind community-engaged, community-participatory, and systems-level interventions, discusses recent findings in the field, offers reflections based on first-hand experience, outlines advances in relevant resources, and lays forth potential and promising directions for future research. It emphasizes the centrality and necessity of community-engaged systems-level interventions in halting and reversing the obesity epidemic. PMID- 26626602 TI - Activity-Friendly Built Environment Attributes and Adult Adiposity. AB - Physically-active and sedentary behaviors are determinants of adult weight gain and are associated with built-environment attributes. We reviewed recent evidence on built-environment attributes with adult adiposity. Of 41 relevant papers identified, 34 reported cross-sectional, six recorded prospective findings, and one included both cross-sectional and prospective designs. In 15 cross-sectional examinations of composite built environment indices (walkability; composite other), seven identified significant positive relationships in the expected direction; of 42 instances examining particular walkability elements (density, connectivity, land use mix), 13 were positive. Of 44 instances examining proximity of utilitarian and recreational destinations, there were 13 positive associations; and, of 41 instances examining pedestrian-environment attributes, 12 were positive. In the seven prospective studies, 20 sets of relationships were identified - nine were significant and in the expected direction. Evidence on built environment/adiposity relationships remains modest and could be strengthened through improvements in measurement methods and with further evidence from prospective studies. PMID- 26626604 TI - Worksite Environmental Interventions for Obesity Prevention and Control: Evidence from Group Randomized Trials. AB - Worksites provide multiple advantages to prevent and treat obesity and to test environmental interventions to tackle its multiple causal factors. We present a literature review of group-randomized and non-randomized trials that tested worksite environmental, multiple component interventions for obesity prevention and control paying particular attention to the conduct of formative research prior to intervention development. The evidence on environmental interventions on measures of obesity appears to be strong since most of the studies have a low (4/8) and unclear (2/8) risk of bias. Among the studies reviewed whose potential risk of bias was low, the magnitude of the effect was modest and sometimes in the unexpected direction. None of the four studies describing an explicit formative research stage with clear integration of findings into the intervention was able to demonstrate an effect on the main outcome of interest. We present alternative explanation for the findings and recommendations for future research. PMID- 26626605 TI - Hypothalamic Inflammation: Is There Evidence for Human Obesity? AB - With increasing awareness of the obesity epidemic have come research efforts to understand the pathophysiology of body weight and appetite regulation. Clinical trials of diet-induced weight loss demonstrate the difficulty of achieving long term success in obese and overweight individuals, leading investigators to examine the question of what mechanisms makes weight loss so difficult. This has lead to a greater focus on neurologic and hormonal reasons that could explain why maintenance of lost weight is so challenging. Injury to the hypothalamic areas known to play a role in feeding and body weight regulation is being studied. Mechanisms of hypothalamic injury include increased inflammation, gliosis/scarring, and apoptosis of anorexigenic neurons in rodent models of diet induced obesity. Although there is evidence of hypothalamic damage due to interference of cell signaling and eventual loss of weight regulating neurons in rodent models, there is limited data thus far on whether we can apply this mechanism of injury to human obesity. PMID- 26626607 TI - The BMI: Is It Time to Scratch for a More Accurate Assessment of Metabolic Dysfunction? AB - The body mass index (BMI = Kg/M(2)) is not a valid measure for clinical decisions, especially whether a patient will benefit from bariatric surgery. The measure, as used, discriminates against the muscular, the aged, women, and racial groups such as Asians and African Americans. The requirement must be eliminated since it denies many patients the only currently available therapy. This chapter provides the bibliographic data to support this argument and should prove useful in convincing carriers that the BMI is an inaccurate and, too often, cruel guideline. PMID- 26626606 TI - Food Classification Systems Based on Food Processing: Significance and Implications for Policies and Actions: A Systematic Literature Review and Assessment. AB - This paper is the first to make a systematic review and assessment of the literature that attempts methodically to incorporate food processing into classification of diets. The review identified 1276 papers, of which 110 were screened and 21 studied, derived from five classification systems. This paper analyses and assesses the five systems, one of which has been devised and developed by a research team that includes co-authors of this paper. The quality of the five systems is assessed and scored according to how specific, coherent, clear, comprehensive and workable they are. Their relevance to food, nutrition and health, and their use in various settings, is described. The paper shows that the significance of industrial food processing in shaping global food systems and supplies and thus dietary patterns worldwide, and its role in the pandemic of overweight and obesity, remains overlooked and underestimated. Once food processing is systematically incorporated into food classifications, they will be more useful in assessing and monitoring dietary patterns. Food classification systems that emphasize industrial food processing, and that define and distinguish relevant different types of processing, will improve understanding of how to prevent and control overweight, obesity and related chronic non communicable diseases, and also malnutrition. They will also be a firmer basis for rational policies and effective actions designed to protect and improve public health at all levels from global to local. PMID- 26626608 TI - Putting Meaning Back Into the Mean: A Comment on the Misuse of Elementary Statistics in a Sample of Manuscripts Submitted to Clinical Therapeutics. AB - PURPOSE: Errors in the statistical presentation and analyses of data in the medical literature remain common despite efforts to improve the review process, including the creation of guidelines for authors and the use of statistical reviewers. This article discusses common elementary statistical errors seen in manuscripts recently submitted to Clinical Therapeutics and describes some ways in which authors and reviewers can identify errors and thus correct them before publication. METHODS: A nonsystematic sample of manuscripts submitted to Clinical Therapeutics over the past year was examined for elementary statistical errors. FINDINGS: Clinical Therapeutics has many of the same errors that reportedly exist in other journals. IMPLICATIONS: Authors require additional guidance to avoid elementary statistical errors and incentives to use the guidance. Implementation of reporting guidelines for authors and reviewers by journals such as Clinical Therapeutics may be a good approach to reduce the rate of statistical errors. PMID- 26626609 TI - Preoperative Cognitive and Frailty Screening in the Geriatric Surgical Patient: A Narrative Review. AB - PURPOSE: The identification of older patients who may have deficits in cognitive or functional domains will become more pressing as increasing numbers of these patients present for preoperative evaluations. The number of older adults with deficiencies in these areas is projected to grow, and more of these patients will present for assessment in preoperative clinics with the expectation that surgeries will be performed. METHODS: We review current outcomes data for preoperative cognitive impairment and frailty. FINDINGS: We point to a number of directions research is taking as systems for the prevention of postoperative cognitive and functional decline are being developed. We also discuss the current status of screening and examine potential instruments that can be used in the setting of the preanesthesia clinic. IMPLICATIONS: Clinicians may anticipate that geriatric screening tools focused on cognitive and functional domains will play a direct role in the ongoing evolution of presurgical assessment and triage. PMID- 26626610 TI - Image-guided volumetric arc radiotherapy of pancreatic cancer with simultaneous integrated boost: Optimization strategies and dosimetric results. AB - PURPOSE: To introduce volumetric modulated arc therapy treatments (VMAT) with simultaneous integrated boost (SIB) for pancreatic cancer and describe dosimetric results on a large patient series. METHODS AND MATERIALS: 45 patients with pancreatic malignancies were treated with 18 MV single-arc VMAT. Image guidance was performed with daily online kilo-volt cone-beam computed tomography (CBCT). The conformity index (CI) and homogeneity index (HI) to the target volumes, PTV45Gy and PTV54Gy, and dose-volume indices to OARs from the QUANTEC task group were reported. The risk of clinical nephritis was evaluated using normal tissue complication probability (NTCP). Treatments were verified in-phantom with the Delta4 system. RESULTS: Average CI was 1.06 with 95% confidence intervals (95% CI) of 0.97-1.22 for PTV45Gy and 1.17 (0.66-1.61) for PTV54Gy. HI of PTV54Gy was 1.06 (1.04-1.10). OAR constraints were achieved in all patients, except for kidneys V12Gy of 48 (35.4-72.3)%. NTCP of the kidneys was 0.98 (0.6-1.7)%. Kidneys V12Gy and V20Gy were inversely related to PTV54Gy CI and maximum dose. All in-phantom tests had gamma pass rates exceeding 95% with global 3% dose difference and 3 mm distance to agreement. Patient shifts measured with CBCT had 95% CI of -0.8, +0.8 in the RL, -0.7, +0.8 in the SI, and -0.8, +0.7 cm in the AP directions. CONCLUSIONS: Dosimetric results of VMAT were excellent on PTVs and organs at risk. The kidneys represent the dose-limiting organ at risk for this technique. NTCP indicates that this technique is safe from radiation-induced side effects to the kidneys. PMID- 26626611 TI - Erratum to: New Treatment Modalities for Hepatocellular Cancer. PMID- 26626612 TI - The association between hemispheric specialization for language production and for spatial attention depends on left-hand preference strength. AB - Cerebral lateralization for language production and spatial attention and their relationships with manual preference strength (MPS) were assessed in a sample of 293 healthy volunteers, including 151 left-handers, using fMRI during covert sentence production (PROD) and line bisection judgment (LBJ) tasks, as compared to high- and low-level reference tasks. At the group level, we found the expected complementary hemispheric specialization (HS) with leftward asymmetries for PROD within frontal and temporal regions and rightward asymmetries for LBJ within frontal and posterior occipito-parieto-temporal regions. Individual hemispheric (HLI) and regional (frontal and occipital) lateralization indices (LI) were then calculated on the activation maps for PROD and LBJ. We found a correlation between the degree of rightward cerebral asymmetry and the leftward behavioral attentional bias recorded during LBJ task. This correlation was found when LBJ-LI was computed over the hemispheres, in the frontal lobes, but not in the occipital lobes. We then investigated whether language production and spatial attention cerebral lateralization relate to each other, and whether manual preference was a variable that impacted the complementary HS of these functions. No correlation was found between spatial and language LIs in the majority of our sample of participants, including right-handers with a strong right-hand preference (sRH, n=97) and mixed-handers (MH, n=97), indicating that these functions lateralized independently. By contrast, in the group of left-handers with a strong left-hand preference (sLH, n= 99), a negative correlation was found between language and spatial lateralization. This negative correlation was found when LBJ-LI and PROD LI were computed over the hemispheres, in the frontal lobes and between the occipital lobes for LBJ and the frontal lobes for PROD. These findings underline the importance to include sLH in the study sample to reveal the underlying mechanisms of complementary HS. PMID- 26626613 TI - Parallel-Serial Memoing: A Novel Approach to Analyzing Qualitative Data. AB - The mechanisms by which talking therapies exert their beneficial effects are largely unknown. In exploring the process of a talking therapy, motivational interviewing (MI), when used to treat and prevent low mood in stroke survivors, we developed, what we believe to be, a novel approach to analyzing transcripts. We illustrate the method using qualitative data from MI sessions with 10 stroke survivors. The approach, drawing on grounded theory, incorporated processes of parallel and serial memoing among a team of researchers to allow a process of validation. This enabled us to describe session content and to develop theoretical interpretations of what was occurring in and across MI sessions. We found that this process can be used to integrate different perspectives in theory building, allowing for a richer description and more robust theoretical interpretation. Others can use and adapt this approach to develop insights into their own inquiry. PMID- 26626614 TI - Researcher Linguistic Vulnerability: A Note on Methodological Implications. AB - We reflect on the experiences of a researcher conducting a pilot exercise project with marginalized research participants within the substance use disorder treatment field, in a language that was nonnative to her. While the project collected and analyzed quantitative data, the researcher was motivated by qualitative inquiry's commitment to reducing participant-researcher distance and power differences. Despite multiple sources of power imbalances favoring the researcher, the ability of participants to speak their native language to a nonnative researcher, and the researcher's active recognition of her linguistic vulnerability, appeared to afford them an unexpected source of power within the context of the project. We discuss the researcher's observations of these power dynamics and their implications for cross-cultural research and when working with marginalized research participants. PMID- 26626615 TI - Developments in the production of mucosal antibodies in plants. AB - Recombinant mucosal antibodies represent attractive target molecules for the development of next generation biopharmaceuticals for passive immunization against various infectious diseases and treatment of patients suffering from mucosal antibody deficiencies. As these polymeric antibodies require complex post translational modifications and correct subunit assembly, they are considered as difficult-to-produce recombinant proteins. Beside the traditional, mammalian based production platforms, plants are emerging as alternative expression hosts for this type of complex macromolecule. Plant cells are able to produce high quality mucosal antibodies as shown by the successful expression of the secretory immunoglobulins A (IgA) and M (IgM) in various antibody formats in different plant species including tobacco and its close relative Nicotiana benthamiana, maize, tomato and Arabidopsis thaliana. Importantly for biotherapeutic application, transgenic plants are capable of synthesizing functional IgA and IgM molecules with biological activity and safety profiles comparable with their native mammalian counterparts. This article reviews the structure and function of mucosal IgA and IgM antibodies and summarizes the current knowledge of their production and processing in plant host systems. Specific emphasis is given to consideration of intracellular transport processes as these affect assembly of the mature immunoglobulins, their secretion rates, proteolysis/degradation and glycosylation patterns. Furthermore, this review provides an outline of glycoengineering efforts that have been undertaken so far to produce antibodies with homogenous human-like glycan decoration. We believe that the continued development of our understanding of the plant cellular machinery related to the heterologous expression of immunoglobulins will further improve the production levels, quality and control of post-translational modifications that are 'human like' from plant systems and enhance the prospects for the regulatory approval of such molecules leading to the commercial exploitation of plant-derived mucosal antibodies. PMID- 26626616 TI - The New Age of Molecular Taxonomy Approaches. PMID- 26626618 TI - Comparing Everolimus to Sunitinib in Non-clear-cell Renal Cell Carcinoma. PMID- 26626617 TI - Everolimus Versus Sunitinib Prospective Evaluation in Metastatic Non-Clear Cell Renal Cell Carcinoma (ESPN): A Randomized Multicenter Phase 2 Trial. AB - BACKGROUND: Sunitinib and everolimus are standard first-line and second-line therapies, respectively, in clear cell renal cell carcinoma (ccRCC). OBJECTIVE: To conduct a randomized phase 2 trial comparing sunitinib and everolimus in non clear cell RCC (non-ccRCC). DESIGN, SETTING, AND PARTICIPANTS: Patients with metastatic, non-ccRCC, or ccRCC with >20% sarcomatoid features (ccSRCC) were randomized to receive sunitinib or everolimus with crossover at disease progression. OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS: Primary end point was progression-free survival (PFS) in first-line therapy; 108 patients were needed to show improvement in median PFS (mPFS) from 12 wk with sunitinib to 20 wk with everolimus. RESULTS AND LIMITATIONS: Interim analysis of 68 patients (papillary [27], chromophobe [12], unclassified [10], translocation [7], ccSRCC [12]) prompted early trial closure. The mPFS in first-line therapy was 6.1 mo with sunitinib and 4.1 mo with everolimus (p=0.6); median overall survival (mOS) was not reached with sunitinib and was 10.5 mo with everolimus, respectively (p=0.014). At final analysis, mOS was 16.2 and 14.9 mo with sunitinib and everolimus, respectively (p=0.18). There were four partial responses (PRs) in first-line therapy (sunitinib: 3 of 33 [9%]; everolimus, 1 of 35 [2.8%]) and four PRs in second-line therapy (sunitinib: 2 of 21 [9.5%]; everolimus, 2 of 23 [8.6%]), with mPFS of 1.8 mo and 2.8 mo, respectively. In patients without sarcomatoid features in their tumors (n=49), mOS was 31.6 mo with sunitinib and 10.5 mo with everolimus (p=0.075). Genomic profiling of a chromophobe RCC from a patient with a PR to first-line everolimus revealed a somatic TSC2 mutation. CONCLUSIONS: In this trial, everolimus was not superior to sunitinib. Both agents demonstrated modest efficacy, underscoring the need for better therapies in non ccRCC. PATIENT SUMMARY: This randomized phase 2 trial provides the first head-to head comparison of everolimus and sunitinib in patients with metastatic non-clear cell renal cell carcinoma (non-ccRCC). The observed very modest efficacy underscores the need to develop more effective therapies for non-ccRCC. PMID- 26626619 TI - A "Chicken or Egg" Conundrum: Race, Molecular Subtype, and Tumor Location in Prostate Cancer. PMID- 26626620 TI - Bio-objectifying European bodies: standardisation of biobanks in the Biobanking and Biomolecular Resources Research Infrastructure. AB - The article traces the genealogy of the Minimum Information About Biobank Data Sharing model, created in the European Biobanking and Biomolecular Resources Research Infrastructure to facilitate collaboration among biobanks and to foster the exchange of biological samples and data. This information model is aimed at the identification of biobanks; unification of databases; and objectification of the information, samples, and related studies - to create a completely new 'bio object infrastructure' within the EU. The paper discusses key challenges in creating a 'universal' information model of such a kind, the most important technical translations of European research policy needed for a standardised model for biobank information, and how this model creates new bio-objects. The author claims that this amounts to redefinition of biobanks and technical governance over virtually bio-objectified European populations. It is argued here that old governance models based on the nation-state need radical reconsideration so that we are prepared for a new and changing situation wherein bodies of information that lack organs flow from one database to another with a click of a mouse. PMID- 26626622 TI - Heterogeneity of tumor endothelial cells and drug delivery. AB - To date anti-angiogenic therapy has been used for cancer therapy widely, yielding promising results. However, it has been elucidated that current anti-angiogenic drug has several issues to be solved, such as side-effects and drug resistance. It has been reported that tumor endothelial cells (TECs) differ from normal counterparts. In addition, it was shown that the TECs are heterogeneous according to the malignancy status of tumor. The development of novel strategy for targeting tumor vasculature is required. Recently, we have developed an active targeting system, which targets TECs specifically. In this review, we will discuss how TECs in tumor vasculature are heterogeneous and offer new perspectives on a drug delivery system, which can target heterogeneous tumor blood vessels from a viewpoint of personalized medicine. PMID- 26626621 TI - Do CSF Biomarkers Predict Progression to Cognitive Impairment in Parkinson's disease patients? A Systematic Review. AB - Many patients with Parkinson's disease (PD) will develop cognitive impairment. Cross-sectional studies have shown that certain protein levels are altered in the cerebrospinal fluid (CSF) of PD patients with dementia and are thought to represent potential biomarkers of underlying pathogenesis. Recent studies suggest that CSF biomarker levels may be predictive of future risk of cognitive decline in non-demented PD patients. However, the strength of this evidence and difference between specific CSF biomarkers is not well delineated. We therefore performed a systematic review to assess if levels of specific CSF protein biomarkers are predictive of progression to cognitive impairment. Nine articles were identified that met inclusion criteria for the review. Findings from the review suggest a convergence of evidence that a low baseline Abeta42 in the CSF of non-demented PD patients predicts development of cognitive impairment over time. Conversely, there is limited evidence that CSF levels of tau, either total tau or phosphorylated tau, is a useful predictive biomarker. There are mixed results for other CSF biomarkers such as alpha-synuclein, Neurofilament light chain, and Heart fatty acid-binding protein. Overall the results of this review show that certain CSF biomarkers have better predictive ability to identify PD patients who are at risk for developing cognitive impairment. Given the interest in developing disease-modifying therapies, identifying this group will be important for clinical trials as initiation of therapy prior to the onset of cognitive decline is likely to be more efficacious. PMID- 26626623 TI - Fault diagnosis method based on FFT-RPCA-SVM for Cascaded-Multilevel Inverter. AB - Thanks to reduced switch stress, high quality of load wave, easy packaging and good extensibility, the cascaded H-bridge multilevel inverter is widely used in wind power system. To guarantee stable operation of system, a new fault diagnosis method, based on Fast Fourier Transform (FFT), Relative Principle Component Analysis (RPCA) and Support Vector Machine (SVM), is proposed for H-bridge multilevel inverter. To avoid the influence of load variation on fault diagnosis, the output voltages of the inverter is chosen as the fault characteristic signals. To shorten the time of diagnosis and improve the diagnostic accuracy, the main features of the fault characteristic signals are extracted by FFT. To further reduce the training time of SVM, the feature vector is reduced based on RPCA that can get a lower dimensional feature space. The fault classifier is constructed via SVM. An experimental prototype of the inverter is built to test the proposed method. Compared to other fault diagnosis methods, the experimental results demonstrate the high accuracy and efficiency of the proposed method. PMID- 26626625 TI - Congenital Myasthenic Syndrome Type 19 Is Caused by Mutations in COL13A1, Encoding the Atypical Non-fibrillar Collagen Type XIII alpha1 Chain. AB - The neuromuscular junction (NMJ) consists of a tripartite synapse with a presynaptic nerve terminal, Schwann cells that ensheathe the terminal bouton, and a highly specialized postsynaptic membrane. Synaptic structural integrity is crucial for efficient signal transmission. Congenital myasthenic syndromes (CMSs) are a heterogeneous group of inherited disorders that result from impaired neuromuscular transmission, caused by mutations in genes encoding proteins that are involved in synaptic transmission and in forming and maintaining the structural integrity of NMJs. To identify further causes of CMSs, we performed whole-exome sequencing (WES) in families without an identified mutation in known CMS-associated genes. In two families affected by a previously undefined CMS, we identified homozygous loss-of-function mutations in COL13A1, which encodes the alpha chain of an atypical non-fibrillar collagen with a single transmembrane domain. COL13A1 localized to the human muscle motor endplate. Using CRISPR-Cas9 genome editing, modeling of the COL13A1 c.1171delG (p.Leu392Sfs(*)71) frameshift mutation in the C2C12 cell line reduced acetylcholine receptor (AChR) clustering during myotube differentiation. This highlights the crucial role of collagen XIII in the formation and maintenance of the NMJ. Our results therefore delineate a myasthenic disorder that is caused by loss-of-function mutations in COL13A1, encoding a protein involved in organization of the NMJ, and emphasize the importance of appropriate symptomatic treatment for these individuals. PMID- 26626627 TI - Metal induction of a Pisolithus albus metallothionein and its potential involvement in heavy metal tolerance during mycorrhizal symbiosis. AB - Metallothioneins (MTs) are small, cysteine-rich peptides involved in intracellular sequestration of heavy metals in eukaryotes. We examined the role in metal homeostasis and detoxification of an MT from the ectomycorrhizal fungus Pisolithus albus (PaMT1). PaMT1 encodes a 35 amino acid-long polypeptide, with 7 cysteine residues; most of them part of a C-x-C motif found in other known basidiomycete MTs. The expression levels of PaMT1 increased as a function of increased external Cu and Cd concentrations and were higher with Cu than with Cd. Heterologous complementation assays in metal-sensitive yeast mutants indicated that PaMT1 encodes a polypeptide capable of conferring higher tolerance to both Cu and Cd. Eucalyptus tereticornis plantlets colonized with P. albus grown in the presence of Cu and Cd showed better growth compared with those with non mycorrhizal plants. Higher PaMT1 expression levels were recorded in mycorrhizal plants grown in the presence of Cu and Cd compared with those in control mycorrhizal plants not exposed to heavy metals. These data provide the first evidence to our knowledge that fungal MTs could protect ectomycorrhizal fungi from heavy metal stress and in turn help the plants to establish in metal contaminated sites. PMID- 26626626 TI - Linking Essential Tremor to the Cerebellum-Neuroimaging Evidence. AB - Essential tremor (ET) is the most common pathological tremor disorder in the world, and post-mortem evidence has shown that the cerebellum is the most consistent area of pathology in ET. In the last few years, advanced neuroimaging has tried to confirm this evidence. The aim of the present review is to discuss to what extent the evidence provided by this field of study may be generalised. We performed a systematic literature search combining the terms ET with the following keywords: MRI, VBM, MRS, DTI, fMRI, PET and SPECT. We summarised and discussed each study and placed the results in the context of existing knowledge regarding the cerebellar involvement in ET. A total of 51 neuroimaging studies met our search criteria, roughly divided into 19 structural and 32 functional studies. Despite clinical and methodological differences, both functional and structural imaging studies showed similar findings but without defining a clear topography of neurodegeneration. Indeed, the vast majority of studies found functional and structural abnormalities in several parts of the anterior and posterior cerebellar lobules, but it remains to be established to what degree these neural changes contribute to clinical symptoms of ET. Currently, advanced neuroimaging has confirmed the involvement of the cerebellum in pathophysiological processes of ET, although a high variability in results persists. For this reason, the translation of this knowledge into daily clinical practice is again partially limited, although new advanced multivariate neuroimaging approaches (machine-learning) are proving interesting changes of perspective. PMID- 26626629 TI - Agatoxin-like peptides in the neuroendocrine system of the honey bee and other insects. AB - We investigated the peptide inventory of the corpora cardiaca (CC) of the honey bee, Apis mellifera, by direct tissue profiling using MALDI-TOF MS combined with proteomic approaches focusing on cysteine-containing peptides. An agatoxin-like peptide (ALP) was identified as a component of the glandular part of the CC and was associated with the presence of the adipokinetic hormone in mass spectra. Although abundant in the CC, ALP does not belong to the toxins observed in the venom gland of A. mellifera. Homologs of ALP are highly conserved in major groups of arthropods and in line with this we detected ALP in the CC of non-venomous insects such as cockroaches and silverfish. In the American cockroach, Periplaneta americana, ALP was also identified in the CNS and stomatogastric nervous system. This is the first report that establishes the presence of ALPs in the neuroendocrine tissues of insects and further studies are necessary to reveal common functions of these peptides, e.g. as antimicrobial agents, ion channel modulators or classical neuropeptides. BIOLOGICAL SIGNIFICANCE: Among the messenger molecules of the nervous system, neuropeptides represent the structurally most diverse class and basically participate in the regulation of all physiological processes. The set of neuropeptides, their functions and spatial distribution are particularly well-studied in insects. Until now, however, several potential neuropeptide receptors remained orphan, which indicates the existence of so far unknown ligands. In our study, we used proteomic methods such as cysteine modification, enzymatic digestion and peptide derivatization, combined with direct tissue profiling by MALDI-TOF mass spectrometry, for the discovery of novel putative messenger molecules in the neuroendocrine system. The described presence of agatoxin-like peptides in the nervous system of the honey bee and other insects was overseen so far and is thus a remarkable addition to the very well studied neuropeptidome of insects. It is not yet clear, if these toxin-like peptides act as antimicrobial agents, ion channel modulators or classical neuropeptides. PMID- 26626624 TI - Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture. AB - Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with PsA and 11 with PsC at genome-wide (GW) significance. Several of these association signals (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A, NFKBIA for PsC) have not previously achieved GW significance. After replication, we also identified a PsV-associated SNP near CDKAL1 (rs4712528, odds ratio [OR] = 1.16, p = 8.4 * 10(-11)). Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 * 10(-19); rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022). The PsA-specific variants were independent of previously identified psoriasis variants near IL23R and TNFAIP3. We also found multiple independent susceptibility variants in the IL12B, NOS2, and IFIH1 regions. These results provide insights into the pathogenetic similarities and differences between PsC and PsA. PMID- 26626628 TI - Glycomics: revealing the dynamic ecology and evolution of sugar molecules. AB - Sugars are the most functionally and structurally diverse molecules in the biological world. Glycan structures range from tiny single monosaccharide units to giant chains thousands of units long. Some glycans are branched, their monosaccharides linked together in many different combinations and orientations. Some exist as solitary molecules; others are conjugated to proteins and lipids and alter their collective functional properties. In addition to structural and storage roles, glycan molecules participate in and actively regulate physiological and developmental processes. Glycans also mediate cellular interactions within and between individuals. Their roles in ecology and evolution are pivotal, but not well studied because glycan biochemistry requires different methods than standard molecular biology practice. The properties of glycans are in some ways convenient, and in others challenging. Glycans vary on organismal timescales, and in direct response to physiological and ecological conditions. Their mature structures are physical records of both genetic and environmental influences during maturation. We describe the scope of natural glycan variation and discuss how studying glycans will allow researchers to further integrate the fields of ecology and evolution. PMID- 26626630 TI - Focal myositis presenting as pseudothrombophlebitis of the arm. AB - We described a 21-year-old woman with a diagnosis of Sjogren syndrome that came for consultation with a localized mass over her left arm of fast growth. Lab results were normal; a Doppler ultrasound showed the presence of partial thrombosis in the left axillary vein; a magnetic resonance imaging showed edema on the biceps muscle and the biopsy of the mass disclosed the presence of severe lymphocyte infiltrate within the connective tissue and scarce muscle fibers. Immunostaining showed positive results for antigeno comun leucocitario in spanish (leukocyte common antigen) (ACL) and CD3. Those results are consistent with the diagnosis of focal myositis. The patient was treated with low doses of prednisone and methotrexate, with good response. PMID- 26626631 TI - Etanercept treatment-related c-ANCA-associated large vessel vasculitis. AB - Anti-tumor necrosis factor (TNF) agents have become central players in the management of autoimmune and rheumatic disease. With the wide use of anti-TNF agents today, we have become aware of rare autoimmune complications as systemic lupus erythematosus and psoriasis, yet rarely has large vessels vasculitis been described. We herein describe a case of cytoplasmic anti-neutrophil cytoplasmic antibody (c-ANCA) (with myeloperoxidase (MPO) antibodies)-associated large vessel vasculitis (aortitis) that developed during anti-TNF treatment for ankylosing spondylitis. Awareness of this rare, but serious, adverse event of these commonly used agents in rheumatic diseases is of importance. PMID- 26626634 TI - After 14 years of work and progress. PMID- 26626632 TI - Juvenile idiopathic arthritis activity and function ability: deleterious effects in periodontal disease? AB - The impact of juvenile idiopathic arthritis (JIA) in periodontal diseases is controversial probably due to gender and age heterogeneity. We therefore evaluated a homogeneous female post-pubertal JIA population for these conditions. Thirty-five JIA patients and 35 gender/age comparable healthy controls were evaluated according to demographic data, complete periodontal evaluation, fasting lipoproteins, and anti-lipoprotein lipase antibodies. JIA scores, laboratorial tests, X-rays, and treatment were also assessed. Current age was similar in JIA patients and controls (11.90 +/- 2.0 vs. 12.50 +/- 3.0 years, p = 0.289). Complete periodontal assessments revealed that gingival index, dental plaque, gingival bleeding, and clinical dental attachment indices were alike in JIA patients and controls (p > 0.05), except for gingival enlargement in former group (p < 0.0001). Further analysis of patients with and without gingivitis revealed that cyclosporine use was more often observed in JIA patients with gingivitis (37 vs. 0%, p = 0.01), whereas no differences were evidenced in demographic, JIA scores, inflammatory markers, and lipid profile in both groups. Of note, two parameters of periodontal assessment were correlated with JIA scores [gingival index (GI) and Childhood Health Assessment Questionnaire (CHAQ) (r s = +0.402, p = 0.020)] and plaque index (PI) and visual analog scale (VAS) physician (r s = +0.430, p = 0.013). In addition, evaluation of dental assessment demonstrated that JIA activity scores had positive correlation with decayed, missing, and filled teeth (DMF-T) and junvenile athritis disease activity score (JADAS) (r s = +0.364,p = 0.037), VAS physician (r s = +0.401,p = 0.021) and VAS patient (r s = +0.364,p = 0.037). We demonstrated, using rigorous criteria, that periodontal and dental condition in JIA is similar to controls. In spite of that, the finding of a correlation with disease parameters provides additional evidence that increased activity and reduced functional ability underlies the deleterious effect of JIA in oral health. PMID- 26626635 TI - The role of zinc in liver cirrhosis. AB - Zinc is an essential trace element playing fundamental roles in cellular metabolism. It acts mostly by binding a wide range of proteins, thus affecting a broad spectrum of biological processes, which include cell division, growth and differentiation. Zinc is critical to a large number of structural proteins, enzymatic processes, and transcription factors. Zinc deficiency can result in a spectrum of clinical manifestations, such as poor of appetite, loss of body hair, altered taste and smell, testicular atrophy, cerebral and immune dysfunction, and diminished drug elimination capacity. These are common symptoms in patients with chronic liver diseases, especially liver cirrhosis. The liver is the main organ responsible for the zinc metabolism which can be affected by liver diseases. On the other hand, zinc deficiency may alter hepatocyte functions and also immune responses in inflammatory liver diseases. Liver cirrhosis represents the most advanced stage of chronic liver diseases and is the common outcome of chronic liver injury. It is associated with energy malnutrition, with numerous metabolic disorders, such as hypoalbuminemia, with imbalance between branched-chain amino acids and aromatic amino acids, and with reduced zinc serum concentrations. All these processes can influence the clinical outcome of patients, such ascites, hepatic encephalopathy and hepatocellular carcinoma. In the present review, we summarize the emerging evidence on the pitoval role of zinc in the pathogenesis of liver cirrhosis. PMID- 26626636 TI - Hepatitis C virus strategies to evade the specific-T cell response: a possible mission favoring its persistence. AB - Hepatitis C virus (HCV) is a small, enveloped RNA virus. The number of HCV infected individuals worldwide is estimated to be approximately 200 million. The vast majority of HCV infections persist, with up to 80% of all cases leading to chronic hepatitis associated with liver fibrosis, cirrhosis, and hepatocellular carcinoma. The interaction between HCV and the host have a pivotal role in viral fitness, persistence, pathogenicity, and disease progression. The control of HCV infection requires both effective innate and adaptive immune responses. The HCV clearance during acute infection is associated with an early induction of the innate and a delayed initiation of the adaptive immune responses. However, in the vast majority of acute HCV infections, these responses are overcome and the virus persistence almost inexorably occurs. Recently, several host- and virus-related mechanisms responsible for the failure of both the innate and the adaptive immune responses have been recognized. Among the latter, the wide range of escape mutations to evade the specific-T-and B-cell responses as well as the T cell anergy and the CD8+ T cell exhaustion together with the interference with its function after prolonged virus exposure hold a pivotal role. Other HCV strategies include the modification or manipulation of molecules playing key roles in the induction of the interferon response and its induced effector proteins. In this review, we attempt to gain insights on the main T cell immune evasion strategies used by the virus in order to favor its persistence. PMID- 26626637 TI - Biochemical non-invasive assessment of liver fibrosis cannot replace biopsy in HIV-HCV coinfected patients. AB - BACKGROUND AND RATIONALE: The liver biopsy has been considered the gold standard for the diagnosis and quantification of fibrosis. However, this method presents limitations. In addition, the non-invasive evaluation of liver fibrosis is a challenge. The aim of this study was to validate the fibrosis cirrhosis index (FCI) index in a cohort of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients, and compare to AST/ALT ratio (AAR), AST to platelet ratio index (APRI) and FIB-4 scores, as a tool for the assessment of liver fibrosis in coinfected patients. MATERIAL AND METHODS: Retrospective cross sectional study including 92 HIV-HCV coinfected patients evaluated in two reference centers for HIV treatment in the Public Health System in Southern Brazil. Patients who underwent liver biopsy for any indication and had concomitant laboratory data in the 3 months prior to liver biopsy, to allow the calculation of studied noninvasive markers (AAR, APRI, FIB-4 and FCI) were included. RESULTS: APRI < 0.5 presents the higher specificity to detect no or minimal fibrosis, whereas APRI > 1.5 presents the best negative predictive value and FCI > 1.25 the best specificity to detect significant fibrosis. The values of noninvasive markers for each Metavir fibrosis stage showed statistically significant differences only for APRI. In conclusion, until better noninvasive markers for liver fibrosis are developed and validated for HIV-HCV coinfected patients, noninvasive serum markers should be used carefully in this population. PMID- 26626638 TI - Hepatitis E virus serum antibodies and RNA prevalence in patients evaluated for heart and kidney transplantation. AB - BACKGROUND: Acute hepatitis E virus (HEV) infection in solid organ transplant recipients is rare, but can cause severe hepatic and extrahepatic complications. We sought to identify the pretransplant prevalence of HEV infection in heart and kidney candidates and any associated risk factors for infection. MATERIAL AND METHODS: Stored frozen serum from patients undergoing evaluation for transplant was tested for HEV immunoglobulin G (IgG) antibodies and HEV RNA. All patients were seen at Mayo Clinic Hospital, Phoenix, Arizona, with 333 patients evaluated for heart (n = 132) or kidney (n = 201) transplant. HEV IgG antibodies (anti-HEV IgG) were measured by enzyme-linked immunosorbent assay, and HEV RNA by a noncommercial nucleic acid amplification assay. RESULTS: The prevalence of anti HEV IgG was 11.4% (15/132) for heart transplant candidates and 8.5% (17/201) for kidney transplant candidates, with an overall seroprevalence of 9.6% (32/333). None of the patients tested positive for HEV RNA in the serum. On multivariable analysis, age older than 60 years was associated with HEV infection (adjusted odds ratio, 3.34; 95% CI, 1.54-7.24; P = 0.002). CONCLUSIONS: We conclude that there was no evidence of acute HEV infection in this pretransplant population and that older age seems to be associated with positive anti-HEV IgG. PMID- 26626639 TI - Risk factors for and management of ischemic-type biliary lesions following orthotopic liver transplantation: A single center experience. AB - INTRODUCTION: Biliary complications can cause morbidity, graft loss, and mortality after liver transplantation. The most troublesome biliary complications are ischemic-type biliary lesions (ITBL), which occur since transplants can now be performed after the donor has undergone circulatory death. The exact origin of this type of biliary complication remains unknown. MATERIAL AND METHODS: A total of 528 patients were retrospectively analyzed following liver transplantation after excluding 30 patients with primary sclerosing cholangitis and those lost to follow-up from January 2007 to January 2014. The incidence of and risk factors for ITBL were evaluated. RESULTS: Cold ischemia time (CIT) (P = 0.042) and warm ischemia time (WIT) (P = 0.006) were found to be independent risk factors for the development of ITBL. Use of the cytochrome P450 (CYP) 3A5 genotype assay to guide individualization of immunosuppressive medications resulted in significantly fewer ITBL (P = 0.027. Autoimmune hepatitis might be a risk factor for ITBL, as determined using univariate analysis (P = 0.047). CONCLUSIONS: Efforts should be taken to minimize risk factors associated with ITBL, such as CIT and WIT. The CYP3A5 genotype assay should be used to guide selection of immunosuppressive therapy in an effort to reduce the occurrence of ITBL. PMID- 26626640 TI - Intrapulmonary vascular dilation in children with chronic liver diseases: pre- and post-liver transplantation. AB - BACKGROUND AND STUDY AIMS: Chronic liver disease (CLD) can cause hepatopulmonary syndrome (HPS), defined as triad of liver disease, hypoxemia, and intrapulmonary vascular dilation (IPVD). The aim of this study was to determine the evidence of IPVD in a cohort of pediatric patients with CLD pre- and post-liver transplantation (LT). MATERIAL AND METHODS: All pediatric patients with CLD listed for LT were studied. Pulse oxygen saturation (SpO(2)), technetium-99m labeled macroaggregated albumin ((99m)Tc- MAA) perfusion scan (positive test: uptake of the isotope >= 6% in the brain), and echocardiography with saline bubble test (SBT) were performed. SBT was re-evaluated at 3-6 months after LT. Grading of SBT included grade 0 (no bubble), I (1-9 bubbles), grade II (10-20 bubbles), and grade III (> 20 bubbles). RESULTS: Eighteen patients, median age 22.5 months (8-108), were enrolled. Most had biliary atresia (77.8%). Pre-LT, all patients had SpO(2) of 100% and none had positive (99)mTc- MAA perfusion scan. Two patients (11%) had negative SBT (grade 0), 1 (5.5%) had grade I, 3 (16.5%) had grade II, and 12 (67%) had grade III, respectively. Post-LT SBT became negative in all survivors (n = 16), (p = 0.0001). CONCLUSIONS: Most cirrhotic children in this cohort study had evidence of IPVD by positive SBT. However, none of these met the criteria for diagnosis of HPS. This evidence of IPVD subsided after LT. PMID- 26626641 TI - Early allograft dysfunction after liver transplantation: an intermediate outcome measure for targeted improvements. AB - BACKGROUND: The term early allograft dysfunction (EAD) identifies liver transplant (LT) allografts with initial poor function and portends poor allograft and patient survival. Aims of this study are to use EAD as an intermediate outcome measure in a large single center cohort and identify donor, recipient and peri-operative risk factors. MATERIAL AND METHODS: In 1950 consecutive primary LT, donor, recipient and peri-operative data were collected. EAD was defined by the presence of one or more of the following: total bilirubin >= 10 mg/dL (171 MUmol/L) or, INR >= 1.6 on day 7, and ALT/AST > 2,000 IU/L within the first 7 days. RESULTS: The incidence of EAD was 26.5%. 1-, 3-, and 5-year allograft and patient survival for patients who developed EAD were significantly inferior to those who did not (P < 0.01 at all time points). Multivariate analysis demonstrated associations in the development of EAD with recipient pre-operative ventilator status, donation after cardiac death allografts, donor age, allograft size, degree of steatosis, operative time and intra-operative transfusion requirements (all P < 0.01). Patients with EAD had a significantly longer hospitalization at 20.9 +/- 38.9 days (median: 9; range: 4-446) compared with 10.7 +/- 13.5 days (median: 7; range: 3-231) in patients with no EAD (P < 0.01). CONCLUSIONS: This is the largest single center experience demonstrating incidence of EAD and identifying factors associated with development of EAD. EAD is a useful intermediate outcome measure for allograft and patient survival. Balancing recipient pretransplant conditions, donor risk factors and intra-operative conditions are necessary for avoiding EAD. PMID- 26626642 TI - Hepatocellular carcinoma <= 4 cm treated with radiofrequency ablation with or without percutaneous ethanol injection. AB - BACKGROUND: To compare the survival of Chinese cirrhotic patients with hepatocellular carcinoma (HCC) <= 4 cm who underwent radiofrequency ablation (RFA) alone or a combination of RFA with percutaneous ethanol injection (PEI). MATERIAL AND METHODS: Retrospective analysis was performed for 681 cases with HCC <= 4 cm who were treated with RFA alone or RFA combined with PEI (RFA + PEI) between 2004 and 2011. RESULTS: As a result, 180 patients in each group were selected after propensity score matching (PSM). Higher overall survival (OS) and recurrence-free survival (RFS) rates were achieved by RFA + PEI compared with RFA alone (P = 0.019 and 0.009, respectively). The 1-, 3-, and 5-year cumulative OS rates were 78.0, 44.4, and 30.1% for patients in RFA group and 88.2, 58.0, and 41.1% for patients in RFA + PEI group, respectively. Besides, the 1-, 3-, and 5 year cumulative RFS rates were 77.0, 43.8, and 29.2% in RFA group, and 87.9, 57.6, and 38.4% in RFA + PEI group, respectively. The local recurrence, complete ablation and five-year mortality showed no distinct differences between RFA and RFA + PEI groups in three subgroups classified with tumor size. Moreover, Cox regression multivariate analysis results showed that sex and treatment approach were significantly related to OS, whereas sex, status of HBsAg, local recurrence, and number of tumor nodule were related to RFS. CONCLUSION: Therefore, the combination of RFA and PEI yielded better OS and RFS rates than RFA alone for Chinese patients with HCC <= 4 cm. PMID- 26626643 TI - Suppression of trophoblast cell surface antigen 2 enhances proliferation and migration in liver fluke-associated cholangiocarcinoma. AB - BACKGROUND AND AIM: Trophoblast cell surface antigen 2 (TROP2) or tumor associated calcium signal transducer 2 (TACSTD2) is a 36-kDa type I transmembrane glycoprotein and exerts dual functions as an oncogene and tumor suppressor in cancer cells. In this study, we investigated the expression and functions of TROP2 in liver fluke-associated cholangiocarcinoma (CCA). MATERIAL AND METHODS: TROP2 expression in 85 CCA tissues was detected by using immunohistochemistry. The methylation status of TROP2 promoter was studied in 15 matched pairs of normal and CCA formalin fixed paraffin embedded (FFPE) tissues using the bisulfite genomic sequencing (BGS) method. The functions of TROP2 on cancer cell behavior were investigated using siRNA in CCA cell lines. Proliferation, migration and invasion assays were performed. A PCR array was used to evaluate the impact of TROP2 knockdown on the gene expression profiles. RESULTS: TROP2 was highly expressed in all normal bile duct epithelia, but significantly down regulated in CCA cells. Sixty percent of CCA revealed promoter hypermethylation compared to the corresponding adjacent normal tissues. TROP2 knockdown significantly enhanced the proliferation and migration in CCA cell lines, and altered the expressions of MARCK, EMP1 and FILIP1L. CONCLUSION: We provide new evidence that TROP2 is epigenetically down-regulated and operates as a negative regulator of cell proliferation and migration in liver fluke-associated CCA. PMID- 26626644 TI - Treatment allocation in hepatocellular carcinoma: Assessment of the BCLC algorithm. AB - BACKGROUND AND AIMS: The Barcelona Clinic Liver Cancer (BCLC) staging system is the algorithm most widely used to manage patients with hepatocellular carcinoma (HCC). We aimed to investigate the extent to which the BCLC recommendations effectively guide clinical practice and assess the reasons for any deviation from the recommendations. MATERIAL AND METHODS: The first-line treatments assigned to patients included in the prospective Bern HCC cohort were analyzed. RESULTS: Among 223 patients included in the cohort, 116 were not treated according to the BCLC algorithm. Eighty percent of the patients in BCLC stage 0 (very early HCC) and 60% of the patients in BCLC stage A (early HCC) received recommended curative treatment. Only 29% of the BCLC stage B patients (intermediate HCC) and 33% of the BCLC stage C patients (advanced HCC) were treated according to the algorithm. Eighty-nine percent of the BCLC stage D patients (terminal HCC) were treated with best supportive care, as recommended. In 98 patients (44%) the performance status was disregarded in the stage assignment. CONCLUSION: The management of HCC in clinical practice frequently deviates from the BCLC recommendations. Most of the curative therapy options, which have well-defined selection criteria, were allocated according to the recommendations, while the majority of the palliative therapy options were assigned to patients with tumor stages not aligned with the recommendations. The only parameter which is subjective in the algorithm, the performance status, is also the least respected. PMID- 26626645 TI - The mystery of the Hawaii liver disease cluster in summer 2013: A pragmatic and clinical approach to solve the problem. AB - BACKGROUND AND AIM: In the fall of 2013, the US Centers for Disease Control and Prevention (CDC) published a preliminary report on a cluster of liver disease cases that emerged in Hawaii in the summer 2013. This report claimed a temporal association as sufficient evidence that OxyELITE Pro (OEP), a dietary supplement (DS) mainly for weight loss, was the cause of this mysterious cluster. However, the presented data were inconsistent and required a thorough reanalysis. MATERIAL AND METHODS: To further investigate the cause(s) of this cluster, we critically evaluated redacted raw clinical data of the cluster patients, as the CDC report received tremendous publicity in local and nationwide newspapers and television. This attention put regulators and physicians from the medical center in Honolulu that reported the cluster, under enormous pressure to succeed, risking biased evaluations and hasty conclusions. RESULTS: We noted pervasive bias in the documentation, conclusions, and public statements, also poor quality of case management. Among the cases we reviewed, many causes unrelated to any DS were evident, including decompensated liver cirrhosis, acute liver failure by acetaminophen overdose, acute cholecystitis with gallstones, resolving acute hepatitis B, acute HSV and VZV hepatitis, hepatitis E suspected after consumption of wild hog meat, and hepatotoxicity by acetaminophen or ibuprofen. Causality assessments based on the updated CIOMS scale confirmed the lack of evidence for any DS including OEP as culprit for the cluster. CONCLUSIONS: Thus, the Hawaii liver disease cluster is now best explained by various liver diseases rather than any DS, including OEP. PMID- 26626646 TI - Hypothermia is better than ischemic preconditioning for preventing early hepatic ischemia/reperfusion in rats. AB - BACKGROUND: Topical hypothermia (TH) and ischemic preconditioning (IPC) are used to decrease I/R injury. The efficacy of isolated or combined use of TH and IPC in the liver regarding inflammation and cytoprotection in early ischemia/reperfusion (I/R) injury needs to be evaluated. MATERIAL AND METHODS: Wistar rats underwent 70% liver ischemia for 90 min followed by 120 min of reperfusion. Livers of animals allocated in the sham, normothermic ischemia (NI), IPC, TH, and TH+IPC groups were collected for molecular analyses by ELISA and Western blot, aiming to compare proinflammatory, anti-inflammatory, and antioxidant profiles. RESULTS: Compared with NI, TH presented decreased tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and IL-12 concentrations and increased IL-10 levels. TH animals displayed lower inducible nitric oxide synthase (iNOS) and higher endothelial nitric oxide synthase (eNOS) expressions. NAD(P)H-quinone oxidoreductase-1(NQO1) expression was also lower with TH. Isolated IPC and NI were similar regarding all these markers. TH+IPC was associated with decreased IL 12 concentration and reduced iNOS and NQO1 expressions, similarly to isolated TH. Expression of Kelch-like ECH-associated protein (Keap)-1 was increased and expression of nuclear and cytosolic nuclear erythroid 2-related factor 2 (Nrf2) was decreased with TH+IPC vs. NI. CONCLUSION: TH was the most effective method of protection against early I/R injury. Isolated IPC entailed triggering of second line antioxidant defense enzymes. Combined TH+IPC seemed to confer no additional advantage over isolated TH in relation to the inflammatory process, but had the advantage of completely avoid second-line antioxidant defense enzymes. PMID- 26626647 TI - A rare case of idiopathic granulomatous hepatitis presenting as tumoral lesion detected by 18F-FDG-PET/CT. PMID- 26626648 TI - Acute liver failure associated with Garcinia cambogia use. AB - Millions of Americans regularly use herbal supplements, but many are unaware of the potential hidden dangers. Numerous supplements have been associated with hepatotoxicity and, indeed dietary/herbal supplements represent an increasingly common source of acute liver injury. We report a case of acute liver failure requiring liver transplantation associated with the use of Garcinia cambogia, a supplement widely promoted for weight loss. When patients present with acute hepatitis or liver failure from an unknown etiology, a careful history of supplement use should be performed. PMID- 26626649 TI - Direct intrahepatic portocaval shunt for treatment of portal thrombosis and Budd Chiari syndrome. AB - Budd-Chiari syndrome (BCS) refers to hepatic venous outflow obstruction that in severe cases can lead to acute liver failure prompting consideration of revascularization or transplantation. Here, a 22 year old female with angiographically proven BCS secondary to JAK2/V617F positive Polycythemia vera on therapeutic warfarin presented with acute liver failure (ALF). Imaging revealed a new, near complete thrombotic occlusion of the main portal vein with extension into the superior mesenteric vein. An emergent direct intrahepatic portocaval shunt (DIPS) was created and liver function promptly normalized. She has been maintained on rivaroxaban since that time. Serial assessment over 1 year demonstrated continued shunt patency and improved flow in the mesenteric vasculature on ultrasound as well as normal liver function. DIPS is a viable alternative in the treatment of ALF from BCS when standard recanalization is not feasible. Improved blood flow may also improve portal/mesenteric clot burden. While further investigation is needed, new targeted anticoagulants may be viable as a long term anticoagulation strategy. PMID- 26626650 TI - Liver transplantation utilizing a severely fractured graft: every organ counts. AB - In our current era where shortage of liver grafts is commonplace, utilization of traumatic liver grafts may represent an opportunity to expand the organ donor pool without compromising graft survival. However, data on liver transplantation using a fractured liver allograft is scarce, with only small case series and reports found in the literature. In this report, we describe our experience with utilizing a liver graft with grade IV hepatic fracture for transplantation. At 12 months follow up, the recipient has excellent graft function and has regained an excellent quality of life. We demonstrated that the ability to safely use a fractured liver graft represents an additional avenue for expansion of the deceased donor population, especially in regions with prolonged waitlist times. PMID- 26626651 TI - When to perform gastroscopy in the PSC patient. PMID- 26626652 TI - Contribution on the topic of hypovitaminosis D in chronic hepatitis C. PMID- 26626653 TI - Reply to contribution on the topic of hypovitaminosis D in chronic hepatitis C. PMID- 26626654 TI - Mice studies disentangle the role of estrogen in gallstone formation. PMID- 26626655 TI - PEGylated hyperbranched polyphosphoester based nanocarriers for redox-responsive delivery of doxorubicin. AB - Redox-responsive polymers exhibit great potential as drug delivery systems. Herein, a redox-responsive PEGylated hyperbranched polyphosphoester (PPE) was synthesized through (A2 + B3) type polycondensation. The obtained hyperbranched PPE can self-assemble into nanoparticles in water. The biocompatibility of the nanoparticles was evaluated. The hydrophobic chemotherapy drug doxorubicin (DOX) can be efficiently encapsulated into the obtained nanoparticles. Such DOX-loaded nanoparticles exhibited excellent stability due to the PEGylation, and showed redox-responsive drug release behavior. In addition, flow cytometric analyses demonstrated that the redox-responsive nanoparticles could be efficiently internalized into the human breast cancer cell line MDA-MB-231, and intracellular glutathione enhanced the intracellular drug release from the redox-responsive hyperbranched PPE based nanoparticles. Therefore, such nanoparticles resulted in the enhanced inhibition of tumor cell growth, suggesting the potential of redox responsive PEGylated hyperbranched PPE in anticancer drug delivery. PMID- 26626657 TI - Introduction: Coarse-Graining in Molecular Modeling and Simulation. PMID- 26626656 TI - Progressive Changes in the Plasma Metabolome during Malnutrition in Juvenile Pigs. AB - Severe acute malnutrition (SAM) is one of the leading nutrition-related causes of death in children under five years of age. The clinical features of SAM are well documented, but a comprehensive understanding of the development from a normal physiological state to SAM is lacking. Characterizing the temporal metabolomic change may help to understand the disease progression and to define nutritional rehabilitation strategies. Using a piglet model we hypothesized that a progressing degree of malnutrition induces marked plasma metabolite changes. Four week-old weaned pigs were fed a nutrient-deficient maize diet (MAL) or nutritionally optimized reference diet (REF) for 7 weeks. Plasma collected weekly was subjected to LC-MS for a nontargeted profiling of metabolites with abundance differentiation. The MAL pigs showed markedly reduced body-weight gain and lean mass proportion relative to the REF pigs. Levels of eight essential and four nonessential amino acids showed a time-dependent deviation in the MAL pigs from that in the REF. Choline metabolites and gut microbiomic metabolites generally showed higher abundance in the MAL pigs. The results demonstrated that young malnourished pigs had a profoundly perturbed metabolism, and this provides basic knowledge about metabolic changes during malnourishment, which may be of help in designing targeted therapeutic foods for refeeding malnourished children. PMID- 26626658 TI - Simulating Membrane Dynamics in Nonhomogeneous Hydrodynamic Environments. AB - Two previously introduced simulation algorithms for the dynamics of elastic membrane sheets embedded in a fluid medium are extended to account for inhomogeneous hydrodynamic environments. We calculate the height autocorrelation function for a lipid bilayer randomly pinned to a flat substrate and the influence of fluid confinement by the spectrin cytoskeleton on short wavelength membrane undulations of the human red blood cell. Altering the hydrodynamic environment of the membrane leads to significant changes in dynamics, and we discuss these effects in the context of recent experiments. PMID- 26626659 TI - Calculation of Point-to-Point Short-Time and Rare Trajectories with Boundary Value Formulation. AB - Sampling rare, short-time, and reactive trajectories is of considerable interest in molecular simulations. These trajectories, which are also called "activated", hop between stable states separated by energy or entropy barriers. Simulations of activated trajectories with random sampling of initial conditions are inefficient, since most initial conditions lead to trajectories that do not pass the barrier in short times. A boundary value formulation is proposed that selects these rare trajectories, making the sampling of point-to-point reactive trajectories more effective. Earlier boundary value formulations by one of us focused on computations of approximate trajectories. In the proposed method, trajectories are accurate even when we employ a relatively large integration step (by a factor of about 100 compared to initial value methods). The boundary value solutions to short-time reactive trajectories tend to be unique and have significant statistical weights compared to other reactive trajectories of the microcanonical ensemble. Three numerical examples are considered: a transition in the Mueller potential, a conformational change in alanine dipeptide, and an isomerization in a Lennard-Jones cluster. PMID- 26626660 TI - Lattice-Boltzmann Simulations of Ionic Current Modulation by DNA Translocation. AB - We present a numerical study of the effect of DNA translocation on the ionic current through a nanopore. We use a coarse-grained model to solve the electrokinetic equations at the Poisson-Boltzmann level for the microions, coupled to a lattice-Boltzmann equation for the solvent hydrodynamics. In most cases, translocation leads to a reduction in the ionic current. However, at low salt concentrations (large screening lengths) we find ionic current enhancement due to translocation. In an unstructured pore, translocation of the helical charge distribution of the DNA has no effect on the ionic current. However, if a localized charge probe is placed on the wall of the nanopore, we observe ionic current modulations that, though weak, should be experimentally observable. PMID- 26626661 TI - A Coarse-Grained Molecular Dynamics Study of Carbon Nanoparticle Aggregation. AB - A multiscale coarse-graining procedure is used to study carbonaceous nanoparticle assembly. The computational methodology is applied to an ensemble of 10 000 nanoparticles (or effectively 2 million total carbon atoms) to simulate the agglomeration of carbonaceous nanoparticles using coarse-grained atomistic-scale information. In particular, with the coarse-graining approach, we are able to assess the influence of nanoparticle morphology and temperature on the agglomeration process. The coarse-graining of the interparticle force field is accomplished applying a force-matching procedure to data obtained from trajectories and forces from all-atom molecular dynamics simulation. The coarse grained molecular dynamics results show rich and varied clustering behaviors for different particle morphologies. They are shown to reproduce accurately the structural properties of the nanoparticles systems studied, while allowing for molecular dynamics simulations of much larger self-assembled nanoparticles systems. PMID- 26626662 TI - An Analytical Electrostatic Model for Salt Screened Interactions between Multiple Proteins. AB - We present a new general analytical solution for computing the screened electrostatic interaction between multiple macromolecules of arbitrarily complex charge distributions, assuming they are well described by spherical low dielectric cavities in a higher dielectric medium in the presence of a Debye Huckel treatment of salt. The benefits to this approach are 3-fold. First, by exploiting multipole expansion theory for the screened Coulomb potential, we can describe direct charge-charge interactions and all significant higher-order cavity polarization effects between low dielectric spherical cavities containing their charges, while treating these higher order terms correctly at all separation distances. Second, our analytical solution is general to arbitrary numbers of macromolecules, is efficient to compute, and can therefore simultaneously provide on-the-fly updates to changes in charge distributions due to protein conformational changes. Third, we can change spatial resolutions of charge description as a function of separation distance without compromising the desired accuracy. While the current formulation describes solutions based on simple spherical geometries, it appears possible to reformulate these electrostatic expressions to smoothly increase spatial resolution back to greater molecular detail of the dielectric boundaries. PMID- 26626663 TI - Parametrization and Validation of Coarse Grained Force-Fields Derived from ab Initio Calculations. AB - A novel multisite interaction potential, suitable for computer simulations of complex materials as liquid crystals or polymers, is proposed and parametrized. Its validation is achieved through Monte Carlo numerical experiments at constant temperature and pressure, performed on the p-n-phenyls series and a typical mesogenic molecule (5CB). The model is constructed by connecting an array of anisotropic Gay-Berne sites and a collection of isotropic Lennard-Jones sites. The former mimics the rigid planar six-membered rings of the molecule, while the latter represents the flexible chain, if present. Such intermolecular potential, coupled with an intramolecular part to account for molecular flexibility, is parametrized from ab initio information only, obtained through the recently proposed Fragmentation-Reconstruction Method (FRM). Computer simulations are performed on all systems by exploring phase behavior at several temperatures and by comparing the resulting thermodynamic and structural properties with the relevant experimental data. Despite the simplicity of the present models, the good agreement with the experimental measures suggests the possibility of adopting such hybrid potentials for those systems with a large number of atoms, where high computational cost does not allow the use of more accurate atomistic potentials. PMID- 26626664 TI - A Local Galilean Invariant Thermostat. AB - The thermostat introduced recently by Stoyanov and Groot (J. Chem. Phys. 2005, 122, 114112) is analyzed for inhomogeneous systems. This thermostat has one global feature, because the mean temperature used to drive the system toward equilibrium is a global average. The consequence is that the thermostat locally conserves energy rather than temperature. Thus, local temperature variations can be long-lived, although they do average out by thermal diffusion. To obtain a faster local temperature equilibration, a truly local thermostat must be introduced. To conserve momentum and, hence, to simulate hydrodynamic interactions, the thermostat must be Galilean invariant. Such a local Galilean invariant thermostat is studied here. It is shown that, by defining a local temperature on each particle, the ensemble is locally isothermal. The local temperature is obtained from a local square velocity average around each particle. Simulations on the ideal gas show that this local Nose-Hoover algorithm has a similar artifact as dissipative particle dynamics: the ideal gas pair correlation function is slightly distorted. This is attributed to the fact that the thermostat compensates fluctuations that are natural within a small cluster of particles. When the cutoff range rc for the square velocity average is increased, systematic errors decrease proportionally to rc(-)(3/2); hence, the systematic error can be made arbitrary small. PMID- 26626665 TI - Exploring Model Energy and Geometry Surfaces Using Sum of Squares Decompositions. AB - The difficulty in exploring potential energy surfaces, which are nonconvex, stems from the presence of many local minima, typically separated by high barriers and often disconnected in configurational space. We obtain the global minimum on model potential energy surfaces without sampling any minima a priori. Instead, a different problem is derived, which is convex and hence easy to solve, but which is guaranteed to either have the same solution or to be a lower bound to the true solution. A systematic way for improving the latter solutions is also given. Because many nonconvex problems are projections of higher dimensional convex problems, Parrilo has recently shown that by obtaining a sum of squares decomposition of the original problem, which can be subsequently transformed to a semidefinite program, a large class of nonconvex problems can be solved efficiently. The semidefinite duality formulation also provides a proof that the global minimum of the energy surface has either been found exactly or has been bounded from below. It additionally provides physical insight into the problem through a geometric interpretation. The sum of squares polynomial representation of the potential energy surface may further reveal information about the nature of the potential energy surface. We demonstrate the applicability of this approach to low-dimensional potential energy landscapes and discuss its merits and shortcomings. We further show how to apply it to geometric problems by obtaining the exact distance of closest approach of anisotropic particles. Efficient molecular dynamics simulations of mixtures of ellipsoids are illustrated. PMID- 26626666 TI - How Well Can Coarse-Grained Models of Real Polymers Describe Their Structure? The Case of Polybutadiene. AB - Coarse-graining of chemical structure of macromolecules in the melt is investigated using extensive molecular dynamics simulation data which are based on a united atom force-field model of polybutadiene. Systematically increasing the number, n, of the united atoms approximated by an effective coarse-grained monomer, we study the influence of degree of coarse-graining on the structure functions such as the segment-segment intermolecular and intramolecular correlation functions. These results are compared to Monte Carlo simulations of the corresponding coarse-grained bead-spring model and Chen-Kreglewski potential for chain molecules. In contrast to the atomistic chemically realistic model of polybutadiene, the bending and torsional potentials are not included into the coarse-grained models. Nevertheless, for a range of intermediate values of n a good qualitative agreement between intra- and intermolecular coarse-grained correlations of the atomistic model and the coarse-grained bead-spring model is found on large and intermediate length scales, but deviations occur on length scales well below one nanometer. The structure functions obtained for the Chen Kreglewski chains exhibit many artificial features. PMID- 26626667 TI - Multiscale Modeling of Poly(ethylene oxide)-Poly(propylene oxide)-Poly(ethylene oxide) Triblock Copolymer Micelles in Aqueous Solution. AB - We present a multiscale modeling approach for simulation of poly(ethylene oxide) poly(propylene oxide)-poly(ethylene oxide) triblock copolymer micelles in aqueous solution. We rely on systematic elimination of computationally expensive degrees of freedom yet retain implicitly their influence on the remaining degrees freedom in a coarser-grained model. Quantum chemistry (QC) calculations, atomistic explicit solvent (AES) molecular dynamics (MD) simulations, and coarse-grained implicit solvent (CGIS) simulations have been applied to investigate physical properties of these important self-assembling triblock copolymers. High-level QC calculations have been used to parametrize classical atomistic force fields that implicitly take into account and reproduce the important energetic and structural features due to correlations of electronic degrees of freedom. AES MD simulations utilizing the QC-based force fields have been used to provide structural and conformational properties of polymers in aqueous solution which were subsequently used for parametrization of the CGIS model using the Inverted Boltzmann method. The CGIS simulations were then employed to investigate structural properties of two PEO-PPO-PEO micelles (EO13-PO30-EO13 and EO99-PO65-EO99 also known as Pluronic L64 and F127, respectively) in aqueous solution. PMID- 26626668 TI - Systematic Coarse-Graining of a Polymer Blend: Polyisoprene and Polystyrene. AB - The Iterative Boltzmann Inversion technique (also known as the Inverse Boltzmann Method) is generalized to polymer blends. We systematically optimize a mesoscale model against the structure of the blend. A polyisoprene-polystyrene blend is used as an example. Atomistic simulations of a blend of short chains in the miscible regime under melt conditions are taken as a starting point. We optimize the mesoscale model and study the onset of phase separation with increasing chain length. The mesoscale model phase separates at a chain length of 15 monomers where it was optimized, whereas the atomistic model shows only a preference of chains to aggregate to neighborhoods of like chains. We discuss the differences of the optimization between a blend and a homopolymer system in detail. PMID- 26626669 TI - Coarse Graining of Short Polythylene Chains for Studying Polymer Crystallization. AB - We derive coarse-grained models of polyethylene in the melt state with the aim to study polymer crystallization. This requires a low level of coarse-graining: We use a mapping of two CH2 groups onto one bead. The coarse-grained beads are connected with harmonic springs, an optimized angular potential, and an optional torsional potential. Coarse-grained potentials are derived from detailed all-atom simulations, and an optimized form of the force field is then derived which achieves a good accuracy in reproducing the static properties of the chains. We address the question over which temperature range such models can be used, and in particular if the model is capable of reproducing the phase transition to an ordered state; it is found that the qualitative behavior of short polyethylene chains is well described, and the experimental melting temperature of C44H90 is approached when using the most accurate optimized model. PMID- 26626670 TI - Adsorption and Dynamics of a Single Polyelectrolyte Chain near a Planar Charged Surface: Molecular Dynamics Simulations with Explicit Solvent. AB - The effect of solvent quality on the behavior of a polyelectrolyte chain near a charged surface is studied using molecular dynamics simulation with explicit solvent. The polyion adsorbs completely on the surface for a high enough surface charge density, and the surface charge required for complete adsorption becomes lower as the solvent quality is decreased. Several static and dynamic properties display a nonmonotonic dependence on surface charge density and solvent quality. For a given value of solvent quality the component of the radius of gyration (Rg) parallel to the surface is a nonmonotonic function of the surface charge density, and for a given surface charge density the component of Rg perpendicular to the surface is a nonmonotonic function of the solvent quality. The center-of-mass diffusion coefficient and rotational relaxation time are nonmonotonic functions of the surface charge density. Translational diffusion coefficient increases, and the rotational relaxation time decreases as solvent quality is decreased for a fixed surface charge density. PMID- 26626671 TI - Multiscale Coarse-Graining of Mixed Phospholipid/Cholesterol Bilayers. AB - Coarse-grained (CG) models for mixed dimyristoylphosphatidylcholine (DMPC)/cholesterol lipid bilayers are constructed using the recently developed multiscale coarse-graining (MS-CG) method. The MS-CG method permits a systematic fit of the bonded and nonbonded interactions and system pressure to trajectory and force data derived from an underlying reference all-atom molecular dynamics (MD) simulation. The CG sites for lipid and cholesterol molecules are associated with the centers-of-mass of atomic groups because of the simplicity in the evaluation of the forces acting on them from the atomistic MD data. Corresponding models with four-site and seven-site representations of the cholesterol molecule were also developed. The latter CG models differed by the bonding scheme of CG sites to represent intramolecular interactions. A one-site MS-CG model based on the TIP3P potential was used for water, with the interaction site placed at the molecular geometrical center, and the analytical fit of the model is presented. The MS-CG models were then used to conduct simulations in the constant NPT ensemble which reproduce accurately the structural properties as seen in the full all-atom MD simulation. PMID- 26626672 TI - Resolution Exchange Simulation with Incremental Coarsening. AB - We previously developed an algorithm, called "resolution exchange", which improves canonical sampling of atomic resolution models by swapping conformations between high- and low-resolution simulations. Here, we demonstrate a generally applicable incremental coarsening procedure and apply the algorithm to a larger peptide, met-enkephalin. In addition, we demonstrate a combination of resolution and temperature exchange, in which the coarser simulations are also at elevated temperatures. Both simulations are implemented in a "top-down" mode, to allow efficient allocation of CPU time among the different replicas. PMID- 26626673 TI - Coarse-Grained Model of Coil-to-Helix Kinetics Demonstrates the Importance of Multiple Nucleation Sites in Helix Folding. AB - An extension of a coarse-grained, implicit-solvent peptide model wherein each amino acid residue is represented by four interaction sites is presented and discussed. The model is used to study the coil-to-helix transition of five peptide sequences, ranging from all hydrophobic to all hydrophilic, for a 10 residue peptide. The thermodynamics of the folding transition are analyzed and discussed for each sequence, and the stability of the alpha-helix is correlated with the hydrophobic content of the sequence. In addition, for each sequence, the folding kinetics of the transition from random coil to full alpha-helix are analyzed, and the mean folding time is determined. Folding times vary from 59 ns for the most hydrophobic sequence to 132 ns for the most hydrophilic sequence. These folding times compare very well with those measured in experments. All sequences show single-exponential kinetics. A plot of the mean folding time versus the reciprocal of the Zimm-Bragg parameter sigma [Formula: see text] a measure of the free energy cost of nucleating a helix [Formula: see text] is shown to be nonlinear, in contrast to the predictions of many theories of the coil-to-helix transition. It is proposed that the origin of this nonlinearity is due to multiple helix nucleation sites, indicating that even for short peptides such as those studied here, multiple folding pathways play an important role in the transition from random coil to native state. PMID- 26626674 TI - Sequence-Dependent Effects in the Cyclization of Short DNA. AB - A new, computationally efficient Monte Carlo approach has been developed to estimate the ring-closure properties of short, realistically modeled DNA chains. The double helix is treated at the level of base-pair steps using an elastic potential that accounts for the sequence-dependent variability in the intrinsic structure and elastic moduli of the base-pair steps, including the known coupling of conformational variables. Rather than using traditional Metropolis-Monte Carlo techniques to generate representative configurations, a Gaussian sampling method is introduced to construct three-dimensional structures from linear combinations of the rigid-body parameters defining the relative orientation and displacement of successive base pairs. The computation of the J factor, the well-known ratio of the equilibrium constants for cyclization vs bimolecular association of a linear molecule, takes into account restrictions on the displacement and directions of the base pairs joined in ring closure, including the probability that the end-to-end vector is null and the terminal base pairs coincide. The increased sample sizes needed to assess the likelihood that very short chains satisfy these criteria are attained using the Alexandrowicz half-chain sampling enhancement technique in combination with selective linkage of the two-half-chain segments. The method is used to investigate the cyclization properties of arbitrary-length DNA with greatly enhanced sampling sizes, i.e., O(10(14)) configurations, and to estimate J factors lower than 0.1 pM with high accuracy. The methodology has been checked against classic theoretical predictions of the cyclization properties of an ideal, inextensible, naturally straight, DNA elastic rod and then applied to investigate the extent to which one can account for the unexpectedly large J factors of short DNA chains without the need to invoke significant distortions of double helical structure. Several well-known structural features of DNA [Formula: see text] including the presence of intrinsic curvature, roll-twist coupling, or enhanced pyrimidine-purine deformability [Formula: see text] bring the computed J factors in line with the observed data. Moreover, periodically distributed roll-twist coupling reduces the magnitude of oscillations in J, seen in plots of J vs chain length, to the extent found experimentally. PMID- 26626675 TI - Protein Structure Prediction: The Next Generation. AB - Over the last 10-15 years a general understanding of the chemical reaction of protein folding has emerged from statistical mechanics. The lessons learned from protein folding kinetics based on energy landscape ideas have benefited protein structure prediction, in particular the development of coarse grained models. We survey results from blind structure prediction. We explore how second generation prediction energy functions can be developed by introducing information from an ensemble of previously simulated structures. This procedure relies on the assumption of a funneled energy landscape keeping with the principle of minimal frustration. First generation simulated structures provide an improved input for associative memory energy functions in comparison to the experimental protein structures chosen on the basis of sequence alignment. PMID- 26626676 TI - Classical Trajectory-Based Tunneling Splittings: The Hydrogen Atom Transfer in the Hydroperoxyl Anion. AB - The hydroperoxyl anion HO2(-) is one of the simplest examples for multidimensional hydrogen-atom transfer. This is reflected in the tunneling splittings, which have been theoretically predicted to be highly selective concerning the excitation of either the O-O stretching, the O-H stretching, or the H-O-O bending vibration. Using the available quantum mechanical spectrum up to 5000 cm(-)(1), we scrutinize the performance of a recently proposed trajectory based method to calculate tunneling splittings (Giese, K.; Ushiyama, H.; Kuhn, O. Chem. Phys. Lett. 2003, 371, 681). It is found that this new method is capable of reproducing the general behavior of the tunneling splittings rather well. Furthermore, for this particular system, the error shows a systematic trend, which suggests the applicability of a scaling correction that could be based on a small number of exact splittings. PMID- 26626677 TI - Distributed Replica Sampling. AB - We present a simple and general scheme for efficient Boltzmann sampling of conformational space by computer simulation. Multiple replicas of the system differing in temperature T or reaction coordinate lambda are simulated independently. In addition, occasional stochastic moves of individual replicas in T or lambda space are considered one at a time on the basis of a generalized Hamiltonian containing an extra potential energy term or bias that depends on the distribution of all replicas. The algorithm is inherently suited for shared or heterogeneous computing platforms such as a distributed network. PMID- 26626678 TI - Efficient Generalized Born Models for Monte Carlo Simulations. AB - The Generalized Born Surface Area theory (GBSA) has become a popular method to model the solvation of biomolecules. While efficient in the context of molecular dynamics simulations, GBSA calculations do not integrate well with Monte Carlo simulations because of the nonlocal nature of the Generalized Born energy. We present a method by which Monte Carlo Generalized Born simulations can be made seven to eight times faster on a protein-ligand binding free energy calculation with little or no loss of accuracy. The method can be employed in any type of Monte Carlo or Hybrid Monte Carlo-molecular dynamics simulation and should prove useful in numerous applications. PMID- 26626679 TI - Cation-pi Interactions in Serotonin: Conformational, Electronic Distribution, and Energy Decomposition Analysis. AB - An adiabatic conformational analysis of serotonin (5-hydroxytryptamine, 5-HT) using quantum chemistry led to six stable conformers that can be either +gauche (Gp), -gauche (Gm), and anti (At) depending upon the value taken by ethylamine side chain and 5-hydroxyl group dihedral angles phi1, phi2, and phi4, respectively. Further vibrational frequency analysis of the GmGp, GmGm, and GmAt conformers with the 5-hydroxyl group in the anti position revealed an additional red-shifted N-H stretch mode band in GmGp and GmGm that is absent in GmAt. This band corresponds to the 5-HT side-chain N-H bond involved in an intramolecular nonbonded interaction with the 5-hydroxy indole ring. The influence of this nonbonded interaction on the electronic distribution was assessed by analysis of the spin-spin coupling constants of GmGp and GmGm that show a marked increase for C2-C3 and C8-C9 bonds in GmGm and GmGp, respectively, with a decrease of their double bond character and an increase of their length. The Atoms in Molecules (AIM), Natural Bond Orbital (NBO), and fluorescence and CD spectra (TDDFT method) analyses confirmed the existence in GmGp and GmGm of a through-space charge transfer between the HOMO and the HOMO-1 pi-orbital of the indole ring and the LUMO sigma* N-H antibonding orbital of the ammonium group. The strength of the cation-pi interaction was determined by calculating binding energies of the NH4(+)/5-hydroxyindole complexes extracted from stable conformers. The energy decomposition analysis indicated that cationic-pi interactions in the GmGp and GmGm conformers are governed by the electrostatic term with significant contributions from polarization and charge transfer. The lower stability of the GmGm over the GmGp comes from a higher exchange repulsion and a weaker polarization contributions. Our results provide insight into the nature of intramolecular forces that influence the conformational properties of 5-HT. PMID- 26626680 TI - On the Aromaticity of the Planar Hydrogen-Bonded (HF)3 Trimer. AB - The nuclear magnetic shieldings and magnetically induced ring currents have been calculated for the planar ring-shaped hydrogen fluoride trimer (HF)3 at correlated ab initio and density functional theory levels. Calculations of the magnetically induced current densities using the gauge-including magnetically induced current (GIMIC) method show that, contrary to a recent suggestion, (HF)3 has, at the MP2/TZVPP level, a very small ring-current susceptibility of 0.37 nA/T. Thus, only a weak net current is passing across the H...F hydrogen bond. An external magnetic field perpendicular to the ring plane induces strong edge currents circling around each HF molecule giving rise to a nonvanishing magnetic shielding at the center of the ring. The GIMIC results are supported by calculations of the long-range magnetic shielding function; the long-range magnetic shielding is very small, indicating that the magnetically induced ring current is very weak. The surprisingly large nucleus-independent chemical shift (NICS) value for (HF)3 was recently taken as an indication of "H-bonded aromaticity". The NICS value calculated at the CCSD/QZ2P level is 2.77 ppm. The present GIMIC and aromatic ring-current shielding study shows that some care has to be taken when using NICS values as aromaticity indices. PMID- 26626681 TI - Constrained Density Functional Theory and Its Application in Long-Range Electron Transfer. AB - Recently, we have proposed an efficient method in the Kohn-Sham density functional theory (DFT) to study systems with a constraint on their density (Phys. Rev. A 2005, 72, 24502). In our approach, the constrained state is calculated directly by running a fast optimization of the constraining potential at each iteration of the usual self-consistent-field procedure. Here, we show that the same constrained DFT approach applies to systems with multiple constraints on the density. To illustrate the utility of this approach, we focus on the study of long-range charge-transfer (CT) states. We show that constrained DFT is size-consistent: one obtains the correct long-range CT energy when the donor-acceptor separation distance goes to infinity. For large finite distances, constrained DFT also correctly describes the 1/R dependence of the CT energy on the donor-acceptor separation. We also study a model donor-(amidinium carboxylate)-acceptor complex, where experiments suggest a proton-coupled electron-transfer process. Constrained DFT is used to explicitly calculate the potential-energy curves of both the donor state and the acceptor state. With an appropriate model, we obtain qualitative agreement with experiments and estimate the reaction barrier height to be 7 kcal/mol. PMID- 26626682 TI - The Carbon Allotrope Hexagonite and Its Potential Synthesis from Cold Compression of Carbon Nanotubes. AB - In a previous report, the approximate crystalline structure and electronic structure of a novel, hypothetical hexagonal carbon allotrope has been disclosed. Employing the approximate extended Huckel method, this C structure was determined to be a semiconducting structure. In contrast, a state-of-the-art density functional theory (DFT) optimization reveals the hexagonal structure to be metallic in band profile. It is built upon a bicyclo[2.2.2]-2,5,7-octatriene (barrelene) generating fragment molecule and is a Catalan network, with the Wells point symbol (6(6))2(6(3))3 and the corresponding Schlafli symbol (6, 3.4). As the network is entirely composed of hexagons and, in addition, possesses hexagonal symmetry, lying in space group P6/mmm (space group #191), it has been given the name hexagonite. The present report describes a density functional theory (DFT) optimization of the lattice parameters of the parent hexagonite structure, with the result giving the optimized lattice parameters of a = 0.477 nm and c = 0.412 nm. A calculation is then reported of a simple diffraction pattern of hexagonite from these optimized lattice parameters, with Bragg spacings enumerated for the lattice out to fourth order. Results of a synchrotron diffraction study of carbon nanotubes which underwent cold compression in a diamond anvil cell (DAC) to 100 GPa, in which the carbon nanotubes have evidently collapsed into a hitherto unknown hexagonal C polymorph, are then compared to the calculated diffraction pattern for the DFT optimized hexagonite structure. It is seen that a close fit is obtained to the experimental data, with a standard deviation over the 5 matched reflections being given by sigmax = 0.003107 nm/reflection. PMID- 26626683 TI - H2, Ne, and N2 Energies of Encapsulation into C60 Evaluated with the MPWB1K Functional. AB - The recently suggested MPWB1K functional is tested on H2@C60, Ne@C60, and N2@C60 as a tool for evaluations of stabilization energies upon encapsulation of nonmetallic species into fullerenes. It is found that the MPWB1K (modified Perdew Wang and Becke functionals) values can be within a few kilocalories per mole from the MP2 or SCS-MP2 (spin-component scaled MP2) values so that further applications of the functional are clearly encouraged. The best estimates of the encapsulation-energy gains found for H2@C60, Ne@C60, and N2@C60 are at least 4 kcal/mol, slightly less than 4 kcal/mol, and about 9 kcal/mol, respectively. PMID- 26626684 TI - Analytical Method for Predicting Ferromagnetic Properties of Benzyl-Radical Polymers Based on NBMO Theory. AB - It has been demonstrated that the high-spin stability of benzyl radical oligomers can be predicted without any quantum chemical calculations. This method is composed of three steps: (1) predicting the shapes of nonbonding molecular orbitals (NBMOs), (2) counting up the mixings of NBMOs, and (3) formulating the mixings for the number of radical centers (N). This treatment enables us to predict the high-spin stability evaluated by ab initio MO calculations involving the post-Hartree-Fock method or the density functional theory (DFT) method. PMID- 26626685 TI - Ab Initio Simulations of the (101) Surfaces of Potassium Dihydrogenphosphate (KDP). AB - We have used density functional calculations to examine the (101) surfaces of KDP, under vacuum, nitrogen, and aqueous conditions, and these simulations are found to agree well with nanoscale experimental studies demonstrating that the density functional calculations are providing a good description of the surfaces of this complex inorganic salt. PMID- 26626686 TI - Theoretical DFT Study on the Interaction of NO and Br2 with the Pt(111) Surface. AB - Density functional calculations were performed at the B3LYP level using combined basis sets for the NO and bromine interactions with the Pt(111) surface mimicked by the two-layer Pt10 cluster model. It explains well an attractive bonding interaction not only for bromine and Pt(111) but also for all three adsorption modes of NO on the Pt(111) surface. In accordance with the experimental observations, the calculations predict that the first peak in the IR spectra appears at around 1515 cm(-)(1) at the initial stage of low NO coverage, while it would shift to 1707 cm(-)(1) at high NO coverage. The bonding of NO on the 3-fold hollow fcc and hcp sites of Pt(111) proceeds via predominant back-donation interactions, while for the on-top adsorption, both the donation and back donation interactions become equally important. Energetic criteria show also that the STM tip (made from Pt and Ir alloys) immersed into a bromine solution may contain only dissociated bromine atoms that bind strongly with the surface Pt atoms. As a result, the nuBrBr stretching vibration mode for the bromine molecule may not be seen in the IR spectra because of its dissociation into adsorbed atoms. This leads to an appearance of a blue shifted band centered at ca. 202 cm( )(1). PMID- 26626687 TI - Theoretical Studies on the Nonlinear Optical Properties of Octupolar Tri-s triazines. AB - The first-, second-, and third-order static and frequency-dependent polarizabilities of a series of octupolar tri-s-triazines have been investigated by using the ab initio coupled perturbed Hartree-Fock (CPHF) method. Effects of substitution have also been considered. The results show that alpha, beta, and gamma values for octupolar tri-s-triazines are much larger than those for s triazine in both static and frequency-dependent cases. Attaching groups containing pi systems such as azide and ethenyl to the tri-s-triazine molecule results in a significant increase of first-, second-, and third-order polarizabilities. Our calculations suggest that the octupolar tri-s-triazines may be prospective candidates for nonlinear optical materials. PMID- 26626688 TI - Combining Quantum Mechanics Methods with Molecular Mechanics Methods in ONIOM. AB - The purpose of this paper is 2-fold. First, we present several extensions to the ONIOM(QM:MM) scheme. In its original formulation, the electrostatic interaction between the regions is included at the classical level. Here we present the extension to electronic embedding. We show how the behavior of ONIOM with electronic embedding can be more stable than QM/MM with electronic embedding. We also investigate the link atom correction, which is implicit in ONIOM but not in QM/MM. Second, we demonstrate some of the practical aspects of ONIOM(QM:MM) calculations. Specifically, we show that the potential surface can be discontinuous when there is bond breaking and forming closer than three bonds from the MM region. PMID- 26626689 TI - Rotational g Tensors Calculated Using Hybrid Exchange-Correlation Functionals with the Optimized Effective Potential Approach. AB - The calculation of rotational g tensors using density functional theory (DFT) with hybrid exchange-correlation functionals is considered. A total of 143 rotational g tensor elements in 58 molecules (67 isotopic combinations) are calculated using three standard hybrid functionals. Tensor elements determined using an uncoupled approach with orbitals and eigenvalues calculated from the multiplicative optimized effective potential (OEP) constitute a significant improvement over those determined in the conventional coupled manner with a nonmultiplicative exchange-correlation operator. Relative to experimental results, mean absolute errors are reduced by a factor of 2; mean errors and standard deviations are reduced by more than a factor of 3. The results are also an improvement over those determined using a generalized gradient-approximation functional optimized for magnetic response properties. The influence of orbital exchange is investigated for a representative subset of molecules, yielding an optimal amount near 0.3. Rotational g tensors are also determined from coupled cluster electron densities using a combined DFT/wave-function approach. Being substantially more expensive, they do not offer a notable improvement on the pure DFT values from OEP-based hybrid calculations. PMID- 26626690 TI - Energy-Represented Direct Inversion in the Iterative Subspace within a Hybrid Geometry Optimization Method. AB - A geometry optimization method using an energy-represented direct inversion in the iterative subspace algorithm, GEDIIS, is introduced and compared with another DIIS formulation (controlled GDIIS) and the quasi-Newton rational function optimization (RFO) method. A hybrid technique that uses different methods at various stages of convergence is presented. A set of test molecules is optimized using the hybrid, GEDIIS, controlled GDIIS, and RFO methods. The hybrid method presented in this paper results in smooth, well-behaved optimization processes. The optimization speed is the fastest among the methods considered. PMID- 26626691 TI - Transition Networks for the Comprehensive Characterization of Complex Conformational Change in Proteins. AB - Functionally relevant transitions between native conformations of a protein can be complex, involving, for example, the reorganization of parts of the backbone fold, and may occur via a multitude of pathways. Such transitions can be characterized by a transition network (TN), in which the experimentally determined end state structures are connected by a dense network of subtransitions via low-energy intermediates. We show here how the computation of a TN can be achieved for a complex protein transition. First, an efficient hierarchical procedure is used to uniformly sample the conformational subspace relevant to the transition. Then, the best path which connects the end states is determined as well as the rate-limiting ridge on the energy surface which separates them. Graph-theoretical algorithms permit this to be achived by computing the barriers of only a small number out of the many subtransitions in the TN. These barriers are computed using the Conjugate Peak Refinement method. The approach is illustrated on the conformational switch of Ras p21. The best and the 12 next-best transition pathways, having rate-limiting barriers within a range of 10 kcal/mol, were identified. Two main energy ridges, which respectively involve rearrangements of the switch I and switch II loops, show that switch I must rearrange by threading Tyr32 underneath the protein backbone before the rate limiting switch II rearrangement can occur, while the details of the switch II rearrangement differ significantly among the low-energy pathways. PMID- 26626692 TI - Role of Solvent Dynamics in Stabilizing the Transition State of RNA Hydrolysis by Hairpin Ribozyme. AB - Structural and mechanistic studies of the hairpin ribozyme have been actively pursued over the last two decades to understand its catalytic strategy for RNA hydrolysis. Based on molecular dynamics simulations with the newly developed force field parameters for a vanadium-oxygen complex, we investigate the dynamic properties of the hairpin ribozyme in complex with a transition state analogue for the phosphodiester cleavage. The results indicate that the three nucleobases of the hairpin ribozyme (G8, A9, and A38) stabilize the negatively charged oxygen atoms in the transition state through the formation of five hydrogen bonds, which is consistent with the X-ray crystallographic data. In addition to the three catalytic nucleobases, several solvent molecules are also found to contribute to the catalytic action of the hairpin ribozyme by hydrogen bond stabilization of the negatively charged oxygens as well as by optimally positioning the catalytic nucleobases in the active site. PMID- 26626693 TI - Theoretical Calculation of Hydrogen-Bonding Strength for Drug Molecules. AB - Hydrogen bond is an important type of interaction between drug molecules and their receptors. We present here a computational method for accurately predicting the hydrogen-bonding strength for different acceptors with respect to a given donor or vice versa. The method is based on quantum chemistry DFT calculation of the interaction energy between hydrogen bond donors and acceptors. An excellent linear correlation is observed between the calculated hydrogen-bonding energies and the experimentally measured hydrogen-bonding constants log Kbeta on a variety of known hydrogen bond acceptors and donors. These results not only indicate the predictive power of this method but also shed light on factors that determine the magnitude of experimentally measured hydrogen-bonding constants for different acceptors with respect to a given donor, suggesting a primarily enthalpic contribution from hydrogen-bonding energy. The method can be used for evaluating the effects of steric interference and inhibitor binding geometry on hydrogen bonding strength in drug design. PMID- 26626694 TI - Computing the Amino Acid Specificity of Fluctuations in Biomolecular Systems. AB - We developed a new amino acid specific method for the computation of spatial fluctuations of proteins around their native structures. We show the consistency with experimental values and the increased performance in comparison to an established model, based on statistical estimates for a set of test proteins. We apply the new method to HIV-1 protease in its wild-type form and to a V82F-I84V mutant that shows resistance to protease inhibitors. We further show how the method can be successfully used to explain the molecular biophysics of drug resistance of the mutant. PMID- 26626695 TI - The Stabilities of N-Cl Bonds in Biocidal Materials. AB - N-halamine chemistry has been a research topic of considerable importance in these laboratories for over two decades. N-halamine compounds are useful in preparing biocidal materials. There are three N-Cl moieties available in cyclic N halamine compounds: imide, amide, and amine. The stabilities toward the release of free halogen have been experimentally shown to decrease in the order amine > amide > imide. In this work, this generalization has been tested theoretically at the level of B3LYP/6-31+G(d) and using the conductor-like polarizable continuum aqueous solvation model with UAKS cavities. Excellent accord was observed between theory and experiment. It was also found that the imide and amide N-halamine stabilities on hydantoin rings could be reversed with substitution patterns at the 5 position. PMID- 26626696 TI - Small Carbon Clusters Doped with Vanadium Metal: A Density Functional Study of VCn (n = 1-8). AB - A theoretical study of the different isomers of neutral VCn (n = 1-8) clusters has been carried out. Predictions for their electronic energies, rotational constants, dipole moments, and vibrational frequencies have been made using the B3LYP method with different basis sets. For linear and cyclic VCn clusters, the lowest-lying states correspond to quartet states, with the only exception being VC, which has a (2)Delta ground state. In the fan-type structures, the electronic ground state is found to be a quartet state for even n values, whereas for odd n values, the ground state is a doublet for VC3 and VC5 and a quartet for VC7. From the incremental binding energies, we can deduce an even-odd parity effect, with n even clusters being more stable than n-odd ones in the linear and fan clusters. It was also found that neutral VCn clusters with n <= 6 prefer fan structures over linear and cyclic isomers, whereas cyclic ground states are predicted for the clusters with n > 6. PMID- 26626698 TI - Permanent contraception for women. AB - Permanent methods of contraception are used by an estimated 220 million couples worldwide, and are often selected due to convenience, ease of use and lack of side effects. A variety of tubal occlusion techniques are available for female permanent contraception, and procedures can be performed using a transcervical or transabdominal approach. This article reviews currently available techniques for female permanent contraception and discusses considerations when helping patients choose a contraceptive method and tubal occlusion technique. PMID- 26626697 TI - Stiff substrates enhance monocytic cell capture through E-selectin but not P selectin. AB - The stiffening of blood vessel walls is associated with inflammatory diseases, including atherosclerosis, diabetes, and obesity. These diseases are driven by the excessive recruitment of inflammatory leukocytes out of the bloodstream and into tissues, but whether vascular stiffening plays a direct role in this process is not clear. In this study, we investigated the possibility that leukocyte capture from blood flow is enhanced on stiffer substrates. We modeled blood flow in vitro by perfusing monocytic cells over hydrogels that matched the stiffness of healthy and diseased arteries. The hydrogels were coated with either E selectin or P-selectin, which are the endothelial adhesion proteins known to mediate immune cell capture from flow. Interestingly, we discovered that cell attachment to P-selectin coated gels was not dependent on substrate stiffness, while attachment through E-selectin was enhanced on stiffer gels. Specifically we found that on E-selectin coated gels, cells attached in greater numbers, remained attached for longer time periods, and rolled more slowly on stiff gels than soft gels. These results suggest that vascular stiffening could promote leukocyte adhesion to vessel walls where E-selectin is expressed, but may have less of an effect when P-selectin is also present. PMID- 26626699 TI - An alternative design for long-term stability testing of large molecules: a scientific discussion paper from an EBF Topic Team. AB - AIM: Long-term stability testing of drug candidates in biological matrix is a key parameter in bioanalytical method validation. The European Bioanalysis Forum formed a Topic Team to evaluate the use of isochronic design for long-term stability testing of large molecules. METHOD: Isochronic design is based on storage of samples at a reference temperature (below -130 degrees C) where the samples are considered stable. The stability samples are stored at the intended storage temperature and then transferred to the reference temperature, while a set of reference samples is stored the entire storage period at the reference temperature. Stability and reference samples will then be analyzed in one run at the end of the storage period. The mean concentrations of the stability samples are compared either to their nominal concentrations or to the mean concentrations of the reference samples. CONCLUSION: The design minimizes day-to-day variation, reduces workload and adds to the flexibility in the laboratory. PMID- 26626700 TI - EGFR-Targeted Polymeric Mixed Micelles Carrying Gemcitabine for Treating Pancreatic Cancer. AB - The objective of this study was to design GE11 peptide (YHWYGYTPQNVI) linked micelles of poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-gemcitabine-graft-dodecanol (PEG-b-PCC-g-GEM-g-DC) for enhanced stability and target specificity of gemcitabine (GEM) to EGFR-positive pancreatic cancer cells. GE11-PEG-PCD/mPEG-b-PCC-g-GEM-g-DC mixed micelles showed EGFR dependent enhanced cellular uptake, and cytotoxicity as compared to scrambled peptide HW12-PEG-PCD/mPEG-b-PCC-g-GEM-g-DC mixed micelles and unmodified mPEG-b PCC-g-GEM-g-DC micelles. Importantly, GE11-linked mixed micelles preferentially accumulated in orthotopic pancreatic tumor and tumor vasculature at 24 h post systemic administration. GE11-linked mixed micelles inhibited orthotopic pancreatic tumor growth compared to HW12-linked mixed micelles, unmodified mPEG-b PCC-g-GEM-g-DC micelles, and free GEM formulations. Tumor growth inhibition was mediated by apoptosis of tumor cells and endothelial cells as determined by immunohistochemical staining. In summary, GE11-linked mixed micelles is a promising approach to treat EGFR overexpressing cancers. PMID- 26626701 TI - Solar ultraviolet radiation in Africa: a systematic review and critical evaluation of the health risks and use of photoprotection. AB - Most information on the harmful health effects of solar ultraviolet radiation (UVR) has been obtained in populations in which the majority has fair skin. Here a systematic review of evidence on diseases related to solar UVR in Africa was undertaken, and the appropriateness of effective photoprotection for these people considered. There are few population-based studies on UV-induced skin cancers (melanoma, squamous and basal cell carcinomas) in Africa, although limited reports indicated that they occur, even in people with deeply pigmented skin. The incidence of melanoma is particularly high in the white population living in the Western Cape of South Africa and has increased significantly in recent years. Cataract is extremely common in people of all skin colours and is a frequent cause of blindness, particularly in the elderly. For both skin cancer and cataract, the proportion of the disease risk that is attributable to exposure to solar UVR in African populations, and therefore the health burden caused by UV irradiation is unclear. There was little published information on the use of sun protection in Africa. The potential disease burden attributable to solar UVR exposure of Africans is high, although accurate data to quantify this are sparse. Information is required on the incidence, prevalence and mortality for the range of UV-related diseases in different populations living throughout Africa. Photoprotection is clearly required, at least for those subpopulations at particularly high risk, but may be limited by cost and cultural acceptability. PMID- 26626702 TI - Periconceptional seafood intake and pregnancy complications. AB - OBJECTIVE: To investigate associations of maternal periconceptional shellfish, lean fish and fatty fish intake with risk of pregnancy complications. DESIGN: In this prospective cohort study, we collected information on intake of seafood subtypes using FFQ. We categorized seafood intake into frequencies of 1 servings/week. We ascertained gestational hypertension, pre-eclampsia, gestational diabetes and preterm birth diagnoses from medical records. Using generalized linear models with a log link, the Poisson family and robust standard errors, we estimated risk ratios and 95 % confidence intervals across seafood intake categories. SETTING: The Omega study, a study of risk factors for pregnancy complications among women recruited from prenatal clinics in Washington State, USA, 1996-2008. SUBJECTS: The current study included 3279 participants from the Omega study. RESULTS: Median (interquartile range) shellfish, lean fish and fatty fish intake was 0.3 (0-0.9), 0.5 (0-1.0) and 0.5 (0.1-1.0) servings/week, respectively. Lean fish intake of >1 servings/week (v. <0.2 servings/month) was associated with a 1.55-fold higher risk of preterm birth (95 % CI 1.04, 2.30) and was not associated with the other pregnancy complications. Higher intake of seafood (total or other subtypes) was not associated with pregnancy complications (separately or combined). CONCLUSIONS: Higher intake of lean fish, but not fatty fish or shellfish, was associated with a higher risk of preterm birth; these findings may have significance for preterm birth prevention. Studies of mechanisms and potential contributing factors (including seafood preparation and nutrient/contaminant content) are warranted. PMID- 26626703 TI - Multifunctional Nanostructures for Tumor-Targeted Molecular Imaging and Photodynamic Therapy. AB - A multifunctional ICG-FA-PPD nanostructure is constructed by a facile self assembly method through the negatively charged indocyanine green (ICG)- and positively charged folic acid-modified PEI-PEG-gadoteric acid (FA-PPD). The resulting ICG-FA-PPD is not only able to be used for targeting tumors, magnetic resonance imaging (MRI), and near-infrared imaging, but, more importantly, it enables photodynamic therapy for tumor. PMID- 26626704 TI - A mixed model for the relationship between climate and human cranial form. AB - OBJECTIVES: We expand upon a multivariate mixed model from quantitative genetics in order to estimate the magnitude of climate effects in a global sample of recent human crania. In humans, genetic distances are correlated with distances based on cranial form, suggesting that population structure influences both genetic and quantitative trait variation. Studies controlling for this structure have demonstrated significant underlying associations of cranial distances with ecological distances derived from climate variables. However, to assess the biological importance of an ecological predictor, estimates of effect size and uncertainty in the original units of measurement are clearly preferable to significance claims based on units of distance. Unfortunately, the magnitudes of ecological effects are difficult to obtain with distance-based methods, while models that produce estimates of effect size generally do not scale to high dimensional data like cranial shape and form. METHODS: Using recent innovations that extend quantitative genetics mixed models to highly multivariate observations, we estimate morphological effects associated with a climate predictor for a subset of the Howells craniometric dataset. RESULTS: Several measurements, particularly those associated with cranial vault breadth, show a substantial linear association with climate, and the multivariate model incorporating a climate predictor is preferred in model comparison. CONCLUSIONS: Previous studies demonstrated the existence of a relationship between climate and cranial form. The mixed model quantifies this relationship concretely. Evolutionary questions that require population structure and phylogeny to be disentangled from potential drivers of selection may be particularly well addressed by mixed models. Am J Phys Anthropol 160:593-603, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26626706 TI - Penetration of resin-based materials into initial erosion lesion: A confocal microscopic study. AB - The application of resin-based materials is an alternative of treatment for eroded lesions. Nevertheless, there are no studies about the penetration of these materials into eroded lesion, which might affect its adhesion. Therefore, this study evaluated the penetration of four resin-based materials, with and without enamel etching. By using an in vitro protocol, types of treatment were studied at five levels (AdheSE((r)) , Tetric N-Bond((r)) , Single Bond 2((r)) , Helioseal Clear((r)) , Icon((r)) ) and types of enamel etching in two levels (with and without). Materials were stained with 0.02 mg/mL ethanolic solution of tetramethylrhodamine isothiocyanate. Bovine enamel samples (4 * 4 mm) were immersed in 0.01 M HCl, pH 2.3, for 30 seconds to produce initial eroded lesions. Afterward, the materials were applied on half of sample enamel surface following the manufacturer's instructions. On the other half of sample, the materials were applied without etching the enamel. Materials penetration into the enamel was assessed by Confocal Laser Scanning Microscopy on reflection and fluorescence modes. The penetration depth (PD) was measured using ImageJ software. Data were analyzed by two-way ANOVA and Tukey test (P < 0.05). Regardless of the material, etched enamel resulted in higher PD than non-etched (P < 0.05). Icon((r)) showed the highest PD in enamel followed by Helioseal Clear((r)) (P < 0.05), with significant difference between them (P < 0.05) and no difference was found among AdheSE((r)) , Tetric N-Bond((r)) , and Single Bond 2((r)) (P > 0.05). It can be concluded that prior enamel etching increased the materials penetration into eroded enamel and the Icon((r)) -infiltrant presented highest penetration. PMID- 26626705 TI - Dietary polyphenol morin rescues endothelial dysfunction in a diabetic mouse model by activating the Akt/eNOS pathway. AB - SCOPE: Endothelial dysfunction is a critical factor during the initiation of diabetic cardiovascular complications. Polyphenols may represent beneficial dietary components eliciting cardiovascular protection. Although we previously reported that the polyphenol morin (MO) ameliorated diabetes-induced endothelial dysfunction, the underlying mechanism remains unclear. Here, we investigated protective effects and mechanisms of MO in streptozotocin STZ induced diabetic aorta endothelial dysfunction. METHODS AND RESULTS: Diabetes was induced by tail vein injection of STZ (200 mg/kg). At 12 wk after injection, the thoracic aorta was isolated and endothelial function was assessed by acetylcholine (ACh) induced, endothelial-dependent vasorelaxation in aortas. Nitric oxide (NO) levels and endothelial NO synthase (eNOS), phosphorylated-eNOS (p-eNOS), Akt, and phosphorylated-Akt (p-Akt) levels were also evaluated in aortas. Diabetic aortas showed attenuated endothelial function, which was improved by MO treatment. MO treatment alone increased NO levels and endothelial-dependent relaxation responses via Akt signaling, although ACh did not activate this pathway. Moreover, MO upregulated p-Akt (at Ser473 and Thr308) and p-eNOS (at Ser1177) expression in diabetic aortas, but ACh stimulation had no effect on p-Akt and p eNOS levels. CONCLUSION: These results indicate a novel role for MO in protection against endothelial dysfunction in diabetes. The protective effects of MO are dependent on Akt-dependent activation of eNOS signaling. PMID- 26626707 TI - Letters to the Editor: Genetic polymorphism and soluble urokinase plasminogen activator receptor regulation. PMID- 26626709 TI - Einstein's Letter to the Dean: Welcome to America! PMID- 26626708 TI - Response. PMID- 26626710 TI - Abortion Patients' Experience and Perceptions of Waiting Periods: Survey Evidence before Arizona's Two-visit 24-hour Mandatory Waiting Period Law. AB - BACKGROUND: More than one-half of U.S. states now have laws requiring women to wait at least 24 hours between receiving information about abortion and the actual abortion procedure, with a few requiring longer waits, and one-fourth requiring that women receive this information in person. Although public discussions of waiting periods focus on how they affect women, we know little about abortion patients' perceptions of these requirements. METHODS: We collected data from 379 women seeking abortion care at an abortion facility in Arizona before Arizona's 24-hour waiting period two-visit requirement went into effect. Surveys focused on patients' experiences receiving abortion care before the waiting period and perceptions about how the additional clinic visit would affect them. RESULTS: Most women reported one or more financial or logistical challenges in obtaining abortion care. More than two-thirds reported difficulty paying abortion appointment-related expenses. These expenses prevented or delayed almost one-half from paying other expenses, such as rent, bills, and food, with lower income women more affected. The majority expected that the additional visit would result in additional financial and logistical hardships and delay them in having an abortion, with 90% reporting that the waiting period would lead to at least one hardship. Eight percent reported that the waiting period would have a positive effect on emotional well-being, and more than one-half reported that it would have a negative effect on emotional well-being. CONCLUSION: Only a small minority of women seeking abortion care view a two-visit waiting period law as benefiting them; the overwhelming majority expect a waiting period to have adverse consequences. PMID- 26626711 TI - Prophylaxis for mucositis induced by ambulatory chemotherapy: systematic review. AB - AIM: The aim of this study was to perform a systematic review of clinical trials covering interventions used as prophylaxis for oral mucositis induced by ambulatory antineoplastic chemotherapy. BACKGROUND: Oral mucositis in patients undergoing chemotherapy is a side effect that can impact the quality of treatment and can interfere with eating and therapeutic adherence. DESIGN: Quantitative systematic review. DATA SOURCES: Relevant databases were searched, from January 2002-July 2013, by using the combination of the keywords mucositis, stomatitis, neoplasms, antineoplastic agents, drug therapy, prevention and control and chemotherapy. REVIEW METHODS: Two researchers independently read the titles and abstracts from every cross-reference. The quality of the included studies was analysed by the Jadad Scale and the Cochrane Collaboration Risk of Bias Tool. Data were extracted from the selected studies with a data collection form developed specifically for this purpose. RESULTS: Of the 23 controlled clinical trials that were identified in this study, five articles evaluated the use of oral cryotherapy to prevent oral mucositis and three studies analysed the prophylactic use of glutamine. Interventions of protocols for oral care, palifermin, allopurinol and chlorhexidine were evaluated by two articles each. Interventions of zinc sulphate, amifostine, chewing gum, sucralfate, recombination human intestinal trefoil factor, kefir and vitamin E were evaluated by one article each. CONCLUSION: There is strong evidence that cryotherapy can prevent oral mucositis arising from ambulatory treatment with 5-flurouracil chemotherapy. Other interventions, although showing positive results in preventing oral mucositis, require further study to confirm their conclusions. PMID- 26626712 TI - Procedures for risk management and a review of crisis referrals from the MindSpot Clinic, a national service for the remote assessment and treatment of anxiety and depression. AB - BACKGROUND: The MindSpot Clinic (MindSpot) provides remote screening assessments and therapist-guided treatment for anxiety and depression to adult Australians. Most patients are self-referred. The purpose of this study was to report on the procedures followed to maintain the safety of patients and to examine the circumstances of urgent referrals to local services made by this remote mental health service. METHOD: A description of the procedures used to manage risk, and an audit of case summaries of patients who were urgently referred for crisis intervention. The reported measures were scores on self-report scales of psychological distress (K-10) and depression (PHQ-9), the number reporting suicidal thoughts and plans, and the number of acute referrals. RESULTS: A total of 9061 people completed assessments and consented for analysis of their data in the year from 1 July, 2013 to 30 June, 2014. Of these, 2599 enrolled in online treatment at MindSpot, and the remainder were supported to access local mental health services. Suicidal thoughts were reported by 2366 (26.1 %) and suicidal plans were reported by 213 (2.4 %). There were 51 acute referrals, of whom 19 (37.3 %) lived in regional or remote locations. The main reason for referral was the patients' self-report of imminent suicidal intent. The police were notified in three cases, and in another case an ambulance attended after the patient reported taking an overdose. For the remaining acute referrals, MindSpot therapists were able to identify a local mental health service or a general practitioner, confirm receipt of a written case summary, and confirm that the patient had been contacted, or that the local service intended to contact the patient. CONCLUSIONS: Around 0.6 % of the people seeking assessment or treatment by MindSpot were referred to local mental health services for urgent face to face care. The procedures for identifying and managing those patients were satisfactory, and in every case, either emergency services or local mental health services were able to take over the patient's care. This review suggests that the uncertainty associated with taking responsibility for the remote treatment of patients who disclose active suicidal plans is not a major impediment to providing direct access online treatment for severe forms of anxiety and depression. PMID- 26626713 TI - Mild Synthesis of Pt/SnO2 /Graphene Nanocomposites with Remarkably Enhanced Ethanol Electro-oxidation Activity and Durability. AB - We have designed a new Pt/SnO2 /graphene nanomaterial by using L-arginine as a linker; this material shows the unique Pt-around-SnO2 structure. The Sn(2+) cations reduce graphene oxide (GO), leading to the in situ formation of SnO2 /graphene hybrids. L-Arginine is used as a linker and protector to induce the in situ growth of Pt nanoparticles (NPs) connected with SnO2 NPs and impede the agglomeration of Pt NPs. The obtained Pt/SnO2 /graphene composites exhibit superior electrocatalytic activity and stability for the ethanol oxidation reaction as compared with the commercial Pt/C catalyst owing to the close connected structure between the Pt NPs and SnO2 NPs. This work should have a great impact on the rational design of future metal-metal oxide nanostructures with high catalytic activity and stability for fuel cell systems. PMID- 26626714 TI - Novel risk scores for survival and intracranial failure in patients treated with radiosurgery alone to melanoma brain metastases. AB - PURPOSE: Stereotactic radiosurgery (SRS) alone is an increasingly common treatment strategy for brain metastases. However, existing prognostic tools for overall survival (OS) were developed using cohorts of patients treated predominantly with approaches other than SRS alone. Therefore, we devised novel risk scores for OS and distant brain failure (DF) for melanoma brain metastases (MBM) treated with SRS alone. METHODS AND MATERIALS: We retrospectively reviewed 86 patients treated with SRS alone for MBM from 2009-2014. OS and DF were estimated using the Kaplan-Meier method. Cox proportional hazards modeling identified clinical risk factors. Risk scores were created based on weighted regression coefficients. OS scores range from 0-10 (0 representing best OS), and DF risk scores range from 0-5 (0 representing lowest risk of DF). Predictive power was evaluated using c-index statistics. Bootstrapping with 200 resamples tested model stability. RESULTS: The median OS was 8.1 months from SRS, and 54 (70.1 %) patients had DF at a median of 3.3 months. Risk scores for OS were predicated on performance status, extracranial disease (ED) status, number of lesions, and gender. Median OS for the low-risk group (0-3 points) was not reached. For the moderate-risk (4-6 points) and high-risk (6.5-10) groups, median OS was 7.6 months and 2.4 months, respectively (p < .0001). Scores for DF were predicated on performance status, ED status, and number of lesions. Median time to DF for the low-risk group (0 points) was not reached. For the moderate-risk (1 2 points) and high-risk (3-5 points) groups, time to DF was 4.8 and 2.0 months, respectively (p < .0001). The novel scores were more predictive (c-index = 0.72) than melanoma-specific graded prognostic assessment or RTOG recursive partitioning analysis tools (c-index = 0.66 and 0.57, respectively). CONCLUSIONS: We devised novel risk scores for MBM treated with SRS alone. These scores have implications for prognosis and treatment strategy selection (SRS versus whole brain radiotherapy). PMID- 26626716 TI - Exercise-induced leg pain in sport. PMID- 26626715 TI - The HIV care cascade: a systematic review of data sources, methodology and comparability. AB - INTRODUCTION: The cascade of HIV diagnosis, care and treatment (HIV care cascade) is increasingly used to direct and evaluate interventions to increase population antiretroviral therapy (ART) coverage, a key component of treatment as prevention. The ability to compare cascades over time, sub-population, jurisdiction or country is important. However, differences in data sources and methodology used to construct the HIV care cascade might limit its comparability and ultimately its utility. Our aim was to review systematically the different methods used to estimate and report the HIV care cascade and their comparability. METHODS: A search of published and unpublished literature through March 2015 was conducted. Cascades that reported the continuum of care from diagnosis to virological suppression in a demographically definable population were included. Data sources and methods of measurement or estimation were extracted. We defined the most comparable cascade elements as those that directly measured diagnosis or care from a population-based data set. RESULTS AND DISCUSSIONS: Thirteen reports were included after screening 1631 records. The undiagnosed HIV-infected population was reported in seven cascades, each of which used different data sets and methods and could not be considered to be comparable. All 13 used mandatory HIV diagnosis notification systems to measure the diagnosed population. Population-based data sets, derived from clinical data or mandatory reporting of CD4 cell counts and viral load tests from all individuals, were used in 6 of 12 cascades reporting linkage, 6 of 13 reporting retention, 3 of 11 reporting ART and 6 of 13 cascades reporting virological suppression. Cascades with access to population-based data sets were able to directly measure cascade elements and are therefore comparable over time, place and sub-population. Other data sources and methods are less comparable. CONCLUSIONS: To ensure comparability, countries wishing to accurately measure the cascade should utilize complete population based data sets from clinical data from elements of a centralized healthcare setting, where available, or mandatory CD4 cell count and viral load test result reporting. Additionally, virological suppression should be presented both as percentage of diagnosed and percentage of estimated total HIV-infected population, until methods to calculate the latter have been standardized. PMID- 26626718 TI - Predictors of bacterial resistance using in vitro dynamic models: area under the concentration-time curve related to either the minimum inhibitory or mutant prevention antibiotic concentration. AB - OBJECTIVES: To examine the predictive power of the ratios of the 24 h AUC (AUC24) to the mutant prevention concentration (MPC) and the MIC, the selection of ciprofloxacin-resistant mutants of Pseudomonas aeruginosa was studied in an in vitro dynamic model. METHODS: Four clinical isolates of P. aeruginosa with MPC/MIC ratios from 5.6 to 32 were exposed to twice-daily ciprofloxacin for 3 days over a 100- to 200-fold range of the AUC24/MIC ratio. RESULTS: The emergence of P. aeruginosa resistance to ciprofloxacin was concentration dependent: mutants resistant to 2-16 * MIC were enriched at antibiotic concentrations between the MIC and MPC, but not at concentrations below the MIC or above the MPC. Both AUC24/MIC and AUC24/MPC relationships with the area under the bacterial mutant concentration-time curve (AUBCM) were bell-shaped. These relationships predict highly variable 'anti-mutant' AUC24/MIC and AUC24/MPC ratios: e.g. with mutants resistant to 2 * MIC the ratios ranged from 220 to 1100 and from 7 to 180 h, respectively. Using combined data for the four studied organisms, correlations between AUBCM and AUC24/MIC or AUC24/MPC were established (r(2) = 0.75 and 0.65, respectively). Much stronger correlation was observed between AUC24/MIC and the area between the cut-off level at 10(8) cfu/mL and the time-kill curve (ABBC) as an integral index of the antimicrobial effect of ciprofloxacin on the parental strains (r(2) = 0.93). CONCLUSIONS: Findings obtained with ciprofloxacin-exposed P. aeruginosa are consistent with the mutant selection window hypothesis. AUC24/MIC and AUC24/MPC relationships with resistance were more bacterial strain specific than AUC24/MIC relationships with fluoroquinolone-induced killing of susceptible cells. PMID- 26626717 TI - Selecting appropriate empirical antibiotic regimens for paediatric bloodstream infections: application of a Bayesian decision model to local and pooled antimicrobial resistance surveillance data. AB - OBJECTIVES: The objective of this study was to evaluate the ability of weighted incidence syndromic combination antibiograms (WISCAs) to inform the selection of empirical antibiotic regimens for suspected paediatric bloodstream infections (BSIs) by comparing WISCAs derived using data from single hospitals and from a multicentre surveillance dataset. METHODS: WISCAs were developed by estimating the coverage of five empirical antibiotic regimens for childhood BSI using a Bayesian decision tree. The study used microbiological data on ~2000 bloodstream isolates collected over 2 years from 19 European hospitals. We evaluated the ability of a WISCA to show differences in regimen coverage at two exemplar hospitals. For each, a WISCA was first calculated using only their local data; a second WISCA was calculated using pooled data from all 19 hospitals. RESULTS: The estimated coverage of the five regimens was 72%-86% for Hospital 1 and 79%-94% for Hospital 2, based on their own data. In both cases, the best regimens could not be definitively identified because the differences in coverage were not statistically significant. For Hospital 1, coverage estimates derived using pooled data gave sufficient precision to reveal clinically important differences among regimens, including high coverage provided by a narrow-spectrum antibiotic combination. For Hospital 2, the hospital and pooled data showed signs of heterogeneity and the use of pooled data was judged not to be appropriate. CONCLUSIONS: The Bayesian WISCA provides a useful approach to pooling information from different sources to guide empirical therapy and could increase confidence in the selection of narrow-spectrum regimens. PMID- 26626719 TI - Pharmacokinetics and safety of an 8 week continuous treatment with once-daily versus twice-daily inhalation of tobramycin in cystic fibrosis patients. AB - OBJECTIVES: We evaluated the pharmacokinetics, safety and tolerability of two different continuous treatment regimens of tobramycin inhalation solution (TIS) in 29 cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. PATIENTS AND METHODS: In this randomized, multicentre, open-label, two-period crossover study, TIS (300 mg/5 mL) was administered via PARI eFlow((r)) rapid once daily and twice daily each for 8 weeks. Serum pharmacokinetics of these two regimens was analysed. Tobramycin levels were determined before the morning dose and at 30, 60 and 90 min after the end of nebulization in the middle and at the end of each 8 week cycle. At these timepoints, trough and peak serum tobramycin concentrations (Cmax, mg/L) as well as the area under the curve for 0-90 min of tobramycin (AUC0-90min) were assessed in order to evaluate the risk of systemic toxicity. Safety parameters and forced expiratory volume in 1 s (FEV1) were assessed. RESULTS: For once-daily treatment, tobramycin levels were 10% higher after 8 weeks compared with 4 weeks (AUC0-90min ratio = 1.096, 90% CI = 0.860-1.396, P = 0.5237). For twice-daily treatment, tobramycin levels after 8 weeks showed a 40% decrease compared with 4 weeks (AUC0 90min ratio = 0.608, 90% CI = 0.461-0.802, P = 0.0055). The AUC0-90min ratio at 8 weeks (once daily versus twice daily) did not differ significantly (AUC0-90min ratio = 0.749, 90% CI = 0.514-1.092, P = 0.2009). The mean FEV1 did not differ markedly compared between treatment periods or with baseline. No audiological or nephrotoxic side effects were noted. CONCLUSIONS: Continuous treatment with TIS (once daily or twice daily) over 8 weeks appears to be safe and tolerable. PMID- 26626720 TI - [In memory of Prof. Dr. Hans-Jurgen Eichhorn: honorary member of DEGRO]. PMID- 26626723 TI - Improving cultural competence in end-of-life pain management. PMID- 26626721 TI - Exercise and gut immune function: evidence of alterations in colon immune cell homeostasis and microbiome characteristics with exercise training. AB - There is robust evidence that habitual physical activity is anti-inflammatory and protective against developing chronic inflammatory disease. Much less is known about the effects of habitual moderate exercise in the gut, the compartment that has the greatest immunological responsibility and interactions with the intestinal microbiota. The link between the two has become evident, as recent studies have linked intestinal dysbiosis, or the disproportionate balance of beneficial to pathogenic microbes, with increased inflammatory disease susceptibility. Limited animal and human research findings imply that exercise may have a beneficial role in preventing and ameliorating such diseases by having an effect on gut immune function and, recently, microbiome characteristics. Emerging data from our laboratory show that different forms of exercise training differentially impact the severity of intestinal inflammation during an inflammatory insult (for example, ulcerative colitis) and may be jointly related to gut immune cell homeostasis and microbiota-immune interactions. The evidence we review and present will provide data in support of rigorous investigations concerning the effects of habitual exercise on gut health and disease. PMID- 26626724 TI - Calcium pyrophosphate deposition disease: a review of epidemiologic findings. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize the recent advances in the epidemiology of calcium pyrophosphate deposition disease (CPPD), and to discuss their implications. This review is particularly timely as several epidemiological studies that enhance the understanding of CPPD have been published recently. RECENT FINDINGS: This article will review recent findings on the prevalence of chondrocalcinosis; discuss new data on the associations between bone mineral density and chondrocalcinosis; and between diuretic use, chronic kidney disease 5 and 'pseudogout' (now termed acute calcium pyrophosphate crystal arthritis). It will summarize findings from a large dataset which reported that chondrocalcinosis results from a systemic predisposition, and that the association between chondrocalcinosis and polymorphisms in ANKH gene is independent of age and osteoarthritis. It will also review recent data which suggest that the association between chondrocalcinosis and osteoarthritis may be joint specific, and that chondrocalcinosis associates with radiographic attrition in knees with osteoarthritis. SUMMARY: The studies reviewed suggest that CPPD occurs due to a generalized predisposition, and that it modifies the radiographic phenotype of osteoarthritis. However, further research is required to confirm if CPPD modifies the clinical phenotype of osteoarthritis. PMID- 26626725 TI - Overview of technical solutions and assessment of clinical usefulness of capsule endoscopy. AB - The paper presents an overview of endoscopic capsules with particular emphasis on technical aspects. It indicates common problems in capsule endoscopy such as: (1) limited wireless communication (2) the use of capsule endoscopy in the case of partial patency of the gastrointestinal tract, (3) limited imaging area, (4) external capsule control limitations. It also presents the prospects of capsule endoscopy, the most recent technical solutions for biopsy and the mobility of the capsule in the gastrointestinal tract. The paper shows the possibilities of increasing clinical usefulness of capsule endoscopy resulting from technological limitations. Attention has also been paid to the current role of capsule endoscopy in screening tests and the limitations of its effectiveness. The paper includes the author's recommendations concerning the direction of further research and the possibility of enhancing the scope of capsule endoscopy. PMID- 26626726 TI - Promotion of human mesenchymal stem cell osteogenesis by PI3-kinase/Akt signaling, and the influence of caveolin-1/cholesterol homeostasis. AB - INTRODUCTION: Stem cells are considered an important resource for tissue repair and regeneration. Their utilization in regenerative medicine will be aided by mechanistic insight into their responsiveness to external stimuli. It is likely that, similar to all other cells, an initial determinant of stem cell responsiveness to external stimuli is the organization of signaling molecules in cell membrane rafts. The clustering of signaling molecules in these cholesterol rich membrane microdomains can affect the activity, specificity, cross-talk and amplification of cell signaling. Membrane rafts fall into two broad categories, non-caveolar and caveolar, based on the absence or presence, respectively, of caveolin scaffolding proteins. We have recently demonstrated that caveolin-1 (Cav 1) expression increases during, and knockdown of Cav-1 expression enhances, osteogenic differentiation of human bone marrow derived mesenchymal stem cells (MSCs). The increase in Cav-1 expression observed during osteogenesis is likely a negative feedback mechanism. We hypothesize that focal adhesion signaling pathways such as PI3K/Akt signaling may be negatively regulated by Cav-1 during human MSC osteogenesis. METHODS: Human bone marrow MSCs were isolated from femoral heads obtained after total hip arthroplasty. MSCs were incubated in standard growth medium alone or induced to osteogenically differentiate by the addition of supplements (beta-glycerophosphate, ascorbic acid, dexamethasone, and 1,25-dihydroxyvitamin D3). The activation of and requirement for PI3K/Akt signaling in MSC osteogenesis were assessed by immunoblotting for phosphorylated Akt, and treatment with the PI3K inhibitor LY294002 and Akt siRNA, respectively. The influences of Cav-1 and cholesterol membrane rafts on PI3K/Akt signaling were investigated by treatment with Cav-1 siRNA, methyl-beta-cyclodextrin, or cholesterol oxidase, followed by cellular sub-fractionation and/or immunoblotting for phosphorylated Akt. RESULTS: LY294002 and Akt siRNA inhibited MSC osteogenesis. Methyl-beta-cyclodextrin, which disrupts all membrane rafts, inhibited osteogenesis. Conversely, Cav-1 siRNA and cholesterol oxidase, which displaces Cav-1 from caveolae, enhanced Akt signaling induced by osteogenic supplements. In control cells, phosphorylated Akt began to accumulate in caveolae after 10 days of osteogenic differentiation. CONCLUSIONS: PI3K/Akt signaling is a key pathway required for human MSC osteogenesis, and it is likely that localization of active Akt in non-caveolar and caveolar membrane rafts positively and negatively contributes to osteogenesis, respectively. PMID- 26626727 TI - Targeted silencing of the Aquaporin 2 gene of Rhipicephalus (Boophilus) microplus reduces tick fitness. AB - BACKGROUND: Ticks are blood-feeding arthropods that can affect human and animal health both directly by blood-feeding and indirectly by transmitting pathogens. The cattle tick Rhipicephalus (Boophilus) microplus is one of the most economically important ectoparasites of bovines worldwide and it is responsible for the transmission of the protozoan Babesia bovis, the etiological agent of bovine babesiosis. Aquaporins (AQPs) are water channel proteins implicated in physiological mechanisms of osmoregulation. Members of the AQP family are critical for blood-feeding arthropods considering the extreme osmoregulatory changes that occur during their feeding. We investigated the pattern of expression of a newly identified AQP2 gene of R. microplus (RmAQP2) in different tick tissues and stages. We also examined in vivo the biological implications of silencing expression of RmAQP2 silencing during tick feeding on either uninfected or B. bovis-infected cattle. METHODS: In silico gene analyses were performed by multiple alignments of amino acid sequences and topology prediction. Levels of RmAQP2 transcripts in different tick tissues and stages were analyzed by reverse transcriptase quantitative PCR. Patterns of expression of RmAQP2 protein were investigated by immunoblots. Gene silencing was performed by RNA interference and in vivo functional analyses carried out by feeding ticks on either uninfected or B. bovis-infected cattle. RESULTS: RmAQP2 transcripts were found in unfed larvae, engorged nymphs, and salivary glands and guts of partially engorged females; however, of all tick tissues and stages examined, RmAQP2 protein was found only in salivary glands of partially engorged females. RmAQP2 silencing significantly reduced tick fitness and completely abrogated protein expression. The effect of RmAQP2 silencing on fitness was more pronounced in females fed on a B. bovis infected calf than in ticks fed on an uninfected calf and none of their larval progeny survived. CONCLUSIONS: Collectively, considering the gene expression and tick fitness data, we conclude that RmAQP2 is critical for tick blood feeding and may be a suitable candidate target for the development of novel strategies to control R. microplus and tick-borne parasites. PMID- 26626729 TI - Excess length of stay and economic consequences of adverse events in Dutch hospital patients. AB - BACKGROUND: To investigate the average and extrapolated excess length of stay and direct costs of adverse events (AEs) and preventable AEs in Dutch hospitals, and to evaluate patient characteristics associated with excess length of stay and costs. METHODS: Data of a large retrospective patient record review study on AEs was used. A stratified sample of 20 Dutch hospitals was included. Excess length of stay and costs attributable to AEs and preventable AEs were calculated and extrapolated to a national estimate. The association between patient characteristics and excess length of stay (and costs thereof) attributable to AEs and preventable AEs was investigated through multilevel linear regression analyses. RESULTS: A total of 2975 patient records were included in the analysis, of which 325 experienced one or more AEs. Hospital patients experiencing an AE stayed 5.11 (95% CI 3.91-6.30) more days in hospital and cost ?2600 (95% CI ?1968 ?3232) more compared to those without an AE. There was no significant difference in days and costs between preventable and non-preventable AEs. Extrapolated to a national level, AEs cost more than ?300 million, which was 1.3% of the national hospital care budget. Patients with hospital-acquired infections had a statistically significant longer length of stay compared to the reference group (patients with AEs on the cardiovascular system). CONCLUSIONS: This study showed that AEs lead to substantial excess length of stay and increased costs. Special attention should be paid to patients with AEs due to an hospital-acquired infection. PMID- 26626728 TI - The relationship between pain management and psychospiritual distress in patients with advanced cancer following admission to a palliative care unit. AB - BACKGROUND: Although many cross-sectional studies have demonstrated the association between cancer pain and psychospiritual distress, the time-dependent relationship has not been fully explored. For that reason, this study aims to investigate the time-dependent relationship between psychospiritual distress and cancer pain management in advanced cancer patients. METHODS: This is a prospective observational study. Two hundred thirty-seven advanced cancer patients were recruited from a palliative care unit in Taiwan. Demographic and clinical data were retrieved at admission. Pain and psychospiritual distress (i.e.: anxiety, depression, anger, level of family and social support, fear of death) were assessed upon admission and one week later, by using a "Symptom Reporting Form". Patients were divided into two groups according to the pain status one week post-admission (improved versus not improved groups). RESULTS: One hundred sixty-three (68.8 %) patients were assigned to the improved group, and 74 (31.2 %) patients were assigned to the not improved group. There were no differences in the psychospiritual variables between groups upon admission. In overall patients, all psychospiritual variables improved one week post-admission, but the improvement of depression and family/social support in the not improved group was not significant. Consistent with this, for depression scores, there was a statistically significant pain group x time interaction effect detected, meaning that the pain group effect on depression scores was dependent on time. CONCLUSIONS: We demonstrated a time-dependent relationship between depression and pain management in advanced cancer patients. Our results suggest that poor pain management may be associated with intractable depression. The inclusion of interventions that effectively improve psychospiritual distress may contribute to pain management strategies for advanced cancer patients. PMID- 26626730 TI - MRI thresholds for discrimination between normal and mild temporomandibular joint involvement in juvenile idiopathic arthritis. AB - BACKGROUND: Currently there is no consensus agreement on the degree of enhancement in normal temporomandibular joints (TMJ) in children, which makes it difficult for clinicians to distinguish between the presence/absence of mild synovitis. Quantitative measurements of synovial and condylar enhancement may be useful additions to current qualitative methods on early MRI diagnosis and follow up of TMJ involvement in JIA. The purpose of the study is to establish thresholds/tendencies for quantitative measures that enable distinction between mild TMJ involvement and normal TMJ appearance based on the degree of synovial and bone marrow enhancement in JIA patients. METHODS: TMJ MRI examinations in 67 children with JIA and in 24 non-rheumatologic children who underwent MRI for neurologic/orbit indications were retrospectively assessed. As a priori determined TMJs of JIA patients were categorized into three groups by experienced staff radiologists based on the degree of synovial and condylar enhancement: no active disease (rheumatologic control), mild and moderate/severe findings. The signal intensity (SI) of the synovial tissue around each condyle and of the bone marrow was measured to calculate the enhancement ratio (ER) and relative SI change. The ER was calculated using signal to noise ratios, while relative SI change was calculated using signal intensities alone. Quantitative measurements of synovial and condylar enhancement of TMJs with mild or moderate/severe findings were compared with the rheumatologic and non-rheumatologic controls. RESULTS: Mean ER values were significantly different between the TMJs without active disease and those with mild and moderate/severe synovial enhancement, with highest values in the moderate/severe group (P < 0.0001). Similar findings were seen for condylar enhancement with P < 0.005. Relative SI change was unable to differentiate TMJs with mild synovitis from the two controls (P > 0.10). 27/60 (45%) TMJs without active disease had osteochondral changes. 8/40 (20%) TMJs in the mild group did not demonstrate any synovial thickening. CONCLUSIONS: Quantitative signal to noise ratios of TMJ synovial and condylar enhancement generate thresholds/tendencies, which offer additional information to differentiate mild synovitis from normal TMJs in JIA patients. Osteochondral changes and synovial thickening may not be reliable indicators of active TMJ involvement and should be differentiated from synovial enhancement. PMID- 26626731 TI - Genetic Factors for Enhancement of Nicotine Levels in Cultivated Tobacco. AB - Nicotine has practical applications relating to smoking cessation devices and alternative nicotine products. Genetic manipulation for increasing nicotine content in cultivated tobacco (Nicotiana tabacum L.) may be of value for industrial purposes, including the possibility of enhancing the efficiency of nicotine extraction. Biotechnological approaches have been evaluated in connection with this objective, but field-based results are few. Here, we report characterization of two genes encoding basic-helix-loop-helix (bHLH) transcription factors (TFs), NtMYC2a and NtMYC2b from tobacco. Overexpression of NtMYC2a increased leaf nicotine levels in T1 transgenic lines approximately 2.3 fold in greenhouse-grown plants of tobacco cultivar 'NC 95'. Subsequent field testing of T2 and T3 generations of transgenic NtMYC2a overexpression lines showed nicotine concentrations were 76% and 58% higher than control lines, respectively. These results demonstrated that the increased nicotine trait was stably inherited to the T2 and T3 generations, indicating the important role that NtMYC2a plays in regulating nicotine accumulation in N. tabacum and the great potential of NtMYC2a overexpression in tobacco plants for industrial nicotine production. Collected data in this study also indicated a negative feedback inhibition of nicotine biosynthesis. Further enhancement of nicotine accumulation in tobacco leaf may require modification of the processes of nicotine transport and deposition. PMID- 26626732 TI - Determinants of pre-hospital pharmacological intervention and its association with outcome in acute myocardial infarction. AB - BACKGROUND: The aim of this study was a) To identify predictors of the use of aspirin in the pre-hospital setting in acute myocardial infarction (AMI) and b) To analyze whether the use of any of the recommended medications was associated with outcome. METHODS: All patients with a final diagnosis of AMI, transported by the Emergency Medical Services (EMS) and admitted to the coronary care unit at Sahlgrenska University Hospital in Gothenburg, Sweden, in 2009-2011, were included. RESULTS: 1,726 patients were included. 58 % received aspirin by the EMS. Ischemic heart disease (IHD) was suspected in 84 %. Among patients who did not receive aspirin IHD was still suspected in 67 %. Among patients in whom IHD was suspected, and who were not on chronic treatment with aspirin the following predicted its pre-hospital use: a) age (odds ratio 0.98; 95 % confidence interval (CI) 0.96-0.99); b) a history of myocardial infarction (2.21; 1.21-4.04); c) priority given by EMS (8.07; 5.42-12.02); d) ST-elevation on ECG on admission to hospital (2.22; 1.50-3.29); e) oxygen saturation > 90 % (3.37; 1.81-6.27). After adjusting for confounders among patients who were not on chronic aspirin, only nitroglycerin of the recommended medications was associated with a reduced risk of death within 1 year (hazard ratio 0.40; 95 % CI 0.23-0.70). CONCLUSIONS: Less than six out of ten patients with AMI received pre-hospital aspirin. Five clinical factors were independently associated with the pre-hospital administration of aspirin. This suggests that the decision to treat is multifactorial, and it highlights the lack of accurate diagnostic tools in the pre-hospital environment. Nitroglycerin was independently associated with a reduced risk of death, suggesting that we select the use for a low-risk cohort. PMID- 26626733 TI - Differences in net global warming potential and greenhouse gas intensity between major rice-based cropping systems in China. AB - Double rice (DR) and upland crop-single rice (UR) systems are the major rice based cropping systems in China, yet differences in net global warming potential (NGWP) and greenhouse gas intensity (GHGI) between the two systems are poorly documented. Accordingly, a 3-year field experiment was conducted to simultaneously measure methane (CH4) and nitrous oxide (N2O) emissions and changes in soil organic carbon (SOC) in oil rape-rice-rice and wheat-rice (representing DR and UR, respectively) systems with straw incorporation (0, 3 and 6 t/ha) during the rice-growing seasons. Compared with the UR system, the annual CH4, N2O, grain yield and NGWP were significantly increased in the DR system, though little effect on SOC sequestration or GHGI was observed without straw incorporation. Straw incorporation increased CH4 emission and SOC sequestration but had no significant effect on N2O emission in both systems. Averaged over the three study years, straw incorporation had no significant effect on NGWP and GHGI in the UR system, whereas these parameters were greatly increased in the DR system, i.e., by 108% (3 t/ha) and 180% (6 t/ha) for NGWP and 103% (3 t/ha) and 168% (6 t/ha) for GHGI. PMID- 26626735 TI - Lichen planus of the lower limbs: successful treatment with psoralen cream plus ultraviolet A photochemotherapy. AB - Lichen planus (LP) classifies into different subtypes depending on morphology and localization. Localized LP of the lower limb (LPLL) manifests a great challenge due to persistent itching, therapeutic resistance and the risk to develop into SCC. We report two cases with LPLL refractory to standard topical therapy, which were successfully treated with psoralen cream plus UVA photochemotherapy (cream PUVA). We propose cream-PUVA as an alternative therapeutic option effective for localized LP of the lower limbs. PMID- 26626734 TI - Fusion transcript loci share many genomic features with non-fusion loci. AB - BACKGROUND: Fusion transcripts are found in many tissues and have the potential to create novel functional products. Here, we investigate the genomic sequences around fusion junctions to better understand the transcriptional mechanisms mediating fusion transcription/splicing. We analyzed data from prostate (cancer) cells as previous studies have shown extensively that these cells readily undergo fusion transcription. RESULTS: We used the FusionMap program to identify high confidence fusion transcripts from RNAseq data. The RNAseq datasets were from our (N = 8) and other (N = 14) clinical prostate tumors with adjacent non-cancer cells, and from the LNCaP prostate cancer cell line that were mock-, androgen- (DHT), and anti-androgen- (bicalutamide, enzalutamide) treated. In total, 185 fusion transcripts were identified from all RNAseq datasets. The majority (76%) of these fusion transcripts were 'read-through chimeras' derived from adjacent genes in the genome. Characterization of sequences at fusion loci were carried out using a combination of the FusionMap program, custom Perl scripts, and the RNAfold program. Our computational analysis indicated that most fusion junctions (76%) use the consensus GT-AG intron donor-acceptor splice site, and most fusion transcripts (85%) maintained the open reading frame. We assessed whether parental genes of fusion transcripts have the potential to form complementary base pairing between parental genes which might bring them into physical proximity. Our computational analysis of sequences flanking fusion junctions at parental loci indicate that these loci have a similar propensity as non-fusion loci to hybridize. The abundance of repetitive sequences at fusion and non-fusion loci was also investigated given that SINE repeats are involved in aberrant gene transcription. We found few instances of repetitive sequences at both fusion and non-fusion junctions. Finally, RT-qPCR was performed on RNA from both clinical prostate tumors and adjacent non-cancer cells (N = 7), and LNCaP cells treated as above to validate the expression of seven fusion transcripts and their respective parental genes. We reveal that fusion transcript expression is similar to the expression of parental genes. CONCLUSIONS: Fusion transcripts maintain the open reading frame, and likely use the same transcriptional machinery as non-fusion transcripts as they share many genomic features at splice/fusion junctions. PMID- 26626736 TI - High yield of recombinant human Apolipoprotein A-I expressed in Pichia pastoris by using mixed-mode chromatography. AB - A vast majority of the cardioprotective properties exhibited by High-Density Lipoprotein (HDL) is mediated by its major protein component Apolipoprotein A-I (ApoA1). In order to develop a simplified bioprocess for producing recombinant human Apolipoprotein A-I (rhApoA1) in its near-native form, rhApoA1was expressed without the use of an affinity tag in view of its potential therapeutic applications. Expressed in Pichia pastoris at expression levels of 58.2 mg ApoA1 per litre of culture in a reproducible manner, the target protein was purified by mixed-mode chromatography using CaptoTM MMC ligand with a purity and recovery of 84% and 68%, respectively. ApoA1 purification was scaled up to Mixed-mode Expanded Bed Adsorption chromatography to establish an 'on-line' process for the efficient capture of rhApoA1 directly from the P. pastoris expression broth. A polishing step using anion exchange chromatography enabled the recovery of ApoA1 up to 96% purity. Purified ApoA1 was identified and verified by RPLC-ESI-Q-TOF mass spectrometry. This two-step process would reduce processing times and therefore costs in comparison to the twelve-step procedure currently used for recovering rhApoA1 from P. pastoris. PMID- 26626737 TI - Polarization-controllable Airy beams generated via a photoaligned director variant liquid crystal mask. AB - Researches on Airy beams have grown explosively since the first demonstration in 2007 due to the distinguishing properties of nondiffraction, transverse acceleration and self-healing. To date, a simple and compact approach for generating Airy beams in high quality and efficiency has remained challenging. Here, we propose and demonstrate a liquid crystal (LC) polarization Airy mask (PAM) featured by spatially variant LC azimuthal director. The PAM is fabricated through photoaligning LC via a polarization-sensitive alignment agent suophonic azo dye SD1. Thanks to the special design, a novel feature of polarization controllable switch between dual Airy beams of orthogonal circular polarization is presented. The molecular-level continuity of LC director significantly improves the quality and efficiency of resultant Airy beams. Besides, the PAM can handle intense light due to the absence of absorptive electrodes. Additional merits of compact size, low cost and broad wavelength tolerance are also exhibited. This work settles a fundamental requirement for Airy beam applications of optical manipulations, biology science and even some uncharted territories. PMID- 26626738 TI - Newsletter: President's Message. PMID- 26626739 TI - Promoting Certification Success: Whose Job Is It? PMID- 26626740 TI - Mistaken Identity Between the Maternal and Fetal Heart Rate: Ensuring Awareness of the Safety Features of the Electronic Fetal Heart Monitor. PMID- 26626741 TI - Critique of the STOP-Bang Sleep Apnea Questionnaire. PMID- 26626742 TI - The Past, Present, and Future of Coenzyme Q10 Supplementation Update for the Clinical Nurse Specialist. PMID- 26626743 TI - Diaries for Recovery From Critical Illness. PMID- 26626744 TI - Clinical Nurse Specialists Guide Staff Nurses to Promote Practice Accountability Through Peer Review. AB - PURPOSE: The aim of the study was to describe the clinical nurse specialist role in developing and implementing a staff nurse education program to promote practice accountability using peer review principles. BACKGROUND: Peer review is essential for professional nursing practice demanding a significant culture change. Clinical nurse specialists in a Magnet-designated community hospital were charged with developing a staff nurse peer review education program. RATIONALE: Peer review is a recognized mechanism of professional self-regulation to ensure delivery of quality care. The American Nurses Association strongly urges incorporating peer review in professional nursing practice models. Clinical nurse specialists play a critical role in educating staff nurses about practice accountability. DESCRIPTION: Clinical nurse specialists developed an education program guided by the American Nurses Association's principles of peer review. A baseline needs assessment identified potential barriers and learning needs. Content incorporated tools and strategies to build communication skills, collaboration, practice change, and peer accountability. OUTCOME: The education program resulted in increased staff nurse knowledge about peer review and application of peer review principles in practice. CONCLUSION: Clinical nurse specialists played a critical role in helping staff nurses understand peer review and its application to practice. IMPLICATIONS: The clinical nurse specialist role will continue to be important in sustaining the application of peer review principles in practice. PMID- 26626745 TI - Use of Failure Mode and Effects Analysis to Improve Emergency Department Handoff Processes. AB - PURPOSE/OBJECTIVES: The purpose of this article is to describe a quality improvement process using failure mode and effects analysis (FMEA) to evaluate systems handoff communication processes, improve emergency department (ED) throughput and reduce crowding through development of a standardized handoff, and, ultimately, improve patient safety. BACKGROUND: Risk of patient harm through ineffective communication during handoff transitions is a major reason for breakdown of systems. Complexities of ED processes put patient safety at risk. RATIONALE: An increased incidence of submitted patient safety event reports for handoff communication failures between the ED and inpatient units solidified a decision to implement the use of FMEA to identify handoff failures to mitigate patient harm through redesign. DESCRIPTION: The clinical nurse specialist implemented an FMEA. Handoff failure themes were created from deidentified retrospective reviews. Weekly meetings were held over a 3-month period to identify failure modes and determine cause and effect on the process. A functional block diagram process map tool was used to illustrate handoff processes. An FMEA grid was used to list failure modes and assign a risk priority number to quantify results. OUTCOMES: Multiple areas with actionable failures were identified. A majority of causes for high-priority failure modes were specific to communications. CONCLUSION: Findings demonstrate the complexity of transition and handoff processes. The FMEA served to identify and evaluate risk of handoff failures and provide a framework for process improvement. IMPLICATIONS: A focus on mentoring nurses to quality handoff processes so that it becomes habitual practice is crucial to safe patient transitions. Standardizing content and hardwiring within the system are best practice. The clinical nurse specialist is prepared to provide strong leadership to drive and implement system wide quality projects. PMID- 26626746 TI - Social Support and Adherence for Military Veterans With Hepatitis C. AB - PURPOSE/OBJECTIVES: The aim of this study was to describe military veterans' experiences of support and how those experiences influence their decisions to be adherent, during hepatitis C virus (HCV) treatment. DESIGN: A qualitative phenomenological design was used. Inclusion criteria were veterans 18 years or older, receiving standard treatment for HCV, able to read, write, and communicate in English. SETTING: A US Veterans Administration facility in Texas. SAMPLE: Convenience sampling was used to obtain a final sample of 21 veterans. METHODS: Data collection consisted of 1-time, in-depth interviews with analysis occurring simultaneously. Follow-up phone calls with participants verified that the themes were accurate reflections of their lived experience. RESULTS: Because of the fear of stigma, veterans make choices about to whom they tell their diagnosis. This limits the circle of friends and coworkers who could provide support. For some veterans, family members provide emotional and practical support, but family can also be a burden. In order to cope with family and treatment demands, some veterans hibernate, whereas others socialize with friends and coworkers. Some veterans found providers to be supportive, but others did not. CONCLUSIONS: Veterans experience both supportive and unsupportive reactions from family, friends, and healthcare providers while receiving HCV treatment. Those reactions either support or frustrate efforts to be adherent to treatment. IMPLICATIONS: In order to support treatment adherence, healthcare providers need to assess sources of support, or burden, experienced by military veterans during HCV treatment. When veterans do not have a supportive network, they need to be encouraged to attend a support group or seek counseling. Support services need to be funded by the Veterans Administration. Providers need to practice empathy and caring in order to support adherence during treatment. Further research is needed on how military veterans manage their health after hepatitis C treatment, contrasting successful versus unsuccessful treatment outcomes. PMID- 26626747 TI - Improving Accuracy of Cardiac Electrode Placement: Outcomes of Clinical Nurse Specialist Practice. AB - PURPOSE: The purpose of this quality improvement project was to facilitate a sustainable improvement in the accuracy of cardiac electrode placement for continuous bedside monitoring in intensive care unit patients. BACKGROUND: Continuous cardiac electrocardiograph monitoring is a standard of practice in critical care areas and is essential to accurate interpretation of cardiac dysrhythmias and early detection of myocardial ischemia. Accurate assessment of electrocardiographs depends on precise placement of electrodes; however, electrodes are often placed inaccurately. RATIONALE: Evaluation of baseline practice revealed that cardiac electrodes were placed correctly in only 12.5% of patients. The most frequently misplaced electrode was the V lead, followed by lower limb leads. DESCRIPTION: This project was conducted between July 1, 2013, and October 31, 2013, and involved a multifaceted education program for registered nurse and patient care technician staff on the physiologic basis and technical procedures for cardiac electrode placement. The clinical nurse specialist served as an informal leader, role model, and mentor by developing and empowering unit champions to perform real-time auditing and provide real-time feedback to colleagues. OUTCOME: At 3 months after intervention, the accuracy of cardiac electrode placement was sustained at greater than 85%, representing a 6 fold improvement above the preintervention baseline. CONCLUSION: Sustainable improvement in quality requires creation of a culture that supports quality improvement initiatives. As experts in clinical practice, evidence-based practice, and leadership, clinical nurse specialists are optimally positioned to function as change agents whose initiatives measurably improve outcomes. IMPLICATIONS: This quality improvement project serves as a model for improving accuracy of cardiac electrode placement at the nursing staff level. Future research is necessary to improve outcomes related to accuracy of cardiac electrode placement on the patient and systems levels. PMID- 26626748 TI - Underdeveloped Themes in Qualitative Research: Relationship With Interviews and Analysis. AB - PURPOSE: In this methodological article, the authors address the problem of underdeveloped themes in qualitative studies they have reviewed. Various possible reasons for underdeveloped themes are examined, and suggestions offered. ORGANIZING CONSTRUCT: Each problem area is explored, and literature support is provided. The suggestions that are offered are supported by the literature as well. FINDINGS: The problem with underdeveloped themes in certain articles is related to 3 interconnected issues: (a) lack of clear relationship to the underlying research method, (b) an apparent lack of depth in interviewing techniques, and (c) lack of depth in the analysis. Underdeveloped themes in a qualitative study can lead to a lack of substantive findings that have meaningful implications for practice, research, and the nursing profession, as well as the rejection of articles for publication. Fully developed themes require knowledge about the paradigm of qualitative research, the methodology that is proposed, the effective techniques of interviewing that can produce rich data with examples and experiences, and analysis that goes beyond superficial reporting of what the participants have said. Analytic problem areas include premature closure, anxiety about how to analyze, and confusion about categories and themes. CONCLUSIONS: Effective qualitative research takes time and effort and is not as easy as is sometimes presumed. The usefulness of findings depends on researchers improving their research skills and practices. IMPLICATIONS FOR PRACTICE: Increasingly researchers are using qualitative research to explore clinically important issues. As consumers of research or members of a research team, clinical nurse specialists need to understand the nature of this research that can provide in depth insight and meaning. PMID- 26626749 TI - Scholarship in Clinical Practice: An Update on Recommendations for Doctor of Nursing Practice Programs. PMID- 26626750 TI - Reading The Burghers of Calais Through Touch. PMID- 26626751 TI - Identifying Core Competencies of Infection Control Nurse Specialists in Hong Kong. AB - PURPOSE: To confirm a core competency scale for Hong Kong infection control nurses at the advanced nursing practice level from the core competency items proposed in a previous phase of this study. This would serve as the foundation of competency assurance in Hong Kong hospitals. DESIGN: A cross-sectional survey design was used. SETTING: All public and private hospitals in Hong Kong. SUBJECTS: All infection control nurses in hospitals of Hong Kong. METHODS: The 83 item proposed core competency list established in an earlier study was transformed into a questionnaire and sent to 112 infection control nurses in 48 hospitals in Hong Kong. They were asked to rate the importance of each infection prevention and control item using Likert-style response categories. Data were analyzed using the Rasch model. RESULTS: The response rate of 81.25% was achieved. Seven items were removed from the proposed core competency list, leaving a scale of 76 items that fit the measurement requirements of the unidimensional Rasch model. CONCLUSIONS: Essential core competency items of advanced practice for infection control nurses in Hong Kong were identified based on the measurement criteria of the Rasch model. Several items of the scale that reflect local Hong Kong contextual characteristics are distinguished from the overseas standards. IMPLICATIONS: This local-specific competency list could serve as the foundation for education and for certification of infection control nurse specialists in Hong Kong. Rasch measurement is an appropriate analytical tool for identifying core competencies of advanced practice nurses in other specialties and in other locations in a manner that incorporates practitioner judgment and expertise. PMID- 26626753 TI - Periodontitis-associated septic pulmonary embolism caused by Actinomyces species identified by anaerobic culture of bronchoalveolar lavage fluid: a case report. AB - BACKGROUND: Periodontal disease is a less common but important cause of septic pulmonary embolism (SPE). However, the pathogens causing periodontal disease associated SPE (PD-SPE) have been poorly understood. Actinomyces species are resident microbiota in the oral cavity. Here we report a case of PD-SPE caused by Actinomyces species, which was identified by anaerobic culture of bronchoalveolar lavage fluid (BAL). CASE PRESENTATION: A 64-year-old Asian man, complicated with severe chronic periodontitis, was admitted with chest pain and fever. Chest CT revealed multiple bilateral pulmonary nodules located subpleurally. We diagnosed the case as SPE associated with periodontitis. Although blood cultures were negative for the usual 5-day incubation, anaerobic culture of the BAL fluid sample yielded Actinomyces species. Antibacterial therapy alone did not ameliorate the symptoms; however, additional dental treatment, including tooth extraction, promptly did. The patient was discharged 23 days after admission. The 3-month follow-up revealed no recurrence of the symptoms and complete resolution of the lung lesions. CONCLUSION: This case demonstrated that Actinomyces species can cause PD-SPE. Additionally, clinicians should consider performing appropriate anaerobic culture of BAL fluid to identify the pathogen of SPE, and to ordering dental treatment, if necessary, in addition to antibiotics for the initial management of PD-SPE. PMID- 26626757 TI - ESPR Uroradiology Taskforce--imaging recommendations in paediatric uroradiology, part VIII: retrograde urethrography, imaging disorder of sexual development and imaging childhood testicular torsion. AB - Three new consensus-based recommendations of the European Society of Paediatric Radiology Uroradiology Taskforce and the European Society of Urogenital Radiology Paediatric Working Group on paediatric uroradiology are presented. One deals with indications and technique for retrograde urethrography, one with imaging in the work-up for disorders of sexual development and one with imaging workflow in suspected testicular torsion. The latter is subdivided to suggest a distinct algorithm to deal with testicular torsion in neonates. These proposals aim to outline effective imaging algorithms to optimise diagnostic accuracy and to harmonize diagnostic imaging among institutions and practitioners. PMID- 26626758 TI - Obesity as a Disease. AB - In recent years, obesity and related medical conditions have become leading public health concerns worldwide. Policy measures to combat or prevent obesity have been instated in a number of countries, with varying degrees of success. To stress the importance of obesity as a health issue, many professional health organizations, including the American Medical Association, have defined obesity itself as a disease. While this may be somewhat controversial, the high risk of comorbid conditions in obese individuals, the significant changes from healthy physiology that are present in the obese state, and the need for further public policies to address the public health threat and economic impact of obesity in the population are strong supporting arguments to label obesity as a disease. PMID- 26626759 TI - What is the Role of the Pharmacist in Obesity Management? AB - Obesity rates have increased over the last two decades. Based on NHANES data, 68.8 % of US adults are classified as overweight or obese. Obesity increases the risk of diseases and can contribute to increased morbidity and mortality. This review examines studies published in which pharmacists have provided weight management services alone or in a team. The electronic databases OVID Medline, International Pharmaceutical Abstracts and EMBASE (1946-2014) were searched. Nine articles were identified in which pharmacists delivered a weight management service either alone or in a team, and eight studies collected outcomes. Six studies evaluated the participant's weight loss or satisfaction with the service, and two studies evaluated weight loss associated with a meal-replacement program. The outcomes from these studies are limited and while positive, have failed to provide significant evidence of the impact of pharmacists providing these services. More randomized, controlled trials are needed to document weight management services. PMID- 26626760 TI - Handheld Electronic Technology for Weight Loss in Overweight/Obese Adults. AB - Handheld electronic devices could offer a convenient and scalable platform with which to deliver a weight loss intervention. This paper aims to summarise the evidence provided by randomised trials of such interventions. There is heterogeneity among trials in terms of the components of the intervention package, the theoretical framework, the comparison groups and the duration of follow-up. While in the short term (<6 months) trials have shown some promising findings, two trials (one of a text message intervention and one of a PDA device for dietary self-monitoring) do not indicate clinically significant weight loss in the longer term (1-2 years). Topical issues are discussed including the importance of further research into dietary self-monitoring, the logistics of trialling smartphone applications and considerations of health literacy. There is currently no definitive randomised controlled trial of a smartphone app for weight loss in adults and further research into this approach is warranted. PMID- 26626761 TI - An Update on Bariatric Surgery. AB - Obesity is a serious problem facing patients and healthcare providers around the globe. Bariatric surgery has been an increasingly popular choice in the management of obesity, and the last five years have seen an enormous amount of research on the various procedures. Recently bariatric surgery has been recognized as an important modifier of the metabolic and hormonal states associated with obesity's comorbidities. Consequently, research regarding the effect of bariatric procedures on type 2 diabetes mellitus, dyslipidemia, and the inflammatory state has become more plentiful. As bariatric surgery has matured, a growing body of evidence and experience has accrued. A change in the relative popularity of the four major laparoscopic bariatric procedures; sleeve gastrectomy, roux-en-Y gastric bypass, adjustable gastric band, and biliopancreatic diversion with duodenal switch has taken place. This has been driven by technical factors, as well as the individual procedures' efficacy in weight-loss and improvement in comorbidities. Weight recidivism is an increasingly recognized problem as patients are followed for longer periods following their bariatric operations. This important and costly problem has roots in both technical and patient related factors. PMID- 26626763 TI - Weight Loss Interventions for Rehabilitation Patients with Obesity. AB - This scoping review aims to explore the contributions of rehabilitation interventions and programs to the management of obesity. Studies and review papers describing weight management for patients in rehabilitation programs were identified. Rehabilitation populations for which weight loss interventions were reported included spinal cord injury, osteoarthritis, cardiac, and psychiatric. Evidence exists to support the promotion of weight loss in patients with obesity receiving rehabilitation services. Outcomes associated with weight loss in obese rehabilitation patients include reduced pain, improved mobility, improved performance of activities of daily living, increased self-efficacy for stair climbing and walking and, increased participation in leisure activities. Despite the prevalence of obesity among groups of patients with physical and psychiatric disabilities and the evidence to support weight loss as beneficial to improve function more research is needed to determine the best way in which to provide weight loss interventions to groups of patients with neurological, musculoskeletal, and psychiatric disabilities. Research is needed to gain knowledge about discipline specific interventions and their impact on obesity management in rehabilitation populations. PMID- 26626762 TI - Beyond BMI: The Next Chapter in Childhood Obesity Management. AB - Pediatric obesity treatment has traditionally focused on body mass index (BMI) and has had limited success. Recent research has suggested new ways to approach this topic that focuses more on holistic measures of health and inclusion of a larger population of children. This paper discusses new evidence in the prevention of chronic disease and treatment of obesity that has a body positive and mental health lens as well as integrating research from several areas of health, including the prevention of chronic disease. Practical medical and mental health assessments tools are suggested for clinical use. Implications for an individualized, positive treatment future are presented. PMID- 26626764 TI - Relationship Between Obesity and Driving. AB - Obesity, which has become epidemic throughout many parts of the world, is known to be a risk factor for a range of diseases including hypertension, diabetes, and vascular disease. Based on this review, it also appears that obesity is associated with increased crash risk and increased risk of serious or fatal injury in a crash. The problem is particularly an issue for commercial truck drivers. Data are presented showing the high prevalence of obesity in truck drivers. Inadequate sleep, poor nutrition, lack of exercise, and the sedentary nature of driving all contribute to the risk of obesity. The obesity related condition of obstructive sleep apnea (OSA) is known to increase crash risk. Treatment of this condition has been demonstrated to improve driving performance and to reduce crash risk. Screening truck drivers for obesity related health conditions, such as OSA, would be expected to result in public safety benefits. PMID- 26626765 TI - Influences of Obesity on Job Demands and Worker Capacity. AB - Evidence suggests that the growing prevalence of obesity in the workforce has resulted in an increase in the incidence and cost of musculoskeletal injuries. Obesity can modify job demands and affect worker capacity in terms of anthropometry and occupational biomechanics, which may place workers at greater risk of injury. This paper presents a review of studies quantifying the work relevant impacts of obesity, specifically related to work task demands, capacities, and their potential imbalance. The increased body fat that accompanies obesity leads to larger anthropometric dimensions and inertial parameters, particularly in the trunk and thigh areas. Consequently, individuals who are obese adjust their work postures and motions as an accommodation. These changes may affect the biomechanical demands on the joints and increase the burden on the musculoskeletal system. Independent of job demands, obesity-related differences also occur with respect to strength, fatigue, and task performance. Directions for future research are provided, focusing on the need for workplace redesign to account for changing workforce demographics. PMID- 26626766 TI - Obesity as a Factor Contributing to Falls by Older Adults. AB - The growth of the worldwide population of older adults presents significant challenges, many inter-related, that range from the health of individuals to the health of national economies. In the US, more than one-third of older adults may be obese, a condition that may independently increase the risk for mobility impairment, fall-related injury and, possibly, costs of post-injury treatment and care. The effectiveness of conventional exercise-based fall prevention programs is significant but smaller than both the annual rate of falling of older adults and rate of growth of this population, who are at greatest risk for injurious falls. The anthropometric and functional consequences of obesity may impose limitations on the ability to perform compensatory stepping responses following large postural disturbances. The focus of this paper is the potential of task specific training to improve compensatory stepping responses and reduce falls by obese people given the individual-specific anthropometric and functional consequences of obesity. PMID- 26626767 TI - Musculoskeletal Function and Obesity: Implications for Physical Activity. AB - However quantified, obesity is a global health problem of significant magnitude. The condition is no longer limited to the developed world, with an increasing proportion of low-to-middle income countries burdened by obesity and its comorbidities. Specifically, obesity is a risk factor for a raft of psychosocial, physiological, cardiovascular, and metabolic problems. The carriage of excess body weight, including an unhealthy proportion of body fat, also has important implications for musculoskeletal health. To date, this important relationship has not received as much attention by the research community. Coincidentally, there has been a heightened interest in the role of physical activity and exercise across the lifespan in the prevention, treatment and management of obesity. This paper considers some of the more common musculoskeletal problems in children, adolescents and adults with implications for the overweight and obese and their meaningful engagement in physical activity. PMID- 26626768 TI - Anti-Obesity Agents and the US Food and Drug Administration. AB - Despite the growing market for obesity care, the US Food and Drug Administration (FDA) has approved only two new pharmaceutical agents-lorcaserin and combination phentermine/topiramate-for weight reduction since 2000, while removing three agents from the market in the same time period. This article explores the FDA's history and role in the approval of anti-obesity medications within the context of a public health model of obesity. Through the review of obesity literature and FDA approval documents, we identified two major barriers preventing fair evaluation of anti-obesity agents including: (1) methodological pitfalls in clinical trials and (2) misaligned values in the assessment of anti-obesity agents. Specific recommendations include the use of adaptive (Bayesian) design protocols, value-based analyses of risks and benefits, and regulatory guidance based on a comprehensive, multi-platform obesity disease model. Positively addressing barriers in the FDA approval process of anti-obesity agents may have many beneficial effects within an obesity disease model. PMID- 26626769 TI - Point-of-Purchase Calorie Labeling Has Little Influence on Calories Ordered Regardless of Body Mass Index. AB - The obesity epidemic has incited legislation aimed to inform consumers of the nutritional value of food items available in restaurants and fast food establishments, with the presumption that knowing the caloric content in a meal might enable patrons to make healthier choices when ordering. However, available research shows mixed results regarding consumers' use of calorie information to promote healthier purchases. The aim of this study was to determine whether menu type, specifically having viewed a menu with calorie disclosures or not, would have an impact on how many calories were in a lunch meal ordered by a patron. Additionally, we sought to identify body mass index (BMI) as a moderator of the relationship between viewing a menu with or without calorie information and the number of calories an individual orders for lunch. Two hundred forty-five adults participated in the study and completed the questionnaire. Results indicated neither menu type, nor reporting having seen calorie information, was significantly related to the number of calories in the foods that participants ordered, even after controlling demographic variables age, sex, income, education, race/ethnicity, and BMI. BMI did not serve as a moderator in the relationship between menu type and food calories ordered. Implications for policy change and clinical work with overweight and obese patients are discussed. PMID- 26626770 TI - Cutaneous T cell Lymphoma: an Update on Pathogenesis and Systemic Therapy. AB - Mycosis fungoides (MF) and its leukemic variant, Sezary syndrome (SS), are malignancies of skin-homing T cells that comprise the majority of cutaneous T cell lymphomas (CTCL). Treatment of CTCL is limited and can be approached by skin directed therapy or systemic therapy. Recent investigations into the pathogenesis of MF and SS have broadened the therapeutic targets; here, we review emerging concepts in the pathogenesis of MF and SS as well as novel and traditional systemic therapies for MF and SS. These include histone deacetylase inhibitors (vorinostat, romidepsin, panobinostat, and belinostat), monoclonal antibodies (alemtuzumab, brentuximab vedotin, and mogamulizumab) and single-agent cytotoxic chemotherapeutic agents (e.g., pralatrexate, doxorubicin, bendamustine, and forodesine), as well as multi-agent chemotherapy regimens. PMID- 26626771 TI - Conjunctival structural and functional reconstruction using acellular bovine pericardium graft (Normal GEN(r)) in rabbits. AB - PURPOSE: To evaluate the effectiveness of acellular bovine pericardium grafts (Normal GEN(r)) used as scaffolds for conjunctival reconstruction. METHOD: The acellular bovine pericardium graft and the amnion graft were implanted into the bulbar conjunctival defects of adult rabbits. Conjunctival samples of implanted materials and blank defect controls were observed at day 3, 7, 14, 21, 28, and 56 postoperatively. Histological examination was observed at day 14, 28, and 56 of surgery, including hematoxylin-eosin staining, periodic acid-Schiff staining, and Masson's trichrome staining, while immunofluorescent microscopy was observed at 14 days and 28 days after surgery. Results were compared among the Normal GEN(r), amnion, and blank defect controls. RESULTS: All three groups showed complete conjunctival reconstruction. Wounds that were not grafted closed by formation of conjunctival scar characterized by a linear array of densely packed collagen fibers in Tenon's capsule. Subepithelial tissue in the grafted groups comprised a loosely organized network of randomly oriented collagen that resembled that of the normal bulbar conjunctiva. However, there was a dense layer of aligned collagen between the conjunctival Tenon's capsule and the sclera in the NormalGEN(r) group, about 250 MUm in thickness. CONCLUSIONS: Implantation of the NormalGEN(r) graft promoted the formation of conjunctiva as a kind of scaffold both in structure and in function. It had more advantageous mechanical properties than the amnion, strong and elastic, during the period of conjunctival reconstruction. PMID- 26626773 TI - The Use of Structural Distal Femoral Allograft for Acetabular Reconstruction of Paprosky Type IIIA Defects at a Mean 21 Years of Follow-Up. AB - BACKGROUND: Revision total hip arthroplasty in patients with a nonsupportive superior acetabulum often requires secondary augmentation beyond a hemispherical cup to achieve reliable fixation. Treatment options include using a higher hip center, jumbo cup, custom triflange implant, cages, or filling the superior defect with a bilobed implant, structural allograft, or metal augments. We previously reported a cohort of 31 patients treated with porous-coated hemispherical cups and distal femoral allograft for Paprosky type IIIA acetabular defects. METHODS: The original cohort of 31 hips was retrospectively reviewed. Fourteen patients died with <15 years of follow-up, and 2 were lost to follow-up. This left 15 patients for evaluation including 5 males and 10 females, with an average age of 61 years (range: 37-74 years) at the time of surgery. Acetabular revision was performed with the use of a porous-coated hemispherical cup along with structural distal femoral allograft, cut to resemble the number 7, and secured with 6.5-mm cancellous screws with washers. RESULTS: Overall, 7 hips failed, resulting in a Kaplan-Meier survivorship of 72% at 25 years of follow-up. In surviving patients, radiographs demonstrated components to be well fixed, and average Merle d'Aubigne score increased from 5 to 10 points. There were a subset of patients that failed early (median: 6.2 years), but the remaining patients demonstrated excellent clinical and radiographic results. CONCLUSIONS: The use of distal femoral allograft can be considered in young patients with type IIIA acetabular defects that could benefit from restoration of bone stock. PMID- 26626772 TI - Subfoveal choroidal thickness as a predictor of treatment response to anti vascular endothelial growth factor therapy for polypoidal choroidal vasculopathy. AB - PURPOSE: To investigate whether subfoveal choroidal thickness predicted treatment response to anti-vascular endothelial growth factor (VEGF) in polypoidal choroidal vasculopathy (PCV). METHODS: This retrospective observational case series included 66 eyes of 60 patients who were diagnosed with new-onset PCV and who were followed for a minimum of 6 months. Patients received three monthly intravitreal injections of 0.5 mg ranibizumab or 1.25 mg bevacizumab, at baseline, month 1, and month 2. "Good responders" were defined as those who showed complete resolution of subretinal and/or intraretinal fluid at month 3 after the loading injections, whereas "poor responders" were defined as those who showed persistent retinal fluid on optical coherence tomography (OCT) at month 3 after treatment. Differences in best-corrected visual acuity, indocyanine green angiography, and spectral domain-OCT findings at baseline were analyzed between the two groups. RESULTS: The mean patient age was 68.2 +/- 9.7 years, and the mean follow-up period was 27 +/- 21 months. The mean subfoveal choroidal thickness was 273 +/- 117 MUm, and choroidal vascular hyperpermeability was observed in 35 eyes (53.0 %). Thirty-three eyes (50 %) showed good response to treatment, and a thinner subfoveal choroid at baseline significantly correlated with favorable treatment response (P = 0.024). However, there was no significant relationship between treatment response and choroidal vascular hyperpermeability (P = 0.999). CONCLUSIONS: The subfoveal choroid was found to be significantly thinner among patients who achieved complete resolution of macular exudation after three loading injections of anti-VEGF agents. PMID- 26626774 TI - Association of Epsilon-Aminocaproic Acid With Blood Loss and Risk of Transfusion After Periacetabular Osteotomy: A Retrospective Cohort Study. AB - BACKGROUND: Periacetabular osteotomy (PAO) reorients the acetabular cartilage through a complex series of pelvic osteotomies, which risks significant blood loss often necessitating blood transfusion. Therefore, it is important to identify effective strategies to manage blood loss and decrease morbidity after PAO. The purpose of this study was to determine the association of epsilon aminocaproic acid (EACA), an antifibrinolytic agent, with blood loss from PAO. METHODS: Ninety-three patients out of 110 consecutive patients that underwent unilateral PAO for acetabular dysplasia met inclusion criteria. Fifty patients received EACA intraoperatively. Demographics, autologous blood predonation, anesthetic type, intraoperative estimated blood loss (EBL), cell-saver utilization, and transfusions were recorded. Total blood loss was calculated. Two sample t-test and chi-square or Fisher's exact test were used as appropriate. The associations between EACA administration and calculated EBL, cell-saver utilization, intraoperative EBL, and maximum difference in postoperative hemoglobin were assessed via multiple regression, adjusting for confounders. Post hoc power analysis demonstrated sufficient power to detect a 250-mL difference in calculated EBL between groups. Alpha level was 0.05 for all tests. RESULTS: No demographic differences existed between groups. Mean blood loss and allogeneic transfusion rates were not statistically significant between groups (P = .093 and .170, respectively). There were no differences in cell-saver utilization, intraoperative EBL, and/or postoperative hemoglobin. There was a higher rate of autologous blood utilization in the group not receiving EACA because of a clinical practice change. CONCLUSIONS: EACA administration was not associated with a statistically significant reduction in blood loss or allogeneic transfusion in patients undergoing PAO. PMID- 26626775 TI - The Sphygmomanometer Pain Test: A Simple Method for Identifying Patients at Risk of Excessive Pain after Total knee Arthroplasty. AB - BACKGROUND: Despite the overall success of total knee arthroplasty (TKA), a relatively large proportion of patients remain dissatisfied with the outcome. We hypothesized that patients with a lower threshold for pain were more likely to have worse outcomes after TKA. METHODS: Forty-eight consecutive patients with primary knee osteoarthritis graded a standardized painful stimulus caused by inflating a sphygmomanometer placed on the forearm, on a visual analog scale (VAS) scale before their TKA. We compared the VAS scores to patients' Knee Society scores and Knee Society function scores 2 years after TKA. RESULTS: Patients with a severe VAS score (>74 mm) had significantly worse Knee Society scores compared to patients with mild (0-44 mm) and moderate (45-74 mm) VAS scores (55 +/- 20.5 vs 81.5 +/- 11.1 and 84.8 +/- 13, respectively, P = .04) and worse Knee Society Function scores (34 +/- 20.7 vs 75.2 +/- 17.3 and 77 +/- 17.4, respectively, P = .027) at 2 years after TKA. CONCLUSIONS: Patients with a lower threshold for pain, as determined by a standardized painful stimulus, are more likely to have lower Knee Society pain and function scores after TKA. PMID- 26626776 TI - A Meta-Analysis of Ring Annuloplasty Versus Combined Ring Annuloplasty and Subvalvular Repair for Moderate-to-Severe Functional Mitral Regurgitation. AB - BACKGROUND: A ring annuloplasty (Ring) for moderate-to-severe functional mitral regurgitation (MR) is associated with suboptimal outcomes, and adjunctive subvalvular repair techniques (Ring + Subvalvular) have been advocated to improve repair durability. However, the outcomes of this strategy are not clearly defined. METHODS: A systematic review was performed to identify studies that compared a Ring versus Ring + Subvalvular repair for the treatment of moderate-to severe functional MR. A meta-analysis was conducted on clinical outcomes and echocardiographic measures of follow-up MR and left ventricular reverse remodeling. Risk ratio (RR) and mean difference (MD) were calculated by the Mantel-Haenszel and Inverse Variance methods under a fixed or random effects model, as appropriate. RESULTS: Seven non-randomized studies were identified, with a total of 531 patients (Ring = 301, Ring + Subvalvular = 230). At follow-up (range 30-47 months), a Ring + Subvalvular repair was associated with a lower mortality (RR = 0.59, 95%confidence interval [CI] 0.37-0.94, p = 0.03), greater freedom from moderate or greater MR (RR = 0.44, 95%CI 0.27-0.72, p = 0.001), and improved left ventricular end-diastolic diameter (MD = -3.49 mm, 95%CI -5.45 to 1.53, p = 0.0005) and New York Heart Association functional class (MD = -0.25, 95%CI -0.42 to -0.08, p = 0.004). A trend toward a reduced risk of reoperation for recurrent MR was noted with a combined Ring + Subvalvular repair (RR = 0.28, 95%CI 0.06-1.22, p = 0.09). Finally, a Ring + Subvalvular repair did not impact operative mortality or follow-up left ventricular ejection fraction. CONCLUSION: A combined Ring + Subvalvular repair for moderate-to-severe functional MR can be safely performed, and may improve mid-term outcomes, as compared with Ring alone. PMID- 26626777 TI - Reproducible preparation of nanospray tips for capillary electrophoresis coupled to mass spectrometry using 3D printed grinding device. AB - The use of high quality fused silica capillary nanospray tips is critical for obtaining reliable and reproducible electrospray/MS data; however, reproducible laboratory preparation of such tips is a challenging task. In this work, we report on the design and construction of low-cost grinding device assembled from 3D printed and commercially easily available components. Detailed description and characterization of the grinding device is complemented by freely accessible files in stl and skp format allowing easy laboratory replication of the device. The process of sharpening is aimed at achieving maximal symmetricity, surface smoothness and repeatability of the conus shape. Moreover, the presented grinding device brings possibility to fabricate the nanospray tips of desired dimensions regardless of the commercial availability. On several samples of biological nature (reserpine, rabbit plasma, and the mixture of three aminoacids), performance of fabricated tips is shown on CE coupled to MS analysis. The special interest is paid to the effect of tip sharpness. PMID- 26626778 TI - Temporal trends for donepezil utilization among older people. AB - To examine and characterize overall donepezil and concomitant utilization with beta-blockers, yearly, in older New Zealanders. Deidentified data from the Pharmaceutical claims database and the National Minimum Dataset were obtained for 2011 to 2013 from the Ministry of Health. Population-level data were extracted for donepezil and beta-blockers utilization, measured by defined daily dose (DDD) per thousand older people per day (TOPD). Donepezil utilization increased from 5.2 to 8.2 DDD/TOPD between 2011 and 2013. In 2011, the number of prevalent users was 4634, the mean age was 79.4+/-6.6 years and 57.5% were women. Highest use by age for donepezil was in those aged 85 years or older (2.3 DDD/TOPD), followed by those aged 80-84 years (2.2 DDD/TOPD). The mean utilization volumes were significantly lower for donepezil 5 mg (Student t-test=9.86; P<0.05) and 10 mg (10.90; P<0.05) in the 65- to 69-year age group compared with the 80- to 84-year age group, whereas the proportion of concomitant utilization of donepezil with beta-blockers decreased (17.9% to 5.1%). Donepezil utilization in DDD/TOPD increased by three-fifths between 2011 and 2013. Prescribers appear to be aware of the potential risk of bradycardia with the concomitant use of donepezil and beta-blockers. PMID- 26626779 TI - Effects of Nandrolone Stimulation on Testosterone Biosynthesis in Leydig Cells. AB - Anabolic androgenic steroids (AAS) are among the drugs most used by athletes for improving physical performance, as well as for aesthetic purposes. A number of papers have showed the side effects of AAS in different organs and tissues. For example, AAS are known to suppress gonadotropin-releasing hormone, luteinizing hormone, and follicle-stimulating hormone. This study investigates the effects of nandrolone on testosterone biosynthesis in Leydig cells using various methods, including mass spectrometry, western blotting, confocal microscopy and quantitative real-time PCR. The results obtained show that testosterone levels increase at a 3.9 MUM concentration of nandrolone and return to the basal level a 15.6 MUM dose of nandrolone. Nandrolone-induced testosterone increment was associated with upregulation of the steroidogenic acute regulatory protein (StAR) and downregulation of 17a-hydroxylase/17, 20 lyase (CYP17A1). Instead, a 15.6 uM dose of nandrolone induced a down-regulation of CYP17A1. Further in vivo studies based on these data are needed to better understand the relationship between disturbed testosterone homeostasis and reproductive system impairment in male subjects. PMID- 26626780 TI - Mutational spectrum of intraepithelial neoplasia in pancreatic heterotopia. AB - Heterotopic pancreatic parenchyma recapitulates the normal pancreas in extrapancreatic locations and, on rare occasions, can even give rise to pancreatic adenocarcinoma. The genetic signatures of pancreatic adenocarcinoma and its precursor lesions are well characterized. We explored the genetic alterations in precursor lesions (intraductal papillary mucinous neoplasms [IPMN], pancreatic intraepithelial neoplasia [PanIN]) in patients with pancreatic heterotopias but without concomitant pancreatic ductal adenocarcinomas. This allowed us to determine whether the stereotypical dysplasia--infiltrating carcinoma sequence also occurs in these extrapancreatic foci. Seven cases of heterotopic pancreas with ductal precursor lesions were identified. These included 2 IPMNs with focal high-grade dysplasia and 5 PanINs with low- to moderate-grade dysplasia (PanIN grades 1-2). Neoplastic epithelium was microdissected and genomic DNA was extracted. Sequencing of commonly mutated hotspots (KRAS, TP53, CDKN2A, SMAD4, BRAF, and GNAS) in pancreatic ductal adenocarcinoma and its precursor lesions was performed. Both IPMNs were found to have KRAS codon 12 mutations. The identification of KRAS mutations suggests a genetic pathway shared with IPMN of the pancreas. No mutations were identified in our heterotopic PanINs. One of the possible mechanisms for the development of dysplasia in these lesions is field effect. At the time of these resections, there was no clinical or pathologic evidence of a prior or concomitant pancreatic lesion. However, a clinically undetectable lesion is theoretically possible. Therefore, although a field effect cannot be excluded, there was no evidence for it in this study. PMID- 26626781 TI - Ventricular tachycardia during regadenoson SPECT myocardial perfusion imaging. PMID- 26626782 TI - Cardiovascular risk assessment with regadenoson SPECT MPI in patients with end stage renal disease is safe, effective, and well tolerated: Does it matter? PMID- 26626783 TI - Simultaneous cardiac imaging to detect inflammation and scar tissue with (18)F fluorodeoxyglucose PET/MRI in cardiac sarcoidosis. PMID- 26626786 TI - Special Needs in Adolescents: Where Are We? PMID- 26626785 TI - Myocardial 123I-metaiodobenzylguanidine scintigraphy in patients with homozygous and heterozygous parkin mutations. AB - BACKGROUND: PARK2 is an autosomal recessive parkinsonism caused by parkin gene mutations. Several Parkinson's Disease (PD) cases harbor single parkin mutations, raising a debate about the pathogenic meaning of heterozygous mutations. Here, we evaluate cardiac autonomic innervation in patients with either two or one parkin mutations compared to patients with idiopathic PD (IPD). PATIENTS AND METHODS: Myocardial 123I-metaiodobenzylguanidine (MIBG) scintigraphy was performed in six PD patients with single parkin mutations (HET), four with two mutations (PARK2), and eight with IPD. RESULTS: In comparison to control group, IPD patients showed lower early and late heart-to-mediastinum (H/M) ratios and higher washout rates, whereas HET patients had only lower early H/M ratio, and PARK2 patients were not different for any parameter. At individual level, MIBG findings were abnormal in 7/8 IPD, in 4/6 HET and in 1/4 PARK2 patients. CONCLUSIONS: Preserved cardiac 123I-MIBG uptake confirms that PARK2 pathogenic mechanism, at least partially, differs from that responsible for IPD. HET subjects show intermediate findings, suggesting possible heterogeneity. PMID- 26626787 TI - Contraception Delivery in Pediatric and Specialist Pediatric Practices. AB - STUDY OBJECTIVE: To characterize pediatricians' knowledge, attitudes, and self efficacy around contraception. DESIGN: Cross-sectional survey. SETTING: United States. PARTICIPANTS: National sample of pediatricians. INTERVENTIONS: Assessment of behaviors of providing contraception. MAIN OUTCOME MEASURES: Reproductive health practice score. RESULTS: Two hundred twenty-three usable surveys were received, from 163 contraceptive prescribers and 60 nonprescribers. The mean reproductive health practice score was 43.1 (SD, 8.2; total possible score, 84). Prescribers differed in their mean reproductive health score (46.0; SD, 7.0) from nonprescribers (34.0; SD, 4.5; P < .001). Prescribers vs nonprescribers differed in their attitude and efficacy in providing contraception. More prescribers believed it was their responsibility to ask about patients' need for birth control, were confident in their ability to prescribe contraception options, and provided contraception to minors despite parental disapproval. Neither group was confident in their ability to place intrauterine devices or believed that the literature supports intrauterine device placement in adolescents. Only efficacy was related to prescribing contraception in a multivariate regression analysis (odds ratio, 1.7; P < .001). CONCLUSION: In this study, we showed that most pediatricians are contraception prescribers but the overall reproductive health score was low for prescribers and nonprescribers. The odds of prescribing contraception increased with higher self-efficacy scores rather than knowledge alone. Many prescribers and nonprescribers would not prescribe birth control if parents disapproved and do not believe it is their responsibility to assess patients' need for birth control. In addition very few pediatricians have training in long-acting reversible contraception, despite being the recommended method for adolescents. PMID- 26626789 TI - Beginning the Work of Integration: An Investigation of Primary Care Physicians' Attitudes Toward Psychiatry. AB - OBJECTIVE: The authors sought to better understand the attitudes of primary care physicians toward psychiatrists in order to assess their receptivity for further psychiatric education. METHODS: A survey about attitudes toward psychiatrists in comparison to other specialties was distributed among four family medicine residency programs at Southern Illinois University. RESULTS: Respondents rated psychiatry lower than other specialties in the areas measured. However, family medicine physicians expressed a desire to work with psychiatrists and receive further education in psychiatry. CONCLUSION: Favorable attitudes toward psychiatrists and education in psychiatry suggest the potential for additional family medicine training in psychiatry. PMID- 26626790 TI - Leading Change During Changing Times: Simple Leadership Lessons to Guide Academic Leaders. PMID- 26626791 TI - Teaching Psychosocial Interventions for Opioid Use Disorder in Low and Middle Income Countries: Malaysia and China. PMID- 26626792 TI - Addiction and Chronic Pain: Training Addiction Psychiatrists. AB - OBJECTIVE: Addiction psychiatrists are increasingly asked to address chronic pain in patients with addiction. Because of historic "divisions of labor" between physicians who manage pain and addiction psychiatrists who manage addiction, limited guidance exists for preparing addiction psychiatry trainees to address this comorbidity. METHODS: A 1-h focus group composed of five geographically well distributed addiction psychiatry fellowship directors/faculty was conducted to explore existing curricula, identify themes, and build consensus regarding educational goals for addiction psychiatry fellows in the area of chronic pain management. RESULTS: Discussion resulted in five broad categories of themes involving perceptions of the importance of chronic pain training for addiction psychiatrists; barriers to curriculum development (one notably being that the addiction psychiatrist's role in managing chronic pain is poorly articulated); facilitators to such development; and potential curricular content and roles of addiction psychiatrists in relation to chronic pain training. CONCLUSION: Educators in addiction psychiatry should clarify their role in the management of chronic pain and prioritize training in this area. PMID- 26626793 TI - Structure-Based Prediction of Anti-infective Drug Concentrations in the Human Lung Epithelial Lining Fluid. AB - PURPOSE: Obtaining pharmacologically relevant exposure levels of antibiotics in the epithelial lining fluid (ELF) is of critical importance to ensure optimal treatment of lung infections. Our objectives were to develop a model for the prediction of the ELF-plasma concentration ratio (EPR) of antibiotics based on their chemical structure descriptors (CSDs). METHODS: EPR data was obtained by aggregating ELF and plasma concentrations from historical clinical studies investigating antibiotics and associated agents. An elastic net regularized regression model was used to predict EPRs based on a large number of CSDs. The model was tuned using leave-one-drug-out cross validation, and the predictions were further evaluated using a test dataset. RESULTS: EPR data of 56 unique compounds was included. A high degree of variability in EPRs both between- and within drugs was apparent. No trends related to study design or pharmacokinetic factors could be identified. The model predicted 80% of the within-drug variability (R(2) WDV) and 78.6% of drugs were within 3-fold difference from the observations. Key CSDs were related to molecular size and lipophilicity. When predicting EPRs for a test dataset the R(2) WDV was 75%. CONCLUSIONS: This model is of relevance to inform dose selection and optimization during antibiotic drug development of agents targeting lung infections. PMID- 26626795 TI - Recent Progress in Therapeutics for Inflammation-Associated Preterm Birth: A Review. AB - Preterm birth is one of the most common obstetrical complications, with an incidence of about 5% to 18% of all pregnancies worldwide. Acute chorioamniotic infection is likely antecedent to preterm birth through the local production of inflammatory mediators, followed by uterine contraction and cervical ripening. Microbial chorioamnionitis and local inflammation synergistically form a vicious circle toward preterm birth. Principal therapeutic interventions focus on anti infection and anti-inflammation strategies to block this vicious circle. Anti inflammatory therapeutics include agents that directly inhibit inflammatory cytokine production/reaction and that resolve supraphysiological inflammation toward a normal condition. In particular, naturally produced compounds, including polyphenols, omega-3 polyunsaturated fatty acid metabolites, and statins, are attractive agents in terms of safety for pregnant women and their infants. This review summarizes the mechanisms of perinatal inflammation induced by acute chorioamnionitis and therapeutic resolution of inflammation of the uterus to avoid the harmful exposure of preterm infants to inflammation in utero. PMID- 26626794 TI - Vaginal Dinoprostone Versus Intravenous Oxytocin for Labor Induction in Patients Not Responsive to a First Dose of Dinoprostone: A Randomized Prospective Study. AB - OBJECTIVE: To evaluate the efficacy of 2 different regimens for labor induction in patients with unfavorable cervix not responsive to a first dose of dinoprostone vaginal insert. METHODS: Between November, 2011 and June, 2014, 338 patients underwent induction of labor. After standard 24 hours treatment, 94 singleton term pregnancies remained with a Bishop score <=6 and were randomized into 2 different regimens: repeated vaginal dinoprostone (group A, n = 47) or intravenous oxytocin (group B, n = 47). Primary outcome was vaginal delivery, and the secondary outcomes were interval between labor induction and delivery and operative delivery rates. RESULTS: Vaginal deliveries were significantly higher (group A: 26/47 (55.3%) and group B 16/47 (34.0%), P < .05), and cesarean sections were significantly lower (group A 21/47 (44.7%) and group B 31/47 (66%), P < .05) in patients who received a double dose of dinoprostone. The intervals between labor induction and onset of labor and between labor induction and delivery were lower in the group treated with oxytocin. Neonatal outcomes were similar in the 2 groups. CONCLUSION: A second dinoprostone vaginal insert is an effective and safe choice for patients with unfavorable cervix not responsive to a first 24 hours administration of dinoprostone for cervical ripening, and its use is associated with lower cesarean section rates. PMID- 26626796 TI - Suppressing molecular motions for enhanced room-temperature phosphorescence of metal-free organic materials. AB - Metal-free organic phosphorescent materials are attractive alternatives to the predominantly used organometallic phosphors but are generally dimmer and are relatively rare, as, without heavy-metal atoms, spin-orbit coupling is less efficient and phosphorescence usually cannot compete with radiationless relaxation processes. Here we present a general design rule and a method to effectively reduce radiationless transitions and hence greatly enhance phosphorescence efficiency of metal-free organic materials in a variety of amorphous polymer matrices, based on the restriction of molecular motions in the proximity of embedded phosphors. Covalent cross-linking between phosphors and polymer matrices via Diels-Alder click chemistry is devised as a method. A sharp increase in phosphorescence quantum efficiency is observed in a variety of polymer matrices with this method, which is ca. two to five times higher than that of phosphor-doped polymer systems having no such covalent linkage. PMID- 26626797 TI - Single Layer Bismuth Iodide: Computational Exploration of Structural, Electrical, Mechanical and Optical Properties. AB - Layered graphitic materials exhibit new intriguing electronic structure and the search for new types of two-dimensional (2D) monolayer is of importance for the fabrication of next generation miniature electronic and optoelectronic devices. By means of density functional theory (DFT) computations, we investigated in detail the structural, electronic, mechanical and optical properties of the single-layer bismuth iodide (BiI3) nanosheet. Monolayer BiI3 is dynamically stable as confirmed by the computed phonon spectrum. The cleavage energy (Ecl) and interlayer coupling strength of bulk BiI3 are comparable to the experimental values of graphite, which indicates that the exfoliation of BiI3 is highly feasible. The obtained stress-strain curve shows that the BiI3 nanosheet is a brittle material with a breaking strain of 13%. The BiI3 monolayer has an indirect band gap of 1.57 eV with spin orbit coupling (SOC), indicating its potential application for solar cells. Furthermore, the band gap of BiI3 monolayer can be modulated by biaxial strain. Most interestingly, interfacing electrically active graphene with monolayer BiI3 nanosheet leads to enhanced light absorption compared to that in pure monolayer BiI3 nanosheet, highlighting its great potential applications in photonics and photovoltaic solar cells. PMID- 26626799 TI - A new stage of our journal : A truly multimodal and international platform for the study of gastric cancer. PMID- 26626798 TI - ICE1 of Pyrus ussuriensis functions in cold tolerance by enhancing PuDREBa transcriptional levels through interacting with PuHHP1. AB - ICE1 transcription factor plays an important role in plant cold stress via regulating the expression of stress-responsive genes. In this study, a PuICE1 gene isolated from Pyrus ussuriensis was characterized for its function in cold tolerance. The expression levels of the PuICE1 were induced by cold, dehydration and salt, with the greatest induction under cold conditions. PuICE1 was localized in the nucleus and could bind specifically to the MYC element in the PuDREBa promoter. The PuICE1 fused to the GAL4 DNA-binding domain to have transcriptional activation activity. Ectopic expression of the PuICE1 in tomato conferred enhanced tolerance to cold stress at cold temperatures, less electrolyte leakage, less MDA content, higher chlorophyll content, higher survival rate, higher proline content, higher activities of enzymes. In additon, steady-state mRNA levels of six stress-responsive genes coding for either functional or regulatory genes were induced to higher levels in the transgenic lines by cold stress. Yeast two-hybrid, transient assay, split luciferase complementation and BiFC assays all revealed that PuHHP1 protein can physically interact with PuICE1. Taken together, these results demonstrated that PuICE1 plays a positive role in cold tolerance, which may be due to enhancement of PuDREBa transcriptional levels through interacting with the PuHHP1. PMID- 26626800 TI - Phase II study of adjuvant chemotherapy of S-1 plus oxaliplatin for patients with stage III gastric cancer after D2 gastrectomy. AB - BACKGROUND: The Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) demonstrated a survival benefit by adjuvant S-1 monotherapy in patients who had undergone curative resection of stage II/III gastric cancer, but there is still a need to improve the efficacy of treatment of stage III disease. We investigated the tolerability and safety of S-1 and oxaliplatin as adjuvant chemotherapy for stage III gastric cancer. METHODS: Japanese patients with stage III gastric cancer who had undergone D2 or more extensive lymphadenectomy were enrolled. In the first cycle, S-1 (40-60 mg/m2 twice daily) alone was given orally for 2 weeks of a 3-week cycle. From the second cycle, S-1 was administered as in the first cycle and oxaliplatin (100 mg/m2) was infused intravenously on day 1. Treatment was continued for 8 cycles. The primary end point was the treatment completion rate for eight cycles. RESULTS: Sixty-three patients were enrolled and 62 patients were included in analysis. The treatment completion rate was 74.2 %, which was higher than the expected completion rate of 72.0 %. The median relative dose intensities were 77.1 % for S-1 and 72.6 % for oxaliplatin, with 41.9 and 61.7 % patients requiring dose reduction of S-1 and oxaliplatin, respectively. Neutropenia was the only grade 3 or higher adverse event with an incidence 10 % or greater (32.3 %). There was no grade 3 or higher peripheral sensory neuropathy or treatment-related death. CONCLUSIONS: S-1 and oxaliplatin therapy is suggested to be manageable and safe with optimal dose reduction and delay in selected patients for stage III gastric cancer after D2 gastrectomy, and warrants further evaluation in larger studies. PMID- 26626801 TI - Genetic alterations in endometrial cancer by targeted next-generation sequencing. AB - Many genetic factors play important roles in the development of endometrial cancer. The aim of this study was to investigate genetic alterations in the Taiwanese population with endometrial cancer. DNA was extracted from 10 cases of fresh-frozen endometrial cancer tissue. The exomes of cancer-related genes were captured using the NimbleGen Comprehensive Cancer Panel (578 cancer-related genes) and sequenced using the Illumina Genomic Sequencing Platform. Our results revealed 120 variants in 99 genes, 21 of which were included in the Oncomine Cancer Research Panel used in the National Cancer Institute Match Trial. The 21 genes comprised 8 tumor suppressor candidates (ATM, MSH2, PIK3R1, PTCH1, PTEN, TET2, TP53, and TSC1) and 13 oncogene candidates (ALK, BCL9, CTNNB1, ERBB2, FGFR2, FLT3, HNF1A, KIT, MTOR, PDGFRA, PPP2R1A, PTPN11, and SF3B1). We identified a high frequency of mutations in PTEN (50%) and genes involved in the endometrial cancer-related molecular pathway, which involves the IL-7 signaling pathway (PIK3R1, n=1; AKT2, n=1; FOXO1, n=1). We report the mutational landscape of endometrial cancer in the Taiwanese population. We believe that this study will shed new light on fundamental aspects for understanding the molecular pathogenesis of endometrial cancer and may aid in the development of new targeted therapies. PMID- 26626802 TI - Droplet digital polymerase chain reaction detection of HER2 amplification in formalin fixed paraffin embedded breast and gastric carcinoma samples. AB - RATIONALE: Human epidermal growth factor receptor 2 (HER2) is a key driver of tumorigenesis, and over-expression as a result of HER2 gene amplification has been observed in a number of solid tumors. Recently HER2 has become an important biomarker for the monoclonal antibody treatment of HER2-positive metastatic breast and advanced gastric cancer. The HER2 targeting antibody trastuzumab treatment requires accurate measurement of HER2 levels for proper diagnosis. Droplet digital PCR (ddPCR) with highly direct, precise and absolute nucleic acid quantification could be used to detect HER2 amplification levels. OBJECTIVES: Our objective was to evaluate a robust, accurate and less subjective application of ddPCR for HER2 amplification levels and test the assay performance in clinical formalin-fixed paraffin-embedded (FFPE) breast and gastric carcinoma samples. METHODS: Genomic DNA from HER2 amplified cell line SK-BR-3 was used to set up the ddPCR assays. The copy number of HER2 was compared to the chromosome 17 centromere reference gene (CEP17), expressed as HER2:CEP17 ratio. Genomic DNAs of FFPE specimens from 145 Asian patients with breast and gastric carcinomas were assayed using both standard methods, immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH), and ddPCR. RESULTS: Based on 145 clinical breast and gastric carcinoma cases, our study demonstrated a high concordance of ddPCR results to FISH and IHC. In breast cancer specimens, the ddPCR results had high concordance with FISH and IHC defined HER2 status with a sensitivity of 90.9% (30/33) and a specificity of 100% (77/77). In gastric cancer specimens that were concordant in both FISH and IHC, our assay was 95.5% concordant with FISH and IHC (21/22). CONCLUSIONS: ddPCR has the advantage of automation and also allows levels of HER2 amplification to be easily evaluated in large numbers of samples, and presents a potential option to define HER2 status. PMID- 26626803 TI - Encoding of sound envelope transients in the auditory cortex of juvenile rats and adult rats. AB - Accurate neural processing of time-varying sound amplitude and spectral information is vital for species-specific communication. During postnatal development, cortical processing of sound frequency undergoes progressive refinement; however, it is not clear whether cortical processing of sound envelope transients also undergoes age-related changes. We determined the dependence of neural response strength and first-spike latency on sound rise-fall time across sound levels in the primary auditory cortex (A1) of juvenile (P20 P30) rats and adult (8-10 weeks) rats. A1 neurons were categorized as "all-pass", "short-pass", or "mixed" ("all-pass" at high sound levels to "short-pass" at lower sound levels) based on the normalized response strength vs. rise-fall time functions across sound levels. The proportions of A1 neurons within each of the three categories in juvenile rats were similar to that in adult rats. In general, with increasing rise-fall time, the average response strength decreased and the average first-spike latency increased in A1 neurons of both groups. At a given sound level and rise-fall time, the average normalized neural response strength did not differ significantly between the two age groups. However, the A1 neurons in juvenile rats showed greater absolute response strength, longer first-spike latency compared to those in adult rats. In addition, at a constant sound level, the average first-spike latency of juvenile A1 neurons was more sensitive to changes in rise-fall time. Our results demonstrate the dependence of the responses of rat A1 neurons on sound rise-fall time, and suggest that the response latency exhibit some age-related changes in cortical representation of sound envelope rise time. PMID- 26626804 TI - [Dual localisation of ischaemic fasciitis with local relapse at one site]. AB - INTRODUCTION: Ischaemic fasciitis (IF) is a rare pseudosarcomatous proliferation initially described on the pressure points of long-term bedridden patients. Healing is the rule after surgical excision. No multifocal localisations have been reported to date. Herein, we describe the case of a patient with FI affecting two sites and having recurred at one of them. OBSERVATION: A 50-year old woman with scoliosis and mental retardation consulted for a hard skin lesion next to her right scapula. Elastofibroma was diagnosed on the basis of a surgical biopsy sample. Early local recurrence led to a second resection four months later. Histologically, central fibrinoid necrosis was observed, surrounded by collagenous tissue containing occasionally atypical fibroblasts and numerous capillaries. The diagnosis of ischaemic fasciitis was made by a national expert. Six months later, we observed a 13-cm purplish erythematous infiltrated mass with a 6-cm ulceration at the surgical site. A second 6-cm non-ulcerated indurated purplish lesion was visible next to the right greater trochanter. The scan showed deep soft-tissue infiltration with subfascial extension and contact with the greater trochanter. Superficial biopsies of both lesions showed only an appearance of granulation tissue. MRI performed after five months showed an extension of lesions at the two sites with an appearance evocative of ischaemic fasciitis. Surgical excision was refused by the patient and her family. DISCUSSION: We report a rare case of ischaemic fasciitis at two separate sites with local relapse after surgical excision. PMID- 26626805 TI - The reproductive potential of patients with Mayer-Rokitansky-Kuster-Hauser syndrome using gestational surrogacy: a systematic review. AB - Women with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome may reproduce after uterine transplantation or IVF using a gestational surrogate. As uterine transplantation is still an experimental procedure, data on their clinical outcome using assisted reproduction techniques are imperative to allow evidence based counselling. For this purpose, a systematic non-restricted electronic literature search was conducted. The 14 studies included in this review were published between 1988 and 2011. From a cohort of 140 patients with MRKH syndrome, mostly from the the USA and Israel, only four studies contained data on more than 10 patients; the others were case reports or small series. In the studies reviewed, 125 patients underwent 369 cycles of IVF with gestational surrogacy, and delivered 71 newborns. The reporting of outcome of patients with MRKH syndrome undergoing assisted reproduction techniques in the available literature is less than optimal and is characterized by bias of publication, inconsistent reports, including few patients, treated over a long time span, and lacking systematic reports from large IVF centres. None of the national registries contain specific outcome data on patients with MRKH syndrome. The paucity of data limits the possibility to draw firm conclusions but substantiates the need for a systematic multicentre reporting system. PMID- 26626806 TI - A novel tool for continuous fracture aftercare - Clinical feasibility and first results of a new telemetric gait analysis insole. AB - Weight bearing after lower extremity fractures still remains a highly controversial issue. Even in ankle fractures, the most common lower extremity injury no standard aftercare protocol has been established. Average non weight bearing times range from 0 to 7 weeks, with standardised, radiological healing controls at fixed time intervals. Recent literature calls for patient-adapted aftercare protocols based on individual fracture and load scenarios. We show the clinical feasibility and first results of a new, insole embedded gait analysis tool for continuous monitoring of gait, load and activity. Ten patients were monitored with a new, independent gait analysis insole for up to 3 months postoperatively. Strict 20 kg partial weight bearing was ordered for 6 weeks. Overall activity, load spectrum, ground reaction forces, clinical scoring and general health data were recorded and correlated. Statistical analysis with power analysis, t-test and Spearman correlation was performed. Only one patient completely adhered to the set weight bearing limit. Average time in minutes over the limit was 374 min. Based on the parameters load, activity, gait time over 20 kg weight bearing and maximum ground reaction force high and low performers were defined after 3 weeks. Significant difference in time to painless full weight bearing between high and low performers was shown. Correlation analysis revealed a significant correlation between weight bearing and clinical scoring as well as pain (American Orthopaedic Foot and Ankle Society (AOFAS) Score rs=0.74; Olerud Molander Score rs=0.93; VAS pain rs=-0.95). Early, continuous gait analysis is able to define aftercare performers with significant differences in time to full painless weight bearing where clinical or radiographic controls could not. Patient compliance to standardised weight bearing limits and protocols is low. Highly individual rehabilitation patterns were seen in all patients. Aftercare protocols should be adjusted to real-time patient conditions, rather than fixed intervals and limits. With a real-time measuring device high performers could be identified and influenced towards optimal healing conditions early, while low performers are recognised and missing healing influences could be corrected according to patient condition. PMID- 26626807 TI - Temporal trends in falls cases seen by EMS in Melbourne: The effect of residence on time of day and day of week patterns. AB - BACKGROUND: Injury due to falls is a major public health problem, especially for older people. We aimed to determine the accuracy of the ambulance call taker triage algorithm relative to paramedic assessment, and characterise variation in ambulance service demand for falls cases involving older adults over time and by residence type. METHOD: We obtained all ambulance case records for January 2008 to December 2011 for adults aged 65 or over in Melbourne, Australia. Data elements comprised age, gender, date and time of emergency call, dispatch category, location of incident and the patient's clinical condition as ascertained by paramedics. We compared cases coded as falls by the call taker triage algorithm with those identified by paramedics. We also examined temporal variation (hour of day and day of week) in ambulance service demand for cases involving older adults, and compared community-dwelling cases and those from Residential Aged Care Facilities (RACFs). We used negative binomial regression to compare counts and trigonometric regression to compare temporal variation patterns. RESULTS: Over the four-year study period 77,891 falls cases involved older adults (6.5% of overall ambulance demand). Eighty-seven per cent of paramedic-assessed falls cases were correctly identified by the triage system. The RACF population was older (median age 87 years, IQR 82-91 vs. 82 years, IQR 76-87), had higher hospital transport rates (89.5% vs. 75.8%) and a higher incidence of falls at any age than the community-dwelling population. The temporal pattern for fall cases for all residence types peaked between 6:00 and 12:00, but fall cases from RACFs showed an additional peak in the evening between 17:00 and 20:00. CONCLUSION: Falls by older people are the second-biggest contributor to ambulance demand in Melbourne, consuming significant operational resources. Using call taker triage data instead of paramedic case records to calculate falls cases may underestimate the true incidence of falls by up to 13%. Temporal patterns can inform ambulance service policy and practice, falls referral and prevention programmes to optimise service delivery which will lessen the number of future falls cases. PMID- 26626809 TI - [Rapidly evolving tinea corporis]. PMID- 26626808 TI - Fall injuries in Baghdad from 2003 to 2014: Results of a randomised household cluster survey. AB - INTRODUCTION: Falls incur nearly 35 million disability-adjusted life-years annually; 75% of which occur in low- and middle-income countries. The epidemiology of civilian injuries during conflict is relatively unknown, yet important for planning prevention initiatives, health policy and humanitarian assistance. This study aimed to determine the death and disability and household consequences of fall injuries in post-invasion Baghdad. METHODS: A two-stage, cluster randomised, community-based household survey was performed in May of 2014 to determine the civilian burden of injury from 2003 to 2014 in Baghdad. In addition to questions about household member death, households were interviewed regarding injury specifics, healthcare required, disability, relatedness to conflict and resultant financial hardship. RESULTS: Nine hundred households totaling 5148 individuals were interviewed. There were 138 fall injuries (25% of all injuries reported); fall was the most common mechanism of civilian injury in Baghdad. The rate of serious fall injuries increased from 78 to 466 per 100,000 persons in 2003 and 2013, respectively. Fall was the most common mechanism among the injured elderly (i.e. >=65 years; 15/24 elderly unintentional injuries; 63%). However, 46 fall injuries were children aged <15 years (49% of unintentional injuries) and 77 were respondents aged 15-64 years (36%). Respondents who spent significant time within the home (i.e. unemployed, retired, homemaker) had three times greater odds of having suffered a fall injury than student referents (aOR 3.34; 95%CI 1.30-8.60). Almost 80% of fall injured were left with life-limiting disability. Affected households often borrowed substantial sums of money (34 households; 30% of affected households) and/or suffered food insecurity after a family member's fall (52; 46%). CONCLUSION: Falls were the most common cause of civilian injury in Baghdad. In part due to the effect of prolonged insecurity on a fragile health system, many injuries resulted in life-limiting disabilities. In turn, households shouldered much of the burden after fall injury due to loss of income and/or medical expenditure, often resulting in food insecurity. Given ongoing conflict, civilian injury control initiatives, trauma care strengthening efforts and support for households of the injured is urgently needed. PMID- 26626810 TI - Determinants of recycling common types of plastic product waste in environmental horticulture industry: The case of Georgia. AB - Environmental horticulture firms provide a variety of commercial/residential landscape products and services encompassing ornamental plant production, design, installation, and maintenance. The companies generate tons of waste including plastic containers, trays, and greenhouse/field covers, creating the need to reduce and utilize plastic waste. Based on survey data collected in Georgia in 2013, this paper investigates determinants of the environmental horticulture firms' recycling decision (plastic containers, flats, and greenhouse poly). Our findings indicate that the decision to discard vs. recycle plastic containers, flats, and greenhouse poly is significantly influenced by firm scope, size, location, and partnership with recycling providers, as well as whether recycling providers offer additional waste pickup services. Insights from this study are of use to local governments and environmental organizations interested in increasing horticultural firm participation in recycling programs and lowering the volume of plastic destined for landfills. PMID- 26626811 TI - Valorization of solid wastes from chestnut industry processing: Extraction and optimization of polyphenols, tannins and ellagitannins and its potential for adhesives, cosmetic and pharmaceutical industry. AB - The aim of the current study was to evaluate the potential of chestnut peels to produce pomaces enhanced with tannins to be used in the formulations of wood adhesives, leather tanning or as natural antioxidants in food, cosmetic and pharmaceutical industry. An analytical procedure was planned as 2 factorial design to analyze the influence of solvent (water, Na2SO3 and NaOH at different concentrations of 1, 2, 4, and 8% in water) and extraction time (30, 60, and 120, 240, 480 and 960min) on extraction yield, pH, Stiasny index, and tannins. HPLC diode array detector equipped with an ionization mass spectrophotometer was used to assess the polyphenol composition. Our results showed that both extraction properties and phytochemicals were significantly affected (P<0.001) by all independent factors. The main tannins identified were the hydrolyzable gallic acid, vescalagin castalagin and ellagic acid, and the condensed epigallocatechin, catechin and epicatechin. The solvent 1% Na2SO3 was more effective to extract the condensed tannins whilst hydrolyzable tannins were extracted efficiently by 1% NaOH. The multivariable analysis and the Pearson's correlation coefficients showed a direct association between Stiasny number and the average levels of condensed tannins. PMID- 26626812 TI - WEEE management in Europe and China - A comparison. AB - Over the last years Europe and China have developed specific regulations to address the challenge of managing Waste Electrical and Electronic Equipment (WEEE). Households in today's urban China are similarly equipped with electrical and electronic appliances as households in European metropolitan areas, which in turn will lead to similar per capita generation rates in WEEE. While the challenge is a similar one, the systems, technologies and legislation in place in Europe and China are partly different, partly aligned to each other. In Europe WEEE collection is based on existing municipal structures. Additionally, retail and other take-back channels are in place. In China the informal sector dominates WEEE collection, being more competitive and flexible and offering pecuniary reimbursement to consumers. In Europe manual dismantling as a first treatment step has been gradually replaced by mechanical break up of appliances, followed by sorting out of hazardous and valuable components. In the subsequent second treatment level, cathode ray tubes are separated, whereby compound materials like motors and coils are mechanically treated, printed circuit boards go to special smelters, and plastics are separated and partly recycled. In China large formal dismantling capacities have been set up in recent years. There dismantling practices follow similar principles as in European plants; however, further processing is only partly implemented in Chinese recycling facilities. Specifically metallurgical treatment of printed circuit boards is still not existent in China. Companies selling electrical and electronic products within the EU are obliged to organise collection and treatment. This has led to a larger number of producer responsibility organisations. Financed and controlled by producers and importers, these systems aim to fulfil legal requirements at optimised costs subject to compliance with environmental standards and monitoring requirements. The Chinese system is built on a state controlled fund which subsidies formal recyclers. For these recyclers this financial support is essential to compete with informal recyclers, who operate at lower costs and do not necessarily comply with environmental standards. PMID- 26626813 TI - Endoscopic Management of Spontaneous Clival Cerebrospinal Fluid Leaks: Case Series and Literature Review. AB - OBJECTIVE: Spontaneous cerebrospinal fluid leaks are most commonly located along the anterior skull base. Sphenoidal localization is less common, and clival localization is even rarer. We analyzed a group of patients with spontaneous leaks and selected patients with clival localization. This article discusses surgical management of these entities and provides a brief literature review regarding spontaneous clival leaks. METHODS: Of a cohort of 67 patients who presented to our departments with a spontaneous leak during the period 2005-2014, a retrospective data analysis was performed on 6 patients with clival localization of the defect. A skull base repair with a multilayered reconstruction was performed in 3 patients, and a single-layered reconstruction using a pedicled nasoseptal flap was performed in 3 patients. RESULTS: The patients included 6 women with a mean age of 60 years (range, 36-91 years). The mean length of the follow-up period was 69.5 months (range, 22-114 months). The overall success rate of the primary endoscopic repair was 83.3% (5 of 6 patients); this increased to 100% after revision surgery. CONCLUSIONS: This series, although numerically limited, suggests that a minimally invasive endoscopic repair of idiopathic clival leaks may be accomplished with an acceptable rate of morbidity and excellent outcomes. Moreover, the pedicled nasoseptal flap has been confirmed to be the "workhorse" for the reconstruction of clival defects. PMID- 26626814 TI - Dear Colleagues. PMID- 26626815 TI - The effects of objectively-measured, free-living daily ambulatory movement on mortality in a national sample of adults with diabetes. AB - Previous research demonstrates that self-reported physical activity is protective against premature mortality among the general population, as well as those with diabetes. This confirmatory research study examines the relationship between physical activity and all-cause mortality risk among a national sample of diabetics while employing an objective measure of physical activity (ActiGraph 7164). Data from the 2003-2006 NHANES were employed, with follow-up through 2011.Among the 712 diabetics, 134 died during the median follow-up period of 79months. For every 60min increase in daily ambulatory movement, adults with diabetes had a 29% reduced risk of premature all-cause mortality (HRadjusted=0.71; 95% CI: 0.60-0.85). These confirmatory findings underscore the importance of physical activity promotion among adults with diabetes. PMID- 26626816 TI - Dysregulation of Neuregulin-1/ErbB signaling in the prefrontal cortex and hippocampus of rats exposed to chronic unpredictable mild stress. AB - Exposure to chronic stress increases the likelihood of developing depression, but the underlying mechanisms remain equivocal. While recent evidence has indicated that Neuregulin-1 (NRG1) and its ErbB receptors play an essential role in neural development and function, and NRG1 has emerged as a novel modulator involved in the response of brain to stress, there is limited evidence concerning the effects of chronic stress exposure on NRG1/ErbB signaling. To fill this critical gap, we examined the protein expression of NRG1 and ErbB receptors in the brain of rats following chronic unpredictable mild stress (CUMS) exposure. After 6weeks of CUMS procedures, the rats were induced to a depression-like state. The stressed rats displayed elevated expression of NRG1 and phosphorylated ErbB4 (pErbB4) in the prefrontal cortex, whereas ErbB2 and pErbB2 were inhibited. In the hippocampus, CUMS also attenuated activation of the both ErbB receptors and suppressed the downstream Akt and ERK phosphorylation. Meanwhile, administration of sertraline enhanced NRG1/ErbB signaling and partly normalized the stress-induced behavioral changes and the disturbances of NRG1/ErbB system in CUMS rats. Combined, our data firstly showed the aberrant changes of NRG1/ErbB system in the brain of the animal model of depression, providing new evidence for the involvement of NRG1/ErbB pathway in the development and treatment of depression. PMID- 26626817 TI - Development and calibration of a dietary nitrate and nitrite database in the NIH AARP Diet and Health Study. AB - OBJECTIVE: Nitrate and nitrite are probable human carcinogens when ingested under conditions that increase the formation of N-nitroso compounds. There have been limited efforts to develop US databases of dietary nitrate and nitrite for standard FFQ. Here we describe the development of a dietary nitrate and nitrite database and its calibration. DESIGN: We analysed data from a calibration study of 1942 members of the NIH-AARP (NIH-AARP, National Institutes of Health-AARP) Diet and Health Study who reported all foods and beverages consumed on the preceding day in two non-consecutive 24 h dietary recalls (24HR) and completed an FFQ. Based on a literature review, we developed a database of nitrate and nitrite contents for foods reported on these 24HR and for food category line items on the FFQ. We calculated daily nitrate and nitrite intakes for both instruments, and used a measurement error model to compute correlation coefficients and attenuation factors for the FFQ-based intake estimates using 24HR-based values as reference data. RESULTS: FFQ-based median nitrate intake was 68.9 and 74.1 mg/d, and nitrite intake was 1.3 and 1.0 mg/d, in men and women, respectively. These values were similar to 24HR-based intake estimates. Energy-adjusted correlation coefficients between FFQ- and 24HR-based values for men and women respectively were 0.59 and 0.57 for nitrate and 0.59 and 0.58 for nitrite; energy-adjusted attenuation factors were 0.59 and 0.57 for nitrate and 0.47 and 0.38 for nitrite. CONCLUSIONS: The performance of the FFQ in assessing dietary nitrate and nitrite intakes is comparable to that for many other macro- and micronutrients. PMID- 26626818 TI - Catalytic self-assembly of a DNA dendritic complex for efficient gene silencing. AB - A catalytic self-assembled DNA dendritic complex was herein reported and used for siRNA-based gene silencing. This kind of one-pot DNA dendrimer can be conveniently prepared as needed, and it was demonstrated to have better silencing efficiency and lower cytotoxicity than commercial cationic lipid transfection agents. PMID- 26626819 TI - [Use of emergency departments for elderly patients with multiple morbidity in Spain]. PMID- 26626820 TI - [An 83 year old woman with dyspnoea and oedema of the lower limbs]. PMID- 26626821 TI - Thermoresponsive Agarose Based Microparticles for Antibody Separation. AB - We report the development of thermoresponsive 4-mercaptoethylpyridine (MEP)-based chromatographic microsphere based resins for antibody separation that show switchable release abilities by adsorbing immunoglobulins at 40 degrees C and releasing the proteins at 5 degrees C. The thermoswitchable release properties were introduced to the porous resins by the grafting of linear poly(N isopropylacrylamide) (PNIPAM) chains synthesized via reversible addition fragmentation chain transfer (RAFT) polymerization, which were modified to possess MEP end functionalities. Adsorption of gamma-globulins as a model antibody on the shortest PNIPAM-MEP (3 kDa) grafted microparticles display binding capacities of up to 20 g L(-1) at 40 degrees C and a significant decrease in binding capacity to less than 2.5 g L(-1) at 5 degrees C. By switching the temperature to 5 degrees C, the release of bound gamma-globulins is shown to be as high as 90%. The effects of polymer chain length on the binding capacity are studied in detail and found to be critical as they influence the density of MEP functionalities on the particle surfaces. PMID- 26626822 TI - How parents process child health and nutrition information: A grounded theory model. AB - The aim of the present study was to investigate low-income parents' experiences receiving, making meaning of, and applying sociocultural messages about childhood health and nutrition. Semi-structured interviews were conducted with parents from 16 low-income Early Head Start families. Verbatim interview transcripts, observations, field notes, documentary evidence, and follow-up participant checks were used during grounded theory analysis of the data. Data yielded a potential theoretical model of parental movement toward action involving (a) the culture and context influencing parents, (b) parents' sources of social and cultural messages, (c) parental values and engagement, (d) parental motivation for action, (e) intervening conditions impacting motivation and application, and (f) parent action taken on the individual and social levels. Parent characteristics greatly impacted the ways in which parents understood and applied health and nutrition information. Among other implications, it is recommended that educators and providers focus on a parent's beliefs, values, and cultural preferences regarding food and health behaviors as well as his/her personal/family definition of "health" when framing recommendations and developing interventions. PMID- 26626823 TI - Sustained satiety induced by food foams is independent of energy content, in healthy adults. AB - Our previous research demonstrated high, sustained satiety effects of stabilized food foams relative to their non-aerated compositions. Here we test if the energy and macronutrients in a stabilized food foam are critical for its previously demonstrated satiating effects. In a randomized, crossover design, 72 healthy subjects consumed 400 mL of each of four foams, one per week over four weeks, 150 min after a standardized breakfast. Appetite ratings were collected for 180 min post-foam. The reference was a normal energy food foam (NEF1, 280 kJ/400 mL) similar to that used in our previous research. This was compared to a very low energy food foam (VLEF, 36 kJ/400 mL) and 2 alternative normal energy foams (NEF2 and NEF3) testing possible effects of compositional differences other than energy (i.e. emulsifier and carbohydrate source). Appetite ratings were quantified as area under the curve (AUC) and time to return to baseline (TTRTB). Equivalence to NEF1 was predefined as the 90% confidence interval of between-treatment differences in AUC being within -5 to +5 mm/min. All treatments similarly affected appetite ratings, with mean AUC for fullness ranging between 49.1 and 52.4 mm/min. VLEF met the statistical criterion for equivalence to NEF1 for all appetite AUC ratings, but NEF2 and NEF3 did not. For all foams the TTRTB for satiety and fullness were consistently between 150 and 180 min, though values were shortest for NEF2 and especially NEF3 foams for most appetite scales. In conclusion, the high, sustained satiating effects of these food foams are independent of energy and macronutrient content at the volumes tested. PMID- 26626825 TI - A twist-bend nematic to an intercalated, anticlinic, biaxial phase transition in liquid crystal bimesogens. AB - In this article we describe for bimesogens the first observed transition from a "heliconical" twist-bend nematic liquid crystal to a novel biaxial, anticlinic, intercalated lamellar phase. The phase behaviour and structures of both polymorphs is similar to that of polymers, confirming that bimesogens can act as model systems for main chain liquid crystal polymers, and in principle are separate soft-matter branches of self-organising systems. PMID- 26626824 TI - Dietary energy density was associated with diet quality in Brazilian adults and older adults. AB - Cross-sectional and longitudinal studies present association of low dietary energy density with higher intake of vitamins, minerals and dietary fiber, lower intake of fat, and better balance of macronutrients. The objective of this study was to verify the relationship between dietary energy density and diet quality measured by an index of diet quality. This study used data from 496 adults and 445 older adults of cross-sectional population-based survey from Sao Paulo conducted in 2008-2009, Brazil. Dietary intake data was assessed by two 24-h dietary recalls. Dietary energy density values were calculated based on foods only method. Dietary energy density and revised Brazilian Health Eating Index and its components, were estimated by usual intake using Multiple Source Method. The relationship between dietary energy density and the total revised Brazilian Health Eating Index and its components were assessed by Gaussian family log-link model for each age group. The analyses showed an inverse association between dietary energy density and total revised Brazilian Health Eating Index in adults (T2:beta = 0.96, p < 0.001; T2:beta = 0.86, p < 0.001) and older adults (T2:beta = 0.96, p < 0.001; T2:beta = 0.90, p < 0.001), and an inverse association between dietary energy density and nine of twelve revised Brazilian Health Eating Index components in adult and/or older adults groups. Dietary energy density was associated with diet quality in Brazilian adults and older adults regardless of sex, per capita household income, body mass index, physical activity level, current smoking habits status, alcohol beverage drinking status and usual energy intake (kilocalories) from beverages. PMID- 26626826 TI - Biocompatible fluorinated polyglycerols for droplet microfluidics as an alternative to PEG-based copolymer surfactants. AB - In droplet-based microfluidics, non-ionic, high-molecular weight surfactants are required to stabilize droplet interfaces. One of the most common structures that imparts stability as well as biocompatibility to water-in-oil droplets is a triblock copolymer surfactant composed of perfluoropolyether (PFPE) and polyethylene glycol (PEG) blocks. However, the fast growing applications of microdroplets in biology would benefit from a larger choice of specialized surfactants. PEG as a hydrophilic moiety, however, is a very limited tool in surfactant modification as one can only vary the molecular weight and chain-end functionalization. In contrast, linear polyglycerol offers further side-chain functionalization to create custom-tailored, biocompatible droplet interfaces. Herein, we describe the synthesis and characterization of polyglycerol-based triblock surfactants with tailored side-chain composition, and exemplify their application in cell encapsulation and in vitro gene expression studies in droplet based microfluidics. PMID- 26626827 TI - Identification case of evidence in timber tracing of Pinus radiate, using high resolution melting (HRM) analysis. AB - Fast, accurate detection of plant species and their hybrids using molecular tools will facilitate assessment and monitoring of timber tracing evidence. In this study the origin of unknown pine samples is determined for a case of timber theft in the region of Araucania southern Chile. We evaluate the utility of the trnL marker region for species identification applied to pine wood based on High Resolution Melting. This efficient tracing methods can be incorporated into forestry applications such as certification of origin. The object of this work was genotype identification using high-resolution melting (HRM) and trnL approaches for Pinus radiata (Don) in timber tracing evidence. Our results indicate that trnL is a very sensitive marker for delimiting species and HRM analysis was used successfully for genotyping Pinus samples for timber tracing purposes. Genotyping samples by HRM analysis with the trnL1 approach allowed us to differentiate two wood samples from the Pinaceae family: Pinus radiata (Don) and Pseudotsuga menziesii (Mirb.) Franco. The same approach with Pinus trnL wood was not able to discriminate between samples of Pinus radiata, indicating that the samples were genetically indistinguishable, possibly because they have the same genotype at this locus. Timber tracing with HRM analysis is expected to contribute to future forest certification schemes, control of illegal trading, and molecular traceability of Pinus spp. PMID- 26626828 TI - Controlling Shear Stress in 3D Bioprinting is a Key Factor to Balance Printing Resolution and Stem Cell Integrity. AB - A microvalve-based bioprinting system for the manufacturing of high-resolution, multimaterial 3D-structures is reported. Applying a straightforward fluid dynamics model, the shear stress at the nozzle site can precisely be controlled. Using this system, a broad study on how cell viability and proliferation potential are affected by different levels of shear stress is conducted. Complex, multimaterial 3D structures are printed with high resolution. This work pioneers the investigation of shear stress-induced cell damage in 3D bioprinting and might help to comprehend and improve the outcome of cell-printing studies in the future. PMID- 26626829 TI - Recent advances in 2D-LC for bioanalysis. AB - This article summarizes the most important developments in the use of 2D-LC for bioanalysis in the last 5 years. While several interesting and powerful applications have been developed recently, this work has been supported by continued, significant development of theoretical concepts, instrument development and practical aspects of method development. Some of the most exciting applications have been focused on the use of 2D-LC and characterize proteins both as biotherapeutic drug substances, and in formulations. These materials are inherently complex, difficult to resolve chromatographically and present problems that are essentially unknown (e.g., aggregation) in the small molecule world, thus 2D-LC can be leveraged very effectively to address these challenges. PMID- 26626830 TI - Computational Improvements to Quantum Wave Packet ab Initio Molecular Dynamics Using a Potential-Adapted, Time-Dependent Deterministic Sampling Technique. AB - In a recent publication, we introduced a computational approach to treat the simultaneous dynamics of electrons and nuclei. The method is based on a synergy between quantum wave packet dynamics and ab initio molecular dynamics. Atom centered density-matrix propagation or Born-Oppenheimer dynamics can be used to perform ab initio dynamics. In this paper, wave packet dynamics is conducted using a three-dimensional direct product implementation of the distributed approximating functional free-propagator. A fundamental computational difficulty in this approach is that the interaction potential between the two components of the methodology needs to be calculated frequently. Here, we overcome this problem through the use of a time-dependent deterministic sampling measure that predicts, at every step of the dynamics, regions of the potential which are important. The algorithm, when combined with an on-the-fly interpolation scheme, allows us to determine the quantum dynamical interaction potential and gradients at every dynamics step in an extremely efficient manner. Numerical demonstrations of our sampling algorithm are provided through several examples arranged in a cascading level of complexity. Starting from a simple one-dimensional quantum dynamical treatment of the shared proton in [Cl-H-Cl](-) and [CH3-H-Cl](-) along with simultaneous dynamical treatment of the electrons and classical nuclei, through a complete three-dimensional treatment of the shared proton in [Cl-H-Cl](-) as well as treatment of a hydrogen atom undergoing donor-acceptor transitions in the biological enzyme, soybean lipoxygenase-1 (SLO-1), we benchmark the algorithm thoroughly. Apart from computing various error estimates, we also compare vibrational density of states, inclusive of full quantum effects from the shared proton, using a novel unified velocity-velocity, flux-flux autocorrelation function. In all cases, the potential-adapted, time-dependent sampling procedure is seen to improve the computational scheme tremendously (by orders of magnitude) with minimal loss of accuracy. PMID- 26626831 TI - Comparative Static and Dynamic Study of a Prototype SN2 Reaction. AB - Ab initio molecular-dynamic simulations, using density functional theory (DFT) and the recent atom-centered density-matrix propagation method (ADMP), were used to study the bond formation process in a prototypical SN2 reaction, namely the Walden inversion. Using the real space partition schemes of both electronic density and electron localization function gradient fields, we analyzed different quantum chemical topology (QCT) properties along the ADMP trajectory. In particular, atomic charges derived from the Bader's atoms-in-molecules (AIM) theory were used to analyze intra- and intermolecular charge transfers between atoms, while the electronic population of the forming bonding basin obtained from the electron localization function (ELF) gradient field was employed to describe the bond formation process. These results were compared to the corresponding QCT properties issuing from a static approach based on the intrinsic reaction path (IRP). Although similar features are found for both static and dynamic approaches, the dynamic QCT analysis provides some explanation of the differences observed during the formation of the ion-molecule complex. In particular, it suggests a stronger electron exchange leading to an effective maximization of both covalent and noncovalent interactions. PMID- 26626832 TI - What NMR Relaxation Can Tell Us about the Internal Motion of an RNA Hairpin: A Molecular Dynamics Simulation Study. AB - Classical molecular dynamics simulations of a 14-mer UUCG RNA hairpin are performed to study its conformational dynamics and corresponding NMR relaxation parameters. The direct calculation of the relaxation rates from the trajectory yields good agreement with experiment, indicating the validity of the theoretical model. Various ways to provide a link between theory and experiment are considered, including the "model-free approach" of Lipari and Szabo and Gaussian axial fluctuation model of Bruschweilwer. It is studied if the underlying assumptions of these approaches are satisfied in the case of a flexible RNA hairpin. Being consistent with the analysis of the NMR experiments, Lipari-Szabo fits of the first 100 or 1000 ps of the internal correlation functions lead to a nice agreement between calculated and experimental order parameters and internal correlation times. Finally, the relation between NMR order parameters and the underlying internal motion of the RNA hairpin is discussed in detail. A principal component analysis reveals that the principal motions of the molecule account only partially for the measured NMR order parameters, because the latter are insensitive to internal dynamics occurring on a nanosecond time scale due to molecular tumbling. PMID- 26626833 TI - Multiconfiguration Molecular Mechanics Based on Combined Quantum Mechanical and Molecular Mechanical Calculations. AB - The multiconfiguration molecular mechanics (MCMM) method is a general algorithm for generating potential energy surfaces for chemical reactions by fitting high level electronic structure data with the help of molecular mechanical (MM) potentials. It was previously developed as an extension of standard MM to reactive systems by inclusion of multidimensional resonance interactions between MM configurations corresponding to specific valence bonding patterns, with the resonance matrix element obtained from quantum mechanical (QM) electronic structure calculations. In particular, the resonance matrix element is obtained by multidimensional interpolation employing a finite number of geometries at which electronic-structure calculations of the energy, gradient, and Hessian are carried out. In this paper, we present a strategy for combining MCMM with hybrid quantum mechanical molecular mechanical (QM/MM) methods. In the new scheme, electronic-structure information for obtaining the resonance integral is obtained by means of hybrid QM/MM calculations instead of fully QM calculations. As such, the new strategy can be applied to the studies of very large reactive systems. The new MCMM scheme is tested for two hydrogen-transfer reactions. Very encouraging convergence is obtained for rate constants including tunneling, suggesting that the new MCMM method, called QM/MM-MCMM, is a very general, stable, and efficient procedure for generating potential energy surfaces for large reactive systems. The results are found to converge well with respect to the number of Hessians. The results are also compared to calculations in which the resonance integral data are obtained by pure QM, and this illustrates the sensitivity of reaction rate calculations to the treatment of the QM-MM border. For the smaller of the two systems, comparison is also made to direct dynamics calculations in which the potential energies are computed quantum mechanically on the fly. PMID- 26626834 TI - Calculation of Standard Binding Free Energies: Aromatic Molecules in the T4 Lysozyme L99A Mutant. AB - Calculations of the binding free energy of various nonpolar aromatic ligands with the L99A mutant of T4 lysozyme using molecular dynamics (MD) simulation are presented. To ensure better convergence, biasing potentials are used to restrain the ligand orientation and center-of-mass movement relative to the binding site when the ligand is decoupled from its environment in the binding pocket. The bias introduced by the restraint potentials is removed once the ligand fully interacts with the rest of the system and the calculated binding free energy is independent of the applied restraints. To decrease the computational cost, the simulations are generated with a reduced system in which protein and water atoms within a 15 A-radius sphere around the ligand are included explicitly, while the rest of the system is treated with the generalized solvent boundary potential (GSBP). For all the ligands, the precision of the calculated free energy is less than 0.5 kcal/mol. For small nonpolar ligands such as benzene, toluene, and ethylbenzene, the calculated binding free energies are within 1.1 kcal/mol of the experimental values. For larger ligands, the computed binding free energies are slightly more favorable than the experimental values. The nonbinding polar molecule, phenol, has a calculated binding free energy of -0.88 kcal/mol. The simulation protocol presented here provides a way to calculate the binding free energy of small molecules to receptors at moderate computational cost. PMID- 26626836 TI - Geometries of Transition-Metal Complexes from Density-Functional Theory. AB - Several levels of density functional theory, i.e., various combinations of exchange-correlation functionals and basis sets, have been employed to compute equilibrium geometries for a diverse set of 32 metal complexes from the first transition row, for which precise gas-phase geometries are known from electron diffraction or microwave spectroscopy. Most DFT levels beyond the local density approximation can reproduce the 50 metal-ligand bond distances selected in this set with reasonable accuracy, as assessed by mean and standard deviations of optimized vs observed values. The ranking of some popular functionals, ordered according to decreasing standard deviation, is BLYP ~ HCTH > B3LYP > BP86 > TPSS ~ TPSSh. Together with its hybrid variant, the recently introduced meta-GGA functional TPSS performs best of all tested functionals, with mean and standard deviations of -0.5 and 1.4 pm, respectively. Even smaller errors are found for a more compact but less diverse set of transition-metal mono- and dihalides, for which experimentally derived equilibrium geometries are available. PMID- 26626835 TI - Time-Dependent Properties of Liquid Water: A Comparison of Car-Parrinello and Born-Oppenheimer Molecular Dynamics Simulations. AB - A series of 30 ps first principles molecular dynamics simulations in the microcanonical ensemble were carried out to investigate transport and vibrational properties of liquid water. To allow for sufficient sampling, the thermodynamic constraints were set to an elevated temperature of around 423 K and a density of 0.71 g cm(-)(3) corresponding to the saturated liquid density for the Becke-Lee Yang-Parr (BLYP) representation of water. Four simulations using the Car Parrinello molecular dynamics (CPMD) technique with varying values of the fictitious electronic mass (MU) and two simulations using the Born-Oppenheimer molecular dynamics (BOMD) technique are analyzed to yield structural and dynamical information. At the selected state point, the simulations are found to exhibit nonglassy dynamics and yield consistent results for the liquid structure and the self-diffusion coefficient, although the statistical uncertainties in the latter quantity are quite large. Consequently, it can be said that the CPMD and BOMD methods produce equivalent results for these properties on the time scales reported here. However, it was found that the choice of MU affects the frequency spectrum of the intramolecular modes, shifting them slightly to regions of lower frequency. Using a value of MU = 400 au results in a significant drift in the electronic kinetic energy of the system over the course of 30 ps and a downward drift in the ionic temperature. Therefore, for long trajectories at elevated temperatures, lower values of this parameter are recommended for CPMD simulations of water. PMID- 26626837 TI - Electron Transmission through Aromatic Molecules. AB - A prominent feature of aromatic compounds is the ring current that can be observed indirectly in nuclear magnetic resonance experiments. This current is generated by an external magnetic field. In molecular electronics, molecules serve as conductors, and they are connected to metallic contacts that act as electron sources and electron sinks. We show that ring currents can also be found in molecular electronic devices containing cyclic pi-electron systems. The circular currents are related to interference phenomena that can render the molecule impenetrable to electrons. While only small currents pass through the molecule, large internal circular currents are stimulated. We conjecture that the internal currents should result in experimentally observable magnetic moments. PMID- 26626838 TI - Reaction of H2 with a Binuclear Zirconium Dinitrogen Complex - Evaluation of Theoretical Models and Hybrid Approaches. AB - Molecular orbital and hybrid ONIOM (both IMOMO and IMOMM) calculations have been carried out on the important reaction of H2 with a binuclear zirconium dinitrogen complex to test the efficacy of several structural models of the ancillary ligand. The complete experimental ligand, PhP(CH2SiMe2NSiMe2CH2)2PPh, in the zirconium complex has been treated at the IMOMM level, while two smaller approximations of the ligand, HP(CH2SiH2NSiH2CH2)2PH and (PH3)2(NH2)2, have received the full molecular orbital treatment. The mechanism of dihydrogen addition has been compared with our earlier study (Basch, Musaev, and Morokuma J. Am. Chem. Soc. 1999, 121, 5754-5761). We find that the substituent effects do cause some small changes in both the structures of the complexes studied and the activation energies of the transition structures. However for the most part the potential energy profiles are very similar to our earlier study and lend support to our use of simple theoretical models to represent moderately large experimental structures. PMID- 26626839 TI - Performance Evaluation of the Three-Layer ONIOM Method: Case Study for a Zwitterionic Peptide. AB - The performance of the three-layer ONIOM method was systematically investigated by comparing the optimized geometries and calculated deprotonation energy of a zwitterionic peptide molecule, NH3(+)-CH(n)Bu-CO-NH-CH2-CO-NH-CH(n)Bu-COO(-), using all possible combinations of B3LYP/6-31G* as the high-level quantum (HQ), AM1 as the low-level quantum (LQ), and Amber as the MM method. Results show that the three-layer ONIOM(HQ:LQ:MM) method, which includes a medium-level quantum method in the middle system to take into account the electronic effects of the middle layer and to keep the problematic QM-MM boundary away from the action region, is more reliable and more stable than the QM:MM:MM or generic QM/MM method and is the best compromise between accuracy and computational cost. PMID- 26626840 TI - First Excited State Properties and Static Hyperpolarizability of Ruthenium(II) Ammine Complexes. AB - First principles calculations were used to study the electronic excitation energies (E), transition dipole moments (MU), and difference of dipole moments between ground and excited states (DeltaMU) for low-lying singlets of the series of ruthenium(II) ammine complexes. Both cases of the gas phase and the acetonitrile solution were investigated in order to explain the discrepancy between the recent experimental and theoretical results and to develop the optimal way of estimation for the first static hyperpolarizability in the framework of a two-state model introduced by Oudar and Chemla. The present calculations reveal that the effect of solvent on the electronic properties of investigated compounds is not only the change of the excitation energy but also the increasing of ground-state molecular polarization and intensification of metal-to-ligand intramolecular charge transfer for electronic excitations. These effects lead to increasing of the values of DeltaMU and ground-state dipole moment MUg in solution as compared with the gas-phase ones. The proposed theoretical approach gives good agreement with experiment and allows one to apply it for designing a new perspective nonlinear optical active organometallics. PMID- 26626841 TI - Study of the Topological Properties of Some Pseudohalides. AB - The pseudohalide principle has been used extensively in nonmetal chemistry to predict the structure and stability of many molecular species. The 1,2,3,4 thiatriazole-5-thiolate anion, CS2N3(-), is of particular interest. In a short communication we have recently reported the topological study of some CS2N3( )containing species reported by Crawford et al. Previous reports on these compounds showed that in covalent derivatives not only does the ring remain intact but also the site of attachment of the R group is most likely at the exocyclic sulfur atom in contrast to the previously suggested N-R connectivity. Therefore, the structure and bonding of derivatives of the CS2N3(-) moiety is clearly an important question. With that in our mind, we undertook a topological analysis, based on the AIM theory, to gain more insight into the bonding in covalent derivatives of the CS2N3(-) moiety, trying to find an explanation to the origin of the N-H and S-H connectivities. The question is which is the reason that makes all the covalent derivatives prefer the S-R connectivity while the hydracid has an N-H one. PMID- 26626842 TI - Density-Functional Theory Investigation of the Geometric, Energetic, and Optical Properties of the Cobalt(II)tris(2,2'-bipyridine) Complex in the High-Spin and the Jahn-Teller Active Low-Spin States. AB - State-of-the-art generalized gradient approximation (GGA) (PBE, OPBE, RPBE, OLYP, and HCTH), meta-GGA (VSXC and TPSS), and hybrid (B3LYP, B3LYP*, O3LYP, and PBE0) functionals are compared for the determination of the structure and the energetics of the D3 [Co(bpy)3](2+) complex in the (4)A2 and (4)E trigonal components of the high-spin (4)T1g([Formula: see text] [Formula: see text] ) state and in the low-spin (2)E state of octahedral (2)Eg([Formula: see text] [Formula: see text] ) parentage. Their comparison extends also to the investigation of the Jahn-Teller instability of the (2)E state through the characterization of the extrema of C2 symmetry of this spin state's potential energy surface. The results obtained for [Co(bpy)3](2+) in either spin manifold are very consistent among the functionals used and are in good agreement with available experimental data. The functionals, however, perform very differently with respect to the spin-state energetics because the calculated values of the high-spin/low-spin energy difference Delta[Formula: see text] vary between -3212 and 3919 cm(-)(1). Semilocal functionals tend to give too large Delta[Formula: see text] values and thus fail to correctly predict the high-spin state as the ground state of the isolated complex, while hybrid functionals tend to overestimate the stability of the high-spin state with respect to the low-spin state. Reliable results are, however, obtained with the OLYP, HCTH, B3LYP*, and O3LYP functionals which perform best for the description of the isolated complex. The optical properties of [Co(bpy)3](2+) in the two spin states are also analyzed on the basis of electronic excitation calculations performed within time dependent density functional response theory. The calculated absorption and circular dichroism spectra agree well with experimental results. PMID- 26626843 TI - The Basis Set Convergence of Spin-Spin Coupling Constants Calculated by Density Functional Methods. AB - The previously proposed polarization-consistent basis sets, optimized for density functional calculations, are evaluated for calculating indirect nuclear spin-spin coupling constants. The basis set limiting values can be obtained by performing a series of calculations with increasingly larger basis sets, but the convergence can be significantly improved by adding functions with large exponents. An accurate calculation of the Fermi-contact contribution requires the addition of tight s functions, while the paramagnetic spin-orbit contribution is sensitive to the presence of tight p functions. The spin-dipolar contribution requires the addition of p, d, and f functions. The optimal exponents for the tight functions can be obtained by optimizing the absolute sum of all contributions to the spin spin coupling constant. On the basis of a series of test cases, we propose a standard set of tight s, p, d, and f functions to be added to the polarization consistent basis sets. The resulting pcJ-n basis sets should be suitable for calculating spin-spin coupling constants with density functional methods. PMID- 26626844 TI - An Efficient Linear-Scaling Electrostatic Coupling for Treating Periodic Boundary Conditions in QM/MM Simulations. AB - A new linear-scaling method based on a multigrid approach to treat long-range electrostatic interactions in hybrid quantum mechanics/molecular mechanics (QM/MM) simulations is described. The scheme has been implemented in the context of a QM calculation based on density functional theory (DFT). The method is tested on an analytical model to validate the new algorithm. Two realistic problems in alpha-quartz crystals and a zwitterionic dipeptide (GLY-ALA) in water have been chosen as further tests. Results from QM/MM calculations with periodic boundary conditions (PBC) show that the use of PBC is essential when studying highly ordered crystal structures, unless a carefully designed MM crystal is used for the calculation. With a general shaped MM subsystem, the absence of PBC leads to an incorrect description of Kohn-Sham band gaps and charge density. The present method allows periodic boundary conditions to be used in molecular simulations of biological and material science systems. PMID- 26626845 TI - Active Role of Hydrogen Bonds in Rupe and Meyer-Schuster Rearrangements. AB - Rupe and Meyer-Schuster rearrangements for the R2C(OH) [Formula: see text] C?C [Formula: see text] H + H3O(+) and (H2O)9 model (R = methyl and phenyl groups) have been investigated by the use of density functional theory calculations. In the substrate R2C(OH) [Formula: see text] C?CH catalyzed by H3O(+)(H2O), three reaction channels, the two rearrangements and SN (nucleophilic substitution), were predicted by the frontier molecular orbital theory. The SN (the OH-group exchange) path was found to have a large activation energy. For 2-methylbut-3-yn 2-ol (R = Me), the Rupe rearrangement has been found to be much more favorable than the Meyer-Schuster rearrangement. For 1,1-diphenylprop-2-yn-1-ol (R = Ph), the occurrence of Meyer-Schuster rearrangement is very likely with the small activation energy. Both rearrangements do not involve the carbonium ion intermediates. However, the calculated geometries of the first transition state are carbonium-ion-like. Dehydration and hydration may occur via the intermolecular proton relay along the hydrogen-bond chains. Minimal models were proposed to represent reaction mechanisms of both rearrangements. PMID- 26626846 TI - Oxygen Reduction on Pd0.75Co0.25 (111) and Pt0.75Co0.25 (111) Surfaces: An ab Initio Comparative Study. AB - Density functional theory studies of adsorption of oxygen electroreduction intermediates and free energy profiles are used to discuss possible reaction mechanisms: one leading directly to H2O production and another having H2O2 as an intermediate, on (111) surfaces of pure Pt, pure Pd, and bimetallic systems Pd0.75Co0.25 and Pt0.75Co0.25. It is found that the calculated affinities toward the different ORR intermediates in the studied surfaces follow the Hammer-Norskov d-band model predictions. The calculated free energy profiles and the magnitude of the barriers in both mechanisms seem to favor the hypothesis that both the direct and series O2 reduction mechanisms might be operating in parallel. The highest thermodynamic barriers at (1)/4 of a monolayer atomic oxygen coverage and without solvent are located in the first hydrogenation reaction for both mechanisms. PMID- 26626847 TI - Computational Study of Aqueous Reactions in Tocopherol Regeneration. AB - The alpha-tocopheroxyl radical, resulting from the scavenging of the peroxyl radical by alpha-tocopherol (vitamin E) in the cell membrane, will further react with the peroxyl radical to form tocopherones. A computational study is presented of the aqueous proton-transfer reactions of the alpha-8a-(hydro-dioxy)tocopherone and alpha-8a-(methyl-dioxy)tocopherone to produce 1-benzopyrylium, the subsequent hydrolysis to 2H-1-benzopyran-6(8aH)-one, and the terminating rearrangement of 8a hydroxytocopherone to 2,5-cyclohexadiene-1,4-dione. The alkyl tail of true tocopherol is replaced by methyl in these studies. Calculations of the structures and energies along the reaction pathways were first performed at the BP86/TZVP/DGA1 level with a COSMO solvent model, and additional solvent corrections from COSMO-RS theory were subsequently added. The proposed mechanism is found to be thermodynamically and kinetically feasible in water. The ion mediated steps are found to have free-energies of activation under 3 kcal mol( )(1), with kinetics likely to be diffusion-limited. The unimolecular rearrangement is the slow step, with a predicted reaction rate constant of 0.056 min(-)(1) at 298 K, in excellent agreement with the experimental value of 0.046 min(-)(1). Kinetic and thermodynamic properties of the ion-mediated steps are shown to rely strongly on the use of an accurate continuum solvation model. Distinct entropy and enthalpy contributions are determined from the temperature dependence of the predicted free energies. PMID- 26626848 TI - Ligand Field Effects on the Aqueous Ru(III)/Ru(II) Redox Couple from an All-Atom Density Functional Theory Perspective. AB - The [RuCl6](4)(-)(aq) -> [RuCl6](3)(-)(aq) + e(-) and [Ru(CN)6](4)(-)(aq) -> [Ru(CN)6](3)(-)(aq) + e(-) half redox reactions are investigated using density functional based ab initio molecular dynamics methods. The aim is to understand at a microscopic level how the difference in pi-bonding of these ligands is reflected in the redox chemistry. To this end, we have computed the redox and reorganization free energies using a method derived from the Marcus theory of electron transfer. The resulting estimate of the free energy change of the full redox reaction between the two coordination complexes is compared to experiment. Our findings indicate that ligand character has an important effect on the vertical ionization chemistry but less on the relaxation of the system after removal or addition of electrons. This enables us to correlate the redox free energies with the HOMO energy levels of the combined solute + solvent system and analyze the redox chemistry in terms of the corresponding energy level diagram. PMID- 26626849 TI - Intrinsic Viscosity of Proteins and Platonic Solids by Boundary Element Methods. AB - The boundary element (BE) method is used to implement a very precise computation of the intrinsic viscosity for rigid molecules of arbitrary shape. The formulation, included in our program BEST, is tested against the analytical Simha formula for ellipsoids of revolution, and the results are essentially numerically exact. Previously unavailable, very precise results for a series of Platonic solids are also presented. The formulation includes the optional determination of the center of viscosity; however, for globular proteins, the difference compared to the computation based on the centroid is insignificant. The main application is to a series of 30 proteins ranging in molecular weight from 12 to 465 kD. The computation starts from the crystal structure as obtained from the Protein Data Bank, and a hydration thickness of 1.1 A obtained in previous work with BEST was used. The results (extrapolated to an infinite number of triangular boundary elements) for the proteins are separated into two groups: monomeric and multimeric proteins. The agreement with experimental measurements of the intrinsic viscosity in the case of monomeric proteins is excellent and within experimental error of 5%, demonstrating that the solution and crystal structure are hydrodynamically equivalent. However, for some multimeric proteins, we observe strong systematic deviations around -20%, which we interpret as a systematic deviation of the solution structure from the crystal structure. A possible description of the structural change is deduced by using simple ellipsoid model parameters. A method to obtain intrinsic viscosity values for proteins to 1-2% accuracy (better than experimental error) on the basis of a single BE computation (avoiding the need for an extrapolation on the number of surface triangles) is also presented. PMID- 26626850 TI - Automatic Control of Solvent Density in Grand Canonical Ensemble Monte Carlo Simulations. AB - We present automated methods for determining the value of Adams' B parameter corresponding to a target solvent density in grand canonical ensemble Monte Carlo simulations. The method found to work best employs a proportional-integral control equation commonly used in industrial process control applications. We show here that simulations employing this method rapidly converge to the desired target density. We further show that this method is robust over a wide range of system sizes. This advance reduces the overall CPU time and user effort in determining the equilibrium excess chemical potential in these systems. PMID- 26626851 TI - Calculation of the Relative Binding Affinity of Enzyme Inhibitors Using the Generalized Linear Response Method. AB - The generalized linear response (GLR) method initially developed for hydration free energy calculations has been adapted for binding free energy calculations. The calculations employ the concept of thermodynamic cycle. To obtain the value of the relative binding free energy between two ligands, we run molecular dynamics simulations at only four "midpoint" states along the thermodynamic pathways connecting the two ligands in the unbound and bound states, respectively. This approach significantly simplifies and accelerates the calculations as compared to the traditional free energy simulations where significantly more intermediate states are usually sampled. We show that each of these "midpoint" states can be approximately defined by a modified force field function in which both the van der Waals and electrostatic interactions between the variant part of a ligand and its environment, either binding site or aqueous solution, are scaled by a factor of 0.5. We tested this new approach to relative binding affinity calculations on the HIV-1 protease complex with its inhibitor JG365 as a starting point for the following two structural transformations: (a) the critical chiral center on the central residue was changed from (S) to (R) configuration, and (b) the C terminal valine residue was deleted. In both cases, the GLR method afforded calculated values that were in good agreement with the experimental data. PMID- 26626852 TI - Influence of Stacking on the Hydrogen Bond Donating Potential of Nucleic Bases. AB - Hydrogen bonding is the dominant interaction in the pairing of nucleic bases and largely determines the stability of the double-helical structure of DNA. In a previous study, we used the molecular electrostatic potential (MEP) near a hydrogen-bond (HB) acceptor to demonstrate that the intrastrand pi-pi stacking interaction influences the interstrand HB accepting capacity of DNA/RNA bases. In the present work, we first examined at the MP2/6-31G(d) level whether the MEP near a HB donating site of an aromatic or nucleic base can be used as a computationally inexpensive measure for its HB donating potential, quantified as the interaction energy with an HB acceptor probe, and whether this also holds in the presence of a stacking partner. A good correlation was found for substituted anilines in a vacuum, and this seemed to hold for cytosine, stacked with substituted benzenes. However, when stacked pairs of nucleic bases were studied, no correlation between the MEP and the HB strength was found. This turned out to be caused by the direct interaction of the HB donor's stacking partner with the probe molecule as well as its influence on the MEP. After this perturbation was eliminated, a significant correlation was found. The influence of stacking on the HB donating potential was shown to be dominated by the stacking geometry and not by the nature of the stacking partner. The present findings suggest that the pi pi interaction on itself does not have an overall strengthening on H bonding in DNA. PMID- 26626853 TI - Molecular Dynamics Simulations of the Orientation of Ni(II)*Gly-Gly-His and Ni(II)*Arg-Gly-His Metallopeptide-DNA Association. AB - Ni(II)*Xaa-Gly-His metallopeptides (where Xaa is any alpha-amino acid) bind selectively to the minor groove of A/T-rich DNA regions as a function of their amino acid composition and chirality. Molecular dynamics simulations were performed to clarify the most likely binding orientations of Ni(II)*Gly-Gly-His and Ni(II)*L-Arg-Gly-His upon association with the B-form oligonucleotide d(CGCGAATTCGCG)2. Upon examination of four possible docking orientations (I-IV), these studies indicated that both metallopeptides favor association with DNA via I, involving insertion of the edge of the metallopeptide containing the amino terminal N-H and the imidazole pyrrole N-H group of His into the minor groove. These metallopeptide moieties play important roles in this DNA recognition mode by functioning as H-bond donors to minor groove acceptors such as the N3 of adenine or the O2 of thymine located on the floor of the minor groove. The positively charged side chain of L-Arg was found to enhance DNA recognition relative to that exhibited by Ni(II)*Gly-Gly-His through an increased electrostatic interaction, its favorable stereochemistry, and by providing a third point of contact with the minor groove floor. The simulation of orientation I was found to reproduce the experimentally supported DNA-metallopeptide orientation, revealing factors that are important for the further development of DNA-binding ligands. PMID- 26626854 TI - Effects of Zero-Point and Thermal Vibrational Averaging on Computed NMR Properties of a Model Compound for Purine Nucleosides. AB - A method for the incorporation of thermal averaging into the calculation of nuclear magnetic resonance properties is given. These properties are computed using density functional theory, anharmonic first-order perturbation corrections to a normal-mode analysis, and standard statistical mechanical averaging. The method is applied to the calculation of chemical shieldings and spin-spin coupling constants (J couplings) of 1'-imidazolyl-2'-deoxy-beta-ribofuranose (IDR), a model compound for purine nucleosides, at the B3LYP/6-311++G(2d,p) level of theory. Thermal averaging causes substantial changes in the values of computed parameters. The calculated harmonic normal modes of IDR are also investigated; we find reasonable agreement with published results from vibrational spectroscopy on DNA fragments. Finally, the calculated magnetic and structural data regarding the reported hydrogen bond between H8 on the imidazole ring and O5' on the sugar ring are investigated; we find that such data do not strongly support the formation of a hydrogen bond between these two atoms. PMID- 26626855 TI - Heterogeneity in phage induction enables the survival of the lysogenic population. AB - Lysogeny by temperate phages provides novel functions for bacteria and shelter for phages. However, under conditions that activate the phage lytic cycle, the benefit of lysogeny becomes a paradox that poses a threat for bacterial population survival. Using Escherichia coli lysogens for Shiga toxin (Stx) phages as model, we demonstrate how lysogenic bacterial populations circumvent extinction after phage induction. A fraction of cells maintains lysogeny, allowing population survival, whereas the other fraction of cells lyse, increasing Stx production and spreading Stx phages. The uninduced cells were still lysogenic for the Stx phage and equally able to induce phages as the original cells, suggesting heterogeneity of the E. coli lysogenic population. The bacterial population can modulate phage induction under stress conditions by the stress regulator RpoS. Cells overexpressing RpoS reduce Stx phage induction and compete with and survive better than cells with baseline RpoS levels. Our observations suggest that population heterogeneity in phage induction could be widespread among other bacterial genera and we propose this is a mechanism positively selected to prevent the extinction of the lysogenic population that can be modulated by environmental conditions. PMID- 26626857 TI - Intrauterine contraception. AB - Intrauterine devices (IUDs) are effective, reversible forms of contraception with high patient satisfaction and continuation. IUDs can be safely used by most women and should be considered the first-line method of contraception for all women. This descriptive review will discuss the clinical issues associated with IUDs - including management of side effects, noncontraceptive uses and insertion and removal. When the burdens of cost are removed, women are more likely to select and IUDs. Health policy changes that increase insurance coverage for contraception will improve access to IUDs. IUDs remain an underutilized form of contraception in USA and efforts to improve availability and access to long acting reversible contraception methods is needed to optimize their use. PMID- 26626859 TI - Incorporating Hardy-Weinberg Equilibrium Law to Enhance the Association Strength for Ordinal Trait Genetic Study. AB - The conventional method to examine whether genetic variants are associated with the ordinal traits is the proportional odds model. Such analyses are often conducted by assuming an additive genetic mode of inheritance. However, how the genetic variants influence the risk of occurrence of a disease is impossible to know in practice. Using an improper model might result in a low-power test, thus it reduces the probability of detecting the deleterious genetic markers. To address these concerns, we propose a two-phase procedure (TPP) for ordinal trait genetic studies. In the first phase, we used a linear combination to weight the Hardy-Weinberg equilibrium tests in case groups and formed an omnibus test to classify the genetic models. Then based on the chosen model, the corresponding score test was used to identify the associations. To control the false positive rate, we derived the joint distribution of the test used for selecting the genetic model and that used for identifying the associations. We also obtained the closed forms of two other robust tests, MAX3 and CHI2. Extensive computer simulations were carried out and the results showed that the true selection rates of genetic models are satisfactory and the proposed TPP is more robust than MAX3 and CHI2. Finally, we demonstrated the advantage of our proposed method by applying it to analyse the antibody reactivity to cyclic citrullinated peptides data. PMID- 26626856 TI - Improved motor and cognitive performance with sodium nitrite supplementation is related to small metabolite signatures: a pilot trial in middle-aged and older adults. AB - Advancing age is associated with reductions in nitric oxide bioavailability and changes in metabolic activity, which are implicated in declines in motor and cognitive function. In preclinical models, sodium nitrite supplementation (SN) increases plasma nitrite and improves motor function, whereas other nitric oxide boosting agents improve cognitive function. This pilot study was designed to translate these findings to middle-aged and older (MA/O) humans to provide proof of-concept support for larger trials. SN (10 weeks, 80 to 160 mg/day capsules, TheraVasc, Inc.) acutely and chronically increased plasma nitrite and improved performance on measures of motor and cognitive outcomes (all p<0.05 or better) in healthy MA/O adults (62 +/- 7 years). Untargeted metabolomics analysis revealed that SN significantly altered 33 (160 mg/day) to 45 (80 mg/day) different metabolites, 13 of which were related to changes in functional outcomes; baseline concentrations of 99 different metabolites predicted functional improvements with SN. This pilot study provides the first evidence that SN improves aspects of motor and cognitive function in healthy MA/O adults, and that these improvements are associated with, and predicted by, the plasma metabolome. Our findings provide the necessary support for larger clinical trials on this promising pharmacological strategy for preserving physiological function with aging. PMID- 26626861 TI - Clinical Efficacy, Safety, and Feasibility of Using Video Glasses during Interventional Radiologic Procedures: A Randomized Trial. AB - PURPOSE: To evaluate the clinical efficacy, safety, and feasibility of implementing video glasses in a variety of interventional radiologic (IR) procedures. MATERIALS AND METHODS: Between August 2012 and August 2013, 83 patients undergoing outpatient IR procedures were randomized to a control group (n = 44) or an experimental group outfitted with video glasses (n = 39). State Trait Anxiety Inventory (STAI) scores, sedation and analgesia doses, mean arterial pressure (MAP), heart rate (HR), respiratory rate (RR), pain scores, and procedure times were obtained. Complications and adverse events related to the use of video glasses were recorded. Postprocedural staff surveys and patient satisfaction surveys were completed. RESULTS: Women had greater preprocedural anxiety than men (P = .0056), and patients undergoing vascular interventions had greater preprocedural anxiety than those undergoing nonvascular interventions (P = .0396). When assessed after the procedure, patients who wore video glasses had significantly reduced levels of anxiety (-7.7 vs -4.4, respectively; P = .0335) and average MAP (-6.3 vs 2.1, respectively; P = .0486) compared with control patients. There was no significant difference in amount of sedation and analgesia, HR, RR, pain score, or procedure time between groups. No significant adverse events related to the use of video glasses were observed. Postprocedural surveys showed that video glasses were not distracting and did not interfere or pose a safety issue during procedures. Patients enjoyed using the video glasses and would use them again for a future procedure. CONCLUSIONS: Video glasses can be safely implemented during IR procedures to reduce anxiety and improve a patient's overall experience. PMID- 26626860 TI - Image-Guided Biopsy in the Era of Personalized Cancer Care: Proceedings from the Society of Interventional Radiology Research Consensus Panel. PMID- 26626862 TI - Antidepressive-like effects and antioxidant activity of green tea and GABA green tea in a mouse model of post-stroke depression. AB - SCOPE: Growing evidence suggests that oxidative stress plays a role in the development of chronic diseases such as cardiovascular disease and some psychiatric disorders. Tea consumption exerts beneficial effects against damage induced by cerebral ischemia-reperfusion in ischemic stroke and depressive symptoms in depression. The aim of this study was to evaluate, in vivo, the protective activity of green tea (GT) and GABA green tea (GGT) against post stroke depression (PSD), a common consequence of stroke. METHODS AND RESULTS: The antidepressive-like effects of GT and GGT were determined by behavioral tests in a mouse model of post-stroke depression. The antioxidant activity was evaluated by GSH, SOD, and TBARS measurements on mouse brain. The chemical composition of tea extracts was characterized through chromatographic methods. GGT and GT resulted active in the modulation of depressive symptoms and the reduction of oxidative stress, restoring normal behavior, and at least in part, antioxidant endogenous defenses. The higher polyphenol, theanine, glutamine, and caffeine content may justify the higher activity found in GGT. CONCLUSIONS: This work represents the first attempt to demonstrate the positive effect of tea, and especially GGT, on post-stroke depression and to correlate this effect with the antioxidant activity and phytochemical composition of tea. PMID- 26626863 TI - Hindlimb musculature of the largest living rodent Hydrochoerus hydrochaeris (Caviomorpha): Adaptations to semiaquatic and terrestrial styles of life. AB - The caviomorph species Hydrochoerus hydrochaeris (Cavioidea), or capybara, is the largest living rodent. This species is widely distributed, from northern South America to Uruguay and eastern Argentina, inhabiting in a wide variety of densely vegetated lowlands habitats in the proximity of water. Hydrochoerus hydrochaeris not only runs with agility, like other members of the Cavioidea, but it can also swim and dive easily. For these reasons, it has been classified as a cursorial as well as semiaquatic species. However, comprehensive anatomical descriptions of the osteology and myology of the capybara are not available in the literature and analyses on its swimming abilities are still required. We hypothesize that some of the characters of the hindlimb of H. hydrochaeris could reveal a unique morphological arrangement associated with swimming abilities. In this study, an anatomical description of the hindlimb musculature of H. hydrochaeris, and a discussion of the possible functional significance of the main muscles is provided. In addition, we explore the evolution of some myological and osteological characters of the capybara in the context of the cavioids. We concluded that most of the muscular and osteological features of the hindlimb of H. hydrochaeris are neither adaptations to a specialized cursoriality, nor major modifications for an aquatic mode of life. Hydrochoerus hydrochaeris share several features with other cavioids, being a generalized cursorial species in the context of this clade. However, it shows some adaptations of the hindlimb for enhancing propulsion through water, of which the most notable seems to be the shortening of the leg, short tendons of most muscles of the leg, and a well developed soleus muscle. These adaptations to a semiaquatic mode of life could have been acquired during the most recent evolutionary history of the hydrochoerids. PMID- 26626864 TI - Neurometabolic characteristics in the anterior cingulate gyrus of Alzheimer's disease patients with depression: a (1)H magnetic resonance spectroscopy study. AB - BACKGROUND: Depression is a common comorbid psychiatric symptom in patients with Alzheimer's disease (AD), and the prevalence of depression is higher among people with AD compared with healthy older adults. Comorbid depression in AD may increase the risk of cognitive decline, impair patients' function, and reduce their quality of life. However, the mechanisms of depression in AD remain unclear. Here, our aim was to identify neurometabolic characteristics in the brain that are associated with depression in patients with mild AD. METHODS: Thirty-seven patients were evaluated using the Neuropsychiatric Inventory (NPI) and Hamilton Depression Rating Scale (HAMD-17), and divided into two groups: 17 AD patients with depression (D-AD) and 20 non-depressed AD patients (nD-AD). Using proton magnetic resonance spectroscopy, we characterized neurometabolites in the anterior cingulate gyrus (ACG) of D-AD and nD-AD patients. RESULTS: Compared with nD-AD patients, D-AD patients showed lower N acetylaspartate/creatine (NAA/Cr) and higher myo-inositol/creatine (mI/Cr) in the left ACG. NPI score correlated with NAA/Cr and mI/Cr in the left ACG, while HAMD correlated with NAA/Cr. CONCLUSIONS: Our findings show neurometabolic alterations in D-AD patients. Thus, D-AD pathogenesis may be attributed to abnormal activity of neurons and glial cells in the left ACG. PMID- 26626870 TI - 2015 SNMMI Highlights Lecture: Oncology, Part II. PMID- 26626866 TI - Iodide Recognition and Sensing in Water by a Halogen-Bonding Ruthenium(II)-Based Rotaxane. AB - The synthesis and anion-recognition properties of the first halogen-bonding rotaxane host to sense anions in water is described. The rotaxane features a halogen-bonding axle component, which is stoppered with water-solubilizing permethylated beta-cyclodextrin motifs, and a luminescent tris(bipyridine)ruthenium(II)-based macrocycle component. (1) H NMR anion-binding titrations in D2 O reveal the halogen-bonding rotaxane to bind iodide with high affinity and with selectively over the smaller halide anions and sulfate. The binding affinity trend was explained through molecular dynamics simulations and free-energy calculations. Photo-physical investigations demonstrate the ability of the interlocked halogen-bonding host to sense iodide in water, through enhancement of the macrocycle component's Ru(II) metal-ligand charge transfer (MLCT) emission. PMID- 26626865 TI - Dosimetric impact of different CT datasets for stereotactic treatment planning using 3D conformal radiotherapy or volumetric modulated arc therapy. AB - BACKGROUND: The purpose of this study was to assess the impact on dose to the planning target volume (PTV) and organs at risk (OAR) by using four differently generated CT datasets for dose calculation in stereotactic body radiotherapy (SBRT) of lung and liver tumors. Additionally, dose differences between 3D conformal radiotherapy and volumetric modulated arc therapy (VMAT) plans calculated on these CT datasets were determined. METHODS: Twenty SBRT patients, ten lung cases and ten liver cases, were retrospectively selected for this study. Treatment plans were optimized on average intensity projection (AIP) CTs using 3D conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT). Afterwards, the plans were copied to the planning CTs (PCT), maximum intensity projection (MIP) and mid-ventilation (MidV) CT datasets and dose was recalculated keeping all beam parameters and monitor units unchanged. Ipsilateral lung and liver volumes and dosimetric parameters for PTV (Dmean, D2, D98, D95), ipsilateral lung and liver (Dmean, V30, V20, V10) were determined and statistically analysed using Wilcoxon test. RESULTS: Significant but small mean differences were found for PTV dose between the CTs (lung SBRT: <=2.5 %; liver SBRT: <=1.6 %). MIPs achieved the smallest lung and the largest liver volumes. OAR mean doses in MIP plans were distinctly smaller than in the other CT datasets. Furthermore, overlapping of tumors with the diaphragm results in underestimated ipsilateral lung dose in MIP plans. Best agreement was found between AIP and MidV (lung SBRT). Overall, differences in liver SBRT were smaller than in lung SBRT and VMAT plans achieved slightly smaller differences than 3D CRT plans. CONCLUSIONS: Only small differences were found for PTV parameters between the four CT datasets. Larger differences occurred for the doses to organs at risk (ipsilateral lung, liver) especially for MIP plans. No relevant differences were observed between 3D-CRT or VMAT plans. MIP CTs are not appropriate for OAR dose assessment. PCT, AIP and MidV resulted in similar doses. If a 4DCT is acquired PCT can be omitted using AIP or MidV for treatment planning. PMID- 26626871 TI - Management of haemodynamically stable patients with penetrating abdominal stab injuries: review of practice at an Australian major trauma centre. AB - INTRODUCTION: The management of haemodynamically stable patients who present following a penetrating abdominal injury (PAI) remains variable between mandatory surgical exploration and more selective non-operative approaches. The primary aim of this study was to assess compliance with an algorithm guiding selective non operative management of haemodynamically stable patients with PAI. The secondary aim was to examine the association between compliance and unnecessary laparotomies. METHODS: This was a retrospective cohort study involving all patients with PAI that presented to a major trauma centre from January 2007 to December 2011. Data were extracted from the trauma registry and patients' electronic medical records. RESULTS: There were 189 patients included in the study, of which 79 (41.8 %) patients complied with the algorithm. The laparotomy rate in the setting of algorithm compliance was significantly lower than algorithm non-compliance (12.7 vs. 68.2 %; p < 0.01) as were unnecessary laparotomy rates (0 vs. 33.3 %; p = 0.03). CONCLUSION: Among haemodynamically stable patients presenting with PAI, compliance with an algorithm guiding selective non-operative management was low, but associated with lower laparotomy and lower unnecessary laparotomy rates. Improved compliance with algorithms directed towards selective non-operative management of PAI should be encouraged with stringent vigilance towards patient safety. PMID- 26626872 TI - Analysis of 41 suicide attempts by wrist cutting: a retrospective analysis. AB - PURPOSE: Self-cutting injuries have a low mortality rate, but this type of injuries has special clinical significance because they have the potential of leading to devastating disability and repeated suicide attempts. The purpose of this study is to analyze the nature and outcomes of wrist-cutting injuries. MATERIAL AND METHOD: A retrospective study was designed in order to investigate 41 suicide attempts by wrist cutting attended to Uludag University Faculty of Medicine Emergency Department between June 2008 and December 2014. The patients were analyzed for age, gender, alcohol intake, psychological state, prior suicide attempts, and clinical features such as injury side, injury pattern, and used tool. RESULTS: It was seen that the severity of wrist-cutting injury variates between gender and age. CONCLUSION: Alcohol or drug consumption and having a diagnosed psychiatric disorder create a higher risk for extensive wrist lacerations. It was seen that skin only lacerations were most likely to repeat the act and therefore are most in need of psychiatric intervention. LEVEL OF EVIDENCE: Level III, retrospective study. PMID- 26626873 TI - Poverty identification for a pro-poor health insurance scheme in Tanzania: reliability and multi-level stakeholder perceptions. AB - BACKGROUND: Many low income countries have policies to exempt the poor from user charges in public facilities. Reliably identifying the poor is a challenge when implementing such policies. In Tanzania, a scorecard system was established in 2011, within a programme providing free national health insurance fund (NHIF) cards, to identify poor pregnant women and their families, based on eight components. Using a series of reliability tests on a 2012 dataset of 2,621 households in two districts, this study compares household poverty levels using the scorecard, a wealth index, and monthly consumption expenditures. METHODS: We compared the distributions of the three wealth measures, and the consistency of household poverty classification using cross-tabulations and the Kappa statistic. We measured errors of inclusion and exclusion of the scorecard relative to the other methods. We also gathered perceptions of the scorecard criteria through qualitative interviews with stakeholders at multiple levels of the health system. FINDINGS: The distribution of the scorecard was less skewed than other wealth measures and not truncated, but demonstrated clumping. There was a higher level of agreement between the scorecard and the wealth index than consumption expenditure. The scorecard identified a similar number of poor households as the "basic needs" poverty line based on monthly consumption expenditure, with only 45 % errors of inclusion. However, it failed to pick up half of those living below the "basic needs" poverty line as being poor. Stakeholders supported the inclusion of water sources, income, food security and disability measures but had reservations about other items on the scorecard. CONCLUSION: In choosing poverty identification strategies for programmes seeking to enhance health equity it's necessary to balance between community acceptability, local relevance and the need for such a strategy. It is important to ensure the strategy is efficient and less costly than alternatives in order to effectively reduce health disparities. PMID- 26626874 TI - Specific microRNAs as novel biomarkers for combination chemotherapy resistance detection of colon adenocarcinoma. AB - BACKGROUND AND OBJECTIVES: Colon cancer is a frequently occurring primary malignant tumor. Chemotherapy can reduce the risk of local and distant relapse. Therefore, it is very important to find new biomarkers that can predict chemoresistance and help in individuate treatment decision. DESIGN AND SETTING: Retrospective analysis of 126 patients, who were treated at our department between June 2010 and December 2014. PATIENTS AND METHODS: In this study, we examined the expression levels of 1200 human miRNAs in colon cancer tissues, using laser capture microdissection and microRNA profiling arrays. A validation study was done to corroborate a subset of the results, including expression levels of miR-4299, miR-196b, miR-324-5p, miR-455-3p and miR-939, through analyzing stage IV colon adenocarcinoma tissues (not responding and responding to the chemotherapy) with laser capture microdissection and quantitative real-time PCR. We analyze the relationship between the expression levels of these miRNAs and the survival rate of colon cancer patients by Kaplan-Meier method. RESULTS: We found that miR-4299 and -196b have significant diagnostic value in chemoresistant colon cancer. MiR-4299 yielded an AUC (the areas under the ROC curve) of 0.810 and miR-196b yielded an AUC of 0.726 in discriminating chemoresistant colon cancer from controls. Combined with ROC analyses of these 2 miRNAs revealed an elevated AUC of 0.877 with 71.4 % sensitivity and 95.5 % specificity in discriminating chemoresistant colon cancer. The low level of miR 4299 expression and the high level of -196b expression are significantly correlated with better survival of colon cancer patients. DISCUSSION: These data suggest that miR-4299 and -196b have strong potential as novel biomarkers for chemoresistance detection of colon cancer. PMID- 26626875 TI - Biosynthetic origin of anthracimycin: a tricyclic macrolide from Streptomyces sp. PMID- 26626876 TI - In vitro activity of dalbavancin and five comparator agents against common and uncommon Gram-positive organisms isolated from cancer patients. AB - Dalbavancin is a long acting, bactericidal lipoglycopeptide. Its in vitro activity was compared with that of vancomycin, daptomycin, linezolid, trimethoprim/sulfamethoxazole (TMP/SMX) and levofloxacin against 241 Gram positive organisms isolated from cancer patients. The rank order of potency for the glycopeptides based on MIC90 (MUg ml(-1)), that is, the concentration of antimicrobial agent required to inhibit 90% of isolates tested was dalbavancin (0.12 MUg ml(-1))>daptomycin (1.0 MUg ml(-1))>vancomycin (2.0 MUg ml(-1)) for coagulase-negative staphylococci and Staphylococcus aureus isolates (including methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) strains). Dalbavancin had potent activity against staphylococcal isolates with vancomycin MICs?1.0 MUg ml(-1). TMP/SMX also had potent activity against staphylococci including methicillin-resistant strains, whereas levofloxacin had moderate to poor anti-staphylococcal activity. Dalbavancin also exhibited more potent activity than vancomycin and daptomycin against Bacillus spp., Corynebacterium spp., Micrococcus spp. and various streptococci (including Streptococcus pneumoniae, viridans group streptococci (VGS), beta-hemolytic streptococci and gamma-hemolytic streptococci). MBC determinations showed that dalbavancin had potent bactericidal activity against MRSA with no tolerance being detected. These data suggest that dalbavancin may be considered as an alternative to vancomycin, especially in institutions wherein a substantial proportion of infections are caused by organisms with vancomycin MICs?1.0 MUg ml(-1). PMID- 26626877 TI - Palliative care consultation services in hospitals in the Netherlands: the design of the COMPASS study. AB - BACKGROUND: Patients with an advanced incurable disease are often hospitalised for some time during the last phase of life. Care in hospitals is generally focussed at curing disease and prolonging life and may therefore not in all cases adequately address the needs of such patients. We present the COMPASS study, a study on the effects and costs of consultation teams for palliative care in hospitals. This observational study aims to investigate the use, effects and costs of PCT consultation services for hospitalized patients with incurable cancer in the Netherlands. METHODS/DESIGN: The study consists of 3 parts: 1. A questionnaire, interviews and a focus group discussion to investigate the characteristics of PCT consultation in 12 hospitals. PCTs will register their activities to calculate the costs of PCT consultation. 2. Cancer patients for whom the attending physician would not be surprised that they would die within 12 month will be included in a medical file search in three hospitals. Medical records will be investigated to compare care, treatment and hospital costs between patients with and patients without PCT consultation. 3. In the other nine hospitals, we will perform a longitudinal study, and compare quality of life between 100 patients for whom a PCT was consulted with 200 patients without PCT consultation. Propensity score matching will be used to adjust for differences between both patient groups. Patients will be followed for three months after inclusion. Quality of life will be assessed with the Palliative Outcome Scale, the EuroQol-5d and the EORTC-QLQ-C15 PAL. Satisfaction with care in the hospital is measured with the IN-PATSAT32. The cost impact of PCT consultation will also be explored. DISCUSSION: This is the first multicenter study on PCT consultation in the Netherlands. The study will give valuable insight in the process, effects and costs of PCT consultation in hospitals. It is anticipated that PCT consultation has a positive effect on patients' quality of life and satisfaction with care and will lead to less hospital care costs. PMID- 26626878 TI - Teichoic acid is the major polysaccharide present in the Listeria monocytogenes biofilm matrix. AB - The aim of this study was to characterize the Listeria monocytogenes biofilm and particularly the nature of the carbohydrates in the biofilm extracellular matrix and culture supernatant versus to cell wall carbohydrates. Listeria monocytogenes serotype 1/2a and 4b strains were able to form complex biofilms embedded in an extracellular matrix. The soluble carbohydrates from biofilm extracellular matrix and culture supernatant were identified as teichoic acids, structurally identical to cell wall teichoic acids. In addition, the DSS 1130 BFA2 strain had a serotype 1/2a teichoic acid lacking N-acetyl glucosamine glycosylation due to a mutation in the lmo2550 gene. Consequently, we hypothesized that the extracellular teichoic acids in L. monocytogenes biofilms have the same origin as cell wall teichoic acid. PMID- 26626879 TI - Bacteriophages of Soft Rot Enterobacteriaceae-a minireview. AB - Soft rot Enterobacteriaceae (Pectobacterium spp. and Dickeya spp., formerly pectinolytic Erwinia spp.) are ubiquitous necrotrophic bacterial pathogens that infect a large number of different plant species worldwide, including economically important crops. Despite the fact that these bacteria have been studied for more than 50 years, little is known of their corresponding predators: bacteriophages, both lytic and lysogenic. The aim of this minireview is to critically summarize recent ecological, biological and molecular research on bacteriophages infecting Pectobacterium spp. and Dickeya spp. with the main focus on current and future perspectives in that field. PMID- 26626880 TI - The phlebotomine sand flies fauna in Parque Estadual do Rio Doce, Minas Gerais, Brazil. AB - BACKGROUND: Phlebotomine sand flies are dipterans of the family Psychodidae. They are very important to veterinary medicine because some species are vectors of infective forms of Leishmania spp., the etiological agents of leishmaniasis. The Parque Estadual do Rio Doce is located in an area with constant reports of cases of leishmaniasis. In order to better understanding the phlebotamine sand fly fauna of the park, the present work was undertaken with the goal of analyzing phlebotomine sand flies collected there, verifying their seasonality and correlating their presence with forest and/or anthropic areas. METHODS: To analyze the fauna of phlebotomine sand flies, HP-type, model CDC light traps were distributed along the Juquita trail of PERD. Twelve traps were installed between September 2012 and February 2014, and captured specimens were identified to species. RESULTS AND DISCUSSIONS: A total of 1993 phlebotomine sand flies of 30 species were captured. The most abundant species were Pressatia choti, Psychodopygus davisi and Nyssomyia intermedia. The high number of Nyssomyia intermedia captured drew attention because they are considered one of the vectors of the infective Leishmania braziliensis present at PERD. No seasonality was observed in the occurrence of phlebotomine sand flies captured at PERD. The number of captured specimens of vector species, and the distance of traps from the forest boarder, were negatively correlated, showing that these vectors (Nyssomyia intermedia, Nyssomyia whitmani and Migonemyia migonei) were less common inside the forest area and that attention should be drawn to other potential vector species in the forest. CONCLUSION: These results can contribute to leishmaniasis prevention strategies directed at the visitors and professionals at or near PERD. The finding of the presence of Leishmania vectors in the park area must be given attention, since disease transmission can threaten people who visit PERD and its surroundings. Therefore, information on the prevention of leishmaniasis needs to be provided to all people who go there. PMID- 26626882 TI - GreenLight laser for prostates over 100 ml: what is the evidence? AB - PURPOSE OF REVIEW: GreenLight photoselective vaporization of the prostate (PVP) has emerged as a minimally invasive, well tolerated, efficacious alternative to transurethral resection of the prostate (TURP) or simple prostatectomy for the treatment of benign prostatic hyperplasia. However, some authors have expressed concern with the use of PVP in large prostates. In this review, we present the most relevant recent literature regarding PVP for treatment of benign prostatic hyperplasia in prostates over 100 ml. RECENT FINDINGS: Recent studies have found that the subjective and objective outcomes of GreenLight PVP, including International Prostate Symptom Score, quality of lifescore, maximum urinary flow rate, and postvoid residual are comparable in large and small prostates. Though larger glands require increased operative time, energy delivery, and fiber use, the short duration of hospitalization and catheterization does not vary with prostate size. The overall complication rates do not increase with prostate size, though some studies have reported increased conversion to electrocautery TURP hemostasis. The trend toward increased retreatment rates in some studies of PVP in large prostates may be because of inadequate energy density delivered. SUMMARY: GreenLight photoselective PVP is a well tolerated and efficacious procedure regardless of prostate size, and should therefore be considered as a viable alternative to TURP, holmium laser enucleation of the prostate, or simple prostatectomy in large prostates. PMID- 26626883 TI - Oral anticoagulation therapy and laser surgery for benign prostatic hyperplasia: stop, replace, or continue? AB - PURPOSE OF REVIEW: To update on the available literature that assessed laser surgery for benign prostatic obstruction (BPO) in patients under antithrombotic. RECENT FINDINGS: All types of laser might be suitable to decrease the bleeding risk in patients under antithrombotic. However, there is no consensus on the appropriate perioperative management of antithrombotic. Most of the studies mixed patients with coumarin derivatives or platelet aggregation inhibitors and did not discriminate the results according to the type of antithrombotic. The continuation of low-dose aspirin is feasible and might not increase bleeding risk during the perioperative period. Conversely, the literature is still too sparse and the protocols reported are too heterogeneous to provide any firm recommendation regarding the continuation, withdrawn, or bridging of clopidogrel and coumarin derivatives during laser procedures for BPO. The approach with new oral anticoagulants is even more uncertain as no data are available in this setting. SUMMARY: The decision to stop, continue, or replace antithrombotic should rely on both thrombotic and hemorrhagic risks. Therefore, urologist, cardiologist, and anesthesiologist should discuss altogether each case. Further studies are needed to provide a high level of evidence regarding the perioperative management of antithrombotic in the era of laser BPO procedures. PMID- 26626884 TI - Editorial: 'New techniques in contemporary stone management'. PMID- 26626881 TI - Epistasis analysis links immune cascades and cerebral amyloidosis. AB - BACKGROUND: Several lines of evidence suggest the involvement of neuroinflammatory changes in Alzheimer's disease (AD) pathophysiology such as amyloidosis and neurodegeneration. In fact, genome-wide association studies (GWAS) have shown a link between genes involved in neuroinflammation and AD. In order to further investigate whether interactions between candidate genetic variances coding for neuroinflammatory molecules are associated with brain amyloid beta (Abeta) fibrillary accumulation, we conducted an epistasis analysis on a pool of genes associated with molecular mediators of inflammation. METHODS: [(18)F]Florbetapir positron emission tomography (PET) imaging was employed to assess brain Abeta levels in 417 participants from ADNI-GO/2 and posteriorly 174 from ADNI-1. IL-1beta, IL4, IL6, IL6r, IL10, IL12, IL18, C5, and C9 genes were chosen based on previous studies conducted in AD patients. Using the [(18)F]florbetapir standardized uptake value ratio (SUVR) as a quantitative measure of fibrillary Abeta, epistasis analyses were performed between two sets of markers of immune-related genes using gender, diagnosis, and apolipoprotein E (APOE) as covariates. Voxel-based analyses were also conducted. The results were corrected for multiple comparison tests. Cerebrospinal fluid (CSF) Abeta1 42/phosphorylated tau (p-tau) ratio concentrations were used to confirm such associations. RESULTS: Epistasis analysis unveiled two significant single nucleotide polymorphism (SNP)-SNP interactions (false discovery rate (FDR) threshold 0.1), both interactions between C9 gene (rs261752) and IL6r gene (rs4240872, rs7514452). In a combined sample, the interactions were confirmed (p <= 10-5) and associated with amyloid accumulation within cognitively normal and AD spectrum groups. Voxel-based analysis corroborated initial findings. CSF biomarker (Abeta1-42/p-tau) confirmed the genetic interaction. Additionally, rs4240872 and rs7514452 SNPs were shown to be associated with CSF and plasma concentrations of IL6r protein. CONCLUSIONS: Certain allele combinations involving IL6r and C9 genes are associated with Abeta burden in the brain. Hypothesis-driven search for epistasis is a valuable strategy for investigating imaging endophenotypes in complex neurodegenerative diseases. PMID- 26626885 TI - Treatment expectations and health-related quality of life in stone formers. AB - PURPOSE OF REVIEW: The objective of this article is to address patients' expectations of stone treatment - both surgical and medical - and their health related quality of life (HRQOL). We present a rationale for greater inclusion of measures to assess patient expectations, satisfaction, and HRQOL into surgical and medical management for patients with recurrent urolithiasis. RECENT FINDINGS: Patients' treatment expectations and HRQOL are fundamental and progressive new areas of interest in urolithiasis. Patients whose treatment regimens result in outcomes that match their expectations are likely to be more satisfied, which may influence their HRQOL, a valid and valuable outcome of any medical treatment or procedure. Patient perceptions of treatment effects for stones, whether surgical or medical, are complex and may not reflect only stone-free rates, surgical complication rates, and side-effects, the outcomes of traditional interest in urology. SUMMARY: If we understand the issues of most importance to our patients, we can provide appropriate information and education that ensures the most realistic expectations, minimizes disappointment and risk, and contributes most to the patients' HRQOL. PMID- 26626886 TI - Impact of ureteral stenting in ureteroscopy. AB - PURPOSE OF REVIEW: We review new therapies and biomaterials designed to reduce ureteral stent symptoms in patients undergoing ureteroscopy. RECENT FINDINGS: Pharmacologically, alpha blockers and antimuscarinics have been shown to have a synergistic effect and be more effective than either medication alone in reducing stent-related symptoms. Prestenting patients prior to ureterosocpy has been shown to be beneficial for patients with renal stones, offering a better stone-free rate and reduced complications, but not for ureteral stones. Stenting after use of a ureteral access sheath reduced complications and unscheduled emergency visits. Nonsteroidal anti-inflammatories have been shown to prevent pain after stent removal. Surveys showed that patients preferred to remove their own stents via dangle strings at home or undergo cystoscopic removal in the operating room with some type of anesthesia. New materials such as gel-based or biodegradable ureteral stents are being developed to deal with stent-related pain, encrustation, and infection. Antirefluxing stents eliminate vesicoureteric reflux in patients during voiding and may reduce symptoms of back and flank pain. Ureteral stents are involved in many procedures in urology and particularly kidney stone treatments. SUMMARY: Advances in materials and medications will help improve the patient experience for those who receive a ureteral stent. PMID- 26626887 TI - New technology in ureteroscopy and percutaneous nephrolithotomy. AB - PURPOSE OF REVIEW: New developments of retrograde intrarenal and percutaneous endoscopic surgery for nephrolithiasis have significantly enhanced the indications of endourology compared to extracorporeal shock wave lithotripsy. We want to review the most significant new technologies RECENT FINDINGS: New technology to access the renal collecting system includes marker-based tracking with iPAD, laser-guided puncture on (Uro)Dyna-CT, electromagnetic tracking (only experimental), and optical tracking for ultrasound-guided puncture. Miniaturization percutaneous nephrolithotomy has been further extended and classified to Midi-PCNL (20-22F/L), Mini-PCNL (16-18F/M), Ultra/Super-mini-PCNL (12-14F/S), and Micro-PCNL (8-10F/XS). Knowledge of Ho:YAG-laser lithotripsy including power settings for fragmentation (depending on stone composition), dusting (0.5J/20Hz), and popcorn-effect/laser-burst (1J/30Hz) becomes mandatory. Also hydrodynamic mechanisms for retrieval of fragments (active/passive washout, purging, vacuum-cleaner-effect) have gained importance. Improvements of FURS focus on digital-HD-video-technology with post-processing software (NBI/SPIES) providing better resolution and increased optical field, further miniaturization of endoscopes to fit in smaller access sheath (12/14F), additional tip-less Nitinol baskets and graspers, and introduction of a robotic device (Avicenna Roboflex) to improve ergonomics of the procedure. SUMMARY: Based on recent technical developments, percutaneous nephrolithotomy and particularly flexible ureteroscopy will further gain preference in management of urolithiasis compared to ESWL. Endourology may offer a higher rate of primary success with minimal side effects which could weigh out the slightly higher degree of invasiveness. PMID- 26626890 TI - Phosphor-free white-light emitters using in-situ GaN nanostructures grown by metal organic chemical vapor deposition. AB - Realization of phosphor-free white-light emitters is becoming an important milestone on the road to achieve high quality and reliability in high-power white light-emitting diodes (LEDs). However, most of reported methods have not been applied to practical use because of their difficulties and complexity. In this study we demonstrated a novel and practical growth method for phosphor-free white light emitters without any external processing, using only in-situ high-density GaN nanostructures that were formed by overgrowth on a silicon nitride (SiNx) interlayer deposited by metal organic chemical vapor deposition. The nano-sized facets produced variations in the InGaN thickness and the indium concentration when an InGaN/GaN double heterostructure was monolithically grown on them, leading to white-color light emission. It is important to note that the in-situ SiNx interlayer not only facilitated the GaN nano-facet structure, but also blocked the propagation of dislocations. PMID- 26626889 TI - In vitro Dynamic Pharmacokinetic/Pharmacodynamic (PK/PD) study and COPD of Marbofloxacin against Haemophilus parasuis. AB - BACKGROUND: Haemophilus parasuis (H. parasuis) can invade the body and cause systemic infection under stress conditions. Marbofloxacin has been recommended for the treatment of swine infections. However, few studies have investigated the PK/PD characteristics and PK/PD cutoff (COPD) of this drug against H. parasuis. RESULTS: MICs of marbofloxacin against 198 H. parasuis isolates were determined. The MIC50 and MIC90 were 2 and 8 mg/L, respectively. An in vitro dynamic PK/PD model was established to study the PK/PD relationship of marbofloxacin against H. parasuis. The PK/PD surrogate markers Cmax/MIC, Cmax/MPC (the maximum concentration divided by MIC or mutant prevention concentration (MPC)) and AUC 24h/MIC, AUC 24h/MPC (the area under the curve during the first 24 h divided by MIC or MPC) simulated the antimicrobial effect of marbofloxacin successfully with the R(2) of 0.9928 and 0.9911, respectively. The target values of 3-log10-unit and 4-log10-unit reduction for AUC 24h/MPC were 33 and 42, while the same efficacy for AUC 24h/MIC were 88 and 110. The COPD deduced from Monte Carlo simulation (MCS) for marbofloxacin against H. parasuis was 0.5 mg/L. The recommended dose of marbofloxacin against H. parasuis with MIC <= 2 mg/L was 16 mg/kg body weight (BW). CONCLUSIONS: The PK/PD surrogate markers AUC 24h/MIC, Cmax/MIC and AUC 24h/MPC, Cmax/MPC properly described the effects of marbofloxacin. Marbofloxacin can achieve the best efficacy at dosage of 16 mg/kg BW for strains with MIC values <= 2 mg/L, therefore, it is obligatory to know the sensitivity of the pathogen and to treat animals as early as possible. The very first COPD provide fundamental data for marbofloxacin breakpoint determination. PMID- 26626892 TI - History of Tick Bite: A Gift or a Red Herring? AB - Fever of unknown origin can be challenging to the emergency medicine physician and the array of both benign and potentially life-threatening diagnoses on the differential can lead to a costly, time-consuming work-up. In this article, we present a case of potentially fatal tick-borne illness with a focus on history, physical exam, and laboratory findings that would differentiate this diagnosis from other causes of fever of unknown origin and aid in early and efficient initiation of treatment for patients. PMID- 26626893 TI - Acute Salpingitis in a Nonsexually Active Adolescent. AB - Acute salpingitis is an uncommon cause of an acute surgical abdomen, especially in an adolescent who is not sexually active. The following is a case of a 12-year old girl who denied sexual activity, had a remote history of an appendectomy, and a recent diagnosis of a large, right-sided ovarian cyst, who presented with acute abdominal pain, urinary symptoms, and fever. The patient was ill-appearing and progressed to uncompensated septic shock in the emergency department despite aggressive fluid resuscitation and empiric antibiotics. She ultimately underwent an exploratory laparotomy and was diagnosed with acute bilateral salpingitis. This case highlights the diagnostic dilemmas facing those caring for an adolescent girl with abdominal pain and presents an extremely rare etiology for abdominal pain in a nonsexually active adolescent. PMID- 26626891 TI - Candidate chemosensory genes identified in Colaphellus bowringi by antennal transcriptome analysis. AB - BACKGROUND: Since chemosensory genes play key roles in insect behaviour, they can potentially be used as new targets for pest control. The cabbage beetle, Colaphellus bowringi, is a serious insect pest of cruciferous vegetables in China and other Asian countries. However, a systematic identification of the chemosensory genes expressed in the antennae has not been reported. RESULTS: We assembled the antennal transcriptome of C. bowringi by using Illumina sequencing technology and identified 104 candidate chemosensory genes by analyzing transcriptomic data, which included transcripts encoding 26 odorant-binding proteins (OBPs), 12 chemosensory proteins (CSPs), four sensory neuron membrane proteins (SNMPs), 43 odorant receptors (ORs), nine ionotropic receptors (IRs), and ten gustatory receptors (GRs). The data obtained are similar to those found in other coleopteran species, suggesting that our approach successfully identified the chemosensory genes of C. bowringi. The expression patterns of 43 OR genes, some of which were predominately found in the antenna or associated with sex-biased expression, were analyzed using quantitative real time RT-PCR (qPCR). CONCLUSIONS: Our study revealed that a large number of chemosensory genes are expressed in C. bowringi. These candidate chemosensory genes and their expression profiles in various tissues provide further information on understanding their function in C. bowringi as well as other insects, and identifying potential targets to disrupt the odorant system in C. bowringi so that new methods for pest management can be developed. PMID- 26626894 TI - Pediatric Homonymous Superior Quadrantanopia in the Presence of Acute Vertebral Artery Dissection. AB - OBJECTIVE: Spontaneous dissection of the vertebral artery is a dangerous and often underdiagnosed cause of posterior circulation and occipital lobe stroke in the young. Vertebral artery dissection should be considered in young patients with a history of minor, nontraumatic changes in head position and visual disturbances. METHODS: Clinical records for this patient were retrospectively reviewed at Miami Children's Hospital and associated pediatric ophthalmology clinic. RESULTS: A previously healthy 8-year-old boy presented to the emergency department with a 2-day history of headache and blurred vision that developed after going on a high-velocity amusement park ride. Confrontation visual field testing showed a subtle superior visual field deficit superiorly. Computer topography scan of the head without contrast was performed and showed bilateral occipital hypodense lesions consistent with ischemic infarction. A filling defect was seen in the transverse portion of the right vertebral artery at the level of C2 as it exited the right transverse foramen, consistent with an acute arterial dissection at this level. Automated visual field testing showed macular sparing left homonymous superior quadrantanopia. CONCLUSIONS: Most patients with vertebral artery dissection present with signs of posterior circulation ischemia consisting of neurological deficits, headaches, or neck pain. This case report highlights the unique clinical features and diagnostic imaging seen in the work up of this rare disease process and exemplifies the importance of identifying acute visual symptoms in an emergency situation. PMID- 26626895 TI - Hyponatremia in a Teenager: A Rare Diagnosis. AB - INTRODUCTION: Hyponatremia is a common electrolyte alteration which has the potential for significant morbidity and mortality. Endocrine disorders, such as primary hypothyroidism and adrenal insufficiency are uncommon causes of hyponatremia. We present the case of a teenager with symptomatic hyponatremia caused by a rare disorder. CASE: A 17-year-old boy was admitted to the emergency department with abdominal pain, nausea and vomiting, asthenia, and weight loss. He was in poor general condition, hypotensive, and he had dry mucous membranes and skin as well as mucosa hyperpigmentation. The laboratory findings showed severe hyponatremia, hyperkalemia, and renal dysfunction. The patient started inotropic support and antibiotics. Plasma cortisol and corticotropin levels allowed the diagnosis of primary adrenal insufficiency. He began replacement therapy with hydrocortisone and fludrocortisone, with gradual symptom resolution. An abdominal computed tomography scan showed adrenal hypoplasia. Findings for antiadrenal and antithyroid antibodies were positive, allowing the diagnosis of autoimmune polyglandular syndrome type II. DISCUSSION: Adrenal insufficiency is a rare disease, especially in children, and its clinical manifestations are due to glucocorticoid and mineralocorticoid deficiency. In most of the cases, symptoms are nonspecific, requiring a high index of clinical suspicion. If the diagnosis and treatment are delayed, acute adrenal insufficiency carries a high morbidity and mortality. PMID- 26626896 TI - Ultrasound-Guided Femoral Nerve Blocks. AB - Pediatric acute femur fractures are a relatively common major orthopedic injury seen in emergency departments. Providing adequate and safe analgesia is essential while patients await definitive management of these fractures. Opioid medications are typically used to treat fracture-associated pain but have well-known adverse effects including respiratory and central nervous system depression, pruritus, nausea, and allergic reactions. Dose titration of opioids in pediatric patients may be difficult and requires frequent nursing and physician reassessments. Regional anesthesia using ultrasound guidance has been proposed as a reliable and safe method to provide pain relief for this population and to decrease reliance on opioid medications. There is a growing body of literature on the utility and safety of ultrasound-guided femoral nerve blocks for pediatric patients in the acute care setting. This review article covers recent literature on point-of-care ultrasound-guided femoral nerve blocks for pediatric patients, with a discussion of the indications, sonographic anatomy, selection of anesthetics, nerve block technique, and complications. This review supplements the expert supervision and practice required to gain competency. PMID- 26626898 TI - Emergency Point-of-Care Ultrasound Assessment of Whiteout Lung in the Pediatric Emergency Department. AB - Point-of-care ultrasound is being used more frequently in pediatric emergency medicine departments. It has become an important adjunct for clinical diagnoses and procedural guidance. We present a case series of 3 patients who presented to a pediatric emergency department and on chest radiographs had whiteout lung. Point-of-care ultrasound was able to differentiate fluid from consolidation, facilitating the appropriate investigations and interventions for these children. PMID- 26626899 TI - Developing a Research Agenda to Optimize Diagnostic Imaging in the Emergency Department: An Executive Summary of the 2015 Academic Emergency Medicine Consensus Conference. AB - The 2015 Academic Emergency Medicine consensus conference, "Diagnostic Imaging in the Emergency Department: A Research Agenda to Optimize Utilization" was held on May 12, 2015, with the goal of developing a high-priority research agenda on which to base future research. The specific aims of the conference were to (1) understand the current state of evidence regarding emergency department (ED) diagnostic imaging use and identify key opportunities, limitations, and gaps in knowledge; (2) develop a consensus-driven research agenda emphasizing priorities and opportunities for research in ED diagnostic imaging; and (3) explore specific funding mechanisms available to facilitate research in ED diagnostic imaging. Over a 2-year period, the executive committee and other experts in the field convened regularly to identify specific areas in need of future research. Six content areas within emergency diagnostic imaging were identified before the conference and served as the breakout groups on which consensus was achieved: clinical decision rules; use of administrative data; patient-centered outcomes research; training, education, and competency; knowledge translation and barriers to imaging optimization; and comparative effectiveness research in alternatives to traditional computed tomography use. The executive committee invited key stakeholders to assist with the planning and to participate in the consensus conference to generate a multidisciplinary agenda. There were a total of 164 individuals involved in the conference and spanned various specialties, including general emergency medicine, pediatric emergency medicine, radiology, surgery, medical physics, and the decision sciences. PMID- 26626900 TI - New-Onset Hypoglycemia in a Medically Complex 6-Year-Old Girl. Glimepiride poisoning. PMID- 26626901 TI - Pediatric Emergency Medicine: Legal Briefs. PMID- 26626902 TI - ECGs in the ED. PMID- 26626903 TI - Thanks to Trauma: A Delayed Diagnosis of Pott Disease. PMID- 26626904 TI - Celiac Disease and Juvenile Absence Epilepsy. PMID- 26626905 TI - Computed Tomography for Suspected Appendicitis in Children: Do Not Forget Radiation Exposure. PMID- 26626906 TI - Importance of C-3 Epimer of 25-Hydroxyvitamin D to Assess Vitamin D Deficiency in Children With Fractures. PMID- 26626908 TI - How effective is ustekinumab in controlling psoriatic arthritis? AB - Recently ustekinumab has been approved for the therapy of psoriatic arthritis (PsA). Some case series have been published reporting new onset of inflammatory arthritis in psoriasis patients treated with ustekinumab. In addition, flare of joint inflammation in PsA patients has also been reported. We describe a case series of seven patients affected by PsA who experienced either a worsening or a flare of inflammatory arthritis during treatment with ustekinumab. PMID- 26626910 TI - High prevalence of Bordetella pertussis in children under 5 years old hospitalized with acute respiratory infections in Lima, Peru. AB - BACKGROUND: Pertussis diagnosis may go unrecognized when other pathogens, such as respiratory syncytial virus (RSV) circulate. METHODS: A prospective cross sectional study was conducted in Lima, Peru from January 2009 to September 2010. A total of 596 children under 5 years old admitted with clinical diagnoses of acute respiratory infections were test for B. pertussis and RSV detection by polymerase chain reaction (PCR). RESULTS: The pertussis toxin and IS481 genes were detected in 19.12% (114/596) of the cases and the respiratory syncytial viruses (RSV-A and RSV-B) were identified in 17.28% (103/596) of patients. Infants under 3 months old were the most frequently affected by this pathogens in 43% (49/114) and 35.9% (37/103) respectively. An increase of B. pertussis was observed from February to March and from October to November with a Seasonal index between 1.32 and 1.51 and 1.24-3.5 respectively. CONCLUSIONS: Epidemiologic surveillance for B. pertussis is essential in Peru, especially in children that could most benefit from the vaccine. B. pertussis should be suspected in infants hospitalized for acute respiratory symptoms for early treatment and prevent complications. PMID- 26626909 TI - Animal Models of Nonalcoholic Steatohepatitis: Eat, Delete, and Inflame. AB - With the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become a public health problem with increasing prevalence. The mechanism of disease progression remains obscure and effective therapy is lacking. Therefore, there is a need to understand the pathogenic mechanisms responsible for disease development and progression in order to develop innovative therapies. To accomplish this goal, experimental animal models that recapitulate the human disease are necessary, especially, since causative mechanistic studies of NAFLD are more difficult or unethical to perform in humans. A large number of studies regarding the pathophysiology and treatment of nonalcoholic steatohepatitis (NASH) have been undertaken in mice to model human NAFLD and NASH. This review discusses the known dietary, genetic, and inflammation-based animal models of NASH described in recent years, with a focus on the major advances made in this field. PMID- 26626911 TI - Nutrient Limitation in Surface Waters of the Oligotrophic Eastern Mediterranean Sea: an Enrichment Microcosm Experiment. AB - The growth rates of planktonic microbes in the pelagic zone of the Eastern Mediterranean Sea are nutrient limited, but the type of limitation is still uncertain. During this study, we investigated the occurrence of N and P limitation among different groups of the prokaryotic and eukaryotic (pico-, nano , and micro-) plankton using a microcosm experiment during stratified water column conditions in the Cretan Sea (Eastern Mediterranean). Microcosms were enriched with N and P (either solely or simultaneously), and the PO4 turnover time, prokaryotic heterotrophic activity, primary production, and the abundance of the different microbial components were measured. Flow cytometric and molecular fingerprint analyses showed that different heterotrophic prokaryotic groups were limited by different nutrients; total heterotrophic prokaryotic growth was limited by P, but only when both N and P were added, changes in community structure and cell size were detected. Phytoplankton were N and P co limited, with autotrophic pico-eukaryotes being the exception as they increased even when only P was added after a 2-day time lag. The populations of Synechococcus and Prochlorococcus were highly competitive with each other; Prochlorococcus abundance increased during the first 2 days of P addition but kept increasing only when both N and P were added, whereas Synechococcus exhibited higher pigment content and increased in abundance 3 days after simultaneous N and P additions. Dinoflagellates also showed opportunistic behavior at simultaneous N and P additions, in contrast to diatoms and coccolithophores, which diminished in all incubations. High DNA content viruses, selective grazing, and the exhaustion of N sources probably controlled the populations of diatoms and coccolithophores. PMID- 26626912 TI - Plant Host Species and Geographic Distance Affect the Structure of Aboveground Fungal Symbiont Communities, and Environmental Filtering Affects Belowground Communities in a Coastal Dune Ecosystem. AB - Microbial symbionts inhabit tissues of all plants and animals. Their community composition depends largely on two ecological processes: (1) filtering by abiotic conditions and host species determining the environments that symbionts are able to colonize and (2) dispersal-limitation determining the pool of symbionts available to colonize a given host and community spatial structure. In plants, the above- and belowground tissues represent such distinct habitats for symbionts that we expect different effects of filtering and spatial structuring on their symbiont communities. In this study, we characterized above- and belowground communities of fungal endophytes--fungi living asymptomatically within plants--to understand the contributions of filtering and spatial structure to endophyte community composition. We used a culture-based approach to characterize endophytes growing in leaves and roots of three species of coastal beachgrasses in dunes of the USA Pacific Northwest. For leaves, endophyte isolation frequency and OTU richness depended primarily on plant host species. In comparison, for roots, both isolation frequency and OTU richness increased from the nutrient-poor front of the dune to the higher-nutrient backdune. Endophyte community composition in leaves exhibited a distance-decay relationship across the region. In a laboratory assay, faster growth rates and lower spore production were more often associated with leaf- than root-inhabiting endophytes. Overall, our results reveal a greater importance of biotic filtering by host species and dispersal limitation over regional geographic distances for aboveground leaf endophyte communities and stronger effects of abiotic environmental filtering and locally patchy distributions for belowground root endophyte communities. PMID- 26626913 TI - Effects of immobilization and aerobic training on proteins related to intramuscular substrate storage and metabolism in young and older men. AB - PURPOSE: Aging and inactivity lead to skeletal muscle metabolic inflexibility, but the underlying molecular mechanisms are not entirely elucidated. Therefore, we investigated how muscle lipid and glycogen stores and major regulatory proteins were affected by short-term immobilization followed by aerobic training in young and older men. METHODS: 17 young (23 +/- 1 years, 24 +/- 1 kg m(-2), and 20 +/- 2% body fat) and 15 older men (68 +/- 1 years; 27 +/- 1 kg m(-2), and 29 +/- 2% body fat) underwent 2 weeks' one leg immobilization followed by 6 weeks' cycle training. Biopsies were obtained from m. vastus lateralis just before immobilization (at inclusion), after immobilization, and the after 6 weeks' training. The biopsies were analyzed for muscle substrates; muscle perilipin protein (PLIN), glycogen synthase (GS), synaptosomal-associated protein of 23 kDa (SNAP23) protein content, and muscle 3-hydroxyacyl-CoA dehydrogenase (HAD) activity RESULTS: The older men had higher intramuscular triglyceride (IMTG) (73 %) and Glycogen (16%) levels compared to the young men, and IMTG tended to increase with immobilization. PLIN2 and 3 protein content increased with immobilization in the older men only. The young men had higher GS (74%) protein compared to the older men. Immobilization decreased and training restored HAD activity, GS and SNAP23 protein content in young and older men. CONCLUSION: Evidence of age-related metabolic inflexibility is presented, seen as body fat and IMTG accumulation. The question arises as to whether IMTG accumulation in the older men is caused by or leading to the increase in PLIN2 and 3 protein content. Training decreased body fat and IMTG levels in both young and older men; hence, training should be prioritized to reduce the detrimental effect of aging on metabolism. PMID- 26626914 TI - Aspects of Cardiometabolic Risk in Women with Polycystic Ovary Syndrome. AB - Women with polycystic ovary syndrome (PCOS), the most common endocrine disorder among women of reproductive age, exhibit an adverse cardiovascular risk profile characteristic of the cardiometabolic syndrome. These women, compared with age- and body mass index-matched women without PCOS, appear to present a higher risk of insulin resistance, glucose intolerance, and dyslipidemia, and possibly a higher rate of type 2 diabetes mellitus and cardiovascular disease. However, despite the presence of cardiovascular risk factors and increased surrogate markers of cardiovascular disease, it is unclear whether they have accelerated atherosclerosis and greater mortality, the latter mainly because of a lack of endpoint studies. This article addresses, summarizes, and discusses salient data from the existing literature, including gaps and uncertainties, aspects, and mechanisms related to the spectrum of adverse cardiometabolic profile factors in women with PCOS. PMID- 26626915 TI - Impact of Adiposity and Fat Distribution on the Dynamics of Adrenocorticotropin and Cortisol Rhythms. AB - Obesity impacts many hormonal systems, including pituitary hormones, as well as insulin and leptin. In this review we discuss articles which investigate the influence of obesity on the hypothalamic-pituitary-adrenal (HPA) axis. Different techniques have been used to assess the function of the HPA-axis in obesity, including measuring fasting and/or late evening levels of adrenocorticotropic hormone (ACTH) and (free) cortisol in plasma and saliva, studying feedback with dexamethasone or cortisol, and evaluating responsiveness of the system to corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) or ACTH 1 29. In addition, more elaborate studies investigated 24-h secretion patterns, analyzed with deconvolution techniques to quantitate pulsatile secretion rates of cortisol and less often ACTH. Other investigators used timed infusions of labeled cortisol for the estimation of the 24-h secretion rate, clearance rate and distribution volume. Many studies relied on the 24-h urinary excretion of free cortisol, but for quantitation of the 24-h secretion, measurement of all cortisol derived metabolites is required. Several studies have applied modern liquid chromatography-tandem-mass spectrometry techniques to measure these metabolites. The picture emerging from all these studies is that, first, ACTH secretion is amplified, likely via enhanced forward drive; and, second, serum cortisol levels are normal or even low, associated with a normal 24-h cortisol secretion per liter distribution volume determined by deconvolution, but enhanced when based on the increased total distribution volume associated with obesity. Increased cortisol secretion was also established by isotope dilution studies and reports based on the measurement of all urinary cortisol metabolites. The responsiveness of the adrenal gland to ACTH is diminished. The studies do not address quantitative aspects of cortisol-cortisone metabolism on individual organs, including liver, central and peripheral fat, intestine, skin, and muscle. PMID- 26626916 TI - Androgens, body fat Distribution and Adipogenesis. AB - Androgens are regulators of important adipocyte functions such as adipogenesis, lipid storage, and lipolysis. Through depot-specific impact on the cells of each fat compartment, androgens could modulate body fat distribution patterns in humans. Testosterone and dihydrotestosterone have been shown to inhibit the differentiation of preadipocytes to lipid-storing adipocytes in several models including primary cultures of human adipocytes from both men and women. Androgen effects have also been observed on some markers of lipid metabolism such as LPL activity, fatty acid uptake, and lipolysis. Possible depot-specific and sex specific effects have been observed in some but not all models. Transformation of androgen precursors to active androgens or their inactivation by enzymes that are expressed and functional in adipose tissue may contribute to modulate the local availability of active hormones. These phenomena, along with putative depot specific interactions with glucocorticoids may contribute to human body fat distribution patterns. PMID- 26626917 TI - Predictors of Ectopic Fat in Humans. AB - In the last decade there has been increasing focus on body fat distribution, rather than on the degree of obesity. More recently, great interest has also been dedicated to ectopic fat deposition in overnourished individuals that reflects a failure of the system of intracellular lipid homeostasis, which, in normal conditions, prevents lipotoxicity in the organs, by confining lipid overload to cells specifically designed to store large quantities of surplus calories, the white adipocytes. Consequently, excess body weight leads to fat infiltration of multiple organs including liver, pancreas, skeletal muscle, and heart thus forming "ectopic fat". Although overfeeding is considered the main predictor of ectopic fat deposition, other factors may be also involved. The purpose of this review is to evaluate the current available data on the predictors of ectopic fat deposition in humans. PMID- 26626918 TI - New Physiological Aspects of Brown Adipose Tissue. AB - Brown adipose tissue is specialised for the generation of heat by non-shivering mechanisms. In rodents, the tissue plays a role in energy balance and the development of obesity, as well as in thermoregulation. Studies using fluorodeoxyglucose positron emission tomography (FDG-PET), together with the identification of uncoupling protein-1, have provided definitive evidence that brown adipose tissue is present in adult humans. Brown fat activity is stimulated by cold exposure, declines with age and is inversely proportional to BMI. This has led to renewed interest in the tissue as a therapeutic target for the treatment of obesity. Brown adipose tissue also plays a role in glucose disposal and triglyceride clearance, implicating it in the metabolic syndrome. A potential mechanism for increasing thermogenesis is by the 'browning' of white adipose depots through the recruitment of the recently identified third type of adipocyte - the brite (or beige) fat cell. PMID- 26626919 TI - Low-Grade Inflammation, Obesity, and Diabetes. AB - Obesity and its comorbidities are closely related to the inflammatory environment created by expanded adipose tissue. Several mechanisms trigger inflammation in adipose tissue, including excess fatty acids, hypoxia, and activation of the inflammasome. Inflammation is characterized by the abundance of immune cells, particularly M1 macrophages and T lymphocytes, which have increased secretion of proinflammatory cytokines that act to perpetuate systemic inflammation and induce insulin resistance. The gut microbiota is also involved in obesity-induced inflammation via LPS-related endotoxemia that induces cytokine secretion and insulin resistance. Innate lymphoid type 2 cells, regulatory T cells, and interleukine (IL)-10 counteract the inflammation and insulin resistance, establishing classical or metabolically healthy obesity. PMID- 26626920 TI - Evaluating the Health Impacts of Food and Beverage Taxes. AB - Several jurisdictions are now imposing taxes on food and beverages to prevent obesity (and related conditions). Existing evidence concerning their effects comes largely from simulation studies and trials in closed settings, both of which have limitations. Rigorous evaluation of actual taxes may provide richer evidence with greater external validity to support policy making. This article describes existing evaluation studies and outlines an implicit underlying theoretical framework for how taxes are expected to affect health. It then explores three important issues for future studies: selection of an appropriate evaluative perspective (comparing realist and biomedical experimental paradigms); approaches to causal inference; and the challenge of a low signal-to-noise ratio. We argue that evaluation should be informed by a realist perspective as well as making appropriate use of established empirical quasi-experimental approaches to testing causal effects. This should be underpinned by a theoretical framework that acknowledges complexity and the potential diversity of impacts. PMID- 26626921 TI - Food and Beverage Marketing to Youth. AB - After nearly a decade of concern over the role of food and beverage marketing to youth in the childhood obesity epidemic, American children and adolescents - especially those from communities of color - are still immersed in advertising and marketing environments that primarily promote unhealthy foods and beverages. Despite some positive steps, the evidence shows that the food and beverage industry self-regulation alone is not likely to significantly reduce marketing of unhealthy foods and beverages to youth. A variety of research is needed to monitor industry marketing of unhealthy products to young people, and identify the most promising approaches to improve children's food marketing environments. The continued presence of unhealthy marketing toward children despite years of industry self-regulation suggests it is time for stronger action by policymakers to protect young people from harmful marketing practices. PMID- 26626922 TI - Food Away from Home and Childhood Obesity. AB - Childhood obesity is associated with a number of serious health risks that can persist into adulthood. While trends in food away from home and fast-food consumption have paralleled trends in childhood obesity, it is important to identify whether this is a causal relationship. This paper reviews recent literature in this area to summarize if there is a consensus in research findings. We group the literature into two areas - consumption of and access to food away from home (FAFH). While no consensus findings have been reached in either area, the evidence of an association between FAFH consumption and childhood obesity has gained strength. Further, there is evidence that FAFH meals add calories to children's diets. The literature on the role of FAFH access and childhood obesity has continued producing mixed results. PMID- 26626923 TI - Monolith disk chromatography separates PEGylated protein positional isoforms within minutes at low pressure. AB - Although PEGylation makes proteins drugs more effective, the PEGylation reaction must be controlled carefully in order to obtain a desired PEGylated protein form since various different PEGylated forms may be produced during the reaction. For monitoring the PEGylation reaction, a method with monolith disk ion exchange chromatography, which can separate positional isomers as well as PEGmers, has been developed as a process analytical tool (PAT). The method was optimized for separation of randomly PEGylated protein (lysozyme) isoforms based on the number of resolved peaks, peak resolution, analysis time and pressure drop. In order to increase the retention of mono- and di-PEGylated protein isomers the mobile phase was decreased to pH 4.5, where a large number of mono- and di-PEGylated isomers were resolved within a few minutes. Based on the linear gradient elution optimization model, the following values were determined: gradient slope 0.016 M/mL, disk thickness 3 mm (single disk) and flow rate 10 mL/min. Under these optimal conditions, the analysis was completed within ca. 4 min while the pressure drop was below 1 MPa. As the method was successfully applied to monitoring mono and di-PEGylated positional isoforms in the reaction mixture of random PEGylation of lysozyme, it is expected to be an efficient PAT tool. PMID- 26626924 TI - CORR Insights((r)): What Is the Radiographic Prevalence of Incidental Kienbock Disease? PMID- 26626925 TI - Value-based Healthcare: The Value of Considering Patient Preferences and Circumstances in Orthopaedic Surgery. PMID- 26626926 TI - Letter to the Editor: Surgical Technique: Tscherne-Johnson Extensile Approach for Tibial Plateau Fractures. PMID- 26626927 TI - Development and assessment of a pediatric emergency medicine simulation and skills rotation: meeting the demands of a large pediatric clerkship. AB - OBJECTIVE: To implement a curriculum using simulation and skills training to augment a Pediatric Emergency Medicine (PEM) rotation within a pediatric clerkship. BACKGROUND: PEM faculty are often challenged with a high learner to teacher ratio in a chaotic clinical setting. This challenge was heightened when our pediatric clerkship's traditional 1-week PEM rotation (consisting of 4 students completing four 8-hour ED shifts/week) expanded to 8 students every 2 weeks. We sought to meet this challenge by integrating simulation-based education into the rotation. METHODS: Clerkship students from March to June 2012 completed our traditional rotation. Students between July and October 2012 completed the new PEM-SIM curriculum with 19 hours ED shifts/week and 16 hours/week of simulation/skills training. Pre/post-tests evaluated 1) medical management/procedural comfort (five-point Likert scale); and 2) PEM knowledge (15 multiple-choice questions). RESULTS: One hundred and nine students completed the study (48 traditional, 61 PEM-SIM). Improvement in comfort was significantly higher for the PEM-SIM group than the traditional group for 6 of 8 (75%) medical management items (p<0.05) and 3 of 7 (43%) procedures, including fracture splinting, lumbar puncture, and abscess incision/drainage (p<0.05). PEM-SIM students had significantly more improvement in mean knowledge compared to the traditional group (p<0.001). CONCLUSIONS: We have successfully integrated 16 hours/week of faculty-facilitated simulation-based education into a PEM rotation within our clerkship. This curriculum is beneficial in clinical settings with high learner to teacher ratios and when patient care experiences alone are insufficient for all students to meet rotation objectives. PMID- 26626928 TI - Cation-cation clusters in ionic liquids: Cooperative hydrogen bonding overcomes like-charge repulsion. AB - Direct spectroscopic evidence for H-bonding between like-charged ions is reported for the ionic liquid, 1-(2-hydroxyethyl)-3-methylimidazolium tetrafluoroborate. New infrared bands in the OH frequency range appear at low temperatures indicating the formation of H-bonded cation-cation clusters similar to those known for water and alcohols. Supported by DFT calculations, these vibrational bands can be assigned to attractive interaction between the hydroxyl groups of the cations. The repulsive Coulomb interaction is overcome by cooperative hydrogen bonding between ions of like charge. The transition energy from purely cation-anion interacting configurations to those including cation-cation H-bonds is determined to be 3-4 kJmol(-1). The experimental findings and DFT calculations strongly support the concept of anti-electrostatic hydrogen bonds (AEHBs) as recently suggested by Weinhold and Klein. The like-charge configurations are kinetically stabilized with decreasing temperatures. PMID- 26626929 TI - Visual Findings in Chiasmal Syndromes. PMID- 26626930 TI - Endoscopic Approach to Pituitary Tumors. PMID- 26626931 TI - Radiation Therapy in the Management of Pituitary Tumors. PMID- 26626932 TI - Compressive Optic Neuropathy in Thyroid Eye Disease. PMID- 26626933 TI - Thyroid Eye Disease: Optic Neuropathy and Orbital Decompression. PMID- 26626934 TI - Radiation Therapy for Orbitopathy of Thyroid Eye Disease. PMID- 26626936 TI - Preface: Endocrinologic Disorders and Their Relationship With Ophthalmic Findings. PMID- 26626937 TI - Querying Co-regulated Genes on Diverse Gene Expression Datasets Via Biclustering. AB - Rapid development and increasing popularity of gene expression microarrays have resulted in a number of studies on the discovery of co-regulated genes. One important way of discovering such co-regulations is the query-based search since gene co-expressions may indicate a shared role in a biological process. Although there exist promising query-driven search methods adapting clustering, they fail to capture many genes that function in the same biological pathway because microarray datasets are fraught with spurious samples or samples of diverse origin, or the pathways might be regulated under only a subset of samples. On the other hand, a class of clustering algorithms known as biclustering algorithms which simultaneously cluster both the items and their features are useful while analyzing gene expression data, or any data in which items are related in only a subset of their samples. This means that genes need not be related in all samples to be clustered together. Because many genes only interact under specific circumstances, biclustering may recover the relationships that traditional clustering algorithms can easily miss. In this chapter, we briefly summarize the literature using biclustering for querying co-regulated genes. Then we present a novel biclustering approach and evaluate its performance by a thorough experimental analysis. PMID- 26626940 TI - Assessment of the Impact of Skeletonization on Pleuropulmonary Changes after Bilateral Internal Thoracic Artery Harvest for Coronary Artery Bypass Grafting. AB - BACKGROUND AND AIMS: Skeletonization has been proposed as a technique to minimize the risk of sternal devascularization during bilateral internal thoracic artery harvest for coronary artery bypass grafting. The impact of this strategy on late radiologic pleuropulmonary changes has not been addressed. MATERIAL AND METHODS: Post-operative chest radiographs from patients (n = 253 per group) undergoing bilateral internal thoracic artery harvest using skeletonized and non skeletonized techniques were reviewed by blinded radiologists. The primary outcome was the incidence of atelectasis and pleural effusion. Multivariable linear regression models were derived to assess the relationship of radiologic pleuropulmonary outcomes to patients and operative variables. RESULTS AND CONCLUSION: Patients in the skeletonized group were older (p < 0.0001), had a lower preoperative hematocrit (p = 0.014), had higher prevalence of peripheral vascular disease (p = 0.001), were of female gender (p = 0.015), underwent off pump surgery (p < 0.001), had urgent/emergent status (p = 0.024), and had chronic obstructive pulmonary disease (p = 0.019). There was no difference in the incidence of post-operative complications, ventilation time, or intensive care unit stay. There was no difference in the severity of post-operative atelectasis in both groups. More patients in the non-skeletonized group had a grade 2/3 left pleural effusion on the late post-operative chest X-ray (p = 0.007). The independent effect of skeletonization on the development of a late left pleural effusion was significant (odds ratio = 0.558, 95% confidence interval = 0.359 0.866, p = 0.009). Skeletonization results in a decreased incidence of late post operative left pleural effusion with no difference in early or late atelectasis. Further studies are warranted to assess the mechanism of these pleuropulmonary changes and the impact of other factors such as pleural violation during surgery. PMID- 26626941 TI - Characterization of Bacterial Communities in Deep-Sea Hydrothermal Vents from Three Oceanic Regions. AB - Deep-sea hydrothermal vents are considered to be one of the most spectacular ecosystems on Earth. Microorganisms form the basis of the food chain in vents controlling the vent communities. However, the diversity of bacterial communities in deep-sea hydrothermal vents from different oceans remains largely unknown. In this study, the pyrosequencing of 16S rRNA gene was used to characterize the bacterial communities of the venting sulfide, seawater, and tubeworm trophosome from East Pacific Rise, South Atlantic Ridge, and Southwest Indian Ridge, respectively. A total of 23,767 operational taxonomic units (OTUs) were assigned into 42 different phyla. Although Proteobacteria, Actinobacteria, and Bacteroidetes were the predominant phyla in all vents, differences of bacterial diversity were observed among different vents from three oceanic regions. The sulfides of East Pacific Rise possessed the most diverse bacterial communities. The bacterial diversities of venting seawater were much lower than those of vent sulfides. The symbiotic bacteria of tubeworm Ridgeia piscesae were included in the bacterial community of vent sulfides, suggesting their significant ecological functions as the primary producers in the deep-sea hydrothermal vent ecosystems. Therefore, our study presented a comprehensive view of bacterial communities in deep-sea hydrothermal vents from different oceans. PMID- 26626939 TI - Induced Pluripotency and Epigenetic Reprogramming. AB - Induced pluripotency defines the process by which somatic cells are converted into induced pluripotent stem cells (iPSCs) upon overexpression of a small set of transcription factors. In this article, we put transcription factor-induced pluripotency into a historical context, review current methods to generate iPSCs, and discuss mechanistic insights that have been gained into the process of reprogramming. In addition, we focus on potential therapeutic applications of induced pluripotency and emerging technologies to efficiently engineer the genomes of human pluripotent cells for scientific and therapeutic purposes. PMID- 26626942 TI - Nuclear Phosphatidylinositol Signaling: Focus on Phosphatidylinositol Phosphate Kinases and Phospholipases C. AB - Phosphatidylinositol (PI) metabolism represents the core of a network of signaling pathways which modulate many cellular functions including cell proliferation, cell differentiation, apoptosis, and membrane trafficking. An array of kinases, phosphatases, and lipases acts on PI creating an important number of second messengers involved in different cellular processes. Although, commonly, PI signaling was described to take place at the plasma membrane, many evidences indicated the existence of a PI cycle residing in the nuclear compartment of eukaryotic cells. The discovery of this mechanism shed new light on many nuclear functions, such as gene transcription, DNA modifications, and RNA expression. As these two PI cycles take place independently of one another, understanding how nuclear lipid signaling functions and modulates nuclear output is fundamental in the study of many cellular processes. J. Cell. Physiol. 231: 1645-1655, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26626938 TI - Cell Death Signaling. AB - In multicellular organisms, cell death is a critical and active process that maintains tissue homeostasis and eliminates potentially harmful cells. There are three major types of morphologically distinct cell death: apoptosis (type I cell death), autophagic cell death (type II), and necrosis (type III). All three can be executed through distinct, and sometimes overlapping, signaling pathways that are engaged in response to specific stimuli. Apoptosis is triggered when cell surface death receptors such as Fas are bound by their ligands (the extrinsic pathway) or when Bcl2-family proapoptotic proteins cause the permeabilization of the mitochondrial outer membrane (the intrinsic pathway). Both pathways converge on the activation of the caspase protease family, which is ultimately responsible for the dismantling of the cell. Autophagy defines a catabolic process in which parts of the cytosol and specific organelles are engulfed by a double-membrane structure, known as the autophagosome, and eventually degraded. Autophagy is mostly a survival mechanism; nevertheless, there are a few examples of autophagic cell death in which components of the autophagic signaling pathway actively promote cell death. Necrotic cell death is characterized by the rapid loss of plasma membrane integrity. This form of cell death can result from active signaling pathways, the best characterized of which is dependent on the activity of the protein kinase RIP3. PMID- 26626943 TI - Drug Signature-based Finding of Additional Clinical Use of LC28-0126 for Neutrophilic Bronchial Asthma. AB - In recent decades, global pharmaceutical companies have suffered from an R&D innovation gap between the increased cost of a new drug's development and the decreased number of approvals. Drug repositioning offers another opportunity to fill the gap because the approved drugs have a known safety profile for human use, allowing for a reduction of the overall cost of drug development by eliminating rigorous safety assessment. In this study, we compared the transcriptional profile of LC28-0126, an investigational drug for acute myocardial infarction (MI) at clinical trial, obtained from healthy male subjects with molecular activity profiles in the Connectivity Map. We identified dyphilline, an FDA-approved drug for bronchial asthma, as a top ranked connection with LC28-0126. Subsequently, we demonstrated that LC28-0126 effectively ameliorates the pathophysiology of neutrophilic bronchial asthma in OVALPS-OVA mice accompanied with a reduction of inflammatory cell counts in the bronchoalveolar lavage fluid (BALF), inhibition of the release of proinflammatory cytokines, relief of airway hyperactivity, and improvement of histopathological changes in the lung. Taken together, we suggest that LC28-0126 could be a potential therapeutic for bronchial asthma. In addition, this study demonstrated the potential general utility of computational drug repositioning using clinical profiles of the investigational drug. PMID- 26626944 TI - Is Alice in Wonderland? A new cause for burns due to "Bonzai abuse". PMID- 26626946 TI - Microassay for ketamine and metabolites in plasma and serum based on enantioselective capillary electrophoresis with highly sulfated gamma cyclodextrin and electrokinetic analyte injection. AB - For the assessment of stereoselective aspects of the metabolism of ketamine, an enantioselective CE-based microassay for determination of the stereoisomers of ketamine and three of its major metabolites in plasma and serum was developed. The assay is based on liquid/liquid extraction of the analytes of interest at alkaline pH from 0.05 mL plasma or serum followed by electrokinetic sample injection of the analytes from the extract across a buffer plug without chiral selector. Separation occurs cationically at normal polarity in a pH 3.0 phosphate buffer containing 0.66% of highly sulfated gamma-cyclodextrin (HS-gamma-CD). Key parameters for optimization are identified as being the amount of HS-gamma-CD in the BGE, the length of the buffer plug and its concentration, the duration of electrokinetic injection, and the extraction medium. Diluted buffer in the plug is employed to ascertain sufficient analyte stacking due to a combination of field amplification and complexation. The newly developed microassay is robust (intraday and interday RSD < 5% and <9%, respectively) and well suited to determine enantiomer levels of ketamine and its metabolites down to 10 ng/mL. It is more sensitive, uses less plasma or serum, organic solvent, and analysis time compared to previous CE-based assays and was successfully applied to monitor ketamine, norketamine, 5,6-dehydronorketamine (DHNK), and 6-hydroxynorketamine (6HNK) stereoisomer levels in plasma of a Beagle dog that received a bolus of racemic ketamine or S-ketamine after sevoflurane anesthesia. The data suggest that the formation of DHNK and 6HNK occur stereoselectively. PMID- 26626945 TI - Structural insight into the mechanism of synergistic autoinhibition of SAD kinases. AB - The SAD/BRSK kinases participate in various important life processes, including neural development, cell cycle and energy metabolism. Like other members of the AMPK family, SAD contains an N-terminal kinase domain followed by the characteristic UBA and KA1 domains. Here we identify a unique autoinhibitory sequence (AIS) in SAD kinases, which exerts autoregulation in cooperation with UBA. Structural studies of mouse SAD-A revealed that UBA binds to the kinase domain in a distinct mode and, more importantly, AIS nestles specifically into the KD-UBA junction. The cooperative action of AIS and UBA results in an 'alphaC out' inactive kinase, which is conserved across species and essential for presynaptic vesicle clustering in C. elegans. In addition, the AIS, along with the KA1 domain, is indispensable for phospholipid binding. Taken together, these data suggest a model for synergistic autoinhibition and membrane activation of SAD kinases. PMID- 26626947 TI - Gratitude, depression and PTSD: Assessment of structural relationships. AB - Gratitude, the tendency to appreciate positive occurrences in one's life that can be partially attributed to another person, has been shown to be a robust predictor of greater well-being. Researchers have also found gratitude to be inversely related to several emotional disorders, including major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Both of these emotional disorders are highly comorbid and share dysphoric symptoms (e.g., restricted affect, detachment, anhedonia) that could account for deficits in the experience and expression of gratitude. We used confirmatory factor analysis to test the relationships between gratitude and the symptom factors of PTSD (using the DSM-5 model) and MDD in a sample of trauma-exposed college students (N=202). Results indicated that gratitude is more strongly related to PTSD's negative alterations in mood and cognition (NAMC) factor than to other PTSD factors. Implications of these findings for the study of gratitude and trauma are discussed, including whether gratitude and gratitude-based interventions might prove particularly suited to targeting depressive symptoms. PMID- 26626948 TI - Benefits of adjunctive N-acetylcysteine in a sub-group of clozapine-treated individuals diagnosed with schizophrenia. PMID- 26626950 TI - Association between social contact frequency and negative symptoms, psychosocial functioning and quality of life in patients with schizophrenia. AB - The lack of social contacts may be an important element in the presumed vicious circle aggravating, or at least stabilising negative symptoms in patients with schizophrenia. A European 2-year cohort study collected negative symptom scores, psychosocial functioning scores, objective social contact frequency scores and quality of life scores every 6 months. Bivariate analyses, correlation analyses, multivariate regressions and random effects regressions were conducted to describe relations between social contact and outcomes of interest and to gain a better understanding of this relation over time. Using data from 1208 patients with schizophrenia, a link between social contact frequency and negative symptom scores, functioning and quality of life at baseline was established. Regression models confirmed the significant association between social contact and negative symptoms as well as psychosocial functioning. This study aimed at demonstrating the importance of social contact for deficient behavioural aspects of schizophrenia. PMID- 26626951 TI - Development and initial validation of a measure of metacognitive beliefs in health anxiety: The MCQ-HA. AB - Metacognitive beliefs have been shown to correlate with emotional disorders and more recently have been implicated in health anxiety. Research exploring these beliefs have tended to use the Metacognition Questionnaire (MCQ), which is a general measure. To facilitate research on the metacognitive model applied to health anxiety the present study reports on the development and initial evaluation of a new specific metacognitive measure of health anxiety, the Metacognitions Questionnaire-Health Anxiety (MCQ-HA). Principal components analysis identified 14 suitable items to be explored. Subsequent exploratory factor analysis of the MCQ-HA identified three factors: "Beliefs that Thoughts can cause Illness", "Beliefs about Biased thinking", and "Beliefs that Thoughts are Uncontrollable". Confirmatory factor analysis supported the three factor model with all selected goodness-of-fit statistics equivalent to or better than recommended values. Preliminary evidence suggests good internal-consistency, incremental, convergent and discriminant validity in relation to associated measures. The MCQ-HA appears to be a potentially useful predictor of health anxiety. PMID- 26626952 TI - [Are our medical centres for fitness to drive and firearms licences effective?]. AB - OBJECTIVES: This article aimed to evaluate the effectiveness of medical centres in the assessment of medical fitness for driving and gun licences, as well as describing the differences between them. METHOD: Using a crossover design and a representative sample of holders of driving and firearms licences in the province of Malaga during 2014 (363 reports for driving licenses and 626 for firearms licenses), an assessment was made of fitness report issued by the centres by comparing it with the records of the Andalusian public health service. The proportion of those that would not meet the legal eligibility requirements was calculated. An analysis was made of the origin of the disagreements as regards the information made available by the centres. RESULTS: The discordance in the assessment of fitness to drive was estimated as 15.4% (95% CI: 12.0 to 19.4), while for firearms licenses it was 2.7 times higher (41.4%). The origin of the discordance is related to the information provided to the centres, rather than the assessment made by them. CONCLUSIONS: The limited effectiveness of the centres in the assessment of fitness for driving and, especially, for firearms licenses, could be improved by increased monitoring of their activity, providing health workers with adequate training and access to healthcare records of applicants. PMID- 26626949 TI - Evaluating the relationship between cannabis use and IQ in youth and young adults at clinical high risk of psychosis. AB - Among people with psychosis, those with a history of cannabis use show better cognitive performance than those who are cannabis naive. It is unknown whether this pattern is present in youth at clinical high risk (CHR) of psychosis. We evaluated relationships between IQ and cannabis use while controlling for use of other substances known to impact cognition in 678 CHR and 263 healthy control (HC) participants. IQ was estimated using the Vocabulary and Block Design subtests of the Wechsler Abbreviated Scale of Intelligence. Drug and alcohol use severity and frequency were assessed with the Alcohol and Drug Use Scale, and we inquired participants' age at first use. CHR were further separated into early and late age at onset of cannabis use sub-groups, and low-, moderate- and high frequency sub-groups. No significant differences in IQ emerged between CHR or HC cannabis users vs. non-users, or between use frequency groups. CHR late-onset users showed significantly higher IQ than CHR early-onset users. Age at onset of cannabis use was significantly and positively correlated with IQ in CHR only. Results suggest that age at onset of cannabis may be a more important factor for IQ than use current use or use frequency in CHR. PMID- 26626953 TI - [Other reasons for our Spanish primary care appreciation]. PMID- 26626954 TI - Effects of mild wintering conditions on body mass and corticosterone levels in a temperate reptile, the aspic viper (Vipera aspis). AB - Temperate ectotherms are expected to benefit from climate change (e.g., increased activity time), but the impacts of climate warming during the winter have mostly been overlooked. Milder winters are expected to decrease body condition upon emergence, and thus to affect crucial life-history traits, such as survival and reproduction. Mild winter temperature could also trigger a state of chronic physiological stress due to inadequate thermal conditions that preclude both dormancy and activity. We tested these hypotheses on a typical temperate ectothermic vertebrate, the aspic viper (Vipera aspis). We simulated different wintering conditions for three groups of aspic vipers (cold: ~6 degrees C, mild: ~14 degrees C and no wintering: ~24 degrees C) during a one month long period. We found that mild wintering conditions induced a marked decrease in body condition, and provoked an alteration of some hormonal mechanisms involved in emergence. Such effects are likely to bear ultimate consequences on reproduction, and thus population persistence. We emphasize that future studies should incorporate the critical, albeit neglected, winter season when assessing the potential impacts of global changes on ectotherms. PMID- 26626955 TI - Seasonal dietary shifting in yellow-rumped warblers is unrelated to macronutrient targets. AB - Dietary shifting, for example from insects to fruits, is a common mechanism used in migratory songbirds to accumulate fat to fuel migratory flights. We examined a potential underlying cause of dietary shifting in yellow-rumped warblers (Setophaga coronata) by comparing energy and protein intake goals of birds during fall migration and winter. We offered captive warblers pairs of three diets differing in macronutrient composition in both the fall and winter. Using the principles of the geometric framework of nutrition we evaluated protein and energy intake to determine if consumption of the diet pairs was adjusted to meet an energy or protein intake target, and if the target differed seasonally. Regardless of season, the warblers preferred the diet with the lowest protein content and highest carbohydrate content. Total energy intake was maintained relatively constant during migration, at around 60 kJ/day, regardless of diet combination, and at about 50 kJ/day during winter. This suggests that warblers consume macronutrients available to them without protein limitations to reach their total energy intake target. When the diet combination offered allows, the warblers mixed their diet intake to consume roughly 0.5 g/day of protein, regardless of season, which suggested a constant protein target. Our findings suggest that songbirds prefer to alter non-protein energy intake proportionally to meet changing energy demand, rather than an overall increase in macronutrient intake. Additionally, they have the ability to shift their diet based on availability, resulting in high flexibility in their macronutrient intakes to maintain energy intake. PMID- 26626956 TI - The Spear Horizon: First spatial analysis of the Schoningen site 13 II-4. AB - The Spear Horizon (Schoningen 13 II-4) from Schoningen, Lower Saxony, Germany, is one of the most important archeological sites dating to the Middle Pleistocene. Until today, the numerous finds have only been published individually, often outside of their context. Here we present for the first time the distribution map of the Spear Horizon together with a spatial analysis of the different categories of remains (flint, bones, and woods). The finds are situated in a 10 m wide belt, which runs parallel to a former lakeshore. The distribution of faunal remains correlates closely with the distribution of flint artifacts and wooden objects. We have been able to distinguish five different sectors that can be aligned with different events or activities. The greatest density of finds was evident within an area of 11 * 15 m, where most of the horse skulls were recovered. Some of the square meters contain more than 150 finds. During the excavation the profiles were continually documented and these data help us to reconstruct the shoreline of the paleo-lake with considerable accuracy. Over a distance of 60 m, the thickness and density of the organic mud and peat layers could be reconstructed in high resolution. The distribution of finds shows no preferred orientation or selection through size. The analyses only indicate small-scale dislocations and limited taphonomic alterations. The fraction of lithic artifacts with size ranges less than 2 cm are preserved, while some smaller bone fragments are missing. Most of the wooden artifacts are in-situ, but were deformed by the ice load during the Saalian ice age. While some small charcoal remains as well as a burnt artifact have been observed, there is no evidence of burnt bones. Our results allow a first insight into the formation history of the site. PMID- 26626957 TI - Bone taphonomy of the Schoningen "Spear Horizon South" and its implications for site formation and hominin meat provisioning. AB - This paper presents the faunal remains from the new excavation area at the Lower Paleolithic site of Schoningen. The focus of the study is on the southern extension of the main find horizon (Spear Horizon South), which includes the layer that yielded the famous Schoningen spears (13 II-4). Taxonomic data corroborate previous studies, that hominins primarily hunted Equus mosbachensis, a large Pleistocene horse. Equid body part representation at the site suggests that the animals were hunted and butchered locally. There is no evidence for density-mediated attrition in the assemblage. Weathering damage is uncommon, though there is ample evidence that carnivores had access to the bone. Carnivore bite sizes were measured and compared to experimental data provided by previous authors. Based on relationships between bite size and carnivore behavior and body size, we conclude that the primary modifying agents were large carnivores (i.e., wolves or saber-toothed cats). Previous studies show that carnivores often had secondary access to the remains, after hominins. Cut marks are commonly arranged haphazardly on the bones. This may indicate that multiple hominins participated in the butchery of horse skeletons, or that they were butchered over the course of hours or days. Cut marks on axial elements are more "orderly," which probably reflects the physical logistics of orienting one's body in relation to a large carcass. These data differ from sites formed by Middle and Upper Paleolithic hominins, which might suggest that in later times, a system of organized meat provisioning was already in place. Taken together, the faunal evidence from the Spear Horizon South indicates that late Lower Paleolithic hominins using the site understood the behaviors of different prey species, hunted socially to take down large game, and successfully competed with large carnivores on the landscape for primary access to ungulate remains. PMID- 26626958 TI - Saltwater icephobicity: Influence of surface chemistry on saltwater icing. AB - Most studies on icephobicity focus on ice formation with pure water. This manuscript presents studies to understand the influence of surfaces on saltwater ice nucleation and propagation. Experiments are conducted to quantify the influence of surface chemistry on saltwater ice nucleation and to understand the utility of superhydrophobic surfaces for saltwater icephobicity. These experiments are conducted with pure water and two sodium chloride solutions, which represent the salinity of seawater and briny produced water. It is seen that the presence of salt slows down the ice front propagation velocity significantly. Saltwater droplet impact dynamics on superhydrophobic surfaces are also different from pure water. Saltwater droplets retract more and a greater fraction of impacting liquid is repelled from the superhydrophobic surface. It is seen that the greater bounciness of saltwater droplets is a result of slower ice nucleation propagation kinetics. These experiments indicate that superhydrophobic surfaces will have better resistance to impact icing with saltwater than pure water and can remain useful at temperatures as low as -40 degrees C. Overall, this work is a starting point for further studies on heterogeneous nucleation in saltwater and serves as a bridge between the widely studied freshwater icephobic surfaces and saltwater-related applications. PMID- 26626959 TI - Dextran sulfate sodium upregulates MAPK signaling for the uptake and subsequent intracellular survival of Brucella abortus in murine macrophages. AB - Brucellosis is one of the major zoonoses worldwide that inflicts important health problems in animal and human. Here, we demonstrated that dextran sulfate sodium (DSS) significantly increased adhesion of Brucella (B.) abortus in murine macrophages compared to untreated cells. Even without infection, Brucella uptake into macrophages increased and F-actin reorganization was induced compared with untreated cells. Furthermore, DSS increased the phosphorylation of MAPKs (ERK1/2 and p38alpha) in Brucella-infected, DSS-treated cells compared with the control cells. Lastly, DSS markedly increased the intracellular survival of Brucella abortus in macrophages by up to 48 h. These results suggest that DSS enhanced the adhesion and phagocytosis of B. abortus into murine macrophages by stimulating the MAPK signaling proteins phospho-ERK1/2 and p38alpha and that DSS increased the intracellular survival of B. abortus by inhibiting colocalization of Brucella containing vacuoles (BCVs) with the late endosome marker LAMP-1. This study emphasizes the enhancement of the phagocytic and intracellular modulatory effects of DSS, which may suppress the innate immune system and contribute to prolonged Brucella survival and chronic infection. PMID- 26626960 TI - Correlation between clinical symptoms and peripheral immune response in HAM/TSP. AB - HTLV-1 infects principally CD4+ T cells that are the main reservoirs of the virus in vivo, which play an important role in the immunological response. Most of the infected patients are asymptomatic. However, 2-3% of patients will develop HAM/TSP or Adult T lymphoma. HAM/TSP is a chronic inflammatory disease of the central nervous system, which is characterized by unremitting myelopathic symptoms. Studies have shown that cytokines levels alterations (IFN-gamma and TNF alpha) were associated with tissue injury in HAM/TSP. The aims of this study were to compare the gene expression of IFN-gamma, IL-4 and IL-10 of asymptomatic and HAM/TSP HTLV-1 infected patients, and to correlate the gene expression with those of clinical symptoms. 28 subjects were included, 20 asymptomatic HTLV-1 and 8 with HAM/TSP. Spasticity was evaluated using the Modified Ashworth Scale and the degree of walking aid was classified on a progressive scale. The relative gene expression of IFN-gamma, IL-4, and IL-10 was measured by Real-Time PCR. Results showed high gene expression of IFN-gamma for all patients, but it was higher among HAM/TSP. A significant correlation was observed between IFN-gamma gene expression and the degree of walking aid, and IFN-gamma gene expression was higher among wheelchair users compared to non-wheelchair users. No association was found with IL-4 and IL-10. These findings indicate that HAM/TSP patients express higher amounts of IFN-gamma than asymptomatic patients, and more importantly, the expression of this cytokine was strongly correlated with the need of walking aid. PMID- 26626961 TI - Procedural and clinical outcomes after use of the glycoprotein IIb/IIIa inhibitor abciximab for saphenous vein graft interventions. AB - BACKGROUND: Percutaneous coronary intervention (PCI) of saphenous vein grafts (SVG) poses a high-risk for distal coronary thromboembolic events. Glycoprotein IIb/IIIa inhibitors are frequently used in hope of reducing the impact of this, although the safety and efficacy of these drugs to improve outcomes in this setting are understudied. METHODS: Patients were included if they had prior coronary artery bypass surgery and subsequently underwent PCI of >=1 SVG graft at a Dutch academic center between 1997 and 2008. These patients were matched 1:1 based on peri-procedural use of abciximab using a propensity-score matching algorithm based on 17 variables. Conditional logistic regression and Cox regression stratified on matched pairs were performed to evaluate the association between abciximab use and MACCE (the composite measure of mortality, myocardial infarction, stroke and repeat revascularization) at 30days and up to 1year. RESULTS: The composite of 30-day MACCE occurred in 18 patients (15.3%) in the abciximab group and 16 patients (13.6%) in the propensity matched control group (OR: 1.13, 95% CI: 0.57-2.21, p=0.73). At 1-year follow-up, MACCE rates were also similar (32.5% vs. 33.9%, HR: 0.97, 95% CI: 0.59-1.59). Major bleeding (BARC types 3a-c) was higher in the abciximab group (11.9% vs. 4.2%, OR: 2.80, 95% CI: 1.01-7.77). Ischemic outcomes did not differ among patients with acute coronary syndromes. CONCLUSION: The use of intravenous abciximab was not associated with improved clinical outcomes up to 1-year among patients undergoing SVG PCI, but was related to more bleeding. PMID- 26626962 TI - Pregnancy associated thrombotic thrombocytopenic purpura: Practical issues for patient management. AB - Thrombotic thrombocytopenic purpura (TTP) is a severe, life-threatening disease that needs urgent diagnosis and prompt therapeutic intervention. In pregnant women TTP may complicate the course of gestation putting mother and child at vital risk. Differential diagnosis with other obstetric and medical disorders may be difficult due to the overlap of several clinical and laboratory findings. Our understanding of the pathophysiology of TTP has allowed ADAMTS13 testing to have a central role in confirming the clinical diagnosis but the main limitation is that an ADAMTS13 assay is not available in "real time". Here we report the clinical course and treatment outcome of two young women with clinical manifestations of pregnancy associated TTP and briefly discuss the main topics of disease diagnosis and management. PMID- 26626963 TI - Sustained benefits of autologous serum eye drops on self-reported ocular symptoms and vision-related quality of life in Australian patients with dry eye and corneal epithelial defects. AB - BACKGROUND: This research examined the effect of autologous serum eye drops (ASED) on ocular symptoms, visual-related functioning and quality of life for patients failing other therapies. METHODS: Patients (N = 77) were asked to complete a survey prior to ASED use, and 2 and 12 months post-treatment. RESULTS: Significant improvements in symptom frequency and severity were documented for dryness, ocular pain and grittiness at 2 and 12 months. Patients felt more in control and required less help from others at 12 months. CONCLUSIONS: ASED produce sustained benefits to dry eye symptoms, improve feelings of control and reduce requirements for assistance from others. PMID- 26626964 TI - Therapeutic apheresis in pregnancy. PMID- 26626965 TI - A patient focused application of a non-conventional blood components- autologous serum eye drops--and current opinions on substances used for clinical management of acute haemorrhage for shock/trauma. PMID- 26626966 TI - Apheresis in high risk antiphospholipid syndrome pregnancy and autoimmune congenital heart block. AB - In the first part a prospective cohort study was reported to evaluate the efficacy and safety of a treatment protocol including plasma exchange (PE) or PE plus intravenous immunoglobulins (IVIG) or immunoadsorption (IA) plus IVIG administered in addition to conventional therapy to 22 pregnant women with high risk APS. The results indicate that PE or IA treatments administered along with IVIG and conventional antithrombotic therapy could be a valuable and safe therapeutic option in pregnant APS women with triple antiphospholipid antibody positivity along with a history of thrombosis and/or one or more severe pregnancy complications. In the second part the efficacy and safety of PE combined with IVIG and steroids were evaluated for the treatment of 10 patients with autoimmune congenital heart block (CHB) by comparing maternal features, pregnancy outcome and side effects with those of 24 CHB patients treated with steroids only. The patients treated with the combined therapy showed a statistically significant regression of 2nd degree blocks, an increase in heart rate at birth and a significantly lower prevalence of pacing in the first year of life. Moreover, no side effects were observed except for a few steroid-related events. If these results are confirmed by large-scale studies, the apheretic procedures could lead to improved outcomes in the treatment of these devastating diseases. PMID- 26626967 TI - My pregnancy in the apheresis unit. PMID- 26626968 TI - Severe dyslipidemia in pregnancy: The role of therapeutic apheresis. AB - During pregnancy physiological changes occur in the lipid metabolism due to changing hormonal conditions: the LDL cholesterol (LDL-C), triglycerides (TG) and lipoprotein(a) [Lp(a)] increase throughout pregnancy. Common lipoprotein disorders are associated in pregnancy with two major clinical disorders: severe hypertriglyceridemia (SHTG) is a potent risk factor for development of acute pancreatitis and elevated cholesterol due to greater concentrations of LDL and remnant lipoproteins and reduced levels of HDL promote atherosclerosis. The combination of homozygous Familial Hypercholesterolemia (HoFH) and pregnancy can be a fatal condition. Therapeutic plasma exchange (TPE) may be used for an urgent need of a fast and effective lowering of TG levels in order to prevent a severe pancreatitis episode or hypertriglyceridemia-induced complications during pregnancy. LDL apheresis can decrease LDL-C and prevent complications and can be considered in the treatment of pregnancies complicated by high LDL-C. These conditions are configured in patients with HeFH who were taking statins before pregnancy (selected cases), patients already receiving apheresis before pregnancy suffering from HoFH, patients suffering from hypertriglyceridemia due to familial hyperlipoproteinemia types I and V, and cases of hypertriglyceridemia secondary to diabetes. PMID- 26626969 TI - Quantifying the effect of ionic screening with protein-decorated graphene transistors. AB - Liquid-based applications of biomolecule-decorated field-effect transistors (FETs) range from biosensors to in vivo implants. A critical scientific challenge is to develop a quantitative understanding of the gating effect of charged biomolecules in ionic solution and how this influences the readout of the FETs. To address this issue, we fabricated protein-decorated graphene FETs and measured their electrical properties, specifically the shift in Dirac voltage, in solutions of varying ionic strength. We found excellent quantitative agreement with a model that accounts for both the graphene polarization charge and ionic screening of ions adsorbed on the graphene as well as charged amino acids associated with the immobilized protein. The technique and analysis presented here directly couple the charging status of bound biomolecules to readout of liquid-phase FETs fabricated with graphene or other two-dimensional materials. PMID- 26626970 TI - Dopamine biosensor based on surface functionalized nanostructured nickel oxide platform. AB - A dopamine biosensor has been developed using nickel oxide nanoparticles (NPs) and tyrosinase enzyme conjugate. Nickel oxide (NiO) NPs were synthesized by sol gel method using anionic surfactant, sodium dodecyl sulphate (SDS), as template to control the size of synthesized nanoparticles. The structural and morphological studies of the prepared NPs were carried out using X-ray diffraction (XRD), transmission electron microscopy (TEM) and dynamic light scattering (DLS) techniques. Afterwards, tyrosinase enzyme molecules were adsorbed on NiO NPs surface and enzyme coated NPs were deposited on indium tin oxide (ITO) coated flexible polyethylene terephthalate (PET) substrate by solution casting method. The formation of enzyme-NPs conjugate was investigated by atomic force microscopy (AFM) and Fourier transform infrared spectroscopy (FTIR) techniques and used in selective detection and estimation of neurochemical dopamine by electrochemical method. The fabricated Tyrosinase/NiO/ITO electrode exhibits high sensitivity of 60.2nA/uM in linear detection range (2-100MUM) with a detection limit of 1.038MUM. The proposed sensor had a response time of 45s, long shelf life (45 days) with good reproducibility and selectivity in presence of interfering substances and was validated with real samples. The tyrosinase enzyme functionalized NiO platform has good bio-sensing efficacy and can be used in detection of other catecholamines and phenolic neurochemicals. PMID- 26626971 TI - Oxidative stress in multiple sclerosis: Central and peripheral mode of action. AB - Accumulating evidence suggests that oxidative stress plays a major role in the pathogenesis of multiple sclerosis (MS). Reactive oxygen species (ROS), which if produced in excess lead to oxidative stress, have been implicated as mediators of demyelination and axonal damage in both MS and its animal models. One of the most studied cell populations in the context of ROS-mediated tissue damage in MS are macrophages and their CNS companion, microglia cells. However, and this aspect is less well appreciated, the extracellular and intracellular redox milieu is integral to many processes underlying T cell activation, proliferation and apoptosis. In this review article we discuss how oxidative stress affects central as well as peripheral aspects of MS and how manipulation of ROS pathways can potentially affect the course of the disease. It is our strong belief that the well-directed shaping of ROS pathways has the potential to ameliorate disease progression in MS. PMID- 26626972 TI - Low-dose, continual enzyme delivery ameliorates some aspects of established brain disease in a mouse model of a childhood-onset neurodegenerative disorder. AB - AIM: To determine the capacity of continual low-dose lysosomal enzyme infusion into the cerebrospinal fluid of mucopolysaccharidosis type IIIA (MPS IIIA) mice to reverse established neurodegenerative disease. The rationale behind the study is that there is only limited animal model-derived evidence supporting treatment of symptomatic patients, principally because few studies have been designed to examine disease reversibility. METHODS: Twelve-week old MPS IIIA mice were implanted with indwelling unilateral intra-ventricular cannulae. These were connected to subcutaneous mini-osmotic pumps infusing recombinant human sulphamidase. Pump replacement was carried out in some mice at 16-weeks of age, enabling treatment to continue for a further month. Control affected/unaffected mice received vehicle via the same method. Behavioural, neuropathological and biochemical parameters of disease were assessed. RESULTS: Improvement in some, but not all, behavioural parameters occurred. Sulphamidase infusion mediated a statistically significant reduction in primary (heparan sulphate) and secondary (gangliosides GM2, GM3) substrate accumulation in the brain, with small reductions in micro- but not astro-gliosis. There was no change in axonal spheroid number. All mice developed a humoural response, however the antibodies were non-neutralising and no adverse clinical effects were observed. CONCLUSIONS: Continual infusion of replacement enzyme partially ameliorates clinical, histological and biochemical aspects of MPS IIIA mice, when treatment begins at an early symptomatic stage. PMID- 26626973 TI - Pregnancy-related anxiety: A concept analysis. AB - OBJECTIVES: Evidence suggests that pregnancy-related anxiety is more strongly associated with maternal and child outcomes than general anxiety and depression are and that pregnancy-related anxiety may constitute a distinct concept. However, because of its poor conceptualization, the measurement and assessment of pregnancy-related anxiety have been limited. Efforts to analyze this concept can significantly contribute to its theoretical development. The first objective of this paper was to clarify the concept of pregnancy-related anxiety and identify its characteristics and dimensions. The second aim was to examine the items of current pregnancy-related anxiety measures to determine the dimensions and attributes that each scale addresses, noting any gaps between the current assessment and the construct of the concept. DESIGN: A concept analysis was conducted to examine the concept of pregnancy-related anxiety. DATA SOURCES: To obtain the relevant evidence, several databases were searched including MEDLINE, PsycINFO, EBSCO's SocINDEX, Psychological and Behavioral Sciences Collection, CINAHL, SCOPUS, and EMBASE. REVIEW METHODS: A modified approach based on Walker and Avant (Strategies for theory construction in nursing. 5th ed; 2011) was used. Qualitative or quantitative studies published in English that explored or examined anxiety during pregnancy or its dimensions prospectively or retrospectively were included. RESULTS: Thirty eight studies provided data for the concept analysis. Three critical attributes (i.e., affective responses, cognitions, and somatic symptoms), three antecedents (i.e., a real or anticipated threat to pregnancy or its outcomes, low perceived control, and excessive cognitive activity, and four consequences (i.e., negative attitudes, difficulty concentrating, excessive reassurance-seeking behavior, and avoidance behaviors) were identified. Nine dimensions for pregnancy-related anxiety were determined, and a definition of the concept was proposed. The most frequently reported dimensions included anxiety about fetal health, fetal loss, childbirth, and parenting and newborn care. The content of five scales was analyzed to determine the attributes and dimensions measured by each tool. Our findings suggest that the Pregnancy-Related Anxiety Scale tapping five dimensions of pregnancy-related anxiety and the Pregnancy Outcome Questionnaire with six items pertaining to the consequences of pregnancy-related anxiety can respectively be considered the most useful tools for assessing the existence and severity of the concept. CONCLUSIONS: The critical attributes of pregnancy-related anxiety are similar to those defined for anxiety disorders. However, the behavioral consequences of pregnancy-related anxiety appear to apply only some women and may serve as important indicators of the severity of the condition. Current tools are useful instruments to determine whether the concept exists and to capture selected domains of pregnancy-related anxiety. A tool that includes all dimensions of the concept and examines the severity of pregnancy-related anxiety is needed. PMID- 26626974 TI - Last Call. PMID- 26626975 TI - Health Services Research, Medicare, and Medicaid: A Deep Bow and a Rechartered Agenda. PMID- 26626976 TI - Health Care Reform and the American Congress. PMID- 26626977 TI - A Blueprint for Repair and Renovation of the ACA. PMID- 26626978 TI - Meeting the ACA's Goals. PMID- 26626979 TI - Accountability for Health. PMID- 26626980 TI - The Importance of Physicians' Financial Disclosure for the Public's Health. PMID- 26626981 TI - Clash of the Titans: State All-Payer Claims Reporting Systems Meet ERISA Preemption. PMID- 26626982 TI - A Tale of Two Diseases: Mental Illness and HIV/AIDS. PMID- 26626983 TI - Potential Policies and Laws to Prohibit Weight Discrimination: Public Views from 4 Countries. AB - CONTEXT: People viewed as "overweight" or "obese" are vulnerable to weight-based discrimination, creating inequities and adverse health outcomes. Given the high rates of obesity recorded globally, studies documenting weight discrimination in multiple countries, and an absence of legislation to address this form of discrimination, research examining policy remedies across different countries is needed. Our study provides the first multinational examination of public support for policies and legislation to prohibit weight discrimination. METHODS: Identical online surveys were completed by 2,866 adults in the United States, Canada, Australia, and Iceland. We assessed public support for potential laws to prohibit weight-based discrimination, such as adding body weight to existing civil rights statutes, extending disability protections to persons with obesity, and instituting legal measures to prohibit employers from discriminating against employees because of body weight. We examined sociodemographic and weight-related characteristics predicting support for antidiscrimination policies, and the differences in these patterns across countries. FINDINGS: The majority of participants in the United States, Canada, and Australia agreed that their government should have specific laws in place to prohibit weight discrimination. At least two-thirds of the participants in all 4 countries expressed support for policies that would make it illegal for employers to refuse to hire, assign lower wages, deny promotions, or terminate qualified employees because of body weight. Women and participants with higher body weight expressed more support for antidiscrimination measures. Beliefs about the causes of obesity were also related to support for these laws. CONCLUSIONS: Public support for legal measures to prohibit weight discrimination can be found in the United States, Canada, Australia, and Iceland, especially for laws to remedy this discrimination in employment. Our findings provide important information for policymakers and interest groups both nationally and internationally and can help guide discussions about policy priorities to reduce inequities resulting from weight discrimination. PMID- 26626984 TI - Walking the Line: Navigating Market and Gift Economies of Care in a Consumer Directed Home-Based Care Program for Older Adults. AB - CONTEXT: Paid caregivers of low-income older adults navigate their role at what Hochschild calls the "market frontier": the fuzzy line between the "world of the market," in which services are exchanged for monetary compensation, and the "world of the gift," in which caregiving is uncompensated and motivated by emotional attachment. We examine how political and economic forces, including the reduction of long-term services and supports, shape the practice of "walking the line" among caregivers of older adults. METHODS: We used data from a longitudinal qualitative study with related and nonrelated caregivers (n = 33) paid through California's In-Home Supportive Services (IHSS) program and consumers of IHSS care (n = 49). We analyzed the semistructured interviews (n = 330), completed between 2010 and 2014, using a constructivist grounded theory approach. FINDINGS: Related and nonrelated caregivers are often expected to "gift" hours of care above and beyond what is compensated by formal services. Cuts in formal services and lapses in pay push caregivers to further "walk the line" between market and gift economies of care. Both related and nonrelated caregivers who choose to stay on and provide more care without pay often face adverse economic and health consequences. Some, including related caregivers, opt out of caregiving altogether. While some consumers expect that caregivers would be willing to "walk the line" in order to meet their needs, most expressed sympathy for them and tried to alter their schedules or go without care in order to limit the caregivers' burden. CONCLUSIONS: Given economic and health constraints, caregivers cannot always compensate for cuts in formal supports by providing uncompensated time and resources. Similarly, low-income older adults are not competitive in the caregiving marketplace and, given the inadequacy of compensated hours, often depend on unpaid care. Policies that restrict formal long-term services and supports thus leave the needs of both caregivers and consumers unmet. PMID- 26626985 TI - Do March-In Rights Ensure Access to Medical Products Arising From Federally Funded Research? A Qualitative Study. AB - CONTEXT: The high cost of new prescription drugs and other medical products is a growing health policy issue. Many of the most transformative drugs and vaccines had their origins in public-sector funding to nonprofit research institutions. Although the Bayh-Dole Act of 1980 provides for "march-in rights" through which the government can invoke some degree of control over the patents protecting products developed from public funding to ensure public access to these medications, the applicability of this provision to current policy options is not clear. METHODS: We conducted a primary-source document review of the Bayh-Dole Act's legislative history as well as of hearings of past march-in rights petitions to the National Institutes of Health (NIH). We then conducted semistructured interviews of 12 key experts in the march-in rights of the Bayh Dole Act to identify the sources of the disputes and the main themes in the statute's implementation. We analyzed the interview transcripts using standard qualitative techniques. FINDINGS: Since 1980, the NIH has fully reviewed only 5 petitions to invoke governmental march-in rights for 4 health-related technologies or medical products developed from federally funded research. Three of these requests related to reducing the high prices of brand-name drugs, one related to relieving a drug shortage, and one related to a potentially patent infringing medical device. In each of these cases, the NIH rejected the requests. Interviewees were split on the implications of these experiences, finding the NIH's reluctance to implement its march-in rights to be evidence of either a system working as intended or of a flawed system needing reform. CONCLUSIONS: The Bayh-Dole Act's march-in rights continue to be invoked by policymakers and health advocates, most recently in the context of new,high-cost products originally discovered with federally funded research. We found that the existence of march in rights may select for government research licensees more likely to commercialize the results and that they can be used to extract minor concessions from licensees. But as currently specified in the statute, such march-in rights are unlikely to serve as a counterweight to lower the prices of medical products arising from federally funded research. PMID- 26626986 TI - Composite Measures of Health Care Provider Performance: A Description of Approaches. AB - CONTEXT: Since the Institute of Medicine's 2001 report Crossing the Quality Chasm, there has been a rapid proliferation of quality measures used in quality monitoring, provider-profiling, and pay-for-performance (P4P) programs. Al-though individual performance measures are useful for identifying specific processes and outcomes for improvement and tracking progress, they do not easily provide an accessible overview of performance. Composite measures aggregate individual performance measures into a summary score. By reducing the amount of data that must be processed, they facilitate (1) benchmarking of an organization's performance, encouraging quality improvement initiatives to match performance against high-performing organizations, and (2) profiling and P4P programs based on an organization's overall performance. METHODS: We describe different approaches to creating composite measures,discuss their advantages and disadvantages, and provide examples of their use. FINDINGS: The major issues in creating composite measures are (1) whether to aggregate measures at the patient level through all-or-none approaches or the facility level, using one of the several possible weighting schemes; (2) when combining measures on different scales, how to rescale measures (using z scores,range percentages, ranks, or 5 star categorizations); and (3) whether to use shrinkage estimators, which increase precision by smoothing rates from smaller facilities but also decrease transparency. CONCLUSIONS: Because provider rankings and rewards under P4P programs may be sensitive to both context and the data, careful analysis is warranted before deciding to implement a particular method. A better understanding of both when and where to use composite measures and the incentives created by composite measures are likely to be important areas of research as the use of composite measures grows. PMID- 26626987 TI - How Effective Are Incident-Reporting Systems for Improving Patient Safety? A Systematic Literature Review. AB - CONTEXT: Incident-reporting systems (IRSs) are used to gather information about patient safety incidents. Despite the financial burden they imply, however,little is known about their effectiveness. This article systematically reviews the effectiveness of IRSs as a method of improving patient safety through organizational learning. METHODS: Our systematic literature review identified 2 groups of studies: (1)those comparing the effectiveness of IRSs with other methods of error reporting and (2) those examining the effectiveness of IRSs on settings, structures, and outcomes in regard to improving patient safety. We used thematic analysis to compare the effectiveness of IRSs with other methods and to synthesize what was effective, where, and why. Then, to assess the evidence concerning the ability of IRSs to facilitate organizational learning, we analyzed studies using the concepts of single-loop and double-loop learning. FINDINGS: In total, we identified 43 studies, 8 that compared IRSs with other methods and 35 that explored the effectiveness of IRSs on settings, structures,and outcomes. We did not find strong evidence that IRSs performed better than other methods. We did find some evidence of single-loop learning, that is, changes to clinical settings or processes as a consequence of learning from IRSs, but little evidence of either improvements in outcomes or changes in the latent managerial factors involved in error production. In addition, there was insubstantial evidence of IRSs enabling double-loop learning, that is, a cultural change or a change in mind-set. CONCLUSIONS: The results indicate that IRSs could be more effective if the criteria for what counts as an incident were explicit, they were owned and ledby clinical teams rather than centralized hospital departments, and they were embedded within organizations as part of wider safety programs. PMID- 26626988 TI - David Sackett's Unintended Impacts on Health Policy. PMID- 26626991 TI - A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. AB - ACE910 is a recombinant humanized bispecific antibody that binds to activated factor IX and factor X and mimics the cofactor function of factor VIII (FVIII). This first-in-human study examined the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ACE910 in healthy male adults. A total of 40 Japanese and 24 white subjects were randomized to receive a single subcutaneous injection of ACE910 (Japanese: 0.001, 0.01, 0.1, 0.3, or 1 mg/kg; white: 0.1, 0.3, or 1 mg/kg; n = 6 per dose group) or placebo (n = 2 per dose group). ACE910 exhibited a linear PK profile and had a half-life of ~4 to 5 weeks. In FVIII neutralized plasma, ACE910 shortened activated partial thromboplastin time and increased peak height of thrombin generation in a dose-dependent manner. All adverse events were nonserious and did not lead to any subject's withdrawal. Neither clinical findings nor laboratory abnormalities indicating hypercoagulability were observed. Two of 48 subjects receiving ACE910 (1 Japanese and 1 white) were positive for anti-ACE910 antibodies (anti-drug antibodies [ADAs]). One subject tested positive for ADAs both before and after ACE910 administration, whereas the other became ADA positive after receiving ACE910. The PK and PD profiles of ACE910 were similar in healthy Japanese and white subjects and suggest that ACE910 will be an effective and convenient prophylactic treatment of hemophilia A. This trial was registered at www.clinicaltrials.jp as #JapicCTI-121934. PMID- 26626992 TI - Lin- CD34hi CD117int/hi FcepsilonRI+ cells in human blood constitute a rare population of mast cell progenitors. AB - Mast cells are rare tissue-resident immune cells that are involved in allergic reactions, and their numbers are increased in the lungs of asthmatics. Murine lung mast cells arise from committed bone marrow-derived progenitors that enter the blood circulation, migrate through the pulmonary endothelium, and mature in the tissue. In humans, mast cells can be cultured from multipotent CD34(+) progenitor cells. However, a population of distinct precursor cells that give rise to mast cells has remained undiscovered. To our knowledge, this is the first report of human lineage-negative (Lin(-)) CD34(hi) CD117(int/hi) FcepsilonRI(+) progenitor cells, which represented only 0.0053% of the isolated blood cells in healthy individuals. These cells expressed integrin beta7 and developed a mast cell-like phenotype, although with a slow cell division capacity in vitro. Isolated Lin(-) CD34(hi) CD117(int/hi) FcepsilonRI(+) blood cells had an immature mast cell-like appearance and expressed high levels of many mast cell-related genes as compared with human blood basophils in whole-transcriptome microarray analyses. Furthermore, serglycin, tryptase, and carboxypeptidase A messenger RNA transcripts were detected by quantitative reverse transcription-polymerase chain reaction. Altogether, we propose that the Lin(-) CD34(hi) CD117(int/hi) FcepsilonRI(+) blood cells are closely related to human tissue mast cells and likely constitute an immediate precursor population, which can give rise to predominantly mast cells. Furthermore, asthmatics with reduced lung function had a higher frequency of Lin(-) CD34(hi) CD117(int/hi) FcepsilonRI(+) blood mast cell progenitors than asthmatics with normal lung function. PMID- 26626994 TI - Natural heterogeneity of alpha2-antiplasmin: functional and clinical consequences. AB - Human alpha2-antiplasmin (alpha2AP, also called alpha2-plasmin inhibitor) is the main physiological inhibitor of the fibrinolytic enzyme plasmin. alpha2AP inhibits plasmin on the fibrin clot or in the circulation by forming plasmin antiplasmin complexes. Severely reduced alpha2AP levels in hereditary alpha2AP deficiency may lead to bleeding symptoms, whereas increased alpha2AP levels have been associated with increased thrombotic risk. alpha2AP is a very heterogeneous protein. In the circulation, alpha2AP undergoes both amino terminal (N-terminal) and carboxyl terminal (C-terminal) proteolytic modifications that significantly modify its activities. About 70% of alpha2AP is cleaved at the N terminus by antiplasmin-cleaving enzyme (or soluble fibroblast activation protein), resulting in a 12-amino-acid residue shorter form. The glutamine residue that serves as a substrate for activated factor XIII becomes more efficient after removal of the N terminus, leading to faster crosslinking of alpha2AP to fibrin and consequently prolonged clot lysis. In approximately 35% of circulating alpha2AP, the C terminus is absent. This C terminus contains the binding site for plasmin(ogen), the key component necessary for the rapid and efficient inhibitory mechanism of alpha2AP. Without its C terminus, alpha2AP can no longer bind to the lysine binding sites of plasmin(ogen) and is only a kinetically slow plasmin inhibitor. Thus, proteolytic modifications of the N and C termini of alpha2AP constitute major regulatory mechanisms for the inhibitory function of the protein and may therefore have clinical consequences. This review presents recent findings regarding the main aspects of the natural heterogeneity of alpha2AP with particular focus on the functional and possible clinical implications. PMID- 26626993 TI - Effect of lenalidomide treatment on clonal architecture of myelodysplastic syndromes without 5q deletion. AB - Non-del(5q) transfusion-dependent low/intermediate-1 myelodysplastic syndrome (MDS) patients achieve an erythroid response with lenalidomide in 25% of cases. Addition of an erythropoiesis-stimulating agent could improve response rate. The impact of recurrent somatic mutations identified in the diseased clone in response to lenalidomide and the drug's effects on clonal evolution remain unknown. We investigated recurrent mutations by next-generation sequencing in 94 non-del(5q) MDS patients randomized in the GFM-Len-Epo-08 clinical trial to lenalidomide or lenalidomide plus epoetin beta. Clonal evolution was analyzed after 4 cycles of treatment in 42 cases and reanalyzed at later time points in 18 cases. The fate of clonal architecture of single CD34(+)CD38(-) hematopoietic stem cells was also determined in 5 cases. Mutation frequency was >10%: SF3B1 (74.5%), TET2 (45.7%), DNMT3A (20.2%), and ASXL1 (19.1%). Analysis of variant allele frequencies indicated a decrease of major mutations in 15 of 20 responders compared with 10 of 22 nonresponders after 4 cycles. The decrease in the variant allele frequency of major mutations was more significant in responders than in nonresponders (P < .001). Genotyping of single CD34(+)CD38(-) cell-derived colonies showed that the decrease in the size of dominant subclones could be associated with the rise of founding clones or of hematopoietic stem cells devoid of recurrent mutations. These effects remained transient, and disease escape was associated with the re-emergence of the dominant subclones. In conclusion, we show that, although the drug initially modulates the distribution of subclones, loss of treatment efficacy coincides with the re-expansion of the dominant subclone. This trial was registered at www.clinicaltrials.gov as #NCT01718379. PMID- 26626995 TI - Transfusion of fresher vs older red blood cells in hospitalized patients: a systematic review and meta-analysis. AB - The impact of transfusing fresher vs older red blood cells (RBCs) on patient important outcomes remains controversial. Two recently published large trials have provided new evidence. We summarized results of randomized trials evaluating the impact of the age of transfused RBCs. We searched MEDLINE, EMBASE, CINAHL, the Cochrane Database for Systematic Reviews, and Cochrane CENTRAL for randomized controlled trials enrolling patients who were transfused fresher vs older RBCs and reported outcomes of death, adverse events, and infection. Independently and in duplicate, reviewers determined eligibility, risk of bias, and abstracted data. We conducted random effects meta-analyses and rated certainty (quality or confidence) of evidence using the GRADE approach. Of 12 trials that enrolled 5229 participants, 6 compared fresher RBCs with older RBCs and 6 compared fresher RBCs with current standard practice. There was little or no impact of fresher vs older RBCs on mortality (relative risk [RR], 1.04; 95% confidence interval [CI], 0.94 1.14; P = .45; I(2) = 0%, moderate certainty evidence) or on adverse events (RR, 1.02; 95% CI, 0.91-1.14; P = .74; I(2) = 0%, low certainty evidence). Fresher RBCs appeared to increase the risk of nosocomial infection (RR, 1.09; 95% CI, 1.00-1.18; P = .04; I(2) = 0%, risk difference 4.3%, low certainty evidence). Current evidence provides moderate certainty that use of fresher RBCs does not influence mortality, and low certainty that it does not influence adverse events but could possibly increase infection rates. The existing evidence provides no support for changing practices toward fresher RBC transfusion. PMID- 26626996 TI - Discovery of a Novel Inhibitor of the Protein Tyrosine Phosphatase Shp2. AB - Shp2 is a ubiquitously expressed protein tyrosine phosphatase (PTP) related to adult acute myelogenous leukemia and human solid tumors. In this report, we describe identification of a potent Shp2 inhibitor, Fumosorinone (Fumos) from entomogenous fungi, which shows selective inhibition of Shp2 over other tested PTPs. Using a surface plasmon resonance analysis, we further confirmed the physical interaction between Shp2 and Fumos. Fumos inhibits Shp2-dependent activation of the Ras/ERK signal pathway downstream of EGFR, and interrupts EGF induced Gab1-Shp2 association. As expected, Fumos shows little effects on the Shp2-independent ERK1/2 activation induced by PMA or oncogenic Ras. Furthermore, Fumos down-regulates Src activation, inhibits phosphorylation of Paxillin and prevents tumor cell invasion. These results suggest that Fumos can inhibit Shp2 dependent cell signaling in human cells and has a potential for treatment of Shp2 associated diseases. PMID- 26626997 TI - Neuroprotective effects of caffeine in MPTP model of Parkinson's disease: A (13)C NMR study. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of nigrostriatal dopaminergic neurons with an accompanying neuroinflammation leading to loss of dopamine in the basal ganglia. Caffeine, a well-known A2A receptor antagonist is reported to slow down the neuroinflammation caused by activated microglia and reduce the extracellular glutamate in the brain. In this study, we have evaluated the neuroprotective effect of caffeine in the MPTP model of PD by monitoring the region specific cerebral energy metabolism. Adult C57BL6 mice were treated with caffeine (30 mg/kg, i.p.) 30 min prior to MPTP (25 mg/kg, i.p.) administration for 8 days. The paw grip strength of mice was assessed in order to evaluate the motor function after various treatments. For metabolic studies, mice were infused with [1,6-(13)C2]glucose, and (13)C labeling of amino acids was monitored using ex vivo(1)H-[(13)C]-NMR spectroscopy. The paw grip strength was found to be reduced following the MPTP treatment. The caffeine pretreatment showed significant protection against the reduction of paw grip strength in MPTP treated mice. The levels of GABA and myo inositol were found to be elevated in the striatum of MPTP treated mice. The (13)C labeling of GluC4, GABAC2 and GlnC4 from [1,6-(13)C2]glucose was decreased in the cerebral cortex, striatum, olfactory bulb, thalamus and cerebellum suggesting impaired glutamatergic and GABAergic neuronal activity and neurotransmission of the MPTP treated mice. Most interestingly, the pretreatment of caffeine maintained the (13)C labeling of amino acids to the control values in cortical, olfactory bulb and cerebellum regions while it partially retained in striatal and thalamic regions in MPTP treated mice. The pretreatment of caffeine provides a partial neuro-protection against severe striatal degeneration in the MPTP model of PD. PMID- 26626998 TI - Reversible Micro- and Nano- Phase Programming of Anthraquinone Thermochromism Using Blended Block Copolymers. AB - Here, we present an approach to generate materials with programmable thermochromic transition temperatures (TTTs), based on the reversible microcrystallization of anthraquinone dyes with the assistance of blended Pluronic block copolymers. At temperatures above block copolymer critical micellization temperature (CMT), hydrophobic anthraquinone dyes, including Sudan blue II, were dispersed in copolymer micelles, whereas at lower temperature, the dyes formed microcrystals driven by dye-dye and dye-Pluronic molecular interactions. The crystallization process altered the optical properties of the dye with bathochromatic shifts detectable by eye and the thermochromic process was fully reversible. Not only could Pluronic reversibly incorporate the anthraquinone dyes into micelles at elevated temperatures, but it also modulated the crystallization process and resulting morphology of microcrystals via tuning the molecular interactions when the temperature was lowered. Crystal melting transition points (and TTTs) were in agreement with the CMTs, demonstrating that the thermochromism was dependent on block copolymer micellization. Thermochromism could be readily programmed over a broad range of temperatures by changing the CMT by using different types and concentrations of Pluronics and combinations thereof. PMID- 26626999 TI - Advanced prostate cancer presented with hemolytic uremic syndrome. PMID- 26627001 TI - Corrigendum. AB - Pages H1237-H1250: Leone M, Magadum A, Engel FB. Cardiomyocyte proliferation in cardiac development and regeneration: a guide to methodologies and interpretations. Am J Physiol Heart Circ Physiol 309: H1237-H1250, 2015. First published September 4, 2015; doi:10.1152/ajpheart.00559.2015 (http://ajpheart.physiology.org/content/309/8/H1237.long).-Under Newborn mouse heart regeneration, the value for the increase in cell number upon Meis1 deletion is corrected as shown in boldface as follows: In fact, the cell number data indicate that Meis1 deletion induced the production of 0.2 million cardiomyocytes in less than 5 wk by an H3P as well as Aurora B fold increase of less than fourfold. PMID- 26627000 TI - Age correlates with hypotension during propofol-based anesthesia for endoscopic retrograde cholangiopancreatography. AB - OBJECTIVE: Endoscopic retrograde cholangiopancreatography (ERCP) is a procedure used for diagnostic and therapeutic purposes. Most of the patients may feel pain, anxiety, and discomfort during this procedure, so conscious sedation is usually used during ERCP. General anesthesia would be considered if conscious sedation fails to achieve the requirement of the endoscopists. Several studies showed that propofol-based sedation could provide a better recovery profile. However, propofol has a narrow therapeutic window and complications may occur beyond this window. The present study aimed to find out the complications and the associated risk factors during ERCP procedure under propofol-based deep sedation. METHODS: We retrospectively reviewed data from anesthetic and procedure records of the patients who underwent ERCP under propofol-based deep sedation from January 2006 to July 2010 at Far Eastern Memorial Hospital, Taipei, Taiwan. All propofol-based deep sedations were conducted by anesthesiologists. The incidence of complications was determined and the independent risk factors identified by the multivariable logistic regression model. RESULT: Propofol-based deep sedation was provided for 552 patients who received ERCP procedure. The majority of the patients were male, the mean age was 60 +/- 16 years and American Society of Anesthesiologists physical status II-III. Almost 30% of patients experienced hypotension during the procedure, although no mortality or morbidity was associated with this complication. Sex, age, anesthetic time, American Society of Anesthesiologists status, hypertension, and arrhythmia were significantly different (p < 0.05) between patients with hypotension and without hypotension during the procedure. Multivariable logistic regression identified sex and age to be the independent predictors of hypotension. CONCLUSION: Hypotension was the most frequent anesthetic complication during procedure under propofol-based deep sedation, but this method was safe and effective under appropriate monitoring. Age is the strongest predictor of hypotension and therefore propofol-based deep sedation should be conducted with caution in the elderly. PMID- 26627002 TI - Developing a performance framework for measuring comprehensive, community-based primary healthcare for people with HIV. AB - OBJECTIVES: People with human immunodeficiency virus (HIV) are living longer lives and like many other patients, need a health system better adapted for the management of complex chronic conditions. A key element of system transformation is measuring and reporting on system performance indicators relevant to the different stakeholders. Our objective was to produce a performance measurement framework for assessing the quality of comprehensive community-based primary healthcare for people with HIV. METHODS: Semi-structured interviews were performed with HIV providers, advocates, and policy-makers to obtain input on a draft performance framework, constructed using existing HIV-specific indicators, as well as the use of performance data in improving care for people with HIV. RESULTS: Stakeholders were overwhelmingly supportive of the framework's comprehensiveness. Many noted the absence of indicators addressing social determinants of health and had mixed opinions on the importance of indicators addressing access to after-hours care and the frequency of routine screening for behavioural risk factors. The draft framework was modified to reflect stakeholder input, triangulated against expert opinion and recently released HIV care guidelines, and finalized at 79 indicators. The resources and infrastructure to collect and use performance data will have to be improved for performance measurement to contribute to improving care for people with HIV. CONCLUSIONS: This framework presents a comprehensive though not exhaustive tool to support performance measurement and improvement in the care for people with HIV. However, advances in data collection and use across the system will be needed to support performance measurement driving quality improvement. PMID- 26627003 TI - Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium. AB - Uranium has radiological and non-radiological effects within biological systems and there is increasing evidence for genotoxic and carcinogenic properties attributable to uranium through its heavy metal properties. In this study, we report that low concentrations of uranium (as uranyl acetate; <10 MUM) is not cytotoxic to human embryonic kidney cells or normal human keratinocytes; however, uranium exacerbates DNA damage and cytotoxicity induced by hydrogen peroxide, suggesting that uranium may inhibit DNA repair processes. Concentrations of uranyl acetate in the low micromolar range inhibited the zinc finger DNA repair protein poly(ADP-ribose) polymerase (PARP)-1 and caused zinc loss from PARP-1 protein. Uranyl acetate exposure also led to zinc loss from the zinc finger DNA repair proteins Xeroderma Pigmentosum, Complementation Group A (XPA) and aprataxin (APTX). In keeping with the observed inhibition of zinc finger function of DNA repair proteins, exposure to uranyl acetate enhanced retention of induced DNA damage. Co-incubation of uranyl acetate with zinc largely overcame the impact of uranium on PARP-1 activity and DNA damage. These findings present evidence that low concentrations of uranium can inhibit DNA repair through disruption of zinc finger domains of specific target DNA repair proteins. This may provide a mechanistic basis to account for the published observations that uranium exposure is associated with DNA repair deficiency in exposed human populations. PMID- 26627004 TI - Evaluation of microRNAs-208 and 133a/b as differential biomarkers of acute cardiac and skeletal muscle toxicity in rats. AB - Conventional circulating biomarkers of cardiac and skeletal muscle (SKM) toxicity lack specificity and/or have a short half-life. MicroRNAs (miRNAs) are currently being assessed as biomarkers of tissue injury based on their long half-life in blood and selective expression in certain tissues. To assess the utility of miRNAs as biomarkers of cardiac and SKM injury, male Sprague-Dawley rats received a single dose of isoproterenol (ISO); metaproterenol (MET); allylamine (AAM); mitoxantrone (MIT); acetaminophen (APAP) or vehicle. Blood and tissues were collected from rats in each group at 4, 24 and 48h. ISO, MET, and AAM induced cardiac and SKM lesions and APAP induced liver specific lesions. There was no evidence of tissue injury with MIT by histopathology. Serum levels of candidate miRNAs were compared to conventional serum biomarkers of SKM/cardiac toxicity. Increases in heart specific miR-208 only occurred in rats with cardiac lesions alone and were increased for a longer duration than cardiac troponin and FABP3 (cardiac biomarkers). ISO, MET and AAM induced increases in MyL3 and skeletal muscle troponin (sTnl) (SKM biomarkers). MIT induced large increases in sTnl indicative of SKM toxicity, but sTnl levels were also increased in APAP-treated rats that lacked SKM toxicity. Serum levels of miR-133a/b (enriched in cardiac and SKM) increased following ISO, MET, AAM and MIT treatments but were absent in APAP-treated rats. Our results suggest that miR-133a/b are sensitive and specific markers of SKM and cardiac toxicity and that miR-208 used in combination with miR 133a/b can be used to differentiate cardiac from SKM toxicity. PMID- 26627005 TI - PC-TraFF: identification of potentially collaborating transcription factors using pointwise mutual information. AB - BACKGROUND: Transcription factors (TFs) are important regulatory proteins that govern transcriptional regulation. Today, it is known that in higher organisms different TFs have to cooperate rather than acting individually in order to control complex genetic programs. The identification of these interactions is an important challenge for understanding the molecular mechanisms of regulating biological processes. In this study, we present a new method based on pointwise mutual information, PC-TraFF, which considers the genome as a document, the sequences as sentences, and TF binding sites (TFBSs) as words to identify interacting TFs in a set of sequences. RESULTS: To demonstrate the effectiveness of PC-TraFF, we performed a genome-wide analysis and a breast cancer-associated sequence set analysis for protein coding and miRNA genes. Our results show that in any of these sequence sets, PC-TraFF is able to identify important interacting TF pairs, for most of which we found support by previously published experimental results. Further, we made a pairwise comparison between PC-TraFF and three conventional methods. The outcome of this comparison study strongly suggests that all these methods focus on different important aspects of interaction between TFs and thus the pairwise overlap between any of them is only marginal. CONCLUSIONS: In this study, adopting the idea from the field of linguistics in the field of bioinformatics, we develop a new information theoretic method, PC-TraFF, for the identification of potentially collaborating transcription factors based on the idiosyncrasy of their binding site distributions on the genome. The results of our study show that PC-TraFF can succesfully identify known interacting TF pairs and thus its currently biologically uncorfirmed predictions could provide new hypotheses for further experimental validation. Additionally, the comparison of the results of PC-TraFF with the results of previous methods demonstrates that different methods with their specific scopes can perfectly supplement each other. Overall, our analyses indicate that PC-TraFF is a time-efficient method where its algorithm has a tractable computational time and memory consumption. The PC-TraFF server is freely accessible at http://pctraff.bioinf.med.uni-goettingen.de/. PMID- 26627006 TI - IL15 and T-cell Stemness in T-cell-Based Cancer Immunotherapy. AB - Preclinical models revealed that the immune system can mediate rejection of established tumors, but direct evidence in humans has been limited to largely immunogenic tumors, such as melanoma. The recent success of immune checkpoint inhibitors and adoptive T-cell transfer immunotherapy in clinical trials has instilled new hope for the use of T-cell immunotherapy in the treatment of cancer. IL15, a potent immunostimulatory cytokine, both potentiates host T-cells and natural killer (NK) cell immune responses and promotes the generation of long lived memory T cells with superior functional capacity, with potential use in adoptive T-cell transfer protocols. IL15 has been recently tested in the clinic and showed dramatic effects at the level of responding NK and CD8(+) memory T cells. The recent advances in the knowledge of IL15-dependent regulation of T cell responses, gene expression, and metabolic adaptation have important implications for the use of IL15 in T-cell-based immunotherapy of cancer. PMID- 26627007 TI - Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations. AB - Large-scale sequencing efforts are uncovering the complexity of cancer genomes, which are composed of causal "driver" mutations that promote tumor progression along with many more pathologically neutral "passenger" events. The majority of mutations, both in known cancer drivers and uncharacterized genes, are generally of low occurrence, highlighting the need to functionally annotate the long tail of infrequent mutations present in heterogeneous cancers. Here we describe a mutation assessment pipeline enabled by high-throughput engineering of molecularly barcoded gene variant expression clones identified by tumor sequencing. We first used this platform to functionally assess tail mutations observed in PIK3CA, which encodes the catalytic subunit alpha of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) frequently mutated in cancer. Orthogonal screening for PIK3CA variant activity using in vitro and in vivo cell growth and transformation assays differentiated driver from passenger mutations, revealing that PIK3CA variant activity correlates imperfectly with its mutation frequency across breast cancer populations. Although PIK3CA mutations with frequencies above 5% were significantly more oncogenic than wild-type in all assays, mutations occurring at 0.07% to 5.0% included those with and without oncogenic activities that ranged from weak to strong in at least one assay. Proteomic profiling coupled with therapeutic sensitivity assays on PIK3CA variant expressing cell models revealed variant-specific activation of PI3K signaling as well as other pathways that include the MEK1/2 module of mitogen-activated protein kinase pathway. Our data indicate that cancer treatments will need to increasingly consider the functional relevance of specific mutations in driver genes rather than considering all mutations in drivers as equivalent. PMID- 26627008 TI - Penfluridol: An Antipsychotic Agent Suppresses Metastatic Tumor Growth in Triple Negative Breast Cancer by Inhibiting Integrin Signaling Axis. AB - Metastasis of breast cancer, especially to the brain, is the major cause of mortality. The inability of anticancer agents to cross the blood-brain-barrier represents a critical challenge for successful treatment. In the current study, we investigated the antimetastatic potential of penfluridol, an antipsychotic drug frequently prescribed for schizophrenia with anticancer activity. We show that penfluridol induced apoptosis and reduced the survival of several metastatic triple-negative breast cancer (TNBC) cell lines. In addition, penfluridol treatment significantly reduced the expression of integrin alpha6, integrin beta4, Fak, paxillin, Rac1/2/3, and ROCK1 in vitro. We further evaluated the efficacy of penfluridol in three different in vivo tumor models. We demonstrate that penfluridol administration to an orthotopic model of breast cancer suppressed tumor growth by 49%. On the other hand, penfluridol treatment inhibited the growth of metastatic brain tumors introduced by intracardiac or intracranial injection of breast cancer cells by 90% and 72%, respectively. Penfluridol-treated tumors from all three models exhibited reduced integrin beta4 and increased apoptosis. Moreover, chronic administration of penfluridol failed to elicit significant toxic or behavioral side effects in mice. Taken together, our results indicate that penfluridol effectively reduces the growth of primary TNBC tumors and especially metastatic growth in the brain by inhibiting integrin signaling, and prompt further preclinical investigation into repurposing penfluridol for the treatment of metastatic TNBC. PMID- 26627009 TI - Preclinical Models Provide Scientific Justification and Translational Relevance for Moving Novel Therapeutics into Clinical Trials for Pediatric Cancer. AB - Despite improvements in survival rates for children with cancer since the 1960s, progress for many pediatric malignancies has slowed over the past two decades. With the recent advances in our understanding of the genomic landscape of pediatric cancer, there is now enthusiasm for individualized cancer therapy based on genomic profiling of patients' tumors. However, several obstacles to effective personalized cancer therapy remain. For example, relatively little data from prospective clinical trials demonstrate the selective efficacy of molecular targeted therapeutics based on somatic mutations in the patient's tumor. In this commentary, we discuss recent advances in preclinical testing for pediatric cancer and provide recommendations for providing scientific justification and translational relevance for novel therapeutic combinations for childhood cancer. Establishing rigorous criteria for defining and validating druggable mutations will be essential for the success of ongoing and future clinical genomic trials for pediatric malignancies. PMID- 26627010 TI - Essential Components of Cancer Education. AB - Modern cancer therapy/care involves the integration of basic, clinical, and population-based research professionals using state-of-the-art science to achieve the best possible patient outcomes. A well-integrated team of basic, clinical, and population science professionals and educators working with a fully engaged group of creative junior investigators and trainees provides a structure to achieve these common goals. To this end, the structure provided by cancer-focused educational programs can create the integrated culture of academic medicine needed to reduce the burden of cancer on society. This summary outlines fundamental principles and potential best practice strategies for the development of integrated educational programs directed at achieving a work force of professionals that broadly appreciate the principals of academic medicine spanning the breadth of knowledge necessary to advance the goal of improving the current practice of cancer care medicine. PMID- 26627011 TI - Dependence Receptors and Cancer: Addiction to Trophic Ligands. AB - Data accumulating over the last 20 years support the notion that some transmembrane receptors are activated not only by their respective ligands but also, differentially, by the withdrawal or absence of these same ligands. In this latter setting, these receptors actively trigger apoptosis. They have been dubbed dependence receptors because their expression confers a state of ligand dependence for survival on the expressing cells. Twenty of these receptors have been identified to date, and several have been shown to inhibit tumor progression by inducing apoptosis. As a corollary, these receptors, or their transduced death signals, are frequently silenced in cancer cells as a selective mechanism to prevent cell death, allowing invasion and metastasis. Drugs aimed at inducing programmed cell death in neoplastic cells by re-engaging the proapoptotic activity induced by unliganded dependence receptors are in late-stage preclinical tests, poised for clinical evaluation. This approach may offer novel opportunities for patient treatments. In this review, we discuss the implications of dependence receptors in limiting cancer progression and address the therapeutic perspectives brought to light by this paradigm. PMID- 26627012 TI - Melphalan, Antimelanoma Immunity, and Inflammation--Letter. PMID- 26627014 TI - Melphalan, Antimelanoma Immunity, and Inflammation--Response. PMID- 26627013 TI - The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia. AB - Translocations of the mixed lineage leukemia (MLL) gene occur in 60% to 80% of all infant acute leukemias and are markers of poor prognosis. MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regulatory proteins, including histone deacetylases (HDAC), histone methyltransferases, bromodomain-containing proteins, and transcription elongation factors to mediate chromatin remodeling and regulate tumorigenic gene expression programs. We conducted a small-molecule inhibitor screen to test the ability of candidate pharmacologic agents targeting epigenetic and transcriptional regulatory proteins to induce apoptosis in leukemic cells derived from genetically engineered mouse models of MLL-AF9-driven acute myeloid leukemia (AML). We found that the CDK inhibitor dinaciclib and HDAC inhibitor panobinostat were the most potent inducers of apoptosis in short-term in vitro assays. Treatment of MLL-rearranged leukemic cells with dinaciclib resulted in rapidly decreased expression of the prosurvival protein Mcl-1, and accordingly, overexpression of Mcl-1 protected AML cells from dinaciclib-induced apoptosis. Administration of dinaciclib to mice bearing MLL-AF9-driven human and mouse leukemias elicited potent antitumor responses and significantly prolonged survival. Collectively, these studies highlight a new therapeutic approach to potentially overcome the resistance of MLL-rearranged AML to conventional chemotherapies and prompt further clinical evaluation of CDK inhibitors in AML patients harboring MLL fusion proteins. PMID- 26627015 TI - UV-Associated Mutations Underlie the Etiology of MCV-Negative Merkel Cell Carcinomas. AB - Merkel cell carcinoma (MCC) is an uncommon, but highly malignant, cutaneous tumor. Merkel cell polyoma virus (MCV) has been implicated in a majority of MCC tumors; however, viral-negative tumors have been reported to be more prevalent in some geographic regions subject to high sun exposure. While the impact of MCV and viral T-antigens on MCC development has been extensively investigated, little is known about the etiology of viral-negative tumors. We performed targeted capture and massively parallel DNA sequencing of 619 cancer genes to compare the gene mutations and copy number alterations in MCV-positive (n = 13) and -negative (n = 21) MCC tumors and cell lines. We found that MCV-positive tumors displayed very low mutation rates, but MCV-negative tumors exhibited a high mutation burden associated with a UV-induced DNA damage signature. All viral-negative tumors harbored mutations in RB1, TP53, and a high frequency of mutations in NOTCH1 and FAT1. Additional mutated or amplified cancer genes of potential clinical importance included PI3K (PIK3CA, AKT1, PIK3CG) and MAPK (HRAS, NF1) pathway members and the receptor tyrosine kinase FGFR2. Furthermore, looking ahead to potential therapeutic strategies encompassing immune checkpoint inhibitors such as anti-PD-L1, we also assessed the status of T-cell-infiltrating lymphocytes (TIL) and PD-L1 in MCC tumors. A subset of viral-negative tumors exhibited high TILs and PD-L1 expression, corresponding with the higher mutation load within these cancers. Taken together, this study provides new insights into the underlying biology of viral-negative MCC and paves the road for further investigation into new treatment opportunities. PMID- 26627016 TI - Evaluation of serum NGAL and hepcidin levels in chronic kidney disease patients. AB - Cardiovascular disease is the major cause of death in chronic kidney disease (CKD) patients. The main underlying reason is inflammation. In CKD, interleukin-6 and hypersensitive C-reactive protein are known to be used for the evaluation of inflammation and serum levels increase with decreased creatinine clearance. Neutrophil gelatinase-associated lipocalin (NGAL) and hepcidin are also considered to be effective in the assessment of inflammatory conditions. The possible interactions of NGAL and hepcidin with inflammatory markers in CKD patients including the kidney transplants, which have not been thoroughly explained up to date wereevaluated in this study. Serum creatinine, iron, unsaturated iron binding capacity, interleukin-6, hypersensitive C-reactive protein, NGAL, hepcidin and pro-hepcidin levels were measured in a cohort of 163 CKD patients including transplant patients and 82 healthy volunteers. Clinical evaluation and classification of the patients were done according to the NFK/KDOQI guideline. Serum hepcidin, Prohepcidin, NGAL, hypersensitive C-reactive protein and interleukin-6 levels were higher in patient groups compared to the control group. In patient groups, while hepcidin, NGAL, interleukin-6, hypersensitive C-reactive protein levels were correlated with creatinine and glomerular filtration rate, iron metabolism parameters were not correlated with the inflammation biomarkers. Inflammation related hepcidin and NGAL weakly correlated with creatinine clearance. Our results demonstrated that serum NGAL and hepcidin levels might be valuable for the evaluation of inflammation in CKD, and these new inflammation parameters are not related through iron metabolism. PMID- 26627017 TI - Quality Assurance for Biomolecular Simulations. AB - Contemporary structural biology has an increased emphasis on high-throughput methods. Biomolecular simulations can add value to structural biology via the provision of dynamic information. However, at present there are no agreed measures for the quality of biomolecular simulation data. In this Letter, we suggest suitable measures for the quality assurance of molecular dynamics simulations of biomolecules. These measures are designed to be simple, fast, and general. Reporting of these measures in simulation papers should become an expected practice, analogous to the reporting of comparable quality measures in protein crystallography. We wish to solicit views and suggestions from the simulation community on methods to obtain reliability measures from molecular dynamics trajectories. In a database which provides access to previously obtained simulations [Formula: see text] for example BioSimGrid ( http://www.biosimgrid.org/ ) [Formula: see text] the user needs to be confident that the simulation trajectory is suitable for further investigation. This can be provided by the simulation quality measures which a user would examine prior to more extensive analyses. PMID- 26627018 TI - Feynman-Kleinert Linearized Path Integral (FK-LPI) Algorithms for Quantum Molecular Dynamics, with Application to Water and He(4). AB - The Feynman-Kleinert Linearized Path Integral (FK-LPI) representation of quantum correlation functions is extended in applications and algorithms. Diffusion including quantum effects for a flexible simple point charge model of liquid water is explored, including new tests of internal consistency. An ab initio quantum correction factor (QCF) is also obtained to correct the far-infrared spectrum of water. After correction, a spectrum based on a classical simulation is in good agreement with the experiment. The FK-LPI QCF is shown to be superior to the so-called harmonic QCF. New computational algorithms are introduced so that the quantum Boltzmann Wigner phase-space density, the central object in the implementation, can be obtained for arbitrary potentials. One scheme requires only that the standard classical force routine be replaced when turning from one molecular problem to another. The new algorithms are applied to the calculation of the Van Hove spectrum of liquid He(4) at 27 K. The spectrum moments are in very good agreement with the experiment. These observations indicate that the FK LPI approach can be broadly effective for molecular problems involving the dynamics of light nuclei. PMID- 26627019 TI - On the Competition between Predissociation and Direct Dissociation in Deuterium Chloride Ions (DCl(+)). AB - The competition between direct dissociation and predissociation in DCl(+) ions prepared in the A(2)Sigma(+) state has been investigated numerically by solving the time dependent Schrodinger equation. This work concentrates on the rovibronic states (vA;NA) with vA = 8 and NA = 60-65, which are close to the top of a centrifugal barrier. We find that the relative yield of D(+) (by direct dissociation) and Cl(+) (by predissociation) strongly depends on the excitation frequency, intensity, and duration. Investigation of the time dependence of the product yields provides evidence for significant multichannel interactions. PMID- 26627020 TI - Halide, Ammonium, and Alkali Metal Ion Parameters for Modeling Aqueous Solutions. AB - A complete set of Lennard Jones parameters for the halide ions, F(-), Cl(-), Br( ), and I(-), ammonium ion, and the alkali metal ions is reported. The parameters have been optimized using Monte Carlo simulations and free energy perturbation theory with the TIP4P water model to reproduce experimental free energies of hydration and locations of the first maxima of the ion-oxygen radial distribution functions, to provide water coordination numbers consistent with experimental ranges, and to exhibit gas-phase monohydrate energies in reasonable agreement with ab initio values. Average errors for absolute and relative free energies of hydration for the ions are ca. 1 kcal/mol. For the halides, this is the first self-consistent set of parameters that has been optimized for aqueous-phase performance. The good results for relative free energies of hydration are particularly auspicious for use of the new parameters in a wide variety of liquid phase simulations where halide and alkali cations are systematically varied. PMID- 26627021 TI - Performance of the Effective Core Potentials of Ca, Hg, and Pb in Complexes with Ligands Containing N and O Donor Atoms. AB - This paper presents a systematic study of the performance of the relativistic effective core potentials (RECPs) proposed by Dolg-Stoll-Preuss, Christiansen Ermler, and Hay-Wadt for Ca(2+), Hg(2+), and Pb(2+). The RECPs performance is studied when these cations are combined with ethyleneglycol, 2-aminoethanol, and ethylenediamine to form bidentate complexes. First, the description of the bidentate ligands is analyzed with the Kohn-Sham method by using SVWN, BLYP, and B3LYP exchange-correlation functionals, and they are compared with the Moller Plesset perturbation theory (MP2); for all these methods the TZVP basis set was used. We found that the BLYP exchange-correlation functional gives similar results like those obtained by the B3LYP and MP2 methods. Thus, the bidentate metal complexes were studied with the BLYP method combined with the RECPs. To compare RECPs performance, all the systems considered in this work were studied with the relativistic all-electron Douglas-Kroll (DK3) method. We observed that the Christiansen-Ermler and Dolg-Stoll-Preuss RECPs give the best energetic and geometrical description for Ca and Hg complexes when compared with the all electron method. For Pb complexes the spin-orbit effect and the basis set superposition error must be taken into account in the RECP calculations. In general, the trend showed in the complexation energies with the all-electron method is followed by the complexation energies computed with all the pseudopotentials tested in this work. PMID- 26627022 TI - Macroscopic pKa Calculations for Fluorescein and Its Derivatives. AB - This study describes the calculation of the microscopic dissociation and tautomerization constants of fluorescein and its derivatives, 2',7' dichlorofluorescein (DCF) and 2',7'-difluorofluorescein (DFF), in an aqueous environment. In vacuo free energies were obtained using complete basis set (CBS) and DFT-based methods, while free energies of solvation were calculated with the CPCM implicit solvation protocol using the UAHF, UAKS, and Pauling radii sets. Our results indicate that the different vacuum protocols give free energy changes upon dissociation within 1 kcal/mol of each other for a given molecule. Therefore, we suggest that the computationally less intensive PBE1PBE/6 311+G(2d,2p)//PBE1PBE/6-31+G(d) model chemistry may reasonably be used in pKa calculations of larger molecules. The calculations also provided a rigorous test of the implicit solvation models. Relative calculations of dissociation constants gave results in good agreement with experiment; absolute values deviated from experimental data by 1-3 pKa units. Consistently better results were obtained with the Pauling radii set. The influence of geometry relaxation on going from vacuum to solvent is negligible for pKa2 and larger for pKa1 but still smaller than the variation due to the radii set. Calculation of tautomerization constants gave more variable results, with none of the solvation methods able to reproduce experimental values consistently, although certain individual constants were correctly calculated. PMID- 26627023 TI - 2-Phenylpyridine: To Twist or Not To Twist? AB - Density functional theory methods were used to investigate the structures associated with 2-phenylpyridine, ppy, and several of its electronic states. The structure of ppy has the aromatic rings twisted with respect to one another by ~21 degrees , which is about half the value found for biphenyl. In comparison with ppy, both the isoelectronic cation, ppyH(+), and anion, ppy(-), have larger twist angles. The extent of twisting is governed by the delicate balance between pi conjugation and repulsive orbital/steric interactions, and the magnitudes of these interactions were investigated by examining the torsional energy barriers for all three molecular species. In contrast, every one of the investigated open shell structures [Formula: see text] ppy(*)(+), ppy(*)(-), ppy*, ppyH(+)*, and ppy(-)* [Formula: see text] has coplanar aromatic rings, that is, no twist angle. Frontier molecular orbital analyses reveal that the pi-type bonding between the bridging carbons becomes dominant over any repulsive orbital and steric interactions, thereby leading to coplanar rings. Also, the energetics associated with ppy and its various electronic states were investigated and reported. PMID- 26627024 TI - Nonlinearity of the Bifunctional of the Nonadditive Kinetic Energy: Numerical Consequences in Orbital-Free Embedding Calculations. AB - The bifunctional of the nonadditive kinetic energy in the reference system of noninteracting electrons ([Formula: see text] [rhoA, rhoB] = Ts[rhoA + rhoB] - Ts[rhoA] - Ts[rhoB]) is the key quantity in orbital-free embedding calculations because they hinge on approximations to[Formula: see text] [rhoA,rhoB]. Since[Formula: see text] [rhoA,rhoB] is not linear in rhoA, the associated potential (functional derivative)[Formula: see text] [rho,rhoB]/deltarho|rho=rhoA(r?) changes if rhoA varies. In this work, for two approximations to[Formula: see text] [rhoA,rhoB], which are nonlinear in rhoA (gradient-free and gradient-dependent), their linearized versions are constructed, and the resulting changes (linearization errors) in various properties of embedded systems (orbital energies, dipole moments, interaction energies, and electron densities) are analyzed. The considered model embedded systems represent typical nonbonding interactions: van der Waals contacts, hydrogen bonds, complexes involving charged species, and intermolecular complexes of the charge-transfer character. For van der Waals and hydrogen bonded complexes, the linearization of[Formula: see text] [rhoA,rhoB] affects negligibly the calculated properties. Even for complexes, for which large complexation induced changes of the electron density can be expected, such as the water molecule in the field of a cation, the linearization errors are about 2 orders of magnitude smaller than the interaction induced shifts of the corresponding properties. Linearization of[Formula: see text] [rhoA,rhoB] is shown to be inadequate for the complexes of a strong charge-transfer character. Compared to gradient-free approximation to[Formula: see text] [rhoA,rhoB], introduction of gradients increases the linearization error. PMID- 26627025 TI - Elimination of Translational and Rotational Motions in Nuclear Orbital Plus Molecular Orbital Theory: Contribution of the First-Order Rovibration Coupling. AB - The translation- and rotation-free nuclear orbital plus molecular orbital (TRF NOMO) theory was developed to determine nonadiabatic nuclear and electronic wave functions. This study implemented a computational program for the TRF-NOMO method including first-order rotational terms, which corresponds to rovibronic coupling. Numerical assessments of first-order TRF-NOMO Hartree-Fock as well as second order Moller-Plesset perturbation methods were carried out for several small molecules. The first-order contributions give small corrections in energy. Thus, we confirm that the approximate zeroth-order treatment is sufficient for eliminating the rotational contamination. PMID- 26627026 TI - A Barrier-Free Atomic Radical-Molecule Reaction: F + Propene. AB - The possible reaction mechanism of atomic radical F with propene is investigated theoretically by a detailed potential energy surface (PES) calculation at the UMP2/6-311++G(d,p) and CCSD(T)/cc-pVTZ (single-point) levels using ab initio quantum chemistry methods and transition-state theory. Various possible reaction paths including addition-isomerization-elimination reactions and direct H-atom abstraction reactions are considered. Among them, the most feasible pathway should be the atomic radical F ((2)F) attacking on the C [Formula: see text] C double bond in propene (CH3CH [Formula: see text] CH2) to form a weakly bound complex I1 with no barrier, followed by atomic radical F addition to the C [Formula: see text] C double bond to form the low-lying intermediate isomer 3 barrierlessly. Starting from intermediate isomer 3, the most competitive reaction pathway is the dissociation of the C2-C3 single bond via transition state TS3-P5, leading to the product P5, CH3 + CHF [Formula: see text] CH2. However, in the direct H-atom abstraction reactions, the atomic radical F picking up the b allylic hydrogen of propene barrierlessly is the most feasible pathway from thermodynamic consideration. The other reaction pathways on the doublet PES are less competitive because of thermodynamical or kinetic factors. No addition elimination mechanism exists on the potential energy surface. Because the intermediates and transition states involved in the major pathways are all lower than the reactants in energy, the title reaction is expected to be rapid. Furthermore, on the basis of the analysis of the kinetics of all channels through which the addition and abstraction reactions proceed, we expect that the competitive power of reaction channels may vary with experimental conditions for the title reaction. The present study may be helpful for probing the mechanisms of the title reaction and understanding the halogen chemistry. PMID- 26627027 TI - Analysis of the Primary Photocycle Reactions Occurring in the Light, Oxygen, and Voltage Blue-Light Receptor by Multiconfigurational Quantum-Chemical Methods. AB - The photocycle reactions occurring between the flavin mononucleotide cofactor and the reactive cysteine residue in the blue-light photoreceptor domain light, oxygen, and voltage (LOV) were modeled for a system consisting of lumiflavin and thiomethanol. The electronic structure and energies of the reactive species were estimated using the CASSCF and MCQDPT2 quantum-chemical methods. The reaction pathway for the S-C4a covalent adduct formation in the triplet state was determined. Concerted electron and proton transfer from the thiol to the flavin in the triplet electronic state results in a biradical complex that is, however, unstable because its structure corresponds to a triplet-singlet crossing. The covalent adduct dissociation in the ground electronic state is a reverse of the photoreaction proceeding via a single energy barrier for hydrogen transfer. Thus, both photo- and dark reactions were found to be single-step chemical transformations occurring without stable intermediates. The photoreaction yielding the S-C4a covalent adduct is an intrinsic property of the isoalloxazine thiol complex in the specific geometry arranged by the protein in LOV. The S-C4a covalent adduct between lumiflavin and thiomethanol is rather stable implying that in LOV its dissociation is facilitated by the protein. PMID- 26627028 TI - Allylic H-Abstraction Mechanism: The Potential Energy Surface of the Reaction of Propene with OH Radical. AB - The allylic H-atom abstraction reaction plays a more dominant role, especially at lower temperature, than addition reactions in the case of the CH2 [Formula: see text] CH-CH3 + *OH system. Different computational methods including ab initio as well as density functional methods have been used to examine allylic H abstraction. Both the energetically less favorable direct H-abstraction and the more favorable indirect H-abstractions have been investigated. Using first principles computations, for the indirect abstraction, a stable pi- or reactantlike as well as a late productlike complex were found on the potential energy surface. Based on higher level single point calculations (QCISD(T)/6 311+G(3df,2p)), a new activation enthalpy value, Delta(?)H degrees = 0.3 +/- 2 kJ/mol, is suggested for the title reaction. The computed reaction enthalpy DeltarH degrees = -124.7 +/- 2 kJ/mol is in good agreement with the experimental value. The stability of the initial pi-complex was found to be DeltaH degrees pi complex = -7.1 kJ/mol. The product complex between the transition state and the product was found with the stability of -127.2 kJ/mol. PMID- 26627029 TI - Atomic Level Anisotropy in the Electrostatic Modeling of Lone Pairs for a Polarizable Force Field Based on the Classical Drude Oscillator. AB - Electron pairs in the valence shell of an atom that do not participate in the bonding of a molecule ("lone pairs") give rise to a concentrated electron density away from the atom center. To account for the asymmetry in the electron charge density that arises from lone pairs, an electrostatic model is developed that is parametrically anisotropic at the atomic level. The model uses virtual interaction sites with partial charges that are associated but not coincident with the nuclei. In addition, the model incorporates anisotropic atomic polarizabilities. The protocol previously outlined in Anisimov et al. [J. Chem. Theory Comput. 2005, 1, 153] for parametrizing the electrostatic potential energy of a polarizable force field using classical Drude oscillators is extended to incorporate additional lone pair parameters. To probe the electrostatic environment around the lone pairs, the static (molecule alone) and perturbed (molecule in the presence of a test charge) electrostatic potential (ESP) are evaluated and compared to high level quantum mechanical (QM) electronic structure calculations. The parametrization of the virtual sites relies on data from the QM static ESP. The contribution to the perturbed ESP from the electronic polarization of the molecule is used to resolve the components of the atomic polarizability tensor. The model is tested in the case of four molecules: methanol, acetone, methylamine, and pyridine. Interaction energies with water and sodium are used to assess the accuracy of the model. The results are compared with simpler models placing all the charge on the nuclei as well as using only isotropic atomic polarizabilities. Analysis shows that the addition of virtual sites reduces the average error relative to the QM calculations. In contrast to models with atom centered charges, the virtual site models correctly predict the minimum energy conformation for acetone and methanol, with water, to be closely coordinated with the lone pair direction. Furthermore, addition of anisotropic atomic polarizabilities to the virtual site model allows for precise fitting to the local perturbed QM ESP. PMID- 26627030 TI - Ab Initio Finite-Temperature Electronic Absorption Spectrum of Formamide. AB - A combination of Car-Parrinello molecular dynamics (CP-MD) and high-level ab initio quantum chemical calculations has been used to calculate the electronic absorption spectrum of formamide at finite temperatures. Thermally broadened spectra have been obtained by averaging over a large number of single-point multireference configuration interaction excitation energies calculated for geometries sampled from a CP-MD simulation. Electronic excitation spectra of possible contaminants ammonia and formamidic acid have also been computed. Ammonia exhibits a strong peak in the shoulder region of the experimental formamide spectrum at 6.5 eV, and formamidic acid has a strong absorption above 7.5 eV. The calculations reproduce the shape of the experimental absorption spectrum, in particular, the low-energy shoulder of the main peak, and demonstrate how finite-temperature electronic absorption spectra can be computed from first principles. PMID- 26627031 TI - Classical Calculation of Transient Absorption Spectra Monitoring Ultrafast Electron Transfer Processes. AB - Classical formulations are considered that allow for the calculation of time- and frequency-resolved pump-probe spectra of nonadiabatically coupled molecular systems. When the semiclassical Franck-Condon approximation in the theoretical framework of the doorway-window formalism is employed, various first- and second order expressions for the classical doorway and window functions are derived. Moreover, a classical analogue of the electronic dipole transition operator is employed. When established models describing ultrafast photoinduced electron transfer are adopted, it is found that the first-order approximations give rise to spurious structures of the time-resolved signal, which indicate that these approximations fail to correctly account for the averaging effect caused by finite pulses. The higher-order approximations, on the other hand, are shown to give a fairly accurate description of the transient absorption spectrum. By comparing to exact quantum-mechanical calculations, the merits and shortcomings of the various approaches as well as the generally achievable accuracy of a classical modeling of optical spectra is discussed. PMID- 26627032 TI - Ewald Summation for Uniformly Charged Surface. AB - We have developed an algorithm to calculate the long-range Coulomb interactions for the slab system with a uniformly charged surface that is periodic in two dimensions and finite extent in the third dimension. This method, which is a modification of the three-dimensional Ewald summation with a correction term, is tested via molecular dynamics simulations of the adsorption of co-ions on the charged surface. The simulation results of counterion distribution show a good agreement with theoretical prediction especially at low surface charge density. Furthermore, we compute the force exerted on the particles for different systems. The consistency of results demonstrates that the proposed algorithm is applicable to the system with a smoothly charged surface in only two dimensions and is benefited from the widely used Ewald summation method in all three dimensions. PMID- 26627033 TI - Simulation of Interaction Forces between Nanoparticles: End-Grafted Polymer Modifiers. AB - The interaction forces between nanoscale colloidal particles coated with end grafted Lennard-Jones homopolymers are calculated using off-lattice Monte Carlo simulations in the NVT ensemble. The focus of this work is on grafted polymers that are of approximately the same size as the nanoparticle, a regime intermediate to the star-polymer and Derjaguin limits. The effects of chain length (N), nanoparticle diameter (sigmac), grafting density (rhoa), and colloid polymer and polymer-polymer interaction energies (epsiloncp and epsilonpp) on the polymer-induced force between the nanoparticles are explored. The inclusion of attractive dispersion interactions between the particle and polymeric modifier results in either long-ranged attraction and short-ranged repulsion or pure repulsion, depending on the molecular parameters. The polymer-induced attraction occurs even under good solvent conditions below a threshold grafting density (rhoa) and chain length (N) and could be attributed to both bridging (colloid polymer) and intersegmental (polymer-polymer) attraction. Above the threshold rhoa and N values, chain entropy and excluded volume effects begin to dominate and lead eventually to polymer-induced repulsion and, consequently, nanoparticle stabilization. These results point to the importance of considering dispersion attractions between grafted segments and the nanoparticle surface in modeling these high-curvature colloid interactions. PMID- 26627034 TI - Radical Addition to Thioketones: Computer-Aided Design of Spin Traps for Controlling Free-Radical Polymerization. AB - An extensive study has been undertaken of the radical affinity of a number of thioketones (S [Formula: see text] C(X)(Y)) with the aim of selecting combinations of X and Y that render the substrate suitable for the mediation of free radical polymerizations. Using high level ab initio molecular orbital calculations, enthalpies at 0 K were determined for the reactions R(*) + S [Formula: see text] C(X)(Y) -> R-S-C(*)(X)(Y) for R(*) = CH3, CH2OH, CH2CN, and benzyl, in reactions with a variety of thioketones, including various combinations of X and Y taken from H, CH3, Ph, CN, OCH3, C(CH3)3 and para-CN-Ph as well as several compounds in which the X and Y are bonded, namely xanthene-9 thione, fluorine-9-thione, and cyclopenta[def]phenanthrene-4-thione. The radical affinities of the various thioketones has been discussed in terms of the radical stabilization energies (RSEs) of the adduct radicals and stabilities of the S [Formula: see text] C bonds. From these studies, the two thioketones S [Formula: see text] C(CN)(Ph) and fluorene-9-thione were selected as being potentially suitable candidates for use in controlling free radical polymerizations due to their high radical affinities. However, based on transition state theory calculations of the rate coefficients for homo/copolymerization of S [Formula: see text] C(CN)(Ph) with itself and styrene at 333.15 K, this substrate was deemed to be unsuitable, as it was likely to undergo side reactions. Instead, the more-hindered fluorine-9-thione was identified as the ideal thioketone, and the equilibrium constants at 333.15 K for the reactions of the styryl and vinyl acetate dimer radicals with fluorine-9-thione were made. These two reactions, at 333.15 K, displayed equilibrium constants in the vicinity of 10(14) L mol(-)(1) and 10(16) L mol(-)(1), respectively, indicating that there is significant scope within the thioketone class of compounds to mediate free radical polymerizations via radical stability alone. PMID- 26627035 TI - Particle-Based Implicit Solvent Model for Biosimulations: Application to Proteins and Nucleic Acids Hydration. AB - In addition to the simulation of two proteins described previously, we report on the application of our recently developed particle-based implicit solvent model to the simulations of four nucleic acid molecules, the 17 bases anticodon hairpin of the Asp-tRNA, the decamer d(CCGCCGGCGG) in both A and B form, and the containing EcoRI restriction site dodecamer d(CGCGAATTCGCG). The solvent is represented by a fluid of Lennard-Jones polarizable pseudoparticles of molecular size, the induced dipoles of which are sensitive to the solute electric field but not to each other. When implemented in a molecular dynamics algorithm with the Amber94 force field, the model allows to simulate efficiently the conformational evolution of the nucleic acids, yielding stable three-dimensional structures in agreement with experiments and other simulations in explicit solvent. In the same run, it is also able to provide estimations of the electrostatic solvation free energy within short time windows which correlate well with the Poisson-Boltzmann calculations. In addition, the molecular aspect of the solvent model allows for the reproduction of the highly localized water molecules in the major or minor grooves of the nucleic acid double helices, despite the absence of explicit water hydrogen bonds. PMID- 26627036 TI - Computational Study of the Effects of Mutations A156T, D168V, and D168Q on the Binding of HCV Protease Inhibitors. AB - The effect of the resistance mutations A156T, D168V, and D168Q in HCV protease on the binding of SCH 6, SCH 503034, VX-950, BILN-2061, and compound 1 was evaluated using the free energy perturbation (FEP) approach. All the inhibitors are highly potent against the wild-type enzyme, but their activity was affected differently by the mutants. A156T reduced the activity of SCH 503034, BILN-2061, and VX950 drastically (200-1000-fold) but that of SCH 6 only moderately (27-fold). SCH 503034, SCH 6, and VX-950 were not affected by either mutation D168V or D168Q, but these mutations conferred a high level of resistance to BILN-2061. Comparison of BILN-2061 with its acyclic analogue compound 1 emphasized the importance of inhibitor flexibility in overcoming drug resistance arising from the D168Q mutation. The results from FEP calculations compared well with experimental binding potencies within an error of <1 kcal/mol. Structural analysis was carried out to relate the resistance profiles to the atomic changes in the mutants. PMID- 26627037 TI - Stationary Points on the PES of N-Methoxy Peptides and Their Boron Isosteres: An Ab Initio Study. AB - The conformational space of N-methoxy-N-methylacetamide [CH3-CO-N(OCH3)CH3, NMA NOM] and its boron isostere [CH3-CO-B(OCH3)CH3, BMA-BOM] has been studied at the HF, B3LYP, and MP2 levels of theory with the 6-31+G* basis set. The minima, saddle points, and rotation barriers on the PES of these molecules have been located, and the energy barriers estimated. The omega rotation barrier is relatively lower in the boron isostere than in NMA-NOM. The difference in the rotation barrier has been attributed to second-order orbital interactions, like negative hyperconjugation, as revealed by NBO calculations. As an extension, N acetyl-N'-methoxy-N'-methylamide of alanine (Ala-NOM) and its boron isostere (B Ala-BOM) have been adopted as model peptides to study the conformational preferences about the phi and psi torsion angles. The study reveals a strong preference for conformations of type-V beta turn and left-handed alpha-helix for Ala-NOM. B-Ala-BOM, on the other hand, favors conformations of type-Va beta turn, mirror image of Poly-L-Pro II helix, and structures with positive phi and extended psi. The replacement of nitrogen by boron changes the electronic and conformational properties of the peptide, extends greater flexibility around the omega angle, induces a strong preference for positive phi values, and shifts the site of nucleophilic attack from the carbonyl group to boron. PMID- 26627038 TI - The Low-Barrier Double-Well Potential of the O(delta)(1)-H-O(delta)(1) Hydrogen Bond in Unbound HIV Protease: A QM/MM Characterization. AB - The presence of a low-barrier hydrogen bond (LBHB) in aspartyl proteases and its implications in drug design have been the subject of intense study. Here, we present a combined quantum mechanical/molecular mechanical (QM/MM)-Numerov procedure and use it to characterize the O(delta)(1)-H-O(delta)(1) hydrogen bond (HB) in unbound HIV protease. The QM/MM scheme fully traces the shape of the HB's potential energy curve. The potential is used to obtain numerical solutions to the wave functions and vibrational energies of hydrogen, deuterium, and tritium. The vibrational eigenfunctions are used to compute expectation values for interatomic distances and vibrationally and thermally averaged spectroscopic properties of the O(delta)(1)-H-O(delta)(1) HB. Our work corroborates previous results by Piana and Carloni who found a LBHB via an ab initio molecular dynamics simulation (Piana, S.; Carloni, P. Proteins 2000, 39, 26-36). Our predictions of isotope effects on the chemical shift of unbound HIV protease are consistent with experimental measurements in similar HBs. These results support the predictive power of this method and its potential use in screening inhibitors of aspartyl proteases. PMID- 26627039 TI - Validation of Linear Scaling Semiempirical LocalSCF Method. AB - The numerical accuracy of linear scaling semiempirical methods LocalSCF and MOZYME is analyzed in comparison to conventional matrix diagonalization with respect to a variety of molecular properties including conformational energy, dipole moment, atomic charges, and bond orders. Major semiempirical MNDO, AM1, PM3, and PM5 Hamiltonians were considered in the study. As the numerical tests demonstrate, both LocalSCF and MOZYME reasonably reproduce matrix diagonalization results with the deviations being below the accuracy of semiempirical methods. However, the economical LocalSCF memory consumption and faster calculations are more beneficial for the quantum-mechanical modeling of large biological systems. The computational performance of the LocalSCF method is tested on the conformational energy calculation of a series of molecular dynamics snapshots of insulin in a large box of water. PMID- 26627040 TI - A Second Look at Canonical Sampling of Biomolecules Using Replica Exchange Simulation [J. Chem. Theory Comput. 2, 1200-1202 (2006)]. PMID- 26627041 TI - Acceptability and utility of an electronic psychosocial assessment (myAssessment) to increase self-disclosure in youth mental healthcare: a quasi-experimental study. AB - BACKGROUND: Technology is increasingly being used in youth mental healthcare to support service delivery and improve health outcomes. The current study trialed a new electronic psychosocial application (myAssessment) that aims to provide a holistic assessment of relevant risk and protective factors in youth mental healthcare. The study aimed to determine whether myAssessment was acceptable to all users, and whether it affected: reporting of certain behaviors and ratings of self-disclosure; youth ratings of control, fears of judgmental reactions or time efficiency; clinician ratings of time-efficiency or their ability to formulate a treatment plan; and the therapeutic alliance. METHOD: The application was tested at a youth mental health service using a quasi-experimental two phase Treatment as-Usual/Intervention design. Three hundred thirty nine youth and 13 clinicians participated across both phases. Reporting of behaviors, self-disclosure, youth control, judgmental reactions, time efficiency, ability to formulate treatment plans, and the therapeutic alliance were compared between groups. RESULTS: myAssessment was found to be widely accepted by both young people and clinicians. Use of myAssessment resulted in reporting of behaviors that were 2.78 through 10.38 times higher for a variety of substances (use of tobacco, alcohol, cannabis, sedatives, hallucinogens, and opioids), in identifying non-heterosexual sexual orientation, having had sex, an STI check, sex without a condom, having felt pressured to have sex in the past, having self-harmed, and in having put themselves in an unsafe situation. Participants who used the application also reported being less likely to lie on past experiences of being bullied, substance use, and self-harm. Use of the application resulted in improved youth ratings of time efficiency in session. The application was found to have no impact on youth control, judgmental reactions, formulation of treatment plans, or the therapeutic alliance. CONCLUSIONS: Electronic psychosocial assessments can increase rates of self-disclosure and, therefore, provide an earlier and more comprehensive picture of young people's risks without negatively impacting the therapeutic alliance. Additionally, this type of technology has been shown to be widely accepted by both young people and clinicians and can improve youth beliefs that there is enough time in session to speak about what is most important to them. PMID- 26627042 TI - ERCC2 polymorphisms and radiation-induced adverse effects on normal tissue: systematic review with meta-analysis and trial sequential analysis. AB - BACKGROUND: The relationship between ERCC2 polymorphisms and the risk of radiotoxicity remains inconclusive. The aim of our study is to systematically evaluate the association between ERCC2 polymorphisms and the risk of radiotoxicity. METHODS: Publications were identified through a search of the PubMed and Web of Science databases up to August 15, 2015. The pooled odds ratios (ORs) with corresponding 95 % confidence intervals (CIs) were calculated to evaluate the association between ERCC2 polymorphisms and radiotoxicity. Trial sequential analysis (TSA) and power calculation were performed to evaluate the type 1 and type 2 errors. RESULTS: Eleven studies involving 2584 patients were ultimately included in this meta-analysis. Conventional meta-analysis identified a significant association between ERCC2 rs13181 polymorphism and radiotoxicity (OR = 0.71, 95 % CI: 0.55-0.93, P = 0.01), but this association failed to get the confirmation of TSA. CONCLUSIONS: The minor allele of rs13181 polymorphism may confer a protect effect against radiotoxicity. To confirm this correlation at the level of OR = 0.71, an overall information size of approximate 2800 patients were needed. PMID- 26627043 TI - Carbon constrains fungal endophyte assemblages along the timberline. AB - The alpha diversity of foliar fungal endophytes (FEs) in leaves of Betula ermanii in a subalpine timberline ecotone on Changbai Mountain, China increased with elevation. There were also significant differences in beta diversity along the elevation gradient. Among the environmental variables analysed, leaf carbon significantly increased with elevation, and was the most significant environmental factor that constrained the alpha and beta diversity in the FE communities. Tree height and the cellulose, lignin, and carbon/nitrogen ratio of the leaves also affected the FE assemblages. When controlled for the effects of elevation, leaf carbon was still the main driver of changes in evenness, Shannon diversity and FE community composition. The results offered clues of the carbon acquisition strategy of the foliar FEs across this cold terrain. There was strong multicollinearity between both annual precipitation and temperature, with elevation (|Pearson r| > 0.986), so the effects of these climatic variables were impossible to separate; however, they may play key roles, and the direct effects of both warrant further investigation. As pioneer decomposers of leaf litter, variations in diversity and community composition of FE measured here may feedback and influence carbon cycling and dynamics in these forest ecosystems. PMID- 26627044 TI - Macular Atrophy Progression and 7-Year Vision Outcomes in Subjects From the ANCHOR, MARINA, and HORIZON Studies: The SEVEN-UP Study. PMID- 26627045 TI - Reply. PMID- 26627046 TI - Inkjet printing of UV-curable adhesive and dielectric inks for microfluidic devices. AB - Bonding of polymer-based microfluidics to polymer substrates still poses a challenge for Lab-On-a-Chip applications. Especially, when sensing elements are incorporated, patterned deposition of adhesives with curing at ambient conditions is required. Here, we demonstrate a fabrication method for fully printed microfluidic systems with sensing elements using inkjet and stereolithographic 3D printing. PMID- 26627047 TI - Combined incubation of cadmium, docosahexaenoic and eicosapentaenoic acid results in increased uptake of cadmium and elevated docosapentaenoic acid content in hepatocytes in vitro. AB - BACKGROUND: Human hepatocellular cells Hep G2 were used to mimic and investigate the effect of the intake of cadmium (Cd(2+)) contaminated fish on cytotoxicity, fatty acid (FA) and phospholipid class composition. METHODS: Cells were incubated with a combination of Cd(2+) and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) fish specific FA. RESULTS: We measured a significant increased proportion of EPA and DHA in the treated cells compared to the control line confirming the uptake. While doses of 25 MUM DHA showed to be toxic to the cells, repeated short term incubations (2 h) at lower doses resulted in an increased uptake of DHA. The resarzurin assay, evaluating cell viability, showed a significant decrease in cell viability between Cd(2+) incubation time and, further, the pre-incubation with BSA-FA complex resulted in significantly increased cell viability. On the metabolic level, increased concentrations of EPA and DHA resulted in an increased proportion of docosapentaenoic acid (DPA) which indicated an increased metabolism. Also 24-h combined incubations of 5 MUM Cd(2+) and EPA and DHA showed a significant increase DPA in the total lipid fraction of the cells. In addition, incubation with 5 MUM Cd(2+) for 24 h also decreased the total cardiolipin (CL) fraction from the identified phospholipids. CONCLUSIONS: We confirmed that the applied FA were taken up by the cells. A combination of EPA, DHA and Cd(2+) influenced lysosomal integrity, cell viability and lipid metabolism in the cells. The most important finding is that DHA and EPA reduced the detrimental effect of Cd(2+) on cell viability. The exact effects and kinetics behind our observations still need further evaluation. PMID- 26627048 TI - Summary of Sloan symposium: healthy buildings 2015-Europe. AB - The Sloan Symposium, "Microbiology of the Indoor Environment," was held to facilitate dialog on biological research between scientists and practitioners in the field which was complementary to the adjoining activities of the ISIAQ Healthy Buildings Europe conference, Eindhoven, Netherlands, on 20-21 May 2015. Multi-media archives of these special adjunct proceedings are presented. PMID- 26627049 TI - 2015 White Paper on recent issues in bioanalysis: focus on new technologies and biomarkers (Part 2 - hybrid LBA/LCMS and input from regulatory agencies). AB - The 2015 9th Workshop on Recent Issues in Bioanalysis (9th WRIB) took place in Miami, Florida with participation of over 600 professionals from pharmaceutical and biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. It is once again a 5-day week long event - a full immersion bioanalytical week - specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches including the focus on biomarkers and immunogenicity. This 2015 White Paper encompasses recommendations that emerged from the extensive discussions held during the workshop, and is aimed at providing the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to advance scientific excellence, improve quality and deliver better regulatory compliance. Due to its length, the 2015 edition of this comprehensive White Paper has been divided into three parts. Part 2 covers the recommendations for hybrid LBA/LCMS and regulatory agencies' inputs. Part 1 (small molecule bioanalysis using LCMS) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) will be published in volume 7 of Bioanalysis, issues 22 and 24, respectively. PMID- 26627051 TI - Site-specific synthesis of a hybrid boron-graphene salt. AB - We report the first example of an ionic graphene salt containing boron. An anionic charge is introduced to the graphene surface by means of 7,8-nido [C2B9H11](-) carborane clusters covalently and electronically bound to the graphene lattice, and this new material was isolated as its Cs(+) salt. PMID- 26627050 TI - Longitudinal Changes in Body Composition in Patients After Initiation of Hemodialysis Therapy: Results From an International Cohort. AB - OBJECTIVE: In patients with advanced kidney disease, metabolic and nutritional derangements induced by uremia interact and reinforce each other in a deleterious vicious circle. Literature addressing the effect of dialysis initiation on changes in body composition (BC) is limited and contradictory. The aim of this study was to evaluate changes in BC in a large international cohort of incident hemodialysis patients. METHODS: A total of 8,227 incident adult end-stage renal disease patients with BC evaluation within the initial first 6 months of baseline, defined as 6 months after renal replacement therapy initiation, were considered. BC, including fat tissue index (FTI) and lean tissue index (LTI), were evaluated by Body Composition Monitor (BCM, Fresenius Medical Care, Bad Homburg, Germany). Exclusion criteria at baseline were lack of a BCM measurement before or after baseline, body mass index (BMI) < 18.5 kg/m(2), presence of metastatic solid tumors, treatment with a catheter, and prescription of less or more than 3 treatments per week. Maximum follow-up was 2 years. Descriptive analysis was performed comparing current values with the baseline in each interval (delta analysis). Linear mixed models considering the correlation structure of the repeated measurements were used to evaluate factors associated with different trends in FTI and LTI. RESULTS: BMI increased about 0.6 kg/m(2) over 24 months from baseline. This was associated with increase in FTI of about 0.95 kg/m(2) and a decrease in LTI of about 0.4 kg/m(2). Female gender, diabetic status, and low baseline FTI were associated with a significant greater increase of FTI. Age > 67 years, diabetes, male gender, high baseline LTI, and low baseline FTI were associated with a significant greater decrease of LTI. CONCLUSIONS: With the transition to hemodialysis, end-stage renal disease patients presented with distinctive changes in BC. These were mainly associated with gender, older age, presence of diabetes, low baseline FTI, and high baseline LTI. BMI increases did not fully represent the changes in BC. PMID- 26627052 TI - Chemotherapy compliance in high-risk Merkel cell carcinoma treated with chemoradiotherapy. AB - OBJECTIVE: To evaluate chemotherapy (CT) compliance in patients treated with chemoradiotherapy (CRT) for high-risk Merkel cell cancer (MCC). METHODS: Data from three prospective clinical trials in high-risk MCC performed by the Trans Tasman Radiation Oncology Group were included in this analysis. Patients were treated with one of two carboplatin-based CT schedules and standardised radiotherapy (RT) to the primary site and nodes to a dose of 50-60 Gy in 25-30 fractions. Patients' baseline characteristics were analysed using chi2 tests to determine compliance factors for completing CT. A Cox univariate analysis was performed to assess the impact of CT compliance on time to locoregional failure, time-to-distant failure, time-to-recurrence and time-to-death. RESULTS: A total of 88 patients were identified, with a median follow up of 38.5 months. Of these, 75 (85%) completed CT (median age 64.2 years, range 62.0-66.4), while 13 did not (median age 72 years, range 68.1-75.9), P = 0.006. Women comprised 18/75 patients who completed CT and 7/13 patients who did not complete it (P = 0.03). Performance status, site, stage, surgical margins, RT dose and toxicity did not impact on their CT compliance. At 5 years, 26% of patients had locoregional relapse, 26% had distant failure and 34% had died. CONCLUSIONS: In this small cohort of patients treated with CRT for high-risk MCC, older age and female sex were associated with failure to complete CT. Severe acute skin and haematological toxicity did not correlate with failure to complete CT. PMID- 26627053 TI - Regulation of endoplasmic reticulum functions. PMID- 26627054 TI - Expectations and satisfaction with antenatal care among pregnant women with a focus on vulnerable groups: a descriptive study in Ghent. AB - BACKGROUND: Previous studies demonstrate that people's satisfaction with healthcare influences their further use of that healthcare system. Satisfied patients are more likely to take part in the decision making process and to complete treatment. One of the important determinants of satisfaction is the fulfillment of expectations. This study aims to analyse both expectations and satisfaction with antenatal care among pregnant women, with a particular focus on vulnerable groups. METHODS: A quantitative descriptive study was conducted in 155 women seeking antenatal care at the University Hospital of Ghent (Belgium), of whom 139 completed the questionnaire. The statistical program SPSS-21 was used for data analysis. RESULTS: Women had high expectations relating to continuity of care and women-centered care, while expectations regarding availability of other services and complete care were low. We observed significantly lower expectations among women without higher education, with low income, younger than 26 years and women who reported intimate partner violence. General satisfaction with antenatal care was high. Women were satisfied with their relationship with the healthcare worker, however ; they evaluated the information received during the consultation and the organizational aspects of antenatal care as less satisfactory. CONCLUSIONS: In order to improve satisfaction with antenatal care, organizational aspects of antenatal care (e.g. reducing waiting times and increasing accessibility) need to be improved. In addition, women would appreciate a better provision of information during consultation. More research is needed for an in depth understanding of the determinants of satisfaction and the relationship with low socio economic status (SES). PMID- 26627055 TI - The use of bio-monitoring to assess exposure in the electroplating industry. AB - Workers in the electroplating industry are potentially exposed to a range of hazardous substances including nickel and hexavalent chromium (chromium VI) compounds. These can cause serious health effects, including cancer, asthma and dermatitis. This research aimed to investigate whether repeat biological monitoring (BM) over time could drive sustainable improvements in exposure control in the industry. BM was performed on multiple occasions over 3 years, at 53 electroplating companies in Great Britain. Surface and dermal contamination was also measured, and controls were assessed. Air monitoring was undertaken on repeat visits where previous BM results were of concern. There were significant reductions in urinary nickel and chromium levels over the lifetime of this work in the subset of companies where initially, control deficiencies were more significant. Increased risk awareness following provision of direct feedback to individual workers and targeted advice to companies is likely to have contributed to these reductions. This study has shown that exposures to chromium VI and nickel in the electroplating industry occur via a combination of inhalation, dermal and ingestion routes. Surface contamination found in areas such as canteens highlights the potential for transferral from work areas, and the importance of a regular cleaning regime. PMID- 26627056 TI - Epidemiological and therapeutic studies of camel mange in Fafan zone, Eastern Ethiopia. AB - BACKGROUND: Camel mange is an economically important parasitic disease affecting productivity in camel rearing areas of the world if appropriate treatment is not instituted. METHODS: A cross-sectional and a controlled field trial were carried out to study the epidemiology of camel mange in Fafan zone, Eastern Ethiopia, and evaluate the efficacy of ivermectin and diazinon in the control of mange infestation in camels on the basis of clinical and parasitological evidence, respectively. Three groups of naturally infested camels and one group of healthy camels each composed of 6 individuals were enrolled: the two infested groups received either ivermectin or diazinon, and the other groups remained untreated. RESULTS: The overall prevalence rate of mange in camels in the study area was 31.5% and the only identified species was Sarcoptes scabiei. The prevalence rate was found to significantly vary (p < 0.05) in relation to body condition and herd size of camels. Both drugs showed significant variation (p < 0.05) on improving clinical and body condition scores. Clearance of mange lesions occurred with both drugs; however, re-infestation was observed in diazinon treated group. Ivermectin significantly improved (p < 0.05) both body condition and clinical scores whereas diazinon markedly improved only the later. CONCLUSION: In conclusion, camels in the study area harbored considerable level of S. scabiei which warrants institution of an integrated control approach by administration of ivermectin while also sanitating the animal environment. PMID- 26627057 TI - 3D-Printed Biodegradable Polymeric Vascular Grafts. AB - Congenital heart defect interventions may benefit from the fabrication of patient specific vascular grafts because of the wide array of anatomies present in children with cardiovascular defects. 3D printing is used to establish a platform for the production of custom vascular grafts, which are biodegradable, mechanically compatible with vascular tissues, and support neotissue formation and growth. PMID- 26627058 TI - Antileishmanial, DNA Interaction, and Docking Studies of Some Ferrocene-Based Heteroleptic Pentavalent Antimonials. AB - A series of ferrocenyl pentavalent antimonials (1-8) were synthesized and characterized by elemental analysis, FT-IR, and multinuclear ((1) H and (13) C) NMR spectroscopy. These antimonials were evaluated for their antileishmanial potential against Leishmania tropica KWH23, and by biocompatibility and membrane permeability assays. Moreover, mechanistic studies were carried out, mediated by DNA targeting followed by computational docking of ferrocenyl antimonials against the leishmanial trypanothione reductase enzyme. It was observed that the antimonials 1-8 were 390-fold more efficacious (IC50 ) as compared with the standard antimonial drug used. Cytotoxicity results showed that these antimonials are highly active even at low concentrations and are biocompatible with human macrophages. Antimonials 1-8 exhibited extensive intercalation with DNA and, furthermore, docking interactions highlighted the potential interactive binding of the anitimonials within the trypanothione reductase active site, with van der Waals interactions contributing significantly to the process. Hence, it is suggested that the reported antimonials demonstrate high efficacy, less toxicity, and target multiple sites of the Leishmania parasite. PMID- 26627059 TI - Low serum ficolin-3 levels are associated with severity and poor outcome in traumatic brain injury. AB - BACKGROUND: Ficolin-mediated activation of the lectin pathway of complement contributes to the complement-independent inflammatory processes of traumatic brain injury. Lower serum ficolin-3 levels have been demonstrated to be highly associated with unfavorable outcome after ischemic stroke. This prospective observatory study was designed to investigate the relationships between serum ficolin-3 levels and injury severity and clinical outcomes after severe traumatic brain injury. METHODS: Serum ficolin-3 levels of 128 patients and 128 healthy controls were measured by sandwich immunoassays. An unfavorable outcome was defined as Glasgow Outcome Scale score of 1-3. Study endpoints included mortality at 1 week and 6 months and unfavorable outcome at 6 months after head trauma. Injury severity was assessed by Glasgow Coma Scale score. Multivariate logistic models were structured to evaluate the relationships between serum ficolin-3 levels and study endpoints and injury severity. RESULTS: Compared with the healthy controls, serum ficolin-3 levels on admission were statistically decreased in patients with severe traumatic brain injury. Serum ficolin-3 levels were independently correlated with Glasgow Coma Scale scores. Ficolin-3 was also identified as an independent prognostic predictor for 1-week mortality, 6-month mortality, and 6-month unfavorable outcome. Under receiver operating characteristics curves, ficolin-3 has similar prognostic predictive values for all study endpoints compared with Glasgow Coma Scale scores. CONCLUSIONS: It was proposed that lower serum ficolin-3 levels, correlated with injury severity, had the potential to be the useful, complementary tool to predict short- or long-term clinical outcomes after severe traumatic brain injury. PMID- 26627060 TI - Piperine alleviates osteoclast formation through the p38/c-Fos/NFATc1 signaling axis. AB - Increased bone fracture is one of the health risk factors in patients with bone loss related disorders such as osteoporosis and breast cancer metastasis to bone. Over activity of osteoclasts leads to uncoupling of bone remodeling favoring bone loss over bone formation. Receptor activator of nuclear factor-kappabeta ligand (RANKL) triggers the differentiation pathway leading to multinucleated osteoclast formation. Modulation of RANKL or its downstream signaling pathways involved in osteoclast formation is of significant interest in the development of anti resorptive agents. In this study, the effects of piperine, an alkaloid present in Piper nigrum L. on osteoclast formation was investigated. Piperine inhibited tartrate-resistant acid phosphatase-positive multinucleated osteoclast formation in murine RAW264.7 macrophages and human CD14+ monocytes induced by RANKL and breast cancer cells. Piperine attenuated the p38-mitogen activated protein kinase pathway activation, while the extracellular-signal-regulated kinase, c-Jun N terminal kinase, or NF-kappabeta pathways downstream of RANKL remained unaffected. Concomitantly, expression of c-Fos and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), the key transcription factors involved in osteoclastogenesis were remarkably inhibited by piperine. Furthermore, piperine disrupted the actin ring structure and bone resorption, a characteristic hallmark of osteoclasts. Collectively, these results suggested that piperine inhibited osteoclast differentiation by suppressing the p38/NFATc1/c-Fos signaling axis.. PMID- 26627061 TI - Biochemical and molecular investigation of thermal manipulation protocols during broiler embryogenesis and subsequent thermal challenge. AB - BACKGROUND: The aim of the current study was to evaluate the effect of different thermal manipulation (TM) protocols during embryogenesis on thermotolerance acquisition parameters during subsequent thermal challenge (TC) at posthatch day 28. A total of 1500 fertile chicken eggs were divided randomly into five treatments (300 eggs each): control was maintained at 37.8 degrees C and 56 % relative humidity (RH) whereas, TM1, TM2, TM3 and TM4 were subjected to 38.5, 39, 39.5 and 40 degrees C for 18 h and 65 % RH daily during embryonic days ED 12-18. Hatched chicks from each treatment group allocated randomly into two sub treatment groups (thermo-neutral, naive (TN) and thermal challenge (TC). At day 28 of age, chicks subjected to TC by adjusting room temperature to 42 degrees C for 6 h while naive chicks kept under regular conditions (22 +/- 1 degrees C and 50-60 % RH). Chick's response to TC evaluated by determination of plasma T3, T4, corticosterone, total proteins, albumin, selected enzymes and some electrolytes at the beginning (0 h) and after 1, 3 and 5 h of TC in TM and TN chicks. Furthermore, pectoral and thigh muscles mRNA expression of Atrogin-1, CK, avUCP, DIO3, DIO2 were evaluated in TC and TN sub-treatment groups. RESULTS: TM induced a significant reduction in free T3 and elevation in total proteins and albumin in plasma with significant down-regulation of Atrogin-1 and DIO2 and significant up regulation of DIO3 mRNA expression in muscle of TM chicks compare to control. During TC at day 28, decrease in the concentrations of plasma free T3, total proteins and albumin with increase in T4 have been detected in control and TM chicks. TC induced up-regulation of Atrogin-1 and DIO3 with down-regulation of DIO2 gene expression in muscles of all TC chicks. CONCLUSION: The present study indicated that, TM improved thermotolerance acquisition by decreasing basal metabolic rate and muscle injury during thermal stress. Basal metabolic rate decreased via reduction of plasma T3 concentration with up and down regulation of expression of DIO3 and DIO2, respectively in muscles. Muscle injury protected by stimulation of protein biosynthesis and down-regulation of Atrogin-1 expression. PMID- 26627063 TI - A New Year Begins. PMID- 26627062 TI - Mulberry and cherry anthocyanin consumption prevents oxidative stress and inflammation in diet-induced obese mice. AB - SCOPE: This study aimed to determine whether cherry anthocyanin (CA) and mulberry anthocyanin (MA) can alleviate oxidative stress and inflammation associated with developing obesity in mice fed with high-fat diet (HFD). METHODS AND RESULTS: CA and MA were added in the daily food of mice throughout the experiment. Sixty mice were randomly divided into two groups: a low-fat diet (LFD, n = 12) group and HFD (n = 48) group. Mice in the HFD group were supplied with a HFD for 8 wks to induce obesity. The HFD-fed mice were then divided into four subgroups for another 8-wk experiment. The subgroups included the control group, HFD plus Orlistat group, and HFD plus CA or MA group, with each group consisting of 12 mice. Consumption of CA and MA at 200 mg/kg food reduced bodyweight gain by 29.6 and 32.7%, respectively, in HFD-fed C57BL/6 mice. CA and MA supplementation could effectively improve the lipid profiles, decrease serum glucose and leptin levels, reduce MDA production, increase SOD and GPX activities, and down-regulate the expression of the TNFalpha, IL-6, iNOS, and NF-kB genes. CONCLUSION: Therefore, MA and CA can potentially alter bodyweight by alleviating oxidative stress and inflammation in diet-induced obesity. PMID- 26627064 TI - 2016 Guide to Nursing Certification Boards by Specialty. AB - Membership in a professional organization creates opportunities for individuals to grow in countless ways. Often, it allows us to develop new knowledge and form networks that change our lives. There are many advantages of becoming a member of a specialty organization. Each year, Dimensions of Critical Care Nursing is proud to provide an updated list of our professional nursing organizations. PMID- 26627065 TI - Mobilizing Patients Along the Continuum of Critical Care. AB - The progressive care unit implemented an evidenced-based intensive care unit mobility protocol with their chronically critically ill patient population. The labor/workload necessary to meet mobility standards was an identified barrier to implementation. Workflow redesign of patient care technicians, interdisciplinary teamwork, and creating a culture of meeting mobility standards led to the successful implementation of this protocol. Data revealed that mobility episodes increased from 1.4 at preinitiative to 4.7 at 12 months postinitiative, surpassing the goal of 3 episodes per 24 hours. PMID- 26627066 TI - Chronic Obstructive Pulmonary Disease and Ventilator-Associated Pneumonia: An Analysis and Literature Review Into the Intensive Care Unit Exacerbation Progression and Acute Pulmonary Management. AB - The occurrence of ventilator-associated pneumonia (VAP) infections in mechanically ventilated patients has significantly affected how medical providers manage the severe acute pulmonary pathology in chronic obstructive pulmonary disease (COPD) and implement medical interventions to prevent infectious transmission to these patients in the intensive care unit. Severe COPD is present in more than 65 million people worldwide, thereby placing these individuals at an increased risk of intensive care unit admission and VAP contraction. Chronic obstructive pulmonary disease is well known as a risk factor for developing VAP and is related to adverse risk factors such as developing multiple drug-resistant bacteria. Evidence shows that COPD immunosuppression continues to be associated with pulmonary infection, but multiple modalities are available to combat and treat acute exacerbations before decompensation begins, thereby preventing prolonged endotracheal mechanical ventilation. PMID- 26627068 TI - My Professor Said to Submit My Paper (We Hope They Also Told You This). PMID- 26627070 TI - Oral Chlorhexidine Use to Prevent Ventilator-Associated Pneumonia in Adults: Review of the Current Literature. AB - Ventilator-associated pneumonia (VAP) describes pneumonia in patients requiring mechanical ventilation that was not present prior to intubation. Ventilator associated pneumonia concurrently increases patient mortality, hospital length of stay, and health care costs. Ventilator-associated pneumonia also contributes to patient morbidity, which is challenging the progression of patient care in intensive care units throughout the United States. Through critique of current literature, suitable interventions for intensive care unit implementation to prevent VAP are clearly identified. Oral health was shown in this literature to greatly contribute to the development or prevention of VAP; it can be compromised by critical illness and mechanical ventilation while being influenced by nursing care. Oral health is managed by proper oral care using oral chlorhexidine in order to decrease oral bacteria and potential oropharynx colonization. The previously mentioned literature review demonstrates a decrease in VAP rates with the use of such oral interventions as chlorhexidine. These research results will support and influence patient care practices considering nursing and medicine are driven by evidence rather than experience to prevent avoidable patient harm. PMID- 26627071 TI - What Factors Are Associated With the Development of Pressure Ulcers in a Medical Intensive Care Unit? AB - STATEMENT OF THE PROBLEM: Instruments used to determine the risk of pressure ulcer development are universally applied to adult patients. These instruments do not differentiate between intensive and acute care patients. BACKGROUND: Pressure ulcers contribute to negative outcomes such as increases in pain and discomfort, risk of infection, hospital length of stay and costs, and a decrease in quality of life. Appropriately identifying risk factors is paramount to implementing a targeted care plan to avoid pressure ulcer development as well as pinpointing appropriate treatments if an ulcer develops. OBJECTIVE: The purpose of this nursing research study was to identify factors associated with pressure ulcer development in a medical intensive care unit. METHODS: A 15-month retrospective chart review of patients with pressure ulcers in a medical intensive care unit was performed. Statistics were computed on demographics and variables of interest including: pressure ulcer stage, vasopressor infusion, oxygen requirement, comorbidities, primary diagnosis, length of stay, mortality, age, gender, weight, Braden scores, and albumin level. RESULTS: The characteristics of 76 patients who developed pressure ulcers were evaluated. An equal number of men (n = 38) and women (n = 38) were included. Forty-seven percent had a stage II pressure ulcer. The presence of hemodynamic support with vasopressor administration (P = .016) and the length of stay (P = .021) were noted as the most significant factors in pressure ulcer development in this study. CONCLUSIONS: Vasopressor use and length of stay are not factors that are accounted for in current pressure ulcer risk assessment instruments. The administration of vasopressor support and patient length of stay are potential contributory factors that need to be considered when assessing patients. Instruments specific to intensive care unit pressure ulcer risk stratification are warranted and should include the unique characteristics of a critically ill patient. PMID- 26627072 TI - Understanding Uncertainty Among Critically Ill Patients in the Intensive Care Unit Using Mishel's Theory of Uncertainty of Illness. AB - BACKGROUND: The concept uncertainty has been explored in critical care but only among patients with myocardial infarction and post-cardiac catheterization using the Uncertainty in Illness Theory. Uncertainty is also a finding of numerous studies conducted in intensive care units (ICUs) that included only family members as participants of the research. OBJECTIVES: The purpose of this article is to explore, describe, and understand the concept of uncertainty among patients and family members during critical illness in the ICU from the perspective of a phenomenological study with support from other studies published in the literature using Mishel's Theory of Uncertainty in Illness. METHODS: The concept "uncertainty" as the topic for this article is one of the specific themes illuminated from a qualitative phenomenological study conducted in the ICU in 2010. Five from each category of patients, family members, and nurses were interviewed until data saturation was achieved. The data were analyzed using van Manen's wholistic, selective, and detailed line-by-line approach until themes were illuminated. RESULTS: Uncertainty is a patient-specific theme illuminated in this qualitative phenomenological study not noted among the family members. The patients perceived that they "do not know what is going to happen," "if they are progressing or not," or "if they will make it or not." DISCUSSION: Uncertainty among patients related to critical illness should be further explored. Patients with different critical care diagnosis should be included as participants. PMID- 26627074 TI - The Work of Writing. PMID- 26627075 TI - Brodalumab versus ustekinumab in psoriasis. PMID- 26627077 TI - Sustainable cultivation of microalgae by an insulated glazed glass plate photobioreactor. AB - Microalgae growth in closed photobioreactors is greatly inhibited by elevated temperatures caused mainly by the infra-red portion of light. Current passive evaporative cooling systems for temperature control in outdoor photobioreactors are neither economical nor sustainable. Here we built a novel flat plate photobioreactor with its illumination surface customized with insulated glazing units (IGP). The IGP design enabled transmission of more than 50% of visible light while blocking 90% of ultraviolet and infrared radiations. The growth and productivity of Nannochloropsis sp. (MUR 267) in the IGP was compared against conventional flat plate photobioreactors subjected to the full spectrum (HLP) and also externally modified spectrum (CLP) of halogen lights. High temperature (up to 42 degrees C) resulted in no growth in the HLP. Biomass productivities of Nannochloropsis sp. grown in the CLP was significantly higher than the IGP due to higher light transmission and lower temperature profiles recorded in the CLP. Lipid content of Nannochloropsis was highest in the CLP (60.23%) while protein was highest in the IGP (42.43%). All photosynthesis parameters were negatively affected in the HLP. The IGP's ability to remove infrared (heat) makes this newly developed photobioreactor a promising and sustainable cultivation system for mass algal production especially for high value products. PMID- 26627076 TI - Proteomic analysis of Chromobacterium violaceum and its adaptability to stress. AB - BACKGROUND: Chromobacterium violaceum (C. violaceum) occurs abundantly in a variety of ecosystems, including ecosystems that place the bacterium under stress. This study assessed the adaptability of C. violaceum by submitting it to nutritional and pH stresses and then analyzing protein expression using bi dimensional electrophoresis (2-DE) and Maldi mass spectrometry. RESULTS: Chromobacterium violaceum grew best in pH neutral, nutrient-rich medium (reference conditions); however, the total protein mass recovered from stressed bacteria cultures was always higher than the total protein mass recovered from our reference culture. The diversity of proteins expressed (repressed by the number of identifiable 2-DE spots) was seen to be highest in the reference cultures, suggesting that stress reduces the overall range of proteins expressed by C. violaceum. Database comparisons allowed 43 of the 55 spots subjected to Maldi mass spectrometry to be characterized as containing a single identifiable protein. Stress-related expression changes were noted for C. violaceum proteins related to the previously characterized bacterial proteins: DnaK, GroEL-2, Rhs, EF-Tu, EF-P; MCP, homogentisate 1,2-dioxygenase, Arginine deiminase and the ATP synthase beta-subunit protein as well as for the ribosomal protein subunits L1, L3, L5 and L6. The ability of C. violaceum to adapt its cellular mechanics to sub optimal growth and protein production conditions was well illustrated by its regulation of ribosomal protein subunits. With the exception of the ribosomal subunit L3, which plays a role in protein folding and maybe therefore be more useful in stressful conditions, all the other ribosomal subunit proteins were seen to have reduced expression in stressed cultures. Curiously, C. violeaceum cultures were also observed to lose their violet color under stress, which suggests that the violacein pigment biosynthetic pathway is affected by stress. CONCLUSIONS: Analysis of the proteomic signatures of stressed C. violaceum indicates that nutrient-starvation and pH stress can cause changes in the expression of the C. violaceum receptors, transporters, and proteins involved with biosynthetic pathways, molecule recycling, energy production. Our findings complement the recent publication of the C. violeaceum genome sequence and could help with the future commercial exploitation of C. violeaceum. PMID- 26627078 TI - Serum phosphate and social deprivation independently predict all-cause mortality in chronic kidney disease. AB - BACKGROUND: Hyperphosphataemia is linked to cardiovascular disease and mortality in chronic kidney disease (CKD). Outcome in CKD is also affected by socioeconomic status. The objective of this study was to assess the associations between serum phosphate, multiple deprivation and outcome in CKD patients. METHODS: All adult patients currently not on renal replacement therapy (RRT), with first time attendance to the renal outpatient clinics in the Glasgow area between July 2010 and June 2014, were included in this prospective study. Area socioeconomic status was assessed as quintiles of the Scottish Index of Multiple Deprivation (SIMD). Outcomes were all-cause and cardiovascular mortality and commencement of RRT. RESULTS: The cohort included 2950 patients with a median (interquartile range) age 67.6 (53.6-76.9) years. Median (interquartile range) eGFR was 38.1 (26.3 63.5) ml/min/1.73 m(2), mean (+/- standard deviation) phosphate was 1.13 (+/- 0.24) mmol/L and 31.6 % belonged to the most deprived quintile (SIMD quintile I). During follow-up 375 patients died and 98 commenced RRT. Phosphate >= 1.50 mmol/L was associated with all-cause (hazard ratio (HR) 2.51; 95 % confidence interval (CI) 1.63-3.89) and cardiovascular (HR 5.05; 95 % CI 1.90-13.46) mortality when compared to phosphate 0.90-1.09 mmol/L in multivariable analyses. SIMD quintile I was independently associated with all-cause mortality. Phosphate did not weaken the association between deprivation index and mortality, and there was no interaction between phosphate and SIMD quintiles. Neither phosphate nor SIMD predicted commencement of RRT. CONCLUSIONS: Multiple deprivation and serum phosphate were strong, independent predictors of all-cause mortality in CKD and showed no interaction. Phosphate also predicted cardiovascular mortality. The results suggest that phosphate lowering should be pursued regardless of socioeconomic status. PMID- 26627079 TI - Phase I trial of volasertib, a Polo-like kinase inhibitor, in Japanese patients with advanced solid tumors. AB - PURPOSE: This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical effects of volasertib, a selective Polo-like kinase inhibitor that induces mitotic arrest and apoptosis, in Japanese patients with advanced solid tumors (NCT01348347; 1230.15). METHODS: In this phase I, open label, dose-escalation trial, sequential patient cohorts (3 + 3 dose-escalation design) received volasertib (200-350 mg) as a single dose by intravenous infusion over 2 h on day 1 every 21 days until disease progression or unacceptable toxicity. The primary endpoint was the MTD of volasertib in Japanese patients with an advanced solid tumor; secondary endpoints included safety, pharmacokinetics, and clinical benefit. RESULTS: Fifteen patients with an advanced solid tumor were treated. Dose-limiting toxicities of grade 4 neutropenia for >=7 days and grade 4 thrombocytopenia were both experienced by 2/6 patients in the 350 mg cohort. The MTD of volasertib in Japanese patients was 300 mg. The most common (>=3 patients) drug-related non-hematologic adverse events included fatigue, decreased appetite, and nausea. Exposure to volasertib and its metabolite increased with increasing doses. A partial response in a patient with gastric cancer and stable disease in eleven patients were observed. CONCLUSIONS: Volasertib had a manageable safety profile up to the MTD determined as 300 mg. Exposure to volasertib and its metabolite increased with increasing doses. The safety profile of volasertib in Japanese patients is comparable with those previously obtained in Caucasian patients. These data support enrollment of Japanese patients in global clinical trials without dose modification. PMID- 26627080 TI - Phase I, dose-escalating study of elisidepsin (Irvalec((r))), a plasma membrane disrupting marine antitumor agent, in combination with erlotinib in patients with advanced malignant solid tumors. AB - OBJECTIVE: To determine the recommended dose for phase II trials of elisidepsin (PM02734, Irvalec(r)) in combination with erlotinib in patients with advanced malignant solid tumors. METHODS: Open-label, dose-escalating, phase I study of intravenous elisidepsin administered weekly (days 1, 8 and 15) over 3 h as a flat dose (FD) and daily oral erlotinib, every 3 weeks. A pharmacokinetic analysis was done on blood samples collected around the first elisidepsin infusion. RESULTS: Thirty patients were treated across six different dose levels (DLs) ranging from elisidepsin 0.33-2.25 mg/erlotinib 100-150 mg. Two patients had dose-limiting toxicities: grade 3 bilirubin increase (DL3: 0.75 mg/150 mg) and a dose omission for > 2 weeks due to grade 3 alanine aminotransferase increase (DL6: 2.25 mg/100 mg). The daily erlotinib dose was escalated to 150 mg at DL2-DL5, but decreased to 100 mg at DL6, as most grade 3 toxicities were related to this agent only. The most frequent toxicities were transaminase increases (related to elisidepsin), and rash, pruritus and diarrhea (related to erlotinib). No objective responses were observed. Despite no overlapping toxicities, the combination was declared unfeasible due to frequent elisidepsin dose delays. The pharmacokinetics of elisidepsin/erlotinib was not significantly different from that of each agent alone. CONCLUSION: The difficulty in combining elisidepsin with the standard dose of erlotinib (150 mg), together with the lack of antitumor activity, made the combination unattractive for further development. The trial was closed without having determined a recommended dose. PMID- 26627081 TI - Molecular imaging of EGFR and CD44v6 for prediction and response monitoring of HSP90 inhibition in an in vivo squamous cell carcinoma model. AB - PURPOSE: Heat shock protein 90 (HSP90) is essential for the activation and stabilization of numerous oncogenic client proteins. AT13387 is a novel HSP90 inhibitor promoting degradation of oncogenic proteins upon binding, and may also act as a radiosensitizer. For optimal treatment there is, however, the need for identification of biomarkers for patient stratification and therapeutic response monitoring, and to find suitable targets for combination treatments. The aim of this study was to assess the response of surface antigens commonly expressed in squamous cell carcinoma to AT13387 treatment, and to find suitable biomarkers for molecular imaging and radioimmunotherapy in combination with HSP90 inhibition. METHODS: Cancer cell proliferation and radioimmunoassays were used to evaluate the effect of AT13387 on target antigen expression in vitro. Inhibitor effects were then assessed in vivo in mice-xenografts. Animals were treated with AT13387 (5 * 50 mg/kg), and were imaged with PET using either (18)F-FDG or (124)I labelled tracers for EGFR and CD44v6, and this was followed by ex-vivo biodistribution analysis and immunohistochemical staining. RESULTS: AT13387 exposure resulted in high cytotoxicity and possible radiosensitization with IC50 values below 4 nM. Both in vitro and in vivo AT13387 effectively downregulated HSP90 client proteins. PET imaging with (124)I-cetuximab showed a significant decrease of EGFR in AT13387-treated animals compared with untreated animals. In contrast, the squamous cell carcinoma-associated biomarker CD44v6, visualized with (124)I-AbD19384 as well as (18)F-FDG uptake, were not significantly altered by AT13387 treatment. CONCLUSION: We conclude that AT13387 downregulates HSP90 client proteins, and that molecular imaging of these proteins may be a suitable approach for assessing treatment response. Furthermore, radioimmunotherapy targeting CD44v6 in combination with AT13387 may potentiate the radioimmunotherapy outcome due to radiosensitizing effects of the drug, and could potentially lead to a lower dose to normal tissues. PMID- 26627082 TI - Radiolabelled choline and FDG PET/CT: two alternatives for the assessment of lymph node metastases in patients with upper urinary tract urothelial carcinoma. PMID- 26627083 TI - Modeling the Transitions between Collective and Solitary Migration Phenotypes in Cancer Metastasis. AB - Cellular plasticity during cancer metastasis is a major clinical challenge. Two key cellular plasticity mechanisms -Epithelial-to-Mesenchymal Transition (EMT) and Mesenchymal-to-Amoeboid Transition (MAT) - have been carefully investigated individually, yet a comprehensive understanding of their interconnections remains elusive. Previously, we have modeled the dynamics of the core regulatory circuits for both EMT (miR-200/ZEB/miR-34/SNAIL) and MAT (Rac1/RhoA). We now extend our previous work to study the coupling between these two core circuits by considering the two microRNAs (miR-200 and miR-34) as external signals to the core MAT circuit. We show that this coupled circuit enables four different stable steady states (phenotypes) that correspond to hybrid epithelial/mesenchymal (E/M), mesenchymal (M), amoeboid (A) and hybrid amoeboid/mesenchymal (A/M) phenotypes. Our model recapitulates the metastasis-suppressing role of the microRNAs even in the presence of EMT-inducing signals like Hepatocyte Growth Factor (HGF). It also enables mapping the microRNA levels to the transitions among various cell migration phenotypes. Finally, it offers a mechanistic understanding for the observed phenotypic transitions among different cell migration phenotypes, specifically the Collective-to-Amoeboid Transition (CAT). PMID- 26627084 TI - Morbidity of hepatic resection for intermediate and advanced hepatocellular carcinoma. AB - PURPOSE: According to current treatment guidelines, surgical resection of hepatocellular carcinoma (HCC) is mostly restricted to a limited subgroup of patients. Due to improved surgical techniques and perioperative management, liver resections may also be performed more extendedly and also in cirrhotic livers with clinical signs of portal hypertension in selected patients. In this study, the clinical and long-term outcomes of liver resection in HCC patients with or without liver cirrhosis were evaluated. METHODS: One hundred fifty-eight patients undergoing liver resection for primary HCC at our institution were identified. Logistic and Cox regression analyses were used to identify prognostic parameters for postoperative complications and survival. RESULTS: In our cohort of patients, there was no association between clinical parameters or extent of surgical resection and postoperative morbidity. Only Barcelona Clinic Liver Cancer (BCLC) stage C patients were at significantly higher risk for major complications (OR 5.27, P = 0.009). Risk factors influencing long-term survival were patient age (HR 1.026, P = 0.027) and BCLC stage C (HR 3.47, P = 0.002). Compared to patients without liver cirrhosis, BCLC stage A and B patients undergoing resection were at similar risk for the development of severe complications and long-term mortality. CONCLUSION: Liver resection as potentially curative therapy can be performed in selected patients in BCLC stage B, as well as in patients with clinical signs of portal hypertension. The resection of HCC-classified BCLC stage C is feasible but associated with significant morbidity and mortality. PMID- 26627085 TI - The Influence on Population Weight Gain and Obesity of the Macronutrient Composition and Energy Density of the Food Supply. AB - Rates of overweight and obesity have increased dramatically in all regions of the world over the last few decades. Almost all of the world's population now has ubiquitous access to low-cost, but highly-processed, energy-dense, nutrient-poor food products. These changes in the food supply, rather than decreases in physical activity, are most likely the primary driver of population weight gain and obesity. To-date, the majority of prevention efforts focus on personalised approaches targeting individuals. Population-wide food supply interventions addressing sodium and trans fat reduction have proven highly effective and comparable efforts are now required to target obesity. The evidence suggests that strategies focusing upon reducing the energy density and portion size of foods will be more effective than those targeting specific macronutrients. Government leadership, clearly specified targets, accountability and transparency will be the key to achieving the food supply changes required to address the global obesity epidemic. PMID- 26627086 TI - The Influence of Portion Size and Timing of Meals on Weight Balance and Obesity. AB - This review focuses on the influence of portion size and temporal distribution of food intake on weight balance and obesity in adults. The inconsistency of definitions in the area of meal patterns is also discussed. The conclusion is that regular eating habits might facilitate weight balance, while unplanned snacking as well as consuming the major part of the energy intake at the end of the day seem to be unfavourable. Altogether, the research suggests that large portions promote over-consumption and, therefore, limiting portion size of energy dense foods and drinks with added sugar could be recommended. Even if more research is needed, these factors should be taken into consideration in recommendations for obesity prevention. PMID- 26627087 TI - The Influence of Nutrition Labeling and Point-of-Purchase Information on Food Behaviours. AB - Point-of-purchase information on packaged food has been a highly debated topic. Various types of nutrition labels and point-of-purchase information have been studied to determine their ability to attract consumers' attention, be well understood and promote healthy food choices. Country-specific regulatory and monitoring frameworks have been implemented to ensure reliability and accuracy of such information. However, the impact of such information on consumers' behaviour remains contentious. This review summarizes recent evidence on the real-world effectiveness of nutrition labels and point-of-purchase information. PMID- 26627088 TI - New Media but Same Old Tricks: Food Marketing to Children in the Digital Age. AB - 'New media' refers to digital technologies, which offer unmatched opportunities for food companies to engage with young people. This paper explores the emergence of food marketing using new media, the potential impact of this marketing on young people, and current and potential policy responses to limit exposure to these promotions. Foremost in any informed policy discussion is the need for robust evidence to demonstrate the need for intervention. In this case, such evidence relates to the extent of children's exposures to commercial food promotions via new media, and the nature of these promotions. Approaches to, and challenges of, collecting and assessing these data are discussed. There is accumulating evidence that food marketing on new media is increasing and influences children's food preferences and choices. The impact of integrated campaigns, which reinforce commercial messages across multiple platforms, and of new media, which engage personally with potential consumers, is likely to be greater than that of traditional marketing. PMID- 26627090 TI - Food Retailers and Obesity. AB - We live in an 'obesogenic environment' where we are constantly bombarded with choices that encourage us to move less and eat more. Many factors influence our dietary choices, including the expert marketers who advise manufacturers on ways to encourage the population to buy more, especially profitable, palatable 'ultra processed' foods. Supermarkets themselves have become skilled in manipulating buying behaviour, using their layout and specific product placement as well as advertising to maximise purchases of particular foods. Increasingly, supermarkets push their own 'house' brands. Those marketing fast foods also use persuasive tactics to attract customers, especially children who they entice with non-food items such as promotional or collectable toys. There is no mystery to the increase in obesity: our energy intake from foods and drinks has increased over the same period that energy output has decreased. Obesity has a range of relevant factors, but there is little doubt that marketing from supermarkets and fast food retailers has played a role. PMID- 26627089 TI - Rural and Remote Food Environments and Obesity. AB - Within most developed countries, rural residents are more likely to be obese and overweight compared to their urban counterparts. Studies of specific rural communities have found that the limited availability of healthy foods in the community and home as well as individual characteristics and preferences contribute to poor diet and overweight. The rural food environment is varied and may be affected by climate, regional and cultural preferences, transportation access, and remoteness among other factors. Given this diversity and the vulnerabilities of rural residents, who are more likely to have low-income, substandard housing or low educational attainment compared to their urban counterparts, policy and programmatic interventions should target specific needs and communities. This review will describe the rural community, home, and individual food environments and what is known about their roles in healthy eating. PMID- 26627091 TI - Obesity and Maternal Weight Gain. AB - Pregnancy is a time when women may be receptive to health advice and interventions. This article considers the evidence for interventions to affect body weight in obese and overweight women delivered either or both pre- and post natally. The increasing prevalence of obesity across the adult population has affected many sectors of society and increasing numbers of obese and overweight pregnant women are evident. Obesity in pregnancy is frequently associated with excessive gestational weight gains and increases the risk of developing adverse pregnancy outcomes in terms of both maternal and infant health. Pregnancy has been described as providing "a teachable moment" when women may be receptive to health advice. Some lifestyle approaches, largely incorporating strategies to alter dietary and physical activity to challenge excess body weight before and during pregnancy, have been developed and tested. While a few have shown promise with limited success in reducing body weight prior to pregnancy and post-natally, and minimising excessive weight gains during pregnancy, all interventions are not sufficiently robust and effective to justify routine inclusion in clinical practice. Weight management pre- and post-natally appears largely overlooked in usual care. PMID- 26627092 TI - Self-Weighing: Helpful or Harmful for Psychological Well-Being? A Review of the Literature. AB - Conflicting views as to the helpfulness or harmfulness of self-weighing for the control of body weight have been presented in the fields of obesity and eating disorders. Because self-weighing is increasingly being considered as an intervention to promote weight loss or prevent weight gain, it is timely to consider unintended psychological outcomes and behavioral correlates of this behavior. Twenty articles from the published literature examining self-weighing and psychological outcomes or weight control behaviors were reviewed. In evaluating self-weighing and affect (ten studies), self-esteem (four studies) and body evaluation (ten studies), and eating behaviors/cognitions (13 studies), in total, most studies found a negative relationship between self-weighing and outcomes (affect: 4/10, self-esteem: 3/4, body evaluation: 4/10, eating behaviors/cognitions: 6/13). Themes that emerged included relationships between self-weighing and negative outcomes for women and younger individuals, and lack of a relationship or positive outcomes for overweight, treatment seeking individuals. Though self-weighing has shown promise in aiding weight control, the degree to which weight loss, and not self-weighing, affects psychological outcomes is not clear. Further assessment of psychological outcomes in self weighing research may be warranted, as this review suggests the potential for adverse effects of self-weighing in some individuals. PMID- 26627093 TI - The 'Fat Mass and Obesity Related' (FTO) gene: Mechanisms of Impact on Obesity and Energy Balance. AB - A cluster of single nucleotide polymorphisms (SNPs) in the first intron of the fat mass and obesity related (FTO) gene were the first common variants discovered to be associated with body mass index and body fatness. This review summarises what has been later discovered about the biology of FTO drawing together information from both human and animal studies. Subsequent work showed that the 'at risk' alleles of these SNPs are associated with greater food intake and increased hunger/lowered satiety, but are not associated with altered resting energy expenditure or low physical activity in humans. FTO is an FE (II) and 2 oxoglutarate dependent DNA/RNA methylase. Contrasting the impact of the SNPs on energy balance in humans, knocking out or reducing activity of the Fto gene in the mouse resulted in lowered adiposity, elevated energy expenditure with no impact on food intake (but the impact on expenditure is disputed). In contrast, overexpression of the gene in mice led to elevated food intake and adiposity, with no impact on expenditure. In rodents, the Fto gene is widely expressed in the brain including hypothalamic nuclei linked to food intake regulation. Since its activity is 2-oxoglutarate dependent it could potentially act as a sensor of citrate acid cycle flux, but this function has been dismissed, and instead it has been suggested to be much more likely to act as an amino acid sensor, linking circulating AAs to the mammalian target of rapamycin complex 1. This may be fundamental to its role in development but the link to obesity is less clear. It has been recently suggested that although the obesity related SNPs reside in the first intron of FTO, they may not only impact FTO but mediate their obesity effects via nearby genes (notably RPGRIP1L and IRX3). PMID- 26627094 TI - Alcohol, Appetite and Loss of Restraint. AB - Alcoholic beverages have long been associated with feasts, celebration and marking special events. Today, it is commonplace to consume alcoholic beverages before, with and/or after a meal. Alcohol provides additional pleasure to the meal and enhances appetite. However, consuming an alcoholic beverage with or before a meal is associated with poor short-term energy compensation; energy from alcohol is additive to total energy intake with the added property of stimulating further eating. Limiting alcohol intake is an obvious means to reduce total energy intake for those who wish to lose weight. However, dieters and restrained eaters drink more and report greater binge drinking than unrestrained eaters despite employing cognitive strategies to reduce their intake. Increased intake may be attributable to greater attentional bias to alcohol related cues as well as to food cues, since these are more salient to those limiting intake. Alcohol increases energy intake in dieters, in part due to abandonment of restraint (disinhibition) and consumption of forbidden items including alcohol exacerbates attempts to resist temptation. Paradoxically, links between binge drinking or increased drinking frequency to overweight and obesity may be mediated by dietary restraint. Efforts to limit food and alcohol intake for weight control appear to be unsuccessful and have the net effect of promoting overconsumption. The potential role of restrained eating in the association between alcohol, appetite and obesity has been overlooked by much of the current research and further investigation of this is therefore warranted. PMID- 26627095 TI - Is Sugar the new Tobacco? Insights from Laboratory Studies, Consumer Surveys and Public Health. AB - In the Americas, mean energy intake from added sugar exceeds recent World Health Organization recommendations for free sugars in the diet. As a leading contributor to this excess, sugar-sweetened beverage (SSB) overconsumption represents a risk for the population's health. This article provides an overview of clinical and epidemiological evidence, marketing practices, corporate influence and prevention strategies related to added sugar and SSB. For each aspect of this multidimensional profile, we briefly compare SSB to the case of tobacco pointing to similarities but also major differences. Tobacco control has demonstrated the effectiveness of long term multifaceted prevention strategies in multiple settings supported by strong public policies which may be applied to the consumption of SSB. However, translating these policies to the specific case of SSB is urgently needed, to inform preventive actions, decide which intervention mix will be used, and evaluate the process and impact of the chosen strategy. PMID- 26627096 TI - Expected Satiety: Application to Weight Management and Understanding Energy Selection in Humans. AB - Recent advances in the approaches used to quantify expectations of satiation and satiety have led to a better understanding of how humans select and consume food, and the associated links to energy intake regulation. When compared calorie for calorie some foods are expected to deliver several times more satiety than others, and multiple studies have demonstrated that people are able to discriminate between similar foods reliably and with considerable sensitivity. These findings have implications for the control of meal size and the design of foods that can be used to lower the energy density of diets. These methods and findings are discussed in terms of their implications for weight management. The current paper also highlights why expected satiety may also play an important role beyond energy selection, in moderating appetite sensations after a meal has been consumed, through memory for recent eating and the selection of foods across future meals. PMID- 26627097 TI - Mindfulness, Eating Behaviours, and Obesity: A Review and Reflection on Current Findings. AB - Mindfulness and mindful eating have become popular in recent years. In this review, we first explore what mindfulness is in the context of psychological research, and why it offers promise for eating behaviours and weight loss. Second, we review the main empirical findings for weight loss in mindfulness based intervention programmes. Third, contradictions in the findings are explored in more depth, and suggestions are made regarding why they may be occurring. Fourth, the benefits of adding self-compassion (and compassion) training to mindfulness practise to assist weight loss is discussed. Finally, the limitations of the research literature (and possible solutions) are explored. Overall, it is concluded that while mindfulness meditations that specifically focus on eating may be extremely helpful in promoting better eating behaviours, and assist in weight regulation, work is still needed to make such interventions appeal to a wider audience. PMID- 26627098 TI - Evolutionary morphology of podocytes and primary urine-producing apparatus. AB - Excretory organs were acquired in the early phase of metazoan evolution, and they play a crucial role in the maintenance of homeostasis of body fluids. In general, these organs consist of two functional components, the primary-urine producing apparatus and the modulating tubule. This basic organization of the excretory organs is conserved among most metazoans. Herein, we present an overview of the morphological evolution of the primary urine-producing apparatus in metazoans and describe the acquisition of the renal glomerulus-a specialized primary urine producing apparatus-in vertebrates. We also describe the advancement of the glomerular structure and function in higher vertebrates. PMID- 26627099 TI - Increased diet-induced fatty streak formation in female mice with deficiency of liver-derived insulin-like growth factor-I. AB - The role of endocrine IGF-I for atherosclerosis is unclear. We determined the importance of circulating, liver-derived IGF-I for fatty streak formation in mice. Mice with adult, liver-specific IGF-I inactivation (LI-IGF-I(-/-) mice, serum IGF-I reduced by approximately 80 %) and control mice received an atherogenic (modified Paigen) diet between 6 and 12 months of age. At study end, Oil Red O staining of aortic root cryosections showed increased fatty streak area and lipid deposition in female but not in male LI-IGF-I(-/-) mice compared to controls. Mac-2 staining of aortic root and measurements of CD68 mRNA level in femoral artery revealed increased macrophage accumulation in proportion to the increased fatty streak area in female LI-IGF-I(-/-) mice. Moreover, female LI-IGF I(-/-) mice displayed increased serum cholesterol and interleukin-6 as well as increased vascular cell-adhesion molecule 1 (VCAM1) mRNA levels in the femoral artery and elevated VCAM1 protein expression in the aortic root. Thus, increased diet-induced fatty streak formation in female LI-IGF-I(-/-) mice was associated with increased serum cholesterol and signs of systemic inflammation, endothelial activation, lipid deposition, and macrophage infiltration in the vascular wall. PMID- 26627100 TI - Antithrombotic Effects of Amaranthus hypochondriacus Proteins in Rats. AB - Cardiovascular disease (CVD) is a major cause of disability and premature death throughout the world. Diets with antithrombotic components offer a convenient and effective way of preventing and reducing CVD incidence. The aim of the present work was to assess in vivo and ex vivo effects of Amaranthus hypochondriacus proteins on platelet plug formation and coagulation cascade. Amaranth proteins were orally administrated to rats (AG, 8 animals) and bleeding time was determined showing no significant difference compared with control rats (CG, 7 animals). However, results show a strong tendency, suggesting that amaranth proteins are involved in the inhibition of thrombus formation. Non-anticoagulated blood extracted from animals was analyzed with the hemostatometer, where AG parameters obtained were twice the values showed by CG. The clotting tests, thrombin time (TT) and activated partial thromboplastin time (APTT), presented a 17 and 14% clotting formation increase respectively when comparing AG with CG. The ex-vivo assays confirm the hypothesis inferring that amaranth proteins are a potential antithrombotic agent. PMID- 26627101 TI - The role of cancer-associated fibroblasts in breast cancer pathobiology. AB - The role of the tumor microenvironment (TME) is critical in cancer pathobiology. Of the components of the TME, cancer-associated fibroblasts (CAFs) play a major role. Breast cancer is a typical tumor type, forming abundant tumor stroma, and CAFs are involved in various aspects of breast cancer, including carcinogenesis, tumor progression, invasion, metastasis, inflammation, metabolism, therapy resistance, and prognosis. Various factors, such as growth factors, cytokines, hormones secreted from CAFs, paracrine effects promoted by the extracellular matrix (ECM), and mechanical pressure, are involved in cancer development, and there are various crosstalk and signaling pathways among CAFs, cancer cells, epithelial cells, and the ECM. Recent studies have evaluated the potential of CAFs as therapeutic targets in breast cancer. In this review, we discuss the role of CAFs and their clinical implications. PMID- 26627102 TI - Inflammation Perturbs the IL-7 Axis, Promoting Senescence and Exhaustion that Broadly Characterize Immune Failure in Treated HIV Infection. AB - BACKGROUND: HIV-infected patients who fail to normalize CD4 T cells despite suppressive antiretroviral therapy have impaired immune homeostasis: diminished naive T-cell numbers, elevated T-cell turnover, senescence, and inflammation. METHODS: Blood samples from immune failures (n = 60), immune successes (n = 20), and healthy controls (n = 20) were examined for plasma interleukin (IL)-7 levels, for cellular expression of the IL-7Ralpha chain (CD127), for the exhaustion and senescence markers programed death 1 (PD-1) and CD57, and for the survival factor Bcl2. Because both inflammatory and homeostatic cytokines can induce T-cell cycling, we also examined the effects of these mediators on exhaustion and senescence markers. RESULTS: Plasma levels of IL-7 were elevated and both CD4 and CD8 T-cell CD127 expression was decreased in immune failure. Plasma levels of IL 7 correlated directly with naive CD4 T-cell counts in immune success and inversely with T-cell cycling (Ki67) in healthy controls and immune success, but not in immune failure. CD4 T-cell density of PD-1 was increased and Bcl2+ CD4 T cells were decreased in immune failure but not in immune success, whereas the proportion of T cells expressing CD57 was increased in immune failure. PD-1 and CD57 were induced on CD4 but not CD8 T cells by stimulation in vitro with inflammatory IL-1beta or homeostatic (IL-7) cytokines. CONCLUSIONS: Perturbation of the IL-7/IL-7 receptor axis, increased T-cell turnover, and increased senescence may reflect dysregulated responses to both homeostatic and inflammatory cytokines in immune failure patients. PMID- 26627104 TI - Implementation and Operational Research: A Comparison of Two Task-Shifting Models of Pharmaceutical Care in Antiretroviral Treatment Programs in South Africa. AB - BACKGROUND: The severe shortage of pharmacists is an important limitation to providing antiretroviral treatment (ART) in resource-limited countries. Two task shifting pharmaceutical care models have been developed to address this in South Africa, namely indirectly supervised pharmacist assistant (ISPA) and nurse managed models. This study compared pharmaceutical care quality, patient clinical outcomes, and provider staff costs between these models. METHODS: An analysis of pharmaceutical quality audits, patient clinical data, and staff costing data collected at 7 ISPA and 8 nurse-managed facilities was undertaken. Pharmaceutical audits were conducted by pharmacists using a standardized tool. Routine clinical data were collected prospectively at patient visits, and staff human resources costs were analyzed. RESULTS: Overall pharmaceutical care quality scores were higher at ISPA sites than nurse-managed sites; 88.8% vs. 79.9%, respectively; risk ratio (ISPA vs. nurse) = 1.11 (95% confidence interval: 1.09 to 1.13; P < 0.0001). Mean provider pharmaceutical-related human resources costs per patient visit and per item dispensed were 29% and 49% lower, respectively, at ISPA facilities. At ISPA facilities, patient attrition was observed to be lower and viral suppression higher than at nurse-managed sites. CONCLUSION: The ISPA model had a higher quality of pharmaceutical care and was less costly to implement. Further expansion of this model or integrating it with nurse-managed ART may enhance the cost-efficient scale-up of ART programs in Sub-Saharan Africa. PMID- 26627103 TI - Duration of cART Before Delivery and Low Infant Birthweight Among HIV-Infected Women in Lusaka, Zambia. AB - OBJECTIVE: To estimate the association between duration of combination antiretroviral therapy (cART) during pregnancy and low infant birthweight (LBW), among women >=37 weeks of gestation. DESIGN: We conducted a retrospective cohort study of HIV-infected women who met eligibility criteria based on CD4 count <=350 but had not started cART at entry into antenatal care. Our cohort was restricted to births that occurred >=37 weeks of gestation. METHODS: We used Poisson models with robust variance estimators to estimate risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: Of 50,765 HIV-infected women with antenatal visits between January 2009 and September 2013, 4474 women met the inclusion criteria. LBW occurred in 302 pregnancies (7%). Nearly two-thirds of women (62%) eligible to initiate cART never started treatment. Overall, 14% were on cART for <=8 weeks, 22% for 9-20 weeks, and 2% for 21-36 weeks. There was no evidence of an increased risk of LBW for women receiving cART for <=8 weeks (RR = 1.22; 95% CI: 0.77 to 1.91), 9-20 weeks (RR = 1.23; 95% CI: 0.82 to 1.83), or 21-36 weeks (RR = 0.87; 95% CI: 0.22 to 3.46), compared with women who never initiated treatment. These findings were consistent across several sensitivity analyses. CONCLUSIONS: Longer duration of cART was not associated with poor fetal growth among term pregnancies in our cohort. However, the relationship between cART and adverse pregnancy outcomes remains complicated. Continued work is required to investigate causality. An understanding cART's impact on adverse pregnancy outcomes is essential as cART becomes the cornerstone of preventing mother-to-child transmission programs globally. PMID- 26627105 TI - Elevations in Serum Creatinine With Tenofovir-Based HIV Pre-Exposure Prophylaxis: A Meta-Analysis of Randomized Placebo-Controlled Trials. PMID- 26627106 TI - Barriers to Routine HIV Testing in Healthcare Settings and Potential Solutions from the Get Tested Coachella Valley Campaign. PMID- 26627107 TI - Switching to Tenofovir Alafenamide, Coformulated With Elvitegravir, Cobicistat, and Emtricitabine, in HIV-Infected Patients With Renal Impairment: 48-Week Results From a Single-Arm, Multicenter, Open-Label Phase 3 Study. AB - BACKGROUND: Tenofovir alafenamide (TAF) is a novel tenofovir prodrug with improved renal and bone safety compared with TDF-containing regimens. We report the 48 week safety and efficacy of a once-daily single tablet regimen of elvitegravir 150 mg (E), cobicistat 150 mg (C), emtricitabine 200 mg (F), and TAF 10 mg (E/C/F/TAF) in HIV-1-infected patients with mild to moderate renal impairment. METHODS: We enrolled virologically suppressed HIV-1-infected subjects with estimated creatinine clearance (CrCl) 30-69 mL/min in a single-arm, open label study to switch regimens to E/C/F/TAF. The primary endpoint was the change from baseline in glomerular filtration rate estimated using various formulae. This study is registered with ClinicalTrials.gov, number NCT01818596. FINDINGS: We enrolled and treated 242 patients with mean age 58 years, 18% Black, 39% hypertension, 14% diabetes. Through week 48, no significant change in estimated CrCl was observed. Two patients (0.8%) discontinued study drug for decreased creatinine clearance, neither had evidence of renal tubulopathy and both had uncontrolled hypertension. Subjects had significant improvements in proteinuria, albuminuria, and tubular proteinuria (P < 0.001 for all). Hip and spine bone mineral density significantly increased from baseline to week 48 (mean percent change +1.47 and +2.29, respectively, P < 0.05). Ninety-two percent (222 patients) maintained HIV-1 RNA <50 copies per milliliter at week 48. INTERPRETATION: Switch to E/C/F/TAF was associated with minimal change in GFR. Proteinuria, albuminuria and bone mineral density significantly improved. These data support the efficacy and safety of once daily E/C/F/TAF in HIV+ patients with mild or moderate renal impairment without dose adjustment. PMID- 26627108 TI - Genetic and molecular characterization of H9N2 and H5 avian influenza viruses from live poultry markets in Zhejiang Province, eastern China. AB - Live poultry markets (LPMs) are a key source of reassorted avian influenza viruses (AIVs) because of the density of terrestrial and aquatic poultry and the frequency of AIV infection. H9N2 viruses are prevalent in terrestrial poultry throughout Asia and have been isolated from poultry outbreaks worldwide. They infect both avian and mammalian species and may be significant donors of genetic material to emerging human pathogens. LPMs in Zhejiang Province were surveyed from 2013-2014 for AIVs. Three hundred seventy-four (374) AIV strains were isolated from 3,328 samples. Whole-genome sequencing and phylogenetic analyses were performed. We identified a novel H9N2 virus genotype that had undergone reassortment with gene segments from Qa/HK/G1/97-like, Ck/BJ/1/94-like, and Dk/HK/Y439/97-like viruses. Phylogenetic analyses suggested the H9N2 viruses had undergone reassortments with other AIV subtypes. The results also suggested that two different clades (2.3.2 and 2.3.4.6) of H5 viruses were co-circulating in Zhejiang Province. Given that reassorted H5 AIVs were detected in geese and ducks, it is possible that apparently healthy birds contribute to emerging H5 AIVs. Continued surveillance is required in poultry in eastern China. PMID- 26627109 TI - A retrospective and consecutive analysis of the epidemiology and management of spinal cavernomas over the last 20 years in a single center. AB - Spinal cavernous malformations (SCM) are rare lesions often presenting with acute onset of symptoms and progressive neurological deterioration due to hemorrhage into the spinal cord. With the aid of modern techniques, their surgical removal became much safer. The present study was undertaken to analyze the outcome of our series of surgically and conservatively treated patients with SCM. Over a period of 20 years, 20 surgically treated and 5 conservatively managed patients with spinal cavernous malformations were identified and enrolled into this analysis. Demographic data, clinical symptoms, localization and extension of the cavernoma, as well as pre- and postoperative neurological status were obtained. The clinical status was assessed using the Frankel score. Patients were followed up clinically and by MRI. Before surgery, 90% (18/20) of our surgical patients were classified as Frankel D (93.8%), whereas two patients (10%) were graded C. None of the patients had a worse Frankel score at the time of discharge. Eighty percent of them (16 cases) remained unchanged, and 20% (4 patients) improved during the first follow-up (mean 6.3 months, range 2-17 months). All improved patients had a superficially located SCM and were operated early (<=3 months). No worsening was observed during extended follow-up (range 9-134 months, mean 44.7 months). Five nonsurgically treated patients showed no significant clinical deterioration over a period of 6.7 years (mean, range 2.9-8 years). SCM localization and number of involved segments had no influence on outcome. Our data show that SCM can be resected with favorable neurological outcome by using intraoperative neuromonitoring. Within the follow-up period, patients treated conservatively remained in a stable neurological condition. PMID- 26627110 TI - Remote cerebellar hemorrhage after spinal procedures (part 2): a systematic review. AB - A remote cerebellar hemorrhage (RCH) is a spontaneous bleeding in the posterior fossa, which can be rarely observed as a complication of spine surgery. As well as for RCH reported after supratentorial procedures, it shows a characteristic bleeding pattern defined "zebra sign". Nowadays, RCH pathophysiology still remains unknown. We performed a comprehensive review, collecting all cases of RCH after spine surgery reported in literature in order to identify the procedures most frequently associated with RCH and the possible risk factors. We assessed percentages of incidence and 95 % confidence interval of all demographic, neuroradiological, and clinical features. Univariate and multivariate analyses were used to evaluate their association with outcome. We included 44 articles reporting 57 patients with mean age of 57.6 +/- 13.9 years and a male/female ratio of 23/34. A RCH was more frequently reported as a complication of decompressive procedures for spinal canal stenosis, particularly when associated with instrumented fusion, followed by spinal tumor debulking and disc herniation removal. In the majority of cases, RCH occurrence was characterized by progressive impairment of consciousness, whereas some patients complained non specific symptoms. Coagulation disorders, hypertension, and placement of postoperative subfascial drainages were the most frequently reported risk factors. The occurrence of intraoperative dural lesions was described in about 93 % of patients. Zebra sign was the most common bleeding pattern (about 43 % of cases) followed by parenchymal hematoma (37.5 %) and mixed hemorrhage (about 20 %). Impairment of consciousness at clinical onset and intake of anticoagulants/antiplatelets appeared associated with poor outcome at univariate analysis. However, more than 75 % of patients showed a good outcome and a RCH often appeared as a benign and self-limiting condition, which usually did not require surgical treatment, but only prolonged clinical surveillance, unless of the occurrence of complications. PMID- 26627111 TI - Return to Play and Performance After Jones Fracture in National Basketball Association Athletes. AB - BACKGROUND: Basketball players are at risk for foot injuries, including Jones fractures. It is unknown how this injury affects the future play and performance of athletes. HYPOTHESIS: National Basketball Association (NBA) players who sustain Jones fractures of the base of the fifth metatarsal have high rates of return to play and do not experience a decrease in performance on return to competition when compared with preinjury and with control-matched peers. STUDY DESIGN: Retrospective cohort study. LEVEL OF EVIDENCE: Level 5. METHODS: Data on 26 elite basketball players with Jones fractures over 19 NBA seasons (1994-1995 to 2012-2013) were obtained from injury reports, press releases, player profiles, and online public databases. Variables included age, body mass index (BMI), player position, experience, and surgical treatment. Individual season statistics pre- and postinjury were collected. Twenty-six controls were identified by matched player position, age, and performance statistics. RESULTS: The mean age at the time of injury was 24.8 years, mean BMI was 24.7 kg/m(2), and the mean experience prior to injury was 4.1 NBA seasons. Return to previous level of competition was achieved by 85% of athletes. There was no change in player efficiency rating (PER) when pre- and postinjury performance was compared. When compared with controls, no decline in PER measured performance was identified. CONCLUSION: The majority of NBA players sustaining a Jones fracture return to their preinjury level of competition. These elite athletes demonstrate no decrease in performance on their return to play. CLINICAL RELEVANCE: Jones fractures are well-studied injuries in terms of etiology, diagnosis, and management. However, the effect of these injuries on future performance of athletes is unknown. Using the findings of our study, orthopaedic surgeons may be better prepared to counsel and educate elite athletes who sustain a Jones fracture. PMID- 26627113 TI - [Isolation of enteropathogenic Escherichia coli O157:H16 identified in a diarrhea case in a child and his household contacts in La Pampa Province, Argentina]. AB - Enteropathogenic Escherichia coli (EPEC) is a major causative agent of acute diarrhea in children in developing countries. This pathotype is divided into typical EPEC (tEPEC) and atypical EPEC (aEPEC), based on the presence of the bfp virulence factor associated with adhesion, encoded in the pEAF plasmid. In the present study, the isolation of aEPEC O157:H16 from a bloody diarrhea case in a child and his household contacts (mother, father and sister) is described. The strain was characterized as E. coli O157:H16 eae-E-positive, sorbitol fermenter with beta-glucuronidase activity, susceptible to all antimicrobials tested, and negative for virulence factors stx1, stx2, ehxA and bfp. XbaI-PFGE performed on all isolates showed the AREXHX01.1040 macrorestriction pattern, with 100% similarity. These results highlight the importance of epidemiological surveillance of E. coli O157-associated diarrhea cases identified in children and their family contacts, as well as the incorporation of molecular techniques that allow the detection of the different E. coli pathotypes. PMID- 26627114 TI - [Serological evidence of St. Louis encephalitis virus circulation in birds from Buenos Aires City, Argentina]. AB - Our goal was to determine the presence of neutralizing antibodies against St. Louis encephalitis virus (SLEV) and West Nile virus (WNV) in sera of wild and domestic birds from Buenos Aires City, Argentina. From October 2012 to April 2013, 180 samples were collected and processed by the microneutralization technique. A 7.2% of the sampled birds were seropositive for SLEV, while no seropositive birds for WNV were detected. PMID- 26627115 TI - Support not corresponding to transition to a new treatment: Women's perceptions of support provided by their male partners during hormonal therapy. AB - Women with breast cancer receive support from their partners to deal with the side effects of therapies over the cancer trajectory. Hormonal therapy (HT) is usually given after completing other treatments, and women receiving HT reclaim their normal life. This may lead to changes in support from their partners. Therefore, we explored women's perceptions of the support provided by their male partners in managing the side effects of adjuvant HT. We conducted semi structured interviews with 10 women who received HT and recognized their partners as a main source of support. An interview guide was used to explore their experiences of treatment side effects, the contents of support received from their partners, their need for support, and their overall relationship with their partners. Interviews were analysed by content analysis. A theme on how participants perceived support from their partners was formulated as "Support not corresponding to transition to a new treatment" with the following categories: "Shrinking support," "Primacy of partner," and "Solitary new treatment." Participants felt lack of support from their partners because their partners did not understand their experience of the side effects induced by HT. Unlike the side effects of past treatments such as surgery and chemotherapy, side effects of HT cannot be observed and are highly subjective. Their partners often failed to notice these symptoms and provided little support. Nevertheless, participants aimed to accept the existing support without asking for more. They were left alone in the continuing trajectory of breast cancer. After starting HT, women entered a new treatment phase in which less understanding and support was provided by partners. Educational support for couples may enable sharing of subjective symptoms that are not obvious to partners and improve outcomes by facilitating partner engagement and support. PMID- 26627116 TI - Molecular Structure and Regulation of P2X Receptors With a Special Emphasis on the Role of P2X2 in the Auditory System. AB - The P2X purinergic receptors are cation-selective channels gated by extracellular adenosine 5'-triphosphate (ATP). These purinergic receptors are found in virtually all mammalian cell types and facilitate a number of important physiological processes. Within the past few years, the characterization of crystal structures of the zebrafish P2X4 receptor in its closed and open states has provided critical insights into the mechanisms of ligand binding and channel activation. Understanding of this gating mechanism has facilitated to design and interpret new modeling and structure-function experiments to better elucidate how different agonists and antagonists can affect the receptor with differing levels of potency. This review summarizes the current knowledge on the structure, activation, allosteric modulators, function, and location of the different P2X receptors. Moreover, an emphasis on the P2X2 receptors has been placed in respect to its role in the auditory system. In particular, the discovery of three missense mutations in P2X2 receptors could become important areas of study in the field of gene therapy to treat progressive and noise-induced hearing loss. J. Cell. Physiol. 231: 1656-1670, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26627117 TI - Ca(2+) -complex stability of GAPAGPLIVPY peptide in gas and aqueous phase, investigated by affinity capillary electrophoresis and molecular dynamics simulations and compared to mass spectrometric results. AB - Strong, sequence-specific gas-phase bindings between proline-rich peptides and alkaline earth metal ions in nanoESI-MS experiments were reported by Lehmann et al. (Rapid Commun. Mass Spectrom. 2006, 20, 2404-2410), however its relevance for physiological-like aqueous phase is uncertain. Therefore, the complexes should also be studied in aqueous solution and the relevance of the MS method for binding studies be evaluated. A mobility shift ACE method was used for determining the binding between the small peptide GAPAGPLIVPY and various metal ions in aqueous solution. The findings were compared to the MS results and further explained using computational methods. While the MS data showed a strong alkaline earth ion binding, the ACE results showed nonsignificant binding. The proposed vacuum state complex also decomposed during a molecular dynamic simulation in aqueous solution. This study shows that the formed stable peptide metal ion adducts in the gas phase by ESI-MS does not imply the existence of analogous adducts in the aqueous phase. Comparing peptide-metal ion interaction under the gaseous MS and aqueous ACE conditions showed huge difference in binding behavior. PMID- 26627118 TI - Visible light photoactivity of Polypropylene coated Nano-TiO2 for dyes degradation in water. AB - The use of Polypropylene as support material for nano-TiO2 photocatalyst in the photodegradation of Alizarin Red S in water solutions under the action of visible light was investigated. The optimization of TiO2 pastes preparation using two commercial TiO2, Aeroxide P-25 and Anatase, was performed and a green low-cost dip-coating procedure was developed. Scanning electron microscopy, Atomic Force Microscopy and X-Ray Diffraction analysis were used in order to obtain morphological and structural information of as-prepared TiO2 on support material. Equilibrium and kinetics aspects in the adsorption and successive photodegradation of Alizarin Red S, as reference dye, are described using polypropylene-TiO2 films in the Visible/TiO2/water reactor showing efficient dyes degradation. PMID- 26627119 TI - Correlation of the Dysphonia Severity Index (DSI), Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V), and Gender in Brazilians With and Without Voice Disorders. AB - OBJECTIVES: This study aims to analyze the Dysphonia Severity Index (DSI) in Brazilians with or without voice disorders and investigate DSI's correlation with gender and auditory-perceptual evaluation data obtained via the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) protocol. STUDY DESIGN: A total of 66 Brazilian adults from both genders participated in the study, including 24 patients with dysphonia confirmed on laryngeal examination (dysphonic group [DG]) and 42 volunteers without voice or hearing complaints and without auditory perceptual voice disorders (nondysphonic group [NDG]). METHODS: The vocal tasks included in CAPE-V and DSI were performed and recorded. Data were analyzed by means of the independent t test, the Mann-Whitney U test, and Pearson correlation at the 5% significance level. RESULTS: Differences were found in the mean DSI values between the DG and the NDG. Differences were also found in all DSI items between the groups, except for the highest frequency parameter. In the DG, a moderate negative correlation was detected between overall dysphonia severity (CAPE-V) and DSI value, and between breathiness and DSI value, and a weak negative correlation was detected between DSI value and roughness. In the NDG, the maximum phonation time was higher among males. In both groups, the highest frequency parameter was higher among females. CONCLUSIONS: The DSI discriminated among Brazilians with or without voice disorders. A correlation was found between some aspects of the DSI and the CAPE-V but not between DSI and gender. PMID- 26627120 TI - Pregnancy outcomes decline with increasing body mass index: analysis of 239,127 fresh autologous in vitro fertilization cycles from the 2008-2010 Society for Assisted Reproductive Technology registry. AB - OBJECTIVE: To examine the effect of body mass index (BMI) on IVF outcomes in fresh autologous cycles. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 239,127 fresh IVF cycles from the 2008-2010 Society for Assisted Reproductive Technology registry were stratified into cohorts based on World Health Organization BMI guidelines. Cycles reporting normal BMI (18.5-24.9 kg/m(2)) were used as the reference group (REF). Subanalyses were performed on cycles reporting purely polycystic ovary syndrome (PCOS)-related infertility and those with purely male-factor infertility (34,137 and 89,354 cycles, respectively). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation rate, clinical pregnancy rate, pregnancy loss rate, and live birth rate. RESULT(S): Success rates and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for all pregnancy outcomes were most favorable in cohorts with low and normal BMIs and progressively worsened as BMI increased. Obesity also had a negative impact on IVF outcomes in cycles performed for PCOS and male-factor infertility, although it did not always reach statistical significance. CONCLUSION(S): Success rates in fresh autologous cycles, including those done for specifically PCOS or male-factor infertility, are highest in those with low and normal BMIs. Furthermore, there is a progressive and statistically significant worsening of outcomes in groups with higher BMIs. More research is needed to determine the causes and extent of the influence of BMI on IVF success rates in other patient populations. PMID- 26627121 TI - First trimester pregnancy loss after fresh and frozen in vitro fertilization cycles. AB - OBJECTIVE: To characterize risks for early pregnancy loss after fresh and frozen IVF cycles and to investigate whether risk is modified by infertility diagnoses or transfer of embryos in fresh versus frozen cycles. DESIGN: Retrospective cohort study using data from the National Assisted Reproductive Technology (ART) Surveillance System. SETTING: Fertility centers. PATIENT(S): Clinical pregnancies achieved with fresh and frozen IVF cycles between 2007 and 2012 (N = 249,630). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): First trimester pregnancy loss. RESULT(S): A diagnosis of uterine factor was associated with an increased risk of loss in women aged 40 years and younger (<30 years: adjusted risk ratio (aRR) = 1.24, 95% confidence interval (CI) 1.04-1.48; 30-34 years: aRR = 1.27, 95% CI 1.17-1.38; 35-37 years: aRR = 1.12, 95% CI 1.03-1.21; 38-40 years: aRR = 1.08, 95% CI 1.01-1.17). There was an increased risk of loss in women with diminished ovarian reserve aged 30-34 years (aRR = 1.08, 95% CI 1.01-1.15) and in women with ovulatory dysfunction younger than 35 years (<30 years: aRR = 1.12, 95% CI 1.05 1.19; 30-34 years: aRR = 1.07, 95% CI 1.02-1.13). There was an increased risk of loss after frozen ETs versus fresh among women younger than 38 years, but this remained significant in the subanalysis of similar quality embryos only in women younger than 30 years (aRR = 1.16, 95% CI 1.04-1.32). CONCLUSION(S): Uterine factor had the largest increased risk of loss among infertility diagnoses, although the magnitudes of all risks were small. When transferring embryos of similar quality, the risks of loss were similar between fresh and frozen cycles. PMID- 26627122 TI - Climate change, water and security in the Mediterranean: Introduction to the special issue. PMID- 26627123 TI - Review of the scientific evidence to support environmental risk assessment of shale gas development in the UK. AB - Interest in the development of shale gas resources using hydraulic fracturing techniques is increasing worldwide despite concerns about the environmental risks associated with this activity. In the United Kingdom (UK), early attempts to hydraulically fracture a shale gas well resulted in a seismic event that led to the suspension of all hydraulic fracturing operations. In response to this occurrence, UK regulators have requested that future shale gas operations that use hydraulic fracturing should be accompanied by a high-level environmental risk assessment (ERA). Completion of an ERA can demonstrate competency, communicate understanding, and ultimately build trust that environmental risks are being managed properly, however, this assessment requires a scientific evidence base. In this paper we discuss how the ERA became a preferred assessment technique to understand the risks related to shale gas development in the UK, and how it can be used to communicate information between stakeholders. We also provide a review of the evidence base that describes the environmental risks related to shale gas operations, which could be used to support an ERA. Finally, we conclude with an update of the current environmental risks associated with shale gas development in the UK and present recommendations for further research. PMID- 26627124 TI - Mechanisms of resistance to fluconazole in Candida albicans clinical isolates from Iranian HIV-infected patients with oropharyngeal candidiasis. AB - OBJECTIVES: The opportunistic pathogen Candida albicans is the major agent of oropharyngeal candidiasis (OPC) in HIV/AIDS patients. The increased use of fluconazole can lead to the emergence of azole-resistant strains and treatment failures in PLWH (people living with HIV) receiving long-term therapy for OPC. The purpose of this study was to evaluate CDR1, CDR2, MDR1, and ERG11 gene expression in C. albicans clinically isolated from HIV-infected patients in Iran. PATIENTS AND METHODS: In this study, we evaluated the molecular mechanisms of azole resistance in 20 fluconazole-resistant C. albicans isolates obtained from Iranian HIV-infected patients with oropharyngeal candidiasis by Real-Time polymerase chain reaction. RESULTS: The overexpression of drug efflux pump CDR1 gene was found to be the major resistance mechanism observed in these isolates. The overexpression of the CDR1 gene correlated strongly with increasing resistance to fluconazole (P<0.05). Additionally, an increased level of mRNA in ERG11 was not observed in any of the tested isolates. CONCLUSIONS: Our findings suggested that the CDR1 gene expression to fluconazole resistance in C. albicans is greater than other known genes. PMID- 26627125 TI - Boundaries can steer active Janus spheres. AB - The advent of autonomous self-propulsion has instigated research towards making colloidal machines that can deliver mechanical work in the form of transport, and other functions such as sensing and cleaning. While much progress has been made in the last 10 years on various mechanisms to generate self-propulsion, the ability to steer self-propelled colloidal devices has so far been much more limited. A critical barrier in increasing the impact of such motors is in directing their motion against the Brownian rotation, which randomizes particle orientations. In this context, here we report directed motion of a specific class of catalytic motors when moving in close proximity to solid surfaces. This is achieved through active quenching of their Brownian rotation by constraining it in a rotational well, caused not by equilibrium, but by hydrodynamic effects. We demonstrate how combining these geometric constraints can be utilized to steer these active colloids along arbitrary trajectories. PMID- 26627126 TI - Exposure to gemfibrozil and atorvastatin affects cholesterol metabolism and steroid production in zebrafish (Danio rerio). AB - The commonly used lipid-lowering pharmaceuticals gemfibrozil (GEM) and atorvastatin (ATV) are detected in the aquatic environment; however, their potential effects on non-target fish species are yet to be fully understood. This study examined the effects of GEM and/or ATV on female and male adult zebrafish after a 30d dietary exposure. The exposure led to changes in several biochemical parameters, including reduction in cholesterol, triglycerides, cortisol, testosterone, and estradiol. Changes in cholesterol and triglycerides were also associated with changes in transcript levels of key genes involved with cholesterol and lipid regulation, including SREBP2, HMGCR1, PPARalpha, and SREBP1. We also noted higher CYP3A65 and atrogin1 mRNA levels in drug-treated male fish. Sex differences were apparent in some of the examined parameters at both biochemical and molecular levels. This study supports these drugs affecting cholesterol metabolism and steroid production in adult zebrafish. We conclude that the reduction in cortisol may impair the ability of these fish to mount a suitable stress response, whereas the reduction of sex steroids may negatively affect reproduction. PMID- 26627127 TI - Expression of mitochondria-related genes is elevated in overfeeding-induced goose fatty liver. AB - Mitochondrion, the power house of the cell, is an important organelle involving in energy homeostasis. Change in mitochondrial mass and function may lead to metabolic disorders. Previous studies indicate that mitochondrial mass loss and dysfunction are associated with non-alcoholic fatty liver disease (NAFLD) in human and mouse. However, it is unclear whether mitochondrial genes are involved in the development of goose fatty liver. To address this, we determined the response of goose mitochondrial genes to overfeeding and other fatty liver related factors (e.g., hyperinsulinemia, hyperglycemia, and hyperlipidemia). We first employed RNA-seq technology to determine the differentially expressed genes in the livers from normally-fed vs. overfed geese, followed by bioinformatics analysis and quantitative PCR validation. Data indicated that a majority of mitochondrial genes in the liver were induced by overfeeding. To understand how these genes are regulated in the context of fatty liver, we treated goose primary hepatocytes with high levels of glucose, fatty acids and insulin. The results indicated that these factors had an influence on the expression of some mitochondria related genes. Together, these findings suggest that the induction of mitochondrial gene expression by overfeeding is required for the development of goose fatty liver, and this induction is partially attributable to hyperglycemia, hyperlipidemia and hyperinsulinemia. PMID- 26627128 TI - Structure, molecular evolution, and hydrolytic specificities of largemouth bass pepsins. AB - The nucleotide sequences of largemouth bass pepsinogens (PG1, 2 and 3) were determined after molecular cloning of the respective cDNAs. Encoded PG1, 2 and 3 were classified as fish pepsinogens A1, A2 and C, respectively. Molecular evolutionary analyses show that vertebrate pepsinogens are classified into seven monophyletic groups, i.e. pepsinogens A, F, Y (prochymosins), C, B, and fish pepsinogens A and C. Regarding the primary structures, extensive deletion was obvious in S'1 loop residues in fish pepsin A as well as tetrapod pepsin Y. This deletion resulted in a decrease in hydrophobic residues in the S'1 site. Hydrolytic specificities of bass pepsins A1 and A2 were investigated with a pepsin substrate and its variants. Bass pepsins preferred both hydrophobic/aromatic residues and charged residues at the P'1 sites of substrates, showing the dual character of S'1 sites. Thermodynamic analyses of bass pepsin A2 showed that its activation Gibbs energy change (?G(?)) was lower than that of porcine pepsin A. Several sites of bass pepsin A2 moiety were found to be under positive selection, and most of them are located on the surface of the molecule, where they are involved in conformational flexibility. The broad S'1 specificity and flexible structure of bass pepsin A2 are thought to cause its high proteolytic activity. PMID- 26627129 TI - Three cDNAs encoding vitellogenin homologs from Antarctic copepod, Tigriopus kingsejongensis: Cloning and transcriptional analysis in different maturation stages, temperatures, and putative reproductive hormones. AB - Three full-length cDNAs encoding lipoprotein homologs were identified in Tigriopus kingsejongensis, a newly identified copepod from Antarctica. Structural and transcriptional analyses revealed homology with two vitellogenin-like proteins, Tik-Vg1 and Tik-Vg2, which were 1855 and 1795 amino acids in length, respectively, along with a third protein, Tik-MEP, which produced a 1517-residue protein with similarity to a melanin engaging protein (MEP) in insects Phylogenetic analysis showed that Vgs in Maxillopods including two Tik-Vgs belong to the arthropod vitellogenin-like clade, which includes clottable proteins (CPs) in decapod crustaceans and vitellogenins in insects. Tik-MEP clustered together with insect MEPs, which appear to have evolved before the apoB-like and arthropod Vg-like clades. Interestingly, no genes orthologous to those found in the apoB clade were identified in Maxillopoda, suggesting that functions of large lipid transfer proteins (LLTPs) in reproduction and lipid metabolism may be different from those in insect and decapod crustaceans. As suggested by phylogenetic analyses, the two Tik-Vgs belonging to the arthropod Vg-like clade appear to play major roles in oocyte maturation, while Vgs belonging to the apoB clade function primarily in the reproduction of decapod crustaceans. Transcriptional analysis of Tik-Vg expression revealed a 24-fold increase in mature and ovigerous females compared with immature female, whereas expression of Tik-MEP remained low through all reproductive stages. Acute temperature changes did not affect the transcription of Tik-Vg genes, whereas Tik-MEP appeared to be affected by temperature change. Among the three hormones thought to be involved in molting and reproduction in arthropods, only farnesoic acid (FA) induced transcription of the two Tik-Vg genes. Regardless of developmental stage and hormone treatment, Tik-Vg1 and Tik-Vg2 exhibited a strong positive correlation in expression, suggesting that expression of these genes may be regulated by the same transcriptional machinery. PMID- 26627130 TI - Mitochondrial toxicity of diclofenac and its metabolites via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria: Possible role in drug induced liver injury (DILI). AB - Diclofenac is a widely prescribed NSAID, which by itself and its reactive metabolites (Phase-I and Phase-II) may be involved in serious idiosyncratic hepatotoxicity. Mitochondrial injury is one of the mechanisms of drug induced liver injury (DILI). In the present work, an investigation of the inhibitory effects of diclofenac (Dic) and its phase I [4-hydroxy diclofenac (4'-OH-Dic) and 5-hydroxy diclofenac (5-OH-dic)] and Phase-II [diclofenac acyl glucuronide (DicGluA) and diclofenac glutathione thioester (DicSG)] metabolites, on ATP synthesis in rat liver mitochondria was carried out. A mechanism based inhibition of ATP synthesis is exerted by diclofenac and its metabolites. Phase-I metabolite (4'-OH-Dic) and Phase-II metabolites (DicGluA and DicSG) showed potent inhibition (2-5 fold) of ATP synthesis, where as 5-OH-Dic, one of the Phase-I metabolite, was a less potent inhibitor as compared to Dic. The calculated kinetic constants of mechanism based inhibition of ATP synthesis by Dic showed maximal rate of inactivation (Kinact) of 2.64 +/- 0.15 min(-1) and half maximal rate of inactivation (KI) of 7.69 +/- 2.48 MUM with Kinact/KI ratio of 0.343 min(-1) MUM( 1). Co-incubation of mitochondria with Dic and reduced GSH exhibited a protective effect on Dic mediated inhibition of ATP synthesis. Our data from this study strongly indicate that Dic as well as its metabolites could be involved in the hepato-toxic action through inhibition of ATP synthesis. PMID- 26627132 TI - A Case of Plasmacytoid Variant of Bladder Cancer With a Single Penile Metastasis and a Complete Response to Carboplatin-Based Chemotherapy and Review of the Literature. PMID- 26627133 TI - Inter and intra-observer reliability in assessment of the position of the lateral sesamoid in determining the severity of hallux valgus. AB - BACKGROUND: The position of the lateral sesamoid on standard dorso-plantar weight bearing radiographs, with respect to the lateral cortex of the first metatarsal, has been shown to correlate well with the degree of the hallux valgus angle. This study aimed to assess the inter- and intra-observer error of this new classification system. METHODS: Five orthopaedic consultants and five trainee orthopaedic surgeons were recruited to assess and document the degree of displacement of the lateral sesamoid on 144 weight-bearing dorso-plantar radiographs on two separate occasions. The severity of hallux valgus was defined as normal (0%), mild (<=50%), moderate (51-<=99%) or severe (>=100%) depending on the percentage displacement of the lateral sesamoid body from the lateral cortical border of the first metatarsal. RESULTS: Consultant intra-observer variability showed good agreement between repeated assessment of the radiographs (mean Kappa=0.75). Intra-observer variability for trainee orthopaedic surgeons also showed good agreement with a mean Kappa=0.73. Intraclass correlations for consultants and trainee surgeons was also high. CONCLUSION: The new classification system of assessing the severity of hallux valgus shows high inter and intra-observer variability with good agreement and reproducibility between surgeons of consultant and trainee grades. PMID- 26627131 TI - Mast Cells Participate in Corneal Development in Mice. AB - The development of the cornea, a highly specialized transparent tissue located at the anterior of the eye, is coordinated by a variety of molecules and cells. Here, we report that mast cells (MCs), recently found to be involved in morphogenesis, played a potentially important role in corneal development in mice. We show that two different waves of MC migration occurred during corneal development. In the first wave, MCs migrated to the corneal stroma and became distributed throughout the cornea. This wave occurred by embryonic day 12.5, with MCs disappearing from the cornea at the time of eyelid opening. In the second wave, MCs migrated to the corneal limbus and became distributed around limbal blood vessels. The number of MCs in this region gradually increased after birth and peaked at the time of eyelid opening in mice, remaining stable after postnatal day 21. We also show that integrin alpha4beta7 and CXCR2 were important for the migration of MC precursors to the corneal limbus and that c-Kit-dependent MCs appeared to be involved in the formation of limbal blood vessels and corneal nerve fibers. These data clearly revealed that MCs participate in the development of the murine cornea. PMID- 26627134 TI - Hydrogen Impurity Defects in Rutile TiO2. AB - Hydrogen-related defects play crucial roles in determining physical properties of their host oxides. In this work, we report our systematic experimental and theoretical (based on density functional theory) studies of the defect states formed in hydrogenated-rutile TiO2 in gaseous H2 and atomic H. In gas hydrogenated TiO2, the incorporated hydrogen tends to occupy the oxygen vacancy site and negatively charged. The incorporated hydrogen takes the interstitial position in atom-hydrogenated TiO2, forming a weak O-H bond with the closest oxygen ion, and becomes positive. Both states of hydrogen affect the electronic structure of TiO2 mainly through changes of Ti 3d and O 2p states instead of the direct contributions of hydrogen. The resulted electronic structures of the hydrogenated TiO2 are manifested in modifications of the electrical and optical properties that will be useful for the design of new materials capable for green energy economy. PMID- 26627135 TI - BMA temporarily suspends strike action. PMID- 26627136 TI - Use of botulinum toxin type A in symptomatic accessory soleus muscle: first five cases. AB - Symptomatic accessory soleus muscle (ASM) can cause exercise-induced leg pain due to local nerve/vascular compression, muscle spasm, or local compartment syndrome. As intramuscular injections of botulinum toxin type A (BTX-A) can reduce muscle tone and mass, we investigated whether local BTX-A injections relieve the pain associated with symptomatic ASM. We describe five patients presenting peri/retromalleolar exertional pain and a contractile muscle mass in the painful region. Com-pression neuropathy was ruled out by electromyo-graphic analysis of the lower limb muscles. Doppler ultrasonography was normal, excluding a local vascular compression. ASM was confirmed by magnetic resonance imaging. After a treadmill stress test, abnormal intramuscular pressure values in the ASM, confirmed the diagnosis of compartment syndrome only in one patient. All five patients received BTX-A injections in two points of the ASM. The treatment efficacy was evaluated based on the disappearance of exercise-induced pain and the resumption of normal physical and sports activities. After BTX-A injection, exertional pain disappeared and all five patients resumed their normal level of physical and sports performances. Neither side effects nor motor deficits were observed. BTX-A is well tolerated in patients with ASM and could be used as a new conservative therapeutic strategy for the treatment of symptomatic ASM before surgery. PMID- 26627138 TI - Ebola: lessons learned and future challenges for Europe. AB - The Ebola virus epidemic has topped media and political agendas for months; several countries in west Africa have faced the worst Ebola epidemic in history. At the beginning of the disease outbreak, European Union (EU) policies were notably absent regarding how to respond to the crisis. Although the epidemic is now receding from public view, this crisis has undoubtedly changed the European public perception of Ebola virus disease, which is no longer regarded as a bizarre entity confined in some unknown corner in Africa. Policy makers and researchers in Europe now have an opportunity to consider the lessons learned. In this Personal View, we discuss the EU's response to the Ebola crisis in west Africa. Unfortunately, although ample resources and opportunities for humanitarian and medical action existed, the EU did not use them to promote a rapid and well coordinated response to the Ebola crisis. Lessons learned from this crisis should be used to improve the role of the EU in similar situations in the future, ensuring that European aid can be effectively deployed to set up an improved emergency response system, and supporting the establishment of sustainable health-care services in west Africa. PMID- 26627137 TI - In vivo and ex vivo measurements: noninvasive assessment of alcoholic fatty liver using 1H-MR spectroscopy. AB - PURPOSE: We aimed to evaluate the ability of 1H-magnetic resonance spectroscopy (1H-MRS) to detect and quantify hepatic fat content in vivo and ex vivo in an experimental rat model of alcoholic fatty liver using histopathology, biochemistry, and laboratory analyses as reference. METHODS: Alcoholic fatty liver was induced within 48 hours in 20 Lewis rats; 10 rats served as control. Intrahepatic fat content determined by 1H-MRS was expressed as the percent ratio of the lipid and water peaks and was correlated with intrahepatic fat content determined histologically and biochemically. Liver enzymes were measured in serum. RESULTS: Fatty liver could be detected in vivo as well as ex vivo using 1H MRS, in all 20 animals. Histologic analysis showed a fatty liver in 16 of 20 animals. Histology and 1H-MRS results were highly correlated (in vivo, r=0.93, P = 0.0005; ex vivo, r=0.92, P = 0.0006). Also a strong correlation was noted between in vivo 1H-MRS measurements and the fat content determined biochemically (r=0.96, P = 0.0003). Ex vivo results showed a similarly strong correlation between 1H-MRS and biochemistry (r=0.89, P = 0.0011). CONCLUSION: 1H-MRS can be carried out in ex vivo models, as well as in vivo, to detect and quantify intrahepatic fat content in the acute fatty liver. PMID- 26627139 TI - Evidence of reactive oxygen species (ROS) mediated apoptosis in Setaria cervi induced by green silver nanoparticles from Acacia auriculiformis at a very low dose. AB - Green synthesis of silver nanomaterial plays a pivotal role in the growing field of nanotechnology. Development of anti-parasitic drugs from plant metabolites has been in regular practice from the ancient period but most of them were discarded due to their inefficiency to control diseases effectively. At present, nanoparticles are used for developing anti-parasitic therapy for their unique properties such as smallest in size, bio-ability, bio-compatibility and penetration capacity into a cell. The present study aims at synthesis of silver nanoparticles (AgNPs) by using funicles extract of Acacia auriculiformis and tests its efficacy as antifilarial. Experimental evidence show that AgNPs are effective at a very low concentration compared to crude plant extracts. Synthesis of these nanoparticles is a single-step, biogenic, cost effective and eco friendly process. Synthesized nanoparticles were characterized by UV-Vis spectroscopy, TEM, SAED, FTIR, EDX, FESEM and Z-potential. The antifilarial efficacy of AgNPs was tested against different life cycle stages of bovine filarial parasite Setaria cervi by morphological study, motility assessment and viability assay. These nanoparticles are found to have antifilarial activity with LC50 of 5.61 MUg/mL and LC90 of 15.54 MUg/mL against microfilaria of S. cervi. The microscopic findings and the detailed molecular studies confirmed that green synthesized AgNPs were effective enough to induce apoptosis through up regulation of ROS (reactive oxygen species). PMID- 26627140 TI - Safety study of Ciprofloxacin in newborn mice. AB - Ciprofloxacin, a broad-spectrum antimicrobial agent belonging to the fluoroquinolone family, is prescribed off-label in infants less than one year of age. Ciprofloxacin is included in the European Medicines Agency priority list of off-patent medicinal products requiring evaluation in neonates. This evaluation is undergoing within the TINN (Treat Infections in Neonates) FP7 EU project. As part of the TINN project, the present preclinical study was designed to assess the potential adverse effects of Ciprofloxacin on neurodevelopment, liver and joints in mice. Newborn mice received subcutaneous Ciprofloxacin at 10, 30 and 100 mg/kg/day from 2 to 12 postnatal days. Peak plasma levels of Ciprofloxacin were in the range of levels measured in human neonates. We examined vital functions in vivo, including cardiorespiratory parameters and temperature, psychomotor development, exploratory behavior, arthro-, nephro- and hepato-toxic effects. We found no effect of Ciprofloxacin at 10 and 30 mg/kg/day. In contrast, administration at 100 mg/kg/day delayed weight gain, impaired cardiorespiratory and psychomotor development, caused inflammatory infiltrates in the connective tissues surrounding the knee joint, and moderately increased extramedullary hematopoiesis. The present study pleads for careful watching of cardiorespiratory and motor development in neonates treated with Ciprofloxacin, in addition to the standard surveillance of arthrotoxicity. PMID- 26627141 TI - Restrictive Dermopathy. PMID- 26627142 TI - Impact of adding nitrate or increasing the lipid content of two contrasting diets on blood methaemoglobin and performance of two breeds of finishing beef steers. AB - Adding nitrate to the diet or increasing the concentration of dietary lipid are effective strategies for reducing enteric methane emissions. This study investigated their effect on health and performance of finishing beef cattle. The experiment was a two*two*three factorial design comprising two breeds (CHX, crossbred Charolais; LU, Luing); two basal diets consisting of (g/kg dry matter (DM), forage to concentrate ratios) 520 : 480 (Mixed) or 84 : 916 (Concentrate); and three treatments: (i) control with rapeseed meal as the main protein source replaced with either (ii) calcium nitrate (18 g nitrate/kg diet DM) or (iii) rapeseed cake (RSC, increasing acid hydrolysed ether extract from 25 to 48 g/kg diet DM). Steers (n=84) were allocated to each of the six basal diet*treatments in equal numbers of each breed with feed offered ad libitum. Blood methaemoglobin (MetHb) concentrations (marker for nitrate poisoning) were monitored throughout the study in steers receiving nitrate. After dietary adaptation over 28 days, individual animal intake, performance and feed efficiency were recorded for a test period of 56 days. Blood MetHb concentrations were low and similar up to 14 g nitrate/kg diet DM but increased when nitrate increased to 18 g nitrate/kg diet DM (P0.05). Neither basal diet nor treatment affected carcass quality (P>0.05), but CHX steers achieved a greater killing out proportion (P<0.001) than LU steers. Thus, adding nitrate to the diet or increasing the level of dietary lipid through the use of cold-pressed RSC, did not adversely affect health or performance of finishing beef steers when used within the diets studied. PMID- 26627144 TI - Green foot ulcers. PMID- 26627143 TI - Cardiac conduction in isolated hearts of genetically modified mice--Connexin43 and salts. AB - Physiologic variations in perfusate composition have been identified as a new and important modulator of cardiac conduction velocity (CV), particularly when gap junctions (GJ) are reduced. We recently demonstrated in ex vivo hearts that perfusates with low sodium and high potassium preferentially slow ventricular CV in mice genetically engineered to express 50% less of the gap junction protein, connexin43 (Cx43). We also reported the possible role of calcium in modulating CV. In this review we discuss previous murine studies that explored the CV-GJ relationship in isolated mouse heart preparations with approximately 50% reduced Cx43. Studies were grouped according to the type of perfusate utilized, and CV during GJ uncoupling was compared. Studies in Group A preferentially used perfusates with low sodium, high potassium and non-physiologic calcium, and found CV slows and arrhythmias increase in mouse hearts with reduced Cx43. Studies in Group B used solutions with high sodium, low potassium and physiologic calcium, and did not observe CV slowing nor increased arrhythmia risk with loss of Cx3. Studies in Group C used solutions with low sodium, low potassium, physiologic calcium, creatine, taurine, and insulin. CV slowing was not observed, nor was arrhythmia risk increased with loss of Cx43. We suggest that perfusate ion composition may be a major determinant of whether CV slows when Cx43 is reduced. Furthermore, the review of these studies highlights important theoretical developments in the understanding of cardiac conduction and suggests that ionic milieu can conceal electrophysiologic remodeling secondary to reduced Cx43 expression as occurs in many cardiac diseases. PMID- 26627145 TI - Prevalence and determinants of the metabolic syndrome among subjects with advanced nondiabetes-related chronic kidney disease in Gran Canaria, Spain. AB - BACKGROUND: The relationship between the metabolic syndrome and mild chronic kidney disease (CKD) has been extensively studied. This study was aimed to estimate the prevalence and factors associated with the metabolic syndrome among subjects with advanced stages of nondiabetes-related CKD. METHODS: Study population was composed of incident patients with advanced CKD not related to diabetes in a tertiary hospital from Gran Canaria (Spain) since February 2011 to December 2014. Participants fulfilled a survey questionnaire and underwent physical examination and biochemical evaluation. RESULTS: The sample was composed of 167 subjects (mean age 63.9 +/- 13.7 years; estimated glomerular filtration rate 21.9 +/- 6.6 mL/min/1.73 m(2)). The prevalence of the metabolic syndrome was 68.9% (65.2% in men and 73.3% in women). Highest rates were observed in groups with chronic interstitial nephropathy (80%), CKD of uncertain etiology (76.7%) and CKD related to vascular causes (76.2%). Subjects with metabolic syndrome were older, had higher values of C-reactive protein and more often reported to have first-degree relatives with diabetes and to be physically inactive. In multivariate analyses, age (OR: 1.034 [CI 95%: 1.004-1.065]; p = 0.024) and family history of diabetes (OR: 2.550 [1.159-5.608]; p = 0.020) were independently associated with the metabolic syndrome. CONCLUSIONS: The prevalence of the metabolic syndrome among subjects with advanced nondiabetes-related CKD is high, and greater than that observed in general Canarian population of similar age groups. Age and family history of diabetes are the two factors more strongly associated with the metabolic syndrome in this population. PMID- 26627146 TI - Using Molecular Dynamics Simulations To Provide New Insights into Protein Structure on the Nanosecond Timescale: Comparison with Experimental Data and Biological Inferences for the Hyaluronan-Binding Link Module of TSG-6. AB - Link module domains play an essential role in extracellular matrix assembly and remodeling by binding to the flexible glycosaminoglycan hyaluronan. A high resolution NMR-structure of the Link module from the protein product of tumor necrosis factor-stimulated gene-6 (Link_TSG6) has been determined, but a fuller appreciation of protein dynamics may be necessary to understand its hyaluronan binding. Therefore, we have performed a 0.25 MUs MD simulation, starting from the lowest-energy NMR-derived solution structure of Link_TSG6, with explicit water and ions, using the CHARMM22 protein force field. The simulation was as good a fit to the NMR data as the ensemble from simulated annealing, except in the beta5 beta6 loop. Furthermore, analysis revealed that secondary structure elements extended further than previously reported and underwent fast picosecond time scale dynamics, whereas nanosecond dynamics was found in certain loops. In particular, surface side chains proposed to interact with glycosaminoglycans were predicted to be highly mobile and be directed away from the protein surface. Furthermore, the hyaluronan-binding beta4-beta5 loop remained in a closed conformation, favoring an allosteric interaction mechanism. This enhanced view of the Link module provides general insight into protein dynamics and may be helpful for understanding the dynamic molecular basis of tissue assembly, remodeling, and disease processes. PMID- 26627147 TI - Temperature-Dependent Probabilistic Roadmap Algorithm for Calculating Variationally Optimized Conformational Transition Pathways. AB - In this paper we present a method to calculate a temperature-dependent optimized conformational transition pathways. This method is based on the maximization of the flux derived from the Smoluchowski equation and is implemented with a probabilistic roadmap algorithm. We have tested the algorithm on four systems [Formula: see text] the Muller potential, the three-hole potential, alanine dipeptide, and the folding of beta-hairpin. Comparison is made with existing algorithms designed for the calculation of protein conformational transition and folding pathways. The applications demonstrate the ability of the algorithm to isolate a temperature-dependent optimal reaction path with improved sampling and efficiency. PMID- 26627148 TI - Use of the Weighted Histogram Analysis Method for the Analysis of Simulated and Parallel Tempering Simulations. AB - The growing adoption of generalized-ensemble algorithms for biomolecular simulation has resulted in a resurgence in the use of the weighted histogram analysis method (WHAM) to make use of all data generated by these simulations. Unfortunately, the original presentation of WHAM by Kumar et al. is not directly applicable to data generated by these methods. WHAM was originally formulated to combine data from independent samplings of the canonical ensemble, whereas many generalized-ensemble algorithms sample from mixtures of canonical ensembles at different temperatures. Sorting configurations generated from a parallel tempering simulation by temperature obscures the temporal correlation in the data and results in an improper treatment of the statistical uncertainties used in constructing the estimate of the density of states. Here we present variants of WHAM, STWHAM and PTWHAM, derived with the same set of assumptions, that can be directly applied to several generalized ensemble algorithms, including simulated tempering, parallel tempering (better known as replica-exchange among temperatures), and replica-exchange simulated tempering. We present methods that explicitly capture the considerable temporal correlation in sequentially generated configurations using autocorrelation analysis. This allows estimation of the statistical uncertainty in WHAM estimates of expectations for the canonical ensemble. We test the method with a one-dimensional model system and then apply it to the estimation of potentials of mean force from parallel tempering simulations of the alanine dipeptide in both implicit and explicit solvent. PMID- 26627149 TI - Stereoelectronic Substituent Effects in Saturated Main Group Molecules: Severe Problems of Current Kohn-Sham Density Functional Theory. AB - The Hartree-Fock method, two common density functionals (PBE and B3LYP), and two new functionals (B97-D and B2PLYP) together with very large AO basis sets are used to compute the isomerization energies for substituted (R [Formula: see text] H, F, Cl) branched to linear alkanes and silanes. The results of accurate SCS-MP2 computations are taken as reference. These reactions are an important test of how nonlocal electron correlation effects on medium-range lengths scales in saturated molecules are treated by approximate quantum chemical methods. It is found that the unacceptably large errors observed previously for hydrocarbons persist also for the here considered more polar systems. Although the B97-D and B2PLYP functionals provide improved energetics, the problem is not fully solved, and thus these systems are suggested as mandatory benchmarks for future density functionals. PMID- 26627150 TI - Electrostatically Embedded Many-Body Expansion for Large Systems, with Applications to Water Clusters. AB - The use of background molecular charge to incorporate environmental effects on a molecule or active site is widely employed in quantum chemistry. In the present article we employ this practice in conjunction with many-body expansions. In particular, we present electrostatically embedded two-body and three-body expansions for calculating the energies of molecular clusters. The system is divided into fragments, and dimers or trimers of fragments are calculated in a field of point charges representing the electrostatic potential of the other fragments. We find that including environmental point charges can lower the errors in the electrostatically embedded pairwise additive (EE-PA) energies for a series of water clusters by as much as a factor of 10 when compared to the traditional pairwise additive approximation and that for the electrostatically embedded three-body (EE-3B) method the average mean unsigned error over nine different levels of theory for a set of six tetramers and one pentamer is only 0.05 kcal/mol, which is only 0.4% of the mean unsigned net interaction energy. We also test the accuracy of the EE-PA and EE-3B methods for a cluster of 21 water molecules and find that the errors relative to a full MP2/aug'-cc-pVTZ calculation to be only 2.97 and 0.38 kcal/mol, respectively, which are only 1.5% and 0.2%, respectively, of the net interaction energy. This method offers the advantage over some other fragment-based methods in that it does not use an iterative method to determine the charges and thus provides substantial savings for large clusters. The method is convenient to adapt to a variety of electronic structure methods and program packages, it has N(2) or N(3) computational scaling for large systems (where N is the number of fragments), it is easily converted to an O(N) method, and its linearity allows for convenient analytic gradients. PMID- 26627151 TI - A Density Functional Study of Methanol Clusters. AB - The potential energy surfaces of methanol clusters, (CH3OH)n, n = 2-12, have been studied using density functional theory at the B3LYP/6-31G(d) and higher levels of theory. Cyclic clusters in which n methanol molecules are joined in a ring structure formed by n hydrogen bonds are shown to be more stable than structures of the same number of methanol molecules where one or more methanol molecules are outside the ring and are hydrogen-bonded to oxygens of methanols in rings of n - 1, n - 2, and so forth. So-called chain structures are generally even less stable. Furthermore, the hydrogen-bonding energy per methanol molecule of the n ring clusters is shown to converge to an asymptotic value of about 27 kJ/mol at B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) after five to six methanols are included in the cluster. As expected, there are many minima on the potential energy surfaces of the methanol clusters, the number increasing rapidly with n. A cyclic cluster of five to six methanol molecules appears to be sufficient to mimic liquid behavior as far as vibrational frequencies are concerned. PMID- 26627152 TI - The Optical Rotation of Glucose Prototypes: A Local or a Global Property? AB - In this work, we present a quantum-mechanical study of the optical rotation (OR) of model systems representing glucose prototypes with one and two chiral centers. The ONIOM method is used to evaluate the property and to analyze its local or global character. Different ONIOM partitions are tested and compared to better appreciate differences and similarities between mono- and bichiral prototypes. The local versus global character of OR is investigated and compared to other properties such as energies and nuclear magnetic shieldings, which have been deeply studied in previous applications of the ONIOM method. PMID- 26627153 TI - Local Moller-Plesset Perturbation Theory: A Massively Parallel Algorithm. AB - A massively parallel algorithm is presented for computation of energies with local second-order Moller-Plesset (LMP2) perturbation theory. Both the storage requirement and the computational time scale linearly with the molecular size. The parallel algorithm is designed to be scalable, employing a distributed data scheme for the two-electron integrals, avoiding communication bottlenecks, and distributing tasks in all computationally significant steps. A sparse data representation and a set of generalized contraction routines have been developed to allow efficient massively parallel implementation using distributed sparse multidimensional arrays. High parallel efficiency of the algorithm is demonstrated for applications employing up to 100 processors. PMID- 26627154 TI - Spin-Component Scaling Methods for Weak and Stacking Interactions. AB - New scaling parameters are presented for use in the spin-component scaled (SCS) variant of density fitted local second-order Moller-Plesset perturbation theory (DF-LMP2) that have been optimized for use in evaluating the interaction energy between nucleic acid base pairs. The optimal set of parameters completely neglects the contribution from antiparallel-spin electron pairs to the MP2 energy while scaling the parallel contribution by 1.76. These spin-component scaled for nucleobases (SCSN) parameters are obtained by minimizing, with respect to SCS parameters, the rms interaction energy error relative to the best available literature values, over a set of ten stacked nucleic acid base pairs. The applicability of this scaling to a wide variety of noncovalent interactions is verified through evaluation of a larger set of model complexes, including those dominated by dispersion and electrostatics. PMID- 26627155 TI - Density-Functional and Coupled-Cluster Singles-and-Doubles Calculations of the Nuclear Shielding and Indirect Nuclear Spin-Spin Coupling Constants of o-Benzyne. AB - Density-functional theory (DFT) and coupled-cluster singles-and-doubles (CCSD) theory are applied to compute the nuclear magnetic resonance (NMR) shielding and indirect nuclear spin-spin coupling constants of o-benzyne, whose biradical nature makes it difficult to study both experimentally and theoretically. Because of near-equilibrium triplet instabilities that follow from its biradical character, the calculated DFT NMR properties of o-benzyne are unusually sensitive to details of the exchange-correlation functional. However, this sensitivity is greatly reduced if these properties are calculated at the equilibrium of the chosen functional. A strong correlation is demonstrated between the quality of the calculated indirect spin-spin coupling constants and the quality of the calculated lowest triplet excitation energy in o-benzyne. Orbital-unrelaxed coupled-cluster theory should be less affected by such instabilities, and the CCSD NMR properties were only calculated at the experimental equilibrium geometry. For the shielding constants, the results in best agreement with experimental results are obtained with CCSD theory and with the Keal-Tozer KT1 and KT2 functionals. For the triply bonded carbon atoms, these models yield an isotropic shielding of 1.3, -3.3, and -1.2 ppm, respectively, compared with the experimentally observed shielding of 3.7 ppm for incarcerated o-benzyne. For the indirect spin-spin coupling constants, the CCSD model and the Perdew-Burke Ernzerhof functional both yield reliable results; for the most interesting spin spin coupling constant, (1)J (C?C), we obtain 210 and 209 Hz with these two models, respectively, somewhat above the recently reported experimental value of 177.9 +/- 0.7 Hz for o-benzyne inside a molecular container, suggesting large incarceration effects. PMID- 26627156 TI - Theoretical Investigations of the Nature of Interaction of ClF with HF, H2O, and NH3. AB - The interactions of the first-row hydrides (HF, H2O, and NH3) with ClF have been investigated by performing calculations at the second-order perturbation theory based on the Moller-Plesset partition of the Hamiltonian with the aug-cc-pVTZ basis set. The geometries and vibrational frequencies in the present study were obtained by carrying out explicit counterpoise-corrected optimization. In order to understand that the Cl-X-type (X = F, O, and N) structure is more stable than the corresponding hydrogen-bonded structure in these complexes, the electronic properties were also investigated. Furthermore, the symmetry-adapted perturbation theory calculations were performed to gain more insight into the nature of the hydrogen-bond and Cl-X-type interactions. The analysis of the interaction energy components indicates that, in contrast to the hydrogen-bonded complexes, the inductive and dispersive interaction is the most important term in the Cl-X-type complexes, as we progress from HF to NH3. PMID- 26627157 TI - Molecular Structures and Energetics Associated with Hydrogen Atom Addition to the Guanine-Cytosine Base Pair. AB - The radicals generated by hydrogen-atom addition to the Watson-Crick guanine cytosine (G-C) DNA base pair were studied theoretically using an approach that has proved effective in predicting molecular structures and energetics. All optimized structures were confirmed to be minima via vibrational frequency analysis. The dissociation energies of the base-pair radicals are predicted and compared with that of the neutral G-C base pair. The lowest-energy base-pair radical is that with the hydrogen atom attached to the C8 position of guanine, resulting in the nitrogen radical designated G(C8)-C. In this, the most favorable radical, the G-C pair C8 [Formula: see text] N7 distance of 1.310 A increases to 1.453 A when the pi bond is broken upon hydrogen-atom addition. This radical has a dissociation energy of 28 kcal/mol, which may be compared with 27 kcal/mol for neutral G-C. The other (GC + H)(*) radical dissociation energies range downward to 8 kcal/mol. Significant structural changes were observed when the hydrogen was added to the sites where the interstrand hydrogen bonds are formed. For example, "butterfly"-shape structures were found when the hydrogen atom was added to the C4 or C5 sites of guanine. The formation of radical G(C2)-C may cause a single strand break because of significant strain in the closely stacked base pairs. Radical G(C8)-C is of biological importance because it may be an intermediate in the formation of 8-oxo guanine. PMID- 26627158 TI - Evaluation of Two Computational Models Based on Different Effective Core Potentials for Use in Organocesium Chemistry. AB - The performance of two computational models was evaluated in describing some aggregated structures, the bond lengths and dimerization energies of cesium halides, aquation energies of the cesium cation, and protonation energies of a range of organocesium compounds. One model used the Hay-Wadt (HW) effective core potential (ECP) and a double-zeta valence basis set on Cs; the other used the Ross ECP with two polarization functions on Cs. In both models, the standard 6 31+G** basis was used for the other atoms. At the Hartree-Fock (HF) level, the Ross ECP was found to give geometries and energies in good agreement with experimental results. Second-order Moller-Plesset calculations with this model gave only modestly improved results compared to HF; the B3LYP level gave variable results with unsatisfactory energies. Although the HW model is generally less satisfactory, it often shows comparable trends to those of the Ross model. PMID- 26627159 TI - Elucidation of Rate Variations for a Diels-Alder Reaction in Ionic Liquids from QM/MM Simulations. AB - The impact of acidic and basic ionic liquid 1-ethyl-3-methylimidazolium chloride (EMIC) melts upon cyclopentadiene and methyl acrylate Diels-Alder reaction rates has been investigated using QM/MM calculations. The ability of the ionic liquid to act as a hydrogen bond donor (cation effect), moderated by its hydrogen bond accepting ability (anion effect), has been proposed previously to explain observed endo/exo ratios. However, the molecular factors that endow ionic liquids with their rate enhancing potential remain unknown. New OPLS-AA force field parameters in conjunction with potentials of mean force (PMF) derived from free energy perturbation calculations in Monte Carlo simulations (MC/FEP) are used to compute activation energies. QM/MM simulations using a periodic box of ions reproduce relative rate enhancements for the EMIC melts compared to water and 1 chlorobutane that reproduce kinetic experiments. Solute-solvent interactions in acidic and basic ionic liquid melts have been analyzed at key stationary points along the reaction coordinate. The reaction rate was found to be greater in the acidic rather than the basic melt due to less-dominant ion-pairing in the acidic melt, enabling the EMI cation to better coordinate to the dienophile at the transition state. The simulations suggest that the hydrogen on C2 of the EMI cation does not contribute to stabilization of the transition state, as previously believed, and the interactions with the more sterically exposed hydrogens on C4 and C5 play a larger role. In addition, the relative stabilization of the transition state through electrostatic interactions with the EMI cation in the acidic melt is also greater than that afforded by the weaker Lewis-acid effect provided by hydrogen bonding with water molecules in aqueous solution. PMID- 26627160 TI - Density Functional Theory Study of the Formation of Naphthalene and Phenanthrene from Reactions of Phenyl with Vinyl- and Phenylacetylene. AB - Reaction pathways for polycyclic aromatic hydrocarbon growth from reactions of either vinyl- or phenylacetylene with a phenyl radical are proposed and investigated using density functional theory (DFT). B3LYP/TZVP calculations are performed to obtain structures of minima and saddle points as well as kinetic data, supplemented with BMK/TZVP single-point energy calculations. The pathways include a cis-trans isomerization via a radicalic four-membered ring intermediate, which has so far not been considered in the literature. The DFT approach is validated against coupled-cluster calculations of a model system representing this intermediate. The coupled-cluster calculations include single and double excitations as well as perturbative corrections for connected triples and are performed in a correlation-consistent cc-pVTZ basis. PMID- 26627161 TI - Computational Investigation of Mechanisms for Ring-Opening Polymerization of epsilon-Caprolactone: Evidence for Bifunctional Catalysis by Alcohols. AB - Stepwise addition/elimination and concerted mechanisms for the methanolysis of epsilon-caprolactone, as a model for the initiation and propagation of ring opening polymerization (ROP), have been investigated computationally using the B3LYP/6-31G* density functional method, with assistance from one or two ancillary methanol molecules. The effects of specific solvation by these extra methanols in cyclic hydrogen-bonded clusters are very significant, with barrier height reductions of about 50 kJ mol(-)(1). However, the effects of bulk solvation as treated by the polarized continuum model are almost negligible. Increasing the ring size lowers the barriers for both the addition and elimination steps of the stepwise mechanism but does not do so for the concerted mechanism; a stepwise mechanism is preferred for methanol-assisted ROP. The essential catalytic role of solvent molecules in this reaction is to avoid the unfavorable accumulation or separation of charges. PMID- 26627162 TI - Optimizing the Poisson Dielectric Boundary with Explicit Solvent Forces and Energies: Lessons Learned with Atom-Centered Dielectric Functions. AB - Accurate implicit solvent models require parameters that have been optimized in a system- or atom-specific manner on the basis of experimental data or more rigorous explicit solvent simulations. Models based on the Poisson or Poisson Boltzmann equation are particularly sensitive to the nature and location of the boundary which separates the low dielectric solute from the high dielectric solvent. Here, we present a novel method for optimizing the solute radii, which define the dielectric boundary, on the basis of forces and energies from explicit solvent simulations. We use this method to optimize radii for protein systems defined by AMBER ff99 partial charges and a spline-smoothed solute surface. The spline-smoothed surface is an atom-centered dielectric function that enables stable and efficient force calculations. We explore the relative performance of radii optimized with forces alone and those optimized with forces and energies. We show that our radii reproduce the explicit solvent forces and energies more accurately than four other parameter sets commonly used in conjunction with the AMBER force field, each of which has been appropriately scaled for spline smoothed surfaces. Finally, we demonstrate that spline-smoothed surfaces show surprising accuracy for small, compact systems but may have limitations for highly solvated protein systems. The optimization method presented here is efficient and applicable to any system with explicit solvent parameters. It can be used to determine the optimal continuum parameters when experimental solvation energies are unavailable and the computational costs of explicit solvent charging free energies are prohibitive. PMID- 26627163 TI - Structures and Electronic States of Permethyloligosilane Radical Ions with All Trans Form Sin(CH3)2n+2(+/-) (n = 2-6): A Density Functional Theory Study. AB - Hybrid density functional theory (DFT) calculations have been carried out for the radical cation and anion of permethyloligosilane Sin(CH3)2n+2(+/-) (n = 2-6) to elucidate the electronic structures at ground and low-lying excited states, and the results were compared with the corresponding experimental values. In particular, the assignment of electronic transition appeared at near-IR and visible regions, which is strongly correlated to hole and electron conductivity, and was carried out on the basis of time-dependent DFT calculation. The structure of oligosilane was generated at 300 K by direct PM3 molecular dynamics calculations, and then the geometry was fully optimized at the DFT(B3LYP)/6 311+G(d,p) level. It was found that the hole in the radical cation and the electron in the radical anion of oligosilane are delocalized over the Si skeleton. The proton-hyperfine coupling constants calculated were in good agreement with those obtained by an electron spin resonance experiment. It was also found that the g-anisotropy of the radical anion was significantly larger than that of the radical cation. The IR bands of radical ions were assigned on the basis of theoretical calculations. PMID- 26627164 TI - Molecular Thermodynamics of Methane Solvation in tert-Butanol-Water Mixtures. AB - We studied solvation structure and thermodynamics of methane in mixtures of tert butanol and water using computer simulations. We show that for alcohol mole fractions below 20%, methane is preferentially solvated by hydrated alcohol clusters. Because methane expels water molecules from these clusters, a large endothermic solvent reorganization enthalpy occurs. This process is responsible for the experimentally observed maximum of the heat of methane solvation close to 5% alcohol in the mixture and contributes to a positive entropy change relative to solvation in pure water. Because the structural solvent reorganization enthalpy is enthalpy-entropy compensating, the methane solvation free energy is a smoothly varying function of the alcohol/water solution composition. PMID- 26627165 TI - A Distributed Computing Method for Crystal Structure Prediction of Flexible Molecules: An Application to N-(2-Dimethyl-4,5-dinitrophenyl) Acetamide. AB - In this paper, we describe a new distributed computing framework for crystal structure prediction that is capable of performing crystal structure searches for flexible molecules within any space group and with an arbitrary number of molecules in the asymmetric unit. The distributed computing framework includes a series of tightly integrated computer programs for generating the molecule's force field, sampling possible crystal structures using a distributed parallel genetic algorithm, locally minimizing these structures and classifying, sorting, and archiving the most relevant ones. As an example, we report the results of its application to the prediction of the crystal structure of the elusive N-(2 dimethyl-4,5-dinitrophenyl) acetamide, a molecule for which its crystal structure proved to be one of the most difficult cases in the last CSP2004 blind test for crystal structure prediction. PMID- 26627166 TI - Transferability of Orthogonal and Nonorthogonal Tight-Binding Models for Aluminum Clusters and Nanoparticles. AB - Several semiempirical tight-binding models are parametrized and tested for aluminum clusters and nanoparticles using a data set of 808 accurate AlN (N = 2 177) energies and geometries. The effects of including overlap when solving the secular equation and of incorporating many-body (i.e., nonpairwise) terms in the repulsion and electronic matrix elements are studied. Pairwise orthogonal tight binding (TB) models are found to be more accurate and their parametrizations more transferable (for particles of different sizes) than both pairwise and many-body nonorthogonal tight-binding models. Many-body terms do not significantly improve the accuracy or transferability of orthogonal TB, whereas some improvement in the nonorthogonal models is observed when many-body terms are included in the electronic Hamiltonian matrix elements. PMID- 26627167 TI - Theoretical Investigation of Excited States of Large Polyene Cations as Model Systems for Lightly Doped Polyacetylene. AB - Electronic excitations of polyene cations with chain lengths of up to 101 CH units were investigated as model systems for lightly doped polyacetylene (PA). Since high level ab initio calculations such as complete active space perturbation theory (CASPT2) are limited to systems with about 14 CH units, the performances of time-dependent Hartree-Fock (TDHF) and time-dependent density functional theory (TDDFT) were evaluated. It turned out that TDDFT excitations energies are much more accurate for polyene cations than for neutral polyenes. The difference between TDHF and TDDFT excitation energies for the first allowed excited state of C49H51(+) is only 0.30 eV with pure DFT and 0.21 eV with a hybrid functional. For open-shell systems, pure DFT is found to be superior to DFT-hybrid functionals because it does not suffer from spin-contamination. Pure TDDFT excitation energies and oscillator strengths for small open-shell polyene cations compare well with high level ab initio results. Excitation energies are found to be almost independent of the geometry, i.e., the size of the defect. Localization of the defect, however, shifts oscillator strengths from the HOMO LUMO transition to higher lying excited states of the same symmetry. Lightly doped PA is predicted to exhibit several strong absorptions below 1 eV. PMID- 26627168 TI - A Theoretical Databank of Transferable Aspherical Atoms and Its Application to Electrostatic Interaction Energy Calculations of Macromolecules. AB - A comprehensive version of the theoretical databank of transferable aspherical pseudoatoms is described, and its first application to protein-ligand interaction energies is discussed. The databank contains all atom types present in natural amino acid residues and other biologically relevant molecules. Each atom type results from averaging over a family of chemically unique pseudoatoms, taking into account both first and second neighbors. The spawning procedure is used to ensure that close transferability is obeyed. The databank is applied to the syntenin PDZ2 domain complexed with four-residue peptides and to the PDZ2 dimer. Analysis of the electrostatic interactions energies calculated by the exact potential/multipole-moment-databank method stresses the importance of the P0 and P-2 residues of the peptide in establishing the interaction, whereas the P-1 residue is shown to play a much smaller role. Unexpectedly, the charged P-3 residue contributes significantly to the interaction. The class I and II peptides are bound with the same strength by the syntenin PDZ2 domain, though the electrostatic interaction energy of the P-2 residue is smaller for class I peptides. There is no difference between the interaction energies of the peptides with PDZ2 domains from single-domain protein fragments and those from PDZ1-PDZ2 tandems. PMID- 26627169 TI - Computational Analysis of Current and Noise Properties of a Single Open Ion Channel. AB - This paper presents a computational analysis of the noise associated with the ion current in single open ion channels. The study is performed by means of a coupled molecular dynamics/Monte Carlo approach able to simulate the conduction process on the basis of all microscopic information today available from protein structural data and atomistic simulations. The case of potassium ions permeating the KcsA channel is considered in the numerical calculations. The results show a noise spectrum different from what is theoretically predicted for Poisson noise, confirmed by the existence of a correlation in ion-exit events. PMID- 26627170 TI - Linear Interaction Energy (LIE) Models for Ligand Binding in Implicit Solvent: Theory and Application to the Binding of NNRTIs to HIV-1 Reverse Transcriptase. AB - Expressions for Linear Interaction Energy (LIE) estimators for the binding of ligands to a protein receptor in implicit solvent are derived based on linear response theory and the cumulant expansion expression for the free energy. Using physical arguments, values of the LIE linear response proportionality coefficients are predicted for the explicit and implicit solvent electrostatic and van der Waals terms. Motivated by the fact that the receptor and solution media may respond differently to the introduction of the ligand, a novel form of the LIE regression equation is proposed to model independently the processes of insertion of the ligand in the receptor and in solution. We apply these models to the problem of estimating the binding free energy of two non-nucleoside classes of inhibitors of HIV-1 RT (HEPT and TIBO analogues). We develop novel regression models with greater predictive ability than more standard LIE formulations. The values of the regression coefficients generally conform to linear response predictions, and we use this fact to develop a LIE regression equation with only one adjustable parameter (excluding the intercept parameter) which is superior to the other models we tested and to previous results in terms of predictive accuracy for the HEPT and TIBO compounds individually. The new models indicate that, due to the different effects of induced steric strain of the receptor, an increase of ligand size alone opposes binding for ligands of the HEPT class, whereas it favors binding for ligands of the TIBO class. PMID- 26627171 TI - Human Cytomegalovirus Protease: Why is the Dimer Required for Catalytic Activity? AB - Human cytomegalovirus (HCMV) is a pathogenic agent responsible for morbidity and mortality in immunocompromised and immunosuppressed individuals. HCMV encodes a serine protease that is essential for the production of infectious virions. In this work, we applied molecular dynamics (MD) simulations on HCMV protease models in order to investigate the experimentally observed (i) catalytic activity of the enzyme homodimer and (ii) induced-fit mechanism upon the binding of substrates and peptidyl inhibitors. Long and stable trajectories were obtained for models of the monomeric and dimeric states, free in solution and bound covalently and noncovalently to a peptidyl-activated carbonyl inhibitor, with very good agreement between theoretical and experimental results. The MD results suggest that HCMV protease indeed operates by an induced-fit mechanism. Also, our analysis indicates that the catalytic activity of the dimer is a result of more favorable interactions between the oxyanion in the covalently bound state and the backbone nitrogen of Arg165, resulting in a reaction that is 7.0 kcal/mol more exergonic and a more significant thermodynamic driving force. The incipient oxyanion in the transition state should also benefit from the stronger interactions with Arg165, reducing in this manner the intrinsic activation barrier for the reaction in the dimeric state. PMID- 26627172 TI - Density Functionals for Noncovalent Interaction Energies of Biological Importance. AB - Forty density functionals and one wavefunction method are assessed against a recently published database of accurate noncovalent interaction energies of biological importance. The comparison shows that two newly developed density functional theory (DFT) methods, PWB6K and M05-2X, give the best performance for this benchmark database of 22 noncovalent complexes, including both hydrogen bonding and dispersion-dominated complexes. In contrast, the more popular B3LYP and PBEh functionals fail to describe the interactions in the dispersion dominated complexes. The local spin density approximation and BHandH functionals give good performance for dispersion-dominated interactions at the expense of a large error for hydrogen bonding. PWB6K and M05-2X constitute a new generation of DFT methods based on simultaneously optimized exchange and correlation functionals that include kinetic energy density in both the exchange and correlation functional, and the present study confirms that they have greatly improved performance for noncovalent interactions as compared to previous DFT methods. We interpret this as being due to an improved treatment of medium-range correlation effects by the exchange-correlation functional. We recommend the PWB6K and M05-2X methods for investigating large biological systems and soft materials. PMID- 26627173 TI - Computational Analysis of the Mechanism and Thermodynamics of Inhibition of Phosphodiesterase 5A by Synthetic Ligands. AB - Phosphodiesterases are a large class of enzymes mediating a number of physiological processes ranging from immune response to platelet aggregation to cardiac and smooth muscle relaxation. In particular, phosphodiesterase 5 (PDE5) plays an important role in mediating sexual arousal, and it is the central molecular target in treatments of erectile dysfunction. In this study, we look at the mechanism and thermodynamics of the binding of selective inhibitors sildenafil (Viagra) and vardenafil (Levitra) to PDE5 using molecular dynamics simulations. Our simulations of PDE5 with and without sildenafil suggest a binding mechanism in which two loops surrounding the binding pocket of the enzyme (H loop, residues 660-683, and M loop, 787-812) execute sizable conformational changes (~1 nm), clamping the ligand in the pocket. Also, we note significant changes in the coordination pattern of the divalent ions in the active site of the enzyme, as well as marked changes in the collective motions of the enzyme when the ligand is bound. Using the thermodynamic integration approach we calculate the relative free energies of binding of sildenafil, vardenafil, and demethyl-vardenafil, providing a test of the quality of the force field and the ligand parametrization used. Finally, using the single-step perturbation (SSP) technique, we calculate the relative binding free energies of these three ligands as well. In particular, we focus on critical evaluation of the SSP technique and examine the effects of computational parallelization on the efficiency of the technique. As a technical improvement, we demonstrate that an ensemble of relatively short SSP trajectories (10 * 0.5 ns) markedly outperforms a single trajectory of the same total length (1 * 5 ns) when it comes to sampling efficiency, resulting in significant real-time savings. PMID- 26627174 TI - Assessment of Detection and Refinement Strategies for de novo Protein Structures Using Force Field and Statistical Potentials. AB - De novo predictions of protein structures at high resolution are plagued by the problem of detecting the native conformation from false energy minima. In this work, we provide an assessment of various detection and refinement protocols on a small subset of the second-generation all-atom Rosetta decoy set (Tsai et al. Proteins 2003, 53, 76-87) using two potentials: the all-atom CHARMM PARAM22 force field combined with generalized Born/surface-area (GB-SA) implicit solvation and the DFIRE-AA statistical potential. Detection schemes included DFIRE-AA conformational scoring and energy minimization followed by scoring with both GB-SA and DFIRE-AA potentials. Refinement methods included short-time (1-ps) molecular dynamics simulations, temperature-based replica exchange molecular dynamics, and a new computational unfold/refold procedure. Refinement methods include temperature-based replica exchange molecular dynamics and a new computational unfold/refold procedure. Our results indicate that simple detection with only minimization is the best protocol for finding the most nativelike structures in the decoy set. The refinement techniques that we tested are generally unsuccessful in improving detection; however, they provide marginal improvements to some of the decoy structures. Future directions in the development of refinement techniques are discussed in the context of the limitations of the protocols evaluated in this study. PMID- 26627175 TI - Scalable analysis of Big pathology image data cohorts using efficient methods and high-performance computing strategies. AB - BACKGROUND: We describe a suite of tools and methods that form a core set of capabilities for researchers and clinical investigators to evaluate multiple analytical pipelines and quantify sensitivity and variability of the results while conducting large-scale studies in investigative pathology and oncology. The overarching objective of the current investigation is to address the challenges of large data sizes and high computational demands. RESULTS: The proposed tools and methods take advantage of state-of-the-art parallel machines and efficient content-based image searching strategies. The content based image retrieval (CBIR) algorithms can quickly detect and retrieve image patches similar to a query patch using a hierarchical analysis approach. The analysis component based on high performance computing can carry out consensus clustering on 500,000 data points using a large shared memory system. CONCLUSIONS: Our work demonstrates efficient CBIR algorithms and high performance computing can be leveraged for efficient analysis of large microscopy images to meet the challenges of clinically salient applications in pathology. These technologies enable researchers and clinical investigators to make more effective use of the rich informational content contained within digitized microscopy specimens. PMID- 26627176 TI - Surgical Strategy and Outcome for Aortic Root in Patients Undergoing Repair of Acute Type A Aortic Dissection. AB - BACKGROUND: This study evaluated the relevance of our indication of aortic root operations for acute type A aortic dissection and compared early and long-term outcomes of emergency type A aortic dissection operations between patients who underwent aortic root operations and those who did not. METHODS: We retrospectively reviewed 316 consecutive patients who underwent emergency aortic operations for acute type A aortic dissection between January 2009 and September 2013. We performed simultaneous aortic root operations when the aortic root diameter was greater than 45 mm or an intimal tear was present in the aortic root, or both. After this indication, we performed aortic repair involving the aortic root in 40 patients (aortic root replacement [ARR] group, 12.7%) and not involving the aortic root in 276 patients (non-ARR group, 87.3%). We analyzed early and long-term outcomes, including late aortic root events. RESULTS: In hospital mortality was 12.5% (5 of 40) in the ARR group and 4.7% (13 of 276) in non-ARR group (p = 0.05). Overall survival at 3 and 5 years was 84.8% and 84.8%, respectively in ARR group and was 91.9% and 91.9%, respectively, in the non-ARR group (p = 0.078). Late aortic root events, defined as aortic root dilatation (>= 3 mm/y), reoperation of the aortic root, aortic regurgitation (moderate or higher), and pseudoaneurysm, were observed in no patients in the ARR group and in 32 patients (11.6%) in the non-ARR group (p = 0.029). In the non-AAR group, dissection of 2 or more aortic sinuses was the only independent predictor of a late aortic root event (hazard ratio, 2.20; 95% confidence interval, 1.08 to 4.61; p = 0.03). CONCLUSIONS: Simultaneous aortic root operations significantly reduced the incidence of late aortic root events. The dissection of 2 or more sinuses of Valsalva was associated with a late aortic root event in patients who did not undergo aortic root operations. PMID- 26627177 TI - Invited Commentary. PMID- 26627178 TI - Oral Anticoagulation After Successful Atrial Fibrillation Ablation Operations: Is It Necessary? AB - BACKGROUND: This study analyzed the results of atrial fibrillation (AF) ablation concomitant to open heart operations using continuous monitoring. METHODS: We investigated 70 consecutive patients (mean age, 72.1 +/- 6 years; European System for Cardiac Operative Risk Evaluation II: 9.7% +/- 8.2%) who underwent AF ablation concomitant to cardiac operations in our institution between February 2012 and February 2013. For precise rhythm analysis we implanted Reveal XT devices (Medtronic Inc, Minneapolis, MN) in all patients at the end of operations. Twenty-two patients had paroxysmal (31.4%), 20 persistent (28.6%) and 28 longstanding-persistent AF (40%). AF duration time was at a median 18 months. Cardiac rhythm data were obtained by telemonitoring at 1-month intervals, and the AF burden was calculated at 3, 6, and 9 months and at 1 year postoperatively (ablation procedure success was defined as a burden of <= 0.5%). Further, a neurologic follow-up was performed at 1 year postoperatively. RESULTS: Overall survival was 95.7% at 30 days and 84.3% at 1 year. At 1 year, 66.7% of patients were in stable sinus rhythm, and AF burden was significantly reduced even in nonresponders: 88.2% of patients were off antiarrhythmic drugs, and oral anticoagulation had been stopped in 92.1%. No late neurologic events had occurred. Sinus rhythm at discharge and paroxysmal type of AF were predictive for later sinus rhythm (p = 0.04 and p = 0.048, respectively). CONCLUSIONS: Considering the long AF duration and the high proportion of longstanding persistent AF, the overall success of ablation procedures was satisfactory. Even though oral anticoagulation was stopped in most patients, no neurologic events were detected. PMID- 26627179 TI - Revisiting demand rules for gene regulation. AB - Starting with Savageau's pioneering work regarding demand rules for gene regulation from the 1970s, here, we choose the simplest transcription network and ask: how does the cell choose a particular regulatory topology from all available possibilities? According to the demand rules, a cell chooses an activator based regulation of a target if the target protein is required for most of the time. On the other hand, if the target protein is only required sporadically, its control tends to be via a repressor-based regulatory topology. We study the natural distribution of topologies at genome, systems, and micro-levels in E. coli and observe deviations from demand rules. Analyzing the regulation of amino acid biosynthesis, transport, and carbon utilization in E. coli and B. subtilis, and comparing choice of topology with demand, we observe an alternate pattern emerging. Simulations of networks are used to help explain the natural distribution of topologies in nature. Overall, our results indicate that the choice of topology is drawn randomly from a pool of all networks which satisfy the dynamic requirements of the cell, as dictated by physiology. In short, our results suggest that the cell picks "whatever works". PMID- 26627180 TI - Prophages of the genus Bifidobacterium as modulating agents of the infant gut microbiota. AB - Phage predation is one of the key forces that shape genetic diversity in bacterial genomes. Phages are also believed to act as modulators of the microbiota composition and, consequently, as agents that drive bacterial speciation in complex bacterial communities. Very little is known about the occurrence and genetic variability of (pro)phages within the Bifidobacterium genus, a dominant bacterial group of the human infant microbiota. Here, we performed cataloguing of the predicted prophage sequences from the genomes of all currently recognized bifidobacterial type strains. We analysed their genetic diversity and deduced their evolutionary development, thereby highlighting an intriguing origin. Furthermore, we assessed infant gut microbiomes for the presence of (pro)phage sequences and found compelling evidence that these viral elements influence the composition of bifidobacterial communities in the infant gut microbiota. PMID- 26627181 TI - Meta-analysis of the association between second-hand smoke exposure and ischaemic heart diseases, COPD and stroke. AB - BACKGROUND: Second-hand smoke (SHS) is the most important contaminant of indoor air in first world countries. The risks associated with SHS exposure are highly relevant, because many people are regularly, and usually involuntarily, exposed to SHS. This study aims to quantify the effects of SHS exposure. Therefore, its impact on ischaemic heart diseases (IHD), chronic obstructive pulmonary diseases (COPD) and stroke will be considered. METHODS: A systematic literature review was conducted to identify articles dealing with the association between SHS and the three outcomes IHD, COPD and stroke. Overall, 24 articles were included in a meta analysis using a random effects model. Effect sizes stratified for sex and for both sexes combined were calculated. RESULTS: The synthesis of primary studies revealed significant effect sizes for the association between SHS exposure and all three outcomes. The highest RR for both sexes combined was found for COPD (RR = 1.66, 95 % CI: 1.38-2.00). The RR for both sexes combined was 1.35 (95 % CI: 1.22-1.50) for stroke and 1.27 (95 % CI: 1.10-1.48) for IHD. The risks were higher in women than in men for all three outcomes. CONCLUSIONS: This is the first study to calculate effect sizes for the association between SHS exposure and the disease outcomes IHD, COPD, and stroke at once. Overall, the effect sizes are comparable with previous findings in meta-analyses and therefore assumed to be reliable. The results indicate the high relevance of public health campaigns and legislation to protect non-smokers from the adverse health effects attributable to SHS exposure. PMID- 26627183 TI - DNA methylation and transcription in HERV (K, W, E) and LINE sequences remain unchanged upon foreign DNA insertions. AB - AIM: DNA methylation and transcriptional profiles were determined in the regulatory sequences of the human endogenous retroviral (HERV-K, -W, -E) and LINE 1.2 elements and were compared between non-transgenomic and plasmid-transgenomic cells. METHODS: DNA methylation profiles in the HERV (K, W, E) and LINE sequences were determined by bisulfite genomic sequencing. The transcription of these genome segments was assessed by quantitative real-time PCR. RESULTS: In HERV-K, HERV-W and LINE-1.2 the levels of DNA methylation ranged between 75 and 98%, while in HERV-E they were around 60%. Nevertheless, the HERV and LINE-1.2 sequences were actively transcribed. No differences were found in comparisons of HERV and LINE-1.2 CpG methylation and transcription patterns between non transgenomic and plasmid-transgenomic HCT116 cells. CONCLUSION: The insertion of a 5.6 kbp plasmid into the HCT116 genome had no effect on the HERV and LINE-1.2 methylation and transcription profiles, although other parts of the HCT116 genome had shown marked changes. These repetitive sequences are transcribed, probably because the large number of HERV and LINE-1.2 elements harbor copies with non- or hypo-methylated long terminal repeat sequences. PMID- 26627182 TI - Zellweger spectrum disorders: clinical overview and management approach. AB - Zellweger spectrum disorders (ZSDs) represent the major subgroup within the peroxisomal biogenesis disorders caused by defects in PEX genes. The Zellweger spectrum is a clinical and biochemical continuum which can roughly be divided into three clinical phenotypes. Patients can present in the neonatal period with severe symptoms or later in life during adolescence or adulthood with only minor features. A defect of functional peroxisomes results in several metabolic abnormalities, which in most cases can be detected in blood and urine. There is currently no curative therapy, but supportive care is available. This review focuses on the management of patients with a ZSD and provides recommendations for supportive therapeutic options for all those involved in the care for ZSD patients. PMID- 26627184 TI - Options for Incidental Moderate Aortic Stenosis During Concomitant Valve Surgery: A Clinical Update for the Perioperative Echocardiographer. PMID- 26627185 TI - [((Cl)Im(Dipp))P=P(Dipp)][GaCl4]: a polarized, cationic diphosphene. AB - The reaction of the neutral diphosphanide [((Cl)Im(Dipp))P-P(Cl)(Dipp)] (6) ((Cl)Im(Dipp) = 4,5-dichloro-1,3-bis(Dipp)-imidazol-2-yl; Dipp = 2,6-di-iso propylphenyl) with methyl triflate (MeOTf) leads to the formation of cationic diphosphane [((Cl)Im(Dipp))(Me)P-P(Cl)(Dipp)](+) (8+) in a stereoselective methylation. In contrast, reacting with the Lewis acid GaCl3 yields cationic diphosphene [((Cl)Im(Dipp))P=P(Dipp)](+) (7+), which is explained by a low P-Cl bond dissociation energy. The significantly polarized P=P double bond in 7+ allows for its utilization as an acceptor for nucleophiles - the reaction with Cl(-) regenerates diphosphanide and the reaction with PMe3 gives cation [((Cl)Im(Dipp))P-P(PMe3)(Dipp)] (9+). In depth DFT investigation provides detailed insights into the bonding situation of the reported compounds. PMID- 26627186 TI - Inferior epigastric artery: Surface anatomy, prevention and management of injury. AB - The anatomical position of the inferior epigastric artery (IEA) subjects it to risk of injury during abdominal procedures that are close to the artery, such as laparoscopic trocar insertion, insertion of intra-abdominal drains, Tenckhoff((r)) catheter (peritoneal dialysis catheter) and paracentesis. This article aims to raise the awareness of the anatomical variations of the course of the IEA in relation to abdominal landmarks in order to define a safer zone for laparoscopic ancillary trocar placement. Methods of managing the IEA injury as well as techniques to minimise the risk of injury to the IEA are reviewed and discussed. PMID- 26627187 TI - Long-term dietary supplementation with saury oil attenuates metabolic abnormalities in mice fed a high-fat diet: combined beneficial effect of omega-3 fatty acids and long-chain monounsaturated fatty acids. AB - BACKGROUND: Pacific saury is a common dietary component in East Asia. Saury oil contains considerable levels of n-3 unsaturated fatty acids (PUFA) and long-chain monounsaturated fatty acids (LCMUFA) with aliphatic tails longer than 18 carbons. In our previous study, consumption of saury oil for 4 to 6 wk improved insulin sensitivity and the plasma lipid profile in mice. However, the long-term effects of saury oil on metabolic syndrome (MetS) risk factors remain to be demonstrated. In the current study, we examined the long-term effects of saury oil on mice fed a high-fat diet, and compared the effect of n-3 PUFA EPA and LCMUFA on MetS risk factor in diet-induced obese mice. METHODS AND RESULTS: In Experiment 1, male C57BL/6 J mice were fed either a 32% lard diet (control) or a diet containing 22% lard plus 10% saury oil (saury oil group) for 18 weeks. Although no differences were found in body weight and energy expenditure between the control and saury oil groups, the saury oil diet decreased plasma insulin, non-HDL cholesterol, hepatic steatosis, and adipocyte size, and altered levels of mRNA transcribed from genes involved in insulin signaling and inflammation in adipose tissue. Organ and plasma fatty acid profile analysis revealed that consumption of saury oil increased n-3 PUFA and LCMUFA (especially n-11 LCMUFA) levels in multiple organs, and decreased the fatty acid desaturation index (C16:1/C16:0; C18:1/C18:0) in liver and adipose tissue. In Experiment 2, male C57BL/6 J mice were fed a 32% lard diet (control), a diet containing 28% lard plus 4% EPA (EPA group), or a diet containing 20% lard plus 12% LCMUFA concentrate (LCMUFA group) for 8 weeks. EPA or LCMUFA intake increased organ levels of EPA and LCMUFA, respectively. Consumption of EPA reduced plasma lipid levels and hepatic lipid deposition, and decreased the fatty acid desaturation index in liver and adipose tissue. Consumption of LCMUFA decreased plasma non-HDL cholesterol, improved hyperinsulinemia, and decreased the fatty acid desaturation index in adipose tissue. EPA accumulated mainly in liver, and LCMUFA (especially n-11 LCMUFA) accumulated mainly in white adipose tissue, suggesting their possible individual biological effects for improving MetS. CONCLUSION: Our results suggest that saury oil-mediated improvement of metabolic syndrome in diet-induced obese mice may possibly be due to a combined effect of n-3 PUFA and LCMUFA. PMID- 26627188 TI - Water heater temperature set point and water use patterns influence Legionella pneumophila and associated microorganisms at the tap. AB - BACKGROUND: Lowering water heater temperature set points and using less drinking water are common approaches to conserving water and energy; yet, there are discrepancies in past literature regarding the effects of water heater temperature and water use patterns on the occurrence of opportunistic pathogens, in particular Legionella pneumophila. Our objective was to conduct a controlled, replicated pilot-scale investigation to address this knowledge gap using continuously recirculating water heaters to examine five water heater set points (39-58 degrees C) under three water use conditions. We hypothesized that L. pneumophila levels at the tap depend on the collective influence of water heater temperature, flow frequency, and the resident plumbing ecology. RESULTS: We confirmed temperature setting to be a critical factor in suppressing L. pneumophila growth both in continuously recirculating hot water lines and at distal taps. For example, at 51 degrees C, planktonic L. pneumophila in recirculating lines was reduced by a factor of 28.7 compared to 39 degrees C and was prevented from re-colonizing biofilm. However, L. pneumophila still persisted up to 58 degrees C, with evidence that it was growing under the conditions of this study. Further, exposure to 51 degrees C water in a low-use tap appeared to optimally select for L. pneumophila (e.g., 125 times greater numbers than in high use taps). We subsequently explored relationships among L. pneumophila and other ecologically relevant microbes, noting that elevated temperature did not have a general disinfecting effect in terms of total bacterial numbers. We documented the relationship between L. pneumophila and Legionella spp., and noted several instances of correlations with Vermamoeba vermiformis, and generally found that there is a dynamic relationship with this amoeba host over the range of temperatures and water use frequencies examined. CONCLUSIONS: Our study provides a new window of understanding into the microbial ecology of potable hot water systems and helps to resolve past discrepancies in the literature regarding the influence of water temperature and stagnation on L. pneumophila, which is the cause of a growing number of outbreaks. This work is especially timely, given society's movement towards "green" buildings and the need to reconcile innovations in building design with public health. PMID- 26627189 TI - Solitary metastasis from melanoma causing bowel perforation. AB - INTRODUCTION: Skin melanoma can metastasize to any organ or tissue. The median survival in patient with intestinal metastases is inferior to 7 months compared to other sites metastasis. A wide intestinal resection including the resection of the mesentery with lymph nodes remains the main treatment due to the low morbidity and mortality rate it is also associated with. CASE REPORT: We took under analysis a recent case of acute abdomen for small bowel perforation from intestinal metastases in a patient with metastatic melanoma who was under treatment with Pemrolizumab. A bowel resection was performed and no other lesions were found in the abdominal examination. However, the chemotherapy was stopped due to the advanced age of the patient, presence of brain metastases that worsening his performance status and the bowel involvement. DISCUSSION: Preoperative diagnoses of metastatic or small intestine melanoma tend to often be difficult to perform. Before considering a possible elective surgery, in case of non-urgent symptoms, it is important to value first intestinal or extraintestinal spread. The previous report of bowel perforation from melanoma metastases showed an intraoperative finding of multiple widespread brown lesions. There are not reports about the possible involvement of Pembrolizumab in bowel perforation, which leads to the conclusion that it was probably the ingrown of the metastasis to cause it. CONCLUSION: The treatment of metastatic melanoma includes chemotherapy, immunotherapy and target-therapy. It will be useful to do a multicenter study on the survival after complete resection to better define the surgical indication for the treatment of the metastatic disease. KEY WORDS: Intestinal perforation, Melanoma, Metastasis. PMID- 26627190 TI - Effect of the Chinese traditional prescription Suo Quan Wan on TRPV1 expression in the bladder of rats with bladder outlet obstruction. AB - BACKGROUND: Suo Quan Wan (SQW) is a Chinese traditional prescription that has been used in clinical treatment of lower urinary tract symptoms for centuries. However, scientific basis of SQW efficacy and mechanism is still needed. This study investigated the effect of SQW on bladder function and transient receptor potential vanilloid 1 (TRPV1) expression in the bladder of rats with bladder outlet obstruction (BOO). The induced changes in bladder function in overactive bladder (OAB) rat model were observed following different periods of outlet obstruction to obtain an appropriate rat model. METHODS: This study was carried out in two parts. In the first part, female Sprague-Dawley rats received sham operations or partial BOO operations. Two, four, and six weeks later, the OAB model groups and control were subjected to urodynamic tests to measure differences in bladder functions. Once the appropriate rat model was obtained, the second part of the experiment was performed. The rat model was recreated and treated with SQW. Urodynamic assessment was conducted, and the bladders of the rats were then removed. Immunofluorescence staining, real-time PCR, and Western blot were performed to localize and quantify the expression of TRPV1 in the bladder. RESULTS: Results of the first part indicated that at 2 and 4 weeks, the OAB model group exhibited significant differences in urodynamic parameters, including bladder pressure, maximum voiding pressure, and maximum bladder capacity, compared with the sham group. At 4 and 6 weeks, the OAB model group exhibited significant differences in residual volume (RV) and non-voiding contraction frequency. Six-week OAB model group showed much more RV but less voiding efficiency when compared with 6-week sham group or 2-and 4-week OAB model group. Rats that underwent BOO exhibited similarities with the compensated state before four weeks and may have entered decompensated state at six weeks. Studies conducted with 4-week OAB model were appropriate. In part two of the experiment, unstable bladder in the OAB model group recovered bladder stability after SQW treatment, accompanied by improved bladder hypertrophy, as well as corrected urodynamic parameters. Expression of TRPV1 mRNA and proteins in the bladder was significantly greater in the OAB model group than that in the control group, which subsequently decreased significantly with SQW treatment in BOO-induced rats. CONCLUSIONS: SQW can modulate the expression of TRPV1 in accordance with the recovery of bladder function. PMID- 26627191 TI - Rare idiopathic interstitial pneumonias: LIP and PPFE and rare histologic patterns of interstitial pneumonias: AFOP and BPIP. AB - In the 2013 reclassification of the idiopathic interstitial pneumonias (IIPs), two rare IIPs (idiopathic lymphoid interstitial pneumonia (LIP), idiopathic pleuroparenchymal fibroelastosis (IPPFE)) and two rare histologic patterns (acute fibrinous and organizing pneumonia (AFOP), bronchiolocentric pattern of interstitial pneumonia (BPIP)) are described. All these entities are rare with small series published to date, mostly containing primary and secondary forms of disease. LIP is histologically characterized by diffuse polyclonal lymphoid cell infiltrate surrounding the airways and expanding the interstitium. Thin-walled cysts and diffuse ground glass are considered the typical radiologic features. The clinical course is highly variable with corticosteroid responsiveness evident in approximately half of cases. IPPFE is defined histologically by coexisting upper lobe pleural and intra-alveolar fibrosis with elastosis. Dense subpleural irregular fibrosis and consolidation are the cardinal radiologic features. A history of recurrent lower respiratory tract infection is frequent. Responses to immunomodulation have not been reported and the rate of progression appears to be highly variable. AFOP is a rare histologic pattern lying within the spectrum of acute/subacute lung injury, characterized by organizing pneumonia and intra alveolar fibrin deposition without hyaline membranes. BPIP is characterized histologically by fibrosis and/or inflammation confined to the alveolar interstitium around bronchovascular bundles, overlapping with peribronchial metaplasia and fibrosis in some series. Currently, AFOP and BPIP are both best viewed as histological entities rather than true clinical disorders, in the absence of characteristic associated imaging patterns and clinical features. PMID- 26627192 TI - In Vivo Gene-Silencing in Fibrotic Liver by siRNA-Loaded Cationic Nanohydrogel Particles. AB - Cationic nanohydrogel particles loaded with anti-Col1alpha1 siRNA suppress collagen synthesis and deposition in fibrotic mice: Systemically administered 40 nm sized nanogel particles accumulate in collagen-expressing cells in the liver. Their siRNA payload induces a sequence specific in vivo gene knockdown affording an efficient antifibrotic effect in mice with liver fibrosis. PMID- 26627193 TI - Anaplerotic Accumulation of Tricarboxylic Acid Cycle Intermediates as Well as Changes in Other Key Metabolites During Heterotopic Ossification. AB - Heterotopic ossification (HO) is the de novo formation of bone that occurs in soft tissue, through recruitment, expansion, and differentiation of multiple cells types including transient brown adipocytes, osteoblasts, chondrocytes, mast cells, and platelets to name a few. Much evidence is accumulating that suggests changes in metabolism may be required to accomplish this bone formation. Recent work using a mouse model of heterotopic bone formation reliant on delivery of adenovirus-transduced cells expressing low levels of BMP2 showed the immediate expansion of a unique brown adipocyte-like cell. These cells are undergoing robust uncoupled oxidative phosphorylation to a level such that oxygen in the microenvironment is dramatically lowered creating areas of hypoxia. It is unclear how these oxygen changes ultimately affect metabolism and bone formation. To identify the processes and changes occurring over the course of bone formation, HO was established in the mice, and tissues isolated at early and late times were subjected to a global metabolomic screen. Results show that there are significant changes in both glucose levels, as well as TCA cycle intermediates. Additionally, metabolites necessary for oxidation of stored lipids were also found to be significantly elevated. The complete results of this screen are presented here, and provide a unique picture of the metabolic changes occurring during heterotopic bone formation. PMID- 26627195 TI - Analysis of phytochemical variations in dioecious Tinospora cordifolia stems using HPLC/QTOF MS/MS and UPLC/QqQLIT -MS/MS. AB - INTRODUCTION: The stem of dioecious Tinospora cordifolia (Menispermaceae) is a commonly used traditional Ayurvedic medicine in India having several therapeutic properties. OBJECTIVE: To develop and validate LC-MS methods for the identification and simultaneous quantitation of various secondary metabolites and to study metabolomic variations in the stem of male and female plants. METHODS: Ethanolic extract of stems were analysed by HPLC/ESI-QTOF-MS/MS for rapid screening of bioactive phytochemicals. High resolution MS and MS/MS in positive ESI mode were used for structural investigation of secondary metabolites. An UPLC/ESI-QqQ(LIT) -MS/MS method in MRM mode was developed and validated for the simultaneous quantitation of five bioactive alkaloids. RESULTS: Identification and characterisation of 36 metabolites including alkaloids, sesquiterpenes and phytoecdysteroids were performed using LC-MS and MS/MS techniques. The bioactive alkaloids such as jatrorrhizine, magnoflorine, isocorydine, palmatine and tetrahydropalmatine were successfully quantified in male and female plants. The mean abundances of magnoflorine jatrorrhizine, and oblongine were significantly (P < 0.05) higher in male plants while mean abundances of tetrahydropalmatine, norcoclaurine, and reticuline were significantly (P < 0.05) higher in female plants. CONCLUSIONS: Phytochemicals in the stem of male and female Tinospora cordifolia showed significant qualitative and quantitative variations. LC-MS and MS/MS methods can be used to differentiate between male and female plants based on their chemical profiles and quantities of the marker bioactive alkaloids. This chemical composition difference was also evident during vegetative stage when there were no male and female flowers. PMID- 26627194 TI - "Salivary gland cellular architecture in the Asian malaria vector mosquito Anopheles stephensi". AB - BACKGROUND: Anopheles mosquitoes are vectors for malaria, a disease with continued grave outcomes for human health. Transmission of malaria from mosquitoes to humans occurs by parasite passage through the salivary glands (SGs). Previous studies of mosquito SG architecture have been limited in scope and detail. METHODS: We developed a simple, optimized protocol for fluorescence staining using dyes and/or antibodies to interrogate cellular architecture in Anopheles stephensi adult SGs. We used common biological dyes, antibodies to well conserved structural and organellar markers, and antibodies against Anopheles salivary proteins to visualize many individual SGs at high resolution by confocal microscopy. RESULTS: These analyses confirmed morphological features previously described using electron microscopy and uncovered a high degree of individual variation in SG structure. Our studies provide evidence for two alternative models for the origin of the salivary duct, the structure facilitating parasite transport out of SGs. We compare SG cellular architecture in An. stephensi and Drosophila melanogaster, a fellow Dipteran whose adult SGs are nearly completely unstudied, and find many conserved features despite divergence in overall form and function. Anopheles salivary proteins previously observed at the basement membrane were localized either in SG cells, secretory cavities, or the SG lumen. Our studies also revealed a population of cells with characteristics consistent with regenerative cells, similar to muscle satellite cells or midgut regenerative cells. CONCLUSIONS: This work serves as a foundation for linking Anopheles stephensi SG cellular architecture to function and as a basis for generating and evaluating tools aimed at preventing malaria transmission at the level of mosquito SGs. PMID- 26627196 TI - Impaired recovery from peritoneal inflammation in a mouse model of mild dietary zinc restriction. AB - SCOPE: Mild dietary zinc (Zn) deficiency is wide-spread in human populations, but the effect on Zn-dependent processes of immune function and healing are not well understood. The consequences of mild dietary Zn restriction were examined in two mouse models of inflammation and recovery. METHODS AND RESULTS: Male C57BL/6 mice were fed a Zn adequate diet (ZA, 30 mg Zn/kg diet), or diets containing sub optimal Zn levels (ZM, 15 mg Zn/kg diet; ZD, 10 mg Zn/kg diet) for 30 days before a thioglycollate peritonitis challenge. Plasma lipid profiles were distinct, with greater Zn restriction resulting in a greater impact on metabolites. The milder ZM diet was selected for immune studies. Peritoneal macrophages from ZM mice displayed increased phagocytosis and amplified pro-inflammatory cytokine (IL 1beta, IL-6, and TNFalpha) release compared to ZA, at baseline and after a secondary LPS challenge. Splenocytes isolated from ZM mice displayed an increase in IL-6 and a reduction in anti-inflammatory IL-4 compared to ZA. Cytokine levels in plasma were unaltered. Following mechanical manipulation of the intestines to induce ileus, ZM mice had delayed intestinal transit compared to ZA. CONCLUSION: Mild Zn deficiency enhances local inflammatory responses, amplifying macrophage functions and delaying recovery from acute insults within the peritoneum. PMID- 26627197 TI - Molecular Characterization, Antimicrobial Resistance and Caco-2 Cell Invasion Potential of Campylobacter jejuni/coli from Young Children with Diarrhea. AB - BACKGROUND: Campylobacter is a major cause of bacterial gastroenteritis worldwide. Young children represent a particular age group affected by Campylobacter infection because of their limited diets and weak immune systems. METHODS: In this study, a total of 110 Campylobacter (80 Campylobacter jejuni and 30 Campylobacter coli) isolated from children younger than 5 years of age with diarrhea in Shanghai, China in 2011 were examined for their genetic relationship and antimicrobial susceptibility. The presence of virulence genes and its association with invasion potential in Caco-2 cell were also determined. RESULTS: Multilocus sequence typing revealed 62 sequence types (STs) under 14 clonal complexes from C. jejuni and 15 STs under 2 clonal complexes from C. coli. High resistance rates among the 110 isolates were observed to nalidixic acid (88.2%), ciprofloxacin (87.3%) and tetracycline (87.3%), followed by ampicillin (30.9%), gentamicin (28.2%), clindamycin (21.8%), erythromycin (21.8%) and chloramphenicol (8.2%). Compared with that of C. jejuni (32.5%), a larger proportion of C. coli (83.3%) were resistant to multiple antimicrobials, including 16 isolates of ST 828 complex resistant to 6 antimicrobials: ciprofloxacin, clindamycin, erythromycin, gentamicin, nalidixic acid and tetracycline. Furthermore, 57 Campylobacter isolates were selected based on their distinct STs and the presence of virulence genes to determine their abilities to adhere to and invade Caco-2 cells. The level of invasion varied widely among isolates and had relatively weak correlation with the genotype data. CONCLUSION: Our findings provided baseline data on Campylobacter among young children. Active surveillance of Campylobacter is needed to better understand the epidemiology and antimicrobial resistance trends of this significant pathogen to help control and protect young children from such infections. PMID- 26627198 TI - Juvenile generalized pustular psoriasis with IL36RN mutation treated with short term infliximab. AB - A 8-year-old Chinese boy with generalized pustular psoriasis (GPP) refractory to cyclosporine and methylprednisolone was treated successfully with two infusions of infliximab 3.3 mg/kg. He remained in remission for 21 months. Direct sequencing of IL36RN gene showed a homozygous mutation, c.115 + 6T>C. Juvenile GPP is a rare severe form of psoriasis occasionally associated with life threatening complications. Like acitretin, cyclosporine and methotrexate, infliximab has been reported to be effective for juvenile GPP in case reports. However, there is a lack of data in the optimal treatment course of infliximab for juvenile GPP. Prolonged administration of these medications may cause toxic or fatal complications. We suggest that short-term infliximab regimen should be recommended as a choice for acute juvenile GPP refractory to traditional systemic therapies. WBC count and CRP are sensitive parameters to reflect the disease activity and evaluate the effectiveness of treatment. Monitoring CD4 T lymphocyte count, preventing and correcting CD4 lymphocytopenia are important in the treatment course of juvenile GPP. PMID- 26627199 TI - Thalamic inflammation after brain trauma is associated with thalamo-cortical white matter damage. AB - BACKGROUND: Traumatic brain injury can trigger chronic neuroinflammation, which may predispose to neurodegeneration. Animal models and human pathological studies demonstrate persistent inflammation in the thalamus associated with axonal injury, but this relationship has never been shown in vivo. FINDINGS: Using [(11)C]-PK11195 positron emission tomography, a marker of microglial activation, we previously demonstrated thalamic inflammation up to 17 years after traumatic brain injury. Here, we use diffusion MRI to estimate axonal injury and show that thalamic inflammation is correlated with thalamo-cortical tract damage. CONCLUSIONS: These findings support a link between axonal damage and persistent inflammation after brain injury. PMID- 26627200 TI - TGF-beta induces HLA-G expression through inhibiting miR-152 in gastric cancer cells. AB - BACKGROUND: Mounting evidences have showed the important role of transforming growth factor-beta (TGF-beta) in immunological surveillance of tumors. Some studies have also indicated human leukocyte antigen (HLA)-G-associated immune escape involving TGF-beta management in gastric cancer (GC). However, the mechanism underlying it is unclear. This study aims to verify the correlations between HLA-G and TGF-beta, involving the potential targeting of miR-152 on HLA G. RESULTS: TGF-beta and HLA-G levels were analyzed in blood samples from twenty GC patients with ELISA assays, while TGF-beta showed directly proportional to HLA G levels in GC patients, and TGF-beta induced HLA-G up-regulation was also confirmed in GC cell lines. Furthermore, miR-152 expression could be inhibited by TGF-beta, and the negative post-transcriptionally regulation of miR-152 on HLA-G was also demonstrated through gain- and loss-of-function studies. Besides, miR 152 overexpression repressed HLA-G up-regulation induced by TGF-beta. And, miR 152 expression levels showed inversely proportional to both HLA-G and also TGF beta levels in GC patients. CONCLUSION: TGF-beta could induce HLA-G expression in GC by inhibiting miR-152, involving its negative regulation on HLA-G. Since TGF beta induced HLA-G up-regulation plays important role in immune escape, a potential application of miR-152 was suggested in GC treatment, or miR-152 might be one potential biomarker for GC. PMID- 26627201 TI - High-yield secretion of recombinant proteins expressed in tobacco cell culture with a designer glycopeptide tag: Process development. AB - Low-yield protein production remains the most significant economic hurdle with plant cell culture technology. Fusions of recombinant proteins with hydroxyproline-O-glycosylated designer glycopeptide tags have consistently boosted secreted protein yields. This prompted us to study the process development of this technology aiming to achieve productivity levels necessary for commercial viability. We used a tobacco BY-2 cell culture expressing EGFP as fusion with a glycopeptide tag comprised of 32 repeat of "Ser-Pro" dipeptide, or (SP)32 , to study cell growth and protein secretion, culture scale-up, and establishment of perfusion cultures for continuous production. The BY-2 cells accumulated low levels of cell biomass (~7.5 g DW/L) in Schenk & Hildebrandt medium, but secreted high yields of (SP)32 -tagged EGFP (125 mg/L). Protein productivity of the cell culture has been stable for 6.0 years. The BY-2 cells cultured in a 5-L bioreactor similarly produced high secreted protein yield at 131 mg/L. Successful operation of a cell perfusion culture for 30 days was achieved under the perfusion rate of 0.25 and 0.5 day(-1) , generating a protein volumetric productivity of 17.6 and 28.9 mg/day/L, respectively. This research demonstrates the great potential of the designer glycopeptide technology for use in commercial production of valuable proteins with plant cell cultures. PMID- 26627202 TI - Efficiency and safety of surgical intervention to patients with Non-Cystic Fibrosis bronchiectasis: a meta-analysis. AB - No quantitative systematic review was found to report the efficiency and safety of surgical resection in the management of non-cystic fibrosis (non-CF) bronchiectasis. We therefore conducted a meta-analysis to assess the effects of operative intervention to patients with non-CF bronchiectasis. PubMed, the Cochrane library and Web of Science databases were searched up to July 8th, 2015. The pooled mortality from 34 studies recruiting 4788 patients was 1.5% (95% CI, 0.9-2.5%). The pooled morbidity from 33 studies consisting of 4583 patients was 16.7% (95% CI, 14.8-18.6%). The pooled proportion of patients from 35 studies, consisting of 4614 patients who were free of symptoms was 66.5% (95% CI, 61.3 71.7%) after surgery. The summary proportion of patients from 35 articles including 4279 participants who were improved was 27.5% (95% CI, 22.5-32.5%), and 9.1% (95% CI, 7.3-11.5%) showed no clinical improvement. In conclusion, our analysis indicated that lung resection in the management of non-CF bronchiectasis is associated with significant improvements in symptoms, low risk of mortality and acceptable morbidity. PMID- 26627203 TI - Phage adsorption and lytic propagation in Lactobacillus plantarum: could host cell starvation affect them? AB - BACKGROUND: Bacteriophages constitute a great threat to the activity of lactic acid bacteria used in industrial processes. Several factors can influence the infection cycle of bacteriophages. That is the case of the physiological state of host cells, which could produce inhibition or delay of the phage infection process. In the present work, the influence of Lactobacillus plantarum host cell starvation on phage B1 adsorption and propagation was investigated. RESULT: First, cell growth kinetics of L. plantarum ATCC 8014 were determined in MRS, limiting carbon (S-N), limiting nitrogen (S-C) and limiting carbon/nitrogen (S) broth. L. plantarum ATCC 8014 strain showed reduced growth rate under starvation conditions in comparison to the one obtained in MRS broth. Adsorption efficiencies of > 99 % were observed on the starved L. plantarum ATCC 8014 cells. Finally, the influence of cell starvation conditions in phage propagation was investigated through one-step growth curves. In this regard, production of phage progeny was studied when phage infection began before or after cell starvation. When bacterial cells were starved after phage infection, phage B1 was able to propagate in L. plantarum ATCC 8014 strain in a medium devoid of carbon source (S N) but not when nitrogen (S-C broth) or nitrogen/carbon (S broth) sources were removed. However, addition of nitrogen and carbon/nitrogen compounds to starved infected cells caused the restoration of phage production. When bacterial cells were starved before phage infection, phage B1 propagated in either nitrogen or nitrogen/carbon starved cells only when the favorable conditions of culture (MRS) were used as a propagation medium. Regarding carbon starved cells, phage propagation in either MRS or S-N broth was evidenced. CONCLUSIONS: These results demonstrated that phage B1 could propagate in host cells even in unfavorable culture conditions, becoming a hazardous source of phages that could disseminate to industrial environments. PMID- 26627204 TI - Accuracy of intracranial pressure monitoring: systematic review and meta analysis. AB - INTRODUCTION: Intracranial pressure (ICP) measurement is used to tailor interventions and to assist in formulating the prognosis for traumatic brain injury patients. Accurate data are therefore essential. The aim of this study was to verify the accuracy of ICP monitoring systems on the basis of a literature review. METHODS: A PubMed search was conducted from 1982 to 2014, plus additional references from the selected papers. Accuracy was defined as the degree of correspondence between the pressure read by the catheter and a reference "real" ICP measurement. Studies comparing simultaneous readings from at least two catheters were included. Drift was defined as the loss of accuracy over the monitoring period. Meta-analyses of data from the studies were used to estimate the overall mean difference between simultaneous ICP measurements and their variability. Individual studies were weighted using both a fixed and a random effects model. RESULTS: Of 163 articles screened, 83 compared two intracranial catheters: 64 reported accuracy and 37 drift (some reported both). Of these, 10 and 17, respectively, fulfilled the inclusion criteria for accuracy and zero drift analysis. The combined mean differences between probes were 1.5 mmHg (95 % confidence interval (CI) 0.7-2.3) with the random effects model and 1.6 mmHg (95 % CI 1.3-1.9) with the fixed effects model. The reported mean drift over a long observation period was 0.75 mmHg. No relation was found with the duration of monitoring or differences between various probes. CONCLUSIONS: This study confirms that the average error between ICP measures is clinically negligible. The random effects model, however, indicates that a high percentage of readings may vary over a wide range, with clinical implications both for future comparison studies and for daily care. PMID- 26627206 TI - Landscape ecological security response to land use change in the tidal flat reclamation zone, China. AB - As coastal development becomes a national strategy in Eastern China, land use and landscape patterns have been affected by reclamation projects. In this study, taking Rudong County, China as a typical area, we analyzed land use change and its landscape ecological security responses in the tidal flat reclamation zone. The results show that land use change in the tidal flat reclamation zone is characterized by the replacement of natural tidal flat with agricultural and construction land, which has also led to a big change in landscape patterns. We built a landscape ecological security evaluation system, which consists of landscape interference degree and landscape fragile degree, and then calculated the landscape ecological security change in the tidal flat reclamation zone from 1990 to 2008 to depict the life cycle in tidal flat reclamation. Landscape ecological security exhibited a W-shaped periodicity, including the juvenile stage, growth stage, and maturation stage. Life-cycle analysis demonstrates that 37 years is required for the land use system to transform from a natural ecosystem to an artificial ecosystem in the tidal flat reclamation zone. PMID- 26627205 TI - The chronic kidney disease epidemiology collaboration equation combining creatinine and cystatin C accurately assesses renal function in patients with cirrhosis. AB - BACKGROUND: Accurate measurement of renal function in cirrhotic patients is still challenging. To find the best test for the determination of the true glomerular filtration rate (GFR) in cirrhotic patients this study prospectively compared measured (m)GFR, the gold standard, with estimated (e)GFR using equations based on serum levels of creatinine and cystatin C. METHODS: GFR was measured by sinistrin clearance using the bolus method in 50 patients with cirrhosis (Child Turcotte Pugh score A, B and C) and 24 age-matched healthy subjects as controls. Measured (m)GFR was compared to eGFR using bias, accuracy 10 % and 30 %, as well as correlation coefficients. RESULTS: Creatinine-based equations generally overestimated GFR in patients with cirrhosis and showed a bias (average difference between mGFR and eGFR) of -40 (CG), -12 (MDRD) and -9 (CKD-EPI-Cr) ml/min/1.73 m(2). Cystatin C-based equations underestimated GFR, especially in patients with Child Turcotte Pugh score C (bias 17 ml/min/1.73 m(2)for CKD-EPI CysC). Of these equations, the CKD-EPI equation that combines creatinine and cystatin C (CKD-EPI-Cr-CysC) showed a bias of 0.12 ml/min/1.73 m(2) as compared to measured GFR. CONCLUSIONS: The CKD-EPI equation that combines serum creatinine and cystatin C measurements shows the best performance for accurate estimation of GFR in cirrhosis, especially at advanced stages. PMID- 26627207 TI - Hydrogeochemical investigations and groundwater quality assessment of Torbat Zaveh plain, Khorasan Razavi, Iran. AB - Hydrogeochemical investigations of groundwater in Torbat-Zaveh plain have been carried out to assess the water quality for drinking and irrigation purposes. In this study, 190 groundwater samples were collected and analyzed for physicochemical parameters and major ion concentrations. The abundance of major cations and anions was in the following order: Na(+) > Mg(2+) > Ca(2+) > K(+), and Cl(-) > [Formula: see text] > [Formula: see text] > [Formula: see text]. As a result, alkaline element (Na(+)) exceeds alkaline earth elements (Mg(2+) and Ca(2+)), and strong acids (Cl(-) and [Formula: see text]) dominate weak acids ([Formula: see text] and [Formula: see text]) in majority of the groundwater samples. Statistical analyses including Spearman correlation coefficients and factor analysis display good correlation between physicochemical parameters (EC, TDS and TH) and Na(+), Mg(2+), Ca(2+), Cl(-) and [Formula: see text]. The results display that rock-weathering interactions and ion-exchange processes play important role in controlling groundwater chemistry. Saturation index values also indicate that water chemistry is significantly affected by carbonate minerals such as calcite, aragonite and dolomite. US Salinity Laboratory(USSL) and Wilcox diagrams together with permeability index values reveal that most of the groundwater samples are suitable for irrigation purpose. However, in some regions, the water samples do not indicate required irrigational quality. PMID- 26627208 TI - Metal distribution and bioavailability in surface sediments from the Huaihe River, Anhui, China. AB - This study presents the total concentrations and chemical fractionations of metals (Cu, Pb, Zn, Ni, Fe, and Mn) in 54 surface sediment samples collected from the Huaihe River (Anhui Province) in eastern China. Compared with the average shale values, Zn and Pb exhibited the most substantial anthropogenic enrichment, especially in Fengtai and Huainan areas, the main industrial districts along the Huaihe River (Anhui Province). Low levels of Cu and Ni were observed in the sediments. Based on risk assessment code (RAC), the metals associated with weak acid soluble (F1) in the Huaihe River sediments followed the order: Mn > Zn > Cu > Pb > Ni > Fe. Manganese presented the most potential for releasing into the aqueous environment and can easily enter the food chain. Copper, zinc, nickel, and iron were found dominant in the residual fraction, implying that these four metals were strongly bound to the sediments. Lead showed a different partitioning pattern from that of other metals studied, with a large percentage in Fe-Mn oxide fraction, indicating that slight redox potential changes may make significant influence on the removability of Pb. Moreover, Cu in oxidizable (F3) and residual (F4) fractions presented high positive correlation with organic matter, which can explain the high percentage of Cu in these two fractions. PMID- 26627209 TI - Assessing public aesthetic preferences towards some urban landscape patterns: the case study of two different geographic groups. AB - Landscape aesthetics is closely linked to people's daily life, and a large body of studies has been conducted to understand the public's landscape preferences. These studies commonly focused on comprehensive landscape configuration, yet limited emphasis was placed on the patterns of individual landscape features. This research explored people's preferences towards the composition and patterns of some specific urban features. Questionnaire-based survey was conducted in two cities: Cambridge, UK and Nanjing, China and more than 180 responses were collected, respectively. Respondents from both sites showed similar preferences towards freely growing trees, individual houses, gable roofs and mixed design of green spaces. On the other hand, respondents from Cambridge and Nanjing have different preferences towards the height of trees, the size of green spaces, and the height diversity of buildings. This survey also proved that the factors of age, education, status and length of living have larger influences on landscape preferences than the factors of gender, and major. Furthermore, strong correlations were found between people's aesthetic preferences towards comparative landscape patterns, building types, tree shapes and roof structures. The existence of generally shared landscape preferences makes it feasible to conduct international and standardized projects for acquiring comparable and transferable criteria. The methodology and findings of this research provides landscape planners and decision makers with useful reference to compare, evaluate and improve urban landscape configurations to meet people's needs. PMID- 26627210 TI - Rice cropping density and intensity lessened in southeast China during the twenty first century. AB - Accurate and updated time series maps of paddy rice distribution and planting intensity will greatly improve our knowledge. Unfortunately, spatiotemporal explicit information on rice fields is relatively limited, and considerable uncertainties still exist as regards to its inter-annual variations in China. In this study, an improved rice mapping methodology was proposed through combined consideration of vegetation phenology and surface moisture variations from different seasonal rice. This method was applied to southeast China based on 500 m 8 day composite Moderate Resolution Imaging Spectroradiometer (MODIS) Enhance Vegetation Indices with two bands (EVI2) during the period 2001-2013. Its efficiency was validated with 763 ground survey sites, with an overall accuracy of 95.02 % and the kappa index of 0.9217. Spatiotemporal analysis indicated that rice cropping density and intensity lessened in southeast China during the period 2001-2013. Particularly, the paddy rice-planted areas reduced by 30.09 %, changing from 231,005 to 161,484 km(2). Among them, the planted areas of double rice decreased by 49.34 %, changing from 34,215 to 17,335 km(2). Therefore, averaged rice cropping intensity in southeast China decreased from 1.148 to 1.107. The primary dynamic patterns were from single rice or a rotation of rice plus other crops to non-rice (93,386 km(2)) and double rice to non-double rice (24,132 km(2)). When analyzed at provincial and altitudinal gradient levels, it was obvious that areas with greater rice cropping density or intensity were associated with more remarkable reductions. Graphical abstract The left graph shows that the rice cropping density lessened in Hubei, Hunan, Guangdong, Jiangxi, Anhui, Jiangsu, Henan provinces and other three provincial-level administrative units (Zhejiang, Fujian and Shanghai) from 2001 to 2013. The middle graph indicates the movement of gravity center as well as the variations in the total planted areas of single rice, rice plus others and double rice. The right graph denotes that the rice cropping intensity decreased in each provincial level administrative unit from 2001 to 2013. PMID- 26627212 TI - Increasing Children's Physical Activity During the School Day. AB - Insufficient levels of daily physical activity (PA) among children in the USA and worldwide have profound implications for pediatric obesity and children's health and well-being more generally. Public health recommendations highlight the central role that schools play in providing equitable opportunities for PA for all children. This review identifies evidence-based approaches for increasing children's PA throughout the school day and discusses multilevel factors that support implementation of such approaches. Opportunities to increase school-day PA span not only in-school time (e.g., quality recess and physical education, classroom activity breaks) but also time before school (e.g., active commuting initiatives) and after school (e.g., intramural and interscholastic sports programs). For such approaches to impact children's PA, dimensions of implementation such as adoption, fidelity, penetration, implementation costs, and sustainability are critical. Multilevel factors that influence implementation include policies, school environment and organizational factors, teacher and classroom factors, child and family characteristics, and attributes of the PA approach itself. Research and field observations reinforce the importance of understanding challenges specific to working with schools, including multiple stakeholders, competing priorities, limited facilities and staff capacity, and heterogeneity of students. Thus, while schools hold promise as promoters and equalizers of PA engagement for all children, more research is needed on the levers that influence implementation of effective school-based PA policies and programs. PMID- 26627211 TI - How drought and salinity affect arbuscular mycorrhizal symbiosis and strigolactone biosynthesis? AB - MAIN CONCLUSION: This paper reviews the importance of AM symbiosis in alleviating plant stress under unfavourable environmental conditions, making emphasis on the role of strigolactones. A better understanding of the mechanisms that regulate this beneficial association will increase its potential use as an innovative and sustainable strategy in modern agriculture. Plants are very dynamic systems with a great capacity for adaptation to a constantly changing environment. This phenotypic plasticity is particularly advantageous in areas damaged or subjected to intensive agriculture. Nowadays, global crop production systems are intensifying the impact on natural resources, such as water availability. Therefore, there is an urgent need to find more sustainable alternatives. One of the plant strategies to improve phenotypic plasticity is to establish mutualistic beneficial associations with soil microorganisms, such as the arbuscular mycorrhizal (AM) fungi. The establishment of AM symbiosis requires a complex network of interconnected signalling pathways, in which phytohormones play a key role. Strigolactones (SLs) are plant hormones acting as modulators of the coordinated development under nutrient shortage. SLs also act as host detection signals for AM fungi, favouring symbiosis establishment. In this review, current knowledge on the effect of water-related stresses, such as drought and salinity, in AM symbiosis and in SL production is discussed. Likewise, how the symbiosis helps the host plant to alleviate stress symptoms is also reviewed. Finally, we highlight how interactions between hormonal signalling pathways modulate all these responses, especially in the cross-talk between SLs and abscisic acid (ABA). Understanding the intricate mechanisms that regulate the establishment of AM symbiosis and the plant responses under unfavourable conditions will contribute to implement the use of AM fungi as bioprotective agents against these stresses. PMID- 26627213 TI - Health Consequences of Weight Stigma: Implications for Obesity Prevention and Treatment. AB - Despite decades of research documenting consistent stigma and discrimination against individuals with obesity, weight stigma is rarely considered in obesity prevention and treatment efforts. In recent years, evidence has examined weight stigmatization as a unique contributor to negative health outcomes and behaviors that can promote and exacerbate obesity. This review summarizes findings from published studies within the past 4 years examining the relationship between weight stigma and maladaptive eating behaviors (binge eating and increased food consumption), physical activity, weight status (weight gain and loss and development of obesity), and physiological stress responses. Research evaluating the effects of weight stigma present in obesity-related public health campaigns is also highlighted. Evidence collectively demonstrates negative implications of stigmatization for weight-related health correlates and behaviors and suggests that addressing weight stigma in obesity prevention and treatment is warranted. Key questions for future research to further delineate the health effects of weight stigmatization are summarized. PMID- 26627214 TI - Childhood Obesity Prevention in Childcare Settings: the Potential of Policy and Environmental Change Interventions. AB - Current obesity rates in young children are a serious public health concern; developing and implementing obesity prevention interventions in childcare settings is a promising avenue to address this issue. In recent years, there has been increasing focus on environmental and policy change interventions for this setting. Improving access to and quality of outdoor play spaces and implementing the Nutrition and Physical Activity Self-Assessment for Child Care (NAP SACC) are two promising environmental change strategies in this setting. Laws at the local, state, and federal level have also been implemented; New York City and Delaware are two jurisdictions that have passed policies and provided preliminary evidence of the potential of policy interventions to change child outcomes. A combination of programmatic, environmental, and policy change strategies will likely be most effective in maximizing the potential of childcare settings to promote healthy weight in children. PMID- 26627215 TI - Prevention of Weight Regain Following Bariatric Surgery. AB - Bariatric surgery is an effective treatment for patients with severe or moderate obesity; however, long-term studies have identified that weight regain occurs post-operatively among a portion of patients. The underlying factors that influence weight regain following bariatric surgery are multifactorial and include endocrine/metabolic alterations, anatomic surgical failure, nutritional indiscretion, mental health issues, and physical inactivity. The extent and significance of these factors is currently uncertain and likely varies between individuals and the operative procedure performed. Multiple observational and non randomized studies and a few randomized controlled trials have been reported that focus on improving post-operative weight loss. Across all of the behavioral and group support studies, patients in the treatment groups showed either no benefit or modestly greater weight loss than patients in the control groups. There are no randomized controlled trials that have specifically targeted weight regain. Additional clinical research is needed to identify etiological factors and interventional strategies. PMID- 26627216 TI - Does Breastfeeding Protect Against Childhood Obesity? Moving Beyond Observational Evidence. AB - Human milk is the optimal feeding choice for infants, as it dynamically provides the nutrients, immunity support, and other bioactive factors needed for infants at specific stages during development. Observational studies and several meta analyses have suggested that breastfeeding is protective against development of obesity in childhood and beyond. However, these findings are not without significant controversy. This review includes an overview of observational findings to date, then focuses on three specific pathways that connect human milk and infant physiology: maternal obesity, microbiome development in the infant, and the development of taste preference and diet quality. Each of these pathways involves complex interactions between mother and infant, includes both biologic and non-biologic factors, and may have both direct and indirect effects on obesity risk in the offspring. This type of integrated approach to examining breastfeeding and childhood obesity is necessary to advance research in this area beyond observational findings. PMID- 26627217 TI - The Whitening of Brown Fat and Its Implications for Weight Management in Obesity. AB - Systemic inflammation resulting from dysfunction of white adipose tissue (WAT) accelerates the pathologies of diabetes and cardiovascular diseases. In contrast to WAT, brown adipose tissue (BAT) is abundant in mitochondria that produce heat by uncoupling respiratory chain process of ATP synthesis. Besides BAT's role in thermogenesis, accumulating evidence has shown that it is involved in regulating systemic metabolism. Studies have analyzed the "browning" processes of WAT as a means to combat obesity, whereas few studies have focused on the impact and molecular mechanisms that contribute to obesity-linked BAT dysfunction--a process that is associated with the "whitening" of this tissue. Compared to WAT, a dense vascular network is required to support the high energy consumption of BAT. Recently, vascular rarefaction was shown to be a significant causal factor in the whitening of BAT in mouse models. Vascular insufficiency leads to mitochondrial dysfunction and loss in BAT and contributes to systemic insulin resistance. These data suggest that BAT "whitening," resulting from vascular dysfunction, can impact obesity and obesity-linked diseases. Conversely, agents that promote BAT function could have utility in the treatment of these conditions. PMID- 26627218 TI - Adaptive Thermogenesis in Resistance to Obesity Therapies: Issues in Quantifying Thrifty Energy Expenditure Phenotypes in Humans. AB - Dieting and exercise are likely to remain the core approaches in the management of obesity in the foreseeable future despite their well-documented failures for achieving long-term weight loss. Explanations for such poor prognosis are centered on patient's self-regulatory failure and lack of compliance to the prescribed diet or exercise regimen. While a role for physiological adaptations leading to diminished rates of heat production has also been advocated, there are considerable uncertainties about the quantitative importance of such regulated heat production (i.e., adaptive thermogenesis) to the less-than-expected weight loss and ease for weight regain. This paper first reviews the most compelling evidence of what is often considered as weight loss-induced adaptive thermogenesis in various compartments of daily energy expenditure. It then discusses the major limitations and issues in quantifying such thrifty energy expenditure phenotypes and underscores the plausibility of diminished core temperature as a thrifty metabolic trait in resistance to weight loss. Although an accurate quantification of adaptive thermogenesis will have to await the applications of deep body composition phenotyping and better discrimination of physical activity energy expenditures, the magnitude of diminished energy expenditure in response to weight loss in certain individuals is large enough to support the concept that adaptive thermogenesis contribute importantly to their resistance to obesity therapies. PMID- 26627219 TI - Racial/Ethnic Differences in Insulin Resistance and Beta Cell Function: Relationship to Racial Disparities in Type 2 Diabetes among African Americans versus Caucasians. AB - Both biological and sociocultural factors have been implicated in the well documented racial disparity in incidence and prevalence of type 2 diabetes (T2D) between African Americans (AA) and non-Hispanic whites (NHW). This review examines the extent to which biological differences in glucose metabolism, specifically insulin resistance and beta cell function (BCF), contribute to this disparity. The majority of available data suggests that AA are more insulin resistant and have upregulated BCF compared to NHW. Increasing evidence implicates high insulin secretion as a cause rather than consequence of T2D; therefore, upregulated BCF in AA may specifically confer increased risk of T2D in this cohort. Racial disparities in the metabolic characteristics of T2D have direct implications for the treatment and health consequences of this disease; therefore, future research is needed to determine whether strategies to reduce insulin secretion in AA may prevent or delay T2D and lessen racial health disparities. PMID- 26627220 TI - What is the Mechanism Behind Weight Loss Maintenance with Gastric Bypass? AB - Obesity is an epidemic on the rise. With the failure of non-surgical strategies, bariatric surgery has emerged as the most effective therapeutic option for the treatment of severe obesity. Among various surgical options, Roux-en-Y gastric bypass (RYGB) results in sustained weight loss and profound metabolic improvements. The traditional view that gastric bypass and bariatric surgery in general works primarily through restriction/malabsorption of nutrients has become obsolete. It is now increasingly recognised that its mechanisms of action are primarily physiologic, not mechanic. In fact, clinical and translational studies over the last decade have shown that a number of gastrointestinal mechanisms, including changes in gut hormones, neural signalling, intestinal flora, bile acid and lipid metabolism can play a significant role in the effects of this procedure on energy homeostasis. The clinical efficacy and mechanisms of action of RYGB provide a compelling evidence for the role of the gastrointestinal tract in the regulation of appetite and satiety, body weight and glucose metabolism. This review discusses the physiologic changes that occur after RYGB and that contribute to its mechanisms of action. PMID- 26627221 TI - The Interplay Between Sex, Ethnicity, and Adipose Tissue Characteristics. AB - The obesity epidemic in the USA affects disproportionately women and the ethnic minorities. On the other hand, female sex is traditionally associated with a favorable fat distribution preferentially in the subcutaneous depots of the lower body and with improved endocrine and metabolic function of the adipose tissue. However, these data are derived from predominantly non-Hispanic white populations. This review discusses fat distribution patterns in women of diverse ethnic backgrounds, together with data on the release of adipokines from adipose tissue in these populations. Very little information is available on how the metabolic function of the adipocyte differs depending on ethnicity. Thus, it becomes clear that future clinical and translational research should explicitly discuss and take into account the sex and ethnic background of the populations studied. PMID- 26627222 TI - Differences in Weight Loss and Gut Hormones: Rouen-Y Gastric Bypass and Sleeve Gastrectomy Surgery. AB - Bariatric surgery is arguably the most effective therapy for weight loss, and Rouen-Y gastric bypass (RYGB) is considered the "gold-standard" procedure. However, sleeve gastrectomy (SG) surgery has become more prevalent in recent years and it is unclear if weight loss differences occur between these procedures. Herein, we discuss evidence from randomized clinical trials comparing the effectiveness of RYGB and SG on weight loss. Moreover, we highlight gut hormones (e.g., GLP-1, ghrelin, bile acids, etc.) as potentially important mechanisms that contribute to the durability of decreased appetite and opposed fat storage following RYGB and SG. Collectively, although a subtle (~ 3-5 kg) weight loss difference may exist in favor of RYGB up to 3 years post-operation, it appears that RYGB and SG induce comparable weight loss and changes in gut physiology that parallel reduced disease risk. These findings are clinically relevant for optimizing treatment strategies that combat obesity-related diabetes and cardiovascular disease. PMID- 26627224 TI - Health-related quality of life in Parkinson's: impact of 'off' time and stated treatment preferences. AB - PURPOSE: Long-term levodopa therapy and related fluctuating plasma concentrations are associated with between-dose periods of 'off time' resulting in substantial variation in symptoms and functioning throughout the day in people with Parkinson's (PwP). METHODS: PwP across UK, France, Spain and Italy completed an online survey to explore: the impact of 'off time' on (1) health-related quality of life (HRQL) and (2) on functioning and ability to undertake usual activities; (3) the value of 'off time' relative to other factors associated with Parkinson's through a stated preference discrete choice experiment (SPDCE). RESULTS: In total, 305 PwP completed the online survey. Overall mean HRQL (utility) score was significantly lower for 'off time' (0.37) than for 'on time' (0.60). All attributes within the SPDCE were significant predictors of treatment choice, although increased duration of 'on time' (per hour per day: odds ratio (OR) = 1.40) and predictability of 'off time' to within 30 min (OR = 1.42) were valued most highly. CONCLUSIONS: 'On time' and predictability of 'off time' are highly valued by PwP. Due to substantial diurnal variation of Parkinson's symptoms, standard patient-reported outcome (PRO) assessments may not adequately capture the impact of 'off time' on HRQL and participation in daily activities. PMID- 26627225 TI - Structure, Process, and Culture Differences of Pediatric Trauma Centers Participating in an International Comparative Effectiveness Study of Children with Severe Traumatic Brain Injury. AB - BACKGROUND: Traumatic brain injury (TBI) is an important worldwide cause of death and disability for children. The Approaches and Decisions for Acute Pediatric TBI (ADAPT) Trial is an observational, cohort study to compare the effectiveness of six aspects of TBI care. Understanding the differences between clinical sites including their structure, clinical processes, and culture differences-will be necessary to assess differences in outcome from the study and can inform the overall community regarding differences across academic centers. METHODS: We developed a survey and queried ADAPT site principal investigators with a focus on six domains: (i) hospital, (ii) pediatric intensive care unit (PICU), (iii) medical staff characteristics, (iv) quality of care, (v) medication safety, and (vi) safety culture. Summary statistics were used to describe differences between centers. RESULTS: ADAPT clinical sites that enrolled a subject within the first year (32 US-based, 11 international) were studied. A wide variation in site characteristics was observed in hospital and ICU characteristics, including an almost sevenfold range in ICU size (8-55 beds) and more than fivefold range of overall ICU admissions (537-2623). Nursing staffing (predominantly 1:1 or 1:2) and the presence of pharmacists within the ICU (79 %) were less variable, and most sites "strongly agreed" or "agreed" that Neurosurgery and Critical Care teams worked well together (81.4 %). However, a minority of sites (46 %) used an explicit protocol for treatment of children with severe TBI care. CONCLUSIONS: We found a variety of inter-center structure, process, and culture differences. These intrinsic differences between sites may begin to explain why interventional studies have failed to prove efficacy of experimental therapies. Understanding these differences may be an important factor in analyzing future ADAPT trial results and in determining best practices for pediatric severe TBI. PMID- 26627223 TI - Weight Loss and the Prevention and Treatment of Type 2 Diabetes Using Lifestyle Therapy, Pharmacotherapy, and Bariatric Surgery: Mechanisms of Action. AB - Weight loss, whether achieved by lifestyle intervention, pharmacotherapy, or bariatric surgery, is highly effective as a primary interventional strategy in both the prevention and treatment of type 2 diabetes. In high-risk patients with prediabetes and/or metabolic syndrome, weight loss effectively prevents progression to type 2 diabetes mellitus (T2DM) and improves cardiovascular risk factors. These benefits are the result of improvements in insulin resistance, which is central to the pathophysiology of cardiometabolic disease. In patients with T2DM, weight loss improves glycemia, while reducing the need for conventional glucose-lowering medicines, by affecting all three processes that produce and sustain the hyperglycemic state, namely via increments in peripheral insulin sensitivity with improvements in insulin signal transduction at the cellular level, more robust insulin secretory responses, and reduced rates of hepatic glucose production. In both nondiabetic and diabetic subjects, hypocaloric feeding (e.g., treatment with very low-calorie diet or bariatric surgery) produces a rapid improvement in insulin sensitivity due to mobilization of fat from the intramyocellular, intrahepatocellular, and intra-abdominal compartments, and via a more long-term mechanism that correlates with the loss of total body fat. In diabetes, by improving glycemia, weight loss also enhances glucose homeostasis by reversing the defects in insulin action and secretion attributable to glucose toxicity. Regardless of the therapeutic approach, weight loss of ~ 10 % maximally prevents future diabetes in patients with prediabetes or metabolic syndrome. In T2DM, greater degrees of weight loss lead to progressive improvements in glucose homeostasis. Therefore, when accompanied by greater weight loss, the metabolic benefits following bariatric surgery are generally more pronounced than those achieved following lifestyle and medical treatment. In addition, the mechanisms by which bariatric operations improve diabetes may include both weight-dependent and weight-independent mechanisms, and the latter may involve changes in gut hormones, bile acids, or gut microflora. PMID- 26627226 TI - Erythropoietin Inhibits the Increase of Pulmonary Labile Zinc and the Expression of Inflammatory Mediators Following Subarachnoid Hemorrhage in Rats. AB - BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) is a common condition with relatively poor clinical outcome. Pulmonary complication after SAH is an important contributor to poor outcome. Previous studies have shown that labile zinc and inflammatory mediators participate in many pathophysiological processes. The present study investigated the effects of SAH on the levels of labile zinc and certain proinflammatory factors in rat lung and determined the effect of erythropoietin (EPO) on the pulmonary labile zinc and the inflammatory factor after SAH in rats. METHODS: Experiment 1 aimed to investigate the time course of increase of pulmonary labile zinc, wet/dry weight ratio, and the expression of inflammatory mediators after SAH. In Experiment 2, we chose the maximum time point which lung injury was maximally severity and assessed the effect of EPO on regulation of the pulmonary labile zinc, inflammatory reaction, and wet/dry weight ratio after SAH. RESULTS: SAH caused a gradual increase of pulmonary labile zinc as demonstrated by fluorescence staining with Zinpyr-4. The levels of TNF-alpha and IL-8 and the lung wet/dry weight ratios were higher in the SAH groups compared to the control group and peaked on 3 days following SAH (p < 0.05). EPO significantly reduced the pulmonary labile zinc, the inflammatory mediators, and the lung wet/dry weight ratio compared with SAH group (p < 0.05). CONCLUSIONS: EPO can protect lung from SAH-induced injury by attenuating pulmonary inflammation and labile zinc accumulation in vivo. PMID- 26627227 TI - Effects of Red Blood Cell Transfusion on Long-Term Disability of Patients with Traumatic Brain Injury. AB - BACKGROUND: This 3-year prospective study examined the association between red blood cell transfusion (RBCT) and 1-year neurocognitive and disability levels in 309 patients with traumatic brain injury (TBI) admitted to the neurological intensive care unit (NICU). METHODS: Using a telephone interview-based survey, functional outcomes were assessed by the Glasgow Outcome Scale (GOS), Rancho Los Amigos Levels of Cognitive Functioning Scale (RLCFS), and Disability Rating Scale (DRS) and dichotomized as favorable and unfavorable (dependent variable). The adjusted influence of RBCT on unfavorable results was assessed by conventional logistic regression, controlling for illness severity and propensity score (introduced as a continuous variable and by propensity score-matched patients). RESULTS: Overall, 164 (53 %) patients received >=1 unit of RBCT during their NICU stay. One year postinjury, transfused patients exhibited significantly higher unfavorable GOS (46.0 vs. 22.0 %), RLCFS (37.4 vs. 15.4 %), and DRS (39.6 vs. 18.7 %) scores than nontransfused patients. Although transfused patients were more severely ill upon admission, their adjusted odds ratios (95 % confidence intervals) for unfavorable GOS, RLCFS, and DRS scores were 2.5 (1.2-5.1), 3.0 (1.4-6.3), and 2.3 (1.1-4.8), respectively. These odds ratios remained largely unmodified when the calculated propensity score was incorporated as an independent continuous variable into the multivariate analysis. Furthermore, in 76 pairs of propensity score-matched patients, the rate of an unfavorable RLCFS score at the 1-year (but not 6-month) follow-up was significantly higher in transfused than nontransfused patients [3.0 (1.1-8.2)]. CONCLUSION: Our results strongly suggest an independent association between RBCT and unfavorable long term functional outcomes of patients with TBI. PMID- 26627228 TI - Opinion: To feed the world in 2050 will require a global revolution. PMID- 26627230 TI - Anomalous anisotropic compression behavior of superconducting CrAs under high pressure. AB - CrAs was observed to possess the bulk superconductivity under high-pressure conditions. To understand the superconducting mechanism and explore the correlation between the structure and superconductivity, the high-pressure structural evolution of CrAs was investigated using the angle-dispersive X-ray diffraction (XRD) method. The structure of CrAs remains stable up to 1.8 GPa, whereas the lattice parameters exhibit anomalous compression behaviors. With increasing pressure, the lattice parameters a and c both demonstrate a nonmonotonic change, and the lattice parameter b undergoes a rapid contraction at ~ 0.18-0.35 GPa, which suggests that a pressure-induced isostructural phase transition occurs in CrAs. Above the phase transition pressure, the axial compressibilities of CrAs present remarkable anisotropy. A schematic band model was used to address the anomalous compression behavior of CrAs. The present results shed light on the structural and related electronic responses to high pressure, which play a key role toward understanding the superconductivity of CrAs. PMID- 26627231 TI - Ab initio optimization of phonon drag effect for lower-temperature thermoelectric energy conversion. AB - Although the thermoelectric figure of merit zT above 300 K has seen significant improvement recently, the progress at lower temperatures has been slow, mainly limited by the relatively low Seebeck coefficient and high thermal conductivity. Here we report, for the first time to our knowledge, success in first-principles computation of the phonon drag effect--a coupling phenomenon between electrons and nonequilibrium phonons--in heavily doped region and its optimization to enhance the Seebeck coefficient while reducing the phonon thermal conductivity by nanostructuring. Our simulation quantitatively identifies the major phonons contributing to the phonon drag, which are spectrally distinct from those carrying heat, and further reveals that although the phonon drag is reduced in heavily doped samples, a significant contribution to Seebeck coefficient still exists. An ideal phonon filter is proposed to enhance zT of silicon at room temperature by a factor of 20 to ~ 0.25, and the enhancement can reach 70 times at 100 K. This work opens up a new venue toward better thermoelectrics by harnessing nonequilibrium phonons. PMID- 26627232 TI - Space station image captures a red tide ciliate bloom at high spectral and spatial resolution. AB - Mesodinium rubrum is a globally distributed nontoxic ciliate that is known to produce intense red-colored blooms using enslaved chloroplasts from its algal prey. Although frequent enough to have been observed by Darwin, blooms of M. rubrum are notoriously difficult to quantify because M. rubrum can aggregate into massive clouds of rusty-red water in a very short time due to its high growth rates and rapid swimming behavior and can disaggregate just as quickly by vertical or horizontal dispersion. A September 2012 hyperspectral image from the Hyperspectral Imager for the Coastal Ocean sensor aboard the International Space Station captured a dense red tide of M. rubrum (10(6) cells per liter) in surface waters of western Long Island Sound. Genetic data confirmed the identity of the chloroplast as a cryptophyte that was actively photosynthesizing. Microscopy indicated extremely high abundance of its yellow fluorescing signature pigment phycoerythrin. Spectral absorption and fluorescence features were related to ancillary photosynthetic pigments unique to this organism that cannot be observed with traditional satellites. Cell abundance was estimated at a resolution of 100 m using an algorithm based on the distinctive yellow fluorescence of phycoerythrin. Future development of hyperspectral satellites will allow for better enumeration of bloom-forming coastal plankton, the associated physical mechanisms, and contributions to marine productivity. PMID- 26627233 TI - A cross-hazard analysis of terse message retransmission on Twitter. AB - For decades, public warning messages have been relayed via broadcast information channels, including radio and television; more recently, risk communication channels have expanded to include social media sites, where messages can be easily amplified by user retransmission. This research examines the factors that predict the extent of retransmission for official hazard communications disseminated via Twitter. Using data from events involving five different hazards, we identity three types of attributes--local network properties, message content, and message style--that jointly amplify and/or attenuate the retransmission of official communications under imminent threat. We find that the use of an agreed-upon hashtag and the number of users following an official account positively influence message retransmission, as does message content describing hazard impacts or emphasizing cohesion among users. By contrast, messages directed at individuals, expressing gratitude, or including a URL were less widely disseminated than similar messages without these features. Our findings suggest that some measures commonly taken to convey additional information to the public (e.g., URL inclusion) may come at a cost in terms of message amplification; on the other hand, some types of content not traditionally emphasized in guidance on hazard communication may enhance retransmission rates. PMID- 26627234 TI - Relaxed genetic control of cortical organization in human brains compared with chimpanzees. AB - The study of hominin brain evolution has focused largely on the neocortical expansion and reorganization undergone by humans as inferred from the endocranial fossil record. Comparisons of modern human brains with those of chimpanzees provide an additional line of evidence to define key neural traits that have emerged in human evolution and that underlie our unique behavioral specializations. In an attempt to identify fundamental developmental differences, we have estimated the genetic bases of brain size and cortical organization in chimpanzees and humans by studying phenotypic similarities between individuals with known kinship relationships. We show that, although heritability for brain size and cortical organization is high in chimpanzees, cerebral cortical anatomy is substantially less genetically heritable than brain size in humans, indicating greater plasticity and increased environmental influence on neurodevelopment in our species. This relaxed genetic control on cortical organization is especially marked in association areas and likely is related to underlying microstructural changes in neural circuitry. A major result of increased plasticity is that the development of neural circuits that underlie behavior is shaped by the environmental, social, and cultural context more intensively in humans than in other primate species, thus providing an anatomical basis for behavioral and cognitive evolution. PMID- 26627235 TI - Compromising the phosphodependent regulation of the GABAAR beta3 subunit reproduces the core phenotypes of autism spectrum disorders. AB - Alterations in the efficacy of neuronal inhibition mediated by GABAA receptors (GABAARs) containing beta3 subunits are continually implicated in autism spectrum disorders (ASDs). In vitro, the plasma membrane stability of GABAARs is potentiated via phosphorylation of serine residues 408 and 409 (S408/9) in the beta3 subunit, an effect that is mimicked by their mutation to alanines. To assess if modifications in beta3 subunit expression contribute to ASDs, we have created a mouse in which S408/9 have been mutated to alanines (S408/9A). S408/9A homozygotes exhibited increased phasic, but decreased tonic, inhibition, events that correlated with alterations in the membrane stability and synaptic accumulation of the receptor subtypes that mediate these distinct forms of inhibition. S408/9A mice exhibited alterations in dendritic spine structure, increased repetitive behavior, and decreased social interaction, hallmarks of ASDs. ASDs are frequently comorbid with epilepsy, and consistent with this comorbidity, S408/9A mice exhibited a marked increase in sensitivity to seizures induced by the convulsant kainic acid. To assess the relevance of our studies using S408/9A mice for the pathophysiology of ASDs, we measured S408/9 phosphorylation in Fmr1 KO mice, a model of fragile X syndrome, the most common monogenetic cause of ASDs. Phosphorylation of S408/9 was selectively and significantly enhanced in Fmr1 KO mice. Collectively, our results suggest that alterations in phosphorylation and/or activity of beta3-containing GABAARs may directly contribute to the pathophysiology of ASDs. PMID- 26627236 TI - Architecture of the human XPC DNA repair and stem cell coactivator complex. AB - The Xeroderma pigmentosum complementation group C (XPC) complex is a versatile factor involved in both nucleotide excision repair and transcriptional coactivation as a critical component of the NANOG, OCT4, and SOX2 pluripotency gene regulatory network. Here we present the structure of the human holo-XPC complex determined by single-particle electron microscopy to reveal a flexible, ear-shaped structure that undergoes localized loss of order upon DNA binding. We also determined the structure of the complete yeast homolog Rad4 holo-complex to find a similar overall architecture to the human complex, consistent with their shared DNA repair functions. Localized differences between these structures reflect an intriguing phylogenetic divergence in transcriptional capabilities that we present here. Having positioned the constituent subunits by tagging and deletion, we propose a model of key interaction interfaces that reveals the structural basis for this difference in functional conservation. Together, our findings establish a framework for understanding the structure-function relationships of the XPC complex in the interplay between transcription and DNA repair. PMID- 26627237 TI - A meningococcal vaccine antigen engineered to increase thermal stability and stabilize protective epitopes. AB - Factor H binding protein (FHbp) is part of two vaccines recently licensed for prevention of sepsis and meningitis caused by serogroup B meningococci. FHbp is classified in three phylogenic variant groups that have limited antigenic cross reactivity, and FHbp variants in one of the groups have low thermal stability. In the present study, we replaced two amino acid residues, R130 and D133, in a stable FHbp variant with their counterparts (L and G) from a less stable variant. The single and double mutants decreased thermal stability of the amino- (N-) terminal domain compared with the wild-type protein as measured by scanning calorimetry. We introduced the converse substitutions, L130R and G133D, in a less stable wild-type FHbp variant, which increased the transition midpoint (Tm) for the N-terminal domain by 8 and 12 degrees C; together the substitutions increased the Tm by 21 degrees C. We determined the crystal structure of the double mutant FHbp to 1.6 A resolution, which showed that R130 and D133 mediated multiple electrostatic interactions. Monoclonal antibodies specific for FHbp epitopes in the N-terminal domain had higher binding affinity for the recombinant double mutant by surface plasmon resonance and to the mutant expressed on meningococci by flow cytometry. The double mutant also had decreased binding of human complement Factor H, which in previous studies increased the protective antibody responses. The stabilized mutant FHbp thus has the potential to stabilize protective epitopes and increase the protective antibody responses to recombinant FHbp vaccines or native outer membrane vesicle vaccines with overexpressed FHbp. PMID- 26627238 TI - Identification and characterization of functional homologs of nitrogenase cofactor biosynthesis protein NifB from methanogens. AB - Nitrogenase biosynthesis protein NifB catalyzes the radical S-adenosyl-L methionine (SAM)-dependent insertion of carbide into the M cluster, the cofactor of the molybdenum nitrogenase from Azotobacter vinelandii. Here, we report the identification and characterization of two naturally "truncated" homologs of NifB from Methanosarcina acetivorans (NifB(Ma)) and Methanobacterium thermoautotrophicum (NifB(Mt)), which contain a SAM-binding domain at the N terminus but lack a domain toward the C terminus that shares homology with NifX, an accessory protein in M cluster biosynthesis. NifB(Ma) and NifB(Mt) are monomeric proteins containing a SAM-binding [Fe4S4] cluster (designated the SAM cluster) and a [Fe4S4]-like cluster pair (designated the K cluster) that can be processed into an [Fe8S9] precursor to the M cluster (designated the L cluster). Further, the K clusters in NifB(Ma) and NifB(Mt) can be converted to L clusters upon addition of SAM, which corresponds to their ability to heterologously donate L clusters to the biosynthetic machinery of A. vinelandii for further maturation into the M clusters. Perhaps even more excitingly, NifB(Ma) and NifB(Mt) can catalyze the removal of methyl group from SAM and the abstraction of hydrogen from this methyl group by 5'-deoxyadenosyl radical that initiates the radical based incorporation of methyl-derived carbide into the M cluster. The successful identification of NifB(Ma) and NifB(Mt) as functional homologs of NifB not only enabled classification of a new subset of radical SAM methyltransferases that specialize in complex metallocluster assembly, but also provided a new tool for further characterization of the distinctive, NifB-catalyzed methyl transfer and conversion to an iron-bound carbide. PMID- 26627239 TI - Effects of confinement on models of intracellular macromolecular dynamics. AB - The motions of particles in a viscous fluid confined within a spherical cell have been simulated using Brownian and Stokesian dynamics simulations. High volume fractions mimicking the crowded interior of biological cells were used. Importantly, although confinement yields an overall slowdown in motion, the qualitative effects of motion in the interior of the cell can be effectively modeled as if the system were an infinite periodic system. However, we observe layering of particles at the cell wall due to steric interactions in the confined space. Motions of nearby particles are also strongly correlated at the cell wall, and these correlations increase when hydrodynamic interactions are modeled. Further, particles near the cell wall have a tendency to remain near the cell wall. A consequence of these effects is that the mean contact time between particles is longer at the cell wall than in the interior of the cell. These findings identify a specific way that confinement affects the interactions between particles and points to a previously unidentified mechanism that may play a role in signal transduction and other processes near the membrane of biological cells. PMID- 26627240 TI - Secondary PDZ domain-binding site on class B plexins enhances the affinity for PDZ-RhoGEF. AB - PDZ domains are abundant protein interaction modules and typically recognize a short motif at the C terminus of their ligands, with a few residues in the motif endowing the binding specificity. The sequence-based rules, however, cannot fully account for the specificity between the vast number of PDZ domains and ligands in the cell. Plexins are transmembrane receptors that regulate processes such as axon guidance and angiogenesis. Two related guanine nucleotide exchange factors (GEFs), PDZ-RhoGEF and leukemia-associated RhoGEF (LARG), use their PDZ domains to bind class B plexins and play critical roles in signaling. Here, we present the crystal structure of the full-length cytoplasmic region of PlexinB2 in complex with the PDZ domain of PDZ-RhoGEF. The structure reveals that, in addition to the canonical C-terminal motif/PDZ interaction, the 3D domain of PlexinB2 forms a secondary interface with the PDZ domain. Our biophysical and cell-based assays show that the secondary interface contributes to the specific interaction between plexin and PDZ-RhoGEF and to signaling by plexin in the cell. Formation of secondary interfaces may be a general mechanism for increasing affinity and specificity of modular domain-mediated interactions. PMID- 26627241 TI - Genomic insights into the evolutionary origin of Myxozoa within Cnidaria. AB - The Myxozoa comprise over 2,000 species of microscopic obligate parasites that use both invertebrate and vertebrate hosts as part of their life cycle. Although the evolutionary origin of myxozoans has been elusive, a close relationship with cnidarians, a group that includes corals, sea anemones, jellyfish, and hydroids, is supported by some phylogenetic studies and the observation that the distinctive myxozoan structure, the polar capsule, is remarkably similar to the stinging structures (nematocysts) in cnidarians. To gain insight into the extreme evolutionary transition from a free-living cnidarian to a microscopic endoparasite, we analyzed genomic and transcriptomic assemblies from two distantly related myxozoan species, Kudoa iwatai and Myxobolus cerebralis, and compared these to the transcriptome and genome of the less reduced cnidarian parasite, Polypodium hydriforme. A phylogenomic analysis, using for the first time to our knowledge, a taxonomic sampling that represents the breadth of myxozoan diversity, including four newly generated myxozoan assemblies, confirms that myxozoans are cnidarians and are a sister taxon to P. hydriforme. Estimations of genome size reveal that myxozoans have one of the smallest reported animal genomes. Gene enrichment analyses show depletion of expressed genes in categories related to development, cell differentiation, and cell-cell communication. In addition, a search for candidate genes indicates that myxozoans lack key elements of signaling pathways and transcriptional factors important for multicellular development. Our results suggest that the degeneration of the myxozoan body plan from a free-living cnidarian to a microscopic parasitic cnidarian was accompanied by extreme reduction in genome size and gene content. PMID- 26627242 TI - microRNA classifiers are powerful diagnostic/prognostic tools in ALK-, EGFR-, and KRAS-driven lung cancers. AB - microRNAs (miRNAs) can act as oncosuppressors or oncogenes, induce chemoresistance or chemosensitivity, and are major posttranscriptional gene regulators. Anaplastic lymphoma kinase (ALK), EGF receptor (EGFR), and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) are major drivers of non-small cell lung cancer (NSCLC). The aim of this study was to assess the miRNA profiles of NSCLCs driven by translocated ALK, mutant EGFR, or mutant KRAS to find driver specific diagnostic and prognostic miRNA signatures. A total of 85 formalin fixed, paraffin-embedded samples were considered: 67 primary NSCLCs and 18 matched normal lung tissues. Of the 67 primary NSCLCs, 17 were echinoderm microtubule-associated protein-like 4-ALK translocated (ALK(+)) lung cancers; the remaining 50 were not (ALK(-)). Of the 50 ALK(-) primary NSCLCs, 24 were EGFR and KRAS mutation-negative (i.e., WT; triple negative); 11 were mutant EGFR (EGFR(+)), and 15 were mutant KRAS (KRAS(+)). We developed a diagnostic classifier that shows how miR-1253, miR-504, and miR-26a-5p expression levels can classify NSCLCs as ALK-translocated, mutant EGFR, or mutant KRAS versus mutation free. We also generated a prognostic classifier based on miR-769-5p and Let-7d-5p expression levels that can predict overall survival. This classifier showed better performance than the commonly used classifiers based on mutational status. Although it has several limitations, this study shows that miRNA signatures and classifiers have great potential as powerful, cost-effective next-generation tools to improve and complement current genetic tests. Further studies of these miRNAs can help define their roles in NSCLC biology and in identifying best performing chemotherapy regimens. PMID- 26627245 TI - Improved signaling as a result of randomness in synaptic vesicle release. AB - The probabilistic nature of neurotransmitter release in synapses is believed to be one of the most significant sources of noise in the central nervous system. We show how p0, the probability of release per docked vesicle when an action potential arrives, affects the dynamics of the rate of vesicle release in response to changes in the rate of arrival of action potentials. Furthermore, we examine the theoretical capability of a synapse in the estimation of desired signals using information from the stochastic vesicle release events under the framework of optimal linear filter theory. We find that a small p0, such as 0.1, reduces the error in the reconstruction of the input, or in the reconstruction of the time derivative of the input, from the time series of vesicle release events. Our results imply that the probabilistic nature of synaptic vesicle release plays a direct functional role in synaptic transmission. PMID- 26627244 TI - Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3. AB - FoxP3(+) T regulatory (Treg) cells have a fundamental role in immunological tolerance, with transcriptional and functional phenotypes that demarcate them from conventional CD4(+) T cells (Tconv). Differences between these two lineages in the signaling downstream of T-cell receptor-triggered activation have been reported, and there are different requirements for some signaling factors. Seeking a comprehensive view, we found that Treg cells have a broadly dampened activation of several pathways and signaling nodes upon TCR-mediated activation, with low phosphorylation of CD3zeta, SLP76, Erk1/2, AKT, or S6 and lower calcium flux. In contrast, STAT phosphorylation triggered by interferons, IL2 or IL6, showed variations between Treg and Tconv in magnitude or choice of preferential STAT activation but no general Treg signaling defect. Much, but not all, of the Treg/Tconv difference in TCR-triggered responses could be attributed to lower responsiveness of antigen-experienced cells with CD44(hi) or CD62L(lo) phenotypes, which form a greater proportion of the Treg pool. Candidate regulators were tested, but the Treg/Tconv differential could not be explained by overexpression in Treg cells of the signaling modulator CD5, the coinhibitors PD 1 and CTLA4, or the regulatory phosphatase DUSP4. However, transcriptome profiling in Dusp4-deficient mice showed that DUSP4 enhances the expression of a segment of the canonical Treg transcriptional signature, which partially overlaps with the TCR-dependent Treg gene set. Thus, Treg cells, likely because of their intrinsically higher reactivity to self, tune down TCR signals but seem comparatively more attuned to cytokines or other intercellular signals. PMID- 26627246 TI - Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity. AB - Excitatory amino acids play a key role in both adaptive and deleterious effects of stressors on the brain, and dysregulated glutamate homeostasis has been associated with psychiatric and neurological disorders. Here, we elucidate mechanisms of epigenetic plasticity in the hippocampus in the interactions between a history of chronic stress and familiar and novel acute stressors that alter expression of anxiety- and depressive-like behaviors. We demonstrate that acute restraint and acute forced swim stressors induce differential effects on these behaviors in naive mice and in mice with a history of chronic-restraint stress (CRS). They reveal a key role for epigenetic up- and down-regulation of the putative presynaptic type 2 metabotropic glutamate (mGlu2) receptors and the postsynaptic NR1/NMDA receptors in the hippocampus and particularly in the dentate gyrus (DG), a region of active neurogenesis and a target of antidepressant treatment. We show changes in DG long-term potentiation (LTP) that parallel behavioral responses, with habituation to the same acute restraint stressor and sensitization to a novel forced-swim stressor. In WT mice after CRS and in unstressed mice with a BDNF loss-of-function allele (BDNF Val66Met), we show that the epigenetic activator of histone acetylation, P300, plays a pivotal role in the dynamic up- and down-regulation of mGlu2 in hippocampus via histone-3 lysine-27-acetylation (H3K27Ac) when acute stressors are applied. These hippocampal responses reveal a window of epigenetic plasticity that may be useful for treatment of disorders in which glutamatergic transmission is dysregulated. PMID- 26627247 TI - Responsiveness of G protein-coupled odorant receptors is partially attributed to the activation mechanism. AB - Mammals detect and discriminate numerous odors via a large family of G protein coupled odorant receptors (ORs). However, little is known about the molecular and structural basis underlying OR response properties. Using site-directed mutagenesis and computational modeling, we studied ORs sharing high sequence homology but with different response properties. When tested in heterologous cells by diverse odorants, MOR256-3 responded broadly to many odorants, whereas MOR256-8 responded weakly to a few odorants. Out of 36 mutant MOR256-3 ORs, the majority altered the responses to different odorants in a similar manner and the overall response of an OR was positively correlated with its basal activity, an indication of ligand-independent receptor activation. Strikingly, a single mutation in MOR256-8 was sufficient to confer both high basal activity and broad responsiveness to this receptor. These results suggest that broad responsiveness of an OR is at least partially attributed to its activation likelihood. PMID- 26627243 TI - Genome of Rhodnius prolixus, an insect vector of Chagas disease, reveals unique adaptations to hematophagy and parasite infection. AB - Rhodnius prolixus not only has served as a model organism for the study of insect physiology, but also is a major vector of Chagas disease, an illness that affects approximately seven million people worldwide. We sequenced the genome of R. prolixus, generated assembled sequences covering 95% of the genome (~ 702 Mb), including 15,456 putative protein-coding genes, and completed comprehensive genomic analyses of this obligate blood-feeding insect. Although immune deficiency (IMD)-mediated immune responses were observed, R. prolixus putatively lacks key components of the IMD pathway, suggesting a reorganization of the canonical immune signaling network. Although both Toll and IMD effectors controlled intestinal microbiota, neither affected Trypanosoma cruzi, the causal agent of Chagas disease, implying the existence of evasion or tolerance mechanisms. R. prolixus has experienced an extensive loss of selenoprotein genes, with its repertoire reduced to only two proteins, one of which is a selenocysteine-based glutathione peroxidase, the first found in insects. The genome contained actively transcribed, horizontally transferred genes from Wolbachia sp., which showed evidence of codon use evolution toward the insect use pattern. Comparative protein analyses revealed many lineage-specific expansions and putative gene absences in R. prolixus, including tandem expansions of genes related to chemoreception, feeding, and digestion that possibly contributed to the evolution of a blood-feeding lifestyle. The genome assembly and these associated analyses provide critical information on the physiology and evolution of this important vector species and should be instrumental for the development of innovative disease control methods. PMID- 26627248 TI - The bone-sparing effects of estrogen and WNT16 are independent of each other. AB - Wingless-type MMTV integration site family (WNT)16 is a key regulator of bone mass with high expression in cortical bone, and Wnt16(-/-) mice have reduced cortical bone mass. As Wnt16 expression is enhanced by estradiol treatment, we hypothesized that the bone-sparing effect of estrogen in females is WNT16 dependent. This hypothesis was tested in mechanistic studies using two genetically modified mouse models with either constantly high osteoblastic Wnt16 expression or no Wnt16 expression. We developed a mouse model with osteoblast specific Wnt16 overexpression (Obl-Wnt16). These mice had several-fold elevated Wnt16 expression in both trabecular and cortical bone compared with wild type (WT) mice. Obl-Wnt16 mice displayed increased total body bone mineral density (BMD), surprisingly caused mainly by a substantial increase in trabecular bone mass, resulting in improved bone strength of vertebrae L3. Ovariectomy (ovx) reduced the total body BMD and the trabecular bone mass to the same degree in Obl Wnt16 mice and WT mice, suggesting that the bone-sparing effect of estrogen is WNT16-independent. However, these bone parameters were similar in ovx Obl-Wnt16 mice and sham operated WT mice. The role of WNT16 for the bone-sparing effect of estrogen was also evaluated in Wnt16(-/-) mice. Treatment with estradiol increased the trabecular and cortical bone mass to a similar extent in both Wnt16(-/-) and WT mice. In conclusion, the bone-sparing effects of estrogen and WNT16 are independent of each other. Furthermore, loss of endogenous WNT16 results specifically in cortical bone loss, whereas overexpression of WNT16 surprisingly increases mainly trabecular bone mass. WNT16-targeted therapies might be useful for treatment of postmenopausal trabecular bone loss. PMID- 26627250 TI - Persistent states in vision break universality and time invariance. AB - Studies of perception usually emphasize processes that are largely universal across observers and--except for short-term fluctuations--stationary over time. Here we test the universality and stationarity assumptions with two families of ambiguous visual stimuli. Each stimulus can be perceived in two different ways, parameterized by two opposite directions from a continuous circular variable. A large-sample study showed that almost all observers have preferred directions or biases, with directions lying within 90 degrees of the bias direction nearly always perceived and opposite directions almost never perceived. The biases differ dramatically from one observer to the next, and although nearly every bias direction occurs in the population, the population distributions of the biases are nonuniform, featuring asymmetric peaks in the cardinal directions. The biases for the two families of stimuli are independent and have distinct population distributions. Following external perturbations and spontaneous fluctuations, the biases decay over tens of seconds toward their initial values. Persistent changes in the biases are found on time scales of several minutes to 1 hour. On scales of days to months, the biases undergo a variety of dynamical processes such as drifts, jumps, and oscillations. The global statistics of a majority of these long-term time series are well modeled as random walk processes. The measurable fluctuations of these hitherto unknown degrees of freedom show that the assumptions of universality and stationarity in perception may be unwarranted and that models of perception must include both directly observable variables as well as covert, persistent states. PMID- 26627249 TI - Critical role of Chlamydomonas reinhardtii ferredoxin-5 in maintaining membrane structure and dark metabolism. AB - Photosynthetic microorganisms typically have multiple isoforms of the electron transfer protein ferredoxin, although we know little about their exact functions. Surprisingly, a Chlamydomonas reinhardtii mutant null for the ferredoxin-5 gene (FDX5) completely ceased growth in the dark, with both photosynthetic and respiratory functions severely compromised; growth in the light was unaffected. Thylakoid membranes in dark-maintained fdx5 mutant cells became severely disorganized concomitant with a marked decrease in the ratio of monogalactosyldiacylglycerol to digalactosyldiacylglycerol, major lipids in photosynthetic membranes, and the accumulation of triacylglycerol. Furthermore, FDX5 was shown to physically interact with the fatty acid desaturases CrDelta4FAD and CrFAD6, likely donating electrons for the desaturation of fatty acids that stabilize monogalactosyldiacylglycerol. Our results suggest that in photosynthetic organisms, specific redox reactions sustain dark metabolism, with little impact on daytime growth, likely reflecting the tailoring of electron carriers to unique intracellular metabolic circuits under these two very distinct redox conditions. PMID- 26627251 TI - Enhancing potency of siRNA targeting fusion genes by optimization outside of target sequence. AB - Canonical siRNA design algorithms have become remarkably effective at predicting favorable binding regions within a target mRNA, but in some cases (e.g., a fusion junction site) region choice is restricted. In these instances, alternative approaches are necessary to obtain a highly potent silencing molecule. Here we focus on strategies for rational optimization of two siRNAs that target the junction sites of fusion oncogenes BCR-ABL and TMPRSS2-ERG. We demonstrate that modifying the termini of these siRNAs with a terminal G-U wobble pair or a carefully selected pair of terminal asymmetry-enhancing mismatches can result in an increase in potency at low doses. Importantly, we observed that improvements in silencing at the mRNA level do not necessarily translate to reductions in protein level and/or cell death. Decline in protein level is also heavily influenced by targeted protein half-life, and delivery vehicle toxicity can confound measures of cell death due to silencing. Therefore, for BCR-ABL, which has a long protein half-life that is difficult to overcome using siRNA, we also developed a nontoxic transfection vector: poly(lactic-coglycolic acid) nanoparticles that release siRNA over many days. We show that this system can achieve effective killing of leukemic cells. These findings provide insights into the implications of siRNA sequence for potency and suggest strategies for the design of more effective therapeutic siRNA molecules. Furthermore, this work points to the importance of integrating studies of siRNA design and delivery, while heeding and addressing potential limitations such as restricted targetable mRNA regions, long protein half-lives, and nonspecific toxicities. PMID- 26627252 TI - The structural kinetics of switch-1 and the neck linker explain the functions of kinesin-1 and Eg5. AB - Kinesins perform mechanical work to power a variety of cellular functions, from mitosis to organelle transport. Distinct functions shape distinct enzymologies, and this is illustrated by comparing kinesin-1, a highly processive transport motor that can work alone, to Eg5, a minimally processive mitotic motor that works in large ensembles. Although crystallographic models for both motors reveal similar structures for the domains involved in mechanochemical transduction- including switch-1 and the neck linker--how movement of these two domains is coordinated through the ATPase cycle remains unknown. We have addressed this issue by using a novel combination of transient kinetics and time-resolved fluorescence, which we refer to as "structural kinetics," to map the timing of structural changes in the switch-1 loop and neck linker. We find that differences between the structural kinetics of Eg5 and kinesin-1 yield insights into how these two motors adapt their enzymologies for their distinct functions. PMID- 26627253 TI - Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress. AB - The experience of psychological stress triggers neuroendocrine, inflammatory, metabolic, and transcriptional perturbations that ultimately predispose to disease. However, the subcellular determinants of this integrated, multisystemic stress response have not been defined. Central to stress adaptation is cellular energetics, involving mitochondrial energy production and oxidative stress. We therefore hypothesized that abnormal mitochondrial functions would differentially modulate the organism's multisystemic response to psychological stress. By mutating or deleting mitochondrial genes encoded in the mtDNA [NADH dehydrogenase 6 (ND6) and cytochrome c oxidase subunit I (COI)] or nuclear DNA [adenine nucleotide translocator 1 (ANT1) and nicotinamide nucleotide transhydrogenase (NNT)], we selectively impaired mitochondrial respiratory chain function, energy exchange, and mitochondrial redox balance in mice. The resulting impact on physiological reactivity and recovery from restraint stress were then characterized. We show that mitochondrial dysfunctions altered the hypothalamic pituitary-adrenal axis, sympathetic adrenal-medullary activation and catecholamine levels, the inflammatory cytokine IL-6, circulating metabolites, and hippocampal gene expression responses to stress. Each mitochondrial defect generated a distinct whole-body stress-response signature. These results demonstrate the role of mitochondrial energetics and redox balance as modulators of key pathophysiological perturbations previously linked to disease. This work establishes mitochondria as stress-response modulators, with implications for understanding the mechanisms of stress pathophysiology and mitochondrial diseases. PMID- 26627254 TI - Rad51 recombinase prevents Mre11 nuclease-dependent degradation and excessive PrimPol-mediated elongation of nascent DNA after UV irradiation. AB - After UV irradiation, DNA polymerases specialized in translesion DNA synthesis (TLS) aid DNA replication. However, it is unclear whether other mechanisms also facilitate the elongation of UV-damaged DNA. We wondered if Rad51 recombinase (Rad51), a factor that escorts replication forks, aids replication across UV lesions. We found that depletion of Rad51 impairs S-phase progression and increases cell death after UV irradiation. Interestingly, Rad51 and the TLS polymerase poleta modulate the elongation of nascent DNA in different ways, suggesting that DNA elongation after UV irradiation does not exclusively rely on TLS events. In particular, Rad51 protects the DNA synthesized immediately before UV irradiation from degradation and avoids excessive elongation of nascent DNA after UV irradiation. In Rad51-depleted samples, the degradation of DNA was limited to the first minutes after UV irradiation and required the exonuclease activity of the double strand break repair nuclease (Mre11). The persistent dysregulation of nascent DNA elongation after Rad51 knockdown required Mre11, but not its exonuclease activity, and PrimPol, a DNA polymerase with primase activity. By showing a crucial contribution of Rad51 to the synthesis of nascent DNA, our results reveal an unanticipated complexity in the regulation of DNA elongation across UV-damaged templates. PMID- 26627255 TI - Murine germinal center B cells require functional Fms-like tyrosine kinase 3 signaling for IgG1 class-switch recombination. AB - Switched antibody classes are important for efficient immune responses. Aberrant antibody production to otherwise harmless antigens may result in autoimmunity. The protein kinase fms-like tyrosine kinase 3 receptor (Flt3) has an important role during early B-cell development, but the role of Flt3 in peripheral B cells has not been assessed before. Herein we describe a previously unappreciated role for Flt3 in IgG1 class-switch recombination (CSR) and production. We show that Flt3 is reexpressed on B-cell lymphoma 6(+) germinal center B cells in vivo and following LPS activation of peripheral B cells in vitro. Absence of Flt3 signaling in Flt3 ligand-deficient mice results in impaired IgG1 CSR and accumulation of IgM-secreting plasma cells. On activated B cells, Flt3 is coexpressed and functions in synergy with the common-gamma chain receptor family. B cells from Flt3 ligand-deficient mice have impaired IL-4R signaling, with reduced phosphorylation of signal transducer and activator of transcription (Stat) 6, and demonstrate a failure to initiate CSR to IgG1 with low expression of gamma1 germ-line transcripts, resulting in impaired IgG1 production. Thus, functional synergy between Flt3 and IL-4R signaling is critical for Stat-mediated regulation of sterile gamma1 germ-line transcripts and CSR to IgG1. PMID- 26627256 TI - Post-conversion sialylation of prions in lymphoid tissues. AB - Sialylated glycans on the surface of mammalian cells act as part of a "self associated molecular pattern," helping the immune system to recognize "self" from "altered self" or "nonself." To escape the host immune system, some bacterial pathogens have evolved biosynthetic pathways for host-like sialic acids, whereas others recruited host sialic acids for decorating their surfaces. Prions lack nucleic acids and are not conventional pathogens. Nevertheless, prions might use a similar strategy for invading and colonizing the lymphoreticular system. Here we show that the sialylation status of the infectious, disease-associated state of the prion protein (PrP(Sc)) changes with colonization of secondary lymphoid organs (SLOs). As a result, spleen-derived PrP(Sc) is more sialylated than brain derived PrP(Sc). Enhanced sialylation of PrP(Sc) is recapitulated in vitro by incubating brain-derived PrP(Sc) with primary splenocytes or cultured macrophage RAW 264.7 cells. General inhibitors of sialyltranserases (STs), the enzymes that transfer sialic acid residues onto terminal positions of glycans, suppressed extrasialylation of PrP(Sc). A fluorescently labeled precursor of sialic acid revealed ST activity associated with RAW macrophages. This study illustrates that, upon colonization of SLOs, the sialylation status of prions changes by host STs. We propose that this mechanism is responsible for camouflaging prions in SLOs and has broad implications. PMID- 26627257 TI - Dissecting neural pathways for forgetting in Drosophila olfactory aversive memory. AB - Recent studies have identified molecular pathways driving forgetting and supported the notion that forgetting is a biologically active process. The circuit mechanisms of forgetting, however, remain largely unknown. Here we report two sets of Drosophila neurons that account for the rapid forgetting of early olfactory aversive memory. We show that inactivating these neurons inhibits memory decay without altering learning, whereas activating them promotes forgetting. These neurons, including a cluster of dopaminergic neurons (PAM beta'1) and a pair of glutamatergic neurons (MBON-gamma4>gamma1gamma2), terminate in distinct subdomains in the mushroom body and represent parallel neural pathways for regulating forgetting. Interestingly, although activity of these neurons is required for memory decay over time, they are not required for acute forgetting during reversal learning. Our results thus not only establish the presence of multiple neural pathways for forgetting in Drosophila but also suggest the existence of diverse circuit mechanisms of forgetting in different contexts. PMID- 26627259 TI - Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours. AB - The molecular mechanisms underlying the events through which alterations in diurnal activities impinge on peripheral circadian clocks (PCCs), and reciprocally how the PCCs affect metabolism, thereby generating pathologies, are still poorly understood. Here, we deciphered how switching the diurnal feeding from the active to the rest phase, i.e., restricted feeding (RF), immediately creates a hypoinsulinemia during the active phase, which initiates a metabolic reprogramming by increasing FFA and glucagon levels. In turn, peroxisome proliferator-activated receptor alpha (PPARalpha) activation by free fatty acid (FFA), and cAMP response element-binding protein (CREB) activation by glucagon, lead to further metabolic alterations during the circadian active phase, as well as to aberrant activation of expression of the PCC components nuclear receptor subfamily 1, group D, member 1 (Nr1d1/RevErbalpha), Period (Per1 and Per2). Moreover, hypoinsulinemia leads to an increase in glycogen synthase kinase 3beta (GSK3beta) activity that, through phosphorylation, stabilizes and increases the level of the RevErbalpha protein during the active phase. This increase then leads to an untimely repression of expression of the genes containing a RORE DNA binding sequence (DBS), including the Bmal1 gene, thereby initiating in RF mice a 12-h PCC shift to which the CREB-mediated activation of Per1, Per2 by glucagon modestly contributes. We also show that the reported corticosterone extraproduction during the RF active phase reflects an adrenal aberrant activation of CREB signaling, which selectively delays the activation of the PPARalpha-RevErbalpha axis in muscle and heart and accounts for the retarded shift of their PCCs. PMID- 26627258 TI - Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain. AB - 17-beta estradiol (E2) has been implicated as neuroprotective in a variety of neurodegenerative disorders. However, the underlying mechanism remains unknown. Here, we provide genetic evidence, using forebrain-specific knockout (FBKO) mice, that proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), an estrogen receptor coregulator protein, is essential for the extranuclear signaling and neuroprotective actions of E2 in the hippocampal CA1 region after global cerebral ischemia (GCI). E2-mediated extranuclear signaling (including activation of extracellular signal-regulated kinase and Akt) and antiapoptotic effects [such as attenuation of JNK signaling and increase in phosphorylation of glycogen synthase kinase-3beta (GSK3beta)] after GCI were compromised in PELP1 FBKO mice. Mechanistic studies revealed that PELP1 interacts with GSK3beta, E2 modulates interaction of PELP1 with GSK3beta, and PELP1 is a novel substrate for GSK3beta. RNA-seq analysis of control and PELP1 FBKO mice after ischemia demonstrated alterations in several genes related to inflammation, metabolism, and survival in PELP1 FBKO mice, as well as a significant reduction in the activation of the Wnt/beta-catenin signaling pathway. In addition, PELP1 FBKO studies revealed that PELP1 is required for E2-mediated neuroprotection and for E2-mediated preservation of cognitive function after GCI. Collectively, our data provide the first direct in vivo evidence, to our knowledge, of an essential role for PELP1 in E2-mediated rapid extranuclear signaling, neuroprotection, and cognitive function in the brain. PMID- 26627260 TI - Shifting eating to the circadian rest phase misaligns the peripheral clocks with the master SCN clock and leads to a metabolic syndrome. AB - The light-entrained master central circadian clock (CC) located in the suprachiasmatic nucleus (SCN) not only controls the diurnal alternance of the active phase (the light period of the human light-dark cycle, but the mouse dark period) and the rest phase (the human dark period, but the mouse light period), but also synchronizes the ubiquitous peripheral CCs (PCCs) with these phases to maintain homeostasis. We recently elucidated in mice the molecular signals through which metabolic alterations induced on an unusual feeding schedule, taking place during the rest phase [i.e., restricted feeding (RF)], creates a 12 h PCC shift. Importantly, a previous study showed that the SCN CC is unaltered during RF, which creates a misalignment between the RF-shifted PCCs and the SCN CC-controlled phases of activity and rest. However, the molecular basis of SCN CC insensitivity to RF and its possible pathological consequences are mostly unknown. Here we deciphered, at the molecular level, how RF creates this misalignment. We demonstrate that the PPARalpha and glucagon receptors, the two instrumental transducers in the RF-induced shift of PCCs, are not expressed in the SCN, thereby preventing on RF a shift of the master SCN CC and creating the misalignment. Most importantly, this RF-induced misalignment leads to a misexpression (with respect to their normal physiological phase of expression) of numerous CC-controlled homeostatic genes, which in the long term generates in RF mice a number of metabolic pathologies including diabetes, obesity, and metabolic syndrome, which have been reported in humans engaged in shift work schedules. PMID- 26627263 TI - TRAF6 promotes the invasion and metastasis and predicts a poor prognosis in gastric cancer. AB - PURPOSE: This study investigated the relationships of TRAF6 expression with clinical pathologic parameters and the prognosis of patients with gastric cancer. This study also explored the roles of TRAF6 in cell apoptosis and invasiveness, as well as underlying molecular mechanism of gastric cancer cell line in vitro. METHODS: A total of 90 cases of tissue microarrays were immunohistochemically analyzed for TRAF6 expression. Cell proliferation was measured by MTT assay. Flow cytometry was used for analyzing cell apoptosis and cell invasion ability was detected by a Transwell invasion assay. Protein expression was assessed by Western blotting. RESULTS: TRAF6 was expressed in 53 of 90 (58.9%) cases of gastric cancer. TRAF6 expression was significantly positively correlated with advanced N stage, pathological stage and a poor prognosis, but not an independent predictor of a poor prognosis in gastric cancer (p=0.083). The knockdown of TRAF6 increased cell apoptosis and reduced invasive ability of BGC-823 cell. Moreover, TRAF6 down-regulation decreased protein levels of phosphor-Akt, Bcl-2 and MMP9 and up-regulation of Bax in BGC-823 cell. Inversely, overexpression of TRAF6 in SGC-7901 cells increased protein levels of phosphor-Akt, Bcl-2 and MMP9 and down regulation of Bax. CONCLUSIONS: The expression of TRAF6 was positively correlated with an advanced N stage and acted as a predictor of a poor prognosis in patients with gastric cancer. Moreover, TRAF6 regulating cell apoptosis and invasive ability of gastric cancer cells might be associated with Akt activation and alterations of protein expression of Bcl2, Bax and MMP9. PMID- 26627261 TI - Resting-state functional connectivity predicts longitudinal change in autistic traits and adaptive functioning in autism. AB - Although typically identified in early childhood, the social communication symptoms and adaptive behavior deficits that are characteristic of autism spectrum disorder (ASD) persist throughout the lifespan. Despite this persistence, even individuals without cooccurring intellectual disability show substantial heterogeneity in outcomes. Previous studies have found various behavioral assessments [such as intelligence quotient (IQ), early language ability, and baseline autistic traits and adaptive behavior scores] to be predictive of outcome, but most of the variance in functioning remains unexplained by such factors. In this study, we investigated to what extent functional brain connectivity measures obtained from resting-state functional connectivity MRI (rs-fcMRI) could predict the variance left unexplained by age and behavior (follow-up latency and baseline autistic traits and adaptive behavior scores) in two measures of outcome--adaptive behaviors and autistic traits at least 1 y postscan (mean follow-up latency = 2 y, 10 mo). We found that connectivity involving the so-called salience network (SN), default-mode network (DMN), and frontoparietal task control network (FPTCN) was highly predictive of future autistic traits and the change in autistic traits and adaptive behavior over the same time period. Furthermore, functional connectivity involving the SN, which is predominantly composed of the anterior insula and the dorsal anterior cingulate, predicted reliable improvement in adaptive behaviors with 100% sensitivity and 70.59% precision. From rs-fcMRI data, our study successfully predicted heterogeneity in outcomes for individuals with ASD that was unaccounted for by simple behavioral metrics and provides unique evidence for networks underlying long-term symptom abatement. PMID- 26627262 TI - Global impacts of energy demand on the freshwater resources of nations. AB - The growing geographic disconnect between consumption of goods, the extraction and processing of resources, and the environmental impacts associated with production activities makes it crucial to factor global trade into sustainability assessments. Using an empirically validated environmentally extended global trade model, we examine the relationship between two key resources underpinning economies and human well--being-energy and freshwater. A comparison of three energy sectors (petroleum, gas, and electricity) reveals that freshwater consumption associated with gas and electricity production is largely confined within the territorial boundaries where demand originates. This finding contrasts with petroleum, which exhibits a varying ratio of territorial to international freshwater consumption, depending on the origin of demand. For example, although the United States and China have similar demand associated with the petroleum sector, international freshwater consumption is three times higher for the former than the latter. Based on mapping patterns of freshwater consumption associated with energy sectors at subnational scales, our analysis also reveals concordance between pressure on freshwater resources associated with energy production and freshwater scarcity in a number of river basins globally. These energy-driven pressures on freshwater resources in areas distant from the origin of energy demand complicate the design of policy to ensure security of fresh water and energy supply. Although much of the debate around energy is focused on greenhouse gas emissions, our findings highlight the need to consider the full range of consequences of energy production when designing policy. PMID- 26627264 TI - Focal hepatic glycogenosis associated with metastatic insulinoma presenting as mass lesions. AB - One of the important functions of the liver is glycogen storage. Most processes associated with increased hepatic glycogen, or glycogenoses, are metabolic and affect the entire liver leading to diffuse glycogenosis. We present a case in which the liver contained multiple small pale nodules that on initial assessment were recognized to be composed of glycogenated hepatocytes. Most of the known causes of hepatic glycogenosis were not pertinent to this case. After cutting many deeper levels and obtaining additional sections, small foci of insulinoma were revealed in the center of each of these lesions. The glycogenosis surrounding the foci of insulinoma can be best explained as a local effect of insulin on the hepatocytes, a phenomenon that has been previously described in primate models, but not in human subjects. Here, we report the first case of metastatic insulinoma causing local hepatic glycogenosis. PMID- 26627265 TI - Plasma levels of neutrophil gelatinase-associated lipocalin in children with heart failure. AB - INTRODUCTION: Data about plasma levels of neutrophil gelatinase-associated lipocalin (NGAL) in children with heart failure (HF) are very limited. NGAL is used widely as a biomarker for the diagnosis of renal injury in numerous clinical studies. The aim of this study is to investigate the plasma NGAL in children with HF caused by idiopathic dilated cardiomyopathy (IDCM) and its relation to the severity of HF. MATERIAL AND METHODS: In a case-control study, 30 nondiabetic children, aged -16 years (all have IDCM) recruited from the pediatric department of our institute together with 30 healthy children were prospectively enrolled in this study. Patients underwent a detailed history taking, clinical examination, New York Heart Association (NYHA) class assessment and echocardiographic evaluation. Plasma levels of NGAL were measured by enzyme-linked immunosorbent assay. RESULTS: Plasma levels of NGAL were significantly higher in children with HF compared with healthy controls (mean: 290.97 versus 144.33, p < 0.0001). The relationship between NGAL and the severity of HF was investigated. However, we did not find any statistically significant relationship between plasma NGAL levels and indices of myocardial function. CONCLUSIONS: NGAL levels were significantly increased in children with HF caused by IDCM. However, there was no significant relationship between plasma NGAL levels and indices of myocardial function. Future multicenter clinical studies in a large population addressing the natural course of NGAL in HF and its potential as a treatment target are needed in the near future. PMID- 26627267 TI - Implementation of the 2015 Dietary Guidelines: Who, What, Why, Where, and When. PMID- 26627268 TI - When the Earth is our patient. PMID- 26627269 TI - The stability of regular GPs. PMID- 26627270 TI - [Re: What exactly is myalgic encephalomyelitis?]. PMID- 26627271 TI - [T. Egeland and colleagues reply]. PMID- 26627272 TI - [Re: What exactly is myalgic encephalomyelitis?]. PMID- 26627273 TI - [T. Egeland and colleagues reply]. PMID- 26627274 TI - [Re: What exactly is myalgic encephalomyelitis?]. PMID- 26627275 TI - [Re: What exactly is myalgic encephalomyelitis?]. PMID- 26627276 TI - [Re: Criteria-based diagnostics generate excessive and incorrect diagnoses]. PMID- 26627277 TI - [P. Gjerden replies]. PMID- 26627278 TI - [Re: Choice of specialty--a choice for life]. PMID- 26627279 TI - [Re: Telemedicine brings specialist healthcare services to patients' homes]. PMID- 26627280 TI - [I. Irgens & H. Sorli reply]. PMID- 26627281 TI - [Re: First generalized tonic-clonic seizure]. PMID- 26627282 TI - [Re: Who has misled Trond Mohn?]. PMID- 26627284 TI - [Electronic multidose and e-dialog with the pharmacy is on the way!]. PMID- 26627283 TI - [J. Breivik replies]. PMID- 26627286 TI - [A call to anonymous sperm donors]. PMID- 26627287 TI - Genome sequencing in research requires a new approach to consent. PMID- 26627288 TI - [What requirements do we set for intensive care competence?]. PMID- 26627291 TI - [Not Available]. PMID- 26627289 TI - [Guidelines in the wrong direction]. PMID- 26627292 TI - Duration of general practitioner contracts. AB - BACKGROUND: The regular GP scheme is intended to promote continuity in the relationship between doctor and patient. The duration of GP contracts is therefore a key factor in the success of the scheme. This study examines how long the GP contracts last and whether their duration varies according to doctors' gender and age, municipality size and list size. MATERIAL AND METHOD: The study encompasses 7,359 GP contracts throughout Norway, entered into between municipalities and doctors in the period 1 May 2001 - 1 May 2014. Duration is measured as the time from which the contract was signed until its expiry or the end of the study period. The material was analysed with measures of central tendencies and dispersion, Kaplan-Meier survival curve analysis and Cox proportional hazards regression. RESULTS: Median duration of a GP contract at the time of the study was 5.91 years. It varied between 2.75 years in the smallest municipalities and 8.37 years in the largest ones. The duration of a GP contract increased significantly if the doctor was a woman, or with the doctor's age at the start of the contract, increased municipality size and increased list size. INTERPRETATION: If it is assumed that continuity in the doctor-patient relationship provides a qualitatively better GP service, the results indicate that patients in small municipalities are generally offered a lower-quality service than patients in large municipalities. PMID- 26627293 TI - Hepatitis C treatment at three Norwegian hospitals 2000-2011. AB - BACKGROUND: In the period 2000 - 2011, chronic hepatitis C virus infection (HCV infection) was primarily treated with a combination of pegylated interferon and ribavirin. New antiviral drugs, which are effective but very expensive, are in the process of replacing this regimen. We have investigated the results pegylated interferon and ribavirin have yielded in ordinary clinical practice and examined the part this treatment may play in the near future. MATERIAL AND METHOD: We included in this retrospective study HCV-RNA-positive, treatment-naive patients at Stavanger University Hospital, Akershus University Hospital and Ostfold Hospital who received at least one dose of pegylated interferon in combination with ribavirin in the period 2000 - 2011. The primary endpoint was sustained virologic response (SVR). Predictors for SVR were identified by means of logistic regression analysis. RESULTS: Of 588 included patients, 69.6% (409/588) achieved SVR, 14.3% (84/588) suffered relapse and 16.1% (95/588) showed non-response. In a multivariate analysis, genotypes 2 or 3 and low age at treatment start were independent predictors of SVR. A total of 85.4% of patients aged <= 40 years with genotype 2 or 3 had SVR. INTERPRETATION: We found good results for treatment of young patients with genotype 2 or 3 with pegylated interferon and ribavirin. Low age and viral genotype were predictors of sustained virologic response (SVR). PMID- 26627294 TI - Landau-Kleffner syndrome. PMID- 26627295 TI - Problems with paint. PMID- 26627296 TI - A young woman who drank Strep test reagents. PMID- 26627297 TI - A man in his sixties with severe hypotension and oedema. PMID- 26627298 TI - [Irreducible, incarserated or strangled?]. PMID- 26627299 TI - [Not Available]. PMID- 26627302 TI - [Not Available]. PMID- 26627300 TI - [Not Available]. PMID- 26627303 TI - [Good work environment--good treatment?]. PMID- 26627304 TI - [Medical education in Trondheim 1975-2015]. PMID- 26627306 TI - Micro-fractional, directional skin tightening: A porcine model. AB - BACKGROUND AND OBJECTIVE: Skin changes are among the most visible signs of aging. Fractional ablative lasers improve skin quality by making small skin wounds that heal rapidly without scarring. While they improve skin texture and discoloration, there is minimal effect on skin laxity. This study was performed to assess skin shrinkage performed by removing multiple small full-thickness skin columns with coring needles combined with wound closure. MATERIALS AND METHODS: In 5 swine 116 squares (3 cm(2) ) were demarcated for treatment and control sites. In treatment sites 10% of the skin was removed by full-thickness skin coring needles (19 gauge) and afterwards closed and compressed with an elastic adhesive dressing. This procedure was compared to puncturing the skin with standard hypodermic needles (without tissue removal) and subsequent closure with compressive dressing. Area and shape of sites were measured before and 28 days after treatment. RESULTS: Test and control sites healed within a week without scarring. Coring with wound closure caused significant shrinkage after 28 days. The treated skin area was reduced by 9% (P < 0.0001) and the direction of shrinkage was influenced by the direction of wound closure. Coring without wound closure and puncturing the skin without tissue removal produced an insignificant 3% decrease in area. CONCLUSION: Significant minimally invasive skin tightening in a preferred direction can be achieved by removing skin with coring needles followed by wound closure. The direction of shrinkage is influenced by the direction of micro-hole closure, irrespective of the skin tension lines. This approach may allow reshaping the skin in a desired direction without scarring. PMID- 26627307 TI - Controllable Phase Separation by Boc-Modified Lipophilic Acid as a Multifunctional Extractant. AB - While phase separation of immiscible liquid-liquid systems has become increasingly significant in diverse areas, the irreversible nature limits their further application in controllable extraction-concentration or capture-release fields. There is a need for the development of simple, efficient and reversible methods for numerous research and industrial extraction and separation applications. We envisioned Boc-modified lipophilic acids as a simple model for such use based on the studies of the multi-phase transitions of Boc-modified supramolecular polymeric systems. Here, we demonstrate that in the presence of Boc-7-aminoheptanoic acid (Boc-7), phase separation occurs in mixtures of miscible organic solvent and water. The separation behavior was confirmed by differential colorimetric development in aqueous and organic phases using methyl orange staining assays. Component substitution experiments verified that the phase separation results from the subtle balance between the aggregation and the solvation forces of Boc-7, and is reversible by adjusting the solution pH. Owing to the intrinsic hydrophobic properties of the organic phase and the hydrogen bonding-forming ability of the carboxyl group of Boc-7, the phase separation system captures and releases Sudan Red, fluorescein, and streptavidin in a controllable manner. Consequently, a reversible and simple phase separation system can be designed as a multifunctional extractant. PMID- 26627308 TI - Thymosin beta4 Prevents Angiotensin II-Induced Cardiomyocyte Growth by Regulating Wnt/WISP Signaling. AB - Thymosin beta-4 (Tbeta4) is a ubiquitous protein with many properties relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory mediators. However, the role of Tbeta4 in cardiomyocyte hypertrophy is currently unknown. The purpose of this study was to determine the cardio protective effect of Tbeta4 in angiotensin II (Ang II)-induced cardiomyocyte growth. Neonatal rat ventricular cardiomyocytes (NRVM) were pretreated with Tbeta4 followed by Ang II stimulation. Cell size, hypertrophy marker gene expression and Wnt signaling components, beta-catenin, and Wnt-induced secreted protein-1 (WISP-1) were evaluated by quantitative real-time PCR, Western blotting and fluorescent microscopy. Pre-treatment of Tbeta4 resulted in reduction of cell size, hypertrophy marker genes and Wnt-associated gene expression, and protein levels; induced by Ang II in cardiomyocyte. WISP-1 was overexpressed in NRVM and, the effect of Tbeta4 in Ang II-induced cardiomyocyte growth was evaluated. WISP-1 overexpression promoted cardiomyocytes growth and was reversed by pretreatment with Tbeta4. This is the first report which demonstrates that Tbeta4 targets Wnt/WISP-1 to protect Ang II-induced cardiomyocyte growth. J. Cell. Physiol. 231: 1737-1744, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26627309 TI - Time-Resolved Decoding of Two Processing Chains during Dual-Task Interference. AB - The human brain exhibits fundamental limitations in multitasking. When subjects engage in a primary task, their ability to respond to a second stimulus is degraded. Two competing models of multitasking have been proposed: either cognitive resources are shared between tasks, or they are allocated to each task serially. Using a novel combination of magneto-encephalography and multivariate pattern analyses, we obtained a precise spatio-temporal decomposition of the brain processes at work during multitasking. We discovered that each task relies on a sequence of brain processes. These sequences can operate in parallel for several hundred milliseconds but beyond ~ 500 ms, they repel each other: processes evoked by the first task are shortened, while processes of the second task are either lengthened or postponed. These results contradict the resource sharing model and further demonstrate that the serial model is incomplete. We therefore propose a new theoretical framework for the computational architecture underlying multitasking. PMID- 26627312 TI - Medial Orbitofrontal Cortex Mediates Outcome Retrieval in Partially Observable Task Situations. AB - Choice between actions often requires the ability to retrieve action consequences in circumstances where they are only partially observable. This capacity has recently been argued to depend on orbitofrontal cortex; however, no direct evidence for this hypothesis has been reported. Here, we examined whether activity in the medial orbitofrontal cortex (mOFC) underlies this critical determinant of decision-making in rats. First, we simulated predictions from this hypothesis for various tests of goal-directed action by removing the assumption that rats could retrieve partially observable outcomes and then tested those predictions experimentally using manipulations of the mOFC. The results closely followed predictions; consistent deficits only emerged when action consequences had to be retrieved. Finally, we put action selection based on observable and unobservable outcomes into conflict and found that whereas intact rats selected actions based on the value of retrieved outcomes, mOFC rats relied solely on the value of observable outcomes. PMID- 26627311 TI - Monolithically Integrated MULEDs on Silicon Neural Probes for High-Resolution Optogenetic Studies in Behaving Animals. AB - We report a scalable method to monolithically integrate microscopic light emitting diodes (MULEDs) and recording sites onto silicon neural probes for optogenetic applications in neuroscience. Each MULED and recording site has dimensions similar to a pyramidal neuron soma, providing confined emission and electrophysiological recording of action potentials and local field activity. We fabricated and implanted the four-shank probes, each integrated with 12 MULEDs and 32 recording sites, into the CA1 pyramidal layer of anesthetized and freely moving mice. Spikes were robustly induced by 60 nW light power, and fast population oscillations were induced at the microwatt range. To demonstrate the spatiotemporal precision of parallel stimulation and recording, we achieved independent control of distinct cells ~ 50 MUm apart and of differential somato dendritic compartments of single neurons. The scalability and spatiotemporal resolution of this monolithic optogenetic tool provides versatility and precision for cellular-level circuit analysis in deep structures of intact, freely moving animals. PMID- 26627313 TI - Recent advances in ablation of ventricular tachycardia associated with structural heart disease: overcoming the challenges of functional and fixed barriers. AB - PURPOSE OF REVIEW: Ablation of ventricular tachycardia in structural heart disease has evolved to include techniques to ablate the myocardial substrate in sinus rhythm for ventricular tachycardias that are noninducible or hemodynamically unstable. The intricacies of the complex functional and fixed components of the myocardial scar involved in the arrhythmic mechanisms require careful consideration in identifying targets for substrate ablation identified in sinus rhythm. RECENT FINDINGS: The substrate ablation approach referred to as 'scar homogenization' aims to thoroughly abolish any abnormal electrical activity inside the scar. However, this extensive approach may target bystander abnormal activity that is not necessarily related to arrhythmias. Recently, different substrate ablation strategies have been developed to more selectively target areas of the scar responsible for ventricular tachycardia. New technologies have also been introduced to provide offline analysis of the electroanatomical substrate, and to improve high-density mapping of the myocardial scar. SUMMARY: Recent advances have improved the ability to ablate ventricular tachycardia using techniques that allow targeting the responsible myocardial substrate while in sinus rhythm. Further research using higher-density mapping with more sophisticated online and offline analysis will aid in the assessment of the complex arrhythmogenicity of the scar and improve efficacy of ventricular tachycardia ablation. PMID- 26627310 TI - JAKMIP1, a Novel Regulator of Neuronal Translation, Modulates Synaptic Function and Autistic-like Behaviors in Mouse. AB - Autism spectrum disorder (ASD) is a heritable, common neurodevelopmental disorder with diverse genetic causes. Several studies have implicated protein synthesis as one among several of its potential convergent mechanisms. We originally identified Janus kinase and microtubule-interacting protein 1 (JAKMIP1) as differentially expressed in patients with distinct syndromic forms of ASD, fragile X syndrome, and 15q duplication syndrome. Here, we provide multiple lines of evidence that JAKMIP1 is a component of polyribosomes and an RNP translational regulatory complex that includes fragile X mental retardation protein, DEAD box helicase 5, and the poly(A) binding protein cytoplasmic 1. JAKMIP1 loss dysregulates neuronal translation during synaptic development, affecting glutamatergic NMDAR signaling, and results in social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors in the mouse. These findings define an important and novel role for JAKMIP1 in neural development and further highlight pathways regulating mRNA translation during synaptogenesis in the genesis of neurodevelopmental disorders. PMID- 26627314 TI - First-trimester screening for congenital heart disease. AB - Advances over the last decade in technology, training, and availability of prenatal care have led to a focus on the detection of congenital heart defects (CHD) and its prenatal management for improved pregnancy outcomes. First trimester transvaginal heart screening is feasible and well tolerated. Due to advances in the diagnosis of trisomy by nonultrasound methods, a significant effort will now be focused on CHD detection in the first trimester of otherwise uncomplicated pregnancies. PURPOSE OF REVIEW: Detection of CHD is not being accomplished by heart screening training or postnatal protocols. First-trimester evaluation of fetuses is becoming more common, and a method of evaluation of the heart would improve selection of those who need later fetal echocardiography. RECENT FINDINGS: Equipment advances are resulting in excellent visualization of the fetal circulatory system even at 12-13 weeks, gestation. SUMMARY: Improved first-trimester fetal heart screening will result in a jump in CHD detection and in improved care of these patients during gestation and prior to their cardiac surgery. PMID- 26627315 TI - Advances in neonatal cardiac surgery: recent advances, the low-hanging fruit, what is on the horizon and the next moonshot. AB - PURPOSE OF REVIEW: To review the recent advances in neonatal cardiac surgery and identify future directions of this subspecialty of congenital heart surgery. RECENT FINDINGS: Recent advances in neonatal cardiac surgery have included the right ventricular to pulmonary artery conduit, the hybrid procedure and antegrade cerebral perfusion. In addition to refining the indications and techniques for these strategies, we can advance the field through collaborative learning between neonatal heart surgery centers. Collaborative learning is the low-hanging fruit that we can all use to advance the care of this patient population. On the horizon are a variety of strategies that will improve our management of this complex patient population. Among these improvements are better anticoagulation strategies targeting the unique hemostatic system of the neonate. The next transformative change, the next moonshot, may well be regenerative therapy that unlocks the body's ability to regenerate specific tissue such as valves and heart muscle to correct congenital defects and repair damaged muscle. SUMMARY: The current state of the specialty of neonatal cardiac surgery will be reviewed, and the possible future directions based on their ease and likelihood: specifically, the low-hanging fruit, what is on the horizon and the next moonshot. PMID- 26627316 TI - Operations for improving left ventricular diastolic function. AB - PURPOSE OF REVIEW: With a combination of fetal catheter interventions and postnatal catheter and surgical interventions, the left ventricle in patients with hypoplastic left heart can undergo significant increase in size and remodeling to support cardiac output. However, some will have persistent high left atrial pressures resulting in pulmonary edema and high pulmonary artery pressures, that is, diastolic dysfunction. RECENT FINDINGS: The manuscript details the medical and surgical strategies to diagnose and treat diastolic dysfunction in this patient population to promote biventricular circulations. SUMMARY: Often times, this diastolic dysfunction is related to the presence of endocardial fibroelastosis, which affects left ventricular filling and mitral valve function. Ongoing research is investigating what causes and promotes the development of endocardial fibroelastosis, and means to improve the medical and surgical treatment of diastolic dysfunction. PMID- 26627317 TI - Retrograde Pedal Access and Endovascular Revascularization: A Safe and Effective Technique for High-Risk Patients with Complex Tibial Vessel Disease. AB - BACKGROUND: Endovascular revascularization is an established approach for limb salvage in the setting of critical limb ischemia. However, failure rate of antegrade recanalization in complex femoropopliteal to infrapopliteal occlusions is as high as 20%. We report a series of 21 patients who underwent retrograde pedal access and recanalization of below-the-knee chronic total occlusions after failed antegrade attempts. METHODS: This is a retrospective review of prospectively maintained data for all patients who underwent ultrasound-guided percutaneous pedal access for retrograde endovascular treatment of advanced tibial vessel disease between 2011 and 2014. All patients had undergone prior unsuccessful attempts at antegrade revascularization. Pedal vessel access was followed by angioplasty with selective stenting and completion angiogram. Patients were followed up with duplex ultrasound to evaluate for patency. Time dependent outcomes were determined by Kaplan-Meier survival analyses. Median follow-up was 9 months. RESULTS: A total of 21 patients (17 men, 4 women, mean age 68) underwent retrograde tibial recanalization. Eighty-one percent of the patients presented with Rutherford category 4, 5, or 6 critical limb ischemia. The average Prevent III amputation risk score was 7.0 +/- 2.9. Eighteen patients (86%) were medium or high risk (Prevent III amputation risk score >= 4). Retrograde pedal access was successful in 95% of the patients (dorsalis pedis = 11, posterior tibial = 5, anterior tibial = 4). Retrograde revascularization was achieved in 14 patients (67%) using balloon angioplasty (n = 14) and additional stent placement (n = 2). Revascularization failed in 7 patients (33%). There were no pedal access site complications. Forty-eight percent of the patients experienced improvement or resolution of their symptoms. The 30-day major adverse cardiac events (MACE), major adverse limb events (MALE), and amputations were all 5%. At 1 year, limb salvage was 88 +/- 8% with amputation-free survival of 61 +/- 12% and freedom from MALE of 81 +/- 10%. Primary assisted and secondary patencies were both 84 +/- 10% at 1 year. CONCLUSIONS: Early outcomes for ultrasound-guided retrograde pedal access show that it is safe, with low 30-day mortality, and a low rate of MACE. Freedom from MALE and limb salvage are both high at 1-year follow-up. This technique expands revascularization options after failed conventional endovascular antegrade approaches. PMID- 26627318 TI - Surgical Fenestration for Lower Limb Ischemia Developing from Chronic Type B Aortic Dissection: A Report of 2 Cases. AB - Lower limb ischemia caused by type B aortic dissection typically presents with a leg-threatening condition in the acute phase. However, in some cases, lower limb ischemia symptom develops as intermittent claudication in the chronic phase. Although surgical fenestration has been used for treating ischemic complications of aortic dissection, it has recently become an alternative option for such cases because of the significant advance of endovascular treatments. We report 2 cases of chronic type B aortic dissection complicated by lower limb ischemia. Two male patients aged 57 and 43 years presented with intermittent claudication more than 2 weeks after the onset of the disease. On the basis of anatomic condition of the dissected aorta, we successfully performed surgical fenestration through a median laparotomy. In the current endovascular era, surgical fenestration remains an effective and durable option for treating lower limb ischemia caused by chronic type B aortic dissection. PMID- 26627319 TI - Emergency Embolization of a Ruptured Aneurysm of the Internal Iliac Artery by Direct Ultrasound-Guided Puncture: Report of a Case. AB - We report the emergency embolization of a ruptured aneurysm of the internal iliac artery in a patient at high surgical risk. Admission computed tomography scan showed that the ostium of the aneurysmal internal iliac artery was covered by a covered stent. In this patient, we chose to carry out an embolization of the aneurysm and its efferent arteries by direct puncture of the aneurysmal sac using an antero-external abdominal approach under ultrasound guidance. Short-term results were favorable and we consider that this technique is one of the therapeutic options to discuss in such situation. PMID- 26627320 TI - Axillary Artery Deployment of Endovascular Aortic Repair Iliac Limb for Preservation of Internal Iliac Artery Blood Flow. AB - The axillary artery approach has been used for access for complex endovascular aortic procedures such as thoracic endovascular aortic repair with poor anatomy for traditional deployment as well as for fenestrated and branched abdominal aortic endografts. We report the first case of an iliac graft limb deployment through the axillary artery during an endovascular aortic repair for maintenance of anterograde internal iliac flow in a patient with a symptomatic abdominal aortic aneurysm and chronic occlusion of both the external iliac and common femoral arteries. PMID- 26627321 TI - Endovascular Embolization of a Large High-Flow Splenic Arteriovenous Fistula and Aneurysm Using the Amplatzer Vascular Plug II. AB - We describe the use of an Amplatzer Vascular Plug (AVP) II for embolizing a large high-flow splenic arteriovenous fistula and an aneurysm in a young patient. This patient presented to our center with persistent mild abdominal discomfort, 5 years after open splenectomy. Contrast-enhanced computed tomography angiography showed the presence of a fistula between the splenic arterial and splenic venous remnants and a resultant fusiform aneurysmal dilatation of the residual splenic vein. We decide to embolize the splenic artery with a 12-mm diameter AVP II with an oversizing by 70% of the vessel diameter. Celiac angiography performed 5 min postembolization revealed complete obliteration of the splenic artery and closure of the arteriovenous fistula. The overall procedure time was 40 min, and overall radiation exposure was 32 Gy cm(2) (dose-area product). PMID- 26627322 TI - True Aneurysm of the Left Internal Thoracic Artery. AB - Aneurysms of the internal thoracic artery (ITA) are rare and can have many etiologies. Hyperflow is an exceptional etiology. We report the case of a 56-year old woman who presented with a stress-induced ischemia of the left arm. Computed tomography angiography showed occlusion of the subclavian artery and a true aneurysm of the ITA. The ITA aneurysm was resected without restoration of the ITA continuity and a carotid-subclavian bypass was performed. Pathological examination of the aneurysm sac was not specific. PMID- 26627323 TI - Long-Term Outcomes of Catheter-Directed Thrombolysis for Acute Lower Extremity Occlusions of Native Arteries and Prosthetic Bypass Grafts. AB - BACKGROUND: Catheter-directed thrombolysis is a well-accepted treatment for acute lower extremity occlusions of native arteries and bypass grafts. Several variables that affect outcomes of thrombolysis have been identified. The hypothesis of this study was that the long-term outcome after catheter-directed thrombolysis would be better for acute lower extremity occlusions of native arteries compared with prosthetic bypass grafts. METHODS: This observational study retrospectively analyzed 159 consecutive patients (114 men), median age, 65 years (range 57-73 years), with 89 native artery (56%), and 70 prosthetic bypass graft (44%) occlusions of the lower extremity. All patients were treated with catheter-directed thrombolysis between 2006 and 2009 in 2 vascular referral centers in the Netherlands. The severity of ischemia was Rutherford class I (52%), class IIa (27%), class IIb (12%) and unknown (9%) in native arteries and class I (64%), class IIa (19%), class IIb (1%), and unknown (16%) in bypass grafts. Median (range) duration of symptoms before the start of thrombolysis was 3.5 (1-14) days in native arteries and 3 (1-9) days in bypass grafts. All patients were treated with a continuous dosage of urokinase (100,000 IU/h). Amputation-free survival was estimated by conduit type using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using a Cox proportional hazards model. RESULTS: Complete (>95%) lysis was achieved in 69% of native arteries and bypass grafts (P = 1.00). Major hemorrhagic complications occurred in 12% (4% hemorrhagic strokes, of which 2% were fatal) of native arteries and in 7% (0% hemorrhagic stroke) of bypass grafts (P = 0.28). The 30-day mortality rate was 6% in native arteries and 1% in bypass grafts (P = 0.17), and the 30-day amputation rate was 10% in native arteries and 13% in bypass grafts (P = 0.45). Mean follow-up was 27 +/- 19 months. Amputation free survival at 1 year was 76% for native arteries and 78% for bypass grafts and at 5 years was 65% for native arteries and 51% for bypass grafts (P = 0.32). Multivariate analysis showed 2 negative predictors for amputation-free survival: age >65 years and cerebrovascular disease. Conduit type was not an independent predictor for amputation-free survival (P = 0.78). CONCLUSIONS: Despite initial promising results, long-term follow-up of catheter-directed thrombolysis for acute lower extremity occlusions showed a disappointing amputation-free survival. In multivariate analysis, no significant differences in amputation-free survival between native arteries and prosthetic bypass grafts were determined. PMID- 26627324 TI - Aneurysm Sac Enlargement after Endovascular Abdominal Aortic Aneurysm Repair. AB - The aim of this study is to give an overview of current knowledge regarding abdominal aortic aneurysm (AAA) growth after endovascular aortic aneurysm repair (EVAR) that could potentially lead to aortic rupture. A search on Pubmed was performed. A total of 705 articles were found after initial search, of which 49 were included in the final selection. Reports on the incidence of aneurysm enlargement after EVAR vary between 0.2% and 41%. Continuous growth could lead to rupture of the aneurysm sac. There are several supposed risk factors for growth after EVAR. Endoleaks remain a hot topic as these could lead to persistent pressurization of the aneurysm sac causing growth. Various types of endoleak exist, of which each kind requires an individual treatment approach, other risk factors for aneurysm growth include endotension and the use of EVAR outside instructions for use (IFU). Reinterventions after EVAR are common; however, it is unclear how frequently these are required because of aneurysm enlargement. Aneurysm enlargement after EVAR remains a subject of debate, as this could lead to aortic rupture. This emphasizes the need for life-long radiologic surveillance during follow-up. Aortic growth after EVAR is often a result of endoleak; however, in some cases, no endoleak is detectable. Endoleak in combination with aortic growth >5 mm generally requires reintervention. A cause of concern is the liberal use of endovascular devices outside the IFU that may result in increased risk of AAA growth after EVAR. PMID- 26627325 TI - The History of Incidentally Discovered Penetrating Aortic Ulcers of the Abdominal Aorta. AB - BACKGROUND: The management of incidentally discovered penetrating ulcers of the abdominal aorta (PUAA) is not well described. METHODS: A search of computed tomography (CT) angiography imaging reports for the words "penetrating ulcer" was performed from October 2010 to August 2011. Patients with a PUAA were identified, and their clinical course was followed through December 2014 (n = 53). No specific intervention for the ulcers was sought unless additional aortic pathology necessitated intervention. Prospective and retrospective review of imaging was performed by dedicated vascular radiologists. Aortic diameters and ulcer dimensions were measured for patients with repeat imaging. Mann-Whitney U, Fisher's exact, and Pearson correlation coefficient tests were performed for statistical analysis. RESULTS: The calculated incidence of PUAA for patients undergoing CT imaging was 0.48%. Age at diagnosis was 71.6 +/- 10.5 years in a population that included 35 (66.0%) males. Repeat imaging was performed for 29 (54.7%) patients. Median clinical and imaging follow-up was 36 (1-127) months and 34 (1-89) months. A history of hypertension (92.5%), hyperlipidemia (77.4%), and tobacco use (81.8%) was common. Twenty-seven (50.9%) had concomitant aneurysms not necessarily associated with PUAA. No aortic aneurysm or PUAA rupture occurred, but the population was sick with 19 patients (35.8%) deceased at the end of the study. Median aortic diameter growth rate through the PUAA was 0.5 (0 11.4) mm/year. No difference in mortality or aortic pathology was detected in patients with aortic growth rates >1 mm/year compared with <1 mm/year (P = 0.21 and P = 0.71, respectively). CONCLUSIONS: Patients with PUAA in general are elderly with multiple comorbidities. A large percentage of patients have concurrent, separate, aortic pathology, most frequently aortic aneurysms. Small changes in the appearance of the PUAA were frequent but did not equate with abdominal aortic catastrophe. Long-term mortality for this population was high, but the ulcer growth during follow-up did not suggest PUAA treatment would improve survival. PMID- 26627326 TI - Laparoscopic Left Renal Vein Transposition for Nutcracker Syndrome. AB - The left renal vein (LRV) reimplantation into the distal inferior vena cava is considered to be the gold standard of care for symptomatic nutcracker syndrome (NCS). The vast majority of these surgical procedures are performed by open surgery. Experiences with minimally invasive laparoscopic surgery in this field are very limited. We present a case of a 17-year-old boy with NCS in whom the transposition of the LRV was done laparoscopically. The patient suffered from left flank pain, painful left-sided varicocele, microscopic hematuria, proteinuria, and oligoasthenospermia. There were no intraoperative complications, and the postoperative course was uneventful. At 12-month follow-up, hematuria, left flank pain, and left testicular pain resolved. Duplex ultrasonography revealed patent LRV. Laparoscopic LRV transposition appears to be safe, feasible, and has favorable postoperative course. PMID- 26627327 TI - Charge filling factors in clean and disordered arrays of tunnel junctions. AB - We simulate one-dimensional arrays of tunnel junctions using the kinetic Monte Carlo method to study charge filling behaviour in the large charging energy limit. By applying a small fixed voltage bias and varying the offset voltage, we investigate this behaviour in clean and disordered arrays (both weak and strong disorder effects). The offset voltage dependent modulation of the current is highly sensitive to background charge disorder and exhibits substantial variation depending on the strength of the disorder. We show that while small fractional charge filling factors are likely to be washed out in experimental devices due to strong background charge disorder, larger factors may be observable. PMID- 26627328 TI - An Unexpected Cause of Chronic Diarrhea. PMID- 26627329 TI - An Enlarged Appendix Owing to a Nonlifting Polyp. PMID- 26627330 TI - A Patient with a Solitary Lump in the Sigmoid Colon. PMID- 26627331 TI - A Duodenal Tumor That Causes Partial Obstruction. PMID- 26627333 TI - Recurrent Fevers After Infliximab Therapy for Ulcerative Colitis. PMID- 26627334 TI - Ectopic Tissue in the Stomach Wall Harbors Stunning Diagnosis. PMID- 26627335 TI - Effectiveness of daily eccentric contractions induced via kilohertz frequency transcutaneous electrical stimulation on muscle atrophy. AB - The effects of daily repeated bouts of concentric, isometric, or eccentric contractions induced by high frequency (kilohertz) transcutaneous electrical stimulation in ameliorating atrophy of the soleus muscle in hindlimb unloaded rats were determined. Five groups of male rats were studied: control, hindlimb unloaded for 2 weeks (HU), or HU plus two daily bouts of concentric, isometric, or eccentric high-frequency electrical stimulation-induced contractions of the calf musculature. Soleus mass and fiber size were smaller, the levels of phosphorylated Akt1 and FoxO3a lower, and atrogin-1 and ubiquitinated proteins higher in the HU, and the HU plus concentric or isometric contraction groups than in the control group. In contrast, daily bouts of eccentric contractions maintained these values at near control levels and all measures were significantly different from all other HU groups. These results indicate that daily bouts of eccentric contractions induced by high-frequency stimulation inhibited the ubiquitin-proteasome catabolic pathway and enhanced the Akt1/FoxO3a anabolic pathway that resulted in a prevention of the atrophic response of the soleus muscle to chronic unloading. PMID- 26627336 TI - Antifungal susceptibilities of Candida species isolated from the patients with vaginal candidiasis. AB - There have been the current Japanese data on susceptibility testing for Candida isolates from vaginal candidiasis. The in vitro activities of therapeutic antifungal drugs for vulvovaginal candidiasis (VVC); miconazole (MCZ), itraconazole (ITCZ), fluconazole (FLCZ), clotrimazole (CTZ), oxiconazole (OCZ), isoconazole (ICZ) and bifonazole (BFZ) against vaginal isolates. Fifty-four strains Candida albicans and 19 strains of Candida glabrata were evaluated using a broth microdilution method specified by Clinical Laboratories Standard Institute (CLSI) document M27-A3. The MIC90 of each drug, MCZ, ITCZ, FLCZ, CTZ, OCZ, ICZ and BFZ, against C. albicans and C. glabrata isolates were 0.25, 0.12, 1, 0.06, 0.12, 0.12 and 1 MUg/ml and 1, 1, 8, 0.5, 0.25, 0.5 and 1 MUg/ml respectively. The activities of these drugs, except for BFZ, against C. glabrata were lower than that of C. albicans. There was one azole-resistant isolate in C. glabrata of which MIC of FLCZ is > 64 MUg/ml and this isolate had cross resistance to other antifungal drugs tested. These results suggest that antifungal drugs for treatment of VVC continues to have potent antifungal activities against C. albicans and C. glabrata isolates from vaginitis. CTZ, OCZ and ICZ susceptibility of FLCZ low susceptibility C. glabrata are relatively higher than MCZ, ITCZ and FLCZ. PMID- 26627338 TI - Timing of antiretroviral therapy initiation after diagnosis of recent human immunodeficiency virus infection and CD4(+) T-cell recovery. AB - We retrospectively examined the timing of antiretroviral therapy (ART) initiation and CD4(+) T-cell recovery over 36 months among recent human immunodeficiency virus (HIV) infections using BED (HIV-1 subtypes B, E and D) immunoglobulin G capture enzyme immunoassay (BED-CEIA). Regardless of baseline CD4(+) counts, individuals (n = 393) who initiated ART >2 months after diagnosis had significantly decreased probability and rate of achieving CD4(+) counts >=900 cells/MUL or >=600 cells/MUL than those individuals (n = 135) who started ART earlier (<=2 months). But the mean CD4(+) counts in two groups converged after 30 months of treatment. Early ART initiation leads to accelerated CD4(+) recovery, but does not offer a long-term advantage in CD4(+) counts. PMID- 26627339 TI - Response to antiviral therapy in haematopoietic stem cell transplant recipients with cytomegalovirus (CMV) reactivation according to the donor CMV serological status. AB - Pre-emptive antiviral treatment efficiently prevents occurrence of cytomegalovirus (CMV) disease in allogeneic stem cell transplant recipients. However, successive treatment courses can be necessary. The current study was aimed at determining factors that could influence the response to antiviral treatment, in particular the donor CMV serostatus. A total of 147 consecutive CMV seropositive recipients (R+) were included and prospectively monitored for 6 months after transplantation. Reactivation of CMV occurred in 111 patients, 61 of 78 with a CMV-positive donor (D+) and in 50 of 69 with a CMV-negative donor (D-) (p 0.45). Baseline viral loads and initial viral doubling times did not differ between D+/R+ and D-/R+. Fifteen D+/R+ and four D-/R+ had self-resolving CMV infections. A total of 92 patients received antiviral treatment and 81 (88%) had a significant decrease in CMV load under therapy. Repeated CMV episodes were observed in 67% of those and were significantly more frequent in D-/R+ than in D+/R+ (p <0001). Half-life of CMV under treatment was significantly longer in D /R+ than in D+/R+. Treatment failure observed in eight recipients was associated with low leucocyte count at reactivation onset, and was significantly more frequent in D-/R+ (six patients) than in D+/R+ (two patients) (p <0.0001). CMV strains resistant to antivirals were found in two D-/R+. Donor CMV serostatus influenced neither CMV reactivation occurrence nor the kinetics of CMV DNA load in the early phase of CMV replication but had a significant impact on response to antiviral therapy. Virological drug-resistance remained rare. PMID- 26627337 TI - Sympathetic regulation during thermal stress in human aging and disease. AB - Humans control their core temperature within a narrow range via precise adjustments of the autonomic nervous system. In response to changing core and/or skin temperature, several critical thermoregulatory reflex effector responses are initiated and include shivering, sweating, and changes in cutaneous blood flow. Cutaneous vasomotor adjustments, mediated by modulations in sympathetic nerve activity (SNA), aid in the maintenance of thermal homeostasis during cold and heat stress since (1) they serve as the first line of defense of body temperature and are initiated before other thermoregulatory effectors, and (2) they are on the efferent arm of non-thermoregulatory reflex systems, aiding in the maintenance of blood pressure and organ perfusion. This review article highlights the sympathetic responses of humans to thermal stress, with a specific focus on primary aging as well as impairments that occur in both heart disease and type 2 diabetes mellitus. Age- and pathology-related changes in efferent muscle and skin SNA during cold and heat stress, measured directly in humans using microneurography, are discussed. PMID- 26627340 TI - Laboratory diagnosis, clinical management and infection control of the infections caused by extensively drug-resistant Gram-negative bacilli: a Chinese consensus statement. AB - Extensively drug-resistant (XDR) Gram-negative bacilli (GNB) are defined as bacterial isolates susceptible to two or fewer antimicrobial categories. XDR-GNB mainly occur in Enterobacteriaceae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. The prevalence of XDR-GNB is on the rise in China and in other countries, and it poses a major public health threat as a result of the lack of adequate therapeutic options. A group of Chinese clinical experts, microbiologists and pharmacologists came together to discuss and draft a consensus on the laboratory diagnosis, clinical management and infection control of XDR-GNB infections. Lists of antimicrobial categories proposed for antimicrobial susceptibility testing were created according to documents from the Clinical Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the United States Food and Drug Administration (FDA). Multiple risk factors of XDR-GNB infections are analyzed, with long-term exposure to extended-spectrum antimicrobials being the most important one. Combination therapeutic regimens are summarized for treatment of XDR-GNB infections caused by different bacteria based on limited clinical studies and/or laboratory data. Most frequently used antimicrobials used for the combination therapies include aminoglycosides, carbapenems, colistin, fosfomycin and tigecycline. Strict infection control measures including hand hygiene, contact isolation, active screening, environmental surface disinfections, decolonization and restrictive antibiotic stewardship are recommended to curb the XDR-GNB spread. PMID- 26627343 TI - Practice, evidence and creativity in tropical and remote settings. PMID- 26627342 TI - A pseudo-outbreak of disseminated cryptococcal disease after orthotopic heart transplantation. AB - Cryptococcal infection is the third most common invasive fungal infection (IFI) among solid-organ transplant (SOT) recipients and is considered an important opportunistic infection due to its significant morbidity and mortality. To determine whether a cluster of cryptococcosis in heart transplant patients was of nosocomial nature, three cases of orthotopic heart transplant recipients with postoperative disseminated cryptococcal infection were investigated and paired with an environmental survey in a tertiary care hospital. The infection prevention department conducted a multidisciplinary investigation, which did not demonstrate any evidence of health care-associated environmental exposure. Moreover, multilocus sequence typing showed that one isolate was unique and the two others, although identical, were not temporally related and belong to the most common type seen in the Southern US. Additionally, all three patients had preexisting abnormalities of the CT chest scan and various degrees of acute and chronic rejection. Reactivation was suggested in all three patients. Screening methods may be useful to identify at risk patients and trigger a prophylactic or preemptive approach. However, more data is needed. PMID- 26627341 TI - Preventive effects of vitamin D treatment on bleomycin-induced pulmonary fibrosis. AB - Patients with pulmonary fibrosis often have low vitamin D levels, the effects of which are largely unknown. We here report that early vitamin D supplementation significantly reduced the severity of pulmonary fibrosis and inflammatory cell accumulationin in the bleomycin-induced pulmonary fibrosis mouse model on supplementary days 14, 21 and 28 (P < 0.001). Vitamin D supplementation also prevented some ultrastructural changes in response to bleomycin administration, including basement membrane thickening, interstitial fibrin deposition and microvilli flattening or disappearance on days 14, 21 and 28, and lamellar body swelling or vacuolation on days 21 and 28. The bleomycin group had rising hydroxyproline level on days 14, 21 and 28, whereas the vitamin D treatment group showed consistently lower hydroxyproline level but still higher than that of the control group (P < 0.001). Our immunohistochemistry and densitometry analyses showed less staining for alpha-smooth muscle actin, a myofibroblast marker, in the vitamin D group compared to the bleomycin group (P < 0.001). Thus, vitamin D treatment could prevent bleomycin-induced pulmonary fibrosis by delaying or suppressing ultrastructural changes, as well as attenuating hydroxyproline accumulation and inhibiting myofibroblastic proliferation. These data further our understanding of the roles of vitamin D in pulmonary fibrogenesis and in the treatment of pulmonary fibrosis. PMID- 26627344 TI - The determinants of change for indigenous mental health. PMID- 26627350 TI - Use of the urine drug screen in psychiatry emergency service 2. PMID- 26627352 TI - From the President. PMID- 26627351 TI - The use of psychoactive drug testing in acute mental health services. PMID- 26627355 TI - Voting rights for Associates (trainees) and Affiliates at RANZCP annual general meeting and in Board elections. PMID- 26627356 TI - Reflections on visiting the Northern Territory. PMID- 26627357 TI - RANZCP renews its commitment to constitutional recognition and reconciliation. PMID- 26627358 TI - New College policy and advocacy work contributes to addressing methamphetamine related harms in Australia and New Zealand. PMID- 26627359 TI - New online resources on self-care for rural psychiatrists. PMID- 26627360 TI - Talking with Dr Mark Cross. PMID- 26627363 TI - Doctors oppose IMA meeting scheduled for Thai resort. PMID- 26627364 TI - Dr No: double drug fails to eliminate status epilepticus. PMID- 26627365 TI - Reflex seizures, traits, and epilepsies: from physiology to pathology. AB - Epileptic seizures are generally unpredictable and arise spontaneously. Patients often report non-specific triggers such as stress or sleep deprivation, but only rarely do seizures occur as a reflex event, in which they are objectively and consistently modulated, precipitated, or inhibited by external sensory stimuli or specific cognitive processes. The seizures triggered by such stimuli and processes in susceptible individuals can have different latencies. Once seizure suppressing mechanisms fail and a critical mass (the so-called tipping point) of cortical activation is reached, reflex seizures stereotypically manifest with common motor features independent of the physiological network involved. The complexity of stimuli increases from simple sensory to complex cognitive emotional with increasing age of onset. The topography of physiological networks involved follows the posterior-to-anterior trajectory of brain development, reflecting age-related changes in brain excitability. Reflex seizures and traits probably represent the extremes of a continuum, and understanding of their underlying mechanisms might help to elucidate the transition of normal physiological function to paroxysmal epileptic activity. PMID- 26627367 TI - Mechanical characterisation of Dacron graft: Experiments and numerical simulation. AB - Experimental and numerical analyses focused on the mechanical characterisation of a woven Dacron vascular graft are presented. To that end, uniaxial tensile tests under different orientations have been performed to study the anisotropic behaviour of the material. These tests have been used to adjust the parameters of a hyperelastic anisotropic constitutive model which is applied to predict through numerical simulation the mechanical response of this material in the ring tensile test. The obtained results show that the model used is capable of representing adequately the nonlinear elastic region and, in particular, it captures the progressive increase of the rigidity and the anisotropy due to the stretching of the Dacron. The importance of this research lies in the possibility of predicting the graft's mechanical response under generalized loading such as those that occur under physiological conditions after surgical procedures. PMID- 26627366 TI - Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial. AB - BACKGROUND: Generalised convulsive status epilepticus (GCSE) should be treated quickly. Benzodiazepines are the only drug treatment available so far that is effective before admission to hospital. We assessed whether addition of the antiepileptic drug levetiracetam to the benzodiazepine clonazepam would improve prehospital treatment of GCSE. METHODS: We did a prehospital, randomised, double blind, phase 3, placebo-controlled, superiority trial to determine the efficacy of adding intravenous levetiracetam (2.5 g) to clonazepam (1 mg) in treatment of GCSE in 13 emergency medical service centres and 26 hospital departments in France. Randomisation was done at the Paris Descartes Clinical Research Unit with a list of random numbers generated by computer. Adults with convulsions lasting longer than 5 min were randomly assigned (1:1) by prehospital physicians to receive levetiracetam or placebo in combination with clonazepam. All physicians and paramedics were masked to group assignments. If the status epilepticus lasted beyond 5 min after drug injection, a second dose of 1 mg clonazepam was given. The primary outcome was cessation of convulsions within 15 min of drug injection. We analysed the modified intention-to-treat population that had received at least one injection of clonazepam and levetiracetam or placebo, excluding patients without valid consent and those randomised more than once. The trial is registered at EudraCT, number 2007-005782-35. FINDINGS: Between July 20, 2009, and Dec 15, 2012, 107 patients were randomly assigned to receive placebo and 96 were assigned to receive levetiracetam. The trial was discontinued on Dec 15, 2012 when interim analysis showed no evidence of a treatment difference, and 68 patients in each group were included in the modified intention-to-treat analysis. Convulsions stopped at 15 min of drug injection in 57 of 68 patients (84%) receiving clonazepam and placebo and in 50 of 68 patients (74%) receiving clonazepam and levetiracetam (percentage difference -10.3%, 95% CI -24.0 to 3.4). Three deaths, 19 of 47 (40 %) serious adverse events, and 90 of 197 (46%) non serious events were reported in the levetiracetam group, and four deaths, 28 of 47 (60%) serious events, and 107 of 197 (54%) non-serious events were reported in the placebo group. INTERPRETATION: The addition of levetiracetam to clonazepam treatment presented no advantage over clonazepam treatment alone in the control of GCSE before admission to hospital. Future prehospital trials could assess the efficacy of clonazepam alone as a first-line treatment in status epilepticus and the efficacy of a second injection of clonazepam with another antiepileptic drug as second-line treatment. FUNDING: UCB Pharma. PMID- 26627368 TI - Biomechanical profile of cancer stem-like cells derived from MHCC97H cell lines. AB - Biomechanical properties and cytoskeletal organization of cancer cells are known to be closely related with their aggressive phenotype. In this study, based on atomic force microscopy (AFM), we aimed to evaluate the mechanical property of liver cancer stem-like cells (LCSCs) and compare it with human hepatoma cells (HHCs). LCSCs were enriched from human hepatoma cell line MHCC97H through a sphere culture system. AFM nanoindentation was investigated as a method for measuring the cell stiffness, and reflecting by Young's modulus. Microfilament bundles of F-actin were observed with immunofluorescence staining by confocal microscopy. We found that LCSCs show lower Young's modulus and higher migration ability compared to MHCC97H cells. Moreover, the decrease in Young's modulus is accompanied with a dramatic decline in F-actin content. These results demonstrated a close relationship between the cell Young's modulus and metastatic potential of HHCs, which suggest that Young's modulus detected by AFM can be used to evaluate metastatic potential of cancer cells. PMID- 26627370 TI - Rates of acute respiratory illnesses of infectious and allergic etiologies after permanent changes of duty assignments, active component, U.S. Army, Air Force, and Marine Corps, January 2005-September 2015. AB - Throughout history, acute respiratory illnesses (ARIs) have disproportionately affected military populations, particularly those in recruit training camps. A similar dynamic can affect non-trainee military settings. When military members are reassigned, they often develop ARIs within the first weeks of their arrivals at their new assignments. To assess the natures and magnitudes of the risks associated with new assignments, this analysis compared the experiences of service members within their first full calendar months at new assignments and during the same months at the same locations 1 year later. The results do not support the hypothesis that ARIs of infectious etiologies consistently occur more frequently soon after arriving at new assignments compared to 1 year later at the same locations. In contrast, during two-thirds of the 117 months considered here, rates of ARIs of presumed allergic etiologies (e.g., allergic rhinitis, asthma) were higher during the first months of new assignments compared to 1 year later. The limitations of the study methodology as well as the possible implications of the findings are discussed. PMID- 26627369 TI - From Help-Seekers to Influential Users: A Systematic Review of Participation Styles in Online Health Communities. AB - BACKGROUND: Understanding how people participate in and contribute to online health communities (OHCs) is useful knowledge in multiple domains. It is helpful for community managers in developing strategies for building community, for organizations in disseminating information about health interventions, and for researchers in understanding the social dynamics of peer support. OBJECTIVE: We sought to determine if any patterns were apparent in the nature of user participation across online health communities. METHODS: The current study involved a systematic review of all studies that have investigated the nature of participation in an online health community and have provided a quantifiable method for categorizing a person based on their participation style. A systematic search yielded 20 papers. RESULTS: Participatory styles were classified as either multidimensional (based on multiple metrics) or unidimensional (based on one metric). With respect to the multidimensional category, a total of 41 different participation styles were identified ranging from Influential Users who were leaders on the board to Topic-Focused Responders who focused on a specific topic and tended to respond to rather than initiate posts. However, there was little overlap in participation styles identified both across OHCs for different health conditions and within OHCs for specific health conditions. Five of the 41 styles emerged in more than one study (Hubs, Authorities, Facilitators, Prime Givers, and Discussants), but the remainder were reported in only one study. The focus of the unidimensional studies was on level of engagement and particularly on high engaged users. Eight different metrics were used to evaluate level of engagement with the greatest focus on frequency of posts. CONCLUSIONS: With the exception of high-engaged users based on high post frequency, the current review found little evidence for consistent participatory styles across different health communities. However, this area of research is in its infancy, with most of the studies included in the review being published in the last 2 years. Nevertheless, the review delivers a nomenclature for OHC participation styles and metrics and discusses important methodological issues that will provide a basis for future comparative research in the area. Further studies are required to systematically investigate a range of participatory styles, to investigate their association with different types of online health communities and to determine the contribution of different participatory styles within and across online health communities. PMID- 26627371 TI - Completeness and timeliness of reporting of notifiable medical conditions, active component, U.S. Armed Forces, 2008-2014. AB - The complete and timely reporting of notifiable medical conditions occurring among U.S. military service members is important for the control of communicable and preventable diseases and injuries. The Defense Medical Surveillance System (DMSS) was used to identify all hospital and ambulatory care encounters among service members occurring during 2008-2014. Incident encounters with diagnoses of Department of Defense notifiable medical conditions were matched to reportable medical events entered through the Disease Reporting System Internet. Over this time period, the Services reported 47.6% of notifiable hospitalized cases and 57.2% of notifiable ambulatory care cases. Timeliness of reporting improved over the time period with 40.0% of notifiable hospitalized cases reported within 1 week in 2008 and 73.6% in 2014. For ambulatory care cases, 62.3% were reported within 1 week in 2008 and 81.3% in 2014. PMID- 26627372 TI - The Recommendations of the 2015 American Urological Association Working Group on Genitourinary Congenitalism. AB - OBJECTIVE: To develop consensus recommendations for index congenital urological cases seen in adulthood and to generate discussion among providers who treat these patients across the lifespan. This manuscript reviews the proceedings and recommendations of the 2015 American Urological Association Working Group on Urological Congenitalism. METHODS: Index cases were selected to highlight controversies in the management of different congenital patients in adulthood. Cases were presented and participants were randomized to groups to avoid clustering of individuals of similar background and experience. Expert panelists (representing backgrounds in pediatric and adult care of congenital patients) also discussed the cases. After that, a facilitated discussion was held with the entire group in an attempt to develop consensus recommendations for the questions raised in each case. RESULTS: Recommendations were generated related to management of pregnancy in young woman with bladder exstrophy and one with reflux nephropathy, as well as a young man with spina bifida with chronic kidney disease seeking undiversion. CONCLUSION: Given the lack of long-term data for patients with congenital genitourinary diseases, management of complex urological disease in these patients can be difficult. Consensus discussion with urological providers across the spectrum of the life course of these patients may help provide clinical guidance. PMID- 26627373 TI - New Therapeutic Perspectives in Premature Ejaculation. AB - OBJECTIVE: To review potential therapeutic targets and future therapeutic molecules in premature ejaculation (PE). PE is the most prevalent sexual dysfunction and affects about 23% of the male population. It is a universal disorder: it is independent of age and social or marital status. Men with PE typically refer associated comorbidities and report a significant impact not only on their quality of life but also on the satisfaction of the partner. Although common and treatable in most cases, the drugs currently available may affect sexual spontaneity and the cost can prove to be a hindrance. MATERIALS AND METHODS: A comprehensive literature revision was performed using PubMed and Scopus to identify relevant articles published in the fields of PE and its treatment until May 2015. RESULTS: The main central targets identified include serotonergic, dopaminergic, and oxytocinergic neurotransmitters, opioid receptors, and mechanisms involved in the control of the spinal ejaculatory generator, located at the T12-L1-2 spinal cord level. On the other hand, peripheral interventions at semen's transport may also delay ejaculation by decreasing sequential contractions of the epididymis, vas deferens, seminal vesicles, prostate, and bladder neck. CONCLUSION: There is a wide range of future options with regard to the treatment of PE. Molecules like DA-8031, Promescent, silodosin, Botulinum toxin-A, and resiniferatoxin may be near future treatments for this disorder. PMID- 26627374 TI - Studer Orthotopic Neobladder: A Modified Surgical Technique. AB - OBJECTIVE: To describe a modified technique for orthotopic ileal neobladder preparation. The Studer technique is the method most frequently used worldwide and seems to be an ideal reconstructive solution after radical cystectomy. METHODS: After radical cystectomy, urinary diversion is attained by means of a detubulized ileal segment. About 40 cm are used to create the reservoir and 15 cm for a tubular afferent limb. A spheroidal-shaped reservoir is then obtained with a conic distal part that will be anastomized to the urethral stump. After the reconstructive part, the neobladder and the afferent limb are attached to the levator ani and psoas muscles, respectively. Postoperative results on a series of 36 patients are reported. RESULTS: The final shape of the reservoir was roughly spherical. A small amount of anastomotic strictures was registered. Renal function was not impaired after surgery, even at late follow-up. CONCLUSION: Even if the Studer technique is already well described, we believe that our technical changes may improve urinary tract restoration, and potentially decrease complications typical of urinary orthotopic diversion. Further cases are required to confirm possible advantages of the modified technique. PMID- 26627375 TI - Computed Tomography Imaging Appearance of a Unique Variant of Retroiliac Ureter. AB - Retroiliac ureter is a rare condition where the ureter passes behind the iliac vessels. The diagnosis is usually intraoperative and the reports of preoperative imaging diagnosis are scarce. Herein, we report the computed tomography appearance of a unique variant in which the right ureter partially encircles the right common iliac artery bifurcation; passing first in front of the common iliac artery and then medial to the artery and finally posterior to the external iliac artery, and then regains its normal course in the pelvis. PMID- 26627376 TI - Mapping the heparin-binding site of the osteoinductive protein NELL1 by site directed mutagenesis. AB - Neural epidermal growth factor-like (NEL)-like 1 (NELL1) is a secretory osteogenic protein comprising an N-terminal thrombospondin-1-like (TSPN) domain, four von Willebrand factor type C domains, and six epidermal growth factor-like repeats. NELL1 shows heparin-binding activity; however, the biological significance remains to be explored. In this report, we demonstrate that NELL1 binds to cell surface proteoglycans through its TSPN domain. Major heparin binding sites were identified on the three-dimensional structural model of the TSPN domain of NELL1. Mutant analysis of the heparin-binding sites indicated that the heparin-binding activity of the TSPN domain is involved in interaction of NELL1 with cell surface proteoglycans. PMID- 26627377 TI - Ochratoxin A-induced cytotoxicity, genotoxicity and reactive oxygen species in kidney cells: An integrative approach of complementary endpoints. AB - Ochratoxin A (OTA) is a well-known nephrotoxic and potential carcinogenic agent but no consensus about the molecular mechanisms underlying its deleterious effects has been reached yet. The aim of this study is to integrate several endpoints concerning OTA-induced toxicological effects in Vero kidney cells in order to obtain additional mechanistic data, especially regarding the influence of reactive oxygen species (ROS). One innovative aspect of this work is the use of the superoxide dismutase mimic (SODm) MnTnHex-2-PyP as a mechanistic tool to clarify the involvement of oxidative stress in OTA toxicity. The results showed concentration and time-dependent cytotoxic effects of OTA (crystal violet, neutral red and LDH leakage assays). While the SODm mildly increased cell viability, trolox and ascorbic acid had no effect with regards to this endpoint. OTA induced micronuclei formation. Using the FPG modified comet assay, OTA modestly increased the % of DNA in tail, revealing the presence of oxidative DNA lesions. This mycotoxin increased apoptosis, which was attenuated by SODm. In addition, the SODm decreased the ROS accumulation observed in DHE assay. Taken together, our data suggest that ROS partially contribute to the cytotoxicity and genotoxicity of OTA, although other mechanisms may be relevant in OTA-induced deleterious effects. PMID- 26627379 TI - [Trend in potentially avoidable hospitalisations for chronic conditions in Spain]. AB - OBJECTIVE: To analyse the trend in potentially avoidable hospitalisations (PAH) in frail patients or those with chronic conditions in Spain during the period 2002-2013. METHODS: An observational, ecological study was conducted to analyse the trend in age-sex standardised rates of PAH affecting six clinical conditions, and their variation, in the 203 health care areas composing the publicly-funded health system in Spain. RESULTS: During the period 2002-2013, overall PAH standardised rates decreased by 35%, but systematic variation remained moderately high, around 13% above that expected by chance. Angina admissions showed the largest reduction, followed by those for asthma and chronic obstructive pulmonary disease. In contrast, the prevalence of admissions for dehydration doubled. CONCLUSIONS: Despite the decrease in PAH rates, systematic variation among areas remains, indicating differences in chronic care management that lead to distinct healthcare outcomes. PMID- 26627380 TI - [Health education in primary school: Alicante city (Spain) teachers' opinions]. AB - OBJECTIVE: This study explores the opinions of primary school teachers about health activities carried out in schools in Alicante city (Spain). METHODS: An exploratory study was conducted through qualitative content analysis. Three focus groups were conducted with 25 primary school teachers (14 women and 11 men) working in 14 public and 7 private schools in the city of Alicante. Participants were asked about the health activities carried on in their schools. RESULTS: Teachers distinguished between health education activities promoted by the school and those included in external programmes promoted by public and private institutions. External programmes were considered as impositions, lacking continuity and chosen according to passing fads. Although teachers demonstrated a more positive attitude towards activities arising from their own initiative, they identified health education as a secondary task. Teachers considered that improving their own health education training and promoting the involvement of parents, health professionals and public institutions were the most appropriate ways to promote health education in the school. CONCLUSION: Teachers showed a more positive opinion and greater commitment towards health activities that complement and facilitate their teaching tasks. Their didactic programme and opinion should be taken into account to maximise the efficiency of the health promotion and education activities promoted by external organisations. PMID- 26627381 TI - [Efficiency of a pharmaceutical care program for long-acting parenteral antipsychotics in the health area of Santiago de Compostela]. AB - In the healthcare area of Santiago de Compostela (Spain), the therapeutic subgroup "other antipsychotics" represented the fifth largest outpatient expenditure in 2013. More than half of this expenditure corresponded to long acting parenteral forms of paliperidone and risperidone. Over a 12-month period, the implementation of a pharmaceutical care program based on process management and coordination of actions between health professionals in both levels of care represented savings of ? 636,391.01 for the organization and a direct saving of ? 16,767.36 and 9,008 trips to the pharmacy for patients. This study shows the efficiency of the program, which was facilitated by its situation in an area of integrated management and the use the unified medical records and electronic prescription, elements that will enable the future implementation of similar programmes. The new registries and healthcare interventions will allow reliable evaluation of their effectiveness in terms of treatment adherence, relapses and hospitalisations. PMID- 26627383 TI - Special Issue in Honor of Dennis R. Salahub for His 60th Birthday. PMID- 26627382 TI - Use of field data in pig genomic selection schemes: a simulation study. AB - The aim of this study was to test how genetic gain for a trait not measured on the nucleus animals could be obtained within a genomic selection pig breeding scheme. Stochastic simulation of a pig breeding program including a breeding nucleus, a multiplier to produce and disseminate semen and a production tier where phenotypes were recorded was performed to test (1) the effect of obtaining phenotypic records from offspring of nucleus animals, (2) the effect of genotyping production animals with records for the purpose of including them in a genomic selection reference population or (3) to combine the two approaches. None of the tested strategies affected genetic gain if the trait under investigation had a low economic value of only 10% of the total breeding goal. When the relative economic weight was increased to 30%, a combination of the methods was most effective. Obtaining records from offspring of already genotyped nucleus animals had more impact on genetic gain than to genotype more distant relatives with phenotypes to update the reference population. When records cannot be obtained from offspring of nucleus animals, genotyping of production animals could be considered for traits with high economic importance. PMID- 26627384 TI - Quantum Dynamics of Electron Transfer from Bacteriochlorophyll to Pheophytin in Bacterial Reaction Centers. AB - We extend our previous works on the early electron-transfer steps in bacterial photosynthetic reaction centers to the dynamics of electron transfer from the bacteriochlorophyll anion to pheophytin. The approach employed here takes into account the whole set of normal coordinates of the acceptor and donor groups, in order to reliably account both for shifts and mixing of the normal coordinates and for changes in vibrational frequencies upon electron transfer. It is shown that intramolecular modes provide not only a discrete set of states strongly coupled to the initial state but also a quasi-continuum of weakly coupled states, which account for faster dephasing effects. Detuning effects are accounted for by averaging the computed probability over a small range of the electronic energy difference. The computed transition probability is of the same order of magnitude, a few picoseconds, as the observed one. PMID- 26627385 TI - Theoretical Study of Intramolecular, CH [Formula: see text] X (X = N, O, Cl), Hydrogen Bonds in Thiazole Derivatives. AB - CH [Formula: see text] X (X = N, O, or Cl) hydrogen bonds formed intramolecularly in 2-methyl-4-(2-chloro-4,5-dimethoxyphenyl)thiazole (Ia), 2-amino-4-(2-chloro 4,5-dimethoxy phenyl)thiazole (Ib), 2-amino-4-(2,4,5-trimethoxyphenyl)thiazole (Ic), and 2-methyl-4-(2,4,5-trimethoxyphenyl)thiazole (Id) were studied by means of all-electron calculations performed with the B3LYP/6-311++G(d,p) method. Computed ground states, in the gas phase, show the presence of a single H-bond, CH [Formula: see text] Cl, in each Ia and Ib moiety, and two H-bonds, CH [Formula: see text] N and CH [Formula: see text] O, for each Ic and Id molecule. H [Formula: see text] Cl, H [Formula: see text] N, and H [Formula: see text] O distances are shorter than the sum of the X and H van der Waals radii. H-bond energies of ?2.0 kcal/mol were estimated for Ia and Ib and ?4.0 kcal/mol for Ic and Id. These results agree with those of the theory of atoms in molecules, since bond critical points were found for these H [Formula: see text] X bonds. Finally, the chemical shifts in the (1)H NMR were calculated by the GIAO method; in Ia and Ib they are merely due to the different topological positions of the H atoms. But in Ic and Id the shifts of H [Formula: see text] N and H [Formula: see text] O have signatures of H-bond formations. PMID- 26627386 TI - Electronic Structure of Trigonal-Planar Transition-Metal-Imido Complexes: Spin State Energetics, Spin-Density Profiles, and the Remarkable Performance of the OLYP Functional. AB - We have carried out a detailed multifunctional density functional theory study of first-row transition-metal (Cr to Cu) beta-diketiminato ("nacnac") imido and oxo complexes. All the complexes studied exhibit essentially the same d-orbital energy ordering, which is a1 (dx(2)-z(2)) <= a2 (dxy) <= a1 (dy2) < b2 (dyz) < b1 (dxz), where the metal-imido vector is identified with the z axis and metal-N3 plane is identified with the xz plane. A curious aspect of this orbital ordering is that the metal dx(2)-z(2) orbital, one of whose lobes points directly at the imido nitrogen, is considerably lower in energy than the dpi orbitals. We have determined that the remarkable stability of the dsigma-type orbitals owes largely to the way these orbitals hybridize or "shape-shift" as a result of the absence of ligands trans or equatorial with respect to the imido (or oxo) group. Of the many functionals examined, OLYP and OPBE, based on the Handy-Cohen OPTX exchange functional, appear to provide the best overall description of the spin-state energetics of the various complexes. In particular, these two functionals predict an S = (3)/2 ground state for Fe(III) nacnac imido complexes and an S = 0 ground state for Co(III) nacnac imido complexes, as observed experimentally. In contrast, classic pure functionals such as PW91 predict S = (1)/2 ground states or at best equienergetic S = (1)/2 and S = (3)/2 states for the Fe(III) imido complexes, while hybrid functionals such as B3LYP and O3LYP predict S = 1 or 2 ground states for the Co(III) nacnac imido complexes. PMID- 26627387 TI - On the Possibility of Electronic DNA Nanobiochips. AB - We have considered as a theoretical possibility for the development of a nanobiochip the operation principle of which is based on measuring conductance in single-stranded and double-stranded DNA. Calculations have demonstrated that in the majority of cases the conductance of double-stranded nucleotides considerably exceeds that of single-stranded ones. The results obtained are in agreement with recent experiments on measuring the oligonucleotide conductance. It has been shown that an electronic biochip containing 11 nucleotide pairs will recognize ~97% sequences. It has also been demonstrated that the percentage of identifiable sequences will grow with the sequence length. PMID- 26627388 TI - Metal-Molecule Interactions To Produce Hydrogen: What Do They Have in Common? AB - The main purpose of this work is to study metal-molecule interactions that can lead to the production of molecular hydrogen. Two systems were chosen for this analysis: yttrium atom and clusters interacting with the simple electron donor ammonia (NH3) and copper atoms and ions with imidazole. For yttrium with ammonia as well as for copper with imidazole there is a charge-transfer process from the metal to the molecule that promotes the dissociation of the hydrogen atoms. PMID- 26627389 TI - Density Functional Static Dipole Polarizability and First-Hyperpolarizability Calculations of Nan (n = 2, 4, 6, 8) Clusters Using an Approximate CPKS Method and its Comparison with MP2 Calculations. AB - We report the static dipole polarizability and first-hyperpolarizability of the sodium atom clusters, Nan, n = 2, 4, 6 and 8, using our recent implementation of a numerical-analytical approach to the coupled-perturbed Kohn-Sham (CPKS) equations in deMon2k. The calculations are reported for VWN and BP86 exchange correlation functionals using Sadlej and TZVP-FIP1 basis sets which have been previously optimized for polarizability calculations. All-electron calculations were performed for the optimizations at the VWN/DZVP/A2 and PW86/DZVP/A2 levels. Comparisons are made with Hartree-Fock (HF) and MP2 benchmark calculations. PMID- 26627390 TI - Peculiarities of the Electronic Structure of Cytochrome P450 Compound I: CASPT2 and DFT Modeling. AB - CASSCF/CASPT2 ab initio formalism has been applied to a thiolate model of cytochrome P450 compound I. A2u ground state of porphyrin radical character was found in agreement with experimental results. A strong mixing of CASSCF reference states in multistate CASPT2 was observed, which is an interesting phenomenon, rare for the ground state near the equilibrium geometry. Details of the CASSCF/CASPT2 procedure (including the construction of the active space) are discussed. Parallel DFT calculations revealed that relative energies and the scheme of spin coupling are qualitatively reproduced by hybrid DFT (B3LYP); however, results from nonhybrid functionals (BLYP, BP86) are significantly different in these aspects. PMID- 26627391 TI - Equilibrium Geometries of Noncovalently Bound Intermolecular Complexes Derived from Subsystem Formulation of Density Functional Theory. AB - The subsystem formulation of density functional theory is used to obtain equilibrium geometries and interaction energies for a representative set of noncovalently bound intermolecular complexes. The results are compared with literature benchmark data. The range of applicability of two considered approximations to the exchange-correlation- and nonadditive kinetic energy components of the total energy is determined. Local density approximation, which does not involve any empirical parameters, leads to excellent intermolecular equilibrium distances for hydrogen-bonded complexes (maximal error 0.13 A for NH3 NH3). It is a method of choice for a wide class of weak intermolecular complexes including also dipole-bound and the ones formed by rare gas atoms or saturated hydrocarbons. The range of applicability of the chosen generalized gradient approximation, which was shown in our previous works to lead to good interaction energies in such complexes, where pi-electrons are involved in the interaction, remains limited to this group because it improves neither binding energies nor equilibrium geometries in the wide class of complexes for which local density approximation is adequate. An efficient energy minimization procedure, in which optimization of the geometry and the electron density of each subsystem is made simultaneously, is proposed and tested. PMID- 26627392 TI - Improved meta-GGA Correlation Functional of the Lap Family. AB - A new correlation functional of the Lap series is derived based on a more elaborated form of correlation wave vectors. Its validation is carried out within two different codes: deMon-KS3 and Q-Chem 3.0. In deMon the implementation in a post-SCF manner is similar to the preceding BLap3 and Bmtau1 schemes. In Q-Chem the new functional is programmed self-consistently using the integration by parts procedure for the matrix elements. The post-SCF version of the functional deals with three fitting parameters; the previous Lap3 and tau1 functionals have four and five parameters, respectively. The SCF implementation requires only two fitting parameters. Preliminary comparative tests are discussed. PMID- 26627393 TI - Interaction between n-Alkane Chains: Applicability of the Empirically Corrected Density Functional Theory for Van der Waals Complexes. AB - The geometries, interaction energies, and vibrational frequencies of a series of n-alkane dimers up to dodecane have been calculated using density functional theory (DFT) augmented with an empirical dispersion energy term (DFT-D). The results obtained from this method for ethane to hexane dimers are compared with those provided by the MP2 level of theory and the combined Gaussian-3 approach with CCSD(T) being the highest correlation method [G3(CCSD(T))]. Two types of dimer isomers have been studied. The most stable isomers have the two carbon chains in parallel planes, whereas the second ones have the two carbon chains in the same plane. Butane is found to be the shortest carbon chain to form dimers with similar properties, that is, a constant average distance between the monomer carbon skeletons, a similar increment per CH2 unit for the dimer interaction energy, and comparable dimer symmetric stretching frequencies. The values and trends obtained from the DFT-D approach agree very well with those obtained from MP2 for the geometries and vibrational frequencies and from the G3(CCSD(T)) method for the energies, validating the use of DFT-D for the study of large hydrocarbon complexes. PMID- 26627394 TI - Restricted Ensemble-Referenced Kohn-Sham versus Broken Symmetry Approaches in Density Functional Theory: Magnetic Coupling in Cu Binuclear Complexes. AB - The performance of density functional theory in estimating the magnetic coupling constant in a series of Cu(II) binuclear complexes is investigated by making use of two open shell formalisms: the broken symmetry and the spin-restricted ensemble-referenced Kohn-Sham methods. The strong dependence of the calculated magnetic coupling constants with respect to the exchange-correlation functional is confirmed and found to be independent of whether spin symmetry is imposed or not. The use of a method which guarantees the spin state does not improve the correlation with the experiment and indeed shows some worsening due to an overestimation of the ferromagnetic interactions. However, with the present exchange-correlation functionals, a rather systematic deviation is found. Therefore, it would be possible to develop improved density functionals which will allow for a rigorous treatment of open shell systems in density functional theory. PMID- 26627395 TI - Structure and Electron Delocalization in Al4(2-) and Al4(4.). AB - Structure, dynamics, and electron delocalization of Al4(2-) and Al4(4-) based clusters are investigated. Gradient-corrected Density-Functional Born-Oppenheimer Molecular Dynamics simulations indicate that Al4(2-) based clusters have a rigid planar Al framework, while the Al4(4-) based moieties show large distortions from planarity. The induced magnetic field analysis of these species indicates that both systems have diatropic sigma-systems, while the pi-system is diatropic for Al4(2-) and paratropic for Al4(4-). The total magnetic response is diatropic for Al4(2-), while Al4(4-) is "bitropic": it has typical antiaromatic long-range cones, while the magnetic field in the Al4(4-) ring plane is similar to that of aromatic annulenes. PMID- 26627396 TI - Theoretical Study of the Magnetic Properties of an Mn12 Single-Molecule Magnet with a Loop Structure: The Role of the Next-Nearest Neighbor Interactions. AB - The magnetic properties of a Mn12 single-molecule magnet with a loop structure are characterized by a computational study based on density functional theory. A study of the two reported crystal structures of such a complex correctly reproduces the experimental spin ground state. We have analyzed the effect of the choice of spin configurations employed for the calculations, as well as the influence of the inclusion of the next-nearest neighbor interactions on the calculated exchange coupling constants. Quantum Monte Carlo simulations performed with the calculated exchange coupling constants show that the best agreement with the experimental susceptibility curve is achieved by using the hybrid B3LYP functional. PMID- 26627397 TI - DFT Method Estimation of Standard Redox Potential of Metal Ions and Metal Complexes. AB - The DFT method calculation was carried out to evaluate standard redox potential (SRP) for metal-to-metal cation and metal-to-metal complex systems. With the Born Haber cycle, standard redox potential was composed of the cohesive energy, ionization energy, and solvation energy. The ligand exchange energy was added in case of metal complex. The solvent effects were incorporated by the self consistent reaction field theory at the level of the polarized continuum model (PCM). At the highest level of calculations, the geometry optimization and harmonic frequency analysis were evaluated under the PCM. Utilizing experimental values of the cohesive energy of metals, the standard deviations between the calculated and experimental SRP values were 0.20-0.27 V depending on the calculation levels and basis sets used. For three Ag complexes with CN(-), S2O3(2 ), and NH3 ligands, the discrepancy was within 0.3 V. PMID- 26627398 TI - High-Density Limit of Two-Electron Systems: Results from the Extended Overhauser Approach. AB - The "extended Overhauser model" [Overhauser, A. W. Can. J. Phys. 1995, 73, 683] for the calculation of the spherically and system-averaged pair density (APD) has been recently combined with the Kohn-Sham equations to yield realistic APD and correlation energies. In this work we test this approach in the high-density (weakly correlated) limit of the He isoelectronic series and of the Hooke's atom isoelectronic series. Unlike many of the commonly used energy functionals, the Overhauser approach yields accurate correlation energies for both series. PMID- 26627399 TI - Radical-Induced Damage in 3'dTMP [Formula: see text] Insights into a Mechanism for DNA Strand Cleavage. AB - DNA strand scission and base release in 3'dTMP, induced by H and OH radical addition to thymine, is studied at the DFT B3LYP/6-31+G(d,p) level in the gas phase and in solution. In particular the mechanism of H atom transfer subsequent to radical formation, from C2' on the sugar to the C6 site on the base, is explored. Bulk solvation is found to lower the barrier by up to 5 kcal mol(-1) and the reaction energy by up to 12 kcal mol(-1) for the hydroxyl radical adducts. The strengths of the N1-C1'(N1-glycosidic bond) and C3'-O(P) bonds are calculated, showing that homolytic bond breaking processes are largely favored in both cases. The barrier for C3'-O(P) bond rupture is approximately 18.2 kcal mol( 1), and its breakage is preferred by 10-15 kcal mol(-1) over that of N1 glycosidic bond cleavage in both the gas phase and solvents, which is consistent with the changes in C3'-O(P) and N1-C1' bond lengths during the H transfer reactions. Mulliken spin densities, NPA charges, and vertical electron affinities are calculated to clarify the reactive properties of the intramolecular H transfer radicals. PMID- 26627400 TI - CO2 Activation by Nb(+) and NbO(+) in the Gas Phase. A Case of Two-State Reactivity Process. AB - Gas-phase carbon dioxide activation by Nb(+) and NbO(+) was studied at the density functional level of theory using the hybrid exchange correlation functional B3LYP. Three reaction profiles corresponding to the quintet, triplet, and singlet multiplicities were investigated in order to ascertain the presence of some spin inversion during the CO2 reduction. Carbon dioxide activation mediated by metal cations was found to be an exothermic spin-forbidden process resulting from a crossing between quintet and triplet energetic profiles. The endothermic reaction of NbO(+) with carbon dioxide was a barrierless process involving spin inversion. Geometries of minima along potential energy surfaces and reaction heats were in agreement with those from experimental studies carried out by using a guided ion beam tandem mass spectrometer. PMID- 26627401 TI - Lewis Acid and Substituent Effects on the Molecular Mechanism for the Nazarov Reaction of Penta-1,4-dien-3-one and Derivatives. A Topological Analysis Based on the Combined Use of Electron Localization Function and Catastrophe Theory. AB - The joint use of the topological analysis provided by the electron localization function (ELF) and catastrophe theory (CT), at the B3LYP/6-31G(d) calculation level, allows us to examine the Lewis acid (protonation H(+) and presence of BH3) and the role of an electron donor substituent (-OCH3) at alpha and beta positions along the course of the molecular mechanism for the Nazarov rearrangement of penta-1,4-dien-3-one and eight derivatives. The progress of the reaction is monitored by the changes of the ELF structural stability domains (SSDs), each change being controlled by a turning point derived from CT. These SSDs and the corresponding turning points are associated with a sequence of elementary chemical steps. Along the cyclization path of penta-1,4-diene-3-one, four SSDs as well as three turning points (cusp1-fold1-cusp2) have been characterized. The first and second SSDs correspond to a polarization of the C-O bond and electronic redistribution among the C-C bonds, respectively, and they can be associated with the formation of an oxyallyl structure. The third and fourth SSDs can be assigned to the ring closure process. Protonation of the oxygen atom shifts the reactive directly into the second SSD, greatly reducing the activation and reaction energies. The electronic effects due to Lewis acids and electron donor substituents have been rationalized in terms of calculations of mesomeric structures from ELF basin populations. The combination of Lewis acids together with alpha and beta -OCH3 substitutions renders a cooperative and competitive effect on activation and reaction free energies, respectively. PMID- 26627402 TI - Toward a Separate Reproduction of the Contributions to the Hartree-Fock and DFT Intermolecular Interaction Energies by Polarizable Molecular Mechanics with the SIBFA Potential. AB - Following recent refinements of the SIBFA intermolecular potential to the multipolar electrostatic contribution by inclusion of an explicit 'penetration' component, the short-range repulsion term is augmented with a S(2)/R(2) component. The SIBFA potential, and the behaviors of its individual contributions encompassing polarization and charge transfer, were evaluated in a diversity of hydrogen-bonded complexes as well as in a model stacked complex by comparisons with results from ab initio quantum-chemical (QC) computations with energy decomposition. Close agreements between SIBFA and QC results are found on both the interaction energies and their contributions. Extensions to computations at the DFT level are also presented. PMID- 26627403 TI - New Investigations of Geometric, Electronic, and Spectroscopic Properties of Tetrapyrrolic Macrocycles by a TD-DFT Approach. Carbon, Nitrogen, and Chalcogen (O, S, Se) Peripheral Substitution Effects on Ni(II) Porphyrazinato Complexes. AB - The electronic structure of five complexes [M(oXHpz)] [M = Ni(2+); oXHpz(2)(-) = 2,3,7,8,12,13,17,18-octakis-substituted (X = CH2, NH, O, S, Se)-5,10,15,20 tetraazaporphyrinate dianion] has been investigated using a density functional approach. All the geometries have been obtained minimizing the total intramolecular energy using a nonlocal hybrid functional (B3LYP) at the 6-31g* level. The electronic configuration of Ni(2+) is (dx(2) y(2))(0)(dxy)(2)(dxz,dyz)(4)(dz(2))(2). Optimized geometries exhibit a planar conformation and are all above the threshold for ruffling, which is described by a Ni-Np bond distance of 1.85-1.87 A for sterically unhindered porphyrazines. Indeed, the smallest bond distance is 1.880 A for Ni(oOHpz). Peripheral substituents yield modifications to the "core" of the macrocycle and to the energy levels, changing sigma and pi interactions. Furthermore, within a time dependent density functional theory approach, excited states of Ni(oXHpz) [X = CH2, NH, O, S, Se,] complexes have been studied and compared with available experimental UV-vis spectra. PMID- 26627404 TI - Vibronic Quasi-Free Rotation Effects in Biphenyl-Like Molecules. TD-DFT Study of Bifluorene. AB - In this paper, we investigate the vibronic shape of the lowest UV-visible absorption band of biphenyl-like systems, using the bifluorene molecule as a workhorse. The molecule is here regarded as a one-dimensional two-level system, whose ground and excited states are simulated with time-dependent density functional theory and semiempirical methods. The vibrational Schrodinger equation is then numerically solved along the torsional coordinate, and the vibronic shape of the absorption band is modeled. Comparisons with the harmonic approximation, with or without the Franck-Condon approximation, are performed. This study confirms that a vibronic effect is most likely responsible for the strong dissymmetry of the lowest UV-visible absorption band of biphenyl-like systems and that, for such systems, the experimental data should be extracted using the whole absorption band, instead of a Gaussian fit on the first part of the band, as it is often done when a superposition between several electronic transitions is suspected. PMID- 26627405 TI - Absorption Spectra of the Potential Photodynamic Therapy Photosensitizers Texaphyrins Complexes: A Theoretical Analysis. AB - A systematic study of a class of divalent transition-metal texaphyrin complexes (M-Tex(+), M = Mn, Fe, Co, Ni, Cu, Zn), recently proposed as active photosensitizers in photodynamic therapy (PDT), was undertaken for the ground and excited electronic states. Geometry optimizations were performed by using the PBE0 exchange-correlation functional coupled with the 6-31G(d) basis set, while electronic excitations energies were evaluated by means of time-dependent density functional response theory (TD-DFT) at the PBE0/6-31+G(d) // PBE0/6-31G(d) level of theory. Solvent effects on excitation energies were taken into account in two ways: by considering solvent molecules explicitly coordinated to the metal center and as bulk effects, within the conductor-like polarizable continuum model (C-PCM). The influence of the metal cation on the so-called Q-band, localized in the near-red visible region of the spectrum, was carefully examined since it plays a basic role in the drug design of new photodynamic therapy photosensitizers. The differences between experimental and computed excitation energies were found to be within 0.3 eV. PMID- 26627406 TI - Optical Properties of Phthalocyanine and Naphthalocyanine Compounds. AB - Phthalocyanines, naphthalocyanins, and their derivatives are frequently used as light modulating materials. These compounds, with their stable planar square structure and highly delocalized pi-electron system, are being used in numerous technological applications, such as pigments in chemical sensors, and more recently as photosensitizers for photodynamic therapy. The nonlinear optical properties (NLO) of these compounds are of particular importance. Using density functional method (DFT), we calculated the optical properties of phthalocyanine and naphthalocyanine complexes with Si as a central atom. We examined the effect of hydrophilic axial substituents and the size of polycyclic aromatic hydrocarbons surrounding the porphyrazine-Si kernel on the optical properties of title molecules. Both UV-vis and RSA spectra are calculated and are compared with available experimental results. The time-dependent DFT (TDDFT) with the B3LYP functional predicts that the characteristic UV-vis absorption maxima are blue shifted; however, the relative error is almost constant for phthalocyanine and naphthalocyanine compounds. The TDDFT triplet-triplet absorption spectra of Si phthalocyanine and Si-naphthalocyanine complexes reproduce experimental data well. PMID- 26627407 TI - Dissociative Adsorption of Hydrogen and Oxygen on Palladium Clusters: A Comparison with the (111) Infinite Surface. AB - We report a density-functional study of some properties of the dissociative interaction of hydrogen and oxygen molecules on small palladium clusters (n = 5, 7, and 10). The calculated physisorption and chemisorption energies are compared with those of the infinite (111) palladium surface. First, adsorption of atomic hydrogen and oxygen is investigated on the Pd5, Pd7, and Pd10 clusters. Second, the interaction between H2 (O2) and the small Pd5 cluster is examined and compared to the process occurring on an infinite (111) surface. Finally, the simultaneous adsorption of two hydrogen (oxygen) atoms is analyzed in detail. As shown in a previous work, the binding energy of the first hydrogen (oxygen) atom does not depend significantly on the cluster size, and small two-layer clusters (n <= 10) can be used to determine with accuracy the interaction of atomic adsorbates with an infinite (111) palladium surface. In this study, we show that the dissociative chemisorption of H2 and more especially of O2 on a small palladium cluster may lead to erroneous binding energy: the cluster's size may prevent an accurate description of the adsorbate-adsorbate interaction as a function of their distance. It is demonstrated that a good choice of both the size and the shape of the cluster is preponderant for a good description of the dissociative adsorption of H2 and O2 on an infinite (111) surface. PMID- 26627408 TI - Backbone Importance for Protein-Protein Binding. AB - Although a number of studies have focused on the physical and chemical properties of protein-protein interfaces of complexes to determine their unique features, the importance of the backbone hydrogen bonds to protein-protein binding has been neglected due to the difficulty of quantitatively measuring their contribution to the free binding energy. In this study we are presenting a computational approach that allows the estimation of the contribution to the free binding energy of the CO and NH groups of the backbone of various proteic complexes. A correlation between the quantitative calculated free binding energy contribution of the CO and NH backbone groups of the interfacial residues and the qualitative values expected for this kind of interaction was achieved. The contribution of the backbone to the DeltaDeltaGbinding is significant. The average DeltaDeltaGbinding contribution of the intermolecular hydrogen bonds of the backbone is 1.77 kcal/mol, which is very similar to the average contribution of the different side chains to the DeltaDeltaGbinding, with a value of 1.75 kcal/mol. Therefore, the application of this computational approach as well as an alanine scanning mutagenesis study is essential to a more detailed comprehensive knowledge of proteic complex formation. PMID- 26627409 TI - Density Functional Study of 2-[(R-Phenyl)amine]-1,4-naphthalenediones. AB - The molecular and electronic structures of a series of 2-[(R-phenyl)amine]-1,4 naphthalenediones (R = m-Me, p-Me, m-Et, p-CF3, p-Hex, p-Et, m-F, m-Cl, p-OMe, p COMe, p-Bu, m-COOH, p-Cl, p-COOH, p-Br, m-NO2, m-CN, and p-NO2) and their anions are investigated in the framework of density functional theory. The calculations are of all-electron type using a double zeta valence polarization basis set optimized for density functional theory methods. The theoretical study shows that all compounds are nonplanar. The nonplanarity can be rationalized in terms of occupied pi orbitals. A linear correlation between the measured half-wave potentials and the calculated gas-phase electron affinities is found. It holds for local as well as generalized gradient corrected functionals. Structural parameters, harmonic vibrational frequencies, and adiabatic and vertical electron affinities as well as orbital and spin density plots of the studied compounds are presented. PMID- 26627410 TI - Density Functional Study of the Structure and Properties of Cu9 and Cu9(-) . AB - This work presents a study of the structure of neutral and anionic copper cluster nonamers with density functional theory calculations. The structure optimization and frequency analysis were performed at the local density approximation (LDA) level of theory with the exchange correlation functional by Vosko, Wilk, and Nusair (VWN). Improved calculations for the structure stability were based on the generalized gradient approximation (GGA) where the exchange correlation functional of Perdew and Wang (PW) was used. For both neutral and anionic clusters, new isomers are found that are more stable than those already presented in the literature. Adiabatic and vertical electron affinities are calculated and compared with the experimental value reported for Cu9. The calculated values are in good agreement with the available experimental data. An analysis of the most relevant molecular orbitals (MOs) of the low-lying neutral and anionic copper cluster nonamers is reported, too. PMID- 26627412 TI - Trends in Energies and Geometric Structures of Neutral and Charged Aluminum Clusters. AB - The minimum energy geometric structures of Aln, A[Formula: see text] , and A[Formula: see text] (4 <= n <= 15) are predicted from the results of "Tabu Search" (TS) global optimizations performed directly on the BPW91/LANL2DZ potential energy surface. In 24 of the 36 cases investigated, the TS delivered a lower energy structure than previously reported, in one case (A[Formula: see text] ) it failed to find the global minimum, and in the remaining 11 cases TS confirmed previous structures. All clusters (with 4 <= n <= 15) have the lowest spin state as their ground state except Al4 (triplet), A[Formula: see text] (quartet), A[Formula: see text] (triplet), and maybe A[Formula: see text] (singlet and triplet are degenerate). The 20-electron A[Formula: see text] and 40 electron A[Formula: see text] clusters are relatively stable compared to other clusters, on several criteria; to a lesser degree, Al7, Al12, and A[Formula: see text] are also stable. PMID- 26627411 TI - Quantum Chemical Description of Oxygen Activation Process on Co, Mn, and Mo Porphyrins. AB - The aim of the present theoretical study is to examine the dioxygen activation process occurring at the metalloporphyrin complexes as the first step of the selective oxidation of hydrocarbons, with the stress put on how this may be affected by the type of the central metal. In order to do so, the properties of the porphyrin complexes of Mn, Mo, and Co are discussed by means of quantum chemical calculations within Density Functional Theory (DFT). As a first step, the dioxygen binding by the above-mentioned systems is considered, followed by the study of the interactions of one and two hydrogen atoms with different types of the adsorbed O2 molecule onto the porphyrin complex. Finally, the stability of the formed oxo species is discussed. PMID- 26627413 TI - Structural and Thermodynamic Analysis of the First Mononuclear Aqueous Aluminum Citrate Complex Using DFT Calculations. AB - Structural and thermodynamic properties of the mononuclear Al/citrate complexes have been theoretically investigated aiming to understand the coordination mechanism at an atomic level. GGA-DFT/PCM calculations have been performed for the different conformations and tautomers arising from the Al(3+) and citric acid (H3L) interaction in aqueous solution. The Gibbs reaction energies were estimated based on the reaction of the trigonal planar Al(OH)3 and H3L to form different Al citrate complexes. The estimated Gibbs free reaction energies for the [AlL], [AlHL](+), and [Al(OH)L](-) species are in good agreement with the experimental values. In these species, the Al(3+) center is coordinated by two carboxylic and the tertiary hydroxyl groups of the citrate. Conversely to what has been proposed based on the experiments, the present theoretical calculations indicate that the citric acid hydroxyl group remains protonated upon the coordination of Al(3+). In fact, our model turns out to be more consistent with the relative pKa values of citrate protonation groups and with the hydrolysis constant of the H2O bound to Al(3+) leading to better agreement with the available experimental data. PMID- 26627414 TI - Global Potential Energy Surfaces with Correct Permutation Symmetry by Multiconfiguration Molecular Mechanics. AB - In the framework of the previously developed multiconfiguration molecular mechanics (MCMM) method, we present a new algorithm for constructing global potential energy surfaces that are invariant with respect to the exchange of identical nuclei. We illustrate the new algorithm by its application to the HOH' ' + H' -> OH + H'H' ', OH' + HH' ', OH' ' + HH', HOH' + H' ', and H' 'OH' + H reactions. As part of the MCMM methodology, the new scheme can be used to generate multidimensional global PESs for both small and large systems where a few reaction pathways need to be treated as symmetrically equivalent. PMID- 26627415 TI - An Integrated Path Integral and Free-Energy Perturbation-Umbrella Sampling Method for Computing Kinetic Isotope Effects of Chemical Reactions in Solution and in Enzymes. AB - An integrated centroid path integral and free-energy perturbation-umbrella sampling (PI-FEP/UM) method for computing kinetic isotope effects (KIEs) for chemical reactions in solution and in enzymes is presented. The method is based on the bisection sampling in centroid path integral simulations to include nuclear quantum effects to the classical potential of mean force. The required accuracy for computing kinetic isotope effects is achieved by coupled free-energy perturbation and umbrella sampling for reactions involving different isotopes. The use of FEP with respect to different masses results in relatively small statistical uncertainties, whereas if KIEs are computed directly by the difference in free energies obtained from the quantum mechanical potentials of mean force for different isotopes, the statistical errors are significantly greater. The PI-FEP/UM method is illustrated in two applications. The first reaction is the decarboxylation of N-methyl picolinate in water, for which the primary (13)C and secondary (15)N KIEs have been determined. The second reaction is the proton-transfer reaction between nitroethane and an acetate ion in water. In both cases, the computational results are in accord with experimental data, and the findings provide further insight into the mechanism of these reactions in water. PMID- 26627416 TI - Validation of Molecular Dynamics Simulations of Biomolecules Using NMR Spin Relaxation as Benchmarks: Application to the AMBER99SB Force Field. AB - Biological function of biomolecules is accompanied by a wide range of motional behavior. Accurate modeling of dynamics by molecular dynamics (MD) computer simulations is therefore a useful approach toward the understanding of biomolecular function. NMR spin relaxation measurements provide rigorous benchmarks for assessing important aspects of MD simulations, such as the amount and time scales of conformational space sampling, which are intimately related to the underlying molecular mechanics force field. Until recently, most simulations produced trajectories that exhibited too much dynamics particularly in flexible loop regions. Recent modifications made to the backbone phi and psi torsion angle potentials of the AMBER and CHARMM force fields indicate that these changes produce more realistic molecular dynamics behavior. To assess the consequences of these changes, we performed a series of 5-20 ns molecular dynamics trajectories of human ubiquitin using the AMBER99 and AMBER99SB force fields for different conditions and water models and compare the results with NMR experimental backbone N-H S(2) order parameters. A quantitative analysis of the trajectories shows significantly improved agreement with experimental NMR data for the AMBER99SB force field as compared to AMBER99. Because NMR spin relaxation data (T1, T2, NOE) reflect the combined effects of spatial and temporal fluctuations of bond vectors, it is found that comparison of experimental and back-calculated NMR spin-relaxation data provides a more objective way of assessing the quality of the trajectory than order parameters alone. Analysis of a key mobile beta hairpin in ubiquitin demonstrates that the dynamics of mobile sites are not only reduced by the modified force field, but the extent of motional correlations between amino acids is also markedly diminished. PMID- 26627417 TI - Dependence of Spurious Charge-Transfer Excited States on Orbital Exchange in TDDFT: Large Molecules and Clusters. AB - Time-dependent density functional theory (TDDFT) is a powerful tool allowing for accurate description of excited states in many nanoscale molecular systems; however, its application to large molecules may be plagued with difficulties that are not immediately obvious from previous experiences of applying TDDFT to small molecules. In TDDFT, the appearance of spurious charge-transfer states below the first optical excited state is shown to have significant effects on the predicted absorption and emission spectra of several donor-acceptor substituted molecules. The same problem affects the predictions of electronic spectra of molecular aggregates formed from weakly interacting chromophores. For selected benchmark cases, we show that today's popular density functionals, such as purely local (Local Density Approximation, LDA) and semilocal (Generalized Gradient Approximation, GGA) models, are qualitatively wrong. Nonlocal hybrid approximations including both semiempirical (B3LYP) and ab initio (PBE1PBE) containing a small fraction (20-25%) of Fock-like orbital exchange are also susceptible to such problems. Functionals that contain a larger fraction (50%) of orbital exchange like the early hybrid (BHandHLYP) are shown to exhibit far fewer spurious charge-transfer (CT) states at the expense of accuracy. Based on the trends observed in this study and our previous experience we formulate several practical approaches to overcome these difficulties providing a reliable description of electronic excitations in nanosystems. PMID- 26627418 TI - Quartic-Scaling Analytical Energy Gradient of Scaled Opposite-Spin Second-Order Moller-Plesset Perturbation Theory. AB - The analytical gradient of the "scaled opposite spin" (SOS-) and "modified opposite spin" (MOS-) second-order Moller-Plesset perturbation theory (MP2) methods is derived and implemented. Both energy and the first derivative can be evaluated efficiently with a fourth-order scaling algorithm by using a combination of auxiliary basis expansions and Laplace transformation techniques as opposed to the traditional fifth-order approach of MP2. A statistical analysis of 178 small molecules suggests that the new gradient scheme provides geometries of MP2 quality, indicating the reliability of the method in general chemical applications. A more specific study of the group VI transition metal carbonyl complexes indicates that the new scheme improves the MP2 description relative to available experimental data and higher-order theories. The proposed gradient scheme thus endeavors to obtain improved structural features at reduced computational cost. PMID- 26627419 TI - Fitting Molecular Electrostatic Potentials from Quantum Mechanical Calculations. AB - We develop here a new method to fit the molecular electrostatic potentials obtained in quantum mechanical calculations to a set of classical electrostatic multipoles, usually point charges located at atomic positions. We define an object function of fitting as an integration of the difference of electrostatic potentials in the entire 3-dimensional physical space. The object function is thus rotationally invariant with respect to the molecular orientation and varies smoothly with respect to molecular geometric fluctuations. Compared with commonly employed methods such as the Merz-Singh-Kollman and CHELPG schemes, this new method, while possessing comparable accuracy, shows greatly improved numerical stability with respect to the molecular positions and geometries. The method can be used in the fitting of electrostatic potentials for the molecular mechanics force fields and also can be applied to the calculation of electrostatic polarizabilites of molecular or atomic systems. PMID- 26627420 TI - Semiempirical Molecular Orbital Scheme To Study Lanthanide(III) Complexes: PM3 Parameters for Europium, Gadolinium, and Ytterbium. AB - Semiempirical parameters for europium, gadolinium, and ytterbium have been developed for use in the PM3 method to allow the structure and energetics of complexes containing lanthanide(III) ions to be accurately modeled. At the semiempirical level, the lanthanide(III) ion is represented by a +3 core and has a minimal basis of 6s5d6p (9 atomic orbitals), the 4f electrons being included within the electronic core. Training sets containing up to 19 lanthanide complexes, with data computed at the density functional theory (DFT) level, have been employed for each lanthanide(III) ion. A gradient-based optimization algorithm has been used, and important modifications of the core repulsion function have been highlighted. The derived parameters lead in general to good predictions of the structure of the complexes and demonstrate improvements in the prediction of water binding energies compared to the AM1/sparkle model. For the 28 Eu(III), 28 Gd(III), and 29 Yb(III) complexes optimized at the DFT level, the PM3 average unsigned mean errors for all interatomic distances between the lanthanide(III) ion and the ligand atoms of the first coordination sphere are 0.04, 0.03, and 0.03 A, respectively. The derived parameters are shown to be comparable to small-basis set DFT calculations in predicting the experimental structures of various lanthanide(III) complexes. The derived parameter sets provide a starting point should greater accuracy for a more restricted range of compounds be required. PMID- 26627421 TI - Computation of Accurate Activation Barriers for Methyl-Transfer Reactions of Sulfonium and Ammonium Salts in Aqueous Solution. AB - The energetics of methyl-transfer reactions from dimethylammonium, tetramethylammonium, and trimethylsulfonium to dimethylamine were computed with density functional theory, MP2, CBS-QB3, and quantum mechanics/molecular mechanics (QM/MM) Monte Carlo methods. At the CBS-QB3 level, the gas-phase activation enthalpies are computed to be 9.9, 15.3, and 7.9 kcal/mol, respectively. MP2/6-31+G(d,p) activation enthalpies are in best agreement with the CBS-QB3 results. The effects of aqueous solvation on these reactions were studied with polarizable continuum model, generalized Born/surface area (GB/SA), and QM/MM Monte Carlo simulations utilizing free-energy perturbation theory in which the PDDG/PM3 semiempirical Hamiltonian for the QM and explicit TIP4P water molecules in the MM region were used. In the aqueous phase, all of these reactions proceed more slowly when compared to the gas phase, since the charged reactants are stabilized more than the transition structure geometries with delocalized positive charges. In order to obtain the aqueous-phase activation free energies, the gas-phase activation free energies were corrected with the solvation free energies obtained from single-point conductor-like polarizable continuum model and GB/SA calculations for the stationary points along the reaction coordinate. PMID- 26627422 TI - Active-Space Equation-of-Motion Coupled-Cluster Methods through Quadruples for Excited, Ionized, and Electron-Attached States. AB - Several variants of the equation-of-motion coupled-cluster (EOM-CC) method with singles (one-hole or one-particle), doubles (two-hole-one-particle or two particle-one-hole), and a selected set of triples (three-hole-two-particle or three-particle-two-hole) and/or quadruples (four-hole-three-particle or four particle-three-hole) have been implemented by computerized symbolic algebra. They are applicable to excitation energies (EE), ionization potentials (IP), and electron affinities (EA), excited-state dipole moments, and transition dipole moments of both closed- and open-shell species and are abbreviated as EE/IP/EA EOM-CCSDt, EE/IP/EA-EOM-CCSDtq, and EE/IP/EA-EOM-CCSDTq, where the small letters indicate the use of active-space cluster and EE/IP/EA operators. They are also parallel executable and accelerated by the use of spin, spatial, and permutation symmetries. The remarkable effectiveness of the methods in capturing nondynamical correlation effects has been demonstrated by their applications to the vertical excitation energies of C2, the adiabatic excitation energies and dipole moments of the CH radical, the adiabatic excitation energies of the CH2 diradical, the adiabatic excitation energies and dipole moments of formaldehyde, the vertical ionization energies of N2, and the vertical electron affinities of C2. The effectiveness is found to decline when the basis set is extended, causing the active space to become relatively small and also less well-defined. As a remedy, we propose a composite method that combines higher-rank active-space methods with smaller basis sets for nondynamical correlation and lower-rank nonactive-space methods with larger basis sets for dynamical correlation, which is shown to work well for an excited-state potential energy curve of hydrogen fluoride. PMID- 26627423 TI - Self-Consistent Strictly Localized Orbitals. AB - Among all the Quantum Mechanics/Molecular Mechanics (QM/MM) methods available to describe large molecular systems, the Local Self-Consistent Field/MM (LSCF/MM) one uses frozen doubly occupied Strictly Localized Bonding Orbital (SLBO) to connect the QM fragment to the one treated at the MM level. This approach is correct as long as the QM part is large enough to minimize the artifacts that could arise because of the fixed SLBO. If one wants to decrease the size of the QM subsystem, one clearly needs to help the SLBO to relax according to the variations of the global wave function. Also, the SLBO have to adjust itself according to the modification of the surrounding if we want to improve the method. Here, we present a modification of the original LSCF method called Optimized LSCF (OLSCF) where each SLBO is allowed to mix with its corresponding Strictly Localized Anti Bonding Orbital (SLABO) resulting in an adjustment of the two-electron bond described by a self-consistent SLBO (SCSLBO). We test the new methodology against the modification of the QM part (internal perturbation) and against the variation of the surroundings (external perturbation) represented either by a dielectric continuum or by a classical point charge. In each case the initial SLBO is the symmetric C-C SLBO of the ethane molecule. It is shown that the optimized SCSLBO presents a final polarity in perfect agreement with what could be expected as the result of a reaction to the internal or external perturbation. PMID- 26627424 TI - The Hydrated Electron as a Pseudo-Atom in Cavity-Bound Water Clusters. AB - Anionic water clusters, (H2O)n(-), of various sizes, n = 1-8, have been investigated using high-level ab initio calculations and the quantum theory of atoms in molecules, which provides a topological analysis of the electron density. The results of the current study indicate that the distribution of the excess electron is dependent on the geometry of the cluster. Non-nuclear attractors (NNAs), with associated pseudo-atomic basins and populations, are observed only in the highly symmetric clusters in which several non-hydrogen bonded (NHB) hydrogen atoms are oriented toward a central cavity. For the latter cases, the non-nuclear attractor can be considered a pseudo-atom, possessing a significant portion of the excess electron within the cavity, consistent with the cavity-bound model of the solvated electron. In some cases, the population of the NNA is more than 0.2 electrons, and it contributes in excess of 20 kJ/mol to the energy of the system. Furthermore, the less symmetric systems, which tend to orient the NHB hydrogen atoms away from the center of the cluster, tend to delocalize the excess electron to a greater extent over several atoms at the surface of the cluster, consistent with the surface-bound model of the excess electron. PMID- 26627425 TI - Exploiting QM/MM Capabilities in Geometry Optimization: A Microiterative Approach Using Electrostatic Embedding. AB - We present a microiterative adiabatic scheme for quantum mechanical/molecular mechanical (QM/MM) energy minimization that fully optimizes the MM part in each QM macroiteration. This scheme is applicable not only to mechanical embedding but also to electrostatic and polarized embedding. The electrostatic QM/MM interactions in the microiterations are calculated from electrostatic potential charges fitted on the fly to the QM density. Corrections to the energy and gradient expressions ensure that macro- and microiterations are performed on the same energy surface. This results in excellent convergence properties and no loss of accuracy compared to standard optimization. We test our implementation on water clusters and on two enzymes using electrostatic embedding, as well as on a surface example using polarized embedding with a shell model. Our scheme is especially well-suited for systems containing large MM regions, since the computational effort for the optimization is almost independent of the MM system size. The microiterations reduce the number of required QM calculations typically by a factor of 2-10, depending on the system. PMID- 26627426 TI - Structural, Energetic, and Infrared Spectra Insights into Methanol Clusters (CH3OH)n, for n = 2-12, 16, 20. ONIOM as an Efficient Method of Modeling Large Methanol Clusters. AB - An investigation of gas-phase methanol clusters (CH3OH)n, where n = 2-12, 16, and 20, was completed with a range of computational methods: PM3, Hartree-Fock, B3LYP, MP2, and their combination using an ONIOM (our own n-layered integrated molecular orbital and molecular mechanics) method. Geometries, binding energies, and vibrational frequencies are reported. For all ab initio optimized structures, the cyclic isomer was found to be the most stable structure of all isomers investigated. The scaled OH frequency shift for n = 1-4 is found to be in good agreement with experimentally measured shifts. An ONIOM method, with the methyl group calculated at the low level and the hydroxyl group at the high level, proved to be an excellent way of reducing computational expense. The calculated enthalpies, geometries, and infrared spectra using an ONIOM method were comparable to that of a high-level calculation. Clusters were solvated using the integral equation formalism for the polarized continuum model method to compare with the microsolvation studies. PMID- 26627427 TI - Alchemical Variations of Intermolecular Energies According to Molecular Grand Canonical Ensemble Density Functional Theory. AB - Molecular grand-canonical density functional theory [J. Chem. Phys. 2006, 125, 154104] is employed for the alchemical variation of intermolecular energies due to changes in the chemical composition of small molecules. We investigate the interaction of a fixed binding target, formic acid, with a restricted chemical space, corresponding to an isoelectronic 10-proton system which includes molecules such as CH4, NH3, H2O, and HF. Differential expressions involving the nuclear chemical potential are derived, numerically evaluated, tested with respect to finite difference results, and discussed regarding their suitability as gradients of the intermolecular energy with respect to compositional variations. PMID- 26627428 TI - Stabilities and Spin Distributions of Benzannulated Benzyl Radicals. AB - The effects have been studied of mono- and dibenzannulation of a benzyl radical with hybrid density functional theory (B3LYP) and quadratic configuration interaction theory (QCISD). Bond dissociation energies and enthalpies are reported that were determined at the common level QCISD/6-311G**//B3LYP/6-31G* for the benzylic C-H bonds of toluene 1H, the monobenzannulated polycyclic aromatic hydrocarbons (PAH) 1- and 2-methylnaphthalene 2H and 3H, the dibenzannulated PAHs 9-methylanthracene 4H and 9-methylphenanthrene 5H, and the model hydrocarbons 1-phenylpropene 6H and propene 7H. The conformational preferences and the symmetries of 1H-7H and of their corresponding radicals 1-7 have been determined. The analysis of the electron and spin density distributions of radicals 1-7 at the QCI level are reported, and these high-level data are discussed in comparison to results obtained with density functional theory and with an awareness of a general perception shaped by Huckel molecular orbital theory. The results show in a compelling fashion that electron and spin delocalization onto an annulated arene is not the decisive principle for stabilization of the benzyl radicals formed by homolysis of the methylated PAHs C10H7-CH3 and C14H9-CH3, and instead, the analysis of QCI spin density distributions suggests that spin delocalization onto annulated arenes is avoided as much as possible while spin polarization does occur to a significant extent. PMID- 26627429 TI - Energy Conservation in Adaptive Hybrid Atomistic/Coarse-Grain Molecular Dynamics. AB - Multiscale computer simulation algorithms are required to describe complex molecular systems with events occurring over a range of time and length scales. True multiscale simulations must solve the interface, or hand-shaking, problem of coupling together different levels of description in different spatial regions of the system. If the spatial regions of different resolution move over time, or if material is allowed to flow over the inter-region boundaries, a mechanism must be introduced into the multiscale algorithm to allow material to dynamically change its representation. While such a mechanism is highly desirable in many instances, it is fraught with technical difficulties. Here, we present a molecular dynamics simulation algorithm which is multiscale in both time and space. We supplement the potential and kinetic energy expressions with auxiliary terms in order to recover the total energy as a conserved quantity, even when the total number of degrees of freedom changes during the simulation. This is crucial for a proper assessment of the quality of adaptive hybrid algorithms, and in particular, it allows us to tune the hierarchy of RESPA levels to optimize the integration scheme. PMID- 26627430 TI - Improving Docking Accuracy through Molecular Mechanics Generalized Born Optimization and Scoring. AB - Docking methods are typically used within the biopharmaceutical industry for the challenging purposes of suggesting putative binding modes of new chemotypes and for virtual screening. When attempting to satisfy the far more simplistic yet fundamentally important goal of reproducing and identifying the correct binding mode from a cocrystal, all docking methods fail at a rather significant rate, demonstrating room for further improvement in docking methodology. We report a hierarchical method that yields results comparable to the industry-leading docking packages GOLD, Glide, and Surflex. By first using a fast, simple, well established method, UCSF DOCK 4.0, to rigidly dock conformational ensembles, we successfully generate the correct binding mode in all but 4 of a standard, publicly available set of 79 cocrystals from the PDB. Among these 4 failures (1glq, 1tmn, 1rds, and 8gch), all are highly flexible, highly charged, and not druglike. Subsequently, all resultant docking poses were optimized and scored in the protein with molecular mechanics, using a standard MMGB energy function. In total, this hierarchical method identified the correct binding in 71 of 79 cases (90%), an unprecedented level of accuracy on this highly benchmarked test set. Furthermore, the publicly available energy functions employ only physically based force fields without parameter fitting from this or any other docking test sets. PMID- 26627431 TI - Additive and Classical Drude Polarizable Force Fields for Linear and Cyclic Ethers. AB - Empirical force field parameters consistent with the CHARMM additive and classical Drude based polarizable force fields are presented for linear and cyclic ethers. Initiation of the optimization process involved validation of the aliphatic parameters based on linear alkanes and cyclic alkanes. Results showed the transfer to cyclohexane to yield satisfactory agreement with target data; however, in the case of cyclopentane direct transfer of the Lennard-Jones parameters was not sufficient due to ring strain, requiring additional optimization of these parameters for this molecule. Parameters for the ethers were then developed starting with the available aliphatic parameters, with the nonbond parameters for the oxygens optimized to reproduce both gas- and condensed phase properties. Nonbond parameters for the polarizable model include the use of an anisotropic electrostatic model on the oxygens. Parameter optimization emphasized the development of transferable parameters between the ethers of a given class. The ether models are shown to be in satisfactory agreement with both pure solvent and aqueous solvation properties, and the resulting parameters are transferable to test molecules. The presented force field will allow for simulation studies of ethers in condensed phase and provides a basis for ongoing developments in both additive and polarizable force fields for biological molecules. PMID- 26627432 TI - Improved Boundary Element Methods for Poisson-Boltzmann Electrostatic Potential and Force Calculations. AB - A patch representation differing from the traditional treatments in the boundary element method (BEM) is presented, which we call the constant "node patch" method. Its application to solving the Poisson-Boltzmann equation (PBE) demonstrates considerable improvement in speed compared with the constant element and linear element methods. In addition, for the node-based BEMs, we propose an efficient interpolation method for the calculation of the electrostatic stress tensor and PB force on the solvated molecular surface. This force calculation is simply an O(N) algorithm (N is the number of elements). Moreover, our calculations also show that the geometric factor correction in the boundary integral equations significantly increases the accuracy of the potential solution on the boundary, and thereby the PB force calculation. PMID- 26627433 TI - Theoretical Investigation of Excited States of Oligothiophenes and of Their Monocations. AB - Excitation energies of neutral thiophene oligomers with chain lengths of up to 25 rings and charged thiophene oligomers with chain lengths of up to 20 rings were calculated with time-dependent Hartree-Fock and time-dependent density functional theory (TDDFT). As recently for polyene cations, very good agreement is found between TDDFT and high-level ab initio calculations and with experimental results wherever data are available. For short thiophene oligomer cations, two sub-band transitions are predicted; for long chains, a third transition develops. Defects are found to be delocalized in bare cations; the inclusion of counterions induces localization. Despite the strong influence of counterions on the geometry, the influence of counterions on the spectra is small for the first two sub-band peaks. Since counterions are directly involved in the electron transitions contributing to the third sub-band peak of longer oligomers, the inclusion of counterions lowers the energy of this absorption peak. The agreement between theoretical spectra based on delocalized geometries and experimental spectra shows that defect localization (electron phonon coupling) is not the underlying cause of the two sub-band transitions. Investigation of the electronic configurations that contribute to the excited states does not confirm the nature of the transitions predicted with the polaron model. PMID- 26627434 TI - Theory for Quantum Interference Signal from an Inhomogeneously Broadened Two Level System Excited by an Optically Phase-Controlled Laser-Pulse Pair. AB - A useful expression for the quantum interference (QI) signal was derived for an inhomogeneously broadened two-level system when it was excited by an optically phase-controlled laser-pulse pair. It was shown that the QI signal oscillates as a function of a relative optical phase, with the reduced angular frequency given by the relation omegaa = (Gamma(2)omega0 + gammag(2)Omega)/(gammag(2) + Gamma(2)), where gammag and Gamma are standard deviations of the system's absorption and the laser spectra both having a Gaussian line shape, respectively, and omega0 and Omega are the center angular frequency of the system absorption and the carrier angular frequency of the laser, respectively. PMID- 26627435 TI - Revised Implicit Solvent Model for the Simulation of Surfactants in Aqueous Solutions. 2. Modeling of Charged Headgroups at Oil-Water Interface. AB - The revised implicit solvent model (ISM-2) for the simulation of cationic surfactants in water was proposed in the previous study (J. Phys. Chem. B 2005, 109, 11762): no water molecules of the solvent are explicitly treated, and their effects are incorporated using the solvent-averaged interactions between the surfactant segments in water, where the interactions between the hydrocarbon sites of the surfactants are allowed to vary depending on their surroundings. In the present study, the representation of a charged headgroup at the liquid-liquid interface between the hydrocarbon oil and the implicit water has been improved, where the free energy change due to the transfer of the charged headgroup across the interface is taken into account. The present model (ISM-3) has been applied to the molecular dynamics simulations of (i) the single preformed micelle of 30 n decyltrimethylammonium chloride (C10TAC) cationic surfactants in water and (ii) 343 C10TAC surfactants uniformly dispersed in water, where the corresponding systems are also simulated using the ISM-2 for comparison. The first simulations showed that the ISM-3 as well as the ISM-2 is applicable to the simulation of the preformed micelle of the average aggregate size for C10TAC. The second simulations demonstrated that the ISM-3 can represent the surfactant self assembling plausibly, while the ISM-2 fails to do so because of the rude treatment of the charged headgroups at the interface. The results will be compared with those from experiments and atomistic model simulations. PMID- 26627436 TI - A Base-Sugar-Phosphate Three-Layer ONIOM Model for Cation Binding: Relative Binding Affinities of Alkali Metal Ions for Phosphate Anion in DNA. AB - A three-layer ONIOM approach was used to study the interactions of hydrated alkali metal ions such as Li(+), Na(+), and K(+) with a DNA fragment containing two phosphate groups, three sugar units, and a G**C base pair modeled in the anion and dianion states. Among the three metal-binding combinations studied herein (outer-sphere, inner-sphere monodentate, and inner-sphere bidentate), the outer-sphere binding mode showed the highest binding energy (BE) for hydrated Li(+) ions (103.1 kcal/mol) while the hydrated Na(+) and K(+) ions preferred the inner-sphere monodentate binding modes to the phosphate group of the anionic DNA fragment (BE = 87.9 and 98.2 kcal/mol for Na(+) and K(+), respectively). These data on the binding mechanisms of Li(+), Na(+), and K(+) ions and the higher binding affinity of Li(+) ions compared to Na(+) and K(+) ions in the anion model system of DNA are in good agreement with the previous experimental findings. On the other hand, in the dianion state, Li(+) preferred inner-sphere monodentate, whereas Na(+) and K(+) ions preferred the outer-sphere structures. The neutral anion model ion revealed a more realistic picture of DNA-alkali metal ion interactions compared to the non-neutral dianion model systems. PMID- 26627437 TI - De novo Folding of Two-Helix Potassium Channel Blockers with Free-Energy Models and Molecular Dynamics. AB - We report the predictive de novo folding of three two-helix proteins using the free-energy protein forcefield PFF01. Starting from random initial conformations 40-90% of the members of the simulated ensembles converge to near-native conformations. The energetically lowest conformations approach the conserved part of the native conformations to within 1.64, 1.86, and 1.84 A for 1WQC, 1WQD, and 1WQE, respectively. An analysis of the low-lying conformations predicts the correct topology of the disulfide bridges, which are formed in additional simulations with a constraining potential. The free energy landscapes of these proteins are very simple, suggesting them as candidates for all-atom molecular dynamics simulations. In five independent simulations we find the formation of the correct secondary structure and several folding events into the tertiary structure. PMID- 26627438 TI - Rapid, Accurate, and Precise Calculation of Relative Binding Affinities for the SH2 Domain Using a Computational Grid. AB - We describe and apply a method that reduces the time taken to calculate binding free energies using thermodynamic integration. This method uses a stack of grid software, which we call STIMD, that allows the scientist to easily distribute the necessary simulations around a computational grid thereby accelerating the process. We use this method to study how a series of phosphopeptides binds to the Src SH2 domain. The binding of phosphopeptides to the Src SH2 domain is described by the "two-pronged plug two-holed socket" model, and we investigate this model by reducing the length of the aliphatic side chain that engages the second of the two sockets through two successive alchemical mutations. Seven different values of DeltaDeltaG have been calculated, and we report good agreement with experiment. We then propose an extension to this model using the insights gained from a free energy component analysis. PMID- 26627439 TI - Calculation of a Complete Enzymic Reaction Surface: Reaction and Activation Free Energies for Hydride-Ion Transfer in Dihydrofolate Reductase. AB - We present a two-dimensional grid method for the calculation of complete free energy surfaces for enzyme reactions using a hybrid quantum mechanical/molecular mechanical (QM/MM) potential within the semiempirical (PM3) QM approximation. This implementation is novel in that parallel processing with multiple trajectories (replica-exchange molecular dynamics simulations) is used to sample configuration space. The free energies at each grid point are computed using the thermodynamic integration formalism. From the free-energy surface, the minimum free-energy pathway for the reaction can be defined, and the computed activation and reaction energies can be compared with experimental values. We illustrate its use in a study of the hydride-transfer step in the reduction of dihydrofolate to tetrahydrofolate catalyzed by Escherichia coli dihydrofolate reductase with bound nicotinamide adenine dinucleotide phosphate cofactor. We investigated the effects of changing the QM region, ionization state of the conserved active-site Asp27 residue, and polarization contributions to the activation and reaction free energy. The results clearly show the necessity for including the complete substrate and cofactor molecules in the QM region, and the importance of the overall protein (MM) electrostatic environment in determining the free energy of the transition state (TS) and products relative to reactants. For the model with ionized Asp27, its inclusion in the QM region is essential. We found that the reported [Garcia-Viloca, M.; Truhlar, D. G.; Gao, J. J. Mol. Biol. 2003, 327, 549] stabilization of the TS due to polarization is an artifact that can be attributed to truncation of the electrostatic interactions between the QM and MM atoms. For neutral (protonated) Asp27, our calculated reaction free energy of -4 +/- 2 kcal/mol agrees well with the experimental value of -4.4 kcal/mol, although the corresponding activation free-energy estimate is still high at 21 +/- 2 kcal/mol compared with the experimental value of 13.4 kcal/mol. The results are less supportive of the ionized Asp27 model, which gives rise to a much higher activation barrier and favors the reverse reaction. PMID- 26627440 TI - Structural and Energetic Properties of Organometallic Ruthenium(II) Diamine Anticancer Compounds and Their Interaction with Nucleobases. AB - We rationalize the chemoselectivity of the monofunctional ruthenium anticancer compound [(eta(6)-arene)Ru(II)(en)(OH2)](2+) (en=ethylenediamine; arene=benzene 1, p-cymene 2) toward guanine, using static DFT (BP86) and MP2 calculations together with Car-Parrinello molecular dynamics. The calculated binding energies for the three investigated nucleobases (G, A, C) decreases in the order G(N7) ? C(O2) ~ C(N3) > A(N7) > G(O6) > OH2. The G(N7) complex is the most stable product due to a hydrogen bond of its O6 with one of the H2N-amine groups of en, while the corresponding NH2-H2N(en) interaction in the adenine complex is repulsive. A very low rotational barrier of 0.17 kcal/mol (BP86) and 0.64 kcal/mol (MP2) was calculated for the arene rotation in [(eta(6)-C6H6)Ru(en)(Cl)](+) (3) allowing complexes containing arenes with bulky side chains like p-cymene to minimize steric interactions with, e.g., DNA by simple arene rotation. All [(eta(6) arene)Ru(en)(L)](2+) compounds exist in two stable conformers obtained for different diamine dihedral angle (NCCN) orientation, which, in the case of asymmetric ligands L, differ by up to ~2.8 kcal/mol. Car-Parrinello dynamics reveal a chelating transition state for the interconversion between N7 and O6 binding of guanine to [(eta(6)-arene)Ru(en)](2+). PMID- 26627441 TI - Stochastic Search for Isomers of the sec-Butyl Cation. AB - A stochastic search procedure for locating energy minimum structures was applied to the sec-butyl cation. A previously unreported structure 3' with strong H hyperconjugative stabilization of the carbocation center was found at several levels of theory (HF, B3LYP, and MP2). The theoretical equilibrium isotope effect (EIE) for the monodeutero isotopomer of 3' (Keq = 1.4; t = -130 degrees C) indicates that the new structure is likely to be largely responsible for the experimentally observed EIE. PMID- 26627442 TI - Polymorphisms in NADPH oxidase CYBA gene modify the risk of ESRD in patients with chronic glomerulonephritis. AB - End-stage renal disease (ESRD) was defined as start of renal replacement therapy or death due to kidney disease. However, death due to acute kidney injury was not included. It typically occurs when chronic renal failure progresses to a point where the kidneys are permanently functioning at less than 10% of their capacity. Oxidative stress (OS) plays a crucial role in ESRD. Nicotinamide adenine dinucleotide phosphate (NADPH) is one of the most important enzymes during oxidative stress. Cytochrome b light chain (CYBA), encoded by a polymorphic gene, which is a critical component of the nicotinamide adenine dinucleotide (NADH)/NADPH oxidase system and plays an important role in electron transport and superoxide anion production, is located on chromosome band 16q24 and has six exons spanning almost 7.76 kb of genomic DNA. CYBA gene polymorphisms can influence the activity of NADPH oxidase. To evaluate the association between CYBA gene polymorphisms and ESRD, we genotyped five CYBA polymorphisms using TaqMan allelic discrimination assay on DNA samples from 306 healthy controls and 332 patients with ESRD. Our results suggested that rs1049255 polymorphism of CYBA modified the risk of ESRD (p = 0.019; OR = 0.625; 95%CI = 0.424-0.921). GG genotype and G allele might be a protective factor against the risk of ESRD, especially in patients with chronic glomerulonephritis. PMID- 26627444 TI - Co-infections and transmission dynamics in a tick-borne bacterium community exposed to songbirds. AB - We investigated the transmission dynamics of a community of tick-borne pathogenic bacteria in a common European songbird (Parus major). Tick-naive birds were infested with three successive batches (spaced 5 days apart) of field-collected Ixodes ricinus nymphs, carrying the following tick-borne bacteria: Rickettsia helvetica (16.9%), Borrelia garinii (1.9%), Borrelia miyamotoi (1.6%), Anaplasma phagocytophilum (1.2%) and Candidatus Neoehrlichia mikurensis (0.4%). Fed ticks were screened for the pathogens after moulting to the next developmental phase. We found evidence for early transmission (within 2.75 days after exposure) of R. helvetica and B. garinii, and to a lesser extent of A. phagocytophilum based on the increased infection rates of ticks during the first infestation. The proportion of ticks infected with R. helvetica remained constant over the three infestations. In contrast, the infection rate of B. garinii in the ticks increased over the three infestations, indicating a more gradual development of host tissue infection. No interactions were found among the different bacterium species during transmission. Birds did not transmit or amplify the other bacterial species. We show that individual birds can transmit several pathogenic bacterium species at the same time using different mechanisms, and that the transmission facilitation by birds increases the frequency of co-infections in ticks. PMID- 26627443 TI - GigaTON: an extensive publicly searchable database providing a new reference transcriptome in the pacific oyster Crassostrea gigas. AB - BACKGROUND: The Pacific oyster, Crassostrea gigas, is one of the most important aquaculture shellfish resources worldwide. Important efforts have been undertaken towards a better knowledge of its genome and transcriptome, which makes now C. gigas becoming a model organism among lophotrochozoans, the under-described sister clade of ecdysozoans within protostomes. These massive sequencing efforts offer the opportunity to assemble gene expression data and make such resource accessible and exploitable for the scientific community. Therefore, we undertook this assembly into an up-to-date publicly available transcriptome database: the GigaTON (Gigas TranscriptOme pipeliNe) database. DESCRIPTION: We assembled 2204 million sequences obtained from 114 publicly available RNA-seq libraries that were realized using all embryo-larval development stages, adult organs, different environmental stressors including heavy metals, temperature, salinity and exposure to air, which were mostly performed as part of the Crassostrea gigas genome project. This data was analyzed in silico and resulted into 56621 newly assembled contigs that were deposited into a publicly available database, the GigaTON database. This database also provides powerful and user-friendly request tools to browse and retrieve information about annotation, expression level, UTRs, splice and polymorphism, and gene ontology associated to all the contigs into each, and between all libraries. CONCLUSIONS: The GigaTON database provides a convenient, potent and versatile interface to browse, retrieve, confront and compare massive transcriptomic information in an extensive range of conditions, tissues and developmental stages in Crassostrea gigas. To our knowledge, the GigaTON database constitutes the most extensive transcriptomic database to date in marine invertebrates, thereby a new reference transcriptome in the oyster, a highly valuable resource to physiologists and evolutionary biologists. PMID- 26627445 TI - Highly sensitive self-complementary DNA nanoswitches triggered by polyelectrolytes. AB - Dimerization of two homologous strands of genomic DNA/RNA is an essential feature of retroviral replication. Herein we show that a cationic comb-type copolymer (CCC), poly(L-lysine)-graft-dextran, accelerates the dimerization of self complementary stem-loop DNA, frequently found in functional DNA/RNA molecules, such as aptamers. Furthermore, an anionic polymer poly(sodium vinylsulfonate) (PVS) dissociates CCC from the duplex shortly within a few seconds. Then single stem-loop DNA spontaneously transforms from its dimer. Thus we can easily control the dimer and stem-loop DNA by switching on/off CCC activity. Both polyelectrolytes and DNA concentrations are in the nanomole per liter range. The polyelectrolyte-assisted transconformation and sequences design strategy ensures the reversible state control with rapid response and effective switching under physiologically relevant conditions. A further application of this sensitive assembly is to construct an aptamer-type drug delivery system, bind or release functional molecules responding to its transconformation. PMID- 26627446 TI - Targeting chemokine receptors for HIV: past, present and future. PMID- 26627447 TI - A Community "Hub" Network Intervention for HIV Stigma Reduction: A Case Study. AB - We describe the implementation of a community "hub" network intervention to reduce HIV stigma in the Tlokwe Municipality, North West Province, South Africa. A holistic case study design was used, focusing on community members with no differentiation by HIV status. Participants were recruited through accessibility sampling. Data analyses used open coding and document analysis. Findings showed that the HIV stigma-reduction community hub network intervention successfully activated mobilizers to initiate change; lessened the stigma experience for people living with HIV; and addressed HIV stigma in a whole community using a combination of strategies including individual and interpersonal levels, social networks, and the public. Further research is recommended to replicate and enhance the intervention. In particular, the hub network system should be extended, the intervention period should be longer, there should be a stronger support system for mobilizers, and the multiple strategy approach should be continued on individual and social levels. PMID- 26627448 TI - NHPI and palladium cocatalyzed aerobic oxidative acylation of arenes through a radical process. AB - The NHPI and palladium cocatalyzed radical oxidative acylation of arenes with aldehydes and alcohols as acyl equivalents via selective C-H functionalization has been described. Molecular oxygen, the most environmentally friendly oxidant, was used as the terminal oxidant in this catalytic cycle. PMID- 26627449 TI - A cost-benefit analysis of a proposed overseas refugee latent tuberculosis infection screening and treatment program. AB - BACKGROUND: This study explored the effect of screening and treatment of refugees for latent tuberculosis infection (LTBI) before entrance to the United States as a strategy for reducing active tuberculosis (TB). The purpose of this study was to estimate the costs and benefits of LTBI screening and treatment in United States bound refugees prior to arrival. METHODS: Costs were included for foreign and domestic LTBI screening and treatment and the domestic treatment of active TB. A decision tree with multiple Markov nodes was developed to determine the total costs and number of active TB cases that occurred in refugee populations that tested 55, 35, and 20 % tuberculin skin test positive under two models: no overseas LTBI screening and overseas LTBI screening and treatment. For this analysis, refugees that tested 55, 35, and 20 % tuberculin skin test positive were divided into high, moderate, and low LTBI prevalence categories to denote their prevalence of LTBI relative to other refugee populations. RESULTS: For a hypothetical 1-year cohort of 100,000 refugees arriving in the United States from regions with high, moderate, and low LTBI prevalence, implementation of overseas screening would be expected to prevent 440, 220, and 57 active TB cases in the United States during the first 20 years after arrival. The cost savings associated with treatment of these averted cases would offset the cost of LTBI screening and treatment for refugees from countries with high (net cost-saving: $4.9 million) and moderate (net cost-saving: $1.6 million) LTBI prevalence. For low LTBI prevalence populations, LTBI screening and treatment exceed expected future TB treatment cost savings (net cost of $780,000). CONCLUSIONS: Implementing LTBI screening and treatment for United States bound refugees from countries with high or moderate LTBI prevalence would potentially save millions of dollars and contribute to United States TB elimination goals. These estimates are conservative since secondary transmission from tuberculosis cases in the United States was not considered in the model. PMID- 26627450 TI - A phase II study of cyclophosphamide, etoposide, vincristine and prednisone (CEOP) Alternating with Pralatrexate (P) as front line therapy for patients with peripheral T-cell lymphoma (PTCL): final results from the T- cell consortium trial. AB - Peripheral T-cell lymphomas (PTCL) have suboptimal outcomes using conventional CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. The anti-folate pralatrexate, the first drug approved for patients with relapsed/refractory PTCL, provided a rationale to incorporate it into the front line setting. This phase 2 study evaluated a novel front-line combination whereby cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternated with pralatrexate (CEOP-P) in PTCL. Patients achieving a complete or partial remission (CR/PR) were eligible for consolidative stem cell transplantation (SCT) after 4 cycles. Thirty-three stage II-IV PTCL patients were treated: 21 PTCL-not otherwise specified (64%), 8 angioimmunoblastic T cell lymphoma (24%) and 4 anaplastic large cell lymphoma (12%). The majority (61%) had stage IV disease and 46% were International Prognostic Index high/intermediate or high risk. Grade 3-4 toxicities included anaemia (27%), thrombocytopenia (12%), febrile neutropenia (18%), mucositis (18%), sepsis (15%), increased creatinine (12%) and liver transaminases (12%). Seventeen patients (52%) achieved a CR. The 2-year progression-free survival and overall survival, were 39% (95% confidence interval 21-57) and 60% (95% confidence interval 39-76), respectively. Fifteen patients (45%) (12 CR) received SCT and all remained in CR at a median follow-up of 21.5 months. CEOP-P did not improve outcomes compared to historical data using CHOP. Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need. PMID- 26627451 TI - Genotype and phenotype analysis of Taiwanese patients with osteogenesis imperfecta. AB - BACKGROUND: Osteogenesis imperfecta (OI) is a congenital disorder characterized by increased bone fragility and low bone mass. METHODS: The presence of COL1A1 or COL1A2 mutation was investigated by direct sequencing in 72 patients with OI type I, III, or IV (27 males and 45 females; age range 0.2-62 years) from 37 unrelated families. The clinical features of these patients were also recorded. RESULTS: Thirty-seven COL1A1 and COL1A2 mutations were identified, including 28 COL1A1 mutations and 9 COL1A2 mutations. Fifteen (41%) were novel mutations, and twelve (32%) were familial mutations. A review of their medical records revealed that the 72 patients could be classified into OI type I (n = 42), III (n = 5), and IV (n = 25). Twenty-nine patients had helical mutations (caused by the substitution of a glycine within the Gly-X-Y triplet domain of the triple helix), and 42 had haploinsufficiency mutations (caused by frameshift, nonsense, and splice-site mutations). Compared with haploinsufficiency, the patients with helical mutations had more severely impaired skeletal phenotypes, including shorter height, lower bone mineral density, poorer walking ability, more frequent manifestations of dentinogenesis imperfecta and scoliosis (p < 0.05). CONCLUSIONS: Genotype and phenotype databases are expected to promote better genetic counseling and medical care of patients with OI. PMID- 26627452 TI - Interneuron Transplantation as a Treatment for Epilepsy. AB - Stem-cell therapy has extraordinary potential to address critical, unmet needs in the treatment of human disease. One particularly promising approach for the treatment of epilepsy is to increase inhibition in areas of the epileptic brain by grafting new inhibitory cortical interneurons. When grafted from embryos, young gamma-aminobutyric acid (GABA)ergic precursors disperse, functionally mature into host brain circuits as local-circuit interneurons, and can stop seizures in both genetic and acquired forms of the disease. These features make interneuron cell transplantation an attractive new approach for the treatment of intractable epilepsies, as well as other brain disorders that involve increased risk for epilepsy as a comorbidity. Here, we review recent efforts to isolate and transplant cortical interneuron precursors derived from embryonic mouse and human cell sources. We also discuss some of the important challenges that must be addressed before stem-cell-based treatment for human epilepsy is realized. PMID- 26627454 TI - Has the Rate of Human Aging Already Been Modified? AB - In recent years, three hypotheses have been set forth positing variations on a common question-Has the rate of human aging already been modified? There is no disputing that people now live longer than ever before in history, and considerable variation in duration of life persists as a fundamental attribute of human longevity, but are these events caused by a measurable and verifiable difference in the rate at which people age, or are there other reasons why they occur? In this article, I explore the historical record involving changes in survival and life expectancy at older ages dating back to 1900, and examine what factors will likely contribute to changes in longevity in the United States through 2040. Evidence suggests that despite the absence of verifiable metrics of biological age, delayed aging is unlikely to be a cause of secular increases in life expectancy, but it could explain variation in survival among population subgroups, and it is the most likely explanation for why exceptionally long-lived people experience less disease and live longer than the rest of the population. If genetic heterogeneity explains any significant part of current variation in longevity, this opens the door to the development of therapeutic interventions that confer these advantages to the rest of the population. PMID- 26627453 TI - The Role of the Microenvironmental Niche in Declining Stem-Cell Functions Associated with Biological Aging. AB - Aging is strongly correlated with decreases in neurogenesis, the process by which neural stem and progenitor cells proliferate and differentiate into new neurons. In addition to stem-cell-intrinsic factors that change within the aging stem-cell pool, recent evidence emphasizes new roles for systemic and microenvironmental factors in modulating the neurogenic niche. This article focuses on new insights gained through the use of heterochronic parabiosis models, in which an old mouse and a young circulatory system are joined. By studying the brains of both young and old mice, researchers are beginning to uncover circulating proneurogenic "youthful" factors and "aging" factors that decrease stem-cell activity and neurogenesis. Ultimately, the identification of factors that influence stem-cell aging may lead to strategies that slow or even reverse age-related decreases in neural-stem-cell (NSC) function and neurogenesis. PMID- 26627455 TI - Tumor specific liposomes improve detection of pancreatic adenocarcinoma in vivo using optoacoustic tomography. AB - BACKGROUND: Pancreatic cancer often goes undiagnosed until late stage disease due in part to suboptimal early detection. Our goal was to develop a Syndecan-1 tagged liposome containing fluorescent dye as an improved contrast agent for detection of pancreatic adenocarcinoma in vivo using multispectral optoacoustic tomography. RESULTS: The diagnostic capabilities and specificity to pancreatic adenocarcinoma of Syndecan-1 targeted liposomes were evaluated both in vitro and in vivo. Immunocytochemistry showed that liposomes preferentially bound to and released their contents into cells expressing high levels of insulin-like growth factor 1 receptor. We determined that the contents of the liposome were released into the cell as noted by the change in propidium iodide fluorescence from green to red based upon nucleic acid binding. In an orthotopic mouse model, the liposomes preferentially targeted the pancreatic tumor with little off-target binding in the liver and spleen. Peak accumulation of the liposomes in the tumor occurred at 8 h post-injection. Multispectral optoacoustic tomographic imaging was able to provide high-resolution 3D images of the tumor and liposome location. Ex vivo analysis showed that non-targeted liposomes accumulated in the liver, suggesting that specificity of the liposomes for pancreatic adenocarcinoma was due to the presence of the Syndecan-1 ligand. CONCLUSIONS: This study demonstrated that Syndecan-1 liposomes were able to release cargo into IGF1-R expressing tumor cells. The Syndecan-1 liposomes demonstrated tumor specificity in orthotopic pancreatic cancer as observed using multispectral optoacoustic tomography with reduced kidney and liver uptake. By targeting the liposome with Syndecan-1, this nanovehicle has potential as a targeted theranostic nanoparticle for both drug and contrast agent delivery to pancreatic tumors. PMID- 26627457 TI - A STING-dependent innate-sensing pathway mediates resistance to corneal HSV-1 infection via upregulation of the antiviral effector tetherin. AB - Type 1 interferons (IFNs; IFNalpha/beta) mediate immunological host resistance to numerous viral infections, including herpes simplex virus type 1 (HSV-1). The pathways responsible for IFNalpha/beta signaling during the innate immune response to acute HSV-1 infection in the cornea are incompletely understood. Using a murine ocular infection model, we hypothesized that the stimulator of IFN genes (STING) mediates resistance to HSV-1 infection at the ocular surface and preserves the structural integrity of this mucosal site. Viral pathogenesis, tissue pathology, and host immune responses during ocular HSV-1 infection were characterized by plaque assay, esthesiometry, pachymetry, immunohistochemistry, flow cytometry, and small interfering RNA transfection in wild-type C57BL/6 (WT), STING-deficient (STING(-/-)), and IFNalpha/beta receptor-deficient (CD118(-/-)) mice at days 3-5 postinfection. The presence of STING was critical for sustained control of HSV-1 replication in the corneal epithelium and resistance to viral neuroinvasion, but loss of STING had a negligible impact with respect to gross tissue pathology. Auxiliary STING-independent IFNalpha/beta signaling pathways were responsible for maintenance of corneal integrity. Lymphatic vessels, mast cells, and sensory innervation were compromised in CD118(-/-) mice concurrent with increased tissue edema. STING-dependent signaling led to the upregulation of tetherin, a viral restriction factor we identify is important in containing the spread of HSV-1 in vivo. PMID- 26627459 TI - Intestinal FoxO signaling is required to survive oral infection in Drosophila. AB - The intestinal immune system is tailored to fight pathogens effectively while tolerating the indigenous microbiota. Impairments of this homeostatic interaction may contribute to the etiology of various diseases including inflammatory bowel diseases. However, the molecular architecture underlying this complex regulatory interaction is not well understood. Here, we show that the fruit fly Drosophila melanogaster has a multilayered intestinal immune system that ensures strictly localized antimicrobial responses. Enterocytes, a major cell population of the intestine, produced antimicrobial peptides (AMPs) in a FoxO- but not NF-kappaB dependent manner. Consequently, animals impaired in FoxO-mediated signaling had a significantly lowered resistance to intestinal infections; they were unable to increase the expression of AMP genes and males showed an increased bacterial load in response to an infection. Conventional innate immune signaling converging onto NF-kappaB activation was operative in only a few regions of the intestine, comprising the proventriculus, copper cells, and intestinal stem cells. Taken together, our results imply that danger-mediated as well as conventional innate immune signaling constitute modules that contribute to the fruit fly's intestinal immune system. We propose that this special architecture ensures localized and efficient antimicrobial responses against invasive pathogens while preserving the microbiota. PMID- 26627458 TI - Control of local immunity by airway epithelial cells. AB - The lung is ventilated by thousand liters of air per day. Inevitably, the respiratory system comes into contact with airborne microbial compounds, most of them harmless contaminants. Airway epithelial cells are known to have innate sensor functions, thus being able to detect microbial danger. To avoid chronic inflammation, the pulmonary system has developed specific means to control local immune responses. Even though airway epithelial cells can act as proinflammatory promoters, we propose that under homeostatic conditions airway epithelial cells are important modulators of immune responses in the lung. In this review, we discuss epithelial cell regulatory functions that control reactivity of professional immune cells within the microenvironment of the airways and how these mechanisms are altered in pulmonary diseases. Regulation by epithelial cells can be divided into two mechanisms: (1) mediators regulate epithelial cells' innate sensitivity in cis and (2) factors are produced that limit reactivity of immune cells in trans. PMID- 26627460 TI - Lung epithelium and myeloid cells cooperate to clear acute pneumococcal infection. AB - The Gram-positive bacterium Streptococcus pneumoniae causes life-threatening infections, especially among immunocompromised patients. The host's immune system senses S. pneumoniae via different families of pattern recognition receptors, in particular the Toll-like receptor (TLR) family that promotes immune cell activation. Yet, while single TLRs are dispensable for initiating inflammatory responses against S. pneumoniae, the central TLR adapter protein myeloid differentiation factor 88 (MyD88) is of vital importance, as MyD88-deficient mice succumb rapidly to infection. Since MyD88 is ubiquitously expressed in hematopoietic and non-hematopoietic cells, the extent to which MyD88 signaling is required in different cell types to control S. pneumoniae is unknown. Therefore, we used novel conditional knockin mice to investigate the necessity of MyD88 signaling in distinct lung-resident myeloid and epithelial cells for the initiation of a protective immune response against S. pneumoniae. Here, we show that MyD88 signaling in lysozyme M (LysM)- and CD11c-expressing myeloid cells, as well as in pulmonary epithelial cells, is critical to restore inflammatory cytokine and antimicrobial peptide production, leading to efficient neutrophil recruitment and enhanced bacterial clearance. Overall, we show a novel synergistic requirement of compartment-specific MyD88 signaling in S. pneumoniae immunity. PMID- 26627461 TI - Posttranscriptional control of NLRP3 inflammasome activation in colonic macrophages. AB - Colonic macrophages (cMPs) are important for intestinal homeostasis as they kill microbes and yet produce regulatory cytokines. Activity of the NLRP3 (nucleotide binding leucine-rich repeat-containing pyrin receptor 3) inflammasome, a major sensor of stress and microorganisms that results in pro-inflammatory cytokine production and cell death, must be tightly controlled in the intestine. We demonstrate that resident cMPs are hyporesponsive to NLRP3 inflammasome activation owing to a remarkable level of posttranscriptional control of NLRP3 and pro-interleukin-1beta (proIL-1beta) protein expression, which was also seen for tumor necrosis factor-alpha and IL-6, but lost during experimental colitis. Resident cMPs rapidly degraded NLRP3 and proIL-1beta proteins by the ubiquitin/proteasome system. Finally, blocking IL-10R-signaling in vivo enhanced NLRP3 and proIL-1beta protein but not mRNA levels in resident cMPs, implicating a role for IL-10 in environmental conditioning of cMPs. These data are the first to show dramatic posttranscriptional control of inflammatory cytokine production by a relevant tissue-derived macrophage population and proteasomal degradation of proIL-1beta and NLRP3 as a mechanism to control inflammasome activation, findings which have broad implications for our understanding of intestinal and systemic inflammatory diseases. PMID- 26627462 TI - The 2013 measles outbreak in Sri Lanka: experience from a rural district and implications for measles elimination goals. AB - BACKGROUND: Sri Lanka was the first country in the Southeast Asian region to achieve its measles elimination goal in 2011. In 2012, the measles immunization schedule changed from a measles vaccine at 9 months to a measles, mumps and rubella vaccine at 12 months. However in 2013, Sri Lanka reported its worst recent outbreak of measles. This study investigated a part of this outbreak in order to describe its epidemiology. METHODS: A prospective study was carried out at the university medical unit of the Teaching Hospital, Anuradhapura (THA), the third largest hospital in Sri Lanka, from October 2013 until March 2014. An epidemiological profile of patients was constructed, case confirmation was done on all suspected cases and the basic demographic details of these suspected cases were obtained from the available records. RESULTS: From January 2013 to March 2014, 101 measles suspects were admitted to the THA. Until June 2013, all suspected cases were aged below 12 months of age. During the study period (15 months), the total number of patients aged below 9 months, 9 to 12 months, 1 to 11 years, 12-29 years and over 29 years were 10 (9.9 %), 11 (10.9 %), 6 (5.9 %), 37 (36.6 %) and 36 (35.6 %), respectively (data missing-1). Out of the 33 patients clinically suspected, 32 tested positive for measles. Common clinical features included: fever (n = 33, 100 %), maculopapular rash (n = 33), conjunctivitis (n = 31), posterior cervical lymphadenopathy (n = 23) and Koplik's spots (n = 8). Features suggestive of pneumonia were observed among 30 (90.9 %) patients and 26 (78.8 %) had diarrhoea. Two patients (6.1 %) who developed severe pneumonia received care at an intensive care unit due to respiratory difficulties. Out of 33 patients, 15 (45.5 %) had prior immunization for measles, two (6.1 %) reported that they never had a measles immunization and 16 (48.5 %) were unsure about their immunization status. Out of those who reported they were previously immunized, 11 (73.3 %) belonged to the age group of 12-2 years. CONCLUSION: Because the first cases of this outbreak were infants, an increase in susceptible infants due to the change in the vaccine schedule could partly explain the outbreak. PMID- 26627464 TI - First Japanese case of Zellweger syndrome with a mutation in PEX14. AB - Zellweger syndrome, one of the peroxisome biogenesis disorders, is an autosomal recessive disease caused by mutations in PEX genes. It is characterized by severe hypotonia, failure to thrive, psychomotor retardation, liver dysfunction, and sensorineural hearing impairment. Most of the patients with this disease die before the age of 1 year. PEX14 is the 13th PEX gene responsible for peroxisome biogenesis disorders. Thus far, only two patients with PEX14 deficiency have been reported. Here, we report the first case of a Japanese patient with a PEX14 mutation who showed severe hypotonia, psychomotor retardation, demyelination, and developed rickets at the age of 5 months. An increased excretion of 3,6 epoxydicarboxylic acids leads to the diagnosis of Zellweger syndrome and a mutation analysis of PEX14 revealed a homozygous mutation of c.538C>T (p.Q180X). The patient survived for a prolonged period of time but died of liver failure at the age of 46 months. PMID- 26627465 TI - Morphological and transcriptional responses of Lycopersicon esculentum to hexavalent chromium in agricultural soil. AB - The carcinogenic, teratogenic, and mutagenic effects of hexavalent chromium (Cr[VI]) on living organisms through the food chain raise the immediate need to assess the potential toxicological impacts of Cr(VI) on human health. Therefore, the concentration-dependent responses of 12 Cr(VI)-responsive genes selected from a high-throughput Lycopersicon esculentum complementary DNA microarray were examined at different Cr concentrations. The results indicated that most of the genes were differentially expressed from 0.1 mg Cr/kg soil, whereas the lowest observable-adverse-effect concentrations of Cr(VI) were 1.6 mg Cr/kg soil, 6.4 mg Cr/kg soil, 3.2 mg Cr/kg soil, and 0.4 mg Cr/kg soil for seed germination, root elongation, root biomass, and root morphology, respectively, implying that the transcriptional method was more sensitive than the traditional method in detecting Cr(VI) toxicity. Dose-dependent responses were observed for the relative expression of expansin (p = 0.778), probable chalcone-flavonone isomerase 3 (p = -0.496), and 12S seed storage protein CRD (p = -0.614); therefore, the authors propose the 3 genes as putative biomarkers in Cr(VI) contaminated soil. Environ Toxicol Chem 2016;35:1751-1758. (c) 2015 SETAC. PMID- 26627466 TI - Emergence of cutaneous neosporosis in a dog receiving immunosuppressive therapy: molecular identification and management. AB - BACKGROUND: Neosporosis is a multisystemic disease caused by the intracellular protozoan Neospora caninum. In dogs the disease primarily affects the central nervous system. Canine cutaneous neosporosis is a rare condition often associated with old age or concurrent immunosuppressive treatments for different underlying conditions. ANIMALS: A 10-year-old female spayed golden retriever dog affected by primary immune-mediated myelofibrosis and treated with immunosuppressive therapies for 6 weeks that developed severe cutaneous lesions. METHODS: Definitive diagnosis was based on several investigation techniques including serology (immunoblotting), immunohistochemistry (IHC), species-specific conventional and real-time PCR, and DNA sequencing. RESULTS: Remission of cutaneous neosporosis was obtained with the administration of clindamycin while the concurrent immunosuppressive therapy was maintained to manage the underlying primary condition. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors' knowledge this is the first report of species-specific PCR and DNA sequencing used as diagnostic methods for canine cutaneous neosporosis emerging in a dog receiving immunosuppressive therapy. PMID- 26627467 TI - Quercetin oppositely regulates insulin-mediated glucose disposal in skeletal muscle under normal and inflammatory conditions: The dual roles of AMPK activation. AB - SCOPE: Quercetin is a dietary flavonoid whose role in the regulation of the activity of insulin remains controversial. Our study aimed to investigate how quercetin and its major metabolite quercetin-3-glucuronide (Q-3-G) regulate insulin-mediated glucose disposal in skeletal muscle under normal and inflammatory conditions. METHODS AND RESULTS: Under normal conditions, quercetin impaired glucose and insulin tolerance and attenuated insulin-mediated phosphorylation of Akt substrate of 160 kDa (AS160) and TBC1D1 without affecting Akt activity in male Institute of Cancer Research (ICR) mice. However, under inflammatory conditions, quercetin exhibited an opposite effect in these animals. In C2C12 cells, quercetin also decreased insulin-stimulated AS160 and TBC1D1 phosphorylation and glucose uptake in the absence of an inflammatory insult, whereas it improved the action of insulin under inflammatory conditions. Knockdown of adenosine 5'-monophosphate-activated protein kinase alpha (AMPKalpha) blocked the differential effects of quercetin under both conditions. Unlike quercetin, Q-3-G had no influence on insulin-induced phosphorylation of AS160 and TBC1D1 and glucose uptake in C2C12 myotubes under normal conditions. Q 3-G displayed a similar regulation with quercetin in glucose disposal under inflammatory conditions. CONCLUSION: Quercetin suppressed insulin-mediated glucose disposal in skeletal muscle tissue/cells under normal conditions while it ameliorated impaired glucose uptake under inflammatory conditions with activation of AMPK. In contrast, Q-3-G ameliorated insulin resistance in skeletal cells under inflammatory conditions without affecting glucose disposal under normal conditions. PMID- 26627468 TI - In vitro synergism of magnolol and honokiol in combination with antibacterial agents against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA). AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a problematic pathogen posing a serious therapeutic challenge in the clinic. It is often multidrug-resistant (MDR) to conventional classes of antibacterial agents and there is an urgent need to develop new agents or strategies for treatment. Magnolol (ML) and honokiol (HL) are two naturally occurring diallylbiphenols which have been reported to show inhibition of MRSA. In this study their synergistic effects with antibacterial agents were further evaluated via checkerboard and time-kill assays. METHODS: The susceptibility spectrum of clinical MRSA strains was tested by the disk diffusion method. The minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of ML and HL were assayed by broth microdilution. The synergy was evaluated through checkerboard microdilution and time-killing experiments. RESULTS: ML and HL showed similar activity against both MSSA and MRSA with MIC/MBC at 16 ~ 64 mg/L, with potency similar to amikacin (AMK) and gentamicin (GEN). When they were used in combination with conventional antibacterial agents, they showed bacteriostatic synergy with FICIs between 0.25 ~ 0.5, leading to the combined MICs decreasing to as low as 1 ~ 2 and 1 ~ 16 mg/L for ML (HL) and the agents, respectively. MIC50 of the combinations decreased from 16 mg/L to 1 ~ 4 mg/L for ML (HL) and 8 ~ 128 mg/L to 2 ~ 64 mg/L for the antibacterial agents, which exhibited a broad spectrum of synergistic action with aminoglycosides (AMK, etilmicin (ETM) and GEN), floroquinolones (levofloxacin (LEV), ciprofloxacin and norfloxacin), fosfomycin (FOS) and piperacillin. The times of dilution (TOD, the extent of decreasing in MIC value) were determined up to 16 for the combined MIC. A more significant synergy after combining was determined as ML (HL) with AMK, ETM, GEN and FOS. ML (HL) combined with antibacterial agents did not show antagonistic effects on any of the ten MRSA strains. Reversal effects of MRSA resistance to AMK and GEN by ML and HL were also observed, respectively. All the combinations also showed better dynamic bactericidal activity against MRSA than any of single ML (HL) or the agents at 24 h incubation. The more significant synergy of combinations were determined as HL (ML) + ETM, HL + LEV and HL + AMK (GEN or FOS), with ?LC24 of 2.02 ~ 2.25. CONCLUSION: ML and HL showed synergistic potentiation of antibacterial agents against clinical isolates of MRSA and warrant further pharmacological investigation. PMID- 26627470 TI - Auditory Discrimination of Lexical Stress Patterns in Hearing-Impaired Infants with Cochlear Implants Compared with Normal Hearing: Influence of Acoustic Cues and Listening Experience to the Ambient Language. AB - OBJECTIVES: To assess discrimination of lexical stress pattern in infants with cochlear implant (CI) compared with infants with normal hearing (NH). While criteria for cochlear implantation have expanded to infants as young as 6 months, little is known regarding infants' processing of suprasegmental-prosodic cues which are known to be important for the first stages of language acquisition. Lexical stress is an example of such a cue, which, in hearing infants, has been shown to assist in segmenting words from fluent speech and in distinguishing between words that differ only the stress pattern. To date, however, there are no data on the ability of infants with CIs to perceive lexical stress. Such information will provide insight to the speech characteristics that are available to these infants in their first steps of language acquisition. This is of particular interest given the known limitations that the CI device has in transmitting speech information that is mediated by changes in fundamental frequency. DESIGN: Two groups of infants participated in this study. The first group included 20 profoundly hearing-impaired infants with CI, 12 to 33 months old, implanted under the age of 2.5 years (median age of implantation = 14.5 months), with 1 to 6 months of CI use (mean = 2.7 months) and no known additional problems. The second group of infants included 48 NH infants, 11 to 14 months old with normal development and no known risk factors for developmental delays. Infants were tested on their ability to discriminate between nonsense words that differed on their stress pattern only (/doti/ versus /doti/ and /doti/ versus /doti/) using the visual habituation procedure. The measure for discrimination was the change in looking time between the last habituation trial (e.g., /doti/) and the novel trial (e.g., /doti/). RESULTS: (1) Infants with CI showed discrimination between lexical stress pattern with only limited auditory experience with their implant device, (2) discrimination of stress patterns in infants with CI was reduced compared with that of infants with NH, (3) both groups showed directional asymmetry in discrimination, that is, increased discrimination from the uncommon to the common stress pattern in Hebrew (/doti/ versus /doti/) compared with the reversed condition. CONCLUSIONS: The CI device transmitted sufficient acoustic information (amplitude, duration, and fundamental frequency) to allow discrimination between stress patterns in young hearing impaired infants with CI. The present pattern of results is in support of a discrimination model in which both auditory capabilities and "top-down" interactions are involved. That is, the CI infants detected changes between stressed and unstressed syllables after which they developed a bias for the more common weak-strong stress pattern in Hebrew. The latter suggests that infants with CI were able to extract the statistical distribution of stress patterns by listening to the ambient language even after limited auditory experience with the CI device. To conclude, in relation to processing of lexical stress patterns, infants with CI followed similar developmental milestones as hearing infants thus establishing important prerequisites for early language acquisition. PMID- 26627471 TI - Deciphering the Sensitivity and Specificity of the Implantable Doppler in Free Flap Monitoring. AB - INTRODUCTION: The efficacy of implantable Dopplers (iD) remains an area of considerable debate. Our study aims to decipher the sensitivity and specificity of the iD for free flap monitoring. METHODS: A retrospective review of all free flaps with an iD was performed between 2000-2012. RESULTS: A Cook-Swartz iD was used in 439 patients (head and neck: n=364, breast: n=53, and extremity: n=22), and demonstrated equivalent sensitivity and specificity between flap types. The overall sensitivity and specificity was 77.8% and 88.4% respectively. The iD was placed on the artery in 267 patients, the vein in 101 patients, and 71 patients had a Doppler placed on both the artery and vein with significantly greater specificity for monitoring the artery than the vein (94.2% vs. 74.0%, p<0.001), but no difference between monitoring both the artery and the vein. Venous monitoring was significantly associated with a takeback (OR: 3.17, CI: 1.70-5.91; p=0.0003). There were 284 flaps that also had a monitoring segment in addition to the iD which significantly increased specificity for microvascular complications (OR: 17.71, CI: 3.39-92.23; p=0.0006). The specificity (90.5% vs. 84.8%) and sensitivity (80.0% vs. 66.7%) were significantly higher for clinically monitored flaps. The takeback rate was 13.0%, with positive findings in 59.6%, and 5.2% total flap loss. CONCLUSIONS: The use of implantable Dopplers has high sensitivity and specificity for buried free flap despite positive findings in less than 60% of take backs. Monitoring the artery is preferable to the vein, but clinical exam remains the gold standard for flap monitoring. PMID- 26627469 TI - Distribution Characteristics of Air-Bone Gaps: Evidence of Bias in Manual Audiometry. AB - OBJECTIVES: Five databases were mined to examine distributions of air-bone gaps obtained by automated and manual audiometry. Differences in distribution characteristics were examined for evidence of influences unrelated to the audibility of test signals. DESIGN: The databases provided air- and bone conduction thresholds that permitted examination of air-bone gap distributions that were free of ceiling and floor effects. Cases with conductive hearing loss were eliminated based on air-bone gaps, tympanometry, and otoscopy, when available. The analysis is based on 2,378,921 threshold determinations from 721,831 subjects from five databases. RESULTS: Automated audiometry produced air bone gaps that were normally distributed suggesting that air- and bone-conduction thresholds are normally distributed. Manual audiometry produced air-bone gaps that were not normally distributed and show evidence of biasing effects of assumptions of expected results. In one database, the form of the distributions showed evidence of inclusion of conductive hearing losses. CONCLUSIONS: Thresholds obtained by manual audiometry show tester bias effects from assumptions of the patient's hearing loss characteristics. Tester bias artificially reduces the variance of bone-conduction thresholds and the resulting air-bone gaps. Because the automated method is free of bias from assumptions of expected results, these distributions are hypothesized to reflect the true variability of air- and bone-conduction thresholds and the resulting air-bone gaps. PMID- 26627472 TI - Resolution of vitiligo following excision of halo congenital melanocytic nevus: a rare case report. AB - Halo congenital melanocytic nevus (CMN) associated with vitiligo is rare, especially with regard to CMN excision. Only two reports of excision of halo CMN following repigmentation of vitiligo are found in the literature. We present a case of a girl with halo CMN and periorbital vitiligo. The halo CMN was excised and followed by spontaneous improvement of vitiligo. The result suggests excision of the inciting lesion may be a promising way to control vitiligo. PMID- 26627473 TI - Aedes aegypti has spatially structured and seasonally stable populations in Yogyakarta, Indonesia. AB - BACKGROUND: Dengue fever, the most prevalent global arboviral disease, represents an important public health problem in Indonesia. Control of dengue relies on the control of its main vector, the mosquito Aedes aegypti, yet nothing is known about the population history and genetic structure of this insect in Indonesia. Our aim was to assess the spatio-temporal population genetic structure of Ae. aegypti in Yogyakarta, a densely populated region on Java with common dengue outbreaks. METHODS: We used multiple marker systems (microsatellites, nuclear and mitochondrial genome-wide single nucleotide polymorphisms generated via Restriction-site Associated DNA sequencing) to analyze 979 Ae. aegypti individuals collected from the Yogyakarta city and the surrounding hamlets during the wet season in 2011 and the following dry season in 2012. We employed individual- and group-based approaches for inferring genetic structure. RESULTS: We found that Ae. aegypti in Yogyakarta has spatially structured and seasonally stable populations. The spatial structuring was significant for the nuclear and mitochondrial markers, while the temporal structuring was non-significant. Nuclear markers identified three main genetic clusters, showing that hamlets have greater genetic isolation from each other and from the inner city sites. However, one hamlet experienced unrestricted mosquito interbreeding with the inner city, forming a single genetic cluster. Genetic distance was poorly correlated with the spatial distance among mosquito samples, suggesting stronger influence of human assisted gene flow than active mosquito movement on spatial genetic structure. A star-shaped mitochondrial haplotype network and a significant R(2) test statistic (R(2) = 0.0187, P = 0.001) support the hypothesis that Ae. aegypti in Yogyakarta originated from a small or homogeneous source and has undergone a relatively recent demographic expansion. CONCLUSION: We report the first insights into the spatio-temporal genetic structure and the underlying processes in the dengue fever mosquito from Yogyakarta, Indonesia. Our results provide valuable information on the effectiveness of local control measures as well as guidelines for the implementation of novel biocontrol strategies such as release of Wolbachia-infected mosquitoes. PMID- 26627474 TI - Freestanding stacked mesh-like hydrogel sheets enable the creation of complex macroscale cellular scaffolds. AB - Hydrogel-based bottom-up tissue engineering depends on assembly of cell-laden modules for complex three-dimensional tissue reconstruction. Though sheet-like hydrogel modules enable rapid and controllable assembly, they have limitations in generating spatial microenvironments and mass transport. Here, we describe a simple method for forming large-scale cell-hydrogel assemblies via stacking cell embedded mesh-like hydrogel sheets to create complex macroscale cellular scaffolds. Freestanding stacked hydrogel sheets were fabricated for long-term cell culturing applications using a facile stacking process where the micropatterned hydrogel sheets (8.0 mm * 8.7 mm) were aligned using a polydimethylsiloxane drainage well. The stacked hydrogel sheets were precisely aligned so that the openings could facilitate mass transport through the stacked sheets. Despite the relatively large height of the stacked structure (400-700 MUm), which is larger than the diffusion limit thickness of 150-200 MUm, the freestanding cell-ydrogel assemblies maintained cell viability and exhibited enhanced cellular function compared with single hydrogel sheets. Furthermore, a three-dimensional co-culture system was constructed simply by stacking different cell-containing hydrogel sheets. These results show that stacked hydrogel sheets have significant potential as a macroscale cell-culture and assay platform with complex microenvironments for biologically relevant in vitro tissue-level drug assays and physiological studies. PMID- 26627475 TI - LON is the master protease that protects against protein aggregation in human mitochondria through direct degradation of misfolded proteins. AB - Maintenance of mitochondrial protein homeostasis is critical for proper cellular function. Under normal conditions resident molecular chaperones and proteases maintain protein homeostasis within the organelle. Under conditions of stress however, misfolded proteins accumulate leading to the activation of the mitochondrial unfolded protein response (UPR(mt)). While molecular chaperone assisted refolding of proteins in mammalian mitochondria has been well documented, the contribution of AAA+ proteases to the maintenance of protein homeostasis in this organelle remains unclear. To address this gap in knowledge we examined the contribution of human mitochondrial matrix proteases, LONM and CLPXP, to the turnover of OTC-?, a folding incompetent mutant of ornithine transcarbamylase, known to activate UPR(mt). Contrary to a model whereby CLPXP is believed to degrade misfolded proteins, we found that LONM, and not CLPXP is responsible for the turnover of OTC-? in human mitochondria. To analyse the conformational state of proteins that are recognised by LONM, we examined the turnover of unfolded and aggregated forms of malate dehydrogenase (MDH) and OTC. This analysis revealed that LONM specifically recognises and degrades unfolded, but not aggregated proteins. Since LONM is not upregulated by UPR(mt), this pathway may preferentially act to promote chaperone mediated refolding of proteins. PMID- 26627476 TI - Trazodone regulates neurotrophic/growth factors, mitogen-activated protein kinases and lactate release in human primary astrocytes. AB - BACKGROUND: In the central nervous system, glial cells provide metabolic and trophic support to neurons and respond to protracted stress and insults by up regulating inflammatory processes. Reactive astrocytes and microglia are associated with the pathophysiology of neuronal injury, neurodegenerative diseases and major depression, in both animal models and human brains. Several studies have reported clear anti-inflammatory effects of anti-depressant treatment on astrocytes, especially in models of neurological disorders. Trazodone (TDZ) is a triazolopyridine derivative that is structurally unrelated to other major classes of antidepressants. Although the molecular mechanisms of TDZ in neurons have been investigated, it is unclear whether astrocytes are also a TDZ target. METHODS: The effects of TDZ on human astrocytes were investigated in physiological conditions and following inflammatory insult with lipopolysaccharide (LPS) and tumour necrosis factor-alpha (TNF-alpha). Astrocytes were assessed for their responses to pro-inflammatory mediators and cytokines, and the receptors and signalling pathways involved in TDZ-mediated effects were evaluated. RESULTS: TDZ had no effect on cell proliferation, but it decreased pro inflammatory mediator release and modulated trophic and transcription factor mRNA expression. Following TDZ treatment, the AKT pathway was activated, whereas extracellular signal-regulated kinase and c-Jun NH2-terminal kinase were inhibited. Most importantly, a 72-h TDZ pre-treatment before inflammatory insult completely reversed the anti-proliferative effects induced by LPS-TNF-alpha. The expression or the activity of inflammatory mediators, including interleukin-6, c Jun NH2-terminal kinase and nuclear factor kappaB, were also reduced. Furthermore, TDZ affected astrocyte metabolic support to neurons by counteracting the inflammation-mediated lactate decrease. Finally, TDZ protected neuronal-like cells against neurotoxicity mediated by activated astrocytes. These effects mainly involved an activation of 5-HT1A and an antagonism at 5-HT2A/C serotonin receptors. Fluoxetine, used in parallel, showed similar final effects nevertheless it activates different receptors/intracellular pathways. CONCLUSIONS: Altogether, our results demonstrated that TDZ directly acts on astrocytes by regulating intracellular signalling pathways and increasing specific astrocyte-derived neurotrophic factor expression and lactate release. TDZ may contribute to neuronal support by normalizing trophic and metabolic support during neuroinflammation, which is associated with neurological diseases, including major depression. PMID- 26627477 TI - Deletion of the 2-acyl-glycerophosphoethanolamine cycle improve glucose metabolism in Escherichia coli strains employed for overproduction of aromatic compounds. AB - BACKGROUND: As a metabolic engineering tool, an adaptive laboratory evolution (ALE) experiment was performed to increase the specific growth rate (u) in an Escherichia coli strain lacking PTS, originally engineered to increase the availability of intracellular phosphoenolpyruvate and redirect to the aromatic biosynthesis pathway. As result, several evolved strains increased their growth fitness on glucose as the only carbon source. Two of these clones isolated at 120 and 200 h during the experiment, increased their MU by 338 and 373 %, respectively, compared to the predecessor PB11 strain. The genome sequence and analysis of the genetic changes of these two strains (PB12 and PB13) allowed for the identification of a novel strategy to enhance carbon utilization to overcome the absence of the major glucose transport system. RESULTS: Genome sequencing data of evolved strains revealed the deletion of chromosomal region of 10,328 pb and two punctual non-synonymous mutations in the dhaM and glpT genes, which occurred prior to their divergence during the early stages of the evolutionary process. Deleted genes related to increased fitness in the evolved strains are rppH, aas, lplT and galR. Furthermore, the loss of mutH, which was also lost during the deletion event, caused a 200-fold increase in the mutation rate. CONCLUSIONS: During the ALE experiment, both PB12 and PB13 strains lost the galR and rppH genes, allowing the utilization of an alternative glucose transport system and allowed enhanced mRNA half-life of many genes involved in the glycolytic pathway resulting in an increment in the MU of these derivatives. Finally, we demonstrated the deletion of the aas-lplT operon, which codes for the main components of the phosphatidylethanolamine turnover metabolism increased the further fitness and glucose uptake in these evolved strains by stimulating the phospholipid degradation pathway. This is an alternative mechanism to its regeneration from 2-acyl-glycerophosphoethanolamine, whose utilization improved carbon metabolism likely by the elimination of a futile cycle under certain metabolic conditions. The origin and widespread occurrence of a mutated population during the ALE indicates a strong stress condition present in strains lacking PTS and the plasticity of this bacterium that allows it to overcome hostile conditions. PMID- 26627478 TI - Messenger RNA profile analysis deciphers new Esrrb responsive genes in prostate cancer cells. AB - BACKGROUND: Orphan nuclear receptor estrogen related receptor beta (Esrrb or ERRbeta) is well known in stem cells and early embryonic development. However, little is known about its function in cancer. METHOD: We investigated the mRNA profile alterations induced by Esrrb expression and its synthetic ligand DY131 in human prostate cancer DU145 cells via RNA-Seq analysis. RESULTS: We distinguished 67 mRNAs differentially expressed by Esrrb alone. Although DY131 alone did not change any gene, treatment of DY131 in the presence of Esrrb altered 1161 mRNAs. These observations indicated Esrrb had both ligand-independent and ligand dependent activity. When Esrrb was expressed, DY131 treatment further regulated 15 Esrrb-altered mRNAs. DY131 acted as an antagonist for 11 of 15 mRNAs (wdr52, f13a1, pxdn, spns2, loc100506599, tagln, loc441454, tkel1, sema3f, zcwpw2, sdc2) and as an agonist for 4 of the 15 mRNAs (rarres3, oasl, padi2, ddx60). Gene ontology analyses showed altered genes are related to transcription and translation regulation, cell proliferation and apoptosis regulation, and cellular metabolism. CONCLUSION: Our results characterized mRNA profiles in DU145 prostate cancer cells driven by Esrrb expression and Esrrb ligand DY131, and provided multiple markers to characterize Esrrb's function in Esrrb research. PMID- 26627479 TI - Mammographic density adds accuracy to both the Tyrer-Cuzick and Gail breast cancer risk models in a prospective UK screening cohort. AB - INTRODUCTION: The Predicting Risk of Cancer at Screening study in Manchester, UK, is a prospective study of breast cancer risk estimation. It was designed to assess whether mammographic density may help in refinement of breast cancer risk estimation using either the Gail model (Breast Cancer Risk Assessment Tool) or the Tyrer-Cuzick model (International Breast Intervention Study model). METHODS: Mammographic density was measured at entry as a percentage visual assessment, adjusted for age and body mass index. Tyrer-Cuzick and Gail 10-year risks were based on a questionnaire completed contemporaneously. Breast cancers were identified at the entry screen or shortly thereafter. The contribution of density to risk models was assessed using odds ratios (ORs) with profile likelihood confidence intervals (CIs) and area under the receiver operating characteristic curve (AUC). The calibration of predicted ORs was estimated as a percentage [(observed vs expected (O/E)] from logistic regression. RESULTS: The analysis included 50,628 women aged 47-73 years who were recruited between October 2009 and September 2013. Of these, 697 had breast cancer diagnosed after enrolment. Median follow-up was 3.2 years. Breast density [interquartile range odds ratio (IQR-OR) 1.48, 95 % CI 1.34-1.63, AUC 0.59] was a slightly stronger univariate risk factor than the Tyrer-Cuzick model [IQR-OR 1.36 (95 % CI 1.25-1.48), O/E 60 % (95 % CI 44-74), AUC 0.57] or the Gail model [IQR-OR 1.22 (95 % CI 1.12-1.33), O/E 46 % (95 % CI 26-65 %), AUC 0.55]. It continued to add information after allowing for Tyrer-Cuzick [IQR-OR 1.47 (95 % CI 1.33-1.62), combined AUC 0.61] or Gail [IQR-OR 1.45 (95 % CI 1.32-1.60), combined AUC 0.59]. CONCLUSIONS: Breast density may be usefully combined with the Tyrer-Cuzick model or the Gail model. PMID- 26627480 TI - Genetic predisposition to acute kidney injury--a systematic review. AB - BACKGROUND: The risk of an individual to develop an acute kidney injury (AKI), or its severity, cannot be reliably predicted by common clinical risk factors. Whether genetic risk factors have an explanatory role poses an interesting question, however. Thus, we conducted a systematic literature review regarding genetic predisposition to AKI or outcome of AKI patients. METHODS: We searched Ovid SP (MEDLINE) and EMBASE databases and found 4027 references to AKI. Based on titles and abstracts, we approved 37 articles for further analysis. Nine were published only as abstracts, leaving 28 original articles in the final analysis. We extracted the first author, year of publication, study design, clinical setting, number of studied patients, patients with AKI, ethnicity of patients, studied polymorphisms, endpoints, AKI definition, phenotype, significant findings, and data for quality scoring from each article. We summarized the findings and scored the quality of articles. RESULTS: The articles were quite heterogeneous and of moderate quality (mean 6.4 of 10). CONCLUSIONS: Despite different gene polymorphisms with suggested associations with development or severity or outcome of AKI, definitive conclusions would require replication of associations in independent cohort studies and, preferably a hypothesis-free study design. PMID- 26627482 TI - Modulation effect of the SORL1 gene on functional connectivity density in healthy young adults. AB - The sortilin-related receptor 1 (SORL1) gene has been associated with late-onset Alzheimer's disease (LOAD) and structural impairments in several ethnic populations. However, how this gene affects brain function properties remains unclear. We investigated associations of SORL1 rs2070045 with functional connectivity density (FCD) in healthy young adults. This single-nucleotide polymorphism was selected because it is the SORL1 variant that has been frequently associated with LOAD in several populations, including the Chinese Han population. A total of 275 healthy young Chinese Han subjects with successful genotyping and MRI examinations were included. The effect of SORL1 rs2070045 was explored using a voxel-wise FCD analysis. A significant effect of SORL1 rs2070045 on the FCD was found in the right inferior temporal gyrus. The risk G allele carriers of the rs2070045 exhibited a lower FCD than the protective TT carriers. This effect was independent of the status of apolipoprotein E. This study provides the first evidence that the SORL1 gene is associated with brain FCD differences in healthy young adults. In the genetic risk subjects, connectivity impairment already starts during young adulthood, which may predispose the risk allele carriers to be susceptible to LOAD after several decades. PMID- 26627481 TI - Artesunate Protects Against Sepsis-Induced Lung Injury Via Heme Oxygenase-1 Modulation. AB - Artesunate, a derivative of artemisinin, has anti-inflammatory properties and exerts protective roles in sepsis. Heme oxygense-1 (HO-1) inhibits the inflammatory response through reduction of proinflammatory cytokines and leukocyte influx into tissues. The present study investigated the effects of artesunate on HO-1 and septic lung injury. Cecal ligation and puncture (CLP) was employed to induce septic lung injury. Mice pretreated with artesunate (AS) (15 mg/kg) exhibited decreased sepsis-induced mortality and lung injury and alleviated lung pathological changes and neutrophil infiltration. In addition, AS lowered the levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the serum and bronchoalveolar lavage fluid (BALF) and inhibited cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase isoform (iNOS) expression and NF-kappaB activation in lung tissue. In addition, AS enhanced NF E2-related factor-2 (Nrf2) activation and HO-1 expression and enzymatic activity in lung tissue. However, the protective effects of AS on sepsis-induced lung injury were eliminated by ZnPP IX, an HO-1 competitive inhibitor. Therefore, AS plays protective roles in septic lung injury related to the upregulation of HO-1. These findings suggest an effective and applicable treatment to sepsis-induced lung injury and provide new insights into the molecular mechanisms and actions of AS. PMID- 26627484 TI - Transjugular Intrahepatic Portosystemic Shunt Flow Reduction with Adjustable Polytetrafluoroethylene-Covered Balloon-Expandable Stents Using the "Sheath Control" Technique. AB - PURPOSE: A complication of transjugular intrahepatic portosystemic shunts (TIPS) placement is refractory portosystemic encephalopathy (PSE) often requiring TIPS reduction. We report the results of a "sheath control technique" utilizing constraining sheaths during deployment of polytetrafluoroethylene (PTFE)-covered balloon-expandable stents, minimizing stent migration, and providing additional procedural control. METHODS: TIPS reduction was performed in 10 consecutive patients for PSE using Atrium iCast covered stents (Atrium Maquet Getinge Group, Germany). Within the indwelling TIPS stent, a 9 mm * 59 mm iCast stent was deployed with 2 cm exposed from the sheath's distal end and the majority of the stent within the sheath to create the distal hourglass shape. During balloon retraction, the stent was buttressed by the sheath. The proximal portion of the stent was angioplastied to complete the hourglass configuration, and the central portion of the stent was dilated to 5 mm. Demographics, pre- and post-procedure laboratory values, and outcomes were recorded. RESULTS: Ten patients underwent TIPS reduction with 100 % technical success. There was no stent migration during stent deployment. All patients experienced initial improvement of encephalopathy. One patient ultimately required complete TIPS occlusion for refractory PSE, and another developed TIPS occlusion 36 days post-procedure. There was no significant trend toward change in patients' MELD scores immediately post-procedure or at 30 days (p = 0.46, p = 0.47, respectively). CONCLUSION: TIPS reduction using Atrium iCast PTFE balloon-expandable stents using the "sheath control technique" is safe and effective, and minimizes the risk of stent migration. PMID- 26627483 TI - The extreme capsule fiber complex in humans and macaque monkeys: a comparative diffusion MRI tractography study. AB - We compared the course and cortical projections of white matter fibers passing through the extreme capsule in humans and macaques. Previous comparisons of this tract have suggested a uniquely human posterior projection, but these studies have always employed different techniques in the different species. Here we used the same technique, diffusion MRI, in both species to avoid attributing differences in techniques to differences in species. Diffusion MRI-based probabilistic tractography was performed from a seed area in the extreme capsule in both human and macaques. We compared in vivo data of humans and macaques as well as one high-resolution ex vivo macaque dataset. Tractography in the macaque was able to replicate most results known from macaque tracer studies, including selective innervation of frontal cortical areas and targets in the superior temporal cortex. In addition, however, we also observed some tracts that are not commonly reported in macaque tracer studies and that are more reminiscent of results previously only reported in the human. In humans, we show that the ventrolateral prefrontal cortex innervations are broadly similar to those in the macaque. These results suggest that evolutionary changes in the human extreme capsule fiber complex are likely more gradual than punctuated. Further, they demonstrate both the potential and limitations of diffusion MRI tractography. PMID- 26627485 TI - Functional Imaging of the Foot with Perfusion Angiography in Critical Limb Ischemia. AB - PURPOSE: To report on the first clinical experience with perfusion angiography (PA) of the foot in patients with chronic critical limb ischemia. MATERIALS AND METHODS: PA is a post-processing software algorithm and no extra digital subtraction angiography (DSA) has to be performed for this analysis. The data used to test the feasibility of PA were obtained from a consecutive group of 89 patients with CLI who were treated with standard below the knee angioplasty and 12 separate patients who were not suitable for endovascular revascularization. RESULTS: Motion artifacts in the dataset of the DSA made post-procedural analysis impossible in 10 % intervention. In the majority of patients (59/68) PA showed an increase in volume flow in the foot after successful angioplasty of the crural vessels. However, in 9/68 patients no increase was seen after successful angioplasty. With the use of a local administered competitive alpha-adrenergic receptor antagonist, it is also possible to test and quantify the capillary resistance index which is a parameter for the remaining functionality of the microcirculation in CLI patients. CONCLUSION: PA might be used as a new endpoint for lower limb revascularization and can also be used to test the functionality the microcirculation to identify sub-types of patients with CLI. Clinical evaluation and standardization of PA is mandatory before introduction in daily practice. PMID- 26627486 TI - Who, when, and how to reverse non-vitamin K oral anticoagulants. AB - Non-vitamin K oral anticoagulants (NOACs) have been a major addition to our therapeutic armamentarium. They are at least as effective as warfarin in the thromboprophylaxis of non-valvular atrial fibrillation and management of thromboembolic disease, with a more favorable safety profile. Their predictable pharmacokinetics and pharmacodynamics allow for a fixed oral dosing without the need for anticoagulation monitoring. A major concern regarding NOACs is the lack of a readily available antidote to reverse their anticoagulation effect in case of life-threatening bleeding or need for emergent surgery. In this review, we summarize preclinical and clinical data on (a) hemostatic agents used to reverse NOACs, and (b) novel, target-specific NOACs reversal agents under development. The prothrombin complex concentrates, activated prothrombin complex concentrates and recombinant activated factor VII are hemostatic agents that have been assessed in reversing NOACs. Preclinical studies with hemostatic agents report variable results and there is only limited clinical data available to date. Idarucizumab and andexanet alfa are NOAC-specific reversal agents designed to reverse dabigatran and factor Xa inhibitors accordingly. Aripazine is a universal anticoagulation reversal agent. Preclinical studies show promising results and these agents are already in different stages of clinical development. Phase I and II clinical trials demonstrate efficacy in reversing NOACs without major side effects. Until these agents become commercially available, management of patients receiving NOACs who present with major bleeding or require emergent surgery should focus on (a) immediate discontinuation of NOACs, (b) supportive measures or postponing surgery for 12-24 h after the last NOAC dose, and/or PMID- 26627488 TI - Social Entrepreneurship for Obesity Prevention: What Are the Opportunities? AB - In recent years, social entrepreneurship has emerged as a new field to address social and public health challenges. Social entrepreneurship, which harnesses traditional business practices and market forces to address social challenges, may produce solutions that are more cost-effective and sustainable than those produced by governmental and nonprofit sectors. In this paper, we discuss whether and how social entrepreneurship can be harnessed for obesity prevention by defining and briefly reviewing the rise of social entrepreneurship in the USA, outlining the threat that obesity poses to US society and offering some examples of how social ventures are addressing the problem of obesity. Additional untapped opportunities are also discussed and recommendations given for how social entrepreneurship might impact obesity prevention in the future. PMID- 26627487 TI - An Overview of Links Between Obesity and Mental Health. AB - The American Medical Association recently recognized obesity as both an illness and a leading cause of preventable death and chronic disease. This association is not only linked to physical health outcomes, however, as obesity has also been extensively associated with mental illness as well. Both obesity and severe mental illness decrease quality of life and are associated with an increase in disability, morbidity, and mortality, and when they occur together, these adverse health outcomes are magnified. Despite educational campaigns, increased awareness, and improved treatment options, the high prevalence of mental illness and comorbid obesity remains a serious problem. This review examines this overlap, highlighting clinical and biological factors that have been linked to this association in order to improve our understanding and help elucidate potential therapeutic avenues. PMID- 26627489 TI - Obesity Genes, Personalized Medicine, and Public Health Policy. AB - The personalized medicine movement-also known as precision medicine and personalized genomics-has embraced the belief that genetic risk information can be used to motivate healthier choices and meaningful behaviour change. While a genuinely exciting area of research, there are numerous policy issues associated with a focus on the use of genetic risk information to personalize approaches to obesity prevention. PMID- 26627490 TI - Ethical Issues for Public Health Approaches to Obesity. AB - Obesity is a major public health concern worldwide. Because individual-level interventions have been unsuccessful at curbing obesity rates, there is an emphasis on public health approaches. In addition to testing the effectiveness of any public health interventions, it is important to consider the ethical implications of these interventions in order to protect the public's rights and promote overall well-being. In this paper, we review public health approaches to obesity in three broad domains (changes to the socio-communicative environment, changes to the economic environment, and changes to the physical environment/access) and consider the potential ethical issues that arise in each of those domains. We suggest that interventions that target the physical environment/access (making it easier for people to engage in healthy behaviors), that target the entire population (rather than just individuals with obesity), and that focus on health behaviors (rather than on weight) have the least potential for ethical concerns. PMID- 26627491 TI - Long-Term Outcomes of Obesity Surgery and Implications for Health System Planning. AB - Weight loss surgery is currently the only treatment that offers significant and sustained weight loss for those with severe and complex obesity. Obesity levels have reached a sustained high, whereby several percent of a country's population would qualify for surgery based upon current national guidelines. Worldwide, the provision of surgery is highly variable and to treat all the affected population, it would require at least a 100-fold increase in the provision of services. This has important cost and commissioning implications for health-care planners. Reliable level 1 evidence of the long-term effects of obesity surgery is still lacking, and the long-term complication profiles and re-operation rates unclear, which could have significant impact on health-care systems in the future. The chronic disease management of obesity in a population must be integrated with education and prevention and the brief intervention of weight loss surgery and the management of its sequelae, to prevent significant future morbidity and mortality. PMID- 26627492 TI - The Double Burden of Undernutrition and Overnutrition in Developing Countries: an Update. AB - Many developing countries have achieved a remarkable improvement in nutrition status in the past decades. However, the prevalence of undernutrition remains a serious problem. At the same time, the prevalence of obesity is increasing substantially, and in some countries, it has approached that of developed countries. This article provides an update on this double burden of malnutrition (DBMN) in developing nations. One hundred countries (lower, middle-lower, and upper-middle income countries) were selected and analysed, and to support the analysis, a systematic review of current published studies was performed. The results show that DBMN already exists in almost all developing countries and that the DBMN ratio (i.e., overweight/underweight) has increased as income per capita has increased. DBMN may manifest within the community, household, or individual. In addition to common factors, poor nutrition in early childhood is suggested as another important driving factor behind the rising obesity rate in most developing countries. A life-course approach has been proposed to prevent undernutrition and overnutrition and should be integrated into the development of health systems to control double burden in developing countries. PMID- 26627493 TI - A Review of the Relationship Between Socioeconomic Position and the Early-Life Predictors of Obesity. AB - A range of important early-life predictors of later obesity have been identified. Children of lower socioeconomic position (SEP) have a steeper weight gain trajectory from birth with a strong socioeconomic gradient in child and adult obesity prevalence. An assessment of the association between SEP and the early life predictors of obesity has been lacking. The review involved a two-stage process: Part 1, using previously published systematic reviews, we developed a list of the potentially modifiable determinants of obesity observable in the pre natal, peri-natal or post-natal (pre-school) periods; and part 2, conducting a literature review of evidence for socioeconomic patterning in the determinants identified in part 1. Strong evidence was found for an inverse relationship between SEP and (1) pre-natal risk factors (pre-pregnancy maternal body mass index (BMI), diabetes and pre-pregnancy diet), (2) antenatal/peri natal risk factors (smoking during pregnancy and low birth weight) and (3) early-life nutrition (including breastfeeding initiation and duration, early introduction of solids, maternal and infant diet quality, and some aspects of the home food environment), and television viewing in young children. Less strong evidence (because of a lack of studies for some factors) was found for paternal BMI, maternal weight gain during pregnancy, child sleep duration, high birth weight and lack of physical activity in young children. A strong socioeconomic gradient exists for the majority of the early-life predictors of obesity suggesting that the die is cast very early in life (even pre-conception). Lifestyle interventions targeting disadvantaged women at or before child-bearing age may therefore be particularly important in reducing inequality. Given the likely challenges of reaching this target population, it may be that during pregnancy and their child's early years are more feasible windows for engagement. PMID- 26627494 TI - Overweight and Obesity: Prevalence, Consequences, and Causes of a Growing Public Health Problem. AB - This review considers a variety of perspectives on overweight and obesity (OW/obesity), including measurement and classification; prevalence and changes in prevalence in recent years; genetic, biological, medical, individual, and social correlates of OW/obesity; and treatment approaches. Despite increased attention, OW/obesity is escalating in prevalence worldwide, and the causes are exceedingly complex. A range of innovative studies, including basic research on gut microflora, dietary composition, pharmacologic interventions, and surgical procedures, is generating findings with potential for future prevention and treatment of OW/obesity. Social system changes such as school programs and the awareness of the roles of personal, family, health provider, and cultural experiences related to OW/obesity have also gained traction for vital prevention and treatment efforts over the past decade. PMID- 26627495 TI - How Can We Better Prevent Obesity in Children? AB - The aim of this review is to discuss the state of the art regarding the field of health promotion in the context of childhood obesity prevention in order to learn how we can better prevent childhood obesity. Challenges have been identified that exist within the different steps of health promotion programme development and implementation. Important steps forward include studying behaviours and determinants of behaviours as clusters, upgrading the importance of distal environmental factors in modelling determinants and understanding determinants as a dynamic system: a complex of interacting elements. An important note is that the process of implementation and the analysis thereof should more often come before the analysis of behaviours and the determinants of behaviour. In applied research, the expertise from the 'real world' practitioners should be used in an early stage to find out whether the answers on research questions really help us in preventing childhood obesity. PMID- 26627496 TI - Weight Management in Older Adults. AB - As the number of older adults increases rapidly, the national epidemic of obesity is also affecting our aging population. This is particularly concerning given the numerous health risks and increased costs associated with this condition. Weight management is extremely important for older adults given the risks associated with abdominal adiposity, which is a typical fat redistribution during aging, and the prevalence of comorbid conditions in this age group. However, approaches to weight loss must be considered critically given the dangers of sarcopenia (a condition that occurs when muscle mass and quality are lost), the increased risk of hip fracture with weight loss, and the association between reduced mortality and increased BMI in older adults. This overview highlights the challenges and implications of measuring adiposity in older adults and the dangers and benefits of weight loss in this population and provides an overview of the new Medicare Obesity Benefit. In addition, we provide a summary of outcomes from successful weight loss interventions for older adults and discuss implications for advancing clinical practice. PMID- 26627497 TI - Evaluation of a follow-up protocol for patients on chloroquine and hydroxychloroquine treatment. AB - OBJECTIVE: To review the problems found after a new follow-up protocol for patients on chloroquine and hydroxychloroquine treatment. METHOD: Retrospective study was conducted between May 2012 and January 2013 on the clinical files, retinographies, fundus auto-fluorescence (FAF) images, and central-10 degree visual fields (VF) of patients who were referred to the Ophthalmology Department as they had started treatment with hydroxychloroquine. RESULTS: One hundred twenty-six patients were included; 94.4% were referred from the Rheumatology Department and 5.6% from Dermatology. Mean age was 59.7 years, and 73.8% were women. All of them were on hydroxychloroquine treatment, and 300mg was the most frequent daily dose. Rheumatoid arthritis was the most common diagnosis (40.5%), followed by systemic lupus erythematosus (15.9%). The mean Snellen visual acuity was 0.76, and 26 patients had lens opacities. The VF were normal in 97 patients, 8 had mild to moderate defects with no definite pattern, and in 9 the results were unreliable. Of the 51 patients older than 65years, 16 (31.4%) had altered or unreliable VF. The FAF was normal in 104 patients (82.5%), and abnormal, but consistent with ophthalmoscopic features, in 12 patients (pathological myopia, age related changes, early, middle or late age-related macular degeneration). CONCLUSIONS: Visual fields as a reference test for the diagnosis of AP toxicity are not quite reliable for patients over 65. Therefore, the FAF is recommended as primary test, perhaps combined with another objective test, such as SD-OCT instead of VF. PMID- 26627499 TI - The reasons why cardiologists should consider prematurity at birth and intrauterine growth retardation among risk factors. AB - The survival percentage of infants born preterm has risen steadily worldwide thanks to the giant steps forward made in the field of perinatal (the period immediately after birth) and neonatal (the first 4 weeks of birth following delivery) medicine. However, prematurity at birth and consequent low birth weight still represent the major causes of neonatal morbidity and mortality. Infants born preterm are at high risk of developing neurological, ophthalmological, and gastrointestinal complications as well. Furthermore, extensive more recent epidemiological findings have demonstrated an increase in risk factors and a higher mortality rate due to cardiovascular causes in patients born preterm and/or with intrauterine growth restriction. The aim of this review is to provide scientific evidence about how the cardiovascular system may be negatively influenced by prematurity and by a low birth weight that should by rights be viewed as new cardiovascular risk factors. This condition is referred to as 'cardiovascular perinatal programming'. In the light of the above, an early, constant, and prolonged cardiovascular follow-up should be implemented in former preterm individuals. PMID- 26627498 TI - Partial MHC Constructs Treat Thromboembolic Ischemic Stroke Characterized by Early Immune Expansion. AB - Inflammation and thrombosis are tightly linked, with inflammation contributing to thromboembolism and to stroke outcome. Thromboembolism is a frequent cause of ischemic stroke; yet, the most used occlusion mouse models of experimental stroke do not effectively replicate thromboembolism. Our group recently described a novel thromboembolic mouse model of stroke that successfully occludes the middle cerebral artery with high reproducibility. In the current study, we characterize the peripheral and local immune outcomes as well as the ischemic response to immune therapy in a clinically relevant mouse model of thromboembolic stroke. Brain and spleen tissues were harvested 24 h after thromboembolic stroke and cells immunophenotyped by flow cytometry. We observed a significant increase in neutrophils and early activated T cells in the spleen and an increase in neutrophils and activated monocytes/microglia in the ischemic cortex after thromboembolic stroke. Moreover, as was shown previously for transient MCAO models, treatment of thromboembolic stroke with partial MHC constructs significantly reduced ischemic damage indicating an equivalent effect of this immune-based therapy in the thromboembolic model that better mimics the pathophysiology of human stroke. PMID- 26627500 TI - Prognostic role of multiple biomarkers in stable patients undergoing fractional flow reserve-guided coronary angioplasty. AB - AIMS: Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI), along with optimal medical therapy, improves clinical outcome by targeting ischemia-inducing stenosis. Yet, plaque progression or stent failure may cause recurring cardiac events. We assessed the potential prognostic role of different inflammatory biomarkers, known to be associated with plaque progression or stent failure, in patients undergoing FFR-guided PCI. METHODS: We prospectively enrolled 169 stable angina patients with intermediate coronary stenosis at angiography undergoing FFR-guided PCI. PCI was performed if FFR was 0.80 or less, deferred if FFR was more than 0.80. Serum baseline levels of high-sensitivity C reactive protein (hs-CRP), eosinophil cationic protein (ECP), cystatin-C (Cys-C), and thromboxane A2 (TXA2) were assessed. Rate of major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, recurrent myocardial infarction, and target vessel revascularization (TVR), was evaluated. RESULTS: PCI was performed in 78 patients (46%) (mean age 69 +/- 10 years, men 73%) and deferred in 91 patients (54%) (mean age 64 +/- 11 years, men 53%). Mean clinical follow-up was 31 +/- 11 months. Within the PCI group, patients with MACE (n = 14 [18%]) had significantly higher ECP levels than those without (14.4 [9.3 19.5] vs. 4.9 [2.8-10.9] mg/l, P < 0.001), and ECP was a significant predictor of MACE (hazard ratio: 1.05, 95% confidence interval [1.01-1.09], P = 0.021). Within the deferred group, patients with MACE (n = 8 [9%]) had significantly higher CRP levels than those without (15 [6.5-31.9] vs. 1.6 [0.9-2.9] mg/l, P < 0.001) and CRP was a significant predictor of MACE (hazard ratio: 1.04, 95% confidence interval [1.01-1.07], P = 0.015). Cys-C and TXA2 were not significantly different between the two groups. CONCLUSION: Assessing inflammatory biomarkers allows the identification of patients remaining at residual higher risk of MACE after FFR guided PCI. PMID- 26627502 TI - Medical education: Knowledge, skills and attitude. PMID- 26627501 TI - Safety of warfarin therapy in chronic hemodialysis patients: a prospective cohort study. AB - BACKGROUND: We conducted a multicenter prospective cohort study to assess the safety of warfarin therapy in Japanese hemodialysis (HD) patients. METHODS: Chronic HD patients on warfarin therapy (warfarin users) were recruited from 111 HD centers in Japan. Two dialysis-vintage-matched warfarin non-users (non-users) were selected from the same HD center as each warfarin user. Clinical data were collected upon registration and every 12 months thereafter for up to 36 months. RESULTS: The final cohort consisted of 365 warfarin users and 692 non-users and was followed for an average of 27.7 months. The mean age of warfarin users (68.8 +/- 10.6 years) was significantly higher than that of non-users (66.9 +/- 11.0 years, p < 0.001). The analyses by multivariate Cox proportional-hazard models showed that the age [hazard ratio (HR) = 1.07 for each 1-year increase, 95 % confidence interval (CI) 1.05-1.08, p < 0.001] was significantly associated with the death from any cause, but warfarin use (1.08, CI 0.75-1.57, p = 0.68) was not when being adjusted for sex, diabetes mellitus, antiplatelet use, and atrial fibrillation. The risk of composite events, which included death from any cause, stroke, cardiovascular disease, and peripheral arterial disease, was also associated with age but was not associated with warfarin use. CONCLUSION: The results of this study suggested that warfarin use by HD patients might not be harmful in chronic state, while the safety for the initiation of warfarin therapy in HD patients remained to be determined. PMID- 26627503 TI - Management of spinal tuberculosis - a metropolitan city based survey among orthopaedic and neurosurgeons. AB - OBJECTIVE: To explore the core understanding of spinal tuberculosis and its current management plans by orthopaedics and neurosurgeons. METHODS: The questionnaire-based study was conducted from July 2011 to November 2012 in Karachi and comprised consultant orthopaedics and neurosurgeons belonging to 4 private and 3 government tertiary care teaching hospitals and having a minimum five years of post-fellowship experience. A pre-designed questionnaire was used to explore the current practice in spinal tuberculosis regarding its clinical presentation, diagnosis and treatment. SPSS 15 was used for statistical analysis. RESULTS: There were 48 subjects in the study; 24(50%) orthopaedic surgeons and 24(50%) neurosurgeons. According to 44(91.70%) respondents, common age for spinal tuberculosis was second and third decades of life, and 37(77.08%)reported refractory back pain with or without neurological deficits as the commonest clinical finding. Typical magnetic resonance imaging findings was the uniform observation of all the 48(100%) respondents. Diagnosis was made by histopathological findings by 39(81.25%) respondents. Anti-tuberculosis therapy was started empirically on the basis of clinical, laboratory and radiological findings by 33(68.75%) respondents. Those in favour of giving anti-tuberculosis therapy for 18 months were 32(66.7%) respondents, and 33(68.75%) thought surgery does not expedite recovery. CONCLUSIONS: Extremely variable tools of diagnosis and diversified approaches for the treatment are alarming signs for the possible development of resistant strains and complications of spinal tuberculosis. PMID- 26627504 TI - Patient safety: Perceptions of Medical Students of Dow Medical College, Karachi. AB - OBJECTIVE: To assess medical students' perceptions about patient safety issues before the teaching of "patient safety" can be recommended. METHODS: The cross sectional survey was undertaken at the Dow Medical College and Civil Hospital, Karachi, in September, 2013. Data collection tool was a structured questionnaire administered to medical students. The main outcome measures were students' perceptions about patient safety issues and their attitude towards teaching of patient safety curriculum. RESULTS: There were 229 medical students in the study with a response rate of 100%. Overall, 129(57%) students agreed that medical errors were inevitable, but 106 (46.9) thought competent physicians do not make errors. While 167(74%) students said medical errors should be reported, 204(90%) thought reporting systems do not reduce future errors. Besides, 90(40%) students thought only physicians can determine the causes of error and nearly 177(78%)% said physicians should not tolerate uncertainty in patient care. Overall, 217(96%) agreed that patient safety is an important topic; 210(93%) agreed that it should be part of medical curriculum; 197(87%) said they would like to learn how to disclose medical errors to patients and 203(90%) to faculty members. CONCLUSIONS: A significant knowledge gap existed among medical students regarding patient safety issues. The teaching of 'patient safety' was highly supported by students and needs to be included in medical curriculum on an urgent basis. PMID- 26627505 TI - Duration effect of Acacia nilotica leaves extract and glibenclamide as hypolipidaemic and hypoglycaemic activity in alloxan induced diabetic rats. AB - OBJECTIVE: To compare the duration and effects of aqueous methanol Acacia nilotica leaves extract and glibenclamide as hypoglycaemic and hypolipidaemic activity in diabetic rats. METHODS: The experimental study was conducted at Shifa International Hospital in collaboration with National Institute of Health, Islamabad, from September 2010 to August 2011.Male Sprague Dawley albino rats were taken and divided into 8 equal groups. Groups I and II were the normal and diabetic control rats. Diabetes mellitus was induced in group II to VIII by administering 110 mg/kg body weight alloxanand at day 4, fasting blood glucose level of >200 mg/dl confirmed diabetes. Acacia-nilotica leaves extract was given to group III, IV and V and glibenclamide to group VI to VIII for a period of 1-3 weeks. Blood samples were analysed for lipid profile using enzymatic calorimetric method and serum insulin by enzyme-linked immunosorbent assay on days 0, 7, 14, and 21. RESULTS: There were 64 rats in the study, with 8(12.5%) in each group. Statistically significant decreases in fasting blood glucose, total cholesterol, triglyceride, phospholipids, low density lipoprotein, very low density lipoprotein and an increase in high density lipoprotein and serum insulin levels were observed in diabetic rats compared to diabetic controls after 2 weeks of treatment with plant extract and glibenclamide (p<0.05 each).When plant extract and drug treated diabetic rats were compared, a significant difference in the levels of blood glucose, insulin, total cholesterol and triglyceride levels were noted after 2 and 3 weeks of treatment. CONCLUSIONS: Acacia-nilotica leaves extract resulted in hypoglycaemic and hypolipidaemic effect in alloxan-induced diabetic rats similar to glibenclamide. PMID- 26627506 TI - Bacteraemia caused by Escherichia coli in cancer patients at a specialist center in Pakistan. AB - OBJECTIVE: To analyse the antimicrobial susceptibility patterns of Escherichia coli bacteraemia among cancer patients, and to assess the risk factors and outcomes of multidrug-resistant Escherichia coli bacteraemia. METHODS: The retrospective study was conducted at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, and comprised medical records of patients with Escherichia coli bacteraemia presenting between December 2012 and November 2013. Multivariable logistic regression analyses were used to determine the factors associated with the development and 30-day mortality of multidrug-resistant Escherichia coli bacteraemia. RESULTS: Out of 1603 episodes of bacteraemia, 227(35.6%) were caused by E.coli, of which 98(43.2%) were multidrug-resistant. In multivariable analysis, age less than 18 years (adjusted odds ratio 3.92; 95% confidence interval 1.43-10.68), presence of central venous catheter (adjusted odds ratio 2.12; 95% confidence interval 1.04-4.33) and exposure to piperacillin/tazobactam within 90 days prior to infection (adjusted odds ratio 2.37; 95% confidence interval 1.15-4.86) were identified as independent risk factors for acquisition of multidrug-resistant Escherichia coli bacteraemia. The overall 30 day mortality rate was 35.2% (80/227). Risk factors for mortality were intensive care unit admission (adjusted odds ratio 3.95; 95% confidence interval 1.79-8.71) and profound neutropenia (adjusted odds ratio 4.03; 95% confidence interval 1.55-10.49). CONCLUSIONS: Bloodstream infections with multidrug resistant Escherichia coli were common in cancer patients. However it was not a predictor of mortality. PMID- 26627507 TI - Introducing regular formative assessment to enhance learning among dental students at Islamic International Dental College. AB - OBJECTIVE: To evaluate the effectiveness of Formative Assessment in enhancing learning among dental students, and to interpret the assessment from students' perspective in this regard. METHODS: The experimental non-randomised controlled study was conducted from January to June 2013 at Islamic International Dental College, Islamabad, and comprised first year Bachelor of Dental Surgery students attending regular physiology lectures and tutorials. Summative assessments conducted at the end of each unit were included as pre-intervention tests. After one month's planning, central nervous system unit was delivered in a month's trial with four formative assessment and feedback sessions (one per week). Likert scale-based student feedback questionnaire was administered. Post-intervention summative assessment was done by Multiple Choice and Short Essay Questions. Data was analysed using SPSS 17. RESULTS: Out of 68 students, 64(94.1%) agreed that a conducive environment was maintained and 62(90%) agreed that such sessions should be continued throughout the year; 59(87%) reflected that the feedback provided by the teacher was timely and positive and ensured equitable participation; 56(82%)agreed that it enhanced their interest in the subject; 56(68%) agreed that they were now more focussed; and43(63%)were of the opinion that they have progressed in the subject through these sessions. There was highly significant improvement in the monthly post-intervention test scores compared to pre intervention test (p=0.000). CONCLUSIONS: Formative assessment sessions enhanced motivation and learning in first year dental students. Organised regular sessions with students' feedback may contribute to the development of pedagogic practice. PMID- 26627508 TI - The role of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in exacerbation of chronic obstructive pulmonary disease. AB - OBJECTIVE: To investigate whether neutrophil-lymphocyte ratio and platelet lymphocyte ratio like C-reactive protein can be used as markers of acute exacerbation in chronic obstructive pulmonary disease. METHODS: The cross sectional study was conducted at Konya Training and Research Hospital, Konya, Turkey, between December 2012 and April 2013, and comprised patients with stable and acute chronic obstructive pulmonary disease. All participants were male and aged >40 years. Patients were included prospectively from outpatient and emergency units according to recent Initiative for Chronic Obstructive Lung Disease 2013 criteria. C-reactive protein, neutrophil-lymphocyte ratio and platelet-lymphocyte ratio of each group were measured and compared. RESULTS: Of the 94 patients, 48(51%) had stable disease with a mean age of 66.65+/-10.17 years (range: 49-79 years), and 46(49%) had acute exacerbation with a mean age of 62.67+/-9.41 years (range: 48-92 years). Mean levels of C-reactive protein, neutrophil-lymphocyte ratio and platelet-lymphocyte ratio were 5.04+/-6.65, 2.75+/-1.11 and 137.39+/-65.42 for stable disease, and 57.68+/-58.49, 7.99+/-5.72 and 231.18+/-141.36 for those with acute exacerbation (p=0.001). Cut-off values were neutrophil-lymphocyte ratio =3.3, platelet-lymphocyte ratio =150, and C reactive protein =5 mg/dl. Positive predictive values for C-reactive protein, neutrophil-lymphocyte ratio and platelet-lymphocyte ratio were determined as 82% (odds ratio: 27.4); 85% (odds ratio: 32.5); and 73% (odds ratio: 6.3) . Receiver operating characteristic curve showed a significantly more area under curve of neutrophil-lymphocyte ratio (0.88) compared to platelet-lymphocyte ratio (0.74) (p<0.05). CONCLUSIONS: During acute exacerbations of chronic obstructive pulmonary disease, neutrophil-lymphocyte ratio may be used as an easily measurable, available and cost-effective parameter with high prognostic accuracy in clinical practice. PMID- 26627509 TI - The decision-making matrix of propensity to outsourcing hospital services in Bandar Abbas, Iran. AB - OBJECTIVE: To determine the level of managers' propensity for outsourcing the services in hospitals using decision-making matrix. METHODS: The applied, cross sectional study was conducted at three hospitals affiliated to Bandar Abbas University of Medical Sciences, Iran, in 2013, and comprised managers and employees of four service units: radiology, laboratory, nursing, and nutrition services. Data was collected using two questionnaires and face-to-face interviews. Data was analysed using SPSS 16 and by using decision-making matrix. RESULTS: Of the 122 subjects in the study, 12(9.8%) were managers and 110(90.2%) were other employees. The highest and lowest propensities for outsourcing were related to nutrition (66.6%) and nursing services one (8.33%). The decision making matrix showed low outsourcing of the nursing, radiology, and laboratory services based on the services' features. However, there were difference between the results obtained from laboratory service decision-making matrix and the propensity for laboratory service outsourcing. CONCLUSIONS: The difference between the results obtained from the matrix and managers' viewpoint can be due to the lack of managers' sufficient attention to the features of hospital services when making decisions on outsourcing them. PMID- 26627510 TI - Variability study between Pap smear, Colposcopy and Cervical Histopathology findings. AB - OBJECTIVE: To determine the agreement/variability between colposcopic findings, Pap smear cytology and histopathological diagnosis in gynaecology patients. METHODS: The cross-sectional cohort study was conducted from October 2010 to September 2011 at the Fauji Foundation Hospital, Rawalpindi, and comprised women who presented to the out-patient department with various gynaecological complaints. Colposcopy was performed in all women with unhealthy cervix during gynaecological examination, abnormal Pap smear report, recurrent vaginal discharge and postcoital bleeding. Pap smear was performed before colposcopy if not done earlier. Colposcopic findings were recorded on a specially-designed proforma. Biopsies from abnormal areas were taken and sent for histopathology. Colposcopic findings were compared with histopathology and Pap smear reports The agreement between the methods was evaluated by using Kappa coefficient and chi square test at a significance level of 5%. RESULTS: The mean age of the 143 women was 44 8.5 years (range: 25-72 years). Colposcopic findings were normal in 66(46%) women, while 77(54%) had abnormal findings and among the latter, 62(80.5%) had abnormal histopathology, indicating strong agreement (K=0.65; p<0.001). Pap smear report was abnormal in 48(33.5%) cases and among them histopathology was abnormal in 28(58%). In the remaining 95(66.4%) patients with normal Pap smear, histopathology was abnormal in 44((46%), indicating weak agreement between Pap smear and histopathological diagnosis (K=0.10; p=0.08). CONCLUSIONS: There was a strong agreement between colposcopic findings and histopathological diagnosis. However, agreement between cytological findings and colposcopic findings and cytology and histopathological diagnosis remained weak. PMID- 26627511 TI - Prevalence of hypothyroidism in a cohort of Saudi women with heart failure and effect on systolic and diastolic function. AB - OBJECTIVE: To determine the prevalence of hypothyroidism in a cohort of Saudi women with heart failure; to define the demographic variables associated with heart failure; and the impact of hypothyroidism on systolic function in relation to non-hypothyroidism group. METHODS: The cross-sectional cohort study was conducted at King Abdulaziz University Hospital, Jeddah, Saudi Arabia, and comprised all women diagnosed with heart failure who were seen in the Cardiology outpatients clinic between February 2010 and March 2013. All of them were subjected to complete medical history and clinical examination, including complete cardiac clinical examination, electrocardiogram, echocardiography, blood pressure reading as well as thyroid examination. Laboratory tests were performed for thyroid stimulating hormone, total cholesterol, triglycerides, low-density lipoprotein and high-density lipoprotein. RESULTS: Of the 111 patients, 37 (33.3%) had hypothyroidism (p<0.001), and 16(14.4%) of them showed subclinical hypothyroidism. The mean value for thyroid stimulating hormone was 4.79+/ 4.98U/L. There was a significant negative correlation between thyroid stimulating hormone and ejection fraction. CONCLUSIONS: There was close relation between hypothyroidism and heart failure. Further large-scale studies are recommended for early detection of hypothyroidism. PMID- 26627512 TI - H. pylori positivity and various pathological, endoscopic and clinical features correlated with each other. AB - OBJECTIVE: To investigate the relationship between dyspepsia symptom scores and endoscopic appearances, and histopathological findings and helicobacter pylori positivity in patients having dyspepsia symptom. METHODS: The study was conducted at the gastroenterology outpatient clinic of Adnan Menderes University, School of Medicine, Aydin, Turkey from April 2012 to July 2012 and comprised patients between 18-65 years of age who were admitted with dyspepsia. Glasgow dyspepsia severity scoring was done with questions posed orally to the patients. In histopathological evaluation of biopsy specimens according to Sydney criteria, chronic inflammation, activity, atrophy, intestinal metaplasia and helicobacter pylori parameters were used. Total number of eosinophils and number of mast cells were recorded. RESULTS: Of the 60 patients with dyspepsia, 38(63.3%) were female and 22(36.7%) were male. The degree of activation and severity of inflammation increased significantly with increasing helicobacter pylori positivity(r=0.459'p<0.0001; r=0.475'p<0.0001). A significant relationship was found between inflammation, activation and the number of mast cells (p<0.05).There was no relationship between helicobacter pylori intensity and the eosinophil count (r=0.171; p=0.093). There was also a statistically significant correlation between severity of inflammation and activation and the number of eosinophils (r=0.313;p=0.002;r=0.245;p=0.016). CONCLUSIONS: Mast cell density was seen to have a role in the inflammatory processes of helicobacter pylori infection. PMID- 26627513 TI - Effective communication of critical radiology results: The implementation of panic alert mechanism. AB - OBJECTIVE: To establish an effective channel of timely communication of life threatening emergencies to primary physicians by radiology team. METHODS: The observational study was conducted at Aga Khan Hospital for Women and Children, Kharadar, Karachi. Data was collected from the log book from July 2012 to June 2013.Amultidisciplinary "Panic Alert" protocol was formulated and implemented in the Radiology unit. All radiological examinations were screened as soon as possible and panic alerts [provisional findings] were communicated to their primary care taker/relevant nursing staff, attendants within 30 minutes from the time of completion of examination. Complete log was maintained. Data was analysed on SPSS 13. RESULTS: A total of 22,474 patients were seen, and 77(0.34%) had panic provisional findings. The mean time for communicating the panic reporting was 19.5+/-8 minutes. Implementation of the designed protocol, effective communication and proper follow-up resulted in 100% coverage of panic results. CONCLUSIONS: Life-threatening emergencies identified by radiological imaging can be managed effectively if alerts are generated in time. PMID- 26627514 TI - Effect of raised body fat on vitamin D, leptin and bone mass. AB - OBJECTIVE: To estimate leptin, vitamin D and bone mineral density levels in individuals with high fat mass, and to assess any correlation. METHODS: The cross sectional study was conducted at the Basic Medical Sciences Institute, Jinnah Post Graduate Medical Centre, Karachi, and Aga Khan University, Karachi, from August 2012 to July 2014, and comprised healthy male volunteers between the ages of 18-60 years. Body fat percentage was determined using bioelectrical impedance analysis and the participants were classified as: Group A (15-21.9); Group B (22 27.9); and Group C (>28). Bone mineral density was calculated by ultrasound bone densitometer (T-score between +1 and ?1 considered normal). Enzyme-linked immunosorbent assay kits were used to determine the levels of vitamin D and leptin. SPSS 19 was used for statistical analysis. RESULTS: A total of 132 male subjects participated in this study, with each of the 3 groups having 44(33.3%). Despite all groups having low Vitamin D, a marked decrease was observed in group C compared to groups A and B (p <0.018). Bone mineral density T-score was <-1; total calcium was within normal range in all three groups. Serum leptin was raised in Group C compared to group A and B (p=0.03). Body fat percentage was negatively associated with vitamin D (p=0.004; r = -0.351), while it was positively correlated with leptin (p =0.038; r = 0.256). CONCLUSIONS: Excess of body fat percentage led to decreased vitamin D and raised leptin. However, bone mineral density and calcium levels were within normal range, suggesting that other factors might have played a role in maintaining bone mass in obese individuals, such as leptin. PMID- 26627515 TI - Prevalence of recognised and unrecognised depression among medical and surgical patients in a tertiary care hospital. AB - OBJECTIVE: To observe the prevalence of recognised and unrecognised depression among in-patients. METHODS: The cross-sectional study was conducted from June 2012 to May 2013 at a tertiary care hospital in Karachi, and comprised patients admitted in the Medicine and Surgical departments at the time. Patients with known history of depression or on anti-depressants or on anti-psychotics, or with suicidal attempt were excluded. The prevalence of unrecognised depression was then perceived using Patient Health Qurstionnaire-9. Statistical analysis was performed using SPSS 20. RESULTS: Of the 1180 patients, 432(36.6%) either had history of depression or on were on anti-depressants. The study sample, as such, comprised 748(65%), and of them 399(53%) were from the Medicine and 349(47%) patients were from Surgery department. Prevalence of recognised depression was 36.6%; 48% in Medical and 14% in Surgical patients. Unrecognised depression was 51.2%; 45.3% in Medical and 53.6 in Surgical patients. Overall prevalence was 87.9%; 93.4% in Medical and 53% in Surgical patients. Gender was not found to be significantly associated with depression in Medical (p= 0.367) and Surgical (p=0.606) patients. No depression was found in 48(12%) Medical patients and 131(37.5%) Surgical patients. CONCLUSIONS: More than one-third of in-patients had co-morbid depression diagnoses, mostly unrecognised by their clinicians. PMID- 26627516 TI - Early autologous cranioplasty after decompressive hemi-craniectomy for severe traumatic brain injury. AB - OBJECTIVE: To evaluate the outcome of early replacement of autologous bone flap for decompressive hemicraniectomy in severe traumatic brain injury patients. METHODS: The observational cross-sectional prospective study was conducted at the Neurosurgical Unit of the Combined Military Hospital, Rawalpindi, Pakistan, from July 2011, to June 2014, and comprised patients who underwent cranioplasty after decompressive hemicraniectomy for trauma. Patients over 20 years of age and of either gender were included. Cranioplasty was timed in all these patients using native bone flap preserved in the abdominal wall after decompressive craniectomy. Parameters recorded were mortality, wound infection, subdural collection, wound dehiscence, ventriculomegaly, bone resorption, cosmetic deformity and neurological outcome. SPSS 17 was used for data analysis. RESULTS: Of the 30 patients in the study, 28(93.3%) were males. The overall mean age was age 32.03+/ 8.01 years (range: 20-48 years). Mean cranioplasty time was 66.2+/-11.50 days (range: 44-89 days). Major infection necessitating bone flap removal was found in 1(3.33%) patient, while minor scalp wound infections, treated with antibiotics and dressings were found in 2(6.66%). Cosmetic18 deformity was seen in 3(10%). Improved neurological outcome was noted in 21(70 %) patients; 6(20%) survived with a moderate to severe disability and 3(10%) remained in a vegetative state. No mortality was found after the procedure. CONCLUSIONS: Early autologous bone replacement for decompressive hemicraniectomy in severe traumatic brain injury patients offered cost-effective, acceptable surgical and improve dneurological outcome. PMID- 26627517 TI - FSH/LH ratio in females and intracytoplasmic sperm injection. AB - OBJECTIVE: To observe the effect of follicle stimulating hormone-luteinizing hormone ratio on oocyte parameters, quality of embryo, implantation and clinical pregnancy rate after intracytoplasmic sperm injection. METHODS: The retrospective study was conducted at a fertility clinic in Islamabad, Pakistan, and comprised data of primary infertile females who underwent intracytoplasmic sperm injection from June 2011 to March 2013. All subjects had duration of infertility more than two years, and age range was 20-40 years. Follicle stimulating hormone and luteinizing hormone were estimated by enzyme-linked immunosorbent assay on day 3 of the cycle and the ratio was calculated. Groups were stratified on the basis of median ratio into groups I <1.26 and group II >1.26. SPSS 20 was used for data analysis. RESULTS: Of the 282 females, 143(51%) were in group I and 139(49%) in group II. Pregnancy was acquired by 79(55%) and 22(16%) females in group I and II respectively. The number of retrieved, metaphase, fertilised oocytes, cleaved embryos and endometrial thickness was significantly larger in group I (p< 0.0001). CONCLUSIONS: Follicle stimulating hormone-luteinizing hormone ratio less than 1.26 was associated with good oocyte parameters, top quality embryo and implantation after intracytoplasmic sperm injection. PMID- 26627518 TI - Perceptions of faculty and students regarding Problem Based Learning: A mixed methods study. AB - OBJECTIVE: To determine perception of faculty and students regarding problem based learning. METHODS: The study was conducted at Northern Border University, Arar, Kingdom of Saudi Arabia, from May 21to November 21, 2014. Data was collected on a structured close-ended questionnaire from faculty members. Application of problem-based learning by the faculty was assessed through observations of first such session of medical students. Observations were recorded on a structured checklist. Perceptions of students about learning methodology were determined through focused group discussion which was audio taped and transcribed. Qualitative data was analysed through content analysis and quantitative data through SPSS 16. RESULTS: Of the 60 faculty members, 44(73%) took part in the study. Of them, 35(79.5%) were males and 9(20.5) were females. There were 23(52%) assistant professors and 31(70.45%) were trained in problem based learning. Overall, 22(50%) faculty members thought that it was better than lecture-based learning; and 32(72.7%) stated that they conducted problem-based learning in classic seven jumps. In focus group discussions, students appreciated learning subject content but could not identify other benefits of problem-based learning. CONCLUSIONS: Faculty still had to come to terms with application of problem-based learning methodology. PMID- 26627519 TI - Implementation of the Mental Health Act; are we ready? AB - After the 18th amendment in the constitution health becomes a provincial subject in Pakistan. Sindh Provincial Assembly took the lead and passed the Mental Health Act on 19th September 2013. On 10 April 2015, Sindh assembly passed an amendment that a person who attempts to kill himself or be accused of blasphemy should be examined by a psychiatrist and given treatment if found suffering from a mental illness. It is clear that the act is aimed to help in improving the delivery of mental health care and to protect the rights of mentally ill individuals. Will it meet its intended aims? We have discussed the challenges that lie ahead with special reference to Pakistan. Until we understand these challenges, we will not be able to propose the possible solutions to reach the intended goal of this Act and could avoid the failure of implementation of a similar law "the Mental Health Ordinance 2001". PMID- 26627520 TI - Overcrowding in the emergency departments: Challenges and opportunities for improvement. AB - With the advent of Emergency Medicine, one can observe an increase in the number of Emergency Departments (ED) across the country. However, most EDs struggle due to an overwhelming number of patients. Overcrowding can lead to delays in patient care. For a city like Karachi which is an active disaster zone, preemptive preparedness is required in the face of terror threats and such overcrowding needs to be decreased to a bare minimum. The most frequent causes of prolonged length of stay (LOS) in the ED include non-availability of in-hospital beds, delays in response to subspecialty consultations and escalating medical expenses. All of these can negatively impact patient care by putting patient safety at risk and patient care in jeopardy. There is an increased risk of unintentional medical errors and a concomitant increase in unwanted lawsuits. A few simple interventions which may help alleviate this situation to some extent have been discussed. PMID- 26627521 TI - Developing paediatric emergency medicine - an opinion from a developing country tertiary care center. PMID- 26627522 TI - Kikuchi disease. AB - Kikuchi-Fujimoto Disease or Necrotizing Lymphadenitis is a rare, benign, self limiting disease. It usually effects young females in the third decade of life. The most common presentation is cervical lymphadenopathy, though the etiology of the disease is still controversial. Clinical findings, histological diagnosis and immunohistochemistry help in diagnosis. Once diagnosed, steroids have been found to alleviate symptoms in patients with systemic manifestations. Antibiotics should not be prescribed until infective element is identified. We report the case of a female patient who presented with tender cervical lymphadenopathy. She was diagnosed on excision biopsy of one of her lymph nodes. Anti-inflammatory drugs were started but the disease relapsed briefly after. Her symptoms have improved remarkably after initiation of steroid therapy, since her relapse. PMID- 26627523 TI - The use of corticosteroids in management of Herpes associated Erythema Multiforme. AB - Erythema multiforme (EM) is an acute self-limiting condition considered to be hypersensitivity reaction associated commonly with infections or medications. It is characterized by skin lesions, with oral or other mucous membrane involvement. Occasionally EM may involve the mouth alone. We report a ten year-old healthy male child who developed skin lesions of both palms and soles associated with oral ulcerative lesions. The patient first noticed the lesions on the palms and soles followed by involvement of the oral cavity in form of multiple haemorrhagic crusting ulcerations involving lips and buccal mucosa. The diagnosis was established clinically based on the signs and symptoms as erythema multiforme minor associated with herpes simplex infection. Systemic corticosteroids as a treatment modality should always be considered for the treatment of erythema multiforme minor. PMID- 26627524 TI - Enterolith causing bladder outlet obstruction in patient with imperforate anus. A rare case presentation. AB - Imperforate anus is a rare anomaly associated with defects commonly referred to as vertebral defects, anal atresia, cardiac defects, tracheo-oesophageal fistula, renal anomalies and limb abnormalities (VACTERL). With modern surgical procedures the overall outcome is excellent. Permanent colostomy which is required in some cases of this disease can result in some rare complications such as enteroliths formation, as illustrated in the case we are presenting here related to a 28-year old male who reported at urology emergency with features of urinary and acute large bowel obstruction. On investigation he was found to have two enteroliths in his distal loop of sigmoid colostomy. The more distal of the two enteroliths caused urinary retention and hence acute renal failure, and the proximal one caused large bowel obstruction by compressing the proximal loop of colostomy. This case demonstrates that the blind distal sigmoid colostomy loop can grow enteroliths secondary to stasis of its own contents over a long period. PMID- 26627525 TI - Acute caecal volvulus: A diagnostic paradigm. AB - Acute Caecal Volvulus is a rare etiology in cases of Intestinal obstruction. We are presenting the data of 11 cases out of 1032 cases of intestinal obstruction between June 2008 to June 2013, who presented in the emergency department of Bahawal Victoria Hospital Bahawalpur. The mean age was 36+/-3.38 years with female preponderance in this retrospective study. The persistent distinctive features were chronic intermittent pain followed by the passage of flatus (54%), severe right lower quadrant colicky pain (31%) and abdominal distention (59%). Radiologically the dilated caecum with air fluid level (68%) was persistent finding with lateralization of small gut in few patients (12%). Cecopexy (18%), right Hemicolectomy with primary anastomosis (63.63%) and Ileostomy with mucous fistula (18%) were offered. Wound sepsis (27%) and chest infection (18%) were common sequele. Acute Caecal Volvulus diagnosis requires a heightened clinical suspicion on the basis of symptoms like RLQ pain/mass which is relieved by passage of flatus and early radiological assistance in all cases of intestinal obstruction. PMID- 26627526 TI - Ambulatory glucose profile: Flash glucose monitoring. AB - Ambulatory glucose profile (AGP) is a novel way of assessing glycaemic levels on a 24 hour basis, through a minimally invasive method, known as flash glucose monitoring. This review describes the unique features of AGP, differentiates it from existing methods of glucose monitoring, and explains how it helps pursue the glycaemic pentad. The review suggests pragmatic usage of this technology, including pre-test, intra-test, and post-test counselling, and lists specific clinical scenarios where the investigation seems to be of immense benefit. PMID- 26627527 TI - Initiation of insulin. PMID- 26627528 TI - Counselling: An issue that needs emphasis. PMID- 26627529 TI - Endotracheal intubation - A life saving procedure, still potential hazardous to upper airway: A case report. AB - Endotracheal intubation plays a key role in the management of upper airway obstruction in emergency situations. It is non-invasive and easily learned technique by medical professionals as compared to other more skilled, surgical procedures, e.g., tracheostomy and cricothyrotomies etc. But prolonged intubation may result in numerous complications, most notorious being tracheoesophageal fistula and narrowing of subglottic area. We report a profile of a patient who had been diagnosed as case of Guillian-Barre Syndrome, had difficulty in breathing due to paralysis of respiratory muscles. The patient was admitted in Medical Intensive Care Unit (MICU) for 40 days and was kept on artificial breathing through endotracheal intubation, which remained in place for 19 days. Later tracheostomy was performed. Patient ultimately developed severe subglottic stenosis and became dependent on tracheostomy tube. PMID- 26627530 TI - Intracoronary infusion of Wharton's jelly-derived mesenchymal stem cells: a novel treatment in patients of acute myocardial infarction. PMID- 26627531 TI - Flourishing in later life. AB - OBJECTIVE: Flourishing is a relatively new concept in positive psychology that considers hedonic and eudaimonic aspects of well-being. The current study aims to identify the prevalence and socio-demographic and health factors associated with flourishing among older Malaysians. METHODS: The sample for this study consisting of 2202 community-dwelling older Malaysians was obtained from a national survey entitled "Identifying Psychosocial and Identifying Economic Risk Factor of Cognitive Impairment among Elderly", conducted from May 2013 to April 2014. Data analyses were conducted using the IBM SPSS Version 22.0 and AMOS Version 22.0. RESULTS: The average age of the respondents was 69.05 (SD=6.24) years. Descriptive results showed that 50.1% of the respondents were flourishing in life, 36.3% were languishing, 8.4% were struggling, and 5.2% were floundering in life. The results of Multiple logistic regression analysis revealed that gender, employment status, level of education, having living children, and chronic medical conditions are significantly associated with flourishing. However, age, marital status, living alone, and economic status did not have much impact on flourishing. CONCLUSION: To the best of our knowledge, the current study is one of the first studies that conceptualizes and assesses flourishing among older adults in Malaysia. The findings from the present study make important contributions to the existing literature on well-being. It is suggested that health and social care professionals working with older adults adopt a comprehensive approach to identify and propel non-flourishing people toward flourishing in life. PMID- 26627532 TI - Effect of laser therapy on immune cells infiltrate after excisional wounds in diabetic rats. AB - BACKGROUND AND OBJECTIVE: Diabetes alters innate and specific immunity, causing an imbalanced tissue repair process. Very active neutrophils and macrophages are found for a long time in chronic wounds in those individuals. The aim of this study was to evaluate the response of the main effector cells of immunity (neutrophils, macrophages, and T lymphocytes) and to compare the effects of two laser therapy regimens in the postoperative treatment of excision wounds. METHOD: Diabetes was induced in female Wistar rats and a punch was used to cause wounds in the dorsum of each individual. The animals were randomly allocated to a control group (CG), in which the wound was untreated, a single-dose laser group (SLG), in which the wound was submitted to single dose of laser therapy at wavelength of 660 nm, output power of 30 mW, energy density of 4 J/cm(2), and 26 second exposure time, and a fractionated-dose laser group (FLG), submitted to 1 J/cm(2) of laser therapy on Days 1, 3, 8, and 10. Euthanasia was performed on five animals from each group Days 1, 3, 8, 10, 15, and 22. The wound was removed and routinely processed for immunohistochemistry against elastase, CD3, CD68, and CD206 antibodies. The samples were photographed and labeled cells were counted by a blinded observer. The Kruskal-Wallis test was used for the statistical analysis. RESULTS: Neutrophils were predominant in the SLG on Day 1, whereas these cells were mostly found in the CG on Day 3 (P < 0.05). The T lymphocyte count was similar in all groups in the throughout the experiment. On Day 3, the SLG exhibited a greater number of total macrophages (CD68+) (P < 0.05), whereas the macrophage count was similar among the different groups on the other evaluation days. The CD206 + cell counts revealed that the SLG had more M2 macrophages than the CG on Day 8 (P < 0.05), whereas the FLG exhibited more M2 macrophages than the CG on Day 10 (P < 0.05). CONCLUSION: The present findings demonstrate that laser therapy can alter the composition of inflammatory infiltrate in diabetic wounds, leading to a more balanced response transiting from a rapid neutrophil infiltration through to M2 macrophage polarization, especially with a single application of 4 J/cm(2) in the immediate postoperative period. PMID- 26627533 TI - Anchoring structure of the calvarial periosteum revealed by focused ion beam/scanning electron microscope tomography. AB - An important consideration in regeneration therapy is the fact that the tissue surrounding an organ supports its function. Understanding the structure of the periosteum can contribute to more effective bone regeneration therapy. As a cellular source, the periosteum also assists bone growth and fracture healing; this further necessitates its direct contact with the bone. However, its anchoring strength appears to be inexplicably stronger than expected. In this study, we used focused ion beam/scanning electron microscope tomography to investigate ultrathin serial sections as well as the three dimensional ultrastructure of the periosteum to clarify the architecture of its anchoring strength, as such assessments are challenging using conventional methods. We discovered perforating fibres that arise from the bone surface at 30 degree angles. Additionally, the fibres across the osteoblast layer were frequently interconnected to form a net-like structure. Fibroblast processes were observed extending into the perforating fibres; their morphologies were distinct from those of typical fibroblasts. Thus, our study revealed novel ultrastructures of the periosteum that support anchorage and serve as a cellular source as well as a mechanical stress transmitter. PMID- 26627536 TI - The promises and problems of transpulmonary pressure measurements in acute respiratory distress syndrome. AB - PURPOSE OF REVIEW: The optimal strategy for assessing and preventing ventilator induced lung injury in the acute respiratory distress syndrome (ARDS) is controversial. Recent investigative efforts have focused on personalizing ventilator settings to individual respiratory mechanics. This review examines the strengths and weaknesses of using transpulmonary pressure measurements to guide ventilator management in ARDS. RECENT FINDINGS: Recent clinical studies suggest that adjusting ventilator settings based on transpulmonary pressure measurements is feasible, may improve oxygenation, and reduce ventilator-induced lung injury. SUMMARY: The measurement of transpulmonary pressure relies upon esophageal manometry, which requires the acceptance of several assumptions and potential errors. Notably, this includes the ability of localized esophageal pressures to represent global pleural pressure. Recent investigations demonstrated improved oxygenation in ARDS patients when positive end-expiratory pressure was adjusted to target specific end-inspiratory or end-expiratory transpulmonary pressures. However, there are different methods for estimating transpulmonary pressure and different goals for positive end-expiratory pressure titration among recent studies. More research is needed to refine techniques for the estimation and utilization of transpulmonary pressure to guide ventilator settings in ARDS patients. PMID- 26627535 TI - MicroRNAs and Endothelial (Dys) Function. AB - Accumulating evidence indicates that microRNAs (miRs)-non-coding RNAs that can regulate gene expression via translational repression and/or post-transcriptional degradation-are becoming one of the most fascinating areas of physiology, given their fundamental roles in countless pathophysiological processes. The relative roles of different miRs in vascular biology as direct or indirect post transcriptional regulators of fundamental genes implied in vascular remodeling designate miRs as potential biomarkers and/or promising drug targets. The mechanistic importance of miRs in modulating endothelial cell (EC) function in physiology and in disease is addressed here. Drawbacks of currently available therapeutic options are also discussed, pointing at the challenges and clinical opportunities provided by miR-based treatments. J. Cell. Physiol. 231: 1638-1644, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26627537 TI - Management of acute hypercapnic respiratory failure. AB - PURPOSE OF REVIEW: The objective of this article is to review the most recent literature regarding the management of acute hypercapnic respiratory failure (AHRF). RECENT FINDINGS: In the field of AHRF management, noninvasive ventilation (NIV) has become the standard method of providing primary mechanical ventilator support. Recently, extracorporeal carbon dioxide removal (ECCO2R) devices have been proposed as new therapeutic option. SUMMARY: NIV is an effective strategy in specific settings and in selected population with AHRF. To date, evidence on ECCO2R is based only on case reports and case-control trials. Although the preliminary results using ECCO2R to decrease the rate of NIV failure and to wean hypercapnic patients from invasive ventilation are remarkable; further randomized studies are needed to assess the effects of this technique on both short-term and long-term clinical outcomes. PMID- 26627538 TI - Acute respiratory distress syndrome: the heart side of the moon. AB - PURPOSE OF REVIEW: Circulatory failure is a frequent complication during acute respiratory distress syndrome (ARDS) and is associated with a poor outcome. This review aims at clarifying the mechanisms of circulatory failure during ARDS. RECENT FINDINGS: For the past decades, the right ventricle (RV) has gained a crucial interest since many authors confirmed the high incidence of acute cor pulmonale during ARDS and showed a potential role of the acute cor pulmonale in the poor outcome of ARDS patients. The most important recent progress demonstrated in ARDS ventilatory strategy is represented by the prone position, which has a huge beneficial effect on RV afterload. This review will focus on the mechanisms responsible for the RV dysfunction/failure during ARDS and on the strategy, which allows improving the right ventricular function. SUMMARY: The RV has a pivotal role in the circulatory failure of ARDS patients. The ventilatory strategy during ARDS has to pay a peculiar attention to the RV to rigorously control its afterload. PMID- 26627539 TI - Patient-ventilator asynchrony. AB - PURPOSE OF REVIEW: The purpose of the review is to alert clinicians to the prevalent and frequently underrecognized problem of asynchrony in mechanically ventilated patients. To provide a mechanistic model of patient-ventilator asynchrony to help personnel understand how different asynchronies develop. To provide practical advice on how to recognize and solve different asynchronies in different contexts. RECENT FINDINGS: Patient-ventilator asynchrony is a serious problem that is associated with prolonged mechanical ventilation, prolonged ICU and hospital stays, and increased mortality. Asynchronies can occur in all modes of invasive and noninvasive ventilation in all care contexts. SUMMARY: The review provides insights into the causes of patient-ventilator asynchrony and mechanisms involved in the development of specific types of asynchrony. It explores the effects of sedation on the development of asynchrony and the impact of new ventilator modes. It also discusses the prevalence of asynchrony and its effects on outcome. PMID- 26627540 TI - Ventilator-induced diaphragmatic dysfunction: what have we learned? AB - PURPOSE OF REVIEW: The purpose of the review is to summarize and discuss recent research regarding the role of mechanical ventilation in producing weakness and atrophy of the diaphragm in critically ill patients, an entity termed ventilator induced diaphragmatic dysfunction (VIDD). RECENT FINDINGS: Severe weakness of the diaphragm is frequent in mechanically ventilated patients, in whom it contributes to poor outcomes including increased mortality. Significant progress has been made in identifying the molecular mechanisms responsible for VIDD in animal models, and there is accumulating evidence for occurrence of the same cellular processes in the diaphragms of human patients undergoing prolonged mechanical ventilation. SUMMARY: Recent research is pointing the way to novel pharmacologic therapies as well as nonpharmacologic methods for preventing VIDD. The next major challenge in the field will be to move these findings from the bench to the bedside in critically ill patients. PMID- 26627541 TI - Brugada syndrome: More than 20 years of scientific excitement. AB - In 1992 we reported on eight patients with a particular electrocardiograph (ECG) showing ST segment elevation in the right precordial leads. All patients had a structurally normal heart and had survived one or multiple episodes of near sudden death caused by ventricular fibrillation. We showed 6 years later that this disease, known nowadays as Brugada syndrome, was caused by mutations in the SCN5A gene which encodes for the cardiac sodium channel. Other genes where mutations result in the same ECG have been also identified, with at present more than 17 different genes published. These data show that Brugada syndrome is a genetically heterogeneous disease as is also the case in the long QT syndrome. In Brugada syndrome, the clue to the initial clinical diagnosis remains the abnormal ECG. However, it was evident from the beginning that the ECG of Brugada syndrome is variable and sensitive to many autonomic, drug, exercise, emotions and other external influences such as a meal, fever, changes in heart rate from any cause, and even body position. When followed intensively, all patients with a Brugada ECG will show a completely normal ECG at one or another moment in their lives. The spontaneous normalization of the ECG represents a major diagnostic challenge, because a patient with Brugada syndrome seen during normalization of the ECG may fail to get the correct diagnosis. In these more than 20 years great challenges have been overcome but some remain, mainly the approach to the asymptomatic individual with a diagnosis of Brugada syndrome. In 30-50% of individuals who die suddenly because of documented or suspected Brugada syndrome, sudden death is the first manifestation of the disease. Thus, these individuals were fully asymptomatic until the first fatal event. PMID- 26627542 TI - Her Aching Bones: Atypical Parathyroid Adenoma. PMID- 26627543 TI - Structural Insight into the interaction of Flavonoids with Human Telomeric Sequence. AB - Flavonoids are a group of naturally available compounds that are an attractive source for drug discovery. Their potential to act as anti-tumourigenic and anti proliferative agents has been reported previously but is not yet fully understood. Targeting human telomeric G-quadruplex DNA could be one of the mechanisms by which these flavonoids exert anticancer activity. We have performed detailed biophysical studies for the interaction of four representative flavonoids, Luteolin, Quercetin, Rutin and Genistein, with the human telomeric G quadruplex sequence tetramolecular d-(T2AG3T) (Tel7). In addition, we used NMR spectroscopy to derive the first model for the complex formed between Quercetin and G-quadruplex sequence. The model showed that Quercetin stabilises the G quadruplex structure and does not open the G-tetrad. It interacts with the telomeric sequence through pi-stacking at two sites: between T1pT2 and between G6pT7. Based on our findings, we suggest that Quercetin could be a potent candidate for targeting the telomere and thus, act as a potent anti-cancer agent. PMID- 26627544 TI - Folic acid supplementation influences the distribution of neural tube defect subtypes: A registry-based study. AB - Periconceptional folic acid (FA) reduces neural tube defect (NTD) risk, but seems to have a varying effect per NTD subtype. We aimed to study the effect of FA supplementation on NTD subtype distribution using data from EUROCAT Northern Netherlands. We included all birth types with non-syndromal NTDs born in 1997 2012. By Fisher's exact test we analyzed possible differences in NTD subtype distribution between a correct FA supplementation group and incorrect FA supplementation group. We found proportionally fewer cervical/thoracic spina bifida cases and more lumbar/sacral spina bifida cases in the correct FA supplementation group, irrespective of the presence of the main NTD risk factors. The effect on NTD subtype distribution was only seen when FA supplementation was started before conception. We conclude that FA not only prevents the occurrence of a significant proportion of NTDs, but might also decrease the severity of NTDs, as long as supplementation is started before conception. PMID- 26627545 TI - Corticosteroid therapy and airflow obstruction influence the bronchial microbiome, which is distinct from that of bronchoalveolar lavage in asthmatic airways. AB - BACKGROUND: The lung has a diverse microbiome that is modest in biomass. This microbiome differs in asthmatic patients compared with control subjects, but the effects of clinical characteristics on the microbial community composition and structure are not clear. OBJECTIVES: We examined whether the composition and structure of the lower airway microbiome correlated with clinical characteristics of chronic persistent asthma, including airflow obstruction, use of corticosteroid medications, and presence of airway eosinophilia. METHODS: DNA was extracted from endobronchial brushings and bronchoalveolar lavage fluid collected from 39 asthmatic patients and 19 control subjects, along with negative control samples. 16S rRNA V4 amplicon sequencing was used to compare the relative abundance of bacterial genera with clinical characteristics. RESULTS: Differential feature selection analysis revealed significant differences in microbial diversity between brush and lavage samples from asthmatic patients and control subjects. Lactobacillus, Pseudomonas, and Rickettsia species were significantly enriched in samples from asthmatic patients, whereas Prevotella, Streptococcus, and Veillonella species were enriched in brush samples from control subjects. Generalized linear models on brush samples demonstrated oral corticosteroid use as an important factor affecting the relative abundance of the taxa that were significantly enriched in asthmatic patients. In addition, bacterial alpha-diversity in brush samples from asthmatic patients was correlated with FEV1 and the proportion of lavage eosinophils. CONCLUSION: The diversity and composition of the bronchial airway microbiome of asthmatic patients is distinct from that of nonasthmatic control subjects and influenced by worsening airflow obstruction and corticosteroid use. PMID- 26627546 TI - Defective sirtuin-1 increases IL-4 expression through acetylation of GATA-3 in patients with severe asthma. PMID- 26627548 TI - Therapy: Reaching for the stars--effective HCV drugs for all? PMID- 26627549 TI - Intestinal tract: Gut endothelial cells--another line of defence. PMID- 26627547 TI - Oropharyngeal dysphagia: manifestations and diagnosis. AB - Swallowing disorders (dysphagia) have been recognized by the WHO as a medical disability associated with increased morbidity, mortality and costs of care. With increasing survival rates and ageing of the population, swallowing disorders and their role in causing pulmonary and nutritional pathologies are becoming exceedingly important. Over the past two decades, the study of oropharyngeal dysphagia has been approached from various disciplines with considerable progress in understanding its pathophysiology. This Review describes the most frequent manifestations of oropharyngeal dysphagia and the clinical as well as instrumental techniques that are available to diagnose patients with dysphagia. However, the clinical value of these diagnostic tests and their sensitivity to predict outcomes is limited. Despite considerable clinical research efforts, conventional diagnostic methods for oropharyngeal dysphagia have limited proven accuracy in predicting aspiration and respiratory disease. We contend that incorporation of measurable objective assessments into clinical diagnosis is needed and might be key in developing novel therapeutic strategies. PMID- 26627551 TI - Neurogastroenterology: Improving glucose tolerance via the gut-brain axis. PMID- 26627553 TI - Omental herniation following intrauterine transfusion. PMID- 26627554 TI - A review of approaches to optimise chest compressions in the resuscitation of asphyxiated newborns. AB - OBJECTIVE: Provision of chest compressions (CCs) and/or medications in the delivery room is associated with poor outcomes. Based on the physiology of perinatal asphyxia, we aimed to provide an overview of current recommendations and explore potential determinants of effective neonatal cardiopulmonary resuscitation (CPR): balancing ventilations and CC, CC rate, depth, full chest recoil, CC technique and adrenaline. DESIGN: A search in the databases MEDLINE (Ovid) and EMBASE until 10 April 2015. SETTING: Delivery room. PATIENTS: Asphyxiated newborn infants. INTERVENTIONS: CCs. MAIN OUTCOME MEASURES: Haemodynamics, recovery and survival. RESULTS: Current evidence is derived from mathematical models, manikin and animal studies, and small case series. No randomised clinical trials examining neonatal CC have been performed. There is no evidence to refute a CC to ventilation (C:V) ratio of 3:1. Raising the intrathoracic pressure, for example, by superimposing a sustained inflation on uninterrupted CC, and a CC rate >120/min may be beneficial. The optimal neonatal CC depth is unknown, but factors influencing depth and consistency include the C:V ratio. Incomplete chest wall recoil can cause less negative intrathoracic pressure between CC and reduced CPR effectiveness. CC should be performed with the two-thumb method over the lower third of the sternum. The optimal dose, route and timing of adrenaline administration remain to be determined. CONCLUSIONS: Successful CPR requires the delivery of high-quality CC, encompassing optimal (A) C:V ratio (B) rate, (C) depth, (D) chest recoil between CC, (E) technique and (F) adrenaline dosage. More animal studies with high translational value and randomised clinical trials are needed. PMID- 26627555 TI - Alendronate prevents angiotensin II-induced collagen I production through geranylgeranylation-dependent RhoA/Rho kinase activation in cardiac fibroblasts. AB - Collagen I is the main component of extracellular matrix in cardiac fibrosis. Our previous studies have reported inhibition of farnesylpyrophosphate synthase prevents angiotensin II-induced cardiac fibrosis, while the exact molecular mechanism was still unclear. This paper was designed to investigate the effect of alendronate, a farnesylpyrophosphate synthase inhibitor, on regulating angiotensin II-induced collagen I expression in cultured cardiac fibroblasts and to explore the underlying mechanism. By measuring the mRNA and protein levels of collagen I, we found that alendronate prevented angiotensin II-induced collagen I production in a dose-dependent manner. The inhibitory effect on collagen I expression was reversed by geranylgeraniol, and mimicked by inhibitors of RhoA/Rho kinase pathway including C3 exoenzyme and GGTI-286. Thus we suggested geranylgeranylation-dependent RhoA/Rho kinase activation was involved in alendronate-mediated anti-collagen I synthetic effect. Furthermore, we accessed the activation status of RhoA in alendronate-, geranylgeraniol- and GGTI-286 treated cardiac fibroblasts and gave an indirect evidence for RhoA activation via geranylgeranylation. Then we came to the conclusion that in cardiac fibroblasts, alendronate could protect against angiotensin II-induced collagen I synthesis through inhibition of geranylgeranylation and inactivation of RhoA/Rho kinase signaling. Targeting geranylgeranylation and RhoA/Rho kinase signaling will hopefully serve as therapeutic strategies to reduce fibrosis in heart remodeling. PMID- 26627556 TI - Plus ca change.... PMID- 26627552 TI - Growth and development in children born very low birthweight. AB - OBJECTIVE: To examine the relationships between growth (birth to age 2 years) and developmental outcomes in children born with very low birthweight (VLBW). DESIGN: Motor and mental development in children born with VLBW were regressed on anthropometric measurements at birth, 9 months and 2 years using multivariable regression. SETTING: The Early Childhood Longitudinal Study-Birth Cohort, a longitudinal cohort, community sample, designed to be representative of children born across the USA. PATIENTS: 950 children born with VLBW (<1500 g). MAIN OUTCOME MEASURES: Motor and cognitive scores on the Bayley Scales at 9 months and 24 months chronological age. RESULTS: A high proportion of children exhibited poor growth, with length-for-age z-scores <-2 (ie, stunting) in 21.3% of children at 9 months (adjusted for prematurity) and 34.2% of children at 2 years. Compared with children having z-scores >-2, children with growth shortfalls in head circumference, length and weight had a higher adjusted OR (aOR) of low Bayley motor scores at 9 months and 2 years (aOR ranging from 1.8 to 3.3, all p<0.05), while low Bayley cognitive scores were predicted by 9-month deficits in length and weight (aOR 2.0 and 2.4, respectively, both p<0.01) and 2-year deficits in length and head circumference (aOR 2.9 and 2.8, both p<0.05). CONCLUSION: Anthropometric measures of growth were linked to current and future neurodevelopmental outcomes in children born with VLBW. While careful length measures may be a particularly useful marker, deficits in all anthropometric measures were risk factors for developmental delays. PMID- 26627558 TI - Sonic hedgehog processing and release are regulated by glypican heparan sulfate proteoglycans. PMID- 26627550 TI - Immunopathogenesis of IBD: current state of the art. AB - IBD is a chronic inflammatory condition of the gastrointestinal tract encompassing two main clinical entities: Crohn's disease and ulcerative colitis. Although Crohn's disease and ulcerative colitis have historically been studied together because they share common features (such as symptoms, structural damage and therapy), it is now clear that they represent two distinct pathophysiological entities. Both Crohn's disease and ulcerative colitis are associated with multiple pathogenic factors including environmental changes, an array of susceptibility gene variants, a qualitatively and quantitatively abnormal gut microbiota and a broadly dysregulated immune response. In spite of this realization and the identification of seemingly pertinent environmental, genetic, microbial and immune factors, a full understanding of IBD pathogenesis is still out of reach and, consequently, treatment is far from optimal. An important reason for this unsatisfactory situation is the currently limited comprehension of what are the truly relevant components of IBD immunopathogenesis. This article will comprehensively review current knowledge of the classic immune components and will expand the concept of IBD immunopathogenesis to include various cells, mediators and pathways that have not been traditionally associated with disease mechanisms, but that profoundly affect the overall intestinal inflammatory process. PMID- 26627560 TI - Leading tobacco firm is accused of bribery. PMID- 26627559 TI - A novel method to determine residual detergent in biological samples post endotoxin reduction treatment and evaluation of strategies for subsequent detergent removal. AB - Endotoxin removal using detergent washes and extractions are well-established, efficient, and cost-effective methods; however, removing residual detergent post treatment has been shown to be a challenge. In this communication, we show a simple and fast method for determining the detergent concentration in a protein solution post treatment and highlight strategies for detergent removal to achieve levels below the critical micelle concentration (CMC), the minimum concentration at which detergent micelles form. PMID- 26627561 TI - Unified functional network and nonlinear time series analysis for complex systems science: The pyunicorn package. AB - We introduce the pyunicorn (Pythonic unified complex network and recurrence analysis toolbox) open source software package for applying and combining modern methods of data analysis and modeling from complex network theory and nonlinear time series analysis. pyunicorn is a fully object-oriented and easily parallelizable package written in the language Python. It allows for the construction of functional networks such as climate networks in climatology or functional brain networks in neuroscience representing the structure of statistical interrelationships in large data sets of time series and, subsequently, investigating this structure using advanced methods of complex network theory such as measures and models for spatial networks, networks of interacting networks, node-weighted statistics, or network surrogates. Additionally, pyunicorn provides insights into the nonlinear dynamics of complex systems as recorded in uni- and multivariate time series from a non-traditional perspective by means of recurrence quantification analysis, recurrence networks, visibility graphs, and construction of surrogate time series. The range of possible applications of the library is outlined, drawing on several examples mainly from the field of climatology. PMID- 26627562 TI - The equal combination synchronization of a class of chaotic systems with discontinuous output. AB - This paper investigates the equal combination synchronization of a class of chaotic systems. The chaotic systems are assumed that only the output state variable is available and the output may be discontinuous state variable. By constructing proper observers, some novel criteria for the equal combination synchronization are proposed. The Lorenz chaotic system is taken as an example to demonstrate the efficiency of the proposed approach. PMID- 26627563 TI - Bifurcation analysis and potential landscapes of the p53-Mdm2 module regulated by the co-activator programmed cell death 5. AB - The dynamics of p53 play important roles in the regulation of cell fate decisions in response to various stresses, and programmed cell death 5 (PDCD5) functions as a co-activator of p53 that modulates p53 dynamics. In the present paper, we investigated how p53 dynamics are modulated by PDCD5 during the deoxyribose nucleic acid damage response using methods of bifurcation analysis and potential landscape. Our results revealed that p53 activities display rich dynamics under different PDCD5 levels, including monostability, bistability with two stable steady states, oscillations, and the coexistence of a stable steady state (or two states) and an oscillatory state. The physical properties of the p53 oscillations were further demonstrated by the potential landscape in which the potential force attracts the system state to the limit cycle attractor, and the curl flux force drives coherent oscillation along the cyclic trajectory. We also investigated the efficiency with which PDCD5 induced p53 oscillations. We show that Hopf bifurcation can be induced by increasing the PDCD5 efficiency and that the system dynamics exhibited clear transition features in both barrier height and energy dissipation when the efficiency was close to the bifurcation point. PMID- 26627564 TI - Driving-based generalized synchronization in two-layer networks via pinning control. AB - Synchronization of complex networks has been extensively investigated in various fields. In the real world, one network is usually affected by another one but coexists in harmony with it, which can be regarded as another kind of synchronization--generalized synchronization (GS). In this paper, the GS in two layer complex networks with unidirectional inter-layer coupling via pinning control is investigated based on the auxiliary-system approach. Specifically, for two-layer networks under study, one is considered as the drive network and the other is the response one. According to the auxiliary-system approach, output from the drive layer is designed as input for the response one, and an identical duplication of the response layer is constructed, which is driven by the same driving signals. A sufficient condition for achieving GS via pinning control is presented. Numerical simulations are further provided to illustrate the correctness of the theoretical results. It is also revealed that the least number of pinned nodes needed for achieving GS decreases with the increasing density of the response layer. In addition, it is found that when the intra-layer coupling strength of the response network is large, nodes with larger degrees should be selected to pin first for the purpose of achieving GS. However, when the coupling strength is small, it is more preferable to pin nodes with smaller degrees. This work provides engineers with a convenient approach to realize harmonious coexistence of various complex systems, which can further facilitate the selection of pinned systems and reduce control cost. PMID- 26627565 TI - Multi-attribute integrated measurement of node importance in complex networks. AB - The measure of node importance in complex networks is very important to the research of networks stability and robustness; it also can ensure the security of the whole network. Most researchers have used a single indicator to measure the networks node importance, so that the obtained measurement results only reflect certain aspects of the networks with a loss of information. Meanwhile, because of the difference of networks topology, the nodes' importance should be described by combining the character of the networks topology. Most of the existing evaluation algorithms cannot completely reflect the circumstances of complex networks, so this paper takes into account the degree of centrality, the relative closeness centrality, clustering coefficient, and topology potential and raises an integrated measuring method to measure the nodes' importance. This method can reflect nodes' internal and outside attributes and eliminate the influence of network structure on the node importance. The experiments of karate network and dolphin network show that networks topology structure integrated measure has smaller range of metrical result than a single indicator and more universal. Experiments show that attacking the North American power grid and the Internet network with the method has a faster convergence speed than other methods. PMID- 26627566 TI - A highly specific test for periodicity. AB - We present a method that allows to distinguish between nearly periodic and strictly periodic time series. To this purpose, we employ a conservative criterion for periodicity, namely, that the time series can be interpolated by a periodic function whose local extrema are also present in the time series. Our method is intended for the analysis of time series generated by deterministic time-continuous dynamical systems, where it can help telling periodic dynamics from chaotic or transient ones. We empirically investigate our method's performance and compare it to an approach based on marker events (or Poincare sections). We demonstrate that our method is capable of detecting small deviations from periodicity and outperforms the marker-event-based approach in typical situations. Our method requires no adjustment of parameters to the individual time series, yields the period length with a precision that exceeds the sampling rate, and its runtime grows asymptotically linear with the length of the time series. PMID- 26627567 TI - Trajectory-probed instability and statistics of desynchronization events in coupled chaotic systems. AB - Complex systems, such as financial markets, earthquakes, and neurological networks, exhibit extreme events whose mechanisms of formation are not still completely understood. These mechanisms may be identified and better studied in simpler systems with dynamical features similar to the ones encountered in the complex system of interest. For instance, sudden and brief departures from the synchronized state observed in coupled chaotic systems were shown to display non normal statistical distributions similar to events observed in the complex systems cited above. The current hypothesis accepted is that these desynchronization events are influenced by the presence of unstable object(s) in the phase space of the system. Here, we present further evidence that the occurrence of large events is triggered by the visitation of the system's phase space trajectory to the vicinity of these unstable objects. In the system studied here, this visitation is controlled by a single parameter, and we exploit this feature to observe the effect of the visitation rate in the overall instability of the synchronized state. We find that the probability of escapes from the synchronized state and the size of those desynchronization events are enhanced in attractors whose shapes permit the chaotic trajectories to approach the region of strong instability. This result shows that the occurrence of large events requires not only a large local instability to amplify noise, or to amplify the effect of parameter mismatch between the coupled subsystems, but also that the trajectories of the system wander close to this local instability. PMID- 26627568 TI - Effects of bursting dynamic features on the generation of multi-clustered structure of neural network with symmetric spike-timing-dependent plasticity learning rule. AB - In this paper, the generation of multi-clustered structure of self-organized neural network with different neuronal firing patterns, i.e., bursting or spiking, has been investigated. The initially all-to-all-connected spiking neural network or bursting neural network can be self-organized into clustered structure through the symmetric spike-timing-dependent plasticity learning for both bursting and spiking neurons. However, the time consumption of this clustering procedure of the burst-based self-organized neural network (BSON) is much shorter than the spike-based self-organized neural network (SSON). Our results show that the BSON network has more obvious small-world properties, i.e., higher clustering coefficient and smaller shortest path length than the SSON network. Also, the results of larger structure entropy and activity entropy of the BSON network demonstrate that this network has higher topological complexity and dynamical diversity, which benefits for enhancing information transmission of neural circuits. Hence, we conclude that the burst firing can significantly enhance the efficiency of clustering procedure and the emergent clustered structure renders the whole network more synchronous and therefore more sensitive to weak input. This result is further confirmed from its improved performance on stochastic resonance. Therefore, we believe that the multi-clustered neural network which self-organized from the bursting dynamics has high efficiency in information processing. PMID- 26627569 TI - Phase space trajectories and Lyapunov exponents in the dynamics of an alpha helical protein lattice with intra- and inter-spine interactions. AB - The nonlinear dynamics of intra- and inter-spine interaction models of alpha helical proteins is investigated by proposing a Hamiltonian using the first quantized operators. Hamilton's equations of motion are derived, and the dynamics is studied by constructing the trajectories and phase space plots in both cases. The phase space plots display a chaotic behaviour in the dynamics, which opens questions about the relationship between the chaos and exciton-exciton and exciton-phonon interactions. This is verified by plotting the Lyapunov characteristic exponent curves. PMID- 26627570 TI - An entropy based clustering order parameter for finite ensembles of oscillators. AB - Based on the entropy concept, we define a new clustering order parameter, denoted by c, feasible for finite systems of interacting oscillators. Unlike the generalized synchronization order parameters of the Kuramoto type, this new order parameter singles out the splay state as the unique state with c = 0, thus yielding a positive value whenever there is some kind of cluster formation in the system. It is therefore proposed to be monitored alongside the Kuramoto order parameters as a means to quantify the overall amount of clustering in the system. PMID- 26627571 TI - Characterizing general scale-free networks by vertex-degree sequences. AB - Many complex networks possess a scale-free vertex-degree distribution in a power law form of ck(-gamma), where k is the vertex-degree variable and c and gamma are constants. To better understand the mechanism of the power-law formation in scale free networks, it is important to understand and analyze their vertex-degree sequences. We had shown before that, for a scale-free network of size N, if its vertex-degree sequence is k1 1, then the length l of the vertex-degree sequence is of order log N. In the present paper, we further study complex networks with a more general vertex-degree distribution, not restricted to the power-law, and prove that the same conclusion holds as well. In addition, we verify the new result by real data from a large number of real-world examples. We finally discuss some potential applications of the new finding in various fields of science, technology, and society. PMID- 26627572 TI - Designing a stochastic genetic switch by coupling chaos and bistability. AB - In stem cell differentiation, a pluripotent stem cell becomes progressively specialized and generates specific cell types through a series of epigenetic processes. How cells can precisely determine their fate in a fluctuating environment is a currently unsolved problem. In this paper, we suggest an abstract gene regulatory network to describe mathematically the differentiation phenomenon featuring stochasticity, divergent cell fates, and robustness. The network consists of three functional motifs: an upstream chaotic motif, a buffering motif of incoherent feed forward loop capable of generating a pulse, and a downstream motif which is bistable. The dynamic behavior is typically a transient chaos with fractal basin boundaries. The trajectories take transiently chaotic journeys before divergently settling down to the bistable states. The ratio of the probability that the high state is achieved to the probability that the low state is reached can maintain a constant in a population of cells with varied molecular fluctuations. The ratio can be turned up or down when proper parameters are adjusted. The model suggests a possible mechanism for the robustness against fluctuations that is prominently featured in pluripotent cell differentiations and developmental phenomena. PMID- 26627573 TI - Exact period-four solutions of a family of n-dimensional quadratic maps via harmonic balance and Grobner bases. AB - Analytical solutions of the period-four orbits exhibited by a classical family of n-dimensional quadratic maps are presented. Exact expressions are obtained by applying harmonic balance and Grobner bases to a single-input single-output representation of the system. A detailed study of a generalized scalar quadratic map and a well-known delayed logistic model is included for illustration. In the former example, conditions for the existence of bistability phenomenon are also introduced. PMID- 26627574 TI - Diversity of solitons in a generalized nonlinear Schrodinger equation with self steepening and higher-order dispersive and nonlinear terms. AB - In this article, we show that if the nonlinear Schrodinger (NLS) equation is generalized by simultaneously taking into account higher-order dispersion, a quintic nonlinearity, and self-steepening terms, the resulting equation is interesting as it has exact soliton solutions which may be (depending on the values of the coefficients) stable or unstable, standard or "embedded," fixed or "moving" (i.e., solitons which advance along the retarded-time axis). We investigate the stability of these solitons by means of a modified version of the Vakhitov-Kolokolov criterion, and numerical tests are carried out to corroborate that these solitons respond differently to perturbations. It is shown that this generalized NLS equation can be derived from a Lagrangian density which contains an auxiliary variable, and Noether's theorem is then used to show that the invariance of the action integral under infinitesimal gauge transformations generates a whole family of conserved quantities. Finally, we study if this equation has the Painleve property. PMID- 26627575 TI - Entry routes for Zika virus in Brazil after 2014 world cup: New possibilities. PMID- 26627576 TI - Limits to the thermal tolerance of corals adapted to a highly fluctuating, naturally extreme temperature environment. AB - Naturally extreme temperature environments can provide important insights into the processes underlying coral thermal tolerance. We determined the bleaching resistance of Acropora aspera and Dipsastraea sp. from both intertidal and subtidal environments of the naturally extreme Kimberley region in northwest Australia. Here tides of up to 10 m can cause aerial exposure of corals and temperatures as high as 37 degrees C that fluctuate daily by up to 7 degrees C. Control corals were maintained at ambient nearshore temperatures which varied diurnally by 4-5 degrees C, while treatment corals were exposed to similar diurnal variations and heat stress corresponding to ~20 degree heating days. All corals hosted Symbiodinium clade C independent of treatment or origin. Detailed physiological measurements showed that these corals were nevertheless highly sensitive to daily average temperatures exceeding their maximum monthly mean of ~31 degrees C by 1 degrees C for only a few days. Generally, Acropora was much more susceptible to bleaching than Dipsastraea and experienced up to 75% mortality, whereas all Dipsastraea survived. Furthermore, subtidal corals, which originated from a more thermally stable environment compared to intertidal corals, were more susceptible to bleaching. This demonstrates that while highly fluctuating temperatures enhance coral resilience to thermal stress, they do not provide immunity to extreme heat stress events. PMID- 26627577 TI - Direct comparison of galactomannan performance in concurrent serum and bronchoalveolar lavage samples in immunocompromised patients at risk for invasive pulmonary aspergillosis. AB - Invasive pulmonary aspergillosis (IPA) is a life-threatening infection mainly affecting immunocompromised patients. Early diagnosis is critical, but the diagnostic gold standard (histopathology and culture) is time consuming and cannot offer early confirmation of IPA. Fungal biomarkers like galactomannan (GM) are a promising extension to the diagnostic repertoire. However, it still remains under discussion if biomarker analysis from the site of the infection is superior to testing blood samples. We retrospectively evaluated the diagnostic performance of concurrent serum GM and bronchoalveolar lavage (BAL) GM (obtained within 24 h) of immunocompromised patients at high risk of IPA. Twenty-six proven/probable patients and eight patients with no IPA according to the EORTC/MSG 2008 criteria were included in this study. Sensitivity, specificity, positive predictive value, negative predictive value and diagnostic odds ratio were for BAL GM: 85%, 88%, 96%, 64% and 38.5, and for serum GM: 23%, 88%, 88%, 26% and 2.1 respectively. BAL GM proved to be significantly more sensitive for the detection of IPA compared to same-day serum GM in patients at high risk of IPA (P < 0.0001). Our data show that BAL GM testing is significantly superior to serum GM implying that diagnostic efforts should focus on specimens from the site of infection. PMID- 26627578 TI - Design and synthesis of environmentally sensitive fluorescent 2 naphthylethynylated 2'-deoxyadenosines: Detection of target DNA via changes in fluorescence intensity and wavelength. AB - Various C2-naphthylethynylated 2'-deoxyadenosines were synthesized as environmentally sensitive fluorescent (ESF) nucleosides and their photophysical properties were examined. Among the ESF nucleosides synthesized, four exhibited strong solvatochromicity, two of which were incorporated into oligodeoxynucleotides (ODNs). These ODN probes were able to detect target DNA through distinct changes in fluorescence intensity and wavelength and acted as effective reporter probes. PMID- 26627579 TI - Synthesis and multiparametric evaluation of thiadiazoles and oxadiazoles as diacylglycerol acyltransferase type 1 inhibitors. AB - Chemical modulation of a formerly disclosed DGAT-1 inhibitor resulted in the identification of a compound with a suitable profile for preclinical development. Optimisation of solubility is discussed and a PK/PD study is presented. PMID- 26627580 TI - Synthesis and fluorescent study of 5-phenyl furocoumarin derivatives as vasodilatory agents. AB - Two series of 5-phenyl furocoumarin derivatives were designed and prepared based on our previous research. All new compounds were characterized by (1)H NMR, (13)C NMR and mass spectra. Furthermore, they were screened for their vasodilatory activity on the mesenteric artery of Sprague-Dawley rats, and they all presented with moderate vasodilatory activity. Fluorescent properties of the target compounds were tested in methanol. The fluorescence variation of 4a was investigated in different solvents, various pH and the migration time was determined. All results indicated that this type of fluorescent compound can be used as vasodilatory agents and probes simultaneously after further structural modifications. PMID- 26627581 TI - Consecutive incorporation of functionalized nucleotides with amphiphilic side chains by novel KOD polymerase mutant. AB - Recently, 7-substituted 7-deazapurine nucleoside triphosphates and 5-substituted pyrimidine nucleoside triphosphates (dN(am)TPs) were synthesized to extend enzymatically using commercially available polymerase. However, extension was limited when we attempted to incorporate the substrates consecutively. To address this, we have produced a mutant polymerase that can efficiently accept the modified nucleotide with amphiphilic groups as substrates. Here we show that the KOD polymerase mutant, KOD exo(-)/A485L, had the ability to incorporate dN(am)TP continuously over 50nt, indicating that the mutant is sufficient for generating functional nucleic acid molecules. PMID- 26627582 TI - Superhydrophilic molecularly imprinted polymers based on a water-soluble functional monomer for the recognition of gastrodin in water media. AB - In this study, the first successfully developed superhydrophilic molecularly imprinted polymers (MIPs) for gastrodin recognition have been described. MIPs were prepared via the bulk polymerization process in an aqueous solution using alkenyl glycosides glucose (AGG) as the water-soluble functional monomer. The non imprinted polymers (NIPs) were also synthesized using the same method without the use of the template. The dynamic water contact angles and photographs of the dispersion properties confirmed that the molecularly imprinted polymers displayed excellent superhydrophilicity. The results demonstrated that the MIPs exhibited high selectivity and an excellent imprinting effect. A molecularly imprinted solid phase extraction (MISPE) method was established. Optimization of various parameters affecting MISPE was investigated. Under the optimized conditions, a wide linear range (0.001-100.0MUgmL(-1)) and low limits of detection (LOD) and quantification (LOQ) (0.03 and 0.09ngmL(-1), respectively) were achieved. When compared with the NIPs, higher recoveries (90.5% to 97.6%) of gastrodin with lower relative standard deviations values (below 6.4%) using high performance liquid chromatography were obtained at three spiked levels in three blank samples. These results demonstrated one efficient, highly selective and environmentally-friendly MISPE technique with excellent reproducibility for the purification and pre-concentration of gastrodin from an aqueous extract of Gastrodia elata roots. PMID- 26627583 TI - Editorial on "Descriptors for ions and ion-pairs for use in linear free energy relationships" by Michael H. Abraham and William E. Acree. PMID- 26627584 TI - Robust estimation of thermodynamic parameters (DeltaH, DeltaS and DeltaCp) for prediction of retention time in gas chromatography - Part I (Theoretical). AB - An approach that is commonly used for calculating the retention time of a compound in GC departs from the thermodynamic properties DeltaH, DeltaS and DeltaCp of phase change (from mobile to stationary). Such properties can be estimated by using experimental retention time data, which results in a non linear regression problem for non-isothermal temperature programs. As shown in this work, the surface of the objective function (approximation error criterion) on the basis of thermodynamic parameters can be divided into three clearly defined regions, and solely in one of them there is a possibility for the global optimum to be found. The main contribution of this study was the development of an algorithm that distinguishes the different regions of the error surface and its use in the robust initialization of the estimation of parameters DeltaH, DeltaS and DeltaCp. PMID- 26627585 TI - Editorial on "Evaluation of steroidomics by liquid chromatography hyphenated to mass spectrometry as a powerful analytical strategy for measuring human steroid perturbations" by Fabienne Jeanneret, David Tonoli, Michel F. Rossier, Martial Saugy, Julien Boccard and S. Rudaz. PMID- 26627586 TI - A europium- and terbium-coated magnetic nanocomposite as sorbent in dispersive solid phase extraction coupled with ultra-high performance liquid chromatography for antibiotic determination in meat samples. AB - A new magnetic dispersive solid-phase extraction approach based on Eu- and Tb coated magnetic nanocomposites, combined with ultra-high performance liquid chromatography with fluorometric detection, is reported for the extraction and simultaneous determination of veterinary antibiotics. The method is aimed at monitoring of potential residues of three tetracyclines, namely oxytetracycline, tetracycline, chlortetracycline and three acidic quinolones, such as oxolinic acid, nalidixic acid and flumequine, chosen as model analytes, in animal muscle samples. The nanocomposites were obtained by synthesizing magnetic nanoparticles by a co-precipitation method and their coating with terbium and europium ions. The limits of detection obtained using standard solutions were: 1.0, 1.5, 3.8, 0.25, 0.7 and 1.2ngmL(-1), which corresponds to 3.3, 5.0, 12.7, 0.8, 2.3 and 4.0MUgkg(-1) for oxytetracycline, tetracycline, chlortetracycline, oxolinic acid, nalidixic acid and flumequine, respectively, in meat samples. The precision values, obtained in the presence of the sample matrix, were in the ranges 0.12 2.0% and 2.6-15.4% for retention times and areas, respectively. The selectivity of the method was checked by assaying different veterinary drugs, finding that most of them did not interfere at the same concentration levels as that of analytes. A recovery study was performed in the presence of chicken and pork muscle samples, which provided values in the range of 61.5-102.6%. PMID- 26627587 TI - Preparation of polyhedral oligomeric silsesquioxane based imprinted monolith. AB - Polyhedral oligomeric silsesquioxane (POSS) was successfully applied, for the first time, to prepare imprinted monolithic column with high porosity and good permeability. The imprinted monolithic column was synthesized with a mixture of PSS-(1-Propylmethacrylate)-heptaisobutyl substituted (MA 0702), naproxon (template), 4-vinylpyridine, and ethylene glycol dimethacrylate, in ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM]BF4). The influence of synthesis parameters on the retention factor and imprinting effect, including the amount of MA 0702, the ratio of template to monomer, and the ratio of monomer to crosslinker, was investigated. The greatest imprinting factor on the imprinted monolithic column prepared with MA 0702 was 22, about 10 times higher than that prepared in absence of POSS. The comparisons between MIP monoliths synthesized with POSS and without POSS were made in terms of permeability, column efficiency, surface morphology and pore size distribution. In addition, thermodynamic and Van Deemter analysis were used to evaluate the POSS-based MIP monolith. PMID- 26627588 TI - Separation of chiral nanotubes with an opposite handedness by chiral oligopeptide adsorption: A molecular dynamics study. AB - The separation of enantiomeric chiral nanotubes that can form non-covalent complexes with an unlike stability upon adsorption of chiral molecules is a process of potential interest in different fields and applications. Using fully atomistic molecular dynamics simulations, we report in this paper a theoretical study of the adsorption and denaturation of an oligopeptide formed by 16 chiral amino acids having a helical structure in the native state on both the inner and the outer surface of the chiral (10, 20) and (20, 10) single-walled carbon nanotubes having an opposite handedness, and of the armchair (16, 16) nanotube with a similar diameter for comparison. In the final adsorbed state, the oligopeptide loses in all cases its native helical conformation, assuming elongated geometries that maximize its contact with the surface through all the 16 amino acids. We find that the complexes formed by the two chiral nanotubes and the chosen oligopeptide have a strongly unlike stability both when adsorption takes place on the outer convex surface of the nanotube, and when it occurs on the inner concave surface. Thus, our molecular simulations indicate that separation of chiral, enantiomeric carbon nanotubes for instance by chromatographic methods can indeed be carried out using oligopeptides of a sufficient length. PMID- 26627589 TI - Vortex-assisted surfactant-enhanced emulsification microextraction based on solidification of floating organic drop combined with high performance liquid chromatography for determination of naproxen and nabumetone. AB - A novel, rapid, simple and green vortex-assisted surfactant-enhanced emulsification microextraction method based on solidification of floating organic drop was developed for simultaneous separation/preconcentration and determination of ultra trace amounts of naproxen and nabumetone with high performance liquid chromatography-fluorescence detection. Some parameters influencing the extraction efficiency of analytes such as type and volume of extractant, type and concentration of surfactant, sample pH, KCl concentration, sample volume, and vortex time were investigated and optimized. Under optimal conditions, the calibration graph exhibited linearity in the range of 3.0-300.0ngL(-1) for naproxen and 7.0-300.0ngL(-1) for nabumetone with a good coefficient of determination (R(2)>0.999). The limits of detection were 0.9 and 2.1ngL(-1). The relative standard deviations for inter- and intra-day assays were in the range of 5.8-10.1% and 3.8-6.1%, respectively. The method was applied to the determination of naproxen and nabumetone in urine, water, wastewater and milk samples and the accuracy was evaluated through recovery experiments. PMID- 26627590 TI - Inverse gas chromatography for natural fibre characterisation: Identification of the critical parameters to determine the Brunauer-Emmett-Teller specific surface area. AB - Inverse gas chromatography (IGC) is an alternative technique to determine the specific surface area of natural fibres. Natural fibres have a complex surface chemistry and unique microstructure that challenge the current capabilities to perform surface characterisation. This study investigated the influence of multiple parameters on the measured Brunauer-Emmett-Teller (BET) specific surface area for samples of flax, kenaf and BioMid((r)) cellulose fibres using IGC. The BET surface area of kenaf and flax differed with 0.51m(2)g(-1) and 1.35m(2)g(-1) respectively, the former being similar to the cellulose fibres (0.54m(2)g(-1)). The data was calculated under conditions where the BET equation showed good linearity (R(2)?0.995). Repeatability was excellent so that two runs sufficed to obtain representative BET surface area values. The findings showed the choice of solvent was important for all specimens to avoid any misleading data comparison due to molecular orientation effects that impact the adsorbent-adsorbate interactions. The higher surface area of the flax sample, and its higher variability, was correlated with a higher surface roughness observed under optical microscopy. Packing the chromatography column with long or chopped fibres produced results that were statistically insignificant. PMID- 26627591 TI - Human Resource Information Systems in Health Care: Protocol for a Systematic Review. AB - BACKGROUND: Compared with the eHealth literature as a whole, there has been relatively little published research on the use and impact of information and communication technologies (ICTs) designed to support business functions within health organizations. Human resource information systems (HRISs) have the potential to improve organizational efficiency and effectiveness by facilitating workforce planning, financial and operational administration, staff training, and management analytics. However, the evidence base regarding HRIS in health care is widely distributed across disciplinary boundaries and previous reviews have been somewhat limited in scope. This rigorous systematic review will identify, appraise, and synthesize existing international research on the implementation and impacts of HRIS in health organizations, to provide insights and recommendations that may guide future purchasers, commissioners, implementers, evaluators, and users of such systems. OBJECTIVE: The objectives of this review are threefold: (1) to determine the prevalence and scope of existing research and evaluation pertaining to HRIS in health organizations; (2) to analyze, classify, and synthesize existing evidence on the processes and impacts of HRIS development, implementation, and adoption; and (3) to generate recommendations for HRIS research, practice, and policy, with reference to the needs of different stakeholders and communities of practice. METHODS: A high-level scoping review was first undertaken to inform a draft search strategy, which was refined through several cycles of piloting and iteration to optimize its sensitivity and specificity. This was used by the first author, with the help of a medical librarian, to search international electronic databases indexing medical, business, ICT, and multi-disciplinary research. Sources of gray literature and reference lists of included studies were also searched. There were no restrictions on language or publication year. Two reviewers are now screening and coding titles and abstracts for potentially eligible studies, for which full text articles will be retrieved. Reasons for exclusion will be noted for the remaining articles. A structured form will be used to summarize and classify the articles. Any disagreements between reviewers will be resolved through consensus or arbitration by a third reviewer. A PRISMA flow diagram will illustrate the study selection process and ensure transparency of the review. Finally, content experts will be consulted to ensure that important articles have not been missed. RESULTS: The initial searches have now been completed and the results are being analyzed. The review is expected to be completed and published by the end of 2015. CONCLUSIONS: By synthesizing the existing evidence base, identifying areas in which knowledge is currently lacking, and generating recommendations for research and practice, this review will be a useful resource for decision makers and managers considering or implementing HRIS, as well as encouraging new research in this area. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews: CRD42015023581; http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015023581#.VYu1BPlV DU (Archived by WebCite at http://www.webcitation.org/6ckJCDdCL). PMID- 26627592 TI - Giant Centrifugal and Necrotizing Cutaneous Metastases of Melanoma: A Brief Review of the Literature and a Case Report. AB - BACKGROUND: Melanoma is a neoplasm derived from melanocytes of the skin and other sites. In the natural history of melanoma, cutaneous metastases occur relatively frequently and can arise in early or late stages of the disease. OBJECTIVE AND METHODS: Melanoma skin metastases have a variable appearance. Several clinical appearances are described in the literature. RESULTS AND CONCLUSION: We describe an unusual clinical pattern of cutaneous melanoma metastasis, defined as giant, centrifugal, and necrotizing, and we provide a brief review of the literature. PMID- 26627593 TI - Mycobacterium peregrinum Skin Infection: Case Report. AB - BACKGROUND: Mycobacterium peregrinum is a rapidly growing mycobacterium (RGM) that rarely causes skin infections. The correct identification of the specific RGM infecting the skin will enhance therapeutic success. OBJECTIVE: To highlight the importance of rapid and precise identification of the Mycobacterium involved in skin infections in order to enhance therapeutic success. METHODS: We describe an RGM skin infection in an immunocompetent patient. RESULTS: Classic methods (biochemical tests and culture) of RGM identification are time-consuming, and the histopathological features are not specific. Some molecular methods are reliable but expensive. The PRAhsp-65 is a simple procedure that is helpful in identifying the specific agent of an RGM. CONCLUSION: Although skin infections caused by M peregrinum are rare, they represent a substantial clinical challenge. Specific and more effective treatment options depend on the development of precise and rapid methods for identifying mycobacterial species. PMID- 26627595 TI - Development of the Student Evidence-based Practice Questionnaire (S-EBPQ). AB - BACKGROUND: The assessment of learning and teaching of Evidence-based Practice (EBP) in nursing is an important issue, yet few tools have been developed specifically for use with student nurses. Therefore, the Evidence-based Practice Questionnaire (EBPQ), which has been successfully used to measure EBP in nurses and nurse educators, was revised to develop a Student version (S-EBPQ). OBJECTIVE: The purpose of the study was to develop a student version of the Evidence-based Practice Questionnaire (EBPQ) and test its psychometric properties with a UK undergraduate student population. DESIGN: Instrument development study. PARTICIPANTS AND METHOD: Two hundred and forty-four undergraduate nursing students from an English University were recruited over a three year period to complete the EBPQ. This data was submitted to reliability analysis based on Item Response Theory and Exploratory Factor Analysis to explore construct validity. RESULTS: Principal Component Analysis demonstrated evidence for the S-EBPQ's construct validity, and analyses comparing the subscale scores of students in their first and second years of studies identified evidence for the tool's convergent validity. Descriptive statistics, correlation coefficients and reliability estimates demonstrated evidence for the S-EBPQ's internal reliability, and item facility and discrimination. CONCLUSION: The S-EBPQ appears to be a psychometrically robust measure of EBP use, attitudes, and knowledge and skills (regarding the retrieval and evaluation of evidence, and the application and sharing of EBP). It may therefore provide an effective means of evaluating learning of EBP with undergraduate nursing students. PMID- 26627594 TI - The Dlk1-Gtl2 Locus Preserves LT-HSC Function by Inhibiting the PI3K-mTOR Pathway to Restrict Mitochondrial Metabolism. AB - The mammalian imprinted Dlk1-Gtl2 locus produces multiple non-coding RNAs (ncRNAs) from the maternally inherited allele, including the largest miRNA cluster in the mammalian genome. This locus has characterized functions in some types of stem cell, but its role in hematopoietic stem cells (HSCs) is unknown. Here, we show that the Dlk1-Gtl2 locus plays a critical role in preserving long term repopulating HSCs (LT-HSCs). Through transcriptome profiling in 17 hematopoietic cell types, we found that ncRNAs expressed from the Dlk1-Gtl2 locus are predominantly enriched in fetal liver HSCs and the adult LT-HSC population and sustain long-term HSC functionality. Mechanistically, the miRNA mega-cluster within the Dlk1-Gtl2 locus suppresses the entire PI3K-mTOR pathway. This regulation in turn inhibits mitochondrial biogenesis and metabolic activity and protects LT-HSCs from excessive reactive oxygen species (ROS) production. Our data therefore show that the imprinted Dlk1-Gtl2 locus preserves LT-HSC function by restricting mitochondrial metabolism. PMID- 26627596 TI - 3D Computer aided treatment planning in endodontics. AB - OBJECTIVES: Obliteration of the root canal system due to accelerated dentinogenesis and dystrophic calcification can challenge the achievement of root canal treatment goals. This paper describes the application of 3D digital mapping technology for predictable navigation of obliterated canal systems during root canal treatment to avoid iatrogenic damage of the root. METHODS: Digital endodontic treatment planning for anterior teeth with severely obliterated root canal systems was accomplished with the aid of computer software, based on cone beam computer tomography (CBCT) scans and intra-oral scans of the dentition. On the basis of these scans, endodontic guides were created for the planned treatment through digital designing and rapid prototyping fabrication. RESULTS: The custom-made guides allowed for an uncomplicated and predictable canal location and management. CONCLUSION: The method of digital designing and rapid prototyping of endodontic guides allows for reliable and predictable location of root canals of teeth with calcifically metamorphosed root canal systems. CLINICAL SIGNIFICANCE: The endodontic directional guide facilitates difficult endodontic treatments at little additional cost. PMID- 26627597 TI - CTAB-assisted synthesis of novel ultrathin MoSe2 nanosheets perpendicular to graphene for the adsorption and photodegradation of organic dyes under visible light. AB - A novel nanostructure of perpendicular ultrathin MoSe2 nanosheets directly grown on graphene was produced by a facile hydrothermal method in the presence of CTAB. The vertically-oriented and ultrathin MoSe2 nanosheets distribute uniformly on the surface of graphene, and the nanosheets are typically 2-3 layers, which is confirmed by TEM and red shift of the A1g Raman peak. In comparison with pure MoSe2 and MoSe2 nanospheres on graphene, vertically oriented MoSe2 nanosheets on graphene show enhanced organic dye adsorption ability and photocatalytic performance in the degradation of MB, RhB and MO under dark conditions and visible light irradiation. The excellent photocatalytic activity may be contributed by the unique perpendicular MoSe2 nanosheets with fully exposed active edges and hybridized with graphene for reduced electron-hole pair recombination. PMID- 26627598 TI - Bacterial nanocellulose-pectin bionanocomposites as prebiotics against drying and gastrointestinal condition. AB - Various encapsulating materials have been suggested to protect probiotics, but the potential of nanomaterials is yet to be exploited. This study aimed to improve the survivability of Bacillus coagulans entrapping into bionanocomposites comprising of bacterial nanocellulose (BNC), pectin and Schizophyllum commune extract were investigated as new matrices to protect probiotics. The bionanocomposite design was optimized to obtain the highest prebiotic score and survivability of probiotic under drying process and gastrointestinal condition using the simplex-lattice mixture method. The optimal bionanocomposite formulation was obtained by mixing 20% pectin with 80% BNC. High survival rate of B. coagulans after microwave drying (99.43%) and sequential digestion under stimulated gastrointestinal fluids (94.76%) with optimum prebiotic score for B. coagulans (1.00) and for Escherichia coli (0.99), were obtained. Nanoscale properties of BNC, high crystallinity and available surface area resulted in high probiotic protection. Stability test during storage period at ambient temperature, 4 degrees C and -20 degrees C performed viability reduction, respectively, 1.3, 1.7 and 1.8 log CFU/g, which inferred the optimal bionanocomposite could be candidate as useful probiotics protection system in a variety of temperature during long time. PMID- 26627599 TI - Effect of extraction method on structure and antioxidant activity of Hohenbuehelia serotina polysaccharides. AB - The impacts of four extraction methods (hot water, enzyme assistance, ultrasonic assistance and ultrasonic-enzyme assistance) on the extraction yields, preliminary structure and antioxidant activities of the Hohenbuehelia serotina polysaccharides (HW-HSP, EA-HSP, UA-HSP and UEA-HSP) were systematically investigated. The yield of the polysaccharides (20.70+/-0.17%) obtained by ultrasonic-enzyme assistance was higher than the polysaccharides by other methods'. Four kinds of polysaccharides possessed the different preliminary structural characteristics including molecular weight distributions, monosaccharide compositions, crystallization and spiral structures, while different surface morphology. Through the measurements of antioxidant activities in vitro, UEA-HSP exhibited the most significant scavenging capacities on non physiological ABTS free radicals and physiological hydroxyl radicals. These data showed that ultrasonic-enzyme assistance was more beneficial to enhance the extraction yields of the polysaccharides, and obtain higher bioactive polysaccharides. The results also suggested that H. serotina polysaccharides possessed potential healthcare application in food field due to their antioxidant activities. PMID- 26627600 TI - Sodium alginate/graphene oxide aerogel with enhanced strength-toughness and its heavy metal adsorption study. AB - Ordered porous sodium alginate/graphene oxide (SAGO) aerogel was fabricated by in situ crosslinking and freeze-drying method. GO, as reinforcing filler, can be easily incorporated with SA matrix by self-assembly via hydrogen bonding interaction. Compared with pure SA aerogel, the as-prepared SAGO exhibited excellent mechanical strength and elasticity, and the compression strength of SAGO can reach up to 324 kPa and remain 249 kPa after five compression cycles when 4 wt% GO was added, which were considered significant improvements. SEM result presents that the addition of GO obviously improves the porous structures of aerogel, which is beneficial for the enhancement of strength-toughness and adsorbability. As a consequence, the adsorption process of SAGO is better described by pseudo-second-order kinetic model and Langmuir isotherm, with maximum monolayer adsorption capacities of 98.0 mg/g for Cu2+ and 267.4 mg/g for Pb2+, which are extremely high adsorption capacities for metal ions and show far more promise for application in sewage treatment. PMID- 26627601 TI - Antidiabetic effect of polysaccharides from Pleurotus ostreatus in streptozotocin induced diabetic rats. AB - This study was performed to evaluate the effects of total polysaccharides extracted from Pleurotus ostreatus on type 2 diabetes. Rats were administered with high-fat diet and streptozotocin (STZ) to induce diabetes. The rats were then treated with 100, 200, and 400 mg/kg/d POP or vehicle for 4 weeks. Our experiments indicated that POP reduces hyperglycemia and hyperlipidemia levels, improves insulin resistance, and increases glycogen storage by activating GSK3 phosphorylation and GLUT4 translocation. Moreover, POP reduces the risk of oxidative damage by increasing superoxide dismutase(SOD), catalase(CAT), and glutathione peroxidase(GSH-Px) activities and decreasing malonaldehyde(MDA) level. These results suggest that POP exerts antidiabetic effect on STZ-induced diabetic rats. PMID- 26627602 TI - Swelling of whey and egg white protein hydrogels with stranded and particulate microstructures. AB - Swelling of protein hydrogels in alkaline conditions strongly depends on the gel microstructure. Stranded transparent gels swell as predicted using a modified Flory-Rehner model with the net protein charge. Particulate opaque gels swell very differently, with a sudden increase at a narrow pH range. Its swelling is not controlled by the protein charge, but by the destruction of the non-covalent interactions. Comparable dissolution thresholds, one with pH and another with the degree of swelling, are observed in both types of microstructures. These conclusions are valid for both whey protein isolate (WPI) gels and egg white gels, suggesting that they are universal for all globular proteins that can form such microscructures. Differences are observed, however, from the prevalent chemical crosslinks in each protein system. Non-covalent interactions dominate WPI gels; when such interactions are destroyed at pH>=11.5 the gels swell extensively and eventually dissolve. In egg white gels, the higher degree of disulphide crosslinking allows extensive swelling when non-covalent interactions are destroyed, but dissolution only occurs at pH>=13 when covalent crosslinks are cleaved. The current study highlights that the microstructure of protein hydrogels, a unique particularity of protein systems compared to other synthetic hydrogels, defines swelling. PMID- 26627603 TI - Adsorption of histones on natural polysaccharides: The potential as agent for multiple organ failure in sepsis. AB - Histones are intracellular proteins that are structural elements of nuclear chromatin and regulate gene transcription. However, the extracellular histones released in response to bacterial challenges have been identified as mediators contributing to endothelial dysfunction, organ failure, and death during sepsis. In the present study, the adsorption of histones as well as plasma proteins (alpha1-acid glycoprotein (AGP), albumin, and gamma-globulin) on alginic acid, pectin, dextran, and chitosan was examined in order to evaluate the potential of natural polysaccharides as therapeutic agents for multiple organ failure in sepsis. Alginic acid and pectin strongly adsorbed histones, whereas the adsorption abilities of dextran and chitosan toward histones were very low or negligible. Among the natural polysaccharides examined, only alginic acid did not adsorb any of the plasma proteins. These results demonstrated that alginic acid strongly adsorbed histones, but not plasma proteins; therefore, it has potential as a candidate drug for the treatment of multiple organ failure in sepsis. PMID- 26627604 TI - Optimization for ultrasonic-microwave synergistic extraction of polysaccharides from Cornus officinalis and characterization of polysaccharides. AB - Ultrasonic-microwave synergistic extraction (UMSE) of polysaccharides from Cornus officinalis was optimized by response surface methodology (RSM). The effect of four different factors on the yield of C. officinalis polysaccharides (COP) was studied. RSM results showed that the optimal conditions were extraction time of 31.49823 min, microwave power of 99.39769 W, and water-to-raw material ratio of 28.16273. The COP yield was 11.38+/-0.31% using the modified optimal conditions, which was consistent with the value predicted by the model. The crude COP was purified by DEAE-Cellulose 52 chromatography and Sephadex G-100 chromatography. Five fractions, namely, crude COP, COP-1, COP-2, COP-3, and COP-4, were obtained. Monosaccharide composition analysis revealed that the COP was composed of glucose, arabinose, fucose, xylose, mannose, and rhamnose. Preliminary structural characterizations of COP were conducted by scanning electron microscopy and Fourier transform infrared spectroscopy. PMID- 26627606 TI - Epithelial Transforming Growth Factor-beta Signaling Does Not Contribute to Liver Fibrosis but Protects Mice From Cholangiocarcinoma. AB - BACKGROUND & AIMS: Transforming growth factor-beta (TGFbeta) exerts key functions in fibrogenic cells, promoting fibrosis development in the liver and other organs. In contrast, the functions of TGFbeta in liver epithelial cells are not well understood, despite their high level of responsiveness to TGFbeta. We sought to determine the contribution of epithelial TGFbeta signaling to hepatic fibrogenesis and carcinogenesis. METHODS: TGFbeta signaling in liver epithelial cells was inhibited by albumin-Cre-, K19-CreERT-, Prom1-CreERT2-, or AAV8-TBG-Cre mediated deletion of the floxed TGFbeta receptor II gene (Tgfbr2). Liver fibrosis was induced by carbon tetrachloride, bile duct ligation, or disruption of the multidrug-resistance transporter 2 gene (Mdr2). Hepatocarcinogenesis was induced by diethylnitrosamine or hepatic deletion of PTEN. RESULTS: Deletion of Tgfbr2 from liver epithelial cells did not alter liver injury, toxin-induced or biliary fibrosis, or diethylnitrosamine-induced hepatocarcinogenesis. In contrast, epithelial deletion of Tgfbr2 promoted tumorigenesis and reduced survival of mice with concomitant hepatic deletion of Pten, accompanied by an increase in tumor number and a shift from hepatocellular carcinoma to cholangiocarcinoma. Surprisingly, both hepatocyte- and cholangiocyte-specific deletion of Pten and Tgfbr2 promoted the development of cholangiocarcinoma, but with different latencies. The prolonged latency and the presence of hepatocyte-derived cholangiocytes after AAV8-TBG-Cre-mediated deletion of Tgfbr2 and Pten indicated that cholangiocarcinoma might arise from hepatocyte-derived cholangiocytes in this model. Pten deletion resulted in up-regulation of Tgfbr2, and deletion of Tgfbr2 increased cholangiocyte but not hepatocyte proliferation, indicating that the main function of epithelial TGFBR2 is to restrict cholangiocyte proliferation. CONCLUSIONS: Epithelial TGFbeta signaling does not contribute to the development of liver fibrosis or formation of hepatocellular carcinomas in mice, but restricts cholangiocyte proliferation to prevent cholangiocarcinoma development, regardless of its cellular origin. PMID- 26627605 TI - Hsp90 and hepatobiliary transformation during sea lamprey metamorphosis. AB - BACKGROUND: Biliary atresia (BA) is a human infant disease with inflammatory fibrous obstructions in the bile ducts and is the most common cause for pediatric liver transplantation. In contrast, the sea lamprey undergoes developmental BA with transient cholestasis and fibrosis during metamorphosis, but emerges as a fecund adult. Therefore, sea lamprey liver metamorphosis may serve as an etiological model for human BA and provide pivotal information for hepatobiliary transformation and possible therapeutics. RESULTS: We hypothesized that liver metamorphosis in sea lamprey is due to transcriptional reprogramming that dictates cellular remodeling during metamorphosis. We determined global gene expressions in liver at several metamorphic landmark stages by integrating mRNA Seq and gene ontology analyses, and validated the results with real-time quantitative PCR, histological and immunohistochemical staining. These analyses revealed that gene expressions of protein folding chaperones, membrane transporters and extracellular matrices were altered and shifted during liver metamorphosis. HSP90, important in protein folding and invertebrate metamorphosis, was identified as a candidate key factor during liver metamorphosis in sea lamprey. Blocking HSP90 with geldanamycin facilitated liver metamorphosis and decreased the gene expressions of the rate limiting enzyme for cholesterol biosynthesis, HMGCoA reductase (hmgcr), and bile acid biosynthesis, cyp7a1. Injection of hsp90 siRNA for 4 days altered gene expressions of met, hmgcr, cyp27a1, and slc10a1. Bile acid concentrations were increased while bile duct and gall bladder degeneration was facilitated and synchronized after hsp90 siRNA injection. CONCLUSIONS: HSP90 appears to play crucial roles in hepatobiliary transformation during sea lamprey metamorphosis. Sea lamprey is a useful animal model to study postembryonic development and mechanisms for hsp90 induced hepatobiliary transformation. PMID- 26627607 TI - Sequential Functions of CPEB1 and CPEB4 Regulate Pathologic Expression of Vascular Endothelial Growth Factor and Angiogenesis in Chronic Liver Disease. AB - BACKGROUND & AIMS: Vascular endothelial growth factor (VEGF) regulates angiogenesis, yet therapeutic strategies to disrupt VEGF signaling can interfere with physiologic angiogenesis. In a search for ways to inhibit pathologic production or activities of VEGF without affecting its normal production or functions, we investigated the post-transcriptional regulation of VEGF by the cytoplasmic polyadenylation element-binding proteins CPEB1 and CPEB4 during development of portal hypertension and liver disease. METHODS: We obtained transjugular liver biopsies from patients with hepatitis C virus-associated cirrhosis or liver tissues removed during transplantation; healthy human liver tissue was obtained from a commercial source (control). We also performed experiments with male Sprague-Dawley rats and CPEB-deficient mice (C57BL6 or mixed C57BL6/129 background) and their wild-type littermates. Secondary biliary cirrhosis was induced in rats by bile duct ligation, and portal hypertension was induced by partial portal vein ligation. Liver and mesenteric tissues were collected and analyzed in angiogenesis, reverse transcription polymerase chain reaction, polyA tail, 3' rapid amplification of complementary DNA ends, Southern blot, immunoblot, histologic, immunohistochemical, immunofluorescence, and confocal microscopy assays. CPEB was knocked down with small interfering RNAs in H5V endothelial cells, and translation of luciferase reporters constructs was assessed. RESULTS: Activation of CPEB1 promoted alternative nuclear processing within noncoding 3'-untranslated regions of VEGF and CPEB4 messenger RNAs in H5V cells, resulting in deletion of translation repressor elements. The subsequent overexpression of CPEB4 promoted cytoplasmic polyadenylation of VEGF messenger RNA, increasing its translation; the high levels of VEGF produced by these cells led to their formation of tubular structures in Matrigel assays. We observed increased levels of CPEB1 and CPEB4 in cirrhotic liver tissues from patients, compared with control tissue, as well as in livers and mesenteries of rats and mice with cirrhosis or/and portal hypertension. Mice with knockdown of CPEB1 or CPEB4 did not overexpress VEGF or have signs of mesenteric neovascularization, and developed less-severe forms of portal hypertension after portal vein ligation. CONCLUSIONS: We identified a mechanism of VEGF overexpression in liver and mesentery that promotes pathologic, but not physiologic, angiogenesis, via sequential and nonredundant functions of CPEB1 and CPEB4. Regulation of CPEB4 by CPEB1 and the CPEB4 autoamplification loop induces pathologic angiogenesis. Strategies to block the activities of CPEBs might be developed to treat chronic liver and other angiogenesis-dependent diseases. PMID- 26627608 TI - A Risk-Scoring System Combined With a Fecal Immunochemical Test Is Effective in Screening High-Risk Subjects for Early Colonoscopy to Detect Advanced Colorectal Neoplasms. AB - BACKGROUND & AIMS: Age, sex, smoking, and family history are risk factors for colorectal cancer in Asia. The Asia-Pacific Colorectal Screening (APCS) scoring system was developed to identify subjects with a high risk for advanced neoplasm (AN). We tested an algorithm that combined APCS scores with fecal immunochemical test (FIT) in colorectal cancer screening. METHODS: We performed a multicenter prospective study, enrolling asymptomatic individuals older than 40 years old in 12 Asia-Pacific regions from December 2011 to December 2013. APCS scores were calculated for each individual (0-1 = low risk [LR], 2-3 = medium risk [MR], and 4-7 = high risk [HR] for AN). LR and MR subjects were offered FIT and referred for early colonoscopies if FIT results were positive. HR subjects were offered colonoscopies. The proportions of subjects with ANs were determined for each group based on colonoscopy findings; odd ratios for LR and MR subjects were calculated compared to LR individuals. We calculated the sensitivity of the APCS FIT algorithm in identifying subjects with AN. RESULTS: A total of 5657 subjects were recruited: 646 subjects (11.4%) were considered LR, 3243 subjects (57.3%) were considered MR, and 1768 subjects (31.3%) were considered HR for AN. The proportions of individuals with an AN in these groups were 1.5%, 5.1%, and 10.9%, respectively. Compared with LR group, MR and HR subjects had a 3.4-fold increase and a 7.8-fold increase in risk for AN, respectively. A total of 70.6% subjects with AN (95% confidence interval: 65.6%-75.1%) and 95.1% subjects with invasive cancers (95% confidence interval: 82.2%-99.2%) were correctly instructed to undergo early colonoscopy examination. CONCLUSIONS: The APCS scoring system, which is based on age, sex, family history, and smoking, is a useful tool for determining risk for colorectal cancer and advanced adenoma in asymptomatic subjects. Use of the APCS score-based algorithm in triaging subjects for FIT or colonoscopy can substantially reduce colonoscopy workload. PMID- 26627610 TI - Protein-Ligand Complexes: Computation of the Relative Free Energy of Different Scaffolds and Binding Modes. AB - A methodology for the calculation of the free energy difference between a pair of molecules of arbitrary topology is proposed. The protocol relies on a dual topology paradigm, a softening of the intermolecular interactions, and a constraint that prevents the perturbed molecules from drifting away from each other at the end states. The equivalence and the performance of the methodology against a single-topology approach are demonstrated on a pair of harmonic oscillators, the calculation of the relative solvation free energy of ethane and methanol, and the relative binding free energy of two congeneric inhibitors of cyclooxygenase 2. The stability of two alternative binding modes of an inhibitor of cyclin-dependent kinase 2 is then investigated. Finally, the relative binding free energy of two structurally different inhibitors of cyclin-dependent kinase 2 is calculated. The proposed methodology allows the study of a range of problems that are beyond the reach of traditional relative free energy calculation protocols and should prove useful in drug design studies. PMID- 26627609 TI - Development and Validation of a Classification System to Identify High-Grade Dysplasia and Esophageal Adenocarcinoma in Barrett's Esophagus Using Narrow-Band Imaging. AB - BACKGROUND & AIMS: Although several classification systems have been proposed for characterization of Barrett's esophagus (BE) surface patterns based on narrow band imaging (NBI), none have been widely accepted. The Barrett's International NBI Group (BING) aimed to develop and validate an NBI classification system for identification of dysplasia and cancer in patients with BE. METHODS: The BING working group, composed of NBI experts from the United States, Europe, and Japan, met to develop a validated, consensus-driven NBI classification system for identifying dysplasia and cancer in BE. The group reviewed 60 NBI images of nondysplastic BE, high-grade dysplasia, and esophageal adenocarcinoma to characterize mucosal and vascular patterns visible by NBI; these features were used to develop the BING criteria. We then recruited adult patients undergoing surveillance or endoscopic treatment for BE at 4 institutions in the United States and Europe, obtaining high-quality NBI images and performing histologic analysis of biopsies. Experts individually reviewed 50 NBI images to validate the BING criteria, and then evaluated 120 additional NBI images (not previously viewed) to determine whether the criteria accurately predicted the histology results. RESULTS: The BING criteria identified patients with dysplasia with 85% overall accuracy, 80% sensitivity, 88% specificity, 81% positive predictive value, and 88% negative predictive value. When dysplasia was identified with a high level of confidence, these values were 92%, 91%, 93%, 89%, and 95%, respectively. The overall strength of inter-observer agreement was substantial (kappa = 0.681). CONCLUSIONS: The BING working group developed a simple, internally validated system to identify dysplasia and EAC in patients with BE based on NBI results. When images are assessed with a high degree of confidence, the system can classify BE with >90% accuracy and a high level of inter-observer agreement. PMID- 26627611 TI - Density Functional and Semiempirical Molecular Orbital Methods Including Dispersion Corrections for the Accurate Description of Noncovalent Interactions Involving Sulfur-Containing Molecules. AB - We describe the use of density functional theory (DFT-D) and semiempirical (AM1-D and PM3-D) methods having an added empirical dispersion correction, to treat noncovalent interactions between molecules involving sulfur atoms. The DFT-D method, with the BLYP and B3LYP functionals, was judged against a small-molecule database involving sulfur-pi, S-H...S, and C-H...S interactions for which high level MP2 or CCSD(T) estimates of the structures and binding or interaction energies are available. This database was also used to develop appropriate AM1-D and PM3-D parameters for sulfur. The DFT-D, AM1-D, and PM3-D methods were further assessed by calculating the structures and binding energies for a set of eight sulfur-containing base pairs, for which high-level ab initio data are available. The mean absolute deviations (MAD) for both sets of structures shown by the DFT-D methods are 0.04 A for the intermolecular distances and less than 0.7 kcal mol( )(1) for the binding and interaction energies. The corresponding values are 0.3 A and 1.5 kcal mol(-)(1) for the semiempirical methods. For the complexes studied, the dispersion contributions to the overall binding and interaction energies are shown to be important, particularly for the complexes involving sulfur-pi interactions. PMID- 26627612 TI - Empirical Correction to Molecular Interaction Energies in Density Functional Theory (DFT) for Methane Hydrate Simulation. AB - A general and empirical method is proposed for correction of London dispersion and other deficiencies in density functional theory (DFT). This method is based on the existing Lennard-Jones (L-J) equation and van der Waals parameters. The benchmark of energy correction is set as the energy difference between DFT and more accurate methods, for example CCSD(T). The energy correction includes all differences between CCSD(T) and DFT, dispersion energy, configuration interaction, induction interaction, residual correlation, and other effects. The energy correction is expressed as a linear combination of van der Waals potentials of nonbonded atomic pairs. The combination coefficients are determined using a least-squares approach in a training set of molecular pairs. The coefficients then can be used for the energy corrections in DFT calculations in a molecular family. Three correction equations of molecular pair interaction energy, water-water, water-methane, and methane-methane, are derived for methane hydrate simulation. The correction equation of the water-water pair is applied in the DFT calculation of water pentamer, yielding good intermolecular potential energy surfaces (PES), very close to the results of CCSD(T) over the active interaction range from 2.1 A to 8.0 A. PMID- 26627613 TI - Weakly Bonded Complexes of Aliphatic and Aromatic Carbon Compounds Described with Dispersion Corrected Density Functional Theory. AB - Interaction energies and structural properties of van der Waals complexes of aliphatic hydrocarbons molecules and crystals of aromatic hydrocarbon compounds are studied using density functional theory augmented with dispersion corrected atom centered potentials (DCACPs). We compare the performance of two sets of DCACPs, (a) DCACP-MP2, a correction for carbon only, generated using MP2 reference data and a penalty functional that includes only equilibrium properties and (b) DCACP-CCSD(T), a set that has been calibrated against CCSD(T) reference data using a more elaborate penalty functional that explicitly takes into account some long-range properties and uses DCACP corrections for hydrogen and carbon atoms. The agreement between our results and high level ab initio or experimental data illustrates the transferability of the DCACP scheme for the gas and condensed phase as well as for different hybridization states of carbon. The typical error of binding energies for gas-phase dimers amounts to 0.3 kcal/mol. This work demonstrates that only one DCACP per element is sufficient to correct for weak interactions in a large variety of systems, irrespective of the hybridization state. PMID- 26627614 TI - Simple Methods To Reduce Charge-Transfer Contamination in Time-Dependent Density Functional Calculations of Clusters and Liquids. AB - Using as benchmarks a series of increasingly large hydrated uracil clusters, we examine the nature and extent of charge-transfer (CT) contamination in condensed phase, time-dependent density-functional theory. These calculations are plagued by a large number of spurious CT excitations at energies comparable to (and sometimes below) the valence excitation energies, even when hybrid density functionals are used. Spurious states below the first npi* and pipi* states of uracil are observed in clusters as small as uracil-(H2O)4. Reasonable electronic absorption spectra can still be obtained, upon configurational averaging, despite pervasive CT contamination, but the spurious states add significantly to the cost of the calculations and severely complicate attempts to locate optically dark npi* states. The extent of CT contamination is reduced substantially by introducing an electrostatic (point charge) description of an extended solvent network, even in cases where the region of solvent described by density functional theory is large (>120 atoms). Alternatively, CT contamination may be reduced by eliminating certain excitation amplitudes from the linear response equations, with minimal loss of accuracy (<0.1 eV) in the valence excitation energies. PMID- 26627615 TI - Nuclear Magnetoelectric Shieldings for Chiral Discrimination in NMR Spectroscopy. Theoretical Study of (Ra)-1,3-Dimethylallene, (2R)-2-Methyloxirane, and (2R)-N Methyloxaziridine Molecules. AB - Dynamic magnetoelectric shieldings at the nuclei, having the same magnitude but opposite sign in d and l enantiomers, have been evaluated at the random-phase approximation level of accuracy for three chiral molecules of medium size. For frequencies normally operated in nuclear magnetic resonance spectroscopy, calculated values are probably too small to be detectable in disordered phase. Within the same experimental conditions, the isotropic part of nuclear magnetic shielding polarizability and a related pseudoscalar provide contributions 3 orders of magnitude bigger than the average magnetoelectric shieldings to (i) the magnetic field induced at a resonant nucleus and (ii) the induced electric dipole of electrons rotating at the Larmor frequency; therefore, nuclear magnetic shielding polarizabilities are probably more suitable than nuclear magnetoelectric shieldings for chiral discrimination in nuclear magnetic resonance spectroscopy. PMID- 26627617 TI - Nitrogen Fixation by a Molybdenum Catalyst Mimicking the Function of the Nitrogenase Enzyme: A Critical Evaluation of DFT and Solvent Effects. AB - Compounds mimicking the enzyme nitrogenase represent promising alternative routes to the current Haber-Bosch industrial synthesis of ammonia from molecular hydrogen and nitrogen. In this work, we investigated the full catalytic cycle of one of such compounds, Mo(HIPTN3N) (with HIPT = hexaisopropylterphenyl), by means of DFT calculations. Our results suggest these large ligands to exert mainly a steric influence on the structural properties of the catalyst. In addition, we provided a structural and electronic characterization of the putative reaction intermediates along with a picture of the electronic mechanism of molecular nitrogen N-N bond breaking. A large discrepancy was observed between calculated and experimental reaction free energies, suggesting that in the present case the predictability of DFT reaction energies is limited. Investigation of explicit solvation of specific catalytic intermediates as well as of the protonation and reducing agents reveal the crucial role played by the solvent molecules (benzene and heptane) particularly for protonation steps. Furthermore, the analysis of several DFT functionals indicates that these have to be carefully chosen in order to reproduce the energetic profile of reduction steps. This study shows how DFT calculations may be a powerful tool to describe structural and electronic properties of the intermediates of the catalytic cycle, yet, due to the complexity of the system, reaction energies cannot be easily reproduced without a careful choice of the solvation model and the exchange-correlation functional. PMID- 26627616 TI - Finite-Field Spin-Flip Configuration Interaction Calculation of the Second Hyperpolarizabilities of Singlet Diradical Systems. AB - Ab initio spin-flip configuration interaction (SF-CI) methods with the finite field (FF) scheme are applied to the calculation of static second hyperpolarizabilities (gamma) of several singlet diradical systems, i.e., the model H2 molecule under dissociation, p-quinodimethane, o-quinoid five-membered ring, and 1,4-bis(imidazole-2-ylidene)cyclohexa-2,5-diene (BI2Y) models. The SF CI method using the UHF reference wave function provides the qualitatively correct diradical character (y) dependence of gamma in a wide range of a diradical character region for H2 under dissociation and p-quinodimethane as well as o-quinoid five-membered ring models. For BI2Y, which is a real diradical system, a non-negligible spin contamination is found in the spin-unrestricted Hartree-Fock (UHF) triplet state, which results in overestimations (SF-CIS) or underestimations (SF-CIS(D)) of gamma. Such deficiencies are significantly reduced when using the pure spin state, i.e., the restricted open-shell HF (ROHF) triplet wave function as the reference wave function. These results indicate the applicability of the FF-SF-CI method starting with a pure or a nearly pure high spin state to provide qualitative or semiquantitative gamma for large-size diradical systems. For selected systems, these SF-CI results are also compared to the SF equation of motion coupled cluster singles and doubles (SF-EOM-CCSD) and to SF time-dependent density functional theory (SF-TDDFT) schemes. In particular, large amounts of Hartree-Fock exchange in the functional are required to obtain qualitatively correct dependence of gamma on y in the case of p-quinodimethane. PMID- 26627618 TI - Kinetics from Implicit Solvent Simulations of Biomolecules as a Function of Viscosity. AB - Kinetic properties of alanine dipeptide, the B1 domain of streptococcal protein G, and ubiquitin are compared between explicit solvent and implicit solvent simulations with the generalized Born molecular volume (GBMV) method. The results indicate that kinetics from explicit solvent simulations and experiments can be matched closely when the implicit solvent simulations are combined with Langevin dynamics and a friction coefficient near 10 ps(-1). Smaller and larger friction coefficients accelerate and slow down conformational sampling. It is found that local conformational exploration without the crossing of significant barriers can be accelerated by a factor of 4-5; however, the acceleration of barrier crossings is limited to about a factor of 2. The use of a Nose-Hoover thermostat instead of Langevin dynamics greatly enhances local conformational sampling but slows down the crossing of barriers by at least an order of magnitude because of the lack of solute-solvent stochastic collisions. PMID- 26627619 TI - Meta-Optimization of Evolutionary Strategies for Empirical Potential Development: Application to Aqueous Silicate Systems. AB - The use of evolutionary strategy optimizations in fitting empirical potentials against first-principles data is considered. Empirical potentials can involve a large number of interdependent quantities, the number varying with the complexity of the potential, and the optimization of these presents a challenging numerical problem. Evolutionary strategies are a general class of optimization methods that mimic natural selection by stochastically evolving a population of trial solutions according to rules that select for high values of some fitness function. In this work we apply a variety of evolutionary optimization methods to a representative "parametrization problem" in order to determine which such methods are well-suited to such applications. Prior work on the design of evolutionary strategies has generally focused on finding the extrema of relatively simple mathematical functions, and the findings of such studies may not be transferable to chemical applications of very high dimensionality. The test problem consists of parametrization of the Feuston-Garofalini all-atom potential developed for simulation of silicic acid oligomerization in aqueous solution (Feuston, B. P.; Garofalini, S. H. J. Phys. Chem. 1990, 94, 5351). "Meta optimization" of the evolutionary method is first considered by fitting this potential against itself, using a wide variety of population sizes, recombination algorithms, mutation-size control methods, and selection methods. Simulated annealing is also considered as an alternative approach. Optimal choices of population size, recombination operator, mutation size control approach, and selection method are discussed, as well as the quantity of data required for the parametrization. It is clear from comparisons of multiple independent optimizations that, even when fitting this potential against itself, there are a considerable number of local extrema in the fitness function. Evolutionary methods are found to be competitive with simulated annealing and are more easily parallelized. Finally, the potential is reparametrized against reference data taken from a Car-Parrinello Molecular Dynamics trajectory of several relevant silicate species in aqueous solution, again using several variant algorithms. PMID- 26627620 TI - General Transition-State Force Field for Cytochrome P450 Hydroxylation. AB - We have developed force-field parameters for the hydrogen-abstraction transition state of aliphatic hydroxylation by cytochrome P450 using the Q2MM approach. The parametrization is based on quantum chemical (B3LYP) transition-state structures and Hessian matrices for 24 diverse substrate models (14 in the training set and 10 in the test set). The force field is intended to be applicable to any druglike molecule by the use of the general Amber force field (GAFF) for the substrates. The parameters reproduce the geometries within 0.1 A and 1.2 degrees for bond lengths and angles, respectively, with no significant differences between the training and test sets. The Hessian matrix is also well reproduced with a correlation coefficient of 0.99. The parametrization is performed by the ideal iterative approach of Norrby and Liljefors, which we have implemented for the Amber software. PMID- 26627621 TI - Force Field Modeling of Amino Acid Conformational Energies. AB - The conformational degrees of freedom for four amino acids in a model peptide environment have been sampled with density functional and second-order Moller Plesset methods. Geometries have been optimized with an augmented double-zeta basis set and relative energies estimated by extrapolation of results using double, triple, and quadruple-zeta basis sets and including higher order correlation effects. In addition, the effects of vibrational zero point energies and solvation have been considered. The density functional method is unable to locate all the minima found at the MP2 level, which most likely is due to the inability for describing dispersion interactions. The use of basis sets smaller than augmented polarized double-zeta with the MP2 method may also in some cases lead to artifacts. The effects on relative energies by enlarging the basis set beyond an augmented triple-zeta and including higher order correlation beyond MP2 is small. The MP2/aug-cc-pVTZ level is recommended as a level of theory capable of an accuracy of ~1 kJ/mol for relative conformational energies. Eight different force fields are tested for reproducing the electronic structure reference data. Force fields that represent the electrostatic energy by fixed partial charges typically only account for half of the conformations, while the AMOEBA force field, which includes multipole moments and polarizability, can reproduce ~80% of the conformations in terms of geometry. This not only suggests that multipole moments and polarizability are important factors in designing new force fields but also indicates that there is still room for improvements. PMID- 26627622 TI - Atomistic Force Field for Azobenzene Compounds Adapted for QM/MM Simulations with Applications to Liquids and Liquid Crystals. AB - An atomistic force field has been adapted for use in molecular dynamics simulations of molecular materials that contain azobenzene (AB) functional groups. Force field parameters for bonded interactions and partial charges in the AB unit have been derived from ab initio molecular dynamics reference calculations. First applications of the new force field to liquid trans- and cis AB are presented, both using a purely classical approach (MM) and a hybrid quantum-classical (QM/MM) simulation scheme. Detailed structural analysis confirms that QM/MM and purely MM simulations yield results that are in good agreement with each other. The force field of the AB core has been extended to include aliphatic chains that are attached via ether bridges to the two AB benzene rings. This allows for studying temperature induced phase transitions in the liquid-crystalline 8AB8 system. Using replica exchange techniques the new force field has successfully reproduced the smectic to isotropic-phase transition. PMID- 26627623 TI - Parametrization and Validation of Intramolecular Force Fields Derived from DFT Calculations. AB - The energy and its first and second geometrical derivatives obtained by DFT calculations for a number of conformations of a single molecule are used to parametrize intramolecular force fields, suitable for computer simulations. A systematic procedure is proposed to adequately treat either fully atomistic or more simplified force fields, as within the united atom approach or other coarse grained models. The proposed method is tested and validated by performing molecular dynamics simulations on several different molecules, comparing the results with literature force fields and relevant experimental data. Particular emphasis is given to the united atom approach for flexible molecules characterized by "soft" torsional potentials which are known to retain a high degree of chemical specificity. PMID- 26627624 TI - Equilibrium Geometries and Structural Stability of the AlmNan (m = 2-4; n = 1-8) Clusters. AB - The stable geometries and formation processes of the AlmNan (m = 2-4; n = 1-8) clusters were investigated using the density functional theory (DFT). The Alm (m = 2-4) structures are maintained in the clusters. The Na atoms are attached to the Al-Al bond or Al plane for less than n = 4 in the AlmNan (m = 2-4) clusters. The odd electron of the attached Na atom is transferred to the Alm part for n <= 4 or 5 in the AlmNan (m = 2-4) clusters since the Alm part becomes stable. The Na Na bonding is formed by the attached Na atom after saturation of the Al-Al bonds or Al atoms. The Al2Na5, Al3Na5, Al3Na6, Al3Na7, and Al3Na8 clusters have a characteristic structure. The Na wing is formed in the Al3Nan (n = 5-8) clusters. The 2S shell containing the 3s orbital of the Na atom and the 3p orbital of the Al atom becomes stable before the occupation of the 1D shell because the electrons are delocalized on the Na plane for n >= 5 in the AlmNan (m = 2-4) clusters. The stability of the AlmNan (m = 2-4; n = 1-8) clusters was evaluated by comparison of the vertical ionization potential (IP), HOMO-LUMO gap, adsorption energy of the Na atom, and binding energy per atom. PMID- 26627625 TI - Assessment of Approximate Density Functional Methods for the Study of the Interactions of Al(III) with Aromatic Amino Acids. AB - Four approximate Density Functional Theory methods, the standard hybrid B3LYP functional, the hybrid mPW1PW91 functional designed to account for van der Waals forces, the one-parameter meta hybrid TPSSh functional, the general-purpose meta hybrid MPWB1K functional and one Molecular Orbital Theory method, the standard Moller-Plesset perturbation theory up to second-order MP2, have been assessed for studying the complexation modes of the highly acidic Al(III) cation with the three aromatic amino acids, phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp). Based on their performance toward the prediction of the geometrical structure of a number of lowest energy isomers and their relative binding energies, it is concluded that the B3LYP approximate functional renders the desired accuracy at the minimum computational cost. PMID- 26627626 TI - Peptide Hydrolysis in Thermolysin: Ab Initio QM/MM Investigation of the Glu143 Assisted Water Addition Mechanism. AB - Thermolysin (TLN) is one of the best-studied zinc metalloproteases. Yet the mechanism of action is still under debate. In order to investigate the energetic feasibility of the currently most favored mechanism, we have docked a tripeptide to the active site of TLN and computed the free energy profile at the quantum mechanics/molecular mechanics level of theory. The mechanism consists of three distinct steps: (i) a Zn-bound water molecule is deprotonated by Glu143 and attacks the carbonyl bond of the substrate; (ii) Glu143 transfers the proton to the amide nitrogen atom; (iii) the nitrogen atom is protonated and the peptide bond is irreversibly broken. The free energy barriers for steps i and iii have almost equal heights, 14.8 and 14.7 kcal/mol, respectively, and are in good agreement with the effective experimental activation barrier obtained for similar substrates, 12.1-13.6 kcal/mol. Transition state stabilization for nucleophilic attack is achieved by formation of a weak coordination bond between the substrate carbonyl oxygen atom and the Zn ion and of three strong hydrogen bonds between the substrate and protonated His231 and two solvent molecules. The transition state for the nucleophilic attack (step i) is more tightly bonded than the enzyme substrate complex, implying that TLN complies with Pauling's hypothesis regarding transition-state stabilization. Glu143, at first unfavorably oriented for protonation of the amide nitrogen atom, displayed large structural fluctuations that facilitated reorganization of the local hydrogen-bond network and transport of the proton to the leaving group on the nanosecond time scale. The present simulations give further evidence that Glu143 is a highly effective proton shuttle which should be assigned a key role in any reaction mechanism proposed for TLN. PMID- 26627627 TI - Spontaneous Formation of KCl Aggregates in Biomolecular Simulations: A Force Field Issue? AB - Realistic all-atom simulation of biological systems requires accurate modeling of both the biomolecules and their ionic environment. Recently, ion nucleation phenomena leading to the rapid growth of KCl or NaCl clusters in the vicinity of biomolecular systems have been reported. To better understand this phenomenon, molecular dynamics simulations of KCl aqueous solutions at three (1.0, 0.25, and 0.10 M) concentrations were performed. Two popular water models (TIP3P and SPC/E) and two Lennard-Jones parameter sets (AMBER and Dang) were combined to produce a total of 80 ns of molecular dynamics trajectories. Results suggest that the use of the Dang cation Lennard-Jones parameters instead of those adopted by the AMBER force-field produces a more accurate description of the ionic solution. In the later case, formation of salt aggregates is probably indicative of an artifact resulting from misbalanced force-field parameters. Because similar results were obtained with two different water parameter sets, the simulations exclude a water model dependency in the formation of anomalous ionic clusters. Overall, the results strongly suggest that for accurate modeling of ions in biomolecular systems, great care should be taken in choosing balanced ionic parameters even when using the most popular force-fields. These results invite a reexamination of older data obtained using available force-fields and a thorough check of the quality of current parameters sets by performing simulations at finite (>0.25 M) instead of minimal salt conditions. PMID- 26627628 TI - Demonstrated Convergence of the Equilibrium Ensemble for a Fast United-Residue Protein Model. AB - Because of the time-scale limitations of all-atom simulation of proteins, there has been substantial interest in coarse-grained approaches. Some methods, like "resolution exchange" (Lyman, E.; Ytreberg, F. M.; Zuckerman, D. M. Phys. Rev. Lett. 2006, 96, 028105-1-4), can accelerate canonical all-atom sampling but require properly distributed coarse ensembles. We therefore demonstrate that full sampling can indeed be achieved in a sufficiently simplified protein model, as verified by a recently developed convergence analysis. The model accounts for protein backbone geometry, in that rigid peptide planes rotate according to atomistically defined dihedral angles, but there are only two degrees of freedom (phi and psi dihedrals) per residue. Our convergence analysis indicates that small proteins (up to 89 residues in our tests) can be simulated for more than 50 "structural decorrelation times" in less than a week on a single processor. We show that the fluctuation behavior is reasonable, and we discuss applications, limitations, and extensions of the model. PMID- 26627629 TI - Coarse-Graining the Accessible Surface and the Electrostatics of Proteins for Protein-Protein Interactions. AB - This study is concerned with the development and test of a coarse-grained representation specifically constructed for proteins and peptides, where each amino acid of the sequence is represented by a charged dipolar sphere. The model was parametrized from the physical properties of individual amino acids and applied to the study of the interaction between solvated proteins. Using an implicit solvent approach and our coarse-grained model, we computed the potential of mean force for the association of well-known proteins, such as the Cu-Zn superoxide dismutase, lysozyme, and basic pancreatic trypsin inhibitor, and a peptide, Abeta7. The coarse-grained potentials of mean force were systematically compared with their all-atoms counterpart. For both the polar and nonpolar contributions to this potential, the results of our calculations show that the coarse-grained model provides a good approximation of the all-atoms potential when the distance between the molecule surfaces is greater than a solvent molecular diameter. For shorter distances and for specific interactions, like those found between the SOD monomers, the electrostatic desolvation effect appears to be underestimated by our coarse-grained representation. The possibility of a very short range all-atom refinement to better describe the interaction at close contact is explored. We find also that the most important contribution to the association free-energy comes from the hydrophobic solvent accessible surface area term, which is well reproduced by our coarse-grained approach. PMID- 26627630 TI - Delayed luminescence induced by complex domains in water and in TEOS aqueous solutions. AB - Many recent studies on water have conjectured a complex structure composed of hydrogen bonded low- and high-density domains. In this work the structure of pure water and aqueous solutions of silica gel (TEOS) has been investigated by using delayed luminescence, which has previously shown a significant increase in aqueous salt solutions where low-density domain formation is expected. Photon emission shows an Arrhenius trend with an activation energy in water-TEOS solutions larger than in pure water and salt-water solutions. Moreover, delayed photon emission decay shows an intrinsic lifetime of about 5 MUs both in solutions and in pure water that, along with secondary lifetimes induced by the presence of TEOS, could be related to the formation of different domains. PMID- 26627631 TI - Effects of acute kidney injury on clinical outcomes in patients with upper gastrointestinal bleeding. AB - AIM: Upper gastrointestinal bleeding (UGIB) is a very frequently encountered condition that has a high morbidity and which increases treatment costs. Duration of hospital stay and mortality increases in patients with UGIB complicated by acute kidney injury (AKI). The aim of this study was to reveal risk factors in patients with UGIB developing AKI and to compare clinical outcomes and hospital costs between patients with UGIB developing AKI and those with UGIB not developing AKI. MATERIAL AND METHODS: This retrospective study included 245 patients admitted to the emergency unit and the intensive care unit for internal diseases at Ankara Numune Education and Research Hospital, Turkey. RESULTS: The difference in mortality rates between the patients with AKI and those without AKI was significant (p < 0.001). The mean duration of intensive care unit stay was 0.2 +/- 1.1 days in the patients without AKI (n = 143) and 2.5 +/- 5.6 days in the patients with AKI. It was significantly higher in the patients with AKI (p < 0.001). Hospital stay was significantly longer in the patients with AKI than those without AKI, and as severity of AKI increased, hospital stay became considerably longer (p < 0.001). Hospital costs were significantly higher in the patients with AKI than those without AKI, and as severity of AKI increased, hospital costs considerably rose (p < 0.001). CONCLUSION: AKI is a condition that lengthens hospital stay, increases hospital costs and creates a burden on health care systems. Detect kidney injury earlier and administering an appropriate treatment can improve clinical outcomes in patients with UGIB developing AKI. PMID- 26627632 TI - Impact of OmpR on the membrane proteome of Yersinia enterocolitica in different environments: repression of major adhesin YadA and heme receptor HemR. AB - Enteropathogenic Yersinia enterocolitica is able to grow within or outside the mammalian host. Previous transcriptomic studies have indicated that the regulator OmpR plays a role in the expression of hundreds of genes in enterobacteria. Here, we have examined the impact of OmpR on the production of Y. enterocolitica membrane proteins upon changes in temperature, osmolarity and pH. Proteomic analysis indicated that the loss of OmpR affects the production of 120 proteins, a third of which are involved in uptake/transport, including several that participate in iron or heme acquisition. A set of proteins associated with virulence was also affected. The influence of OmpR on the abundance of adhesin YadA and heme receptor HemR was examined in more detail. OmpR was found to repress YadA production and bind to the yadA promoter, suggesting a direct regulatory effect. In contrast, the repression of hemR expression by OmpR appears to be indirect. These findings provide new insights into the role of OmpR in remodelling the cell surface and the adaptation of Y. enterocolitica to different environmental niches, including the host. PMID- 26627633 TI - To biopsy or not to biopsy, that is the question in myeloma cast nephropathy. PMID- 26627634 TI - The impact of dialysis on the survival of patients with immunoglobulin light chain (AL) amyloidosis undergoing autologous stem cell transplantation. AB - BACKGROUND: Acute renal failure requiring dialysis is associated with high mortality during autologous stem cell transplantation (ASCT). This study examined the association between acute renal failure and mortality in immunoglobulin light chain (AL) amyloidosis during ASCT. METHODS: Between 1996 and 2010, 408 ASCT patients were evaluated. Data were collected from electronic medical records. RESULTS: Dialysis was performed on 72 (17.6%) patients. Eight patients started dialysis >30 days prior to ASCT (Group II), 36 started +/-30 days after ASCT (Group III) and 28 initiated dialysis >1 month after ASCT (Group IV). Patients who never dialyzed were assigned to Group I. There were no significant age or sex differences. Median overall survival (OS) had not been reached in Groups I and II but was 7.0 months in Group III and 48.5 months in Group IV (P < 0.001). Treatment-related mortality (TRM) was observed in 44.4% of the patients in Group III, 6-fold higher than the next highest group (P < 0.001). The most common causes of TRM were cardiac and sepsis. In the multivariate analysis, only hypoalbuminemia (<2.5 g/dL, P < 0.001) and estimated glomerular filtration rate (eGFR) <40 mL/min/1.73 m(2) (P < 0.001) were independently associated with starting dialysis within 30 days of ASCT. CONCLUSIONS: The study found significant differences in the OS depending on when the acute renal failure occurred. Patients who required dialysis within 30 days of ASCT had the highest rate of TRM. Screening with serum albumin and eGFR may reduce the risk. PMID- 26627636 TI - Revisiting the Iodine Global Network's definition of iodine status by country. PMID- 26627635 TI - Cardiovascular and all-cause mortality in patients with type 2 diabetes mellitus in the MADIABETES Cohort Study: Association with chronic kidney disease. AB - AIMS: To assess the prevalence of stage 3-5 chronic kidney disease (CKD) at baseline and to identify associated risk factors. To determine the effect of CKD and CKD stage according to estimated glomerular filtration rate (eGFR) and albuminuria categories on all-cause and cardiovascular mortality after a 5-year follow-up. METHODS: Prospective cohort study of 3443 outpatients with type 2 diabetes mellitus. RESULTS: The prevalence of CKD was 28.32% (95% CI, 26.84 29.86); and variables most strongly associated were: age >74 years (OR, 19.88; 95% CI, 12.89-30.68) and albuminuria (OR, 2.27; 95% CI, 1.72-3.00). During follow up, 221 CKD patients (22.90%) died compared with 203 non-CKD patients (8.31%) (p<0.01). The adjusted HR of CKD for cardiovascular and all-cause mortality was 1.82 (95% CI, 1.36-2.44) and 2.11 (95% CI, 1.61-2.76) for those with LDL cholesterol =135 mg/dl, respectively. The adjusted HR of very-high-risk CKD for all-cause mortality was 4.44 (95% CI, 2.31-8.53) in aged <75 years and 1.80 (95% CI, 1.19-2.72) in aged >=75 years. CONCLUSIONS: CKD at baseline is an independent risk factor for all-cause and cardiovascular mortality in the overall cohort, men and women, or in primary and secondary prevention of coronary heart disease. Albuminuria is an independent risk factor for all-cause and cardiovascular mortality only in primary prevention. PMID- 26627637 TI - The association between mental health, chronic disease and sleep duration in Koreans: a cross-sectional study. AB - BACKGROUND: Sleep duration holds considerable importance as an indicator of mental/physical health. The objective of this study was to investigate the association between sleep duration, mental health, and chronic disease prevalence in Koreans. METHODS: Of 31,596 subjects eligible for the Korean National Health and Nutrition Examination Survey V (2010-2012), 17,638 participants who answered items on sleep duration (aged >= 19 yrs) were analyzed in a cross-sectional study. Association between sleep duration, mental health, and chronic disease prevalence was assessed using logistic regression, and adjusted for various socioeconomic and lifestyle characteristics. RESULTS: Short or long sleep duration showed correlations with mental health, and items of significance showed gender-specific patterns. Women displayed significant associations with stress and depressive symptoms, and men with stress, thoughts of suicide, and psychiatric counseling. While stress was related with short sleep duration in both genders, depressive symptoms showed a relationship with long duration in men, and short duration in women. Prevalence of any chronic disease was associated with <= 6 h sleep when adjusted for factors including mental health, and among chronic diseases, cancer and osteoarthritis showed associations with short sleep duration, while diabetes and dyslipidemia were associated with normal sleep duration. CONCLUSIONS: Mental health problems were associated with sleep duration with gender-specific patterns. Associations with osteoarthritis, cancer, diabetes, dyslipidemia and abnormal sleep duration persisted after adjustment for mental health. PMID- 26627639 TI - Treatment rates of paediatric acute myeloid leukaemia: a view from three tertiary centres in India - response to Gupta et al. PMID- 26627638 TI - Identification of novel CSF biomarkers for neurodegeneration and their validation by a high-throughput multiplexed targeted proteomic assay. AB - BACKGROUND: Currently there are no effective treatments for many neurodegenerative diseases. Reliable biomarkers for identifying and stratifying these diseases will be important in the development of future novel therapies. Lewy Body Dementia (LBD) is considered an under diagnosed form of dementia for which markers are needed to discriminate LBD from other forms of dementia such as Alzheimer's Disease (AD). This work describes a Label-Free proteomic profiling analysis of cerebral spinal fluid (CSF) from non-neurodegenerative controls and patients with LBD. Using this technology we identified several potential novel markers for LBD. These were then combined with other biomarkers from previously published studies, to create a 10 min multiplexed targeted and translational MRM LC-MS/MS assay. This test was used to validate our new assay in a larger cohort of samples including controls and the other neurodegenerative conditions of Alzheimer's and Parkinson's disease (PD). RESULTS: Thirty eight proteins showed significantly (p < 0.05) altered expression in LBD CSF by proteomic profiling. The targeted MRM-LC-MS/MS assay revealed 4 proteins that were specific for the identification of AD from LBD: ectonucleotide pyrophosphatase/phosphodiesterase 2 (p < 0.0001), lysosome-associated membrane protein 1 (p < 0.0001), pro-orexin (p < 0.0017) and transthyretin (p < 0.0001). Nineteen proteins were elevated significantly in both AD and LBD versus the control group of which 4 proteins are novel (malate dehydrogenase 1, serum amyloid A4, GM2-activator protein, and prosaposin). Protein-DJ1 was only elevated significantly in the PD group and not in either LBD or AD samples. Correlations with Alzheimer-associated amyloid beta 42 levels, determined by ELISA, were observed for transthyretin, GM2 activator protein and IGF2 in the AD disease group (r(2) >= 0.39, p <= 0.012). Cystatin C, ubiquitin and osteopontin showed a strong significant linear relationship (r(2) >= 0.4, p <= 0.03) with phosphorylated-tau levels in all groups, whilst malate dehydrogenase and apolipoprotein E demonstrated a linear relationship with phosphorylated-tau and total-tau levels in only AD and LBD disease groups. CONCLUSIONS: Using proteomics we have identified several potential and novel markers of neurodegeneration and subsequently validated them using a rapid, multiplexed mass spectral test. This targeted proteomic platform can measure common markers of neurodegeneration that correlate with existing diagnostic makers as well as some that have potential to show changes between AD from LBD. PMID- 26627642 TI - Correction: CD38 in Hairy Cell Leukemia Is a Marker of Poor Prognosis and a New Target for Therapy. PMID- 26627641 TI - Serum Immunoregulatory Proteins as Predictors of Overall Survival of Metastatic Melanoma Patients Treated with Ipilimumab. AB - Treatment with ipilimumab improves overall survival (OS) in patients with metastatic melanoma. Because ipilimumab targets T lymphocytes and not the tumor itself, efficacy may be uniquely sensitive to immunomodulatory factors present at the time of treatment. We analyzed serum from patients with metastatic melanoma (247 of 273, 90.4%) randomly assigned to receive ipilimumab or gp100 peptide vaccine. We quantified candidate biomarkers at baseline and assessed the association of each using multivariate analyses. Results were confirmed in an independent cohort of similar patients (48 of 52, 92.3%) treated with ipilimumab. After controlling for baseline covariates, elevated chemokine (C-X-C motif) ligand 11 (CXCL11) and soluble MHC class I polypeptide-related chain A (sMICA) were associated with poor OS in ipilimumab-treated patients [log10 CXCL11: HR, 1.88; 95% confidence interval (CI), 1.14-3.12; P = 0.014; and log10 sMICA quadratic effect P = 0.066; sMICA (>= 247 vs. 247): HR, 1.75; 95% CI, 1.02-3.01]. Multivariate analysis of an independent ipilimumab-treated cohort confirmed the association between log10 CXCL11 and OS (HR, 3.18; 95% CI, 1.13-8.95; P = 0.029), whereas sMICA was less strongly associated with OS [log10 sMICA quadratic effect P = 0.16; sMICA (>= 247 vs. 247): HR, 1.48; 95% CI, 0.67-3.27]. High baseline CXCL11 and sMICA were associated with poor OS in patients with metastatic melanoma after ipilimumab treatment but not vaccine treatment. Thus, pretreatment CXCL11 and sMICA may represent predictors of survival benefit after ipilimumab treatment as well as therapeutic targets. PMID- 26627643 TI - Ethanol exposure during the third trimester equivalent does not affect GABAA or AMPA receptor-mediated spontaneous synaptic transmission in rat CA3 pyramidal neurons. AB - BACKGROUND: Ethanol exposure during the rodent equivalent to the 3(rd) trimester of human pregnancy (i.e., first 1-2 weeks of neonatal life) has been shown to produce structural and functional alterations in the CA3 hippocampal sub-region, which is involved in associative memory. Synaptic plasticity mechanisms dependent on retrograde release of brain-derived neurotrophic factor (BDNF) driven by activation of L-type voltage-gated Ca(2+) channels (L-VGCCs) are thought to play a role in stabilization of both GABAergic and glutamatergic synapses in CA3 pyramidal neurons. We previously showed that ethanol exposure during the first week of life blocks BDNF/L-VGCC-dependent long-term potentiation of GABAA receptor-mediated synaptic transmission in these neurons. Here, we tested whether this effect is associated with lasting alterations in GABAergic and glutamatergic transmission. METHODS: Rats were exposed to air or ethanol for 3 h/day between postnatal days three and five in vapor inhalation chambers, a paradigm that produces peak serum ethanol levels near 0.3 g/dl. Whole-cell patch-clamp electrophysiological recordings of spontaneous inhibitory and excitatory postsynaptic currents (sIPSCs and sEPSCs, respectively) were obtained from CA3 pyramidal neurons in coronal brain slices prepared at postnatal days 13-17. RESULTS: Ethanol exposure did not significantly affect the frequency, amplitude, rise-time and half-width of either sIPSCs or sEPSCs. CONCLUSIONS: We show that an ethanol exposure paradigm known to inhibit synaptic plasticity mechanisms that may participate in the stabilization of GABAergic and glutamatergic synapses in CA3 pyramidal neurons does not produce lasting functional alterations in these synapses, suggesting that compensatory mechanisms restored the balance of excitatory and inhibitory synaptic transmission. PMID- 26627644 TI - Transformation and patterning of supermicelles using dynamic holographic assembly. AB - Although the solution self-assembly of block copolymers has enabled the fabrication of a broad range of complex, functional nanostructures, their precise manipulation and patterning remain a key challenge. Here we demonstrate that spherical and linear supermicelles, supramolecular structures held together by non-covalent solvophobic and coordination interactions and formed by the hierarchical self-assembly of block copolymer micelle and block comicelle precursors, can be manipulated, transformed and patterned with mediation by dynamic holographic assembly (optical tweezers). This allows the creation of new and stable soft-matter superstructures far from equilibrium. For example, individual spherical supermicelles can be optically held in close proximity and photocrosslinked through controlled coronal chemistry to generate linear oligomeric arrays. The use of optical tweezers also enables the directed deposition and immobilization of supermicelles on surfaces, allowing the precise creation of arrays of soft-matter nano-objects with potentially diverse functionality and a range of applications. PMID- 26627645 TI - A structural view of the dissociation of Escherichia coli tryptophanase. AB - Tryptophanase (Trpase) is a pyridoxal 5'-phosphate (PLP)-dependent homotetrameric enzyme which catalyzes the degradation of L-tryptophan. Trpase is also known for its cold lability, which is a reversible loss of activity at low temperature (2 degrees C) that is associated with the dissociation of the tetramer. Escherichia coli Trpase dissociates into dimers, while Proteus vulgaris Trpase dissociates into monomers. As such, this enzyme is an appropriate model to study the protein protein interactions and quaternary structure of proteins. The aim of the present study was to understand the differences in the mode of dissociation between the E. coli and P. vulgaris Trpases. In particular, the effect of mutations along the molecular axes of homotetrameric Trpase on its dissociation was studied. To answer this question, two groups of mutants of the E. coli enzyme were created to resemble the amino-acid sequence of P. vulgaris Trpase. In one group, residues 15 and 59 that are located along the molecular axis R (also termed the noncatalytic axis) were mutated. The second group included a mutation at position 298, located along the molecular axis Q (also termed the catalytic axis). Replacing amino-acid residues along the R axis resulted in dissociation of the tetramers into monomers, similar to the P. vulgaris Trpase, while replacing amino-acid residues along the Q axis resulted in dissociation into dimers only. The crystal structure of the V59M mutant of E. coli Trpase was also determined in its apo form and was found to be similar to that of the wild type. This study suggests that in E. coli Trpase hydrophobic interactions along the R axis hold the two monomers together more strongly, preventing the dissociation of the dimers into monomers. Mutation of position 298 along the Q axis to a charged residue resulted in tetramers that are less susceptible to dissociation. Thus, the results indicate that dissociation of E. coli Trpase into dimers occurs along the molecular Q axis. PMID- 26627646 TI - Unravelling the shape and structural assembly of the photosynthetic GAPDH-CP12 PRK complex from Arabidopsis thaliana by small-angle X-ray scattering analysis. AB - Oxygenic photosynthetic organisms produce sugars through the Calvin-Benson cycle, a metabolism that is tightly linked to the light reactions of photosynthesis and is regulated by different mechanisms, including the formation of protein complexes. Two enzymes of the cycle, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and phosphoribulokinase (PRK), form a supramolecular complex with the regulatory protein CP12 with the formula (GAPDH-CP122-PRK)2, in which both enzyme activities are transiently inhibited during the night. Small-angle X-ray scattering analysis performed on both the GAPDH-CP12-PRK complex and its components, GAPDH-CP12 and PRK, from Arabidopsis thaliana showed that (i) PRK has an elongated, bent and screwed shape, (ii) the oxidized N-terminal region of CP12 that is not embedded in the GAPDH-CP12 complex prefers a compact conformation and (iii) the interaction of PRK with the N-terminal region of CP12 favours the approach of two GAPDH tetramers. The interaction between the GAPDH tetramers may contribute to the overall stabilization of the GAPDH-CP12-PRK complex, the structure of which is presented here for the first time. PMID- 26627647 TI - Sent packing: protein engineering generates a new crystal form of Pseudomonas aeruginosa DsbA1 with increased catalytic surface accessibility. AB - Pseudomonas aeruginosa is an opportunistic human pathogen for which new antimicrobial drug options are urgently sought. P. aeruginosa disulfide-bond protein A1 (PaDsbA1) plays a pivotal role in catalyzing the oxidative folding of multiple virulence proteins and as such holds great promise as a drug target. As part of a fragment-based lead discovery approach to PaDsbA1 inhibitor development, the identification of a crystal form of PaDsbA1 that was more suitable for fragment-soaking experiments was sought. A previously identified crystallization condition for this protein was unsuitable, as in this crystal form of PaDsbA1 the active-site surface loops are engaged in the crystal packing, occluding access to the target site. A single residue involved in crystal-packing interactions was substituted with an amino acid commonly found at this position in closely related enzymes, and this variant was successfully used to generate a new crystal form of PaDsbA1 in which the active-site surface is more accessible for soaking experiments. The PaDsbA1 variant displays identical redox character and in vitro activity to wild-type PaDsbA1 and is structurally highly similar. Two crystal structures of the PaDsbA1 variant were determined in complex with small molecules bound to the protein active site. These small molecules (MES, glycerol and ethylene glycol) were derived from the crystallization or cryoprotectant solutions and provide a proof of principle that the reported crystal form will be amenable to co-crystallization and soaking with small molecules designed to target the protein active-site surface. PMID- 26627648 TI - X-ray-induced catalytic active-site reduction of a multicopper oxidase: structural insights into the proton-relay mechanism and O2-reduction states. AB - During X-ray data collection from a multicopper oxidase (MCO) crystal, electrons and protons are mainly released into the system by the radiolysis of water molecules, leading to the X-ray-induced reduction of O2 to 2H2O at the trinuclear copper cluster (TNC) of the enzyme. In this work, 12 crystallographic structures of Thermus thermophilus HB27 multicopper oxidase (Tth-MCO) in holo, apo and Hg bound forms and with different X-ray absorbed doses have been determined. In holo Tth-MCO structures with four Cu atoms, the proton-donor residue Glu451 involved in O2 reduction was found in a double conformation: Glu451a (~7 A from the TNC) and Glu451b (~4.5 A from the TNC). A positive peak of electron density above 3.5sigma in an Fo - Fc map for Glu451a O(E2) indicates the presence of a carboxyl functional group at the side chain, while its significant absence in Glu451b strongly suggests a carboxylate functional group. In contrast, for apo Tth-MCO and in Hg-bound structures neither the positive peak nor double conformations were observed. Together, these observations provide the first structural evidence for a proton-relay mechanism in the MCO family and also support previous studies indicating that Asp106 does not provide protons for this mechanism. In addition, eight composite structures (Tth-MCO-C1-8) with different X-ray-absorbed doses allowed the observation of different O2-reduction states, and a total depletion of T2Cu at doses higher than 0.2 MGy showed the high susceptibility of this Cu atom to radiation damage, highlighting the importance of taking radiation effects into account in biochemical interpretations of an MCO structure. PMID- 26627649 TI - Small-angle scattering determination of the shape and localization of human cytochrome P450 embedded in a phospholipid nanodisc environment. AB - Membrane proteins reconstituted into phospholipid nanodiscs comprise a soluble entity accessible to solution small-angle X-ray scattering (SAXS) studies. It is demonstrated that using SAXS data it is possible to determine both the shape and localization of the membrane protein cytochrome P450 3A4 (CYP3A4) while it is embedded in the phospholipid bilayer of a nanodisc. In order to accomplish this, a hybrid approach to analysis of small-angle scattering data was developed which combines an analytical approach to describe the multi-contrast nanodisc with a free-form bead-model description of the embedded protein. The protein shape is then reconstructed ab initio to optimally fit the data. The result of using this approach is compared with the result obtained using a rigid-body description of the CYP3A4-in-nanodisc system. Here, the CYP3A4 structure relies on detailed information from crystallographic and molecular-dynamics studies of CYP3A4. Both modelling approaches arrive at very similar solutions in which the alpha-helical anchor of the CYP3A4 systematically stays close to the edge of the nanodisc and with the large catalytic domain leaning over the outer edge of the nanodisc. The obtained distance between the globular domains of CYP3A4 is consistent with previously published theoretical calculations. PMID- 26627650 TI - An enzyme captured in two conformational states: crystal structure of S-adenosyl L-homocysteine hydrolase from Bradyrhizobium elkanii. AB - S-Adenosyl-L-homocysteine hydrolase (SAHase) is involved in the enzymatic regulation of S-adenosyl-L-methionine (SAM)-dependent methylation reactions. After methyl-group transfer from SAM, S-adenosyl-L-homocysteine (SAH) is formed as a byproduct, which in turn is hydrolyzed to adenosine (Ado) and homocysteine (Hcy) by SAHase. The crystal structure of BeSAHase, an SAHase from Bradyrhizobium elkanii, which is a nitrogen-fixing bacterial symbiont of legume plants, was determined at 1.7 A resolution, showing the domain organization (substrate binding domain, NAD(+) cofactor-binding domain and dimerization domain) of the subunits. The protein crystallized in its biologically relevant tetrameric form, with three subunits in a closed conformation enforced by complex formation with the Ado product of the enzymatic reaction. The fourth subunit is ligand-free and has an open conformation. The BeSAHase structure therefore provides a unique snapshot of the domain movement of the enzyme induced by the binding of its natural ligands. PMID- 26627651 TI - Structure-function relationships in Gan42B, an intracellular GH42 beta galactosidase from Geobacillus stearothermophilus. AB - Geobacillus stearothermophilus T-6 is a Gram-positive thermophilic soil bacterium that contains a battery of degrading enzymes for the utilization of plant cell wall polysaccharides, including xylan, arabinan and galactan. A 9.4 kb gene cluster has recently been characterized in G. stearothermophilus that encodes a number of galactan-utilization elements. A key enzyme of this degradation system is Gan42B, an intracellular GH42 beta-galactosidase capable of hydrolyzing short beta-1,4-galactosaccharides into galactose units, making it of high potential for various biotechnological applications. The Gan42B monomer is made up of 686 amino acids, and based on sequence homology it was suggested that Glu323 is the catalytic nucleophile and Glu159 is the catalytic acid/base. In the current study, the detailed three-dimensional structure of wild-type Gan42B (at 2.45 A resolution) and its catalytic mutant E323A (at 2.50 A resolution), as determined by X-ray crystallography, are reported. These structures demonstrate that the three-dimensional structure of the Gan42B monomer generally correlates with the overall fold observed for GH42 proteins, consisting of three main domains: an N terminal TIM-barrel domain, a smaller mixed alpha/beta domain, and the smallest all-beta domain at the C-terminus. The two catalytic residues are located in the TIM-barrel domain in a pocket-like active site such that their carboxylic functional groups are about 5.3 A from each other, consistent with a retaining mechanism. The crystal structure demonstrates that Gan42B is a homotrimer, resembling a flowerpot in general shape, in which each monomer interacts with the other two to form a cone-shaped tunnel cavity in the centre. The cavity is ~35 A at the wide opening and ~5 A at the small opening and ~40 A in length. The active sites are situated at the interfaces between the monomers, so that every two neighbouring monomers participate in the formation of each of the three active sites of the trimer. They are located near the small opening of the cone tunnel, all facing the centre of the cavity. The biological relevance of this trimeric structure is supported by independent results obtained from gel-permeation chromatography. These data and their comparison to the structural data of related GH42 enzymes are used for a more general discussion concerning structure-activity aspects in this GH family. PMID- 26627652 TI - Crystal structure and kinetic studies of a tetrameric type II beta-carbonic anhydrase from the pathogenic bacterium Vibrio cholerae. AB - Carbonic anhydrase (CA) is a zinc enzyme that catalyzes the reversible conversion of carbon dioxide to bicarbonate (hydrogen carbonate) and a proton. CAs have been extensively investigated owing to their involvement in numerous physiological and pathological processes. Currently, CA inhibitors are widely used as antiglaucoma, anticancer and anti-obesity drugs and for the treatment of neurological disorders. Recently, the potential use of CA inhibitors to fight infections caused by protozoa, fungi and bacteria has emerged as a new research direction. In this article, the cloning and kinetic characterization of the beta-CA from Vibrio cholerae (VchCAbeta) are reported. The X-ray crystal structure of this new enzyme was solved at 1.9 A resolution from a crystal that was perfectly merohedrally twinned, revealing a tetrameric type II beta-CA with a closed active site in which the zinc is tetrahedrally coordinated to Cys42, Asp44, His98 and Cys101. The substrate bicarbonate was found bound in a noncatalytic binding pocket close to the zinc ion, as reported for a few other beta-CAs, such as those from Escherichia coli and Haemophilus influenzae. At pH 8.3, the enzyme showed a significant catalytic activity for the physiological reaction of the hydration of CO2 to bicarbonate and protons, with the following kinetic parameters: a kcat of 3.34 * 10(5) s(-1) and a kcat/Km of 4.1 * 10(7) M(-1) s(-1). The new enzyme, on the other hand, was poorly inhibited by acetazolamide (Ki of 4.5 uM). As this bacterial pathogen encodes at least three CAs, an alpha-CA, a beta-CA and a gamma CA, these enzymes probably play an important role in the life cycle and pathogenicity of Vibrio, and it cannot be excluded that interference with their activity may be exploited therapeutically to obtain antibiotics with a different mechanism of action. PMID- 26627653 TI - Octameric structure of Staphylococcus aureus enolase in complex with phosphoenolpyruvate. AB - Staphylococcus aureus is a Gram-positive bacterium with strong pathogenicity that causes a wide range of infections and diseases. Enolase is an evolutionarily conserved enzyme that plays a key role in energy production through glycolysis. Additionally, enolase is located on the surface of S. aureus and is involved in processes leading to infection. Here, crystal structures of Sa_enolase with and without bound phosphoenolpyruvate (PEP) are presented at 1.6 and 2.45 A resolution, respectively. The structure reveals an octameric arrangement; however, both dimeric and octameric conformations were observed in solution. Furthermore, enzyme-activity assays show that only the octameric variant is catalytically active. Biochemical and structural studies indicate that the octameric form of Sa_enolase is enzymatically active in vitro and likely also in vivo, while the dimeric form is catalytically inactive and may be involved in other biological processes. PMID- 26627654 TI - Sequence-dependent structural changes in a self-assembling DNA oligonucleotide. AB - DNA has proved to be a remarkable molecule for the construction of sophisticated two-dimensional and three-dimensional architectures because of its programmability and structural predictability provided by complementary Watson Crick base pairing. DNA oligonucleotides can, however, exhibit a great deal of local structural diversity. DNA conformation is strongly linked to both environmental conditions and the nucleobase identities inherent in the oligonucleotide sequence, but the exact relationship between sequence and local structure is not completely understood. This study examines how a single nucleotide addition to a class of self-assembling DNA 13-mers leads to a significantly different overall structure under identical crystallization conditions. The DNA 13-mers self-assemble in the presence of Mg(2+) through a combination of Watson-Crick and noncanonical base-pairing interactions. The crystal structures described here show that all of the predicted Watson-Crick base pairs are present, with the major difference being a significant rearrangement of noncanonical base pairs. This includes the formation of a sheared A-G base pair, a junction of strands formed from base-triple interactions, and tertiary interactions that generate structural features similar to tandem sheared G-A base pairs. The adoption of this alternate noncanonical structure is dependent in part on the sequence in the Watson-Crick duplex region. These results provide important new insights into the sequence-structure relationship of short DNA oligonucleotides and demonstrate a unique interplay between Watson-Crick and noncanonical base pairs that is responsible for crystallization fate. PMID- 26627655 TI - Structural characterization of a mitochondrial 3-ketoacyl-CoA (T1)-like thiolase from Mycobacterium smegmatis. AB - Thiolases catalyze the degradation and synthesis of 3-ketoacyl-CoA molecules. Here, the crystal structures of a T1-like thiolase (MSM-13 thiolase) from Mycobacterium smegmatis in apo and liganded forms are described. Systematic comparisons of six crystallographically independent unliganded MSM-13 thiolase tetramers (dimers of tight dimers) from three different crystal forms revealed that the two tight dimers are connected to a rigid tetramerization domain via flexible hinge regions, generating an asymmetric tetramer. In the liganded structure, CoA is bound to those subunits that are rotated towards the tip of the tetramerization loop of the opposing dimer, suggesting that this loop is important for substrate binding. The hinge regions responsible for this rotation occur near Val123 and Arg149. The Lalpha1-covering loop-Lalpha2 region, together with the Nbeta2-Nalpha2 loop of the adjacent subunit, defines a specificity pocket that is larger and more polar than those of other tetrameric thiolases, suggesting that MSM-13 thiolase has a distinct substrate specificity. Consistent with this finding, only residual activity was detected with acetoacetyl-CoA as the substrate in the degradative direction. No activity was observed with acetyl CoA in the synthetic direction. Structural comparisons with other well characterized thiolases suggest that MSM-13 thiolase is probably a degradative thiolase that is specific for 3-ketoacyl-CoA molecules with polar, bulky acyl chains. PMID- 26627656 TI - Atomic resolution crystal structure of Sapp2p, a secreted aspartic protease from Candida parapsilosis. AB - The virulence of the Candida pathogens is enhanced by the production of secreted aspartic proteases, which therefore represent possible targets for drug design. Here, the crystal structure of the secreted aspartic protease Sapp2p from Candida parapsilosis was determined. Sapp2p was isolated from its natural source and crystallized in complex with pepstatin A, a classical aspartic protease inhibitor. The atomic resolution of 0.83 A allowed the protonation states of the active-site residues to be inferred. A detailed comparison of the structure of Sapp2p with the structure of Sapp1p, the most abundant C. parapsilosis secreted aspartic protease, was performed. The analysis, which included advanced quantum chemical interaction-energy calculations, uncovered molecular details that allowed the experimentally observed equipotent inhibition of both isoenzymes by pepstatin A to be rationalized. PMID- 26627657 TI - The first crystal structure of the peptidase domain of the U32 peptidase family. AB - The U32 family is a collection of over 2500 annotated peptidases in the MEROPS database with unknown catalytic mechanism. They mainly occur in bacteria and archaea, but a few representatives have also been identified in eukarya. Many of the U32 members have been linked to pathogenicity, such as proteins from Helicobacter and Salmonella. The first crystal structure analysis of a U32 catalytic domain from Methanopyrus kandleri (gene mk0906) reveals a modified (betaalpha)8 TIM-barrel fold with some unique features. The connecting segment between strands beta7 and beta8 is extended and helix alpha7 is located on top of the C-terminal end of the barrel body. The protein exhibits a dimeric quaternary structure in which a zinc ion is symmetrically bound by histidine and cysteine side chains from both monomers. These residues reside in conserved sequence motifs. No typical proteolytic motifs are discernible in the three-dimensional structure, and biochemical assays failed to demonstrate proteolytic activity. A tunnel in which an acetate ion is bound is located in the C-terminal part of the beta-barrel. Two hydrophobic grooves lead to a tunnel at the C-terminal end of the barrel in which an acetate ion is bound. One of the grooves binds to a Strep Tag II of another dimer in the crystal lattice. Thus, these grooves may be binding sites for hydrophobic peptides or other ligands. PMID- 26627658 TI - Serial crystallographic analysis of protein isomorphous replacement data from a mixture of native and derivative microcrystals. AB - A post-experimental identification/purification procedure similar to that described in Zhang et al. [(2015), IUCrJ, 2, 322-326] has been proposed for use in the treatment of multiphase protein serial crystallography (SX) diffraction snapshots. As a proof of concept, the procedure was tested using theoretical serial femtosecond crystallography (SFX) data from a mixture containing native and derivatized crystals of a protein. Two known proteins were taken as examples. Multiphase diffraction snapshots were subjected to two rounds of indexing using the program CrystFEL [White et al. (2012). J. Appl. Cryst. 45, 335-341]. In the first round, an ab initio indexing was performed to derive a set of approximate primitive unit-cell parameters, which are roughly the average of those from the native protein and the derivative. These parameters were then used in a second round of indexing as input to CrystFEL. The results were then used to separate the diffraction snapshots into two subsets corresponding to the native and the derivative. For each test sample, integration of the two subsets of snapshots separately led to two sets of three-dimensional diffraction intensities, one belonging to the native and the other to the derivative. Based on these two sets of intensities, a conventional single isomorphous replacement (SIR) procedure solved the structure easily. PMID- 26627659 TI - Native sulfur/chlorine SAD phasing for serial femtosecond crystallography. AB - Serial femtosecond crystallography (SFX) allows structures to be determined with minimal radiation damage. However, phasing native crystals in SFX is not very common. Here, the structure determination of native lysozyme from single wavelength anomalous diffraction (SAD) by utilizing the anomalous signal of sulfur and chlorine at a wavelength of 1.77 A is successfully demonstrated. This sulfur SAD method can be applied to a wide range of proteins, which will improve the determination of native crystal structures. PMID- 26627660 TI - Structural insights into the synthesis of FMN in prokaryotic organisms. AB - Riboflavin kinases (RFKs) catalyse the phosphorylation of riboflavin to produce FMN. In most bacteria this activity is catalysed by the C-terminal module of a bifunctional enzyme, FAD synthetase (FADS), which also catalyses the transformation of FMN into FAD through its N-terminal FMN adenylyltransferase (FMNAT) module. The RFK module of FADS is a homologue of eukaryotic monofunctional RFKs, while the FMNAT module lacks homologyto eukaryotic enzymes involved in FAD production. Previously, the crystal structure of Corynebacterium ammoniagenes FADS (CaFADS) was determined in its apo form. This structure predicted a dimer-of-trimers organization with the catalytic sites of two modules of neighbouring protomers approaching each other, leading to a hypothesis about the possibility of FMN channelling in the oligomeric protein. Here, two crystal structures of the individually expressed RFK module of CaFADS in complex with the products of the reaction, FMN and ADP, are presented. Structures are complemented with computational simulations, binding studies and kinetic characterization. Binding of ligands triggers dramatic structural changes in the RFK module, which affect large portions of the protein. Substrate inhibition and molecular-dynamics simulations allowed the conformational changes that take place along the RFK catalytic cycle to be established. The influence of these conformational changes in the FMNAT module is also discussed in the context of the full-length CaFADS protomer and the quaternary organization. PMID- 26627661 TI - Release of primary microplastics from consumer products to wastewater in the Netherlands. AB - The authors estimate the release of primary microplastics from consumer products cosmetics and personal care products, cleaning agents, and paint and coatings-via sewage effluent as an expected relevant route to the marine environment. Total estimated concentrations in the 3 scenarios are 0.2 MUg/L, 2.7 MUg/L, and 66 MUg/L in sewage-treatment plant (STP) effluent, respectively. All product categories relevantly contribute. Predicted concentrations are compared with reported actual concentrations in STP effluents. Environ Toxicol Chem 2016;35:1627-1631. (c) 2015 SETAC. PMID- 26627666 TI - Maternal rare inherited bleeding disorders and neonatal complications. AB - AIM: The aim of this study was to examine the association between maternal inherited bleeding disorders and neonatal complications. MATERIAL AND METHODS: This was a historical cohort study. The rare inherited bleeding disorders (RIBD) group consisted of a total of 100 women suffering from inherited bleeding disorders, aged 20-45 years who experienced pregnancy. In the healthy control group, 200 age- and body mass index-matched women were selected. Details of demographic and obstetric characteristics of the samples in both groups were collected using their medical records. RESULTS: The mean ages of the women in the RIBD and healthy control groups were 32.6 (7.07) and 32.4 (7.3) years, respectively. No statistically significant differences were found in terms of age and other demographic characteristics of the women between the groups. The mean neonatal birthweight in the RIBD group was statistically lower than that in the healthy control group, 3018.2 (546.9) g vs. 3299.4 (456.8) g, respectively (P = 0.021). The prevalence of low birthweight in the RIBD group was statistically higher in comparison to that in the healthy control group (P = 0.041). After adjustment for potential confounders, it was found that maternal bleeding disorder had significant negative effects on birthweight in newborns (odds ratio, 1.05; 95% confidence interval, 1.01-3.43, P = 0.001). Those infants were statistically more likely to experience head bleeding, early hyperbilirubinemia and hospitalization than the healthy group (P = 0.001). CONCLUSIONS: Maternal rare inherited bleeding disorders may have a devastating consequence for neonates. PMID- 26627667 TI - Pustular dermatitis in dogs affected by leishmaniosis: 22 cases. AB - BACKGROUND: Skin lesions in canine leishmaniosis (CanL) are diverse, including exfoliative, ulcerative, nodular and papular dermatitides. An uncommon pustular form has also been reported. HYPOTHESES/OBJECTIVES: We hypothesized that CanL infection can produce a pustular reaction pattern in the skin of dogs. The aim of this retrospective study was to describe the clinicopathological features of dogs with CanL infection and pustular dermatitis, and correlate them with response to therapy. ANIMALS: Twenty two affected dogs. METHODS: Retrospective review of medical records and examination of archived biopsy materials or previously processed glass slides was performed. Cytological examinations had been recorded for all cases. Specimens were available for histopathological examination in 17 of 22 cases and for immunohistochemical detection of Leishmania amastigotes in 13 of 22 cases. RESULTS: All dogs presented with multifocal to diffuse pustular dermatitis. CanL was diagnosed by IFAT serology (20 cases), bone marrow cytology (one case) or bone marrow PCR (one case). Cytological and/or histopathological examinations revealed acantholytic keratinocytes within pustules in 18 of 22 cases. Bacterial and fungal cultures were not performed. Leishmania amastigotes were identified by histopathology within the dermis in three cases; immunohistochemistry was positive in four cases. All dogs underwent concurrent anti-leishmanial and immunosuppressive therapy to control the pustular dermatitis, with favourable outcome in 11 of 22 cases. CONCLUSIONS AND CLINICAL IMPORTANCE: Due to the retrospective nature of this study it is not possible to either accept or reject the hypothesis that CanL is the direct cause of pustular dermatitis. PMID- 26627668 TI - Recent Progresses in Organ Donation and Transplantation in Korea. PMID- 26627670 TI - Tracking Donor-Reactive T Cells: Perspectives for the Development of Tolerance Protocols. PMID- 26627671 TI - TCR Spectratyping in Transplantation. PMID- 26627672 TI - Elmi Muller, MBChB, MMED: Head, Transplantation Service, Groote Schuur Hospital and Professor of Surgery, University of Cape Town, South Africa. PMID- 26627673 TI - Dick W. van Bekkum, 1925-2015. PMID- 26627674 TI - Infectious Diseases in Transplantation--Report of the 20th Nantes Actualites Transplantation Meeting. AB - The 20th Nantes Actualites Transplantation (NAT) meeting was held on June 11, 2015, and June 12, 2015. This year, the local organizing committee selected an update on infectious diseases in solid organ and hematopoietic stem cell transplantation. With an attendance of close to 170 clinicians, researchers, students, engineers, technicians, invited speakers, and guests from North and South America, Germany, Switzerland, Netherlands, and France, the meeting was well attended. Invited speakers' expertise covered basic as well as translational microbiology, immunology, transplantation, and intensive care medicine. This report identifies a number of advances presented during the meeting in the care and management of infectious diseases in transplantation and immunocompromised patients. New antiviral immune responses and their modulation by pathogens in addition to novel antimicrobial therapeutic strategies, cell therapies, and genomic analysis were discussed. PMID- 26627675 TI - Multivariable Regression Models in Clinical Transplant Research: Principles and Pitfalls. PMID- 26627676 TI - Variability in Pressure of Arterial Oxygen to Fractional Inspired Oxygen Concentration Ratio During Cellular Ex Vivo Lung Perfusion: Implication for Decision Making. AB - BACKGROUND: The pressure of arterial oxygen to fractional inspired oxygen concentration (PaO2/FiO2, P/F) ratio has been the gold standard in the assessment of transplant suitability in ex vivo lung perfusion (EVLP) with red blood cells. However, several reports using mathematical models and clinical data analysis suggest that the P/F ratio fluctuates at different FiO2. The purpose of this study was to examine the variations in P/F ratio at different FiO2 during EVLP and develop a practicable decision making algorithm in the EVLP. METHODS: Porcine lungs (n = 16) were perfused in cellular EVLP for 2 hours after a combination of warm ischemia (20-420 min) and cold ischemia (120-600 min). The P/F ratio, vascular/airway parameters, shunt fraction, alveolar-arterial gradient and oxygenation index were measured at FiO2 of 0.21, 0.4 and 1.0 at 1 hour. All 16 cases were divided into two groups according to the relationship between P/F0.21 and P/F1.0; P/F0.21 < P/F1.0, P/F0.21 > P/F1.0. RESULTS: The P/F ratio was not constant at different FiO2. The pattern of P/F0.21 < P/F1.0 was significantly associated with higher P/F ratio, higher pulmonary compliance, lower shunt fraction, lower alveoli-arterial gradient and lower oxygenation index compared to the pattern of P/F0.21 > P/F1.0 in porcine lungs (P < 0.05, each). In nonsuitable group, pulmonary vascular resistance was increased at FiO2 of 0.21 compared to FiO2 of 1.0. CONCLUSIONS: The P/F ratio must be considered in combination with the FiO2. The relationship between P/F0.21 and P/F1.0 might be a complementary indicator of lung function in cellular EVLP. PMID- 26627677 TI - History of anaesthesia: Amedeo Avogadro (1776-1856) - Do his accomplishments match his reputation? PMID- 26627678 TI - Isoflurane for ICU sedation - dead or alive? PMID- 26627679 TI - Variation in corticosterone response and corticosteroid binding-globulin during different breeding sub-stages in Eurasian tree sparrow (Passer montanus). AB - In free-living animals, it has been well demonstrated that the intensity of the adrenocortical response to acute restraint stress can vary with reproductive investment during breeding. The parental care hypothesis posits that the stress response is negatively correlated with parental investment in avian species. To further test this hypothesis, we examined changes in both free and total corticosterone (CORT) at baseline and stress-induced levels (maximal CORT) and corticosteroid-binding globulin (CBG) capacities, in both sexes of a multi brooded Eurasian tree sparrows (Passer montanus), during the nest building, the early nestling, the later egg-laying, and the later nestling stages. Our results showed Eurasian tree sparrows did not exhibit any differences between sexes in CORT and CBG levels during the egg-laying or nestling stages. Both sexes had lowered CBG capacities and females exhibited lower maximal CORT during the early compared to later nestling stages. In addition, both sexes had lower maximal free CORT levels during the nest building stage than those of the early nestling stages, and males expressed higher total maximal CORT levels than females during nest building stage. The variation in CORT response and CBG levels during different breeding sub-stages in Eurasian tree sparrow may correlate with their energetic situations and parental investments. J. Exp. Zool. 325A:75-83, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26627680 TI - Wavelength and orientation dependent capture of light by diatom frustule nanostructures. AB - The ecological success of diatoms is emphasized by regular blooms of many different species in all aquatic systems, but the reason behind their success is not fully understood. A special feature of the diatom cell is the frustule, a nano-patterned cell encasement made of amorphous biosilica. The optical properties of a cleaned single valve (one half of a frustule) from the diatom Coscinodiscus centralis were studied using confocal micro-spectroscopy. A photonic crystal function in the frustule was observed, and analysis of the hyperspectral mapping revealed an enhancement of transmitted light around 636 and 663 nm. These wavelengths match the absorption maxima of chlorophyll a and c, respectively. Additionally, we demonstrate that a highly efficient light trapping mechanism occurred, resulting from strong asymmetry between the cribrum and foramen pseudo-periodic structures. This effect may prevent transmitted light from being backscattered and in turn enhance the light absorption. Based on our results, we hypothesize that the multi-scaled layered structure of the frustule improves photosynthetic efficiency by these three mechanisms. The optical properties of the frustule described here may contribute to the ecological success of diatoms in both lentic and marine ecosystems, and should be studies further in vivo. PMID- 26627681 TI - Lower body function as a predictor of mortality over 13 years of follow up: Findings from Hispanic Established Population for the Epidemiological Study of the Elderly. AB - AIM: The objective of this research was to investigate the effect of lower body function on mortality over 13 years of follow-up study. METHODS: Data from the Hispanic Established Population for the Epidemiological Study of the Elderly were used, and the Cox proportional hazard model of mortality on age sex, education, body mass index, Center for Epidemiological Studies Depression Scale, Mini-Mental State Examination, any activities of daily living, walk score and short physical performance battery was applied. RESULTS: Results showed lower body function to be a strong predictor of mortality over 13 years, as indicated by walk and short physical performance battery scores, as well as any activities of daily living, depression and cognitive function. Furthermore, overweight or obese participants tended to live significantly longer over the long term. CONCLUSIONS: Lower body function significantly impacts mortality at 2, 7 and 13 years of follow-up study, but this association decreases in magnitude over time. Geriatr Gerontol Int 2016; 16: 1324-1331. PMID- 26627682 TI - Effects of polyphenols and lipids from Pennisetum glaucum grains on T-cell activation: modulation of Ca(2+) and ERK1/ERK2 signaling. AB - BACKGROUND: Pearl millet (PM), i.e., Pennisetum glaucum, is widely grown in Africa and known for its anti-oxidant and anti-hyperlipidemic properties. METHODS: The P. glaucum grains were obtained from the region of Ouled Aissa (South of Algeria). We assessed the effects of phenolic compounds and lipids, extracted from seeds of P. glaucum, on rat lymphocyte proliferation, activated by phorbol 12-myristate 13-acetate and ionomycin. In order to explore signaling pathway, triggered by these compounds, we assessed interleukin-2 (IL-2) mRNA expression and extracellular signal-regulated kinase-1/2 (ERK1/ERK2) phosphorylation. Finally, we determined increases in free intracellular Ca(2+) concentrations, [Ca(2+)]i, by employing Fura-2/AM in rat lymphocytes. RESULTS: The composition of P. glaucum grains in polyphenols was estimated to be 1660 ug gallic acid equivalents (GAE)/g. Lipids represented 4.5 %, and more than 72% of the fatty acids belonged to unsaturated family. Our investigation showed that both lipid and phenolic compounds inhibited mitogen-induced T-cell proliferation. Compared with phenolic compounds, lipids exerted weaker effects on ERK-1/ERK2 phosphorylation and Ca(2+) signaling in mitogen-activated T-cells. CONCLUSION: We conclude that the immunomodulatory effects of P. glaucum could be contributed by its phenolic and lipid contents. PMID- 26627684 TI - The effect of parameter variability in the allometric projection of leaf growth rates for eelgrass (Zostera marina L.) II: the importance of data quality control procedures in bias reduction. AB - BACKGROUND: Eelgrass grants important ecological benefits including a nursery for waterfowl and fish species, shoreline stabilization, nutrient recycling and carbon sequestration. Upon the exacerbation of deleterious anthropogenic influences, re-establishment of eelgrass beds has mainly depended on transplantation. Productivity estimations provide valuable information for the appraisal of the restoration of ecological functions of natural populations. Assessments over early stages of transplants should preferably be nondestructive. Allometric scaling of eelgrass leaf biomass in terms of matching length provides a proxy that reduces leaf biomass and productivity estimations to simple measurements of leaf length and its elongation over a period. We examine how parameter variability impacts the accuracy of the considered proxy and the extent on what data quality and sample size influence the uncertainties of the involved allometric parameters. METHODS: We adapted a Median Absolute Deviation data quality control procedure to remove inconsistencies in the crude data. For evaluating the effect of parametric uncertainty we performed both a formal exploration and an analysis of the sensitivity of the allometric projection method to parameter changes. We used parameter estimates obtained by means of nonlinear regression from crude as well as processed data. RESULTS: We obtained reference leaf growth rates by allometric projection using parameter estimates produced by the crude data, and then considered changes in fitted parameters bounded by the modulus of the vector of the linked standard errors, we found absolute deviations up to 10% of reference values. After data quality control, the equivalent maximum deviation was under 7% of corresponding reference rates. Therefore, the addressed allometric method is robust. Even the smaller sized samples in the quality controlled dataset produced better accuracy levels than the whole set of crude data. CONCLUSIONS: We propose quality control of data as a highly recommended step in the overall procedure that leads to reliable allometric surrogates of eelgrass leaf growth rates. The proliferation of inconsistent replicates in the crude data points towards the importance of discarding incomplete leaves. We also recommend avoiding errors in estimating the biomass of small leaves for which precision of the used analytical scale might be an issue. PMID- 26627683 TI - Genetic diversity of transmission-blocking vaccine candidate Pvs48/45 in Plasmodium vivax populations in China. AB - BACKGROUND: The male gamete fertilization factor P48/45 in malaria parasites is a prime transmission-blocking vaccine (TBV) candidate. Efforts to develop antimalarial vaccines are often thwarted by genetic diversity of the target antigens. Here we evaluated the genetic diversity of Pvs48/45 gene in global Plasmodium vivax populations. METHODS: We determined 200 Pvs48/45 sequences collected from temperate and subtropical parasite populations in China. Population genetic and evolutionary analyses were performed to determine the levels of genetic diversity, potential signature of selection, and population differentiation. RESULTS: Analysis of the Pvs48/45 sequences from 200 P. vivax parasites collected in a temperate and a tropical region revealed a low level of genetic diversity (pi = 0.0012) with 14 single nucleotide polymorphisms, of which 11 were nonsynonymous. Analysis of 344 Pvs48/45 sequences from nine worldwide P. vivax populations detected a total of 38 haplotypes, of which 13 haplotypes were present only once. Multiple tests for selection confirmed a signature of positive selection on Pvs48/45 with selection skewed to the second cysteine domain. Haplotype network analysis and Wright's fixation index showed large geographical differentiation with the presence of continent-or region-specific mutations in this gene. CONCLUSIONS: Pvs48/45 displays low levels of genetic diversity with the presence of region-specific mutations. Some of the mutations may be potential epitope targets based on their positions in the predicted structure, highlighting the need for future evaluation of these mutations in designing Pvs48/45-based TBV. PMID- 26627685 TI - Methanol regulated yeast promoters: production vehicles and toolbox for synthetic biology. AB - Promoters are indispensable elements of a standardized parts collection for synthetic biology. Regulated promoters of a wide variety of well-defined induction ratios and expression strengths are highly interesting for many applications. Exemplarily, we discuss the application of published genome scale transcriptomics data for the primary selection of methanol inducible promoters of the yeast Pichia pastoris (Komagataella sp.). Such a promoter collection can serve as an excellent toolbox for cell and metabolic engineering, and for gene expression to produce heterologous proteins. PMID- 26627686 TI - Overexpression of alpha-synuclein in oligodendrocytes does not increase susceptibility to focal striatal excitotoxicity. AB - BACKGROUND: Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disease characterized by alpha-synuclein (alpha-syn) positive oligodendroglial cytoplasmic inclusions. The latter are associated with a neuronal multisystem neurodegeneration targeting central autonomic, olivopontocerebellar and striatonigral pathways, however the underlying mechanisms of neuronal cell death are poorly understood. Previous experiments have shown that oligodendroglial alpha-syn pathology increases the susceptibility to mitochondrial stress and proteasomal dysfunction leading to enhanced MSA-like neurodegeneration. Here we analyzed whether oligodendroglial alpha-syn overexpression in a transgenic mouse model of MSA synergistically interacts with focal neuronal excitotoxic damage generated by a striatal injection of quinolinic acid (QA) to affect the degree of striatal neuronal loss. RESULTS: QA injury led to comparable striatal neuronal loss and optical density of astro- and microgliosis in the striatum of transgenic and control mice. Respectively, no differences were identified in drug-induced rotation behavior or open field behavior between the groups. CONCLUSIONS: The failure of oligodendroglial alpha syn pathology to exacerbate striatal neuronal loss resulting from QA excitotoxicity contrasts with enhanced striatal neurodegeneration due to oxidative or proteolytic stress, suggesting that enhanced vulnerability to excitotoxicity does not occur in oligodendroglial alpha-synucleinopathy like MSA. PMID- 26627687 TI - Tenofovir is associated with increased tubular proteinuria and asymptomatic renal tubular dysfunction in Ghana. AB - BACKGROUND: HIV infection is associated with increased risk of renal dysfunction, including tubular dysfunction (TD) related to antiretroviral therapy (ART). Tenofovir disoproxil fumarate (TDF) is becoming available for ART in sub-Saharan Africa, although data on its long-term safety there is limited. We aimed to study the prevalence of HIV-associated renal dysfunction in Ghana and explore associations between proteinuria or TD and potential risk factors, including TDF use. METHODS: A single-centre cross-sectional observational study of patients taking ART was undertaken. Creatinine clearance (CrCl) was calculated and proteinuria detected with dipsticks. Spot urinary albumin and protein:creatinine ratios (uACR/uPCR) were measured and further evidence of TD (defined as having two or more characteristic features) sought. Logistic regression analysis identified factors associated with proteinuria or TD. RESULTS: In 330 patients, of whom 101 were taking TDF (median 20 months), the prevalence of CrCl < 60 ml/min/1.73 m(2), dipstick proteinuria and TD was 7 %, 37 % and 15 %. Factors associated with proteinuria were baseline CD4-count [aOR 0.86/100 cell increment (95 % CI, 0.74-0.99)] and TDF use [aOR 2.74 (95 % CI, 1.38-5.43)]. The only factor associated with TD was TDF use [aOR 3.43 (95 % CI, 1.10-10.69)]. In a subset with uPCR measurements, uPCRs were significantly higher in patients taking TDF than those on other drugs (10.8 vs. 5.7 mg/mmol, p < 0.001), and urinary albuin:protein ratios significantly lower (0.24 vs. 0.58, p < 0.001). CONCLUSIONS: Both proteinuria and TD are common and associated with TDF use in Ghana. Further longitudinal studies to determine whether proteinuria, TD or TDF use are linked to progressive decline in renal function or other adverse outcomes are needed in Africa. PMID- 26627688 TI - Evaluation of the retinal ganglion cell and choroidal thickness in young Turkish adults with hyperopic anisometropic amblyopia. AB - The purpose of this study is to compare the choroidal thickness (CT) and ganglion cell complex (GCC) thickness of the normal fellow eyes and the amblyopic eyes using enhanced depth imaging optical coherence tomography (EDI-OCT) in young Turkish adults with hyperopic anisometropic amblyopia. Patients with unilateral hyperopic anisometropic amblyopia were enrolled and underwent a full ophthalmological assessment, including best-corrected visual acuity, cycloplegic refraction, and axial length (AL) measurements. Cirrus EDI-OCT was used to obtain subfoveal CT, GCC thickness, retinal nerve fiber layer (RNFL), and central macular thickness (CMT) measurements. Comparison was performed between the amblyopic eyes and the normal fellow eyes. Forty-three hyperopic anisometropic amblyopic patients were enrolled in this study. Mean age of 23 female and 20 male patients was 24.8 +/- 7.4 years. Mean AL was 21.9 +/- 1.3 and 22.4 +/- 0.9 mm in amblyopic and fellow eyes, respectively (P < 0.05). Mean subfoveal CT measurements were 325.4 +/- 44.2 and 317.9 +/- 42.7 u in amblyopic and fellow eyes, respectively. There was no statistically significant difference between the groups (P > 0.05). Mean GCC thickness was 83.8 +/- 3.6 u in amblyopic eyes and 83.5 +/- 3.9 u in the fellow eyes. Statistically significant difference was not seen between the groups (P > 0.05). Mean RNFL and mean CMT measurements were also similar in two groups (P > 0.05). Subfoveal CT, CMT, RNFL, and GCC thickness measurements were not statistically significant between hyperopic anisometropic amblyopic eyes and normal fellow eyes. PMID- 26627689 TI - Clinical characteristics and surgical outcomes of pediatric rhegmatogenous retinal detachment. AB - The objective of this study was to analyze the characteristics and surgical results of pediatric rhegmatogenous retinal detachment (RRD). The medical records of 30 eyes of 29 patients younger than 18 years of age who underwent vitreoretinal surgery due to RRD were analyzed. The gender, age, laterality, duration of presenting symptom, etiology, ocular and systemic co-morbidities, type of breaks, lens status, presence of proliferative vitreoretinopathy (PVR) and its grade, initial and final best-corrected visual acuities (BCVAs), surgical management, number of operations, duration of follow-up, functional and anatomical success, and complications were noted. As the most common predisposing factors were trauma (trauma group) and myopia (myopia group), the data of these patients were further analyzed. The mean age was 12.6 +/- 3.0 years. There were 23 male (79.3 %) and 6 female (20.6 %) subjects. The most common etiologic factors were high myopia (40 %) and trauma (36.6 %). Functional success rate was 70 % (n = 21) after the primary surgeries and was 80 % (n = 24) after the secondary surgeries. There were no significant differences between the trauma and myopia groups regarding the presence of total retinal detachment, macula-off status, and the rate of PVR worse than grade C. Although the preoperative mean BCVA and the initial and final retinal reattachment rates of the groups were statistically similar, trauma group had significantly higher postoperative mean BCVA compared to myopia group (p = 0.013). Myopia and trauma were the most common etiologic factors for RRD in children. The visual outcomes of trauma-associated RRD were better than those of myopia-associated RRD. PMID- 26627690 TI - Prevalence of camel trypanosomosis (surra) and associated risk factors in Borena zone, southern Ethiopia. AB - A study was made to determine the prevalence of camel trypanosomosis (surra) and its associated risk factors in Borena zone, southern Ethiopia during 2013-2014. A total of 2400 blood samples were collected and examined by the buffy coat and thin blood film laboratory methods, and data were analyzed using the SPSS statistical software. The overall prevalence of camel trypanosomosis in the area was found to be 2.33 %. Prevalence was significantly different among the surveyed districts (P = 0.000), the pastoral associations (F = 6.408, P = 0.000), altitudinal divisions (P = 0.000), age groups (P = 0.034), and between animals possessing packed cell volume (PCV) values greater than 25 % and less than 25 % (P = 0.000); whereas, prevalence of the disease was not statistically significantly different between the sexes (P = 0.311) and among the body condition score groups (P = 0.739). The PCV of trypanosome positive and trypanosome negative camels differ significantly (P = 0.001), and prevalence of trypanosomosis was seen to be negatively correlated with packed cell volume (r = 0.069, P = 0.000) revealing the effect of camel trypanosomosis on anemia state of parasitized animals. In conclusion, camel trypanosomosis is a serious and economically important disease hampering camel production and productivity in southern Ethiopia. Further studies involving more sensitive molecular techniques to reveal the precise magnitude of the disease and to identify the vector species of the parasite are recommended. PMID- 26627692 TI - Microsurgical anatomy of the Adamkiewicz artery-anterior spinal artery junction. AB - PURPOSE: The aim of this study is to describe the anterior spinal artery Adamkiewicz artery (ASA-AKA) junction and establish a classification allowing defining the neurological risk in either thoracoabdominal aorta aneurysm treatment and in anterior or transforaminal thoracolumbar spine surgery. METHODS: Fifteen spinal cords of fresh cadavers were dissected. Both lumbar arteries and ASA were injected with strongly diluted red-colored silicon. RESULTS: The dural crossing of AKA was located on the left side in 86 % of cases, between T8 and T10 in 73.33 % of cases and L1-L2 in 26.67 % of cases. The average diameter of the ascending branch of AKA was 1.10 mm (range 0.8-1.9 mm), and its average length was 30.27 mm (range 12.3-60 mm). The AKA's arch average diameter was 11.3 mm (range 9-20 mm) with an open downward angle average of 20.1 degrees (range 11 degrees -30 degrees ). The descending branch of AKA which was a continuation of ASA had an average diameter of 1.33 mm (range 0.8-1.86 mm). The ASA at the top of the arch had an average diameter of 0.74 mm (range 0.2-1.77 mm). According to these findings, we have proposed a new classification with two types of junctions. The type I and its variant correlated to high neurological risk were present in 93.33 % of cases. The type II, correlated to medium or low neurological risk, was present in 6.67 % of cases. CONCLUSION: These anatomical findings allow a planning of the neurological risk before thoracoabdominal aorta aneurysm or thoracolumbar anterior or transforaminal spine surgery. PMID- 26627691 TI - Genetic deviation in geographically close populations of the dengue vector Aedes aegypti (Diptera: Culicidae): influence of environmental barriers in South India. AB - Mosquitoes are vectors of devastating pathogens and parasites, causing millions of deaths every year. Dengue is a mosquito-borne viral infection found in tropical and subtropical regions around the world. Recently, dengue transmission has strongly increased in urban and semiurban areas, becoming a major international public health concern. Aedes aegypti (Diptera: Culicidae) is a primary vector of dengue. Shedding light on genetic deviation in A. aegypti populations is of crucial importance to fully understand their molecular ecology and evolution. In this research, haplotype and genetic analyses were conducted using individuals of A. aegypti from 31 localities in the north, southeast, northeast and central regions of Tamil Nadu (South India). The mitochondrial DNA region of cytochrome c oxidase 1 (CO1) gene was used as marker for the analyses. Thirty-one haplotypes sequences were submitted to GenBank and authenticated. The complete haplotype set included 64 haplotypes from various geographical regions clustered into three groups (lineages) separated by three fixed mutational steps, suggesting that the South Indian Ae. aegypti populations were pooled and are linked with West Africa, Columbian and Southeast Asian lineages. The genetic and haplotype diversity was low, indicating reduced gene flow among close populations of the vector, due to geographical barriers such as water bodies. Lastly, the negative values for neutrality tests indicated a bottle-neck effect and supported for low frequency of polymorphism among the haplotypes. Overall, our results add basic knowledge to molecular ecology of the dengue vector A. aegypti, providing the first evidence for multiple introductions of Ae. aegypti populations from Columbia and West Africa in South India. PMID- 26627693 TI - Multiple variations of the coeliac axis, hepatic and renal vasculature as incidental findings illustrated by MDCTA. AB - Vascular anatomical variations are not uncommon and may affect any organ's arterial or venous vasculature. The coexistence of variations in different organic systems is less commonly found, but of great clinical significance in a series of clinical conditions like organ transplantation and surgical preoperative planning. Multidetector computed tomography angiography (MDCTA) has emerged as a valuable alternative to the conventional angiography for accurate evaluation of vascular anatomy and pathology. Radiologists should be familiar with each organ's vascular variations and always report them to the clinician, even if they represent an incidental finding. This case report presents a 52-year old female patient undergoing abdominal MDCTA for characterization of a renal lesion. This examination revealed the presence of three hilar arteries on the left kidney, a main renal vein in combination with an additional renal vein in both sides along with a replaced right hepatic artery originating from the superior mesenteric artery. Moreover, both inferior phrenic arteries were found originating from the coeliac axis. 3D volume rendering technique images were used in the evaluation of vascular anatomy as illustrated in this case report. PMID- 26627694 TI - [Characterization of patients who died of invasive pneumococcal disease in the child population of Bogota, Colombia]. AB - INTRODUCTION: Streptococcus pneumoniae (S. pneumoniae), also known as pneumococcus, is one of the main bacteria associated with mortality in children under 2 years of age, with a morbidity and mortality incidence that varies according to demographics and exposure to risk, or protective factors. OBJECTIVE: To describe the child mortality due to invasive pneumococcal disease (IPD) between 2008 -2014 (6 years), in 8 Medical Centres in Bogota, Colombia. PATIENTS AND METHOD: Descriptive observational case series of patients who died of IPD, aged 28 days to 18 years, in 8 tertiary care institutions in Bogota, Colombia. The study period was from 1 January 2008 to 15 January 2014. SAMPLE SIZE: 239 patients. RESULTS: A total of 239 registered cases of IPD were reviewed, showing a mortality of 8% (n 18). The mean age of patients that died was 43.7 months, with an age range from 2 to 176 months (14 years), with 66% of the cases being male. Serotypes were identified in 8 patients, finding: 6A, 6B, 10A, 14, 18C, 23B, 23F, and 35B. The most common clinical presentation of the cases was meningitis with mortality of 33% (6 cases), followed by bacteraemia without focus in 28% (5 cases), and pneumonia with 27% (5 cases). Combined clinical situations were presented, such as pneumonia and meningitis in 11% (2 cases). Two of the patients had clearly documented risk factors for IPD (asplenia and chronic respiratory disease). CONCLUSIONS: IPD mortality is particularly high in children under 2 years in male patients, especially when presented with a meningeal focus (44%). Serotyping was not possible in all patients who died, since no strain isolated was sent to the National Institute of Health. Continuous and systematic vigilance is required to evaluate the impact of vaccination and possible changes in the pattern of presentation of disease. PMID- 26627695 TI - [Hospital morbidity and mortality in children with Down's syndrome: Experience in a university hospital in Chile]. AB - INTRODUCTION: Children with Down's syndrome (DS) have a higher risk of congenital malformations and acute diseases, with increased risk of hospital admissions compared with the general population. This study describes patterns of hospital admissions for children and adolescents with DS. PATIENTS AND METHODS: A retrospective study of hospital admissions of children with DS, younger than 15 years old, and cared for by the Paediatric Department of the Hospital Clinico Pontificia Universidad Catolica de Chile, between 2008 and 2011. RESULTS: There were 222 admissions of 161 patients with DS during the study period, of which 110 were girls. The median age was 8 months, and the median hospital stay was 6 days. Just over half (56.7%) of the hospital stays were in the Paediatric Critic Care Unit. Heart surgery was performed on 59.4%, and the principal congenital heart defect attended was atrioventricular canal. The principal diagnosis, other than heart surgery, was lower respiratory tract infection. In this series, 3 children died. CONCLUSIONS: Children with DS are a relevant group for inpatient care, because their high incidence in Chile, their respiratory and cardiovascular risk, prolonged hospitalizations, high frequency of critical care days and mortality risk. This group has special and complex needs during their hospitalizations and it is necessary to create a multidisciplinary team with competences to take care the particular characteristics of this vulnerable group. PMID- 26627696 TI - Use of functional gene expression and respirometry to study wastewater nitrification activity after exposure to low doses of copper. AB - Autotrophic nitrification in biological nitrogen removal systems has been shown to be sensitive to the presence of heavy metals in wastewater treatment plants. Using transcriptase-quantitative polymerase chain reaction (RT-qPCR) data, we examined the effect of copper on the relative expression of functional genes (i.e., amoA, hao, nirK, and norB) involved in redox nitrogen transformation in batch enrichment cultures obtained from a nitrifying bioreactor operated as a continuous reactor (24-h hydraulic retention time). 16S ribosomal RNA (rRNA) gene next-generation sequencing showed that Nitrosomonas-like populations represented 60-70% of the bacterial community, while other nitrifiers represented <5%. We observed a strong correspondence between the relative expression of amoA and hao and ammonia removal in the bioreactor. There were no considerable changes in the transcript levels of amoA, hao, nirK, and norB for nitrifying samples exposed to copper dosages ranging from 0.01 to 10 mg/L for a period of 12 h. Similar results were obtained when ammonia oxidation activity was measured via specific oxygen uptake rate (sOUR). The lack of nitrification inhibition by copper at doses lower than 10 mg/L may be attributed to the role of copper as cofactor for ammonia monooxygenase or to the sub-inhibitory concentrations of copper used in this study. Overall, these results demonstrate the use of molecular methods combined with conventional respirometry assays to better understand the response of wastewater nitrifying systems to the presence of copper. PMID- 26627697 TI - The concentration and chemical speciation of arsenic in the Nanpan River, the upstream of the Pearl River, China. AB - The concentration and chemical speciation of arsenic (As) in different environmental matrixes (water, sediment, agricultural soils, and non-agricultural soils) were investigated in the Nanpan River area, the upstream of Pearl River, China. The results did not show any obvious transport of As along the flow direction of the river (from upstream to downstream). Total As concentrations in sediment were significantly different from those in agricultural soil. According to the comparison to quality standards, the As in sediments of the studied area have potential ecological risks and a minority of the sampling sites of agricultural soils in the studied area were polluted with As. As speciations were analyzed using sequential extraction and the percentage of non-residual fraction in sediment predominated over residual fraction. We thus believe that As in the studied area was with low mobility and bioavailability in sediment, agricultural soils, and non-agricultural soils. However, the bioavailability and mobility of As in sediment were higher than in both agricultural and non-agricultural soils, and thus, special attention should be paid for the risk assessment of As in the river in future studies. PMID- 26627698 TI - Terrestrial humic substances in Daliao River and its estuary: optical signatures and photoreactivity to UVA light. AB - Fluorescent dissolved organic matter (FDOM) components were identified by Parallel Factor Analysis (PARAFAC) in surface water of Daliao River and its estuary with a focus on terrestrial humic substance-(HS)-like FDOM identified under two contrasting hydrological conditions. The hydrological conditions did not have noticeable effect on the spectral features of the terrestrial HS-like FDOM, but did affect the components' intensities and photoreactivity: (1) the intensities of terrestrial HS-like components were higher in the normal flow period than in the high flow period, and (2) a spectrally similar terrestrial HS like FDOM identified under the two contrasting hydrological conditions showed distinct photoreactivity to the same dose of UVA illumination. The findings indicated that terrestrial HS was generated at lower intensities at the terrestrial sources during the high flow period than during the normal flow period and that the transport of terrestrial HS material through the river estuary system was affected dominantly by seawater dilution along the salinity gradient while fine-tuned by solar UVA illumination. This study exemplifies the effect of hydrological conditions on optical signatures of terrestrial HS-like FDOM and their photoreactivity towards UVA illumination, improving our understanding of the dynamics of terrestrial HS material in river-estuary systems in the framework of the currently proposed new conceptual model for terrestrial organic matter. PMID- 26627699 TI - Misleading Gastrointestinal Symptoms: The Ongoing Story of Chronic Lead Intoxication. AB - Inorganic lead intoxication has emerged as an important and challenging clinical problem owing to increased awareness of lead and enhanced surveillance of exposed individuals. However, recognition may not be very difficult when there is an obvious history of exposure. Our interest began a few years ago when we could trace an outbreak, following a patient who was admitted with colickly abdominal pain, convulsions, and coma. After that, 16 more cases were identified and characterized. All patients recovered completely after adequate chelation therapy. Although the clinical picture of lead intoxication is pleomorphic, the increased awareness of gastroenterologists in this subject may possibly bring chronically complaining difficult patients to an earlier, unexpected, and fairly treatable disease. PMID- 26627700 TI - A Case of Intrahepatic Arterioportal Fistula After Liver Biopsy. PMID- 26627701 TI - Lymphoepithelioma-Like Cholangiocarcinoma: A Rare Finding With Good Outcomes. PMID- 26627702 TI - Gadoxetate for direct tumor therapy and tracking with real-time MRI-guided stereotactic body radiation therapy of the liver. AB - SBRT is increasingly utilized in liver tumor treatment. MRI-guided RT allows for real-time MRI tracking during therapy. Liver tumors are often poorly visualized and most contrast agents are transient. Gadoxetate may allow for sustained tumor visualization. Here, we report on the first use of gadoxetate during real-time MRI-guided SBRT. PMID- 26627703 TI - Sensitivity study of prompt gamma imaging of scanned beam proton therapy in heterogeneous anatomies. AB - BACKGROUND AND PURPOSE: To investigate the use of a fast analytical prediction algorithm in the evaluation of the accuracy in Bragg peak position estimation using prompt gamma imaging in realistic anatomies. MATERIAL AND METHODS: Brain, nasal cavity and lung spot scanning treatments were planned on an anthropomorphic phantom. Plan delivery in a clinical proton therapy facility was monitored using a prompt gamma camera. A pencil-beam algorithm was developed to simulate prompt gamma acquisition. For each spot, the sensitivity to setup and CT conversion errors was evaluated based on error scenarios. RESULTS: Good agreement was found between simulations and measurements (average shift of 0.4mm on whole-layer profiles). The spots with greatest sensitivity to setup or CT conversion errors could be identified. The comparison between expected and estimated shifts showed that the errors in shift estimation due to heterogeneities were in average lower than 1mm in all cases except the lung. In the lung case, only 40% of the spots showed accuracy better than 2mm. CONCLUSIONS: The analytical prediction algorithm was successfully used to simulate prompt gamma acquisitions of scanned treatment plans. The accuracy in Bragg peak position estimation was generally sub millimeter in heterogeneous anatomies, except in lung tissues. PMID- 26627704 TI - What is This Rash? PMID- 26627705 TI - Enhanced production of phenazine-like metabolite produced by Streptomyces aurantiogriseus VSMGT1014 against rice pathogen, Rhizoctonia solani. AB - The efficacy of a rhizobacterium Streptomyces aurantiogriseus VSMGT1014 for the production of bioactive metabolites with antifungal properties was evaluated under in vitro conditions. The production of bioactive metabolites by S. aurantiogriseus VSMGT1014 in International Streptomyces Project-2 (ISP-2) broth, supplemented with glucose and ammonium acetate was found to be the most suitable carbon and nitrogen sources for the maximum production of bioactive metabolites against rice pathogen, Rhizoctonia solani. The zone of inhibition range from 23.5 to 28.5 mm and 10.3 to 18.3 mm for glucose and ammonium acetate supplemented media, respectively. The culture filtrate of S. aurantiogriseus VSMGT1014 at pH 7.5, 37 degrees C at 120 rpm in 6 days of incubation showed the maximum production of bioactive metabolites with antagonistic potential. The crude metabolite was characterized by different spectral studies such as Ultraviolet spectrum, infrared-spectrum and based on the different analytical techniques, including thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) with the retention time 29.4 and the bioactive metabolite was identified as phenazine, which was confirmed by pure phenazine compound as positive control. PMID- 26627706 TI - Folic Acid Alters Methylation Profile of JAK-STAT and Long-Term Depression Signaling Pathways in Alzheimer's Disease Models. AB - Dementia has emerged as a major societal issue because of the worldwide aging population and the absence of any effective treatment. DNA methylation is an epigenetic mechanism that evidently plays a role in Alzheimer's disease (AD). Folate acts through one-carbon metabolism to support the methylation of multiple substrates including DNA. We aimed to test the hypothesis that folic acid supplementation alters DNA methylation profiles in AD models. Mouse Neuro-2a cells expressing human APP695 (N2a-APP cells) were incubated with folic acid (2.8 20 MUmol/L). AD transgenic mice were fed either folate-deficient or control diets and gavaged daily with water or folic acid (600 MUg/kg). Gene methylation profiles were determined by methylated DNA immunoprecipitation-DNA microarray (MeDIP-chip). Differentially methylated regions (DMRs) were determined by Quantitative Differentially Methylated Regions analysis, and differentially methylated genes (DMGs) carrying at least three DMRs were selected for pathway analysis. Folic acid up-regulated DNA methylation levels in N2a-APP cells and AD transgenic mouse brains. Functional network analysis of folic acid-induced DMGs in these AD models revealed subnetworks composed of 24 focus genes in the janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway and 12 focus genes in the long-term depression (LTD) signaling pathway. In conclusion, these results revealed a role for folic acid in the JAK-STAT and LTD signaling pathways which may be relevant to AD pathogenesis. This novel finding may stimulate reinvestigation of folic acid supplementation as a prophylactic or therapeutic treatment for AD. PMID- 26627707 TI - Productivity and sustainability of rainfed wheat-soybean system in the North China Plain: results from a long-term experiment and crop modelling. AB - A quantitative understanding of yield response to water and nutrients is key to improving the productivity and sustainability of rainfed cropping systems. Here, we quantified the effects of rainfall, fertilization (NPK) and soil organic amendments (with straw and manure) on yields of a rainfed wheat-soybean system in the North China Plain (NCP), using 30-years' field experimental data (1982-2012) and the simulation model-AquaCrop. On average, wheat and soybean yields were 5 and 2.5 times higher in the fertilized treatments than in the unfertilized control (CK), respectively. Yields of fertilized treatments increased and yields of CK decreased over time. NPK + manure increased yields more than NPK alone or NPK + straw. The additional effect of manure is likely due to increased availability of K and micronutrients. Wheat yields were limited by rainfall and can be increased through soil mulching (15%) or irrigation (35%). In conclusion, combined applications of fertilizer NPK and manure were more effective in sustaining high crop yields than recommended fertilizer NPK applications. Manure applications led to strong accumulation of NPK and relatively low NPK use efficiencies. Water deficiency in wheat increased over time due to the steady increase in yields, suggesting that the need for soil mulching increases. PMID- 26627708 TI - Comparison of different platelet transfusion thresholds prior to insertion of central lines in patients with thrombocytopenia. AB - BACKGROUND: Patients with a low platelet count (thrombocytopenia) often require the insertion of central lines (central venous catheters (CVCs)). CVCs have a number of uses; these include: administration of chemotherapy; intensive monitoring and treatment of critically-ill patients; administration of total parenteral nutrition; and long-term intermittent intravenous access for patients requiring repeated treatments. Current practice in many countries is to correct thrombocytopenia with platelet transfusions prior to CVC insertion, in order to mitigate the risk of serious procedure-related bleeding. However, the platelet count threshold recommended prior to CVC insertion varies significantly from country to country. This indicates significant uncertainty among clinicians of the correct management of these patients. The risk of bleeding after a central line insertion appears to be low if an ultrasound-guided technique is used. Patients may therefore be exposed to the risks of a platelet transfusion without any obvious clinical benefit. OBJECTIVES: To assess the effects of different platelet transfusion thresholds prior to the insertion of a central line in patients with thrombocytopenia (low platelet count). SEARCH METHODS: We searched for randomised controlled trials (RCTs) in CENTRAL (The Cochrane Library 2015, Issue 2), MEDLINE (from 1946), EMBASE (from 1974), the Transfusion Evidence Library (from 1950) and ongoing trial databases to 23 February 2015. SELECTION CRITERIA: We included RCTs involving transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis, and given to prevent bleeding in patients of any age with thrombocytopenia requiring insertion of a CVC. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: One RCT was identified that compared different platelet transfusion thresholds prior to insertion of a CVC in people with chronic liver disease. This study is still recruiting participants (expected recruitment: up to 165 participants) and is due to be completed in December 2017. There were no completed studies. There were no studies that compared no platelet transfusions to a platelet transfusion threshold. AUTHORS' CONCLUSIONS: There is no evidence from RCTs to determine whether platelet transfusions are required prior to central line insertion in patients with thrombocytopenia, and, if a platelet transfusion is required, what is the correct platelet transfusion threshold. Further randomised trials with robust methodology are required to develop the optimal transfusion strategy for such patients. The one ongoing RCT involving people with cirrhosis will not be able to answer this review's questions, because it is a small study that assesses one patient group and does not address all of the comparisons included in this review. To detect an increase in the proportion of participants who had major bleeding from 1 in 100 to 2 in 100 would require a study containing at least 4634 participants (80% power, 5% significance). PMID- 26627709 TI - Kynurenic acid modulates experimentally induced inflammation in the trigeminal ganglion. AB - BACKGROUND: The trigeminal ganglion (TG) plays a central role in cranial pain. Administration of complete Freund's adjuvant (CFA) into the temporomandibular joint (TMJ) elicits activation of TG. Kynurenic acid (KYNA) is an endogenous excitatory amino acid receptor blocker, which may have an anti-inflammatory effect. We hypothesize that KYNA may reduce CFA-induced activation within the TG. METHODS: A local inflammation was induced by administration of CFA into the TMJ in rats. KYNA and kynurenic acid amide 2 (KYNAA2) were intraperitoneally administered. We investigated changes of mitogen-activated protein kinases (MAPKs as ERK1/2, p38 and SAPK/JNK), NF-kappaB, CaMKII and DREAM, in addition to calcitonin gene-related peptide (CGRP) and its receptor components calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in the TG, with immunohistochemistry and Western blot at 2 and 10 days post-CFA injection. RESULTS: We showed CFA-induces increases in pERK1/2, pp38, CaMKII, NF kappaB and DREAM immunohistochemistry after 2 and 10 days. KYNAA2 displayed stronger effects on MAPKs than KYNA. Increased expression of CaMKII, NF-kappaB and DREAM were found in the neurons. Western blot showed significantly increase in pERK expression at 10 days post-CFA, which decreased after 10 days of KYNA treatment. Two days post-CFA, a significantly increase in pp38 expression was found, which decreased after 2 days of KYNA and KYNAA2 treatment. CONCLUSIONS: The CFA-induced inflammatory model for the TG activation provided a time-related expression of MAPK (pERK1/2, pp38) and NF-kappaB. It involves both the neuronal and glial activation, which points to possible neuron-glia interactions during this process. The administration of the endogenous NMDA-receptor antagonists, KYNA and its derivative KYNAA2, resulted in the inhibition of the induced signaling system of the TG, which further points the importance of the glutamate receptors in this mechanism. PMID- 26627711 TI - Retirees, rest, respiration and ROS: does age or inactivity drive mitochondrial dysfunction? PMID- 26627710 TI - Impact of headache disorders in Italy and the public-health and policy implications: a population-based study within the Eurolight Project. AB - BACKGROUND: Migraine, tension-type headache (TTH) and medication-overuse headache (MOH) are disabling lifelong illnesses. The Eurolight project, a partnership activity within the Global Campaign against Headache, assessed the impact of headache disorders in ten countries in Europe using a structured questionnaire coupled with various sampling methods. Here we present the findings from the Italian population. METHODS: Questionnaires were distributed to a stratified sample (N = 3500) of the adult (18-65 years) inhabitants of Pavia province (1.05 % of the general population), randomly selected in cooperation with the local health service. Questions included demographic and diagnostic enquries, and assessment of various aspects of impact and health-care utilisation. RESULTS: Altogether 500 questionnaires were returned of which 487 were adequately completed for analysis (58 % female, 42 % male). Among these, gender-adjusted lifetime prevalence of headache was 82.5 %, higher in females than in males (91.2 % vs 72.4 %; p < 0.0001). Gender-adjusted 1-year prevalence was 74.2 % (females 87.7 %, males 61.1 %; p < 0.0001). The most prevalent headache type was migraine (gender-adjusted 1-year prevalence 42.9 %; females 54.6 %, males 32.5 %; p < 0.0001), followed by TTH (28.6 %; no gender-related difference); all causes of headache on >=15 days/month were reported by 7.0 % of participants (females 10.6 %, males 2.0 %; p = 0.0002), of whom 2.1 %,, all female (p = 0.0064) concomitantly overused acute medications (therefore probable MOH). Only 16.6 % of responders reporting headache had received a diagnosis from a doctor, and very few (2.4 %) were taking preventative medications. Headache had negative impacts on different aspects of life: education, career and earnings, family and social life. Each person with headache had lost, on average, 2.3 days from paid work and 2.4 days from household work, and missed social occasions on 1.2 days, in the preceding 3 months. An increasing gradient for impact was observed from episodic to chronic forms of headache. CONCLUSIONS: Our study reveals that in Italy, as in other countries, migraine, TTH and MOH are highly prevalent and are associated with significant personal impact. These findings have important implications for health policy in Italy. PMID- 26627712 TI - Why right is never left: the systemic right ventricle in transposition of the great arteries. PMID- 26627713 TI - Preserving neuroplasticity: Role of glucocorticoids and neurotrophins via phosphorylation. PMID- 26627715 TI - Kohn-Sham approach to quantum electrodynamical density-functional theory: Exact time-dependent effective potentials in real space. AB - The density-functional approach to quantum electrodynamics extends traditional density-functional theory and opens the possibility to describe electron-photon interactions in terms of effective Kohn-Sham potentials. In this work, we numerically construct the exact electron-photon Kohn-Sham potentials for a prototype system that consists of a trapped electron coupled to a quantized electromagnetic mode in an optical high-Q cavity. Although the effective current that acts on the photons is known explicitly, the exact effective potential that describes the forces exerted by the photons on the electrons is obtained from a fixed-point inversion scheme. This procedure allows us to uncover important beyond-mean-field features of the effective potential that mark the breakdown of classical light-matter interactions. We observe peak and step structures in the effective potentials, which can be attributed solely to the quantum nature of light; i.e., they are real-space signatures of the photons. Our findings show how the ubiquitous dipole interaction with a classical electromagnetic field has to be modified in real space to take the quantum nature of the electromagnetic field fully into account. PMID- 26627714 TI - Stonefish toxin defines an ancient branch of the perforin-like superfamily. AB - The lethal factor in stonefish venom is stonustoxin (SNTX), a heterodimeric cytolytic protein that induces cardiovascular collapse in humans and native predators. Here, using X-ray crystallography, we make the unexpected finding that SNTX is a pore-forming member of an ancient branch of the Membrane Attack Complex Perforin/Cholesterol-Dependent Cytolysin (MACPF/CDC) superfamily. SNTX comprises two homologous subunits (alpha and beta), each of which comprises an N-terminal pore-forming MACPF/CDC domain, a central focal adhesion-targeting domain, a thioredoxin domain, and a C-terminal tripartite motif family-like PRY SPla and the RYanodine Receptor immune recognition domain. Crucially, the structure reveals that the two MACPF domains are in complex with one another and arranged into a stable early prepore-like assembly. These data provide long sought after near-atomic resolution insights into how MACPF/CDC proteins assemble into prepores on the surface of membranes. Furthermore, our analyses reveal that SNTX like MACPF/CDCs are distributed throughout eukaryotic life and play a broader, possibly immune-related function outside venom. PMID- 26627716 TI - Type I interferons mediate pancreatic toxicities of PERK inhibition. AB - The great preclinical promise of the pancreatic endoplasmic reticulum kinase (PERK) inhibitors in neurodegenerative disorders and cancers is marred by pancreatic injury and diabetic syndrome observed in PERK knockout mice and humans lacking PERK function and suffering from Wolcott-Rallison syndrome. PERK mediates many of the unfolded protein response (UPR)-induced events, including degradation of the type 1 interferon (IFN) receptor IFNAR1 in vitro. Here we report that whole-body or pancreas-specific Perk ablation in mice leads to an increase in IFNAR1 protein levels and signaling in pancreatic tissues. Concurrent IFNAR1 deletion attenuated the loss of PERK-deficient exocrine and endocrine pancreatic tissues and prevented the development of diabetes. Experiments using pancreas specific Perk knockouts, bone marrow transplantation, and cultured pancreatic islets demonstrated that stabilization of IFNAR1 and the ensuing increased IFN signaling in pancreatic tissues represents a major driver of injury triggered by Perk loss. Neutralization of IFNAR1 prevented pancreatic toxicity of PERK inhibitor, indicating that blocking the IFN pathway can mitigate human genetic disorders associated with PERK deficiency and help the clinical use of PERK inhibitors. PMID- 26627718 TI - Designer and natural peptide toxin blockers of the KcsA potassium channel identified by phage display. AB - Peptide neurotoxins are powerful tools for research, diagnosis, and treatment of disease. Limiting broader use, most receptors lack an identified toxin that binds with high affinity and specificity. This paper describes isolation of toxins for one such orphan target, KcsA, a potassium channel that has been fundamental to delineating the structural basis for ion channel function. A phage-display strategy is presented whereby ~1.5 million novel and natural peptides are fabricated on the scaffold present in ShK, a sea anemone type I (SAK1) toxin stabilized by three disulfide bonds. We describe two toxins selected by sorting on purified KcsA, one novel (Hui1, 34 residues) and one natural (HmK, 35 residues). Hui1 is potent, blocking single KcsA channels in planar lipid bilayers half-maximally (Ki) at 1 nM. Hui1 is also specific, inhibiting KcsA-Shaker channels in Xenopus oocytes with a Ki of 0.5 nM whereas Shaker, Kv1.2, and Kv1.3 channels are blocked over 200-fold less well. HmK is potent but promiscuous, blocking KcsA-Shaker, Shaker, Kv1.2, and Kv1.3 channels with Ki of 1-4 nM. As anticipated, one Hui1 blocks the KcsA pore and two conserved toxin residues, Lys21 and Tyr22, are essential for high-affinity binding. Unexpectedly, potassium ions traversing the channel from the inside confer voltage sensitivity to the Hui1 off-rate via Arg23, indicating that Lys21 is not in the pore. The 3D structure of Hui1 reveals a SAK1 fold, rationalizes KcsA inhibition, and validates the scaffold-based approach for isolation of high-affinity toxins for orphan receptors. PMID- 26627717 TI - Tissue mechanics govern the rapidly adapting and symmetrical response to touch. AB - Interactions with the physical world are deeply rooted in our sense of touch and depend on ensembles of somatosensory neurons that invade and innervate the skin. Somatosensory neurons convert the mechanical energy delivered in each touch into excitatory membrane currents carried by mechanoelectrical transduction (MeT) channels. Pacinian corpuscles in mammals and touch receptor neurons (TRNs) in Caenorhabditis elegans nematodes are embedded in distinctive specialized accessory structures, have low thresholds for activation, and adapt rapidly to the application and removal of mechanical loads. Recently, many of the protein partners that form native MeT channels in these and other somatosensory neurons have been identified. However, the biophysical mechanism of symmetric responses to the onset and offset of mechanical stimulation has eluded understanding for decades. Moreover, it is not known whether applied force or the resulting indentation activate MeT channels. Here, we introduce a system for simultaneously recording membrane current, applied force, and the resulting indentation in living C. elegans (Feedback-controlled Application of mechanical Loads Combined with in vivo Neurophysiology, FALCON) and use it, together with modeling, to study these questions. We show that current amplitude increases with indentation, not force, and that fast stimuli evoke larger currents than slower stimuli producing the same or smaller indentation. A model linking body indentation to MeT channel activation through an embedded viscoelastic element reproduces the experimental findings, predicts that the TRNs function as a band-pass mechanical filter, and provides a general mechanism for symmetrical and rapidly adapting MeT channel activation relevant to somatosensory neurons across phyla and submodalities. PMID- 26627719 TI - Physics of active jamming during collective cellular motion in a monolayer. AB - Although collective cell motion plays an important role, for example during wound healing, embryogenesis, or cancer progression, the fundamental rules governing this motion are still not well understood, in particular at high cell density. We study here the motion of human bronchial epithelial cells within a monolayer, over long times. We observe that, as the monolayer ages, the cells slow down monotonously, while the velocity correlation length first increases as the cells slow down but eventually decreases at the slowest motions. By comparing experiments, analytic model, and detailed particle-based simulations, we shed light on this biological amorphous solidification process, demonstrating that the observed dynamics can be explained as a consequence of the combined maturation and strengthening of cell-cell and cell-substrate adhesions. Surprisingly, the increase of cell surface density due to proliferation is only secondary in this process. This analysis is confirmed with two other cell types. The very general relations between the mean cell velocity and velocity correlation lengths, which apply for aggregates of self-propelled particles, as well as motile cells, can possibly be used to discriminate between various parameter changes in vivo, from noninvasive microscopy data. PMID- 26627721 TI - Deterring Future Incidents of Intimate Partner Violence: Does Type of Formal Intervention Matter? AB - Few studies examine the comparative effectiveness of different formal interventions for domestic violence. Using arrest and civil protection order data, we compare three intervention scenarios (arrest, civil protection order, and both). Results suggest that intervention type has no substantive influence on the odds of reoffending. However, subsequent domestic violence is significantly associated with offender age, sex, and prior offense history as well as victim age and sex. We discuss our findings and their policy implications, noting that responding agencies should be sensitive to the characteristics that increase the odds of reoffending among those they come into contact with. PMID- 26627720 TI - The K+ channel KIR2.1 functions in tandem with proton influx to mediate sour taste transduction. AB - Sour taste is detected by a subset of taste cells on the tongue and palate epithelium that respond to acids with trains of action potentials. Entry of protons through a Zn(2+)-sensitive proton conductance that is specific to sour taste cells has been shown to be the initial event in sour taste transduction. Whether this conductance acts in concert with other channels sensitive to changes in intracellular pH, however, is not known. Here, we show that intracellular acidification generates excitatory responses in sour taste cells, which can be attributed to block of a resting K(+) current. We identify KIR2.1 as the acid sensitive K(+) channel in sour taste cells using pharmacological and RNA expression profiling and confirm its contribution to sour taste with tissue specific knockout of the Kcnj2 gene. Surprisingly, acid sensitivity is not conferred on sour taste cells by the specific expression of Kir2.1, but by the relatively small magnitude of the current, which makes the cells exquisitely sensitive to changes in intracellular pH. Consistent with a role of the K(+) current in amplifying the sensory response, entry of protons through the Zn(2+) sensitive conductance produces a transient block of the KIR2.1 current. The identification in sour taste cells of an acid-sensitive K(+) channel suggests a mechanism for amplification of sour taste and may explain why weak acids that produce intracellular acidification, such as acetic acid, taste more sour than strong acids. PMID- 26627722 TI - Identification of potassium and chloride channels in eccrine sweat glands. PMID- 26627723 TI - Impaired function of regulatory T cells in patients with psoriasis is mediated by phosphorylation of STAT3. AB - BACKGROUND: Psoriasis is a T cell-mediated chronic inflammatory skin disease. Regulatory T cells (Tregs) are crucial in suppressing immune response to maintain the immune balance. Wheras Tregs from psoriatic patients showed poorly activity in suppressing activation of responder T cells (Tresp), the mechanisms involved in this process are still unknown. OBJECTIVES: In this study, we investigated the possible role of STAT3 pathway in the pathogenesis of dysfunctional Tregs in psoriasis. METHODS: The suppressive function and the proliferative activity of Tregs were detected from psoriatic patients and normal healthy controls. Expression of phospho-STAT3 in psoriatic Tregs was evaluated by flow cytometry and immunofluorescence. Furthermore, Tregs were treated with Stattic V (STAT3 inhibitor) in order to investigate the role of STAT3 pathway in the function of Tregs. In addition, IL-6, IL-21 and IL-23 treatments were performed to identify the upstream molecules of STAT3 pathway in Tregs. RESULTS: Tregs from peripheral blood of psoriatic patients showed decreased suppressive function, together with phosphorylation of STAT3. In addition, Tregs isolated from psoriatic patients could produce IFN-gamma, TNF-alpha and IL-17. In the co-culture system of Tregs and Tresp isolated from psoriatic patients, addition of STAT3 inhibitor partially restored the suppressive function of Tregs and restrained the expressions of IFN gamma, TNF-alpha and IL-17 in psoriatic patients. Moreover, we found that IL-6, IL-21 and IL-23 induced the phosphorylation of STAT3 in Tregs. CONCLUSIONS: Our findings suggest that psoriatic Tregs experience a predominant STAT3 phosphorylation by exposure to pro-inflammatory cytokines, leading to their impaired functions in suppressing Tresp activation. PMID- 26627724 TI - Chromogranin A: any relevance in neuroendocrine tumors? AB - PURPOSE OF REVIEW: The review summarizes the utility and limitations of chromogranin A (CgA) as a circulating biomarker for neuroendocrine tumors (NETs). RECENT FINDINGS: Blood CgA measurement has numerous clinical limitations including poor assay reproducibility, low sensitivity (meta-analysis: 73%, 95% confidence interval: 0.71-0.76), and a paucity of prospective validation studies. A recent study noted elevation in 27% of NETs with a predictive value of 50% for metastases. These findings are consistent with its efficacy primarily as a monoanalyte secretory rather than multidimensional neoplastic marker. An automated CgA assay (KRYPTOR) exhibits similar metrics to the DAKO assay but is only useful in serum and routine storage diminishes its accuracy. Current studies indicate that CgA is more effective as a biomarker for cardiac disease. Given the diverse limitations of CgA, NET biomarker focus has evolved toward measurement of multiple analytes, for example, transcripts. Multianalyte algorithmic analyses perform significantly better as diagnostic (>95%) and prognostic markers (>90%) than CgA (30-74 and ~50%, respectively) since they delineate different aspects of the biological behavior of NETs, (e.g., proliferome and metabolome). SUMMARY: CgA is neither a reliable nor robust NET biomarker. As a monoanalyte, it is restricted by poor metrics and has limited predictive value. Its current clinical utility appears optimal in cardiovascular disease. The significance of CgA in NET disease is diminishing as other analytical approaches, particularly transcript multianalyte assays or other strategies, evolve to supersede it. PMID- 26627725 TI - Impact of bariatric surgery on fetal growth restriction: experience of a perinatal and bariatric surgery center. AB - BACKGROUND: Bariatric surgery is known to improve some pregnancy outcomes, but there is concern that it may increase the risk of small for gestational age. OBJECTIVE: To assess the impact of bariatric surgery on pregnancy outcomes and specifically of the type of bariatric surgery on the risk of fetal growth restriction. STUDY DESIGN: A single-center retrospective case-control study. The study group comprised all deliveries in women who had undergone bariatric surgery. To investigate the effects of weight loss on pregnancy outcomes, we compared the study group with a control group matched for presurgery body mass index. Secondly, to assess the specific impact of the type of surgery on the incidence of fetal growth restriction in utero, we distinguished subgroups with restrictive and malabsorptive bariatric surgery, and compared outcomes for each of these subgroups with a second control group, matched for prepregnancy body mass index. RESULTS: Among 139 patients operated, 58 had a malabsorptive procedure (gastric bypass) and 81 a purely restrictive procedure (72 a gastric banding and 9 a sleeve gastrectomy). Compared with controls matched for presurgery body mass index, the study group had a decreased rate of gestational diabetes (12% vs 23%, P = .02) and large for gestational age >90th percentile (11% vs 22%, P = .01) but an increased rate of small for gestational age <10th percentile. The incidence of small for gestational age was higher after gastric bypass (29%) than it was after restrictive surgery (9%) or in controls matched for prepregnancy body mass index (6%) (P < .01 between bypass and controls). In multivariable analysis, after adjustment for other risk factors, gastric bypass remained strongly associated with small for gestational age (adjusted odds ratio, 7.16; 95% confidence interval, 2.74-18.72). CONCLUSION: Malabsorptive bariatric surgery was associated with an increased risk of fetal growth restriction. PMID- 26627726 TI - Familiality analysis of provoked vestibulodynia treated by vestibulectomy supports genetic predisposition. AB - BACKGROUND: Provoked vestibulodynia is a poorly understood disease that affects 8 15% of women in their lifetime. There is significant inflammation and nerve growth in vestibular biopsies from affected women treated by vestibulectomy compared with matched female population controls without vestibulodynia. The triggers leading to this neurogenic inflammation are unknown, but they are likely multifactorial. OBJECTIVE: Our objective was to determine whether vestibulodynia is more common in close and distantly related female relatives of women diagnosed with the disease and those specifically treated by vestibulectomy. Excess familial clustering would support a potential genetic predisposition for vestibulodynia and warrant further studies to isolate risk alleles. STUDY DESIGN: Using population-based genealogy linked to University of Utah Hospital CPT coded data, we estimated the relative risk of vestibulectomy in female relatives of affected women. We also compared the average pairwise relatedness of cases to the expected relatedness of the population and identified high-disease-burden pedigrees. RESULTS: A total of 183 potential vestibulectomy probands were identified using CPT codes. The relative risk of vestibulectomy was elevated in first-degree (20 [6.6-47], P < .00001), second-degree (4.5 [0.5-16], P = .07), and third-degree female relatives (3.4 [1.2-8.8], P = .03). Seventy of these 183 CPT-based probands had available clinical history to confirm a diagnosis of moderate to severe vestibulodynia. Notably, this smaller group of confirmed probands (n = 70) revealed a similar familiality in first-degree (54 [17.5-126], P < .00001), second-degree (19.7 [2.4-71], P = .005), and third-degree relatives (12 [3.3-31], P = .0004), despite less statistical power for analysis. Overall, the average pairwise relatedness of affected women was significantly higher than expected (P < .001) and a number of high-disease-burden Utah families were identified. CONCLUSION: Our data suggest that vestibulodynia treated by vestibulectomy has a genetic predisposition. Future studies will identify candidate genes by linkage analysis in affected families and sequencing of distantly related probands. PMID- 26627727 TI - Effect of a multi-modal intervention on immunization rates in obstetrics and gynecology clinics. AB - BACKGROUND: There is increasing attention on immunizations by obstetrician gynecologists and a need to improve vaccination rates for all women. OBJECTIVE: To evaluate the effect of a multimodal intervention on rates of immunization with tetanus, diphtheria, and acellular pertussis (Tdap); human papillomavirus (HPV); and influenza in outpatient obstetrics and gynecology clinics. STUDY DESIGN: Immunization rates at 2 clinics were compared pre- and post-implementation of multiple interventions at a public integrated health-care system. Study interventions began on June 6, 2012 and concluded on May 31, 2014; the preimplementation time period used was June 6, 2010 to June 5, 2012. Interventions included stocking of immunizations in clinics, revision and expansion of standing orders, creation of a reminder/recall program, identification of an immunization champion to give direct provider feedback, expansion of a payment assistance program, and staff education. All women aged 15 and older who made a clinic visit during influenza season were included in the influenza cohort; women who delivered an infant during the study time period and had at least 1 prenatal visit within 9 months preceding delivery were included in the Tdap cohort; each clinic visit by a nonpregnant woman aged 15-26 years was assessed and included in the HPV analysis as an eligible visit if the patient was lacking any of the 3 HPV vaccines in the series. The primary outcome was receipt of influenza and Tdap vaccine per current American College of Obstetricians and Gynecologists guidelines and receipt of HPV vaccine during eligible visits. Influenza and Tdap were assessed with overall coverage rates at the institutional level, and HPV was assessed at the visit level by captured opportunities. All analyses included generalized estimating equations and the primary outcome was assessed with time as a covariate in all models. RESULTS: A total of 19,409 observations were included in the influenza cohort (10,231 pre- and 9178 post intervention), 2741 in the Tdap cohort (1248 pre- and 1493 post-intervention), and 12,443 in the HPV cohort (7966 pre- and 4477 post-intervention). Our population was largely Hispanic, English-speaking, and publicly insured. The rate of influenza vaccination increased from 35.4% pre-intervention to 46.0% post intervention (P < .001). The overall rate for Tdap vaccination increased from 87.6% pre-intervention to 94.5% post-intervention until the recommendation to vaccinate during each pregnancy was implemented (z = 4.58, P < .0001). The average Tdap up-to-date rate after that recommendation was 75.0% (z = -5.77, P < .0001). The overall rate of HPV vaccination with an eligible visit increased from 7.1% before to 23.7% after the intervention. CONCLUSION: Using evidence-based practices largely established in other settings, our intervention was associated with increased rates of influenza, Tdap, and HPV vaccination in outpatient underserved obstetrics and gynecology clinics. Integrating such evidence-based practices into routine obstetrics and gynecology care could positively impact preventive health for many women. PMID- 26627728 TI - Cervical pessary to prevent preterm birth in women with twin gestation and sonographic short cervix: a multicenter randomized controlled trial (PECEP Twins). AB - BACKGROUND: Spontaneous preterm birth (SPB) is the leading cause of perinatal morbidity and mortality. In twins, the rate of preterm birth is higher than in singletons; interventions to prevent preterm birth are needed in this high-risk population. OBJECTIVE: We sought to test whether a cervical pessary reduces the preterm birth rate in twin pregnancies with sonographic short cervix. STUDY DESIGN: A prospective, open-label, multicenter, randomized clinical trial was conducted in 5 hospitals in Spain. The ethics committees of all participating hospitals approved the protocol. The trial was registered as ClinicalTrials.gov, number NCT01242410. Eligible women were scanned in Spain. The primary outcome was SPB <34 weeks of gestation. Neonatal morbidity and mortality were also evaluated. RESULTS: Cervical length was measured in 2287 women; 137 pregnant women with a sonographic cervical length <=25 mm (of 154 detected with a short cervix) were randomly assigned to receive a cervical pessary or expectant management (1:1 ratio). SPB <34 weeks of gestation was significantly less frequent in the pessary group than in the expectant management group (11/68 [16.2%] vs 26/66 [39.4%]; relative risk, 0.41; 95% confidence interval, 0.22-0.76). Pessary use was associated with a significant reduction in the rate of birthweight <2500 g (P = .01). No significant differences were observed in composite neonatal morbidity outcome (8/136 [5.9%] vs 12/130 [9.1%]; relative risk, 0.64; 95% confidence interval, 0.27-1.50) or neonatal mortality (none) between the groups. No serious adverse effects associated with the use of a cervical pessary were observed. CONCLUSION: The insertion of a cervical pessary was associated with a significant reduction in the SPB rate. We propose the use of a cervical pessary for preventing preterm birth in twin pregnancies of mothers with a short cervix. PMID- 26627729 TI - Phase-specific healthcare costs of cervical cancer: estimates from a population based study. AB - BACKGROUND: There is a lack of evidence on the economic burden of managing cervical cancer in the public payer Canadian setting. OBJECTIVE: We used individual patient-level data to obtain a comprehensive estimate of the cost of managing cervical cancer in the province of Ontario, identifying main cost drivers and predictors of increased costs. STUDY DESIGN: The cost-of-illness technique was used to estimate the incremental costs associated with cervical cancer in 4 phases: prediagnosis, initial care, continuing care, and terminal care. All patients with cervical cancer diagnosed between 2005 and 2009 in the province of Ontario were propensity-score matched to 5 noncancer controls on birth year, income quintile, rurality, comorbidities, and patterns of healthcare utilization pattern during the 2 years before cancer diagnosis. Both cases and the noncancer comparison group were followed to death or March 31, 2013. Costs for all healthcare services paid for by the Ontario Ministry of Health and Long term Care during the follow-up period were estimated by the use of linked administrative data. Incremental costs for managing cervical cancer were calculated through generalized estimating equations. Predictors of greater health costs were explored using multivariate quantile regression models. RESULTS: All costs were presented in 2012 Canadian dollars ($1.00CDN = $1.00USD). The total incremental costs for managing cervical cancer were $362 in the pre-diagnosis phase, $15,722 in the initial phase, $3924 per year in the continuing phase, and $52,539 in the terminal phase. Inpatient care accounted for 34%, 28%, and 52% of total healthcare cost in the initial, continuing, and terminal phase, respectively. Physician services ranked first in the continuing phase (30%) and second in the initial (26%) and terminal (13%) phases. Advanced age, advanced cancer stage at diagnosis, and comorbidities were significant predictors of greater costs in most care phases. CONCLUSION: Aggregate costs of care for cervical cancer are substantial and vary by cancer stage, phase of care, patient age at diagnosis, and comorbidities before diagnosis. These estimates can serve as baseline data in economic analyses that aim to evaluate interventions for managing cervical cancer. PMID- 26627730 TI - Competing risks model in screening for preeclampsia by maternal factors and biomarkers at 19-24 weeks' gestation. AB - BACKGROUND: Preeclampsia (PE) affects 2-3% of all pregnancies and is a major cause of maternal and perinatal morbidity and mortality. The traditional approach to screening for PE is to use a risk-scoring system based on maternal demographic characteristics and medical history (maternal factors), but the performance of such an approach is very poor. OBJECTIVE: To develop a model for PE based on a combination of maternal factors with second-trimester biomarkers. STUDY DESIGN: The data for this study were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit at 19-24 weeks' gestation in 3 maternity hospitals in England between January 2006 and July 2014. We had data from maternal factors, uterine artery pulsatility index (UTPI), mean arterial pressure (MAP), serum placental growth factor (PLGF), and serum soluble fms-like tyrosine kinase-1 (SFLT) from 123,406, 67,605, 31,120, 10,828, and 8079 pregnancies, respectively. Bayes' theorem was used to combine the a priori risk from maternal factors with various combinations of biomarker multiple of the median (MoM) values. The modeled performance of screening for PE requiring delivery at <32, <37, and >=37 weeks' gestation was estimated. The modeled performance was compared to the empirical one, which was derived from 5 fold cross validation. We also examined the performance of screening based on risk factors from the medical history, as recommended by the American Congress of Obstetricians and Gynecologists (ACOG). RESULTS: In pregnancies that developed PE, the values of MAP, UTPI, and SFLT were increased and PLGF was decreased. For all biomarkers the deviation from normal was greater for early than for late PE, and therefore the performance of screening was inversely related to the gestational age at which delivery became necessary for maternal and/or fetal indications. Screening by maternal factors predicted 52%, 47%, and 37% of PE at <32, <37, and >=37 weeks' gestation, respectively, at a false-positive rate of 10%. The respective values for combined screening with maternal factors and MAP, UTPI, and PLGF were 99%, 85%, and 46%; the performance was not improved by the addition of SFLT. In our population of 123,406 pregnancies, the DR of PE at <32, <37, and >=37 weeks with the ACOG recommendations was 91%, 90%, and 91%, respectively, but at a screen positive rate of 67%. CONCLUSION: The performance of screening for PE by maternal factors and biomarkers in the middle trimester is superior to taking a medical history. PMID- 26627731 TI - Oocyte donation pregnancies and the risk of preeclampsia or gestational hypertension: a systematic review and metaanalysis. AB - The purpose of this study was to determine whether pregnancies that were achieved via oocyte donation, compared with pregnancies achieved via other assisted reproductive technology methods or natural conception, demonstrate increased risk of preeclampsia or gestational hypertension. Comparative studies of pregnancies that were achieved with oocyte donation vs other methods of assisted reproductive technology or natural conception with preeclampsia or gestational hypertension were included as 1 of the measured outcomes. Abstracts and unpublished studies were excluded. Two reviewers independently selected studies, which were assessed for quality with the use of methodological index for non-randomized studies, and extracted the data. Statistical analysis was conducted. Of the 523 studies that were reviewed initially, 19 comparative studies met the predefined inclusion and exclusion criteria and were included in the metaanalysis, which allowed for analysis of a total of 86,515 pregnancies. Our pooled data demonstrated that the risk of preeclampsia is higher in oocyte-donation pregnancies compared with other methods of assisted reproductive technology (odds ratio, 2.54; 95% confidence interval, 1.98-3.24; P < .0001) or natural conception (odds ratio, 4.34; 95% confidence interval, 3.10-6.06; P < .0001). The risk of gestational hypertension was also increased significantly in oocyte donation pregnancies in comparison with other methods of assisted reproductive technology (odds ratio, 3.00; 95% confidence interval, 2.44-3.70; P < .0001) or natural conception (odds ratio, 7.94; 95% confidence interval, 1.73-36.36; P = .008). Subgroup analysis that was conducted for singleton and multiple gestations demonstrated a similar risk for preeclampsia and gestational hypertension in both singleton and multiple gestations. This metaanalysis provides further evidence that supports that egg donation increases the risk of preeclampsia and gestational hypertension compared with other assisted reproductive technology methods or natural conception. PMID- 26627732 TI - Loss of CARD9-mediated innate activation attenuates severe influenza pneumonia without compromising host viral immunity. AB - Influenza virus (IFV) infection is a common cause of severe viral pneumonia associated with acute respiratory distress syndrome (ARDS), which is difficult to control with general immunosuppressive therapy including corticosteroids due to the unfavorable effect on viral replication. Studies have suggested that the excessive activation of the innate immunity by IFV is responsible for severe pathologies. In this study, we focused on CARD9, a signaling adaptor known to regulate innate immune activation through multiple innate sensor proteins, and investigated its role in anti-IFV defense and lung pathogenesis in a mouse model recapitulating severe influenza pneumonia with ARDS. We found that influenza pneumonia was dramatically attenuated in Card9-deficient mice, which showed improved mortality with reduced inflammatory cytokines and chemokines in the infected lungs. However, viral clearance, type-I interferon production, and the development of anti-viral B and T cell immunity were not compromised by CARD9 deficiency. Syk or CARD9-deficient DCs but not macrophages showed impaired cytokine but not type-I interferon production in response to IFV in vitro, indicating a possible role for the Syk-CARD9 pathway in DCs in excessive inflammation of IFV-infected lungs. Therefore, inhibition of this pathway is an ideal therapeutic target for severe influenza pneumonia without affecting viral clearance. PMID- 26627733 TI - Re: Use of Phosphodiesterase Type 5 Inhibitors May Adversely Impact Biochemical Recurrence after Radical Prostatectomy: U. Michl, F. Molfenter, M. Graefen, P. Tennstedt, S. Ahyai, B. Beyer, L. Budaus, A. Haese, H. Heinzer, S. J. Oh, G. Salomon, T. Schlomm, T. Steuber, I. Thederan, H. Huland and D. Tilki J Urol 2015;193:479-483. PMID- 26627734 TI - Spontaneous Activity of Cochlear Hair Cells Triggered by Fluid Secretion Mechanism in Adjacent Support Cells. AB - Spontaneous electrical activity of neurons in developing sensory systems promotes their maturation and proper connectivity. In the auditory system, spontaneous activity of cochlear inner hair cells (IHCs) is initiated by the release of ATP from glia-like inner supporting cells (ISCs), facilitating maturation of central pathways before hearing onset. Here, we find that ATP stimulates purinergic autoreceptors in ISCs, triggering Cl(-) efflux and osmotic cell shrinkage by opening TMEM16A Ca(2+)-activated Cl(-) channels. Release of Cl(-) from ISCs also forces K(+) efflux, causing transient depolarization of IHCs near ATP release sites. Genetic deletion of TMEM16A markedly reduces the spontaneous activity of IHCs and spiral ganglion neurons in the developing cochlea and prevents ATP dependent shrinkage of supporting cells. These results indicate that supporting cells in the developing cochlea have adapted a pathway used for fluid secretion in other organs to induce periodic excitation of hair cells. PMID- 26627735 TI - beta-Cell Insulin Secretion Requires the Ubiquitin Ligase COP1. AB - A variety of signals finely tune insulin secretion by pancreatic beta cells to prevent both hyper-and hypoglycemic states. Here, we show that post-translational regulation of the transcription factors ETV1, ETV4, and ETV5 by the ubiquitin ligase COP1 (also called RFWD2) in beta cells is critical for insulin secretion. Mice lacking COP1 in beta cells developed diabetes due to insulin granule docking defects that were fully rescued by genetic deletion of Etv1, Etv4, and Etv5. Genes regulated by ETV1, ETV4, or ETV5 in the absence of mouse COP1 were enriched in human diabetes-associated genes, suggesting that they also influence human beta-cell pathophysiology. In normal beta cells, ETV4 was stabilized upon membrane depolarization and limited insulin secretion under hyperglycemic conditions. Collectively, our data reveal that ETVs negatively regulate insulin secretion for the maintenance of normoglycemia. PMID- 26627736 TI - Gene Essentiality Is a Quantitative Property Linked to Cellular Evolvability. AB - Gene essentiality is typically determined by assessing the viability of the corresponding mutant cells, but this definition fails to account for the ability of cells to adaptively evolve to genetic perturbations. Here, we performed a stringent screen to assess the degree to which Saccharomyces cerevisiae cells can survive the deletion of ~1,000 individual "essential" genes and found that ~9% of these genetic perturbations could in fact be overcome by adaptive evolution. Our analyses uncovered a genome-wide gradient of gene essentiality, with certain essential cellular functions being more "evolvable" than others. Ploidy changes were prevalent among the evolved mutant strains, and aneuploidy of a specific chromosome was adaptive for a class of evolvable nucleoporin mutants. These data justify a quantitative redefinition of gene essentiality that incorporates both viability and evolvability of the corresponding mutant cells and will enable selection of therapeutic targets associated with lower risk of emergence of drug resistance. PMID- 26627737 TI - High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities. AB - The ability to perturb genes in human cells is crucial for elucidating gene function and holds great potential for finding therapeutic targets for diseases such as cancer. To extend the catalog of human core and context-dependent fitness genes, we have developed a high-complexity second-generation genome-scale CRISPR Cas9 gRNA library and applied it to fitness screens in five human cell lines. Using an improved Bayesian analytical approach, we consistently discover 5-fold more fitness genes than were previously observed. We present a list of 1,580 human core fitness genes and describe their general properties. Moreover, we demonstrate that context-dependent fitness genes accurately recapitulate pathway specific genetic vulnerabilities induced by known oncogenes and reveal cell-type specific dependencies for specific receptor tyrosine kinases, even in oncogenic KRAS backgrounds. Thus, rigorous identification of human cell line fitness genes using a high-complexity CRISPR-Cas9 library affords a high-resolution view of the genetic vulnerabilities of a cell. PMID- 26627738 TI - Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors. AB - Within the bone marrow, stem cells differentiate and give rise to diverse blood cell types and functions. Currently, hematopoietic progenitors are defined using surface markers combined with functional assays that are not directly linked with in vivo differentiation potential or gene regulatory mechanisms. Here, we comprehensively map myeloid progenitor subpopulations by transcriptional sorting of single cells from the bone marrow. We describe multiple progenitor subgroups, showing unexpected transcriptional priming toward seven differentiation fates but no progenitors with a mixed state. Transcriptional differentiation is correlated with combinations of known and previously undefined transcription factors, suggesting that the process is tightly regulated. Histone maps and knockout assays are consistent with early transcriptional priming, while traditional transplantation experiments suggest that in vivo priming may still allow for plasticity given strong perturbations. These data establish a reference model and general framework for studying hematopoiesis at single-cell resolution. PMID- 26627739 TI - Identification of rearranged sequences of HPV16 DNA in precancerous and cervical cancer cases. AB - Integration of HPV16 DNA into the host chromosome is considered to be a crucial step towards genomic instability and cervical cancer development. Aim of the present study was to investigate the presence of HPV16 rearranged intra-viral sequences in HPV16-positive normal, precancerous and cervical cancer samples using the method of Restriction Site-PCR (RS-PCR). Sequence analysis of HPV16 integrants revealed for the first time in clinical samples two distinct rearranged intra-viral sequences, concerning the conjunction of E2 and L1 genes and the conjunction of E1 and L1 genes with inverted orientation. Furthermore mapping analysis of the E1 and E2 genes in cervical samples with rearranged intra viral sequences of HPV16 genome was conducted in order to determine the integrity of viral genes. The identification of intra-viral rearrangements provides valuable information regarding the HPV16 DNA integration, and may be a significant biomarker for the presence of chromosomal instability and DNA damages in clinical samples. PMID- 26627740 TI - Intensified removal of copper from waste water using activated watermelon based biosorbent in the presence of ultrasound. AB - Copper is one of the most toxic heavy metals having significant effects on the living organisms and hence effective removal of copper from waste water is crucial. The current work investigates the application of activated watermelon shell based biosorbent for the removal of copper from aqueous solution. The effect of activation using calcium hydroxide and citric acid as well as the effect of operating parameters like contact time, adsorbent dosage, temperature, pH, initial concentration and ultrasonic power on the extent of removal has been investigated. Experiments performed in the presence of ultrasound to investigate the degree of intensification as compared to the conventional agitation based treatment revealed that the adsorption rate significantly increases in the presence of ultrasound and also the time required for reaching the equilibrium reduces from 60 min in conventional approach to only 20 min in the presence of ultrasound. The extent of adsorption of Cu(II) on adsorbents was found to increase with an increase in the operating pH till an optimum value of 5. The extent of adsorption also increased with a decrease in the initial concentration and particle size as well as with an increase in ultrasonic power till an optimum. Kinetics and isotherm study revealed that all the experimental data was found to best fit the pseudo second order kinetics and Langmuir adsorption isotherm model respectively. Maximum adsorption capacity was found to be 31.25mg/g for watermelon treated with calcium hydroxide and 27.027 mg/g for watermelon treated with citric acid. Overall present study established that activated watermelon is an environmentally friendly, low cost and highly efficient biosorbent that can be successfully applied for the removal of copper from aqueous solution with intensification benefits based on the ultrasound assisted approach. PMID- 26627741 TI - Asymmetric interaural generalization of learning gains in a speech-in-noise identification task. AB - The pattern of generalization of learning gains to untrained conditions in adult human perceptual skill learning has been used as an effective behavioral probe for studying the functional organization of the learning system. Learning gains were previously reported to generalize symmetrically between the ears for tonal stimuli. However, given the open question concerning the specialization of the hemispheres in the processing of speech sounds, it is not clear whether symmetrical interaural generalization will follow training on such stimuli. Here the effect of monaural single-session training on the identification of consonant vowel stimuli in noise was examined. Participants showed similar robust gains in performance at 24 h post-training in both trained ears. There was, however, an asymmetrical generalization of the learning gains from the trained to the untrained ear, with more transfer from the right-trained to the left-untrained ear than vice versa. Training and transfer gains were retained for both ears over an interval of several months, although for the untrained ear a brief exposure was necessary to relearn the task. These results provide first-time evidence for an asymmetry in interaural generalization for speech sounds following training and provide further support to the lateralization of speech sounds along the auditory system. PMID- 26627742 TI - Robust auditory localization using probabilistic inference and coherence-based weighting of interaural cues. AB - Robust sound source localization is performed by the human auditory system even in challenging acoustic conditions and in previously unencountered, complex scenarios. Here a computational binaural localization model is proposed that possesses mechanisms for handling of corrupted or unreliable localization cues and generalization across different acoustic situations. Central to the model is the use of interaural coherence, measured as interaural vector strength (IVS), to dynamically weight the importance of observed interaural phase (IPD) and level (ILD) differences in frequency bands up to 1.4 kHz. This is accomplished through formulation of a probabilistic model in which the ILD and IPD distributions pertaining to a specific source location are dependent on observed interaural coherence. Bayesian computation of the direction-of-arrival probability map naturally leads to coherence-weighted integration of location cues across frequency and time. Results confirm the model's validity through statistical analyses of interaural parameter values. Simulated localization experiments show that even data points with low reliability (i.e., low IVS) can be exploited to enhance localization performance. A temporal integration length of at least 200 ms is required to gain a benefit; this is in accordance with previous psychoacoustic findings on temporal integration of spatial cues in the human auditory system. PMID- 26627743 TI - Simultaneous localization of multiple broadband non-impulsive acoustic sources in an ocean waveguide using the array invariant. AB - The array invariant method, previously derived for instantaneous range and bearing estimation of a single broadband impulsive source in a horizontally stratified ocean waveguide, can be generalized to simultaneously localize multiple uncorrelated broadband noise sources that are not necessarily impulsive in the time domain by introducing temporal pulse compression and an image processing technique similar to the Radon transform. This can be done by estimating the range and bearing of broadband non-impulsive sources from measured beam-time migration lines of modal arrivals along a horizontal array arising from differences in modal group velocity and modal polar angle for each propagating mode. The generalized array invariant approach is used to estimate the range of a vertical source array and vocalizing humpback whales over wide areas from measurements made by a towed horizontal receiver array during the Gulf of Maine 2006 Experiment. The localization results are shown to have roughly 12% root-mean squared errors from Global Positioning System measured ground truth positions for controlled source transmissions and less than 10% discrepancy from those obtained independently via moving array triangulation for vocalizing humpbacks, respectively. PMID- 26627744 TI - Dynamic acousto-elastic testing applied to a highly dispersive medium and evidence of shell buckling of lipid-coated gas microbubbles. AB - Dynamic acousto-elastic testing is applied to a mixture of lipid-coated microbubbles in water. A dynamic change of ambient pressure is produced by a 16 kHz pressure wave having a peak pressure amplitude of 28 kPa. The induced changes of phase velocity and attenuation are captured by a sequence of short ultrasound pulses with a center frequency of 4 MHz. As a consequence of the dispersion brought about by the resonance of microbubbles at a frequency close to 2 MHz, time-domain approaches like the cross-correlation method are shown to be unsuited to determine the variation in ultrasound wavespeed. A frequency-domain analysis shows that the acousto-elastic effect (first order pressure derivative of ultrasound phase velocity) depends on the ultrasound frequency. The acousto elastic effect tends to that measured in water for an ultrasound frequency above the resonance frequency of microbubbles, while it is two orders of magnitude larger for an ultrasound frequency close to or below the resonance frequency of microbubbles. Besides the large magnitude of the acousto-elastic effect observed for an ultrasound frequency below the resonance frequency of microbubbles, the first order pressure derivative of ultrasound phase velocity is negative. This supports the occurrence of shell buckling of lipid-coated microbubbles induced by the 16 kHz pressure wave. PMID- 26627745 TI - Equal latency contours for bottlenose dolphins (Tursiops truncatus) and California sea lions (Zalophus californianus). AB - Loudness perception by non-human animals is difficult to study directly. Previous research efforts have instead focused on estimating loudness perception using simple reaction time (RT) data. These data are used to generate equal latency contours that serve as a proxy for equal loudness contours. To aid the design of auditory weighting functions for marine mammals, equal latency contours were generated using RT data for two marine mammal species that are representative of broader functional hearing groups: the bottlenose dolphin (under water) and California sea lion (in air). In all cases, median RT decreased with increasing tone sound pressure level (SPL). The equal latency contours corresponding to near threshold SPLs were similar to audiograms for both species. The sea lion contours showed some compression at frequencies below 1 kHz; however, a similar pattern was not apparent in the more variable data for dolphins. Equal latency contours for SPLs greater than approximately 40 dB above threshold diverged from predicted equal loudness contours, likely due to the asymptotic nature of RT at the highest tested SPLs. The results suggest that auditory threshold data, potentially augmented with compression at low frequencies, may provide a useful way forward when designing auditory weighting functions for marine mammals. PMID- 26627746 TI - Speech-in-noise enhancement using amplification and dynamic range compression controlled by the speech intelligibility index. AB - In many speech communication applications, such as public address systems, speech is degraded by additive noise, leading to reduced speech intelligibility. In this paper a pre-processing algorithm is proposed that is capable of increasing speech intelligibility under an equal-power constraint. The proposed AdaptDRC algorithm comprises two time- and frequency-dependent stages, i.e., an amplification stage and a dynamic range compression stage that are both dependent on the Speech Intelligibility Index (SII). Experiments using two objective measures, namely, the extended SII and the short-time objective intelligibility measure (STOI), and a formal listening test were conducted to compare the AdaptDRC algorithm with a modified version of a recently proposed algorithm in three different noise conditions (stationary car noise and speech-shaped noise and non-stationary cafeteria noise). While the objective measures indicate a similar performance for both algorithms, results from the formal listening test indicate that for the two stationary noises both algorithms lead to statistically significant improvements in speech intelligibility and for the non-stationary cafeteria noise only the proposed AdaptDRC algorithm leads to statistically significant improvements. A comparison of both objective measures and results from the listening test shows high correlations, although, in general, the performance of both algorithms is overestimated. PMID- 26627747 TI - Underwater sound scattering and absorption by a coated infinite plate with attached periodically located inhomogeneities. AB - This paper extends previous work of Zhang and Pan [J. Acoust. Soc. Am. 133(4), 2082-2096 (2013)] on sound scattering and absorption by an underwater coated plate with a single attached distributed-inhomogeneity to that with periodically located distributed-inhomogeneities. A comparison is made among cases of a plate without inhomogeneities, a plate with inhomogeneities, and one with inhomogeneities ignoring the mutual coupling. Results show that coupling of the structural waves scattered by the inhomogeneities plays an important role in modifying the sound absorption and scattering of surface sound pressure, especially at low frequencies and/or the resonance frequencies of the trapped modes of the plate. The sound absorption of the plate is dependent on the distance between the adjacent inhomogeneities, the length of the inhomogeneity, and the angle of the incident sound. On the surface of the inhomogeneities, the scattered/total sound pressure is generally enhanced. On the surface in between the inhomogeneities, the pressure is also enhanced at low frequencies but is nearly unchanged at higher frequencies. Results also show that the coupling induced variation of scattered/total pressure is significant only at the resonance frequencies of the global modes and trapped modes. The surface normal velocity is presented to explain the coupling-induced variations in the vibration and pressure fields. PMID- 26627748 TI - Calls of Bryde's whale (Balaenoptera edeni) recorded in the Gulf of California (L). AB - A total of 109 recordings aiming to identify Bryde's whale calls were collected from the Gulf of California, Mexico, during field trips performed from January 2010 to June 2014. Vocalizations were recorded only when no calves were observed. Four types of calls were identified. Calls similar to the Be4 call type previously reported for the Eastern Tropical Pacific region and South of California were recorded. In addition, three calls, not reported in previous studies of the Bryde's whale, have also been identified. The identification of these calls, which were labeled Be10, Be11, and Be12, enables expansion of the known acoustic repertoire of this species, which is currently poorly documented. The identification of three previously unreported calls and the confidence given by careful visual confirmation of the whale species and number of individuals contribute to make this study a significant contribution toward the acoustic monitoring of Bryde's whale. PMID- 26627749 TI - A fast boundary element method for the scattering analysis of high-intensity focused ultrasound. AB - High-intensity focused ultrasound (HIFU) techniques are promising modalities for the non-invasive treatment of cancer. For HIFU therapies of, e.g., liver cancer, one of the main challenges is the accurate focusing of the acoustic field inside a ribcage. Computational methods can play an important role in the patient specific planning of these transcostal HIFU treatments. This requires the accurate modeling of acoustic scattering at ribcages. The use of a boundary element method (BEM) is an effective approach for this purpose because only the boundaries of the ribs have to be discretized instead of the standard approach to model the entire volume around the ribcage. This paper combines fast algorithms that improve the efficiency of BEM specifically for the high-frequency range necessary for transcostal HIFU applications. That is, a Galerkin discretized Burton-Miller formulation is used in combination with preconditioning and matrix compression techniques. In particular, quick convergence is achieved with the operator preconditioner that has been designed with on-surface radiation conditions for the high-frequency approximation of the Neumann-to-Dirichlet map. Realistic computations of acoustic scattering at 1 MHz on a human ribcage model demonstrate the effectiveness of this dedicated BEM algorithm for HIFU scattering analysis. PMID- 26627750 TI - Measurement of circumferential Lamb waves using a line-focus poly(vinylidene fluoride) transducer and cross correlation waveform analysis. AB - This paper presents a method for measuring circumferential Lamb waves propagating on a cylindrically curved thin plate. The measurement is carried out using a wideband and line-focused poly(vinylidene fluoride) transducer along with a defocusing waveform measurement method. After synthesizing the acquired waveforms, interference patterns can be obtained and a cross correlation method is developed to accurately extract the wave velocity as a function of wave frequency. Using three stainless steel thin plates of different thicknesses (100, 150, and 300 MUm) and a radius of curvature of 10 mm, dispersion curves for several fundamental and higher order modes of circumferential Lamb waves are simultaneously determined. Theoretical dispersion curves are also calculated and compared with their experimental counterparts. Very good agreements are observed, which concludes the measurement accuracy of this measurement method. PMID- 26627751 TI - Simplified analytical model for sound level prediction at shielded urban locations involving multiple diffraction and reflections. AB - Accurate and efficient prediction of the sound field in shadow zones behind obstacles is a challenging task but essential to produce urban noise maps. A simplified method is presented to predict sound levels at shielded urban locations, including multi-edge diffraction over successive buildings and multiple reflections between parallel facades. The model is essentially based on Pierce's diffraction theory, where the Fresnel Integral is approximated by trigonometric functions for efficient evaluation, and parameterized for urban environments. The model has been validated for idealized urban configurations by comparing to the results of Pierce's theory and a full-wave numerical method. In case of multi-edge diffraction over buildings in absence of a source or receiver canyon, deviations from the full-wave simulations are smaller than 2 dB for the octave bands with central frequencies ranging from 125 to 1000 Hz. However, larger errors are made when receivers are close to the extension line from the diffraction edge closest to the receiver. In case of combining the simplified multi-edge diffraction model with an efficient approach for including the series of mirror sources and mirror receivers, based on the Hurwitz-Lerch transcendent, this same accuracy is obtained. PMID- 26627752 TI - Acoustophoresis of disk-shaped microparticles: A numerical and experimental study of acoustic radiation forces and torques. AB - Disk-shaped microparticles experience an acoustic radiation force and torque in an ultrasonic standing wave. Hence, they are translated by the acoustic field, an effect called acoustophoresis, and rotated. The torque effect is also known from the "Rayleigh disk" which is described in literature for sound intensity measurements. In this paper, inviscid numerical simulations of acoustic radiation forces and torques for disks with radius ? wavelength in water are developed in good agreement with former analytical solutions, and the dependence on disk geometry, density, and orientation is discussed. Experiments with alumina disks (diameter 7.5 MUm), suspended in an aqueous liquid in a silicon microchannel, confirm the theoretical results qualitatively at the microscale and ultrasonic frequencies around 2 MHz. These results can potentially be applied for the synthesis of disk-reinforced composite materials. The insights are also relevant for the acoustic handling of various disk-shaped particles, such as red blood cells. PMID- 26627753 TI - Predicting playing frequencies for clarinets: A comparison between numerical simulations and simplified analytical formulas. AB - When designing a wind instrument such as a clarinet, it can be useful to be able to predict the playing frequencies. This paper presents an analytical method to deduce these playing frequencies using the input impedance curve. Specifically there are two control parameters that have a significant influence on the playing frequency, the blowing pressure and reed opening. Four effects are known to alter the playing frequency and are examined separately: the flow rate due to the reed motion, the reed dynamics, the inharmonicity of the resonator, and the temperature gradient within the clarinet. The resulting playing frequencies for the first register of a particular professional level clarinet are found using the analytical formulas presented in this paper. The analytical predictions are then compared to numerically simulated results to validate the prediction accuracy. The main conclusion is that in general the playing frequency decreases above the oscillation threshold because of inharmonicity, then increases above the beating reed regime threshold because of the decrease of the flow rate effect. PMID- 26627754 TI - Auditory detection of non-speech and speech stimuli in noise: Effects of listeners' native language background. AB - This study investigated whether native listeners processed speech differently from non-native listeners in a speech detection task. Detection thresholds of Mandarin Chinese and Korean vowels and non-speech sounds in noise, frequency selectivity, and the nativeness of Mandarin Chinese and Korean vowels were measured for Mandarin Chinese- and Korean-native listeners. The two groups of listeners exhibited similar non-speech sound detection and frequency selectivity; however, the Korean listeners had better detection thresholds of Korean vowels than Chinese listeners, while the Chinese listeners performed no better at Chinese vowel detection than the Korean listeners. Moreover, thresholds predicted from an auditory model highly correlated with behavioral thresholds of the two groups of listeners, suggesting that detection of speech sounds not only depended on listeners' frequency selectivity, but also might be affected by their native language experience. Listeners evaluated their native vowels with higher nativeness scores than non-native listeners. Native listeners may have advantages over non-native listeners when processing speech sounds in noise, even without the required phonetic processing; however, such native speech advantages might be offset by Chinese listeners' lower sensitivity to vowel sounds, a characteristic possibly resulting from their sparse vowel system and their greater cognitive and attentional demands for vowel processing. PMID- 26627755 TI - Acoustic properties of vowel production in prelingually deafened Mandarin speaking children with cochlear implants. AB - The present study examined the acoustic features of vowel production in Mandarin speaking children with cochlear implants (CIs). The subjects included 14 native Mandarin-speaking, prelingually deafened children with CIs (2.9-8.3 yr old) and 60 age-matched, normal-hearing (NH) children (3.1-9.0 years old). Each subject produced a list of monosyllables containing seven Mandarin vowels: [i, a, u, y, ?, ?, ?]. Midpoint F1 and F2 of each vowel token were extracted and normalized to eliminate the effects of different vocal tract sizes. Results showed that the CI children produced significantly longer vowels and less compact vowel categories than the NH children did. The CI children's acoustic vowel space was reduced due to a retracted production of the vowel [i]. The vowel space area showed a strong negative correlation with age at implantation (r = -0.80). The analysis of acoustic distance showed that the CI children produced corner vowels [a, u] similarly to the NH children, but other vowels (e.g., [?, ?]) differently from the NH children, which suggests that CI children generally follow a similar developmental path of vowel acquisition as NH children. These findings highlight the importance of early implantation and have implications in clinical aural habilitation in young children with CIs. PMID- 26627756 TI - Transmission of ultrasonic waves at oblique incidence to composite laminates with spring-type interlayer interfaces. AB - The transmission characteristics of ultrasonic waves at oblique incidence to composite laminates are analyzed theoretically by the stiffness matrix method. The analysis takes into account the presence of thin resin-rich regions between adjacent plies as spring-type interfaces with normal and shear stiffnesses. The amplitude transmission coefficient of longitudinal wave through a unidirectional laminate immersed in water is shown to be significantly influenced by the frequency, the interlayer interfacial stiffnesses, and the incident angle. Using Floquet's theorem, the dispersion relation of the infinitely extended laminate structure is calculated and compared to the transmission coefficient of laminates of finite thickness. This reveals that the ranges of frequency and interfacial stiffnesses where the Floquet waves lie in the band-gaps agree well with those where the transmission coefficient of the finite layered structure is relatively small, indicating that the band-gaps appear even in the laminate with a finite number of plies. The amplitude transmission coefficient for an 11-ply carbon epoxy unidirectional composite laminate is experimentally obtained for various frequencies and incident angles. The low-transmission zones observed in the experimental results, which are due to the critical angle of the quasi longitudinal wave and the Bragg reflection, are shown to be favorably compared with the theory. PMID- 26627757 TI - Imaging textural variation in the acoustoelastic coefficient of aluminum using surface acoustic waves. AB - Much interest has arisen in nonlinear acoustic techniques because of their reported sensitivity to variations in residual stress, fatigue life, and creep damage when compared to traditional linear ultrasonic techniques. However, there is also evidence that the nonlinear acoustic properties are also sensitive to material microstructure. As many industrially relevant materials have a polycrystalline structure, this could potentially complicate the monitoring of material processes when using nonlinear acoustics. Variations in the nonlinear acoustoelastic coefficient on the same length scale as the microstructure of a polycrystalline sample of aluminum are investigated in this paper. This is achieved by the development of a measurement protocol that allows imaging of the acoustoelastic response of a material across a samples surface at the same time as imaging the microstructure. The development, validation, and limitations of this technique are discussed. The nonlinear acoustic response is found to vary spatially by a large factor (>20) between different grains. A relationship is observed when the spatial variation of the acoustoelastic coefficient is compared to the variation in material microstructure. PMID- 26627758 TI - Optimized vector sound intensity measurements with a tetrahedral arrangement of microphones in a spherical shell. AB - Recent times have seen the introduction of small spherical arrays whose usefulness as sound intensity probes is the focus of this paper. The presented probe consists of a spherical shell, 30 mm in diameter, housing four 14 in. microphones arranged in a regular tetrahedral configuration. Classical formulae may be used to estimate the sound intensity vector, as may methods based on spherical harmonics decomposition. Results are shown to be comparable to those obtained from classical sound intensity probes. The existence of an analytical model for a plane wave's diffraction about a sphere provides a means for adopting common optimization techniques for potentially improving the intensity vector estimate, however. This paper examines the validity of non-linear least squares optimization in conjunction with the proposed spherical sound intensity probe when placed in the following sound fields: (1) a simple plane wave; (2) a plane wave corrupted by noise; and (3) multiple incident plane waves. Under certain conditions, the probe is shown to greatly extend the operational frequency range of classical sound intensity probes. The optimization algorithm is found to lack robustness against deviations from plane wave conditions, however. PMID- 26627759 TI - Comparison of Indo-Pacific humpback dolphin (Sousa chinensis) whistles from two areas of western Peninsular Malaysia. AB - Differences in the acoustic variables of whistles emitted by Indo-Pacific humpback dolphins (Sousa chinensis) from two coastal locations along western Peninsular Malaysia were investigated. Duration, frequency, and frequency modulation variables were extracted from and used to characterize recordings of free-ranging humpback dolphins that were made using a broadband towed hydrophone. A total of 960 whistles from Matang Mangroves and 823 whistles from Langkawi Island were used in analyses. The whistles of Malaysian humpback dolphins covered frequencies from 1231 to 27 120 Hz with durations from 0.010-1.575 s. Significant multivariate differences were found in whistles emitted between locations. Significant differences were also found between dolphins of the two locations in their whistle duration, frequency modulation, and all frequency variables except for minimum frequency, which is likely under morphological constraints. The differences in whistles may be related to adaptations to the local acoustic habitat or unique whistles may have developed due to social interactions within each location, or broader scale differences resulting from geographic separation between the locations. PMID- 26627760 TI - Performance of a planar virtual sound barrier at the baffled opening of a rectangular cavity. AB - This paper proposes to reduce the radiation of a sound source inside a cavity through the baffled opening by using an array of loudspeakers and microphones. The system is called a planar virtual sound barrier because it acts like a concrete sound barrier to block the transmission of sound but does not affect light and air circulation. An analytical model for the planar virtual sound barrier is developed based on the modal superposition method to calculate the sound field in and outside a rectangular cavity with a baffled opening. After the model is verified with numerical simulations, a performance study of the planar virtual sound barrier is carried out based on the proposed analytical model, and then the results are confirmed by experiments. The mechanisms of the planar virtual sound barrier are investigated and it is found that three mechanisms work together in the system, including changing the impedance of the primary source, modal control, and modal rearrangement. It is also found that there exist some frequencies where the sound cannot be controlled if all the secondary sources are on the same plane parallel to the opening, and the reasons behind the phenomenon are explained. PMID- 26627761 TI - Enhanced multi-channel model for auditory spectrotemporal integration. AB - In psychoacoustics, a multi-channel model has traditionally been used to describe detection improvement for multicomponent signals. This model commonly postulates that energy or information within either the frequency or time domain is transformed into a probabilistic decision variable across the auditory channels, and that their weighted linear summation determines optimum detection performance when compared to a critical value such as a decision criterion. In this study, representative integration-based channel models, specifically focused on signal processing properties of the auditory periphery are reviewed (e.g., Durlach's channel model). In addition, major limitations of the previous channel models are described when applied to spectral, temporal, and spectrotemporal integration performance by human listeners. Here, integration refers to detection threshold improvements as the number of brief tone bursts in a signal is increased. Previous versions of the multi-channel model underestimate listener performance in these experiments. Further, they are unable to apply a single processing unit to signals which vary simultaneously in time and frequency. Improvements to the previous channel models are proposed by considering more realistic conditions such as correlated signal responses in the auditory channels, nonlinear properties in system performance, and a peripheral processing unit operating in both time and frequency domains. PMID- 26627762 TI - Linear multivariate evaluation models for spatial perception of soundscape. AB - Soundscape is a sound environment that emphasizes the awareness of auditory perception and social or cultural understandings. The case of spatial perception is significant to soundscape. However, previous studies on the auditory spatial perception of the soundscape environment have been limited. Based on 21 native binaural-recorded soundscape samples and a set of auditory experiments for subjective spatial perception (SSP), a study of the analysis among semantic parameters, the inter-aural-cross-correlation coefficient (IACC), A-weighted equal sound-pressure-level (L(eq)), dynamic (D), and SSP is introduced to verify the independent effect of each parameter and to re-determine some of their possible relationships. The results show that the more noisiness the audience perceived, the worse spatial awareness they received, while the closer and more directional the sound source image variations, dynamics, and numbers of sound sources in the soundscape are, the better the spatial awareness would be. Thus, the sensations of roughness, sound intensity, transient dynamic, and the values of Leq and IACC have a suitable range for better spatial perception. A better spatial awareness seems to promote the preference slightly for the audience. Finally, setting SSPs as functions of the semantic parameters and Leq-D-IACC, two linear multivariate evaluation models of subjective spatial perception are proposed. PMID- 26627763 TI - Wave-speed dispersion associated with an attenuation obeying a frequency power law. AB - An attenuation scaling as a power of frequency, |omega|(beta), over an infinite bandwidth is neither analytic nor square-integrable, thus calling into question the application of the Kramers-Kronig dispersion relations for determining the frequency dependence of the associated phase speed. In this paper, three different approaches are developed, all of which return the dispersion formula for the wavenumber, K(omega). The first analysis relies on the properties of generalized functions and the causality requirement that the impulse response, k(t), the inverse Fourier transform of -iK(omega), must vanish for t < 0. Second, a wave equation is introduced that yields the phase-speed dispersion associated with a frequency-power-law attenuation. Finally, it is shown that, with minor modification, the Kramers-Kronig dispersion relations with no subtractions (the Plemelj formulas) do in fact hold for an attenuation scaling as |omega|(beta), yielding the same dispersion formula as the other two derivations. From this dispersion formula, admissible values of the exponent beta are established. Physically, the inadmissible values of beta, which include all the integers, correspond to attenuation-dispersion pairs whose Fourier components cannot combine in such a way as to make the impulse response, k(t), vanish for t < 0. There is no upper or lower limit on the value that beta may take. PMID- 26627764 TI - Combined neural and behavioural measures of temporal pitch perception in cochlear implant users. AB - Four experiments measured the perceptual and neural correlates of the temporal pattern of electrical stimulation applied to one cochlear-implant (CI) electrode, for several subjects. Neural effects were estimated from the electrically evoked compound action potential (ECAP) to each pulse. Experiment 1 attenuated every second pulse of a 200-pps pulse train. Increasing attenuation caused pitch to drop and the ECAP to become amplitude modulated, thereby providing an estimate of the relationship between neural modulation and pitch. Experiment 2 showed that the pitch of a 200-pps pulse train can be reduced by delaying every second pulse, so that the inter-pulse-intervals alternate between longer and shorter intervals. This caused the ECAP to become amplitude modulated, but not by enough to account for the change in pitch. Experiment 3 replicated the finding that rate discrimination deteriorates with increases in baseline rate. This was accompanied by an increase in ECAP modulation, but by an amount that produced only a small effect on pitch in experiment 1. Experiment 4 showed that preceding a pulse train with a carefully selected "pre-pulse" could reduce ECAP modulation, but did not improve rate discrimination. Implications for theories of pitch and for limitations of pitch perception in CI users are discussed. PMID- 26627766 TI - Broadband acoustic holography from intensity measurements with a three dimensional pressure-velocity probe. AB - Near-field acoustic holography requires one or more reference signals corresponding to sound sources to help get the phase of complex pressure on the hologram plane, while broadband acoustic holography from intensity measurements (BAHIM) breaks through this restriction by getting the phase from the quadratic pressure and tangential components of sound intensity. However, in the conventional BAHIM all the sound sources are confined to one side of the hologram plane. In the present paper, by utilizing a three-dimensional pressure-velocity (3D p-u) probe that is composed of one pressure microphone and three orthogonally placed particle velocity sensors, the BAHIM is extended to be applicable to the situation that the disturbing sources exist on the opposite side of the hologram plane. The validity of the extended BAHIM is examined both numerically and experimentally. The results demonstrate that, by using the extended BAHIM, the complex pressure as well as the normal particle velocity on the hologram plane can be measured with a 3D p-u probe without using any reference signal, the pressure radiated by the target source can be extracted from the mixed sound field, and the sound field of interest can be reconstructed effectively. PMID- 26627765 TI - A quantitative acoustic analysis of the vocal repertoire of the common marmoset (Callithrix jacchus). AB - The common marmoset (Callithrix jacchus), a highly vocal New World primate species, has emerged in recent years as a promising animal model for studying brain mechanisms underlying perception, vocal production, and cognition. The present study provides a quantitative acoustic analysis of a large number of vocalizations produced by marmosets in a social environment within a captive colony. Previous classifications of the marmoset vocal repertoire were mostly based on qualitative observations. In the present study a variety of vocalizations from individually identified marmosets were sampled and multiple acoustic features of each type of vocalization were measured. Results show that marmosets have a complex vocal repertoire in captivity that consists of multiple vocalization types, including both simple calls and compound calls composed of sequences of simple calls. A detailed quantification of the vocal repertoire of the marmoset can serve as a solid basis for studying the behavioral significance of their vocalizations and is essential for carrying out studies that investigate such properties as perceptual boundaries between call types and among individual callers as well as neural coding mechanisms for vocalizations. It can also serve as the basis for evaluating abnormal vocal behaviors resulting from diseases or genetic manipulations. PMID- 26627767 TI - Supersonic surface acoustic waves on the 001 and 110 surfaces of cubic crystals. AB - Criteria are reported here for the existence of supersonic surface acoustic waves (SSAW) on the (001) and (110) surfaces of cubic crystals. These are the common crystal cuts for which SSAW have been observed experimentally using surface Brillouin scattering and other techniques. Two categories of SSAW are distinguished. Symmetry protected SSAW exist by virtue of being located in high symmetry crystallographic directions for which the coupling to the phase matched bulk wave, which would otherwise result in their attenuation, is suppressed by symmetry. Secluded SSAW occur in lower-symmetry directions, where the reason for the vanishing of their coupling to their phase matched bulk wave is less evident. The stability domain for the elastic constant ratios a=C11/C44 and b=C12/C44 is subdivided into a number of regions in which various symmetry protected and secluded SSAW exist. Some of the boundaries between these regions are expressible in analytical form, others have been established purely numerically. PMID- 26627768 TI - Efficient localization and spectral estimation of an unknown number of ocean acoustic sources using a graphics processing unit. AB - This paper develops a matched-field approach to localization and spectral estimation of an unknown number of ocean acoustic sources employing massively parallel implementation on a graphics processing unit (GPU) for real-time efficiency. A Bayesian formulation is developed in which the locations and complex spectra of multiple sources and noise variances are considered unknown random variables, and the Bayesian information criterion is minimized to estimate these parameters, as well as the number of sources present. Optimization is carried out using simulated annealing and includes steps that attempt to add/delete sources to/from the model. Closed-form maximum-likelihood (ML) solutions for source spectra and noise variances in terms of the source locations allow these parameters to be sampled implicitly, substantially reducing the dimensionality of the inversion. Source sampling, addition, and deletion are based on joint conditional probability distributions for source range and depth, which incorporate the ML spectral estimates. Computing these conditionals requires solving a very large number of systems of equations, which is carried out in parallel on a GPU, improving efficiency by 2 orders of magnitude. Simulated examples illustrate localizations and spectral estimation for a large number of sources (up to eight), and investigate mitigation of environmental mismatch via efficient multiple-frequency inversion. PMID- 26627771 TI - A study of sound transmission in an abstract middle ear using physical and finite element models. AB - The classical picture of middle ear (ME) transmission has the tympanic membrane (TM) as a piston and the ME cavity as a vacuum. In reality, the TM moves in a complex multiphasic pattern and substantial pressure is radiated into the ME cavity by the motion of the TM. This study explores ME transmission with a simple model, using a tube terminated with a plastic membrane. Membrane motion was measured with a laser interferometer and pressure on both sides of the membrane with micro-sensors that could be positioned close to the membrane without disturbance. A finite element model of the system explored the experimental results. Both experimental and theoretical results show resonances that are in some cases primarily acoustical or mechanical and sometimes produced by coupled acousto-mechanics. The largest membrane motions were a result of the membrane's mechanical resonances. At these resonant frequencies, sound transmission through the system was larger with the membrane in place than it was when the membrane was absent. PMID- 26627769 TI - An analysis of cochlear response harmonics: Contribution of neural excitation. AB - In this report an analysis of cochlear response harmonics is developed to derive a mathematical function to estimate the gross mechanics involved in the in vivo transfer of acoustic sound into neural excitation (f(Tr)). In a simulation it is shown that the harmonic distortion from a nonlinear system can be used to estimate the nonlinearity, supporting the next phase of the experiment: Applying the harmonic analysis to physiologic measurements to derive estimates of the unknown, in vivo f(Tr). From gerbil ears, estimates of f(Tr) were derived from cochlear response measurements made with an electrode at the round window niche from 85 Hz tone bursts. Estimates of f(Tr) before and after inducing auditory neuropathy-loss of auditory nerve responses with preserved hair cell responses from neurotoxic treatment with ouabain-showed that the neural excitation from low frequency tones contributes to the magnitude of f(Tr) but not the sigmoidal, saturating, nonlinear morphology. PMID- 26627772 TI - An analysis of control using the weighted sum of spatial gradients in active structural acoustic control for flat panels. AB - Active structural acoustic control uses a control metric that when minimized reduces the radiated sound. Previous research has identified the weighted sum of spatial gradients (WSSG) control metric and has shown that it is effective in attenuating the radiated sound power from a plate. The WSSG control metric is computed using weighted measurements of the structural response from four closely spaced accelerometers. In this work, it is shown that the weights used to compute WSSG directly impact the control performance and further understanding into choosing appropriate weights is presented. Weights optimized for single frequencies are investigated and shown to achieve nearly the same performance as minimizing sound power. A set of parameter-based weights for broadband frequency control is also proposed and analyzed. These parameter-based weights are inversely proportional to the square of the flexural wavenumber and can be computed using the ratio of the flexural rigidity to the mass per unit area. Both numerical and experimental results are presented using parameter-based weights for simply supported and clamped plates. The results show that the WSSG control using parameter-based weights is easy to implement and works more effectively than previous methods. PMID- 26627773 TI - Theory and investigation of acoustic multiple-input multiple-output systems based on spherical arrays in a room. AB - Spatial attributes of room acoustics have been widely studied using microphone and loudspeaker arrays. However, systems that combine both arrays, referred to as multiple-input multiple-output (MIMO) systems, have only been studied to a limited degree in this context. These systems can potentially provide a powerful tool for room acoustics analysis due to the ability to simultaneously control both arrays. This paper offers a theoretical framework for the spatial analysis of enclosed sound fields using a MIMO system comprising spherical loudspeaker and microphone arrays. A system transfer function is formulated in matrix form for free-field conditions, and its properties are studied using tools from linear algebra. The system is shown to have unit-rank, regardless of the array types, and its singular vectors are related to the directions of arrival and radiation at the microphone and loudspeaker arrays, respectively. The formulation is then generalized to apply to rooms, using an image source method. In this case, the rank of the system is related to the number of significant reflections. The paper ends with simulation studies, which support the developed theory, and with an extensive reflection analysis of a room impulse response, using the platform of a MIMO system. PMID- 26627774 TI - Localization of acoustic sensors from passive Green's function estimation. AB - A number of methods have recently been developed for passive localization of acoustic sensors, based on the assumption that the acoustic field is diffuse. This article presents the more general case of equipartition fields, which takes into account reflections off boundaries and/or scatterers. After a thorough discussion on the fundamental differences between the diffuse and equipartition models, it is shown that the method is more robust when dealing with wideband noise sources. Finally, experimental results show, for two types of boundary conditions, that this approach is especially relevant when acoustic sensors are close to boundaries. PMID- 26627775 TI - Interactions between landscape elements and tranquility evaluation based on eye tracking experiments (L). AB - Visual attention in tranquility evaluations has been examined by eye tracking experiments using audiovisual materials collected in traditional villages of China. The results show that without sound stimuli, the attention areas in tranquility evaluations are more concentrated, compared with those in visual aesthetic quality evaluations. With sound stimuli, the attention areas of tranquility evaluations disperse significantly from those without sound stimuli, where artificial sounds tend to expand the visual attention area on corresponding artificial landscape elements, whereas natural sounds promote larger attention areas on natural landscape elements. During information extraction for tranquility evaluations, both with and without sound stimuli, buildings and facilities, the sky, and vegetation are attractive landscape elements. PMID- 26627776 TI - Talker information influences spectral contrast effects in speech categorization. AB - Spectral contrast effects, the perceptual magnification of spectral differences between sounds, have been widely shown to influence speech categorization. However, whether talker information alters spectral contrast effects was recently debated [Laing, Liu, Lotto, and Holt, Front. Psychol. 3, 1-9 (2012)]. Here, contributions of reliable spectral properties, between-talker and within-talker variability to spectral contrast effects in vowel categorization were investigated. Listeners heard sentences in three conditions (One Talker/One Sentence, One Talker/200 Sentences, 200 Talkers/200 Sentences) followed by a target vowel (varying from /i/-/E/ in F1, spoken by a single talker). Low-F1 or high-F1 frequency regions in the sentences were amplified to encourage /E/ or /i/ responses, respectively. When sentences contained large reliable spectral peaks (+20 dB; experiment 1), all contrast effect magnitudes were comparable. Talker information did not alter contrast effects following large spectral peaks, which were likely attributed to an external source (e.g., communication channel) rather than talkers. When sentences contained modest reliable spectral peaks (+5 dB; experiment 2), contrast effects were smaller following 200 Talkers/200 Sentences compared to single-talker conditions. Constant recalibration to new talkers reduced listeners' sensitivity to modest spectral peaks, diminishing contrast effects. Results bridge conflicting reports of whether talker information influences spectral contrast effects in speech categorization. PMID- 26627777 TI - A parametric analysis of waves propagating in a porous solid saturated by a three phase fluid. AB - This paper presents an analysis of a model for the propagation of waves in a poroelastic solid saturated by a three-phase viscous, compressible fluid. The constitutive relations and the equations of motion are stated first. Then a plane wave analysis determines the phase velocities and attenuation coefficients of the four compressional waves and one shear wave that propagate in this type of medium. A procedure to compute the elastic constants in the constitutive relations is defined next. Assuming the knowledge of the shear modulus of the dry matrix, the other elastic constants in the stress-strain relations are determined by employing ideal gedanken experiments generalizing those of Biot's theory for single-phase fluids. These experiments yield expressions for the elastic constants in terms of the properties of the individual solid and fluids phases. Finally the phase velocities and attenuation coefficients of all waves are computed for a sample of Berea sandstone saturated by oil, gas, and water. PMID- 26627778 TI - Similarity and pleasantness assessments of water-fountain sounds recorded in urban public spaces. AB - Water fountains are potential tools for soundscape improvement, but little is known about their perceptual properties. To explore this, sounds were recorded from 32 fountains installed in urban parks. The sounds were recorded with a sound field microphone and were reproduced using an ambisonic loudspeaker setup. Fifty seven listeners assessed the sounds with regard to similarity and pleasantness. Multidimensional scaling of similarity data revealed distinct groups of soft variable and loud steady-state sounds. Acoustically, the soft variable sounds were characterized by low overall levels and high temporal variability, whereas the opposite pattern characterized the loud steady-state sounds. The perceived pleasantness of the sounds was negatively related to their overall level and positively related to their temporal variability, whereas spectral centroid was weakly correlated to pleasantness. However, the results of an additional experiment, using the same sounds set equal in overall level, found a negative relationship between pleasantness and spectral centroid, suggesting that spectral factors may influence pleasantness scores in experiments where overall level does not dominate pleasantness assessments. The equal-level experiment also showed that several loud steady-state sounds remained unpleasant, suggesting an inherently unpleasant sound character. From a soundscape design perspective, it may be advisable to avoid fountains generating such sounds. PMID- 26627779 TI - Direction-of-arrival estimation of passive acoustic sources in reverberant environments based on the Householder transformation. AB - This paper presents an approach to the direction-of-arrival (DOA) estimation problem in acoustic environments using microphone arrays. It works in the short time Fourier transform (STFT) domain. It first transforms the noisy speech signals received at the array into the STFT domain. A Householder transformation is then constructed and applied to the multichannel STFT coefficients in each subband. This transformation converts the multichannel STFT coefficients into two components: one is a single coefficient that is dominated by the signal of interest and the other consists of the M - 1 coefficient that is dominated by noise (or even consists of noise-only if there is no reverberation), where M is the number of sensors. A cost function is then formed from the outputs of the Householder transformation and the DOA information can subsequently be obtained by searching the extremum value of this cost function in the angle range between 0 degrees and 180 degrees . Simulation results are provided to illustrate the performance of this approach. PMID- 26627781 TI - A hybrid approach for simulating fluid loading effects on structures using experimental modal analysis and the boundary element method. AB - Many structural acoustics problems involve a vibrating structure in a heavy fluid. However, obtaining fluid-loaded natural frequencies and damping experimentally can be difficult and expensive. This paper presents a hybrid experimental-numerical approach to determine the heavy-fluid-loaded resonance frequencies and damping of a structure from in-air measurements. The approach combines in-air experimentally obtained mode shapes with simulated in-water acoustic resistance and reactance matrices computed using boundary element (BE) analysis. The procedure relies on accurate estimates of the mass-normalized, in vacuo mode shapes using singular value decomposition and rational fraction polynomial fitting, which are then used as basis modes for the in-water BE analysis. The method is validated on a 4.445 cm (1.75 in.) thick nickel-aluminum bronze rectangular plate by comparing natural frequencies and damping obtained using the hybrid approach to equivalent data obtained from actual in-water measurements. Good agreement is shown for the fluid-loaded natural frequencies and one-third octave loss factors. Finally, the limitations of the hybrid approach are examined. PMID- 26627780 TI - Neural-scaled entropy predicts the effects of nonlinear frequency compression on speech perception. AB - The Neural-Scaled Entropy (NSE) model quantifies information in the speech signal that has been altered beyond simple gain adjustments by sensorineural hearing loss (SNHL) and various signal processing. An extension of Cochlear-Scaled Entropy (CSE) [Stilp, Kiefte, Alexander, and Kluender (2010). J. Acoust. Soc. Am. 128(4), 2112-2126], NSE quantifies information as the change in 1-ms neural firing patterns across frequency. To evaluate the model, data from a study that examined nonlinear frequency compression (NFC) in listeners with SNHL were used because NFC can recode the same input information in multiple ways in the output, resulting in different outcomes for different speech classes. Overall, predictions were more accurate for NSE than CSE. The NSE model accurately described the observed degradation in recognition, and lack thereof, for consonants in a vowel-consonant-vowel context that had been processed in different ways by NFC. While NSE accurately predicted recognition of vowel stimuli processed with NFC, it underestimated them relative to a low-pass control condition without NFC. In addition, without modifications, it could not predict the observed improvement in recognition for word final /s/ and /z/. Findings suggest that model modifications that include information from slower modulations might improve predictions across a wider variety of conditions. PMID- 26627782 TI - Theory and design of compact hybrid microphone arrays on two-dimensional planes for three-dimensional soundfield analysis. AB - Soundfield analysis based on spherical harmonic decomposition has been widely used in various applications; however, a drawback is the three-dimensional geometry of the microphone arrays. In this paper, a method to design two dimensional planar microphone arrays that are capable of capturing three dimensional (3D) spatial soundfields is proposed. Through the utilization of both omni-directional and first order microphones, the proposed microphone array is capable of measuring soundfield components that are undetectable to conventional planar omni-directional microphone arrays, thus providing the same functionality as 3D arrays designed for the same purpose. Simulations show that the accuracy of the planar microphone array is comparable to traditional spherical microphone arrays. Due to its compact shape, the proposed microphone array greatly increases the feasibility of 3D soundfield analysis techniques in real-world applications. PMID- 26627784 TI - Automated detection of Antarctic blue whale calls. AB - This paper addresses the problem of automated detection of Z-calls emitted by Antarctic blue whales (B. m. intermedia). The proposed solution is based on a subspace detector of sigmoidal-frequency signals with unknown time-varying amplitude. This detection strategy takes into account frequency variations of blue whale calls as well as the presence of other transient sounds that can interfere with Z-calls (such as airguns or other whale calls). The proposed method has been tested on more than 105 h of acoustic data containing about 2200 Z-calls (as found by an experienced human operator). This method is shown to have a correct-detection rate of up to more than 15% better than the extensible bioacoustic tool package, a spectrogram-based correlation detector commonly used to study blue whales. Because the proposed method relies on subspace detection, it does not suffer from some drawbacks of correlation-based detectors. In particular, it does not require the choice of an a priori fixed and subjective template. The analytic expression of the detection performance is also derived, which provides crucial information for higher level analyses such as animal density estimation from acoustic data. Finally, the detection threshold automatically adapts to the soundscape in order not to violate a user-specified false alarm rate. PMID- 26627785 TI - Optimization of the directivity in binaural sound reproduction beamforming. AB - Microphone arrays usually combine multiple input signals into one output signal, such that spatial information on the sound sources is not included in the output signal. Since spatial information on the sound sources may increase the intelligibility of a speech signal that is perceived by a human listener, recent works aim to include this spatial information in the output of the microphone array by utilizing binaural cues preservation. More current works apply binaural sound reproduction (BSR) using spherical microphone arrays by incorporating the head related transfer functions (HRTFs) in the weight function of a conventional maximum-directivity beamformer. However, the HRTFs may affect the optimality of beamformers that were already designed to provide a maximal directivity without the HRTFs. This work presents a more general mathematical framework than previously presented for the incorporation of HRTFs in the weight function, which allows the optimization of the weight function using an averaged maximum directivity criterion under the condition that the HRTFs are already incorporated. It is shown that the proposed optimized BSR beamformer achieves higher directivity index. PMID- 26627783 TI - Using individual differences to test the role of temporal and place cues in coding frequency modulation. AB - The question of how frequency is coded in the peripheral auditory system remains unresolved. Previous research has suggested that slow rates of frequency modulation (FM) of a low carrier frequency may be coded via phase-locked temporal information in the auditory nerve, whereas FM at higher rates and/or high carrier frequencies may be coded via a rate-place (tonotopic) code. This hypothesis was tested in a cohort of 100 young normal-hearing listeners by comparing individual sensitivity to slow-rate (1-Hz) and fast-rate (20-Hz) FM at a carrier frequency of 500 Hz with independent measures of phase-locking (using dynamic interaural time difference, ITD, discrimination), level coding (using amplitude modulation, AM, detection), and frequency selectivity (using forward-masking patterns). All FM and AM thresholds were highly correlated with each other. However, no evidence was obtained for stronger correlations between measures thought to reflect phase locking (e.g., slow-rate FM and ITD sensitivity), or between measures thought to reflect tonotopic coding (fast-rate FM and forward-masking patterns). The results suggest that either psychoacoustic performance in young normal-hearing listeners is not limited by peripheral coding, or that similar peripheral mechanisms limit both high- and low-rate FM coding. PMID- 26627786 TI - Acoustic property reconstruction of a pygmy sperm whale (Kogia breviceps) forehead based on computed tomography imaging. AB - Computed tomography (CT) imaging and sound experimental measurements were used to reconstruct the acoustic properties (density, velocity, and impedance) of the forehead tissues of a deceased pygmy sperm whale (Kogia breviceps). The forehead was segmented along the body axis and sectioned into cross section slices, which were further cut into sample pieces for measurements. Hounsfield units (HUs) of the corresponding measured pieces were obtained from CT scans, and regression analyses were conducted to investigate the linear relationships between the tissues' HUs and velocity, and HUs and density. The distributions of the acoustic properties of the head at axial, coronal, and sagittal cross sections were reconstructed, revealing that the nasal passage system was asymmetric and the cornucopia-shaped spermaceti organ was in the right nasal passage, surrounded by tissues and airsacs. A distinct dense theca was discovered in the posterior dorsal area of the melon, which was characterized by low velocity in the inner core and high velocity in the outer region. Statistical analyses revealed significant differences in density, velocity, and acoustic impedance between all four structures, melon, spermaceti organ, muscle, and connective tissue (p < 0.001). The obtained acoustic properties of the forehead tissues provide important information for understanding the species' bioacoustic characteristics. PMID- 26627787 TI - Performance and strategy comparisons of human listeners and logistic regression in discriminating underwater targets. AB - To improve the design of underwater target recognition systems based on auditory perception, this study compared human listeners with automatic classifiers. Performances measures and strategies in three discrimination experiments, including discriminations between man-made and natural targets, between ships and submarines, and among three types of ships, were used. In the experiments, the subjects were asked to assign a score to each sound based on how confident they were about the category to which it belonged, and logistic regression, which represents linear discriminative models, also completed three similar tasks by utilizing many auditory features. The results indicated that the performances of logistic regression improved as the ratio between inter- and intra-class differences became larger, whereas the performances of the human subjects were limited by their unfamiliarity with the targets. Logistic regression performed better than the human subjects in all tasks but the discrimination between man made and natural targets, and the strategies employed by excellent human subjects were similar to that of logistic regression. Logistic regression and several human subjects demonstrated similar performances when discriminating man-made and natural targets, but in this case, their strategies were not similar. An appropriate fusion of their strategies led to further improvement in recognition accuracy. PMID- 26627788 TI - Investigation of auditory distance perception and preferences in concert halls by using virtual acoustics. AB - Virtual acoustics with multichannel sound reproduction was used to study auditory distance perception in four concert halls with multiple sound sources on stage. Eight subjects reported apparent auditory distances in five seating positions from 10 to 26 m to the middle of the sources on stage. The distance estimates were collected by absolute distance estimation procedure as well as a free modulus estimation procedure including both within and between halls evaluations. In addition, pairwise preferences were collected for two positions within each hall and for one position between halls. Results reveal that the perception of distance is dependent on the hall acoustics and show how the strength factor G and direct-to-reverberant energy ratio covary in relation to perceptual distances in these halls. The results also indicate that in such large spaces the overestimation of short distances may continue up to and further than 10 m from the sound sources. Preference results show that closer seats were liked more than further ones and that the strength of this preference is associated with the difference in perceptual distances. PMID- 26627789 TI - Reconstruction of an acoustic pressure field in a resonance tube by particle image velocimetry. AB - A technique for estimating an acoustic field in a resonance tube is suggested. The estimation of an acoustic field in a resonance tube is important for the development of the thermoacoustic engine, and can be conducted employing two sensors to measure pressure. While this measurement technique is known as the two sensor method, care needs to be taken with the location of pressure sensors when conducting pressure measurements. In the present study, particle image velocimetry (PIV) is employed instead of a pressure measurement by a sensor, and two-dimensional velocity vector images are extracted as sequential data from only a one- time recording made by a video camera of PIV. The spatial velocity amplitude is obtained from those images, and a pressure distribution is calculated from velocity amplitudes at two points by extending the equations derived for the two-sensor method. By means of this method, problems relating to the locations and calibrations of multiple pressure sensors are avoided. Furthermore, to verify the accuracy of the present method, the experiments are conducted employing the conventional two-sensor method and laser Doppler velocimetry (LDV). Then, results by the proposed method are compared with those obtained with the two-sensor method and LDV. PMID- 26627790 TI - Viscous-to-viscoelastic transition in phononic crystal and metamaterial band structures. AB - The dispersive behavior of phononic crystals and locally resonant metamaterials is influenced by the type and degree of damping in the unit cell. Dissipation arising from viscoelastic damping is influenced by the past history of motion because the elastic component of the damping mechanism adds a storage capacity. Following a state-space framework, a Bloch eigenvalue problem incorporating general viscoelastic damping based on the Zener model is constructed. In this approach, the conventional Kelvin-Voigt viscous-damping model is recovered as a special case. In a continuous fashion, the influence of the elastic component of the damping mechanism on the band structure of both a phononic crystal and a metamaterial is examined. While viscous damping generally narrows a band gap, the hereditary nature of the viscoelastic conditions reverses this behavior. In the limit of vanishing heredity, the transition between the two regimes is analyzed. The presented theory also allows increases in modal dissipation enhancement (metadamping) to be quantified as the type of damping transitions from viscoelastic to viscous. In conclusion, it is shown that engineering the dissipation allows one to control the dispersion (large versus small band gaps) and, conversely, engineering the dispersion affects the degree of dissipation (high or low metadamping). PMID- 26627791 TI - A noise delivery system for multi-animal multi-level whole body ototoxicity studies. AB - The Naval Medical Research Unit Dayton (NAMRU-D) at Wright-Patterson Air Force Base, Ohio, in conjunction with the U.S. Air Force, studied ototoxic effects of JP-8 in rats. NAMRU-D used a multi-chamber whole body exposure facility for up to 96 test animals and 32 control animals at different exposure levels. The objective was to design a noise delivery system that could provide a white noise source one octave band wide, centered at 8 kHz frequency, delivered from outside the exposure chambers. Sound pressure levels were required to be within +/-2 dB at all exposure points within each chamber and within +/-2 dB over a 6-h run. Electrodynamic shakers were used to produce input noise in exposure chambers by inducing vibration in chamber plenums. Distribution of sound pressure levels across exposure points was controlled within a +/-1.5dB prediction interval (alpha = 0.05) or better. Stability at a central reference point was controlled over 6-h runs within a +/-1 dB prediction interval (alpha = 0.05) or better. The final system allowed NAMRU-D to deliver noise and whole-body aerosol exposures to multiple animals at different levels simultaneously and study the effects that ototoxins may have on hearing loss. PMID- 26627792 TI - Interplay of lancet furrows and shape change in the horseshoe bat noseleaf. AB - Horseshoe bats emit biosonar pulses through the nostrils and diffract the outgoing ultrasonic pulses with baffles, so-called "noseleaves," that surround the nostrils. The noseleaves have complex static geometries and can furthermore undergo dynamic shape changes during emission of the biosonar pulses. The posterior noseleaf part, the lancet, has been shown to carry out anterior posterior flicking motions during biosonar emissions with average lancet tip displacements of about 1 mm. Here, the acoustic effects of the interplay between the lancet furrows and shape change (lancet rotation) on the emission beam were investigated using the animated digital models obtained from the noseleaves of greater horseshoe bats (Rhinolophus ferrumequinum). It was found that forward lancet rotations increase the amount of sound energy allocated to secondary amplitude maxima (sidelobes) in the beampattern, but only in the presence of the furrows. The interaction between static and dynamic features can be readily quantified by roughness (standard deviation about local mean) of the amplitude distribution of the beampatterns. This effect goes beyond the static impact of the furrows on the width of the mainlobe. It could allow the bats to send out their pulses through a sequence of qualitatively different beampatterns. PMID- 26627793 TI - Effects of symmetrical foundation on sound radiation from a submarine hull structure. AB - The effects of a passive noise control method for suppressing sound radiation from a submarine hull structure are investigated. The control method is realized by symmetrizing the foundation about the horizontal plane. The coupled finite element method and boundary element method are adopted to compute the acoustic characteristics of the submerged hull. From the numerical results, the symmetrical foundation has advantages in sound radiation reduction when the hull is subjected to the axial load, but has little influences in the vertical and transverse load cases. Using the modal decomposition technique, the contributions of each individual mode to the sound radiation are analyzed to reveal the mechanism of the control method. PMID- 26627794 TI - Investigation of interfacial stiffnesses of a tri-layer using Zero-Group Velocity Lamb modes. AB - Zero-Group Velocity (ZGV) Lamb waves are studied in a structure composed of two plates bonded by an adhesive layer. The dispersion curves are calculated for a Duralumin/epoxy/Duralumin sample, where the adhesion is modeled by a normal and a tangential spring at both interfaces. Several ZGV modes are identified and their frequency dependence on interfacial stiffnesses and on the bonding layer thickness is numerically studied. Then, experiments achieved with laser ultrasonic techniques are presented. Local resonances are measured using a superimposed source and probe. Knowing the thicknesses and elastic constants of the Duralumin and epoxy layers, the comparison between theoretical and experimental ZGV resonances leads to an evaluation of the interfacial stiffnesses. A good agreement with theoretical dispersion curves confirms the identification of the resonances and the parameter estimations. This non-contact technique is promising for the local evaluation of bonded structures. PMID- 26627796 TI - Model-based waveform design for optimal detection: A multi-objective approach to dealing with incomplete a priori knowledge. AB - This work considers the design of optimal, energy-constrained transmit signals for active sensing for the case when the designer has incomplete or uncertain knowledge of the target and/or environment. The mathematical formulation is that of a multi-objective optimization problem, wherein one can incorporate a plurality of potential targets, interference, or clutter models and in doing so take advantage of the wide range of results in the literature related to modeling each. It is shown, via simulation, that when the objective function of the optimization problem is chosen to maximize the minimum (i.e., maxmin) probability of detection among all possible model combinations, the optimal waveforms obtained are advantageous. The advantage results because the maxmin waveforms judiciously allocate energy to spectral regions where each of the target models respond strongly and each of the environmental models affect minimal detection performance degradation. In particular, improved detection performance is shown compared to linear frequency modulated transmit signals and compared to signals designed with the wrong target spectrum assumed. Additionally, it is shown that the maxmin design yields performance comparable to an optimal design matched to the correct target/environmental model. Finally, it is proven that the maxmin problem formulation is convex. PMID- 26627795 TI - Tone-burst auditory brainstem response wave V latencies in normal-hearing and hearing-impaired ears. AB - The metric used to equate stimulus level [sound pressure level (SPL) or sensation level (SL)] between ears with normal hearing (NH) and ears with hearing loss (HL) in comparisons of auditory function can influence interpretation of results. When stimulus level is equated in dB SL, higher SPLs are presented to ears with HL due to their reduced sensitivity. As a result, it may be difficult to determine if differences between ears with NH and ears with HL are due to cochlear pathology or level-dependent changes in cochlear mechanics. To the extent that level dependent changes in cochlear mechanics contribute to auditory brainstem response latencies, comparisons between normal and pathologic ears may depend on the stimulus levels at which comparisons are made. To test this hypothesis, wave V latencies were measured in 16 NH ears and 15 ears with mild-to-moderate HL. When stimulus levels were equated in SL, latencies were shorter in HL ears. However, latencies were similar for NH and HL ears when stimulus levels were equated in SPL. These observations demonstrate that the effect of stimulus level on wave V latency is large relative to the effect of HL, at least in cases of mild-to moderate HL. PMID- 26627797 TI - Weakly nonlinear acoustic wave propagation in a nonlinear orthotropic circular cylindrical waveguide. AB - Nonlinear acoustic wave propagation is considered in an infinite orthotropic thin circular cylindrical waveguide. The modes are non-planar having small but finite amplitude. The fluid is assumed to be ideal and inviscid with no mean flow. The cylindrical waveguide is modeled using the Donnell's nonlinear theory for thin cylindrical shells. The approximate solutions for the acoustic velocity potential are found using the method of multiple scales (MMS) in space and time. The calculations are presented up to the third order of the small parameter. It is found that at some frequencies the amplitude modulation is governed by the Nonlinear Schrodinger Equation (NLSE). The first objective is to study the nonlinear term in the NLSE, as the sign of the nonlinear term determines the stability of the amplitude modulation. On the other hand, at other specific frequencies, interactions occur between the primary wave and its higher harmonics. Here, the objective is to identify the frequencies of the higher harmonic interactions. Lastly, the linear terms in the NLSE obtained using the MMS calculations are validated. All three objectives are met using an asymptotic analysis of the dispersion equation. PMID- 26627799 TI - Whistle characteristics of the spinner dolphin population in the Comoros Archipelago. AB - Observed variations in dolphin acoustic signals may be associated with behavior, social composition, and local differences in habitat features. This study aims at characterizing whistles emitted by the spinner dolphin population occurring in the waters of the main island of the Archipelago of Comoros (Mozambique Channel, Indian Ocean) and to assess factors possibly influencing the acoustic structure of signals. All parameters examined on 953 whistles significantly differed in relation to environmental conditions, group size, and behavior. By mixed model analysis, it was found that only habitat characteristics play a role in the variation of frequency parameters, and exerted on the acoustic structure of whistles stronger influence than socio-behavioral factors. Spinner dolphins occurring in the Comoros archipelago use higher frequencies and show longer signal duration compared to those from the Pacific and the Atlantic. Results suggest that frequency parameters are distinctive of the local population and reflect the habitat use of the species in the area. In conclusion, acoustic measurements may be crucial elements to be included in monitoring programs to identify local peculiarities of dolphins' populations. PMID- 26627798 TI - The effects of ipsilateral, contralateral, and bilateral broadband noise on the mid-level hump in intensity discrimination. AB - Previous psychoacoustical and physiological studies indicate that the medial olivocochlear reflex (MOCR), a bilateral, sound-evoked reflex, may lead to improved sound intensity discrimination in background noise. The MOCR can decrease the range of basilar-membrane compression and can counteract effects of neural adaptation from background noise. However, the contribution of these processes to intensity discrimination is not well understood. This study examined the effect of ipsilateral, contralateral, and bilateral noise on the "mid-level hump." The mid-level hump refers to intensity discrimination Weber fractions (WFs) measured for short-duration, high-frequency tones which are poorer at mid levels than at lower or higher levels. The mid-level hump WFs may reflect a limitation due to basilar-membrane compression, and thus may be decreased by the MOCR. The noise was either short (50 ms) or long (150 ms), with the long noise intended to elicit the sluggish MOCR. For a tone in quiet, mid-level hump WFs improved with ipsilateral noise for most listeners, but not with contralateral noise. For a tone in ipsilateral noise, WFs improved with contralateral noise for most listeners, but only when both noises were long. These results are consistent with MOCR-induced WF improvements, possibly via decreases in effects of compression and neural adaptation. PMID- 26627800 TI - The Uniform geometrical Theory of Diffraction for elastodynamics: Plane wave scattering from a half-plane. AB - Diffraction phenomena studied in electromagnetism, acoustics, and elastodynamics are often modeled using integrals, such as the well-known Sommerfeld integral. The far field asymptotic evaluation of such integrals obtained using the method of steepest descent leads to the classical Geometrical Theory of Diffraction (GTD). It is well known that the method of steepest descent is inapplicable when the integrand's stationary phase point coalesces with its pole, explaining why GTD fails in zones where edge diffracted waves interfere with incident or reflected waves. To overcome this drawback, the Uniform geometrical Theory of Diffraction (UTD) has been developed previously in electromagnetism, based on a ray theory, which is particularly easy to implement. In this paper, UTD is developed for the canonical elastodynamic problem of the scattering of a plane wave by a half-plane. UTD is then compared to another uniform extension of GTD, the Uniform Asymptotic Theory (UAT) of diffraction, based on a more cumbersome ray theory. A good agreement between the two methods is obtained in the far field. PMID- 26627801 TI - Linear-response reflection coefficient of the recorder air-jet amplifier. AB - In a duct-flute such as the recorder, steady-state oscillations are controlled by two parameters, the blowing pressure and the frequency of the acoustic resonator. As in most feedback oscillators, the oscillation amplitude is determined by gain saturation of the amplifier, and thus it cannot be controlled independently of blowing pressure and frequency unless the feedback loop is opened. In this work, the loop is opened by replacing the recorder body with a waveguide reflectometer: a section of transmission line with microphones, a signal source, and an absorbing termination. When the mean flow from the air-jet into the transmission line is not blocked, the air-jet amplifier is unstable to edge-tone oscillations through a feedback path that does not involve the acoustic resonator. When it is blocked, the air-jet is deflected somewhat outward and the system becomes stable. It is then possible to measure the reflection coefficient of the air-jet amplifier versus blowing pressure and acoustic frequency under linear response conditions, avoiding the complication of gain-saturation. The results provide a revealing test of flute drive models under the simplest conditions and with few unknown parameters. The strengths and weaknesses of flute drive models are discussed. PMID- 26627802 TI - Judging sound rotation when listeners and sounds rotate: Sound source localization is a multisystem process. AB - In four experiments listeners were rotated or were stationary. Sounds came from a stationary loudspeaker or rotated from loudspeaker to loudspeaker around an azimuth array. When either sounds or listeners rotate the auditory cues used for sound source localization change, but in the everyday world listeners perceive sound rotation only when sounds rotate not when listeners rotate. In the everyday world sound source locations are referenced to positions in the environment (a world-centric reference system). The auditory cues for sound source location indicate locations relative to the head (a head-centric reference system), not locations relative to the world. This paper deals with a general hypothesis that the world-centric location of sound sources requires the auditory system to have information about auditory cues used for sound source location and cues about head position. The use of visual and vestibular information in determining rotating head position in sound rotation perception was investigated. The experiments show that sound rotation perception when sources and listeners rotate was based on acoustic, visual, and, perhaps, vestibular information. The findings are consistent with the general hypotheses and suggest that sound source localization is not based just on acoustics. It is a multisystem process. PMID- 26627805 TI - Solving the hypersingular boundary integral equation for the Burton and Miller formulation. AB - This paper presents an easy numerical implementation of the Burton and Miller (BM) formulation, where the hypersingular Helmholtz integral is regularized by identities from the associated Laplace equation and thus needing only the evaluation of weakly singular integrals. The Helmholtz equation and its normal derivative are combined directly with combinations at edge or corner collocation nodes not used when the surface is not smooth. The hypersingular operators arising in this process are regularized and then evaluated by an indirect procedure based on discretized versions of the Calderon identities linking the integral operators for associated Laplace problems. The method is valid for acoustic radiation and scattering problems involving arbitrarily shaped three dimensional bodies. Unlike other approaches using direct evaluation of hypersingular integrals, collocation points still coincide with mesh nodes, as is usual when using conforming elements. Using higher-order shape functions (with the boundary element method model size kept fixed) reduces the overall numerical integration effort while increasing the solution accuracy. To reduce the condition number of the resulting BM formulation at low frequencies, a regularized version alpha = ik/(k(2 )+ lambda) of the classical BM coupling factor alpha = i/k is proposed. Comparisons with the combined Helmholtz integral equation Formulation method of Schenck are made for four example configurations, two of them featuring non-smooth surfaces. PMID- 26627804 TI - Speech perception at positive signal-to-noise ratios using adaptive adjustment of time compression. AB - Positive signal-to-noise ratios (SNRs) characterize listening situations most relevant for hearing-impaired listeners in daily life and should therefore be considered when evaluating hearing aid algorithms. For this, a speech-in-noise test was developed and evaluated, in which the background noise is presented at fixed positive SNRs and the speech rate (i.e., the time compression of the speech material) is adaptively adjusted. In total, 29 younger and 12 older normal hearing, as well as 24 older hearing-impaired listeners took part in repeated measurements. Younger normal-hearing and older hearing-impaired listeners conducted one of two adaptive methods which differed in adaptive procedure and step size. Analysis of the measurements with regard to list length and estimation strategy for thresholds resulted in a practical method measuring the time compression for 50% recognition. This method uses time-compression adjustment and step sizes according to Versfeld and Dreschler [(2002). J. Acoust. Soc. Am. 111, 401-408], with sentence scoring, lists of 30 sentences, and a maximum likelihood method for threshold estimation. Evaluation of the procedure showed that older participants obtained higher test-retest reliability compared to younger participants. Depending on the group of listeners, one or two lists are required for training prior to data collection. PMID- 26627803 TI - Effect of audibility on spatial release from speech-on-speech masking. AB - This study investigated to what extent spatial release from masking (SRM) deficits in hearing-impaired adults may be related to reduced audibility of the test stimuli. Sixteen adults with sensorineural hearing loss and 28 adults with normal hearing were assessed on the Listening in Spatialized Noise-Sentences test, which measures SRM using a symmetric speech-on-speech masking task. Stimuli for the hearing-impaired listeners were delivered using three amplification levels (National Acoustic Laboratories - Revised Profound prescription (NAL-RP) +25%, and NAL-RP +50%), while stimuli for the normal-hearing group were filtered to achieve matched audibility. SRM increased as audibility increased for all participants. Thus, it is concluded that reduced audibility of stimuli may be a significant factor in hearing-impaired adults' reduced SRM even when hearing loss is compensated for with linear gain. However, the SRM achieved by the normal hearers with simulated audibility loss was still significantly greater than that achieved by hearing-impaired listeners, suggesting other factors besides audibility may still play a role. PMID- 26627806 TI - Adaptive reverberation noise delay estimation for reverberation suppression in dual band ultrasound imaging. AB - The behavior of the propagation delays introduced in dual frequency band ultrasound imaging is discussed. In particular, the delay of reverberation noise components is examined. Using a delay corrected subtraction (DCS) method, it is possible to suppress the reverberation noise if the behavior of the propagation delays is known. Here, a signal adaptive estimation for the reverberation delay is introduced and applied through DCS to suppress reverberation noise in a numerically simulated signal. The reverberation reduction is compared to DCS suppression using a simpler delay estimation and shows that a signal based adaptive estimation yields a improved suppression of reverberation noise. The study indicates that the advantage of the adaptive estimation is highest when the medium has changing nonlinearity with depth. PMID- 26627808 TI - Humpback whale (Megaptera novaeangliae) song unit and phrase repertoire progression on a subarctic feeding ground. AB - The songs of the male humpback whales have traditionally been associated with breeding activities at low latitude breeding grounds during winter. This study provides the first detailed analysis of humpback whale songs recorded in the subarctic waters of Iceland using passive acoustic recorders. Recordings were collected during three winter seasons: 2008-2009, 2009-2010, and 2011 during which singing was detected in all seasons. Peak song occurrence was during January-February in all years; this coincides with the timing of the peak breeding season of humpback whales in the Northern hemisphere. A total of 2810 song units from all years were measured and statistically divided into 14 groups, which constructed 25 phrases. The song unit repertoires included stable song unit types that occurred frequently in songs during all years while the occurrence of other song unit types varied more between years. Around 60% of the phrases were conserved between the first two study seasons, while the majority of phrases found during the last study season had not been observed before. This study indicates the importance of a subarctic feeding ground for song progression and song exchange and possibly as an opportunistic mating ground for migrating or overwintering humpback whales. PMID- 26627809 TI - Using redundancy of round-trip ultrasound signal for non-continuous arrays: Application to gap and blockage compensation. AB - In ultrasound imaging, an array of elements is used to image a medium. If part of the array is blocked by an obstacle, or if the array is made from several sub arrays separated by a gap, grating lobes appear and the image is degraded. The grating lobes are caused by missing spatial frequencies, corresponding to the blocked or non-existing elements. However, in an active imaging system, where elements are used both for transmitting and receiving, the round trip signal is redundant: different pairs of transmit and receive elements carry similar information. It is shown here that, if the gaps are smaller than the active sub apertures, this redundancy can be used to compensate for the missing signals and recover full resolution. Three algorithms are proposed: one is based on a synthetic aperture method, a second one uses dual-apodization beamforming, and the third one is a radio frequency (RF) data based deconvolution. The algorithms are evaluated on simulated and experimental data sets. An application could be imaging through ribs with a large aperture. PMID- 26627810 TI - A two-way coupled mode formalism that satisfies energy conservation for impedance boundaries in underwater acoustics. AB - This paper shows that energy conservation and the derivation of the two-way coupled mode range equations can be extended in three dimensions to complex mode functions and eigenvalues. Furthermore, the energy in the coupled mode formulation is conserved for finite thickness fluid ocean waveguides with a penetrable bottom boundary beneath any range dependence. The derivations rely on completeness and a modified orthonormality statement. The mode coupling coefficients are specified solely and explicitly by the waveguide range dependence. The statement of energy conservation is applied to a numerical coupled mode calculation. PMID- 26627811 TI - The ambient acoustic environment in Laguna San Ignacio, Baja California Sur, Mexico. AB - Each winter gray whales (Eschrichtius robustus) breed and calve in Laguna San Ignacio, Mexico, where a robust, yet regulated, whale-watching industry exists. Baseline acoustic environments in LSI's three zones were monitored between 2008 and 2013, in anticipation of a new road being paved that will potentially increase tourist activity to this relatively isolated location. These zones differ in levels of both gray whale usage and tourist activity. Ambient sound level distributions were computed in terms of percentiles of power spectral densities. While these distributions are consistent across years within each zone, inter-zone differences are substantial. The acoustic environment in the upper zone is dominated by snapping shrimp that display a crepuscular cycle. Snapping shrimp also affect the middle zone, but tourist boat transits contribute to noise distributions during daylight hours. The lower zone has three source contributors to its acoustic environment: snapping shrimp, boats, and croaker fish. As suggested from earlier studies, a 300 Hz noise minimum exists in both the middle and lower zones of the lagoon, but not in the upper zone. PMID- 26627812 TI - Extensional-wave stopband broadening across the joint of pipes of different thickness. AB - The stopband of pipe extensional waves is an interesting natural phenomenon. This study demonstrates an important extension of this phenomenon. That is, the stopband can be effectively broadened by transmitting the waves across the joint of pipes of different thickness. The theoretical and experimental results reveal the detailed process of stopband forming along the pipe and the band broadening across the pipe joint. The result can be utilized to provide a method for logging while drilling acoustic isolation design. PMID- 26627813 TI - Low frequency, ca. 40 Hz, pulse trains recorded in the humpback whale assembly in Hawaii. AB - During studies of humpback whale song and social sounds in Hawaii, bouts of low frequency (ca. 40 Hz) pulses were periodically recorded. One example was made near an active group of eight adults (included 22 bouts, 2-13 s long, over 90 min); another close to an adult male-female pair (12 bouts, 9-93 s long, over 22 min). The mean peak and center frequencies (39 to 40 Hz) and bandwidth (13 Hz) were similar in both, but the organization of the pulses differed. Song components, social sounds, bubble trains, or other species do not provide a ready explanation for this sound. PMID- 26627814 TI - Level considerations for chimeric processing: Temporal envelope and fine structure contributions to speech intelligibility. AB - Chimeric processing is used to assess the respective role of the acoustic temporal envelope (ENV) and the temporal fine structure (TFS) by adding noise to either component. An acoustic analysis demonstrates that adding noise to the ENV results in noise degradation of the ENV and overall signal attenuation, whereas adding noise to the TFS results in only noise degradation of the TFS. Young normal hearing adults were then tested using a modified chimeric strategy to maintain speech levels. Results partially confirm the primary role of the ENV in determining speech intelligibility but demonstrate significant TFS contributions during selective ENV masking. PMID- 26627815 TI - Spectro-temporal modulation detection in children. AB - Children's performance on psychophysical tasks improves with age. The relationship of spectro-temporal modulation detection to age, particularly in children who are hard of hearing, is not well-established. In this study, children with normal hearing (N = 22) and with sensorineural hearing loss (N = 15) completed measures of spectro-temporal modulation detection. Measures of aided audibility were completed in the children who are hard of hearing. Pearson product-moment correlations were completed with listener age and aided audibility as parameters. Spectro-temporal modulation detection performance increased with listener age and with greater aided audibility. PMID- 26627816 TI - Accuracy of a bistatic scattering substitution technique for calibration of focused receivers. AB - A recent method for calibrating single-element, focused passive cavitation detectors (PCD) compares bistatic scattering measurements by the PCD and a reference hydrophone. Here, effects of scatterer properties and PCD size on frequency-dependent receive calibration accuracy are investigated. Simulated scattering from silica and polystyrene spheres was compared for small hydrophone and spherically focused PCD receivers to assess the achievable calibration accuracy as a function of frequency, scatterer size, and PCD size. Good agreement between measurements was found when the scatterer diameter was sufficiently smaller than the focal beamwidth of the PCD; this relationship was dependent on the scatterer material. For conditions that result in significant disagreement between measurements, the numerical methods described here can be used to correct experimental calibrations. PMID- 26627817 TI - Converging measures of binaural detection yield estimates of precision of coding of interaural temporal disparities. AB - This presentation reports binaural detection data obtained using a special set of three stimulus configurations. The configurations are shown to yield "converging" measures that allow one to describe how precision of coding of interaural temporal disparities (ITDs) changes as a function of both reference ITD and the center frequency of the stimuli. PMID- 26627818 TI - Generation of a reference radiation pattern of string instruments using automatic excitation and acoustic centering. AB - Radiation patterns of musical instruments are important for the understanding of music perception in concert halls, and may be used to improve the plausibility of virtual acoustic systems. Many attempts have been performed to measure the spatial response of musical instruments using surrounding spherical microphone arrays with a limited number of microphones. This work presents a high-resolution spatial sampling of the radiation pattern of an electrically excited violin, and addresses technical problems that arise due to mechanical reasons of the excitation apparatus using acoustic centering. PMID- 26627819 TI - The bag-of-frames approach: A not so sufficient model for urban soundscapes. AB - The "bag-of-frames" (BOF) approach, which encodes audio signals as the long-term statistical distribution of short-term spectral features, is commonly regarded as an effective and sufficient way to represent environmental sound recordings (soundscapes). The present paper describes a conceptual replication of a use of the BOF approach in a seminal article using several other soundscape datasets, with results strongly questioning the adequacy of the BOF approach for the task. As demonstrated in this paper, the good accuracy originally reported with BOF likely resulted from a particularly permissive dataset with low within-class variability. Soundscape modeling, therefore, may not be the closed case it was once thought to be. PMID- 26627820 TI - Headache and amaurosis fugax in an obese woman. PMID- 26627821 TI - Mon1-Ccz1 activates Rab7 only on late endosomes and dissociates from the lysosome in mammalian cells. AB - Rab GTPases act as molecular switches regulating various aspects of membrane trafficking. Among them, Rab5 and Rab7 play central roles in the endolysosomal network. Although many effectors downstream of Rab7 have been elucidated, our present understanding of the mechanism regulating Rab7 activity is extremely limited. It has only recently been accepted that the Mon1-Ccz1 complex is a Rab7 guanine nucleotide exchange factor, but it still remains unclear what the location where Mon1-Ccz1 works with Rab7 is. To address what kind of change or switch exists in the regulatory mechanism upstream of Rab7 during its transition from the late endosome to lysosome, we examined Rab7 activity in steady-state cells and during EGF-induced macropinocytosis using a newly developed FRET sensor. A combination of a Rab7 sensor and confocal FRET imaging techniques revealed that the activation of Rab7 on late endosomes depends on Mon1-Ccz1 and is implicated in late-endosome-lysosome fusion. In contrast, Rab7 activity on lysosomes was independent of Mon1-Ccz1 and active Rab7 played a role in perinuclear clustering of lysosomes. PMID- 26627822 TI - Conformational Destabilization of Immunoglobulin G Increases the Low pH Binding Affinity with the Neonatal Fc Receptor. AB - Crystallographic evidence suggests that the pH-dependent affinity of IgG molecules for the neonatal Fc receptor (FcRn) receptor primarily arises from salt bridges involving IgG histidine residues, resulting in moderate affinity at mildly acidic conditions. However, this view does not explain the diversity in affinity found in IgG variants, such as the YTE mutant (M252Y,S254T,T256E), which increases affinity to FcRn by up to 10*. Here we compare hydrogen exchange measurements at pH 7.0 and pH 5.5 with and without FcRn bound with surface plasmon resonance estimates of dissociation constants and FcRn affinity chromatography. The combination of experimental results demonstrates that differences between an IgG and its cognate YTE mutant vary with their pH sensitive dynamics prior to binding FcRn. The conformational dynamics of these two molecules are nearly indistinguishable upon binding FcRn. We present evidence that pH-induced destabilization in the CH2/3 domain interface of IgG increases binding affinity by breaking intramolecular H-bonds and increases side-chain adaptability in sites that form intermolecular contacts with FcRn. Our results provide new insights into the mechanism of pH-dependent affinity in IgG-FcRn interactions and exemplify the important and often ignored role of intrinsic conformational dynamics in a protein ligand, to dictate affinity for biologically important receptors. PMID- 26627823 TI - Analysis of the Effects of the Bruton's tyrosine kinase (Btk) Inhibitor Ibrutinib on Monocyte Fcgamma Receptor (FcgammaR) Function. AB - The irreversible Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has shown efficacy against B-cell tumors such as chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma. Fcgamma receptors (FcgammaR) on immune cells such as macrophages play an important role in tumor-specific antibody-mediated immune responses, but many such responses involve Btk. Here we tested the effects of ibrutinib on FcgammaR-mediated activities in monocytes. We found that ibrutinib did not affect monocyte FcgammaR-mediated phagocytosis, even at concentrations higher than those achieved physiologically, but suppressed FcgammaR-mediated cytokine production. We confirmed these findings in macrophages from Xid mice in which Btk signaling is defective. Because calcium flux is a major event downstream of Btk, we tested whether it was involved in phagocytosis. The results showed that blocking intracellular calcium flux decreased FcgammaR-mediated cytokine production but not phagocytosis. To verify this, we measured activation of the GTPase Rac, which is responsible for actin polymerization. Results showed that ibrutinib did not inhibit Rac activation, nor did the calcium chelator 1,2 bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester). We next asked whether the effect of ibrutinib on monocyte FcgammaR mediated cytokine production could be rescued by IFNgamma priming because NK cells produce IFNgamma in response to antibody therapy. Pretreatment of monocytes with IFNgamma abrogated the effects of ibrutinib on FcgammaR-mediated cytokine production, suggesting that IFNgamma priming could overcome this Btk inhibition. Furthermore, in monocyte-natural killer cell co-cultures, ibrutinib did not inhibit FcgammaR-mediated cytokine production despite doing so in single cultures. These results suggest that combining ibrutinib with monoclonal antibody therapy could enhance chronic lymphocytic leukemia cell killing without affecting macrophage effector function. PMID- 26627824 TI - Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption. AB - Notch receptors are determinants of cell fate and function and play a central role in skeletal development and bone remodeling. Hajdu Cheney syndrome, a disease characterized by osteoporosis and fractures, is associated with NOTCH2 mutations resulting in a truncated stable protein and gain-of-function. We created a mouse model reproducing the Hajdu Cheney syndrome by introducing a 6955C->T mutation in the Notch2 locus leading to a Q2319X change at the amino acid level. Notch2(Q2319X) heterozygous mutants were smaller and had shorter femurs than controls; and at 1 month of age they exhibited cancellous and cortical bone osteopenia. As the mice matured, cancellous bone volume was restored partially in male but not female mice, whereas cortical osteopenia persisted in both sexes. Cancellous bone histomorphometry revealed an increased number of osteoclasts and bone resorption, without a decrease in osteoblast number or bone formation. Osteoblast differentiation and function were not affected in Notch2(Q2319X) cells. The pre-osteoclast cell pool, osteoclast differentiation, and bone resorption in response to receptor activator of nuclear factor kappaB ligand in vitro were increased in Notch2(Q2319X) mutants. These effects were suppressed by the gamma-secretase inhibitor LY450139. In conclusion, Notch2(Q2319X) mice exhibit cancellous and cortical bone osteopenia, enhanced osteoclastogenesis, and increased bone resorption. PMID- 26627825 TI - Extracellular Fibrinogen-binding Protein (Efb) from Staphylococcus aureus Inhibits the Formation of Platelet-Leukocyte Complexes. AB - Extracellular fibrinogen-binding protein (Efb) from Staphylococcus aureus inhibits platelet activation, although its mechanism of action has not been established. In this study, we discovered that the N-terminal region of Efb (Efb N) promotes platelet binding of fibrinogen and that Efb-N binding to platelets proceeds via two independent mechanisms: fibrinogen-mediated and fibrinogen independent. By proteomic analysis of Efb-interacting proteins within platelets and confirmation by pulldown assays followed by immunoblotting, we identified P selectin and multimerin-1 as novel Efb interaction partners. The interaction of both P-selectin and multimerin-1 with Efb is independent of fibrinogen. We focused on Efb interaction with P-selectin. Excess of P-selectin extracellular domain significantly impaired Efb binding by activated platelets, suggesting that P-selectin is the main receptor for Efb on the surface of activated platelets. Efb-N interaction with P-selectin inhibited P-selectin binding to its physiological ligand, P-selectin glycoprotein ligand-1 (PSGL-1), both in cell lysates and in cell-free assays. Because of the importance of P-selectin-PSGL-1 binding in the interaction between platelets and leukocytes, we tested human whole blood and found that Efb abolishes the formation of platelet-monocyte and platelet-granulocyte complexes. In summary, we present evidence that in addition to its documented antithrombotic activity, Efb can play an immunoregulatory role via inhibition of P-selectin-PSGL-1-dependent formation of platelet-leukocyte complexes. PMID- 26627826 TI - The Sensorless Pore Module of Voltage-gated K+ Channel Family 7 Embodies the Target Site for the Anticonvulsant Retigabine. AB - KCNQ (voltage-gated K(+) channel family 7 (Kv7)) channels control cellular excitability and underlie the K(+) current sensitive to muscarinic receptor signaling (the M current) in sympathetic neurons. Here we show that the novel anti-epileptic drug retigabine (RTG) modulates channel function of pore-only modules (PMs) of the human Kv7.2 and Kv7.3 homomeric channels and of Kv7.2/3 heteromeric channels by prolonging the residence time in the open state. In addition, the Kv7 channel PMs are shown to recapitulate the single-channel permeation and pharmacological specificity characteristics of the corresponding full-length proteins in their native cellular context. A mutation (W265L) in the reconstituted Kv7.3 PM renders the channel insensitive to RTG and favors the conductive conformation of the PM, in agreement to what is observed when the Kv7.3 mutant is heterologously expressed. On the basis of the new findings and homology models of the closed and open conformations of the Kv7.3 PM, we propose a structural mechanism for the gating of the Kv7.3 PM and for the site of action of RTG as a Kv7.2/Kv7.3 K(+) current activator. The results validate the modular design of human Kv channels and highlight the PM as a high-fidelity target for drug screening of Kv channels. PMID- 26627827 TI - Epiregulin Recognition Mechanisms by Anti-epiregulin Antibody 9E5: STRUCTURAL, FUNCTIONAL, AND MOLECULAR DYNAMICS SIMULATION ANALYSES. AB - Epiregulin (EPR) is a ligand of the epidermal growth factor (EGF) family that upon binding to its epidermal growth factor receptor (EGFR) stimulates proliferative signaling, especially in colon cancer cells. Here, we describe the three-dimensional structure of the EPR antibody (the 9E5(Fab) fragment) in the presence and absence of EPR. Among the six complementarity-determining regions (CDRs), CDR1-3 in the light chain and CDR2 in the heavy chain predominantly recognize EPR. In particular, CDR3 in the heavy chain dramatically moves with cis trans isomerization of Pro(103). A molecular dynamics simulation and mutational analyses revealed that Arg(40) in EPR is a key residue for the specific binding of 9E5 IgG. From isothermal titration calorimetry analysis, the dissociation constant was determined to be 6.5 nm. Surface plasmon resonance analysis revealed that the dissociation rate of 9E5 IgG is extremely slow. The superimposed structure of 9E5(Fab).EPR on the known complex structure of EGF.EGFR showed that the 9E5(Fab) paratope overlaps with Domains I and III on the EGFR, which reveals that the 9E5(Fab).EPR complex could not bind to the EGFR. The 9E5 antibody will also be useful in medicine as a neutralizing antibody specific for colon cancer. PMID- 26627828 TI - Hyaluronan Does Not Regulate Human Epidermal Keratinocyte Proliferation and Differentiation. AB - Hyaluronan (HA) is synthesized by three HA synthases (HAS1, HAS2, and HAS3) and secreted in the extracellular matrix. In human skin, large amounts of HA are found in the dermis. HA is also synthesized by keratinocytes in the epidermis, although its epidermal functions are not clearly identified yet. To investigate HA functions, we studied the effects of HA depletion on human keratinocyte physiology within in vitro reconstructed human epidermis. Inhibition of HA synthesis with 4-methylumbelliferone (4MU) did not modify the expression profile of the epidermal differentiation markers involucrin, keratin 10, and filaggrin during tissue reconstruction. In contrast, when keratinocytes were incubated with 4MU, cell proliferation was decreased. In an attempt to rescue the proliferation function, HA samples of various mean molecular masses were added to keratinocyte cultures treated with 4MU. These samples were unable to rescue the initial proliferation rate. Furthermore, treatments with HA-specific hyaluronidase, although removing almost all HA from keratinocyte cultures, did not alter the differentiation or proliferation processes. The differences between 4MU and hyaluronidase effects did not result from differences in intracellular HA, sulfated glycosaminoglycan concentration, apoptosis, or levels of HA receptors, all of which remained unchanged. Similarly, knockdown of UDP-glucose 6 dehydrogenase (UGDH) using lentiviral shRNA effectively decreased HA production but did not affect proliferation rate. Overall, these data suggest that HA levels in the human epidermis are not directly correlated with keratinocyte proliferation and differentiation and that incubation of cells with 4MU cannot equate with HA removal. PMID- 26627829 TI - Mitochondrial Translocator Protein (TSPO) Function Is Not Essential for Heme Biosynthesis. AB - Function of the mammalian translocator protein (TSPO; previously known as the peripheral benzodiazepine receptor) remains unclear because its presumed role in steroidogenesis and mitochondrial permeability transition established using pharmacological methods has been refuted in recent genetic studies. Protoporphyrin IX (PPIX) is considered a conserved endogenous ligand for TSPO. In bacteria, TSPO was identified to regulate tetrapyrrole metabolism and chemical catalysis of PPIX in the presence of light, and in vertebrates, TSPO function has been linked to porphyrin transport and heme biosynthesis. Positive correlation between high TSPO expression in cancer cells and susceptibility to photodynamic therapy based on their increased ability to convert the precursor 5 aminolevulinic acid (ALA) to PPIX appeared to reinforce this mechanism. In this study, we used TSPO knock-out (Tspo(-/-)) mice, primary cells, and different tumor cell lines to examine the role of TSPO in erythropoiesis, heme levels, PPIX biosynthesis, phototoxic cell death, and mitochondrial bioenergetic homeostasis. In contrast to expectations, our results demonstrate that TSPO deficiency does not adversely affect erythropoiesis, heme biosynthesis, bioconversion of ALA to PPIX, and porphyrin-mediated phototoxic cell death. TSPO expression levels in cancer cells do not correlate with their ability to convert ALA to PPIX. In fibroblasts, we observed that TSPO deficiency decreased the oxygen consumption rate and mitochondrial membrane potential (DeltaPsim) indicative of a cellular metabolic shift, without a negative impact on porphyrin biosynthetic capability. Based on these findings, we conclude that mammalian TSPO does not have a critical physiological function related to PPIX and heme biosynthesis. PMID- 26627830 TI - His499 Regulates Dimerization and Prevents Oncogenic Activation by Asparagine Mutations of the Human Thrombopoietin Receptor. AB - Ligand binding to the extracellular domain of the thrombopoietin receptor (TpoR) imparts a specific orientation on the transmembrane (TM) and intracellular domains of the receptors that is required for physiologic activation via receptor dimerization. To map the inactive and active dimeric orientations of the TM helices, we performed asparagine (Asn)-scanning mutagenesis of the TM domains of the murine and human TpoR. Substitution of Asn at only one position (S505N) activated the human receptor, whereas Asn substitutions at several positions activated the murine receptor. Second site mutational studies indicate that His(499) near the N terminus of the TM domain is responsible for protecting the human receptor from activation by Asn mutations. Structural studies reveal that the sequence preceding His(499) is helical in the murine receptor but non-helical in peptides corresponding to the TM domain of the inactive human receptor. The activating S505N mutation and the small molecule agonist eltrombopag both induce helix in this region of the TM domain and are associated with dimerization and activation of the human receptor. Thus, His(499) regulates the activation of human TpoR and provides additional protection against activating mutations, such as oncogenic Asn mutations in the TM domain. PMID- 26627831 TI - Channel Gating Regulation by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) First Cytosolic Loop. AB - In this study, we present data indicating a robust and specific domain interaction between the cystic fibrosis transmembrane conductance regulator (CFTR) first cytosolic loop (CL1) and nucleotide binding domain 1 (NBD1) that allows ion transport to proceed in a regulated fashion. We used co-precipitation and ELISA to establish the molecular contact and showed that binding kinetics were not altered by the common clinical mutation F508del. Both intrinsic ATPase activity and CFTR channel gating were inhibited severely by CL1 peptide, suggesting that NBD1/CL1 binding is a crucial requirement for ATP hydrolysis and channel function. In addition to cystic fibrosis, CFTR dysregulation has been implicated in the pathogenesis of prevalent diseases such as chronic obstructive pulmonary disease, acquired rhinosinusitis, pancreatitis, and lethal secretory diarrhea (e.g. cholera). On the basis of clinical relevance of the CFTR as a therapeutic target, a cell-free drug screen was established to identify modulators of NBD1/CL1 channel activity independent of F508del CFTR and pharmacologic rescue. Our findings support a targetable mechanism of CFTR regulation in which conformational changes in the NBDs cause reorientation of transmembrane domains via interactions with CL1 and result in channel gating. PMID- 26627832 TI - Non-native Conformers of Cystic Fibrosis Transmembrane Conductance Regulator NBD1 Are Recognized by Hsp27 and Conjugated to SUMO-2 for Degradation. AB - A newly identified pathway for selective degradation of the common mutant of the cystic fibrosis transmembrane conductance regulator (CFTR), F508del, is initiated by binding of the small heat shock protein, Hsp27. Hsp27 collaborates with Ubc9, the E2 enzyme for protein SUMOylation, to selectively degrade F508del CFTR via the SUMO-targeted ubiquitin E3 ligase, RNF4 (RING finger protein 4) (1). Here, we ask what properties of CFTR are sensed by the Hsp27-Ubc9 pathway by examining the ability of NBD1 (locus of the F508del mutation) to mimic the disposal of full length (FL) CFTR. Similar to FL CFTR, F508del NBD1 expression was reduced 50-60% by Hsp27; it interacted preferentially with the mutant and was modified primarily by SUMO-2. Mutation of the consensus SUMOylation site, Lys(447), obviated Hsp27 mediated F508del NBD1 SUMOylation and degradation. As for FL CFTR and NBD1 in vivo, SUMO modification using purified components in vitro was greater for F508del NBD1 versus WT and for the SUMO-2 paralog. Several findings indicated that Hsp27-Ubc9 targets the SUMOylation of a transitional, non-native conformation of F508del NBD1: (a) its modification decreased as [ATP] increased, reflecting stabilization of the nucleotide-binding domain by ligand binding; (b) a temperature-induced increase in intrinsic fluorescence, which reflects formation of a transitional NBD1 conformation, was followed by its SUMO modification; and (c) introduction of solubilizing or revertant mutations to stabilize F508del NBD1 reduced its SUMO modification. These findings indicate that the Hsp27-Ubc9 pathway recognizes a non-native conformation of mutant NBD1, which leads to its SUMO-2 conjugation and degradation by the ubiquitin-proteasome system. PMID- 26627833 TI - Oxidative Stress Attenuates Lipid Synthesis and Increases Mitochondrial Fatty Acid Oxidation in Hepatoma Cells Infected with Hepatitis C Virus. AB - Cytopathic effects are currently believed to contribute to hepatitis C virus (HCV)-induced liver injury and are readily observed in Huh7.5 cells infected with the JFH-1 HCV strain, manifesting as apoptosis highly correlated with growth arrest. Reactive oxygen species, which are induced by HCV infection, have recently emerged as activators of AMP-activated protein kinase. The net effect is ATP conservation via on/off switching of metabolic pathways that produce/consume ATP. Depending on the scenario, this can have either pro-survival or pro apoptotic effects. We demonstrate reactive oxygen species-mediated activation of AMP-activated kinase in Huh7.5 cells during HCV (JFH-1)-induced growth arrest. Metabolic labeling experiments provided direct evidence that lipid synthesis is attenuated, and beta-oxidation is enhanced in these cells. A striking increase in nuclear peroxisome proliferator-activated receptor alpha, which plays a dominant role in the expression of beta-oxidation genes after ligand-induced activation, was also observed, and we provide evidence that peroxisome proliferator-activated receptor alpha is constitutively activated in these cells. The combination of attenuated lipid synthesis and enhanced beta-oxidation is not conducive to lipid accumulation, yet cellular lipids still accumulated during this stage of infection. Notably, the serum in the culture media was the only available source for polyunsaturated fatty acids, which were elevated (2-fold) in the infected cells, implicating altered lipid import/export pathways in these cells. This study also provided the first in vivo evidence for enhanced beta-oxidation during HCV infection because HCV-infected SCID/Alb-uPA mice accumulated higher plasma ketones while fasting than did control mice. Overall, this study highlights the reprogramming of hepatocellular lipid metabolism and bioenergetics during HCV infection, which are predicted to impact both the HCV life cycle and pathogenesis. PMID- 26627834 TI - Enzymatic and Structural Characterization of the Major Endopeptidase in the Venus Flytrap Digestion Fluid. AB - Carnivorous plants primarily use aspartic proteases during digestion of captured prey. In contrast, the major endopeptidases in the digestive fluid of the Venus flytrap (Dionaea muscipula) are cysteine proteases (dionain-1 to -4). Here, we present the crystal structure of mature dionain-1 in covalent complex with inhibitor E-64 at 1.5 A resolution. The enzyme exhibits an overall protein fold reminiscent of other plant cysteine proteases. The inactive glycosylated pro-form undergoes autoprocessing and self-activation, optimally at the physiologically relevant pH value of 3.6, at which the protective effect of the pro-domain is lost. The mature enzyme was able to efficiently degrade a Drosophila fly protein extract at pH 4 showing high activity against the abundant Lys- and Arg-rich protein, myosin. The substrate specificity of dionain-1 was largely similar to that of papain with a preference for hydrophobic and aliphatic residues in subsite S2 and for positively charged residues in S1. A tentative structure of the pro-domain was obtained by homology modeling and suggested that a pro-peptide Lys residue intrudes into the S2 pocket, which is more spacious than in papain. This study provides the first analysis of a cysteine protease from the digestive fluid of a carnivorous plant and confirms the close relationship between carnivorous action and plant defense mechanisms. PMID- 26627835 TI - Calcineurin Agamma is a Functional Phosphatase That Modulates Synaptic Vesicle Endocytosis. AB - Variation in PPP3CC, the gene that encodes the gamma isoform of the calcineurin catalytic subunit, has been reported to be associated with schizophrenia. Because of its low expression level in most tissues, there has been little research devoted to the specific function of the calcineurin Agamma (CNAgamma) versus the calcineurin Aalpha (CNAalpha) and calcineurin Abeta (CNAbeta) catalytic isoforms. Consequently, we have a limited understanding of the role of altered CNAgamma function in psychiatric disease. In this study, we demonstrate that CNAgamma is present in the rodent and human brain and dephosphorylates a presynaptic substrate of calcineurin. Through a combination of immunocytochemistry and immuno EM, we further show that CNAgamma is localized to presynaptic terminals in hippocampal neurons. Critically, we demonstrate that RNAi-mediated knockdown of CNAgamma leads to a disruption of synaptic vesicle cycling in cultured rat hippocampal neurons. These data indicate that CNAgamma regulates a critical aspect of synaptic vesicle cycling and suggest that variation in PPP3CC may contribute to psychiatric disease by altering presynaptic function. PMID- 26627836 TI - Distinct Elements in the Proteasomal beta5 Subunit Propeptide Required for Autocatalytic Processing and Proteasome Assembly. AB - Eukaryotic 20S proteasome assembly remains poorly understood. The subunits stack into four heteroheptameric rings; three inner-ring subunits (beta1, beta2, and beta5) bear the protease catalytic residues and are synthesized with N-terminal propeptides. These propeptides are removed autocatalytically late in assembly. In Saccharomyces cerevisiae, beta5 (Doa3/Pre2) has a 75-residue propeptide, beta5pro, that is essential for proteasome assembly and can work in trans. We show that deletion of the poorly conserved N-terminal half of the beta5 propeptide nonetheless causes substantial defects in proteasome maturation. Sequences closer to the cleavage site have critical but redundant roles in both assembly and self-cleavage. A conserved histidine two residues upstream of the autocleavage site strongly promotes processing. Surprisingly, although beta5pro is functionally linked to the Ump1 assembly factor, trans-expressed beta5pro associates only weakly with Ump1-containing precursors. Several genes were identified as dosage suppressors of trans-expressed beta5pro mutants; the strongest encoded the beta7 proteasome subunit. Previous data suggested that beta7 and beta5pro have overlapping roles in bringing together two half proteasomes, but the timing of beta7 addition relative to half-mer joining was unclear. Here we report conditions where dimerization lags behind beta7 incorporation into the half-mer. Our results suggest that beta7 insertion precedes half-mer dimerization, and the beta7 tail and beta5 propeptide have unequal roles in half-mer joining. PMID- 26627838 TI - Maternal Intimate Partner Violence Victimization Before and During Pregnancy and Postbirth Child Welfare Contact: A Population-Based Assessment. AB - We conducted a population-based prospective cohort study to help elucidate the predictive relationship between a maternal prebirth self-reported history of intimate partner violence (IPV) and any postbirth reported allegation to Child Protective Services (CPS) by age 2. We linked data from the 2009-2010 Alaska Pregnancy Risk Assessment Monitoring System with CPS data through 2012. Among this cohort, we found that 8.0%w self-reported experiencing IPV 12 months prior or during pregnancy, and 8.0%w of the offspring experienced at least one CPS report of alleged maltreatment during the study period. The predictive relationship varied by maternal educational attainment. Among mothers with 12+ years education completed, the odds of a CPS report were 3.9 times compared to those with no IPV, while among mothers with <12 years education completed, no association was noted. These results suggest that for a subset of Alaskan families, maternal history of IPV is a strong independent predictor of future CPS contact. PMID- 26627839 TI - A Study of Diabetes Teaching in Canadian Medical Schools. AB - PURPOSE: To assess the current status of diabetes teaching in Canadian medical schools. METHODS: Faculty primarily responsible for teaching undergraduate diabetes education were identified at all 17 Canadian medical schools and were asked to provide their undergraduate diabetes curricula. The curricula were analyzed by method of teaching. RESULTS: Reponses were obtained from14 of 17 (82%) medical schools. The average number of teaching hours in the entire undergraduate program was 15.4 and ranged from 7 to 22.5 hours. Formats included lectures, small groups, workshops, assigned readings, problem-based learning and laboratory studies. Lectures made up 48% of the curriculum, followed by small groups at 26%. CONCLUSIONS: There has been an increased use of small group sessions in undergraduate diabetes education, in keeping with generalized changes in medical school curricula. Future study is warranted in assessing the impact of differing undergraduate teaching methods on eventual competency. PMID- 26627837 TI - A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli. AB - Increasing antibacterial resistance presents a major challenge in antibiotic discovery. One attractive target in Gram-negative bacteria is the unique asymmetric outer membrane (OM), which acts as a permeability barrier that protects the cell from external stresses, such as the presence of antibiotics. We describe a novel beta-hairpin macrocyclic peptide JB-95 with potent antimicrobial activity against Escherichia coli. This peptide exhibits no cellular lytic activity, but electron microscopy and fluorescence studies reveal an ability to selectively disrupt the OM but not the inner membrane of E. coli. The selective targeting of the OM probably occurs through interactions of JB-95 with selected beta-barrel OM proteins, including BamA and LptD as shown by photolabeling experiments. Membrane proteomic studies reveal rapid depletion of many beta barrel OM proteins from JB-95-treated E. coli, consistent with induction of a membrane stress response and/or direct inhibition of the Bam folding machine. The results suggest that lethal disruption of the OM by JB-95 occurs through a novel mechanism of action at key interaction sites within clusters of beta-barrel proteins in the OM. These findings open new avenues for developing antibiotics that specifically target beta-barrel proteins and the integrity of the Gram negative OM. PMID- 26627840 TI - Nucleosomes Are Essential for Proper Regulation of a Multigated Promoter in Saccharomyces cerevisiae. AB - Nucleosome-depleted regions (NDRs) are present immediately adjacent to the transcription start site in most eukaryotic promoters. Here we show that NDRs in the upstream promoter region can profoundly affect gene regulation. Chromatin at the yeast HO promoter is highly repressive and numerous coactivators are required for expression. We modified the HO promoter with segments from the well-studied CLN2 NDR, creating chimeric promoters differing in nucleosome occupancy but with binding sites for the same activator, SBF. Nucleosome depletion resulted in substantial increases in both factor binding and gene expression and allowed activation from a much longer distance, probably by allowing recruited coactivators to act further downstream. Nucleosome depletion also affected sequential activation of the HO promoter; HO activation typically requires the ordered recruitment of activators first to URS1, second to the left-half of URS2 (URS2-L), and finally to the right-half of URS2 (URS2-R), with each region representing distinct gates that must be unlocked to achieve activation. The absence of nucleosomes at URS2-L resulted in promoters no longer requiring both the URS1 and URS2-L gates, as either gate alone is now sufficient to promote binding of the SBF factor to URS2-R. Furthermore, nucleosome depletion at URS2 altered the timing of HO expression and bypassed the regulation that restricts expression to mother cells. Our results reveal insight into how nucleosomes can create a requirement for ordered recruitment of factors to facilitate complex transcriptional regulation. PMID- 26627841 TI - The Double-Strand Break Landscape of Meiotic Chromosomes Is Shaped by the Paf1 Transcription Elongation Complex in Saccharomyces cerevisiae. AB - Histone modification is a critical determinant of the frequency and location of meiotic double-strand breaks (DSBs), and thus recombination. Set1-dependent histone H3K4 methylation and Dot1-dependent H3K79 methylation play important roles in this process in budding yeast. Given that the RNA polymerase II associated factor 1 complex, Paf1C, promotes both types of methylation, we addressed the role of the Paf1C component, Rtf1, in the regulation of meiotic DSB formation. Similar to a set1 mutation, disruption of RTF1 decreased the occurrence of DSBs in the genome. However, the rtf1 set1 double mutant exhibited a larger reduction in the levels of DSBs than either of the single mutants, indicating independent contributions of Rtf1 and Set1 to DSB formation. Importantly, the distribution of DSBs along chromosomes in the rtf1 mutant changed in a manner that was different from the distributions observed in both set1 and set1 dot1 mutants, including enhanced DSB formation at some DSB-cold regions that are occupied by nucleosomes in wild-type cells. These observations suggest that Rtf1, and by extension the Paf1C, modulate the genomic DSB landscape independently of H3K4 methylation. PMID- 26627842 TI - The Role of Recombination in Evolutionary Rescue. AB - How likely is it that a population escapes extinction through adaptive evolution? The answer to this question is of great relevance in conservation biology, where we aim at species' rescue and the maintenance of biodiversity, and in agriculture and medicine, where we seek to hamper the emergence of pesticide or drug resistance. By reshuffling the genome, recombination has two antagonistic effects on the probability of evolutionary rescue: it generates and it breaks up favorable gene combinations. Which of the two effects prevails depends on the fitness effects of mutations and on the impact of stochasticity on the allele frequencies. In this article, we analyze a mathematical model for rescue after a sudden environmental change when adaptation is contingent on mutations at two loci. The analysis reveals a complex nonlinear dependence of population survival on recombination. We moreover find that, counterintuitively, a fast eradication of the wild type can promote rescue in the presence of recombination. The model also shows that two-step rescue is not unlikely to happen and can even be more likely than single-step rescue (where adaptation relies on a single mutation), depending on the circumstances. PMID- 26627843 TI - The effect of clinical characteristics on the performance of galactomannan and PCR for the diagnosis of invasive aspergillosis in febrile neutropenic patients. AB - Rapid diagnosis and early treatment of invasive aspergillosis is crucial for the management of the patients with haematological malignancy. We evaluated 358 sera from 78 febrile neutropenic episodes in patient with invasive aspergillosis (IA) (one proven, 17 probable, and 60 possible) and 83 episodes in patients with no IA according to the EORTC/MSG criteria. Patient's specimens were tested by Mycassay Aspergillus PCR (first commercial real-time PCR test) and in house real-time PCR to investigate the presence of Aspergillus DNA, and by ELISA for detect the galactomannan (GM) antigen. We systematically investigated the medical background that can be effective on the test results. The hospitalisation period was longer in proven/probable episodes when compared with no IA (P = 0.001) and possible episodes. With regard to duration of neutropenia, the differences between both proven/probable with no IA (P = 0.023) and possible with no IA (P = 0.002) were highly significant. Similarly, the rates of T cell suppressant therapy in group proven/probable and possible episodes were significantly higher than in no IA (P = 0.005). There are significant differences in the performance of GM and PCR based tests among studies, and standardisation is required. Therefore, it can be useful to determine the effective factors on these tests. The use of larger volume of sera improved the performance of real-time PCR for detection of Aspergillus DNA in high-risk adult patients in the present study. Some host factors such as duration of neutropenia and administration of T cell suppressants related to the development of IA. PMID- 26627844 TI - Improved meal presentation increases food intake and decreases readmission rate in hospitalized patients. AB - BACKGROUND: Reduced food intake is a frequent problem at a hospital setting, being a cause and/or consequence of malnutrition. Food presentation can affect food intake and induce nutritional benefit. OBJECTIVES: To investigate the effect of improved meal presentation supported by gastronomy expertise on the food intake in adults hospitalized in internal medicine departments. DESIGN: Controlled before and after study. METHODS: Two hundred and six newly hospitalized patients in internal medicine departments were included and divided in two groups, a) control: receiving the standard lunch from the hospital and b) experimental: receiving a lunch improved in terms of presentation by the advices received by the Institut Paul Bocuse, Ecully, Lyon, France together with the hospital kitchen of the Beilinson Hospital, without change in the composition of the meal. The amount of food left at the participants' plates was estimated using the Digital Imaging Method, which consisted in photographing the plates immediately to previous tray collection by the researcher. In addition, the nutritionDay questionnaire was used to measure other variables concerned to their food intake during hospitalization. Charlson Comorbidity Index was calculated. RESULTS: There was no significant difference between the groups regarding demography or Charlson Comorbidity Index. Patients who received the meal with the improved presentation showed significantly higher food intake than those who received the standard meal, despite reported loss in appetite. Participants from the experimental group left on their plate less starch (0.19 +/- 0.30 vs. 0.52 + 0.41) (p < 0.05) and less from the main course than the control group (0.18 + 0.31 vs. 0.46 + 0.41) (p < 0.05). However, both of the groups left the same amount of vegetables (0.37 + 0.36 vs. 0.29 + 0.35) (p > 0.05). Both of the groups were asked how hungry they were before the meal and no significance was shown. More participants from the experimental group reported their meal to be tasty in comparison to those in the control group (49.5% vs. 33.7% p < 0.005). Length of stay was not different but readmission rate decreased significantly in the study group (p < 0.02) from 31.2% to 13.5%. CONCLUSION: Improvement of meal presentation at a hospital setting can increase food intake, reduce waste food substantially and reduce readmission rate to hospital. PMID- 26627845 TI - Specific immunotherapy in combination with Clostridium butyricum inhibits allergic inflammation in the mouse intestine. AB - The current therapy on allergic inflammation is unsatisfactory. Probiotics improve the immunity in the body. This study aims to test a hypothesis that administration with Clostridium butyricum (C. butyricum) enforces the effect of specific immunotherapy (SIT) on intestinal allergic inflammation. In this study, an ovalbumin (OVA) specific allergic inflammation mouse model was created. The mice were treated with SIT or/and C. butyricum. The results showed that the intestinal allergic inflammation was only moderately alleviated by SIT, which was significantly enforced by a combination with C. butyricum; treating with C. butyricum alone did not show much inhibitory efficacy. The increase in the frequency of the interleukin (IL)-10-producing OVA-specific B cell (OVAsBC) was observed in mice in parallel to the inhibitory effect on the intestinal allergic inflammation. The in vitro treatment of the OVAsBCs with OVA increased the histone deacetylase-1 (HDAC1) phosphorylation, modulated the transcription of the Bcl6 gene, and triggered the OVAsBCs to differentiate to the IgE-producing plasma cells. Exposure to both OVA and butyrate sodium in the culture increased the expression of IL-10 in OVAsBCs. In conclusion, administration with C. butyricum enforces the inhibitory effect of SIT on allergic inflammation in the mouse intestine. PMID- 26627846 TI - Reaction norms of host immunity, host fitness and parasite performance in a mouse -intestinal nematode interaction. AB - The outcome of the encounter between a host and a parasite depends on the synergistic effects of the genetics of the two partners and the environment (sensulato) where the interaction takes place. Reaction norms can depict how host and parasite traits vary across environmental ranges for different genotypes. Here, we performed a large scale experiment where three strains of laboratory mice (SJL, BALB/c and CBA) were infected with four doses of the intestinal nematode Heligmosomoides polygyrus. An increasing infective dose can be considered as a proxy for the environment-dependent risk incontracting the infection. We looked at the fitness traits of hosts and parasites, and assessed the underlying immunological functions likely to affect the observed pattern of resistance/susceptibility/tolerance. We found that the infective dose had a strong effect on both host fitness and parasite performance. Interestingly, for most traits, host genotypes did not rank consistently across the increasing infective doses and according to the expected pattern of strain-specific resistance/susceptibility/tolerance. Analyses of cytokine production allowed better understanding of the mechanistic basis underlying variations in fitness linked traits. The infective dose affected the shape of the reaction norms of the cytokines IL-4, IL-10 and IL-6. Dose-dependent variation in cytokine production explained, moreover, the strain-specific pattern of infection cost, host resistance and parasite performance. As long as the infective dose increased, there was a marked shift towards a pro-inflammatory status in the SJL strain of mice that was positively correlated with cost of the infection and parasite performance. Overall, our study strongly suggests that the notion of host resistance is labile and depends on the environmental conditions where the interaction takes place. Moreover, integrating information on fitness-linked traits and the underlying mechanisms seems essential for a better understanding of host and parasite adaptations across variable environments. PMID- 26627847 TI - High major histocompatibility complex class I polymorphism despite bottlenecks in wild and domesticated populations of the zebra finch (Taeniopygia guttata). AB - BACKGROUND: Two subspecies of zebra finch, Taeniopygia guttata castanotis and T. g. guttata are native to Australia and the Lesser Sunda Islands, respectively. The Australian subspecies has been domesticated and is now an important model system for research. Both the Lesser Sundan subspecies and domesticated Australian zebra finches have undergone population bottlenecks in their history, and previous analyses using neutral markers have reported reduced neutral genetic diversity in these populations. Here we characterize patterns of variation in the third exon of the highly variable major histocompatibility complex (MHC) class I alpha chain. As a benchmark for neutral divergence, we also report the first mitochondrial NADH dehydrogenase 2 (ND2) sequences in this important model system. RESULTS: Despite natural and human-mediated population bottlenecks, we find that high MHC class I polymorphism persists across all populations. As expected, we find higher levels of nucleotide diversity in the MHC locus relative to neutral loci, and strong evidence of positive selection acting on important residues forming the peptide-binding region (PBR). Clear population differentiation of MHC allele frequencies is also evident, and this may be due to adaptation to new habitats and associated pathogens and/or genetic drift. Whereas the MHC Class I locus shows broad haplotype sharing across populations, ND2 is the first locus surveyed to date to show reciprocal monophyly of the two subspecies. CONCLUSIONS: Despite genetic bottlenecks and genetic drift, all surveyed zebra finch populations have maintained high MHC Class I diversity. The diversity at the MHC Class I locus in the Lesser Sundan subspecies contrasts sharply with the lack of diversity in previously examined neutral loci, and may thus be a result of selection acting to maintain polymorphism. Given uncertainty in historical population demography, however, it is difficult to rule out neutral processes in maintaining the observed diversity. The surveyed populations also differ in MHC Class I allele frequencies, and future studies are needed to assess whether these changes result in functional immune differences. PMID- 26627848 TI - Differential expression of vascular endothelial growth factor A, its receptors VEGFR-1, -2, and -3 and co-receptors neuropilin-1 and -2 does not predict bevacizumab response in human astrocytomas. AB - BACKGROUND: A major hallmark of malignant progression in human astrocytomas is the formation of new blood vessels. Antiangiogenic therapy using the anti vascular endothelial growth factor (VEGF)-antibody bevacizumab leads to increased progression-free survival in glioblastoma patients but does not influence their overall survival. To date, it is unclear why antiangiogenic therapy fails in many glioblastoma patients, while a small subpopulation profits considerably from this treatment. METHODS: The aim of our study was to determine the expression of VEGF A and its (co-) receptors by immunohistochemistry and to test the association with patient survival in 350 glioma patients. Additionally, VEGF-A expression was analyzed by in-situ hybridization. In 18 patients, the protein expression was compared with the bevacizumab response according to extended and modified RANO criteria. RESULTS: We found a heterogeneous expression pattern of VEGF and its receptors in glioblastoma patients with significantly lower levels in WHO grade II and III tumors and normal-appearing brain tissue (P < .001). Pilocytic astrocytomas (WHO grade I) showed significantly higher VEGFR-1, -2 and neuropilin 1 levels as compared to WHO grade II and III astrocytomas (P < .01) but at lower levels than glioblastomas. The expression of neuropilin-2 was low in all tumors. There was neither a significant correlation between protein expression and patient survival nor between protein levels and bevacizumab response after modified RANO criteria. CONCLUSION: Since our data indicate that beneficial response to bevacizumab treatment is independent of the expression of VEGF-A and its (co-) receptors, further investigation is needed to decipher the underlying mechanisms of antiangiogenic treatment response. PMID- 26627849 TI - Relationship between pulmonary exacerbations and daily physical activity in adults with cystic fibrosis. AB - BACKGROUND: The aim of this study was to examine the relationship between pulmonary exacerbations and physical activity (PA) in adults with cystic fibrosis (CF). METHODS: We grouped adults with CF according to their exacerbation status in the year before study enrollment: (1) <1 exacerbation/year; (2) 1-2 exacerbations/year; and (3) >2 exacerbations/year. PA was assessed objectively by means of an accelerometer at the time of study enrollment. RESULTS: Patients with >2 exacerbations/year spent less time in PA; specifically, fewer activities of mild intensity [>3 metabolic equivalents (METs)], and lower active energy expenditure (P = 0.01 and P = 0.03, respectively). After correcting for relevant confounders, PA levels were not related to the exacerbation frequency in the preceding year. PA at moderate intensity (4.8-7.2 METs) or greater (> 7.2 METs) was independently associated with gender and FEV1 % predicted (P = 0.007 and P = 0.04, respectively). Compared with men, women had reduced vigorous activities (P = 0.01) and active energy expenditure (P = 0.01). CONCLUSIONS: Adult CF patients with more pulmonary exacerbations in the preceding year have more advanced disease and are less active than their peers. PA was independently associated with gender and airflow obstruction. Gender differences in PA are evident in CF adults. PMID- 26627850 TI - Loss of parkin promotes lipid rafts-dependent endocytosis through accumulating caveolin-1: implications for Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is characterized by progressive loss of midbrain dopaminergic neurons, resulting in motor dysfunctions. While most PD is sporadic in nature, a significant subset can be linked to either autosomal dominant or recessive mutations. PARK2, encoding the E3 ubiquitin ligase, parkin, is the most frequently mutated gene in autosomal recessive early onset PD. It has recently been reported that PD-associated gene products such as PINK1, alpha synuclein, LRRK2, and DJ-1, as well as parkin associate with lipid rafts, suggesting that the dysfunction of these proteins in lipid rafts may be a causal factor of PD. Therefore here, we examined the relationship between lipid rafts related proteins and parkin. RESULTS: We identified caveolin-1 (cav-1), which is one of the major constituents of lipid rafts at the plasma membrane, as a substrate of parkin. Loss of parkin function was found to disrupt the ubiquitination and degradation of cav-1, resulting in elevated cav-1 protein level in cells. Moreover, the total cholesterol level and membrane fluidity was altered by parkin deficiency, causing dysregulation of lipid rafts-dependent endocytosis. Further, cell-to-cell transmission of alpha-synuclein was facilitated by parkin deficiency. CONCLUSIONS: Our results demonstrate that alterations in lipid rafts by the loss of parkin via cav-1 may be a causal factor of PD, and cav-1 may be a novel therapeutic target for PD. PMID- 26627852 TI - Chemical characteristics and enhanced hepatoprotective activities of Maillard reaction products derived from milk protein-sugar system. AB - The objective of this study was to investigate the characteristics, antioxidative properties, and hepatoprotective effects of Maillard reaction products (MRP) from milk protein reacted with sugars. The MRP were obtained from milk protein, whey protein concentrates and sodium caseinate, using 2 types of sugars, lactose and glucose, by heating the mixture at 55 degrees C for 7d in a sodium phosphate buffer (pH 7.4). Changes in the chemical modification of the milk protein were monitored by measuring the protein-bound carbonyls and PAGE protein profiles. The results showed that the amount of protein-bound carbonyls increased after Maillard reaction (MR). In addition, sodium dodecyl sulfate-PAGE analysis indicated a formation of high-molecular weight complexes through MR. The modification sites induced by MR of milk protein were monitored by matrix assisted laser desorption/ionization time-of-flight mass spectrometry analysis of tryptic-digested gel spots of MRP. As a result, modification and their localization in AA sequence of MRP was identified. Also, the MRP showed higher antioxidant activities than the intact milk protein, and they reduced intracellular reactive oxygen species production and inhibited the depletion of the reduced glutathione concentrations in the HepG2 cells. In particular, glucose sodium caseinate MRP showed the highest biological activities among all MRP. Therefore, these results suggest that the MRP from milk protein reacting with sugars possess effective antioxidant activity and have a protective ability against oxidative damage. PMID- 26627851 TI - Physiological and transcriptional responses and cross protection of Lactobacillus plantarum ZDY2013 under acid stress. AB - Acid tolerance responses (ATR) in Lactobacillus plantarum ZDY2013 were investigated at physiological and molecular levels. A comparison of composition of cell membrane fatty acids (CMFA) between acid-challenged and unchallenged cells showed that acid adaptation evoked a significantly higher percentage of saturated fatty acids and cyclopropane fatty acids in acid-challenged than in unchallenged cells. In addition, reverse transcription-quantitative PCR analysis in acid-adapted cells at different pH values (ranging from 3.0 to 4.0) indicated that several genes were differently regulated, including those related to proton pumps, amino acid metabolism, sugar metabolism, and class I and class III stress response pathways. Expression of genes involved in fatty acid synthesis and production of alkali was significantly upregulated. Upon exposure to pH 4.5 for 2 h, a higher survival rate (higher viable cell count) of Lactobacillus plantarum ZDY2013 was achieved following an additional challenge to 40 mM hydrogen peroxide for 60 min, but no difference in survival rate of cells was found with further challenge to heat, ethanol, or salt. Therefore, we concluded that the physiological and metabolic changes of acid-treated cells of Lactobacillus plantarum ZDY2013 help the cells resist damage caused by acid, and further initiated global response signals to bring the whole cell into a state of defense to other stress factors, especially hydrogen peroxide. PMID- 26627853 TI - Does supplemental 18:0 alleviate fish oil-induced milk fat depression in dairy ewes? AB - Supplementation of dairy ewe diet with marine lipids may be an effective strategy for modulating milk fatty acid composition but induces milk fat depression (MFD). This syndrome has been associated with a shortage of 18:0 for uptake and Delta(9) desaturation that may impair the capacity of the mammary gland to achieve an adequate fluidity for milk fat secretion. On this basis, it was suggested that supplemental 18:0 may contribute to alleviate marine lipid-induced MFD in sheep. To test this hypothesis, 12 lactating ewes were allocated to 1 of 3 lots and used in a 3*3 Latin square design with 3 periods of 28 d each and 3 experimental treatments: a total mixed ration without lipid supplementation (control) or supplemented with 20 g/kg of DM of fish oil alone (FO) or in combination with 20 g/kg of DM of 18:0 (FOSA). Diets were offered ad libitum, and animal performance and rumen and milk fatty acid composition were studied at the end of each period. After completing the Latin square trial and following a change-over design, the in vivo digestibility of supplemental 18:0 was estimated using 6 lactating sheep. As expected, diet supplementation with fish oil increased the milk content of some potentially health-promoting fatty acids (e.g., cis-9,trans-11 18:2, trans 11 18:1, 20:5n-3, 22:5n-3, and 22:6n-3), but reduced milk fat concentration and yield (-20% in both FO and FOSA treatments). Thus, although reductions in milk 18:0 and cis-9 18:1 output caused by FO (-81 and -51%, respectively) were partially reversed with FOSA diet (-49 and -27%, respectively), the addition of 18:0 to the diet did not prove useful to alleviate MFD. This response, which could not be fully accounted for by the low digestibility coefficient of supplemental 18:0, may challenge the theory of a shortage of this fatty acid as a mechanism to explain fish oil-induced MFD in sheep. Effects of FO and FOSA on rumen and milk fatty acid composition would support that increases in the concentration of some candidate milk fat inhibitors (e.g., cis-9 16:1 or 10-oxo 18:0) might play a relevant role in this type of MFD. PMID- 26627854 TI - Effects of replacing lactose from milk replacer by glucose, fructose, or glycerol on energy partitioning in veal calves. AB - Calf milk replacers contain 40 to 50% lactose. Fluctuating dairy prices are a major economic incentive to replace lactose from milk replacers by alternative energy sources. Our objective was, therefore, to determine the effects of replacement of lactose with glucose, fructose, or glycerol on energy and protein metabolism in veal calves. Forty male Holstein-Friesian calves (114+/-2.4 kg) were fed milk replacer containing 46% lactose (CON) or 31% lactose and 15% of glucose (GLUC), fructose (FRUC), or glycerol (GLYC). Solid feed was provided at 10 g of dry matter (DM)/kg of metabolic body weight (BW(0.75)) per day. After an adaptation of 48 d, individual calves were harnessed, placed in metabolic cages, and housed in pairs in respiration chambers. Apparent total-tract disappearance of DM, energy, and N and complete energy and N balances were measured. The GLUC, FRUC, and GLYC calves received a single dose of 1.5 g of [U-(13)C]glucose, [U (13)C]fructose, or [U-(13)C]glycerol, respectively, with their milk replacer at 0630 h and exhaled (13)CO2 and (13)C excretion with feces was measured. Apparent total-tract disappearance was decreased by 2.2% for DM, 3.2% for energy, and 4.2% for N in FRUC compared with CON calves. Energy and N retention did not differ between treatments, and averaged 299+/-16 kJ/kg of BW(0.75) per day and 0.79+/ 0.04 g/kg of BW(0.75) per day, respectively, although FRUC calves retained numerically less N (13%) than other calves. Recovery of (13)C isotopes as (13)CO2 did not differ between treatments and averaged 72+/-1.6%. The time at which the maximum rate of (13)CO2 production was reached was more than 3 h delayed for FRUC calves, which may be explained by a conversion of fructose into other substrates before being oxidized. Recovery of (13)C in feces was greater for FRUC calves (7.7+/-0.59%) than for GLUC (1.0+/-0.27%) and GLYC calves (0.5+/-0.04%), indicating incomplete absorption of fructose from the small intestine resulting in fructose excretion or fermentation. In conclusion, energy and N retention was not affected when replacing >30% of the lactose with glucose, fructose, or glycerol. Increased fecal losses of DM, energy, and N were found in FRUC calves compared with CON, GLUC, and GLYC calves. Postabsorptive losses occurred with the urine for glucose and glycerol, which caused a lower respiratory quotient for GLUC calves during the night. Fructose was oxidized more slowly than glucose and glycerol, probably as a result of conversion into other substrates before oxidation. PMID- 26627855 TI - The effects of a ration change from a total mixed ration to pasture on health and production of dairy cows. AB - In pasture-based dairy production systems, dairy cows often receive a silage- and concentrate-based ration [total mixed ration (TMR)] during wintertime and are gradually introduced to fresh herbage in spring. The present study aimed to investigate how the transition to this new nutritional situation influenced different production and health indicators. A 10-wk trial was performed in spring 2014, including 60 dairy cows of the German Holstein breed (166+/-23 d in milk, 23.5+/-3.7 kg of milk/d; means +/- SD). The cows were divided into a pasture and a confinement group (PG and CG, respectively). The CG stayed on a TMR-based diet (35% corn silage, 35% grass silage, 30% concentrate; DM basis), whereas the PG was gradually transitioned from a TMR- to a pasture-based ration (wk 1=TMR-only, wk 2=3 h/d on pasture, wk 3 and 4=12 h/d on pasture, wk 5-10=pasture-only). A continuous grazing system was implemented on a ryegrass dominated pasture and temperature humidity indices were assessed based on continuous recording of temperature and humidity indoors as well as outdoors. Dry matter intake (DMI) from TMR, milk production, body weight (BW), and body condition score decreased as soon as the PG had partial access to pasture. Milk production and BW decreased even further in the first week on a full grazing ration, but thereafter BW increased again and milk production stabilized. The DMI estimation using the n alkane method in wk 7 and 9 revealed an increase in DMI from pasture between the 2 time points and indicates an adaptation of grazing behavior and metabolism over several weeks. Increased serum beta-hydroxybutyrate and fatty acids concentrations at several time points, as well as a continuous body condition score decrease during the whole course of the trial, indicate an energy deficit in the PG. A significant correlation between serum glucose concentrations and the temperature humidity indices was observed. An increase in serum and milk urea concentrations as well as an increase in the urine total N to creatinine ratio occurred in the PG. To assess possible negative effects of the ration change on metabolic and liver health, different clinical chemistry variables and complete blood counts were assessed. No biologically relevant changes were observed for serum albumin, total protein, cholesterol, aspartate transaminase, gamma glutamyltransferase, and glutamate dehydrogenase concentrations, as well as for white and red blood cell counts. PMID- 26627856 TI - A survey of silage management practices on California dairies. AB - The aim of the present study was to gather baseline information on corn silage management practices to develop an outreach curriculum for dairy producers and growers. In spring 2013, dairy producers in the San Joaquin Valley (California) were surveyed on their silage-management practices. Response rate was 14.5% (n=160) and herd size averaged 1,512 milking cows. Harvest date was set solely by the dairy producer (53.4%) or with the assistance of the crop manager, custom chopper, or nutritionist (23.3%). On some dairies (23.3%), the dairy producer delegated the harvest date decision. Most dairies (75.0%) estimated crop dry matter before harvest, and the preferred method was milk line evaluation. Dairy producers were mostly unfamiliar with harvest rate but the number [1 (35.9%), 2 (50.3%), or 3 to 5 (13.8%)] and size [6-row (17.7%), 8-row (67.3%), or 10-row (15.0%)] of choppers working simultaneously was reported. Most dairies used a single packing tractor (68.8%) and weighed every load of fresh chopped corn delivered to the silage pit (62%). During harvest, dry matter (66.9%), particle length (80.4%), and kernel processing (92.5%) were monitored. Most dairies completed filling their largest silage structure in less than 3 d (48.5%) or in 4 to 7 d (30.9%). Silage covering was completed no later than 7 2h after structure completion in all dairies, and was often completed within 24 h (68.8%). Packed forage was covered as filled in 19.6% of dairies. Temporary covers were used on some dairies (51.0%), with filling durations of 1 to 60 d. When temporary covers were not used, structures were filled in no more than 15 d. After structure closure, silage feedout started in 1 to 3 wk (44.4%), 4 to 5 wk (31.4%), or 8 or more wk (24.2%). Future considerations included increasing the silage storage area (55.9%), increasing the number of packing tractors (37.0%), planting brown mid-rib varieties (34.4%), buying a defacer to remove silage (33.1%), and creating drive-over piles (32.6%). Survey results will serve to develop and disseminate targeted information on silage management practices at harvest, packing, covering, and feedout on California's San Joaquin Valley dairies. PMID- 26627857 TI - Glucose supplementation stimulates peripheral branched-chain amino acid catabolism in lactating dairy cows during essential amino acid infusions. AB - To determine how glucose modulates protein synthesis when essential AA are in abundant supply, 5 early-lactation, rumen-fistulated Holstein dairy cows were fed a diet containing 6.95 MJ/kg of net energy for lactation and 12.4% crude protein and abomasally infused for 5 d with saline, 844 or 1,126 g/d of a complete essential AA mix, with and without the inclusion of 1,000 g/d of glucose, in a 5*5 Latin square design. Infusion of essential AA increased milk yield by 4.1 kg/d, milk protein by 256 g/d, milk fat by 95 g/d, and milk urea nitrogen by 70% compared with saline, with no differences between the level of essential AA infusion. The addition of glucose to essential AA infusate did not stimulate milk protein yield or concentration, but reduced milk urea nitrogen by 17% and decreased milk fat yield. Arterial concentrations of total essential AA increased 3- to 4-fold, mammary clearance decreased 61%, and mammary uptake of essential AA increased 65% in response to essential AA infusion. Arterial branched-chain AA concentrations declined 29% in response to glucose and mammary clearance increased 48%, but mammary AA uptake was unchanged. Essential AA infusion increased plasma 3-methylhistidine by 50% and reduced muscle branched-chain alpha keto acid dehydrogenase kinase abundance by 14%, indicating stimulation of muscle protein turnover and branched-chain AA catabolism, respectively. Glucose had no further effect on muscle branched-chain alpha-keto acid dehydrogenase kinase abundance but decreased mRNA expression of branched chain aminotransferase 1. Lack of further increases in plasma 3-methylhistidine or greater stimulation of muscle branched-chain AA catabolism indicates that muscle protein degradation was unchanged with glucose but that accretion may have been stimulated. The decrease in circulating branched-chain AA concentrations and nitrogen excretion in response to glucose suggests that surplus essential AA were redirected to peripheral, extra-mammary tissues. PMID- 26627858 TI - Feeding nitrate and docosahexaenoic acid affects enteric methane production and milk fatty acid composition in lactating dairy cows. AB - An experiment was conducted to study potential interaction between the effects of feeding nitrate and docosahexaenoic acid (DHA; C22:6 n-3) on enteric CH4 production and performance of lactating dairy cows. Twenty-eight lactating Holstein dairy cows were grouped into 7 blocks of 4 cows. Within blocks, cows were randomly assigned to 1 of 4 treatments: control (CON; urea as alternative nonprotein N source to nitrate), NO3 [21 g of nitrate/kg of dry matter (DM)], DHA (3 g of DHA/kg of DM and urea as alternative nonprotein N source to nitrate), or NO3 + DHA (21 g of nitrate/kg of DM and 3 g of DHA/kg of DM, respectively). Cows were fed a total mixed ration consisting of 21% grass silage, 49% corn silage, and 30% concentrates on a DM basis. Feed additives were included in the concentrates. Cows assigned to a treatment including nitrate were gradually adapted to the treatment dose of nitrate over a period of 21 d during which no DHA was fed. The experimental period lasted 17 d, and CH4 production was measured during the last 5d in climate respiration chambers. Cows produced on average 363, 263, 369, and 298 g of CH4/d on CON, NO3, DHA, and NO3 + DHA treatments, respectively, and a tendency for a nitrate * DHA interaction effect was found where the CH4-mitigating effect of nitrate decreased when combined with DHA. This tendency was not obtained for CH4 production relative to dry matter intake (DMI) or to fat- and protein corrected milk (FPCM). The NO3 treatment decreased CH4 production irrespective of the unit in which it was expressed, whereas DHA did not affect CH4 production per kilogram of DMI, but resulted in a higher CH4 production per kilogram of fat- and protein-corrected milk (FPCM) production. The FPCM production (27.9, 24.7, 24.2, and 23. 8 kg/d for CON, NO3, DHA, and NO3 + DHA, respectively) was lower for DHA-fed cows because of decreased milk fat concentration. The proportion of saturated fatty acids in milk fat was decreased by DHA, and the proportion of polyunsaturated fatty acids was increased by both nitrate and DHA. Milk protein concentration was lower for nitrate-fed cows. In conclusion, nitrate but not DHA decreased enteric CH4 production and no interaction effects were found on CH4 production per kilogram of DMI or per kilogram of FPCM. PMID- 26627859 TI - Diagnostic test performance of somatic cell count, lactate dehydrogenase, and N acetyl-beta-D-glucosaminidase for detecting dairy cows with intramammary infection. AB - The main objective of this study was to investigate the diagnostic test performance of somatic cell count (SCC), lactate dehydrogenase (LDH), and N acetyl-beta-D-glucosaminidase (NAGase), analyzed in composite test milking samples, for detecting dairy cows with or without intramammary infection (IMI). A second objective was to investigate whether an adjustment of these udder health indicators according to their associations with different influential factors (i.e., parity, days in milk, and season) improved their test performance. Moreover, we wanted to investigate whether test performance of SCC improved if SCC results from previous adjacent test milkings were included in the model. Such test milking data were not available for LDH or NAGase. In this cross-sectional study, quarter milk samples for bacteriological examination were taken from almost 1,000 cows from 25 dairy herds during 3 consecutive days: the day before test milking, the day of test milking, and the day after test milking. From each cow, a composite test milking sample was analyzed for milk composition, SCC, LDH, and NAGase. Among the cows sampled, 485 were IMI negative and 256 were IMI positive in one or more udder quarters according to the definitions used. The remaining cows had inconclusive IMI status. To assess the test performance of SCC, LDH, and NAGase to identify IMI-negative and IMI-positive cows, univariable generalized estimating equation models were used with the udder health indicator of interest as outcome and IMI status as explanatory variable. From these models, receiver-operator characteristic curves were created and the area under cure (AUC) was calculated. From each model, a cut-off was chosen for calculations of the sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and accuracy (ACC) for each udder health indicator. The AUC was similar for the adjusted SCC (0.84), nonadjusted SCC (0.83) and geometric mean SCC (0.80-0.81), but much lower for LDH (0.66) and NAGase (0.62). The highest Se, Sp, PPV, NPV, and ACC were obtained using SCC. Adjustment of the udder health indicators for influential factors (e.g., parity) did not improve the test performance markedly, whereas adding information about SCC from previous adjacent test milkings improved the test performance of SCC slightly. In conclusion, of the udder health indicators investigated, SCC had the best overall ability to correctly identify IMI-negative and IMI-positive dairy cows. PMID- 26627860 TI - Tea polyphenols inactivate Cronobacter sakazakii isolated from powdered infant formula. AB - This study evaluated the antimicrobial activity of tea polyphenols (TP) against 4 Cronobacter sakazakii strains with different sequence types (ST) isolated from powdered infant formula (PIF). The results showed that in normal saline, 5mg/mL of TP (pH 3.44) could eliminate approximately 7.0 log cfu/mL of C. sakazakii within 1 h; in rehydrated PIF, after acidification with HCl (pH 3.55), TP showed a stronger antibacterial activity compared with the controls (malic acid, ascorbic acid, and citric acid). Further, some differences were obvious in tolerance to TP between C. sakazakii strains with different ST. The tolerance of C. sakazakii CE1 (ST4) to TP was found to be greater than that of the other 3 C. sakazakii strains (ST1, ST8, and ST64). The results of recovered test and transmission electron microscope analysis revealed that the action of TP against C. sakazakii was an irreversible bactericidal process caused by leakage of cytoplasm. Taken together, these results indicated that TP had an effective bactericidal effect against C. sakazakii, and provided a new idea for preventing and inactivating C. sakazakii in PIF. PMID- 26627861 TI - Dry period plane of energy: Effects on glucose tolerance in transition dairy cows. AB - Overfeeding energy in the dry period can affect glucose metabolism and the energy balance of transition dairy cows with potential detrimental effects on the ability to successfully adapt to early lactation. The objectives of this study were to investigate the effect of different dry cow feeding strategies on glucose tolerance and on resting concentrations of blood glucose, glucagon, insulin, nonesterified fatty acids (NEFA), and beta-hydroxybutyrate (BHB) in the peripartum period. Cows entering second or greater lactation were enrolled at dry off (57 d before expected parturition) into 1 of 3 treatment groups following a randomized block design: cows that received a total mixed ration (TMR) formulated to meet but not exceed energy requirements during the dry period (n=28, controlled energy); cows that received a TMR supplying approximately 150% of energy requirements during the dry period (n=28, high energy); and cows that were fed the same diet as the controlled energy group for the first 28 d, after which the TMR was formulated to supply approximately 125% of energy requirements until calving (n=28, intermediate energy). Intravenous glucose tolerance tests (IVGTT) with rapid administration of 0.25 g of glucose/kg of body weight were performed 28 and 10d before expected parturition, as well as at 4 and 21 d after calving. Area under the curve for insulin and glucose, maximal concentration and time to half-maximal concentration of insulin and glucose, and clearance rates were calculated. Insulin resistance (IR) indices were calculated from baseline samples obtained during IVGTT and Spearman rank correlations determined between IVGTT parameters and IR indices. Treatment did not affect IVGTT parameters at any of the 4 time points. Correlation between IR indices and IVGTT parameters was generally poor. Overfeeding cows energy in excess of predicted requirements by approximately 50% during the entire dry period resulted in decreased postpartum basal plasma glucose and insulin, as well as increased glucagon, BHB, and NEFA concentrations after calving compared with cows fed a controlled energy diet during the dry period. In conclusion, overfeeding energy during the entire dry period or close-up period alone did not affect glucose tolerance as assessed by IVGTT but energy uptake during the dry period was associated with changes in peripartal resting concentrations of glucose, as well as postpartum insulin, glucagon, NEFA, and BHB concentrations. PMID- 26627862 TI - The genetic structure of longevity in dairy cows. AB - Longevity of dairy cows is determined by culling. Previous studies have shown that culling of dairy cows is not an unambiguous trait but rather the result of several reasons including diseases and selection decisions. The relative importance of these reasons is not stable over time, implying that genetic background of culling may vary over lifetime. Data of 7.6 million German Holstein cows were used to assess the detailed genetic correlation structure among 18 survival traits defined for the first 3 parities. Differences of genetic factors which determine survival of different production periods were found, showing a pattern with 3 genetically distinct periods within each parity: early lactation (calving until d 59), mid lactation (d 60 to 299), and late lactation (d 300 until next calving). Survival in first and later parities were found to be slightly genetically different from each other. The identified patterns were in good accordance with distributions of reasons for disposal, and correlations of estimated breeding values of survival traits for different periods to production and functional traits were generally plausible compared with literature regarding effects on the risk of culling. The study shows that genetic background of survival is variable not only across but also within parities. The results of the study can help developing more accurate models for routine genetic evaluations of longevity that account for nonunity genetic correlations between survival of different periods. PMID- 26627863 TI - Short communication: Effect of on-farm feeding practices on rumen protected lysine products. AB - Two independent studies were conducted to determine whether mechanical mixing of total mixed ration (TMR) or TMR dry matter alters Lys release from 6 rumen protected Lys (RPL) products (A, B, C, D, E, and F). In the first study, routine mixing procedures were simulated to determine if inclusion of RPL products in TMR altered in situ release of Lys. Following mixing, Dacron bags containing RPL products were ruminally incubated for 0, 6, 12, or 24 h to determine Lys release. The second study occurred independently of the first, in which Lys release from RPL products was evaluated when incorporated into a TMR that differed in dry matter (DM) content. Bags containing TMR and RPL product mixture were stored at room temperature for 0, 6, 18, and 24 h to simulate RPL product exposure to TMR when mixed and delivered once per day. Concentration of free Lys in both studies was determined using ultra-performance liquid chromatography. Following mechanical mixing, ruminal Lys release was significantly greater for C and tended to increase for F. Mechanical mixing did not alter ruminal Lys release from other RPL products evaluated. Hours of ruminal incubation significantly altered Lys release for all products evaluated, and a significant interaction of mechanical mixing and hours of ruminal incubation was observed for A and C. Exposure to lower TMR DM (40.5 versus 51.8%) significantly increased Lys release from B but did not alter Lys release from the other RPL products evaluated. Moreover, time of exposure to TMR significantly increased Lys release from all RPL products evaluated, and a significant interaction of TMR DM and time of exposure to TMR was observed for B and E. These data suggest mechanical mixing and variation in TMR DM may compromise the rumen protection of RPL products; therefore, on-farm feeding practices may alter efficacy of RPL products in dairy rations. PMID- 26627864 TI - Hedonic analysis of the price of UHT-treated milk in Italy. AB - The Italian market for UHT milk has been growing thanks to both consumers' interest in products with an extended shelf life and to the lower prices of these products compared with refrigerated, pasteurized milk. However, because the lower prices of UHT milk can hinder producers' margins, manufacturers have introduced new versions of UHT milk products such as lactose-free options, vitamin-enriched products, and milk for infants, with the goal of differentiating their products, escaping the price competition, and gaining higher margins. In this paper, we estimated the contribution of different attributes to UHT milk prices in Italy by using a database of Italian UHT milk sales and a hedonic price model. In our analysis, we considered 2 UHT milk market segments: products for infants and those for the general population. We found premiums varied with the milk's attributes as well as between the segments analyzed: n-3 fatty acids, organic, and added calcium were the most valuable product features in the general population segment, whereas in the infant segment fiber, glass packaging, and the targeting of newborns delivered the highest premiums. Finally, we present recommendations for UHT milk manufacturers. PMID- 26627865 TI - Comparing brains by matching connectivity profiles. AB - The great promise of comparative neuroscience is to understand why brains differ by investigating the relations between variations in the organization of different brains, their evolutionary history, and their current ecological niche. For this approach to be successful, the organization of different brains needs to be quantifiable. Here, we present an approach to formally comparing the connectivity of different cortical areas across different brains. We exploit the fact that cortical regions can be characterized by the unique pattern of connectivity, the so-called connectivity fingerprint. By comparing connectivity fingerprints between cortical areas in the human and non-human primate brain we can identify between-species homologs, but also illustrate that is driving differences between species. We illustrate the approach by comparing the organization of the frontal cortex between humans and macaques, showing general similarities combined with some differences in the lateral frontal pole. PMID- 26627866 TI - Dissociating memory traces and scenario construction in mental time travel. AB - There has been a persistent debate about how to define episodic memory and whether it is a uniquely human capacity. On the one hand, many animal cognition studies employ content-based criteria, such as the what-where-when criterion, and argue that nonhuman animals possess episodic memory. On the other hand, many human cognition studies emphasize the subjective experience during retrieval as an essential property of episodic memory and the distinctly human foresight it purportedly enables. We propose that both perspectives may examine distinct but complementary aspects of episodic memory by drawing a conceptual distinction between episodic memory traces and mental time travel. Episodic memory traces are sequential mnemonic representations of particular, personally experienced episodes. Mental time travel draws on these traces, but requires other components to construct scenarios and embed them into larger narratives. Various nonhuman animals may store episodic memory traces, and yet it is possible that only humans are able to construct and reflect on narratives of their lives - and flexibly compare alternative scenarios of the remote future. PMID- 26627867 TI - Transcranial Direct Current Stimulation for Chronic Continuous Antipsychotic Refractory Auditory Hallucinations in Alcoholic Hallucinosis. PMID- 26627870 TI - A co-sol-emulsion-gel synthesis of tunable and uniform hollow carbon nanospheres with interconnected mesoporous shells. AB - Monodispersed mesoporous hollow spheres of polymer-silica and carbon-silica nanocomposites with an "interpenetration twin" nanostructure have been successfully synthesized by a co-sol-emulsion-gel method. The obtained mesoporous hollow carbon spheres (MHCSs) exhibited an open interconnected mesoporous shell that is endowed with high specific surface area (SBET, 2106-2225 m(2) g(-1)) and large pore volume (1.95-2.53 cm(3) g(-1)). Interestingly, the diameter of the uniform MHCSs could be precisely tuned on demand, as an effective electrode material in supercapacitors, MHCSs with a diameter of 90 nm deliver the shortest time constant (tau0 = 0.75 s), which is highly beneficial for rate capacitance (180 F g(-1) at 100 A g(-1), a full charge-discharge within 0.9 s) and cyclic retainability (3% loss after 20,000 cycles). The newly developed synthesis route leads to unique interconnected mesoporous hollow carbonaceous spheres with open framework structures, providing a new material platform in energy storage. PMID- 26627868 TI - Strategies for the production of cell wall-deconstructing enzymes in lignocellulosic biomass and their utilization for biofuel production. AB - Microbial cell wall-deconstructing enzymes are widely used in the food, wine, pulp and paper, textile, and detergent industries and will be heavily utilized by cellulosic biorefineries in the production of fuels and chemicals. Due to their ability to use freely available solar energy, genetically engineered bioenergy crops provide an attractive alternative to microbial bioreactors for the production of cell wall-deconstructing enzymes. This review article summarizes the efforts made within the last decade on the production of cell wall deconstructing enzymes in planta for use in the deconstruction of lignocellulosic biomass. A number of strategies have been employed to increase enzyme yields and limit negative impacts on plant growth and development including targeting heterologous enzymes into specific subcellular compartments using signal peptides, using tissue-specific or inducible promoters to limit the expression of enzymes to certain portions of the plant or certain times, and fusion of amplification sequences upstream of the coding region to enhance expression. We also summarize methods that have been used to access and maintain activity of plant-generated enzymes when used in conjunction with thermochemical pretreatments for the production of lignocellulosic biofuels. PMID- 26627872 TI - Clinical trial preparedness in facioscapulohumeral muscular dystrophy: Clinical, tissue, and imaging outcome measures 29-30 May 2015, Rochester, New York. PMID- 26627873 TI - Targeted next-generation sequencing assay for detection of mutations in primary myopathies. AB - Mutations in more than 100 different genes are known to cause hereditary primary myopathies. In patients with less distinct phenotypes several genes may have to be sequenced in order to make the correct diagnosis. The large number of possible candidate genes and overlapping phenotypes, as well as an enormous size of some of the genes such as DMD, TTN and NEB, constitute difficult challenges for molecular genetic diagnostics using conventional sequencing. Molecular characterization is nevertheless important for the final diagnosis and accurate management of the diseases. Targeted next-generation sequencing is a rapid and cost-effective method to sequence large numbers of genes simultaneously. We developed a targeted next-generation sequencing assay, MyoCap, for the coding exons and UTRs of 180 myopathy related genes including 42 novel genes that have not yet been associated with myopathies. DNA samples of four controls with known mutations and 61 patients negative for previous candidate gene approaches were sequenced. The genetic defect was totally or partly clarified in 21 patients with nine of them having potential disease-causing mutations in TTN. MyoCap provides higher read depth and coverage with lower price in the myopathy related genes compared to the whole exome sequencing and is thus very suitable for diagnostic use. PMID- 26627871 TI - Towards a compendium of essential genes - From model organisms to synthetic lethality in cancer cells. AB - Essential genes are defined by their requirement to sustain life in cells or whole organisms. The systematic identification of essential gene sets not only allows insights into the fundamental building blocks of life, but may also provide novel therapeutic targets in oncology. The discovery of essential genes has been tightly linked to the development and deployment of various screening technologies. Here, we describe how gene essentiality was addressed in different eukaryotic model organisms, covering a range of organisms from yeast to mouse. We describe how increasing knowledge of evolutionarily divergent genomes facilitate identification of gene essentiality across species. Finally, the impact of gene essentiality and synthetic lethality on cancer research and the clinical translation of screening results are highlighted. PMID- 26627874 TI - A qualitative examination of the content validity of the EQ-5D-5L in patients with type 2 diabetes. AB - BACKGROUND: The EQ-5D is frequently used to derive utilities for patients with type 2 diabetes (T2D). Despite widely available quantitative psychometric data on the EQ-5D, little is known about content validity in this population. Thus, the purpose of this qualitative study was to examine content validity of the EQ-5D in patients with T2D. METHODS: Patients with T2D in the UK completed concept elicitation interviews, followed by administration of the EQ-5D-5L and cognitive interviewing focused on the instrument's relevance, clarity, and comprehensiveness. RESULTS: A total of 25 participants completed interviews (52.0 % male; mean age = 53.5 years). Approximately half (52 %) reported that the EQ-5D 5L was relevant to their experience with T2D. When asked if each individual item was relevant to their experience with T2D, responses varied widely (24.0 % said the self-care item was relevant; 68.0 % said the anxiety/depression item was relevant). Participants frequently said items were not relevant to themselves, but could be relevant to patients with more severe diabetes. Most participants (92.0 %) reported that T2D and/or its treatment/monitoring requirements had an impact on their quality of life that was not captured by the EQ-5D-5L. Common missing concepts included food awareness/restriction (n = 13, 52.0 %); activities (n = 11, 44.0 %); emotional functioning other than depression/anxiety (n = 8, 32.0 %); and social/relationship functioning (n = 8, 32.0 %). CONCLUSIONS: The results highlight strengths and potential limitations of the EQ-5D-5L, including missing content that could be important for some patients with T2D. Suggestions for addressing limitations are provided. PMID- 26627875 TI - Synapsin Isoforms and Synaptic Vesicle Trafficking. AB - Synapsins were the first presynaptic proteins identified and have served as the flagship of the presynaptic protein field. Here we review recent studies demonstrating that different members of the synapsin family play different roles at presynaptic terminals employing different types of synaptic vesicles. The structural underpinnings for these functions are just beginning to be understood and should provide a focus for future efforts. PMID- 26627876 TI - Positron emission mammography in the diagnosis of breast cancer. Is maximum PEM uptake value a valuable threshold for malignant breast cancer detection? AB - AIM: To evaluate the diagnostic value (sensitivity, specificity) of positron emission mammography (PEM) in a single site non-interventional study using the maximum PEM uptake value (PUVmax). PATIENTS, METHODS: In a singlesite, non interventional study, 108 patients (107 women, 1 man) with a total of 151 suspected lesions were scanned with a PEM Flex Solo II (Naviscan) at 90 min p.i. with 3.5 MBq 18F-FDG per kg of body weight. In this ROI(region of interest)-based analysis, maximum PEM uptake value (PUV) was determined in lesions, tumours (PUVmaxtumour), benign lesions (PUVmaxnormal breast) and also in healthy tissues on the contralateral side (PUVmaxcontralateral breast). These values were compared and contrasted. In addition, the ratios of PUVmaxtumour / PUVmaxcontralateral breast and PUVmaxnormal breast / PUVmaxcontralateral breast were compared. The image data were interpreted independently by two experienced nuclear medicine physicians and compared with histology in cases of suspected carcinoma. RESULTS: Based on a criteria of PUV>1.9, 31 out of 151 lesions in the patient cohort were found to be malignant (21%). A mean PUVmaxtumour of 3.78 +/- 2.47 was identified in malignant tumours, while a mean PUVmaxnormal breast of 1.17 +/- 0.37 was reported in the glandular tissue of the healthy breast, with the difference being statistically significant (p < 0.001). Similarly, the mean ratio between tumour and healthy glandular tissue in breast cancer patients (3.15 +/- 1.58) was found to be significantly higher than the ratio for benign lesions (1.17 +/- 0.41, p < 0.001). CONCLUSION: PEM is capable of differentiating breast tumours from benign lesions with 100% sensitivity along with a high specificity of 96%, when a threshold of PUVmax >1.9 is applied. PMID- 26627877 TI - [Double button Fixation with minimally invasive acromioclavicular cerclage: Arthroscopically-assisted treatment of acute acromioclavicular joint instability]. PMID- 26627878 TI - Blood Pressure Control and Risk of Stroke or Systemic Embolism in Patients With Atrial Fibrillation: Results From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. AB - BACKGROUND: Patients with atrial fibrillation (AF) and hypertension are at high risk for stroke. Previous studies have shown elevated risk of stroke in patients with AF who have a history of hypertension (regardless of blood pressure [BP] control) and in patients with elevated BP. We assessed the association of hypertension and BP control on clinical outcomes. METHODS AND RESULTS: In ARISTOTLE (n=18 201), BP was evaluated as history of hypertension requiring treatment and elevated BP (systolic >=140 and/or diastolic >=90 mm Hg) at study entry and any point during the trial. Hazard ratios (HRs) were derived from Cox proportional hazards models including BP as a time-dependent covariate. A total of 15 916 (87.5%) patients had a history of hypertension requiring treatment. In patients with elevated BP measurement at any point during the trial, the rate of stroke or systemic embolism was significantly higher (HR, 1.53; 95% confidence interval [CI], 1.25-1.86), as was hemorrhagic stroke (HR 1.85; 95% CI, 1.26-2.72) and ischemic stroke (HR, 1.50; 95% CI, 1.18-1.90). Rates of major bleeding were lower in patients with a history of hypertension (HR, 0.80; 95% CI, 0.66-0.98) and nonsignificantly lower in patients with elevated BP at study entry (HR, 0.89; 95% CI, 0.77-1.03). The benefit of apixaban versus warfarin on preventing stroke or systemic embolism was consistent among patients with and without a history of hypertension (P interaction=0.27), BP control at baseline (P interaction=0.43), and BP control during the trial (P interaction=0.97). CONCLUSIONS: High BP measurement at any point during the trial was independently associated with a substantially higher risk of stroke or systemic embolism. These results strongly support efforts to treat elevated BP as an important strategy to optimally lower risk of stroke in patients with AF. CLINICAL TRIAL REGISTRATION: URL: https://ClinicalTrials.gov/. Unique identifier: NCT00412984. PMID- 26627879 TI - Apixaban Reduces Hospitalizations in Patients With Venous Thromboembolism: An Analysis of the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) Trial. AB - BACKGROUND: In the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial, apixaban was noninferior to enoxaparin/warfarin in preventing recurrent symptomatic venous thromboembolism (VTE) or venous thromboembolism-related death, with significantly less bleeding. This analysis evaluated the effects of apixaban versus enoxaparin/warfarin on all-cause hospitalizations during AMPLIFY. METHODS AND RESULTS: Of the 5365 patients included, 2676 received apixaban and 2689 received enoxaparin/warfarin. All-cause hospitalizations during the treatment period after the index event were captured using dedicated case report forms. Outcomes included all-cause hospitalizations and time from randomization to first hospitalization. Patients were censored at death, loss to follow-up, or end of study, whichever came first. Treatment effects were assessed using Cox proportional hazards regression models. During the treatment period after the index event, 343 patients were hospitalized at least once: 153 (5.72%) in the apixaban group and 190 (7.07%) in the enoxaparin/warfarin group. Compared with enoxaparin/warfarin, apixaban significantly reduced all-cause hospitalizations (hazard ratio 0.804, 95% CI=0.650-0.995, P=0.045). All-cause hospitalization rates within the first 30 days after the index event were 2.28% and 3.35% in the apixaban and enoxaparin/warfarin groups, respectively (hazard ratio 0.676, 95% CI=0.488-0.935, P=0.018). For all patients, the average per-patient estimated mean length of hospital stay was also shorter with apixaban than enoxaparin/warfarin (0.57 days versus 1.01 days, P<0.0001). CONCLUSIONS: Apixaban significantly reduced all-cause hospitalizations versus enoxaparin/warfarin, and shortened the length of hospital stay in patients with acute venous thromboembolism. CLINICAL TRIAL REGISTRATION: URL: https://Clinicaltrials.Gov/. Unique identifier: NCT00643201. PMID- 26627880 TI - Diagnostic Accuracy of Commercially Available Automated External Defibrillators. AB - BACKGROUND: Although automated external defibrillators (AEDs) have contributed to a better survival of out-of-hospital cardiac arrests, there have been reports of their malfunctioning. We investigated the diagnostic accuracy of commercially available AEDs using surface ECGs of ventricular fibrillation (VF), ventricular tachycardia (VT), and supraventricular tachycardia (SVT). METHODS AND RESULTS: ECGs(VF 31, VT 48, SVT 97) were stored during electrophysiological studies and transmitted to 4 AEDs, the LifePak CR Plus (CR Plus), HeartStart FR3 (FR3), and CardioLife AED-2150 (CL2150) and -9231 (CL9231), through the pad electrode cables. For VF, the CL2150 and CL9231 advised shocks in all cases, and the CR Plus and FR3 advised shocks in all but one VF case. For VTs faster than 180 bpm, the ratios for advising shocks were 79%, 36%, 89%, and 96% for the CR Plus, FR3, CL2150, and CL9231, respectively. The FR3 and CR Plus did not advise shocks for narrow QRS SVTs, whereas the CL9231 tended to treat high-rate tachycardias faster than 180 bpm even with narrow QRS complexes. The characteristics of the shock advice for the FR3 differed from that for the CL9231 (kappa coefficient [kappa]=0.479, P<0.001), and the CR Plus and CL2150 had characteristics somewhere between the 2 former AEDs (kappa=0.818, P<0.001). CONCLUSIONS: Commercially available AEDs diagnosed VF almost always correctly. For VT and SVT diagnoses, a discrepancy was evident among the 4 investigated AEDs. The differences in the arrhythmia diagnosis algorithms for differentiating SVT from VT were thought to account for these differences. PMID- 26627881 TI - Providing Rapid Out of Hospital Acute Cardiovascular Treatment 4 (PROACT-4). AB - BACKGROUND: Whether prehospital point-of-care (POC) troponin further accelerates the time to diagnosis in patients with chest pain (CP) is unknown. We conducted a randomized trial of POC-Troponin testing in the ambulance. METHODS AND RESULTS: Patients with chest pain presenting by ambulance were randomized to usual care (UC) or POC-Troponin; ST-elevation myocardial infarction patients or those with noncardiovascular symptoms were excluded. Pre-hospital high-sensitivity troponin was analyzed on a POC device and available to the paramedic and emergency department (ED) staff. The final diagnosis was centrally adjudicated. The primary endpoint was time from first medical contact to discharge from ED or admission to hospital. We randomized 601 patients in 19 months; 296 to UC and 305 to POC Troponin. After ambulance arrival, the first troponin was available in 38 minutes in POC-Troponin and 139 minutes in UC. In POC-Troponin, the troponin was >0.01 ng/mL in 17.4% and >0.03 ng/mL in 9.8%. Patients spent a median of 9.0 hours from first medical contact to final disposition, and 165 (27.4%) were admitted to the hospital. The primary endpoint was shorter in patients randomized to POC-Troponin (median 8.8 hours [6.2-10.8] compared to UC (median 9.1 hours [6.7-11.2]; P=0.05). There was no difference in the secondary endpoint of repeat ED visits, hospitalizations, or death in the next 30 days. CONCLUSIONS: In this broad population of patients with CP, ambulance POC-Troponin accelerated the time to final disposition. Enhanced and more cost-effective early ED discharge of the majority of patients with CP calling 911 is an unrealized opportunity. CLINICAL TRIAL REGISTRATION: URL: https://www.ClinicalTrials.gov/. Unique identifier: NCT01634425. PMID- 26627882 TI - Antioxidative phytochemicals from Rhododendron oldhamii Maxim. leaf extracts reduce serum uric acid levels in potassium oxonate-induced hyperuricemic mice. AB - BACKGROUND: Some of the genus Rhododendron was used in traditional medicine for arthritis, acute and chronic bronchitis, asthma, pain, inflammation, rheumatism, hypertension and metabolic diseases and many species of the genus Rhododendron contain a large number of phenolic compounds and antioxidant properties that could be developed into pharmaceutical products. METHODS: In this study, the antioxidative phytochemicals of Rhododendron oldhamii Maxim. leaves were detected by an online HPLC-DPPH method. In addition, the anti-hyperuricemic effect of the active phytochemicals from R. oldhamii leaf extracts was investigated using potassium oxonate (PO)-induced acute hyperuricemia. RESULTS: Six phytochemicals, including (2R, 3R)-epicatechin (1), (2R, 3R)-taxifolin (2), (2R, 3R)-astilbin (3), hyposide (4), guaijaverin (5), and quercitrin (6), were isolated using the developed screening method. Of these, compounds 3, 4, 5, and 6 were found to be major bioactive phytochemicals, and their contents were determined to be 130.8 +/ 10.9, 105.5 +/- 8.5, 104.1 +/- 4.7, and 108.6 +/- 4.0 mg per gram of EtOAc fraction, respectively. In addition, the four major bioactive phytochemicals at the same dosage (100 mmol/kg) were administered to the abdominal cavity of potassium oxonate (PO)-induced hyperuricemic mice, and the serum uric acid level was measured after 3 h of administration. H&E staining showed that PO-induced kidney injury caused renal tubular epithelium nuclear condensation in the cortex areas or the appearance of numerous hyaline casts in the medulla areas; treatment with 100 mmol/kg of EtOAc fraction, (2R, 3R)-astilbin, hyposide, guaijaverin, and quercitrin significantly reduced kidney injury. In addition, the serum uric acid level was significantly suppressed by 54.1, 35.1, 56.3, 56.3, and 53.2 %, respectively, by the administrations of 100 mmol/kg EtOAc fraction and the derived major phytochemicals, (2R, 3R)-astilbin, hyposide, guaijaverin, and quercitrin, compared to the PO group. The administration of 10 mg/kg benzbromarone, a well-known uricosuric agent, significantly reduced the serum uric acid level by 45.5 % compared to the PO group. CONCLUSION: The in vivo decrease in uric acid was consistent with free radical scavenging activity, indicating that the major phytochemicals of R. oldhamii leave extracts and the derived phytochemicals possess potent hypouricemic effects, and they could be potential candidates for new hypouricemic agents. PMID- 26627883 TI - World AIDS Day 2015. PMID- 26627885 TI - GENDER-RELATED FACTORS INFLUENCING WOMEN'S HEALTH SEEKING FOR TUBERCULOSIS CARE IN EBONYI STATE, NIGERIA. AB - This is a qualitative, descriptive study to explore gender-related factors that influence health seeking for tuberculosis (TB) care by women in Ebonyi State, Nigeria. In-depth interviews based on interview guides were conducted with participants selected through purposive sampling in communities in the state. The results show that gender relations prohibit women from seeking care for symptoms of TB and other diseases outside their community without their husbands' approval. Gender norms on intra-household resource ownership and control divest women of the power to allocate money for health care seeking. Yet, the same norms place the burden of spending on health care for minor illnesses on women, and such repeated, out-of-pocket expenditures on health care at the village level make it difficult for women to save money for use for health care seeking for major illnesses such as TB, which, even if subsidized, still involves hidden costs such as transport fare. The opening hours of TB clinics do not favour their use by most women as they are open when women are usually engaged in income generating activities. Attending the clinics may therefore entail opportunity costs for many women. People with chronic, infectious diseases such as TB and HIV are generally stigmatized and avoided. Women suffer more stigma and discrimination than men. Stigma and discrimination make women reluctant to seek care for TB until the disease is advanced. Policies and programmes aimed at increasing women's access to TB services should not only take these gender norms that disempower women into explicit consideration but also include interventions to address them. The programmes should integrate flexible opening hours for TB treatment units, including introduction of evening consultation for women. Interventions should also integrate anti-stigma strategies led by the community members themselves. PMID- 26627884 TI - Transgene silencing of sucrose synthase in alfalfa (Medicago sativa L.) stem vascular tissue suggests a role for invertase in cell wall cellulose synthesis. AB - BACKGROUND: Alfalfa (Medicago sativa L.) is a widely adapted perennial forage crop that has high biomass production potential. Enhanced cellulose content in alfalfa stems would increase the value of the crop as a bioenergy feedstock. We examined if increased expression of sucrose synthase (SUS; EC 2.4.1.13) would increase cellulose in stem cell walls. RESULTS: Alfalfa plants were transformed with a truncated alfalfa phosphoenolpyruvate carboxylase gene promoter (PEPC7-P4) fused to an alfalfa nodule-enhanced SUS cDNA (MsSUS1) or the beta-glucuronidase (GUS) gene. Strong GUS expression was detected in xylem and phloem indicating that the PEPC7-P4 promoter was active in stem vascular tissue. In contrast to expectations, MsSUS1 transcript accumulation was reduced 75-90 % in alfalfa plants containing the PEPC7-P4::MsSUS1 transgene compared to controls. Enzyme assays indicated that SUS activity in stems of selected down-regulated transformants was reduced by greater than 95 % compared to the controls. Although SUS activity was detected in xylem and phloem of control plants by in situ enzyme assays, plants with the PEPC7-P4::MsSUS1 transgene lacked detectable SUS activity in post-elongation stem (PES) internodes and had very low SUS activity in elongating stem (ES) internodes. Loss of SUS protein in PES internodes of down regulated lines was confirmed by immunoblots. Down-regulation of SUS expression and activity in stem tissue resulted in no obvious phenotype or significant change in cell wall sugar composition. However, alkaline/neutral (A/N) invertase activity increased in SUS down-regulated lines and high levels of acid invertase activity were observed. In situ enzyme assays of stem tissue showed localization of neutral invertase in vascular tissues of ES and PES internodes. CONCLUSIONS: These results suggest that invertases play a primary role in providing glucose for cellulose biosynthesis or compensate for the loss of SUS1 activity in stem vascular tissue. PMID- 26627886 TI - FACTORS ASSOCIATED WITH HIV VOLUNTARY DISCLOSURE TO ONE'S STEADY SEXUAL PARTNER IN MALI: RESULTS FROM A COMMUNITY-BASED STUDY. AB - Despite the widespread dissemination of HIV information through public awareness campaigns in Mali, disclosing seropositivity to one's steady sexual partner (SSP) remains difficult for people living with HIV (PLHIV). Disclosure is a public health concern with serious implications and is also strongly linked to the quality of life of PLHIV. This study aimed to analyse factors associated with voluntary HIV disclosure to one's SSP, using a community-based cross-sectional study on 300 adult PLHIV in contact with a Malian community-based organization working in the field of AIDS response. A 125-item questionnaire was administered by trained personnel to study participants between May and October 2011. Analysis was restricted to the 219 participants who both reported having a SSP and answered to the question on disclosure to their SSP. A weighted multivariate logistic regression was used to determine variables independently associated with disclosure. In total, 161 participants (73%) reported HIV disclosure to their SSP. Having children (odds ratio [95% confidence interval]: 4.52 [1.84-11.12]), being accompanied to the survey site (3.66 [1.00-13.33]), knowing others who had publicly declared their seropositivity (3.12 [1.59-6.12]), having higher self esteem (1.55 [1.09-2.19]) and using means other than anti-retroviral treatment to treat HIV (0.33 [0.11-1.00]) were independently associated with disclosure. This study identified several factors that should be considered for the design of interventions aimed at facilitating disclosure if/when desired in this cultural context. PMID- 26627887 TI - CONSANGUINITY AND INBREEDING COEFFICIENT IN TRIBAL PASHTUNS INHABITING THE TURBULENT AND WAR-AFFECTED TERRITORY OF BAJAUR AGENCY, NORTH-WEST PAKISTAN. AB - The north-western populations of Pakistan in the Federally Administered Tribal Areas (FATA) adjoining the Pakistan-Afghanistan border are an amalgamation of native and migrated Pashtun tribes. These tribal populations are in transition due to war conditions and geo-political turmoil on both sides of the border since the Soviet invasion in 1979. Bio-demographic and epidemiological data for these tribes are scarce. A prospective cross-sectional sample of 967 males was selected from a representative Pashtun population of Bajaur Agency, and information obtained on bio-demographic variables and marital union types. Analysis of these data revealed that consanguinity was 22.34% and the inbreeding coefficient F was calculated to be 0.0134. The inbreeding coefficient was observed to be higher in subjects who were illiterate, had unskilled jobs and who belonged to younger age categories, extended families and the Tarkalani tribe. Further analyses with respect to temporal variables like subject's age, year of marriage and age at marriage revealed that after a transition in marital union types in the early 80s, there has been a declining trend in the rate of consanguineous unions. Further, consanguineous unions in the parental generation were only 5%, but parental marriage types were predictors of subjects' marital union types. The data further establish that, contrary to a general notion about a high consanguinity rate in Pakistan, consanguineous unions are not common in Bajaur Agency and first cousin marriage is not the preferred type. Furthermore, this research shows that there is a great regional variation in the pattern of consanguinity in Pakistan that needs to be documented in order to draw a more comprehensive picture of the inbreeding coefficient in the country. PMID- 26627888 TI - A tyrosine-tryptophan dyad and radical-based charge transfer in a ribonucleotide reductase-inspired maquette. AB - In class 1a ribonucleotide reductase (RNR), a substrate-based radical is generated in the alpha2 subunit by long-distance electron transfer involving an essential tyrosyl radical (Y122O.) in the beta2 subunit. The conserved W48 beta2 is ~10 A from Y122OH; mutations at W48 inactivate RNR. Here, we design a beta hairpin peptide, which contains such an interacting tyrosine-tryptophan dyad. The NMR structure of the peptide establishes that there is no direct hydrogen bond between the phenol and the indole rings. However, electronic coupling between the tyrosine and tryptophan occurs in the peptide. In addition, downshifted ultraviolet resonance Raman (UVRR) frequencies are observed for the radical state, reproducing spectral downshifts observed for beta2. The frequency downshifts of the ring and CO bands are consistent with charge transfer from YO. to W or another residue. Such a charge transfer mechanism implies a role for the beta2 Y-W dyad in electron transfer. PMID- 26627889 TI - Depressive Symptoms in Adolescence: Longitudinal Links with Maternal Empathy and Psychological Control. AB - Building on self-determination theory (Deci and Ryan in Psychological Inquiry, 11, 227-268. doi: 10.1207/S15327965PLI1104_01 , 2000), the aim of the current study was to examine the role of maternal affective and cognitive empathy in predicting adolescents' depressive symptoms, through mothers' psychological control use. Less empathic mothers may be less sensitive to adolescents' need for psychological autonomy, and thus prone to violating this need using psychological control, which may in turn predict adolescents' depressive symptoms. Moreover, according to interpersonal theory of depression (Coyne in Journal of Abnormal Psychology, 85, 186-193. doi: 10.1037/0021-843x.85.2.186 , 1976), adolescents' depressive symptoms may elicit rejecting responses, such as mothers' psychological control. For six waves, 497 adolescents (57 % boys, M age T1 = 13.03) annually completed questionnaires on depressive symptoms and maternal psychological control, while mothers reported on their empathy. Cross-lagged path analyses showed that throughout adolescence, both mothers' affective and cognitive empathy indirectly predicted boys' and girls' depressive symptoms, through psychological control. Additionally, depressive symptoms predicted psychological control for boys, and early adolescent girls. These results highlight the importance of (1) mothers' affective and cognitive empathy in predicting adolescents' depressive symptoms, and (2) taking gender into account when examining adolescent-effects. PMID- 26627890 TI - Isolation and characterization of a serine protease-producing marine bacterium Marinomonas arctica PT-1. AB - A serine protease-producing marine bacterial strain named as PT-1 was isolated and identified as a family of Marinomonas arctica, based on molecular characterization of 16S rRNA gene sequence, phylogenetic tree, and fatty acid composition analyses. Optimized culture conditions for growth of the bacterium PT 1 and production of protease (ProA) were determined to be pH 8.0 in the presence of 5 % NaCl, at 37 degrees C during 24 h of incubation in the presence of 1.0 % skim milk. The molecular weight of the purified ProA was estimated to be 63-kDa as a major band by SDS-PAGE. We were intrigued to find that the activity of ProA was not inhibited by pepstatin A, chymostatin, and leupeptin known as inhibitors for cysteine protease. However, phenylmethylsulfonyl fluoride (PMSF) completely inhibited protease activity, suggesting that the ProA is like a serine protease. To the best of our knowledge, this is the first report on serine protease of Marinomonas species. PMID- 26627891 TI - Analysis of the efficiency and costs of antifungal prophylaxis and mycological diagnostics in patients undergoing allogeneic haematopoietic cell transplantation: "real life" evaluation. AB - Antifungal prophylaxis/therapy (AP/AT) raises the cost of allogeneic haematopoietic cell transplantation (alloHCT). Its efficacy, different approaches for AP/AT, diagnostic measures and cost-effectiveness must still be evaluated. In 2010, we conducted a prospective study with 106 consecutive patients receiving an alloHCT analysing AP/AT, choice and costs of diagnostics applied including CT scans, galactomannan (Gal) and beta-D-glucan (beta-D) testing. Antifungal prophylaxis in 91 patients consisted of fluconazole (FLU) or L-AMB (AmBisomeTM 1 or 3 mg/kg/day b.w.), and antifungal therapy had to be initiated in 38 % of the FLU/L-AMB-1-mg patients but in none with L-AMB 3 mg. Empirical AT consisted of L AMB 1 mg/kg (n = 12) and preemptive AT of L-AMB 3 mg/kg (n = 17) and proved very efficacious with no further antifungal drug escalation in 89.6 %. Mean costs of diagnostic measures were 402 ?/alloHCT; however, only 22 % of the CT scans, 4 % of beta-D and 3 % of galactomannan testing were positive. We detected one proven, 17 probable and 14 possible fungal infections. Due to the German diagnosis related group system with additional compensation, all our AP/AT strategies were adequately reimbursed. While clinical symptoms and CT scans are the most commonly used, inexpensive decision-making tools for starting AT, the expensive laboratory diagnostic procedures are ineffective; we have therefore discontinued regular GAL/beta-D testing and changed our AP in patients at risk. PMID- 26627892 TI - Targeting vivax malaria in the Asia Pacific: The Asia Pacific Malaria Elimination Network Vivax Working Group. AB - The Asia Pacific Malaria Elimination Network (APMEN) is a collaboration of 18 country partners committed to eliminating malaria from within their borders. Over the past 5 years, APMEN has helped to build the knowledge, tools and in-country technical expertise required to attain this goal. At its inaugural meeting in Brisbane in 2009, Plasmodium vivax infections were identified across the region as a common threat to this ambitious programme; the APMEN Vivax Working Group was established to tackle specifically this issue. The Working Group developed a four stage strategy to identify knowledge gaps, build regional consensus on shared priorities, generate evidence and change practice to optimize malaria elimination activities. This case study describes the issues faced and the solutions found in developing this robust strategic partnership between national programmes and research partners within the Working Group. The success of the approach adopted by the group may facilitate similar applications in other regions seeking to deploy evidence-based policy and practice. PMID- 26627894 TI - Assessment of cardiac mass from tagged magnetic resonance images. AB - PURPOSE: Tagged and cine magnetic resonance imaging (tMRI and cMRI) techniques are used for evaluating regional and global heart function, respectively. Measuring global function parameters directly from tMRI is challenging due to the obstruction of the anatomical structure by the tagging pattern. The purpose of this study was to develop a method for processing the tMRI images to improve the myocardium-blood contrast in order to estimate global function parameters from the processed images. MATERIALS AND METHODS: The developed method consists of two stages: (1) removing the tagging pattern based on analyzing and modeling the signal distribution in the image's k-space, and (2) enhancing the blood myocardium contrast based on analyzing the signal intensity variability in the two tissues. The developed method is implemented on images from twelve human subjects. RESULTS: Ventricular mass measured with the developed method showed good agreement with that measured from gold-standard cMRI images. Further, preliminary results on measuring ventricular volume using the developed method are presented. CONCLUSION: The promising results in this study show the potential of the developed method for evaluating both regional and global heart function from a single set of tMRI images, with associated reduction in scan time and patient discomfort. PMID- 26627895 TI - Case report of vasovagal syncope associated with single pulse transcranial magnetic stimulation in a healthy adult participant. AB - BACKGROUND: Non-invasive brain stimulation-related seizures or syncopal events are rare. However, we report on a syncopal event in a healthy female during a transcranial magnetic stimulation single-pulse testing session. CASE PRESENTATION: A 47-year-old healthy female presented for a transcranial magnetic stimulation session involving single-pulse assessment of cortical excitability. During the session, the participant appeared to have a brief event involving fainting and myoclonic jerks of the upper extremities. Orthostatic assessment was performed after the event and physician evaluation determined that this was a vasovagal syncopal event. The ethical aspects of this neurophysiology testing protocol were reviewed by the University of Minnesota Institutional Review Board (IRB), and formal IRB approval was deemed unnecessary for single-pulse assessment of healthy control participants not directly involved in a research study. Informed consent was obtained by the participant, including review of potential adverse events. CONCLUSION: Although rare and rarely reported, vasovagal syncopal events surrounding non-invasive brain stimulation do occur. Thorough pre screening should incorporate assessment of history of syncope and a plan for risk mitigation if such an event should occur. A complete assessment of the impact of stimulation on the autonomic nervous system is unknown. As such studies expand into patients with myriad neurologic diagnoses, further studies on this effect, in both healthy control and patient populations, are warranted. Such knowledge could contribute to identification of the optimal study participant, and improvements in techniques of stimulation administration. PMID- 26627896 TI - Steroid-resistant nephrotic syndrome caused by novel WT1 mutation inherited from a mosaic parent. AB - Steroid-resistant nephrotic syndrome (SRNS) is a severe childhood disorder frequently progressing toward renal failure. Among its genetic causes are mutations in the Wilms tumor gene, WT1, which codes for a transcription factor with key role for the embryonic development of the genitourinary tract as well as for maintaining podocyte differentiation and slit diaphragm structure in adults. Defects in WT1 are associated with sporadic cases of both syndromic and isolated SRNS. We report here a novel WT1 mutation associated with SRNS in a female patient, which leads to a Cys428Ser substitution on protein level, affecting one of the cysteine residues responsible for zinc binding in the second zinc finger domain. Surprisingly, the mutation identified in the patient was found to be inherited from the healthy mosaic mother. The presence of mosaicism was confirmed using quantitative polymerase chain reaction (PCR) high-resolution melting. The clinical implications of this finding for the family are discussed. PMID- 26627897 TI - Comment on: negative health implications of sickle cell trait in high income countries: from the football field to the laboratory. PMID- 26627893 TI - The essence of the Japan Radiological Society/Japanese College of Radiology Imaging Guideline. AB - Diagnostic imaging is undoubtedly important in modern medicine, and final clinical decisions are often made based on it. Fortunately, Japan has the highest numbers of diagnostic imaging instruments, such as CT and MRI devices, and boasts easy access to them as well as a high level of diagnostic accuracy. In consequence, a very large number of imaging examinations are performed, but diagnostic instruments are installed in so many medical facilities that expert management of these examinations tends to be insufficient. Particularly, in order to avoid risks, clinicians have recently become indifferent to indications of imaging modalities and tend to rely on CT or MRI resulting in increasing the number of imaging examinations in Japan. This is a serious problem from the viewpoints of avoidance of unnecessary exposure and medical economy. Under these circumstances, the Japan Radiological Society and Japanese College of Radiology jointly initiated the preparation of new guidelines for diagnostic imaging. However, the field of diagnostic imaging is extremely wide, and it is impossible to cover all diseases. Therefore, in drafting the guidelines, we selected important diseases and focused on "showing evidence and suggestions in the form of clinical questions (CQs)" concerning clinically encountered questions and "describing routine imaging techniques presently considered to be standards to guarantee the quality of imaging examinations". In so doing, we adhered to the basic principles of assuming the readers to be "radiologists specializing in diagnostic imaging", "simultaneously respecting the global standards and attending to the situation in Japan", and "making the guidelines consistent with those of other scientific societies related to imaging". As a result, the guidelines became the largest ever, consisting of 152 CQs, nine areas of imaging techniques, and seven reviews, but no other guidelines in the world summarize problems concerning diagnostic imaging in the form of CQs. In this sense, the guidelines are considered to reflect the abilities of diagnostic radiologists in Japan. The contents of the guidelines are essential knowledge for radiologists, but we believe that they are also of use to general clinicians and clinical radiological technicians. While the number and contents of CQs are still insufficient, and while chapters such as those on imaging in children and emergency imaging need to be supplemented, the guidelines will be serially improved through future revisions. Lastly, we would like to extend our sincere thanks to the 153 members of the drafting committee who authored the guidelines, 12 committee chairpersons who coordinated their efforts, six members of the secretariat, and affiliates of related scientific societies who performed external evaluation. PMID- 26627898 TI - Prevalence and correlates of abuse screening items among community-dwelling Hong Kong Chinese older adults. AB - AIM: The present study aims to describe the prevalence of potential elder abuse, and to examine correlates of abuse screening items among Chinese community dwelling older adults. METHODS: We analyzed the data of 3435 older persons aged >=60 years who had first applied for the long-term care services in Hong Kong and completed the screening tool (Minimum Data Set-Home Care) in 2006. For each of the five abuse screening items ("fearful of a family member/caregiver," "unexplained injuries/broken bones/burns," "physically restrained," "unusually poor hygiene" and "neglected/abused/mistreated"), we examined its relationship with four types of factors: older person, perpetrator, relationship and environment. RESULTS: The rates of individual abuse screening items ranged from 3.9% for physically restrained to 0.03% for unexplained injures/broken bones/burns. Physically restrained was positively associated with activities of daily living impairments, instrumental activities of daily living impairments, perceived poor health, physically abusive behavior and caregiver mental health. Unusually poor hygiene was positively associated with socially inappropriate behavior and actively resisted care. "Fearful of a family member/caregiver" was positively associated with perceived poor health, conflicting relationship and mental health, and negatively with care activities. Neglected/abused/mistreated was positively associated with age and informal care, and negatively with care activities. CONCLUSIONS: We identified a number of associated factors of different abuse screening items among older adults. Our findings could inform healthcare practitioners in identifying those older persons who might be at higher risk of abuse, and provide a knowledge base on which to develop effective preventive measures in the Chinese population. Geriatr Gerontol Int 2017; 17: 150 160. PMID- 26627899 TI - Comparing different methods of human breast milk fortification using measured v. assumed macronutrient composition to target reference growth: a randomised controlled trial. AB - The variable content of human breast milk suggests that its routine fortification may result in sub-optimal nutritional intakes and growth. In a pragmatic trial, we randomised infants born below 30 weeks of gestation to either the intervention (Igp) of fortifying milk on measured composition according to birth weight criteria and postmenstrual age (PMA) or our routine practice (RPgp) of fortifying on assumed milk composition to target 3.8-4.4 g protein/kg per d and 545-629 kJ/kg per d. Milk composition was measured using the MIRIS(r) Human Milk Analyser. Percentage fat mass (%FM) was measured using PEA POD (COSMED). The effects of macronutrient intakes and clinical variables on growth were assessed using mixed model analysis. Mean measured protein content (1.6 g/100 ml) was higher than the assumed value (1.4 g/100 ml), often leading to lower amounts of fortifier added to the milk of intervention infants. At discharge (Igp v. RPgp), total protein (3.2 (SD 0.3) v. 3.4 (SD 0.4) g; P=0.067) and energy (456 (SD 39) v. 481 (SD 48) kJ; P=0.079) intakes from all nutrition sources, weight gain velocity (11.4 (SD 1.4) v. 12.1 (SD 1.6) g/kg per d; P=0.135) and %FM (13.7 (SD 3.6) v.13.6 (SD 3.5) %; P=0.984) did not significantly differ between groups. A protein intake >3.4 g/kg per d reduced %FM by 2%. Nutrition and growth was not improved by targeting milk fortification according to birth weight criteria and PMA using measured milk composition, compared with routine practice. Targeting fortification on measured composition is labour intensive, requiring frequent milk sampling and precision measuring equipment, perhaps reasons for its limited practice. Guidance around safe upper levels of milk fortification is needed. PMID- 26627900 TI - Influenza B-associated acute necrotizing encephalopathy of childhood: a report from North America. PMID- 26627901 TI - An EPR study of ampullosporin A, a medium-length peptaibiotic, in bicelles and vesicles. AB - Ampullosporin A is a medium-length (14-amino acid long) hydrophobic peptide of the peptaibol family. In this work, electron paramagnetic resonance and circular dichroism spectroscopies were applied to study the interaction of synthetic ampullosporin A and three spin-labeled analogs with small unilamellar vesicles and bicelles. Zwitterionic vesicles were used to investigate the conformation and the penetration depth of the peptide at room temperature. Bicelles were employed in combination with EPR spectroscopy to study the order, dynamics, orientation, aggregation and the 3D-structure of the peptide at near physiological temperature. In the membrane, the peptide adopts a helical structure that changes in nature depending on the thickness of the membrane-mimetic system, from mostly alpha-helical in vesicles to a more elongated helix in bicelles, suggesting an increase in the 310-helical content. The orientation assumed by the peptide also shows a dependence on the membrane-mimetic system: in bicelles, ampullosporin A has a transmembrane orientation at a peptide-to-lipid (P : L) ratio of 1 : 100 and higher, while in vesicles it undergoes a transition from a parallel to a transmembrane orientation as a function of the P : L ratio. In bicelles, the peptide was found to be monomeric at a P : L ratio of 1 : 25 and lower. Overall, the comparison of the results obtained in the two membrane-mimetic systems showed that ampullosporin A has a rather flexible structure that readily adapts to the bilayer thickness. PMID- 26627902 TI - High-resolution accurate mass spectrometry as a technique for characterization of complex lysimeter leachate samples. AB - Lysimeter studies can be used to identify and quantify soil degradates of agrochemicals (metabolites) that have the potential to leach to groundwater. However, the apparent metabolic profile of such lysimeter leachate samples will often be significantly more complex than would be expected in true groundwater samples. This is particularly true for S-metolachlor, which has an extremely complex metabolic pathway. Consequently, it was not practically possible to apply a conventional analytical approach to identify all metabolites in an S metolachlor lysimeter study, because there was insufficient mass to enable the use of techniques such as nuclear magnetic resonance. Recent advances in high resolution accurate mass spectrometry, however, allow innovative screening approaches to characterize leachate samples to a greater extent than previously possible. Leachate from the S-metolachlor study was screened for accurate masses (+/-5 ppm of the nominal mass) corresponding to more than 400 hypothetical metabolite structures. A refined list of plausible metabolites was constructed from these data to provide a comprehensive description of the most likely metabolites present. The properties of these metabolites were then evaluated using a principal component analysis model, based on molecular descriptors, to visualize the entire chemical space and to cluster the metabolites into a number of subclasses. This characterization and principal component analysis evaluation enabled the selection of suitable representative metabolites that were subsequently used as exemplars to assess the toxicological relevance of the leachate as a whole. Environ Toxicol Chem 2016;35:1401-1412. (c) 2015 SETAC. PMID- 26627903 TI - Drugs of abuse in maternal hair and paired neonatal meconium: an objective assessment of foetal exposure to gestational consumption. AB - In a prospective sample of 80 mother-infant dyads, we investigated whether drugs of abuse in maternal hair measured during the pregnancy trimesters were also present in neonatal meconium. Principal drugs of abuse were analyzed in the three consecutive maternal hair segments and meconium samples by ultra-performance liquid chromatography tandem mass spectrometry assay. Of the 80 mothers, 32 (40%) presented one or more hair shafts with at least one of the analyzed drugs of abuse and/or its metabolites. The drug of abuse with a higher prevalence in our study population was methamphetamine: 19 mothers had methamphetamine in one or more hair segments (59.4%). The second most detected drug of abuse was cocaine; nine mothers presented cocaine in one or more hair segments (28.1%). Nineteen pregnant women consumed at least one drug of abuse during the first trimester, ten continued consuming drugs of abuse during the second trimester; and nine consumed until the end of pregnancy. Five of the nine newborns from mothers who consumed drugs during the whole pregnancy showed drugs of abuse in meconium samples. Newborns from the 23 remaining mothers with one or two hair shafts positive to drugs of abuse did not present drugs in their meconium. Indeed from these results, it seems that discontinuous and/or sporadic consumption during pregnancy could produce a negligible transplacental passage and hence negative results in meconium. Furthermore, the role of placenta in the metabolism and excretion of drugs of abuse is still to be precisely investigated. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26627904 TI - Cancer and Employment Issues: Perspectives from Cancer Patient Navigators. AB - Among individuals diagnosed with cancer, 40 % are working-age adults who will face numerous challenges in returning to work, yet oncology providers report limited guidance and uncoordinated communication processes in addressing patients' work-related issues. Cancer patient navigators are uniquely positioned to fill this care and communication gap due to their focus on both practical matters and clinical care. This cross-sectional study utilized survey methodology to collect quantitative and qualitative data from 58 cancer patient navigators to (1) identify patients' cancer and employment issues that commonly challenge navigators and (2) identify the necessary training navigators felt would allow them to more effectively help patients deal with cancer and employment issues. Participants from the southeast USA were invited to complete a paper survey while in attendance at a statewide cancer patient navigator conference or online via the state comprehensive cancer coalition's cancer patient navigator listserv. Results suggest financial burdens, work and treatment conflicts, taking unpaid leave for cancer care, and working through treatment were common concerns among their patients. Navigators also identified employment, legal, government programs, and financial resources as important training and education topics that would help them address their clients' employment and cancer conflicts. Given the fact that employment issues remain one of the most common unmet need of survivors and the increasing presence of navigators across the USA, it is important to address the role of navigators in meeting patients' needs regarding cancer and employment and ensure they are provide with adequate training and resources. PMID- 26627905 TI - Prostate Cancer Ambassadors: Enhancing a Theory-Informed Training Program for Informed Decision-Making. AB - Despite the high burden of prostate cancer in African American communities, there is a paucity of knowledge about prostate health. This paper describes the enhancement of a curriculum for training lay health advisors, called prostate cancer ambassadors, on informed decision-making for prostate cancer screening. Adult learning theory informed the structuring of the training sessions to be interactive, self-directed, and engaging. Trainings were developed in a manner that made the material relevant to the learners and encouraged co-learning. The research team developed strategies, such as using discussions and interactive activities, to help community members weigh the pros and cons of prostate specific antigen (PSA) screening and to make an informed decision about screening. Furthermore, activities were developed to bolster four social cognitive theory constructs: observational learning, self-efficacy for presenting information to the community and for making an informed decision themselves, collective efficacy for presenting information to the community, and outcome expectations from those presentations. Games, discussions, and debates were included to make learning fun and encourage discovery. Practice sessions and team building activities were designed to build self-efficacy for sharing information about informed decision-making. Topics added to the original curriculum included updates on prostate cancer screening, informed decision-making for screening, skills for being a lay health advisor, and ethics. This dynamic model and approach to lay health advisor (ambassador) training is flexible: while it was tailored for use with prostate cancer education, it can be adjusted for use with other types of cancer and even other diseases. PMID- 26627906 TI - New shifts in the Journal of Plant Research. PMID- 26627907 TI - Lysyl oxidase propeptide stimulates osteoblast and osteoclast differentiation and enhances PC3 and DU145 prostate cancer cell effects on bone in vivo. AB - Lysyl oxidase pro-enzyme is secreted by tumor cells and normal cells as a 50 kDa pro-enzyme into the extracellular environment where it is cleaved into the ~30 kDa mature enzyme (LOX) and 18 kDa pro-peptide (LOX-PP). Extracellular LOX enzyme activity is required for normal collagen and elastin extracellular cross-linking and maturation of the extracellular matrix. Extracellular LOX-PP acts as a tumor suppressor and can re-enter cells from the extracellular environment to induce its effects. The underlying hypothesis is that LOX-PP has the potential to promote bone cell differentiation, while inhibiting cancer cell effects in bone. Here we investigate the effect of LOX-PP on bone marrow cell proliferation and differentiation towards osteoblasts or osteoclasts, and LOX-PP modulation of prostate cancer cell conditioned media-induced alterations of proliferation and differentiation of bone marrow cells in vitro. Effects of overexpression of rLOX PP in DU145 and PC3 prostate cancer cell lines on bone structure in vivo after intramedullary injections were determined. Data show that prostate cancer cell conditioned media inhibited osteoblast differentiation in bone marrow-derived cells, which was reversed by rLOX-PP treatment. Prostate cancer conditioned media stimulated osteoclast differentiation which was further enhanced by rLOX-PP treatment. rLOX-PP stimulated osteoclast differentiation by inhibiting OPG expression, up-regulating CCN2 expression, and increasing osteoclast fusion. In vivo studies indicate that rLOX-PP expression by PC3 cells implanted into the tibia of mice further enhanced PC3 cell ability to resorb bone, while rLOX-PP expression in DU145 cells resulted in non-significant increases in net bone formation. rLOX-PP enhances both osteoclast and osteoblast differentiation. rLOX PP may serve to enhance coupling interactions between osteoclasts and osteoblasts helping to maintain a normal bone turnover in health, while contributing to bone abnormalities in disease. PMID- 26627908 TI - Conserved targeting information in mammalian and fungal peroxisomal tail-anchored proteins. AB - The targeting signals and mechanisms of soluble peroxisomal proteins are well understood, whereas less is known about the signals and targeting routes of peroxisomal membrane proteins (PMP). Pex15 and PEX26, tail-anchored proteins in yeast and mammals, respectively, exert a similar cellular function in the recruitment of AAA peroxins at the peroxisomal membrane. But despite their common role, Pex15 and PEX26 are neither homologs nor they are known to follow similar targeting principles. Here we show that Pex15 targets to peroxisomes in mammalian cells, and PEX26 reaches peroxisomes when expressed in yeast cells. In both proteins C-terminal targeting information is sufficient for correct sorting to the peroxisomal membrane. In yeast, PEX26 follows the pathway that also ensures correct targeting of Pex15: PEX26 enters the endoplasmic reticulum (ER) in a GET dependent and Pex19-independent manner. Like in yeast, PEX26 enters the ER in mammalian cells, however, independently of GET/TRC40. These data show that conserved targeting information is employed in yeast and higher eukaryotes during the biogenesis of peroxisomal tail-anchored proteins. PMID- 26627909 TI - Detection of high-risk human papillomavirus using menstrual blood in women with high-grade squamous intraepithelial lesions or high-risk human papillomavirus infections: A pilot study. AB - AIM: Few studies have reported that human papillomavirus (HPV) tests using menstrual blood (MB) may be a convenient and effective screening modality for cervical cancer. Therefore, we aimed to investigate the efficacy of detecting high-risk (HR)-HPV from MB in women with high-grade squamous intraepithelial lesions or HR-HPV infections dependent on menstrual days. MATERIALS AND METHODS: In this prospective exploratory pilot study, a clinical trial was conducted in 19 women. On enrollment into the study, gynecologists collected cervical cells. On the first and second day of menstruation, MB was self-collected by patients using a sanitary pad with a filter. The distribution of HPVs from MB and the accuracy of menstrual HR-HPV tests were evaluated using HPV genotyping. The agreement rate of detecting HR-HPVs using cervical and MB samples was also investigated. RESULTS: The sensitivity, specificity, positive and negative predictive values of the MB HR-HPV test for detecting cervical intraepithelial neoplasia (CIN) 3 or worse were 87.5%, 45.5%, 53.8%, and 83.3%, respectively, during both menstrual cycle day (MCD) 1 and 2 and MCD 1 only; and 62.5%, 27.3%, 38.5%, and 50.0%, respectively, during MCD 2 only. For CIN 3 or worse, the agreement rate between positive cervical and MB HR-HPV test results was 87.5% during MCD 1 and 62.5% during MCD 2. CONCLUSIONS: We demonstrated the possibility of using the MB HPV test as a screening modality for cervical cancer. PMID- 26627910 TI - Experimental observation of weak non-Markovianity. AB - Non-Markovianity has recently attracted large interest due to significant advances in its characterization and its exploitation for quantum information processing. However, up to now, only non-Markovian regimes featuring environment to system backflow of information (strong non-Markovianity) have been experimentally simulated. In this work, using an all-optical setup we simulate and observe the so-called weak non-Markovian dynamics. Through full process tomography, we experimentally demonstrate that the dynamics of a qubit can be non Markovian despite an always increasing correlation between the system and its environment which, in our case, denotes no information backflow. We also show the transition from the weak to the strong regime by changing a single parameter in the environmental state, leading us to a better understanding of the fundamental features of non-Markovianity. PMID- 26627913 TI - Conversion Reaction-Based Oxide Nanomaterials for Lithium Ion Battery Anodes. AB - Developing high-energy-density electrodes for lithium ion batteries (LIBs) is of primary importance to meet the challenges in electronics and automobile industries in the near future. Conversion reaction-based transition metal oxides are attractive candidates for LIB anodes because of their high theoretical capacities. This review summarizes recent advances on the development of nanostructured transition metal oxides for use in lithium ion battery anodes based on conversion reactions. The oxide materials covered in this review include oxides of iron, manganese, cobalt, copper, nickel, molybdenum, zinc, ruthenium, chromium, and tungsten, and mixed metal oxides. Various kinds of nanostructured materials including nanowires, nanosheets, hollow structures, porous structures, and oxide/carbon nanocomposites are discussed in terms of their LIB anode applications. PMID- 26627911 TI - Prenatal cocaine exposure, illicit-substance use and stress and craving processes during adolescence. AB - BACKGROUND: Prenatal cocaine exposure (PCE) is associated with increased rates of illicit-substance use during adolescence. In addition, both PCE and illicit substance use are associated with alterations in cortico-striato-limbic neurocircuitry, development of which is ongoing throughout adolescence. However, the relationship between illicit-substance use, PCE and functional neural responses has not previously been assessed concurrently. METHODS: Sixty-eight adolescents were recruited from an ongoing longitudinal study of childhood and adolescent development. All participants had been followed since birth. Functional magnetic resonance imaging (fMRI) data were acquired during presentation of personalized stressful, favorite-food and neutral/relaxing imagery scripts and compared between 46 PCE and 22 non-prenatally-drug-exposed (NDE) adolescents with and without lifetime illicit-substance use initiation. Data were analyzed using multi-level ANOVAs (pFWE<.05). RESULTS: There was a significant three-way interaction between illicit-substance use, PCE status and cue condition on neural responses within primarily cortical brain regions, including regions of the left and right insula. Among PCE versus NDE adolescents, illicit-substance use was associated with decreased subcortical and increased cortical activity during the favorite-food condition, whereas the opposite pattern of activation was observed during the neutral/relaxing condition. Among PCE versus NDE adolescents, illicit-substance use during stress processing was associated with decreased activity in cortical and subcortical regions including amygdala, hippocampus and prefrontal cortex. Neural activity within cortico striato-limbic regions was significantly negatively associated with subjective ratings of anxiety and craving among illicit-substance users, but not among non users. CONCLUSIONS: These findings suggest different neural substrates of experimentation with illicit drugs between adolescents with and without in utero cocaine exposure. PMID- 26627912 TI - Chronic ethanol self-administration in macaques shifts dopamine feedback inhibition to predominantly D2 receptors in nucleus accumbens core. AB - BACKGROUND: Given the high level of homology between nonhuman primates and humans in regard to anatomy, physiology and ethanol drinking patterns, nonhuman primates represent an unparalleled preclinical model for examining the neurobiological basis of ethanol abuse. METHODS: Here we examined the neurochemical consequences of chronic daily ethanol use using fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens core or dorsolateral caudate taken from male cynomolgus macaques following ethanol drinking. RESULTS: We found that in both regions the ability of ethanol to decrease dopamine release was unchanged, indicating that ethanol self-administration does not produce tolerance or sensitization to ethanol effects on dopamine release at the dopamine terminal at this time point. We also found that in the nucleus accumbens core, autoregulation of dopamine release was shifted from equal D2 and D3 receptor involvement in control animals to primarily D2 receptor-mediated in drinkers. Specifically, the effect quinpirole, a D2/D3 receptor agonist, on dopamine release was equal across groups; however, dopamine signals were reversed to a greater extent by the selective D3 receptor antagonist SB-277,011A in control animals, indicating a greater contribution of D2 receptors in quinpirole-induced inhibition following ethanol self-administration. In the dorsolateral caudate, the effects of quinpirole and reversal with SB-277,011A was not different between ethanol and control slices. CONCLUSIONS: This work provides novel insight into the dopaminergic adaptations resulting from chronic ethanol use in nonhuman primates and indicates that alterations in D2/D3 dopamine autoreceptor signaling may be an important neurochemical adaptation to ethanol consumption during early use. PMID- 26627914 TI - Preparation of crosslinked enzyme aggregates (CLEAs) of acid urease with urethanase activity and their application. AB - An acid urease from Providencia rettgeri JN-B815 was purified via ultrasonication, ethanol precipitation, and DEAE ion-exchange column chromatography. It was found that the enzyme exhibits not only urease activity, but also urethanase activity, which made it possible to reduce EC already existed or would produce and its precursor urea at the same time. Then, crosslinked enzyme aggregates of P. rettgeri urease (PRU-CLEAs) were prepared using genipin as crosslinking agent. The purification process of acid urease, the effects of genipin concentration, and crosslinking time on PRU-CLEAs activity were investigated. The crosslinking was performed at pH 4.5 for 2.5 h, using 0.3% genipin as crosslinking agent, and 0.3 g . L(-1) bovine serum albumin as protein feeder. Using the obtained PRU-CLEAs, the removal rate of urea was up to 9.31 mg . L(-1) . h(-1). The removal rate of urea was still up to 7.56 mg . L(-1) . h(-1) after PRU-CLEAs was re-used for 6 times. When PRU-CLEAs were applied in a batch stirred and membrane reactor, the removal rate of urea in rice wine reached 5.16 mg . L(-1) . h(-1) and the removal rate of EC was 9.21 MUg . L(-1) . h(-1). Furthermore, the treatment with PRU-CLEAs revealed no significant change of volatile flavor substances in Chinese rice wine. Thus PRU-CLEAs have great potential in the elimination of EC in Chinese rice wine. PMID- 26627915 TI - Impact of nitrous oxide on the haemodynamic consequences of venous carbon dioxide embolism: An experimental study. AB - BACKGROUND: Nitrous oxide (N2O) is still considered an important component of general anaesthesia. However, should gas embolisation occur as result of carbon dioxide (CO2) pneumoperitoneum, N2O may compromise safety, as the consequences of a gas embolus consisting of a combination of CO2 and N2O may be more severe than CO2 alone. OBJECTIVE: This experimental study was designed to compare the cardiopulmonary consequences of gas embolisation with a N2O/CO2 mixture, or CO2 alone. DESIGN: Experimental study. SETTING: Research Institute Against Digestive Cancer laboratory, Strasbourg, France. ANIMALS: Seven Large-White pigs receiving standardised inhalation anaesthesia. INTERVENTIONS: Each animal, acting as its own control, was studied in two successive experimental conditions - intravenous gas injections of 2 ml kg of 100% CO2 and 2 ml kg of a gas mixture consisting of 10% N2O and 90% CO2. MAIN OUTCOMES MEASURES: Haemodynamic and ventilatory consequences of embolisation with the gases. RESULTS: We found that the haemodynamic (heart rate, mean arterial blood pressure, central venous pressure, mean pulmonary artery pressure, pulmonary artery occlusion pressure and transoesophageal echocardiography parameters) and ventilatory (arterial oxygen saturation, end-tidal CO2 concentration and mixed venous oxygen saturation) consequences of embolisation with either 100% CO2 or 10% N2O with 90% CO2 were similar. CONCLUSION: The findings of this study may alleviate concerns that the use of N2O, as a part of a balanced general anaesthesia technique, may have greater adverse consequences should embolisation of pneumoperitoneal gas containing N2O occur. PMID- 26627916 TI - High rate of burnout among anaesthesiologists in Belgrade teaching hospitals: Results of a cross-sectional survey. AB - BACKGROUND: Decisions by anaesthesiologists directly impact the treatment, safety, recovery and quality of life of patients. Physical or mental collapse due to overwork or stress (burnout) in anaesthesiologists may, therefore, be expected to negatively affect patients, departments, healthcare facilities and families. OBJECTIVES: To evaluate the prevalence of burnout among anaesthesiologists in Belgrade public teaching hospitals. DESIGN: A cross-sectional survey. SETTING: Anaesthesiologists in 10 Belgrade teaching hospitals. MAIN OUTCOME MEASURES: Burnout was assessed using Maslach Burnout Inventory-Human Services Survey. RESULTS: The response rate was 76.2% (205/272) with the majority of respondents women (70.7%). The prevalence of total burnout among anaesthesiologists in Belgrade teaching hospitals was 6.34%. Measured level of burnout as assessed by high emotional exhaustion, high depersonalisation and low personal accomplishment was 52.7, 12.2 and 28.8%, respectively. More than a quarter of the studied population responded in each category with symptoms of moderate burnout. We detected that sex, additional academic education, marital status and working conditions were risk factors for emotional exhaustion and depersonalisation. Ageing increased the likelihood of burnout by 21.3% with each additional year. Shorter professional experience and increased educational accomplishment increased the risk of total burnout by 272%. CONCLUSION: Burnout rates in Belgrade teaching hospitals among anaesthesiologists are higher than in foreign hospitals. Emotional and/or physical breakdowns can have serious effects when these individuals care for patients in extremely stressed situations that may occur perioperatively. Causes for burnout should be examined more closely and means implemented to reverse this process. PMID- 26627917 TI - Electrical stimulation of the heart 7 acupuncture site for preventing emergence agitation in children: A randomised controlled trial. AB - BACKGROUND: Emergence agitation is common in children recovering from general anaesthesia. The prevention of emergence agitation remains an important challenge in the field of paediatric anaesthesia. OBJECTIVE: We aimed to examine the effectiveness of electrically stimulating the heart 7 (HT7) acupuncture site with a peripheral nerve stimulator (PNS) during surgery, for preventing emergence agitation in paediatric patients recovering from general anaesthesia. DESIGN: A double-blind, randomised, controlled, parallel-group trial. SETTING: Kanagawa Children's Medical Centre, Yokohama, Japan. PATIENTS: One hundred and twenty patients aged 18 to 96 months (American Society of Anesthesiologists physical status I or II) undergoing minor elective surgery under general anaesthesia with sevoflurane. INTERVENTION: Patients were randomly assigned to either undergo bilateral stimulation of HT7 with two PNS devices (1 Hz, 50 mA) during surgery (Group HT7) or a control group that did not undergo electrical stimulation of HT7 during surgery. MAIN OUTCOME MEASURES: The primary outcome was the incidence of emergence agitation evaluated in the postanaesthesia care unit (PACU) using the Paediatric Anaesthesia Emergence Delirium scale. The secondary outcomes were the time from operation completion to tracheal extubation, PACU stay duration and postoperative pain scores. RESULTS: The incidence of emergence agitation was significantly lower in the HT7 group compared with the control group (31.7 vs. 56.7%, respectively; P = 0.010). The risk ratio was 0.56 (95% confidence interval 0.36 to 0.86) and the number needed to treat was 4 (95% confidence interval 3 to 13). There were no statistically significant differences between groups in time from operation completion to tracheal extubation, PACU stay duration or postoperative pain. CONCLUSION: Bilateral electrical stimulation of HT7 using two PNS devices significantly decreases the incidence of emergence agitation. TRIAL REGISTRATION: UMIN Clinical Trial Registry (registry number: UMIN000011704). PMID- 26627918 TI - Predicting Development of Glaucomatous Visual Field Conversion Using Baseline Fourier-Domain Optical Coherence Tomography. AB - PURPOSE: To predict the development of glaucomatous visual field (VF) defects using Fourier-domain optical coherence tomography (FD OCT) measurements at baseline visit. DESIGN: Multicenter longitudinal observational study. Glaucoma suspects and preperimetric glaucoma participants in the Advanced Imaging for Glaucoma Study. METHODS: The optic disc, peripapillary retinal nerve fiber layer (NFL), and macular ganglion cell complex (GCC) were imaged with FD OCT. VF was assessed every 6 months. Conversion to perimetric glaucoma was defined by VF pattern standard deviation (PSD) or glaucoma hemifield test (GHT) outside normal limits on 3 consecutive tests. Hazard ratios were calculated with the Cox proportional hazard model. Predictive accuracy was measured by the area under the receiver operating characteristic curve (AUC). RESULTS: Of 513 eyes (309 participants), 55 eyes (46 participants) experienced VF conversion during 41 +/- 23 months of follow-up. Significant (P < .05, Cox regression) FD OCT risk factors included all GCC, NFL, and disc variables, except for horizontal cup-to-disc ratio. GCC focal loss volume (FLV) was the best single predictor of conversion (AUC = 0.753, P < .001 for test against AUC = 0.5). Those with borderline or abnormal GCC-FLV had a 4-fold increase in conversion risk after 6 years (Kaplan Meier). Optimal prediction of conversion was obtained using the glaucoma composite conversion index (GCCI) based on a multivariate Cox regression model that included GCC-FLV, inferior NFL quadrant thickness, age, and VF PSD. GCCI significantly improved predictive accuracy (AUC = 0.783) over any single variable (P = .04). CONCLUSIONS: Reductions in NFL and GCC thickness can predict the development of glaucomatous VF loss in glaucoma suspects and preperimetric glaucoma patients. PMID- 26627920 TI - How to deal with large colorectal polyps: snare, endoscopic mucosal resection, and endoscopic submucosal dissection; resect or refer? AB - PURPOSE OF REVIEW: The importance of accurate polyp detection and removal is paramount to preventing colon cancer. Resection of large polyps can be challenging to the endoscopist based on their size, shape, or location. Large polyps have the potential of harboring malignancy and a higher risk of complications with resection. Careful assessment of each lesion and meticulous resection using the appropriate tools and techniques is essential. RECENT FINDINGS: Over the last 15 years, the development of endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) techniques has presented the endoscopist with the opportunity to manage patients with large and flat lesions thereby avoiding the need for surgery. However, these techniques are complex and require extensive knowledge and skill in the use of various devices to resect a lesion completely and manage bleeding and perforation associated with these procedures. SUMMARY: Large colon polyps manifest as either polypoid or nonpolypoid (flat) lesions. Polypoid lesions, especially those with pedicles, are removed with snare resection, whereas flat lesions may require the use of EMR or ESD. Resection of large polyps (>1 cm) requires additional tools and techniques to ensure safe and complete resection. We will discuss our approach to dealing with large colorectal polyps: snare, EMR, and ESD; resect or refer? PMID- 26627919 TI - Contribution of postsynaptic T-type calcium channels to parallel fibre-Purkinje cell synaptic responses. AB - KEY POINTS: At the parallel fibre-Purkinje cell glutamatergic synapse, little or no Ca(2+) entry takes place through postsynaptic neurotransmitter receptors, although postsynaptic calcium increases are clearly involved in the synaptic plasticity. Postsynaptic voltage-gated Ca(2+) channels therefore constitute the sole rapid postsynaptic Ca(2+) signalling mechanism, making it essential to understand how they contribute to the synaptic signalling. Using a selective T type calcium channel antagonist, we describe a T-type component of the EPSC that is activated by the AMPA receptor-mediated depolarization of the spine and thus will contribute to the local calcium dynamics. This component can amount up to 20% of the EPSC, and this fraction is maintained even at the high frequencies sometimes encountered in sensory processing. Modelling based on our biophysical characterization of T-type calcium channels in Purkinje cells suggests that the brief spine EPSCs cause the activated T-type channels to deactivate rather than inactivate, enabling repetitive activation. ABSTRACT: In the cerebellum, sensory information is conveyed to Purkinje cells (PC) via the granule cell/parallel fibre (PF) pathway. Plasticity at the PF-PC synapse is considered to be a mechanism of information storage in motor learning. The induction of synaptic plasticity in the cerebellum and elsewhere usually involves intracellular Ca(2+) signals. Unusually, postsynaptic Ca(2+) signalling in PF-PC spines does not involve ionotropic glutamatergic receptors because postsynaptic NMDA receptors are absent and the AMPA receptors are Ca(2+) -impermeable; postsynaptic voltage gated Ca(2+) channels therefore constitute the sole rapid Ca(2+) signalling mechanism. Low-threshold activated T-type calcium channels are present at the synapse, although their contribution to PF-PC synaptic responses is unknown. Taking advantage of 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl) 4-fluoro-piperidin-4-ylmethyl]-benzamide, a selective T-type channel antagonist, we show in the mouse that inhibition of these channels reduces PF-PC excitatory postsynaptic currents and excitatory postsynaptic potentials by 15-20%. This contribution was preserved during sparse input and repetitive activity. We characterized the biophysical properties of native T-type channels in young animals and modelled their activation during simulated dendritic excitatory postsynaptic potential waveforms. The comparison of modelled and observed synaptic responses suggests that T-type channels only activate in spines that are strongly depolarized by their synaptic input, a process requiring a high spine neck resistance. This brief and local activation ensures that T-type channels rapidly deactivate, thereby limiting inactivation during repetitive synaptic activity. T-type channels are therefore ideally situated to provide synaptic Ca(2+) entry at PF-PC spines. PMID- 26627922 TI - Re: Prenatal features of isolated subependymal pseudocysts associated with adverse pregnancy outcome. H. Esteban, E. Blondiaux, E. Audureau, C. Sileo, M. L. Moutard, A. Gelot, J. M. Jouannic, H. Ducou le Pointe and C. Garel. Ultrasound Obstet Gynecol 2015; 46: 678-687. PMID- 26627923 TI - Re: Cervical condition and fetal cerebral Doppler as determinants of adverse perinatal outcome after labor induction for late-onset small-for-gestational-age fetuses. R. Garcia-Simon, F. Figueras, S. Savchev, E. Fabre, E. Gratacos and D. Oros. Ultrasound Obstet Gynecol 2015; 46: 713-717. PMID- 26627924 TI - Chronic intermittent maternofetal hyperoxygenation (Kohl procedure) for the treatment of flow-related cardiovascular hypoplasia in human fetuses. PMID- 26627925 TI - Reply: To PMID 25296951. PMID- 26627926 TI - Re: 'Post-LA space index' as a potential novel marker for the prenatal diagnosis of isolated total anomalous pulmonary venous connection. PMID- 26627927 TI - Reply: To PMID 24604577. PMID- 26627930 TI - Cell biology to disease and back. PMID- 26627932 TI - Plasmonic field confinement for separate absorption-multiplication in InGaAs nanopillar avalanche photodiodes. AB - Avalanche photodiodes (APDs) are essential components in quantum key distribution systems and active imaging systems requiring both ultrafast response time to measure photon time of flight and high gain to detect low photon flux. The internal gain of an APD can improve system signal-to-noise ratio (SNR). Excess noise is typically kept low through the selection of material with intrinsically low excess noise, using separate-absorption-multiplication (SAM) heterostructures, or taking advantage of the dead-space effect using thin multiplication regions. In this work we demonstrate the first measurement of excess noise and gain-bandwidth product in III-V nanopillars exhibiting substantially lower excess noise factors compared to bulk and gain-bandwidth products greater than 200 GHz. The nanopillar optical antenna avalanche detector (NOAAD) architecture is utilized for spatially separating the absorption region from the avalanche region via the NOA resulting in single carrier injection without the use of a traditional SAM heterostructure. PMID- 26627933 TI - Vaginal mucus from ewes treated with progestogen sponges affects quality of ram spermatozoa. AB - The use of intravaginal sponges (IS) to synchronize estrous onset in ewes provokes vaginitis, an increase in the vaginal bacterial load, and growth of bacterial species that are not present during spontaneous estrous behavior. The objective of the study was to compare the functional sperm parameters after incubating it with mucus collected from the vagina of ewes during spontaneous estrus or estrous synchronized with IS. Pooled spermatozoa were co-incubated with: (1) vaginal mucus collected from ewes in spontaneous estrus; (2) vaginal mucus collected from ewes in estrus pretreated with progestogen-impregnated IS; (3) synthetic mucus; and (4) medium without mucus as a control group. Sperm samples were evaluated after incubating it for 30 and 90 minutes. The number of colony-forming units (CFUs/mL), pH, and osmolality were greater in the mucus collected from ewes treated with IS than from those untreated (P = 0.046; P < 0.0001, and P < 0.0001, respectively). The percentage of sperm with progressive motility was lower after incubation with vaginal mucus collected from estrous ewes treated with IS than in the other three treatments both, 30 and 90 minutes after incubation (P = 0.0009 and P < 0.0001, respectively). The sample incubated for 30 minutes with mucus from ewes treated with IS had a lower percentage of sperm with intact plasma membrane than all the other treatments (P < 0.0001). The percentage of sperm with functional membrane was significantly lower in the sample incubated for 30 minutes with vaginal mucus from ewes treated with IS than in the other three treatments (P < 0.0001). After 90 minutes, the percentage was still lower than that in the sample collected from ewes during their spontaneous estrus (P = 0.0005). The lowest percentages of sperm with acrosome damage were observed in sperm incubated with mucus collected from sheep in spontaneous estrus for 30 and 90 minutes (P < 0.0001 and P = 0.008, respectively). The percentage of apoptotic spermatozoa was greater in samples incubated during 30 minutes with vaginal mucus collected from ewes treated with IS than in the other three groups (P = 0.0005). The functionality and the viability of ram sperm is negatively affected by the cervical mucus of ewes pretreated with progestagen-impregnated IS used in estrous synchronization treatments. This may partially explain the decrease in conception rate obtained with treatments with IS. PMID- 26627931 TI - Structure and function of ER membrane contact sites with other organelles. AB - The endoplasmic reticulum (ER) is the largest organelle in the cell, and its functions have been studied for decades. The past several years have provided novel insights into the existence of distinct domains between the ER and other organelles, known as membrane contact sites (MCSs). At these contact sites, organelle membranes are closely apposed and tethered, but do not fuse. Here, various protein complexes can work in concert to perform specialized functions such as binding, sensing and transferring molecules, as well as engaging in organelle biogenesis and dynamics. This Review describes the structure and functions of MCSs, primarily focusing on contacts of the ER with mitochondria and endosomes. PMID- 26627934 TI - Controversies in Candida management. AB - Invasive candidiasis (IC) is associated with increased morbidity and mortality. Although advances in diagnosis and management of this infection have been reached, there remain several controversies. The aim of this review is to tackle some of these controversies and shed light on studies that support the different sides of the arguments. Regarding central line-associated candidaemia, the current evidence appears to be more in favour of early central line removal whenever possible. Otherwise, antifungal agents such as echinocandins or polyenes should be the preferred agents. In the setting of infection with Candida parapsilosis and in light of the high minimum inhibitory concentrations (MICs) to echinocandins, azoles have been considered the preferred treatment agents. However, a recent study appears to indicate that empirical echinocandin use was not associated with a worse outcome when the isolated species was C. parapsilosis. Different strategies of antifungal treatment have been considered, namely prophylactic, empirical, pre-emptive or directed therapies. Whilst there is consensus on the need for prophylaxis in high-risk cancer patients, especially haematological malignancy and stem cell transplant populations, it remains debatable whether prophylaxis is of benefit in very low birthweight infants and in intensive care unit (ICU) patients. In the era of antifungal resistance and where antifungal stewardship has been advocated, pre-emptive therapy based on predictive models with various Candida risk scores and sensitive non-culture based biomarkers such as beta-d-glucan appears to be a more cost-effective approach. Future efforts should be directed to optimise clinical predictive models and reliable biomarkers for early detection of IC. PMID- 26627935 TI - Long-term effect of PROLI/NO on cellular proliferation and phenotype after arterial injury. AB - Vascular interventions are associated with high failure rates from restenosis secondary to negative remodeling and neointimal hyperplasia. Periadventitial delivery of nitric oxide (NO) inhibits neointimal hyperplasia, preserving lumen patency. With the development of new localized delivery vehicles, NO-based therapies remain a promising therapeutic avenue for the prevention of restenosis. While the time course of events during neointimal development has been well established, a full characterization of the impact of NO donors on the cells that comprise the arterial wall has not been performed. Thus, the aim of our study was to perform a detailed assessment of proliferation, cellularity, inflammation, and phenotypic cellular modulation in injured arteries treated with the short-lived NO donor, PROLI/NO. PROLI/NO provided durable inhibition of neointimal hyperplasia for 6 months after arterial injury. PROLI/NO inhibited proliferation and cellularity in the media and intima at all of the time points studied. However, PROLI/NO caused an increase in adventitial proliferation at 2 weeks, resulting in increased cellularity at 2 and 8 weeks compared to injury alone. PROLI/NO promoted local protein S-nitrosation and increased local tyrosine nitration, without measurable systemic effects. PROLI/NO predominantly inhibited contractile smooth muscle cells in the intima and media, and had little to no effect on vascular smooth muscle cells or myofibroblasts in the adventitia. Finally, PROLI/NO caused a delayed and decreased leukocyte infiltration response after injury. Our results show that a short-lived NO donor exerts durable effects on proliferation, phenotype modulation, and inflammation that result in long-term inhibition of neointimal hyperplasia. PMID- 26627936 TI - Exploring the redox balance inside gram-negative bacteria with redox-sensitive GFP. AB - Aerobic bacteria are continuously fighting potential oxidative stress due to endogenous and exogenous reactive oxygen species (ROS). To achieve this goal, bacteria possess a wide array of defenses and stress responses including detoxifying enzymes like catalases and peroxidases; however until now, the dynamics of the intra-bacterial redox balance remained poorly understood. Herein, we used redox-sensitive GFP (roGFP2) inside a variety of gram-negative bacteria to study real-time redox dynamics immediately after a challenge with hydrogen peroxide. Using this biosensor, we determined the individual contributions of catalases and peroxidases and found that each enzyme contributes more to rapid detoxification or to prolonged catalytic activity. We also found that the total catalytic power is affected by environmental conditions. Additionally, using a Salmonella strain that is devoid of detoxifying enzymes, we examined endogenous ROS production. By measuring endogenous ROS production, we assessed the role of oxidative stress in toxicity of heavy metals and antibiotics. We found that exposure to nickel induced significant oxidative stress whereas cobalt (which was previously implicated to induce oxidative stress) did not induce ROS formation. Since a turbulent debate evolves around oxidative stress as a general killing mechanism by antibiotics (aminoglycosides, fluoroquinolones and beta-lactams), we measured oxidative stress in bacteria that were challenged with these antibiotics. Our results revealed that antibiotics do not induce ROS formation in bacteria thereby disputing a role for oxidative stress as a general killing mechanism. Together, our results expose how the intra-bacterial redox balance in individual microorganisms is affected by environmental conditions and encounters with stress-inducing compounds. These findings demonstrate the significant potential of roGFP2 as a redox biosensor in gram-negative bacteria to investigate redox dynamics under a variety of circumstances. PMID- 26627937 TI - Mechanism of neem limonoids-induced cell death in cancer: Role of oxidative phosphorylation. AB - We have previously reported that neem limonoids (neem) induce multiple cancer cell death pathways. Here we dissect the underlying mechanisms of neem-induced apoptotic cell death in cancer. We observed that neem-induced caspase activation does not require Bax/Bak channel-mediated mitochondrial outer membrane permeabilization, permeability transition pore, and mitochondrial fragmentation. Neem enhanced mitochondrial DNA and mitochondrial biomass. While oxidative phosphorylation (OXPHOS) Complex-I activity was decreased, the activities of other OXPHOS complexes including Complex-II and -IV were unaltered. Increased reactive oxygen species (ROS) levels were associated with an increase in mitochondrial biomass and apoptosis upon neem exposure. Complex-I deficiency due to the loss of Ndufa1-encoded MWFE protein inhibited neem-induced caspase activation and apoptosis, but cell death induction was enhanced. Complex II deficiency due to the loss of succinate dehydrogenase complex subunit C (SDHC) robustly decreased caspase activation, apoptosis, and cell death. Additionally, the ablation of Complexes-I, -III, -IV, and -V together did not inhibit caspase activation. Together, we demonstrate that neem limonoids target OXPHOS system to induce cancer cell death, which does not require upregulation or activation of proapoptotic Bcl-2 family proteins. PMID- 26627938 TI - Entrapment of alpha1-acid glycoprotein in high-performance affinity columns for drug-protein binding studies. AB - A slurry-based method was developed for the entrapment of alpha1-acid glycoprotein (AGP) for use in high-performance affinity chromatography to study drug interactions with this serum protein. Entrapment was achieved based on the physical containment of AGP in hydrazide-activated porous silica supports and by using mildly oxidized glycogen as a capping agent. The conditions needed for this process were examined and optimized. When this type of AGP column was used in binding studies, the association equilibrium constant (Ka) measured by frontal analysis at pH 7.4 and 37 degrees C for carbamazepine with AGP was found to be 1.0 (+/-0.5)*10(5)M(-1), which agreed with a previously reported value of 1.0 (+/ 0.1)*10(5)M(-1). Binding studies based on zonal elution were conducted for several other drugs with such columns, giving equilibrium constants that were consistent with literature values. An entrapped AGP column was also used in combination with a column containing entrapped HSA in a screening assay format to compare the binding of various drugs to AGP and HSA. These results also agreed with previous data that have been reported in literature for both of these proteins. The same entrapment method could be extended to other proteins and to the investigation of additional types of drug-protein interactions. Potential applications include the rapid quantitative analysis of biological interactions and the high-throughput screening of drug candidates for their binding to a given protein. PMID- 26627939 TI - Metabolite ratios in the posterior cingulate cortex do not track cognitive decline in Parkinson's disease in a clinical setting. AB - INTRODUCTION: Parkinson's Disease (PD) is classified as a motor disorder, but most patients develop cognitive impairment, and eventual dementia (PDD). Predictive neurobiomarkers may be useful in the identification of those patients at imminent risk of PDD. Given the compromised cerebral integrity in PDD, we investigated whether brain metabolites track disease progression over time. METHODS: Proton Magnetic Resonance Spectroscopy (MRS) was used to identify brain metabolic changes associated with cognitive impairment and dementia in PD. Forty nine healthy participants and 130 PD patients underwent serial single voxel proton MRS and neuropsychological testing. At baseline patients were classified as either having normal cognitive status (PDN, n = 77), mild cognitive impairment (PDMCI, n = 33), or dementia (PDD, n = 20). Posterior cingulate cortex (PCC) was examined to quantify N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and myo-inositol (mI). A hierarchical Bayesian model was used to assess whether cognitive ability and other covariates were related to baseline MRS values and changes in MRS over time. RESULTS: At baseline, relative to controls, PDD had significantly decreased NAA/Cr and increased Cho/Cr. However, these differences did not remain significant after accounting for age, sex, and MDS-UPDRS III. At follow-up, no significant changes in MRS metabolite ratios were detected, with no relationship found between MRS measures and change in cognitive status. CONCLUSIONS: Unlike Alzheimer's disease, single voxel MR spectroscopy of the PCC failed to show any significant association with cognitive status at baseline or over time. This suggests that MRS of PCC is not a clinically useful biomarker for tracking or predicting cognitive impairment in Parkinson's disease. PMID- 26627940 TI - From sweet to sweat: Hedonic olfactory range is impaired in Parkinson's disease. AB - INTRODUCTION: Olfactory dysfunction and neuropsychological symptoms like depression and anhedonia are common non-motor symptoms in Parkinson's disease (PD). The assessment of both functional domains includes clinical examination, olfactory testing, and standardized questionnaires. While olfaction is readily assessed by functional tests, the distinction of anhedonia as a separate symptom from other depressive symptoms is challenging. Thus, a test focusing on the assessment of hedonic olfaction may be helpful in the assessment of neuropsychological symptoms in PD. METHODS: We examined anhedonia by evaluating the perception of pleasantness of odors in PD patients (n = 57) and healthy controls (n = 46). Pleasantness of odors was registered on a visual 9-point scale. For the assessment of anhedonia we used the Snaith-Hamilton-Pleasure-Scale (SHAPS). Depression was evaluated with the Zung Self-Rating Depression Scale and the Beck Depression Inventory II. RESULTS: PD patients showed a substantial reduction in hedonic olfaction compared to controls (hedonic score: 1.5 vs. 2.2). Hyposmia, one of the most prevalent non-motor symptoms in PD, was a confounding factor. However, even normosmic PD patients showed a reduced hedonic olfaction compared to controls (hedonic score: 1.6 vs. 2.2). Furthermore, we observed a correlation between hedonic olfaction and the SHAPS-score for PD patients even though positive SHAPS-rating was observed in 9% of PD patients only, while no correlation to depression was present. CONCLUSION: These findings suggest that reduced hedonic olfaction might be an additional neuropsychological feature, probably giving insights into changes in hedonic tone complementary to hyposmia and depression in PD. PMID- 26627942 TI - Communication: Probing the absolute configuration of chiral molecules at aqueous interfaces. AB - We demonstrate that the enantiomers of chiral macromolecules at an aqueous interface can be distinguished with monolayer sensitivity using heterodyne detected vibrational sum-frequency generation (VSFG). We perform VSFG spectroscopy with a polarization combination that selectively probes chiral molecular structures. By using frequencies far detuned from electronic resonances, we probe the chiral macromolecular structures with high surface specificity. The phase of the sum-frequency light generated by the chiral molecules is determined using heterodyne detection. With this approach, we can distinguish right-handed and left-handed helical peptides at a water-air interface. We thus show that heterodyne-detected VSFG is sensitive to the absolute configuration of complex, interfacial macromolecules and has the potential to determine the absolute configuration of enantiomers at interfaces. PMID- 26627943 TI - Communication: Polarizable polymer chain under external electric field in a dilute polymer solution. AB - We study the conformational behavior of polarizable polymer chain under an external homogeneous electric field within the Flory type self-consistent field theory. We consider the influence of electric field on the polymer coil as well as on the polymer globule. We show that when the polymer chain conformation is a coil, application of external electric field leads to its additional swelling. However, when the polymer conformation is a globule, a sufficiently strong field can induce a globule-coil transition. We show that such "field-induced" globule coil transition at the sufficiently small monomer polarizabilities goes quite smoothly. On the contrary, when the monomer polarizability exceeds a certain threshold value, the globule-coil transition occurs as a dramatic expansion in the regime of first-order phase transition. The developed theoretical model can be applied to predicting polymer globule density change under external electric field in order to provide more efficient processes of polymer functionalization, such as sorption, dyeing, and chemical modification. PMID- 26627941 TI - Association of Parkinson disease age of onset with DRD2, DRD3 and GRIN2B polymorphisms. AB - INTRODUCTION: Dopamine and glutamate are crucial neurotransmitters in Parkinson disease (PD). While recent large meta-analyses reported that genetic variation of dopamine (DRD2, DRD3) and glutamine (NMDA, GRIN2B) neurotransmitter receptors was not associated with PD risk, they could conceivably influence PD phenotype. We studied the association of these receptor polymorphisms relating to PD age of onset. METHODS: There were 664 PD patients and 718 controls, all Caucasian, with stored DNA at Mayo Clinic, Jacksonville, Florida. Genotyping was performed for DRD2 (Taq 1A, rs1800497), DRD3 (rs6280), and NMDA (GRIN2B, rs7301328) polymorphisms with ABI Taqman assays. Single nucleotide polymorphism associations with age of onset were evaluated using dominant, recessive, and additive genotypic models. RESULTS: DRD3 variant carriers had an approximate 4.4-year decrease in mean age of onset when both copies of the minor allele were present (P = 0.0034) and an approximate 1.5-year decrease in mean age at onset for every additional minor allele (P = 0.023) (recessive and additive models, respectively). There was no association with age of onset for DRD2 or GRIN2B under any statistical model (all P >= 0.22). CONCLUSIONS: The DRD3 (rs6280) polymorphism, but not DRD2 (Taq1A) or GRIN2B, influences younger PD age of onset in the US Caucasian population. Validation of these findings in larger studies with other ethnic groups is indicated. PMID- 26627944 TI - Permutation blocking path integral Monte Carlo approach to the uniform electron gas at finite temperature. AB - The uniform electron gas (UEG) at finite temperature is of high current interest due to its key relevance for many applications including dense plasmas and laser excited solids. In particular, density functional theory heavily relies on accurate thermodynamic data for the UEG. Until recently, the only existing first principle results had been obtained for N = 33 electrons with restricted path integral Monte Carlo (RPIMC), for low to moderate density, rs=r-/aB?1. These data have been complemented by configuration path integral Monte Carlo (CPIMC) simulations for rs <= 1 that substantially deviate from RPIMC towards smaller rs and low temperature. In this work, we present results from an independent third method-the recently developed permutation blocking path integral Monte Carlo (PB PIMC) approach [T. Dornheim et al., New J. Phys. 17, 073017 (2015)] which we extend to the UEG. Interestingly, PB-PIMC allows us to perform simulations over the entire density range down to half the Fermi temperature (theta = kBT/EF = 0.5) and, therefore, to compare our results to both aforementioned methods. While we find excellent agreement with CPIMC, where results are available, we observe deviations from RPIMC that are beyond the statistical errors and increase with density. PMID- 26627945 TI - Vibrationally resolved NEXAFS at C and N K-edges of pyridine, 2-fluoropyridine and 2,6-difluoropyridine: A combined experimental and theoretical assessment. AB - In the present work, the near edge X-ray absorption spectroscopy (NEXAFS) spectra at both C and N K-edges of pyridine, 2-fluoropyridine, and 2,6-difluoropyridine have been studied both experimentally and theoretically. From an electronic point of view, both transition potential density functional theory and time-dependent density functional theory approaches lead to reliable results provided that suitable basis sets and density functionals are employed. In this connection, the global hybrid B3LYP functional in conjunction with the EPR-III basis set appears particularly suitable after constant scaling of the band positions. For the N K edge, vertical energies obtained at these levels and broadened by symmetric Gaussian distributions provide spectra in reasonable agreement with the experiment. Vibronic contributions further modulate the band-shapes leading to a better agreement with the experimental results, but are not strictly necessary for semi-quantitative investigations. On the other hand, vibronic contributions are responsible for strong intensity redistribution in the NEXAFS C K-edge spectra, and their inclusion is thus mandatory for a proper description of experiments. In this connection, the simple vertical gradient model is particularly appealing in view of its sufficient reliability and low computational cost. For more quantitative results, the more refined vertical Hessian approach can be employed, and its effectiveness has been improved thanks to a new least-squares fitting approach. PMID- 26627946 TI - Accelerating the convergence of higher-order coupled cluster methods. AB - The problem of the generally inferior convergence behavior of higher-order coupled cluster methods, such as CCSDT and CCSDTQ, compared to CCSD is analyzed in terms of Moller-Plesset perturbation theory. A new structure for the CCSDT and CCSDTQ equations (and various approximations of these) is proposed which reorders contributions between the various cluster amplitudes and emphasizes lower-order corrections to the energy at each iteration. Numerical testing of the proposed method compared to the widely used direct inversion in the iterative subspace convergence acceleration technique shows significant improvement in the rate of convergence and total time-to-solution, especially for methods including quadruple excitations. PMID- 26627947 TI - Comparison of the Marcus and Pekar partitions in the context of non-equilibrium, polarizable-continuum solvation models. AB - The Marcus and Pekar partitions are common, alternative models to describe the non-equilibrium dielectric polarization response that accompanies instantaneous perturbation of a solute embedded in a dielectric continuum. Examples of such a perturbation include vertical electronic excitation and vertical ionization of a solution-phase molecule. Here, we provide a general derivation of the accompanying polarization response, for a quantum-mechanical solute described within the framework of a polarizable continuum model (PCM) of electrostatic solvation. Although the non-equilibrium free energy is formally equivalent within the two partitions, albeit partitioned differently into "fast" versus "slow" polarization contributions, discretization of the PCM integral equations fails to preserve certain symmetries contained in these equations (except in the case of the conductor-like models or when the solute cavity is spherical), leading to alternative, non-equivalent matrix equations. Unlike the total equilibrium solvation energy, however, which can differ dramatically between different formulations, we demonstrate that the equivalence of the Marcus and Pekar partitions for the non-equilibrium solvation correction is preserved to high accuracy. Differences in vertical excitation and ionization energies are <0.2 eV (and often <0.01 eV), even for systems specifically selected to afford a large polarization response. Numerical results therefore support the interchangeability of the Marcus and Pekar partitions, but also caution against relying too much on the fast PCM charges for interpretive value, as these charges differ greatly between the two partitions, especially in polar solvents. PMID- 26627948 TI - Large deviations of Rouse polymer chain: First passage problem. AB - The purpose of this paper is to investigate several analytical methods of solving first passage (FP) problem for the Rouse model, a simplest model of a polymer chain. We show that this problem has to be treated as a multi-dimensional Kramers' problem, which presents rich and unexpected behavior. We first perform direct and forward-flux sampling (FFS) simulations and measure the mean first passage time tau(z) for the free end to reach a certain distance z away from the origin. The results show that the mean FP time is getting faster if the Rouse chain is represented by more beads. Two scaling regimes of tau(z) are observed, with transition between them varying as a function of chain length. We use these simulation results to test two theoretical approaches. One is a well known asymptotic theory valid in the limit of zero temperature. We show that this limit corresponds to fully extended chain when each chain segment is stretched, which is not particularly realistic. A new theory based on the well known Freidlin Wentzell theory is proposed, where dynamics is projected onto the minimal action path. The new theory predicts both scaling regimes correctly, but fails to get the correct numerical prefactor in the first regime. Combining our theory with the FFS simulations leads us to a simple analytical expression valid for all extensions and chain lengths. One of the applications of polymer FP problem occurs in the context of branched polymer rheology. In this paper, we consider the arm-retraction mechanism in the tube model, which maps exactly on the model we have solved. The results are compared to the Milner-McLeish theory without constraint release, which is found to overestimate FP time by a factor of 10 or more. PMID- 26627950 TI - Linear-scaling time-dependent density-functional theory beyond the Tamm-Dancoff approximation: Obtaining efficiency and accuracy with in situ optimised local orbitals. AB - We present a solution of the full time-dependent density-functional theory (TDDFT) eigenvalue equation in the linear response formalism exhibiting a linear scaling computational complexity with system size, without relying on the simplifying Tamm-Dancoff approximation (TDA). The implementation relies on representing the occupied and unoccupied subspaces with two different sets of in situ optimised localised functions, yielding a very compact and efficient representation of the transition density matrix of the excitation with the accuracy associated with a systematic basis set. The TDDFT eigenvalue equation is solved using a preconditioned conjugate gradient algorithm that is very memory efficient. The algorithm is validated on a small test molecule and a good agreement with results obtained from standard quantum chemistry packages is found, with the preconditioner yielding a significant improvement in convergence rates. The method developed in this work is then used to reproduce experimental results of the absorption spectrum of bacteriochlorophyll in an organic solvent, where it is demonstrated that the TDA fails to reproduce the main features of the low energy spectrum, while the full TDDFT equation yields results in good qualitative agreement with experimental data. Furthermore, the need for explicitly including parts of the solvent into the TDDFT calculations is highlighted, making the treatment of large system sizes necessary that are well within reach of the capabilities of the algorithm introduced here. Finally, the linear-scaling properties of the algorithm are demonstrated by computing the lowest excitation energy of bacteriochlorophyll in solution. The largest systems considered in this work are of the same order of magnitude as a variety of widely studied pigment-protein complexes, opening up the possibility of studying their properties without having to resort to any semiclassical approximations to parts of the protein environment. PMID- 26627949 TI - Multiscale Gaussian network model (mGNM) and multiscale anisotropic network model (mANM). AB - Gaussian network model (GNM) and anisotropic network model (ANM) are some of the most popular methods for the study of protein flexibility and related functions. In this work, we propose generalized GNM (gGNM) and ANM methods and show that the GNM Kirchhoff matrix can be built from the ideal low-pass filter, which is a special case of a wide class of correlation functions underpinning the linear scaling flexibility-rigidity index (FRI) method. Based on the mathematical structure of correlation functions, we propose a unified framework to construct generalized Kirchhoff matrices whose matrix inverse leads to gGNMs, whereas, the direct inverse of its diagonal elements gives rise to FRI method. With this connection, we further introduce two multiscale elastic network models, namely, multiscale GNM (mGNM) and multiscale ANM (mANM), which are able to incorporate different scales into the generalized Kirchhoff matrices or generalized Hessian matrices. We validate our new multiscale methods with extensive numerical experiments. We illustrate that gGNMs outperform the original GNM method in the B factor prediction of a set of 364 proteins. We demonstrate that for a given correlation function, FRI and gGNM methods provide essentially identical B-factor predictions when the scale value in the correlation function is sufficiently large. More importantly, we reveal intrinsic multiscale behavior in protein structures. The proposed mGNM and mANM are able to capture this multiscale behavior and thus give rise to a significant improvement of more than 11% in B factor predictions over the original GNM and ANM methods. We further demonstrate the benefits of our mGNM through the B-factor predictions of many proteins that fail the original GNM method. We show that the proposed mGNM can also be used to analyze protein domain separations. Finally, we showcase the ability of our mANM for the analysis of protein collective motions. PMID- 26627951 TI - Non-Markovian closure kinetics of flexible polymers with hydrodynamic interactions. AB - This paper presents a theoretical analysis of the closure kinetics of a polymer with hydrodynamic interactions. This analysis, which takes into account the non Markovian dynamics of the end-to-end vector and relies on the preaveraging of the mobility tensor (Zimm dynamics), is shown to reproduce very accurately the results of numerical simulations of the complete nonlinear dynamics. It is found that Markovian treatments based on a Wilemski-Fixman approximation significantly overestimate cyclization times (up to a factor 2), showing the importance of memory effects in the dynamics. In addition, this analysis provides scaling laws of the mean first cyclization time (MFCT) with the polymer size N and capture radius b, which are identical in both Markovian and non-Markovian approaches. In particular, it is found that the scaling of the MFCT for large N is given by T ~ N(3/2)ln(N/b(2)), which differs from the case of the Rouse dynamics where T ~ N(2). The extension to the case of the reaction kinetics of a monomer of a Zimm polymer with an external target in a confined volume is also presented. PMID- 26627952 TI - A dual cryogenic ion trap spectrometer for the formation and characterization of solvated ionic clusters. AB - A new experimental approach is presented in which two separate cryogenic ion traps are used to reproducibly form weakly bound solvent clusters around electrosprayed ions and messenger-tag them for single-photon infrared photodissociation spectroscopy. This approach thus enables the vibrational characterization of ionic clusters comprised of a solvent network around large and non-volatile ions. We demonstrate the capabilities of the instrument by clustering water, methanol, and acetone around a protonated glycylglycine peptide. For water, cluster sizes with greater than twenty solvent molecules around a single ion are readily formed. We further demonstrate that similar water clusters can be formed around ions having a shielded charge center or those that do not readily form hydrogen bonds. Finally, infrared photodissociation spectra of D2-tagged GlyGlyH(+)?(H2O)1-4 are presented. They display well-resolved spectral features and comparisons with calculations reveal detailed information on the solvation structures of this prototypical peptide. PMID- 26627953 TI - Rotationally inelastic scattering of NO(A(2)Sigma(+)) + Ar: Differential cross sections and rotational angular momentum polarization. AB - We present the implementation of a new crossed-molecular beam, velocity-map ion imaging apparatus, optimized for collisions of electronically excited molecules. We have applied this apparatus to rotational energy transfer in NO(A(2)Sigma(+), v = 0, N = 0, j = 0.5) + Ar collisions, at an average energy of 525 cm(-1). We report differential cross sections for scattering into NO(A(2)Sigma(+), v = 0, N' = 3, 5, 6, 7, 8, and 9), together with quantum scattering calculations of the differential cross sections and angle dependent rotational alignment. The differential cross sections show dramatic forward scattered peaks, together with oscillatory behavior at larger scattering angles, while the rotational alignment moments are also found to oscillate as a function of scattering angle. In general, the quantum scattering calculations are found to agree well with experiment, reproducing the forward scattering and oscillatory behavior at larger scattering angles. Analysis of the quantum scattering calculations as a function of total rotational angular momentum indicates that the forward scattering peak originates from the attractive minimum in the potential energy surface at the N end of the NO. Deviations in the quantum scattering predictions from the experimental results, for scattering at angles greater than 10 degrees , are observed to be more significant for scattering to odd final N'. We suggest that this represents inaccuracies in the potential energy surface, and in particular in its representation of the difference between the N- and O-ends of the molecule, as given by the odd-order Legendre moments of the surface. PMID- 26627954 TI - Quantum-mechanical study of energies, structures, and vibrational spectra of the H(D)Cl complexed with dimethyl ether. AB - Interaction energies, molecular structure and vibrational frequencies of the binary complex formed between H(D)Cl and dimethyl ether have been obtained using quantum-chemical methods. Equilibrium and vibrationally averaged structures, harmonic and anharmonic wavenumbers of the complex and its deuterated isotopomer were calculated using harmonic and anharmonic second-order perturbation theory procedures with Density Functional Theory B3LYP and B2PLYP-D and ab initio Moller Plesset second-order methods, and a 6-311++G(3d,3p) basis set. A phenomenological model describing anharmonic-type vibrational couplings within hydrogen bonds was developed to explain the unique broadening and fine structure, as well as the isotope effect of the Cl-H and Cl-D stretching IR absorption bands in the gaseous complexes with dimethyl ether, as an effect of hydrogen bond formation. Simulations of the rovibrational structure of the Cl-H and Cl-D stretching bands were performed and the results were compared with experimental spectra. PMID- 26627955 TI - Kinetics of chemi-ionization reactions of lanthanide metals (Nd, Sm) from 150 to 450 K. AB - The kinetics of chemi-ionization reactions of neodymium and samarium atoms with an oxygen atom to yield a metal monoxide cation and electron were studied using a flow tube apparatus over a temperature range of 150-450 K. Nd reacts efficiently with O, near the hard-sphere collision limit at all temperatures, with a rate constant of 3 * 10(-10) cm(3) s(-1) at 300 K and a slight positive temperature dependence. No chemi-ionization of Nd with N2O was observed, despite the reaction being exothermic. Chemi-ionization of Sm with O is slow, with a rate constant at 300 K determined to be 7 * 10(-12) cm(3) s(-1), although with large uncertainty. The Sm reaction also shows a slightly positive temperature dependence, described by a small activation energy of 60 meV. Although not definitive, the data suggest that excited states of Sm react efficiently whereas ground state Sm reacts inefficiently. PMID- 26627956 TI - Electronic spectra of azaindole and its excited state mixing: A symmetry-adapted cluster configuration interaction study. AB - Electronic structures of azaindole were studied using symmetry-adapted cluster configuration interaction theory utilizing Dunning's cc-pVTZ basis set augmented with appropriate Rydberg spd functions on carbon and nitrogen atoms. The results obtained in the present study show good agreement with the available experimental values. Importantly, and contrary to previous theoretical studies, the excitation energy calculated for the important n-pi(*) state agrees well with the experimental value. A recent study by Pratt and co-workers concluded that significant mixing of pi-pi(*) and n-pi(*) states leads to major change in the magnitude and direction of the dipole moment of the upper state vibrational level in the 0,0 + 280 cm(-1) band in the S1<-S0 transition when compared to that of the zero-point level of the S1 state. The present study, however, shows that all the four lowest lying excited states, (1)Lb pi-pi(*), (1)La pi-pi(*), n-pi(*), and pi-sigma(*), cross each other in one way or another, and hence, significant state mixing between them is likely. The upper state vibrational level in the 0,0 + 280 cm(-1) band in the S1<-S0 transition benefits from this four-state mixing and this can explain the change in magnitude and direction of the dipole moment of the S1 excited vibrational level. This multistate mixing, and especially the involvement of pi-sigma(*) state in mixing, could also provide a route for hydrogen atom detachment reactions. The electronic spectra of benzimidazole, a closely related system, were also investigated in the present study. PMID- 26627957 TI - Cold and ultracold dynamics of the barrierless D(+) + H2 reaction: Quantum reactive calculations for ~R(-4) long range interaction potentials. AB - Quantum reactive and elastic cross sections and rate coefficients have been calculated for D(+) + H2 (v = 0, j = 0) collisions in the energy range from 10( 8) K (deep ultracold regime), where only one partial wave is open, to 150 K (Langevin regime) where many of them contribute. In systems involving ions, the ~R(-4) behavior extends the interaction up to extremely long distances, requiring a special treatment. To this purpose, we have used a modified version of the hyperspherical quantum reactive scattering method, which allows the propagations up to distances of 10(5) a0 needed to converge the elastic cross sections. Interpolation procedures are also proposed which may reduce the cost of exact dynamical calculations at such low energies. Calculations have been carried out on the PES by Velilla et al. [J. Chem. Phys. 129, 084307 (2008)] which accurately reproduces the long range interactions. Results on its prequel, the PES by Aguado et al. [J. Chem. Phys. 112, 1240 (2000)], are also shown in order to emphasize the significance of the inclusion of the long range interactions. The calculated reaction rate coefficient changes less than one order of magnitude in a collision energy range of ten orders of magnitude, and it is found in very good agreement with the available experimental data in the region where they exist (10-100 K). State-to-state reaction probabilities are also provided which show that for each partial wave, the distribution of HD final states remains essentially constant below 1 K. PMID- 26627958 TI - On the origin of donor O-H bond weakening in phenol-water complexes. AB - Matrix isolation infrared spectroscopy has been used to investigate intermolecular interactions in a series of binary O-H?O hydrogen bonded phenol water complexes where water is the common acceptor. The interaction at the binding site has been tuned by incorporating multiple fluorine substitutions at different aromatic ring sites of the phenol moiety. The spectral effects for the aforesaid chemical changes are manifested in the infrared spectra of the complexes as systematic increase in spectral shift of the phenolic O-H stretching fundamental (DeltanuO-H). While nuO-H bands of the monomers of all the fluorophenols appear within a very narrow frequency range, the increase in DeltanuO-H of the complexes from phenol to pentafluorophenol is very large, nearly 90%. The observed values of DeltanuO-H do not show a linear correlation with the total binding energies (DeltaEb) of the complexes, expected according to Badger-Bauer rule. However, in the same DeltanuO-H vs DeltaEb plot, nice linear correlations are revealed if the complexes of ortho-fluorophenols are treated separately from their meta/para-substituted analogues. The observations imply that in spite of having the same binding site (O-H?O) and the same chemical identities (phenolic), the complexes of ortho and non-ortho fluorophenols do not belong, from the viewpoint of detailed molecular interactions, to a homologous series. Linear correlations of DeltanuO-H are, however, observed with respect to the electrostatic component of DeltaEb as well as the quantum mechanical charge transfer interaction energy (ECT). From quantitative viewpoint, the latter correlation along with the associated electronic structure parameters appears more satisfactory. It has also been noted that the observed DeltanuO-H values of the complexes display a linear relationship with the aqueous phase pKa values of the respective phenol derivatives. PMID- 26627959 TI - The infrared spectrum of the Ne-C2D2 complex. AB - Infrared spectra of Ne-C2D2 are observed in the region of the nu3 fundamental band (asymmetric C-D stretch, ~2440 cm(-1)) using a tunable optical parametric oscillator to probe a pulsed supersonic slit jet expansion from a cooled nozzle. Like helium-acetylene, this system lies close to the free rotor limit, making analysis tricky because stronger transitions tend to pile up close to monomer (C2D2) rotation-vibration transitions. Assignments are aided by predicted rotational energies calculated from a published ab initio intermolecular potential energy surface. The analysis extends up to the j = 3<-2 band, where j labels C2D2 rotation within the dimer, and is much more complete than the limited infrared assignments previously reported for Ne-C2H2 and Ne-C2HD. Two previous microwave transitions within the j = 1 state of Ne-C2D2 are reassigned. Coriolis model fits to the theoretical levels and to the spectrum are compared. Since the variations observed as a function of C2D2 vibrational excitation are comparable to those noted between theory and experiment, it is evident that more detailed testing of theory will require vibrational averaging over the acetylene intramolecular modes. PMID- 26627960 TI - Rotational dynamics of a diatomic molecular ion in a Paul trap. AB - We present models for a heteronuclear diatomic molecular ion in a linear Paul trap in a rigid-rotor approximation, one purely classical and the other where the center-of-mass motion is treated classically, while rotational motion is quantized. We study the rotational dynamics and their influence on the motion of the center-of-mass, in the presence of the coupling between the permanent dipole moment of the ion and the trapping electric field. We show that the presence of the permanent dipole moment affects the trajectory of the ion and that it departs from the Mathieu equation solution found for atomic ions. For the case of quantum rotations, we also evidence the effect of the above-mentioned coupling on the rotational states of the ion. PMID- 26627961 TI - Control of multiple excited image states around segmented carbon nanotubes. AB - Electronic image states around segmented carbon nanotubes can be confined and shaped along the nanotube axis by engineering the image potential. We show how several such image states can be prepared simultaneously along the same nanotube. The inter-electronic distance can be controlled a priori by engineering tubes of specific geometries. High sensitivity to external electric and magnetic fields can be exploited to manipulate these states and their mutual long-range interactions. These building blocks provide access to a new kind of tailored interacting quantum systems. PMID- 26627962 TI - The configuration exchanging theory for transport properties and glass formation temperature of ionic liquids. AB - Understanding molecular motion in terms of molecular structure is an important issue for microscopic understanding of the nature of transport properties and glass transition, and for design of structured materials to meet specific demands in various applications. Herein, a novel molecular mechanism is proposed to connect macroscopic motion in ionic liquids with molecular structure via conformational conversions of the constituent ions or of the cation-anion pairs. New equations for description of relaxation time, diffusion coefficient, molar conductivity, and viscosity of ionic liquids are established. The equation parameters, which were determined from the temperature dependent heat capacities, self-diffusion coefficients, molar conductivities, and viscosities of typical ionic liquids, were used to produce predictions for the corresponding properties of other ionic liquids and for the glass transition temperatures of representative ionic liquids. All predictions are in nice agreements with the experimental results. PMID- 26627963 TI - Multi-scale lattice Boltzmann and mode-coupling theory calculations of the flow of a glass-forming liquid. AB - We present a hybrid-lattice Boltzmann (LB) algorithm for calculating the flow of glass-forming fluids that are governed by integral constitutive equations with pronounced nonlinear, non-Markovian dependence of the stresses on the flow history. The LB simulation for the macroscopic flow fields is combined with the mode-coupling theory (MCT) of the glass transition as a microscopic theory, in the framework of the integration-through transients formalism. Using the combined LB-MCT algorithm, pressure-driven planar channel flow is studied for a schematic MCT model neglecting spatial correlations in the microscopic dynamics. The cessation dynamics after removal of the driving pressure gradient shows strong signatures of oscillatory flow both in the macroscopic fields and the microscopic correlation functions. PMID- 26627964 TI - A theoretical study of the dissociation of the sI methane hydrate induced by an external electric field. AB - Molecular dynamics simulations in the equilibrium isobaric-isothermal (NPT) ensemble were used to examine the strength of an external electric field required to dissociate the methane hydrate sI structure. The water molecules were modeled using the four-site TIP4P/Ice analytical potential and methane was described as a simple Lennard-Jones interaction site. A series of simulations were performed at T = 260 K with P = 80 bars and at T = 285 K with P = 400 bars with an applied electric field ranging from 1.0 V nm(-1) to 5.0 V nm(-1). For both (T,P) conditions, applying a field greater than 1.5 V nm(-1) resulted in the orientation of the water molecules such that an ice Ih-type structure was formed, from which the methane was segregated. When the simulations were continued without the external field, the ice-like structures became disordered, resulting in two separate phases: gas methane and liquid water. PMID- 26627965 TI - Comparison of alpha and beta tin for lithium, sodium, and magnesium storage: An ab initio study including phonon contributions. AB - We present a comparative ab initio study of Li, Na, and Mg storage in tin, including phononic effects and phase competition between alpha and beta Sn. Mg doping at low concentration is found to stabilize the beta phase. On the contrary, Li and Na doping is shown to reverse the stability of the phases at room temperature: Li/Na-doped alpha-Sn is more stable than Li/Na-doped beta-Sn up to a temperature of around 380/400 K. This may rationalize the formation of alpha Sn upon lithiation and delithiation of beta-Sn anodes reported in experimental studies. The changes in phase stability with Li/Na/Mg doping are directly related to the intercalation energies of Li/Na/Mg in one phase versus the other: at 300 K, Li/Na is easier intercalated in alpha-Sn (-0.37/-0.08 eV) than in beta-Sn (0.06/0.49 eV), while Mg intercalation energy is, although positive (i.e., unfavored intercalation), lower in beta-Sn (0.53 eV) than in alpha-Sn (0.66 eV). The temperature effect is found to affect significantly the intercalation energy, by up to 0.13 eV at 300 K. Analysis of diffusion barriers shows that Li, Na, and Mg diffusion in beta-Sn is anisotropic with migration barriers along the (001) direction (respectively, 0.01, 0.22, and 0.07 eV) significantly lower than those in alpha-Sn (respectively, 0.20, 0.52, and 0.40 eV). PMID- 26627966 TI - Structure sensitivity in oxide catalysis: First-principles kinetic Monte Carlo simulations for CO oxidation at RuO2(111). AB - We present a density-functional theory based kinetic Monte Carlo study of CO oxidation at the (111) facet of RuO2. We compare the detailed insight into elementary processes, steady-state surface coverages, and catalytic activity to equivalent published simulation data for the frequently studied RuO2(110) facet. Qualitative differences are identified in virtually every aspect ranging from binding energetics over lateral interactions to the interplay of elementary processes at the different active sites. Nevertheless, particularly at technologically relevant elevated temperatures, near-ambient pressures and near stoichiometric feeds both facets exhibit almost identical catalytic activity. These findings challenge the traditional definition of structure sensitivity based on macroscopically observable turnover frequencies and prompt scrutiny of the applicability of structure sensitivity classifications developed for metals to oxide catalysis. PMID- 26627967 TI - Thermokinetics of heterogeneous droplet nucleation on conically textured substrates. AB - Within the framework of the classical theory of heterogeneous nucleation, a thermokinetic model is developed for line-tension-associated droplet nucleation on conical textures considering growth or shrinkage of the formed cluster due to both interfacial and peripheral monomer exchange and by considering different geometric configurations. Along with the principle of free energy extremization, Katz kinetic approach has been employed to study the effect of substrate conicity and wettability on the thermokinetics of heterogeneous water droplet nucleation. Not only the peripheral tension is found to have a considerable effect on the free energy barrier but also the substrate hydrophobicity and hydrophilicity are observed to switch over their roles between conical crest and trough for different growth rates of the droplet. Besides, the rate of nucleation increases and further promotes nucleation for negative peripheral tension as it diminishes the free energy barrier appreciably. Moreover, nucleation inhibition can be achievable for positive peripheral tension due to the enhancement of the free energy barrier. Analyzing all possible geometric configurations, the hydrophilic narrower conical cavity is found to be the most preferred nucleation site. These findings suggest a physical insight into the context of surface engineering for the promotion or the suppression of nucleation on real or engineered substrates. PMID- 26627968 TI - Structural, electronic and optical properties of well-known primary explosive: Mercury fulminate. AB - Mercury Fulminate (MF) is one of the well-known primary explosives since 17th century and it has rendered invaluable service over many years. However, the correct molecular and crystal structures are determined recently after 300 years of its discovery. In the present study, we report pressure dependent structural, elastic, electronic and optical properties of MF. Non-local correction methods have been employed to capture the weak van der Waals interactions in layered and molecular energetic MF. Among the non-local correction methods tested, optB88-vdW method works well for the investigated compound. The obtained equilibrium bulk modulus reveals that MF is softer than the well known primary explosives Silver Fulminate (SF), silver azide and lead azide. MF exhibits anisotropic compressibility (b > a > c) under pressure, consequently the corresponding elastic moduli decrease in the following order: C22 > C11 > C33. The structural and mechanical properties suggest that MF is more sensitive to detonate along c axis (similar to RDX) due to high compressibility of Hg?O non-bonded interactions along that axis. Electronic structure and optical properties were calculated including spin-orbit (SO) interactions using full potential linearized augmented plane wave method within recently developed Tran-Blaha modified Becke-Johnson (TB mBJ) potential. The calculated TB-mBJ electronic structures of SF and MF show that these compounds are indirect bandgap insulators. Also, SO coupling is found to be more pronounced for 4d and 5d-states of Ag and Hg atoms of SF and MF, respectively. Partial density of states and electron charge density maps were used to describe the nature of chemical bonding. Ag-C bond is more directional than Hg-C bond which makes SF to be more unstable than MF. The effect of SO coupling on optical properties has also been studied and found to be significant for both (SF and MF) of the compounds. PMID- 26627969 TI - Conformation of a flexible polymer in explicit solvent: Accurate solvation potentials for Lennard-Jones chains. AB - The conformation of a polymer chain in solution is coupled to the local structure of the surrounding solvent and can undergo large changes in response to variations in solvent density and temperature. The many-body effects of solvent on the structure of an n-mer polymer chain can be formally mapped to an exact n body solvation potential. Here, we use a pair decomposition of this n-body potential to construct a set of two-body potentials for a Lennard-Jones (LJ) polymer chain in explicit LJ solvent. The solvation potentials are built from numerically exact results for 5-mer chains in solvent combined with an approximate asymptotic expression for the solvation potential between sites that are distant along the chain backbone. These potentials map the many-body chain-in solvent problem to a few-body single-chain problem and can be used to study a chain of arbitrary length, thereby dramatically reducing the computational complexity of the polymer chain-in-solvent problem. We have constructed solvation potentials at a large number of state points across the LJ solvent phase diagram including the vapor, liquid, and super-critical regions. We use these solvation potentials in single-chain Monte Carlo (MC) simulations with n <= 800 to determine the size, intramolecular structure, and scaling behavior of chains in solvent. To assess our results, we have carried out full chain-in-solvent MC simulations (with n <= 100) and find that our solvation potential approach is quantitatively accurate for a wide range of solvent conditions for these chain lengths. PMID- 26627970 TI - Intrinsic conductivity of carbon nanotubes and graphene sheets having a realistic geometry. AB - The addition of carbon nanotubes (CNTs) and graphene sheets (GSs) into polymeric materials can greatly enhance the conductivity and alter the electromagnetic response of the resulting nanocomposite material. The extent of these property modifications strongly depends on the structural parameters describing the CNTs and GSs, such as their shape and size, as well as their degree of particle dispersion within the polymeric matrix. To model these property modifications in the dilute particle regime, we determine the leading transport virial coefficients describing the conductivity of CNT and GS composites using a combination of molecular dynamics, path-integral, and finite-element calculations. This approach allows for the treatment of the general situation in which the ratio between the conductivity of the nanoparticles and the polymer matrix is arbitrary so that insulating, semi-conductive, and conductive particles can be treated within a unified framework. We first generate ensembles of CNTs and GSs in the form of self-avoiding worm-like cylinders and perfectly flat and random sheet polymeric structures by using molecular dynamics simulation to model the geometrical shapes of these complex-shaped carbonaceous nanoparticles. We then use path-integral and finite element methods to calculate the electric and magnetic polarizability tensors (alphaE, alphaM) of the CNT and GS nanoparticles. These properties determine the conductivity virial coefficient sigma in the conductive and insulating particle limits, which are required to estimate sigma in the general case in which the conductivity contrast Delta between the nanoparticle and the polymer matrix is arbitrary. Finally, we propose approximate relationships for alphaE and alphaM that should be useful in materials design and characterization applications. PMID- 26627971 TI - Compression induced phase transition of nematic brush: A mean-field theory study. AB - Responsive behavior of polymer brush to the external compression is one of the most important characters for its application. For the flexible polymer brush, in the case of low grafting density, which is widely studied by the Gaussian chain model based theory, the compression leads to a uniform deformation of the chain. However, in the case of high grafting density, the brush becomes anisotropic and the nematic phase will be formed. The normal compression tends to destroy the nematic order, which leads to a complex responsive behaviors. Under weak compression, chains in the nematic brush are buckled, and the bending energy and Onsager interaction give rise to the elasticity. Under deep compression, the responsive behaviors of the nematic polymer brush depend on the chain rigidity. For the compressed rigid polymer brush, the chains incline to re-orientate randomly to maximize the orientational entropy and its nematic order is destroyed. For the compressed flexible polymer brush, the chains incline to fold back to keep the nematic order. A buckling-folding transition takes place during the compressing process. For the compressed semiflexible brush, the chains are collectively tilted to a certain direction, which leads to the breaking of the rotational symmetry in the lateral plane. These responsive behaviors of nematic brush relate to the properties of highly frustrated worm-like chain, which is hard to be studied by the traditional self-consistent field theory due to the difficulty to solve the modified diffusion equation. To overcome this difficulty, a single chain in mean-field theory incorporating Monte Carlo simulation and mean field theory for the worm-like chain model is developed in present work. This method shows high performance for entire region of chain rigidity in the confined condition. PMID- 26627972 TI - Publisher's Note: "Self-organization in suspensions of end-functionalized semiflexible polymers under shear flow" [J. Chem. Phys. 143, 243117 (2015)]. PMID- 26627973 TI - Erratum: "Van der Waals effects in ab initio water at ambient and supercritical conditions" [J. Chem. Phys. 135, 154503 (2011)]. PMID- 26627975 TI - Fostering interpersonal trust on social media: physicians' perspectives and experiences. AB - BACKGROUND: The problem of developing and sustaining mutual trust is one of the main barriers to knowledge sharing on social media platforms such as blogs, wikis, micro-blogs and social networking websites. While many studies argue that mutual trust is necessary for online communication and knowledge sharing, few have actually explored and demonstrated how physicians can establish and sustain trusted relationships on social media. OBJECTIVES: To identify approaches through which physicians establish interpersonal trust on social media. METHODS: Twenty four physicians, who were active users of social media, were interviewed using a semi-structured approach between 2013 and 2014. Snowball sampling was employed for participant recruitment. The data were analysed using a thematic analysis approach. RESULTS: Physicians trust their peers on social media in a slightly different way than in face-to-face communication. The study found that the majority of participants established trust on social media mainly through previous personal interaction, authenticity and relevancy of voice, professional standing, consistency of communication, peer recommendation, and non-anonymous and moderated sites. CONCLUSIONS: Healthcare professionals need to approach social media carefully when using it for knowledge sharing, networking and developing trusted relations with like-minded peers. PMID- 26627976 TI - Aprepitant for postoperative nausea and vomiting: a systematic review and meta analysis. AB - Postoperative nausea and vomiting (PONV) is an important clinical problem. Aprepitant is a relatively new agent for this condition which may be superior to other treatment. A systematic review was performed after searching a number of medical databases for controlled trials comparing aprepitant with conventional antiemetics published up to 25 April 2015 using the following keywords: 'Aprepitant for PONV', 'Aprepitant versus 5-HT3 antagonists' and 'NK-1 versus 5 HT3 for PONV'. The primary outcome for the pooled analysis was efficacy of aprepitant in preventing vomiting on postoperative day (POD) 1 and 2. 172 potentially relevant papers were identified of which 23 had suitable data. For the primary outcome, 14 papers had relevant data. On POD1, 227/2341 patients (9.7%) patients randomised to aprepitant had a vomiting episode compared with 496/2267 (21.9%) controls. On POD2, the rate of vomiting among patients receiving aprepitant was 6.8% compared with 12.8% for controls. The OR for vomiting compared with controls was 0.48 (95% CI 0.34 to 0.67) on POD1 and 0.54 (95% CI 0.40 to 0.72) on POD2. Aprepitant also demonstrated a better profile with a lower need for rescue antiemetic and a higher complete response. Efficacy for vomiting prevention was demonstrated for 40 mg, 80 mg and 125 mg without major adverse effects. For vomiting comparison there was significant unexplainable heterogeneity (67.9% and 71.5% for POD1 and POD2, respectively). We conclude that (1) aprepitant reduces the incidence of vomiting on both POD1 and POD2, but there is an unexplained heterogeneity which lowers the strength of the evidence; (2) complete freedom from PONV on POD1 is highest for aprepitant with minimum need for rescue; and (3) oral aprepitant (80 mg) provides an effective and safe sustained antivomiting effect. PMID- 26627977 TI - Comprehensive spending review and the NHS. PMID- 26627978 TI - How many mechanosensory organs in the bushcricket leg? Neuroanatomy of the scolopidial accessory organ in Tettigoniidae (Insecta: Orthoptera). AB - The subgenual organ and associated scolopidial organs are well studied in Orthoptera and related taxa. In some insects, a small accessory organ or Nebenorgan is described posterior to the subgenual organ. In Tettigoniidae (Ensifera), the accessory organ has only been noted in one species though tibial sensory organs are well studied for neuroanatomy and physiology. Here, we use axonal tracing to analyse the posterior subgenual organ innervated by the main motor nerve. Investigating seven species from different groups of Tettigoniidae, we describe a small group of scolopidial sensilla (5-9 sensory neurons) which has features characteristic of the accessory organ: posterior tibial position, innervation by the main leg nerve rather than by the tympanal nerve, orientation of dendrites in proximal or ventro-proximal direction in the leg, and commonly association with a single campaniform sensillum. The neuroanatomy is highly similar between leg pairs. We show differences in the innervation in two species of the genus Poecilimon as compared to the other species. In Poecilimon, the sensilla of the accessory organ are innervated by one nerve branch together with the subgenual organ. The results suggest that the accessory organ is part of the sensory bauplan in the leg of Tettigoniidae and probably Ensifera. PMID- 26627979 TI - Clinical Trial Assessment of Infrastructure Matrix Tool to Improve the Quality of Research Conduct in the Community. AB - PURPOSE: Several publications have described minimum standards and exemplary attributes for clinical trial sites to improve research quality. The National Cancer Institute (NCI) Community Cancer Centers Program (NCCCP) developed the clinical trial Best Practice Matrix tool to facilitate research program improvements through annual self-assessments and benchmarking. The tool identified nine attributes, each with three progressive levels, to score clinical trial infrastructural elements from less to more exemplary. The NCCCP sites correlated tool use with research program improvements, and the NCI pursued a formative evaluation to refine the interpretability and measurability of the tool. METHODS: From 2011 to 2013, 21 NCCCP sites self-assessed their programs with the tool annually. During 2013 to 2014, NCI collaborators conducted a five step formative evaluation of the matrix tool. RESULTS: Sites reported significant increases in level-three scores across the original nine attributes combined (P<.001). Two specific attributes exhibited significant change: clinical trial portfolio diversity and management (P=.0228) and clinical trial communication (P=.0281). The formative evaluation led to revisions, including renaming the Best Practice Matrix as the Clinical Trial Assessment of Infrastructure Matrix (CT AIM), expanding infrastructural attributes from nine to 11, clarifying metrics, and developing a new scoring tool. CONCLUSION: Broad community input, cognitive interviews, and pilot testing improved the usability and functionality of the tool. Research programs are encouraged to use the CT AIM to assess and improve site infrastructure. Experience within the NCCCP suggests that the CT AIM is useful for improving quality, benchmarking research performance, reporting progress, and communicating program needs with institutional leaders. The tool model may also be useful in disciplines beyond oncology. PMID- 26627980 TI - Health-care access among adults with epilepsy: The U.S. National Health Interview Survey, 2010 and 2013. AB - INTRODUCTION: Community-based and other epidemiologic studies within the United States have identified substantial disparities in health care among adults with epilepsy. However, few data analyses addressing their health-care access are representative of the entire United States. This study aimed to examine national survey data about adults with epilepsy and to identify barriers to their health care. MATERIALS AND METHODS: We analyzed data from U.S. adults in the 2010 and the 2013 National Health Interview Surveys, multistage probability samples with supplemental questions on epilepsy. We defined active epilepsy as a history of physician-diagnosed epilepsy either currently under treatment or accompanied by seizures during the preceding year. We employed SAS-callable SUDAAN software to obtain weighted estimates of population proportions and rate ratios (RRs) adjusted for sex, age, and race/ethnicity. RESULTS: Compared to adults reporting no history of epilepsy, adults reporting active epilepsy were significantly more likely to be insured under Medicaid (RR=3.58) and less likely to have private health insurance (RR=0.58). Adults with active epilepsy were also less likely to be employed (RR=0.53) and much more likely to report being disabled (RR=6.14). They experience greater barriers to health-care access including an inability to afford medication (RR=2.40), mental health care (RR=3.23), eyeglasses (RR=2.36), or dental care (RR=1.98) and are more likely to report transportation as a barrier to health care (RR=5.28). CONCLUSIONS: These reported substantial disparities in, and barriers to, access to health care for adults with active epilepsy are amenable to intervention. PMID- 26627981 TI - Sustainable Redox Mediation for Lithium-Oxygen Batteries by a Composite Protective Layer on the Lithium-Metal Anode. AB - A synergic combination of a soluble -redox mediator and a protected Li metal electrode to prevent the self-discharge of the redox mediator is realized by exploiting a 2,2,6,6-tetramethylpiperidinyl 1-oxyl (TEMPO) redox mediator and an Al2 O3 /PVdF-HFP composite -protective layer (CPL). Stabilization of Li metal by simple CPL coating is effective at -suppressing the chemical reduction of the oxidized TEMPO and opens up the possibility of sustainable redox mediation for robust cycling of Li-O2 batteries. PMID- 26627982 TI - The effectiveness of Corticosteroids on mortality in patients with acute respiratory distress syndrome or acute lung injury: a secondary analysis. AB - The development of acute respiratory distress syndrome (ARDS) is associated with dys-regulated inflammation. Since corticosteroids are potent anti-inflammatory drugs, they are thought to be beneficial for ARDS patients. The study aimed to investigate the effectiveness of corticosteroids on mortality outcome in ARDS patients. The study was a secondary analysis of a prospective randomized controlled trial (NCT00979121). ARDS patients with invasive mechanical ventilation were enrolled. Corticosteroids use was defined as IV or PO administration of corticosteroids totaling more than 20 mg methylprednisolone equivalents during one calendar day. Missing data were handled using multiple imputation technique. Multivariable model was built to adjust for confounding covariates. A total of 745 patients were enrolled, including 540 survivors and 205 non-survivors. Patients in the non-survivor group were more likely to use corticosteroids (38% vs. 29.8%; p = 0.032). After adjustment for other potential confounders, corticosteroids showed no statistically significant effect on mortality outcome (OR: 1.18; 95% CI: 0.81-1.71). Furthermore, we investigated the interaction between corticosteroid use and variables of vasopressor and PaO2. The result showed that there was no significant interaction. In conclusion, the study failed to identify any beneficial effects of corticosteroids on mortality outcome in patients with ARDS. PMID- 26627983 TI - Biochemistry and Cell Wall Changes Associated with Noni (Morinda citrifolia L.) Fruit Ripening. AB - Quality and compositional changes were determined in noni fruit harvested at five ripening stages, from dark-green to thaslucent-grayish. Fruit ripening was accompanied by acidity and soluble solids accumulation but pH diminution, whereas the softening profile presented three differential steps named early (no significant softening), intermediate (significant softening), and final (dramatic softening). At early step the extensive depolymerization of hydrosoluble pectins and the significantly increment of pectinase activities did not correlate with the slight reduction in firmness. The intermediate step showed an increment of pectinases and hemicellulases activities. The final step was accompanied by the most significant reduction in the yield of alcohol-insoluble solids as well as in the composition of uronic acids and neutral sugars; pectinases increased their activity and depolymerization of hemicellulosic fractions occurred. Noni ripening is a process conducted by the coordinated action of pectinases and hemicellulases that promote the differential dissasembly of cell wall polymers. PMID- 26627984 TI - Enhanced sialylation of a human chimeric IgG1 variant produced in human and rodent cell lines. AB - Glycosylation of the IgG-Fc is essential for optimal binding and activation of Fcgamma receptors and the C1q component of complement. However, it has been reported that the effector functions are down-regulated when the Fc glycans terminate in sialic acid residues and that sialylated IgG mediates anti inflammatory effects of intravenous immunoglobulin (IVIG). Although recombinant IgG is hypo-sialylated, Fc sialylation is shown to be markedly increased when a mouse/human chimeric IgG3 Phe243Ala (F243A) variant is expressed in Chinese hamster ovary (CHO)-K1 cells. Here we investigate whether sialylation is increased in IgG1 F243A when expressed in CHO-K1, mouse myeloma J558L and human embryonic kidney (HEK) 293. Although the sialylation level was 2-5% for IgG1 wild type (WT), it was increased to 31%, 10% and 33% for the variant from CHO-K1, J558L and HEK293 cells, respectively. Interestingly, an increased addition of bisecting GlcNAc and alpha(1-3)-galactose residues to the Fc glycan was observed for HEK293-derived and J558L-derived IgG1 F243A, respectively. Fucosylation of HEK293-derived IgG1 F243A was maintained despite increased bisecting GlcNAc content. Although sialic acid and bisecting GlcNAc residues are reported to have an opposing effect on antibody-dependent cellular cytotoxicity (ADCC), IgG1 F243A showed 7 times lower ADCC activities than IgG1 WT, irrespective of bisecting GlcNAc residue. Thus, highly sialylated, human cell-derived IgG1 F243A with lowered ADCC activity may be of interest for the development of therapeutic antibodies with anti-inflammatory properties as an alternative to IVIG. PMID- 26627986 TI - Small molecules with anti-inflammatory properties in clinical development. AB - Inflammation is a crucial physiological response of our body to any kind of noxa be it an infection or tissue injury. However, this physiological process can be detrimental if dysregulated, and when the acute inflammatory response fails to resolve the cause of inflammation, there can be a switch to chronification. According to ICD 10 (WHO) over 3.000 diseases exist with the suffix "-itis" which terms an inflammatory disease. For the treatment of inflammation, non-steroidal anti-inflammatory drugs (NSAIDs) are the most widespread drugs while glucocorticoids are among our strongest weapons against inflammation, making them emergency treatments for acute episodes of chronic inflammation. For the treatment of many inflammatory disorders, both are not satisfying. Consequently, industrial and academic research on anti-inflammatory drugs is very intensive. In this review, we evaluate current treatments and unmet needs of chronic inflammatory diseases with high prevalence (rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease, inflammatory bowel disease, and psoriasis), and systematically review small molecules with anti-inflammatory properties presently in clinical trials for the aforementioned diseases. As the pathophysiological knowledge of diseases increased over the last decades, a more specific intervention of inflammatory pathways becomes possible. After one hundred years of NSAIDs and over fifty years of glucocorticoids, more specific drugs for anti-inflammatory therapy such as roflumilast or fingolimod are rising. The aim of this article is to critically review the literature on small anti inflammatory molecules in clinical trials to generate an idea of what we can expect in the future. PMID- 26627988 TI - Treatment of Small Surgical Valves: Clinical Considerations for Achieving Optimal Results in Valve-in-Valve Procedures. PMID- 26627985 TI - H3ABioNet, a sustainable pan-African bioinformatics network for human heredity and health in Africa. AB - The application of genomics technologies to medicine and biomedical research is increasing in popularity, made possible by new high-throughput genotyping and sequencing technologies and improved data analysis capabilities. Some of the greatest genetic diversity among humans, animals, plants, and microbiota occurs in Africa, yet genomic research outputs from the continent are limited. The Human Heredity and Health in Africa (H3Africa) initiative was established to drive the development of genomic research for human health in Africa, and through recognition of the critical role of bioinformatics in this process, spurred the establishment of H3ABioNet, a pan-African bioinformatics network for H3Africa. The limitations in bioinformatics capacity on the continent have been a major contributory factor to the lack of notable outputs in high-throughput biology research. Although pockets of high-quality bioinformatics teams have existed previously, the majority of research institutions lack experienced faculty who can train and supervise bioinformatics students. H3ABioNet aims to address this dire need, specifically in the area of human genetics and genomics, but knock-on effects are ensuring this extends to other areas of bioinformatics. Here, we describe the emergence of genomics research and the development of bioinformatics in Africa through H3ABioNet. PMID- 26627987 TI - Gut microbiome in health and disease: Linking the microbiome-gut-brain axis and environmental factors in the pathogenesis of systemic and neurodegenerative diseases. AB - The gut microbiome comprises the collective genome of the trillions of microorganisms residing in our gastrointestinal ecosystem. The interaction between the host and its gut microbiome is a complex relationship whose manipulation could prove critical to preventing or treating not only various gut disorders, like irritable bowel syndrome (IBS) and ulcerative colitis (UC), but also central nervous system (CNS) disorders, such as Alzheimer's and Parkinson's diseases. The purpose of this review is to summarize what is known about the gut microbiome, how it is connected to the development of disease and to identify the bacterial and biochemical targets that should be the focus of future research. Understanding the mechanisms behind the activity and proliferation of the gut microbiome will provide us new insights that may pave the way for novel therapeutic strategies. PMID- 26627989 TI - Bleeding Outcomes After Left Atrial Appendage Closure Compared With Long-Term Warfarin: A Pooled, Patient-Level Analysis of the WATCHMAN Randomized Trial Experience. AB - OBJECTIVES: The purpose of this study was to compare the relative risk of major bleeding with left atrial appendage (LAA) closure compared with long-term warfarin therapy. BACKGROUND: LAA closure is an alternative approach to chronic oral anticoagulation for the prevention of thromboembolism in patients with atrial fibrillation (AF). METHODS: We conducted a pooled, patient-level analysis of the 2 randomized clinical trials that compared WATCHMAN (Boston Scientific, Natick, Massachusetts) LAA closure with long-term warfarin therapy in AF. RESULTS: A total of 1,114 patients were included, with a median follow-up of 3.1 years. The overall rate of major bleeding from randomization to the end of follow up was similar between treatment groups (3.5 events vs. 3.6 events per 100 patient-years; rate ratio [RR]: 0.96; 95% confidence interval [CI]: 0.66 to 1.40; p = 0.84). LAA closure significantly reduced bleeding >7 days post-randomization (1.8 events vs. 3.6 events per 100 patient-years; RR: 0.49; 95% CI: 0.32 to 0.75; p = 0.001), with the difference emerging 6 months after randomization (1.0 events vs. 3.5 events per 100 patient-years; RR: 0.28; 95% CI: 0.16 to 0.49; p < 0.001), when patients assigned to LAA closure were able to discontinue adjunctive oral anticoagulation and antiplatelet therapy. The reduction in bleeding with LAA closure was directionally consistent across all patient subgroups. CONCLUSIONS: There was no difference in the overall rate of major bleeding in patients assigned to LAA closure compared with extended warfarin therapy over 3 years of follow-up. However, LAA closure significantly reduced bleeding beyond the procedural period, particularly once adjunctive pharmacotherapy was discontinued. The favorable effect of LAA closure on long-term bleeding should be considered when selecting a stroke prevention strategy for patients with nonvalvular AF. (WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients With Atrial Fibrillation; NCT00129545; and Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy [PREVAIL]; NCT01182441). PMID- 26627990 TI - Go Set a Watchman? PMID- 26627991 TI - Drug-Coated Balloon Angioplasty for De Novo Stenosis: The Balloon is Back...Reloaded! PMID- 26627992 TI - How Can We Help a Patient With a Small Failing Bioprosthesis?: An In Vitro Case Study. AB - OBJECTIVES: The aim of this study was to investigate the hemodynamic performance of a transcatheter heart valve (THV) deployed at different valve-in-valve positions in an in vitro model using a small surgical bioprosthesis. BACKGROUND: Patients at high surgical risk with failing 19-mm surgical aortic bioprostheses are not candidates for valve-in-valve transcatheter aortic valve replacement, because of risk for high transvalvular pressure gradients (TVPGs) and patient prosthesis mismatch. METHODS: A 19-mm stented aortic bioprosthesis was mounted into the aortic chamber of a pulse duplicator, and a 23-mm low-profile balloon expandable THV was deployed (valve-in-valve) in 4 positions: normal (bottom of the THV stent aligned with the bottom of the surgical bioprosthesis sewing ring) and 3, 6, and 8 mm above the normal position. Under controlled hemodynamic status, the effect of these THV positions on valve performance (mean TVPG, geometric orifice area, and effective orifice area), thrombotic potential (sinus shear stress), and migration risk (pullout force and embolization flow rate) were assessed. RESULTS: Compared with normal implantation, a progressive reduction of mean TVPG was observed with each supra-annular THV position (normal: 33.10 mm Hg; 3 mm: 24.69 mm Hg; 6 mm: 19.16 mm Hg; and 8 mm: 12.98 mm Hg; p < 0.001). Simultaneously, we observed increases in geometric orifice area (normal: 0.83 cm(2); 8 mm: 1.60 cm(2); p < 0.001) and effective orifice area (normal: 0.80 cm(2); 8 mm: 1.28 cm(2); p < 0.001) and reductions in sinus shear stresses (normal: 153 dyne/cm(2); 8 mm: 40 dyne/cm(2); p < 0.001), pullout forces (normal: 1.55 N; 8 mm: 0.68 N; p < 0.05), and embolization flow rates (normal: 32.91 l/min; 8 mm: 26.06 l/min; p < 0.01). CONCLUSIONS: Supra-annular implantation of a THV in a small surgical bioprosthesis reduces mean TVPG but may increase the risk for leaflet thrombosis and valve migration. A 3- to 6-mm supra-annular deployment could be an optimal position in these cases. PMID- 26627993 TI - Gluing of an Aortic Perforation During Transcatheter Aortic Valve Replacement: An Alternative Treatment for Annular Rupture? PMID- 26627994 TI - Thoracoscopic Atriclip Closure of Left Atrial Appendage After Failed Ligation via LARIAT. PMID- 26627995 TI - Progression of Intimal Hyperplasia and Multiple-Channel Formation After Fogarty Thrombectomy: Insight Into Vasculopathy From Optical Coherence Tomography and Intravascular Ultrasound Findings. PMID- 26627996 TI - Overlapping-Stent Intervention Treatment of a Giant Right Coronary Artery Pseudoaneurysm. PMID- 26627997 TI - Effect of Drug-Coated Balloons in Native Coronary Artery Disease Left With a Dissection. AB - OBJECTIVES: The authors sought to understand the clinical and angiographic outcomes of dissections left after drug-coated balloon (DCB) angioplasty. BACKGROUND: Second-generation DCB may be an alternative to stents in selected populations for the treatment of native coronary lesions. However, the use of these devices may be hampered by a certain risk of acute vessel recoil or residual coronary dissection. Moreover, stenting after DCB has shown limited efficacy. Little is known about when a non-flow-limiting dissection is left after DCB angioplasty. METHODS: This was a prospective observational study whose aim was to investigate the outcome of a consecutive series of patients with native coronary artery disease treated with second-generation DCB and residual coronary dissection at 2 Italian centers. We evaluated patient clinical conditions at 1 and 9 months, and angiographic follow up was undertaken at 6 months. RESULTS: Between July 2012 and July 2014, 156 patients were treated with DCB for native coronary artery disease. Fifty-two patients had a final dissection, 4 of which underwent prosthesis implantation and 48 were left untreated and underwent angiographic follow-up after 201 days (interquartile range: 161 to 250 days). The dissections were all type A to C, and none determined an impaired distal flow. Complete vessel healing at angiography was observed in 45 patients (93.8%), whereas 3 patients had persistent but uncomplicated dissections, and 3 had binary restenosis (6.2%). Late lumen loss was 0.14 mm (-0.14 to 0.42). Major adverse cardiovascular events occurred in 11 patients in the entire cohort and in 4 of the dissection cohort (7.2% vs. 8.1%; p = 0.48). We observed 8 and 3 target lesion revascularizations, respectively (5.3% vs. 6.2%; p = 0.37). CONCLUSIONS: In this cohort of consecutive patients treated with new-generation DCB and left with a final dissection, this strategy of revascularization seemed associated with the sealing of most of dissections and without significant neointimal hyperplasia. PMID- 26627998 TI - Within-species divergence in the seminal fluid proteome and its effect on male and female reproduction in a beetle. AB - BACKGROUND: Male seminal fluid proteins (SFPs), transferred to females during mating, are important reproductive proteins that have multifarious effects on female reproductive physiology and that often show remarkably rapid and divergent evolution. Inferences regarding natural selection on SFPs are based primarily on interspecific comparative studies, and our understanding of natural within species variation in SFPs and whether this relates to reproductive phenotypes is very limited. Here, we introduce an empirical strategy to study intraspecific variation in and selection upon the seminal fluid proteome. We then apply this in a study of 15 distinct populations of the seed beetle Callosobruchus maculatus. RESULTS: Phenotypic assays of these populations showed significant differences in reproductive phenotypes (male success in sperm competition and male ability to stimulate female fecundity). A quantitative proteomic study of replicated samples of male accessory glands revealed a large number of potential SFPs, of which >=127 were found to be transferred to females at mating. Moreover, population divergence in relative SFP abundance across populations was large and remarkably multidimensional. Most importantly, variation in male SFP abundance across populations was associated with male sperm competition success and male ability to stimulate female egg production. CONCLUSIONS: Our study provides the first direct evidence for postmating sexual selection on standing intraspecific variation in SFP abundance and the pattern of divergence across populations in the seminal fluid proteome match the pattern predicted by the postmating sexual selection paradigm for SFP evolution. Our findings provide novel support for the hypothesis that sexual selection on SFPs is an important engine of incipient speciation. PMID- 26627999 TI - Cortical hypertrophy with a short, curved uncemented hip stem does not have any clinical impact during early follow-up. AB - BACKGROUND: Short stems have become more and more popular for cementless total hip arthroplasty in the past few years. While conventional, uncemented straight stems for primary total hip arthroplasty (THA) have shown high survival rates in the long term, it is not known whether uncemented short stems represent a reasonable alternative. As cortical hypertrophy has been reported for short stems, the aim of this study was to determine the radiographic prevalence of cortical hypertrophy and to assess the clinical outcome of a frequently used short, curved hip stem. METHODS: We retrospectively studied the clinical and radiographic results of our first 100 consecutive THAs (97 patients) using the Fitmore(r) hip stem. Mean age at the time of index arthroplasty was 59 years (range, 19 - 79 years). Clinical outcome and radiographic results were assessed with a minimum follow-up of 2 years, and Kaplan-Meier survivorship analysis was used to estimate survival for different endpoints. RESULTS: After a mean follow up of 3.3 years (range, 2.0 - 4.4 years), two patients (two hips) had died, and three patients (four hips) were lost to follow-up. Kaplan-Meier analysis estimated a survival rate of 100 % at 3.8 years, with revision for any reason as the endpoint. No femoral component showed radiographic signs of loosening. No osteolysis was detected. Cortical hypertrophy was found in 50 hips (63 %), predominantly in Gruen zone 3 and 5. In the cortical hypertrophy group, two patients (two hips; 4 %) reported some thigh pain in combination with pain over the greater trochanter region during physical exercise (UCLA Score 6 and 7). There was no significant difference concerning the clinical outcome between the cortical hypertrophy and no cortical hypertrophy group. CONCLUSIONS: The survival rate and both clinical and the radiographic outcome confirm the encouraging results for short, curved uncemented stems. Postoperative radiographs frequently displayed cortical hypertrophy but it had no significant effect on the clinical outcome in the early follow-up. Further clinical and radiographic follow-up is necessary to detect possible adverse, long-term, clinical effects of cortical hypertrophy. PMID- 26628000 TI - Stable expression of silencing-suppressor protein enhances the performance and longevity of an engineered metabolic pathway. AB - Transgenic engineering of plants is important in both basic and applied research. However, the expression of a transgene can dwindle over time as the plant's small (s)RNA-guided silencing pathways shut it down. The silencing pathways have evolved as antiviral defence mechanisms, and viruses have co-evolved viral silencing-suppressor proteins (VSPs) to block them. Therefore, VSPs have been routinely used alongside desired transgene constructs to enhance their expression in transient assays. However, constitutive, stable expression of a VSP in a plant usually causes pronounced developmental abnormalities, as their actions interfere with endogenous microRNA-regulated processes, and has largely precluded the use of VSPs as an aid to stable transgene expression. In an attempt to avoid the deleterious effects but obtain the enhancing effect, a number of different VSPs were expressed exclusively in the seeds of Arabidopsis thaliana alongside a three step transgenic pathway for the synthesis of arachidonic acid (AA), an omega-6 long chain polyunsaturated fatty acid. Results from independent transgenic events, maintained for four generations, showed that the VSP-AA-transformed plants were developmentally normal, apart from minor phenotypes at the cotyledon stage, and could produce 40% more AA than plants transformed with the AA transgene cassette alone. Intriguingly, a geminivirus VSP, V2, was constitutively expressed without causing developmental defects, as it acts on the siRNA amplification step that is not part of the miRNA pathway, and gave strong transgene enhancement. These results demonstrate that VSP expression can be used to protect and enhance stable transgene performance and has significant biotechnological application. PMID- 26628001 TI - Ellagic acid protects against arsenic toxicity in isolated rat mitochondria possibly through the maintaining of complex II. AB - Chronic arsenic exposure has been linked to many health problems including diabetes and cancer. In the present study, we assessed the protective effect of ellagic acid (EA) against toxicity induced by arsenic in isolated rat liver mitochondria. Reactive oxygen species (ROS) and mitochondrial membrane potential decline were assayed using dichlorofluorescein diacetate and rhodamine 123, respectively, and dehydrogenase activity obtained by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide conversion assay. Arsenic increased ROS levels and mitochondrial dysfunction, which led to a reduction in mitochondrial total dehydrogenase activity. Mitochondria pretreated with EA exposed to arsenic at various concentrations led to a reversal of ROS production and mitochondrial damage. Our results showed that mitochondria were significantly affected when exposed to arsenic, which resulted in excessive ROS production and mitochondrial membrane disruption. Pretreatment with EA, reduced ROS amounts, mitochondrial damage, and restored total dehydrogenase activity specifically associated with mitochondrial complex II. EA protective characteristics may be accomplished particularly throughout the mitochondrial maintenance either directly by its antioxidant property or indirectly through its maintaining of complex II. These findings also suggest a potential role for EA in treating or preventing mitochondria associated disorders. PMID- 26628002 TI - Proposal for a new mechanism of action for aluminum phosphide (ALP) for causing local injuries in ALP poisoning: Should treatment strategies be modified? PMID- 26628004 TI - Operator for stroke interventions. PMID- 26628005 TI - Highly stretchable MoS2 kirigami. AB - We report the results of classical molecular dynamics simulations focused on studying the mechanical properties of MoS2 kirigami. Several different kirigami structures were studied based upon two simple non-dimensional parameters, which are related to the density of cuts, as well as the ratio of the overlapping cut length to the nanoribbon length. Our key findings are significant enhancements in tensile yield (by a factor of four) and fracture strains (by a factor of six) as compared to pristine MoS2 nanoribbons. These results, in conjunction with recent results on graphene, suggest that the kirigami approach may be generally useful for enhancing the ductility of two-dimensional nanomaterials. PMID- 26628003 TI - Loss of Munc18-1 long splice variant in GABAergic terminals is associated with cognitive decline and increased risk of dementia in a community sample. AB - BACKGROUND: Presynaptic terminals contribute to cognitive reserve, balancing the effects of age-related pathologies on cognitive function in the elderly. The presynaptic protein Munc18-1, alternatively spliced into long (M18L) or short (M18S) isoforms, is a critical modulator of neurotransmission. While subtle alterations in Munc18-1 have been shown to cause severe neuropsychiatric disorders with cognitive impairment, little information is known regarding the specific roles of Munc18-1 splice variants. We first investigated functional and anatomical features evidencing the divergent roles of M18L and M18S, and then evaluated their contribution to the full range of age-related cognitive impairment in the dorsolateral prefrontal cortex of a large sample of participants from a community-based aging study, including subjects with no-(NCI, n = 90), or mild-(MCI, n = 86) cognitive impairment, or with clinical dementia (n = 132). Finally, we used APP23 mutant mice to study the association between M18L/S and the time-dependent accumulation of common Alzheimer's disease pathology. RESULTS: Using isoform-specific antibodies, M18L was localized to the synaptosomal fraction, with a distribution matching lipid raft microdomains. M18S was found widely across cytosolic and synaptosomal compartments. Immunocytochemical studies identified M18L in perisomatic, GABAergic terminals, while M18S was broadly distributed in GABAergic and glutamatergic terminals. Using regression models taking into account multiple age-related pathologies, age, education and sex, global cognitive function was associated with the level of M18L (p = 0.006) but not M18S (p = 0.88). Mean M18L in dementia cases was 51 % lower than in NCI cases (p < 0.001), and each unit of M18L was associated with a lower likelihood of dementia (odds ratio = 0.68, 95 % confidence interval = 0.50 0.90, p = 0.008). In contrast, M18S balanced across clinical and pathologically diagnosed groups. M18L loss may not be caused by age-related amyloid pathology, since APP23 mice (12- and 22-months of age) had unchanged cortical levels of M18L/S compared with wild-type animals. CONCLUSIONS: M18L was localized to presynaptic inhibitory terminals, and was associated with cognitive function and protection from dementia in an elderly, community-based cohort. Lower M18L in inhibitory presynaptic terminals may be an early, independent contributor to cognitive decline. PMID- 26628007 TI - Speed Determines Leadership and Leadership Determines Learning during Pigeon Flocking. AB - A key question in collective behavior is how individual differences structure animal groups, affect the flow of information, and give some group members greater weight in decisions. Depending on what factors contribute to leadership, despotic decisions could either improve decision accuracy or interfere with swarm intelligence. The mechanisms behind leadership are therefore important for understanding its functional significance. In this study, we compared pigeons' relative influence over flock direction to their solo flight characteristics. A pigeon's degree of leadership was predicted by its ground speeds from earlier solo flights, but not by the straightness of its previous solo route. By testing the birds individually after a series of flock flights, we found that leaders had learned straighter homing routes than followers, as we would expect if followers attended less to the landscape and more to conspecifics. We repeated the experiment from three homing sites using multiple independent flocks and found individual consistency in leadership and speed. Our results suggest that the leadership hierarchies observed in previous studies could arise from differences in the birds' typical speeds. Rather than reflecting social preferences that optimize group decisions, leadership may be an inevitable consequence of heterogeneous flight characteristics within self-organized flocks. We also found that leaders learn faster and become better navigators, even if leadership is not initially due to navigational ability. The roles that individuals fall into during collective motion might therefore have far-reaching effects on how they learn about the environment and use social information. PMID- 26628008 TI - Endogenous Delta/Theta Sound-Brain Phase Entrainment Accelerates the Buildup of Auditory Streaming. AB - In many natural listening situations, meaningful sounds (e.g., speech) fluctuate in slow rhythms among other sounds. When a slow rhythmic auditory stream is selectively attended, endogenous delta (1-4 Hz) oscillations in auditory cortex may shift their timing so that higher-excitability neuronal phases become aligned with salient events in that stream [1, 2]. As a consequence of this stream-brain phase entrainment [3], these events are processed and perceived more readily than temporally non-overlapping events [4-11], essentially enhancing the neural segregation between the attended stream and temporally noncoherent streams [12]. Stream-brain phase entrainment is robust to acoustic interference [13-20] provided that target stream-evoked rhythmic activity can be segregated from noncoherent activity evoked by other sounds [21], a process that usually builds up over time [22-27]. However, it has remained unclear whether stream-brain phase entrainment functionally contributes to this buildup of rhythmic streams or whether it is merely an epiphenomenon of it. Here, we addressed this issue directly by experimentally manipulating endogenous stream-brain phase entrainment in human auditory cortex with non-invasive transcranial alternating current stimulation (TACS) [28-30]. We assessed the consequences of these manipulations on the perceptual buildup of the target stream (the time required to recognize its presence in a noisy background), using behavioral measures in 20 healthy listeners performing a naturalistic listening task. Experimentally induced cyclic 4-Hz variations in stream-brain phase entrainment reliably caused a cyclic 4-Hz pattern in perceptual buildup time. Our findings demonstrate that strong endogenous delta/theta stream-brain phase entrainment accelerates the perceptual emergence of task-relevant rhythmic streams in noisy environments. PMID- 26628006 TI - Dysregulation of microRNA biogenesis machinery in cancer. AB - MicroRNAs (miRNAs) are integral to the gene regulatory network. A single miRNA is capable of controlling the expression of hundreds of protein coding genes and modulate a wide spectrum of biological functions, such as proliferation, differentiation, stress responses, DNA repair, cell adhesion, motility, inflammation, cell survival, senescence and apoptosis, all of which are fundamental to tumorigenesis. Overexpression, genetic amplification, and gain-of function mutation of oncogenic miRNAs ("onco-miRs") as well as genetic deletion and loss-of-function mutation of tumor suppressor miRNAs ("suppressor-miRs") are linked to human cancer. In addition to the dysregulation of a specific onco-miR or suppressor-miRs, changes in global miRNA levels resulting from a defective miRNA biogenesis pathway play a role in tumorigenesis. The function of individual onco-miRs and suppressor-miRs and their target genes in cancer has been described in many different articles elsewhere. In this review, we primarily focus on the recent development regarding the dysregulation of the miRNA biogenesis pathway and its contribution to cancer. PMID- 26628009 TI - Estimating the Environmental Costs of Africa's Massive "Development Corridors". AB - In sub-Saharan Africa, dozens of major "development corridors" have been proposed or are being created to increase agricultural production [1-4], mineral exports [5-7], and economic integration. The corridors involve large-scale expansion of infrastructure such as roads, railroads, pipelines, and port facilities and will open up extensive areas of land to new environmental pressures [1, 4, 8]. We assessed the potential environmental impacts of 33 planned or existing corridors that, if completed, would total over 53,000 km in length and crisscross much of the African continent. We mapped each corridor and estimated human occupancy (using the distribution of persistent night-lights) and environmental values (endangered and endemic vertebrates, plant diversity, critical habitats, carbon storage, and climate-regulation services) inside a 50-km-wide band overlaid onto each corridor. We also assessed the potential for each corridor to facilitate increases in agricultural production. The corridors varied considerably in their environmental values, and many were only sparsely populated. Because of marginal soils or climates, some corridors appear to have only modest agricultural potential. Collectively, the corridors would bisect over 400 existing protected areas and could degrade a further ~1,800 by promoting habitat disruption near or inside the reserves. We conclude that many of the development corridors will promote serious and largely irreversible environmental changes and should proceed only if rigorous mitigation and protection measures can be employed. Some planned corridors with high environmental values and limited agricultural benefits should possibly be cancelled altogether. VIDEO ABSTRACT. PMID- 26628010 TI - A Unifying Model of Orientation Crowding in Peripheral Vision. AB - Peripheral vision is fundamentally limited not by the visibility of features, but by the spacing between them [1]. When too close together, visual features can become "crowded" and perceptually indistinguishable. Crowding interferes with basic tasks such as letter and face identification and thus informs our understanding of object recognition breakdown in peripheral vision [2]. Multiple proposals have attempted to explain crowding [3], and each is supported by compelling psychophysical and neuroimaging data [4-6] that are incompatible with competing proposals. In general, perceptual failures have variously been attributed to the averaging of nearby visual signals [7-10], confusion between target and distractor elements [11, 12], and a limited resolution of visual spatial attention [13]. Here we introduce a psychophysical paradigm that allows systematic study of crowded perception within the orientation domain, and we present a unifying computational model of crowding phenomena that reconciles conflicting explanations. Our results show that our single measure produces a variety of perceptual errors that are reported across the crowding literature. Critically, a simple model of the responses of populations of orientation selective visual neurons accurately predicts all perceptual errors. We thus provide a unifying mechanistic explanation for orientation crowding in peripheral vision. Our simple model accounts for several perceptual phenomena produced by crowding of orientation and raises the possibility that multiple classes of object recognition failures in peripheral vision can be accounted for by a single mechanism. PMID- 26628011 TI - Amino Acid Export in Developing Arabidopsis Seeds Depends on UmamiT Facilitators. AB - Essential amino acids cannot be synthesized by humans and animals. They often are limiting in plant-derived foods and determine the nutritional value of a given diet. Seeds and fruits often represent the harvestable portion of plants. In order to improve the amino acid composition of these tissues, it is indispensable to understand how these substrates are transported within the plant. Amino acids result from nitrogen assimilation, which often occurs in leaves, the source tissue. They are transported via the vasculature, the xylem, and the phloem into the seeds, the so-called sink tissue, where they are stored or consumed. In seeds, several tissues are symplasmically isolated, i.e., not connected by plasmodesmata, channels in the cell walls that enable a cytoplasmic continuum in plants. Consequently, amino acids must be exported from cells into the apoplast and re-imported many times to support seed development. Several amino acid importers are known, but exporters remained elusive. Here, we characterize four members of the plant-specific UmamiT transporter family from Arabidopsis, related to the amino acid facilitator SIAR1 and the vacuolar auxin transporter WAT1. We show that the proteins transport amino acids along their (electro)chemical potential across the plasma membrane. In seeds, they are found in tissues from which amino acids are exported. Loss-of-function mutants accumulate high levels of free amino acids in fruits and produce smaller seeds. Our results strongly suggest a crucial role for the UmamiTs in amino acid export and possibly a means to improve yield quality. PMID- 26628012 TI - Treatment and Diagnosis of Panner's Disease. A Report of Three Cases. AB - Avascular necrosis of the humeral capitellum (Panner's disease), a relatively rare disorder in the juvenile. We diagnosed three patients using radiographs and magnetic resonance imaging, who were previously misdiagnosed with osteochondritis dissecans of the humeral capitellum. All patients were successfully treated by restriction of sports activities using the upper extremities. It is often difficult to distinguish Panner's disease from osteochondritis dissecans of the humeral capitellum. Panner's disease has been reported to occur in boys between 7 and 10 years old, which is younger than susceptible age of osteochondritis dissecans. In MRI, low intensity area in the ossification center of the humeral capitellum in T1-weighted image is useful findings for diagnosis. For the treatment, the conservative treatment has been recommended in the early stage of Panner's disease, while surgical intervention is required in some cases of osteochondritis dissecans. PMID- 26628013 TI - A Case of Bilateral Decidualized Endometriomas during Pregnancy: Radiologic pathologic Correlation. AB - Clinical differentiation between decidualized endometrioma and malignant transformation still poses difficulties as both are intracystic vascularized excrescences of an endometrial cyst and exhibit similar characteristics on color flow Doppler sonography. This is a characteristic sonographic finding associated with ovarian cancer, but MRI can provide further information about mural excrescences that can aid in their differential diagnosis; for example, the signal of decidualized endometriomas is isointense with the placenta within the uterus on all sequences and the apparent diffusion coefficient is higher than that of malignant mural nodules. Thus, MRI should be an aid in deciding whether to intervene during pregnancy. However, considering that it is not yet possible to clearly differentiate decidualized endometriomas from ovarian cancer, surgery or watchful observation may still be needed to exclude the possibility of malignancy. PMID- 26628014 TI - Stable Somatic Gene Expression in Mouse Lungs Following Electroporation-mediated Tol2 Transposon Delivery. AB - Gene delivery to the lung has rapidly progressed as an important method for studying various chronic lung diseases. Viral vectors, albeit highly efficient, are limited by the host immune response. Electroporation, a well-known non-viral method, can efficiently deliver genes to the lung, but is unable to induce stable gene expression. The Tol2 transposon is another non-viral method that can induce stable gene expression by reinserting its genes into the host genome. In this study, we combined electroporation and Tol2 transposons to obtain stable, high level gene expression in the mouse lung. Tol2 transposon plasmids (pT2A-EGFP; Tol2, pCAGGS-TP; transposase) were optimized in vitro, and the electroporation procedure (pCAG-EGFP) was optimized in mouse lungs. After optimization, a combination of electroporation plus the Tol2 transposon was used in a comparative analysis with electroporation plus pCAG-EGFP. GFP expression levels were quantified and visualized on days 4 and 7 post-electroporation. We successfully reproduced the Tol2 transposon system in vitro and the electroporation procedure in vivo. We observed sustainable GFP expression using electroporation plus the Tol2 transposon on days 4 and 7, while electroporation plus pCAG-EGFP resulted in decreased GFP expression on day 7. We were able to induce high-level, stable gene expression in mouse lungs using a combination of electroporation and the Tol2 transposon. This represents a safer method for lung gene delivery that can be used as an alternative to viral vectors. PMID- 26628015 TI - Characterization of Tamoxifen as an Antifungal Agent Using the Yeast Schizosaccharomyces Pombe Model Organism. AB - Tamoxifen, a selective estrogen receptor modulator used for managing breast cancer, is known to have antifungal activity. However, its molecular mechanism remains unknown. Using the fission yeast Schizosaccharomyces pombe as a model organism, we have explored the mechanism involved in antifungal action of tamoxifen. Since tamoxifen was shown to inhibit the binding of calmodulin to calcineurin in fungi, we first examined involvement of these molecules and found that overexpression of a catalytic subunit of calcineurin and its constitutively active mutant as well as calmodulin increases tamoxifen sensitivity. Since terbinafine and azoles inhibit enzymes for ergosterol biosynthesis, Erg1 and Erg11, for their antifungal actions, we also examined involvement of these molecules. Overexpression of Erg1 and Erg11 reduced the sensitivity to terbinafine and azoles, respectively, but increased tamoxifen sensitivity, suggesting that ergosterol biosynthesis is differently related to the action of tamoxifen and those of terbinafine and azoles. To elucidate molecules involved in tamoxifen action, we performed a genome-wide screen for altered sensitivity to tamoxifen using a fission yeast gene deletion library, and identified various hypersensitive and resistant mutants to this drug. Notably, these mutants are rarely overlapped with those identified in similar genetic screens with currently used antifungals, suggesting a novel mode of antifungal action. Furthermore, tamoxifen augmented antifungal actions of terbinafine and azoles, suggesting synergetic actions between these drugs. Therefore, our findings suggest that calmodulin-calcineurin pathway and ergosterol biosynthesis are related to antifungal action of tamoxifen, and propose novel targets for antifungal development as well as combined therapy with tamoxifen for fungal diseases. PMID- 26628016 TI - Nitrogen topdressing and application ways of fluazifop-p-butyl + fomesafen in weed control and agronomic performance of common bean. AB - The objective of this study was to investigate the effect of interaction between nitrogen topdressing and different application ways (active ingredients) a.i. fluazifop-p-butyl + fomesafen in weed control and agronomic performance of common bean. The experiment was conducted during winter 2003 in Selviria/MS. The experimental design used was a randomized block design with four replications in a factorial scheme 2 x 7. The first factor was composed by the absence or presence of nitrogen topdressing, while the second factor consisted of different application ways of fluazifop-p-butyl + fomesafen. The following variables were measured: leaf N content, dry matter of plants, yield components (number of pods plant(-1), number of grains plant(-1), the average number of grains pod(-1) and mass of 100 grains), grain yield, phytotoxicity and weed control percentage. The nitrogen topdressing with 75 kg ha(-1) provided higher dry matter of plants, higher weed control and higher common bean yield of irrigated winter. In the absence of nitrogen topdressing in the application of urea before or together to fluazifop-p-butyl + fomesafen increased their effectiveness in controlling weeds without interference in the agronomic performance of common bean. PMID- 26628017 TI - Floristic and structural patterns in South Brazilian coastal grasslands. AB - The natural vegetation of Southern Brazil's coastal region includes grasslands formations that are poorly considered in conservation policy, due to the lack of knowledge about these systems. This study reports results from a regional-scale survey of coastal grasslands vegetation along a 536 km gradient on southern Brazil. We sampled 16 sites along the coastal plain with 15 plots (1 m2) per site. All sites were grazed by cattle. We estimated plant species cover, vegetation height, percentage of bare soil, litter and manure, and classified species according to their growth forms. We found 221 species, 14 of them exotic and two threatened. The prostate grasses: Axonopus aff.affinis, Paspalum notatum and P. pumilumwere among the most important species. Prostrate graminoids species represented the most important vegetation cover, followed by cespitose grasses. Vegetation height, bare soil, litter and manure were similar among all areas, highlighting the homogeneity of sampling sites due to similar management. In comparison to other grasslands formations in Southern Brazil, the coastal grasslands presented rather low species richness. The presence of high values for bare soil at all sampling sites indicates the need to discuss management practices in the region, especially with regard to the intensity of livestock grazing. PMID- 26628018 TI - Phosphorus availability and microbial immobilization in a Nitisol with the application of mineral and organo-mineral fertilizers. AB - The aim of this study was to evaluate P availability, P and C contained in the microbial biomass, and enzymatic activity (acid phosphatases and beta glucosidases) in a Nitisol with the application of mineral and organo-mineral fertilizers. The experiment was performed in a protected environment with control over air temperature and soil moisture. The experimental design was organized in a "5 x 4" factorial arrangement with five sources of P and four times of soil incubation. The sources were: control (without P), triple superphosphate, diammonium phosphate, natural Arad reactive rock phosphate, and organo-mineral fertilizer. The experimental units consisted of PVC columns filled with agricultural soil. The columns were incubated and broken down for analysis at 1, 20, 40, and 60 days after application of the fertilizers. In each column, samples were taken at the layers of 0-2.5, 2.5-5.0, and 5.0-15.0 cm below the zone of the fertilizers. The application of soluble phosphates and organo-mineral fertilizer temporarily increased P availability in the zone near the fertilizers (0-2.5 cm), with maximum availability occurring at approximately 32 days. Microbial immobilization showed behavior similar to P availability, and the greatest immobilizations occurred at approximately 30 days. The organo-mineral fertilizer was not different from soluble phosphates. PMID- 26628019 TI - Investigation of local anesthetic and antimycobacterial activity of Ottonia martiana Miq. (Piperaceae). AB - Ottonia martiana is a plant popularly known in Brazil by the use for toothache. Ethanolic extract (EE), hexane fraction (HF), dichloromethane fraction (DF) and piperovatine obtained from O. martiana were assayed in vitro and in vivo. The acute toxicity of EE was determined, and LD50 values of 164.5 and 65.0 mg/kg by the oral and intraperitoneal routes, respectively, indicated a high toxicity for EE in vivo, explaining its popular use by topical administration only. A local anesthetic-like effect of EE and its fractions was observed in experimental models using pain induction, and such effect involved an analgesic action. The antimycobacterial activity of EE, HF, DF and piperovatine was evaluated against Mycobacterium tuberculosis H37Rv ATCC 27924. EE, HF, DF, and piperovatine showed a potential antimycobacterial effect with MICs of 16.0, 62.0, 62.0 and 8.0 MUg/mL, respectively. Piperovatine was more effective than the EE or the other fractions. The selectivity index (SI=IC50/MIC) values calculated for EE, HF, DF and piperovatine based on the MICs and the cytotoxicity against J774 macrophages (IC50 by MTT assay) revealed values of 6.43, 2.34, 1.5 and 9.66, respectively. PMID- 26628020 TI - Occurrence and evolutionary inferences about Kranz anatomy in Cyperaceae (Poales). AB - Cyperaceae is an angiosperm family with the greatest diversity of species with Kranz anatomy. Four different types of Kranz anatomy (chlorocyperoid, eleocharoid, fimbristyloid and rhynchosporoid) have been described for this angiosperm family, and the occurrence and structural characteristics of these types are important to trace evolutionary hypotheses. The purpose of this study was to examine the available data on Cyperaceae Kranz anatomy, emphasizing taxonomy, geographic distribution, habitat and anatomy, to infer the potential origin of the Kranz anatomy in this family. The results showed that the four types of Kranz anatomy (associated with C4 photosynthesis) in Cyperaceae emerged numerous times in unrelated phylogenetic groups. However, the convergence of these anatomical types, except rhynchosporoid, was observed in certain groups. Thus, the diverse origin of these species might result from different environmental pressures that promote photorespiration. Greater variation in occurrence of Kranz anatomy and anatomical types was observed in Eleocharis, whose emergence of the C4 pathway was recent compared with other genera in the family, and the species of this genus are located in aquatic environments. PMID- 26628021 TI - Characterization of alpha-actin isoforms in white and red skeletal muscle types of Leporinus macrocephalus (Characiformes, Anostomidae). AB - Two alpha-actin genes of the fish Leporinus macrocephalus, referring to white and red muscle tissues, were isolated. Actin isoforms, that mainly differed by a Ser/Ala155 substitution, can have a functional significance related to actin-ATP interaction. An Ala155 residue, as observed in the alpha-skeletal actin from red muscle, results in a decrease in actin's affinity for ATP, which may also be associated to the slow contractile performance of this tissue. Furthermore, a Phe/Ile262 substitution at the red muscle actin leads to a hydrophobicity variation at the D-plug of the protein, which could alter its stability. Data on qRT-PCR evidenced a significant higher actin mRNA level in white muscle when compared to red muscle (T=105 Mann Whitney; p<0.001). This finding could be related to the energetic demands of the white muscle tissue, with fast contraction fibers and glycolytic metabolism for energy supply. Available data on muscle actins lead to the proposal that white and red alpha-skeletal actins are genetically and functionally distinguishable in fish species, a feature that is not found in other vertebrate groups. PMID- 26628022 TI - Physiological and biochemical changes during the loss of desiccation tolerance in germinating Adenanthera pavonina L. seeds. AB - We investigated the loss of desiccation tolerance (DT) in Adenanthera pavonina seeds during germination. Seeds were subjected to imbibition for 0, 24, 36, 48, 60 and 81 h, then dried to their initial moisture content (13%), rehydrated and evaluated for survival (resumption of growth and development of normal seedlings) and membrane system integrity (electrolyte leakage). Embryonic axes of seeds subjected only to imbibition during the same early time periods were used to investigate the electrophoretic patterns of heat-stable proteins and the relative nuclear DNA content. In A. pavonina seeds, DT remained unchanged until 36 h of imbibition (resulting in germination and 82% normal seedlings), after which it was progressively lost, and seeds with a protruded radicle length of 1 mm did not withstand dehydration. The loss of desiccation tolerance could not be related to either membrane damage caused by drying or the resumption of the cell cycle during germination. However, the decrease in heat-stable protein contents observed throughout germination may be related to the loss of DT in A. pavonina seeds. PMID- 26628023 TI - Food consumption as an indicator of the conservation of natural resources in riverine communities of the Brazilian Amazon. AB - The present study analyzed and compared the daily consumption of foods of animal origin in eleven communities of the Lower Amazon, Trombetas and Purus Rivers, representing three different management systems and levels of conservation in the Brazilian Amazon. All food items of animal origin were weighed by at least 10% of the families in the study communities during a week in each period of the flood cycle between 2006 and 2008. Fish was the most important food, and was consumed during six days of the week, with an average rate of 169 kg.person(-1).year(-1). Game was second in importance, with 37 kg.person(-1).year-(1). This yearly rate of fish consumption is one of the highest in the world and is almost double the minimum recommended by the World Health Organization. The dietary patterns reflect both the isolation of the communities from large urban centers and the better preservation of the local environments due to the existence of protected areas. Environmental degradation may thus have effects on the health and food security of local populations. The study emphasizes the need for the implementation of public policies and participative management initiatives. PMID- 26628024 TI - Plant-hummingbird interactions and temporal nectar availability in a restinga from Brazil. AB - Hummingbirds are the most important and specialized group of pollinating birds in the Neotropics and their interactions with plants are key components to many communities. In the present study we identified the assemblage of plants visited by hummingbirds and investigated the temporal availability of floral resources in an area of restinga, sandy plain coastal vegetation associated with the Atlantic forest, in Southeastern Brazil. We recorded flower and nectar features, flowering phenology and interactions between plants and hummingbirds and estimated the amount of calories produced per hectare from June 2005 to August 2006. Ten plant species were visited by two hummingbirds, Amazilia fimbriata and Eupetomena macroura. Resource availability was highly variable among plant species and over time. Nectar volume and concentration per flower were similar to other Neotropical hummingbird-visited plant assemblages. The estimated nectar resource availability between months varied from 0.85 to 5.97 Kcal per hectare/day, demanding an area between one and 6.8 ha to support a single hummingbird. Our study reports an unusual tropical setting where almost all interactions between hummingbirds and plants were performed by a single hummingbird species, A. fimbriata. Hence, the variable nectar availability is probably influencing hummingbird movements, its foraging area, and consequently plant pollination. PMID- 26628025 TI - Spatial Distribution of Eggs of Alabama argillacea Hubner and Heliothis virescens Fabricius (Lepidoptera: Noctuidae) on Bt and non-Bt Cotton. AB - Among the options to control Alabama argillacea (Hubner, 1818) and Heliothis virescens (Fabricius, 1781) on cotton, insecticide spraying and biological control have been extensively used. The GM'Bt' cotton has been introduced as an extremely viable alternative, but it is yet not known how transgenic plants affect populations of organisms that are interrelated in an agroecosystem. For this reason, it is important to know how the spatial arrangement of pests and beneficial insect are affected, which may call for changes in the methods used for sampling these species. This study was conducted with the goal to investigate the pattern of spatial distribution of eggs of A. argillacea and H. virescens in DeltaOpalTM (non-Bt) and DP90BTM Bt cotton cultivars. Data were collected during the agricultural year 2006/2007 in two areas of 5,000 m2, located in in the district of Nova America, Caarapo municipality. In each sampling area, comprising 100 plots of 50 m2, 15 evaluations were performed on two plants per plot. The sampling consisted in counting the eggs. The aggregation index (variance/mean ratio, Morisita index and exponent k of the negative binomial distribution) and chi-square fit of the observed and expected values to the theoretical frequency distribution (Poisson, Binomial and Negative Binomial Positive), showed that in both cultivars, the eggs of these species are distributed according to the aggregate distribution model, fitting the pattern of negative binomial distribution. PMID- 26628026 TI - Geochemical behaviour of trace elements during fractional crystallization and crustal assimilation of the felsic alkaline magmas of the state of Rio de Janeiro, Brazil. AB - This paper presents geochemical behaviour of trace elements of the felsic alkaline rocks of the state of Rio de Janeiro, Brazil, with special attention of fractional crystallization and continental crust assimilation. Fractionation of leucite and K-feldspar increases Rb/K and decreases K2O/(K2O+Na2O). Primitive nepheline syenite magmas have low Zr/TiO2, Sr, and Ba. On the Nb/Y vs. Zr/TiO2 diagram, these rocks are projected on the field of alkaline basalt, basanite, and nephelinite, instead of phonolite. Well-fractionated peralkaline nepheline syenite has high Zr/TiO2 but there are no zircon. The diagrams of silica saturation index (SSI) distinguish the trends originated form fractional crystallization and crustal assimilation. In the field of SSI<-200, Zr/TiO2 and Ba/Sr have negative correlations to SSI in consequence of fractional crystallization. In the field of SSI>-200, they show positive correlations due to continental crust assimilation. Total REEs (Rare Earth Elements) is nearly 10 times that of granitic rocks, but LaN/SmN and LaN/YbN are similar. REE trend is linear and Eu anomaly is irrelevant. The pegmatitic liquid generated by country rock partial melting is SiO2-oversaturated and peraluminous with high Ba, Sr, Ba/Sr, Zr/TiO2, and SSI, with high content of fluids. This model justifies the peraluminous and SiO2-oversaturated composition of the rocks with relevant effects of continental crust assimilation. PMID- 26628027 TI - Environmental factors related to the production of a complex set of spicules in a tropical freshwater sponge. AB - Adverse natural conditions will, generally, induce gemmulation in freshwater sponges. Because of this environmental dependence, gemmoscleres are given exceptional value in taxonomic, ecological and paleoenvironmental studies. Other spicules categories such as microscleres and beta megascleres have received little attention with regard to their occurrence and function during the sponge biological cycle. Metania spinata, a South American species common to bog waters in the Cerrado biome, produces alpha and beta megascleres, microscleres and gemmoscleres. To detect the environmental factors triggering the production of all these kinds of spicules, the species annual seasonal cycle was studied. Artificial substrates were devised, supplied with gemmules and placed in Lagoa Verde pond which contained a natural population of M. spinata. Field monitoring was conducted for eight months in order to observe the growth of sponges and spicules formation. Samples of water were taken monthly for physical and chemical parameters determination. The appearance of the alpha megascleres was sequentially followed by that of microscleres, gemmoscleres and beta megascleres. The first ones built the new sponge skeleton, the last three were involved in keeping inner moisture in the sponge body or its gemmules. The water level, temperature and the silicon (Si) concentration in the pond were the most important factors related to this sequential production of spicules, confirming environmental reconstructions based on the presence or absence of alpha megascleres and gemmoscleres in past sediments. PMID- 26628028 TI - Gelatin in replacement of bovine heart in feed training of Lophiosilurus alexandri in different water salinities. AB - The aim of this study was to evaluate commercial gelatin in the total replacement of bovine heart in feed training of "pacama" Lophiosilurus alexandri in different water salinities. A completely randomized experimental design, in a 2 * 3 factorial arrangement, was performed using two types of moist ingredients (bovine heart and gelatin) and three water salinities (0.0; 2.0 and 4.0 g of salt L(-1)) with three replications. Juveniles (2.39 +/- 0.08 cm standard length and 0.20 +/- 0.03 g of weight) were conditioned to accept commercial diets by the technique of the gradual transition of ingredients. At the end of 36 days no differences were observed to weight gain, length gain and specific growth rate. The feed training efficiency was better (P < 0.05) with the gelatin use, 100.0%. There was a negative effect of salinity on the survival rate and management efficiency in the concentration of 4 g of salt L(-1), with values of 58.6 +/- 12.0 % and 58.0 +/- 12.0 %, respectively. Lophiosilurus alexandri juveniles could be feed-trained to accept commercial diets with gelatin in the total replacement of bovine heart in freshwater or salinity of 2 g of salt L(-1). PMID- 26628029 TI - Feeding and reproductive patterns of Astyanax intermedius in a headwater stream of Atlantic Rainforest. AB - In this paper, we determined diet composition, reproductive periodicity and fecundity of Astyanax intermedius in a headwater stream of a State Park of an Atlantic rainforest. We also evaluated the influence of rainfall, water temperature and fish size on niche width and niche overlap. Sampling was conducted monthly throughout one year in the Ribeirao Grande stream, southeastern Brazil. Diet consisted of 31 food items with equal contribution of allochthonous and autochthonous items. Females were larger than males, and the mean sizes at first maturation were 4.44 cm and 3.92 cm, respectively. Based on 212 pairs of mature ovaries, the number of oocytes per female ranged from 538 to 6,727 (mean = 2,688.7). Niche width and niche overlap were not related to rainfall nor water temperature and only niche width increased with fish size, suggesting that as fish grow, more items are included in diet. Our results suggested that A. intermedius fit as a typical opportunistic strategist which may explain the prevalence of this species in several isolated headwater basins of vegetated Atlantic forested streams where food resources are abundant and distributed throughout the year. PMID- 26628030 TI - Population structure and allometry of Podocnemis unifilis (Testudines, Podocnemididae) in a protected area upstream Belo Monte dam in Xingu River, Brazil. AB - Amazon river turtles are increasingly threatened by habitat loss and alteration due to the Brazilian energy policy based on construction of hydroelectric dams, meanwhile, populational studies remain scarce. We described the population structure, and established body allometric relationships of Podocnemis unifilis in the Terra do Meio Ecological Station in the Iriri River, tributary of the Xingu River upstream the Belo Monte dam under construction Turtles were captured by hand net and diving in 2012 and 2013 dry seasons, and 2013 rainy season. A total of 728 males, 296 females and four juveniles were captured. Adult sex ratio was male-biased by 9.15 ?:1 ?. Females were significantly larger than males. Mean straight carapace length was 268.9 +/- 46.7 mm (165 - 403) for females; and 232.7 +/- 24.8 mm (167 - 303) for males. The sexes were morphologically distinct in function of a proportionally larger plastron, and higher carapace, on females. Allometric relationships between straight carapace length and other morphometric traits were strong for males (R2 range = 0.87 - 0.96 and females (R2 range =0.79 0.98. Exploitation of P. unifilis in biomass extirpated from the Middle Xingu River may be estimated from body parts found post-consumption by the presented regressions. PMID- 26628031 TI - Ontogenic development of kidney, thymus and spleen and phenotypic expression of CD3 and CD4 receptors on the lymphocytes of cobia (Rachycentroncanadum). AB - In the present study was evaluated the ontogenic of immunocompetent organs of cobia up to 53 days after hatching (dah) through histology and immunohistochemistry techniques. The kidney was the first lymphohematopoietic organ to appear, at 1 dah, followed by the spleen at 5 dah and the thymus at 7 dah. The first CD3 receptors on the lymphocytes were observed in 27% of the thymic tissue at 7 dah and in 99% at 53 dah. The phenotypic expression of CD3 receptors was registered in 10% of the kidney at 8 dah and in 32% at 53 dah. CD4 receptors were observed in 5% and 63% of the thymic area at 7 and 53 dah, respectively. In the kidney, T4 lymphocytes were first observed at 13 dah in 9% of the organ and in 28% at 53 dah, defining the functional development of the specific system associated with immunological memory capacity. PMID- 26628032 TI - Lifespan and population dynamics of the endemic South American shrimp Artemesia longinaris (Crustacea: Penaeidae) in southeastern Brazil. AB - The present study investigated the growth, longevity and reproductive dynamics of Artemesia longinaris in the southeastern coast of Brazil over a two-year period. Monthly collections were conducted in Ubatuba and Caraguatatuba using a shrimp fishing boat equipped with "double-rig" nets. Each region was divided into 7 sampling stations up to 35 m deep. Size frequency distributions, growth, longevity, sex ratio, and abundance of individuals in each demographic class, were compared. The relationship between abiotic factors and abundance of each demographic class was assessed using a Canonical Correlation Analysis. A total of 64,641 individuals were collected (6,928 measured) with an estimated longevity of 1.30 (Ubatuba) and 1.14 (Caraguatatuba) years for females and 1.03 years for males in both regions. There was a statistically significant bias in sex ratio toward females (Chi-squared test, p < 0.05) in both regions. The Canonical Correlation Analysis resulted in a canonical correlation coefficient of 0.31 (p = 0.00002). Salinity and temperature showed high correlation mainly with the presence of reproductive females. In general, this demographic class was most common in conditions of low temperature and high salinity. These findings, as well as other studies carried out in colder regions with the same species, are consistent with classical latitudinal paradigm. PMID- 26628033 TI - Floristic units and their predictors unveiled in part of the Atlantic Forest hotspot: implications for conservation planning. AB - We submitted tree species occurrence and geoclimatic data from 59 sites in a river basin in the Atlantic Forest of southeastern Brazil to ordination, ANOVA, and cluster analyses with the goals of investigating the causes of phytogeographic patterns and determining whether the six recognized subregions represent distinct floristic units. We found that both climate and space were significantly (p <= 0.05) important in the explanation of phytogeographic patterns. Floristic variations follow thermal gradients linked to elevation in both coastal and inland subregions. A gradient of precipitation seasonality was found to be related to floristic variation up to 100 km inland from the ocean. The temperature of the warmest quarter and the precipitation during the coldest quarter were the main predictors. The subregions Sandy Coastal Plain, Coastal Lowland, Coastal Highland, and Central Depression were recognized as distinct floristic units. Significant differences were not found between the Inland Highland and the Espinhaco Range, indicating that these subregions should compose a single floristic unit encompassing all interior highlands. Because of their ecological peculiarities, the ferric outcrops within the Espinhaco Range may constitute a special unit. The floristic units proposed here will provide important information for wiser conservation planning in the Atlantic Forest hotspot. PMID- 26628035 TI - What Expands in an Expanding Universe? AB - In the present investigation, the possible effects of the expansion of the Universe on systems bonded either by gravitational or electromagnetic forces, are reconsidered. It will be shown that the acceleration (positive or negative) of the expanding background, is the determinant factor affecting planetary orbits and atomic sizes. In the presently accepted cosmology (LambdaCDM) all bonded systems are expanding at a decreasing rate that tends to be zero as the universe enters in a de Sitter phase. It is worth mentioning that the estimated expansion rates are rather small and they can be neglected for all practical purposes. PMID- 26628034 TI - India ink induces apoptosis in the yellow clam Mesodesma mactroides (Deshayes, 1854). Optical and ultrastructural study. AB - This paper reports on the acute inflammatory and cellular process in the yellow clam, Mesodesma mactroides, induced by injection of India ink into the muscular foot. Histological observations with optical and electronic microscopy were made at 24 and 48 h after injection. The induced cellular inflammatory response consisted of a general hemocyte infiltration without necrosis and apoptotic activity. Migration of ink-laden phagocytes across the intestinal epithelium was recorded. It appeared that the yellow clam "excreted" ink particles through the gill and kidney. The positive staining for apoptosis was observed in the digestive gland. Electronic microscopy revealed ultrastructural changes of endoplasmic reticulum stress and apoptotic bodies in the digestive gland. The mechanism by which the India ink particles induce apoptosis remains unknown, but might possibly be associated with the endoplasmic reticulum stress. This work has highlighted features that require further discussion in the restricted field the inflammatory responses of mollusks. PMID- 26628036 TI - Growth curve by Gompertz nonlinear regression model in female and males in tambaqui (Colossoma macropomum). AB - Was evaluated the pattern of growth among females and males of tambaqui by Gompertz nonlinear regression model. Five traits of economic importance were measured on 145 animals during the three years, totaling 981 morphometric data analyzed. Different curves were adjusted between males and females for body weight, height and head length and only one curve was adjusted to the width and body length. The asymptotic weight (a) and relative growth rate to maturity (k) were different between sexes in animals with +/- 5 kg; slaughter weight practiced by a specific niche market, very profitable. However, there was no difference between males and females up to +/- 2 kg; slaughter weight established to supply the bigger consumer market. Females showed weight greater than males (+/- 280 g), which are more suitable for fish farming purposes defined for the niche market to larger animals. In general, males had lower maximum growth rate (8.66 g / day) than females (9.34 g / day), however, reached faster than females, 476 and 486 days growth rate, respectively. The height and length body are the traits that contributed most to the weight at 516 days (P <0.001). PMID- 26628037 TI - Local anesthetic thoracoscopy for the diagnosis of metastatic pleural melanoma originated from oral malignant melanoma: case report and comments. AB - BACKGROUND: Oral malignant melanoma (OMM) is an aggressive tumor with very low survival rate and easy to metastasize. Pleural metastatic melanoma via primary OMM is rare. CASE PRESENTATION: In this report, we presented a case of metastatic malignant melanoma of the pleura originated from OMM. A 54-year-old man without primary skin lesion was diagnosed multiple nodular shadows, pleural invasion, and pleural effusion by chest computed tomography (CT). One cyst-form tumor on the tongue base was observed by bronchoscopy, which was diagnosed as OMM by pathological examination and then was resected. After getting the tumor tissues from the pleura by pleural biopsy surgery, the diagnosis of pathological examination was pleural metastatic melanoma. Furthermore, tumor cells displayed a positive immunoreaction for melanocytic markers S100 and HMB-45 combining with positive vimentin and cytokeratin AE1/AE3. The patient was therefore diagnosed with metastatic melanoma of the left pleura and the primary melanoma was OMM. CONCLUSIONS: According to this case, we could draw the conclusion that pleural metastasis from OMM was very rare and thoracoscopy preceded under local anesthesia is an important method for its accurate diagnosis. PMID- 26628038 TI - The in-vitro effects of cAMP and cGMP modulators on inter-cellular dye transfer and gene expression levels in rat cumulus cell--oocyte complexes. AB - Supplementation of in-vitro maturation medium with reagents that inhibit meiotic resumption whilst supporting normal function of cumulus cell-oocyte complexes (COC) is challenging. This study compared the in-vitro effects of synthetic and physiologically-relevant reagents on meiotic resumption, gap junction activity and gene expression of rat COC. Higher doses of forskolin reduced gap junction activity. Whilst addition of phosphodiesterase inhibitors initially promoted gap junction activity, this decreased with time in-vitro. Moreover despite oocytes remaining in meiotic arrest, there was a concomitant decline in expression of genes critical for oocyte maturation, and evidence of a reduction in overall transcription rate. Similarly, supplementing media with C-type natriuretic peptide and/or oestradiol delayed meiotic resumption and only initially maintained gap junction activity. In contrast, several key genes were stimulated and overall transcription rates remained constant with time in-vitro. In summary, supplementation of media with physiologically-relevant reagents may better enable normal functions of the COC. PMID- 26628039 TI - GPER mediates the effects of 17beta-estradiol in cardiac mitochondrial biogenesis and function. AB - Considering the sexual dimorphism described in cardiac mitochondrial function and oxidative stress, we aimed to investigate the role of 17beta-estradiol (E2) in these sex differences and the contribution of E2 receptors to these effects. As a model of chronic deprivation of ovarian hormones, we used ovariectomized (OVX) rats, half of which were treated with E2. Ovariectomy decreased markers of cardiac mitochondrial biogenesis and function and also increased oxidative stress, whereas E2 counteracted these effects. In H9c2 cardiomyocytes we observed that G-protein coupled estrogen receptor (GPER) agonist mimicked the effects of E2 in enhancing mitochondrial function and biogenesis, whereas GPER inhibitor neutralized them. These data suggest that E2 enhances mitochondrial function and decreases oxidative stress in cardiac muscle, thus it could be responsible for the sexual dimorphism observed in mitochondrial biogenesis and function in this tissue. These effects seem to be mediated through GPER stimulation. PMID- 26628040 TI - Differential thyroid hormone sensitivity of fast cycling progenitors in the neurogenic niches of tadpoles and juvenile frogs. AB - Adult neurogenesis occurs in neural stem cell (NSC) niches where slow cycling stem cells give rise to faster cycling progenitors. In the adult mouse NSC niche thyroid hormone, T3, and its receptor TRalpha act as a neurogenic switch promoting progenitor cell cycle completion and neuronal differentiation. Little is known about whether and how T3 controls proliferation of differentially cycling cells during xenopus neurogenesis. To address this question, we first used Sox3 as a marker of stem cell and progenitor populations and then applied pulse-chase EdU/IdU incorporation experiments to identify Sox3-expressing slow cycling (NSC) and fast cycling progenitor cells. We focused on the lateral ventricle of Xenopus laevis and two distinct stages of development: late embryonic development (pre-metamorphic) and juvenile frogs (post-metamorphic). These stages were selected for their relatively stable thyroid hormone availability, either side of the major dynamic phase represented by metamorphosis. TRalpha expression was found in both pre and post-metamorphic neurogenic regions. However, exogenous T3 treatment only increased proliferation of the fast cycling Sox3+ cell population in post-metamorphic juveniles, having no detectable effect on proliferation in pre-metamorphic tadpoles. We hypothesised that the resistance of proliferative cells to exogenous T3 in pre metamorphic tadpoles could be related to T3 inactivation by the inactivating Deiodinase 3 enzyme. Expression of dio3 was widespread in the tadpole neurogenic niche, but not in the juvenile neurogenic niche. Use of a T3-reporter transgenic line showed that in juveniles, T3 had a direct transcriptional effect on rapid cycling progenitors. Thus, the fast cycling progenitor cells in the neurogenic niche of tadpoles and juvenile frogs respond differentially to T3 as a function of developmental stage. PMID- 26628042 TI - [Inpatient psychotherapy]. AB - In German-speaking countries inpatient psychotherapy plays a major role in the mental healthcare system. Due to its characteristic features, i. e. multiprofessionalism, multimodality and method integration, the inpatient approach represents a unique and independent type of psychotherapy. In order to be helpful, the manifold verbal and non-verbal methods need to be embedded into an overall treatment plan. Additionally, the therapeutic milieu of the hospital represents an important effective factor and its organization requires a more active construction. The indications for inpatient psychotherapy are not only based on the mental disorder but also on illness, setting and healthcare system related criteria. In integrative concepts, the multiprofessional team is a key component with many functions. The effectiveness of psychotherapeutic hospital treatment has been proven by meta-analysis studies; however, 20-30% of patients do not benefit from inpatient psychotherapy and almost 13% drop-out prematurely. PMID- 26628041 TI - Peripheral Serotonin: a New Player in Systemic Energy Homeostasis. AB - Whole body energy balance is achieved through the coordinated regulation of energy intake and energy expenditure in various tissues including liver, muscle and adipose tissues. A positive energy imbalance by excessive energy intake or insufficient energy expenditure results in obesity and related metabolic diseases. Although there have been many obesity treatment trials aimed at the reduction of energy intake, these strategies have achieved only limited success because of their associated adverse effects. An ancient neurotransmitter, serotonin is among those traditional pharmacological targets for anti-obesity treatment because it exhibits strong anorectic effect in the brain. However, recent studies suggest the new functions of peripheral serotonin in energy homeostasis ranging from the endocrine regulation by gut-derived serotonin to the autocrine/paracrine regulation by adipocyte-derived serotonin. Here, we discuss the role of serotonin in the regulation of energy homeostasis and introduce peripheral serotonin as a possible target for anti-obesity treatment. PMID- 26628043 TI - [Gender-inclusive care of victims of violence : The model project "Gender Gewaltkonzept" at the University Hospital Aachen]. AB - Violence is a topic of great social relevance, frequently causing tremendous health consequences for those affected and high consequential costs for health care and the national economy. The established consulting and assistance services are usually restricted to offers for ambulant supply, mainly from private agencies or societies. As a result, there is no identification and care for patients who have experienced violence and who are treated in hospital. Another deficiency is the identification and care of male victims of violence. Despite wide-ranging offers of assistance, only very few gender-specific consulting and support services have been available to date.Therefore, the model project "Gender Gewaltkonzept" was initiated at Aachen University Hospital to assess the prevalence of violence and the potential consequences of the violence experienced on the patients' health. In addition, we investigated whether males and females are in need of different supply requirements.Based on the results of the project "Gender Gewaltkonzept" so far, and on prevalence estimates proving that there is a high rate of violent experiences in both males and females, this overview is aimed at presenting the aid and protection concepts available for victims of violence, in addition to the existing deficiencies of the care system. We present approaches to resolving these deficiencies to be able to establish all encompassing gender-appropriate support for victims of violence. PMID- 26628044 TI - [Non-withdrawal-related delirium : Evidence on prevention and therapy]. AB - Delirium is a severe and common yet under-diagnosed disorder in the clinical routine. Multiple factors may contribute to the development of delirium, which is associated with increased mortality and high healthcare costs. Treatment of delirium is often provided with delay and limited to pharmacological interventions. This article summarizes the key symptoms for delirium as well as risk factors and highlights the pharmacological and non-pharmacological options for treatment and prevention. PMID- 26628045 TI - [Tricyclic antidepressants for initial treatment of depressive episodes? Pro]. PMID- 26628046 TI - [Tricyclic antidepressants for initial treatment of depressive episodes? Con]. PMID- 26628047 TI - Broadband chirality-coded meta-aperture for photon-spin resolving. AB - The behaviour of light transmitted through an individual subwavelength aperture becomes counterintuitive in the presence of surrounding 'decoration', a phenomenon known as the extraordinary optical transmission. Despite being polarization-sensitive, such an individual nano-aperture, however, often cannot differentiate between the two distinct spin-states of photons because of the loss of photon information on light-aperture interaction. This creates a 'blind-spot' for the aperture with respect to the helicity of chiral light. Here we report the development of a subwavelength aperture embedded with metasurfaces dubbed a 'meta aperture', which breaks this spin degeneracy. By exploiting the phase-shaping capabilities of metasurfaces, we are able to create specific meta-apertures in which the pair of circularly polarized light spin-states produces opposite transmission spectra over a broad spectral range. The concept incorporating metasurfaces with nano-apertures provides a venue for exploring new physics on spin-aperture interaction and potentially has a broad range of applications in spin-optoelectronics and chiral sensing. PMID- 26628048 TI - High Seeding Density Induces Local Hypoxia and Triggers a Proinflammatory Response in Isolated Human Islets. AB - Hypoxia is the main threat to morphological and functional integrity of isolated pancreatic islets. Lack of oxygen seems to be of particular importance for functionality of encapsulated islets. The present study was initiated as an experimental model for the environment experienced by human islets in a confined space present during culture, shipment, and in an implanted macrodevice. Quadruplicate aliquots of isolated human islets (n = 12) were cultured for 24 h at 37 degrees C under normoxic conditions using 24-well plates equipped with 8-um pore size filter inserts and filled with islet aliquots adjusted to obtain a seeding density of 75, 150, 300, or 600 IEQ/cm(2). After culture viability, glucose-stimulated insulin release, DNA content as well as Bax and Bcl-2 gene expression were measured. Culture supernatants were collected to determine production of VEGF and MCP-1. Viability correlated inversely with IEQ seeding density (r = -0.71, p < 0.001), while the correlation of VEGF and MCP-1 secretion with seeding density was positive (r = 0.78, p < 0.001; r = 0.54, p < 0.001). Decreased viability corresponded with a significant increase in the Bax/Bcl-2 mRNA ratio at 300 and 600 IEQ/cm(2) and with a sigificantly reduced glucose stimulated insulin secretion and insulin content compared to 75 or 150 IEQ/cm(2) (p < 0.01). The present study demonstrates that the seeding density is inversely correlated with islet viability and in vitro function. This is associated with a significant increase in VEGF and MCP-1 release suggesting a hypoxic and proinflammatory islet microenvironment. PMID- 26628050 TI - Management of wastes from hospitals: A case study in Pakistan. AB - Proper management of hospital waste is a critical concern in many countries of the world. Pakistan is the sixth most populous country in the world, with one of the highest urbanisation and population growth rates in South Asia. Data and analyses regarding hospital waste management practices in Pakistan are scarce in scientific literature. This study was meant to determine waste management practices at selected hospitals in a major city in Pakistan, Gujranwala. A total of 12 different hospitals were selected for the survey, which involved quantification of waste generation rates and investigation of waste management practices. The results were analysed using linear regression. The weighted average total, general and infectious hospital waste generation rates were found to be 0.667, 0.497 and 0.17 kg bed-day(-1), respectively. Of the total, 73.85% consisted of general, 25.8% consisted of hazardous infectious and 0.87% consisted of sharps waste. The general waste consisted of 15.76% paper, 13.41% plastic, 21.77% textiles, 6.47% glass, 1.99% rubber, 0.44% metal and 40.17% others. Linear regression showed that waste generation increased with occupancy and decreased with number of beds. Small, private and specialised hospitals had relatively greater waste generation rates. Poor waste segregation, storage and transportation practices were observed at all surveyed hospitals. PMID- 26628049 TI - Incorporating prognosis in the care of older adults with multimorbidity: description and evaluation of a novel curriculum. AB - BACKGROUND: Prognosis is a critical consideration in caring for older adults with multiple chronic conditions, or "multimorbidity". Clinicians are not adequately trained in this area. We describe an innovative curriculum that teaches internal medicine residents how to incorporate prognosis in the care of older adults with multimorbidity. METHODS: The curriculum includes three small-group sessions and a clinical exercise; it focuses on the assessment, communication, and application of prognosis to inform clinical decisions. The curriculum was implemented with 20 first-year residents at one university-based residency (intervention group). Fifty-two first-year residents from a separate residency affiliated with the same university served as controls. Evaluation included three components. A survey assessed acceptability. A pre/post survey assessed attitude, knowledge, and self reported skills (Impact survey). Comparison of baseline and follow-up results used paired t-test and McNemar test; comparison of inter-group differences used t test and Fisher's exact test. A retrospective, blinded pre/post chart review assessed documentation behavior; abstracted outcomes were analyzed using Fisher's exact test. RESULTS: The curriculum was highly rated (4.5 on 5-point scale). Eighteen intervention group residents (90 %) and 29 control group residents (56 %) responded to the Impact survey. At baseline, there were no significant inter group differences in any of the responses. The intervention group improved significantly in prognosis communication skills (5.2 to 6.6 on 9-point scale, p < 0.001), usage of evidence-based prognostic tools (1/18 to 14/18 responses, p < 0.001), and prognostic accuracy (1/18 to 9/18 responses, p = 0.005). These responses were significantly different from the control group at follow-up. Of 71 charts reviewed in each group, prognosis documentation in the intervention group increased from 1/25 charts (4 %) at baseline to 8/46 charts (17 %) at follow-up (p = 0.15). No prognosis documentation was identified in the control group at either time point. Inter-group difference was significant at follow-up (p = 0.006). CONCLUSION: We developed and implemented a novel prognosis curriculum that had significant short-term impact on the residents' knowledge and communication skills as compared to a control group. This innovative curriculum addresses an important educational gap in incorporating prognosis in the care of older adults with multimorbidity. PMID- 26628051 TI - Characteristics of waste automotive glasses as silica resource in ferrosilicon synthesis. AB - This fundamental research on end-of-life automotive glasses, which are difficult to recycle, is aimed at understanding the chemical and physical characteristics of waste glasses as a resource of silica to produce ferrosilicon. Laboratory experiments at 1550 degrees C were carried out using different automotive glasses and the results compared with those obtained with pure silica. In situ images of slag-metal separation showed similar behaviour for waste glasses and silica bearing pellets. Though X-ray diffraction (XRD) showed different slag compositions for glass and silica-bearing pellets, formation of ferrosilicon was confirmed. Synthesized ferrosilicon alloy from waste glasses and silica were compared by Raman, X-ray photoelectron spectroscopy and scanning electron microscopy (SEM) analysis. Silicon concentration in the synthesized alloys showed almost 92% silicon recovery from the silica-bearing pellet and 74-92% silicon recoveries from various waste glass pellets. The polyvinyl butyral (PVB) plastic layer in the windshield glass decomposed at low temperature and did not show any detrimental effect on ferrosilicon synthesis. This innovative approach of using waste automotive glasses as a silica source for ferrosilicon production has the potential to create sustainable pathways, which will reduce specialty glass waste in landfill. PMID- 26628052 TI - Potential mercury emissions from fluorescent lamps production and obsolescence in mainland China. AB - The use of fluorescent lamps has expanded rapidly all over the world in recent years, because of their energy-saving capability. Consequently, however, mercury emissions from production, breakage, and discard of the lamps are drawing increasing concern from the public. This article focuses on evaluating the amount of mercury used for fluorescent lamp production, as well as the potential mercury emissions during production and breakage, in mainland China. It is expected to provide a comprehensive understanding about the risks present in the mercury from fluorescent lamps, and to know about the impacts of the policies on fluorescent lamps after their implementation. It is estimated that, in 2020, mercury consumption will be about 11.30-15.69 tonnes, a significant reduction of 34.9% 37.4% from that used in 2013, owing to improvement in mercury dosing dosage technology and tighter limitations on mercury content in fluorescent lamps. With these improvements, the amount of mercury remaining in fluorescent lamps and released during production is estimated to be 10.71-14.86 and 0.59-0.83 tonnes, respectively; the mercury released from waste fluorescent lamps is estimated to be about 5.37-7.59 tonnes. Also, a significant reduction to the mercury emission can be expected when a collection and treatment system is well established and conducted in the future. PMID- 26628053 TI - Heat supply from municipal solid waste incineration plants in Japan: Current situation and future challenges. AB - The use of waste-to-energy technology as part of a municipal solid waste management strategy could reduce the use of fossil fuels and contribute to prevention of global warming. In this study, we examined current heat and electricity production by incineration plants in Japan for external use. Herein, we discuss specific challenges to the promotion of heat utilisation and future municipal solid waste management strategies. We conducted a questionnaire survey to determine the actual conditions of heat production by incineration plants. From the survey results, information of about 498 incineration plants was extracted. When we investigated the relationship between heat production for external use and population density where incineration plants were located, we found that regions with a population density <1000 persons (km(2))(-1) produce <500 MJ t(-1) of heat. We also found that external use of such energy for factories, markets, and related use, was noted in cities with a population density of 2000 to 4000 persons (km(2))(-1). Several incineration plants have poor performance for heat production because there are few facilities near them to provide demand for the energy. This is the result of redundant capacity, and is reflected in the heat production performance. Given these results, we discussed future challenges to creating energy demand around incineration plants where there is presently none. We also examined the challenges involved in increasing heat supply beyond the present situation. PMID- 26628054 TI - The use of reverse logistics for waste management in a Brazilian grocery retailer. AB - Retail growth is a result of the diversification of departments with the intention to look to consumer's needs and level of demand. Pressed by consumers and by the law, the adoption of environmental preservation practices is becoming stronger among grocery retailers. The objective of this research was to analyse the practices of reverse logistics performed by a retailer and measure the amount of waste generated by each department. To reach the proposed goal, a field research study was conducted to directly observe a grocery retailer in the state of Sao Paulo, Brazil, for a period of 6 months and monitor the amounts of cardboard and plastic discarded by each department. Using the Wuppertal method, the first result observed was that the retailer stopped its monthly production of approximately 20 tonne of biotic and abiotic material, which influence global warming and degradation of the ozone layer. Another result observed with the implementation of reverse logistics, was that the general grocery department mostly used cardboard and plastic. This sector includes products such as food cupboard, drinks, household, health and beauty, and pet articles. The fresh fruit and vegetable department and the meat, chicken and frozen department were increasingly using less plastic and cardboard packaging, increasing the use of returnable and durable packaging and thus promoting sustainability. PMID- 26628056 TI - Bloodstream infections in patients with malignancies: implications for antibiotic treatment in a Ghanaian tertiary setting. AB - BACKGROUND: Bloodstream infections (BSI) remain a major cause of mortality in patients with malignancies. We present the first report on the microbiological profile of bacteraemia and fungaemia among cancer patients in Ghana. METHODS: From January 2010 through December 2013, we retrospectively analyzed the spectrum of bloodstream pathogens in cancer patients from Korle-Bu Teaching Hospital, Ghana--focusing on multidrug resistant isolates (MDRs). RESULTS: Overall BSI were confirmed in 22% (n = 93/453) of total blood cultures. Our data highlights a co dominance of Gram-negative (n = 49/93, 52.6%) and Gram-positive (n = 40/93, 43.0%) bacteria with the former less likely to infect children than adults [odds ratio (OR), 0.56; 95% confidence interval (CI) 0.14-0.91; p value = 0.027]. Staphylococcus epidermidis was the most isolated bacteria (30.1%; n = 28/93). About 61% (n = 25/41) of Enterobacteriaceae isolates were resistant to cefotaxime; a majority (n = 24/25, 96%) of which were MDRs and mostly susceptible to amikacin and levofloxacin. Four (80 %) penicillin resistant streptococci were found; 2 of which were MDRs and sensitive to erythromycin and cefuroxime. Methicillin resistant Staphylococcus aureus and vancomycin resistant enterococci were not identified. In multivariate analysis, the Enterobacteriaceae compared to other organisms were significantly associated with multidrug resistance (adjusted OR, 33.6; 95% CI 6.41-88.73; p value 0.001). CONCLUSION: MDRs, especially cefotaxime resistant Enterobacteriaceae, are common among patients with cancer in our institution but vary among different patient populations. The results show that empiric antibiotic treatment for cancer patients cannot be done effectively without regard for selective antimicrobial use based on local epidemiologic data. PMID- 26628055 TI - Integrative molecular profiling indicates a central role of transitory starch breakdown in establishing a stable C/N homeostasis during cold acclimation in two natural accessions of Arabidopsis thaliana. AB - BACKGROUND: The variation of growth and cold tolerance of two natural Arabidopsis accessions, Cvi (cold sensitive) and Rschew (cold tolerant), was analysed on a proteomic, phosphoproteomic and metabolomic level to derive characteristic information about genotypically distinct strategies of metabolic reprogramming and growth maintenance during cold acclimation. RESULTS: Growth regulation before and after a cold acclimation period was monitored by recording fresh weight of leaf rosettes. Significant differences in the shoot fresh weight of Cvi and Rschew were detected both before and after acclimation to low temperature. During cold acclimation, starch levels were found to accumulate to a significantly higher level in Cvi compared to Rschew. Concomitantly, statistical analysis revealed a cold-induced decrease of beta-amylase 3 (BAM3; AT4G17090) in Cvi but not in Rschew. Further, only in Rschew we observed an increase of the protein level of the debranching enzyme isoamylase 3 (ISA3; AT4G09020). Additionally, the cold response of both accessions was observed to severely affect ribosomal complexes, but only Rschew showed a pronounced accumulation of carbon and nitrogen compounds. The abundance of the Cold Regulated (COR) protein COR78 (AT5G52310) as well as its phosphorylation was observed to be positively correlated with the acclimation state of both accessions. In addition, transcription factors being involved in growth and developmental regulation were found to characteristically separate the cold sensitive from the cold tolerant accession. Predicted protein-protein interaction networks (PPIN) of significantly changed proteins during cold acclimation allowed for a differentiation between both accessions. The PPIN revealed the central role of carbon/nitrogen allocation and ribosomal complex formation to establish a new cold-induced metabolic homeostasis as also observed on the level of the metabolome and proteome. CONCLUSION: Our results provide evidence for a comprehensive multi-functional molecular interaction network orchestrating growth regulation and cold acclimation in two natural accessions of Arabidopsis thaliana. The differential abundance of beta-amylase 3 and isoamylase 3 indicates a central role of transitory starch degradation in the coordination of growth regulation and the development of stress tolerance. Finally, our study indicates naturally occurring differential patterns of C/N balance and protein synthesis during cold acclimation. PMID- 26628057 TI - Adolescent health experience after abortion or delivery (AHEAD) trial: formative protocol for intervention development to prevent rapid, repeat pregnancy. AB - BACKGROUND: There is a high unmet need for modern contraception among adolescents, and adolescent girls who have already been pregnant are especially vulnerable to a rapid, repeat pregnancy (defined as a subsequent pregnancy within two years). The Adolescent Health Experience after Abortion or Delivery (AHEAD) trial will design, pilot, finalize, and ultimately evaluate an intervention targeted at reducing rapid repeat pregnancy. This protocol presents the methods for the first phase--formative research to identify key determinants of contraceptive use and rapid, repeat unintended pregnancy among adolescents. METHODS/DESIGN: The determinants of adolescent pregnancy are known to vary by context; therefore, a dissimilar set of three countries will be selected to enable evaluation of the intervention in diverse cultural, political and economic environment, and to allow the intervention to be tested with a fuller range of ever-pregnant adolescents, including those who have chosen to terminate their pregnancy as well as those who are mothers. We will also consider marital status in settings where it is common for adolescents to marry. Focus group discussions (FGDs) will be conducted to examine barriers and facilitators to using contraception; preferred methods of overcoming these barriers; and perceptions of the services and information received. Key informant (KI) interviews will take place with various cadres of healthcare providers, health and education officials, and members of key youth and health organizations that work with adolescents. These interviews will focus on perceptions of pregnant adolescents; perceived information, skills, and motivations required for adolescent uptake of contraception; and experiences, challenges, and attitudes encountered during interactions. DISCUSSION: The findings from this first formative phase will be used to develop an intervention for preventing rapid, repeat unintended pregnancy among adolescents. This intervention will be piloted in a second phase of the AHEAD trial. PMID- 26628060 TI - The role of the uncertainty of measurement of serum creatinine concentrations in the diagnosis of acute kidney injury. AB - Uncertainty of measurement is the numeric expression of the errors associated with all measurements taken in clinical laboratories. Serum creatinine concentration is the most common diagnostic marker for acute kidney injury. The goal of this study was to determine the effect of the uncertainty of measurement of serum creatinine concentrations on the diagnosis of acute kidney injury. We calculated the uncertainty of measurement of serum creatinine according to the Nordtest Guide. Retrospectively, we identified 289 patients who were evaluated for acute kidney injury. Of the total patient pool, 233 were diagnosed with acute kidney injury using the AKIN classification scheme and then were compared using statistical analysis. We determined nine probabilities of the uncertainty of measurement of serum creatinine concentrations. There was a statistically significant difference in the number of patients diagnosed with acute kidney injury when uncertainty of measurement was taken into consideration (first probability compared to the fifth p = 0.023 and first probability compared to the ninth p = 0.012). We found that the uncertainty of measurement for serum creatinine concentrations was an important factor for correctly diagnosing acute kidney injury. In addition, based on the AKIN classification scheme, minimizing the total allowable error levels for serum creatinine concentrations is necessary for the accurate diagnosis of acute kidney injury by clinicians. PMID- 26628059 TI - T-wave reversal in the augmented unipolar right arm electrocardiographic lead is associated with increased risk of sudden death. AB - BACKGROUND: Repolarization abnormalities are associated with ventricular arrhythmias, and published studies report that a reversal of T wave polarity (positive or flat T wave) in lead aVR may be linked to increased cardiovascular mortality. We evaluated whether a positive or flat T wave in aVR is a risk marker for sudden cardiac death (SCD). METHODS: SCD cases from the Oregon Sudden Unexpected Death Study (catchment population ~1 million) were compared to geographic controls with coronary artery disease and no history of SCD. Archived electrocardiograms performed prior and unrelated to the SCD event were evaluated. RESULTS: SCD cases (n = 691, 67.6 +/- 14.9 years, 69% male) were more likely than controls (n = 663, 66.2 +/- 11.6 years, 67% male) to have diabetes (40 vs 32%; p < 0.01), left ventricular ejection fraction (LVEF) <=35% (27 vs 11 %; p < 0.01), prolonged QTc (>=450 ms; 54 vs 28%; p < 0.01) and positive (19 vs 13%; p < 0.01) or flat T wave (14 vs 7%; p < 0.01) in aVR. On multivariable analysis, a positive/flat T wave in aVR was independently associated with SCD (OR 1.9, 95% CI 1.3-2.8, p < 0.01). However, a positive T wave alone lost statistical significance in patients with LVEF <= 35% and QTc >= 450 ms. In a subgroup analysis among patients with normal LVEF, QTc, and no diabetes, a positive T wave in aVR (but not a flat T wave) remained associated with SCD (OR 2.8, 95% CI 1.2 6.1, p < 0.01). CONCLUSIONS: A positive or flat T wave in lead aVR was associated with SCD in subsets of patients. This simple ECG marker in this often-ignored lead may contribute to enhancement of SCD risk stratification, and warrants further evaluation. PMID- 26628058 TI - The estrous cycle surpasses sex differences in regulating the transcriptome in the rat medial prefrontal cortex and reveals an underlying role of early growth response 1. AB - BACKGROUND: Males and females differ in cognitive functions and emotional processing, which in part have been associated with baseline sex differences in gene expression in the medial prefrontal cortex. Nevertheless, a growing body of evidence suggests that sex differences in medial prefrontal cortex-dependent cognitive functions are attenuated by hormonal fluctuations within the menstrual cycle. Despite known genomic effects of ovarian hormones, the interaction of the estrous cycle with sex differences in gene expression in the medial prefrontal cortex remains unclear and warrants further investigations. RESULTS: We undertake a large-scale characterization of sex differences and their interaction with the estrous cycle in the adult medial prefrontal cortex transcriptome and report that females with high and low ovarian hormone levels exhibited a partly opposed sexually biased transcriptome. The extent of regulation within females vastly exceeds sex differences, and supports a multi-level reorganization of synaptic function across the estrous cycle. Genome-wide analysis of the transcription factor early growth response 1 binding highlights its role in controlling the synapse-related genes varying within females. CONCLUSIONS: We uncover a critical influence of the estrous cycle on the adult rat medial prefrontal cortex transcriptome resulting in partly opposite sex differences in proestrus when compared to diestrus females, and we discovered a direct role for Early Growth Response 1 in this opposite regulation. In addition to illustrating the importance of accounting for the estrous cycle in females, our data set the ground for a better understanding of the female specificities in cognition and emotional processing. PMID- 26628061 TI - Identification of novel biomarkers in chronic immune thrombocytopenia (ITP) by microarray-based serum protein profiling. AB - The pathological mechanisms underlying the development of immune thrombocytopenia (ITP) are unclear and its diagnosis remains a process of exclusion. Currently, there are no known specific biomarkers for ITP to support differential diagnosis and treatment decisions. Profiling of serum proteins may be valuable for identifying such biomarkers. Sera from 46 patients with primary chronic ITP and 34 healthy blood donors were analysed using a microarray of 755 antibodies. We identified 161 differentially expressed proteins. In addition to oncoproteins and tumour-suppressor proteins, including apoptosis regulator BCL2, breast cancer type 1 susceptibility protein (BRCA1), Fanconi anaemia complementation group C (FANCC) and vascular endothelial growth factor A (VEGFA), we detected six anti nuclear autoantibodies in a subset of ITP patients: anti-PCNA, anti-SmD, anti Ro/SSA60, anti-Ro/SSA52, anti-La/SSB and anti-RNPC antibodies. This finding may provide a rational explanation for the association of ITP with malignancies and other autoimmune diseases. While RUNX1mRNA expression in the peripheral blood mononuclear cells (PBMC) of patients was significantly downregulated, an accumulation of RUNX1 protein was observed in the platelets of ITP patients. This may indicate dysregulation of RUNX1 expression in PBMC and megakaryocytes and may lead to an imbalanced immune response and impaired thrombopoiesis. In conclusion, we provide novel insights into the pathogenic mechanisms of ITP that warrant further exploration. PMID- 26628063 TI - Comparison between two-dimensional synthetic mammography reconstructed from digital breast tomosynthesis and full-field digital mammography for the detection of T1 breast cancer. AB - OBJECTIVE: To evaluate the interpretative performance of two-dimensional (2D) synthetic mammography (SM) reconstructed from digital breast tomosynthesis (DBT) in the detection of T1-stage invasive breast cancers, compared to 2D full-field digital mammography (FFDM). METHODS: This retrospective study enrolled 214 patients. For each patient, FFDM and DBT were performed between January and June 2013, and SM was reconstructed from DBT data. Three radiologists interpreted images and recorded visibility scores and morphologies of cancers. Diagnostic performances of SM and FFDM were compared. Percentages of detected cancers and visibility scores were compared for tumour size, and presence of calcifications for each observer. RESULTS: Observer sensitivity showed no difference for detection with SM and FFDM (P > 0.05). One observer showed a higher specificity (P = 0.02) and higher positive predictive value with SM (95 % CI 0.6-16.4), but the differences in the corresponding values between SM and FFDM for the other observers were not statistically significant. In subgroup analyses according to tumour size and presence of calcifications, percentages of detected cancers and visibility scores were not significantly different. CONCLUSIONS: Diagnostic performances of SM and FFDM are comparable for detecting T1-stage breast cancers. Therefore, our results indicate that SM may eliminate the need for additional FFDM during DBT-based imaging. KEY POINTS: * DBT plus FFDM increases radiation dose compared to FFDM alone. * Detecting T1-stage cancers with only SM is comparable to detection with FFDM. * Two-dimensional SM may replace dose requiring FFDM in DBT-based imaging. PMID- 26628064 TI - Diagnostic impact of digital tomosynthesis in oncologic patients with suspected pulmonary lesions on chest radiography. AB - OBJECTIVES: To assess the actual diagnostic impact of digital tomosynthesis (DTS) in oncologic patients with suspected pulmonary lesions on chest radiography (CXR). METHODS: A total of 237 patients (135 male, 102 female; age, 70.8 +/- 10.4 years) with a known primary malignancy and suspected pulmonary lesion(s) on CXR and who underwent DTS were retrospectively identified. Two radiologists (experience, 10 and 15 years) analysed in consensus CXR and DTS images and proposed a diagnosis according to a confidence score: 1 or 2 = definitely or probably benign pulmonary or extrapulmonary lesion, or pseudolesion; 3 = indeterminate; 4 or 5 = probably or definitely pulmonary lesion. DTS findings were proven by CT (n = 114 patients), CXR during follow-up (n = 105) or histology (n = 18). RESULTS: Final diagnoses included 77 pulmonary opacities, 26 pulmonary scars, 12 pleural lesions and 122 pulmonary pseudolesions. DTS vs CXR presented a higher (P < 0.05) sensitivity (92 vs 15 %), specificity (91 vs 9 %), overall accuracy (92 vs 12 %), and diagnostic confidence (area under ROC, 0.997 vs 0.619). Mean effective dose of CXR vs DTS was 0.06 vs 0.107 mSv (P < 0.05). CONCLUSIONS: DTS improved diagnostic accuracy and confidence in comparison to CXR alone in oncologic patients with suspected pulmonary lesions on CXR with only a slight, though significant, increase in radiation dose. KEY POINTS: * Digital tomosynthesis (DTS) improves accuracy of chest radiography (CXR) in oncologic patients. * DTS improves confidence of CXR in oncologic patients. * DTS allowed avoidance of CT in about 50 % of oncologic patients. PMID- 26628065 TI - The thoracic duct: clinical importance, anatomic variation, imaging, and embolization. AB - The thoracic duct is the body's largest lymphatic conduit, draining upwards of 75 % of lymphatic fluid and extending from the cisterna chyli to the left jugulovenous angle. While a typical course has been described, it is estimated that it is present in only 40-60% of patients, often complicating already challenging interventional procedures. The lengthy course predisposes the thoracic duct to injury from a variety of iatrogenic disruptions, as well as spontaneous benign and malignant lymphatic obstructions and idiopathic causes. Disruption of the thoracic duct frequently results in chylothoraces, which subsequently cause an immunocompromised state, contribute to nutritional depletion, and impair respiratory function. Although conservative dietary treatments exist, the majority of thoracic duct disruptions require embolization in the interventional suite. This article provides a comprehensive review of the clinical importance of the thoracic duct, relevant anatomic variants, imaging, and embolization techniques for both diagnostic and interventional radiologists as well as for the general medical practitioner. KEY POINTS: * Describe clinical importance, embryologic origin, and typical course of the thoracic duct. * Depict common/lesser-known thoracic duct anatomic variants and discuss their clinical significance. * Outline the common causes of thoracic duct injury and indications for embolization. * Review the thoracic duct embolization procedure including both pedal and intranodal approaches. * Present and illustrate the success rates and complications associated with the procedure. PMID- 26628066 TI - Computed tomography findings for a gastric lymphoepithelioma-like carcinoma: How often does it present as a submucosal mass? AB - OBJECTIVES: To describe the anatomical location, size, tumour characteristics and morphology on CT of gastric lymphoepithelioma-like carcinoma (LELC) in order to determine the proportion of lesions that present as submucosal masses, and to review the clinicopathological findings. METHODS: This retrospective study reviewed CT images of 186 lesions from 178 patients with LELC. CT morphologies and other findings were also analyzed. Pathology and medical records were reviewed. A pathology slide review of the lesions that presented with submucosal masses was performed. RESULTS: Gastric LELC presenting as a submucosal mass was found in 9.1 %. The most common CT morphology was eccentric wall thickening (67.7 %). On the pathology review, 14/17 submucosal mass lesions (82.4 %) had a central ulceration. 105 lesions were T1/T2 stage (94.1 %), and N0 stage was diagnosed in 66.1 %. Fifty-six of 63 metastatic lymph nodes (LNs) (88.9 %) demonstrated homogeneous enhancement, regardless of size. Male predominance (85.4 %), upper stomach location (45.7 %) and multiplicity (4.5 %) were found. CONCLUSIONS: Gastric LELC presenting as a submucosal mass is only detected in a small portion of all patients, and the most common finding is eccentric wall thickening. Central ulceration and enlarged LNs with homogeneous enhancement are occasionally other features on CT. KEY POINTS: * LELCs as submucosal masses on CT were detected in only 9.1 %. * The most common CT finding was eccentric wall thickening (67.7 %). * Central ulceration and enlarged LNs with homogeneous enhancement might be seen. PMID- 26628067 TI - Molecular evaluation of thrombosis using X-ray phase contrast imaging with microbubbles targeted to P-selectin in mice. AB - OBJECTIVES: X-ray phase contrast imaging (PCI) provides excellent image contrast by utilizing the phase shift. The introduction of microbubbles into tissues can cause a phase shift to make microbubbles visibly identified on PCI. In this study, we assessed the feasibility of targeted microbubble-based PCI for the detection of thrombosis. METHODS: The absorption and phase contrast images of P selectin-targeted microbubbles (MBP) were obtained and compared in vitro. MBP, control IgG-targeted microbubbles (MBC), and unbound microbubbles (MBU) were tested for binding specificity on thrombi expressing P-selectin. MBP were used as molecular PCI probes to evaluate P-selectin expression in a mouse model of arteriovenous shunt thrombosis that was created using PE tubes in the bypass outside of the mouse body. RESULTS: PCI clearly showed the microbubbles not viewable via absorption contrast imaging (ACI). In vitro attachment of MBP (91.60 +/- 11.63) to thrombi was significantly higher than attachment of MBC (17.80 +/- 4.02, P < 0.001) or MBU (9.80 +/- 2.59, P < 0.001). In the mouse model of arteriovenous shunt thrombosis, the binding affinity of MBP (15.50 +/- 6.25) was significantly greater than that of MBC (0.50 +/- 0.84, P < 0.001) or MBU (0.33 +/ 0.52, P < 0.001). CONCLUSIONS: Our results indicate that molecular PCI may be considered as a novel and promising imaging modality for the investigation of thrombosis. KEY POINTS: * Small thrombi are rarely detected by conventional radiography. * Phase contrast imaging (PCI) provides higher contrast and spatial resolution than conventional radiography. * P-selectin targeted microbubbles detected by PCI may suggest early thrombosis. PMID- 26628068 TI - Prescription practices for malaria in Mozambique: poor adherence to the national protocols for malaria treatment in 22 public health facilities. AB - BACKGROUND: Current World Health Organization and national protocols recommend the 'test and treat' strategy for the management of uncomplicated malaria, to reduce over prescription of artemisinin-based combination treatment (ACT). Therefore, adherence to these protocols varies in different sub-Saharan African countries and no information is available for Mozambique. This study was conducted with the aim to evaluate the prescription practices of ACT in Mozambique. METHODS: Retrospective audit of medical records corresponding to the period between July and December 2011 was conducted in 22 health units across 11 provinces in Mozambique. Two health units were selected per province according to availability of laboratory data (performing microscopy and rapid diagnostics testing-RDT or RDT only) and geographic setting (rural versus urban). At each facility, demographic data, laboratory results (blood smear or RDT), and prescription of ACT were all collected from the existing records. RESULTS: Between July and December 2011, a total of 61,730 cases were tested for malaria, of which 42.7 % (26,369/61,730) were positive. A total of 35.361 patients were malaria negative, and ACT was prescribed to 72.0 % (25.448/35.361) of them. Prescription of ACT to malaria negative patients was higher in the central region of the country as compared to the northern and southern (81.1 % in the central region versus 72.4 and 63.7 % in the northern and southern, respectively, p = 0.000) and in urban settings (88.7 % in rural versus 58.0 % in urban settings, p = 0.000). Stock out of RDT was observed in six (27.3 %) of the health facilities. When no RDT was available, patients were empirically treated with ACT. CONCLUSION: Findings from this study demonstrate that health care worker's adherence to the new guidelines for malaria treatment is poor in Mozambique and prescription of ACT to malaria negative patients remains very high. Enhanced training and supervision activities, community education and external quality assurance might lead to significant improvements in the clinician's adherence to the new guideline for malaria treatment in Mozambique. PMID- 26628069 TI - Speech perception enhancement in elderly hearing aid users using an auditory training program for mobile devices. AB - AIMS: The goal of the present study was to develop an auditory training program using a mobile device and to test its efficacy by applying it to older adults suffering from moderate-to-severe sensorineural hearing loss. METHODS: Among the 20 elderly hearing-impaired listeners who participated, 10 were randomly assigned to a training group (TG) and 10 were assigned to a non-training group (NTG) as a control. As a baseline, all participants were measured by vowel, consonant and sentence tests. In the experiment, the TG had been trained for 4 weeks using a mobile program, which had four levels and consisted of 10 Korean nonsense syllables, with each level completed in 1 week. In contrast, traditional auditory training had been provided for the NTG during the same period. To evaluate whether a training effect was achieved, the two groups also carried out the same tests as the baseline after completing the experiment. RESULTS: The results showed that performance on the consonant and sentence tests in the TG was significantly increased compared with that of the NTG. Also, improved scores of speech perception were retained at 2 weeks after the training was completed. However, vowel scores were not changed after the 4-week training in both the TG and the NTG. CONCLUSIONS: This result pattern suggests that a moderate amount of auditory training using the mobile device with cost-effective and minimal supervision is useful when it is used to improve the speech understanding of older adults with hearing loss. Geriatr Gerontol Int 2017; 17: 61-68. PMID- 26628070 TI - The Outcomes of Ultralow Anterior Resection or an Abdominoperineal Pull-Through Resection and Coloanal Anastomosis for Radiation-Induced Recto-Vaginal Fistula Patients. AB - PURPOSE: The purpose of this study was to evaluate the outcomes of patients who underwent colorectal resections and coloanal anastomosis for radiation-induced recto-vaginal fistulas (RVFs). The effect of the surgical treatment technique on bowel function, fecal continence, and quality of life of patients was also evaluated. METHODS: Twenty-one female patients, who received adjuvant chemotherapy and external beam pelvic radiation for cervix carcinoma after radical hysterectomy + pelvic/paraaortic lymph node dissection, having RVF but without tumor recurrence, were included. All patients underwent an ultralow anterior resection (n = 11) or an abdominoperineal pull-through resection and straight coloanal anastomosis (n = 10). A bowel functions questionnaire and a Fecal Incontinence Quality of Life (FIQLI) questionnaire were applied to patients pre-operatively and also 6 months after the ileostomy closure procedures. RESULTS: No recurrent RVF was observed in a mean follow-up period of 20 months after ostomy reversal procedures. The FIQLI depression, lifestyle, and embarrassment scores were significantly improved on the follow-up questionnaire. The mean pre- and post-operative incontinence scores were not significantly different. CONCLUSIONS: The spontaneous closure rate after a simple diverting stoma is quite low and local repair procedures usually result in failure. In selected patients, performing a nearly total rectum resection and maintaining the intestinal continuity with a coloanal anastomosis may be accepted as a safe and curative option. Recurrence-free outcome and the improvement of the quality of life of the patients represent the efficiency of this treatment modality. PMID- 26628071 TI - Screening or Symptoms? How Do We Detect Colorectal Cancer in an Equal Access Health Care System? AB - BACKGROUND: Detection of colorectal cancer ideally occurs at an early stage through proper screening. We sought to establish methods by which colorectal cancers are diagnosed within an equal access military health care population and evaluate the correlation between TNM stage at colorectal cancer diagnosis and diagnostic modality (i.e., symptomatic detection vs screen detection). MATERIALS AND METHODS: A retrospective chart review of all newly diagnosed colorectal cancer patients from January 2007 to August 2014 was conducted at the authors' equal access military institution. We evaluated TNM stage relative to diagnosis by screen detection (fecal occult blood test, flexible sigmoidoscopy, CT colonography, colonoscopy) or symptomatic evaluation (diagnostic colonoscopy or surgery). RESULTS: Of 197 colorectal cancers diagnosed (59 % male; mean age 62 years), 50 (25 %) had stage I, 47 (24 %) had stage II, 70 (36 %) had stage III, and 30 (15 %) had stage IV disease. Twenty-five percent of colorectal cancers were detected via screen detection (3 % by fecal occult blood testing (FOBT), 0.5 % by screening CT colonography, 17 % by screening colonoscopy, and 5 % by surveillance colonoscopy). One hundred forty-eight (75 %) were diagnosed after onset of signs or symptoms. The preponderance of these was advanced-stage disease (stages III-IV), although >50 % of stage I-II disease also had signs or symptoms at diagnosis. The most common symptoms were rectal bleeding (45 %), abdominal pain (35 %), and change in stool caliber (27 %). The most common overall sign was anemia (60 %). Screening FOBT (odds ratio (OR) 8.7, 95 % confidence interval (CI) 1.0-78.3; P = 0.05) independently predicted early diagnosis with stage I-II disease. Patient gender and ethnicity were not associated with cancer stage at diagnosis. CONCLUSIONS: Despite equal access to colorectal cancer screening, diagnosis after development of symptomatic cancer remains more common. Fecal occult blood screen detection is associated with early stage at colorectal cancer diagnosis and is the focus for future initiatives. PMID- 26628072 TI - Postresection Outcomes of Combined Hepatocellular Carcinoma-Cholangiocarcinoma, Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. AB - INTRODUCTION: Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is rare. This study investigated the clinicopathological features of cHCC-CC and compared the postresection survival outcomes of cHCC-CC, hepatocellular carcinoma (HCC), and intrahepatic cholangiocarcinoma (IHC). METHODS: Between January 2000 and September 2012, 53 patients with cHCC-CC underwent tumor resection, accounting for 1.1 % of surgeries for primary liver malignancies. Control groups included patients with HCC (n = 1452) and IHC (n = 149) who underwent R0 resection of stage I/II tumors <=5 cm. RESULTS: Mean tumor diameter of cHCC-CC group was 5.5 +/- 2.9 cm, and single tumor was identified in 50. Pathological classification included combined (n = 41), mixed (n = 11), and double (n = 1) tumors. The 1-, 3-, 5-, and 10-year tumor recurrence rates were 60.8, 71.8, 80.7, and 80.7 %, respectively. The 1-, 3-, 5-, and 10-year overall survival rates were 73.3, 35.6, 30.5, and 11.1 %, respectively. Tumor recurrence and patient survival did not differ significantly according to AJCC tumor staging and histological type (all p >= 0.2). Tumor recurrence rates did not differ significantly between the cHCC-CC, HCC, and IHC groups (p = 0.43), whereas differences in survival rates were significant (p = 0.000), with a median survival after tumor recurrence of 8, 51, and 6 months, respectively (p = 0.000). CONCLUSIONS: Patients with cHCC CC showed similar recurrence rates to those of control patients with HCC and IHC, whereas their survival outcomes were worse than those of control HCC patients because of poor responses to recurrence treatment. Further evaluation of differences in tumor characteristics and tumor biology is necessary to accurately predict the prognosis of patients with cHCC-CC. PMID- 26628073 TI - Evaluation of a screener to assess diet quality in the Netherlands. AB - Generally, there is a need for short questionnaires to estimate diet quality in the Netherlands. We developed a thirty-four-item FFQ--the Dutch Healthy Diet FFQ (DHD-FFQ)--to estimate adherence to the most recent Dutch guidelines for a healthy diet of 2006 using the DHD-index. The objectives of the present study were to evaluate the DHD-index derived from the DHD-FFQ by comparing it with the index based on a reference method and to examine associations with participant characteristics, nutrient intakes and levels of cardiometabolic risk factors. Data of 1235 Dutch men and women, aged between 20 and 70 years, participating in the Nutrition Questionnaires plus study were used. The DHD-index was calculated from the DHD-FFQ and from a reference method consisting of a 180-item FFQ combined with a 24-h urinary Na excretion value. Ranking was studied using Spearman's correlations, and absolute agreement was studied using a Bland-Altman plot. Nutrient intakes derived from the 180-item FFQ were studied according to quintiles of the DHD-index using DHD-FFQ data. The correlation between the DHD index derived from the DHD-FFQ and the reference method was 0.56 (95% CI 0.52, 0.60). The Bland-Altman plot showed a small mean overestimation of the DHD-index derived from the DHD-FFQ compared with the reference method. The DHD-index score was in the favourable direction associated with most macronutrient and micronutrient intakes when adjusted for energy intake. No associations between the DHD-index score and cardiometabolic risk factors were observed. In conclusion, the DHD-index derived from the DHD-FFQ was considered acceptable in ranking but relatively poor in individual assessment of diet quality. PMID- 26628077 TI - Endohedrally doped gold nanocages: efficient catalysts for O2 activation and CO oxidation. AB - Gold nanocages are the most attractive catalytic materials as all the atoms in the cage type clusters reside on the surface, making them available for chemisorption by reacting molecules. Due to a hollow space at the center, their chemical and catalytic properties can be tuned effectively and easily by endohedral doping. While a significant experimental and theoretical understanding is currently available on the structural and electronic properties of doped gold cages, very little information is available on their reactivity and catalytic behavior. In the present work, with the help of density functional theory calculations we demonstrate that endohedral doping leads to a notable increase in the binding energy of molecular oxygen on the gold nanocages. The enhancement in the O2 binding energy on the doped gold cages is also confirmed by a significant decrease in the Au-O and an increase in the O-O bond lengths, corroborated by a red shift (~250 cm(-1)) in the O-O stretching frequency as compared to the pristine cage. Furthermore, interestingly, the doped gold cages show very low activation barriers for the environmentally important CO oxidation reaction as compared to the pristine gold cage. Importantly, the decrease in the barrier height is comparatively greater for the rate limiting step of O-O-C-O intermediate formation and as a result the CO oxidation is expected to be more facile on the doped gold cages. Thus, the current study highlights the role of heteroatom doping in imparting new chemical and catalytic properties to gold cages and is expected to spur further research in the design of efficient gold nanocatalysts. PMID- 26628074 TI - Maternal super-obesity and perinatal outcomes in Australia: a national population based cohort study. AB - BACKGROUND: Super-obesity is associated with significantly elevated rates of obstetric complications, adverse perinatal outcomes and interventions. The purpose of this study was to determine the prevalence, risk factors, management and perinatal outcomes of super-obese women giving birth in Australia. METHODS: A national population-based cohort study. Super-obese pregnant women (body mass index (BMI) >50 kg/m(2) or weight >140 kg) who gave birth between January 1 and October 31, 2010 and a comparison cohort were identified using the Australasian Maternity Outcomes Surveillance System (AMOSS). Outcomes included maternal and perinatal morbidity and mortality. Prevalence estimates calculated with 95% confidence intervals (CIs). Adjusted odds ratios (ORs) were calculated using multivariable logistic regression. RESULTS: 370 super-obese women with a median BMI of 52.8 kg/m(2) (range 40.9-79.9 kg/m(2)) and prevalence of 2.1 per 1 000 women giving birth (95% CI: 1.96-2.40). Super-obese women were significantly more likely to be public patients (96.2%), smoke (23.8%) and be socio-economically disadvantaged (36.2%). Compared with other women, super-obese women had a significantly higher risk for obstetric (adjusted odds ratio (AOR) 2.42, 95% CI: 1.77-3.29) and medical (AOR: 2.89, 95% CI: 2.64-4.11) complications during pregnancy, birth by caesarean section (51.6%) and admission to special care (HDU/ICU) (6.2%). The 372 babies born to 365 super-obese women with outcomes known had significantly higher rates of birthweight >= 4500 g (AOR 19.94, 95 % CI: 6.81-58.36), hospital transfer (AOR 3.81, 95 % CI: 1.93-7.55) and admission to Neonatal Intensive Care Unit (NICU) (AOR 1.83, 95% CI: 1.27-2.65) compared to babies of the comparison group, but not prematurity (10.5% versus 9.2%) or perinatal mortality (11.0 (95% CI: 4.3-28.0) versus 6.6 (95% CI: 2.6- 16.8) per 1 000 singleton births). CONCLUSIONS: Super-obesity in pregnancy in Australia is associated with increased rates of pregnancy and birth complications, and with social disadvantage. There is an urgent need to further address risk factors leading to super-obesity among pregnant women and for maternity services to better address pre-pregnancy and pregnancy care to reduce associated inequalities in perinatal outcomes. PMID- 26628076 TI - [Role of general practitioners in cancer screening: A survey in the French armed forces]. AB - INTRODUCTION: The French Military Health Service organizes medical survey of 340,000 military men. The aim of the present study was to evaluate the practices of solid cancer screening of general practitioners in military medical units and to compare the results with the recommendations of the French National Institute of Cancer. METHODS: We conducted a prospective, observational study among general practitioners in Army Medical Unit by sending them a self-assessment questionnaire. Physicians should report on their practices for screening cancers with official screening recommendations. Compliance rates with the recommendations were reviewed. Screening practices for other cancers (prostate cancer, melanoma, thyroid cancer, lung cancer, testicular cancer) were assessed. RESULTS: A total of 133 questionnaires were analyzed. Despite a strong involvement of army general health practitioners, guidelines adherence rates (examination frequency, ages of screening beginning and ending) were of 4% for cervical cancer, 7% for breast cancer, and 37% for colorectal cancer. Those rates are comparable to those reported with civilian general practitioners. For cancers without screening recommendation, practitioners felt highly concerned, especially for the most common cancers among the military population. One third of physicians stated that they had diagnosed a testicular cancer through routine screening. CONCLUSION: Military general health practitioners feel themselves concerned by solid cancer screening, and more particularly for cancers that are the most prevalent in young adults. However, current guidelines are neither known nor applied in routine. PMID- 26628078 TI - Peripheral nerve stimulation characteristics of an asymmetric head-only gradient coil compatible with a high-channel-count receiver array. AB - PURPOSE: To characterize peripheral nerve stimulation (PNS) of an asymmetric head only gradient coil that is compatible with a commercial high-channel-count receive-only array. METHODS: Two prototypes of an asymmetric head-only gradient coil set with a 42-cm inner diameter were constructed for brain imaging at 3T with maximum performance specifications of up to 85 mT/m and 708 T/m/s. Tests were performed in 24 volunteers to measure PNS thresholds with the transverse (x = left-right; y = anterior-posterior [A/P]) gradient coils of both prototypes. Fourteen of these 24 volunteers were also tested for the z-gradient PNS in the second prototype and were scanned with high-slew-rate echo planar imaging (EPI) immediately after the PNS tests. RESULTS: For both prototypes, the y-gradient PNS threshold was markedly higher than the x-gradient threshold. The z-gradient threshold was intermediate between those for the x- and y-coils. Of the 24 volunteers, only two experienced y-gradient PNS at 80 mT/m and 500 T/m/s. All volunteers underwent the EPI scan without PNS when the readout direction was set to A/P. CONCLUSION: Measured PNS characteristics of asymmetric head-only gradient coil prototypes indicate that such coils, especially in the A/P direction, can be used for fast EPI readout in high-performance neuroimaging scans with substantially reduced PNS concerns compared with conventional whole body gradient coils. Magn Reson Med 76:1939-1950, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26628081 TI - Time-Resolved Particle Image Velocimetry Measurements with Wall Shear Stress and Uncertainty Quantification for the FDA Nozzle Model. AB - We present advanced particle image velocimetry (PIV) processing, post-processing, and uncertainty estimation techniques to support the validation of computational fluid dynamics analyses of medical devices. This work is an extension of a previous FDA-sponsored multi-laboratory study, which used a medical device mimicking geometry referred to as the FDA benchmark nozzle model. Experimental measurements were performed using time-resolved PIV at five overlapping regions of the model for Reynolds numbers in the nozzle throat of 500, 2000, 5000, and 8000. Images included a twofold increase in spatial resolution in comparison to the previous study. Data was processed using ensemble correlation, dynamic range enhancement, and phase correlations to increase signal-to-noise ratios and measurement accuracy, and to resolve flow regions with large velocity ranges and gradients, which is typical of many blood-contacting medical devices. Parameters relevant to device safety, including shear stress at the wall and in bulk flow, were computed using radial basis functions. In addition, in-field spatially resolved pressure distributions, Reynolds stresses, and energy dissipation rates were computed from PIV measurements. Velocity measurement uncertainty was estimated directly from the PIV correlation plane, and uncertainty analysis for wall shear stress at each measurement location was performed using a Monte Carlo model. Local velocity uncertainty varied greatly and depended largely on local conditions such as particle seeding, velocity gradients, and particle displacements. Uncertainty in low velocity regions in the sudden expansion section of the nozzle was greatly reduced by over an order of magnitude when dynamic range enhancement was applied. Wall shear stress uncertainty was dominated by uncertainty contributions from velocity estimations, which were shown to account for 90-99% of the total uncertainty. This study provides advancements in the PIV processing methodologies over the previous work through increased PIV image resolution, use of robust image processing algorithms for near-wall velocity measurements and wall shear stress calculations, and uncertainty analyses for both velocity and wall shear stress measurements. The velocity and shear stress analysis, with spatially distributed uncertainty estimates, highlights the challenges of flow quantification in medical devices and provides potential methods to overcome such challenges. PMID- 26628080 TI - Defending against pathogens - immunological priming and its molecular basis in a sea anemone, cnidarian. AB - Cnidarians, in general, are long-lived organisms and hence may repeatedly encounter common pathogens during their lifespans. It remains unknown whether these early diverging animals possess some type of immunological reaction that strengthens the defense response upon repeated infections, such as that described in more evolutionary derived organisms. Here we show results that sea anemones that had previously encountered a pathogen under sub-lethal conditions had a higher survivorship during a subsequently lethal challenge than naive anemones that encountered the pathogen for the first time. Anemones subjected to the lethal challenge two and four weeks after the sub-lethal exposure presented seven and five-fold increases in survival, respectively, compared to the naive anemones. However, anemones challenged six weeks after the sub-lethal exposure showed no increase in survivorship. We argue that this short-lasting priming of the defense response could be ecologically relevant if pathogen encounters are restricted to short seasons characterized by high stress. Furthermore, we discovered significant changes in proteomic profiles between naive sea anemones and those primed after pathogen exposure suggesting a clear molecular signature associated with immunological priming in cnidarians. Our findings reveal that immunological priming may have evolved much earlier in the tree of life than previously thought. PMID- 26628082 TI - Assessment of age-specific safety of laparoscopic surgery in elderly patients with ovarian tumors. AB - AIM: We assessed the age-specific safety of laparoscopic surgery in elderly patients with ovarian tumors. MATERIAL AND METHODS: We performed a retrospective analysis of 55 elderly patients treated by laparoscopic salpingo-oophorectomy under the diagnosis of an ovarian tumor between January 2009 and December 2014. We divided patients into three groups: "young-elderly" (aged 65-74), "old elderly" (aged 75-84), and "super-elderly" (aged 85-105) and assessed clinical characteristics, surgical results and postoperative course. Statistical significance of categorical variables was examined by the Student's t-test, Mann Whitney U test, or Fisher's exact test. Multiple regression analysis was used for multivariate analysis. RESULTS: Of a total of 55 patients who underwent laparoscopic surgery, there were 36 patients in the young-elderly group, 17 in the old-elderly group, and two in the super-elderly group. Statistical analysis was performed between the young-elderly and the old-elderly groups because of the small number in the super-elderly group. More frequent comorbidities were found in the patients in the old-elderly than in the young-elderly group (Fisher's exact test, P = 0.007). There were no significant differences in operative time, estimated blood loss and postoperative hospital stay between the young-elderly and old-elderly groups. Intraoperative complications only occurred in the young elderly group. Postoperative complications occurred in all groups. CONCLUSIONS: Although patients in the old-elderly group had a significantly higher risk for surgery, they had equivalent surgical results to the young-elderly group for laparoscopic salpingo-oophorectomy. PMID- 26628084 TI - Molecular origin of contact line stick-slip motion during droplet evaporation. AB - Understanding and controlling the motion of the contact line is of critical importance for surface science studies as well as many industrial engineering applications. In this work, we elucidate the molecular origin of contact line stick-slip motion during the evaporation of liquid droplets on flexible nano pillared surfaces using molecular dynamics simulations. We demonstrate that the evaporation-induced stick-slip motion of the contact line is a consequence of competition between pinning and depinning forces. Furthermore, the tangential force exerted by the pillared substrate on the contact line was observed to have a sawtooth-like oscillation. Our analysis also establishes that variations in the pinning force are accomplished through the self-adaptation of solid-liquid intermolecular distances, especially for liquid molecules sitting directly on top of the solid pillar. Consistent with our theoretical analysis, molecular dynamics simulations also show that the maximum pinning force is quantitatively related to both solid-liquid adhesion strength and liquid-vapor surface tension. These observations provide a fundamental understanding of contact line stick-slip motion on pillared substrates and also give insight into the microscopic interpretations of contact angle hysteresis, wetting transitions and dynamic spreading. PMID- 26628083 TI - Methods on Skull Stripping of MRI Head Scan Images-a Review. AB - The high resolution magnetic resonance (MR) brain images contain some non-brain tissues such as skin, fat, muscle, neck, and eye balls compared to the functional images namely positron emission tomography (PET), single photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI) which usually contain relatively less non-brain tissues. The presence of these non brain tissues is considered as a major obstacle for automatic brain image segmentation and analysis techniques. Therefore, quantitative morphometric studies of MR brain images often require a preliminary processing to isolate the brain from extra-cranial or non-brain tissues, commonly referred to as skull stripping. This paper describes the available methods on skull stripping and an exploratory review of recent literature on the existing skull stripping methods. PMID- 26628086 TI - The conditioned medium from osteo-differentiating human mesenchymal stem cells affects the viability of triple negative MDA-MB231 breast cancer cells. AB - This study aimed to investigate the effect of conditioned media (CM) from osteo differentiating and adipo-differentiating human mesenchymal stem cells (MSCs) isolated from lipoaspirates of healthy female donors on the viability of triple negative breast cancer cells MDA-MB231. The CM of undifferentiated and differentiating MSCs were collected after 7, 14, 21 and 28 days of culture. The effects of MSC CM on cell proliferation were assessed using an 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay after 24 h. The effects of osteo-differentiating cell CM on apoptotic promotion, cell cycle impairment, mitochondrial transmembrane potential dissipation, production of reactive oxygen species and autophagosome accumulation were analysed by flow cytometry and Western blot. MTT assay showed that only CM collected from osteo induced cells at day 28 (d28O-CM) reduced tumour cell viability. Treatment with d28O-CM restrained cell cycle progression through G2 phase, elicited a caspase-8 driven apoptotic effect already after 5 h of culture, and down-regulated autophagosome accumulation and beclin-1 expression. The finding that factor(s) secreted by osteo-differentiating MSCs shows properties of an apoptotic inducer and autophagy inhibitor on triple-negative breast cancer cells may have an important applicative potential that deserves further investigation. PMID- 26628087 TI - Disengagement of general practitioners in cervical cancer screening. AB - In the absence of organized cervical cancer screening (CCS) programs, gynecologists remain principal actors in obtaining a Pap smear, followed by general practitioners (GPs). In France, with the growing scarcity of gynecologists and social inequalities in access to opportunistic screening, GPs are valuable resources for women's gynecologic follow-up. We aimed to investigate the characteristics of GPs who do not perform CCS, analyzing the effect of GPs' sex and their evolution over time. On the basis of data from three cross sectional surveys conducted among representative samples of French GPs in 1998, 2002, and 2009 (n=5199), we constructed univariate and multivariate logistic mixed models (level 2: county, level 1: GP) with random intercept stratified on GPs' sex to investigate the characteristics of the GPs associated with no practice of CCS ever. Almost one-third of all GPs did not perform CCS ever and it increased with time. Male GPs were always more likely not to perform it (odds ratio=0.50, 95% confidence interval=0.42-0.59). The percentage of GPs not performing CCS increased more markedly among male than among female GPs, and increased more among the youngest age group. Increasingly fewer GPs engage in CCS when the growing scarcity of medical gynecologists calls for more participation. Female GPs remain significantly more active in CCS than male GPs. The participation in CCS is determined differently according to the practitioner's sex. PMID- 26628088 TI - Human papillomavirus infection by anatomical site among Greek men and women: a systematic review. AB - We systematically reviewed the literature on anal, penile, cervical, and oropharyngeal human papillomavirus (HPV) infection in Greece to provide a comprehensive overview of HPV prevalence and to explore the reporting of HPV in Greek men and women. A total of five databases, including PubMed and Scopus, were searched up until 1 January 2015 for studies looking at HPV prevalence, incidence, or risk factors by anatomical site. We identified 50 eligible studies for inclusion. The majority of them were cervical studies (n=26) followed by head and neck studies (n=13) with only two studies exclusively focusing on anal sites and two on penile sites. The remaining studies examined prevalence from multiple sites. Most studies looked at small, high-risk populations, and HPV prevalence ranged from 2.5-43.4% for cervical studies; 0-91% for head and neck studies; 54.6 78.4% for anal studies; and 20.3-66.7% for penile studies. Age, smoking, and number of sexual partners were the commonly assessed risk factors. There were significant sex and anatomic site disparities in the reporting of HPV prevalence. Given the relationship between HPV infection and the increasing incidence of anal cancer in men, more research is needed to reveal the prevalence of HPV at these sites in Greek men, especially given the reports of the declining health of the Greek population. PMID- 26628089 TI - How to make an oligodendrocyte. AB - Oligodendrocytes produce myelin, an insulating sheath required for the saltatory conduction of electrical impulses along axons. Oligodendrocyte loss results in demyelination, which leads to impaired neurological function in a broad array of diseases ranging from pediatric leukodystrophies and cerebral palsy, to multiple sclerosis and white matter stroke. Accordingly, replacing lost oligodendrocytes, whether by transplanting oligodendrocyte progenitor cells (OPCs) or by mobilizing endogenous progenitors, holds great promise as a therapeutic strategy for the diseases of central white matter. In this Primer, we describe the molecular events regulating oligodendrocyte development and how our understanding of this process has led to the establishment of methods for producing OPCs and oligodendrocytes from embryonic stem cells and induced pluripotent stem cells, as well as directly from somatic cells. In addition, we will discuss the safety of engrafted stem cell-derived OPCs, as well as approaches by which to modulate their differentiation and myelinogenesis in vivo following transplantation. PMID- 26628091 TI - Dynamic microRNA-101a and Fosab expression controls zebrafish heart regeneration. AB - Cardiovascular disease is the leading cause of morbidity and mortality in the Western world owing to the limited regenerative capacity of the mammalian cardiovascular system. In lieu of new muscle synthesis, the human heart replaces necrotic tissue with deposition of a noncontractile scar. By contrast, the adult zebrafish is endowed with a remarkable regenerative capacity, capable of de novo cardiomyocyte (CM) creation and scar tissue removal when challenged with an acute injury. In these studies, we examined the contributions of the dynamically regulated microRNA miR-101a during adult zebrafish heart regeneration. We demonstrate that miR-101a expression is rapidly depleted within 3 days post amputation (dpa) but is highly upregulated by 7-14 dpa, before returning to uninjured levels at the completion of the regenerative process. Employing heat inducible transgenic strains and antisense oligonucleotides, we demonstrate that decreases in miR-101a levels at the onset of cardiac injury enhanced CM proliferation. Interestingly, prolonged suppression of miR-101a activity stimulates new muscle synthesis but with defects in scar tissue clearance. Upregulation of miR-101a expression between 7 and 14 dpa is essential to stimulate removal of the scar. Through a series of studies, we identified the proto-oncogene fosab (cfos) as a potent miR-101a target gene, stimulator of CM proliferation, and inhibitor of scar tissue removal. Importantly, combinatorial depletion of fosab and miR-101a activity rescued defects in scar tissue clearance mediated by miR-101a inhibition alone. In summation, our studies indicate that the precise temporal modulation of the miR-101a/fosab genetic axis is crucial for coordinating CM proliferation and scar tissue removal during zebrafish heart regeneration. PMID- 26628090 TI - Morphogen rules: design principles of gradient-mediated embryo patterning. AB - The Drosophila blastoderm and the vertebrate neural tube are archetypal examples of morphogen-patterned tissues that create precise spatial patterns of different cell types. In both tissues, pattern formation is dependent on molecular gradients that emanate from opposite poles. Despite distinct evolutionary origins and differences in time scales, cell biology and molecular players, both tissues exhibit striking similarities in the regulatory systems that establish gene expression patterns that foreshadow the arrangement of cell types. First, signaling gradients establish initial conditions that polarize the tissue, but there is no strict correspondence between specific morphogen thresholds and boundary positions. Second, gradients initiate transcriptional networks that integrate broadly distributed activators and localized repressors to generate patterns of gene expression. Third, the correct positioning of boundaries depends on the temporal and spatial dynamics of the transcriptional networks. These similarities reveal design principles that are likely to be broadly applicable to morphogen-patterned tissues. PMID- 26628092 TI - Cardiac contraction activates endocardial Notch signaling to modulate chamber maturation in zebrafish. AB - Congenital heart disease often features structural abnormalities that emerge during development. Accumulating evidence indicates a crucial role for cardiac contraction and the resulting fluid forces in shaping the heart, yet the molecular basis of this function is largely unknown. Using the zebrafish as a model of early heart development, we investigated the role of cardiac contraction in chamber maturation, focusing on the formation of muscular protrusions called trabeculae. By genetic and pharmacological ablation of cardiac contraction, we showed that cardiac contraction is required for trabeculation through its role in regulating notch1b transcription in the ventricular endocardium. We also showed that Notch1 activation induces expression of ephrin b2a (efnb2a) and neuregulin 1 (nrg1) in the endocardium to promote trabeculation and that forced Notch activation in the absence of cardiac contraction rescues efnb2a and nrg1 expression. Using in vitro and in vivo systems, we showed that primary cilia are important mediators of fluid flow to stimulate Notch expression. Together, our findings describe an essential role for cardiac contraction-responsive transcriptional changes in endocardial cells to regulate cardiac chamber maturation. PMID- 26628094 TI - Src64 controls a novel actin network required for proper ring canal formation in the Drosophila male germline. AB - In many organisms, germ cells develop as cysts in which cells are interconnected via ring canals (RCs) as a result of incomplete cytokinesis. However, the molecular mechanisms of incomplete cytokinesis remain poorly understood. Here, we address the role of tyrosine phosphorylation of RCs in the Drosophila male germline. We uncover a hierarchy of tyrosine phosphorylation within germline cysts that positively correlates with RC age. The kinase Src64 is responsible for mediating RC tyrosine phosphorylation, and loss of Src64 causes a reduction in RC diameter within germline cysts. Mechanistically, we show that Src64 controls an actin network around the RCs that depends on Abl and the Rac/SCAR/Arp2/3 pathway. The actin network around RCs is required for correct RC diameter in cysts of developing germ cells. We also identify that Src64 is required for proper germ cell differentiation in the Drosophila male germline independent of its role in RC regulation. In summary, we report that Src64 controls actin dynamics to mediate proper RC formation during incomplete cytokinesis during germline cyst development in vivo. PMID- 26628095 TI - Stage II differentiated thyroid cancer: A mixed bag. AB - BACKGROUND AND OBJECTIVES: AJCC-TNM Stage II well-differentiated thyroid cancer (WDTC) comprises T2N0M0 tumors in patients >=45 years of age or metastatic WDTC in patients younger than 45 years. The objectives of this study were to assess the oncological outcome of stage II WDTC and to compare the oncological outcome of metastatic WDTC in patient younger (stage II) and older (stage IVC) than 45 years. METHODS: This study involved review of clinical presentation and oncological outcome of population cohort of 2,128 consecutive WDTC, diagnosed during 1970-2010 that includes 215 Stage II WDTC and 61 metastatic WDTC. Cox proportional hazard model was used to assess independent impact of prognostic factors on disease-specific survival (DSS) and disease-free survival (DFS) as calculated by Kaplan-Meier method. RESULTS: Metastatic and non-metastatic stage II WDTC had a 15-year DSS of 41.7% and 96.7%, respectively (P < 0.001). Multivariable analysis showed a 52 times higher risk of death in metastatic stage II WDTC and the DSS of metastatic stage II WDTC was not statistically different from that of stage IVC WDTC. CONCLUSION: Metastatic stage II WDTC is very different from non-metastatic stage II WDTC with oncological outcome similar to stage IVC WDTC. PMID- 26628093 TI - Brg1 coordinates multiple processes during retinogenesis and is a tumor suppressor in retinoblastoma. AB - Retinal development requires precise temporal and spatial coordination of cell cycle exit, cell fate specification, cell migration and differentiation. When this process is disrupted, retinoblastoma, a developmental tumor of the retina, can form. Epigenetic modulators are central to precisely coordinating developmental events, and many epigenetic processes have been implicated in cancer. Studying epigenetic mechanisms in development is challenging because they often regulate multiple cellular processes; therefore, elucidating the primary molecular mechanisms involved can be difficult. Here we explore the role of Brg1 (Smarca4) in retinal development and retinoblastoma in mice using molecular and cellular approaches. Brg1 was found to regulate retinal size by controlling cell cycle length, cell cycle exit and cell survival during development. Brg1 was not required for cell fate specification but was required for photoreceptor differentiation and cell adhesion/polarity programs that contribute to proper retinal lamination during development. The combination of defective cell differentiation and lamination led to retinal degeneration in Brg1-deficient retinae. Despite the hypocellularity, premature cell cycle exit, increased cell death and extended cell cycle length, retinal progenitor cells persisted in Brg1 deficient retinae, making them more susceptible to retinoblastoma. ChIP-Seq analysis suggests that Brg1 might regulate gene expression through multiple mechanisms. PMID- 26628096 TI - Bioluminescent kinase strips: A novel approach to targeted and flexible kinase inhibitor profiling. AB - In addition to target efficacy, drug safety is a major requirement during the drug discovery process and is influenced by target specificity. Therefore, it is imperative that every new drug candidate be profiled against various liability panels that include protein kinases. Here, an effective methodology to streamline kinase inhibitor profiling is described. An accessible standardized profiling system for 112 protein kinases covering all branches of the kinome was developed. This approach consists of creating different sets of kinases and their corresponding substrates in multi-tube strips. The kinase stocks are pre standardized for optimal kinase activity and used for inhibitor profiling using a bioluminescent ADP detection assay. We show that these strips can routinely generate inhibitor selectivity profiles for small or broad kinase family panels. Lipid kinases were also assembled in strip format and profiled together with protein kinases. We identified two specific PI3K inhibitors that have off-target effects on CK2 that were not reported before and would have been missed if compounds were not profiled against lipid and protein kinases simultaneously. To validate the accuracy of the data generated by this method, we confirmed that the inhibition potencies observed are consistent with published values produced by more complex technologies such as radioactivity assays. PMID- 26628097 TI - Aggression in fragile X syndrome. AB - BACKGROUND: Individuals with fragile X syndrome (FXS), especially men, have long been described as presenting with significant behavioural challenges. Despite this known aspect of the phenotype, there has been little research exploring the prevalence, frequency, nature or consequences of aggressive behaviour in FXS. METHODS: This study used survey methodology to gather caregiver reports on the types, frequency and severity of aggressive behaviour in 774 individuals with FXS. RESULTS: Based on caregiver report, nearly all (>90%) male and female individuals were reported to have engaged in some aggression over the previous 12 months, with a third of male cases and slightly fewer than 20% of female cases being described as engaging in moderate to severe aggression or being diagnosed or treated for aggression. Further, aggressive behaviours in male individuals were serious enough that 30% had caused injuries to caregivers and 22% had caused injuries to peers or friends. Sensory issues and hyperactivity were significant predictors of the frequency of aggressive acts, while sensory issues and anxiety were predictive of the severity of aggression. Traditional behaviour management techniques as well as medication was described as the most common and successful treatment options. CONCLUSIONS: Aggressive behaviours are a significant concern for a subsample of both male and female individuals with FXS. Given that sensory concerns were predictive of both the frequency and the severity of aggression suggests these behaviours may be a reactive means of escaping uncomfortable situations. PMID- 26628098 TI - Crystal structure of FadD32, an enzyme essential for mycolic acid biosynthesis in mycobacteria. AB - Fatty acid degradation protein D32 (FadD32), an enzyme required for mycolic acid biosynthesis and essential for mycobacterial growth, has recently been identified as a valid and promising target for anti-tuberculosis drug development. Here we report the crystal structures of Mycobacterium smegmatis FadD32 in the apo and ATP-bound states at 2.4 A and 2.25 A resolution, respectively. FadD32 consists of two globular domains connected by a flexible linker. ATP binds in a cleft at the interface between the N- and C-terminal domains and its binding induces significant local conformational changes in FadD32. The binding sites of meromycolic acid and phosphopantetheine are identified by structural comparison with other members of the adenylating enzyme superfamily. These results will improve our understanding of the catalytic mechanism of FadD32 and help in the design of inhibitors of this essential enzyme. PMID- 26628099 TI - Rhythm and bugs: circadian clocks, gut microbiota, and enteric infections. AB - PURPOSE OF REVIEW: To highlight recent developments in understanding the dynamic relationship between circadian rhythms, the gut microbiome, and gastrointestinal infections. RECENT FINDINGS: In humans and mice, the composition and functions of the intestinal microbiome display diurnal rhythms orchestrated by feeding behaviors and host circadian gene expression. Jet lag, or circadian disruption, perturbs these rhythms to produce gut dysbiosis. When mice are orally infected with Salmonella typhimurium in the morning (the beginning of their rest period) they show higher levels of colonization and gut inflammation vs. infection at other times of day. At the cellular level, recent studies highlight circadian regulation of innate and adaptive gut immunity in coordination with the microbiome, as well as intestinal stem cell growth and regeneration. SUMMARY: Taken together, these reports support a key role for circadian rhythms in regulating the gut microbiome and host responses to gastrointestinal pathogens. Further research is needed to translate these findings to improving outcomes for patients with gastrointestinal infections by guiding the right interventions for the right patients at the right time. PMID- 26628100 TI - Chronic unexplained diarrhea: a logical and cost-effective approach to assessment. AB - PURPOSE OF REVIEW: The workup of chronic unexplained diarrhea can be equally frustrating for care providers and patients. It carries a physical, financial, and social toll. In this review we provide a sensible approach to evaluating and managing chronic diarrhea. RECENT FINDINGS: Bile acid diarrhea is becoming increasingly recognized as a potential cause behind some cases of chronic diarrhea. SUMMARY: A detailed history and physical examination can provide clues that guide a logical approach to the evaluation. We suggest a cost-effective approach to the workup and management of chronic diarrhea based on individual patient factors related to clinical history and physical exam. We find that this approach leads to initiation of treatment in a time-efficient fashion and avoids unnecessary testing. PMID- 26628101 TI - The long-term functional consequences of acute infectious diarrhea. AB - PURPOSE OF REVIEW: The study reviews recent publications that build on previous studies showing that acute enteric infection can produce persistent dysfunction in the lower gut (postinfectious irritable bowel syndrome) and proximal gut (postinfectious functional dyspepsia). The review addresses risk factors, the pathophysiological basis of persistent gut dysfunction, and the factors that initiate and maintain it. RECENT FINDINGS: Recent work has identified several loci of host genetic predisposition to these syndromes that focus attention on host immune responses that may lead to gut dysfunction, including changes in intestinal barrier function and cytokine responses to the initial infection. Human and animal studies identify changes in the serotonergic and cannabinoid pathways regulating visceral pain responses and gut motility. Recent work has also focused attention on the putative role of the intestinal microbiota or dysbiosis in maintaining gut dysfunction and this is reviewed in depth. SUMMARY: The development of long-term consequences following an acute episode of gastroenteritis reflects a convergence of host factors that include genetic predisposition and psychological factors, as well as the development of intestinal dysbiosis. It is anticipated that future research will generate biomarkers of susceptibility as well as novel microbiota-directed preventive and therapeutic strategies. PMID- 26628102 TI - Problems after restorative proctocolectomy: assessment and therapy. AB - PURPOSE OF REVIEW: Restorative proctocolectomy with ileal pouch-anal anastomosis is the surgical treatment of choice for patients with ulcerative colitis or familial adenomatous polyposis who require colectomy. Although the surgical procedure significantly improves the patients' quality of life, complications are common. Mechanical or structural complications related to surgical techniques as well as chronic pouchitis are common after the procedure. RECENT FINDINGS: Recent literature has suggested some of those mechanical complications, along with chronic pouchitis, may share similar risk factors, particularly between anastomotic leak or sinus and chronic pouchitis. Those factors include male gender, obesity, weight gain, and Clostridium difficile infection. SUMMARY: Mounting clinical evidence suggests that ischemia or excessive fat deposition plays an important role in the development of the surgical procedure-associated mechanical complication as well as chronic antibiotic-refractory pouchitis. Those findings along with the theory of ischemia/fat deposition will shed some light on the pathogenesis of the complex pouch disorders, providing the guidance for the risk stratification, prevention, diagnosis, and management. PMID- 26628103 TI - Advances in colonic disease: some light at the end of the tunnel at the end of the light! PMID- 26628104 TI - What Role do Hurricanes Play in Sediment Delivery to Subsiding River Deltas? AB - The Mississippi River Delta (MRD) has undergone tremendous land loss over the past century due to natural and anthropogenic influences, a fate shared by many river deltas globally. A globally unprecedented effort to restore and sustain the remaining subaerial portions of the delta is now underway, an endeavor that is expected to cost $50-100B over the next 50 yr. Success of this effort requires a thorough understanding of natural and anthropogenic controls on sediment supply and delta geomorphology. In the MRD, hurricanes have been paradoxically identified as both substantial agents of widespread land loss, and vertical marsh sediment accretion. We present the first multi-decadal chronostratigraphic assessment of sediment supply for a major coastal basin of the MRD that assesses both fluvial and hurricane-induced contributions to sediment accumulation in deltaic wetlands. Our findings indicate that over multidecadal timescales, hurricane-induced sediment delivery may be an important contributor for deltaic wetland vertical accretion, but the contribution from hurricanes to long-term sediment accumulation is substantially less than sediment delivery supplied by existing and planned river-sediment diversions at present-day river-sediment loads. PMID- 26628105 TI - Time-dependent miR-16 serum fluctuations together with reciprocal changes in the expression level of miR-16 in mesocortical circuit contribute to stress resilient phenotype in chronic mild stress - An animal model of depression. AB - MicroRNAs (miRNAs) are involved in stress-related pathologies. However, the molecular mechanisms underlying stress resilience are elusive. Using chronic mild stress (CMS), an animal model of depression, we identified animals exhibiting a resilient phenotype. We investigated serum levels of corticosterone, melatonin and 376 mature miRNAs to find peripheral biomarkers associated with the resilient phenotype. miR-16, selected during screening step, was assayed in different brain regions in order to find potential relationship between brain and peripheral alterations in response to stress. Two CMS experiments that lasted for 2 and 7 consecutive weeks were performed. During both CMS procedures, sucrose consumption levels were significantly decreased in anhedonic-like animals (p<0.0001) compared with unstressed animals, whereas the drinking profiles of resilient rats did not change despite the rats being stressed. Serum corticosterone measurements indicated that anhedonic-like animals had blunted hypothalamic-pituitary-adrenal (HPA) axis activity, whereas resilient animals exhibited dynamic responses to stress. miRNA profiling revealed that resilient animals had elevated serum levels of miR-16 after 7 weeks of CMS (adjusted p-value<0.007). Moreover, resilient animals exhibited reciprocal changes in miR-16 expression level in mesocortical pathway after 2 weeks of CMS (p<0.008). A bioinformatic analysis showed that miR 16 regulates genes involved in the functioning of the nervous system in both humans and rodents. Resilient animals can actively cope with stress on a biochemical level and miR-16 may contribute to a "stress-resistant" behavioral phenotype by pleiotropic modulation of the expression of genes involved in the function of the nervous system. PMID- 26628106 TI - Role of the endocannabinoid 2-arachidonoylglycerol in aversive responses mediated by the dorsolateral periaqueductal grey. AB - 2-arachidonoylglycerol (2-AG) is an endogenous ligand of the cannabinoid CB1 receptor. This endocannabinoid and its hydrolyzing enzyme, monoacylglycerol lipase (MAGL), are present in encephalic regions related to psychiatric disorders, including the midbrain dorsolateral periaqueductal grey (dlPAG). The dlPAG is implicated in panic disorder and its stimulation results in defensive responses proposed as a model of panic attacks. The present work verified if facilitation of 2-AG signalling in the dlPAG counteracts panic-like responses induced by local chemical stimulation. Intra-dlPAG injection of 2-AG prevented panic-like response induced by the excitatory amino acid N-methyl-d-aspartate (NMDA). This effect was mimicked by the 2-AG hydrolysis inhibitor (MAGL preferring inhibitor) URB602. The anti-aversive effect of URB602 was reversed by the CB1 receptor antagonist, AM251. Additionally, a combination of sub-effective doses of 2-AG and URB602 also prevented NMDA-induced panic-like response. Finally, immunofluorescence assay showed a significant increase in c-Fos positive cells in the dlPAG after local administration of NMDA. This response was also prevented by URB602. These data support the hypothesis that 2-AG participates in anti-aversive mechanisms in the dlPAG and reinforce the proposal that facilitation of endocannabinoid signalling could be a putative target for developing additional treatments against panic and other anxiety-related disorders. PMID- 26628107 TI - Developmental pathways from prenatal tobacco and stress exposure to behavioral disinhibition. AB - Prenatal tobacco exposure (PTE) and prenatal stress exposure (PSE) both have been linked to externalizing behavior, although their effects generally have been considered in isolation. Here, we aimed to characterize the joint or interactive roles of PTE and PSE in early developmental pathways to behavioral disinhibition, a profile of cognitive and behavioral under-control that presages severe externalizing behavior. As part of a prospective, longitudinal study, 296 children were assessed at a mean age of 5 years. Exposures were assessed via repeated interviews across the prenatal period and bioassays of cotinine were obtained. Behavioral disinhibition was assessed using temperament measures in infancy, performance-based executive control tasks and measures of disruptive and inattentive behavior. PSE was associated with a higher probability of difficult temperament in infancy. Each exposure independently predicted poorer executive control at age 5 years. Difficult temperament and executive control difficulties in turn predicted elevated levels of disruptive behavior, although links from PTE and PSE to parent-reported attention problems were less robust. Children who experienced these prenatal exposures in conjunction with higher postnatal stress exposure showed the lowest executive control and highest levels of disruptive behavior. Findings highlight the compounding adverse impact of PTE and PSE on children's behavioral trajectories. Given their high concordance, prenatal health campaigns should target these exposures in tandem. PMID- 26628108 TI - CREB-binding protein regulates lung cancer growth by targeting MAPK and CPSF4 signaling pathway. AB - CBP (CREB-binding protein) is a transcriptional co-activator which possesses HAT (histone acetyltransferases) activity and participates in many biological processes, including embryonic development, growth control and homeostasis. However, its roles and the underlying mechanisms in the regulation of carcinogenesis and tumor development remain largely unknown. Here we investigated the molecular mechanisms and potential targets of CBP involved in tumor growth and survival in lung cancer cells. Elevated expression of CBP was detected in lung cancer cells and tumor tissues compared to the normal lung cells and tissues. Knockdown of CBP by siRNA or inhibition of its HAT activity using specific chemical inhibitor effectively suppressed cell proliferation, migration and colony formation and induced apoptosis in lung cancer cells by inhibiting MAPK and activating cytochrome C/caspase-dependent signaling pathways. Co immunoprecipitation and immunofluorescence analyses revealed the co-localization and interaction between CBP and CPSF4 (cleavage and polyadenylation specific factor 4) proteins in lung cancer cells. Knockdown of CPSF4 inhibited hTERT transcription and cell growth induced by CBP, and vice versa, demonstrating the synergetic effect of CBP and CPSF4 in the regulation of lung cancer cell growth and survival. Moreover, we found that high expression of both CBP and CPSF4 predicted a poor prognosis in the patients with lung adenocarcinomas. Collectively, our results indicate that CBP regulates lung cancer growth by targeting MAPK and CPSF4 signaling pathways. PMID- 26628110 TI - Serum bisphenol A as a predictor of chronic kidney disease progression in primary hypertension: a 6-year prospective study. AB - OBJECTIVE: Hypertensive nephropathy is one of the major causes of chronic kidney disease (CKD). Bisphenol A (BPA) is associated with elevated blood pressure and urinary albuminuria. The aim of this study is to evaluate the association between serum BPA with the progression of CKD in patients with primary hypertension. METHODS: In this prospective study, 302 patients with primary hypertension were followed up for 6 years (195 men and 107 women, 65.29 +/- 9.78 years at baseline). The baseline values of serum BPA were measured. Renal function was measured as estimated glomerular filtration rate (eGFR) calculated by the Chronic Kidney Disease Epidemiology Collaboration creatinine-cystatin C equation (eGFRcr cys). Regression models were used to calculate associations of serum BPA with the annual change in eGFR and the risk of CKD progression. RESULTS: Baseline serum BPA concentration was 0.61(0.26, 2.44) ng/ml and was significantly negatively correlated with the annual change in eGFR (R = -0.197, P < 0.001). After adjusting for clinical factors, baseline serum BPA level had a significant negative association with the annual change in eGFR (beta = -0.132, P = 0.007). Univariate logistic regression analysis showed that the baseline age, SBP, eGFR, and serum BPA levels were predictors of CKD stage 3 or greater. In multivariate logistic regression analysis, patients with high serum BPA levels exhibited a five-fold increased risk of developing CKD stage 3 or greater compared with patients with low serum BPA levels [odds ratio 4.79 (95% confidence interval 1.81, 14.25), P = 0.004]. CONCLUSION: Serum BPA may be a predictor of CKD progression in patients with primary hypertension. PMID- 26628109 TI - Adverse effect of diabetes and hyperglycaemia on arterial stiffness in Europeans, South Asians, and African Caribbeans in the SABRE study. AB - OBJECTIVES: Ethnic minority groups in the U.K. experience marked differences in cardiovascular disease risk. We investigated differences in arterial central haemodynamics, stiffness, and load in a tri-ethnic population-based cohort. METHODS: A total of 1312 participants (70 +/- 6 years) underwent echocardiography and measurement of brachial and central blood pressure to assess central arterial haemodynamics including central pulse pressure (cPP), arterial stiffness [cPP/stroke volume (SV)], systemic vascular resistance (SVR), and load (Ea). RESULTS: Brachial and central SBPs were similar in all ethnic groups. Compared with Europeans, cPP, cPP/SV, and Ea were higher in South Asians. In contrast, cPP/SV was lower in African Caribbeans despite higher mean arterial pressure, higher SVR, and higher diabetes prevalence. cPP/SV and Ea remained significantly higher in South Asians and significantly lower in African Caribbeans after multivariate adjustment. Diabetes and higher HbA1c were more strongly associated with higher cPP/SV in South Asians than in Europeans (Pinteraction = 0.045 and 0.005, respectively); higher HbA1c was also more strongly associated with increased Ea in South Asians than Europeans (Pinteraction = 0.01). There was no evidence of an interaction between glycaemia and cPP/SV in African Caribbeans. CONCLUSIONS: Compared with Europeans, South Asians have unfavorable arterial function. Diabetes and hyperglycaemia have a more deleterious effect on cPP/SV and Ea in South Asians. In contrast, African Caribbeans have more favourable arterial function than Europeans and South Asians. These differences may contribute to the differential ethnic rates of cardiovascular disease. PMID- 26628111 TI - Threat and the Body: How the Heart Supports Fear Processing. AB - Mental processes depend upon a dynamic integration of brain and body. Emotions encompass internal physiological changes which, through interoception (sensing bodily states), underpin emotional feelings, for example, cardiovascular arousal can intensify feelings of fear and anxiety. The brain is informed about how quickly and strongly the heart is beating by signals from arterial baroreceptors. These fire in bursts after each heartbeat, and are quiet between heartbeats. The processing of fear stimuli is selectively enhanced by these phasic signals, and these inhibit the processing of other types of stimuli including physical pain. Behavioural and neuroimaging studies detail this differential impact of heart signals on the processing of salient stimuli, and add to knowledge linking rhythmic activity in brain and body to perceptual consciousness. PMID- 26628113 TI - Corrigendum. PMID- 26628114 TI - Retraction. PMID- 26628112 TI - Ethological Action Maps: A Paradigm Shift for the Motor Cortex. AB - The map of the body in the motor cortex is one of the most iconic images in neuroscience. The map, however, is not perfect. It contains overlaps, reversals, and fractures. The complex pattern suggests that a body plan is not the only organizing principle. Recently a second organizing principle was discovered: an action map. The motor cortex appears to contain functional zones, each of which emphasizes an ethologically relevant category of behavior. Some of these complex actions can be evoked by cortical stimulation. Although the findings were initially controversial, interest in the ethological action map has grown. Experiments on primates, mice, and rats have now confirmed and extended the earlier findings with a range of new methods. PMID- 26628115 TI - Improving the counting efficiency in time-correlated single photon counting experiments by dead-time optimization. AB - Time-Correlated Single Photon Counting (TCSPC) has been long recognized as the most sensitive method for fluorescence lifetime measurements, but often requiring "long" data acquisition times. This drawback is related to the limited counting capability of the TCSPC technique, due to pile-up and counting loss effects. In recent years, multi-module TCSPC systems have been introduced to overcome this issue. Splitting the light into several detectors connected to independent TCSPC modules proportionally increases the counting capability. Of course, multi-module operation also increases the system cost and can cause space and power supply problems. In this paper, we propose an alternative approach based on a new detector and processing electronics designed to reduce the overall system dead time, thus enabling efficient photon collection at high excitation rate. We present a fast active quenching circuit for single-photon avalanche diodes which features a minimum dead time of 12.4 ns. We also introduce a new Time-to Amplitude Converter (TAC) able to attain extra-short dead time thanks to the combination of a scalable array of monolithically integrated TACs and a sequential router. The fast TAC (F-TAC) makes it possible to operate the system towards the upper limit of detector count rate capability (~80 Mcps) with reduced pile-up losses, addressing one of the historic criticisms of TCSPC. Preliminary measurements on the F-TAC are presented and discussed. PMID- 26628116 TI - Three-parameter error analysis method based on rotating coordinates in rotating birefringent polarizer system. AB - We propose error analysis using a rotating coordinate system with three parameters of linearly polarized light--incidence angle, azimuth angle on the front surface, and angle between the incidence and vibration planes--and demonstrate the method on a rotating birefringent prism system. The transmittance and angles are calculated plane-by-plane using a birefringence ellipsoid model and the final transmitted intensity equation is deduced. The effects of oblique incidence, light interference, beam convergence, and misalignment of the rotation and prism axes are discussed. We simulate the entire error model using MATLAB and conduct experiments based on a built polarimeter. The simulation and experimental results are consistent and demonstrate the rationality and validity of this method. PMID- 26628117 TI - Measurement of colloidal phenomena during flow through refractive index matched porous media. AB - Colloidal phenomena in porous media, natural or engineered, are important in a breadth of science and technology applications, but fundamental understanding is hampered by the difficulty in measuring colloid deposit morphology in situ. To partially address this need, this paper describes a static light scattering apparatus using a flow cell filled with refractive index matched (RIM) porous media, allowing real-time measurement of colloidal phenomena as a function of depth within the flow cell. A laser interacts with the colloids in the pore space and their structures, but not with the RIM media. The intensity of scattered light is measured as a function of scattering angle, which allows characterization of colloid deposit morphology as a fractal dimension and a radius of gyration. In parallel, fluid discharge rate and pressure drop are recorded to determine permeability, a key parameter for any application involving flow through porous media. This apparatus should prove useful in any application requiring characterization of colloidal phenomena within porous media. Additionally, this paper describes how to use granular Nafion as RIM porous media. PMID- 26628118 TI - Modulation index optimization for optical fringe suppression in wavelength modulation spectroscopy. AB - Optical fringes constitute one of the major obstacles in the gas detection based on wavelength modulation spectroscopy (WMS). In order to suppress optical fringes, a convenient method of modulation index optimization was presented, using the signal-fringe ratio as a criterion. In addition to suppressing optical fringes, the optimized modulation index enables the detection of gas absorption. This method was demonstrated in a WMS based oxygen sensor. By comparing the sensor performances with and without the use of the optimized modulation index, we showed that the optical fringes are reduced by using the optimized modulation index; furthermore, the system stability and detection limit are improved. More specifically, the long-term fluctuation of the sensor measurement is dramatically reduced by a factor of 8, and a detection limit of as low as 120 ppm (with effective optical path length of 32 cm and integral time of 2.6 s), characterized by the Allan variance, was derived. This method can be applied in other existing WMS systems without the need for additional devices or complex algorithms and has the potential to be used in both laboratory and industrial settings. PMID- 26628119 TI - Characterization of a detector chain using a FPGA-based time-to-digital converter to reconstruct the three-dimensional coordinates of single particles at high flux. AB - We report on the development of a novel FPGA-based time-to-digital converter and its implementation in a detection chain that records the coordinates of single particles along three dimensions. The detector is composed of micro-channel plates mounted on top of a cross delay line and connected to fast electronics. We demonstrate continuous recording of the timing signals from the cross delay line at rates up to 4.1 * 10(6) s(-1) and three-dimensional reconstruction of the coordinates up to 3.2 * 10(6) particles per second. From the imaging of a calibrated structure we measure the in-plane resolution of the detector to be 140(20) MUm at a flux of 3 * 10(5) particles per second. In addition, we analyze a method to estimate the resolution without placing any structure under vacuum, a significant practical improvement. While we use UV photons here, the results of this work apply to the detection of other kinds of particles. PMID- 26628120 TI - Self-referenced spectral interferometry for single-shot measurement of sub-5-fs pulses. AB - We demonstrate a novel approach for the extension of self-referenced spectral interferometry to the temporal characterization of few-optical cycle pulses. The new experimental setup is characterized by low dispersion and a collinear geometry. 4-fs pulses have been characterized by performing single-shot measurements, with high dynamic range on a broad temporal region. An independent measurement of the pulse duration, obtained by using attosecond streaking, allowed us to cross-check the experimental technique. PMID- 26628121 TI - Spectrometer for shot-to-shot photon energy characterization in the multi-bunch mode of the free electron laser at Hamburg. AB - The setup and first results from commissioning of a fast online photon energy spectrometer for the vacuum ultraviolet free electron laser at Hamburg (FLASH) at DESY are presented. With the use of the latest advances in detector development, the presented spectrometer reaches readout frequencies up to 1 MHz. In this paper, we demonstrate the ability to record online photon energy spectra on a shot-to-shot base in the multi-bunch mode of FLASH. Clearly resolved shifts in the mean wavelength over the pulse train as well as shot-to-shot wavelength fluctuations arising from the statistical nature of the photon generating self amplified spontaneous emission process have been observed. In addition to an online tool for beam calibration and photon diagnostics, the spectrometer enables the determination and selection of spectral data taken with a transparent experiment up front over the photon energy of every shot. This leads to higher spectral resolutions without the loss of efficiency or photon flux by using single-bunch mode or monochromators. PMID- 26628122 TI - Polarization-dependent differential reflectance spectroscopy for real-time monitoring of organic thin film growth. AB - By monitoring the reflectance of a sample surface during deposition of a thin organic film, one can obtain information with submonolayer resolution in real time. A special kind of optical spectroscopy is Differential Reflectance Spectroscopy (DRS), which compares the reflectance before and during deposition of a thin film or any other change of the surface optical properties. In this work, we present an extended DRS setup that allows monitoring simultaneously both linear polarization states (s and p) of the reflected light. We implement polarization-dependent DRS to monitor the growth of perflouropentacene thin films on a Ag(110) single crystal. The setup allows us to deduce the optical anisotropy of the sample and, in particular, the preferred orientation of the molecules on the surface. PMID- 26628123 TI - Studies on space charge neutralization and emittance measurement of beam from microwave ion source. AB - A 2.45 GHz microwave ion source together with a beam transport system has been developed at VECC to study the problems related with the injection of high current beam into a compact cyclotron. This paper presents the results of beam profile measurement of high current proton beam at different degrees of space charge neutralisation with the introduction of neon gas in the beam line using a fine leak valve. The beam profiles have been measured at different pressures in the beam line by capturing the residual gas fluorescence using a CCD camera. It has been found that with space charge compensation at the present current level (~5 mA at 75 keV), it is possible to reduce the beam spot size by ~34%. We have measured the variation of beam profile as a function of the current in the solenoid magnet under the neutralised condition and used these data to estimate the rms emittance of the beam. Simulations performed using equivalent Kapchinsky Vladimirsky beam envelope equations with space charge neutralization factor are also presented to interpret the experimental results. PMID- 26628124 TI - Non-destructive single-pass low-noise detection of ions in a beamline. AB - We have conceived, built, and operated a device for the non-destructive single pass detection of charged particles in a beamline. The detector is based on the non-resonant pick-up and subsequent low-noise amplification of the image charges induced in a cylindrical electrode surrounding the particles' beam path. The first stage of the amplification electronics is designed to be operated from room temperature down to liquid helium temperature. The device represents a non destructive charge counter as well as a sensitive timing circuit. We present the concept and design details of the device. We have characterized its performance and show measurements with low-energy highly charged ions (such as Ar(13+)) passing through one of the electrodes of a cylindrical Penning trap. This work demonstrates a novel approach of non-destructive, low noise detection of charged particles which is, depending on the bunch structure, suitable, e.g., for ion traps, low-energy beamlines or accelerator transfer sections. PMID- 26628125 TI - High current density ion beam obtained by a transition to a highly focused state in extremely low-energy region. AB - A high current density (~3 mA/cm(2)) hydrogen ion beam source operating in an extremely low-energy region (E(ib) ~ 150-200 eV) has been realized by using a transition to a highly focused state, where the beam is extracted from the ion source chamber through three concave electrodes with nominal focal lengths of ~350 mm. The transition occurs when the beam energy exceeds a threshold value between 145 and 170 eV. Low-level hysteresis is observed in the transition when E(ib) is being reduced. The radial profiles of the ion beam current density and the low temperature ion current density can be obtained separately using a Faraday cup with a grid in front. The measured profiles confirm that more than a half of the extracted beam ions reaches the target plate with a good focusing profile with a full width at half maximum of ~3 cm. Estimation of the particle balances in beam ions, the slow ions, and the electrons indicates the possibility that the secondary electron emission from the target plate and electron impact ionization of hydrogen may play roles as particle sources in this extremely low energy beam after the compensation of beam ion space charge. PMID- 26628126 TI - Study of imaging plate detector sensitivity to 5-18 MeV electrons. AB - Imaging plates (IPs) are commonly used as passive detectors in laser-plasma experiments. We calibrated at the ELSA electron beam facility (CEA DIF) the five different available types of IPs (namely, MS-SR-TR-MP-ND) to electrons from 5 to 18 MeV. In the context of diagnostic development for the PETawatt Aquitaine Laser (PETAL), we investigated the use of stacks of IP in order to increase the detection efficiency and get detection response independent from the neighboring materials such as X-ray shielding and detector supports. We also measured fading functions in the time range from a few minutes up to a few days. Finally, our results are systematically compared to GEANT4 simulations in order to provide a complete study of the IP response to electrons over the energy range relevant for PETAL experiments. PMID- 26628127 TI - Beam emittance reduction during operation of Indus-2. AB - Indus-2 storage ring is a 2.5 GeV third generation synchrotron radiation source. This source was commissioned using a moderate optics. Beam injection was accomplished using an off momentum electron beam to avoid difficulties faced in storage of beam at 550 MeV. The injection procedure and relevant beam dynamical studies are discussed. The switch over from the moderate optics to low emittance optics is done at 2.5 GeV after storing the electron beam. The procedure evolved to reduce the beam emittance and its implementation during the operation is discussed. PMID- 26628128 TI - Generation of neutral atomic beams utilizing photodetachment by high power diode laser stacks. AB - We demonstrate the use of high power diode laser stacks to photodetach fast hydrogen and carbon anions and produce ground term neutral atomic beams. We achieve photodetachment efficiencies of ~7.4% for H(-) at a beam energy of 10 keV and ~3.7% for C(-) at 28 keV. The diode laser systems used here operate at 975 nm and 808 nm, respectively, and provide high continuous power levels of up to 2 kW, without the need of additional enhancements like optical cavities. The alignment of the beams is straightforward and operation at constant power levels is very stable, while maintenance is minimal. We present a dedicated photodetachment setup that is suitable to efficiently neutralize the majority of stable negative ions in the periodic table. PMID- 26628129 TI - Ion angle distribution measurement with a planar retarding field analyzer. AB - A new technique is presented to measure the angular distribution of plasma ions bombarding the substrate surface with a planar retarding field analyzer. By varying the effective aspect ratio of the analyzer's aperture, ions with different angular spread that are allowed through the device for detection are controlled. The analytical theory developed to define the ion current as a function of incident ion angle, ion energy, aperture geometry, and aspect ratio is shown. The method used to vary the effective aspect ratio of the aperture is also discussed. The mathematical theory is derived and the numerical solution discussed. Ion energy distributions, as a function of ion angle, with resolution as low as 3 degrees can be measured. PMID- 26628130 TI - Real time capable infrared thermography for ASDEX Upgrade. AB - Infrared (IR) thermography is widely used in fusion research to study power exhaust and incident heat load onto the plasma facing components. Due to the short pulse duration of today's fusion experiments, IR systems have mostly been designed for off-line data analysis. For future long pulse devices (e.g., Wendelstein 7-X, ITER), a real time evaluation of the target temperature and heat flux is mandatory. This paper shows the development of a real time capable IR system for ASDEX Upgrade. A compact IR camera has been designed incorporating the necessary magnetic and electric shielding for the detector, cooler assembly. The camera communication is based on the Camera Link industry standard. The data acquisition hardware is based on National Instruments hardware, consisting of a PXIe chassis inside and a fibre optical connected industry computer outside the torus hall. Image processing and data evaluation are performed using real time LabVIEW. PMID- 26628131 TI - Dusty Plasma Experimental (DPEx) device for complex plasma experiments with flow. AB - A versatile table-top dusty plasma experimental device to study flow induced excitations of linear and nonlinear waves/structures in a complex plasma is presented. In this Pi-shaped apparatus, a DC glow discharge plasma is produced between a disc shaped anode and a grounded long cathode tray by applying a high voltage DC in the background of a neutral gas (argon) and subsequently a dusty plasma is created by introducing micron sized dust particles that get charged and levitated in the sheath region. A flow of the dust particles is induced in a controlled manner by adjusting the pumping speed and the gas flow rate into the device. A full characterisation of the plasma, using Langmuir and emissive probe data, and that of the dusty plasma using particle tracking data with the help of an idl based (super) Particle Identification and Tracking (sPIT) code is reported. Experimental results on the variation of the dust flow velocity as a function of the neutral pressure and the gas flow rate are given. The neutral drag force acting on the particles and the Epstein coefficient are estimated from the initial acceleration of the particles. The potential experimental capabilities of the device for conducting fundamental studies of flow induced instabilities are discussed. PMID- 26628132 TI - A near infra-red video system as a protective diagnostic for electron cyclotron resonance heating operation in the Wendelstein 7-X stellarator. AB - The Wendelstein 7-X stellarator is a large nuclear fusion device based at Max Planck-Institut fur Plasmaphysik in Greifswald in Germany. The main plasma heating system for steady state operation in W7-X is electron cyclotron resonance heating (ECRH). During operation, part of plama facing components will be directly heated by the non-absorbed power of 1 MW rf beams of ECRH. In order to avoid damages of such components made of graphite tiles during the first operational phase, a near infra-red video system has been developed as a protective diagnostic for safe and secure ECRH operation. Both the mechanical design housing the camera and the optical system are very flexible and respect the requirements of steady state operation. The full system including data acquisition and control system has been successfully tested in the vacuum vessel, including on-line visualization and data storage of the four cameras equipping the ECRH equatorial launchers of W7-X. PMID- 26628133 TI - Understanding reliability and some limitations of the images and spectra reconstructed from a multi-monochromatic x-ray imager. AB - Temperature and density asymmetry diagnosis is critical to advance inertial confinement fusion (ICF) science. A multi-monochromatic x-ray imager (MMI) is an attractive diagnostic for this purpose. The MMI records the spectral signature from an ICF implosion core with time resolution, 2-D space resolution, and spectral resolution. While narrow-band images and 2-D space-resolved spectra from the MMI data constrain temperature and density spatial structure of the core, the accuracy of the images and spectra depends not only on the quality of the MMI data but also on the reliability of the post-processing tools. Here, we synthetically quantify the accuracy of images and spectra reconstructed from MMI data. Errors in the reconstructed images are less than a few percent when the space-resolution effect is applied to the modeled images. The errors in the reconstructed 2-D space-resolved spectra are also less than a few percent except those for the peripheral regions. Spectra reconstructed for the peripheral regions have slightly but systematically lower intensities by ~6% due to the instrumental spatial-resolution effects. However, this does not alter the relative line ratios and widths and thus does not affect the temperature and density diagnostics. We also investigate the impact of the pinhole size variation on the extracted images and spectra. A 10% pinhole size variation could introduce spatial bias to the images and spectra of ~10%. A correction algorithm is developed, and it successfully reduces the errors to a few percent. It is desirable to perform similar synthetic investigations to fully understand the reliability and limitations of each MMI application. PMID- 26628134 TI - Technique for fabrication of ultrathin foils in cylindrical geometry for liner plasma implosion experiments with sub-megaampere currents. AB - In this work, we describe a technique for fabricating ultrathin foils in cylindrical geometry for liner-plasma implosion experiments using sub-MA currents. Liners are formed by wrapping a 400 nm, rectangular strip of aluminum foil around a dumbbell-shaped support structure with a non-conducting center rod, so that the liner dimensions are 1 cm in height, 6.55 mm in diameter, and 400 nm in thickness. The liner-plasmas are imploded by discharging ~600 kA with ~200 ns rise time using a 1 MA linear transformer driver, and the resulting implosions are imaged four times per shot using laser-shadowgraphy at 532 nm. This technique enables the study of plasma implosion physics, including the magneto Rayleigh Taylor, sausage, and kink instabilities on initially solid, imploding metallic liners with university-scale pulsed power machines. PMID- 26628135 TI - Robust regression with CUDA and its application to plasma reflectometry. AB - In many applications, especially those involving scientific instrumentation data with a large experimental error, it is often necessary to carry out linear regression in the presence of severe outliers which may adversely affect the results. Robust regression methods do exist, but they are much more computationally intensive, making it difficult to apply them in real-time scenarios. In this work, we resort to graphics processing unit (GPU)-based computing to carry out robust regression in a time-sensitive application. We illustrate the results and the performance gains obtained by parallelizing one of the most common robust regression methods, namely, least median of squares. Although the method has a complexity of O(n(3)logn), with GPU computing, it is possible to accelerate it to the point that it becomes usable within the required time frame. In our experiments, the input data come from a plasma diagnostic system installed at Joint European Torus, the largest fusion experiment in Europe, but the approach can be easily transferred to other applications. PMID- 26628136 TI - Diagnosing x-ray power and energy of tungsten wire array z-pinch with a flat spectral response x-ray diode. AB - Fast z-pinch is a very efficient way of converting electromagnetic energy to radiation. With an 8-10 MA current on primary test stand facility, about 1 MJ electromagnetic energy is delivered to vacuum chamber, which heats z-pinch plasma to radiate soft x-ray. To develop a pulsed high power x-ray source, we studied the applicability of diagnosing x-ray power from tungsten wire array z-pinch with a flat spectral response x-ray diode (FSR-XRD). The detector was originally developed to diagnose radiation of a hohlraum in SG-III prototype laser facility. It utilized a gold cathode XRD and a specially configured compound gold filter to yield a nearly flat spectral response in photon energy range of 0.1-4 keV. In practice, it was critical to avoid surface contamination of gold cathode. It is illustrated that an exposure of an XRD to multiple shots caused a significant change of response. Thus, in diagnosing x-ray power and energy, we used each XRD in only one shot after calibration. In a shot serial, output of FSR-XRD was compared with output of a nickel bolometer. In these shots, the outputs agreed with each other within their uncertainties which were about 12% for FSR-XRD and about 15% for bolometer. Moreover, the ratios between the FSR-XRD and the bolometer among different shots were explored. In 8 shots, the standard deviation of the ratio was 6%. It is comparable to XRD response change of 7%. PMID- 26628137 TI - Low energy, high power hydrogen neutral beam for plasma heating. AB - A high power, relatively low energy neutral beam injector was developed to upgrade of the neutral beam system of the gas dynamic trap device and C2-U experiment. The ion source of the injector produces a proton beam with the particle energy of 15 keV, current of up to 175 A, and pulse duration of a few milliseconds. The plasma emitter of the ion source is produced by superimposing highly ionized plasma jets from an array of four arc-discharge plasma generators. A multipole magnetic field produced with permanent magnets at the periphery of the plasma box is used to increase the efficiency and improve the uniformity of the plasma emitter. Multi-slit grids with 48% transparency are fabricated from bronze plates, which are spherically shaped to provide geometrical beam focusing. The focal length of the Ion Optical System (IOS) is 3.5 m and the initial beam diameter is 34 cm. The IOS geometry and grid potentials were optimized numerically to ensure accurate beam formation. The measured angular divergences of the beam are +/-0.01 rad parallel to the slits and +/-0.03 rad in the transverse direction. PMID- 26628138 TI - Dynamic granularity of imaging systems. AB - Imaging systems that include a specific source, imaging concept, geometry, and detector have unique properties such as signal-to-noise ratio, dynamic range, spatial resolution, distortions, and contrast. Some of these properties are inherently connected, particularly dynamic range and spatial resolution. It must be emphasized that spatial resolution is not a single number but must be seen in the context of dynamic range and consequently is better described by a function or distribution. We introduce the "dynamic granularity" G(dyn) as a standardized, objective relation between a detector's spatial resolution (granularity) and dynamic range for complex imaging systems in a given environment rather than the widely found characterization of detectors such as cameras or films by themselves. This relation can partly be explained through consideration of the signal's photon statistics, background noise, and detector sensitivity, but a comprehensive description including some unpredictable data such as dust, damages, or an unknown spectral distribution will ultimately have to be based on measurements. Measured dynamic granularities can be objectively used to assess the limits of an imaging system's performance including all contributing noise sources and to qualify the influence of alternative components within an imaging system. This article explains the construction criteria to formulate a dynamic granularity and compares measured dynamic granularities for different detectors used in the X-ray backlighting scheme employed at Sandia's Z-Backlighter facility. PMID- 26628139 TI - Electrostatic microprobe for determining charge domains on surfaces. AB - An electrostatic microprobe was developed to measure charge on wipes and various test surfaces. The device is constructed on an optical microscope platform utilizing a computer controlled XY stage. Test surfaces can be optically imaged to identify microscopic features that can be correlated to the measured charge domain maps. The ultimate goal is to quantify charge on wipe cloths to determine the influence of electrostatic forces on wipe sampling efficiency. We found that certain wipe materials do not extensively charge while others accumulate charge by making contact with other surfaces (through the triboelectric effect). Charge domains are found to be nonuniform. PMID- 26628140 TI - A miniaturized, high frequency mechanical scanner for high speed atomic force microscope using suspension on dynamically determined points. AB - One of the major limitations in the speed of the atomic force microscope (AFM) is the bandwidth of the mechanical scanning stage, especially in the vertical (z) direction. According to the design principles of "light and stiff" and "static determinacy," the bandwidth of the mechanical scanner is limited by the first eigenfrequency of the AFM head in case of tip scanning and by the sample stage in terms of sample scanning. Due to stringent requirements of the system, simply pushing the first eigenfrequency to an ever higher value has reached its limitation. We have developed a miniaturized, high speed AFM scanner in which the dynamics of the z-scanning stage are made insensitive to its surrounding dynamics via suspension of it on specific dynamically determined points. This resulted in a mechanical bandwidth as high as that of the z-actuator (50 kHz) while remaining insensitive to the dynamics of its base and surroundings. The scanner allows a practical z scan range of 2.1 MUm. We have demonstrated the applicability of the scanner to the high speed scanning of nanostructures. PMID- 26628141 TI - A hybrid continuous-wave terahertz imaging system. AB - A hybrid (active-passive mode) terahertz (THz) imaging system and an algorithm for imaging synthesis are proposed to enhance the THz image quality. The concept of image contrast is used to compare active and passive THz imaging. Combining the measurement of the self-emitted radiation of the object with the back scattered source radiation measurement, it becomes possible to use the THz image to retrieve maximum information about the object. The experimental results confirm the advantages of hybrid THz imaging systems, which can be generalized for a wide range of applications in the material sciences, chemical physics, bio systems, etc. PMID- 26628142 TI - Development of an in situ temperature stage for synchrotron X-ray spectromicroscopy. AB - In situ characterization of micro- and nanoscale defects in polycrystalline thin film materials is required to elucidate the physics governing defect formation and evolution during photovoltaic device fabrication and operation. X-ray fluorescence spectromicroscopy is particularly well-suited to study defects in compound semiconductors, as it has a large information depth appropriate to study thick and complex materials, is sensitive to trace amounts of atomic species, and provides quantitative elemental information, non-destructively. Current in situ methods using this technique typically require extensive sample preparation. In this work, we design and build an in situ temperature stage to study defect kinetics in thin-film solar cells under actual processing conditions, requiring minimal sample preparation. Careful selection of construction materials also enables controlled non-oxidizing atmospheres inside the sample chamber such as H2Se and H2S. Temperature ramp rates of up to 300 degrees C/min are achieved, with a maximum sample temperature of 600 degrees C. As a case study, we use the stage for synchrotron X-ray fluorescence spectromicroscopy of CuIn(x)Ga(1-x)Se2 (CIGS) thin-films and demonstrate predictable sample thermal drift for temperatures 25-400 degrees C, allowing features on the order of the resolution of the measurement technique (125 nm) to be tracked while heating. The stage enables previously unattainable in situ studies of nanoscale defect kinetics under industrially relevant processing conditions, allowing a deeper understanding of the relationship between material processing parameters, materials properties, and device performance. PMID- 26628143 TI - Development of a detachable high speed miniature scanning probe microscope for large area substrates inspection. AB - We have developed a high speed, miniature scanning probe microscope (MSPM) integrated with a Positioning Unit (PU) for accurately positioning the MSPM on a large substrate. This combination enables simultaneous, parallel operation of many units on a large sample for high throughput measurements. The size of the MSPM is 19 * 45 * 70 mm(3). It contains a one-dimensional flexure stage with counter-balanced actuation for vertical scanning with a bandwidth of 50 kHz and a z-travel range of more than 2 MUm. This stage is mechanically decoupled from the rest of the MSPM by suspending it on specific dynamically determined points. The motion of the probe, which is mounted on top of the flexure stage is measured by a very compact optical beam deflection (OBD). Thermal noise spectrum measurements of short cantilevers show a bandwidth of 2 MHz and a noise of less than 15 fm/Hz(1/2). A fast approach and engagement of the probe to the substrate surface have been achieved by integrating a small stepper actuator and direct monitoring of the cantilever response to the approaching surface. The PU has the same width as the MSPM, 45 mm and can position the MSPM to a pre-chosen position within an area of 275*30 mm(2) to within 100 nm accuracy within a few seconds. During scanning, the MSPM is detached from the PU which is essential to eliminate mechanical vibration and drift from the relatively low-resonance frequency and low-stiffness structure of the PU. Although the specific implementation of the MSPM we describe here has been developed as an atomic force microscope, the general architecture is applicable to any form of SPM. This high speed MSPM is now being used in a parallel SPM architecture for inspection and metrology of large samples such as semiconductor wafers and masks. PMID- 26628144 TI - Deformation in lead zirconate titanate ceramics under large signal electric field loading measured by digital image correlation. AB - Digital image correlation, a noncontact and nondestructive method, was employed to monitor the deformation of lead zirconate titanate piezoelectric ceramics. This method is based on imaging a speckle pattern on the specimen surface during the test and subsequently correlating each image of the deformed pattern to that in the reference state. In our work, both longitudinal and transverse strains were calculated from imaging a bulk sample under a +/-2 kV/mm electric field. Compared with linear variable displacement transducer data, the results from this correlation method were validated. At the same time, based on this optical technique, different strain-electric field butterfly loops can be drawn from correspondingly selected regions of interest. Combined with contour plots of strain on the surface of the sample, the deformation of bulk ceramic sample under uniaxial electric field loading without any mechanical constraints is proven to be highly homogenous under macro-observing scale. PMID- 26628145 TI - A modular reactor design for in situ synchrotron x-ray investigation of atomic layer deposition processes. AB - Synchrotron characterization techniques provide some of the most powerful tools for the study of film structure and chemistry. The brilliance and tunability of the Advanced Photon Source allow access to scattering and spectroscopic techniques unavailable with in-house laboratory setups and provide the opportunity to probe various atomic layer deposition (ALD) processes in situ starting at the very first deposition cycle. Here, we present the design and implementation of a portable ALD instrument which possesses a modular reactor scheme that enables simple experimental switchover between various beamlines and characterization techniques. As first examples, we present in situ results for (1) X-ray surface scattering and reflectivity measurements of epitaxial ZnO ALD on sapphire, (2) grazing-incidence small angle scattering of MnO nucleation on silicon, and (3) grazing-incidence X-ray absorption spectroscopy of nucleation regime Er2O3 ALD on amorphous ALD alumina and single crystalline sapphire. PMID- 26628146 TI - High-field magneto-thermo-mechanical testing system for characterizing multiferroic bulk alloys. AB - Multiferroic meta-magnetic shape memory alloys are well known for exhibiting large magnetic field induced actuation strains, giant magnetocaloric effects, magneto-resistance, and structural and magnetic glassy behaviors. Thus, they are candidates for improving modern day sensing, actuation, magneto-resistance, and solid-state refrigeration processes. Until now, however, experimental apparatuses have typically been able to probe a limited ferroic parameter space in these materials, i.e., only concurrent thermal and mechanical responses, or magnetic and thermal responses. To overcome this barrier and better understand the coupling of multiple fields on materials behavior, a magneto-thermo-mechanical characterization device has been designed and implemented. This device is capable of compressing a specimen at load levels up to 5300 N collinearly with applied fields up to 9 T between temperatures of -100 degrees C and 120 degrees C. Uniaxial stress, strain, temperature, magnetic field, and the volumetric average magnetization have been simultaneously measured under mixed loading conditions on a NiCoMnIn meta-magnetic shape memory alloy and a few selected results are presented here. PMID- 26628147 TI - An apparatus for spatially resolved, temperature dependent reflectance measurements for identifying thermochromism in combinatorial thin film libraries. AB - A metrology and data analysis protocol is described for high throughput determination of thermochromic metal-insulator phase diagrams for lightly substituted VO2 thin films. The technique exploits the abrupt change in near infrared optical properties, measured in reflection, as an indicator of the temperature- or impurity-driven metal-insulator transition. Transition metal impurities were introduced in a complementary combinatorial synthesis process for producing thin film libraries with the general composition space V(1-x y)M(x)M'(y)O2, with M and M' being transition metals and x and y varying continuously across the library. The measurement apparatus acquires reflectance spectra in the visible or near infrared at arbitrarily many library locations, each with a unique film composition, at temperatures of 1 degrees C-85 degrees C. Data collection is rapid and automated; the measurement protocol is computer controlled to automate the collection of thousands of reflectance spectra, representing hundreds of film compositions at tens of different temperatures. A straightforward analysis algorithm is implemented to extract key information from the thousands of spectra such as near infrared thermochromic transition temperatures and regions of no thermochromic transition; similarly, reflectance to the visible spectrum generates key information for materials selection of smart window materials. The thermochromic transition for 160 unique compositions on a thin film library with the general formula V(1-x-y)M(x)M'(y)O2 can be measured and described in a single 20 h experiment. The resulting impurity composition-temperature phase diagrams will contribute to the understanding of metal-insulator transitions in doped VO2 systems and to the development of thermochromic smart windows. PMID- 26628148 TI - Containment system for experiments on radioactive and other hazardous materials in a Paris-Edinburgh press. AB - Recent technical developments using the large volume Paris-Edinburgh press platform have enabled x-ray synchrotron studies at high pressure and temperature conditions. However, its application to some materials of interest, such as high hazard materials that require special handling due to safety issues, reactivity, or other challenges, has not been feasible without the introduction of special containment systems to eliminate the hazards. However, introduction of a containment system is challenging due to the requirement to provide full safety containment for operation in the variety of environments available, while not hindering any of the experimental probes that are available for inert sample measurement. In this work, we report on the development and implementation of a full safety enclosure for a Paris-Edinburgh type press. During the initial development and subsequent application stage of work, experiments were performed on both cerium dioxide (CeO2) and uranium (U). This device allows for full implementation of all currently available experimental probes involving the Paris Edinburgh press at the High Pressure Collaborative Access Team sector of the Advanced Photon Source. PMID- 26628150 TI - Collection-efficient, axisymmetric vacuum sublimation module for the purification of solid materials. AB - A vacuum sublimation module of axisymmetric geometry was developed and employed to purify solid-phase materials. The module provides certain practical advantages and it comprises: a metering valve, glass collector, glass lower body, main seal, threaded bushing, and glass internal cartridge (the latter to contain starting material). A complementary process was developed to de-solvate, sublime, weigh, and collect solid chemical materials exemplified by oxalic acid, ferrocene, pentachlorobenzene, chrysene, and urea. The oxalic acid sublimate was analyzed by titration, melting range, Fourier Transform Infrared (FT-IR) Spectroscopy, cyclic voltammetry, and its (aqueous phase) electrolytically generated gas. The analytical data were consistent with a high-purity, anhydrous oxalic acid sublimate. Cyclic voltammograms of 0.11 mol. % oxalic acid in water displayed a 2.1 V window on glassy carbon electrode beyond which electrolytic decomposition occurs. During module testing, fifteen relatively pure materials were sublimed with (energy efficient) passive cooling and the solid-phase recovery averaged 95 mass %. Key module design features include: compact vertical geometry, low-angle conical collector, uniformly compressed main seal, modest power consumption, transparency, glovebox compatibility, cooling options, and preferential conductive heat transfer. To help evaluate the structural (module) heat transfer, vertical temperature profiles along the dynamically evacuated lower body were measured versus electric heater power: for example, an input of 18.6 W generated a temperature 443-K at the bottom. Experimental results and engineering calculations indicate that during sublimation, solid conduction is the primary mode of heat transfer to the starting material. PMID- 26628149 TI - Quantification of protein interaction kinetics in a micro droplet. AB - Characterization of protein interactions is essential to the discovery of disease biomarkers, the development of diagnostic assays, and the screening for therapeutic drugs. Conventional flow-through kinetic measurements need relative large amount of sample that is not feasible for precious protein samples. We report a novel method to measure protein interaction kinetics in a single droplet with sub microliter or less volume. A droplet in a humidity-controlled environmental chamber is replacing the microfluidic channels as the reactor for the protein interaction. The binding process is monitored by a surface plasmon resonance imaging (SPRi) system. Association curves are obtained from the average SPR image intensity in the center area of the droplet. The washing step required by conventional flow-through SPR method is eliminated in the droplet method. The association and dissociation rate constants and binding affinity of an antigen antibody interaction are obtained by global fitting of association curves at different concentrations. The result obtained by this method is accurate as validated by conventional flow-through SPR system. This droplet-based method not only allows kinetic studies for proteins with limited supply but also opens the door for high-throughput protein interaction study in a droplet-based microarray format that enables measurement of many to many interactions on a single chip. PMID- 26628151 TI - Time differentiated nuclear resonance spectroscopy coupled with pulsed laser heating in diamond anvil cells. AB - Developments in pulsed laser heating applied to nuclear resonance techniques are presented together with their applications to studies of geophysically relevant materials. Continuous laser heating in diamond anvil cells is a widely used method to generate extreme temperatures at static high pressure conditions in order to study the structure and properties of materials found in deep planetary interiors. The pulsed laser heating technique has advantages over continuous heating, including prevention of the spreading of heated sample and/or the pressure medium and, thus, a better stability of the heating process. Time differentiated data acquisition coupled with pulsed laser heating in diamond anvil cells was successfully tested at the Nuclear Resonance beamline (ID18) of the European Synchrotron Radiation Facility. We show examples applying the method to investigation of an assemblage containing epsilon-Fe, FeO, and Fe3C using synchrotron Mossbauer source spectroscopy, FeCO3 using nuclear inelastic scattering, and Fe2O3 using nuclear forward scattering. These examples demonstrate the applicability of pulsed laser heating in diamond anvil cells to spectroscopic techniques with long data acquisition times, because it enables stable pulsed heating with data collection at specific time intervals that are synchronized with laser pulses. PMID- 26628152 TI - Improved vertical optical fiber borehole strainmeter design for measuring Earth strain. AB - Fiber-based interferometers provide the means to sense very small displacements over long baselines, and have the advantage of being nearly completely passive in their operation, making them particularly well suited for geophysical applications. A new 250 m, interferometric vertical borehole strainmeter has been developed based completely on passive optical components. Details of the design and deployment at the Pinon Flat Observatory are presented. Power spectra show an intertidal noise level of -130 dB (re. 1 epsilon(2)/Hz), consistent within 1-3 dB between redundant components. Examination of its response to Earth tides and earthquakes relative to the areal strain recorded by an orthogonal pair of collocated, 730 m horizontal laser strainmeters yield a Poisson's ratio for local near surface material of 0.25 that is consistent with previous results. PMID- 26628153 TI - Characterizing the complex permittivity of high-kappa dielectrics using enhanced field method. AB - This paper proposed a method to characterize the complex permittivities of samples based on the enhancement of the electric field strength. The enhanced field method significantly improves the measuring range and accuracy of the samples' electrical properties. Full-wave simulations reveal that the resonant frequency is closely related to the dielectric constant of the sample. In addition, the loss tangent can be determined from the measured quality factor and the just obtained dielectric constant. Materials with low dielectric constant and very low loss tangent are measured for benchmarking and the measured results agree well with previous understanding. Interestingly, materials with extremely high dielectric constants (epsilon(r) > 50), such as titanium dioxide, calcium titanate, and strontium titanate, differ greatly as expected. PMID- 26628154 TI - Signal acquisition module design for multi-channel surface magnetic resonance sounding system. AB - To obtain a precise 2D/3D image of fissure or karst water, multi-channel magnetic resonance sounding (MRS) systems using edge-to-edge or overlapping receiving coils are needed. Thus, acquiring a nano-volt signal for a small amount of the aquifer and suppressing the mutual coupling between adjacent coils are two important issues for the design of the signal acquisition module in the system. In the present study, we propose to use a passive low pass filter, consisted of a resistance (R) and capacitance (C), to inhibit the mutual coupling effects of the coils. Four low-noise operational amplifiers LT1028, OPA124, AD745, and OP27 were compared with respect to achieving the lowest system noise. As a result, 3 pieces of LT1028 were chosen and connected in parallel to serve as preamplifier, with a sensitivity of 1.4 nV/?Hz at 2 kHz. Experimental results are presented for 2D MRS groundwater investigations conducted in the suburb of Changchun, China. The inversion result is consistent with the result of drilling log, suggesting that the signal acquisition module is well developed. PMID- 26628155 TI - A high-overtone bulk acoustic wave resonator-oscillator-based 4.596 GHz frequency source: Application to a coherent population trapping Cs vapor cell atomic clock. AB - This article reports on the design and characterization of a high-overtone bulk acoustic wave resonator (HBAR)-oscillator-based 4.596 GHz frequency source. A 2.298 GHz signal, generated by an oscillator constructed around a thermally controlled two-port aluminum nitride-sapphire HBAR resonator with a Q-factor of 24,000 at 68 degrees C, is frequency multiplied by 2-4.596 GHz, half of the Cs atom clock frequency. The temperature coefficient of frequency of the HBAR is measured to be -23 ppm/ degrees C at 2.298 GHz. The measured phase noise of the 4.596 GHz source is -105 dB rad(2)/Hz at 1 kHz offset and -150 dB rad(2)/Hz at 100 kHz offset. The 4.596 GHz output signal is used as a local oscillator in a laboratory-prototype Cs microcell-based coherent population trapping atomic clock. The signal is stabilized onto the atomic transition frequency by tuning finely a voltage-controlled phase shifter implemented in the 2.298 GHz HBAR oscillator loop, preventing the need for a high-power-consuming direct digital synthesis. The short-term fractional frequency stability of the free-running oscillator is 1.8 * 10(-9) at one second integration time. In locked regime, the latter is improved in a preliminary proof-of-concept experiment at the level of 6.6 * 10(-11) tau(-1/2) up to a few seconds and found to be limited by the signal to-noise ratio of the detected CPT resonance. PMID- 26628156 TI - A reliable, compact, and repetitive-rate high power microwave generation system. AB - A compact high power microwave (HPM) generation system is described in this paper. The main parts of the HPM system are a Marx generator with a pulse forming line and a magnetron with diffraction output. The total weight and length of the system are 250 kg and 120 cm, respectively. The output microwave power of the HPM system at 550 kV of applied voltage and 0.33 T of magnetic field reaches 1 GW at 2.32 GHz of central frequency with 38 ns of pulse duration, 23% of power conversion efficiency, and Gaussian radiation pattern. In the bursts operation, both time and amplitude jitters are less than 4 ns and lower than 1.5 dB, respectively. PMID- 26628157 TI - A short-circuited coplanar waveguide to measure the permeability of magnetic thin films: Comparison with short-circuited microstrip line. AB - A short-circuited coplanar waveguide jig was proposed due to its simple structure and potential applications, which was successfully used to measure the permeability spectra of magnetic thin film. The result obtained from the coplanar waveguide (CPW) jig exhibits typical ferromagnetic resonance spectra, which can be well fitted by a trade-off equation because the measured permeability spectra have a bit of asymmetry because of the special intensity distribution of the microwave magnetic field in the CPW. In order to confirm the availability of the shorted CPW jig, a previous short-circuited microstrip line jig was used to measure the permeability spectra of the same sample. The dynamic permeability results obtained by using different jigs are commendably consistent, and the accurate and valid results are also confirmed by using the vector network analyzer ferromagnetic resonance method. PMID- 26628158 TI - A 6 GW nanosecond solid-state generator based on semiconductor opening switch. AB - In this paper, a nanosecond all solid-state generator providing peak power of up to 6 GW, output voltage of 500-900 kV, pulse length (full width at half maximum) of ~7 ns across external loads of 40-100 Omega, and pulse repetition frequency up to 1 kHz in burst operation mode is described. The output pulse is generated by a semiconductor opening switch (SOS). A new SOS pumping circuit based on a double forming line (DFL) is proposed and its implementation described. As compared with a lumped capacitors-based pumping circuit, the DFL allows minimization of the inductance and stray capacitance of the reverse pumping circuit, and thus, an increase in the SOS cutoff current amplitude and generator output peak power as a whole. The pumping circuit provides a reverse current increasing through the SOS up to 14 kA within ~12 ns. The SOS cuts off the current in ~2 ns; the current cutoff rate reaches 7 kA/ns. The SOS braking power (the product of peak voltage and cutoff current) for an external load above 100 Omega is 13 GW. PMID- 26628159 TI - Determination of acoustic properties of thin polymer films utilizing the frequency dependence of the reflection coefficient of ultrasound. AB - This paper reports on a technique to measure the acoustic properties of a thin polymer film utilizing the frequency dependence of the reflection coefficient of ultrasound reflected back from a system comprising a reflection plate, the film, and a material that covers the film. The frequency components of the echo reflected from the back of the plate, where the film is attached, take their minimum values at the resonant frequency, and from these frequency characteristics, the acoustic impedance, sound velocity, and the density of the film can be determined. We applied this technique to characterize an ion exchange membrane, which has high water absorbability, and successfully determined the acoustic properties of the membrane without getting it wet. PMID- 26628160 TI - Dancing the tight rope on the nanoscale--Calibrating a heat flux sensor of a scanning thermal microscope. AB - We report on a precise in situ procedure to calibrate the heat flux sensor of a near-field scanning thermal microscope. This sensitive thermal measurement is based on 1omega modulation technique and utilizes a hot wire method to build an accessible and controllable heat reservoir. This reservoir is coupled thermally by near-field interactions to our probe. Thus, the sensor's conversion relation V(th)(Q(GS)*) can be precisely determined. V(th) is the thermopower generated in the sensor's coaxial thermocouple and Q(GS)* is the thermal flux from reservoir through the sensor. We analyze our method with Gaussian error calculus with an error estimate on all involved quantities. The overall relative uncertainty of the calibration procedure is evaluated to be about 8% for the measured conversion constant, i.e., (2.40 +/- 0.19) MUV/MUW. Furthermore, we determine the sensor's thermal resistance to be about 0.21 K/MUW and find the thermal resistance of the near-field mediated coupling at a distance between calibration standard and sensor of about 250 pm to be 53 K/MUW. PMID- 26628161 TI - Simultaneous moduli measurement of elastic materials at elevated temperatures using an ultrasonic waveguide method. AB - A novel technique for simultaneously measuring the moduli of elastic isotropic material, as a function of temperature, using two ultrasonic guided wave modes that are co-generated using a single probe is presented here. This technique can be used for simultaneously measuring Young's modulus (E) and shear modulus (G) of different materials over a wide range of temperatures (35 degrees C-1200 degrees C). The specimens used in the experiments have special embodiments (for instance, a bend) at one end of the waveguide and an ultrasonic guided wave generator/detector (transducer) at the other end for obtaining reflected signals in a pulse-echo mode. The orientation of the transducer can be used for simultaneously generating/receiving the L(0,1) and/or T(0,1) using a single transducer in a waveguide on one end. The far end of the waveguides with the embodiment is kept inside a heating device such as a temperature-controlled furnace. The time of flight difference, as a function of uniform temperature distribution region (horizontal portion) of bend waveguides was measured and used to determine the material properties. Several materials were tested and the comparison between values reported in the literature and measured values were found to be in agreement, for both elastic moduli (E and G) measurements, as a function of temperature. This technique provides significant reduction in time and effort over conventional means of measurement of temperature dependence of elastic moduli. PMID- 26628162 TI - A closed-loop phase-locked interferometer for wide bandwidth position sensing. AB - This article describes a position sensitive interferometer with closed-loop control of the reference mirror. A calibrated nanopositioner is used to lock the interferometer phase to the most sensitive point in the interferogram. In this configuration, large low-frequency movements of the sensor mirror can be detected from the control signal applied to the nanopositioner and high-frequency short range signals can be measured directly from the photodiode. It is demonstrated that these two signals are complementary and can be summed to find the total displacement. The resulting interferometer has a number of desirable characteristics: it is optically simple, does not require polarization or modulation to detect the direction of motion, does not require fringe-counting or interpolation electronics, and has a bandwidth equal to that of the photodiode. Experimental results demonstrate the frequency response analysis of a high-speed positioning stage. The proposed instrument is ideal for measuring the frequency response of nanopositioners, electro-optical components, MEMs devices, ultrasonic devices, and sensors such as surface acoustic wave detectors. PMID- 26628163 TI - Fiber optic sensing in rapidly rotating mechanical structures. AB - A novel, generic approach for fiber-optical sensing in rapidly rotating structures is presented. This approach does not require optical ingress via the central rotation axis. In this work, strain sensing at rotation speeds of up to 5000 rpm is demonstrated, and higher speeds should be possible. We demonstrate measurement of the rotation-induced strain in a rotating body at 500 rpm intervals up to 5000 rpm, and results agree very well with predictions. PMID- 26628164 TI - An absolute calibration method of an ethyl alcohol biosensor based on wavelength modulated differential photothermal radiometry. AB - In this work, laser-based wavelength-modulated differential photothermal radiometry (WM-DPTR) is applied to develop a non-invasive in-vehicle alcohol biosensor. WM-DPTR features unprecedented ethanol-specificity and sensitivity by suppressing baseline variations through a differential measurement near the peak and baseline of the mid-infrared ethanol absorption spectrum. Biosensor signal calibration curves are obtained from WM-DPTR theory and from measurements in human blood serum and ethanol solutions diffused from skin. The results demonstrate that the WM-DPTR-based calibrated alcohol biosensor can achieve high precision and accuracy for the ethanol concentration range of 0-100 mg/dl. The high-performance alcohol biosensor can be incorporated into ignition interlocks that could be fitted as a universal accessory in vehicles in an effort to reduce incidents of drinking and driving. PMID- 26628165 TI - Genetic algorithm based fast alignment method for strap-down inertial navigation system with large azimuth misalignment. AB - In order to shorten the alignment time and eliminate the small initial misalignment limit for compass alignment of strap-down inertial navigation system (SINS), which is sometimes not easy to satisfy when the ship is moored or anchored, an optimal model based time-varying parameter compass alignment algorithm is proposed in this paper. The contributions of the work presented here are twofold. First, the optimization of compass alignment parameters, which involves a lot of trial-and-error traditionally, is achieved based on genetic algorithm. On this basis, second, the optimal parameter varying model is established by least-square polynomial fitting. Experiments are performed with a navigational grade fiber optical gyroscope SINS, which validate the efficiency of the proposed method. PMID- 26628166 TI - Dynamic nozzles for drop generators. AB - In this paper, a novel mechanism allowing greater control over the formation of droplets is presented. This is achieved via the use of a dynamic nozzle of adjustable diameter. It is demonstrated that, by using such a nozzle, it is possible to greatly modify the formation and breakup of the ligament behind the main drop, leading to an overall reduction in the number of satellite droplets. Furthermore, by adjusting the delay between the beginning of the forming of the drop and the start of the nozzle constriction, a greater control over both the number of satellites and the size of the main drop can be achieved. It is also shown that only a minimal reduction of the nozzle's effective diameter is required in order to exploit the positive effects of the technique presented here. This opens the possibility of incorporating the technique into current droplet generator systems, e.g., via the use of piezoelectric driven nozzles or other micro-mechanical actuation technology. PMID- 26628167 TI - A 128-channel picoammeter system and its application on charged particle beam current distribution measurements. AB - A 128-channel picoammeter system is constructed based on instrumentation amplifiers. Taking advantage of a high electric potential and narrow bandwidth in DC energetic charged beam measurements, a current resolution better than 5 fA can be achieved. Two sets of 128-channel strip electrodes are implemented on printed circuit boards and are employed for ion and electron beam current distribution measurements. Tests with 60 keV O(3+) ions and 2 keV electrons show that it can provide exact boundaries when a positive charged particle beam current distribution is measured. PMID- 26628168 TI - Oxygen pump based on stabilized zirconia. AB - When a DC voltage is applied across a zirconia ceramic layer, an electrical field is established to drive oxygen species through the layer. Taking advantage of this electrochemical phenomenon, we have designed and developed an oxygen pump that offers continuously adjustable oxygen partial pressure from 1 bar down to 10(-24) bar in the temperature range of 650-1100 degrees C. Demonstrated with electrical conductivity measurements on Fe-doped SrTiO3, these excellent capabilities of the oxygen pump are valuable for investigations on the defect chemistry of electroceramics. PMID- 26628169 TI - Determination of the separation efficiencies of a single-stage cryogenic distillation setup to remove krypton out of xenon by using a (83m)Kr tracer method. AB - The separation of krypton and xenon is of particular importance for the field of direct dark matter search with liquid xenon detectors. The intrinsic contamination of the xenon with radioactive (85)Kr makes a significant background for these kinds of low count-rate experiments and has to be removed beforehand. This can be achieved by cryogenic distillation, a technique widely used in industry, using the different vapor pressures of krypton and xenon. In this paper, we present an investigation on the separation performance of a single stage distillation system using a radioactive (83m)Kr-tracer method. The separation characteristics under different operation conditions are determined for very low concentrations of krypton in xenon at the level of (83m)Kr/Xe = 1.9 ? 10(-15), demonstrating, that cryogenic distillation in this regime is working. The observed separation is in agreement with the expectation from the different volatilities of krypton and xenon. This cryogenic distillation station is the first step on the way to a multi-stage cryogenic distillation column for the next generation of direct dark matter experiment XENON1T. PMID- 26628170 TI - A progressively reduced pretension method to fabricate Bradbury-Nielsen gates with uniform tension. AB - A Bradbury-Nielsen gate (BNG) is often used to modulate ion beams. It consists of two interleaved and electrically isolated sets of wires with uniform tension, which ideally keep parallel, equidistant, and coplanar over a wide temperature range, making the BNG reliable and robust. We have previously analyzed the non uniformity problem of wire tensions with sequentially winding method and developed a template-based transfer method to solve this problem. In this paper, we introduced a progressively reduced pretension method, which allows directly and sequentially fixing wires onto the substrate without using a template. Theoretical analysis shows that by applying proper pretension to each wire when fixing it, the final wire tensions of all wires can be uniform. The algorithm and flowchart to calculate the pretension sequence are given, and the fabrication process is introduced in detail. Pretensions are generated by weight combination with a weaving device. A BNG with stainless steel wire and a printed circuit board substrate is constructed with this method. The non-uniformity of the final wire tensions is less than 2.5% in theory. The BNG is successfully employed in our ion mobility spectrometer, and the measured resolution is 33.5 at a gate opening time of 350 MUs. Compared to the template-based method, this method is simpler, faster, and more flexible with comparable production quality when manufacturing BNGs with different configurations. PMID- 26628171 TI - Compact field programmable gate array-based pulse-sequencer and radio-frequency generator for experiments with trapped atoms. AB - We present a compact field-programmable gate array (FPGA) based pulse sequencer and radio-frequency (RF) generator suitable for experiments with cold trapped ions and atoms. The unit is capable of outputting a pulse sequence with at least 32 transistor-transistor logic (TTL) channels with a timing resolution of 40 ns and contains a built-in 100 MHz frequency counter for counting electrical pulses from a photo-multiplier tube. There are 16 independent direct-digital synthesizers RF sources with fast (rise-time of ~60 ns) amplitude switching and sub-mHz frequency tuning from 0 to 800 MHz. PMID- 26628172 TI - Ultrafast image-based dynamic light scattering for nanoparticle sizing. AB - An ultrafast sizing method for nanoparticles is proposed, called as UIDLS (Ultrafast Image-based Dynamic Light Scattering). This method makes use of the intensity fluctuation of scattered light from nanoparticles in Brownian motion, which is similar to the conventional DLS method. The difference in the experimental system is that the scattered light by nanoparticles is received by an image sensor instead of a photomultiplier tube. A novel data processing algorithm is proposed to directly get correlation coefficient between two images at a certain time interval (from microseconds to milliseconds) by employing a two dimensional image correlation algorithm. This coefficient has been proved to be a monotonic function of the particle diameter. Samples of standard latex particles (79/100/352/482/948 nm) were measured for validation of the proposed method. The measurement accuracy of higher than 90% was found with standard deviations less than 3%. A sample of nanosilver particle with nominal size of 20 +/- 2 nm and a sample of polymethyl methacrylate emulsion with unknown size were also tested using UIDLS method. The measured results were 23.2 +/- 3.0 nm and 246.1 +/- 6.3 nm, respectively, which is substantially consistent with the transmission electron microscope results. Since the time for acquisition of two successive images has been reduced to less than 1 ms and the data processing time in about 10 ms, the total measuring time can be dramatically reduced from hundreds seconds to tens of milliseconds, which provides the potential for real-time and in situ nanoparticle sizing. PMID- 26628173 TI - Characterization method of hydrophobic anti-icing coatings. AB - For anti-icing, supercooled water should be removed before frozen onto the contact surface. We use a hydrophobic coating for anti-icing and introduce the static- and dynamic-evaluation methods. The methods describe the contact surface between the hydrophobic surface and a supercooled-water droplet. The former is based on the contact angle, and the latter is based on the sliding angle. The temperature factor is included in these models to evaluate the hydrophobic coating under the supercooled conditions. Four hydrophobic coatings are experimentally evaluated based on the static- and dynamic evaluation methods: C1 C3 (commercial fluorocarbon coatings), and Jaxa coating (original fluorocarbon coating). These are evaluated under the supercooled conditions of -10 to 0 degrees C. The static-evaluation shows variations in the temperature. However, change in the contact angle by the temperature is relatively small compared to that of the sliding angle for the dynamic evaluation. Only C3 and Jaxa coatings are tolerant to the sliding angle under the supercooled conditions tested. The dynamic evaluation shows that even if the coating is hydrophobic, the dynamic evaluation should be included to understand the characteristic of removal for a supercooled-water droplet. PMID- 26628174 TI - A 10 nN resolution thrust-stand for micro-propulsion devices. AB - We report on the development of a nano-Newton thrust-stand that can measure up to 100 MUN thrust from different types of microthrusters with 10 nN resolution. The compact thrust-stand measures the impingement force of the particles emitted from a microthruster onto a suspended plate of size 45 mm * 45 mm and with a natural frequency over 50 Hz. Using a homodyne (lock-in) readout provides strong immunity to facility vibrations, which historically has been a major challenge for nano Newton thrust-stands. A cold-gas thruster generating up to 50 MUN thrust in air was first used to validate the thrust-stand. Better than 10 nN resolution and a minimum detectable thrust of 10 nN were achieved. Thrust from a miniature electrospray propulsion system generating up to 3 MUN of thrust was measured with our thrust-stand in vacuum, and the thrust was compared with that computed from beam diagnostics, obtaining agreement within 50 nN to 150 nN. The 10 nN resolution obtained from this thrust-stand matches that from state-of-the-art nano-Newton thrust-stands, which measure thrust directly from the thruster by mounting it on a moving arm (but whose natural frequency is well below 1 Hz). The thrust-stand is the first of its kind to demonstrate less than 3 MUN resolution by measuring the impingement force, making it capable of measuring thrust from different types of microthrusters, with the potential of easy upscaling for thrust measurement at much higher levels, simply by replacing the force sensor with other force sensors. PMID- 26628175 TI - Highly sensitive pseudo-differential ac-nanocalorimeter for the study of the glass transition. AB - We present a nanocalorimeter designed for the measurement of the dynamic heat capacity of thin films. The microfabricated sensor, the thermal conditioning of the sensor, as well as the highly stable and low noise electronic chain allow measurements of the real and imaginary parts of the complex specific heat with a resolution Delta C/C of about 10(-5). The performances of this quasi-differential nanocalorimeter were tested on a model of polymeric glass-former, the polyvinyl acetate (PVAc). The high stability and low noise of the device are essential for accurate studies on non-equilibrium slow relaxing systems such as glasses. PMID- 26628176 TI - SPECTRON, a neutron noise measurement system in frequency domain. AB - This paper is dedicated to the presentation and validation of SPECTRON, a novel neutron noise measurement system developed at CEA Cadarache. The device is designed for the measurement of the beta(eff) parameter (effective fraction of delayed neutrons) of experimental nuclear reactors using the Cohn-alpha method. An integrated electronic system is used to record the current from fission chambers. Spectra computed from measurement data are processed by a dedicated software in order to estimate the reactor transfer function and then the effective fraction of delayed neutrons as well as the prompt neutron generation time. After a review of the pile noise measurement method in current mode, the SPECTRON architecture is presented. Then, the validation procedure is described and experimental results are shown, supporting the proper functioning of this new measurement system. It is shown that every technical requirement needed for correct measurement of neutron noise is fulfilled. Measurements performed at MINERVE and EOLE, two experimental nuclear reactors at CEA Cadarache, in real conditions allowed us to validate SPECTRON. PMID- 26628177 TI - A new B-dot probe-based diagnostic for amplitude, polarization, and wavenumber measurements of ion cyclotron range-of frequency fields on ASDEX Upgrade. AB - A new B-dot probe-based diagnostic has been installed on an ASDEX Upgrade tokamak to characterize ion cyclotron range-of frequency (ICRF) wave generation and interaction with magnetized plasma. The diagnostic consists of a field-aligned array of B-dot probes, oriented to measure fast and slow ICRF wave fields and their field-aligned wavenumber (k(//)) spectrum on the low field side of ASDEX Upgrade. A thorough description of the diagnostic and the supporting electronics is provided. In order to compare the measured dominant wavenumber of the local ICRF fields with the expected spectrum of the launched ICRF waves, in-air near field measurements were performed on the newly installed 3-strap ICRF antenna to reconstruct the dominant launched toroidal wavenumbers (k(tor)). Measurements during a strap current phasing scan in tokamak discharges reveal an upshift in k(//) as strap phasing is moved away from the dipole configuration. This result is the opposite of the k(tor) trend expected from in-air near-field measurements; however, the near-field based reconstruction routine does not account for the effect of induced radiofrequency (RF) currents in the passive antenna structures. The measured exponential increase in the local ICRF wave field amplitude is in agreement with the upshifted k(//), as strap phasing moves away from the dipole configuration. An examination of discharges heated with two ICRF antennas simultaneously reveals the existence of beat waves at 1 kHz, as expected from the difference of the two antennas' operating frequencies. Beats are observed on both the fast and the slow wave probes suggesting that the two waves are coupled outside the active antennas. Although the new diagnostic shows consistent trends between the amplitude and the phase measurements in response to changes applied by the ICRF antennas, the disagreement with the in-air near-field measurements remains. An electromagnetic model is currently under development to address this issue. PMID- 26628178 TI - Peristaltic pump-based low range pressure sensor calibration system. AB - Peristaltic pumps were normally used to pump liquids in several chemical and biological applications. In the present study, a peristaltic pump was used to pressurize the chamber (positive as well negative pressures) using atmospheric air. In the present paper, we discuss the development and performance study of an automatic pressurization system to calibrate low range (millibar) pressure sensors. The system includes a peristaltic pump, calibrated pressure sensor (master sensor), pressure chamber, and the control electronics. An in-house developed peristaltic pump was used to pressurize the chamber. A closed loop control system has been developed to detect and adjust the pressure leaks in the chamber. The complete system has been integrated into a portable product. The system performance has been studied for a step response and steady state errors. The system is portable, free from oil contaminants, and consumes less power compared to existing pressure calibration systems. The veracity of the system was verified by calibrating an unknown diaphragm based pressure sensor and the results obtained were satisfactory. PMID- 26628179 TI - A method for evaluating the thrust of a space propulsion device with wide range time variations using a disturbance observer. AB - A new method for evaluating thrust with high-frequency variations beyond the resonant frequency using a disturbance observer is presented. Setpoint control is applied to a conventional pendulum-type thrust stand to keep the pendulum at the target position using a solenoid actuator. During control, pendulum acceleration and solenoid-actuator current are measured, and the disturbance observer determines thrust with a wide range of frequency variations. The method allows thrust to be evaluated not only with constant and low-frequency variations, but also with high-frequency variations outside the resonant frequency. A thrust measurement device is prototyped to investigate accuracy over a wide frequency range from 0 to 100 Hz and the effects of the proportional-derivative-integral (PID) controller design. Calibration yields thrust measurement errors of 20% below 90 Hz. PID controller design has a smaller influence on the accuracy of the proposed method than the conventional null-balance method, so the proposed method requires the same stability under PID control as that for the null-balance method. PMID- 26628180 TI - Simplified equations of the compliant matrix for right elliptical flexure hinges. AB - The simplified compliance matrix for right elliptical hinges is presented in this paper by nonlinear curve fitting on the basis of the equations derived by Chen et al. [Rev. Sci. Instrum. 79, 095103 (2008)]. The equations of the rotation stiffness are then confirmed by comparison with results from finite element analysis and experimental measurements. Percentage errors between theoretical predictions and results from both the finite element analysis and experimental testing are within 5% for a range of geometries with the ratio s (b/t) between 1 and 14. The geometric parameter optimization for the purposes of maximizing the rotation stiffness for one universal hinge is utilized to illustrate the application of the simplified equations. The theoretical predictions are in good agreement with both the result of simulation and experiment for the universal hinge: the error between them is within 6.5%. PMID- 26628181 TI - Compact flat-panel gas-gap heat switch operating at 295 K. AB - Heat switches are devices that can change from a thermally conducting (on-) state to an insulating (off-) state whenever the need arises. They enable adaptive thermal management strategies in which cooling rates are altered either spatially or temporally, leading to a substantial reduction in the energy and mass budget of a large range of systems. State-of-the-art heat switches are only rarely employed in thermal system architectures, since they are rather bulky and have a limited thermal performance (expressed as the heat transfer ratio between the on- and off-state heat conductance). Using selective laser melting additive manufacturing technology, also known as 3D printing, we developed a compact flat panel gas-gap heat switch that offers superior thermal performance, is simpler and more economic to produce and assemble, contains no moving parts, and is more reliable because it lacks welded joints. The manufactured rectangular panel heat switch has frontal device dimensions of 10 cm by 10 cm, thickness of 3.2 mm and weighs just 121 g. An off heat conductance of 0.2 W/K and on-off heat conductance ratio of 38 is observed at 295 K. PMID- 26628182 TI - Note: Device for obtaining volumetric, three-component velocity fields inside cylindrical cavities. AB - We describe a device designed and built to obtain the three-component, steady state velocity field in the whole volume occupied by a fluid in motion contained in a cavity with cylindrical walls. The prototype comprises a two-camera stereoscopic particle image velocimetry system mounted on a platform that rotates around the volume under analysis and a slip ring arrangement that transmits data from the rotating sensors to the data storage elements. Sample observations are presented for natural convection in a cylindrical container but other flows can be analyzed. PMID- 26628183 TI - Note: A kinematic shaker system for high amplitude, low frequency vibration testing. AB - This note describes a shaker system capable of high peak-velocity, large amplitude, low frequency, near-sinusoidal excitation that has been constructed and employed in experiments on the inhibition of Rayleigh-Benard convection using acceleration modulation. The production of high peak-velocity vibration is of interest in parametric excitation problems of this type and reaches beyond the capabilities of standard electromagnetic shakers. The shaker system described employs a kinematic linkage to two counter-rotating flywheels, driven by a variable-speed electrical motor, producing peak-to-peak displacements of 15.24 cm to a platform mounted on two guide rails. In operation, this shaker has been demonstrated to produce peak speeds of up to 3.7 m/s without failure. PMID- 26628184 TI - Note: Thermally stable thin-film filters for high-power extreme-ultraviolet applications. AB - We investigated several types of thin-film filters for high intensity work in the extreme-ultraviolet (EUV) spectral range. In our application, with a peak EUV intensity of 2.7 W cm(-2), Ni-mesh-backed Zr filters have a typical lifetime of 20 h, at which point they suffer from pinholes and a 50% loss of transmission. Initial trials with Si filters on Ni meshes resulted in rupture of the filters in less than an hour. A simple thermal calculation showed that the temperature rise in those filters to be about 634 K. A similar calculation indicated that using a finer mesh with thicker wires and made of Cu reduces the temperature increase to about 60 K. We have exposed a Si filter backed by such a mesh for more than 60 h with little loss of transmission and no leaks. PMID- 26628185 TI - Note: A monoenergetic proton backlighter for the National Ignition Facility. AB - A monoenergetic, isotropic proton source suitable for proton radiography applications has been demonstrated at the National Ignition Facility (NIF). A deuterium and helium-3 gas-filled glass capsule was imploded with 39 kJ of laser energy from 24 of NIF's 192 beams. Spectral, spatial, and temporal measurements of the 15-MeV proton product of the (3)He(d,p)(4)He nuclear reaction reveal a bright (10(10) protons/sphere), monoenergetic (DeltaE/E = 4%) spectrum with a compact size (80 MUm) and isotropic emission (~13% proton fluence variation and <0.4% mean energy variation). Simultaneous measurements of products produced by the D(d,p)T and D(d,n)(3)He reactions also show 2 * 10(10) isotropically distributed 3-MeV protons. PMID- 26628186 TI - Note: Wide band amplifier for quartz tuning fork sensors with digitally controlled stray capacitance compensation. AB - We presented a preamplifier design for quartz tuning fork (QTF) sensors in which the stray capacitance is digitally compensated. In this design, the manually controlled variable capacitor is replaced by a pair of varicap diodes, whose capacitance could be accurately tuned by a bias voltage. A tuning circuit including a single side low power operational amplifier, a digital-to-analog converter, and a microprocessor is also described, and the tuning process can be conveniently carried out on a personal computer. For the design, the noise level was investigated experimentally. PMID- 26628187 TI - Note: A novel technique for analysis of aqueous solutions by laser-induced breakdown spectroscopy. AB - Surface-enhanced Raman spectroscopy (SERS) substrates typically consist of gold or silver nanoparticles deposited on a non-conductive substrate. In Raman spectroscopy, the nanoparticles produce an enhancement of the electromagnetic field which, in turn, leads to greater electronic excitation of molecules in the local environment. Here, we show that these same surfaces can be used to enhance the signal-to-noise ratio obtained in laser-induced breakdown spectroscopy of aqueous solutions. In this case, the SERS substrates not only lower breakdown thresholds and lead to more efficient plasma initiation but also provide an appropriately wettable surface for the deposition of the liquid. We refer to this technique as surface-enhanced laser-induced breakdown spectroscopy. PMID- 26628188 TI - Note: A novel and robust circuit for jitter reduction in copper vapor laser system. AB - A novel circuit scheme is presented to improve timing jitter performance of high voltage pulse power supply utilizing semiconductor switches and magnetic pulse compressors, for pumping pulsed copper vapor lasers. The circuit effectively handles reflected energy from the laser load and achieves better jitter performance. The proposed circuit scheme had typical jitter value of +/-2 ns whereas the standard circuit used earlier had jitter of more than +/-10 ns under similar conditions. Performance of the circuit scheme is studied on a copper vapor laser operating at average laser power of 40 W. PMID- 26628190 TI - Erratum: "Experimental study on parasitic mode suppression using FeSiAl in relativistic klystron amplifier" [Rev. Sci. Instrum. 86, 034707 (2015)]. PMID- 26628191 TI - How Acas helped restart negotiations over the junior doctor contract. PMID- 26628192 TI - Transcriptional profiles discriminate patients with pulmonary tuberculosis from non-tuberculous individuals depending on the presence of non-insulin diabetes mellitus. AB - Our objective was to identify transcriptional biomarkers in peripheral blood mononuclear cells (PBMC) that discriminate individuals with latent tuberculosis infection (LTBI) from those with pulmonary tuberculosis (PTB) in subjects with non-insulin-dependent diabetes mellitus (NIDDM) and in individuals without NIDDM. Using gene expression microarrays we identified differentially expressed genes from lungs of mice infected with Mycobacterium tuberculosis (Mtb) or a mutant (DeltasigH) representing a non-inflammatory model. Genes expressed in blood, with inflammatory related functions were evaluated in humans by RT-qPCR. NCF1 and ORM transcripts have the better discriminatory capacity to identify PTB subjects from LTBI and non-infected controls (NICs) independently of the presence of NIDDM. The sequential evaluation of the mRNA levels of NCF1 and ORM as multiple diagnostic tests showed 95% Sensitivity (Se) and 80% Specificity (Sp). In addition, FPR2 promises to be a good biomarker for the PTB detection in subjects with NIDDM (Se=100%; Sp=90%). PMID- 26628193 TI - Ventilation strategies in paediatric inhalation injury. AB - Inhalation injury increases morbidity and mortality in burns victims. While the diagnosis remains largely clinical, bronchoscopy is also helpful to diagnose and grade the severity of any injury. Inhalation injury results from direct thermal injury or chemical irritation of the respiratory tract, systemic toxicity from inhaled substances, or a combination of these factors. While endotracheal intubation is essential in cases where upper airway obstruction may occur, it has its own risks and should not be performed prophylactically in all cases of inhalation injury. The evidence-base informing the selection of optimal ventilation strategy in inhalation injury is sparse, and most recommendations are based on extrapolation from (largely adult) studies in acute respiratory distress syndrome (ARDS). Conventional ventilation using a lung-protective approach (i.e. low tidal volume, limited plateau pressure, and permissive hypercarbia) is recommended as the initial approach if invasive ventilation is required; various rescue strategies may become necessary if there is a poor response. The efficacy of many widely used pharmacologic adjuncts in inhalation injury remains uncertain. Further research is urgently required to address these gaps in our knowledge. PMID- 26628194 TI - Leukotriene receptor antagonists as maintenance or intermittent treatment in pre school children with episodic viral wheeze. PMID- 26628195 TI - Highly Efficient Organic Solar Cells with Improved Vertical Donor-Acceptor Compositional Gradient Via an Inverted Off-Center Spinning Method. AB - A novel, yet simple solution fabrication technique to address the trade-off between photocurrent and fill factor in thick bulk heterojunction organic solar cells is described. The inverted off-center spinning technique promotes a vertical gradient of the donor-acceptor phase-separated morphology, enabling devices with near 100% internal quantum efficiency and a high power conversion efficiency of 10.95%. PMID- 26628196 TI - Stage-Specific Fatty Acid Fluxes Play a Regulatory Role in Glycerolipid Metabolism during Seed Development in Jatropha curcas L. AB - The present study describes the changes in lipid profile as well as fatty acid fluxes during seed development in Jatropha curcas L. Endosperm from 34, 37, and 40 days after anthesis (DAA), incubated with [(14)C]acetate, showed significant synthesis of phosphatidylcholine (PC) at seed maturation. The fatty acid methyl ester profile showed PC from 34 DAA was rich in palmitic acid (16:0), whereas PC from 37 and 40 DAA was rich in oleic acid (18:1n-9). Molecular species analysis of diacylglycerol (DAG) indicated DAG (16:0/18:2n-6) was in abundance at 34 DAA, whereas DAG (18:1n-9/18:2n-6) was significantly high at 40 DAA. Triacylglycerol (TAG) analysis revealed TAG (16:0/18:2n-6/16:0) was abundant at 34 DAA, whereas TAG (18:1n-9/18:2n-6/18:1n-9) formed the majority at 40 DAA. Expression of two types of diacylglycerol acyltransferases varied with seed maturation. These data demonstrate stage-specific distinct pools of PC and DAG synthesis during storage TAG accumulation in Jatropha seed. PMID- 26628198 TI - Eight free flaps in 24 hours: a training concept for postgraduate teaching of how to raise microvascular free flaps. AB - Microvascular free flaps are complex but important tools in oral and maxillofacial surgery (OMFS), and though techniques to raise flaps are challenging surgeons often have little structured training. In this study we have evaluated a structured, three-day, hands-on, practical training course on raising flaps. Five human, Thiel-embalmed cadavers were used for training in how to raise the following flaps: radial forearm, anterolateral thigh, lateral arm, fibular, latissimus dorsi, scapular, iliac crest, and rectus abdominis. The total duration of the course was 24 hours over three days. All participants were asked to evaluate the design and conduct of the course, their own learning curve, and general questions about their knowledge of how to raise flaps and microsurgery. There was a significant increase in participants' assessments of how they raised all free flaps, except the lateral arm flap (4.74 (0.68) compared with 2.42 (0.81); p=0.052) before and after the course. The radial forearm flap was thought to be the most relevant in clinical practice (n=40; 75%), followed by the anterolateral thigh (n=5; 9%) and fibular (n=4; 8%) flaps. Comparisons between residents and consultants showed unsurprising differences in experience with microsurgery and self-assessment in raising particular free flaps before the course. We have shown that a structured, hands-on course using a well-established simulation model can significantly improve postgraduate surgeons' skills in raising free flaps. PMID- 26628197 TI - Rearfoot posture of Australopithecus sediba and the evolution of the hominin longitudinal arch. AB - The longitudinal arch is one of the hallmarks of the human foot but its evolutionary history remains controversial due to the fragmentary nature of the fossil record. In modern humans, the presence of a longitudinal arch is reflected in the angular relationships among the major surfaces of the human talus and calcaneus complex, which is also known as the rearfoot. A complete talus and calcaneus of Australopithecus sediba provide the opportunity to evaluate rearfoot posture in an early hominin for the first time. Here I show that A. sediba is indistinguishable from extant African apes in the angular configuration of its rearfoot, which strongly suggests that it lacked a longitudinal arch. Inferences made from isolated fossils support the hypothesis that Australopithecus afarensis possessed an arched foot. However, tali attributed to temporally younger taxa like Australopithecus africanus and Homo floresiensis are more similar to those of A. sediba. The inferred absence of a longitudinal arch in A. sediba would be biomechanically consistent with prior suggestions of increased midtarsal mobility in this taxon. The morphological patterns in talus and calcaneus angular relationships among fossil hominins suggest that there was diversity in traits associated with the longitudinal arch in the Plio-Pleistocene. PMID- 26628199 TI - Carney's triad with paraganglioma. PMID- 26628200 TI - Assessment of magnetic resonance images of displacement of the disc of the temporomandibular joint in different types of condylar fracture. AB - To evaluate the displacement of the disc of the temporomandibular joint (TMJ) in different types of condylar fracture we studied 160 patients (222 joints) from May 2009-June 2014. All patients had computed tomographic scans (CT) and magnetic resonance images (MRI) taken preoperatively, and 24 patients (32 joints) had MRI postoperatively. CT scans were reviewed to categorise the types of condylar fracture (intracapsular, condylar neck, and subcondylar), and intracapsular condylar fractures were further classified into subtypes A, B, C, and M. MRI were then reviewed to record the position of the disc in each type of condylar fracture. The results were compared using the chi square test. There were 160 intracapsular condylar fractures, 40 fractures of the condylar neck, and 22 subcondylar fractures. Of the intracapsular condylar fractures, 75 were type A, 49 type B, 11 type C, and 25 type M. Discs were displaced in 153 intracapsular condylar fractures, 17 fractures of the condylar neck, and eight subcondylar fractures. Among the type A intracapsular condylar fractures, discs were displaced in 71/75, type B in 47/49, type C in 10/11, and in all 25 type M. The incidence of displaced discs between intracapsular condylar fractures on the one hand, and those of the condylar neck or subcondylar region on the other, was significant (p<0.001), but there were no differences among the various subtypes of intracapsular condylar fractures. Postoperative MRI showed successful results in 28/32 joints. Intracapsular condylar fractures were more likely to have displaced discs than the other types. But there were no differences among different subtypes of intracapsular condylar fractures. PMID- 26628201 TI - Cross-specialty developments: a summary of the mutually relevant recent literature from the journal of plastic, reconstructive and aesthetic surgery. AB - Keeping abreast of current developments is increasingly challenging when the volume of specialty articles being published is rising exponentially, and it is most acute when surgical specialties overlap, as in the case of head, neck, and facial reconstructive surgery. Here, the potential for missing key developments presents a compelling case for a summary article that highlights articles likely to be of mutual relevance. We evaluated 129 original studies and 6 reviews published in the Journal of Plastic, Reconstructive, and Aesthetic Surgery between September 2012 and August 2014, and summarised the main papers of interest and merit under the subheadings of head and neck reconstruction, cleft lip and palate, craniomaxillofacial surgery, facial palsy, facial trauma, and aesthetic surgery. Most of the evidence presented (86%) is level 4. PMID- 26628202 TI - Diagnosing perforated appendicitis in pediatric patients: a new model. AB - OBJECTIVE: Studies have investigated sensitivity and specificity of symptoms and tests for diagnosing appendicitis in children. Less is known with regard to the predictive value of these symptoms and tests with respect to the severity of appendicitis. The aim of this study was to determine the predictive value of patient's characteristics and tests for discriminating between perforated and nonperforated appendicitis in children. PATIENTS AND METHODS: Pediatric patients who underwent an appendectomy at Spaarne Hospital Hoofddorp, the Netherlands, between January 1, 2009 and December 31, 2013, were included. Baseline patient's characteristics, history, physical examination, laboratory data and results of ultrasounds were collected. Univariate and multivariate logistic regressions were used to determine predictors of perforation. RESULTS: In total, 375 patients were included in this study of which 97 children (25.9%) had significant signs of perforation. Univariate analysis showed that age, duration of complaints, temperature, vomiting, CRP, WBC, different findings on ultrasound and the diameter of the appendix were good predictors of a perforated appendicitis. The final multivariate prediction model included temperature, CRP, clearly visible appendix and free fluids on ultrasound and diameter of the appendix and resulted in an area under the curve (AUC) of 0.91 showing sensitivity and specificity of respectively 85.2% and 81.2%. CONCLUSION: This prediction model can be used for identification of 'high-risk' children for a perforated appendicitis and might be helpful to prevent complications and longer hospitalization by bringing these children to theater earlier. PMID- 26628203 TI - Patch tracheoplasty in body tissue engineering using collagenous connective tissue membranes (biosheets). AB - BACKGROUND: Collagenous connective tissue membranes (biosheets) are useful for engineering cardiovascular tissue in tissue engineering. The aim was to evaluate the use of biosheets as a potential tracheal substitute material in vivo in a rabbit model. METHODS: Group 1: Rectangular-shaped Gore-Tex (4*7mm) was implanted into a 3*6mm defect created in the midventral portion of the cervical trachea. Group 2: Rectangular-shaped dermis was implanted into a tracheotomy of similar size. Group 3: Biosheets were prepared by embedding silicone moulds in dorsal subcutaneous pouches in rabbits for 1month. Rectangular-shaped biosheets were implanted into a tracheotomy of similar size in an autologous fashion. All groups (each containing 10 animals) were sacrificed 4weeks after implantation. MAIN RESULTS: All materials maintained airway structure for up to 4weeks after implantation. Regenerative cartilage in implanted Biosheets in group 3 was confirmed by histological analysis. Tracheal epithelial regeneration occurred in the internal lumen of group 3. There were significant differences in the amounts of collagen type II and glycosaminoglycan between group 3 and group 1 or 2. CONCLUSION: We confirm that cartilage can self-regenerate onto an airway patch using Biosheets. PMID- 26628204 TI - Prospective assessment of complications on a daily basis is essential to determine morbidity and mortality in routine pediatric surgery. AB - AIMS OF THE STUDY: We aimed to assess postoperative complications prospectively on a daily basis and hypothesized that this would lead to an increase in the number of detected complications. METHODS: Surgical complications were assessed prospectively during a period of 8months. Systematic documentation was carried out daily during a team meeting (period S). Data were compared to those of a preceding period of 8-months of nonsystematic assessment (period N) in which complications had been documented in a self-reporting fashion. Complications were classified according to the Clavien-Dindo classification. RESULTS: A total of 1291 patients (mean age: 6.6years) were included. During period S complications were determined in 16% of 790 operations compared to 4% of 741 procedures in period N (p<0.01). This difference was owing to an increased detection of minor complications (grade I-III), i.e. wound infection, dysuria after hypospadias repair or postoperative bleeding. In contrast, the incidence of severe complications (grade IV+V) was not significantly different between the time periods (1.3% in period S and 0.8% in period N). Most frequent major complications were cardiopulmonary arrest, enterocolitis, and death. Severe complications accounted for 8% of complications discussed during weekly morbidity and mortality conferences in period S versus 22% in period N (p<0.05). CONCLUSION: Our results indicate that a systematic documentation of complications on a daily basis reveals a more realistic picture of the incidence of pediatric surgical complications and should be the method of choice. PMID- 26628205 TI - Transmission of an expanding donor-derived del(20q) clone through allogeneic hematopoietic stem cell transplantation without the development of a hematologic neoplasm. AB - Donor cell leukemia is a rare complication of allogeneic hematopoietic stem cell transplantation (HSCT), which may result from the development of a new malignancy in previously healthy donor cells after transplant into the recipient, or it may derive from the transmission of an occult leukemia from donor to recipient. We report a case of donor derived 20q11.2 deletion in a male patient who received an allogeneic HSCT from his HLA-identical sister for the treatment of his chronic lymphocytic leukemia. Bone marrow cells from the donor were found to contain the 20q deletion that expanded over time, but which was absent in her peripheral blood cells. Although cases of donor cell leukemia after HSCT have been reported, in this case there has been no evidence of an associated hematologic neoplasm in either the donor or recipient. Pre-transplant donor bone marrow evaluations are not practical or warranted, however the finding of new cytogenetic abnormalities after transplant mandates a thorough evaluation of the donor. PMID- 26628207 TI - Methyl donor supplementation in rats reverses the deleterious effect of maternal separation on depression-like behaviour. AB - Adverse early life events are associated with altered stress responsiveness and metabolic disturbances in the adult life. Dietary methyl donor supplementation could be able to reverse the negative effects of maternal separation by affecting DNA methylation in the brain. In this study, maternal separation during lactation reduced body weight gain in the female adult offspring without affecting food intake, and altered total and HDL-cholesterol levels. Also, maternal separation induced a cognitive deficit as measured by NORT and an increase in the immobility time in the Porsolt forced swimming test, consistent with increased depression like behaviour. An 18-week dietary supplementation with methyl donors (choline, betaine, folate and vitamin B12) from postnatal day 60 also reduced body weight without affecting food intake. Some of the deleterious effects induced by maternal separation, such as the abnormal levels of total and HDL-cholesterol, but especially the depression-like behaviour as measured by the Porsolt test, were reversed by methyl donor supplementation. Also, the administration of methyl donors increased total DNA methylation (measured by immunohistochemistry) and affected the expression of insulin receptor in the hippocampus of the adult offspring. However, no changes were observed in the DNA methylation status of insulin receptor and corticotropin-releasing hormone (CRH) promoter regions in the hypothalamus. In summary, methyl donor supplementation reversed some of the deleterious effects of an early life-induced model of depression in rats and altered the DNA methylation profile in the brain. PMID- 26628206 TI - Effects of Problem-Solving Therapy and Clinical Case Management on Disability in Low-Income Older Adults. AB - OBJECTIVE: To test the following hypotheses: (1) Clinical case management integrated with problem-solving therapy (CM-PST) is more effective than clinical case management alone (CM) in improving functional outcomes in disabled, impoverished patients and (2) improvement in depression, self-efficacy, and problem-solving skills mediates improvement of disability. METHODS: Using a randomized controlled trial with a parallel design, 271 individuals were screened and 171 were randomized to 12 weekly sessions of either CM or CM-PST at 1:1 ratio. Raters were blind to patients' assignments. Participants were at least age 60 years with major depression, had at least one disability, were eligible for home-based meals services, and had income no more than 30% of their counties' median. The WHO Disability Assessment Scale was used. RESULTS: Both interventions resulted in improved functioning by 12 weeks (t = 4.28, df = 554, p = 0.001), which was maintained until 24 weeks. Contrary to hypothesis, CM was noninferior to CM-PST (one-sided p = 0.0003, t = -3.5, df = 558). Change in disability was not affected by baseline depression severity, cognitive function, or number of unmet social service needs. Improvements in self efficacy (t = -2.45, df = 672, p = 0.021), problem-solving skill (t = -2.44, df = 546, p = 0.015), and depression symptoms (t = 2.25, df = 672, p = .025) by week 9 predicted improvement in function across groups by week 12. CONCLUSION: CM is noninferior to CM-PST for late-life depression in low-income populations. The effect of these interventions occur early, with benefits in functional status maintained as long as 24 weeks after treatment initiation (clinicaltrials.gov; NCT00540865). PMID- 26628208 TI - Behavioral characterization of CD36 knockout mice with SHIRPA primary screen. AB - CD36 is a member of the class B scavenger receptor family of cell surface proteins, which plays a major role in fatty acid, glucose and lipid metabolism. Besides, CD36 functions as a microglial surface receptor for amyloid beta peptide. Regarding this, we suggest CD36 might also contribute to neuropsychiatric disease. The aim of this study was to achieve a behavioral phenotype of CD36 knockout (CD36(-/-)) mice. We characterized the behavior of CD36(-/-) mice and C57BL/6J mice by subjecting them to a series of tests, which include SHIRPA primary behavioral screen test, 1% sucrose preference test, elevated plus-maze test, open-field test and forced swimming test. The results showed that CD36(-/-) mice traversed more squares, emitted more defecation, exhibited higher tail elevation and had more aggressive behaviors than C57BL/6J mice. The CD36(-/-) mice spent more time and traveled longer distance in periphery zone in the open-field test. Meanwhile, the numbers that CD36(-/-) mice entered in the open arms of elevated plus-maze were reduced. These findings suggest that CD36(-/-) mice present an anxious phenotype and might be involved in neuropsychiatric disorders. PMID- 26628209 TI - Genes involved in virulence of the entomopathogenic fungus Beauveria bassiana. AB - Pest insects cause severe damage to global crop production and pose a threat to human health by transmitting diseases. Traditionally, chemical pesticides (insecticides) have been used to control such pests and have proven to be effective only for a limited amount of time because of the rapid spread of genetic insecticide resistance. The basis of this resistance is mostly caused by (co)dominant mutations in single genes, which explains why insecticide use alone is an unsustainable solution. Therefore, robust solutions for insect pest control need to be sought in alternative methods such as biological control agents for which single-gene resistance is less likely to evolve. The entomopathogenic fungus Beauveria bassiana has shown potential as a biological control agent of insects, and insight into the mechanisms of virulence is essential to show the robustness of its use. With the recent availability of the whole genome sequence of B. bassiana, progress in understanding the genetics that constitute virulence toward insects can be made more quickly. In this review we divide the infection process into distinct steps and provide an overview of what is currently known about genes and mechanisms influencing virulence in B. bassiana. We also discuss the need for novel strategies and experimental methods to better understand the infection mechanisms deployed by entomopathogenic fungi. Such knowledge can help improve biocontrol agents, not only by selecting the most virulent genotypes, but also by selecting the genotypes that use combinations of virulence mechanisms for which resistance in the insect host is least likely to develop. PMID- 26628210 TI - Perkinsus olseni and P. chesapeaki detected in a survey of perkinsosis of various clam species in Galicia (NW Spain) using PCR-DGGE as a screening tool. AB - A survey on perkinsosis was performed involving 15 locations scattered along the Galician coast (NW Spain) and four clam species with high market value (Ruditapes decussatus, Ruditapes philippinarum, Venerupis corrugata and Polititapes rhomboides). The prevalence of Perkinsus parasites was estimated by PCR using genus-specific primers. The highest percentage of PCR-positive cases for perkinsosis corresponded to clams R. decussatus and V. corrugata, while lower values were detected in R. philippinarum and no case was found in P. rhomboides. The discrimination of Perkinsus species was performed by PCR-RFLP and by a new PCR-DGGE method developed in this study. Perkinsus olseni was identified in every clam species, except in P. rhomboides, using both PCR-DGGE and PCR-RFLP. Additionally, Perkinsus chesapeaki was only detected by PCR-DGGE infecting two Manila clams R. philippinarum from the same location, reporting the first case in Galicia. P. chesapeaki identification was further confirmed by in situ hybridisation assay and phylogenetic analysis of ITS region and LSU rDNA. PMID- 26628211 TI - Synthesis of SnO2 pillared carbon using long chain alkylamine grafted graphene oxide: an efficient anode material for lithium ion batteries. AB - With the objective of developing new advanced composite materials that can be used as anodes for lithium ion batteries (LIBs), herein we describe the synthesis of SnO2 pillared carbon using various alkylamine (hexylamine; dodecylamine and octadecylamine) grafted graphene oxides and butyl trichlorotin precursors followed by its calcination at 500 degrees C for 2 h. While the grafted alkylamine induces crystalline growth of SnO2 pillars, thermal annealing of alkylamine grafted graphene oxide results in the formation of amorphous carbon coated graphene. Field emission scanning electron microscopy (FE-SEM) results reveal the successful formation of SnO2 pillared carbon on the graphene surface. X-ray diffraction (XRD), transmission electron microscopy (TEM) and Raman spectroscopy characterization corroborates the formation of rutile SnO2 crystals on the graphene surface. A significant rise in the BET surface area is observed for SnO2 pillared carbon, when compared to pristine GO. Electrochemical characterization studies of SnO2 pillared carbon based anode materials showed an enhanced lithium storage capacity and fine cyclic performance in comparison with pristine GO. The initial specific capacities of SnO2 pillared carbon are observed to be 1379 mA h g(-1), 1255 mA h g(-1) and 1360 mA h g(-1) that decrease to 750 mA h g(-1), 643 mA h g(-1) and 560 mA h g(-1) depending upon the chain length of grafted alkylamine on the graphene surface respectively. Electrochemical impedance spectral analysis reveals that the exchange current density of SnO2 pillared carbon based electrodes is higher, corroborating its enhanced electrochemical activity in comparison with GO based electrodes. PMID- 26628213 TI - Clinical evaluation of prostate cancer gene 3 score in diagnosis among Chinese men with prostate cancer and benign prostatic hyperplasia. AB - BACKGROUND: Prostate cancer is the second most common diagnosed cancer in men. Due to the low specificity of current diagnosis methods for detecting prostate cancer, identification of new biomarkers is highly desirable. The study was conducted to determine the clinical utility of the prostate cancer gene 3 (PCA3) assay to predict biopsy-detected cancers in Chinese men. METHODS: The study included men who had a biopsy at The Affiliated Sixth People's Hospital of Shanghai Jiao Tong University from January 2013 to December 2013. Formalin-fixed, paraffin-embedded tissue blocks were used to test PCA3 and prostate-specific antigen (PSA) mRNA. The diagnostic accuracy of the PCA3 score for predicting a positive biopsy outcome was studied using sensitivity and specificity, and it was compared with PSA. RESULTS: The probability of a positive biopsy increased with increasing PCA3 scores. The mean PCA3 score was significantly higher in men with prostate cancer (198.03, 95 % confidence interval [CI] 74.79-321.27) vs benign prostatic hyperplasia (BPH) (84.31, 95 % CI 6.47-162.15, P < 0.01). The PCA3 score (cutoff 35) had a sensitivity of 85.7 % and specificity of 62.5 %. Receiver operating characteristic analysis showed higher areas under the ROC curve for the PCA3 score vs PSA, but without statistical significance. CONCLUSIONS: Increased PCA3 in biopsy tissue correlated with prostate cancer and the PCA3 assay may improve the diagnosis efficacy as the PCA3 score being independent of PSA level. The diagnostic significance of urinary PCA3 testing should be explored in future study to determine the prediction value in guiding biopsy decision as the clinical relevance of current study was limited for PCA3 testing based on biopsy tissue in a limited number of Chinese men. PMID- 26628212 TI - Serum bilirubin concentration is modified by UGT1A1 haplotypes and influences risk of type-2 diabetes in the Norfolk Island genetic isolate. AB - BACKGROUND: Located in the Pacific Ocean between Australia and New Zealand, the unique population isolate of Norfolk Island has been shown to exhibit increased prevalence of metabolic disorders (type-2 diabetes, cardiovascular disease) compared to mainland Australia. We investigated this well-established genetic isolate, utilising its unique genomic structure to increase the ability to detect related genetic markers. A pedigree-based genome-wide association study of 16 routinely collected blood-based clinical traits in 382 Norfolk Island individuals was performed. RESULTS: A striking association peak was located at chromosome 2q37.1 for both total bilirubin and direct bilirubin, with 29 SNPs reaching statistical significance (P < 1.84 * 10(-7)). Strong linkage disequilibrium was observed across a 200 kb region spanning the UDP-glucuronosyltransferase family, including UGT1A1, an enzyme known to metabolise bilirubin. Given the epidemiological literature suggesting negative association between CVD-risk and serum bilirubin we further explored potential associations using stepwise multivariate regression, revealing significant association between direct bilirubin concentration and type-2 diabetes risk. In the Norfolk Island cohort increased direct bilirubin was associated with a 28% reduction in type-2 diabetes risk (OR: 0.72, 95% CI: 0.57-0.91, P = 0.005). When adjusted for genotypic effects the overall model was validated, with the adjusted model predicting a 30% reduction in type-2 diabetes risk with increasing direct bilirubin concentrations (OR: 0.70, 95% CI: 0.53-0.89, P = 0.0001). CONCLUSIONS: In summary, a pedigree based GWAS of blood-based clinical traits in the Norfolk Island population has identified variants within the UDPGT family directly associated with serum bilirubin levels, which is in turn implicated with reduced risk of developing type-2 diabetes within this population. PMID- 26628214 TI - 3D navigation of endoscopic rhizotomy at the lumbar spine. AB - We present a detailed description of the surgical technique and the preliminary results of an endoscopic denervation for patients with chronic low back pain (CLBP) originating from the facet joints (FJ). Endoscopic denervation of the medial branches of the dorsal rami supplying the FJ has recently been appraised as providing excellent intraoperative visualization and long term pain relief for these patients. Conventional endoscopic rhizotomy has been expanded to include a the precise localization of 3D navigation. A surgical description and the results of our first four patients treated with 3D navigated endoscopic rhizotomy (3DNER) are presented. Four patients with a mean age of 59years and a follow-up time of 2months were included. All patients reported pain reduction in the immediate postoperative period, while three patients (75%) had long lasting relief. The patient without persisting relief had previously sustained a lumbar disc prolapse and only achieved minor pain relief with preoperative FJ infiltration, compared to the significant relief that was seen in the other patients. In contrast to conventional rhizotomy, 3DNER enables the surgeon to ablate more precisely and extensively, which is especially useful if scar tissue is present from previous injuries or surgeries. When successful, this technique may provide long lasting pain relief, especially if the preoperative FJ infiltrations are followed by a substantial pain reduction. PMID- 26628215 TI - Periparturient stress and immune suppression as a potential cause of retained placenta in highly productive dairy cows: examples of prevention. AB - The immune system during the periparturient period is impaired. At this time the most important factor causing immune-suppression in highly productive cows is metabolic stress resulting from hormonal and metabolic fluctuations, a negative energy balance, shortage of proteins, minerals and vitamins which are required to meet the demands of the fetus as well as the onset of lactation. This stress can activate the hypothalamic-pituitary-adrenocortical axis (HPA), which results in increase plasma corticosteroids. As a result, the cortisol concentration during the periparturient period increases by several folds particularly on the day of calving. Cortisol is a powerful immune-suppressive agent. During stress, this hormone causes depression of the leukocyte proliferation and their functions. Decreased phagocytosis of neutrophils, decreased cytotoxic ability of lymphocytes, as well as depressed activity of their cytokines, make it impossible for the normal, efficient maternal immune recognition and rejection of fetal membranes (as a foreign, allogeneic tissue expressed fetal antigens-MHC class I proteins by trophoblast cells) and finally results in their retention in cows. The metabolic periparturient stress also activates production of catecholamines, especially adrenalin. Adrenalin activates adrenoreceptors of the myometrium and then causes hypotony or atony of the uterus. Thus, cortisol and adrenalin inhibit rejection and expulsion of fetal membranes and cause their retention. These mechanisms of retained placenta (RP) often have a metabolic etiology and occur in herds, where important infectious diseases causing placentitis are absent or prevented. The aim of this article is to show the fundamental mechanisms occurring during periparturient stress and the accompanied immune-suppression in cows, as well as their consequences in relation to RP. The paper also gives examples of the symptomatic prevention of RP in cows caused by metabolic and immune suppressive factors. The prevention of RP was carried out using drugs which inhibit the activity of cortisol or adrenalin in dairy cows during calving. PMID- 26628216 TI - The effect of the financial crisis on physical health: Perceived impact matters. AB - The impact of the financial crisis on health was investigated ( N = 312). Intraindividual intercept, slope, and quadratic parameters capturing trends in income, subjective financial situation, and perceived stress across the period predicted physical health, controlling for baseline health. For those experiencing a decline in financial situation, a decrease in financial situation and an increase in perceived stress predicted poorer health; neither financial situation nor perceived stress predicted health in those not experiencing this decline. Although we cannot intervene in contextual factors like the financial crisis, health outcomes may be improved by targeting perceived impact and stress levels in those who feel affected. PMID- 26628217 TI - Landscape structure in the Pirapo, Paranapanema 3 and 4 Hydrographic Unit, in the state of Parana, Brazil. AB - The aim of this study is to characterize the Pirapo, Paranapanema 3 and 4 Hydrographic Unit, emphasizing its physical attributes and processes of use and occupation, responsible for the structure of the current landscape and the state of its water resources. The recognition of the landscape's spatial structure in the hydrographic unit and its drainage basins was obtained by integrated analysis of the main elements that compose it: geology, landforms (hypsometric and slope), soils, climate and land use. Analysis revealed that within each drainage basin several variations in the spatial structure of the landscape occur which produce an internal compartmentalization. Each compartment is defined by its own geo ecological structure, physiognomic standards and dynamics, reflected in its potentialities and vulnerabilities and in the conditions of water resources in the wake of occupation and use over time. PMID- 26628218 TI - Effect of water temperature and salinity in oviposition, hatching success and infestation of Aphanoblastella mastigatus (Monogenea, Dactylogyridae) on Rhamdia quelen. AB - Several environmental parameters may influence biological processes of several aquatic invertebrates, such as the Monogenea. Current analysis investigates oviposition, hatching success and infestation of Aphanoblastella mastigatus, a parasite of the silver catfish Rhamdia quelen at different temperatures (~ 24 and 28 degrees C) and salinity (by adding sodium chloride to water, at concentrations 0, 5 and 9 g/L) in laboratory. There was no significant difference in oviposition rate and in A. mastigatus infestation success at 24 and 28 degrees C. On the other hand, the concentration 9 g/L of sodium chloride in the water impaired the parasite's survival and the viability of the eggs. Results show that its usage is efficient as a possible prophylactic treatment. Eclosion rate of A. mastigatus's eggs was significantly higher at 28 degrees C, although it was significantly less from 5 g/L. Two oviposition peaks (06h15 and 18h15) occurred during a 24-hour period, or rather, during the highest variations in luminosity. Further studies are recommended with greater temperature intervals and more intense experimental infestations to verify the effects of temperature in the life span and infestation success of A. mastigatus. PMID- 26628219 TI - Multitemporal analysis of estimated soil loss for the river Mourao watershed, Parana - Brazil. AB - The multitemporal behavior of soil loss by surface water erosion in the hydrographic basin of the river Mourao in the center-western region of the Parana state, Brazil, is analyzed. Forecast was based on the application of the Universal Soil Loss Equation (USLE) with the data integration and estimates within an Geography Information System (GIS) environment. Results had shown high mean annual rain erosivity (10,000 MJ.mm.ha(-1).h(-1).year(-1)), with great concentration in January and December. As a rule, soils have average erodibilities, exception of Dystroferric Red Latisol (low class) and Dystrophic Red Argisol (high class). Although the topographic factor was high (>20), rates lower than 1 were predominant. Main land uses comprise temporal crops and pasture throughout the years. The watershed showed a natural potential for low surface erosion. When related to usage types, yearly soil loss was also low (<50 ton.ha( 1).year(-1)), with more critical scores that reach rates higher than 150 ton.ha( 1).year(-1). Soil loss over the years did not provide great distinctions in distribution standards, although it becames rather intensified in some sectors, especially in the center-eastern and southwestern sections of the watershed. PMID- 26628220 TI - Is otolith microchemistry (Sr: Ca and Ba:Ca ratios) useful to identify Mugil curema populations in the southeastern Caribbean Sea? AB - The aim of the present study was to evaluate the potential use of otolith microchemistry (Sr:Ca and Ba:Ca ratios) to identify silver mullet, Mugil curema, populations in Southeastern Caribbean Sea. Fish samples were collected in 7 areas of Nueva Esparta State (Venezuela). The otolith Sr:Ca and Ba:Ca ratios and water Sr:Ca were determined (by ICP-OES and EDTA volumetric method). Otoliths Sr:Ca and Ba:Ca ratios and Sr:Ca partition coefficient of mullets in Cubagua island (south of the State) were significantly different from ratios in La Guardia (north of the State). A discriminant analysis of otolith Sr:Ca and Ba:Ca ratios separated Cubagua Island from La Guardia values. These results suggest the existence of different mullet groups in the Southeastern Caribbean Sea. For this, the simultaneous use of Sr:Ca and Ba:Ca ratios could be a potential tool to identify populations in the study area. PMID- 26628221 TI - Monitoring of urban and rural basins: water quality of Mourao basin. AB - The Mourao River basin is located on the central western region of the Parana State - Brazil, between coordinates 23o 44' - 24o 25 South latitude and 52o 12' - 52o 30' West longitude, between 270 and 820 m above sea level, and 1,648.21 km2 drainage area. Water quality was evaluated by monitoring physical, chemical and microbiological parameters. Monthly samplings were performed for a year at five sites in the basin for analysis of: pH, temperature, dissolved oxygen, biochemical oxygen demand, total nitrogen, ammoniacal nitrogen, nitrite, nitrate, total phosphorus, turbidity, total solids, volatile solids and fecal coliforms. The results of the evaluated parameters showed higher values than the limits set by CONAMA Resolution 357 from 2005 for Class 2 in some samples. The Water Quality Index (WQI) indicated that 72% of samples had average quality and 28% had good quality for the Mourao River basin. Higher values of WQI were observed after rainfall period with median of 75 compared to the dry period with median of 62. The source of the Mourao River is contaminated with fecal coliforms, evidencing the real need to treat sewage in rural areas. PMID- 26628222 TI - Influence of antifouling paint on freshwater invertebrates (Mytilidae, Chironomidae and Naididae): density, richness and composition. AB - We conducted a study about invertebrates on artificial substrates with different antifouling paints in order to answer the following questions 1) is there lower accumulation of organic matter on substrates with antifouling paints, 2) is invertebrate colonization influenced by the release of biocides from antifouling paints, 3) is the colonization of aquatic invertebrates positively influenced by the material accumulated upon the substrate surface and 4) is the assemblage composition of invertebrates similar among the different antifouling paints? To answer these questions, four structures were installed in the Baia River in February 1st, 2007. Each structure was composed of 7 wood boards: 5 boards painted with each type of antifouling paints (T1, T2, T3, T4 and T5), one painted only with the primer (Pr) and the other without any paint (Cn). After 365 days, we observed a greater accumulation of organic matter in the substrates with T2 and T3 paint coatings. Limnoperna fortunei was recorded in all tested paints, with higher densities in the control, primer, T2 and T3. The colonization of Chironomidae and Naididae on the substrate was positively influenced by L. fortunei density. The non-metric multidimensional scaling (NMDS) of the invertebrate community provided evidence of the clear distinction of invertebrate assemblages among the paints. Paints T2 and T3 were the most similar to the control and primer. Our results suggest that antifouling paints applied on substrates hinder invertebrate colonization by decreasing the density and richness of invertebrates. PMID- 26628223 TI - Microbiological and faunal soil attributes of coffee cultivation under different management systems in Brazil. AB - Brazil is the biggest coffee producer in the world and different plantation management systems have been applied to improve sustainability and soil quality. Little is known about the environmental effects of these different management systems, therefore, the goal of this study was to use soil biological parameters as indicators of changes. Soils from plantations in Southeastern Brazil with conventional (CC), organic (OC) and integrated management systems containing intercropping of Brachiaria decumbens (IB) or Arachis pintoi (IA) were sampled. Total organic carbon (TOC), microbial biomass carbon (MBC) and nitrogen (MBN), microbial activity (C-CO2), metabolic quotient (qCO2), the enzymes dehydrogenase, urease, acid phosphatase and arylsulphatase, arbuscular mycorrhizal fungi (AMF) colonization and number of spores and soil fauna were evaluated. The greatest difference between the management systems was seen in soil organic matter content. The largest quantity of TOC was found in the OC, and the smallest was found in IA. TOC content influenced soil biological parameters. The use of all combined attributes was necessary to distinguish the four systems. Each management presented distinct faunal structure, and the data obtained with the trap method was more reliable than the TSBF (Tropical Soils) method. A canonic correlation analysis showed that Isopoda was correlated with TOC and the most abundant order with OC. Isoptera was the most abundant faunal order in IA and correlated with MBC. Overall, OC had higher values for most of the biological measurements and higher populations of Oligochaeta and Isopoda, corroborating with the concept that the OC is a more sustainable system. PMID- 26628224 TI - Aspects of the ecology of Penelope superciliaris temminck, 1815 (Aves: Cracidae) in the Araripe National Forest, Ceara, Brazil. AB - Guans are large frugivorous birds that inhabit Neotropical forests and play a fundamental role in seed dispersal and forest regeneration. Despite their ecological importance, the natural populations of these birds are increasingly threatened by deforestation and hunting pressure. The present study was conducted in the Araripe National Forest, Ceara (Brazil), with the objective of estimating population parameters (density and total population size) in the Rusty-margined Guan (Penelope superciliaris) and the White-browed Guan (Penelope jacucaca), as well as providing data on their feeding ecology, including seasonal variation and fruit morphology. The study was based on the monthly collection of data between November, 2011, and October, 2012. Population parameters were estimated using line transect surveys, while feeding ecology was studied by direct observation, and the collection of plant and fecal samples. The estimated population density of P. superciliaris was 19.17 individuals/km2 (CV=13.98%), with a mean of 0.13 sightings per 10 km walked. Penelope jacucaca was not encountered during the surveys. A total of 14 plant species were recorded in the diet of P. superciliaris, 12 by direct observation, and two from fecal samples. Fruit diameter varied from 6.3 +/- 1.35 mm (Miconia albicans) to 29.9 +/- 1.7 mm (Psidium sp.). Yellow was the most frequent fruit color (41.6%, n=5), with two species each (16.6%) providing black, green, and red fruits. Fleshy fruits of the baccate (50.0%, n=6) and drupe (33.3%, n=4) types were the most consumed. The data on population parameters and feeding ecology collected in the present study provide an important database for the development of effective management strategies by environmental agencies for the conservation of the populations of the two guan species. PMID- 26628225 TI - Preliminary assessment of pseudo-total and bioavailable metals in depth in the sediment of Luiz Rau stream in Novo Hamburgo (RS). AB - The Luiz Rau stream is one of the main streams of Novo Hamburgo. In the stream industrial effluents are released from various sectors, from paint and adhesive industries, metallurgy and leather industry, besides receiving a large amount of domestic sewage. The emissions of these pollutants contribute to decrease water and sediment quality. Within this context, this study evaluated the conditions of the Luiz Rau stream bed sediments, with the determination of the metals like cadmium, lead, chromium and nickel, in depth. To perform the evaluation three points were chosen for sampling along the stream course. The sampling sites were identified as Point A, in Roselandia district and this corresponds to one of the springs and therefore considered as reference value, Point B, in Santo Afonso district being a midpoint of the stream, and Point C also located in Santo Afonso district, near the outfall in Rio dos Sinos river. Cadmium was not detected in any point. At the A and C points chromium was the metal observed in higher concentration in the sediment, up to 45.14 mg kg(-1) concentration. In the B point, the metal that was observed in the highest amount was nickel in the concentration of 20.69 mg kg(-1). PMID- 26628226 TI - Water level effect on herbaceous plant assemblages at an artificial reservoir Lago Azul State Park, Southern Brazil. AB - This study presents the effect of water level variation on the assemblages of herbaceous species in Mourao I Reservoir, Lago Azul State Park, Southern Brazil. The structure and distribution of populations was examined in February (dry period) and April (rainy period), 2011, in two transects. These transects started at the forest edge towards the center of the lake. The end of the transect coincided with the end of the plants within the lake. On every two meters along of the transects we sampled a wooden square of 0.25 m(2) for species biomass analysis.The macrophyte stand was composed entirely of emergent species. Considering the periods, most species were less frequent in the rainy period (April), but Ipomea ramosissima (Poir.) Choisy, Commelina nudiflora L., Eleocharis acuntagula (Roxb.) Schult. and Verbena litorales (Kunth.) had their frequency increased during this period, probably due to their resistance. The influence of flood as measured by the NMDS point out that both before and after the flood, there are plots with distinct compositions and biomass. The water level variation affects the dynamics of plant composition and structure in marginal areas of the Reservoir. PMID- 26628227 TI - Microhabitats occupied by Myxomycetes in the Brazilian Atlantic Forest: Heliconiaceae inflorescences. AB - The occurrence of Myxomycetes in Heliconia psittacorum L.f. inflorescences was researched within four conservation units located in Northeast Brazil, aiming at evaluating the occupation of this microhabitat in fragments of Atlantic Forest along an altitude between 30-750 m. Inflorescences attached to the plant were examined; dead flowers and bracts were collected to assemble moist chambers (368). Four families, four genera and 10 species were recorded. A preference was evidenced for a basic pH substrate and a predominance of calcareous species (5:1). The composition of the myxobiota in fragments pertaining to altitudes above 400 m was similar and differed significantly from the one found in fragments of lowland forests (<100 m). Physarum compressum and Arcyria cinerea are the most characteristic species of the studied myxobiota. PMID- 26628228 TI - Water quality assessment of the Sinos River - RS, Brazil. AB - Worldwide environmental pollution is increasing at the same rate as social and economic development. This growth, however, is disorganized and leads to increased degradation of water resources. Water, which was once considered inexhaustible, has become the focus of environmental concerns because it is essential for life and for many production processes. This article describes monitoring of the water quality at three points along the Sinos River (RS, Brazil), one in each of the upper, middle and lower stretches. The points were sampled in 2013 and again in 2014. The water samples were analyzed to determine the following physical and chemical parameters plus genotoxicity to fish: metals (Cr, Fe, Al), chemical oxygen demand, biochemical oxygen demand, chlorides, conductivity, total suspended solids, total phosphorous, total and fecal coliforms, pH, dissolved oxygen, turbidity, total Kjeldahl nitrogen nitrate and ammoniacal nitrogen. Genotoxicity was tested by exposing individuals of the species Astyanax jacuhiensis to water samples and then comparing them with a control group exposed to water from the public water supply. The results confirmed the presence of substances with genotoxic potential at the sample points located in the middle and lower stretches of the river. The results for samples from the upper stretch, at P1, did not exhibit differences in relation to the control group. The physical and chemical analyses did not detect reductions in water quality in the lower stretch, as had been expected in view of the large volumes of domestic and industrial effluents discharged into this part of the river. PMID- 26628229 TI - Growth of tropical tree species and absorption of copper in soil artificially contaminated. AB - Reclamation of copper contaminated sites using forest species may be an efficient alternative to reduce the negative impact. The aim of this study was to quantify the growth and evaluate the quality of seedlings of native species at different doses of copper in the soil. The experimental design was completely randomized, with seven replications in a factorial arrangement (3*9), using three indigenous species of plants (Anadenanthera macrocarpa, Mimosa scabrella and Apuleia leiocarpa) and nine doses of copper in the soil (0, 60, 120, 180, 240, 300, 360, 420 and 480 mg kg-1).The experiment was carried out in a greenhouse which the seedlings were grown for 180 days. The experimental units were plastic pots of 125 cm3 filled with Oxisol. The results indicated that the levels of copper applied to the soil decreased the quality of seedlings and growth of Apuleia leiocarpato a lesser extent compared with Mimosa scabrella and Anadenanthera macrocarpa. Anadenanthera macrocarpa was the forest species that resulted in the lowest copper translocation from roots to shoots. In addition, the Apuleia leiocarpa exhibited high resistance and tolerance for copper in the soil and also, it is highlighted an ability for copper phytoremediation. PMID- 26628230 TI - The leaf breakdown of Picramnia sellowii (Picramniales: Picramniaceae) as index of anthropic disturbances in tropical streams. AB - There are few studies in tropical regions exploring the use of leaf breakdown process as a functional tool to assess anthropic disturbance on aquatic ecosystems. We assessed the effects of water pollution due to human activities on the leaf breakdown rate of Picramnia sellowii in streams of the southeastern Brazil. The experiment was carried out for 60 days in three reference streams and three streams impaired by organic pollution and absence of riparian vegetation. Three litter bags were incubated in each stream containing 3 +/- 0.05 g of P. sellowii leaves. The reference streams presented higher values of dissolved oxygen and lower values of nutrients, turbidity, electrical conductivity, total impermeable area and water temperature. The leaf breakdown rate (k) differed significantly between the reference (k = 0.014 +/- 0.003 d-1) and impaired streams (k = 0.005 +/- 0.001 d-1). The leaves incubated in the reference streams contained greater fungal biomass (measured as ergosterol concentration) and abundance of invertebrates, as well as greater presence of shredders, with k values being related to the biomass of these organisms. Overall, there were clear differences between the leaf mass loss in the reference and impaired streams. These results reinforce the negative effect of urbanization on leaf breakdown and fungal and shredder biomass. PMID- 26628231 TI - Biomonitoring the genotoxic potential of the air on Tradescantia pallida var. purpurea under climatic conditions in the Sinos River basin, Rio Grande do Sul, Brazil. AB - The present study evaluated the genotoxic effects of the atmospheric air on Tradescantia pallida var. purpurea in urban areas with different intensities of vehicular traffic and in riparian forest fragments in the Sinos River Basin (Rio Grande do Sul, Brazil), considering the influence of climatic conditions prevailing in these environments. Bimonthly, from May 2012 to March 2013, cuttings with flower buds were exposed for 8 h in urban and riparian forest environments in the municipalities of Caraa, Taquara and Campo Bom in the upper, middle and lower sections, respectively, of the Sinos River Basin. Simultaneously, negative controls were made and climatic data were recorded. Micronuclei (MCN) frequencies were determined in young tetrads of pollen mother cells and expressed as MCN/100 tetrads. Significantly higher MCN frequencies were observed in buds exposed in urban and riparian forest environments in Taquara (up to 7.23 and 4.80, respectively) and Campo Bom (up to 4.90 and 4.23, respectively) than in buds exposed in Caraa (up to 2.90 and 2.50, respectively), in the majority of samplings, and in relation to the negative control (up to 1.93) in all months. Over the course of the period monitored, there were significant variations in MCN frequencies at all sampling points, with the exception of the urban environment in Caraa. For the urban environments, relation between the MCN frequency, vehicular traffic and mean temperature was observed. For the riparian forest fragments, there was no association between MCN frequency and climatic factors. Tradescantia pallida var. purpurea can be considered a useful tool to point out areas with increased atmospheric pollution, since the exposure of plants under severe climatic conditions is avoided to minimize their negative influence on the formation of micronuclei. PMID- 26628232 TI - First record of Porocephalus cf. clavatus (Pentastomida: Porocephalida) as a parasite on Bothrops asper (Squamata: Viperidae) in Costa Rica. AB - Pentastomids are parasites that infect respiratory cavities of vertebrates, they are pretty common but poorly known in wildlife veterinary. A Bothrops asper snake (Garman, 1884) was captured in the Caribbean region of Costa Rica and had its lung infested with pentastomids, identified as ca Porocephalus clavatus (Wyman, 1845). This represents the first record of Porocephalus (Humboldt, 1812) on B. asper as well as P. cf. clavatus in Costa Rica. Further studies are needed to clarify their taxonomic position, images and scanning electron microscopy photographs (SEM) of the specimens are given. PMID- 26628233 TI - Concentrations of PM2.5-10 and PM2.5 and metallic elements around the Schmidt Stream area, in the Sinos River Basin, southern Brazil. AB - This research aimed to evaluate the air quality, by determining the concentrations of PM2.5-10, PM2.5 and the metallic elements Al, Ba, Cd, Cr, Cu, Fe, Mn, Ni, Pb, Zn and Hg in the leaf part of ryegrass (Lolium multiflorum) in an area close to Schmidt Stream, at the lower section of Sinos River Basin (SRB), in a research campaign of six months, from October 2013 to March 2014. The particles collected in the PM sampling were analyzed by Scanning Electron Microscopy (SEM) combined with Energy Dispersive X-ray Spectrometry (EDS), in order to study their morphology and chemical composition. The mean concentration of PM2.5-10 was 9.1 ug m(-3), with a range of 2.2 ug m(-3) to 15.4 ug m(-3) and the mean concentration of PM2.5 was 4.7 ug m(-3), with a range of 1.9 ug m(-3) to 8.2 ug m(-3). Concentrations of metallic elements, especially Pb, Cr and Zn, were classified as Class 4 (very high pollution levels), according to the classification proposed by Klumpp et al. (2004). Chemical and morphological analysis of PM revealed the presence of particles of biological origin, soot (Cr, Fe, Ni, Zn, Cd, Hg and Pb), salts (KCl) and soil resuspension (Al and Si). The integrated study methodology, employing environmental variables, such as PM and ryegrass, can be of help in the preparation of wide-ranging environmental diagnoses, in addition providing information needed to develop precautionary measures designed to minimize the effects of atmospheric pollution that takes into consideration the environment's supportive capacity and environmental quality. PMID- 26628234 TI - Shell occupation by the hermit crab Dardanus insignis (Decapoda, Diogenidae) from the north Coast of Sao Paulo state, Brazil. AB - The pattern of shell occupation by the hermit crab Dardanus insignis (Saussure, 1858) from the subtropical region of southeastern coast of Brazil was investigated in the present study. The percentage of shell types that were occupied and the morphometric relationships between hermit crabs and occupied shells were analyzed from monthly collections conducted during two years (from January 1998 to December 1999). Individuals were categorized according to sex and gonadal maturation, weighed and measured with respect to their cephalothoracic shield length (CSL) and wet weight (CWW). Shells were measured regarding their aperture width (SAW), dry weight (SDW) and internal volume (SIV). A total of 1086 hermit crabs was collected, occupying shells of 11 gastropod species. Olivancillaria urceus (Roding, 1798) was most commonly used by the hermit crab D. insignis, followed by Buccinanops cochlidium (Dillwyn, 1817), and Stramonita haemastoma (Linnaeus, 1767). The highest determination coefficients (r2 > 0.50, p < 0.01) were recorded particularly in the morphometric relationships between CSL vs. CWW and SAW vs. SIV, which are important indication that in this D. insignis population the great majority the animals occupied adequate shells during the two years analysed. The high number of used shell species and relative plasticity in pattern of shell utilization by smaller individuals of D. insignis indicated that occupation is influenced by the shell availability, while larger individuals demonstrated more specialized occupation in Tonna galea (Linnaeus, 1758) shell. PMID- 26628235 TI - Influence of urban area on the water quality of the Campo River basin, Parana State, Brazil. AB - The Campo River basin is located on the third plateau of the Parana State or trap plateau of Parana, at the middle portion between the rivers Ivai and Piquiri, southern Brazil, between the coordinates 23 degrees 53 and 24 degrees 10' South Latitude and 52 degrees 15' and 52 degrees 31' West Longitude. The basin has 384 Km2 area, being 247 km2 in the municipality of Campo Mourao and 137 km2 in the municipality of Peabiru, in Parana State. The Campo River is a left bank tributary of the Mourao River, which flows into the Ivai River. The objective of this study was to monitor water quality in the Km 119 River and the Campo River, tributaries of the Mourao River, with monthly collection of water samples to determine pH, temperature, turbidity, biochemical oxygen demand, dissolved oxygen, fecal coliforms, total solids, total nitrogen, ammoniacal nitrogen, nitrite, nitrate and total phosphorus. The results obtained were compared with the indices established by the environmental legislation and applied in the determination of the Water Quality Index (WQI) used by the Water Institute of Parana State, regulating environmental agency. Poor water quality in these rivers presents a worrying scenario for the region, since this river is the main source of water supply for the public system. Results of organic matter, fecal coliforms and total phosphorus were higher than the limits established by Resolution CONAMA 357/2005 to river class 2, specially at downstream of the Km 119 River and the Campo River, due to the significant influence of the urban anthropic activity by the lack of tertiary treatment and also rural by the lack of basic sanitation in this area. Results of WQI of Km 119 River and do Campo River indicated that water quality can be classified as average in 71% and good in 29% of the sites evaluated. PMID- 26628236 TI - Pollen analysis of honey and pollen collected by Apis mellifera linnaeus, 1758 (Hymenoptera, Apidae), in a mixed environment of Eucalyptus plantation and native cerrado in Southeastern Brazil. AB - Eucalyptus plantations are frequently used for the establishment of bee yards. This study was carried on at Fazenda Brejao, northwestern region of the State of Minas Gerais, Brazil. This farm is covered both with native Cerrado vegetation (Brazilian savanna) and eucalyptus plantations. This paper reports on the botanic origin of pollen pellets and honey collected from honeybee (Apis mellifera) hives along a thirteen-month period (January 2004 to January 2005). The most frequent pollen types found in the pollen pellets during the rainy season were Trema micrantha (Ulmaceae), Copaifera langsdorffii (Fabaceae), an unidentified Poaceae, unidentified Asteraceae-2, Cecropia sp. 1 (Cecropiaceae) and Eucalyptus spp. (Myrtaceae); during the dry season the most frequent pollen types were Acosmium dasycarpum (Fabaceae), Cecropia sp. 1 (Cecropiaceae) and Eucalyptus spp. (Myrtaceae). Pollen grains of Baccharis sp. (Asteraceae), Cecropia sp. 1 (Cecropiaceae), Copaifera langsdorffii (Fabaceae), Mimosa nuda (Fabaceae), Eucalyptus spp. (Myrtaceae) and Trema micrantha (Ulmaceae) were present in the honey samples throughout the study period. PMID- 26628237 TI - Effects of the organophosphorus pesticide Folisuper 600 (methyl parathion) on the heart function of bullfrog tadpoles, Lithobates catesbeianus (Shaw, 1802). AB - The aim of this work was to evaluate whether the heart function of bullfrog tadpoles (25 Gosner stage) is affected by their acute exposure (48 h) to a sub lethal concentration (10 ug.L-1) of the active principle of the organophosphorus pesticide Folisuper 600R (methyl parathion - MP). Our results demonstrated that MP causes not only a reduction in tadpoles' cardiac ventricular mass, resulting in a marked reduction in their cardiac twitch force, but also impairs their swimming performance, irrespective of increasing their heart rate. Together, these findings indicate that low and realistic concentration of MP have a negative impact on tadpoles' performance, jeopardizing their survival. PMID- 26628238 TI - Myxomycetes from mangroves: species occurring in the state of Maranhao, northeastern Brazil. AB - Mangrove swamps and forests cover over 137,000 km2 distributed latitudinally among subtropical zones, 7% of which are in Brazil, with a greater density in the country's northernmost region. Considering that the community of Myxomycetes recorded for this environment is hardly known, three areas located in the state of Maranhao were investigated. Two field trips were conducted, one at the beginning of the rainy season and another during the dry season. In each area, two plots (125 m2) equidistant 100 m apart from each other were surveyed. In these areas, standing dead tree trunks and dead branches still attached to the mother plant that were above the tideline, were examined. On these same occasions, samples of the aerial litter and from the cortex of living trees (Rhizophora) were collected for the preparation of moist chambers cultures. Twenty-one specimens were obtained from field and moist chambers, belonging to 11 species, distributed in nine genera and five families. Seven species are new records from Maranhao. There was a predominance of r-strategist (73%) over K strategist (27%) species. Cribraria violacea, Comatricha tenerrima, Echinostelium minutum, and Fuligo septica are new worldwide records from mangrove environments, and Oligonema flavidum is reported for the first time from Brazil. PMID- 26628240 TI - Degradation and inactivation of adenovirus in water by photo-electro-oxidation. AB - The present study analyzed the efficiency of the photo-electro-oxidation process as a method for degradation and inactivation of adenovirus in water. The experimental design employed a solution prepared from sterile water containing 5.107 genomic copies/L (gc/L) of a standard strain of human adenovirus type 5 (HAdV-5) divided into two equal parts, one to serve as control and one treated by photo-electro-oxidation (PEO) for 3 hours and with a 5A current. Samples collected throughout the exposure process were analyzed by real-time polymerase chain reaction (qPCR) for viral genome identification and quantitation. Prior to gene extraction, a parallel DNAse treatment step was carried out to assess the integrity of viral particles. Integrated cell culture (ICC) analyses assessed the viability of infection in a cell culture. The tested process proved effective for viral degradation, with a 7 log10 reduction in viral load after 60 minutes of treatment. The DNAse-treated samples exhibited complete reduction of viral load after a 75 minute exposure to the process, and ICC analyses showed completely non viable viral particles at 30 minutes of treatment. PMID- 26628241 TI - Physical characterization of a watershed through GIS: a study in the Schmidt stream, Brazil. AB - Remote sensing and geoprocessing are essential tools for obtaining and maintaining records of human actions on space over the course of time; these tools offer the basis for diagnoses of land use, environmental interference and local development. The Schmidt stream watershed, located in the Sinos River basin, in southern Brazil, has an environmental situation similar to that of the majority of small streams draining rural and urban areas in southern Brazil: agricultural and urbanization practices do not recognize the riparian area and there is removal of original vegetation, disregarding the suitability of land use; removal of wetlands; intensive water use for various activities; and lack of control and monitoring in the discharge of wastewater, among other factors, deteriorate the quality of this important environment.This article aims to achieve a physical characterization of the Schmidt stream watershed (Sinos river basin) identifying elements such as land use and occupation, soil science, geology, climatology, extent and location of watershed, among others, so as to serve as the basis for a tool that helps in the integrated environmental management of watersheds. By applying geographic information system - GIS to the process of obtaining maps of land use and occupation, pedologicaland geological, and using climatological data from the Campo Bom meteorological station, field visit, review of literature and journals, and publicly available data, the physical characterization of the Schmidt stream watershed was performed, with a view to the integrated environmental management of this watershed. Out of the total area of the Schmidt stream watershed (23.92 km(2)), in terms of geology, it was observed that 23.7% consist of colluvial deposits, 22.6% consist of grass facies, and 53.7% consist of Botucatu formation. Major soil types of the watershed: 97.4% Argisols and only 2.6% Planosols. Land use and occupation is characterized by wetland (0.5%), Native Forest (12.83%), Native Forest + Rural Anthropic + Secondary Vegetation + Forestry (43.81%), Urban Anthropic/Urban Area (39.85%), and also Urban Anthropic/Expansion areas (3.01%). Mean annual rainfall is 1337 mm, maximum temperatures range from 10.5 degrees C to 41.6 degrees C and minimum temperatures range from -1.80 degrees C and 26 degrees C, weak winds, occasionally over 5 m/s. Conducting an environmental assessment in this watershed is essential for environmental and land management. However, these assessments are not conducted in all watersheds and, when they are, their frequency is not sufficiency to allow for continuous monitoring, in order to model and predict scenarios, with a view to adopt medium and long-term measures for environmental protection. PMID- 26628242 TI - Cytotoxicity assays to evaluate tannery effluents treated by photoelectrooxidation. AB - The advanced oxidation process (AOP) is used to increase the treatment efficiency of effluents however, it is necessary to compare the toxicity of treated and untreated effluents to evaluate if the decontamination process does not cause any biological harm. Cultured cells have been previously used to assess the genotoxic and cytotoxic potential of various compounds. Hence, the aim of this work was to assess the applicability of cytotoxicity assays to evaluate the toxicity related to the AOP treatment. Samples of an industrial effluent were collected after their treatment by a conventional method. Cytotoxicity of standard and AOP treated effluents was assessed in CRIB and HEp-2 cell line using the MTT and neutral red assays. We observed decrease at cell viability in the both assays (50% MTT and 13% NRU) when cells were exposed to the AOP treatment in the highest concentration. Thus, cytotoxic assays in cultured cells can be explored as an useful method to evaluate toxicity as well as to optimize effluents treatment process. PMID- 26628243 TI - Habitat or matrix: which is more relevant to predict road-kill of vertebrates? AB - We believe that in tropics we need a community approach to evaluate road impacts on wildlife, and thus, suggest mitigation measures for groups of species instead a focal-species approach. Understanding which landscape characteristics indicate road-kill events may also provide models that can be applied in other regions. We intend to evaluate if habitat or matrix is more relevant to predict road-kill events for a group of species. Our hypothesis is: more permeable matrix is the most relevant factor to explain road-kill events. To test this hypothesis, we chose vertebrates as the studied assemblage and a highway crossing in an Atlantic Forest region in southeastern Brazil as the study site. Logistic regression models were designed using presence/absence of road-kill events as dependent variables and landscape characteristics as independent variables, which were selected by Akaike's Information Criterion. We considered a set of candidate models containing four types of simple regression models: Habitat effect model; Matrix types effect models; Highway effect model; and, Reference models (intercept and buffer distance). Almost three hundred road-kills and 70 species were recorded. River proximity and herbaceous vegetation cover, both matrix effect models, were associated to most road-killed vertebrate groups. Matrix was more relevant than habitat to predict road-kill of vertebrates. The association between river proximity and road-kill indicates that rivers may be a preferential route for most species. We discuss multi-species mitigation measures and implications to movement ecology and conservation strategies. PMID- 26628244 TI - Ethnozoology in Brazil: analysis of the methodological risks in published studies. AB - There has been a growth in the field of Ethnozoology throughout the years, especially in Brazil, where a considerable number of scientific articles pertaining to this subject has been published in recent decades. With this increase in publications comes the opportunity to assess the quality of these publications, as there are no known studies assessing the methodological risks in this area. Based on this observation, our objectives were to compile the papers published on the subject of ethnozoology and to answer the following questions: 1) Do the Brazilian ethnozoological studies use sound sampling methods?; 2) Is the sampling quality influenced by characteristics of the studies/publications? The studies found in databases and using web search engines were compiled to answer these questions. The studies were assessed based on their nature, sampling methods, use of hypotheses and tests, journal's impact factor, and animal group studied. The majority of the studies analyzed exhibited problems associated with the samples, as 144 (66.98%) studies were classified as having a high risk of bias. With regard to the characteristics analyzed, we determined that a quantitative nature and the use of tests are essential components of good sampling. Most studies classified as moderate and low risk either did not provide these data or provided data that were not clear; therefore, these studies were classified as being of a quali-quantitative nature. Studies performed with vertebrate groups were of high risk. Most of the papers analyzed here focused on fish, insects, and/or mollusks, thus highlighting the difficulties associated with conducting interviews regarding tetrapod vertebrates. Such difficulties are largely related to the extremely strict Brazilian laws, justified by the decline and extinction of some species, related to the use of wild tetrapod vertebrates. PMID- 26628245 TI - Genetic analysis of MC1R variants in Chinese Han patients with sporadic Parkinson's disease. AB - Parkinson's disease (PD, OMIM 168600) is a neurodegenerative disorder featured by degeneration of melanin-positive dopaminergic neurons. Epidemiologic studies have suggested that PD and malignant melanoma (MM) might share common genetic components. Recently, the p.R160W variant in the melanocortin 1 receptor gene (MC1R, OMIM 155555), a risk factor for MM, has been identified to be associated with PD in Spanish population. To explore whether the MC1R variants are associated with sporadic PD in Chinese population, we designed a case-control comparison study and studied three variants, including rs3212366 (p.F196L), rs33932559 (p.I120T) and rs34090186 (p.R67Q), in the MC1R gene in 512 Chinese Han patients with sporadic PD and 512 age, gender and ethnicity matched normal controls. For rs3212366, only the TT genotype was identified in both PD and control cohorts. For variants rs33932559 and rs34090186, we did not identify any statistically significant difference in either genotypic distribution or allelic distribution between the PD cohort and control cohort, and in addition, we did not identify any related haplotype that would either increase the risk for PD or play a protective role against PD. Our data suggest that none of the three variants of the MC1R gene and related haplotypes be associated with sporadic form of PD in Chinese Han population from Mainland China. PMID- 26628246 TI - Novel ATM mutations with ataxia-telangiectasia. AB - Ataxia telangiectasia is an autosomal recessive multisystem disorder characterized by progressive cerebellar ataxia with onset in childhood, oculocutaneous telangiectasia, increased serum alpha-fetoprotein, immunodeficiency, chromosomal instability, and radiation hypersensitivity. Ataxia telangiectasia mutated gene (ATM) is one of the known genes to be associated with ataxia telangiectasia. We reported the clinical and genetic findings of three early-onset Chinese patients who demonstrated ataxia, oculomotor apraxia, choreoathetosis, myoclonus and telangiectasia of eyes. Sequence analysis of ATM revealed two known nonsense mutations c.8287C>T and c.9139C>T in the siblings. Though the siblings carried the same mutations, they showed different clinical features involving strephenopodia, exotropia, torsion dystonia, myoclonus and extrapyramidal impairments. The other patient was compound heterozygotes for ATM: c.8911C>T and c.7141_7151delAATGGAAAAAT, both of which were not reported previously and not found in 200 control chromosomes. This study widens the spectrum of mutations and phenotypes in ataxia telangiectasia. PMID- 26628247 TI - Age-dependent effects on sensory axonal excitability in normal mice. AB - Serial recordings were performed to measure sensory excitability in peripheral nerves and elucidate age-dependent changes in neuronal ion currents in the peripheral sensory nervous system. The threshold tracking technique was used to measure multiple excitability indices in the tail sensory nerves of five normal male mice at four time points (6, 10, 14, and 19 weeks of age). A separate group of four mice was also measured at 43 weeks and at 60 weeks of age. Maturation was accompanied by an increase in early hyperpolarization and superexcitability at 10 weeks. At 60 weeks, the hyperpolarizing electrotonus shifted downward, while superexcitability became greater and subexcitability (double stimuli) decreased. Computer modeling showed that the most notable age-related interval changes in excitability parameters were Barrett-Barrett, H, and slow K(+) conductances. Understanding age-related changes in the excitability of sensory axons may provide a platform for understanding age-dependent sensory symptoms and developing age-specific channel-targeting therapies. PMID- 26628248 TI - A meta-analysis of mismatch negativity in children with attention deficit hyperactivity disorders. AB - Mismatch negativity (MMN) is an optimal neurophysiological signal to assess the integrity of auditory sensory memory and involuntary attention switch. The generation of MMN is independent of overt behavioral requirements, concentration or motivation, and thus serves as a suitable tool to study the perceptual function in children with attention deficit-hyperactivity disorders (ADHD). It remains unclear whether ADHD children showed altered MMN responses. Therefore we performed a meta-analysis of peer-reviewed MMN studies that had targeted both typically developed and ADHD children to examine the pooled effect size. The published articles between 1990 and 2014 were searched in PubMed, Medline, Cochrane, and CINAHL. The mean effect size and a 95% confidence interval (CI) were estimated. Six studies, consisting of 10 individual investigations, were included in the final analysis. A significant effect size of 0.28 was found (p=0.028, 95% CI at 0.03-0.53). These results were also free from publication bias or heterogeneity. In conclusion, our meta-analysis results suggest ADHD children demonstrated a reduced MMN amplitude compared to healthy controls. PMID- 26628249 TI - Mediators of Treatment Effects in a Randomized Clinical Trial of Multisystemic Therapy-Health Care in Adolescents With Poorly Controlled Asthma: Disease Knowledge and Device Use Skills. AB - OBJECTIVE: Determine whether Multisystemic Therapy-Health Care (MST-HC) improved asthma knowledge and controller device use skills among African-American youth with poorly controlled asthma and whether any improvements mediated changes in illness management. METHODS: A randomized controlled trial was conducted with 170 adolescents with moderate to severe asthma. Families were randomized to MST-HC or attention control. Data were collected at baseline and 6 and 12 months after intervention completion. RESULTS: In linear mixed models, adolescents in the MST HC group had increases in asthma knowledge; asthma knowledge was unchanged for attention control. Controller device use skills increased for adolescents in the MST-HC group, while skills declined for attention control. Both knowledge and skills mediated the relationship between intervention condition and changes in illness management. CONCLUSIONS: Tailored, home-based interventions that include knowledge and skills building components are one means by which illness management in African-American youth with poorly controlled asthma can be improved. PMID- 26628250 TI - A Longitudinal Examination of Hope and Optimism and Their Role in Type 1 Diabetes in Youths. AB - OBJECTIVES: To test the longitudinal associations between hope and optimism and health outcomes (i.e., HbA1c and self-monitored blood glucose [SMBG]) among youths with Type 1 diabetes mellitus (T1DM) over a 6-month period. METHODS: A total of 110 participants (aged 10-16 years) completed study measures at Time 1, and 81 completed measures at Time 2. Analyses examined hope and optimism as predictors of change in health outcomes, and examined SMBG as a mediator of the relationship between hope and optimism, and HbA1c. RESULTS: Change in hope, but not optimism, was associated with change in SMBG and HbA1c. Change in SMBG mediated the relationship between change in hope and HbA1c, but not between optimism and HbA1c. CONCLUSIONS: It may be beneficial to assess hope in pediatric T1DM patients to identify youths who may be at risk for poor diabetes management, and to test the benefit of hope-based intervention efforts in clinical studies. PMID- 26628251 TI - Estimated Cost-Effectiveness of Intensive Interdisciplinary Behavioral Treatment for Increasing Oral Intake in Children With Feeding Difficulties. AB - OBJECTIVE : To examine the cost-effectiveness of intensive interdisciplinary behavioral treatment (IIBT) to address severe pediatric feeding difficulties and lead to the removal or prevention of gastrostomy tubes (G tubes) from the perspective of the insurance company. METHODS : Costs associated with G tubes and IIBT were compiled from the available literature and national databases. Costs were updated to price at the start of 2015 to allow data from different years to be analyzed on the same scale. RESULTS : One-way sensitivity and two way threshold analyses demonstrated that IIBT may be a cost-effective treatment for prevention and removal of G tubes over 5 and 10 years. DISCUSSION : Data from this study can be used to justify cost of services for IIBT, and programs can use these data to discuss conservative savings of IIBT based on their treatment model and level of effectiveness. PMID- 26628252 TI - A Homogeneous Immunoassay Method for Detecting Interferon-Gamma in Patients with Latent Tuberculosis Infection. AB - IFN-gamma release assays (IGRAs) have been developed as viable alternative diagnostic tools for detecting latent tuberculosis infection (LTBI). A customized homogeneous sandwich luminescent oxygen channeling immunoassay (LOCI) was used to quantify IFN-gamma levels in IGRAs. Samples were collected from healthy volunteers (n = 40) who were T-Spot-negative and T-Spot-positive patients (n = 32) at rest. Then the amount of IFN-gamma in the supernatant of IGRAs was measured by LOCI. The results demonstrated a low background, and high sensitivity, specificity, accuracy, and reproducibility, and a short assay time (only 30 min) with LOCI for IFN-gamma. The recovery range was 81.63-102.06%, the coefficients of variation were below 5%, and the limit of detection was 19.0 mIU/ml. Excellent agreement between LOCI IFN-gamma and the T-SPOT.TB test was obtained (97.2% agreement, kappa = 0.94). The LOCI IFN-gamma concentrations were significantly higher in T-Spot-positive patients than in the healthy group (p < 0.001). Moreover, as observed for the comparative LOCI IFN-gamma assay, IFN-gamma concentrations were related to the numbers of T-SPOT.TB spots. We have established an in vitro blood test for LTBI diagnosis, defined as LOCI IFN-gamma. A high level of agreement between the LOCI IFN-gamma method and T-SPOT.TB assay was observed in clinical studies that showed the LOCI IFN-gamma method could determine LTBI. This study shows acceptable performance characteristics of the LOCI IFN-gamma assay to diagnose LTBI. PMID- 26628253 TI - Magnesium Uptake by the Green Microalga Chlorella vulgaris in Batch Cultures. AB - The accumulation (internal and superficial distribution) of magnesium ions (Mg(2+)) by the green freshwater microalga Chlorella vulgaris (C. vulgaris) was investigated under autotrophic culture in a stirred photobioreactor. The concentrations of the three forms of Mg(2+) (dissolved, extracellular, and intracellular) were determined with atomic absorption spectroscopy during the course of C. vulgaris growth. The proportions of adsorbed (extracellular) and absorbed (intracellular) Mg(2+) were quantified. The concentration of the most important pigment in algal cells, chlorophyll a, increased over time in proportion to the increase in the biomass concentration, indicating a constant chlorophyll/biomass ratio during the linear growth phase. The mean-average rate of Mg(2+) uptake by C. vulgaris grown in a culture medium starting with 16 mg/l of Mg(2+) concentration was measured. A clear relationship between the biomass concentration and the proportion of the Mg(2+) removal from the medium was observed. Of the total Mg(2+) present in the culture medium, 18% was adsorbed on the cell wall and 51% was absorbed by the biomass by the end of the experiment (765 h). Overall, 69% of the initial Mg(2+) were found to be removed from the medium. This study supported the kinetic model based on a reversible first-order reaction for Mg(2+) bioaccumulation in C. vulgaris, which was consistent with the experimental data. PMID- 26628254 TI - Isolation and Characterization of Bacteriophages Against Pseudomonas syringae pv. actinidiae Causing Bacterial Canker Disease in Kiwifruit. AB - Pseudomonas syringae pv. actinidiae causes bacterial canker disease in kiwifruit. Owing to the prohibition of agricultural antibiotic use in major kiwifruit cultivating countries, alternative methods need to be developed to manage this disease. Bacteriophages are viruses that specifically infect target bacteria and have recently been reconsidered as potential biological control agents for bacterial pathogens owing to their specificity in terms of host range. In this study, we isolated bacteriophages against P. syringae pv. actinidiae from soils collected from kiwifruit orchards in Korea and selected seven bacteriophages for further characterization based on restriction enzyme digestion patterns of genomic DNA. Among the studied bacteriophages, two belong to the Myoviridae family and three belong to the Podoviridae family, based on morphology observed by transmission electron microscopy. The host range of the selected bacteriophages was confirmed using 18 strains of P. syringae pv. actinidiae, including the Psa2 and Psa3 groups, and some were also effective against other P. syringae pathovars. Lytic activity of the selected bacteriophages was sustained in vitro until 80 h, and their activity remained stable up to 50 degrees C, at pH 11, and under UV-B light. These results indicate that the isolated bacteriophages are specific to P. syringae species and are resistant to various environmental factors, implying their potential use in control of bacterial canker disease in kiwifruits. PMID- 26628255 TI - Nickel-Catalyzed Borylation of Aryl- and Benzyltrimethylammonium Salts via C-N Bond Cleavage. AB - By developing a mild Ni-catalyzed system, a method for direct borylation of sp(2) and sp(3) C-N bonds has been established. The key to this hightly efficient C-N bond borylative cleavage depends on the appropriate choice of the nickel catalyst Ni(COD)2, ICy.HCl as a ligand, and the use of 2-ethoxyethanol as the cosolvent. This transformation shows good functional group compatibility and can serve as a powerful synthetic tool for gram-scale synthesis and late-stage C-N borylation of complex compounds. PMID- 26628256 TI - Structural diversity in binary superlattices self-assembled from polymer-grafted nanocrystals. AB - Multicomponent nanocrystal superlattices represent an interesting class of material that derives emergent properties from mesoscale structure, yet their programmability can be limited by the alkyl-chain-based ligands decorating the surfaces of the constituent nanocrystals. Polymeric ligands offer distinct advantages, as they allow for more precise tuning of the effective size and 'interaction softness' through changes to the polymer's molecular weight, chemical nature, architecture, persistence length and surrounding solvent. Here we show the formation of 10 different binary nanocrystal superlattices (BNSLs) with both two- and three-dimensional order through independent adjustment of the core size of spherical nanocrystals and the molecular weight of densely grafted polystyrene ligands. These polymer-brush-based ligands introduce new energetic contributions to the interparticle potential that stabilizes various BNSL phases across a range of length scales and interparticle spacings. Our study opens the door for nanocrystals to become modular elements in the design of functional particle brush solids with controlled nanoscale interfaces and mesostructures. PMID- 26628258 TI - Isolated mediastinal tuberculous lymphadenitis. PMID- 26628257 TI - Evaluation of 18F-FDG uptake for detecting lymph node metastasis of gastric cancer: a prospective pilot study for one-to-one comparison of radiation dose and pathological findings. AB - BACKGROUND: Gastric cancer exhibits various degrees of fluorine F-18 fluorodeoxyglucose ((18)F-FDG) uptake on positron emission tomography/computed tomography (PET/CT). We evaluated the relationship between (18)F-FDG uptake and the presence/absence of metastasis in individual lymph nodes (LN) on a one-to-one basis. METHODS: We analyzed 21 patients with gastric cancer. We injected (18)F FDG intravenously in the morning, and gastrectomy with LN dissection was performed in the afternoon of the same day. Radiation doses were measured at each LN using a well-type counter, and we then compared (18)F-FDG uptake, the shortest diameter, and pathological examination results for each LN. RESULTS: In our study, 906 LNs were analyzed, including 115 metastatic LNs. Metastatic LNs showed significantly higher (18)F-FDG uptake (P < 0.0001), and were significantly enlarged (P < 0.0001). The receiver operating characteristics (ROC) curve had a larger area under the curve (0.71) for (18)F-FDG uptake than for the shortest LN diameter (0.60). Considering histology, the ROC curve for intestinal type adenocarcinoma had a larger area under the curve than that for diffuse type (0.75 vs 0.61). CONCLUSIONS: F-FDG uptake is potentially a more useful variable than LN diameter for discriminating between LN with and without metastasis, especially in intestinal type gastric cancer cases. PMID- 26628259 TI - [Modern magnetic resonance imaging of the liver]. AB - Magnetic resonance imaging (MRI) of the liver has become an essential tool in the radiological diagnostics of both focal and diffuse diseases of the liver and is subject to constant change due to technological progress. Recently, important improvements could be achieved by innovations regarding MR hardware, sequences and postprocessing methods. The diagnostic spectrum of MRI could be broadened particularly due to new examination sequences, while at the same time scanning time could be shortened and image quality has been improved. The aim of this article is to explain both the technological background and the clinical application of recent MR sequence developments and to present the scope of a modern MRI protocol for the liver. PMID- 26628261 TI - A novel quantitative PCR assay for the detection of Streptococcus pneumoniae using the competence regulator gene target comX. AB - Streptococcus pneumoniae is responsible for an estimated 1.6 million deaths worldwide every year. While rapid detection and timely treatment with appropriate antibiotics is preferred, this is often difficult due to the amount of time that detection with blood cultures takes. In this study, a novel quantitative PCR assay for the detection of Streptococcus pneumoniae was developed. To identify novel targets, we analysed the pneumococcal genome for unique, repetitive DNA sequences. This approach identified comX, which is conserved and present in duplicate copies in Streptococcus pneumoniae but not in other bacterial species. Comparison with lytA, the current 'gold standard' for detection by quantitative PCR, demonstrated an analytic specificity of 100% for both assays on a panel of 10 pneumococcal and 18 non-pneumococcal isolates, but a reduction of 3.5 quantitation cycle values (+/- 0.23 sem), resulting in an increased analytical detection rate of comX. We validated our assay on DNA extracted from the serum of 30 bacteraemic patients who were blood culture positive for Streptococcus pneumoniae and 51 serum samples that were culture positive for other bacteria. This resulted in a similar clinical sensitivity between the comX and lytA assays (47%) and in a diagnostic specificity of 98.2 and 100% for the lytA and comX assays, respectively. In conclusion, we have developed a novel quantitative PCR assay with increased analytical sensitivity for the detection of Streptococcus pneumoniae, which may be used to develop a rapid bedside test for the direct detection of Streptococcus pneumoniae in clinical specimens. PMID- 26628260 TI - [Functional magnetic resonance imaging of the kidneys]. AB - Interest in functional renal magnetic resonance imaging (MRI) has significantly increased in recent years. This review article provides an overview of the most important functional imaging techniques and their potential clinical applications for assessment of native and transplanted kidneys, with special emphasis on the clarification of renal tumors. PMID- 26628262 TI - A competency framework for colonoscopy training derived from cognitive task analysis techniques and expert review. AB - BACKGROUND: Colonoscopy is a difficult cognitive-perceptual-motor task. Designing an appropriate instructional program for such a task requires an understanding of the knowledge, skills and attitudes underpinning the competency required to perform the task. Cognitive task analysis techniques provide an empirical means of deriving this information. METHODS: Video recording and a think-aloud protocol were conducted while 20 experienced endoscopists performed colonoscopy procedures. "Cued-recall" interviews were also carried out post-procedure with nine of the endoscopists. Analysis of the resulting transcripts employed the constant comparative coding method within a grounded theory framework. The resulting draft competency framework was modified after review during semi structured interviews conducted with six expert endoscopists. RESULTS: The proposed colonoscopy competency framework consists of twenty-seven skill, knowledge and attitude components, grouped into six categories (clinical knowledge; colonoscope handling; situation awareness; heuristics and strategies; clinical reasoning; and intra- and inter-personal). CONCLUSIONS: The colonoscopy competency framework provides a principled basis for the design of a training program, and for the design of formative assessment to gauge progress towards attaining the knowledge, skills and attitudes underpinning the achievement of colonoscopy competence. PMID- 26628263 TI - Anaesthetic injection versus ischemic compression for the pain relief of abdominal wall trigger points in women with chronic pelvic pain. AB - BACKGROUND: Chronic pelvic pain is a common condition among women, and 10 to 30 % of causes originate from the abdominal wall, and are associated with trigger points. Although little is known about their pathophysiology, variable methods have been practiced clinically. The purpose of this study was to evaluate the efficacy of local anaesthetic injections versus ischemic compression via physical therapy for pain relief of abdominal wall trigger points in women with chronic pelvic pain. METHODS: We conducted a parallel group randomized trial including 30 women with chronic pelvic pain with abdominal wall trigger points. Subjects were randomly assigned to one of two intervention groups. One group received an injection of 2 mL 0.5 % lidocaine without a vasoconstrictor into a trigger point. In the other group, ischemic compression via physical therapy was administered at the trigger points three times, with each session lasting for 60 s, and a rest period of 30 s between applications. Both treatments were administered during one weekly session for four weeks. Our primary outcomes were satisfactory clinical response rates and percentages of pain relief. Our secondary outcomes are pain threshold and tolerance at the trigger points. All subjects were evaluated at baseline and 1, 4, and 12 weeks after the interventions. The study was conducted at a tertiary hospital that was associated with a university providing assistance predominantly to working class women who were treated by the public health system. RESULTS: Clinical response rates and pain relief were significantly better at 1, 4, and 12 weeks for those receiving local anaesthetic injections than ischemic compression via physical therapy. The pain relief of women treated with local anaesthetic injections progressively improved at 1, 4, and 12 weeks after intervention. In contrast, women treated with ischemic compression did not show considerable changes in pain relief after intervention. In the local anaesthetic injection group, pain threshold and tolerance improved with time in the absence of significant differences between groups. CONCLUSION: Lidocaine injection seems to be better for reducing the severity of chronic pelvic pain secondary to abdominal wall trigger points compared to ischemic compression via physical therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00628355. Date of registration: February 25, 2008. PMID- 26628265 TI - Retinal ganglion cell topography and spatial resolving power in the oriental fire bellied toad Bombina orientalis. AB - The vertebrate visual system is determined by two main factors, a species' lifestyle and phylogenetic legacy. Studying the visual system in outgroup lineages may shed some light on the balance of these factors within a certain radiation. We studied the topography of retinal ganglion cells (RGCs) in the retina of the oriental fire-bellied toad Bombina orientalis. These toads belong to the ancient superfamily Discoglossoidea, a sister group to all extant Anura except for two small families. RGCs were retrogradely labeled with tetramethylrhodamine- dextran amine (TMR-DA) and examined in retinal wholemounts. RGCs occurred all over the retina except for the far periphery. Their total number was [Formula: see text] ([Formula: see text], [Formula: see text]). They comprised 73-77% of all cells in the ganglion cell layer. The spatial density of GCs increased gradually from the dorsal and ventral retinal periphery toward the equator to form a weak visual streak and a moderately pronounced area centralis. The minimum density was [Formula: see text], and the maximum, [Formula: see text]. The maximum density gradient was [Formula: see text]. The spatial resolution was minimum in the dorsal and ventral periphery ([Formula: see text] and [Formula: see text] cycles per degree in water and air, respectively). Intermediate values of spatial resolving power were found within the visual streak ([Formula: see text] and [Formula: see text] cycles per degree) and reached a peak in area centralis ([Formula: see text] and [Formula: see text] cycles per degree). This is sufficient for efficient prey location and capture. The relatively high RGC density and the presence of specialized retinal regions in oriental fire-bellied toads are consistent with their highly visual behavior. A brief review comparing the phylogeny and ecology of this with other anuran species suggests that the main factor shaping the RGC distribution in Anura is phylogenetic legacy; the environmental pressure results mainly in adjusting the maximum spatial density of RGCs (and hence the visual acuity) to meet the species' needs. PMID- 26628264 TI - Body mass index and dental caries in children aged 5 to 8 years attending a dental paediatric referral practice in the Netherlands. AB - BACKGROUND: Obesity and dental caries are widely-recognised problems that affect general health. The prevention of both dental caries and obesity have proven very difficult: children and their parents may need professional support to achieve behaviour change. To find out whether both dental caries and overweight in childhood can be targeted using a common risk factor approach, it is necessary to establish whether the two diseases are indeed linked. The aim of the present study was therefore to use anthropometric data obtained professionally to investigate the association between Body Mass Index and dental caries experience in children aged 5-8 years receiving treatment in a referral centre for paediatric dental care in the Netherlands. METHODS: Children's dmft and dmfs scores were calculated using dental records and sociodemographic data were also extracted from these records. Dentists were trained to measure standing height and weight in a standardised way. Body Mass Index was calculated by dividing kilograms by height squared (kg/m(2)). Extended International (International Obesity Task Force) body mass index cut-offs were used to define 'no overweight' and 'overweight' (with the latter category including obesity). RESULTS: No statistically significant differences were found between the mean dmft or dmfs scores of the two groups (overweight and non-overweight), even after correction for the effect of the potential confounders sex, socio-economic status and ethnicity. The percentage of caries-active children in the non-overweight group was almost the same as in the overweight group. No statistically significant differences were found. CONCLUSIONS: We hypothesised to find a positive association between body mass index and dental caries experience in children aged 5-8 years attending our practice. However, this study did not find a relationship of this kind. A common risk factor approach for the prevention of caries and overweight is therefore not supported by our study. PMID- 26628266 TI - ASXL1 and CBL mutations are independently predictive of inferior survival in advanced systemic mastocytosis. PMID- 26628267 TI - Contribution of inter-muscular synchronization in the modulation of tremor intensity in Parkinson's disease. AB - BACKGROUND: Involuntary central oscillations at single and double tremor frequencies drive the peripheral neuromechanical system of muscles and joints to cause tremor in Parkinson's disease (PD). The central signal of double tremor frequency was found to correlate more directly to individual muscle EMGs (Timmermann et al. 2003). This study is aimed at investigating what central components of oscillation contribute to inter-muscular synchronization in a group of upper extremity muscles during tremor in PD patients. METHODS: 11 idiopathic, tremor dominant PD subjects participated in this study. Joint kinematics during tremor in the upper extremity was recorded along with EMGs of six upper arm muscles using a novel experimental apparatus. The apparatus provided support for the upper extremity on a horizontal surface with reduced friction, so that resting tremor in the arm can be recorded with a MotionMonitor II system. In each subject, the frequencies of rhythmic firings in upper arm muscles were determined using spectral analysis. Paired and pool-averaged coherence analyses of EMGs for the group of muscles were performed to correlate the level of inter-muscular synchronization to tremor amplitudes at shoulder and elbow. The phase shift between synchronized antagonistic muscle pairs was calculated to aid coherence analysis in the muscle pool. RESULTS: Recorded EMG revealed that rhythmic firings were present in most recorded muscles, which were either synchronized to form phase-locked bursting cycles at a subject specific frequency, or unsynchronized with a random phase distribution. Paired coherence showed a stronger synchronization among a subset of recorded arm muscles at tremor frequency than that at double tremor frequency. Furthermore, the number of synchronized muscles in the arm was positively correlated to tremor amplitudes at elbow and shoulder. Pool-averaged coherence at tremor frequency also showed a better correlation with the amplitude of resting tremor than that of double tremor frequency, indicating that the neuromechanical coupling in peripheral neuromuscular system was stronger at tremor frequency. CONCLUSIONS: Both paired and pool-averaged coherences are more consistent indexes to correlate to tremor intensity in a group of upper extremity muscles of PD patients. The central drive at tremor frequency contributes mainly to synchronize peripheral muscles in the modulation of tremor intensity. PMID- 26628268 TI - Internet-based cognitive behavioural therapy (iCBT) for posttraumatic stress disorder versus waitlist control: study protocol for a randomised controlled trial. AB - BACKGROUND: This randomised controlled trial (RCT) with two parallel arms will evaluate the efficacy of an internet-delivered six-lesson 10-week cognitive behavioural therapy (iCBT) intervention for posttraumatic stress disorder (PTSD). It will also investigate the association between changes in PTSD symptoms, intolerance of uncertainty (IU) and emotion regulation. METHODS/DESIGN: Patients with PTSD will be recruited via the research arm of a not-for-profit clinical and research unit in Australia and randomised to a treatment group or waitlist control group. The minimum sample size for each group (alpha 0.05, power 0.80 for a g of 0.47) was identified as 72, but 10 % more will be recruited to hedge against expected attrition. PTSD diagnosis will be determined using the PTSD module from the Mini International Neuropsychiatric Interview version 5.0.0. The PTSD Checklist - Civilian version (PCL-C) will be used to measure PTSD symptoms (the primary outcome measure), with the Intolerance of Uncertainty Scale 12-item version (IUS-12) and the Emotion Regulation Questionnaire (ERQ) used to measure intolerance of uncertainty and emotion regulation, respectively. The PCL-C will be administered to the treatment group before each lesson of the PTSD program and at 3-month follow-up. The IUS-12 and ERQ will be administered before lessons 1 and 4, at post-treatment and at 3-month follow-up. The waitlist control group will complete these measures at week 1, week 5 and week 11 of the waitlist period. PTSD program efficacy will be determined using intent-to-treat mixed models. Maintenance of gains will be assessed at 3-month follow-up. Mediation analyses using PROCESS will be used to examine the association between change in PTSD symptoms over treatment and change in each of IU and emotion regulation ability in separate analyses. DISCUSSION: The current RCT seeks to replicate previous efficacy findings of iCBT for PTSD in a formally assessed PTSD sample from the general population. Findings may point to future lines of enquiry for the role of IU and emotion regulation in the mechanism of PTSD symptom change during CBT. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12614001213639 , registered 18 November 2014. This trial protocol is written in compliance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. PMID- 26628269 TI - Transcutaneous PTCCO2 measurement in combination with arterial blood gas analysis provides superior accuracy and reliability in ICU patients. AB - Hyper or hypoventilation may have serious clinical consequences in critically ill patients and should be generally avoided, especially in neurosurgical patients. Therefore, monitoring of carbon dioxide partial pressure by intermittent arterial blood gas analysis (PaCO2) has become standard in intensive care units (ICUs). However, several additional methods are available to determine PCO2 including end tidal (PETCO2) and transcutaneous (PTCCO2) measurements. The aim of this study was to compare the accuracy and reliability of different methods to determine PCO2 in mechanically ventilated patients on ICU. After approval of the local ethics committee PCO2 was determined in n = 32 ICU consecutive patients requiring mechanical ventilation: (1) arterial PaCO2 blood gas analysis with Radiometer ABL 625 (ABL; gold standard), (2) arterial PaCO2 analysis with Immediate Response Mobile Analyzer (IRMA), (3) end-tidal PETCO2 by a Propaq 106 EL monitor and (4) transcutaneous PTCCO2 determination by a Tina TCM4. Bland-Altman method was used for statistical analysis; p < 0.05 was considered statistically significant. Statistical analysis revealed good correlation between PaCO2 by IRMA and ABL (R2 = 0.766; p < 0.01) as well as between PTCCO2 and ABL (R2 = 0.619; p < 0.01), whereas correlation between PETCO2 and ABL was weaker (R2 = 0.405; p < 0.01). Bland-Altman analysis revealed a bias and precision of 2.0 +/- 3.7 mmHg for the IRMA, 2.2 +/- 5.7 mmHg for transcutaneous, and -5.5 +/- 5.6 mmHg for end-tidal measurement. Arterial CO2 partial pressure by IRMA (PaCO2) and PTCCO2 provided greater accuracy compared to the reference measurement (ABL) than the end-tidal CO2 measurements in critically ill in mechanically ventilated patients patients. PMID- 26628270 TI - Ventilation monitoring during moderate sedation in GI patients. AB - Sedation in locations outside the operating room (OR) is common. Guidelines for safe patient monitoring have been updated by the American Society of Anesthesiology to include monitoring of ventilation and/or carbon dioxide (CO2). Although technologies exist to monitor these variables, the quality and/or availability of these measurements in non-OR settings is not optimal. This quality improvement project assessed the value of impedance technology for monitoring minute ventilation (MV) compared to standard end-tidal monitoring of CO2 (ETCO2). Patients undergoing GI exams with moderate sedation provided by anesthesia providers were monitored for MV with a respiratory volume monitor (ExSpiron 1Xi, Respiratory Motion, Waltham, MA) and ETCO2 via nasal cannula (NC). Calibration and baseline data were collected prior to sedation. Continuous MV and ETCO2 data were collected and averaged, providing minute values after sedation medications throughout the procedure. Stable periods of reduced MV were averaged and used in comparison to ETCO2. Data from 20 patients were evaluated. After sedation, the expected decrease in MV after sedation was observed in 18 of 20 patients (average -47.82 %), while an increase in ETCO2 was observed in just 10 of 20 patients (average -5.17 mm Hg). The correlation coefficient between changes in MV and ETCO2 in response to sedation administration was positive and not significant, r = 0.223. Ventilation monitoring may provide an element of safety for earlier and more reliable detection of reduced ventilation compared to a surrogate for hypoventilation, ETCO2, in patients undergoing sedation for GI procedures outside of the OR. PMID- 26628271 TI - The complete genome of a viable archaeum isolated from 123-million-year-old rock salt. AB - Live microbes have been isolated from rock salt up to Permian age. Only obligatory cellular functions can be performed in halite-buried cells. Consequently, their genomic sequences are likely to remain virtually unchanged. However, the available sequence information from these organisms is scarce and consists of mainly ribosomal 16S sequences. Here, live archaea were isolated from early Cretaceous (~ 123 million years old) halite from the depth of 2000 m in Qianjiang Depression, Hubei Province, China. The sample was radiologically dated and subjected to rigorous surface sterilization before microbe isolation. The isolates represented a single novel species of Halobacterium, for which we suggest the name Halobacterium hubeiense, type strain Hbt. hubeiense JI20-1. The species was closely related to a Permian (225-280 million years old) isolate, Halobacterium noricense, originating from Alpine rock salt. This study is the first one to publish the complete genome of an organism originating from surface sterilized ancient halite. In the future, genomic data from halite-buried microbes can become a key factor in understanding the mechanisms by which these organisms are able to survive in harsh conditions deep underground or possibly on other celestial bodies. PMID- 26628272 TI - Relevance of fruits, vegetables and flavonoids from fruits and vegetables during early life, mid-childhood and adolescence for levels of insulin-like growth factor (IGF-1) and its binding proteins IGFBP-2 and IGFBP-3 in young adulthood. AB - The growth hormone (GH) insulin-like growth factor (IGF) axis has been linked to insulin metabolism and cancer risk. Experimental evidence indicates that the GH IGF axis itself can be influenced by dietary flavonoids. As fruit and vegetable (FV) intake is a major source of flavonoid consumption, FV's beneficial health effects may be explained via flavonoids' influence on the GH-IGF axis, but observational evidence is currently rare. We used data from Dortmund Nutritional and Anthropometric Longitudinally Designed Study participants to analyse prospective associations between FV, fruit intake and flavonoid intake from FV (FlavFV) with IGF-1 and its binding proteins IGFBP-2 and IGFBP-3. Subjects needed to provide a fasting blood sample in adulthood (18-39 years) and at least two 3-d weighed dietary records in early life (0.5-2 years, n 191), mid-childhood (3-7 years, n 265) or adolescence (girls: 9-15 years, boys: 10-16 years, n 261). Additional analyses were conducted among those providing at least three 24-h urine samples in adolescence (n 236) to address the predictor urinary hippuric acid (HA), a biomarker of polyphenol intake. Higher fruit intake in mid-childhood and adolescence was related to higher IGFBP-2 in adulthood (P=0.03 and P=0.045). Comparable trends (P=0.045-0.09) were discernable for FV intake (but not FlavFV) in all three time windows. Similarly, higher adolescent HA excretion tended to be related (P=0.06) to higher adult IGFBP-2 levels. Regarding IGFBP-3, a marginal (P=0.08) positive association was observed with FlavFV in mid-childhood only. None of the investigated dietary factors was related to IGF-1. In conclusion, higher fruit and FV intakes during growth may be relevant for adult IGFBP-2, but probably not for IGFBP-3 or IGF-1. PMID- 26628273 TI - [Basic psychosomatic care in ophthalmology. Relevance, training and case examples]. AB - BACKGROUND: The incidence of psychosomatic disorders and their impact on society are increasing. Many patients suffer from psychosomatic symptoms. Medical studies and most notably medical training for ophthalmologists do not sufficiently cover these topics and do not adequately prepare doctors for dealing with patients suffering from psychosomatic disorders. OBJECTIVE: Training in basic psychosomatic care can be absolved by all physicians irrespective of specialization. The structure, benefits and importance of this professional training are explained. MATERIAL AND METHODS: The curriculum of the German Medical Association forms the basis of training in basic psychosomatic care. The personal experiences of the authors after completing the training as well as case studies are presented. RESULTS AND CONCLUSION: Training in basic psychosomatic care conveys practical skills for dealing with patients with psychosomatic symptoms, which are often not acquired during medical training for ophthalmologists, where technical procedures predominate. Thus the professional ability is broadened with an immediate positive effect not only on the physician patient relationship but also on the professional and private environment. Training in basic psychosomatic care should be obligatory in the specialist training of ophthalmologists. PMID- 26628275 TI - Acceptability and effectiveness of a monofilament, polyethylene insecticide treated wall lining for malaria control after six months in dwellings in Vhembe District, Limpopo Province, South Africa. AB - BACKGROUND: South Africa uses indoor residual spraying (IRS) for vector control in its malaria control programme (MCP). Insecticide-treated wall linings (ITWLs) offer possible advantages over IRS and long-lasting, insecticide-treated nets (LLINs). This study assessed the user acceptability and perceived effectiveness, and the durability, including efficacy through bioassays, of a newly developed, monofilament polyethylene ITWL. METHODS: Four ITWL formulations/treatments, two incorporated with deltamethrin and two with alpha-cypermethrin in concentrations ranging from 0.29 to 0.85 wt%, and untreated linings were randomly installed on the inner walls of traditional mud huts (n = 20) and modern brick houses (n = 20) in a community village in Vhembe District, Limpopo Province. The linings were exposed to conditions within these dwellings over 6 months. Data were collected monthly through questionnaires and entomological residual efficacy analysis of ITWL, as part of durability testing, was done bimonthly using WHO prescribed bioassays. RESULTS: Monofilament polyethylene ITWLs were successfully installed in traditional sleeping huts and in bedrooms of modern type brick houses. ITWL remained intact throughout the entire 6 months of the study. Participants did not express any dissatisfaction towards the linings although two participants indicated the product should be fitted at a lower level for better results. User perceived effectiveness was very high with participants reporting observed mortality of mosquitoes and other nuisance insects. This perception coincided with results obtained through residual efficacy bioassays where a 100 % knockdown and mortality of mosquitoes was recorded throughout the trial period. Acceptability regarding appearance, including colour, position and attachment method, was also satisfactory with some participants citing the lining as decorative. All participants opted to keep ITWL and residual long-term efficacy will be determined annually for a further 3 years. CONCLUSIONS: The newly developed ITWLs are highly accepted amongst participants in an unsprayed section of a village in a malaria-endemic area. The perceived effectiveness that coincides with results obtained through bioassays and acceptance of the overall appearance of ITWL will be evaluated over a longer term to determine sustainability. With further developing and testing, this ITWL has the potential to become a sustainable and safer alternative vector control method. PMID- 26628276 TI - A neonate with poor weight gain and hyperkalemia: Questions. PMID- 26628277 TI - Macroscopic hematuria with normal renal biopsy-following the chain to the diagnosis: Questions. AB - BACKGROUND: Alport syndrome (AS) is an inherited glomerular disease associated with hearing and eye defects; its morbidity is a public health issue in developed countries. AS results from mutations in COL4A3, COL4A4, or COL4A5 genes, respectively encoding the alpha-3, alpha-4, and alpha-5 chains of type IV collagen, a major component of the renal glomerular basement membrane (GBM). The diagnosis is usually confirmed by a renal biopsy showing a thinning/thickening of the GBM, with a longitudinal splitting of the lamina densa. CASE DIAGNOSIS: We report the case of a 10-year-old patient who presented multiple episodes of macroscopic hematuria. On renal biopsy, the electron microscopy analysis of the GBM was normal, as was the COL4A5 immunofluorescence assay. Genetic analyses showed a homozygous duplication of exons 44 to 47 of the COL4A3 gene, confirming the diagnosis of autosomal recessive AS. CONCLUSIONS: Our report suggests that, in patients with clinical evidence of AS, genetic testing should be performed whenever pathological analysis is not in favor of AS diagnosis. This will ensure that AS patients benefit from an early diagnosis, adequate treatment, and that end-stage renal disease (ESRD) onset is delayed. PMID- 26628278 TI - A neonate with poor weight gain and hyperkalemia: Answers. PMID- 26628279 TI - Long-term outcome of idiopathic steroid-resistant nephrotic syndrome in children: response to comments. PMID- 26628280 TI - Macroscopic hematuria with normal renal biopsy-following the chain to the diagnosis: Answers. AB - BACKGROUND: Alport syndrome (AS) is an inherited glomerular disease associated with hearing and eye defects; its morbidity is a public health issue in developed countries. AS results from mutations in COL4A3, COL4A4, or COL4A5 genes, respectively encoding the alpha-3, alpha-4, and alpha-5 chains of type IV collagen, a major component of the renal glomerular basement membrane (GBM). The diagnosis is usually confirmed by a renal biopsy showing a thinning/thickening of the GBM, with a longitudinal splitting of the lamina densa. CASE DIAGNOSIS: We report the case of a 10-year-old patient who presented multiple episodes of macroscopic hematuria. On the renal biopsy, the electron microscopy analysis of the GBM was normal, as was the COL4A5 immunofluorescence assay. Genetic analyses showed a homozygous duplication of exons 44 to 47 of the COL4A3 gene, confirming the diagnosis of autosomal recessive AS. CONCLUSIONS: Our report suggests that in patients with clinical evidence of AS, genetic testing should be performed whenever pathological analysis is not in favor of AS diagnosis. This will ensure that AS patients benefit from an early diagnosis, adequate treatment, and that end-stage renal disease (ESRD) onset is delayed. PMID- 26628281 TI - Inequalities in access to pediatric ESRD care: a global health challenge. AB - The increasing attention paid to chronic kidney disease (CKD) as a major cause of mortality and disability, as well as the advances in management of CKD in children, have created a growing demand for pediatric renal replacement therapy (RRT) worldwide. A study by Koch Nogueira and colleagues of children on the transplant waiting list showed large disparities in access to pediatric kidney transplantation between regions in Brazil. This finding raises a wider question about inequalities in access to CKD care in children. Here we review the available data on the global burden of end-stage renal disease in children, the need for pediatric RRT, and its actual provision worldwide. We focus on inequalities in access to renal care for children that currently exist between and within countries. Reduction in worldwide inequalities in access to RRT in children remains a challenge, which requires greater awareness and effective interventions and policies. PMID- 26628282 TI - Cinacalcet as adjunctive therapy in pseudohypoparathyroidism type 1b. AB - BACKGROUND: In patients with pseudohypoparathyroidism type 1b (PHP1b) due to a tissue-specific imprinting defect in the G-protein alpha-subunit, skeletal disorders can arise from the bones being sensitive to parathyroid hormone (PTH) while the kidneys remain resistant to this hormone. CASE-DIAGNOSIS/TREATMENT: We report a 4.8-year-old girl with PHP1b who presented with an abnormal gait, severe skeletal changes and elevated levels of serum PTH (2844 pg/ml), phosphate (7.2 mg/dl) and bone turnover markers. Traditional treatment with calcium and calcitriol failed to suppress PTH secretion, which was still elevated at 2877 pg/ml after 14 months of therapy, nor did it correct the other clinical, biochemical and radiographic abnormalities. The addition of cinacalcet to the treatment regimen over the subsequent 32 months resulted in normalization of serum PTH (58 ng/ml), phosphate (4.9 mg/dl) and bone turnover markers, and resolution of the radiographic changes, with no adverse effects noted. CONCLUSIONS: Due to its ease of administration, we recommend the addition of cinacalcet into the armamentarium of medications available to treat children with PHP1b. PMID- 26628283 TI - Remedial operations for failed endovascular therapy of 32 renal artery stenoses in 24 children. AB - BACKGROUND: Percutaneous transluminal angioplasty (PTA) for the treatment of pediatric renovascular hypertension (RVH) in contemporary practice is accompanied with ill-defined complications. This study examines the mode of pediatric renal PTA failures and the results of their surgical management. METHODS: Twenty-four children underwent remedial operations at the University of Michigan from 1996 to 2014 for failures of renal PTA. Their clinical courses were retrospectively reviewed and results analyzed. RESULTS: Renal PTA of 32 arteries, including 13 with stenting, was performed for severe RVH in 12 boys and 12 girls, having a mean age of 9.3 years. Developmental ostial stenoses affected 22 children. PTA failures included: 27 restenoses and five thromboses. Remedial operations included: 13 renal artery-aortic reimplantations, one segmental renal artery-main renal artery reimplantation, ten aortorenal bypasses, one arterioplasty, one iliorenal bypass, and six nephrectomies for unreconstructable arteries; the latter all in children younger than 10 years. Follow-up averaged 2.1 years. Postoperatively, hypertension was cured, improved, or unchanged in 25, 54, and 21 %, respectively. There was no perioperative renal failure or mortality. CONCLUSIONS: Renal PTA for the treatment of pediatric RVH due to ostial disease may be complicated by failures requiring complex remedial operations or nephrectomy, the latter usually affecting younger children. PMID- 26628284 TI - Microalbuminuria among HIV-infected antiretroviral therapy-naive children in the Democratic Republic of Congo. AB - BACKGROUND: To determine the prevalence of microalbuminuria and associated factors among Congolese human immunodeficiency virus (HIV)-infected children. METHODS: This was a cross-sectional study in which 77 HIV-infected antiretroviral therapy-naive children and 89 uninfected controls were enrolled. Microalbuminuria was assessed using the immune-turbidimetry method, and associated factors were studied by logistic regression. RESULTS/CONCLUSION: The prevalence of microalbuminuria was 18% in the HIV-infected children and 2% in the HIV uninfected children. No common determinants of proteinuria were significantly associated with microalbuminuria. PMID- 26628285 TI - Photoinduced charge separation in an oligophenylenevinylene-based Hamilton-type receptor supramolecularly associating two C60-barbiturate guests. AB - The supramolecular association of an oligophenylene-vinylene (OPV)-based Hamilton type receptor 1 with C60-barbiturate 2, via six hydrogen bonds per OPV terminal, forming C60/OPV/C60 complex 3 is presented. The particular host-guest motif expressed in 3 ensures strong interactions between the discrete components of the complex based on the multiple hydrogen bonding interactions as conveyed by an association constant greater than 10(5) M(-1). Furthermore, femto- and nano second transient absorption studies disclose photoinduced charge separation from (1)OPV* to C60 within 9.4 ps. The observed ultrafast charge separation phenomena in the C60/OPV/C60 complex open up wide avenues toward the efficient construction of new materials for optoelectronic and solar cell applications. PMID- 26628286 TI - The effect of dissolved oxygen on the relaxation rates of blood plasma: Implications for hyperoxia calibrated BOLD. AB - PURPOSE: To determine the contribution of paramagnetic dissolved oxygen in blood plasma to blood-oxygenation-level-dependent (BOLD) signal changes in hyperoxic calibrated BOLD studies. METHODS: Bovine blood plasma samples were prepared with partial pressures of oxygen (pO2 ) ranging from 110 to 600 mmHg. R1 , R2 , and R2* of the plasma with dissolved oxygen were measured using quantitative MRI sequences at 3 Tesla. Simulations were performed to predict the relative effects of dissolved oxygen and deoxyhemoglobin changes in hyperoxia calibrated BOLD. RESULTS: The relaxivities of dissolved oxygen in plasma were found to be r1,O2 =1.97 +/- 0.09 *10-4 s-1 mmHg-1 , r2,O2 =2.3 +/- 0.7 *10-4 s-1 mmHg-1 , and r2,O2* = 2.3 +/- 0.7 *10-4 s-1 mmHg-1 . Simulations predict that neither the transverse nor longitudinal relaxation rates of dissolved oxygen contribute significantly to the BOLD signal during hyperoxia. CONCLUSION: During hyperoxia, the increases in R2 and R2* of blood from dissolved oxygen in plasma are considerably less than the decreases in R2 and R2* from venous deoxyhemoglobin. R1 effects due to dissolved oxygen are also predicted to be negligible. As a result, dissolved oxygen in arteries should not contribute significantly to the hyperoxic calibrated BOLD signal. Magn Reson Med 76:1905-1911, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26628287 TI - Recent decline in prostate cancer incidence in the United States, by age, stage, and Gleason score. AB - Prostate cancer incidence is sensitive to screening practices, however the impact of recent screening recommendations from the United States Preventative Services Task Force on prostate cancer incidence by age, stage, race, and Gleason score is unknown. This study described the timing and magnitude of changes in prostate cancer incidence trends in the United States by month of diagnosis, and evaluated trends by age, Gleason score, and stage at diagnosis. We analyzed prostate cancer incidence trends using Surveillance, Epidemiology, and End Results (SEER) program data for men diagnosed with invasive prostate cancer from 2007 through 2012. JoinPoint analysis was used to detect changes in the rate of annual percent change (APC) in prostate cancer incidence for all diagnoses and by age, Gleason score, race, and stage. Prostate cancer incidence declined at an estimated -19.6% APC beginning May 2011. This decline was observed in all age groups. Low-grade tumors (Gleason score <=6) showed a steeper decline (-29.1% APC) than high-grade tumors (Gleason score 8-10: -10.8% APC). Only stage I/II and stage III tumors saw declines (-24.2% and -16.7% APC, respectively). A sharp decline in prostate cancer incidence began before release of the United States Preventative Services Task Force October 2011 draft and May 2012 final screening recommendation. The greatest change occurred with incidence of low-grade tumors, although there is concern that some high-grade tumors may now go undetected. PMID- 26628288 TI - Biogenic mixing induced by intermediate Reynolds number swimming in stratified fluids. AB - We study fully resolved motion of interacting swimmers in density stratified fluids using an archetypal swimming model called "squirmer". The intermediate Reynolds number regime is particularly important, because the vast majority of organisms in the aphotic ocean (i.e. regions that are 200 m beneath the sea surface) are small (mm-cm) and their motion is governed by the balance of inertial and viscous forces. Our study shows that the mixing efficiency and the diapycnal eddy diffusivity, a measure of vertical mass flux, within a suspension of squirmers increases with Reynolds number. The mixing efficiency is in the range of O(0.0001-0.04) when the swimming Reynolds number is in the range of O(0.1-100). The values of diapycnal eddy diffusivity and Cox number are two orders of magnitude larger for vertically swimming cells compared to horizontally swimming cells. For a suspension of squirmers in a decaying isotropic turbulence, we find that the diapycnal eddy diffusivity enhances due to the strong viscous dissipation generated by squirmers as well as the interaction of squirmers with the background turbulence. PMID- 26628290 TI - Alport syndrome and pregnancy: Good obstetric and nephrological outcomes in a pregnant woman with homozygous autosomal recessive Alport syndrome. AB - We describe the course of pregnancy in a 27-year-old woman with homozygous autosomal recessive Alport syndrome. Genetic analysis revealed a homozygous COL4A4 mutation in exon 36 (c.3307G > A) with p.G1102R inherited from her parents (who were parallel cousins) 1 year before conception. Before pregnancy, the patient's renal function and blood pressure were normal, and her urinary protein excretion was below 2 g/day. The pregnancy course was uneventful in the first and second trimesters. She was detected to have nephrotic-range proteinuria during the third trimester, but was observed closely on an outpatient basis without any medications, as her general condition was good, her renal function and blood pressure remained stable, and the fetal well-being was maintained. At 39(+0) weeks of pregnancy, she vaginally gave birth to an appropriate-birthweight infant and her urinary protein excretion returned to pre-pregnancy level. This is the first report of pregnancy in a patient with autosomal recessive Alport syndrome with good obstetric and nephrological outcomes in the absence of any treatment or hospitalization. PMID- 26628289 TI - Treatment of nausea in pregnancy: a cross-sectional multinational web-based study of pregnant women and new mothers. AB - BACKGROUND: The factors related to the treatment of nausea during pregnancy have not yet been investigated in several countries simultaneously. The present study aimed to describe differences in self-reported nausea during pregnancy and the patterns of use for both conventional and herbal medicines across countries. The factors related to nausea and its treatment and the relationships between different self-reported co-morbidities and nausea were also investigated. METHODS: This cross-sectional study used data collected by a web-based questionnaire distributed between October 2011 and February 2012 in several countries within five regions: Western, Northern, and Eastern Europe, North America, and Australia. Women who were pregnant or had a child less than one year old were eligible to participate. RESULTS: A total of 9113 women were included in the study, whereof 6701 (73.5%) had experienced nausea during pregnancy. Among respondents with nausea, conventional medicines were used by 1201 (17.9%) women and herbal medicines by 556 (8.3%) women. The extent of self-reported nausea and its treatment varied by country. Education, working status, and folic acid use were significantly associated with the use of conventional medicines against nausea. Respondents who had nausea also had a high burden of co-morbidity. CONCLUSION: The prevalence of nausea was high across all participating countries but its treatment varied, possibly due to cultural differences and differences in attitudes towards medicines. A high degree of co-morbidity was found among respondents with nausea. PMID- 26628291 TI - Conjunction of standing wave and resonance in asymmetric nanowires: a mechanism for thermal rectification and remote energy accumulation. AB - As an important way to control and manage heat transport, thermal rectification has become an elementary issue in the field of phononics and plays a key role in the designing of thermal devices. Here we investigate systematically the standing wave and the accompanying resonance process in asymmetric nanowires to understand the standing wave itself and its great effect on thermal rectification. Results show that the standing wave is sensitive to both the structural and thermal properties of the material, and its great effect on enhancing the thermal rectification is realized not only by the energy-localization nature of the standing wave, but also by the resonance-caused large amplitude and high energy of the standing wave. PMID- 26628292 TI - Dental anthropology of a Brazilian sample: Frequency of nonmetric traits. AB - Dental elements are valuable tools in a study of ancient populations and species, and key-features for human identification; among the dental anthropology field, nonmetric traits, standardized by ASUDAS, are closely related to ancestry. This study aimed to analyze the frequency of six nonmetric traits in a sample from Southeast Brazil, composed by 130 dental casts from individuals aged between 18 and 30, without foreign parents or grandparents. A single examiner observed the presence or absence of shoveling, Carabelli's cusp, fifth cusp, 3-cusped UM2, sixth cusp, and 4-cusped LM2. The frequencies obtained were different from the ones shown by other researches to Amerindian and South American samples, and related to European and sub-Saharan frequencies, showing the influence of this groups in the current Brazilian population. Sexual dimorphism was found in the frequencies of Carabelli's cusp, 3-cusped UM2, and sixth cusp. PMID- 26628293 TI - Sumatriptan/Naproxen Sodium: A Review in Migraine. AB - Sumatriptan/naproxen sodium (Treximet(r)) is a fixed-dose combination of a serotonin 5-HT1B/1D receptor agonist (sumatriptan) and an NSAID (naproxen sodium), approved in the USA for the acute treatment of migraine with or without aura in adolescents and adults. In a randomized, phase 3 trial in adolescents, significantly more sumatriptan/naproxen sodium than placebo recipients were pain free at 2 h. Similarly, in a pair of randomized phase 3 trials in adults, significantly more sumatriptan/naproxen sodium than placebo recipients had relief from migraine symptoms at 2 h, and the combination was more effective than individual components in terms of sustained (2-24 h) pain-free response rate. Sumatriptan/naproxen sodium was generally well tolerated, with <=11 % of adolescents and <=22 % of adults reporting treatment-related adverse events in the key clinical trials. The most common adverse reactions were nasopharyngitis, hot flushes and muscle tightness in adolescents, and dizziness, pain or pressure sensations, nausea, somnolence, dry mouth, dyspepsia and paraesthesia in adults. Based on current data, sumatriptan/naproxen sodium is a useful option for the acute treatment of migraine in adolescents and adults. The fixed-dose combination may reduce pill burden and improve adherence in some patients. PMID- 26628294 TI - Prucalopride: A Review in Chronic Idiopathic Constipation. AB - Prucalopride (Resolor(r)), a highly selective serotonin 5-HT4 receptor agonist, is indicated in the European Economic Area for the treatment of adults with chronic idiopathic constipation (CIC) in whom laxatives have failed to provide adequate relief. This article reviews the pharmacological properties of prucalopride and its clinical efficacy and tolerability in patients with CIC. In five well-designed, 12-week trials in patients with CIC, oral prucalopride 2 mg/day was significantly more effective than placebo at improving bowel function, including the number of bowel movements and a range of other constipation symptoms, as well as health-related quality of life and patient satisfaction; however, no significant differences in bowel function measures were observed between prucalopride and placebo in a 24-week trial. Oral PEG-3350 + electrolytes reconstituted powder was found to be noninferior but not superior to prucalopride according to primary endpoint data from a 4-week, controlled-environment trial. Prucalopride was generally well tolerated in clinical trials; the most common adverse events were headache, diarrhoea, nausea and abdominal pain. No cardiovascular safety issues have arisen with prucalopride treatment. Although further long-term and comparative data would be beneficial, prucalopride provides an additional treatment option for patients with CIC. PMID- 26628295 TI - Quercetin induces apoptosis and enhances 5-FU therapeutic efficacy in hepatocellular carcinoma. AB - Quercetin (Q), a flavonoid compound, which is obtained in variety of fruits, seeds, and vegetables, has been reported to possess many pharmacological properties including cancer-preventive and anticancer effects. However, studies on the anticancer effects and underlying mechanisms of Q in human hepatocellular carcinoma (HCC) are still limited. The present study is conducted to investigate the anticancer efficacy and adjuvant chemotherapy action of Q in HCC. HCC cell lines HepG2 and SMCC-7721 were treated with different concentrations of Q. The antiproliferative effects of Q were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT), and the apoptosis and cell cycle dynamics were assessed by flow cytometry; the expression of apoptosis-associated proteins were evaluated by Western blot and immunohistochemistry staining; the tumor growth in vivo was evaluated in a xenograft mouse model. Our results showed that Q effectively inhibited human HCC cell proliferation and induced apoptosis by upregulating the expression of Bad and Bax and downregulating the expression of Bcl-2 and Survivin in vitro. Furthermore, Q obviously inhibited the tumor growth and enhanced the 5-fluorouracil (5-FU) therapeutic efficacy in vitro and in vivo. Taken together, our findings highlight that Q effectively inhibited the growth of tumor and enhanced the sensitivity to thermotherapy, indicating Q is a potential treatment option for HCC. PMID- 26628296 TI - Serum microRNAs as potential noninvasive biomarkers for glioma. AB - Gliomas are derived from astroglial precursors or astrocytes, accounting for 40 % central nervous system tumors. MicroRNAs (miRNAs) are a class of endogenous, small (19- to 23-nucleotides) non-coding RNAs involved in cancer progression. Recent studies show that circulating miRNAs are associated with the clinicopathological features and prognosis of gliomas. Serum miRNAs may serve as novel biomarkers for gliomas diagnosis. This review explores the possibilities of using serum miRNAs as prognostic, diagnostic markers, and therapeutic targets in gliomas. PMID- 26628297 TI - Enhanced Wnt signaling by methylation-mediated loss of SFRP2 promotes osteosarcoma cell invasion. AB - Wnt signaling is essential for the initiation and progression of osteosarcoma (OS) tumors and is suppressed by the secreted frizzled-related proteins (SFRPs). The methylation-induced protein degradation reduces the activity of SFRPs and subsequently increases the activity of Wnt signaling. However, whether the methylation of SFRP2, a member of SFRPs, may be involved in the pathogenesis of OS is not known. Here, we investigated the expression levels of SFRP2 in OS specimens. We found that SFRP2 mRNA was significantly decreased and methylation of SFRP2 gene was significantly increased in malignant OS tumors as compared to the paired adjacent non-tumor tissue. Moreover, SFRP2 expression was significantly decreased in the malignant OS cell lines, SAOS2, MG63, and U2OS, but not in the primary osteoblast cells. The demethylation of SFRP2 gene by 5' aza-deoxycytidine (5-aza-dCyd) in OS cell lines restored SFRP2 expression, at both mRNA and protein levels, and suppressed cell invasion. Furthermore, the demethylation of SFRP2 gene appeared to inhibit nuclear retention of a key Wnt signaling factor, beta-catenin, in OS cell lines. Together, these data suggest that SFRP2 may function as an OS invasion suppressor by interfering with Wnt signaling, and the methylation of SFRP2 gene may promote pathogenesis of OS. PMID- 26628298 TI - Overexpression of iASPP-SV in glioma is associated with poor prognosis by promoting cell viability and antagonizing apoptosis. AB - Inhibitor of apoptosis-stimulating protein of p53 (iASPP), encoded by PPP1R13L gene, is often overexpressed in human cancers. From the PPP1R13L gene, at least two isoforms, iASPP-L and iASPP-SV, are produced through alternative splicing. However, the role of these isoforms in glioma is still elusive. In this study, we examined the expression of iASPP-SV in astrocytic glioma tissues with different grades and normal human cerebral tissues. The result showed a higher messenger RNA (mRNA) expression level of iASPP-SV in astrocytic glioma patients with World Health Organization (WHO) grade II to IV in comparison to the normal controls. Additionally, mRNA expression level of iASPP-SV was gradually increased with the raise of the grade in glioma. High mRNA expression level of iASPP-SV was significantly associated with malignant WHO grades (P < 0.001). The protein expression level of iASPP-SV was consistent with the mRNA expression level. The Kaplan-Meier analysis revealed that high iASPP-SV mRNA expression significantly affected overall survival and progression-free survival (both P < 0.001). Furthermore, multivariate analysis indicated that the mRNA expression of iASPP-SV was an independent prognostic marker in glioma (P < 0.001). To further explore the role of iASPP-SV in glioma, U87 cells were transfected with iASPP-SV by lentivirus and then treated with temozolomide (TMZ). Overexpression of iASPP-SV promoted the cell viability and downregulated the expression of pro-apoptosis genes (Bax, Puma, p21, and Noxa) to inhibit apoptosis induced by TMZ. Our study provides the first evidence that high iASPP-SV expression may be a novel prognostic factor and therapeutic target for glioma. PMID- 26628299 TI - Overexpression of Sphk2 is associated with gefitinib resistance in non-small cell lung cancer. AB - Lung cancer is the major cause of cancer-related death worldwide, and 80 % of them are non-small cell lung cancer (NSCLC) cases. Recent studies have shown that sphingosine kinase 2 (SphK2) could promote tumor progression; however, whether SphK2 could affect the chemoresistance of NSCLC to chemotherapy remains unclear. To determine whether SphK2 serves as a potential therapeutic target of NSCLC, we utilized small interference RNA (siRNA) to knock down SphK2 expression in human NSCLC cells and analyzed their phenotypic changes. The data demonstrated that knockdown of SphK2 led to decreased proliferation and enhanced chemosensitivity and apoptosis to gefitinib in NSCLC cells. In this study, we describe the findings that overexpression of SphK2 promotes chemoresistance in NSCLC cells. Inhibition of SphK2 might be considered as a strategy in NSCLC treatment with gefitinib. PMID- 26628300 TI - Inflammation and chemerin in colorectal cancer. AB - Chemerin is expressed mainly in the adipose tissue. It is an agonist of chemokine like receptor-1, which is expressed by the immune system cells. Chemerin stimulates the chemotaxis of the immune system cells, and this indicates the function of chemerin and chemokine-like receptor-1 in the immune response. The tumor microenvironment is very important for determining cancer cell growth and spreading. Therefore, we aimed to investigate the association between colorectal cancer, inflammation, and adipokines including chemerin, adiponectin, and vaspin. The study group consisted of patients with colon cancer, whereas the control subjects consisted of patients with benign conditions, diagnosed with colonoscopy. The two groups were compared in terms of the C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, adiponectin, chemerin, and vaspin. A total of 41 (28 men, 13 women) patients with confirmed colon cancer, and 27 (15 men, 12 women) controls without, confirmed by colonoscopy, were enrolled. The median chemerin levels were found significantly higher in the study group than the controls (390 vs. 340 ng/mL, p = 0.032), whereas the mean vaspin and adiponectin levels were not significantly different. The median values for the CRP, fibrinogen, and ESR were significantly higher in the patients with colon cancer, when compared to the control group (6.08 vs. 1.4 mg/L, p < 0.0001; 408 vs. 359 mg/dL, p = 0.002; and 30 vs. 8 mm/h, p < 0.0001, respectively). Our results show that higher levels of circulating chemerin, CRP, fibrinogen, and ESR are associated with an increased risk of developing colorectal cancer. PMID- 26628302 TI - Distinguishing between stochasticity and determinism: Examples from cell cycle duration variability. AB - We describe a recent approach for distinguishing between stochastic and deterministic sources of variability, focusing on the mammalian cell cycle. Variability between cells is often attributed to stochastic noise, although it may be generated by deterministic components. Interestingly, lineage information can be used to distinguish between variability and determinism. Analysis of correlations within a lineage of the mammalian cell cycle duration revealed its deterministic nature. Here, we discuss the sources of such variability and the possibility that the underlying deterministic process is due to the circadian clock. Finally, we discuss the "kicked cell cycle" model and its implication on the study of the cell cycle in healthy and cancerous tissues. PMID- 26628301 TI - Inhibitory effects of Arhgap6 on cervical carcinoma cells. AB - Ras homology GTPase activation protein 6 (Arhgap6), as a member of the rhoGAP family of proteins, performs vital functions on the regulation of actin polymerization at the plasma membrane during several cellular processes. The role of Arhgap6 in the progression and development of cancer remains nearly unknown. This study aimed at exploring the effects of Arhgap6 on cervical carcinoma. Human cervical cancer cells HeLa and SiHa were transduced with a lentivirus targeting Arhgap6 (Arhgap6+), while CaSki and C4-1 cells were transfected with miRNA. Cell proliferation was identified by Cell Counting Kit-8 (CCK-8). Cell cycle distribution and cell apoptosis were identified by flow cytometry. The capacity of cell migration, invasion, and adhesion were detected by Transwell assay. Further, quantitative real-time PCR (qRT-PCR) and western blot were used to analyze the expression levels of Arhgap6 and several tumor-related genes. Co immunoprecipitation assay was performed to validate the interaction between Arhgap6 and Rac3 (Ras-related C3 botulinum toxin substrate 3). Results showed that Arhgap6 inhibited cell proliferation, migration, invasion, and adhesion of cervical carcinoma, induced cell apoptosis, and caused cell cycle arrest in the G0/G1 phase (n = 3, p < 0.05). Expression of the tumor suppressor genes and oncogenes were up- and down-regulated respectively by Arhgap6, and Rac3 was proved to be the target of Arhgap6. Besides, in in vivo assays, tumor size and weight were destructed in Arhgap6+ athymic nude mouse. This study indicated that Arhgap6 may play a role in the treatment of cervical cancer as a tumor supressor. PMID- 26628303 TI - Dislocation of the proximal tibiofibular joint, do not miss it. AB - We present a case of a 45-year-old woman with a right proximal tibiofibular dislocation she sustained after a fall during roller skating. Anteroposterior and lateral radiographs confirmed the diagnosis; there were no other injuries. The dislocation was reduced by direct manipulation after intra-articular infiltration, in our emergency department. The patient was treated with a long, non-weight bearing leg cast for 1 week. After 4 weeks, she had no pain and a full range of motion of the knee. PMID- 26628304 TI - Small cell osteosarcoma of the parietal region: a unique case at an unusual site. AB - Small cell osteosarcoma is a rare tumour that histologically mimics Ewing sarcoma, mesenchymal chondrosarcoma and lymphoma, the presence of osteoid being diagnostic. This variant needs different management protocol, being non radiosensitive and behaving more aggressively than conventional osteosarcoma. The aim of this article is to highlight such an entity at an unusual site--the parietal region--with unique diagnostic, treatment and prognostic considerations in a 16-year-old girl. PMID- 26628305 TI - Life-threatening haemorrhage in patients without pulmonary embolism who received anticoagulants. AB - Local and international guidelines recommend that anticoagulation should be initiated before diagnostic work up has been completed, in patients with high clinical probability of pulmonary embolism (PE). However, many patients receiving anticoagulants for suspected PE do not have this disease. We present three cases of life-threatening bleeding complications after treatment with low-molecular weight heparins for suspected PE. A 35-year-old woman had acute chest pain and died of a ruptured thoracic aneurysm. A man with herpes encephalitis developed acute dyspnoea, and died of intracerebral haemorrhage. And a woman with mild chest trauma had a complicated recovery after life-threatening intrapleural haemorrhage. Neither of these patients had PE. These cases emphasise that delaying diagnostics may pose a risk in patients with acute chest symptoms. An early CT scan may avoid unnecessary anticoagulation in patients without PE, and may help to direct attention to the actual cause. PMID- 26628306 TI - Endobronchial valves in the management of bronchial fistulae caused by bronchopulmonary aspergillosis. AB - Following an aggressive episode of bronchopulmonary aspergillosis, a 54-year-old man developed a symptomatic air leak via a tunnel between the left upper lobe and an extra chest wall cavity. Following the failure of several surgical procedures to close the tunnel, endobronchial valves normally used in management of emphysema were used to successfully treat the air leak. PMID- 26628307 TI - A calcified mass. PMID- 26628308 TI - Live kidney donation from a person with haemophilia. AB - There are many documented cases of a person with haemophilia successfully receiving a solid organ transplant, including liver and kidney. However, there is no literature reporting live organ donation by a person with haemophilia. Presumably, this is because the associated risks of excessive bleeding, inhibitor development after a period of intensive treatment with factor replacement and the possibility of variant Creutzfeldt-Jakob disease transmission in those previously treated with blood products, are considered excessive. This case describes a 24 year-old man who was diagnosed with mild haemophilia A during his pretransplant work up as a potential live kidney donor to his sister. He then went on to successfully donate his kidney, without complications. To the best of our knowledge, this is the first description of a person with haemophilia being a living organ donor. PMID- 26628309 TI - Cautionary tale: subdural haematoma following frequent hypoglycaemia from insulin induced lipohypertrophy. PMID- 26628310 TI - Leucapheresis for management of retinopathy in chronic myeloid leukaemia. AB - Chronic myeloid leukaemia is a myeloproliferative neoplasm characterised by granulocytic hyperplasia in the bone marrow and the presence of a specific cytogenetic abnormality known as Philadelphia chromosome with fusion of breakpoint cluster region (BCR) and ableson (ABL) genes. Retinopathy is a rare sight-threatening complication of chronic myeloid leukaemia, which occurs due to leucostasis in retinal blood vessels. We report a case of a patient who presented with visual impairment due to leucostasis, who was successfully managed by leucapheresis along with BCR-ABL tyrosine kinase inhibitor. PMID- 26628311 TI - Dynamic left ventricular outflow obstruction in situs inversus with levocardia. AB - A 69-year-old man with situs inversus, levocardia and inverted great arteries developed severe dynamic left ventricular outflow tract (LVOT) obstruction with systolic anterior motion of the anterior mitral leaflet. There was no asymmetric septal hypertrophy. A possible mechanism of the LOVT obstruction in the present case may have been related to an abnormally long and bent outflow tract resulting from overriding of the right ventricle over the LVOT due to a congenital malposition of the heart. Mitral valve replacement with septal myectomy was performed in order to eliminate systolic anterior motion. The postoperative course has been excellent. PMID- 26628312 TI - An intriguing case of locked jaw secondary to melioidosis. AB - A 56-year-old woman presented with fever, pain and restriction of movement of the right temporomandibular joint. She was premorbidly diagnosed to have type 2 diabetes mellitus and rheumatoid arthritis. Local examination revealed a poorly demarcated severely tender, erythematous swelling in the right preauricular region. All haematological and biochemical investigations were within normal limits. MRI of the neck revealed the presence of a masticator space infection with intramuscular abscess involving the masseter and the temporalis muscles along with intracranial extension. Osteomyelitic changes were detected in the right mandibular condyle, temporal bone and in the temporomandibular joint. Melioidosis was suspected due to this unique clinical presentation of an abscess at an unusual and atypical site. Blood cultures identified the Gram-negative bacilli Burkholderia pseudomallei, which established the diagnosis of Melioidosis. Remarkable improvement was attained with antibiotics meropenem and cotrimoxazole, deferring the need for any surgical intervention. PMID- 26628313 TI - Adrenocortical carcinoma with inferior vena cava tumour thrombus: multidetector CT (MDCT) evaluation and management. PMID- 26628314 TI - Intermittent unspecific osteitis and cortex atrophy of the proximal phalanx after surgical pulley repair. AB - Climbing athletes frequently suffer from pulley ruptures, as the shear stress on the finger flexor tendon pulley system is extremely high, especially in the 'crimping position'. Studies showed that surgery only has to be performed in a multiple pulley rupture situation (grade IV injuries). This case describes a complication that appeared after performing a 'bone-encircling' technique recommended for climbers (modified 'one-and-a-half-loop' technique). Simultaneously with resumption of full-strength training after surgery and rehabilitation, the dorsolateral cortex of the proximal phalanx, to which the tendon transplant (palmaris longus tendon surrounding bone and flexor tendon of the finger) is entangled, developed an osteitis and atrophy. We investigated two athletes with the same complaints and symptoms. PMID- 26628316 TI - The role of emergency physicians in the institutionalization of emergency medicine. AB - OBJECTIVES: Emergency medicine is a fast-growing medical profession. Nevertheless, the clinical activities emergency physicians (EPs) carry out and the responsibilities they have differ considerably between hospitals. This article addresses the question how the role of EPs is shaped and institutionalized in the everyday context of acute care in hospitals. METHODS: A cross-case ethnographic study was conducted, comprising observations, document analysis, and in-depth interviews in three emergency departments in the Netherlands. RESULTS: Drawing on the theoretical concept of institutional work, we show that managers, already established medical specialties, and EPs all conduct institutional work to enhance private interests, which both restricts and enlarges EPs' work domain. These actions are strategic and intentional, as well as unintentional and part of EPs' everyday work in acute care delivery. It is in this very process that tasks and responsibilities are redistributed and the role of the EP is shaped. DISCUSSION: In contemporary literature it is often argued that the role and status of EPs should be enhanced by strengthening regulation and improving training programs. This article shows that attention should also be paid to the more subtle everyday processes of role development. PMID- 26628315 TI - Walking the line. Palliative sedation for existential distress: still a controversial issue? AB - Adequate symptom relief is a central aspect of medical care of all patients especially in those with an incurable disease. However, as an illness progresses and the end of life approaches, physical or psychoexistential symptoms may remain uncontrollable requiring palliative sedation. Although palliative sedation has become an increasingly implemented practice in the care of terminally ill patients, sedation in the management of refractory psychological symptoms and existential distress is still a controversial issue and much debated. This case report presents a patient who received palliative sedation for the treatment of existential distress and discusses considerations that may arise from such a therapeutic approach. PMID- 26628317 TI - Out-of-hospital cardiopulmonary resuscitation strategies using one-handed chest compression technique for children suffering a cardiac arrest. AB - OBJECTIVE: We evaluated the decrease in chest compression depth during 30 : 2 compression-to-ventilation ratio one-handed chest compression (OHCC) in an out-of hospital pediatric arrest setting, and whether switching hands every other cycle could maintain compression depth. METHODS: A 5-year-old child-sized manikin was used, and 50 medical students participated in the present study. First, the participants performed 5 min OHCC with a 30 : 2 compression-to-ventilation ratio on the floor (baseline test). Second, the compression technique was changed from the OHCC to the two-handed chest compression when they became subjectively fatigued (test 1). Third, the compression hand was alternated every other cycle (test 2). Average compression depth (ACD) data were recorded using an accelerometer device. RESULTS: ACD changed significantly during the baseline test (0-1 min: 44.5+/-5.3 mm, 1-2 min: 43.7+/-6.1 mm, 2-3 min: 43.4+/-6.5 mm, 3-4 min: 43.2+/-6.5 mm, and 4-5 min: 42.3+/-6.5 mm, P=0.012). However, no significant differences were observed during test 1 or test 2. The baseline ACD value for the 4-5-min interval [95% confidence interval (CI), 40.5-44.2 mm] was significantly lower than those in test 1 (95% CI, 43.0-45.9 mm, P=0.004) and test 2 (95% CI, 42.4-45.9 mm, P=0.004). No differences in the ACDs at any interval were observed between test 1 and test 2. CONCLUSION: Compression depth decreased significantly after 4 min during 30 : 2 ratio OHCC. However, it was maintained by changing from the OHCC to the two-handed chest compression or by alternating compression hands every other cycle. PMID- 26628318 TI - Oncologic outcomes after nipple-sparing mastectomy: A single-institution experience. AB - INTRODUCTION: Long-term oncologic outcomes in nipple-sparing mastectomy (NSM) continue to be defined. Rates of locoregional recurrence for skin-sparing mastectomy (SSM) and NSM in the literature range from 0% to 14.3%. We investigated the outcomes of NSM at our institution. METHODS: Patients undergoing NSM at our institution from 2006 to 2014 were identified and outcomes were analyzed. RESULTS: From 2006 to 2014, 319 patients (555 breasts) underwent NSM. One-hundered and fourty-one patients (237 breasts) had long-term follow-up available. Average patient age and BMI were 47.78 and 24.63. Eighty-four percent of patients underwent mastectomy primarily for a therapeutic indication. Average tumor size was 1.50 cm with the most common histologic type being invasive ductal carcinoma (62.7%) followed by DCIS (23.7%). Average patient follow-up was 30.73 months. There was one (0.8%) incidence of ipsilateral chest-wall recurrence. There were 0.37 complications per patient. CONCLUSIONS: We examined our institutional outcomes with NSM and found a locoregional recurrence rate of 0.8% with no nipple-areolar complex recurrence. This rate is lower than published rates for both NSM and SSM. PMID- 26628319 TI - A description of teaching methods using an on-site instructor versus a distant site instructor to train laryngoscopy to medical students in Hanoi, Vietnam, from Omaha, Nebraska, by video communication. AB - This study demonstrated a method to train medical students at Hanoi Medical School in airway management from Omaha, Nebraska, using tele-mentoring techniques. Correct placement of the endotracheal tube was documented by tele broncoscopy following intubation. This technology may increase medical training capabilities in remote or developing areas of the world. Medical care delivery could be performed using this technology by tele-mentoring a lesser trained medical provider at a distant site enabling them to accomplish complex medical tasks. PMID- 26628320 TI - Academic affairs and global health: how global health electives can accelerate progress towards ACGME milestones. AB - Global health electives (GHEs) have become a standard offering in many residency programs. Residency electives should aid residents in achieving outcomes in the Accreditation Council for Graduate Medical Education (ACGME) competency domains. In this paper, the authors review existing literature and provide expert opinion to highlight how global health electives can complement traditional training programs to assist residents in achieving ACGME milestones, using emergency medicine residency as an example. Recommendations are provided for identifying exemplary global health electives and for the development of institutional global health elective curricula in order to facilitate milestone achievement. Global health electives can advance progress towards ACGME milestones; however, they may vary greatly in terms of potential for learner advancement. Electives should thus be rigorously vetted to ensure they meet standards that will facilitate this process. Given that milestones are a newly introduced tool for assessing resident educational achievement, very little research is available currently to directly determine impacts, and further study will be needed. PMID- 26628321 TI - Cellular toxicity of yeast prion protein Rnq1 can be modulated by N-terminal wild type huntingtin. AB - Aggregation of the N-terminal human mutant huntingtin and the consequent toxicity in the yeast model of Huntington's disease (HD) requires the presence of Rnq1 protein (Rnq1p) in its prion conformation [RNQ1(+)]. The understanding of interaction of wild-type huntingtin (wt-Htt) with the amyloidogenic prion has some gaps. In this work, we show that N-terminal fragment of wt-Htt (N-wt-Htt) ameliorated the toxic effect of [RNQ1(+)] depending on expression levels of both proteins. When the expression of N-wt-Htt was high, it increased the expression and delayed the aggregation of [RNQ1(+)]. As the expression of N-wt-Htt was reduced, it formed high molecular weight aggregates along with the prion. Even when sequestered by [RNQ1(+)], the beneficial effect of N-wt-Htt on expression of Rnq1p and on cell survival was evident. Huntingtin protein ameliorated toxicity due to the prion protein [RNQ1(+)] in yeast cells in a dose-dependent manner, resulting in increase in cell survival, hinting at its probable role as a component of the proteostasis network of the cell. Taking into account the earlier reports of the beneficial effect of expression of N-wt-Htt on the aggregation of mutant huntingtin, the function of wild-type huntingtin as an inhibitor of protein aggregation in the cell needs to be explored. PMID- 26628322 TI - The association between contact and intellectual disability literacy, causal attributions and stigma. AB - BACKGROUND: Contact is seen as a key route to tackling stigma and discrimination. Contact theory states that the quality and type of contact, as well as circumstance of the contact experience, influence the effect of contact on prejudice. The majority of research in intellectual disabilities though has focused on contact as present or absent only. METHOD: A total of 1264 adult members of the UK general population completed measures of symptom recognition, social distance (as measure of external stigma) and causal beliefs in response to a diagnostically unlabelled vignette, depicting someone with intellectual disabilities. RESULTS: A nuanced contact variable, including frequency of contact and closeness and nature of the contact relationship, explained more of the variance in social distance, compared to the binary variable (contact as present or absent). Only the closeness of the relationship was individually predictive though, and the models explained only relatively small amounts of the variance. Structural equation modelling of contact, recognition, social distance and causal beliefs demonstrated that the model including the nuanced variable was an adequate fit for the data. CONCLUSIONS: Future research aimed at increasing our understanding of intellectual disability stigma should avoid assessing contact as a binary variable only, but consider other factors, particularly the closeness of contact relationships. Anti-stigma interventions may benefit from focussing on causal attributions as a method of reducing stigma. PMID- 26628323 TI - The height limit of a siphon. AB - The maximum height of a siphon is generally assumed to be dependent on barometric pressure-about 10 m at sea level. This limit arises because the pressure in a siphon above the upper reservoir level is below the ambient pressure, and when the height of a siphon approaches 10 m, the pressure at the crown of the siphon falls below the vapour pressure of water causing water to boil breaking the column. After breaking, the columns on either side are supported by differential pressure between ambient and the low-pressure region at the top of the siphon. Here we report an experiment of a siphon operating at sea level at a height of 15 m, well above 10 m. Prior degassing of the water prevented cavitation. This experiment provides conclusive evidence that siphons operate through gravity and molecular cohesion. PMID- 26628325 TI - HIV replication: a game of hide and sense. AB - PURPOSE OF REVIEW: The goal of this review is to summarize recent progress in our understanding of innate sensing of HIV. Furthermore, we present the mechanisms that HIV has evolved to attenuate innate immune responses and discuss open questions. RECENT FINDINGS: Toll-like receptors (TLRs) and various cytosolic sensors induce an antiviral interferon response upon detection of genomic HIV RNA or intermediates of reverse transcription. HIV limits activation of these sensing pathways by interfering with TLR signaling and by cloaking viral nucleic acids in the cytoplasm, before proviral dsDNA translocates into the nucleus. Furthermore, the viral accessory protein Vpu mitigates antiviral gene expression by inhibiting canonical nuclear factor kappa B (NF-kappaB) signaling. These evasion mechanisms, however, are imperfect and HIV infection almost inevitably triggers the activation of IRF3, NF-kappaB and other key transcription factors of antiviral immunity. Notably, the interplay of these processes plays a critical role in the induction of chronic inflammation that drives progression to AIDS. SUMMARY: HIV has evolved sophisticated but imperfect mechanisms to evade and counteract innate sensing. Whether virus-induced immune activation represents merely a suboptimal adaptation of HIV to its human host or even facilitates HIV replication, for example by increasing the number of viral target cells, remains to be clarified. PMID- 26628324 TI - Genital inflammation, immune activation and risk of sexual HIV acquisition. AB - PURPOSE OF REVIEW: Women who have genital inflammation are at increased risk of sexual HIV infection. The purpose of this review is to evaluate the mechanisms for this relationship, causes of genital inflammation, and strategies to manage this condition. RECENT FINDINGS: We have recently shown in a cohort of South African women that HIV seroconversion was associated with persistently raised genital inflammatory cytokines (including MIP-1alpha, MIP-1beta, and IP-10). Elevated inflammatory cytokine concentrations may facilitate HIV infection by recruiting and activating HIV target cells and disrupting the mucosal epithelial barrier. Bacterial vaginosis and sexually transmitted infections (STIs), which are predominantly asymptomatic in women, cause lower genital tract inflammation and increased HIV acquisition risk. In Africa, where syndromic management of STIs and bacterial vaginosis is standard-of-care, the substantial burden of asymptomatic infections has likely contributed to high-HIV incidence rates. SUMMARY: A genital inflammatory profile contributes to the high risk of HIV acquisition in African women. STIs and bacterial vaginosis are poorly managed in Africa and other developing nations and as such remain major drivers of persistent genital inflammation and HIV acquisition among these women. PMID- 26628326 TI - Sub-10 nm near-field localization by plasmonic metal nanoaperture arrays with ultrashort light pulses. AB - Near-field localization by ultrashort femtosecond light pulses has been investigated using simple geometrical nanoapertures. The apertures employ circular, rhombic, and triangular shapes to localize the distribution of surface plasmon. To understand the geometrical effect on the localization, aperture length and period of the nanoapertures were varied. Aperture length was shown to affect the performance more than aperture period due mainly to intra-aperture coupling of near-fields. Triangular apertures provided the strongest spatial localization below 10 nm in size as well as the highest enhancement of field intensity by more than 7000 times compared to the incident light pulse. Use of ultrashort pulses was found to allow much stronger light localization than with continuous-wave light. The results can be used for super-localization sensing and imaging applications where spatially localized fields can break through the limits in achieving improved sensitivity and resolution. PMID- 26628327 TI - The medical response to multisite terrorist attacks in Paris. PMID- 26628329 TI - Not all probiotic strains prevent necrotising enterocolitis in premature infants. PMID- 26628330 TI - Impacts of electrical parameters on the electroformation of giant vesicles on ITO glass chips. AB - A "sandwich" structure device consisted of ITO electrodes and PDMS spacer was designed and used to explore the impact of different electrical parameters (intensity and frequency) on the electroformation of GUVs (giant unilamellar vesicles). Theoretical analysis of the dielectrophoretic effect (DEPE) and the electrohydrodynamic effect (EHE) on the electroformation process indicated that the characteristic frequency of the system could maximize the mutual effect of the both, which might benefit the formation of GUVs. The calculated value of the characteristic frequency (13.3 kHz) was very close to the experimental one (11 kHz). We demonstrated that for a given electroformation system, large amount of well-distributed GUVs can be obtained by optimizing the electrical parameters. In this paper, when choosing the optimal electrical parameters (11 kHz frequency and 5V/mm intensity), the amount of GUVs could reach 65/mm(2), and the diameters of most GUVs (>70%) were 50-70 MUm. PMID- 26628331 TI - Study of stiffness effects of poly(amidoamine)-poly(n-isopropyl acrylamide) hydrogel on wound healing. AB - The mechanical miss-match between the host and an implanted foreign body is one of the primary causes for implantation failure. To enhance the efficacy in wound repair, we developed stiffness-tunable temperature-sensitive hydrogels composed of poly(amidoamine) (PAA)-based poly(n-isopropyl acrylamide) (PNIPAM). PNIPAM-PAA hydrogels with three different stiffness fabricated by varying the concentrations of poly(amidoamine) were chosen for morphology and rheology tests. The degradation rate and cell compatibility of gels were also characterized. The PAA PNIPAM hydrogels were then tested in a wound healing model of mice with full thickness skin loss. We found that the stiffness of hydrogels has an impact on the wound healing process mainly by regulating the cell activities in the proliferation phase. PNIPAM-PAA hydrogels with appropriate stiffness reduce scar formation and improve wound healing by promoting myofibroblast transformation, keratinocytes proliferation, extracellular matrix synthesis and remodeling. Moreover, the stiffness of hydrogels impact on the secretion of TGF-beta1 and bFGF, which play an important role in skin wound healing. These results suggest that the therapeutic effects of hydrogels in skin wound healing can by regulated by hydrogels' stiffness. PMID- 26628332 TI - Sequestration of bovine seminal plasma proteins by different assemblies of phosphatidylcholine: A new technical approach. AB - Binder of SPerm (BSP) proteins, the main proteins from bovine seminal plasma, are known to partially intercalate into the outer leaflet of the spermatozoa membrane and bind to choline-containing lipids being present therein. This insertion generates a negative effect on semen quality after cryopreservation by inducing an early-stage capacitation of spermatozoa. The assumption of surface properties exhibited by BSP proteins was checked by tensiometry measurements: BSP proteins are highly surface active. This suggests that BSP proteins can reach the interface covered by phospholipids not only by interactions between one and each other but also due to their own surface activity. The insertion of BSP proteins into the lipid domains outer leaflet of spermatozoa was reproduced on a biomimetic system such as Langmuir monolayers. The insertion of BSP proteins can be performed in the compressible fluid domains which contain choline-bearing lipids. Monolayer films were used as well to study the complexation of BSP proteins by two phospholipid assemblies: low density lipoprotein (LDLs) from egg yolk or liposomes produced from egg phospholipids. Irrespective of the phospholipid structure (lipoprotein or liposome), BSP was hindered to alter the structure of the membrane. Only the overall ratio BSP proteins:phosphatidylcholine was important. The difference between the two sequestering agents lies on their surface properties: LDL have a strong tendency to merge with the outer layer whereas liposomes mainly remain in the bulk on the same time scale. PMID- 26628333 TI - A novel injectable phospholipid gel co-loaded with doxorubicin and bromotetrandrine for resistant breast cancer treatment by intratumoral injection. AB - Systemically administered anticancer treatments were greatly limited by extensive side effects mainly due to nonspecific distributions in vivo, and multidrug resistance in various tumors. A phospholipids-based in situ-forming gel platform has been developed for the concurrent delivery of doxorubicin (DOX) and bromotetrandrin (W198). Phospholipid gel containing DOX and W198 remained in a solution (sol) state before injection and underwent rapid gelation after injection in vivo. The release of DOX and W198 from phospholipid gel (PG) was sustained in vitro for over 20 days (d). DOX and W198 from PG achieved prolonged release for over two weeks in rats via subcutaneous injection. Compared with repeated injections of free drug, eliminated cardiac toxicity and less bone marrow inhibition were observed for DOX and W198-loaded PG (DOX/W198-PG) in normal rats via subcutaneous injection. Also, a single intratumoral injection of DOX/W198-PG in the resistant MCF-7/Adr xenograft-bearing mice showed much better antitumor efficacy compared to other treatment groups. In sum, DOX/W198-PG was well demonstrated to achieve sustained drug release both in vitro and in vivo with eliminated toxicity and improved antitumor efficacy by reversing the multidrug resistance in breast cancers. PMID- 26628334 TI - PROMIS fatigue, pain intensity, pain interference, pain behavior, physical function, depression, anxiety, and anger scales demonstrate ecological validity. AB - OBJECTIVES: Ecological validity refers to the degree to which instruments faithfully capture information in respondents' natural environments. We examined the ecological validity of eight instruments from the Patient Reported Outcomes Measurement Information System (PROMIS), most of which use 7-day reporting periods, by comparing PROMIS scores with daily diary data as a standard. STUDY DESIGN AND SETTING: Five groups of approximately 100 respondents each completed daily diaries and weekly PROMIS instruments for 4 consecutive weeks: community residents; osteoarthritis patients; women experiencing premenstrual syndrome; men undergoing hernia surgery; and breast cancer patients receiving chemotherapy. The last three groups experienced events (menses, surgery, or chemotherapy, respectively) at standardized times in the protocol to examine symptom changes attributable to these events. RESULTS: We examined the ability of the PROMIS scales to replicate between-group differences in diaries, to replicate week-to week changes in diaries, and the correlation between diary and PROMIS scales. As a secondary aim, we examined known-group differences with the PROMIS measures. All three types of ecological validity were strongly confirmed, as was known group validity for the PROMIS recall scales. CONCLUSION: This study adds to the growing literature supporting the reliability and validity of the family of PROMIS instruments. PMID- 26628328 TI - Bifidobacterium breve BBG-001 in very preterm infants: a randomised controlled phase 3 trial. AB - BACKGROUND: Probiotics may reduce necrotising enterocolitis and late-onset sepsis after preterm birth. However, there has been concern about the rigour and generalisability of some trials and there is no agreement about whether or not they should be used routinely. We aimed to test the effectiveness of the probiotic Bifidobacterium breve BBG-001 to reduce necrotising enterocolitis, late onset sepsis, and death in preterm infants. METHODS: In this multicentre, randomised controlled phase 3 study (the PiPS trial), we recruited infants born between 23 and 30 weeks' gestational age within 48 h of birth from 24 hospitals in southeast England. Infants were randomly assigned (1:1) to probiotic or placebo via a minimisation algorithm randomisation programme. The probiotic intervention was B breve BBG-001 suspended in dilute elemental infant formula given enterally in a daily dose of 8.2 to 9.2 log10 CFU; the placebo was dilute infant formula alone. Clinicians and families were masked to allocation. The primary outcomes were necrotising enterocolitis (Bell stage 2 or 3), blood culture positive sepsis more than 72 h after birth; and death before discharge from hospital. All primary analyses were by intention to treat. This trial is registered with ISRCTN, number 05511098 and EudraCT, number 2006-003445-17. FINDINGS: Between July 1, 2010, and July 31, 2013, 1315 infants were recruited; of whom 654 were allocated to probiotic and 661 to placebo. Five infants had consent withdrawn after randomisation, thus 650 were analysed in the probiotic group and 660 in the placebo group. Rates of the primary outcomes did not differ significantly between the probiotic and placebo groups. 61 infants (9%) in the probiotic group had necrotising enterocolitis compared with 66 (10%) in the placebo group (adjusted risk ratio 0.93 (95% CI 0.68-1.27); 73 (11%) infants in the probiotics group had sepsis compared with 77 (12%) in the placebo group (0.97 (0.73-1.29); and 54 (8%) deaths occurred before discharge home in the probiotic group compared with 56 (9%) in the placebo group (0.93 [0.67-1.30]). No probiotic associated adverse events were reported. INTERPRETATION: There is no evidence of benefit for this intervention in this population; this result does not support the routine use of B breve BBG-001 for prevention of necrotising enterocolitis and late-onset sepis in very preterm infants. FUNDING: UK National Institute for Health Research Health Technology Assessment programme. PMID- 26628335 TI - Problems in detecting misfit of latent class models in diagnostic research without a gold standard were shown. AB - OBJECTIVES: The objective of this study was to evaluate the performance of goodness-of-fit testing to detect relevant violations of the assumptions underlying the criticized "standard" two-class latent class model. Often used to obtain sensitivity and specificity estimates for diagnostic tests in the absence of a gold reference standard, this model relies on assuming that diagnostic test errors are independent. When this assumption is violated, accuracy estimates may be biased: goodness-of-fit testing is often used to evaluate the assumption and prevent bias. STUDY DESIGN AND SETTING: We investigate the performance of goodness-of-fit testing by Monte Carlo simulation. The simulation scenarios are based on three empirical examples. RESULTS: Goodness-of-fit tests lack power to detect relevant misfit of the standard two-class latent class model at sample sizes that are typically found in empirical diagnostic studies. The goodness-of fit tests that are based on asymptotic theory are not robust to the sparseness of data. A parametric bootstrap procedure improves the evaluation of goodness of fit in the case of sparse data. CONCLUSION: Our simulation study suggests that relevant violation of the local independence assumption underlying the standard two-class latent class model may remain undetected in empirical diagnostic studies, potentially leading to biased estimates of sensitivity and specificity. PMID- 26628336 TI - A prognostic model based on readily available clinical data enriched a pre emptive pharmacogenetic testing program. AB - OBJECTIVES: We describe the development, implementation, and evaluation of a model to pre-emptively select patients for genotyping based on medication exposure risk. STUDY DESIGN AND SETTING: Using deidentified electronic health records, we derived a prognostic model for the prescription of statins, warfarin, or clopidogrel. The model was implemented into a clinical decision support (CDS) tool to recommend pre-emptive genotyping for patients exceeding a prescription risk threshold. We evaluated the rule on an independent validation cohort and on an implementation cohort, representing the population in which the CDS tool was deployed. RESULTS: The model exhibited moderate discrimination with area under the receiver operator characteristic curves ranging from 0.68 to 0.75 at 1 and 2 years after index dates. Risk estimates tended to underestimate true risk. The cumulative incidences of medication prescriptions at 1 and 2 years were 0.35 and 0.48, respectively, among 1,673 patients flagged by the model. The cumulative incidences in the same number of randomly sampled subjects were 0.12 and 0.19, and in patients over 50 years with the highest body mass indices, they were 0.22 and 0.34. CONCLUSION: We demonstrate that prognostic algorithms can guide pre emptive pharmacogenetic testing toward those likely to benefit from it. PMID- 26628337 TI - Chronic Myelogenous Leukemia Relapse Presenting With Central Nervous System Blast Crisis and Bilateral Optic Nerve Infiltration. AB - Bilateral, simultaneous optic nerve sheath infiltration as a manifestation of leukemia relapse is very rare. A 45-year-old woman with chronic myelogenous leukemia was successfully treated to cytogenetic bone marrow remission 1 year previously and maintained on imatinib. She developed total bilateral blindness with marked, bilateral optic disc edema and evidence of bilateral optic nerve infiltration on magnetic resonance imaging. Cerebrospinal fluid cytology confirmed central nervous system (CNS) blast crisis. She recovered visual acuity of 20/20 in the right eye, and 20/25 in the left eye with salvage systemic and intrathecal chemotherapy before radiation therapy. Our report underscores the importance of timely and aggressive intervention of blast crisis of the CNS and the need for CNS penetrating induction and maintenance therapy. PMID- 26628338 TI - Novel technique to measure horizontal corneal diameter using a Scheimpflug image on the Pentacam. AB - PURPOSE: A new method to measure the horizontal corneal diameter using a Scheimpflug image (SFI) was introduced and compared with the automated iris camera photo (ICP) method on the Pentacam. METHODS: Each one eye of 88 subjects without significant abnormality in the cornea was included. In SFI, diameters were measured manually using the built-in software tool with the edge-filter option. ICP value read from the overview display. Repeatability was determined from the first two measurements of each eye. The accuracy was assessed using Bland-Altman plot in comparison with caliper measurements. RESULTS: The measurement failure rate of ICP was aggravated by pupil dilation, while that of SFI was unrelated to pupil dilation. Repeatability coefficients of ICP and SFI were 0.1mm and 0.12mm, respectively. The mean difference between ICP values and caliper values was not significant. SFI values were greater than caliper measurements by a mean of 0.13mm. CONCLUSIONS: New SFI was reliable and could complement ICP in dilated pupil. The measurement failure rates of Pentacam need to be improved. PMID- 26628339 TI - Energy value of poultry byproduct meal and animal-vegetable oil blend for broiler chickens by the regression method. AB - The energy values of poultry byproduct meal (PBM) and animal-vegetable oil blend (A-V blend) were determined in 2 experiments with 288 broiler chickens from d 19 to 25 post hatching. The birds were fed a starter diet from d 0 to 19 post hatching. In each experiment, 144 birds were grouped by weight into 8 replicates of cages with 6 birds per cage. There were 3 diets in each experiment consisting of one reference diet (RD) and 2 test diets (TD). The TD contained 2 levels of PBM (Exp. 1) or A-V blend (Exp. 2) that replaced the energy sources in the RD at 50 or 100 g/kg (Exp. 1) or 40 or 80 g/kg (Exp. 2) in such a way that the same ratio were maintained for energy ingredients across experimental diets. The ileal digestible energy (IDE), ME, and MEn of PBM and A-V blend were determined by the regression method. Dry matter of PBM and A-V blend were 984 and 999 g/kg; the gross energies were 5,284 and 9,604 kcal/kg of DM, respectively. Addition of PBM to the RD in Exp. 1 linearly decreased (P < 0.05) DM, ileal and total tract of DM, energy and nitrogen digestibilities and utilization. In Exp. 2, addition of A V blend to the RD linearly increased (P < 0.001) ileal digestibilities and total tract utilization of DM, energy and nitrogen as well as IDE, ME, and MEn. Regressions of PBM-associated IDE, ME, or MEn intake in kcal against PBM intake were: IDE = 3,537x + 4.953, r(2) = 0.97; ME = 3,805x + 1.279, r(2) = 0.97; MEn = 3,278x + 0.164, r(2) = 0.90; and A-V blend as follows: IDE = 10,616x + 7.350, r(2) = 0.96; ME = 10,121x + 0.447, r(2) = 0.99; MEn = 10,124x + 2.425, r(2) = 0.99. These data indicate the respective IDE, ME, MEn values (kcal/kg of DM) of PBM evaluated to be 3,537, 3,805, and 3,278, and A-V blend evaluated to be 10,616, 10,121, and 10,124. PMID- 26628340 TI - Dietary L-arginine levels affect the liver protein turnover and alter the expression of genes related to protein synthesis and proteolysis of laying hens. AB - Amino acids are considered to be anabolic factors that affect protein turnover. The aim of this study was to test the effects of dietary L-arginine (Arg) levels on protein metabolism in the liver of laying hens and the expression of genes related to protein synthesis and proteolysis. Xinyang black commercial laying hens (n = 864, 31 wk of age) were randomly allotted to 6 treatments with 4 replicates of 36 birds. The dietary treatments were corn-corn gluten meal based diets containing 0.64, 0.86, 1.03, 1.27, 1.42, and 1.66% L-Arg, respectively. Serum concentrations of total protein and albumin were maximized in the 1.27% L Arg group, and serum concentration of urea acid was the lowest in the 1.27% L-Arg group. The 1.27% L-Arg group had the highest fractional protein synthesis rate and fractional protein gain rate in the liver. Consistent with the data on protein turnover, mRNA abundances of target of rapamycin (TOR) and ribosomal protein S6 kinase 1 increased in the liver of layers fed 1.27% L-Arg, while mRNA abundances of cathepsin B and 20S proteasome decreased at the same dietary L-Arg level. In conclusion, the dietary level of L-Arg increased the liver fractional protein synthesis rate and fractional protein gain rate of laying hens, and the action of an appropriate level of dietary L-Arg involves upregulating the gene expression of the TOR signaling pathway accompanied by suppressing the mRNA expression of cathepsin B and 20S proteasome in the liver. PMID- 26628341 TI - Campylobacter epidemiology from breeders to their progeny in Eastern Spain. AB - While horizontal transmission is a route clearly linked to the spread of Campylobacter at the farm level, few studies support the transmission of Campylobacter spp. from breeder flocks to their offspring. Thus, the present study was carried out to investigate the possibility of vertical transmission. Breeders were monitored from the time of housing day-old chicks, then throughout the laying period (0 to 60 wk) and throughout their progeny (broiler fattening, 1 to 42 d) until slaughter. All samples were analyzed according with official method ISO 10272:2006. Results revealed that on breeder farms, Campylobacter isolation started from wk 16 and reached its peak at wk 26, with 57.0% and 93.2% of positive birds, respectively. After this point, the rate of positive birds decreased slightly to 86.0% at 60 wk. However, in broiler production all day-old chicks were found negative for Campylobacter spp, and the bacteria was first isolated at d 14 of age (5.0%), with a significant increase in detection during the fattening period with 62% of Campylobacter positive animals at the end of the production cycle. Moreover, non-positive sample was determined from environmental sources. These results could be explained because Campylobacter may be in a low concentration or in a non-culturable form, as there were several studies that successfully detected Campylobacter DNA, but failed to culture. This form can survive in the environment and infect successive flocks; consequently, further studies are needed to develop more modern, practical, cost-effective and suitable techniques for routine diagnosis. PMID- 26628342 TI - A method of production of boneless chicken wings (drumettes and winglets) by separation of periosteum from bone without cutting skin and muscles. PMID- 26628344 TI - Risk factors associated with keel bone and foot pad disorders in laying hens housed in aviary systems. AB - Aviary systems for laying hens offer space and opportunities to perform natural behaviors. However, hen welfare can be impaired due to increased risk for keel bone and foot pad disorders in those systems. This cross-sectional study (N = 47 flocks) aimed to assess prevalences of keel bone and foot pad disorders in laying hens housed in aviaries in Belgium to identify risk factors for these disorders and their relation to egg production. Information on housing characteristics and egg production were obtained through questionnaire-based interviews, farm records, and measurements in the henhouse. Keel bone (wounds, hematomas, fractures, deviations) and foot pad disorders (dermatitis, hyperkeratosis) were assessed in 50 randomly selected 60-week-old laying hens per flock. A linear model with stepwise selection procedure was used to investigate associations between risk factors, production parameters, and the keel bone and foot pad disorders. The flock mean prevalences were: hematomas 41.2%, wounds 17.6%, fractures 82.5%, deviations 58.9%, hyperkeratosis 42.0%, dermatitis 27.6%, and bumble foot 1.2%. Identified risk factors for keel bone disorders were aviary type (row vs. portal), tier flooring material (wire mesh vs. plastic slats), corridor width, nest box perch, and hybrid. Identified risk factors for foot pad disorders were aviary type (row vs. portal), free-range, and hybrid. Percentage of second-quality eggs was negatively associated with keel bone deviations (P = 0.029) at the flock level. Keel bone and foot pad disorders were alarmingly high in aviary housing. The identification of various risk factors suggests improvements to aviary systems may lead to better welfare of laying hens. PMID- 26628343 TI - Comparison of methionine sources around requirement levels using a methionine efficacy method in 0 to 28 day old broilers. AB - The addition of methionine in the poultry feed industry is still facing the relative efficacy dilemma between DL-methionine (DLM) and hydroxy-methionine (HMTBA). The aim of this study was to compare the effect of dietary DLM and HMTBA on broiler performance at different levels of total sulfur amino acids (TSAA). The treatments consisted of a basal diet without methionine addition, and 4 increasing methionine doses for both sources resulting in TSAA/Lysine ratios from 0.62 to 0.73 in the starter phase and 0.59 to 0.82 in the grower phase. The comparison of product performance was performed by three-way ANOVA analysis and by methionine efficacy calculation as an alternative method of comparison. Growth results obtained during the starter phase with the different methionine supplementations did not show significant growth responses to TSAA levels, indicating a lower methionine requirement in the starter phase than currently assumed. However, a significant methionine dose effect was obtained for the period 10 to 28 day of age and for the entire growth period of 0 to 28 day of age. Excepting a significant gender effect, the statistical analysis did not allow for the discrimination of methionine sources, and no interaction between source and dose level was observed up to 28 days of age. A significant interaction between source and dose level was observed for methionine efficacy for the grower phase, and the total growth period showed better HMTBA efficacy at higher TSAA value. The exponential model fitted to each methionine source for body weight response depending on methionine intake or for feed conversion ratio (FCR) depending on methionine doses did not allow the methionine sources to be distinguished. Altogether, these results conclude that methionine sources lead to similar performances response when compared at TSAA values around the broiler requirement level. These results also showed that at TSAA values above requirement, HMTBA had a better methionine efficacy value than DLM, caused by the different properties of that molecule, whereas below the TSAA requirement levels, the opposite was observed in females. PMID- 26628345 TI - The effects of water deprivation on the behavior of laying hens. AB - Freedom from thirst is one of the most undeniable welfare requirements. Nevertheless, the welfare implication of water deprivation because of a particular situation (e.g., transport) or as an involuntary consequence (e.g., sick, injured, or subordinate animals) remains unclear. This experiment investigated the behavioral changes in laying hens following various durations of water deprivation by using a motivation test based on passing through a narrow, vertical gap to access water. Twenty laying hens were subjected to water deprivation for various durations (0, 12, 18, 24, or 32 h) and the cost of access was varied by changing the width of the vertical gap (150, 135, 120, or 100 mm) to access the water side of the testing cage. An incomplete randomized block design was used with two tests per hen per wk for 5 wk. The testing apparatus was identical to their home cage but with two cages connected through an adjustable vertical gap and a drinker on the other side. Hens spent more time in the control side rather than the water side at 100 mm compared to 120 mm (P = 0.03). The hens' willingness to pass through a narrow vertical gap in order to access water did not vary according to the duration of water deprivation. Nonetheless, water deprivation duration had a marked effect on the hens' location and behavior. Hens spent more time in the vicinity of the drinker at 18, 24, and 32 h compared to 0 and 12 h (P < 0.05). Hens spent more time drinking at 24 h and 32 h, followed by 18, 12, and finally 0 h (P < 0.05). Drinking latency and frequency were higher for all water-deprivation durations as compared to the 0 h control (P < 0.05). Water deprivation can be characterized by behavioral changes such as drinking duration, reaching a plateau at 24 h. Complementary physiological data are warranted to fully assess the impact of water deprivation on hen welfare. PMID- 26628346 TI - Nutrient flow and distribution in conventional cage, enriched colony, and aviary layer houses. AB - This study was carried out to measure the mass flow and distribution of nutrients (N, C, S, P, and K) as well as solids and moisture in conventional cage (CC), enriched colony (EC), and aviary (AV) laying-hen houses with Lohmann LSL lite hens located on a commercial laying-hen farm in Iowa. The weight of consumed feed and water, and amounts of eggs and manure production were collected weekly from each house for 2 entire flocks for a total of 28 mo. Samples of feed, egg, manure, litter, and hens were regularly taken and analyzed for total solids and nutrients (N, C, S, P, and K). The nutrient losses to the atmosphere were calculated using a mass balance approach. The losses of nutrients were calculated by subtracting the nutrient contents in eggs, manure, and layer body weight gain from the nutrients intake. The research results showed that the feed intake and manure production rates were similar in the 3 houses. The average nutrient intake in feed, in g d(-1) hen(-1), for the 3 houses was 42.0 C, 2.96 N, 0.36 S, 0.55 P, and 0.79 K. The nutrient intake was partitioned as follow: C - 18% in eggs, 28% in manure, and 54% in air losses; N - 34% in eggs, 58% in manure, and 8% in air losses; S - 26% in eggs, 68% in manure, and 6% in air losses; P - 17% in eggs, 79% in manure, and 3.1% in air losses; and K - 9% in eggs, 89% in manure, and 1.6% in air losses. Manure removed from the EC house was drier than manure from the CC or AV house. Among the 3 hen houses studied, the EC house had the lowest nutrient losses and the AV house had the highest losses. Nutrient loss in CC was statistically similar to EC. But loss of N, C, and S in AV differed from CC and EC. Furthermore, the loss of P and K in the 3 housing systems was statistically similar. The AV had a doubled mortality rate compared to CC and EC. PMID- 26628347 TI - Potential environmental benefits of prospective genetic changes in broiler traits. AB - A system approach-based Life Cycle Assessment (LCA) framework, combined with a simple mechanistic model of bird energy balance was used to predict the potential effects of 15 y prospective broiler breeding on the environmental impacts of the standard UK broiler production system. The year 2014 Ross 308 genotype was used as a baseline, and a future scenario was specified from rates of genetic improvement predicted by the industry. The scenario included changes in the traits of growth rate (reducing the time to reach a target weight 2.05 kg from 34 d to 27 d), body lipid content, carcass yield, mortality and the number of chicks produced by a breeder hen. Diet composition was adjusted in order to accommodate the future nutrient requirements of the birds following the genetic change. The results showed that predicted changes in biological performance due to selective breeding could lead to reduced environmental impacts of the broiler production chain, most notably in the Eutrophication Potential (by 12%), Acidification Potential (by 10%) and Abiotic Resource Use (by 9%) and Global Warming Potential (by 9%). These reductions were mainly caused by the reduced maintenance energy requirement and thus lower feed intake, resulting from the shorter production cycle, together with the increased carcass yield. However, some environmental benefits were limited by the required changes in feed composition (e.g., increased inclusion of soy meal and vegetable oil) as a result of the changes in bird nutrient requirements. This study is the first one aiming to link the mechanistic animal modeling approach to predicted genetic changes in order to produce quantitative estimates of the future environmental impacts of broiler production. Although a more detailed understanding on the mechanisms of the potential changes in bird performance and their consequences on feeding and husbandry would be still be needed, the modeling framework produced in this study provides a starting point for predictions of the effects of prospective genetic progress. PMID- 26628348 TI - Thoracic spinal primitive neuroectodermal tumor with dural tail mimicking meningioma: a missed diagnosis. PMID- 26628349 TI - A Computational and Experimental Study of Thieno[3,4-b]thiophene as a Proaromatic pi-Bridge in Dye-Sensitized Solar Cells. AB - Four D-pi-A dyes (D=donor, A=accpetor) based on a 3,4-thienothiophene pi-bridge were synthesized for use in dye-sensitized solar cells (DSCs). The proaromatic building block 3,4-thienothiophene is incorporated to stabilize dye excited-state oxidation potentials. This lowering of the excited-state energy levels allows for deeper absorption into the NIR region with relatively low molecular weight dyes. The influence of proaromatic functionality is probed through a computational analysis of optimized bond lengths and nucleus independent chemical shifts (NICS) for both the ground- and excited- states. To avoid a necessary lowering of the TiO2 semiconductor conduction band (CB) to promote efficient dye-TiO2 electron injection, strong donor functionalities based on triaryl- and diarylamines are employed in the dye designs to raise both the ground- and excited-state oxidation potentials of the dyes. Solubility, aggregation, and TiO2 surface protection are addressed by examining an ethylhexyl alkyl chain in comparison to a simple ethyl chain on the 3,4-thienothiophene bridge. Power conversion efficiencies of up to 7.8 % are observed. PMID- 26628351 TI - New contract negotiations must be meaningful to avoid future strikes, junior doctors say. PMID- 26628350 TI - Human embryonic stem cell-derived mesenchymal cells preserve kidney function and extend lifespan in NZB/W F1 mouse model of lupus nephritis. AB - Adult tissue-derived mesenchymal stromal cells (MSCs) are showing promise in clinical trials for systemic lupus erythematosus (SLE). However, the inability to manufacture large quantities of functional cells from a single donor as well as donor-dependent variability in quality limits their clinical utility. Human embryonic stem cell (hESC)-derived MSCs are an alternative to adult MSCs that can circumvent issues regarding scalability and consistent quality due to their derivation from a renewable starting material. Here, we show that hESC-MSCs prevent the progression of fatal lupus nephritis (LN) in NZB/W F1 (BWF1) mice. Treatment led to statistically significant reductions in proteinuria and serum creatinine and preserved renal architecture. Specifically, hESC-MSC treatment prevented disease-associated interstitial inflammation, protein cast deposition, and infiltration of CD3(+) lymphocytes in the kidneys. This therapy also led to significant reductions in serum levels of tumor necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6), two inflammatory cytokines associated with SLE. Mechanistically, in vitro data support these findings, as co-culture of hESC-MSCs with lipopolysaccharide (LPS)-stimulated BWF1 lymphocytes decreased lymphocyte secretion of TNFalpha and IL-6, and enhanced the percentage of putative regulatory T cells. This study represents an important step in the development of a commercially scalable and efficacious cell therapy for SLE/LN. PMID- 26628352 TI - Compassion for others, self-compassion, quality of life and mental well-being measures and their association with compassion fatigue and burnout in student midwives: A quantitative survey. AB - BACKGROUND: compassion fatigue and burnout can impact on the performance of midwives, with this quantitative paper exploring the relationship between self compassion, burnout, compassion fatigue, self-judgement, self-kindness, compassion for others, professional quality of life and well-being of student midwives. METHOD: a quantitative survey measured relationships using questionnaires: (1) Professional Quality of Life Scale; (2) Self-Compassion Scale; (3) Short Warwick and Edinburgh Mental Well-being Scale; (4) Compassion For Others Scale. PARTICIPANTS: a purposive and convenience sample of student midwives (n=103) studying at university participated in the study. RESULTS: just over half of the sample reported above average scores for burnout. The results indicate that student midwives who report higher scores on the self-judgement sub scale are less compassionate towards both themselves and others, have reduced well-being, and report greater burnout and compassion fatigue. Student midwives who report high on measures of self-compassion and well-being report less compassion fatigue and burnout. CONCLUSION: student midwives may find benefit from 'being kinder to self' in times of suffering, which could potentially help them to prepare for the emotional demands of practice and study. IMPLICATIONS: developing, creating and cultivating environments that foster compassionate care for self and others may play a significant role in helping midwives face the rigours of education and clinical practice during their degree programme. PMID- 26628353 TI - Birth preparedness and place of birth in rural Mysore, India: A prospective cohort study. AB - BACKGROUND: India accounts for almost a third of the global deaths among newborns on their first day of birth. In spite of making significant progress in increasing institutional births, large numbers of rural Indian women are still electing to give birth at home. The aim of this study was to identify factors associated with place of birth among women who had recently given birth in rural Mysore, India. METHODS: Between January 2009 and 2011, 1675 rural pregnant women enrolled in a prospective cohort study in Mysore District completed interviewer administered questionnaires on maternity care services. Ethical approval of the original study was obtained from the Institutional Review Boards of Vikram Hospital and Florida International University. Logistic regression analyses were conducted to identify factors associated with place of birth among the 1654 (99%) women that were successfully followed up after childbirth. FINDINGS: The median age of the women was 20 years; the majority were educated (87%), low-income (52%), and multiparous (56%). The prevalence of home births was low (4%). Half of the women giving birth at home did not adequately plan for transportation (55%), finances (48%), or birthing with a skilled provider (55%). Multiparous women had greater odds of giving birth at home compared to public (adjusted odds ratio [AOR]=7.83, p<0.001) and private institutions (AOR=7.05, p<0.001). Women attending >=4 antenatal consultations had greater odds of giving birth at public (AOR=2.53, p=0.036) and private institutions (AOR=3.58, p=0.010). Those with higher scores of birth preparedness also had greater odds of giving birth at public (AOR=2.53, p<0.001) and private institutions (AOR=3.00, p<0.001). CONCLUSIONS AND IMPLICATIONS: As a means to reduce newborn mortality, maternal health interventions in India and similar populations should focus on increasing birth preparedness and institutional births among rural women, particularly among those from lower socio-economic status. PMID- 26628354 TI - Reply: Intrapartum and neonatal mortality in primary midwife-led and secondary obstetrician-led care in the Amsterdam region of the Netherlands: a retrospective cohort study. PMID- 26628355 TI - Consumption of Chinese herbal medicines during pregnancy and postpartum: A prospective cohort study in China. AB - OBJECTIVE: to investigate usage patterns and factors associated with maternal consumption of Chinese herbal medicines in China. DESIGN: prospective cohort study. Information on the use of Chinese herbal medicines was collected from mothers by personal interview at hospital discharge and followed up by telephone at one, three and six months postpartum. SETTING: seven hospitals in Jiangyou, Sichuan Province of China. PARTICIPANTS: 695 mothers who gave birth to a singleton infant. MEASUREMENTS: prevalence, type, frequency and duration of herbal medicine usage. Logistic mixed regression analyses were performed to determine factors affecting the use. FINDINGS: a total of 43.5% and 45.0% of mothers consumed Chinese herbal medicines during pregnancy and postpartum, respectively. Angelica sinsensis was the most popular herbal medicine among the participants (pregnancy 28.8%, postpartum 26.8%). Although herbal medicines were taken more regularly by postpartum users, the median usage duration varied from two to three months during pregnancy but 1-1.6 months postpartum. The majority of users (pregnancy 42.9%, postpartum 55.1%) were advised by their mother or mother in-law to take Chinese herbal medicines. Antenatal alcohol drinking (adjusted odds ratio 2.75, 95% confidence interval 1.01-7.53) was associated with a marginally higher prevalence of herbal consumption during pregnancy, whereas mothers with a lower family income (adjusted odds ratio 1.52, 95% confidence interval 1.12-2.04) were more likely to consume Chinese herbal medicines in the postpartum period. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: consumption of Chinese herbal medicines appears to be prevalent among Chinese mothers, especially those drinking alcohol whilst pregnant and women from a lower income household. Maternity health professionals need to be aware of the lack of evidence to support the use of Chinese herbal medicines during pregnancy and postpartum, and to provide their clients with scientifically based advice regarding herbal medicine use. PMID- 26628356 TI - Durability of internally stented pericardial aortic valves: Prosthesis size matters. PMID- 26628357 TI - Endovascular rescue for complications during endovascular repair of type B dissection. PMID- 26628358 TI - Forewarned is forearmed: Benefits of remote ischemic preconditioning. PMID- 26628359 TI - Halophilic Protein Adaptation Results from Synergistic Residue-Ion Interactions in the Folded and Unfolded States. AB - Halophilic organisms thrive in environments with extreme salt concentrations and have adapted by allowing molar quantities of cosolutes, mainly KCl, to accumulate in their cytoplasm. To cope with this high intracellular salinity, halophilic organisms modified the chemical composition of their proteins to enrich their surface with acidic and short polar side chains, while lysines and bulky hydrophobic residues got depleted. We have emulated the evolutionary process of haloadaptation with natural and designed halophilic polypeptides and applied novel nuclear magnetic resonance (NMR) methodology to study the different mechanisms contributing to protein haloadaptation at a per residue level. Our analysis of an extensive set of NMR observables, determined over several proteins, allowed us to disentangle the synergistic contributions of protein haloadaptation: cation exclusion and electrostatic repulsion between negatively charged residues destabilize the denatured state ensemble while cumulative weak cation-protein interactions stabilize the folded conformations. PMID- 26628360 TI - Unsaturated Lipid Assimilation by Mycobacteria Requires Auxiliary cis-trans Enoyl CoA Isomerase. AB - Mycobacterium tuberculosis (Mtb) can survive in hypoxic necrotic tissue by assimilating energy from host-derived fatty acids. While the expanded repertoire of beta-oxidation auxiliary enzymes is considered crucial for Mtb adaptability, delineating their functional relevance has been challenging. Here, we show that the Mtb fatty acid degradation (FadAB) complex cannot selectively break down cis fatty acyl substrates. We demonstrate that the stereoselective binding of fatty acyl substrates in the Mtb FadB pocket is due to the steric hindrance from Phe287 residue. By developing a functional screen, we classify the family of Mtb Ech proteins as monofunctional or bifunctional enzymes, three of which complement the FadAB complex to degrade cis fatty acids. Crystal structure determination of two cis-trans enoyl coenzyme A (CoA) isomerases reveals distinct placement of active site residue in Ech enzymes. Our studies thus reveal versatility of Mtb lipid remodeling enzymes and identify an essential role of stand-alone cis-trans enoyl CoA isomerases in mycobacterial biology. PMID- 26628361 TI - Exogenous Expression of Human Protamine 1 (hPrm1) Remodels Fibroblast Nuclei into Spermatid-like Structures. AB - Protamines confer a compact structure to the genome of male gametes. Here, we find that somatic cells can be remodeled by transient expression of protamine 1 (Prm1). Ectopically expressed Prm1 forms scattered foci in the nuclei of fibroblasts, which coalescence into spermatid-like structures, concomitant with a loss of histones and a reprogramming barrier, H3 lysine 9 methylation. Protaminized nuclei injected into enucleated oocytes efficiently underwent protamine to maternal histone TH2B exchange and developed into normal blastocyst stage embryos in vitro. Altogether, our findings present a model to study male specific chromatin remodeling, which can be exploited for the improvement of somatic cell nuclear transfer. PMID- 26628362 TI - H4K44 Acetylation Facilitates Chromatin Accessibility during Meiosis. AB - Meiotic recombination hotspots are associated with histone post-translational modifications and open chromatin. However, it remains unclear how histone modifications and chromatin structure regulate meiotic recombination. Here, we identify acetylation of histone H4 at Lys44 (H4K44ac) occurring on the nucleosomal lateral surface. We show that H4K44 is acetylated at pre-meiosis and meiosis and displays genome-wide enrichment at recombination hotspots in meiosis. Acetylation at H4K44 is required for normal meiotic recombination, normal levels of double-strand breaks (DSBs) during meiosis, and optimal sporulation. Non modifiable H4K44R results in increased nucleosomal occupancy around DSB hotspots. Our results indicate that H4K44ac functions to facilitate chromatin accessibility favorable for normal DSB formation and meiotic recombination. PMID- 26628363 TI - The Binding Interface between Human APOBEC3F and HIV-1 Vif Elucidated by Genetic and Computational Approaches. AB - APOBEC3 family DNA cytosine deaminases provide overlapping defenses against pathogen infections. However, most viruses have elaborate evasion mechanisms such as the HIV-1 Vif protein, which subverts cellular CBF-beta and a polyubiquitin ligase complex to neutralize these enzymes. Despite advances in APOBEC3 and Vif biology, a full understanding of this direct host-pathogen conflict has been elusive. We combine virus adaptation and computational studies to interrogate the APOBEC3F-Vif interface and build a robust structural model. A recurring compensatory amino acid substitution from adaptation experiments provided an initial docking constraint, and microsecond molecular dynamic simulations optimized interface contacts. Virus infectivity experiments validated a long lasting electrostatic interaction between APOBEC3F E289 and HIV-1 Vif R15. Taken together with mutagenesis results, we propose a wobble model to explain how HIV-1 Vif has evolved to bind different APOBEC3 enzymes and, more generally, how pathogens may evolve to escape innate host defenses. PMID- 26628364 TI - Identification of the HIV-1 Vif and Human APOBEC3G Protein Interface. AB - Human cells express natural antiviral proteins, such as APOBEC3G (A3G), that potently restrict HIV replication. As a counter-defense, HIV encodes the accessory protein Vif, which binds A3G and mediates its proteasomal degradation. Our structural knowledge on how Vif and A3G interact is limited, because a co structure is not available. We identified specific points of contact between Vif and A3G by using functional assays with full-length A3G, patient-derived Vif variants, and HIV forced evolution. These anchor points were used to model and validate the Vif-A3G interface. The resultant co-structure model shows that the negatively charged beta4-alpha4 A3G loop, which contains primate-specific variation, is the core Vif binding site and forms extensive interactions with a positively charged pocket in HIV Vif. Our data present a functional map of this viral-host interface and open avenues for targeted approaches to block HIV replication by obstructing the Vif-A3G interaction. PMID- 26628366 TI - RNA-Seq and Mass-Spectrometry-Based Lipidomics Reveal Extensive Changes of Glycerolipid Pathways in Brown Adipose Tissue in Response to Cold. AB - Cold exposure greatly alters brown adipose tissue (BAT) gene expression and metabolism to increase thermogenic capacity. Here, we used RNA sequencing and mass-spectrometry-based lipidomics to provide a comprehensive resource describing the molecular signature of cold adaptation at the level of the transcriptome and lipidome. We show that short-term (3-day) cold exposure leads to a robust increase in expression of several brown adipocyte genes related to thermogenesis as well as the gene encoding the hormone irisin. However, pathway analysis shows that the most significantly induced genes are those involved in glycerophospholipid synthesis and fatty acid elongation. This is accompanied by significant changes in the acyl chain composition of triacylglycerols (TAGs) as well as subspecies-selective changes of acyl chains in glycerophospholipids. These results indicate that cold adaptation of BAT is associated with significant and highly species-selective remodeling of both TAGs and glycerophospholipids. PMID- 26628365 TI - Multinucleated Giant Cells Are Specialized for Complement-Mediated Phagocytosis and Large Target Destruction. AB - Multinucleated giant cells (MGCs) form by fusion of macrophages and are presumed to contribute to the removal of debris from tissues. In a systematic in vitro analysis, we show that IL-4-induced MGCs phagocytosed large and complement opsonized materials more effectively than their unfused M2 macrophage precursors. MGC expression of complement receptor 4 (CR4) was increased, but it functioned primarily as an adhesion integrin. In contrast, although expression of CR3 was not increased, it became functionally activated during fusion and was located on the extensive membrane ruffles created by excess plasma membrane arising from macrophage fusion. The combination of increased membrane area and activated CR3 specifically equips MGCs to engulf large complement-coated targets. Moreover, we demonstrate these features in vivo in the recently described complement-dependent therapeutic elimination of systemic amyloid deposits by MGCs. MGCs are evidently more than the sum of their macrophage parts. PMID- 26628367 TI - Human Telomerase RNA Processing and Quality Control. AB - The non-coding RNA subunit of telomerase provides the template for telomerase activity. In diverse fungi, 3' end processing of telomerase RNA involves a single cleavage by the spliceosome. Here, we examine how human telomerase RNA (hTR) primary transcripts are processed into the mature form of precisely 451 nt. We find that the splicing inhibitor isoginkgetin mimics the effects of RNA exosome inhibition and causes accumulation of long hTR transcripts. Depletion of exosome components and accessory factors reveals functions for the cap binding complex (CBC) and the nuclear exosome targeting (NEXT) complex in hTR turnover. Whereas longer transcripts are predominantly degraded, shorter precursor RNAs are oligo adenylated by TRF4-2 and either processed by poly(A)-specific ribonuclease (PARN) or degraded by the exosome. Our results reveal that hTR biogenesis involves a kinetic competition between RNA processing and degradation and suggest treatment options for telomerase insufficiency disorders. PMID- 26628368 TI - A Polyadenylation-Dependent 3' End Maturation Pathway Is Required for the Synthesis of the Human Telomerase RNA. AB - Telomere maintenance by the telomerase reverse transcriptase requires a noncoding RNA subunit that acts as a template for the synthesis of telomeric repeats. In humans, the telomerase RNA (hTR) is a non-polyadenylated transcript produced from an independent transcriptional unit. As yet, the mechanism and factors responsible for hTR 3' end processing have remained largely unknown. Here, we show that hTR is matured via a polyadenylation-dependent pathway that relies on the nuclear poly(A)-binding protein PABPN1 and the poly(A)-specific RNase PARN. Depletion of PABPN1 and PARN results in telomerase RNA deficiency and the accumulation of polyadenylated precursors. Accordingly, a deficiency in PABPN1 leads to impaired telomerase activity and telomere shortening. In contrast, we find that hTRAMP-dependent polyadenylation and exosome-mediated degradation function antagonistically to hTR maturation, thereby limiting telomerase RNA accumulation. Our findings unveil a critical requirement for RNA polyadenylation in telomerase RNA biogenesis, providing alternative approaches for telomerase inhibition in cancer. PMID- 26628369 TI - A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor Specific Hsp90 Species. AB - Acute myeloid leukemia (AML) is a heterogeneous and fatal disease with an urgent need for improved therapeutic regimens given that most patients die from relapsed disease. Irrespective of mutation status, the development of aggressive leukemias is enabled by increasing dependence on signaling networks. We demonstrate that a hyperactive signalosome drives addiction of AML cells to a tumor-specific Hsp90 species (teHsp90). Through genetic, environmental, and pharmacologic perturbations, we demonstrate a direct and quantitative link between hyperactivated signaling pathways and apoptotic sensitivity of AML to teHsp90 inhibition. Specifically, we find that hyperactive JAK-STAT and PI3K-AKT signaling networks are maintained by teHsp90 and, in fact, gradual activation of these networks drives tumors increasingly dependent on teHsp90. Thus, although clinically aggressive AML survives via signalosome activation, this addiction creates a vulnerability that can be exploited with Hsp90-directed therapy. PMID- 26628370 TI - ATM Localization and Heterochromatin Repair Depend on Direct Interaction of the 53BP1-BRCT2 Domain with gammaH2AX. AB - 53BP1 plays multiple roles in mammalian DNA damage repair, mediating pathway choice and facilitating DNA double-strand break repair in heterochromatin. Although it possesses a C-terminal BRCT2 domain, commonly involved in phospho peptide binding in other proteins, initial recruitment of 53BP1 to sites of DNA damage depends on interaction with histone post-translational modifications- H4K20me2 and H2AK13/K15ub--downstream of the early gammaH2AX phosphorylation mark of DNA damage. We now show that, contrary to current models, the 53BP1-BRCT2 domain binds gammaH2AX directly, providing a third post-translational mark regulating 53BP1 function. We find that the interaction of 53BP1 with gammaH2AX is required for sustaining the 53BP1-dependent focal concentration of activated ATM that facilitates repair of DNA double-strand breaks in heterochromatin in G1. PMID- 26628371 TI - Methylome-wide Sequencing Detects DNA Hypermethylation Distinguishing Indolent from Aggressive Prostate Cancer. AB - A critical need in understanding the biology of prostate cancer is characterizing the molecular differences between indolent and aggressive cases. Because DNA methylation can capture the regulatory state of tumors, we analyzed differential methylation patterns genome-wide among benign prostatic tissue and low-grade and high-grade prostate cancer and found extensive, focal hypermethylation regions unique to high-grade disease. These hypermethylation regions occurred not only in the promoters of genes but also in gene bodies and at intergenic regions that are enriched for DNA-protein binding sites. Integration with existing RNA-sequencing (RNA-seq) and survival data revealed regions where DNA methylation correlates with reduced gene expression associated with poor outcome. Regions specific to aggressive disease are proximal to genes with distinct functions from regions shared by indolent and aggressive disease. Our compendium of methylation changes reveals crucial molecular distinctions between indolent and aggressive prostate cancer. PMID- 26628372 TI - Asymmetric PI3K Signaling Driving Developmental and Regenerative Cell Fate Bifurcation. AB - Metazoan sibling cells often diverge in activity and identity, suggesting links between growth signals and cell fate. We show that unequal transduction of nutrient-sensitive PI3K/AKT/mTOR signaling during cell division bifurcates transcriptional networks and fates of kindred cells. A sibling B lymphocyte with stronger signaling, indexed by FoxO1 inactivation and IRF4 induction, undergoes PI3K-driven Pax5 repression and plasma cell determination, while its sibling with weaker PI3K activity renews a memory or germinal center B cell fate. PI3K-driven effector T cell determination silences TCF1 in one sibling cell, while its PI3K attenuated sibling self-renews in tandem. Prior to bifurcations achieving irreversible plasma or effector cell fate determination, asymmetric signaling during initial divisions specifies a more proliferative, differentiation-prone lymphocyte in tandem with a more quiescent memory cell sibling. By triggering cell division but transmitting unequal intensity between sibling cells, nutrient sensitive signaling may be a frequent arbiter of cell fate bifurcations during development and repair. PMID- 26628373 TI - Extracellular Mipp1 Activity Confers Migratory Advantage to Epithelial Cells during Collective Migration. AB - Multiple inositol polyphosphate phosphatase (Mipp), a highly conserved but poorly understood histidine phosphatase, dephosphorylates higher-order IPs (IP4-IP6) to IP3. To gain insight into the biological roles of these enzymes, we have characterized Drosophila mipp1. mipp1 is dynamically expressed in the embryonic trachea, specifically in the leading cells of migrating branches at late stages, where Mipp1 localizes to the plasma membrane and filopodia. FGF signaling activates mipp1 expression in these cells, where extensive filopodia form to drive migration and elongation by cell intercalation. We show that Mipp1 facilitates formation and/or stabilization of filopodia in leading cells through its extracellular activity. mipp1 loss decreases filopodia number, whereas mipp1 overexpression increases filopodia number in a phosphatase-activity-dependent manner. Importantly, expression of Mipp1 gives cells a migratory advantage for the lead position in elongating tracheal branches. Altogether, these findings suggest that extracellular pools of inositol polyphosphates affect cell behavior during development. PMID- 26628374 TI - Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1alpha upon LPS Activation in the Presence of Ample Oxygen. AB - Both hypoxic and inflammatory conditions activate transcription factors such as hypoxia-inducible factor (HIF)-1alpha and nuclear factor (NF)-kappaB, which play a crucial role in adaptive responses to these challenges. In dendritic cells (DC), lipopolysaccharide (LPS)-induced HIF1alpha accumulation requires NF-kappaB signaling and promotes inflammatory DC function. The mechanisms that drive LPS induced HIF1alpha accumulation under normoxia are unclear. Here, we demonstrate that LPS inhibits prolyl hydroxylase domain enzyme (PHD) activity and thereby blocks HIF1alpha degradation. Of note, LPS-induced PHD inhibition was neither due to cosubstrate depletion (oxygen or alpha-ketoglutarate) nor due to increased levels of reactive oxygen species, fumarate, and succinate. Instead, LPS inhibited PHD activity through NF-kappaB-mediated induction of the iron storage protein ferritin and subsequent decrease of intracellular available iron, a critical cofactor of PHD. Thus, hypoxia and LPS both induce HIF1alpha accumulation via PHD inhibition but deploy distinct molecular mechanisms (lack of cosubstrate oxygen versus deprivation of co-factor iron). PMID- 26628375 TI - GRP94 Regulates Circulating Cholesterol Levels through Blockade of PCSK9-Induced LDLR Degradation. AB - Clearance of circulating low-density lipoprotein cholesterol (LDLc) by hepatic LDL receptors (LDLR) is central for vascular health. Secreted by hepatocytes, PCSK9 induces the degradation of LDLR, resulting in higher plasma LDLc levels. Still, it remains unknown why LDLR and PCSK9 co-exist within the secretory pathway of hepatocytes without leading to complete degradation of LDLR. Herein, we identified the ER-resident GRP94, and more precisely its client-binding C terminal domain, as a PCSK9-LDLR inhibitory binding protein. Depletion of GRP94 did not affect calcium homeostasis, induce ER stress, nor did it alter PCSK9 processing or its secretion but greatly increased its capacity to induce LDLR degradation. Accordingly, we found that hepatocyte-specific Grp94-deficient mice have higher plasma LDLc levels correlated with ~ 80% reduction in hepatic LDLR protein levels. Thus, we provide evidence that, in physiological conditions, binding of PCSK9 to GRP94 protects LDLR from degradation likely by preventing early binding of PCSK9 to LDLR within the ER. PMID- 26628376 TI - Brown Adipose Tissue Thermogenic Capacity Is Regulated by Elovl6. AB - Although many transcriptional pathways regulating BAT have been identified, the role of lipid biosynthetic enzymes in thermogenesis has been less investigated. Whereas cold exposure causes changes in the fatty acid composition of BAT, the functional consequences of this remains relatively unexplored. In this study, we demonstrate that the enzyme Elongation of Very Long Chain fatty acids 6 (Elovl6) is necessary for the thermogenic action of BAT. Elovl6 is responsible for converting C16 non-essential fatty acids into C18 species. Loss of Elovl6 does not modulate traditional BAT markers; instead, it causes reduced expression of mitochondrial electron transport chain components and lower BAT thermogenic capacity. The reduction in BAT activity appears to be counteracted by increased beiging of scWAT. When beige fat is disabled by thermoneutrality or aging, Elovl6 KO mice gain weight and have increased scWAT mass and impaired carbohydrate metabolism. Overall, our study suggests fatty acid chain length is important for BAT function. PMID- 26628377 TI - Identification of Different Classes of Luminal Progenitor Cells within Prostate Tumors. AB - Primary prostate cancer almost always has a luminal phenotype. However, little is known about the stem/progenitor properties of transformed cells within tumors. Using the aggressive Pten/Tp53-null mouse model of prostate cancer, we show that two classes of luminal progenitors exist within a tumor. Not only did tumors contain previously described multipotent progenitors, but also a major population of committed luminal progenitors. Luminal cells, sorted directly from tumors or grown as organoids, initiated tumors of adenocarcinoma or multilineage histological phenotypes, which is consistent with luminal and multipotent differentiation potentials, respectively. Moreover, using organoids we show that the ability of luminal-committed progenitors to self-renew is a tumor-specific property, absent in benign luminal cells. Finally, a significant fraction of luminal progenitors survived in vivo castration. In all, these data reveal two luminal tumor populations with different stem/progenitor cell capacities, providing insight into prostate cancer cells that initiate tumors and can influence treatment response. PMID- 26628378 TI - Intravacuolar Membranes Regulate CD8 T Cell Recognition of Membrane-Bound Toxoplasma gondii Protective Antigen. AB - Apicomplexa parasites such as Toxoplasma gondii target effectors to and across the boundary of their parasitophorous vacuole (PV), resulting in host cell subversion and potential presentation by MHC class I molecules for CD8 T cell recognition. The host-parasite interface comprises the PV limiting membrane and a highly curved, membranous intravacuolar network (IVN) of uncertain function. Here, using a cell-free minimal system, we dissect how membrane tubules are shaped by the parasite effectors GRA2 and GRA6. We show that membrane association regulates access of the GRA6 protective antigen to the MHC I pathway in infected cells. Although insertion of GRA6 in the PV membrane is key for immunogenicity, association of GRA6 with the IVN limits presentation and curtails GRA6-specific CD8 responses in mice. Thus, membrane deformations of the PV regulate access of antigens to the MHC class I pathway, and the IVN may play a role in immune modulation. PMID- 26628379 TI - Ventral Subiculum Stimulation Promotes Persistent Hyperactivity of Dopamine Neurons and Facilitates Behavioral Effects of Cocaine. AB - The ventral subiculum (vSUB) plays a key role in addiction, and identifying the neuronal circuits and synaptic mechanisms by which vSUB alters the excitability of dopamine neurons is a necessary step to understand the motor changes induced by cocaine. Here, we report that high-frequency stimulation of the vSUB (HFSvSUB) over-activates ventral tegmental area (VTA) dopamine neurons in vivo and triggers long-lasting modifications of synaptic transmission measured ex vivo. This potentiation is caused by NMDA-dependent plastic changes occurring in the bed nucleus of the stria terminalis (BNST). Finally, we report that the modification of the BNST-VTA neural circuits induced by HFSvSUB potentiates locomotor activity induced by a sub-threshold dose of cocaine. Our findings unravel a neuronal circuit encoding behavioral effects of cocaine in rats and highlight the importance of adaptive modifications in the BNST, a structure that influences motivated behavior as well as maladaptive behaviors associated with addiction. PMID- 26628380 TI - Endothelin-B Receptor Activation in Astrocytes Regulates the Rate of Oligodendrocyte Regeneration during Remyelination. AB - Reactive astrogliosis is an essential and ubiquitous response to CNS injury, but in some cases, aberrant activation of astrocytes and their release of inhibitory signaling molecules can impair endogenous neural repair processes. Our lab previously identified a secreted intercellular signaling molecule, called endothelin-1 (ET-1), which is expressed at high levels by reactive astrocytes in multiple sclerosis (MS) lesions and limits repair by delaying oligodendrocyte progenitor cell (OPC) maturation. However, as ET receptors are widely expressed on neural cells, the cell- and receptor-specific mechanisms of OPC inhibition by ET-1 action remain undefined. Using pharmacological approaches and cell-specific endothelin receptor (EDNR) ablation, we show that ET-1 acts selectively through EDNRB on astrocytes--and not OPCs--to indirectly inhibit remyelination. These results demonstrate that targeting specific pathways in reactive astrocytes represents a promising therapeutic target in diseases with extensive reactive astrogliosis, including MS. PMID- 26628381 TI - CXCL12 regulates platelet activation via the regulator of G-protein signaling 16. AB - The regulators of G protein signaling (RGS) protein superfamily negatively controls G protein-coupled receptor signal transduction pathways. One of the members of this family, RGS16, is highly expressed in megakaryocytes and platelets. Studies of its function in platelet and megakaryocyte biology have been limited, in part, due to lack of pharmacological inhibitors. For example, RGS16 overexpression inhibited CXC chemokine receptor 4 (CXCR4)-mediated megakaryocyte migration. More recent studies showed that the chemokine stromal cell-derived factor (SDF1alpha or CXCL12) regulates platelet function via CXCR4. Based on these considerations, the present study investigated the capacity of RGS16 to regulate CXCL12-dependent platelet function, using the RGS16 knockout mouse model (Rgs16(-/-)). RGS16-deficient platelets had increased protease activated receptor 4 and collagen-induced aggregation, as well as increased CXCL12-dependent agonist-induced aggregation, dense and alpha granule secretion, integrin alphaIIbbeta3 activation and phosphatidylserine exposure compared to those from WT littermates. CXCL12 alone did not stimulate aggregation or secretion in either RGS16-deficient or WT platelets. Furthermore, platelets from Rgs16(-/-) mice displayed enhanced phosphorylation of ERK and Akt following CXCL12 stimulation relative to controls. Finally, we also found that PKCdelta is involved in regulating CXCL12-dependent activation of ERK and Akt, in the Rgs16 deficient platelets. Collectively, our findings provide the first evidence that RGS16 plays an important role in platelet function by modulating CXCL12-dependent platelet activation. PMID- 26628382 TI - Promoting respect and preventing mistreatment during childbirth. PMID- 26628383 TI - Body Mass Index and Adverse Outcomes in Elderly Patients With Atrial Fibrillation: The AMADEUS Trial. AB - BACKGROUND AND PURPOSE: Obesity has been associated with increased cardiovascular risk in atrial fibrillation, but little is known in elderly patients with atrial fibrillation. METHODS: Post hoc analysis of data from the AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) trial. RESULTS: We studied 1588 elderly patients, who were categorized as normal body mass index (BMI, 18.5-25 kg/m(2); n=515 [32.4%]), overweight (BMI, 25-30 kg/m(2); n=711 [44.8%]), and obese (BMI>=30 kg/m(2); n=362 [22.8%]). There was a significant reduction in the composite outcome of cardiovascular death and stroke/systemic embolism with increasing BMI category, being 5.0%, 3.2%, and 1.5% per 100 patient-years, respectively (P for trend=0.01). Cox proportional hazards analysis found obesity to be associated with a lower risk of the primary composite outcome (hazard ratio, 0.29; 95% confidence interval, 0.11-0.77; P=0.01). In the warfarin arm (n=814), multivariate logistic regression analysis demonstrated that obesity was independently related to higher odds of time in therapeutic range >=60% (odds ratio, 1.84; 95% confidence interval, 1.21-2.80; P=0.004). CONCLUSION: Obesity was associated with a lower stroke and mortality rate in elderly anticoagulated atrial fibrillation patients. Obesity was related to good quality anticoagulation control. PMID- 26628385 TI - Peroxisome Proliferator-Activated Receptor beta/delta Alleviates Early Brain Injury After Subarachnoid Hemorrhage in Rats. AB - BACKGROUND AND PURPOSE: Early brain injury is proposed to be the primary cause of the poor outcome after subarachnoid hemorrhage (SAH), which is closely related to the neural apoptosis. To date, the relationship between peroxisome proliferator activated receptor beta/delta (PPARbeta/delta) and nuclear factor-kappaB/matrix metalloproteinase-9 (NF-kappaB/MMP-9) pathway, both of which are closely related to apoptotic effects, has been poorly studied in SAH. The present study was undertaken to evaluate the effects of PPARbeta/delta on early brain injury and NF kappaB/MMP-9 pathway after SAH in rats. METHODS: SAH model was established by injecting nonheparinized autologous arterial blood into the prechiasmatic cistern in male Sprague-Dawley rats. Adenoviruses or small interfering RNAs were injected into the right lateral cerebral ventricle to, respectively, up- or downregulate PPARbeta/delta expression before SAH. All animals were assessed with a neurological score and then killed at 24 hours after SAH surgery. The indexes of brain water content, blood-brain barrier permeability, and apoptosis were used to detect brain injury. The expression of PPARbeta/delta, NF-kappaB, and MMP-9 were measured by immunohistochemistry, gelatin zymography, and Western Blot methods, respectively. In addition, GW0742, a specific agonist of PPARbeta/delta, was used to treat SAH in rats, the effects of which were evaluated by neurological scoring and Evans blue extravasation. RESULTS: Overexpression of PPARbeta/delta by adenoviruses treatment significantly ameliorated brain injury with improvement in neurological deficits, brain edema, blood-brain barrier impairment, and neural cell apoptosis at 24 hours after SAH in rats, whereas downregulation of PPARbeta/delta by small interfering RNAs administration resulted in the reverse effects of the above. The expression levels of NF-kappaB and MMP-9 were markedly downregulated when PPARbeta/delta increased after PPARbeta/delta adenovirus transfection and upregulated when PPARbeta/delta decreased by PPARbeta/delta small interfering RNAs treatment. Moreover, GW0742 improved neurological deficits and reduced Evans blue extravasation at 24 hours after SAH. CONCLUSIONS: PPARbeta/delta's overexpression may attenuate early brain injury after rats' SAH administration, which reduces neural apoptosis possibly through blocking NF kappaB/MMP-9 pathway. PMID- 26628384 TI - Prevalence of Depression Among Stroke Survivors: Racial-Ethnic Differences. AB - BACKGROUND AND PURPOSE: Although poststroke depression is common, racial-ethnic disparities in depression among stroke survivors remain underexplored. Thus, we investigated the relationship between race/ethnicity and depression in a multiracial-ethnic stroke cohort. METHODS: Baseline survey data of validated scales of depression and functional status, demographics, comorbidities, and socioeconomic status were used from a recurrent stroke prevention study among community-dwelling urban stroke/transient ischemic attack survivors. RESULTS: The cohort included 556 participants with a mean age of 64 years. The majorities were black (44%) or latino (42%) and female (60%), had their last stroke/transient ischemic attack nearly 2 years before study enrollment, and lived below the poverty level (58%). Nearly 1 in 2 latinos, 1 in 4 blacks, and 1 in 8 whites were depressed. Multivariate logistic regression showed that survivors who were younger, were female, had >=3 comorbid conditions, were functionally disabled from stroke, lacked emotional-social support, and who took antidepressants before study entry had higher risk of depression. Time since last stroke/transient ischemic attack did not affect the chance of depression. After adjusting for all above risk factors, latinos had 3* the odds of depression (95% confidence interval: 1.18-6.35) than whites; blacks and whites had similar odds of depression. CONCLUSIONS: This study reveals that latino stroke survivors have a significantly higher prevalence of depression compared with their non-latino counterparts. PMID- 26628387 TI - In Vitro Assessment of Histology Verified Intracranial Atherosclerotic Disease by 1.5T Magnetic Resonance Imaging: Concentric or Eccentric? AB - BACKGROUND AND PURPOSE: Clinical trial studies show that plaque eccentricity (symmetry) is among the plaque features that have been associated with more frequent cerebrovascular events. Plaque eccentricity of intracranial atherosclerotic disease is unclear because of lacking of cerebral artery specimens. METHODS: 1.5T magnetic resonance imaging was performed in the postmortem brains to scan the cross sections of middle cerebral artery. Plaque eccentricity of histology-verified middle cerebral artery atherosclerosis was calculated on T1-weighted fat-suppressed sequence. RESULTS: Validated by histology, concentric atherosclerotic plaques were identified in 46 middle cerebral arteries (63.9%) on magnetic resonance imaging and eccentric plaques in 26 arteries (26.1%). Eccentric plaques showed higher maximum wall thickness and lower minimum wall thickness than concentric plaques (both P<0.001). Plaque burden and brain infarctions were similar between concentric and eccentric plaques. CONCLUSIONS: Intracranial atherosclerosis presents as eccentric or concentric in geometry, which may be not linked to intracranial plaque risk. Further in vivo imaging studies are needed to identify morphological features of intracranial plaques and to verify its association with brain infarctions. PMID- 26628386 TI - Comparison Between the Original and Shortened Versions of the National Institutes of Health Stroke Scale in Ischemic Stroke Patients of Intermediate Severity. AB - BACKGROUND AND PURPOSE: The 15-item National Institutes of Health Stroke Scale (NIHSS) has been critiqued for its complexity and variability, and shortened versions have been proposed. This study aimed to compare the measurement properties of the original version with 3 shortened versions with 11, 8, and 5 items, respectively. METHODS: Analyses were performed using data from an international, double-blind randomized controlled trial investigating the efficacy of MLC601 on stroke recovery in patients with ischemic stroke of intermediate severity (Chinese Medicine Neuroaid Efficacy on Stroke recovery [CHIMES]). To compare discriminative ability and responsiveness to change, the effect sizes of the NIHSS scores in relation to modified Rankin Scale, mini mental status examination, and Barthel index were estimated using regression analysis. RESULTS: For both discriminative ability and responsiveness to change, the original version exhibited a larger effect size (0.55 and 0.84) in relation to modified Rankin Scale than the other 3 shortened versions (0.35-0.46 and 0.74 0.78). CONCLUSIONS: The original 15-item NIHSS retained information that made it more discriminative and responsive to change than the shortened versions. We recommend future clinical researchers to use the full version NIHSS to evaluate patients' stroke severity. CLINICAL TRIAL REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00554723. PMID- 26628388 TI - Seladin-1/DHCR24 Is Neuroprotective by Associating EAAT2 Glutamate Transporter to Lipid Rafts in Experimental Stroke. AB - BACKGROUND AND PURPOSE: 3beta-Hydroxysteroid-Delta24 reductase (DHCR24) or selective alzheimer disease indicator 1 (seladin-1), an enzyme of cholesterol biosynthetic pathway, has been implicated in neuroprotection, oxidative stress, and inflammation. However, its role in ischemic stroke remains unexplored. The aim of this study was to characterize the effect of seladin-1/DHCR24 using an experimental stroke model in mice. METHODS: Dhcr24(+/-) and wild-type (WT) mice were subjected to permanent middle cerebral artery occlusion. In another set of experiments, WT mice were treated intraperitoneally either with vehicle or U18666A (seladin-1/DHCR24 inhibitor, 10 mg/kg) 30 minutes after middle cerebral artery occlusion. Brains were removed 48 h after middle cerebral artery occlusion for infarct volume determination. For protein expression determination, peri infarct region was obtained 24 h after ischemia, and Western blot or cytometric bead array was performed. RESULTS: Dhcr24(+/-) mice displayed larger infarct volumes after middle cerebral artery occlusion than their WT littermates. Treatment of WT mice with the seladin-1/DHCR24 inhibitor U18666A also increased ischemic lesion. Inflammation-related mediators were increased after ischemia in Dhcr24(+/-) mice compared with WT counterparts. Consistent with a role of cholesterol in proper function of glutamate transporter EAAT2 in membrane lipid rafts, we found a decreased association of EAAT2 with lipid rafts after ischemia when DHCR24 is genetically deleted or pharmacologically inhibited. Accordingly, treatment with U18666A decreases [(3)H]-glutamate uptake in cultured astrocytes. CONCLUSIONS: These results support the idea that lipid raft integrity, ensured by seladin-1/DHCR24, plays a crucial protective role in the ischemic brain by guaranteeing EAAT2-mediated uptake of glutamate excess. PMID- 26628389 TI - Posterior Reversible Encephalopathy Syndrome as an Overlooked Complication of Induced Hypertension for Cerebral Vasospasm: Systematic Review and Illustrative Case. AB - BACKGROUND AND PURPOSE: Delayed cerebral ischemia associated with cerebral vasospasm is a common cause of secondary neurological decline after aneurysmal subarachnoid hemorrhage (SAH). Triple-H therapy, induced hypertension, hypervolemia, and hemodilution, is often used to treat cerebral vasospasm. However, hypertensive treatment may carry significant medical morbidity, including cardiopulmonary, renal, and intracranial complications. Posterior reversible encephalopathy syndrome (PRES) is a reversible intracranial complication that has rarely been reported in the setting of induced hypertension. METHODS: We present an illustrative case of PRES in a patient with induced hypertension for SAH-related cerebral vasospasm and performed a systematic review. Furthermore, the electronic database MEDLINE was searched for additional data in published studies of PRES after induced hypertension. RESULTS: Overall, 7 case reports presenting 10 patients who developed PRES secondary to induced hypertension were found. Eighty-two percent of the patients were women. In all cases, the clinical symptoms were attributed to cerebral vasospasm before the diagnosis of PRES. The time from onset of induced hypertension to the development of PRES was 7.8+/-3.8 days. After the diagnosis of PRES and careful taper down of the blood pressure, the neurological symptoms resolved almost completely within a few days in all patients. CONCLUSIONS: PRES in the setting of SAH is an overlooked complication of hypertensive therapy for the treatment of vasospasm. However, the diagnosis of this phenomenon is crucial given the necessity to reverse hypertensive therapy, which is contrary to the usual management of patients with vasospasm. PMID- 26628390 TI - Ultrafast direct fabrication of flexible substrate-supported designer plasmonic nanoarrays. AB - Fabrication of plasmonic nanostructures has been an important topic for their potential applications in photonic and optoelectronic devices. Among plasmonic materials, gold is one of the most promising materials due to its low ohmic loss at optical frequencies and high oxidation resistance. However, there are two major bottlenecks for its industrial applications: (1) the need for large-scale fabrication technology for high-precision plasmonic nanostructures; and (2) the need to integrate the plasmonic nanostructures on various substrates. While conventional top-down approaches involve high cost and give low throughput, bottom-up approaches suffer from irreproducibility and low precision. Herein, we report laser shock induced direct imprinting of large-area plasmonic nanostructures from physical vapor deposited (PVD) gold thin film on a flexible commercial free-standing aluminum foil. Among the important characteristics of the laser-shock direct imprinting is their unique capabilities to reproducibly deliver designer plasmonic nanostructures with extreme precision and in an ultrafast manner. Excellent size tunability (from several MUm down to 15 nm) has been achieved by varying mold dimensions and laser parameters. The physical mechanism of the hybrid film imprinting is elaborated by finite element modeling. A mechanical robustness test of the hybrid film validates a significantly improved interfacial contact between gold arrays and the underlying substrate. The strong optical field enhancement was realized in the large-area fabricated engineered gold nanostructures. Low concentration molecular sensing was investigated employing the fabricated structures as surface-enhanced Raman scattering (SERS) substrates. The ability to ultrafast direct imprint plasmonic nanoarrays on a flexible substrate at multiscale is a critical step towards roll to-roll manufacturing of multi-functional devices which is poised to inspire several emerging applications. PMID- 26628391 TI - Target Selection during Protein Quality Control. AB - Protein quality control (QC) pathways survey the cellular proteome to selectively recognize and degrade faulty proteins whose accumulation can lead to various diseases. Recognition of the occasional aberrant protein among an abundant sea of similar normal counterparts poses a considerable challenge to the cell. Solving this problem requires protein QC machinery to assay multiple molecular criteria within a spatial and temporal context. Although each QC pathway has unique criteria and mechanisms for distinguishing right from wrong, they appear to share several general concepts. We discuss principles of high-fidelity target recognition, the decisive event of all protein QC pathways, to guide future work in this area. PMID- 26628392 TI - On the relevance of technical variation due to building pools in microarray experiments. AB - BACKGROUND: Pooled samples are frequently used in experiments measuring gene expression. In this method, RNA from different individuals sharing the same experimental conditions and explanatory variables is blended and their concentrations are jointly measured. As a matter of principle, individuals are represented in equal shares in each pool. However, some degree of disproportionality may arise from the limits of technical precision. As a consequence a special kind of technical error occurs, which can be modelled by a respective variance component. Previously published theory - allowing for variable pool sizes - has been applied to four microarray gene expression data sets from different species in order to assess the practical relevance of this type of technical error in terms of significance and size of this variance component. RESULTS: The number of transcripts with a significant variance component due to imperfect blending was found to be 4329 (23 %) in mouse data and 7093 (49 %) in honey bees, but only 6 in rats and none whatsoever in human data. These results correspond to a false discovery rate of 5 % in each data set. The number of transcripts found to be differentially expressed between treatments was always higher when the blending error variance was neglected. Simulations clearly indicated overly-optimistic (anti-conservative) test results in terms of false discovery rates whenever this source of variability was not represented in the model. CONCLUSIONS: Imperfect equality of shares when blending RNA from different individuals into joint pools of variable size is a source of technical variation with relevance for experimental design, practice at the laboratory bench and data analysis. Its potentially adverse effects, incorrect identification of differentially expressed transcripts and overly-optimistic significance tests, can be fully avoided, however, by the sound application of recently established theory and models for data analysis. PMID- 26628393 TI - Assessment of the diagnostic value of diffusion tensor imaging in patients with spinal cord compression: a meta-analysis. AB - We investigated the diagnostic value of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) of magnetic resonance diffusion tensor imaging (DTI) in patients with spinal cord compression (SCC) using a meta-analysis framework. Multiple scientific literature databases were exhaustively searched to identify articles relevant to this study. Mean values and standardized mean differences (SMDs) were calculated for the ADC and FA in normal and diseased tissues. The STATA version 12.0 software was used for statistical analysis. Of the 41 articles initially retrieved through database searches, 11 case-control studies were eligible for the meta-analysis and contained a combined total of 645 human subjects (394 patients with SCC and 251 healthy controls). All 11 studies reported data on FA, and 9 contained data related to the ADC. The combined SMDs of the ADC and FA showed that the ADC was significantly higher and the FA was lower in patients with SCC than in healthy controls. Subgroup analysis based on the b value showed higher ADCs in patients with SCC than in healthy controls at b values of both <=500 and >500 s/mm2. In summary, the main findings of this meta analysis revealed an increased ADC and decreased FA in patients with SCC, indicating that DTI is an important diagnostic imaging tool to assess patients suspected to have SCC. PMID- 26628394 TI - Prognostic effect of high-flux hemodialysis in patients with chronic kidney disease. AB - We investigated the prognostic effects of high-flux hemodialysis (HFHD) and low flux hemodialysis (LFHD) in patients with chronic kidney disease (CKD). Both an electronic and a manual search were performed based on our rigorous inclusion and exclusion criteria to retrieve high-quality, relevant clinical studies from various scientific literature databases. Comprehensive meta-analysis 2.0 (CMA 2.0) was used for the quantitative analysis. We initially retrieved 227 studies from the database search. Following a multi-step screening process, eight high quality studies were selected for our meta-analysis. These eight studies included 4967 patients with CKD (2416 patients in the HFHD group, 2551 patients in the LFHD group). The results of our meta-analysis showed that the all-cause death rate in the HFHD group was significantly lower than that in the LFHD group (OR=0.704, 95%CI=0.533-0.929, P=0.013). Additionally, the cardiovascular death rate in the HFHD group was significantly lower than that in the LFHD group (OR=0.731, 95%CI=0.616-0.866, P<0.001). The results of this meta-analysis clearly showed that HFHD decreases all-cause death and cardiovascular death rates in patients with CKD and that HFHD can therefore be implemented as one of the first therapy choices for CKD. PMID- 26628395 TI - Overexpression of myeloid differentiation protein 88 in mice induces mild cardiac dysfunction, but no deficit in heart morphology. AB - Cardiac remodeling involves changes in heart shape, size, structure, and function after injury to the myocardium. The proinflammatory adaptor protein myeloid differentiation protein 88 (MyD88) contributes to cardiac remodeling. To investigate whether excessive MyD88 levels initiate spontaneous cardiac remodeling at the whole-organism level, we generated a transgenic MyD88 mouse model with a cardiac-specific promoter. MyD88 mice (male, 20-30 g, n=~80) were born at the expected Mendelian ratio and demonstrated similar morphology of the heart and cardiomyocytes with that of wild-type controls. Although heart weight was unaffected, cardiac contractility of MyD88 hearts was mildly reduced, as shown by echocardiographic examination, compared with wild-type controls. Moreover, the cardiac dysfunction phenotype was associated with elevation of ANF and BNP expression. Collectively, our data provide novel evidence of the critical role of balanced MyD88 signaling in maintaining physiological function in the adult heart. PMID- 26628396 TI - Effect of (+)-dehydrofukinone on GABAA receptors and stress response in fish model. AB - (+)-Dehydrofukinone (DHF) is a major component of the essential oil of Nectandra grandiflora (Lauraceae), and exerts a depressant effect on the central nervous system of fish. However, the neuronal mechanism underlying DHF action remains unknown. This study aimed to investigate the action of DHF on GABAA receptors using a silver catfish (Rhamdia quelen) model. Additionally, we investigated the effect of DHF exposure on stress-induced cortisol modulation. Chemical identification was performed using gas chromatography-mass spectrometry and purity was evaluated using gas chromatography with a flame ionization detector. To an aquarium, we applied between 2.5 and 50 mg/L DHF diluted in ethanol, in combination with 42.7 mg/L diazepam. DHF within the range of 10-20 mg/L acted collaboratively in combination with diazepam, but the sedative action of DHF was reversed by 3 mg/L flumazenil. Additionally, fish exposed for 24 h to 2.5-20 mg/L DHF showed no side effects and there was sustained sedation during the first 12 h of drug exposure with 10-20 mg/L DHF. DHF pretreatment did not increase plasma cortisol levels in fish subjected to a stress protocol. Moreover, the stress induced cortisol peak was absent following pretreatment with 20 mg/L DHF. DHF proved to be a relatively safe sedative or anesthetic, which interacts with GABAergic and cortisol pathways in fish. PMID- 26628397 TI - Diabetes mellitus affects the biomechanical function of the callus and the expression of TGF-beta1 and BMP2 in an early stage of fracture healing. AB - Transforming growth factor beta 1 (TGF-beta1) and bone morphogenetic protein-2 (BMP-2) are important regulators of bone repair and regeneration. In this study, we examined whether TGF-beta1 and BMP-2 expressions were delayed during bone healing in type 1 diabetes mellitus. Tibial fractures were created in 95 diabetic and 95 control adult male Wistar rats of 10 weeks of age. At 1, 2, 3, 4, and 5 weeks after fracture induction, five rats were sacrificed from each group. The expressions of TGF-beta1 and BMP2 in the fractured tibias were measured by immunohistochemistry and quantitative reverse-transcription polymerase chain reaction, weekly for the first 5 weeks post-fracture. Mechanical parameters (bending rigidity, torsional rigidity, destruction torque) of the healing bones were also assessed at 3, 4, and 5 weeks post-fracture, after the rats were sacrificed. The bending rigidity, torsional rigidity and destruction torque of the two groups increased continuously during the healing process. The diabetes group had lower mean values for bending rigidity, torsional rigidity and destruction torque compared with the control group (P<0.05). TGF-beta1 and BMP-2 expression were significantly lower (P<0.05) in the control group than in the diabetes group at postoperative weeks 1, 2, and 3. Peak levels of TGF-beta1 and BMP-2 expression were delayed by 1 week in the diabetes group compared with the control group. Our results demonstrate that there was a delayed recovery in the biomechanical function of the fractured bones in diabetic rats. This delay may be associated with a delayed expression of the growth factors TGF-beta1 and BMP-2. PMID- 26628398 TI - Concomitant stress potentiates the preference for, and consumption of, ethanol induced by chronic pre-exposure to ethanol. AB - Ethanol abuse is linked to several acute and chronic injuries that can lead to health problems. Ethanol addiction is one of the most severe diseases linked to the abuse of this drug. Symptoms of ethanol addiction include compulsive substance intake and withdrawal syndrome. Stress exposure has an important role in addictive behavior for many drugs of abuse (including ethanol), but the consequences of stress and ethanol in the organism when these factors are concomitant results in a complex interaction. We investigated the effects of concomitant, chronic administration of ethanol and stress exposure on the withdrawal and consumption of, as well as the preference for, ethanol in mice. Male Swiss mice (30-35 g, 8-10 per group) were exposed to an ethanol liquid diet as the only source of food for 15 days. In the final 5 days, they were exposed to forced swimming stress. Twelve hours after removal of the ethanol liquid diet, animals were evaluated for ethanol withdrawal by measuring anxiety-related behaviors and locomotor activity. Twenty-four hours after evaluation of ethanol withdrawal, they were evaluated for voluntary consumption of ethanol in a "three bottle choice" paradigm. Mice exposed to chronic consumption of ethanol had decreased locomotor activity during withdrawal. Contrary to our expectations, a concomitant forced swimming stress did not aggravate ethanol withdrawal. Nevertheless, simultaneous ethanol administration and stress exposure increased voluntary consumption of ethanol, mainly solutions containing high concentrations of ethanol. These results showed that stressful situations during ethanol intake may aggravate specific addiction-related behaviors. PMID- 26628399 TI - Personality traits and psychiatric comorbidities in alcohol dependence. AB - Non-adaptive personality traits may constitute risk factors for development of psychiatric disorders such as depression and anxiety. We aim to evaluate associations and the predictive value of personality traits among alcohol dependent individuals, with or without psychiatric comorbidities. The convenience sample comprised two groups of males over 18 years of age: one with subjects who had an alcohol dependence diagnosis (AG, n=110), and a control group without abuse and/or alcohol dependence diagnosis (CG, n=110). The groups were assessed by means of the Structured Clinical Interview DSM-IV (SCID-IV). AG participants were recruited among outpatients from the university hospital, whereas CG participants were recruited from a primary healthcare program. Data collection was done individually with self-assessment instruments. Parametric statistics were performed, and a significance level of P=0.05 was adopted. A positive correlation was observed between openness and the length of time that alcohol has been consumed, as were significant and negative correlations between conscientiousness and both the length of time alcohol has been consumed and the number of doses. For alcoholics, extraversion emerged as a protective factor against depression development (P=0.008) and tobacco abuse (P=0.007), whereas openness worked as a protective factor against anxiety (P=0.02). The findings point to specific deficits presented by alcoholics in relation to personality traits with or without psychiatric comorbidities and to the understanding that therapeutic approaches should favor procedures and/or preventive measures that allow more refined awareness about the disorder. PMID- 26628400 TI - OSO paradigm--A rapid behavioral screening method for acute psychosocial stress reactivity in mice. AB - Chronic psychosocial stress is an important environmental risk factor for the development of psychiatric diseases. However, studying the impact of chronic psychosocial stress in mice is time consuming and thus not optimally suited to 'screen' increasing numbers of genetically manipulated mouse models for psychiatric endophenotypes. Moreover, many studies focus on restraint stress, a strong physical stressor with limited relevance for psychiatric disorders. Here, we describe a simple and a rapid method based on the resident-intruder paradigm to examine acute effects of mild psychosocial stress in mice. The OSO paradigm (open field--social defeat--open field) compares behavioral consequences on locomotor activity, anxiety and curiosity before and after exposure to acute social defeat stress. We first evaluated OSO in male C57Bl/6 wildtype mice where a single episode of social defeat reduced locomotor activity, increased anxiety and diminished exploratory behavior. Subsequently, we applied the OSO paradigm to mouse models of two schizophrenia (SZ) risk genes. Transgenic mice with neuronal overexpression of Neuregulin-1 (Nrg1) type III showed increased risk-taking behavior after acute stress exposure suggesting that NRG1 dysfunction is associated with altered affective behavior. In contrast, Tcf4 transgenic mice displayed a normal stress response which is in line with the postulated predominant contribution of TCF4 to cognitive deficits of SZ. In conclusion, the OSO paradigm allows for rapid screening of selected psychosocial stress-induced behavioral endophenotypes in mouse models of psychiatric diseases. PMID- 26628401 TI - Enhancing switching abilities: Improving practice effect by stimulating the dorsolateral pre frontal cortex. AB - Task switching is our ability to abandon an old, irrelevant task in order to perform a new, more relevant one. Data from neuropsychology and neuroimaging studies indicate hemispheric asymmetries in task switching, however the neural mechanisms subtending switching, and in particular protocols to improve switching abilities are yet to be established. The present study aimed to assess hemispheric asymmetry and practice effects in task switching by using transcranial direct current stimulation (tDCS). To this end, tDCS has been applied to the dorsolateral prefrontal cortex (DLPFC) of both hemispheres while subjects were performing a well-established task-switching paradigm. The task was repeated three times in three separate sessions in order to test practice effects with and without stimulation. Results show that increased hemispheric asymmetry in dorsolateral prefrontal areas improved switching performance as measured by a better practice effect, compared to sham condition. Our results support the hypothesis of dynamic hemispheric asymmetry in task switching and reinforce the notion of utilizing brain stimulation with traditional training methods in order to enhance cognitive abilities. PMID- 26628402 TI - Adaptive down-regulation of the serotonin transporter in the 6-hydroxydopamine induced rat model of preclinical stages of Parkinson's disease and after chronic pramipexole treatment. AB - Our recent study has indicated that a moderate lesion induced by bilateral 6 hydroxydopamine (6-OHDA) injections into the ventrolateral region of the caudate putamen (CP) in rats, modeling preclinical stages of Parkinson's disease, induces a "depressive-like" behavior which is reversed by chronic treatment with pramipexole (PRA). The aim of the present study was to examine the influence of the above lesion and chronic PRA treatment on binding to the serotonin transporter (SERT) in different brain regions. As before, 6-OHDA (15 MUg/2.5 MUl) was administered bilaterally into the CP. PRA (1mg/kg) was injected subcutaneously twice a day for 2 weeks. Serotonergic and dopaminergic neurons of the dorsal raphe (DR) were immunostained for tryptophan hydroxylase and tyrosine hydroxylase, respectively, and were counted stereologically. Binding of [(3)H]GBR 12,935 to the dopamine transporter (DAT) and [(3)H]citalopram to SERT was analyzed autoradiographically. Intrastriatal 6-OHDA injections decreased the number of dopaminergic, but not serotonergic neurons in the DR. 6-OHDA reduced the DAT binding in the CP, and SERT binding in the nigrostriatal system (CP, substantia nigra (SN)), limbic system (ventral tegmental area (VTA), nucleus accumbens (NAC), amygdala, prefrontal cortex (PFCX), habenula, hippocampus) and DR. A significant positive correlation was found between DAT and SERT binding in the CP. Chronic PRA did not influence DAT binding but reduced SERT binding in the above structures, and deepened the lesion-induced losses in the core region of the NAC, SN, VTA and PFCX. The present study indicates that both the lesion of dopaminergic neurons and chronic PRA administration induce adaptive down regulation of SERT binding. Moreover, although involvement of stimulation of dopaminergic transmission by chronic PRA in its "antidepressant" effect seems to be prevalent, additional contribution of SERT inhibition cannot be excluded. PMID- 26628403 TI - Sensorimotor learning in children and adults: Exposure to frequency-altered auditory feedback during speech production. AB - Auditory feedback plays an important role in the acquisition of fluent speech; however, this role may change once speech is acquired and individuals no longer experience persistent developmental changes to the brain and vocal tract. For this reason, we investigated whether the role of auditory feedback in sensorimotor learning differs across children and adult speakers. Participants produced vocalizations while they heard their vocal pitch predictably or unpredictably shifted downward one semitone. The participants' vocal pitches were measured at the beginning of each vocalization, before auditory feedback was available, to assess the extent to which the deviant auditory feedback modified subsequent speech motor commands. Sensorimotor learning was observed in both children and adults, with participants' initial vocal pitch increasing following trials where they were exposed to predictable, but not unpredictable, frequency altered feedback. Participants' vocal pitch was also measured across each vocalization, to index the extent to which the deviant auditory feedback was used to modify ongoing vocalizations. While both children and adults were found to increase their vocal pitch following predictable and unpredictable changes to their auditory feedback, adults produced larger compensatory responses. The results of the current study demonstrate that both children and adults rapidly integrate information derived from their auditory feedback to modify subsequent speech motor commands. However, these results also demonstrate that children and adults differ in their ability to use auditory feedback to generate compensatory vocal responses during ongoing vocalization. Since vocal variability also differed across the children and adult groups, these results also suggest that compensatory vocal responses to frequency-altered feedback manipulations initiated at vocalization onset may be modulated by vocal variability. PMID- 26628404 TI - Role of estradiol in intrinsic hindbrain AMPK regulation of hypothalamic AMPK, metabolic neuropeptide, and norepinephrine activity and food intake in the female rat. AB - This study addressed the hypothesis that dorsomedial hindbrain adenosine 5' monophosphate-activated protein kinase (AMPK) imposes inherent estradiol dependent control of hypothalamic AMPK, neuropeptide, and norepinephrine (NE) activity and feeding in the female rat. Estradiol (E)- or oil (O)-implanted ovariectomized rats were injected with the AMPK inhibitor compound c (Cc) or vehicle into the caudal fourth ventricle (CV4) prior to micropunch-dissection of individual hypothalamic metabolic loci or assessment of food intake. Cc decreased hindbrain dorsal vagal complex phosphoAMPK (pAMPK) in both E and O; tissue ATP levels were reduced by this treatment in O only. In E/Cc, pAMPK expression was diminished in the lateral hypothalamic area (LHA) and ventromedial (VMH) and paraventricular (PVH) nuclei; only PVH pAMPK was suppressed by this treatment in O/Cc. Cc decreased PVH corticotropin-releasing hormone and arcuate (ARH) proopiomelanocortin (POMC) and neuropeptide Y in O, but suppressed only POMC in E. O/Cc exhibited both augmented (PVH, VMH) and decreased (LHA, ARH) hypothalamic NE content, whereas Cc treatment of E elevated preoptic and dorsomedial hypothalamic nucleus NE. Cc completely or incompletely repressed feeding in E versus O, respectively. Results implicate dorsomedial hindbrain AMPK in physiological stimulus-induced feeding in females. Excepting POMC, hypothalamic neuropeptide responses to this sensor may be contingent on estrogen. Estradiol likely designates hypothalamic targets of altered NE signaling due to hindbrain AMPK activation. Divergent changes in NE content of hypothalamic loci in O/Cc uniquely demonstrate sensor-induced bimodal catecholamine signaling to those sites. PMID- 26628405 TI - Screening of Target Genes and Regulatory Function of miRNAs as Prognostic Indicators for Prostate Cancer. AB - BACKGROUND MicroRNAs expression profiling of prostate cancer is becoming increasingly used due to its usefulness in diagnosis, staging, prognosis, and response to treatment. The aim of this study was to screen differentially expressed miRNAs in prostate cancer and analyze the functions and signal pathways of their target genes. MATERIAL AND METHODS High-throughput data of miRNAs were downloaded from The Cancer Genome Atlas (TCGA) database. A total of 551 samples (52 normal and 499 prostate cancer cases) and 1046 miRNAs expression values were selected for further analysis. Differentially expressed miRNAs between normal and prostate cancer tissues were identified using SAMR. StarBase and TargetScan software were used to predict the miRNAs' target group and target genes, respectively. GO functional and KEGG pathway analysis was conducted on up/down regulated expressed miRNA with DAVID. Finally, survival analysis was performed to evaluate the association of differently expressed miRNAs signature and overall survival of prostate cancer patients. RESULTS A total of 162 miRNAs were differentially expressed between normal and prostate cancer samples, including 128 up-regulated and 38 down-regulated ones; hsa-mir-153-2, hsa-mir-92a-1, and hsa-mir-182 (up-regulated); and hsa-mir-29a, hsa-mir-10a, and hsa-mir-221 (down regulated) were identified as good biomarkers. In GO and KEGG analysis, target genes of down-regulated miRNAs were significantly enriched in positive ion combination and JAK-STAT pathway annotation, respectively; the ones with up regulated miRNAs were significantly enriched in the function of plasma membrane and MARK signaling pathway annotation, respectively. Patients were categorized into low- or high-score groups according to their risk scores from each miRNA. The patients in the low-score group had better overall survival compared with those in high-score group. CONCLUSIONS The 6 differentially expressed miRNAs and their target genes were used to define important molecular targets that could serve as prognostic and predictive markers in the treatment of prostate cancer. Further research on the function of the target genes in the MAPK signal pathway could provide references for treatment of prostate cancer. PMID- 26628406 TI - Receptor Occupancy of the kappa-Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050. AB - The kappa-opioid receptor (KOR) is thought to play an important therapeutic role in a wide range of neuropsychiatric and substance abuse disorders, including alcohol dependence. LY2456302 is a recently developed KOR antagonist with high affinity and selectivity and showed efficacy in the suppression of ethanol consumption in rats. This study investigated brain penetration and KOR target engagement after single oral doses (0.5-25 mg) of LY2456302 in 13 healthy human subjects. Three positron emission tomography scans with the KOR antagonist radiotracer (11)C-LY2795050 were conducted at baseline, 2.5 hours postdose, and 24 hours postdose. LY2456302 was well tolerated in all subjects without serious adverse events. Distribution volume was estimated using the multilinear analysis 1 method for each scan. Receptor occupancy (RO) was derived from a graphical occupancy plot and related to LY2456302 plasma concentration to determine maximum occupancy (rmax) and IC50. LY2456302 dose dependently blocked the binding of (11)C-LY2795050 and nearly saturated the receptors at 10 mg, 2.5 hours postdose. Thus, a dose of 10 mg of LY2456302 appears well suited for further clinical testing. Based on the pharmacokinetic (PK)-RO model, the rmax and IC50 of LY2456302 were estimated as 93% and 0.58 ng/ml to 0.65 ng/ml, respectively. Assuming that rmax is 100%, IC50 was estimated as 0.83 ng/ml. PMID- 26628407 TI - The early career researcher's toolkit: translating tissue engineering, regenerative medicine and cell therapy products. AB - Although the importance of translation for the development of tissue engineering, regenerative medicine and cell-based therapies is widely recognized, the process of translation is less well understood. This is particularly the case among some early career researchers who may not appreciate the intricacies of translational research or make decisions early in development which later hinders effective translation. Based on our own research and experiences as early career researchers involved in tissue engineering and regenerative medicine translation, we discuss common pitfalls associated with translational research, providing practical solutions and important considerations which will aid process and product development. Suggestions range from effective project management, consideration of key manufacturing, clinical and regulatory matters and means of exploiting research for successful commercialization. PMID- 26628409 TI - Three-dimensional isotropic fast spin-echo MR lymphangiography of T1-weighted and intermediate-weighted pulse sequences in patients with lymphoedema. AB - AIM: To evaluate the feasibility of magnetic resonance (MR) lymphangiography acquired using three-dimensional (3D) isotropic T1-weighted fast spin-echo (FSE) and 3D isotropic intermediate-weighted FSE sequences, as the new method of MR lymphangiography, and to compare the results of these two methods in patients with lymphoedema. MATERIALS AND METHODS: Thirty-three extremities of 27 patients with primary or secondary lymphoedema and who had undergone radionuclide lymphoscintigraphy and MR lymphangiography with 3D isotropic T1-weighted FSE and 3D isotropic intermediate-weighted FSE were included in the study. The results of both imaging techniques were independently reviewed by two readers in consensus who rated the lymphatic drainage pattern, the quality of the depiction of lymphatic vessels and lymph nodes, and the level of lymph vessel enhancement. The assessment scores of each imaging sequence were compared using the Wilcoxon signed-rank test. The results were expressed as means with standard deviations. RESULTS: More lymphatic vessels were visualised on T1-weighted FSE than on intermediate-weighted FSE (p<0.001). As more lymphatic vessels were detected on T1-weighted FSE, the per-extremity grade of the lymphatic drainage pattern was higher (p=0.046) and the visible levels of lymph-vessel enhancement were also significantly higher (p=0.004) on the T1-weighted FSE sequence, whereas the conspicuity of lymph nodes was superior on intermediate-weighted FSE (p=0.004). CONCLUSION: MR lymphangiography using the 3D FSE pulse sequence is a feasible and noticeable new technique of MR lymphangiography. Between the two applicable protocols used, T1-weighted FSE provided better information regarding lymphatic vessels and their drainage, whereas intermediate-weighted FSE has the advantage of depicting lymph nodes in lymphoedematous extremities. PMID- 26628410 TI - Abnormal regional homogeneity in Parkinson's disease: a resting state fMRI study. AB - AIM: To examine the functional brain alterations in Parkinson's disease (PD) by measuring blood oxygenation level dependent (BOLD) functional MRI (fMRI) signals at rest while controlling for the structural atrophy. MATERIALS AND METHODS: Twenty-three PD patients and 20 age, gender, and education level matched normal controls (NC) were included in this study. Resting state fMRI and structural MRI data were acquired. The resting state brain activity was measured by the regional homogeneity (ReHo) method and the grey matter (GM) volume was attained by the voxel-based morphology (VBM) analysis. Two-sample t-test was then performed to detect the group differences with structural atrophy as a covariate. RESULTS: VBM analysis showed GM volume reductions in the left superior frontal gyrus, left paracentral lobule, and left middle frontal gyrus in PD patients as compared to NC. There were widespread ReHo differences between NC and PD patients. Compared to NC, PD patients showed significant alterations in the motor network, including decreased ReHo in the right primary sensory cortex (S1), while increased ReHo in the left premotor area (PMA) and left dorsolateral prefrontal cortex (DLPFC). In addition, a cluster in the left superior occipital gyrus (SOG) also showed increased ReHo in PD patients. CONCLUSION: The current findings indicate that significant changes of ReHo in the motor and non-motor cortices have been detected in PD patients, independent of age, gender, education level, and structural atrophy. The present study thus suggests ReHo abnormalities as a potential biomarker for the diagnosis of PD and further provides insights into the biological mechanism of the disease. PMID- 26628411 TI - STM investigation of structural isomers: alkyl chain position induced self assembly at the liquid/solid interface. AB - Investigating and regulating the self-assembly structure is of great importance in 2D crystal engineering and it is also gaining significant interest in surface studies. In this work, we systematically explored the variation of self-assembled patterns induced by the changeable side chain position. Moreover, molecules with different alkyl chain lengths (n = 15, 16) were also synthesized and probed for the purpose of understanding how an odd/even number of carbon atoms in the peripheral chains can affect the molecular adlayers. Structural isomers of bis substituted anthraquinone derivatives 1,8-A-2OCn, 2,6-A-2OCn, 1,4-A-2OCn and 1,5 A-2OCn (n = 15, 16) were used and investigated by STM. 1,8-A-2OC16 and 1,8-A 2OC15 molecules adopted Z-like I and Linear I structures, respectively. 2,6-A 2OC16 and 2,6-A-2OC15 molecules were severally arranged in Linear II and Linear III configurations. 1,4-A-2OCn (n = 15, 16) molecules were staggered in a Z-like II fashion and 1,5-A-2OCn (n = 15, 16) molecules displayed a Linear IV nanostructure. Therefore, we arrive at a conclusion that self-assembly structures of anthraquinone isomers are chain-position-dependent, and designing isomeric compounds can be taken into consideration in regulating assembled structures. Besides, 2D nanopatterns of 1,8-A-2OCn and 2,6-A-2OCn can be regulated by the odd/even property of the side chains, but this is not the case for 1,4-A-2OCn and 1,5-A-2OCn, ascribed to the difference in driving forces for them. It is believed that the results are of significance to the alkyl chain position induced assembly configurations and surface research studies of structural isomers. PMID- 26628412 TI - Psychologists' Contributions to Patient-Centered Medical Homes. AB - Mounting evidence supports the value of integrated healthcare and the need for interprofessional practice within patient-centered medical homes (PCMH). Incorporating behavioral health services is key to fully implementing the PCMH concept. Unfortunately, psychologists have not been front and center in this integrative and interprofessional care movement nor have they typically received adequate training or experience to work effectively in these integrated care programs. This article builds the case for the value of PCMHs, particularly those that incorporate behavioral health services. Attention is paid to the diverse roles psychologists play in these settings, including as direct service providers, consultants, teachers/supervisors, scholars/program evaluators, and leaders. There is a discussion of the competencies psychologists must possess to play these roles effectively. Future directions are discussed, with a focus on ways psychologists can bolster the PCMH model by engaging in interprofessional partnerships related to education and training, practice, research, and leadership. PMID- 26628413 TI - Delayed vasculogenesis and impaired angiogenesis due to altered Ang-2 and VE cadherin levels in the chick embryo model following exposure to cadmium. AB - PURPOSE: Cadmium (Cd) causes chick embryo malformation and abnormal extra embryonic vasculature. This study investigates the effect of Cd on vasculogenesis, quantifies extra-embryonic vascular development following exposure to cadmium acetate (CdAc). METHODS: After 48 or 60 h incubation, chicks were explanted and treated with 50 ul of 50 uM CdAc or equimolar sodium acetate. Embryos were again incubated then re-examined 4, 8, 24 and 48 h later. Gross morphological and histological manifestations were noted. Vasculogenesis was assessed by the development of omphalomesenteric vessels from blood islands. Sinus terminalis (ST), area vasculosa (AV), vessel density and embryo crown-rump length (CRL) were measured. Ang-2 and VE-cadherin mRNA expression was analysed by RT-PCR. RESULTS: Vasculogenesis was delayed on gross and histological examination. ST length, AV area, vessel density and CRL were significantly reduced in the Cd group. Ang-2 was increased 4 h after exposure to Cd, whereas VE cadherin was reduced. CONCLUSION: Cd exposure inhibits normal development of extra-embryonic vasculature in line with growth retardation of the chick embryo in association with altered expression of Ang-2 and VE-cadherin. PMID- 26628414 TI - Weight Loss Decreases Excess Pancreatic Triacylglycerol Specifically in Type 2 Diabetes. AB - OBJECTIVE: This study determined whether the decrease in pancreatic triacylglycerol during weight loss in type 2 diabetes mellitus (T2DM) is simply reflective of whole-body fat or specific to diabetes and associated with the simultaneous recovery of insulin secretory function. RESEARCH DESIGN AND METHODS: Individuals listed for gastric bypass surgery who had T2DM or normal glucose tolerance (NGT) matched for age, weight, and sex were studied before and 8 weeks after surgery. Pancreas and liver triacylglycerol were quantified using in-phase, out-of-phase MRI. Also measured were the first-phase insulin response to a stepped intravenous glucose infusion, hepatic insulin sensitivity, and glycemic and incretin responses to a semisolid test meal. RESULTS: Weight loss after surgery was similar (NGT: 12.8 +/- 0.8% and T2DM: 13.6 +/- 0.7%) as was the change in fat mass (56.7 +/- 3.3 to 45.4 +/- 2.3 vs. 56.6 +/- 2.4 to 43.0 +/- 2.4 kg). Pancreatic triacylglycerol did not change in NGT (5.1 +/- 0.2 to 5.5 +/- 0.4%) but decreased in the group with T2DM (6.6 +/- 0.5 to 5.4 +/- 0.4%; P = 0.007). First-phase insulin response to a stepped intravenous glucose infusion did not change in NGT (0.24 [0.13-0.46] to 0.23 [0.19-0.37] nmol ? min(-1) ? m( 2)) but normalized in T2DM (0.08 [-0.01 to -0.10] to 0.22 [0.07-0.30]) nmol ? min(-1) ? m(-2) at week 8 (P = 0.005). No differential effect of incretin secretion was observed after gastric bypass, with more rapid glucose absorption bringing about equivalently enhanced glucagon-like peptide 1 secretion in the two groups. CONCLUSIONS: The fall in intrapancreatic triacylglycerol in T2DM, which occurs during weight loss, is associated with the condition itself rather than decreased total body fat. PMID- 26628415 TI - Breaking Up Prolonged Sitting With Standing or Walking Attenuates the Postprandial Metabolic Response in Postmenopausal Women: A Randomized Acute Study. AB - OBJECTIVE: To determine whether breaking up prolonged sitting with short bouts of standing or walking improves postprandial markers of cardiometabolic health in women at high risk of type 2 diabetes. RESEARCH DESIGN AND METHODS: Twenty-two overweight/obese, dysglycemic, postmenopausal women (mean +/- SD age 66.6 +/- 4.7 years) each participated in two of the following treatments: prolonged, unbroken sitting (7.5 h) or prolonged sitting broken up with either standing or walking at a self-perceived light intensity (for 5 min every 30 min). Both allocation and treatment order were randomized. The incremental area under the curves (iAUCs) for glucose, insulin, nonesterified fatty acids (NEFA), and triglycerides were calculated for each treatment condition (mean +/- SEM). The following day, all participants underwent the 7.5-h sitting protocol. RESULTS: Compared with a prolonged bout of sitting (iAUC 5.3 +/- 0.8 mmol/L ? h), both standing (3.5 +/- 0.8 mmol/L ? h) and walking (3.8 +/- 0.7 mmol/L ? h) significantly reduced the glucose iAUC (both P < 0.05). When compared with prolonged sitting (548.2 +/- 71.8 mU/L ? h), insulin was also reduced for both activity conditions (standing, 437.2 +/- 73.5 mU/L ? h; walking, 347.9 +/- 78.7 mU/L ? h; both P < 0.05). Both standing (-1.0 +/- 0.2 mmol/L ? h) and walking (-0.8 +/- 0.2 mmol/L ? h) attenuated the suppression of NEFA compared with prolonged sitting (-1.5 +/- 0.2 mmol/L ? h) (both P < 0.05). There was no significant effect on triglyceride iAUC. The effects on glucose (standing and walking) and insulin (walking only) persisted into the following day. CONCLUSIONS: Breaking up prolonged sitting with 5-min bouts of standing or walking at a self-perceived light intensity reduced postprandial glucose, insulin, and NEFA responses in women at high risk of type 2 diabetes. This simple, behavioral approach could inform future public health interventions aimed at improving the metabolic profile of postmenopausal, dysglycemic women. PMID- 26628416 TI - Umbilical Cord Mesenchymal Stromal Cell With Autologous Bone Marrow Cell Transplantation in Established Type 1 Diabetes: A Pilot Randomized Controlled Open-Label Clinical Study to Assess Safety and Impact on Insulin Secretion. AB - OBJECTIVE: To determine the safety and effects on insulin secretion of umbilical cord (UC) mesenchymal stromal cells (MSCs) plus autologous bone marrow mononuclear cell (aBM-MNC) stem cell transplantation (SCT) without immunotherapy in established type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Between January 2009 and December 2010, 42 patients with T1D were randomized (n = 21/group) to either SCT (1.1 * 10(6)/kg UC-MSC, 106.8 * 10(6)/kg aBM-MNC through supraselective pancreatic artery cannulation) or standard care (control). Patients were followed for 1 year at 3-month intervals. The primary end point was C-peptide area under the curve (AUC(C-Pep)) during an oral glucose tolerance test at 1 year. Additional end points were safety and tolerability of the procedure, metabolic control, and quality of life. RESULTS: The treatment was well tolerated. At 1 year, metabolic measures improved in treated patients: AUCC-Pep increased 105.7% (6.6 +/- 6.1 to 13.6 +/- 8.1 pmol/mL/180 min, P = 0.00012) in 20 of 21 responders, whereas it decreased 7.7% in control subjects (8.4 +/- 6.8 to 7.7 +/- 4.5 pmol/mL/180 min, P = 0.013 vs. SCT); insulin area under the curve increased 49.3% (1,477.8 +/- 1,012.8 to 2,205.5 +/- 1,194.0 mmol/mL/180 min, P = 0.01), whereas it decreased 5.7% in control subjects (1,517.7 +/- 630.2 to 1,431.7 +/- 441.6 mmol/mL/180 min, P = 0.027 vs. SCT). HbA1c decreased 12.6% (8.6 +/- 0.81% [70.0 +/- 7.1 mmol/mol] to 7.5 +/- 1.0% [58.0 +/- 8.6 mmol/mol], P < 0.01) in the treated group, whereas it increased 1.2% in the control group (8.7 +/- 0.9% [72.0 +/- 7.5 mmol/mol] to 8.8 +/- 0.9% [73 +/- 7.5 mmol/mol], P < 0.01 vs. SCT). Fasting glycemia decreased 24.4% (200.0 +/- 51.1 to 151.2 +/- 22.1 mg/dL, P < 0.002) and 4.3% in control subjects (192.4 +/- 35.3 to 184.2 +/- 34.3 mg/dL, P < 0.042). Daily insulin requirements decreased 29.2% in only the treated group (0.9 +/- 0.2 to 0.6 +/- 0.2 IU/day/kg, P = 0.001), with no change found in control subjects (0.9 +/- 0.2 to 0.9 +/- 0.2 IU/day/kg, P < 0.01 vs. SCT). CONCLUSIONS: Transplantation of UC-MSC and aBM-MNC was safe and associated with moderate improvement of metabolic measures in patients with established T1D. PMID- 26628418 TI - Determinants of Diabetes Remission and Glycemic Control After Bariatric Surgery. AB - OBJECTIVE: Eligibility criteria for bariatric surgery in diabetes include BMI >=35 kg/m(2) and poorly controlled glycemia. However, BMI does not predict diabetes remission, and thus, predictors need to be identified. RESEARCH DESIGN AND METHODS: Seven hundred twenty-seven patients were included in a database merged from the Swedish Obese Subjects (SOS) study and two randomized controlled studies, with 415 surgical and 312 medical patients in total. Bariatric operations were divided into gastric only (GO) and gastric plus diversion (GD). RESULTS: Sixty-four percent of patients in the surgical arm and 15.0% in the medical arm experienced diabetes remission (P < 0.001). GO yielded 60% remission, and GD yielded 76% remission. The best predictors of diabetes remission were lower baseline glycemia and shorter diabetes duration. However, when operation type was considered, GD predicted a higher likelihood of remission and greater weight loss. Patients in remission (responders) lost more weight (25% vs. 17%) and waist circumference (18% vs. 13%) and experienced better insulin sensitivity than nonresponders. CONCLUSIONS: Surgery is more effective than medical treatment in achieving diabetes remission and tighter glycemic control. Shorter diabetes duration, lower fasting glycemia before surgery, and GD versus GO procedures independently predict higher rates of remission, whereas baseline HbA1c and waist circumference predict improved glycemic control. The results show the advantage of an early operation together with better controlled glycemia on diabetes remission independently of BMI. PMID- 26628419 TI - Alogliptin, a Dipeptidyl Peptidase 4 Inhibitor, Prevents the Progression of Carotid Atherosclerosis in Patients With Type 2 Diabetes: The Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A). AB - OBJECTIVE: Recent experimental studies have shown that dipeptidyl peptidase 4 (DPP-4) inhibitors have antiatherosclerotic benefits in glucagon-like peptide 1 dependent and -independent manners. The current study investigated the effects of alogliptin, a DPP-4 inhibitor, on the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: This prospective, randomized, open-label, blinded-end point, multicenter, parallel group, comparative study included 341 patients with T2DM free of a history of apparent cardiovascular diseases recruited at 11 clinical units and randomly allocated to treatment with alogliptin (n = 172) or conventional treatment (n = 169). Primary outcomes were changes in mean common and maximum intima-media thickness (IMT) of the carotid artery measured by carotid arterial echography during a 24-month treatment period. RESULTS: Alogliptin treatment had a more potent glucose-lowering effect than the conventional treatment (-0.3 +/- 0.7% vs. -0.1 +/- 0.8%, P = 0.004) without an increase of hypoglycemia. Changes in the mean common and the right and left maximum IMT of the carotid arteries were significantly greater after alogliptin treatment than after conventional treatment (-0.026 mm [SE 0.009] vs. 0.005 mm [SE 0.009], P = 0.022; -0.045 mm [SE 0.018] vs. 0.011 mm [SE 0.017], P = 0.025, and -0.079 mm [SE 0.018] vs. -0.015 mm [SE 0.018], P = 0.013, respectively). CONCLUSIONS: Alogliptin treatment attenuated the progression of carotid IMT in patients with T2DM free of apparent cardiovascular disease compared with the conventional treatment. PMID- 26628421 TI - Human thermal comfort conditions and urban planning in hot-humid climates-The case of Cuba. AB - Climate regional characteristics, urban environmental conditions, and outdoors thermal comfort requirements of residents are important for urban planning. Basic studies of urban microclimate can provide information and useful resources to predict and improve thermal conditions in hot-humid climatic regions. The paper analyzes the thermal bioclimate and its influence as urban design factor in Cuba, using Physiologically Equivalent Temperature (PET). Simulations of wind speed variations and shade conditions were performed to quantify changes in thermal bioclimate due to possible modifications in urban morphology. Climate data from Havana, Camaguey, and Santiago of Cuba for the period 2001 to 2012 were used to calculate PET with the RayMan model. The results show that changes in meteorological parameters influence the urban microclimate, and consequently modify the thermal conditions in outdoors spaces. Shade is the predominant strategy to improve urban microclimate with more significant benefits in terms of PET higher than 30 degrees C. For climatic regions such as the analyzed ones, human thermal comfort can be improved by a wind speed modification for thresholds of PET above 30 degrees C, and by a wind speed decreases in conditions below 26 degrees C. The improvement of human thermal conditions is crucial for urban sustainability. On this regards, our study is a contribution for urban designers, due to the possibility of taking advantage of results for improving microclimatic conditions based on urban forms. The results may enable urban planners to create spaces that people prefer to visit, and also are usable in the reconfiguration of cities. PMID- 26628420 TI - Racial Differences in the Performance of Existing Risk Prediction Models for Incident Type 2 Diabetes: The CARDIA Study. AB - OBJECTIVE: In 2010, the American Diabetes Association (ADA) added hemoglobin A1c (A1C) to the guidelines for diagnosing type 2 diabetes. However, existing models for predicting diabetes risk were developed prior to the widespread adoption of A1C. Thus, it remains unknown how well existing diabetes risk prediction models predict incident diabetes defined according to the ADA 2010 guidelines. Accordingly, we examined the performance of an existing diabetes prediction model applied to a cohort of African American (AA) and white adults from the Coronary Artery Risk Development Study in Young Adults (CARDIA). RESEARCH DESIGN AND METHODS: We evaluated the performance of the Atherosclerosis Risk in Communities (ARIC) diabetes risk prediction model among 2,456 participants in CARDIA free of diabetes at the 2005-2006 exam and followed for 5 years. We evaluated model discrimination, calibration, and integrated discrimination improvement with incident diabetes defined by ADA 2010 guidelines before and after adding baseline A1C to the prediction model. RESULTS: In the overall cohort, re-estimating the ARIC model in the CARDIA cohort resulted in good discrimination for the prediction of 5-year diabetes risk (area under the curve [AUC] 0.841). Adding baseline A1C as a predictor improved discrimination (AUC 0.841 vs. 0.863, P = 0.03). In race-stratified analyses, model discrimination was significantly higher in whites than AA (AUC AA 0.816 vs. whites 0.902; P = 0.008). CONCLUSIONS: Addition of A1C to the ARIC diabetes risk prediction model improved performance overall and in racial subgroups. However, for all models examined, discrimination was better in whites than AA. Additional studies are needed to further improve diabetes risk prediction among AA. PMID- 26628422 TI - Age-related fragility fracture: insights from the natural homeostatic system in the skeleton. PMID- 26628417 TI - Pregnancy Outcomes in Youth With Type 2 Diabetes: The TODAY Study Experience. AB - OBJECTIVE: We evaluated pregnancy outcomes, maternal and fetal/neonatal, during the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. RESEARCH DESIGN AND METHODS: The TODAY study was a randomized controlled trial comparing three treatment options for youth with type 2 diabetes. Informed consent included the requirement for contraception, including abstinence; this was reinforced at each visit. Following informed consent, self-reported data related to the mother's prenatal care and delivery and the infant's health were retrospectively collected. When permitted, maternal medical records and infant birth records were reviewed. RESULTS: Of the 452 enrolled female participants, 46 (10.2%) had 63 pregnancies. Despite continued emphasis on adequate contraception, only 4.8% of the pregnant participants reported using contraception prior to pregnancy. The mean age at first pregnancy was 18.4 years; the mean diabetes duration was 3.17 years. Seven pregnancies were electively terminated; three pregnancies had no data reported. Of the remaining 53 pregnancies, 5 (9.4%) resulted in early pregnancy loss, and 7 (13%) resulted in loss with inadequate pregnancy duration data. Two pregnancies ended in stillbirth, at 27 and 37 weeks, and 39 ended with a live-born infant. Of the live-born infants, six (15.4%) were preterm and eight (20.5%) had a major congenital anomaly. CONCLUSIONS: Despite diabetes-specific information recommending birth control and the avoidance of pregnancy, 10% of the study participants became pregnant. Pregnancies in youth with type 2 diabetes may be especially prone to result in congenital anomalies. Reasons for the high rate of congenital anomalies are uncertain, but may include poor metabolic control and extreme obesity. PMID- 26628423 TI - Collider-stratification Bias Due to Censoring in Prospective Cohort Studies. PMID- 26628424 TI - Does Mother Know Best? Treatment Adherence as a Function of Anticipated Treatment Benefit. AB - BACKGROUND: We describe bias resulting from individualized treatment selection, which occurs when treatment has heterogeneous effects and individuals selectively choose treatments of greatest benefit to themselves. This pernicious bias may confound estimates from observational studies and lead to important misinterpretation of intent-to-treat analyses of randomized trials. Despite the potentially serious threat to inferences, individualized treatment selection has rarely been formally described or assessed. METHODS: The Moving To Opportunity trial randomly assigned subsidized rental vouchers to low-income families in high poverty public housing. We assessed the Kessler-6 psychological distress and Behavior Problems Index outcomes for 2,829 adolescents 4-7 years after randomization. Among families randomly assigned to receive vouchers, we estimated probability of moving (treatment), predicted by prerandomization characteristics (c statistic = 0.63). We categorized families into tertiles of this estimated probability of moving, and compared instrumental variable effect estimates for moving on behavior problems index and Kessler-6 across tertiles. RESULTS: Instrumental variable estimated effects of moving on behavioral problems index were most adverse for boys least likely to move (b = 0.93; 95% confidence interval: 0.33, 1.53) compared with boys most likely to move (b = 0.14; 95% confidence interval: -0.15, 0.44; P = 0.02 for treatment * tertile interaction). Effects on Kessler-6 were more beneficial for girls least likely to move compared with girls most likely to move (-0.62 vs. 0.02; interaction; P = 0.03). CONCLUSIONS: Evidence of individualized treatment selection differed by child gender and outcome and should be evaluated in randomized trial reports, especially when heterogeneous treatment effects are likely and nonadherence is common. PMID- 26628425 TI - Commentary: Diesel, Cars, and Public Health. PMID- 26628426 TI - Commentary: Weight Loss and Coronary Heart Disease: Uncontrolled Confounding by Undiagnosed Disease May Not Be All It's Cracked up to Be. PMID- 26628427 TI - A Sensitivity Analysis to Assess Bias Due to Selecting Subjects Based on Treatment Received. PMID- 26628428 TI - Weight Loss and Coronary Heart Disease: Sensitivity Analysis for Unmeasured Confounding by Undiagnosed Disease. AB - BACKGROUND: Evidence for the effect of weight loss on coronary heart disease (CHD) or mortality has been mixed. The effect estimates can be confounded due to undiagnosed diseases that may affect weight loss. METHODS: We used data from the Nurses' Health Study to estimate the 26-year risk of CHD under several hypothetical weight loss strategies. We applied the parametric g-formula and implemented a novel sensitivity analysis for unmeasured confounding due to undiagnosed disease by imposing a lag time for the effect of weight loss on chronic disease. Several sensitivity analyses were conducted. RESULTS: The estimated 26-year risk of CHD did not change under weight loss strategies using lag times from 0 to 18 years. For a 6-year lag time, the risk ratios of CHD for weight loss compared with no weight loss ranged from 1.00 (0.99, 1.02) to 1.02 (0.99, 1.05) for different degrees of weight loss with and without restricting the weight loss strategy to participants with no major chronic disease. Similarly, no protective effect of weight loss was estimated for mortality risk. In contrast, we estimated a protective effect of weight loss on risk of type 2 diabetes. CONCLUSION: We estimated that maintaining or losing weight after becoming overweight or obese does not reduce the risk of CHD or death in this cohort of middle-age US women. Unmeasured confounding, measurement error, and model misspecification are possible explanations but these did not prevent us from estimating a beneficial effect of weight loss on diabetes. PMID- 26628429 TI - Presence of an H+/Quinidine Antiport System in Madin-Darby Canine Kidney Cells. AB - BACKGROUND AND OBJECTIVES: We have recently found an H+/quinidine antiport system in human kidney HEK 293 cells. The aim of the present study was to evaluate whether the H+/quinidine antiport system is expressed in Madin-Darby canine kidney (MDCK) cells. METHODS: We investigated the uptake and efflux of quinidine in MDCK cells. RESULTS: The uptake of 100 uM quinidine into MDCK cells was decreased by acidification of extracellular pH or alkalization of intracellular pH. In addition, the uptake of quinidine was highly temperature sensitive, but was extracellular Na+ and membrane potential independent. Furthermore, tetraethylammonium, a typical substrate of renal organic cation transporters, did not inhibit the uptake of quinidine in MDCK cells. On the other hand, lipophilic cationic drugs, such as clonidine, bisoprolol, diphenhydramine, pyrilamine, and imipramine, significantly decreased the uptake of quinidine in MDCK cells. The uptake of quinidine was saturable, and the Michaelis-Menten constant was estimated to be approximately 0.5 mM. In addition, the efflux of quinidine from MDCK cells was increased by the acidification of extracellular pH, suggesting that the transport system mediates not only the uptake, but also secretion of quinidine. CONCLUSIONS: The present findings suggested that the renal new antiport system is involved in the bidirectional membrane transport of quinidine in MDCK cells. PMID- 26628430 TI - Hyperthermic Intraperitoneal Chemotherapy after Secondary Cytoreduction in Epithelial Ovarian Cancer: A Single-center Comparative Analysis. AB - BACKGROUND: Although the standard of care after recurrence of epithelial ovarian cancer (EOC) is chemotherapy, increasing data suggest that combining cytoreductive surgery with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising option for patients with recurrent EOC. Our aim was to determine the prognostic value of the addition of HIPEC to secondary cytoreductive surgery (SCR) in recurrent EOC. METHODS: We analyzed a series of 79 patients with platinum-sensitive recurrent EOC who were treated from May 2000 to January 2014. Fifty patients who underwent SCR were compared to 29 who had SCR in combination with HIPEC. RESULTS: The SCR group had a higher median age (58.4 years) compared to the SCR + HIPEC group (51.6 years) (p = 0.006). The median hospital stay length was longer for SCR + HIPEC versus SCR patients (11 and 8 days, respectively; p = 0.009). More subjects experienced National Cancer Institute grade III-IV morbidity in the SCR + HIPEC group (34.5 %) compared to the SCR group (10.6 %) (p = 0.015). Conversely, there were no deaths in the SCR + HIPEC group and 2 (4.0 %) deaths the SCR group. The median disease-free survival did not differ between SCR and SCR + HIPEC patients (18.6 and 15.8 months, respectively; p = 0.82); nor did median overall survival (59.3 and 58.3 months, respectively; p = 0.95). The presence of carcinomatosis was the only variable that remained linked to a higher risk of recurrence and death in the multivariate analysis. CONCLUSIONS: Our data suggest that the addition of HIPEC to cytoreduction in patients with recurrent platinum-sensitive EOC does not improve survival. PMID- 26628431 TI - Microscopic Positive Tumor Margin Does Not Increase the Risk of Recurrence in Patients with T1-T2 Well-Differentiated Thyroid Cancer. AB - BACKGROUND: Incomplete surgical resection with gross positive tumor margin increases the risk of recurrence in patients with well-differentiated thyroid cancer (WDTC); however, it is not clear whether a microscopic positive margin found only on final pathology has similar implications on patient outcomes. METHODS: We conducted a single-institution retrospective review of all patients undergoing total thyroidectomy for T1-T2 WDTC (January 2000-January 2010). Factors that may influence the risk of locoregional recurrence or distant metastasis were evaluated by univariate and multivariate analysis. RESULTS: Of 1000 consecutive patients undergoing surgical resection for WDTC, 684 T1-T2 cancers were included. Mean age was 46 years and 81 % were women. Of this total cohort, 78 (11 %) patients had microscopic positive margins. Radioactive iodine (RAI) was administered in 47/78 (60 %) patients with positive margins versus 312/606 (51 %) patients without positive margins. After a mean follow-up of 46 months, 53 (8 %) patients developed recurrent disease (1 local and 52 nodal). On multivariate analysis, nodal metastases (N1, odds ratio [OR] 7.7) and contralateral multifocality (OR 3.7) were independent risk factors for recurrent disease. A microscopic positive margin was not a risk factor for recurrence. CONCLUSIONS: A microscopic positive margin found only on final pathological analysis does not increase the risk of recurrence in T1-T2 WDTC. Clinicians should interpret such pathology findings accordingly when considering further surveillance and treatment decisions such as the use of RAI ablation. PMID- 26628432 TI - Residual Mammographic Microcalcifications and Enhancing Lesions on MRI After Neoadjuvant Systemic Chemotherapy for Locally Advanced Breast Cancer: Correlation with Histopathologic Residual Tumor Size. AB - PURPOSE: To evaluate the accuracy of residual microcalcifications on mammogram (MG) in predicting the extent of the residual tumor after neoadjuvant systemic treatment (NST) in patients with locally advanced breast cancer and to evaluate factors affecting the accuracy of MG microcalcifications using magnetic resonance imaging (MRI) as a reference. METHODS: The patients who underwent NST and showed suspicious microcalcifications on MG comprised our study population. Clinicopathologic and imaging (MG, MRI) findings were investigated. Agreement between image findings and pathology was assessed and factors affecting the discrepancy were analyzed. RESULTS: Among 207 patients, 196 had residual invasive ductal carcinoma or ductal carcinoma-in-situ (mean size, 3.78 cm). The overall agreement of residual microcalcifications on MG predicting residual tumor extents was lower than MRI in all tumor subtypes (intraclass correlation coefficient [ICC] = 0.368 and 0.723, p < 0.0001). The agreement of residual MG microcalcifications and pathology was highest in HR(+)/HER2(+) tumors and lowest in the triple-negative tumors (ICC = 0.417 and 0.205, respectively). Multivariate linear regression analysis revealed that a size discrepancy between microcalcifications and histopathology was correlated with molecular subtype (p = 0.005). In HR(+)/HER2(-) and triple-negative subtypes, the mean extents of residual microcalcification were smaller than residual cancer, and overestimation of tumor extent was more frequent in HR(+)/HER2(+) and HR(-)/HER2(+) tumors. CONCLUSIONS: The extent of microcalcifications on MG after NST showed an overall lower correlation with the extent of the pathologic residual tumor than enhancing lesions on MRI. The accuracy of residual tumor evaluation after NST with MG and MRI is affected by their molecular subtype. PMID- 26628433 TI - An Evaluation of Postoperative Complications and Cost After Short-Stay Thyroid Operations. AB - BACKGROUND: Concern for postoperative complications causing airway compromise has limited widespread acceptance of ambulatory thyroid surgery. We evaluated differences in outcomes and hospital costs in those monitored for a short stay of 6 h (SS), inpatient observation of 6-23 h (IO), or inpatient admission of >23 h (IA). METHODS: We retrospectively reviewed all patients undergoing thyroidectomy from 2006 to 2012. The incidence of postoperative hemorrhage, nerve dysfunction, and hypocalcemia were evaluated, as well as cost data comparing the SS and IO groups. RESULTS: Of 1447 thyroidectomies, 880 (60.8 %) were performed as SS, 401 (27.7 %) as IO, and 166 (11.5 %) as IA. Fewer patients in the SS group (59 %) underwent total thyroidectomy than IO (73 %) and IA (71 %; p < 0.01), and SS patients had smaller thyroid weights (27.9 g) compared with IO and IA (47.2 and 98.9 g, respectively; p < 0.01). Ten (0.69 %) patients developed hematomas requiring reoperation, five of the ten patients received antiplatelet or anticoagulant therapy perioperatively. Only one patient in the IA group bled within the 6- to 23-h period, and no patients with bleeding who were discharged at 6 h would have benefitted from 23-h observation. Twenty-four (1.66 %) recurrent laryngeal nerve injuries were identified, 16 with temporary neuropraxias. In addition, 24 (1.66 %) patients had symptomatic hypocalcemia, which was transient in 17 individuals. Financial data showed higher payments and lower costs associated with SS compared with IO. CONCLUSIONS: Selective SS thyroidectomy can be safe and cost effective, with few overall complications in patients undergoing more complex operations involving larger thyroids who were admitted to hospital. PMID- 26628434 TI - Long-Term Follow-Up Evaluation of 68 Patients with Uveal Melanoma Liver Metastases Treated with Isolated Hepatic Perfusion. AB - BACKGROUND: This report describes the outcomes and long-term follow-up data from all isolated hepatic perfusions (IHPs) performed at a single institution in Sweden between the years 1989 and 2013 for patients with isolated uveal melanoma metastases. METHODS: A total of 68 patients (median age, 61 years) were treated consecutively at Sahlgrenska University Hospital. Of the 68 patients, 67 % had fewer than 10 tumors. The median diameter of the largest lesion was 2.5 cm. The patients underwent IHP with either melphalan alone or the addition of either tumor necrosis factor-alpha or cisplatin. The response was assessed after 8-12 weeks by computed tomography or magnetic resonance imaging. RESULTS: The overall response rate was 67 and 20 % of the patients had a complete response. The median times to local and systemic progression were respectively 10 and 14 months. The prognostic factors for time to local recurrence were response and number of tumors. The median survival time was 22 months. The prognostic factors for survival were response, largest tumor diameter, and number of tumors. Five patients (7 %) died within 30 days, and six patients (9 %) experienced major complications (Clavien-Dindo 3/4). CONCLUSIONS: Isolated hepatic perfusion is a treatment option with high response rates and tolerable mortality and morbidity. Whether IHP has a survival benefit compared with other treatment options currently is being investigated in a randomized trial. PMID- 26628435 TI - Resectability of Peritoneal Carcinomatosis: Learnings from a Prospective Cohort of 533 Consecutive Patients Selected for Cytoreductive Surgery. AB - PURPOSE: The aim of this study was to identify the risk factors and causes of unresectability in a large cohort of patients with peritoneal carcinomatosis (PC) selected for cytoreductive surgery (CRS), and to assess the contribution of the different imaging modalities to the patient-selection process. METHODS: The pre- and intraoperative data of 533 consecutive patients with PC planned for CRS at a single institution were reviewed. All patients underwent computed tomography (CT) magnetic resonance imaging and/or positron emission tomography/CT within the 2 days prior to surgery. RESULTS: Among the 533 patients, 436 (82 %) underwent complete CRS, 86 (16 %) underwent exploratory laparotomy without CRS because of multiple small-bowel involvement (n = 31), invasion of different digestive segments (n = 15), an elevated PC index (n = 14), invasion of the mesenteric root (n = 12), or another cause (n = 14), and 11 (2 %) did not undergo laparotomy because of disease progression on preoperative imaging findings. On univariate analysis, elevated levels of tumor markers and a short delay between the last cycle of chemotherapy and the scheduled surgery were identified as predictors of unresectability for the colonic PC population, while a younger age was identified in patients with gastric PC. Multivariate analysis disclosed the use of neoadjuvant chemotherapy and a younger age as independent predictors of unresectability in the colonic PC population. CONCLUSIONS: The current modalities for the assessment of PC resectability, including functional imaging examinations, have a low impact on patient selection for CRS. New tools are needed to decrease the rate of open-close procedures. PMID- 26628436 TI - Effects of bariatric surgery on hepatic and intestinal lipoprotein particle metabolism. AB - PURPOSE OF REVIEW: Insulin resistance and type 2 diabetes, driven largely by obesity, are characterized by an increase in triglyceride-rich lipoproteins (TRLs) due to both reduced TRL clearance from the circulation and increased production by the liver (apoB-100 containing VLDLs) and intestine (apoB-48 containing chylomicrons). Bariatric surgery is the only treatment currently that leads to marked, sustained weight loss. Here, we will review the effects of bariatric surgery on circulating triglyceride/TRL and TRL production and clearance. RECENT FINDINGS: Bariatric surgery leads to a marked reduction in fasting and postprandial plasma triglyceride. Only one study to date has assessed TRL kinetics after bariatric surgery and has reported a reduction in TRL apoB-100 concentration (i.e. the number of VLDL particles) due to reduced production and increased clearance and reduced TRL apoB-48 concentration (the number of chylomicron particles) due to reduced production. Some bariatric surgery studies have reported no/weak correlation between weight loss and improvements in triglyceride/TRL, suggesting that as yet unidentified factors beyond weight loss may contribute to the marked changes in TRL that occur postbariatric surgery. SUMMARY: Available data suggest that bariatric surgery reduces triglyceride and intestinal and hepatic TRL production with increased clearance of hepatic TRL particles. These effects of bariatric surgery on TRL kinetics need to be confirmed with additional studies. Further studies are also needed to compare the effects of various bariatric surgery procedures on TRL kinetics and to elucidate underlying mechanisms. PMID- 26628437 TI - Central nervous system regulation of intestinal lipid and lipoprotein metabolism. AB - PURPOSE OF REVIEW: In response to nutrient availability, the small intestine and brain closely communicate to modulate energy homeostasis and metabolism. The gut brain axis involves complex nutrient sensing mechanisms and an integration of neuronal and hormonal signaling. This review summarizes recent evidence implicating the gut-brain axis in regulating lipoprotein metabolism, with potential implications for the dyslipidemia of insulin resistant states. RECENT FINDINGS: The intestine and brain possess distinct mechanisms for sensing lipid availability, which triggers subsequent regulation of feeding, glucose homeostasis, and adipose tissue metabolism. More recently, central receptors, neuropeptides, and gut hormones that communicate with the brain have been shown to modulate hepatic and intestinal lipoprotein metabolism via parasympathetic and sympathetic signaling. Gut-derived glucagon-like peptides appear to be particularly important in modulating the intestinal secretion of chylomicron particles via a novel brain-gut axis. Dysregulation of these pathways may contribute to postprandial diabetic dyslipidemia. SUMMARY: Emerging evidence implicates the central and enteric nervous systems in controlling many aspects of lipid and lipoprotein metabolism. Bidirectional communication between the gut and brain involving neuronal pathways and gut peptides is critical for regulating feeding and metabolism, and forms a neuroendocrine circuit to modulate dietary fat absorption and intestinal production of atherogenic chylomicron particles. PMID- 26628438 TI - Development of an Ointment Formulation Using Hot-Melt Extrusion Technology. AB - Ointments are generally prepared either by fusion or by levigation methods. The current study proposes the use of hot-melt extrusion (HME) processing for the preparation of a polyethylene glycol base ointment. Lidocaine was used as a model drug. A modified screw design was used in this process, and parameters such as feeding rate, barrel temperature, and screw speed were optimized to obtain a uniform product. The product characteristics were compared with an ointment of similar composition prepared by conventional fusion method. The rheological properties, drug release profile, and texture characteristics of the hot-melt extruded product were similar to the conventionally prepared product. This study demonstrates a novel application of the hot-melt extrusion process in the manufacturing of topical semi-solids. PMID- 26628439 TI - Serum Vitamin D Depends Less on Latitude Than on Skin Color and Dietary Intake During Early Winter in Northern Europe. AB - OBJECTIVES: To evaluate if dietary vitamin D intake is adequate for sufficient vitamin D status during early winter in children living in Sweden, irrespective of latitude or skin color. METHODS: As part of a prospective, comparative, 2 center intervention study in northern (63 degrees N) and southern (55 degrees N) Sweden, dietary intake, serum 25-hydroxyvitamin D (S-25(OH) D), associated laboratory variables, and sociodemographic data were studied in 5 to 7-year-old children with fair and dark skin in November and December. RESULTS: Two hundred six children with fair/dark skin were included, 44/41 and 64/57 children in northern and southern Sweden, respectively. Dietary vitamin D intake was higher in northern than southern Sweden (P = 0.001), irrespective of skin color, partly due to higher consumption of fortified foods, but only met 50-70% of national recommendations (10 MUg/day). S-25(OH) D was higher in northern than southern Sweden, in children with fair (67 vs 59 nmol/L; P < 0.05) and dark skin (56 vs 42 nmol/L; P < 0.001). S-25(OH) D was lower in dark- than fair-skinned children at both sites (P < 0.01), and below 50 nmol/L in 40 and 75% of dark-skinned children in northern and southern Sweden, respectively. CONCLUSIONS: Insufficient vitamin D status was common during early winter in children living in Sweden, particularly in those with dark skin. Although, higher dietary vitamin D intake in northern than southern Sweden attenuated the effects of latitude, a northern country of living combined with darker skin and vitamin D intake below recommendations are important risk factors for vitamin D insufficiency. PMID- 26628440 TI - Cow's Milk Allergy Prescribing Is Influenced by Regional and National Guidance. AB - OBJECTIVES: Cow's milk allergy (CMA) is the most common food allergy in children with many clinical manifestations, leading to misdiagnoses such as gastro oesophageal reflux, infantile colic, and lactose intolerance with inappropriate prescribing. We aimed to determine the impact of infant feeding guidelines on CMA prescribing in UK primary care using a simple and inexpensive training package. METHODS: Prospectively collected data of infant feeding prescriptions in Northern Ireland from June 2012 to March 2014 were analysed with the intervention period between November 2012 and March 2013. A comparison was made between hypoallergenic formulae, appropriate for CMA, versus alternative prescriptions including antiregurgitation and colic products, lactose-free and partially hydrolysed milks, or infant Gaviscon. RESULTS: Comparing pre- and postintervention period, the total quantity of hypoallergenic formulae increased by 63.2% and alternative prescriptions decreased by 44.6% (P < 0.001). The total amount of all prescribed products decreased by 41.0% (P < 0.001). During the study period, the proportion of recommended CMA treatment increased from 3.4% before training to 9.8% in the short- and long-term follow-up (P < 0.001). The overall increase was L33,508 per year or L95.5 per general practitioner's surgery. CONCLUSIONS: We present the first study evaluating the impact of infant feeding guidelines on CMA prescribing in UK primary care. Practical advice and teaching of health professionals allowed for effective implementation of regional and national guidelines, with a significant impact on prescription patterns. This study shows promising results for prospective research on a national scale, including socioeconomical impact and cost-effectiveness. PMID- 26628441 TI - Epigenetics in Paediatric Gastroenterology, Hepatology, and Nutrition: Present Trends and Future Perspectives. AB - Epigenetics can be defined as stable, potentially heritable changes in the cellular phenotype caused by mechanisms other than alterations to the underlying DNA sequence. As such, any observed phenotypic changes including organ development, aging, and the occurrence of disease could be driven by epigenetic mechanisms in the presence of stable cellular DNA sequences. Indeed, with the exception of rare mutations, the human genome-sequence has remained remarkably stable over the past centuries. In contrast, substantial changes to our environment as part of our modern life style have not only led to a significant reduction of certain infectious diseases but also seen the exponential increase in complex traits including obesity and multifactorial diseases such as autoimmune disorders. It is becoming increasingly clear that epigenetic mechanisms operate at the interface between the genetic code and our environment, and a large body of existing evidence supports the importance of environmental factors such as diet and nutrition, infections, and exposure to toxins on human health. This seems to be particularly the case during vulnerable periods of human development such as pregnancy and early life. Importantly, as the first point of contact for many of such environmental factors including nutrition, the digestive system is being increasingly linked to a number of "modern" pathologies. In this review article, we aim to give a brief introduction to the basic molecular principals of epigenetics and provide a concise summary of the existing evidence for the role of epigenetic mechanisms in gastrointestinal health and disease, hepatology, and nutrition. PMID- 26628442 TI - Health-related Quality of Life in Infants With Chronic Liver Disease. AB - OBJECTIVE: The objective of the present study was to report on the health-related quality of life (HRQOL) of infants with chronic liver disease using the PedsQL (Pediatric Quality of Life Inventory) Infant Scales. METHODS: The 36-item (ages 1 12 months) and 45-item (ages 13-24 months) PedsQL Infant Scales (physical functioning, physical symptoms, emotional functioning, social functioning, cognitive functioning) were completed by 50 parents of infants with chronic liver disease. RESULTS: Infants ages 1 to 12 months had significantly lower HRQOL scores compared with a matched healthy sample. Infants 13 to 24 months trended to lower physical HRQOL scores that did not reach statistical significance. Recent hospitalizations had an impact on the majority of HRQOL subscales, as did ascites, and failure to thrive. CONCLUSIONS: Infants ages 1 to 12 months with chronic liver disease demonstrate lower HRQOL compared with healthy children with physical subscales being most severely affected. The PedsQL Infant Scales allow the definition of HRQOL during a critical period of an infants' development that has been heretofore difficult to measure. PMID- 26628443 TI - More Target, More Treatment. PMID- 26628444 TI - Occult Blood and Perianal Examination. PMID- 26628445 TI - Intensive, Manual-based Intervention for Pediatric Feeding Disorders: Results From a Randomized Pilot Trial. AB - OBJECTIVES: The aim of this pilot study was to investigate feasibility and preliminary efficacy of an intensive, manual-based behavioral feeding intervention for children with chronic food refusal and dependence on enteral feeding or oral nutritional formula supplementation. METHODS: Twenty children ages 13 to 72 months (12 boys and 8 girls) meeting criteria for avoidant/restrictive food intake disorder were randomly assigned to receive treatment for 5 consecutive days in a day treatment program (n = 10) or waitlist (n = 10). A team of trained therapists implemented treatment under the guidance of a multidisciplinary team. Parent training was delivered to support generalization of treatment gains. We tracked parental attrition and attendance, as well as therapist fidelity. Primary outcome measures were bite acceptance, disruptions, and grams consumed during meals. RESULTS: Caregivers reported high satisfaction and acceptability of the intervention. Three participants (1 intervention; 2 waitlist) dropped out of the study before endpoint. Of the expected 140 treatment meals for the intervention group, 137 (97.8%) were actually attended. The intervention group showed significantly greater improvements (P < 0.05) on all primary outcome measures (d = 1.03-2.11) compared with waitlist (d = -1.13-0.24). A 1-month follow-up suggested stability in treatment gains. CONCLUSIONS: Results from this pilot study corroborate evidence from single-subject and nonrandomized studies on the positive effects of behavioral intervention. Findings support the feasibility and preliminary efficacy of this manual-based approach to intervention. These results warrant a large-scale randomized trial to test the safety and efficacy of this intervention. PMID- 26628446 TI - Helicobacter pylori Infection and Children's Growth: An Overview. AB - OBJECTIVES: Helicobacter pylori infection is acquired in early childhood, yet its role in children's health is still not fully clear. In this narrative review, we focused on the association between H pylori infection and children's growth. METHODS: A literature search of the Ovid MEDLINE (till June 2015) and EMBASE (till August 2015) databases was performed using the terms "Helicobacter pylori, growth, body height, growth disorders and child development." Original studies that addressed the association between H pylori infection or eradication and children's growth were reviewed and the risk of bias of each study was assessed. RESULTS: The existing evidence is based on observational studies (N = 48) and suggests that H pylori infection may adversely influence children's growth; findings were more consistent across studies with low risk of bias. Regarding linear growth, observational studies have repeatedly linked between H pylori infection and slower or diminished linear growth; yet, it is not known whether this association is causal. The association between H pylori infection and ponderal growth has been less consistent. Scarce evidence exists on the effect of H pylori eradication on children's skeletal growth and weight gain, but there is an indication that H pylori eradication may benefit nutritional status. CONCLUSIONS: H pylori infection may impair children's growth. Additional studies, especially clinical trials, are needed to elucidate the role of H pylori eradication in children's growth, and the mechanisms that may be involved in such. PMID- 26628447 TI - Serum Autotaxin Activity Correlates With Pruritus in Pediatric Cholestatic Disorders. AB - OBJECTIVE: Pruritus is a common symptom of cholestatic liver disorders. The present study aimed at evaluating autotaxin (ATX), a lysophospholipase recently identified as potential cause for cholestatic pruritus, in pediatric cholestatic diseases presenting with or without itching. METHODS: A cohort of 45 children consisting of 14 patients experiencing itching (Alagille syndrome [n = 10], complete extrahepatic biliary atresia [n = 2], neonatal sclerosing cholangitis (n = 1), progressive familial intrahepatic cholestasis type 2 [n = 1]), 9 patients with bile acid synthesis defects (3beta-hydroxy-C27-steroid-oxidoreductase [n = 7] and Delta-3-oxosteroid-5beta-reductase deficiency [n = 2]), and 22 healthy children were studied. Serum ATX activity and total serum bile salt were determined enzymatically, ATX protein content was semiquantified by Western blotting. Using real-time polymerase chain reaction, ATX mRNA expression was studied in HepG2 cells treated with farnesoid-X-receptor agonists or vehicle. RESULTS: Serum ATX activity was increased in pruritic children with Alagille and other cholestatic syndromes (mean +/- standard deviation: 16.1 +/- 4.3 nmol . mL . min) compared with children with nonpruritic cholestatic diseases with bile acid synthesis defects (10.4 +/- 4.7 nmol . mL . min; P < 0.01) and healthy controls (7.6 +/- 2.3 nmol . mL . min; P < 0.001). ATX protein levels closely correlated with serum ATX activity. Serum ATX activity and total serum bile salt showed a linear correlation with itch intensity (r = 0.66, P < 0.001 and r = 0.80, P < 0.001, respectively). No correlation was observed between ATX activity and bilirubin. ATX mRNA expression in HepG2 cells was not induced by farnesoid-X receptor ligands. CONCLUSIONS: Serum ATX activity correlated with itch intensity in children with cholestatic diseases. Bile salts did not increase ATX expression in vitro. ATX inhibitors may be useful antipruritic agents in pediatric cholestatic disorders. PMID- 26628448 TI - Validation of a Nutritional Screening Tool for Ambulatory Use in Pediatrics. AB - OBJECTIVES: To evaluate the use of Screening Tool for the Assessment of Malnutrition in Pediatrics (STAMP) in a primary health care clinic in the community and to assess the impact of its use on medical staff's awareness of nutritional status. METHODS: STAMP scoring system was tested as is and with modifications in the ambulatory setting. Nutritional risk according to STAMP was compared with a detailed nutritional assessment performed by a registered dietitian. Recording of nutrition-related data and anthropometric measurements in medical files were compared prior and post implementation. RESULTS: Sixty children were included (31 girls, 52%), ages between 1 and 6 years, mean age 2.8 +/- 1.5 (mean +/- SD). STAMP scores yielded a fair agreement between STAMP and the dietitian's nutritional assessment: kappa = 0.47 (95% confidence interval [CI] 0.24-0.7), sensitivity of 47.62% (95% CI 28.34-67.63). Modified STAMP yielded more substantial agreement: kappa = 0.57 (95% CI 0.35-0.79), sensitivity of 76.19% (95% CI 54.91-89.37), specificity of 82.05% (95% CI 67.33-91.02). The use of STAMP resulted in an increase in recording of appetite, dietary intake, and anthropometric measurements. CONCLUSIONS: Modification of the STAMP improved nutritional risk evaluation in community setting. The use of STAMP in a primary health care clinic raised clinician's awareness to nutritional status. Further work will identify whether this could be translated into lower malnutrition rates and better child care. PMID- 26628449 TI - Double-balloon Enteroscopy for Pediatric Patients: Evaluation of Safety and Efficacy in 257 Cases. AB - OBJECTIVES: The safety and efficacy of double-balloon enteroscopy (DBE) in pediatric patients has not been well documented. We aimed to evaluate the clinical efficacy and safety of DBE in children, especially those under 10. METHODS: We retrospectively analyzed our database of DBE procedures performed between September 2000 and September 2013. Procedures performed in pediatric patients (under 18) were selected from a total of 3980, including double-balloon endoscopic retrograde cholangioscopy (DBERC). RESULTS: Two hundred fifty-seven DBE procedures were performed in 117 pediatric patients (median age 12.5 years). Antegrade (oral-route) DBE was performed in 166 procedures including 104 DBERC procedures (lowest body weight 13.5 kg, youngest age 3 years), and retrograde (anal-route) DBE in 91 (lowest body weight 12.0 kg, youngest age 2 years). The overall diagnostic yield for obscure gastrointestinal bleeding and abdominal pain was 58.8%. The purpose of DBERC was achieved in 76.9% of procedures. The overall complication rate in our series was 5.4% (1.9% with the DBERC cases removed); in patients under 10, it was 10.4% (7/67). No severe complications associated with enteroscope insertion and sedation were observed. Serum amylase levels tended to be elevated in patients who underwent oral-route DBE. CONCLUSIONS: DBE is safe and feasible for diagnostic evaluation of small bowel disorders in pediatric patients, even those younger than 10 years. Special attention for possible complications must, however, be paid during therapeutic DBE procedures, including DBERC, especially for patients under 10. PMID- 26628450 TI - Microscopic Assessment in Inflammatory Bowel Disease: The More the Merrier? PMID- 26628451 TI - Successful intubation of a difficult airway due to a large obstructive vocal cord polyp augmented by the delivery of a transtracheal injection of local anaesthetic. AB - We describe a case of a very difficult intubation which was safely navigated through careful planning. Our patient presented initially with increasing hoarseness and shortness of breath over a 6-month period. This was investigated and the patient was found to have a large vocal cord mass and was referred for urgent microlaryngoscopy and vocal cord polypectomy. On the day of surgery the obstruction was noted and awake fiberoptic bronchoscopy was used with a remifentanil infusion. Given the mass was large and increased in size with expiration, the time frame to pass the tube was extremely short. We delivered a transtracheal injection of local anaesthesia. This approach allowed for safe passage of the endotracheal tube. In patients such as this it may be worth considering the use of a transtracheal injection in the first instance. PMID- 26628452 TI - A case of acquired laryngomalacia in an infant, with endoscopy before and after establishing the diagnosis for the first time. AB - A 12-week-old infant girl born at 27 weeks gestation, with multiple comorbidities, was referred to the paediatric otolaryngology team due to stridor and feeding difficulties. Initial airway endoscopy was performed, showing no abnormal findings. The infant underwent frequent hospitalisations for recurrent cyanotic spells. Despite initial laryngoscopy and bronchoscopy not showing abnormalities, a repeat endoscopy demonstrated laryngomalacia, significant enough to require a supraglottoplasty. This is the first report to confirm, with video evidence, that some cases of laryngomalacia are acquired rather than congenital, even in infancy. PMID- 26628453 TI - Flow diverter placement for management of dissecting ruptured aneurysm in a non fused basilar artery. AB - Intracranial vertebral artery dissection can be associated with subarachnoid hemorrhage (SAH) and pseudoaneurysm formation. Dissecting aneurysms have a high risk of rebleeding in the acute phase. To our knowledge, the management of an acute vertebrobasilar junction dissecting aneurysm associated with a basilar non fusion has not been previously reported. We report here a case of SAH due to rupture of a dissecting aneurysm involving the vertebrobasilar junction and extending to involve the right limb and proximal junction of a non-fused basilar artery, managed by insertion of a flow-diverting stent with excellent clinical outcome and long-term patency of the flow diverter. PMID- 26628454 TI - Direct carotid-cavernous fistulas occurring during neurointerventional procedures. AB - This study shows the frequency and types of carotid-cavernous fistula (CCF) complications that occurred during endovascular treatment. Transarterial endovascular surgeries involving the anterior circulation were performed for 1071 cases at our hospitals during four years. CCFs occurred in nine of 1071 cases (0.8%). CCF risk factors were female sex (p=0.032), aneurysmal location in the paraclinoid portion (p<0.001), and use of a distal access catheter (DAC) (p<0.001). There were no significant correlations between CCF risk and procedure type (p=0.411-1.0) and balloon use or nonuse (p=0.492). Eighty-nine percent (eight of nine) of the CCFs occurred at the genu of a cavernous internal carotid artery (ICA). Two cases of CCF disappeared spontaneously. The shunt was decreased by balloon expansion in one case, no additional treatment was required in one case, and five cases required transarterial fistula coil embolization. It is necessary to remember that a CCF may occur especially in aneurysmal treatment using a DAC in a female patient. The DAC and the 0.035-inch guidewire should be kept proximal to the carotid siphon and not go beyond it. When we cannot avoid navigating beyond it, we should consider using a softer DAC. In the case of a CCF caused by a DAC, it may be cured spontaneously or is treatable by transarterial coil embolization. PMID- 26628455 TI - Successful endovascular treatment of a dissecting aneurysm of vertebral artery associated with double origin of the posterior inferior cerebellar artery. AB - BACKGROUND: Double origin of the posterior inferior cerebellar artery (DOPICA) has been rarely reported in the literature, with a reported incidence of 1.45%. In contrast, a high concurrence rate of DOPICA and vertebral artery dissecting aneurysm has been reported. CLINICAL PRESENTATION: A 61-year old woman presented with vomiting and diplopia with preceding headache. Magnetic resonance imaging (MRI) showed fresh infarction of the left lateral medulla and a vertebral artery dissecting aneurysm of the left vertebral artery. The next day, she exhibited transient loss of consciousness and worsening of headache, and MRI depicted subarachnoid hemorrhage. Four-vessel digital subtraction angiography showed a posterior inferior cerebellar artery (PICA) arising both intracranially and extracranially from the left vertebral artery. Although the dissecting lesion involved the V3 and V4 portion, it did not involve an extracranially originating PICA. Internal trapping of the V3 and V4 portion was chosen as the extracranial channel was expected to supply the PICA territory. This procedure was safely performed. CONCLUSION: Early endovascular intervention should be considered in the treatment of dissecting aneurysm of vertebral artery associated with DOPICA for patients with relatively long lesions even in unruptured cases. PMID- 26628456 TI - Inferior petrosal sinus route microcatheterization study and embolization for primary orbital varix. AB - PURPOSE: Primary orbital varix is a rare lesion but difficult to treat. Our main aim was to demonstrate the varices and their central venous communication and to explore the feasibility of embolization of these lesions. METHOD: In four patients with clinical suspicion of varix, in whom MRI showed retro-global vascular channels, microcatheter digital subtraction angiography (DSA) of the varices was performed using femoral venous access. Embolization was carried out in two patients. RESULTS: In all four patients orbital varices could be accessed with a microcatheter through inferior petrosal sinus and ophthalmic vein (superior or inferior) route. Microcatheter angiography showed opacification of varices and demonstrated their central venous communication. Two patients were treated with coil embolization. Complete resolution of symptoms was seen in one patient and partial relief in the other. CONCLUSION: The study presents microcatheterization of orbital varices via the inferior petrosal sinus-cavernous sinus-ophthalmic vein route with injections into distal ophthalmic veins for demonstration of these variceal sacs and their central venous connection. Coiling to disconnect the venous communication should be the primary goal of embolization. PMID- 26628457 TI - Metal coverage ratio of pipeline embolization device for treatment of unruptured aneurysms: Reality check. AB - BACKGROUND AND PURPOSE: The metal coverage ratio (MCR) of a flow diverter influences the intra-aneurysmal hemodynamics; a high MCR will occlude an aneurysm early, while a low MCR may delay aneurysm occlusion. The true MCR of a pipeline embolization device (PED) could be lower due to oversize, device deformation, or aneurysm location. In this study deviation of the true MCR from the nominal MCR is assessed and whether their difference affects aneurysm occlusion rate is determined. METHODS: A total of 40 consecutive patients, each of them treated by one PED for their aneurysms at the internal carotid artery (ICA), were retrospectively analyzed. The DynaCT images of these deployed PEDs were used to determine their true dimensions and estimate three MCRs (local, mean, and nominal). These data were compared in two groups of patients who had different aneurysm outcomes at six months. RESULTS: The difference in the local MCR between two groups is small, but statistically significant (24.5% vs 21.6%, p=05). The local MCR is consistently lower than the nominal MCRs (23.2% vs 30.2%, p<0.001); however, the difference between the mean and local MCRs is small (23.9% vs 23.2%). CONCLUSIONS: An expectation that a PED can achieve a MCR of 30% may not be reasonable. Device oversize and deformation during deployment lower the local MCR by 5-7%. A lowered MCR affects the aneurysm occlusion rate at six months. PMID- 26628458 TI - PrEP on demand cuts HIV transmission in high risk men, study finds. PMID- 26628461 TI - Using venous blood gas analysis in the assessment of COPD exacerbations: a prospective cohort study. AB - INTRODUCTION: Identifying acute hypercapnic respiratory failure is crucial in the initial management of acute exacerbations of COPD. Guidelines recommend obtaining arterial blood samples but these are more difficult to obtain than venous. We assessed whether blood gas values derived from venous blood could replace arterial at initial assessment. METHODS: Patients requiring hospital treatment for an exacerbation of COPD had paired arterial and venous samples taken. Bland Altman analyses were performed to assess agreement between arterial and venous pH, CO2 and HCO3-. The relationship between SpO2 and SaO2 was assessed. The number of attempts and pain scores for each sample were measured. RESULTS: 234 patients were studied. There was good agreement between arterial and venous measures of pH and HC)3- (mean difference 0.03 and -0.04, limits of agreement 0.05 to 0.11 and -2.90 to 2.82, respectively), and between SaO2 and SpO2 (in patients with an SpO2 of >80%). Arterial sampling required more attempts and was more painful than venous (mean pain score 4 (IQR 2-5) and 1 (IQR 0-2), respectively, p<0.001). CONCLUSIONS: Arterial sampling is more difficult and more painful than venous sampling. There is good agreement between pH and HCO3- values derived from venous and arterial blood, and between pulse oximetry and arterial blood gas oxygen saturations. These agreements could allow the initial assessment of COPD exacerbations to be based on venous blood gas analysis and pulse oximetry, simplifying the care pathway and improving the patient experience. PMID- 26628462 TI - Reply to S. Iwase et al. PMID- 26628463 TI - Hematologic Malignancies in Pregnancy: Management Guidelines From an International Consensus Meeting. AB - PURPOSE: The incidence of hematologic malignancies during pregnancy is 0.02%. However, this figure is increasing, as women delay conception until a later age. Systemic symptoms attributed to the development of a hematologic cancer may overlap with physiologic changes of pregnancy. A favorable prognosis is contingent upon early diagnosis and treatment. Therefore, a high index of suspicion is required by health care providers. Although timely, accurate diagnosis followed by appropriate staging is essential and should not be delayed due to pregnancy, management guidelines are lacking due to insufficient evidence based research. Consequently, treatment is delayed, posing significant risks to maternal and fetal health, and potential pregnancy termination. This report provides guidelines for clinical management of hematologic cancers during the perinatal period, which were developed by a multidisciplinary team including an experienced hematologist/oncologist, a high-risk obstetrics specialist, a neonatologist, and experienced nurses, social workers, and psychologists. METHODS: These guidelines were developed by experts in the field during the first International Consensus Meeting of Prenatal Hematologic Malignancies, which took place in Leuven, Belgium, on May 23, 2014. RESULTS AND CONCLUSION: This consensus summary equips health care professionals with novel diagnostic and treatment methodologies that aim for optimal treatment of the mother, while protecting fetal and pediatric health. PMID- 26628464 TI - When Patients Leave. PMID- 26628465 TI - Preoperative Breast Magnetic Resonance Imaging and Contralateral Breast Cancer Occurrence Among Older Women With Breast Cancer. AB - PURPOSE: Preoperative magnetic resonance imaging (MRI) detects occult contralateral breast cancers (CBCs) in women with breast cancer, but the impact of detection on long-term CBC events is unclear. We examined whether MRI use decreases the occurrence of CBCs and the detection of stages II to IV disease among women who develop a CBC. PATIENTS AND METHODS: Analyzing the SEER-Medicare database, we assessed overall, synchronous (< 6 months after primary cancer diagnosis), and subsequent (ie, metachronous) stage-specific CBC occurrences in women who were diagnosed with stages I and II breast cancer during 2004-2009 and who were observed through 2011. RESULTS: Among 38,971 women with breast cancer, 6,377 (16.4%) received preoperative MRI. After propensity score matching, and compared with women who did not undergo MRI, preoperative MRI use was significantly associated with a higher synchronous CBC detection rate (126.4 v 42.9 per 1,000 person-years, respectively; hazard ratio, 2.85; P < .001) but a lower subsequent CBC detection rate (3.3 v 4.5 per 1,000 person-years, respectively; hazard ratio, 0.68; P = .002). However, the 5-year cumulative incidence of CBC remained significantly higher among women undergoing MRI compared with those not undergoing MRI (7.2% v 4.0%, respectively; P < .001). The analyses of projected CBC events for 10,000 patients who receive MRI indicated that, after a 5-year follow-up, MRI use would detect an additional 192 in situ CBCs (95% CI, 125 to 279) and 120 stage I CBCs (95% CI, 62 to 193) but would not have a significant impact on stages II to IV CBC occurrences (~ 6; 95% CI, -21 to 47). CONCLUSION: An increased synchronous CBC detection rate, attributable to MRI, was not offset by a decrease of subsequent CBC occurrence among older women with early-stage breast cancer, suggesting that preoperative MRI in women with breast cancer may lead to overdiagnosis. PMID- 26628466 TI - Outcomes After Stereotactic Body Radiotherapy or Radiofrequency Ablation for Hepatocellular Carcinoma. AB - PURPOSE: Data guiding selection of nonsurgical treatment of hepatocellular carcinoma (HCC) are lacking. We therefore compared outcomes between stereotactic body radiotherapy (SBRT) and radiofrequency ablation (RFA) for HCC. PATIENTS AND METHODS: From 2004 to 2012, 224 patients with inoperable, nonmetastatic HCC underwent RFA (n = 161) to 249 tumors or image-guided SBRT (n = 63) to 83 tumors. We applied inverse probability of treatment weighting to adjust for imbalances in treatment assignment. Freedom from local progression (FFLP) and toxicity were retrospectively analyzed. RESULTS: RFA and SBRT groups were similar with respect to number of lesions treated per patient, type of underlying liver disease, and tumor size (median, 1.8 v 2.2 cm in maximum diameter; P = .14). However, the SBRT group had lower pretreatment Child-Pugh scores (P = .003), higher pretreatment alpha-fetoprotein levels (P = .04), and a greater number of prior liver-directed treatments (P < .001). One- and 2-year FFLP for tumors treated with RFA were 83.6% and 80.2% v 97.4% and 83.8% for SBRT. Increasing tumor size predicted for FFLP in patients treated with RFA (hazard ratio [HR], 1.54 per cm; P = .006), but not with SBRT (HR, 1.21 per cm; P = .617). For tumors >= 2 cm, there was decreased FFLP for RFA compared with SBRT (HR, 3.35; P = .025). Acute grade 3+ complications occurred after 11% and 5% of RFA and SBRT treatments, respectively (P = .31). Overall survival 1 and 2 years after treatment was 70% and 53% after RFA and 74% and 46% after SBRT. CONCLUSION: Both RFA and SBRT are effective local treatment options for inoperable HCC. Although these data are retrospective, SBRT appears to be a reasonable first-line treatment of inoperable, larger HCC. PMID- 26628467 TI - Associations of Breast Cancer Risk Prediction Tools With Tumor Characteristics and Metastasis. AB - PURPOSE: The association between established risk factors for breast cancer and subtypes or prognosis of the disease is not well known. We analyzed whether the Tyrer-Cuzick-predicted 10-year breast cancer risk score (TCRS), mammographic density (MD), and a 77-single nucleotide polymorphism polygenic risk score (PRS) were associated with breast cancer tumor prognosticators and risk of distant metastasis. PATIENTS AND METHODS: We used a case-only design in a population based cohort of 5,500 Swedish patients with breast cancer. Logistic and multinomial logistic regression of outcomes, estrogen receptor (ER) status, lymph node involvement, tumor size, and grade was performed with TCRS, PRS, and percent MD as exposures. Cox proportional hazard models were used to estimate hazard ratios (HRs) of distant metastasis. RESULTS: Women at high risk for breast cancer based on PRS and/or TCRS were significantly more likely to be diagnosed with favorable prognosticators, such as ER-positive and low-grade tumors. In contrast, PRS weighted on ER-negative disease was associated with ER-negative tumors. When stratifying by age, the associations of TCRS with favorable prognosticators were restricted to women younger than age 50. Women scoring high in both TCRS and PRS had a lower risk of distant metastasis (HR, 0.69; 95% CI, 0.49 to 0.98). MD was not associated with any of the examined prognosticators. CONCLUSION: Women at high risk for breast cancer based on genetic and lifestyle factors were significantly more likely to be diagnosed with breast cancers with a favorable prognosis. Better knowledge of subtype-specific risk factors could be vital for the success of prevention programs aimed at lowering mortality. PMID- 26628468 TI - Reply to M.C. Chamberlain. PMID- 26628469 TI - Survival Impact of Increasing Time to Treatment Initiation for Patients With Head and Neck Cancer in the United States. AB - PURPOSE: To estimate the overall survival (OS) impact from increasing time to treatment initiation (TTI) for patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Using the National Cancer Data Base (NCDB), we examined patients who received curative therapy for the following sites: oral tongue, oropharynx, larynx, and hypopharynx. TTI was the number of days from diagnosis to initiation of curative treatment. The effect of TTI on OS was determined by using Cox regression models (MVA). Recursive partitioning analysis (RPA) identified TTI thresholds via conditional inference trees to estimate the greatest differences in OS on the basis of randomly selected training and validation sets, and repeated this 1,000 times to ensure robustness of TTI thresholds. RESULTS: A total of 51,655 patients were included. On MVA, TTI of 61 to 90 days versus less than 30 days (hazard ratio [HR], 1.13; 95% CI, 1.08 to 1.19) independently increased mortality risk. TTI of 67 days appeared as the optimal threshold on the training RPA, statistical significance was confirmed in the validation set (P < .001), and the 67-day TTI was the optimal threshold in 54% of repeated simulations. Overall, 96% of simulations validated two optimal TTI thresholds, with ranges of 46 to 52 days and 62 to 67 days. The median OS for TTI of 46 to 52 days or fewer versus 53 to 67 days versus greater than 67 days was 71.9 months (95% CI, 70.3 to 73.5 months) versus 61 months (95% CI, 57 to 66.1 months) versus 46.6 months (95% CI, 42.8 to 50.7 months), respectively (P < .001). In the most recent year with available data (2011), 25% of patients had TTI of greater than 46 days. CONCLUSION: TTI independently affects survival. One in four patients experienced treatment delay. TTI of greater than 46 to 52 days introduced an increased risk of death that was most consistently detrimental beyond 60 days. Prolonged TTI is currently affecting survival. PMID- 26628471 TI - Mapisal Versus Urea Cream as Prophylaxis for Capecitabine-Associated Hand-Foot Syndrome. PMID- 26628470 TI - Complete Surgical Excision Is Essential for the Management of Patients With Breast Implant-Associated Anaplastic Large-Cell Lymphoma. AB - PURPOSE: Breast implant-associated anaplastic large-cell lymphoma (BI-ALCL) is a rare type of T-cell lymphoma that arises around breast implants. The optimal management of this disease has not been established. The goal of this study is to evaluate the efficacy of different therapies used in patients with BI-ALCL to determine an optimal treatment approach. PATIENTS AND METHODS: In this study, we applied strict criteria to pathologic findings, assessed therapies used, and conducted a clinical follow-up of 87 patients with BI-ALCL, including 50 previously reported in the literature and 37 unreported. A Prentice, Williams, and Peterson model was used to assess the rate of events for each therapeutic intervention. RESULTS: The median and mean follow-up times were 45 and 30 months, respectively (range, 3 to 217 months). The median overall survival (OS) time after diagnosis of BI-ALCL was 13 years, and the OS rate was 93% and 89% at 3 and 5 years, respectively. Patients with lymphoma confined by the fibrous capsule surrounding the implant had better event-free survival (EFS) and OS than did patients with lymphoma that had spread beyond the capsule (P = .03). Patients who underwent a complete surgical excision that consisted of total capsulectomy with breast implant removal had better OS (P = .022) and EFS (P = .014) than did patients who received partial capsulectomy, systemic chemotherapy, or radiation therapy. CONCLUSION: Surgical management with complete surgical excision is essential to achieve optimal EFS in patients with BI-ALCL. PMID- 26628472 TI - Harmonization of Renal Function Assessment Is Needed During Early Clinical Development of Oncology Drugs. PMID- 26628473 TI - Radiation of the Internal Mammary Nodes: Is There a Benefit? PMID- 26628474 TI - Intermittent Androgen Deprivation in Prostate Cancer: Are We Ready to Quit? PMID- 26628475 TI - CNS Metastases in Patients With Non-Small-Cell Lung Cancer and ALK Gene Rearrangement. PMID- 26628476 TI - Minimizing Cardiac Risks With Contemporary Radiation Therapy for Hodgkin Lymphoma. PMID- 26628477 TI - Similar Trials With Differing Outcomes: Reconciliation in Glioblastoma. PMID- 26628479 TI - Corrigendum. PMID- 26628480 TI - More computer use during consultations is linked to lower patient satisfaction. PMID- 26628481 TI - Alcohol Use Predicts 10-Year Depressive Symptom Trajectories in the Health and Retirement Study. AB - OBJECTIVE: To determine effects of late-middle-aged adults' baseline drinking behavior on their subsequent 10-year depressive symptom trajectories. METHOD: Health and Retirement Study participants (N = 7,939) were assessed on baseline demographic, health, and drinking characteristics, and biennially assessed for the next 10 years on their depressive symptoms. RESULTS: Growth mixture modeling generated four classes of depressive symptom trajectories: Consistently low (72%), consistently elevated (6%), increasing (12%), and decreasing (10%). Baseline abstinence from alcohol, possibly enforced by poorer health and a history of drinking problems, and heavier drinking, "binge" drinking, and having a history of drinking problems, raised risk of membership in the "consistently elevated" class. Abstinence by participants without history of drinking problems and light, moderate, and heavier drinking-protected against membership in the "increasing" class. Abstinence by participants without history of drinking problems elevated-and moderate drinking reduced-likelihood of membership in the "decreasing" class. DISCUSSION: Late-middle-aged adults' alcohol use is associated with the subsequent long-term course of their depressive symptoms. PMID- 26628483 TI - Severe post-treatment leukopenia associated with the development of encephalopathy following ifosfamide infusion. AB - Ifosfamide has been shown to be associated with encephalopathy in 10-40% of patients. Although it is a well-documented toxicity associated with ifosfamide therapy, an anecdotal upsurge in its occurrence at our institution prompted us to review ifosfamide usage. A 1-year single-center retrospective study was performed to assess the incidence of and potential risk factors for ifosfamide-induced encephalopathy (IIE). A total of 28 inpatients received ifosfamide-based chemotherapy over 47 separate treatment sessions. During those treatment sessions, seven cases of IIE (14.9%) were observed, which presented a significant increase compared with historical data from our institution (<=3.3%). On the basis of these data, we switched from the ifosfamide product made from Sicor's liquid formulation for injection to that made from a different manufacturer's powder formulation for injection in 2010. Since this switch in the ifosfamide formulation was made, we have observed a reduction in the rate and severity of IIE at our institution. It is noteworthy that the infusions associated with encephalopathy showed a significantly higher degree of post-treatment leukopenia compared with those that did not. In the absence of chromatography analysis and/or potency analysis, we could not definitely attribute the high rate of IIE observed in our study to the liquid ifosfamide formulation; nevertheless, practitioners should be more vigilant about unexpected rates of chemotherapy adverse events when switching to a different manufacturer's product. We have also observed an association between severe post-treatment leukopenia and the development of IIE, which has not been reported previously. PMID- 26628478 TI - Lapatinib in Combination With Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma: TRIO-013/LOGiC--A Randomized Phase III Trial. AB - PURPOSE: To evaluate the efficacy of adding lapatinib to capecitabine and oxaliplatin (CapeOx) in patients with previously untreated human epidermal growth factor receptor 2 (HER2) -amplified advanced gastroesophageal adenocarcinoma. PATIENTS AND METHODS: Patients with HER2-positive advanced gastroesophageal adenocarcinoma were randomly assigned at a one-to-one ratio to CapeOx plus lapatinib 1,250 mg or placebo daily. Primary end point was overall survival (OS) in patients with centrally confirmed HER2 amplification in the primary efficacy population. RESULTS: A total of 545 patients were randomly assigned, and 487 patients comprised the primary efficacy population. Median OS in the lapatinib and placebo arms was 12.2 (95% CI, 10.6 to 14.2) and 10.5 months (95% CI, 9.0 to 11.3), respectively, which was not significantly different (hazard ratio, 0.91; 95% CI, 0.73 to 1.12). Median progression-free survival in the lapatinib and placebo arms was 6.0 (95% CI, 5.6 to 7.0) and 5.4 months (95% CI, 4.4 to 5.7), respectively (hazard ratio, 0.82; 95% CI, 0.68 to 1.00; P = .0381). Response rate was significantly higher in the lapatinib arm: 53% (95% CI, 46.4 to 58.8) compared with 39% (95% CI, 32.9 to 45.3) in the placebo arm (P = .0031). Preplanned exploratory subgroup analyses showed OS in the lapatinib arm was prolonged in Asian and younger patients. No correlation was observed between HER2 immunohistochemistry status and survival. There were increased toxicities in the lapatinib arm, particularly diarrhea. CONCLUSION: Addition of lapatinib to CapeOx did not increase OS in patients with HER2-amplified gastroesophageal adenocarcinoma. There were clear differences in the effect of lapatinib depending on region and age. Future studies could examine this correlation. PMID- 26628482 TI - Chromoanasynthetic Genomic Rearrangement Identified in a N-Ethyl-N-Nitrosourea (ENU) Mutagenesis Screen in Caenorhabditis elegans. AB - Chromoanasynthesis is a recently discovered phenomenon in humans with congenital diseases that is characterized by complex genomic rearrangements (CGRs) resulting from aberrant repair of catastrophic chromosomal damage. How these CGRs are induced is not known. Here, we describe the structure and function of dpDp667, a causative CGR that emerged from a Caenorhabditis elegans dauer suppressor screen in which animals were treated with the point mutagen N-ethyl-N-nitrosourea (ENU). dpDp667 comprises nearly 3 Mb of sequence on the right arm of the X chromosome, contains three duplications and one triplication, and is devoid of deletions. Sequences from three out of the four breakpoint junctions in dpDp667 reveal microhomologies that are hallmarks of chromoanasynthetic CGRs. Our findings suggest that environmental insults and physiological processes that cause point mutations may give rise to chromoanasynthetic rearrangements associated with congenital disease. The relatively subtle phenotype of animals harboring dpDp667 suggests that the prevalence of CGRs in the genomes of mutant and/or phenotypically unremarkable animals may be grossly underestimated. PMID- 26628484 TI - Subdural hematoma in a patient taking imatinib for GIST: a case report and discussion of risk with other chemotherapeutics. AB - Although anticancer drugs have existed for over 50 years, targeted drugs have only recently been marketed, and their side effects may not be completely understood. The patient is a 56-year-old woman with a gastrointestinal stromal tumor who presented with headache, nausea, and vomiting lasting 2 weeks. An MRI to rule out brain metastasis found a large right-hemispheric subdural hematoma without metastases. She denied trauma, seizures, or alcohol abuse. Laboratory test results were normal. Eight months prior, she had begun a dose escalation of imatinib, which became the suspected cause of her hemorrhage. The literature was reviewed for reports of intracranial hemorrhage with targeted chemotherapeutics excluding metastases, anticoagulation, and trauma. Multiple events have been documented but only one for imatinib with gastrointestinal stromal tumor. Imatinib is believed to cause platelet dysfunction (missed by standard testing), leading to intracranial hemorrhage. Intracranial hemorrhage risk may be under reported and neurosurgical consultation for immediate treatment and oncology for reinitiation of chemotherapy are recommended. PMID- 26628485 TI - Tobacco marketing hits poor countries hardest. PMID- 26628486 TI - Apoptosis in Early Salivary Gland Duct Morphogenesis and Lumen Formation. AB - Salivary glands are essential for the maintenance of oral health by providing lubrication and antimicrobial protection to the mucosal and tooth surfaces. Saliva is modified and delivered to the oral cavity by a complex multifunctional ductal system. During development, these ducts form as solid tubes, which undergo cavitation to create lumens. Apoptosis has been suggested to play a role in this cavitation process along with changes in cell polarity. Here, we show that apoptosis occurs from the very earliest stages of mouse salivary gland development, much earlier than previously reported. Apoptotic cells were observed in the center of the first epithelial stalk at early-stage embryonic day 12.5 (E12.5) according to both TUNEL staining and cleaved caspase 3 immunofluorescence. The presumptive lumen space was highlighted by the colocalization of a predictive lumen marker, cytokeratin 7. At E14.5, as lumens start to form throughout the glands, apoptotic expression decreased while cytokeratin 7 remained positive. In vitro inhibition of all caspases in E12.5 and E13.5 salivary glands resulted in wider ducts, as compared with the controls, and a defect in lumen formation. In contrast, no such defect in lumen formation was observed at E14.5. Our data indicate that apoptosis is involved during early stages of gland formation (E12.5 onward) and appears important for shaping the forming ducts. PMID- 26628487 TI - Chronic CSF leak causing syringomyelia and pseudo-Arnold-Chiari malformation. PMID- 26628488 TI - Lou Gehrig and the ALS split hand. PMID- 26628489 TI - Owl's eye sign: A rare neuroimaging finding in flail arm syndrome. PMID- 26628490 TI - Epilepsy after aneurysmal subarachnoid hemorrhage: A population-based, long-term follow-up study. PMID- 26628491 TI - Migraine prevention with a supraorbital transcutaneous stimulator: A randomized controlled trial. PMID- 26628492 TI - Pearls & Oy-sters: Cerebral venous sinus thrombosis involving a persistent falcine sinus. PMID- 26628493 TI - Clinical Reasoning: A 48-year-old man with walking difficulty. PMID- 26628494 TI - Clinical Reasoning: Juvenile neurocognitive decline: A "snaky" diagnosis. PMID- 26628495 TI - Tobacco retail outlet density and risk of youth smoking in New Zealand. AB - INTRODUCTION: Evidence suggests inconsistent findings on the relationship between density of tobacco outlets around schools and risk of smoking among students. This study examines the density of tobacco outlets around secondary schools in New Zealand (NZ) and current smoking, experimental smoking, susceptibility to smoking, and attempted and successful tobacco purchasing. METHODS: Smoking data came from the 2012 ASH Year 10 survey, a national survey of youth smoking in NZ. Geographic Information Systems were used to map tobacco retail outlets; a layer of secondary school locations was obtained from Koordinates.com. Logistic regression examined the relationship between density of outlets around schools and smoking behaviours, adjusting for individual-level and school-level confounders. RESULTS: Of the 27 238 students surveyed, 3.5% (952) were current smokers, 4.1% (n=1 128) were experimental smokers, and 39.8% (10 454) of nonsmokers were susceptible to smoking. An inverse relationship was found between the density of tobacco retail outlets and current smoking. Current smokers were significantly more likely to attempt to purchase tobacco if the density of tobacco retail outlets around their school was high. Non-smoking students were more likely to be susceptible to smoking if the density of tobacco outlets around their school was high. There was no statistically significant association between density of tobacco outlets and successful purchasing, nor experimental smoking. CONCLUSIONS: Restricting the permitted density of tobacco retail outlets around schools should be part of comprehensive tobacco control. In this regard, both smokers and non-smokers support the introduction of increased regulation of the tobacco retail environment to achieve our national smoke-free 2025 goal. PMID- 26628496 TI - Adolescents' and adults' perceptions of 'natural', 'organic' and 'additive-free' cigarettes, and the required disclaimers. AB - OBJECTIVES: We sought to investigate adolescents' and adults' perceptions of an American Spirit advertisement with 'natural', 'organic' and 'additive-free' descriptors and related disclaimers. METHODS: We conducted nine focus group discussions in the Southern USA, with 59 participants aged 13-64 years (30 male, 29 female), stratified by age, smoking status and susceptibility to smoking. We conducted thematic content analysis of the transcripts. RESULTS: Many participants were sceptical or confused about the 'natural', 'organic' and 'additive-free' descriptors. Many participants viewed American Spirit cigarettes as being less, or possibly less harmful than other cigarettes, even though the ad contained disclaimers explicitly stating that these cigarettes are not safer. Some participants said that people tend to ignore disclaimers, a few expressed doubt that the disclaimers were fully true, and others did not notice the disclaimers. A few smokers said they smoke American Spirit cigarettes because they think they are not as bad for them as other cigarettes. CONCLUSIONS: Disclaimers intended to prevent consumers from attributing a health benefit to cigarettes labelled as 'natural', 'additive-free', or 'organic' may be insufficient. A ban on these descriptors may be a more appropriate remedy than disclaimers. PMID- 26628497 TI - Cigarette demand is responsive to higher prices: findings from a survey of University students in Jordan. AB - OBJECTIVE: To estimate the price elasticity of cigarette demand for university students aged 18-24 years in Jordan. METHODS: Questions from the Global Adult Tobacco Survey were adapted and administered to students from 10 public universities in Jordan in 2014. A two-part econometric model of cigarette demand was estimated. RESULTS: Nearly one-third of university students in Jordan smoke, purchasing 33.2 packs per month and paying 1.70 Jordanian dinars on average (US$2.40) for a pack of 20 cigarettes. The price elasticity of cigarette demand was estimated to be -1.15. CONCLUSIONS: Higher taxes may be particularly effective in reducing smoking among University students in Jordan. PMID- 26628499 TI - Editor's Note. PMID- 26628498 TI - Breastfeeding and Complementary Feeding Practices among HIV-Exposed Infants in Coastal Tanzania. AB - BACKGROUND: Appropriate infant feeding is a persistent challenge for human immunodeficiency virus (HIV)-infected mothers in sub-Saharan Africa. OBJECTIVE: This study aimed to describe correlates of infant feeding among HIV-infected mothers in coastal Tanzania. METHODS: HIV-infected women (n = 400) with infants younger than 18 months were enrolled from June to November 2011 from 3 public health facilities in Pwani, Tanzania: Tumbi Regional Hospital (TRH), Chalinze Health Center (CHC), and Bagamoyo District Hospital (BDH). Participants were surveyed about sociodemographics and infant feeding behavior at enrollment; infant feeding data were collected prospectively and retrospectively in the month of study follow-up. RESULTS: Statistically significant correlates of exclusive breastfeeding (EBF) were infant age (months) (adjusted odds ratio [AOR] = 0.6; 95% confidence interval [CI], 0.5-0.9), enrollment facility (TRH: reference; CHC: AOR = 5.0, 95% CI, 1.2-20.8; BDH: AOR = 11.6, 95% CI, 2.3-59.9), and HIV disclosure to one's mother (AOR = 0.2; 95% CI, 0.1-0.6). Exclusive breastfeeding prevalence among infants younger than 6 months was 77%, but 50% of infants older than 6 months no longer receiving breast milk did not receive animal source foods (ASF) daily. Enrollment facility (TRH: reference; CHC: AOR = 0.2, 95% CI, 0.1 1.0; BDH: AOR = 0.1, 95% CI, 0.01-0.4) and HIV disclosure (to mother-in-law: AOR = 0.2, 95% CI, 0.1-0.8; to brother: AOR = 0.3, 95% CI, 0.1-0.8) were negatively associated with ASF provision. CONCLUSION: High prevalence of EBF suggests that it is an attainable behavior, whereas low prevalence of daily ASF provision suggests that adequate diets are difficult to achieve after breastfeeding cessation. These findings support current recommendations for HIV-infected mothers in resource-poor regions to continue breastfeeding for at least 1 year and suggest the need for greater support with complementary feeding. Associations between HIV disclosure and infant feeding merit further exploration, and correlations between enrollment facility and infant feeding highlight the potential influence of clinics on achieving infant feeding recommendations. PMID- 26628501 TI - Tolerance of eCry3.1Ab in Reciprocal Cross Offspring of eCry3.1Ab-Selected and Control Colonies of Diabrotica virgifera virgifera (Coleoptera: Chrysomelidae). AB - Two new insect colonies were created by separating virgin western corn rootworm, Diabrotica virgifera virgifera LeConte, males and females from both a selected laboratory colony that was being reared on eCry3.1Ab-expressing corn (Zea mays L.) and a control colony reared on its near-isoline corn. Females from the selected colony were paired with males of the control colony and vice versa to create both a selected female by control male colony (Sel?) and control female by selected male colony (Con?). Both colonies along with their parental colonies (eCry3.1Ab-selected and control) were evaluated on eCry3.1Ab-expressing corn and its near-isoline in seedling assays. Larvae from each colony were also used in diet toxicity experiments in order to determine the LC50 and EC50 values for the eCry3.1Ab toxin for each. Statistical analysis of seedling assay experiments did not indicate any significant colony*corn interaction but did show a significant main effect of corn type for both larval recovery and larval head capsule widths. Results from the diet toxicity assays showed the control colony to have a significantly lower LC50 value than the selected and cross colonies and a significantly lower EC50 than the selected and Con? colonies. Calculations of dominance values (h) of eCry3.1Ab resistance traits from seedling assays indicated that the two reciprocal cross colonies have a dominance value (h) of ~1, suggesting dominance of the eCry3.1Ab resistance trait. PMID- 26628500 TI - Population Development of Zabrotes subfasciatus (Coleoptera: Chrysomelidae) in Landrace Bean Varieties Occurring in Southwestern Amazonia. AB - The common bean, Phaseolus vulgaris (L.), is one of the most important sources of protein worldwide, and Latin America is one of the recognized centers of diversity of this species. However, storage of this product after harvest is not feasible because of bruchid attacks. This study determined the accumulated normalized rate of emergence and the daily emergence rate of Zabrotes subfasciatus (Boheman) (Coleoptera: Chrysomelidae:Bruchinae) in five landrace varieties of common bean (BRL 01, SNA 01, RDR 01, RBC 01, and RBC 13) that occurin southwestern Amazonia. These varieties were selected for this study because they are well-distributed throughout the Amazonian communities. Beans of each variety were infested with 50 unsexed adults, and the insects were removed 13 d after beginning the bioassays. The adult progeny obtained from the feeding substrate were counted and removed every other day after the first emergence, until the end of the emergence period. Differences were observed in the calculated rates of development; however, the time required for development and emergence of the insects was independent. Of the five varieties of bean investigated, we observed that the RDR 01, BRL 01, and SNA 01 cultivars are resistant to Z. subfasciatus; the results indicate that the use of these three varieties can reduce problems associated with bruchid attacks and enable storage of the product after harvesting. PMID- 26628502 TI - Phenyl Propionate and Sex Pheromone for Monitoring Navel Orangeworm (Lepidoptera: Pyralidae) in the Presence of Mating Disruption. AB - The recent availability of sex pheromone lures for the navel orangeworm, Amyelois transitella (Walker) (Lepidoptera: Pyralidae), improves options for monitoring this key pest in conventionally managed almonds. These lures are, however, minimally effective in the presence of mating disruption. Experiments were conducted to determine if phenyl propionate (PPO), an attractant for the navel orangeworm, acts in an additive or synergistic manner when presented together with the pheromone. In the absence of mating disruption, traps baited with PPO captured significantly fewer adults than traps baited with a sex pheromone lure. There was no difference in the number of adults captured in traps with both attractants when mating disruption was not used. In the presence of mating disruption, pheromone traps were completely suppressed, yet traps with both pheromone and PPO captured significantly more adults than traps baited with only PPO. Traps with only PPO captured equal numbers of both sexes, whereas traps with both attractants had significantly more males. These findings demonstrate that PPO is likely to be useful for monitoring navel orangeworm in fields treated with mating disruption. PMID- 26628503 TI - Nutritional Value of Pupae Versus Larvae of Tenebrio molitor (Coleoptera: Tenebrionidae) as Food for Rearing Podisus maculiventris (Heteroptera: Pentatomidae). AB - Life-table analysis yielded demographic parameter values that indicate that Tenebrio molitor (L.) pupae are potentially more suitable factitious prey to mass produce the predator Podisus maculiventris (Say) and are more suitable prey than the larvae. P. maculiventris developed faster (23.2 vs. 25.5 d), weighed more (females 80.9 vs. 66.6 mg and males 64.7 vs. 53.7 mg), and had a higher survival rate (0.88 vs. 0.7), fecundity, and reproductive output (87.1 vs. 22.8 eggs/female) when reared on pupae compared with larvae of T. molitor. The total protein content and soluble protein content were significantly higher in pupae (60.2 and 23%, respectively) than larvae (53.1 and 14.4%, respectively). Lipid content was significantly lower in pupae (32.1%) than larvae (35.9%), and larvae had more polyunsaturated fatty acids (83.6 vs. 56.6 mg/g) and less oleic (0.1 mg/g) and steric (6.1 mg/g) acids than pupae (37.3 and 12.3 mg/g, respectively). The total sugar content was not significantly different between pupae and larvae. However, larvae had significantly more fructose than pupae, but pupae had more galactose, glucosamine, glucose, mannose, and trehalose than larvae. Differences in nutritional composition and its impact on predator demographic parameters are potential factors that make the pupal stage a better food source. PMID- 26628506 TI - An acutely collapsed patient. PMID- 26628505 TI - A girl with gastric distension and hyperamylasemia. PMID- 26628504 TI - Common Polymorphisms in the Solute Carrier SLC30A10 are Associated With Blood Manganese and Neurological Function. AB - Manganese (Mn) is an essential nutrient in humans, but excessive exposure to Mn may cause neurotoxicity. Despite homeostatic regulation, Mn concentrations in blood vary considerably among individuals. We evaluated if common single nucleotide polymorphisms (SNPs) in SLC30A10, which likely encodes an Mn transporter, influence blood Mn concentrations and neurological function. We measured blood Mn concentrations by ICP-MS or atomic absorption spectroscopy and genotyped 2 SLC30A10 non-coding SNPs (rs2275707 and rs12064812) by TaqMan PCR in cohorts from Bangladesh (N = 406), the Argentinean Andes (N = 198), and Italy (N = 238). We also measured SLC30A10 expression in whole blood by TaqMan PCR in a sub-group (N = 101) from the Andean cohort, and neurological parameters (sway velocity and finger-tapping speed) in the Italian cohort. The rs2275707 variant allele was associated with increased Mn concentrations in the Andes (8%, P = .027) and Italy (10.6%, P = .012), but not as clear in Bangladesh (3.4%, P = .21; linear regression analysis adjusted for age, gender, and plasma ferritin). This allele was also associated with increased sway velocity (15%, P = .033; adjusted for age and sex) and reduced SLC30A10 expression (-24.6%, P = .029). In contrast, the rs12064812 variant homozygous genotype was associated with reduced Mn concentrations, particularly in the Italian cohort (-18.4%, P = .04), and increased finger-tapping speed (8.7%, P = .025). We show that common SNPs in SLC30A10 are associated with blood Mn concentrations in 3 unrelated cohorts and that their influence may be mediated by altered SLC30A10 expression. Moreover, the SNPs appeared to influence neurological functions independent of blood Mn concentrations, suggesting that SLC30A10 could regulate brain Mn levels. PMID- 26628507 TI - NICE clinical guideline: bronchiolitis in children. PMID- 26628508 TI - Structural robustness of the gut mucosal microbiota is associated with Crohn's disease remission after surgery. AB - OBJECTIVES: Preventing postoperative recurrence after ileocolonic resection (ICR) for Crohn's disease (CD) is challenging. Defining the disturbances of the microbial composition and community structure after ICR and their link with early disease recurrence is crucial. DESIGN: Microbiota composition (fingerprinting and 16S rDNA sequencing) and community structure (correlation networks of bacterial species) were assessed from ileal mucosa sampled in 20 patients undergoing ICR and 6 months later during endoscopy from above (neoterminal ileum) and below (subanastomotic colon) the surgical anastomosis. RESULTS: ICR had a dramatic effect on gut microbial ecosystem. At surgery, CD mucosa harboured a dysbiotic microbiota with high proportions of alpha/beta Proteobacteria and Bacilli. Six months later, half of the patients had recurrent lesions at ileocolonoscopy and presented higher numbers of Lachnospiraceae. Recurrence of endoscopic lesions was associated with enrichment in Enterococcus durans while patients in remission had increased proportions of Dorea longicatena and Bacteroides plebeius. Structural differences were striking between recurrence and remission microbiota; while the microbiota of patients with CD recurrence exhibited a loose community structure, the microbiota of patients in remission displayed communities that were robustly correlated to each other. Microbiota colonising the neoterminal ileum and subanastomotic colon 6 months after ICR only differed in patients with recurrence. CONCLUSIONS: ICR modifies the gut microbiome. Remission after 6 months was associated with homogenous bacterial distribution around the anastomosis. Community structure and bacterial networks highlight target species, including Faecalibacterium prausnitzii and Ruminococcus gnavus, which may allow precise modulations of the overall microbial ecosystem towards remission pattern. PMID- 26628509 TI - Reduced risk of pancreatic cancer associated with asthma and nasal allergies. AB - OBJECTIVE: Studies indicate an inverse association between ductal adenocarcinoma of the pancreas (PDAC) and nasal allergies. However, controversial findings are reported for the association with asthma. Understanding PDAC risk factors will help us to implement appropriate strategies to prevent, treat and diagnose this cancer. This study assessed and characterised the association between PDAC and asthma and corroborated existing reports regarding the association between allergies and PDAC risk. DESIGN: Information about asthma and allergies was collated from 1297 PDAC cases and 1024 controls included in the PanGenEU case control study. Associations between PDAC and atopic diseases were studied using multilevel logistic regression analysis. Meta-analyses of association studies on these diseases and PDAC risk were performed applying random-effects model. RESULTS: Asthma was associated with lower risk of PDAC (OR 0.64, 95% CI 0.47 to 0.88), particularly long-standing asthma (>=17 years, OR 0.39, 95% CI 0.24 to 0.65). Meta-analysis of 10 case-control studies sustained our results (metaOR 0.73, 95% CI 0.59 to 0.89). Nasal allergies and related symptoms were associated with lower risk of PDAC (OR 0.66, 95% CI 0.52 to 0.83 and OR 0.59, 95% CI 0.46 to 0.77, respectively). These results were supported by a meta-analysis of nasal allergy studies (metaOR 0.6, 95% CI 0.5 to 0.72). Skin allergies were not associated with PDAC risk. CONCLUSIONS: This study shows a consistent inverse association between PDAC and asthma and nasal allergies, supporting the notion that atopic diseases are associated with reduced cancer risk. These results point to the involvement of immune and/or inflammatory factors that may either foster or restrain pancreas carcinogenesis warranting further research to understand the molecular mechanisms driving this association. PMID- 26628510 TI - A novel prepless X-ray imaging capsule for colon cancer screening. PMID- 26628511 TI - Balancing Contamination and Referral Bias in a Randomized Clinical Trial: An Application of Pseudo-Cluster Randomization. AB - In randomized trials of provider-focused clinical interventions, treatment allocation often cannot be blinded to participants, study staff, or providers. The choice of unit of randomization (patient, provider, or clinic) entails tradeoffs in cost, power, and bias. Provider- or clinic-level randomization can minimize contamination, but it incurs the equally problematic potential for referral bias; that is, because arm assignment of future participants generally cannot be concealed, differences between arms may arise in the types of patients enrolled. Pseudo-cluster randomization is a novel study design that balances these competing validity threats. Providers are randomly assigned to an imbalanced proportion of intervention-arm participants (e.g., 80% or 20%). Providers can be masked to the imbalance, avoiding referral bias. Contamination is reduced because only a minority of control-arm participants are treated by majority-intervention providers. Pseudo-cluster randomization was implemented in a randomized trial of a decision support intervention to manage depression among patients receiving human immunodeficiency virus care in the southern United States in 2010-2014. The design appears successful in avoiding referral bias (participants were comparable between arms on important characteristics) and contamination (key depression treatment indicators were comparable between usual care participants managed by majority-intervention and majority-usual care providers and were markedly different compared with intervention participants). PMID- 26628512 TI - Is Surgical Menopause Associated With Future Levels of Cardiovascular Risk Factor Independent of Antecedent Levels? The CARDIA Study. AB - In the present study, we compared changes in risk factors for cardiovascular disease (CVD) before and after natural menopause (NM), hysterectomy with at least 1 ovary conserved (HOC), or hysterectomy with bilateral oophorectomy (HBSO). Data were obtained from women 18-30 years of age who were enrolled in the Coronary Artery Risk Development in Young Adults Study (1985-2011). Piecewise linear mixed models were used to examine changes in CVD risk factors from baseline to the index visit (the first visit after the date of NM or hysterectomy) and after index visit until the end of follow-up. During 25 years of follow-up, 1,045 women reached menopause (for NM, n = 588; for HOC, n = 304; and for HBSO, n = 153). At baseline, women with either type of hysterectomy had less favorable values for CVD risk factors. When comparing the annual rates of change of all CVD risk factors from baseline until the index visit to those from the index visit to the end of follow-up, we saw a small increase in rate of change for high-density lipoprotein cholesterol (beta = 0.28 mg/dL; P = 0.002) and a decrease for triglycerides (beta =-0.006 mg/dL; P = 0.027) for all groups. Hysterectomy was not associated with risk factors for CVD after accounting for baseline values. However, antecedent young-adult levels of CVD risk factors were strong predictors of levels of postmenopausal risk factors. PMID- 26628513 TI - Planning for the Future of Epidemiology in the Era of Big Data and Precision Medicine. AB - We live in the era of genomics and big data. Evaluating the impact on health of large-scale biological, social, and environmental data is an emerging challenge in the field of epidemiology. In the past 3 years, major discussions and plans for the future of epidemiology, including with several recommendations for actions to transform the field, have been launched by 2 institutes within the National Institutes of Health. In the present commentary, I briefly explore the themes of these recommendations and their effects on leadership, resources, cohort infrastructure, and training. Ongoing engagement within the epidemiology community is needed to determine how to shape the evolution of the field and what truly matters for changing population health. We also need to assess how to leverage existing epidemiology resources and develop new studies to improve human health. Readers are invited to examine these recommendations, consider others that might be important, and join in the conversation about the future of epidemiology. PMID- 26628514 TI - Pneumococcal Acquisition Among Infants Exposed to HIV in Rural Malawi: A Longitudinal Household Study. AB - The prevalence of Streptococcus pneumoniae (pneumococcus) carriage is higher in adults who are infected with human immunodeficiency virus (HIV) than in adults who are not. We hypothesized that infants exposed to HIV become carriers of nasopharyngeal pneumococcus earlier and more frequently than infants who are not exposed to HIV. We compared infant pneumococcal acquisition by maternal HIV status and household exposure in Karonga District, Malawi, in 2009-2011, before the introduction of pneumococcal conjugate vaccine. Nasopharyngeal swabs were collected every 4-6 weeks in the first year of life from infants with known HIV exposure status, their mothers, and other household members. We studied infant pneumococcal acquisition by maternal HIV status, serotype-specific household exposure, and other risk factors, including seasonality. We recruited 54 infants who were exposed to HIV and 131 infants who were not. There was no significant difference in pneumococcal acquisition by maternal HIV status (adjusted rate ratio (aRR) = 1.00, 95% confidence interval (CI): 0.87, 1.15). Carriage by the mother was associated with greater acquisition of the same serotype (aRR = 3.09, 95% CI: 1.47, 6.50), but the adjusted population attributable fraction was negligible (1.9%, 95% CI: 0.0, 4.3). Serotype-specific exposure to children under 5 years of age was associated with higher acquisition (aRR = 4.30, 95% CI: 2.80, 6.60; adjusted population attributable fraction = 8.8%, 95% CI: 4.0, 13.4). We found no evidence to suggest that maternal HIV infection would affect the impact of pneumococcal vaccination on colonization in this population. PMID- 26628515 TI - Impacts of the Adventive Psyllid Arytainilla spartiophila (Hemiptera: Psyllidae) on Growth of the Invasive Weed Cytisus scoparius Under Controlled and Field Conditions in California. AB - The postrelease impact of weed biological control agents on their target weeds is rarely assessed. This study focuses on the impacts of the univoltine broom psyllid Arytainilla spartiophila Forster on the growth of its target weed, the invasive shrub Scotch broom, Cytisus scoparius (L.) Link (Fabaceae), in California. Arytainilla spartiophila is an adventive species that has been present in North America for several decades. In a greenhouse experiment, plant growth as measured by both height and total stem length (height + length of all branches) was reduced on plants that received psyllids, and psyllid densities were negatively correlated to proportional change in plant height. There were no effects on number of leaves, however. Furthermore, the psyllid had no statistically detectable impacts on plant growth parameters in a field experiment, underscoring how results obtained under controlled conditions may not fully predict the performance of biological control agents in the field. The high psyllid mortality that occurred at higher psyllid densities in both the greenhouse and the field suggests that the impacts of A. spartiophila may be moderated by intraspecific competition. PMID- 26628516 TI - Depression Symptomatology and Anterior Cruciate Ligament Injury: Incidence and Effect on Functional Outcome--A Prospective Cohort Study. AB - BACKGROUND: Recent literature has recognized a correlation with depression and poor self-reported functional outcome after orthopaedic procedures. However, the effect of depression on anterior cruciate ligament reconstruction (ACLR) outcome has never been studied. PURPOSE: To quantify the incidence of major depressive disorder (MDD) and correlate depression symptoms with patient-rated knee function in patients undergoing ACLR. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: In this multicenter prospective cohort study, 64 consecutive adult patients undergoing primary ACLR were given the 16-item self-report Quick Inventory of Depressive Symptomatology (QIDS) to assess MDD symptoms preoperatively and at 6 weeks, 12 weeks, 24 weeks, and 1 year postoperatively. Lysholm and International Knee Documentation Committee (IKDC) subjective scores were obtained at the same time points to assess self-reported knee function. A QIDS score >=6 served as a validated threshold for diagnosis of MDD. MDD and non MDD group assignment was based on preoperative QIDS score. Student t test analysis was performed to compare ACLR outcomes between MDD and non-MDD patients. Correlation among QIDS, Lysholm, and IKDC scores was determined with Spearman r value. RESULTS: A total of 27 patients (42%) were categorized in the MDD group. At baseline, the MDD group reported mean Lysholm (50.8) and IKDC (43.7) scores that were significantly lower than those (64.9 and 57.0, respectively) reported by the non-MDD group (P < .05). Both cohorts showed similar and significant absolute improvement from baseline to 1 year postoperatively (MDD vs non-MDD, increase in mean Lysholm: +24.4 vs +23.5 [P = .63]; MDD vs non-MDD, increase in mean IKDC: +28.1 vs +32.3 [P = .21]). While Lysholm and IKDC scores improved in both groups, at 1-year follow-up, MDD patients reported significantly lower mean Lysholm (75.2 vs 88.4; P = .04) and mean IKDC (71.8 vs 89.3; P = .001) scores as compared with their non-MDD counterparts. In addition, a moderate inverse correlation was found between QIDS and Lysholm scores (r = -0.50) and between QIDS and IKDC scores (r = -0.54). Interestingly, 4 patients experienced complications in the MDD cohort (15%), while there were no complications in the non-MDD group. CONCLUSION: This study suggests that ACLR may be an equally effective intervention for MDD and non-MDD patients, given their similar significant absolute improvements in functional scores from baseline to 1 year after ACLR. However, MDD patients still reported significantly lower self reported functional scores at baseline and 1 year postoperatively. PMID- 26628517 TI - Genetic variation in transpiration efficiency and relationships between whole plant and leaf gas exchange measurements in Saccharum spp. and related germplasm. AB - Fifty-one genotypes of sugarcane (Saccharum spp.) or closely related germplasm were evaluated in a pot experiment to examine genetic variation in transpiration efficiency. Significant variation in whole plant transpiration efficiency was observed, with the difference between lowest and highest genotypes being about 40% of the mean. Leaf gas exchange measurements were made across a wide range of conditions. There was significant genetic variation in intrinsic transpiration efficiency at a leaf level as measured by leaf internal CO2 (Ci) levels. Significant genetic variation in Ci was also observed within subsets of data representing narrow ranges of stomatal conductance. Ci had a low broad sense heritability (Hb = 0.11) on the basis of single measurements made at particular dates, because of high error variation and genotype * date interaction, but broad sense heritability for mean Ci across all dates was high (Hb = 0.81) because of the large number of measurements taken at different dates. Ci levels among genotypes at mid-range levels of conductance had a strong genetic correlation ( 0.92 +/- 0.30) with whole plant transpiration efficiency but genetic correlations between Ci and whole plant transpiration efficiency were weaker or not significant at higher and lower levels of conductance. Reduced Ci levels at any given level of conductance may result in improved yields in water-limited environments without trade-offs in rates of water use and growth. Targeted selection and improvement of lowered Ci per unit conductance via breeding may provide longer-term benefits for water-limited environments but the challenge will be to identify a low-cost screening methodology. PMID- 26628518 TI - Transcriptomic and anatomical complexity of primary, seminal, and crown roots highlight root type-specific functional diversity in maize (Zea mays L.). AB - Maize develops a complex root system composed of embryonic and post-embryonic roots. Spatio-temporal differences in the formation of these root types imply specific functions during maize development. A comparative transcriptomic study of embryonic primary and seminal, and post-embryonic crown roots of the maize inbred line B73 by RNA sequencing along with anatomical studies were conducted early in development. Seminal roots displayed unique anatomical features, whereas the organization of primary and crown roots was similar. For instance, seminal roots displayed fewer cortical cell files and their stele contained more meta xylem vessels. Global expression profiling revealed diverse patterns of gene activity across all root types and highlighted the unique transcriptome of seminal roots. While functions in cell remodeling and cell wall formation were prominent in primary and crown roots, stress-related genes and transcriptional regulators were over-represented in seminal roots, suggesting functional specialization of the different root types. Dynamic expression of lignin biosynthesis genes and histochemical staining suggested diversification of cell wall lignification among the three root types. Our findings highlight a cost efficient anatomical structure and a unique expression profile of seminal roots of the maize inbred line B73 different from primary and crown roots. PMID- 26628522 TI - The Effect of a Mechanical Arm System on Portable Grinder Vibration Emissions. AB - Mechanical arm systems are commonly used to support powered hand tools to alleviate ergonomic stressors related to the development of workplace musculoskeletal disorders. However, the use of these systems can increase exposure times to other potentially harmful agents such as hand-transmitted vibration. To examine how these tool support systems affect tool vibration, the primary objectives of this study were to characterize the vibration emissions of typical portable pneumatic grinders used for surface grinding with and without a mechanical arm support system at a workplace and to estimate the potential risk of the increased vibration exposure time afforded by the use of these mechanical arm systems. This study also developed a laboratory-based simulated grinding task based on the ISO 28927-1 (2009) standard for assessing grinder vibrations; the simulated grinding vibrations were compared with those measured during actual workplace grinder operations. The results of this study demonstrate that use of the mechanical arm may provide a health benefit by reducing the forces required to lift and maneuver the tools and by decreasing hand-transmitted vibration exposure. However, the arm does not substantially change the basic characteristics of grinder vibration spectra. The mechanical arm reduced the average frequency-weighted acceleration by about 24% in the workplace and by about 7% in the laboratory. Because use of the mechanical arm system can increase daily time-on-task by 50% or more, the use of such systems may actually increase daily time-weighted hand-transmitted vibration exposures in some cases. The laboratory acceleration measurements were substantially lower than the workplace measurements, and the laboratory tool rankings based on acceleration were considerably different than those from the workplace. Thus, it is doubtful that ISO 28927-1 is useful for estimating workplace grinder vibration exposures or for predicting workplace grinder acceleration rank orders. PMID- 26628523 TI - Pain exposure physical therapy (PEPT) compared to conventional treatment in complex regional pain syndrome type 1: a randomised controlled trial. AB - OBJECTIVE: To compare the effectiveness of pain exposure physical therapy (PEPT) with conventional treatment in patients with complex regional pain syndrome type 1 (CRPS-1) in a randomised controlled trial with a blinded assessor. SETTING: The study was conducted at a level 1 trauma centre in the Netherlands. PARTICIPANTS: 56 adult patients with CRPS-1 participated. Three patients were lost to follow up. INTERVENTIONS: Patients received either PEPT in a maximum of five treatment sessions, or conventional treatment following the Dutch multidisciplinary guideline. MEASUREMENTS: Outcomes were assessed at baseline and at 3, 6 and 9 months after randomisation. The primary outcome measure was the Impairment level Sum Score--Restricted Version (ISS-RV), consisting of visual analogue scale for pain (VAS-pain), McGill Pain Questionnaire, active range of motion (AROM) and skin temperature. Secondary outcome measures included Pain Disability Index (PDI); muscle strength; Short Form 36 (SF-36); disability of arm, shoulder and hand; Lower Limb Tasks Questionnaire (LLTQ); 10 m walk test; timed up-and-go test (TUG) and EuroQol-5D. RESULTS: The intention-to-treat analysis showed a clinically relevant decrease in ISS-RV (6.7 points for PEPT and 6.2 points for conventional treatment), but the between-group difference was not significant (0.96, 95% CI -1.56 to 3.48). Participants allocated to PEPT experienced a greater improvement in AROM (between-group difference 0.51, 95% CI 0.07 to 0.94; p=0.02). The per protocol analysis showed larger and significant between-group effects on ISS-RV, VAS-pain, AROM, PDI, SF-36, LLTQ and TUG. CONCLUSIONS: We cannot conclude that PEPT is superior to conventional treatment for patients with CRPS-1. Further high-quality research on the effects of PEPT is warranted given the potential effects as indicated by the per protocol analysis. TRIAL REGISTRATION NUMBERS: NCT00817128 and NTR 2090. PMID- 26628525 TI - Leadership and followership in the healthcare workplace: exploring medical trainees' experiences through narrative inquiry. AB - OBJECTIVES: To explore medical trainees' experiences of leadership and followership in the interprofessional healthcare workplace. DESIGN: A qualitative approach using narrative interviewing techniques in 11 group and 19 individual interviews with UK medical trainees. SETTING: Multisite study across four UK health boards. PARTICIPANTS: Through maximum variation sampling, 65 medical trainees were recruited from a range of specialties and at various stages of training. Participants shared stories about their experiences of leadership and followership in the healthcare workplace. METHODS: Data were analysed using thematic and narrative analysis. RESULTS: We identified 171 personal incident narratives about leadership and followership. Participants most often narrated experiences from the position of follower. Their narratives illustrated many factors that facilitate or inhibit developing leadership identities; that traditional medical and interprofessional hierarchies persist within the healthcare workplace; and that wider healthcare systems can act as barriers to distributed leadership practices. CONCLUSIONS: This paper provides new understandings of the multiple ways in which leadership and followership is experienced in the healthcare workplace and sets out recommendations for future leadership educational practices and research. PMID- 26628524 TI - Assessing the effects of the Spanish partial smoking ban on cardiovascular and respiratory diseases: methodological issues. AB - OBJECTIVE: Recent research has assessed the impact of tobacco laws on cardiovascular and respiratory morbidity. In this study, we also examined whether the association between the implementation of the 2005 Spanish smoking ban and hospital admissions for cardiovascular and respiratory diseases varies according to the adjustment for potential confounders. DESIGN: Ecological time series analysis. SETTING: Residents of Madrid and Barcelona cities (Spain). OUTCOME: Data on daily emergency room admissions for acute myocardial infarction, cerebrovascular disease, chronic obstructive pulmonary disease (COPD), and asthma derived from the 2003-2006 Spanish hospital admissions registry. METHODS: Changes in admission rates between 2006 and the 2003-2005 period were estimated using additive Poisson models allowing for overdispersion adjusted for secular trend in admission, seasonality, day of the week, temperature, number of flu and acute respiratory infection cases, pollution levels, tobacco consumption prevalence and, for asthma cases, pollen count. RESULTS: In Madrid, fully adjusted models failed to detect significant changes in hospital admission rates for any disease during the study period. In Barcelona, however, hospital admissions decreased by 10.2% (95% CI 3.8% to 16.1%) for cerebrovascular diseases and by 16.0% (95% CI 7.0% to 24.1%) for COPD. Substantial changes in effect estimates were observed on adjustment for linear or quadratic trend. Effect estimates for asthma-related admissions varied substantially when adjusting for pollen count in Madrid, and for seasonality and tobacco consumption in Barcelona. CONCLUSIONS: Our results confirm that the potential impact of a smoking ban must be adjusted for the underlying secular trend. In asthma-related admissions, pollen count, seasonality and tobacco consumption must be specified in the model. The substantial variability in effects detected between the two cities of Madrid and Barcelona lends strong support for a nationwide study to assess the overall effect of a smoking ban in Spain and identify the causes of the observed heterogeneity. PMID- 26628526 TI - A cross-sectional mixed methods study protocol to generate learning from patient safety incidents reported from general practice. AB - INTRODUCTION: Incident reports contain descriptions of errors and harms that occurred during clinical care delivery. Few observational studies have characterised incidents from general practice, and none of these have been from the England and Wales National Reporting and Learning System. This study aims to describe incidents reported from a general practice care setting. METHODS AND ANALYSIS: A general practice patient safety incident classification will be developed to characterise patient safety incidents. A weighted-random sample of 12,500 incidents describing no harm, low harm and moderate harm of patients, and all incidents describing severe harm and death of patients will be classified. Insights from exploratory descriptive statistics and thematic analysis will be combined to identify priority areas for future interventions. ETHICS AND DISSEMINATION: The need for ethical approval was waivered by the Aneurin Bevan University Health Board research risk review committee given the anonymised nature of data (ABHB R&D Ref number: SA/410/13). The authors will submit the results of the study to relevant journals and undertake national and international oral presentations to researchers, clinicians and policymakers. PMID- 26628528 TI - Junior doctors' experiences of managing patients with medically unexplained symptoms: a qualitative study. AB - OBJECTIVES: To explore junior doctors' knowledge about and experiences of managing patients with medically unexplained symptoms (MUS) and to seek their recommendations for improved future training on this important topic about which they currently receive little education. DESIGN: Qualitative study using in-depth interviews analysed using the framework method. SETTING: Participants were recruited from three North Thames London hospitals within the UK. PARTICIPANTS: Twenty-two junior doctors undertaking the UK foundation two-year training programme (FY1/FY2). RESULTS: The junior doctors interviewed identified a significant gap in their training on the topic of MUS, particularly in relation to their awareness of the topic, the appropriate level of investigations, possible psychological comorbidities, the formulation of suitable explanations for patients' symptoms and longer term management strategies. Many junior doctors expressed feelings of anxiety, frustration and a self-perceived lack of competency in this area, and spoke of over-investigating patients or avoiding patient contact altogether due to the challenging nature of MUS and a difficulty in managing the accompanying uncertainty. They also identified the negative attitudes of some senior clinicians and potential role models towards patients with MUS as a factor contributing to their own attitudes and management choices. Most reported a need for more training during the foundation years, and recommended interactive case-based group discussions with a focus on providing meaningful explanations to patients for their symptoms. CONCLUSIONS: There is an urgent need to improve postgraduate training about the topics of MUS and avoiding over-investigation, as current training does not equip junior doctors with the necessary knowledge and skills to effectively and confidently manage patients in these areas. Training needs to focus on practical skill development to increase clinical knowledge in areas such as delivering suitable explanations, and to incorporate individual management strategies to help junior doctors tolerate the uncertainty associated with MUS. PMID- 26628531 TI - PTJ Has No Silo. PMID- 26628532 TI - Health Services Research: Physical Therapy Has Arrived! PMID- 26628527 TI - Study protocol for a phase III multicentre, randomised, open-label, blinded-end point trial to evaluate the efficacy and safety of immunoglobulin plus cyclosporin A in patients with severe Kawasaki disease (KAICA Trial). AB - INTRODUCTION: Kawasaki disease (KD) is an acute, self-limited vasculitis of unknown aetiology that predominantly affects infants and young children. We hypothesise that cyclosporin A (CsA) may be effective in treating KD by regulating the Ca(2+)/NFAT signalling pathway. This trial compares the current standard therapy of intravenous immunoglobulin (IVIG) and the combined IVIG+CsA therapy in paediatric patients with severe KD. METHODS AND ANALYSIS: This trial is a phase III, multicentre, randomised, open-label, blinded-end point trial that evaluates the efficacy and safety of IVIG+CsA therapy. Patients with severe KD who satisfy the eligibility criteria are randomised (1:1) to receive either CsA (5 mg/kg/day for 5 days; Neoral) plus high-dose IVIG (2 g/kg for 24 h and aspirin 30 mg/kg/day), or high-dose IVIG alone (2 g/kg for 24 h and aspirin 30 mg/kg/day). The primary end point is the frequency of occurrence of coronary artery abnormalities during the trial period. An independent end point review committee will be in charge of the trial assessment. ETHICS AND DISSEMINATION: The protocol was approved by the Institutional Review Board of each institution. The trial was notified and registered at the Pharmaceutical and Medical Devices Agency, in Japan. The trial is currently on-going and is scheduled to finish in April 2017. The findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: JMA-IIA00174; Pre results. PMID- 26628533 TI - Rebbeck T, Moloney N, Azoory R, et al. Clinical ratings of pain sensitivity correlate with quantitative measures in people with chronic neck pain and healthy controls: cross-sectional study. Phys Ther. 2015;95:1536-1546. PMID- 26628534 TI - Transferring patients home to die: what is the potential population in UK critical care units? AB - OBJECTIVES: Most people when asked, express a preference to die at home, but little is known about whether this is an option for critically ill patients. A retrospective cohort study was undertaken to describe the size and characteristics of the critical care population who could potentially be transferred home to die if they expressed such a wish. METHODS: Medical notes of all patients who died in, or within 5 days of discharge from seven critical care units across two hospital sites over a 12-month period were reviewed. Inclusion/exclusion criteria were developed and applied to identify the number of patients who had potential to be transferred home to die and demographic and clinical data (eg, conscious state, respiratory and cardiac support therapies) collected. RESULTS: 7844 patients were admitted over a 12-month period. 422 (5.4%) patients died. Using the criteria developed 100 (23.7%) patients could have potentially been transferred home to die. Of these 41 (41%) patients were diagnosed with respiratory disease. 53 (53%) patients were conscious, 47 (47%) patients were self-ventilating breathing room air/oxygen via a mask. 20 (20%) patients were ventilated via an endotracheal tube. 76 (76%) patients were not requiring inotropes/vasopressors. Mean time between discussion about treatment withdrawal and time of death was 36.4 h (SD=46.48). No patients in this cohort were transferred home. CONCLUSIONS: A little over 20% of patients dying in critical care demonstrate potential to be transferred home to die. Staff should actively consider the practice of transferring home as an option for care at end of life for these patients. PMID- 26628535 TI - Supporting and improving community health services-a prospective evaluation of ECHO technology in community palliative care nursing teams. AB - INTRODUCTION: Project ECHO (Extension for Community Healthcare Outcomes) uses teleconferencing technology to support and train healthcare providers (HCPs) remotely, and has improved care across the USA. A 6-month pilot was trialled in a community palliative care nursing setting to determine if ECHO would be effective in the UK in providing education and support to community hospice nurses (CHN). METHODS: The pilot involved weekly 2 hour sessions of teaching and case-based discussions facilitated by hospice staff linking with nine teams of CHN using video conferencing technology. A mixed-methods prospective longitudinal cohort study was used to evaluate the pilot. Each CHN provided demographic data, and completed a written knowledge assessment and a self-efficacy tool before and after the pilot. Two focus groups were also performed after the pilot. RESULTS: 28 CHNs completed the evaluation. Mean knowledge score improved significantly from 71.3% to 82.7% (p=0.0005) as did overall self-efficacy scores following the ECHO pilot. Pre-ECHO (p=0.036) and Retro-Pretest ECHO (p=0.0005) self-efficacy were significantly lower than post-ECHO. There was no significant difference between Pretest and Retro-Pretest ECHO self-efficacy (p=0.063). 96% recorded gains in learning, and 90% felt that ECHO had improved the care they provided for patients. 83% would recommend ECHO to other HCPs. 70% stated the technology used in ECHO had given them access to education that would have been hard to access due to geography. CONCLUSIONS: This study supports the use of Project ECHO for CHNs in the UK by demonstrating how a 6-month pilot improved knowledge and self efficacy. As a low-cost high-impact model, ECHO provides an affordable solution to addressing growing need. PMID- 26628537 TI - What Standard of Care? PMID- 26628536 TI - Evaluation of Facial Volume Changes after Rejuvenation Surgery Using a 3 Dimensional Camera. AB - BACKGROUND: Surgical rejuvenation alters facial volume distribution to achieve more youthful aesthetic contours. These changes are routinely compared subjectively. The introduction of 3-dimensional (3D) stereophotogrammetry provides a novel method for measuring and comparing surgical results. OBJECTIVES: We sought to quantify how specific facial areas are changed after rejuvenation surgery using the 3D camera. METHODS: Patients undergoing facial rejuvenation were imaged preoperatively and postoperatively with 3D stereophotogrammetry. Images were registered using facial surface landmarks unaltered by surgery. Colorimetric 3D analysis depicting postoperative volume changes was performed utilizing the 3D imaging software and quantitative volume measurements were constructed. RESULTS: Nine patients who underwent combined facelift procedures and fat grafting were evaluated. Median time for postoperative imaging was 4.8 months. Positive changes in facial volume occurred in the forehead, temples, and cheeks (median changes, 0.9 mL +/- 4.3 SD; 0.8 mL +/- 0.47 SD; and 1.4 mL +/- 1.6 SD, respectively). Negative changes in volume occurred in the nasolabial folds, marionette basins, and neck/submental regions (median changes, -1.0 mL +/- 0.37 SD; -0.4 mL +/- 0.9 SD; and -2.0 mL +/- 4.3 SD, respectively). CONCLUSIONS: The technique of 3D stereophotogrammetry provides a tool for quantifying facial volume distribution after rejuvenation procedures. Areas of consistent volume increase include the forehead, temples, and cheeks; areas of negative volume change occur in the nasolabial folds, marionette basins, and submental/chin regions. This technology may be utilized to better understand the dynamic changes that occur with facial rejuvenation and quantify longevity of various rejuvenation techniques. LEVEL OF EVIDENCE: 4 Diagnostic. PMID- 26628538 TI - Diagnostic Errors: Improving Diagnostic Practice. PMID- 26628540 TI - A Gift From the Heart for Years to Come. PMID- 26628541 TI - Corrections. PMID- 26628542 TI - Restoring Speech to Tracheostomy Patients. AB - Tracheostomies may be established as part of an acute or chronic illness, and intensive care nurses can take an active role in helping restore speech in patients with tracheostomies, with focused nursing assessments and interventions. Several different methods are used to restore speech, whether a patient is spontaneously breathing, ventilator dependent, or using intermittent mechanical ventilation. Restoring vocal communication allows patients to fully express themselves and their needs, enhancing patient satisfaction and quality of life. PMID- 26628543 TI - Prone Positioning of Patients With Acute Respiratory Distress Syndrome. AB - Effectively treating critically ill patients with acute respiratory distress syndrome (ARDS) is a challenge for many intensive care nurses. Multiple disease processes and injuries contribute to the complexity of ARDS and often complicate therapy. As a means of supportive care for ARDS, practitioners resort to rescue therapies to improve oxygenation and salvage the patient. The pathophysiology of ARDS and the use of prone positioning to improve pulmonary ventilation and oxygenation in ARDS patients are described. Educating nursing and medical staff on the use of prone positioning allows ease of patient placement with an emphasis on safety of both patients and staff. Scrupulous assessment of patients coupled with judicious timing of prone positioning expedites weaning from ventilatory support and contributes to positive outcomes for patients. PMID- 26628544 TI - Managing Spaghetti Syndrome in Critical Care With a Novel Device: A Nursing Perspective. AB - BACKGROUND: Managing "spaghetti syndrome," the tangle of therapeutic cables, tubes, and cords at patients' bedsides, can be challenging. OBJECTIVES: To assess nurses' perceptions of the effectiveness of a novel banding device in management of spaghetti syndrome. METHODS: A simple color-coded elastomeric banding strap with ribbed flaps was attached to bed rails of adult critical care patients to help organize therapeutic cables, tubes, wires, and cords. Nurses were surveyed before and after use of the bands and after the nursing shift to assess the burden of spaghetti syndrome and the effectiveness of using the bands. RESULTS: Use of the bands decreased the time spent untangling cords, reduced the frequency of contact of tubing with the floor, and diminished disruptions in care. CONCLUSIONS: Use of a simple flexible latex-free elastomeric band may help organize therapeutic tubing at patients' bedsides and may promote improvements in nursing care. PMID- 26628545 TI - Caring for Pediatric Patients' Families at the Child's End of Life. AB - Nurses play an important role in supporting families who are faced with the critical illness and death of their child. Grieving families desire compassionate, sensitive care that respects their wishes and meets their needs. Families often wish to continue relationships and maintain lasting connections with hospital staff following their child's death. A structured bereavement program that supports families both at the end of their child's life and throughout their grief journey can meet this need. PMID- 26628546 TI - Making It Meaningful: Finding Quality Improvement Projects Worthy of Your Time, Effort, and Expertise. AB - This article is the second of a 4-part quality improvement resource series for critical care nurses interested in implementing system process or performance improvement projects. The article is a brainstorming session on paper, written to assist nurses and managers in identifying possible quality improvement projects that are meaningful to them and will make a real difference in their critical care units. Every unit and institution has its own unique mix of resources, culture, physical environment, patient population, technology, documentation processes, health care providers, and multiple other factors. Thus specific patient care and safety challenges must be identified and prioritized individually for quality improvement by each unit. Projects also must be manageable and within the scope of time, effort, and expertise available-no quality improvement project is "too small" if it is applicable to your critical care area and will improve outcomes. PMID- 26628548 TI - Best Practices: Full-Dose Delivery of Intravenous Medications via Infusion Pumps. PMID- 26628549 TI - Glutamine Supplementation for Critically Ill Adults: A summary of findings from the Cochrane Library with implications for critical care nursing. PMID- 26628551 TI - I Am a Critical Care Nurse. PMID- 26628550 TI - Bedside Nurse-Driven Protocol for Management of Alcohol/Polysubstance Abuse Withdrawal. PMID- 26628552 TI - Effect of patient-centred bedside rounds on hospitalised patients' decision control, activation and satisfaction with care. AB - IMPORTANCE: Though interprofessional bedside rounds have been promoted to enhance patient-centred care for hospitalised patients, few studies have been conducted in adult hospital settings and evidence of impact is lacking. OBJECTIVE: To evaluate the effect of patient-centred bedside rounds (PCBRs) on measures of patient-centred care. DESIGN AND SETTING: Cluster randomised controlled trial involving four similar non-teaching hospitalist service units in a large urban hospital. PARTICIPANTS: Hospitalised general medical patients. INTERVENTION: We assembled working groups on two intervention units, consisting of professionals and patient/family members, to determine the optimal timing, duration and format for PCBR. Nurses and hospitalists rounded together in PCBR using a communication tool to provide a framework for discussion and unit leaders joined PCBR to provide coaching during initial weeks of implementation. MAIN OUTCOMES: Using patient interviews, we assessed preferred and experienced roles in medical decision-making using the Control Preferences Scale, activation using the Short Form of the Patient Activation Measure, and satisfaction. We also compared postdischarge patient satisfaction survey items related to teamwork, involvement in decisions and overall care. We assessed nurses', physicians' and advanced practice providers' (APP) perceptions of PCBR using a survey developed for this study. RESULTS: Overall, 650 patients were approached for structured interview during hospitalisation: 284 were excluded because of disorientation, 54 were excluded because of non-English language, 72 declined to participate and 4 withdrew from the study after enrolment. Interview data were available for 236 (122 control and 114 intervention unit) patients, and postdischarge satisfaction survey data were available for 493 (274 control and 219 intervention unit) patients. We found no significant differences in patients' perceptions of shared decision-making, activation or satisfaction with care. Results were similar in analyses based on whether PCBR had been performed (ie, per protocol). We also found no difference in postdischarge patient satisfaction items. Results were similar in multivariate analyses controlling for patient characteristics and clustering of patients within study units. A majority of nurses (78.6%), but only about half of hospitalist physicians and APPs felt that PCBR improved communication with patients (47.4%). A minority of nurses (46.4%) and physicians and APPs (36.8%) agreed that PCBR had improved the efficiency of their workday. CONCLUSIONS: PCBR had no impact on patients' perceptions of shared decision making, activation or satisfaction with care. Additional research is needed to identify optimal approaches that can be reliably implemented in hospital settings to improve patient-centred care. PMID- 26628554 TI - Response to: 'Mapping search terms to review goals is essential' by Geiger et al. PMID- 26628553 TI - Associations between exemption and survival outcomes in the UK's primary care pay for-performance programme: a retrospective cohort study. AB - OBJECTIVES: The UK's Quality and Outcomes Framework permits practices to exempt patients from financially-incentivised performance targets. To better understand the determinants and consequences of being exempted from the framework, we investigated the associations between exception reporting, patient characteristics and mortality. We also quantified the proportion of exempted patients that met quality targets for a tracer condition (diabetes). DESIGN: Retrospective longitudinal study, using individual patient data from the Clinical Practice Research Datalink. SETTING: 644 general practices, 2006/7 to 2011/12. PARTICIPANTS: Patients registered with study practices for at least one year over the study period, with at least one condition of interest (2 460 341 in total). MAIN OUTCOME MEASURES: Exception reporting rates by reason (clinical contraindication, patient dissent); all-cause mortality in year following exemption. Analyses with logistic and Cox proportional-hazards regressions, respectively. RESULTS: The odds of being exempted increased with age, deprivation and multimorbidity. Men were more likely to be exempted but this was largely attributable to higher prevalence of conditions with high exemption rates. Modest associations remained, with women more likely to be exempted due to clinical contraindication (OR 0.90, 99% CI 0.88 to 0.92) and men more likely to be exempted due to informed dissent (OR 1.08, 99% CI 1.06 to 1.10). More deprived areas (both for practice location and patient residence) were non-linearly associated with higher exception rates, after controlling for comorbidities and other covariates, with stronger associations for clinical contraindication. Compared with patients with a single condition, odds ratios for patients with two, three, or four or more conditions were respectively 4.28 (99% CI 4.18 to 4.38), 16.32 (99% CI 15.82 to 16.83) and 68.69 (99% CI 66.12 to 71.37) for contraindication, and 2.68 (99% CI 2.63 to 2.74), 4.02 (99% CI 3.91 to 4.13) and 5.17 (99% CI 5.00 to 5.35) for informed dissent. Exempted patients had a higher adjusted risk of death in the following year than non-exempted patients, regardless of whether this exemption was for contraindication (hazard ratio 1.37, 99% CI 1.33 to 1.40) or for informed dissent (1.20, 99% CI 1.17 to 1.24). On average, quality standards were met for 48% of exempted patients in the diabetes domain, but there was wide variation across indicators (ranging from 8 to 80%). CONCLUSIONS: Older, multimorbid and more deprived patients are more likely to be exempted from the scheme. Exception reported patients are more likely to die in the following year, whether they are exempted by the practice for a contraindication or by themselves through informed dissent. Further research is needed to understand the relationship between exception reporting and patient outcomes. PMID- 26628555 TI - Comparative study of the neuroprotective and nootropic activities of the carboxylate and amide forms of the HLDF-6 peptide in animal models of Alzheimer's disease. AB - A comparative study of the neuroprotective and nootropic activities of two pharmaceutical substances, the HLDF-6 peptide (HLDF-6-OH) and its amide form (HLDF-6-NH2), was conducted. The study was performed in male rats using two models of a neurodegenerative disorder. Cognitive deficit in rats was induced by injection of the beta-amyloid fragment 25-35 (betaA 25-35) into the giant-cell nucleus basalis of Meynert or by coinjection of betaA 25-35 and ibotenic acid into the hippocampus. To evaluate cognitive functions in animals, three tests were used: the novel object recognition test, the conditioned passive avoidance task and the Morris maze. Comparative analysis of the data demonstrated that the neuroprotective activity of HLDF-6-NH2, evaluated by improvement of cognitive functions in animals, surpassed that of the native HLDF-6-OH peptide. The greater cognitive/ behavioral effects can be attributed to improved kinetic properties of the amide form of the peptide, such as the character of biodegradation and the half-life time. The effects of HLDF-6-NH2 are comparable to, or exceed, those of the reference compounds. Importantly, HLDF-6-NH2 exerts its effects at much lower doses than the reference compounds. PMID- 26628558 TI - Model parameters of molecular evolution explain genomic correlations. AB - One long-standing research focus in evolutionary genomics is trying to resolve how biological variables (expression, essentiality, protein-protein interaction, structural stability, etc.) determine the rate of protein evolution. While these studies have considerably deepened our understanding of molecular evolution, many issues remain unsolved. In this opinion article, after having a brief survey of literatures, we establish relationships between model parameters of molecular evolution and genomic variables, based on which, most-observed genomic correlations and confounds can be explained by model parameter combinations under different conditions, which include the strength of stabilizing selection, mutational variance, expression sufficiency, gene pleiotropy, as well as the effective population size. We suggest that the problem to discern biological variable(s) that may determine the rate of protein evolution can be tackled at two levels. The first level, as discussed here, is to demonstrate how the model of molecular evolution can predict potential genomic correlations under various conditions. And the second level is to estimate genome-wide variations of model parameters (or combinations) that help to identify canonical biological variables that may underlie the rate variation among genes that ranges up to at least three magnitudes. PMID- 26628557 TI - Evaluation of preprocessing, mapping and postprocessing algorithms for analyzing whole genome bisulfite sequencing data. AB - Cytosine methylation regulates many biological processes such as gene expression, chromatin structure and chromosome stability. The whole genome bisulfite sequencing (WGBS) technique measures the methylation level at each cytosine throughout the genome. There are an increasing number of publicly available pipelines for analyzing WGBS data, reflecting many choices of read mapping algorithms as well as preprocessing and postprocessing methods. We simulated single-end and paired-end reads based on three experimental data sets, and comprehensively evaluated 192 combinations of three preprocessing, five postprocessing and five widely used read mapping algorithms. We also compared paired-end data with single-end data at the same sequencing depth for performance of read mapping and methylation level estimation. Bismark and LAST were the most robust mapping algorithms. We found that Mott trimming and quality filtering individually improved the performance of both read mapping and methylation level estimation, but combining them did not lead to further improvement. Furthermore, we confirmed that paired-end sequencing reduced error rate and enhanced sensitivity for both read mapping and methylation level estimation, especially for short reads and in repetitive regions of the human genome. PMID- 26628559 TI - Current Progress in Bioinformatics 2016. PMID- 26628556 TI - Regulation of blood-testis barrier by actin binding proteins and protein kinases. AB - The blood-testis barrier (BTB) is an important ultrastructure in the testis, since the onset of meiosis and spermiogenesis coincides with the establishment of a functional barrier in rodents and humans. It is also noted that a delay in the assembly of a functional BTB following treatment of neonatal rats with drugs such as diethylstilbestrol or adjudin also delays the first wave of spermiation. While the BTB is one of the tightest blood-tissue barriers, it undergoes extensive remodeling, in particular, at stage VIII of the epithelial cycle to facilitate the transport of preleptotene spermatocytes connected in clones across the immunological barrier. Without this timely transport of preleptotene spermatocytes derived from type B spermatogonia, meiosis will be arrested, causing aspermatogenesis. Yet the biology and regulation of the BTB remains largely unexplored since the morphological studies in the 1970s. Recent studies, however, have shed new light on the biology of the BTB. Herein, we critically evaluate some of these findings, illustrating that the Sertoli cell BTB is regulated by actin-binding proteins (ABPs), likely supported by non-receptor protein kinases, to modulate the organization of actin microfilament bundles at the site. Furthermore, microtubule-based cytoskeleton is also working in concert with the actin-based cytoskeleton to confer BTB dynamics. This timely review provides an update on the unique biology and regulation of the BTB based on the latest findings in the field, focusing on the role of ABPs and non-receptor protein kinases. PMID- 26628560 TI - Biology Education Research 2.0. PMID- 26628561 TI - Caution, Student Experience May Vary: Social Identities Impact a Student's Experience in Peer Discussions. AB - In response to calls for implementing active learning in college-level science, technology, engineering, and mathematics courses, classrooms across the country are being transformed from instructor centered to student centered. In these active-learning classrooms, the dynamics among students becomes increasingly important for understanding student experiences. In this study, we focus on the role a student prefers to assume during peer discussions, and how this preferred role may vary given a student's social identities. In addition we explore whether three hypothesized barriers to participation may help explain participation difference in the classroom. These barriers are 1) students are excluded from the discussion by actions of their groupmates; 2) students are anxious about participating in peer discussion; and 3) students do not see value in peer discussions. Our results indicate that self-reported preferred roles in peer discussions can be predicted by student gender, race/ethnicity, and nationality. In addition, we found evidence for all three barriers, although some barriers were more salient for certain students than others. We encourage instructors to consider structuring their in-class activities in ways that promote equity, which may require more purposeful attention to alleviating the current differential student experiences with peer discussions. PMID- 26628562 TI - The Role of Scientific Communication Skills in Trainees' Intention to Pursue Biomedical Research Careers: A Social Cognitive Analysis. AB - Scientific communication (SciComm) skills are indispensable for success in biomedical research, but many trainees may not have fully considered the necessity of regular writing and speaking for research career progression. Our purpose was to investigate the relationship between SciComm skill acquisition and research trainees' intentions to remain in research careers. We used social cognitive career theory (SCCT) to test a model of the relationship of SciComm skills to SciComm-related cognitive variables in explaining career intentions. A sample of 510 graduate students and postdoctoral fellows at major academic health science centers in the Texas Medical Center, Houston, Texas, were surveyed online. Results suggested that interest in performing SciComm tasks, SciComm outcome expectations (SCOEs), and SciComm productivity predicted intention to remain in a research career, while SciComm self-efficacy did not directly predict career intention. SCOEs also predicted interest in performing SciComm tasks. As in other SCCT studies, SciComm self-efficacy predicted SCOEs. We conclude that social cognitive factors of SciComm skill acquisition and SciComm productivity significantly predict biomedical trainees' intentions to pursue research careers whether within or outside academia. While further studies are needed, these findings may lead to evidence-based interventions to help trainees remain in their chosen career paths. PMID- 26628563 TI - Deviant Processing in the Primary Somatosensory Cortex. AB - Stimulus-specific adaptation (SSA) to repetitive stimulation has been proposed to separate behaviorally relevant features from a stream of continuous sensory information. However, the exact mechanisms giving rise to SSA and cortical deviance detection are not well understood. We therefore used an oddball paradigm and multicontact electrodes to characterize single-neuron and local field potential responses to various deviant stimuli across the rat somatosensory cortex. Changing different single-whisker stimulus features evoked robust SSA in individual cortical neurons over a wide range of stimulus repetition rates (0.25 80 Hz). Notably, SSA was weakest in the granular input layer and significantly stronger in the supra- and infragranular layers, suggesting that a major part of SSA is generated within cortex. Moreover, we found a small subset of neurons in the granular layer with a deviant-specific late response, occurring roughly 200 ms after stimulus offset. This late deviant response exhibited true-deviance detection properties that were not explained by depression of sensory inputs. Our results show that deviant responses are actively amplified within cortex and contain an additional late component that is sensitive for context-specific sensory deviations. This strongly implicates deviance detection as a feature of intracortical stimulus processing beyond simple sensory input depression. PMID- 26628564 TI - Comparison of Transcutaneous and Capillary Measurement of PCO2 in Hypercapnic Subjects. AB - BACKGROUND: Measurement of PCO2 is vital in determining effective alveolar ventilation. However, obtaining capillary PCO2 by a skin prick of the earlobe is painful, and nocturnal measurements disturb sleep. End-expiratory measurement of PCO2 is also well established, but there is a low precision in predicting arterial or capillary CO2. The purpose of the study was to evaluate nocturnal measurement of noninvasive, transcutaneous PCO2 (PtcCO2 ) measurement in hypercapnic subjects. METHODS: In this prospective study, 31 subjects with chronic hypercapnic failure--in a stable phase of the underlying disease--and a control group of 12 healthy volunteers were included. Transcutaneous measurements were taken by the Tosca sensor (Radiometer, Copenhagen, Denmark) over a period of at least 6 h during the night. A capillary blood gas was measured at midnight and 4:00 am. RESULTS: The mean nocturnal capillary PCO2 (PcapCO2 ) of subjects was 50.6 +/- 10.2 mm Hg. In the 31 subjects with known hypercapnic respiratory failure, the correlation between PtcCO2 and PcapCO2 at midnight was 0.86 and at 4:00 am r = 0.80. The bias of the hypercapnic subjects was d = + 4.5 with a limit(s) of agreement of 2 SD = 13.0. The process of blood sampling caused no significant change in PtcCO2 . CONCLUSIONS: Our study evaluated transcutaneous capnography as a continuous nocturnal measurement in hypercapnic subjects. We found a good agreement between the methods. Because CO2 is not constant in patients with respiratory failure, but instead fluctuates, we would recommend the continuous transcutaneous measurement of PCO2 as our method of choice in the diagnosis of nocturnal hypercapnia. PMID- 26628565 TI - Spirometry-Adjusted Fraction of Exhaled Nitric Oxide Allows Asthma Diagnosis in Children, Adolescents, and Young Adults. AB - BACKGROUND: Recently, it has been proved that fractional exhaled nitric oxide (FENO) results are in disagreement with other measurements of asthma control. The objective of this work is to present and validate new lung function/lung inflammation ratios. METHODS: This is a retrospective, cross-sectional study in which we evaluated data from medical documentation of 1,529 pediatric and adolescent subjects and a small number (2% of the studied population) of young adults, who presented symptoms suggestive of asthma (age range 4-24 y). We are the first to analyze results obtained in this manner (before the introduction of controlled medication): FENO, spirometry, specific resistance of the airways, diagnosis of allergic diseases, and allergen sensitization (specific immunoglobulin E results). RESULTS: Cut-off points for the new indicators allowed us to diagnose asthma in the study participants: for FVC/FENO ratio, 0.17 L/ppb; for FEV1/FENO ratio, 0.15 L/ppb; for forced expiratory flow during the middle half of the FVC maneuver (FEF25-75%)/FENO ratio, 0.16 L/s/ppb; for FENO/FVC ratio, 11.00 ppb/L; for FENO/FEV1 ratio, 12.53 ppb/L; and for FENO/FEF25-75% ratio, 11.81 ppb/L/s. Only the ratios described above were closely correlated with the diagnosis of asthma and with one another. They significantly differed between subjects with asthma and healthy subjects as well as between females and males. Only FEF25-75%/FENO and FENO/FEF25-75% values were significant predictors of any sensitization in the studied subjects. We found higher sensitivity than specificity and higher positive predictive value than negative predictive value for FVC/FENO, FEV1/FENO, and FEF25-75%/FENO and found a mirror image for reverse parameters. However, the positive predictive values and negative predictive values were not clearly convincing with respect to diagnostic accuracy in the case of the new parameters proposed. CONCLUSIONS: We propose new lung function/lung inflammation ratios by which it may become possible to diagnose asthma in children and adolescents on the basis of a subject's spirometry and FENO measurements. We believe that our ratios are only supportive of the universally used parameters in the process of diagnosing asthma. (ClinicalTrials.gov registration NCT01805635.). PMID- 26628567 TI - Establishing a Fecal Microbiota Transplant Service for the Treatment of Clostridium difficile Infection. AB - Recurrent or refractory Clostridium difficile infection (CDI) has become an increasing problem in the past decade. Fecal microbiota transplant (FMT) is a highly efficacious treatment for recurrent CDI; however, a number of technical, logistical, and regulatory issues have hampered the development of an FMT capability at many hospitals. The development of a frozen stool bank of screened donor stool is an important step in the standardization of the procedure. This gives clinicians rapid access to thoroughly screened donor stool when needed, without the ethical and logistical problems associated with patient-selected donors. We describe the practicalities of establishing such a service using a stool bank of prescreened donor stool including detail regarding donor recruitment and screening, stool preparation, and delivery of the FMT. PMID- 26628568 TI - The coronary circulation: plaques, collaterals, and the microcirculation. PMID- 26628566 TI - The Impact of Enhanced Screening and Treatment on Hepatitis C in the United States. AB - BACKGROUND: The effectiveness of interferon-free direct-acting antivirals (DAA) in treating chronic hepatitis C virus (HCV) is limited by low screening and treatment rates, particularly among people who inject drugs (PWIDs). METHODS: To evaluate the levels of screening and treatment with interferon-free DAAs that are required to control HCV incidence and HCV-associated morbidity and mortality, we developed a transmission model, stratified by age and by injection drug use, and calibrated it to epidemiological data in the United States from 1992 to 2014. We quantified the impact of administration of DAAs at current and at enhanced screening and treatment rates, focusing on outcomes of HCV incidence, prevalence, compensated and decompensated cirrhosis, hepatocellular carcinoma, liver transplants, and mortality from 2015 to 2040. RESULTS: Increasing annual treatment of patients 4-fold-from the approximately 100 000 treated historically to 400 000-is predicted to prevent 526 084 (95% confidence interval, 466 615-593 347) cases of cirrhosis and 256 315 (201 589-316 114) HCV-associated deaths. By simultaneously increasing treatment capacity and increasing the number of HCV infections diagnosed, total HCV prevalence could fall to as low as 305 599 (222 955-422 110) infections by 2040. Complete elimination of HCV transmission in the United States through treatment with DAAs would require nearly universal screening of PWIDs, with an annual treatment rate of at least 30%. CONCLUSIONS: Interferon-free DAAs are projected to achieve marked reductions in HCV-associated morbidity and mortality. Aggressive expansion in HCV screening and treatment, particularly among PWIDs, would be required to eliminate HCV in the United States. PMID- 26628569 TI - Nobel Prize laureate Elizabeth H. Blackburn's: A Journey to Stockholm at ESC Congress London. PMID- 26628570 TI - A genetic form of achlorhydria and gastritis. PMID- 26628571 TI - Reply to R Schiffmann. PMID- 26628572 TI - Compensation in physical activity energy expenditure after active video games: role of sample size and analysis. PMID- 26628573 TI - Reply to VB Paravidino et al. PMID- 26628574 TI - Aspartic acid, phenylalanine, and early menarche. PMID- 26628575 TI - Reply to RE Kleinman. PMID- 26628576 TI - Comment on the multiple problems of multiplicity. PMID- 26628577 TI - Reply to AV Frane. PMID- 26628579 TI - Impact of tobacco smoking on response to tumour necrosis factor-alpha inhibitor treatment in patients with ankylosing spondylitis: results from the Danish nationwide DANBIO registry. AB - OBJECTIVES: To investigate the association between tobacco smoking and disease activity, treatment adherence and treatment responses in patients with AS treated with their first tumour necrosis factor-alpha inhibitor (TNFi) therapy in routine care. METHODS: Observational cohort study based on the Danish nationwide DANBIO registry. Kaplan-Meier plots, Cox and logistic regression analyses by smoking status (current/never/previous) were calculated for treatment adherence and BASDAI 50%/20 mm-response. Additional stratified analyses were performed for gender and TNFi-type. RESULTS: Of 1576 AS patients included in the study, 1425(90%) had known smoking status (current/never/previous: 43%/41%/16%). The median follow-up time was 2.02 years (IQR 0.69-5.01). At baseline, current smokers compared with never smokers had longer disease duration (4 years (1-12)/2 years (0-10)), higher BASDAI (61 mm (47-73)/58 mm (44-70)), BASFI (53 mm (35 69)/46 mm (31-66)) and BASMI (40 mm (20-60)/30 mm (10-50)) scores (all P < 0.01). Current and previous smokers had shorter treatment adherence than never smokers (current: 2.30 years (1.81-2.79) (median (95% CI)); previous: 2.48 years (1.56 3.40), never: 4.12 years (3.29-4.95)), P < 0.0001). Similar results were found in multivariate analyses (current versus never smokers, HR 1.41 (95% CI 1.21-1.65), P < 0.001), most pronounced among men. Current smokers had poorer 6 months' BASDAI50%/20 mm-response rate than never smokers (42%/58%, P < 0.001). In multivariate analyses, current smokers had lower odds of achieving BASDAI50%/20 mm-response than never smokers, both overall (OR 0.48 (95% CI 0.35-0.65), P < 0.0001) and for the different TNFi-types (adalimumab 0.45 (0.27-0.76)/etanercept 0.24 (0.10-0.61)/infliximab 0.57 (0.34-0.95)). CONCLUSION: In this study of TNFi treated AS patients in clinical practice, current and previous smokers had significantly poorer patient-reported outcomes at baseline, shorter treatment adherence and poorer treatment response compared with never smokers. PMID- 26628580 TI - Efficacy and safety of biological agents for systemic juvenile idiopathic arthritis: a systematic review and meta-analysis of randomized trials. AB - OBJECTIVE: To define the optimal biologic agent for systemic JIA (sJIA) based on safety and efficacy data from a randomized controlled trial (RCT). METHODS: Through a systematic literature search, sJIA RCTs evaluating biologic agents were identified. The primary efficacy outcome was defined as a 30% improvement according to the modified American College of Rheumatology Paediatric 30 response criteria (JIA ACR30). The primary safety outcome was defined as serious adverse events (SAEs). Outcomes were analysed by pairwise and network meta-analyses. The quality of evidence between biologic agents was assessed by applying the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. RESULTS: From the 493 citations originally identified, 5 RCTs were eligible for inclusion-one each for anakinra, canakinumab and tocilizumab and two for rilonacept: all vs placebo. While all were effective, the network meta-analysis indicated with low-quality evidence (due to indirect comparison and inconsistency) that rilonacept-treated patients were less likely to respond than those treated with canakinumab [odds ratio (OR) 0.10 (95% CI 0.02, 0.38), P = 0.001] or tocilizumab [OR 0.12 (95% CI 0.03, 0.44), P = 0.001]. Risks of SAEs were similar among the biologic agents (supported by very low-quality evidence) and not different from placebo. CONCLUSION: Despite heterogeneous eligibility criteria and study designs across the five studies and different modified JIA ACR30 criteria, this meta-analysis of short-term RCTs presents empirical evidence that canakinumab and tocilizumab are more effective than rilonacept. Biologic agents in sJIA seem safe and comparable with respect to SAE risk in the short term. PMID- 26628581 TI - Continuous Rapid Quantification of Stroke Volume Using Magnetohydrodynamic Voltages in 3T Magnetic Resonance Imaging. AB - BACKGROUND: To develop a technique to noninvasively estimate stroke volume in real time during magnetic resonance imaging (MRI)-guided procedures, based on induced magnetohydrodynamic voltages (VMHD) that occur in ECG recordings during MRI exams, leaving the MRI scanner free to perform other imaging tasks. Because of the relationship between blood flow (BF) and VMHD, we hypothesized that a method to obtain stroke volume could be derived from extracted VMHD vectors in the vectorcardiogram (VCG) frame of reference (VMHDVCG). METHODS AND RESULTS: To estimate a subject-specific BF-VMHD model, VMHDVCG was acquired during a 20-s breath-hold and calibrated versus aortic BF measured using phase-contrast magnetic resonance in 10 subjects (n=10) and 1 subject diagnosed with premature ventricular contractions. Beat-to-beat validation of VMHDVCG-derived BF was performed using real-time phase-contrast imaging in 7 healthy subjects (n=7) during 15-minute cardiac exercise stress tests and 30 minutes after stress relaxation in 3T MRIs. Subject-specific equations were derived to correlate VMHDVCG with BF at rest and validated using real-time phase-contrast. An average error of 7.22% and 3.69% in stroke volume estimation, respectively, was found during peak stress and after complete relaxation. Measured beat-to-beat BF time history derived from real-time phase-contrast and VMHD was highly correlated using a Spearman rank correlation coefficient during stress tests (0.89) and after stress relaxation (0.86). CONCLUSIONS: Accurate beat-to-beat stroke volume and BF were estimated using VMHDVCG extracted from intra-MRI 12-lead ECGs, providing a means to enhance patient monitoring during MR imaging and MR-guided interventions. PMID- 26628582 TI - Improving Appropriateness and Quality in Cardiovascular Imaging: A Review of the Evidence. AB - High-quality cardiovascular imaging requires a structured process to ensure appropriate patient selection, accurate and reproducible data acquisition, and timely reporting which answers clinical questions and improves patient outcomes. Several guidelines provide frameworks to assess quality. This article reviews interventions to improve quality in cardiovascular imaging, including methods to reduce inappropriate testing, improve accuracy, reduce interobserver variability, and reduce diagnostic and reporting errors. PMID- 26628583 TI - Serum PTH reference values established by an automated third-generation assay in vitamin D-replete subjects with normal renal function: consequences of diagnosing primary hyperparathyroidism and the classification of dialysis patients. AB - OBJECTIVE: To determine parathyroid hormone (PTH) reference values in French healthy adults, taking into account serum 25-hydroxyvitamin D (25OHD), renal function, age, gender, and BMI. PARTICIPANTS AND MAIN BIOLOGICAL MEASUREMENTS: We studied 898 healthy subjects (432 women) aged 18-89 years with a normal BMI and estimated glomerular filtration rate (eGFR), 81 patients with surgically proven primary hyperparathyroidism (PHPT), and 264 dialysis patients. 25OHD and third generation PTH assays were implemented on the LIAISON XL platform. RESULTS: Median PTH and 25OHD values in the 898 healthy subjects were 18.8 ng/l and 23.6 ng/ml respectively. PTH was lower in subjects with 25OHD >=30 ng/ml than in those with lower values. Among the 183 subjects with 25OHD >=30 ng/ml, those aged >=60 years (n=31) had higher PTH values than younger subjects, independent of 25OHD, BMI, and eGFR (P<0.001). Given the small number of subjects aged >=60 years, we adopted the 95% CI of PTH values for the entire group of 183 vitamin D replete subjects (9.4-28.9 ng/l) as our reference values. With 28.9 ng/l as the upper limit of normal (ULN) rather than the manufacturer's ULN of 38.4 ng/l, the percentage of PHPT patients with 'high' PTH values rose to 90.1% from 66.6% (P<0.001), and 18.6% of the dialysis patients were classified differently in view of the KDIGO target range (two to nine times the ULN). CONCLUSION: When only subjects with 25OHD >=30 ng/ml were included in the reference population, the PTH ULN fell by 22.4%, diagnostic sensitivity for PHPT improved, and the classification of dialysis patients was modified. PMID- 26628585 TI - An automated workflow for parallel processing of large multiview SPIM recordings. AB - Selective Plane Illumination Microscopy (SPIM) allows to image developing organisms in 3D at unprecedented temporal resolution over long periods of time. The resulting massive amounts of raw image data requires extensive processing interactively via dedicated graphical user interface (GUI) applications. The consecutive processing steps can be easily automated and the individual time points can be processed independently, which lends itself to trivial parallelization on a high performance computing (HPC) cluster. Here, we introduce an automated workflow for processing large multiview, multichannel, multiillumination time-lapse SPIM data on a single workstation or in parallel on a HPC cluster. The pipeline relies on snakemake to resolve dependencies among consecutive processing steps and can be easily adapted to any cluster environment for processing SPIM data in a fraction of the time required to collect it. AVAILABILITY AND IMPLEMENTATION: The code is distributed free and open source under the MIT license http://opensource.org/licenses/MIT The source code can be downloaded from github: https://github.com/mpicbg-scicomp/snakemake-workflows Documentation can be found here: http://fiji.sc/Automated_workflow_for_parallel_Multiview_Reconstruction CONTACT: : schmied@mpi-cbg.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26628586 TI - LedPred: an R/bioconductor package to predict regulatory sequences using support vector machines. AB - Supervised classification based on support vector machines (SVMs) has successfully been used for the prediction of cis-regulatory modules (CRMs). However, no integrated tool using such heterogeneous data as position-specific scoring matrices, ChIP-seq data or conservation scores is currently available. Here, we present LedPred, a flexible SVM workflow that predicts new regulatory sequences based on the annotation of known CRMs, which are associated to a large variety of feature types. LedPred is provided as an R/Bioconductor package connected to an online server to avoid installation of non-R software. Due to the heterogeneous CRM feature integration, LedPred excels at the prediction of regulatory sequences in Drosophila and mouse datasets compared with similar SVM based software. AVAILABILITY AND IMPLEMENTATION: LedPred is available on GitHub: https://github.com/aitgon/LedPred and Bioconductor: http://bioconductor.org/packages/release/bioc/html/LedPred.html under the MIT license. CONTACT: aitor.gonzalez@univ-amu.fr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26628584 TI - MECHANISMS IN ENDOCRINOLOGY: Alternative splicing: the new frontier in diabetes research. AB - Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic beta cells are killed by infiltrating immune cells and by cytokines released by these cells. This takes place in the context of a dysregulated dialogue between invading immune cells and target beta cells, but the intracellular signals that decide beta cell fate remain to be clarified. Alternative splicing (AS) is a complex post-transcriptional regulatory mechanism affecting gene expression. It regulates the inclusion/exclusion of exons into mature mRNAs, allowing individual genes to produce multiple protein isoforms that expand the proteome diversity. Functionally related transcript populations are co-ordinately spliced by master splicing factors, defining regulatory networks that allow cells to rapidly adapt their transcriptome in response to intra and extracellular cues. There is a growing interest in the role of AS in autoimmune diseases, but little is known regarding its role in T1D. In this review, we discuss recent findings suggesting that splicing events occurring in both immune and pancreatic beta cells contribute to the pathogenesis of T1D. Splicing switches in T cells and in lymph node stromal cells are involved in the modulation of the immune response against beta cells, while beta cells exposed to pro-inflammatory cytokines activate complex splicing networks that modulate beta cell viability, expression of neoantigens and susceptibility to immune-induced stress. Unveiling the role of AS in beta cell functional loss and death will increase our understanding of T1D pathogenesis and may open new avenues for disease prevention and therapy. PMID- 26628587 TI - IKAP: A heuristic framework for inference of kinase activities from Phosphoproteomics data. AB - MOTIVATION: Phosphoproteomics measurements are widely applied in cellular biology to detect changes in signalling dynamics. However, due to the inherent complexity of phosphorylation patterns and the lack of knowledge on how phosphorylations are related to functions, it is often not possible to directly deduce protein activities from those measurements. Here, we present a heuristic machine learning algorithm that infers the activities of kinases from Phosphoproteomics data using kinase-target information from the PhosphoSitePlus database. By comparing the estimated kinase activity profiles to the measured phosphosite profiles, it is furthermore possible to derive the kinases that are most likely to phosphorylate the respective phosphosite. RESULTS: We apply our approach to published datasets of the human cell cycle generated from HeLaS3 cells, and insulin signalling dynamics in mouse hepatocytes. In the first case, we estimate the activities of 118 at six cell cycle stages and derive 94 new kinase-phosphosite links that can be validated through either database or motif information. In the second case, the activities of 143 kinases at eight time points are estimated and 49 new kinase-target links are derived. AVAILABILITY AND IMPLEMENTATION: The algorithm is implemented in Matlab and be downloaded from github. It makes use of the Optimization and Statistics toolboxes. https://github.com/marcel mischnik/IKAP.git. CONTACT: marcel.mischnik@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26628588 TI - Representation and inference of cellular architecture for metabolic reconstruction and modeling. AB - MOTIVATION: Metabolic modeling depends on accurately representing the cellular locations of enzyme-catalyzed and transport reactions. We sought to develop a representation of cellular compartmentation that would accurately capture cellular location information. We further sought a representation that would support automated inference of the cellular compartments present in newly sequenced organisms to speed model development, and that would enable representing the cellular compartments present in multiple cell types within a multicellular organism. RESULTS: We define the cellular architecture of a unicellular organism, or of a cell type from a multicellular organism, as the collection of cellular components it contains plus the topological relationships among those components. We developed a tool for inferring cellular architectures across many domains of life and extended our Cell Component Ontology to enable representation of the inferred architectures. We provide software for visualizing cellular architectures to verify their correctness and software for editing cellular architectures to modify or correct them. We also developed a representation that records the cellular compartment assignments of reactions with minimal duplication of information. AVAILABILITY AND IMPLEMENTATION: The Cell Component Ontology is freely available. The Pathway Tools software is freely available for academic research and is available for a fee for commercial use. CONTACT: pkarp@ai.sri.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26628589 TI - Capsule Formats May Hamper Green Tea Catechin Bioavailability. PMID- 26628591 TI - One-Year Clinical and Computed Tomography Angiographic Outcomes After Bioresorbable Vascular Scaffold Implantation During Primary Percutaneous Coronary Intervention for ST-Segment-Elevation Myocardial Infarction: The PRAGUE-19 Study. AB - BACKGROUND: Bioresorbable vascular scaffolds (BVS) represent promising new technology, but data on their long-term outcomes in ST-segment-elevation myocardial infarction (STEMI) setting are missing. The aim was to analyze 1-year clinical and computed tomographic angiographic outcomes after BVS implantation in STEMI. METHODS AND RESULTS: PRAGUE-19 is a prospective multicenter single-arm study enrolling consecutive STEMI patients undergoing primary percutaneous coronary intervention (pPCI) with intention-to-implant BVS. A total of 343 STEMI patients were screened during 15 months enrollment period, and 70 patients (mean age 58.6+/-10.3 and 74% males) fulfilled entry criteria and BVS was successfully implanted in 96% of them. All patients were invited for clinical and computed tomographic angiographic control 1 year after BVS implantation. Restenosis was defined as >=75% area stenosis within the scaffolded segment. Three events were potentially related to BVS: 1 in-stent restenosis (treated 7 months after pPCI with drug-eluting balloon), 1 stent thrombosis (treated 2 weeks after pPCI by balloon dilatation-this patient stopped all medications after pPCI), and 1 sudden death at home 9 months after pPCI. Four other patients had events definitely unrelated to BVS. Overall, 1-year mortality was 2.9%. Computed tomographic angiography after 1 year was performed in 59 patients. All BVS were widely patent, and binary restenosis rate was 2% (the only restenosis mentioned above). Mean in-scaffold minimal luminal area was 7.8+/-2.6 mm(2), area stenosis was 20.1+/-16.3%, minimal luminal diameter was 3.0+/-0.6 mm, and diameter stenosis was 12.8+/-11.1%. CONCLUSIONS: BVS implantation in STEMI is feasible and safe and offers excellent 1-year clinical and angiographic outcomes. PMID- 26628592 TI - High-Risk Percutaneous Coronary Interventions in Modern Day Clinical Practice: Current Concepts and Challenges. PMID- 26628593 TI - The Genetic Epidemiological Landscape of Hip and Knee Osteoarthritis: Where Are We Now and Where Are We Going? AB - Osteoarthritis (OA) is a complex disease that affects the whole joint, with multiple biological and environmental factors contributing to its development. The heritable component for primary OA accounts for ~50% of susceptibility. So far, candidate gene studies and genome-wide association scans have established 18 OA-associated loci. These findings account for 11% of the heritability, explaining a rather small fraction of the genetic component. To further unravel the genetic architecture of OA, the field needs to facilitate more precise phenotypic definitions, high genome coverage, and large sample metaanalyses, expecting the identification of rare and low frequency variants with potentially higher penetrance, and more accurate methods for calculating phenotype-genotype correlation. Expression analysis, epigenetics, and investigation of interactions can also help clarify the implicated transcriptional regulatory pathways and provide insights into further novel pathogenic OA mechanisms leading to diagnostic biomarker identification and new, more focused therapeutic disease approaches. PMID- 26628594 TI - Novel Ultrasound Joint Selection Methods Using a Reduced Joint Number Demonstrate Inflammatory Improvement when Compared to Existing Methods and Disease Activity Score at 28 Joints. AB - OBJECTIVE: A pilot study testing novel ultrasound (US) joint-selection methods in rheumatoid arthritis. METHODS: Responsiveness of novel [individualized US (IUS) and individualized composite US (ICUS)] methods were compared with existing US methods and the Disease Activity Score at 28 joints (DAS28) for 12 patients followed for 3 months. IUS selected up to 7 and 12 most ultrasonographically inflamed joints, while ICUS additionally incorporated clinically symptomatic joints. RESULTS: The existing, IUS, and ICUS methods' standardized response means were -0.39, -1.08, and -1.11, respectively, for 7 joints; -0.49, -1.00, and 1.16, respectively, for 12 joints; and -0.94 for DAS28. CONCLUSION: Novel methods effectively demonstrate inflammatory improvement when compared with existing methods and DAS28. PMID- 26628595 TI - Coronary, Carotid, and Lower-extremity Atherosclerosis and Their Interrelationship in Danish Patients with Systemic Lupus Erythematosus. AB - OBJECTIVE: Atherosclerosis is highly prevalent among patients with systemic lupus erythematosus (SLE), but has been demonstrated predominantly in non-European SLE cohorts and few investigations have included more than 1 imaging modality. We aimed to investigate the prevalence of atherosclerosis in 3 frequently affected vascular territories, the coronary, carotid, and lower-extremity arteries, in a Danish, predominantly population-based SLE cohort. METHODS: Patients with SLE without prior cardiovascular disease (CVD; n = 103) were screened for coronary artery calcification, carotid intima-media thickening and plaque, and abnormal ankle-brachial index by means of cardiac computed tomography, ultrasound of the carotid arteries, and ankle systolic blood pressure. RESULTS: In patients with SLE, the prevalence of atherosclerosis in any vascular territory was 41%. The distribution of the atherosclerotic manifestations showed an overlap with 45% of the patients having involvement in more than 1 vascular territory. However, more than one-third of the patients with SLE with coronary, carotid, or lower extremity atherosclerosis exclusively demonstrated this particular manifestation. Based on a multiple logistic regression model, age (p < 0.001), current smoking (p = 0.009), and the Systemic Lupus International Collaborating Clinics (SLICC; p = 0.008) were significant independent risk factors for atherosclerosis at any vascular territory. CONCLUSION: Atherosclerosis is highly prevalent among Danish patients with SLE without prior CVD. Screening for atherosclerosis in 1 vascular territory is insufficient in diagnosing atherosclerosis in patients with SLE. In Danish patients with SLE, the presence of atherosclerosis was not only assigned to traditional CV risk factors, but also associated with SLICC. PMID- 26628596 TI - Summary Findings of a Systematic Literature Review of the Ultrasound Assessment of Bone Erosions in Rheumatoid Arthritis. AB - OBJECTIVE: Bone erosions in rheumatoid arthritis (RA) have been studied in an increasing amount of research. Both earlier and present classification criteria of RA contain erosions as a significant classification component. Ultrasound (US) can detect bone changes in accessible surfaces. Therefore, the study group performed a systematic literature review of assessment of RA bone erosions with US. METHODS: A systematic search of PubMed and Embase was performed. Data on the definitions of RA bone erosions, their size, scoring, relation to synovitis, comparators, and elements of the OMERACT (Outcome Measures in Rheumatology Clinical Trials) filter were collected and analyzed. RESULTS: The selection process identified 58 original research papers. The assessed joints were most frequently metacarpophalangeal (MCP; 41 papers), proximal interphalangeal (19 papers), and metatarsophalangeal joints (MTP; 18 papers). The OMERACT definition of RA bone erosion on US was used most often (17 papers). Second and fifth MCP and fifth MTP were recommended as target joints. Conventional radiography was the most frequently used comparator (27 papers), then magnetic resonance imaging (17 papers) and computed tomography (5 papers). Reliability of assessment was presented in 20 papers and sensitivity to change in 11 papers. CONCLUSION: This paper presents results of a systematic literature review of bone erosion assessment in RA with US. The survey suggests that US can be a helpful adjunct to the existing methods of imaging bone erosions in RA. It analyzes definitions, scoring systems, used comparators, and elements of the OMERACT filter. It also presents recommendations for a future research agenda based on the results of the review. PMID- 26628597 TI - A Population-based Study of Intensive Care Unit Admissions in Rheumatoid Arthritis. AB - OBJECTIVE: We aimed to determine the incidence of and mortality after critical illness in rheumatoid arthritis (RA) compared with the general population, and to describe the risks for and characteristics of critical illness in patients with RA. METHODS: We used population-based administrative data from the Data Repository at the Manitoba Centre for Health Policy from 1984 to 2010, and linked clinical data from an intensive care unit (ICU) database to identify all persons with RA in the province requiring ICU admission. We identified a population-based control group, matched by age, sex, socioeconomic status, and region of residence. The incidence of ICU admission, reasons for, and mortality after ICU admission were compared between populations using age- and sex-standardized rates, rate ratios, Cox proportional hazards models, and logistic regression models. RESULTS: We identified 10,078 prevalent and 5560 incident cases of RA. After adjustment, the risk for ICU admission was higher for RA (HR 1.65, 95% CI 1.50-1.83) versus the matched general population. From 2000-2010, the annual incidence of ICU admission among prevalent patients was about 1% in RA, with a crude 10-year incidence of 8%. Compared with the general population admitted to ICU, 1 year after ICU admission, mortality was increased by 40% in RA. Cardiovascular disorders were the most common reason for ICU admission in RA. CONCLUSION: Patients with RA have a higher risk for admission to the ICU than the general population and increased mortality 1 year after admission. Even with advances in management, RA remains a serious disease with significant morbidity. PMID- 26628598 TI - MicroRNA-10a Regulation of Proinflammatory Mediators: An Important Component of Untreated Juvenile Dermatomyositis. AB - OBJECTIVE: To identify differentially expressed microRNA (miRNA) in muscle biopsies (MBx) from 15 untreated children with juvenile dermatomyositis (JDM) compared with 5 controls. METHODS: Following MBx miRNA profiling, differentially expressed miRNA and their protein targets were validated by quantitative real time PCR (qRT-PCR) and immunological assay. The association of miRNA-10a and miRNA-10b with clinical data was evaluated, including Disease Activity Score (DAS), von Willebrand factor antigen (vWF:Ag), nailfold capillary end row loops, duration of untreated disease, and tumor necrosis factor (TNF)-alpha-308A allele. RESULTS: In JDM, 16/362 miRNA were significantly differentially expressed [false discovery rate (FDR) < 0.05]. Among these, miRNA-10a was the most downregulated miRNA in both FDR and ranking of fold change: miRNA-10a = -2.27-fold, miRNA-10b = -1.80-fold. Decreased miRNA-10a and miRNA-10b expressions were confirmed using q RT-PCR: -4.16 and -2.59 fold, respectively. The qRT-PCR documented that decreased miRNA-10a expression was related to increased vascular cell adhesion molecule 1 in 13 of these JDM cases (correlation -0.67, p = 0.012), unlike miRNA-10b data (not significant). Concurrent JDM plasma contained increased levels of interleukin (IL) 6 (p = 0.0363), IL-8 (p = 0.0005), TNF-alpha (p = 0.0011), and monocyte chemoattractant proteins 1 (p = 0.0139). Decreased miRNA-10a, but not miRNA-10b, was associated with the TNF-alpha-308A allele (p = 0.015). In the 15 JDM, a trend of association of miRNA-10a (but not miRNA-10b) with vWF:Ag and DAS was observed. CONCLUSION: MiRNA-10a downregulation is an important element in untreated JDM muscle pathophysiology. We speculate that muscle miRNA expression in adult dermatomyositis differs from muscle miRNA expression in untreated childhood JDM. PMID- 26628599 TI - Is Disease Activity in Rheumatoid Arthritis during Pregnancy and after Delivery Predictive for Disease Activity in a Subsequent Pregnancy? AB - OBJECTIVE: To determine whether disease activity in women with rheumatoid arthritis (RA) in 1 pregnancy is predictive for disease activity in a subsequent pregnancy. METHODS: In the Pregnancy-induced Amelioration of Rheumatoid Arthritis study, there are prospective data on 27 patients who participated twice. Improvement and deterioration is determined by changes in the Disease Activity Score in 28 joints. RESULTS: Only 4 patients (14.8%) had comparable disease courses in both pregnancies, whereas treatment remained mostly similar. In contrast, a flare postpartum after the first pregnancy was predictive for a flare after the second pregnancy (p = 0.003). CONCLUSION: RA disease course in following pregnancies cannot be predicted based upon previous pregnancies. However, a flare postpartum seems to predict subsequent flares. PMID- 26628600 TI - The Performance and Association Between Patient-reported and Performance-based Measures of Physical Functioning in Research on Individuals with Arthritis. AB - OBJECTIVE: To evaluate the association between patient-reported outcome (PRO) and performance-based (PB) measures of physical functioning (PF) among individuals with self-identified arthritis to inform decisions of which to use when evaluating the effectiveness of a physical activity intervention. METHODS: Secondary data analysis of a nonrandomized 2-arm pre-post community trial of 462 individuals who self-identified as having arthritis and participated in the Walk with Ease (WWE) intervention. Two PRO and 8 PB assessments were collected at baseline (preintervention) and at 6-week followup. We calculated correlations between PB and PRO measures, assessed how measures identified changes in PF from baseline to followup, and compared PRO and PB measures to arthritis symptoms of pain, stiffness, and fatigue. RESULTS: Strength of correlations between PB and PRO measures varied depending on the PB measure, ranging from 0.21 to 0.54. PRO and PB measures identified PF improvements from baseline to followup, but none showed significant differences between the 2 WWE modalities (instructor-led or self-directed groups). Correlations with arthritis symptoms were stronger for PRO (0.30-0.46) than PB measures (0.03-0.31). CONCLUSION: PRO measures may provide us with insights into aspects of PF that are not identified by PB measures alone. Use of PRO measures allows patients to communicate their perceptions of PF, which may provide a more accurate representation of overall PF. Our study does not suggest abandoning the use of PB measures to characterize PF in patients with self-identified arthritis, but recommends that PRO measures may serve as complementary or surrogate endpoints for some studies. PMID- 26628601 TI - Healthcare Resource Use and Direct Costs in Patients with Ankylosing Spondylitis and Psoriatic Arthritis in a Large US Cohort. AB - OBJECTIVE: Direct costs of ankylosing spondylitis (AS) and psoriatic arthritis (PsA) have not been well characterized in the United States. This study assessed healthcare resource use and direct cost of AS and PsA, and identified predictors of all-cause medical and pharmacy costs. METHODS: Adults aged >= 18 with a diagnosis of AS and PsA were identified in the MarketScan databases between October 1, 2011, and September 30, 2012. Patients were continuously enrolled with medical and pharmacy benefits for 12 months before and after the index date (first diagnosis). Baseline demographics and comorbidities were identified. Direct costs included hospitalizations, emergency room and office visits, and pharmacy costs. Multivariable regression was used to determine whether baseline covariates were associated with direct costs. RESULTS: Patients with AS were younger and mostly men compared with patients with PsA. Hypertension and hyperlipidemia were the most common comorbidities in both cohorts. A higher percentage of patients with PsA used biologics and nonbiologic disease-modifying drugs (61.1% and 52.4%, respectively) compared with patients with AS (52.5% and 21.8%, respectively). Office visits were the most commonly used resource by patients with AS and PsA (~11 visits). Annual direct medical costs [all US dollars, mean (SD)] for patients with AS and PsA were $6514 ($32,982) and $5108 ($22,258), respectively. Prescription drug costs were higher for patients with PsA [$14,174 ($15,821)] compared with patients with AS [$11,214 ($14,249)]. Multivariable regression analysis showed higher all-cause direct costs were associated with biologic use, age, and increased comorbidities in patients with AS or PsA (all p < 0.05). CONCLUSION: Biologic use, age, and comorbidities were major determinants of all-cause direct costs in patients with AS and PsA. PMID- 26628603 TI - Development of a Prediction Model to Estimate the Risk of Walking Limitations in Patients with Total Knee Arthroplasty. AB - OBJECTIVE: Early and accurate risk prediction of walking limitations after total knee arthroplasty (TKA) is important for clinical and economic reasons. However, to our knowledge, no studies have systematically integrated multiple predictors into a single, clinically practical model. Our study aimed to develop a prediction model to estimate the risk of post-TKA walking limitations. METHODS: We performed a prospective cohort study of 1096 patients who underwent elective, primary TKA between July 2013 and September 2014. Candidate predictors included patient demographics, surgical factors, and pre- and early (1-mo) post-TKA functional measures. The outcome of interest was self-reported walking limitations at 6 months of post-TKA. We used multivariable proportional odds regression with bootstrap internal validation to develop the model. RESULTS: In all, 12% of patients reported walking limitations (maximum walk time <= 15 min) at 6 months postsurgery. The main predictors of increasing levels of walking limitations were preoperative walking limitations (overall p < 0.001), higher levels of body mass index [interquartile range (IQR)-OR 1.3, 95% CI 1.2-1.5], lower values of 1-month post-TKA gait speed (IQR-OR 1.9, 95% CI 1.3-2.6), the presence of contralateral knee pain (OR 1.9, 95% CI 1.2-3.0), and the use of a quadstick preoperatively (OR 3.5, 95% CI 1.7-7.3). The prediction model had an optimism-corrected concordance index of 0.71. CONCLUSION: A small but sizable proportion of patients with TKA had persistent mobility limitations. Our prediction model may help to risk-stratify patients, and external validation is required before the model can be used in clinical practice. PMID- 26628602 TI - Diagnostic Arthrocentesis for Suspicion of Gout Is Safe and Well Tolerated. AB - OBJECTIVE: To determine the frequency of adverse events of diagnostic arthrocentesis in patients with possible gout. METHODS: Consecutive patients underwent arthrocentesis and were evaluated at 6 weeks to determine adverse events. The 95% CI were obtained by bootstrapping. RESULTS: Arthrocentesis was performed in 910 patients, and 887 (97.5%) were evaluated for adverse events. Any adverse event was observed in 12 participants (1.4%, 95% CI 0.6-2.1). There was 1 case (0.1%, 95% CI 0-0.34) of septic arthritis. CONCLUSIONS: Diagnostic arthrocentesis is associated with a low frequency of adverse events. Septic arthritis rarely occurs. PMID- 26628604 TI - Effectiveness and Feasibility Associated with Switching to a Second or Third TNF Inhibitor in Patients with Psoriatic Arthritis: A Cohort Study from Southern Sweden. AB - OBJECTIVE: Because new modes of action for the treatment of psoriatic arthritis (PsA) are emerging, it is important to understand the use of switching to a second or third antitumor necrosis factor (anti-TNF) agent. This study investigated drug survival and treatment response rates of patients with PsA undergoing second- and third-line anti-TNF therapy. METHODS: Patients with PsA were monitored in a prospective, observational study. Patients who switched anti TNF therapy once (first-time switchers, n = 217) or twice (second-time switchers, n = 57) between January 2003 and March 2012 were studied. American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) good response at 3 and 6 months, as well as drug survival, were reported and further analyzed using the Cox and logistic regression models. RESULTS: Median age for first-time switchers was 47 years and 42% were men. The corresponding values for second-time switchers were 48 years and 40% men. Three-month ACR20 Lund Efficacy Index (LUNDEX) response was achieved by 47% of first-time and 22% of second-time switchers; ACR50 LUNDEX rates were 21% and 14%, ACR70 LUNDEX rates were 12% and 2%, and EULAR good LUNDEX rates were 26% and 10%, respectively. Median drug survival time for patients switching anti-TNF for the first time was 64 months (95% CI 31-97) compared with 14 months (95% CI 5-23) for second-time switchers. Identified baseline predictor of ACR20 response to second-line treatment was the 28-joint Disease Activity Score values at baseline (OR 1.45, 95% CI 1.01-2.10), while higher Health Assessment Questionnaire scores predicted premature drug withdrawal (HR 1.60, 95% CI 1.03-2.48). CONCLUSION: Response rates of first-time anti-TNF switchers are moderate, while the inferior response rates of second-time switchers suggest other therapeutic options should be considered in this situation. PMID- 26628605 TI - Patients with Rheumatoid Arthritis have Similar Excellent Outcomes after Total Knee Replacement Compared with Patients with Osteoarthritis. AB - OBJECTIVE: Although new treatments for rheumatoid arthritis (RA) are extremely effective in preventing disease progression, rates of total knee replacement (TKR) continue to rise. The ongoing need for TKR is problematic, especially as functional outcomes in patients with RA have been reported to be worse than in patients with osteoarthritis (OA). The purpose of this study is to assess pain, function, and quality of life 2 years after TKR in contemporary patients with RA compared with patients with OA. METHODS: Primary TKR cases enrolled between May 1, 2007 and July 1, 2010 in a single institution TKR registry were eligible for this study. Validated RA cases were compared with OA at baseline and at 2 years. RESULTS: We identified 4456 eligible TKR, including 136 RA. Compared with OA, RA TKR had significantly worse preoperative Western Ontario and McMaster Universities Osteoarthritis Index pain (55.9 vs 46.6, p < 0.0001) and function (58.7 vs 47.3, p < 0.0001); however, there were no differences at 2 years. Within RA, there was no difference for patients who were treated with biologic disease modifying antirheumatic drugs versus those who did not in pain (p = 0.41) or function (p = 0.39) at 2 years. In a multivariate regression, controlling for multiple potential confounders, there was no independent association of RA with 2 year pain (p = 0.18) or function (p = 0.71). Satisfaction was high for both RA and OA. CONCLUSION: Patients with RA undergoing primary TKR have excellent 2-year outcomes, comparable with OA, in spite of worse preoperative pain and function. In this contemporary cohort, RA is not an independent risk factor for poor outcomes. PMID- 26628606 TI - Fat Mass Is Associated with Foot Pain in Men: The Geelong Osteoporosis Study. AB - OBJECTIVE: Foot pain is a common complaint in adults. Evidence suggests that body composition is involved in the development of foot pain. However, whether this is the case in men remains unclear because previous studies mainly examined women. The aim of this cross-sectional study was to determine the relationship between body composition and foot pain in men while accounting for important risk factors. METHODS: Among 978 men (median age 60 yrs, range 24-98) from the Geelong Osteoporosis Study who participated in a followup study in 2006 to 2011, 796 provided responses to questions on health status and foot pain. Foot pain was determined using the Manchester Foot Pain and Disability Index, and body composition was measured using dual-energy x-ray absorptiometry. RESULTS: Of the 796 respondents, 177 (22%) had foot pain. Risk factors for foot pain were age (OR 1.03, 95% CI 1.02-1.04), self-reported depression (OR 2.05, 95% CI 1.30-3.20), decreased mobility (OR 1.54, 95% CI 1.05-2.24), and lower education (OR 1.47, 95% CI 1.03-2.09). Foot pain was associated with body mass index (OR 1.05, 95% CI 1.00-1.10), fat mass (OR 1.02, 95% CI 1.03-1.05), and fat mass index (OR 1.08, 95% CI 1.01-1.15), but not fat-free mass (OR 1.01, 95% CI 0.98-1.04) or fat-free mass index (OR 1.05, 95% CI 0.95-1.15) after appropriate adjustments were made. CONCLUSION: Fat mass is associated with foot pain in men. These findings complement those in studies that have mainly examined women, and provide further evidence for the relationship between obesity and foot pain. PMID- 26628608 TI - Test-retest Reliability and Correlations of 5 Global Measures Addressing At-work Productivity Loss in Patients with Rheumatic Diseases. AB - OBJECTIVE: Several global measures to assess at-work productivity loss or presenteeism in patients with rheumatic diseases have been proposed, but the comparative validity is hampered by the lack of data on test-retest reliability and comparative concurrent and construct validity. Our objective was to test retest 5 global measures of presenteeism and to compare the association between these scales and health-related well-being. METHODS: Sixty-five participants with inflammatory arthritis or osteoarthritis in paid employment were recruited from 7 countries (UK, Canada, Netherlands, France, Sweden, Romania, and Italy). At baseline and 2 weeks later, 5 global measures of presenteeism were evaluated: the Work Productivity Scale-Rheumatoid Arthritis (WPS-RA), Work Productivity and Activity Impairment Questionnaire (WPAI), Work Ability Index (WAI), Quality and Quantity questionnaire (QQ), and the WHO Health and Performance Questionnaire (HPQ). Agreement between the 2 timepoints was assessed using single-measure intraclass correlations (ICC) and correlated between each other and with visual analog scale general well-being scores at followup by Spearman correlation. RESULTS: ICC between measures ranged from fair (HPQ 0.59) to excellent (WPS-RA 0.78). Spearman correlations between measures were moderate (Qquality vs WAI, r = 0.51) to strong (WPS-RA vs WPAI, r = 0.88). Correlations between measures and general well-being were low to moderate, ranging from -0.44 <= r <= 0.66. CONCLUSION: Test-retest results of 4 out of 5 global measures were good, and the correlations between these were moderate. The latter probably reflect differences in the concepts, recall periods, and references used in the measures, which implies that some measures are probably not interchangeable. PMID- 26628607 TI - Effect of Milnacipran on Pain in Patients with Rheumatoid Arthritis with Widespread Pain: A Randomized Blinded Crossover Trial. AB - OBJECTIVE: Clinical trials have shown that serotonin norepinephrine reuptake inhibitors, such as milnacipran, decrease pain in noninflammatory pain conditions such as fibromyalgia and osteoarthritis. We examined the effect of milnacipran on self-reported pain intensity and experimental pain sensitivity among patients with rheumatoid arthritis (RA) with widespread pain and stable RA disease activity. METHODS: In this double-blind, crossover study, patients with RA with widespread pain, receiving a stable treatment regimen, were randomized (by a random number generator) to receive milnacipran 50 mg twice daily or placebo for 6 weeks, followed by a 3-week washout and crossed over to the other arm for the remaining 6 weeks. The primary outcome was change in average pain intensity, assessed by the Brief Pain Inventory short form. The sample size was calculated to detect a 30% improvement in pain with power = 0.80 and alpha = 0.05. RESULTS: Of the 43 randomized subjects, 41 received the study drug, and 32 completed the 15-week study per protocol. On a 0-10 scale, average pain intensity decreased by 0.39 (95% CI -1.27 to 0.49, p = 0.37) more points during 6 weeks of milnacipran treatment compared with placebo. In the subgroup of subjects with swollen joint count <= 1, average pain intensity decreased by 1.14 more points during 6 weeks of milnacipran compared with placebo (95% CI -2.26 to -0.01, p = 0.04). Common adverse events included nausea (26.8%) and loss of appetite (9.7%). CONCLUSION: Compared with placebo, milnacipran did not improve overall, self-reported pain intensity among subjects with widespread pain receiving stable RA medications. TRIAL REGISTRATION: ClinicalTrials.gov NCT01207453. PMID- 26628609 TI - Asparagine Metabolic Pathways in Arabidopsis. AB - Inorganic nitrogen in the form of ammonium is assimilated into asparagine via multiple steps involving glutamine synthetase (GS), glutamate synthase (GOGAT), aspartate aminotransferase (AspAT) and asparagine synthetase (AS) in Arabidopsis. The asparagine amide group is liberated by the reaction catalyzed by asparaginase (ASPG) and also the amino group of asparagine is released by asparagine aminotransferase (AsnAT) for use in the biosynthesis of amino acids. Asparagine plays a primary role in nitrogen recycling, storage and transport in developing and germinating seeds, as well as in vegetative and senescence organs. A small multigene family encodes isoenzymes of each step of asparagine metabolism in Arabidopsis, except for asparagine aminotransferase encoded by a single gene. The aim of this study is to highlight the structure of the genes and encoded enzyme proteins involved in asparagine metabolic pathways; the regulation and role of different isogenes; and kinetic and physiological properties of encoded enzymes in different tissues and developmental stages. PMID- 26628610 TI - DESIGN DEVELOPMENT OF A PASSIVE NEUTRON DOSEMETER FOR THE USE AT HIGH-ENERGY ACCELERATORS. AB - For the radiation survey at intermediate and high-energy accelerators, there is a need for a neutron dosemeter which provides reliable readings of the neutron dose in a wide energy range for continuous and pulsed radiation. The objective of this development is to find a dosemeter that fulfils the necessary requirements and can be reliably used to prove that the radiation levels in areas around accelerators are in accordance with the limits of the respective radiation protection legislation. A simple layout with small dimensions and light weight as well as the usage of common materials to lower the production costs is to be achieved. PMID- 26628611 TI - COMPUTATIONAL ASSESSMENT OF PREGNANT WOMAN MODELS EXPOSED TO UNIFORM ELF-MAGNETIC FIELDS: COMPLIANCE WITH THE EUROPEAN CURRENT EXPOSURE REGULATIONS FOR THE GENERAL PUBLIC AND OCCUPATIONAL EXPOSURES AT 50 Hz. AB - The Recommendation 1999/529/EU and the Directive 2013/35/EU suggest limits for both general public and occupational exposures to extremely low-frequency magnetic fields, but without special limits for pregnant women. This study aimed to assess the compliance of pregnant women to the current regulations, when exposed to uniform MF at 50 Hz (100 MUT for EU Recommendation and 1 and 6 mT for EU Directive). For general public, exposure of pregnant women and fetus always resulted in compliance with EU Recommendation. For occupational exposures, (1) Electric fields in pregnant women were in compliance with the Directive, with exposure variations due to fetal posture of <10 %, (2) electric fields in fetuses are lower than the occupational limits, with exposure variations due to fetal posture of >40 % in head tissues, (3) Electric fields in fetal CNS tissues of head are above the ICNIRP 2010 limits for general public at 1 mT (in 7 and 9 months gestational age) and at 6 mT (in all gestational ages). PMID- 26628612 TI - A MONTE-CARLO SIMULATION FRAMEWORK FOR JOINT OPTIMISATION OF IMAGE QUALITY AND PATIENT DOSE IN DIGITAL PAEDIATRIC RADIOGRAPHY. AB - In paediatric radiography, according to the as low as reasonably achievable (ALARA) principle, the imaging task should be performed with the lowest possible radiation dose. This paper describes a Monte-Carlo simulation framework for dose optimisation of imaging parameters in digital paediatric radiography. Patient models with high spatial resolution and organ segmentation enable the simultaneous evaluation of image quality and patient dose on the same simulated radiographic examination. The accuracy of the image simulation is analysed by comparing simulated and acquired images of technical phantoms. As a first application example, the framework is applied to optimise tube voltage and pre filtration in newborn chest radiography. At equal patient dose, the highest CNR is obtained with low-kV settings in combination with copper filtration. PMID- 26628613 TI - MEDXVIEWER: PROVIDING A WEB-ENABLED WORKSTATION ENVIRONMENT FOR COLLABORATIVE AND REMOTE MEDICAL IMAGING VIEWING, PERCEPTION STUDIES AND READER TRAINING. AB - MedXViewer (Medical eXtensible Viewer) has been developed to address the need for workstation-independent, picture archiving and communication system (PACS)-less viewing and interaction with anonymised medical images. The aim of this paper is to describe the design and features of MedXViewer as well as to introduce the new features available in the latest release (version 1.2). MedXViewer currently supports digital mammography and tomosynthesis. The flexible software design used to develop MedXViewer allows it to be easily extended to support other imaging modalities. Regions of interest can be drawn by a user, and any associated information about a mark, an image or a study can be added. The questions and settings can be easily configured depending on the need of the research allowing both ROC and FROC studies to be performed. Complex tree-like questions can be asked where a given answer presents the user to new questions. The hanging protocol can be specified for each study. Panning, windowing, zooming and moving through slices are all available while modality-specific features can be easily enabled, e.g. quadrant zooming in digital mammography and tomosynthesis studies. MedXViewer can integrate with a web-based image database OPTIMAM Medical Image Database allowing results and images to be stored centrally. The software can, alternatively, run without a network connection where the images and results can be encrypted and stored locally on a machine or external drive. MedXViewer has been used for running remote paper-less observer studies and is capable of providing a training infrastructure and coordinating remote collaborative viewing sessions. PMID- 26628615 TI - OCT imaging of aorto-coronary vein graft pathology modified by external stenting: 1-year post-surgery. AB - AIMS: The Venous External Support Trial (VEST) evaluated whether a novel external stent attenuated saphenous vein graft (SVG) disease assessed with intravascular ultrasound 1 year following coronary artery bypass graft (CABG) surgery. This sub study assessed SVGs with and without external stenting using optical coherence tomography (OCT). The aim of this study was to accurately compare quantitative and qualitative features of SVGs with and without a novel external stent using OCT. METHODS AND RESULTS: Twenty-four of 30 patients (65 +/- 8 years) enrolled in VEST underwent coronary angiography with OCT imaging using a non-occlusive technique. Quantitative analysis of lumen area was performed in one frame every 10 mm along the length of the graft, from distal to proximal anastomosis, and pathological features within the lumen were noted. Mean cross-sectional area was greater in unstented vs. stented grafts (8.4 +/- 3 vs. 7.6 +/- 2.7 mm; P = 0.005). The lumen of the stented grafts was more homogeneous (difference between maximum and minimum lumen diameter was significantly smaller in stented compared with unstented grafts, 0.28 +/- 0.19 vs. 0.33 +/- 0.23 mm, respectively, P = 0.006), and more circular (mean eccentricity index 0.08 +/- 0.06 vs. 0.10 +/- 0.06, stented vs. unstented; P = 0.019). Adherent thrombus was identified in three grafts (all unstented). CONCLUSION: Our findings highlight the early changes occurring in SVGs after implantation of aorto-coronary bypass conduits, changes that may accelerate vein graft failure. External stenting resulted in a more homogeneous and less eccentric lumen with no thrombus formation. PMID- 26628614 TI - Safety and Tolerability of ACP-501, a Recombinant Human Lecithin:Cholesterol Acyltransferase, in a Phase 1 Single-Dose Escalation Study. AB - RATIONALE: Low high-density lipoprotein-cholesterol (HDL-C) in patients with coronary heart disease (CHD) may be caused by rate-limiting amounts of lecithin:cholesterol acyltransferase (LCAT). Raising LCAT may be beneficial for CHD, as well as for familial LCAT deficiency, a rare disorder of low HDL-C. OBJECTIVE: To determine safety and tolerability of recombinant human LCAT infusion in subjects with stable CHD and low HDL-C and its effect on plasma lipoproteins. METHODS AND RESULTS: A phase 1b, open-label, single-dose escalation study was conducted to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of recombinant human LCAT (ACP-501). Four cohorts with stable CHD and low HDL-C were dosed (0.9, 3.0, 9.0, and 13.5 mg/kg, single 1-hour infusions) and followed up for 28 days. ACP-501 was well tolerated, and there were no serious adverse events. Plasma LCAT concentrations were dose proportional, increased rapidly, and declined with an apparent terminal half-life of 42 hours. The 0.9-mg/kg dose did not significantly change HDL-C; however, 6 hours after doses of 3.0, 9.0, and 13.5 mg/kg, HDL-C was elevated by 6%, 36%, and 42%, respectively, and remained above baseline <=4 days. Plasma cholesteryl esters followed a similar time course as HDL-C. ACP-501 infusion rapidly decreased small- and intermediate-sized HDL, whereas large HDL increased. Pre beta-HDL also rapidly decreased and was undetectable <=12 hours post ACP-501 infusion. CONCLUSIONS: ACP-501 has an acceptable safety profile after a single intravenous infusion. Lipid and lipoprotein changes indicate that recombinant human LCAT favorably alters HDL metabolism and support recombinant human LCAT use in future clinical trials in CHD and familial LCAT deficiency patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01554800. PMID- 26628616 TI - Diastolic function improvement is associated with favourable outcomes in patients with acute non-ischaemic cardiomyopathy: insights from the multicentre IMAC-2 trial. AB - AIMS: Patients with recent onset non-ischaemic cardiomyopathy have a variable clinical course with respect to recovery of left ventricular ejection fraction (LVEF). The aim of this study was to understand whether temporal changes in diastolic function (DF) are associated with clinical outcomes independent of LVEF recovery. METHODS AND RESULTS: The Intervention in Myocarditis and Acute Cardiomyopathy (IMAC)-2 study was a prospective, multicentre trial investigating myocardial recovery in subjects with symptoms onset of <6 months and LVEF <=40% of non-ischaemic dilated cardiomyopathy related to idiopathic cardiomyopathy or myocarditis. LVEF and DF were measured at presentation and at 6-month follow-up. Of 147 patients (mean age 46 +/- 14 years, 40% female), baseline LVEF was 23 +/- 8%. At 6 months, LVEF improved to 41 +/- 12%, with 71% increasing by at least 10% ejection fraction units. DF improved in 58%, was unchanged in 28%, and worsened in 14%. Over a mean follow-up of 1.8 +/- 1.2 years, there were 18 events: 11 heart failure (HF) hospitalizations, 3 deaths, and 4 heart transplants. LVEF (HR = 0.94, 95% CI 0.91-0.98, P = 0.002) and DF improvements at 6 months (HR = 0.32, 95% CI 0.11-0.92, P = 0.03) were independently associated with lower likelihood for the combined end point of death, transplantation, and HF hospitalization. Diastolic functional improvement at 6-month follow-up was as prognostically important as LVEF recovery for these patients, and provided incremental prognostic value to the risk stratification (X(2) increased from 12.6 to 18, P = 0.02). CONCLUSION: In patients with recent onset non-ischaemic cardiomyopathy, DF recovery was associated with favourable outcomes independent of LVEF improvement, adding incremental prognostic value to these patients. PMID- 26628617 TI - Diagnostic accuracy of cadmium-zinc-telluride-based myocardial perfusion SPECT: impact of attenuation correction using a co-registered external computed tomography. AB - INTRODUCTION: Computed tomography (CT)-based attenuation correction (AC) improves the accuracy of standard myocardial perfusion SPECT. Most dedicated cadmium-zinc telluride (CZT) SPECT cameras are not equipped with an integrated CT component. We aimed to determine the impact of AC on diagnostic performance of CZT SPECT using co-registration with an external low-dose CT. METHODS: Sixty patients underwent CZT SPECT (GE Discovery 530c) with (99m)Tc-sestamibi at rest and following regadenoson stress. Using commercial software, SPECT images were co registered with a low-dose CT acquired on a separate system (GE Discovery 670NMCT). Attenuation corrected and non-corrected (NC) images were reconstructed using an iterative algorithm. Accuracy was measured in 44 patients who had undergone invasive angiography within 6 months. Normalcy was compared in the remaining 16 patients who had a low pre-test likelihood (<5%) of coronary artery disease (CAD). RESULTS: Summed stress and rest scores were significantly lower in AC images (9 +/- 8 vs. 13 +/- 9 and 6 +/- 7 vs. 10 +/- 9, P = 0.01), while summed difference score did not differ. According to angiography, 38 patients had significant CAD in 71 vascular territories. Attenuation correction improved accuracy globally (P = 0.03) and in RCA territory (P = 0.008). Specificity improved both globally (100 vs. 40%, P < 0.05) and in each individual territory (LAD: 63 vs. 36%, LCX: 70 vs. 33%, RCA: 81 vs. 19%, P < 0.01). Normalcy was 100% for AC and 62.5% for NC images (P < 0.05). CONCLUSION: Attenuation correction with a co-registered external CT is feasible using CZT cameras and improves diagnostic accuracy mostly by improving specificity over uncorrected images. PMID- 26628618 TI - Cardiac CT for the detection of vulnerable plaque. PMID- 26628620 TI - beta-Adrenergic Receptors Cooperate With Transcription Factors: The "STAT" of Their Union. PMID- 26628619 TI - Evaluation of a Portable Armband Device to Assess Resting Energy Expenditure in Patients With Anorexia Nervosa. AB - BACKGROUND: In women with anorexia nervosa (AN), resting energy expenditure (REE) is decreased due to reduced energy intake and severe underweight. The assessment of REE allows estimating individual metabolic downregulation and better understanding body weight regulatory mechanisms in severely underweight patients with AN. However, REE predictive equations are known to have considerable shortcomings in patients with AN. Our aim was to evaluate a portable armband device (SenseWear armband [SWA]; BodyMedia, Inc, Pittsburgh, PA) for the assessment of REE against the measurement with indirect calorimetry (IC) as the reference method. METHODS: We assessed REE simultaneously by IC and SWA in 50 women with AN at the start of inpatient therapy and calculated REE using 2 predictive equations. RESULTS: Reliable data for IC measurement were obtained for 34 patients (age: 27.0 +/- 8.0 years; body mass index: 14.4 +/- 2.0 kg/m2). REE assessed with SWA was overestimated by 23% +/- 27% compared with REE measured by IC (1166 +/- 174 vs 979 +/- 198 kcal/d, P < .001). REE estimation with SWA gave an accurate prediction within 10% deviation of REE measured with IC in 35% of the patients. In contrast, REE calculated with 2 predictive equations underestimated REE measured with IC by -26% +/- 17% and -5% +/- 20%, respectively. CONCLUSIONS: A mean difference of 187 kcal/d between both techniques for the assessment of REE may be of methodological relevance. Therefore, SWA and IC are not interchangeable methods for the assessment of REE in underweight females with AN. PMID- 26628621 TI - Critical Roles of STAT3 in beta-Adrenergic Functions in the Heart. AB - BACKGROUND: beta-Adrenergic receptors (betaARs) play paradoxical roles in the heart. On one hand, betaARs augment cardiac performance to fulfill the physiological demands, but on the other hand, prolonged activations of betaARs exert deleterious effects that result in heart failure. The signal transducer and activator of transcription 3 (STAT3) plays a dynamic role in integrating multiple cytokine signaling pathways in a number of tissues. Altered activation of STAT3 has been observed in failing hearts in both human patients and animal models. Our objective is to determine the potential regulatory roles of STAT3 in cardiac betaAR-mediated signaling and function. METHODS AND RESULTS: We observed that STAT3 can be directly activated in cardiomyocytes by beta-adrenergic agonists. To follow up this finding, we analyzed betaAR function in cardiomyocyte-restricted STAT3 knockouts and discovered that the conditional loss of STAT3 in cardiomyocytes markedly reduced the cardiac contractile response to acute betaAR stimulation, and caused disengagement of calcium coupling and muscle contraction. Under chronic beta-adrenergic stimulation, Stat3cKO hearts exhibited pronounced cardiomyocyte hypertrophy, cell death, and subsequent cardiac fibrosis. Biochemical and genetic data supported that Galphas and Src kinases are required for betaAR-mediated activation of STAT3. Finally, we demonstrated that STAT3 transcriptionally regulates several key components of betaAR pathway, including beta1AR, protein kinase A, and T-type Ca(2+) channels. CONCLUSIONS: Our data demonstrate for the first time that STAT3 has a fundamental role in betaAR signaling and functions in the heart. STAT3 serves as a critical transcriptional regulator for betaAR-mediated cardiac stress adaption, pathological remodeling, and heart failure. PMID- 26628623 TI - PEPRs spice up plant immunity. AB - Some pattern recognition receptors (PRRs) in plants, such as PEPRs, sense endogenous, damage-associated molecular patterns (DAMPs) that are released during pathogen infection. In this issue of The EMBO Journal, Yamada and colleagues show that genetic or pathogen-induced depletion of Arabidopsis BAK1, a co-receptor for multiple PRRs, primes immune activation through PEPRs. The work illustrates a link between pathogen-induced perturbation of BAK1 and DAMP signaling. PMID- 26628624 TI - The extent of stretched lamellar cleavage and visual acuity in macular pseudoholes. AB - BACKGROUND/AIMS: To evaluate the extent of lamellar cleavage and its association with preoperative and postoperative visual acuity (VA) in macular pseudoholes. METHODS: One eye each of 50 patients with macular pseudohole who underwent vitrectomy was retrospectively investigated. Preoperative macular pseudoholes were evaluated using spectral-domain optical coherence tomography (SD-OCT) images taken radially around the central fovea at 30 degrees intervals. The macular pseudoholes were categorised into stage 1 (no cleavage), stage 2 (localised cleavage with (2b) and without (2a) crossing central fovea) and stage 3 (diffuse cleavage). RESULTS: Among the 50 macular pseudoholes, 14, 13, 9 and 14 were categorised into stages 1, 2a, 2b and 3, respectively. The extent of stretched cleavages was associated with worse baseline VA (p=0.0049 by multiple regression model). After surgery, the stretched lamellar cleavage disappeared in 32 patients out of 36 who were postoperatively examined by SD-OCT. In addition, the extensive cleavage (stage 2b/3) independently predicted larger postoperative VA recovery at 3 months by 0.105 logMAR compared with no/mild cleavage (stage 1/2a, p=0.030 by multiple regression model). CONCLUSIONS: Although advanced cleavage in macular pseudohole is associated with worse VA before surgery, even an advanced pseudohole could show favourable visual recovery after surgery. PMID- 26628625 TI - Long-term visual acuity, retention and complications observed with the type-I and type-II Boston keratoprostheses in an Irish population. AB - AIM: To evaluate the outcomes of the type-I and type-II Boston keratoprostheses in a single Irish centre. METHODS: A retrospective chart review of keratoprosthesis implantations carried out in our institution from November 2002 to March 2014 was performed. All procedures were performed by a single surgeon (WP). RESULTS: Thirty-four keratoprosthesis implantations were carried out in 31 patients with a mean follow-up of 42+/-31 months (range 2-110 months). Seventeen patients were female (54.8%) and 14 were male (45.2%). The majority of keratoprostheses implanted were type-I (31/34, 91.2%), and three were type-II (3/34, 8.8%). Twenty-nine patients (85.3%) had an improvement in distance best corrected visual acuity (BCVA) from baseline. Fifty per cent (17/34) of patients had a best-ever BCVA of at least 6/12. Eighteen patients (64.3%) retained a BCVA of at least 6/60 at 1 year. Over the course of follow-up, six keratoprostheses were explanted from six eyes of five patients, one of which was a type-II keratoprosthesis. Twenty-six patients (76.5%) developed postoperative complications. Complications included retroprosthetic membrane (18 patients, 52.9%), an exacerbation or new diagnosis of glaucoma (6 patients, 17.6%), endophthalmitis (5 patients, 14.7%) and retinal detachment (2 patients, 5.9%). CONCLUSIONS: These data demonstrate excellent visual acuity and retention outcomes in a cohort with a long follow-up period in a single centre. Complications remain a considerable source of morbidity. These outcomes provide further evidence for the long-term stability of type-I and type-II Boston keratoprostheses in the management of patients in whom a traditional graft is likely to fail. PMID- 26628622 TI - Spatiotemporal regulation of posttranslational modifications in the DNA damage response. AB - A timely and accurate cellular response to DNA damage requires tight regulation of the action of DNA damage response (DDR) proteins at lesions. A multitude of posttranslational modifications (PTMs) of chromatin and chromatin-associated proteins coordinates the recruitment of critical proteins that dictate the appropriate DNA repair pathway and enable the actual repair of lesions. Phosphorylation, ubiquitylation, SUMOylation, neddylation, poly(ADP ribosyl)ation, acetylation, and methylation are among the DNA damage-induced PTMs that have taken center stage as important DDR regulators. Redundant and multivalent interactions of DDR proteins with PTMs may not only be a means to facilitate efficient relocalization, but also a feature that allows high temporal and spatial resolution of protein recruitment to, and extraction from, DNA damage sites. In this review, we will focus on the complex interplay between such PTMs, and discuss the importance of their interconnectivity in coding DNA lesions and maintaining the integrity of the genome. PMID- 26628626 TI - Correlation of central visual function and ROP risk factors in prematures with and without acute ROP at the age of 6-13 years: the Giessen long-term ROP study. AB - AIM: To correlate light increment sensitivity (LIS) and visual acuity (VA) with birth weight (BW), gestational age (GA) and stage of acute retinopathy of prematurity (ROP) (STG) in premature children at school age. METHODS: 180 children (150 former prematures and 30 age-matched term-born children) were enrolled at age 6-13 years. Former prematures were categorised by the results of the initial ROP screening based on digital wide-field fundus imaging: absence of ROP (n=100) and spontaneously resolved ROP (n=50). The latter group was further subdivided according to their STG (Stg 1; Stg 2; Stg 3). Both groups were categorised into sectors by BW (<1000 g; 1000-1500 g; >1500 g), and GA (<=28 weeks; >28<32 weeks; >=32 weeks). VA was assessed with Early Treatment of Diabetic Retinopathy Study letters, LIS was measured at 0 degrees , 2.8 degrees and 8 degrees in the visual field (Microperimeter MP1, Nidek Technologies), and spherical equivalent refraction assessed with a Nidek autorefractor (Nidek, Italy). RESULTS: Central and pericentral LIS (0 degrees and 2.8 degrees ) and VA were significantly lower in all groups and sectors compared with term-born controls except for BW >1500 g for LIS and GA >28 to <32 W for VA. No significant differences were found for LIS at 8 degrees in all groups. No correlation was found between LIS and VA on an individual basis. CONCLUSIONS: Low BW, GA and increasing severity of spontaneously resolving ROP were associated with significantly decreased central visual function. In addition to VA, LIS measurement further describes foveal function and is a unique parameter to assess parafoveal function. PMID- 26628627 TI - Assessing visual function in children with complex disabilities: the Bradford visual function box. AB - BACKGROUND: Assessment of children with complex and severe learning disabilities is challenging and the children may not respond to the monochrome stimuli of traditional tests. The International Association of Scientific Studies on Intellectual Disability recommends that visual function assessment in poorly or non-cooperative children should be undertaken in an objective manner. We have developed a functional visual assessment tool to assess vision in children with complex and multiple disabilities. METHODS: The Bradford visual function box (BVFB) comprises a selection of items (small toys) of different size and colour, which are presented to the child and the response observed. The aim of this study is to establish its intertester validity in children with severe learning disability. The visual function of 22 children with severe learning disability was assessed using the BVFB. The children were assessed by experienced practitioners on two separate occasions. The assessors were unaware of each other's findings. RESULTS: In 15/22 of the children, no difference was found in the results of the two assessors. The test was shown to have a good intertester agreement, weighted kappa=0.768. CONCLUSIONS: The results of this clinical study show that the BVFB is a reliable tool for assessing the visual function in children with severe learning disability in whom other tests fail to elicit a response. The need for a tool which is quick to administer and portable has previously been highlighted. The BVFB offers an option for children for whom other formal tests are unsuccessful in eliciting a response. PMID- 26628628 TI - Investigation of the association of Vogt-Koyanagi-Harada syndrome with IL23R C1orf141 in Han Chinese Singaporean and ADO-ZNF365-EGR2 in Thai. AB - BACKGROUND: We performed a multistage genome-wide association study of Vogt Koyanagi-Harada (VKH) syndrome in a Han Chinese population and identified two novel non-human leukocyte antigen candidate regions previously. The aim of the study was to replicate the association of IL23R-C1orf141 and ADO-ZNF365-EGR2 with VKH syndrome in four sets of multinational populations in Asia. METHOD: We conducted a candidate genes association study involving 185 patients with VKH syndrome and 287 normal controls from Han Chinese Singaporeans, non-Han Chinese, Thais and Koreans. Genotyping of 16 single nucleotide polymorphisms (SNPs) within IL23R-C1orf141 and ADO-ZNF365-EGR2 loci was performed using the Sequenom MassARRAY system or by Taqman SNP assays. RESULTS: Eight SNPs in IL23R-Clorf141 showed an association with VKH syndrome only in Han Chinese Singaporeans (p=8.49*10(-5) to 1.02*10(-3), pcorrection=1.69*10(-4) to 2.04*10(-3)) but not in the other groups tested. One SNP rs1884444 in IL23R-Clorf141 was found to be weakly associated with VKH syndrome in the Han Chinese Singaporeans, but significance was lost following Bonferroni correction for multiple comparisons. Five SNPs in ADO-ZNF365-EGR2 were found to be associated with VKH syndrome in Thai patients with VKH (p=0.014, pc=0.028) but not in the other three ethnic groups tested. CONCLUSIONS: This study confirmed the genetic associations between SNPs in IL23R-C1orf141 and VKH syndrome in Han Chinese Singaporeans but not in other Asian populations. In addition, we also successfully replicated the association of VKH syndrome with ADO-ZNF365-EGR2 in a Thai population. PMID- 26628629 TI - A comparison of the efficacy of fixed versus removable functional appliances in children with Class II malocclusion: A systematic review. AB - OBJECTIVES: To systematically compare the efficacy of fixed and removable functional appliances in Class II malocclusion in terms of morphological and patient-centred outcomes. SEARCH METHODS: A comprehensive search of electronic databases without language or time restrictions was undertaken, applying a pre specified search strategy. Supplementary electronic searching of orthodontics journals and references list of included studies was performed. SELECTION CRITERIA: Randomized (RCTs) and controlled (CCTs) clinical trials involving children under 16 years with Class II malocclusion and overjet more than 5mm were included. DATA COLLECTION AND ANALYSIS: A range of clinician- and patient-centred outcomes were evaluated and compared. Risk of bias assessment was carried out using the Cochrane Collaboration tool. RESULTS: Only four clinical trials were found to meet our criteria, of which two were RCTs, comparing the Herbst and the Twin Block appliances. Two further CCTs, compared the Activator to the Forsus and the Twin Force Bite Corrector, respectively. One study was assessed to be at unclear and the remaining at high risk of bias, precluding meta-analysis. There was also significant clinical heterogeneity in terms of methodology, type of intervention and the measured outcomes. Both modalities were effective in correcting the overjet with little differences found in cephalometric changes and a shortage of data concerning patient-centred outcomes. CONCLUSION: There is little evidence concerning the relative effectiveness of fixed and functional appliances or in relation to patient experiences and perceptions of these treatment modalities. Further well-designed clinical trials assessing the relative merits of both clinician- and patient-centred outcomes are needed. PMID- 26628630 TI - Myeloproliferative neoplasms and personalized medicine: the perfect match? PMID- 26628632 TI - Efficacy of rituximab maintenance therapy for aggressive B-cell lymphoma depends on use of rituximab in induction therapy: a meta-analysis of randomized controlled trials. PMID- 26628633 TI - The impact of introducing combined first-trimester trisomy 21 screening in the French population. AB - BACKGROUND: French state health insurance has funded trisomy 21 prenatal screening for all pregnant women since decades. First-trimester combined screening was introduced nationally and funded in 2010. OBJECTIVE: To evaluate the impact of the introduction, of a national policy of prenatal trisomy 21 first trimester screening on the reduction of invasive prenatal diagnostic procedures. METHODS: The results of all prenatal trisomy 21 screening and invasive diagnostic procedures were collected for the whole country over the period 2009-12. The screen-positive rates (risk cut-off 1 : 250, including isolated nuchal translucency >= 3.5 mm), positive predictive values and percentage of cases diagnosed prenatally were calculated. RESULTS: Over the study period the number of women undergoing serum screening (including first- and second-trimester screening tests) increased from 678 803 to 689 651 (83 to 85% of deliveries, P < 0.0001). By 2012, first-trimester combined screening accounted for 70% of all trisomy 21 screening. The screen-positive rate decreased from 9.5 to 4.8% (P < 0.001) resulting in a 37 478 (47%) drop (P < 0.001) in the number of invasive diagnostic procedures. The positive predictive value of screening increased from 2.6 to 6.1% from 2009 to 2012 (P < 0.001), due to the higher positive predictive value of first-trimester over second-trimester screening (9.1 vs. 1.8% over the period 2010-12, P < 0.001). The percentage of prenatally diagnosed cases remained high at around 80% between 2010 and 2012. CONCLUSIONS: The policy shift from second-trimester to first-trimester trisomy 21 screening allowed to reduce the number of invasive tests. The number of antenatal trisomy 21 diagnoses increased (+2.7%) over the study period. PMID- 26628631 TI - The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia is a malignancy of mature auto-reactive B cells. Genetic and functional studies implicate B-cell receptor signaling as a pivotal pathway in its pathogenesis. Full B-cell receptor activation requires tumor microenvironment interactions in lymphoid tissues. Spleen tyrosine kinase, Bruton's tyrosine kinase, and the phosphatidylinositol 3-kinase (PI3K) delta isoform are essential for B-cell receptor signal transduction but also mediate the effect of other pathways engaged in chronic lymphocytic leukemia cells in the tissue-microenvironment. Orally bioavailable inhibitors of spleen tyrosine kinase, Bruton's tyrosine kinase, or PI3Kdelta, induce high rates of durable responses. Ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, and idelalisib, a selective inhibitor of PI3Kdelta, have obtained regulatory approval in chronic lymphocytic leukemia. Ibrutinib and idelalisib are active in patients with high-risk features, achieving superior disease control in difficult-to-treat patients than prior best therapy, making them the preferred agents for chronic lymphocytic leukemia with TP53 aberrations and for patients resistant to chemoimmunotherapy. In randomized trials, both ibrutinib, versus ofatumumab, and idelalisib in combination with rituximab, versus placebo with rituximab improved survival in relapsed/refractory chronic lymphocytic leukemia. Responses to B-cell receptor inhibitors are mostly partial, and within clinical trials treatment is continued until progression or occurrence of intolerable side effects. Ibrutinib and idelalisib are, overall, well tolerated; notable adverse events include increased bruising and incidence of atrial fibrillation on ibrutinib and colitis, pneumonitis and transaminase elevations on idelalisib. Randomized trials investigate the role of B-cell receptor inhibitors in first-line therapy and the benefit of combinations. This review discusses the biological basis for targeted therapy of chronic lymphocytic leukemia with B-cell receptor inhibitors, and summarizes the clinical experience with these agents. PMID- 26628634 TI - Gene-targeting pharmaceuticals for single-gene disorders. AB - The concept of orphan drugs for treatment of orphan genetic diseases is perceived enthusiastically at present, and this is leading to research investment on the part of governments, disease-specific foundations and industry. This review attempts to survey the potential to use traditional pharmaceuticals as opposed to biopharmaceuticals to treat single-gene disorders. The available strategies include the use of antisense oligonucleotides (ASOs) to alter splicing or knock down expression of a transcript, siRNAs to knock-down gene expression and drugs for nonsense mutation read-through. There is an approved drug for biallelic knock down of the APOB gene as treatment for familial hypercholesterolemia. Both ASOs and siRNAs are being explored to knock-down the transthyretin gene to prevent the related form of amyloidosis. The use of ASOs to alter gene-splicing to treat spinal muscular atrophy is in phase 3 clinical trials. Work is progressing on the use of ASOs to activate the normally silent paternal copy of the imprinted UBE3A gene in neurons as a treatment for Angelman syndrome. A gene-activation or gene specific ramp-up strategy would be generally helpful if such could be developed. There is exciting theoretical potential for converting biopharmaceutical strategies such gene correction and CRISPR-Cas9 editing to a synthetic pharmaceutical approach. PMID- 26628635 TI - Assessment of primary health care from the perspective of patients hospitalized for ambulatory care sensitive conditions. AB - BACKGROUND: The hospitalization for ambulatory care sensitive conditions (ACSC) has been used to assess the effectiveness of primary health care (PHC). Due to the existence of different models of organization of PHC in Brazil, it is important to develop indicators and tools for their assessment. OBJECTIVE: Assessment PHC from the perspective of patients hospitalized for ACSC. METHODS: A cross-sectional study was carried out. The patients were interviewed for assessment of PHC quality using the primary care assessment tool and a questionnaire. Descriptive analyses were performed and the Primary Health Care Index (PHCI) was calculated according to the health service modality, either the traditional primary health care (TPHC) or the Family Health Program (FHP). The PHCI of the two health care models were compared. RESULTS: A total of 314 ACSC patients were interviewed 26.4% from the FHP and 73.6% from the TPHC. In general, the PHCI dimension with the lowest score was health service access. There was no significant difference in the general PHCI for the two modalities of services (P = 0.16); however, comprehensiveness was better assessed in the TPHC, while longitudinality, family focus and community orientation were better evaluated by FHP users (P <= 0.05). CONCLUSION: The FHP was found to be better qualified to establish longitudinality in the community, an important dimension for continued care. However, promoting access to and consolidating a proactive care model focussed on family shows to be a great challenge for the implementation of a quality and resolutive PHC in large urban centres. PMID- 26628636 TI - The liver sinusoidal endothelium reappears after being eclipsed by the Kupffer cell: a 20th century biological delusion corrected. PMID- 26628637 TI - Editorial: Ephs, ephrins, and early T cell development. PMID- 26628638 TI - Editorial: Breaching their way through: Neutrophils destroy intercellular junctions to transmigrate rapidly across lymphatic endothelium. PMID- 26628639 TI - Suppression of NLRP3 inflammasome by gamma-tocotrienol ameliorates type 2 diabetes. AB - The Nod-like receptor 3 (NLRP3) inflammasome is an intracellular sensor that sets off the innate immune system in response to microbial-derived and endogenous metabolic danger signals. We previously reported that gamma-tocotrienol (gammaT3) attenuated adipose tissue inflammation and insulin resistance in diet-induced obesity, but the underlying mechanism remained elusive. Here, we investigated the effects of gammaT3 on NLRP3 inflammasome activation and attendant consequences on type 2 diabetes. gammaT3 repressed inflammasome activation, caspase-1 cleavage, and interleukin (IL) 1beta secretion in murine macrophages, implicating the inhibition of NLRP3 inflammasome in the anti-inflammatory and antipyroptotic properties of gammaT3. Furthermore, supplementation of leptin-receptor KO mice with gammaT3 attenuated immune cell infiltration into adipose tissue, decreased circulating IL-18 levels, preserved pancreatic beta-cells, and improved insulin sensitivity. Mechanistically, gammaT3 regulated the NLRP3 inflammasome via a two pronged mechanism: 1) the induction of A20/TNF-alpha interacting protein 3 leading to the inhibition of the TNF receptor-associated factor 6/nuclear factor kappaB pathway and 2) the activation of AMP-activated protein kinase/autophagy axis leading to the attenuation of caspase-1 cleavage. Collectively, we demonstrated, for the first time, that gammaT3 inhibits the NLRP3 inflammasome thereby delaying the progression of type 2 diabetes. This study also provides an insight into the novel therapeutic values of gammaT3 for treating NLRP3 inflammasome-associated chronic diseases. PMID- 26628640 TI - Promoter targeted bisulfite sequencing reveals DNA methylation profiles associated with low sperm motility in asthenozoospermia. AB - STUDY QUESTION: Is there an association between sperm DNA methylation profiles and asthenozoospermia? SUMMARY ANSWER: DNA methylation, at specific CpGs but not at the global level, was significantly different between low motile sperm cells of asthenozoospermic individuals and high motile sperm cells of normozoospermic controls. WHAT IS KNOWN ALREADY: Aberrant DNA methylation, both globally and restricted to a specific gene locus, has been associated with male infertility and abnormal semen parameters. STUDY DESIGN, SIZE, DURATION: This was a case control study investigating the differences in DNA methylation at CpGs in promoter regions between high and low motile sperm cells from eight normozoospermic controls and seven asthenozoospermic patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: The liquid hybridization capture-based bisulfite sequencing method was used to determine DNA methylation at CpGs in promoter regions. The global inter-individual and intra-individual methylation variability were estimated by evaluating the methylation variance between and within different motile sperm fractions from the same or different individuals. Asthenozoospermia-associated differentially methylated or variable CpGs and differentially methylated regions were identified by comparing the DNA methylation of high motile sperm cells from normozoospermic controls with that of low motile sperm cells from asthenozoospermic patients. MAIN RESULTS AND THE ROLE OF CHANCE: In this study, we determined the global DNA methylation level (24.7%), inter-individual variance (14.4%) and intra-individual differences between high and low motile sperm fractions (3.9%). We demonstrated that there were no statistically significant differences in either the global DNA methylation level or global methylation variability between sperm from men with normozoospermia or asthenozoospermia. Between high motile sperm from men with normozoospermia and low motile sperm from men with asthenozoospermia, we identified 134 differentially methylated CpGs, 41 differentially methylated regions and 134 differentially variable CpGs. The genomic distribution patterns of the differential methylation spectrum suggested that gene expression may be affected in low motile sperm cells of asthenozoospermic patients. Finally, through a functional analysis, we detected 16 differentially methylated or variable genes that are required for spermatogenesis and sperm motility or dominantly expressed in testis. LIMITATIONS, REASONS FOR CAUTION: The sample size in this study was limited, although the participants in the two groups were carefully selected and well matched. Our results must be verified in larger cohorts with the use of different techniques. Furthermore, our results were descriptive, and follow-up studies will be needed to elucidate the effect of differential methylation profiles on asthenozoospermia. WIDER IMPLICATIONS OF THE FINDINGS: Our study identified asthenozoospermia-associated DNA methylation profiles and proposed a list of genes, which were suggested to be involved in the regulation of sperm motility through an alteration of DNA methylation. These results will provide promising clues for understanding the effect of DNA methylation on sperm motility and asthenozoospermia. STUDY FUNDING/COMPETING INTERESTS: This study was funded primarily by the National Natural Science Foundation of China, Shenzhen Project of Science and Technology and the National Basic Research Program of China. The authors have no competing interests. PMID- 26628641 TI - Influence of follicle stage on artificial ovary outcome using fibrin as a matrix. AB - STUDY QUESTION: Do primordial-primary versus secondary follicles embedded inside a fibrin matrix have different capabilities to survive and grow after isolation and transplantation? SUMMARY ANSWER: Mouse primordial-primary follicles showed a lower recovery rate than secondary follicles, but both were able to grow. WHAT IS KNOWN ALREADY: Fresh isolated mouse follicles and ovarian stromal cells embedded in a fibrin matrix are capable of surviving and developing after short-term autografting. STUDY DESIGN, SIZE, DURATION: In vivo experimental model using 11 donor Naval Medical Research Institute (NMRI) mice and 11 recipient severe combined immunodeficiency (SCID) mice. Both ovaries from all NMRI mice were mechanically disrupted and primordial-primary and secondary follicles were isolated with ovarian stromal cells. They were then encapsulated in a fibrin matrix composed of 12.5 mg/ml of fibrinogen (F12.5) and 1 IU/ml of thrombin (T1) (F12.5/T1), and grafted to the inner part of the peritoneum of SCID mice for 2 and 7 days. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was conducted at the Gynecology Research Unit, Universite Catholique de Louvain. All materials were used to conduct histological (H-E staining) and immunohistochemical (Ki67, TUNEL) analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Although all grafted fibrin clots were recovered, the follicle recovery rate on day 2 was 16 and 40% for primordial-primary and secondary follicles respectively, while on day 7, it was 6 and 28%. The secondary group showed a significantly higher recovery rate than the primordial-primary group (23%, P-value <0.001). Follicles found in both groups were viable, as demonstrated by live/dead assays, and no difference was observed in the apoptosis rate between groups, as evidenced by TUNEL. Their growth to further stages was confirmed by Ki67 immunostaining. LIMITATIONS, REASONS FOR CAUTION: As demonstrated by our results, secondary follicles appear to be more likely to survive and develop than primordial-primary follicles in a fibrin matrix after both periods of grafting. These findings may also be attributed to the specific features of the fibrin matrix, which could benefit larger follicles, but not smaller follicles. WIDER IMPLICATIONS OF THE FINDINGS: This study is essential to understanding possible impairment caused by factors such as the isolation procedure or fibrin matrix composition to the survival and development of different follicle stages. It therefore provides the basis for further investigations with longer periods of grafting. STUDY FUNDING/COMPETING INTERESTS: This study was supported by grants from the Fonds National de la Recherche Scientifique de Belgique (grant Televie No. 7.4578.14 and 7.4627.13, grant 5/4/150/5 awarded to Marie-Madeleine Dolmans), Fonds Speciaux de Recherche, Fondation St Luc, the Foundation Against Cancer, and the Region Wallone (Convention N degrees 6519-OVART) and donations from Mr Pietro Ferrero, Baron Frere and Viscount Philippe de Spoelberch. None of the authors have any competing interests to declare. PMID- 26628643 TI - Rationally engineered Cas9 nucleases with improved specificity. AB - The RNA-guided endonuclease Cas9 is a versatile genome-editing tool with a broad range of applications from therapeutics to functional annotation of genes. Cas9 creates double-strand breaks (DSBs) at targeted genomic loci complementary to a short RNA guide. However, Cas9 can cleave off-target sites that are not fully complementary to the guide, which poses a major challenge for genome editing. Here, we use structure-guided protein engineering to improve the specificity of Streptococcus pyogenes Cas9 (SpCas9). Using targeted deep sequencing and unbiased whole-genome off-target analysis to assess Cas9-mediated DNA cleavage in human cells, we demonstrate that "enhanced specificity" SpCas9 (eSpCas9) variants reduce off-target effects and maintain robust on-target cleavage. Thus, eSpCas9 could be broadly useful for genome-editing applications requiring a high level of specificity. PMID- 26628644 TI - Best Practices: a series of theory, evidence, and implementation. PMID- 26628642 TI - When minds matter for moral judgment: intent information is neurally encoded for harmful but not impure acts. AB - Recent behavioral evidence indicates a key role for intent in moral judgments of harmful acts (e.g. assault) but not impure acts (e.g. incest). We tested whether the neural responses in regions for mental state reasoning, including the right temporoparietal junction (RTPJ), are greater when people evaluate harmful vs impure violations. In addition, using multivoxel pattern analysis, we investigated whether the voxel-wise pattern in these regions distinguishes intentional from accidental actions, for either kind of violation. The RTPJ was preferentially recruited in response to harmful vs impure acts. Moreover, although its response was equally high for intentional and accidental acts, the voxel-wise pattern in the RTPJ distinguished intentional from accidental acts in the harm domain but not the purity domain. Finally, we found that the degree to which the RTPJ discriminated between intentional and accidental acts predicted the impact of intent information on moral judgments but again only in the harm domain. These findings reveal intent to be a uniquely critical factor for moral evaluations of harmful vs impure acts and shed light on the neural computations for mental state reasoning. PMID- 26628645 TI - Reform in teaching preclinical pathophysiology. AB - Pathophysiology is a scientific discipline that studies the onset and progression of pathological conditions and diseases, and pathophysiology is one of the core courses in most preclinical medical curricula. In China, most medical schools house a Department of Pathophysiology, in contrast to medical schools in many developed countries. The staff in Chinese Departments of Pathophysiology generally consists of full-time instructors or lecturers who teach medical students. These lecturers are sometimes lacking in clinic knowledge and experiences. To overcome this, in recent years, we have been trying to bring new trends in teaching pathophysiology into our curriculum. Our purpose in writing this article was to share our experiences with our colleagues and peers worldwide in the hope that the insights we have gained in pathophysiology teaching will be of some value to educators who advocate teaching reform in medical schools. PMID- 26628646 TI - A physiologist's view of homeostasis. AB - Homeostasis is a core concept necessary for understanding the many regulatory mechanisms in physiology. Claude Bernard originally proposed the concept of the constancy of the "milieu interieur," but his discussion was rather abstract. Walter Cannon introduced the term "homeostasis" and expanded Bernard's notion of "constancy" of the internal environment in an explicit and concrete way. In the 1960s, homeostatic regulatory mechanisms in physiology began to be described as discrete processes following the application of engineering control system analysis to physiological systems. Unfortunately, many undergraduate texts continue to highlight abstract aspects of the concept rather than emphasizing a general model that can be specifically and comprehensively applied to all homeostatic mechanisms. As a result, students and instructors alike often fail to develop a clear, concise model with which to think about such systems. In this article, we present a standard model for homeostatic mechanisms to be used at the undergraduate level. We discuss common sources of confusion ("sticky points") that arise from inconsistencies in vocabulary and illustrations found in popular undergraduate texts. Finally, we propose a simplified model and vocabulary set for helping undergraduate students build effective mental models of homeostatic regulation in physiological systems. PMID- 26628647 TI - Venous return and clinical hemodynamics: how the body works during acute hemorrhage. AB - Venous return is a major determinant of cardiac output. Adjustments within the venous system are critical for maintaining venous pressure during loss in circulating volume. This article reviews two factors that are thought to enable the venous system to compensate during acute hemorrhage: 1) changes in venous elastance and 2) mobilization of unstressed blood volume into stressed blood volume. We show that mobilization of unstressed blood volume is the predominant and more effective mechanism in preserving venous pressure. Preservation of mean circulatory filling pressure helps sustain venous return and thus cardiac output during significant hemorrhage. PMID- 26628648 TI - Harnessing the power of an online teaching community: connect, share, and collaborate. PMID- 26628649 TI - Tracking undergraduate student achievement in a first-year physiology course using a cluster analysis approach. AB - A cluster analysis data classification technique was used on assessment scores from 157 undergraduate nursing students who passed 2 successive compulsory courses in human anatomy and physiology. Student scores in five summative assessment tasks, taken in each of the courses, were used as inputs for a cluster analysis procedure. We aimed to group students into high-achieving (HA) and low achieving (LA) clusters and to determine the ability of each summative assessment task to discriminate between HA and LA students. The two clusters identified in each semester were described as HA (n = 42) and LA (n = 115) in semester 1 (HA1 and LA1, respectively) and HA (n = 91) and LA (n = 42) in semester 2 (HA2 and LA2, respectively). In both semesters, HA and LA means for all inputs were different (all P < 0.001). Nineteen students moved from the HA1 group into the LA2 group, whereas 68 students moved from the LA1 group into the HA2 group. The overall order of importance of inputs that determined group membership was different in semester 1 compared with semester 2; in addition, the within-cluster order of importance in LA groups was different compared with HA groups. This method of analysis may 1) identify students who need extra instruction, 2) identify which assessment is more effective in discriminating between HA and LA students, and 3) provide quantitative evidence to track student achievement. PMID- 26628651 TI - Matters of taste: bridging molecular physiology and the humanities. AB - Taste perception was the focus of an undergraduate course in the health sciences that bridged the sciences and humanities. A problem-based learning approach was used to study the biological issues, whereas the cultural transmutations of these molecular mechanisms were explored using a variety of resources (novels, cookbooks, and films). Multiple evaluation procedures were used: problem summaries and problem-solving exercises (tripartite problem-solving exercise) for the problem-based learning component and group tasks and individual exercises for the cultural issues. Self-selected groups chose specific tasks from a prescribed list of options (setting up a journal in molecular gastronomy, developing an electronic tongue, designing a restaurant for synesthetes, organizing a farmers' market, marketing a culinary tour, framing hedonic scales, exploring changing tastes through works of art or recipe books, and crafting beers for space travel). Individual tasks were selected from a menu of options (book reviews, film reviews, conversations, creative writing, and oral exams). A few guest lecturers (wine making, cultural anthropology, film analysis, and nutritional epidemiology) added more flavor. The course was rated highly for its learning value (8.5 +/- 1.2, n = 62) and helped students relate biological mechanisms to cultural issues (9.0 +/- 0.9, n = 62). PMID- 26628650 TI - Developing best practices teaching procedures for skinfold assessment: observational examination using the Think Aloud method. AB - Skinfold assessment is valid and economical; however, it has a steep learning curve, and many programs only include one exposure to the technique. Increasing the number of exposures to skinfold assessment within an undergraduate curriculum would likely increase skill proficiency. The present study combined observational and Think Aloud methodologies to quantify procedural and cognitive characteristics of skinfold assessment. It was hypothesized that 1) increased curricular exposure to skinfold assessment would improve proficiency and 2) the combination of an observational and Think Aloud analysis would provide quantifiable areas of emphasis for instructing skinfold assessment. Seventy-five undergraduates with varied curricular exposure performed a seven-site skinfold assessment on a test subject while expressing their thoughts aloud. A trained practitioner recorded procedural observations, with transcripts generated from audio recordings to capture cognitive information. Skinfold measurements were compared with a criterion value, and bias scores were generated. Participants whose total bias fell within +/-3.5% of the criterion value were proficient, with the remainder nonproficient. An independent-samples t-test was used to compare procedural and cognitive observations across experience and proficiency groups. Additional curricular exposure improved performance of skinfold assessment in areas such as the measurement of specific sites (e.g., chest, abdomen, and thigh) and procedural (e.g., landmark identification) and cognitive skills (e.g., complete site explanation). Furthermore, the Think Aloud method is a valuable tool for determining curricular strengths and weaknesses with skinfold assessment and as a pedagogical tool for individual instruction and feedback in the classroom. PMID- 26628652 TI - Establishing common course objectives for undergraduate exercise physiology. AB - Undergraduate exercise physiology is a ubiquitous course in undergraduate kinesiology/exercise science programs with a broad scope and depth of topics. It is valuable to explore what is taught within this course. The purpose of the present study was to facilitate an understanding of what instructors teach in undergraduate exercise physiology, how it compares with various guidelines, and to continue the conversation regarding what should be taught. A survey was created using course outcomes from the American Society of Exercise Physiologists, National Association for Sport and Physical Education, Ivy's 2007 Quest article, the National Athletic Training Association, the National Council for Accreditation of Teacher Education, and 36 undergraduate exercise physiology course syllabi. The 134-item survey was disseminated to individuals who use exercise physiology: university faculty members, clinical exercise physiologists, researchers, and other practitioners on various exercise physiology lists; 2,009 surveys were sent, and 322 surveys were completed (16% rate of return). There was a high degree of agreement about a lot of important content in undergraduate exercise physiology. Instructors of exercise physiology should focus their curriculum on regulation and homeostasis (including adaptation, fatigue, and recovery), aerobic systems, bioenergetics, muscle physiology, and fitness principles. In addition, attention should be paid to performance and technical skills. In conclusion, it is up to exercise physiologists to ensure quality of knowledge and practice. Doing so will improve the uniformity and quality of practitioners within the various kinesiology/exercise science fields and increase the value of a Kinesiology/Exercise Science degree and set it apart from other healthcare providers and fitness professionals. PMID- 26628653 TI - Self-testing produces superior recall of both familiar and unfamiliar muscle information. AB - Dozens of studies have found learning strategies based on the "testing effect" promote greater recall than those that rely solely on reading; however, the advantages of testing are often only observed after a delay (e.g., 2-7 days later). In contrast, our research, which has focused on kinesiology students learning kinesiology information that is generally familiar to them, has consistently demonstrated that testing-based strategies produce greater recall both immediately and after a delay. In an attempt to understand the discrepancies in the literature, the purpose of the present study was to determine if the time related advantages of a testing-based learning strategy vary with one's familiarity with the to-be-learned information. Participants used both read-only and testing-based strategies to repeatedly study three different sets of information: 1) previously studied human muscle information (familiar information), 2) a mix of previously studied and previously unstudied human muscle information (mixed information), and 3) previously unstudied muscle information that is unique to sharks (unfamiliar information). Learning was evaluated via free recall assessments administered immediately after studying and again after a 1-wk delay and a 3-wk delay. Across those three assessments, the read-only strategy resulted in mean scores of 29.26 +/- 1.43, 15.17 +/- 1.29, and 5.33 +/- 0.77 for the familiar, mixed, and unfamiliar information, respectively, whereas the testing-based strategy produced scores of 34.57 +/- 1.58, 16.90 +/- 1.31, and 8.33 +/- 0.95, respectively. The results indicate that the testing based strategy produced greater recall immediately and up through the 3-wk delay regardless of the participants' level of familiarity with the muscle information. PMID- 26628654 TI - Medical student service learning program teaches secondary students about career opportunities in health and medical fields. AB - Engagement of academic medical centers in community outreach provides the public with a better understanding of basic terms and concepts used in biomedical sciences and increases awareness of important health information. Medical students at one academic medical center initiated an educational outreach program, called PULSE, that targets secondary students to foster their interest in healthcare and medicine. High school student participants are engaged in a semester-long course that relies on interactive lectures, problem-based learning sessions, mentoring relationships with medical students, and opportunities for shadowing healthcare providers. To date, the curriculum has been offered for 7 consecutive years. To determine the impact that participation in the curriculum has had on college/career choices and to identify areas for improvement, an electronic questionnaire was sent to former participants. Based on a 32% response rate, 81% of former participants indicated that participation in the course influenced their decision to pursue a medical/science-related career. More than half (67%) of respondents indicated intent to pursue a MD/PhD or other postgraduate degree. Based on responses obtained, additional opportunities to incorporate laboratory-based research and simulation sessions should be explored. In addition, a more formalized mentoring component has been added to the course to enhance communication between medical students and mentees. Health/medicine related educational outreach programs targeting high school students may serve as a pipeline to introduce or reinforce career opportunities in healthcare and related sciences. PMID- 26628655 TI - On being examined: do students and faculty agree? AB - Students measure out their lives, not with coffee spoons, but with grades on examinations. But what exams mean and whether or not they are a bane or a boon is moot. Senior undergraduates (A. Perrella, J. Koenig, and H. Kwon) designed and administered a 15-item survey that explored the contrasting perceptions of both students (n = 526) and faculty members (n = 33) in a 4-yr undergraduate health sciences program. A series of statements gauged the level of agreement on a 10 point scale. Students and faculty members agreed on the value of assessing student learning with a variety of methods, finding new information to solve problems, assessing conceptual understanding and logical reasoning, having assessments with no single correct answer, and having comments on exams. Clear differences emerged between students and faculty members on specific matters: rubrics, student choice of exam format, assessing creativity, and transfer of learning to novel situations. A followup questionnaire allowed participants to clarify their interpretation of select statements, with responses from 71 students and 17 faculty members. All parties strongly agreed that exams should provide a good learning experience that would help them prepare for the future (students: 8.64 +/- 1.71 and faculty members: 8.03 +/- 2.34). PMID- 26628656 TI - Open problem-based instruction impacts understanding of physiological concepts differently in undergraduate students. AB - Student populations are diverse such that different types of learners struggle with traditional didactic instruction. Problem-based learning has existed for several decades, but there is still controversy regarding the optimal mode of instruction to ensure success at all levels of students' past achievement. The present study addressed this problem by dividing students into the following three instructional groups for an upper-level course in animal physiology: traditional lecture-style instruction (LI), guided problem-based instruction (GPBI), and open problem-based instruction (OPBI). Student performance was measured by three summative assessments consisting of 50% multiple-choice questions and 50% short-answer questions as well as a final overall course assessment. The present study also examined how students of different academic achievement histories performed under each instructional method. When student achievement levels were not considered, the effects of instructional methods on student outcomes were modest; OPBI students performed moderately better on short answer exam questions than both LI and GPBI groups. High-achieving students showed no difference in performance for any of the instructional methods on any metric examined. In students with low-achieving academic histories, OPBI students largely outperformed LI students on all metrics (short-answer exam: P < 0.05, d = 1.865; multiple-choice question exam: P < 0.05, d = 1.166; and final score: P < 0.05, d = 1.265). They also outperformed GPBI students on short-answer exam questions (P < 0.05, d = 1.109) but not multiple-choice exam questions (P = 0.071, d = 0.716) or final course outcome (P = 0.328, d = 0.513). These findings strongly suggest that typically low-achieving students perform at a higher level under OPBI as long as the proper support systems (formative assessment and scaffolding) are provided to encourage student success. PMID- 26628657 TI - The effectiveness of concept mapping and retrieval practice as learning strategies in an undergraduate physiology course. AB - Concept mapping and retrieval practice are both educational methods that have separately been reported to provide significant benefits for learning in diverse settings. Concept mapping involves diagramming a hierarchical representation of relationships between distinct pieces of information, whereas retrieval practice involves retrieving information that was previously coded into memory. The relative benefits of these two methods have never been tested against each other in a classroom setting. Our study was designed to investigate whether or not concept mapping or retrieval practice produced a significant learning benefit in an undergraduate physiology course as measured by exam performance and, if so, was the benefit of one method significantly greater than the other. We found that there was a trend toward increased exam scores for the retrieval practice group compared with both the control group and concept mapping group, and that trend achieved statistical significance for one of the four module exams in the course. We also found that women performed statistically better than men on the module exam that contained a substantial amount of material relating to female reproductive physiology. PMID- 26628658 TI - Evaluating the effectiveness of a laboratory-based professional development program for science educators. AB - The process of developing effective science educators has been a long-standing objective of the broader education community. Numerous studies have recommended not only depth in a teacher's subject area but also a breadth of professional development grounded in constructivist principles, allowing for successful student-centered and inquiry-based instruction. Few programs, however, have addressed the integration of the scientific research laboratory into the science classroom as a viable approach to professional development. Additionally, while occasional laboratory training programs have emerged in recent years, many lack a component for translating acquired skills into reformed classroom instruction. Given the rapid development and demand for knowledgeable employees and an informed population from the biotech and medical industries in recent years, it would appear to be particularly advantageous for the physiology and broader science education communities to consider this issue. The goal of this study was to examine the effectiveness of a laboratory-based professional development program focused on the integration of reformed teaching principles into the classrooms of secondary teachers. This was measured through the program's ability to instill in its participants elevated academic success while gaining fulfillment in the classroom. The findings demonstrated a significant improvement in the use of student-centered instruction and other reformed methods by program participants as well as improved self-efficacy, confidence, and job satisfaction. Also revealed was a reluctance to refashion established classroom protocols. The combination of these outcomes allowed for construction of an experiential framework for professional development in applied science education that supports an atmosphere of reformed teaching in the classroom. PMID- 26628659 TI - Redox signaling in skeletal muscle: role of aging and exercise. AB - Skeletal muscle contraction is associated with the production of ROS due to altered O2 distribution and flux in the cell. Despite a highly efficient antioxidant defense, a small surplus of ROS, such as hydrogen peroxide and nitric oxide, may serve as signaling molecules to stimulate cellular adaptation to reach new homeostasis largely due to the activation of redox-sensitive signaling pathways. Recent research has highlighted the important role of NF-kappaB, MAPK, and peroxisome proliferator-activated receptor-gamma coactivator-1alpha, along with other newly discovered signaling pathways, in some of the most vital biological functions, such as mitochondrial biogenesis, antioxidant defense, inflammation, protein turnover, apoptosis, and autophagy. There is evidence that the inability of the cell to maintain proper redox signaling underlies some basic mechanisms of biological aging, during which inflammatory and catabolic pathways eventually predominate. Physical exercise has been shown to activate various redox signaling pathways that control the adaptation and remodeling process. Although this stimulatory effect of exercise declines with aging, it is not completed abolished. Thus, aged people can still benefit from regular physical activity in the appropriate forms and at proper intensity to preserve muscle function. PMID- 26628660 TI - Taking nanomedicine teaching into practice with atomic force microscopy and force spectroscopy. AB - Atomic force microscopy (AFM) is a useful and powerful tool to study molecular interactions applied to nanomedicine. The aim of the present study was to implement a hands-on atomic AFM course for graduated biosciences and medical students. The course comprises two distinct practical sessions, where students get in touch with the use of an atomic force microscope by performing AFM scanning images of human blood cells and force spectroscopy measurements of the fibrinogen-platelet interaction. Since the beginning of this course, in 2008, the overall rating by the students was 4.7 (out of 5), meaning a good to excellent evaluation. Students were very enthusiastic and produced high-quality AFM images and force spectroscopy data. The implementation of the hands-on AFM course was a success, giving to the students the opportunity of contact with a technique that has a wide variety of applications on the nanomedicine field. In the near future, nanomedicine will have remarkable implications in medicine regarding the definition, diagnosis, and treatment of different diseases. AFM enables students to observe single molecule interactions, enabling the understanding of molecular mechanisms of different physiological and pathological processes at the nanoscale level. Therefore, the introduction of nanomedicine courses in bioscience and medical school curricula is essential. PMID- 26628661 TI - PowerPoint presentation in learning physiology by undergraduates with different learning styles. AB - PowerPoint presentations (PPTs) have become routine in medical colleges because of their flexible and varied presentation capabilities. Research indicates that students prefer PPTs over the chalk-and-talk method, and there is a lot of debate over advantages and disadvantages of PPTs. However, there is no clear evidence that PPTs improve student learning/performance. Furthermore, there are a variety of learning styles with sex differences in classrooms. It is the responsibility of teacher/facilitator and student to be aware of learning style preferences to improve learning. The present study asked the following research question: do PPTs equally affect the learning of students with different learning styles in a mixed sex classroom? After we assessed students' predominant learning style according to the sensory modality that one most prefers to use when learning, a test was conducted before and after a PPT to assess student performance. The results were analyzed using Student's t-test and ANOVA with a Bonferroni post hoc test. A z-test showed no sex differences in preferred learning styles. There was significant increase in posttest performance compared with that of the pretest in all types of learners of both sexes. There was also a nonsignificant relationship among sex, learning style, and performance after the PPT. A PPT is equally effective for students with different learning style preferences and supports mixed sex classrooms. PMID- 26628662 TI - Two-compartment model as a teaching tool for cholesterol homeostasis. AB - Cholesterol is a vital structural and functional molecule in the human body that is only slightly soluble in water and therefore does not easily travels by itself in the bloodstream. To enable cholesterol's targeted delivery to cells and tissues, it is encapsulated by different fractions of lipoproteins, complex particles containing both proteins and lipids. Maintaining cholesterol homeostasis is a highly regulated process with multiple factors acting at both molecular and tissue levels. Furthermore, to regulate the circulatory transport of cholesterol in lipoproteins, the amount of cholesterol present depends on and is controlled by cholesterol dietary intake, de novo synthesis, usage, and excretion; abnormal and/or unbalanced cholesterol levels have been shown to lead to severe outcomes, e.g., cardiovascular diseases. To investigate cholesterol transport in the circulatory system, we have previously developed a two compartment mathematical model. Here, we show how this model can be used as a teaching tool for cholesterol homeostasis. Using the model and a hands-on approach, students can familiarize themselves with the basic components and mechanisms behind balanced cholesterol circulatory transport as well as investigate the consequences of and countermeasures to abnormal cholesterol levels. Among others, various treatments of high blood cholesterol levels can be simulated, e.g., with commonly prescribed de novo cholesterol synthesis inhibitors. PMID- 26628663 TI - Correlation of self-assessment with attendance in an evidence-based medicine course. AB - In previous studies, correlations between attendance and grades in lectures have given variable results and, when statistically significant, the correlation has been weak. In some studies, a sex effect has been reported. Lectures are a teacher-centered learning activity. Therefore, it appeared interesting to evaluate if a stronger correlation between attendance and grades would occur in a face-to-face "evidence-based medicine" course with few lectures and more time dedicated to active learning methods. Small-group work and peer learning were used to foster deep learning and to engage students in their own learning process. Most of the time, students worked in small groups solving contextualized problems and critically analyzing the quality of published medical literature. Peer learning was also developed in collaborative evaluations, and constant feedback was provided. Therefore, it was hypothesized that high attenders would develop a higher self-perception of learning and obtain higher marks than low attenders. Student self-perceptions of their capacity to apply evidence-based medicine were measured by the application of an online self-assessment survey, and objective learning was measured as the grades obtained in a final accumulative individual test. It was found that male students obtained higher grades and were more confident in their achievements than their female peers, despite male and female student attendance being similar. In addition, attendance was correlated with the perceived capacity to apply evidence-based medicine only in male students and was not correlated with academic outcome. PMID- 26628664 TI - A multidisciplinary guided practical on type I diabetes engaging students in inquiry-based learning. AB - In the present article, we describe a 3-day experimental workshop on type I diabetes aimed at helping high school students to understand how fundamental research on glycemia regulation contributes to the development of scientific knowledge and therapeutic strategies. The workshop engaged students in open-ended investigations and guided experiments. Each class was divided into three or four groups, with each group working with a trained doctoral student or postdoctoral fellow. During an initial questioning phase, students observed slides depicting the glycemia of individuals in various situations. Students identified hyperglycemic individuals relative to the average glycemia of the displayed population. Students were asked to devise a treatment for these diabetics. They quickly realized that they couldn't experiment on patients and understood the need for laboratory models. Each group gave ideas of experiments to perform. We then explained, taking into account their propositions, the protocols students could execute to address one of the following questions: Which criteria must an animal model of diabetes fulfill? How do pancreatic cells maintain glycemia? Is there a way to produce an insulin protein similar to the one released by human pancreatic cells? We used two different evaluation metrics of the workshop: a questionnaire filled out by the students before and after the workshop and a poster produced by students at the end of the workshop. We found that this educational approach successfully improved student awareness and understanding of the scientific reasoning and research process. PMID- 26628665 TI - Using ultrasound to teach medical students cardiac physiology. AB - Ultrasound is being incorporated more into undergraduate medical education. Studies have shown that medical students have positive perceptions about the value of ultrasound in teaching courses like anatomy and physiology. The purpose of the present study was to provide objective evidence of whether ultrasound helps students learn cardiac physiology. In this study, 20 medical students took a pretest to assess their background knowledge of cardiac physiology. Next, they acquired ultrasound video loops of the heart. Faculty members taught them nonelectrical aspects of cardiac physiology using those loops. Finally, students took a posttest to evaluate for improvements in their knowledge. Students also completed an anonymous questionnaire about their experience. The mean pretest score was 4.8 of 9 (53.3%). The mean posttest score was 7.35 of 9 (81.7%). The mean difference was significant at P < 0.0001. Student feedback was very positive about the ultrasound laboratory. Ninety-five percent of the students agreed or strongly agreed that the ultrasound laboratory was a valuable teaching tool and that it improved their understanding of cardiac physiology. All students agreed or strongly agreed the laboratory was helpful from a visual learning standpoint. A hands-on ultrasound laboratory can indeed help medical students learn the nonelectrical components of cardiac physiology. PMID- 26628666 TI - Starting physiology: bioelectrogenesis. AB - From a Cartesian perspective of rational analysis, the electric potential difference across the cell membrane is one of the fundamental concepts for the study of physiology. Unfortunately, undergraduate students often struggle to understand the genesis of this energy gradient, which makes the teaching activity a hard task for the instructor. The topic of bioelectrogenesis encompasses multidisciplinary concepts, involves several mechanisms, and is a dynamic process, i.e., it never turns off during the lifetime of the cell. Therefore, to improve the transmission and acquisition of knowledge in this field, I present an alternative didactic model. The design of the model assumes that it is possible to build, in a series of sequential steps, an assembly of proteins within the membrane of an isolated cell in a simulated electrophysiology experiment. Initially, no proteins are inserted in the membrane and the cell is at a baseline energy state; the extracellular and intracellular fluids are at thermodynamic equilibrium. Students are guided through a sequence of four steps that add key membrane transport proteins to the model cell. The model is simple at the start and becomes progressively more complex, finally producing transmembrane chemical and electrical gradients. I believe that this didactic approach helps instructors with a more efficient tool for the teaching of the mechanisms of resting membrane potential while helping students avoid common difficulties that may be encountered when learning this topic. PMID- 26628667 TI - Observing and understanding arterial and venous circulation differences in a physiology laboratory activity. AB - The purpose of the present article is to describe three simple practical experiments that aim to observe and discuss the anatomic and physiological functions and differences between arteries and veins as well as the alterations observed in skin blood flow in different situations. For this activity, students were divided in small groups. In each group, a volunteer is recruited for each experiment. The experiments only require a sphygmomanometer, rubber bands, and a clock and allow students to develop a hypothesis to explain the different responses to the interruption of arterial and venous blood flow. At the end, students prepare a short report, and the results are discussed. This activity allows students to perceive the presence of physiology in their daily lives and helps them to understand the concepts related to the cardiovascular system and hemodynamics. PMID- 26628668 TI - Maximize a team-based learning gallery walk experience: herding cats is easier than you think. PMID- 26628669 TI - Interactive intragroup tutorials: a need-based modification to enhance learning in physiology. PMID- 26628670 TI - Using order of magnitude calculations to extend student comprehension of laboratory data. PMID- 26628671 TI - Physiology should be taught as science is practiced: an inquiry-based activity to investigate the "alkaline tide". PMID- 26628672 TI - Hypertension: Update 2016. PMID- 26628673 TI - Circulating Adipokines and Vascular Function: Cross-Sectional Associations in a Community-Based Cohort. AB - Adipokines may be potential mediators of the association between excess adiposity and vascular dysfunction. We assessed the cross-sectional associations of circulating adipokines with vascular stiffness in a community-based cohort of younger adults. We related circulating concentrations of leptin and leptin receptor, adiponectin, retinol-binding protein 4, and fatty acid-binding protein 4 to vascular stiffness measured by arterial tonometry in 3505 Framingham Third Generation cohort participants free of cardiovascular disease (mean age 40 years, 53% women). Separate regression models estimated the relations of each adipokine to mean arterial pressure and aortic stiffness, as carotid femoral pulse wave velocity, adjusting for age, sex, smoking, heart rate, height, antihypertensive treatment, total and high-density lipoprotein cholesterol, diabetes mellitus, alcohol consumption, estimated glomerular filtration rate, glucose, and C reactive protein. Models evaluating aortic stiffness also were adjusted for mean arterial pressure. Mean arterial pressure was positively associated with blood retinol-binding protein 4, fatty acid-binding protein 4, and leptin concentrations (all P<0.001) and inversely with adiponectin (P=0.002). In fully adjusted models, mean arterial pressure was positively associated with retinol binding protein 4 and leptin receptor levels (P<0.002 both). In fully adjusted models, aortic stiffness was positively associated with fatty acid-binding protein 4 concentrations (P=0.02), but inversely with leptin and leptin receptor levels (P<=0.03 both). In our large community-based sample, circulating concentrations of select adipokines were associated with vascular stiffness measures, consistent with the hypothesis that adipokines may influence vascular function and may contribute to the relation between obesity and hypertension. PMID- 26628674 TI - Regulation of Blood Pressure, Appetite, and Glucose by Leptin After Inactivation of Insulin Receptor Substrate 2 Signaling in the Entire Brain or in Proopiomelanocortin Neurons. AB - Insulin receptor substrate 2 (IRS2) is one of the 3 major leptin receptor signaling pathways, but its role in mediating the chronic effects of leptin on blood pressure, food intake, and glucose regulation is unclear. We tested whether genetic inactivation of IRS2 in the entire brain (IRS2/Nestin-cre mice) or specifically in proopiomelanocortin (POMC) neurons (IRS2/POMC-cre mice) attenuates the chronic cardiovascular, metabolic, and antidiabetic effects of leptin. Mice were instrumented with telemetry probes for measurement of blood pressure and heart rate and with venous catheters for intravenous infusions. After a 5-day control period, mice received leptin infusion (2 MUg/kg per minute) for 7 days. Compared with control IRS2(flox/flox) mice, IRS2/POMC-cre mice had similar body weight and food intake (33+/-1 versus 35+/-1 g and 3.6+/-0.5 versus 3.8+/-0.2 g per day) but higher mean arterial pressure (MAP) and heart rate (110+/-2 versus 102+/-2 mm Hg and 641+/-9 versus 616+/-5 bpm). IRS2/Nestin-cre mice were heavier (38+/-2 g), slightly hyperphagic (4.5+/-1.0 g per day), and had higher MAP and heart rate (108+/-2 mm Hg and 659+/-9 bpm) compared with control mice. Leptin infusion gradually increased MAP despite decreasing food intake by 31% in IRS2(flox/flox) and in Nestin-cre control mice. In contrast, leptin infusion did not change MAP in IRS2/Nestin-cre or IRS2/POMC-cre mice. The anorexic and antidiabetic effects of leptin, however, were similar in all 3 groups. These results indicate that IRS2 signaling in the central nervous system, and particularly in POMC neurons, is essential for the chronic actions of leptin to raise MAP but not for its anorexic or antidiabetic effects. PMID- 26628675 TI - Impaired Endothelial Repair Capacity of Early Endothelial Progenitor Cells in Hypertensive Patients With Primary Hyperaldosteronemia: Role of 5,6,7,8 Tetrahydrobiopterin Oxidation and Endothelial Nitric Oxide Synthase Uncoupling. AB - Although hyperaldosteronemia exerts detrimental impacts on vascular endothelium in addition to elevating blood pressure, the effects and molecular mechanisms of hyperaldosteronemia on early endothelial progenitor cell (EPC)-mediated endothelial repair after arterial damage are yet to be determined. The aim of this study was to investigate the endothelial repair capacity of early EPCs from hypertensive patients with primary hyperaldosteronemia (PHA). In vivo endothelial repair capacity of early EPCs from PHAs (n=20), age- and blood pressure-matched essential hypertension patients (n=20), and age-matched healthy subjects (n=20) was evaluated by transplantation into a nude mouse carotid endothelial denudation model. Endothelial function was evaluated by flow-mediated dilation of brachial artery in human subjects. In vivo endothelial repair capacity of early EPCs and flow-mediated dilation were impaired both in PHAs and in essential hypertension patients when compared with age-matched healthy subjects; however, the early EPC in vivo endothelial repair capacity and flow-mediated dilation of PHAs were impaired more severely than essential hypertension patients. Oral spironolactone improved early EPC in vivo endothelial repair capacity and flow-mediated dilation of PHAs. Increased oxidative stress, oxidative 5,6,7,8-tetrahydrobiopterin degradation, endothelial nitric oxide synthase uncoupling and decreased nitric oxide production were found in early EPCs from PHAs. Nicotinamide adenine dinucleotide phosphate oxidase subunit p47(phox) knockdown or 5,6,7,8 tetrahydrobiopterin supplementation attenuated endothelial nitric oxide synthase uncoupling and enhanced in vivo endothelial repair capacity of early EPCs from PHAs. In conclusion, PHAs exhibited more impaired endothelial repair capacity of early EPCs than did essential hypertension patients independent of blood pressure, which was associated with mineralocorticoid receptor-dependent oxidative stress and subsequently 5,6,7,8-tetrahydrobiopterin degradation and endothelial nitric oxide synthase uncoupling. PMID- 26628677 TI - Retinal Microvasculature Is Associated With Long-Term Survival in the General Adult Dutch Population. AB - Retinal vascular diameters are associated with (sub)clinical cardiovascular disease and short-term cardiovascular mortality, but their association with long term mortality is uncertain. We studied the association of retinal vascular diameters with cause-specific mortality in the general adult Dutch population during 25 years of follow-up. From 1990 to 1993, arteriolar and venular diameters were measured semiautomatically on digitized images in 5674 persons (mean age 68.0 years, 59% women) from the population-based Rotterdam study. Follow-up for mortality was complete till March 2015. Associations between vascular diameters and mortality were examined using Cox proportional hazards models, adjusting for age, sex, cardiovascular risk factors, and the fellow vessel diameter. During 85 770 person-years (mean+/-SD: 15.1+/-6.67), 3794 (66.8%) persons died, of whom 1034 due to cardiovascular causes. We found that narrower arterioles and wider venules were associated with higher risk of mortality (adjusted hazard ratio [95% confidence interval] per SD decrease 1.04 [1.00-1.08] and increase 1.07 [1.03 1.12], respectively). For arterioles, these associations were strongest for cardiovascular mortality, whereas venules showed consistent associations for cardiovascular and noncardiovascular mortality. Importantly, these associations remained unchanged after excluding the first 10 years of follow-up as immortal person-time. We found evidence for effect modification with stronger associations in persons <70 years (venules only) and smokers (P value for interaction<0.01). We replicated our findings in another independent cohort from the Rotterdam Study of 3106 persons with 19 880 person-years of follow-up and 144 deaths (hazard ratio for venules 1.22 [1.00-1.49]). Markers of retinal microvasculature are associated with long-term mortality in the general adult Dutch population. PMID- 26628676 TI - Urinary Proteolytic Activation of Renal Epithelial Na+ Channels in Chronic Heart Failure. AB - One of the key mechanisms involved in renal Na(+) retention in chronic heart failure (CHF) is activation of epithelial Na(+) channels (ENaC) in collecting tubules. Proteolytic cleavage has an important role in activating ENaC. We hypothesized that enhanced levels of proteases in renal tubular fluid activate ENaC, resulting in renal Na(+) retention in rats with CHF. CHF was produced by left coronary artery ligation in rats. By immunoblotting, we found that several urinary serine proteases were significantly increased in CHF rats compared with sham rats (fold increases: furin 6.7, prostasin 23.6, plasminogen 2.06, and plasmin 3.57 versus sham). Similar increases were observed in urinary samples from patients with CHF. Whole-cell patch clamp was conducted in cultured renal collecting duct M-1 cells to record Na(+) currents. Protease-rich urine (from rats and patients with CHF) significantly increased the Na(+) inward current in M 1 cells. Two weeks of protease inhibitor treatment significantly abrogated the enhanced diuretic and natriuretic responses to ENaC inhibitor benzamil in rats with CHF. Increased podocyte lesions were observed in the kidneys of rats with CHF by transmission electron microscopy. Consistent with these results, podocyte damage markers desmin and podocin expressions were also increased in rats with CHF (increased ~2-folds). These findings suggest that podocyte damage may lead to increased proteases in the tubular fluid, which in turn contributes to the enhanced renal ENaC activity, providing a novel mechanistic insight for Na(+) retention commonly observed in CHF. PMID- 26628678 TI - Effects of beta-Blockers With and Without Vasodilating Properties on Central Blood Pressure: Systematic Review and Meta-Analysis of Randomized Trials in Hypertension. AB - beta-Blockers are less effective than other antihypertensive drug classes in reducing central systolic blood pressure (cSBP) as compared with peripheral SBP (pSBP). Whether this effect is less pronounced with vasodilating beta-blockers (VBB) when compared with nonvasodilating beta-blockers (NVBB) remains unsettled. We conducted a systematic review and meta-analysis of randomized trials exploring the effects of beta-blockers on both pSBP and cSBP in hypertension. We selected 20 studies, for a total of 32 treatment arms (n=21 for NVBB, n=11 for VBB) and 1263 participants (n=962 for NVBB, n=301 for VBB). pSBP decreased from 150 to 133 mm Hg for NVBB and from 145 to 134 mm Hg for VBB. cSBP decreased from 137 to 126 mm Hg for NVBB and from 132 to 123 mm Hg for VBB. SBP amplification (pSBP-cSBP) decreased significantly under VBB (-5.6 mm Hg; 95% confidence interval, -7.8, 3.4 mm Hg), but not under NVBB (-1.1 mm Hg; 95% confidence interval, -3.4, +1.2 mm Hg; P<0.01 versus NVBB). There was high heterogeneity both within and between beta-blockers subclasses. In a meta-regression model, the weighted difference in treatment-induced changes in SBP amplification between NVBB and VBB lost its significance after adjustment for mean age and baseline pSBP and heart rate ( 2.9+/-2.3 mm Hg; P=0.22) and was almost abolished after adjustment for treatment induced heart rate changes (-0.1+/-0.5 mm Hg; P=0.78). In conclusion, NVBBs, but not VBBs, determine a lower reduction in cSBP than in pSBP. However, the difference in treatment-induced SBP amplification changes between NVBB and VBB is nearly abolished after accounting for differences in heart rate changes. PMID- 26628679 TI - Fingerprinting G protein-coupled receptor signaling. AB - Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) control a wide diversity of cellular responses throughout biology. Each GPCR couples to a distinct array of members of the G protein family to control the specificity and diversity of these responses and ultimately determines the therapeutic efficacy of drugs that target these receptors. In this issue of Science Signaling, Masuho et al. developed an approach to broadly defining these GPCR coupling fingerprints. PMID- 26628680 TI - Inhibition of the kinase ITK in a mouse model of asthma reduces cell death and fails to inhibit the inflammatory response. AB - Interleukin-2 (IL-2)-inducible T cell kinase (ITK) mediates T cell receptor (TCR) signaling primarily to stimulate the production of cytokines, such as IL-4, IL-5, and IL-13, from T helper 2 (TH2) cells. Compared to wild-type mice, ITK knockout mice are resistant to asthma and exhibit reduced lung inflammation and decreased amounts of TH2-type cytokines in the bronchoalveolar lavage fluid. We found that a small-molecule selective inhibitor of ITK blocked TCR-mediated signaling in cultured TH2 cells, including the tyrosine phosphorylation of phospholipase C gamma1 (PLC-gamma1) and the secretion of IL-2 and TH2-type cytokines. Unexpectedly, inhibition of the kinase activity of ITK during or after antigen rechallenge in an ovalbumin-induced mouse model of asthma failed to reduce airway hyperresponsiveness and inflammation. Rather, in mice, pharmacological inhibition of ITK resulted in T cell hyperplasia and the increased production of TH2-type cytokines. Thus, our studies predict that inhibition of the kinase activity of ITK may not be therapeutic in patients with asthma. PMID- 26628681 TI - Distinct profiles of functional discrimination among G proteins determine the actions of G protein-coupled receptors. AB - Members of the heterotrimeric guanine nucleotide-binding protein (G protein) coupled receptor (GPCR) family play key roles in many physiological functions and are extensively exploited pharmacologically to treat diseases. Many of the diverse effects of individual GPCRs on cellular physiology are transduced by heterotrimeric G proteins, which are composed of alpha, beta, and gamma subunits. GPCRs interact with and stimulate the binding of guanosine triphosphate (GTP) to the alpha subunit to initiate signaling. Mammalian genomes encode 16 different G protein alpha subunits, each one of which has distinct properties. We developed a single-platform, optical strategy to monitor G protein activation in live cells. With this system, we profiled the coupling ability of individual GPCRs for different alpha subunits, simultaneously quantifying the magnitude of the signal and the rates at which the receptors activated the G proteins. We found that individual receptors engaged multiple G proteins with varying efficacy and kinetics, generating fingerprint-like profiles. Different classes of GPCR ligands, including full and partial agonists, allosteric modulators, and antagonists, distinctly affected these fingerprints to functionally bias GPCR signaling. Finally, we showed that intracellular signaling modulators further altered the G protein-coupling profiles of GPCRs, which suggests that their differential abundance may alter signaling outcomes in a cell-specific manner. These observations suggest that the diversity of the effects of GPCRs on cellular physiology may be determined by their differential engagement of multiple G proteins, coupling to which produces signals with varying signal magnitudes and activation kinetics, properties that may be exploited pharmacologically. PMID- 26628683 TI - Reference change values using more than two results. PMID- 26628684 TI - Apical hypertrophic cardiomyopathy presenting as acute coronary syndrome. AB - Apical hypertrophic cardiomyopathy is a rare variant of hypertrophic cardiomyopathy. It is characterized by a local hypertrophy of the apical segments and displays typical electrocardiographic and imaging patterns. The clinical manifestations are variable and range from an asymptomatic course to sudden cardiac death. The most frequent symptom is chest pain and thus apical hypertrophic cardiomyopathy can mimic the symptoms and repolarization disturbances indicative of acute coronary syndrome. PMID- 26628682 TI - Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases. AB - Protein kinase autophosphorylation is a common regulatory mechanism in cell signaling pathways. Crystal structures of several homomeric protein kinase complexes have a serine, threonine, or tyrosine autophosphorylation site of one kinase monomer located in the active site of another monomer, a structural complex that we call an "autophosphorylation complex." We developed and applied a structural bioinformatics method to identify all such autophosphorylation complexes in x-ray crystallographic structures in the Protein Data Bank (PDB). We identified 15 autophosphorylation complexes in the PDB, of which five complexes had not previously been described in the publications describing the crystal structures. These five complexes consist of tyrosine residues in the N-terminal juxtamembrane regions of colony-stimulating factor 1 receptor (CSF1R, Tyr(561)) and ephrin receptor A2 (EPHA2, Tyr(594)), tyrosine residues in the activation loops of the SRC kinase family member LCK (Tyr(394)) and insulin-like growth factor 1 receptor (IGF1R, Tyr(1166)), and a serine in a nuclear localization signal region of CDC-like kinase 2 (CLK2, Ser(142)). Mutations in the complex interface may alter autophosphorylation activity and contribute to disease; therefore, we mutated residues in the autophosphorylation complex interface of LCK and found that two mutations impaired autophosphorylation (T445V and N446A) and mutation of Pro(447) to Ala, Gly, or Leu increased autophosphorylation. The identified autophosphorylation sites are conserved in many kinases, suggesting that, by homology, these complexes may provide insight into autophosphorylation complex interfaces of kinases that are relevant drug targets. PMID- 26628685 TI - Interspecific Interactions Between Adult Aedes albopictus and Culex quinquefasciatus (Diptera: Culicidae). AB - Single and mixed species densities of adult Aedes albopictus and Culex quinquefasciatus were manipulated to determine if different combinations affected their egg laying preference or mortality rates. Oviposition was measured in environments that contained containers of different surface areas (small cups vs. larger bowls), and the number of eggs (Aedes) and egg rafts or larvae (Culex) deposited by each species was examined with respect to intra- and interspecific density treatment levels. Mixed species densities did not have an effect on survivorship, but single species densities did affect longevity, with higher densities leading to shorter life spans in Cx. quinquefasciatus: Cx. quinquefasciatus lived longer than Ae. albopictus overall. There was no significant effect of density combinations on oviposition patterns in either species, but Cx. quinquefasciatus laid more rafts in bowls compared with cups. There is little evidence of adult interactions between these species; however, future experimental work is necessary to more fully characterize the possible effects of adult interactions on these species. PMID- 26628686 TI - Research antibodies: do not use them to stain your reputation. PMID- 26628687 TI - Ending lethal discrimination against people with serious mental illness. AB - Each year in England 33 000 people diagnosed with a serious mental illness (SMI) die from causes that could have been avoided. Our mental-health-specific Atlas of Variation is the first to demonstrate the extent to which these inequalities and inequities affect mortality nationally. PMID- 26628688 TI - Health inequalities and psychosis: time for action. AB - People with psychosis face a life-restricting and life-shortening epidemic of obesity, diabetes and cardiovascular disease. This can be predicted by the associated antecedent risk factors evident from early in psychosis, yet remain largely ignored. Greater coordination between primary care, secondary care and public health to systematically prevent and intervene earlier for these physical illnesses offers a realistic solution to reduce this health inequality. PMID- 26628689 TI - Out of sight, out of mind. AB - As a result of the psychiatric hospital closure programme the use of private sector facilities for those needing longer-term care and support has increased. However, local rehabilitation services may be a better solution than out of area treatment. PMID- 26628690 TI - Case study of posts before and after a suicide on a Swedish internet forum. AB - Websites and discussion forums have become an important and sometimes controversial source of information on suicide. Using a case report, our aim was to examine the responses, attitudes and beliefs that were communicated on a forum before, during and after a suicide act. We undertook two related analyses: a qualitative investigation of the messages that were posted before the suicide and a combined qualitative-quantitative analysis of the messages posted during and after the suicide. Nearly half the posted messages before the suicide encouraged the victim to complete the suicidal act, and a surprising number of posts after the suicide expressed excitement, although around half of the posts considered the suicide to be tragic. It is of great importance to increase awareness of suicide signals and understanding about how to respond to individuals who communicate suicide intentions on different forums on the internet. PMID- 26628692 TI - Mental state decoding impairment in major depression and borderline personality disorder: meta-analysis. AB - BACKGROUND: Patients with major depression and borderline personality disorder are characterised by a distorted perception of other people's intentions. Deficits in mental state decoding are thought to be the underlying cause of this clinical feature. AIMS: To examine, using meta-analysis, whether mental state decoding abilities in patients with major depression and borderline personality disorder differ from those of healthy controls. METHOD: A systematic review of 13 cross-sectional studies comparing Reading in the Mind of the Eyes Test (RMET) accuracy performance of patients with major depression or borderline personality disorder and healthy age-matched controls (n = 976). Valence scores, where reported, were also assessed. RESULTS: Large significant deficits were seen for global RMET performance in patients with major depression (d = -0.751). The positive RMET valence scores of patients with depression were significantly worse; patients with borderline personality disorder had worse neutral scores. Both groups were worse than controls. Moderator analysis revealed that individuals with comorbid borderline personality disorder and major depression did better than those with borderline personality disorder alone on accuracy. Those with comorbid borderline personality disorder and any cluster B or C personality disorder did worse than borderline personality disorder alone. Individuals with both borderline personality disorder and major depression performed better then those with borderline personality disorder without major depression for positive valence. CONCLUSIONS: These findings highlight the relevance of RMET performance in patients with borderline personality disorder and major depression, and the importance of considering comorbidity in future analysis. PMID- 26628693 TI - De praestigiis daemonum: the origins of psychiatric history-taking. PMID- 26628696 TI - Has mental health harnessed the digital revolution? PMID- 26628697 TI - Selective reporting of results in guidelines. PMID- 26628698 TI - Authors' reply. PMID- 26628699 TI - Does previous experience of antidepressants form the expectations necessary for a placebo response? PMID- 26628700 TI - Authors' reply. PMID- 26628701 TI - Methodological considerations in determining the effects of films with suicidal content. PMID- 26628703 TI - Kaleidoscope. PMID- 26628702 TI - Authors' reply. PMID- 26628706 TI - Can Methotrexate Prevent Knee Arthroplasties in Patients with Rheumatoid Arthritis? PMID- 26628707 TI - The Difficult Task of Assessing Psoriatic Arthritis. PMID- 26628708 TI - Maffucci Syndrome. PMID- 26628709 TI - Specificity of Systemic Sclerosis Classification Criteria. PMID- 26628710 TI - Dr. Hoffmann-Vold replies. PMID- 26628711 TI - On the Relationship of Male Sexual Dysfunction and Ankylosing Spondylitis. PMID- 26628712 TI - Mr. Fan and Mr. Xin, et al reply. PMID- 26628713 TI - Diagnostic Challenges of SAPHO Syndrome. PMID- 26628714 TI - Solitary fibrous tumor of the pancreas. AB - Solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms of fibroblastic origin. Most commonly they affect the pleura but they been described in other viscera. SFT of the pancreas is extremely rare, and only eight cases have been reported to date. We perform a literature review and report a ninth case. The patient is a 54-year-old African-American female who presented with several months of abdominal pain. Abdominal radiography demonstrated a lesion in the head of the pancreas, and she underwent a Whipple operation. Pathology demonstrated SFT of the pancreas. She is alive and well 1 year post-operatively. SFT of the pancreas predominately affects middle-aged women. These tumors are difficult to distinguish radiologically from neuroendocrine tumors. While SFT of the pancreas tend to have an indolent course, there is the potential for malignancy. We recommend complete surgical excision. PMID- 26628715 TI - Blunt trauma resulting in pneumothorax with progression to pneumoperitoneum: a unique diagnosis with predicament in management. AB - Here, we present a case of pneumoperitoneum caused by traumatic pneumothorax after a fall. The patient is an 82-year-old male who was brought into the emergency department after being found at the bottom of a flight of stairs with a bleeding scalp laceration. Upon presentation, the patient underwent emergent intubation followed by tube thoracostomy placement, had necessary imaging and was transferred to the surgical intensive care unit (SICU). Imaging revealed signs of pneumomediastinum and pneumoperitoneum in addition to the partially resolved pneumothorax. In the SICU, the patient became hemodynamically unstable requiring vasopressor support, which in the face of documented pneumoperitoneum without a clear cause mandated exploration. He was taken to the operating room for suspected viscus perforation, though none was found after extensively searching during an exploratory laparotomy. We suspect the patient developed pneumomediastinum and pneumoperitoneum as a result of traumatic pneumothorax, hastened by his subsequent intubation and mechanical ventilation. PMID- 26628716 TI - Transabdominal approach assisted by thoracoscopic drainage for lower esophageal perforation. AB - The effectiveness of use of thoracoscopy for esophageal perforation has not been fully evaluated. We herein report a case of esophageal perforation for which a transabdominal approach assisted by thoracoscopic drainage was performed. PMID- 26628717 TI - Olson et al. Outbreak of Mycoplasma pneumoniae-Associated Stevens Johnson Syndrome. Pediatrics. 2015;136(2):e386-394. PMID- 26628718 TI - Chocolate Milk in Schools. PMID- 26628719 TI - Authors' Response: Reply to: Chocolate Milk in Schools. PMID- 26628720 TI - Differing Opinions on Upper Age Limit for Pediatrics. PMID- 26628721 TI - Authors' Response: Re: Differing Opinions on Upper Age Limit for Pediatrics. PMID- 26628724 TI - Emergence of the Same Successful Clade among Distinct Populations of emm89 Streptococcus pyogenes in Multiple Geographic Regions. PMID- 26628723 TI - Gene Loss and Error-Prone RNA Editing in the Mitochondrion of Perkinsela, an Endosymbiotic Kinetoplastid. AB - Perkinsela is an enigmatic early-branching kinetoplastid protist that lives as an obligate endosymbiont inside Paramoeba (Amoebozoa). We have sequenced the highly reduced mitochondrial genome of Perkinsela, which possesses only six protein coding genes (cox1, cox2, cox3, cob, atp6, and rps12), despite the fact that the organelle itself contains more DNA than is present in either the host or endosymbiont nuclear genomes. An in silico analysis of two Perkinsela strains showed that mitochondrial RNA editing and processing machineries typical of kinetoplastid flagellates are generally conserved, and all mitochondrial transcripts undergo U-insertion/deletion editing. Canonical kinetoplastid mitochondrial ribosomes are also present. We have developed software tools for accurate and exhaustive mapping of transcriptome sequencing (RNA-seq) reads with extensive U-insertions/deletions, which allows detailed investigation of RNA editing via deep sequencing. With these methods, we show that up to 50% of reads for a given edited region contain errors of the editing system or, less likely, correspond to alternatively edited transcripts. IMPORTANCE: Uridine insertion/deletion-type RNA editing, which occurs in the mitochondrion of kinetoplastid protists, has been well-studied in the model parasite genera Trypanosoma, Leishmania, and Crithidia. Perkinsela provides a unique opportunity to broaden our knowledge of RNA editing machinery from an evolutionary perspective, as it represents the earliest kinetoplastid branch and is an obligatory endosymbiont with extensive reductive trends. Interestingly, up to 50% of mitochondrial transcripts in Perkinsela contain errors. Our study was complemented by use of newly developed software designed for accurate mapping of extensively edited RNA-seq reads obtained by deep sequencing. PMID- 26628725 TI - Musser et al. Reply to "Emergence of the Same Successful Clade among Distinct Populations of emm89 Streptococcus pyogenes in Multiple Geographic Regions". PMID- 26628727 TI - Turner et al. Reply to "Emergence of the Same Successful Clade among Distinct Populations of emm89 Streptococcus pyogenes in Multiple Geographic Regions". PMID- 26628728 TI - Being a Pediatrician in an Ebola Epidemic. PMID- 26628726 TI - Gammaherpesvirus Infection of Human Neuronal Cells. AB - Gammaherpesviruses human herpesvirus 4 (HHV4) and HHV8 are two prominent members of the herpesvirus family associated with a number of human cancers. HHV4, also known as Epstein-Barr virus (EBV), a ubiquitous gammaherpesvirus prevalent in 90 to 95% of the human population, is clinically associated with various neurological diseases such as primary central nervous system lymphoma, multiple sclerosis, Alzheimer's disease, cerebellar ataxia, and encephalitis. However, the possibility that EBV and Kaposi's sarcoma-associated herpesvirus (KSHV) can directly infect neurons has been largely overlooked. This study has, for the first time, characterized EBV infection in neural cell backgrounds by using the Sh-Sy5y neuroblastoma cell line, teratocarcinoma Ntera2 neurons, and primary human fetal neurons. Furthermore, we also demonstrated KSHV infection of neural Sh-Sy5y cells. These neuronal cells were infected with green fluorescent protein expressing recombinant EBV or KSHV. Microscopy, genetic analysis, immunofluorescence, and Western blot analyses for specific viral antigens supported and validated the infection of these cells by EBV and KSHV and showed that the infection was efficient and productive. Progeny virus produced from infected neuronal cells efficiently infected fresh neuronal cells, as well as peripheral blood mononuclear cells. Furthermore, acyclovir was effective at inhibiting the production of virus from neuronal cells similar to lymphoblastoid cell lines; this suggests active lytic replication in infected neurons in vitro. These studies represent a potentially new in vitro model of EBV- and KSHV associated neuronal disease development and pathogenesis. IMPORTANCE: To date, no in vitro study has demonstrated gammaherpesvirus infection of neuronal cells. Moreover, worldwide clinical findings have linked EBV to neuronal pathologies, including multiple sclerosis, primary central nervous system lymphoma, and Alzheimer's disease. In this study, for the first time, we have successfully demonstrated the in vitro infection of Sh-Sy5y and Ntera2 cells, as well as human primary neurons. We have also determined that the infection is predominately lytic. Additionally, we also report infection of neuronal cells by KSHV in vitro similar to that by EBV. These findings may open new avenues of consideration related to neuronal pathologies and infection with these viruses. Furthermore, their contribution to chronic infection linked to neuronal disease will provide new clues to potential new therapies. PMID- 26628729 TI - Apnea of Prematurity. AB - Apnea of prematurity is one of the most common diagnoses in the NICU. Despite the frequency of apnea of prematurity, it is unknown whether recurrent apnea, bradycardia, and hypoxemia in preterm infants are harmful. Research into the development of respiratory control in immature animals and preterm infants has facilitated our understanding of the pathogenesis and treatment of apnea of prematurity. However, the lack of consistent definitions, monitoring practices, and consensus about clinical significance leads to significant variation in practice. The purpose of this clinical report is to review the evidence basis for the definition, epidemiology, and treatment of apnea of prematurity as well as discharge recommendations for preterm infants diagnosed with recurrent apneic events. PMID- 26628730 TI - Cigarette Tax Increase and Infant Mortality. AB - BACKGROUND AND OBJECTIVE: Maternal smoking increases the risk for preterm birth, low birth weight, and sudden infant death syndrome, which are all causes of infant mortality. Our objective was to evaluate if changes in cigarette taxes and prices over time in the United States were associated with a decrease in infant mortality. METHODS: We compiled data for all states from 1999 to 2010. Time series models were constructed by infant race for cigarette tax and price with infant mortality as the outcome, controlling for state per-capita income, educational attainment, time trend, and state random effects. RESULTS: From 1999 through 2010, the mean overall state infant mortality rate in the United States decreased from 7.3 to 6.2 per 1000 live births, with decreases of 6.0 to 5.3 for non-Hispanic white and 14.3 to 11.3 for non-Hispanic African American infants (P < .001). Mean inflation-adjusted state and federal cigarette taxes increased from $0.84 to $2.37 per pack (P < .001). In multivariable regression models, we found that every $1 increase per pack in cigarette tax was associated with a change in infant deaths of -0.19 (95% confidence interval -0.33 to -0.05) per 1000 live births overall, including changes of -0.21 (-0.33 to -0.08) for non-Hispanic white infants and -0.46 (-0.90 to -0.01) for non-Hispanic African American infants. Models for cigarette price yielded similar findings. CONCLUSIONS: Increases in cigarette taxes and prices are associated with decreases in infant mortality rates, with stronger impact for African American infants. Federal and state policymakers may consider increases in cigarette taxes as a primary prevention strategy for infant mortality. PMID- 26628731 TI - A Multicenter Collaborative to Reduce Unnecessary Care in Inpatient Bronchiolitis. AB - BACKGROUND AND OBJECTIVE: Evidence-based Guidelines for acute viral bronchiolitis recommend primarily supportive care, but unnecessary care remains well documented. Published quality improvement work has been accomplished in children's hospitals, but little broad dissemination has been reported outside of those settings. We sought to use a voluntary collaborative strategy to disseminate best practices to reduce overuse of unnecessary care in children hospitalized for bronchiolitis in community settings. METHODS: This project was a quality improvement collaborative consisting of monthly interactive webinars with online data collection and feedback. Data were collected by chart review for 2 bronchiolitis seasons, defined as January, February, and March of 2013 and 2014. Patients aged <24 months hospitalized for bronchiolitis and without chronic illness, prematurity, or intensive care use were included. Results were analyzed using run charting, analysis of means, and nonparametric statistics. RESULTS: There were 21 participating hospitals contributing a total of 1869 chart reviews to the project, 995 preintervention and 874 postintervention. Mean use of any bronchodilator declined by 29% (P = .03) and doses per patient decreased 45% (P < .01). Mean use of any steroids declined by 68% (P < .01), and doses per patient decreased 35% (P = .04). Chest radiography use declined by 44% (P = .05). Length of stay decreased 5 hours (P < .01), and readmissions remained unchanged. CONCLUSIONS: A voluntary collaborative was effective in reducing unnecessary care among a cohort of primarily community hospitals. Such a strategy may be generalizable to the settings where the majority of children are hospitalized in the United States. PMID- 26628732 TI - Meningitis. AB - Based on strong evidence, blood cultures usually recover the causative organism of bacterial meningitis in children not pretreated with antibiotics. Based on moderate evidence, pretreatment does not adversely affect the cerebrospinal fluid cell count, but it decreases the positive test result for cerebrospinal fluid culture, especially for meningococcal meningitis. Based on some research evidence as well as consensus, children with suspected bacterial meningitis and no clinical signs of brain herniation do not need neuroimaging as part of their initial clinical evaluation. Dexamethasone adjunctive therapy in children with pneumococcal meningitis is controversial. Some experts recommend neuroimaging toward the end of therapy for all neonates with bacterial meningitis. Based on some research evidence as well as consensus, home intravenous antimicrobial therapy may be an option in selected cases of pediatric bacterial meningitis. PMID- 26628733 TI - Pain and Symptom Management in Pediatric Palliative Care. AB - Pain and symptom management is considered one of the cornerstones of palliative and hospice medicine. However, general clinicians and specialists are not usually comfortable addressing the most common forms of pain seen in the pediatric population. In addition, non-pain symptom management, especially when related to underlying chronic medical conditions, can be managed by the general clinician and specialists. The goal of this article is to educate clinicians about pain categories, taking a detailed pain history, and developing a plan for treatment, including nonpharmacologic methods. Finally, we discuss common symptoms in patients with chronic medical conditions, including first-line treatment options. PMID- 26628734 TI - Substance Abuse, General Principles. PMID- 26628735 TI - Case 1: Clavicular Pain of 2 Months' Duration in a 9-year-old Girl. PMID- 26628736 TI - Case 2: Recurrent Anemia in a 10-year-old Girl. PMID- 26628738 TI - Correction. PMID- 26628737 TI - Case 3: Abnormal Eye Movements and Congestion in a 3-month-old Boy. PMID- 26628739 TI - Upper Respiratory Tract Infections. PMID- 26628740 TI - Visual Diagnosis: A 2-month-old Boy With an Unusual Rash. AB - Congenital syphilis should be considered in the differential diagnosis of common newborn rashes, especially if the palms and soles are involved. As soon as the diagnosis is confirmed, a lumbar puncture should be performed to rule out neurosyphilis and intravenous antibiotics started pending confirmatory testing. PMID- 26628743 TI - Flavonols Mediate Root Phototropism and Growth through Regulation of Proliferation-to-Differentiation Transition. AB - Roots normally grow in darkness, but they may be exposed to light. After perceiving light, roots bend to escape from light (root light avoidance) and reduce their growth. How root light avoidance responses are regulated is not well understood. Here, we show that illumination induces the accumulation of flavonols in Arabidopsis thaliana roots. During root illumination, flavonols rapidly accumulate at the side closer to light in the transition zone. This accumulation promotes asymmetrical cell elongation and causes differential growth between the two sides, leading to root bending. Furthermore, roots illuminated for a long period of time accumulate high levels of flavonols. This high flavonol content decreases both auxin signaling and PLETHORA gradient as well as superoxide radical content, resulting in reduction of cell proliferation. In addition, cytokinin and hydrogen peroxide, which promote root differentiation, induce flavonol accumulation in the root transition zone. As an outcome of prolonged light exposure and flavonol accumulation, root growth is reduced and a different root developmental zonation is established. Finally, we observed that these differentiation-related pathways are required for root light avoidance. We propose that flavonols function as positional signals, integrating hormonal and reactive oxygen species pathways to regulate root growth direction and rate in response to light. PMID- 26628744 TI - POLYPRENOL REDUCTASE2 Deficiency Is Lethal in Arabidopsis Due to Male Sterility. AB - Dolichol is a required cofactor for protein glycosylation, the most common posttranslational modification modulating the stability and biological activity of proteins in all eukaryotic cells. We have identified and characterized two genes, PPRD1 and -2, which are orthologous to human SRD5A3 (steroid 5alpha reductase type 3) and encode polyprenol reductases responsible for conversion of polyprenol to dolichol in Arabidopsis thaliana. PPRD1 and -2 play dedicated roles in plant metabolism. PPRD2 is essential for plant viability; its deficiency results in aberrant development of the male gametophyte and sporophyte. Impaired protein glycosylation seems to be the major factor underlying these defects although disturbances in other cellular dolichol-dependent processes could also contribute. Shortage of dolichol in PPRD2-deficient cells is partially rescued by PPRD1 overexpression or by supplementation with dolichol. The latter has been discussed as a method to compensate for deficiency in protein glycosylation. Supplementation of the human diet with dolichol-enriched plant tissues could allow new therapeutic interventions in glycosylation disorders. This identification of PPRD1 and -2 elucidates the factors mediating the key step of the dolichol cycle in plant cells which makes manipulation of dolichol content in plant tissues feasible. PMID- 26628741 TI - Analysis of Major Histocompatibility Complex (MHC) Immunopeptidomes Using Mass Spectrometry. AB - The myriad of peptides presented at the cell surface by class I and class II major histocompatibility complex (MHC) molecules are referred to as the immunopeptidome and are of great importance for basic and translational science. For basic science, the immunopeptidome is a critical component for understanding the immune system; for translational science, exact knowledge of the immunopeptidome can directly fuel and guide the development of next-generation vaccines and immunotherapies against autoimmunity, infectious diseases, and cancers. In this mini-review, we summarize established isolation techniques as well as emerging mass spectrometry-based platforms (i.e. SWATH-MS) to identify and quantify MHC-associated peptides. We also highlight selected biological applications and discuss important current technical limitations that need to be solved to accelerate the development of this field. PMID- 26628745 TI - Core Promoter Plasticity Between Maize Tissues and Genotypes Contrasts with Predominance of Sharp Transcription Initiation Sites. AB - Core promoters are crucial for gene regulation, providing blueprints for the assembly of transcriptional machinery at transcription start sites (TSSs). Empirically, TSSs define the coordinates of core promoters and other regulatory sequences. Thus, experimental TSS identification provides an essential step in the characterization of promoters and their features. Here, we describe the application of CAGE (cap analysis of gene expression) to identify genome-wide TSSs used in root and shoot tissues of two maize (Zea mays) inbred lines (B73 and Mo17). Our studies indicate that most TSS clusters are sharp in maize, similar to mice, but distinct from Arabidopsis thaliana, Drosophila melanogaster, or zebra fish, in which a majority of genes have broad-shaped TSS clusters. We established that ~38% of maize promoters are characterized by a broader TATA-motif consensus, and this motif is significantly enriched in genes with sharp TSSs. A noteworthy plasticity in TSS usage between tissues and inbreds was uncovered, with ~1500 genes showing significantly different dominant TSSs, sometimes affecting protein sequence by providing alternate translation initiation codons. We experimentally characterized instances in which this differential TSS utilization results in protein isoforms with additional domains or targeted to distinct subcellular compartments. These results provide important insights into TSS selection and gene expression in an agronomically important crop. PMID- 26628746 TI - Nitro-Fatty Acids in Plant Signaling: Nitro-Linolenic Acid Induces the Molecular Chaperone Network in Arabidopsis. AB - Nitro-fatty acids (NO2-FAs) are the product of the reaction between reactive nitrogen species derived of nitric oxide (NO) and unsaturated fatty acids. In animal systems, NO2-FAs are considered novel signaling mediators of cell function based on a proven antiinflammatory response. Nevertheless, the interaction of NO with fatty acids in plant systems has scarcely been studied. Here, we examine the endogenous occurrence of nitro-linolenic acid (NO2-Ln) in Arabidopsis and the modulation of NO2-Ln levels throughout this plant's development by mass spectrometry. The observed levels of this NO2-FA at picomolar concentrations suggested its role as a signaling effector of cell function. In fact, a transcriptomic analysis by RNA-seq technology established a clear signaling role for this molecule, demonstrating that NO2-Ln was involved in plant defense response against different abiotic-stress conditions, mainly by inducing heat shock proteins and supporting a conserved mechanism of action in both animal and plant defense processes. Bioinformatics analysis revealed that NO2-Ln was also involved in the response to oxidative stress conditions, mainly depicted by H2O2, reactive oxygen species, and oxygen-containing compound responses, with a high induction of ascorbate peroxidase expression. Closely related to these results, NO2-Ln levels significantly rose under several abiotic-stress conditions such as wounding or exposure to salinity, cadmium, and low temperature, thus validating the outcomes found by RNA-seq technology. Jointly, to our knowledge, these are the first results showing the endogenous presence of NO2-Ln in Arabidopsis (Arabidopsis thaliana) and supporting the strong signaling role of these molecules in the defense mechanism against different abiotic-stress situations. PMID- 26628747 TI - Grapevine Plasticity in Response to an Altered Microclimate: Sauvignon Blanc Modulates Specific Metabolites in Response to Increased Berry Exposure. AB - In this study, the metabolic and physiological impacts of an altered microclimate on quality-associated primary and secondary metabolites in grape (Vitis vinifera) 'Sauvignon Blanc' berries was determined in a high-altitude vineyard. The leaf and lateral shoot removal in the bunch zones altered the microclimate by increasing the exposure of the berries. The physical parameters (berry diameter and weight), primary metabolites (sugars and organic acids), as well as bunch temperature and leaf water potential were predominantly not affected by the treatment. The increased exposure led to higher levels of specific carotenoids and volatile terpenoids in the exposed berries, with earlier berry stages reacting distinctly from the later developmental stages. Plastic/nonplastic metabolite responses could be further classified to identify metabolites that were developmentally controlled and/or responded to the treatment in a predictable fashion (assessed over two consecutive vintages). The study demonstrates that grapevine berries exhibit a degree of plasticity within their secondary metabolites and respond physiologically to the increased exposure by increasing metabolites with potential antioxidant activity. Taken together, the data provide evidence that the underlying physiological responses relate to the maintenance of stress pathways by modulating antioxidant molecules in the berries. PMID- 26628750 TI - Novel insights into mammalian embryonic neural stem cell division: focus on microtubules. AB - During stem cell divisions, mitotic microtubules do more than just segregate the chromosomes. They also determine whether a cell divides virtually symmetrically or asymmetrically by establishing spindle orientation and the plane of cell division. This can be decisive for the fate of the stem cell progeny. Spindle defects have been linked to neurodevelopmental disorders, yet the role of spindle orientation for mammalian neurogenesis has remained controversial. Here we explore recent advances in understanding how the microtubule cytoskeleton influences mammalian neural stem cell division. Our focus is primarily on the role of spindle microtubules in the development of the cerebral cortex. We also highlight unique characteristics in the architecture and dynamics of cortical stem cells that are tightly linked to their mode of division. These features contribute to setting these cells apart as mitotic "rule breakers," control how asymmetric a division is, and, we argue, are sufficient to determine the fate of the neural stem cell progeny in mammals. PMID- 26628748 TI - An Optimal Frequency in Ca2+ Oscillations for Stomatal Closure Is an Emergent Property of Ion Transport in Guard Cells. AB - Oscillations in cytosolic-free Ca(2+) concentration ([Ca(2+)]i) have been proposed to encode information that controls stomatal closure. [Ca(2+)]i oscillations with a period near 10 min were previously shown to be optimal for stomatal closure in Arabidopsis (Arabidopsis thaliana), but the studies offered no insight into their origins or mechanisms of encoding to validate a role in signaling. We have used a proven systems modeling platform to investigate these [Ca(2+)]i oscillations and analyze their origins in guard cell homeostasis and membrane transport. The model faithfully reproduced differences in stomatal closure as a function of oscillation frequency with an optimum period near 10 min under standard conditions. Analysis showed that this optimum was one of a range of frequencies that accelerated closure, each arising from a balance of transport and the prevailing ion gradients across the plasma membrane and tonoplast. These interactions emerge from the experimentally derived kinetics encoded in the model for each of the relevant transporters, without the need of any additional signaling component. The resulting frequencies are of sufficient duration to permit substantial changes in [Ca(2+)]i and, with the accompanying oscillations in voltage, drive the K(+) and anion efflux for stomatal closure. Thus, the frequency optima arise from emergent interactions of transport across the membrane system of the guard cell. Rather than encoding information for ion flux, these oscillations are a by-product of the transport activities that determine stomatal aperture. PMID- 26628749 TI - Why should cell biologists study microbial pathogens? AB - One quarter of all deaths worldwide each year result from infectious diseases caused by microbial pathogens. Pathogens infect and cause disease by producing virulence factors that target host cell molecules. Studying how virulence factors target host cells has revealed fundamental principles of cell biology. These include important advances in our understanding of the cytoskeleton, organelles and membrane-trafficking intermediates, signal transduction pathways, cell cycle regulators, the organelle/protein recycling machinery, and cell-death pathways. Such studies have also revealed cellular pathways crucial for the immune response. Discoveries from basic research on the cell biology of pathogenesis are actively being translated into the development of host-targeted therapies to treat infectious diseases. Thus there are many reasons for cell biologists to incorporate the study of microbial pathogens into their research programs. PMID- 26628751 TI - Forty-five years of cell-cycle genetics. AB - In the early 1970s, studies in Leland Hartwell's laboratory at the University of Washington launched the genetic analysis of the eukaryotic cell cycle and set the path that has led to our modern understanding of this centrally important process. This 45th-anniversary Retrospective reviews the steps by which the project took shape, the atmosphere in which this happened, and the possible morals for modern times. It also provides an up-to-date look at the 35 original CDC genes and their human homologues. PMID- 26628752 TI - Correction. PMID- 26628753 TI - Correction. PMID- 26628754 TI - Early goal-directed therapy: Sorting through confusion. PMID- 26628755 TI - Assessment of phagocytic activity of neutrophils in chronic obstructive pulmonary disease. AB - AIM: To assess the phagocytic activity of neutrophils in subjects with chronic obstructive pulmonary disease (COPD). BACKGROUND/NEED OF STUDY: There is a paucity of data in relation to phagocytic function in COPD. By this multidisciplinary study, a better understanding about the etiology of lung destruction among COPD patients is being sought. MATERIALS AND METHODS: The study was conducted among 28 subjects with COPD and 25 controls in a private tertiary hospital in Chennai after obtaining Institutional Ethical Clearance. Known cases of COPD as proven by clinical findings and spirometry were included in the study, and subjects with any other source of infection, recent surgery, or chronic granulomatous disease were excluded. The study subjects were divided into three groups based on the severity of COPD as determined by spirometry, and healthy volunteers were taken as Group 4. After obtaining informed consent, validated respiratory health questionnaire was administered. The phagocytic function was assessed by Candida phagocytic test and Nitroblue Tetrazolium (NBT) Reduction Test. RESULTS: Significantly impaired phagocytic function as indicated by lower phagocytic, lytic indices and decreased NBT reduction of neutrophils was seen in COPD subjects compared to normal healthy controls (P < .001). CONCLUSION: This study showed that there is phagocytic dysfunction in COPD subjects when compared with normal subjects. This could be due to underlying inflammation in human airway. Understanding the role of neutrophils may lead to improved understanding of the pathogenesis of COPD, which in turn may pave way for implementing modified therapeutic intervention strategies. PMID- 26628756 TI - Epidemiological study of prevalence, determinants, and outcomes of infections in medical ICU at a tertiary care hospital in India. AB - OBJECTIVES: To determine the prevalence of infections, risk factors, and outcomes in a medical intensive care unit (ICU), we performed a hospital-based study. MATERIALS AND METHODS: Consecutive patients were enrolled and details of risk factors and bacteriological data were obtained. Outcomes were death/transfer to palliative care or recovery. Statistical analyses were performed. RESULTS: Four hundred and eighty-seven patients were admitted during the study period (age 55.6 +/- 19 yr, men 68%). Diseases responsible were respiratory (37%), gastrointestinal/liver (22%), neurological (20%), renal (8%), and trauma (6%) related. Majority of admissions were direct (45%) or transfers from other hospitals (41%). Most important comorbidities were hypertension (41%), diabetes (31%), and chronic obstructive pulmonary disease (15%). Median APACHE-2 score was 13.0 (IQR 1-25). Antibiotics were administered in 98%. Bacteriological cultures were positive in 28% (n = 623). Respiratory infections were the most common (45.5%) followed by blood (23.3%) and urinary (16.1%). Gram-negative bacteria were common-Acinetobacter baumannii (20.9%), Klebsiella pneumoniae (19.7%), Escherichia coli (18.3%), and Pseudomonas aeruginosa (14.0%). There a high prevalence of resistance to common antibiotics. Patients with positive cultures were older, transferees (46 vs 37%, P = 0.07), with respiratory disease (48 vs. 33%, P = 0.003), with more than two comorbidities (33 vs 21%, P = 0.009), and higher APACHE-2 score (17.7 +/- 8 vs. 13.3 +/- 8, P = 0.07). Three hundred and fifty-two (72.3%) recovered, 68 (13.9%) died, and 67 (13.8%) were transferred to palliative care. Survival was associated with younger age, lower APACHE-2 score, negative cultures, and shorter duration in ICU (P < 0.05). Mortality was greater in patients with Acinetobacter (OR 2.36, 1.17-4.73), Klebsiella (OR 2.81, 1.33 5.92), Pseudomonas (OR 8.03, 2.83-22.76), or Enterobacter (OR 6.73, 1.29-35.12) infection. CONCLUSIONS: There is high prevalence of infections in patients in a medical ICU in India. Gram-negative bacteria are the most prevalent and resistance to antibiotics is high. Risk factors are age, hospital transfers, APACHE-2 score, and multiple comorbidities. PMID- 26628757 TI - Analysis of HLA association among North Indian HIV-positive individuals co infected with Mycobacterium tuberculosis. AB - BACKGROUND: Genetic variation in HLA genes influence the immune response and may thus contribute to differential development of tuberculosis (TB) in HIV-infected individuals. The study was designed to determine whether HLA polymorphisms influence the development of Mycobacterium tuberculosis infection in HIV-infected individuals. MATERIALS AND METHODS: Fifty HIV-positive individuals without TB (HIV+TB-), 50 HIV patients co-infected with TB (HIV+TB+) and 50 control subjects (HIV-TB-) were analyzed for HLA Class I and II polymorphisms. RESULTS: In HLA Class II, frequency of occurrence of DRB1*13 (OR 3.165, CI 1.176-8.518, P value 0.019), DRB5 (OR 2.253, CI 1.011-5.019, P value 0.045) and DQB1*06 (OR 2.705, CI 1.197-6.113, P value 0.016) were increased in HIV+TB+compared to HIV+TB-. HLA DQB1*02 (OR 0.436, CI 0.185-1.029, P value 0.05) on the other hand conferred a protective role. In HLA Class I, frequency of B*15 (OR 2.705, CI 1.040-7.036, P value 0.038) was increased, whereas B*51 (OR 0.148, CI 0.031-0.706, P value 0.007) was decreased in HIV+TB+group compared to HIV+TB-. These differences however were not significant when compared with healthy controls. CONCLUSION: HLA polymorphisms independently did not account for the susceptibility to either of the disease mostly, although they seem to play a role once the infection(s) has established in a particular individual. Further studies are needed on a larger sample size to confirm these observations. PMID- 26628758 TI - Transbronchial lung biopsy in patients with diffuse parenchymal lung disease without 'idiopathic pulmonary fibrosis pattern' on HRCT scan - Experience from a tertiary care center of North India. AB - BACKGROUND: Diffuse parenchymal lung diseases (DPLD) are a group of disorders characterized by chest radiological findings of bilateral diffuse shadowing. Lung biopsy is generally required to make an etiological diagnosis of DPLD's. Transbronchial lung biopsy (TBLB) is a minimally invasive method to achieve a lung sample which has been found to be a useful diagnostic tool in patients with DPLD. As per American Thoracic Society guidelines for management of idiopathic interstitial pneumonias, TBLB is not required in patients who have findings consistent with idiopathic pulmonary fibrosis (IPF) on HRCT scan thorax. Some Indian researchers have evaluated, on a small number of subjects, the role of TBLB in patients with DPLD, but they had not excluded patients with 'IPF pattern'. This study was planned to assess TBLB in patients with DPLD after excluding patients with 'IPF pattern'. MATERIALS AND METHODS: A prospective non randomized study on 49 patients with DPLD without a characteristic 'IPF pattern' were subjected to TBLB. RESULTS: The overall diagnostic yield of TBLB was 85.7%. Non-specific interstitial pneumonitis, tuberculosis and sarcoidosis were the most common histology patterns found (22.4, 18.4 and 16.3%, respectively). Procedure related mortality was nil. Iatrogenic pneumothorax occurred in five patients (10.2%). Minor complications included hemorrhage and transient hypoxia. CONCLUSION: TBLB is a safe and effective tool in the diagnosis of DPLD. PMID- 26628759 TI - Study of computerized spirometric parameters of traffic police personnel of Saurashtra region, Gujarat, India. AB - BACKGROUND AND OBJECTIVES: Air pollution due to road traffic is a serious health hazard and air quality crisis in cities is mainly due to vehicular emission. Thus the persons who are continuously exposed are at an increased risk. The study was carried out to evaluate the extent of impairment in lung function in traffic police personnel compared to matched unexposed control group. MATERIALS AND METHODS: A cross-sectional study was conducted to measure the spirometric parameters of 100 traffic police personnel, aged 20-55 years, working in Saurashtra region, as compared to matched control group, consisting of 100 unexposed males. Measurement of lung volumes and capacities was done with SPIROEXCEL. The statistical analysis was carried out with Graph pad instat 3. RESULTS: Traffic police personnel had significantly declined forced vital capacity (FVC), forced expiratory volume in one second (FEV 1), slow vital capacity (SVC) and maximum voluntary ventilation (MVV) when compared with predictive normal values, which is probably due to exposure to vehicular exhaust. Comparison of test values between groups showed significantly reduced FVC, MVV and increased FEV1/FVC ratio and insignificantly declined FEV1 and SVC in cases as compared to controls. Traffic personnel with longer duration of exposure showed significantly reduced lung functions than those with shorter duration. Smokers showed lower test values as compared to non-smokers with significance only in unexposed group. CONCLUSION: The effect of pollution by vehicular exhausts may be responsible for these pulmonary function impairments and traffic police personnel should be offered personal protective or preventive measures. PMID- 26628760 TI - Secondary laryngeal tuberculosis revisited. AB - INTRODUCTION: Laryngeal tuberculosis is often misdiagnosed and is a highly contagious public health problem. The changing pattern of the clinical involvement of this disease poses a diagnostic challenge. The authors report four cases of laryngeal tuberculosis encountered in a short span of one month. MATERIALS AND METHODS: All the four patients who presented to us with hoarseness had underlying active lesions in the lung. In spite of that they presented with mainly laryngeal symptoms and a multitude of findings on laryngeal examination. A diagnosis could be established owing to a high index of clinical suspicion, and due consideration given to the chest findings and positive sputum examination. The patients showed an excellent response to antituberculous therapy. RESULTS AND CONCLUSIONS: This study underlines the varied nature of laryngeal tuberculosis and the importance of addressing the hoarseness of a patient at the earliest, for the prompt diagnosis of this infectious condition. PMID- 26628761 TI - Outcomes associated with acute exacerbations of chronic obstructive pulmonary disorder requiring hospitalization. AB - BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disorder (AECOPD) are known to be associated with increased morbidity and mortality and have a significant socioeconomic impact. The factors that determine frequent hospital readmissions for AECOPD are poorly understood. The present study was done to ascertain failures rates following AECOPD and to evaluate factors associated with frequent readmissions. MATERIALS AND METHODS: We conducted a prospective study among 186 patients with COPD with one or more admissions for acute exacerbations in a tertiary care hospital. Frequency of previous re admissions for AECOPD in the past year, and clinical characteristics, including spirometry were ascertained in the stable state both before discharge and at 6 month post-discharge. Failure rates following treatment were ascertained during the follow-up period. All the patients were followed up for a period of 2 years after discharge to evaluate re-admissions for the AECOPD. RESULTS: Of 186 COPD patients admitted for AECOPD, 54% had one or more readmission, and another 45% had two or more readmissions over a period of 2 years. There was a high prevalence of current or ex-heavy smokers, associated co-morbidity, underweight patients, low vaccination prevalence and use of domiciliary oxygen therapy among COPD patients. A total of 12% mortality was observed in the present study. Immediate failure rates after first exacerbation was observed to be 34.8%. Multivariate analysis showed that duration >20 years (OR = 0.37; 95% CI: 0.10 0.86), use of Tiotropium (OR = 2.29; 95% CI: 1.12-4.69) and use of co-amoxiclav during first admission (OR = 2.41; 95% CI: 1.21-4.79) were significantly associated with higher immediate failure rates. The multivariate analysis for repeated admissions revealed that disease duration >10 years (OR = 0.50; 95% CI: 0.27-0.93), low usage of inhaled ICS + LABA (OR = 2.21; 95% CI: 1.08-4.54), and MRC dyspnea grade >3 (OR = 2.51; 95% CI: 1.08-5.82) were independently associated with frequent re-admissions for AECOPD. CONCLUSIONS: The outcomes of patients admitted for an acute exacerbation of COPD were poor. The major factors influencing frequency of repeated COPD exacerbations were disease duration, low usage of inhaled ICS + LABA, and MRC dyspnea grade >3. PMID- 26628762 TI - Enhancing indoor air quality -The air filter advantage. AB - Air pollution has become the world's single biggest environmental health risk, linked to around 7 million deaths in 2012 according to a recent World Health Organisation (WHO) report. The new data further reveals a stronger link between, indoor and outdoor air pollution exposure and cardiovascular diseases, such as strokes and ischemic heart disease, as well as between air pollution and cancer. The role of air pollution in the development of respiratory diseases, including acute respiratory infections and chronic obstructive pulmonary diseases, is well known. While both indoor and outdoor pollution affect health, recent statistics on the impact of household indoor pollutants (HAP) is alarming. The WHO factsheet on HAP and health states that 3.8 million premature deaths annually - including stroke, ischemic heart disease, chronic obstructive pulmonary disease (COPD) and lung cancer are attributed to exposure to household air pollution. Use of air cleaners and filters are one of the suggested strategies to improve indoor air quality. This review discusses the impact of air pollutants with special focus on indoor air pollutants and the benefits of air filters in improving indoor air quality. PMID- 26628764 TI - Cervico mediastinal teratoma in adult: A very rare presentation. AB - Teratoma is a rare presentation in adult, specifically in cervico-mediastinal region. We reported two adult patients with diagnosis of cervico-mediastinal teratoma and operated them. In adult patients who present with cervico mediastinal mass, benign teratoma could be one of a differential diagnosis although it is a rare presentation. PMID- 26628763 TI - Fluro-deoxygenase-positron emission tomography/computed tomography in hard metal lung disease. AB - We report a case of a diamond polisher where FDG-PET/CT was helpful in identifying active inflammation in hard metal lung disease (HMLD) caused by cobalt exposure. PMID- 26628765 TI - Mesenchymal stromal stem cell therapy in advanced interstitial lung disease - Anaphylaxis and short-term follow-up. AB - There are limited treatment options for advanced interstitial lung disease (ILD). We describe a patient of ILD treated with mesenchymal stromal stem cell infusion. The index patient had end-stage ILD due to a combination of insults including treatment with radiotherapy and a tyrosine kinase inhibitor Erlotinib. He was oxygen-dependent and this was hampering his quality of life. He tolerated the first infusion stem cells without any problem. During the second infusion he developed anaphylactic shock, which was appropriately managed. At 6-months follow up he had no improvement in oxygenation, pulmonary function or CT scan parameters. In view of anaphylaxis, further infusions of MSC were withheld. A longer follow-up may reveal long-term benefits or side effects, if any. However the occurrence of anaphylaxis is of concern suggesting that further trials should be conducted with intensive monitoring. PMID- 26628766 TI - Brocho-biliary fistula: A rare complication after ruptured liver abscess in a 31/2 year old child. AB - Bronchobiliary fistula (BBF) is a rare condition, defined by the presence of abnormal communication between biliary tract and bronchial tree. We describe a 31/2-year-old child who developed BBF after rupture of liver abscess. She underwent exploratory laparotomy and peritoneal wash for ruptured liver abscess. Seven months later she presented with fever and cough with yellow-colored expectoration (bilioptysis). An abnormal communication between right branch of the hepatic duct and a branch of right main bronchus was identified. Child underwent right lateral thoracotomy and right lower lobectomy with surgical excision of sinus tract. On follow-up child was asymptomatic and doing well. PMID- 26628767 TI - Miliary tuberculosis in an Indian lady: Looking beyond miliary tuberculosis. AB - Presence of miliary shadows in chest imaging in the appropriate clinical setting is often taken as a marker of miliary tuberculosis. If sputum is negative for acid -fast bacillus, empirical anti-tubercular therapy is given without securing a histological or microbiological diagnosis. We report a young female with human immunodeficiency virus infection who had miliary infiltrates on chest radiography. She was started on empirical anti-tubercular therapy. But an alternate diagnosis was achieved later with invasive sampling and ATT was stopped. This case illustrates the need for physicians to remain alert to diseases which mimic tuberculosis in presentation. PMID- 26628768 TI - Eosinophilic leukemoid reaction in a male adolescent with Loeffler syndrome. AB - The Loeffler syndrome is characterized by pulmonary infiltrates on a chest x-ray accompanied with peripheral eosinophilia. In this article, we have highlighted the Loeffler syndrome complicated with a eosinophilic leukemoid reaction in a previously healthy boy. The patient was treated with albendazole for five days, with a successful result. In countries where parasitic diseases are endemic, the Loeffler syndrome must always be considered in patients who present with a eosinophilic leukemoid reaction. PMID- 26628769 TI - Primary pulmonary myoepithelial carcinoma in a child: An ambiguous entity. AB - Primary myoepithelial carcinoma (MC) of the lung is exceedingly rare. We report here, to the best of our knowledge, the first pediatric case having primitive pulmonary MC. The originality of our case was the disappearance of the pulmonary opacity spontaneously, without any treatment. The difficulties in our case were the diagnosis of this rare entity and its subsequent treatment. In fact, given the rarity of these tumors, recommendations regarding chemotherapy or radiation, were difficult to formulate. PMID- 26628770 TI - Case-based discussion: Lymphocytic interstitial pneumonia a rare presentation in an immunocompetent adult male. AB - Lymphocytic interstitial pneumonia (LIP) is a rare form of interstitial lung disease usually associated with other systemic diseases; however, idiopathic cases are being reported. As per recent ATS/ERS 2013 guidelines, diagnostic criteria of clinical, radiological and histopathological for LIP is same as 2002 except some cystic changes on HRCT chest. Many cases diagnosed in the past as LIP now turn out to be NSIP; therefore as per new ATS/ERS classification whenever anybody report a case of LIP, NSIP should always be kept in mind as differential diagnosis. Here we present a case of LIP in an immunocompetent adult male presented with history of persistent dry cough and breathlessness on exertion, confirmed on HRCT chest and histopathologically, treated successfully with steroids. PMID- 26628771 TI - Myelomatous pleural effusion - Thoracoscopic evaluation of a rare entity. AB - Multiple myeloma is a malignant neoplasm of plasma cell origin that mainly affects bone marrow and skeletal system, producing large amount of light chain immunoglobulins. Pleural involvement in multiple myeloma is a rare complication which carries very poor prognosis. We report a case of multiple myeloma who presented with recurrent pleural effusion that was evaluated by means of thoracoscopy. PMID- 26628772 TI - Endobronchial tuberculosis mimicking malignancy. AB - Endobronchial tuberculosis has a very varied presentation. Diagnosis is often very challenging as typical radiological features are absent and sputum smear for acid-fast bacilli is often negative. However, detection is essential as it may lead to long-term sequelae such as bronchial stenosis. Bronchoscopy is a very useful investigation in such cases. Our case is a rare manifestation of endobronchial tuberculosis as it mimicked malignancy. PMID- 26628773 TI - Cryo-recanalization in a case of carcinoid tumor - An interesting case report. AB - The term "cryotherapy" comes from the Greek cryo (kapparhoupsilonomicron) meaning cold, and therapy (thetaepsilonrhoalphapiepsiloniotaalpha) meaning cure. Cryosurgery is the application of extreme cold to destroy abnormal or diseased tissue. Carcinoid tumors of the lung are a fascinating but uncommon group of pulmonary neoplasms. In the past, these tumors were grouped with benign or less aggressive malignant pulmonary tumors, namely bronchial adenomas. Recent studies have revealed that carcinoid lung tumors are the most indolent form of a spectrum of bronchopulmonary neuroendocrine tumors that, at its extreme, include small cell carcinoma of the lung as its most malignant member. They commonly present as endobronchial obstructions, and if complete, can be life-threatening and require immediate intervention.[1] Recently, we have treated a patient of carcinoid tumor of lung who was managed with cryo-recanalization with excellent response. PMID- 26628774 TI - A rare case of pulmonary cysticercosis manifesting as lung cavity with pleural effusion. AB - Isolated pulmonary cysticercosis is extremely rare manifestation of a rather common disease which is distributed worldwide. Most common sites which provide perfect nourishment for the growth of cysticercosis are muscle and brain followed by eye. Pulmonary involvement in cysticercosis is very rare and if at all present, then ill-defined nodular shadows distributed throughout the lung is the usual radiological presentation. No case of cysticercosis presenting as lung cavity with pleural effusion has been reported so far in literature. We came across a rarest presentation of cysticercosis as cavity in the lung with effusion. After nullifying all the differential diagnosis of cavitary lung lesions, a diagnosis of pulmonary cysticercosis was made by histopathological examination of the lung cavity aspirate and enzyme linked immunosorbent assay (ELISA) for cysticercosis. Case was successfully treated with albendazole (15mg/kg) with steroid cover. PMID- 26628775 TI - Miliary nodules on chest radiographs: A diagnostic dilemma. PMID- 26628776 TI - "Early goal-directed therapy" versus "Early" and "goal-directed" therapy for severe sepsis and septic shock: Time to rationalize. PMID- 26628777 TI - Triple hit effect. PMID- 26628778 TI - Cavitating lung metastasis secondary to ameloblastoma. PMID- 26628779 TI - Allergic bronchopulmonary aspergillosis or pulmonary tuberculosis: A case of mistaken identity? PMID- 26628780 TI - A case of granulomatosis with polyangiitis (Wegener's granulomatosis) with marked infiltration of Tracheo-bronchial tree. PMID- 26628781 TI - Sarcomatoid carcinoma of lung - A case report and review of epidermal growth factor receptor mutation status. PMID- 26628782 TI - Metastatic ampullary adenocarcinoma in exfoliative sputum cytology: A rare presentation. PMID- 26628783 TI - Pulmonary cryptococcoma presenting as endobronchial mass mimicking malignancy in immunocompetent host. PMID- 26628784 TI - Unilateral hyperlucent lung: An unusual cause. PMID- 26628785 TI - Has the attitude of school students toward smoking changed after a decade since the framework convention of tobacco control? PMID- 26628787 TI - Age and sex matching in case-control studies. PMID- 26628786 TI - Rise of academic plagiarism in India: Reasons, solutions and resolution. PMID- 26628788 TI - An insight into the sites of noncuffed hemodialysis catheters. PMID- 26628789 TI - Urinary liver-type fatty acid binding protein and chronic kidney disease. PMID- 26628790 TI - A comparative study of central versus posterior approach for internal jugular hemodialysis catheter insertion. AB - Internal jugular (IJ) catheter insertion for hemodialysis (HD) is an indispensable procedure in the management of patients with renal failure. The central approach is favored over posterior approach to insert IJ catheters. There are no studies comparing the outcomes between the two approaches. The aim of this study was to compare central approach with posterior approach for IJ HD catheter insertion and to analyze various outcomes like procedure-related complication rates, catheter insertion failure rates, interruptions during dialysis due to blood flow obstruction and catheter infection rates between the two methods among patients receiving HD. All patients requiring IJ HD catheter insertion during a 1 month period were randomly assigned to undergo catheter insertion via either conventional central approach or posterior approach. Patients were followed-up till the removal of the catheter. Among 104 patients included in the study, 54 were assigned to the central approach group and 50 to the posterior approach group. The central approach group had higher rate of procedure-related complications (14.81% vs. 6%, P = 0.04). Catheter insertion failure rates were marginally higher in posterior approach group (20% vs. 12.96%, P = 0.07). One or more instance of interruption during HD due to obstruction in blood flow was more common in posterior approach (46% vs. 9.25%, P < 0.01). Catheter infection rates were similar between the two groups; 16.66% (n = 9) in central group vs. 14% (n = 7) in posterior group. Posterior approach is a reasonable alternative to conventional central approach in IJ cannulation for HD catheter. It is, however, associated with a significantly high rate of interruption in HD blood flow and catheter insertion failure rates. The posterior approach can be used in patients with local exit site infection or in failed attempts to cannulate IJ vein via the conventional central approach. PMID- 26628791 TI - Clinical significance of urinary liver-type fatty acid binding protein at various stages of nephropathy. AB - This cross-sectional study was to evaluate the levels of urinary liver-type fatty acid binding protein (u-LFABP pg/mg urine creatinine ratio) at different stages of diabetic nephropathy and to see its correlation with other clinical parameters in South Indian patients with type 2 diabetes mellitus (T2DM). A total of 65 (M: F; 42:23) T2DM subjects were divided into three groups, and were compared with 13 (M: F; 3:10) nondiabetic controls. The study groups were as follows: normoalbuminuric (n = 22), microalbuminuric (n = 22) and macroalbuminuric (n = 21). Estimated glomerular filtration rate (eGFR) was calculated using Cockcroft and Gault formula. u-LFABP levels in spot urine samples were measured with a solid phase enzyme linked immunosorbent assay. This study showed that u-LFABP levels were undetectable in healthy controls and was very low in the normoalbuminuric subjects. Elevated levels of u-LFABP are evident from the microalbuminuric stage indicating tubular damage. The levels of u-LFABP increased gradually with declining renal function. Geometric mean (95% confidence interval) for normoalbuminuria was 0.65 (0.47-0.97), microalbuminuria was 0.99 (0.55-1.97) and macroalbuminuria was 5.16 (1.8-14.5), (P = 0.005). In conclusion, u-LFABP levels were elevated in patients with reduced eGFR and showed a positive correlation with systolic blood pressure and protein to creatinine ratio in the total study subjects. PMID- 26628792 TI - Endemic chronic kidney disease of unknown etiology in Sri Lanka: Correlation of pathology with clinical stages. AB - Chronic kidney disease of unknown etiology (CKDU) is endemic among the rural farming communities in several localities in and around the North Central region of Sri Lanka. This is an interstitial type renal disease and typically has an insidious onset and slow progression. This study was conducted to identify the pathological features in the different clinical stages of CKDU. This is a retrospective study of 251 renal biopsies identified to have a primary interstitial disease from regions endemic for CKDU. Pathological features were assessed and graded in relation to the clinical stage. The mean age of those affected by endemic CKDU was 37.3 +/- 12.5 years and the male to female ratio was 3.3:1. The predominant feature of stage I disease was mild and moderate interstitial fibrosis; most did not have interstitial inflammation. The typical stage II disease had moderate interstitial fibrosis with or without mild interstitial inflammation. Stage III disease had moderate and severe interstitial fibrosis, moderate interstitial inflammation, tubular atrophy and some glomerulosclerosis. Stage IV disease typically had severe interstitial fibrosis and inflammation, tubular atrophy and glomerulosclerosis. The mean age of patients with stage I disease (27 +/- 10.8 years) was significantly lower than those of the other stages. About 79.2%, 55%, 49.1% and 50% in stage I, II, III and IV disease respectively were asymptomatic at the time of biopsy. PMID- 26628793 TI - Drug-induced acute interstitial nephritis: A clinicopathological study and comparative trial of steroid regimens. AB - Steroids are used in the management of drug-induced acute interstitial nephritis (AIN). The present study was undertaken to compare the efficacy of pulse methyl prednisolone with oral prednisolone in the treatment of drug-induced AIN. Patients with biopsy-proven AIN with a history of drug intake were randomized to oral prednisolone (Group 1) 1 mg/kg for 3 weeks or a pulse methyl prednisolone (Group II) 30 mg/kg for 3 days followed by oral prednisolone 1 mg/kg for 2 weeks, tapered over 3 weeks. Kidney biopsy scoring was done for interstitial edema, infiltration and tubular damage. The response was reported as complete remission (CR) (improvement in estimated glomerular filtration rate [eGFR] to >=60 ml/min/1.73 m(2)), partial remission (PR) (improvement but eGFR <60 ml/min/1.73 m(2)) or resistance (no CR/PR). A total of 29 patients, Group I: 16 and Group II: 13 were studied. Offending drugs included nonsteroidal anti-inflammatory drugs, herbal drugs, antibiotics, diuretic, rifampicin and omeprazole. There was no difference in the baseline parameters between the two groups. The biopsy score in Groups I and II was 5.9 +/- 1.1 and 5.1 +/- 1.2, respectively. At 3 months in Group I, eight patients each (50%) achieved CR and PR. In Group II, 8 (61%) achieved CR and 5 (39%) PR. This was not significantly different. Percentage fall in serum creatinine at 1 week (56%) was higher in CR as compared to (42%) those with PR. (P = 0.14). Patients with neutrophil infiltration had higher CR compared to patients with no neutrophil infiltration (P = 0.01). Early steroid therapy, both oral and pulse steroid, is equally effective in achieving remission in drug induced AIN. PMID- 26628794 TI - Nitric oxide status in patients with chronic kidney disease. AB - Patients with chronic kidney disease (CKD) are at an increased risk of cardiovascular (CVD) morbidity and mortality, mainly due to atherosclerosis. Decreased production or reduced bioavailability of nitric oxide (NO) can result in endothelial dysfunction (ED). Multiple mechanisms are known to cause a state of NO deficiency in patients with CKD. Patients in various stages of CKD grouped as group-1 (CKD stage 1 and 2), group-2 (CKD stage 3 and 4), group-3 (CKD stage 5) and healthy controls were included in the study. Each group of patients and controls comprised 25 subjects. Plasma nitrites, L-arginine, asymmetric dimethyl arginine (ADMA) and citrulline were measured in all the subjects. Patients in all stages of CKD had lower NO and higher ADMA levels compared to controls. Further, group-2 and group-3 patients had lower levels of NO and higher levels of ADMA than group-1 patients. L-arginine levels showed no difference between patients and controls. However, group-3 patients had lower L-arginine levels compared to group-1 patients. Citrulline levels were decreased in group-3 patients. NO production was decreased in patients in all stages of CKD. The decrease could be due to decreased availability of the substrate, L-arginine or due to an increased ADMA, a potent inhibitor of endothelial NO synthase. Therapeutic interventions directed towards improvement of NO production in addition to management of other CVD risk factors may prevent development of ED and facilitate proper management of CKD patients who are at increased risk for CVD. PMID- 26628795 TI - The role of neutrophil-gelatinase-associated lipocalin in early diagnosis of contrast nephropathy. AB - Neutrophil-gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury. The aim of this study was to define a cut-off for NGAL in the early diagnosis of contrast-induced nephropathy (CIN) in patients with normal kidney function. We enrolled 121 patients with normal serum creatinine who underwent coronary angiography. NGAL was measured in urine before the procedure and 12 and 24 h afterward. CIN was defined as a 0.3 mg/dl increase in serum creatinine within 48 h after the procedure. Seven of 121 patients had CIN (5.8%). The NGAL levels in the 12- and 24-h urine samples of these patients were 30 (5-45) and 20 (15-40) ng/ml, respectively, whereas those in patients without CIN were 15 (5-45) and 15 (10-51) ng/ml, respectively (P = 0.8). In patients with CIN, the sensitivity and specificity of NGAL with a cut-off of 22.5 ng/ml were 71.4% and 57.9% in 12-h urine samples, with the negative predictive values (NPV) and positive predictive values (PPV) of 97.1% and 9.4%, respectively. In conclusion, we suggest that urine NGAL with cut-off point of 22.5 ng/ml has acceptable sensitivity and specificity for early diagnosis of CIN in patients with normal serum creatinine, but regarding NPV and PPV the best performance of this value is to rule out the CIN in patients at risk who received contrast media. PMID- 26628796 TI - Pyoderma gangrenosum in a renal transplant recipient: A case report and review of literature. AB - Pyoderma gangrenosum (PG) is a rare disorder of unknown etiology characterized by multiple cutaneous ulcers with mucopurulent or hemorrhagic exudate. This sterile neutrophilic dermatosis is known to occur in association with malignancy, infection, autoimmune disorders and drugs. Occurrence of PG in a renal transplant recipient, who is already on immunosuppressants, is rare. We hereby report a renal transplant recipient who developed PG 1-month after transplant and responded well to treatment with escalated dose of oral steroid. PMID- 26628797 TI - Bardet-Biedl syndrome presenting with steroid sensitive nephrotic syndrome. AB - Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by postaxial polydactyly, retinitis pigmentosa, central obesity, mental retardation, hypogonadism, and renal involvement. Renal involvement in various forms has been seen in BBS. Cases with nephrotic range proteinuria not responding to steroid have been described in this syndrome. Here we report a case of BBS who presented with nephrotic range proteinuria. The biopsy findings were suggestive of minimal change disease. The child responded well to steroid therapy and remains in remission. PMID- 26628798 TI - Immunoglobulin G4 related tubulointerstitial nephritis. AB - Tubulointerstitial nephritis is an uncommon manifestation of IgG4 related disease. A case of tubulointerstitial nephritis with special features including isolated renal involvement in this multisystem disorder and the absence of response to steroid therapy in a young male is reported here. There was no nephromegaly, eosinophilia or other organ involvement. The importance of early detection and treatment for preservation of kidney function is highlighted. PMID- 26628799 TI - Drug induced pseudoporphyria in CKD: A case report. AB - Pseudoporphyria (PP) is used to describe a photodistributed bullous disorder with clinical and histologic features of porphyria cutanea tarda (PCT) but without accompanying biochemical porphyrin abnormalities. Medications, excessive sun and ultraviolet radiation exposure, have all been reported to develop PP. We report a case of PP in a 49-year-old man with CKD stage 3a, caused due to torsemide intake. This is probably the first reported case of PP developing in a dialysis naive patient CKD due to torsemide intake from India. PMID- 26628800 TI - Spontaneous nontraumatic subarachnoid hemorrhage without cerebrovascular malformations in a maintenance hemodialysis patient. AB - Nontraumatic subarachnoid hemorrhage (SAH) in a dialysis patient is an uncommon occurrence and is often associated with high mortality. We report for the first time in India, a case of spontaneous nontraumatic, nonaneurysmal SAH without any cerebrovascular malformation in a maintenance hemodialysis patient, following a session of hemodialysis. The dialysis prescription needs to be modified in these patients, in order to prevent worsening of cerebral edema and progression of hemorrhage. Where available, continuous forms of renal replacement therapies, with regional anticoagulation seem to be the best option for such patients, till neurologic stabilization is achieved. PMID- 26628801 TI - Bouquet of flowers: Clue to medullary sponge kidneys. PMID- 26628802 TI - Gitelman syndrome in an infant. PMID- 26628803 TI - Gangrene and bacteremia due to Corynebacterium jeikeium in a patient on maintenance hemodialysis. PMID- 26628805 TI - Government initiatives for child health care and the role of pediatric surgeons. PMID- 26628804 TI - Hemodialysis catheter-related bacteremia caused by Stenotrophomonas maltophilia. PMID- 26628806 TI - Non-rhabdomyosarcoma soft-tissue sarcomas in children: Contemporary appraisal and experience from a single centre. AB - Nonrhabdmyosarcoma soft tissue sarcomas (NRSTS) include a cluster of different types of soft tissue sarcomas clubbed together due to the rarity of individual subtypes. The diagnostic accuracy is lately reinforced due to the availability of immunohistochemical and molecular markers. Surgery is the central modality of treatment since many of them are insensitive to chemotherapy. With the availability of rational risk stratification system, efforts are in progress to evaluate the role of neoadjuvant chemotherapy and radiotherapy to improve outcomes especially for the locally advanced disease. The survival remains dismal for metastatic disease. This review highlights the current status of NRSTS and also describes the experience from a single centre in treatment of NRSTS. PMID- 26628807 TI - A new, simple operative approach for bilateral inguinal hernia repair in girls: A single transverse supra-pubic incision. AB - BACKGROUND: Inguinal hernia repair remains one of the most common operations performed by pediatric surgeons. We described a new surgical approach for treating bilateral inguinal hernias in girls through a small single transverse supra-pubic incision. MATERIALS AND METHODS: A new approach was performed on female children 12-years-old and younger with bilateral inguinal hernias between January 2005 and April 2012. TECHNIQUE: A single transverse suprapubic incision (1-1.5 cm) was made. Using sharp and blunt dissection bilateral hernias were exposed and repaired using a standard high ligation. RESULTS: Ninety-nine girls with a preoperative clinical diagnosis of bilateral inguinal hernia were included. Median age was 2 years (range: 1 month to 12 years). All patients underwent general anesthesia. Median operative time was 12 minutes (range 5-22). There were no intra-operative complications or misdiagnosis. Two patients had bilateral sliding hernias and the remainder had indirect hernias. Post operatively two patients developed non-expanding small hematomas, both treated non-operatively without sequelae. There were zero hernia recurrence and median follow-up was 5 years (range: 1-8 years) on 99% of patients. CONCLUSION: We described a new, safe, simple, and rapid approach for bilateral inguinal hernia repair in female pediatric population. A single transverse suprapubic skin incision was adequate for exposing both inguinal regions with excellent postoperative results. PMID- 26628808 TI - Enteric duplication in children: Experience from a tertiary center in South India. AB - BACKGROUND: Enteric duplications (EDs) are rare aberrations of the embryonic gut. This study was undertaken to define the clinical characteristics and management challenges of this unusual entity in the Indian population. MATERIALS AND METHODS: Hospital records of 35 children with 38 ED operated between 2003 and 2014 were analyzed and followed up. RESULTS: The median age at presentation was 285 days (range 1-day to 16 years) with male preponderance (71%). Small bowel duplications were the most common (44%), and thoracoabdominal duplications were seen in 8% children compared to 2% in the literature. The median duration of symptoms was 18 days (interquartile range [IQR] 3-210 days). Associated anomalies were seen in 49% children with vertebral and spinal anomalies being the most common. Ultrasonogram (US) was done in 83% children and had a sensitivity of 55%. In the presence of a gastrointestinal bleed, Technetium(99m) pertechnetate scintigraphy scan had a positive predictive value of 80%. Thirty-five lesions were completely removed. Mucosectomy was done in two children, and one total colonic duplication was left in situ after providing adequate internal drainage. There was no postoperative mortality. The follow-up was possible in 66% children. CONCLUSIONS: EDs are uncommon and have varied, nonspecific symptoms. Thoracoabdominal duplications are more common in the Indian population. The US is a good screening tool but requires a high index of suspicion where complete excision is not possible; the provision of adequate internal drainage is an acceptable alternative. The long-term prognosis of children with ED depends on the extent of physiological disturbance due to associated anomalies. PMID- 26628809 TI - Free radicals and antioxidants status in neonates with congenital malformation. AB - BACKGROUND: Several studies using animal models have shown that oxidative stress during pregnancy may play an important role in causing birth defects. Congenital anomalies affect an estimated 270,000 newborns who die during the first 28 days of life every year from different birth defects. Hence, at present many research works are going on to reduce the infant mortality from congenital anomaly.[1]. OBJECTIVE: The objective was to measure the oxidant and antioxidant level in the serum of newborn babies with the congenital anomaly and compare these levels with age and sex matched normal neonates. This is to identify any role of oxidative stress in the causation of congenital anomaly. MATERIALS AND METHODS: This case control study included 159 participants: 106 newborns with the congenital anomaly and 53 healthy newborns. The markers of oxidative stress like serum malondialdehyde (MDA) level, protein carbonyl (PC) level, and the activity of antioxidants such as Vitamin C, glutathione were measured in both cases (neonates with congenital anomaly) and controls (normal healthy neonates). These parameters were statistically compared. RESULTS: MDA levels and PC levels were significantly higher (P < 0.0001), and Vitamin C and reduced glutathione levels were significantly lower (P < 0.0001), in newborns with congenital malformation than in healthy newborns. CONCLUSIONS: Increased lipid peroxidation and protein carbonylation might play an important role in the pathogenesis of congenital anomaly. Impairment of the free radical/antioxidant balance is leading to increased free radical damage in neonates with congenital malformation. PMID- 26628810 TI - Correlation of pre- and post-operative liver function, duct diameter at porta hepatis, and portal fibrosis with surgical outcomes in biliary atresia. AB - BACKGROUND AND AIMS: Extrahepatic biliary atresia is one of the most challenging conditions in pediatric surgery. The definition of prognostic factors is controversial. Surgical outcomes after bilioenteric drainage procedures are variable. This study attempts to correlate the pre- and post-operative liver histology with clinical factors in order to define early predictors of success. MATERIALS AND METHODS: Twenty consecutive patients, treated by Kasai's portoenterostomy (KP) over a 3 years period were included in this study. Tissue obtained from the porta hepatis was analyzed for duct size using an optical micrometer and was categorized into three types: I-No demonstrable ducts; II - <50 MU; III - >50 MU. Pre- and post-operative liver biopsy was analyzed for architectural changes and fibrosis; hepatic fibrosis was quantified using existing criteria. Pre- and post-operative liver function tests (LFTs) were also done. Surgical outcomes were defined as: (A) Disappearance of jaundice within 3 months; (B) initial disappearance of jaundice with recurrence by 6 months and (C) persistence of jaundice. Duct diameters, fibrosis score, and LFT were correlated with age and clinical outcomes. RESULTS: The surgical outcomes were: A-6 patients (30%), B-6 patients (30%), C-8 patients (40%). The duct size at the porta was I-3 patients, II-11 patients, and III-4 patients (tissue was not available in 2 cases). The change in total serum bilirubin (mg%) from pre- to post-operative period was 13.6 +/- 3.9 (Group A), 4.6 +/- 2.8 (Group B), and 3.4 +/- 3.9 (group C) (P < 0.001) and direct and indirect fractions followed a similar trend; the changes in liver enzymes were not significant. The changes in hepatic histopathological changes (ballooning of hepatocytes, giant cells, cholestasis, portal tract infiltration, ductular proliferation, lobular necrosis, and fibrosis) were also not significant but there was a definite trend in the change in fibrosis -1.500 +/- 1.643 (Group A), 0.667 +/- 2.582 (Group B), and 1.500 +/- 1.852 (Group C) - reduction of fibrosis with good results and progression of fibrosis with poor results. CONCLUSIONS: Following KP, jaundice persisted in 40% patients; it disappeared in 60% patients but reappeared in half of these patients 6 months postoperatively. The duct size at the porta hepatis did not correlate with age or surgical outcome. Serum bilirubin showed the best correlation with surgical outcome. Postoperative changes in hepatic fibrosis seem to have some bearing on surgical outcomes-progressive fibrosis is a poor prognostic factor. PMID- 26628811 TI - Intermuscular lipoma in a 4-year-old child presenting like Spigelian hernia. AB - Lipomas are commonest benign tumor and can occur at any part of the body, but intermuscular lipomas are very rare and usually occur at middle age or later. Intermuscular lipomas remain hidden till they attain a large size. They commonly appear on anterior abdominal wall. We treated a case of intermuscular lipoma in a 4-year-old girl. It presented as a bulge at right iliac fossa during straining; its location and symptoms were similar to that of Spigelian hernia. Actual diagnosis was made under general anesthesia and complete surgical excision was done. This is a rare mode of presentation of an intermuscular lipoma. Intermuscular lipoma of the abdominal wall at this young age was not reported earlier. PMID- 26628812 TI - Robotic excision of paraesophageal bronchogenic cyst in a 9-year-old child. AB - Bronchogenic cysts are often asymptomatic and discovered as an incidental finding. They may become symptomatic due to esophageal compression as they increase in size or from development of infection. We report a case of a 9-year old male with an asymptomatic bronchogenic cyst who underwent successful robotic assisted thoracoscopic excision. PMID- 26628813 TI - Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon in a neonate of life- and limb-threatening nature: A case report. AB - Kaposiform hemangioendothelioma involving whole of a leg in a neonate with Kasabach-Merritt phenomenon causing limb and life-threatening situation has not been reported. One such case and its successful management is presented in this case report. Literature review is made. PMID- 26628814 TI - Bilateral Wilms' tumors in an infant with Denys-Drash syndrome and rarely seen truncation mutation in the WT1 gene-exon 6. PMID- 26628815 TI - Congenital anterior urethral diverticulum: A case report. PMID- 26628816 TI - Internal hernia as a cause of bowel strangulation in pediatric age group. PMID- 26628817 TI - Posterior ectopic anus: Myth or reality? PMID- 26628818 TI - Use of 'Romodrain' for intercostal drainage in infants. PMID- 26628819 TI - Noninvasive ventilation as first-line treatment for acute respiratory distress syndrome: The time is not ripe yet! PMID- 26628820 TI - Bacterial resistance in India: Studying plasma antibiotic levels. PMID- 26628821 TI - Assessment of the EuroSCORE risk scoring system for patients undergoing coronary artery bypass graft surgery in a group of Iranian patients. AB - BACKGROUND AND AIMS: Previous studies around the world indicated validity and accuracy of European System for Cardiac Operative Risk Evaluation (EuroSCORE) risk scoring system we evaluated the EuroSCORE risk scoring system for patients undergoing coronary artery bypass graft (CABG) surgery in a group of Iranian patients. MATERIALS AND METHODS: In this cohort 2220 patients more than 18 years, who were performed CABG surgery in Massih Daneshvari Hospital, from January 2004 to March 2010 were recruited. Predicted mortality risk scores were calculated using logistic EuroSCORE and Acute Physiology and Chronic Health Evaluation II (APACHE II) and compared with observed mortality. Calibration was measured by the Hosmer-Lemeshow (HL) test and discrimination by using the receiver operating characteristic (ROC) curve area. RESULTS: Of the 2220 patients, in hospital deaths occurred in 270 patients (mortality rate of 12.2%). The accuracy of mortality prediction in the logistic EuroSCORE and APACHE II model was 89.1%; in the local EuroSCORE (logistic) was 91.89%; and in the local EuroSCORE support vector machines (SVM) was 98.6%. The area under curve for ROC curve, was 0.724 (95% confidence interval [CI]: 0.57-0.88) for logistic EuroSCORE; 0.836 (95% CI: 0.731-0.942) for local EuroSCORE (logistic); 0.978 (95% CI: 0.937-1) for Local EuroSCORE (SVM); and 0.832 (95% CI: 0.723-0.941) for APACHE II model. The HL test showed good calibration for the local EuroSCORE (SVM), APACHE II model and local EuroSCORE (logistic) (P = 0.823, P = 0.748 and P = 0.06 respectively); but there was a significant difference between expected and observed mortality according to EuroSCORE model (P = 0.033). CONCLUSION: We detected logistic EuroSCORE risk model is not applicable on Iranian patients undergoing CABG surgery. PMID- 26628822 TI - Patterns of central venous oxygen saturation, lactate and veno-arterial CO2 difference in patients with septic shock. AB - BACKGROUND AND AIMS: Tissue hypoperfusion is reflected by metabolic parameters such as lactate, central venous oxygen saturation (ScvO2) and the veno-arterial CO2 (vaCO2) difference. We studied the relation of these parameters over time and with outcome in patients with severe septic shock. MATERIALS AND METHODS: In this single-center, prospective observational cohort study, adult patients (>=18 years) with circulatory shock were included. Echocardiography and simultaneous arterial and venous blood gases were done on enrolment (0 h) and at 24, 48 and 72 h. The partial pressure of CO2, lactate and ScvO2 were recorded from the central venous blood samples. The vaCO2 was calculated as the difference in CO2 between paired venous and arterial blood gas samples. RESULTS: Of the 104 patients with circulatory shock, 79 patients (44 males) with septic shock aged 49.8 (standard deviation +/- 14.6) years and with sequential organ failure assessment (SOFA) score of 11.0 +/- 3.4 were included. 71 patients (89.9%) were ventilated (11.4 +/ 12.3 ventilator-free days). The duration of hospitalization was 16.6 +/- 12.8 days and hospital mortality 50.6%. Lactate significantly decreased over time with a greater decrement in survivors than nonsurvivors (-0.35 vs. -0.10, P < 0.001). For every l/min increase in cardiac output, vaCO2 decreased by 0.34 mmHg (P = 0.006). There was no association between ScvO2 and mortality (P = 0.930). 0 h SOFA and vaCO2 <=6 mmHg were strongly associated (P = 0.005, P = 0.018, respectively) with higher odds of mortality. However, this association was evident only in those with ScvO2 >70% and not in ScvO2 <=70%. CONCLUSION: In septic shock, vaCO2 <=6 mmHg is independently associated with mortality, particularly in those with normalized ScvO2 consistent with metabolic microcirculatory abnormalities in these patients. PMID- 26628823 TI - Pharmacokinetic/pharmacodynamic profiling of imipenem in patients admitted to an intensive care unit in India: A nonrandomized, cross-sectional, analytical, open labeled study. AB - BACKGROUND AND AIM: Widespread use of imipenem in intensive care units (ICUs) in India has led to the development of numerous carbapenemase-producing strains of pathogens. The altered pathophysiological state in critically ill patients could lead to subtherapeutic antibiotic levels. Hence, the aim of this study was to investigate the variability in the pharmacokinetic and pharmacodynamic profile of imipenem in critically ill patients admitted to an ICU in India. MATERIALS AND METHODS: Plasma concentration of imipenem was determined in critically ill patients using high performance liquid chromatography, at different time points, by grouping them according to their locus of infection. The elimination half-life (t?) and volume of distribution (Vd) values were also computed. The patients with imipenem trough concentration values below the minimum inhibitory concentration (MIC) and 5 times the MIC for the isolated pathogen were determined. RESULTS: The difference in the plasma imipenem concentration between the gastrointestinal and the nongastrointestinal groups was significant at 2 h (P = 0.015) following drug dosing; while the difference was significant between the skin/cellulitis and nonskin/cellulitus groups at 2 h (P = 0.008), after drug dosing. The imipenem levels were above the MIC and 5 times the MIC for the isolated organism in 96.67% and 50% of the patients, respectively. CONCLUSIONS: The pharmacokinetic profile of imipenem does not vary according to the locus of an infection in critically ill patients. Imipenem, 3 g/day intermittent dosing, maintains a plasma concentration which is adequate to treat most infections encountered in patients admitted to an ICU. However, a change in the dosing regimen is suggested for patients infected with organisms having MIC values above 4 mg/L. PMID- 26628824 TI - A study on the role of noninvasive ventilation in mild-to-moderate acute respiratory distress syndrome. AB - AIM: There is sparse data on the role of noninvasive ventilation (NIV) in acute respiratory distress syndrome (ARDS) from India. Herein, we report our experience with the use of NIV in mild to moderate ARDS. MATERIALS AND METHODS: This was a prospective observational study involving consecutive subjects of ARDS treated with NIV using an oronasal mask. Patients were monitored clinically with serial arterial blood gas analysis. The success of NIV, duration of NIV use, Intensive Care Unit stay, hospital mortality, and improvement in clinical and blood gas parameters were assessed. The success of NIV was defined as prevention of endotracheal intubation. RESULTS: A total of 41 subjects (27 women, mean age: 30.9 years) were included in the study. Tropical infections followed by abdominal sepsis were the most common causes of ARDS. The use of NIV was successful in 18 (44%) subjects, while 23 subjects required intubation. The median time to intubation was 3 h. Overall, 19 (46.3%) deaths were encountered, all in those requiring invasive ventilation. The mean duration of ventilation was significantly higher in the intubated patients (7.1 vs. 2.6 days, P = 0.004). Univariate analysis revealed a lack of improvement in PaO2/FiO2 at 1 h and high baseline Acute Physiology and Chronic Health Evaluation II (APACHE II) as predictors of NIV failure. CONCLUSIONS: Use of NIV in mild to moderate ARDS helped in avoiding intubation in about 44% of the subjects. A baseline APACHE II score of >17 and a PaO2/FiO2 ratio <150 at 1 h predicts NIV failure. PMID- 26628825 TI - Venoarterial extracorporeal membrane oxygenation support for neonatal and pediatric refractory septic shock. AB - OBJECTIVE: To report our institutional experience of veno-arterial extracorporeal membrane oxygenation (VA ECMO) in children with refractory septic shock. MATERIALS AND METHODS: We retrospectively reviewed our ECMO database to identify patients who received VA ECMO for septic shock from January 2004 to June 2013 at our Pediatric Intensive Care Unit in Armand-Trousseau Hospital. We included all neonates and children up to the age of 18 years who received VA ECMO for septic shock. For each patient, we collected the pre-ECMO inotrope score, clinical circulatory and ventilatory parameters, infecting organism, ECMO duration and complications, and length of hospital stay. MAIN RESULTS: The study included 14 neonates and 8 older children (the pediatric population, with a mean age of 30 months, range: 1-113 months). Survival was 64% among newborns and 50% among pediatric patients. Multiorgan failure or severity scores did not show any correlation with mortality (Pediatric Logistic Organ Dysfunction score, P = 0.94; the score for neonatal acute physiology-perinatal extension II, P = 0.34). In the pediatric population, the inotrope score was higher in the survivor group (127.5 vs. 332.5, P = 0.07). Blood samples taken shortly before cannulation showed that pH (P = 0.27), lactate level (P = 0.33), PaO2/FiO2 ratio (P = 0.49), or oxygenation index (P = 0.35) showed no correlation to success or failure of ECMO. CONCLUSION: ECMO can be safely used to resuscitate and support children with refractory septic shock. We recommend that patients with oliguria whose lactate level has not decreased within 6 h of starting maximum drug therapy be transferred to an ECMO referral center. PMID- 26628827 TI - The dynamics of changing internal jugular veins diameter based on increasing head elevation angle. AB - CONTEXT: Venous outflow from the cranial cavity occurs mainly through the internal jugular vein (IJV). The increase in venous outflow through IJV is possible by head elevation. IJV collapse may indicate the reduction of blood volume in the vein and show the head elevation effectiveness. AIMS: The aim of this study is to examine the impact of head elevation on IJV size. SUBJECTS AND METHODS: IJV ultrasound scanning in 31 healthy volunteers was carried after gradual head elevation at 15 degrees , 30 degrees , and 45 degrees . Maximum and minimum IJV diameters were recorded. Mean +/- standard deviation, median, range, and collapsibility index were calculated. RESULTS: Thirty-one volunteers were involved (19 males), their average age was 37.0 +/- 11.5 years. Increasing the head elevation angle by 15 degrees , 30 degrees and 45 degrees resulted in a decrease in IJV diameter in the right and left sides in all patients. The occurrence of the vein walls collapse corresponds to the collapsibility index equal to 100%. The results showed that 100% collapsibility index was recorded in 6 patients (19%) at 15 degrees head elevation, in 12 patients (39%) at 30 degrees , in 11 patients (35%) at 45 degrees . In two volunteers (6%), 100% collapsibility index was not recorded even at maximum 45 degrees head elevation. CONCLUSIONS: Ultrasound IJV scanning during gradual head elevation together with the collapsibility index calculation could be useful guidance for the venous outflow assessment. In order to prove and extend the study findings, more research is needed. PMID- 26628826 TI - Right heart failure in acute respiratory distress syndrome: An unappreciated albeit a potential target for intervention in the management of the disease. AB - Mortality from acute respiratory distress syndrome (ARDS) has gone down recently. In spite of this trend, the absolute numbers continue to be high even with improvements in ventilator strategies and a better understanding of fluid management with this disease. A possible reason for this could be an under recognized involvement of the pulmonary vasculature and the right side of the heart in ARDS. The right heart is not designed to function under situations leading to acute elevations in afterload as seen in ARDS, and hence it decompensates. This brief review focuses on the magnitude of the problem, its detection in the intensive care unit, and recognizes the beneficial effect of prone-positioning on the pulmonary vasculature and right heart. PMID- 26628828 TI - Continuous renal replacement therapy in children with severe sepsis and multiorgan dysfunction - A pilot study on timing of initiation. AB - OBJECTIVE: Scanty literature is available regarding continuous renal replacement therapy (CRRT) utility in severe sepsis with multiorgan dysfunction syndrome (MODS) from developing countries. Author unit's experience in pediatric CRRT is described and outcome of early initiation of CRRT with sepsis and MODS is assessed. MATERIALS AND METHODS: Children aged <16 years with sepsis and MODS who required CRRT from September 2010 to February 2015 were analyzed on demographic factors, timing of initiation of CRRT, mode of CRRT, effect of CRRT onhemodynamics, oxygenation parameters, and outcome. RESULTS: Twenty-seven children required CRRT (male - 16). The median age was 11 years (range 1.1-16). Twenty-one had severe sepsis with MODS. Eighteen patients were given CRRT within 48 h of admission to Intensive Care Unit (ICU). Statistically significant improvement in the P/F ratio, decrement in plateau pressure and vasoactive inotropic score were noted in survivor group compared to nonsurvivor group (P = 0.022, 0.00, and 0.03, respectively). There was no statistically significant difference in duration of ICU stay, fluid overload, CRRT duration, PRISM score at 12 and 24 h, percentage of decrease in inotrope score, plateau pressure, and percentage of increase in P/F ratio in relation to timing of CRRT initiation. However, the survival rate was 61.1% (11/18) who received CRRT within 48 h of ICU admission compared to 33.3% (3/9) who received after 48 h (P = 0.0001). CONCLUSION: Our study emphasizes the CRRT role in improving the oxygenation status and hemodynamics. Survival benefit may be expected in those children who receive CRRT early in the course of sepsis. However, multicenter RCTs are required to prove mortality benefit. PMID- 26628829 TI - Successful lumbar puncture with Taylor's approach for the diagnostic workup of meningitis in a patient with Ankylosing spondylitis. AB - Meningitis and encephalitis are the neurological emergencies. As the clinical findings lack specificity, once suspected, cerebrospinal fluid (CSF) analysis should be performed and parenteral antimicrobials should be administered without delay. Lumbar puncture can be technically challenging in patients with ankylosing spondylitis due to ossification of ligaments and obliteration of interspinous spaces. Here, we present a case of ankylosing spondylitis where attempts for lumbar puncture by conventional approach failed. CSF sample was successfully obtained by Taylor's approach. PMID- 26628830 TI - A rare case of idiopathic cluster of differentiation 4(+) T-cell lymphocytopenia presenting with disseminated tubercular infection. AB - Idiopathic cluster of differentiation 4(+) (CD4(+)) T-cell lymphocytopenia is a rare heterogeneous clinical syndrome characterized by low absolute CD4 counts on two different occasions without any evidence of other known cause of immunodeficiency including human immunodeficiency virus (HIV), infections or drugs associated with fall in CD4(+) count. Also referred to as severe unexplained HIV seronegative immune suppression by the World Health Organization, it was first described by Centers for Disease Control in 1992 in patients with opportunistic infections who were negative for HIV but had low CD4 counts. Patients typically present with opportunistic infections, malignancies, or autoimmune disorders. There have been case reports on opportunistic infections such as cryptococcal meningitis or non-Mycobacterium tuberculosis infections in these patients. However, no case of disseminated M. tuberculosis has been reported as such in Indian literature. We present a case of disseminated tuberculosis with low CD4 counts without any evidence of HIV infection. PMID- 26628831 TI - Correlation of measurement of optic nerve sheath diameter with ultrasound and magnetic resonance imaging. PMID- 26628832 TI - Consent in cognitively intact quadriplegic patient: Is it different. PMID- 26628833 TI - Masseter spasm after muscle relaxant. PMID- 26628834 TI - Retraction: Successful management of massive intraoperative pulmonary fat embolism with percutaneous cardiopulmonary support. AB - [This retracts the article on p. 136 in vol. 12, PMID: 19742250.]. PMID- 26628835 TI - Fluorine-18 Fluorodeoxyglucose Uptake in Hepatocellular Carcinoma: Correlation with Glucose Transporters and p53 Expression. AB - INTRODUCTION: Hepatocellular Carcinoma (HCC) is one of most lethal cancers worldwide. The prognosis is very poor and therapeutic options are limited. The aim of this study was to determine the correlation of the [(18)F]FDG uptake profile of three HCC cell lines with p53 and glucose transporters (GLUTs) 1, 2, 3, 5 and 12 expression and with the glucose level present in the cell culture medium. METHODS: Cell lines used are HepG2 (wp53), HuH7 (overexpress p53) and Hep3B2.1-7 (p53null). An immunocytochemical analysis was performed to evaluate p53 expression. Through uptake studies were analyzed the [(18)F]FDG uptake profiles of all cell lines under study. The expression of GLUTs were quantified by flow cytometry. The [(18)F]FDG uptake studies GLUTs expression analysis were performed on cells that grew in a high and low glucose medium in order to determine the effect of glucose concentration on GLUTs expression and on [(18)F]FDG uptake. RESULTS: Immunocytochemical analysis confirmed the p53 expression profiles of all cell lines. It was found out that for all cell lines, [(18)F]FDG uptake is higher when cells grow in low glucose medium, however, the glucose level doesn't affect mostly the GLUTs expression. The Hep3B2.1-7 (p53null) is always the one that have higher [(18)F]FDG uptake. It was found that not always GLUT1 and GLUT3 are the most expressed by these cell lines. CONCLUSIONS: Our results shown that the p53 expression influences [(18)F]FDG uptake. This suggests that [(18)F]FDG may be used in HCC diagnosis, and may even provide some information about the genetic profile of the tumor. PMID- 26628836 TI - Remogliflozin Etabonate Improves Fatty Liver Disease in Diet-Induced Obese Male Mice. AB - BACKGROUND: Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) are serious conditions and are being diagnosed at an increased rate. The etiology of these hepatic disorders is not clear but involves insulin resistance and oxidative stress. Remogliflozin etabonate (Remo) is an inhibitor of the sodium glucose-dependent renal transporter 2 (SGLT2), and improves insulin sensitivity in type 2 diabetics. In the current study, we examined the effects of Remo in a diet-induced obese mouse model of NAFLD. METHODS: After 11-weeks on High-Fat-Diet 32 (HFD32), C57BL/6J mice were obese and displayed characteristics consistent with NAFLD. Cohorts of obese animals were continued on HFD32 for an additional 4-week treatment period with or without Remo. RESULTS: Treatment with Remo for 4 weeks markedly lowered both plasma alanine aminotransferase (76%) and aspartate aminotransferase (48%), and reduced both liver weight and hepatic triglyceride content by 42% and 40%, respectively. Remo also reduced hepatic mRNA content for tumor necrosis factor (TNF)-alpha (69%), and monocyte chemoattractant protein (MCP)-1 (69%). The diet-induced increase in thiobarbituric acid-reactive substances, a marker of oxidative stress, was reduced following treatment with Remo, as measured in both liver homogenates (22%) and serum (37%). Finally, the oxygen radical absorbance capacity (ORAC) in three different SGLT2 inhibitors was determined: remogliflozin, canagliflozin and dapagliflozin. Only remogliflozin had any significant ORAC activity. CONCLUSIONS: Remo significantly improved markers associated with NAFLD in this animal model, and may be an effective compound for the treatment of NASH and NAFLD due to its insulin-sensitizing and antioxidant properties. PMID- 26628837 TI - Management Patterns of Hepatic Encephalopathy: A Nationwide Survey in India. AB - INTRODUCTION AND AIM: Hepatic encephalopathy (HE) is a common complication of cirrhosis. There is no standard practice for its management. This survey was done to determine the diagnostic and therapeutic practices of physicians treating patients with HE in patients with cirrhosis. MATERIAL AND METHOD: We designed a 21-item questionnaire, which was given to physicians working in academic and non academic institutes and regularly treating patients with HE. RESULTS: Of 500 printed questionnaires, we received 451 questionnaires [323 (72%) general physicians and 128 (28%) gastroenterologists] from academic and non-academic institutes. Commonest precipitating event of HE was upper gastrointestinal bleed (47%), constipation (18%) and spontaneous bacterial peritonitis (12%). Arterial ammonia was always measured at admission by 156 (35%) physicians, never measured by 128 (28%) and sometimes by 167 (37%). Prophylactic antibiotics were used by 54% of physicians on the day of admission irrespective of any precipitating event, and 13% used antibiotics only if cultures were positive while others used antibiotics only if patient needs intubation or had variceal bleed as the cause of precipitation of HE. Disaccharides remained the mainstay of treatment in the management of HE and were always used by 87% (n = 391) followed by LOLA (n = 297, 66%) and rifaximin (n = 276, 61%). Combination of therapy was used by 84% of respondents. Lactulose enema was used in patients with HE by 280 (62%) physicians and was thought to be as good as giving lactulose by mouth or nasogastric tube in the treatment of HE. Regarding the recovery of HE with the present mode of therapy, of 451 responses, only 11% (n = 49) got 90-100% response to present therapy for the recovery of HE, while 70-90% response was seen by n = 152 (34%) and 50-70% response was seen by n = 183 (41%). Lactulose was prescribed as secondary prophylaxis agent more by gastroenterologists than non gastroenterologists (76% vs 41%, P = 0.001). Similarly, rifaximin was more prescribed by gastroenterologists at discharge compared to non gastroenterologists (32% vs 17%, P = 0.001). CONCLUSION: Non-absorbable disaccharides are the most commonly prescribed treatment for HE and for secondary prophylaxis of HE. Combination of therapy (lactulose and LOLA or lactulose and rifaximin) was commonly used by treating physicians. PMID- 26628838 TI - Addition of Somatostatin After Successful Endoscopic Variceal Ligation Does not Prevent Early Rebleeding in Comparison to Placebo: A Double Blind Randomized Controlled Trial. AB - BACKGROUND: Efficacy of endoscopic sclerotherapy in controlling acute variceal bleeding is significantly improved when vasoactive drug is added. Endoscopic variceal ligation (EVL) is superior to sclerotherapy. Whether efficacy of EVL will also improve with addition of somatostatin is not known. We compared EVL plus somatostatin versus EVL plus placebo in control of acute variceal bleeding. METHODS: Consecutive cirrhotic patients with acute esophageal variceal bleeding were enrolled. After emergency EVL, patients were randomized to receive either somatostatin (250 mcg/hr) or placebo infusion. Primary endpoint was treatment failure within 5 days. Treatment failure was defined as fresh hematemesis >=2 h after start of therapy, or a 3 gm drop in Hb, or death. RESULTS: 61 patients were enrolled (EVL plus somatostatin group, n = 31 and EVL plus placebo group, n = 30). The baseline characteristics were similar. Within the initial 5-day period, the frequency of treatment failure was similar in both the groups (EVL plus somatostatin group 8/31 [26%] versus EVL plus placebo group 7/30 [23%]; P = 1.000). The mortality was also similar in the two groups (3/31 [10%] vs. 3/30 [10%]; P = 1.000). Baseline HVPG >=19 mm Hg and active bleeding at index endoscopy were independent predictors of treatment failure. CONCLUSIONS: Addition of somatostatin infusion to EVL therapy does not offer any advantage in control of acute variceal bleeding or reducing mortality. The reason for this may be its failure to maintain sustained reduction in portal pressure for five days. Active bleeding at index endoscopy and high baseline HVPG should help choose early alternative treatment options. Trial registered with ClincalTrials.gov vide NCT01267669. PMID- 26628839 TI - HBsAg Level as Predictor of Liver Fibrosis in HBeAg Positive Patients With Chronic Hepatitis B Virus Infection. AB - BACKGROUND AND AIMS: Preliminary data suggests lower serum hepatitis B surface antigen level is associated with more severe liver fibrosis in HBeAg positive patients. We evaluated the association of HBsAg level with biochemical, virological, and histological features in asymptomatic patients with chronic HBV infection. METHODS: HBsAg levels were measured at baseline in 481 asymptomatic, treatment naive patients with chronic HBV infection. Subjects were followed-up prospectively (median, 12; range, 8-36 months). Phases of HBV infection were defined after regular monitoring of HBV-DNA and transaminases. Liver histology was scored using the METAVIR system. RESULTS: HBeAg positive (n, 126) patients were significantly younger than HBeAg negative (n, 355), median age 26 vs 30 years; P < 0.01. HBV genotype could be determined in 350 patients, 240 (68.57%) had genotype D and 100 (28.57%) had genotype A. HBsAg level had modest correlation with serum HBV DNA(r = 0.6 vs 0.4 in eAg positive & negative respectively). HBeAg + ve patients with fibrosis score >= F2 showed significantly lower median serum HBsAg levels and serum HBV DNA levels compared with patients with F0-F1 score (median, range; 4.51, 2.99-6.10 vs 5.06, 4.13-5.89, P < 0.01) and (8.39, 3.85-10.60, P < 0.01) respectively. Significant inverse correlation of HBsAg level was found with liver fibrosis in eAg positive group (r = -0.76; P < 0.001). HBsAg level cut off value 4.7 log10 IU/ml predicted moderate to advance fibrosis (F >= 2) with 92% sensitivity, 85% specificity & 91% negative predictive value. CONCLUSION: Lower HBsAg level might reflect the status of advanced liver fibrosis in HBeAg positive chronic hepatitis B subjects. PMID- 26628840 TI - Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection in 2015. AB - Overall prevalence of HCV infection in India has been estimated to be approximately 1.3% in the general population. Recent introduction of sofosbuvir in India at a relatively affordable price has led to great optimism about prospects of cure for these patients. This drug is likely to form the backbone of current and future treatment regimes for HCV infection, displacing pegylated interferon. Availability of directly acting antiviral drugs (DAAs) has necessitated revision of INASL guidelines for the treatment of HCV published in 2014, as has happened across the world. Current considerations for the treatment of HCV in India include the poorer response of genotype 3, nonavailability of many of the DAAs recommended by other guidelines and the cost of therapy. Since only one DAA, sofosbuvir, is available in India, only two sofosbuvir-based regimes are possible: either dual drug therapy in combination with ribavirin alone for 6 months or triple drug therapy in combination with ribavirin and pegylated interferon for 3 months. The utility of these regimes in various situations has been discussed. Availability of a few other newer DAAs, expected in 2016, is expected to lead to more widespread use of these agents. Current guidance will be updated once newer DAAs, newer evidence with DAAs and 'real-life experience' with use of DAAs accumulate in India. PMID- 26628841 TI - Animal Models Correlating Immune Cells for the Development of NAFLD/NASH. AB - This review mainly elaborates on the animal models available for understanding the pathogenesis of the second hit of non-alcoholic fatty liver disease (NAFLD) involving immune system. This is known to be a step forward from simple steatosis caused during the first hit, which leads to the stage of inflammation followed by more serious liver conditions like non-alcoholic steatohepatitis (NASH) and cirrhosis. Immune-deficient animal models serve as an important tool for understanding the role of a specific cell type or a cytokine in the progression of NAFLD. These animal models can be used in combination with the already available animal models of NAFLD, including dietary models, as well as genetically modified mouse models. Advancements in molecular biological techniques enabled researchers to produce several new animal models for the study of NAFLD, including knockin, generalized knockout, and tissue-specific knockout mice. Development of NASH/NAFLD in various animal models having compromised immune system is discussed in this review. PMID- 26628843 TI - Complications of Catheter Drainage for Amoebic Liver Abscess. AB - Per-cutaneously inserted catheter drainage is an accepted treatment modality for a large amoebic liver abscess. Complications that can arise are; secondary infection, bleeding into the abscess cavity, inadvertent catheter misplacement into the IVC and rupture of abscess with spillage into the peritoneal cavity. We report a case of a large amoebic liver abscess that presented with complications related to per-cutaneously inserted catheter drainage. PMID- 26628842 TI - Magnetic Resonance Imaging: Principles and Techniques: Lessons for Clinicians. AB - The development of magnetic resonance imaging (MRI) for use in medical investigation has provided a huge forward leap in the field of diagnosis, particularly with avoidance of exposure to potentially dangerous ionizing radiation. With decreasing costs and better availability, the use of MRI is becoming ever more pervasive throughout clinical practice. Understanding the principles underlying this imaging modality and its multiple applications can be used to appreciate the benefits and limitations of its use, further informing clinical decision-making. In this article, the principles of MRI are reviewed, with further discussion of specific clinical applications such as parallel, diffusion-weighted, and magnetization transfer imaging. MR spectroscopy is also considered, with an overview of key metabolites and how they may be interpreted. Finally, a brief view on how the use of MRI will change over the coming years is presented. PMID- 26628844 TI - Acute Portal Vein Thrombosis, No Longer a Contraindication for Transjugular Intrahepatic Porto-Systemic Shunt (TIPS) Insertion. AB - Portal vein thrombosis, once considered as a contraindication to transjugular intrahepatic porto-systemic shunt (TIPS) is now considered as an indication. We report a case with clinical and technical success in a patient with Budd Chiari syndrome and acute portal venous thrombosis. Though it is a well-established option, with the best of our knowledge, we could not find a report from India. PMID- 26628845 TI - Attack of the Clone: HCC Tract Seeding Following RFA. PMID- 26628846 TI - Intestinal FXR: A New Therapeutic Target for Nonalcoholic Fatty Liver Disease. PMID- 26628847 TI - Hepatobiliary Quiz (Answers)-15 (2015). PMID- 26628848 TI - Epidemiology of Liver Cirrhosis. PMID- 26628849 TI - Salivary pH and Buffering Capacity as Risk Markers for Early Childhood Caries: A Clinical Study. AB - BACKGROUND: The diagnostic utility of saliva is currently being explored in various branches of dentistry, remarkably in the field of caries research. This study was aimed to determine if assessment of salivary pH and buffering capacity would serve as reliable tools in risk prediction of early childhood caries (ECC). MATERIALS AND METHODS: Paraffin-stimulated salivary samples were collected from 50 children with ECC (group I) and 50 caries free children (group II). Salivary pH and buffering capacity (by titration with 0.1 N hydrochloric acid) were assessed using a handheld digital pH meter in both groups. The data obtained were subjected to statistical analysis. RESULTS: Statistically, no significant difference was observed between both the groups for all salivary parameters assessed, except for the buffering capacity level at 150 MUl titration of 0.1 N hydrochloric acid (p = 0.73; significant at 1% level). CONCLUSION: Salivary pH and buffering capacity may not serve as reliable markers for risk prediction of ECC. How to cite this article: Jayaraj D, Ganesan S. Salivary pH and Buffering Capacity as Risk Markers for Early Childhood Caries: A Clinical Study. Int J Clin Pediatr Dent 2015;8(3):167-171. PMID- 26628850 TI - Prevalence and Etiology of Traumatic Injuries to the Anterior Teeth among 5 to 8 Years Old School Children in Mathura City, India: An Epidemiological Study. AB - OBJECTIVES: To assess the prevalence of traumatic injuries to the anterior teeth among the 5 to 8 years old children attending the schools in Mathura city. STUDY DESIGN: A total of 1657 children of the age groups: 5, 6, 7 and 8 years from 20 schools situated in various parts of Mathura city were included in this study, utilizing stratified cluster random sampling method. RESULTS: The prevalence of traumatic injuries to the anterior teeth in 5 to 8 years old age group was found to be 2.7%. Males accounted for 3.1% whereas females accounted for 2.3%. Overall, males experienced more traumatic injuries than the females with male to female ratio of 1.8:1. The etiology of traumatic injuries was mostly due to falls, followed by bicycle accidents, collisions, violence and bike accidents in that order. How to cite this article: Gojanur S, Yeluri R, Munshi AK. Prevalence and Etiology of Traumatic Injuries to the Anterior Teeth among 5 to 8 Years Old School Children in Mathura City, India: An Epidemiological Study. Int J Clin Pediatr Dent 2015;8(3):172-175. PMID- 26628851 TI - Comparative Evaluation of Obturating Techniques in Primary Teeth: An in vivo Study. AB - AIM: The present study was undertaken to compare two methods of obturation in primary teeth by using lentulospirals and pressure syringe, radiographically. MATERIALS AND METHODS: Sixty teeth in subjects with mean age of 5.88 +/- 1.58 years were obturated randomly using two different obturating techniques, i.e. group I: Thirty teeth obturated with pressure syringe, and group II: Thirty teeth obturated with lentulospiral. Quality of obturation and presence or absence of voids were assessed by taking radiographs after obturation was done using both the techniques. RESULTS of quality of obturation were statistically analyzed using Chi-square test and Mann-Whitney's test, whereas voids were analyzed using Chi-square test. RESULTS: No statistically significant difference between the quality of obturation using pressure syringe or lentulospiral (p > 0.05) was observed. However, significantly higher number of voids were found for lentulospiral technique as compared to pressure syringe (p < 0.01). CONCLUSION: Both the techniques were found to be equally efficient statistically, though lentulospiral produced more voids. How to cite this article: Vashista K, Sandhu M, Sachdev V. Comparative Evaluation of Obturating Techniques in Primary Teeth: An in vivo Study. Int J Clin Pediatr Dent 2015;8(3): 176-180. PMID- 26628852 TI - Comparison of Effectiveness of Manual Orthodontic, Powered and Sonic Toothbrushes on Oral Hygiene of Fixed Orthodontic Patients. AB - INTRODUCTION: Maintenance of good oral hygiene is important for patients undergoing fixed orthodontic treatment. AIM: The aim of this study was to evaluate the effectiveness of a manual orthodontic toothbrush, powered toothbrush with oscillating head and sonic toothbrush in controlling plaque, gingivitis and interdental bleeding in patients undergoing fixed orthodontic treatment, and to compare their relative efficacy. MATERIALS AND METHODS: Sixty subjects, who were to receive orthodontic treatment with both upper and lower fixed appliances, were randomly divided into three study groups, with 20 patients in each group. Groups I to III were given manual orthodontic, powered and sonic toothbrushes, respectively. Plaque index (PI), gingival index (GI) and interdental bleeding index were scored to assess the level of plaque accumulation, gingival health and interdental bleeding at baseline; 4 and 8 weeks recall visits after fixed appliance bonding. Paired t-tests and one-way analysis of variance (ANOVA) tests were used for intragroup and intergroup comparisons. The level of statistical significance was set at p < 0.05. RESULTS: This study showed that a significant reduction in all the three indices scores was found from baseline to 4 and 8 weeks in group III. On intergroup comparison, no statistically significant differences were detected between the three groups for any of the parameters assessed. CONCLUSION: On intragroup comparison, sonic brushes performed superiorly in reducing gingivitis, plaque and interdental bleeding as compared to the manual orthodontic and powered brushes. On intergroup comparison, the relative comparative effectiveness was found to be similar for all the three brushes. How to cite this article: Sharma R, Trehan M, Sharma S, Jharwal V, Rathore N. Comparison of Effectiveness of Manual Orthodontic, Powered and Sonic Toothbrushes on Oral Hygiene of Fixed Orthodontic Patients. Int J Clin Pediatr Dent 2015;8(3):181-189. PMID- 26628853 TI - A Study of Correlation of Various Growth Indicators with Chronological Age. AB - INTRODUCTION: The aim of this study was to assess the relationship of chronological age with cervical vertebrae skeletal maturation, frontal sinus width and antegonial notch depth and a correlation, if any, among the three variables. MATERIALS AND METHODS: The samples were derived from lateral cephalometric radiographs of 80 subjects (40 males, 40 females; age range: 10 to 19 years). Cervical vertebral development was evaluated by the method of Hassel and Farman, frontal sinus width was measured by the method described by Erturk and antegonial notch depth as described by Singer et al. The Pearson's correlation coefficients were estimated to assess the relationship of chronological age with cervical vertebrae skeletal maturation, frontal sinus width and antegonial notch depth. RESULTS: The Pearson's correlation coefficient were 0.855 (p < 0.001) between chronological age and cervical vertebrae skeletal maturation, and 0.333 (p < 0.001) between chronological age and frontal sinus width. CONCLUSION: A highly significant positive correlation was found between chronological age and cervical vertebrae skeletal maturation, and between chronological age and frontal sinus width. Nonsignificant correlation was found between chronological age and antegonial notch depth. How to cite this article: Singh S, Sandhu N, Puri T, Gulati R, Kashyap R. A Study of Correlation of Various Growth Indicators with Chronological Age. Int J Clin Pediatr Dent 2015;8(3): 190 195. PMID- 26628854 TI - Effect of One Percent Chlorhexidine Addition on the Antibacterial Activity and Mechanical Properties of Sealants: An in vitro Study. AB - AIM: The aim of the study was to evaluate the effect of addition of 1% chlorhexidine digluconate solution on the antibacterial activity and mechanical properties of glass ionomer and resin based sealant. MATERIALS AND METHODS: Conventional glass ionomer sealant (GIS) (Fuji VII, Japan) and resin sealant (Clinpro 3M ESPE, USA) were used in this study. Chlorhexidine digluconate (CHX) (20%) liquid was added to both the sealants, and the concentration of chlorhexidine in sealants was adjusted to 1%. The sealants were divided into four groups as: group A (GIS), group B (GIS + 1% CHX), group C (resin sealant), group D (resin sealant + 1% CHX). Five cylindrical specimens were prepared in each group. Their antibacterial activity against Streptococcus mutans and Lactobacillus acidophilus, and their mechanical properties (compressive strength and diametrical tensile strength) were assessed. Mann-Whitney and Wilcoxon signed rank test were used appropriately for statistical analysis (SPSS version 19). RESULT: Addition of one percent chlorhexidine significantly increased the antibacterial activity of both the sealants. There was a significant difference between groups A and B (p < 0.009), and groups C and D (p < 0.008). There was no significant difference in the mechanical properties of the sealants. CONCLUSION: Addition of one percent chlorhexidine to the glass ionomer and resin based sealants provided sufficient antibacterial activity, without significantly affecting the mechanical property of the sealants. How to cite this article: Shanmugaavel AK, Asokan S, John JB, Geetha Priya PR, Gnana Devi J. Effect of one percent Chlorhexidine Addition on the Antibacterial Activity and Mechanical Properties of Sealants: An in vitro Study. Int J Clin Pediatr Dent 2015;8(3):196 201. PMID- 26628855 TI - Computed Tomographic Morphometry of the Internal Anatomy of Mandibular Second Primary Molars. AB - Need for the study: The most important procedure for a successful endodontic treatment is the cleaning and shaping of the canal system. Understanding the internal anatomy of teeth provides valuable information to the clinician that would help him achieve higher clinical success during endodontic therapy. AIMS: To evaluate by computed tomography-the internal anatomy of mandibular second primary molars with respect to the number of canals, cross-sectional shape of canals, cross-sectional area of canals and the root dentin thickness. MATERIALS AND METHODS: A total of 31 mandibular second primary molars were subjected to computed-tomographic evaluation in the transverse plane, after mounting them in a prefabricated template. The images, thus, obtained were analyzed using De-winter Bio-wizard(r) software. RESULTS: All the samples demonstrated two canals in the mesial root, while majority of the samples (65.48%) demonstrated two canals in the distal root. The cross-sectional images of the mesial canals demonstrated a round shape, while the distal canals demonstrated an irregular shape. The root dentin thickness was highly reduced on the distal aspect of mesial and mesial aspect of distal canals. CONCLUSION: The mandibular second primary molars demonstrated wide variation and complexities in their internal anatomy. A thorough understanding of the complexity of the root canal system is essential for understanding the principles and problems of shaping and cleaning, determining the apical limits and dimensions of canal preparations, and for performing successful endodontic procedures. How to cite this article: Kurthukoti AJ, Sharma P, Swamy DF, Shashidara R, Swamy EB. Computed Tomographic Morphometry of the Internal Anatomy of Mandibular Second Primary Molars. Int J Clin Pediatr Dent 2015;8(3):202-207. PMID- 26628856 TI - Preterm Birth: A Primary Etiological Factor for Delayed Oral Growth and Development. AB - Preterm and low birthweight children comprise approximately 6% of all live births. It is now a well-known fact that premature children experience many oral complications associated with their preterm births. Prematurely born infants have a short prenatal development period and they are prone to many serious medical problems during the neonatal period, which may affect the development of oral tissues. Adverse perinatal factors, premature birth and exceptional early adaptation to extra-uterine life and functional activity may influence dental occlusal development and symmetry in the jaws. Thus, the goal of the present paper is to elucidate further the effect of preterm birth on the development of the dentition. How to cite this article: Zaidi I, Thayath MN, Singh S, Sinha A. Preterm Birth: A Primary Etiological Factor for Delayed Oral Growth and Development. Int J Clin Pediatr Dent 2015;8(3): 215-219. PMID- 26628858 TI - Characterizing Cancer-Specific Networks by Integrating TCGA Data. AB - The Cancer Genome Atlas (TCGA) generates comprehensive genomic data for thousands of patients over more than 20 cancer types. TCGA data are typically whole-genome measurements of multiple genomic features, such as DNA copy numbers, DNA methylation, and gene expression, providing unique opportunities for investigating cancer mechanism from multiple molecular and regulatory layers. We propose a Bayesian graphical model to systemically integrate multi-platform TCGA data for inference of the interactions between different genomic features either within a gene or between multiple genes. The presence or absence of edges in the graph indicates the presence or absence of conditional dependence between genomic features. The inference is restricted to genes within a known biological network, but can be extended to any sets of genes. Applying the model to the same genes using patient samples in two different cancer types, we identify network components that are common as well as different between cancer types. The examples and codes are available at https://www.ma.utexas.edu/users/yxu/software.html. PMID- 26628857 TI - Mutations in GRM6 identified in consanguineous Pakistani families with congenital stationary night blindness. AB - PURPOSE: This study was undertaken to investigate the causal mutations responsible for autosomal recessive congenital stationary night blindness (CSNB) in consanguineous Pakistani families. METHODS: Two consanguineous families with multiple individuals manifesting symptoms of stationary night blindness were recruited. Affected individuals underwent a detailed ophthalmological examination, including fundus examination and electroretinography. Blood samples were collected and genomic DNA was extracted. Exclusion analyses were completed by genotyping closely spaced microsatellite markers, and two-point logarithm of odds (LOD) scores were calculated. All coding exons, along with the exon-intron boundaries of GRM6, were sequenced bidirectionally. RESULTS: According to the medical history available to us, affected individuals in both families had experienced night blindness from the early years of their lives. Fundus photographs of affected individuals in both the families appeared normal, with no signs of attenuated arteries or bone spicule pigmentation. The scotopic electroretinogram (ERG) response were absent in all of the affected individuals, while the photopic measurements show reduced b-waves. During exclusion analyses, both families localized to a region on chromosome 5q that harbors GRM6, a gene previously associated with autosomal recessive CSNB. Bidirectional sequencing of GRM6 identified homozygous single base pair changes, specifically c.1336C>T (p.R446X) and c.2267G>A (p.G756D) in families PKRP170 and PKRP172, respectively. CONCLUSIONS: We identified a novel nonsense and a previously reported missense mutation in GRM6 that were responsible for autosomal recessive CSNB in patients of Pakistani decent. PMID- 26628859 TI - Multigroup Equivalence Analysis for High-Dimensional Expression Data. AB - Hypothesis tests of equivalence are typically known for their application in bioequivalence studies and acceptance sampling. Their application to gene expression data, in particular high-dimensional gene expression data, has only recently been studied. In this paper, we examine how two multigroup equivalence tests, the F-test and the range test, perform when applied to microarray expression data. We adapted these tests to a well-known equivalence criterion, the difference ratio. Our simulation results showed that both tests can achieve moderate power while controlling the type I error at nominal level for typical expression microarray studies with the benefit of easy-to-interpret equivalence limits. For the range of parameters simulated in this paper, the F-test is more powerful than the range test. However, for comparing three groups, their powers are similar. Finally, the two multigroup tests were applied to a prostate cancer microarray dataset to identify genes whose expression follows a prespecified trajectory across five prostate cancer stages. PMID- 26628861 TI - The very-rapid and the ultra-rapid virologic response to two treatment options in patients with chronic hepatitis C: an interim report of a prospective randomized comparative effectiveness study. AB - BACKGROUND: We aimed in this interim report to compare two registered generic sofosbuvir products for the degree and speed of virologic response to a dual antiviral treatment protocol within the first 2 weeks of treatment. METHODS: Data collected during the period of this interim report from the first 25 patients randomized to either one of two generic sofosbuvir products (Grateziano or Gratisovir) at a daily dose of one 400 mg tablet plus a weight-based ribavirin dose were analyzed for both the degree and speed of virus load reduction at the end of 1 and 2 weeks from starting treatment. RESULTS: The baseline Log10 transformed virus load (Log polymerase chain reaction) showed a fairly similar marked and significant reduction in both groups by more than 4 and 5 Logs at the end of week 1 and 2 of starting treatment, respectively. The differences between the two treatment groups at both analysis points were not statistically significant (P>0.05) by repeated measures factorial analysis of variance test. The differences in proportions of patients with ultra-rapid virologic response at the end of week 1 and very-rapid virologic response at the end of week 2 in both groups were also not statistically significant (P>0.05). CONCLUSION: We can conclude from this interim report that the two generic products Gratisovir and Grateziano are almost equally fast and efficacious in reducing the hepatitis C virus load in our study setting. PMID- 26628862 TI - Obesity Correlation With Metastases Development and Response to First-Line Metastatic Chemotherapy in Breast Cancer. AB - STUDY OBJECTIVES: To compare breast cancer metastases between obese and nonobese women and to evaluate the effect of first-line metastatic chemotherapy in each group. METHOD: A retrospective study was performed in an educational institute in Ireland. The study consisted of two parts: the first part was a comparative analysis of metastases development in obese (arm A) and nonobese patients (arm B). The second part was a comparison between both arms in relation to their response to first-line metastatic chemotherapy and their survival data. RESULTS: Between 2009 and 2014, we reviewed 118 patients with metastatic breast cancer. All the patients fulfilled our inclusion criteria. In all, 48% of patients were obese and 52% were nonobese. There were no statistically significant differences between the two groups. For arms A and B, the median interval between initial cancer diagnosis and distant metastases development (distant metastases-free survival) was 5.8 versus 7.6 years, respectively (Pvalue 0.04). Earlier visceral (liver and lung) metastases were observed in obese compared to nonobese women (Pvalues were 0.05 and 0.04, respectively). The most commonly used chemotherapy was weekly paclitaxel. Our treatments showed significantly better treatment response and better survival results in nonobese women than in obese ones, who were premenopausal with performance state 2, pathological grade 3, and four or more positive lymph nodes. CONCLUSION: Obesity is linked with visceral metastases development, especially lung and liver metastases. Furthermore, first-line metastatic chemotherapy achieved better results in nonobese patients. PMID- 26628863 TI - Are patients receiving the right care in the right place at the right time? PMID- 26628860 TI - c-Met as a Target for Personalized Therapy. AB - MET and its ligand HGF are involved in many biological processes, both physiological and pathological, making this signaling pathway an attractive therapeutic target in oncology. Downstream signaling effects are transmitted via mitogen-activated protein kinase (MAPK), PI3K (phosphoinositide 3-kinase protein kinase B)/AKT, signal transducer and activator of transcription proteins (STAT), and nuclear factor-kappaB. The final output of the terminal effector components of these pathways is activation of cytoplasmic and nuclear processes leading to increases in cell proliferation, survival, mobilization and invasive capacity. In addition to its role as an oncogenic driver, increasing evidence implicates MET as a common mechanism of resistance to targeted therapies including EGFR and VEGFR inhibitors. In the present review, we summarize the current knowledge on the role of the HGF-MET signaling pathway in cancer and its therapeutic targeting (HGF activation inhibitors, HGF inhibitors, MET antagonists and selective/nonselective MET kinase inhibitors). Recent advances in understanding the role of this pathway in the resistance to current anticancer strategies used in lung, kidney and pancreatic cancer are discussed. PMID- 26628864 TI - Using a family history questionnaire to identify adult patients with increased genetic risk for sarcoma. AB - BACKGROUND: Sarcomas in adults can be associated with hereditary cancer syndromes characterized by early-onset predisposition to numerous types of cancer. Because of variability in familial presentation and the largely unexplained genetic basis of sarcomas, ascertainment of patients for whom a genetics evaluation is most indicated poses challenges. We assessed the utility of a Sarcoma Clinic Genetic Screening (scgs) questionnaire in facilitating that task. METHODS: Between 2008 and 2012, 169 patients (median age: 53 years; range: 17-88 years) completed a self-administered scgs questionnaire. A retrospective chart review was completed for all respondents, and descriptive statistics were reported. Probands were divided into two groups depending on whether they did or did not report a family history of Li-Fraumeni syndrome-type cancers. RESULTS: A family history of cancer (as far as 3rd-degree relatives) was reported in 113 of 163 sarcoma patients (69%). Eeles Li-Fraumeni-like (lfl) criteria were fulfilled in 46 probands (28%), Chompret lfl in 21 (13%), Birch lfl in 8 (5%), and classic Li-Fraumeni in none. In the 10 probands tested for TP53 mutations, 1 pathogenic mutation was found. Further investigation of selected families led to the discovery of germline mutations in MLH1, MSH2, and APC genes in 3 individuals. CONCLUSIONS: The scgs questionnaire was useful for ascertaining probands with sarcoma who could benefit from a genetic assessment. The tool allowed us to identify high-risk families fitting the criteria for lfl and, surprisingly, other hereditary cancer syndromes. Similar questionnaires could be used in other cancer-specific clinics to increase awareness of the genetic component of these cancers. PMID- 26628865 TI - Population-based estimates of survival and cost for metastatic melanoma. AB - BACKGROUND: Fewer than half of all patients with metastatic melanoma survive more than 1 year. Standard treatments have had little success, but recent therapeutic advances offer the potential for an improved prognosis. In the present study, we used population-based administrative data to establish real-world baseline estimates of survival outcomes and costs against which new treatments can be compared. METHODS: Data from administrative databases and patient registries were used to find a cohort of patients with metastatic melanoma in Ontario. To identify individuals most likely to receive new treatments, we focused on patients eligible for second-line treatment. The identified cohort had two characteristics: no surgical resection beyond primary skin excision, and receipt of first-line systemic therapy. RESULTS: Patient characteristics, Kaplan-Meier survival curves, and mean costs are reported. Of the 33,585 patients diagnosed with melanoma in Ontario from 1 January 1991 to 31 December 2010, 278 met the study inclusion criteria. Average age was 63 years, and 62% of the patients were men. Overall survival was estimated to be 19%, 12%, and 6% at 12, 24, and 60 months respectively. Mean survival time was 11.5 months, and mean cost was $30,685. CONCLUSIONS: Our baseline estimates indicate that survival outcomes are poor and costs are high for patients receiving standard treatment. Understanding the relative improvement accruing from any new treatment requires a comparison with the existing standard of care. PMID- 26628866 TI - Causes of death and subsequent treatment after initial radical or palliative therapy of stage III non-small-cell lung cancer. AB - INTRODUCTION: Stage iii lung cancer is the most advanced stage of lung cancer for which radical (potentially curative) treatment is often discussed. Understanding the reasons for mortality and subsequent treatments in patients with stage iii non-small-cell lung cancer (nsclc) is important. METHODS: This retrospective cohort study extracted demographic, clinical, treatment, and outcomes data for patients with newly diagnosed stage iii nsclc diagnosed between 1 January 2008 and 31 December 2012 at a single institution. RESULTS: The study included 237 patients with stage iii nsclc, 130 of whom were not treated with radical or curative intent (55%). Median survival in the entire cohort was 14 months from diagnosis. For patients treated with radical-intent therapy, causes of death varied with the time period. The hazard rate for death was approximately 2.8 per 100 person-months of follow-up over the entire disease course and was highest between 6 months and 24 months. Over the entire time period, local causes accounted for 29% of deaths; systemic non-central nervous system metastases, for 25%; and brain metastases, for 14%. For patients treated with palliative intent, the overwhelming cause of death was local disease complications or progression (56% of deaths). Only 12% of patients in the palliative treatment group who progressed received subsequent chemotherapy; 23% of patients in the radical group who progressed received palliative chemotherapy. The most frequent subsequent treatment in both groups was radiation therapy. CONCLUSIONS: The eventual life ending event in stage iii nsclc varied for the patients who qualified for, and were treated with, radical or curative intent and for the patients who received palliative-intent therapy. Utilization of systemic chemotherapy in patients not fit for radical therapy is low. PMID- 26628867 TI - Quality of end-of-life cancer care in Canada: a retrospective four-province study using administrative health care data. AB - BACKGROUND: The quality of data comparing care at the end of life (eol) in cancer patients across Canada is poor. This project used identical cohorts and definitions to evaluate quality indicators for eol care in British Columbia, Alberta, Ontario, and Nova Scotia. METHODS: This retrospective cohort study of cancer decedents during fiscal years 2004-2009 used administrative health care data to examine health service quality indicators commonly used and previously identified as important to quality eol care: emergency department use, hospitalizations, intensive care unit admissions, chemotherapy, physician house calls, and home care visits near the eol, as well as death in hospital. Crude and standardized rates were calculated. In each province, two separate multivariable logistic regression models examined factors associated with receiving aggressive or supportive care. RESULTS: Overall, among the identified 200,285 cancer patients who died of their disease, 54% died in a hospital, with British Columbia having the lowest standardized rate of such deaths (50.2%). Emergency department use at eol ranged from 30.7% in Nova Scotia to 47.9% in Ontario. Of all patients, 8.7% received aggressive care (similar across all provinces), and 46.3% received supportive care (range: 41.2% in Nova Scotia to 61.8% in British Columbia). Lower neighbourhood income was consistently associated with a decreased likelihood of supportive care receipt. INTERPRETATION: We successfully used administrative health care data from four Canadian provinces to create identical cohorts with commonly defined indicators. This work is an important step toward maturing the field of eol care in Canada. Future work in this arena would be facilitated by national-level data-sharing arrangements. PMID- 26628868 TI - The changing landscape of brachytherapy for cervical cancer: a Canadian practice survey. AB - BACKGROUND: We documented changes in practice from 2009 to 2012 for cervical cancer brachytherapy in Canada. METHODS: Centres with gynecologic brachytherapy services were sent an e-mail questionnaire querying their 2012 practice. Responses are reported and compared with practice patterns identified in a similar survey for 2009. RESULTS: The response rate was 77% (24 of 31 centres). Almost all use high-dose-rate brachytherapy (92%); low-dose-rate brachytherapy has been completely phased out. Most continue to move patients from the site of applicator insertion to the radiation treatment simulation suite (75%) or to a diagnostic imaging department (29%), or both. In 2012, the imaging modalities used for dose specification were computed tomography [ct (75%)], magnetic resonance imaging [mri (38%)], plain radiography (21%), and cone-beam ct (8%). The number of institutions using mri guidance has markedly increased during the period of interest (9 vs. 1). Most respondents (58% vs. 14%) prescribed using guidelines from the Groupe Europeen de Curietherapie and the European Society for Therapeutic Radiology and Oncology, but they also used point A as a reference. Commonly used high-dose radiation regimens included 30 Gy in 5 fractions and 24 Gy in 3 fractions. CONCLUSIONS: In Canada, image-guided brachytherapy for cervical cancer continues to evolve. Although ct-based imaging remains the most commonly used modality, many centres have adopted mri for at least 1 brachytherapy treatment. More centres are using fewer fractions and a slightly lower biologically effective dose, but are still achieving EQD2 (2-Gy equivalent) doses of 80-90 Gy in combination with external-beam radiation therapy. PMID- 26628869 TI - Wait times for prostate cancer treatment and patient perceptions of care in Canada: a mixed-methods report. AB - BACKGROUND: Access to cancer care is a significant concern for Canadians. Prolonged delays between cancer diagnosis and treatment have been associated with anxiety, stress, and perceived powerlessness for patients and their family members. Longer wait times can also be associated with poorer prognosis, although the evidence is inconclusive. Here, we report national wait times for radiation therapy and surgery for localized prostate cancer (pca) and the effect of wait time on patient perceptions of their care. RESULTS: Treatment wait times showed substantial interprovincial variation. The longest 90th percentile wait times for radiation therapy and surgery were, respectively, 40 days and 105 days. In all provinces, waits for radiation therapy were longer for pca patients than for patients with breast, colorectal, or lung cancer. In the focus groups and interviews conducted with 47 men treated for pca, many participants did not perceive that wait times for treatment were prolonged. Those who experienced delays between diagnosis and treatment voiced issues with a lack of communication about when they would receive treatment and a lack of support or information to make an informed decision about treatment. Minimizing treatment delays was an aspect of the cancer journey that participants would like to change because of the stress it caused. CONCLUSIONS: Although wait time statistics are useful, a review of cancer control in Canada cannot be considered complete unless an effort is made to give voice to the experiences of individuals with cancer. The findings presented here are intended to provide a snapshot of national care delivery for localized pca and to identify opportunities for improvement in clinical practice. PMID- 26628870 TI - The mammography debate, round two: science, smoke and mirrors. PMID- 26628871 TI - Has screening mammography become obsolete? PMID- 26628872 TI - Utilization of magnetic resonance imaging in breast cancer screening. PMID- 26628873 TI - Pleural fluid tumour markers in malignant pleural effusion with inconclusive cytologic results. AB - BACKGROUND: The presence of tumour cells in pleural fluid or tissue defines an effusion as malignant. Cytology analysis of the pleural fluid has about 60% diagnostic sensitivity. Several tests have been proposed to improve diagnosis among them, the concentrations of tumour markers in pleural fluid. We evaluated whether the concentrations of tumour markers in pleural fluid could improve the diagnosis of malignant pleural effusion (mpe) when cytology is doubtful. METHODS: Lymphocytic pleural fluids secondary to tuberculosis or malignancy from 156 outpatients were submitted for cytology and tumour marker quantification [carcinoembryonic antigen (cea), cancer antigen 15-3 (ca15-3), carbohydrate antigen 19-9 (ca19-9), cancer antigen 72-4 (ca72-4), cancer antigen 125 (ca125), and cyfra 21-1). Oneway analysis of variance, the Student t-test or Mann-Whitney test, and receiver operating characteristic curves were used in the statistical analysis. RESULTS: Concentrations of the tumour markers cea, ca15-3, ca125, and cyfra 21-1 were higher in mpes than they were in the benign effusions (p < 0.001), regardless of cytology results. The markers ca19-9 and ca72-4 did not discriminate malignant from benign effusions. When comparing the concentrations of tumour markers in mpes having positive, suspicious, or negative cytology with concentrations in benign effusions, we observed higher levels of cea, ca15-3, cyfra 21-1, and ca125 in malignant effusions with positive cytology (p = 0.003, p = 0.001, p = 0.002, and p = 0.001 respectively). In pleural fluid, only ca125 was higher in mpes with suspicious or negative cytology (p = 0.001) than in benign effusions. CONCLUSIONS: Given high specificity and a sensitivity of about 60%, the concentrations of tumour markers in pleural effusions could be evaluated in cases of inconclusive cytology in patients with a high pre-test chance of malignancy or a history of cancer. PMID- 26628874 TI - Physician preferences for bone metastasis drug therapy in Canada. AB - BACKGROUND: Currently in Canada, several bone-targeted agents (btas) with varying characteristics are available for the prevention of skeletal-related events (sres) in patients with bone metastasis secondary to solid tumours. In the present study, we evaluated the preferences of physicians in Canada for the various attributes of the available btas. METHODS: Physicians treating patients with bone metastasis from solid tumours were invited to complete an online discrete-choice experiment. Respondents were asked to choose between pairs of hypothetical medications for virtual patients. Each hypothetical medication was described based on predefined key attributes: time until first sre, time until worsening of pain, medication-related annual risk of osteonecrosis of the jaw (onj), medication-related annual risk of renal impairment, and mode of administration. A random-parameters logit model was used to analyze the choices between hypothetical medications and thus infer physician preferences for medication attributes. RESULTS: Responses from the 200 physicians who completed the discrete-choice experiment suggested that months until first sre, risk of renal impairment, and months until worsening of pain were considered the most important attributes affecting choice of bta. The annual risk of onj was considered the least important attribute. CONCLUSIONS: When making treatment decisions about the choice of bta for patients with bone metastasis from solid tumours, delaying sres and worsening of pain, and reducing the risk of renal impairment are primary considerations for physicians in Canada. PMID- 26628875 TI - Palliative chemotherapy for patients 70 years of age and older with metastatic colorectal cancer: a single-centre experience. AB - BACKGROUND: Metastatic colorectal cancer (mcrc) commonly affects elderly people, an understudied subset of patients. We analyzed the survival impact of the first and subsequent lines of chemotherapy in eligible non-trial patients 70 years of age and older with mcrc treated between 2004 and 2012. METHODS: This single centre retrospective analysis estimated overall survival (os) and progression free survival (pfs) using the Kaplan-Meier method. Multivariate analysis was used to adjust for age, sex, Eastern Cooperative Oncology Group performance status, score on the Charlson comorbidity index, dependency in activities of daily living, and exposure to 1 or more chemotherapy doublets, capecitabine alone, or best supportive care (bsc). RESULTS: Of 109 patients identified, 29 elected bsc, and 80 received chemotherapy. In multivariate analysis, age was not associated with os [hazard ratio (hr): 0.99; 95% confidence interval (ci): 0.92 to 1.05], but a performance status of 2 or higher was associated with a decreased likelihood of survival (hr: 3.12; 95% ci: 1.87 to 5.76), and exposure to 1 or more doublets was associated with improved survival (hr: 0.33; 95% ci: 0.17 to 0.66). In univariate analysis, a trend toward improved os was observed for first line doublet chemotherapy compared with capecitabine (hr: 0.66; 95% ci: 0.41 to 1.07), and pfs was superior (hr: 0.46; 95% ci: 0.26 to 0.84). Compared with exposure to 1 doublet, exposure to the 3 potential cytotoxic chemotherapies was not associated with improved os (hr: 0.77; 95% ci: 0.41 to 1.43). The incidence of neutropenia with first-line folfiri was 40%; the incidences of bevacizumab related arterial and venous thrombosis were both 8%. CONCLUSIONS: Exposure to 1 or more doublet chemotherapies for mcrc was associated with better outcomes in non-trial patients 70 years of age and older. Elderly patients treated with palliative chemotherapy and bevacizumab should be monitored carefully for arterial and venous thrombotic events. PMID- 26628876 TI - Human albumin eye drops as a therapeutic option for the management of keratoconjunctivitis sicca secondary to chronic graft-versus-host disease after stem-cell allografting. AB - BACKGROUND: Keratoconjunctivitis sicca from chronic graft-versus-host disease (cgvhd) after allogeneic stem cell transplantation is common, leading to severe corneal damage and blindness if not treated. We retrospectively examined the efficacy and safety of pooled human albumin eye drops (haeds) for symptom relief in 40 stem-cell transplantation patients after other alternatives had failed. METHODS: The Common Terminology Criteria for Adverse Events (version 4.0) and the cgvhd grading scale were used to compare response in the patients during January 2000 and July 2013. In addition, on days 1 and 30, the haeds were subjected to quality assurance testing for sterility, oncotic pressure, albumin measurement, viscosity, pH, and purity by protein electrophoresis. RESULTS: Use of haeds resulted in symptom relief for 37 patients (92.5%); 3 patients (7.5%) failed to improve with use of haeds (p <= 0.0001). Of the 37 patients having symptom relief, 7 (19%) improved from grade 3 to no dry eye symptoms. Proportionately, post-treatment symptom improvement by two grade levels, from 3 to 1 (70%), was significantly higher than improvement by one grade level, from 3 to 2 (11%) or from 2 to 1 (19%, p <= 0.0001). Time to symptom relief ranged from 2 weeks to 28 weeks. Of the 40 patients, 38 (95%) had no adverse reactions. Days 1 and 30 quality assurance testing results were equivalent. CONCLUSIONS: Complications of keratoconjunctivitis sicca were well managed and well tolerated with haeds when other remedies failed. Quality assurance testing confirmed that haeds were safe and stable in extreme conditions. PMID- 26628877 TI - Using tablet-based technology in patient education about systemic therapy options for early-stage breast cancer: a pilot study. AB - BACKGROUND: Patient education in early-stage breast cancer has been shown to improve patient well-being and quality of life, but it poses a challenge given the increasingly complex regimens and time constraints in clinical practice. Technology-aided teaching in the clinic could help to improve the understanding of adjuvant systemic therapy for patients. In this prospective pilot study, we used a clinician-administered, tablet-based teaching aid to teach patients with early-stage breast cancer about adjuvant systemic therapy. METHODS: Participation was offered to newly diagnosed patients with early-stage breast cancer presenting for their first medical oncology visit at a provincial cancer centre. Participants were shown a tablet-based presentation describing procedures, rationales, risks, and benefits of adjuvant systemic therapy as an adjunct to a discussion with the medical oncologist. After the clinic visit, participants completed a questionnaire measuring satisfaction with the visit and knowledge of the treatment plan discussed. RESULTS: The 25 patients recruited for the study had a mean age of 57 years. An offer of upfront chemotherapy alone was made to 12 participants (48%), chemotherapy with trastuzumab to 4 (16%), and hormonal therapy to 9 (36%). Correct answers to all questions related to treatment knowledge were given by 22 patients (88%). Satisfaction with the clinic visit was high (mean satisfaction score: 4.53 +/- 0.1 of a possible 5). CONCLUSIONS: We found that a tablet-based presentation about adjuvant systemic therapy was satisfactory to patients with early-stage breast cancer and that knowledge retention after the clinic visit was high. Tablet-based teaching could be a feasible and effective way of educating patients in the breast oncology clinic and warrants further investigation in randomized studies. PMID- 26628878 TI - Preliminary results of proton-beam therapy for stage III non-small-cell lung cancer. AB - BACKGROUND: We conducted a preliminary retrospective evaluation of the efficacy and toxicity of proton-beam therapy (pbt) for stage iii non-small-cell lung cancer. METHODS: Between January 2009 and August 2013, 27 patients (26 men, 1 woman) with stage iii non-small-cell lung cancer underwent pbt. The relative biologic effectiveness value of the proton beam was defined as 1.1. The beam energy and spread-out Bragg peak were fine-tuned such that the 90% isodose volume of the prescribed dose encompassed the planning target volume. Of the 27 patients, 11 underwent neoadjuvant chemotherapy. Cumulative survival curves were calculated using the Kaplan-Meier method. Treatment toxicities were evaluated using version 4 of the Common Terminology Criteria for Adverse Events. RESULTS: Median age of the patients was 72 years (range: 57-91 years), and median follow up was 15.4 months (range: 7.8-36.9 months). Clinical stage was iiia in 14 patients (52%) and iiib in 13 (48%). The median dose of pbt was 77 GyE (range: 66 86.4 GyE). The overall survival rate in the cohort was 92.3% at 1 year and 51.1% at 2 years. Locoregional failure occurred in 7 patients, and distant metastasis, in 10. In 2 patients, initial failure was both locoregional and distant. The 1 year and 2-year rates of local control were 68.1% and 36.4% respectively. The 1 year and 2-year rates of progression-free survival were 39.9% and 21.4% respectively. Two patients experienced grade 3 pneumonitis. CONCLUSIONS: For patients with stage iii non-small-cell lung cancer, pbt can be an effective and safe treatment option. PMID- 26628879 TI - Breast cancer screening panels continue to confuse the facts and inject their own biases. PMID- 26628880 TI - To screen or not to screen for breast cancer? How do modelling studies answer the question? AB - Breast cancer screening is a topic of hot debate, and currently no general consensus has been reached on starting and ending ages and screening intervals, in part because of a lack of precise estimations of the benefit-harm ratio. Simulation models are often applied to account for the expected benefits and harms of regular screening; however, the degree to which the model outcomes are reliable is not clear. In a recent systematic review, we therefore aimed to assess the quality of published simulation models for breast cancer screening of the general population. The models were scored according to a framework for qualitative assessment. We distinguished seven original models that utilized a common model type, modelling approach, and input parameters. The models predicted the benefit of regular screening in terms of mortality reduction; and overall, their estimates compared well to estimates of mortality reduction from randomized controlled trials. However, the models did not report on the expected harms associated with regular screening. We found that current simulation models for population breast cancer screening are prone to many pitfalls; their outcomes bear a high overall risk of bias, mainly because of a lack of systematic evaluation of evidence to calibrate the input parameters and a lack of external validation. Our recommendations concerning future modelling are therefore to use systematically evaluated data for the calibration of input parameters, to perform external validation of model outcomes, and to account for both the expected benefits and the expected harms so as to provide a clear balance and cost effectiveness estimation and to adequately inform decision-makers. PMID- 26628881 TI - PEComa of the terminal ileum mesentery as a secondary tumour in an adult survivor of embryonal rhabdomyosarcoma. AB - Perivascular epithelioid cell tumours (pecomas) are rare mesenchymal tumours that are characterized by perivascular epithelioid cell differentiation and immunoreactivity to myogenic and melanocytic markers. These tumours can be classified as benign, uncertain malignant potential, or malignant. Because of the rarity of pecomas, their cause and clinical prognosis remain unclear. To the best of our knowledge, no reports in the literature describe a pecoma of the terminal ileum mesentery as a secondary tumour in an adult survivor of childhood embryonal rhabdomyosarcoma, let alone any childhood cancer. Here, we present the case of a 27-year-old man with a pecoma involving the mesentery of the terminal ileum. At the age of 5, he had been treated with a combination of chemotherapy and high dose pelvic radiation therapy for embryonal rhabdomyosarcoma, most likely arising from the posterior bladder wall. During routine follow-up 22 years after this patient's initial treatment, computed tomography imaging revealed a mass within the terminal ileum mesentery. The tumour was successfully treated with surgical resection, and pathology examination determined the mass to be a pecoma with uncertain malignant potential. This first case of a pecoma of the terminal ileum mesentery arising within a high-dose radiation therapy field as a secondary tumour in an adult survivor of childhood cancer highlights the importance of screening and surveillance in high-risk childhood cancer survivors treated with high-dose radiation therapy. Further research to build a better understanding of this remarkably rare tumour is warranted. PMID- 26628882 TI - A primary intravascular synovial sarcoma causing deep-vein thrombosis and pulmonary embolism in a 20-year-old woman. AB - Primary intravascular synovial sarcoma is a rare malignancy with only a few cases documented in the literature. On presentation, this tumour usually resembles a deep venous thrombosis (dvt) or pulmonary embolism (pe). Here, we report the case of a 20-year-old woman complaining of shortness of breath who had a history of dvt 6 weeks before presentation at our institution. Vascular ultrasound detected a suspicious mass in the right groin, which was identified as a monophasic synovial sarcoma by surgical biopsy. The tumour extended from the right superficial femoral vein into the common iliac vein, profound femoral vein, and great saphenous vein. It caused pe with near-total occlusion of the right pulmonary artery. After initial treatment on the cardiac intensive care unit, the patient was referred to the oncology department for neoadjuvant radiochemotherapy with doxorubicin-ifosfamide according to the Interdisziplinare Arbeitsgemeinschaft Weichteilsarkome [Interdisciplinary AG Sarcomas] protocol and surgical resection of the tumour. No signs of tumour recurrence were found during the subsequent course of the disease, but the patient died from treatment complications approximately 15 months after initial presentation. This case underlines the importance of screening for malignancies even in young patients presenting with dvt or pe. We also recommend whole-leg compression ultrasonography in patients with suspected dvt or pe (as opposed to venography or simple four-point ultrasound examination in the groin and popliteal fossa) to detect possible underlying causes for thrombosis. PMID- 26628883 TI - Stereotactic ablative radiotherapy with CyberKnife for advanced thymic carcinoma: a case report. AB - Thymic carcinoma is a rare but lethal mediastinal cancer. The optimal treatment for advanced thymic carcinoma is not yet established. This report is the first known of stereotactic ablative radiotherapy (sabr) with CyberKnife (Accuray, Sunnyvale, CA, U.S.A.) as definitive therapy for thymic carcinoma. The patient, a 70-year-old woman with thymic carcinoma, invasion into neighboring organs, and pleural metastases-underwent CyberKnife sabr at 40 Gy in 5 fractions for two lesions, one in the thymus and one in the right paraspinal pleura. After 61 months of observation, a partial response was observed in the irradiated fields. However, disease progression in the non-irradiated pleura was noted. The patient underwent salvage CyberKnife sabr for the four initially nonirradiated pleural lesions. Computed tomography images obtained 10 months after the salvage therapy revealed a partial response. The patient is living, with progression-free irradiated lesions and no radiation-related toxicity. CyberKnife sabr is feasible for patients who are unable to undergo either surgery or conventionally fractionated radiation therapy. PMID- 26628884 TI - Imatinib for highly chemoresistant Kaposi sarcoma in a patient with long-term HIV control: a case report and literature review. AB - Kaposi sarcoma (ks) is a vascular tumour caused by oncogenic human herpesvirus type 8; it often occurs with hiv-associated immunosuppression. Numerous cellular signalling pathways are involved in the pathogenesis of ks, among which receptor tyrosine kinases such as the c-Kit and platelet-derived growth factor receptors play an important role. Imatinib mesylate, a tyrosine kinase inhibitor, has resulted in partial regression of ks lesions in one third of treated patients, but its mechanism of action remains unclear. Here, we report the case of a white man with recurrent ks despite well-suppressed hiv infection and multiple chemotherapies who received imatinib and showed a complete and sustained tumour response. To our knowledge, this report is the first showing the value of imatinib in the management of ks in the context of long-lasting hiv control with adequate quantitative CD4 recovery. Our case indicates that imatinib can be a treatment option for highly chemoresistant recurrent ks in patients on long-term antiretroviral therapy. PMID- 26628885 TI - Response to: "Counterpoint re: 'Mammography screening-sticking to the science'". PMID- 26628886 TI - Response to: "Beyond the mammography debate: a moderate perspective". PMID- 26628887 TI - Mammography, Martin Yaffe, and me: response and appreciation. PMID- 26628888 TI - Current definition of locally advanced breast cancer. PMID- 26628889 TI - Response to: "Current definition of locally advanced breast cancer". PMID- 26628890 TI - Found in translation: a medical student's reflection on the emotional realities of translational cancer research. PMID- 26628891 TI - White. PMID- 26628892 TI - The calcified eggshell matrix proteome of a songbird, the zebra finch (Taeniopygia guttata). AB - BACKGROUND: The proteins of avian eggshell organic matrices are thought to control the mineralization of the eggshell in the shell gland (uterus). Proteomic analysis of such matrices identified many candidates for such a role. However, all matrices analyzed to date come from species of one avian family, the Phasianidae. To analyze the conservation of such proteins throughout the entire class Aves and to possibly identify a common protein toolkit enabling eggshell mineralization, it is important to analyze eggshell matrices from other avian families. Because mass spectrometry-based in-depth proteomic analysis still depends on sequence databases as comprehensive and accurate as possible, the obvious choice for a first such comparative study was the eggshell matrix of zebra finch, the genome sequence of which is the only songbird genome published to date. RESULTS: The zebra finch eggshell matrix comprised 475 accepted protein identifications. Most of these proteins (84 %) were previously identified in species of the Phasianidae family (chicken, turkey, quail). This also included most of the so-called eggshell-specific proteins, the ovocleidins and ovocalyxins. Ovocleidin-116 was the second most abundant protein in the zebra finch eggshell matrix. Major proteins also included ovocalyxin-32 and -36. The sequence of ovocleidin-17 was not contained in the sequence database, but a presumptive homolog was tentatively identified by N-terminal sequence analysis of a prominent 17 kDa band. The major proteins also included three proteins similar to ovalbumin, the most abundant of which was identified as ovalbumin with the aid of two characteristic phosphorylation sites. Several other proteins identified in Phasianidae eggshell matrices were not identified. When the zebra finch sequence database contained a sequence similar to a missing phasianid protein it may be assumed that the protein is missing from the matrix. This applied to ovocalyxin 21/gastrokine-1, a major protein of the chicken eggshell matrix, to EDIL3 and to lactadherin. In other cases failure to identify a particular protein may be due to the absence of this protein from the sequence database, highlighting the importance of better, more comprehensive sequence databases. CONCLUSIONS: The results indicate that ovocleidin-116, ovocleidin-17, ovocalyxin-36 and ovocalyxin 32 may be universal avian eggshell-mineralizing proteins. All the more important it is to elucidate the role of these proteins at the molecular level. This cannot be achieved by proteomic studies but will need application of other methods, such as atomic force microscopy or gene knockouts. However, it will also be important to analyze more eggshell matrices of different avian families to unequivocally identify other mineralization toolkit proteins apart from ovocleidins and ovocalyxins. Progress in this respect will depend critically on the availability of more, and more comprehensive, sequence databases. The development of faster and cheaper nucleotide sequencing methods has considerably accelerated genome and transcriptome sequencing, but this seems to concur with frequent publication of incomplete and fragmented sequence databases. PMID- 26628893 TI - Alteration of actin dependent signaling pathways associated with membrane microdomains in hyperlipidemia. AB - BACKGROUND: Membrane microdomains represent dynamic membrane nano-assemblies enriched in signaling molecules suggesting their active involvement in not only physiological but also pathological molecular processes. The hyperlipidemic stress is a major risk factor of atherosclerosis, but its exact mechanisms of action at the membrane microdomains level remain elusive. The aim of the present study was to determine whether membrane-cytoskeleton proteome in the pulmonary tissue could be modulated by the hyperlipidemic stress, a major risk factor of atherosclerosis. RESULTS: High resolution mass spectrometry based proteomics analysis was performed for detergent resistant membrane microdomains isolated from lung homogenates of control, ApoE deficient and statin treated ApoE deficient mice. The findings of the study allowed the identification with high confidence of 1925 proteins, 291 of which were found significantly altered by the modified genetic background, by the statin treatment or both conditions. Principal component analysis revealed a proximal partitioning of the biological replicates, but also a distinct spatial scattering of the sample groups, highlighting different quantitative profiles. The statistical significant over representation of Regulation of actin cytoskeleton, Focal adhesion and Adherens junction Kyoto Encyclopedia of Genes and Genomes signaling pathways was demonstrated through bioinformatics analysis. The three inter-relation maps comprised 29 of regulated proteins, proving membrane-cytoskeleton coupling targeting and alteration by hyperlipidemia and/or statin treatment. CONCLUSIONS: The findings of the study allowed the identification with high confidence of the main proteins modulated by the hyperlipidemic stress involved in the actin dependent pathways. Our study provides the basis for future work probing how the protein activities at the membrane-cytoskeleton interface are dependent upon genetic induced hyperlipidemia. PMID- 26628894 TI - Hepatocytes respond differently to major dietary trans fatty acid isomers, elaidic acid and trans-vaccenic acid. AB - BACKGROUND: It has been discussed if the adverse health effect associated with the ingestion of trans fatty acids correlates with the food source, as the composition of the isomers varies in different foods. We have investigated the hepatocellular responses to the predominant trans fatty acid isomers in industrially produced partially hydrogenated vegetable oils (elaidic acid) and products of ruminant origin (trans-vaccenic acid). RESULTS: The responses of HepG2-SF cells exposed to 100 MUM fatty acids during 7 days were examined. Elaidic acid decreased the cellular proliferation rate while trans-vaccenic acid had no effect. Analysis of cellular triacylglycerol fractions showed, that both trans fatty acids were metabolized by HepG2-SF cells, although elaidic acid, to a higher degree than trans-vaccenic, accumulated in the triacylglycerol fraction. Proteome analysis revealed that the overlap of differentially regulated proteins only contained four proteins, suggesting that the two trans fatty acid isomers affect the cells in different ways. The data are available via ProteomeXchange with identifier PXD000760. CONCLUSIONS: Our investigations revealed that the hepatocellular response to the two most abundant dietary positional C18:1 trans fatty acid isomers differ substantially. In addition, the results suggest that trans-vaccenic acid does not affect cholesterol metabolism adversely compared to elaidic acid. PMID- 26628895 TI - Rural-urban differentials in pregnancy-related mortality in Zambia: estimates using data collected in a census. AB - BACKGROUND: The use of census data to measure maternal mortality is a recent phenomenon, implemented in settings with non-functional vital registration systems and driven by needs for trend data. The 2010 round of population and housing censuses recorded a significant increase in the number of countries collecting maternal mortality data. The objective of this study was to estimate rural-urban differentials in pregnancy-related mortality in Zambia using census data. METHODS: We used data from the Zambia 2000 and 2010 censuses. Both censuses recorded the female population by age, the number of children ever born, and live births 12 months prior to the census. The 2010 census further recorded, by age, household, and pregnancy-related deaths 12 months prior to the census. We evaluated and adjusted recorded live births using the cohort Parity Fertility ratio method, and household deaths using deaths distribution methods (General Growth Balance and Synthetic Extinct Generation). Adult female mortality and pregnancy-related mortality for rural and urban areas were estimated for the period October 2009 to October 2010. RESULTS: Data evaluation showed errors in recorded population age, age-at-death, live births, and deaths, and appropriate adjustments were made. Adjusted adult female mortality was high; an adolescent aged 15 years had a one-in-three chance of dying before her 50th birthday in rural areas and one-in-four chance in urban areas. Pregnancy-related deaths comprised 15.3 % of all deaths among reproductive-age women overall; 17.9 % in rural areas and 9.8 % in urban areas. The pregnancy-related mortality ratio for the period was 789 deaths/100,000 live births overall: 960/100,000 live births in rural areas and 470/100,000 live births in urban areas. CONCLUSIONS: Census-based estimates show very high adult female mortality and particularly high pregnancy related mortality in both rural and urban areas of Zambia 12 months prior to the 2010 census. Future censuses should pay greater attention to strategies for improving data quality. PMID- 26628896 TI - Erratum. AB - [This corrects the article DOI: 10.1159/000437382.]. PMID- 26628897 TI - Cognitive Function and 3-Tesla Magnetic Resonance Imaging Tractography of White Matter Hyperintensities in Elderly Persons. AB - BACKGROUND/AIMS: This study used 3-Tesla magnetic resonance imaging (MRI) tractography to determine if there was an association between tracts crossing white matter hyperintensities (WMH) and cognitive function in elderly persons. METHODS: Brain T2-weighted fluid-attenuated inversion recovery (FLAIR) and diffusion tensor MRI scans were acquired in participants above the age of 60 years. Twenty-six persons had WMH identified on T2 FLAIR scans. They completed a battery of neuropsychological tests and were classified as normal controls (n = 15) or with Alzheimer's dementia (n = 11). Tractography was generated by the Fiber Assignment by Continuous Tracking method. All tracts that crossed WMH were segmented. The average fractional anisotropy and average mean diffusivity of these tracts were quantified. We studied the association between cognitive test scores with the average mean diffusivity and average fractional anisotropy of tracts while controlling for age, total WMH volume and diagnosis. RESULTS: An increased mean diffusivity of tracts crossing WMH was associated with worse performance on the Wechsler Memory Scale-III Longest Span Forward (p = 0.02). There was no association between the fractional anisotropy of tracts and performance on cognitive testing. CONCLUSION: The mean diffusivity of tracts crossing WMH measured by tractography is a novel correlate of performance on the Wechsler Memory Scale-III Longest Span Forward in elderly persons. PMID- 26628899 TI - Quantitative Electroencephalography as a Diagnostic Tool for Alzheimer's Dementia in Adults with Down Syndrome. AB - BACKGROUND: Assessment of dementia in individuals with intellectual disability is complex due to great inter-individual variability in cognitive function prior to dementia and a lack of standardized instruments. Studies have indicated that quantitative electroencephalography (qEEG) results may be used as a diagnostic marker for dementia. The aim of this study was to examine the value of qEEG in the diagnostic evaluation of dementia in patients with Down syndrome (DS). METHOD: The study included 21 patients with DS and mild-to-moderate dementia due to Alzheimer's disease (DS-AD) and 16 age-matched adults with DS without cognitive deterioration assessed by the informant-based Dementia Screening Questionnaire in Intellectual Disability (DSQIID). Conventional EEG was performed and analysed quantitatively using fast Fourier transformation. Outcomes were centroid frequency, peak frequency, absolute power, and relative power. RESULTS: In several regions of the brain, a significant decrease in the theta-1 band (4-7 Hz) was identified for the centroid frequency. A significant negative correlation was demonstrated between the mean of the centroid frequency of the theta-1 band and the total DSQIID score. CONCLUSION: We found that qEEG can detect a significant decrease in centroid frequency in a sample of patients with DS-AD as compared to a sample of adults with DS and no cognitive deterioration. PMID- 26628898 TI - Set-Shifting Ability Is Associated with Gray Matter Volume in Older People with Mild Cognitive Impairment. AB - BACKGROUND/AIMS: An understanding of the association between gray matter volume and executive functioning could provide strategies to reduce dementia risk in older people with mild cognitive impairment (MCI). METHODS: In a cross-sectional analysis, we assessed executive functioning in 83 older people with MCI using three standard neuropsychological tests: set shifting (difference between Trail Making Test Parts B and A), working memory (difference between Digit Span forward and backward from the Wechsler Adult Intelligence Scale-IV), and selective attention/response inhibition (difference between the second and third conditions of the color- and picture-word Stroop test). Gray matter volume was computed from brain MRIs and SIENAX from FSL software. RESULTS: Gray matter volume was significantly associated with set-shifting performance after accounting for age, gender, body mass index, education, and global cognition (standardized beta = 0.376, p = 0.001), but not with working memory or selective attention/response inhibition. CONCLUSION: The executive function of set-shifting ability was correlated with gray matter volume in older people with MCI. PMID- 26628900 TI - Neuropsychological Evaluation and Cerebral Blood Flow Effects of Apolipoprotein E4 in Alzheimer's Disease Patients after One Year of Treatment: An Exploratory Study. AB - BACKGROUND: Alzheimer's disease (AD) is affected by apolipoprotein E (ApoE); however, its effects assessed by means of cognitive tests and by neuroimaging have not been sufficiently studied. METHODS: We administered the Alzheimer's Disease Assessment Scale (ADAS) and single-photon emission computed tomography imaging in patients with AD medicated with donepezil at baseline and after 1 year. Patients were classified as with or without ApoE4 and we evaluated the progress of AD. RESULTS: Analysis of covariance showed that cerebral blood flow after 1 year in subjects with ApoE4 is significantly reduced in some areas including the left lenticular nucleus, left thalamus, and right hippocampus compared with subjects without ApoE4. Paired t tests showed significantly reduced blood flow in several regions including the right hippocampus in subjects with ApoE4 and significant deterioration of ideational praxis in subjects without ApoE4. CONCLUSION: This study provides evidence that supports the notion of ApoE4 playing an important role in the progress of AD. PMID- 26628901 TI - Partial purification and functional characterization of Ts19 Frag-I, a novel toxin from Tityus serrulatus scorpion venom. AB - BACKGROUND: The yellow scorpion Tityus serrulatus (Ts) is responsible for the highest number of accidents and the most severe scorpion envenoming in Brazil. Although its venom has been studied since the 1950s, it presents a number of orphan peptides that have not been studied so far. The objective of our research was to isolate and identify the components present in the fractions VIIIA and VIIIB of Ts venom, in order to search for a novel toxin. The major isolated toxins were further investigated for macrophage modulation. METHODS: The fractions VIIIA and VIIIB, obtained from Ts venom cation exchange chromatography, were rechromatographed on a C18 column (4.6 * 250 mm) followed by a reversed phase chromatography using another C18 column (2.1 * 250 mm). The main eluted peaks were analyzed by MALDI-TOF and Edman's degradation and tested on macrophages. RESULTS: The previously described toxins Ts2, Ts3-KS, Ts4, Ts8, Ts8 propeptide, Ts19 Frag-II and the novel peptide Ts19 Frag-I were isolated from the fractions VIIIA and VIIIB. Ts19 Frag-I, presenting 58 amino acid residues, a mass of 6,575 Da and a theoretical pI of 8.57, shares high sequence identity with potassium channel toxins (KTx). The toxins Ts4, Ts3-KS and the partially purified Ts19 Frag-I did not produce cytotoxic effects on macrophage murine cells line (J774.1). On the other hand, Ts19 Frag-I induced the release of nitric oxide (NO) by macrophages, while Ts4 and Ts3-KS did not affect the NO production at the tested concentration (50 MUg/mL). At the same concentration, Ts19 Frag-I and Ts3 KS increased the production of interleukin-6 (IL-6). Ts19 Frag-I and Ts4 did not induce the release of IL-10, IL-1beta or tumor necrosis factor-alpha by macrophage cells using the tested concentration (50 MUg/mL). CONCLUSIONS: We partially purified and determined the complete sequence and chemical/physical parameters of a new beta-KTx, denominated Ts19 Frag-I. The toxins Ts4, Ts3-KS and Ts19 Frag-I showed no cytotoxicity toward macrophages and induced IL-6 release. Ts19 Frag-I also induced the release of NO, suggesting a pro-inflammatory activity. PMID- 26628902 TI - Third-line antiretroviral therapy in Africa: effectiveness in a Southern African retrospective cohort study. AB - BACKGROUND: An increasing number of patients in Africa are experiencing virologic failure on second-line antiretroviral therapy (ART) and those who develop resistance to protease inhibitors (PI) will require third-line ART, but no data on the outcomes of third-line are available from the region. We assessed the virologic outcomes and survival of patients started on salvage ART in a Southern African private sector disease management programme. METHODS: Retrospective observational cohort study with linkage to the national death register. Adults (>=18 years) who started salvage ART between July 2007 and December 2011 were included. Salvage ART was defined by inclusion of darunavir or tipranavir in an ART regimen after having failed another PI. For Kaplan-Meier (KM) analysis, patients were followed up until event, or censored at death (only for virologic outcomes), leaving the programme, or April 2014. RESULTS: 152 patients were included. Subtype was known for 113 patients: 111 (98 %) were infected with subtype C. All 152 had a genotype resistance test demonstrating major PI resistance mutations. Salvage drugs included were: darunavir/ritonavir (n = 149), tipranavir/ritonavir (n = 3), raltegravir (n = 58), and etravirine (n = 8). Median follow-up was 2.5 years (IQR = 1.5-3.3). 82.9 % achieved a viral load <=400 copies/ml and 71.1 % <=50 copies/ml. By the end of the study 17 (11.2 %) of the patients had died. The KM estimate of cumulative survival was 87.2 % at 2000 days. CONCLUSIONS: Virologic suppression was comparable to that demonstrated in clinical trials and observational studies of salvage ART drugs conducted in other regions. Few deaths occurred during short term follow-up. Third-line regimens for patients with multidrug resistant subtype C HIV in Africa are virologically and clinically effective. PMID- 26628903 TI - Performance of single and multi-atlas based automated landmarking methods compared to expert annotations in volumetric microCT datasets of mouse mandibles. AB - BACKGROUND: Here we present an application of advanced registration and atlas building framework DRAMMS to the automated annotation of mouse mandibles through a series of tests using single and multi-atlas segmentation paradigms and compare the outcomes to the current gold standard, manual annotation. RESULTS: Our results showed multi-atlas annotation procedure yields landmark precisions within the human observer error range. The mean shape estimates from gold standard and multi-atlas annotation procedure were statistically indistinguishable for both Euclidean Distance Matrix Analysis (mean form matrix) and Generalized Procrustes Analysis (Goodall F-test). Further research needs to be done to validate the consistency of variance-covariance matrix estimates from both methods with larger sample sizes. CONCLUSION: Multi-atlas annotation procedure shows promise as a framework to facilitate truly high-throughput phenomic analyses by channeling investigators efforts to annotate only a small portion of their datasets. PMID- 26628904 TI - Review: Miglitol has potential as a therapeutic drug against obesity. AB - The number of obese patients has increased annually worldwide. Therefore, there is a strong need to develop a new effective and safe anti-obesity drug. Miglitol is an alpha-glucosidase inhibitor (alphaGI) that is commonly used as an anti diabetic drug, and there is growing evidence that it also has anti-obesity effects. Miglitol has been shown to reduce body weight and ameliorate insulin resistance in both clinical trials with adult patients and in rodent models of obesity. Although the specific mechanism of action of this effect remains unclear, some mechanisms have been suggested through experimental results. Miglitol has been shown to inhibit adipogenesis of white adipocytes in vitro, activate brown adipose tissue (BAT) in mice, influence bile acid metabolism in mice, and regulate the secretion of incretin hormones in humans. Among these results, we consider that BAT activation is likely the definitive mediator of miglitol's anti-obesity effect. A unique advantage of miglitol is that it is already used as an anti-diabetic drug with no severe side effects, whereas many of the anti-obesity drugs developed to date have been withdrawn because of their severe side effects. Miglitol is currently used clinically in a limited number of countries. In this review, we provide an overview of the state of research on miglitol for obesity treatment, emphasizing that it warrants more detailed attention. Overall, we demonstrate that miglitol shows good potential as a therapeutic for the treatment of obesity. Thus, we believe that further investigations of how it exerts its anti-obesity effect will likely contribute to the development of a new class of safe and effective drugs against obesity. PMID- 26628906 TI - Fasting total ghrelin levels are increased in patients with adolescent idiopathic scoliosis. AB - BACKGROUND: A control study was designed to investigate circulating Ghrelin levels in adolescent girls with adolescent idiopathic scoliosis (AIS) and controls. Eating behavioral disorders, endocrine disorders, abnormal growth pattern and osteopenia have been well documented in AIS. Ghrelin is an orexigenic hormone produced by the stomach which reflects body weight changes and stimulates growth hormone secretion. Recently, it has been shown to be associated with bone metabolism and eating behavior. However, the circulating levels of ghrelin have never been evaluated in AIS patients. METHODS: Forty nine AIS girls and 15 controls were included. Anthropometric parameters and fasting circulating total ghrelin were measured. Curve severity was evaluated in AIS girls. The relationships between ghrelin and age, body weight, height, body mass index (BMI), BMI Z-score and corrected anthropometric parameters were analyzed in AIS girls and controls. RESULTS: There was no significant difference in body weight, height, BMI or BMI Z-score between AIS and controls. Serum ghrelin level was 1.8 fold higher in AIS girls than in controls. Elevation of ghrelin levels remained significant when corrected BMI or corrected BMI Z-score were considered. Unlike in controls, positive correlations were found between ghrelin and age in AIS girls with a gradual increase of circulating ghrelin with age. CONCLUSIONS: We have observed significantly higher circulating ghrelin levels in AIS than in controls with a positive correlation with age. This pilot-study suggests that ghrelin signaling might play a role in the initiation or development of AIS. Further studies are needed to validate theses results. PMID- 26628907 TI - Critically ill patients with acute cholecystitis are at increased risk for extensive gallbladder inflammation. AB - BACKGROUND: Acute cholecystitis is a common diagnosis and surgery is the standard of care for young and fit patients. However, due to high risk of postoperative morbidity and mortality, surgical management of critically ill patients remains a controversy. It is not clear, whether the increased risk of perioperative complications associated with the management of critically ill patients with acute cholecystitis is secondary to reduced physiologic reserve per se or to the severity of gallbladder inflammation. METHODS: A retrospective analysis of prospectively collected data of patients undergoing laparoscopic cholecystectomy for acute cholecystitis in a university hospital over a three-year-period was performed. The ASA scores at the time of presentation were used to categorize patients into two groups. The study group consisted of critically ill patients with ASA 3 and 4, while the control group was made up of fit patients with ASA 1 and 2. Both groups were compared with regard to perioperative data, postoperative outcome and extent of gallbladder inflammation on histopathology. RESULTS: Two hundred and seventeen cases of acute cholecystitis with complete charts were available for analysis. The study group included 67 critically ill patients with ASA 3 and 4, while the control group included 150 fit patients with ASA 1 and 2. Both groups were comparable with regard to perioperative data. Histopathology confirmed severe cholecystitis in a significant number of cases in the study group compared to the control group (37 % vs. 18 %, p = 0.03). Significantly higher rates of morbidity and mortality were recorded in the study group (p < 0.05). Equally, significantly more patients from the study group were managed in the ICU (40 % vs. 8 %, p = 0.001). CONCLUSION: Critically ill patients presenting with acute cholecystitis are at increased risk for extensive gallbladder inflammation. The increased risk of morbidity and mortality seen in such patients might partly be secondary to severe acute cholecystitis. PMID- 26628908 TI - Authentication of commercial processed Glehniae Radix (Beishashen) by DNA barcodes. AB - BACKGROUND: The radix of Glehnia littoralis Fr. Schmidt ex Miq. (Beishashen), is often misidentified and adultered in Chinese medicine. Its seven common adulterants include Chuanminshen violaceum Sheh et Shan (Chuanmingshen), Changium smyrnioides Wolff (Mingdangshen), Sphallerocarpus gracilis (Bess.) K.-Pol. (Miguoqin), Adenophora polyantha Nakai (Shishashen), Silene tatarinowii Regel (Shishengyingzicao), Adenophora tetraphylla (Thunb.) Fisch (Lunyeshashen) and Adenophora stricta Miq. (Shashen). This study aims to evaluate the feasibility of the second internal transcribed spacer (ITS2) DNA barcoding to discriminate between Glehniae Radix and its common adulterants. METHODS: In this study, we collected 46 samples of G. littoralis and 59 samples of its seven common adulterants. Genomic DNA sequences were extracted from samples, including original plants and commercially processed crude drugs. The ITS2 of the ribosomal DNA sequences were amplified and sequenced bi-directionally. The sequences were assembled by CodonCode Aligner 3.5.7. The descriptive data analysis was conducted and neighbor-joining (NJ) phylogenetic tree was constructed by MEGA 5.0 in accordance with the kimura 2 -parameter (K2P) model. The identification efficiency was evaluated based on the BLAST1 methods. The ITS2 secondary structures were predicted and compared between Glehniae Radix and its adulterants by the ITS2 database. RESULTS: As the 46 ITS2 sequences of G. littoralis were identical to each other, the identification efficiency of the ITS2 region was 100 %. A NJ tree based on the ITS2 sequences, and the predicted secondary structures of ITS2, distinguished Glehniae Radix from its adulterants. CONCLUSION: DNA barcoding based on ITS2 distinguished commercial processed Glehniae Radix from common herbal adulterants. PMID- 26628909 TI - What do we understand from clinical and mechanistic studies on acupuncture treatment for hypertension? AB - The outcome of acupuncture on hypertension treatment is inconclusive. This study aims to evaluate the influence of acupuncture on hypertension, based on findings from mechanistic studies over the course of decades particularly those conducted at the University of California, Irvine. Low-current and low-frequency electroacupuncture (EA) at P5-6 (overlying the median nerve) and S36-37 (overlying the deep peroneal nerve) reduced high blood pressure in a subset of patients (~70 %) with mild-to-moderate hypertension, in a slow-onset (4-8 weeks) but long-lasting (1-2 months) manner. EA inhibited cardiovascular sympathoexcitatory neurons through activation of neurons in the arcuate nucleus of the hypothalamus, the ventrolateral periaqueductal gray in the midbrain and the nucleus raphe pallidus in the medulla, through inhibiting the activity of premotor sympathetic neurons in the rostral ventrolateral medulla (rVLM). Several neurotransmitters such as glutamate, acetylcholine, opioids, GABA, nociceptin, serotonin and endocannabinoids were involved in this EA-induced hypotensive response. The long-lasting inhibition of hypertension induced by EA was related to opioids and GABA in the rVLM, neural circuitry between the arcuate and ventrolateral periaqueductal gray, and prolongation of the increase in preproenkephalin mRNA levels and enkephalin levels in the rVLM and arcuate. Moreover, the long-lasting inhibition of sympathetic activity by EA was confirmed in EA-treated hypertensive patients with decreased levels of norepinephrine, renin and aldosterone. PMID- 26628910 TI - Minimally invasive facet restoration implant for chronic lumbar zygapophysial pain: 1-year outcomes. AB - BACKGROUND: The zygapophysial (facet) joint is the primary pain generator in one third of chronic low back pain cases. Current treatment options include temporarily palliative nonsurgical approaches, facet injections, radiofrequency denervation, and, rarely, lumbar arthrodesis. The purpose of this study was to assess the safety and effectiveness of a minimally invasive implant intended to restore facet joint function in patients with chronic lumbar facetogenic pain. METHODS: This prospective, multi-center feasibility study enrolled patients with confirmed lumbar facetogenic joint pain at 1 or 2 levels who underwent at least 6 months of unsuccessful nonoperative care. Patients received a minimally invasive implant (Glyder(r) Facet Restoration Device, Zyga Technology, Inc., Minnetonka, MN) intended to restore facet joint function while preserving the native anatomy. Main outcomes included back pain severity using a visual analogue scale, back specific disability using the Oswestry Disability Index (ODI), and adverse events adjudicated by an independent Clinical Events Committee. RESULTS: Of 40 enrolled patients, 37 patients received the facet restoration implant and 34 patients had complete 1-year follow-up data available. Over the 1-year follow-up period, back pain severity decreased 41% and ODI decreased 34%, on average. Freedom from a device- or procedure-related serious adverse event through 1 year was 84%. Implant migration was observed in 3 patients and implant expulsion from the facet joint occurred in 3 patients. In total, 2 (5.4%) patients underwent implant removal through 1 year post-treatment. CONCLUSIONS: A minimally invasive facet restoration implant is a promising treatment option in select patients with chronic lumbar zygapophysial pain who have exhausted nonsurgical treatments, with therapeutic benefit persisting at 1 year follow-up. PMID- 26628905 TI - The neurocognitive functioning in bipolar disorder: a systematic review of data. AB - BACKGROUND: During the last decades, there have been many different opinions concerning the neurocognitive function in Bipolar disorder (BD). The aim of the current study was to perform a systematic review of the literature and to synthesize the data in a comprehensive picture of the neurocognitive dysfunction in BD. METHODS: Papers were located with searches in PubMed/MEDLINE, through June 1st 2015. The review followed a modified version of the recommendations of the Preferred Items for Reporting of Systematic Reviews and Meta-Analyses statement. RESULTS: The initial search returned 110,403 papers. After the deletion of duplicates, 11,771 papers remained for further evaluation. Eventually, 250 were included in the analysis. CONCLUSION: The current review supports the presence of a neurocognitive deficit in BD, in almost all neurocognitive domains. This deficit is qualitative similar to that observed in schizophrenia but it is less severe. There are no differences between BD subtypes. Its origin is unclear. It seems it is an enduring component and represents a core primary characteristic of the illness, rather than being secondary to the mood state or medication. This core deficit is confounded (either increased or attenuated) by the disease phase, specific personal characteristics of the patients (age, gender, education, etc.), current symptomatology and its treatment (especially psychotic features) and long term course and long-term exposure to medication, psychiatric and somatic comorbidity and alcohol and/or substance abuse. PMID- 26628911 TI - A novel bifunctional GH51 exo-alpha-l-arabinofuranosidase/endo-xylanase from Alicyclobacillus sp. A4 with significant biomass-degrading capacity. AB - BACKGROUND: Improving the hydrolytic performance of xylanolytic enzymes on arabinoxylan is of importance in the ethanol fermentation industry. Supplementation of debranching (arabinofuranosidase) and depolymerizing (xylanase) enzymes is a way to address the problem. In the present study, we identified a bifunctional alpha-l-arabinofuranosidase/endo-xylanase (Ac-Abf51A) of glycoside hydrolase family 51 in Alicyclobacillus sp. strain A4. Its biochemical stability and great hydrolysis efficiency against complex biomass make it a potential candidate for the production of biofuels. RESULTS: The gene encoding Ac-Abf51A was cloned. The comparison of its sequence with reference proteins having resolved 3D-structures revealed nine key residues involved in catalysis and substrate-binding interaction. Recombinant Ac-Abf51A produced in Escherichia coli showed optimal activity at pH 6.0 and 60 degrees C with 4 nitrophenyl-alpha-l-arabinofuranoside as the substrate. The enzyme exhibited an exo-type mode of action on polyarabinosides by catalyzing the cleavage of alpha 1,2- and alpha-1,3-linked arabinofuranose side chains in sugar beet arabinan and water-soluble wheat arabinoxylan and alpha-1,5-linked arabinofuranosidic bonds in debranched sugar beet arabinan. Surprisingly, it had capacity to release xylobiose and xylotriose from wheat arabinoxylan and was active on xylooligosaccharides (xylohexaose 1.2/mM/min, xylopentaose 6.9/mM/min, and xylotetraose 19.7/mM/min), however a lower level of activity. Moreover, Ac-Abf51A showed greater synergistic effect in combination with xylanase (2.92-fold) on wheat arabinoxylan degradation than other reported enzymes, for the amounts of arabinose, xylose, and xylobiose were all increased in comparison to that by the enzymes acting individually. CONCLUSIONS: This study for the first time reports a GH51 enzyme with both exo-alpha-l-arabinofuranosidase and endo-xylanase activities. It was stable over a broad pH range and at high temperature, and showed greater synergistic effect with xylanase on the degradation of wheat arabinoxylan than other counterparts. The distinguished synergy might be ascribed to its bifunctional alpha-l-arabinofuranosidase/xylanase activity, which may represent a possible way to degrade biomass at lower enzyme loadings. PMID- 26628912 TI - Metabolic engineering of Acinetobacter baylyi ADP1 for removal of Clostridium butyricum growth inhibitors produced from lignocellulosic hydrolysates. AB - BACKGROUND: Pretreatment of lignocellulosic biomass can produce inhibitory compounds that are harmful for microorganisms used in the production of biofuels and other chemicals from lignocellulosic sugars. Selective inhibitor removal can be achieved with biodetoxification where microorganisms catabolize the inhibitors without consuming the sugars. We engineered the strictly aerobic Acinetobacter baylyi ADP1 for detoxification of lignocellulosic hydrolysates by removing the gene for glucose dehydrogenase, gcd, which catalyzes the first step in its glucose catabolism. RESULTS: The engineered A. baylyi ADP1 strain was shown to be incapable of consuming the main sugar components of lignocellulosic hydrolysates, i.e., glucose, xylose, and arabinose, but rapidly utilized acetate and formate. Formate was consumed during growth on acetate and by stationary phase cells, and this was enhanced in the presence of a common aromatic inhibitor of lignocellulosic hydrolysates, 4-hydroxybenzoate. The engineered strain tolerated glucose well up to 70 g/l, and the consumption of glucose, xylose, or arabinose was not observed in prolonged cultivations. The engineered strain was applied in removal of oxygen, a gaseous inhibitor of anaerobic fermentations. Co-cultivation with the A. baylyi ADP1 gcd knockout strain under initially aerobic conditions allowed the strictly anaerobic Clostridium butyricum to grow and produce hydrogen (H2) from sugars of the enzymatic rice straw hydrolysate. CONCLUSIONS: We demonstrated that the model organism of bacterial genetics and metabolism, A. baylyi ADP1, could be engineered to be an efficient biodetoxification strain of lignocellulosic hydrolysates. Only one gene knockout was required to completely eliminate sugar consumption and the strain could be used in production of anaerobic conditions for the strictly anaerobic hydrogen producer, C. butyricum. Because of these encouraging results, we believe that A. baylyi ADP1 is a promising candidate for the detoxification of lignocellulosic hydrolysates for bioprocesses. PMID- 26628913 TI - Metasecretome analysis of a lignocellulolytic microbial consortium grown on wheat straw, xylan and xylose. AB - BACKGROUND: Synergistic action of different enzymes is required to complete the degradation of plant biomass in order to release sugars which are useful for biorefining. However, the use of single strains is often not efficient, as crucial parts of the required enzymatic machinery can be absent. The use of microbial consortia bred on plant biomass is a way to overcome this hurdle. In these, secreted proteins constitute sources of relevant enzyme cocktails. Extensive analyses of the proteins secreted by effective microbial consortia will contribute to a better understanding of the mechanism of lignocellulose degradation. RESULTS: Here, we report an analysis of the proteins secreted by a microbial consortium (metasecretome) that was grown on either wheat straw (RWS), xylose or xylan as the carbon sources. Liquid chromatography-tandem mass spectrometry was used to analyze the proteins in the supernatants. Totals of 768 (RWS), 477 (xylose) and 103 (xylan) proteins were identified and taxonomically and functionally classified. In RWS, the proteins were mostly affiliated with Sphingobacterium-like consortium members (~50 %). Specific abundant protein clusters were predicted to be involved in polysaccharide transport and/or sensing (TonB-dependent receptors). In addition, proteins predicted to degrade plant biomass, i.e. endo-1,4-beta-xylanases, alpha-l-arabinofuranosidases and alpha-l fucosidases, were prominent. In the xylose-driven consortium, most secreted proteins were affiliated with those from Enterobacteriales (mostly Klebsiella species), whereas in the xylan-driven one, they were related to Flavobacterium like ones. Notably, the metasecretomes of the consortia growing on xylose and xylan contained proteins involved in diverse metabolic functions (e.g. membrane proteins, isomerases, dehydrogenases and oxidoreductases). CONCLUSIONS: An analysis of the metasecretomes of microbial consortia originating from the same source consortium and subsequently bred on three different carbon sources indicated that the major active microorganisms in the three final consortia differed. Importantly, diverse glycosyl hydrolases, predicted to be involved in (hemi)cellulose degradation (e.g. of CAZy families GH3, GH10, GH43, GH51, GH67 and GH95), were identified in the RWS metasecretome. Based on these results, we catalogued the RWS consortium as a true microbial enzyme factory that constitute an excellent source for the production of an efficient enzyme cocktail for the pretreatment of plant biomass. PMID- 26628914 TI - Effects of overexpression of a bHLH transcription factor on biomass and lipid production in Nannochloropsis salina. AB - BACKGROUND: Microalgae are considered promising alternative energy sources because they consume CO2 and accumulate large amounts of lipids that can be used as biofuel. Nannochloropsis is a particularly promising microalga due to its high growth rate and lipid content, and the availability of genomic information. Transcription factors (TFs) are global regulators of biological pathways by up- or down-regulation of related genes. Among these, basic helix-loop-helix (bHLH) TFs regulate growth, development, and stress responses in plants and animals, and have been identified in microalgae. We identified two bHLH TFs in the genome of N. salina CCMP1776, NsbHLH1, and NsbHLH2, and characterized functions of NsbHLH2 that may be involved in growth and nutrient uptake. RESULTS: We obtained NsbHLH2 overexpressing transformants of N. salina CCMP1776 by particle bombardment and confirmed that these were stable transformants. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting using antibodies against the FLAG tag that was attached at the end of the coding sequence confirmed the expression of the NsbHLH2 protein under various culture conditions. The qRT-PCR results also indicated that the endogenous and transgenic expression of NsbHLH2 was reduced under stressed conditions. Overexpression of NsbHLH2 led to increased growth rate in the early growth period, and concomitantly higher nutrient uptake, than wild type (WT). These enhanced growth and nutrient uptake resulted in increased productivities of biomass and FAME. For example, one of the transformants, NsbHLH2 3-6, showed increased biomass productivity by 36 % under the normal condition, and FAME productivity by 33 % under nitrogen limitation condition. Conclusively, the improved growth in the transformants can be associated with the enhanced nutrient uptake. We are currently assessing their potential for scale-up cultivation with positive outcomes. CONCLUSION: Overexpression of NsbHLH2 led to enhanced growth rate and nutrient uptake during the early growth phase, and increased biomass and FAME productivity, especially in the later period under normal and stressed conditions. Based on these results, we postulate that NsbHLH2 can be employed for the industrial production of biodiesel from N. salina. PMID- 26628915 TI - Utilising the native plasmid, pCA2.4, from the cyanobacterium Synechocystis sp. strain PCC6803 as a cloning site for enhanced product production. AB - BACKGROUND: The use of photosynthetic autotrophs and in particular the model organism Synechocystis PCC6803 is receiving much attention for the production of sustainable biofuels and other economically useful products through metabolic engineering. Optimisation of metabolic-engineered organisms for high-level sustained production of product is a key element in the manipulation of this organism. A limitation to the utilisation of metabolically-engineered Synechocystis PCC6803 is the availability of strong controllable promoters and stable gene dosage methods for maximising gene expression and subsequent product formation following genetic manipulation. RESULTS: A native Synechocystis PCC6803 small plasmid, pCA2.4, is consistently maintained at a copy level of up to 7 times that of the polyploid chromosome. As this plasmid is stable during cell division, it is potentially an ideal candidate for maximising gene dosage levels within the organism. Here, we describe the construction of a novel expression vector generated from the native plasmid, pCA2.4. To investigate the feasibility of this new expression system, a yellow fluorescent protein (YFP) encoding gene was cloned downstream of the strong Ptrc promoter and integrated into a predicted neutral site within the pCA2.4 plasmid. The stability of the integrated construct was monitored over time compared to a control strain containing an identical YFP expressing construct integrated at a known neutral site in a chromosomal location. CONCLUSIONS: A significantly higher fluorescence level of the yellow fluorescent protein was observed when its encoded gene was integrated into the pCA2.4 native plasmid when compared to the isogenic chromosomally integrated control strain. On average, a minimum of 20-fold higher fluorescence level could be achieved from integration into the native plasmid. Fluorescence was also monitored as a function of culture time and demonstrated to be stable over multiple sub-cultures even after the removal of selective pressure. Therefore, the native small plasmid, pCA2.4 may be utilised to stably increase gene expression levels in Synechocystis PCC6803. With the complementary utilisation of an inducible promoter system, rapid generation of commodity-producing Synechocystis PCC6803 strains having high level, controlled expression may be more achievable. PMID- 26628916 TI - Engineering a novel glucose-tolerant beta-glucosidase as supplementation to enhance the hydrolysis of sugarcane bagasse at high glucose concentration. AB - BACKGROUND: Most beta-glucosidases reported are sensitive to the end product (glucose), making it the rate limiting component of cellulase for efficient degradation of cellulose through enzymatic route. Thus, there are ongoing interests in searching for glucose-tolerant beta-glucosidases, which are still active at high glucose concentration. Although many beta-glucosidases with different glucose-tolerance levels have been isolated and characterized in the past decades, the effects of glucose-tolerance on the hydrolysis of cellulose are not thoroughly studied. RESULTS: In the present study, a novel beta-glucosidase (Bgl6) with the half maximal inhibitory concentration (IC 50) of 3.5 M glucose was isolated from a metagenomic library and characterized. However, its poor thermostability at 50 degrees C hindered the employment in cellulose hydrolysis. To improve its thermostability, random mutagenesis was performed. A thermostable mutant, M3, with three amino acid substitutions was obtained. The half-life of M3 at 50 degrees C is 48 h, while that of Bgl6 is 1 h. The K cat/K m value of M3 is 3-fold higher than that of Bgl6. The mutations maintained its high glucose tolerance with IC 50 of 3.0 M for M3. In a 10-h hydrolysis of cellobiose, M3 completely converted cellobiose to glucose, while Bgl6 reached a conversion of 80 %. Then their synergistic effects with the commercial cellulase (Celluclast 1.5 L) on hydrolyzing pretreated sugarcane bagasse (SCB) were investigated. The supplementation of Bgl6 or mutant M3 to Celluclast 1.5 L significantly improved the SCB conversion from 64 % (Celluclast 1.5 L alone) to 79 % (Bgl6) and 94 % (M3), respectively. To further evaluate the application potential of M3 in high solids cellulose hydrolysis, such reactions were performed at initial glucose concentration of 20-500 mM. Results showed that the supplementation of mutant M3 enhanced the glucose production from SCB under all the conditions tested, improving the SCB conversion by 14-35 %. CONCLUSIONS: These results not only clearly revealed the significant role of glucose-tolerance in cellulose hydrolysis, but also showed that mutant M3 may be a potent candidate for high solids cellulose refining. PMID- 26628917 TI - Comparative assessment of native and heterologous 2-oxo acid decarboxylases for application in isobutanol production by Saccharomyces cerevisiae. AB - BACKGROUND: Decarboxylation of alpha-ketoisovalerate to isobutyraldehyde is a key reaction in metabolic engineering of Saccharomyces cerevisiae for isobutanol production with published studies relying on overexpression of either the native ARO10 gene or of the Lactococcus lactis kivD decarboxylase gene resulting in low enzymatic activities. Here, we compare relevant properties for isobutanol production of Aro10, KivD and an additional, less studied, L. lactis decarboxylase KdcA. RESULTS: To eliminate interference by native decarboxylases, each 2-oxo acid decarboxylase was overexpressed in a 'decarboxylase-negative' (pdc1Delta pdc5Delta pdc6Delta aro10Delta) S. cerevisiae background. Kinetic analyses in cell extracts revealed a superior V max/K m ratio of KdcA for alpha ketoisovalerate and a wide range of linear and branched-chain 2-oxo acids. However, KdcA also showed the highest activity with pyruvate which, in engineered strains, can contribute to formation of ethanol as a by-product. Removal of native decarboxylase genes eliminated growth on valine as sole nitrogen source and subsequent complementation of this growth impairment by expression of each decarboxylase indicated that based on the increased growth rate, the in vivo activity of KdcA with alpha-ketoisovalerate was higher than that of KivD and Aro10. Moreover, during oxygen-limited incubation in the presence of glucose, strains expressing kdcA or kivD showed a ca. twofold higher in vivo rate of conversion of alpha-ketoisovalerate into isobutanol than an ARO10-expressing strain. Finally, cell extracts from cultures grown on different nitrogen sources revealed increased activity of constitutively expressed KdcA after growth on both valine and phenylalanine, while KivD and Aro10 activity was only increased after growth on phenylalanine suggesting a difference in the regulation of these enzymes. CONCLUSIONS: This study illustrates important differences in substrate specificity, enzyme kinetics and functional expression between different decarboxylases in the context of isobutanol production and identifies KdcA as a promising alternative decarboxylase not only for isobutanol production but also for other branched-chain and linear alcohols. PMID- 26628918 TI - Emergence of clonal chromosomal alterations during the mesenchymal stromal cell cultivation. AB - BACKGROUND: Use of human mesenchymal stromal cells (MSCs) is a promising strategy for cell therapy in injured tissues recovery. However, MSCs acquire genetic changes when cultivated in vitro that make them more susceptible to undergo neoplastic transformation. Therefore, genomic integrity of stem cells should be monitored carefully for the use in basic research and clinical trials, including karyotype analysis to confirm the absence of genetic instability. Here, we report a case of a male 67-year-old patient selected to join the study: "Autologous transplantation of mesenchymal cells for treatment of severe and refractory ischemic cardiomyopathy". He underwent nephrectomy for malignant tumor on the right kidney. Cytogenetic analysis on a bone marrow sample showed a normal karyotype: 46,XY[20]. However, the MSC at second passage showed a hyperdiploid clone, with clonal trisomies of chromosomes 4, 5, 10 and X. In order to investigate more, another sample from the same patient was used for a second cultivation and, at third passage, these cells showed a clonal translocation t(9;18)(p24;q11). The recurrent aberrations in MSC may indicate the beginning of a spontaneous transformation in culture, so, these cells were not used for cell therapy. Several analyses were performed at the Center for Cell Technology (152 samples), however this was the only case to show clonal cytogenetic abnormalities. Interestingly, two distinct clonal alterations were seen in two parallel cell cultivations from the same patient, suggesting a propensity for genetic instability. This highlights the need to evaluate these cells on a case by-case basis, especially in patients with a history of cancer. Although there is controversy about the use of cells with cytogenetic abnormality for therapy, because their tumorigenic doubtful potential, we decided against the use of these cells for regenerative medicine. CASE PRESENTATION: Here, we report a case of a male 67-year-old patient selected to join the study: "Autologous transplantation of mesenchymal cells for treatment of severe and refractory ischemic cardiomyopathy". He underwent nephrectomy for malignant tumor on the right kidney. Cytogenetic analysis on a bone marrow sample showed a normal karyotype: 46,XY[20]. However, the MSC at second passage showed a hyperdiploid clone, with clonal trisomies of chromosomes 4, 5, 10 and X. In order to investigate more, another sample from the same patient was used for a second cultivation and, at third passage, these cells showed a clonal translocation t(9;18)(p24;q11). The recurrent aberrations in MSC may indicate the beginning of a spontaneous transformation in culture, so, these cells were not used for cell therapy. Several analyses were performed at the Center for Cell Technology(152 samples), however this was the only case to show clonal cytogenetic abnormalities. Interestingly, two distinct clonal alterations were seen in two parallel cell cultivations from the same patient, suggesting a propensity for genetic instability. This highlights the need to evaluate these cells on a case-by-case basis, especially in patients with a history of cancer. CONCLUSIONS: Although there is controversy about the use of cells with cytogenetic abnormality for therapy, because their tumorigenic doubtful potential, we decided against the use of these cells forregenerative medicine. PMID- 26628919 TI - A novel biclustering algorithm of binary microarray data: BiBinCons and BiBinAlter. AB - The biclustering of microarray data has been the subject of a large research. No one of the existing biclustering algorithms is perfect. The construction of biologically significant groups of biclusters for large microarray data is still a problem that requires a continuous work. Biological validation of biclusters of microarray data is one of the most important open issues. So far, there are no general guidelines in the literature on how to validate biologically extracted biclusters. In this paper, we develop two biclustering algorithms of binary microarray data, adopting the Iterative Row and Column Clustering Combination (IRCCC) approach, called BiBinCons and BiBinAlter. However, the BiBinAlter algorithm is an improvement of BiBinCons. On the other hand, BiBinAlter differs from BiBinCons by the use of the EvalStab and IndHomog evaluation functions in addition to the CroBin one (Bioinformatics 20:1993-2003, 2004). BiBinAlter can extracts biclusters of good quality with better p-values. PMID- 26628920 TI - A single bolus of high dose levothyroxine (L-T4) as a test in cases of suspected poor compliance to L-T4 therapy. AB - BACKGROUND: Though compliance (or adherence) problems, as well as inappropriate levothyroxine (L-T4) intake (e.g. with meal, other drugs or certain foods that can significantly affect absorption) are very common, the issue is often either not mentioned or even frankly denied by patients. CASE PRESENTATION: We describe three cases of patients who presented with high TSH (ranging from about 30 to 200 mIU/l), with concomitantly either high, normal or low free thyroxine (FT4), despite treatment with high doses of L-T4. The above mentioned problems with adjustment of L-T4 dose persisted for several months or even years. Coeliac disease screen was negative in all cases. In all these patients administration of a single bolus of L-T4 (1000 MUg) or two doses of 1000 MUg of L-T4 within 48 h resulted in a quick increase in FT4 (thus confirming proper absorption) and in normalization of TSH within a week. No adverse effects of administration of these high doses of L-T4 were observed. CONCLUSIONS: Our data support the efficacy, as well as safety of administration of single bolus of high dose L-T4 as a test for possible compliance/adherence problems. PMID- 26628921 TI - ADMIRE: analysis and visualization of differential methylation in genomic regions using the Infinium HumanMethylation450 Assay. AB - BACKGROUND: DNA methylation at cytosine nucleotides constitutes epigenetic gene regulation impacting cellular development and a wide range of diseases. Cytosine bases of the DNA are converted to 5-methylcytosine by the methyltransferase enzyme, acting as a reversible regulator of gene expression. Due to its outstanding importance in the epigenetic field, a number of lab techniques were developed to interrogate DNA methylation on a global range. Besides whole-genome bisulfite sequencing, the Infinium HumanMethylation450 Assay represents a versatile and cost-effective tool to investigate genome-wide changes of methylation patterns. RESULTS: Analysis of DNA Methylation In genomic REgions (ADMIRE) is an open source, semi-automatic analysis pipeline and visualization tool for Infinium HumanMethylation450 Assays with a special focus on ease of use. It features flexible experimental settings, quality control, automatic filtering, normalization, multiple testing, and differential analyses on arbitrary genomic regions. Publication-ready graphics, genome browser tracks, and table outputs include summary data and statistics, permitting instant comparison of methylation profiles between sample groups and the exploration of methylation patterns along the whole genome. ADMIREs statistical approach permits simultaneous large-scale analyses of hundreds of assays with little impact on algorithm runtimes. CONCLUSIONS: The web-based version of ADMIRE provides a simple interface to researchers with limited programming skills, whereas the offline version is suitable for integration into custom pipelines. ADMIRE may be used via our freely available web service at https://bioinformatics.mpi-bn.mpg.de without any limitations concerning the size of a project. An offline version for local execution is available from our website or GitHub (https://github.molgen.mpg.de/loosolab/admire). PMID- 26628922 TI - A rapid passage through a two-active-X-chromosome state accompanies the switch of imprinted X-inactivation patterns in mouse trophoblast stem cells. AB - BACKGROUND: In female mice, while the presence of two-active X-chromosomes characterises pluripotency, it is not tolerated in most other cellular contexts. In particular, in the trophoblastic lineage, impairment of paternal X (X(P)) inactivation results in placental defects. RESULTS: Here, we show that Trophoblast Stem (TS) cells can undergo a complete reversal of imprinted X inactivation without detectable change in cell-type identity. This reversal occurs through a reactivation of the X(P) leading to TS clones showing two active Xs. Intriguingly, within such clones, all the cells rapidly and homogeneously either re-inactivate the X(P) or inactivate, de novo, the X(M). CONCLUSION: This secondary non-random inactivation suggests that the two-active-X states in TS and in pluripotent contexts are epigenetically distinct. These observations also reveal a pronounced plasticity of the TS epigenome allowing TS cells to dramatically and accurately reprogram gene expression profiles. This plasticity may serve as a back-up system when X-linked mono-allelic gene expression is perturbed. PMID- 26628923 TI - Alteration of the foot center of pressure trajectory by an unstable shoe design. AB - BACKGROUND: Unstable sole designs have been used as functional or therapeutic tools for improving body stability during locomotion. It has been suggested that the narrow base of support under the feet generate perturbations that challenge the instability of different joints during motion, thereby forcing the body to modify its movement in order to maintain a stable gait. The purpose of the present study was to explore the correlation between the stability of the footwear-device and the magnitude of perturbation conveyed during gait. METHODS: Various levels of dynamic instability were achieved using a novel foot-worn platform with two adjustable convex rubber elements attached to its sole. A total of 20 healthy male adults underwent direct in-shoe pressure measurements while walking with the footwear device. Foot center of pressure (COP) and stride to stride variability measures were extracted to examine the correlation between the magnitude of the instability and the imposed perturbations during gait. RESULTS: A counterintuitive but significant correlation was found between stride to stride variability and the instability of the biomechanical elements. Moreover, there was significant correlation between the instability of the elements and the perturbations found in the COP trajectory. The linear model describing this correlation was found to be statistically significant. CONCLUSION: There was significantly negative correlation between the level of instability induced by the shoe design and the amount of perturbations conveyed during gait. This suggests that the external perturbation must remain within a certain range limit. Exceeding this limit can negatively affect the treatment and probably lead to opposite results. PMID- 26628924 TI - A comparative study of the feet of middle-aged women in Korea and the Maasai tribe. AB - BACKGROUND: Members of the Maasai tribe spend their days either barefoot or wearing traditional shoes made from recycled car tires. Although they walk long distances (up to 60 km) daily, they do not generally experience foot ailments. Here, we compared parameters associated with the feet, ankles, and gait of middle aged women in Korea and the Maasai tribe. METHODS: Foot length, calf circumference, hindfoot alignment, step length, cadence, and walking velocity were compared among 20 middle-aged Korean and bush-living Maasai women. Static and dynamic Harris mat footprints were taken to determine the distribution of forefoot pressure patterns during walking. We also compared several radiographic parameters with standing foot and ankle radiographs. RESULTS: The mean foot length and width were significantly longer in Maasai women. Interestingly, 38 ft (96 %) in the Maasai group showed a claw deformity of the toe (s). There were no statistically significant differences in gait-related indices and Harris mat findings between the two groups. On radiographic analysis, tibial anterior surface angle, tibial lateral surface angle, talonavicular coverage angle, talo first metatarsal angle, Meary angle, and naviculo-cuboidal overlap were significantly greater in the Maasai group, whereas hallux valgus angle and the first and second intermetatarsal angle were greater in the Korean group. CONCLUSIONS: Middle-aged women from the Maasai tribe showed a higher prevalence of abducted forefeet, everted hindfeet, and fallen medial longitudinal arches than did Korean women, while Korean women showed a higher prevalence of hallux valgus, a preserved medial longitudinal arch, and toes that are free from claw deformity. PMID- 26628925 TI - A note on utilising binary features as ligand descriptors. AB - It is common in cheminformatics to represent the properties of a ligand as a string of 1's and 0's, with the intention of elucidating, inter alia, the relationship between the chemical structure of a ligand and its bioactivity. In this commentary we note that, where relevant but non-redundant features are binary, they inevitably lead to a classifier capable of capturing only a linear relationship between structural features and activity. If, instead, we were to use relevant but non-redundant real-valued features, the resulting predictive model would be capable of describing a non-linear structure-activity relationship. Hence, we suggest that real-valued features, where available, are to be preferred in this scenario. PMID- 26628926 TI - The Application of Wavelet-Domain Hidden Markov Tree Model in Diabetic Retinal Image Denoising. AB - The wavelet-domain Hidden Markov Tree Model can properly describe the dependence and correlation of fundus angiographic images' wavelet coefficients among scales. Based on the construction of the fundus angiographic images Hidden Markov Tree Models and Gaussian Mixture Models, this paper applied expectation-maximum algorithm to estimate the wavelet coefficients of original fundus angiographic images and the Bayesian estimation to achieve the goal of fundus angiographic images denoising. As is shown in the experimental result, compared with the other algorithms as mean filter and median filter, this method effectively improved the peak signal to noise ratio of fundus angiographic images after denoising and preserved the details of vascular edge in fundus angiographic images. PMID- 26628927 TI - Medical Images Fusion with Patch Based Structure Tensor. AB - Nowadays medical imaging has played an important role in clinical use, which provide important clues for medical diagnosis. In medical image fusion, the extraction of some fine details and description is critical. To solve this problem, a modified structure tensor by considering similarity between two patches is proposed. The patch based filter can suppress noise and add the robustness of the eigen-values of the structure tensor by allowing the use of more information of far away pixels. After defining the new structure tensor, we apply it into medical image fusion with a multi-resolution wavelet theory. The features are extracted and described by the eigen-values of two multi-modality source data. To test the performance of the proposed scheme, the CT and MR images are used as input source images for medical image fusion. The experimental results show that the proposed method can produce better results compared to some related approaches. PMID- 26628928 TI - The Influence of Corn Silk Polysaccharide on Signal Pathway of TGF-beta1 in Type 2 Diabetic Mellitus Rat. AB - In prevention stage, comparing with normal control group, triglycerides, blood sugar (BG), 24-hour urinary protein and cholesterol (CHO) were higher in T2DM group, but weight and urea nitrogen (BUN) was less in it. 24-hour urinary protein and cholesterol (CHO) were higher in T2DM group than the intervention group. 24 hour urinary protein and BG in the intervention group were higher than normal control group, but BUN is less than normal control group; In the intervention group the weight of kidney and weight of rat were also higher than T2DM group, but CHO and 24-hour urinary protein were less than T2DM group. The expression of TGF-beta1 in T2DM group were more than the other groups. In treatment stage, serum creatinine (Cr), weight, BG and CHO, TGand 24-hour urinary protein quantitative were significantly higher in the DN rats than those in the normal control rats (P>0.05). The expression level of TGF-beta1 and triglyceride level in the corn silk dihydroxycorn silk3 treated group were obviously lower than those in the DN rats. PMID- 26628929 TI - Research on an Improved Medical Image Enhancement Algorithm Based on P-M Model. AB - Image enhancement can improve the detail of the image and so as to achieve the purpose of the identification of the image. At present, the image enhancement is widely used in medical images, which can help doctor's diagnosis. IEABPM (Image Enhancement Algorithm Based on P-M Model) is one of the most common image enhancement algorithms. However, it may cause the lost of the texture details and other features. To solve the problems, this paper proposes an IIEABPM (Improved Image Enhancement Algorithm Based on P-M Model). Simulation demonstrates that IIEABPM can effectively solve the problems of IEABPM, and improve image clarity, image contrast, and image brightness. PMID- 26628930 TI - Workspace Analysis and Optimization of 3-PUU Parallel Mechanism in Medicine Base on Genetic Algorithm. AB - A novel 3-PUU parallel robot was put forward, on which kinematic analysis was conducted to obtain its inverse kinematics solution, and on this basis, the limitations of the sliding pair and the Hooke joint on the workspace were analyzed. Moreover, the workspace was solved through the three dimensional limit search method, and then optimization analysis was performed on the workspace of this parallel robot, which laid the foundations for the configuration design and further analysis of the parallel mechanism, with the result indicated that this type of robot was equipped with promising application prospect. In addition that, the workspace after optimization can meet more requirements of patients. PMID- 26628931 TI - Biological Monitoring of Air Pollutants and Its Influence on Human Beings. AB - Monitoring air pollutants via plants is an economic, convenient and credible method compared with the traditional ways. Plants show different damage symptoms to different air pollutants, which can be used to determine the species of air pollutants. Besides, pollutants mass concentration scope can be estimated by the damage extent of plants and the span of polluted time. Based on the domestic and foreign research, this paper discusses the principles, mechanism, advantages and disadvantages of plant-monitoring, and exemplifies plenty of such plants and the minimum mass concentration and pollution time of the plants showing damage symptoms. Finally, this paper introduced the human health effects of air pollutants on immune function of the body, such as decrease of the body's immune function, decline of lung function, respiratory and circulatory system changes, inducing and promoting human allergic diseases, respiratory diseases and other diseases. PMID- 26628932 TI - Liquid Fermentation of Ganoderma applanatum and Antioxidant Activity of Exopolysaccharides. AB - The medium composition and fermentation conditions of Ganoderma applanatum(GA) strain were optimized by the liquid shake flask fermentation, and the antioxidant activity of exopolysaccharides was investigated. The results showed that the optimal conditions of the liquid fermentation of GA strain were as follows: Carbon source was corn powder, nitrogen source was soy powder, the initial pH was 6.0, the inoculum size was 8%, the fermentation temperature was 32(o)C, the fermentation time was 7 d. The exopolysaccharides of GA strain could scavenge hydroxyl radicals(HR) and superoxide anion radicals(SAR), and the concentration of exopolysaccharides was positively related to the antioxidant activity. PMID- 26628933 TI - Early Detection of Lung Cancer Using Nano-Nose - A Review. AB - Lung cancer is one of the malignancies causing deaths worldwide. The yet to be developed non-invasive diagnostic techniques, are a challenge for early detection of cancer before it progresses to its later stages. The currently available diagnostic methods are expensive or invasive, and are not fit for general screening purposes. Early identification not only helps in detecting primary cancer, but also in treating its secondaries; which creates a need for easily applicable tests to screen individuals at risk. A detailed review of the various screening methods, including the latest trend of breath analysis using gold nanoparticles, to identify cancer at its early stage, are studied here. The VOC based breath biomarkers are used to analyze the exhaled breath of the patients. These biomarkers are utilized by Chemiresistors coated with gold nanoparticles, which are found to be the most suited technique for early detection of lung cancer. This technique is highly accurate and is relatively easy to operate and was tested on smokers and non-smokers. This review also gives as an outline of the fabrication and working of the device Na-Nose. The Chemiresistors coated with Gold nanoparticles, show a great potential in being an non-invasive and cost effective diagnostic technique for early detection of lung cancer. PMID- 26628934 TI - Effect of Pixel's Spatial Characteristics on Recognition of Isolated Pixelized Chinese Character. AB - The influence of pixel's spatial characteristics on recognition of isolated Chinese character was investigated using simulated prosthestic vision. The accuracy of Chinese character recognition with 4 kinds of pixel number (6*6, 8*8, 10*10, and 12*12 pixel array) and 3 kinds of pixel shape (Square, Dot and Gaussian) and different pixel spacing were tested through head-mounted display (HMD). A captured image of Chinese characters in font style of Hei were pixelized with Square, Dot and Gaussian pixel. Results showed that pixel number was the most important factor which could affect the recognition of isolated pixelized Chinese Chartars and the accuracy of recognition increased with the addition of pixel number. 10*10 pixel array could provide enough information for people to recognize an isolated Chinese character. At low resolution (6*6 and 8*8 pixel array), there were little difference of recognition accuracy between different pixel shape and different pixel spacing. While as for high resolution (10*10 and 12*12 pixel array), the fluctuation of pixel shape and pixel spacing could not affect the performance of recognition of isolated pixelized Chinese Character. PMID- 26628935 TI - The Research on the High-Protein Low-Calorie Food Recipe for Teenager Gymnastics Athletes. AB - In order to prevent teenager gymnastics athletes getting fat deposition, weight gain, they should supply a rational food. This paper considers the normal growth and development of athletes, body fat deposition proteins and hunger feel, configured high-protein low-calorie food recipe. Then analysis the composition and the essential amino acids of the recipe. In the final choiced 18 adolescent gymnastics athletes as subjects, to verify the validity of the formula. And analysis the experimental results. The experimental results analysis shows that this recipe basically meets the design requirements. PMID- 26628936 TI - The Research on the Impact of Management Level's Charismatic Leadership Style on Miners' Unsafe Behavior. AB - The aim of this study is research the impact of management level's charismatic leadership style on miners' unsafe behavior by using the questionnaires on charismatic leadership style, safety attitude and the miners' unsafe behavior measurement to investigate 200 employees in Shen Dong Company. The research results suggest that management level's charismatic leadership style have very important influence on miners' unsafe behavior and the influence is affected by the safety attitude which is the intermediary function. In the end, this study propose advice on how to improve the coal mine enterprise managers charismatic leadership style in the coal mine enterprise's safety management work, including attach great importance to a variety of incentive methods, set up safety moral models, practice of inductive leadership concept, create a good atmosphere of safety, etc for reference for coal mining enterprises. PMID- 26628938 TI - Medical Device Integration Model Based on the Internet of Things. AB - At present, hospitals in our country have basically established the HIS system, which manages registration, treatment, and charge, among many others, of patients. During treatment, patients need to use medical devices repeatedly to acquire all sorts of inspection data. Currently, the output data of the medical devices are often manually input into information system, which is easy to get wrong or easy to cause mismatches between inspection reports and patients. For some small hospitals of which information construction is still relatively weak, the information generated by the devices is still presented in the form of paper reports. When doctors or patients want to have access to the data at a given time again, they can only look at the paper files. Data integration between medical devices has long been a difficult problem for the medical information system, because the data from medical devices are lack of mandatory unified global standards and have outstanding heterogeneity of devices. In order to protect their own interests, manufacturers use special protocols, etc., thus causing medical decices to still be the "lonely island" of hospital information system. Besides, unfocused application of the data will lead to failure to achieve a reasonable distribution of medical resources. With the deepening of IT construction in hospitals, medical information systems will be bound to develop towards mobile applications, intelligent analysis, and interconnection and interworking, on the premise that there is an effective medical device integration (MDI) technology. To this end, this paper presents a MDI model based on the Internet of Things (IoT). Through abstract classification, this model is able to extract the common characteristics of the devices, resolve the heterogeneous differences between them, and employ a unified protocol to integrate data between devices. And by the IoT technology, it realizes interconnection network of devices and conducts associate matching between the data and the inspected at the device terminal in a timely manner. PMID- 26628937 TI - Diagnosis and Treatment of Vascular Surgery Related Infection. AB - Surgical site infection (SSI) is an important component of infections acquired from hospital. The most significant feature of vascular surgery different from other surgeries is frequent application of artificial grafts. Once SSI occurs after vascular operations with grafts, it might results in a serious disaster. Staphylococcus aureus and coagulase-negative Staphylococcus are the most common pathogenic bacteria for SSI after vascular surgery. Although SSI in vascular surgery often lacks of typical clinical characters, some clinical symptoms, laboratory data and certain imaging procedures may help to diagnose. In most cases of SSI after vascular procedures, the artificial grafts must be removed and sensitive antibiotics should be administered. However, for different cases, personalized management plan should be made depending on the severity and location of SSI. PMID- 26628939 TI - [Not Available]. PMID- 26628940 TI - Dexmedetomidine for antiemesis in gynecologic surgery: a meta-analysis of randomized controlled trials. AB - PURPOSE: Postoperative nausea and vomiting (PONV) is a common complication after gynecological surgeries. This meta-analysis was conducted to evaluate the efficacy of dexmedetomidine on PONV after gynecological surgeries. METHODS: Three main electronic databases including Pub Med, Embase and Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) were searched by two researchers independently. The metaanalysis was completed using Review Manager. RESULTS: Eleven RCTs with 692 patients were included in this metaanalysis. Dexmedetomidine a bridged postoperative nausea [Risk Ratio (RR)=0.59, 95% confidence interval (CI): 0.44 to 0.79] and vomiting [RR=0.48, 95% CI: 0.36 to 0.64] compared with placebo. Despite of higher incidence of intra operative bradycardia [RR 2.87, 95% CI 1.08 to 7.58] and hypotension [RR 4.26, 95% CI 1.43 to 12.69], we found significant decrease in postoperative shivering [RR 0.23, 95% CI 0.13 to 0.40] and pruritus [RR 0.40, 95% CI 0.17 to 0.93] in dexmedetomidine group, as well as the pain scores [standard mean difference (SMD)-0.96, 95% CI 1.37 to-0.54]. Significant reductions in the need for intraoperative fentanyl (RR 0.10, 95% CI 0.01-0.76, I(2) 0%), antiemetic (RR 0.62, 95% CI 0.39-0.99, I(2) 0%) and postoperative analgesic (RR 0.18, 95% CI 0.08-0.42, I(2) 0%) were also elicited. CONCLUSIONS: The current meta-analysis exhibits that dexmedetomidine is superiority to placebo in attenuating the incidence of PONV, postoperative shivering, pruritus, as well as the pain scores in patients undergoing gynecological surgeries. Still, the potential cardiovascular complications should be taken seriously. PMID- 26628941 TI - Puerarin injection for treatment of unstable angina pectoris: a meta-analysis and systematic review. AB - BACKGROUND: Puerarin is an effective ingredient isolated from Radix Puerariae, a leguminous plant. In China, a large number of early studies suggest that puerarin may be used in the treatment of coronary heart disease. In recent years, puerarin injection has been widely used to treat coronary heart disease and angina pectoris. OBJECTIVE: To systematically evaluate the clinical efficacy and safety of puerarin injection in the treatment of unstable angina pectoris (UAP). METHODS: Data were retrieved from digital databases, including PubMed, Excerpt Medica Database (EMBASE), China Biology Medicine (CBM), the Cochrane Library, and Chinese databases. RESULTS: Compared with patients who were treated with conventional Western medicines alone, the patients who were treated with conventional Western medicines in combination with puerarin injection exhibited significant improvements in the incidence of angina pectoris, electrocardiogram findings, nitroglycerin consumption and plasma endothelin levels. CONCLUSIONS: Strong evidence suggests that, the use of puerarin in combination with conventional Western medicines is a better treatment option for treating UAP, compared with the use of conventional Western medicines alone. PMID- 26628942 TI - Clinicopathological and prognostic value of programmed death ligand-1 (PD-L1) in renal cell carcinoma: a meta-analysis. AB - BACKGROUND: Recently, the association of immunological checkpoint marker programmed death ligand-1 (PD-L1) and the prognosis of various cancers has always been a research hotspot. The objective of this study is to assess the clinical value of PD-L1 as a novel prognostic biomarker of renal cell carcinoma (RCC). METHODS: Medline/PubMed, EMBASE, the Cochrane Library databases and Grey literature were searched up to 30 March 2015 for eligible studies of the association between PD-L1 expression and cancer-specific survival (CSS) in RCC. The risk ratio (RR) and its 95% confidence interval (CI) were calculated from the included studies. Moreover, the odds ratio (OR) was also extracted to evaluate the association between the clinicopathological parameters of participants and PDL1 expression. RESULTS: Five studies involving 1073 patients were included in the meta-analysis. The pooled results showed that positive/higher PD-L1 expression was a negative predictor for CSS with RR of 2.90 (95% CI: 1.64-5.13; Pheterogeneity. <= 0.001). Additionally, increased PD-L1 was found to be significantly associated with large tumor size (OR = 2.28, 95% CI: 1.61-3.23; Pheterogeneity. = 0.645), high TNM stage (OR = 4.37, 95% CI: 2.99-6.39; Pheterogeneity. = 0.676), poor nuclear grade (OR = 7.58, 95% CI: 5.26-10.92; Pheterogeneity. = 0.203) and present tumor necrosis (OR = 6.77, 95% CI: 4.73 9.71; Pheterogeneity. = 0.111) in renal cell carcinoma patients. CONCLUSION: The meta-analysis suggested that PD-L1 could act as a significant biomarker in the worse prognosis and adverse clinicopathologic features of renal cell carcinoma. PMID- 26628943 TI - Comparison of single-bundle versus double-bundle anterior cruciate ligament reconstruction after a minimum of 3-year follow-up: a meta-analysis of randomized controlled trials. AB - Both single-bundle (SB) and double-bundle (DB) procedures have been widely used in the treatment of anterior cruciate ligament (ACL) rupture; however, the optimal repair strategy remains considerably controversial. In this meta-analysis of published studies, we compared the results of these two techniques. After systematic review of electronic databases and websites, a total of 8 RCTs reporting data on 941 subjects were included. The objective and subjective functional recovery outcomes were meta-analyzed. The methodological quality was evaluated using the CBRG scale. The overall pooled data showed superiority in rotational stability, the degree of osteoarthritis (OA) changes, and subjective function score postoperatively in patients managed with DB compared with the SB procedure (pivot shift test, P = 0.02; degree of OA, P = 0.02; Lysholm score, P = 0.04; and Tegner scale, P = 0.002, respectively). However, subgroup analysis suggested no difference between the treatment procedures at long-term follow-up. This meta-analysis demonstrated that the DB technique could result in better rotational stability and higher subjective function score and was effective in preventing OA compared to SB in the mid-term treatment of the injured ACL. Further studies with better design involving larger sample sizes and longer-term follow-up are required. PMID- 26628944 TI - Effect of fusion following decompression for lumbar spinal stenosis: a meta analysis and systematic review. AB - PURPOSE: The surgical methods of degenerative lumbar spinal stenosis include spinal decompression with or without instrumented or non-instrumented spinal fusion. Previous meta-analysis and systematic reviews have reported the contrast between surgical management and nonsurgical management for degenerative lumbar spinal stenosis, while no literature did among surgical managements. And it is evidenced that whether fusion should be added to spinal decompression in patients of lumbar spinal stenosis is still divisive. So our purpose is to identify whether spinal fusion with or without decompression has a better effect than decompression alone for patients with degenerative lumbar spinal stenosis. METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) for reports before November 2014 and PubMed, EMBASE, GOOGLE SCHOLAR for those before December 2014. We also searched the reference lists included in studies and previous reviews. Randomized Controlled Trials and prospective or retrospective cohort studies of patients with degenerative lumbar spinal stenosis after spinal decompression with or without fusion were eligible. Abstracted outcomes from retrieved articles included clinical outcome and reoperation rate of two aspects. Both random-effects and fixed-effects models were used to calculate the end-points. RESULTS: We identified 23 studies with data collected from 61576 patients. The combined relative risk (RR) of clinical outcome for the spinal fusion compared with the spinal decompression was 0.91 (95% confidence interval [CI]: 0.85 to 0.98), and little evidence of heterogeneity was observed. Namely, a satisfactory clinical outcome was significantly more likely with fusion than with decompression alone. But there was a trend toward a higher reoperation rate with fusion compared with decompression alone (RR: 0.93; 95% CI: 0.88 to 0.97). CONCLUSION: This meta-analysis provides robust evidence of a better clinical outcome but a higher reoperation rate for spinal fusion compared with decompression alone. PMID- 26628945 TI - Association of serum parathyrine and calcium levels with primary aldosteronism: a meta-analysis. AB - Primary aldosteronism (PA) represents major cause of secondary hypertension, strongly associated with high cardiovascular morbidity and mortality. Aldosterone excess may influence mineral homeostasis, through higher urinary calcium (Ca) excretion reducing calcium plasma levels and leading to secondary increase of parathyrine (PTH). The purpose of the present study is to clarify the association of serum PTH and Ca levels with PA using a metaanalysis approach. We searched articles indexed in the PubMed, OVID and Sciencedirect published as of September 2014 that met our predefined criteria. Six articles with 748 subjects from 8 case control studies were identified. Overall, pooled analysis indicated that subjects with PA had higher serum PTH concentrations and lower Ca levels than controls with essential hypertension (EH) (PTH: SMD = 1.146, 95% CI = [0.774, 1.518]; Ca: SMD = -0.698, 95% CI = [-1.102,-0.294]). Further subgroup analysis stratified by geological location found a similar pattern both in Italy and Austria (Italy: for PTH, SMD = 1.176, 95% CI = [0.758, 1.593], for Ca, SMD = -0.669, 95% CI = [ 1.119,-0.219]; Austria: for PTH, SMD = 1.004, 95% CI = [0.359, 1.648], for Ca, SMD = -0.900, 95% CI = [-1.543,-0.257]). In addition, the subgroup analysis stratified by type of Ca measurement also found a similar pattern by spectrophotometry (SMD = -1.078, 95% CI = [-1.532, -0.623]), but not by ion selective electrode (SMD = -0.248, 95% CI = [-0.810, 0.315]). Sensitivity analysis showed that excluding any one study from the pooled analysis did not vary the results substantially. No evidence of publication bias was observed. In conclusion, this meta-analysis supports a significant association of PTH and Ca concentration with PA. Therefore, the high levels of PTH and low Ca concentrations in serum can be used as a variable predictor for PA. PMID- 26628946 TI - Y chromosome azoospermia factor region microdeletions and transmission characteristics in azoospermic and severe oligozoospermic patients. AB - Spermatogenesis is an essential reproductive process that is regulated by many Y chromosome specific genes. Most of these genes are located in a specific region known as the azoospermia factor region (AZF) in the long arm of the human Y chromosome. AZF microdeletions are recognized as the most frequent structural chromosomal abnormalities and are the major cause of male infertility. Assisted reproductive techniques (ART) such as intra-cytoplasmic sperm injection (ICSI) and testicular sperm extraction (TESE) can overcome natural fertilization barriers and help a proportion of infertile couples produce children; however, these techniques increase the transmission risk of genetic defects. AZF microdeletions and their associated phenotypes in infertile males have been extensively studied, and different AZF microdeletion types have been identified by sequence-tagged site polymerase chain reaction (STS-PCR), suspension array technology (SAT) and array-comparative genomic hybridization (aCGH); however, each of these approaches has limitations that need to be overcome. Even though the transmission of AZF microdeletions has been reported worldwide, arguments correlating ART and the incidence of AZF microdeletions and explaining the occurrence of de novo deletions and expansion have not been resolved. Using the newest findings in the field, this review presents a systematic update concerning progress in understanding the functions of AZF regions and their associated genes, AZF microdeletions and their phenotypes and novel approaches for screening AZF microdeletions. Moreover, the transmission characteristics of AZF microdeletions and the future direction of research in the field will be specifically discussed. PMID- 26628947 TI - Superoxide dismutase 2 gene and cancer risk: evidence from an updated meta analysis. AB - Superoxide dismutase, one of the antioxidant enzymes, plays an important role in defense against reactive oxygen species. Many previous studies reported the association between SOD2 polymorphism and the cancer risk but the results were divergent. Therefore, we performed a meta-analysis to investigate the association between SOD2 polymorphism and the cancer susceptibility. We searched in Electronic database including Pubmed, Embase, google of scholar, and Korean Studies Information Service System (KISS) for this meta-analysis. Odds ratio (OR), 95 confidence interval (CI), and p value were calculated to evaluate the relation between SOD2 polymorphism and risk of cancer using Comprehensive Meta analysis software (Corporation, NJ, USA). The fifty-two studies including 26,865 cancer cases and 32,464 control subjects were analyzed for meta-analysis. Our meta-analysis revealed that SOD2 polymorphism statistically increased or decreased the susceptibility of cancer. In the present study, we could find that SOD2 polymorphism was related to the development of non-Hodgkin lymphoma, lung cancer, and colorectal cancer. It suggested that SOD2 polymorphism might be a candidate marker of cancer. PMID- 26628949 TI - New instrument for percutaneous posterolateral lumbar foraminoplasty: case series of 134 with instrument design, surgical technique and outcomes. AB - Current solutions for treating uncontained lumbar disk herniation include laser assisted endoscopic foraminoplasty and Transforaminal Endoscopic Spine System, both of which have some issues in clinical practice. This study aims to report the design of a new instrument for percutaneous posterolateral foraminoplasty. 148 patients with uncontained lumbar disk herniation were treated with percutaneous foraminoplasty followed by transforaminal endoscopic discectomy. Follow up were obtained for 134 cases. The VAS scores of pre-operative and post operative low back pain and sciatica were compared. Oswestry Disability Index (ODI) and MacNab scores were also obtained. Follow-up was up to 5 years postoperatively. There were 75 of excellent, 49 of good and 5 of fair according to MacNab score system, with total successful rate up to 92.5%. 5 cases with L5S1 disc herniation complained about irritation to the dorsal root ganglion. In conclusion, the new transforaminal endoscopic discectomy instrument is safe and effective for percutaneous foraminoplasty. PMID- 26628950 TI - Bone marrow stem cells delivered into the subarachnoid space via cisterna magna improve repair of injured rat spinal cord white matter. AB - The influence of bone marrow stem cells on regeneration of spinal cord in rats was investigated. Young adult male Wistar rats were used (n=22). Focal injury of spinal cord white matter at Th10 level was produced using our original non laminectomy method by means of high-pressured air stream. Cells from tibial and femoral bone marrow of 1-month old rats (n=3) were cultured, labeled with BrdU/Hoechst and injected into cisterna magna (experimental group) three times: immediately after spinal cord injury and 3 as well as 7 days later. Neurons in brain stem and motor cortex were labeled with FluoroGold (FG) delivered caudally from the injury site a week before the end of experiment. Functional outcome and morphological features of regeneration were analyzed during 12-week follow-up. The lesions were characterized by means of MRI. Maximal distance of expansion of implanted cells in the spinal cord was measured and the number of FG-positive neurons in the brain was counted. Rats treated with stem cells presented significant improvement of locomotor performance and spinal cord morphology when compared to the control group. Distance covered by stem cells was 7 mm from the epicenter of the injury. Number of brain stem and motor cortex FG-positive neurons in experimental group was significantly higher than in control. Obtained data showed that bone marrow stem cells are able to induce the repair of injured spinal cord white matter. The route of cells application via cisterna magna appeared to be useful for their delivery in spinal cord injury therapy. PMID- 26628948 TI - Epstein-Barr Virus-associated lymphoproliferative disorders: experimental and clinical developments. AB - Epstein-Barr Virus (EBV), the first human virus related to oncogenesis, was initially identified in a Burkitt lymphoma cell line in 1964. EBV infects over 90% of the world's population. Most infected people maintain an asymptomatic but persistent EBV infection lifelong. However, in some individuals, EBV infection has been involved in the development of cancer and autoimmune disease. Nowadays, oncogenic potential of EBV has been intensively studied in a wide range of human neoplasms, including Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), etc. EBV encodes a series of viral protein and miRNAs, promoting its persistent infection and the transformation of EBV-infected cells. Although the exact role of EBV in the oncogenesis remains to be clarified, novel diagnostic and targeted therapeutic approaches are encouraging for the management of EBV-related malignancies. This review mainly focuses on the experimental and clinical advances of EBV-associated lymphoproliferative disorders. PMID- 26628951 TI - The safety and efficacy of the preoperative neoadjuvant chemotherapy for patients with cervical cancer: a systematic review and meta analysis. AB - OBJECTIVE: To evaluate the safety and efficacy of the preoperative neoadjuvant chemotherapy for patients with cervical cancer. METHODS: A systematic literature search was conducted using the PubMed, EMBASE and Cochrane databases. Studies comparing combined neoadjuvant chemotherapy treatment (NACT)/radical surgery treatment (RST) with RST alone in patients with cervical cancer were eligible for inclusion. RESULTS: Eight studies were finally included in this meta analysis, involving a total of 1302 patients. Meta analysis shows that NACT might have lower lymph node metastasis than RST [OR=0.57, 95% CI (0.41, 0.79), P=0.0008]. However, there are no differentiation between two groups in operation time [SMD=0.16, 95% CI (-0.08, 0.48), P=0.19], intraoperative estimated blood loss [SMD=0.20, 95% CI (-0.19, 0.58), P=0.48], intraoperative and postoperative complication rates [OR=1.33, 95% CI (0.45, 3.92), P=0.60], overall survival rate [OR=1.07, 95% CI (0.48, 2.41), P=0.86] and recurrence rate [OR=1.06, 95% CI (0.56, 2.03), P=0.85]. CONCLUSIONS: The safety and efficacy of two treatments are similarly. However, NACT can reduce the rate of lymph node metastasis, which is an independent risk factor for cervical cancer prognosis and may improve the prognosis of cervical cancer. PMID- 26628952 TI - Matrine promotes the efficacy and safety of platinum-based doublet chemotherapy for advanced non-small cell lung cancer. AB - PURPOSE: Many studies have investigated the efficacy of matrine combined with platinum-based doublet chemotherapy (PBDC) versus PBDC alone for treating advanced non-small cell lung cancer (NSCLC). This study is an analytic value of available evidence. METHODS: twenty-two studies reporting matrine combined with PBDC versus PBDC alone for treating advanced NSCLC were reviewed. Pooled odds ratios and hazard ratio with 95% confidence intervals were calculated using either the fixed effects model or random effects model. RESULTS: The overall response rate (ORR) and disease control rate (DCR) of matrine combined with PBDC for treating NSCLC were significantly higher than those of PBDC alone, with 15.1% and 19.7% improvement, respectively (P < 0.00001). In addition, the mean survival time (MST) and quality of life (QOL) were improved after the treatment of matrine combined with PBDC (P < 0.00001). The main adverse effects found in this review were hematological reactions, nausea and vomiting. Matrine combined with PBDC had a lower incidence of adverse reactions compared with PBDC alone (P < 0.05). CONCLUSIONS: Matrine combined with PBDC was associated with higher RR, DCR, and MST as well as superior QOL profiles compared with PBDC alone. Matrine combined with PBDC decrease the incidence of adverse reactions compared with PBDC alone. PMID- 26628953 TI - Biological characteristics of tracheal smooth muscle cells regulated by NK-1R in asthmatic rat with airway remodeling. AB - This study aims to investigate the biological characteristic changes of infant rat tracheal smooth muscle cells in asthma airway remodeling and the impact of NK 1R on the mechanism. Ovalbumin (OVA) was used to excited juvenile SD rats by 8 w. Immunofluorescence, MTT assay, transwell chambers, real time quantitative PCR, Western blot and other methods were used to observe the proliferation, migration, synthesis and secretion changes of infant airway remodeling in rat tracheal smooth muscle cell and the Neurokinin 1 receptor (NK-1R) expression. 1. NK-1R mRNA, protein expression of airway smooth muscle cell (ASMC) of each asthma group were higher than that of the control group, especially the asthma 8 w group had highest expression (P<0.01). 2. The average A value of 8 w asthma group measured by MTT method were significantly higher than that of the control group (P<0.05), WIN62577 10(-8) mol/L group had the strongest inhibition of ASMC proliferation (P<0.01). 3. The number of cell migration in the asthma group significantly increased than that in the control group. The number of migrating cells in the NK 1R antagonist group significantly reduced compared with the asthma 8 w group (P<0.05). 4. The average gray value of type III collagen in each asthma group were higher than that of the control group, and the asthma 8 w group had the highest (P<0.01). After NK-1R blocking, the average gray value of type III collagen was significantly lower (P<0.05). ASMC proliferation, migration, synthesis and secretion function increased in the airway remodeling group, and NK 1R played an important role. PMID- 26628954 TI - The failure experience of complex total hip arthroplastyin osteopetrosis: case report and literature review. AB - There is rare literature elaborating the complex total hip arthroplasty (THA) in patients with osteopetrosis who experienced malunion from femoral neck fracture. We have summarized the failure experience of the complex THA in osteopetrosis. Learned from the resurgery in the case reported by this paper, we recommend to highlight the initial stability of the prosthesis and not to overestimate the potency of fracture healing in the complex THA in osteopetrosis. PMID- 26628955 TI - Measurement for natural dental neck data of normal adults and its clinical significance on guiding implant restoration. AB - OBJECTIVE: Provide reference basis for the clinical implant restoration to select implant diameter through measuring each data of 7 teeth in the dental neck of bilateral upper and lower jaws of the young volunteers with normal dentition. METHODS: Select 30 healthy young volunteers with complete dentition but no malocclusion, take cone beam CT (CBCT), measure the mesiodistal and buccolingual distance of the tooth root at 1.5 mm from 14 teeth (bilateral upper and lower jaws) to alveolar crest, trace out the outline of each tooth neck in this layer, calculate the cross sectional area and roundness of each tooth neck according to pixel value calibration, and then carry out statistical processing. RESULTS: Complete the data collection and processing of mesiodistal length, buccolingual width, cross sectional area, and cross sectional roundness of the dental neck at 1.5 mm from these seven teeth of the bilateral upper and lower jaws to the alveolar crest of 30 volunteers, and calculate the mean value, variance, and reference value range of medical science of each index. CONCLUSION: CBCT can effectively obtain the image information of the dental neck. Through mimics 10.0 and Photoshop CS3, it is possible to accurately calculate the dental neck length and width, and cross sectional area of each tooth according to CBCT image information. This result can provide reference basis for the implant restoration of the clinical teeth. PMID- 26628956 TI - Dexmedetomidine alleviates the spinal cord ischemia-reperfusion injury through blocking mast cell degranulation. AB - OBJECTIVE: To investigate the neuro-protective effects of dexmedetomidine (dex) on I/R-induced spinal injury and potential mechanisms. METHODS: sprague-Dawley rats in the treatment group received intraperitoneal injections of 25 mg/kg dexmedetomidine, MC stabilizer cromolyn (100 mg/kg), MCs stimuliser compound 48/80 (80 mg/kg), PBS at 24 h befor IR. Underwent 5 minutes of aortic occlusion via median sternotomy, functional scores were recorded at 12, 24, 36 and 48 hours after reperfusion. Additionally, 3 mice underwent sham surgery with sternotomy and dissection of the aorta and subclavian artery with no occlusion. Spinal cords were examined for protein kinase B (AKT), CREB, and brain-derived neurotrophic factor (BDNF) following treatment alone or ischemia-reperfusion surgery. Collected the serum to observe the expression of pro-inflammation cytokines (TNF alpha, INF-gamma and IL-1beta) and anti-inflammation cytokines (TGF-beta, IL-10 and IL-6). Then the MCs were harvested to test the expression surface molecular of FcepsilonR and MCs' degranulation. RESULTS: Pretreated the rats with dexmedetomidine has higher neurologic function at all time points after I/R injury. We collected the serum of rats then detected the pro-inflammation cytokines TNF-alpha, INF-gamma and IL-1beta levels and anti-inflammation cytokinses TGF-beta, IL-10 and IL-6 levels, found that the pro-inflammation cytokines of dexmedetomidine group was decreased whereas the anti-inflammation cytokinses was increased. At the same time the protect protein of AKT, CREB and mRNA BDNF were increased. They had the same results with cromolyn group, and opposite with the compound 48/80 group. We pretreated MCs with dexmedetomidine in vitro, and found that the activity surface molecular of MCs was down-regulation, and MCs degranulation was decreased. CONCLUSION: We thus demonstrate a possible mechanism by which dexmedetomidine alleviates spinal cord I/R injury through blocking the MCs degranulation. PMID- 26628957 TI - The molecular mechanism of breast cancer cell apoptosis induction by absent in melanoma (AIM2). AB - OBJECTIVE: To determine the molecular mechanism by which absent in melanoma 2 (AIM2) induces breast cancer cell apoptosis. METHODS: Establish Tet-Off(TM) model system to induce AIM2 expression in great quantities, MCF-7 tTA-AIM2 cells were the experimental group; MCF-7 tTA-Luc cells were the control group. The expression and subcellular localization of AIM2 in breast cancer cell lines were determined via Western Blotting. AIM2 protein expression was determined after the addition of interferon-gamma (102 U/ml). Flow cytometry was used to analyze the effects of AIM2 on the cell cycle. Apoptosis detection was performed by staining with Annexin V-FITC and propidium iodide. Apoptosis mechanism was detected via Western Blotting. The XTT assay was used to analyze the effects of AIM2 on cell growth. RESULT: This experiment established Tet-Off guidance system. This system results which promotes AIM2 gene transcription and increased AIM2 protein expression. Four days after induction, AIM2 expression was detected. AIM2 expression increased with the number of days post-induction. AIM2 is present in cytoplasm and nuclei. Interferon-gamma (102 U/ml) induced AIM2 protein expression and significantly increased AIM2 expression. AIM2 expression had no significant effect on the cell cycle, With the increase of Cdk2 expression induced by days were gradually increased, and Cdk4, Cyclin E expression was no significantly difference. AIM2 expression can significantly promote the apoptosis of breast cancer cells. Increased AIM2 expression can inhibit the expression of the anti apoptotic protein Bcl-xL, increase the expression of the apoptosis proteins Bad and Bax, and activate caspases, resulting in cleavage of the DNA repair protein PARP. The XTT assay showed that AIM2 expression slows the rate of cell growth. CONCLUSION: In this breast cancer Tet-Off(TM) system, AIM2 was expressed in the cytoplasm and nucleus, stimulated the mitochondria to promote apoptosis, and influenced cell survival and proliferation. PMID- 26628958 TI - Serum miR-21 level: a potential diagnostic and prognostic biomarker for non-small cell lung cancer. AB - Because lung cancer is the most common cause of cancer death among both men and women, focused efforts are necessary to identify and develop biomarkers that aid in the detection and treatment of this serious disease. Recent research has been aimed at understanding the roles of microRNAs (miRNAs) in tumorigenesis and their utility as cancer biomarkers. Here, miR-21 was investigated as a potential serum biomarker for non-small cell lung cancer (NSCLC). The relative expression level of miR-21 was detected by real-time PCR in the sera of 80 NSCLC patients; sera were also collected from 60 healthy people as a control. The most suitable cut off value and the prognostic value of serum miR-21 levels were analyzed using a receiver-operating curve. The relative serum miR-21 level in NSCLC patients was significantly higher than that in healthy people (P<0.05). For relative miR-21 expression, the area under the ROC curve was 0.812 (95% CI: 0.736-0.888) with a sensitivity of 73.8% and a specificity of 71.7%, based on a cut-off value of 1.22. NSCLC patients were divided into two groups based on miR-21 expression; those with higher relative expression (>=1.22) had significantly lower survival time than those in the lower expression group (P<0.05). Further, serum miR-21 level and survival time were negatively correlated in NSCLC patients (P<0.05). Thus, miR-21 may be useful as a diagnostic and prognostic indicator of NSCLC. PMID- 26628959 TI - Association of COL1A1 polymorphisms with osteoporosis: a meta-analysis of clinical studies. AB - OBJECTIVE: To conduct a meta-analysis of all association studies on two of the collagen 1 alpha 1 (COL1A1) gene polymorphisms, the -1997G/T (rs1107946) and the 1663indelT (rs2412298) polymorphisms and osteoporosis/BMD and fracture. METHODS: PubMed/Medline and Web of Knowledge were searched for relevant association studies published in English. Pooled OR and its corresponding 95% CI or pooled MD and its corresponding 95% CI was calculated with the Cochrane Review Manager (Revman, version 5.2) using a random-effect or a fixed effect model. RESULTS: No significant association between the -1997G/T polymorphism and Lumbar Spine (LS) and Femoral Neck (FN) BMD except for the Caucasian subpopulation wherein subjects with the T allele of the -1997G/T polymorphism was associated with significantly higher LS BMD. Our analysis did reveal that women, especially postmenopausal or perimenopausal women with the GG genotype, had significantly higher Total Hip (TH) BMD than those with the GT. Additionally, our meta-analysis did not show significant association between the -1997G/T polymorphism and risk of fracture, between the -1663indelT polymorphism and LS BMD in postmenopausal or perimenopausal women, or between the -1663indelT polymorphism and the risk of fracture. CONCLUSIONS: Our results suggested the possibility of the COL1A1 1997G/T and the -1663indelT polymorphisms individually playing very little role in osteoporosis and fracture, although more studies are needed especially for the analysis of association between these two polymorphisms and fracture. Haplotype studies may become one important future direction of study to further elucidate whether and how various COL1A1 polymorphisms affect bone health, osteoporosis and fracture. PMID- 26628960 TI - Expression of Jagged1 predicts postoperative clinical outcome of patients with gastric cancer. AB - BACKGROUND: Clinical significance of Notch1 activation in gastric cancer has been elucidated in our previous study, but the role of its ligands remains obscure. This study aims to evaluate the prognostic value of Jagged1 expression in patients with gastric cancer. METHODS: We examined Jagged1 expression in tumor and nontumor tissues in retrospectively enrolled 302 patients with gastric cancer undergoing gastrectomy at Zhongshan Hospital of Fudan University in 2008 by immunohistochemical staining. The Kaplan-Meier method and Cox regression models were used to evaluate the prognostic value of Jagged1 expression and its association with clinicopathological features. We created a predictive nomogram by integrating Jagged1 expression with the TNM staging system for overall survival of gastric cancer patients. RESULTS: Jagged1 expression in gastric cancer was decreased compared with that in nontumor tissues. Low expression of Jagged1 in tumor and nontumor both predicted a dismal outcome. The Jagged1 risk derived from Jagged1 expression in tumor/nontumor tissue gave a further discrimination for the prognosis of gastric cancer patients. By Cox multivariate analysis, the Jagged1 risk was defined as an independent prognostic factor. The generated nomogram performed well in predicting the 3- and 5-year overall survival of gastric cancer patients. CONCLUSION: Jagged1 is a potential prognostic biomarker for overall survival, which could be integrated with TNM stage to give a better risk stratification for gastric cancer patients. PMID- 26628961 TI - Danshensu protects isolated heart against ischemia reperfusion injury through activation of Akt/ERK1/2/Nrf2 signaling. AB - Danshen has been widely used in the treatment of cardiovascular diseases while Danshensu [3(3,4dihydroxyphenyl) 2 hydroxy propanoic acid, DSS], a major water soluble component of Danshen has also been explored as an important compound in Danshen. In the present study, DSS was tested in isolated rat hearts of ischemia reperfusion (I/R) model to investigate its cardioprotective activity and explore the potential molecular mechanism against oxidative stress. The isolated rat hearts were used to perform global ischemia for 30 min, followed by 30 min reperfusion. DSS significantly decreased the level of the marker enzymes (creatine kinase and lactate dehydrogenase) from the coronary effluents and myocardial infarction size. This could markedly contribute to the recovery of cardiac function after I/R injury. DSS also had ROS scavenging activity and boosted endogenous antioxidants such as SOD, CAT, MDA, GSH-PX and HO-1 activities by activating nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway which was mediated by Akt and ERK1/2 in western blot analysis. Our results demonstrated a cardioprotective effect of DSS on isolated heart against oxidative stress during I/R injury. This mechanism might be related to the enhancement of antioxidant defense system by activating Akt/ERK1/2/Nrf2 signaling pathways. This work could provide experimental evidence in treating cardiovascular disease by the use of traditional Chinese medicine particularly in myocardial ischemia reperfusion injury. PMID- 26628962 TI - Anticolorectal cancer effects and pharmacokinetic application of 2, 2-Bis [4-(4 amino-3-hydroxyphenoxy) phenyl] adamantane. AB - 2, 2-Bis (4-(4-amino-3-hydroxyphenoxy) phenyl) adamantane (DPA) induced growth inhibition in human cancer cells using the national cancer institute (NCI) anticancer drug screen. In our previous study, we demonstrated that DPA exerted growth inhibitory activities in the three human colon cancer cell lines (Colo 205, HT-29, and HCT-15). To identify the detailed mechanism, we examined the functional importance of p21 and p53 in DPA-induced anticancer effect. We used three isogenic colon cancer cell lines, HCT-116, HCT-116 p53(-/-), and HCT-116 p21(-/-), to evaluate the roles of p21 and p53 in the in vitro anticancer effects of DPA. DPA dose-dependently inhibited cell growth, cell migration and increased cell cycle at the G0/G1 phase in HCT116 cells but not in p21(-/-) and p53(-/-) isogenic HCT-116 cells. Additionally, Western blot showed that DPA treatment induced the p21, p53, and cyclin-E protein expressions in HCT-116 cells. The p21 associated cell cycle regulatory protein such as cyclin D, CDK4, and pRb were decreased after DPA treatment in HCT-116 cells. DPA decreased cell migration in HCT-116 and HCT-116 p53(-/-) but not in HCT-116 p21(-/-) cells. We observed the up-regulation of E-cadherin, p-p38, and p-Erk in DPA-treated HCT-116 group but not in HCT-116 p21(-/-) and HCT-116 p53(-/-) groups. We assumed that p21 was required for DPA-induced anti-colon cancer effect through the Erk and p38 pathway leading to cell cycle arrest and inhibition of cell motility. Mean (+/- SE) pharmacokinetic parameters of the DPA were as follows: AUC = 64.44 +/- 8.41, Cmax = 1.56 +/- 0.48 and t1/2 = 113.92 +/- 58.19. The pharmacokinetic data suggest DPA can be applied to further clinical study. This is the first pharmacokinetic study of DPA, and indicated that anti-proliferation and the cell mobility inhibition effects of DPA in HCT116 WT cells may result from the induction of p21 through activation of ERK and p38 pathway. PMID- 26628963 TI - Sevoflurane inhibits the phosphorylation of ribosomal protein S6 in neonatal rat brain. AB - Besides neurotoxic effects, inhaled anesthetics might have other adverse effects on the developing brain. Ribosomal protein S6 (rpS6), the first identified ribosomal protein undergoing phosphorylation, has important physiological functions in regulating protein synthesis, cell proliferation, and glucose homeostasis. To date, the function of sevoflurane on rpS6 phosphorylation is unclear. In our present study, we showed that sevoflurane anesthesia inhibited rpS6 phosphorylation in cerebral cortex and CA1 region of the hippocampus. The activity of Akt was detected to be reduced within both cortical and hippocampal regions in the brain with the treatment of sevoflurane. However, the treatment seemed to have no effect on the phosphorylation of mammalian target of rapamycin (mTOR), a downstream effector of Akt. Sevoflurane had a paradoxical effect on ERK activity in the hippocampus and cerebral cortex. Last but not the least, Sevoflurane increased PP1 activity in the cerebral cortex and hippocampus. Thus, the exposure to sevoflurane inhibited dramatically the phosphorylation of rpS6 in neonatal rat brains. The inhibitory effect of sevoflurane on rpS6 phosphorylation might be mediated by the suppression on AKT activity at an mTOR-independent manner and the enhancement of PP1 activity. PMID- 26628964 TI - Optimization modeling of single-chain antibody against hepatoma based on similarity algorithm. AB - The purposes was to establish optimal modeling of single-chain antibody molecules based on similarity algorithm and seek the connecting peptides that had the minimal effect on the structure and bioactivity of the variable region of heavy chain (VH) and that of light chain (VL) in a single-chain antibody against liver cancer. After the Linker with different lengths (n=0~7) had been added into single chain fragment variable (ScFv), modeling of the overall sequences of VH, VL and ScFv were conducted respectively. Meanwhile, the peptide chain structure of (Gly4Ser)n was adopted for the connecting peptide. Then the spatial spherical shell layer alignment algorithm based on spherical polar coordinates was utilized for comparing the structural similarity of VH and VL before and after adding connecting peptide. Equally, in order to determine the stability of VH and VL, MATLAB was applied for analysis of the fore and aft distances and the diffusion radius. Indirect ELISA method was used to detect single-chain antibody immunological activity of Linker with different lengths. The MTT assay was utilized for the examination of the inhibition rate of single-chain antibody with different lengths of Linker to liver cancer cell. When n=4, the structural similarity between VH together with VL and their original ones was the highest. When n=3, the influence of connecting peptide on the stability of VH and VL was minimum. When n>3, the fore and aft distances changed little due to the increase and fold of the length of peptide chain. The results of ELISA detection showed that when n=4, affinity of single chain antibody to liver cancer cells was much higher. The MTT test also indicated that when n=4, the inhibition rate of the connecting peptide on hepatoma carcinoma cell reached the highest, and that came second when n=3. When n=4, the structural stability and biological functions of anti-hepatoma single-chain antibody were both favorable. This study has provided a basis for the design and construction of single-chain antibody. PMID- 26628965 TI - Atorvastatin attenuates inflammation and oxidative stress induced by ischemia/reperfusion in rat heart via the Nrf2 transcription factor. AB - The role of atorvastatin in inflammation and oxidative stress induced by ischemia/reperfusion is currently not well understood. The aim of this study was toinvestigate whether atorvastatin modulates neutrophil accumulation, TNF-alpha induction and oxidative stress and to examine the possible role of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway in an ischemia/reperfusion injured rat heart model. Rats were randomly assigned into tosham operation group, myocardial ischemia/reperfusion (MI/R) group, MI/R + atorvastatin group. Myocardial infarct area, myeloperoxidase (MPO), serum creatinine kinase (CK) and lactate dehydrogenase (LDH) levels were monitored. The results indicate that compared to MI/R, atorvastatin reduced myocardial infarction area, MPO level, serum CK and LDH levels, and both serum and myocardial TNF-alphaproduction. In addition, atorvastatin increased SOD and GSH-PX activity and decreased MDA content. Atorvastatin also enhanced levels of Nrf2 and heme oxygenase-1. In summary, our data suggests that atorvastatin exerts significant cardioprotective effects following myocardial ischemia, possibly through the activation of the Nrf2/ARE signaling pathway. PMID- 26628966 TI - Clinical features and CT/MRI findings of pancreatic acinar cell carcinoma. AB - To retrospectively review the clinical features and computed tomography (CT) and magnetic resonance imaging (MRI) findings of PAAC so as to improve the accuracy of imaging diagnosis. Seventeen patients with pathologically proven PAAC were enrolled. Their clinical and imaging findings were retrospectively reviewed. The median age of the patients was 56 years (range, 7-74 years). The tumors were located in any part of the pancreas or exophyitc growth, with a median maximal diameter of 68 mm. Thirteen masses presented with ovoid shape. Nine masses had less clear boundaries. Eleven masses showed a variable degree of intratumoral hypodense or necrosis before contrast administration on CT images. Five masses showed hypointense on unenhanced T1 weighted images and hyperintense on T2 weighted images. After contrast administration, the most common enhancement pattern was slight enhancement on arterial phase and persistent enhancement on portal vein phase. Infiltration of tumor into duct and vessels was not common. Five and 2 patients developed hepatic metastasis and local lymphadenopathy, respectively. By the end of the last follow-up, 11 patients survived free of disease. PAAC should be included in the differential diagnosis when a bulky, ovoid, heterogeneous mass, with clear or less clear margins, in the pancreas or peripancreas, with slight and persistent enhancement after contrast administration on CT or MRI images is seen, particularly in elder men. PMID- 26628967 TI - Outcome of extralevator abdominoperineal excision over conventional abdominoperineal excision for low rectal tumor: a meta-analysis. AB - OBJECTIVE: A meta-analysis was undertaken to provide an evidence-based basis of clinical trials comparing extralevator abdominoperineal excision with conventional abdominoperineal excision for low rectal tumor. METHODS: We searched through the major medical databases such as PubMed, EMBASE, Medline, Science Citation Index, Web of Science for all published studies without any limit on language from January 2009 until January 2015. The following search terms were used: extralevator abdominoperineal excision or cylindrical abdominoperineal resection or conventional abdominoperineal excision or abdominoperineal excision or rectal cancer. Furthermore, Additional related studies were manually searched in the reference lists of all published reviews and retrieved articles. RESULTS: In this meta-analysis, there are a total number of 1797 patients included: 1099 patients in the ELAPE group and 698 in the APE group, and there are not statistically differences between groups in CRM [RR=0.65, 95% CI (0.41, 1.04), P=0.07] and wound complications [RR=1.14, 95% CI (1.09, 1.66), P=0.45] between ELAPE and APE. However, ELAPE has a lower rate of intraoperation perforation [RR=0.44; 95% CI (0.33, 0.60); P<0.00001] and local recurrence [RR=0.45, 95% CI (0.27, 0.77), P=0.003] than APE in terms of short follow-up time. PMID- 26628968 TI - Experimental study on the toxicity of povidone-iodine solution in brain tissues of rabbits. AB - OBJECTIVE: To determine whether Povidone-iodine was toxic to brain tissues by rinsing the cerebral cortex of New Zealand rabbits with Povidone-iodine Solution of different concentrations. METHODS: 12 New Zealand rabbits were randomly divided into 4 groups (Group A, B, C and D, 3 rabbits each group). In each group, the left cerebral cortex of rabbits was rinsed with physiological saline after the craniotomy; in Group A and B, the right cerebral cortex of rabbits was also locally rinsed with Povidone-iodine Solution (0.01%), in Group C and D, the right cerebral cortex of rabbits was also locally rinsed with Povidone-iodine Solution (0.05%). In Group A and C, the rabbits were sacrificed at D3 after the operation, and the brain was taken out; and in Group B and D, the rabbits were sacrificed at D7 after the operation, and the brain was taken out. Under the optical and electron microscope, the change in micro-structure of brain tissues was observed in each group. RESULTS: In each group, there was no epilepsy or paralysis during and after the operation. At the treatment side of physiological saline, there was no significant cell damage in the local brain tissues. At the treatment side of Povidone-iodine Solution, there was no cell apoptosis or degeneration in the local brain tissues. CONCLUSION: The Povidone-iodine Solution (0.05% and 0.01%) was toxic to brain tissues, with a more obvious damage of brain tissues for the former concentration. The histological sign was more serious at D7 than that at D3. PMID- 26628969 TI - Individualized treatment strategies and predictors of virological response for chronic hepatitis C: a multicenter prospective study from China. AB - Combination therapy comprising pegylated interferon-alpha (PegIFNalpha) and ribavirin (RBV) has been the standard of care for the chronic hepatitis C patients for more than a decade. Recently, direct antiviral agents show better efficacy, tolerance, and shorter treatment duration. However, the prohibitive costs of the regimens limit their use in developing countries where most of the HCV infection exists. Optimizing the treatment and understanding the host- and virus-factors associated with viral clearance were necessary for individualizing therapy to maximize sustained virologic response. To explore individualized antiviral strategies with PegIFNalpha-2a/IFNalpha-2b plus ribavirin for CHC patients, and to clarify predictive factors for virological response. A cohort of 314 patients were included in this open-label, prospective clinical trial, which received individualized doses of PegIFNalpha-2a or IFNalpha-2b combined with RBV according to body weight, disease status and complications, with the duration of 44 weeks after HCV RNA undetectable. All the IL-28B (rs8099917), IL-17A (rs8193036), IL-17B (rs2275913) and PD-1.1 SNPs were genotyped using the TaqMan system. The sustained virological response (SVR) in PegIFNalpha-2a group was significantly higher than that in IFNalpha-2b (85.8% vs 75.0%, P = 0.034), especially in HCV genotype 1 (84.0% vs 64.3%, P = 0.022). However, no significant differences were found in rapid virological response (RVR), complete early virological response (cEVR) and SVR between PegIFNalpha-2a and IFNalpha-2b according to different doses, respectively. The genotype frequency of IL-28B TT in patients with cEVR, SVR was higher than that in non-responsed patients (93.8% vs 78.1%, chi(2) = 7.827, P = 0.005; 95.9% vs 80.4%, chi(2) = 9.394, P = 0.002). No significant correlation between the genotype distribution of IL-17A, IL-17B and PD-1.1 with virological response. Individualized regimens of PegIFNalpha 2a/RBV and IFNalpha-2b/RBV could achieve satisfied virological response in Chinese HCV patients. The IL-28B (rs8099917) TT genotype is a clinical usefully marker for cEVR and SVR. PMID- 26628970 TI - Mitochondrial energy metabolism disorder and apoptosis: a potential mechanism of postoperative ileus. AB - AIM: To explore whether mitochondrial energy metabolism disorder and apoptosis of smooth muscle cells in intestinal muscularis are participated in pathogenesis of postoperative ileus (POI). METHODS: Rats were randomized into three groups: naive controls (NC) group, sham controls (SC) group and intestinal manipulation (IM) group. Gastrointestinal transits were analyzed. Reactive oxygen species (ROS), malondialdehyde (MDA) and adenosine triphosphatases (ATPases) activity in intestinal muscularis were determined. The levels of aldehyde dehydrogenase 2 (ALDH2), Bcl-2 and Bax in intestinal muscularis were measured by real-time PCR assays and western blot analysis. The levels of ATP, ADP and AMP in intestinal muscularis were determined by high performance liquid chromatography. Transmission electron microscopic was used to observe ultrastructure of smooth muscle cells and mitochondria in intestinal muscularis. RESULTS: Delayed gastrointestinal transitoccurred only in IM groups. After IM, increased levels of ROS and MDA were observed in intestinal muscularis. In IM groups, we also observed decreased levels of ALDH2 and Bcl-2/Bax ratio. The levels of ATP and ADP were decreased and level of AMP was increased in IM groups. The activity of ATPases was decreased in IM groups. Abnormal morphological architecture of smooth muscle cells and mitochondria were found in intestinal muscularis of IM groups. CONCLUSION: Our results suggest that mitochondrial energy metabolism disorder and apoptosis of smooth muscle cells in intestinal muscularis may participate in the development of POI. PMID- 26628971 TI - Berberine protects vascular endothelial cells in hypertensive rats. AB - OBJECTIVE: This study is to investigate the effect and mechanism of berberine on vascular endothelial cell injury. METHODS: The isolated aortic endothelial cells were divided into negative control group, spontaneous hypertension group, and berberine group (1.25, 2.5, and 5 MUmol/L berberine). CCK-8 assay was performed to detect cell proliferation. Annexin V-FITC flow cytometry and Hochest33342/PI staining were used to measure cell apoptosis. Expression of TLR4, Myd88, and NF kappaB was detected with Western blotting analysis. Level of IL-6 and TNF-alpha was measured with ELISA. RESULTS: Compared with spontaneous hypertension group, cell proliferation in berberine group was significantly improved (P < 0.05). Flow cytometry showed that cell apoptosis was reduced in berberine group in a dose dependent manner and there was statistically significant difference between spontaneous hypertension group and berberine group (P < 0.05). This result was further confirmed by Hochest33342/PI staining. Expression levels of TLR4, Myd88 and NF-kappaB were increased in spontaneous hypertension group. However, their expression levels were significantly reduced in berberine group than those in spontaneous hypertension group (P < 0.05). Similarly, levels of IL-6 and TNF alpha were increased in spontaneous hypertension group and decreased in berberine group. And, the difference was significant (P < 0.05). Importantly, there were significant differences between negative control group and spontaneous hypertension group in cell proliferation, apoptosis, and expression of TLR4, Myd88, NF-kappaB, IL-6 and TNF-alpha. CONCLUSION: Berberine plays a protective role in vascular endothelial cell injury through inhibiting apoptosis and expression of TLR4, Myd88, NF-kappaB, IL-6 and TNF-alpha. PMID- 26628972 TI - The effects of self-assembling peptide RADA16 hydrogel on malignant phenotype of human hepatocellular carcinoma cell. AB - The aim of this study will provide a self-assembling peptide (RADA16-I) -derived hydrogel as a tool for investigation the malignant phenotype of human hepatocellular carcinoma cell. Characteristic analysis indicated that the peptide consists of a well-defined secondary structure and self-assembly property. Our results showed that these cells cultured in RADA16-I hydrogels showed a spindle shaped phenotype with irregular and radial nuclei. Immunohistochemical results showed that the expression of fibronectin in hepatocellular carcinoma cells is positive cultured in RADA16-I hydrogels, and the expression levels of laminin are weakly positive. DNA contents cultured in RADA16-I hydrogel gradually increased up to Day 9. The expression levels of VEGFA, EGF and FGF2 in three hydrogels showed no statistically significant differences (P > 0.05), and the expression levels of IGF-1 in RADA16-I and collagen-I were significantly lower than those of in the Matrigel hydrogel (P <= 0.05). These findings suggested that the RADA16-I will help to provide a better physiological substrate for hepatocellular carcinoma cell culture, may serve as an ideal model for cancer biology research of tumorigenesis, growth, local invasion, and metastasis. PMID- 26628973 TI - Association between the MYO9B polymorphisms and celiac disease risk: a meta analysis. AB - BACKGROUND: There is no consensus regarding the association between polymorphisms in the myosin IXB (MYO9B) gene and celiac disease (CD) risk. In this study, we performed a meta-analysis to evaluate genetic variants in MYO9B with CD. METHODS: Four MYO9B polymorphisms (rs1545620, rs1457092, rs2305767 and rs2305764) were assessed. A literature search was conducted using PubMed, Scopus, and Web of Science databases until June 2015. Odds ratio (OR) and 95% confidence interval (CI) were used to investigate the strength of the association under dominant, recessive, homozygote and allelic comparison models. RESULTS: Seven case-control studies with a total of 1965 CD patients and 4894 controls were included in this meta-analysis. The results showed that rs1545620 was associated with CD risk in Europeans in dominant (OR=1.31, 95% CI: 1.10-1.58, Pz =0.003), recessive (OR=1.36, 95% CI: 1.08-1.72, Pz =0.009), homozygote (OR=1.55, 95% CI: 1.20-2.01, Pz =0.001), and allelic comparison models (OR=1.24, 95% CI: 1.10-1.40, Pz =0.001), whereas in a Latin American group there were significant associations of CD with rs1457092 in dominant (OR=15.30, 95% CI: 3.51-66.67, Pz <0.001), homozygote (OR=16.55, 95% CI: 3.62-75.65, Pz <0.001), and allelic comparison models (OR=1.95, 95% CI: 1.31-2.91, Pz =0.001), and rs2305767 in dominant (OR=5.35, 95% CI: 2.42-11.86, Pz <0.001) and allelic comparison models (OR=1.65, 95% CI: 1.11-2.45, Pz =0.013). There was no association between rs2305764 and CD risk in either Europeans or the Latin American group. CONCLUSION: rs1545620 is associated with CD risk in Europeans, whereas rs1457092 and rs2305767 are associated with CD risk in a Latin American group. PMID- 26628974 TI - Effect of hyperbaric oxygen on MMP9/2 expression and motor function in rats with spinal cord injury. AB - To study the effect of hyperbaric oxygen intervention on the microenvironment of nerve regeneration after spinal cord injury modeling and to explore the possible mechanism of nerve regeneration and functional recovery in rats with spinal cord injury. In 98 adult female SD rats, 90 successful models were obtained, which were divided into sham group, spinal cord injury group and hyperbaric oxygen group using randomized block method, 30/group. Spinal cord injury rat model was established in accordance with the modified Allen method. Motor function was assessed at the time points of before modeling, one day, three days, one week, two weeks, three weeks and four weeks after modeling respectively by BBB rating, inclined plane test and improved Tarlov score. At 3 days after modeling, apoptosis of neuronal cells in spinal cord injury region in experimental group was detected by TUNEL method; gene and protein expression of MMP9/2 in spinal cord injury and surrounding tissues was detected by RT-PCR and Western blot assay. At 4 weeks after modeling, histopathological morphological changes in spinal cord injury were observed by HE staining; fluorogold retrograde tracing was used to observe the regeneration and distribution of spinal cord nerve fibers and axon regeneration was observed by TEM. The three motor function scores in hyperbaric oxygen group at each time point after two weeks of treatment were significantly increased compared with spinal cord injury group (P < 0.05). At 3 d after modeling, apoptosis index in hyperbaric oxygen group were significantly lower than those in spinal cord injury group (P < 0.05). At 72 h after modeling, compared with spinal cord injury group, MMP9/2 gene and protein expression in hyperbaric oxygen group was significantly lower (P < 0.05). At four weeks after modeling, fluorogold positive nerve fibers were the most sham group, followed by hyperbaric oxygen group and spinal cord injury group in order; the differences among the groups were statistically significant (P < 0.05). Under TEM, newborn unmyelinated and myelinated nerve fibers could be observed in the middle cross section in the sham group and hyperbaric oxygen group; unmyelinated and myelinated nerve fibers in hyperbaric oxygen group were more than those in spinal cord injury group. Hyperbaric oxygen therapy played a protective effect on spinal cord injury through reducing apoptosis of neuronal cells and expression of MMP9/2 gene and protein in rats with spinal cord injury. PMID- 26628975 TI - Interleukin-33 and receptor ST2 as indicators in patients with asthma: a meta analysis. AB - IL33/ST2 axis activates airway eosinophils that exacerbate airway inflammation. The data was obtained from PubMed, EMBASE, Clinical trial, Cochrane Library, Web of science, CNKI and Wanfang database with time restrictions of 1 Jan, 2000 to 15 Feb, 2016. The meta-analysis was performed using Review Manager 5.2 software. After searching, total 15 documents were included into this meta-analysis, involving in 633 asthma patients and 379 healthy people. The meta-analysis results revealed that the serum IL33 or ST2 level was higher in asthma patients compared to that in healthy people. (P=0.02, 95% CI (7.57, 72.74); P<0.0001, 95% CI (31.27, 91.32)). Compared to healthy people, severe, moderate or mild asthma patients had much higher serum IL33 level. (P<0.00001, 95% CI (87.86, 188.09); P<0.00001, 95% CI (31.93, 72.29); P<0.00001, 95% CI (100.51, 153.08), respectively). The serum ST2 level in different asthma progress included severe or moderate was higher, (P<0.00001, 95% CI (50.76, 76.93); P<0.00001, 95% CI (1.02, 1.79), respectively) but nor mild. (P=0.30, 95% CI (-22.37, 72.61)). The meta-analysis result shown the sputum IL33 was not higher in moderate asthma patients than that in healthy people. (P=0.20, 95% CI (-1.99, 9.52)) The meta analysis results shown that there were significantly difference between and among two asthma progress, (P<0.00001, 95% CI (14.02, 19.09), severe vs moderate; P<0.00001, 95% CI (0.52, 1.24), moderate vs mild) However, there was no significant differences between severe group and mild group. (P=0.08, 95% CI ( 20.95, 336.50)). Serum IL33 and ST2 level is relevant to asthma disease. With asthma disease progress, IL33 and ST2 are increased significantly. PMID- 26628976 TI - Effect of early external X-ray radiation on arterial restenosis post percutaneous transluminal angioplasty. AB - BACKGROUND: Arterial restenosis after percutaneous transluminal angioplasty (PTA) significantly reduces its therapeutic efficacy in treating lower extremity atherosclerotic occlusive diseases (LEAOD). Early external X-ray external radiation has demonstrated positive effects on restenosis; however, effective dosing and the mechanism(s) underlying its efficacy remain unknown. This study explored the effect of early external X-ray radiation on preventing post-PTA restenosis in an iliac intimal injury model. METHODS: Twenty rabbits underwent iliac intimal injury via PTA and received five different radiation doses: 0 Gy (n=4), 3 Gy (n=4), 6 Gy (n=4), 9 Gy (n=4), and 12 Gy (n=4). Four rabbits were used as controls. All subjects were fed a high-fat diet prior to PTA and for an additional four-week period post-PTA and then sacrificed for immunohistochemical and Western blotting analysis. RESULTS: Arterial stenosis was significantly improved post-PTA. Alpha smooth muscle actin (alpha-SMA) expression in the 0 Gy to 9 Gy groups was significantly increased post-PTA. Cytochrome C (Cyt C) expression was significantly increased post-PTA and was positively correlated with radiation intensity. Proliferating cell nuclear antigen (PCNA) expression was significantly increased post-PTA with the 0 Gy group showing significantly higher expression than the 3 Gy group. No significant differences were found in CD34 levels between the groups. CONCLUSIONS: Early external X-ray radiation at 6 24 Gy doses effectively restrained VSMC hyperplasia post-PTA, likely through inducing VSMC apoptosis via mitochondrial Cyt C release. However, this technique did not significantly affect the integrity of the vascular endothelium. Therefore, early external X-ray radiation shows promise in preventing post-PTA restenosis. PMID- 26628977 TI - Post-conditioning through lower limb ischemia-reperfusion can alleviate lung ischemia-reperfusion injury. AB - OBJECTIVE: Operation on the infrarenal aorta could cause ischemic-reperfusion (IR) injury in local tissues and remote organs (e.g. the lung). We aim to explore the method of reducing lung ischemia-reperfusion damage after lower limb IR with post conditioning (LIPC). METHODS: Bilateral lower limb ischemia was performed in Sprague-Dawley (SD) rats, and then animals were divided into 4 groups: IR-Sham operated, IR, post conditioned-IR (LIPC) and bilateral lower limb ischemia (LIR). The serum free radical, histological changes, Wet/Dry (W/D) ratio, levels of TNF alpha, IL-6, cytokines and chemokines were tested and compared. RESULTS: Post conditioning could ameliorate histological injuries in the lung when compared to IR group. The serum free radical is significantly lower in LIPC group than IR groups. W/D ratio in LIPC groups is significantly lower. LIPC also could reduce the expression of cytokines and chemokines. CONCLUSION: post conditioning could reduce long-term damages of the lung after lower limb ischemic-reperfusion injury. PMID- 26628978 TI - Role of WNT1-inducible-signaling pathway protein 1 in etoposide resistance in lung adenocarcinoma A549 cells. AB - OBJECT: The aim of this study was to explore the role of WNT1-inducible-signaling Pathway Protein 1 (WISP-1) in etoposide resistance in lung adenocarcinoma A549 cells. METHODS: WISP-1 overexpression A549 lung adenocarcinoma cell was established. After exposure to ultraviolet (UV) and etoposide, cell viability and apoptosis were evaluated. Moreover, western-blot was employed to examine the expression of apoptotic pathway proteins. In addition, a nude mice tumor model was established to examine the effect of WISP-1 overexpression in vivo and TUNEL staining was used to assess cell apoptosis of tumor tissue. RESULTS: WISP-1 overexpression significantly increased cell viability and decreased cell apoptosis after treatment with UV and etoposide. Decreased expression of Bad and Bax and increased expression of Bcl-2 was found after etoposide treatment in WISP 1 overexpressed cells. A significantly increasing of tumor volume in WISP-1 overexpressed group was found and TUNEL staining revealed that decreased cell apoptosis in WISP-1 overexpressed group. CONCLUSION: Our results demonstrated that WISP-1 may have a facilitating role in etoposide resistance through increasing cell viability and decreasing cell apoptosis. PMID- 26628979 TI - XRCC1 polymorphisms and lung cancer risk in Caucasian populations: a meta analysis. AB - X-ray repair cross-complementing group 1 (XRCC1) plays an important role in the base excision repair. Many studies have reported the association of XRCC1 Arg399Gln, Arg194Trp and Arg280His polymorphisms with lung cancer risk, but the results remained controversial. In this meta-analysis, we performed a meta analysis of ten published case-control studies in Caucasian populations to investigate the associations between lung cancer risk and XRCC1 Arg399Gln (2187 cases and 3453 controls from ten studies), Arg194Trp (857 cases and 2108 controls from six studies) and Arg280His (894 cases and 1133 controls from five studies). The results in total population showed that XRCC1 codon 399 polymorphism (OR=0.93, 95% CI=0.82-1.04) and codon 194 (OR=0.94, 95% CI=0.73-1.21) was significantly associated with lung cancer risk. However, no association was found between lung cancer risk and codon 280 (OR=1.17, 95% CI=0.89-1.54). In conclusion, this meta-analysis has demonstrated that codon 399 and codon 194 might have contributed to individual susceptibility to lung cancer in Caucasian populations. To further evaluate effect of XRCC1 polymorphisms, large studies with thousands of subjects are required to get conclusive results. PMID- 26628980 TI - A meta-analysis of the relationship between vitamin D deficiency and obesity. AB - Previous epidemiologic studies suggested that vitamin D deficiency may be a risk factor of obesity. However, the result is still controversial. This meta-analysis aims to provide a comprehensive summary on the association between vitamin D deficiency and obesity. We systematically searched Pubmed database, Chinese Wanfang Data Knowledge Service Platform, and Chinese National Knowledge Infrastructure (CNKI), for the literatures on the relationship between vitamin D deficiency and obesity published from 2010 to 2015. The effect sizes of overall odds ratio (OR) and 95% confidence interval (CI) were estimated using Stata 11.0. Heterogeneity was evaluated using random-effects model and forest plots. Fifteen studies were eligible for inclusion in the meta-analysis, which included 3867 subjects with obesity and 9342 health subjects. Meta-analysis results showed that the prevalence of vitamin D deficiency was difference between obesity group and control group, and the pooled OR (95% CI) was 3.43 (2.33-5.06). The prevalence of vitamin D deficiency was associated with obesity in Asians and European-American, OR (95% CI) were 3.70 (1.98-6.90) and 3.09 (1.89-5.04), respectively. No publication bias was found in our study. vitamin D deficiency may be associated with obesity, irrespective of areas. PMID- 26628981 TI - Curcumin protects against cerebral ischemia-reperfusion injury by activating JAK2/STAT3 signaling pathway in rats. AB - Curcumin (Cur) is the active component in Curcuma longa, and it has been reported to exhibit a variety of biological effects such as anti-inflammation and anti oxidation. This study aims to investigate the effect of Cur on cerebral ischemia reperfusion injury and whether the Janus kinase 2 and signal transducer and activator 3 of transcription (JAK2/STAT3) signaling pathway is involved in the neuroprotective effects of Cur. Rats were subjected to 2 h transient middle cerebral artery occlusion (MCAO), followed by 24 h reperfusion. Rats were randomly assigned into sham group, MCAO group, MCAO + Cur group. AG490, a JAK2 inhibitor, was utilized to throw light upon the underlying mechanism. The results suggested that compared to MCAO, Cur attenuated neurological deficits, reduced cerebral infarction area and lowered brain water content. In addition, Cur reduced the activity of IL-1beta and IL-8. The results of western blot indicated that Cur enhanced the expression of p-JAK2 and p-STAT3, which was abolished by AG490 administration. Our results suggested that Cur protects effects against cerebral I/R injury through the activation of JAK2/STAT3 signaling pathway. PMID- 26628982 TI - Single-incision multiport laparoscopy versus multichannel-tipped single port laparoscopy in gynecologic surgery: outcomes and benefits. AB - OBJECTIVE: To estimate the feasibility and safety of single-incision multiport laparoscopy (SIMPL) used in patients who underwent laparoendoscopic single-site surgery (LESS) for gynecologic disease, and the cosmetic outcome and economic benefit compared with multichannel-tipped single port laparoscopy (MSPL). INTERVENTION: We underwent LESS via a single 2.5- to 3.0-cm umbilical incision with the Single-Incision Multiport Laparoscopic Surgery Trocar available on the market, briefly named MSPL. Since January 2014, we improved the procedure and named SIMPL. In SIMPL group, two traditional laparoscopic trocar (diameter=5 mm) and one mini-laparoscopic trocar (diameter =3 mm) were inserted into the peritoneum separately through a single 1.5- to 1.8-cm umbilical transcutaneous incision. Subject demographics and clinical variables were collected and perioperative outcomes analyzed. In addition, the size of umbilicus was measured in all patients prior to the operation and the levels of cosmetic satisfaction were evaluated at 4 weeks after surgery. MEASUREMENTS AND MAIN RESULTS: From January 2014 to December 2014, there were 32 patients who underwent SIMPL for ovarian cystectomy. Hospital cost was significantly lower in SIMPL group compared with MSPL group (RMB 10207.0 vs 17973.7 yuan), P<0.001. Compared with MSPL group, the SIMPL group reported significantly higher cosmetic satisfaction at 4 weeks afer surgery (P<0.1). Besides, the SIMPL procedures performed in benign gynecologic surgery were myomectomy (n=8), salpingpoophorectomy (n=2), salpingectomy (n=5), adhesiolysis and fimbrioplasty (n=32), ovarian drilling (n=3), salpingotomy for ectopic pregnancy (n=3). All surgeries were completed successfully without conversion to the traditional laparoscopic approach. Two postoperative complications occurred were delay healing of umbilicus incision after myomectomy. The cosmetic satisfactory rate was 100%. CONCLUSION: According to our experience, SIMPL is safe and efficient for simple gynecologic operation, with lower cost and better cosmetic results than MSPL. Beyond cosmetic and economic results, further randomized studies are needed to identify a possible benefit. PMID- 26628983 TI - Interferon-lambda1 suppresses invasion and enhances autophagy in human osteosarcoma cell. AB - OBJECTIVE: The purpose of the present study was to determine whether type III IFN can modulate the autophagic response in human osteosarcoma cell. METHODS: Human osteosarcoma cell were treated with Interferon-lambda1. We investigated that Interferon-lambda1 could inhibit the invasive ability of osteosarcoma cells by Matrigel invasion assay. Autophagy were assessed by acridine orange staining, MDC staining and Transmission electron microscopy. RESULTS: In this study, we found that Interferon-lambda1 could inhibit the invasive ability of osteosarcoma cells. Acridine orange staining and MDC staining showed that Interferon-lambda1 triggered the accumulation of acidic vesicular and autolysosomes in osteosarcoma cell. The acridine orange osteosarcoma cell ratios were 3.6 +/- 0.5%, 4.5 +/- 0.8%, and 12.4 +/- 1.7% after treatment with 1, 10, and 100 ng/mL Interferon lambda1 for 48 h. Osteosarcoma cell cells treated with 100 ng/mL Interferon lambda1 for 48 h developed autophagy some-like characteristics, including single or double-membrane vacuoles containing intact and degraded cellular debris. CONCLUSIONS: Interferon-lambda1 could inhibit the invasive ability of osteosarcoma cells. Autophagy can be induced in a dose-dependent manner by treatment with Interferon-lambda1 in osteosarcoma cell. PMID- 26628984 TI - Anatomic variations in the anterior circulation of the circle of Willis in cadaveric human brains. AB - OBJECTIVE: The Cycle of Willis unites the internal carotid and vertebrobasilar system and maintains the stability of blood supply to the brain. This present study aims to analyze the anatomic variations in the anterior part of the Cycle of Willis. METHODS: Forty five formalin-preserved human brains (90 cerebral hemispheres) with intact dura mater from Chinese adults were dissected under the surgical microscope. The anterior components of the Circle of Willis were observed and measured. Anatomic variations of this segment were observed and photographed. The data collected in this investigation was statistically analyzed. RESULTS: In approximately 13.3% (6/45) of all cerebral samples, a caliber difference of >= 0.5 mm was noted between the left A1 and the right segments. The A2 segments of left and right hemispheres were derived from the contralateral A1 segment in 6.7% (3/45) of the brain specimens. Simple anterior communicating artery (ACoA) was observed in 37.8% (17/45) whereas complex ACoA was noted in 60% (27/45) of cerebral samples. CONCLUSION: As it demonstrates the anatomic variations of ACAC, all surgical approaches should be performed after angiographic demonstrations. Understanding of these anatomic variations plays a pivotal role in neurovascular procedures. PMID- 26628985 TI - Molecular epidemiology of respiratory adenovirus detection in hospitalized children in Shenzhen, China. AB - OBJECTIVE: This study aimed to understand the molecular type of respiratory adenovirus in hospitalized children in Shenzhen and the relation to clinical diagnoses. METHODS: Nasopharyngeal swab specimens were obtained from 6,479 hospitalized children younger than 14 years with respiratory tract diseases in Shenzhen Children's Hospital from December 2012 to November 2013. Nasopharyngeal swabs were routine examined by direct immunofluorescence assay to detect respiratory agents including seven respiratory viruses. Multiplex PCR of adenovirus types 3, 7, 11 and 21 in a single tube based on the sequence of the encoding gene for hexon was used to type for adenovirus positive specimens. For those strains that could not be typed by multiplex PCR, the gene fragment was amplified by a universal primer pair for all adenovirus types and the PCR products were sequenced directly. RESULTS: A total of 1,066 of 6,479 (16.45%) specimens were positive for at least one of the seven viruses and 228 of 6,479 (3.52%) specimens were positive for adenovirus. 86.4% of children with adenovirus infection occurred less than 5 years of age and just over half of the children (54.4%) less than two years old. There was no significant difference in infection rates between males and females. AdV3 (46.3%) and AdV7 (36.3%) were the genotypes most commonly found followed by AdV1 (6.0%), AdV4 (5.0%), AdV2 (3.0%), AdV6 (1.5%), AdV5 (1.5%) and AdV3/7 (0.5%). No type 11, type 21, and other types of adenovirus were detected. Seven children had type 3 or type 7 and one had type 3/7 mixed infection in 15 severe pneumonia cases. CONCLUSIONS: Our study demonstrated that respiratory adenovirus infection is an important cause of hospitalizations in children in Shenzhen, China. Types 3 and 7 were the most common followed by types 1 and 4. AdV3 and AdV7 were similarly contributed to the severe cases. PMID- 26628986 TI - Prospective cohort study to evaluate the efficacy of taxane plus platinum and CPT 11plus platinum regimes and to identify prognostic risk factors in cervical cancer patients. AB - OBJECTIVE: This study was designed to evaluate the response, toxicity and survival of taxanes plus platinum (TP) and CPT-11plus platinum (CP) as neoadjuvant chemotherapies with previously untreated cervical cancer, and to identify prognostic risk factors in these patients. METHODS: A cohort study was performed to evaluate the result of TP and CP regimes in the treatment of cervical cancer patients. RESULTS: The study included 567 patients with locally advanced cervical cancer (LACC) staged as FIGO IB-IIB in our clinical departments. Clinical response was found in 76.1% and 78% of patients in the TP and CP arms, respectively, and no treatment-related deaths were reported. During the follow-up period, disease-free survival (DFS) and overall survival (OS) for the TP and CP arms were not different (P = 0.384 for DFS, P = 0.800 for OS). The CP regime showed higher survival rate for endophytic growth style (P = 0.013 for DFS, P = 0.027 for OS). The CP regime also showed higher DFS and OS for G2 tumor (P = 0.027 for DFS, P = 0.032 for OS). In multivariate cox's proportional hazards regression model, the average death rates were much greater in the non-responder group (HR, 2.68), in the older (> 44 years) group (HR, 2.51), and in the FIGO stage II b patients (HR, 2.84). CONCLUSIONS: The CP regime showed higher survival rate for endophytic growth style or G2 tumor. Clinical response, age and FIGO stage were independent prognostic risk factors in this study for both DFS and OS. PMID- 26628987 TI - The miR-101/RUNX1 feedback regulatory loop modulates chemo-sensitivity and invasion in human lung cancer. AB - The deregulation of miR-101 has been implicated in multiple cancer types including lung cancer, but the exact role, mechanisms and how silencing of miR 101 remain elusive. Here we confirmed miR-101 downregulation in lung cancer cell lines and patient tissues. Restored miR-101 expression remarkably sensitized lung cancer cells to chemotherapy and inhibited invasion. Mechanistically, we indicated that miR-101 inversely correlated with RUNX1 expression, and identified RUNX1 as a novel target of miR-101. RUNX1 impaired the effects of miR-101 on chemotherapeutic sensitization and invasion inhibition. Moreover, RUNX1 knockdown resulted into increase of miR-101 expression and elevation of luciferase activity driven by miR-101 promoter in lung cancer cells, suggesting RUNX1 negatively transcriptionally regulated miR-101 expression via physically binding to miR-101 promoter. These findings support that miR-101 downregulation accelerates the progression of lung cancer via RUNX1 dependent manner and suggest that miR 101/RUNX1 feedback axis may have therapeutic value in treating refractory lung cancer. PMID- 26628988 TI - The abnormal expression of CCR4 and CCR6 on Tregs in rheumatoid arthritis. AB - The study aims to investigate the frequency of CD4(+)CD25(+)Foxp3(+)CD127(-) T regulatory cells (Tregs) and the expression of CCR4, CCR6 and/or other chemokine receptors on Tregs in peripheral blood (PB) in patients with rheumatoid arthritis, as well as in PB, draining lymph nodes (dLNs), lungs and spleens in collagen-induced arthritis (CIA) mice. We also study the possible role of CCR4 and CCR6 abnormal expression on Tregs in RA patients and the underlying mechanisms. The numbers of Tregs and chemokine receptors expression profile on Tregs in PB from RA patients and healthy controls were investigated by flow cytometry (FACS) using three- or four-color intracellular staining. DBA/1 Foxp3(gfp) reporter mice were immunized with collagen II (CII) emulsified with CFA. At day 60 after CII immunization, mice were sacrificed and Foxp3 (GFP) expression in PB, dLNs, Lungs and spleens was examined by FACS. The numbers of Tregs in PB were significantly lower in RA patients than in healthy controls (1.21+/-0.43% vs 3.50+/-0.98%, P<0.05). The levels of chemokine receptor CCR4 or CCR6 expression on Tregs in PB were higher in active RA patients than in healthy controls (91.13+/-2.98% vs 79.45+/-4.72%, P<0.05; or 67.33+/-7.53% vs 42.73+/ 5.60%, P<0.05). The levels of CCR4 or CCR6 expression on Tregs in active RA patients were positively correlated to DAS28 scores (r=0.42, P<0.03; or r=0.58, P<0.02). Similarly, the numbers of CCR6 expression on GFP(+) cells in the spleens, dLNs, lungs and blood of CIA were all increased than those of normal mice (P<0.01). Frequency of CCR4 expression on GFP(+) cells in dLNs of CIA was somehow higher but slightly lower in the spleens of CIA compared to normal mice without significant differences (P>0.05). Frequency of CCR5 expression on GFP(+) cells in the spleens and dLNs of CIA were both increased than those of normal mice, but there were no significant differences (P>0.05). CCR7 or CCR9 expression on Tregs from spleen and dLN of either normal or CIA mice was undetectable. Although the frequency of CD4(+)Foxp3(+)Tregs in peripheral blood was decreased in active rheumatoid arthritis patients, the levels of chemokine receptors such as CCR4 and CCR6 among the Tregs were increased, implicating that Tregs in active RA have obtained the ability migrating to inflammatory joints and may reflect the feedback regulation of the body to local inflammation. Furthermore, CCR4 and CCR6 expressed on Tregs may be related to the activity and severity of RA. PMID- 26628989 TI - Emodin inhibits HMGB1-induced tumor angiogenesis in human osteosarcoma by regulating SIRT1. AB - The anti-cancer effects of emodin, including inhibition of proliferation, invasion, metastasis and angiogenesis, were confirmed by various previous studies. However, the specific mechanisms were not clear. In this study, we investigated emodin's anti-angiogenesis effect and focused on the mechanisms in human osteosarcoma (OS). OS cells were implanted to nude mice to form OS xenografts. Immunofluorescence assay was used to assess vWF expression in tumor tissue. MTT assay was employed to screen proper emodin concentrations unrelated with proliferation inhibition. siRNA technique was utilized to silence SIRT1 expression in OS cells. Expression levels of SIRT1 and VEGF were investigated by real-time PCR and western blotting. H4-k16Ac expression which indicated the deacetylation activity of SIRT1 was also detected by western blotting. As in results, HMGB1 treatment exacerbated OS angiogenesis both in vivo and in vitro. Emodin administration attenuated angiogenesis in both OS and HMGB1 treated OS in vivo and in vitro. After emodin treatment, the expression level and deacetylation activity of SIRT1 were dramatically enhanced. HMGB1-induced angiogenesis was more striking in SIRT1 silenced OS cells. SIRT1 silencing also impaired the anti angiogenesis effect of emodin in OS cells. IN CONCLUSION: SIRT expression and deacetylation activity elevation are involved in emodin's anti-angiogenesis effect in human OS. PMID- 26628990 TI - Neuroprotection by epigallo catechin gallate against bupivacaine anesthesia induced toxicity involves modulation of PI3/Akt/PTEN signalling in N2a and SH SY5Y cells. AB - Bupivacaine, an amide type long-acting local anaesthetic is commonly employed for epidural anesthesia and as well for nerve blockades. However, studies have shown neurotoxicity following local administration of bupivacaine raising concerns over the use of the drug. Compounds that could minimize or inhibit toxic effects of bupivacaine are of high value in operative settings and in pain management. The present study aims to investigate if epigallo catechin gallate (EGCG) could inhibit or prevent bupivacaine toxicity in neuroblastoma cells (N2a and SH-SY5Y). The viability of N2a and SH-SY5Y cells following exposure to EGCG (10-50 uM) were assessed by MTT assay and Annexin V/PI staining. The influence of EGCG on ROS generation was determined. The expression of apoptotic cascade proteins (Caspases 3, -8 and -9, Bcl-xL, Bad, Bax, Bcl-2) and PI3/Akt pathway proteins (Akt, p-Akt, GSK-3beta, p-GSK-3beta, PTEN) were analyzed by western blotting. EGCG improved the viability of the cells and inhibited apoptosis by potentially decreasing the expression of caspases and pro-apoptotic proteins. Bupivacaine induced ROS generations were reduced on EGCG exposure. EGCG significantly promoted the phosphorylation of Akt and GSK-3beta and down-regulated PTEN, thus activating PI3/Akt signalling. EGCG effectively improved the cell viability and inhibited apoptosis of N2a and SH-SY5Y cells via suppression of ROS generation and modulation of PI3K/Akt signalling cascade. PMID- 26628991 TI - In vitro and in vivo effects of ethanol extract combined with Curcumae Radix and Glycyrrhizae Radix et Rhizoma on menopausal metabolic disturbances. AB - Curcumae Radix (CR) and Glycyrrhizae Radix et Rhizoma (GR) extracts have been used as health supplements in traditional medicine. This study was performed to evaluate the effects of combined CR and GR extracts (CR+GR) on metabolic complications related menopausal symptoms. We found a significant results that CR+GR extracted using ethanol stimulated the growth of MCF-7 cells in estrogen activity and was attenuated in lipid deposition of HepG2 cells treated with MbetaCD compared to CR and GR treatments each. To investigate the situation, an experimental menopause rat model with dyslipidemia was induced by surgical bilateral ovariectomy (OVX) and high fat high cholesterol (HFHC) diet in female rats. OVX rats fed HFHC (OVX-HFHC) showed a shift in weight gain, elevated serum cholesterol, altered liver enzymatic parameters and enhanced liver injury compared to the NC and HFHC groups. However, administration of CR+GR, in particular 200 or 450 mg/kg/day, inhibited the increase in body weight gain and lipid metabolic disturbances, lowering total cholesterol (TC), triglycerides (TG) and low density lipoprotein cholesterol (LDL-C) compared to the OVX-HFHC group. Furthermore, CR+GR (200 or 450 mg/kg/day) ameliorated the serum levels of the liver enzymes aspartate aminotransferase (AST) and alanine transaminase (ALT) compared to the OVX-HFHC group. Moreover, CR+GR (200 or 450 mg/kg/day) attenuated not only hepatic steatosis but also larger adipocytes. Our study demonstrated that combined treatment with CR and GR attenuated metabolic complications induced by OVX and HFHC diet, suggesting that this effect may regulate and prevent the acceleration of cardiovascular disease (CVD) after menopause. PMID- 26628992 TI - Hypoxia-induced HMGB1 in would tissues promotes the osteoblast cell proliferation via activating ERK/JNK signaling. AB - High mobility group box-B1 (HMGB1) is upregulated in tumors, inflammations, and other injuries. However, its extracellular role and signaling in wound healing remains unclear. In the present study, we examined the HMGB1 levels in hematoma samples in fractured bones and in human macrophagy U937 cells under hypoxia with enzyme-linked immunosorbent assay (ELISA) and western blotting. Then we investigated the activation of the extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinases (JNK) signaling western blotting in osteoblast MG-63 cells under hypoxia, with or without HMGB1 treatment. And then we assessed the effects of extracellular HMGB1 on cell proliferation of MG-63 cells with CCK-8 assay. It was demonstrated that HMGB1 expression was significantly up regulated in hematoma samples in fractured bones and in U937 cells under hypoxia. MG-63 cells under hypoxia showed an increased HMGB1 in the cytoplasm rather than in nuclei. And the extracellular HMGB1 ameliorated the hypoxia-induced viability reduction and promoted the proliferation of MG-63 cells. Moreover, the MG-63 cells incubated with HMGB1 had increased ERK1/2 phosphorylation, whereas such effect was blocked by the TLR-4 knockout with SIRNA-TLR-4 transfection. In conclusion, we found the up regulation HMGB1 in the hematoma of fractured bones and in macrophage U937 cells under hypoxia, and the hypoxia-up regulated HMGB1 promoted the proliferation of osteoblast MG-63 cells and activated the phosphorylation of ERK and JNK. And the proliferation promotion and the activation of ERK/JNK signaling was TLR-4-dependent. PMID- 26628993 TI - Apoptotic effects of Photofrin-Diomed 630-PDT on SHEEC human esophageal squamous cancer cells. AB - Photodynamic therapy (PDT) using photofrin-II is a clinically effective treatment for both non-neoplastic and neoplastic diseases. Herein, we performed an in vitro experiment to study the anti-tumor effect and mechanisms of photofrin-II mediated PDT for esophageal squamous cell carcinoma (ESCC) cell line, SHEEC. In this study, human ESCC cell line SHEEC and parental normal cell line SHEE were used. The anti-tumor effect of PDT was determined by evaluating cell viability using CCK-8 assay, apoptosis and generation of reactive oxygen species (ROS). PDT induced significant apoptosis in SHEEC and SHEE cells in a time- and photofrin-II dose-dependent manner. Furthermore, PDT treatment induced significant death of SHEEC, instead of SHEE cells. The apoptotic outcome was accompanied by concurrent generation of ROS. In summary, PDT shed light on therapy of ESCC, functioning as a useful tool for ESCC clinical treatment, providing a better understanding of Photofrin-Diomed 630-PDT in SHEEC cells. PMID- 26628994 TI - Lin28B over-expression mediates the repression of let-7 by hepatitis B virus X protein in hepatoma cells. AB - The Let-7 microRNA (miRNA) family is frequently downregulated in multiple human tumors, including hepatocellular carcinoma (HCC). Our previous report demonstrated that hepatitis B virus X protein (HBx) suppressed the expression of let-7 in HepG2 hepatoma cells. However, the underlying mechanisms were not elucidated. Lin28B is known to negatively regulate the maturation of let-7, and this prompted us to determine whether HBx acts through Lin28B to suppress let-7. Real-time reverse-transcription polymerase chain reaction (qRT-PCR) was performed to examine let-7 expression before and after treatment with c-Myc-and Lin28B specific siRNAs in HepG2 cells stably/transiently transfected with HBx. mRNA and protein analyses were employed to determine the correlation of HBx, c-Myc and Lin28B in HCC tissues and cells. Cell cycle and proliferation assays were performed to delineate the consequences of Lin28B repression in HepG2 cells expressing HBx. Lin28B was overexpressed in HBx-transfected cells and HBV infected liver tissues. HBx-c-Myc-Lin28B axis mediated the repression of let-7 in HepG2 cells. Reduced expression of Lin28B inhibited the growth and cell cycle progression of HepG2 cells by derepressing let-7 and repressing c-Myc. There was not only a preliminary HBx-c-Myc-Lin28B-let-7 pathway but also another possible double-negative feedback loop between c-Myc/Lin28B and let-7 in HepG2 cells transfected with HBx, which together induced the deregulation of let-7. Lin28B has the potential to be a novel molecular target in the treatment of HBV(+) HCC. PMID- 26628995 TI - Special computer-aided computed tomography (CT) volume measurement and comparison method for pulmonary tuberculosis (TB). AB - The computed tomography (CT) manifestations in pulmonary tuberculosis (PTB) patients are complex and could not be quantitatively evaluated. We aimed to establish a new method to objectively measure the lung injury level in PTB by thoracic CT and make quantitative comparisons. In the retrospective study, a total of 360 adults were selected and divided into four groups according to their CT manifestations and medical history: Normal group, PTB group, PTB with diabetes mellitus (DM) group and Death caused by PTB group. Five additional patients who had continuous CT scans were chosen for preliminary longitudinal analysis. We established a new computer-aided CT volume measurement and comparison method for PTB patients (CACTV-PTB) which measured lung volume (LV) and thoracic volume (TV). RLT was calculated as the ratio of LV to TV and comparisons were performed among different groups. Standardized RLT (SRLT) was used in the longitudinal analysis among different patients. In the Normal group, LV and TV were positively correlated in linear regression (Y=-0.5+0.46X, R(2)=0.796, P<0.01). RLT values were significantly different among four groups (Normal: 0.40+/-0.05, PTB: 0.37+/ 0.08, PTB+DM: 0.34+/-0.06, Death: 0.23+/-0.04). The curves of SRLT value from different patients shared a same start point and could be compared directly. Utilizing the novel objective method CACTV-PTB makes it possible to compare the severity and dynamic change among different PTB patients. Our early experience also suggested that the lung injury is severer in the PTB+DM group than in the PTB group. PMID- 26628996 TI - High frequency of the SDK1:AMACR fusion transcript in Chinese prostate cancer. AB - Chromosomal rearrangements and fusion genes play important roles in tumor development and progression. Four high-frequency prostate cancer (CaP) specific fusion genes, SDK1:AMACR, RAD50:PDLIM4, CTAGE5:KHDRBS3 and USP9Y:TTTY15 have been reported in Chinese CaP samples through a transcriptome sequencing study. We previously reported that USP9Y:TTTY15 is a transcription-mediated chimeric RNA, which is expressed in both tumor and non-malignant samples, and here we attempted to confirm the existence of the other three fusion genes SDK1:AMACR, RAD50:PDLIM and CTAGE5:KHDRBS3. We detected SDK1:AMACR fusion transcript in 23 of 100 Chinese CaP samples, but did not detect RAD50:PDLIM4 and CTAGE5:KHDRBS3 transcripts in any of those samples. SDK1:AMACR fusion transcript is Chinese CaP specific, which was neither detected in non-malignant prostate tissues adjacent to cancer from Chinese patient nor in CaP samples from UK patients. However, we did not detect genomic rearrangement of SDK1 gene by fluorescence in situ hybridization analysis, indicating that SDK1:AMACR is also a transcription-mediated chimeric RNA. Quantitative analysis demonstrated that high level AMACR expression was associated with SDK1:AMACR fusion status (P=0.004), suggesting that SDK1:AMACR fusion transcript may promote prostate carcinogenesis through increasing AMACR expression. However, the fusion status was not significantly correlated with any poor disease progression clinical features. The identification of the SDK1:AMACR fusion transcript in CaP cases from China but not from UK further supports our previous observation that different genetic alterations contribute to CaP in China and Western countries, although many genetic changes are also shared. Further studies are required to establish if CaPs with SDK1:AMACR represent a distinct subtype. PMID- 26628997 TI - Saikosaponin-d attenuates ventilator-induced lung injury in rats. AB - Saikosaponin-d is one of the main bioactive components in the traditional Chinese medicine Bupleurum falcatum L and possesses anti-inflammatory and immune modulatory properties. The current study aimed to investigate the protective effects of saikosaponin-d on ventilator-induced lung injury (VILI) in rats. We found that saikosaponin-d treatment significantly attenuated the pathological changes of lungs induced by mechanical ventilation. Administration of saikosaponin-d reduced the pulmonary neutrophil infiltration as well as the MPO concentrations. Saikosaponin-d also decreased the expression of pro-inflammatory cytokines including MIP-2, IL-6 and TNF-alpha. Meanwhile, the expression of anti inflammatory mediators, such as TGF-beta1 and IL-10, was obviously elevated after saikosaponin-d administration. Saikosaponin-d remarkably reduced the oxidative stress and apoptosis rate in lung tissues. On the molecular level, saikosaponin-d treatment obviously downregulated the expression of caspases-3 and the pro apoptotic protein bax, and promoted the expression level of anti-apoptotic protein bcl-2. Collectively, our study demonstrated that saikosaponin-d may attenuate ventilator induced lung injury through inhibition of inflammatory responses, oxidative stress and apoptosis. PMID- 26628998 TI - The effect of siRNA-mediated lymphocyte-specific protein tyrosine kinase (Lck) inhibition on pulmonary inflammation in a mouse model of asthma. AB - OBJECTIVE: To explore the effect of siRNA-mediated inhibition of lymphocyte specific protein tyrosine kinase (Lck) on pulmonary inflammation in a mouse model of asthma. METHODS: A total of 32 female BABL/c mice were used in the study. The mouse asthma model was established with ovabumin (OVA), and Lck specific siRNA or nonspecific siRNA was transfected through the tail vein before the first OVA challenge. Two days after the last challenge, mice were sacrificed and bronchoalveolar lavage fluid (BALF), plasma and lung tissue were collected. Levels of Lck mRNA and protein in lung were detected by quantitative real-time PCR and western blot. The levels of IL-4 and IgE in BALF and plasma were detected with ELISA. RESULTS: Lck specific siRNA significantly inhibited expression of Lck mRNA and protein in T cells. In vivo transfection of Lck siRNA down regulated the expression of Lck mRNA and protein in lung parenchymal homogenates. Sensitized mice treated with Lck siRNA prior to OVA challenge had fewer eosinophils in BALF and in lung sections and lower levels of IL-4 and IgE in BALF and plasma compared to those treated with nonspecific siRNA. CONCLUSIONS: Pretreatment of OVA sensitized mice with Lck siRNA results in attenuation of pulmonary inflammation following OVA challenge. Inhibition of Lck gene expression should be investigated further as a potential therapy for asthma. PMID- 26628999 TI - Vitamin C inhibit the proliferation, migration and epithelial-mesenchymal transition of lens epithelial cells by destabilizing HIF-1alpha. AB - Posterior capsular opacification (PCO), the main complication of cataract surgery, is mainly caused by the proliferation, migration, and epithelial mesenchymal transition (EMT) of the residual lens epithelial cells (LECs).Vitamin C was reported to reduce the risk of forming a cataract. However, there has been no study showing the association between vitamin C and PCO. In this study, we found that vitamin C could inhibit the migration and proliferation of human lens epithelial cells. We also found that vitamin C could increase the proline hydroxylation of HIF-1alpha and reduce the activity of HIF-1alpha. Moreover, vitamin C could not inhibit the activity of proline-mutant HIF-1alpha (402/564). Overexpression of wild-type HIF-1alpha or proline-mutant HIF-1alpha was found to increase the proliferation and migration of human lens epithelial cells. Differently, vitamin C could inhibit the proliferation and migration in wild-type HIF-1alpha-overexpressing lens epithelial cells but not the proline-mutant HIF 1alpha-overexpressing cells. Additionally, vitamin C was also found to inhibit the expression of EMT transcription factors TWIST. We then found that vitamin C could repress the EMT phenotypes induced by the overexpression of wild-type HIF 1alpha but not the proline-mutant HIF-1alpha. These results provide evidence that vitamin C plays a role in the repression of proliferation, migration, and EMT of human lens epithelial cells by destabilizing HIF-1alpha. PMID- 26629000 TI - Determination of xanthotoxin using a liquid chromatography-mass spectrometry and its application to pharmacokinetics and tissue distribution model in rat. AB - A simple and selective liquid chromatography mass spectrometry method for determination of xanthotoxin in rat plasma and various tissues for pharmacokinetic was developed. Chromatographic separation was achieved on a C18 (2.1 mm * 150 mm, 5 MUm) column with acetonitrile-0.1% formic acid in water as mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; selective ion monitoring (SIM) mode was used for quantification using target fragment ions m/z 217 for xanthotoxin and m/z 326 for the internal standard. The resulting calibration curves offered satisfactory linearity (R(2) > 0.99) within the test range. Mean recoveries of xanthotoxin in rat plasma were in the range of 79.9%-84.6%. RSD of intra-day and inter-day precision were both < 14%. The accuracy of the method ranged from 87.5% to 109.8%. The assay was successfully applied to the pharmacokinetics and tissue distribution model studies of xanthotoxin in rats. The oral bioavailability of xanthotoxin was 73.2% in rats. PMID- 26629001 TI - Prognostic significance of peripheral monocytic myeloid-derived suppressor cells and monocytes in patients newly diagnosed with diffuse large b-cell lymphoma. AB - OBJECTIVE: The revised International Prognostic Index (R-IPI) aids in predicting the prognosis of patients with diffuse large B cell lymphoma (DLBCL), but R-IPI yields no significant differences in assessing different subtypes of DLBCL. It is necessary to identify patients with a high-risk of DLBCL and alternative therapy should be delivered as early as possible. METHODS: In total, 144 patients newly diagnosed with DLBCL including 63 GCB-DLBCL and 81 non-GCB-DLBCL and 30 healthy controls were enrolled. Peripheral monocytic myeloid-derived suppressor cells (M MDSC) (CD14(+)HLA(-)DR(low/-)) were detected by flow cytometry and the percentage of monocytes (MPhi) was evaluated by completed blood count (CBC). The correlation between M-MDSC% and MPhi% was statistically analyzed. RESULTS: Compared with healthy controls, significant increase was observed in M-MDSC% and MPhi% in DLBCL patients (both P<0.001). Significant difference of M-MDSC% was found between GCB DLBCL and non-GCB-DLBCL patients in both poor (P<0.001) and very good groups (P=0.03), whereas no statistical significance in the good group (P>0.05). The MPhi% in non-GCB-DLBCL patients was significantly higher than that in GCB-DLBCL counterparts merely in the poor group (P<0.001). Positive correlation was noted between MPhi% and M-MDSC in all DLBCL patients rather than in healthy controls (r=0.227 P=0.229). CONCLUSION: The percentage of peripheral MPhi was positively correlated with M-MDSC% in patients with different subtypes and risks of DLBCL. Peripheral MPhi% and M-MDSC% combined with R-IPI score may be useful for predicting the prognosis of patients newly-diagnosed with DLBCL. PMID- 26629002 TI - Association of monocyte chemoattractant protein-1-2518A/G polymorphism and risk of coronary artery disease among the Chinese population: a meta-analysis. AB - BACKGROUND: Numerous studies have evaluated the association between the MCP-1 2518A/G polymorphism and coronary artery disease (CAD) risk; however, the actual association is controversial. To derive a more precise estimation of the relationship in Chinese population, we performed this meta-analysis. METHODS: We searched the PubMed, Embase, Web of Science, and CNKI databases to identify studies that examined the association between the MCP-1-2518A/Gpolymorphism and the risk of CAD. We estimated the pooled odds ratio with its 95% confidence interval to assess this association. RESULTS: Seven studies containing 4024 Chinese subjects (2260 patients with CAD and 1764 controls) were included in this meta-analysis. MCP-1-2518A/G polymorphism was not found to be significantly associated with CAD risk in all comparisons (for G vs A: OR=1.10, 95% CI=0.92 1.32; for AG+GG vs AA: OR=1.10, 95% CI=0.79-1.53; for GG vs AA+AG: OR=1.05, 95% CI=0.91-1.21; for GG vs AA: OR=1.12, 95% CI=0.82-1.54; for AG vs AA: OR=1.05, 95% CI=0.76-1.47). Similarly, no associations were found in subgroup analysis based on source of control and endpoint. CONCLUSIONS: the MCP-1-2518A/G polymorphism was not associated with the risk of CAD in Chinese population. PMID- 26629003 TI - The flavonoid luteolin enhances doxorubicin-induced autophagy in human osteosarcoma U2OS cells. AB - Luteolin (LUT), a flavone, which is universally present as constituent of medicinal plants as well as some vegetables and spices, has been demonstrated display specific anti-carcinogenic effects. However, the mechanisms by which LUT inhibits human osteosarcoma growth remain unknown. The effects of LUT on cell growth in human osteosarcoma U2OS cells were measured by MTT assay and flowcytometry. The effects of LUT on morphological markers of autophagy in U2OS were analyzed by fluorescence microscopy and electron microscopy. Autophagic markers, beclin1 and LC3 were detected by western blotting. Here, we found that LUT induced autophagy in U2OS and acted as an enhancer to sensitize doxorubicin (DOX)-mediated autophagy signaling. The combined treatment of LUT and DOX greatly decreases the growth of U2OS, showing synergistic cytotoxicity. Our results indicate that LUT in combination with DOX maybe a novel strategy for the treatment of human osteosarcoma. PMID- 26629004 TI - MiR181c inhibits ovarian cancer metastasis and progression by targeting PRKCD expression. AB - MicroRNAs (miRNAs) regulate many important cancer related gene expression in the posttranscriptional process. Dysregulated expression of miRNAs has been observed in numerous human cancers including ovarian cancer. In this study, we found that the expression of the miR-181c was significantly decreased in ovarian cancer tissue and in tissues with lymph node metastasis when compared with their control samples, respectively. Moreover, among pathological stages, the expression of miR 181c was significantly decreased in the tissues with IV stage compared with other stages. In vitro, miR-181c significantly inhibited the proliferation, metastasis of A2780 cell line, and induced G1 phase arrest. Through bioinformatics prediction, protein kinase C delta (PRKCD) was identified as a target gene of miR 181c. Western blot results showed that PRKCD was increased in ovarian cancer tissue, in tissues with lymph node metastasis and IV stage of ovarian cancer pathological samples. After knocking down PRKCD, the cell cycle of A2780 cells was also arrested in G1 phase. The proliferation and the metastasis of A2780 cells were reduced. The dual luciferase reporter experiments showed that miR-181c regulated the expression of PRKCD by combining with its 3'UTR. These results indicate that miR-181c inhibits ovarian cancer metastasis and progression by targeting PRKCD expression. PMID- 26629005 TI - Cone beam CT for determining breast cancer margin: an initial experience and its comparison with mammography and specimen radiograph. AB - PURPOSE: To assess the ability of cone beam CT (CBCT) in determining the breast cancer margin using, to compare the results with mammography and specimen radiography, and to explore the clinical potential of CBCT for breast imaging. METHODS: Specimens of 46 breast cancer patients were imaged by using a prototype CBCT system. Each patient underwent mammography, CBCT and X-ray of breast surgical specimen within 6 months. Images of mammography, breast surgical specimen radiography and CBCT were evaluated by an experienced radiologist. Indicators, such as: morphology, glitch, density, invasion, structural distortion and calcification, were observed. RESULT: There was no significant difference of the calcification, glitch and morphology among three methods. However, there was significant difference in indicators of breast tumor invasion among three methods. There was statistical significance in detecting invasions of breast cancer cells in peripheral tissues among three methods. CONCLUSION: CBCT shows no superiority over mammography and specimen radiography in determining tumor's outline and detecting calcification. On the other hand, CBCT demonstrates its advantage in determining the 3 dimensional position of a lesion which could be a potential clinical application in future practices of breast imaging. PMID- 26629006 TI - Follistatin-like 3 suppresses cell proliferation and fibronectin expression via p38MAPK pathway in rat mesangial cells cultured under high glucose. AB - Mesangial cells (MCs) proliferation and extracellular matrix (ECM) accumulation are early features of diabetic nephropathy. Follistatin-like 3 (FSTL3), a member of follistatin family, has been shown to regulate insulin and glucagon sensitivities in diet-induced obesity and insulin resistance. However, the role of FSTL3 in diabetic nephropathy is still unclear. Therefore, in this study, we investigated the effects of FSTL3 on cell proliferation and ECM accumulation expression in rat MCs cultured under high glucose, and elucidated the underlying mechanism. We found that the expression of FSTL3 was decreased significantly in MCs cultured high glucose condition. Overexpression of FSTL3 inhibited high glucose-induced MC proliferation and blocked the G1/S phase transition under high glucose condition. And, FSTL3 overexpression also reduced the expression of alpha smooth muscle actin (alpha-SMA) and fibronectin (FN) induced by high glucose. Furthermore, overexpression of FSTL3 suppressed high-glucose-induced p38 phosphorylation in MCs. Taken together, our present study demonstrated that FSTL3 suppressed high glucose-induced MC proliferation and ECM accumulation via inhibiting the p38MAPK signaling pathway, and that FSTL3 may be a potential therapeutic target for the treatment of diabetic nephropathy. PMID- 26629008 TI - Transcatheter closure of the left atrial appendage: initial experience with the WATCHMAN device. AB - BACKGROUND: Atrial fibrillation (AF) is the most commonly encountered clinical arrhythmia, accounting for approximately one third of hospitalizations for cardiac rhythm disturbance. In patients with non-valvular AF, approximately 90% of thrombi are thought to arise from the left atrial appendage (LAA). Anticoagulation with warfarin has been the mainstay of therapy to reduce stroke risk in these patients; however, it is not without its complications including bleeding and drug interactions. Percutaneous left atrial appendage closure can be an alternative to warfarin treatment in patients with AF at high risk for thromboembolic events and/or bleeding complications. METHODS: Patients with atrial fibrillation and CHADSVASc score >= 2, not eligible for anticoagulation, were submitted to left atrial appendage closure using the WATCHMAN device. The procedure was performed under general anaesthesia, and was guided by fluoroscopy and transoesophageal echocardiography. RESULTS: Percutaneous LAA closure with the WATCHMAN device was performed in all patients. At 45-day follow-up no recurrent major adverse events and especially no thromboembolic events occurred. CONCLUSIONS: Transcatheter closure of the LAA with the WATCHMAN device is generally safe and feasible. Long-term follow-up will further reveal the risk and benefits of this therapy. PMID- 26629009 TI - Accuracy of serum interleukin (IL)-6 in sepsis diagnosis: a systematic review and meta-analysis. AB - OBJECTIVE: To systematic review and estimate the accuracy of Interleukin 6 assay in the diagnosis of sepsis by meta-analysis. METHODS: With the aim to confirm this correlation, this paper performed a meta-analysis of 6 studies and the Sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) with corresponding 95% confidence intervals (CI) of each study were calculated and the pooled sensitivity was calculate using Random Effects Model and Summary receiver operating characteristic curves were constructed. RESULTS: The pooled sensitivity for the diagnosis of sepsis was 80% (95% CI, 77% to 83%) and the specificity of 85% (95% CI, 81% to 88%). For sepsis versus health or infection, the area under the curve was 0.868. In neonate subgroup, IL-6 had a pooled sensitivity of 77.0% (95% CI, 73.0% to 81.0%) and specificity of 91.0% (95% CI, 86.0% to 94.0%) for sepsis diagnosis. In adult, IL 6 had a pooled sensitivity of 85.0% (95% CI, 80.0% to 88.0%) and specificity of 62.0% (95% CI, 55.0% to 68.0%) to identify sepsis. The AUC was 81.0%, and Q was 0.74. CONCLUSIONS: IL6 is a highly accurate diagnostic modality for the identification of sepsis, with promise for integration into routine imaging protocols for thyroid nodules. PMID- 26629007 TI - Modified glasgow prognostic score as a prognostic factor in gastriccancer patients: a systematic review and meta-analysis. AB - OBJECTIVE: Modified Glasgow prognostic score (mGPS) had been reported to associate with the prognosis ofgastric cancer (GC), butits significance in gastric cancer patients has not been studied fully. METHODS: PubMed; EMBASE; Web of Science and CNKI data base were searched to identify studies using the mGPS in gastric cancer patients. Outcome measures that were evaluated included overall survival (OS), lymphatic invasion and venous invasion inpatients with gastric cancer. RESULTS: A total of seven studies comprising 3206 patients were included in the meta-analysisof which all used OS as an outcome measure, three studies reported lymphatic invasionand three evaluated venous invasion. The results show that OS was worse in patients with an mGPS=1 and 2 (odds ratio [OR]=2.54, 95% [CI]: 1.62-3.98 and OR=12.02, 95% [CI]: 6.79-21.28, respectively) compared with those with a score of 0 (both P<0.01). Furthermore, gastric cancer patients with mGPS>=1 have higher rates of lymphatic and venous invasion with ORs of 2.51 (95% CI: 1.80-3.51) and 2.63 (95% CI: 1.35-5.11) respectively (both P<0.01). CONCLUSIONS: Them GPS could be used as a prognosis predictorfor gastric cancer patients and associated lymphatic and venous invasion. PMID- 26629010 TI - MiR-592 represses FOXO3 expression and promotes the proliferation of prostate cancer cells. AB - Prostate cancer (PC) is a serious health problem all over the world. Cell proliferation plays a major role in the tumorigenesis of PC. It is reported that microRNAs (miRNAs) played crucial roles in the regulation of cell proliferation. However, the underlying mechanism of miRNAs in PC has not been intensively investigated. In the present study, the effect of miR-592 on the cell proliferation of PC was investigated. The results showed that miR-592 was significantly upregulated in PC cell and PC tissues. To investigate the biological roles of miR-592, we induced either the up- or downregulation of miR 592 expression by transfecting DU145 PC cells with miR-592 mimics or miR-592 inhibitor. Our results demonstrated that the upregulation of miR-592promoted cell growth, while miR-592 inhibitor showed the opposite effect. Further experiment revealed that miR-592 repressed the expression of FOXO3 by directly targeting the 3'UTR of the FOXO3 transcript, which resulted in upregulating of the expression of cyclin D1 and downregulating of the expression of p21. In sum, our data indicated a novel aspect of the miR-592 in the molecular etiology of PC. PMID- 26629011 TI - Therapeutic efficacy and mechanism of Zhenrenyangzang decoction in rats with experimental ulcerative colitis. AB - Zhenrenyangzang Decoction (ZD) has been used as a classic formula in China for the treatment of gastrointestinal dysfunction such as chronic gastritis. However, there is less study on its application in ulcerative colitis (UC) and the effects are not yet clearly defined. To explore the effectiveness of ZD in trinitrobenzene sulfonic acid (TNBS)-induced UC rats, ZD was administered orally for 8 days at a dosage of 2, 4 or 8 g/kg/day. Following drug administration, the disease activity index (DAI) and tissue damage scores were recorded. In addition, mRNA and protein expression of nuclear factor kappa B (NF-kappaB), p38 mitogen activated protein kinase (p38MAPK) and Toll-like receptor 2 (TLR2) in colon tissues were examined by real time PCR and western blotting assay. As compared with the UC model group, ZD promoted the recovery of colitis and inhibited the colonic inflammation damage in UC rats by reducing the mRNA or protein expression of NF-kappaB and p38MAPK, as well as activating the production of TLR2 in colon tissues. And ZD significantly reduced the DAI and tissue damage scores. The therapeutic effect of ZD was found to be comparable to that of SASP. Our results suggested that ZD could improve colonic mucosa impairment and possesses favorable therapeutic action in TNBS-induced colitis, which provides direct pharmacological evidence for its clinical application. PMID- 26629012 TI - Overexpression of RACK1 inhibits collagen synthesis in keloid fibroblasts via inhibition of transforming growth factor-beta1/Smad signaling pathway. AB - Keloids are benign skin tumors characterized by collagen accumulation and hyperproliferation of fibroblasts. The receptor for activated C-kinase 1 (RACK1) was involved in liver fibrosis. However, the role of RACK1 in dermal fibrosis keloids is still unclear. Therefore, in this study, we investigated the effects of RACK1 on keloid fibroblasts (KFs) and transforming growth factor-beta1 (TGF beta1)-induced collagen expression and explored the underlying mechanism. We found that RACK1 was decreased in KFs, overexpression of RACK1 significantly inhibited TGF-beta1-induced KFs proliferation. RACK1 also obviously inhibited the expression of TGF-beta1-induced TGF-beta receptor I, II, type I collagen and alpha-smooth muscle actin (alpha-SMA) in human KFs. In addition, RACK1 suppressed the expression of TGF-beta1-induced Smad2 and Smad3 phosphorylation in human KFs. Taken together, our study suggested that RACK1 inhibits collagen synthesis in KFs via inhibition the TGF-beta1/Smad signaling pathway, and RACK1 is a potential target for treatment of the keloid disease. PMID- 26629013 TI - Ghrelin protects human umbilical vein endothelial cells against advanced glycation end products-induced apoptosis via NO/cGMP signaling. AB - OBJECTIVES: The aim of this study was to investigate the intracellular mechanism involved in the anti-apoptotic effect of ghrelin on human umbilical vein endothelial cells (HUVECs). METHODS: HUVECs were pretreated with ghrelin before exposure to 200 MUg/ml advanced glycation end products (AGEs)-BSA for 48 h. Cell viability and apoptosis were determined by MTT assay and Annexin V/PI staining. Intracellular cGMP levels evaluation and cGMP analogs were employed to explore possible mechanisms. RESULTS: The inhibitory effect on AGEs induced HUVECs apoptosis could be exerted by ghrelin and co-incubation with growth hormone secretagogue receptor (GHSR)-1a antagonist [D-Lys(3)]-GHRP-6 abolished this inhibition. Decreased cGMP level in AGEs induced HUVECs apoptosis was restored by ghrelin pretreatment and abolished by [D-Lys(3)]-GHRP-6 co-incubation. cGMP analogs (8 Br-cGMP and DB-cGMP) pretreatment also exhibited inhibitory effect on AGEs induced HUVECs apoptosis. CONCLUSIONS: Our results demonstrated that ghrelin produces a protective effect on HUVECs through GHS-R1a and cGMP/NO signaling pathway mediates the effect of ghrelin. These observations suggest a novel intracellular mechanism in the process of AGEs induced HUVECs apoptosis. PMID- 26629014 TI - Assessment of liver fibrosis in the early stages with perfusion CT. AB - OBJECTIVES: This work aims to assess the feasibility of perfusion CT in diagnosis of liver fibrosis in the early stage. MATERIALS AND METHODS: Solutions of carbon tetrachloride (CCL4) were injected into the peritoneum of 45 rabbits to establish rabbit models of liver fibrosis. Perfusion CT were performed at 4-, 8-, 12- and 16- week after injection. The parametric perfusion indices of blood flow (BF), blood volume (BV), arterial liver perfusion (ALP), portal venous perfusion (PVP), and hepatic perfusion index (HPI) on perfusion maps were measured. Liver samples were scored as F0, F1, F2, F3, F4 for fibrosis. RESULTS: In 50 rabbits, 23 rabbits survived. Of these survival rabbits, 5 rabbits were histopathologically scored as F0, 7 rabbits were F1, 8 rabbits were F2, and 3 rabbits were F3. For relatively small number of F3, multiple comparisons were made for F0 vs. F1, F1 vs. F2 and F0 vs. F2. A statistically significant difference was observed in PVP, BV, BF, ALP and HPI between F1 vs. F2 and F0 vs. F2, whereas a significant statistical difference was only achieved in PVP between F0 vs. F1. In the early stage of liver fibrosis PVP decreased with the progression of liver fibrosis, whereas HPI, ALP and BF increased with the progression of liver fibrosis. BV had no marked change. CONCLUSIONS: Perfusion CT is feasible in diagnosis of early stage of liver fibrosis. PVP appears to be the most promising parametric perfusion index. PMID- 26629015 TI - Prognostic role of microRNA-210 in various carcinomas: a meta-analysis. AB - BACKGROUND: MicroRNA (miRNA) expressive alterations are associated with cancer and have potential diagnostic and prognostic values in various malignancies. Here, we summarize the global predictive role of miR-210 expression for survival in patients with a variety of carcinomas. METHODS: Eligible studies were identified through multiple search strategies. Data were assembled from studies investigating the relationship between miR-210 expression and survival in cancer patients. Hazard ratio (HR) was used as the common measure of association across studies: relative risk (RR) was considered equivalent to HR. Combined hazard ratios (HRs) of miR-210 for outcome were analyzed. RESULTS: A total of 10 studies dealing with various carcinomas were included for this global meta-analysis. For overall survival (OS), the pooled hazard ratio (HR) of higher miR-210 expression in cancerous tissue was 2.41 (95% CI: 1.31-4.44), which could significantly predict poorer survival in general carcinomas. For distant-free, relapse-free or progressive-free survival, elevated miR-210 was also a significant predictor, with a pooled HR of 2.84 (95% CI: 2.10-3.83). Importantly, subgroup analysis suggested that higher expression of miR-210 correlated with worse OS in breast cancer: HR 4.34, 95% CI: 1.63-11.55. CONCLUSIONS: Our findings reveal that miR 210 detection has a prognostic value in patients with cancer, especially in breast cancer. PMID- 26629016 TI - Hyperoside enhances the suppressive effects of arsenic trioxide on acute myeloid leukemia cells. AB - Hyperoside (Hyp) is the chief component of some Chinese herbs which has anticancer effect and the present study is to identify whether it could enhance the anti leukemic properties of arsenic trioxide (As2O3) in acute myeloid leukemia (AML). We provide evidence on the concomitant treatment of HL-60 human AML cells with hyperoside potentiates As2O3-dependent induction of apoptosis. The activation of caspase-9, Bcl-2-associated agonist of cell death (BAD), p-BAD, p27 was assessed by Western blot. Results showed that hyperoside inhibited BAD from phosphorylating, reactivated caspase-9, and increased p27 levels. Importantly, hyperoside demonstrated its induction of autophagy effect by upregulation of LC II in HL-60 AML cell line. Taken together, hyperoside may serve as a great candidate of concomitant treatment for leukemia; these effects were probably related to induction of autophagy and enhancing apoptosis-inducing action of As2O3. PMID- 26629017 TI - Association between D-dimer level and portal venous system thrombosis in liver cirrhosis: a retrospective observational study. AB - OBJECTIVE: This study aimed to explore the association between D-dimer levels and presence of portal venous system thrombosis (PVST) in liver cirrhosis. METHODS: All consecutive patients with a diagnosis of liver cirrhosis who underwent D dimer test were retrospectively enrolled. Normal reference range of D-dimer level was 0-0.3 ug/mL. PVST was diagnosed on the basis of contrast-enhanced computed tomography and/or magnetic resonance imaging scans. RESULTS: Of the 66 included patients, 24 were diagnosed with PVST. Mean D-dimer level was 0.51+/-0.72 ug/mL (range: 0.10-3.44). Mean D-dimer level was not significantly different between PVST and non-PVST groups (0.68+/-0.93 ug/mL versus 0.41+/-0.56 ug/mL, P=0.146). Area under the receiver operating curve for D-dimer level for predicting the presence of PVT was 0.606 (95% confidence interval: 0.478-0.724, P=0.1393). The optimal cut-off value for D-dimer was 0.22 with a sensitivity of 58.3% and a specificity of 69.0%. The subgroup analyses of patients without splenectomy or those with different Child-Pugh classes demonstrated no significant difference in the D-dimer level between PVST and non-PVST groups. CONCLUSION: D-dimer might not be useful to identify the presence of PVST in liver cirrhosis. However, given the retrospective nature of this study, further well-designed prospective study should be necessary to confirm this finding. PMID- 26629018 TI - Galectin-3 mediates the effect of PDGF on pulmonary arterial hypertension. AB - AIMS: The present study aimed to perform in vitro experiments to investigate whether Galectin-3 (Gal-3) mediates the effect of platelet-derived growth factor (PDGF) on pulmonary arterial smooth muscle cells (PASMC) proliferation, apoptosis and migration, and to reveal the mechanism of how Gal-3 functions in the pathogenesis of pulmonary arterial hypertension (PAH). METHODS: Pulmonary arterial smooth muscle cells (PASMC) were treated with various concentration of PDGF for indicated times, and the expression of Gal-3 was analyzed by western blotting. Gal-3 siRNA was transfected into the PASMC to knock down endogenous Gal 3. MTT assay was performed to examine cell proliferation. Transwell-migration assay was used to determine cell migration ability. Cell apoptosis rate was determined by flow cytometric analysis. RESULTS: The result showed that the expression of Gal-3 protein was induced by PDGF in a dose- and a time-dependent manner. PDGF contributes to the progression of PAH by inducing cell proliferation and migration, as well as inhibiting cell apoptosis of PASMC. However, these effects of PDGF on PASMC were attenuated by Gal-3 knockdown. CONCLUSION: The present study provided potential evidence about the role of Gal-3 in the pathophysiological mechanisms of PAH. This study firstly demonstrated that Gal-3 could be induced by PDGF in PASMC, and mediates the effect of PDGF on PASMC proliferation, apoptosis and migration, thus contributing to the pathogenesis of PAH. PMID- 26629019 TI - miR-143 regulates proliferation and apoptosis of colorectal cancer cells and exhibits altered expression in colorectal cancer tissue. AB - Colorectal cancer is one of the most commonly diagnosed cancers and a leading cause of death. Studies have shown that abnormal expression of microRNAs, small non-coding RNA molecules that regulate gene expression, is linked to the occurrence of cancer. This study sought to determine the role of microRNA-143 (miR-143) in colorectal cancer. Reduced levels of miR-143 expression were detected in colorectal cancer tissues compared to normal adjacent tissue. Transfection of artificially synthesized miR-143 mimics into SW-480 cells, a colorectal cancer cell line, resulted in increased levels of cell proliferation and apoptosis. Further, cells transfected with miR-143 mimics showed a reduction in the proportion of cells in S phase and an increase in the proportion of cells in G1 phase. The altered expression levels of miR-143 in colorectal cancer and its ability to affect the behavior of colorectal cancer cells suggest miR-143 could be used as a new target for the diagnosis and treatment of colorectal cancer. PMID- 26629020 TI - Hamartoma compress medial and radial nerve in neurofibromatosis type 1. AB - Hamartoma of soft tissue in the extremity is uncommon. We report a 36-year-old female patient with neurofibromatosis type 1 (NF-1). She had had a gradually increased mass in her right forearm and wrist for ten years. The mass increased suddenly after the trauma. As a result, she felt pain and progressive numbness of forearm and hand. Her radial and median nerves were compressed by the mass. We resected the tumor and released the compression of nerves. After the surgery, the patient gained neural functional recovery. Two years after surgery, she had no tumor recurrence. We discuss its clinical diagnosis, radiological features, MRI findings, pathophysiology, and treatment. BACKGROUND: Hamartoma consists of multiple tissue elements. It can develop a bony disorder, rupture the blood vessels and create altered hemodynamics. NF-1 is caused by the mutation of a gene on chromosome 17 that is responsible for the control of cell division. It is also known as von Recklinghausen's disease. No case of the radial and median nerves that are compressed by the forearm hamartoma in NF-1 has been described in the literature before. PMID- 26629021 TI - Interleukin-10 promoter polymorphism and susceptibility to lung cancer: a systematic review and meta-analysis. AB - BACKGROUND: Interleukin-10 (IL-10) is a multifunctional cytokine with both immunosuppressive and anti-angiogenic properties and it plays an important role in the pathogenesis of cancer. A number of studies have examined the association between its promoter -1082/-819/-592 polymorphism and risk of lung cancer. However, the results are inconsistent and inconclusive. The aim of this study was to explore whether the IL-10 gene polymorphism contribute to the susceptibility of lung cancer. METHOD: We searched in PubMed, EMBASE, Cochrane Library as well as Chinese databases including China National Knowledge Infrastructure (CNKI) and Wan Fang database for all the relevant studies up to May 15, 2015. The data were extracted by two independent authors. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) under co-dominant model, dominant model and recessive model were estimated. RESULTS: A total of 8 studies involving 2033 cases and 3100 controls were included in the meta-analysis. The results revealed that the IL-10 592C/A polymorphism was related to lung cancer susceptibility under all models (C allele vs. A allele: OR=1.195, 95% CI=1.075-1.329; CC vs. AA: OR=1.651, 95%=1.290 2.113; CA vs. AA: OR=1.229, 95%=1.029-1.468; CA+AA vs. CC: OR=0.832, 95%=0.704 0.984; CC+CA vs. AA: OR=1.301, 95%=1.100-1.538) and IL-10 -819C/T polymorphism was associated with lung cancer susceptibility under three models (C allele vs. T allele: OR=1.441, 95% CI=1.228-1.691; CC vs. TT: OR=2.444, 95%=1.732-3.449; CC+CT vs. TT: OR=1.496, 95%=1.172-1.908). For IL-10 -1082G/A, there was no significant association between its polymorphism and lung cancer risk. CONCLUSIONS: This meta analysis demonstrated that two polymorphisms (-592C/A and -819C/T) in the promoter region of IL-10 gene were significantly associated with the risk of lung cancer in general population, while -1082G/A polymorphism did not affect susceptibility to lung cancer. PMID- 26629022 TI - Association between resting heart rate and cardiovascular mortality: evidence from a meta-analysis of prospective studies. AB - The results from published studies on resting heart rate (RHR) and risk of cardiovascular mortality are not consistent. We therefore conducted a meta analysis to quantitatively summarize the evidence from prospective studies about the association of RHR with risk cardiovascular mortality. Pertinent studies were identified by a search of Pubmed and Web of Knowledge to January 2015. The random effect model was used. Sensitivity analysis and publication bias were conducted. Dose-response relationship was assessed by restricted cubic spline and variance weighted least squares regression analysis. Twenty prospective articles were included in this meta-analysis. Pooled results suggested that highest RHR level versus lowest levels was significantly associated with the risk of cardiovascular mortality [summary relative risk (RR) = 1.69, 95% CI = 1.42-2.00, I(2) = 87.5%]. Subjects with RHR levels of > 80 bites per minute (bpm) had a RR of 1.49 (1.24 1.79) for cardiovascular mortality. The results for subgroups analysis of geographic locations, sex and duration of follow-up are consistent with the overall results. The linear dose-response analysis indicated that an increase in RHR of 10 bpm was statistically significantly associated with a 6% increase in the risk of developing cardiovascular mortality (summary RR = 1.06, 95% CI = 1.04 1.08). Thus, we conclude that elevated RHR was significantly associated with an increased risk of cardiovascular mortality. PMID- 26629023 TI - Prognostic value of interim (18)F-FDG-PET in diffuse large B cell lymphoma treated with rituximab-based immune-chemotherapy: a systematic review and meta analysis. AB - The prognostic value of an interim fluorine-18-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) for diffuse large B-cell lymphoma (DLBCL) has been assessed by different groups. However, studies have suggested that the use of rituximab could limit the predictive value of interim (18)F-FDG PET for DLBCL. To clarify the prognostic value of interim (18)F-FDG PET in DLBCL patients treated with rituximab based immunochemotherapy, we searched for relevant studies in PubMed, the Cochrane Library and EMBASE. A random versus fixed effects model was applied according to the heterogeneity. According to the literature search strategies, 11 studies were identified. The pooled HR comparing PFS between patients with positive and negative results was 2.96 (95% CI=2.25-3.89). The patients in interim (18)F-FDG PET negative group had a higher CR rates than that in interim (18)F-FDG PET positive group (RR=5.53, 95% CI=2.59-11.80). Consistent evidence favoring interim (18)F-FDG PET-based treatment assessment should be considered in the management of patients with DLBCL. PMID- 26629024 TI - The miR-149 rs2292832 T/C polymorphism may decrease digestive cancer susceptibility: an updated meta-analysis. AB - MicroRNAs (miRNAs) are a class of short non-coding, single stranded RNAs, which perform post-transcriptional regulatory functions as tumor suppressors or oncogenes. Single nucleotide polymorphisms (SNPs) in miRs genes are currently being identified for contributing to cancer risk, prognosis and survival, however, an association between miR-149 rs2292832 T/C SNP and cancer risk is uncertain. Therefore, we performed an updated meta-analysis of all currently publications to clarify this relationship. From PubMed and Chinese language (WanFang) databases, we located articles published up to June 1, 2015, obtaining 21 case-control studies from 20 different articles containing 8913 cases and 9944 controls based on search criteria for cancer susceptibility related to the miR 149 rs2292832 T/C SNP. Odds ratios (OR) and 95% confidence intervals (CI) revealed association strengths. There had no association between this SNP and whole cancer risk. At the same time, in several subgroups, also no association was found in ethnicity, sex and smoking status. Nevertheless, poorly significant association was detected in cancer type (Digestive cancer: OR = 0.90, 95% CI = 0.81-1.00, Pheterogeneity = 0.142 for CT vs. TT) and source of control (population-based: OR = 1.15, 95% CI = 1.00-1.32, Pheterogeneity = 0.427 for CC vs. CT+TT) subgroups. The miR-149 rs2292832 T/C SNP may poorly decrease digestive cancer risk. Studies with larger samples and gene-environment interactions are warranted to understand the role of miR-149 polymorphisms, especially rs2292832 T/C SNP, in whole cancer risk. PMID- 26629025 TI - The diagnosis value of acoustic radiation force impulse (ARFI) elastography for thyroid malignancy without highly suspicious features on conventional ultrasound. AB - OBJECTIVE: The aim of this study was to evaluate the potential diagnostic performance of acoustic radiation force impulse (ARFI) elastography in identifying malignancy in nodules that do not appear highly suspicious on conventional ultrasound (US). METHODS: 330 pathologically confirmed thyroid nodules (40 malignant and 290 benign; mean size, 22.0+/-11.6 mm) not suspicious of malignancy on conventional US in 330 patients (mean age 52.8+/-11.7 years) underwent ARFI elastography before surgery. ARFI elastography included qualitative ARFI-induced strain elastography (SE) and quantitative point shear wave elastography (p-SWE). ARFI-induced SE image was assessed by SE score, while p-SWE was denoted with shear wave velocity (SWV, m/s). The diagnostic performance of four criteria sets was evaluated: criteria set 1 (ARFI-induced SE), criteria set 2 (p-SWE), criteria set 3 (either set 1 or 2), criteria set 4 (both set 1 and 2). Receiver operating characteristic curve (ROC) analyses were performed to assess the diagnostic performance. RESULTS: SE score >=4 was more frequently found in malignant nodules (32/40) than in benign nodules (30/290, P<0.001). The mean SWV of malignant nodules (3.64+/-2.23 m/s) was significantly higher than that of benign nodules (2.02+/-0.69 m/s) (P<0.001). ARFI-induced SE (set 1) had a sensitivity of 80.0% (32/40) and a specificity of 89.7% (260/290) with a cut-off point of SE score >=4; p-SWE (set 2) had a sensitivity of 80.0% (32/40) and a specificity of 57.9% (168/290) with a cut-off point of SWV >=2.15 m/s. When ARFI induced SE and p-SWE were combined, set 3 had the highest sensitivity (92.5%, 37/40) while set 4 had the highest specificity (95.2%, 276/290). CONCLUSION: ARFI elastography can be used for differential diagnosis of malignant thyroid nodules without highly suspicious features on US. The combination of ARFI-induced SE and p-SWE leads to improved sensitivity and specificity. PMID- 26629026 TI - Function of CD163 fragments in porcine reproductive and respiratory syndrome virus infection. AB - Monocyte/macrophage scavenger receptor CD163 plays an important role in porcine reproductive and respiratory syndrome virus (PRRSV) infection. To identify the domains of CD163 involved in PRRSV infection, CD163 fragments P1 (1-798 bp), P2 (790-2046 bp), P3 (2023-3345 bp), Y-P1 (160-798 bp), Y-P2 (790-2046 bp) and Y-P3 (2143-3084 bp) were expressed by eukaryotic and prokaryotic expression systems, respectively. Infection experiments revealed that non-permissive BHK-21 cells transfected with pCD163 could be infected by PRRSV. However, cells with truncated CD163 (P1, P2, or P3) were not susceptible to PRRSV. Meanwhile, Y-P1, Y-P2, and Y P3 were expressed in E. coli and antisera to these peptides were prepared in mice. A virus blocking test showed that Y-P2 protein and anti-Y-P2 mouse serum could block PRRSV infection in a dose-dependent manner, while Y-P3 protein could improve virus infection. PMID- 26629027 TI - Gray matter atrophy in patients with Parkinson's disease and those with mild cognitive impairment: a voxel-based morphometry study. AB - PURPOSE: Mild cognitive impairment is common in Parkinson's disease, but the underlying pathological mechanism has not been fully understood. To examine the gray matter changes in patients with Parkinson's disease and those with mild cognitive impairment (MCI) using voxel based Morphometry (VBM). METHODS: Magnetic resonance images were obtained from 35 patients with PD and 20 age and sex matched healthy control subjects. In the PD group, 14 subjects had no MCI and 21 had MCI. MRI 3D structural images were acquired and analyzed by means of the optimized VBM procedure with Statistical Parametric Mapping (SPM5). RESULTS: Widespread areas of cortical atrophy were found in patients with PD compared with normal controls (in both temporal, occipital, parietal, frontal lobes and right limbic lobes, posterior lobes of the cerebellum and left caudate nucleus). Gray matter reductions were found in bilateral fusiform gyrus and lingual gyrus, left anterior cingulate cortex and insula, and right superior temporal gyrus, orbitofrontal cortex, central gyrus and precuneus in patients with PD with MCI compared with normal controls. Inpatients with PD with MCI, areas of reduced gray matter were found in both precentral gyrus and middle temporal gyrus, right cuneus, precuneus, and orbitofrontal cortex, and left fusiform gyrus compared with those without MCI. CONCLUSIONS: These findings suggest that PD is associated with the gray matter atrophy in the neocortical areas, and that cognitive impairment in patients with PD may be associated with gray matter changes in the parieto-occipital association cortex, right orbitofrontal cortex, and middle temporal gyrus. PMID- 26629028 TI - Characterization and distribution of drug resistance associated beta-lactamase, membrane porin and efflux pump genes in MDR A. baumannii isolated from Zhenjiang, China. AB - BACKGROUND: Acinetobacter baumannii (A. baumannii), especially the multidrug resistant A. baumannii (MDR-AB) is becoming a common opportunistic pathogen in hospital, and constitutes significant public health threats. This study aimed at investigating the relationship between drug resistance with expression of class A D beta-lactamase genes, mutation in membrane porin and over-expression of efflux pump genes among A. baumannii isolated from Zhengjiang, China. METHODS: Antibiotic susceptibility assays were performed using Kirby-Bauer disc diffusion method. PCR was used to detect beta-lactamase genes and carO, oprD, adeR, adeS. Real-time PCR was used to assess the mRNA expression level of efflux pump gene adeB. The software of DNAMAN was applied to assemble oprD and carO sequences, and the sequences were compared with those retrieved from GenBank (http://www.ncbi.nlm.nih.gov/). RESULTS: 27 isolates (61.4%) in this study were MDR-AB, in which five beta-lactamases including TEM, CTX-M-2, ADC, OXA-23 and OXA 51 were found, and the positive rate was 96.3% (26), 14.8% (4), 92.6% (25), 88.9% (24) and 92.6% (25), respectively. In addition, the expression level of adeB mRNA was significantly increased in MDR-AB, it might due to adeR mutation. Some mutations were also found in carO and oprD. CONCLUSION: MDR-AB showed high relationship with beta-lactamase, mutation in membrane porin and overexpression of adeB, which may directly relates to the mutation in regulating gene adeR. PMID- 26629029 TI - Obesity enhances Th2 inflammatory response via natural killer T cells in a murine model of allergic asthma. AB - BACKGROUND: Obesity increases the incidence of asthma, but mechanism between asthma and obesity isn't utterly understood. NKT cells are intermediary activist between the innate and adaptive immune. It may play an equally important role in both obesity and asthma. We studied an obese mouse model of allergic asthma to test whether NKT cells act as a linkage in the development of obesity with asthma. METHODS: Balb/c mice were divided into control group (A), asthma model group (B), the obesity group (C) and obesity with asthma group (D), asthma model made by OVA. Obesity was induced. AHR were measured; HE staining of lung was made; NKT cells were detected and IL-4 and IFN-gamma concentration were determined. RESULTS: Lung histology showed airway inflammatory in obesity with asthma are significant than in asthma. IL-4 levels were increased compared with the control group. IFN-gamma levels were decreased compared with the control group. More CD69+NKT cells of asthma group and obese asthma group correlated to the enhancement of airway inflammation and AHR. IFN-gamma+NKT cells vary in different states not paralleling with CD69+NKT cells. CONCLUSION: The activity level of NKT cells in obesity with asthma mice enhances Th2 Inflammatory response by regulating IL-4 and IFN-gamma secretion. The activation of NKT enhanced asthma TH2 inflammatory responce. NKT cells play an important role in the development of asthma in obesity. PMID- 26629030 TI - ROS/p38/p53/Puma signaling pathway is involved in emodin-induced apoptosis of human colorectal cancer cells. AB - AIM: Emodin was found effective in suppressing proliferation of cancer cells including colorectal cancer (CRC), but the mechanisms were still unclear. This study was aimed to investigate the possible mechanism of emodin's anti-CRC effects. METHODS: Two most frequently used CRC cell lines, SW480 and SW620, were investigated in this study. Serially diluted emodin solutions were used to incubate CRC cells. siRNAs were used to silence the expressions of p38 and Puma respectively. Intracellular ROS production was detected by DCFH-DA staining; proliferation and apoptosis of CRC cells were assessed by MTT assay and Hoechst staining respectively. Western blotting was applied to evaluate the activation of p38/p53/Puma signaling. RESULTS: Both in SW480 and SW620 cells, emodin inhibited proliferation by inducing ROS-mediated apoptosis in a concentration-dependent manner. The p38/p53/Puma signaling was also activated after emodin incubation in a concentration-dependent manner. The ROS scavenger NAC, p38 silencing and Puma silencing impaired the anti-proliferation and apoptosis- inducing effects of emodin. CONCLUSIONS: emodin inhibited proliferation of human CRC cells by inducing cell apoptosis by activating ROS/p38/p53/Puma signaling. PMID- 26629031 TI - In vitro drug susceptibility of 40 international reference rapidly growing mycobacteria to 20 antimicrobial agents. AB - Rapidly growing mycobacteria (RGM) are human pathogens that are relatively easily identified by acid-fast staining but are proving difficult to treat in the clinic. In this study, we performed susceptibility testing of 40 international reference RGM species against 20 antimicrobial agents using the cation-adjusted Mueller-Hinton (CAMH) broth microdilution based on the minimum inhibitory concentration (MIC) assay recommended by the guidelines of the Clinical and Laboratory Standards Institute (CLSI). The results demonstrated that RGM organisms were resistant to the majority of first-line antituberculous agents but not to second-line fluoroquinolones or aminoglycosides. Three drugs (amikacin, tigecycline and linezolid) displayed potent antimycobacterial activity against all tested strains. Capreomycin, levofloxacin and moxifloxacin emerged as promising candidates for the treatment of RGM infections, and cefoxitin and meropenem were active against most strains. Mycobacterium chelonae (M. chelonae), M. abscessus, M. bolletii, M. fortuitum, M. boenickei, M. conceptionense, M. pseudoshottsii, M. septicum and M. setense were the most resistant RGM species. These results provide significant insight into the treatment of RGM species and will assist optimization of clinical criteria. PMID- 26629032 TI - Diagnostic value of urinary microRNAs as non-invasive biomarkers for bladder cancer: a meta-analysis. AB - BACKGROUND: Bladder cancer (BC) is the fifth most common malignancy worldwide. The expression levels of microRNAs (miRNAs) in urine samples of BC patients have been demonstrated to be different from healthy people. Several studies focusing on the diagnostic value of urinary miRNAs for BC detection have been reported. The aim of this meta-analysis was to access the overall diagnostic accuracy comprehensively and quantitatively. METHODS: PubMed, Embase, Web of Science, the Cochrane Library, and CNKI were searched without language restrictions for studies about the diagnostic value of miRNAs for BC. The pooled sensitivity, specificity, positive and negative likelihood ratios (PLR and NLR, respectively), diagnostic odds ratio (DOR) were calculated using the random effects model. The summary receiver operating characteristic (SROC) curve was also generated and the area under the curve (AUC) was also reckoned to assess the diagnosis accuracy. Besides, Chi-square test and I(2) test were used to assess the heterogeneity between studies. Publication bias was evaluated by the Deeks' funnel plot asymmetry test. RESULTS: Fourteen studies were included in this meta-analysis, with a total of 1,128 BC patients and 1,057 matched controls. The overall sensitivity, specificity, PLR, NLR and DOR of urinary miRNAs for the diagnosis of BC were 0.71 (95% CI: 0.67-0.75), 0.75 (95% CI: 0.70-0.79), 2.8 (95% CI: 2.3 3.4), 0.39 (95% CI: 0.33-0.46) and 7 (95% CI: 5-10), respectively. The area under the SROC curve was 0.79. Subgroup analyses suggested that the ethnicity and miRNA profiling had an obvious influence on the diagnostic accuracy. CONCLUSION: The current analysis suggested that urinary miRNA panels may be a promising noninvasive biomarker in the diagnosis of BC. PMID- 26629033 TI - MTSS1 gene regulated by miR-96 inhibits cell proliferation and metastasis in tongue squamous cellular carcinoma Tca8113 cell line. AB - BACKGROUND: Metastasis suppressor-1 (MTSS1) is a novel potential metastasis suppressor gene in several types of human cancers. However, the exact function and regulatory mechanism of MTSS1 in Tongue squamous cellular carcinoma (TSCC) have not been elucidated. MATERIAL/METHODS: We first confirmed the MTSS1 gene expression by using quantitative real time-PCR (qRT-PCR) and immunohistochemical staining. Then we detected the effect of MTSS1 gene on Tca8113 cells proliferation and invasion ability by using MTT, wound healing and invasion assay. Finally by using bioinformatics analysis, luciferase reporter assay and a serial method, we analyzed the targeting of miR-96 on MTSS1 and the ability of miR-96 on MTSS1 gene mediated biological alterations in Tca8113 cells. RESULTS: Our findings showed that the expression of MTSS1 was down-regulated in both TSCC tissues and Tca8113 cells. Forced expression of MTSS1 led to inhibited cell proliferation ability, retarded wound closing and reduced trans-membrane cell numbers. MiR-96 is confirmed to be a direct target of MTSS1 gene and could regulate MTSS1 mediated Tca8113 cells proliferation and metastasis. But miR-96 could not completely restore the invasion ability of Tca8113 cells. CONCLUSIONS: MiR-96 targeting and promoting MTSS1 repression may precipitate in the TSCC tumorigenesis through bypassing cell proliferation and metastasis control. PMID- 26629035 TI - MicroRNA-365 in macrophages regulates Mycobacterium tuberculosis-induced active pulmonary tuberculosis via interleukin-6. AB - The present study is to investigate the relationship between microRNA (miR)-365 expression and the levels of interleukin (IL)-6 mRNA and protein in patients with active tuberculosis. From June 2011 to June 2014, 48 patients with active pulmonary tuberculosis induced by Mycobacterium tuberculosis were included in the study. In addition, 23 healthy subjects were enrolled as control. Macrophages were collected by pulmonary alveolus lavage. In addition, serum and mononuclear cells were isolated from peripheral blood. The levels of miR-365 and IL-6 in macrophages, mononuclear cells and serum were determined using quantitative real time polymerase chain reaction. The protein expression of IL-6 in macrophages and mononuclear cells was measured using Western blotting, while that in serum was detected by enzyme-linked immunoabsorbent assay. Expression of IL-6 mRNA and protein was significantly enhanced in patients with active pulmonary tuberculosis. Increase of IL-6 protein concentration in serum was probably due to the release of IL-6 protein from mononuclear cells in the blood. In addition, miR 365 levels were significantly lowered in patients with active pulmonary tuberculosis. Up-regulated IL-6 expression in macrophages, mononuclear cells and serum in patients with active pulmonary tuberculosis is related to the down regulation of miR-365, suggesting that miR-365 may regulate the occurrence and immune responses of active pulmonary tuberculosis via IL-6. PMID- 26629034 TI - Magnolol reduces bleomycin-induced rodent lung fibrosis. AB - Magnolol, a compound extracted from the Chinese medicinal herb Magnolia officinalis, has been proved to exert multiple pharmacological effects, including anti-oxidant and anti-inflammation activities. In this study, how it influenced bleomycin-induced lung fibrosis of rats was investigated. A single intratracheal instillation of bleomycin (5 mg/Kg, sacrificed 7 and 28 days post bleomycin instillation) caused body weight decrease and lung indices increase. Hodroxyproline content, myeloperoxidase (MPO) activity, tumor necrosis factor alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) levels increased in the rat lung tissues after bleomycin administration, while superoxide dismutase (SOD) activity decreased in the rat lung tissues. Collagen were excessively deposited in rat lung tissues after bleomycin treatment. However, oral administration of magnolol (10 mg/Kg, 20 mg/Kg, 30 mg/Kg) apparently and significantly inhibited the fibrotic process. It partly reversed the bleomycin induced increase of hydroxyproline content, MPO activity, TNF-alpha and TGF-beta levels in the lung tissues, significantly inhibited the bleomycin-induced decrease of SOD activity, Excessive collagen deposition was also inhibited by magnolol administration. In summary, our results suggested that magnolol might be a potent anti-inflammatory and anti-fibrotic agent against bleomycin-induced lung fibrosis. PMID- 26629036 TI - Effect of T-type calcium channel blockers on spiral ganglion neurons of aged C57BL/6J mice. AB - To explore the expression levels of T-type calcium channel receptors in spiral ganglion neurons of C57BL/6J mice and the effect of T-type calcium channel blockers on the spiral ganglion neurons of 42-44-W C57BL/6J mice. We first quantified the subunits of T-type calcium channel blockers in the spiral ganglion neurons of C57BL/6J mice in three groups (6-8 W, 24-26 W, 42-44 W) according to age via RT-PCR. Next, we administered three drugs (zonisamide, felodipine, saline) to the 42-44-W C57BL/6J mice by gavage for four weeks. We observed the changes in the hearing threshold of 42-44-W C57BL/6J mice after treatment. Meanwhile, we measured the expression of calcium-binding proteins of spiral ganglion neurons after treatment. Our results showed that three receptors were expressed in the spiral ganglion neurons of C57BL/6J mice. The expression level of alpha1H was stronger than that of alpha1G and alpha1I. The expression levels of three receptors especially for alpha1G and alpha1H significantly decreased with age. The hearing threshold at 24 kHz was significantly decreased after zonisamide administration. No significant difference in the expression level of calbindin in spiral ganglion neurons was noted. Interestingly, the expression level of calmodulin in spiral ganglion neurons was lower in the zonisamide treated groups than in the felodipine- and saline-treated group. We concluded that the administration of T-type calcium channel blocker for four consecutive weeks can improve the hearing by ameliorating calcium overload on spiral ganglion neurons of 42-44-W C57BL/6J mice. PMID- 26629037 TI - Protective effects of carvacrol and pomegranate against methotrexate-induced intestinal damage in rats. AB - OBJECTIVE: The purpose of this experimental study was to evaluate the efficacy of carvacrol (CVR) and pomegranate (PMG) against methotrexate (MTX)-induced intestinal damage using histopathological and immunohistochemical techniques. METHODS: Thirty-two male Sprague-Dawley rats, weighing 195-250 g, were divided into four groups: control, MTX treatment alone, MTX plus CVR and MTX plus PMG. A single dose of CVR (73 mg/kg) was administered intraperitoneally to group III on the first day of the experiment, PMG (225 mg/kg/day) was administered orogastrically (with a gavage needle) once daily for 7 days and a single dose of MTX (20 mg/kg) was administered intraperitoneally on the second day of the experiment. Intestinal tissues were obtained on 8(th) day, and examined for villus damage, crypt damage, and inflammation. Ki-67 and Caspase 3 staining was used for immunohistochemical evaluation. RESULTS: MTX treatment induced villus shortening and fusion, epithelial atrophy, crypt loss, inflammatory infiltrate in the lamina propria, and goblet cell depletion. The CVR and PMG decreased the severity of intestinal damage caused by MTX treatment. In the MTX-received group, significant inflammatory cell infiltration was observed in the lamina propria. Compared to the MTX-received group, the PMG and CVR groups showed less villus and crypt damage and less inflammation in the lamina propria. Fewer Ki-67 positive cells were observed in the crypts of the MTX-received groups compared to the control group. There were more Ki-67 positive cells in the CVR and PMG groups compared to MTX group. The MTX-received group exhibited more caspase-3 positive cells than the control group, and the number of caspase-3 positive cells were decreased in the CVR and PMG treated groups. CONCLUSION: This study is the first to show that PMG and CVR decrease MTX-related damage and apoptotic activity in intestinal tissue. PMID- 26629038 TI - Pharmacokinetic study of indocyanine Green after intravenous administration by UPLC-MS/MS. AB - Indocyanine Green is widely used in medical diagnosis and to evaluate liver function and other regional blood flows in clinical application or animal experiments. In this work, a sensitive and selective ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for determination of Indocyanine Green in rat plasma was developed and validated. After addition of rutin as an internal standard (IS), protein precipitation by acetonitrile methanol (9:1, v/v) was used to prepare samples. Chromatographic separation was achieved on a UPLC BEH C18 column (2.1 mm * 100 mm, 1.7 MUm) with 0.1% formic acid and acetonitrile as the mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; multiple reactions monitoring (MRM) mode was used for quantification using target fragment ions m/z 753.4->330.2 for Indocyanine Green, and m/z 611.1->303.1 for IS. Calibration plots were linear throughout the range 20-5000 ng/mL for Indocyanine Green in rat plasma. Mean recoveries of Indocyanine Green in rat plasma ranged from 79.5% to 85.4%. RSD of intra-day and inter-day precision were both < 12%. The accuracy of the method was between 95.9% and 113.9%. The method was successfully applied to pharmacokinetic study of Indocyanine Green after intravenous administration. PMID- 26629039 TI - Sevoflurane impairs acquisition learning and memory function in transgenic mice model of Alzheimer's disease by induction of hippocampal neuron apoptosis. AB - OBJECTIVES: To investigate the mechanism and effect of sevoflurane on learning and memory function in transgenic mice model of Alzheimer's disease (AD). METHODS: A total of 45 Tg2576 mice were used and randomly assigned to control, sham, and sevoflurane group. Spatial learning and memory ability were measured before and after sevoflurane exposure using morris water maze (MWM) and Y-maze behavioral tests. Moreover, TUNEL assay was carried out to determine the cell death in hippocampal cornuammonis (CA) 1, CA3, and dentate gyrus (DG) region. Apoptosis-related protein (caspase-3 and Bcl-xL) expression in the hippocampus was analyzed by Western blotting. RESULTS: The MWM results showed that there were no significant differences in the swimming speed after sevoflurane exposure among the three groups. However, the escape latency, time spent in original quadrant, and the number of correct trials (Y-maze) were significantly lower after sevoflurane anesthesia exposure in the sevoflurane group than the sham group and control group (P < 0.05). Besides, the apoptotic cell numbers of the CA1 and CA3 region in the sevoflurane group were significantly higher than those in the sham group and control group (P < 0.05). Western blotting results showed that the protein expression levels of Bcl-xL were significantly higher, but the caspase-3 levels were significantly lower in the sevoflurane group than those in the control group and sham group (both P < 0.05). CONCLUSION: Our results indicate that sevoflurane might impair acquisition learning and memory function in AD by induction of hippocampal neuron apoptosis. PMID- 26629040 TI - ING5 inhibits epithelial-mesenchymal transition in breast cancer by suppressing PI3K/Akt pathway. AB - Epithelial-mesenchymal transition (EMT) is a crucial step in tumor progression and has an important role during cancer invasion and metastasis. The proteins of the inhibitor of growth (ING) candidate tumor suppressor family are involved in multiple cellular functions such as cell cycle regulation and apoptosis. ING5 is a member of the family. However, the role of ING5 in breast cancer is still unclear. Thus, the aim of this study is to explore the role of ING5 in breast cancer. In the present study, we showed that ING5 is involved in the pathogenesis of breast cancer. ING5 is down-regulated in breast cancer tissues and cell lines. Overexpression of ING5 significantly inhibited breast cancer cell migration, invasion, and EMT phenotype, moreover, overexpression of ING5 significantly the phosphorylation of PI3K and Aktin in breast cancer cells. In conclusion, our findings show that ING5 can efficiently inhibit the EMT progression in breast cancer cells by suppressing PI3K/Akt signaling pathway. Therefore, ING5 may be a good molecular target for the prevention and treatment of breast cancer. PMID- 26629041 TI - Apigenin attenuates diabetes-associated cognitive decline in rats via suppressing oxidative stress and nitric oxide synthase pathway. AB - Our present investigation aimed to determine the neuroprotection of apigenin (API) against diabetes-associated cognitive decline (DACD) a diabetic rat model and exploring its potential mechanism. Diabetic rat model was induced by intraperitoneal injection of streptozotocin. All experiment animals treated with vehicle or API by doses of 10, 20 and 40 mg/kg for seven weeks. Firstly, the body weight and blood glucose levels were detected. We used Morris water maze test to evaluate learning and memory function. The oxidative indicators (malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH)), cNOS, iNOS, caspase-3 and caspase-9 were measured in cerebral cortex and hippocampus using corresponding commercial kits. API can increase body weight, reduce the blood glucose levels, and improve the cognitive function in rats induced by diabetes. API decrease the MDA content, and increase SOD activity and GSH level of diabetic animals in the cerebral cortex and hippocampus of diabetic rats. Meanwhile, constitutive nitric oxide synthase (cNOS), inducible nitric oxide synthase (iNOS), caspase-3/9 were markedly exhibited in the cerebral cortex and hippocampus of diabetic rats. In summary, our current work discloses that API attenuates DACD in rats via suppressing oxidative stress, nitric oxide and apoptotic cascades synthase pathway. PMID- 26629042 TI - Effect of Si-RNA-silenced HIF-1alpha gene on myocardial ischemia-reperfusion induced insulin resistance. AB - OBJECTIVE: To explore the effect (expression and implication) of hypoxia inducible factor-1alpha (HIF-1alpha) silence induced by siRNA on the myocardial ischemia-reperfusion-induced insulin resistance in adult rats. METHODS: One-step enzymolysis method was used to isolate adult rat cardiomyocytes; adult rat cardiomyocytes were cultured; HIF-1alpha gene-specific Si-RNA was constructed and transfected into rat cardiomyocytes using liposome method. Myocardial IRI model was prepared. HIF-1alpha and glucose transporter 4 (GLUT-4) mRNA expression was detected by RT-PCR; distribution of GLUT-4 protein expression in adult rat cardiomyocytes was detected by immunofluorescence; Western blot was used for the detection of HIF-1alpha protein expression; isotope tracer assay was used to detect the changes in cell glucose (Glu) uptake rate. RESULTS: This method can stably get 85% to 90% active calcium tolerant adult rat cardiac myocytes, and the cultured cells were proved to be cardiomyocytes. After experiencing ischemia reperfusion injury, HIF-1alpha mRNA expression levels in adult rat hypoxia cardiomyocytes had different degrees of increase compared with the control group (compared with the control group, P < 0.05). Compared with the model group, HIF 1alpha mRNA expression levels after ischemia and reperfusion in HIF-1alphasi-RNA group and empty-vector group were lower than that in the control group and the model group; the expression reached the peak after 60 min of reperfusion, which did not change significantly in the control group. Expression of HIF-1alpha protein in myocardial cells was quite low in the control group; in the model group and intervention group, only after hypoxia-ischemia for 60 min, expression bands could be detected; especially in the model group, the expression had been increased until 60 min after reperfusion and began to decline from the time point of 180 min after reperfusion, but was still higher than that in the control group; in the intervention and empty-vector groups, it also increased rapidly at 60 min, but the expression was significantly lower than that in the model group; at 180 min after reperfusion, its protein expression peaked; while at 8 h after reperfusion, all the expression was extremely low. Compared with the control group, Glut4 mRNA expression in model group, transfected group and empty-vector group was reduced at the time points of T1-T4 (P < 0.05); the decline was the most significant at the time points of T1 and T2, followed by slightly increase at T3 and gradual recovery at T4; Compared with model group, Glut4 mRNA expression in transfection group was significantly reduced (P < 0.05); the decline was the most obvious at T1-T2, and then there was an increasing trend and it was recovered at T5 point. After experiencing ischemia, GLUT-4 protein expression changing trend was as follows: it was significantly reduced on the cell membrane, which was the most obvious from T1 to T3 and began to improve at T3, but still had not reached the level in the control group; it had been reached the levels of the control group at T5. After HIF-1alphasi-RNA transfection and ischemia, GLUT-4 protein expression was increased in plasma and reduced on cell membrane; the decline was slightly improved at T3 and recovered to control distribution level at T5. After cardiac ischemia-reperfusion, glucose uptake rate decreased to varying degrees in myocardial cells and reached the lowest value after 60 min of ischemia, then gradually increased. After 8 h of reperfusion, the level in model group returned to the control level; compared with the model group, glucose concentration increased more serious in transfection group and empty-vector group after reperfusion. CONCLUSION: HIF-1alpha played a central regulatory role in this mechanism; HIF-1alpha may be one of the molecular mechanisms triggering myocardial IR. PMID- 26629043 TI - Expression of human papillomavirus and prognosis of juvenile laryngeal papilloma. AB - The aim of this study was to evaluate the correlation between clinical behavior and expression of human papillomavirus (HPV) in patients with juvenile laryngeal papillomatosis, in an attempt to develop an effective molecular biological method to predict prognosis. We included 37 patients with juvenile laryngeal papillomatosis in the study group and 10 cases each of juvenile vocal cord polyps and juvenile normal laryngeal mucosa as the control group. We detected HPV by immunocytochemistry and in situ hybridization, identified the virus type, and measured HPV-DNA content using a computer-assisted, color pathological image analysis system. Additionally, we conducted a retrospective study with regard to the patients' clinical history to evaluate the prognosis. The data of the 2 groups were compared and statistically analyzed, including a correlation with prognosis. In the study group, 67.3% (25/37) were positive for HPV-Ag by immunocytochemistry; whereas 53.2%, 45.8%, and 25.4% were positive for HPV6b-DNA, HPV11-DNA, and HPV6b+11-DNA, respectively, by in situ hybridization. HPV was not detected in the control group. There was a significant difference between two groups (P < 0.05). Compared to HPV11-DNA-positive cases, those that were positive for HPV6b-DNA and HPV6b+11-DNA showed lower results on average, for age at first diagnosis and self-relief, number of surgeries, and interval between surgeries. Our findings suggest that immunocytochemistry and in situ hybridization are useful methods to evaluate the prognosis of juvenile laryngeal papilloma (JLP) and that HPV6b-positivity can be used as an index to predict the development and outcome of JLP. PMID- 26629044 TI - Vascular endothelial growth factor/bone morphogenetic protein-2 bone marrow combined modification of the mesenchymal stem cells to repair the avascular necrosis of the femoral head. AB - Vascular endothelial cell growth factor (VEGF) combined with bone morphogenetic protein (BMP) was used to repair avascular necrosis of the femoral head, which can maintain the osteogenic phenotype of seed cells, and effectively secrete VEGF and BMP-2, and effectively promote blood vessel regeneration and contribute to formation and revascularization of tissue engineered bone tissues. To observe the therapeutic effect on the treatment of avascular necrosis of the femoral head by using bone marrow mesenchymal stem cells (BMSCs) modified by VEGF-165 and BMP-2 in vitro. The models were avascular necrosis of femoral head of rabbits on right leg. There groups were single core decompression group, core decompression + BMSCs group, core decompression + VEGF-165/BMP-2 transfect BMSCs group. Necrotic bone was cleared out under arthroscope. Arthroscopic observation demonstrated that necrotic bone was cleared out in each group, and fresh blood flowed out. Histomorphology determination showed that blood vessel number and new bone area in the repair region were significantly greater at various time points following transplantation in the core decompression + VEGF-165/BMP-2 transfect BMSCs group compared with single core decompression group and core decompression + BMSCs group (P < 0.05). These suggested that VEGF-165/BMP-2 gene transfection strengthened osteogenic effects of BMSCs, elevated number and quality of new bones and accelerated the repair of osteonecrosis of the femoral head. PMID- 26629045 TI - The effect of nuclear factor of activated T-cells (NFAT) in kidney I/R mediated by C5a/C5aR. AB - To investigate the relationship between NFAT and C5a/C5aR in C5a/C5aR-mediated kidney Ischemia/reperfusion (I/R) injury, the rats' NRK-52E cell line was used in this study and was distributed into 4 groups, I: the normal control (NC), II: the ischemia/reperfusion (I/R) injury cell model (MG), III: the ischemia/reperfusion (I/R) injury cell model treated with C5a (50 nmol/l) (MG + C5a), IV: the ischemia/reperfusion (I/R) injury cell model treated with C5aR antagonist (2.5 MUmol/l) (MG + anti-C5aR). Reverse transcription polymerase chain reaction (RT PCR), western blot, immunofluorescence and flow cytometry were performed. Nuclear Factor Activated T Cell (NFAT), tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL-6) were detected in this study. The results of immunofluorescence showed that NFAT had a nuclear translocation phenomenon during the study. The RT PCR and WB data indicated that the expression of TNF-alpha and IL-6 in group III were higher than any other groups. Apoptosis in group III was much serious than other groups. All the results in this study showed that NFAT plays an important role in ischemia/reperfusion injury, it can be induced to up-regulate the inflammatory factor TNF-alpha and IL-6 by the complement system member C5a/C5aR. PMID- 26629046 TI - Development of hair cells in inner ear is associated with expression and promoter methylation of Notch-1 in postnatal mice. AB - The present study was designed to investigate the correlation among the number of hair cells in inner ear, Notch-1 gene expression levels and its methylation status of the promoter region in the postnatal mice. The hair cells in inner ear were collected from postnatal mice at day 0, 4, 8 and 16 and counted by immunofluorescence. Notch-1 mRNA expression were measured by real-time quantitative polymerize chain reaction (PCR). Methylation levels of CpG islands in Notch-1 promoters were analyzed by matrix-assisted laser desorption/ionization time of flight mass spectrometry. The results showed that the number of hair cells in the inner ear increased gradually after birth, which were positively correlated to Notch-1 mRNA expression. However, analysis on methylation of CpG sites in Notch-1 promoter showed that the methylation rates increased gradually after births, which were correlated with the decreased expression of Notch-1. Drug lesion induced the loss of hair cells, and stimulated the expression of Notch-1 mRNA expression, but didn't influence the methylation rates of Notch-1 promoter. We concluded that the Notch-1 mRNA expression level in inner ear tissues is correlated with the development of hair cells. CpG islands in Notch-1 promoter region manifest hypermethylation status when hair cells in inner ear are mature. PMID- 26629047 TI - Inhibitory effect of salvianolate on human cytochrome P450 3A4 in vitro involving a noncompetitive manner. AB - Salvianolic acid B (Sal B), which is purified from Danshen, is a popular herb extract. Sal B has anti-oxidative, anti-inflammatory, anti-hypoxic, anti arteriosclerotic and anti-apoptotic properties. This substance can also ameliorate brain injury or neurodegenerative diseases. The listed drug Salvianolate, which contains a substantial amount of Sal B, has been used for the treatment of coronary heart disease. Our present work aimed to evaluate the inhibitory effect of salvianolate on seven cytochrome P450 isoforms (CYP450), namely, CYP1A2, CYP2A6, CYP2E1, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, in human liver microsomes (HLMs) and recombinant enzymes through high-performance liquid chromatography (HPLC) assay. Salvianolate have a potent inhibitory effect on CYP3A4 activity with IC50 values of 1.438 (HLMs) and 3.582 (recombinant cDNA expressed CYP3A4) mg/L, respectively. Salvianolate strongly dose, but not time dependently decreased CYP3A4 activity in HLMs. The typical Lineweaver-Burk plots showed that Salvianolate inhibited CYP3A4 activity noncompetitively, with a Ki value of 2.27 mg/L in HLMs. Other CYP450 isoforms are not markedly affected by Salvianolate. These findings indicate that salvianolate may be involved in potential drug interactions when co-administrated with CYP3A4 substrates. PMID- 26629048 TI - MiR-27a-3p promotes esophageal cancer cell proliferation via F-box and WD repeat domain-containing 7 (FBXW7) suppression. AB - Emerging evidence has suggested that dysregulation of microRNA-27a-3p (miR-27a 3p) may contribute to tumor development and progression in various types of cancers. However, its role in esophageal cancer is still unknown. In the present study, miR-27a-3p was significantly increased in esophageal squamous cell carcinoma (ESCC) tissues and cell lines. In esophageal cancer Eca109 cells, ectopic overexpression of miR-27a-3p promoted cell proliferation, meanwhile, cell proliferation was reduced by miR-27a-3p inhibition. Further studies showed that down-regulated miR-27a-3p expression could induced cell cycle arrest at the G1/S transition. In exploring mechanisms underlying the promotive role, our results revealed that miR-27a-3p markedly inhibited the expression of F-box and WD repeat domain-containing 7 (FBXW7). FBXW7, a tumor suppressor, exhibited significantly inhibitory effect on Eca109 cell proliferation. Thus our observations suggested that miR-27a-3p functioned as a tumor suppressor by targeting FBXW7. These findings indicated that miR-27a-3p could be considered as a potential therapeutic strategy for ESCC therapy. PMID- 26629049 TI - Forkhead box protein M1 predicts outcome in human osteosarcoma. AB - PURPOSE: In the present study, we examined both FOXM1 mRNA and protein expression by Real-time quantitative PCR (qRT-PCR) and Western blot and investigate the expression of the human FOXM1 by Immunohistochemistry (IHC), and identify their potential roles in prognosis for patients with osteosarcoma. METHODS: FOXM1 mRNA and protein expression levels were detected by RT-PCR and Western blot assays, respectively. Then, IHC was performed to analyze the association of FOXM1 expression in 83 osteosarcoma tissues with clinicopathological factors and survival of patients. RESULTS: The expression levels of FOXM1 mRNA were found to be significantly increased in osteosarcoma tissues compared to noncancerous bone tissues (P = 0.0313). Simultaneously, western blot analysis showed that the protein level of FOXM1 in osteosarcoma tissues was significantly higher than that in noncancerous bone tissues. Kaplan-Meier analysis with the log-rank test indicated that high FOXM1 expression had a significant impact on overall survival (P = 0.0001). CONCLUSIONS: Our data showed that FoxM1 was upregulated in osteosarcoma tissues, and high expression of FoxM1 was correlated with a poor prognosis of patients with osteosarcoma. FoxM1 may function as a valuable prognostic biomarker for osteosarcoma. PMID- 26629050 TI - Transforming growth factor-beta1 rs1800469 polymorphism and periodontitis risk: a meta-analysis. AB - The association between TGF-beta1 rs1800469 polymorphism and the risk of periodontitis was controversial and inconclusive. This meta-analysis aimed to evaluate the association between the TGF-beta1 rs1800469 polymorphism and periodontitis risk. The electronic databases PubMed, EMBASE, and Web of Science were searched for studies to include in the present meta-analysis. Odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of association between the TGF-beta1 rs1800469 polymorphism and periodontitis risk. A total of 8 publications involving 923 cases and 892 controls met the inclusion criteria and were ultimately analyzed. In this meta-analysis, a significant association was detected between TGF-beta1 rs1800469 polymorphism and periodontitis risk (OR=1.21; 95% CI, 1.05-1.39; P=0.008). In the subgroup analysis by ethnicity, the significant association was only found among Asians (OR=1.23; 95% CI, 1.05-1.44; P=0.01), while no significant association was found among Caucasians (OR=1.16; 95% CI, 0.90-1.49; P=0.25). In the subgroup analysis by type and periodontitis, the significant association was only found among CP patients (OR=1.18; 95% CI, 1.02-1.37; P=0.03), while no significant association was found among AP patients (OR=1.27; 95% CI, 0.98-1.65; P=0.07). In addition, no significant association was found among non-smokers (OR=1.28; 95% CI, 0.93-1.76; P=0.13). In conclusion, this meta-analysis suggests that the TGF-beta1 rs1800469 polymorphism is associated with periodontitis risk. Further studies analyzing gene-gene and gene-environment interactions are required. PMID- 26629051 TI - APC methylation predicts biochemical recurrence of patients with prostate cancer: a meta-analysis. AB - The promoter region of adenomatous polyposis coli (APC) has been found to be frequently methylated in prostate cancer. However, the prognostic role of APC methylation in prostate cancer was still debated. We performed a meta-analysis by searching PubMed and EMBASE databases. Pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CI) were calculated. Seven studies (1227 patients) were included in this study. After calculation, the overall HR was 1.74 (95% CI: 1.31-2.31), implicating that APC methylation has an unfavorable impact on biochemical recurrence of prostate cancer. A subgroup analysis was performed with detection method, combined HR was 1.53 (95% CI: 1.19-1.96) for Methylation Specific PCR (MSP), and 2.08 (95% CI: 1.18-3.64) for quantitative Methylation Specific PCR (qMSP). Another subgroup analysis was conducted according to regions of the patients, combined HR was 2.02 (95% CI: 1.18-3.49) for North America, and 1.64 (95% CI: 1.14-2.36) for European. In conclusion, APC methylation is associated with biochemical recurrence of patients with prostate cancer. PMID- 26629052 TI - Significance of MMP11 and P14(ARF) expressions in clinical outcomes of patients with laryngeal cancer. AB - BACKGROUND: To evaluate the association of MMP11 and P14(ARF) expression in laryngeal squamous cell carcinoma (LSCC) with clinical pathological characteristics and survival. METHODS: The mRNA and protein levels for both genes were determined in 65 LSCC patients. A log-rank test and Cox models were used to compare survival among different groups. RESULTS: The mRNA expressions of MMP11 and P14(ARF) were significantly different between LSCC and their corresponding adjacent tissues (All P < 0.001). The expressions of MMP11 and P14(ARF) were correlated with several clinical characteristics (All P < 0.05). Patients with low MMP11 and high P14(ARF) expression had significantly better survival compared with those with high MMP11 and low P14(ARF) expression, respectively (All P < 0.05). The patients with surgery only had significantly better survival than those with chemoradiotherapy (log rank: P = 0.016), particularly in patients with low MMP11 and high P14(ARF) expression (log rank: P = 0.006). Furthermore, multivariable analysis showed that patients with low MMP11 and high P14(ARF) expression alone had a significantly reduced risk of death compared with those with high MMP11 and low P14(ARF) expression. The reduced risk for overall death was pronounced for patients with low and high expression of both genes (HR, 0.2; 95% CI, 0.1-0.5) compared with any other co-expression status of both genes, particularly for patients with surgery only (HR, 0.1; 95% CI, 0.0-0.9). CONCLUSION: These results suggest that altered expression of MMP11 and P14(ARF) in tumors may individually, or in combination, predict poor prognosis of LSCC, particularly for patients with surgery only. PMID- 26629053 TI - Biological significance of long non-coding RNA FTX expression in human colorectal cancer. AB - The purpose of this study was to determine the expression of long non-coding RNA (lncRNA) FTX and analyze its prognostic and biological significance in colorectal cancer (CRC). A quantitative reverse transcription PCR was performed to detect the expression of long non-coding RNA FTX in 35 pairs of colorectal cancer and corresponding noncancerous tissues. The expression of long non-coding RNA FTX was detected in 187 colorectal cancer tissues and its correlations with clinicopathological factors of patients were examined. Univariate and multivariate analyses were performed to analyze the prognostic significance of Long Non-coding RNA FTX expression. The effects of long non-coding RNA FTX expression on malignant phenotypes of colorectal cancer cells and its possible biological significances were further determined. Long non-coding RNA FTX was significantly upregulated in colorectal cancer tissues, and low long non-coding RNA FTX expression was significantly correlated with differentiation grade, lymph vascular invasion, and clinical stage. Patients with high long non-coding RNA FTX showed poorer overall survival than those with low long non-coding RNA FTX. Multivariate analyses indicated that status of long non-coding RNA FTX was an independent prognostic factor for patients. Functional analyses showed that upregulation of long non-coding RNA FTX significantly promoted growth, migration, invasion, and increased colony formation in colorectal cancer cells. Therefore, long non-coding RNA FTX may be a potential biomarker for predicting the survival of colorectal cancer patients and might be a molecular target for treatment of human colorectal cancer. PMID- 26629054 TI - Simultaneous observation and discrimination of palatovaginal and vomerovaginal canals by transverse CT. AB - This study is to palatovaginal canal and vomerovaginal canal identify by computed tomography (CT) transverse imaging and are often mislabeled by investigators. We used a probe guide method in skull specimens to establish the CT imaging features of the two canals. We also used endoscopy to look deeply into the inside structure of them. Finally, CT images of patients were used to confirm our findings. Based on our results using 20 skull specimens and 70 patients, we established a simple method that can be used to identify the two canals on CT transverse imaging. In the transverse images of skull specimens and of patients, the frequency of simultaneous observation of the two canals was 72.5% and 70.71%. We also identified several mislabeled images of the palatovaginal and vomerovaginal canals in published papers. In summary, we found that the two canals could be observed and distinguished by transverse CT imaging. Furthermore, we established a method that could distinguish them. In conclusion, our findings will have a great impact not only on the accurate identification of the pterygoid canals but also on the early detection of tumor metastasis and palatine artery embolization. PMID- 26629055 TI - Chitosan scaffold enhances growth factor release in wound healing in von Willebrand disease. AB - Chitosan-derived biomaterials have been reported to adhere when in contact with blood by encouraging platelets to adhere, activate and aggregate at the sites of vascular injury, thus enhanced wound healing capacity. This study investigated platelet morphology changes and the expression level of transforming growth factor-beta1 (TGF-beta1) and platelet-derived growth factor-AB (PDGF-AB) in the adherence of two different types of chitosans in von Willebrand disease (vWD): N,O-carboxymethylchitosan (NO-CMC) and oligo-chitosan (O-C). Fourteen vWD voluntary subjects were recruited, and they provided written informed consent. Scanning electron microscopy and enzyme-linked immunosorbent assay test procedures were employed to achieve the objective of the study. The results suggest that the O-C group showed dramatic changes in the platelet's behaviors. Platelets extended filopodia and generated lamellipodia, leading to the formation of grape-like shaped aggregation. The platelet aggregation occurred depending on the severity of vWD. O-C was bound to platelets on approximately 90% of the surface membrane in vWD type 1; there was 70% and 50% coverage in vWD type II and III, respectively. The O-C chitosan group showed an elevated expression level of TGF-beta1 and PDGF-AB. This finding suggests that O-C stimulates these mediators from the activated platelets to the early stage of restoring the damaged cells and tissues. This study demonstrated that the greater expression level of O-C assists in mediating the cytokine complex networks of TGF-beta1 and PDGF-AB and induces platelet activities towards wound healing in vWD. With a better understanding of chitosan's mechanisms of action, researchers are able to accurately develop novel therapies to prevent hemorrhage. PMID- 26629056 TI - The neutrophil to lymphocyte ratio improves the positive predictive value of dobutamine stress echocardiography. AB - The neutrophil to lymphocyte ratio (NLR) predicts cardiovascular events. The aim of this study was to determine whether NLR improved the positive predictive value (PPV) of dobutamine stress echocardiography (DSE) in patients with stable coronary artery disease (CAD). We conducted a retrospective review of laboratory and DSE data from the medical records of 1,012 patients who were divided into two groups according to the presence of ischemia and further subdivided into three groups according to the extent of ischemia (nonischemic segments, 1-3 ischemic segments, or > 3 ischemic segments). NLRs were compared among these groups. NLRs increased in patients with ischemia and correlated with the number of ischemic segments (P < 0.001). The optimal cutoff value of NLR determined using receiver operating characteristic analysis was > 2.04, and the diagnostic value of NLR for discriminating patients with >= 50% coronary stenosis in at least one of the coronary arteries from those without significant CAD was high [area under the curve (AUC) = 0.671, standard error = 0.052, P < 0.001, 95% confidence interval (CI) = 0.569-0.773)]. An NLR cutoff value of > 2.04 predicted CAD presence with significant stenosis (62.10% sensitivity and 64.10% specificity). PPV of DSE for a significant coronary artery lesion identified using coronary angiography was 73.8% (95% CI = 75.1-88.5, P < 0.001, AUC = 0.818). On including a cut-off value of > 2.04 for NLR in this multivariable predictive model, the AUC value slightly increased to 0.905 (95% CI = 85.4-95.6) and PPV of DSE increased from 73.8% to 92.6%. NLR improved PPV of DSE for patients with stable CAD. PMID- 26629057 TI - Impacts of stellate ganglion block on plasma NF-kappaB and inflammatory factors of TBI patients. AB - The aim of this study was to initially explore the regulatory mechanism of brain function protection of SGB from the view of nerve-endocrine-immune network. 50 patients with traumatic brain injury (TBI) were divided into the SGB treatment group and the control group, the changes of serum IL-6, IL-1beta, TNF-alpha and CGRP levels were detected by ELISA, and the changes of lymphocyte NF-kappaB protein expression was detected by Western Blot. The control group exhibited the higher expression of IL-6, IL-1beta and TNF-alpha, while the SGB treatment group exhibited various degrees of reduction. On the second day of TBI, the CGRP expression was significantly increased, which was much more significant in the SGB group, and the duration was much longer. The control group exhibited the increased NF-kappaB p65 and NF-kappaB p50 after TBI; after the SGB treatment, the NF-kappaB p65 protein level was significantly reduced, while the NF-kappaB p50 protein level would not be significantly changed. SGB could chronergically inhibit the excessive inflammatory response in the early post-TBI stage, which suggested that SGB might be involved into the regulation of post-TBI nerve endocrine-immune system dysfunction. PMID- 26629058 TI - Role of diffusion-weighted magnetic resonance imaging and apparent diffusion coefficient values in the detection of gastric carcinoma. AB - OBJECTIVE: The study evaluated the applicability of diffusion-weighted magnetic resonance imaging (DW-MRI) and apparent diffusion coefficient (ADC) values in the diagnosis and staging of gastric carcinoma (GC). METHODS: From December, 2013 to December, 2014, 35 GC patients were selected from the Department of Oncology. Carcinomatous gastric tissues were collected as the case group, and normal gastric tissues were collected as the control group. The DW-MRI examination was performed on a 3.0-T GE Signa Excite MRI scanner. The ADC values of carcinomatous and normal gastric tissues were measured. A statistical meta-analysis was further performed. RESULTS: DW-MRI identified 75.0% (3/4) patients with T1, 75.0% (6/8) patients with T2, 86.4% (19/22) patients with T3, and 100.0% (1/1) patient with T4, showing an accuracy for T staging of 82.9% (29/35); identified 92.9% (13/14) patients of N0, 58.3% (7/12) patents of N1, 62.5% (5/8) patents of N2, and 100.0% (1/1) patients of N3, showing an accuracy for N staging of 74.3% (26/35). The average ADC value in the case group was apparently lower than the control group (P < 0.001); in the poorly differentiated group was lower than the moderately and well differentiated groups (F = 111.1, P < 0.001). Pairwise comparison of the average ADC value between the poorly, moderately and well differentiated groups showed statistical significance (all P < 0.05). Meta-analysis further confirmed a higher average ADC value in the case group than the control group (SMD = -4.136, 95% CI = -5.344~-2.928, P < 0.001). CONCLUSION: DW-MRI is proved to be an attractive, noninvasive, quantitative and useful technique in the diagnosis and staging of GC. PMID- 26629059 TI - miR-429 mediates delta-tocotrienol-induced apoptosis in triple-negative breast cancer cells by targeting XIAP. AB - Vitamin E delta-tocotrienol has been reported to possess anticancer activity both in vitro and in vivo. However, the underlying molecular mechanisms of delta tocotrienol induced apoptosis in triple-negative breast cancer are not fully understood. Here, we reported that microRNA-429 (miR-429) is up-regulated in two TNBC cell lines (MDA-MB-231 and MDA-MB-468), treated with delta-tocotrienol. Inhibition of miR-429 may partially rescue the apoptosis induced by delta tocotrienol in MDA-MB-231 cells. We also showed that the forced expression of miR 429 was sufficient to lead to apoptosis in MDA-MB-231 cells. Furthermore, we identified X-linked inhibitor of apoptosis protein (XIAP) as one of miR-429's target genes. These results suggest that the activation of miR-429 by delta tocotrienol may be an effective approach for the prevention and treatment of triple-negative breast cancer. PMID- 26629060 TI - Prognosis of patients with coronary artery disease treated in different therapy units at department of cardiology: a retrospective cohort study. AB - BACKGROUND: Coronary artery disease (CAD) is a major health problem in global. Benefit from different care unit for various type of CAD is remaining unknown. We investigate if coronary care unit (CCU) reduces the incidence of major adverse cardiovascular events (MACEs). METHOD: 806 CAD patients including stable angina (SA) and acute coronary syndrome (ACS) who treated in department of cardiology were involved in the study as two groups. Each group involved two subgroups according to the therapy unit including CCU and normal unit. 12-48 months follow up was carried out. The primary end point was all cause mortality. RESULTS: For SA, death from any cause occurred in 1.0% of the patients in the normal group (1 of 108), as compared with 5.1% in the CCU group (3 of 59) (hazard ratio [HR], 0.164; 95% confidence interval [CI], 0.017 to 1.580; P=0.118). Kaplan-Meier survival analysis showed that there were no significant differences between the two subgroups with respect to the risk of death (P=0.074), revascularization (P=0.660), stroke (P=0.497), heart failure (P=0.658) and hemorrhage (P=0.096). For ACS, death occurred in 1.9% of the patients in the normal subgroup (5 of 267), as compared with 1.3% in the CCU subgroup (5 of 372) (HR, 1.403; 95% CI, 0.406-4.846; P=0.593). Kaplan-Meier survival analysis showed that there were no significant differences between the two subgroups with respect to the risk of death (P=0.591), revascularization (P=0.996), stroke (P=0.425), heart failure (P=0.625). CONCLUSION: CAD patients treated in CCU obtain little benefits compared with normal. PMID- 26629061 TI - Effects of bacterial and viral co-infections of mycoplasma pneumoniae pneumonia in children: analysis report from Beijing Children's Hospital between 2010 and 2014. AB - The objective of this study was to describe the rates and impact of bacterial and viral co-infections of hospitalized children with Mycoplasma pneumoniae. The clinical characteristics, hospital expenses, and differences between single and co-infection MPP were explored. This study included 5,009 children from 2010 to 2014. Infections with various pathogens were identified by the following tests: positive specimens' culture, direct immunofluorescent antigen test for viruses, mycoplasma or chlamydia detection. The results indicated that 13.6% of them showed positive results, including bacterial pathogens in 2.5% of cases and viral pathogens in 9.8% of cases. The most commonly identified bacteria was Streptococcus pneumonia. Influenza and parainfluenza were the most commonly identified virus. Hospitalization expenses of patients with single infections were less than those who with co-infections. In conclusion, co-infections were more common in recent years. In severe MPP, rates of co-infection were higher than non-severe MPP. The longer the course of infection, the higher the co infection rate. PMID- 26629062 TI - Phase I study of icotinib, an EGFR tyrosine kinase inhibitor combined with IMRT in nasopharyngeal carcinoma. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) is a new target for nasopharyngeal carcinoma (NPC) therapy. This prospective phase I study sought to determine the safety and recommended phase II dose of icotinib, a novel highly selective oral EGFR tyrosine kinase inhibitor, in combination with intensity modulated radiotherapy (IMRT) in patients with NPC. METHODS: Eligible patients with NPC received escalating doses of icotinib during IMRT. We treated six patients at a particular dose level until the maximum tolerated dose (MTD) was determined. The starting dose was 125 mg, once-daily and the dose was escalated to another level 125 mg, twice- and thrice- daily, until dose-limiting toxicity (DLT) occurred in two or more patients at a dose level. Expression and mutation analysis of EGFR were performed in all cases. RESULTS: A total of twelve patients were enrolled. Three patients experienced DLT (250 mg/day cohort) and MTD was 125 mg/day. Mucositis toxicity appears to be the major DLT. While EGFR expression in tumor tissue was detected in 75% (9/12) patients, EGFR mutation was detected in 16.67% (1/6) patients in 125 mg/day cohort, and 50% (3/6) in 250 mg/day cohort. CONCLUSION: The combination of icotinib (125 mg/day) and IMRT in patients with locally NPC had an acceptable safety profile and was well tolerated. PMID- 26629063 TI - Expression of CCL2 is significantly different in five breast cancer genotypes and predicts patient outcome. AB - Breast cancer is one of the most common malignancies in women. Current treatment of breast cancer is mainly based on clinicopathological characteristics, and is not sufficiently customized for individual cases. The concept of genotyping in breast cancer was first proposed in 2001. Five major genotypes of breast cancer have been identified and their study has given rise to a new field of research. In our study, we investigated the expression of 13 chemokines and chemokine receptors, which play important roles in inflammation and tumor progression, in five breast cancer genotypes. Using immunohistochemistry, we found that CCL2 expression was significantly different between the different breast cancer genotypes and was negatively associated with estrogen and progesterone receptor expression. Kaplan Meier analysis showed that a low expression of CCL2 was associated with better outcome in breast cancer patients. Enzyme-linked immunosorbent assay results revealed that CCL2 expression in different breast cancer genotype cell line suspensions was significantly different. PMID- 26629064 TI - Effects of morphine and sufentanil preconditioning against myocardial ischemic reperfusion injury in rabbits. AB - OBJECTIVE: This study aims to explore the treatment method of myocardial ischemia reperfusion injury. METHODS: Myocardial Ischemia-reperfusion rabbit model was established in this study. They were divided into four groups: sham operation (S) group, IRI control (I/R) group and IRI with morphine (MF) group and sufentanil (SF). Myocardial infarct size was compared with HE staining method. TUNEL assay was used to detect cell apoptosis. RESULTS: Myocardial infarct size of control group and morphine and sufetanil group was 36.0+/-3.6, 23.0+/-1.2 and 27.1+/-2.3, respectively. There were significant differences between them (P < 0.01). Apoptotic index of I/R, MF and SF groups was 26.9+/-2.2, 12.5+/-2.3, 15.8+/-2.0, with statistical significance (P < 0.05). The concentration of CK-MB in serum: there were no significant differences of CK-MB between each group at baseline. The concentration of CK-MB after reperfusion were higher than that of baseline, except for group S (P < 0.05); Compared with group S, after reperfusion, the CK MB of other three groups were higher (P < 0.05); The concentration of CK-MB in group MF and SF were lower than group I/R (P < 0.05); In contrast to group MF, the concentration of CK-MB after reperfusion was higher in group SF (P < 0.05). CONCLUSION: Morphine and sufentanil can specifically protect the myocardial function. PMID- 26629065 TI - Reactive oxygen species (ROS) mediates non-freezing cold injury of rat sciatic nerve. AB - Non-freezing cold injury is an injury characterized by neuropathy, developing when patients expose to cold environments. Reactive oxygen species (ROS) has been shown as a contributing factor for the non-freezing cold nerve injury. However, the detailed connections between non-freezing cold nerve injury and ROS have not been described. In order to investigate the relationship between non-freezing cold nerve injury and reactive oxygen species, we study the effects of two cooling methods-the continuous cooling and the intermittent cooling with warming intervals-on rat sciatic nerves. Specifically, we assess the morphological changes and ROS production of the sciatic nerves underwent different cooling treatments. Our data shows both types of cooling methods cause nerve injury and ROS production. However, despite of identical cooling degree and duration, the sciatic nerves processed by intermittent cooling with warming intervals present more ROS production, severer reperfusion injury and pathological destructions than the sciatic nerves processed by continuous cooling. This result indicates reactive oxygen species, as a product of reperfusion, facilitates non-freezing cold nerve injury. PMID- 26629066 TI - CHEK2 mutation and risk of prostate cancer: a systematic review and meta analysis. AB - BACKGROUND: CHEK2 encodes for a G2 checkpoint kinase which plays a critical role in DNA repair. Its mutation confers an increased risk of breast cancer. It has also been suggested to increase risks of prostate cancer, but its involvement with this type of cancer has not been confirmed. METHODS: We performed a systematic review and meta-analysis to clarify the association between CHEK2 1100delC, IVS2+1G>A, I157T mutation and risk of Prostate Cancer. A comprehensive, computerized literature search of PubMed until December 27, 2014 was carried out. Eligible studies were included according to specific inclusion criteria. Pooled hazard ratio was estimated using the fixed effects model or random effects model according to heterogeneity between studies. RESULTS: Eight eligible studies were included in the analysis, all were retrospective studies. The overall meta analysis demonstrated that the CHEK2 1100delC mutation (OR 3.29; 95% confidence interval: 1.85-5.85; P = 0.00) and I157T missense mutation (OR 1.80; 95% confidence interval: 1.51-2.14; P = 0.00) was associated with higher risk of Prostate Cancer, and CHEK2 1100delC mutation is irrelevant to familial aggregation phenomenon of prostate cancer (OR 1.59; 95% confidence interval: 0.79 3.20; P = 0.20). The IVS2+1G>A mutation is also irrelevant to Prostate Cancer (OR = 1.59, 95% CI = 0.93-2.71, P = 0.09). None of the single studies materially altered the original results and no evidence of publication bias was found. CONCLUSION: CHEK2 1100delC mutation and I157T missense mutation in males indicates higher risk of Prostate Cancer, but there's no evidence to prove the CHEK2 1100delC mutation was associated with Familial prostate cancer. PMID- 26629068 TI - A rat model of liver transplantation with a steatotic donor liver after cardiac death. AB - This study aimed to establish a rat liver transplantation model with a steatotic donor liver after cardiac death, reflecting clinical conditions. Rats were fed a high-fat diet for 8 weeks to establish the fatty liver model. This model simulates liver steatosis caused by various factors before clinical donation after cardiac death. A pneumothorax was created in the donor rat to induce hypoxia and cardiac arrest before incising the liver. This simulated the processes of hypoxia and cardiac arrest caused by withdrawal of treatment in actual clinical situations. The harvested cardiac death donor liver was then transplanted using the Kamada technique. Donor operative time was 45.7 +/- 4.2 min; cardiac arrest time, 9 +/- 0.8 min; recipient surgery time, 40.3 +/- 4.9 min; and no-liver time, 15 +/- 2.5 min. Of 40 liver-transplanted rats, 2 died within 24 h, with a surgical success rate of 95%. The transaminase levels on post transplantation days 1, 3, 5, and 7 were 835.4 +/- 71.33 U/L, 1334.5 +/- 102.13 U/L, 536.4 +/- 65.52 U/L, and 218.2 +/- 36.77 U/L, respectively. This rat liver transplantation model with a steatotic donor liver after cardiac death could improve the simulation of the pathophysiological processes of clinical donation after cardiac death, and could be used as a reliable and stable animal model. PMID- 26629067 TI - Multiple-locus variable-number tandem-repeat analysis of Brucella isolates from patients in Xinjiang China. AB - OBJECTIVE: This study is to characterize and identify the human Brucella strains in Xinjiang, China with multiple-locus variable-number tandem-repeat (VNTR) analysis (MLVA) scheme. METHODS: Brucella strains were isolated and cultured from 62 brucellosis patients. The bacteria strains were subjected to the oxidase, catalase, rapid urease, and nitrate reduction tests, and the species identification was performed using the VITEK-2 Compact system. These Brucella strains were further identified and characterized using the 16 VNTR loci in a MLVA-16 methodology. RESULTS: Twelve Brucella strains had been identified out of 62 patients, which were all recognized as Brucella melitensis (B. melitensis) according to the results from the VITEK-2 Compact system. Based on panel 1 (MLVA 8), these 12 Brucella isolates were clustered into three known genotypes and two new genotypes, in which 7 strains were clustered into genotype 45 (1-5-3-12-2-2-3 2), 1 strain was classified as genotype 42 (1-5-3-13-2-2-3-2), 1 stain was with genotype 62 (1-3-3-13-2-2-3-2), and the other 3 trains revealed two new genotypes, i.e., (1-5-3-12-2-3-3-2) and (1-5-3-11-2-3-3-2). Using panel 2A+2B (MLVA-16), we found that no genotypes of these strains were identical to the known genotypes, generally with differences in 2-4 loci. However, three strains shared the same genotype. CONCLUSION: Brucella strains in 62 brucellosis patients from Xinjiang are all identified as B. melitensis. Based on MLVA-8, two new genotypes have been discovered. These findings might contribute to the understanding of the pathogenesis and epidemiology of brucellosis in Xinjiang, China. PMID- 26629069 TI - Expression and significance of miR155 and vascular endothelial growth factor in placenta of rats with preeclampsia. AB - OBJECTIVE: This study is to investigate the expression and significance of miR155 and vascular endothelial growth factor (VEGF) in placenta of preeclampsia (PE) model rats. METHODS: A total of 20 SD rats were randomly divided into normal pregnant group and PE model group. PE model was established by subcutaneous injection of L nitro arginine methyl ester continuously for 4 days with a dosage of 200 mg/Kg.d from the 13th day of pregnancy. Blood pressure, urinary protein and renal function were detected to evaluate fetal development. Real-time fluorescent quantitative polymerase chain reaction was used to test the expression of placental miR155. Western-blot assay and ELISA were performed to detect the expression of placental VEGF protein. RESULTS: Blood pressure, urine protein, blood urea nitrogen and creatinine in PE model group were higher than in normal pregnant group, and there was statistically significant (P < 0.05). Expression of miR155 in PE group was higher than that of normal pregnant group and VEGF protein expression was lower than that in normal pregnant group, both were statistically significant (P < 0.01). CONCLUSION: In PE model group, miR155 expression significantly increases whereas the expression of VEGF decreases. PE might be correlated with the down regulation of VEGF by miR155. PMID- 26629070 TI - Risk of pneumonia in central nervous system injury with alcohol intake: a meta analysis. AB - OBJECTIVE: Central nervous system (CNS) injury can increased the risk of secondary mortality because of its late inflammatory complications. Alcohol intake increases the risk of damage and complications subsequent to a (CNS) injury. How about the risk of pneumonia after CNS injury under the effect of alcoholic drink? Though animal trails of material prosperity and studies for human have been investigated in recent decades, the outcome maintains poor understanding. Pneumonia is one of the serious complication at the time of hospitalization and it should be known as more as possible for steadying patient conditions in intensive care unit and shortening length of stay. Thus, we conducted a meta-analysis of published materials to assess the association between alcohol intake and pneumonia in CNS injury. METHODS: Two authors searched the PUBMED, EMBASE, Cochrane Library, and web of science up to September, 2014 for published literatures without any limitations. Reference lists from identified studies were also screened carefully by us for additional data. The summary relative risks (RRs) and 95% confidence intervals (CI) were calculated by statistical analysis software (Stata 12.0) with fixed-effects models to estimate the risk. RESULT: The results indicated that a higher incidence of pneumonia was found in CNS injury under the influence of alcohol (RR = 1.32, 95% CI = 1.21 1.43), and the risk has no relation to blood alcohol concentration (BAC) (BAC >= 80 mg/dl vs < 80 mg/dl, BAC >= 100 mg/dl vs < 100 mg/dl). CONCLUSION: Traumatic brain injury (TBI) and spinal cord injury patients who are under the influence of alcoholic drink have a higher risk of pneumonia. PMID- 26629071 TI - Correlation of serum 25-hydroxyvitamin D level with vascular calcification in hemodialysis patients. AB - OBJECTIVE: The aim of this study was to analyze the correlation of serum 25 hydroxyvitamin D level with vascular calcification in patients treated with hemodialysis. METHODS: As a cross-sectional study, 126 patients receiving maintenance hemodialysis (MHD) in our hospital were enrolled in this study. According to the serum 25-hydroxyvitamin D level, the patients were divided into 25-hydroxyvitamin D deficiency group (30 etag/ml or less than 30 etag/ml) and 25 hydroxyvitamin D normal level group (>30 etag/ml). All of the subjects underwent lateral lumbar, pelvis and hands X-ray examination to score the degree of calcification (Kauppila score). RESULTS: Among the 126 patients treated with MHD, there were 110 patients with 25-hydroxyvitamin D deficiency and 16 patients with normal 25-hydroxyvitamin D level. There was no significant difference found in gender, age, age of dialysis, active vitamin D treatment, blood calcium, blood phosphorus, blood parathyroid hormone (PTH) and other related indicators between the two groups. The incidence of vascular calcification in patients with 25 hydroxyvitamin D deficiency was significantly higher than that in patients with normal 25-hydroxyvitamin D level (P = 0.001). Serum 25-hydroxyvitamin D level had a negative correlation with the calcification score (r = 0.193, P = 0.193). Logistic regression showed that 25-hydroxyvitamin D was not a risk factor for vascular calcification in MHD patients. Serum 25-hydroxyvitamin D level is generally low in patients with MHD. CONCLUSIONS: Patients with 25-hydroxyvitamin D deficiency have a higher incidence of vascular calcification with a markedly negative correlation. Thus, for the patients treated with MHD, vitamin D deficiency should be actively treated. PMID- 26629072 TI - Thymic stromal lymphopoietin polymorphisms and allergic rhinitis risk: a systematic review and meta-analysis with 6351 cases and 11472 controls. AB - Previous studies suggested a close association between the thymic stromal lymphopoietin (TSLP) genetic variants and allergic diseases. Here, we explored the correlation between the TSLP polymorphisms and allergic rhinitis susceptibility using meta-analysis. We searched PubMed, Ovid, Cochrane libraries, CNKI, Wanfang, and CQVIP databases until Apr 19, 2015. Quality assessment was conducted for each article according to the Strengthening the Reporting of Genetic Association studies (STREGA). The pooled measure was calculated as the inverse variance-weighted mean of the logarithm of the OR with 95% CI to assess the strength of association between TSLP polymorphisms and the risk of allergic rhinitis. Five case-control studies with 6351 cases and 11472 controls were included in this study. TSLP rs1898671 polymorphism was significantly associated with an increased risk of allergic rhinitis (OR=1.13; 95% CI, 1.07-1.20; P<0.0001). In the subgroup analysis by race, TSLP rs1898671 polymorphism was significantly associated with an increased risk of allergic rhinitis in Caucasian (OR=1.14; 95% CI, 1.08-1.21; P<0.00001). In the subgroup analysis by age group, adult individuals with TSLP rs1898671 polymorphism showed increased risk of allergic rhinitis (OR=1.13; 95% CI, 1.07-1.21; P<0.0001). Because only one study investigated the association between other SNPs in TSLP and allergic rhinitis risk, the meta-analyses were not performed. In summary, we demonstrated that TSLP rs1898671 polymorphism was associated with a higher risk for allergic rhinitis. PMID- 26629073 TI - Effects of Rosa laevigata Michx. extract on reactive oxygen species production and mitochondrial membrane potential in lens epithelial cells cultured under high glucose. AB - This study was to investigate the effects of Rosa laevigata Michx. (RLM) extract on reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) in lens epithelial cells (LECs) cultured under high glucose. SRA01/04 cell models of diabetic cataract were established by high glucose culture, and these cells were administrated with RLM extract. Levels of ROS and MMP in SRA01/04 cells were detected with fluorescent probes. HO-1 expression level, Akt phosphorylation, and Nrf2 translocation were detected by Western blot. RLM treatment could exert protective effects on SRA01/04 cells under high glucose condition, decreasing the ROS production and elevating the MMP in these cells. Western blot analysis indicated that the expression level of HO-1 was significantly elevated in SRA01/04 cells after the RLM treatment. Moreover, when HO-1 was interfered with siRNA, the effects of RLM on the levels of ROS and MMP were diminished, indicating that HO-1 induction was necessary for the function of RLM. Furthermore, HO-1 inducing effects of RLM were mediated by the PI3K/Akt and Nrf2/ARE pathways. The effects would be abolished when either pathway was inhibited by pharmacological manipulation or siRNA silencing. RLM inhibits ROS production and elevates MMP, through the induction of HO-1 expression, in LECs under high glucose condition. The protective effects of RLM are mediated by the PI3K/Akt and Nrf2/ARE pathways. Our findings provide theoretic basis and experimental evidence for the application of RLM in the treatment of diabetic cataract. PMID- 26629074 TI - The protective effect of tadalafil on IMA (ischemia modified albumin) levels in experimental renal ischemia-reperfusion injury. AB - INTRODUCTION: To investigate the effect of the tadalafil in experimental renal I/R injury and to evaluate these changes with IMA (nonspesific early biomarker of ischemia), NO and MDA levels. MATERIALS AND METHODS: Twenty four female Wistar rats were randomly divided into 3 groups (n=8): Group I, sham; Group II, 60 min I/R; Group III, 60 min I/R plus tadalafil. Tadalafil was administered via an orogastric tube (10 mg/kg) 24 h prior to the procedure. After ischemia of the left kidney and 1 h of reperfusion, blood samples were obtained, and the kidney was removed. RESULTS: Statistically significant histopathologic changes were exist between groups, with the most severe injury was determined in group II in comparison to the others (X(2)=21,803, P=0.000). Also mean serum IMA levels were higher in group II, but not statistically significant (19.83+/-7.81 U/ml, 22.26+/ 7.14 U/ml and 19.82+/-7.77 U/ml, P=0.613). In addition, NO values were lower in I/R groups (P=0.049). There were no differences among the groups in terms of MDA. CONCLUSIONS: IMA may be used as a nonselective biomarker for IR injury before the occurrence of necrosis. Decreased IMA levels may indicate the nephroprotective effect of tadalafil in renal IR injury. PMID- 26629075 TI - Deoxyribonucleic acid (DNA) methyltransferase contributes to p16 promoter CpG island methylation in lung adenocarcinoma with smoking. AB - In this study, the relationship between CpG island methylation and smoking and DNA methyltransferase in the occurrence and development of lung adenocarcinoma was explored by detecting p16 promoter methylation status. Protein and mRNA levels of p16 were detected by immunohistochemistry and in situ hybridization assays. p16 gene promoter and exon 1 CpG island locus Hap II sites methylation status was analyzed with the methylation-specific PCR. Only 4 of 40 p16-positive cases were detected to methylate on CpG islands with 10% methylating rate whereas 18 of p16-negative cases were methylated up to 36.73% of methylating rate. The methylating rates of both p16-positive and p16-negative groups were significantly different. 17 of 50 cases with smoking from total 89 lung adenocarcinoma cases were detected to methylate on CpG islands while only 5 of the remaining 39 non smokers to methylate. The difference of the methylating rates in both smokers and non-smokers was significant to suggest the closely association of CpG island methylation of p16 with smoking. Furthermore, p16 promoter CpG islands were detected to methylate in 15 of 35 cases with higher DNA methyltransferase activity whereas only 7 detected to methylate in the remaining 54 cases with lower DNA methyltransferase activity. p16 promoter CpG island methylation likely made p16 expressing silence thus contributed to the tumorigenesis of lung adenocarcinoma. Smoking is likely to promote p16 CpG island methylation or by its effect of the activity and metabolism of DNA methyltransferase 1 (DNMT) on CpG island methylation status. PMID- 26629076 TI - Therapeutic effects of PKP on chronic painful osteoporotic vertebral compression fractures with or without intravertebral cleft. AB - This study aims to investigate clinical effects of protruding after percutaneous vertebral plasty (PKP holds) for treatment of chronic painful osteoporotic vertebral compression fractures (CPOVCFs), and assess its safety and effectiveness. One hundred and eighteen CPOVCFs patients were included, and analyzed and followed up therapeutic effects of PKP holds. All of these patients were divided into NIVC (73 cases) and IVC (45 cases) group. Comparing operation time, bone cement perfusion, pain intensity modulus visual grading scoring, Oswestry disability index, fracture fanterior relative height, local convex Angle, and surgical complications between the two groups. There were no significant differences between two groups for operation time of PKP holds (P>0.05). Amount of bone cement injection in IVC groups was significantly higher compared to NIVC group (P<0.05). Pain intensity visual modulus ratings and Oswestry disability index were significantly improved in both groups after surgery and postoperative follow-up period compared to pre-operation (P<0.05). Fracture fanterior margin relative height and local convex angle were also significantly improved (P<0.05). Fracture fanterior margin relative height was also significantly improved for IVC compared to NIVC group (P<0.05). There were no differences for bone cement leakage rate and adjacent segment fracture between two groups (P>0.05). But there was a case of bone cement loose, which needs to be treated for further step. In conclusion, PKP holds is a kind of effective and safe method for the IVC and NIVC patients. Especially for the IVC patients, PKP holds can significantly improve the fracture fanterior margin relative height. PMID- 26629077 TI - HCV core protein represses the apoptosis and improves the autophagy of human hepatocytes. AB - OBJECTIVES: This study aims to investigate the influence on human hepatocytes apoptosis and autophagy by the hepatitis C virus (HCV) core protein. METHODS: QSG 7701, a human-derived non-neoplastic liver cell line, was transfected with PIRES core vector that was a eukaryotic vector to express HCV core protein. Fluorescence microscope was used to observe the changes of nuclei in apoptosis cells by Annex in V-FITC/PI double staining. Flow cytometry was applied to detect the rate of cell apoptosis. Western blotting was used to detect the expression of HCV core protein, transcription factor nuclear factor-kappa B (NF-kappaB), autophagic biomarker microtubule associated protein 1 light chain 3 (LC3), and Beclin-1. RESULTS: The apoptosis rate was significantly lower (P < 0.05) in QSG7701/core group (transfected with PIRES-core vector, (1.34+/-0.07)%) than in QSG7701 group (no transfection, (2.35+/-0.11)%) and in QSG7701 QSG7701/pcDNA3.1 group (transfected with pcDNA3.1 vector, (2.58+/-0.1)%). NF-kappaB expression was up-expressed in QSG7701/core group than in QSG7701/pcDNA3.1 group and QSG7701 group (P < 0.05). LC3-II expression and Beclin-1 expression was significant higher in QSG7701/core group than in the QSG7701/pcDNA3.1 group and QSG7701 group (P < 0.05). CONCLUSION: HCV core protein can repress the apoptosis and improve the autophagy of QSG7701 through up-regulating NF-kappaB and Beclin-1 expression. PMID- 26629078 TI - Associations between the standardized uptake value of (18)F-FDG PET/CT and demographic, clinical, pathological, radiological factors in lung cancer. AB - OBJECTIVES: (18)F-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is extensively used to diagnose and stage of lung cancer. The aim of the current study was to investigate the correlation of demographic, clinical, pathological and radiological factors with primer tumor FDG Uptake in patients with lung cancer. MATERIALS AND METHODS: This cross sectional, clinical study was performed on a total of 57 lung cancer patients newly diagnosed that underwent FDG PET/CT. In addition to descriptive variables, histopathological diagnosis, tumor site and size, hemoglobin level, red cell distribution width, neutrophil to lymphocyte ratio were noted for each patient. The correlation of these variables to SUVmax values in FDG PET/CT was investigated. RESULTS: A total of 57 patients (4 women, 53 men) with an average age of 60.8+/-9.4 (range: 33-89) participated in the study. Histopathological diagnoses were consistent with squamous cell carcinoma (28, 49.1%), adenocarcinoma (15, 26.3%) and small cell cancer (14, 24.6%). The SUVmax of primary tumor was positively correlated with tumor size (P<0.001). The tumor SUVmax of squamous cell carcinoma (SqCC) (17.49+/-8.37) was higher than that of adenocarcinoma (AC) (12.80+/-4.77) and small cell carcinoma (SCC) (12.40+/-5.80) (P=0.038). CONCLUSION: SUVmax value was significantly higher for squamous cell carcinoma and it SUVmax values in PET scans was found to be positively correlated with tumor size. This study suggests that, tumor size and histologic subtype had influences upon FDG uptake in lung cancer. PMID- 26629079 TI - Myocardial ischemic post-conditioning attenuates ischemia reperfusion injury via PTEN/Akt signal pathway. AB - OBJECTIVES: To investigate whether myocardial ischemic post-conditioning attenuates ischemia reperfusion injury via PTEN/Akt signal pathway. DESIGN: Forty five male Sprague-Dawley rats were randomly divided into three groups: Sham, Ischemia reperfusion (I/R) and Ischemic post-conditioning (IPost) group. After the experiment finished, myocardial infarction area was examined. Serum creatine phosphokinase and lactate dehydrogenase activity were detected at baseline and the end of reperfusion. The protein levels of PTEN, Akt, p-Akt, Bax and Bcl-2 were measured by Western blot method. RESULTS: Myocardial infarct size was significantly reduced in IPost as compared to I/R. Results were confirmed by serum creatine phosphokinase and lactate dehydrogenase activity. In addition, PTEN and Bax protein expression were inhibited and the p-Akt and bcl-2 protein expression were enhanced in IPost compared with I/R (P < 0.05). At the same time, the ratio of Bax and Bcl-2 was decreased in IPost (P < 0.05). However, ischemic post conditioning did not affect the total Akt level (P > 0.05). CONCLUSIONS: We confirmed that ischemic post-conditioning protects the heart against reperfusion injury. It is important that we demonstrated that the cardioprotective effect of ischemic post-conditioning was involved in the inhibition of PTEN, activation of the PI3K/Akt pathway and reduction of the cardiomyocyte apoptosis. PMID- 26629080 TI - Lack of an association between XRCC2 R188H polymorphisms and breast cancer: an update meta-analysis involving 35,422 subjects. AB - PURPOSE: Several studies have investigated the associations between XRCC2 R188H polymorphism and the susceptibility to breast cancer, but the results have been inconclusive. To derive a more precise estimation of the relationship, a meta analysis was performed. METHODS: PubMed and China National Knowledge Infrastructure (CNKI) searches were carried out for relevant studies published before March 2015. Meta-analysis was performed with the Stata, version 11.0. RESULTS: A total of 17 case-control studies, including 17,986 cases and 17,436 controls, were selected. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the homozygous model, dominant model, and recessive model. When all the studies were pooled into the meta-analysis, there was no evidence showing a significant association between XRCC2 R188H polymorphism and breast cancer risk (for homozygous model, OR=0.84, 95% CI=0.62-1.14; for dominant model: OR=0.76, 95% CI=0.53-1.09; and for recessive model: OR=1.04, 95% CI=0.98-1.10). In the subgroup analysis by ethnicity, no significant association was found between the polymorphism and breast cancer risk. CONCLUSIONS: In conclusion, this meta-analysis indicates that the XRCC2 R188H polymorphism is not a risk factor for developing of breast cancer. PMID- 26629081 TI - None detectable retrograde transport of Chinese botulinum toxin type A in mice by single intramuscular injection. AB - Botulinum toxin type A (BoNT/A) can specifically cleave synaptosomal associated protein of 25 kDa (SNAP-25) into cleaved SNAP-25 (cl.SNAP-25), thus blocking the synaptic transmission in motor end plate and resulting in paralysis. It has been widely applied in clinical for treatment of various conditions characterized by muscle hyperactivity, such as dystonia and spasticity. BoNT/A is used locally, with little diffusion. Its paralyzing role is considered to be restricted to the nerve muscle junction, or close to the injection site. Recently, more and more studies, however, have suggested that BoNT/A also has central effects. In addition, some investigators have demonstrated that BoNT/A enters into central nervous system via retrograde transport after local intramuscular administration. The retrograde axonal transport of Chinese BoNT/A (CBoNT/A) was studied in this paper, which was rare in report. And the results showed that cl.SNAP-25 appeared not only at the injection site but also in contralateral muscle. Retrograde transport, however, was non-existent or too little to be detected in our study. PMID- 26629082 TI - Comparison between hair follicles and split-thickness skin grafts in cutaneous wound repair. AB - Several clinical research studies have demonstrated that chronic cutaneous wounds can be treated with hair follicle grafts. However, the clinical outcomes of hair follicle grafting compared to split-thickness skin grafting have not been examined. This study sought to compare the clinical outcomes of patients with chronic wounds following hair follicle therapy and split-thickness skin graft therapy in a relatively large cohort of patients. Forty patients were enrolled in the study, a retrospective analysis of all patients underwent therapy with hair follicles (cohort A) and split-thickness skin grafts (cohort B) was performed. Safety, healing duration, skin quality (recipient site), scar formation (donor site) and overall postoperative outcome were analyzed. The wound sites were examined using photography at weeks 2, 8, and 12 after surgery. Five non-biased reviewers estimated the above-mentioned clinical outcomes using a five-point Likert scale. The ages and wound areas were similar between cohorts A (n=20) and B (n=20). Total wound closure was observed and adverse events were rare and controllable in both cohorts. The skin and scar quality were rated significantly higher in the hair follicle cohort than the split-thickness skin graft cohort (4.40 vs 3.45, P<0.05 and 4.65 vs 3.20, P<0.05; respectively). Hair follicle therapy resulted in a significantly higher overall score than split-thickness skin graft treatment (4.45 vs 3.40, P<0.05). This study demonstrated that hair follicles can achieve better skin/scar quality and overall clinical outcomes than split-thickness skin grafts. Hair follicles should be considered an effective surgical technique for the treatment of chronic cutaneous wounds. PMID- 26629083 TI - Effects of asiaticoside on human umbilical vein endothelial cell apoptosis induced by Abeta1-42. AB - This study is to investigate the potential role of asiaticoside (AS) in Abeta1-42 induced apoptosis on the human umbilical vein endothelial cell (HUVEC). HUVEC cells were divided into Abeta1-42 group (treated with 50 MUM Abeta1-42), AS groups (treated with 50 MUM Abeta1-42 and 10 mM, 1 mM, 0.1 mM or 0.01 mM AS), and negative control group (without treatments). Cell proliferation was detected by CCK-8 assay. Apoptosis was analyzed by Hochest33342 staining and flow cytometry. Western Blot was carried out to detect the expression of Bcl-2 and Bax protein. Abeta1-42 treatment inhibited cell proliferation and increased cell apoptosis of HUVEC cells. Interestingly, AS at concentrations of 10 mM, 1 mM, 0.1 mM and 0.01 mM reversed the effects of Abeta1-42 by increasing cell survival rate and reducing apoptosis of HUVEC cells. Furthermore, the expression of Bcl-2 protein was increased whereas the expression of Bax protein was decreased in AS groups. Compared with Abeta1-42 group, the ratio of Bcl-2/Bax was significantly increased in AS groups (P < 0.05). These results suggested that AS may be effective in protecting cells from damage caused by aggregated Abeta1-42. And this effect may be attributed to the increase of Bcl-2 and decrease of Bax under AS treatment. PMID- 26629084 TI - Commonly administered bacille Calmette-Guerin strains induce comparable immune response. AB - Bacille Calmette-Guerin (BCG) is currently the only available vaccine against tuberculosis (TB), but its protective efficacy in adults is highly variable. This study aimed to compare the immune response induced by two widely used BCG strains: BCG China strain (derivative of BCG Danish strain) in DU2-III group and BCG Pasteur in DU2 -IV group. Healthy BALB/c mice were immunized with BCG China strain or BCG Pasteur strain. Specific IgG, IgG1, and IgG2a antibodies titers, the proliferation of splenocytes, the percentages of splenocyte subsets and the concentrations of induced IFN-gamma and IL-4 at 6(th), 8(th), 10(th), and 12(th) weeks after the immunization were detected. We found that BCG Pasteur strain induced higher specific IgG and IgG1 titers, higher proliferation of splenocytes, higher percentages of CD4(+) or CD8(+) T cells, and higher concentration of secreted IFN-gamma than BCG China strain. However, there were no significant differences in IgG2a titer and IL-4 concentration between both strains. In conclusion, our study shows that immune responses to BCG vaccine differ by strain, which may account for variable outcomes of BCG immunization. PMID- 26629085 TI - Therapeutic effects of bone marrow mesenchymal stem cells expressing interleukin 12 in mice bearing malignant ascites tumor. AB - This study is to investigate the therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) expressing interleukin (IL)-12 on malignant ascites tumor bearing mice and the related mechanisms. Malignant ascites tumor mouse model was established by the intraperitoneal inoculation with MethA or H22 tumor cells. Mouse BMSCs were transfected with lentiviral vector containing IL-12, and then transplanted into these mouse models via intraperitoneal injection. The peritoneal permeability in these mice was evaluated and compared. The contents of INF-gamma and VEGF in ascites were determined by ELISA. Mouse models receiving IL 12-expressing BMSCs were rechallenged with tumor cells, and the animal survival was observed and analyzed. In both MethA and H22 tumor cell-induced malignant ascites tumor mouse models, there were no significant differences in the peritoneal permeability between the normal saline (NS), BMSC-control, and BMSC null groups. However, compared with NS control group, the peritoneal permeability was significantly decreased by IL-12-expressing BMSCs. Moreover, ELISA showed that, in both the MethA and H22 tumor cell-induced mouse models, compared with the NS control group, the contents of INF-gamma in ascites were significantly elevated, while the contents of VEGF in ascites were significantly decreased, in the BMSC-IL-12 groups. In addition, IL-12-expressing BMSCs significantly elongated the survival of mouse models after rechallenging with tumor cells. IL 12-expressing BMSCs exert protective effects against malignant ascites tumor, and the anti-tumor effects might be associated with the enhanced anti-tumor immunity. Our findings might bring new insights into the treatment of tumors with immunotherapy. PMID- 26629086 TI - Submucosal tunnelling endoscopic resection (STER) for the treatment of a case of huge esophageal tumor arising in the muscularis propria: a case report and review of literature. AB - BACKGROUND AND AIMS: Endoscopic Interventional Treatment is of little trauma and less complications in the treatment of esophageal tumor and leads to faster recovery and fewer days of hospitalization. This study was aimed to investigate the safety and efficacy of endoscopic interventional therapy for huge esophageal tumor arising in the muscularis propria. METHODS: The patient was treated by submucosal tunneling endoscopic resection (STER). RESULTS: The huge esophageal tumor was resected completely by STER technique, with little trauma and less complications. The size of the resected tumor was 5.5*3.5*3.0 cm. CONCLUSION: Submucosal tunneling endoscopic resection is a safe and efficient technique for treating Huge Esophageal Tumor originating from muscularis propria layer. PMID- 26629087 TI - MiR-146a rs2910164 polymorphism is associated with hepatocellular carcinoma: a meta-analysis. AB - Results of published studies on the association between the miR-146a rs2910164 polymorphism and the risk of hepatocellular carcinoma (HCC) were inclusive. We performed a meta-analysis. A literature research was conducted using PubMed, Cochrane Library, Ovid, Embase, Wanfang and China National Knowledge Infrastructure (CNKI) databases, to identify studies. Statistical analyses were conducted in STATA version 11.0 (Stata Corporation, College station, TX, USA). A total of 12 publications were included in this meta-analysis. The results of this meta-analysis suggested that miR-146a rs2910164 was associated with an increased risk of HCC (OR = 1.09, 95% CI = 1.00-1.19). In sensitivity analysis, the result was still positive when excluding the studies without HWE (OR = 1.12, 95% CI = 1.01-1.23). In conclusion, this meta-analysis suggested a significant association between miR-146a rs2910164 polymorphism and HCC risk. PMID- 26629088 TI - Survivin -31 G/C polymorphism might contribute to colorectal cancer (CRC) risk: a meta-analysis. AB - Published data has shown inconsistent findings about the association of survivin 31 G/C polymorphism with the risk of colorectal cancer (CRC). This meta-analysis quantitatively assesses the results from published studies to provide a more precise estimate of the association between survivin -31 G/C polymorphism as a possible predictor of the risk of CRC. We conducted a literature search in the PubMed, Web of Science, and Cochrane Library databases. Stata 12 software was used to calculate the pooled odds ratios (ORs) with 95% confidence intervals (CIs) based on the available data from each article. Six studies including 1840 cases with CRC and 1804 controls were included in this study. Survivin -31 G/C polymorphism was associated with a significantly increased risk of CRC (OR = 1.78; 95% CI, 1.53-2.07; I(2) = 0%). In the race subgroup analysis, both Asians (OR = 1.72; 95% CI, 1.44-2.05; I(2) = 0%) and Caucasians (OR = 1.93; 95% CI, 1.46 2.55; I(2) = 0%) with survivin -31 G/C polymorphism had increased CRC risk. In the subgroup analysis according to site of CRC, survivin -31 G/C polymorphism was not associated with colon cancer risk (OR = 2.02; 95% CI, 0.79-5.22; I(2) = 82%). However, this polymorphism was significantly associated with rectum cancer risk (OR = 1.98; 95% CI, 1.42-2.74; I(2) = 0%). In the subgroup analysis by clinical stage, both early stage (I+II) and advanced stage (III+IV) were associated with survivin -31 G/C polymorphism (OR = 1.61; 95% CI, 1.20-2.16; I(2) = 0% and OR = 2.30; 95% CI, 1.70-3.13; I(2) = 0%, respectively). In the subgroup analysis by smoke status, both smokers and non-smokers with survivin -31 G/C polymorphism showed increased CRC risk (OR = 1.47; 95% CI, 1.01-2.13; I(2) = 60% and OR = 1.71; 95% CI, 1.28-2.30; I(2) = 0%, respectively). In the subgroup analysis by drink status, both drinkers and non-drinkers with survivin -31 G/C polymorphism showed increased CRC risk (OR = 1.58; 95% CI, 1.06-2.37; I(2) = 8% and OR = 1.61; 95% CI, 1.23-2.11; I(2) = 0%, respectively). In conclusion, this meta-analysis suggested that survivin -31 G/C polymorphism may be associated with the risk of CRC. PMID- 26629089 TI - Aggressive angiomyxoma of the liver: a case report. AB - Aggressive angiomyxoma (AAM) is a rare benign mesenchymal tumor that occurs almost exclusively in the soft tissues of the pelvis and perineum. Very few cases of AAM occurring outside these regions have been reported. The present report presents a case of AAM originating from the liver of a 50-year-old female patient. Tumor resection was performed, and pathological examination revealed microscopic features that were characteristic of AAM. Histopathological examination showed that the tumor was composed of scattered spindle-or stellate shaped cells with thick-walled blood vessels lying in a myxoid stroma. Immunohistochemically, the tumor cells stained positively for CD34, vimentin, and actin. In this paper, we also discuss the differential diagnosis of AAM. To the best of our knowledge, this study is the first to report a case of AAM originating from the liver. PMID- 26629090 TI - Association of coronary artery disease and chronic kidney disease in Lebanese population. AB - BACKGROUND: More evidence is emerging on the strong association between chronic kidney disease (CKD) and cardiovascular disease. We assessed the relationship between coronary artery disease (CAD) and renal dysfunction level (RDL) in a group of Lebanese patients. METHODS: A total of 1268 patients undergoing cardiac catheterization were sequentially enrolled in a multicenter cross sectional study. Angiograms were reviewed and CAD severity scores (CADSS) were determined. Estimated glomerular filtration rate (eGFR) was calculated and clinical and laboratory data were obtained. CKD was defined as eGFR < 60 ml/min. Logistic regression model was performed using multivariate analysis including all traditional risk factors associated with both diseases. ANOVA and the Tukeytestswere used to compare subgroups of patients and to assess the impact of each disease on the severity of the other. RESULTS: Among the 82% patients who exhibited variable degrees of CAD, 20.6% had an eGFR < 60 ml/min. Logistic regression analysis revealed a bidirectional independent association between CAD and CKD with an OR = 2.01 (P < 0.01) and an OR = 1.99 (P < 0.01) for CAD and CKD frequencies, respectively. We observed a steady increase in the CADSS mean as eGFR declined and a progressive reduction in renal function with the worsening of CAD (P < 0.05). This correlation remained highly significant despite considerable inter-patient variability and was at its highest at the most advanced stages of both diseases. CONCLUSIONS: Our results show a strong, independent and graded bidirectional relationship between CAD severity and RDL. We propose to add CAD to the list of risk factors for the development and progression of CKD. PMID- 26629091 TI - A new mode of community continuing care service for COPD patients in China: participation of respiratory nurse specialists. AB - OBJECTIVE: This study explored a community nursing service mode in which respiratory nurse specialists cared for patients with chronic obstructive pulmonary disease (COPD) in a 12-week period after hospital discharge, with the aim of better preventing acute exacerbations, improving health-related quality of life (HRQOL) and reducing medical expenses in these patients. METHODS: We carried out a prospective randomized controlled study in which 68 COPD patients discharged were recruited from a general hospital in Guangzhou, China, were randomized divided into two groups. The control group underwent conventional nursing care, and the intervention group received community continuing care by respiratory nurse specialists. The observation period was 12 weeks. The results of intervention were evaluated using the Seattle Obstructive Lung Disease Questionnaire (SOLDQ) and the COPD Self-Efficacy Scale (CSES). In addition, the frequency of acute exacerbations, emergency treatments or hospitalizations, and medical expenses were recorded in the 12-week observation period. RESULTS: After six weeks, the total and subscale scores (P < 0.05) of SOLDQ and CSES significantly improved compared to the baseline ones in the intervention group. The control group had significantly higher scores in the treatment satisfaction (TS) of SOLDQ, the total score, and the weather/environment and behavioral risk factors of CSES. After 12 weeks, the total and subscale scores of SOLDQ and CSES showed a sustained and significant growth in the intervention group (P < 0.05). The control group had significantly higher scores only in the weather/environment risk factor of CSES. During the 12-week observation, the intervention group had significantly fewer acute exacerbations, emergency treatments or re hospitalizations and significantly lower average medical expenses than the control group (P < 0.05). CONCLUSIONS: Community continuing care by respiratory nurse specialists may improve HRQOL, increase self-efficacy, reduce incidence of acute exacerbation, and lower medical expenses in patients with COPD after hospital discharge. PMID- 26629092 TI - Role of multi-mode ultrasound in the diagnosis of level 4 BI-RADS breast lesions and Logistic regression model. AB - OBJECTIVE: This study is to investigate the diagnostic role of multi-mode ultrasound in level 4 BI-RADS breast lesions and to establish a Logistic regression model. METHODS: Totally 179 patients with 182 sites of breast lesions were enrolled in this study. Preoperatively, the examinations of routine ultrasonography, elastography, contrast-enhanced ultrasonography and three dimensional color Doppler were performed. Postoperatively, the breast lesions were diagnosed as benign and malignant lesions according to pathological results. Diagnostic indicators of each ultrasound analysis were determined and compared. The relationship between these diagnostic indicators and the benign and malignant features of breast lesions was analyzed by single factor analysis. Logistic regression model was established. RESULTS: The diagnostic indicators with high sensitivity and specificity were tumor edge, enhanced range and score of elastography. Four factors of tumor edge, enhanced order, contrast mode and score of elastography were related with the benign and malignant features of breast lesions. The prediction model was Logit (P) = 0.636 + 4.471X1 + 4.337X2 + 3.753X3 + 3.014X4 + 2.525X5 + 2.105X6. Likelihood ratio test showed that the model was statistically significant (chi(2) = 161.876, P < 0.0001). This model could effectively distinguish between benign and malignant tumors (R(2) = 0.813, prediction accuracy 92.3%). The differences in sensitivity and specificity between multi-mode ultrasound diagnosis and routine ultrasound diagnosis were statistically significant (P < 0.001). However, there was no significant difference between Logistic regression model and multi-mode ultrasound diagnosis. CONCLUSION: Multi-mode ultrasound and Logistic regression model are more effective in diagnosing level 4 BI-RADS breast lesions. PMID- 26629093 TI - Role of serum polyunsaturated fatty acids in the development of colorectal cancer. AB - We aimed to investigate the role of serum levels of polyunsaturated fatty acid (PUFA) in the development of colorectal cancer (CRC). Serum levels of n-3 and n-6 PUFA in 69 healthy control (Ctrl), 62 benign colorectal polys (CRP) and 100 CRC patients were detected by gas chromatograph. The adjusted odds ratio (OR) by quartiles of n-3 and n-6 PUFA were analyzed. During the process of Ctrl to CRP, total n-3 PUFA (OR=0.159, P<0.001), total n-6 PUFA (OR=0.190, P<0.001), C20:5 n-3 (OR=0.263, P=0.030), C22:6 n-3 (OR=0.125, P<0.001), and C18:2 n-6 (OR=0.299, P=0.025) were inversely associated with CRP risk. The ratio of total n-6 PUFA and total n-3 PUFA (OR=4.667, P=0.002), and the ratio of C20:4 n-6 and (C20:5 n 3+C22:6 n-3) (OR=6.000, P<0.001) were positively associated with CRP risk. During the process of CRP to CRC, total n-3 PUFA (OR=4.059, P=0.007), total n-6 PUFA (OR=8.146, P<0.001), C22:6 n-3 (OR=3.789, P=0.048), and C18:2 n-6 (OR=3.667, P=0.045) were positively associated with CRC risk. The ratio of C20:4 n-6 and (C20:5 n-3+C22:6 n-3) (OR=0.588, P=0.001) was inversely associated with CRC. In conclusion, our results found that the total n-3 PUFA, C22:6 n-3, the total n-6 PUFA, C18:2 n-6, and the ratio of C20:4 n-6 and (C20:5 n-3 +C22:6 n-3) played controversy role in the process of CRP and the process of CRC, and may provide nutritional intervention suggestions for the clinical practice. PMID- 26629094 TI - The effect of radish sourced 4-(Methylthio)-3-butenyl isothiocyanate on ameliorating the severity of high fat diet inducted nonalcoholic fatty liver disease in rats. AB - The aim of this study is to develop a high fat diet and over nutrition induced nonalcoholic fatty liver disease(NAFLD) in rat, and to investigate the effect of 4-(Methylthio)-3-butenyl isothiocyanate (MTBITC) on ameliorating the NAFLD. Twenty Sprague-Dawley (SD) rats were equally divided into 4 groups (C, M, E1 & E2). Control group (C) were treated with standard restricted diet; Model group (M) were given high fat liquid diet ad libitum; Experimental group (E1 & E2) were treated with high fat liquid diet ad libitum and MTBITC by gavage. The experiment last 9 weeks, and serum chemistry and liver histology were assessed. The rats of M group showed severe lipid deposition and peroxidation in liver. When compared with group C, group M also showed significantly higher serum concentration of low density lipoprotein, tumor necrosis factor-alpha and glucose. Histopathologic sections demonstrated lipid accumulation and macrovascular steatosis with ballooning degeneration in the livers of M. Group E2 presented significantly better conditions when assessed based on the parameters of NAFLD. The data suggested that MTBITC might significantly attenuate fat liquid diet induced NAFLD. PMID- 26629095 TI - Evaluation of tumor metastasis-associated markers for molecular classification in patients with esophageal squamous cell carcinoma. AB - This study aims to ascertain the relationship of tumor metastasis-associated markers cyclin D1, connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF) with the clinicopathologic features and prognosis of patients with esophageal squamous cell carcinoma (ESCC), and to investigate their value in ESCC molecular classification. The expression of cyclin D1, CTGF and VEGF in 100 specimens from patients and 20 from normal esophageal mucosa were detected by immunohistochemistry. The relationship of their expression with prognosis of the patients with ESCC was evaluated by Cox regression model and Kaplan-Meier survival curve analysis. High levels of expression of cyclin D1, CTGF, and VEGF were observed in 61 (61%), 53 (53%), 49 (49%) cases, respectively. Univariate survival analysis indicated that the levels of expression of cyclin D1, CTGF and VEGF were associated with survival (all P value < 0.05). Multivariate analysis indicated that cyclin D1 and VEGF were independent prognostic factors affecting the three-year survival rate of patients (P = 0.001, 0.017, respectively). Furthermore, high level expression of cyclin D1, CTGF and VEGF in stage I patients was found associated with poor three-year survival rate (all P-value < 0.05). The prognosis probably was favorable for patients with low expression of cyclin D1 even in stage III, or VEGF even in stage IV. Tumor metastasis-associated markers such as cyclin D1 and VEGF may be independent prognostic factors affecting survival rate of postoperative ESCC patients. It is possible to judge prognosis better and tailor treatments to each individual patient when these markers were applied to ESCC molecular classification. PMID- 26629096 TI - Prognostic value of total bilirubin in patients with angina pectoris undergoing percutaneous coronary intervention. AB - BACKGROUND: Bilirubin is a potent antioxidant and previous studies have reported the relationship between low serum bilirubin concentration and atherosclerosis. OBJECTIVE: To evaluate the prognostic value of serum total bilirubin (STB) in patients with angina pectoris undergoing percutaneous coronary intervention (PCI). METHODS: In total of 1419 patients (931 men, mean age 60.9+/-10.5 years) with angina pectoris who had undergone successfully percutaneous coronary intervention (PCI) were included in this study. Patients were divided into 2 groups according to the median baseline STB (0.49 mg/dL in this cohort), which was measured before the PCI. Patients with a STB >=0.49 mg/dL were classified into the high STB group and those with a STB <0.49 mg/dL were classified into the low STB group. RESULTS: The incidence of in-hospital mortality and myocardial infraction was similar in the two groups. After a mean follow-up of 29.0+/-7.6 months, the incidence of death/myocardial infarction/stroke was significantly higher in low STB group compared with high STB group. Multivariate Cox regression analysis showed that low STB was an independent predictor of death/myocardial infarction/stroke (hazard ratio (HR) = 1.59, 95% confidence interval (CI) = 1.04 2.41, P = 0.031). The cumulative survival rate free from death/myocardial infarction/stroke was lower in low STB group than in high STB group (P = 0.002). CONCLUSION: Low STB levels before PCI is an independent predictor of long-term adverse clinical outcomes in patients with angina pectoris. PMID- 26629097 TI - Assessment of effect of Zhu-tan Tong-luo decoction on CYP450 isoforms activity of rats. AB - In order to investigate the effects of Zhu-tan Tong-luo decoction on the metabolic capacity of cytochrome P450 (CYP) enzymes, a cocktail method was employed to evaluate the activities of CYP2B6, CYP2C19, CYP1A2, CYP3A4, CYP2C9, CYP2D6. The rats were randomly divided into acute Zhu-Tan Tong-Luo decoction group (Low, High), chronic Zhu-Tan Tong-Luo decoction group (Low, High) and control group. The acute group rats were given 0.6, 1.2 g/kg (Low, High) Zhu-tan Tong-luo decoction by intragastric administration for 1 day, and the chronic group for 14 days. Six probe drugs bupropion, omeprazole, phenacetin, testosterone, tolbutamide, and metroprolol were given to rats through intragastric administration, and the plasma concentrations were determined by UPLC-MS/MS. There statistical pharmacokinetics differences for omeprazole, phenacetin, testosterone, tolbutamide, and metroprolol in rats were observed by comparing acute Zhu-tan Tong-luo decoction group with control group; and statistical pharmacokinetics differences for bupropion, omeprazole, phenacetin, testosterone, tolbutamide, and metroprolol were observed by comparing chronic Zhu Tan Tong-Luo decoction group with control group. After intragastric administration of Zhu-Tan Tong-Luo decoction may slightly induce the activities of CYP2B6, CYP2C19, CYP1A2, CYP3A4, CYP2C9, CYP2D6 of rats. Induction of drug metabolizing enzyme by Zhu-Tan Tong-Luo decoction would reduce the efficacy of other drug. Additional, there no statistical difference for biochemical results after 1 or 14 intragastric administration of Zhu-Tan Tong-Luo decoction. PMID- 26629098 TI - The MIF -173G/C gene polymorphism increase gastrointestinal cancer and hematological malignancy risk: evidence from a meta-analysis and FPRP test. AB - The macrophage migration inhibitory factor (MIF) -173G/C gene polymorphism has been implicated in the susceptibility to cancer, but the results are not conclusive. So the aim of study to investigate the association between MIF 173G/C gene polymorphism and cancer risk by a comprehensive meta-analysis. We searched the PubMed, Embase, Wanfang and China National Knowledge Internet (CNKI) databases, with the last updated search being performed on May 24, 2015. The odds ratio (OR) and 95% confidence interval (95% CI) were used to assess the association. Statistical analysis was performed by STATA 11.0 software. Finally, 7,253 participants from 15 studies were included in the meta-analysis. The results of meta-analysis indicated the significant association between MIF 173G/C gene polymorphism and cancer susceptibility, especially in Asians (C vs. G, OR: 1.22, 95% CI=1.00-1.50). In addition, the significant relationship between MIF -173G/C gene polymorphism and gastrointestinal tumors (CC+CG vs. GG, OR: 1.25, 95% CI=1.05-1.50), hematological malignancy (CC+CG vs. GG, OR: 1.27, 95% CI=1.03-1.56), gynecolgical tumors (CC vs. CG+ GG, OR: 1.51, 95% CI=1.04-2.19) risk was found. However, to avoid the "false positive report", we investigated the significant associations observed in the present meta-analysis by the false positive report probabilities (FPRPs) test. Interestingly, the results of FPRP test indicated the MIF -173G/C gene polymorphism only associated with gastrointestinal cancer and hematological malignancy risk (FPRP=0.132, 0.067 respectively) at the level of a prior probability is 0.1. Therefore, the meta analysis suggested MIF -173G/C gene polymorphism would be a risk factor for the gastrointestinal cancer and hematological malignancy. PMID- 26629099 TI - Associations between frequency of coffee consumption and osteoporosis in Chinese postmenopausal women. AB - BACKGROUND: This study was aimed at estimating the associations between coffee intake and osteoporosis (OP) in Chinese postmenopausal women. METHODS: We conducted a large-scale, community-based, cross-sectional study to investigate the associations by using self-report questionnaire to access frequency of coffee intake. The total of 1817 participants was available to data analysis in this study. Multiple regression models controlling for confounding factors to include frequency of coffee intake variable were performed to investigate the relationships for OP. RESULTS: Positive correlations between frequency of meat food intake and T-score were reported (beta = 0.216, P value < 0.001). Multiple regression analysis indicated that the frequency of meat food intake was significantly associated with OP (P < 0.05 for model 1 and model 2). The postmenopausal women with high frequency of meat food intake had a lower prevalence of OP. CONCLUSION: The findings indicated that frequency of coffee intake was independently and significantly associated with OP. The prevalence of OP was more frequent in Chinese postmenopausal women not preferring coffee habits. PMID- 26629100 TI - The efficacy of high-dose versus moderate-dose chemotherapy in treating osteosarcoma: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate whether the efficacy of high-dose chemotherapy in the treatment of primary well-differentiated osteosarcoma is superior to moderate dose chemotherapy. METHODS: Cochrane systematic review method was used to retrieve literatures from MEDLINE, Embase, OVID, Cochrane Library database of clinical trials, Chinese Biomedical Literature Database CD-ROM, as well as manual searching from "China Oncology", "Chinese Journal of Clinical Oncology", "Cancer" etc. Meta-analysis was performed using the RevMan 5.0 software. RESULTS: A total of four studies, 937 cases of primary, non-metastatic, well-differentiated limb osteosarcoma patients were enrolled in the study. Meta-analysis results suggested that compared with moderate-dose group, 5-year disease-free survival, 5-year overall survival rate, the local recurrence rate, proportion of histologic response in good status, limb salvage rate showed no significant difference in high-dose chemotherapy group (All P > 0.05); good and poor response of preoperative chemotherapy tumor histologic of 5-year disease-free survival showed statistical difference (RR = 1.55; 95% CI: 1.19-2.00; P = 0.0009). CONCLUSION: High-dose chemotherapy for the treatment of primary osteosarcoma is not better than moderate-dose chemotherapy. It is expected that high quality of randomized controlled trials were performed to provide more reliable evidence in the future. PMID- 26629101 TI - The dosimetric comparison of the radiotherapeutic plans between composite and synchronous planning approaches in sequential IMRT for nasopharyngeal carcinoma. AB - The aim of present study was to compare the dosimetric differences of the radiotherapeutic plans between synchronous and composite planning approaches in sequential intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC). Twelve patients with NPC treated by sequential IMRT were enrolled. Two planning approaches were used to design sequential IMRT plan. The first was composite planning approach, in which the initial and boost plans were designed and optimized independently. The second was synchronous planning approach, in which the boost IMRT plan was designed on foundation of the initial IMRT plan, and its optimization would be adjusted based on dose distributions of the initial IMRT plan. Dosimetric comparisons in IMRT plans between composite and synchronous planning approaches were analyzed to evaluate (1) dose coverage, conformity, and homogeneity of the planning target volume (PTV), (2) sparing of organs at risk (OARs), and (3) the number of segments and monitor units (MUs). The results showed that both of the summed plans for the entire treatment course were achieved according to the original planning goals, and the dose coverage, conformity and homogeneity for each PTV was similar. With regard to sparing brain stem, spinal cord and parotid glands, there was no significant difference in the summed plans between two planning approaches. However, the boost IMRT plan by composite planning approach tended to have a higher dose coverage (P = 0.000), conformity (P = 0.000), and homogeneity (P = 0.000) than that of the plan by synchronous planning approach. Moreover, the boost plan by composite planning approach reduced the MUs significantly (P = 0.000). The results indicated that the radiotherapeutic plan by composite planning approach provides better dose coverage, conformity and homogeneity for the PTV in the boost plan than that by synchronous planning approach, and reduced MUs in sequential intensity modulated radiotherapy. PMID- 26629102 TI - Oncological and surgical outcomes of minimally invasive versus open esophagectomy for esophageal squamous cell carcinoma: a matched-pair comparative study. AB - Only a few series have demonstrated the safety and efficacy of minimally invasive esophagectomy (MIE) for esophageal squamous cell carcinoma and the benefits of this approach. This report describes the results of a pair-matched comparative study between minimally invasive and open esophagectomy (OE) for esophageal squamous cell carcinoma. Patients were retrospectively matched in pairs for the following criteria: age, sex, American Society of Anesthesiology (ASA) score, clinical TNM stage, tumor location, and type of resection. A total of 97 patients undergoing MIE were compared with patients undergoing OE during the same period. Operative, postoperative, and oncologic outcomes were compared. Significantly less bleeding was observed in the MIE group (P = 0.001). Transfusion was required for three patients in the MIE group and ten patients in the OE group (P = 0.044). Overall morbidity was similar in the two groups. The hospital stay was significantly shorter for the patients undergoing MIE (P = 0.027). The surgical margin and tumor stage were not affected by MIE. The overall survival rates in the MIE group were 54% at 5 years and 46% in the OE group (P = 0.631). The disease-free survival rates in the MIE group were 45% at 5 years, 41% in the OE group (P = 0.704). In summary, MIE for esophageal squamous cell carcinoma for selected patients gave a better postoperative outcome without oncologic consequences. PMID- 26629103 TI - Utility of contrast-enhanced ultrasound with SonoVue in biopsy of small subpleural nodules. AB - OBJECTIVES: This study aimed to evaluate the diagnostic accuracy and complication rates of contrast-enhanced ultrasound (CEUS)-guided biopsy of small subpleural nodules with SonoVue. METHODS: CEUS-guided biopsies with SonoVue and conventional ultrasound were performed to determine nodule size, texture and biopsy route. After baseline ultrasonography, all patients received an intravenous injection of 4 mL of SonoVue, followed by 5 mL of saline flush. CEUS was obtained using a convex probe and contrast-specific imaging software. The lesion was observed using a contrast agent. Biopsies were performed during real-time visualisation of the target lesion. RESULTS: A total of 51 patients (34 males and 17 females; average age, 54.8 +/- 5.8 years) with subpleural nodules were enrolled. The median nodule size was 1.92 +/- 0.75 cm (0.9-2.5 cm). Forty-eight of 51 procedures (94.1%) provided adequate material for histological analysis. Thirty patients (62.5%) were malignant and 18 patients (37.5%) were benign at the definitive diagnosis. The true positive and true negative result were 28 (58.3%) and 18 (37.5%), no false positive result was seen and two (4.2%) provided a false negative result. The sensitivity, specificity, positive and negative predictive values for the malignant diagnosis were 93.3, 100, 100 and 90%, respectively. The diagnostic accuracy was 95.8% (46/48), the standard error and the 95% CI were 2.8% and 86%-99%. An asymptomatic pneumothorax was present in one patient with no chest tube placement required. A small amount of hemoptysis was observed in another patient, which stopped spontaneously without treatment. CONCLUSIONS: CEUS guided biopsy with SonoVue exhibits high diagnostic accuracy and low complication rates. It is especially advantageous for biopsies of small subpleural nodules. PMID- 26629104 TI - MicroRNA miR-16-1 regulates CCNE1 (cyclin E1) gene expression in human cervical cancer cells. AB - MicroRNAs are involved in diverse biological processes through regulation of gene expression. The microRNA profile has been shown to be altered in cervical cancer (CC). MiR-16-1 belongs to the miR-16 cluster and has been implicated in various aspects of carcinogenesis including cell proliferation and regulation of apoptosis; however, its function and molecular mechanism in CC is not clear. Cyclin E1 (CCNE1) is a positive regulator of the cell cycle that controls the transition of cells from G1 to S phase. In CC, CCNE1 expression is frequently upregulated, and is an indicator for poor outcome in squamous cell carcinomas (SCCs). Thus, in the present brief communication, we determine whether the CCNE1 gene is regulated by miR-16-1 in CC cells. To identify the downstream cellular target genes for upstream miR-16-1, we silenced endogenous miR-16-1 expression in cell lines derived from CC (C-33 A HPV-, CaSki HPV16+, SiHa HPV16+, and HeLa HPV18+ cells), using siRNAs expressed in plasmids. Using a combined bioinformatic analysis and RT-qPCR, we determined that the CCNE1 gene is targeted by miR-16-1 in CC cells. SiHa, CaSki, and HeLa cells demonstrated an inverse correlation between miR-16-1 expression and CCNE1 mRNA level. Thus, miR-16-1 post transcriptionally down-regulates CCNE1 gene expression. These results, suggest that miR-16-1 plays a vital role in modulating cell cycle processes in CC. PMID- 26629105 TI - Epidemiology and genotype distribution of high risk human papillomavirus in population of hospital opportunistic screening. AB - This study aimed to determine the prevalence of high-risk human papillomavirus (HR-HPV) in population of hospital opportunistic screening and to identify the correlation of prevalent genotypes and cervical cytological abnormalities. A cross-sectional study was employed between July 2013 and July 2014 in the Chaoyang hospital, in Beijing. Cervical samples were collected for the Type specific HPV and the cervical cytological analyses in the population of hospital opportunistic screening. Total of 8975 samples from female patients aged 17-86 years were tested. Of these, 10.4% were infected by HR-HPV, the highest prevalence of HR-HPV in the youngest group and decreasing with aging (X(2)=19.68, P=0.02). Of these, 78.73% were single infections and 21.27% were multiple infections. Age-specific prevalence of multiple HPV exhibited a "U" shaped curve (X(2)=19.98, P=0.018). The most prevalent genotype is HPV 52, then descending order of frequency were HPV-58, 16, 39, 51, 56, 59, 18, 31, 33, 35, 68 and 45. 15.9% had an abnormal cytology in HR-HPV positive women, vs 4.13% in HR-HPV negative women. The prevalence of HR-HPV were 9.2%, 26.8%, 32%, 35.3% and 36.4% in normal cell, ASCUS, LSIL, ASC-H and HSIL, respectively (X(2)=234.67, P=0.000). Women with HPV 52, 16, 18, 58, 39, 51, 59, 56, 33, 31 infections related to the abnormal cytology, while the HPV68, 45, 35 didn't. The prevalent characteristic in population of the hospital opportunistic screening is similar to the population of cervical screen, But the most five prevalent genotype in rank are different .Women with HR-HPV infections were more likely to have the cervical abnormal cytology. PMID- 26629106 TI - Experimental study of the functional reserve of median nerve in rats. AB - OBJECTIVE: To study the functional changes of median nerve after removing a certain bundle of it and to explore the functional reserve of median nerves. METHODS: 220 three-month old SD rats were randomly divided into experimental groups and sham groups. And the experimental group was further divided as 1/8 group, 1/4 group, 1/3 group, 1/2 group, and 2/3 group according to ratio of the resection portion, with 22 rats in each group. The section of the lowest level on median nerve trunks were exposed, and a certain portion of it were separated and resected in experimental group, while in sham groups, the nerve was only separated without resection. The general state of health of all rats were observed, and the alpha motor neurons in cornu anterior medullae spinalis were studied 1 week, 2 weeks and 2 months postoperatively. Neuro-electrophysiology and function of dominated muscles were studied 2 weeks, 2 months, 3 months, and 4 months postoperatively. RESULTS: All rats survived without infection and obvious ulcer. The number of the alpha motor neurons in cornuanterior medullae spinalis didn't change (P>0.05), and obvious superstructure changes were observed in early stage in 1/2 and 2/3 group, but restored after 2 months. There was no significant changes in latencies of motor neuron evoked potentials between experimental groups and sham group (P>0.05), however, there is significant difference if the 2 week group was compared with 2 month, 3 month and 4 month group (P<0.05). Moreover, there is also significant difference in terms of the wave amplitude of evoked potential of motor neurons, the maximum wave amplitude and the persistence time of its innervated muscle if the 2 week group was compared with those in 2 month, 3 month and 4 month group (P<0.05), and there is significant difference between different proportion resection groups (P<0.05). CONCLUSIONS: Median nerve has a certain amount of functional reserve, and the quantity of the functional reserve of median nerve without compromise is the 1/3 of the whole trunk. PMID- 26629107 TI - Anterior maxillary segmental distraction in the treatment of severe maxillary hypoplasia secondary to cleft lip and palate. AB - Anterior maxillary segmental distraction (AMSD) is an effective surgical procedure in the treatment of maxillary hypoplasia secondary to cleft lip and palate. Its unique advantage of preserving velopharyngeal function makes this procedure widely applied. In this study, the application of AMSD was described and its long-term stability was explored. Eight patients with severe maxillary hypoplasia secondary to CLP were included in this study. They were treated with AMSD using rigid external distraction (RED) device. Cephalometric analysis was performed twice at three time points for evaluation: before surgery (T1), after distraction (T2), and 2 years after treatment (T3). One-way analysis of variance was used to assess the differences statistically. All the distractions completed smoothly, and maxilla was distracted efficiently. The value of SNA, NA-FH, Ptm-A, U1-PP, overjet and PP (ANS-PNS) increased significantly after the AMSD procedure (P < 0.05), with the mean overjet increased by 14.28 mm. However, comparison of cephalometric analysis between T2 and T3 showed no significant difference (P > 0.05). Changes of palatopharyngeal depth and soft palatal length were insignificant. AMSD with RED device provided an effective way to correct maxillary hypoplasia secondary to CLP, extended the palatal and arch length, avoided damage on velopharyngeal closure function and reduced the relapse rate. It is a promising and valuable technique in this potentially complicated procedure. PMID- 26629108 TI - Laparoscopic colectomy for transverse colon cancer: comparative analysis of short and long-term outcomes. AB - This study evaluated the short- and long-term outcomes of laparoscopic colectomy compared with open colectomy for patients with transverse colon cancer by matched pair analysis. This study enrolled 59 patients who underwent laparoscopic colectomy and compared them with 59 matched patients who underwent open colectomy for transverse colon cancer. The following parameters were matched: clinical stage and type of resection. Both short- and long-term outcomes of laparoscopic colectomy were compared with those of open colectomy. No difference was observed between the two groups in terms of age, gender, ASA score, comorbidity, clinical stage and operative procedures. Regarding short-term outcomes, blood loss, time to first flatus, time to liquid diet and postoperative stay were significantly shorter in the laparoscopy group than in the open group, while operation time was significantly longer in the laparoscopy group than in the open group. Postoperative complication was similar between the two groups. With respect to long-term outcomes, the two groups did not differ significantly in terms of 5 year overall and disease-free survival. In summary, laparoscopic colectomy is a safe and feasible option for selected patients with transverse colon cancer. The short- and long-term outcomes of laparoscopic colectomy are considered to be acceptable. PMID- 26629109 TI - Serum concentrations of matrix metalloproteinase-9 and vascular endothelial growth factor affect the prognosis of primary hepatic carcinoma patients treated with percutaneous ethanol injection. AB - AIMS: The present study is to investigate changes in serum concentrations of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) before and after percutaneous ethanol injection (PEI) in primary hepatic carcinomas (PHC), and their effects on the prognosis. METHODS: A total of 100 patients with PHC received PEI treatment in our hospital between July 2010 and July 2014. Another 100 PHC patients who had PHC resected were included as control group. For PEI treatment, anhydrous ethanol was slowly injected into the tumor every 2-3 days for consecutive 4-10 times. The evaluation of treatment efficacy was performed in accordance with the standards by Union for International Cancer Control. Serum concentrations of MMP-9 and VEGF were determined using enzyme linked immunosorbent assay. The median values of MMP-9 and VEGF concentrations were used as the cutoff value to discriminate high and low MMP-9 and VEGF contents. Kaplan-Meier plots were used to examine how serum concentrations of MMP 9 and VEGF affected postoperative survival of PHC patients. RESULTS: PEI treatment decreased the serum contents of MMP-9 and VEGF after the surgery. PEI had high effectiveness against PHC tumors during the surgery. PEI treatment led to higher survival rate in PHC patients compared with PHC resection. Serum levels of MMP-9 and VEGF were related to different Child grading, Kps scoring, BCLC staging and AFP contents. Lower preoperative serum concentrations of MMP-9 and VEGF might lead to longer survival time of PHC patients after PEI. CONCLUSIONS: PEI treatment alters serum concentrations of MMP-9 and VEGF in PHC patients, which may have great effect on the prognosis. PMID- 26629110 TI - Prognostic significance of EZH2 expression in patients with digestive cancers: a meta-analysis. AB - BACKGROUND: Enhancer of zeste 2 (EZH2), a key component of polycomb repressive complex 2 (PRC2), was of great importance in human cancer pathogenesis. Various studies examined the relationship between EZH2 overexpression with the clinical outcome in patients with digestive cancers, but yielded inconsistent results. METHODS: Electronic databases updated to January 2015 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between EZH2 overexpression and survival of patients with digestive cancers. Survival data were aggregated and quantitatively analyzed. RESULTS: We performed a meta-analysis of 10 studies (n = 1,461 patients) that evaluated the correlation between EZH2 overexpression and survival in patients with digestive cancers. Combined hazard ratios suggested that EZH2 overexpression was associated with poor prognosis of overall survival (HR = 1.54, 95% CI: 1.27-1.81) in patients with esophageal cancer. In the stratified analysis, no significantly risks were found among gastric cancer (HR = 0.66, 95% CI: 0.16-1.15) and colorectal cancer (HR = 0.91, 0.63-1.19), indicating EZH2 was not an indicator of poor prognosis in gastric cancer or colorectal cancer. CONCLUSIONS: EZH2 overexpression indicates a poor prognosis for patients with esophageal cancer, but not among gastric cancer or colorectal cancer. PMID- 26629111 TI - Long-term clinical outcome and risk of catheter ablation in elderly with non paroxysmal atrial fibrillation. AB - BACKGROUND: Catheter ablation of atrial fibrillation (AF) became an effective therapy for patients with drug-refractory AF and Catheter ablation of Non Paroxysmal AF for elderly remains a challenging task. The outcome of AF ablation in Elderly is not clear. OBJECTIVE: The aim of the present study was to investigate the long-term outcomes of catheter ablation in patients with non paroxysmal AF and the predictors of AF termination, and the clinical outcomes associated with termination and non-termination. METHODS: A total of 95 non paroxysmal AF patients who received a stepwise catheter ablation were enrolled. There were 46 patients (48.4%) suffering from recurrences (37 patients with AF and 9 patients with atrial flutter/atrial tachycardia) after single procedure during a median follow-up period of 25.6 months. AF termination by ablation was achieved in 73 of the 95 patients RESULTS: The AF non-termination after procedure and CHA2DS2-VASc scores >=3 were significant predictors of recurrences in the multivariable analysis. In AF termination group: for a CHA2DS2-VASc scores of 0, 1-2, and >=3 the recurrence rates were 29% (8/28), 39% (12/31) and 64% (9/14) respectively. Similarly, In AF non-termination group: for a CHA2DS2-VASc scores of 0, 1-2, and >=3 the recurrence rates were 63% (5/8), 75% (6/8), and 100% (6/6), respectively. Of the patients with CHA2DS2-VASc scores of >=3 in AF non termination group all experienced recurrences within 2 year after the single procedure. CONCLUSIONS: The catheter ablation may be effective in eliminating part of non-paroxysmal AF for elderly. In addition, the present study demonstrated that CHA2DS2-VASc scores and non-termination after procedure were useful predictors of AF recurrence. PMID- 26629112 TI - Characteristics of temporomandibular joint in patients with temporomandibular joint complaint. AB - INTRODUCTION: This study was to investigate whether there was statistical difference between the bilateral temporomandibular joint (TMJ) in patients with unilateral TMJ pain or joint sounds, using cone beam computed tomography (CBCT). METHODS: TMJ CBCT images of 123 cases were used to preliminarily determine the indicators suitable for the measuring method. TMJ CBCT image reconstruction was performed and 19 indicators were measured. Thirty-six cases without TMJ complaint served as controls. The comparison of bilateral TMJs was analyzed by paired t test to find out the indicators without statistical significance. Twenty-nine patients with unilateral TMJ pain or joint sounds who underwent CBCT at the hospital were enrolled for the comparative study. The measured values were analyzed by paired t-test to determine the indicators with statistical difference. RESULTS: In the control group, only radius value of bilateral TMJ was different statistically (P < 0.05). In the TMJ complaint group, the vertical 60 degrees joint space of the bilateral TMJ was statistically different (P < 0.05) and the rest of the measured values showed no statistical difference. CONCLUSIONS: In the patients with unilateral TMJ pain or joint sounds, the vertical 60 degrees joint space of the symptomatic side was significantly increased comparing with the asymptomatic side. PMID- 26629113 TI - Curative effect analysis of different treatments for gefitinib-resistance advanced non-small cell lung cancer patients. AB - OBJECTIVE: Gefitinib is effective epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) for advanced non-small cell lung cancer (NSCLC) patients, but with the drug use, inevitable gefitinib-resistance and severe complications were observed and resulted in failure treatments. The purpose of the present study was to investigate the curative effect of different treatment of navelbine plus cisplatin in combination with gefitinib and gefitinib single on gefitinib-resistance advanced NSCLC patients. METHODS: Total Of 120 patients acquired gefitinib-resistance NSCLC patients treated in Taian City Central Hospital of Shandong province from May, 2010 to June, 2014 were incorporated in our study according to the inclusion and exclusion criteria. The patients were divided into chemotherapeutical group and gefitinib group and the mean follow-up was 12 months (6-39 months), the information of patients was recorded as gender, age, smoking, complications, hepatic metastasis, bone metastasis, brain metastasis and acquired chemotherapy or not. Chi-square test and t-test were performed to analyzed collection data, Log-rank was analyzed significance of survival time among groups and Cox regression was evaluated independent risk factors of survival analysis. RESULTS: The survival time of chemotherapy group was significantly longer than gefitinib group; the survival time among the two groups was 29.06 and 15.23 months (P<0.05), respectively. Multivariate Cox regression analyzed that lesion's metastasis (hepatic metastasis, bone metastasis and brain metastasis) and acquired chemotherapy were independent risk factors influence on patients overall survival time; gender, age, smoking, complications had no significance influence on survival time between the two groups. CONCLUSION: Lesion's metastasis and acquired chemotherapy were independent risk factors influence on patients' overall survival time and the survival time of chemotherapy group was significantly longer than gefitinib group. PMID- 26629114 TI - Immunohistochemical analysis of Bax and AIF in colorectal tumors. AB - BACKGROUND/AIMS: This study had three aims. The first was to determine whether Bax (Bcl-2-associated X protein) and AIF (apoptosis-inducing factor) are expressed in tissue sections of colorectal tumors. The second was to ascertain whether there is any difference in Bax and AIF expression between colorectal polyps, adenomas, and carcinomas. The third aim was to determine whether there is any difference between Bax and AIF expression in colorectal tumors. MATERIALS AND METHODS: Bax and AIF expression were determined in 20 hyperplastic polyps (HPs), 20 adenomatous polyps (APs), 20 samples of colorectal carcinomas, and 20 samples of normal mucosa by immunohistochemical methods. RESULTS: The staining level of Bax and AIF in adenomas and carcinomas was significantly higher than in normal tissues (P<0.01). There was also a significant difference between HPs and APs (P<0.01). The level of Bax and AIF in carcinomas was higher than in adenomas, and the difference was of statistical significance (P<0.01). CONCLUSION: This study may be of interest in future research to confirm whether the changed expression of Bax and/or AIF between benign and malignant tumors can provide valuable information for the evaluation of colon or other tumors. PMID- 26629115 TI - Clinical application of a novel computer-aided detection system based on three dimensional CT images on pulmonary nodule. AB - The aim of this study was to investigate the clinical application effects of a novel computer-aided detection (CAD) system based on three-dimensional computed tomography (CT) images on pulmonary nodule. 98 cases with pulmonary nodule (PN) in our hospital from Jun, 2009 to Jun, 2013 were analysed in this study. All cases underwent PN detection both by the simple spiral CT scan and by the computer-aided system based on 3D CT images, respectively. Postoperative pathological results were considered as the "gold standard", for both two checking methods, the diagnostic accuracies for determining benign and malignant PN were calculated. Under simple spiral CT scan method, 63 cases is malignant, including 50 true positive cases and 13 false positive cases from the "gold standard"; 35 cases is benign, 16 true negative case and 19 false negative cases, the Sensitivity 1 (Se1)=0.725, Specificity1 (Sp1)=0.448, Agreement rate1 (Kappa 1)=0.673, J1 (Youden's index 1)=0.173, LR(+)1=1.616, LR(-)1=0.499. Kappa 1=0.673 between the 0.4 and 0.75, has a moderate consistency. Underwent computer-aided detection (CAD) based on 3D CT method, 67cases is malignant, including 62 true positive cases and 7 false positive cases; 31 cases is benign, 24 true negative case and 7 false negative cases, Sensitivity 2 (Se2)=0.899, Specificity2 (Sp2)=0.828, Agreement rate (Kappa 2)=0.877, J2 (Youden's index 2)=0.727, LR(+)2=5.212, LR(-)2=0.123. Kappa 2=0.877 >0.75, has a good consistency. Computer aided PN detecting system based on 3D CT images has better clinical application value, and can help doctor carry out early diagnosis of lung disease (such as cancer, etc.) through CT images. PMID- 26629116 TI - Influence of mesenchymal stem cells on expression of AQP1 and AQP2 in rats with nephropathy induced by adriamycin. AB - This study aims to explore the therapeutic effect of bone marrow mesenchymal stem cells on adriamycin nephrosis, and the potential mechanism. The rat experimental nephropathy model was established by unilateral nephrectomy combined repeated injecting adriamycin (ADR). Thirty adriamycin nephrosis rats were randomly divided into three groups, including ADR (n=10), MSCs transplantation through peripheral veins groups (M-V, n=10), and MSCs transplantation through right renal artery groups (M-A, n=10), and there was another normal control group (N, n=10). This study lasted 8 weeks, 24 hours urine was collected through simple metabolic cage to measure urinary volume and urine protein quantitation in 24 hours. The levels of plasma albumin (ALB), sodium were measured by biochemical analysis. The expressions of AQP1-2 were measured by immuno-histochemistry assay. Kidney medulla ultramicroscopic structure was observed by TEM. The results indicated that the ALB and 24 h urinary volume have significant increased in M-V and M-A group compared to the ADR group (P<0.05). Furthermore, the serum sodium and urine protein quantitation in 24 hours were decreased in M-V and M-A group compared to ADR group (P<0.05). Protein expression of AQP1-2 had been remarkably decreased (P<0.05). It showed degenerative changes of kidney ultra microscopic structures of the ADR rats, while MSCs transplantation could significantly improve the damage. In conclusion, in adriamycin nephropathy rats, MSCs transplantation exerts its therapeutic effects by decrease urinary albumin excretion, increase ALB, decrease sodium and the expression of AQP1-2 in renal tubules. PMID- 26629117 TI - Effects of cognitive rehabilitation training on schizophrenia: 2 years of follow up. AB - OBJECTIVE: Schizophrenia is a mental disorder and characterized by abnormal social behavior and failure to recognize what is real. The current study was to explore the long-term effects of cognitive rehabilitation training on schizophrenia. METHODS: Eighty six cases of hospitalized patients with schizophrenia were randomly divided into study group and control group. The relapse and employment (attending school) rates were used as indicators to assess the treatment effect. All patients were followed up by 2 years. Kaplan-Meier survival analysis was conducted with relapse and employment (attending school) rates. RESULTS: The rates of relapse in the study group and the control group were 18% and 41%, and relapse free survival time was 22.22 months and 18.55 months; the rates of employment (attending school) were 64% and 43%, and not employment (attending school) time were 10.68 months and 15.74 months, respectively. There was significant difference between the two groups (P<0.05). CONCLUSIONS: We found that the cognitive rehabilitation training could significantly reduce schizophrenic relapse rate, prolong the time of patients without relapse, improve the employment (attending school) rate, and shorten the discharged time, which is a powerful treatment method to improve social competence in schizophrenia patients. PMID- 26629118 TI - Neutrophil to Lymphocyte ratio in the diagnosis of adnexal torsion. AB - Adnexal torsion (AT) is a condition in which there is sometimes difficulty in making a preoperative diagnosis since there are no routine laboratory markers and this condition is usually intraoperatively diagnosed. Many of the studies have indicated that the neutrophil-to-lymphocyte ratio (NLR) is a significant inflammatory marker in various diseases. In this study, we aimed to investigate the diagnostic efficacy of the NLR on the diagnosis of AT. Patients surgically treated for AT were analysed retrospectively. A total of 27 AT patients were included in the study (Group 1). Another 30 patients who were surgically treated for a unilateral ovarian mass and did not have torsion or malignity on the final histopathological examination were assigned to the control group (Group 2). White blood cells (WBCs), neutrophils, lymphocytes and the NLR were compared between groups. The mean WBC values for Groups 1 and 2 were 9.7 +/- 1.8 and 7.6 +/- 1.5 K/uL (P < 0.001), respectively. The mean neutrophil values were also significantly higher in Group 1 (P < 0.001). However, the mean lymphocyte values were significantly higher in Group 2 (P < 0.001). Mean NLR was significantly higher in Group 1 (P < 0.001). Sensitivity and specificity of WBC > 8.8 were 83.3% and 74.1%, respectively. Sensitivity and specificity of NLR > 3 were 88.9% and 100%, respectively. Furthermore, the area under the ROC curve (AUC) was 0.933 for the NLR and 0.830 for WBC. With respect to the diagnosis of adnexal torsion, an NLR > 3 was identified as a more sensitive marker than the high WBC count. Therefore, an NLR > 3 seems to be a valuable marker in cases where it is difficult to diagnose AT. PMID- 26629119 TI - Angiopoietin-like protein 3 is an indicator of prognosis in esophageal cancer patients. AB - Angiopoietin-like protein 3 (ANGPTL3) plays an important role in angiogenesis. This study aimed to examine the protein expression of ANGPTL3, and to evaluate its clinical significance in esophageal cancer. ANGPTL3 expression was detected using immunohistochemistry in 98 pairs of esophageal cancer and adjacent non cancerous tissues. The expression levels of ANGPTL3 in esophageal cancer tissues were significantly higher than those in adjacent noncancerous tissues (P < 0.05). No association was observed between ANGPTL3 expression and clinical features (P > 0.05). Although ANGPTL3-negative patients had longer survival time than ANGPTL3 positive patients, the difference did not reach statistical significance (P = 0.090). Stratified analysis of ANGPTL3 expression according to clinical features revealed that there was significant association between ANGPTL3 expression and overall survival among patients aged 65 years or younger, female, or with lymph node metastasis (P < 0.05). When after adjusted for clinical features, the association remained significant only in patients aged 65 years or younger (P = 0.021).Taken together, our findings provide preliminary evidence of association of ANGPTL3 expression with the prognosis of subgroups of patients with esophageal cancer. PMID- 26629120 TI - Daily iron supplementation on cognitive performance in primary-school-aged children with and without anemia: a meta-analysis. AB - Anemia is an important public health and clinical problem. Observational studies have linked iron deficiency and anemia in children with many poor outcomes, including impaired cognitive development. In this study, we summarize the evidence for the effect of daily iron supplementation on cognitive performance in primary-school-aged children. We searched electronic databases (including MEDLINE and Wangfang database) and other sources (August 2015) for randomized and quasi randomized controlled trials involving daily iron supplementation on cognitive performance in children aged 5-12 years. We combined the data using random effects meta-analysis. We identified 3219 studies; of these, we evaluated 5 full text papers including 1825 children. Iron supplementation cannot improve global cognitive scores (Mean difference 1.05, 95% confidence interval [CI] -2.69 to 4.79, P<0.01). Our analysis suggests that iron supplementation improves global cognitive c outcomes among primary-school-aged children is still unclear. PMID- 26629121 TI - Effect of vacuum sealing drainage in osteofascial compartment syndrome. AB - OBJECTIVES: To investigate the effect of vacuum sealing drainage in the patients with osteofascial compartment syndrome in comparison to conventional treatment. METHODS: Fifty-two patients diagnosed with osteofascial compartment syndrome were enrolled in this study. They were randomly divided into two groups based on treatments: vacuum sealing drainage and conventional treatment. After operation, the length of hospital stay and antibiotics administration were recorded in the two groups, as well as swelling elimination and wound closure. RESULTS: No significant difference was observed in terms of the baseline characteristics between the two groups. There are no obvious local or systemic complications in all cases. In contrast to conventional treatment group, the time of swelling elimination, wound closure, hospital stay and antibiotics application were reduced significantly in vacuum sealing drainage group. No allergic reactions or other side effects were observed after the application of vacuum sealing drainage material, indicating its safety. CONCLUSION: Vacuum sealing drainage is effective in treating osteofascial compartment syndrome with better clinical outcomes than conventional therapy. PMID- 26629122 TI - Recurrent cervicodorsal spinal intradural enterogenous cyst: case report and literature review. AB - This report described a recurrent enterogenous cyst of the cervicodorsal spinal canal occurred in an 8-year-old boy who experienced cervical back pain at the age of 5. He had been operated for mass lesion at the same level 3 years ago. The cervical and thoracic spine MRI showed a large intradural cyst at C7-T1. The cyst was subtotally removed via posterior approach using a laminectomy. Based on the results of immunostaining, it was identified as an enterogenous cyst. A literature review related to spinal cyst is also included. PMID- 26629123 TI - Correlation between CYP4F2 gene rs2108622 polymorphism and susceptibility to ischemic stroke. AB - OBJECTIVE: To conduct a meta-analysis for the correlation between cytochrome P450 4F2 (CYP4F2) rs2108622 (V433M) gene polymorphism and ischemic stroke. METHODS: We retrieved the case-control studies on the correlation between CYP4F2 V433M polymorphism and ischemic stroke included in domestic and international databases before January 2015 and selected the best genetic model, using RevMan 5.2 software for meta-analysis. According to the heterogeneity test results of selected literature, the effect model of consolidated data was selected, and the combined OR and 95% CI were calculated. RESULTS: A total of six documents were included. Recessive model (VM + MM vs. VV) was selected as the best genetic model. The combined results showed that: compared with wild-type VV, there are significant association between ischemic stroke and CYP4F2 polymorphism (OR merge = 1.37, 95% CI: 1.21~1.54, P < 0.001). CONCLUSION: CYP4F2 V433M may be the susceptibility gene for ischemic stroke. PMID- 26629124 TI - The analysis of 146 patients with difficult laparoscopic cholecystectomy. AB - INTRODUCTION: Laparoscopic cholecystectomy (LC) is very commonly performed surgical intervention. Acute or chronic cholecystitis, adhesions due to previous upper abdomen surgeries, Mirrizi's syndrome and obesity are common clinical conditions that can be associated with difficult cholecystectomy. In this study, we evaluated and scored the patients with difficult surgical exploration during laparoscopic cholecystectomy. MATERIAL AND METHOD: All patients who underwent LC from 2010 to 2015 were retrospectively rewieved. According to intraoperative findings DLC cases were described and classified. Class I difficulty: Adhesion of omentum majus, transverse colon, duodenum to the fundus of the gallbladder. Class II difficulty: Adhesions in Calot's triangle and difficulty in dissection of cystic artery and cystic duct Class III difficulty: Difficulty in dissection of gallbladder bed (scleroathrophic gallbladder, hemorrhage from liver during dissection of gallbladder, chirotic liver). Class IV difficulty: Difficulty in exploration of gallbladder due to intraabdominal adhesions including technical problems. RESULTS: A total of 146 patients were operated with DLC. The most common difficulty type was Class I difficulty (88 patients/60.2%). Laparoscopic cholecystectomy was converted to laparotomy in 98 patients. Operation time was found to be related with conversion to open surgery (P<0.05). Wound infection rate was also statistically higher in conversion group (P<0.05). The opertion time was found to be longest with Class II difficulty. Conversion rate to open surgery was also highest with Class II difficulty group. CONCLUSION: Class II difficulty characterized by severe adhesions in calot's triangle is most serious problem among all DLC cases. They have longer operation time and higher conversion rate. PMID- 26629125 TI - Mirror syndrome associated with heart failure in a pregnant woman: a case report. AB - Mirror syndrome is also known as Ballantyne syndrome, maternal hydrops, triple edema and pseudotoxemia. The disease can be difficult to diagnose, is related to pregnancy and can grievously endanger the health of both the mother and fetus. The pathogenesis of the disease has not been fully elucidated, and this disease may be confused with preeclampsia, even though distinguishing features can be identified. In this report case, we describe a pregnant woman who suffered from mirror syndrome associated with heart failure. After delivery, the heart failure symptoms also disappeared. PMID- 26629126 TI - Primary amyloidosis mimicking Crohn's disease: a case report. AB - Amyloidosis is an uncommon disease that results from the extracellular deposition of abnormal fibrillary protein. This paper reports a case of primary amyloidosis with predominant involvement of the gastrointestinal tract and heart as a mimicker of Crohn's disease in a sixty-seven years old man admitted with repeated diarrhea and fatigue. This patient poorly responded to 5-aminosalicylic acid and quickly developed dyspnea and hypotension. The further laboratory test revealed a monoclonal protein detected by serum protein electrophoresis. Biopsy of abdominal wall fat pad revealed amyloid substance deposited and positive Congo red staining, which was diagnosed as primary amyloidosis. PMID- 26629127 TI - Cetuximab combined with chemotherapy is beneficial for patients with advanced non small cell lung cancer after EGFR-tyrosine kinase inhibitors failure. AB - To determine if cetuximab combined with chemotherapy is beneficial for patients with advanced NSCLC after failure of first-line chemotherapy and EGFR-tyrosine kinase inhibitors (TKI). Twenty patients were treated with cetuximab in combination with pemetrexed, and 14 patients were treated with cetuximab in combination with docetaxel. Short-term response rates and long-term survival after salvage therapy were evaluated. Partial response (PR) occurred in 4 patients, stable disease (SD) occurred in 13 patients, and progressive disease (PD) occurred in 17 patients. No patient achieved a complete response (CR). The objective response rate (ORR) was 11.8% (4/34) and the disease control rate (DCR) was 50.0% (17/34). The disease progression rate (DPR) was 50% (17/34). Further analyses showed that the DCR was significantly higher in patients treated with EGFR-TKI for >=6 months compared to patients treated with EGFR-TKI for <6 months (P=0.031). The median follow-up time was 5.5 months. The median progression-free survival (PFS) was 4.1 months. PFS was significantly longer in patients treated with EGFR-TKI for >= 6 months compared to those treated <6 months with EGFR-TKI (5.9 vs. 3.0 months; P=0.004). In general, however, patients tolerated this therapy well and there were no therapy-related deaths. As a salvage therapy, cetuximab combined with chemotherapy is indeed beneficial for patients with advanced NSCLC after first-line chemotherapy and subsequent EGFR-TKI treatment failure. In particular, this salvage regimen is beneficial for patients who were treated with EGFR-TKI for >=6 months, and is well tolerated in these patients. PMID- 26629128 TI - CD36 genotype associated with ischemic stroke in Chinese Han. AB - OBJECTIVE: CD36 is involved in oxidant stress, hyperlipidemia, and thrombosis in the pathology of stroke. CD 36 single nucleotide polymorphisms (SNPs) were reported to be associated with abnormalities of serum FA, triglyceride level and to increase risk of metabolic syndrome, coronary artery disease and type 2 diabetes. Based on these finding we hypothesized that CD36 is an important candidate gene of stroke; therefore, we set out a case-control study to explore the association of CD36 SNPs with ischemic stroke. METHODS: We enrolled 374 patients with atherothrombotic stroke as cases and 1,013 people without stroke as controls. CD36 rs3211842, rs3211870, rs1761667, rs9784998, and rs10499859 loci were detected by PCR-ligase detection reaction. RESULTS: Only rs1761667 (P=0.042) and rs10499859 (P=0.038) polymorphisms were associated with cases of ischemic stroke. Under a dominant genetic model, logistic regression analysis revealed a 1.34-fold increased risk (95% CI 1.05-1.72) of ischemic stroke with rs1761667 A than non-A carriers (P=0.020); the adjusted odds ratio (AOR) was 1.38 (95% CI 1.06-1.78) after adjusting for the covariates age, gender, body mass index (BMI), cigarette smoking, hypertension, and diabetes. For rs10499859, the risk was increased 1.36-fold for G than non-G carriers (P=0.016), and the AOR was 1.39 (95% CI 1.08-1.81) (P=0.012). The 5 SNPs were in strong linkage disequilibrium. CD36 SNPs may have no association with plasma lipid levels and thromboxane B2 (TXB2) expression. CONCLUSION: CD36 rs1761667 and rs10499859 may indicate genetic susceptibility to ischemic stroke among Chinese Han. PMID- 26629129 TI - Performance evaluation of FlowCytomix assays to quantify cytokines in patients with rheumatoid arthritis. AB - OBJECTIVES: To compare the cytokine profile in RA patients and healthy control by using two methods-FlowCytomix assay and traditional ELISA. METHODS: Cytokine levels were evaluated by FlowCytomix assay and ELISA in serum and supernatants of peripheral blood mononuclear cells (PBMC) cultures with and without stimulation by phytohaemagglutinin (PHA). RESULTS: The levels of IL-6, IL-1beta, and TNF alpha were significantly higher in sera of RA patients than those of healthy controls. The levels of IL-22, IL-6, IL-1beta, TNF-alpha, and IL-10 were higher in unstimulated PBMC culture supernatant of RA patients than those of healthy controls. PHA stimulation significantly increased the production of proinflammatory cytokines from PBMC with RA patients. Compared with detectable cytokine levels in sera, cytokine concentration in the supernatant of PBMCs was remarkably higher. FlowCytomix and ELISA showed significant correlation in detecting cytokines. However, the FlowCytomix assay detected more cytokines than ELISA. CONCLUSION: The supernatant of PBMCs provide a fine condition for the study of cytokine production because of the lack of interference factors in sera. The FlowCytomix assay is more sensitive than ELISA in detecting cytokines from RA patients. Multiple cytokine signatures using FlowCytomix assay may represent a more realistic approach in the future of personalized medicine in RA. PMID- 26629130 TI - Study of Evodia hot compress plus electro-acupuncture in patients who have undergone abdominal surgery. AB - BACKGROUND: The importance of postoperative gastrointestinal function recovery is being increasingly recognized. In this multi-center randomized controlled study, we evaluated the efficacy and safety of Evodia hot compress (ECS) plus electro acupuncture (EA) for patients who developed postoperative gastrointestinal tract dysfunction after abdominal surgery. METHODS: 1009 patients who developed postoperative gastrointestinal tract dysfunction after abdominal surgery were enrolled. All patients received conventional therapies for 7 days from the 1st postoperative day and were randomly assigned to receive coarse salt hot compress, Evodia hot compress or Evodia hot compress plus electro-acupuncture twice a day for 7 days. RESULTS: The mean time to first flatus and to first bowel sounds was comparable among the four groups (P>0.05). The control group had a significantly shorter time to defecation compared with patients receiving coarse salt hot compress, Evodia hot compress or Evodia hot compress plus electro-acupuncture (P<0.05). In patients undergoing open hepatectomy, the time to first defecation was the shortest in those who received Evodia hot compress plus electro acupuncture (89.3+/-25.5 h), which was significantly different from that of controls(134+/-31.1 h), those who received coarse salt hot compress (106.7+/-36.4 h) and those who received Evodia hot compress (109.9+/-42.1 h) (P<0.05) in patients undergoingopen cholecystectomy, the time to first defecation was the shortest in those who received Evodia hot compress (73.1+/- 24.7), which was significantly different from that of controls (77.8+/-29.7), those who received coarse salt hot compress 90.5+/-30.2) and those who received Evodia hot compress plus electro-acupunctur (83.9+/-34.0). CONCLUSION: Evodia hot compress plus electro-acupuncture confers benefit in postoperative recovery of gastrointestinal function of patients who have undergone abdominal surgery and it is overall safe to use. TRIAL REGISTRATION: Chinese Clinical Trial RegistryChiCTR-TRC-09000527. PMID- 26629131 TI - Evaluation of different small bowel contrast agents by multi - detector row CT. AB - OBJECTIVE: This study aims to evaluate the effects of different oral small bowel contrast agents towards the intestinal dilatation and intestinal wall structure exhibition by the abdominal multi - detector row CT (MDCT) examination. METHODS: 80 patients were performed the whole abdominal CT examination, then randomly divided into four groups, with 20 patients in each group. 45 minutes before the CT examination, the patients were served with a total of 1800 ml pure water, pure milk, dilute lactulose solution and isotonic mannitol solution, respectively. RESULTS: The images were blinded read by two experienced abdominal radiologists in the workstation, the cross-sectional diameters of duodenum, jejunum, proximal and terminal ends of ileum of each patient were measured, then the analysis of variance was performed to analyze the differences in the intestinal dilatation among the experimental groups. The scoring method was used to score the intestinal dilatation and intestinal structure exhibition. The diluted lactulose solution and 2.5% mannitol exhibited the best intestinal dilation degrees. Similarly, the diluted lactulose solution and 2.5% mannitol exhibited the highest scores in the entire small bowel dilatation degree and intestinal structure exhibition. CONCLUSIONS: 2.5% osmotic mannitol and the diluted lactulose solution enabled the full dilatation of small bowel, and could clearly exhibit the wall structure. PMID- 26629132 TI - Preventive effects of low-dose dexmedetomidine on postoperative cognitive function and recovery quality in elderly oral cancer patients. AB - This study analyzed the preventive effects of low-dose dexmedetomidine on postoperative cognitive function and recovery quality in elderly oral cancer patients by observing the perioperative kinetics of inflammatory cytokines, cortisol and melatonin.A total of 149 elderly oral cancer patients who had undergone tumor resection surgery were selected and randomly divided into 2 groups, Group D and Group S. After surgery, Group D was assigned to take intravenous dexmedetomidine at a dose of 0.2 MUg/kg/h for 12 h, while Group S was administered physiological saline in the same manner. On the day of surgery and for the first three postoperative days, the patients were assessed with the Mini Mental State Examination (MMSE) and a 40-item quality of recovery score questionnaire (QoR40) at 7:00 am every morning. Venous blood was harvested at the same time. Then, IL-6, CRP, cortisol and melatonin levels were measured. There were no significant between-group differences in the baseline characteristics. After surgery, the MMSE and QoR40 scores in Group D were better than those in Group S. No between-group differences were observed in the incidences of severe hypotension and bradycardia. Moreover, respiratory depression was not observed in the 2 groups. The peaks of IL-6, CRP and cortisol concentrations in Group D were lower than those in Group S. However, the melatonin levels did not differ between the 2 groups. In elderly patients, intravenous dexmedetomidine administered postoperatively for 12 h at a dose of 0.2 ug/kg/h could improve postoperative cognitive function and recovery quality by decreasing excessive inflammation and stress levels. PMID- 26629133 TI - Quality of sleep and health-related quality of life in renal transplant recipients. AB - AIMS AND OBJECTIVES: The purpose of this study was to examine the sleep quality and health-related quality of life (HRQOL) in patients after renal transplantation and to explore the relationship between the quality of sleep and the HRQOL. BACKGROUND: Sleep disorders are still an important clinical problem after renal transplantation. Previous studies mainly focused on patients' sleep quality before kidney transplant. More studies are needed to document sleep quality after renal transplantation. DESIGN: A cross-sectional design was used in this study. METHODS: A convenience sample of renal transplant recipients was recruited at an outpatient transplant clinic of a general hospital in Beijing, China. The Pittsburgh Sleep Quality Index (PSQI) was used to measure quality of sleep. The Medical Outcomes Study 36-item Short Form (MOS SF-36) was used to measure health-related quality of life. RESULTS: The average PSQI score of the 204 renal transplant recipients was 5.81+/-3.52, significantly lower than the norm. Fifty (24.5%) recipients were classified as having poor sleep quality (global PSQI > 7). The mean scores of renal transplant recipients for SF-36 Mental Component Summary (MCS) and Physical Component Summary (PCS) were 47.57+/ 6.71 and 48.26+/-9.66 respectively. Compared with residents in Sichuan province, recipients' scores for SF-36 dimensions were statistically lower except the dimension of mental health. SF-36 scores of poor sleepers (PSQI > 7) were significantly lower than the good sleepers (PSQI <= 7) in both the MCS and PCS. Significant differences exist between the groups in physical function, bodily pain, vitality, and mental health dimensions. CONCLUSIONS: Sleep quality and HRQOL of patients after renal transplantation were lower than the norm. Poor sleep is associated with lower HRQOL. RELEVANCE TO CLINICAL PRACTICE: Health professionals need to pay attention to sleep quality and HRQOL in renal transplant recipients and take appropriate measures to improve patients' sleep quality and HRQOL. PMID- 26629134 TI - Genetic polymorphisms of Trim5a are associated with disease progression in acutely and chronically HIV-infected patients. AB - BACKGROUND: The tripartite interaction motif 5a (Trim5a) plays critical roles in restricting various kinds of retroviruses in different species. It has been shown that Trim5a could inhibit HIV-1 inhibition in vitro. METHODS: In this study, 16 SNPs of Trim5a gene were screened in 236 acutely HIV-infected patients (169 common type (CT) patients and 67 patients with rapid disease progression). In addition, they were screened in 162 chronically HIV-infected patients (147 common type patients and 15 long-term non-progressors (LTNP)). The potential effects of polymorphisms at Trim5a genes on HIV-infection disease progression were analyzed. RESULTS: Among all tested SNP sites, 3 SNPs (rs3824949, rs2291841 and rs11038628) were identified to be associated with rapid disease progression in acutely HIV infected patients. Carriage of rs3824949 allele G, rs2291841 allele C or rs11038628 allele T associated with rapid disease progression. In chronically HIV infected patients, Patients carrying rs3802981 allele C or rs3802980 allele A had increased opportunity to be LTNP. We also found that greater age was associated with disease deterioration. CONCLUSIONS: Different genetic polymorphisms of Trim5a may have an impact on the clinical course of both acute and chronic stages of HIV-infection. PMID- 26629135 TI - Fast track surgery vs. conventional management in the perioperative care of retroperitoneal laparoscopic adrenalectomy. AB - OBJECTIVE: It has been demonstrated that fast track (FT) surgery can accelerate the recovery of the patients in limited urologic procedures, but there are no reports regarding FT surgery within retroperitoneal laparoscopic adrenalectomy (RLA). This study aims at evaluating the impact of FT surgery on recovery after RLA. METHODS: One hundred patients in our centre are randomly assigned to FT group and conventional group. The patients who have undergone RLA receive either conventional care or an FT recovery program. Surgical outcome, complications, gastrointestinal function, visual analogue scale (VAS) general state and VAS pain scores are compared between the two groups. In addition, white blood cell count, serum interleukin-6 and C-reactive protein levels are measured. Patients are discharged home when they meet discharge criteria. RESULTS: Compared with the conventional group, the time of first flatus (18.97+/-8.45 vs. 37.66+/-17.17 h), initiation of normal diet (18.76+/-4.94 vs. 53.15+/-15.99 h), the time of first ambulation (19.64+/-6.23 vs. 51.89+/-18.19 h), length of post-operation hospital stay (2.35+/-0.87 vs. 5.23+/-1.62 d), duration of drainage (18.19+/-5.19 vs. 68.10+/-18.06 h) and catheter (17.19+/-4.49 vs. 60.83+/-25.53 h) are markedly shorter in FT group (P<0.01). Post-operative coughing pain scores at 2 h (1.00+/ 0.61 vs. 1.42+/-1.18), 12 h (0.96+/-0.78 vs. 2.00+/-1.40), 24 h (1.10+/-0.97 vs. 4.22+/-1.53) and resting pain scores at 12 h (0.64+/-0.56 vs. 1.44+/-0.91), 24 h (0.66+/-0.63 vs. 1.22+/-0.86) are consistently lower in the FT group. The level of CRP, IL-6 at 2 h and 24 h post-operation are lower than that of control group, and white blood cell count is lower than conventional group at 24 h after surgery (P<0.01). FT patients have a overall higher level of post-operative VAS general state than conventional groups (P<0.01). Age, sex, tumor size and side, BMI, ASA score, operation time, blood loss and complications are similar in both groups. CONCLUSIONS: FT surgery within RLA shortens the length of post-operative hospital stay without increasing the postoperative complication, lowers patients' VAS pain scores, and reduces inflammatory response intensity and improves the general state. Therefore, FT can be applied feasibly and safely in RLA. PMID- 26629136 TI - Prevention of radiation esophagitis by polaprezinc (zinc L-carnosine) in patients with non-small cell lung cancer who received chemoradiotherapy. AB - BACKGROUND: Concurrent chemoradiotherapy (CCRT) plays an important role in multimodality therapy for non-small cell lung cancer. However, esophagitis often develops as a complication of CCRT, causing treatment delays and reducing the patient's quality of life. We examined the efficacy of polaprezinc (PZ), zinc L carnosine used for the therapy of gastric ulcer, against the onset of esophagitis caused by CCRT for lung cancer. PATIENTS AND METHODS: Patients who concurrently underwent chemotherapy with carboplatin and paclitaxel and thoracic radiotherapy at Gifu University Hospital during a period of January 2011 and May 2015 were the subjects of the present study. Patients received a mixture of sodium alginate solution and aluminum-magnesium hydroxide gel with (PZ group) or without (control group) PZ for prevention of radiation esophagitis. RESULTS: PZ significantly inhibited the development of grade >=2 radiation esophagitis (HR 0.397, 95% confidence interval, 0.160-0.990; P=0.047). In addition, PZ lowered the incidence of grade >=2 esophagitis at the time point of 40 Gy irradiation (26.3% versus 63.2%, P=0.05). However, there were no significant differences in the incident rates of other adverse events associated with chemoradiotherapy between the PZ group and control group. Moreover, PZ had no significant influence on the tumor response rate. CONCLUSION: PZ significantly retarded the development as well as the incidence of grade >=2 esophagitis without affecting the tumor response. PMID- 26629137 TI - Genetic polymorphisms and haplotypes of TRAIL gene correlate with NSCLC susceptibility in a group of Chinese patients. AB - The association between genetic polymorphisms and haplotypes of TNF-related apoptosis-inducing ligand (TRAIL) and the NSCLC development was investigated in 592 Chinese patients and the prevalence of G1525A, G1588A, and C1595T gene polymorphisms compared between the NSCLC patients and control group in this study. It was found that the frequencies of variant allele A and genotype GA+AA of G1525A were significantly lower and those of variant alleles A and T of G1588A and C1595T significantly higher in the NSCLC patients compared with those in control. The frequencies of variant allele T and genotype CT+TT of C1595T were significantly higher in stage III and IV than in stage I and II of the patients. Moreover, the frequencies of variant allele A and genotype GA+AA of G1525A were significantly higher in stage III and IV than in stage I and II of the patients. In addition, TRAIL gene variants G1525A/G1588A/C1595T were found to be in complete linkage disequilibrium in all patients. Compared with the healthy people, the frequency of AAT haplotype was significantly lower whereas that of GAT haplotype significantly higher in NSCLC patients. The results indicated that the genetic polymorphisms and haplotypes of TRAIL gene correlated significantly with the NSCLC susceptibility in the group of Chinese patients. PMID- 26629138 TI - Comparison of Incidence of hypoxia during modified rapid sequence induction and an alternative technique: a prospective randomized controlled trial. AB - BACKGROUND: We evaluated the effects and safety of an alternative technique for rapid sequence intubation in children predicting to have high risk of pulmonary aspiration in this prospective, randomized, placebo-controlled study. METHODS: One hundred sixty-five children predicting to have high risk of pulmonary aspiration were randomly allocated to spontaneous breathing maintained induction and intubation group (Group S) and the modified rapid sequence group (Group C). The primary outcome was the incidence of hypoxemia around the intubation period, which was defined as SpO2<90% at any time during the induction and 10 min after the endotracheal intubation. Secondary outcomes included the incidence of pulmonary aspiration, gastroesophageal reflux and other major adverse events associated with the induction and intubation. RESULTS: There were no differences in the incidence of hypoxemia around the intubation period between Group C and Group S; 25.9% vs. 14.8% (P=0.079). The incidence of severe hypoxemia appeared higher in Group C than Group S but not statistical significance, 6.2% vs. 2.5% (P=0.246). Simultaneously, gastroesophageal reflux (upper esophageal pH<=4) was detected in 4.93% children in Group C and 2.47% in group S, which was not significantly different between the two groups (P=0.552). There were no witnessed aspirations in all subjects. CONCLUSION: Sevoflurane based deep sedation with spontaneous respiration maintained technique is not superior to modified rapid sequence induction but can be an alternative technique for anesthesia induction for those predicting to have high risk of aspiration in children. PMID- 26629139 TI - Consequence of dexmedetomidine on emergence delirium following sevoflurane anesthesia in children with cerebral palsy. AB - Children with cerebral palsy can demonstrate irritability following emergence from general anaesthesia. As well, an elevated rate of emergence delirium (ED) in children has been associated with the application of sevoflurane. The current study's intent is to administer dexmedetomidine, in a single dosage administration, at the initial phase of sevoflurane based anesthesia with regard to the occurrence and severity of ED in children afflicted with cerebral palsy. Participating in the study (American Society of Anesthesiologists I-II) are eighty children ranging in ages two through twelve years. They would be anaesthetised with sevoflurane based anesthesia while undergoing lower limb surgical procedures. The participants were equally distributed to either Group c or Group D. Group C was administered 10 ml saline 0.9%, and Group D was administered dexmedetomidine 0.5 MUg*kg(-1). Five minutes prior to commencement of the surgical procedures, the participants received the prescribed pharmaceutical dosages under the anesthesia of sevoflurane. In order to sustain the BIS values in a range of 45 and 55, at 60 second increments, endtidal sevoflurane concentrations (ETsev) were modified. After conclusion of the surgical procedures, in post anesthesia care unit (PACU), the frequency of ED was gauged with Aonos four point scale and the severity of ED was gauged with pediatric anesthesia emergence delirium scale upon admission (T0), after intervals of five minutes (T5), fifteen minutes (T15) and thirty minutes (T30). Extubation time, emergence time and length of at stay at the PACU were assessed. Relative to Group C, participants of Group D exhibited noticeably shortened times of emergence, extubation and PACU duration of stay. Prior to surgical incision, ETsev was elevated in the control group, (1.9+/-0.2 vs 1.6+/-0.3; P = 0.023) and amid the initial 20 minutes following the surgical incision (1.6+/-0.2 vs 1.1+/ 0.2; P = 0.016). At intervals of commencement, T0, of five minutes (T5) and fifteen minutes T15, Group D exhibited lower occurrences and severity of ED than those participants in Group C. Dexmedetomidine, given as a bolus dose post induction, was effective in reducing the occurrence and severity of emergence delirium in children with cerebral palsy who were undergoing lower limb surgical procedures under sevoflurane anaesthesia. PMID- 26629140 TI - Impact of ischemic preconditioning on ischemia-reperfusion injury of the rat sciatic nerve. AB - The aim of this study was to assess the preventive effects of ischemic preconditioning (IPC) on ischemia-reperfusion (IR) injury in the sciatic nerve of the rat hind limb. This study included two experiments. For Experiment 1, 40 Sprague-Dawley (SD) rats were randomly divided into 4 equal groups that received different IPC treatments prior to IR. Serum concentrations of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), malondialdehyde (MDA), and superoxide dismutase (SOD) were assessed following reperfusion. Furthermore, we tested the electrophysiological response and ultrastructural changes in the ipsilateral sciatic nerve after IR. After determining the best IPC protocol for protection, we performed a second experiment with 30 SD rats randomly divided into 3 equal groups. Each group underwent 1, 2, or 3 IPC cycles before prolonged ischemia and reperfusion. The same analyses as in Experiment 1 were performed. In Experiment 1, the AST, LDH, and MDA concentrations were decreased in all IPC groups compared with the control group. Concentration of these enzymes showed decreases with increasing IPC cycle number in Experiment 2; however, the difference between 2 and 3 cycles of IPC did not reach significance. Conversely, SOD activity increased in the rapid and delayed groups, and with increasing cycles of IPC. The electrophysiological test showed a decrease in amplitude and increase in conduction velocity with increasing IPC cycles. Moreover, ultrastructural damage decreased with increasing IPC cycles. IPC protected against IR injury in the peripheral nerves. This effect was positively correlated with the number of IPC cycles. PMID- 26629141 TI - Impact of anxiety level on circadian rhythm of blood pressure in hypertensive patients. AB - INTRODUCTION: Considering the high prevalence rates and growing incidences of hypertension (HT) and anxiety disorders in the modern world, a full understanding of anxiety's relationship to HT is crucial. In this study we aimed to investigate the effects of anxiety level on circadian rhythm of blood pressure (BP) in hypertensive patients. MATERIAL AND METHOD: This cross-sectional study included 160 previously diagnosed essential hypertensive patients (80 female, 80 male, mean age: 55.3+/-15.1 years). All participants underwent 24 h ambulatory blood pressure monitoring (ABPM) and filled State-Trait Anxiety Inventory (STAI) (trait) Questionnaire. The study population was divided into 2 groups according to their STAI scores; an anxiety group (n=97; STAI >=45) and a control group (n=63; STAI<44). Clinical characteristics, laboratory findings and ABPM measurements were compared between the groups. RESULTS: There was no significant difference between the groups for ABPM parameters except morning blood pressure surge (MBPS). Anxiety group had a significantly higher MBPS compared to control group (14.4+/-17.0 vs 9.1+/-11.9 mmHg, P:0.03). Multivariate analysis showed that duration of HT and STAI score were the only independent predictors of MBPS. CONCLUSION: Patients' anxiety level is associated with MBPS which is an independent risk factor for cardiovascular complications. Assessment and control of anxiety seems to be worthy in effective treatment of hypertension. PMID- 26629142 TI - BLCA1 expression is associated with angiogenesis of bladder cancer and is correlated with common pro-angiogenic factors. AB - AIM: To study the association between expression of BLCA1 and clinicopathological parameters of bladder cancer. METHOD: Seventy-seven bladder cancer tissue samples were collected and primary antibody of BLCA1 was generated via animal inoculation. Immunohistochemical staining of BLCA1 and several pro-angiogenic factors were performed and evaluated semi-quantitatively. Statistical analyses were used to reveal the associations therein. RESULTS: Expression of BLCA-1 was not associated with tumor characteristics such as occurrence, size, or onset pattern, but was associated with progression of tumor grade, stage, and with muscle invasion. BLCA1 expression was correlated with expression of VEGF, MMP9, IL1alpha, IL8, and microvessel density (MVD), but not with TNFalpha expression. CONCLUSION: BLCA1 is associated with progression of bladder cancer and paly a role in angiogenesis in bladder cancer. PMID- 26629143 TI - Glycyrrhizin combined with acitretin improve clinical symptom of psoriasis via reducing Th17 cell differentiation and related serum cytokine concentrations. AB - OBJECTIVE: To evaluate the effect of compound glycyrrhizin in combination with acitretin on Th17 cell and related cytokines expressions in patients with psoriasis. METHODS: A total of 100 patients with psoriasis were enrolled in our study and randomized into an acitretin (Aci) group (n = 50) and a compound glycyrrhizin/acitretin combined treatment (Aci + Glyc) group (n = 50). Both groups were medicated with 3 * 10 mg acitretin per day for 8 weeks but the (Aci + Glyc) group received additionally 3 * 75 mg compound glycyrrhizin every day. A total of 50 healthy individuals were selected as the control group. The peripheral blood Th17 cell percentage as well as the IL-6, IL-17, IL-22 and TGF beta serum concentrations in addition to PASI scores were determined before and after medications. RESULTS: The Th17 cell percentages and the serum concentrations of IL-6, IL-17, IL-22 and TGF-beta in the Aci and Aci + Glyc groups were significantly higher than those in the control group before treatments (P < 0.05) and were significantly declined after the treatments (P < 0.05), but to a higher extend in the Aci + Glyc group (P < 0.05). The clinical treatment effective rates in the Aci group and the Aci + Glyc group were 76.0% and 90.0% (P < 0.05) compared to invalid events after treatments. CONCLUSIONS: Compound glycyrrhizin in combination with acitretin can improve the clinical efficacy significantly when compared with of the solely acitretin medication for psoriasis treatments via down regulating Th17 cell differentiation. PMID- 26629144 TI - Analysis of neonatal respiratory distress syndrome among different gestational segments. AB - OBJECTIVE: To find more effective diagnosis and treatment of NRDS through comparatively analyzing the different gestational neonates with respiratory distress syndrome in risk factors, clinical characteristics, treatment and prognosis. METHODS: The clinical data of 232 neonates were retrospectively analyzed who had been admitted into the neonatal intensive care unit and diagnosed with NRDS from January 2008 to December 2010. These cases were divided into three groups according to gestational age, which included full-term group, late preterm and early preterm group. Statistical analysis was used to detect the differences of relative factors among the three groups. RESULTS: For pathogen, the full-term and late preterm infants accounted for more than 50% The majority of full-term infants were less than 39 weeks, taking up 83.7%. As many as 61.1% of the late preterm infants were born at maternal age over 30 years. The incidence of Cesarean section was high among the three groups, especially the full-term (90.7%) and late preterm group (86.1%). For clinical features, full term infants had late onsets more than 12 h after birth. Air bronchogram could be found commonly in early preterm neonates, influencing 92% of them. However, it was rare in the other two groups. The incidence of lung infection in each group was all about 50%. In addition, Gas leakage and PPHN were more common complications in full-term and late preterm group, while for the early preterm group was the bronchopulmonary dysplasia and intracranial hemorrhage. For treatment, the proportions of full-term infants receiving application of HFOV and NO were 57.0% and 24.4%, and for late preterm infants were 36.1% and 22.2%. The application of HFOV and NO was not as much to early preterm infants as other groups. There was no significant difference in the duration of invasive ventilation between all groups. However, the noninvasive ventilation time after extubation was as long as 10.1+/-0.5 days in early preterm infants. The proportions of infants receiving application of PS were 53.5%, 83.3% and 81.8%, respectively. OI values improved greatly 2 h after application of PS on early preterm infants. However, the obvious difference was found only after 24 h for full-term and late preterm infants. CONCLUSION: Besides early preterm infants, full-term and late preterm have the growing trend in the pathogenesis of NRDS. Infants of different gestational age have their own characteristics of the risk factors, which cesarean section impacts greatly on the incidence of term and late preterm infants. The clinical feature, chest X-ray changes and common complications were characteristics between term and premature infants with NRDS. The PS treatment work slower in term and late preterm infants, who needed more HFOV and NO treatment. PMID- 26629145 TI - Comparison of Vitamin D levels in cases with preeclampsia, eclampsia and healthy pregnant women. AB - The aim of this study is to assess vitamin D levels in eclampsia, preeclampsia and healthy pregnant women and the role of vitamin D deficiency in the etiology of preeclampsia (PE). Forty healthy pregnant women, 83 preeclamptic and 32 eclamptic pregnant women were included. Maternal and infant medical records were reviewed. Blood samples were obtained from all groups. Demographics and serum vitamin D levels were compared between the groups. No statistical differences were observed in age, gravidity, parity, weight, height and BMI between the three groups. Week of pregnancy and weight at birth in eclamptic and preeclamptic patients were lower compared to the healthy patients (P<0.001 and P<0.001, respectively). Systolic and diastolic blood pressures were higher in eclamptic (P<0.001) and preeclamptic patients (P<0.001) compared to the healthy pregnant group. The rate of cesarean section was found to be higher in preeclamptic and eclamptic patients (P<0.001). Vitamin D levels were lower in both preeclamptic and eclamptic patients compared to healthy normotensive pregnant women (P<0.001). Preeclamptic and eclamptic women were similar in terms of the data compared. Vitamin D supplementation is considered to decrease the risk of both preeclampsia and eclampsia in the patient population at risk for vitamin D deficiency. PMID- 26629146 TI - Treatment of osteoporotic vertebral compression fractures with percutaneous vertebroplasty under local anesthesia: clinical and radiological results. AB - BACKGROUND: Vertebroplasty (VP) is a commonly used method for the treatment of osteoporotic vertebral fractures (OVF). The aim of this study is to analyze retrospectively the efficacy of PV in symptomatic osteoprotic spine fractures. METHODS: Patients with symptomatic osteoporotic spine fractures were included in our study. Visual analog scale and demographic characteristics were used for clinical examination, local wedge angle and the central height of the vertebral body were measured preoperatively and postoperatively. RESULTS: 95 patients (72 female, 23 male) were included and 118 level vertebroplasty were performed. There was statistical significance in the differences of preoperative VAS scores compared to postoperative first day, first month and sixth month. The radiologic assessment of the mean local wedge angle correction at the postoperative sixth month, was 13.9 and mean increase of mid height of vertebral body was 7.9 mm, but it was not statistically significant. CONCLUSION: VP is at an important point as a minimally invasive method, that provides rapid pain relief in symptomatic osteoporotic vertebral fractures and that prevents the patient being bed dependent. It is a reliable surgical method, being an alternative to open surgery with minimal complications in patients with comorbidities, which can be arapidley applied and decreases the potential spinal deformity after the fracture and prevents the progression of deformity. PMID- 26629147 TI - The Ser326Cys polymorphism of hOGG1 is associated with intrahepatic cholangiocarcinoma susceptibility in a Chinese population. AB - OBJECTIVE: Intrahepatic cholangiocarcinoma is a rare disease whose etiology is far from clear, the Ser326Cys polymorphism in human 8-hydroxyguanine glycosylase (hOGG1) has been shown associated with various cancers, however, the association of Ser326Cys (rsl052133) polymorphism and intrahepatic cholangiocarcinoma susceptibility has not been clarified. The purpose of this study is to investigate whether this polymorphism is related to the genetic susceptibility of intrahepatic cholangiocarcinoma. METHODS: A total 150 patients and 150 normal people were included in this study, the Ser326Cys polymorphisms in each group were genotyped using PCR-RFLP method. RESULTS: We found that individuals carrying Cys/Cys genotype were exposed to higher riskof intrahepatic cholangiocarcinoma (OR=2.924, 95% CI=1.475-5.780) compared with the individuals with wild type genotype Ser/Ser. Further analysis revealed that male individuals carrying Cys/Cys genotype also had increased risk (OR=2.762, 95% CI=1.233-6.173), whereas no significant difference was observed in female group. CONCLUSIONS: Therefore, our data indicates that the Ser326Cys (rs1052133) polymorphism is associated with intrahepatic cholangiocarcinoma susceptibility, and it shows preference in male population. PMID- 26629148 TI - Berberine alleviates preeclampsia possibly by regulating the expression of interleukin-2/interleukin-10 and Bcl-2/Bax. AB - The present study is to investigate the effect of berberine on the expression of inflammatory factors interleukin (IL)-2 and IL-10, and the expression of apoptosis proteins Bcl-2 and Bax. A total of 70 SD rats were randomly divided into 7 equal groups, including normal non-pregnant group, normal pregnant group, preeclampsia group, preeclampsia + berberine (50, 100, and 200 mg/kg/day) groups, and preeclampsia + nifedipine (20 mg/kg/day) group. Blood pressure was measured before pregnancy, and on day 15 and 21 of pregnancy. Urines before pregnancy and on day 15 and 21 of pregnancy were collected for the determination of urine protein levels. Peripheral blood was collected from all rats on day 21 of pregnancy to measure the levels of blood urea nitrogen and creatinine. On day 21 of pregnancy, the weight of fetuses and placentas, and the number of normal fetuses were determined. Enzyme-linked immunosorbent assay was performed to determine the levels of IL-2 and IL-10 in plasma. Western blotting was used to measure the expression of Bcl-2 and Bax proteins in placenta of rats with preeclampsia. Treatment with berberine for seven days reduced blood pressure, urine proteins levels, and kidney function in rats with preeclampsia. Berberine improved the number of normal fetuses and the weight of fetuses and placentas from rats with preeclampsia. Berberine up-regulated IL-10 and down-regulated IL-2 in the peripheral blood of SD rats with preeclampsia. Berberine up-regulated Bcl 2 and down-regulated Bax in the placenta of SD rats with preeclampsia. Berberine increases the number and weight of normal fetuses in rats with preeclampsia, possibly by regulating the balance of IL-2 and IL-10, and inhibiting apoptosis. PMID- 26629149 TI - Can BuCyE conditioning regimen be an alternative treatment to BEAM at autologous transplantation in malignant lymphoma patients?: a single center experience. AB - High-dose chemotherapy (HDC) applied together with autologous stem cell transplantation (ASCT) is a commonly used treatment modality in patients with malignant lymphoma. At present, there is a limited number of studies which compare toxicity and efficacy of various high-dose regimens applied in the treatment of malignant lymphoma. For this reason, the aim of this study was to investigate the efficacy and toxicity of BuCyE (busulfan, cyclophosphamide and etoposide) and BEAM (carmustine, etoposide, cytarabine and melphalan) preparative regimens in the patients with malignant lymphoma scheduled for autologous stem cell transplantation. Between November, 2010 and April, 2015, 42 patients with relapsed or refractory malignant lymphoma who underwent autologous stem cell transplantation following BEAM (n=11) and BuCyE (n=31) preparative regimens were analyzed at Bone Marrow Transplantation Unit of TurgutOzal Medicine Center in Turkey. The groups were compared in terms of patient characteristics, hematopoietic engraftment time, toxicity profiles and survival. No significant differences were detected between the groups with regard to age, gender distribution, international prognostic index, ASCT indications, disease status at the time of ASCT and type of lymphoma (P>0.05). Median number of infused CD34+ cells/kg, neutrophil and platelet engraftment statuses of BuCyE and BEAM groups were found to be similar (P>0.05). More patients in BuCyE group developed mucositis and nausea, but this difference was not statistically significant (P>0.05). A similar statistically insignificant difference was seen in that infectious complications occurred more commonly in BEAM group (P>0.05). Overall survival and event-free survival rates were not significantly different between the groups (P>0.05). BuCyE is a conditioning regimen which can be effectively used as an alternative to BEAM in the patients with malignant lymphoma undergoing ASCT. Moreover, toxicity rates of both regimens are similar. In order to comprehend the effect of each HDC regimen, further evidence-based data obtained from the studies involving larger sample sizes are required. PMID- 26629150 TI - Peripancreatic lymphadenopathy on preoperative radiologic images predicts malignancy in pancreatic solid pseudopapillary neoplasm. AB - OBJECTIVE: To identify clinicopathological characters and risk factors of malignant pancreatic solid pseudopapillary neoplasm (SPN). METHODS: All patients with complete clinicopathological records who underwent surgery for SPN between 2000 and 2010 were retrospective reviewed. Furthermore, we reviewed and classified the histopathology slides of all patients according to the 2010 World Health Organization criteria. RESULTS: Of the 100 patients identified, 84 (84.0%) were female, and the median age was 31 (range, 13-68) years old. Median tumor size was 6.5 (range, 1.5-18) cm. Twenty-four patients (24.0%) were classified to have malignant SPN. Forty-nine patients had lymph node removed in surgery, and four (8.2%) had nodal metastases. On univariate analysis, peripancreatic lymphadenopathy on preoperative computed tomography (CT) and/or magnetic resonance (MR) images was significant risk factor of malignancy (P = 0.025). In the long-term follow up, two patients had evidence of liver metastases and underwent a second laparotomy for metastatic tumor. These two patients were followed up for 24 and 32 months respectively, and never presented with tumor recurrence again. CONCLUSIONS: Peripancreatic lymphadenopathy on preoperative radiologic images was associated with malignancy in patients with SPN. Close follow-up and review periodically were recommended for patients with malignant SPN. PMID- 26629151 TI - The caries prevalence of oral clefts in eastern China. AB - Little information is available concerning the prevalence of caries among patients with oral clefts in Eastern China. Consecutive patients aged 6-18 with oral clefts were recruited. Patients were stratified into 2 groups according to their ages, namely Group I with aged 6-12 and Group II with aged 13-18. For each age group, the children were further divided into three subgroups according to the types of oral clefts they had: cleft lip/cleft lip and alveolus (CL), cleft palate only (CP), and cleft lip and palate (CLP). Dental caries were examined by using the decayed, missing, and filled index for primary teeth (dmft) and Decay, Missing and Filled index for Permanent teeth (DMFT) according to criteria of the World Health Organization. 268 eligible patients with oral clefts were included in the study. The mean DMFT for Group I was 1.77 (SD2.58) while that for Group II was 6.96 (SD4.35). The mean DMFT was statistically significant different between the age group I and age group II (t=12.21, P<0.05). In Group I, the dmft scores was 4.68 (SD3.67) for CL group, while that for the CP group was 7.36 (SD3.93), and that for the CLP group was 5.72 (SD 3.87). The mean dmft was no statistically significant different among cleft types (F=3.13, P>0.05). Also in Group I, the mean DMFT was 1.56 (SD2.18) for CL group, while that for the CP group was 1.24 (SD 1.81) and that for the CLP group was 2.08 (SD2.96). There were no statistically significant different in mean DMFT among different cleft types (F=1.09, P>0.05). In Group II, the mean DMFT was 6.06 (SD3.97) for CL group while that for the CP group was 7.71 (SD 4.94) and that for the CLP group was 7.05 (SD4.32). No significant difference was shown in the mean DMFT among different cleft groups (CL, CP, and CLP) (F=0.55, P>0.05). During assess the prevalence of dental caries among Eastern Chinese with oral clefts; the study confirmed that the prevalence of caries was increased with increasing age for oral clefts patients. It was also demonstrated that there was no significant difference in the mean dmft/DMFT scores among different cleft types. PMID- 26629152 TI - Parathyroid autotransplantation in rats having hypoparathyroidism. AB - Re-implantation techniques of extracted parathyroid tissue were developed in order to prevent temporary hypocalcemia. During thyroid surgery; inadvertently removed or devascularized parathyroid gland is usually implanted in the sternocleidomastoid muscle. In this experimental study using rats with hypoparathyroidism, our aim was to investigate whether the excised parathyroid tissue could be seeded in the liver and in the peritoneum, instead of the SCM muscle. In our study, four different groups, each consisting of 10 Wistar albino rats were used (Control group, sternocleidomastoid muscle group, liver group, peritoneum group). Parathyroidectomy was performed and the parathyroid tissue was seeded into the sternocloid mastoid muscle, liver and peritoneum. After 14 days, the rats were sacrificed and levels of calcium, magnesium, phosphorus, alkaline phosphatase and parathyroid hormone were measured in rats' blood samples. The autotransplanted parathyroid tissue was then excised and examined. In all groups, parathyroid tissues were analyzed histopathologically according to calcification, necrosis, tissue loss, foreign body reaction, inflammation and fibrosis. Regarding Ca, Mg, PO4, ALP; There were no difference between the groups. When we compared control group with the other groups; a difference was observed in the levels of PTH (P<0.05). In pathological examination; regarding tissue loss; there was a difference between liver and peritoneum groups (P<0.05). In our study, we expected better result in plantings inside liver and peritone compared to SKM. However, there were no difference between the groups. PMID- 26629153 TI - Not all anti-T lymphocyte globulin preparations are suitable for use in aplastic anemia: significantly inferior results with jurkat cell-reactive anti-T lymphocyte globulin in clinical practice. AB - BACKGROUND: Immunosuppressive therapy (IST) with anti-T lymphocyte globulin (ATG) plus cyclosporine (CSA) is standard therapy in patients with non-severe aplastic anemia (AA) in need of treatment and severe aplastic anemia (SAA) who do not have an available HLA-matched donor. The aim of this study was to analyze patients submitted to different ATG preparations as first-line treatment. PATIENTS AND METHODS: We retrospectively analyzed adult aplastic anemia (AA) patients who received ATG as first-line treatment between 1999 and 2013 to compare hematologic response and survival. RESULTS: During the time period mentioned 4 different ATG preparations had been used in 38 AA patients (34 severe, 4 non-severe). Responses were better with Lymphoglobulin (6 complete response 1 partial response, 0 refractory disease and 2 death within 3 months after ATG, i.e. during induction), Thymoglobulin (3, 1, 4 and 1, respectively) or ATGAM (1, 2, 1 and 1) compared to the ATG-Fresenius (ATG-F) group (3, 0, 6 and 6) (P = .07). Statistically significant inferior results with ATG-Fresenius (3 complete or partial responses, 6 refractoriness and 6 induction deaths) were evident when other preparations are lumped together (14 complete or partial responses, 5 refractoriness and 4 induction mortalities) (P = .045). Estimated 1 year survival rates were 52.5% versus 76.9%, respectively (P = .13). CONCLUSIONS: These data support the notion that not all ATG preparations are suitable for use in AA. PMID- 26629154 TI - Comparison of anti-reflux mechanism between Double-J-Stent and standart Double-J Stent use for risk of BK nephropathy and urinary tract Infection in kidney transplantation. AB - OBJECTIVES: There are studies that show that double J stenting (DJS) increase BK nephropathy (BKN) 4 fold. DJS may cause vesicoureteral reflux (VUR) with normal bladder contraction. The aim of this study is to comparison risk of BKN, urinary tract infections (UTI) and postoperative urologic complications with the use DJS with anti-reflux device (ARD-DJS) and standart double J stent (St-DJS). Matherial and methods: Ninety patients (male/female: 50/40) that had undergone kidney transplantations in Diyarbakir Training and Research Hospital and Dicle University, Faculty of Medicine Hospital between January 2012 and April 2015 were enrolled in the study. Demographic data, immunosuppression protocols, presence of rejection, graft loss, postoperative urologic complications, UTI, plasma BK levels of the patients were evaluated retrospectively. RESULTS: Median and IQR follow up time for ARD-DJS and St-DJS patients were 14 (12-18) months and 25 (16 30) months respectively. Five cases (5.5%) had BK viremia (P=0.025). All 5 cases with BK viremia were St-DJS users. CONCLUSION: As a result for postoperative UTI and postoperative urinary complication risk there were no statistically significant difference between ARD-DJS use and St-DJS use during ureteral anastomosis. BKN univariate analysis were significantly less than those st-DJS used. Risc factors were evaluated. But results were not statistically significant in the logistic regression analysis. We think that to demonstrate this benefit, we need randomized controlled studies with more patients and longer follow up. PMID- 26629155 TI - AGT M235t polymorphism and heart failure in a cohort of Tunisian population: diagnostic and prognostic value. AB - Activity of the renin-angiotensin Aldosterone system is increased in patients with heart failure (HF). The Angiotensinogen gene and specifically M235T polymorphism has been linked to susceptibility to hypertension, coronary heart disease and atrial fibrillation. Its role in heart failure is not yet sufficiently demonstrated. The aim of the present study was to assess the association between rs699 (M235T) polymorphism and heart failure in terms of diagnosis and prognosis. We included all patients over 20 years old consulting in the Emergency Department for acute dyspnea. According to the results of the B type natriuretic peptide (BNP level), patients were divided into two groups: HF and non-HF group. DNA study was performed for all subjects and their genotypes were identified as TT, CT or CC. Mortality was followed for one year. We included 234 patients. We found the diagnosis of HF in 73 patients out of 160 (45%). Our results showed that the frequency of the T allele was higher in HF group patients than in non-HF group (69% vs. 33%, P<0.01). Patients carrying the TT and CT genotypes had a higher proportion of HF than those carrying the CC genotype (respectively 53% and 31% vs. 15%, P<0.01). According to multivariate analysis, TT genotype presented the highest risk of HF (OR=4.9 95% CI: 2.12-9.1) and the highest risk of death (OR=6.45 95% CI: 3.6-16.4) compared to the other two genotypes. The current study suggests that M235T polymorphism might be associated with increased risk of both HF and death. PMID- 26629156 TI - Serum Sema4D levels are associated with lumbar spine bone mineral density and bone turnover markers in patients with postmenopausal osteoporosis. AB - To investigate the association of serum semaphorin 4D (Sema4D) levels with lumbar spine bone mineral density (BMD) and bone turnover markers in patients with postmenopausal osteoporosis (PO). Lumbar spine BMD was measured by dual-energy X ray absorptiometry in 257 PO patients (aged from 50 to 75) and 90 healthy controls (aged from 51 to 83). Serum Sema4D, BAP, BGP and TRACP-5b levels were measured by enzyme linked immunosorbent assay. Serum cross linked N-telopeptides of type I (NTX), 25-hydroxyvitamin D (25(OH)D) and N-mid fragment of osteocalcin (N-MID-OT) levels were measured using automated electrochemiluminescence system. Sema4D level was significantly higher in PO women compared to healthy controls (1.40+/-0.33 vs. 0.58+/-0.18 MUg/L, P=0.006). Sema4D level was positively correlated with serumTRACP-5b and NTX levels and negatively correlated with lumbar spine BMD and serum BAP and BGP levels. There were no correlations between Sema4D level and age, body mass index, and serum 25(OH)D and N-MID-OT levels. Lumbar spine BMD (beta=-0.354, P<0.001) and serum BAP level (beta=0.127, P=0.019) were independent predictors of serum Sema4D level in PO patients. Sema4D may be involved in the pathogenesis of PO and play a critical role in bone formation and resorption. Sema4D may represent a novel therapeutic target for treatment of PO and function as a predictive indicator of PO. PMID- 26629157 TI - Decreased coronary blood flow velocity in patients with aortic insufficiency but normal coronary arteries: the use of TIMI frame count in aortic insufficiency cases. AB - Patients with aortic insufficiency (AI) may suffer from anginapector is in the absence of obstructive coronaryartery disease. In this study, we aimed to investigate coronary blood flow using the thrombolysis in myocardialinfarction (TIMI) frame count (TFC) method in patients with AI and normal coronaryarteries. The study included 64 patients (Group 1; meanage 62.4 +/- 13.2 years) with moderate to severe AI who had under gonecoronaryangio graphy that resulted in angiographically normal coronaries, and 42 patients with a typical chest pain and angiographically normal coronaryarteriogram (Group 2; meanage 58.8 +/- 9.8 years). All patients under went coronaryangiography either to exclude coronaryartery disease or to evaluate their coronaryanatomy before aorticvalve replacement. TFC was calculated and compared for each artery, including the left anterior descending (LAD), circumflex (LCX), and right coronaryartery (RCA) in both groups. The base line characteristics of the study groups were similar. In both groups, TIMI-3 flow was present in eachartery at the time of arteriography, and the coronaryarteries were entirely normal. LCx and RCA frame counts and corrected LAD frame counts were significantly higher in Group 1 than in Group 2 (26.4 +/- 2.1 vs. 24.3 +/- 3.6, P < 0.05; 22.1 +/- 2.3 vs. 20.5 +/- 2.9, P < 0.05; and 22.5 +/- 1.8 vs. 20.5 +/- 2.4, P < 0.05, respectively). The TFC method may be used as a marker forcoronary flowvelocity in patients with aortic insuffiency and angiographically normal coronaryarteries toestimate decreased coronary blood flowve locity. PMID- 26629158 TI - Brain Natriuretic Peptide as the long-term cause of mortality in patients with cardiovascular disease: a retrospective cohort study. AB - OBJECTIVE: To explore the influence of BNP (Brain Natriuretic Peptide) in plasma on the long-term cause of mortality and prognosis of patients with cardiovascular disease (CVD). METHOD: We performed a retrospective cohort study of 276 inpatients that enrolled in our hospital from March 2003 to December 2004 and had a history of heart disease and received a BNP test. Kaplan-Meier survival curves with Log-Rank test were used to compare the survival rates among different levels of BNP (<100 ng/L, 101~1000 ng/L, 1001~5000 ng/L and >5000 ng/L). Cox proportional hazards regression models were used to estimate HRs and 95% CIs with adjustments for other covariance's. RESULT: After a median follow-up of 7 years, a total of 91 patients died of whom fifty were cardiogenic deaths and 41 were non cardiogenic. The survival rates were of statistical significance (P=0.0000) between the different levels of BNP in the 4 groups, and the mortality rate increased gradually with the increase in BNP concentration. Multivariable Cox regression analysis showed that BNP levels were inversely associated with the survival rate in CVD patients (HR=0.24, 95% CI: 0.13~0.42). In addition, age and left ventricular ejection fraction values were also of statistical significance in the Cox regression model. CONCLUSION: Our findings suggested that high Plasma BNP levels may have an adverse effect on the prognosis of patients with cardiovascular disease. PMID- 26629159 TI - The relationship between the target effective site concentration of rocuronium and the degree of recovery from neuromuscular blockade in elderly patients. AB - OBJECTIVE: To study the relationship between the target effective site concentration (Ce) of rocuronium and the degree of recovery from neuromuscular blockade in elderly patients. METHODS: 50 elderly patients (ASA grade II) scheduled for selective surgical procedure under general anaesthesia were randomly divided into two groups, A and B, with 25 cases in each group. The Ce of rocuronium for intubation was 3 MUg.ml(-1) in both groups, and the Ce during operation were 0.8 and 1.0 MUg.ml(-1) in group A and B, respectively. When target controlled infusion of rocuronium was stopped, without the administration of reversal agents for neuromuscular blockade, the relationship between Ce and the first twitch height (T1) was studied by regression analysis. RESULTS: There was a significant linear relationship between Ce and T1, and there was no statistical difference in regression coefficient and interception between group A and B (P>0.05). CONCLUSION: The degree of recovery from neuromuscular blockade could be judged by the target effective site concentration of rocuronium at the time of reversal from neuromuscular blockade in the elderly patients. PMID- 26629160 TI - Regulation of macrophage cholesterol efflux and liver X receptor alpha activation by nicotine. AB - OBJECTIVE: This study aims to investigate the characteristics of liver X receptor alpha (LXRalpha) and its target gene expression, as well as cholesterol efflux in human macrophages treated by nicotine. METHODS: Human monocyte-derived macrophages were collected. Before apoA-I-mediated human monocyte-derived macrophage cholesterol efflux, and mRNA expression of LXRalpha, and some of its target genes being detected, the macrophages were induced with or without nicotine. RESULTS: Pre-incubation of Human monocyte-derived macrophages with nicotine, cholesterol efflux was suppressed to apolipoprotein AI. Nicotine also inhibited LXRalpha and some of its target genes mRNA expression involved cholesterol metabolism, and facilitated some inflammatory genes expression. CONCLUSION: The changed function of cholesterol efflux and some genes expression may be the pathogenetic cause, and LXR activity of macrophage may offer potential therapeutic benefit in the treatment of atherosclerosis. Thus nicotine can regulate foam cell formation by inhibiting LXR pathway. PMID- 26629161 TI - Serum Cystatin C can detect impaired graft function early after renal transplantation. AB - OBJECTIVES: To study the significance of Cystatin C (Cys C) in early detection of the graft function after renal transplantation. MATERIAL: The concentrations of Cys C, Blood urea nitrogen (BUN), Serum creatinine (SCr), and glomerular filtration rate (GFR) were measured. According to the results of the post transplantation GFR; Seventy renal post-transplanted patients were assigned into 3 groups: group A (31 cases with the normal range of the renal function, GFR>=90 ml/min/1.73 m(2)), group B (27 cases with Scr<133 MUmol/L and 60=133 MUmol/L and 600.05). BMI, dietary habits and I-FABP alleles were independent risk factors of CHD. CONCLUSION: The polymorphism of I-FABP gene existed in the study population. And this genetic variation had influence on lipid metabolism, which was associated with the risk of developing CHD. I-FABP gene polymorphism may contribute to the increased genetic susceptibility to CHD. PMID- 26629164 TI - Serum apelin levels in patients with thyroid dysfunction. AB - Adipocytes are not only for energy storage, but are also functionally active cells, producing biologically active peptides called adipocytokines. Adipocytokines control nutrition, thermogenesis, immunity, thyroid and reproductive hormones, and neuroendocrine functions. One of the most important new members of this family is apelin. In patients with thyroid dysfunctions, there are usually changes in weight, thermogenesis and adipose tissue lipolysis. Here, we investigated the serum apelin levels in different thyroid hormone states. Our study group consisted of the following patients: 32 thyrotoxicosis, 32 subclinical hyperthyroidism, 31 hypothyroidism, 34 subclinical hypothyroidism and 31 healthy control cases. In addition to routine blood tests, serum free T3 (FT3), free T4 (FT4), TSH and apelin levels were measured, and the body mass index (BMI) was recorded. In terms of the demographic characteristics, age and BMI, there was no statistically significant difference between the groups (P>0.05). The mean serum apelin levels of the groups were as follows: thyrotoxicosis group, 4.6+/-1.9 ng/ml; subclinical hyperthyroidism group, 3.7+/ 1.9 ng/ml; hypothyroid group, 4.8+/-2.5 ng/ml; subclinical hypothyroidism group, 4.3+/-2.2 ng/mL; and control group, 3.4+/-1.4 ng/ml, respectively. There was no statistically significant difference in terms of the mean apelin levels between the groups (P>0.05). The hypothyroid group had the highest and the control group had the lowest mean apelin levels. As a result, the apelin levels were higher in both the patients with hypothyroidism and hyperthyroidism, in comparison with the normal population, but without statistical significance. PMID- 26629165 TI - Clinical observation of antibiotics in preventing nosocomial infection in premature infants. AB - OBJECTIVE: To study the possibility of lower the nosocomial infection rate among the premature infants by prophylactic use of antibiotics. METHODS: Retrospectively collect 409 premature infants admitted to the neonatal intensive care unit (NICU) of First Hospital of Jilin University between 1st January in 2009 and 31th December in 2011, who meet inclusion criteria. There were prohylactic group and nonprohylactic group randomly divided and compared the nosocomial infection rates of two groups. RESULTS: The hospital infection rate of the prophylactic group was 62.9%, and the rate of the non-prophylactic group was 47.3%. There was a significant difference between the two groups (P<0.05). On the countrary, the prophylactic use of antibiotics could increase the incidence of the nosocomial infection. CONCLUSION: It does more harm than good that proghylactic use of antibiotics to prevent premature nosocomial infection. PMID- 26629166 TI - Single-nucleotide polymorphisms of TGFbeta1 and ATM associated with radiation induced pneumonitis: a prospective cohort study of thoracic cancer patients in China. AB - BACKGROUND: We examined the effects of the rs1800469 and rs1800470 single nucleotide polymorphisms (SNPs) of the transforming growth factor-beta1 (TGFbeta1) gene and the rs189037 and rs373759 SNPs of the ataxia telangiectasia mutated (ATM) gene on the risk of radiation-induced pneumonitis (RP) in patients who underwent radiotherapy for various thoracic malignancies. METHODS: We determined the genotype and allele distributions of rs1800469 (C-509T), rs1800470 (C869T), rs189037 (A-111G), and rs373759 (126713 G>A) in 141 Han Chinese patients who underwent definitive thoracic radiotherapy (50 to 77 Gy, 5 days/wk) for lung cancer (small cell or non-small cell tumors, n = 97), esophageal squamous cell carcinoma (ESCC, n = 27), or mediastinal cancer (n = 17). Clinical variables were evaluated using multivariate logistic regression models to calculate the relative risk of RP associated with the clinical variables, and a Pearson correlation analysis was used to evaluate the relationship between the SNP genotypes and alleles and the incidence of RP for the various risk factors. RESULTS: The T alleles of rs1800470 (CT/TT) and rs1800469 (CT/TT) and the G allele of rs189037 (GA/GG) were associated with the risk of >= grade-2 RP in the ESCC patients (P = 0.0006, P = 0.0127, and P = 0.0412, respectively), and that the A alleles of rs189037 (AG/AA) and rs373759 (AG/AA) were associated with the risk of >= grade-2 RP in the patients with mediastinal cancer (P = 0.0063 and P = 0.0003, respectively). None of the SNP genotypes were associated with the risk of RP in lung cancer patients. CONCLUSION: The T alleles of the rs1800470 (CT/TT) and rs1800469 (CT/TT) SNPs of TGFbeta1 and the G allele of the rs189037 (GA/GG) SNP of ATM are independent risk factors for RP in Chinese ESCC patients, and the A alleles of the rs189037 (AG/AA) and rs373759 (AG/AA) SNPs of ATM are independent risk factors for RP in Chinese patients with mediastinal cancer. These SNPs might represent useful biomarkers for personalizing radiotherapy regimens for Chinese patients with ESCC or mediastinal cancer to reduce the incidence of RP. Large cohort studies of these SNPs in thoracic cancer patients are warranted. PMID- 26629167 TI - View changes and educational demands on sexual/reproductive health of students at Shanghai Jiaotong University. AB - OBJECTIVES: To determine whether the attitudes to sexual and reproductive health of a cohort of university students had changed from 2005 to 2013. METHODS: Questionnaires (1,000) on sexual and reproductive health attitudes were randomly distributed to students at Shanghai Jiaotong University in May 2013. All participants volunteered for the study and their answers were anonymous. The questionnaire contents included personal information and 72 MCQs, which covered four categories: knowledge about sexual/reproductive health and STDs; attitude to sexual behavior; attitudes to pornographic books/movies; desire of the participants for education on sexual/reproductive health. The participants had not received sexual/reproductive health education since their admission to the university. Their study majors were broadly similar to those participants in the April 2005 survey. The high sensitivity of the content of the questionnaire made it imperative to maintain anonymity and high security of the collected data. RESULTS: The return rate of questionnaires were 98% (request age from 19~21 years). Personal hygiene was much greater in females than in males. The proportion of females and males who held a positive attitude to premarital sexual behavior was significantly increased (P < 0.0001). 80% of the participants understood the need to use condoms with strangers; however, still high proportion of participants lacked of this knowledge (P = 0.142). About one third of the participants still did not believe that unmarried pregnancy was acceptable (no significant change from 2005 to 2013). There was significantly improved knowledge about the way in which AIDS spreads. CONCLUSIONS: College students are more open today compared to the 2003 survey. A higher level of sexual knowledge has been achieved but there scope for further improvement. Sex education should be based on the actual needs of young people, teaching reforms, and special attention paid to practical teaching. PMID- 26629168 TI - Prevalence of prehypertension and associated risk factors among health check-up population in Guangzhou, China. AB - The authors aimed to investigate the prevalence and risk factors of prehypertension among a cohort of patients presenting for a health check-up in Guangzhou. Using an age-and gender-stratified random sample method, 5170 urban adults aged 18-70 years undergoing health examination in Guangzhou were selected. Prehypertension was defined as systolic blood pressure (SBP) of 120-139 mmHg or diastolic blood pressure (DBP) of 80-89 mmHg. Overall prevalence of prehypertension in our study population was 35.15% (43.75% in men, 23.56% in women; P<0.05). Multivariate logistic regression analysis indicated that age (odds ratio [OR] =1.257), female (OR=0.437), fasting blood glucose (OR=1.514), total cholesterol (OR=1.241), triglycerides (OR=1.236), uric acid (OR=1.222), and body mass index (OR=1.778) were risk factors for prehypertension. The prevalence of prehypertension was reported to be higher among men in our study population in Guangzhou. PMID- 26629169 TI - The diagnostic value of neutrophil gelatinase-associated lipocalin and hepcidin in bacteria translocation of liver cirrhosis. AB - OBJECTIVE: Bacterial translocation (BT) or bacterial DNA (bactDNA) translocation is a critical pathogenesis mechanism of spontaneous bacterial peritonitis. Studies of BT or bactDNA translocation are limited in humans. Neutrophil gelatinase associated lipocalin (NGAL) can efficiently distinguish bacterial and nonbacterial ascites in ascitic patients. Hepcidin is a useful marker of bacterial infection in the late-onset sepsis. However, the relationship between NGAL, hepcidin and BT was still unclear. In present study, the levels of NGAL, hepcidin and their relationship with BT or bactDNA translocation were investigated. MATERIAL AND METHODS: Weekly doses of carbon tetrachloride (CCl4) were given to induce liver cirrhosis in Sprague-Dawley rats. Trypticase (blood) soy agars were used to culture bacteria. BactDNA was sequenced by ABIPRISM 310 automated sequencer. The levels of NGAL and hepcidin were assessed by ELISA. Receiver operating characteristic (ROC) curve was used to determine the cut-off values and compare the diagnostic performance of NGAL and hepcidin. RESULTS: 56 cirrhotic and 10 normal rats were included in this study. The levels of both two biomarkers were significantly higher in BT or bactDNA translocation group compared to non-translocation group. The area under ROC curve for the diagnosis of BT was 0.910 for serum NGAL, 0.858 for serum hepcidin and 0.940 for their combination, whereas that for the diagnosis of bactDNA translocation was 0.906 for NGAL, 0.779 for hepcidin and 0.950 for their combination, respectively. The combination of NGAL and hepcidin improved the ability to detect BT or bactDNA presence in MLNs and ascites. CONCLUSION: BT and the presence of bactDNA in MLNs were observed in a rat cirrhotic model. Serum NGAL and hepcidin can serve as sensitive and specific tests for diagnosis of BT or bactDNA translocation. NGAL in combination with hepcidin can improve the accuracy of diagnosis. PMID- 26629170 TI - Relationship of plasma S100B and MBP with brain damage in preterm infants. AB - To study the relationships of MBP and S100B with PVH-IVH and PVL in preterm infants. 385 cases of preterm infants, whose gestational age was less than 34 weeks, were enrolled in the study. The plasma levels of S100B and MBP were detected within 24 hours and on the 3rd, 7th, 14th day after birth. Cranial ultrasound was preformed 2-3 d, 1 week, 2 weeks, 3 weeks and 4 weeks after birth. They also received Cranial MRI examination before discharge or when the correct gestational age reached 40 weeks. According to the exclusion standard, 73 cases were excluded. The included 312 cases were divided into 3 groups (no brain damage group, PVH-IVH group and PVL group) according to the result of cranial ultrasound and MRI. The differences of plasma levels of S100B and MBP among groups were compared, and the relationships of the plasma levels of S100B and MBP with gestational age in no brain damage group were analyzed. The results of cranial ultrasound and/or MRI showed: 204 cases had no brain damage (enrolled in no brain damage group); 69 cases had PVH-IVH (enrolled in PVH-IVH group); 27 cases had PVL and 12 cases had PVL and PVH-IVH (both enrolled in PVL group). The plasma level of S100B: within 24 h and on the 3rd d after birth, the serum levels of S100B in PVH-IVH group were significantly higher than those in no brain damage group (P < 0.05); and the plasma levels of S100B in PVL group were significantly higher than those in no brain damage group and PVH-IVH group (all P < 0.05). On 7th d and 14th d after birth, there were no significant differences between PVH-IVH group and no brain damage group (P > 0.05); and the plasma levels of S100B in PVL group were still significantly higher than those in no brain damage group and PVH-IVH group (all P < 0.05). The plasma levels of MBP: within 24 h and on the 3rd d, 7th d and 14th d after birth, there were no significant differences between PVH-IVH group and no brain damage group (all P > 0.05); and the plasma levels of MBP in PVL group were significantly higher than those in no brain damage group and PVH IVH group (all P < 0.05). Correlation analysis of gestational age and S100B, MBP: the plasma level of S100B in no brain damage group had a negative correlation with gestational age (r = -0.483, P = 0.006), and that of MBP had no correlation with gestational age (r = -0.295, P = 0.105). The plasma levels of S100B and MBP increased significantly in preterm infants with brain damage within 24 h after birth, and the plasma levels of S100B and MBP in PVL infants were higher than those in PVH-IVH infants. The increased plasma levels of S100B and MBP in PVL infants lasted longer than in PVH-IVH infants. The increased plasma levels of S100B and MBP in preterm infants would have certain clinical significance for judging whether early brain damage and PVL would happen. PMID- 26629171 TI - Metabolic products in urine of preterm infants characterized via gas chromatography-mass spectrometry. AB - OBJECTIVE: To characterize the metabolic products of urine associated with preterm birth, thus providing clinical guidelines for intestinal and parenteral nutrition in preterm infants. METHODS: Urine samples of 47 preterm infants and 45 full-term infants were collected and prepared for trimethylsilylation by treatment with urease. The levels of lysine, phenylalanine, histidine, ornithine, fumaric acid, malic acid, succinic acid, lactose, stearic acid, and 4 hydroxyphenylacetic acid were detected by gas chromatography-mass spectrometry (GC/MS), and statistically analyzed. RESULTS: The normalized concentrations of the following metabolites in preterm infant urine samples were significantly lower than that of full-term infant urine samples: lysine (P = 0.003), phenylalanine (P = 0.001), histidine (P = 0.006), ornithine (P = 0.000), fumaric acid (P = 0.002), malic acid (P = 0.006), succinic acid (P = 0.000), lactose (P = 0.000), stearic acid (P = 0.000) and 4-hydroxyphenylacetic acid (P = 0.000). CONCLUSIONS: The results of the GC/MS analysis indicated that amino acid, carbohydrate, and fatty acid metabolism defects exist in preterm infants. The use of GC/MS to determine metabolic products in urine samples could be helpful for prospectively evaluating the nutritional status of preterm infants, and therefore providing clinical guidelines on reasonable nutritional support. PMID- 26629172 TI - Effect of cardiac shock wave therapy on the microvolt T wave alternans of patients with coronary artery disease. AB - OBJECTIVE: The aim of this study was to evaluate the effect of cardiac shock wave therapy (CSWT) on microvolt T wave alternans (MTWA) in patients with coronary artery disease (CAD). METHODS: 87 patients with old myocardial infarction (OMI) were enrolled in this study. Sixty-two patients were randomized into the CSWT group, 32 patients into the regular treatment group (Group A) according to different shock wave procedure, and 30 into the expanding scope treatment group (Group B), and 25 patients were randomized into the control group (Group C). But the shock wave (SW) energy was only applied to the patients in the CSWT group and not to the patients in the control group. Three months was a treatment course, thus patients received a total of 9 CSWT treatment sessions. RESULTS: Technetium 99m sestamibi myocardial perfusion, fluorine-18 fluorodeoxyglucose myocardial metabolism single-photon emission computed tomography (SPECT) were performed to identify segments of myocardial ischemia, myocardial viability, and microvolt T wave alternans (MTWA) before and after CSWT. After CSWT, the rehospitalization rates of CSWT group were lower than control group (P<0.05). The myocardial ischemic segments, metabolism abnormal segments, total radioactive score of perfusion imaging and metabolism imaging, MTWA, and MTWA/HR in CSWT group were reduced significantly (P<0.05). And the heart rate of maximum MTWA, exercise time were increased significantly (P<0.05). All of the parameters in the control group did not change significantly even worsen after the treatment (P>0.05). CONCLUSIONS: CSWT can reduce the MTWA value, improve the heart chronotropic function and increase the threshold of frequency which causes MTWA. PMID- 26629173 TI - Correlation between body mass index and clinicopathological features of papillary thyroid microcarcinoma. AB - OBJECTIVES: To demonstrate the relationships between body mass index (BMI) and the clinicopathological features of papillary thyroid microcarcinoma (PTMC) and papillary thyroid carcinoma (PTC). METHODS: A total of 810 consecutive patients with PTC (501 patients with PTMC) who underwent total thyroidectomy in 2009-2013 were retrospectively reviewed. Height and weight were used to calculate BMI. RESULTS: Increased BMI was strongly associated with i) extrathyroidal invasion (P < 0.001) and advanced TNM stage (P = 0.005) in patients with PTMC (n = 501), and ii) extrathyroidal invasion (P = 0.001), advanced TNM stage (P = 0.001), and multifocality (P = 0.002) in patients with PTC (n = 810). As compared with normal weight patients with PTMC, obese patients with PTMC had greater risks of extrathyroidal invasion (OR = 5.214, P = 0.0270), and overweight patients with PTMC had greater risks of extrathyroidal invasion (OR = 2.165, P = 0.0013) and advanced TNM stage (OR = 2.019, P = 0.0137). As compared with normal-weight patients with PTC, obese patients with PTC had greater risks of extrathyroidal invasion (OR = 3.101, P = 0.0172), and overweight patients with PTC had greater risks of extrathyroidal invasion (OR = 1.486, P = 0.0279), advanced TNM stage (OR = 1.650, P = 0.0347), and multifocality (OR = 1.651, P = 0.0054). CONCLUSIONS: Increased BMI might elevate the risks of aggressive clinicopathological features, such as extrathyroidal invasion and advanced TNM stage. Obesity control may play an important role in preventing the development of aggressive PTMCs and all PTCs. PMID- 26629174 TI - Moxibustion with Chinese herbal has good effect on allergic rhinitis. AB - Allergic rhinitis (AR) is a chronic inflammatory disease of rhino-ocular mucosa, affecting up to 40% of population worldwide. Chinese herbal medicines and Acupuncture, adopted thousands of years in China, has good effect on allergic rhinitis. This study evaluates the effects of Moxibustion with Chinese herbal in treating patients with allergic rhinitis over a 1-year follow-up. A randomized controlled trial was conducted in a sample of 355 participants recruited from Guangdong general hospital of China. After baseline measurements, participants were randomly assigned to treatment-group or control group. Treatment group received Moxibustion with Chinese herbal. Control group received Loratadine. The main outcomes, including symptom severity and quality of life were measured using the Allergic Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). Both moxibustion with Chinese herbal and Loratadine improve nose symptoms such as stuffy/blocked, sneezing, runny nose, itchy nose, sore nose and post-nasal drip in patients with AR. Symptoms fatigue, loss of taste, afraid of cold/wind and cold limb were improved significantly in moxibustion with Chinese herbal group. The mean quality of life scores decreased in both groups after treatment. Compare to control group, moxibustion with Chinese herbal is more effective than Loratadine in improving the quality of life in patients with AR. The results show moxibustion with Chinese herbal was effective to reduce symptoms and enhance quality of life in patients with allergic rhinitis. It is a simple, convenient and economic therapy for patients with AR. Further controlled trials of its effects in patients with allergic rhinitis are recommended. PMID- 26629175 TI - Analysis of high risk factors and characteristics of coronary artery in premenopausal women with coronary artery disease. AB - OBJECTIVE: The aim of this study was to explore the high risk factors and coronary lesion features in premenopausal women with coronary artery disease (CAD) and provide guideline for diagnosis and therapy. METHODS: 114 premenopausal women and 134 postmenopausal women were conducted coronary angiography in our hospital from September, 2012 to September, 2014. According to the results of coronary angiography, premenopausal and postmenopausal women with coronary artery disease were divided into two groups respectively, including 48 premenopausal women with CAD group, 66 premenopausal women with normal coronary artery group, 76 postmenopausal women with CAD group and 58 postmenopausal women with normal coronary artery group. Clinical characteristics and coronary lesion features were analyzed. RESULTS: Incidence rates of hypertension disease and diabetes were higher in premenopausal women with CAD group than control group. Most of premenopausal women suffered from single vessel lesion and the length of impaired vessel was less than 20 mm, meanwhile, postmenopausal women easily confronted from double vessels or mutivessle lesion and the length of impaired vessel was more than 20 mm. Left anterior descending coronary artery lesion was common for premenopausal women. CONCLUSION: Hypertension disease and diabetes were the main high risk factors for premenopausal women and high triglyceride was the optimal predictable factor, furthermore, single vessel lesion and short artery lesion were common in premenopausal women, which often happened in the anterior descending coronary artery. PMID- 26629176 TI - Establishment of lymphatic filarial specific IgG4 indirect ELISA detection method. AB - OBJECTIVE: To establish the lymphatic filarial specific IgG4 indirect ELISA detection method and develop the kits. METHODS: ELISA and the developed specific IgG4 reagent was used to explore the best way for detecting filarial specific IgG4. Combined with the production process of commercialized enzyme immunoassay kit to develop economical lymphatic filarial specific IgG4 test kit, and to explore the value of the kit in the laboratory. RESULTS: We determined the most optimal detective antigen was Malay adult filarial antigen and the optimal concentration of coating antigen was 1.0 MUg/ml. The appropriate serum dilution was 1:20 to 40 and the work titers of specific IgG4 agents was 1:800. We determined the optimal reaction time for substrates and developed a reproducible and stable detection kit with sensitive and specificity, which was easy to operate. CONCLUSION: We successfully established the lymphatic filarial specific IgG4 indirect ELISA detection method and developed the kits with good reproducibility and stable result, which should be widely applied. PMID- 26629177 TI - Clinical utility of a near patient care microarray based diagnostic test for influenza and respiratory syncytial virus infections. AB - In primary care medicine, establishing a diagnosis of influenza and respiratory syncytial virus (RSV) infections is usually based on clinical history and physical examination as well as a consideration of time of the year and circulating respiratory viruses in the community. METHODS: We tested the potential clinical samples using the automated molecular assay which included rapid influenza diagnostic test, Rapid Immunochromatographic Antigen Test, Verigene Respiratory Virus Plus Nucleic Acid Test, BD Veritor(TM) System for Rapid Detection of RSV in the paediatric setting for diagnosis of influenza and respiratory syntactical virus infections when testing was done by the paediatrician seeing the patient. RESULTS: Principally, with respect influenza virus specificity and sensitivity for RIAT were 100% and 68.8%; compared to 100% and 100%, respectively for RV(+). The specificity and sensitivity for 92.23% and 98% for BD Veritor(TM) System for Rapid Detection of RSV as compared to 96.6% and 98.42% for RIDT. CONCLUSION: Therefore, this study confirms the clinical utility of RV(+) in the pediatric setting. PMID- 26629178 TI - Laboratory-based evaluation of MDR strains of Pseudomonas in patients with acute burn injuries. AB - Localization of burn was variable: head and face in 76 patients (29%), trunk in 58 (49%), upper limb in 37 (52%), lower limbs in 44 (41%), hands in 16 (15%), perinea area in 26 (5.5%) and whole body except perinea area in 10 (9%) patients. Inhalation syndrome was present in 56 (44%) patients. Ninety patients (82%) had indwelling venous catheters, 83 (75.5%) patients' arterial catheter and 86 (78%) patients' urinary catheters. By multivariate analysis: age <=4 years, Garces 4, colistin use in documented multiresistant infections, and mechanical ventilation were independent variables related with mortality and graft requirement was a protective factor for mortality. Despite advances in care, gram negative bacterial infections and infection with Pseudomonas aeruginosa remain the most common cause of bacteria related mortality early in the hospital course. Viral infections are also associated with mortality and numbers have remained stable when compared to data from prior years. PMID- 26629179 TI - Association between ErbB3 genetic polymorphisms and coronary artery disease in the Han and Uyghur populations of China. AB - BACKGROUND: ErbB3 is a member of the epidermal growth factor receptor (EGFR/ERBB) family of receptor tyrosine kinases. Recent research has shown that amplification of this gene is related to prostate, bladder and breast cancers, as well as low density lipoprotein cholesterol (LDL-C) metabolism. LDL-C plays a considerable role in the development of cardiovascular disease. Thus, the present study assessed the association between human ErbB3 gene polymorphisms and coronary artery disease (CAD) in Han and Uygur populationsin China. METHODS: We performed two independent case-control studies with a Han population (339 CAD patients and 395 control subjects) and a Uygur population (306 CAD patients and 325 control subjects). All of the CAD patients and controls were genotyped for the same three single nucleotide polymorphisms (rs877636, rs705708, and rs10783779) in the ErbB3 gene by real-time PCR. RESULTS: In the Han population, rs877636 polymorphisms were associated with CAD on the basis of the genotypes, dominant model, additive model, and allele frequency (for genotypes: P = 0.008; for dominant model: P = 0.003; for additive model: P = 0.004; for allele: P = 0.008), and these significant difference was retained (all P < 0.05) after adjusting for the major confounding factors. CONCLUSION: The CT genotype and C allele of rs877636 in the ErbB3 gene could be a genetic marker of CAD risk for the Han population in China. PMID- 26629180 TI - Identification of an SCLC susceptibility rs7963551 genetic polymorphism in a previously GWAS-identified 12p13.33 RAD52 lung cancer risk locus in the Chinese population. AB - As a well-known DNA repair gene, RAD52 plays an essential role in homologous recombination repair of double strand break, maintenance of genomic stability and prevention of cell malignant transformation. Previous genome-wide association studies (GWASs) have identified common genetic variants at 12p13.33 RAD52 locus associated with lung cancer risk in Caucasians. However, little or nothing has been known about the RAD52 single nucleotide polymorphisms (SNPs) in small cell lung cancer (SCLC) in the Chinese population. As a result, we examined the association between six RAD52 SNPs (rs10849605, rs1051669, rs10774474, rs11571378, rs7963551 and rs6489769) and SCLC susceptibility in Chinese. After 520 SCLC cases and 1040 controls in two independent case-control sets were genotyped, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. We found that only the RAD52 rs7963551 SNP was significantly associated with SCLC risk among six RAD52 SNPs genotyped. The odds of having the rs7963551 CA genotype in SCLC patients was 0.38 (95% CI = 0.24 0.62, P = 1.1*10(-4)) compared with the CC genotype. Stratified analyses of association between rs7963551 SNP and SCLC risk indicated that the functional polymorphism was only significantly associated with decreased risk among smokers but not nonsmokers. Our results demonstrated that the functional RAD52 rs7963551 SNP contributes to susceptibility to developing SCLC in the Chinese population. PMID- 26629181 TI - Isorhamnetin attenuates collagen-induced arthritis via modulating cytokines and oxidative stress in mice. AB - Inflammation and oxidative stress were involved in the development and progression of rheumatoid arthritis (RA). Isorhamnetin has anti-inflammatory and anti-oxidative activities, but its effects on RA have not been investigated. In order to observe the possible therapeutic effects of isorhamnetin on RA, we established a collagen-induced arthritis mouse model and treated the animal with isorhamnetin for 3 weeks. Besides, fibroblast-like synoviocytes (FLS) were treated with lipopolysaccharide (LPS) and isorhamnetin. The severity of arthritis was assessed by arthritis score, joint destruction score and inflammation score. Levels of cytokines TNF-alpha, IL-1beta, IL-6, IL-17A, IL-17F, IL-10 and IL-35 in the joint tissue homogenate and cell culture medium as well as anti-type II collagen antibody in serum were measured using ELISA. Contents of H2O2 and malondialdehyde (MDA) in joint tissue homogenate were measured using assay kits. We found collagen immunization induced significant arthritis in mice and isorhamnetin at the dose of 10 and 20 mg/kg/day could significantly attenuate the collagen-induced arthritis. Isorhamnetin also modulated the production of cytokines and suppressed the oxidative stress in the mice with collagen-induced arthritis at the dose of 10 and 20 mg/kg/day. These data suggested that isorhamnetin might be a potential agent for the management of RA. PMID- 26629182 TI - Laparoscopic surgery inhibits the proliferation and metastasis of cervical cancer cells. AB - AIMS: The present study is to investigate the effect of laparoscopic surgery on the proliferation and metastasis of cervical cancer cells. METHODS: A total of 40 patients with phase I squamous cell carcinoma of the cervix were enrolled in the study, and divided evenly into laparoscopic surgery group and laparotomy group. In addition, another 20 patients with benign uterine lesions received laparoscopic panhysterectomy using celoscopes and were enrolled as control group. Cell apoptotic rates were determined using flow cytometry. The expression of N myc, Fas, metastasis-associated gene 1, and nm23-H1 genes in tissues were measured using quantitative real-time polymerase chain reaction. RESULTS: Cervical cancer cell apoptosis was promoted by laparoscopic surgery, but not affected by laparotomy. The expression of apoptosis suppressor gene N-myc in cervical cancer cells was reduced by laparoscopic surgery, but not affected by laparotomy. In addition, the expression of apoptosis promoting gene Fas in cervical cancer cells was enhanced by laparoscopic surgery, but not affected by laparotomy. Similarly, the expression of metastasis promoting gene MTA1 in cervical cancer cells was lowered by laparoscopic surgery, but not affected by laparotomy. Moreover, the expression of metastasis suppressor gene nm23-H1 in cervical cancer cells was increased by laparoscopic surgery, but not affected by laparotomy. Of note, laparoscopic panhysterectomy had no effect on the apoptosis or the expression of N-myc, Fas, MTA1 and nm23-H1 genes in normal cervical cells. CONCLUSIONS: Laparoscopic surgery is a safe treatment method for cervical cancer. It inhibits the proliferation and metastasis of cancer cells, but has no such effects on normal cells. PMID- 26629183 TI - Application of combined rigid choledochoscope and accurate positioning method in the adjuvant treatment of bile duct stones. AB - To explore the clinical effect of percutaneous transhepatic cholangioscopic lithotomy (PTCSL) combined with rigid choledochoscope and accurate positioning in the treatment of calculus of bile duct. This study retrospectively reviewed 162 patients with hepatolithiasis at the First Affiliated Hospital of Guangzhou Medical University between 2001 and 2013 were assigned to hard lens group or traditional PTCSL group. Compared with the traditional PTCSL, PTCSL with rigid choledochoscope can shorten the interval time which limit the PTCSL application. The operation time (45 vs 78, P=0.003), the number of operation (1.62 vs 1.97, P=0.031), and blood loss (37.8 vs 55.1, P=0.022) were better in hard lens group while the stone residual and complication had no significant differences. Rigid choledochoscope is a safe, minimally invasive and effective method in the treatment of bile duct stones. Accurate positioning method can effectively shorten operation process time. PMID- 26629184 TI - Reduction of intraocular pressure and improvement of vision after cataract surgeries in angle closure glaucoma with concomitant cataract patients. AB - OBJECTIVE: This study is to compare the efficacy of three different cataract surgeries in eyes with angle closure glaucoma (ACG) with concomitant cataract. METHODS: A retrospective comparative analysis of 106 ACG patients (112 eyes) with concomitant cataract was conducted between February, 2012 and February, 2014. Clinical outcomes of ACG patients with concomitant cataract underwent phacoemulsification and intraocular lens implantation (group A, n = 34, 36 eyes, angle closure < 180 degrees ); combined phacoemulsification, intraocular lens implantation, and goniosynechialysis (group B, n = 43, 45 eyes, angle closure, 180 degrees ~270 degrees ); and combined phacoemulsification, intraocular lens implantation, and trabeculectomy (group C, n = 29, 31 eyes, angle closure > 270 degrees ) were compared during a 6-month follow-up. RESULTS: There were no statistical differences among the 3 groups in pre-operative or post-operative average visual acuity (VA), intraocular pressure (IOP), anterior chamber depth (ACD), and angle opening distance (AOD) (all P > 0.05). Post-operative VA, IOP, ACD, AOD and the degree of angle opening in the 3 groups were all improved as compared with pre-operative levels (all P < 0.05). No statistical difference was detected among the 3 groups in the incidence of complications (chi(2) = 0.376, P = 0.829). CONCLUSION: Phacoemulsification alone, combined phacoemulsification/goniosynechialysis, and combined phacoemulsification/trabeculectomy provide safe, effective, predictable, and stable options of cataract surgery for treatment of ACG with concomitant cataract. PMID- 26629185 TI - The end-of-treatment telephone response and prognosis of post-radiotherapy nasopharyngeal carcinoma patients in southern China. AB - Nasopharyngeal Carcinoma (NPC) patients' end-of-treatment survival status has drawn more attention in recent years. Telephone follow-up, as a most operative approach among all the clinical follow-ups, is an effective means to extend medical service to patients' home and is thus widely used in clinical practice. This study aimed to analyze the post-radiotherapy NPC patients' phone response rate and its factors, and to discuss the independent prognostic factors of NPC patients' radiotherapy. We prospectively designed a nurses-led telephone follow up to include 2520 NPC patients who received simple radical radiotherapy between Jan. 2007 and Jun. 2012 at Sun Yat-sen University Cancer Center. The patients' response rate and its factors were calculated. Survival analysis was used to estimate the patients' survival and the influencing factors. The overall response rate was 90.5%; Patients with reserved contact type of mobile + landlinephone or landline phone had higher follow-up response rate than patients with mobile contact only; patients with 2 or more reserved contacts, and family cancer history had higher response rate than patients with only 1 number and those without family history. Patients' cumulative survival rate of 1, 3 and 5 years were 98.9%, 75.3%, 50.3%, respectively. T-staging, N-staging, higher clinical staging, with basicranial invasion were the influencing factors of the patients' poor prognosis. The telephone follow-up response was affected by reserved contact type, number of contacts and family medical history; T-staging, N-staging, higher clinical staging, with basicranial invasion were the influencing factors of the patients' poor prognosis. This study provides a scientific basis for increasing the NPC patients' end-of-treatment response and promoting the individualized clinical treatment. PMID- 26629186 TI - Polymorphisms in ApoB gene are associated with risk of myocardial infarction and serum ApoB levels in a Chinese population. AB - Myocardial infarction (MI) is a serious result of coronary artery disease. Recent data from clinical trials have showed that the risk of MI was associated with high plasma apolipoprotein B (apoB) levels. Mutations in ApoB gene were also found to be associated with plasma lipid levels. The aim of this study is to evaluate the effect of ApoB polymorphisms on the risk of MI and plasma apoB levels in a Chinese population. Eight polymorphisms (rs676210, rs679899, rs3791980, rs2854725, rs11676704, rs512535, rs12720841 and rs2678379) in ApoB gene were genotyped in a case-control study in China, including 550 MI cases and 550 healthy controls. Carriers of GG genotype of rs676210 had significant increased risk of MI [odd ratio (OR) = 1.93, 95% confidence interval (CI): 1.23 3.03] compared to carriers of AA genotype. Haplotype analysis also showed that GTTGG (rs676210-rs2854725-rs11676704-rs3791980-rs2678379) haplotype had significant increased risk of MI (OR = 2.82, 95% CI: 1.49-5.33) compared with ATTGA haplotype. Furthermore, apoB rs676210 and rs2678379 polymorphisms were significantly associated with plasma levels of apoB in healthy controls (P = 0.01 and 0.02). Our findings indicated that ApoB mutations may be associated with the risk of MI and plasma ApoB levels in healthy controls in Chinese population. PMID- 26629187 TI - Effect of granulocyte colony stimulating EPC on cardiac function and myocardial energy expenditure in patients with heart failure after myocardial infarction. AB - OBJECTIVE: To study the changes of cardiac function and myocardial energy expenditure following treatment with granulocyte colony stimulating factor (G CSF) in patients with heart failure after myocardial infarction. METHODS: Thirty eight patients with heart failure after myocardial infarction were randomized into G-CSF treatment group and control group. All the patients received conventional treatment (medication and interventional therapy), and the patients in treatment group were given additional G-CSF (600 MUg/day) for 7 consecutive days. The plasma level of brain-type natriuretic peptide (BNP) and the number of endothelial progenitor cells (EPC) in the peripheral blood were detected before and at 7 days and 4 months after the treatment. The cardiac functions (LVEF, FS, LVIDs, PWTs, EDV, SV, ET) was evaluated by ultrasonic imaging before and at 2 weeks and 4 months after the treatment. The MEE and circumferential end-systolic wall stress (cESS) were calculated by correlation formula. RESULTS: The number of EPC was significantly higher in the treatment group than in the control group after the treatment especially at 7 days (P<0.01). In both groups, BNP level was lowered significantly after the treatment to recover the normal level (P<0.01). The cardiac functions and myocardial energy expenditure were improved in all the patients at 2 weeks and 4 months after the treatment, and the improvement was more obvious in the treatment group (P<0.05), especially in terms of the MEE and cESS was significantly lowered in the treatment group than in the control group after the treatment at 2 weeks (P<0.01), the LVEF and FS was significantly increased in the treatment group than in the control group after the treatment at 4 months (P<0.01). CONCLUSION: EPC mobilization by G-CSF can effectively improve the cardiac functions, lessen ventricular remodeling and reduce myocardial energy expenditure in patients with heart failure after myocardial infarction. PMID- 26629188 TI - Polymorphisms of co-inhibitory molecules (CTLA-4/PD-1/PD-L1) and the risk of non small cell lung cancer in a Chinese population. AB - Lung cancer is a leading cause of cancer-related death in China, with non-small cell lung cancer (NSCLC) comprises the most common form. Co-inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1) and its ligand PD-L1, play a key roles in the physiopathological process of tumorigenesis. To investigate whether genetic variations of co-inhibitory molecules are associated with the risk of NSCLC, we analyzed polymorphisms of CTLA-4 (-318, +49), PD-1 (PD-1.1, PD-1.3, PD-1.5, PD-1.9) and PD-L1 (+8293) in a cohort of 528 NSCLC subjects and 600 healthy controls. By restriction fragment length polymorphism (RFLP) method, we found that the distributions of the CTLA-4 and PD-1 gene polymorphisms were similar between NSCLC patients and healthy controls. However, for the PD-L1 8923 A/C polymorphism, frequencies of the AC genotype and C-allele were significantly higher in NSCLC patients than in healthy controls (odds ratio [OR] =1.55; 95% confidence interval [CI] 1.13-2.13; P=0.006; OR=1.52; 95% CI 1.14-2.04; P=0.004, respectively). Stratification analysis revealed that prevalence of the 8923C allele was significantly increased in NSCLC patients who smoke compared to those non-smoking patients (OR=1.51; 95% CI 1.00 2.28; P<0.05). Moreover, NSCLC patients carrying the C-allele had higher risk of regional lymph node metastasis than those carrying the A-allele (OR=5.65; 95% CI 2.45~13.03; P<0.001). These data suggest that PD-L1+8293A>C polymorphism may play a role in the development and progression of NSCLC. PMID- 26629189 TI - Association between rheumatoid arthritics and osteoporosis among Chinese men, a community based study. AB - BACKGROUND: The main purpose of this study was to estimate the associations between rheumatoid arthritics (RA) and osteoporosis (OP) in general Chinese men. METHODS: We conducted a large-scale, community-based, cross-sectional study to investigate the associations by using self-report questionnaire to access medical history. A total of 1041 men were recruited sis in this study. Multiple regression models controlling for confounding factors to include RA were performed to investigate the relationships for OP. RESULTS: Univariate analysis indicated there was no significant association between RA and T-score (P = 0.103), however, significant association between RA and OP was reported (P = 0.005). Multiple regression analysis indicated that RA was significantly associated with OP (P = 0.013, OR = 3.191 95% CI: 1.284-7.932). The men with RA had a significant higher prevalence of OP. CONCLUSION: The findings indicated that RA was independently and significantly associated with OP. The prevalence of OP was less frequent in Chinese men without RA. PMID- 26629190 TI - Therapeutic efficacy of intensified walk training under the electrocardiogram telemetry in stroke induced lower limb dysfunction patients with heart failure. AB - OBJECTIVES: This study aimed to explore the therapeutic efficacy of intensified walk training under the electrocardiogram (ECG) telemetry in stroke induced lower limb dysfunction patients with heart failure. MATERIAL AND METHODS: A total of 40 patients with stroke induced lower limb dysfunction and heart failure were randomized into control group and walk training group (n=20 per group). Besides comprehensive rehabilitation, patients in walk training group received intensified walk training under the ECG telemetry and patients in control group received traditional training. After 5-week treatment, the FMA score of lower limbs, ADL score, 6-min walking distance and left ventricular ejection fraction (EF) by heart ultrasonography were determined. RESULTS: There were no marked differences in the demographics between two groups at baseline, and no severe complications were observed during training in the walk training group. In control group, 6 patients developed lung edema which required further therapy. After 5-week training, the FMA score of lower limbs, ADL score and 6-min walk distance were improved to different extents, but the improvement was more obvious in walk training group (P<0.05). The left ventricular EF remained unchanged in both groups. CONCLUSIONS: In patients with stroke induced lower limb dysfunction and heart failure, routine rehabilitation in combination with additional walk training under the ECG telemetry is helpful to increase the training efficiency and training intensity and improve the low limb function and walk distance when the safety is assured. PMID- 26629191 TI - High PCA3 scores in urine correlate with poor-prognosis factors in prostate cancer patients. AB - BACKGROUND: To improve the prediction of prostate cancer (PCA) risk and pathological type of PCA by non-invasive approaches before performing prostatic biopsy are the current challenges for the management of PCA. The aim of this present study was evaluate the clinical validity of prostate cancer associated 3 (PCA3) gene in the prediction of PCA and the correlations between the PCA3 level and prognostic factors. METHODS: A total of 207 patients with suspected prostate cancer in Ningbo No. 2 hospital between June 2012 and July 2014 were enrolled in this study. All patients included underwent prostate biopsy under the direction of digital rectal examination (DRE) and were divided into PCA group and no evidence of malignancy (NEM) group according to the pathological diagnosis. We analyzed the association between PCA3 score and indicators of prognosis (Gleason score, percentage of positive cores and clinical stage) by multivariate analysis. RESULTS: The levels of total prostate-specific antigen (t-PSA), prostate health index (PHI) and PCA3 score in patients with PCA were significantly higher than those in NEM group (P<0.05). In PCA group, PHI value and t-PSA were both factors significantly correlated with high Gleason score and clinical stage (P<0.05). A high PCA3 score in urine was significantly correlated with a high Gleason score, % positive cores and an advanced clinical stage (P<0.05). CONCLUSION: PCA3 score might be one of useful diagnostic tools for determining suitable therapeutic programs for PCa and predicting the prognosis. PMID- 26629192 TI - A clinical study on the role of psychosomatic therapy in evaluation and treatment of patients with chronic obstructive pulmonary disease complicated with anxiety depression disorder. AB - This study aimed to evaluate the effect of psychotic therapy on patients with chronic obstructive pulmonary disease (COPD) complicated with anxiety-depression disorder by Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), COPD Assessment Test (CAT) and modified British Medical research Council (mMRC). Thirty-five patients with COPD were evaluated by pulmonary physicians with CAT and mMRC. They were further evaluated with HAMD and HAMA by psychologists and diagnosed and grouped into group B and D according to the Global initiative for chronic Obstructive Lung Disease (GOLD) version 2014. Patients were given psychotic therapy and followed up for at least 1 month. Comparison and analysis were performed with clinical data before and after treatment. Fourteen patients were subscribed into B group, while 21 patients were subscribed into D group, accounting for 40% and 60% respectively. After psychotic therapy, the HAMA and MAMD score of patients in both groups improved significantly (P<0.05). The CAT and Mmrc score of 8 patients in B group improved as A, while 10 patients in D group improved as B. The longest follow-up was 12 months. Symptoms were significantly alleviated after combined respiratory and psychotic therapy. COPD complicated with anxiety-depression is of high prevalence. The psychosomatic problems usually aggravate respiratory symptoms. Make better use of the evaluation methods such as HAMA, HAMA, CAT, mMRC may facilitate the treatment for patients. PMID- 26629193 TI - Diabetes, a risk factor for both infectious and major complications after percutaneous nephrolithotomy. AB - BACKGROUND: It is reported that up to one-third of patients might have some postoperative complications after percutaneous nephrolithotomy (PCNL). The predictive factors for infectious and major complications remains conflicted, which was the main objective of this study. METHODS: This was a retrospective analysis using data from enrolled 411 patients diagnosed with renal stones underwent PCNL from 2008 to 2013. The correlation between postoperative complications with demographic characteristics, comorbidities and perioperative features was analyzed by Fisher's exact test or Mann-Whitney test. Logistic regression analysis was used for assessment of risk factors associatedwith infectious and major complications. RESULTS: The mean age of 411 patients included was 53.6 years and male patients occupied 57.9%. Of all the 411 patients enrolled, 145 patients were diagnosed with systemic inflammatory response syndrome (SIRS). The comorbidity of diabetes and complete staghorn calculi were suggested to be independent risk factors for postoperative infectious complications by Logistic regression analysis. The overall complication rate was 31.1% (128/411) and 33 cases (8.0%) was categorized as major complications according to the modified Clavien score. The comorbidity of diabetes and an upper pole tract were risk factors for the occurrence of major complications after PCNL. CONCLUSIONS: The comorbidity of diabetes was significantly associated with an increasing incidence of both infectious and major postoperative complications after PCNL. PMID- 26629194 TI - Treatment results in different surgical approaches for intraspinal tumor in 51 patients. AB - To investigate the treatment results for the different surgical approaches for intraspinal tumor in lumbar spine. We retrospectively reviewed data for 51 patients with intraspinal tumors who were treated with surgery. We used the navigation system (group A) or traditional method (group B) to guide the surgery. Through the comparison of group A (22 patients) and group B (29 patients), we found some differences between the two groups, such as their total resection rate, the placement of pedicle screws, the mean operating time, intraoperative operation loss, JOA scores. In group A, the total resection rate was 95.45%. One hundred and ten pedicle screws were implanted, and no screw injured the nerve tissues or blood vessel; the placement of 94.55% of the pedicle screws was excellent. In group B, the total resection rate was 86.28%. A total of 134 pedicle screws were implanted, including five screws that injured nerve tissues or blood vessels; the placement of 87.31% of the pedicle screws was excellent. The postoperative symptoms were significantly improved in the two groups, and there were no deaths. The operation times were significantly lower in group A than in group B (P < 0.05), and the intraoperative operation loss was significantly lower in group A than in group B (P < 0.01). Additionally, the postoperative improvement in percent evaluated by Japan Orthopaedic Association (JOA) back pain evaluation questionnaire was significantly higher in group A than in group B (P < 0.05). The navigation system can provide crucial help in the treatment of spinal operation as an assisted method, which has great potential to improve the accuracy and safety. PMID- 26629195 TI - Clinical features and prognosis of adult-onset Still's disease: 75 cases from China. AB - This study evaluated the clinical characteristics, treatment outcomes, and complications of patients with adult onset Still's disease (AOSD) in our local Chinese population. Patients with AOSD attending our hospital from 2008 to 2011 were identified and followed up. Their clinical and laboratory features at presentation, as well as their disease progression, treatments, and outcomes were recorded and compared with other reported series. A total of 75 patients with AOSD were identified. Forty-four were female. Thirty-nine had disease onset between 16 and 35 years of age. The most common presenting features were fever (96%), arthritis (57.33%), rash (78.67%), and sore throat (49.3%). The acute phase response was marked in most patients, with elevated erythrocyte sedimentation rates (77.05%) and C-reactive protein levels (84.06%). Hyperferritinemia was present in 74.14% of cases, and serum ferritin (SF) levels declined after treatment in most cases. Liver abnormalities were usually transient, but were more severe in 5 patients. Most patients (92%) required corticosteroid therapy; of these, 33.3% also received disease-modifying antirheumatic drugs or immunosuppressive drugs. Sixty-four and 45.33% patients with AOSD achieved partial and complete remission, respectively, after 2 weeks of treatment, and 92% and 74.67%, respectively, after 1 month. The cumulative relapse rate was 45.3%. Patients with AOSD had complex symptoms with no specific laboratory findings. Reduced SF levels after treatment and liver abnormalities may be used to follow treatment outcome. PMID- 26629196 TI - Comparative analysis of intestinal parasitic infections of outpatients in Guangxi medical university affiliated hospital in 2005 and 2013. AB - OBJECTIVE: To understand the hospital's status and trends of intestinal parasitic infections and to provide a reference for prevention. METHODS: Stool samples were treated by acid-ether centrifugation; iodine staining and direct-smearing were performed; intestinal parasites were examined under a microscope; characteristics of parasitic infections in population were analyzed using the descriptive epidemiological method. RESULTS: 10 kinds of parasites were detected; the infection rate of clonorchissinensis was the highest, followed by B. hominis, hookworm, whipworm and roundworm in order (x(2) = 131.188, 1261.928, 129.386, P < 0.01); The overall infection rates in 2013 and 2005 were 37.08% and 41.07% respectively, and the infection rate in 2013 was lower than that in 2005 (x(2) = 20.5003, P < 0.01); All the infection rates of clonorchissinensis, hookworm, whipworm and roundworm in 2013 were lower than those in 2005 (x(2) = 18.275, 45.449, 34.855, 12.435, P < 0.01); Both in 2005 and 2013, the male infection rate was higher than that in female (x(2) = 12.859, 24.924, P < 0.01); For male, the infection rate of clonorchissinensis was the highest, followed by B. hominis (x(2) = 313.621, 104.409, P < 0.01); for female, the infection rate of B. hominis was the highest, followed by clonorchissinensis (x(2) = 95.293, 43.357, P < 0.01). For male, the age group of 41~ had the highest infection rate of clonorchissinensis in 2005 (x(2) = 5.734, P < 0.05), and the age groups of 31~ and 41~ had the highest infection rate of clonorchissinensis in 2013 (x(2) = 8.908, P < 0.01); for female, both in 2005 and 2013, the age group of 21~, 31~, 41~ and 51~ had the highest infection rate of clonorchissinensis (x(2) = 6.508, 5.145, P < 0.05). There was no difference in male infection rate of B. hominis in 2005 (x(2) = 10.134, P > 0.05); in 2013, the age group of 0~ had the highest infection rate (x(2) = 3.825, P < 0.05); for women, it was the highest in the age groups of 11~, 21~ and 31~ in 2005 (x(2) = 10.459, P < 0.01), 0~ and 11~ in 2013 (x(2) = 53.669, P < 0.01). For Hookworm infection in male, the highest infection rate was found in the age group of 11~ 21~ and 61~ in 2005 (x(2) = 4.547, P < 0.05), 61~ and >= 71~ in 2013 (x(2) = 4.843, P < 0.05); for female, the highest infection rate was found in the age groups of 51~ and 61~ both in 2005 and 2013 (x(2) = 5.709, 5.958, P < 0.05). CONCLUSION: In Nanning city, although there was a decline in the infection rate of intestinal parasites of attenders compared with 8 years ago, the infection rate was still high and intestinal parasites were various; The infection rate of geohelminthes had been reduced to a low level; Clonorchissinensis and B. hominis were still the insect species with the highest infection rate. PMID- 26629197 TI - Associated factors of radiation pneumonitis induced by precise radiotherapy in 186 elderly patients with esophageal cancer. AB - BACKGROUND: Radiation pneumonitis is one of the most severe complications of esophageal cancer. PURPOSE: To explore the factors correlated to radiation pneumonitis induced by precise radiotherapy for elderly patients with esophageal cancer. METHODS: The retrospective analysis was used to collect clinical data from 186 elderly patients with esophageal cancer. The incidence of radiation pneumonitis was observed, followed by statistical analysis through ANVON or multiple regression analysis. RESULTS: 27 in 186 cases of esophageal cancer suffered from radiation pneumonitis, with incidence of 14.52%. The single factor analysis showed that, Karnofsky performance status (KPS) score, chronic obstructive pulmonary disease, concurrent chemoradiotherapy, gross tumor volume (GTV) dose, lung V20, mean lung dose (MLD) and planning target volume (PTV) were associated with radiation pneumonitis. The logistic regression analysis indicated that, concurrent chemoradiotherapy, GTV dose, lung V20 and PTV were the independent factors of radiation pneumonitis. CONCLUSION: The concurrent chemoradiotherapy, GTV dose, lung V20, MLD and PTV are the major risk factors of radiation pneumonitis for elderly patients with esophageal cancer. PMID- 26629198 TI - Recent epidemiological and clinical features of acute hepatitis B in a single center of China. AB - AIM: This study was to investigate the epidemiological and clinical features of acute hepatitis B. METHODS: A retrospective study of 177 acute hepatitis B patients with an average age of 36.03 years and range of 7-62 years was conducted from Jan 2005 to Feb 2011. The epidemiological and clinical parameters were investigated. The serological markers and biochemical tests were examined. RESULTS: 76.84% (n = 136) patients were icteric type, while 23.16% (n = 41) were non-icteric type. Other clinical manifestations for acute hepatitis patients included fatigue (82.49%), gastrointestinal symptoms (66.10%), yellowish discoloration of skin and sclera, fever (31.07%), rash 10 (5.65%), joint pain (2.82%) and headache (1.69%). One case presented with acute renal failure associated with acute hepatitis B. Nine cases suffered from fulminant hepatitis. After treatment, hepatic function was significantly improved (P < 0.05). For serological markers, 54 (30.51%) and 119 (67.23%) patients had HBsAg and HBV-DNA seroconversion respectively. Four deaths occurred due to the severe complications associated by acute infection of HBV during half a year period follow up. CONCLUSIONS: Adult males with occupation of workers and farmers are the high-risk population of acute hepatitis B in China. Several complications associated with acute hepatitis B should be noticed. PMID- 26629199 TI - Role of IL-1beta, IL-6, IL-8 and IFN-gamma in pathogenesis of central nervous system neuropsychiatric systemic lupus erythematous. AB - We discussed the role of IL-1beta, IL-6, IL-8 and IFN-gamma in the pathogenesis of central nervous system neuropsychiatric systemic lupus erythematous (CNS NPSLE). Serum and cerebrospinal fluid samples were collected from CNS-NPSLE patients, non-CNS SLE patients, patients with intracranial infection and normal subjects. Levels of IL-1beta, IL-6, IL-8 and IFN-gamma in serum and cerebrospinal fluid were detected by ELISA, and the results were compared across the groups. All subjects received cerebral MRI. The risk threshold for each cytokine in CNS NPSLE group was set as 2.5%. The positive rates of cytokines for different lesions in cerebral MRI findings in CNS-NPSLE group were compared. The correlations between cytokine levels and cerebral MRI findings were analyzed. All groups did not show significant differences in age and gender (F=1.34, P>0.05; x (2)=2.05, P>0.05); The IL-1beta, IL-6, IL-8 and IFN-gamma levels of serum and cerebrospinal fluid in CNS-NPSLE group were obviously higher than those of the normal control (serum Z14 =6.22, 6.04, 6.22, 5.70; cerebrospinal fluid Z14 =6.38, 7.10, 6.97, 6.34, P<0.0083); IL-1beta, IL-6 and IL-8 levels of cerebrospinal fluid of CNS-NPSLE group were higher than those of the non-CNS SLE group (Z12 =2.73, Z12 =3.18, Z12 =3.86; P<0.0083); IL-1beta, IL-6, IL-8 and IFN-gamma levels of cerebrospinal fluid of CNS-NPSLE group were higher than those of the serum (Z=3.19, 6.30, 5.44, 3.19, P<0.05); IL-6>20.0679 pg/ml and IL-8>87.1811 pg/ml in the cerebrospinal fluid predicted a higher risk of CNS-NPSLE (x (2)=11.98, P<0.05; x (2)=4.65, P<0.05); The positive rates of IL-1beta and IL-6 in the cerebrospinal fluid of CNS-NPSLE patients with demyelinating diseases were considerably higher than those of CNS-NPSLE patients with normal MRI findings (x (2)=10.89, P<0.005; x (2)=18.47, P<0.005). The positive rates of IL-6 and IFN gamma in the cerebrospinal fluid of CNS-NPSLE patients presenting with multiple ischemic foci were significantly higher than those with normal MRI findings (x (2)=5.56, P<0.005; x (2)=14.59, P<0.005). Some cytokines are involved in the pathogenesis of CNS-NPSLE and correlated with cerebral MRI findings in CNS-NPSLE. PMID- 26629200 TI - Age and the neuromuscular blockading effects of cisatracurium. AB - PURPOSE: To investigate the influence of age on the neuromuscular blocking effect of cisatracurium. METHODS: 90 patients with ASA I and II were assigned to the following groups according to their age: adults, children, and infants. Each group was subdivided into three subgroups according to the first dose of cisatracurium. Patients were administrated at a first dose of cisatracurium randomly, and their responses to train-of-four (TOF) stimulation were observed. When the same degree of the first response (T1) continuously repeats three times, the percentage of T1 inhibition was recorded, and the curve of dose-effect relationship and ED95 were calculated. A second dose of cisatracurium was then administrated (total volume 100 MUg/kg). The recovery phase in each patient was observed upon T1 reaching the maximum blocking effect (100%). RESULTS: Once the maximum blocking effect was reached, patients were intubated. There were 83 cases (92.2%) of patients with grade 1 and 7 (7.8%) patients with grade 2 intubating conditions. ED95 was 59.29, 55.88 and 45.39 MUg/kg in adults, children, and infants, respectively. ED95 positively correlated with age. The clinical duration of neuromuscular blockade, effective action duration of neuromuscular blockade, and in vivo action duration of neuromuscular blockade in adults was longer than that in children (P<0.05), but shorter than in infants (P<0.05). However, there were no significant differences in the recovery index among groups (P>0.05). CONCLUSION: Age influences the neuromuscular blocking effects of cisatracurium to a certain extent. PMID- 26629201 TI - Clinical features of ischemic hepatitis caused by shock with four different types: a retrospective study of 328 cases. AB - The aim of the study was to investigate the clinical features of ischemic hepatitis due to shock with four different types (allergic shock, hypovolemic shock, septic shock, and cardiogenic shock). A total of 328 patients (200 males, 128 females, mean age, 65.84 +/- 15.21 years old, range, 15-94 years) diagnosed with shock in Tongji Hospital were retrospectively investigated from Jun 2008 to Feb 2010. The parameters of liver function test, including alanine aminotransferanse (ALT), aspartate aminotransferanse (AST), lactate dehydrogenase (LDH), total bilirubin (TB), alkaline phosphatase (ALP) and gamma glutamyltransferase (gamma-GT), were recorded and analyzed. Besides, the serum levels of C-reactive protein (CRP) and brain natriuretic peptide (BNP) were also measured and relevant correlation analysis was conducted. Among all the cases, 242 (73.8%) patients developed ischemic hepatitis. The mortality of shock patients combined with ischemic hepatitis was significantly higher than the total mortality (26.0% vs 23.8%, P < 0.05). The incidence of hepatic damage was highest in the septic shock (87.5%), while the lowest in thehypovolemic shock (49.4%). The sensitivity of ALT elevation was higher than that of AST. In addition, CRP was positively correlated with the levels of liver function parameters in the septic shock and BNP was positively correlated with that in the cardiogenic shock. Ischemic hepatitis is a common complication of shock, increasing the mortality of shock patients. The septic shock is the most common cause of hepatic damage in shock patients. CRP may be a useful predictor for septic shock, while BNP may be a useful predictor for cardiogenic shock. PMID- 26629202 TI - Association of Adiponectin gene polymorphisms and nonalcoholic fatty liver disease. AB - OBJECTIVE: To investigate the correlation between Adiponectin gene polymorphisms and the genetic susceptibility of nonalcoholic fatty liver disease (NAFLD). METHODS: 357 NAFLD patients from January 2005 to December 2013 and 357 cases of healthy controls among the Han population were collected; polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect three tagSNPs (Rs2241767, rsl501299 and rs3774261) of Adiponectin. Risk factors were analyzed by multivariate logistic regression and haplotype analysis was performed using SHEsis software. RESULTS: Rs2241767, rsl501299 and rs3774261 polymorphisms were associated with the risk of NAFLD. Haplotype analysis showed that, A-T-A haplotype was a protective factor of NAFLD (OR: 0.154, 95% CI: 0.011 0.576, P = 0.004) and G-G-A (OR: 4.012, 95% CI: 2.118-10.324, P < 0.001) and G-T G (OR: 5.219, 95% CI: 2.751-12.651, P < 0.001) haplotype was risk factors of NAFLD. CONCLUSION: There was an association between Adiponectin gene polymorphisms and the genetic susceptibility of NAFLD. PMID- 26629203 TI - Risk factors of nosocomial bloodstream infections in surgical intensive care unit. AB - BACKGROUND: Many studies have examined risk factors of nosocomial bloodstream infections. However risk factors of nosocomial bloodstream infections in surgical intensive care unit have never been reported. The aim of this study was to investigate this topic. METHODS: Retrospective surgical intensive care unit patients' data were collected in a tertiary hospital from January 2010 to August 2014. Infected and non-infected patients were compared with univariate analysis of categorical variables to obtain statistical significance risk factors. Then multivariate logistic regression analysis was performed to acquire the final risk factors. RESULTS: 98 patients were diagnosed with nosocomial bloodstream infections in total. Mortality rate was 29.6% (n=29). The data indicated gram positive cocci were the main pathogens (64.3%; n=63). Multivariate logistic analysis indicated that age (>65 years old) (OR, 2.297; CI95, 0.870 to 6.062), acute physiology and chronic health evaluation II score (>18) (OR, 6.981; CI95, 2.330 to 15.865), multiple organ dysfunction score (>8) (OR, 9.857; CI95, 6.395 to 19.505), mechanical ventilation (OR, 4.583; CI95, 2.134 to 10.956), central venous catheter (OR, 5.875; CI95, 2.212 to 13.456) and selective surgery (OR, 3.455; CI95, 3.442-9.235) were risk factors of nosocomial BSI. CONCLUSIONS: Patients with nosocomial bloodstream infections in surgical intensive care unit setting often have a poor prognosis. Age (>65 years old), chronic health evaluation II score (>18), multiple organ dysfunction score (>8), usage of mechanical ventilation, central venous catheter and selective surgery can be regarded as risk factors. PMID- 26629204 TI - Application of seamless care service with multidisciplinary diagnosis and treatment in patients with gestational diabetes. AB - BACKGROUND: The objective of this article was to explore the effect of trinity seamless care service (TSCS) in patients with gestational diabetes with multidisciplinary diagnosis and treatment (MDT), and thus, to provide basis for improvement in the quality of patient care. MATERIALS AND METHODS: A total of 200 patients were recruited and randomly divided into observation group and control group with 100 cases in each group, who were diagnosed with gestational diabetes through oral glucose tolerance test (OGTT) at 24 to 28 weeks of gestation from September 2012 to September 2014. In order to control blood glucose and weight, patients in the control group received routine treatment and nursing after diagnosis, while those in the observation group received TSCS with MDT. Rate of insulin usage, weight changes and glycemic indexes before and after nursing were compared within the two groups during pregnancy. RESULTS: Compared with the pregnant patients in the control group, the rate of those in the observation group who needed extra insulin to control blood glucose, or the change of body mass index during pregnancy (DeltaBMI) >=6 kg/m(2) and less average weight gain prior to delivery was significantly lower (P<0.05). Glycemic indexes in the observation group after nursing were significantly lower than those in the control group (P<0.05). Incidences of cesarean delivery, polyhydramnios, gestational hypertension and postpartum hemorrhage in the observation group were significantly lower than those in the control group (P<0.05). Incidences of macrosomia, hyperbilirubinemia, fetal distress, stillbirth and teratogeny in the observation group were also significantly lower than those in the control group (P<0.05). CONCLUSION: Application of TSCS with MDT in patients with gestational diabetes helps to keep appropriate weight gain, control blood glucose by improving glycemic indexes, significantly reduce the incidences of maternal perinatal and neonatal complications and improve pregnancy outcomes. PMID- 26629205 TI - The inflammatory response of two different kinds of anesthetics on vascular cognitive impairment rats and the effect on long term cognitive function. AB - Vascular cognitive impairment, caused by vascular injury and inflammation, affects brain function. Present treatment for vascular injury primarily relies on combination therapy of surgery with anesthesia. In this study, we sought to determine the effects of anesthetics, sevoflurane and fentanyl, on long-term cognitive function in brain tissue of rats, and potential correlations with inflammatory factors such as VEGF, IL-1beta, TNF-alpha. We used shuttle box and water maze tests to study the cognitive function of Wistar rats. The results demonstrated that rats treated with sevoflurane or fentanyl performed less shock times and more active escape times compared with rats model undergoing vascular cognitive impairment. Treatment of anesthetics also shortened the periods of learning and memory incubation, suggesting a protective role in cognitive function. In addition, our results unraveled a reducing expression of TNF-alpha and IL-1beta but an increasing level of VEGF in head tissues of rats implemented with anesthetics. These findings underscore the improving role of sevoflurane and fentanyl in the recovery of vascular cognitive impairment rats as well as the cognitive function in rats, by regulating the expression of inflammatory factors. PMID- 26629206 TI - The technique comparison of brachial plexus blocks by ultrasound guided with blocks by nerve stimulator guided. AB - OBJECTIVE: Brachial plexus perineural blocks provide specific analgesia for upper limb surgery. We present our experience with ultrasound-guided supraclavicular brachial plexus perineural blocks for distal upper limb surgery. Although single injection ultrasound-guided supraclavicular blocks have been reported, little is known about the advantages using this approach compared with nerve stimulator guided. METHODS: There were 60 patients who underwent upper limb surgery for orthopedic trauma and received a supraclavicular brachial plexus anesthesia. 30 patients (U-group) were injected by an ultrasound-guided technique with the needle tip remaining under direct vision. 30 patients (NS-group) were inserted by nerve stimulator guided. Recorded the onset time, puncture times, pains cases with tourniquet in each group. Compared the difference between two groups. RESULTS: In U-group, all cases had successful perineural injection. Most of them, effect of anesthesia was fast onset and needed insert only once. No pains were reported under using tourniquet. There were no vessel punctures or other direct procedure-related complications. In NS-group, most injections were successful, but slow onset and needed multiply insert needle. 5 patients said pains under using tourniquet when surgery started and had to add opioid by vein. One patients' lung were puncture and result in pneumothorax. One patient's was intravascular injection. CONCLUSIONS: Supraclavicular brachial plexus perineural insertion using ultrasound guidance is feasible and almost have no complications, deserves further study with a randomized controlled trial comparing this relatively new technique with only using nerve stimulator. PMID- 26629207 TI - Alteration of circulatory platelet microparticles and endothelial microparticles in patients with chronic kidney disease. AB - OBJECTIVE: To compare plasma platelet microparticles (PMPs), P-selectin, endothelial microparticles (EMPs), and von Willebrand factor (vWF) between a normal control group and patients with chronic kidney disease (CKD) and to explore the significance of PMPs and EMPs in CKD. METHODS: Levels of plasma PMPs, P-selectin, EMPs and vWF in 122 CKD patients and 20 normal controls were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Relationships between PMPs, EMPs and blood pressure, creatinine clearance rate, 24-hour urine protein, hemoglobin, and cholesterol were analyzed. RESULTS: (1) Plasma PMPs, P selectin, EMPs and vWF levels in CKD patients were significantly higher than those of the control group. Plasma PMPs and P-selectin levels for nephrotic syndrome (NS) were significantly higher than for other CKD groups. No significant difference was found between other CKD groups. Plasma EMPs and vWF in NS, lupus nephritis (LN) and hypertensive nephropathy groups were significantly higher than that of diabetic nephropathy (DN) and chronic glomerulonephritis (CGN) groups. (2) Plasma PMPs, P-selectin, EMPs and vWF in stage I-II CKD patients were significantly higher than those of stage III-V CKD patients, no significant difference was found within stage I-II CKD patients or stage III-V CKD patients. (3) PMPs and EMPs were positively correlated with blood pressure and 24-hour urinary protein, but no significant correlation was found with the creatinine clearance rate, hemoglobin or cholesterol. P-selectin and vWF were positively correlated with PMPs and EMPs respectively. CONCLUSION: CKD patients have significant platelet activation and endothelial dysfunction, which was involved in CKD's occurrence and development; high blood pressure and proteinuria are important reasons for platelet activation and endothelial dysfunction in patients with CKD; PMPs and EMPs can be used as new markers for dysfunctional platelet activation and endothelium. PMID- 26629208 TI - Doppler ultrasound findings in kidney transplant recipients with and without of new onset diabetes mellitus beyond 5 years after transplantation. AB - OBJECTIVE: Renal Doppler Ultrasound (RDU) indices: resistive index (RI) and pulsatility index (PI) are frequently applied as a noninvasive method that measured possible causes of allograft dysfunction in kidney transplant patients. We aimed to compare long-term prognosis and associated risk factors including the RDU markers in recipients with and without new-onset diabetes after transplantation (NODAT) beyond 5 years after kidney transplantation. METHODS: A prospectively maintained database of 137 kidney allograft recipients, transplanted in a single center, maintained on reduced tacrolimus-based immunosuppressive regimen and angiotensin receptor blocker (ARB) was retrospectively analyzed. The assessment including incidence of NODAT and associated risk factors including RI and PI was compared between 12 recipients with and 125 recipients without NODAT median 77.5 months and 74 months, respectively, after kidney transplantation. RESULTS: NODAT was detected in 12 (9.6%) of the 137 kidney transplant recipients, without gender predilection. In univariate regression analysis recipient age (P < 0.001), recipients weight at the time of NODAT >= 65 kg (P < 0.001), as well as proteinuria (P = 0.026), tacrolimus trough levels (P = 0.005), PI (P = 0.023) were associated with the long-term risk of NODAT and multivariate regression analysis also revealed that recipients weight at the time of NODAT >= 65 kg (P = 0.004) was independent long- term risk factor for NODAT. CONCLUSIONS: Our study demonstrated that beyond 5 years after kidney transplantation the RDU indices: RI and PI are not long-term risk factors for NODAT and the correction of recipient's body weight, the treatment with ARB and maintained reduced TAC doses lowered the incidence of NODAT. PMID- 26629209 TI - Genetic association analysis between polymorphisms of HAIRY-AND-ENHANCER-OF SPLIT 7 and congenital scoliosis. AB - OBJECTIVE: We explored the association between genetic polymorphisms of HAIRY-AND ENHANCER-OF-SPLIT-7 (HES7) and congenital scoliosis (CS) in 246 cases of congenital scoliosis and non-congenital controls, in which the age and sex were fully matched. All participants were Chinese Han population. METHODS: The genome DNA was extracted from peripheral blood sample. Two SNPs were defined for HES7 using NCBI database. The genotypes of two SNPs were determined by SNP stream UHT Genotyping System. RESULTS: Polymorphisms were found in both SNPs and in accordance with Hardy-Weinberg equilibrium. For SNP rs3027279, the difference of two alleles (C and A) frequencies between CS and control groups Was statistically significant. Analysis also showed the difference of two genotypes (C/C and C/A) frequencies between two groups was significant (chi(2)=5.857, P<0.05). For SNP rs1442849, both difference of two alleles (A and G) frequencies and difference of three genotypes (G/G, G/A and AA) frequencies between two groups were shown statistically significant. CONCLUSIONS: The unconditional Logistic regression analysis showed A/A genotype of SNP rsl442849 may be a protective factor (P=0.018<0.05, OR-0.35, 95% CI=0.17-0.74) for the onset of CS, while C/A genotype of SNP rs3027279 increased the onset risk (P=0.015<0.05, OR=1.93, 95% CI=1.13 3.30) of CS. Linkage disequilibrium analysis demonstrated the existence of linkage disequilibrium between the two SNPs. PMID- 26629210 TI - Relationship between adiponectin receptor 1 gene polymorphisms and ischemic stroke. AB - OBJECTIVE: Previous study suggested adiponectin receptor 2 (ADIPOR2) genetic polymorphisms were associated with the risk of ischemic stroke. However, the relation between adiponectin receptor 1 (ADIPOR1) gene polymorphism and stroke remains unclear. METHODS: In the present study, we utilized the polymerase chain reaction-sequencing method to detect rs2275737 and s1342387 genotypes of ADIPOR1 gene in 300 cases of ischemic stroke patients and 300 age- and sex- matched healthy controls. RESULTS: For rs2275737, we found A allele carriers have increased risk to ischemic stroke (OR=2.570, 95% CI: 1.999-3.305); also, we found rs1342387 A allele was associated with the risk for stroke (OR=1.351, 95% CI: 1.074-1.699). After adjusted for confounders such as hypertension, diabetes, and smoking, we found the association remains significant. CONCLUSION: ADIPOR1 genetic polymorphism may increase the risk of ischemic stroke. PMID- 26629211 TI - Correlation between VEGFR2 rs2071559 polymorphism and glioma risk among Chinese population. AB - OBJECTIVE: We investigated the correlation between vascular endothelial growth factor 2 (VEGFR2) polymorphism and glioma risk among Chinese population. METHOD: Case-control study design was adopted, and blood samples and clinical data of 250 glioma cases and 260 control subjects were collected. Epidemiological questionnaire survey was performed, and DNA extraction, concentration normalization and packaging were carried out using Qiagen Blood Kit. TaqMan method was performed for VEGFR2 rs2071559 genotyping. RESULTS: C allele of VEGFR2 rs2071559 genotype was the susceptibility allele contributing to the risk of glioma (OR=1.813, 95% CI: 1.393-2.359, P=0.014). CC genotypes of VEGFR2 rs2071559 were associated with increased risk of glioma (OR=2.068, 95% CI: 1.164-3.674, P=0.014; Adjusted OR=1.883, 95% CI: 1.430~3.013, P=0.018). CONCLUSION: CC genotypes of VEGFR2 rs2071559 were associated with glioma risk among Chinese population. However, the role of VEGFR2 rs2071559 polymorphism in glioma susceptibility remains to be further clarified. PMID- 26629212 TI - Environmental tobacco smoke and pancreatic cancer: a case-control study. AB - BACKGROUND: It has been conformed that active smoking is an established risk factor for pancreatic cancer, but the role of environmental tobacco smok (passive smoking) in pancreatic cancer remains unclear. We intended to study the relationship between passive smoking and pancreatic cancer. METHODS: From Oct. 1991 to Sep. 2014, A hospital-based case-control study on pancreatic cancer was conducted from the inpatient of five hospitals. 1076 cases pancreatic cancer patients. History of exposure to environmental tobacco smoke was assessed through questionnaires. Relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. RESULTS: During 23 years of follow-up (1991-2014), 1076 patients were diagnosed with pancreatic cancer (686 men and 390 women). Compared to paternal smoking (RR, 0.97; 95% CI, 0.77-1.21; P = 0.084), maternal smoking significantly increased the risk of pancreatic cancer (R, 1.56; 95% CI, 1.13-1.98; P = 0.018). Although the risk associated with maternal smoking remained elevated compared to the never smokers (RR, 1.49; 95% CI, 1.07-2.27), there was no statistical significance. CONCLUSIONS: The positive association with maternal smoking suggests that environmental tobacco smoke, potentially in utero or in early life, may be associated with pancreatic cancer. PMID- 26629213 TI - Correlation between GATA4 gene polymorphism and congenital heart disease. AB - OBJECTIVE: The correlation between GATA4 gene polymorphism and congenital heart disease (CHD) was analyzed. METHOD: Clinical data and blood samples were collected from 350 CHD patients who were treated at the Department of Cardiology in Beijing Anzhen Hospital. The control group consisted of 350 healthy subjects receiving physical examination at our hospital during the same period. Polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis for locus rs11392441 of GATA4 gene. RESULTS: Polymorphism of locus rs1139244 of GATA4 gene was detected in CHD patients. The distribution frequencies of GG genotype and G allele were significantly higher than those of the control group. CONCLUSION: Polymorphism of locus rs1139244 of GATA4 gene was correlated with CHD. PMID- 26629214 TI - Possible association between serum alkaline phosphatase concentration and thoracicacute aortic dissection. AB - OBJECTIVES: Alkaline phosphatase (ALP) is an enzyme that catalyzes the hydrolysis of organic pyrophosphate. Accumulating data have demonstrated that the concentration of increased ALP is associated with C-reactive protein (CRP) concentration, and inflammation was complicated in the pathogenesis of acute aortic dissection (ADD). Therefore, the aim of our study was to examine the relationship between serum ALP concentration and thoracic ADD. METHODS: We retrieved demographic data and test results of biochemical data of 68 patients with thoracic ADD and 126 Non-thoracic ADD patients, retrospectively. RESULTS: A total of 194 patients were divided into thoracic ADD groups and non-thoracic ADD groups. Age, creatinine(Cr) and high-density lipoprotein cholesterol (HDL-C) were found to be statistical significance between the two groups. The mean ALP level was significantly higher in patients with thoracic ADD compared with Non-thoracic ADD patients (80.6+/-23.02 Vs. 65.9+/-16.49, P=0.001). Stepwise multiple logistic regression analyses revealed a significantly association of ALP with thoracic ADD (OR=1.038, 95% CI: 1.015-1.062, P=0.001). In addition, HDL-C was negative associated with thoracic ADD in multiple logistic regression analyses after adjustment for age, sex and Cr (OR=-0.083, 95% CI: 0.012-0.560, P=0.011). CONCLUSIONS: The present study suggests that the level of serum ALP is associated with thoracic ADD, and serum ALP concentration may be apotential risk factor for thoracic ADD. PMID- 26629215 TI - Relation between periodontitis and helicobacter pylori infection. AB - OBJECTIVE: The correlation between periodontitis and Helicobacter pylori (H. pylori) infection in the mouth was analyzed. METHOD: 70 elderly patients with periodontitis treated at our hospital from January 2013 to December 2014 were recruited. Dental plaques and gargle were collected for H. pylori detection using PCR technique. Periodontal health status of the patients was recorded. 70 control cases with healthy periodontium were also included. The symptoms of H. pylori infection in the mouth were compared between the two groups, and the results were analyzed statistically. RESULTS: The positive rate of urease C gene of H. pylori in the periodontitis group was 71.4%; the positive rate of cagA gene was 35.7%. The positive rate of urease C gene of H. pylori in the control group was 34.3% and that of cagA gene was 12.9%. The two groups did not show significant differences in these two indicators (P<0.05). The positive detection rate of urease C gene of H. pylori in subgingival plaques was higher than that in supragingival plaques, and the difference was of statistical significance (P<0.05). The positive detection rate of H. pylori in patients with moderate and severe periodontitis was obviously higher than that of patients with mild periodontitis (P<0.05). CONCLUSION: Periodontal health status of elderly people with periodontitis correlated with H. pylori infection in the stomach. PMID- 26629216 TI - Computed tomography appearance of inflammatory myofibroblastic tumor in the abdomen: CT features and pathologic correlation. AB - OBJECTIVE: To evaluate CT findings of abdominal inflammatory myofibroblastic tumor (IMT) and the relationship with morphological character. MATERIALS AND METHODS: CT examinations and pathological findings of ten intra-abdominal IMTs were retrospectively analyzed. The histopathological characteristics of the IMTs were confirmed by two pathologists and two radiologists evaluated CT findings of the lesion, with emphasis on the imaging features compared with the corresponding histopathology. RESULTS: The most common imaging characteristics were presence of heterogeneity, all tumors showed varying degrees of contrast enhancement. Two major different CT patterns were individualized. In type one, the tumor had a distinct boundary without a lobular appearance and displayed hypo-enhanced enhancement after administration of contrast in correlated with the mainly histopathologic findings of spindle cells myxoid and hypocellular fibrous (6/10; 60%). In type two, the lesions exhibited indistinct boundaries or complete capsule, ill-defined growth patterns or low intralesional attenuation with marked heterogeneous or circumferential enhancement, which correlated well with the presence of abundance of micromodule and inflammatory cell infiltration (4/10; 40%). CONCLUSIONS: Two major different contrast enhancement CT patterns were individualized can help to determine the relationships with histopathologic findings, while cannot be reliably differentiated from other solid lesions based solely on the CT appearance, combined with diagnostic biopsy may facilitate to achieve a correct diagnosis and treatment. PMID- 26629217 TI - Surgical treatment of polyostotic craniomaxillofacial fibrous dysplasia in adult: a case report and review of the literature. AB - The lesions of fibrous dysplasia usually stabilize after adolescence, and the surgical treatment of adult patient remains the mainstay. However, the surgical treatment alone may be not enough for patient with polyostotic fibrous dysplasia. We present the case of a surgically treated 36-year-old man with a diagnosis of progressive polyostotic fibrous dysplasia in the craniomaxillofacial region. The patients presented the swelling symptoms originally in the parietal bone at the age of 8 years, and extended gradually to almost all of the craniomaxillofacial bones during the following 28 years without specific treatment for socio-economic reasons. The symptom impelled the patient visit our department in 2009 was the rapidly progressive swelling in the chin during the last 3 years, which severely impacted his speech and feeding. The radiographs showed the typical intramedullary located and ill-defined lesions. The patient was treated with segmental mandibulectomy and reconstruction with vascularized fibular myocutaneous flap; the deformities in other craniomaxillofacial bones were not treated simultaneously. The local recurrence was not present in the chin. The visual acuity of right eye severely deteriorated and the left mandibular ramus continued expanding gradually when the patient was followed up through telephone 5 years later. A combination of surgical and medical treatment may be considered for patients with polyostotic craniomaxillofacial fibrous dysplasia. PMID- 26629218 TI - Artificial pleural effusion in percutaneous microwave ablation of hepatic tumors near the diaphragm under the guidance of ultrasound. AB - OBJECTIVE: To evaluate the feasibility, safety and efficacy of artificial pleural effusion in percutaneous microwave ablation of hepatic tumors near the diaphragm under ultrasound guidance. METHODS: For localization and navigation of tumors near the dome of the diaphragm by ultrasound during microwave ablation in 14 tumors of 11 cases, artificial pleural effusion was performed in the volume of 1000~1500 ml of Normal saline or 5% Glucose injection solution via the right thoracic cavity. The tumor marker, AFP was monitored before and after operation in 6 times in a period of 2 years. We analyzed the successful rate and effectiveness of artificial pleural effusion. RESULTS: The successful rate of artificial pleural effusion was 100% without complications. Artificial hydrothorax on the right eliminated the interference of intrapulmonary gas to the visualization of hepatic tumors near the diaphragm on ultrasound. In the follow up of 2 years, the ablation rate reached to 92.9% with no serious complications. The AFP value before operation was in significant statistical difference with the others after operation (P = 0.000). CONCLUSIONS: Artificial pleural effusion aids the visualization of hepatic tumors near the diaphragm on ultrasound. A good therapeutic effectiveness can be reached in percutaneous microwave ablation of tumors in the hepatic dome under the guidance of ultrasound. PMID- 26629219 TI - Mini-arteriotomy to remove misplaced Gugliemi detachable coils: case report and technical note. AB - Coil-related thromboembolic complications due to misplacement of coils in embolization of the intracranial aneurysms might result in severe neurological deficits. We describe an unusual case of a ruptured posterior communicating artery (PcomA) aneurysm in a woman who underwent a Mini-Arteriotomy to rescue error embolism in the left middle cerebral artery (MCA). This surgical procedure might be considered as an alternative route in selected patients with coil related thromboembolic complications. This novel technology gives us a simple and practical method to remedy the misplacement of coils in a wide region of the cerebral vascular after interventional treatment. PMID- 26629220 TI - Impact of different surgical traumas on postoperative ileus in rats and the mechanisms involved. AB - The degree of postoperative ileus and the underlying pathophysiological mechanism among different types of surgical traumas have not been examined. The aim of this study was to investigate the inflammatory and oxidative stress changes in rat intestinal muscularis and gastrointestinal transit among three types of surgical traumas. Rats were randomized assigned to four groups: control group, intestinal manipulation (IM) group, intestinal ischemia/reperfusion injury (IR) group and peritoneal air exposure (AE) group. Gastrointestinal transit was measured 24 hours after surgery. Malondialdehyde (MDA), glutathione (GSH) and inflammatory mediators in intestinal muscularis were measured. Influx of neutrophil in intestinal muscularis was also determined. The degree of gastrointestinal motility impairment was equal between the IM and AE groups. However, the IR group was subject to a less impairment of gastrointestinal motility compared with the IM and AE groups. The IM group showed the most significant increase of inflammatory response, while the AE group showed the most significant increase of oxidative stress. The IR group showed a moderate increase of inflammatory response and oxidative stress. Rats subjected to IM, IR and AE could all develop into POI. We speculate that oxidative stress should be an equally important pathophysiological mechanism of POI as inflammation. PMID- 26629221 TI - Delayed myelopathy secondary to stab wound with a retained blade tip within the laminae: case report. AB - Delayed neurologic deficit after a stab wound with a retained foreign body near the spinal canal is unusual, adequate radiological examination is fundamental in detecting retained foreign bodies, especially the CT scan, surgical extraction of the foreign body is the primary task and the surgical outcome is satisfactory. Here, we report a rare case of delayed myelopathy caused by spinal stenosis secondary to broken blade tip within thoracic laminae in an old man, who was injured in a knife attack 39 years ago. The incidence, clinical presentation, diagnosis and prognosis are discussed. PMID- 26629222 TI - Concurrence of primary malignant melanoma of the esophagus with adenocarcinoma of sigmoid colon and villous adenoma of cecum: a case presentation. AB - In this paper, a 74 years old male patient with complaints of dysphagia and hemoptysis is presented. Endoscopy revealed black colored mass protruding to the lumen at distal esophagus. Diagnosis of malignant melanoma was confirmed with biopsy. Examinations for staging purposes revealed masses at sigmoid colon and cecum. Biopsy was performed with colonoscopy. The mass at the sigmoid colon was diagnosed as adenocarcinoma and the mass at the cecum was diagnosed as villous adenoma. Although the treatment strategy is not straightforward, surgical treatment is the most important step. For this reason, patient underwent three field esophagectomy, anterior resection and right hemicolectomy in the first place. The patient is currently receiving his adjuvant chemotherapy and immunotherapy at postoperative 6th month. According to our knowledge, concurrence of these tumors with two different origins has only been reported in 1 patient before. Our patient has the significance of being the second reported case. PMID- 26629223 TI - Chorangiocarcinoma: a case report and clinical review. AB - OBJECTIVE: We describe a case of chorangiocarcinoma, a chorangioma covered by an abnormal trophoblastic proliferation, presenting in a term placenta and in an asymptomatic pregnancy. Evidence of metastasis was found on follow-up of the mother. MATERIALS AND METHODS: The lesion Was diagnosed by pathologic examination after cesarian section at term for fetal macrosomia, performed because of the abnormal gross findings in the placenta. After uncomplicated delivery, a thealthy child was born and the placent was expelled completely. There was follow-up in the mother and the child, up to 19 months after delivery. RESULTS: Gross examination of the placenta showed a well-demarcated and grayish yellow-white mass, bulging paracentrally from the fetal surface. Histology revealed a trophoblastic proliferation inside a chorangioma, consisting of extensive central necrosis and high mitotic activity. Immunohistochemical staining showed strong intensity for hCG, PLAP, CK, CD31 (+) and CD34 (+); Ki67 showed a high proliferation index. Follow-up revealed metastasis in the mother and chemotherapy were performed at 3 months postpartum. CONCLUSION: This is only the sixth reported case of chorangiocarcinoma of the placenta in the literature. However, no metastasis were discovered in the reported case, which was not identical to ours. Follow-up revealed metastasis at lung in the mother. Chorangiocarcinoma should be carefully examined and followed-up. PMID- 26629224 TI - Sudden cerebral infarction after interventional vertebral artery embolism for vertebral artery injury during removal of C1-C2 pedicle screw fixation: a case report. AB - Vertebral artery injury (VAI) is a rare but serious complication of cervical spine surgery. Instrumented posterior surgery of the upper cervical spine places the vertebral artery at the highest risk of injury. However, VAI during removal of cervical internal fixation is really rare and unexpected. We present a case of 52-year-old male patient who suffered VAI during removal of C1-C2 pedicle screw fixation. An interventional vertebral artery embolism was performed and the patient suffered a sudden cerebral infarction one day after interventional vertebral artery embolism. From this case, removal of upper cervical pedicle screws of malposition is not recommended if it is not really necessary for some other reasons. Interventional vertebral artery embolism is an effective and less invasive procedure than open ligation surgery in the treatment of haemorrhage resulted from VAI but potential risk of cerebral infarction should not be ignored. PMID- 26629225 TI - Complete response after chemotherapy and radiotherapy of a tonsillar histiocytic sarcoma with regional lymph node involvement: a case report and review of the literature. AB - We describe a case of tonsillar histiocytic sarcoma (HS) with regional lymph node involvement and complete response after multi-disciplinary therapy. Immunohistochemistry showed strong positive tumor staining for CD 68, and negative staining for CD20, CD45R0 and CD30 and non-cohesive proliferation of neoplastic histiocytes. Systemic chemotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOP-E) chemotherapy followed by radiotherapy was delivered to the patient. No evidence of recurrent disease existed on regular follow up three years later. The diagnostic methods and the practical treatment solutions are discussed here. We believe that although HS has been regarded as a potentially fatal disease entity, there remain some cases that do not pursue such an aggressive clinical course. PMID- 26629226 TI - Spontaneous epidural hematoma complicated by systemic lupus erythematosus: one case report. AB - In this study, an unusual case of intracranial hemorrhage is presented. It is spontaneous epidural hemorrhage, the complication of Systemic Lupus Erythematosus. In this case, a 29-year-old female presented with vomiting and continuous headache and computed tomography revealed the right frontal parietal and temporal epidural hematoma. The patient had been diagnosed SLE one year ago. Together, these observations indicated that the patient needs a surgery to reduce the intracranial pressure. Following surgery, the symptoms were eradicated but 7 hours later after surgery the review head CT showed that left epidural hemorrhage. According to the surgery index, we decided to give the patient non operative treatment and the intracranial hemorrhage was under control. We thought this was the surgery complication but it's not. On the eighth day after surgery, the patient had a sudden headache with vomiting again and head CT revealed that left epidural hemorrhage. But this time we just gave non-operative treatment and especially added the dose of glucocorticosteroid. 12 days later, the patient's symptoms were under control and she was discharged from hospital. We also reviewed the literature about spontaneous epidural hemorrhage and bilateral epidural hematomas. PMID- 26629227 TI - Hashimoto's encephalopathy: a report of three cases and relevant literature reviews. AB - Hashimoto's encephalopathy (HE) is a very rate condition characterized by various clinical features consisting of psychiatric manifestations, seizures and focal neurologic deficits. In this study, three Hashimoto's encephalopathy cases were reported, including two female patients and one male patient. The two female patients (22-year-old and 49-year-old) were presented with brainstem involvement and the symptoms progressed gradually. The 70-year-old male patient was diagnosed with space-occupying lesion that seemed to be malignant, but the symptom was substantially ameliorated right after glucocorticoid therapy. Pathological studies indicate abnormal blood vessels are important in the progression of the disease. Compared with current reports, the male case was the first patient diagnosed of Hashimoto's encephalopathy but presented with malignant features and local occupying effect. Intracranial lesions were found in all of the three patients, but these lesions responded well to glucocorticoid therapy. And the lesions were remarkably reduced after treatment. Meanwhile, the prognosis of diffuse Hashimoto's encephalopathy is better than the vascular type. PMID- 26629228 TI - Postoperative recurrence solitary fibrous tumor of the pelvic with malignant transformation. AB - A 48-year-old man with a solitary fibrous tumor of the pelvic underwent resection, but recurrent tumor was found 4 years later. Recurrent solitary fibrous tumor of the pelvic with malignant progression is rare. Solitary fibrous tumor of the pelvic often has an indolent clinical course, so postoperative surveillance may necessitate long-term follow-up because of the potential adverse biological behavior of this tumor, which may lead to repeated recurrences and/or malignant transformation. PMID- 26629229 TI - Diffuse mesangial and endocapillary cell proliferative glomerulonephritis with persistent hypocomplementemia in a child. AB - A 15-year-old boy was admitted to People's Hospital of Dong E with anasarca. The laboratory findings revealed proteinuria, hematuria, hypocomplementemia. Renal biopsy specimen revealed diffuse mesangial and endocapillary cell proliferative glomerulonephritis on light microscopic (LM) examination. On immunofluorescence (IF) examination, deposition of IgG, IgA, C3, C1q and F to capillary wall and subendothelial were observed. By means of electron microscopy (EM), subendothelial electron-dense deposits and segmental fusion of epithelial cell foot process were recognized. He was treated by only some supportive drugs, no ACEI/ARB, without glucocorticoids and immunosuppressive agents. About one month later, complete remission of proteinuria occurred. During next 62-weeks follow up, urinary analysis always showed microscopic hematuria. However, it is interesting to note that the serum complement C3 and C4 levels remained persistently low. PMID- 26629230 TI - Coil embolization for a vast and complex arteriovenous malformation in the posterior mediastinum. AB - Arteriovenous malformation (AVM) is a kind of life threatened disease. Especially AVM in the posterior mediastinum is a rare, painful and it is difficult for treatment. We report a 44-year-old male patient who developed arteriovenous malformation (AVM) in the posterior mediastinum. The patient complained 3 years of mild left back pain and chest congestion, and his pain increased over the last 3 months. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) examinations showed an enhancing vascular lesion in the left posterior mediastinum which in contact with the descending thoracic aorta. It was initially misdiagnosed as lung mass. It was considered to be vascular malformations. His pain was completely resolved after steel coil embolization was successfully administered. PMID- 26629231 TI - Ureteral obstruction by prostate cancer leads to spontaneous ureteric rupture: a case report. AB - Spontaneous ureteric rupture (SUR) is an unusual entity associated with perinephric or retroperitoneal extravasation of urine. Patients with SUR are often presented with severe and progressive abdominal or flank pain. It is commonly related to the obstruction of genitourinary system, among which urinary calculi represents the most frequent cause. Prostate cancer with ureteral orifice invasion can lead to ureteral obstruction, which can also be a threat to SUR. Herein, we present a case of a 68-year-old male with SUR after prostate cancer invaded the left ureteral orifice. To our best knowledge, this is the first case of SUR secondary to ureteral obstruction from prostate cancer. PMID- 26629232 TI - Recurrent meningioma with malignant transformation: a case report and literature review. AB - Meningiomas are common and mostly benign intracranial tumors, but may show a histological progression to malignancy. The mechanisms of malignant transformation remain unclear. Malignant meningiomas usually bear a high recurrence rate and unfavorable prognosis, and multiple surgical resections are required for the treatment. We report on a case of 51-year-old woman with a histologically benign intracranial meningioma. The patient had undergone multiple tumor resections and radiotherapy treatments. After multiple resections, the tumor demonstrated malignant transformation. A rapid tumor growth resulted in extensive tumor invasion of dura, brain and nasal sinus. Impaired brain function and subsequent intracranial hypertension caused serious headache, vomiting and coma. The patient survived 5 years following initial presentation. 3 subtotal resections of meningioma were performed. Radiotherapy was shown to be relatively ineffective during the course. The treatment strategies of recurrent meningiomas are briefly reviewed. PMID- 26629233 TI - Pulmonary arterial hypertension associated with rare cause of ANCA-associated vasculitis misdiagnosed as idiopathic one. AB - Pulmonary arterial hypertension (PAH) and ANCA-associated vasculitis (AAV) are both rare and complex diseases with poor prognosis especially when misdiagnosis. We report a rare case of a young woman presented with idiopathic pulmonary arterial hypertension (IPAH), but who was later found to have PAH associated with AAV. This case reminds us the very importance of differential diagnosis to PAH patients and the identification of rare cause likes ANCA-associated vasculitis. To our knowledge, this patient represents the first published case of misdiagnosis of PAH secondary to ANCA-associated vasculitis. PMID- 26629234 TI - Sphenoid sinus mucocele presenting with oculomotor nerve palsy and affecting the functions of trigeminal nerve: a case report. AB - We report a case of first-episode sphenoid mucocele successfully treated via transnasal endoscopic drainage and marsupialization of the mucocele. A 55 year old female presented with persistent right-side facial numbness (in the areas of the first and second branches of the trigeminal nerve) and right-side ptosis. Computed tomography (CT) imaging and Magnetic resonance imaging (MRI) revealed opacification and expansion of the right-side sphenoid sinus lesion. The lesion was diagnosed as right-side sphenoid mucocele affecting the functions of the trigeminal (first and second branches), and oculomotor nerves. Transnasal endoscopic drainage and marsupialization of the mucocele result in rapid regression of these symptoms. PMID- 26629235 TI - Sympathetic renal denervation in hypertension with chronic kidney disease: a case report and review of literature. AB - Resistant hypertension is defined as systolic blood pressure that is higher than 140 mmHg even though they consume three maximally tolerated anti-hypertensive medication class, including diuretics at an appropriate dose [1]. There are many complications of resistant hypertension such as left ventricular hypertrophy, increased incidence of retinal hemorrhage and kidney damages [2]. A novel catheter-based technique for renal denervation (RDN) as a new therapeutic avenue has great promise for the treatment of refractory hypertension. Despite the fast pace of development in RDN therapies, only initial and very limited clinical data are available. Here, we present the effects of RDN on perivascular nerves of the renal arteries in a 62-year-old male patient. And large gaps in knowledge concerning the long-term effects and consequences of RDN still exist, and solid, randomized data are warranted. PMID- 26629236 TI - Refractory status epilepticus, serious rhabdomyolysis, acute liver injury, and pancytopenia after a massive intake of ethyl methanesulfonate: a case report. AB - Ethyl methanesulfonate is a mutagenic, alkylating agent and considered harmful to humans at levels greater than a certain threshold; however, the toxicity at high doses remains unclear. We report a case of a Japanese man who presented with status epilepticus, rhabdomyolysis, pancytopenia, and hair loss after accidental ingestion of a massive amount of ethyl methanesulfonate. The patient completely recovered with critical care, including multiple antiepileptic drugs, renal replacement therapy, blood transfusion, granulocyte colony-stimulating factor therapy, and antibacterial/fungal prophylaxis. The case indicates that ethyl methanesulfonate causes neurotoxicity, hepatotoxicity, hematotoxicity, and renal toxicity, which can be successfully treated with appropriate palliative therapies. PMID- 26629237 TI - Syncope as initial symptom for nephrotic syndrome: a case report. AB - Although syncope and nephrotic syndrome are frequently encountered independently in pediatric practice, syncope as the initial symptom for nephrotic syndrome is rarely observed in the pediatric age group. In this report, we present the case of 3-year-old boy with nephrotic syndrome who presented with a history of three episodes of syncope before admission. The syncope occurred after excessive fluid loss or inadequate intake of fluids and was relieved spontaneously. History taking revealed that the early morning palpebral edema, and laboratory tests showed decreased plasma protein levels and elevated serum lipid levels. Nephrotic syndrome was diagnosed, but could not be confirmed histopathologically because the patient's parent refused consent for biopsy. The patient was managed with fluid expansion, correction of acidosis, and improvement of microcirculation to prevent recurrence of syncope, and glucocorticoids were administered to prevent disease progression. PMID- 26629238 TI - Effects of the bilateral isokinetic strengthening training on functional parameters, gait, and the quality of life in patients with stroke. AB - OBJECTIVE: To evaluate the effects of the bilateral isokinetic strengthening training applied to knee and ankle muscles on balance, functional parameters, gait, and the quality of in stroke patients. METHODS: Fifty patients (33 M, 17 F) with subacute-chronic stroke and 30 healthy subjects were included. Stroke patients were allocated into isokinetic and control groups. Conventional rehabilitation program was applied to all cases; additionally maximal concentric isokinetic strengthening training was applied to the knee-ankle muscles bilaterally to the isokinetic group 5 days a week for 3 weeks. Biodex System 3 Pro Multijoint System isokinetic dynamometer was used for isokinetic evaluation. The groups were assessed by Functional Independence Measure, Stroke Specific Quality of Life Scale, Timed 10-Meter Walk Test, Six-Minute Walk Test, Stair Climbing Test, Timed up&go Test, Berg Balance Scale, and Rivermead Mobility Index. RESULTS: Compared with baseline, the isokinetic PT values of the knee and ankle on both sides significantly increased in all cases. PT change values were significantly higher in the isokinetic group than the control group (P<0.025). Furthermore, the quality of life, gait, balance and mobility index values improved significantly in both groups, besides the increase levels were found significantly higher in the isokinetic group (P<0.025, P<0.05). CONCLUSION: Bilateral isokinetic strengthening training in addition to conventional rehabilitation program after stroke seems to be effective on strengthening muscles on both sides, improving functional parameters, gait, balance and life quality. PMID- 26629239 TI - KRT6B, a key mediator of notch signaling in honokiol-induced human hepatoma cell apoptosis. AB - The study was performed to investigate the relationship between KRT6B and Notch1 in the development and progress of hepatocellular carcinoma. The cell viability was detected by CCK8 assay. The cell apoptosis was assessed by annexin V-PI double-labeling staining on a flow cytometry. Expression of genes and proteins were analyzed by real-time PCR and Western blotting, respectively. KRT6B gene was overexpressed using a lentiviral expression vector in a human hepatoma cell line in vitro, in order to explore the mechanism by which the KRT6B promoted cell growth. The results of CCK8 and immunohistochemistry showed that honokiol induced cell death in a concentration- dependent manner, and suppressed human hepatoma cells' proliferation. The mRNA and protein expression of Notch1 was significantly lower in human hepatoma cells with honokiol treatment than that in the untreatment group. Activation of Notch-1 by exogenous transfection of Notch1 intracellular domain increased KRT6B expression in human hepatoma cells. Furthermore, cells were transfected with the wild type pLenti-KRT6B vector, the protein expression of KRT6B and NOTCH1 was significantly upregulated in human hepatoma cells with honokiol treatment. Overexpression of KRT6B promoted hepatoma cells' proliferation and showed anti-apoptosis effect. This study demonstrated that honokiol could induce human hepatoma cells' apoptosis. KRT6B, a key mediator of Notch signaling, was downregulated in honokiol-induced hepatocellular carcinoma apoptosis, suggesting that KRT6B might be a novel therapeutic target for the treatment of hepatocellular carcinoma. PMID- 26629240 TI - Clinical role of circulating miR-223 as a novel biomarker in early diagnosis of cancer patients. AB - BACKGROUND: Current diagnostic procedures of cancers are invasive and non specific. MicroRNAs (miRNAs) have become promising molecular markers for gastric cancer (GC) predication. However, there have been inconsistencies in the literature regarding the suitability of circulating miRNAs for early detection of cancers. METHODS: We performed a comprehensive meta-analysis to integrate an evaluation index for diagnostic accuracy of miR-223 in diagnosing cancer patients. Furthermore, we conducted an independent validation set of 50 gastric cancer patients and 50 healthy controls comparing miR-223 expression. We also analyzed miR-223 expression in vitro. RESULTS: A total of 11 studies met the inclusion criteria and therefore included in this meta-analysis. We found that miR-223 yielded a pooled area under ROC curve (AUC) of 0.89 (sensitivity: 81%, specificity: 84%) in discriminating cancer from controls. In our validation test, plasma miR-223 levels in GC patients were significantly higher than that in healthy controls (P<0.01). ROC curve analysis showed that AUC was 0.812 with a sensitivity of 70% and specificity of 80%. Moreover, the expression trend of miR 223 in plasma samples was in accordance with that of tissue and cell samples. CONCLUSION: Current evidences suggested that plasma miR-223 could be a reliable and non-invasive biomarker for cancer diagnosis. Further large-scale prospective studies are necessary to validate their potential applicability in human cancer diagnosis. PMID- 26629241 TI - The implantation of a Nickel-Titanium shape memory alloy ameliorates vertebral body compression fractures: a cadaveric study. AB - OBJECTIVE: To evaluate the effect of a Nickel-Titanium (Ni-Ti) shape memory alloy in the treatment of vertebral body compression fractures. METHODS: The experimental thoracic-lumbar fracture units were made with adult human fresh frozen vertebral specimens. A total of 30 fresh-frozen vertebral units were randomly assigned to 3 experimental groups: control group, percutaneous kyphoplasty group (PKP group), and percutaneous Ni-Ti shape memory alloys implant group (Ni-Ti implant group). Vertebral height and ultimate compression load of the vertebral body before and after procedures were measured to determine the restoration of vertebral heights and compressive strength, respectively. RESULTS: The Ni-Ti implant group achieved a vertebrae endplate reduction effect comparable to the PKP group. The vertebral height of the PKP group was restored from 2.01+/ 0.21 cm to 2.27+/-0.18 cm after procedure, whereas that of the Ni-Ti implant group was restored from 2.00+/-0.18 cm to 2.31+/-0.17 cm. The ultimate loads of the vertebrae body of the PKP and the Ni-Ti implant groups were 2880.75+/-126.17 N and 2888.00+/-144.69 N, respectively, both of which were statistically significantly higher than that of the control group (2017.17+/-163.71 N). There was no significant difference in ultimate compression load of vertebrae body between the Ni-Ti implant and PKP groups. CONCLUSIONS: The implantation of Ni-Ti shape memory alloys of vertebral body induced effective endplate reduction, restored vertebral height, and provided immediate biomechanical spinal stability. PMID- 26629242 TI - The offset of the tibia plateau of osteoarthritis patients: a single-center study. AB - Component position and good fixation are important factors determining the success of a primary or revision total knee arthroplasty (TKA). The aim of this study was to measure the anatomic features of the tibial plateau and to assess variations in the offset of the tibial shaft from the tibial plateau in osteoarthritis (OA) patients. Computed tomography (CT) scan results were obtained from 126 knees of 121 OA patients (72 female, 49 male) with an average age of 65 +/- 7 years. The anatomic features of the tibial plateau were measured and analyzed using three-dimensional reconstruction information derived from a 64 slice spiral CT. The results showed significant variations in proximal tibial anatomy among the subjects. The mean offset was 7.61 +/- 3.04 mm at the resection just distal to the subchondral bone. The mean anteroposterior and mediolateral dimensions of the tibial plateau were 53.05 +/- 4.82 mm and 70.42 +/- 8.33 mm, respectively, at the resection just distal to the subchondral bone. The tibial shaft axis was located anterolateral to the center of the tibial plateau in 62% of knees, while in 36% of these knees, it was located anterior medial to the center of the tibial plateau at the resection just distal to the subchondral bone. Our study shows that anatomic variations should be fully evaluated before performing TKA. A wide range of implant sizes is thus necessary for optimum replacement. PMID- 26629243 TI - A case of Miller Fisher syndrome during preoperative chemotherapy for breast cancer. AB - A 53-year-old woman with breast cancer received FEC treatment (5FU: 500 mg/m(2), epirubicin: 100 mg/m(2), and cyclophosphamide: 500 mg/m(2)) every 3 weeks as preoperative chemotherapy. Fifteen days after her third cycle of FEC, she developed a cold. Diplopia occurred 4 days after developing the cold, and progressive paresthesia of the hands and weakness of the limbs occurred. She had ophthalmoplegia, ataxia, and are flexia and was diagnosed with Miller Fisher Syndrome (MFS). The cause of MFS during chemotherapy is believed to be caused by an immunological response to infection, or drug neurotoxicity. In our case, since the patient underwent an antecedent upper respiratory infection in the period of myelosuppression, her MFS was probably induced by the immunoreaction associated with this infection. Our patient underwent intravenous immunoglobulin therapy. After initiation of the treatment, her neurological symptoms improved, then, she received a fourth cycle of FEC and her remaining neurological symptoms did not worsen. Thus, we report a rare case of MFS developed in immunosuppression by chemotherapy and remind physicians of the alarming triad of MFS symptoms. PMID- 26629244 TI - Normal anatomic relationship between urethral sphincter complex and zones of prostrate in young Chinese males on MRI. AB - Objective In this research, the normal anatomic relationship between urethral sphincter complex and zones of prostrate in young Chinese males has been studied. METHODS: The sagittal, coronal, and axial T2-weighted non-fat suppressed fast spin-echo images of pelvic cavities of 86 Chinese young males were studied. RESULT: Urethral sphincter complex threaded through the prostate and divided it into 2 parts: transition zone (TZ), periurethral glands internal to the urethral sphincter and peripheral zone (PZ), central zone (CZ), anterior fibromuscular stroma (AFS) zone external to the urethral sphincter. The length of urethral striated sphincter is 12.26-20.94 mm (mean 16.59 mm) at membranous urethra. CONCLUSIONS: In this paper, we summarized the normal anatomic relationship between urethral sphincter complex and zones of prostrate in young Chinese males with no urinary control problems. PMID- 26629245 TI - Resveratrol induces apoptosis in K562 cells via the regulation of mitochondrial signaling pathways. AB - Resveratrol, an edible polyphenolic phytoalexin obtained primarily from root extracts of the oriental plant, Polygonum cuspidatum and from grapes and red wine, has been reported as an anticancer compound against several types of cancer, the accurate molecular mechanisms of by which it induces apoptosis are limited. In the present study, the molecular mechanisms of resveratrol on human leukemia K562 cells apoptosis was examined. Our results showed that resveratrol significantly decreased cell viability and triggered cell apoptosis in K562 cells. Resveratrol-induced apoptosis of K562 cells was associated with the dissipation of mitochondrial membrane potential (MMP) and the release of cytochrome c into the cytosol. Furthermore, the up-regulation of Bax/Bcl-2 ratio, the activation of caspase-3 and increased cleaved PARP was also observed in K562 cells treated with resveratrol. Thus, we considered that the resveratrol-induced apoptosis of K562 cells might be mediated through the mitochondria pathway, which gives the rationale for in vivo studies on the utilization of resveratrol as a potential cancer therapeutic compound. PMID- 26629246 TI - A case of laryngeal paraganglioma and literature review. AB - Paragangliomas are common in carotid body, jugular tympanic cavity and cervical vagus nerve, but uncommon in larynx. We report clinical and pathological features of a 40-year-old woman with laryngeal paraganglioma. Tracheotomy combined with vein anesthesia was performed to isolate tumors. The patient was followed up for 3 months after surgery treatment and recovered well. We also provide a better understanding of this disease through a review of relevant literature. Largnx paraganglioma is rare, but should require long-term follow-up for possible recurrence. PMID- 26629247 TI - Serum relaxin levels as a novel biomarker for detection of acute myocardial infarction. AB - Background- AIMS: Little is known about the prognostic significance of elevated serum relaxin in acute myocardial infarction (AMI) patients. The present study is designed to investigate the potential association between serum relaxin levels and the risk of AMI. MATERIALS AND METHODS: We measured circulating relaxin levels in 80 patients (median age 62.3 years) who presented with first-time AMI 8 hours after the incident. The circulating relaxin-2 levels in 80 healthy volunteers (median age 61.5 years) was also measured. Relaxin-2 was detected using enzyme immunoassay in both groups. RESULTS: Serum relaxin levels were significantly higher in patients with AMI (27.4 +/- 6.3 ng/ml) compared to controls (9.2 +/- 2.3 ng/ml) (P < 0.01). We found that a relaxin level > 13.8 ng/ml had a sensitivity of 79% and a specificity of 86% for predicting AMI. Relaxin revealed the higher sensitivity and specificity for diagnosing AMI. CONCLUSIONS: Elevated relaxin in plasma may be a novel biomarker for early detection of AMI. PMID- 26629248 TI - Knockdown of CIP2A sensitizes ovarian cancer cells to cisplatin: an in vitro study. AB - BACKGROUND: CIP2A is a recently characterized oncoprotein which involves in the progression of several human malignancies. CIP2A is overexpressed in human ovarian cancer and regulates cell proliferation and apoptosis. This study was performed to investigate the role of CIP2A in ovarian cancer (OC) chemoresistance. METHODS: Using DDP-resistant SKOV3 cells (SKOV3(DDP)), we first determined the effect of CIP2A silencing by siRNA-mediated knockdown of CIP2A on chemosensitivity in vitro; we then determined the effect of pCDNA3.1-mediated overexpression of CIP2A on chemosensitivity in SKOV3 cells in vitro. To elucidate the molecular mechanisms underlying CIP2A-mediated chemoresistance, the activities of AKT signaling molecules associated with CIP2A were analyzed. RESULTS: Knockdown of endogenous CIP2A in SKOV3(DDP) cells resulted in the reduction in cell growth and increase in the chemosensitivity of SKOV3(DDP) cells to DDP in vitro, which may be caused by CIP2A-induced AKT activity inhibition. Notably, CIP2A overexpression could significantly decrease the sensitivities of SKOV3 cells to cisplatin, which might be ascribed to CIP2A-induced activation of the AKT pathway. CONCLUSIONS: Taken together, the results suggest that CIP2A contributes to cisplatin resistance in OC. Thus, CIP2A is a potential therapeutic target for OC. PMID- 26629249 TI - Genetic associations of FCRL3 polymorphisms with the susceptibility of Graves ophthalmopathy in a Chinese population. AB - BACKGROUND: Graves ophthalmopathy (GO) is a form of autoimmune thyroid disease commonly found in approximately 25-50% patients with Graves' disease. Both the thyroid-specific genes and immune-modulating genes are involved in susceptibility to GO. However, even though FCRL3 polymorphisms were also autoimmune-associated genes, no study has been performed regarding the association of FCRL3 with GO. Therefore, the objective of the current study was to conduct a basic case-control study in a Chinese population. METHODS AND MATERIALS: Seven SNPs were selected in this case-control study and 577 GD patients and 608 controls were recruited. Odds ratio and 95% confidence interval were used to assess the association between susceptibility of GO and FCRL3 polymorphisms with Stata software (Version 11.0, Stata Corp LP, USA). RESULTS: The case-control analysis showed that three polymorphisms, FCRL3_3C, FCRL3_5C, FCRL3_6A, were significantly associated with raised risk of GO in a Chinese Han population in the allelic model [OR = 1.28, 95% CI: 1.09-1.51, P = 0.003; OR = 1.26, 95% CI: 1.07-1.48, P = 0.005; OR = 1.25, 95% CI: 1.06-1.47, P = 0.007]. CONCLUSIONS: This case-control analysis confirmed that the FCRL3_3, FCRL3_5 and FCRL3_6 polymorphisms were associated with significantly increased risk of GO in a Chinese population. PMID- 26629250 TI - Hydroxyflavanone inhibits gastric carcinoma MGC-803 cell proliferation. AB - Gastric carcinoma (GC) is the most common primary malignancy of the digestive tract, with increasing incidence in many countries. 3-(4,5-Dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay was used to assess inhibition of HepG2 cell proliferation by 2'-hydroxyflavanone. The STAT3 pathway was performed. 2'-hydroxyflavanone reduced inhibitory effects on MGC-803 cell proliferation. 2' hydroxyflavanone exhibited the highest inhibition rate. Treatment of MGC-803 cells with 400, 200, and 100 MUg/ml 2'-hydroxyflavanone resulted in 88.9+/-0.7%, 81.2+/-0.5%, 68.4+/-0.5% decrease in cell viability, respectively, indicating an IC50 of 9.3 MUg/ml. The 100 MUg/ml 2'-hydroxyflavanone can significantly inhibit the STAT3 pathway activation. 2'-hydroxyflavanone inhibits MGC-803 cell proliferation by inhibiting STAT3 pathway activation. This extract is therefore a potential drug candidate for treatment of liver cancer. PMID- 26629251 TI - Intravertebral clefts in osteoporotic compression fractures of the spine: incidence, characteristics, and therapeutic efficacy. AB - OBJECTIVE: To determine the pathogenesis and characteristics and to assess the long-term effectiveness of polymethylmethacry late (PMMA) vertebroplasty treatment in patients with intravertebral cleft (IVC) in osteoporotic compression fractures. METHODS: A retrospective analysis of radiological and clinical parameters was performed on 388 patients who underwent percutaneous vertebroplasty or kyphoplasty to treat osteoporotic compression fractures from January 2010 to October 2012. IVC sign was observed in the MRI of 47 patients. Postoperative follow-ups were conducted for at least 2 years after surgery. RESULTS: IVC incidence was associated with older age and lower bone mineral density. Other baseline measurements, such as preoperative visual analogue scale and Oswestry Disability Index (ODI), showed no significant difference between IVC and non-IVC fracture patients. Vertebral height and kyphotic angle were corrected after percutaneous vertebroplasty or kyphoplasty with no significant difference in outcome between the two procedures. Restored vertebral height collapsed and the kyphotic angle became aggravated during the 2 years following surgery in patients with IVC. Similarly, initial improvements in visual analogue scale and ODI decreased over time. Non-IVC patients' had a slight recurrence of compression and kyphosis that began to normalize after 1 year. Visual analogue scale and ODI at 2 years' post-surgery was also significantly lower in non-IVC than IVC patients. CONCLUSION: Polymethylmethacrylate vertebroplasty treatment of osteoporotic compression fractures is initially effective for patients with signs of IVC, but compression and kyphosis gradually reoccur. Therefore, we strongly recommend strict observation and follow-up after vertebroplasty. PMID- 26629252 TI - Correlation between high density lipoprotein and monocyte subpopulations among stable coronary atherosclerotic heart disease patients. AB - High density lipoprotein (HDL) is a structurally and functionally heterogeneous molecular particle whose function is unclear in atherosclerosis at present. Studies show that small HDL functional imbalance may exist in Coronary Atherosclerotic Heart Disease (CAD) patients. Monocyte is considered to play an important role in atherosclerosis, in accordance with the expression of superficial CD14 and CD16, it can be divided into three subpopulations. The purpose of this study was to explore the relation between HDL and monocyte subpopulations among CAD patients. We report 90 cases of stable CAD patients and define the monocyte subpopulations as classical monocyte (CD14++CD16-; CM), intermediate monocyte (CD14+CD16+; IM), and non-classical monocyte (CD14+CD16++; NCM); HDL group is measured by polyacrylamide gel electrophoresis. The results indicated that the small HDL in blood serum has a correlation with proinflammatory NCM in circulation but a negative correction with CM and no relationship with diabetes, saccharify hemoglobin, hypertension, smoking history and taking dose of statins drugs and severity of disease. In conclusion, this study primarily confirms that micromolecule HDL level correlates with the increase of non-classical monocyte subpopulations and decrease of classical monocyte quantity. Thus demonstrates the proinflammatory correlation between micromolecule HDL and internal immunity in the development of stable atherosclerosis. PMID- 26629253 TI - Association between whole grain intake and stroke risk: evidence from a meta analysis. AB - BACKGROUND: Researches of the relationships between dietary whole grains intake and risk of stroke have produced inconsistent results. We therefore conducted a meta-analysis to summarize the evidence from observed studies regarding the association between whole grain intake and stroke risk. METHODS: Pertinent studies were identified by searching Web of Knowledge and PubMed up to May 2015. Random-effect model was used to combine the relative risk (RR) with the corresponding 95% confidence intervals (CI). Publication bias was estimated using Egger's regression asymmetry test. RESULTS: Six prospective studies involving 1635 stroke cases and 247487 participants were included in this meta-analysis. Pooled results suggested that highest category of whole grain intake versus lowest category was significantly associated with reduced the risk of stroke [summary RR = 0.86, 95% CI = 0.73-0.99, I2 = 0.0%]. Inverse associations were also found in the America population [summary RR = 0.81, 95% CI = 0.67-0.98, I(2) = 0.0%] and subgroup analysis of females [summary RR = 0.78, 95% CI = 0.63-0.97, I(2) = 0.0%]. No publication bias was found. CONCLUSION: Our analysis indicated that higher whole grain intake has a protective effect on stroke. PMID- 26629254 TI - Non-secreting multiple myeloma switches to IgD of lamda type: a case report and review of literature. AB - We report a case of a woman, who initially presented with an non-secreting multiple myeloma, 11 months later, she was diagnosed as an IgD-secreting myeloma. In December, 2010, the patient's serum protein quantification and immunofixation electrophoresis (IFE) revealed polyclonal immunoglobulin with no evidence of monoclonal immunoglobulin. However, her bone marrow smears revealed an abnormal proliferation of atypical plasma cells (46.5%), so she was diagnosed as non secreting multiple myeloma. After three cycles of administration of Velcade plus Dexamethasone (VD), she achieved a complete remission (CR). Unfortunately, on October 31, 2011, our patient was found to have a separate peak of monoclonal component on the gamma-region of cellulose-acetate electrophoresis, and the serum immunofixation electrophoresis revealed the monoclonal component was IgD. Several months later, she presented with a large swelling of the left side of her neck. Microscopic examination of a biopsy specimen from the cervical mass showed a neoplastic plasma cell tumor and she died on January 28, 2013 from acute respiratory failure resulting from neoplastic plasma cells infiltration and infection. Here we report this rare case and review the literature for similar cases. PMID- 26629255 TI - Mesenchymal stem cells preconditioned with trimetazidine promote neovascularization of hearts under hypoxia/reoxygenation injury. AB - BACKGROUND: Cell-based angiogenesis is a promising treatment for ischemic diseases; however, survival of implanted cells is impaired by the ischemic microenvironment. In this study, mesenchymal stem cells (MSCs) for cell transplantation were preconditioned with trimetazidine (TMZ). We hypothesized that TMZ enhances the survival rate of MSCs under hypoxic stimuli through up regulation of HIF1-alpha. METHODS AND RESULTS: Bone marrow-derived rat mesenchymal stem cells were preconditioned with 10 MUM TMZ for 6 h. TMZ preconditioning of MSCs remarkably increased cell viability and the expression of HIF1-alpha and Bcl-2, when cells were under hypoxia/reoxygenation (H/R) stimuli. But the protective effects of TMZ were abolished after knocking down of HIF 1alpha. Three days after implantation of the cells into the peri-ischemic zone of rat myocardial ischemia-reperfusion (I/R) injury model, survival of the TMZ preconditioned MSCs was high. Furthermore, capillary density and cardiac function were significantly better in the rats implanted with TMZ-preconditioned MSCs 28 days after cell injection. CONCLUSIONS: TMZ preconditioning increased the survival rate of MSCs, through up-regulation of HIF1-alpha, thus contributing to neovascularization and improved cardiac function of rats subjected to myocardial I/R injury. PMID- 26629256 TI - IGFBP3 polymorphisms and risk of esophageal cancer in a Chinese population. AB - Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. It is very aggressive with a poor prognosis. Besides environmental risk factors, genetic factors might contribute to the esophageal cancer carcinogenesis. To evaluate the association between the risk of esophageal squamous cell carcinoma (ESCC) and genetic variants in IGFBP3, we conducted a hospital-based case-control study to assess the genetic effects of these SNPs. A total of 380 esophageal squamous cell carcinoma (ESCC) cases and 380 controls were recruited for this study. The genotypes were determined using a matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The IGFBP3 single nucleotide polymorphisms (SNPs) rs2270628 C>T, rs10282088 C>A, and rs3110697 G>A were associated with a significantly decreased risk of ESCC. However, our results were obtained with a limited sample size. To confirm the current findings, larger studies with other ethnic populations are required. PMID- 26629258 TI - Comparison of early postoperative period electrophysiological and clinical findings following carpal tunnel syndrome: is EMG necessary? [Retraction]. AB - [This retracts the article on p. 10011 in vol. 8, PMID: 26309691.]. PMID- 26629257 TI - Two cases of endobronchial aspergilloma with lung cancer: a review the literature of endobronchial aspergilloma with underlying malignant lesions of the lung. AB - Endobronchial aspergilloma is a rare disease entity with pulmonary involvement of aspergillus. Few cases of endobronchial aspergilloma associated with malignant lesions have been reported in the literature. We present 2 more cases of endobronchial aspergilloma with underlying lung cancer. And summarize the published literatures to investigate the clinical manifestations, bronchoscopic characters, imaging performances in patients with endobronchial aspergilloma with underlying malignant lesions of the lung. A review of the literature reveals 8 cases of endobronchial aspergilloma with coexisting lung malignant lesions upon presentation. The medical details of the patients including age, sex, clinical symptoms, radiological manifestations bronchoscopic characters, diagnosis and treatment are summarized. Endobronchial aspergilloma is usually incidentally detected in patients with underlying lung disease. With the increasing popularity of flexible bronchoscopy, it is being recognized as a necrotic mass causing bronchial obstruction. We should be paid more attention to prevent misdiagnosis of combined endobronchial aspergilloma and lung malignant diseases. PMID- 26629259 TI - Subcellular neuronal quasicrystals: Implications for consciousness. AB - Neuron neurotransmitter receptors are in general pentameric. This enables them to form pentagonal components in biological quasicrystals (similar to mathematical aperiodic tilings). As quasicrystals have been proposed to require quantum effects to exist this might introduce such effects as a component of neurotransmission and thus consciousness. Microtubules may play a role in the clustering of the receptors into quasicrystals, thus modulating their function and may even form quasicrystals themselves. Other quaiscrystals in neurons are potentially formed by water, cholera toxin complexes, and the cytoskeletal components actin and ankyrin. PMID- 26629260 TI - Conversion of volatile alcohols into their glucosides in Arabidopsis. AB - Exposure of tomato plants to volatile chemicals emitted from common cutworm (Spodoptera litura)-infested conspecifics led to accumulation of the glycoside, (Z)-3-hexenyl vicianoside. Accumulation of (Z)-3-hexenyl vicianoside in the exposed plants has adverse impacts on the performance of the common cutworms. The aglycon of (Z)-3-hexenyl vicianoside is derived from airborne (Z)-3-hexenol emitted from infested plants. The ability to incorporate and convert (Z)-3 hexenol to its corresponding glycoside is widely conserved in an array of plant species. However, the specificity of this ability to discriminate between the chemical structures of different volatile alcohols remains unknown. In this study, we investigated glycosylation of several volatile alcohols in Arabidopsis (Arabidopsis thaliana). The exposure of Arabidopsis to a variety of volatile alcohols, (Z)-2-pentenol, (Z)-3-hexenol, (Z)-3-heptenol, (Z)-3-octenol, (Z)-3 nonenol, cyclohexanol, benzyl alcohol, verbenol, perillyl alcohol, myrtenol, geraniol, or linalool led to the detection of the putative corresponding glucosides. These results suggest that Arabidopsis might convert a broad range of volatile alcohols into the corresponding glucosides. PMID- 26629262 TI - The Sixth Annual Payers' Guide to New FDA Approvals. PMID- 26629263 TI - FDA Approvals of Brand-Name Prescription Drugs in 2014. PMID- 26629261 TI - New Perspectives in the Treatment of Opioid-Induced Respiratory Depression. PMID- 26629264 TI - Afrezza (Insulin Human) Inhalation Powder Approved for the Treatment of Patients with Type 1 or Type 2 Diabetes. PMID- 26629265 TI - Akynzeo (Netupitant and Palonosetron), a Dual-Acting Oral Agent, Approved by the FDA for the Prevention of Chemotherapy-Induced Nausea and Vomiting. PMID- 26629266 TI - Cyramza (Ramucirumab) Approved for the Treatment of Advanced Gastric Cancer and Metastatic Non-Small-Cell Lung Cancer. PMID- 26629267 TI - Once-a-Day Harvoni (Ledipasvir plus Sofosbuvir), a New Oral Combination for the Treament of Patients with Genotype 1 Chronic Hepatitis C Infection. PMID- 26629268 TI - Imbruvica (Ibrutinib), First-in-Class Bruton's Tyrosine Kinase Inhibitor, Receives Expanded Indications for Patients with Relapsed Chronic Lymphocytic Leukemia. PMID- 26629269 TI - Invokamet (Canagliflozin plus Metformin HCl): First Fixed-Dose Combination with an SGLT2 Inhibitor Approved for the Treatment of Patients with Type 2 Diabetes. PMID- 26629270 TI - Jakafi (Ruxolitinib): First FDA-Approved Medication for the Treatment of Patients with Polycythemia Vera. PMID- 26629271 TI - Jardiance (Empagliflozin), an SGLT2 Inhibitor, Receives FDA Approval for the Treatment of Patients with Type 2 Diabetes. PMID- 26629272 TI - Keytruda (Pembrolizumab): First PD-1 Inhibitor Approved for Previously Treated Unresectable or Metastatic Melanoma. PMID- 26629273 TI - Ofev (Nintedanib): First Tyrosine Kinase Inhibitor Approved for the Treatment of Patients with Idiopathic Pulmonary Fibrosis. PMID- 26629274 TI - Otezla (Apremilast), an Oral PDE-4 Inhibitor, Receives FDA Approval for the Treatment of Patients with Active Psoriatic Arthritis and Plaque Psoriasis. PMID- 26629275 TI - Sivextro (Tedizolid Phosphate) Approved for the Treatment of Adults with Acute Bacterial Skin and Skin-Structure Infections. PMID- 26629276 TI - Soolantra (Ivermectin) 1% Cream: A Novel, Antibiotic-Free Agent Approved for the Treatment of Patients with Rosacea. PMID- 26629277 TI - Tanzeum (Albiglutide): A Once-Weekly GLP-1 Receptor Agonist Subcutaneous Injection Approved for the Treatment of Patients with Type 2 Diabetes. PMID- 26629278 TI - Trulicity (Dulaglutide): A New GLP-1 Receptor Agonist Once-Weekly Subcutaneous Injection Approved for the Treatment of Patients with Type 2 Diabetes. PMID- 26629279 TI - Velcade (Bortezomib) Receives 2 New FDA Indications: For Retreatment of Patients with Multiple Myeloma and for First-Line Treatment of Patients with Mantle-Cell Lymphoma. PMID- 26629280 TI - Viekira Pak (Ombitasvir, Paritaprevir, and Ritonavir Tablets; Dasabuvir Tablets): All-Oral Fixed Combination Approved for Genotype 1 Chronic Hepatitis C Infection. PMID- 26629281 TI - Zontivity (Vorapaxar), First-in-Class PAR-1 Antagonist, Receives FDA Approval for Risk Reduction of Heart Attack, Stroke, and Cardiovascular Death. PMID- 26629282 TI - Zydelig (Idelalisib): First-in-Class PI3 Kinase Inhibitor Approved for the Treatment of 3 Hematologic Malignancies. PMID- 26629283 TI - Zykadia (Ceritinib) Approved for Patients with Crizotinib-Resistant ALK -Positive Non-Small-Cell Lung Cancer. PMID- 26629284 TI - Once-Fatal Conditions Have Become Chronic: Early Trends in the FDA's 2015 Approvals. PMID- 26629285 TI - Glyxambi (Empagliflozin/Linagliptin): A Dual-Acting Oral Medication Approved for the Treatment of Patients with Type 2 Diabetes. PMID- 26629286 TI - Lenvima (Lenvatinib), a Multireceptor Tyrosine Kinase Inhibitor, Approved by the FDA for the Treatment of Patients with Differentiated Thyroid Cancer. PMID- 26629287 TI - Opdivo (Nivolumab): Second PD-1 Inhibitor Receives FDA Approval for Unresectable or Metastatic Melanoma. PMID- 26629288 TI - Metastatic pleomorphic adenoma to the supraspinatus muscle: a case report and review of a rare aggressive clinical entity. AB - We report a case of a 65-year-old female with a recurrent right parotid pleomorphic adenoma (PA) 24 years after initial surgical excision. Positron emission tomography (PET) and computed tomography (CT) demonstrated an unusual suspicious FDG-avid erosive rim enhancing mass centered in the right supraspinatus muscle. Cytology from CT-guided aspiration of the mass was consistent with a histologically benign PA, and the patient was diagnosed with metastatic pleomorphic adenoma (MPA). The patient later developed diffuse pulmonary metastases and died within 3 months. MPA, although rare, is recognised as a potentially lethal malignant complication of recurrent or longstanding benign PA. As no biochemical or genetic parameters are predictive of malignant change, patients presenting with recurrent PA should be considered for screening for metastatic disease. PMID- 26629289 TI - Successful technical and clinical outcome using a second generation balloon expandable coronary stent for transplant renal artery stenosis: Our experience. AB - Transplant renal artery stenosis (TRAS) is a vascular complication frequently seen because of increase in the number of renal transplantations. Early diagnosis and management is essential to optimize a proper graft function. Currently, the endovascular treatment of TRAS using angioplasty and/or stenting is considered the treatment of choice with the advantage that it does not preclude subsequent surgical correction. Treatment of TRAS with the use of stents, particularly in tortuous transplant renal anatomy presents a unique challenge to an interventional radiologist. In this study, we present three cases from our practice highlighting the use of a balloon-expandable Multi-Link RX Ultra coronary stent system (Abbott Laboratories, Abbott Park, Illinois, USA) for treating high grade focal stenosis along very tortuous renal arterial segments. Cobalt-Chromium alloy stent scaffold provides excellent radial force, whereas the flexible stent design conforms to the vessel course allowing for optimal stent alignment. PMID- 26629290 TI - Wandering spleen, gastric and pancreatic volvulus and right-sided descending and sigmoid colon. AB - Wandering spleen is a rare condition, characterized by a mobile spleen that is attached only by an elongated vascular pedicle, allowing it to migrate to any part of the abdomen or pelvis. Mesenteroaxial gastric volvulus usually occurs in children and may be associated with wandering spleen. Both entities result from abnormal laxity or absence of the peritoneal attachments due to abnormal fusion of the peritoneal mesenteries. Pancreatic volvulus is a very rare anomaly, with only a few isolated case reports described in association with wandering spleen. Anomalous right sided descending and sigmoid colon is a very rare entity and its association with wandering spleen has not been previously reported. We report a case of wandering spleen associated with mesenteroaxial gastric volvulus, pancreatic volvulus and rightward shift of the splenic flexure of the colon and right sided descending and sigmoid colon in a young female. PMID- 26629291 TI - Contrast-enhanced ultrasound findings of post-transplant lymphoproliferative disorder in a transplanted kidney: A case report and literature review. AB - Post-transplant lymphoproliferative disorder occurs in approximately one percent of kidney transplant recipients. We evaluated a seventy-seven year-old man with a solid mass in his transplant kidney. On contrast enhanced ultrasound, the mass enhanced but remained persistently hypovascular throughout exam. The enhancement pattern of the mass differed from that typical of clear cell renal cell carcinoma, the main differential diagnosis. Final pathology after partial nephrectomy confirmed post-transplant lymphoproliferative disorder. This is the first report of contrast enhanced ultrasound findings in a renal mass diagnosed as post-transplant lymphoproliferative disorder. Contrast enhanced ultrasound has a promising role in imaging of renal masses, particularly relevant in transplant patients due to the lack of nephrotoxicity. PMID- 26629292 TI - Evolution of gout: "malignant" change over time? AB - Gout is a common entity; yet it is such a great mimicker in its imaging features that it can confuse clinicians and radiologists alike, sometimes leading to unnecessary investigations and treatment. We present a case of a 52 year old male renal transplant patient who presented with a slow growing mass in his left shin. The initial radiograph demonstrated a non-aggressive looking calcified lesion. A fine needle aspiration demonstrated this lesion to be gout deposition. The lesion was unchanged in the following eight years until the patient reported a sudden growth in size. Imaging showed features of an aggressive lesion with disruption of the previous calcification as well as enhancement on magnetic resonance imaging. Surgical excision biopsy was performed in view of the worrisome features on imaging and the histology showed tophaceous gout. Following description of our case, we reviewed the clinical and imaging features of gout and discussed its differential diagnoses. PMID- 26629293 TI - Cystoid angiocentric glioma: A case report and literature review. AB - Angiocentric glioma is a rare subtype of neuroepithelial tumor that is associated with a history of epilepsy. We report a case of cystoid angiocentric glioma associated with an area of calcification. This 25 year old male patient presented with tonic clonic spasm. He underwent craniotomy with complete resection of the lesion. Pathologic specimen showed monomorphous bipolar cells with angiocentric growth pattern. PMID- 26629294 TI - Cardiovascular magnetic resonance and computed tomography in the evaluation of aneurysmal coronary-cameral fistula. AB - Coronary artery fistulas represent abnormal communications between a coronary artery and a major vessel like venae cavae, pulmonary arteries or veins, the coronary sinus, or a cardiac chamber. The latter is called coronary cameral fistula is a rare condition and is most of the times congenital but can be also post traumatic or post surgical, especially after cardiovascular interventional procedures. Most patients are asymptomatic and coronary-cameral fistulae are discovered incidentally during angiographic evaluation for coronary vascular disorders, while other patients have a clinical presentation ranging from angina pectoris to heart failure. In this article, we report a rare case of an aneurysmal right coronary cameral fistula draining into the left ventricle. Echocardiography usually represents the first diagnostic imaging approach, but often due to a poor acoustic window may not show the entire course of the fistula which is crucial for the final diagnosis. ECG-gated cardiovascular CT may play an important role in the evaluation of the origin, course, termination and morphology of the fistula, its relation to the adjacent anatomical structures as well as the morphology and contractility of the heart. Cardiac MRI instead plays an additional crucial role regarding not only the above mentioned factors but also in estimating the blood flow within the fistula, providing more detailed information about the cardiac function but also about myocardial wall viability. PMID- 26629295 TI - Heterotaxy Polysplenia Syndrome In An Adult With Unique Vascular Anomalies: Case Report With Review Of Literature. AB - The pattern of anatomical organization of the thoraco-abdominal visceral and vascular structures which is not the expected normal arrangement, is called as situs ambiguous or heterotaxy syndrome. Patients with heterotaxy syndrome exhibit a wide spectrum of anatomical variations involving thoraco-abdominal structures. We present here an incidental finding of heterotaxy syndrome associated with unique vascular anomalies in a 35 year old male patient evaluated initially for nephrolithiasis by ultrasonography, and intravenous pyelography. Further evaluation by multidetector row computed tomography showed bilateral bilobed lungs with hyparterial bronchi, cardiac apex to the left, five branches from left sided aortic arch with retroesophageal right subclavian artery, interrupted inferior vena cava with azygos continuation, left renal vein continuing as hemiazygos vein and replaced common hepatic artery arising from the superior mesenteric artery. Other vascular anomalies include right internal iliac vein joining the left common iliac vein and precaval course of the single main right renal artery. Anomalies involving abdominal organs include right-sided stomach, midline liver, multiple splenules (polysplenia) in right upper quadrant of abdomen, short truncated pancreas, intestinal malrotation, inversion of superior mesenteric vessels and a preduodenal portal vein. To the best of our knowledge this is the first report of association of left renal vein continuing as hemiazygos vein, precaval right renal artery and anomalous branching pattern of aortic arch with heterotaxy syndrome. PMID- 26629296 TI - Hemorrhagic heterotopic pregnancy in a setting of prior tubal ligation and re anastomosis. AB - Heterotopic pregnancy is the occurrence of simultaneous intrauterine and extrauterine pregnancies. Heterotopic pregnancy most commonly occurs during the first trimester of pregnancy in women who have significant risk factors including assisted reproductive therapy, prior ectopic pregnancy, and prior pelvic surgery or pelvic inflammatory disease. Although rare, heterotopic pregnancy must be recognized using ultrasound so as to provide appropriate treatment to the extrauterine pregnancy with the goal of preserving the intrauterine pregnancy. The case presented describes a patient with a pathologically proven (figure 8A and 8B), surgically treated 1st trimester heterotopic pregnancy. PMID- 26629297 TI - Primary synovial sarcoma of the abdominal wall: a case report and literature review. AB - Synovial sarcoma (SS) is the fourth most common type of soft tissue sarcoma, following malignant fibrous histiocytoma, liposarcoma, and rhabdomyosarcoma. It usually occurs in the extremities near the large joints of middle-aged patients. We describe a case of synovial sarcoma of the anterior abdominal wall (SSAW) in an adolescent girl and undertake a review of the literature. PMID- 26629298 TI - A Case of Desmoplastic Small Round Cell Tumor. AB - Desmoplastic small round cell tumor is a rare, aggressive tumor primarily affecting young males. It is considered a childhood cancer, and is characterized by a unique chromosomal translocation which leads to failure to suppress tumor growth. It is classified as a soft tissue sarcoma, sharing some features with other small round cell tumors such as Ewing's Sarcoma and primitive neuroectodermal tumor. Typical imaging findings include multiple heterogeneous, lobular abdominal masses, which can grow very large. Often there is a dominant mass with additional peritoneal, omental, retroperitoneal and retrovesical masses. Prognosis is relatively poor with a 3 year survival rate of 50% in those treated aggressively with surgical resection, chemotherapy, and radiation therapy. The clinical presentation, imaging characteristics and pathology are discussed in regards to a recent case. PMID- 26629299 TI - Perineural tumour spread from colon cancer, an unusual cause of trigeminal neuropathy--a case report. AB - Malignant trigeminal neuralgia due to perineural spread along the branches of the trigeminal nerve, is known to commonly occur secondary to squamous cell carcinomas, lymphomas and adenoid cystic carcinomas in the head and neck region. Rarely metastases to the trigeminal nerve have been reported in breast cancer, prostate cancer and colon cancer. To the best of our knowledge trigeminal neuropathy due to skull base metastases and perineural spread along the maxillary (V2) and mandibular (V3) branches of the trigeminal nerve, secondary to colon cancer, has not been previously reported. The diagnosis in our index case was made on magnetic resonance imaging, and patient was treated accordingly by fractionated stereotactic radiotherapy, with subsequent relief of her pain. PMID- 26629300 TI - Sarcoid tenosynovitis, rare presentation of a common disease. Case report and literature review. AB - Sarcoidosis is an idiopathic inflammatory disorder characterized by the presence of non-caseating tissue granulomas most commonly affecting lungs, lymph nodes and skin. Sarcoid skeletal involvement is relatively uncommon and in particular tenosynovitis. We describe an unusual case of sarcoidosis presenting with granulomatous tenosynovitis as the only manifestation of the disease, illustrating the radiological findings on different modalities followed by a review of the literature. Radiologists and clinicians should be aware of tenosynovitis as a manifestation of sarcoidosis as early and therefore appropriate treatment significantly alters patient's outcome and prognosis. PMID- 26629301 TI - Role of bilateral inferior petrosal sinus sampling (BIPSS) in the diagnosis of Cushing's disease in a patient with double superior vena cava. AB - Cushing's syndrome is known to have a wide spectrum of clinical presentation with debilitating consequences and morbidity if not diagnosed and treated in time. Sometimes the diagnosis of Cushing's syndrome can be challenging to the endocrinologist, especially when the usual battery of biochemical tests and advanced cross-sectional imaging is negative or inconclusive. We described a case in which the use of bilateral inferior petrosal sinus sampling (BIPSS) was conclusive albeit being technically challenging (due to a rare incidental finding of double superior vena cava) and invasive in nature. PMID- 26629302 TI - Maxillary mesenchymal chondrosarcoma presenting with epistaxis in a child. AB - Mesenchymal chondrosarcomas are a rare variant of primary chondrosarcomas and can pose a diagnostic dilemma, especially when the features on conventional imaging are equivocal for an aggressive lesion. There is very little PET-CT experience in mesenchymal chondrosarcomas as per the literature and to the best of our knowledge, we are the first to describe a maxillary mesenchymal chondrosarcoma on PET-CT imaging. We report a case where PET-CT not only complemented conventional imaging in suspecting a malignant osseous lesion, but also was indicative of the grade of the tumor. PMID- 26629303 TI - Diffuse Proliferative Cerebral Angiopathy: A case report and review of the literature. AB - Diffuse proliferative cerebral angiopathy is a distinct entity from cerebral arterio-venous malformations; characterized by multiple small arterial feeders and draining veins with normal brain parenchyma seen in-between the abnormal vessels. It is usually seen in younger age group. Here we report a case of diffuse cerebral proliferative angiopathy in a 78-year-old female patient along with discussion of the neuro-imaging findings and review of the literature. It is important to recognize this entity to avoid aggressive surgery or intervention and thus preventing permanent damage to the normal intermingled brain tissue. PMID- 26629304 TI - Aggressive Metaplastic Carcinoma of the Breast with Osteoclastic Giant Cells. AB - Metaplastic carcinoma of the breast is an uncommon type of malignancy that is aggressive but can mimic other benign breast neoplastic processes on imaging. We present a case of a young female patient who presented with a rapidly progressing metaplastic carcinoma with osteoclastic giant cells subtype. There have been only very rare published reports of this pathologic subtype of metaplastic carcinoma containing osteoclastic giant cells. PMID- 26629305 TI - Incarceration of umbilical hernia: a rare complication of large volume paracentesis. AB - We present two cases of umbilical hernia incarceration following large volume paracentesis (LVP) in patients with cirrhotic ascites. Both patients became symptomatic within 48 hours after the LVP. Although being rare, given the significantly higher mortality rate of cirrhotic patients undergoing emergent herniorrhaphy, this complication of LVP is potentially serious. Therefore, it is recommended that patients be examined closely for the presence of umbilical hernias before removal of ascitic fluid and an attempt should be made for external reduction of easily reducible hernias, if a hernia is present. PMID- 26629306 TI - Mycobacterium kansasii causing chronic monoarticular synovitis in a patient with HIV/AIDS. AB - Mycobacterium kansasii is a nontuberculous mycobacterium that primarily causes pulmonary disease in AIDS patients, however it has also been known, rarely, to result in skeletal infection. When skeletal infection occurs, the time from onset of symptoms to diagnosis is up to 5 years in previously reported cases. We describe a 48-year-old woman with HIV/AIDS who presented with chronic, isolated left knee pain and swelling of over two decades which had recently worsened. Radiographs and magnetic resonance imaging demonstrated marked subarticular erosions, synovial thickening, and bone marrow edema, which had progressed compared with prior imaging done seven years earlier. Synovial biopsy grew Mycobacterium kansasii. Following the presentation of our case, clinical and imaging findings, including the differential diagnosis, of monoarticular arthritis caused by Mycobacterium kansasii are reviewed and discussed. PMID- 26629307 TI - Minimally invasive percutaneous endovascular therapies in the management of complications of non-alcoholic fatty liver disease (NAFLD): A case report. AB - Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of disorders from simple steatosis to inflammation leading to fibrosis, cirrhosis, and even hepatocellular carcinoma. With the progressive epidemics of obesity and diabetes, major risk factors in the development and pathogenesis of NAFLD, the prevalence of NAFLD and its associated complications including liver failure and hepatocellular carcinoma is expected to increase by 2030 with an enormous health and economic impact. We present a patient who developed Hepatocellular carcinoma (HCC) from nonalcoholic steatohepatitis (NASH) cirrhosis. Due to morbid obesity, she was not an optimal transplant candidate and was not initially listed. After attempts for lifestyle modifications failed to lead to weight reduction, a transarterial embolization of the left gastric artery was performed. This is the sixth such procedure in humans in literature. Subsequently she had a meaningful drop in BMI from 42 to 36 over the following 6 months ultimately leading to her being listed for transplant. During this time, the left hepatic HCC was treated with chemoembolization without evidence of recurrence. In this article, we wish to highlight the use of minimally invasive percutaneous endovascular therapies such as transarterial chemoembolization (TACE) in the comprehensive management of the NAFLD spectrum and percutaneous transarterial embolization of the left gastric artery (LGA), a novel method, for the management of obesity. PMID- 26629308 TI - Genome sequence of Bradyrhizobium sp. WSM1253; a microsymbiont of Ornithopus compressus from the Greek Island of Sifnos. AB - Bradyrhizobium sp. WSM1253 is a novel N2-fixing bacterium isolated from a root nodule of the herbaceous annual legume Ornithopus compressus that was growing on the Greek Island of Sifnos. WSM1253 emerged as a strain of interest in an Australian program that was selecting inoculant quality bradyrhizobial strains for inoculation of Mediterranean species of lupins (Lupinus angustifolius, L. princei, L. atlanticus, L. pilosus). In this report we describe, for the first time, the genome sequence information and annotation of this legume microsymbiont. The 8,719,808 bp genome has a G + C content of 63.09 % with 71 contigs arranged into two scaffolds. The assembled genome contains 8,432 protein coding genes, 66 RNA genes and a single rRNA operon. This improved-high-quality draft rhizobial genome is one of 20 sequenced through a DOE Joint Genome Institute 2010 Community Sequencing Project. PMID- 26629309 TI - Complete genome sequence and characterization of the haloacid-degrading Burkholderia caribensis MBA4. AB - Burkholderia caribensis MBA4 was isolated from soil for its capability to grow on haloacids. This bacterium has a genome size of 9,482,704 bp. Here we report the genome sequences and annotation, together with characteristics of the genome. The complete genome sequence consists of three replicons, comprising 9056 protein coding genes and 80 RNA genes. Genes responsible for dehalogenation and uptake of haloacids were arranged as an operon. While dehalogenation of haloacetate would produce glycolate, three glycolate operons were identified. Two of these operons contain an upstream glcC regulator gene. It is likely that the expression of one of these operons is responsive to haloacetate. Genes responsible for the metabolism of dehalogenation product of halopropionate were also identified. PMID- 26629310 TI - Discovery and characterization of the first non-coding RNA that regulates gene expression, micF RNA: A historical perspective. AB - The first evidence that RNA can function as a regulator of gene expression came from experiments with prokaryotes in the 1980s. It was shown that Escherichia coli micF is an independent gene, has its own promoter, and encodes a small non coding RNA that base pairs with and inhibits translation of a target messenger RNA in response to environmental stress conditions. The micF RNA was isolated, sequenced and shown to be a primary transcript. In vitro experiments showed binding to the target ompF mRNA. Secondary structure probing revealed an imperfect micF RNA/ompF RNA duplex interaction and the presence of a non canonical base pair. Several transcription factors, including OmpR, regulate micF transcription in response to environmental factors. micF has also been found in other bacterial species, however, recently Gerhart Wagner and Jorg Vogel showed pleiotropic effects and found micF inhibits expression of multiple target mRNAs; importantly, one is the global regulatory gene lrp. In addition, micF RNA was found to interact with its targets in different ways; it either inhibits ribosome binding or induces degradation of the message. Thus the concept and initial experimental evidence that RNA can regulate gene expression was born with prokaryotes. PMID- 26629311 TI - Targeting amino acid metabolism in cancer growth and anti-tumor immune response. AB - Recent advances in amino acid metabolism have revealed that targeting amino acid metabolic enzymes in cancer therapy is a promising strategy for the development of novel therapeutic agents. There are currently several drugs in clinical trials that specifically target amino acid metabolic pathways in tumor cells. In the context of the tumor microenvironment, however, tumor cells form metabolic relationships with immune cells, and they often compete for common nutrients. Many tumors evolved to escape immune surveillance by taking advantage of their metabolic flexibility and redirecting nutrients for their own advantage. This review outlines the most recent advances in targeting amino acid metabolic pathways in cancer therapy while giving consideration to the impact these pathways may have on the anti-tumor immune response. PMID- 26629312 TI - Regulation of MYC gene expression by aberrant Wnt/beta-catenin signaling in colorectal cancer. AB - The Wnt/beta-catenin signaling pathway controls intestinal homeostasis and mutations in components of this pathway are prevalent in human colorectal cancers (CRCs). These mutations lead to inappropriate expression of genes controlled by Wnt responsive DNA elements (WREs). T-cell factor/Lymphoid enhancer factor transcription factors bind WREs and recruit the beta-catenin transcriptional co activator to activate target gene expression. Deregulated expression of the c-MYC proto-oncogene (MYC) by aberrant Wnt/beta-catenin signaling drives colorectal carcinogenesis. In this review, we discuss the current literature pertaining to the identification and characterization of WREs that control oncogenic MYC expression in CRCs. A common theme has emerged whereby these WREs often map distally to the MYC genomic locus and control MYC gene expression through long range chromatin loops with the MYC proximal promoter. We propose that by determining which of these WREs is critical for CRC pathogenesis, novel strategies can be developed to treat individuals suffering from this disease. PMID- 26629313 TI - Crosstalk between mitochondria and peroxisomes. AB - Mitochondria and peroxisomes are small ubiquitous organelles. They both play major roles in cell metabolism, especially in terms of fatty acid metabolism, reactive oxygen species (ROS) production, and ROS scavenging, and it is now clear that they metabolically interact with each other. These two organelles share some properties, such as great plasticity and high potency to adapt their form and number according to cell requirements. Their functions are connected, and any alteration in the function of mitochondria may induce changes in peroxisomal physiology. The objective of this paper was to highlight the interconnection and the crosstalk existing between mitochondria and peroxisomes. Special emphasis was placed on the best known connections between these organelles: origin, structure, and metabolic interconnections. PMID- 26629314 TI - Modulation of the matrix redox signaling by mitochondrial Ca(2.). AB - Mitochondria sense, shape and integrate signals, and thus function as central players in cellular signal transduction. Ca(2+) waves and redox reactions are two such intracellular signals modulated by mitochondria. Mitochondrial Ca(2+) transport is of utmost physio-pathological relevance with a strong impact on metabolism and cell fate. Despite its importance, the molecular nature of the proteins involved in mitochondrial Ca(2+) transport has been revealed only recently. Mitochondrial Ca(2+) promotes energy metabolism through the activation of matrix dehydrogenases and down-stream stimulation of the respiratory chain. These changes also alter the mitochondrial NAD(P)H/NAD(P)(+) ratio, but at the same time will increase reactive oxygen species (ROS) production. Reducing equivalents and ROS are having opposite effects on the mitochondrial redox state, which are hard to dissect. With the recent development of genetically encoded mitochondrial-targeted redox-sensitive sensors, real-time monitoring of matrix thiol redox dynamics has become possible. The discoveries of the molecular nature of mitochondrial transporters of Ca(2+) combined with the utilization of the novel redox sensors is shedding light on the complex relation between mitochondrial Ca(2+) and redox signals and their impact on cell function. In this review, we describe mitochondrial Ca(2+) handling, focusing on a number of newly identified proteins involved in mitochondrial Ca(2+) uptake and release. We further discuss our recent findings, revealing how mitochondrial Ca(2+) influences the matrix redox state. As a result, mitochondrial Ca(2+) is able to modulate the many mitochondrial redox-regulated processes linked to normal physiology and disease. PMID- 26629315 TI - Signal transducer and activator of transcription 3 regulation by novel binding partners. AB - Signal transducers and activators of transcription (STATs) mediate essential signals for various biological processes, including immune responses, hematopoiesis, and neurogenesis. STAT3, for example, is involved in the pathogenesis of various human diseases, including cancers, autoimmune and inflammatory disorders. STAT3 activation is therefore tightly regulated at multiple levels to prevent these pathological conditions. A number of proteins have been reported to associate with STAT3 and regulate its activity. These STAT3 interacting proteins function to modulate STAT3-mediated signaling at various steps and mediate the crosstalk of STAT3 with other cellular signaling pathways. This article reviews the roles of novel STAT3 binding partners such as DAXX, zipper-interacting protein kinase, Kruppel-associated box-associated protein 1, Y14, PDZ and LIM domain 2 and signal transducing adaptor protein-2, in the regulation of STAT3-mediated signaling. PMID- 26629317 TI - Cyclin A2: At the crossroads of cell cycle and cell invasion. AB - Cyclin A2 is an essential regulator of the cell division cycle through the activation of kinases that participate to the regulation of S phase as well as the mitotic entry. However, whereas its degradation by the proteasome in mid mitosis was thought to be essential for mitosis to proceed, recent observations show that a small fraction of cyclin A2 persists beyond metaphase and is degraded by autophagy. Its implication in the control of cytoskeletal dynamics and cell movement has unveiled its role in the modulation of RhoA activity. Since this GTPase is involved in both cell rounding early in mitosis and later, in the formation of the cleavage furrow, this suggests that cyclin A2 is a novel actor in cytokinesis. Taken together, these data point to this cyclin as a potential mediator of cell-niche interactions whose dysregulation could be taken as a hallmark of metastasis. PMID- 26629316 TI - Global histone post-translational modifications and cancer: Biomarkers for diagnosis, prognosis and treatment? AB - Global alterations in epigenetic landscape are now recognized as a hallmark of cancer. Epigenetic mechanisms such as DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs are proven to have strong association with cancer. In particular, covalent post-translational modifications of histone proteins are known to play an important role in chromatin remodeling and thereby in regulation of gene expression. Further, histone modifications have also been associated with different aspects of carcinogenesis and have been studied for their role in the better management of cancer patients. In this review, we will explore and discuss how histone modifications are involved in cancer diagnosis, prognosis and treatment. PMID- 26629318 TI - Klotho in cardiovascular disease: Current and future perspectives. AB - Protein Klotho, beyond its role as a regulator of the phosphatemia, is also involved in the maintaining of the cardiovascular health, being associated its alterations with the development of cardiovascular damage and increased morbi mortality. For all this, nowadays Klotho is the subject of a thorough research which is focused on uncover its intimate mechanisms of action, and in analyzing the utility of its modulation as a potential strategy with clinical applicability. Molecular mechanisms of Klotho are not well understood but an emerging research area links Klotho deficiency with vascular pathology. Changes in this protein have been associated with cardiovascular-related complications like inflammation, vascular calcification, and endothelial dysfunction. All this is particularly relevant if considering the recent discovery of Klotho expression in vascular tissue. PMID- 26629319 TI - Caldecrin: A pancreas-derived hypocalcemic factor, regulates osteoclast formation and function. AB - Caldecrin was originally isolated from the pancreas as a factor that reduced serum calcium levels. This secreted serine protease has chymotrypsin-like activity and is also known as chymotrypsin C; it belongs to the elastase family. Although intravenous administration of caldecrin decreases the serum calcium concentration even when its protease activity is blocked, this effect does require cleavage of caldecrin's pro-peptide by trypsin, converting it to the mature enzyme. Ectopic intramuscular expression of caldecrin prevented bone resorption in ovariectomized mice. Caldecrin inhibited parathyroid hormone stimulated calcium release from fetal mouse long bone organ cultures. Furthermore, caldecrin suppressed the formation of osteoclasts from bone marrow cells by inhibiting the receptor activator of nuclear factor-kappa B ligand (RANKL)-stimulated phospholipase Cgamma-calcium oscillation-calcineurin-nuclear factor of activated T-cells, cytoplasmic 1 pathway. Caldecrin also suppressed the bone resorption activity of mature osteoclasts by preventing RANKL-stimulated Src activation, calcium entry, and actin ring formation. In vivo and in vitro studies have indicated that caldecrin is a unique multifunctional protease with anti osteoclastogenic activities that are distinct from its protease activity. Caldecrin might be a potential therapeutic target for the treatment of osteolytic diseases such as osteoporosis and osteoarthritis. This mini-review describes caldecrin's historical background and its mechanisms of action. PMID- 26629320 TI - Disruption of NAD(+) binding site in glyceraldehyde 3-phosphate dehydrogenase affects its intranuclear interactions. AB - AIM: To characterize phosphorylation of human glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and mobility of GAPDH in cancer cells treated with chemotherapeutic agents. METHODS: We used proteomics analysis to detect and characterize phosphorylation sites within human GAPDH. Site-specific mutagenesis and alanine scanning was then performed to evaluate functional significance of phosphorylation sites in the GAPDH polypeptide chain. Enzymatic properties of mutated GAPDH variants were assessed using kinetic studies. Intranuclear dynamics parameters (diffusion coefficient and the immobile fraction) were estimated using fluorescence recovery after photobleaching (FRAP) experiments and confocal microscopy. Molecular modeling experiments were performed to estimate the effects of mutations on NAD(+) cofactor binding. RESULTS: Using MALDI-TOF analysis, we identified novel phosphorylation sites within the NAD(+) binding center of GAPDH at Y94, S98, and T99. Using polyclonal antibody specific to phospho-T99 containing peptide within GAPDH, we demonstrated accumulation of phospho-T99 GAPDH in the nuclear fractions of A549, HCT116, and SW48 cancer cells after cytotoxic stress. We performed site-mutagenesis, and estimated enzymatic properties, intranuclear distribution, and intranuclear mobility of GAPDH mutated variants. Site-mutagenesis at positions S98 and T99 in the NAD(+) binding center reduced enzymatic activity of GAPDH due to decreased affinity to NAD(+) (Km = 741 +/- 257 MUmol/L in T99I vs 57 +/- 11.1 umol/L in wild type GAPDH. Molecular modeling experiments revealed the effect of mutations on NAD(+) binding with GAPDH. FRAP (fluorescence recovery after photo bleaching) analysis showed that mutations in NAD(+) binding center of GAPDH abrogated its intranuclear interactions. CONCLUSION: Our results suggest an important functional role of phosphorylated amino acids in the NAD(+) binding center in GAPDH interactions with its intranuclear partners. PMID- 26629321 TI - Connective tissue growth factor differentially binds to members of the cystine knot superfamily and potentiates platelet-derived growth factor-B signaling in rabbit corneal fibroblast cells. AB - AIM: To study the binding of connective tissue growth factor (CTGF) to cystine knot-containing ligands and how this impacts platelet-derived growth factor (PDGF)-B signaling. METHODS: The binding strengths of CTGF to cystine knot containing growth factors including vascular endothelial growth factor (VEGF)-A, PDGF-B, bone morphogenetic protein (BMP)-4, and transforming growth factor (TGF) beta1 were compared using the LexA-based yeast two-hybrid system. EYG48 reporter strain that carried a wild-type LEU2 gene under the control of LexA operators and a lacZ reporter plasmid (p80p-lacZ) containing eight high affinity LexA binding sites were used in the yeast two-hybrid analysis. Interactions between CTGF and the tested growth factors were evaluated based on growth of transformed yeast cells on selective media and colorimetric detection in a liquid beta galactosidase activity assay. Dissociation constants of CTGF to VEGF-A isoform 165 or PDGF-BB homo-dimer were measured in surface plasma resonance (SPR) analysis. CTGF regulation in PDGF-B presentation to the PDGF receptor beta (PDGFRbeta) was also quantitatively assessed by the SPR analysis. Combinational effects of CTGF protein and PDGF-BB on activation of PDGFRbeta and downstream signaling molecules ERK1/2 and AKT were assessed in rabbit corneal fibroblast cells by Western analysis. RESULTS: In the LexA-based yeast two-hybrid system, cystine knot motifs of tested growth factors were fused to the activation domain of the transcriptional factor GAL4 while CTGF was fused to the DNA binding domain of the bacterial repressor protein LexA. Yeast co-transformants containing corresponding fusion proteins for CTGF and all four tested cystine knot motifs survived on selective medium containing galactose and raffinose but lacking histidine, tryptophan, and uracil. In liquid beta-galactosidase assays, CTGF expressing cells that were co-transformed with the cystine knot of VEGF-A had the highest activity, at 29.88 +/- 0.91 fold above controls (P < 0.01). Cells containing the cystine knot of BMP-4 expressed the second most activity, with a 24.77 +/- 0.47 fold increase (P < 0.01). Cells that contained the cystine knot of TGF-beta1 had a 3.80 +/- 0.66 fold increase (P < 0.05) and the ones with the cystine knot of PDGF-B had a 2.64 +/- 0.33 fold increase of beta-galactosidase activity (P < 0.01). Further SPR analysis showed that the association rate between VEGF-A 165 and CTGF was faster than PDGF-BB and CTGF. The calculated dissociation constant (KD) of CTGF to VEGF165 and PDGF-BB was 1.8 and 43 nmol/L respectively. PDGF-BB ligand and PDGFRbeta receptor formed a stable complex with a low dissociation constant 1.4 nmol/L. Increasing the concentration of CTGF up to 263.2 nmol/L significantly the ligand/receptor binding. In addition, CTGF potentiated phosphorylation of PDGFRbeta and AKT in rabbit corneal fibroblast cells stimulated by PDGF-BB in tissue culture condition. In contrast, CTGF did not affect PDGF-B induced phosphorylation of ERK1/2. CONCLUSION: CTGF has a differential binding affinity to VEGF-A, PDGF-B, BMP-4, and TGF-beta. Its weak association with PDGF-B may represent a novel mechanism to enhance PDGF-B signaling. PMID- 26629323 TI - JAK3 inhibitor VI is a mutant specific inhibitor for epidermal growth factor receptor with the gatekeeper mutation T790M. AB - AIM: To identify non-quinazoline kinase inhibitors effective against drug resistant mutants of epidermal growth factor receptor (EGFR). METHODS: A kinase inhibitor library was subjected to screening for specific inhibition pertaining to the in vitro kinase activation of EGFR with the gatekeeper mutation T790M, which is resistant to small molecular weight tyrosine kinase inhibitors (TKIs) for EGFR in non-small cell lung cancers (NSCLCs). This inhibitory effect was confirmed by measuring autophosphorylation of EGFR T790M/L858R in NCI-H1975 cells, an NSCLC cell line harboring the gatekeeper mutation. The effects of a candidate compound, Janus kinase 3 (JAK3) inhibitor VI, on cell proliferation were evaluated using the MTT assay and were compared between T790M-positive and negative lung cancer cell lines. JAK3 inhibitor VI was modeled into the ATP binding pocket of EGFR T790M/L858R. Potential physical interactions between the compound and kinase domains of wild-type (WT) or mutant EGFRs or JAK3 were estimated by calculating binding energy. The gatekeeper residues of EGFRs and JAKs were aligned to discuss the similarities among EGFR T790M and JAKs. RESULTS: We found that JAK3 inhibitor VI, a known inhibitor for JAK3 tyrosine kinase, selectively inhibits EGFR T790M/L858R, but has weaker inhibitory effects on the WT EGFR in vitro. JAK3 inhibitor VI also specifically reduced autophosphorylation of EGFR T790M/L858R in NCI-H1975 cells upon EGF stimulation, but did not show the inhibitory effect on WT EGFR in A431 cells. Furthermore, JAK3 inhibitor VI suppressed the proliferation of NCI-H1975 cells, but showed limited inhibitory effects on the WT EGFR-expressing cell lines A431 and A549. A docking simulation between JAK3 inhibitor VI and the ATP-binding pocket of EGFR T790M/L858R predicted a potential binding status with hydrogen bonds. Estimated binding energy of JAK3 inhibitor VI to EGFR T790M/L858R was more stable than its binding energy to the WT EGFR. Amino acid sequence alignments revealed that the gatekeeper residues of JAK family kinases are methionine in WT, similar to EGFR T790M, suggesting that TKIs for JAKs may also be effective for EGFR T790M. CONCLUSION: Our findings demonstrate that JAK3 inhibitor VI is a gatekeeper mutant selective TKI and offer a strategy to search for new EGFR T790M inhibitors. PMID- 26629322 TI - DNA microarray unravels rapid changes in transcriptome of MK-801 treated rat brain. AB - AIM: To investigate the impact of MK-801 on gene expression patterns genome wide in rat brain regions. METHODS: Rats were treated with an intraperitoneal injection of MK-801 [0.08 (low-dose) and 0.16 (high-dose) mg/kg] or NaCl (vehicle control). In a first series of experiment, the frontoparietal electrocorticogram was recorded 15 min before and 60 min after injection. In a second series of experiments, the whole brain of each animal was rapidly removed at 40 min post injection, and different regions were separated: amygdala, cerebral cortex, hippocampus, hypothalamus, midbrain and ventral striatum on ice followed by DNA microarray (4 * 44 K whole rat genome chip) analysis. RESULTS: Spectral analysis revealed that a single systemic injection of MK-801 significantly and selectively augmented the power of baseline gamma frequency (30-80 Hz) oscillations in the frontoparietal electroencephalogram. DNA microarray analysis showed the largest number (up- and down- regulations) of gene expressions in the cerebral cortex (378), midbrain (376), hippocampus (375), ventral striatum (353), amygdala (301), and hypothalamus (201) under low-dose (0.08 mg/kg) of MK-801. Under high-dose (0.16 mg/kg), ventral striatum (811) showed the largest number of gene expression changes. Gene expression changes were functionally categorized to reveal expression of genes and function varies with each brain region. CONCLUSION: Acute MK-801 treatment increases synchrony of baseline gamma oscillations, and causes very early changes in gene expressions in six individual rat brain regions, a first report. PMID- 26629325 TI - Sex differences in autonomic function following maximal exercise. AB - BACKGROUND: Heart rate variability (HRV), blood pressure variability, (BPV) and heart rate recovery (HRR) are measures that provide insight regarding autonomic function. Maximal exercise can affect autonomic function, and it is unknown if there are sex differences in autonomic recovery following exercise. Therefore, the purpose of this study was to determine sex differences in several measures of autonomic function and the response following maximal exercise. METHODS: Seventy one (31 males and 40 females) healthy, nonsmoking, sedentary normotensive subjects between the ages of 18 and 35 underwent measurements of HRV and BPV at rest and following a maximal exercise bout. HRR was measured at minute one and two following maximal exercise. RESULTS: Males have significantly greater HRR following maximal exercise at both minute one and two; however, the significance between sexes was eliminated when controlling for VO2 peak. Males had significantly higher resting BPV-low-frequency (LF) values compared to females and did not significantly change following exercise, whereas females had significantly increased BPV-LF values following acute maximal exercise. Although males and females exhibited a significant decrease in both HRV-LF and HRV-high frequency (HF) with exercise, females had significantly higher HRV-HF values following exercise. Males had a significantly higher HRV-LF/HF ratio at rest; however, both males and females significantly increased their HRV-LF/HF ratio following exercise. CONCLUSIONS: Pre-menopausal females exhibit a cardioprotective autonomic profile compared to age-matched males due to lower resting sympathetic activity and faster vagal reactivation following maximal exercise. Acute maximal exercise is a sufficient autonomic stressor to demonstrate sex differences in the critical post-exercise recovery period. PMID- 26629324 TI - Phenotypic plasticity and modularity allow for the production of novel mosaic phenotypes in ants. AB - BACKGROUND: The origin of discrete novelties remains unclear. Some authors suggest that qualitative phenotypic changes may result from the reorganization of preexisting phenotypic traits during development (i.e., developmental recombination) following genetic or environmental changes. Because ants combine high modularity with extreme phenotypic plasticity (queen and worker castes), their diversified castes could have evolved by developmental recombination. We performed a quantitative morphometric study to investigate the developmental origins of novel phenotypes in the ant Mystrium rogeri, which occasionally produces anomalous 'intercastes.' Our analysis compared the variation of six morphological modules with body size using a large sample of intercastes. RESULTS: We confirmed that intercastes are conspicuous mosaics that recombine queen and worker modules. In addition, we found that many other individuals traditionally classified as workers or queens also exhibit some level of mosaicism. The six modules had distinct profiles of variation suggesting that each module responds differentially to factors that control body size and polyphenism. Mosaicism appears to result from each module responding differently yet in an ordered and predictable manner to intermediate levels of inducing factors that control polyphenism. The order of module response determines which mosaic combinations are produced. CONCLUSIONS: Because the frequency of mosaics and their canalization around a particular phenotype may evolve by selection on standing genetic variation that affects the plastic response (i.e., genetic accommodation), developmental recombination is likely to play an important role in the evolution of novel castes in ants. Indeed, we found that most mosaics have queen-like head and gaster but a worker-like thorax congruent with the morphology of ergatoid queens and soldiers, respectively. Ergatoid queens of M. oberthueri, a sister species of M. rogeri, could have evolved from intercastes produced ancestrally through such a process. PMID- 26629326 TI - High-grade soft tissue sarcoma arising in a desmoid tumor: case report and review of the literature. AB - Desmoid tumors are rare benign monoclonal fibroblastic tumors. Their aggressiveness is local with no potential for metastasis or dedifferentiation. Here we report on a 61-year-old patient who presented a locally advanced breast desmoid tumor diagnosed 20 years after post-operative radiotherapy for breast carcinoma. After 2 years of medical treatment, a high-grade undifferentiated pleomorphic soft tissue sarcoma arose within the desmoid tumor. Despite extensive surgery removing both tumors, the patient showed locoregional relapse by the sarcoma, followed by multimetastatic progression, then death 25 months after the surgery. The arising of a soft tissue sarcoma in a desmoid tumor is an exceptional event since our case is the fourth one reported so far in literature. It reinforces the need for timely and accurate diagnosis when a new mass develops in the region of a preexisting desmoid tumor, and more generally when a desmoid tumor modifies its clinical or radiological aspect. PMID- 26629327 TI - A survey of energy drink and alcohol mixed with energy drink consumption. AB - BACKGROUND: Energy drink consumption among youth is increasing despite recommendations by the American Academy of Pediatrics to eliminate consumption by youth. This study provides information on consumption of energy drinks and alcohol mixed with energy drinks (AmED) in a sample of Israeli youth and how consumer knowledge about the risks affects consumption rates. METHODS: The study was conducted in three Tel Aviv public schools, with a total enrollment of 1,253 students in grades 8 through 12. Among them, 802 students completed a 49-item questionnaire about energy drink and AmED consumption, for a 64 % response rate Non-responders included 451 students who were absent or refused to participate. All students in the same school were administered the questionnaire on the same day. RESULTS: Energy drinks are popular among youth (84.2 % have ever drunk). More tenth through twelfth grade students consumed energy drinks than eighth and ninth grade students. Students who began drinking in elementary school (36.8 %) are at elevated risk for current energy drink (P < .001) and AmED (P = .002) use. Knowledge about amounts consumed and recommended allowances is associated with less consumption (OR 1.925; 95 %CI 1.18-3.14). DISCUSSION: The association between current AmED consumption and drinking ED at a young age is important. Boys and those who start drinking early have a greater risk of both ED and AmED consumption. The characteristics of early drinkers can help increase awareness of potential at-risk youth, such as junior and senior high school students with less educated or single parents. CONCLUSIONS: Risks posed by early use on later energy drink and AmED consumption are concerning. We suggest that parents should limit accessibility. Increased knowledge about acceptable and actual amounts of caffeine in a single product might decrease consumption. PMID- 26629329 TI - Thoracolumbar partial lateral corpectomy for the treatment of chronic intervertebral disc disease in 107 dogs. AB - BACKGROUND: The purpose of this retrospective study was to assess short-and medium-term outcomes in dogs with chronic ventral thoracolumbar intervertebral disc disease (IVDD) treated by thoracolumbar partial lateral corpectomy (TLPLC). Dogs surgically treated for chronic ventral IVDD by TLPLC were included. For each dog, neurological status evolution and complications were reported. Factors that could have influenced neurological recovery were statistically tested. RESULTS: A total of 107 dogs were included in the study. Before surgery, 67.3 % of the dogs were able to walk, 24.3 % were grade 3, and 8.4 % were grade 4. The median hospitalization time was 3 days, and 82.2 % of the dogs were able to walk at discharge. The medium-term neurological grade was reached at a median time of 2 months. At the medium-term follow-up (median 12 months), 74.3 % of the dogs were neurologically improved, 22.9 % were stable, and 2.8 % were worsened. A total of 91.4 % of dogs were ambulatory, with 58.6 % of dogs having a normal gait. Preoperative neurological grade was significantly associated with the neurological status 24 h after the surgery and at discharge. Dogs with a higher preoperative neurological grade had a better chance of improving but lower odds of walking at 24 h after the surgery and at discharge compared with dogs with a lower preoperative grade. Spinal compression recurrence at the same surgical site was confirmed in 8 cases. CONCLUSION: Even if TLPLC leads to several intra and postoperative complications, this technique is a viable surgical option to treat chronic ventral IVDD. PMID- 26629328 TI - Vascular Notch proteins and Notch signaling in the peri-implantation mouse uterus. AB - BACKGROUND: Angiogenesis is essential for uterine decidualization, the progesterone-mediated transformation of the uterus allowing embryo implantation and initiation of pregnancy. In the current study, we define the vasculature, expression of Notch proteins and Notch ligands, and Notch activity in both endothelial cells and vascular-associated mural cells of blood vessels in the pre implantation endometrium and post-implantation decidua of the mouse uterus. METHODS: We used immunofluorescence to determine the expression of Notch in endothelial cells and mural cells by co-staining for the endothelial cell marker, CD31, the pan-mural cell marker, platelet-derived growth factor receptor beta (PDGFR-beta), the pericyte markers, neural/glial antigen 2 (NG2) and desmin, or the smooth muscle cell marker, alpha smooth muscle actin (SMA). A fluorescein isothiocyanate-labeled dextran tracer, was used to identify functional peri implantation vasculature. CBF:H2B-Venus Notch reporter transgenic mice were used to determine Notch activity. RESULTS: Notch signaling is observed in endothelial cells and pericytes in the peri-implantation uterus. Prior to implantation, Notch1, Notch2 and Notch4 and Notch ligand, Delta-like 4 (Dll4) are expressed in capillary endothelial cells, while Notch3 is expressed in the pericytes. Jagged1 is expressed in both capillary endothelial cells and pericytes. After implantation, Notch1, Notch4 and Dll4 are expressed in endothelial cells of newly formed decidual capillaries. Jagged1 is expressed in endothelial cells of spiral arteries and a subset of decidual pericytes. Notch proteins are not expressed in lymphatic vessels or macrophages in the peri-implantation uterus. CONCLUSIONS: We show Notch activity and distinct expression patterns for Notch proteins and ligands, suggesting unique roles for Notch1, Notch4, Dll4, and Jag1 during decidual angiogenesis and early placentation. These data set the stage for loss of-function and gain-of-function studies that will determine the cell-type specific requirements for Notch proteins in decidual angiogenesis and placentation. PMID- 26594320 TI - A pre-zygotic barrier to hybridization in two con-generic species of scleractinian corals. AB - Hybridization is often cited as a potential source of evolutionary novelty in the order Scleractinia. While hybrid embryos can be produced in vitro, it has been difficult to identify adult hybrids in the wild. Here, we tested the potential for hybridization between two closely related species in the family Fungiidae. We mixed approximately 5000 eggs of Ctenactis echinata with sperm from C. crassa. No hybrid embryos were produced. This observation adds to a growing body of evidence for pre-zygotic barriers to hybridization in corals and challenges the claim that hybridization is a major source of evolutionary novelty in the order. PMID- 26629331 TI - The PDB database is a rich source of alpha-helical anti-microbial peptides to combat disease causing pathogens. AB - The therapeutic potential of alpha-helical anti-microbial peptides (AH-AMP) to combat pathogens is fast gaining prominence. Based on recently published open access software for characterizing alpha-helical peptides (PAGAL), we elucidate a search methodology (SCALPEL) that leverages the massive structural data pre existing in the PDB database to obtain AH-AMPs belonging to the host proteome. We provide in vitro validation of SCALPEL on plant pathogens ( Xylella fastidiosa, Xanthomonas arboricola and Liberibacter crescens) by identifying AH-AMPs that mirror the function and properties of cecropin B, a well-studied AH-AMP. The identified peptides include a linear AH-AMP present within the existing structure of phosphoenolpyruvate carboxylase (PPC20), and an AH-AMP mimicing the properties of the two alpha-helices of cecropin B from chitinase (CHITI25). The minimum inhibitory concentration of these peptides are comparable to that of cecropin B, while anionic peptides used as control failed to show any inhibitory effect on these pathogens. Substitute therapies in place of conventional chemotherapies using membrane permeabilizing peptides like these might also prove effective to target cancer cells. The use of native structures from the same organism largely ensures that administration of such peptides will be better tolerated and not elicit an adverse immune response. We suggest a similar approach to target Ebola epitopes, enumerated using PAGAL recently, by selecting suitable peptides from the human proteome, especially in wake of recent reports of cationic amphiphiles inhibiting virus entry and infection. PMID- 26629332 TI - Following specific podocyte injury captopril protects against progressive long term renal damage. AB - BACKGROUND: Angiotensin converting enzyme inhibitors (ACEi) reduce proteinuria and preserve kidney function in proteinuric renal diseases. Their nephroprotective effect exceeds that attributable to lowering of blood pressure alone. This study examines the potential of ACEi to protect from progression of injury after a highly specific injury to podocytes in a mouse model. METHODS: We created transgenic (Podo-DTR) mice in which graded specific podocyte injury could be induced by a single injection of diphtheria toxin. Transgenic and wild-type mice were given the ACEi captopril in drinking water, or water alone, commencing 24h after toxin injection. Kidneys were examined histologically at 8 weeks and injury assessed by observers blinded to experimental group. RESULTS: After toxin injection, Podo-DTR mice developed acute proteinuria, and at higher doses transient renal impairment, which subsided within 3 weeks to be followed by a slow glomerular scarring process. Captopril treatment in Podo-DTR line 57 after toxin injection at 5ng/g body weight reduced proteinuria and ameliorated glomerular scarring, matrix accumulation and glomerulosclerosis almost to baseline (toxin: 17%; toxin + ACEi 10%, p<0.04; control 7% glomerular scarring). Podocyte counts were reduced after toxin treatment and showed no recovery irrespective of captopril treatment (7.1 and 7.3 podocytes per glomerular cross section in water and captopril-treated animals compared with 8.2 of wild-type controls, p<0.05). CONCLUSIONS: Observations in Podo-DTR mice support the hypothesis that continuing podocyte dysfunction is a key abnormality in proteinuric disease. Our model is ideal for studying strategies to protect the kidney from progressive injury following podocyte depletion. Demonstrable protective effects from captopril occur, despite indiscernible preservation or restoration of podocyte counts, at least after this degree of relatively mild injury. PMID- 26629333 TI - Case Report: Stevens-Johnson syndrome following a single double dosing of nevirapine-containing regimen once in an HIV-infected woman on long-term antiretroviral therapy. AB - A 31-year old HIV-infected African woman on nevirapine, tenofovir and lamivudine for more than 4 years presented with an 8-day history of symptoms and signs of Stevens-Johnson syndrome. She was on no other medication. Her viral load was undetectable and she had maintained a CD4 count of between 356 and 387cells/mm (3) in the preceding 21/2 years. She missed her antiretrovirals 10 days before the onset of her symptoms and subsequently doubled her daily dose the following day. She had been on no other medication in the preceding 8 weeks. Her ARVs were stopped and she fully re-epithelialized with the exception of the lips, over the following 10 days. She was started on a daily single tablet of Odimune(r) (a fixed drug combination antiretroviral containing tenofovir, emtricitabine and efavirenz). Nevirapine is the most common offender in cases of antiretroviral associated SJS in published literature. Lamivudine is very rarely implicated while there are no similar reports with tenofovir. We concluded that nevirapine was by far the most likely offender in this case. Nevirapine toxicity is associated with high CD4 counts, undetectable viral load and high drug plasma level. We postulate that the sudden increase of the plasma levels of nevirapine in a patient with a high CD4 count and undetectable viral load created a perfect storm for the development of SJS in our patient, who had been on the NVP containing regimen for many years. Clinicians should be aware that severe adverse drug reactions are dynamic and can occur even when the drug has been in use for a long time. PMID- 26629334 TI - Individuality, phenotypic differentiation, dormancy and 'persistence' in culturable bacterial systems: commonalities shared by environmental, laboratory, and clinical microbiology. AB - For bacteria, replication mainly involves growth by binary fission. However, in a very great many natural environments there are examples of phenotypically dormant, non-growing cells that do not replicate immediately and that are phenotypically 'nonculturable' on media that normally admit their growth. They thereby evade detection by conventional culture-based methods. Such dormant cells may also be observed in laboratory cultures and in clinical microbiology. They are usually more tolerant to stresses such as antibiotics, and in clinical microbiology they are typically referred to as 'persisters'. Bacterial cultures necessarily share a great deal of relatedness, and inclusive fitness theory implies that there are conceptual evolutionary advantages in trading a variation in growth rate against its mean, equivalent to hedging one's bets. There is much evidence that bacteria exploit this strategy widely. We here bring together data that show the commonality of these phenomena across environmental, laboratory and clinical microbiology. Considerable evidence, using methods similar to those common in environmental microbiology, now suggests that many supposedly non communicable, chronic and inflammatory diseases are exacerbated (if not indeed largely caused) by the presence of dormant or persistent bacteria (the ability of whose components to cause inflammation is well known). This dormancy (and resuscitation therefrom) often reflects the extent of the availability of free iron. Together, these phenomena can provide a ready explanation for the continuing inflammation common to such chronic diseases and its correlation with iron dysregulation. This implies that measures designed to assess and to inhibit or remove such organisms (or their access to iron) might be of much therapeutic benefit. PMID- 26629335 TI - Embryo-lethal phenotypes in early abp1 mutants are due to disruption of the neighboring BSM gene. AB - The Auxin Binding Protein1 (ABP1) has been identified based on its ability to bind auxin with high affinity and studied for a long time as a prime candidate for the extracellular auxin receptor responsible for mediating in particular the fast non-transcriptional auxin responses. However, the contradiction between the embryo-lethal phenotypes of the originally described Arabidopsis T-DNA insertional knock-out alleles ( abp1-1 and abp1-1s) and the wild type-like phenotypes of other recently described loss-of-function alleles ( abp1-c1 and abp1-TD1) questions the biological importance of ABP1 and relevance of the previous genetic studies. Here we show that there is no hidden copy of the ABP1 gene in the Arabidopsis genome but the embryo-lethal phenotypes of abp1-1 and abp1-1s alleles are very similar to the knock-out phenotypes of the neighboring gene, BELAYA SMERT ( BSM). Furthermore, the allelic complementation test between bsm and abp1 alleles shows that the embryo-lethality in the abp1-1 and abp1-1s alleles is caused by the off-target disruption of the BSM locus by the T-DNA insertions. This clarifies the controversy of different phenotypes among published abp1 knock-out alleles and asks for reflections on the developmental role of ABP1. PMID- 26629336 TI - Prediction of solution properties and dynamics of RNAs by means of Brownian dynamics simulation of coarse-grained models: Ribosomal 5S RNA and phenylalanine transfer RNA. AB - BACKGROUND: The possibility of validating biological macromolecules with locally disordered domains like RNA against solution properties is helpful to understand their function. In this work, we present a computational scheme for predicting global properties and mimicking the internal dynamics of RNA molecules in solution. A simple coarse-grained model with one bead per nucleotide and two types of intra-molecular interactions (elastic interactions and excluded volume interactions) is used to represent the RNA chain. The elastic interactions are modeled by a set of Hooke springs that form a minimalist elastic network. The Brownian dynamics technique is employed to simulate the time evolution of the RNA conformations. RESULTS: That scheme is applied to the 5S ribosomal RNA of E. Coli and the yeast phenylalanine transfer RNA. From the Brownian trajectory, several solution properties (radius of gyration, translational diffusion coefficient, and a rotational relaxation time) are calculated. For the case of yeast phenylalanine transfer RNA, the time evolution and the probability distribution of the inter arm angle is also computed. CONCLUSIONS: The general good agreement between our results and some experimental data indicates that the model is able to capture the tertiary structure of RNA in solution. Our simulation results also compare quite well with other numerical data. An advantage of the scheme described here is the possibility of visualizing the real time macromolecular dynamics. PMID- 26629337 TI - Faculty of Prehospital Care, Royal College of Surgeons Edinburgh guidance for medical provision for wilderness medicine. AB - To support leaders and those involved in providing medical care on expeditions in wilderness environments, the Faculty of Pre-Hospital Care (FPHC) of The Royal College of Surgeons of Edinburgh convened an expert panel of leading healthcare professionals and expedition providers. The aims of this panel were to: (1) provide guidance to ensure the best possible medical care for patients within the geographical, logistical and human factor constraints of an expedition environment. (2) Give aspiring and established expedition medics a 'benchmark' of skills they should meet. (3) Facilitate expedition organisers in selecting the most appropriate medical cover and provider for their planned activity. A system of medical planning is suggested to enable expedition leaders to identify the potential medical risks and their mitigation. It was recognised that the scope of practice for wilderness medicine covers elements of primary healthcare, pre hospital emergency medicine and preventative medicine. Some unique competencies were also identified. Further to this, the panel recommends the use of a matrix and advisory expedition medic competencies relating to the remoteness and medical threat of the expedition. This advice is aimed at all levels of expedition medic, leader and organiser who may be responsible for delivering or managing the delivery of remote medical care for participants. The expedition medic should be someone equipped with the appropriate medical competencies, scope of practice and capabilities in the expedition environment and need not necessarily be a qualified doctor. In addition to providing guidance regarding the clinical competencies required of the expedition medic, the document provides generic guidance and signposting to the more pertinent aspects of the role of expedition medic. PMID- 26629338 TI - Evidence that 2-hydroxyglutarate is not readily metabolized in colorectal carcinoma cells. AB - BACKGROUND: Two-hydroxyglutarate (2HG) is present at low concentrations in healthy mammalian cells as both an L and D enantiomer. Both the L and D enantiomers have been implicated in regulating cellular physiology by mechanisms that are only partially characterized. In multiple human cancers, the D enantiomer accumulates due to gain-of-function mutations in the enzyme isocitrate dehydrogenase (IDH) and has been hypothesized to drive malignancy through mechanisms that remain incompletely understood. While much attention has been dedicated to identifying the route of 2HG synthesis, the metabolic fate of 2HG has not been studied in detail. Yet the metabolism of 2HG may have important mechanistic consequences influencing cell function and cancer pathogenesis, such as modulating redox potential or producing unknown products with unique modes of action. RESULTS: By applying our isotope-based metabolomic platform, we unbiasedly and comprehensively screened for products of L- and D-2HG in HCT116 colorectal carcinoma cells harboring a mutation in IDH1. After incubating HCT116 cells in uniformly (13)C-labeled 2HG for 24 h, we used liquid chromatography/mass spectrometry to track the labeled carbons in small molecules. Strikingly, we did not identify any products of 2HG metabolism from the thousands of metabolomic features that we screened. Consistent with these results, we did not detect any significant changes in the labeling patterns of tricarboxylic acid cycle metabolites from wild type or IDH1 mutant cells cultured in (13)C-labeled glucose upon the addition of L, D, or racemic mixtures of 2HG. A more sensitive, targeted analysis revealed trace levels of isotopic enrichment (<1 %) in some central carbon metabolites from (13)C-labeled 2HG. However, we found that cells do not deplete 2HG from the media at levels above our detection limit over a 48 h time period. CONCLUSIONS: Taken together, we conclude that 2HG carbon is not readily transformed in the HCT116 cell line. These data indicate that the phenotypic alterations induced by 2HG are not a result of its metabolic products. PMID- 26629339 TI - Prevalence and predictors of exclusive breastfeeding for the first six months of life among women in Halaba special woreda, Southern Nations, Nationalities and Peoples' Region/SNNPR/, Ethiopia: a community based cross-sectional study. AB - BACKGROUND: Exclusive breastfeeding is defined as feeding infants only breast milk, be it directly from breast or expressed, with no addition of any liquid or solids apart from drops or syrups consisting of vitamins, mineral supplements or medicine, and nothing else. Several studies have shown that exclusive breastfeeding for the first six months plays a great role in preventing morbidity and mortality. In Ethiopia, for example, mortality rates of infant and children younger than five years are high. Understanding the prevalence and predictors that influence exclusive breastfeeding in this is crucial to promoting the practice. OBJECTIVES: To assess the prevalence and predictors of exclusive breastfeeding with in the first six months of life among women in Halaby special woreda, SNNPR (Southern Nations, Nationalities and Peoples' Region) Ethiopia. METHODS: A community-based cross sectional study was conducted between November 2013 and January 2014 among women with infants aged less than 6 months and the sample size was 422 in Halaba special woreda, SNNPR (Southern Nations, Nationalities and Peoples' Region) Ethiopia. A random sampling technique was used in sampling the study subjects. Structured questionnaire was developed and adopted from EDHS 2011 and WHO standard and that all the variables to be assessed were incorporated. Data was entered and analyzed through using Epi Info 7 for Dos version 3.5.1 and Statistical Package for the Social Sciences (SPSS) software for windows version 20 respectively. RESULTS: The prevalence of exclusive breastfeeding was (70.5 %) and awareness of exclusive breastfeeding was (92.4 %). Antenatal follow up (AOR/Adjusted odds ratio = 1.9; 95 % CI, 1.05-3.6), postnatal follow up (AOR/Adjusted odds ratio = 2.2; 95 % CI, 1.25-3.87), initiation of breast feeding immediately within one hour (AOR/Adjusted odds ratio =3.8; 95 % CI, 2.4-6.2), attended formal school (AOR Adjusted odds ratio/=1.9;95 % CI,1.1 3.4), advice about exclusive breastfeeding (AOR Adjusted odds ratio/=6.3;95 % CI,1.3-30.9); and awareness about exclusive breastfeeding (AOR Adjusted odds ratio/= 8.2; 95 % CI 3.34-20), have significant association with exclusive breastfeeding. CONCLUSIONS: Strategies that target improving awareness among women at health facility and community level help to improve exclusive breastfeeding. In addition, promotion of EBF for working mothers through working environment recommended. PMID- 26629340 TI - How well do physical activity questions perform? A European cognitive testing study. AB - BACKGROUND: Only few studies have focused on the cognitive processes of the respondents that are involved when answering physical activity questionnaires (PAQs). This study aimed at examining whether two PAQs work as intended with different segments of the survey population in different cultural settings in Europe. METHODS: The International Physical Activity Questionnaire - Short Form (IPAQ-SF) and the US National Health Interview Survey - Adult Core Physical Activity Questionnaire (NHIS-PAQ) were tested in Belgium, Estonia, Germany and the UK using a standardized cognitive interviewing procedure. IPAQ-SF measures total vigorous physical activity (PA), moderate PA, walking and sitting. NHIS-PAQ measures leisure-time vigorous PA, light and moderate PA and muscle-strengthening PA. In total 62 persons completed cognitive interviews, at least 15 interviews were conducted in each country. RESULTS: Both PAQs performed as intended with young and high-skilled persons and those having a regular exercise schedule. For the others, however, the testing revealed that problems occurred with both PAQs relating to understanding the concepts of '(light and) moderate' and 'vigorous' PA, classifying activities into the provided answer options of different PA intensities, recalling instances of 'normal' activities such as walking and sitting, and calculating the total duration of more than one activity or instance of an activity. The revealed problems with the questionnaires were quite similar in different countries; profound cultural differences were not observed. CONCLUSIONS: Both questionnaires were difficult to answer for many respondents and rather user-unfriendly. They are designed to measure an exactness of PA quantity (frequency and duration) and intensity which would be desirable to obtain from a scientific point of view; however, respondents can hardly provide this information for cognitive reasons. Studies investigating the respondents' perspective are useful for improving physical activity information based on self reports. PMID- 26629341 TI - The role of iron in pulmonary pathology. AB - Respiratory disease accounts for a large proportion of emergency admissions to hospital and diseaseassociated mortality. Genetic association studies demonstrate a link between iron metabolism and pulmonary disease phenotypes. IREB2 is a gene that produces iron regulatory protein 2 (IRP2), which has a key role in iron homeostasis. This review addresses pathways involved in iron metabolism, particularly focusing on the role of IREB2. In addition to this, environmental factors also influence phenotypic variation in respiratory disease, for example inhaled iron from cigarette smoke is deposited in the lung and causes tissue damage by altering iron homeostasis. The effects of cigarette smoke are detailed in this article, particularly in relation to lung conditions that favour the upper lobes, such as emphysema and lung cancer. Clinical applications of iron homeostasis are also discussed in this review, especially looking at the pathophysiology of chronic obstructive pulmonary disease, lung cancer, pulmonary infections and acute respiratory distress syndrome. Promising new treatments involving iron are also covered. PMID- 26629342 TI - Weaning from tracheostomy in subjects undergoing pulmonary rehabilitation. AB - BACKGROUND: Weaning from tracheostomy has implications in management, quality of life, and costs of ventilated patients. Furthermore, endotracheal cannula removing needs further studies. Aim of this study was the validation of a protocol for weaning from tracheostomy and evaluation of predictor factors of decannulation. METHODS: Medical records of 48 patients were retrospectively evaluated. Patients were decannulated in agreement with a decannulation protocol based on the evaluation of clinical stability, expiratory muscle strength, presence of tracheal stenosis/granulomas, deglutition function, partial pressure of CO2, and PaO2/FiO2 ratio. These variables, together with underlying disease, blood gas analysis parameters, time elapsed with cannula, comordibity, Barthel index, and the condition of ventilation, were evaluated in a logistic model as predictors of decannulation. RESULTS: 63 % of patients were successfully decannulated in agreement with our protocol and no one needed to be re cannulated. Three variables were significantly associated with the decannulation: no pulmonary underlying diseases (OR = 7.12; 95 % CI 1.2-42.2), no mechanical ventilation (OR = 9.55; 95 % CI 2.1-44.2) and period of tracheostomy <=10 weeks (OR = 6.5; 95 % CI 1.6-27.5). CONCLUSIONS: The positive course of decannulated patients supports the suitability of the weaning protocol we propose here. The strong predictive role of three clinical variables gives premise for new studies testing simpler decannulation protocols. PMID- 26629343 TI - Emotion dysregulation, self-image and eating disorder symptoms in University Women. AB - BACKGROUND: We studied associations between emotion dysregulation, self-image and eating disorder (ED) symptoms in university women, and contrasted two indirect effect models to examine possible intervening mechanisms to produce ED symptoms. METHODS: 252 female Swedish university students completed the Difficulties in Emotion Regulation Scale (DERS), the Structural Analysis of Social Behavior (SASB) self-image measure, and the Eating Disorder Examination Questionnaire (EDE Q). Correlations between scales were followed by five simple mediation analysis pairs with two possible pathways using five ED symptom variables as outcome. The models posited either self-image or emotion dysregulation as mediator or independent variable, respectively. ED symptoms were EDE-Q Global score, objective binge eating episodes (OBE), subjective binge eating episodes (SBE), and two variants of EDE-Q excessive exercise. RESULTS: Emotion dysregulation and self-image were strongly correlated, and both correlated moderately with EDE-Q Global score. There were distinct indirect effects through self-image on the relationship between emotion dysregulation and ED symptoms, but not vice versa. These indirect effects were evident in relation to cognitive ED symptoms and both OBE and SBE, but not in relation to excessive exercise. CONCLUSIONS: Results suggest that even if closely related, emotion dysregulation and self-image both contribute unique knowledge in relation to ED symptoms. Self-image as an intervening mechanism between emotion dysregulation and ED symptoms is relevant for models of the development, maintenance and treatment of ED, as well as treatment focus. PMID- 26629344 TI - Medication and psychotherapy in eating disorders: is there a gap between research and practice? AB - BACKGROUND: Little research has investigated the use of evidence-based guidelines by eating disorder (ED) therapists, or prescribing of psychotropic medication. Moreover, people with EDs have rarely been surveyed on these topics, and their clinical and demographic features have not been presented. This study investigated perception of psychotherapy, psychotropic medication and the clinical characteristics of a community sample of people with EDs. METHOD: An online survey methodology was used to recruit 253 people with eating disorders in the community. Where feasible, comparisons were made between four types of eating disorder, anorexia nervosa, bulimia nervosa, and two types of atypical or 'sub threshold' eating disorder. RESULTS: Unlike medication, reported psychotherapy showed some congruence with evidence based and other guidance. Most participants were currently receiving either psychotherapy, medication or both, and most had a severe and chronic ED. CONCLUSIONS: Findings are considered in light of use of evidence-based treatment for EDs, calls for greater dissemination of cognitive behaviour therapy (CBT); indications that much may be poor quality; and the importance of what treatments to offer those who are chronically and severely ill. Development of theory and novel treatments is considered a priority. PMID- 26629345 TI - Three-month validation of a turbuhaler electronic monitoring device: implications for asthma clinical trial use. AB - BACKGROUND: Electronic monitoring of inhaled asthma therapy is suggested as the 'gold standard' for measuring patterns of medication use in clinical trials. The SmartTurbo (Adherium (NZ) Ltd, Auckland, New Zealand) is an electronic monitor for use with a turbuhaler device (AstraZeneca, UK). The aim of this study was to determine the accuracy of the SmartTurbo in recording Symbicort actuations over a 12-week period of use. METHODS: Twenty SmartTurbo monitors were attached to the base of 20 Symbicort turbuhalers. Bench testing in a research facility was undertaken on days 0, 5, 6, 7, 8, 9, 14, 21, 28, 56 and 84. Patterns of 'low-use' (2 sets of 2 actuations on the same day) and 'high-use' (2 sets of 8 actuations on the same day) were performed. The date and time of actuations were recorded in a paper diary and compared with data uploaded from the SmartTurbo monitors. RESULTS: 2800 actuations were performed. Monitor sensitivity was 99.9% with a lower 97.5% confidence bound of 99.6%. The positive predictive value was 99.9% with a 97.5% lower confidence bound of 99.7%. Accuracy was not affected by whether the pattern of inhaler use was low or high, or whether there was a delay in uploading the actuation data. CONCLUSIONS: The SmartTurbo monitor is highly accurate in recording and retaining electronic data in this 12-week bench study. It can be recommended for use in clinical trial settings, in which quality control systems are incorporated into study protocols to ensure accurate data acquisition. PMID- 26629346 TI - The combined effect of visit-to-visit variability in HbA1c and systolic blood pressure on the incidence of cardiovascular events in patients with type 2 diabetes. AB - OBJECTIVE: To investigate the association between long-term visit-to-visit variability in glycated hemoglobin (HbA1c) and systolic blood pressure (SBP) and the incidence of cardiovascular disease (CVD) in patients with type 2 diabetes. METHODS: We retrospectively enrolled 632 patients with type 2 diabetes and no history of CVD who first visited our hospital between 1995 and 1996, were followed-up for >=1 year, attended at least 4 clinic visits and had at least 1 visit per year. Patients were followed until June 2012 at the latest, and mailed questionnaires. RESULTS: During the median follow-up period (15.4 years), 81 patients developed CVD. Multivariate analysis revealed that the coefficient of variation (CV) and the variation independent of mean (VIM) for HbA1c and SBP were significant predictors of CVD incidence independent of mean HbA1c and SBP. Patients were classified into 4 groups by median HbA1cCV and SBPCV values and by median HbA1cVIM and SBPVIM values. Among these groups, the HRs were highest in the high-HbA1cCV/high-SBPCV and high-HbA1cVIM/high-SBPVIM groups and were significantly higher compared with those in the low-HbA1cCV/low-SBPCV and low HbA1cVIM/low-SBPVIM groups, respectively. Among patients with mean SBP>=130 mm Hg, the HRs associated with HbA1cCV and HbA1cVIM were drastically elevated compared with those with mean SBP<130 mm Hg (interaction p<0.05). CONCLUSIONS: Long-term visit-to-visit variability in HbA1c and SBP represented a combined and additive risk for CVD incidence in patients with type 2 diabetes. It is suggested that a synergistic effect exists between HbA1c variability and mean SBP levels for CVD incidence. PMID- 26629347 TI - Changes in diabetes care indicators: findings from German National Health Interview and Examination Surveys 1997-1999 and 2008-2011. AB - OBJECTIVES: To investigate changes in type 2 diabetes care indicators over time in Germany. METHODS: Adults aged 45-79 years with type 2 diabetes were identified from two national health examination surveys conducted in 1997-1999 (GNHIES98, n=333) and in 2008-2011 (DEGS1, n=526). We examined diabetes care indicators including treatment and preventive targets (glycemic control, blood pressure (BP), total cholesterol (TC), smoking, weight reduction, sports activity), self management and care process measures (glucose self-monitoring, holding a diabetes passport, annual foot and eye examination; statin use), and the presence of diabetes-specific complications (diabetic nephropathy, retinopathy, neuropathy, diabetic foot, amputations) and comorbid cardiovascular disease (CVD) or chronic kidney disease (CKD). We calculated proportions of persons meeting these care indicators by survey and examined unadjusted and adjusted changes between surveys. RESULTS: Significant improvement (GNHIES98 vs DEGS1) over time was observed for glycated hemoglobin (HbA1c) <7.0% (53 mmol/mol) (32.4% vs 65.4%), BP <130/80 mm Hg (32.0% vs 47.2%), TC <190 mg/dL (13.5% vs 41.9%), statin use (11.7% vs 35.9%), eye (51.1% vs 78.4%) and foot (48.0% vs 61.4%) examination within the past 12 months, diabetes-specific complications (29.7% vs 21.8%), and CVD (44.5% vs 37.1%). Blood glucose self-monitoring significantly increased (37.4% vs 62.8%), while holding a diabetes passport did not change. Current smoking did not change and obesity rose, although sports activity significantly increased over time. Proportions of adults achieving combination goals of HbA1c, BP, TC, and smoking cessation were low in both surveys in spite of significant improvement. CONCLUSIONS: In Germany, the quality of diabetes care improved over time. There is much room for improvement, in particular regarding preventive goals and diabetes self-management. PMID- 26629349 TI - Observational study of the relationship between volume and outcomes using data from the National Audit of Cardiac Rehabilitation. AB - OBJECTIVE: Cardiac rehabilitation (CR) is an evidence-based intervention delivered by a wide range of high-volume and low-volume centres; however, the extent of volume-outcome relationship is yet to be studied. There is a lack of consensus about the effect of volume on outcomes, with evidence of mixed effects in acute and chronic care. The aim of this study is, to investigate the extent of association of outcomes in CR with patient volume. METHODS: Data was validated and extracted from the national audit from 2012 to 2013 for each CR centre. Volume was calculated as the total number of patients entering outpatient CR. Hierarchical multiple regression models were used to test for relationships between volume and outcomes. The outcomes included body mass index, blood pressure, psychosocial well-being, cholesterol, smoking cessation and physical activity. The analyses were adjusted for centre and patient characteristics and confounders. RESULTS: The number of patients included in the volume analysis was 48 476, derived from 178 CR centres. The average age per centre was 66 years with a 70% male distribution of patients enrolled. Regression analysis revealed no volume-outcome relationship, additionally no statistical significance existed. CONCLUSIONS: Unlike cardiac surgery this study, after accounting for staffing, age, gender and comorbidity, shows no effect of volume on outcome following CR delivered by high-volume and low-volume programmes. Based on our data there is no support for centralisation of services. Our findings and methodology can be used as a benchmark for future volume-outcome relationship studies in CR. PMID- 26629348 TI - Clinical implication of blood glucose monitoring in general dental offices: the Ehime Dental Diabetes Study. AB - OBJECTIVE: We examined whether general dentists can contribute to the detection of patients with undiagnosed diabetes and prediabetes by monitoring blood glucose in dental clinics. RESEARCH DESIGN AND METHODS: A total of 716 patients who visited clinics for dental treatment were enrolled and classified into 3 groups (mild, moderate, and severe) according to Kornman's criteria for periodontitis. The correlations between the casual blood glucose level, presence or absence of the history of diabetes, and/or severity of periodontitis were evaluated. RESULTS: 68 patients (9.5%) had hyperglycemia (blood glucose >=200 mg/dL). Of these patients, 20 (29.4%) did not have a history of diabetes. Blood glucose tended to be higher with greater periodontitis severity. Of the 3 groups, the severe periodontitis group had the highest proportion of patients with hyperglycemia (p<0.0001). CONCLUSIONS: Patients with dental problems could be screened for diabetes, especially undiagnosed diabetes. General dentists could function as practitioners to screen for diabetes. TRIAL REGISTRATION NUMBER: UMIN CTR 000014877. PMID- 26629350 TI - Characterising the immune profile of the kidney biopsy at lupus nephritis flare differentiates early treatment responders from non-responders. AB - INTRODUCTION: The kidney biopsy is used to diagnose and guide initial therapy in patients with lupus nephritis (LN). Kidney histology does not correlate well with clinical measurements of kidney injury or predict how patients will respond to standard-of-care immunosuppression. We postulated that the gene expression profile of kidney tissue at the time of biopsy may differentiate patients who will from those who will not respond to treatment. METHODS: The expression of 511 immune-response genes was measured in kidney biopsies from 19 patients with proliferative LN and 4 normal controls. RNA was extracted from formalin-fixed, paraffin-embedded kidney biopsies done at flare. After induction therapy, 5 patients achieved a complete clinical response (CR), 10 had a partial response (PR) and 4 patients were non-responders (NRs). Transcript expression was compared with normal controls and between renal response groups. RESULTS: A principal component analysis showed that intrarenal transcript expression from normal kidney, CR biopsies and NR biopsies segregated from each other. The top genes responsible for CR clustering included several interferon pathway genes (STAT1, IRF1, IRF7, MX1, STAT2, JAK2), while complement genes (C1R, C1QB, C6, C9, C5, MASP2) were mainly responsible for NR clustering. Overall, 35 genes were uniquely expressed in NR compared with CR. Pathway analysis revealed that interferon signalling and complement activation pathways were upregulated in both groups, while BAFF, APRIL, nuclear factor-kappaB and interleukin-6 signalling were increased in CR but suppressed in NR. CONCLUSIONS: These data suggest that molecular profiling of the kidney biopsy at LN flare may be useful in predicting treatment response to induction therapy. PMID- 26629351 TI - Factors associated with pain coping and catastrophising in patients with systemic lupus erythematosus: a cross-sectional study of the LuLa-cohort. AB - OBJECTIVE: The aim of this study was to identify factors associated with pain coping and catastrophising in patients with systemic lupus erythematosus. METHODS: All patients were participants of the lupus erythematosus long-term study, which is based on patient-reported data assessed among members of the German Lupus Erythematosus Self-Help Organization. Assessments were performed by means of a questionnaire. Among self-reported clinical data the Pain-Related Self Statements Scale (PRSS) was included. To depict significant differences univariable analyses were carried out using non-parametrical rank tests. To examine factors influencing our outcome variables, we performed a multivariable stepwise regression model including variables that presented significantly in the univariable analysis. RESULTS: 447 cases (94.9% female) were analysed showing a mean catastrophising score of 1.1 (SD 0.8) and a mean coping score of 2.8 (SD 0.9) in the PRSS subscales. Higher catastrophising quartiles went along with higher experienced pain, lupus activity, fatigue, damage and decreased health related quality of life, whereas they presented inversely for coping. In our multivariable model, factors associated with catastrophising were: number of lupus-specific drugs (p value 0.004), pain in the last 7 days (p value 0.034), the Short Form 12 Health Survey Mental Component Summary (p value <0.001) and disease activity measured by the Systemic Lupus Activity Questionnaire (p value 0.042). Social participation reflected by performed leisure activities such as dancing or bowling had a positive association with coping (p value 0.006). In contrast, other health related physical activities and their extent had no impact on coping. A direct association between the amount of pain coping and catastrophising, as well as a great impact of the catastrophising, respectively, coping level on physical and mental functioning could be shown. CONCLUSIONS: Reduction or increase of detected factors might lead to a modification of pain coping and catastrophising and offer an approach to more effective care in patients with SLE. PMID- 26629353 TI - Life as a new investigator. PMID- 26629352 TI - A proteinuria cut-off level of 0.7 g/day after 12 months of treatment best predicts long-term renal outcome in lupus nephritis: data from the MAINTAIN Nephritis Trial. AB - BACKGROUND: Although an early decrease in proteinuria has been correlated with good long-term renal outcome in lupus nephritis (LN), studies aimed at defining a cut-off proteinuria value are missing, except a recent analysis performed on patients randomised in the Euro-Lupus Nephritis Trial, demonstrating that a target value of 0.8 g/day at month 12 optimised sensitivity and specificity for the prediction of good renal outcome. The objective of the current work is to validate this target in another LN study, namely the MAINTAIN Nephritis Trial (MNT). METHODS: Long-term (at least 7 years) renal function data were available for 90 patients randomised in the MNT. Receiver operating characteristic curves were built to test the performance of proteinuria measured within the 1st year as short-term predictor of long-term renal outcome. We calculated the positive and negative predictive values (PPV, NPV). RESULTS: After 12 months of treatment, achievement of a proteinuria <0.7 g/day best predicted good renal outcome, with a sensitivity and a specificity of 71% and 75%, respectively. The PPV was high (94%) but the NPV low (29%). Addition of the requirement of urine red blood cells <=5/hpf as response criteria at month 12 reduced sensitivity from 71% to 41%. CONCLUSIONS: In this cohort of mainly Caucasian patients suffering from a first episode of LN in most cases, achievement of a proteinuria <0.7 g/day at month 12 best predicts good outcome at 7 years and inclusion of haematuria in the set of criteria at month 12 undermines the sensitivity of early proteinuria decrease for the prediction of good outcome. The robustness of these conclusions stems from the very similar results obtained in two distinct LN cohorts. TRIAL REGISTRATION NUMBER: NCT00204022. PMID- 26629354 TI - A little (up)SET THEORY: a philosophical and psychological pondering of a scientist on the state of our art. PMID- 26629355 TI - Changing and challenging times for Canadian kidney health and disease research. PMID- 26629357 TI - Setting up an academic research laboratory in Canada in 2015. PMID- 26629356 TI - A basic scientist's reflections on research funding. PMID- 26629358 TI - Hepatic decompensation in the absence of obvious precipitants: the potential role of cytomegalovirus infection/reactivation. AB - Details of two patients with alcohol-related and mixed aetiology cirrhosis who developed acute-on-chronic liver failure/hepatic decompensation with no obvious precipitants are reported. Cytomegalovirus (CMV) infection or reactivation was diagnosed in both, and required treatment with ganciclovir in one. Both returned to baseline hepatic function and remain well. Physicians should be alert to the possibility that CMV might cause or contribute to hepatic decompensation in patients with cirrhosis, even if they are not severely immunocompromised, and especially if they are alcohol misusers. PMID- 26629359 TI - Changing trends of hospitalisation of liver cirrhosis in Beijing, China. AB - OBJECTIVE: To examine if the hospitalisation trends of liver cirrhosis are changing with the changes of risk factors of the disease in China. DESIGN: Secondary analysis of hospitalisation records in the 31 top-ranking hospitals in Beijing. RESULTS: Between 2006 and 2010, hospitalisation from viral hepatitis cirrhosis (VHC) decreased by 10% (95% CI=5-14%, p<0.001), but non-viral hepatitis cirrhosis (NVHC) and alcoholic cirrhosis (AC) increased by 35% (26-46%, p<0.001) and 33% (19%- 47%, p<0.001), respectively. The age patterns of hospitalisation varied with different types of liver cirrhosis. The hospitalisation risks for patients with VHC and AC were significantly high in the age groups 40-49 and 50 59 years, but risks for those with NHVC were high in all age groups of 40 years or above. Overall male-to-female hospitalisation ratios for VHC, NVHC and AC were 2.71, 1.14 and 59.9, respectively. The sex ratio became smaller with time from 2006 to 2010 in hospitalised patients with VHC, but it substantially increased in those with NVHC during the same period. CONCLUSIONS: Hospitalisation rates for liver cirrhosis in Beijing are changing with time. The changes of viral hepatitis infection and alcohol consumption in the general population may cause these changes. PMID- 26629360 TI - Re-treatment of patients with chronic hepatitis C virus genotype 4 infection with pegylated interferon and ribavirin: a meta-analysis. AB - BACKGROUND: An estimated 170 million people worldwide are infected with hepatitis C virus (HCV). HCV genotype 4 (HCV-4)-the most prevalent hepatitis C strain in the Middle East and Africa-is difficult to treat, with an estimated sustained virological response (SVR) of 53% when using pegylated interferon and ribavirin (P/R) in treatment-naive patients with HCV-4 infection. In regions where access to direct-acting antivirals is limited, re-treatment of patients who failed therapy with another course of P/R may be an option if the success rate is acceptable. OBJECTIVES: We aimed to determine the SVR from retreatment with P/R in treatment-experienced patients with HCV-4 infection. METHODS: We performed a meta-analysis using MEDLINE and EMBASE searches, and by reviewing article bibliographies and abstracts from recent Liver Society Meetings. Original studies featuring at least 10 adult, treatment-experienced patients with HCV-4 infection failing prior interferon-based therapy and receiving subsequent re-treatment with P/R were included. RESULTS: 3 studies were included. Overall pooled SVR was 32.7%, or 41/126 patients. No significant heterogeneity existed among the studies. One study reported higher SVR of 50% in previous relapsers, compared with 23% in previous non-responders. CONCLUSIONS: As expected, treatment experienced patients achieved lower rate of SVR compared with previously reported SVR for treatment-naive patients with HCV-4 infection. The abysmal rate of success from re-treatment with P/R supports the use of direct-acting antivirals whenever re-treatment is considered, even in resource-limited regions. PMID- 26629361 TI - Occurrence and identification of Emeria species in broiler rearing under traditional system. AB - BACKGROUND: The present study was intended to determine the prevalence and identification of species involved causing coccidiosis in broilers rearing under traditional farming system in Mirpur, Azad Kashmir, Pakistan. For the current study, a convenient sampling technique was carried out. A total of 7814 broilers (aged 1 to 6 weeks) were submitted to the Disease Diagnostic Laboratory of Livestock and Animal husbandry Department Mirpur, Azad Kashmir. RESULTS: From the total screened, 750 were found positive for coccidiosis representing an overall prevalence of 9.59 %. Age-wise highest prevalence (10.88 %) recorded in the middle age birds (0 to 3 week old) were found more susceptible to infection than those aged above 3 weeks. Higher prevalence (12.49 %) of coccidiosis in broilers was observed in spring as compared with 6.60 % in summer season. In this study two main coccidiosis causing species, Emeria tenella and Emeria maxima were identified on the basis of their morphological feature and habitat (caeca and intestine), However, E. tenella was dominant compared to E. maxima. CONCLUSION: The study provides an insight to the occurrence of Emeria species which must be taken into consideration when rearing the broilers. PMID- 26629362 TI - Erratum to: Comparative ileal amino acid digestibility and growth performance in growing pigs fed different level of canola meal. AB - [This corrects the article DOI: 10.1186/s40781-015-0055-3.]. PMID- 26629363 TI - A new classification of HLA-DRB1 alleles based on acid-base properties of the amino acids located at positions 13, 70 and 71: impact on ACPA status or structural progression, and meta-analysis on 1235 patients with rheumatoid from two cohorts (ESPOIR and EAC cohort). AB - OBJECTIVE: To group HLA-DRB1 alleles based on acid-base properties of amino acids at positions 13, 70 and 71 and analyse their association with the presence of anticitrullinated peptide antibodies (ACPA) and structural progression in 2 cohorts of early rheumatoid arthritis (RA). METHODS: Patients with RA (N=612) from ESPOIR cohort and from EAC cohort (n=624) were genotyped for HLA-DRB1 alleles. The alleles containing the RAA sequence at positions 72-74 were classified into 3 groups according to the amino acid at positions 13, 70 and 71: BB encoding basic amino acids at positions 13, 70 and 71; A encoding acidic amino acids at positions 70 and 71; and BN encoding either neutral amino acids at position 13 and basic amino acids at positions 70 and 71, or basic amino acid at position 13 and neutral amino acids at positions 70 and 71. The associations between the different alleles and (1) the ACPA presence, and (2) the structural progression were assessed by chi(2) test; a meta-analysis was performed on the 2 cohorts using the Mantel-Haenszel method. RESULTS: After meta-analysis, BB alleles were significantly associated with ACPA presence (OR (95% CI) 4.08 (3.14 to 5.31)) and structural progression (OR (95% CI) 2.33 (1.76 to 3.09)). The alleles protected significantly against ACPA presence (OR (95% CI) 0.37 (0.28 to 0.50)) and structural progression (OR (95% CI) 0.34 (0.23 to 0.50)). This acid base classification allowed to separate another group BN with an intermediate risk of ACPA production (OR (95% CI) 1.14 (0.91 to 1.44)) and structural progression (OR (95% CI) 1.01 (0.77 to 1.33)). CONCLUSIONS: This new classification permitted to make a hierarchy of HLA-DRB1 alleles in terms of association with ACPA presence or structural progression in early RA. PMID- 26629364 TI - Monitoring rheumatoid arthritis using an algorithm based on patient-reported outcome measures: a first step towards personalised healthcare. AB - OBJECTIVES: The objective of this proof of concept study was to evaluate alerts generated by a patient-reported outcome measure (PROM)-based algorithm for monitoring patients with rheumatoid arthritis (RA). METHODS: The algorithm was constructed using an example PROM score of an equally weighted mean of visual analogue scale (VAS) general health, VAS disease activity and VAS pain. Based on the PROM score, red flags are generated in 2 instances: the target level of disease activity is not met; change in disease activity surpasses an early alert threshold. To reduce false alarms, 3 consecutive red flags are needed to trigger an alert to the physician. Time series data from patients included consecutively in the practice-based Nijmegen Early RA cohort were analysed to select an appropriate autoregressive integrated moving average (ARIMA) model. This allowed for advanced interpolation of PROM scores and weekly data evaluation. Alerts were evaluated against disease-modifying antirheumatic drug (DMARD)/biologic medication intensification registered in the cohort. RESULTS: Data of 165 patients followed in their second year postdiagnosis were analysed. In 89.8% of 716 visits, the algorithm did not generate an alert and medication was not escalated. Positive predictive value, sensitivity and specificity were 24.6%, 55.6% and 69.7%, respectively. Comparable performance was found when analyses were stratified for baseline Disease Activity Score 28-joint count (DAS28) level. CONCLUSIONS: When using the algorithm to screen scheduled visits, the overall chance of missing patients in need of medication intensification is low. These findings provide evidence that an off-site monitoring system could aid in optimising the number and timing of face-to-face consultations of patients with their rheumatologists. PMID- 26629365 TI - Correction. AB - [This corrects the article DOI: 10.1136/rmdopen-2015-000146.]. PMID- 26629366 TI - Discontinuation rates of biologics in patients with rheumatoid arthritis: are TNF inhibitors different from non-TNF inhibitors? AB - OBJECTIVE: To compare discontinuation rates of first and second biologics in rheumatoid arthritis (RA) by tumour-necrosis factor inhibitor (TNFi) status and identify predictors and reasons for discontinuation. METHODS: From 1998 to 2011, self-reported medication use for RA was assessed every 6 months via questionnaire in a longitudinal study in the USA. Time-on-drug analyses were conducted for individual biologics and groups, and annual rates reported. Time to discontinuation of TNFi and non-TNFi was compared, unadjusted and adjusted using propensity score analyses. Baseline and time-varying predictors of biologic discontinuation were derived through Cox regression. RESULTS: Of 2281 patients initiating their first biologic, 1100 (48%) discontinued and of 1097 initiating a second biologic, 537 (49%) discontinued. The annual discontinuation rate was 17% (median 4 years) for first biologic and 20% (median 3.3 years) for second biologic. TNFi had lower discontinuation rates than non-TNFi after propensity score adjustment: HR for first biologic 0.49 (0.34 to 0.71) and 0.68 (0.51 to 0.90) for second biologic. The annual discontinuation rate was significantly lower in patients starting their first biologic before January 2005 vs after (16 vs 25%, p=0.005). Predictors of discontinuation for the first biologic included smoking, higher comorbidity index, worse overall health and not using concomitant methotrexate. CONCLUSIONS: In this large cohort, patients with RA tended to remain on their first and second biologics for relatively long periods suggesting the drugs' effectiveness. Discontinuation rates were lower in patients using TNFi, and all rates increased after January 2005 when the number of biologics available increased. PMID- 26629367 TI - Do patients with ankylosing spondylitis adapt to their disease? Evidence from a 'then-test' in patients treated with TNF inhibitors. AB - OBJECTIVE: To investigate whether patients with ankylosing spondylitis (AS) adapt to their disease, using the 'then-test'. METHODS: Data from patients participating in the AS Study for Evaluation of Recombinant Infliximab Therapy (ASSERT) and continuing in the European AS Infliximab Cohort (EASIC) were used. At 5 assessments in EASIC, patients were asked to rerate their global well-being before the start of infliximab in ASSERT. The patients evaluated their past situation by using a 'then-test' ('retrospective patient global'). Initial and retrospective patient global were compared using a paired t test, and mixed linear models investigated whether the retrospective score of well-being was stable at all follow-up assessments in EASIC. Linear regression analysis explored whether treatment response was associated with the difference between the initial and retrospective score ('gap') while adjusting for possible confounders. RESULTS: 86 patients (mean age 39.8 years (SD=10.4), mean disease duration 10.8 years (SD=8.5)) contributed to the current analyses. At the time of starting infliximab, patients judged their global at 7.0 (SD=1.6), and with the 'then test' at 7.2 (SD=2.3) (p=0.45). Time elapsed did not influence the 'then-test' (p=0.13). Multivariably, the gap was irrespective of treatment response, but associated with initial patient global (p<0.01) and initial Bath AS Disease Activity Index (p=0.02). CONCLUSIONS: Patients with AS accurately judged their global well-being before starting treatment with tumour necrosis factor inhibition, even though substantial time had elapsed. The difference between initial and retrospective judgment was irrespective of treatment response. In this setting, the 'then-test' could not prove adaptation in AS. TRIAL REGISTRATION NUMBER: NCT01286545. PMID- 26629368 TI - Genes and Cardiovascular Disease: Where do we go from here? PMID- 26629369 TI - Self-Experimenting Physicians: Mavericks or martyrs? PMID- 26629370 TI - Echocardiographic Evidence of Early Diastolic Dysfunction in Asymptomatic Children with Osteogenesis Imperfecta. AB - OBJECTIVES: Structural and functional cardiovascular abnormalities have been reported in adults with osteogenesis imperfecta (OI); however, there is a lack of paediatric literature on this topic. This study aimed to investigate cardiovascular abnormalities in children with OI in comparison to a control group. METHODS: This case-control study was conducted at the Sultan Qaboos University Hospital in Muscat, Oman, between May 2013 and August 2014. Data from eight patients with OI and 24 healthy controls were compared using conventional and tissue Doppler echocardiography (TDE). RESULTS: The OI group had significantly lower peak early mitral valve flow velocity (P = 0.027), peak a wave reversal in the pulmonary vein (P = 0.030) and peak early diastolic velocity of the mitral valve and upper septum (P = 0.001 each). The peak late diastolic velocities of the mitral valve (P = 0.002) and the upper septum (P = 0.037) were significantly higher in the OI group; however, the peak early/late diastolic velocity ratios of the mitral valve (P = 0.002) and upper septum (P = 0.001) were significantly lower. Left ventricular dimensions and aortic and pulmonary artery diameters were larger in the OI group when indexed for body surface area. Both groups had normal systolic cardiac function. CONCLUSION: Children with OI had normal systolic cardiac function. However, changes in myocardial tissue Doppler velocities were suggestive of early diastolic cardiac dysfunction. They also had increased left ventricular dimensions and greater vessel diameters. These findings indicate the need for early and detailed structural and functional echocardiographic assessment and follow-up of young patients with OI. PMID- 26629371 TI - Accuracy of Platelet Counting by Optical and Impedance Methods in Patients with Thrombocytopaenia and Microcytosis. AB - OBJECTIVES: Obtaining accurate platelet counts in microcytic blood samples is challenging, even with the most reliable automated haematology analysers. The CELL-DYN(TM) Sapphire (Abbott Laboratories, Chicago, Illinois, USA) analyser uses both optical density and electronic impedance methods for platelet counting. This study aimed to evaluate the accuracy of optical density and electrical impedance methods in determining true platelet counts in thrombocytopaenic samples with microcytosis as defined by low mean corpuscular volume (MCV) of red blood cells. Additionally, the impact of microcytosis on platelet count accuracy was evaluated. METHODS: This study was carried out between February and December 2014 at the Haematology Laboratory of the Sultan Qaboos University Hospital in Muscat, Oman. Blood samples were collected and analysed from 189 patients with thrombocytopaenia and MCV values of <76 femtolitres. Platelet counts were tested using both optical and impedance methods. Stained peripheral blood films for each sample were then reviewed as a reference method to confirm platelet counts. RESULTS: The platelet counts estimated by the impedance method were on average 30% higher than those estimated by the optical method (P <0.001). The estimated intraclass correlation coefficient was 0.52 (95% confidence interval: 0.41-0.62), indicating moderate reliability between the methods. The degree of agreement between methods ranged from -85.5 to 24.3 with an estimated bias of -30, suggesting that these methods generate different platelet results. CONCLUSION: The impedance method significantly overestimated platelet counts in microcytic and thrombocytopaenic blood samples. Further attention is therefore needed to improve the accuracy of platelet counts, particularly for patients with conditions associated with microcytosis. PMID- 26629372 TI - Characterisation of Nicotine and Cancer-Enhancing Anions in the Common Smokeless Tobacco Afzal in Oman. AB - OBJECTIVES: Afzal is a common smokeless tobacco product (STP) available illegally in Oman. This study aimed to assess pH and moisture levels and determine cancer enhancing factors in a randomly selected sample of Afzal. METHODS: This study was carried out at the Sultan Qaboos University in Muscat, Oman, between April and December 2013. A package of Afzal was purchased from a single provider and divided into samples. The pH and moisture content of the samples were measured according to the protocols of the Centers for Disease Control and Prevention. Gas chromatography-mass spectrometry was used to analyse nicotine levels and ion exchange chromatography (IC) was used to determine concentrations of nitrate, nitrite, chloride, fluoride, bromide, sulphate and phosphate anions. RESULTS: The samples had an alkaline pH of 10.46 with high levels of total (48,770.00 ug per g of STP [ug/g]) and unionised (48,590.00 ug/g) nicotine. The concentration of nitrate (8,792.20 ug/g) was alarmingly high. The chloride concentration (33,170.80 ug/g) showed a surge on IC chromatography. The moisture content percentage was 52.00%. CONCLUSION: The moisture content percentage and chloride concentration of Afzal was consistent with those of other STPs. In contrast, nitrite, sulphate and phosphate concentrations were below reported levels of other STPs. All anion concentrations were below the maximum daily limit set by international health organisations. However, the high concentrations of nitrite, nitrate and nicotine and the elevated alkaline pH observed in the analysed Afzal samples suggest that STP users will face health risks as a result of their use. PMID- 26629373 TI - Association of Angiotensin-Converting Enzyme and Glutathione S-Transferase Gene Polymorphisms with Body Mass Index among Hypertensive North Indians. AB - OBJECTIVES: This study aimed to examine the association of angiotensin-converting enzyme (ACE) and glutathione S-transferase (GST) gene polymorphisms with body mass index (BMI) in hypertensive North Indians. METHODS: This case-control study was carried out between May 2013 and November 2014 at the Era's Lucknow Medical College & Hospital, Lucknow, India, and included 378 subjects divided into three groups. One group constituted 253 hypertensive individuals (sustained diastolic blood pressure of >90 mmHg and systolic blood pressure of >140 mmHg) who were subcategorised according to normal (<25 kg/m(2)) or high (>=25 kg/m(2)) BMI. The third group consisted of 125 age-, gender- and ethnically-matched normotensive controls with a normal BMI. Gene polymorphisms were evaluated by polymerase chain reaction. The genotypic and allelic frequency distribution among both groups were analysed. RESULTS: A significant difference was found between GST theta 1-null and GST mu 1-positive genotype frequencies among the hypertensive overweight/obese individuals and controls (P = 0.014 and 0.033, respectively). However, no difference was observed in the frequency of ACE polymorphisms. ACE insertion/insertion genotype (P = 0.006), insertion and deletion alleles (P = 0.007 each) and GST theta 1-null and GST theta 1-positive genotypes (P = 0.006 each) were found to differ significantly between hypertensive cases and controls, regardless of BMI. CONCLUSION: ACE and GST gene polymorphisms were not associated with BMI but were significantly associated with hypertension among the studied group of North Indians. PMID- 26629374 TI - Frequencies of the Arg16Gly, Gln27Glu and Thr164Ile Adrenoceptor beta2 Polymorphisms among Omanis. AB - OBJECTIVES: This study aimed to assess the distribution of missense mutations in the adrenoceptor beta2 (ADRB2) gene in an Omani cohort. METHODS: This study was carried out between May 2014 and March 2015 at the Sultan Qaboos University, Muscat, Oman. Blood samples were taken from 316 unrelated Omani subjects. Genotyping for rs1042713 (c.46A>G, p.Arg16Gly), rs1042714 (c.79C>G, p.Gln27Glu) and rs1800888 (c.491C>T, p.Thr164Ile) polymorphisms was performed by real-time polymerase chain reaction using single nucleotide polymorphism (SNP) genotyping assays. The allelic frequencies of these polymorphisms were estimated on the basis of the observed numbers of specific alleles from the genotype data for male and female subjects. The genotype frequencies for each polymorphism were tested for deviation from the Hardy-Weinberg equilibrium. RESULTS: Gly16 and Glu27 were the most frequent variants found among the cohort (63% and 75%, respectively). The Ile164 variant was not detected in the study population. There was a significant linkage disequilibrium between the rs1042713 and rs1042714 SNPs (r(2) = 0.209; P <=0.001). The most observed haplotypes were Gly16-Gln27 and Arg16 Gln27 (0.37 and 0.38, respectively). The frequency of Gly16-Glu27 was 0.25, comprising all Glu27 carriers. CONCLUSION: The allelic distribution of variants in this Omani cohort was similar to distributions reported among Caucasian populations. PMID- 26629375 TI - Association of Higher Defensin beta-4 Genomic Copy Numbers with Behcet's Disease in Iraqi Patients. AB - OBJECTIVES: Behcet's disease (BD) is an immune-mediated small vessel systemic vasculitis. Human beta-defensins are antimicrobial peptides associated with many inflammatory diseases and are encoded by the beta-defensin family of multiple copy genes. However, their role in BD necessitates further investigation. The aim of the present study was to investigate the possible association of BD in its various clinical forms with defensin beta-4 (DEFB4) genomic copy numbers. METHODS: This case-control study was conducted from January to September 2011 and included 50 control subjects and 27 unrelated Iraqi BD patients registered at Baghdad Teaching Hospital, Bagdad, Iraq. Copy numbers of the DEFB4 gene were determined using the comparative cycle threshold method by duplex real-time polymerase chain reaction technology at the Department of Dermatology of Jena University Hospital, Jena, Germany. RESULTS: DEFB4 genomic copy numbers were significantly higher in the BD group compared to the control group (P = 0.010). However, no statistically significant association was found between copy numbers and clinical variables within the BD group. CONCLUSION: The DEFB4 copy number polymorphism may be associated with BD; however, it is not associated with different clinical manifestations of the disease. PMID- 26629376 TI - Gestational and Pregestational Diabetes Mellitus in Omani Women: Comparison of obstetric and perinatal outcomes. AB - OBJECTIVES: The aim of this study was to assess the prevalence of gestational diabetes mellitus (GDM) and pregestational diabetes mellitus (PGDM) among pregnant women in Oman and compare their obstetric and perinatal outcomes. METHODS: This retrospective study assessed the obstetric and perinatal outcomes of pregnant Omani women with GDM or PGDM who delivered at the Sultan Qaboos University Hospital in Muscat, Oman, between January 2009 and December 2010. RESULTS: There were a total of 5,811 deliveries during the study period. Of the 5,811 women who gave birth, 639 women were found to have diabetes mellitus (11.0%). A total of 581 of the diabetic women had GDM (90.9%) and only 58 (9.1%) had PGDM. Women with PGDM had a significantly higher incidence of pre-eclampsia (P = 0.022), preterm deliveries (P <0.001) and Caesarean sections (P <0.001). Neonatal complications, such as respiratory distress syndrome (RDS), neonatal hypoglycaemia, neonatal jaundice and subsequent admission to a neonatal intensive care unit (NICU) were significantly higher for neonates born to mothers with PGDM compared to those born to mothers with GDM (P <0.001). The corrected perinatal mortality rates for women with PGDM and GDM were 34.5 and 13.7 per 1,000 live births, respectively. CONCLUSION: In this Omani cohort, women with PGDM were at higher risk of developing obstetric and perinatal complications such as pre eclampsia, preterm delivery and Caesarean delivery compared to women with GDM. In addition, neonates who had mothers with PGDM had higher rates of RDS, neonatal hypoglycaemia, neonatal jaundice and admission to the NICU. PMID- 26629377 TI - Safety and Complications of Double-Lumen Tunnelled Cuffed Central Venous Dialysis Catheters: Clinical and radiological perspective from a tertiary centre in Oman. AB - OBJECTIVES: This study aimed to assess the technical success, safety and immediate and delayed complications of double-lumen tunnelled cuffed central venous catheters (TVCs) at the Sultan Qaboos University Hospital (SQUH), Muscat, Oman. METHODS: This retrospective study took place between January 2012 and October 2013. The clinical records and radiological data of all patients who underwent ultrasound- and fluoroscopy-guided TVC placement at SQUH during the study period were reviewed. Demographic data and information regarding catheter placement, technical success and peri- and post-procedure complications (such as catheter-related infections or thrombosis) were collected. RESULTS: A total of 204 TVCs were placed in 161 patients. Of these, 68 were female (42.2%) and 93 were male (57.8%). The mean age of the patients was 54.4 +/- 17.3 years. The most common reason for catheter placement was the initiation of dialysis (63.4%). A total of 203 procedures were technically successful (99.5%). The right internal jugular vein was the most common site of catheter placement (74.9%). Mild haemorrhage which resolved spontaneously occurred in 11 cases (5.4%). No other complications were observed. Subsequent follow-up data was available for 132 catheters (65.0%); of these, thrombosis-related catheter malfunction was observed in 22 cases (16.7%) and catheter-related infection in 29 cases (22.0%). CONCLUSION: Radiological-guided placement of tunnelled haemodialysis catheters can be performed safely with excellent technical success. The success rate of catheter insertion at SQUH was favourable in comparison with other studies reported in the literature. PMID- 26629378 TI - Evaluation of Salivary Secretory Immunoglobulin A Levels in Diabetic Patients and Association with Oral and Dental Manifestations. AB - OBJECTIVES: Oral and dental manifestations in diabetic patients can arise due to numerous factors, including elevated salivary secretory immunoglobulin A (s-IgA) levels. This study aimed to evaluate s-IgA concentrations in patients with type 2 diabetes mellitus (T2DM) and to investigate the association between s-IgA levels and oral and dental manifestations of T2DM. METHODS: This cross-sectional descriptive study was carried out between October 2011 and September 2012 in Kerman, Iran, and included 260 subjects (128 patients with T2DM and 132 healthy controls). Unstimulated salivary samples were collected from all subjects and s IgA levels were determined using the immunoturbidimetric method. The oral cavities and teeth of T2DM patients were evaluated for oral and dental manifestations. RESULTS: Both diabetic and control subjects with higher concentrations of s-IgA had significantly higher numbers of decayed, missing or filled teeth (DMFT) and periodontal index (PDI) scores (P <0.050). s-IgA levels were significantly higher in subjects with oral candidiasis (P <0.050). Among diabetic patients, significantly higher s-IgA levels were concomitant with xerostomia and denture stomatitis (P <=0.050). There were no significant differences between s-IgA concentrations and other oral or dental manifestations in either group. CONCLUSION: Individuals with a greater number of DMFT, a higher PDI score and oral candidiasis had significantly higher s-IgA levels. s-IgA levels were not significantly higher among diabetic patients in comparison to the control group. However, significantly higher s-IgA levels occurred with xerostomia and denture stomatitis in diabetic patients. In addition, s-IgA was significantly higher in patients with uncontrolled diabetes compared to those with controlled diabetes. PMID- 26629379 TI - Serum Zinc Concentrations in Children with Acute Bloody and Watery Diarrhoea. AB - OBJECTIVES: The role of zinc in the pathogenesis of diarrhoea is controversial. This study was conducted to compare serum zinc levels in children with acute diarrhoea to those found in healthy children. METHODS: This case-control study was carried out at the Qazvin Children's Hospital in Qazvin, Iran, between July 2012 and January 2013. A total of 60 children with acute diarrhoea (12 children with bloody diarrhoea and 48 children with watery diarrhoea) and 60 healthy children were included. Zinc levels for all subjects were measured using a flame atomic absorption spectrophotometer and data were analysed and compared between groups. RESULTS: Mean serum zinc levels in the patients with acute bloody diarrhoea, acute watery diarrhoea and the control group were 74.1 +/- 23.7 MUg/dL, 169.4 +/- 62.7 MUg/dL and 190.1 +/- 18.0 MUg/dL, respectively (P = 0.01). Hypozincaemia was observed in 50.0% of children with acute bloody diarrhoea and 12.5% of those with acute watery diarrhoea. None of the patients in the control group had hypozincaemia (P = 0.01). CONCLUSION: Children with acute bloody diarrhoea had significantly reduced serum zinc levels in comparison to healthy children. However, a study with a larger sample size is needed to examine the significance of this trend. PMID- 26629380 TI - The Changing Pattern of Hospital Admission to Medical Wards: Burden of non communicable diseases at a hospital in a developing country. AB - OBJECTIVES: This study aimed to determine the pattern of hospital admissions and patient outcomes in medical wards at Atbara Teaching Hospital in River Nile State, Sudan. METHODS: This retrospective cross-sectional study was conducted from August 2013 to July 2014 and included all patients admitted to medical wards at the Atbara Teaching Hospital during the study period. Morbidity and mortality data was obtained from medical records. Diseases were categorised using the World Health Organization's International Classification of Diseases (ICD) coding system. RESULTS: A total of 2,614 patient records were analysed. The age group with the highest admissions was the 56-65-year-old age group (19.4%) and the majority of patients were admitted for one week or less (86.4%). Non-communicable diseases constituted 71.8% of all cases. According to ICD classifications, patients were admitted most frequently due to infectious or parasitic diseases (19.7%), followed by diseases of the circulatory (16.4%), digestive (16.4%) and genito-urinary (13.8%) systems. The most common diseases were cardiovascular disease (16.4%), malaria (11.3%), gastritis/peptic ulcer disease (9.8%), urinary tract infections (7.2%) and diabetes mellitus (6.9%). The mortality rate was 4.7%. CONCLUSION: The burden of non-communicable diseases was found to exceed that of communicable diseases among patients admitted to medical wards at the Atbara Teaching Hospital. PMID- 26629381 TI - Improvement in Adherence to Surgical Antimicrobial Prophylaxis Guidelines after Implementation of a Multidisciplinary Quality Improvement Project. AB - OBJECTIVES: This study aimed to show the impact of a multidisciplinary quality improvement project on adherence to antimicrobial prophylaxis guidelines in oncological surgery. METHODS: This pre- and post-intervention prospective observational study was carried out at the King Hussein Cancer Centre (KHCC) in Amman, Jordan, between August 2009 and February 2012. The quality improvement project consisted of revising the institutional guidelines for surgical antimicrobial prophylaxis, assigning a clinical pharmacist to the surgical department, establishing an operating room satellite pharmacy and providing education regarding the appropriate utilisation of antibiotics. The medical records of adult cancer patients who underwent surgery were evaluated one month before and one month after the project was implemented to assess adherence to the guidelines with regards to antibiotics prescribed, drug doses and timing and treatment duration. RESULTS: A total of 70 patients were evaluated before and 97 patients were evaluated after the intervention, of which 57 (81.4%) and 95 (97.9%) patients received antibiotics, respectively. In comparing the pre- and post-intervention groups, an improvement was observed in the proportion of patients who received antibiotics at the appropriate time (n = 12 versus n = 79; 21.1% versus 83.2%; P <0.01), for the appropriate duration of time (n = 22 versus n = 94; 38.6% versus 99.0%; P <0.01) and in the appropriate dose (n = 9 versus n = 87; 56.3% versus 98.9%; P <0.01). CONCLUSION: Adherence to the antimicrobial prophylaxis guidelines at KHCC improved significantly after the implementation of a quality improvement project. PMID- 26629382 TI - Comorbidity of Learning Disorders and Attention Deficit Hyperactivity Disorder in a Sample of Omani Schoolchildren. AB - OBJECTIVES: The estimated worldwide prevalence of learning disorders (LDs) is approximately 2-10% among school-aged children. LDs have variable clinical features and are often associated with other disorders. This study aimed to examine the comorbidity of LDs and attention deficit hyperactivity disorder (ADHD) among a sample of schoolchildren in Oman. METHODS: This study was conducted between January 2014 and January 2015 at the Sultan Qaboos University, Muscat, Oman. The Learning Disabilities Diagnostic Inventory (LDDI) and the 28 item version of the Conners' Teacher Rating Scale was completed by classroom teachers to determine the existence of LD and ADHD symptoms in 321 children in grades 1-4 who had been referred to a learning support unit for LDs from elementary schools in Muscat. RESULTS: The mean age of the students was 8.5 years. Among the cohort, 30% were reported to have symptoms of ADHD, including conduct problems (24%), hyperactivity (24%) and inattentive-passive behaviours (41%). Male students reportedly exhibited greater conduct problems and hyperactivity than females. However, there were no gender differences noted between LDDI scores. CONCLUSION: This study suggests that Omani schoolchildren with LDs are likely to exhibit signs of ADHD. The early identification of this disorder is essential considering the chronic nature of ADHD. For interventional purposes, multidisciplinary teams are recommended, including general and special educators, clinical psychologists, school counsellors, developmental or experienced general paediatricians and child psychiatrists. PMID- 26629383 TI - Effectiveness of Misoprostol for Induction of First-Trimester Miscarriages: Experience at a single tertiary care centre in Oman. AB - OBJECTIVES: Non-invasive methods of inducing a miscarriage are now considered an effective alternative to surgical evacuation (dilatation and curettage). This study aimed to evaluate the effectiveness of misoprostol in the termination of first-trimester miscarriages. METHODS: This prospective study was conducted between October 2009 and September 2010 and assessed all patients admitted to the Royal Hospital in Muscat, Oman, for the termination of first-trimester miscarriages during the study period. All patients received misoprostol and the rates of successful termination were measured. Patient satisfaction was assessed using a short questionnaire. RESULTS: A total of 290 women were included in the study. Termination with misoprostol was successful in 61.38% of the subjects. Of the remaining subjects requiring additional surgical evacuation (n = 112), 58.93% required evacuation due to failed termination with misoprostol and 65.18% underwent early evacuation (<=24 hours since their last misoprostol dose). The majority of patients experienced no side-effects due to misoprostol (89.66%). Pain was controlled with simple analgesics in 70.00% of the subjects. A high satisfaction rate (94.83%) with the misoprostol treatment was reported. CONCLUSION: Misoprostol was a well-tolerated drug which reduced the rate of surgical evacuation among the study subjects. This medication can therefore be used safely in the management of incomplete miscarriages. PMID- 26629384 TI - Suction Evacuation with Methotrexate as a Successful Treatment Modality for Caesarean Scar Pregnancies: Case series. AB - Pregnancy resulting from the implantation of an embryo within a scar of a previous Caesarean section is extremely rare. The diagnosis and treatment of Caesarean scar pregnancies (CSPs) are challenging and the optimal course of treatment is still to be determined. We report a case series of six patients with CSPs who presented to the Royal Hospital in Muscat, Oman, between October 2012 and April 2014. All of the patients were successfully treated with systemic methotrexate and five patients underwent suction evacuation either before or after the methotrexate administration. The patients were followed up for a period of 6-9 weeks after treatment and recovered completely without any significant complications. Suction evacuation with methotrexate can therefore be considered an effective treatment option with good maternal outcomes. PMID- 26629385 TI - Eosinophilic Pneumonia in a Patient with Bronchial Myiasis: Case report and literature review. AB - Pulmonary myiasis is an unusual form of myiasis in humans and has been recently identified as a cause of eosinophilic pneumonia. We report the case of a 13-year old Omani boy who presented to the Royal Hospital, Muscat, Oman, in October 2014 with respiratory distress. Bronchial aspirates revealed features of eosinophilic pneumonia. Possible larvae identified in the cytology report, a high immunoglobulin E level and the patient history all indicated bronchial myiasis. The patient was treated with steroids and ventilation and has since been disease free with no long-term side-effects. To the best of the authors' knowledge, this is the first case of bronchial myiasis in Oman. PMID- 26629386 TI - Twin Pregnancy with a Complete Hydatidiform Mole and a Coexisting Live Fetus: Rare entity. AB - A hydatidiform mole with a coexisting live fetus is a rare occurrence and the optimal management for this condition is not yet known. We report the case of a 32-year-old woman (gravida 3, para 2) who presented to the Sultan Qaboos University Hospital, Muscat, Oman, in March 2012 at 13 gestational weeks with abdominal pain and vaginal bleeding. An ultrasound examination revealed a hydatidiform mole pregnancy coexisting with a live fetus. After extensive counselling, the patient and her husband opted for a conservative management approach. Unfortunately, a hysterotomy had to be performed at 17 gestational weeks due to severe haemorrhage. The postoperative period was uneventful and histopathology results confirmed one complete mole with a coexisting fetus and normal placenta. The patient's serum beta-human chorionic gonadotropin level remained normal for 18 months following her surgery. PMID- 26629387 TI - Temporomandibular Joint Ankylosis as a Complication of Neonatal Septic Arthritis: Report of two cases. AB - Temporomandibular joint (TMJ) ankylosis as a complication of neonatal septic arthritis is rarely reported in the literature. We report two clinical cases of unilateral TMJ ankylosis occurring in paediatric patients subsequent to neonatal septic arthritis. The first case was a 15-month-old male infant who presented to the Sultan Qaboos University Hospital, Muscat, Oman, in May 2010. According to the published English scientific literature, he is the youngest person yet to be diagnosed with this condition. The second case was a five-year-old female who presented to the Al-Nahda Hospital, Muscat, Oman, in October 2011. Both cases presented with facial asymmetry and trismus. They subsequently underwent gap arthroplasty and interpositional temporalis muscle and fascia grafts which resulted in an immediate improvement in mouth opening. Postoperatively, the patients underwent active jaw physiotherapy which was initially successful. Both patients were followed up for a minimum of two years following their surgeries. PMID- 26629388 TI - Primary Endometrial Squamous Cell Carcinoma In Situ: Report of a rare disease. AB - Squamous cell carcinoma (SCC) of the endometrium, whether primary or secondary to cervical cancer, is a rare entity. Primary endometrial squamous cell carcinoma in situ is even more uncommon; it usually occurs in postmenopausal women and has a strong association with pyometra. We report a 60-year-old multiparous postmenopausal woman who presented to the Hakeem Abdul Hameed Centenary Hospital, New Delhi, India, in May 2014 with a lower abdominal swelling corresponding in size to a pregnancy of 26 gestational weeks and vaginal discharge of one year's duration. A total abdominal hysterectomy with a bilateral salpingooophorectomy was performed, which revealed an enlarged uterus with pyometra. Histopathology showed that the entire endometrial lining had been replaced with malignant squamous cells without invasion of the myometrium. Immunohistochemistry revealed that the tumour cells were positive for p63 with a high Ki-67 labelling index. No adjuvant therapy was required and the patient was disease-free at a seven-month follow-up. PMID- 26629389 TI - Magnetic Resonance Imaging Abnormalities in a Child with Acute Cerebellitis. PMID- 26629390 TI - Common Peroneal Nerve Mononeuropathy due to an Amniotic Constriction Band. PMID- 26629391 TI - Appearance of Renal Replacement Lipomatosis on Computed Tomography: Rare pseudotumour. PMID- 26629392 TI - Otoneurological and Postural Assessment in Blind Scuba Divers. PMID- 26629393 TI - Diagnosis and Genetic Analysis of Glutaric Acidaemia Type I: Very rarely seen inborn error of metabolism. PMID- 26629394 TI - A refugee's perspective on their neurosurgical care in North America. AB - BACKGROUND: There is a growing population of refugees within North America and an increasing awareness of their unique medical requirements. These requirements include both a well-recognized need to understand the different pathologies that can present in these patients as well as the rarely described need to understand their unique perspective and how this can impact their medical care, especially for routine neurosurgical conditions. This paper highlights a refugee's perspective toward the medical system in North America and documents how several aspects of this unique perspective hindered or delayed the care for the management of this patient with a cervical cord tumor. CASE DESCRIPTION: A 34 year-old female Somalian refugee presented with an ependymoma to Vancouver General Hospital 3 days after arriving in North America. The tumor was removed through a standard posterior cervical laminectomy approach. The patient and her care workers were interviewed 6 months postoperatively to determine if any aspects of care were negatively impacted by her refugee status. Problems related to communication, medical history, mistrust of care workers, familial support, and access to follow-up care were recognized and recommendations for improvements provided. CONCLUSIONS: It is well known that the North American physicians must be familiar with the unique spectrum of medical conditions within the refugee community. This paper highlights that physicians must also be aware that refugees may have a unique perspective on our health care system that can negatively influence their care for even routine neurosurgical conditions. PMID- 26629395 TI - Microsurgical treatment of patients with refractory epilepsy and mesial temporal cavernous malformations: Clinical experience of a tertiary epilepsy center. AB - BACKGROUND: Mesiotemporal cavernous malformation can occur in 10-20% of patients with cerebral cavernomas and are frequently associated with refractory. METHODS: A retrospective investigation was performed in the epilepsy clinic of a Brazilian tertiary referral epilepsy center, from January 2000 to March 2012. RESULTS: A total of 21 patients were included in the study. Thirteen patients (62%) evolved to Engel I; 5 (24%) to Engel II, 2 (10%) to Engel III, and 1 (5%) to Engel IV. We observed that 10 (48%) patients with 12 years or less of epilepsy duration evolved to Engel I and 1 (5%) to Engel II; whereas from a total of 10 patients with epilepsy duration of more than 12 years, 3 (30%) evolved to Engel I and 7 (70%) to Engel II, III, or IV (P < 0.001 [bilateral]; P1 ? P2). CONCLUSION: Postsurgical seizure outcome for temporal lobe epilepsy associated with mesiotemporal cavernomas is very satisfactory. PMID- 26629396 TI - A rare case of giant multiseptated thoracic myelomeningocele with segmental placode. PMID- 26629398 TI - Report on the National Eye Institute Audacious Goals Initiative: Photoreceptor Regeneration and Integration Workshop. AB - The National Eye Institute (NEI) hosted a workshop on May 2, 2015, as part of the Audacious Goals Initiative (AGI) to foster a concerted effort to develop novel therapies for outer retinal diseases. The central goal of this initiative is to "demonstrate by 2025 the restoration of usable vision in humans through the regeneration of neurons and neural connections in the eye and visual system." More specifically, the AGI identified two neural retinal cell classes-ganglion cells and photoreceptors-as challenging, high impact targets for these efforts. A prior workshop and subsequent white paper provided a foundation to begin addressing issues regarding optic nerve regeneration, whereas the major objective of the May 2015 workshop was to review progress toward photoreceptor replacement and identify research gaps and barriers that are limiting advancement of the field. The present report summarizes that discussion and input, which was gathered from a panel of distinguished basic science and clinical investigators with diverse technical expertise and experience with different model systems. Four broad discussion categories were put forth during the workshop, each addressing a critical area of need in the pursuit of functional photoreceptor regeneration: (1) cell sources for photoreceptor regeneration, (2) cell delivery and/or integration, (3) outcome assessment, and (4) preclinical models and target patient populations. For each category, multiple challenges and opportunities for research discovery and tool production were identified and vetted. The present report summarizes the dialogue that took place and seeks to encourage continued interactions within the vision science community on this topic. It also serves as a guide for funding to support the pursuit of cell and circuit repair in diseases leading to photoreceptor degeneration. PMID- 26629399 TI - Ultra-Short-Term Reproducibility of Speckle-Noise Freed Fluid and Tissue Compartmentalization of the Choroid Analyzed by Standard OCT. AB - PURPOSE: We measured reproducibility of speckle-noise freed fluid and tissue compartmentalization of the choroid (choroidal angiography and tissue characterization). METHODS: This study included 26 eyes of 13 healthy females: 13 were used for repeated measurements and 13 were used for side comparison. A semiautomated algorithm removed speckle-noise with structure preservation. RESULTS: Intraclass correlation (ICC), with respect to reproducibility of the method, showed an ICC for choroidal fluid inner space analysis (FISA) of 95.15% (90.01-98.24). The ICC of tissue inner space analysis (TISA) was 99.75% (99.47 99.91). The total choroid ratio (TCR), calculated from volumes of tissue to vessels, showed an ICC of 88.84% (78.28-95.82). Comparison of eyes (left to right) showed a difference for FISA of 0.033 (95% confidence interval [CI] 0.0018-0.0680, P = 0.063), TISA -0.118 (CI -0.2373-0.0023, P = 0.055), and TCR 0.590 (CI -0.9047 to -0.2754, P = 0.004). The ICC for FISA and TISA showed a trend in the difference comparing left and right eyes; however, TCR showed a significant difference between the eyes in the measured area (P < 0.001). Mean overall FISA was 0.58 mm3 (range, 0.25-0.98 mm3, SD = 0.14). Mean TISA was 3.45 mm3 (range, 2.38-5.0 mm3, SD 0.072). Mean TCR was 6.13 (overall range, 3.93-10.2, SD = 1.34). CONCLUSIONS: Differences in choroidal layers between subjects were found mainly due to alterations in choroidal tissue. Reproducibility of speckle noise freed choroidal angiography appeared excellent. TRANSLATIONAL RELEVANCE: Speckle noise is a granular "noise" that appears in a wide range of medical imaging methods as ultrasonography, magnetic resonance, computer tomography, or optical coherence tomography (OCT). Findings from basic science about speckle noise were translated into a novel, medical image postprocessing application that can separate signal from speckle noise with structure preservation with high reproducibility and enhance medical imaging. PMID- 26629400 TI - AstroGenesis: And there was leptin on the sixth day. PMID- 26629401 TI - Adiporedoxin, an upstream regulator of ER oxidative folding and protein secretion in adipocytes. AB - OBJECTIVE: Adipocytes are robust protein secretors, most notably of adipokines, hormone-like polypeptides, which act in an endocrine and paracrine fashion to affect numerous physiological processes such as energy balance and insulin sensitivity. To understand how such proteins are assembled for secretion we describe the function of a novel endoplasmic reticulum oxidoreductase, adiporedoxin (Adrx). METHODS: Adrx knockdown and overexpressing 3T3-L1 murine adipocyte cell lines and a knockout mouse model were used to assess the influence of Adrx on secreted proteins as well as the redox state of ER resident chaperones. The metabolic phenotypes of Adrx null mice were characterized and compared to WT mice. The correlation of Adrx levels BMI, adiponectin levels, and other inflammatory markers from adipose tissue of human subjects was also studied. RESULTS: Adiporedoxin functions via a CXXC active site, and is upstream of protein disulfide isomerase whose direct function is disulfide bond formation, and ultimately protein secretion. Over and under expression of Adrx in vitro enhances and reduces, respectively, the secretion of the disulfide-bonded proteins including adiponectin and collagen isoforms. On a chow diet, Adrx null mice have normal body weights, and glucose tolerance, are moderately hyperinsulinemic, have reduced levels of circulating adiponectin and are virtually free of adipocyte fibrosis resulting in a complex phenotype tending towards insulin resistance. Adrx protein levels in human adipose tissue correlate positively with adiponectin levels and negatively with the inflammatory marker phospho-Jun kinase. CONCLUSION: These data support the notion that Adrx plays a critical role in adipocyte biology and in the regulation of mouse and human metabolism via its modulation of adipocyte protein secretion. PMID- 26629397 TI - A comprehensive review of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease affecting motor neurons with an incidence of about 1/100,000. Most ALS cases are sporadic, but 5-10% of the cases are familial ALS. Both sporadic and familial ALS (FALS) are associated with degeneration of cortical and spinal motor neurons. The etiology of ALS remains unknown. However, mutations of superoxide dismutase 1 have been known as the most common cause of FALS. In this study, we provide a comprehensive review of ALS. We cover all aspects of the disease including epidemiology, comorbidities, environmental risk factor, molecular mechanism, genetic factors, symptoms, diagnostic, treatment, and even the available supplement and management of ALS. This will provide the reader with an advantage of receiving a broad range of information about the disease. PMID- 26629402 TI - Impact of tamoxifen on adipocyte lineage tracing: Inducer of adipogenesis and prolonged nuclear translocation of Cre recombinase. AB - BACKGROUND: The selective estrogen receptor modulator tamoxifen, in combination with the Cre-ER(T2) fusion protein, has been one of the mainstream methods to induce genetic recombination and has found widespread application in lineage tracing studies. METHODS & RESULTS: Here, we report that tamoxifen exposure at widely used concentrations remains detectable by mass-spectrometric analysis in adipose tissue after a washout period of 10 days. Surprisingly, its ability to maintain nuclear translocation of the Cre-ER(T2) protein is preserved beyond 2 months of washout. Tamoxifen treatment acutely leads to transient lipoatrophy, followed by de novo adipogenesis that reconstitutes the original fat mass. In addition, we find a "synthetically lethal" phenotype for adipocytes when tamoxifen treatment is combined with adipocyte-specific loss-of-function mutants, such as an adipocyte-specific PPARgamma knockout. This is observed to a lesser extent when alternative inducible approaches are employed. CONCLUSIONS: These findings highlight the potential for tamoxifen-induced adipogenesis, and the associated drawbacks of the use of tamoxifen in lineage tracing studies, explaining the discrepancy in lineage tracing results from different systems with temporal control of gene targeting. PMID- 26629403 TI - Adipocyte progenitor cells initiate monocyte chemoattractant protein-1-mediated macrophage accumulation in visceral adipose tissue. AB - OBJECTIVE: Macrophages are important producers of obesity-induced MCP-1; however, initial obesity-induced increases in MCP-1 production precede M1 macrophage accumulation in visceral adipose tissue (VAT). The initial cellular source of obesity-induced MCP-1 in vivo is currently unknown. Preliminary reports based on in vitro studies of preadipocyte cell lines and adherent stroma-vascular fraction cells suggest that resident stromal cells express MCP-1. In the past several years, elegant methods of identifying adipocyte progenitor cells (AdPCs) have become available, making it possible to study these cells in vivo. We have previously published that global deletion of transcription factor Inhibitor of Differentiation 3 (Id3) attenuates high fat diet-induced obesity, but it is unclear if Id3 plays a role in diet-induced MCP-1 production. We sought to determine the initial cellular source of MCP-1 and identify molecular regulators mediating MCP-1 production. METHODS: Id3 (+/+) and Id3 (-/-) mice were fed either a standard chow or HFD for varying lengths of time. Flow cytometry, semi quantitative real-time PCR, ELISAs and adoptive transfers were used to assess the importance of AdPCs during diet-induced obesity. Flow cytometry was also performed on a cohort of 14 patients undergoing bariatric surgery. RESULTS: Flow cytometry identified committed CD45(-)CD31 (-) Ter119(-)CD29(+)CD34(+)Sca 1(+)CD24(-) adipocyte progenitor cells as producers of high levels of MCP-1 in VAT. High-fat diet increased AdPC numbers, an effect dependent on Id3. Loss of Id3 increased p21(Cip1) levels and attenuated AdPC proliferation, resulting in reduced MCP-1 and M1 macrophage accumulation in VAT, compared to Id3 (+/+) littermate controls. AdPC rescue by adoptive transfer of 50,000 Id3 (+/+) AdPCs into Id3 (-/-) recipient mice increased MCP-1 levels and M1 macrophage number in VAT. Additionally, flow cytometry identified MCP-1-producing CD45(-)CD31( )CD34(+)CD44(+)CD90(+) AdPCs in human omental and subcutaneous adipose tissue, with a higher percentage in omental adipose. Furthermore, high surface expression of CD44 marked abundant MCP-1 producers, only in visceral adipose tissue. CONCLUSIONS: This study provides the first in vivo evidence, to our knowledge, that committed AdPCs in VAT are the initial source of obesity-induced MCP-1 and identifies the helix-loop-helix transcription factor Id3 as a critical regulator of p21(Cip1) expression, AdPC proliferation, MCP-1 expression and M1 macrophage accumulation in VAT. Inhibition of Id3 and AdPC expansion, as well as CD44 expression in human AdPCs, may serve as unique therapeutic targets for the regulation of adipose tissue inflammation. PMID- 26629404 TI - TUSC5 regulates insulin-mediated adipose tissue glucose uptake by modulation of GLUT4 recycling. AB - OBJECTIVE: Failure to properly dispose of glucose in response to insulin is a serious health problem, occurring during obesity and is associated with type 2 diabetes development. Insulin-stimulated glucose uptake is facilitated by the translocation and plasma membrane fusion of vesicles containing glucose transporter 4 (GLUT4), the rate-limiting step of post-prandial glucose disposal. METHODS: We analyzed the role of Tusc5 in the regulation of insulin-stimulated Glut4-mediated glucose uptake in vitro and in vivo. Furthermore, we measured Tusc5 expression in two patient cohorts. RESULTS: Herein, we report that TUSC5 controls insulin-stimulated glucose uptake in adipocytes, in vitro and in vivo. TUSC5 facilitates the proper recycling of GLUT4 and other key trafficking proteins during prolonged insulin stimulation, thereby enabling proper protein localization and complete vesicle formation, processes that ultimately enable insulin-stimulated glucose uptake. Tusc5 knockout mice exhibit impaired glucose disposal and TUSC5 expression is predictive of glucose tolerance in obese individuals, independent of body weight. Furthermore, we show that TUSC5 is a PPARgamma target and in its absence the anti-diabetic effects of TZDs are significantly blunted. CONCLUSIONS: Collectively, these findings establish TUSC5 as an adipose tissue-specific protein that enables proper protein recycling, linking the ubiquitous vesicle traffic machinery with tissue-specific insulin mediated glucose uptake into adipose tissue and the maintenance of a healthy metabolic phenotype in mice and humans. PMID- 26629405 TI - PGC-1 coactivators in beta-cells regulate lipid metabolism and are essential for insulin secretion coupled to fatty acids. AB - OBJECTIVES: Peroxisome proliferator-activated receptor gamma coactivator 1 (PPARGCA1, PGC-1) transcriptional coactivators control gene programs important for nutrient metabolism. Islets of type 2 diabetic subjects have reduced PGC 1alpha expression and this is associated with decreased insulin secretion, yet little is known about why this occurs or what role it plays in the development of diabetes. Our goal was to delineate the role and importance of PGC-1 proteins to beta-cell function and energy homeostasis. METHODS: We investigated how nutrient signals regulate coactivator expression in islets and the metabolic consequences of reduced PGC-1alpha and PGC-1beta in primary and cultured beta-cells. Mice with inducible beta-cell specific double knockout of Pgc-1alpha/Pgc-1beta (betaPgc-1 KO) were created to determine the physiological impact of reduced Pgc1 expression on glucose homeostasis. RESULTS: Pgc-1alpha and Pgc-1beta expression was increased in primary mouse and human islets by acute glucose and palmitate exposure. Surprisingly, PGC-1 proteins were dispensable for the maintenance of mitochondrial mass, gene expression, and oxygen consumption in response to glucose in adult beta-cells. However, islets and mice with an inducible, beta cell-specific PGC-1 knockout had decreased insulin secretion due in large part to loss of the potentiating effect of fatty acids. Consistent with an essential role for PGC-1 in lipid metabolism, beta-cells with reduced PGC-1s accumulated acyl glycerols and PGC-1s controlled expression of key enzymes in lipolysis and the glycerolipid/free fatty acid cycle. CONCLUSIONS: These data highlight the importance of PGC-1s in coupling beta-cell lipid metabolism to promote efficient insulin secretion. PMID- 26629406 TI - The calcineurin-NFAT pathway controls activity-dependent circadian gene expression in slow skeletal muscle. AB - OBJECTIVE: Physical activity and circadian rhythms are well-established determinants of human health and disease, but the relationship between muscle activity and the circadian regulation of muscle genes is a relatively new area of research. It is unknown whether muscle activity and muscle clock rhythms are coupled together, nor whether activity rhythms can drive circadian gene expression in skeletal muscle. METHODS: We compared the circadian transcriptomes of two mouse hindlimb muscles with vastly different circadian activity patterns, the continuously active slow soleus and the sporadically active fast tibialis anterior, in the presence or absence of a functional skeletal muscle clock (skeletal muscle-specific Bmal1 KO). In addition, we compared the effect of denervation on muscle circadian gene expression. RESULTS: We found that different skeletal muscles exhibit major differences in their circadian transcriptomes, yet core clock gene oscillations were essentially identical in fast and slow muscles. Furthermore, denervation caused relatively minor changes in circadian expression of most core clock genes, yet major differences in expression level, phase and amplitude of many muscle circadian genes. CONCLUSIONS: We report that activity controls the oscillation of around 15% of skeletal muscle circadian genes independently of the core muscle clock, and we have identified the Ca(2+) dependent calcineurin-NFAT pathway as an important mediator of activity-dependent circadian gene expression, showing that circadian locomotor activity rhythms drive circadian rhythms of NFAT nuclear translocation and target gene expression. PMID- 26629407 TI - Human skeletal myotubes display a cell-autonomous circadian clock implicated in basal myokine secretion. AB - OBJECTIVE: Circadian clocks are functional in all light-sensitive organisms, allowing an adaptation to the external world in anticipation of daily environmental changes. In view of the potential role of the skeletal muscle clock in the regulation of glucose metabolism, we aimed to characterize circadian rhythms in primary human skeletal myotubes and investigate their roles in myokine secretion. METHODS: We established a system for long-term bioluminescence recording in differentiated human myotubes, employing lentivector gene delivery of the Bmal1-luciferase and Per2-luciferase core clock reporters. Furthermore, we disrupted the circadian clock in skeletal muscle cells by transfecting siRNA targeting CLOCK. Next, we assessed the basal secretion of a large panel of myokines in a circadian manner in the presence or absence of a functional clock. RESULTS: Bioluminescence reporter assays revealed that human skeletal myotubes, synchronized in vitro, exhibit a self-sustained circadian rhythm, which was further confirmed by endogenous core clock transcript expression. Moreover, we demonstrate that the basal secretion of IL-6, IL-8 and MCP-1 by synchronized skeletal myotubes has a circadian profile. Importantly, the secretion of IL-6 and several additional myokines was strongly downregulated upon siClock-mediated clock disruption. CONCLUSIONS: Our study provides for the first time evidence that primary human skeletal myotubes possess a high-amplitude cell-autonomous circadian clock, which could be attenuated. Furthermore, this oscillator plays an important role in the regulation of basal myokine secretion by skeletal myotubes. PMID- 26629408 TI - Enhanced insulin sensitivity in skeletal muscle and liver by physiological overexpression of SIRT6. AB - OBJECTIVE: Available treatment for obesity and type 2 diabetes mellitus (T2DM) is suboptimal. Thus, identifying novel molecular target(s) exerting protective effects against these metabolic imbalances is of enormous medical significance. Sirt6 loss- and gain-of-function studies have generated confounding data regarding the role of this sirtuin on energy and glucose homeostasis, leaving unclear whether activation or inhibition of SIRT6 may be beneficial for the treatment of obesity and/or T2DM. METHODS: To address these issues, we developed and studied a novel mouse model designed to produce eutopic and physiological overexpression of SIRT6 (Sirt6BAC mice). These mutants and their controls underwent several metabolic analyses. These include whole-blood reverse phase high-performance liquid chromatography assay, glucose and pyruvate tolerance tests, hyperinsulinemic-euglycemic clamp assays, and assessment of basal and insulin-induced level of phosphorylated AKT (p-AKT)/AKT in gastrocnemius muscle. RESULTS: Sirt6BAC mice physiologically overexpress functionally competent SIRT6 protein. While Sirt6BAC mice have normal body weight and adiposity, they are protected from developing high-caloric-diet (HCD)-induced hyperglycemia and glucose intolerance. Also, Sirt6BAC mice display increased circulating level of the polyamine spermidine. The ability of insulin to suppress endogenous glucose production was significantly enhanced in Sirt6BAC mice compared to wild-type controls. Insulin-stimulated glucose uptake was increased in Sirt6BAC mice in both gastrocnemius and soleus muscle, but not in brain, interscapular brown adipose, or epididymal adipose tissue. Insulin-induced p-AKT/AKT ratio was increased in gastrocnemius muscle of Sirt6BAC mice compared to wild-type controls. CONCLUSIONS: Our data indicate that moderate, physiological overexpression of SIRT6 enhances insulin sensitivity in skeletal muscle and liver, engendering protective actions against diet-induced T2DM. Hence, the present study provides support for the anti-T2DM effect of SIRT6 and suggests SIRT6 as a putative molecular target for anti-T2DM treatment. PMID- 26629409 TI - Sex-dependent changes in metabolism and behavior, as well as reduced anxiety after eliminating ventromedial hypothalamus excitatory output. AB - OBJECTIVES: The ventromedial hypothalamic nucleus (VMH) regulates energy homeostasis as well as social and emotional behaviors. Nearly all VMH neurons, including those in the sexually dimorphic ventrolateral VMH (VMHvl) subregion, release the excitatory neurotransmitter glutamate and use the vesicular glutamate transporter 2 (Vglut2). Here, we asked how glutamatergic signaling contributes to the collective metabolic and behavioral responses attributed to the VMH and VMHvl. METHODS: Using Sf1-Cre and a Vglut2 floxed allele, Vglut2 was knocked-out in SF-1 VMH neurons (Vglut2 (Sf1-Cre) ). Metabolic and neurobehavioral assays were carried out initially on Vglut2 (fl/fl) and Vglut2 (Sf1-Cre) mice in a mixed, and then in the C57BL/6 genetic background, which is prone to hyperglycemia and diet induced obesity (DIO). RESULTS: Several phenotypes observed in Vglut2 (Sf1-Cre) mice were largely unexpected based on prior studies that have perturbed VMH development or VMH glutamate signaling. In our hands, Vglut2 (Sf1-Cre) mice failed to exhibit the anticipated increase in body weight after high fat diet (HFD) or the impaired glucose homeostasis after fasting. Instead, there was a significant sex-dependent attenuation of DIO in Vglut2 (Sf1 Cre) females. Vglut2 (Sf1-Cre) males also display a sex-specific loss of conditioned-fear responses and aggression accompanied by more novelty-associated locomotion. Finally, unlike the higher anxiety noted in Sf1 (Nestin-Cre) mice that lack a fully formed VMH, both male and female Vglut2 (Sf1-Cre) mice were less anxious. CONCLUSIONS: Loss of VMH glutamatergic signaling sharply decreased DIO in females, attenuated aggression and learned fear in males, and was anxiolytic in males and females. Collectively, our findings demonstrate that while glutamatergic output from the VMH appears largely dispensable for counter regulatory responses to hypoglycemia, it drives sex-dependent differences in metabolism and social behaviors and is essential for adaptive responses to anxiety-provoking stimuli in both sexes. PMID- 26629410 TI - Ablation of intact hypothalamic and/or hindbrain TrkB signaling leads to perturbations in energy balance. AB - OBJECTIVE: Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), play a paramount role in the central regulation of energy balance. Despite the substantial body of genetic evidence implicating BDNF or TrkB-deficiency in human obesity, the critical brain region(s) contributing to the endogenous role of BDNF/TrkB signaling in metabolic control remain unknown. METHODS: We assessed the importance of intact hypothalamic or hindbrain TrkB signaling in central regulation of energy balance by generating Nkx2.1-Ntrk2 /- and Phox2b-Ntrk2+/- mice, respectively, and comparing metabolic parameters (body weight, adiposity, food intake, energy expenditure and glucose homeostasis) under high-fat diet or chow fed conditions. RESULTS: Our data show that when fed a high-fat diet, male and female Nkx2.1-Ntrk2-/- mice have significantly increased body weight and adiposity that is likely driven by reduced locomotor activity and core body temperature. When maintained on a chow diet, female Nkx2.1 Ntrk2-/- mice exhibit an increased body weight and adiposity phenotype more robust than in males, which is accompanied by hyperphagia that precedes the onset of a body weight difference. In addition, under both diet conditions, Nkx2.1 Ntrk2-/- mice show increased blood glucose, serum insulin and leptin levels. Mice with complete hindbrain TrkB-deficiency (Phox2b-Ntrk2-/-) are perinatal lethal, potentially indicating a vital role for TrkB in visceral motor neurons that control cardiovascular, respiratory, and digestive functions during development. Phox2b-Ntrk2+/- heterozygous mice are similar in body weight, adiposity and glucose homeostasis parameters compared to wild type littermate controls when maintained on a high-fat or chow diet. Interestingly, despite the absence of a body weight difference, Phox2b-Ntrk2+/- heterozygous mice exhibit pronounced hyperphagia. CONCLUSION: Taken together, our findings suggest that the hypothalamus is a key brain region involved in endogenous BDNF/TrkB signaling and central metabolic control and that endogenous hindbrain TrkB likely plays a role in modulating food intake and survival of mice. Our findings also show that female mice lacking TrkB in the hypothalamus have a more robust metabolic phenotype. PMID- 26629411 TI - Leptin potentiates astrogenesis in the developing hypothalamus. AB - BACKGROUND: The proper establishment of hypothalamic feeding circuits during early development has a profound influence on energy homeostasis, and perturbing this process could predispose individuals to obesity and its associated consequences later in life. The maturation of hypothalamic neuronal circuitry in rodents takes place during the initial postnatal weeks, and this coincides with a dramatic surge in the circulating level of leptin, which is known to regulate the outgrowth of key neuronal projections in the maturing hypothalamus. Coincidently, this early postnatal period also marks the rapid proliferation and expansion of astrocytes in the brain. METHODS: Here we examined the effects of leptin on the proliferative capacity of astrocytes in the developing hypothalamus by treating postnatal mice with leptin. Mutant mice were also generated to conditionally remove leptin receptors from glial fibrillary acidic protein (GFAP)-expressing cells in the postnatal period. RESULTS AND CONCLUSIONS: We show that GFAP expressing cells in the periventricular zone of the 3rd ventricle were responsive to leptin during the initial postnatal week. Leptin enhanced the proliferation of astrocytes in the postnatal hypothalamus and conditional removal of leptin receptors from GFAP-expressing cells during early postnatal period limited astrocyte proliferation. While increasing evidence demonstrates a direct role of leptin in regulating astrocytes in the adult brain, and given the essential function of astrocytes in modulating neuronal function and connectivity, our study indicates that leptin may exert its metabolic effects, in part, by promoting hypothalamic astrogenesis during early postnatal development. PMID- 26629413 TI - Identification of functional consequence of a novel selection signature in CYP11b1 gene for milk fat content in Bubalus bubalis. AB - Genomic selection for traits of economic importance is an emerging approach carrying tremendous potentials. Many of polygenic traits as milk fat, protein and yield have been characterize at genomic level and important selection signatures have been identified. Cytochrome P450 enzymes are potential loci for affecting many of dairy capabilities. Present study was conducted for genomic dissection of CYP11b1 gene in riverine buffaloes and seven genetic variations were identified. Out of these, one novel polymorphism (p.A313T) was found well associated with milk fat %age. AB genotyped buffaloes were found to have higher milk fat %age (8.9%) for this loci. p.A313T was further validated at larger data set by restriction digestion using CviAII enzyme. Functional consequences of this locus were also predicted by studying three dimensional structure of CYP11b1 protein. For this purpose, 3D protein model was predicted by homology modeling, secondary structural attributes were determined, signal peptide was predicted and a transmembrane helix was also identified. One of polymorphism (p.Y205L) was found in the vicinity of functionally significant F-G loop region, which is the part of protein gets attached to the inner mitochondrial membrane. But this variation could not be associated and needs further investigation. p.A30V, a popular selection marker in cattle, was found in buffaloes as well but could not be associated and might need further confirmation on larger data set. Results of this study illustrate the impending potential of this gene in determining dairy capabilities of buffaloes and might have a role in selection of superior dairy buffaloes. PMID- 26629412 TI - Methylenetetrahydrofolate reductase gene C677T polymorphism and breast cancer risk: Evidence for genetic susceptibility. AB - There are several evidences supporting the role of 5-10 methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in breast cancer (BC). Case control association studies on breast cancer have been repeatedly performed over the last two decades, but results are inconsistent. We performed a meta-analysis to confirm the association between MTHFR C677T polymorphism and BC risk. The articles were retrieved by searching the PubMed, Google Scholar, and Springer Link databases. Crude odds ratios (OR) with 95% confidence intervals (CIs) was used to assess the strength of association between C677T polymorphism and BC. Publication bias was assessed by Egger's and Begg-Mazumdar tests. Meta-analysis was performed with Open Meta Analyst. Total 75 studies with 31,315 cases and 35, 608 controls were found suitable for the inclusion in the present meta-analysis. The results of meta-analysis suggested that there were moderate significant association between C677T polymorphism and BC risk using overall comparisons in five genetic models (T vs. C: OR = 1.08, 95% CI = 1.03-1.13, p = < 0.001; TT + CT vs. CC: OR = 1.06, 95% CI = 1.02-1.09, p = < 0.001; TT vs. CC: OR = 1.17, 95% CI = 1.06-1.28, p = 0.001; CT vs. CC OR = 1.05, 95% CI = 1.01-1.08, p = 0.005; TT vs. CT + CC: OR = 1.12, 95% CI = 1.03-1.22, p = 0.005). In conclusion, results of present meta-analysis showed modest association between MTHFR C677T polymorphism with breast cancer in total studies. However, sub-group analysis results based on ethnicity showed strong significant association between TT genotype and breast cancer (TT vs. CC; OR degrees = degrees 1.26; 95% CI: 1.06-1.51; p = 0.009) in Asian population but in Caucasian population such association was not observed (TT vs. CC; OR degrees = degrees 1.08; 95% CI: 0.99-1.14; p = 0.05). PMID- 26629414 TI - Genetic and epigenetic variants in the MTHFR gene are not associated with non Hodgkin lymphoma. AB - The methylenetetrahydrofolate reductase (MTHFR) gene codes for the MTHFR enzyme which plays a key role in the pathway of folate and methionine metabolism. Polymorphisms of genes in this pathway affect its regulation and have been linked to lymphoma. In this study we examined whether we could detect an association between two common non-synonymous MTHFR polymorphisms, 677C > T (rs1801133) and 1298A > C (rs1801131), and susceptibility to non-Hodgkin lymphoma (NHL) in an Australian case-control cohort. We found no significant differences between genotype or allele frequencies for either polymorphisms between lymphoma cases and controls. We also explored whether epigenetic modification of MTHFR, specifically DNA methylation of a CpG island in the MTHFR promoter region, is associated with NHL using blood samples from patients. No difference in methylation levels was detected between the case and control samples suggesting that although hypermethylation of MTHFR has been reported in tumour tissues, particularly in the diffuse large B-cell lymphoma subtype of NHL, methylation of this MTHFR promoter CpG island is not a suitable epigenetic biomarker for NHL diagnosis or prognosis in peripheral blood samples. Further studies into epigenetic variants could focus on genes that are robustly associated with NHL susceptibility. PMID- 26629415 TI - Genetic architecture of early pre-inflammatory stage transcription signatures of autoimmune diabetes in the pancreatic lymph nodes of the NOD mouse reveals significant gene enrichment on chromosomes 6 and 7. AB - Autoimmune diseases are characterized by the stimulation of an excessive immune response to self-tissues by inner and/or outer organism factors. Common characteristics in their etiology include a complex genetic predisposition and environmental triggers as well as the implication of the major histocompatibility (MHC) locus on human chromosome 6p21. A restraint number of non-MHC susceptibility genes, part of the genetic component of type 1 diabetes have been identified in human and in animal models, while the complete spectrum of genes involved remains unknown. We elaborate herein patterns of chromosomal organization of 162 genes differentially expressed in the pancreatic lymph nodes of Non-Obese Diabetic mice, carefully selected by early sub-phenotypic evaluation (presence or absence of insulin autoantibodies). Chromosomal assignment of these genes revealed a non-random distribution on five chromosomes (47%). Significant gene enrichment was observed in particular for two chromosomes, 6 and 7. While a subset of these genes coding for secreted proteins showed significant enrichment on both chromosomes, the overall pool of genes was significantly enriched on chromosome 7. The significance of this unexpected gene distribution on the mouse genome is discussed in the light of novel findings indicating that genes affecting common diseases map to recombination "hotspot" regions of mammalian genomes. The genetic architecture of transcripts differentially expressed in specific stages of autoimmune diabetes offers novel venues towards our understanding of patterns of inheritance potentially affecting the pathological disease mechanisms. PMID- 26629416 TI - Current evidence on the cytotoxic T-lymphocyte antigen 4 + 49G > A polymorphism and digestive system cancer risks: a meta-analysis involving 11,923 subjects. AB - Cytotoxic T-lymphocyte antigen (CTLA-4) plays an important role in downregulating T cell activation and proliferation. The CTLA-4 + 49G > A polymorphism is one of the most commonly studied polymorphisms in this gene due to its association with many cancer types, but the association between CTLA-4 + 49G > A polymorphism and digestive system cancer risks remain inconclusive. An updated meta-analysis based on 17 independent case-control studies consisting of 5176 cancer patients and 6747 controls was performed to address this association. Overall, there was no statistically increased risk of digestive system cancers in every genetic comparison. In subgroup analysis, this polymorphism was significantly linked to higher risks for pancreatic cancer (GG vs. AA, OR = 1.976, 95% CI = 1.496-2.611; GA vs. AA, OR = 1.433, 95% CI = 1.093-1.879; GG/GA vs. AA, OR = 1.668, 95% CI = 1.286-2.164; GG vs. GA/AA, OR = 1.502, 95% CI = 1.098-2.054; G vs. A, OR = 1.394, 95% CI = 1.098-1.770). We also observed increased susceptibility of hepatocellular cell carcinoma in homozygote comparison (OR = 1.433, 95% CI = 1.100-1.866) and dominant model (OR = 1.360, 95% CI = 1.059-1.746). According to the source of controls, significant effects were only observed in hospital-based studies (GA/AA vs. GG, OR = 1.257, 95% CI = 1.129-1.399). In the stratified analysis by ethnicity, no significantly increased risks were found in either Asian or Caucasian. Our findings suggest that the CTLA-4 + 49G > A polymorphism may be associated with the risk of pancreatic cancer and hepatocellular cell carcinoma. PMID- 26629417 TI - An efficient protocol to enhance recombinant protein expression using ethanol in Escherichia coli. AB - Bacterial cells can be engineered to express non-native genes, resulting in the production of, recombinant proteins, which have various biotechnological and pharmaceutical applications. In eukaryotes, such as yeast or mammalian cells, which have large genomes, a higher recombinant protein expression can be troublesome. Comparatively, in the Escherichia coli (E. coli) expression system, although the expression is induced with isopropyl beta-d-1-thiogalactopyranoside (IPTG), studies have shown low expression levels of proteins. Irrespective of the purpose of protein production, the production process requires the accomplishment of three individual factors: expression, solubilization and purification. Although several efforts, including changing the host, vector, culture parameters of the recombinant host strain, co-expression of other genes and changing of the gene sequences, have been directed towards enhancing recombinant protein expression, the protein expression is still considered as a significant limiting step. Our protocol explains a simple method to enhance the recombinant protein expression that we have optimized using several unrelated proteins. It works with both T5 and T7 promoters. This protocol can be used to enhance the expressions of most of the proteins. The advantages of this technique are presented below:*It produces several fold increase in the expression of poorly expressed, less expressed or non-expressed recombinant proteins.*It does not employ any additional component such as chaperones, heat shock proteins or co-expression of other genes.*In addition to being inexpensive, easy to manage, universal, and quick to perform, the proposed method does not require any commercial kits and, can be used for various recombinant proteins expressed in the E. coli expression system. PMID- 26629418 TI - Lung cancer diagnostics and treatments 2015: a renaissance of patient care. PMID- 26629419 TI - Lung cancer biomarkers, targeted therapies and clinical assays. AB - Until recently, the majority of genomic cancer research has been in discovery and validation; however, as our knowledge of tumor molecular profiling improves, the idea of genomic application in the clinic becomes increasingly tangible, paralleled with the drug development of newer targeted therapies. A number of profiling methodologies exist to identify biomarkers found within the patient (germ-line DNA) and tumor (somatic DNA). Subsequently, commercially available clinical assays to test for both germ-line and somatic alterations that are prognostic and/or predictive of disease outcome, toxicity or treatment response have significantly increased. This review aims to summarize clinically relevant cancer biomarkers that serve as targets for therapy and their potential relationship to lung cancer. In order to realize the full potential of genomic cancer medicine, it is imperative that clinicians understand these intricate molecular pathways, the therapeutic implication of mutations within these pathways, and the availability of clinical assays to identify such biomarkers. PMID- 26629420 TI - Angiogenesis inhibition as a therapeutic strategy in non-small cell lung cancer (NSCLC). AB - In many cancers, including non-small cell lung cancer (NSCLC), tumor angiogenesis pathways have been identified as important therapeutic targets. Angiogenesis is essential in the process of primary tumor growth, proliferation and metastasis. One of the best characterized group of protein factors for angiogenesis include the members of the vascular endothelial growth factor (VEGF) family, consisting of VEGF-(A-D), and placenta growth factor (PIGF). Targeting tumor angiogenesis has been approached through two primary methods, monoclonal antibodies that block VEGF-vascular endothelial growth factor receptor (VEGFR) binding or small molecule tyrosine kinase inhibitors (TKIs) that inhibit the downstream VEGFR mediated signaling. Many TKIs inhibit multiple pro-angiogenic and pro proliferative pathways such as the mitogen activated protein (MAP) kinase pathway. Bevacizumab and ramucirumab, monoclonal antibodies targeting VEGF and the VEGFR, respectively, have each led to improvements in overall survival (OS) for NSCLC when added to standard first and second line chemotherapy, respectively. Small incremental gains seen with both bevacizumab and ramucirumab may be further improved upon by incorporating novel agents and treatment strategies, and many additional trials are ongoing. PMID- 26629421 TI - Treatment of advanced squamous cell carcinoma of the lung: a review. AB - Lung cancer remains the single deadliest cancer both in the US and worldwide. The great majority of squamous cell carcinoma (SCC) is attributed to cigarette smoking, which fortunately is declining alongside cancer incidence. While we have been at a therapeutic plateau for advanced squamous cell lung cancer patients for several decades, recent observations suggest that we are on the verge of seeing incremental survival improvements for this relatively large group of patients. Current studies have confirmed an expanding role for immunotherapy [including programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition], a potential opportunity for VEGFR inhibition, and even future targets in fibroblast growth factor receptor (FGFR) and PI3K-AKT that collectively should improve survival as well as quality of life for those affected by squamous cell lung cancer over the next decade. PMID- 26629422 TI - Novel therapies in small cell lung cancer. AB - Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor of the lung with a tendency to metastasize widely early in the course of the disease. The VA staging system classifies the disease into limited stage (LS) which is confined to one hemithorax and can be included into one radiation field or extensive stage (ES) which extends beyond one hemithorax. Current standard of care is concurrent chemoradiation for LS disease and chemotherapy alone for ES disease. Only a quarter of patients with LS disease will be cured with current standard treatments and majority of the patients ultimately succumb to their disease. A very complex genetic landscape of SCLC accounts for its resistance to conventional therapy and a high recurrence rate, however, at the same time this complexity can form the basis for effective targeted therapy for the disease. In recent years, several different therapeutic strategies and targeted agents have been under investigation for their potential role in SCLC. Several of them including EGFR TKIs, BCR-ABL TKIs, mTOR inhibitors, and VEGF inhibitors have been unsuccessful in showing a survival advantage in this disease. Several others including DNA repair inhibitors, cellular developmental pathway inhibitors, antibody drug conjugates (ADCs), as well as immune therapy with vaccines, immunomodulators, and immune checkpoint inhibitors are being tested. So far, none of these agents are approved for use in SCLC and the majority are in phase I/II clinical trials, with immune checkpoint inhibitors being the most promising therapeutic strategy. In this article, we will discuss these novel therapeutic agents and currently available data in SCLC. PMID- 26629423 TI - Novel radiotherapy approaches for lung cancer: combining radiation therapy with targeted and immunotherapies. AB - Targeted therapies and immunotherapies have quickly become fixtures in the treatment armamentarium for metastatic non-small cell lung cancer (NSCLC). Targeted therapies directed against epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) translocations, and ROS-1 rearrangements have demonstrated improved progression free survival (PFS) and, in selected populations, improved overall survival (OS) compared with cytotoxic chemotherapy. Immunotherapies, including checkpoint inhibitor monoclonal antibodies against programmed death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1), have now also demonstrated improved survival compared with chemotherapy. The use of these novel systemic agents in non-metastatic patient populations and in combination with radiation therapy is not well defined. As radiation therapy has become more effective and more conformal with fewer toxicities, it has increasingly been used in the oligometastatic or oligoprogression setting. This has allowed improvement in PFS and potentially OS, and in the oligoprogressive setting may overcome acquired drug resistance of a specific lesion(s) to allow patients to remain on their targeted therapies. Molecularly targeted therapies and immunotherapies for patients with metastatic NSCLC have demonstrated much success. Advances in radiation therapy and stereotactic body radiotherapy, radiation therapy have led to combination strategies with targeted therapies among patients with lung cancer. Radiation therapy has also been combined with immunotherapies predominantly in the metastatic setting. In the metastatic population, radiation therapy has the ability to provide durable local control and also augment the immune response of systemic agents, which may lead to an abscopal effect of immune-mediated tumor response in disease sites outside of the radiation field in select patients. PMID- 26629424 TI - New strategies in immunotherapy for non-small cell lung cancer. AB - Treatment for the most common form of cancer (lung cancer) has historically involved use of cytotoxic chemotherapy. With the advent of mutation analysis, more therapies beyond traditional cytotoxics have been discovered. Most recently, the use of immunotherapy has entered the treatment arsenal of non-small cell lung cancer (NSCLC). This review aims to summarize the current and future use of immunotherapy in the treatment of NSCLC. PMID- 26629425 TI - Immune checkpoint inhibitors in clinical practice: update on management of immune related toxicities. AB - Immune checkpoint blockade using inhibitors of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) has shown clinically significant antitumor response and has been approved for the treatment of malignant melanoma and squamous non-small cell lung cancer (NSCLC). These immunotherapies are associated with unique set of toxicities termed immune related adverse events (irAEs) that are very different from toxicities observed with conventional cytotoxic chemotherapy. Prompt recognition and initiation of appropriate management, usually in the form of immunosuppression, usually results in complete reversibility, but failing to do so can lead to severe toxicity or even death. Clinical algorithms describing the management of common irAEs have been published based on clinical trial information and experience in metastatic melanoma with ipilimumab, a human IgG1 monoclonal antibody that binds to CTLA-4 and blocks T cell inhibition. The most common irAEs reported with ipilimumab are dermatologic toxicity, diarrhea/colitis, hepatotoxicity, and endocrinopathies, although other sites can also be affected. Similar irAEs have been observed with agents targeting PD-1. Nivolumab and pembrolizumab are humanized monoclonal antibodies that bind to PD-1 and prevent T cell inactivation. Ipilimumab, pembrolizumab, and nivolumab are approved by the Food and Drug Administration (FDA) for the treatment of advanced melanoma; nivolumab was also recently approved for metastatic squamous NSCLC. This review describes the optimal management of toxicities related to immune checkpoint inhibition from FDA approved agents targeting CTLA-4 and PD-1. PMID- 26629426 TI - Management of hyperglycemia from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) targeting T790M-mediated resistance. AB - Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) patients are associated with sensitivity to small molecule tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib. Although studies show an increased progression free survival (PFS) with use of EGFR TKIs in the first-line setting, most patients will develop resistance to therapy after the first 8-16 months. T790M is an acquired resistance mutation reported in 60 70% of patients who initially responded to a prior EGFR TKI. Recently, EGFR TKIs targeting T790M have been developed to overcome resistance with positive results in PFS and objective response rate in patients who have had disease progression on at least one TKI. Two EGFR TKIs targeting T790M, AZD9291 and rociletinib, are new active treatment options for NSCLC but differ in adverse effect profiles. Dose-limiting hyperglycemia has been reported with rociletinib and has required dose reduction, an oral antihyperglycemic, or both, without discontinuation of therapy. This suggests that patients may be effectively treated chronically for hyperglycemia associated with EGFR TKIs targeting T790M, however, guidelines for treatment of hyperglycemia in this setting have not been published. We discuss mechanisms of hyperglycemia associated with TKIs and initial management of hyperglycemia, including benefits and limitations of oral antihyperglycemic options, adjustment of therapy based on grade of hyperglycemia, and recommendations for follow-up glucose monitoring. PMID- 26629428 TI - Diagnostic and therapeutic value of computed tomography guided coil placement after digital subtraction angiography guided video-assisted thoracoscopic surgery resection for solitary pulmonary nodules. AB - BACKGROUND: With the widespread use of general health examinations, the detection rate of pulmonary nodules has increased; however, locating the pulmonary nodules is still a challenge. METHODS: We reviewed cases that underwent computed tomography (CT)-guided coil localization followed by real-time digital subtraction angiography (DSA)-guided accurate resection of solitary pulmonary nodules (SPNs) using video-assisted thoracoscopic surgery (VATS) at our hospital, and we evaluated the clinical value. From September 2011 to October 2014, 116 cases with SPNs were treated in our unit. The lesion was preoperatively localized using coil placement under CT guidance, and the patients were subsequently transferred to the hybrid operating room. VATS wedge resection with real-time DSA guidance was performed, and further processing was conducted in accordance with the intraoperative pathological diagnosis for these lesions. RESULTS: Coil localization, which averaged 15.30+/-3.20 min, was successful in all patients (100%), while VATS wedge resection took 24.20+/-12.10 min and lobectomy or segmentectomy took 88.8+/-36 min. The pathological results revealed malignant lesions in 61 cases and benign lesions in 55 cases. CONCLUSIONS: Preoperative CT guided coil localization for SPNs had a high accuracy with no serious complications. Following real-time DSA-guided VATS resection, the lesions could be accurately removed with a cutting edge distance of >2 cm to the lesion, which may help diagnose and treat the SPN simultaneously. PMID- 26629429 TI - Interlobar fixation using TachoSil((r)): a novel technique. AB - BACKGROUND: We evaluated the use of TachoSil((r)) for anchoring middle lobe to lower lobe after upper right lobectomy. METHODS: The fixation of middle lobe to lower lobe was required in 39/213 consecutive upper lobectomies. In 19/39 (49%) cases, it was performed with suturing and/or stapler (standard group) and in 20 cases (TachoSil group) with Tachosil((r)) alone. RESULTS: The operative time, complications, length of chest drain and hospital stay were similar between two groups. However, standard compared to TachoSil((r)) group presented a higher incidence of atelectasis (5% vs. 0%, P=0.4) and air leaks (5% vs. 0%, P=0.4) but it did not reach significant difference. Our technique was safe, easy, and quick. CONCLUSIONS: Upon contact with pleura, the clotting factors of TachoSil((r)) dissolved and formed a fibrin network which glued the collagen sponge to the pleura surface. It allowed to fix the middle lobe to lower lobe without restricting lung re-expansion and/or injuring the parenchyma. PMID- 26629427 TI - Circulating DNA in diagnosis and monitoring EGFR gene mutations in advanced non small cell lung cancer. AB - Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are current treatments for advanced non-small cell lung cancer (NSCLC) harboring activating EGFR gene mutations. Histological or cytological samples are the standard tumor materials for EGFR mutation analysis. However, the accessibility of tumor samples is not always possible and satisfactory in advanced NSCLC patients. Moreover, totality of EGFR mutated NSCLC patients will develop resistance to EGFR-TKIs. Repeat biopsies to study genetic evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumor heterogeneity. Thus, exploring accurate and less invasive techniques to (I) diagnosis EGFR mutation if tissue is not available or not appropriate for molecular analysis and to (II) monitor EGFR-TKI treatment are needed. Circulating DNA fragments carrying tumor specific sequence alterations [circulating cell-free tumor DNA (cftDNA)] are found in the cell-free fraction of blood, representing a variable and generally small fraction of the total circulating DNA. cftDNA has a high degree of specificity to detect EGFR gene mutations in NSCLC. Studies have shown the feasibility of using cftDNA to diagnosis of EGFR activating gene mutations and also to monitor tumor dynamics in NSCLC patients treated with EGFR TKIs. These evidences suggested that non-invasive techniques based on blood samples had a great potential in EGFR mutated NSCLC patients. In this review, we summarized these non-invasive approaches and relative scientific data now available, considering their possible applications in clinical practice of NSCLC treatment. PMID- 26629431 TI - Pros: should a medically inoperable patient with a T2N0M0 non-small cell lung cancer central in the lung hilus be treated using stereotactic body radiotherapy? PMID- 26629430 TI - Prognostic value of circulating endothelial cells in non-small cell lung cancer patients: a systematic review and meta-analysis. AB - BACKGROUND: Circulating endothelial cells (CECs) have been indicated as a potential biomarker of vascular damage in a variety of cancers. Several studies have revealed CECs may reflect the extent of tumor angiogenesis; however, the role of CECs in the prognosis of non-small cell lung cancer (NSCLC) is undetermined to date. A meta-analysis has been prepared to determine whether the base level of CECs and the changes of CECs after therapy (?CECs: post-therapeutic value minus the pre- therapeutic value) could be considered as a prognostic tool for patients with NSCLC. METHODS: Systematic reviews of studies published before April 30 2015 were conducted on the association between the levels of CECs or ?CECs and the prognosis of NSCLC in several data bases. Hazard ratios (HRs) and the 95% confidence intervals (CIs) were used to collate the data. Similarly, heterogeneity and publication bias were also evaluated. RESULTS: A total of nine studies, containing eight prospective studies and one retrospective study, involving 515 patients was identified. Patients with higher level of CECs counts at baseline were associated with longer progression-free survival (PFS) (HR 0.71, 95% CI: 0.529-0.891). ?CECs could also be considered a prognostic indicator in NSCLC patients (HR 0.575, 95% CI: 0.401-0.75). The former and the later are without a significant heterogeneity in the data (I(2)=21.2% and 0.0%, P=0.274 and 0.870, respectively). However, there was no correlation between the base level of CECs and the overall survival (OS) (HR 0.914, 95% CI: 0.560-1.267, I(2)=43.6%, P=0.150). CONCLUSIONS: Higher levels of CECs counts at baseline and the ensuing decrease after therapy demonstrated a positive correlation with longer PFS in NSCLC patients. But this phenomenon has not been found in OS. From a certain perspective, CECs counts and ?CECs could be potential prognostic indicators for NSCLC patients. PMID- 26629432 TI - Cons: should a medically inoperable patient with a T2N0M0 non-small cell lung cancer central in the lung hilus be treated using stereotactic body radiotherapy? PMID- 26629433 TI - Rebuttal from Ms Woodford and Dr Senthi. PMID- 26629434 TI - Rebuttal from Dr Nestle and Dr Belderbos. PMID- 26629435 TI - Patient-centered care in lung cancer: exploring the next milestones. AB - In this editorial, the authors comment on a recently published review paper by Molassiotis et al. on the developments made over the past 40 years in supportive care for patients with lung cancer. During this period, a paradigm shift promoting patient-centered care (PCC) has led to an important change in the approach of supportive cancer care, from a purely disease-centered approach, measuring survival-related outcomes, to recognizing the importance of quality of life outcomes as well. This change of understanding in supportive and palliative care for patients with lung cancer can be further advanced through the understanding that there is a need to address bio-psycho-spiritual concerns and health belief models, within the context of the family socio-cultural environment, for both patients and their caregivers. There is also a need to address the psycho-spiritual effects of cancer on those health care professionals treating patients with lung cancer, in order to reduce compassion fatigue and increase resilience. Future directions for supportive care for patients with lung cancer may include the development of a patient-tailored treatment approach, assisted by the integration of a multidisciplinary team of health care providers and evidence-based complementary medicine practices, within conventional supportive care practice. PMID- 26629436 TI - Maintenance sunitinib for extensive-stage small cell lung cancer: a new standard, an option or a step in the right direction? AB - Systemic treatment for extensive-stage small cell lung cancer (ES-SCLC) has been stagnant for several decades. Sunitinib is a small molecule that inhibits a variety of receptor tyrosine kinases relevant in tumor biology. CALGB (Alliance) 30504 is a phase II study that investigated the use of maintenance sunitinib vs. placebo in patients with ES-SCLC after treatment with induction platinum/etoposide chemotherapy. The trial met its primary endpoint with an improvement in median progression free survival (PFS) of 1.6 months over placebo. Toxicity included grade 3 fatigue in 19% of patients. Although PFS may be a meaningful endpoint in this patient population, the modest improvement in PFS identified with maintenance sunitinib combined with the toxicity profile would not change the current standard of care. Changes in future trial design may enhance the ability to identify agents that will preserve patient functionality and prolong survival. PMID- 26629437 TI - Crizotinib as first line therapy for advanced ALK-positive non-small cell lung cancers. PMID- 26629438 TI - PROFILE 1014: lessons for the new era of lung cancer clinical research. AB - PROFILE 1014 compared crizotinib to up to six cycles of standard platinum pemetrexed chemotherapy as the first line treatment of advanced anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC). Overall, PROFILE 1014 has taught us many valuable lessons about the natural history of ALK+ NSCLC, the effectiveness of key therapies and the positive ways in which clinical research in oncogene addicted subtypes of cancer continue to evolve. These lessons include (I) confirming the benefit of using personalized medicine approaches compared to chemotherapy that had already been established in EGFR mutant disease and in ALK+ disease in later lines of therapy; (II) demonstrating that molecular preselection can also affect outcomes from standard chemotherapy in addition to from targeted therapy. Specifically, the benefit of the control arm (platinum-pemetrexed), although inferior to that of crizotinib, was remarkable and expands the dataset on the increased sensitivity of ALK+ NSCLC to pemetrexed; (III) identifying the central nervous system (CNS) as a key battleground for metastatic NSCLC, especially for ALK+ disease. In PROFILE 1014 CNS time to progression (TTP) was included as a prominent secondary endpoint, which showed no difference between crizotinib and chemotherapy but all CNS lesions at baseline had to be both stable and treated, so any apparent stabilizing effect of the drug may be confounded. Ongoing studies with other ALK inhibitors vs. crizotinib that include untreated CNS diseases will provide greater clarity on the true effect of these drugs in the brain. PMID- 26629439 TI - Moving molecularly directed therapies to the first-line in ALK-positive lung cancer: crizotinib is just the beginning. AB - The increasing appreciation of oncogenic driver alterations in non-small cell lung cancer (NSCLC) has resulted in a rapid expansion of therapeutic compounds. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) alterations are the prototypical examples and have driven the paradigm shift in NSCLC management. Early phase studies in previously treated ALK+ patients demonstrated activity and recently Solomon et al. confirmed the superiority of crizotinib over chemotherapy in first line treatment. The phase III PROFILE 1014 represents the culmination of the rapid development of crizotinib and provides lessons for future generation ALK inhibitors and other molecularly directed therapies in NSCLC. Important considerations for second and third generation inhibitors include the ability to overcome known resistance mechanisms, CNS activity, improvement in side effect profile, and safety in possible combination strategies. PMID- 26629440 TI - Customizing chemotherapy in non-small cell lung cancer: the promise is still unmet. AB - A combination of cytotoxic agents with cis-platin remains the cornerstone of treatment for the vast majority of patients with non-small cell lung cancer (NSCLC). Molecular analysis of the primary may lead better prognostication and eventually in more accurate therapeutic approaches. Data from retrospective analysis of randomized trials as well as large patients' series have suggested that chemotherapy may be customized upon molecular-genetic analysis of the tumor cells. The Spanish Lung Cancer Group (SLCG) in collaboration with French lung Cancer Group (FLCG) had conduct randomized, phase III, biomarkers-driven trial and supported simultaneously a randomized phase II trial in collaborating centers in China. Despite the evidence from the preclinical data and the results from the retrospective studies, the results of these trials published recently in Annals of Oncology were in favor of 'standard approach'. The present commentary tries to give some explanation for the disappointing results, provide potential solution for the future trials and explain why the vision of customizing treatment is still alive. PMID- 26629441 TI - What do we know about ground-glass opacity nodules in the lung? AB - Ground-glass opacity nodules (GGNs) in the lung attract clinical attention owing to their increasing incidence, unique natural course, and association with lung adenocarcinoma. A long and indolent course of a GGN makes it difficult to manage. Current extensive clinical, radiological, pathological, and genetic studies on GGNs have shed light on their pathogenesis and allowed development of a reliable strategy of management. The present editorial provides answers to clinical questions related to GGNs, such as the natural course, follow-up, prediction of growth, and resection techniques. Finally, I discuss the etiology of GGNs, which has not been fully elucidated so far. PMID- 26629442 TI - Revisiting the role of COX-2 inhibitor for non-small cell lung cancer. AB - Accumulating preclinical and clinical studies have shown that cyclooxygenase-2 (COX-2) inhibitor has some efficacy for non-small cell lung cancer (NSCLC). However, two phase III clinical trials using COX-2 inhibitor in combination with platinum-based chemotherapy showed no survival benefit for "unselected" patients with advanced NSCLC. Thus, exploratory analyses of the association between biomarker and clinical outcome of NSCLC patients treated with COX-2 inhibitors have been warranted. A report by Edelman recently published in the Journal of Clinical Oncology demonstrated the results of a prospective randomized trial using a combination of chemotherapy (docetaxel or pemetrexed) and either COX-2 inhibitor or a placebo for patients with advanced NSCLC. The remarkable point of this study was that it adopted the eligible criteria requiring decreased urinary levels of prostaglandin E metabolite (PGE-M) after administration of COX-2 inhibitor in a run-in period, as a possible predictive marker for the COX-2 inhibitor. The primary endpoint was progression-free survival (PFS). However, no improvement in PFS was observed between the patients treated with COX-2 inhibitor and those with placebo. A number of efforts from various investigators, including this report, have failed to demonstrate the meaningful clinical effect of COX-2 inhibitor for NSCLC. Is COX-2 inhibitor useless anymore? Here, we address the "difficult" character of this COX-2 inhibitor from various viewpoints and discuss potential future strategy using this drug. PMID- 26629443 TI - Is post-operative radiotherapy of any benefit after R0 resection for N2 disease? PMID- 26629444 TI - Response to "Is post-operative radiotherapy of any benefit after R0 resection for N2 disease?". PMID- 26629446 TI - Stories behind a precious photo. PMID- 26629447 TI - Babesiosis and other protists causing systemic infection. PMID- 26629448 TI - Visceral leishmaniasis. PMID- 26629449 TI - Microethics in medical education and practice. AB - "Microethics" is an avant-garde in the field of ethics. When the term "ethics" is brought into discussion in medical education or clinical practice, it customarily points to the traditional ethics, that is, biomedical ethics that deals with the ethical issues faced during unaccustomed or rare clinical circumstances. In contrast, microethics is a continuous ethical science existing in the physician patient interaction that happens each day in every physician's clinical liaison. These ethical issues of everyday importance need to be introduced in the ethics training programs of medical institutions to provide insight and thereby promoting improvement in medical care and outcome. PMID- 26629450 TI - Diagnosis and management of human babesiosis. AB - Babesiosis is a protozoan parasitic infection affecting humans and animals. These infections are commonly transmitted by various species of Ixodes ticks depending upon the geographical location. They can also be transmitted by packed cell transfusion and transplacental route from mother to child. Various species have been reported to cause human infections, of which Babesia microti is the most common species reported globally. Usually, Babesia infections are asymptomatic or mild, but can be severe/life-threatening in immunosuppressed or splenectomized individuals. A high index of clinical suspicion in residents of endemic areas or individuals who had a recent travel history to such areas, with laboratory confirmation can guide an early institution of appropriate antimicrobial therapy, thereby preventing complications and death. PMID- 26629451 TI - Morphology, epidemiology, and phylogeny of Babesia: An overview. AB - Babesiosis is a tick-borne hemoprotozoan disease of domestic and wild animals. The disease is caused by various species of Babesia and some species of Babesia have also zoonotic significance. The parasite in vertebrate hosts' remains in erythrocytes and the morphology of Babesia spp. is not uniform in all vertebrate hosts. With the advancement of science, particularly the use of molecular techniques made it easy to study the evolution of parasites and thereby reclassifying Babesia spp. as per their phylogeny and to establish the relation of one isolate of Babesia spp. with isolates throughout the world. An attempt also made in this communication to enlighten the readers regarding relationship of one isolate of Babesia spp. of a particular area to another isolate of Babesia spp. of that area or other parts of the world and phylogenetic classification of Babesia spp. was also discussed. It has been concluded that as the study on Babesia is complex in nature so monitoring of the infection with the use of modern techniques is very much needed to control the infection. Second, more research work on phylogenetic relationship of Babesia spp. isolated from different hosts is needed, particularly in India to know the evolution of Babesia spp. of a particular area, as it has great importance to study the trans boundary diseases of animals. PMID- 26629452 TI - Comparative evaluation of staining techniques and polymerase chain reaction for diagnosis of intestinal microsporidiosis in immunocompromised patients. AB - CONTEXT: Microsporidia, which causes chronic diarrhoea in immunocompromised hosts, are often missed. The commonest diagnostic techniques include modified trichrome (MT) stain; however, it requires expertise and does not identify the species, which is important therapeutically. Other diagnostic techniques include Calcoflour white staining and polymerase chain reaction (PCR). Data on comparative utility of different diagnostic techniques are scanty. AIM: Comparison of Calcoflour white, MT staining and PCR for the diagnosis of intestinal microsporidiosis. SUBJECTS AND METHODS: Fecal samples of consecutive immunocompromised patients were evaluated for Microsporidia using Calcoflour white, MT stain and PCR. Species were identified by restriction fragment length polymorphism using HindIII and HinfI. Presence of Microsporidia by two or more techniques was considered true positive. Absence of Microsporidia by all three techniques was taken as true negative. RESULTS: Of 730 patients, Microsporidia was detected in 28 (3.8%), 250 (34.2%) and 30 (4.1%) patients by MT, Calcoflour white stains and PCR, respectively. Enterocytozoon bieneusi was identified in all 30 (4.1%) patients. 30 (4.1%) and 479 (65.6%) patients were true positive and true negative, respectively. Sensitivity and specificity of Calcoflour white, MT stains and PCR were 100%, 93.8%, 96.8% and 68.5%, 100% and 99.8%, respectively. Diagnostic accuracy of MT stain and PCR was superior to Calcoflour white (99.6% vs. 69.8%; P < 0.05). CONCLUSIONS: Though Calcoflour white stain is a highly sensitive, but it is nonspecific technique. MT stain and PCR with high sensitivity, specificity and diagnostic accuracy are useful diagnostic techniques. Furthermore, PCR is useful for species identification, which has therapeutic implications. PMID- 26629453 TI - Pathogenicity of Leishmania donovani is associated with the high expression of a group low molecular weight proteins. AB - BACKGROUND: With few exceptions, members of the Leishmania donovani complex such as L. donovani, L. infantum and L. chagashi are the etiological agents of visceral leishmaniasis or kala-azar. Promastigotes of Leishmania spp. lose their Pathogenicity; the ability to establish infection in a susceptible host, after prolonged culture. The molecular basis of this evolution of pathogenic to nonpathogenic culture has not been very well understood. It has been proposed that the loss of pathogenicity is associated with the gradual disappearance of selective parasite proteins. An alternative hypothesis is that during prolonged culture, the pathogenic clonal population of the parasite is deleted from the mixed population due to their selection pressure. This clonal deletion is proposed to be responsible for the emergence of the nonpathogenic population. STUDY METHODOLOGY AND RESULTS: We have a done a series of two-dimensional polyacrylamide gel electrophoresis followed by western blot experiments to study the antigenic profile of few L. donovani isolates of Indian origin. We observed a gradual and significant downregulation of expression of a group of low molecular weight proteins (LMW, molecular weight 20-30 kDa) which are associated with loss of pathogenicity. These proteins are recognized only by antiserum raised against the whole cell extract of one of the pathogenic Indian L. donovani isolates, Ag83, and remained undetected by antiserum raised against the nonpathogenic AG83 isolates. These LMW proteins were also present in the nonpathogenic extract in very low levels and remained undetected by the virulent serum, indicating a phenomenon of simultaneous downregulation of the expression and altered immunogenicity. LMW proteins were universally expressed in all early passage Indian isolate we tested and also detected in two clones obtained from pathogenic parasite culture. The antigenic patterns of none of the eight clones obtained from nonpathogenic culture were not exactly similar with the pathogenic clones. CONCLUSION: Therefore, our data strongly support the hypothesis that the loss of pathogenicity of L. donovani is associated with a change in antigenic profile, but not due the selective deletion of pathogenic clones. PMID- 26629454 TI - Pulmonary hydatidosis from Southern Argentina. AB - Hydatidosis or cystic echinococcosis is a zoonosis caused by the larval stage of the cestode Echinococcus. Even though different measures are taken including the use of a vaccine in livestock to stop transmission, the continuous diagnoses of cases, mainly of liver and pulmonary hydatidosis, show the failure of the control programs for hydatidosis in our country. A clinical case of pulmonary hydatidosis in a patient from a rural endemic area in Southern Argentina is described. PMID- 26629455 TI - Acute pancreatitis, ascites, and acute renal failure in Plasmodium vivax malaria infection, a rare complication. AB - A 22-year-old male presented with 6 days history of intermittent fever with chills, 2 days history of upper abdomen pain, distension of abdomen, and decreased urine output. He was diagnosed to have Plasmodium vivax malaria, acute pancreatitis, ascites, and acute renal failure. These constellations of complications in P. vivax infection have never been reported in the past. The patient responded to intravenous chloroquine and supportive treatment. For renal failure, he required hemodialysis. Acute pancreatitis, ascites, and acute renal failure form an unusual combination in P. vivax infection. PMID- 26629456 TI - Acute abdomen: An uncommon presentation of a common intestinal nematode. AB - Enterobius vermicularis is a common parasitic infection of the intestine which is rarely symptomatic. It is unusual to find it in the wall or outside the gastrointestinal tract. We encountered five such cases where we observed the worm outside the lumen of the intestine. The pathological findings and the clinical features are discussed. This case series highlight that E. vermicularis can be the cause of pathology within the abdomen and should be considered in the differential diagnosis of some commonly encountered abdominal conditions. PMID- 26629457 TI - Plasmodium vivax induced hemolytic uremic syndrome: An uncommon manifestation that leads to a grave complication and treated successfully with renal transplantation. AB - We are reporting a case of hemolytic uremic syndrome, a rare manifestation of Plasmodium vivax malaria. A young driver was admitted with acute febrile illness, decreased urine output, anemia, thrombocytopenia, jaundice, and increased serum lactate dehydrogenase. He showed a partial response to antimalarial drugs. However, he was readmitted with worsening renal parameters. His kidney biopsy revealed chronic thrombotic microangiopathy. He remained dialysis dependent and later underwent renal transplantation successfully, with excellent graft function at 1-year. PMID- 26629458 TI - Symmetrical peripheral gangrene: A rare complication of plasmodium falciparum malaria. AB - Malaria, the most important of the parasitic diseases of humans, is transmitted in 108 countries containing 3 billion people and causes nearly 1 million deaths each year. With the re-emergence of malaria various life-threatening complications of malaria have been observed. Unarousable coma/cerebral malaria, severe normochromic, normocytic anemia, renal failure, pulmonary edema/adult respiratory distress syndrome, hypoglycemia, hypotension/shock, bleeding/disseminated intravascular coagulation (DIC), hemoglobinuria and jaundice are few of the common complications of severe malaria. Symmetrical peripheral gangrene (SPG) has been reported as a rare complication of malaria. We report a rare and unique case of Plasmodium falciparum malaria complicated by DIC, severe normocytic normochromic anemia, and SPG. PMID- 26629459 TI - Comparison of hematological aspects: Visceral leishmaniasis and healthy children. PMID- 26629460 TI - Case of hemophagocytic lymphohistiocytosis with leishmaniasis. PMID- 26629461 TI - Modified agar plate culture method for culture of Strongyloides stercoralis. PMID- 26629462 TI - An E-mail interview with Prof. Jeremy S. Gray. PMID- 26629463 TI - Case reports and research productivity among Syrian medical students: Review, reality, and suggested solutions. AB - Medical students are precious seeds for better future medical research. Case reports writing may represent a relatively simple first step for beginners. Only 47 case reports are published in the literature by Syrian Medical Institutions compared to more than 500 case reports in a comparable country in the last 5 years. Many obstacles stand against developing fruitful research environment in Syria. Increasing awareness to research productivity in Syria along with comparative analysis is discussed in this article. PMID- 26629464 TI - Three stitch hernioplasty: A novel technique for beginners. AB - OBJECTIVE: To analyze mesh fixation with minimum sutures and postoperative complications. STUDY DESIGN: Prospective study. PLACE AND DURATION OF STUDY: Department of General Surgery, Thanjavur Medical College and Hospital, Tamil Nadu, from July 2010 to June 2012. MATERIALS AND METHODS: All inguinal hernia patients, who fulfilled the sample selection criteria, were admitted and planned for surgery. The prolene mesh is fashioned as in Lichtenstein's repair, placed and fixed only by three prolene stitches. The first stitch is made in the periosteum of pubic tubercle. The second stitch is taken in the inguinal ligament (1.5 cm lateral to the pubic tubercle) and the third stitch is from the medial most part of the conjoint tendon, that is, the mesh is fixed in the medial aspect alone. RESULTS: Majority of the patients fall between the age group of 40 and 60 (72%) years and all are male patients. Of the total cases, 50% were right sided, 25% were left sided, and 25% were bilateral. Of the postoperative complications, 12% had seroma, 4% had hematoma, 2% developed surgical site infection, 2% developed chronic groin pain, 1% presented with recurrence, and none developed foreign body sinus. CONCLUSION: The incidence of long-term complications of three stitch hernioplasty are comparable to that of the other standard, tension-free open hernia repair as well as other laparoscopic procedures. Moreover, the three stitch hernioplasty method is a simple method, easy for the beginners to adopt, has less foreign body reaction, less time consuming, causes less tissue trauma, and lesser chance for vascular injury. PMID- 26629465 TI - Risk factors associated with chronic low back pain in Syria. AB - BACKGROUND: We aimed to identify risk factors associated with chronic low back pain (C-LBP) in Syria. MATERIALS AND METHODS: We conducted the study in a busy outpatient neurology clinic in Damascus city from October 2011 to August 2012. We enrolled all eligible adults presenting with C-LBP along with those who denied any back pain as a controls. We considered C-LBP any LBP lasting over 3 months. We developed our own questionnaire. A clinical nurse interviewed each person and filled in the results. RESULTS: We had a total of 911 subjects; 513 patients and 398 controls. We found that C-LBP increased with age. Having a sibling with C-LBP was a strong predictor of C-LBP. In women obesity, but not overweight, was a risk factor. Number of children was a risk factor for mothers. Higher level of education decreased the chance of C-LBP in women. Sedentary job increased the risk of C-LBP. CONCLUSION: This study sheds some light on risk factors for C-LBP in our population and might help find possible preventive measures. PMID- 26629466 TI - Nutritional status as a predictive marker for surgical site infection in total joint arthroplasty. AB - BACKGROUND: Surgical site infection (SSI) is considered one of the most serious complications in total joint arthroplasty (TJA). This study seeks to analyze the predictive value of preoperative and postoperative nutritional biomarkers for SSI in elective TJA. METHODOLOGY: Nutritional markers were gathered retrospectively utilizing patient's records from the orthopedics department at Benghazi Medical Center (BMC). The sample spanned cases admitted during the 20-month period between January 2012 and August 2013 and had undergone either elective total hip replacement or total knee replacement. The collected lab results included a complete blood count, total lymphocyte count (TLC), and serum albumin (S. alb.) levels. The patients were then divided into two groups based on the occurrence of an SSI. RESULTS: A total of 135 total knee (81.5%, n = 110/135) and total hip (18.5%, n = 25/135) replacements were performed at BMC during the study period. Among these cases, 57% (n = 78/135) had patient records suitable for statistical analysis. The average preoperative TLC was 2.422 *10(3) cells/mm(3) (range = 0.8 4.7 *10(3) cells/mm(3)) whereas that number dropped after the surgery to 1.694 *10(3) cells/mm(3) (range = 0.6-3.8 *10(3) cells/mm(3)). S. alb. levels showed a mean of 3.973 g/dl (range = 2.9-4.7 g/dl) preoperatively and 3.145 g/dl (range = 1.0-4.1 g/dl) postoperatively. The majority of TJA patients did not suffer any complication (67.4%, n = 91/135) while eight cases (5.9%) suffered from a superficial SSI. CONCLUSION: Preoperative S. alb. was identified as the only significant predictor for SSI (P = 0.011). Being a preventable cause of postoperative morbidity, it is recommended that the nutritional status (especially preoperative S. alb.) of TJA patients be used as a screening agent and appropriate measures be taken to avoid SSI. PMID- 26629467 TI - Cabergoline for preventing ovarian hyperstimulation syndrome in women at risk undergoing in vitro fertilization/intracytoplasmic sperm injection treatment cycles: A randomized controlled study. AB - BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is the most serious and potentially life-threatening iatrogenic complication associated with ovarian stimulation during assisted reproductive technology protocols. The aim of this study was to evaluate the role of dopamine agonist as a preventive strategy of OHSS in women at high risk in in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment cycles. METHODS: Seventy women at risk to develop OHSS undergoing IVF/ICSI treatment cycle were included. The study group received 0.5 mg of cabergoline for 8 days from the day of human chorionic gonadotropin administration in comparison to those who undergo no treatment for the prevention of OHSS. The reduction of the incidence of OHSS was the primary outcome. RESULTS: The actual incidence of OHSS was 8.33% in the cabergoline group and 20.58% in the control group. Thus, the incidence of OHSS was significantly reduced, by almost 60%, in the cabergoline group in comparison with the control group (relative ratios: 0.4, 95% confidence interval: 0.18-0.79). CONCLUSION: Prophylactic treatment with the dopamine agonist, cabergoline, reduces the incidence of OHSS in women at high risk undergoing IVF/ICSI treatment. However, the effects of cabergoline on important outcomes, namely, live birth, miscarriage, and congenital abnormalities are still uncertain. PMID- 26629468 TI - Nasal angioma with osseous metaplasia. AB - Nasal angiomas are rare. We report a case showing osseous metaplasia and discuss pathogenesis hypotheses. A 41-year-old woman presented with a right lateronasal firm, immobile mass, and interfering with glass wearing. The computed tomography scan imaging was suggestive of chondroma while the magnetic resonance imaging showed on T1-weighted images nodule isosignal, on T2-weighted images hypersignal, and intense enhancement after contrast substance injection. The lesion was surgically resected. Histological examination revealed a 0.8 cm angioma with multifocal osseous metaplasia. The diagnosis of nasal angiomas with extensive osseous metaplasia is difficult requiring microscopic examination. Conservative surgery is the treatment of choice even at an early stage due to the limited effectiveness of embolization or drugs on the osseous component. PMID- 26629469 TI - Acute promyelocytic leukemia presenting as pulmonary thromboembolism: Not all APLs bleed. AB - We present a rare case of acute promyelocytic leukemia (APL) presenting as pulmonary thromboembolism being misdiagnosed as community-acquired pneumonia. Thrombotic phenomenon in APL are poorly understood and grossly underreported. In our case, following no response to standard antibiotic treatment, the patient was further investigated and detected to have an acute pulmonary thromboembolism following right lower limb deep vein thrombosis (DVT). Though, complete blood picture revealed only mild hyperleukocytosis, bone marrow biopsy and aspiration revealed 60% blasts and a positive t (15,17)(q22,12) and PML retinoic acid receptor alpha (RARA) fusion protein on molecular cytogenetics. He was diagnosed as APL and received treatment with all-transretinoic acid (ATRA) and arsenic trioxide (ATO) and therapeutic anticoagulation. PMID- 26629470 TI - Specialty preferences of 1(st) year medical students in a Saudi Medical School - Factors affecting these choices and the influence of gender. AB - BACKGROUND AND AIMS: In recent years there has been a growing appreciation of the issues of career preference in medicine as it affects student learning and academic performance. Various factors influence the specialty choices of medical students. Some specialties tend to attract students more than others. One possible consequence of this would be a mismatch between health needs and specialist numbers in the region. This study investigated the career preferences of 1(st) year medical students in a Saudi medical school and to assess factors affecting these choices. MATERIALS AND METHODS: The study was a cross-sectional survey carried out on the 1(st) year undergraduate students in the college of medicine, King Faisal University, Saudi Arabia. A total of 109 students (57 female and 52 males) responded to the questionnaire which was initially administered to all the students of the 1(st) year - A total of 120 students (response rate was 90.8%). A mixed method approach was used and qualitative data from open-ended questions were analyzed based on thematic analysis. RESULTS: The top choices were general surgery, internal medicine, and pediatrics. Among female students; the top specialty choices were: General surgery (23%), pediatrics (18%), and dermatology (15%). Among the male students; the top choices were: General surgery (54%) and internal medicine (23%). Of the total, 57% of the students agreed or strongly agreed that primary aptitude was the main factor affecting the choice. Only 31% felt that there was a significant influence of role model, 48% felt that the advice of others - peers and family, would be a factor influencing their choices, and 53% agreed that specialty choice would influence their future learning patterns. Males were more likely to choose a specialty based on actual aptitude for the specialty, financial rewards, and scope for research; and this gender difference was statistically significant. CONCLUSION: Surgery was the top-choice in both genders. Other popular choices included internal medicine, pediatrics, and dermatology. Important factors affecting these choices included - primary aptitude, advice of peers, reputation, financial rewards, and the challenge involved. PMID- 26629471 TI - English language proficiency and academic performance: A study of a medical preparatory year program in Saudi Arabia. AB - INTRODUCTION: All medical schools in Saudi Arabia have English as the primary official medium of instruction. Most of the high school education, however, is delivered in Arabic and hence the transition to an English based learning environment tends to be difficult for some students. Our study aims to correlate English language proficiency with academic performance among medical students in their preparatory year. METHODS: A cross-sectional study design was used. Test scores of 103 preparatory year students (54 female and 49 male) were analyzed after the students completed an English language course and medical introductory course in their preparatory year. The total score obtained in the English course assessment was compared to each component of the medical content assessment. RESULTS: A significantly positive correlation (Spearman's Rho, at 0.01 levels) was seen between the scores of the English exam and the written exam (P <0.001) and the oral exam (P = -0.003) parts respectively of the medical examination. Significant correlation with the English exam score was not obtained for the other components of the medical assessment, namely; student assignments, presentations and portfolios. CONCLUSION: English language proficiency is an important factor in determining academic proficiency of medical students in our college at the preparatory year level. PMID- 26629472 TI - Reader's Forum. PMID- 26629473 TI - Integrated three-dimensional digital assessment of accuracy of anterior tooth movement using clear aligners. AB - OBJECTIVE: To assess the accuracy of anterior tooth movement using clear aligners in integrated three-dimensional digital models. METHODS: Cone-beam computed tomography was performed before and after treatment with clear aligners in 32 patients. Plaster casts were laser-scanned for virtual setup and aligner fabrication. Differences in predicted and achieved root and crown positions of anterior teeth were compared on superimposed maxillofacial digital images and virtual models and analyzed by Student's t-test. RESULTS: The mean discrepancies in maxillary and mandibular crown positions were 0.376 +/- 0.041 mm and 0.398 +/- 0.037 mm, respectively. Maxillary and mandibular root positions differed by 2.062 +/- 0.128 mm and 1.941 +/- 0.154 mm, respectively. CONCLUSIONS: Crowns but not roots of anterior teeth can be moved to designated positions using clear aligners, because these appliances cause tooth movement by tilting motion. PMID- 26629474 TI - Comparison of cone-beam computed tomography cephalometric measurements using a midsagittal projection and conventional two-dimensional cephalometric measurements. AB - OBJECTIVE: This study investigated whether it is possible to use a two dimensional (2D) standard in three-dimensional (3D) analysis, by comparing the angles and lengths measured from a midsagittal projection in 3D cone-beam computed tomography (CBCT) with those measured by 2D lateral cephalometric radiography (LCR). METHODS: Fifty patients who underwent both LCR and CBCT were selected as subjects. CBCT was reoriented in 3 different methods and the measuring-points were projected onto the midsagittal plane. Twelve angle values and 8 length values were measured on both LCR and CBCT and compared. RESULTS: Repeated measures analysis of the variance revealed statistically significant differences in 7 angular and 5 linear measurements among LCR and 3 types of CBCT (p < 0.05). Of these 12 measurements, multiple comparisons showed that 6 measurements (ANB, AB to FH, IMPA, FMA, Co-Gn, Go-Me) were not significantly different in pairwise comparisons. LCR was significantly different from 3 types of CBCT in 3 angular (SN to FH, interincisal angle, FMIA) and 2 linear (S-Go, Co ANS) measurements. The CBCT method was similar for all measurements, except for 1 linear measurement, i.e., S-N. However, the disparity between the mean values for all parameters was within the range of clinical measurement error. CONCLUSIONS: 3D-CBCT analysis, using midsagittal projection, is a useful method in which the 2D-LCR normative values can be used. Although the measurements changed with reorientation, these changes were not clinically significant. PMID- 26629475 TI - Displacement pattern of the anterior segment using antero-posterior lingual retractor combined with a palatal plate. AB - OBJECTIVE: To evaluate and compare the effects of two appliances on the en masse retraction of the anterior teeth anchored by temporary skeletal anchorage devices (TSADs). METHODS: The sample comprised 46 nongrowing hyperdivergent adult patients who planned to undergo upper first premolar extraction using lingual retractors. They were divided into three groups, based on the lingual appliance used: the C-lingual retractor (CLR) group (group 1, n = 16) and two antero posterior lingual retractor (APLR) groups (n = 30, groups 2 and 3). The APLR group was divided by the posterior tube angulation; posterior tube parallel to the occlusal plane (group 2, n = 15) and distally tipped tube (group 3, n = 15). A retrospective clinical investigation of the skeletal, dental, and soft tissue relationships was performed using lateral cephalometric radiographs obtained pretreatment and post en masse retraction of the anterior teeth. RESULTS: All groups achieved significant incisor and canine retraction. The upper posterior teeth did not drift significantly during the retraction period. The APLR group had less angulation change in the anterior dentition, compared to the CLR group. By changing the tube angulation in the APLR, the intrusive force significantly increased in the distally tipped tube of group 3 patients and remarkably reduced the occlusal plane angle. CONCLUSIONS: Compared to the CLR, the APLR provides better anterior torque control and canine tipping while achieving bodily translation. Furthermore, changing the tube angulation will affect the amount of incisor intrusion, even in patients with similar palatal vault depth, without the need for additional TSADs. PMID- 26629476 TI - Resin bonding of metal brackets to glazed zirconia with a porcelain primer. AB - OBJECTIVE: The aims of this study were to compare the shear bond strength between orthodontic metal brackets and glazed zirconia using different types of primer before applying resin cement and to determine which primer was more effective. METHODS: Zirconia blocks were milled and embedded in acrylic resin and randomly assigned to one of four groups: nonglazed zirconia with sandblasting and zirconia primer (NZ); glazed zirconia with sandblasting, etching, and zirconia primer (GZ); glazed zirconia with sandblasting, etching, and porcelain primer (GP); and glazed zirconia with sandblasting, etching, zirconia primer, and porcelain primer (GZP). A stainless steel metal bracket was bonded to each target surface with resin cement, and all specimens underwent thermal cycling. The shear bond strength of the specimens was measured by a universal testing machine. A scanning electron microscope, three-dimensional optical surface-profiler, and stereoscopic microscope were used to image the zirconia surfaces. The data were analyzed with one-way analyses of variance and the Fisher exact test. RESULTS: Group GZ showed significantly lower shear bond strength than did the other groups. No statistically significant differences were found among groups NZ, GP, and GZP. All specimens in group GZ showed adhesive failure between the zirconia and resin cement. In groups NZ and GP, bonding failed at the interface between the resin cement and bracket base or showed complex adhesive and cohesive failure. CONCLUSIONS: Porcelain primer is the more appropriate choice for bonding a metal bracket to the surface of a full-contour glazed zirconia crown with resin cement. PMID- 26629477 TI - Cephalometric predictors of treatment outcome with mandibular advancement devices in adult patients with obstructive sleep apnea: a systematic review. AB - OBJECTIVE: The efficacy of mandibular advancement devices (MADs) in the treatment of obstructive sleep apnea (OSA) ranges between 42% and 65%. However, it is still unclear which predictive factors can be used to select suitable patients for MAD treatment. This study aimed to systematically review the literature on the predictive value of cephalometric analysis for MAD treatment outcomes in adult OSA patients. METHODS: The MEDLINE, Google Scholar, Scopus, and Cochrane Library databases were searched through December 2014. Reference lists from the retrieved publications were also examined. English language studies published in international peer-reviewed journals concerning the predictive value of cephalometric analysis for MAD treatment outcome were considered for inclusion. Two review authors independently assessed eligibility, extracted data, and ascertained the quality of the studies. RESULTS: Fifteen eligible studies were identified. Most of the skeletal, dental, and soft tissue cephalometric measurements examined were widely recognized as not prognostic for MAD treatment outcome; however, controversial and limited data were found on the predictive role of certain cephalometric measurements including cranial base angle, mandibular plane angle, hyoid to mandibular plane distance, posterior nasal spine to soft-palate tip distance, anterior nasal spine to epiglottis base distance, and tongue/oral cross sectional area ratio thus justifying additional studies on these parameters. CONCLUSIONS: Currently available evidence is inadequate for identification of cephalometric parameters capable of reliably discriminating between poor and good responders to MAD treatment. To guide further research, methodological weaknesses of the currently available studies were highlighted and possible reasons for their discordant results were analyzed. PMID- 26629478 TI - Orthodontic treatment of a transposed maxillary canine and first premolar in a young patient with Class III malocclusion. AB - A 12-year-old girl was referred to our clinic for evaluation of an unaesthetic dental appearance. All permanent teeth were erupted, while the deciduous maxillary right canine was retained. Cone-beam computed tomography revealed a complete transposition of the maxillary left canine and first premolar involving both the crowns and the roots. Initial cephalometric analysis showed a skeletal Class III pattern, with a slight maxillary retrusion and a compensated proclination of the upper incisors. The patient's teeth were considered to be in the correct position; therefore, we decided to attempt treatment by correcting the transposition and using only orthodontic compensation of the skeletal Class III malocclusion. After 25 months of active orthodontic treatment, the patient had a Class I molar and canine relationship on both sides, with ideal overbite and overjet values. Her profile was improved, her lips were competent, and cephalometric evaluation showed acceptable maxillary and mandibular incisor inclinations. The final panoramic radiograph showed that good root parallelism was achieved. Two-year follow-up intraoral photography showed stable results. PMID- 26629479 TI - Condylar hyperplasia: An updated review of the literature. AB - Condylar hyperplasia (CH) is a rare disorder characterized by excessive bone growth that almost always presents unilaterally, resulting in facial asymmetry. Classification of the different types of CH can differ depending on the authors. Correct diagnosis is critical in determining the proper treatments and timing. This paper is a review of the recent literature on the epidemiology, etiology, diagnosis, classification, and surgical treatments of CH. PMID- 26629480 TI - The effect of transdermal nitroglycerin on pain control in diabetic patients with peripheral neuropathy. AB - BACKGROUND: Despite high prevalence of diabetic peripheral neuropathy there is no definite treatment for the condition. The present study was conducted to assess the efficacy of transdermal nitroglycerin patch in pain control of patients with DPN. METHODS: This randomized, double-blind, crossover study was conducted on 30 patients with symmetric distal peripheral neuropathy and good glycemic control. The patients were randomly assigned to receive nitroglycerin transdermal and placebo patches in two 4-week stages. The severity of pain and other neuropathic sensory symptoms were assessed at the end of each course. RESULTS: Mean reduction of pain severity was more prominent in the NTG group compared to placebo group of the study (p = 0.048) at least during the first phase of the study. Except for mood and sleep, a significant reduction in all Brief Pain Inventory scores was noted in the drug group (all corrected p < 0.05). SF-MPQ also showed the drug patch to be effective in improving different aspects of pain measured using McGill Pain Questionnaire, except for Role-emotional. CONCLUSIONS: It could be concluded that nitroglycerin plasters can effectively help alleviate pain in patients with diabetic neuropathy. TRIAL REGISTRATION: IRCT201308223213N1. PMID- 26629482 TI - Anti-CD19 Monoclonal Antibodies: a New Approach to Lymphoma Therapy. AB - CD19 is expressed on B- lineage cells and follicular dendritic cells and plays a key role in B cell malignancies and autoimmune diseases. Thus, it has been considered as potential target for several monoclonal antibodies (mAbs). For decades, chemotherapy has been known as one of the major antitumor therapies eradicating high proliferative tumor cells. But, anti- CD19 mAbs developed for treating CD19- positive lymphomas and autoimmune diseases would rank among the most novel area of research and development in the pharmaceutical industry. Moreover, several anti- CD19 mAbs are currently being tested in various clinical trials and this review provides an overview of the research accomplished so far. PMID- 26629481 TI - Adiponectin, leptin and insulin levels at birth and in early postnatal life in neonates with hypoxic ischemic encephalopathy. AB - BACKGROUND: Hypoxic ischemic encephalopathy (HIE) occurs in one to three per 1000 live full-term births. Fifteen to twenty percent will die in the postnatal period, and an additional 25 % will develop severe and permanent neuropsychological sequalae. The control of growth and nutritional status in the fetus and neonate is a complex mechanism, in which also hormones produced by adipose tissue, such as adiponectin and leptin are involved. The aim of this study was to measure the levels of adiponectin, leptin and insulin in neonates with HIE at birth and in early postnatal life and comparing them with normal healthy AGA and SGA neonates. METHODS: This study carried out on 80 full-term neonates born in Minia university hospital during the period from May 2013 to December 2014. They were divided into group I included 25 neonates with HIE and group II included 55 normal healthy neonates (30 appropriate for gestational age (AGA) and 25 small for gestational age (SGA)). Weight, length, head circumference, body mass index (BMI), glucose, adiponectin, leptin and insulin levels were measured for all neonates. Adiponectin, leptin and insulin levels were compared between neonates with HIE and normal healthy neonates as well as between AGA and SGA neonates at birth, 2nd and 6th days of life. RESULTS: Adiponectin and leptin levels were significantly higher at birth then began to decrease during the first postnatal week in all neonates while insulin level increased during the same period. Serum adiponectin levels were significantly lower while serum leptin and insulin levels were significantly higher in neonates with HIE than healthy neonates. In all neonates, the serum adiponectin level was positively correlated at birth with weight, length, BMI and leptin levels but not with insulin level. In neonates with HIE, serum adiponectin level was not correlated with weight, BMI, leptin level or insulin level. In all neonates, the serum leptin level was positively correlated at birth with body weight, height and BMI. In neonates with HIE serum leptin levels were not correlated with weight, BMI or insulin level after birth. There were no correlations between either leptin or adiponectin serum levels or any of the studied parameters in neonates with HIE. CONCLUSIONS: Neonates who are suffering from HIE had lower serum levels of adiponectin and higher serum levels of leptin and insulin than normal healthy neonates at birth and during the early postnatal period. The decline of leptin and increased the insulin levels after birth in all neonates may be important for the stimulation of feeding behavior and the acquisition of energy homeostasis during the early postnatal life. Positive significant correlations between adiponectin, leptin, body weight and body mass indices were present in normal healthy neonates but not in neonates with HIE reflecting the effect of hypoxia on the regulatory mechanisms controlling the adipose tissue functions. PMID- 26629483 TI - Study on KAL1 Gene Mutations in Idiopathic Hypogonadotropic Hypogonadism Patients with X-Linked Recessive Inheritance. AB - Idiopathic hypogonadotropic hypogonadism (IHH) is a condition caused by low doses of hypothalamic gonadotropin-releasing hormone (GnRH) leading to absence or incomplete sexual maturation. One of the disorders leading to IHH is Kallmann syndrome which is characterized by GnRH deficiency with anosmia or hyposmia. This disorder generally occurs as a hereditary syndrome with X-linked recessive inheritance pattern. However, autosomal dominant or recessive and sporadic cases have also been reported. KAL1 is the most common mutated gene among these patients. The aim of this study was to determine the mutation spectrum of KAL1 gene in twenty patients. KAL1 exons were amplified by PCR method and the products were assessed by high resolution melting (HRM) technique. In addition, for one of the patients, all coding exons of the KAL1 gene were sequenced. Deletion of exons 4, 5 and 6 were evident in 5%, 10%, and 10% of patients, respectively. Furthermore, HRM results showed hemizygous mutation of exon 12 with more than 95% probability in 25% of patients. Finding these mutations could be helpful in the early diagnosis and presymptomic treatment of Kallman syndrome. PMID- 26629484 TI - Analysis of rs6725887 in the WD Repeat Protein 12 in Association with Coronary Artery Disease in Iranian Patients. AB - Although genetic variants that affect susceptibility to coronary artery disease (CAD) have been greatly known, a number of these single nucleotide polymorphisms (SNPs) remain to be analyzed in populations with different ethnicities. CAD is influenced by numerous genetic, environmental, and lifestyle factors, and is an important reason for mortality around the globe. In this study, a novel SNP (rs6725887) in the WD Repeat Protein 12 (WDR12) gene was selected to be examined in Iranian patients with CAD. Ninety eigth healthy controls and one hundred and one CAD patients were enrolled from Iranian population, and their clinical data were collected for further comparisons. After DNA extraction from each sample, genotypes were characterized by Taq Man probe real- time PCR assay. Statistical analyses were performed to evaluate genotype and allele frequencies and compared the values with clinical variables. Body mass index, blood pressure, fasting blood sugar, LDL, HDL, cholesterol, and triglyceride significantly differed in CAD and control groups. Genotype and allele frequencies of rs6725887 in CAD patients and controls showed no significant association in the distribution. However, clinical parameters of CAD patients like HDL, LDL, FBS, TG, DBP and SBP had significantly (P<0.05) higher levels compared to control group. The rs6725887 polymorphism is unlikely to play a key role in CAD risk in our population. Further additional samples are required for better appreciation of the influence of WDR12 SNP on CAD occurrence. PMID- 26629485 TI - The Frequency of Exotoxin A and Exoenzymes S and U Genes Among Clinical Isolates of Pseudomonas aeruginosa in Shiraz, Iran. AB - Pseudomonas aeruginosa as an opportunistic pathogen produces several virulence factors. The most important of these factors are exotoxin A and type III secretion system (T3SS). The aim of this study was to determine the frequency of toxA, exoU and exoS genes among clinical isolates of P. aeruginosa. In this cross sectional study from September 2011 to February 2012, 156 P. aeruginosa isolates were recovered from different clinical samples. Susceptibility testing against 10 antibiotics was performed on individual isolates by the disc diffusion method according to CLSI guidelines. Extracted DNA was subjected to PCR assay for determining the presence of toxA, exoU and exoS genes. Overall, the frequency of toxA, exoU and exoS genes were 90.4%, 66.7% and 65.4%, respectively. All of the abdominal and eye isolates were exoS (+). The frequency of exoS (+)/exoU (-) and exoS (-)/exoU (+) genotypes was estimated 19.2% and 16.2%, respectively. Indeed, genotypes exoS (+)/exoU (+) and exoS (-)/exoU (-) were found with frequencies of 48.7% and 15.3%, respectively. The highest and lowest antibiotic resistance rate was seen against azteroenam (94.2%) and amikacin (44.9%), respectively. Fluoroqinolone-resistant isolates were isolated with frequency of 45.8%. Multi drug resistant (MDR) isolates were detected in 62.8% of isolates. The resistance rate in exoU (+) isolates was 86% compared to 66% in exoS (+) isolates. The high frequencies of virulence genes detected in our clinical isolates with notable antibiotic resistance rates indicate the potential risk of these isolates in nosocomial infections. PMID- 26629486 TI - Diversity of Variable Number Tandem Repeat Loci in Shigella Species Isolated from Pediatric Patients. AB - Multilocus variable number tandem repeat (VNTR) analysis (MLVA) is a new typing method with several advantages compared to other methods. Dissemination of Shigella is highly significant in developing countries. Whilst Shigella is becoming increasingly important as an etiologic agent of pediatric shigellosis in Iran, little is known about the genetic diversity of the local strains. Therefore, the aim of this study was to describe the genetic diversity of Shigella species isolated from pediatric patients in Tehran, Iran. A total of 53 Shigella isolates were obtained from 1070 patients with diarrhea (less than 12 years of age). All isolates were identified by routine biochemical and serological tests. The confirmed Shigella isolates were further serogrouped (by the slide agglutination) using slide agglutination method. MLVA assay with the seven loci resolved 53 Shigella isolates into 36 different genotypes. Almost all the isolates were classified into five clonal complexes. Furthermore, our MLVA assay could effectively distinguish the four Shigella species. This study has provided valuable insights into the genetic heterogeneity of Shigella species in Tehran, Iran. Our findings can be helpful for further epidemiological surveillance of Shigella species in this country in the future. PMID- 26629487 TI - Expression of Melanocortin-4 Receptor mRNA in Male Rat Hypothalamus During Chronic Stress. AB - The effects of chronic stress and glucocorticoids receptor antagonist (RU486) on expression of melanocortin 4 receptor (MC4R) mRNA in arcuate nucleus (ARC) of male rats were evaluated. In this study, adult male Sprague Dawley rats were placed into four groups (n=6/group); stress, RU486, stress/RU486, and control groups. In stress group, the rats were restrained, 1 h/day, for 12 days. In RU486 group, the rats were injected RU486 for 12 days. In stress/RU486 group, the rats were injected RU486 1 h before the stress process for 12 days. Relative expression of MC4R mRNA was determined using real-time PCR. Relative expression of MC4R mRNA in the stress group was higher than that of the control rats (P<0.05). Relative expressions of MC4R mRNA were not different between the stress, RU486 and stress/RU486 groups (P>0.05). Chronic restraint stress causes increase in mRNA expression of MC4R in ARC and blockade of glucocorticoid receptors has no effect on this up-regulation. PMID- 26629489 TI - Requirement of a Blocking Step in Affinity Purification of Polyclonal Antibodies. PMID- 26629488 TI - Impact of Propionic Acid on Liver Damage in Rats. AB - Propionic acid (PA) is a short chain fatty acid, a common food preservative and metabolic end product of enteric bacteria in the gut. The present study was undertaken to investigate the effect of PA on liver injury in male rats. Male western albino rats were divided into two groups. The first group served as normal control, the second was treated with PA. The activities of serum hepatospecific markers such as aspartate transaminase, alanine transaminase, and alkaline phosphatase were estimated. Antioxidant status in liver tissues was estimated by determining the level of lipid peroxidation and activities of enzymatic and non-enzymatic antioxidants. Sodium and potassium levels were also measured in liver tissue. PA treatment caused significant changes in all hepatospecific markers. Biochemical analysis of liver homogenates from PA-treated rats showed an increase in oxidative stress markers like lipid peroxidation and lactate dehydrogenase, coupled with a decrease in glutathione, vitamin C and glutathione S- transferase. However, PA exposure caused no change in sodium and potassium levels in liver tissue. Our study demonstrated that PA persuade hepatic damage in rats. PMID- 26629490 TI - Experimental data showing the thermal behavior of a flat roof with phase change material. AB - The selection and configuration of building materials for optimal energy efficiency in a building require some assumptions and models for the thermal behavior of the utilized materials. Although the models for many materials can be considered acceptable for simulation and calculation purposes, the work for modeling the real time behavior of phase change materials is still under development. The data given in this article shows the thermal behavior of a flat roof element with a phase change material (PCM) layer. The temperature and energy given to and taken from the building element are reported. In addition the solid liquid behavior of the PCM is tracked through images. The resulting thermal behavior of the phase change material is discussed and simulated in [1] A. Tokuc, T. Basaran, S.C. Yesugey, An experimental and numerical investigation on the use of phase change materials in building elements: the case of a flat roof in Istanbul, Build. Energy, vol. 102, 2015, pp. 91-104. PMID- 26629491 TI - Lectin staining and Western blot data showing differential sialylation of nutrient-deprived cancer cells to sialic acid supplementation. AB - This report provides data that are specifically related to the differential sialylation of nutrient deprived breast cancer cells to sialic acid supplementation in support of the research article entitled, "Nutrient-deprived cancer cells preferentially use sialic acid to maintain cell surface glycosylation" [1]. Particularly, breast cancer cells, when supplemented with sialic acid under nutrient deprivation, display sialylated glycans at the cell surface, but non-malignant mammary cells show sialylated glycans intracellularly. The impact of sialic acid supplementation under nutrient deprivation was demonstrated by measuring levels of expression and sialylation of two markers, EGFR1 and MUC1. This Data in Brief article complements the main manuscript by providing detailed instructions and representative results for cell-level imaging and Western blot analyses of changes in sialylation during nutrient deprivation and sialic acid supplementation. These methods can be readily generalized for the study of many types of glycosylation and various glycoprotein markers through the appropriate selection of fluorescently-labeled lectins. PMID- 26629492 TI - Optimization of expression and properties of the recombinant acetohydroxyacid synthase of Thermotoga maritima. AB - The data provide additional support of the characterization of the biophysical and biochemical properties of the enzyme acetohydroxyacid synthase from the hyperthermophilic bacterium Thermotoga maritima (Eram et al., 2015) [1]. The genes encoding the enzyme subunits have been cloned and expressed in the mesophilic host Escherichia coli. Detailed data include information about the optimization of the expression conditions, biophysical properties of the enzyme and reconstitution of the holoenzyme from individually expressed and purified subunits. PMID- 26629493 TI - Rapid production of engineered human primary hepatocyte/fibroblast sheets. AB - This data article contains data related to the research article entitled "Vascularized subcutaneous human liver tissue from engineered hepatocyte/fibroblast sheets in mice," published in Biomaterials[1]. Engineered hepatocyte/fibroblast sheets (EHFSs) are used for construction of vascularized subcutaneous liver tissue without a pre-transplant vascularization procedures. Here, we described a rapid production technique of EHFSs by controlling fibroblast density and coating fetal bovine serum (FBS) onto temperature responsive culture dishes (TRCDs). The human fibroblast monolayer formed on FBS coated TRCDs within 1 h when seeded at a high density (at least 1.56*10(5) cells/cm(2)). The most rapid EHFS production was achieved soon after the adhesion of human primary hepatocytes onto the fibroblast layer. PMID- 26629494 TI - High performance solutions and data for nZEBs offices located in warm climates. AB - This data article contains eleven tables supporting the research article entitled: Cost-Optimal Design For Nearly Zero Energy Office Buildings Located In Warm Climates [1]. The data explain the procedure of minimum energy performance requirements presented by the European Directive (EPBD) [2] to establish several variants of energy efficiency measures with the integration of renewable energy sources in order to reach nZEBs (nearly zero energy buildings) by 2020. This files include the application of comparative methodological framework and give the cost-optimal solutions for non-residential building located in Southern Italy. The data describe office sector in which direct the current European policies and investments [3], [4]. In particular, the localization of the building, geometrical features, thermal properties of the envelope and technical systems for HVAC are reported in the first sections. Energy efficiency measures related to orientation, walls, windows, heating, cooling, dhw and RES are given in the second part of the group; this data article provides 256 combinations for a financial and macroeconomic analysis. PMID- 26629495 TI - Construction of a novel coarse grain model for simulations of HIV capsid assembly to capture the backbone structure and inter-domain motions in solution. AB - We show the construction of a novel coarse grain model for simulations of HIV capsid assembly based on four structural models of HIV capsid proteins: isolated hexamer 3H47.pdb, tubular assembly 3J34.pdb, isolated pentamer 3P05.pdb and C terminus dimer 2KOD.pdb. The data demonstrates the derivation of inter-domain motions from all atom Molecular Dynamics simulations and comparison with the motions derived from the analysis of solution NMR results defined in 2M8L.pdb. Snapshots from a representative Monte Carlo simulation with 128 dimeric subunit proteins based on 3J34.pdb are shown in addition to the quantitative analysis of its assembly pathway. Movies of the assembly process are compiled with snapshots of representative simulations of four structural models. The methods and data in this article were utilized in Qiao et al. (in press) [1] to probe the mechanism of polymorphism and curvature control of HIV capsid assembly. PMID- 26629496 TI - Mitochondrial transcripts and associated heteroplasmies of Ancistrus spp. (Siluriformes: Loricariidae). AB - This data-set complements our paper entitled "The use of transcriptomic next generation sequencing data to assembly mitochondrial genomes of Ancistrus spp. (Loricariidae)" [6]. Here, we present the nucleotide sequences of each transcript used for mitogenomes assembly, as well as tables presenting the location of each transcript in the mitogenomes; the frequency, location and codon position of the detected heteroplasmic sites; and the start/stop codons usage, UTR, CDS and poliA tail length for each protein coding gene. Readers are referred to the paper cited above for data interpretation and discussion. PMID- 26629497 TI - New Indications and a Sense of (Re)purpose. PMID- 26629498 TI - Large Scale Genetic Research on Neuropsychiatric Disorders in African Populations is Needed. PMID- 26629499 TI - A Collaborative Approach for "ReSeq-ing" Mycobacterium tuberculosis Drug Resistance: Convergence for Drug and Diagnostic Developers. PMID- 26629500 TI - 4th European Congress of Immunology (ECI), September 6-9, 2015, Vienna, Austria. PMID- 26629501 TI - A Quest for Better Mouse Models of Breast and Ovarian Cancers. PMID- 26629502 TI - RANKL/OPG in Breast Cancer - Extending Its Territory to BRCA Mutation Carriers. PMID- 26629503 TI - Unique Role for a DNA Methyltransferase Isoform in Lung Cancer. PMID- 26629504 TI - Shared Intelligence: A Patient-Derived, Deeply Characterized Glioblastoma Cell Line Resource. PMID- 26629505 TI - Trace Evidence: Identifying Natural Cancer Killers After the Crime. PMID- 26629506 TI - Lung Cancer Early Detection: The Role of Circulating MicroRNAs. PMID- 26629507 TI - Sex-Specific Genetic Control of Diabetic Neuropathic Pain Suggests Subsequent Development of Men-only and Women-Only Analgesic Strategies. PMID- 26629508 TI - Alcohol Dependence and Mortality: Implications for Treatment. PMID- 26629510 TI - Recognizing the Extent of Overlap Between Bipolar Disorder and Anxiety Disorders. PMID- 26629511 TI - Compensation in the course of Huntington's disease - More than just a hypothesis? PMID- 26629512 TI - Neural Compensation in Huntington's Disease: Teaching Mental Disorders New Tricks? PMID- 26629513 TI - Bridging the Gap Between Mouse Behavior and Human Cognition in Neurofibromatosis Type 1. PMID- 26629514 TI - MERS Vaccine Candidate Offers Promise, but Questions Remain. PMID- 26629515 TI - Is the Emergence of the N. meningitidis Serogroup W ST-11 Hajj Outbreak Unraveling in the New Era of WGS? PMID- 26629516 TI - HIV Phylogeographic Analyses and Their Application in Prevention and Early Detection Programmes: The Case of the Tijuana-San Diego Border Region. PMID- 26629517 TI - Paradox of Protection: Preferential Recognition of CD4-induced Epitopes by Anti HIV-1 ADCC Antibodies. PMID- 26629518 TI - HPV Vaccination in Males: Another Step Forward. PMID- 26629519 TI - The 'Dynamic' Marriage Between Varicella and Zoster. PMID- 26629520 TI - In vivo X-Ray Phase Imaging. PMID- 26629521 TI - A Breathe in Cystic Fibrosis Therapy: A New Therapeutic Endeavor for Cysteamine. PMID- 26629522 TI - Relationship of Circulating Fatty Acid Profile to Metabolic Disorders Associated with Insulin Resistance. PMID- 26629523 TI - Gut Inflammation in Primary Sclerosing Cholangitis and Autoimmune Sclerosing Cholangitis-Contrasting Pattern of Liver-gut Cross Talk. PMID- 26629524 TI - Mir-661: A key Factor in Embryo-Maternal dialog With Potential Clinical Application to Predict Implantation Outcome? PMID- 26629525 TI - Response to Burns in the Elderly: What is Pathophysiology and What is Physiology? PMID- 26629526 TI - Cellular Senescence and Inflammatory Burden as Determinants of Mortality in Elderly People Until the Extreme old age. PMID- 26629527 TI - A Mouse Model That Reproduces the Developmental Pathways and Site Specificity of the Cancers Associated With the Human BRCA1 Mutation Carrier State. AB - Predisposition to breast and extrauterine Mullerian carcinomas in BRCA1 mutation carriers is due to a combination of cell-autonomous consequences of BRCA1 inactivation on cell cycle homeostasis superimposed on cell-nonautonomous hormonal factors magnified by the effects of BRCA1 mutations on hormonal changes associated with the menstrual cycle. We used the Mullerian inhibiting substance type 2 receptor (Mis2r) promoter and a truncated form of the Follicle stimulating hormone receptor (Fshr) promoter to introduce conditional knockouts of Brca1 and p53 not only in mouse mammary and Mullerian epithelia, but also in organs that control the estrous cycle. Sixty percent of the double mutant mice developed invasive Mullerian and mammary carcinomas. Mice carrying heterozygous mutations in Brca1 and p53 also developed invasive tumors, albeit at a lesser (30%) rate, in which the wild type alleles were no longer present due to loss of heterozygosity. While mice carrying heterozygous mutations in both genes developed mammary tumors, none of the mice carrying only a heterozygous p53 mutation developed such tumors (P < 0.0001), attesting to a role for Brca1 mutations in tumor development. This mouse model is attractive to investigate cell-nonautonomous mechanisms associated with cancer predisposition in BRCA1 mutation carriers and to investigate the merit of chemo-preventive drugs targeting such mechanisms. PMID- 26629528 TI - Osteoprotegerin (OPG), The Endogenous Inhibitor of Receptor Activator of NF kappaB Ligand (RANKL), is Dysregulated in BRCA Mutation Carriers. AB - Breast cancer development in BRCA1/2 mutation carriers is a net consequence of cell-autonomous and cell nonautonomous factors which may serve as excellent targets for cancer prevention. In light of our previous data we sought to investigate the consequences of the BRCA-mutation carrier state on RANKL/osteoprotegerin (OPG) signalling. We analysed serum levels of RANKL, OPG, RANKL/OPG complex, oestradiol (E2), and progesterone (P) during menstrual cycle progression in 391 BRCA1/2-mutation carriers and 782 noncarriers. These studies were complemented by analyses of RANKL and OPG in the serum and mammary tissues of female cynomolgus macaques (n = 88) and serum RANKL and OPG in postmenopausal women (n = 150). BRCA-mutation carriers had lower mean values of free serum OPG in particular in BRCA1-mutation carriers (p = 0.018) compared with controls. Among BRCA1/2 mutation carriers, lower OPG levels were associated with germline mutation locations known to confer an increased breast cancer risk (p = 0.003). P is associated with low OPG levels in serum and tissue, particularly in BRCA mutation carriers (rho = - 0.216; p = 0.002). Serum OPG levels were inversely correlated (rho = - 0.545, p < 0.001) with mammary epithelial proliferation measured by Ki67 expression and increased (p = 0.01) in postmenopause. The P RANKL/OPG system is dysregulated in BRCA-mutation carriers. These and previously published data provide a strong rationale for further investigation of antiprogestogens or an anti-RANKL antibody such as denosumab for breast cancer prevention. PMID- 26629529 TI - ? DNMT3B4-del Contributes to Aberrant DNA Methylation Patterns in Lung Tumorigenesis. AB - Aberrant DNA methylation is a hallmark of cancer but mechanisms contributing to the abnormality remain elusive. We have previously shown that ?DNMT3B is the predominantly expressed form of DNMT3B. In this study, we found that most of the lung cancer cell lines tested predominantly expressed DNMT3B isoforms without exons 21, 22 or both 21 and 22 (a region corresponding to the enzymatic domain of DNMT3B) termed DNMT3B/?DNMT3B-del. In normal bronchial epithelial cells, DNMT3B/DeltaDNMT3B and DNMT3B/?DNMT3B-del displayed equal levels of expression. In contrast, in patients with non-small cell lung cancer NSCLC), 111 (93%) of the 119 tumors predominantly expressed DNMT3B/DeltaDNMT3B-del, including 47 (39%) tumors with no detectable DNMT3B/?DNMT3B. Using a transgenic mouse model, we further demonstrated the biological impact of ?DNMT3B4-del, the ?DNMT3B-del isoform most abundantly expressed in NSCLC, in global DNA methylation patterns and lung tumorigenesis. Expression of ?DNMT3B4-del in the mouse lungs resulted in an increased global DNA hypomethylation, focal DNA hypermethylation, epithelial hyperplastia and tumor formation when challenged with a tobacco carcinogen. Our results demonstrate ?DNMT3B4-del as a critical factor in developing aberrant DNA methylation patterns during lung tumorigenesis and suggest that ?DNMT3B4-del may be a target for lung cancer prevention. PMID- 26629530 TI - The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes. AB - Glioblastoma (GBM) is the most frequent and malignant form of primary brain tumor. GBM is essentially incurable and its resistance to therapy is attributed to a subpopulation of cells called glioma stem cells (GSCs). To meet the present shortage of relevant GBM cell (GC) lines we developed a library of annotated and validated cell lines derived from surgical samples of GBM patients, maintained under conditions to preserve GSC characteristics. This collection, which we call the Human Glioblastoma Cell Culture (HGCC) resource, consists of a biobank of 48 GC lines and an associated database containing high-resolution molecular data. We demonstrate that the HGCC lines are tumorigenic, harbor genomic lesions characteristic of GBMs, and represent all four transcriptional subtypes. The HGCC panel provides an open resource for in vitro and in vivo modeling of a large part of GBM diversity useful to both basic and translational GBM research. PMID- 26629531 TI - Identification of Anti-tumor Cells Carrying Natural Killer (NK) Cell Antigens in Patients With Hematological Cancers. AB - Natural killer (NK) cells, a cytotoxic lymphocyte lineage, are able to kill tumor cells in vitro and in mouse models. However, whether these cells display an anti tumor activity in cancer patients has not been demonstrated. Here we have addressed this issue in patients with several hematological cancers. We found a population of highly activated CD56(dim)CD16(+) NK cells that have recently degranulated, evidence of killing activity, and it is absent in healthy donors. A high percentage of these cells expressed natural killer cell p46-related protein (NKp46), natural-killer group 2, member D (NKG2D) and killer inhibitory receptors (KIRs) and a low percentage expressed NKG2A and CD94. They are also characterized by a high metabolic activity and active proliferation. Notably, we found that activated NK cells from hematological cancer patients have non-NK tumor cell antigens on their surface, evidence of trogocytosis during tumor cell killing. Finally, we found that these activated NK cells are distinguished by their CD45RA(+)RO(+) phenotype, as opposed to non-activated cells in patients or in healthy donors displaying a CD45RA(+)RO(-) phenotype similar to naive T cells. In summary, we show that CD45RA(+)RO(+) cells, which resemble a unique NK population, have recognized tumor cells and degranulate in patients with hematological neoplasias. PMID- 26629532 TI - A Five-miRNA Panel Identified From a Multicentric Case-control Study Serves as a Novel Diagnostic Tool for Ethnically Diverse Non-small-cell Lung Cancer Patients. AB - Circulating microRNAs (miRNAs) are promising biomarkers for cancer detection. However, multiethnic and multicentric studies of non-small-cell lung cancer (NSCLC) are lacking. We recruited 221 NSCLC patients, 161 controls and 56 benign nodules from both China and America. Initial miRNA screening was performed using the TaqMan Low Density Array followed by confirming individually by RT-qPCR in Chinese cohorts. Finally, we performed a blind trial from an American cohort to validate our findings. RT-qPCR confirmed that miR-483-5p, miR-193a-3p, miR-25, miR-214 and miR-7 were significantly elevated in patients compared to controls. The areas under the curve (AUCs) of the ROC curve of this five-serum miRNA panel were 0.976 (95% CI, 0.939-1.0; P < 0.0001) and 0.823 (95% CI, 0.75-0.896; P < 0.0001) for the two confirmation sets, respectively. In the blind trial, the panel correctly classified 95% NSCLC cases and 84% controls from the American cohort. Most importantly, the panel was capable of distinguishing NSCLC from benign nodules with an AUC of 0.979 (95% CI, 0.959-1.0) in the American cohort and allowed correct prediction of 86% and 95% stage I-II tumors in the Chinese and American cohorts, respectively. This serum miRNA panel holds the potential for diagnosing ethnically diverse NSCLC patients. PMID- 26629533 TI - A Genome-wide Association Study Provides Evidence of Sex-specific Involvement of Chr1p35.1 (ZSCAN20-TLR12P) and Chr8p23.1 (HMGB1P46) With Diabetic Neuropathic Pain. AB - Neuropathic pain is defined as pain arising as a direct consequence of a lesion or a disease affecting the somatosensory system and it affects around 1 in 4 diabetic patients in the UK. The purpose of this genome-wide association study (GWAS) was to identify genetic contributors to this disorder. Cases of neuropathic pain were defined as diabetic patients with a multiple prescription history of at least one of five drugs specifically indicated for the treatment of neuropathic pain. Controls were diabetic individuals who were not prescribed any of these drugs, nor amitriptyline, carbamazepine, or nortriptyline. Overall, 961 diabetic neuropathic pain cases and 3260 diabetic controls in the Genetics of Diabetes Audit and Research Tayside (GoDARTS) cohort were identified. We found a cluster in the Chr1p35.1 (ZSCAN20-TLR12P) with a lowest P value of 2.74 * 10(- 7) at rs71647933 in females and a cluster in the Chr8p23.1, next to HMGB1P46 with a lowest P value of 8.02 * 10(- 7) at rs6986153 in males. Sex-specific narrow sense heritability was higher in males (30.0%) than in females (14.7%). This GWAS on diabetic neuropathic pain provides evidence for the sex-specific involvement of Chr1p35.1 (ZSCAN20-TLR12P) and Chr8p23.1 (HMGB1P46) with the disorder, indicating the need for further research. PMID- 26629534 TI - Risk of All-Cause Mortality in Alcohol-Dependent Individuals: A Systematic Literature Review and Meta-Analysis. AB - BACKGROUND: Alcohol dependence (AD) carries a high mortality burden, which may be mitigated by reduced alcohol consumption. We conducted a systematic literature review and meta-analysis investigating the risk of all-cause mortality in alcohol dependent subjects. METHODS: MEDLINE, MEDLINE In-Process, Embase and PsycINFO were searched from database conception through 26th June 2014. Eligible studies reported all-cause mortality in both alcohol-dependent subjects and a comparator population of interest. Two individuals independently reviewed studies. Of 4540 records identified, 39 observational studies were included in meta-analyses. FINDINGS: We identified a significant increase in mortality for alcohol-dependent subjects compared with the general population (27 studies; relative risk [RR] = 3.45; 95% CI [2.96, 4.02]; p < 0.0001). The mortality increase was also significant compared to subjects qualifying for a diagnosis of alcohol abuse or subjects without alcohol use disorders (AUDs). Alcohol-dependent subjects continuing to drink heavily had significantly greater mortality than alcohol dependent subjects who reduced alcohol intake, even if abstainers were excluded (p < 0.05). INTERPRETATION: AD was found to significantly increase an individual's risk of all-cause mortality. While abstinence in alcohol-dependent subjects led to greater mortality reduction than non-abstinence, this study suggests that alcohol-dependent subjects can significantly reduce their mortality risk by reducing alcohol consumption. PMID- 26629535 TI - A Lifetime Prevalence of Comorbidity Between Bipolar Affective Disorder and Anxiety Disorders: A Meta-analysis of 52 Interview-based Studies of Psychiatric Population. AB - BACKGROUND: Bipolar affective disorder has a high rate of comorbidity with a multitude of psychiatric disorders and medical conditions. Among all the potential comorbidities, co-existing anxiety disorders stand out due to their high prevalence. AIMS: To determine the lifetime prevalence of comorbid anxiety disorders in bipolar affective disorder under the care of psychiatric services through systematic review and meta-analysis. METHOD: Random effects meta-analyses were used to calculate the lifetime prevalence of comorbid generalised anxiety disorder, panic disorder, social anxiety disorder, specific phobia, agoraphobia, obsessive compulsive disorder and posttraumatic stress disorder in bipolar affective disorder. RESULTS: 52 studies were included in the meta-analysis. The rate of lifetime comorbidity was as follows: panic disorder 16.8% (95% CI 13.7 20.1), generalised anxiety disorder 14.4% (95% CI 10.8-18.3), social anxiety disorder13.3% (95% CI 10.1-16.9), post-traumatic stress disorder 10.8% (95% CI 7.3-14.9), specific phobia 10.8% (95% CI 8.2-13.7), obsessive compulsive disorder 10.7% (95% CI 8.7-13.0) and agoraphobia 7.8% (95% CI 5.2-11.0). The lifetime prevalence of any anxiety disorders in bipolar disorder was 42.7%. CONCLUSIONS: Our results suggest a high rate of lifetime concurrent anxiety disorders in bipolar disorder. The diagnostic issues at the interface are particularly difficult because of the substantial symptom overlap. The treatment of co existing conditions has clinically remained challenging. PMID- 26629536 TI - Compensation in Preclinical Huntington's Disease: Evidence From the Track-On HD Study. AB - BACKGROUND: Cognitive and motor task performance in premanifest Huntington's disease (HD) gene-carriers is often within normal ranges prior to clinical diagnosis, despite loss of brain volume in regions involved in these tasks. This indicates ongoing compensation, with the brain maintaining function in the presence of neuronal loss. However, thus far, compensatory processes in HD have not been modeled explicitly. Using a new model, which incorporates individual variability related to structural change and behavior, we sought to identify functional correlates of compensation in premanifest-HD gene-carriers. METHODS: We investigated the modulatory effects of regional brain atrophy, indexed by structural measures of disease load, on the relationship between performance and brain activity (or connectivity) using task-based and resting-state functional MRI. FINDINGS: Consistent with compensation, as atrophy increased performance related activity increased in the right parietal cortex during a working memory task. Similarly, increased functional coupling between the right dorsolateral prefrontal cortex and a left hemisphere network in the resting-state predicted better cognitive performance as atrophy increased. Such patterns were not detectable for the left hemisphere or for motor tasks. INTERPRETATION: Our findings provide evidence for active compensatory processes in premanifest-HD for cognitive demands and suggest a higher vulnerability of the left hemisphere to the effects of regional atrophy. PMID- 26629537 TI - Impairment of Procedural Learning and Motor Intracortical Inhibition in Neurofibromatosis Type 1 Patients. AB - BACKGROUND: Cognitive difficulties are the most common neurological complications in neurofibromatosis type 1 (NF1) patients. Recent animal models proposed increased GABA-mediated inhibition as one underlying mechanism directly affecting the induction of long-term potentiation (LTP) and learning. In most adult NF1 patients, apparent cognitive and attentional deficits, tumors affecting the nervous system and other confounding factors for neuroscientific studies are difficult to control for. Here we used a highly specific group of adult NF1 patients without cognitive or nervous system impairments. Such selected NF1 patients allowed us to address the following open questions: Is the learning process of acquiring a challenging motor skill impaired in NF1 patients? And is such an impairment in relation to differences in intracortical inhibition? METHODS: We used an established non-invasive, double-pulse transcranial magnetic stimulation (dp-TMS) paradigm to assess practice-related modulation of intracortical inhibition, possibly mediated by gamma-minobutyric acid (GABA)ergic neurotransmission. This was done during an extended learning paradigm in a group of NF1 patients without any neuropsychological deficits, functioning normally in daily life and compared them to healthy age-matched controls. FINDINGS: NF1 patients experienced substantial decline in motor skill acquisition (F = 9.2, p = 0.008) over five-consecutives training days mediated through a selective reduction in the early acquisition (online) and the consolidation (offline) phase. Furthermore, there was a consistent decrease in task-related intracortical inhibition as a function of the magnitude of learning (T = 2.8, p = 0.014), especially evident after the early acquisition phase. INTERPRETATIONS: Collectively, the present results provide evidence that learning of a motor skill is impaired even in clinically intact NF1 patients based, at least partially, on a GABAergic-cortical dysfunctioning as suggested in previous animal work. PMID- 26629538 TI - Recombinant Receptor Binding Domain Protein Induces Partial Protective Immunity in Rhesus Macaques Against Middle East Respiratory Syndrome Coronavirus Challenge. AB - BACKGROUND: Development an effective vaccine against Middle East respiratory syndrome coronavirus (MERS-CoV) is urgent and limited information is available on vaccination in nonhuman primate (NHP) model. We herein report of evaluating a recombinant receptor-binding domain (rRBD) protein vaccine in a rhesus macaque model. METHODS: Nine monkeys were randomly assigned to high-dose, low-dose and mock groups,which were immunized with different doses of rRBD plus alum adjuvant or adjuvant alone at different time points (0, 8, 25 weeks). Immunological analysis was conducted after each immunisation. Monkeys were challenged with MERS CoV at 14 days after the final immunisation followed by observation for clinical signs and chest X-rays. Nasal, oropharyngeal and rectal swabs were also collected for analyses. Monkeys were euthanized 3 days after challenge and multiple specimens from tissues were collected for pathological, virological and immunological tests. CONCLUSION: Robust and sustained immunological responses (including neutralisation antibody) were elicited by the rRBD vaccination. Besides, rRBD vaccination alleviated pneumonia with evidence of reduced tissue impairment and clinical manifestation in monkeys. Furthermore, the rRBD vaccine decreased viral load of lung, trachea and oropharyngeal swabs of monkeys. These data in NHP paves a way for further development of an effective human vaccine against MERS-CoV infection. PMID- 26629539 TI - Genomic Epidemiology of Hypervirulent Serogroup W, ST-11 Neisseria meningitidis. AB - Neisseria meningitidis is a leading bacterial cause of sepsis and meningitis globally with dynamic strain distribution over time. Beginning with an epidemic among Hajj pilgrims in 2000, serogroup W (W) sequence type (ST) 11 emerged as a leading cause of epidemic meningitis in the African 'meningitis belt' and endemic cases in South America, Europe, Middle East and China. Previous genotyping studies were unable to reliably discriminate sporadic W ST-11 strains in circulation since 1970 from the Hajj outbreak strain (Hajj clone). It is also unclear what proportion of more recent W ST-11 disease clusters are caused by direct descendants of the Hajj clone. Whole genome sequences of 270 meningococcal strains isolated from patients with invasive meningococcal disease globally from 1970 to 2013 were compared using whole genome phylogenetic and major antigen encoding gene sequence analyses. We found that all W ST-11 strains were descendants of an ancestral strain that had undergone unique capsular switching events. The Hajj clone and its descendants were distinct from other W ST-11 strains in that they shared a common antigen gene profile and had undergone recombination involving virulence genes encoding factor H binding protein, nitric oxide reductase, and nitrite reductase. These data demonstrate that recent acquisition of a distinct antigen-encoding gene profile and variations in meningococcal virulence genes was associated with the emergence of the Hajj clone. Importantly, W ST-11 strains unrelated to the Hajj outbreak contribute a significant proportion of W ST-11 cases globally. This study helps illuminate genomic factors associated with meningococcal strain emergence and evolution. PMID- 26629540 TI - HIV Transmission Networks in the San Diego-Tijuana Border Region. AB - BACKGROUND: HIV sequence data can be used to reconstruct local transmission networks. Along international borders, like the San Diego-Tijuana region, understanding the dynamics of HIV transmission across reported risks, racial/ethnic groups, and geography can help direct effective prevention efforts on both sides of the border. METHODS: We gathered sociodemographic, geographic, clinical, and viral sequence data from HIV infected individuals participating in ten studies in the San Diego-Tijuana border region. Phylogenetic and network analysis was performed to infer putative relationships between HIV sequences. Correlates of identified clusters were evaluated and spatiotemporal relationships were explored using Bayesian phylogeographic analysis. FINDINGS: After quality filtering, 843 HIV sequences with associated demographic data and 263 background sequences from the region were analyzed, and 138 clusters were inferred (2-23 individuals). Overall, the rate of clustering did not differ by ethnicity, residence, or sex, but bisexuals were less likely to cluster than heterosexuals or men who have sex with men (p = 0.043), and individuals identifying as white (p <= 0.01) were more likely to cluster than other races. Clustering individuals were also 3.5 years younger than non-clustering individuals (p < 0.001). Although the sampled San Diego and Tijuana epidemics were phylogenetically compartmentalized, five clusters contained individuals residing on both sides of the border. INTERPRETATION: This study sampled ~ 7% of HIV infected individuals in the border region, and although the sampled networks on each side of the border were largely separate, there was evidence of persistent bidirectional cross-border transmissions that linked risk groups, thus highlighting the importance of the border region as a "melting pot" of risk groups. FUNDING: NIH, VA, and Pendleton Foundation. PMID- 26629541 TI - HIV-specific CD4-induced Antibodies Mediate Broad and Potent Antibody-dependent Cellular Cytotoxicity Activity and Are Commonly Detected in Plasma From HIV infected humans. AB - HIV-specific antibodies (Abs) can reduce viral burden by blocking new rounds of infection or by destroying infected cells via activation of effector cells through Fc-FcR interaction. This latter process, referred to as antibody dependent cellular cytotoxicity (ADCC), has been associated with viral control and improved clinical outcome following both HIV and SIV infections. Here we describe an HIV viral-like particle (VLP)-based sorting strategy that led to identification of HIV-specificmemory B cells encoding Abs that mediate ADCC froma subtype A-infected Kenyan woman at 914 days post-infection. Using this strategy, 12 HIV-envelope-specific monoclonal antibodies (mAbs) were isolated and three mediated potent ADCC activitywhen compared to well-characterized ADCC mAbs. The ADCC-mediating Abs also mediated antibody-dependent cell-mediated virus inhibition (ADCVI), which provides a net measure of Fc receptor-triggered effects against replicating virus. Two of the three ADCC-mediating Abs targeted a CD4 induced (CD4i) epitope also bound by the mAb C11; the third antibody targeted the N-terminus of V3. Both CD4i Abs identified here demonstrated strong cross-clade breadth with activity against 10 of 11 envelopes tested, including those from clades A, B, C, A/D and C/D, whereas the V3-specific antibody showed more limited breadth. Variants of these CD4i, C11-like mAbs engineered to interrupt binding to FcgammaRs inhibited a measurable percentage of the donor's ADCC activity starting as early as 189 days post-infection. C11-like antibodies also accounted for between 18-78% of ADCC activity in 9 chronically infected individuals from the same cohort study. Further, the two CD4i Abs originated from unique B cells, suggesting that antibodies targeting this epitope can be commonly produced. Taken together, these data provide strong evidence that CD4i, C11-like antibodies develop within the first 6 months of infection and they can arise fromunique B cell lineages in the same individual. Further, thesemAbsmediate potent plasma IgG specificADCC breadth and potency and contribute to ADCC activity in other HIV infected individuals. PMID- 26629542 TI - Malaria and Age Variably but Critically Control Hepcidin Throughout Childhood in Kenya. AB - Both iron deficiency (ID) and malaria are common among African children. Studies show that the iron-regulatory hormone hepcidin is induced by malaria, but few studies have investigated this relationship longitudinally. We measured hepcidin concentrations, markers of iron status, and antibodies to malaria antigens during two cross-sectional surveys within a cohort of 324 Kenyan children <= 8 years old who were under intensive surveillance for malaria and other febrile illnesses. Hepcidin concentrations were the highest in the youngest, and female infants, declined rapidly in infancy and more gradually thereafter. Asymptomatic malaria and malaria antibody titres were positively associated with hepcidin concentrations. Recent episodes of febrile malaria were associated with high hepcidin concentrations that fell over time. Hepcidin concentrations were not associated with the subsequent risk of either malaria or other febrile illnesses. Given that iron absorption is impaired by hepcidin, our data suggest that asymptomatic and febrile malaria contribute to the high burden of ID seen in African children. Further, the effectiveness of iron supplementation may be sub optimal in the presence of asymptomatic malaria. Thus, strategies to prevent and eliminate malaria may have the added benefit of addressing an important cause of ID for African children. PMID- 26629543 TI - HPV prophylactic vaccination in males improves the clearance of semen infection. AB - BACKGROUND: Semen represents a reservoir for human papillomavirus (HPV), rising concern in couples eligible for assisted reproduction techniques (ART). Humoral immunity against HPV is considered to protect from reinfection. We investigated the impact of vaccination on virus clearance in a cohort of infertile male patients showing HPV semen infection. METHODS: 179 out of 619 infertile patients, showing HPV-DNA detection in semen by FISH analysis,were enrolled. Subjectswere split into 91 vaccine-sensitive (VSPs) and 88 nonvaccine-sensitive patients (NVSPs) by INNO-LiPA. 19 VSPs showed vaccine-type specific seroconvesion at recruitment. All patients underwent specific counselling. 42 seronegative VSPs were randomly assigned to receive quadrivalent vaccination in 6 months, whilst 49 VSPs, 19 seroconverted and 30 seronegative, served as controls. The prevalence of HPV-DNA semen infection and serology was studied in a follow-up of 24 months. RESULTS: Compared to seronegative patients, VSP seroconverted at recruitment showed absence of multiple infections and reduced prevalence of HPV semen infection at 12 (P = 0.039), 18 (P = 0.034) and 24 months (P = 0.034) of follow up. Vaccinated VSP showed improved healing (P = 0.001 at 6 months and P b 0.001 at 12 months vs seroconverted VSP), achieving clearance in 12 months. DISCUSSION: Humoral immunity has a major role in healing from HPV infection. Elder ART patients with HPV semen infection may benefit by the union of both specific counselling and available prophylactic vaccination. PMID- 26629544 TI - Distribution of Health Effects and Cost-effectiveness of Varicella Vaccination are Shaped by the Impact on Herpes Zoster. AB - INTRODUCTION: Varicella zoster virus (VZV) is the etiological agent of varicella and herpes zoster (HZ). It has been hypothesised that immune boosting of latently infected persons by contact with varicella reduces the probability of HZ. If true, universal varicella vaccination may increase HZ incidence due to reduced VZV circulation. To inform decision-making, we conduct cost-effectiveness analyses of varicella vaccination, including effects on HZ. METHODS: Effects of varicella vaccination are simulated with a dynamic transmission model, parameterised with Dutch VZV seroprevalence and HZ incidence data, and linked to an economic model. We consider vaccination scenarios that differ by whether or not they include immune boosting, and reactivation of vaccine virus. RESULTS: Varicella incidence decreases after introduction of vaccination, while HZ incidence may increase or decrease depending on whether or not immune boosting is present. Without immune boosting, vaccination is expected to be cost-effective or even cost-saving. With immune boosting, vaccination at 95% coverage is not expected to be cost-effective, and may even cause net health losses. CONCLUSIONS: Cost-effectiveness of varicella vaccination depends strongly on the impact on HZ and the economic time horizon. Our findings reveal ethical dilemmas as varicella vaccination may result in unequal distribution of health effects between generations. PMID- 26629545 TI - Grating-based X-ray Dark-field Computed Tomography of Living Mice. AB - Changes in x-ray attenuating tissue caused by lung disorders like emphysema or fibrosis are subtle and thus only resolved by high-resolution computed tomography (CT). The structural reorganization, however, is of strong influence for lung function. Dark-field CT (DFCT), based on small-angle scattering of x-rays, reveals such structural changes even at resolutions coarser than the pulmonary network and thus provides access to their anatomical distribution. In this proof of-concept study we present x-ray in vivo DFCTs of lungs of a healthy, an emphysematous and a fibrotic mouse. The tomographies show excellent depiction of the distribution of structural - and thus indirectly functional - changes in lung parenchyma, on single-modality slices in dark field as well as on multimodal fusion images. Therefore, we anticipate numerous applications of DFCT in diagnostic lung imaging. We introduce a scatter-based Hounsfield Unit (sHU) scale to facilitate comparability of scans. In this newly defined sHU scale, the pathophysiological changes by emphysema and fibrosis cause a shift towards lower numbers, compared to healthy lung tissue. PMID- 26629546 TI - Cysteamine as a Future Intervention in Cystic Fibrosis Against Current and Emerging Pathogens: A Patient-based ex vivo Study Confirming its Antimicrobial and Mucoactive Potential in Sputum. AB - BACKGROUND: Cysteamine has recently been shown to have in vitro properties potentially therapeutically beneficial in cystic fibrosis (CF). In this study we investigated the antimicrobial and mucolytic activity of cysteamine against the complex biologic matrix of CF sputum. METHODS: Sputum samples were obtained from 23 CF adults. Sputum polymicrobial content after in vitro exposure to cysteamine and standard CF antibiotics was assessed after a single exposure and after 14 days low-dose exposure. The effect of cysteamine on sputum spinnbarkeit was assessed. FINDINGS: Cysteamine reduced sputum polymicrobial burden by 3.18 (95% CI 2.30-4. 07, p < 0.001) log10 units after 24 h incubation. Combined cysteamine and tobramycin reduced polymicrobial burden by a further 3.75 (95% CI 2.63-5.07, p < 0 . 001) log10 units above that seen with tobramycin. Repeated low dosing with cysteamine reduced sputum polymicrobial load from day 10 onwards (p = 0.032). Cysteamine reduced CF sputum viscoelasticity, sputum spinnbarkeit cysteamine 11.1 mm/s (95% CI 3.95-18.2) vs DNAse 1.69 mm/s (95% CI 0.73-2.65), p = 0.016. Cysteamine was active against Mycobacterium abscessus as a monotherapy and also potentiated the effects of amikacin and azithromycin. CONCLUSION: Further investigation is required into the therapeutic potential of cysteamine in CF to treat emerging as well as established microbial pathogens and as a mucolytic agent. PMID- 26629547 TI - Circulating Unsaturated Fatty Acids Delineate the Metabolic Status of Obese Individuals. AB - BACKGROUND: Obesity is not a homogeneous condition across individuals since about 25-40% of obese individuals can maintain healthy status with no apparent signs of metabolic complications. The simple anthropometric measure of body mass index does not always reflect the biological effects of excessive body fat on health, thus additional molecular characterizations of obese phenotypes are needed to assess the risk of developing subsequent metabolic conditions at an individual level. METHODS: To better understand the associations of free fatty acids (FFAs) with metabolic phenotypes of obesity, we applied a targeted metabolomics approach to measure 40 serum FFAs from 452 individuals who participated in four independent studies, using an ultra-performance liquid chromatograph coupled to a Xevo G2 quadruple time-of-flight mass spectrometer. FINDINGS: FFA levels were significantly elevated in overweight/obese subjects with diabetes compared to their healthy counterparts. We identified a group of unsaturated fatty acids (UFAs) that are closely correlated with metabolic status in two groups of obese individuals who underwent weight loss intervention and can predict the recurrence of diabetes at two years after metabolic surgery. Two UFAs, dihomo-gamma linolenic acid and palmitoleic acid, were also able to predict the future development of metabolic syndrome (MS) in a group of obese subjects. INTERPRETATION: These findings underscore the potential role of UFAs in the MS pathogenesis and also as important markers in predicting the risk of developing diabetes in obese individuals or diabetes remission after a metabolic surgery. PMID- 26629548 TI - Contrasting Pattern of Chronic Inflammatory Bowel Disease in Primary and Autoimmune Sclerosing Cholangitis. AB - BACKGROUND: Primary sclerosing cholangitis (PSC) and autoimmune sclerosing cholangitis (AISC) are related, but distinct chronic liver diseases. PSC is associated with a high prevalence of ulcerative colitis while the intestinal inflammation associated with AISC is less well characterised. AIMS: To assess and contrast aspects of intestinal inflammation in patients with AISC and PSC and compare the clinical features with those of patients with ulcerative colitis and Crohn's disease. METHODS: 23 and 22 patients with AISC and PSC, respectively, underwent review of colonoscopy and biopsy findings, capsule enteroscopy and assessment of clinical and inflammatory (faecal calprotectin) disease activity, which was compared with that of patients with ulcerative colitis and Crohn's disease (n = 55 each). FINDINGS: Five and 6 patients with AISC and PSC, respectively, had normal colonoscopy and faecal calprotectin levels of 34.4 +/- 8.3 and 39.7 +/- 8.4 MUg/g, respectively (normal < 50 MUg/g), whereas 18 and 16, respectively, had identical variably severe, right sided colitis with frequent rectal sparing, consistent with ulcerative colitis. Mean (+/- SD) faecal calprotectin levels did not differ significantly (p > 0.05) between patients with intestinal inflammation in AISC (588 +/- 549 MUg/g), PSC (421 +/- 351 MUg/g), ulcerative colitis (501 +/- 656 MUg/g) or Crohn's disease (476 +/- 571 MUg/g). Capsule enteroscopy showed that 7 of 18 (39%) (p < 0.03) of those with AISC had small bowel mucosal breaks whereas no patient with PSC had these findings. INTERPRETATION: Collectively these findings lend support to the suggestion that the chronic inflammatory bowel disease associated with PSC and in particular AISC may represent a distinct nosologic entity different from classic ulcerative colitis and Crohn's disease. PMID- 26629549 TI - Human Blastocyst Secreted microRNA Regulate Endometrial Epithelial Cell Adhesion. AB - Successful embryo implantation requires synchronous development and communication between the blastocyst and the endometrium, however the mechanisms of communication in humans are virtually unknown. Recent studies have revealed that microRNAs (miRs) are present in bodily fluids and secreted by cells in culture. We have identified that human blastocysts differentially secrete miRs in a pattern associated with their implantation outcome. miR-661 was the most highly expressed miR in blastocyst culture media (BCM) from blastocysts that failed to implant (non-implanted) compared to blastocysts that implanted (implanted). Our results indicate a possible role for Argonaute 1 in the transport of miR-661 in non-implanted BCM and taken up by primary human endometrial epithelial cells (HEECs). miR-661 uptake by HEEC reduced trophoblast cell line spheroid attachment to HEEC via PVRL1. Our results suggest that human blastocysts alter the endometrial epithelial adhesion, the initiating event of implantation, via the secretion of miR, abnormalities in which result in implantation failure. PMID- 26629552 TI - Dental Stem Cells and Their Applications. AB - Stem cells are unspecialised cells that can divide, renew, and differentiate into more specialised cells. Due to their unique properties, stem cells are known for their use in therapies and treatments for missing tissues and damaged parts of the body. However, due to the invasive nature and other ethical issues with the retrieval process and usage of stem cells, stem cells are clinically being used in a limited manner. Furthermore, due to the invasive nature of the retrieval process elsewhere, dental tissues are one of the most preferred sources for stem cells. This review covers all of the characteristics of dental tissue-derived stem cells and their potential future uses. PMID- 26629550 TI - Pathophysiologic Response to Burns in the Elderly. AB - Over the last decades advancements have improved survival and outcomes of severely burned patients except one population, elderly. The Lethal Dose 50 (LD50) burn size in elderly has remained the same over the past three decades, and so has morbidity and mortality, despite the increased demand for elderly burn care. The objective of this study is to gain insights on why elderly burn patients have had such a poor outcome when compared to adult burn patients. The significance of this project is that to this date, burn care providers recognize the extreme poor outcome of elderly, but the reason remains unclear. In this prospective translational trial, we have determined clinical, metabolic, inflammatory, immune, and skin healing aspects. We found that elderly have a profound increased mortality, more premorbid conditions, and stay at the hospital for longer, p < 0.05. Interestingly, we could not find a higher incidence of infection or sepsis in elderly, p > 0.05, but a significant increased incidence of multi organ failure, p < 0.05. These clinical outcomes were associated with a delayed hypermetabolic response, increased hyperglycemic and hyperlipidemic responses, inversed inflammatory response, immune-compromisation and substantial delay in wound healing predominantly due to alteration in characteristics of progenitor cells, p < 0.05. In summary, elderly have substantially different responses to burns when compared to adults associated with increased morbidity and mortality. This study indicates that these responses are complex and not linear, requiring a multi-modal approach to improve the outcome of severely burned elderly. PMID- 26629553 TI - Guidelines for Root Canal Therapy. AB - Root canal therapy is currently the main method to treat pulpal and periapical diseases. Root canal therapy consists of a series of complex procedures, requires specific equipments, instruments and materials, and should be performed by qualified stomatologists (clinicians). Complicated cases should be referred to endodontic specialists or the clinicians trained by intense endodontic courses. In 2004, the Society of Cariology and Endodontology of Chinese Stomatological Association (CSA) published the 'Practices and evaluation criteria of root canal therapy (Discussion Version)'. Since then, opinions and comments regarding the 'Discussion Version' have been widely circulated within the society. The final version of the guideline was based on systematic reviews of scientific literature and requirements for the edit of technical guidelines, through several rounds of discussions, revisions and supplements. The society recommends this guideline for stomatologists (clinicians) to use during endodontic treatment. PMID- 26629551 TI - Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians. AB - To determine the most important drivers of successful ageing at extreme old age, we combined community-based prospective cohorts: Tokyo Oldest Old Survey on Total Health (TOOTH), Tokyo Centenarians Study (TCS) and Japanese Semi Supercentenarians Study (JSS) comprising 1554 individuals including 684 centenarians and (semi-)supercentenarians, 167 pairs of centenarian offspring and spouses, and 536 community-living very old (85 to 99 years). We combined z scores from multiple biomarkers to describe haematopoiesis, inflammation, lipid and glucose metabolism, liver function, renal function, and cellular senescence domains. In Cox proportional hazard models, inflammation predicted all-cause mortality with hazard ratios (95% CI) 1.89 (1.21 to 2.95) and 1.36 (1.05 to 1.78) in the very old and (semi-)supercentenarians, respectively. In linear forward stepwise models, inflammation predicted capability (10.8% variance explained) and cognition (8(.)6% variance explained) in (semi-)supercentenarians better than chronologic age or gender. The inflammation score was also lower in centenarian offspring compared to age-matched controls with Delta (95% CI) = - 0.795 (- 1.436 to - 0.154). Centenarians and their offspring were able to maintain long telomeres, but telomere length was not a predictor of successful ageing in centenarians and semi-supercentenarians. We conclude that inflammation is an important malleable driver of ageing up to extreme old age in humans. PMID- 26629554 TI - Guidelines for Direct Adhesive Composite Restoration. AB - Direct adhesive composite restoration, a technique to restore tooth defects by bonding composite resin materials, has been widely used in the restoration of dental caries or other tooth defects. Retention of composite resin restoration mainly relies on bonding strength between the materials and dental tissue. The clinical outcomes rely greatly on the regulated clinical practice of dentists. In 2011, the Society of Cariology and Endodontology of Chinese Stomatological Association (CSA) published the 'Practices and evaluation criteria of composite resin bonded restoration (Discussion Version)'. Since then, opinions and comments regarding the 'Discussion Version' have been widely circulated within the Society. The final version of the guideline was based on systematic reviews of scientific literature and requirements for the edit of technical guidelines, and through several rounds of discussions, revisions and supplements. The society recommends this guideline for clinicians to use in their practices, when conducting direct composite restorations. PMID- 26629555 TI - Radiographic and Clinical Outcomes of Ridge Augmentation in Molar Extraction Sockets with Severe Bone Wall Defect. AB - OBJECTIVE: To describe a technique for socket augmentation in molar extraction sockets with severe bone wall defect. METHODS: Five teeth in four patients were included in this study. Each tooth had buccal and/ or lingual bone loss identified by bone sounding and periapical radiographs before removal. After a flapless, minimally invasive tooth extraction, the socket was grafted with deproteinized bovine bone mineral with or without a collagen membrane. At the buccal and/or lingual bone defect area, the buccal and/or lingual gingival walls may act as holders, to support the materials. Finally, colloidal silver gelatin sponge was packed gently on top of the graft or membrane to avoid graft or membrane exposure, without attempting to achieve primary closure of the soft tissue. Six months after augmentation, changes in ridge width, ridge height and keratinised tissue were measured on clinical photographs or radiographs. RESULTS: The alveolar bone widths observed at implant surgery were all greater than 6 mm. All patients showed bone augmentation in terms of ridge height. Keratinised tissue width showed increased or minor reductions. CONCLUSION: Treated with this technique, the deficient socket was re-established in the molar area. Clinically, the quantity and quality of the bone obtained in the grafted sockets allowed for successful implant placement. PMID- 26629556 TI - Simultaneous Occurence of an Autosomal Dominant Inherited MSX1 Mutation and an X linked Recessive Inherited EDA Mutation in One Chinese Family with Non-syndromic Oligodontia. AB - OBJECTIVE: To describe the simultaneous occurence of an autosomal dominant inherited MSX1 mutation and an X-linked recessive inherited EDA mutation in one Chinese family with nonsyndromic oligodontia. METHODS: Clinical data of characteristics of tooth agenesis were collected. MSX1 and EDA gene mutations were detected in a Chinese family of non-syndromic oligodontia. RESULTS: Mild hypodontia in the parents and severe oligodontia in the son was recorded. A novel missense heterozygous mutation c.517C>A (p.Arg173Ser) was detected in the MSX1 gene in the boy and the father. A homozygous missense mutation c.1001G>A (p.Arg334His) was detected in the EDA gene in the boy and the same mutant occurred heterozygously in the mother. CONCLUSION: Simultaneous occurence of two different gene mutations with different inheritence patterns, which both caused oligodontia, which occurred in one subject and in one family, was reported. PMID- 26629557 TI - Effect of Melamine Sponge on Tooth Stain Removal. AB - OBJECTIVES: To investigate the stain removal ability of melamine sponge before aesthetic tooth whitening in extracted teeth. METHODS: Melamine sponge of thickness 40 mm was compressed and the destruction of the partition wall structure during the compression process was examined under a stereoscopic microscope. An extracted human tooth was cleaned by normal polishing or with melamine sponge for 90 s. To evaluate the stain level, the tooth surfaces were photographed under a stereoscopic microscope at 0, 30, 60 and 90 s. The residual stained region was traced in a high-magnification photograph, and the stain intensity was presented as a change, relative to the intensity before the experiment (0 s). RESULTS: Mechanical cleaning by toothbrushing produced polishing scratches on the tooth surface, whereas use of the melamine sponge resulted in only minimal scratches. As the compression level increased, the stain removing effect tended to become stronger. CONCLUSION: Melamine sponge can remove stains from the tooth surface more effectively and less invasively compared to a conventional toothbrush. As no new scratches are made on the tooth surface when using a melamine sponge brush, the risk of re-staining is reduced. Cleaning using a melamine sponge brush can be easily and effectively performed at home and in a dental office. PMID- 26629558 TI - A New Technique for Minimally Invasive Maxillary Lateral Sinus Augmentation: a Case Report. AB - Numerous techniques are described for lateral sinus augmentation, in order to expand bone volume, either by a crestal or lateral approach. A successful surgical procedure is determined by a number of factors. It is reported that different techniques for sinus augmentation have a high percentage of success, but presents a number of intraoperative and postoperative complications such as the Schneiderian membrane perforation and a long operating time. To manage the problem of the insufficient bone height in the posterior maxilla, various bonegrafting materials were applied using different techniques and instruments to elevate the sinus membrane and fill the subsinus cavity thereafter. The article aimed to describe a minimally invasive technique, using a special design bur to wear out the lateral bone safely and elevate the sinus membrane with sophisticated separators. Platelet-rich fibrin (PRF) and decalcified bone allograft was used as grafting material to enhance bone healing. This new technique for the sinus lateral wall osteotomy minimised the incidence of intraoperative and postoperative complications and the mixed use of PRF with decalcified bone allograft showing a satisficatory efficacy. PMID- 26629559 TI - Dr Smillie and colleagues respond:. PMID- 26629560 TI - [Not Available]. PMID- 26629561 TI - [Not Available]. PMID- 26629562 TI - [Not Available]. PMID- 26629563 TI - A Young Man Who Rocks and Rolls at Night. PMID- 26629565 TI - Editor's Comment on: Connections between single-cell biomechanics and human disease states: Gastrointestinal cancer and malaria. PMID- 26629564 TI - Introduction to Acta Biomaterialia 10th year of publication. PMID- 26629566 TI - Editor's Comment on: Extracellular matrix as a biological scaffold material: Structure and function. PMID- 26629567 TI - Editor's Comment on: The history of biodegradable magnesium implants: A review. PMID- 26629568 TI - Editor's Comment on: Development of bioactive peptide amphiphiles for therapeutic cell delivery. PMID- 26629569 TI - Editor's Comment on: Review of bioactive glass: From Hench to hybrids. PMID- 26629570 TI - Raising the Bar: Never High-Five a Porcupine. PMID- 26629571 TI - [Holistic integrative hepatology]. PMID- 26629572 TI - [Noninvasive tests for staging and prognostication of chronic liver diseases: technical innovation-translates into clinical application]. PMID- 26629573 TI - [Commentary on key recommendations and guidelines development methodology of World Health Organization guideline for prevention, care and treatment of persons with chromic hepatitis B infection]. PMID- 26629574 TI - [Key points of 2015 EASL-ALEH clinical practice guidelines: non invasive tests for evaluation of liver severity and prognosis]. PMID- 26629575 TI - Talimogene laherparepvec in the treatment of melanoma. AB - : Metastatic melanoma continues to present a significant therapeutic challenge, with an incidence rate rising faster than that of any other cancer. The last 5 years have seen a revolution in the development of new treatments for advanced melanoma, with oncogene targeted agents and checkpoint inhibitor immunotherapies providing the first convincing evidence of a positive shift in overall survival. The role of oncolytic virotherapy in this rapidly evolving field has long been the subject of debate. However, it is with the development of Talimogene Laheparepvec (T-Vec), an intratumourally administered, genetically modified clinical herpes simplex virus-1 strain that has shown positive results in Phase III testing, that the potential for the use of OV may be realised. AREAS COVERED: This review will outline some of the recent advances in the treatment of advanced melanoma, with a detailed overview of evidence surrounding the development of T Vec. A literature search was conducted using the databases 'Medline' and 'Pubmed', including a subsequent manual search of references to identify papers of further relevance. EXPERT OPINION: As the pivotal OPTiM trial concludes, we outline some of the potential new directions for T-Vec and OV therapy and evaluate the ever-increasing role these novel agents are likely to play in the future landscape of cancer immunotherapy. PMID- 26629576 TI - Ghrelin in the pilosebaceous unit: alteration of ghrelin in patients with acne vulgaris. AB - BACKGROUND: Ghrelin in the pilosebaceous tissues of human skin and ghrelin levels in patients with acne vulgaris have not yet been investigated. OBJECTIVE: The purpose of this study was to screen ghrelin immunoreactivity by immunohistochemistry in human pilosebaceous tissues of human skin and also to determine the quantities of ghrelin in the serum of the patients with acne vulgaris. METHODS: 30 patients presenting with acne vulgaris and 30 control subjects participated in this study. Ghrelin levels were determined by enzyme linked immunosorbent assay (ELISA). Human hair follicles and sebaceous glands were immunohistochemically examined. RESULTS: Immunohistochemistry results showed that there is a strong ghrelin immunoreactivity in the hair follicles and sebaceous glands in sections of human skin. The mean serum ghrelin levels (27.58 ?} 15.44 pg/mL) in patients with acne vulgaris was significantly lower than those of controls (35.62?}20.46 pg/mL). CONCLUSIONS: Ghrelin produced in hair follicles and sebaceous glands of the skin might participate in the pathogenesis of acne vulgaris and also acne vulgaris in humans might be associated with decreased serum ghrelin. PMID- 26629577 TI - Crystalline leaf venation: a dermoscopic clue for diagnosing granuloma annulare. PMID- 26629578 TI - Verifying NG tube placement in children. PMID- 26629579 TI - Appreciating a nurse who went the extra mile. PMID- 26629580 TI - Avoid PCA by proxy. PMID- 26629582 TI - Strengthening the allied health workforce: policy, practice and research issues and opportunities. PMID- 26629581 TI - Hooray for mentors. PMID- 26629583 TI - Allied health: untapped potential in the Australian health system. AB - Although comprising around 20 per cent ofAustralia's health care workforce, allied health and its contribution to improving health outcomes remains poorly understood and largely invisible in the Australian health policy and reform environment. There is strong evidence demonstrating the benefits of allied health in improving patient outcomes, minimising risk and harm from illness and improving health system efficiency and capacity to meet increased demand cost effectively. Despite this, the existing health model, funding and culture prevent us from effectively accessing these benefits at a system level. The untapped potential of allied health represents a major underutilised resource to address many of the challenges facing Australia's health system today. A transformational change in the Australian health system in how, where and by whom care is provided is necessary. Australia's health model and culture needs to shift, to genuinely involve the consumer and make fill use of all three pillars of the patient care workforce. PMID- 26629584 TI - Advanced musculoskeletal physiotherapy clinical education framework supporting an emerging new workforce. AB - OBJECTIVE: A project, funded by the Department of Health and Human Services, was conducted with the aim of developing a clinical education framework that included an agreed competency standard and credentialing process to support advanced musculoskeletal physiotherapy roles. This paper describes the process undertaken to achieve this and presents the outcomes of implementation. METHODS: A multistep approach was taken. Initial steps included conducting a scoping review of the literature and focus groups of advanced musculoskeletal physiotherapists. The project team mapped out the structure of the framework. This was followed by a working party of subject matter experts developing an agreed competency standard. The framework was implemented at six hospitals across Australia and formally evaluated by an external evaluator. RESULTS: The clinical education framework developed includes a competency-based training and assessment program supported by learning resources and a mentoring program. It was successfully implemented across a diverse range of hospitals and received a positive evaluation. CONCLUSIONS: As the prevalence of musculoskeletal conditions increases, a new workforce of advanced musculoskeletal physiotherapists is emerging. A clinical education framework has been developed to address the specific needs of the population, organisations and experienced musculoskeletal physiotherapists recruited to these roles. A competent workforce has direct benefits for the community, healthcare organisations and the physiotherapy profession. PMID- 26629585 TI - [On the occasion of the 65th anniversary of the birth of Valeriy Nikolaevich Rakitskiy]. PMID- 26629586 TI - [On the occasion of the 60th anniversary of the birth of Omor Tilegenovich Kasymov]. PMID- 26629588 TI - High-Temperature Salt Flux Crystal Growth of New Lanthanide Molybdenum Oxides, Ln5Mo2O12 Ln = Eu, Tb, Dy, Ho, and Er: Magnetic Coupling within Mixed Valent Mo(IV/V) Rutile-Like Chains. AB - Five new lanthanide molybdenum oxides containing mixed valent Mo(IV/V) rutile like chains, Ln5Mo2O12 Ln = Eu, Tb, Dy, Ho, and Er, were prepared utilizing a high-temperature molten salt flux synthesis involving an in situ reduction utilizing metallic reducing agents. All five compounds were structurally characterized by single-crystal and powder X-ray diffraction methods and were found to crystallize in the monoclinic space group C2/m. The molybdates all contain rare infinite chains consisting of MoO2O4/2 edge-sharing octahedra. The chains exhibit alternating long and short separations between octahedra caused by the presence of Mo-Mo bonds to form Mo2O10 units containing one unpaired electron. The temperature dependence of the magnetic susceptibility of these compounds was measured, and antiferromagnetic ordering was observed in all cases. PMID- 26629587 TI - Boronic Acid for the Traceless Delivery of Proteins into Cells. AB - The use of exogenous proteins as intracellular probes and therapeutic agents is in its infancy. A major hurdle has been the delivery of native proteins to an intracellular site of action. Herein, we report on a compact delivery vehicle that employs the intrinsic affinity of boronic acids for the carbohydrates that coat the surface of mammalian cells. In the vehicle, benzoxaborole is linked to protein amino groups via a "trimethyl lock." Immolation of this linker is triggered by cellular esterases, releasing native protein. Efficacy is demonstrated by enhanced delivery of green fluorescent protein and a cytotoxic ribonuclease into mammalian cells. This versatile strategy provides new opportunities in chemical biology and pharmacology. PMID- 26629589 TI - Rapid Protein Digestion and Purification with Membranes Attached to Pipet Tips. AB - This paper presents rapid protein purification and proteolysis methods that integrate membrane technology and pipet tips. Pushing a protein-containing solution through a protease-modified membrane at the end of a pipet tip digests proteins in 30 s or less, and the short proteolysis time avoids reformation of disulfide bonds to enable tryptic digestion without alkylation of cysteine residues. Moreover, proteolysis is more complete than digestion for 30 min in solution. Antibody digestion at the end of a pipet tip leads to 100% peptide coverage in MS analyses. Similarly, when membranes contain Ni(2+) complexes, pipetting aqueous polyhistidine-tagged protein through the membrane and subsequent rinsing and elution yield purified polyhistidine-tagged protein in 2 min. These applications demonstrate the potential for combining functional membranes and pipet tips for rapid sample purification and pretreatment. PMID- 26629590 TI - Multiple electrical breakdowns and electrical annealing using high current approximating breakdown current of silver nanowire network. AB - The failure of a silver nanowire (AgNW) random network due to high electric current density is described. The AgNW network breaks down as result of electromigration and Joule heating at junctions, which leads to destroyed interconnections between AgNWs. The AgNW network is not completely destroyed after breakdown, but instead is able to undergo multiple breakdowns after being cooled down, with increased resistance and reduced breakdown current density. The breakdown current density of AgNW network is J(max) = 25 A cm(-2) for a network with R(s) ~ 40 Omega sq(-1) outperforming a CuNW network. An effective electrical annealing method is demonstrated to decrease network resistance by 18% by periodically applying high current that is slightly lower than breakdown current with a period of 1 min for a few cycles. PMID- 26629591 TI - Induced Dipole-Dipole Interactions Influence the Unfolding Pathways of Wild-Type and Mutant Amyloid beta-Peptides. AB - Amyloid-forming proteins undergo a structural transition from alpha-helical to disordered conformations and, ultimately, cross-beta fibrils. The unfolding and aggregation of the amyloid beta-peptide (Abeta) have been implicated in the development and progression of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). However, the events underlying the initial structural transition leading to the disease state remain unclear. Although most cases are sporadic, several genetic variants exist that alter the electrostatic properties of Abeta and lead to more rapid unfolding and more severe phenotypes. In the present study, the enhanced unfolding is shown to be due to the mutated side chains altering the local peptide-bond dipole moments leading to local destabilization of the alpha-helix, as determined from polarizable molecular dynamics (MD) simulations of wild-type (WT) Abeta fragments and several common mutations. The local perturbation of the helix then leads to progressive unwinding of the alpha-helix in a cooperative fashion due to decreases in adjacent (i +/- 1) and hydrogen-bonded (i + 4) peptide-bond dipole moments. Side chain dynamics, subsequent variations in dipole moments, and ultimately the response in the peptide-bond dipole moments are all modulated by solvent dielectric properties based on simulations in water versus ethanol. The polarizable simulation results, along with simulations using the additive CHARMM36 force field, further indicate that cooperativity due to the alignment of peptide bonds leading to enhanced dipole moments is a fundamental force in stabilizing alpha-helices. PMID- 26629592 TI - Preoperative trajectory planning for percutaneous procedures in deformable environments. AB - In image-guided percutaneous interventions, a precise planning of the needle path is a key factor to a successful intervention. In this paper we propose a novel method for computing a patient-specific optimal path for such interventions, accounting for both the deformation of the needle and soft tissues due to the insertion of the needle in the body. To achieve this objective, we propose an optimization method for estimating preoperatively a curved trajectory allowing to reach a target even in the case of tissue motion and needle bending. Needle insertions are simulated and regarded as evaluations of the objective function by the iterative planning process. In order to test the planning algorithm, it is coupled with a fast needle insertion simulation involving a flexible needle model and soft tissue finite element modeling, and experimented on the use-case of thermal ablation of liver tumors. Our algorithm has been successfully tested on twelve datasets of patient-specific geometries. Fast convergence to the actual optimal solution has been shown. This method is designed to be adapted to a wide range of percutaneous interventions. PMID- 26629593 TI - Comparative Metabolism Studies of Hexabromocyclododecane (HBCD) Diastereomers in Male Rats Following a Single Oral Dose. AB - Male Sprague-Dawley rats were dosed orally with 3 mg/kg of one of three hexabromocyclododecane (HBCD) diastereomers. Each diastereomer was well absorbed (73-83%), and distributed preferentially to lipophilic tissues. Feces were the major route of excretion; cumulatively accounting for 42% of dose for alpha-HBCD, 59% for beta-HBCD, and 53% for gamma-HBCD. Urine was also an important route of HBCD excretion, accounting for 13% of dose for alpha-HBCD, 30% for beta-HBCD, and 21% for gamma-HBCD. Total metabolism of HBCD diastereomers followed the rank order beta > gamma > alpha, and was >65% of that administered. The metabolites formed were distinct in male rats: alpha-HBCD did not debrominate or stereoisomerize, but formed two hydroxylated metabolites; beta- and gamma-HBCD were both extensively metabolized via pathways of stereoisomerization, oxidation, dehydrogenation, reductive debromination, and ring opening. beta-HBCD was biotransformed to two mercapturic acid pathway metabolites. The metabolites of beta- and gamma-HBCD were largely distinct, and could possibly be used as markers of exposure. These isomer-specific data suggest that alpha-HBCD would be the most dominant HBCD diastereomer in biological tissues because it was metabolized to the lowest degree and also accumulated from the stereoisomerization of the beta- and gamma- diastereomers. PMID- 26629594 TI - A Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis. AB - This paper describes the identification of 6-(pyrimidin-4-yloxy)-naphthalene-1 carboxamides as a new class of potent and selective human vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitors. In biochemical and cellular assays, the compounds exhibit single-digit nanomolar potency toward VEGFR2. Compounds of this series show good exposure in rodents when dosed orally. They potently inhibit VEGF-driven angiogenesis in a chamber model and rodent tumor models at daily doses of less than 3 mg/kg by targeting the tumor vasculature as demonstrated by ELISA for TIE-2 in lysates or by immunohistochemical analysis. This novel series of compounds shows a potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role. PMID- 26629595 TI - Two new compounds from Xanthium strumarium. AB - One new lignan, fructusol A (1), and one new thiazine derivative, 2-hydroxy xanthiazone (2), along with eight known ones, were isolated from the seeds of Xanthium strumarium. The structures of new compounds were elucidated on the basis of extensive spectroscopic methods. Meanwhile, compounds 1-3 were tested for their antifungal activities against Candida albicans (ATCC 10231) in vitro. No one showed obvious inhibitions (MIC90 > 128 MUg/ml). PMID- 26629596 TI - Mast cells and inflammatory bowel disease. AB - Inflammatory bowel diseases (IBD), consisting of ulcerative colitis (UC) and Crohn's disease (CD), are chronic immune-mediated diseases of the gut. Here, the potential role of mast cells (MC) is discussed, mainly focusing on preclinical studies. MC can be activated by antigen-mediated crosslinking of immunoglobulin receptors, by free light chains of immunoglobulins, stress and ATP. Upon activation, MC release bioactive mediators, of which the serine proteases mMCP-6 and Prss31 were shown to be involved in the development of acute colitis. Inhibition of MCs by activation of the inhibitory receptor LIMR3 or inhibitors of proteases may therefore represent new therapeutic targets to treat IBD. Human data are however lacking. PMID- 26629597 TI - Intestinal inflammation and pain management. AB - Intestinal inflammation results in the production of inflammatory pain-inducing mediators that may directly activate colon sensory neurons. Endogenous opioids produced by mucosal effector CD4(+) T lymphocytes identified as colitogenic may paradoxically counterbalance the local pro-algesic effect of inflammatory mediators by acting on opioid receptors expressed on sensory nerve endings. The review will focus on the endogenous immune-mediated regulation of visceral inflammatory pain, current pain treatments in inflammatory bowel diseases and prospectives on new opioid therapeutic opportunities to alleviate pain but avoiding common centrally-mediated side effects. PMID- 26629598 TI - Safety and efficacy of commonly used antimicrobial agents in the treatment of enterococcal infections: a review. AB - INTRODUCTION: Enterococci have become the second leading cause of nosocomial infections in the U.S, which are associated with higher morbidity, mortality, length of stay, and cost due to escalating resistance to several antimicrobial agents. With limited treatment options, the adverse events associated with the increasing use of available agents must be considered. AREAS COVERED: Safety data about the most commonly used antimicrobial agents to treat enterococcal infections (ampicillin, vancomycin, linezolid, daptomycin, and tigecycline) derived from animal models, clinical trials and post-marketing surveillance are evaluated. However, most of these agents are not FDA approved and have been used for off-label indications in enterococcal infections. EXPERT OPINION: The commonly used antimicrobials to treat enterococcal infections have unique safety profiles and side effects but are generally safe and tolerated in the short-term based on data from clinical trials and post-marketing surveillance. However, serious long-term adverse events may occur, and antibiotic selection should be individualized and based on source of infection, duration, potential drug-related toxicity, and drug-drug interactions to minimize side-effects. Implementing standard precautions and infection control measures, minimizing unnecessary antibiotic exposure, and optimizing treatment and duration with removal of source of infection are essential to prevent the spread of resistance and improve outcomes. PMID- 26629599 TI - Ischemic Heart Disease Mortality and Long-Term Exposure to Source-Related Components of U.S. Fine Particle Air Pollution. AB - BACKGROUND: Fine particulate matter (PM2.5) air pollution exposure has been identified as a global health threat. However, the types and sources of particles most responsible are not yet known. OBJECTIVES: We sought to identify the causal characteristics and sources of air pollution underlying past associations between long-term PM2.5 exposure and ischemic heart disease (IHD) mortality, as established in the American Cancer Society's Cancer Prevention Study-II cohort. METHODS: Individual risk factor data were evaluated for 445,860 adults in 100 U.S. metropolitan areas followed from 1982 through 2004 for vital status and cause of death. Using Cox proportional hazard models, we estimated IHD mortality hazard ratios (HRs) for PM2.5, trace constituents, and pollution source associated PM2.5, as derived from air monitoring at central stations throughout the nation during 2000-2005. RESULTS: Associations with IHD mortality varied by PM2.5 mass constituent and source. A coal combustion PM2.5 IHD HR = 1.05 (95% CI: 1.02, 1.08) per microgram/cubic meter, versus an IHD HR = 1.01 (95% CI: 1.00, 1.02) per microgram/cubic meter PM2.5 mass, indicated a risk roughly five times higher for coal combustion PM2.5 than for PM2.5 mass in general, on a per microgram/cubic meter PM2.5 basis. Diesel traffic-related elemental carbon (EC) soot was also associated with IHD mortality (HR = 1.03; 95% CI: 1.00, 1.06 per 0.26-MUg/m3 EC increase). However, PM2.5 from both wind-blown soil and biomass combustion was not associated with IHD mortality. CONCLUSIONS: Long-term PM2.5 exposures from fossil fuel combustion, especially coal burning but also from diesel traffic, were associated with increases in IHD mortality in this nationwide population. Results suggest that PM2.5-mortality associations can vary greatly by source, and that the largest IHD health benefits per microgram/cubic meter from PM2.5 air pollution control may be achieved via reductions of fossil fuel combustion exposures, especially from coal-burning sources. CITATION: Thurston GD, Burnett RT, Turner MC, Shi Y, Krewski D, Lall R, Ito K, Jerrett M, Gapstur SM, Diver WR, Pope CA III. 2016. Ischemic heart disease mortality and long-term exposure to source-related components of U.S. fine particle air pollution. Environ Health Perspect 124:785-794; http://dx.doi.org/10.1289/ehp.1509777. PMID- 26629600 TI - Reaching a representative sample of college students: A comparative analysis. AB - OBJECTIVE: To explore the feasibility of a random-digit dial (RDD) cellular phone survey in order to reach a national and representative sample of college students. METHODS: Demographic distributions from the 2011 National Young Adult Health Survey (NYAHS) were benchmarked against enrollment numbers from the Integrated Postsecondary Education System (IPEDS). The sample quality was compared with the Harvard School of Public Health College Alcohol Study (1993), National College Health Risk Behavior Survey (1995), and National College Health Assessment (2011). RESULTS: Overall, the NYAHS performed as well, if not better, than previous college health surveys at reaching important demographic subgroups. CONCLUSIONS: Cellular phone RDD is one feasible approach for studies of the general population of college students that can potentially generate national estimates of health behavior. PMID- 26629601 TI - [The carotid body paraganglioma: a rare swelling of the neck]. AB - BACKGROUND: A carotid body paraganglioma is a rare tumour of the neck, which occurs at the level of the carotid bifurcation. CASE DESCRIPTION: A 52-year-old man was referred with a 10-year history of a swelling on the right side of his neck. Imaging revealed that this was a carotid body paraganglioma. The tumour showed no hormonal activity and there were no other paraganglioma localisations. We removed the tumour surgically, and histological examination confirmed the diagnosis of paraganglioma. Genetic investigation revealed that the patient was a carrier of a mutation in the succinate dehydrogenase complex, subunit D (SDHD) gene. CONCLUSION: A paraganglioma of the carotid body is usually benign and slow growing. It is familial in about 50% of cases, with a characteristic mutation in the SDHD-gene. Surgical removal is often the treatment of choice. If there is too high a risk of injury due to surgery, or in cases of inoperability, a "wait and see" policy with radiological follow-up is implemented. Diagnostics, treatment and follow-up demand a multidisciplinary approach. PMID- 26629602 TI - [Is morphine indicated in patients with cardiac asthma? Indications for negative effects from the use of morphine]. AB - According to current Dutch and European guidelines, morphine has a place in the treatment of patients with cardiac asthma. There are no studies showing an improvement in objective parameters with the use of morphine in patients with cardiac asthma. Recent large retrospective cohort studies indicate an increased mortality risk among patients given morphine in the treatment of cardiac asthma, even after correction for confounders. In addition, morphine may be linked to an increased risk of intensive care unit admission. Morphine should be used with caution in patients with cardiac asthma. PMID- 26629603 TI - [Childhood melanoma in the Netherlands]. AB - Childhood melanoma is a rare disorder which is often associated with a diagnostic delay. Worldwide, the incidence of cutaneous melanoma is rising in both adults and children. We describe three cases of childhood melanoma in the Netherlands which illustrate different aetiological aspects of the disease. The epidemiology of childhood melanoma in the Netherlands is discussed. In reviewing the literature, we wish to draw attention to important clinical aspects which may contribute to the early recognition of melanoma in children. PMID- 26629604 TI - [The crystal ball: reflections on the prediction of disease]. AB - How exactly to take the family history so that it renders maximum diagnostic or predictive yield is controversial. This comment discusses a paper that suggests that asking for the presence of risk in children of patients may have added value in terms of predicting first or recurrent cardiovascular events in their parents. PMID- 26629605 TI - [Psychotropic drug prescription to people with intellectual disability in GP practices]. AB - Antipsychotic drugs are more often prescribed in primary care to people with intellectual disability (ID) with challenging behaviour, sometimes even without a diagnosis, than to those with a diagnosed mental illness. This is shown in a large cohort study in the United Kingdom in primary care and in a Dutch study in three residential care facilities. This prescription behaviour is undesirable. There is no evidence for the effectiveness of off-label prescription. Antipsychotic drugs can cause (serious) side effects. Active monitoring for these side effects is required as people with ID seldom complain. Challenging behaviour can be provoked by somatic illnesses. The Dutch study showed that antipsychotic drug reduction in people with ID with challenging behaviour led to improved behaviour and improvement of physical parameters. A skilled multidisciplinary team of professionals can help with alternative management strategies for challenging behaviour. These teams should be made available for primary care services. PMID- 26629606 TI - No association between glucose at age 30 and aortic diameter at age 65 in men: a population-based study. AB - OBJECTIVES: Impaired glucose metabolism and diabetes mellitus has been linked to a decreased risk for abdominal aortic aneurysm development in men. We evaluated potential relationships between blood glucose levels in 1722 men with mean age 34 years and their aortic diameter measured by ultrasound at age 65 years. DESIGN: Prospective cohort study. RESULTS: Mean follow-up between baseline glucose investigation and aortic ultrasound was 32.8 +/- 1.8 years. There was no correlation between baseline blood glucose and later aortic diameter (r = 0.035, p = 0.146), whereas a weak correlation between body mass index (BMI) and aortic diameter was observed (r = 0.097 p < 0.001). In a partial correlation between aortic diameter and glucose levels adjusted for BMI, the correlation did not change (r = 0.011, p = 0.66). Neither were there any significant differences in mean aortic diameter between men belonging to different quartiles of baseline blood glucose levels (19.5, 19.1, 19.6 and 19.7 mm, p = 0.18). CONCLUSION: Fasting blood glucose in 33-year-old men was not associated with their aortic diameter at age 65 years. Potential pathophysiological processes linking disturbed glucose metabolism to a decreased risk for development of abdominal aortic aneurysm in men are therefore probably not relevant until later in life. PMID- 26629607 TI - Chromatographic, Electrophoretic, and Mass Spectrometric Methods for the Analytical Characterization of Protein Biopharmaceuticals. PMID- 26629608 TI - End-of-Life Preferences in Advanced Cancer Patients. PMID- 26629610 TI - Imaging Spatial Variations in the Dissipation and Transport of Thermal Energy within Individual Silicon Nanowires Using Ultrafast Microscopy. AB - Thermal management is an important consideration for most nanoelectronic devices, and an understanding of the thermal conductivity of individual device components is critical for the design of thermally efficient systems. However, it can be difficult to directly probe local changes in thermal conductivity within a nanoscale system. Here, we utilize the time-resolved and diffraction-limited imaging capabilities of ultrafast pump-probe microscopy to determine, in a contact-free configuration, the local thermal conductivity in individual Si nanowires (NWs). By suspending single NWs across microfabricated trenches in a quartz substrate, the properties of the same NW both on and off the substrate are directly compared. We find the substrate has no effect on the recombination lifetime or diffusion length of photogenerated charge carriers; however, it significantly impacts the thermal relaxation properties of the NW. In substrate supported regions, thermal energy deposited into the lattice by the ultrafast laser pulse dissipates within ~10 ns through thermal diffusion and coupling to the substrate. In suspended regions, the thermal energy persists for over 100 ns, and we directly image the time-resolved spatial motion of the thermal signal. Quantitative analysis of the transient images permits direct determination of the NW's local thermal conductivity, which we find to be a factor of ~4 smaller than in bulk Si. Our results point to the strong potential of pump-probe microscopy to be used as an all-optical method to quantify the effects of localized environment and morphology on the thermal transport characteristics of individual nanostructured components. PMID- 26629611 TI - Suppression of allene oxide synthase 3 in potato increases degree of arbuscular mycorrhizal fungal colonization. AB - Arbuscular mycorrhizal (AM) is a mutually beneficial interaction among higher plants and soil fungi of the phylum Glomeromycota. Numerous studies have pointed that jasmonic acid plays an important role in the development of the intraradical fungus. This compound belongs to a group of biologically active compounds known as oxylipins which are derived from the oxidative metabolism of polyunsaturated fatty acids. Studies of the regulatory role played by oxylipins in AM colonization have generally focused on jasmonates, while few studies exist on the 9-LOX pathway of oxylipins during AM formation. Here, the cDNA of Allene oxide synthase 3 (AOS3), a key enzyme in the 9-LOX pathway, was used in the RNA interference (RNAi) system to transform potato plants in order to suppress its expression. Results show increases in AOS3 gene expression and 9-LOX products in roots of wild type potato mycorrhizal plants. The suppression of AOS3 gene expression increases the percentage of root with mycorrhizal colonization at early stages of AM formation. AOS3 RNA interference lead to an induction of LOXA and 13-LOX genes, a reduction in AOS3 derived 9-LOX oxylipin compounds and an increase in jasmonic acid content, suggesting compensation between 9 and 13-LOX pathways. The results in a whole support the hypothesis of a regulatory role for the 9-LOX oxylipin pathway during mycorrhization. PMID- 26629612 TI - Water deficit effects on tomato quality depend on fruit developmental stage and genotype. AB - Many studies have advocated that water deficit (WD) may exert beneficial effects on fruit quality. However, the fruit response to WD at specific developmental stages was seldom investigated, although different mechanisms could be involved at each stage and lead to different effects on final fruit quality. In the present study, a moderate WD (-60% of water supply compared to control) was applied during each of the three major phases of fruit development, namely cell division (CD), cell expansion (CE) and maturation (MT). Two cocktail tomato (Solanum lycopersicum L.) genotypes were studied, one producing poor quality fruits (LA1420), and the other one producing tasty fruits (PlovdivXXIVa named Plovdiv). Contrasted responses were observed between the two genotypes. For both of them, fruit fresh mass and size were not significantly reduced by WD, whatever the developmental phase affected. Osmotic regulations were likely involved in the CD treatment for LA1420 fruits, which accumulated more sugars (both on a dry and fresh matter basis) and less acids (on a dry matter basis). In the CE treatment, other adaptive strategies involving sugar metabolism and sub-cellular compartmentation were suggested. In contrast, the composition of Plovdiv fruits changed only under the MT treatment, with less sugars, acids and carotenoids compared to control fruits (both on a dry and fresh matter basis). Total ascorbic acid (AsA) was not significantly influenced by treatments in both genotypes. On their whole, results suggest that, depending on genotypes, fruits are sweeter and less acidic under WD, but that the nutritive value related to vitamin and carotenoid contents may be lessened. The sensitivity of each developmental phase highly depends on the genotype. All phases were sensitive to WD for LA1420, but only the ripening phase for Plovdiv. Interestingly, major changes in fruit composition were observed in LA1420 which presents poor fruit quality under control conditions. This suggests the onset of fast adaptive response to WD at the fruit level in this genotype. PMID- 26629613 TI - Molecular Evolution Directs Protein Translation Using Unnatural Amino Acids. AB - Unnatural amino acids have in recent years established their importance in a wide range of fields, from pharmaceuticals to polymer science. Unnatural amino acids can increase the number of chemical groups within proteins and thus expand or enhance biological function. Our ability to utilize these important building blocks, however, has been limited by the inherent difficulty in incorporating these molecules into proteins. To address this challenge, researchers have examined how the canonical twenty amino acids are incorporated, regulated, and modified in nature. This review focuses on achievements and techniques used to engineer the ribosomal protein-translation machinery, including the introduction of orthogonal translation components, how directed evolution enhances the incorporation of unnatural amino acids, and the potential utility of ancient biomolecules for this process. PMID- 26629614 TI - Chemical Synthesis of Ubiquitin Chains. AB - Chemical synthesis of complex biomolecules such as proteins is a challenging adventure, yet rewarding in driving various biochemical and biophysical research activities. Over the years, the refinement of peptide synthesis and invention of ligation methodologies have led to the successful synthesis of several complex protein targets. Ubiquitin bioconjugates, which are being studied intensively by many groups due to their involvement in numerous biological processes, represent a fine example where chemistry is greatly aiding these studies. In this article, we describe the synthetic routes and strategies to prepare different ubiquitin analogs with desired modifications, as well as di-ubiquitin chains. PMID- 26629615 TI - Corking Nitrogen-Doped Carbon Nanotube Cups with Gold Nanoparticles for Biodegradable Drug Delivery Applications. AB - Carbon nanomaterials have been proposed as effective drug delivery devices; however their perceived biopersistence and toxicological profile may hinder their applications in medical therapeutics. Nitrogen doping of carbon nanotubes results in a unique "stacked-cup" structure, with cups held together through van der Waals forces. Disrupting these weak interactions yields individual and short stacked nanocups that can subsequently be corked with gold nanoparticles, resulting in sealed containers for delivery of cargo. Peroxidase-catalyzed reactions can effectively uncork these containers, followed by complete degradation of the graphitic capsule, resulting in effective release of therapeutic cargo while minimizing harmful side effects. The protocols reported herein describe the synthesis of stacked nitrogen-doped carbon nanotube cups followed by effective separation into individual cups and gold nanoparticle cork formation resulting in loaded and sealed containers. PMID- 26629617 TI - Advances in our understanding of mechanisms of venous thrombus resolution. AB - Traditionally, venous thrombosis has been seen as the consequence of a regulated cascade of proteolytic steps leading to the polymerization of fibrinogen and fibrin crosslinking that is facilitated by platelets. A new view of thrombosis is providing a more integrated concept, with components of the vascular wall contributing to the vascular remodeling of thrombosis. Angiogenesis and inflammation are two key mechanisms that safeguard venous thrombus resolution and restitution of vascular patency after thrombosis. Disturbance of these processes leads to thrombus persistence and has potentially severe consequences for affected patients. Examples for clinical conditions associated with recurrent or persisting venous thrombosis are post-thrombotic syndrome or chronic thromboembolic pulmonary hypertension. Recently, studies using animal models of venous thrombosis have contributed to a better understanding of thrombus non resolution that will eventually lead to modification of current treatment concepts. For example, recent data suggest that innate immunity is involved in the modification of thrombosis. PMID- 26629616 TI - A Bead-Based Proximity Assay for BRD4 Ligand Discovery. AB - Bromodomain-containing proteins have emerged as desirable targets for anti neoplastic and anti-inflammatory drug discovery. Toward the development of selective inhibitors of the BET family of bromodomains, we optimized bead-based assays to detect interactions between bromodomains and poly-acetylated histone peptides. Donor and acceptor beads bound to target and ligand are brought into proximity by this protein-protein interaction. After laser illumination, singlet oxygen evolved from donor beads travels to the spatially close acceptor beads, resulting in chemiluminesence. This AlphaScreen assay has proven amendable to high-throughput screening, secondary validation, and specificity profiling during lead discovery and optimization. Here we report our protocol for assay development to measure inhibition of ligand binding to bromodomain-containing protein 4 (BRD4). We discuss the discovery of an appropriate probe, optimization of bead, probe, and protein concentrations, and the derivation of protein-probe inhibition curves. Finally, we explore the implementation of this technology for high-throughput screening of potential BRD4 inhibitors. PMID- 26629619 TI - Persistence of Two Isolates of Trichomonas gallinae in Simulated Bird Baths With and Without Organic Material. AB - Trichomonas gallinae, a well-documented protozoan parasite of avian hosts, has been implicated in major passerine mortality events recently and historically throughout the literature. It has been suggested that bird baths and artificial water sources could serve as a source of infection for naive birds; however, trichomonad persistence in water is not well understood. We measured the persistence of T. gallinae isolates from two avian hosts in distilled water and distilled water with the addition of organic material. We inoculated plastic containers in a laboratory setting with 1 * 10(6) trichomonads and then sampled 500 MUl from each container at various time points postinoculation (0-20 hr). The 500-MUl aliquots were inoculated into flasks with 5 ml of modified Diamond media at each time point. Flasks were incubated at 37 C and examined by light microscopy for five consecutive days for the characteristic movements of live trichomonads. The maximum persistence was 16 hr with a Cooper's hawk (Accipiter cooperii) isolate in the organic material treatment, far longer than the 1 hr persistence previously reported. We show that T. gallinae isolates are capable of persisting for long periods of time in water, illustrating that bird baths may be validated as a potential source of transmission in epidemics. PMID- 26629621 TI - Aerosol Disinfection Capacity of Slightly Acidic Hypochlorous Acid Water Towards Newcastle Disease Virus in the Air: An In Vivo Experiment. AB - Existence of bioaerosol contaminants in farms and outbreaks of some infectious organisms with the ability of transmission by air increase the need for enhancement of biosecurity, especially for the application of aerosol disinfectants. Here we selected slightly acidic hypochlorous acid water (SAHW) as a candidate and evaluated its virucidal efficacy toward a virus in the air. Three day-old conventional chicks were challenged with 25 doses of Newcastle disease live vaccine (B1 strain) by spray with nebulizer (particle size <3 MUm in diameter), while at the same time reverse osmosis water as the control and SAHW containing 50 or 100 parts per million (ppm) free available chlorine in pH 6 were sprayed on the treated chicks with other nebulizers. Exposed chicks were kept in separated cages in an isolator and observed for clinical signs. Oropharyngeal swab samples were collected from 2 to 5 days postexposure from each chick, and then the samples were titrated with primary chicken kidney cells to detect the virus. Cytopathic effects were observed, and a hemagglutination test was performed to confirm the result at 5 days postinoculation. Clinical signs (sneezing) were recorded, and the virus was isolated from the control and 50 ppm treatment groups, while no clinical signs were observed in and no virus was isolated from the 100 ppm treatment group. The virulent Newcastle disease virus (NDV) strain Sato, too, was immediately inactivated by SAHW containing 50 ppm chlorine in the aqueous phase. These data suggest that SAHW containing 100 ppm chlorine can be used for aerosol disinfection of NDV in farms. PMID- 26629620 TI - Protection Against Necrotic Enteritis in Broiler Chickens by Regulated Delayed Lysis Salmonella Vaccines. AB - Necrotic enteritis (NE), caused by Gram-positive Clostridium perfringens type A strains, has gained more attention in the broiler industry due to governmental restrictions affecting the use of growth-promoting antibiotics in feed. To date, there is only one commercial NE vaccine available, based on the C. perfringens alpha toxin. However, recent work has suggested that the NetB toxin, not alpha toxin, is the most critical virulence factor for causing NE. These findings notwithstanding, it is clear from prior research that immune responses against both toxins can provide some protection against NE. In this study, we delivered a carboxyl-terminal fragment of alpha toxin and a GST-NetB fusion protein using a novel attenuated Salmonella vaccine strain designed to lyse after 6-10 rounds of replication in the chicken host. We immunized birds with vaccine strains producing each protein individually, a mixture of the two strains, or with a single vaccine strain that produced both proteins. Immunization with strains producing either of the single proteins was not protective, but immunization with a mixture of the two or with a single strain producing both proteins resulted in protective immunity. The vaccine strain synthesizing both PlcC and GST-NetB was able to elicit strong production of intestinal IgA, IgY, and IgM antibodies and significantly protect broilers against C. perfringens challenge against both mild and severe challenges. Although not part of our experimental plan, the broiler chicks we obtained for these studies were apparently contaminated during transit from the hatchery with group D Salmonella. Despite this drawback, the vaccines worked well, indicating applicability to real-world conditions. PMID- 26629622 TI - Serological Surveillance of Wild Waterfowl in Northern Australia for Avian Influenza Virus Shows Variations in Prevalence and a Cyclical Periodicity of Infection. AB - The virological surveillance of 3582 wild waterfowl in northern Australia from 2004 to 2009 for avian influenza virus (AIV) found an apparent prevalence (AP) of 1% (31 of 2989 cloacal swabs; 95% CI: 0.71%-1.47%) using a Taqman Type A real time reverse transcription polymerase chain reaction test and no viral isolations from 593 swabs tested by the embryonating chicken egg culture method. From serological testing using a nucleoprotein competitive enzyme-linked immunosorbent assay for AIV antibody, 1131 of 3645 sera had >= 40% inhibition, indicating an apparent seroprevalence of 31% (95% CI: 29.5%-32.6%). This value suggests that the low AP from virological testing does not reflect the dynamics of AIV infection in these populations. Spatiotemporal and species variations in seroprevalence were found at wetland sampling sites, with consistently higher values at Kununurra in Western Australia (AP = 39%, 95% CI: 36.9%-41.4%) compared to other locations. At Kununurra, seroprevalence values had a two-year cyclical periodicity and suggest this location is a hotspot of AIV activity. From hemagglutination inhibition (HI) testing using multiple subtype antigens, the highest AP of HI reactions were to H6 and H5 subtypes. The phenomenon of cyclic periodicity in NP seroprevalence at Kununurra is hypothesized as being related to the prevalent H6 subtype that may have either become predominant or cycled back into a mostly AIV naive flock. The inclusion of serological testing provided insight into the dynamics of AIV infection in wild birds such as species risk profiles and spatiotemporal patterns, important epidemiological information for a risk-based approach to surveillance. PMID- 26629623 TI - Differential Viral Fitness Between H1N1 and H3N8 Avian Influenza Viruses Isolated from Mallards (Anas platyrhynchos). AB - Homosubtypic and heterosubtypic immunity in mallards (Anas platyrhynchos) play an important role in the avian influenza virus (AIV) diversity. The mechanisms of AIV replication among wild birds and the role of immunity in AIV diversity have thus not been completely clarified. During the monitoring of AI circulation among wild waterfowl in 2007-2008, two viruses (H3N8 and H1N1) were isolated from ducks caught in a funnel trap located in La Hulpe wetland in Belgium. H3N8 viruses were revealed to be more prevalent in the mallard population than was H1N1, which might suggest a better adaptation to this species. In order to investigate this hypothesis, we characterized both isolated viruses biologically by experimental inoculation. Virus excretion and humoral response induced by both isolated viruses were evaluated in mallards after a first infection followed by a homo- or heterosubtypic reinfection under controlled experimental conditions. The H1N1 virus had a delayed peak of excretion of 4 days compared to the H3N8, but the virus shedding was more limited, earlier, and shorter after each reinfection. Moreover, the H3N8 virus could spread to all ducks after homo- or heterosubtypic reinfections and during a longer period. Although the humoral response induced by both viruses after infection and reinfection could be detected efficiently by competitive ELISA, only a minimal H1 antibody response and almost no H3-specific antibodies could be detected by the HI test. Our results suggest that the H3N8 isolate replicates better in mallards under experimental controlled conditions. PMID- 26629624 TI - Vaccine Efficacy Against a New Avian Influenza (H9N2) Field Isolate from the Middle East (Serology and Challenge Studies). AB - Avian influenza subtype H9N2 is endemic in many countries in the Middle East. The reported prevalence of infection was variable between countries and ranged from 28.7% in Tunisia to 71% in Jordan. Several commercial killed whole-virus vaccine products are used as monovalent or bivalent mixed with Newcastle disease virus. Recently, we have noticed that many of the vaccinated broiler flocks did not show a production advantage over nonvaccinated flocks in the field. A new avian influenza field virus (H9N2) was isolated from these vaccinated and infected broiler flocks in 2013. This virus had 89.1% similarity of its hemagglutinin (HA) gene to the classical virus used for manufacturing the classical vaccine. Inactivated autogenous vaccine was manufactured from this new field isolate to investigate its serological response and protection in specific-pathogen-free (SPF) and breeder-male chickens compared to the classical vaccine. Oropharyngeal virus shedding of vaccinated breeder-male chickens was evaluated at 3, 9, 10, and 14 days postchallenge (DPC). Percentage of chickens shedding the virus at 3 DPC was 64%, 50%, and 64% in the classical vaccine group, autogenous vaccine group, and the control challenged group, respectively. At 7 DPC percentage of virus shedding was 42%, 7%, and 64% in the classical vaccine group, autogenous vaccine group, and the control challenged group, respectively. At 10 DPC only 9% of classical vaccine group was shedding the virus and there was no virus shedding in any of the groups at 14 DPC. There was statistical significance difference (P < 0.05) in shedding only at 7 DPC between the autogenous vaccine group and the other two groups. At 42 days of age (14 DPC), average body weight was 2.720, 2.745, 2.290, and 2.760 kg for the classical vaccine group, autogenous vaccine group, control challenged group, and control unchallenged group, respectively. Only the control challenged group had significantly (P < 0.05) lower average body weight. In another experiment, vaccinated SPF chicks had hemagglutination inhibition (HI) geometric mean titers (GMTs), with classical antigen, of 8.7 and 3.1 log 2 for classical and autogenous vaccine groups, respectively. When the autogenous antigen was used for HI, GMTs were 6.0 and 8.1 log 2, respectively. Both vaccines protected against body weight suppression after challenge. However, autogenous vaccine elicited significantly higher HI titer and reduced viral shedding at 7 DPC. In conclusion, it is important to revise the vaccine virus strains used in each region to protect against and control infection from new field strains. Further field experiments are needed to demonstrate the efficacy of new vaccines under field conditions. PMID- 26629625 TI - Historical and Recent Cases of H3 Influenza A Virus in Turkeys in Minnesota. AB - Subtype H3 influenza A viruses (IAVs) are abundant in wild waterfowl and also infect humans, pigs, horses, dogs, and seals. In Minnesota, turkeys are important and frequent hosts of IAV from wild waterfowl and from pigs. Over 48 yr of surveillance history, 11 hemagglutinin (HA) subtypes of IAV from waterfowl, as well as two HA subtypes from swine, H1 and H3, have infected turkeys in Minnesota. However, there have only been two cases of avian-origin H3 IAV infections in turkeys during this 48-yr period. The first avian-origin IAV infection was detected in seven breeder and commercial flocks in 1982 and was caused by a mixed H3H4/N2 infection. In 2013, an avian-origin H3H9/N2 outbreak occurred in five flocks of turkeys between 15 and 56 wk of age. Phylogenetic analysis of the HA gene segment from the 2013 isolate indicated that the virus was related to a wild bird lineage H3 IAV. A meta-analysis of historical H3 infections in domesticated poultry demonstrated that avian-origin H3 infections have occurred in chickens and ducks but were rare in turkeys. H9N2 virus was subsequently selected during the egg cultivation of the 2013 H3H9/N2 mixed virus. A growth curve analysis suggested that passage 3 of A/Turkey/Minnesota/13-20710 2/2013(mixed) had a slightly lower replication rate than a similar avian-origin H3N2. The challenge studies indicated that the infectious dose of avian-origin H3N2 for turkey poults was greater than 10(6) 50% egg infective dose. Considered together, these data suggest that avian-origin H3 introductions to turkeys are rare events. PMID- 26629626 TI - Administration of Poly[di(sodium carboxylatoethylphenoxy)phosphazene] (PCEP) and Avian Beta Defensin as Adjuvants in Inactivated Inclusion Body Hepatitis Virus and its Hexon Protein-Based Experimental Vaccine Formulations in Chickens. AB - Inclusion body hepatitis (IBH) is one of the major infectious diseases adversely affecting the poultry industry of the United States and Canada. Currently, no effective and safe vaccine is available for the control of IBH virus (IBHV) infection in chickens. However, based on the excellent safety and immunogenic profiles of experimental veterinary vaccines developed with the use of new generation adjuvants, we hypothesized that characterization of vaccine formulations containing inactivated IBHV or its capsid protein hexon as antigens, along with poly[di(sodium carboxylatoethylphenoxy)phosphazene] (PCEP) and avian beta defensin 2 (ABD2) as vaccine adjuvants, will be helpful in development of an effective and safe vaccine formulation for IBH. Our data demonstrated that experimental administration of vaccine formulations containing inactivated IBHV and a mixture of PCEP with or without ABD2 as an adjuvant induced significantly higher antibody responses compared with other vaccine formulations, while hexon protein-based vaccine formulations showed relatively lower levels of antibody responses. Thus, a vaccine formulation containing inactivated IBHV with PCEP or a mixture of PCEP and ABD2 (with a reduced dosage of PCEP) as an adjuvant may serve as a potential vaccine candidate. However, in order to overcome the risks associated with whole virus inactivated vaccines, characterization of additional viral capsid proteins, including fiber protein and penton of IBHV along with hexon protein in combination with more new generation adjuvants, will be helpful in further improvements of vaccines against IBHV infection. PMID- 26629627 TI - Relationship of Skeletal Muscle Development and Growth to Breast Muscle Myopathies: A Review. AB - Selection in meat-type birds has focused on growth rate, muscling, and feed conversion. These strategies have made substantial improvements but have affected muscle structure, repair mechanisms, and meat quality, especially in the breast muscle. The increase in muscle fiber diameters has reduced available connective tissue spacing, reduced blood supply, and altered muscle metabolism in the breast muscle. These changes have increased muscle fiber degeneration and necrosis but have limited muscle repair mechanisms mediated by the adult myoblast (satellite cell) population of cells, likely resulting in the onset of myopathies. This review focuses on muscle growth mechanisms and how changes in the cellular development of the breast muscle may be associated with breast muscle myopathies occurring in meat-type birds. PMID- 26629628 TI - Cross-Protection by Infectious Bronchitis Viruses Under Controlled Experimental Conditions. AB - Infectious bronchitis virus (IBV) cross-protection trials were performed in healthy chickens maintained under controlled environmental conditions. Chickens primed or primed and boosted with a Massachusetts (Mass)-type attenuated vaccine were subsequently challenged with either IBV Arkansas (Ark) or GA13-type virulent strains. In addition, Ark-vaccinated chickens were challenged with IBV GA13. Spike protein 1 (S1) amino acid identities between IBV vaccine and challenge strains varied from 76.0% to 77.3%. Contrary to expectations, assessments of clinical signs, viral load, and histopathology indicated a significant level of cross-protection among these antigenically distant IBV strains. Moreover, prime and booster vaccination with Mass protected against GA13 and improved protection against Ark when compared with Mass single vaccination. These results emphasize the need to include both single vaccination control groups and control groups primed and boosted with a single serotype when testing the efficacy of IBV protectotypes and/or novel IBV vaccine combinations against heterologous serotypes under controlled experimental conditions. Such controls are of distinct importance in experiments supporting the introduction of attenuated IBV vaccine strains exotic to regions, since these exotic strains may provide new genetic material for recombination and emergence of novel IBV strains. PMID- 26629629 TI - A Live Salmonella Gallinarum Vaccine Candidate Secreting an Adjuvant Protein Confers Enhanced Safety and Protection Against Fowl Typhoid. AB - Live attenuated vaccines are used for effective protection against fowl typhoid (FT) in domestic poultry. In this study, a lon/cpxR/asd deletion mutant of Salmonella Gallinarum expressing the B subunit of a heat labile toxin (LTB) from Escherichia coli, a known adjuvant, was cloned in a recombinant p15A ori plasmid, JOL1355, and evaluated as a vaccine candidate in chickens. The plasmid was shown to be stable inside the attenuated Salmonella Gallinarum cell after three successive generations. Moreover, from an environmental safety point of view, apart from day 1 the JOL1355 strain was not detected in feces through day 21 postinoculation. For the efficacy of JOL1355, a total of 100 chickens were equally divided into two groups. Group A (control) chickens were intramuscularly inoculated with phosphate-buffered saline at 4 and 8 wk of age. Group B chickens were primed and boosted via the intramuscular route with 200 MUL of a bacterial suspension of JOL1355 containing 1 * 10(8) colony forming units. All the chickens in Group A and B were challenged at 3 wk postbooster by oral inoculation with a wild-type Salmonella Gallinarum strain, JOL420. The JOL1355-immunized group showed significant protection and survival against the virulent challenge compared to the nonimmunized group. In addition, Group B exhibited a significantly higher humoral immune response, and the chickens remained healthy without any symptoms of anorexia, diarrhea, or depression. Group B also exhibited a significantly lower mortality rate of 4% compared to the 46% of the control group, which can be attributed to higher immunogenicity and better protection. The Group B chickens had significantly lower lesion scores for affected organs, such as the liver and spleen, compared to those of the control chickens (P < 0.01). These findings suggest that JOL1355 is a promising candidate for a safe and highly immunogenic vaccine against FT. PMID- 26629630 TI - Multiyear Serological Surveillance of Notifiable Influenza A Viruses in Belgian Poultry: A Retrospective Analysis. AB - Surveillance of notifiable avian influenza (NAI) virus is mandatory in European member states, and each year a serological survey is performed to detect H5 and H7 circulation in poultry holdings. In Belgium, this serological monitoring is a combination of a stratified and a risk-based approach and is applied to commercial holdings with more than 200 birds. Moreover, a competitive nucleoprotein (NP) ELISA has been used as first screening method since 2010. A retrospective analysis of the serological monitoring performed from 2007 through 2013 showed sporadic circulation of notifiable low-pathogenicity avian influenza (LPAI) viruses in Belgian holdings with a fluctuating apparent flock seroprevalence according to years and species. Overall, the highest apparent flock seroprevalence was detected for the H5 subtype in domestic Anatidae, with 20%-50% for breeding geese and 4%-9% for fattening ducks. Positive serology against non-H5/H7 viruses was also observed in the same species with the use of the IDScreen influenza A antibody competition ELISA kit (ID-vet NP ELISA), and confirmed by isolation of H2, H3, H6, and H9 LPAI viruses. Among Galliformes, the apparent flock seroprevalence was lower, ranging between 0.3% and 1.3%. Circulation of notifiable LPAI viruses was only observed in laying hens with a similar seroprevalence for H5 and H7. Based on ID-vet NP ELISA results, no circulation of LPAI viruses, regardless the subtype, was observed in breeding chickens and fattening turkeys. Retrospectively, the use of an ELISA as first line test not only reduced the number of hemagglutination inhibition tests to be performed, but also gave a broader evaluation of the prevalence of LPAI viruses in general, and might help to identify the most at-risk farms. PMID- 26629631 TI - Validation of Single and Pooled Manure Drag Swabs for the Detection of Salmonella Serovar Enteritidis in Commercial Poultry Houses. AB - Single swabs (cultured individually) are currently used in the Food and Drug Administration (FDA) official method for sampling the environment of commercial laying hens for the detection of Salmonella enterica ssp. serovar Enteritidis (Salmonella Enteritidis). The FDA has also granted provisional acceptance of the National Poultry Improvement Plan's (NPIP) Salmonella isolation and identification methodology for samples taken from table-egg layer flock environments. The NPIP method, as with the FDA method, requires single-swab culturing for the environmental sampling of laying houses for Salmonella Enteritidis. The FDA culture protocol requires a multistep culture enrichment broth, and it is more labor intensive than the NPIP culture protocol, which requires a single enrichment broth. The main objective of this study was to compare the FDA single-swab culturing protocol with that of the NPIP culturing protocol but using a four-swab pool scheme. Single and multi-laboratory testing of replicate manure drag swab sets (n = 525 and 672, respectively) collected from a Salmonella Enteritidis-free commercial poultry flock was performed by artificially contaminating swabs with either Salmonella Enteritidis phage type 4, 8, or 13a at one of two inoculation levels: low, x- = 2.5 CFU (range 2.5-2.7), or medium, x- = 10.0 CFU (range 7.5-12). For each replicate, a single swab (inoculated), sets of two swabs (one inoculated and one uninoculated), and sets of four swabs (one inoculated and three uninoculated), testing was conducted using the FDA or NPIP culture method. For swabs inoculated with phage type 8, the NPIP method was more efficient (P < 0.05) for all swab sets at both inoculation levels than the reference method. The single swabs in the NPIP method were significantly (P < 0.05) better than four-pool swabs in detecting Salmonella Enteritidis at the lower inoculation level. In the collaborative study (n = 13 labs) using Salmonella Enteritidis phage type 13a inoculated swabs, there was no significant difference (P > 0.05) between the FDA method (single swabs) and the pooled NPIP method (four-pool swabs). The study concludes that the pooled NPIP method is not significantly different from the FDA method for the detection of Salmonella Enteritidis in drag swabs in commercial poultry laying houses. Consequently based on the FDA's Salmonella Enteritidis rule for equivalency of different methods, the pooled NPIP method should be considered equivalent. Furthermore, the pooled NPIP method was more efficient and cost effective. PMID- 26629641 TI - Asymmetric Radical-Radical Cross-Coupling through Visible-Light-Activated Iridium Catalysis. AB - Combining single electron transfer between a donor substrate and a catalyst activated acceptor substrate with a stereocontrolled radical-radical recombination enables the visible-light-driven catalytic enantio- and diastereoselective synthesis of 1,2-amino alcohols from trifluoromethyl ketones and tertiary amines. With a chiral iridium complex acting as both a Lewis acid and a photoredox catalyst, enantioselectivities of up to 99% ee were achieved. A quantum yield of <1 supports the proposed catalytic cycle in which at least one photon is needed for each asymmetric C-C bond formation mediated by single electron transfer. PMID- 26629642 TI - Elevated Rest Heart Rate in Psychiatric Patients and Different Effects of Psychotropic Medication. AB - INTRODUCTION: Elevated rest heart rate (RHR) is a known risk factor of cardiovascular diseases. The aim of this study was to analyse the effects of different psychiatric disorders and psychotropic medication on RHR. METHODS: In this retrospective study, medical records of 590 inpatients with a psychiatric disorder (309 men, 281 women, mean age 42.11; SD=13.8 years) were evaluated. RHR, the psychiatric diagnosis according to ICD-10, the psychotropic medication and the use of beta blockers were assessed. RESULTS: The average RHR of all patients was 85.62 beats per minute (bpm) (SD=10.60 bpm) which is, according to the literature and the consensus of experts, to be considered as a relevant elevation of RHR. There was a significant negative correlation between age and RHR. Patients treated with monotherapy or with SSRI showed in the multiple regression analysis significant lower RHR than other subjects, whereas both polytherapy with more antipsychotics and the diagnosis of schizophrenia could be identified as an independent risk factor of elevated RHR (p<0.05, 2-tailed). The presence of hypertonia, diabetes, hypercholesterolemia or obesity has no influence on RHR. 6% of the study population received beta blocker during the hospitalization. DISCUSSION: The elevated RHR in psychiatric patients is a common phenomenon and can be observed independently of the use of psychotropic medication but more in patients with schizophrenia. An interesting additional finding could be a possible protective effect of SSRI on RHR in psychiatric patients. PMID- 26629643 TI - Roadside soils show low plant available zinc and copper concentrations. AB - Vehicle combustion and component wear are a major source of metal contamination in the environment, which could be especially concerning where road ditches are actively farmed. The objective of this study was to assess how site variables, namely age, traffic (vehicles day(-1)), and percent carbon (%C) affect metal accumulation in roadside soils. A soil chronosequence was established with sites ranging from 3 to 37 years old and bioavailable, or mobile, concentrations of Zinc (Zn) and Copper (Cu) were measured along major highways in North Carolina using a Mehlich III extraction. Mobile Zn and Cu concentrations were low overall, and when results were scaled via literature values to "total metal", the results were still generally lower than previous roadside studies. This could indicate farming on lands near roads would pose a low plant toxicity risk. Zinc and Cu were not correlated with annual average traffic count, but were positively correlated with lifetime traffic load (the product of site age and traffic count). This study shows an often overlooked variable, site age, should be included when considering roadside pollution accumulation. Zinc and Cu were more strongly associated with %C, than traffic load. Because vehicle combustion is also a carbon source, it is not obvious whether the metals and carbon are simply co-accumulating or whether the soil carbon in roadside soils may facilitate previously overlooked roles in sequestering metals on-site. PMID- 26629644 TI - Cadmium availability in rice paddy fields from a mining area: The effects of soil properties highlighting iron fractions and pH value. AB - Cadmium (Cd) availability can be significantly affected by soil properties. The effect of pH value on Cd availability has been confirmed. Paddy soils in South China generally contain high contents of iron (Fe). Thus, it is hypothesized that Fe fractions, in addition to pH value, may play an important role in the Cd bioavailability in paddy soil and this requires further investigation. In this study, 73 paired soil and rice plant samples were collected from paddy fields those were contaminated by acid mine drainage containing Cd. The contents of Fe in the amorphous and DCB-extractable Fe oxides were significantly and negatively correlated with the Cd content in rice grain or straw (excluding DCB-extractable Fe vs Cd in straw). In addition, the concentration of HCl-extractable Fe(II) derived from Fe(III) reduction was positively correlated with the Cd content in rice grain or straw. These results suggest that soil Fe redox could affect the availability of Cd in rice plant. Contribution assessment of soil properties to Cd accumulation in rice grain based on random forest (RF) and stochastic gradient boosting (SGB) showed that pH value should be the most important factor and the content of Fe in the amorphous Fe oxides should be the second most important factor in affecting Cd content in rice grain. Overall, compared with the studies from temperate regions, such as Europe and northern China, Fe oxide exhibited its unique role in the bioavailability of Cd in the reddish paddy soil from our study area. The exploration of practical remediation strategies for Cd from the perspective of Fe oxide may be promising. PMID- 26629645 TI - Different cesium-137 transfers to forest and stream ecosystems. AB - Understanding the mechanisms of (137)Cs movement across different ecosystems is crucial for projecting the environmental impact and management of nuclear contamination events. Here, we report differential movement of (137)Cs in adjacent forest and stream ecosystems. The food webs of the forest and stream ecosystems in our study were similar, in that they were both dominated by detrital-based food webs and the basal energy source was terrestrial litter. However, the concentration of (137)Cs in stream litter was significantly lower than in forest litter, the result of (137)Cs leaching from litter in stream water. The difference in (137)Cs concentrations between the two types of litter was reflected in the (137)Cs concentrations in the animal community. While the importance of (137)Cs fallout and the associated transfer to food webs has been well studied, research has been primarily limited to cases in a single ecosystem. Our results indicate that there are differences in the flow of (137)Cs through terrestrial and aquatic ecosystems, and that (137)Cs concentrations are reduced in both basal food resources and higher trophic animals in aquatic systems, where primary production is subsidized by a neighboring terrestrial ecosystem. PMID- 26629646 TI - Influence of rice straw amendment on mercury methylation and nitrification in paddy soils. AB - Currently, rice straw return in place of burning is becoming more intensive in China than observed previously. However, little is known on the effect of returned rice straw on mercury (Hg) methylation and microbial activity in contaminated paddy fields. Here, we conduct a microcosm experiment to evaluate the effect of rice straw amendment on the Hg methylation and potential nitrification in two paddy soils with distinct Hg levels. Our results show that amended rice straw enhanced Hg methylation for relatively high Hg content soil, but not for low Hg soil, spiking the same additional fresh Hg. methylmercury (MeHg) concentration was significantly correlated to the dissolved organic carbon (DOC) content and relative abundance of dominant microbes associated with Hg methylation. Similarly, amended rice straw was found to only enhance the potential nitrification rate in soil with relatively high Hg content. These findings provide evidence that amended rice straw differentially modulates Hg methylation and nitrification in Hg contaminated soils possibly resulting from different characteristics in the soil microbial community. This highlights that caution should be taken when returning rice straw to contaminated paddy fields, as this practice may increase the risk of more MeHg production. MAIN FINDING: Rice straw amendment enhanced both Hg methylation and nitrification potential in the relatively high, but not low, Hg soil. PMID- 26629647 TI - Widespread exposure to lead affects the body condition of free-living whooper swans Cygnus cygnus wintering in Britain. AB - Lead poisoning, through the ingestion of spent lead gunshot, is an established cause of morbidity and mortality in waterbirds globally, but the thresholds at which blood levels begin to affect the physiology of birds in the wild are less well known. Here we determine the prevalence of lead exposure in whooper swans and, for the first time, identify the level of blood lead associated with initial reductions in body condition. Blood lead elevated above background levels (i.e. >20 MUg dL(-1)) was found in 41.7% (125/300) of swans tested. Blood lead was significantly negatively associated with winter body condition when levels were >=44 MUg dL(-1) (27/260 = 10%). Our findings indicating that sub-lethal impacts of lead on body condition occur at the lower end of previously established clinical thresholds and that a relatively high proportion of individuals in this population may be affected, reaffirm the importance of reducing contamination of the environment with lead shot. PMID- 26629648 TI - Narrowing of band gap and effective charge carrier separation in oxygen deficient TiO2 nanotubes with improved visible light photocatalytic activity. AB - Oxygen vacancies are introduced into hydrothermally processed TiO2 nanotube by vacuum calcination. Formation of oxygen vacancies modifies the local coordination in TiO2 as evident from Raman spectroscopy and secondary ion mass spectrometry (SIMS) results. The surface area is increased from 172.5m(2)/g in pure to 405.1m(2)/g in defective TiO2 nanotube. The mid-band gap electronic states created by oxygen vacancies are mostly responsible for the effective narrowing of band gap. Charge carrier separation is sufficiently prolonged as the charged oxygen defect states inhibit facile carrier recombination. With high surface area, narrowed band gap and separated charge carriers defective TiO2 nanotube is a suitable candidate in the photodegradation of methylene blue (MB) and phenol under visible light illumination. Photosensitized electron transfer from MB to the conduction band of TiO2 and the photodegradation of MB is facilitated in presence of high density of oxygen vacancies. Unlike MB, phenol absorbs in the UV region and does not easily excited under visible light. Phenol shows activity under visible light by forming charge transfer complex with TiO2. Defect trapped carriers become available at the phenol-TiO2 interface and finally interact with phenol molecule and degrade it. PMID- 26629649 TI - Interrogation of the Substrate Profile and Catalytic Properties of the Phosphotriesterase from Sphingobium sp. Strain TCM1: An Enzyme Capable of Hydrolyzing Organophosphate Flame Retardants and Plasticizers. AB - The most familiar organophosphorus compounds are the neurotoxic insecticides and nerve agents. A related group of organophosphorus compounds, the phosphotriester plasticizers and flame retardants, has recently become widely used. Unlike the neurotoxic phosphotriesters, the plasticizers and flame retardants lack an easily hydrolyzable bond. While the hydrolysis of the neurotoxic organophosphates by phosphotriesterase enzymes is well-known, the lack of a labile bond in the flame retardants and plasticizers renders them inert to typical phosphotriesterases. A phosphotriesterase from Sphingobium sp. strain TCM1 (Sb-PTE) has recently been reported to catalyze the hydrolysis of organophosphorus flame retardants. This enzyme has now been expressed in Escherichia coli, and the activity with a wide variety of organophosphorus substrates has been characterized and compared to the activity of the well-known phosphotriesterase from Pseudomonas diminuta (Pd-PTE). Structure prediction suggests that Sb-PTE has a beta-propeller fold, and homology modeling has identified a potential mononuclear manganese binding site. Sb-PTE exhibits catalytic activity against typical phosphotriesterase substrates such as paraoxon, but unlike Pd-PTE, Sb-PTE is also able to effectively hydrolyze flame retardants, plasticizers, and industrial solvents. Sb-PTE can hydrolyze both phosphorus-oxygen bonds and phosphorus-sulfur bonds, but not phosphorus-nitrogen bonds. The best substrate for Sb-PTE is the flame retardant triphenyl phosphate with a kcat/Km of 1.7 * 10(6) M(-1) s(-1). Quite remarkably, Sb-PTE is also able to hydrolyze phosphotriesters with simple alcohol leaving groups such as tributyl phosphate (kcat/Km = 40 M(-1) s(-1)), suggesting that this enzyme could be useful for the bioremediation of a wide variety of organophosphorus compounds. PMID- 26629650 TI - A Copper-Based Metal-Organic Framework Acts as a Bifunctional Catalyst for the Homocoupling of Arylboronic Acids and Epoxidation of Olefins. AB - A copper(I)-based metal-organic framework ({[Cu2 Br2 (pypz)]n ?nH2 O} (Cu-Br-MOF) [pypz=bis[3,5-dimethyl-4-(4'-pyridyl)pyrazol-1-yl] methane] has been synthesized by using an elongated and flexible bridging ligand. The structure analysis reveals that each pypz ligand acts as a tritopic ligand connected to two Cu2 Br2 dimeric units, forming a one-dimensional zig-zag chain, and these chains further connected by a Cu2 Br2 unit, give a two-dimensional framework on the bc-plane. In the Cu2 Br2 dimeric unit, the copper ions are four coordinated, thereby possessing a tetrahedral geometry; this proves to be an excellent heterogeneous catalyst for the aerobic homocoupling of arylboronic acids under mild reaction conditions. This method requires only 3 mol % of catalyst and it does not require any base or oxidant-compared to other conventional (Cu, Pd, Fe, and Au) catalysts for the transformation of arylboronic acids in very good yields (98 %). The shape and size selectivity of the catalyst in the homocoupling was investigated. The use of the catalyst was further extended to the epoxidation of olefins. Moreover, the catalyst can be easily separated by simple filtration and reused efficiently up to 5 cycles without major loss of reactivity. PMID- 26629656 TI - Postdischarge Cause-of-Death Analysis of Combat-Related Burn Patients. AB - Combat operations in Iraq and Afghanistan have resulted in up to 8.8% of combat related casualties suffering burns. From World War I through Desert Storm, burns have been associated with approximately 4% of the combat-related deaths. Experiencing a blast injury and exposure to killing and death while deployed has been shown to increase suicide risk. Although several studies of military populations have investigated risk factors for death among burn patients during the acute phase, no studies have reported mortality rates, cause-of-death, or the prevalence of suicide after hospital discharge. This study examined the case fatality rate, causes of death, and the prevalence of suicide among 830 combat burn patients discharged from the sole burn center in the U.S. Department of Defense, between March 7, 2003 and March 6, 2013. Cause-of-death was determined through the Armed Forces Medical Examiner's Office and the Office of the Secretary of Defense's National Death Index. A total of 11 deaths occurred among the 830 burn survivors, for an overall case fatality rate of 1.3%. Of the 11 who died, five deaths were related to accidental poisoning by exposure to drugs; three were related to operations of war (two after returning to the war zone), and the remaining three died from other accidental causes (one explosion and two vehicle crashes). There was no indication of suicide or suspicion of suicide as a cause-of-death for the former patients included in this study, suggesting that combat burn injury did not appear to increase the risk of death by suicide in our study population. Further research is needed to understand the factors that contribute to the apparent resilience of combat burn survivors. PMID- 26629640 TI - Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities. AB - IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (<=40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits. PMID- 26629657 TI - Remote Burn Injury Increases Pulmonary Histone Deacetylase 1 and Reduces Histone Acetylation. AB - Dermal burn injury causes profound physiological derangements. Respiratory failure is a primary cause of morbidity and mortality after burn injury, in part, because of excessive and prolonged release of local and systemic proinflammatory mediators. Clinical and preclinical evidence suggests histone deacetylases (HDACs) are key mediators of inflammatory responses. The study objective was to explore the effects of dermal burn injury on pulmonary HDAC activity, identify specific lung HDAC(s) altered by burn, and characterize histone lysine acetylation status. Mice were subjected to a 15% total body surface area scald burn or a sham injury and euthanized 24 hours later. Whole lungs were harvested, or alveolar macrophages were isolated from bronchoalveolar lavage fluid. HDAC specific activity assays were performed, Western blots were run to analyze HDACs1, 2, 3, 4, and 10 or histone lysine acetylation levels, and HDAC1 and phosphorylated-HDAC1 levels and localization were examined by immunofluorescence. Burned mice had higher HDAC specific activity and increased HDAC1 levels compared with controls, but levels of other HDACs were comparable between groups. Burn injury increased levels of HDAC1 and phosphorylated-HDAC1 in bronchioles and alveolar sacs and was associated with global and specific diminished levels of histone H3 and histone H4 lysine acetylation. Our analyses reveal that pulmonary inflammation after burn injury may be modulated by epigenetic mechanisms involving HDACs because HDAC activity, HDAC1 expression and activity, and downstream histone acetylation were all altered after burn. Future studies will explore the role of HDAC inhibitors in reversing inflammatory defects and may ultimately lead to new treatment interventions for burn patients. PMID- 26629658 TI - Distribution and migration of heavy metals in soil and crops affected by acid mine drainage: Public health implications in Guangdong Province, China. AB - Acid mine drainages (AMD) contain high concentrations of heavy metals, and their discharges into streams and rivers constitute serious environmental problems. This article examines the effects of AMD on soil, plant and human health at Dabaoshan mine in Guangdong Province, China. Although the large scale mining was stopped in 2011, the heavy metal pollution in soil continues to endanger crops and human health in that region. The objectives of this study were to elucidate distribution and migration of Cd, Cu, Zn, As and Pb and associated health implications to local inhabitants. We collected and analyzed 74 crop samples including 28 sugarcane, 30 vegetables, 16 paddy rice and the corresponding soil samples, used correlation and linear relationship for transformation process analysis, and applied carcinogenic and non-carcinogenic risk for hazard evaluation. Results showed that the local soils were heavily polluted with Cd, Cu and As (especially for Cd) and the mean Igeo value was as high as 3.77. Cadmium, Cu, and Zn in rice and vegetables were comparable with those found four years ago, while As and Pb in edible parts were 2 to 5 times lower than before. The root uptake of Cd and Zn contributed mainly to their high concentrations in crops due to high exchangeable fraction of soil, while leafy vegetables accumulated elevated As and Pb contents mainly due to the atmospheric deposition. Metal concentrations in sugarcane roots were higher than those in rice and vegetable roots. The risk assessment for crops consumption showed that the hazard quotients values were of 21 to 25 times higher than the threshold level for vegetables and rice, indicating a potential non-carcinogenic risk to the consumers. The estimated mean total cancer risk value of 0.0516 more than 100 times exceeded the USEPA accepted risk level of 1*10(-4), indicating unsuitability of the soil for cultivating the food crops. Therefore, the local agricultural and the land-use policies need to be reevaluated. PMID- 26629659 TI - Exogenous jasmonic acid induces stress tolerance in tobacco (Nicotiana tabacum) exposed to imazapic. AB - Jasmonic acid (JA) is one of the important phytohormones, regulating the stress responses as well as plant growth and development. The aim of this study is to determine the effects of exogenous JA application on stress responses of tobacco plant exposed to imazapic. In this study, phytotoxic responses resulting from both imazapic and imazapic combined with JA treatment are investigated comparatively for tobacco plants. For plants treated with imazapic at different concentrations (0.030, 0.060 and 0.120mM), antioxidant enzyme activities (catalase, ascorbate peroxidase, glutathione S-transferase and glutathione reductase), carotenoids, glutathione and malondialdehyte (MDA) contents, jasmonic acid, abscisic acid and indole-3-acetic acid levels as well as herbicide residue amounts on leaves increased in general compared to the control group. In the plants treated with 45uM jasmonic acid, pigment content, antioxidant activity and phytohormone level increased whereas MDA content and the amount of herbicidal residue decreased compared to the non-treated plants. Our findings show that imazapic treatment induces some phytotoxic responses on tobacco leaves and that exogenous jasmonic acid treatment alleviates the negative effects of herbicide treatment by regulating these responses. PMID- 26629660 TI - Does methyl jasmonate modify the oxidative stress response in Phaseolus coccineus treated with Cu? AB - The contribution of methyl jasmonate (MJ) as a signal molecule able to take part in the defense mechanism against copper (Cu)-imposed oxidative stress was studied in the leaves and roots of runner bean (Phaseolus coccineus) plants. Roots of plants cultivated hydroponically were preincubated in MJ (10uM) for 1h or 24h and subsequently exposed to Cu (50uM) for 5h (short-term experiment) or 5 days (long term experiment). Enzymatic (activity of superoxide dismutase, SOD; catalase, CAT; ascorbate peroxidase, APX; guaiacol peroxidase, POX) and non-enzymatic (accumulation of malondialdehyde, MDA; homoglutathione, hGSH; proline; anthocyanins; low molecular weight organic acids, LMWOAs) responses were determined in the leaves and roots. The antioxidative defense mechanism was significantly activated after Cu supplementation. In most cases, activities of ROS (reactive oxygen species) scavenging enzymes like SOD, CAT, APX, POX, as well as MDA, hGSH and proline concentrations increased following Cu exposure. MJ showed a time-dependent effect on antioxidative enzymes activity. In the short term experiment, MJ elevated CAT, APX and POX activities in the roots, and POX activity in the leaves of non-Cu-treated plants. In the long-term experiment, MJ not only decreased POX and partially CAT activity in the roots, but also increased the MDA level and partially CAT activity in the leaves of the control plants. In Cu-treated plants, MJ reduced APX, but elevated POX activity in the leaves after 5-h exposure. After 5-day-Cu treatment, MJ inhibited POX activity in the leaves and mainly reduced SOD and CAT activities in the roots. Moreover, in the long-term experiment, MJ reduced tartrate and pyruvate in the leaves of Cu stressed plants, but mostly elevated tartrate and malate in the roots comparing with Cu alone treatment. MJ alone and under Cu excess did not alter accumulation of MDA, hGSH and proline comparing with Cu alone, but partially elevated anthocyanin concentration. The results indicated that MJ was both partially potent in modifying the antioxidative enzymes activity and metabolites accumulation in non-stress and Cu-stress conditions. PMID- 26629662 TI - Editorial. PMID- 26629661 TI - Identification of autoantibodies to glial fibrillary acidic protein in spinal cord injury patients. AB - Traumatic spinal cord injury (SCI) is a devastating injury causing significant morbidity and mortality. Experimental studies have demonstrated that SCI induced cellular damage and disruption of the blood-spinal cord barrier can initiate an autoimmune response. This response is thought to be pathogenic and contribute to poor outcome. The objective of this research was to investigate whether human SCI mounts an autoimmune response to self-antigens. Plasma samples were collected longitudinally from SCI patients (n=18) at acute (T1, <48 h) and subacute (T2, 2 4 weeks) time points to probe western blots of human brain homogenates in order to screen patients for the presence of putative autoantibodies. To identify the corresponding antigens, two-dimensional gel electrophoresis, western blot and liquid chromatography coupled with mass spectrometry (LC-MS/MS) analyses were performed. We found that four of 18 patients (22%) had novel immunoreactive bands ranging in size from 36 to 42 kDa present in subacute, but not in acute, plasma samples suggesting postinjury production. To identify the cross-reacting antigens, we separated brain proteins by two-dimensional gel electrophoresis and identified nine immunoreactive spots. Amino acid sequence analysis of these spots identified peptides that mapped to glial fibrillary acidic protein. Our results suggest that ~ 22% of SCI patients generated autoantibodies to glial fibrillary acidic protein. Future studies will be required to determine whether these autoantibodies contribute to the pathogenic sequelae of SCI. PMID- 26629663 TI - Health Promotion in Nursing Education: attitudes among nurse students. AB - BACKGROUND: The World Health Organization (WHO) European Strategy for Nursing and Midwifery has called for the explicit inclusion and application of health promotion in all nursing curricula. However, research indicates that there are deficiencies in nursing education regarding health promotion in both the theoretical and practical elements of education. Insight into the experiences of European nursing students' attitudes, positive or negative, about working in health promotion may provide a clue whether health promotion will be regarded as an important task and to what extent it will have priority in different parts of Europe. AIM: The aim of this study was to compare Italian and Swedish nursing students' attitudes towards health promotion practice on matriculation to nursing school and after a three-year nursing education, and to explore whether attitudes towards health promotion practice correlate with BMI and smoking. METHOD: The study involved students who started their nursing education in autumn 2009 (n =240). Data were collected via a questionnaire. RESULTS: The results show that the Swedish students had a more positive stance on health promotion than Italian students did. After completion of a three-year nursing education programme, Italian students' attitudes on health promotion had improved, while no such development was seen in Sweden. Further, no correlation between lifestyle issues and attitudes to health promotion was found. CONCLUSION: Health promotion in nursing education may have important influence on students' attitudes and thereby on the quantity and quality of future health promotion practice. PMID- 26629664 TI - Tutorship process in health care professions: a survey investigation in Emilia Romagna. AB - The areas that we wanted to investigate include: tasks performed, tools used, formalization of the assignment, workload, empowerment and satisfaction of the function performed, and training. The results clearly show that the processes of tutoring are different for physicians and non-physician healthcare professionals. The first interesting difference is the method of assignment of mentoring. While among medical professions the function is assigned by others, tutors are often non-medical volunteers. This evidence leads to two unanswered questions: what are the criteria by which they are chosen as tutors? Do volunteers really possess the skills and ability to carry out this role? Future research should be directed towards clearly defining the profile of the "tutor" among both doctors and non medical professionals. Another difference is the way the work of the mentor is formalized. If they are doctors, the task is assigned to them; this is not the case for non-medical professions. Despite this difference, a high percentage of both medical professionals and doctors said they did not feel valued for their role of tutor. However, differences emerge: physicians see their role as a paid tutor and / or recognized in their curriculum vitae. For non-medical professions, however, the only reward is a recognition of ECM (Educazione Continua in Medicina)credits. A common feature among professionals is that for both physicians and non-physician healthcare tutors, a system of evaluation is rarely reported. Another common feature is the skills that professionals would like to see improved. Both groups of professionals, in fact, would like to see improved teaching methods, communication strategies and reporting and evaluation systems. Finally, non-physician tutors report the same level of satisfaction, although the non-physician professionals are more satisfied in their relationship with colleagues. The degree of empowerment reveals perceived differences and similarities among the professionals. In fact, both professional groups reported the same levels of competence and impact, but differ in meaning and self determination. More specifically, the non-medical professionals show high scores, while doctors get a higher score for self-determination. These results suggest that for increased attention to the system of evaluation and enhancement of the function tutorial we need not only to increase the satisfaction of those who act as tutors, but also to improve the tutorial process itself. Furthermore, the results suggest the carrying out of training projects for teaching and assessment methods that represent the issues that are most in demand by tutors. The training should include the use of tools for the governance process that project tutorial and apprenticeships. The responses indicate that these tools are already in use, although not as widespread and continuous. PMID- 26629665 TI - Empathy and burnout: an analytic cross-sectional study among nurses and nursing students. AB - BACKGROUND AND AIM: Empathy is an essential element of good nursing care associated with increased patient satisfaction. Burnout represents chronic occupational stress which diminishes interest in work and reduces patient safety and satisfaction. The purpose of this study was to evaluate the correlation between empathy and burnout in nursing students and nurses. METHOD: This cross sectional research was conducted in a sample of 298 nurses and 115 nursing students. Socio-demographic and career information was collected. Balanced Emotional Empathy Scale (BEES) and Maslach Burnout Inventory (MBI) were administered. Data were statistically analysed. RESULTS: 63% of our sample answered questionnaires (54% of nurses and 84% of students). The BEES global mean score was slightly inferior to empathy cut-off of 32. In the student group, two BEES dimension scores were statistically significantly higher than nurses (p=0.011 and p=0.007 respectively, t-test). Empathy was negatively related to age (p=0.001, ANOVA). Emotional exhaustion (EE) scores of MBI reported statistically significantly lower levels for students (p<0.0001, t-test). EE was negatively related to BEES mean total score in students (r=-0.307, p<0.002) and nurses (r= 0.245, p<0.002), personal accomplishment of MBI presented positive correlation with BEES mean total scores in students (r=0.319, p<0.002) and nurses (r=0.266, p<0.001, Pearson's correlation). Female students showed superior empathy capacity in comparison to male students in all 5 dimensions of BEES (p<0.001), whereas females nurses in only one dimension (p<0.001). CONCLUSIONS: Our data suggest empathy declines with age and career. High levels of empathy can be protective against burnout development, which, when presents, reduces empathy. PMID- 26629666 TI - Bio-clinical and psycho-social nursing practice. An experimental research in an Intensive Coronary Care Unit. AB - BACKGROUND AND AIM: The literature on patients with cardiovascular disease emphasizes the importance of providing a bio-medical and a psycho-social nursing care during the three phases of the nursing process (acceptance, assistance, education). How is his multidimensional nursing approach actually used during nursing practice? The present study aimed to evaluate the effects of a nursing educational training and it was finalized to implement a multidimensional care practice of nurses working in Intensive Coronary Care Unit (I.C.C.U.). METHOD: The entire nursing staff of the I.C.C.U of Parma Hospital (N = 17) took part in the research and it has been randomized in two subgroups. A group of 9 nurses participated as experimental group. They filled up a semi-structured questionnaire investigating the bio-clinical and psycho-social nursing activities, before (pre-test, time 1) and after (post-test, time 2) a professional training. 8 nurses participated as control group. They filled out the same questionnaire (at the time 1 and 2), but they did not participate at the professional training. RESULTS: Results indicated how the nursing practice was more related to the bio-clinical (e.g. blood pressure) than to the psycho-social (e.g. mood) activities at the time 1. After the professional training (time 2), only the experimental group changed its professional practice, by integrating the bio-medical with the psycho-social nursing. CONCLUSIONS: The data showed the importance to promote a multidimensional educational path for nurses that assess the impact of the professional training on the professional practice, in order to improve the quality of care delivered to patients affected by cardiovascular disease. PMID- 26629667 TI - The complementary medicine (CAM) for the treatment of chronic pain: scientific evidence regarding the effects of healing touch massage. AB - BACKGROUND AND AIM: Evidence-based medicine offers effective pathways of pharmacological treatment for chronic pain that may compromise the quality of life of patients; this is one of the main reasons why more and more people resort to traditional and complementary approaches, to try to maintain or regain their health. The effectiveness of the various forms of complementary treatments often cannot be proven objectively, which is why, given the need to find more concrete evidence of the effectiveness of complementary therapies with particular reference to the method of healing touch massage, a review of the literature was conducted in order to gather evidence of the efficacy of the specific method regarding pain and other health outcomes of patients with malignant disease to support a proposal for improvement, based on the practice of healing touch massage conducted by nurses. METHOD: Systematic review. RESULTS: There are several examples (in some cases specifically regarding patients with tumors) of the positive effects of healing touch massage on pain, anxiety and fatigue, and also on biochemical parameters. CONCLUSIONS: The way to full recognition by both the institutional and the scientific community seems to promise fairly well, although it should be noted that the achievement of this goal will require further research avoiding the limitations of previous studies. PMID- 26629668 TI - Proposal for the testing of a tool for assessing the risk of dehydration in the elderly patient. AB - BACKGROUND: Dehydration is now the most common fluid and electrolyte disorder in older people. Because it is often associated with high rates of morbidity and mortality, it requires careful control and prevention in the context of a thorough primary care. The main risk factor for dehydration was the low intake of water by mouth for several reasons, such as lack of autonomy, altered mental status, decreased sensation of thirst, social and environmental problems. To this may be added an increase in fluid loss caused by fever, vomiting, diarrhoea, bleeding etc., the use of diuretics or laxatives and the onset of diseases that induce an increase in the loss of urine (e.g. diabetes). This paper aims to locate a tool for assessing the risk among those reported in the literature that is easy to use for the nurse and to experiment with it on a sample of patients. METHODS: An analysis of the literature showed the reliability of an instrument for assessing the risk of dehydration by the name of "Dehydration Risk Appraisal Checklist." In order to verify its usefulness in identifying the risk of dehydration, 2 groups of elderly persons at the OU Geriatrics and long-term care unit of the Azienda USL of Piacenza and the OU complex Geriatric Clinic of the University Hospital of Parma were investigated. Patients in both groups were assessed on admission by the assessment scale MNA (Mini Nutritional Assessment) and by the sheet of quantitative evaluation of the meal consumed. One group was considered as the "control group". Patients belonging to the other group, which was regarded as the "experimental group", in addition to the two above-mentioned instruments, were also assessed by the "Dehydration risk appraisal checklist". In both groups, the presence or absence of four indicators of dehydration measured at the time of and immediately before discharge was then detected. In the presence of each indicator of dehydration one point was awarded for a comprehensive evaluation. The data collected were analyzed using a statistical method. RESULTS AND CONCLUSIONS: The results showed no statistically significant differences in the identification of the risk of dehydration in the two groups. It is believed, however, that the data will guide checklists to consider the above-mentioned instrument valid and useful in nursing practice in order to assess the risk of dehydration in older people and early detection of its onset and thus enable prompt and effective management. It will take more extensive studies of case studies to test this hypothesis. PMID- 26629669 TI - Cultural Competence Assessment Instrument: Initial Italian validation and proposed refinement. AB - BACKGROUND AND AIM OF THE WORK: Italy has become a target of immigration in the last three decades. Accordingly, the Italian population is progressively changing, becoming increasingly culturally different. Cultural competences are a fundamental requirement for many industries and, especially, for healthcare organizations. The aim of this paper is to propose an initial Italian validation of the Cultural Competence Assessment Instrument (CCAI) and to propose a refinement of this scale in terms of measured constructs. METHODS: The CCAI was translated into Italian through a team-based iterative approach and then administered to a sample of 289 nurses with symbolic and realistic threat scale and social dominance orientation scale. An on-line cross-sectional survey questionnaire was used. RESULTS: Confirmatory factor analysis revealed that the original two dimensions of the CCAI can be divided into two other sub-scales, thus leaving us with the following dimensions: cultural awareness, cultural sensitivity, seeking information and active behavior. These dimensions appeared to be sufficiently reliable and independent one from another. Moreover, they showed specific and different correlations with other measured constructs. CONCLUSIONS: The Italian version of the CCAI would seem to be a useful instrument for measuring both attitudes and behavioral intention of nurses with respect to intercultural care. Using four dimensions instead of two appears to increase the understanding of professionals' cultural competence and supply a deeper picture of dimensions which compose cultural competence in healthcare settings. PMID- 26629670 TI - Strategies for pain management: a review. AB - PROBLEM/BACKGROUND: Pain management is a major worldwide health problem. It manifests itself in a variety of forms involving in turn a multiplicity of responses and therapeutic strategies. Following from this, the training of health personnel must deal with this situation and must not only offer technical assistance, but must also deal with the psychological and social aspects of the problem. In recent years various guidelines and protocols have become popular for pain management. The aim of this paper is to present a literature review of the major international databases. Type of research: Systematic review. OBJECTIVE: To identify relevant studies in the literature on pain management and identify the guidelines recognized by the scientific community. MATERIALS AND METHODS: A literature search was conducted using the keywords "pain management" and "nurse" published since 2000 in English and Italian in the following databases: PubMed, CINAHL, Med Line. Excluding items which did not meet the inclusion criteria, 49 articles were included in the review. RESULTS: Despite a growing availability of evidence-based guidelines, drugs for pain control and the enactment of legislation to promote the use of opioid analgesics in pain therapy, a substantial proportion of the European population continues to have pain. Estimates of the prevalence of pain symptoms in the literature show that between 40% and 63% of hospitalized patients reported pain, peaking at 82.3% in cancer patients in advanced stages of the disease or terminally ill (in hospital or at home). Several studies published in recent years have agreed on a definition of some key points in the management of pain. Studies agree that pain should be recognized as the 5th vital sign, hence the need for validated scales whether single or multi-dimensional, quantitative or qualitative. The approach to the management of pain must be multi-professional, and the use of pharmacology must be in accordance with the WHO three-step approach. Several studies have demonstrated that communication and training of operators, associated with accurate information to patients, are effective elements to improve health care delivered to patients. These studies have led to the publication of guidelines by various scientific societies, indicating timely strategies for effective pain management both in hospital and in the territory. A possible development of this research could be to conduct a retrospective study in accordance with the AUDIT methodology so that we can check the implementation of guidelines and propose corrective actions to meet the defined standards. PMID- 26629671 TI - Targeting different RNA motifs by beta carboline alkaloid, harmalol: a comparative photophysical, calorimetric, and molecular docking approach. AB - RNA has attracted recent attention for its key role in gene expression and targeting by small molecules for therapeutic intervention. This work focuses towards understanding interaction of harmalol, a DNA intercalator, with RNAs of different motifs viz. single-stranded A-form poly(A), double-stranded A-form of poly(C).poly(G), and clover leaf tRNAphe by different spectroscopic, calorimetric, and molecular modeling techniques. Results of this study converge to suggest that (i) binding constant varied in the order poly(C).poly(G) > tRNAphe > poly(A), (ii) non-cooperative binding of harmalol to poly(C).poly(G) and poly(A) and cooperative binding with tRNAphe, (iii) significant structural changes of poly(C).poly(G) and tRNAphe with concomitant induction of optical activity in the bound achiral alkaloid molecules, while with poly(A) no induced Circular dichroism (CD) perturbation was observed, (iv) the binding was predominantly exothermic, enthalpy-driven, entropy-favored with poly(C).poly(G), while it was entropy driven with tRNAphe and poly(A), (v) a hydrophobic contribution and comparatively large role of non polyelectrolytic forces to Gibbs energy changes with poly(C).poly(G) and tRNAphe and (vi) intercalated state of harmalol inside poly(C).poly(G) structure as revealed from molecular docking was supported by the viscometric and ferrocyanide quenching data. All these findings unequivocally pointed out that harmalol prefers binding with poly(C).poly(G), compared to tRNAphe and poly(A); this results serve as data for the development of RNA-based antiviral drugs. PMID- 26629672 TI - Near or far: The effect of spatial distance and vocabulary knowledge on word learning. AB - The current study investigated the role of spatial distance in word learning. Two year-old children saw three novel objects named while the objects were either in close proximity to each other or spatially separated. Children were then tested on their retention for the name-object associations. Keeping the objects spatially separated from each other during naming was associated with increased retention for children with larger vocabularies. Children with a lower vocabulary size demonstrated better retention if they saw objects in close proximity to each other during naming. This demonstrates that keeping a clear view of objects during naming improves word learning for children who have already learned many words, but keeping objects within close proximal range is better for children at earlier stages of vocabulary acquisition. The effect of distance is therefore not equal across varying vocabulary sizes. The influences of visual crowding, cognitive load, and vocabulary size on word learning are discussed. PMID- 26629673 TI - An object memory bias induced by communicative reference. AB - In humans, a good proportion of knowledge, including knowledge about objects and object kinds, is acquired via social learning by direct communication from others. If communicative signals raise the expectation of social learning about objects, intrinsic (permanent) features that support object recognition are relevant to store into memory, while extrinsic (accidental) object properties can be ignored. We investigated this hypothesis by instructing participants to memorise shape-colour associations that constituted either an extrinsic object property (the colour of the box that contained the object, Experiment 1) or an intrinsic one (the colour of the object, Experiment 2). Compared to a non communicative context, communicative presentation of the objects impaired participants' performance when they recalled extrinsic object properties, while their incidental memory of the intrinsic shape-colour associations was not affected. Communicative signals had no effect on performance when the task required the memorisation of intrinsic object properties. The negative effect of communicative reference on the memory of extrinsic properties was also confirmed in Experiment 3, where this property was object location. Such a memory bias suggests that referent objects in communication tend to be seen as representatives of their kind rather than as individuals. PMID- 26629674 TI - Magnesium sulphate: too much of a good thing? PMID- 26629675 TI - Perioperative Anemia: How Low Can We Tolerate? PMID- 26629676 TI - Prevalence of Cognitive Impairment Without Dementia and Dementia in Tremembe, Brazil. AB - BACKGROUND: The prevalence of cognitive impairment is insufficiently determined in developing countries. The aim of this study was to ascertain the prevalence of cognitive impairment without dementia and dementia in community-dwelling elderly in Brazil. METHODS: This was a single-phase cross-sectional survey of the elderly (aged 60 years and above) living in the municipality of Tremembe, Brazil. Twenty percent of the households with elderly persons were randomly selected from urban and rural areas, to obtain a homogenous representation of all socioeconomic and cultural levels. RESULTS: We assessed 630 individuals [mean age, 71.3 y (+/ 7.99); mean years of education, 4.9 (+/-4.54)] and found prevalence rates of 17.5% (95% confidence interval, 14.6-20.6) for dementia and 19.5% (95% confidence interval, 16.6-22.8) for cognitive impairment without dementia. These prevalence rates were influenced by age (P<0.001) and by educational level (P<0.001). There was no significant sex difference among diagnostic groups (P=0.166). The prevalence of dementia was higher in relatively younger individuals (below 70 y) when compared with other studies. Besides, dementia was associated with low socioeconomic status, stroke, previous psychiatric disorder, alcoholism, and epilepsy. CONCLUSIONS: The prevalence of dementia in this study was higher than in other studies, particularly among younger elderly. PMID- 26629677 TI - Performance of Cerebrospinal Fluid Biomarkers of Alzheimer Disease in a Memory Clinic in Norway. AB - BACKGROUND: Although Alzheimer disease (AD) remains a clinical diagnosis, biomarkers are in use to support the diagnosis. Three cerebrospinal biomarkers, amyloid-beta (Abeta), total tau (T-tau), and phospho tau (P-tau), reflect neuropathologic changes observed in AD patients. OBJECTIVE: The aim of this study was to explore the performance of the cerebrospinal fluid biomarkers used in a memory clinic setting. METHODS: We included 205 patients who had been through a standardized examination including lumbar puncture. Diagnoses were made blind to the results of the spinal fluid analyses. RESULTS: By combining low Abeta and high T-tau or P-tau values, the sensitivity was 31.9% and the specificity was 92.5% when comparing patients with AD with other patients. In receiver operating characteristic analyses, the AUC for the Abeta was 0.78 (SE=0.04; 95% CI, 0.7 0.85), for T-tau 0.80 (SE=0.03; 95% CI, 0.73-0.86), and for P-tau 0.76 (SE=0.04; 95% CI, 0.69-0.83). A significant difference was found between the sexes, with higher values of Abeta among younger men (under 65 y of age) with AD [799.8 (SD=317.2) vs. 558.9 (SD=123.5) for women, P-value=0.003]. CONCLUSIONS: The present study found a lower performance of the biomarkers than reported previously. PMID- 26629678 TI - [Ge2](4-) Dumbbells with Very Short Ge-Ge Distances in the Zintl Phase Li3NaGe2: A Solid-State Equivalent to Molecular O2. AB - The novel ternary Zintl phase Li3NaGe2 comprises alkali-metal cations and [Ge2](4 ) dumbbells. The diatomic [Ge2](4-) unit is characterized by the shortest Ge-Ge distance (2.390(1) A) ever observed in a Zintl phase and thus represents the first Ge=Ge double bond under such conditions, as also suggested by the (8-N) rule. Raman measurements support these findings. The multiple-bond character is confirmed by electronic-structure calculations, and an upfield (6)Li NMR shift of -10.0 ppm, which was assigned to the Li cations surrounded by the pi systems of three Ge dumbbells, further underlines this interpretation. For the unperturbed, ligand-free dumbbell in Li3NaGe2, the pi- bonding py and pz orbitals are degenerate as in molecular oxygen, which has singly occupied orbitals. The partially filled pi-type bands of the neat solid Li3NaGe2 cross the Fermi level, resulting in metallic properties. Li3NaGe2 was synthesized from the elements as well as from binary reactants and subsequently characterized crystallographically. PMID- 26629680 TI - Stepwise Reduction of an alpha-Phosphonio-Carbocation to a Crystalline Phosphorus Radical Cation and an Acridinyl-Phosphorus Ylide. AB - We have synthesized the dicationic alpha-phosphonio-carbocation 1(2+) , which can be regarded as a two-electron oxidized phosphorus ylide. Carbocation 1(2+) exhibits two reversible reduction waves at -0.28 and -0.90 V (vs. Fc(+) /Fc) indicating that both the radical cation 1(.+) and the neural phosphorus ylide 1 can be generated. Indeed, reduction of 1(2+) with Zn afforded 1(.+) as a dark green solid that was characterized by XRD and EPR spectroscopy, and reduction with Mg(Ant)?(THF)3 gave 1, which was characterized by (1) H and (31) P NMR spectroscopy. Computational analyses reveal the stepwise population of a C-P pi bonding orbital upon reduction of 1(2+) . PMID- 26629682 TI - Uranium remobilization and migration evaluation through aerial spectrometric gamma technique in Syrian Desert (Area-1), Syria. AB - Uranium remobilization and migration in the Syrian Desert (Area-1) has been evaluated through analyzing the data of aerial spectrometric gamma technique and examining different radioactive geophysical approaches. The ten geological units identified on the already established scored map have been well characterized through analyzing their contents of eU, eTh, and K%, and studying the mutual relationships between those elements and their ratios. This is done in order to define the regional variation trends of the uranium migration in Area-1, and to evaluate the degree of uranium remobilization. The uranium potential in the studied Area-1 has been explained by applying and analyzing two prospecting indicators of the uranium favorability index UI and alteration-F. It was demonstrated that uranium remobilization took place in all the described lithological units, but to different degrees. The uranium migration and its haloes redistributions have been explained by establishing different plausible geological model interpretations. Several localities such as wadi Ratka are found to be favorable possible traps for uranium accumulation, which necessitate more further detailed uranium exploration. PMID- 26629683 TI - Ecological impacts of Al-Jalamid phosphate mining, Saudi Arabia: Soil elemental characterization and spatial distribution with INAA. AB - Phosphate (P) industries will be one of the main industrial sectors in Saudi Arabia within the next few years. Al-Jalamid phosphate mine, which started operation a few years ago, is one of the biggest mining locations in the Middle East region. It is planned to mine 12 million tons run of mine ore per year (Mty) and produce about 4.5 Mty of phosphate concentrate for the next 20 years. Long term ecological impacts of phosphate mining activities on soil and groundwater should be investigated. The contaminated soil acts as a long term source of environmental contamination. The main aim of this work was to shed more light on the elemental characterization and spatial distributions in soil areas located in the vicinity of the phosphate mining activities. A total of sixty eight surface and subsurface soil samples from 34 locations around Al-Jalamid phosphate mine have been collected. The elemental characterization of soil samples was achieved using instrumental neutron activation analysis (INAA). Pollution indices, geoaccumulation (I(geo)) and pollution load (PLI) indices were calculated from some elements to evaluate the soil pollution. Until now, there is no existing pre operational elemental characterization in soil to evaluate the foreseen ecological impacts of phosphate mining. Our results are the first to evaluate the present situation that will be the base for the future evaluations. The main aim of this work was to shed more light on the elemental characterization and spatial distributions in soil and their relation to phosphate mining activities, and to better understand the behavior of different elements in soil in an arid environment. PMID- 26629681 TI - Modulation of neuronal excitability by immune mediators in epilepsy. AB - A complex set of inflammatory molecules and their receptors has been described in epileptogenic foci in different forms of pharmacoresistant epilepsies. By activating receptor-mediated pathways in neurons, these molecules have profound neuromodulatory effects that are distinct from their canonical activation of immune functions. Importantly, the neuromodulatory actions of some inflammatory molecules contribute to hyperexcitability in neural networks that underlie seizures. This review summarizes recent findings related to the role of cytokines (IL-1beta and TNF-alpha) and danger signals (HMGB1) in decreasing seizure threshold, thereby contributing to seizure generation and the associated neuropathology. We will discuss preclinical studies suggesting that pharmacological inhibition of specific inflammatory signals may be useful to treat drug-resistant seizures in human epilepsy, and possibly arrest epileptogenesis in individuals at risk of developing the disease. PMID- 26629684 TI - Investigation of activation cross sections of proton induced reactions on indium up to 70 MeV for practical applications. AB - Excitation functions were measured for production of the (113,111,110)Sn, (115m,114m,113m,112m,111g,110g)In and (111m,109)Cd radioisotopes by bombardment of In targets with proton beams up to 70 MeV, some of them for the first time. The new results are compared with the earlier experimental data and with the theoretical data in the TENDL-2014 (Talys1.6 based) library. Thick target yields were deduced and application of the new data for production of medically relevant (110m)In,(111g)In,(113m)In and (114m)In, as well as applicability for thin layer activation (TLA) are discussed. PMID- 26629685 TI - Glycolytic metabolite methylglyoxal inhibits cold and menthol activation of the transient receptor potential melastatin type 8 channel. AB - Methylglyoxal (MG) is a reactive dicarbonyl compound involved in protein modifications linked to diabetes mellitus. The plasma level of MG is elevated in diabetic patients, particularly those with painful diabetic neuropathy. Diabetic neuropathy is often associated with spontaneous pain and altered thermal perception. This study assesses effects of MG on TRPM8, an ion channel involved in innocuous cold sensing and cold allodynia and also in cold-mediated analgesia. Acute treatment with MG inhibited the activation of recombinant rat and human transient receptor potential melastatin type 8 (TRPM8) by cold and chemical agonists. A similar effect was observed when native TRPM8 was investigated in cultured rat dorsal root ganglion (DRG) neurons. DRG neurons treated with MG for 16-24 hr displayed a significant reduction in the fraction of cold- and menthol sensitive neurons, most likely expressing TRPM8. The fraction of allyl isothiocyanate-sensitive neurons was also reduced, and the coexpression among different neuronal populations was affected. The same prolonged exposure to MG significantly reduced the expression of TRPM8 at the mRNA level. Overall, our data provide evidence for decreased activity and expression level of TRPM8 in the presence of MG, which may be linked to some of the alterations in pain and temperature sensing reported by diabetic patients. (c) 2015 Wiley Periodicals, Inc. PMID- 26629687 TI - Intraventricular Sialidase Administration Enhances GM1 Ganglioside Expression and Is Partially Neuroprotective in a Mouse Model of Parkinson's Disease. AB - BACKGROUND: Preclinical and clinical studies have previously shown that systemic administration of GM1 ganglioside has neuroprotective and neurorestorative properties in Parkinson's disease (PD) models and in PD patients. However, the clinical development of GM1 for PD has been hampered by its animal origin (GM1 used in previous studies was extracted from bovine brains), limited bioavailability, and limited blood brain barrier penetrance following systemic administration. OBJECTIVE: To assess an alternative therapeutic approach to systemic administration of brain-derived GM1 to enhance GM1 levels in the brain via enzymatic conversion of polysialogangliosides into GM1 and to assess the neuroprotective potential of this approach. METHODS: We used sialidase from Vibrio cholerae (VCS) to convert GD1a, GD1b and GT1b gangliosides to GM1. VCS was infused by osmotic minipump into the dorsal third ventricle in mice over a 4-week period. After the first week of infusion, animals received MPTP injections (20 mg/kg, s.c., twice daily, 4 hours apart, for 5 consecutive days) and were euthanized 2 weeks after the last injection. RESULTS: VCS infusion resulted in the expected change in ganglioside expression with a significant increase in GM1 levels. VCS-treated animals showed significant sparing of striatal dopamine (DA) levels and substantia nigra DA neurons following MPTP administration, with the extent of sparing of DA neurons similar to that achieved with systemic GM1 administration. CONCLUSION: The results suggest that enzymatic conversion of polysialogangliosides to GM1 may be a viable treatment strategy for increasing GM1 levels in the brain and exerting a neuroprotective effect on the damaged nigrostriatal DA system. PMID- 26629686 TI - Wnt/beta-catenin signaling plays a key role in the development of spondyloarthritis. AB - Spondyloarthritis (SpA) is a group of diseases consisting of psoriatic arthritis (PsA), reactive arthritis, arthritis related to inflammatory bowel disease (a subgroup of juvenile idiopathic arthritis), and ankylosing spondylitis (the prototype of SpA). Axial bone formation and the combination of concurrent erosion and new bone formation are specific characteristics of SpA disease. The use of antiproinflammatory cytokines, such as inhibitors of tumor necrosis factor alpha (TNF-alpha), appears to be the greatest advance in the treatment of SpA over the past 20 years. However, TNF-alpha blockers do not halt new bone formation. Recent clinical observations and animal studies demonstrate that Wnt signaling proteins and natural Wnt inhibitors, such as DKK1 and sclerostin, are likely to play important roles in the process of ankylosis in SpA, and could potentially serve as therapeutic targets for the treatment of SpA. PMID- 26629688 TI - Do Media Use and Physical Activity Compete in Adolescents? Results of the MoMo Study. AB - PURPOSE: The displacement hypothesis predicts that physical activity and media use compete in adolescents; however, findings are inconsistent. A more differentiated approach at determining the co-occurrence of physical activity and media use behaviors within subjects may be warranted. The aim of this study was to determine the co-occurrence of physical activity and media use by identifying clusters of adolescents with specific behavior patterns including physical activity in various settings (school, sports club, leisure time) and different types of media use (watching TV, playing console games, using PC / Internet). METHODS: Cross-sectional data of 2,083 adolescents (11-17 years) from all over Germany were collected between 2009 and 2012 in the Motorik-Modul Study. Physical activity and media use were self-reported. Cluster analyses (Ward's method and K means analysis) were used to identify behavior patterns of boys and girls separately. RESULTS: Eight clusters were identified for boys and seven for girls. The clusters demonstrated that a high proportion of boys (33%) as well as girls (42%) show low engagement in both physical activity and media use, irrespective of setting or type of media. Other adolescents are engaged in both behaviors, but either physical activity (35% of boys, 27% of girls) or media use (31% of boys and girls) predominates. These adolescents belong to different clusters, whereat in most clusters either one specific setting of physical activity or a specific combination of different types of media predominates. CONCLUSION: The results of this study support to some extent the hypothesis that media use and physical activity compete: Very high media use occurred with low physical activity behavior, but very high activity levels co-occurred with considerable amounts of time using any media. There was no evidence that type of used media was related to physical activity levels, neither setting of physical activity was related to amount of media use in any pattern. PMID- 26629689 TI - Molecular Dynamics Simulations of Insulin: Elucidating the Conformational Changes that Enable Its Binding. AB - A sequence of complex conformational changes is required for insulin to bind to the insulin receptor. Recent experimental evidence points to the B chain C terminal (BC-CT) as the location of these changes in insulin. Here, we present molecular dynamics simulations of insulin that reveal new insights into the structural changes occurring in the BC-CT. We find three key results: 1) The opening of the BC-CT is inherently stochastic and progresses through an open and then a "wide-open" conformation--the wide-open conformation is essential for receptor binding, but occurs only rarely. 2) The BC-CT opens with a zipper-like mechanism, with a hinge at the Phe24 residue, and is maintained in the dominant closed/inactive state by hydrophobic interactions of the neighboring Tyr26, the critical residue where opening of the BC-CT (activation of insulin) is initiated. 3) The mutation Y26N is a potential candidate as a therapeutic insulin analogue. Overall, our results suggest that the binding of insulin to its receptor is a highly dynamic and stochastic process, where initial docking occurs in an open conformation and full binding is facilitated through interactions of insulin receptor residues with insulin in its wide-open conformation. PMID- 26629690 TI - Rose Prickles and Asparagus Spines--Different Hook Structures as Attachment Devices in Climbing Plants. AB - Functional morphology and biomechanical properties of hook structures functioning as attachment devices in the leaning climbers Rosa arvensis, Rosa arvensis 'Splendens', Asparagus falcatus and Asparagus setaceus are analysed in order to investigate the variability in closely related species as well as convergent developments of hook structure and properties in distant systematic lineages (monocots and dicots). Prickles and spines were characterised by their size, orientation and the maximum force measured at failure in mechanical tests performed with traction forces applied at different angles. In Rosa arvensis and Rosa arvensis 'Splendens' three types of prickles differing largely in geometrical and mechanical properties are identified (prickles of the wild species and two types of prickles in the cultivar). In prickles of Rosa arvensis no particular orientation of the prickle tip is found whereas in the cultivar Rosa arvensis 'Splendens' prickles gradually gain a downward-orientation due to differential growth in the first weeks of their development. Differences in mechanical properties and modes of failure are correlated to geometrical parameters. In Asparagus falcatus and Asparagus setaceus spines are composed of leaf tissue, stem tissue and tissue of the axillary bud. Between species spines differ in size, orientation, distribution along the stem, tissue contributions and mechanical properties. The prickles of Rosa arvensis and its cultivar and the spines of the studied Asparagus species have several traits in common: (1) a gradual change of cell size and cell wall thickness, with larger cells in the centre and smaller thick-walled cells at the periphery of the hooks, (2) occurrence of a diversity of shape and geometry within one individual, (3) failure of single hooks when submitted to moderate mechanical stresses (Fmax/basal area < 35 N/mm2) and (4) failure of the hooks without severe stem damage (at least in the tested wild species). PMID- 26629691 TI - Deep Sequencing and Bioinformatic Analysis of Lesioned Sciatic Nerves after Crush Injury. AB - The peripheral nerve system has an intrinsic regenerative capacity in response to traumatic injury. To better understand the molecular events occurring after peripheral nerve injury, in the current study, a rat model of sciatic nerve crush injury was used. Injured nerves harvested at 0, 1, 4, 7, and 14 days post injury were subjected to deep RNA sequencing for examining global gene expression changes. According to the temporally differential expression patterns of a huge number of genes, 3 distinct phases were defined within the post-injury period of 14 days: the acute, sub-acute, and post-acute stages. Each stage showed its own characteristics of gene expression, which were associated with different categories of diseases and biological functions and canonical pathways. Ingenuity pathway analysis revealed that genes involved in inflammation and immune response were significantly up-regulated in the acute phase, and genes involved in cellular movement, development, and morphology were up-regulated in the sub-acute stage, while the up-regulated genes in the post-acute phase were mainly involved in lipid metabolism, cytoskeleton reorganization, and nerve regeneration. All the data obtained in the current study may help to elucidate the molecular mechanisms underlying peripheral nerve regeneration from the perspective of gene regulation, and to identify potential therapeutic targets for the treatment of peripheral nerve injury. PMID- 26629693 TI - Correction: Correction: Induction of TLR-2 and TLR-5 Expression by Helicobacter pylori Switches cagPAI-Dependent Signalling Leading to the Secretion of IL-8 and TNF-alpha. PMID- 26629692 TI - From Squid to Mammals with the HH Model through the Nav Channels' Half-Activation Voltage Parameter. AB - The model family analyzed in this work stems from the classical Hodgkin-Huxley model (HHM). for a single-compartment (space-clamp) and continuous variation of the voltage-gated sodium channels (Nav) half-activation-voltage parameter DeltaV1/2, which controls the window of sodium-influx currents. Unlike the baseline HHM, its parametric extension exhibits a richer multitude of dynamic regimes, such as multiple fixed points (FP's), bi- and multi-stability (coexistence of FP's and/or periodic orbits). Such diversity correlates with a number of functional properties of excitable neural tissue, such as the capacity or not to evoke an action potential (AP) from the resting state, by applying a minimal absolute rheobase current amplitude. The utility of the HHM rooted in the giant squid for the descriptions of the mammalian nervous system is of topical interest. We conclude that the model's fundamental principles are still valid (up to using appropriate parameter values) for warmer-blooded species, without a pressing need for a substantial revision of the mathematical formulation. We demonstrate clearly that the continuous variation of the DeltaV1/2 parameter comes close to being equivalent with recent HHM 'optimizations'. The neural dynamics phenomena described here are nontrivial. The model family analyzed in this work contains the classical HHM as a special case. The validity and applicability of the HHM to mammalian neurons can be achieved by picking the appropriate DeltaV1/2 parameter in a significantly broad range of values. For such large variations, in contrast to the classical HHM, the h and n gates' dynamics may be uncoupled--i.e. the n gates may no longer be considered in mere linear correspondence to the h gates. DeltaV1/2 variation leads to a multitude of dynamic regimes--e.g. models with either 1 fixed point (FP) or with 3 FP's. These may also coexist with stable and/or unstable periodic orbits. Hence, depending on the initial conditions, the system may behave as either purely excitable or as an oscillator. DeltaV1/2 variation leads to significant changes in the metabolic efficiency of an action potential (AP). Lower DeltaV1/2 values yield a larger range of AP response frequencies, and hence provide for more flexible neural coding. Such lower values also contribute to faster AP conduction velocities along neural fibers of otherwise comparable-diameter. The 3 FP case brings about an absolute rheobase current. In comparison in the classical HHM the rheobase current is only relative--i.e. excitability is lost after a finite amount of elapsed stimulation time. Lower DeltaV1/2 values translate in lower threshold currents from the resting state. PMID- 26629694 TI - The Role of Family Environment in Depressive Symptoms among University Students: A Large Sample Survey in China. AB - OBJECTIVE: To explore the relationship between family environment and depressive symptoms and to evaluate the influence of hard and soft family environmental factors on depression levels in a large sample of university students in China. METHODS: A multi-stage stratified sampling procedure was used to select 6,000 participants. The response rate was 88.8%, with 5,329 students completing the Beck Depression Inventory (BDI) and the Family Environment Scale Chinese Version (FES-CV), which was adapted for the Chinese population. Differences between the groups were tested for significance by the Student's t-test; ANOVA was used to test continuous variables. The relationship between soft family environmental factors and BDI were tested by Pearson correlation analysis. Hierarchical linear regression analysis was conducted to model the effects of hard environmental factors and soft environmental factors on depression in university students. RESULTS: A total of 11.8% of students scored above the threshold of moderate depression (BDI?14). Hard family environmental factors such as parent relationship, family economic status, level of parental literacy and non-intact family structure were associated with depressive symptoms. The soft family environmental factors--conflict and control--were positively associated with depression, while cohesion was negatively related to depressive symptom after controlling for other important associates of depression. Hierarchical regression analysis indicated that the soft family environment correlates more strongly with depression than the hard family environment. CONCLUSIONS: Soft family environmental factors--especially cohesion, conflict and control--appeared to play an important role in the occurrence of depressive symptoms. These findings underline the significance of the family environment as a source of risk factors for depression among university students in China and suggest that family-based interventions and improvement are very important to reduce depression among university students. PMID- 26629695 TI - Seasonal Patterns of Soil Respiration and Related Soil Biochemical Properties under Nitrogen Addition in Winter Wheat Field. AB - Understanding the changes of soil respiration under increasing N fertilizer in cropland ecosystems is crucial to accurately predicting global warming. This study explored seasonal variations of soil respiration and its controlling biochemical properties under a gradient of Nitrogen addition during two consecutive winter wheat growing seasons (2013-2015). N was applied at four different levels: 0, 120, 180 and 240 kg N ha(-1) year(-1) (denoted as N0, N12, N18 and N24, respectively). Soil respiration exhibited significant seasonal variation and was significantly affected by soil temperature with Q10 ranging from 2.04 to 2.46 and from 1.49 to 1.53 during 2013-2014 and 2014-2015 winter wheat growing season, respectively. Soil moisture had no significant effect on soil respiration during 2013-2014 winter wheat growing season but showed a significant and negative correlation with soil respiration during 2014-2015 winter wheat growing season. Soil respiration under N24 treatment was significantly higher than N0 treatment. Averaged over the two growing seasons, N12, N18 and N24 significantly increased soil respiration by 13.4, 16.4 and 25.4% compared with N0, respectively. N addition also significantly increased easily extractable glomalin-related soil protein (EEG), soil organic carbon (SOC), total N, ammonium N and nitrate N contents. In addition, soil respiration was significantly and positively correlated with beta-glucosidase activity, EEG, SOC, total N, ammonium N and nitrate N contents. The results indicated that high N fertilization improved soil chemical properties, but significantly increased soil respiration. PMID- 26629696 TI - Muscle Regeneration with Intermuscular Adipose Tissue (IMAT) Accumulation Is Modulated by Mechanical Constraints. AB - Sports trauma are able to induce muscle injury with fibrosis and accumulation of intermuscular adipose tissue (IMAT), which affect muscle function. This study was designed to investigate whether hypoactivity would influence IMAT accumulation in regenerating mouse skeletal muscle using the glycerol model of muscle regeneration. The animals were immediately hindlimb unloaded for 21 days after glycerol injection into the tibialis anterior (TA) muscle. Muscle fiber and adipocyte cross-sectional area (CSA) and IMAT accumulation were determined by histomorphometric analysis. Adipogenesis during regenerative processes was examined using RT-qPCR and Western blot quantification. Twenty-one days of hindlimb unloading resulted in decreases of 38% and 50.6% in the muscle weight/body weight ratio and CSA, respectively, in soleus muscle. Glycerol injection into TA induced IMAT accumulation, reaching 3% of control normal loading muscle area. This IMAT accumulation was largely inhibited in unloading conditions (0.09%) and concomitant with a marked reduction in perilipin and FABP4 protein content, two key markers of mature adipocytes. Induction of PPARgamma and C/EBPalpha mRNA, two markers of adipogenesis, was also decreased. Furthermore, the protein expression of PDGFRalpha, a cell surface marker of fibro/adipogenic progenitors, was much lower in regenerating TA from the unloaded group. Exposure of regenerating muscle to hypoactivity severely reduces IMAT development and accumulation. These results provide new insight into the mechanisms regulating IMAT development in skeletal muscle and highlight the importance of taking into account the level of mechanical constraint imposed on skeletal muscle during the regeneration processes. PMID- 26629697 TI - The Immunomodulatory Activity of Jacaric Acid, a Conjugated Linolenic Acid Isomer, on Murine Peritoneal Macrophages. AB - This study aims at demonstrating the immunomodulatory property of jacaric acid, a conjugated linolenic acid (CLNA) isomer that is present in jacaranda seed oil, on murine peritoneal macrophages. Our results showed that jacaric acid exhibited no significant cytotoxicity on the thioglycollate-elicited murine peritoneal macrophages as revealed by the neutral red uptake assay, but markedly increased their cytostatic activity on the T-cell lymphoma MBL-2 cells as measured by the fluorometric CyQuant(r) NF Cell Proliferation Assay Kit. Flow cytometric analysis indicated that jacaric acid could enhance the endocytic activity of macrophages and elevated their intracellular production of superoxide anion. Moreover, jacaric acid-treated macrophages showed an increase in the production of nitric oxide which was accompanied by an increase in the expression level of inducible nitric oxide synthase protein. In addition, the secretion of several pro inflammatory cytokines, including interferon-gamma, interleukin-1beta and tumor necrosis factor-alpha, was up-regulated. Collectively, our results indicated that the naturally-occurring CLNA isomer, jacaric acid, could exhibit immunomodulating activity on the murine peritoneal macrophages in vitro, suggesting that this CLNA isomer may act as an immunopotentiator which can be exploited for the treatment of some immunological disorders with minimal toxicity and fewer side effects. PMID- 26629698 TI - Senescence-Derived Extracellular Molecules as Modulators of Oral Cancer Development: A Mini-Review. AB - Oral cancers are predominantly oral squamous cell carcinomas (OSCCs) derived from keratinocytes, and there is now very detailed knowledge of the genetics and molecular biology of the epithelial tumourigenic component of these cancers, including the identification of cancer stem or tumour-initiating cells. Several key genetic alterations have been identified including the near ubiquitous loss of the CDKN2A/p16INK4A and p53 pathways and telomerase activation, together with frequent inactivation of the NOTCH1 canonical pathway either by somatic genetic alterations or by the presence of human papilloma virus. There is also evidence that OSCCs arise from a 'field' of altered cells and that malignant conversion takes place pre-dominantly at the microscopic level. However, in the last decade, it has been realised that tumour development and progression are influenced by the cells of the microenvironment with cross-talk between the epithelial (tumour) and mesenchymal components. OSCCs, especially those that have bypassed cellular senescence, produce an array of proteins and metabolites that induce cellular senescence in the normal surrounding cells; indeed, senescence is a common property of cancer-associated fibroblasts (CAFs). Cellular senescence is defined as an irreversible cell cycle arrest and is associated with the release of molecules known as the senescence-associated secretory phenotype that can selectively promote the growth of pre-neoplastic keratinocytes (osteopontin) and cancer invasion (transforming growth factor beta, matrix metalloproteinases, interleukin 6 and lactate). In addition, both old and new work has shown that keratinocytes harbouring NOTCH loss-of-function mutations that lead to defective keratinocyte differentiation and loss of squamous epithelial barrier function may act as a tumour-promoting stimulus for initiated cells harbouring RAS pathway mutations by activating a wound response in the tumour mesenchyme. Thus, not all keratinocytes in the tumour tissue may be tumourigenic and may instead act as promoters of tumour growth and progression analogous to the much-studied CAFs which co-evolve with the genetically altered tumourigenic cells. This new data is discussed in relation to attempts to develop novel non-invasive diagnostics and therapeutics for oral cancer. PMID- 26629699 TI - Easy and Rapid Detection of Mumps Virus by Live Fluorescent Visualization of Virus-Infected Cells. AB - Mumps viruses show diverse cytopathic effects (CPEs) of infected cells and viral plaque formation (no CPE or no plaque formation in some cases) depending on the viral strain, highlighting the difficulty in mumps laboratory studies. In our previous study, a new sialidase substrate, 2-(benzothiazol-2-yl)-4-bromophenyl 5 acetamido-3,5-dideoxy-alpha-D-glycero-D-galacto-2-nonulopyranosidonic acid (BTP3 Neu5Ac), was developed for visualization of sialidase activity. BTP3-Neu5Ac can easily and rapidly perform histochemical fluorescent visualization of influenza viruses and virus-infected cells without an antiviral antibody and cell fixation. In the present study, the potential utility of BTP3-Neu5Ac for rapid detection of mumps virus was demonstrated. BTP3-Neu5Ac could visualize dot-blotted mumps virus, virus-infected cells, and plaques (plaques should be called focuses due to staining of infected cells in this study), even if a CPE was not observed. Furthermore, virus cultivation was possible by direct pick-up from a fluorescent focus. In conventional methods, visible appearance of the CPE and focuses often requires more than 6 days after infection, but the new method with BTP3-Neu5Ac clearly visualized infected cells after 2 days and focuses after 4 days. The BTP3 Neu5Ac assay is a precise, easy, and rapid assay for confirmation and titration of mumps virus. PMID- 26629700 TI - Leg and Joint Stiffness in Children with Spastic Diplegic Cerebral Palsy during Level Walking. AB - Individual joint deviations are often identified in the analysis of cerebral palsy (CP) gait. However, knowledge is limited as to how these deviations affect the control of the locomotor system as a whole when striving to meet the demands of walking. The current study aimed to bridge the gap by describing the control of the locomotor system in children with diplegic CP in terms of their leg stiffness, both skeletal and muscular components, and associated joint stiffness during gait. Twelve children with spastic diplegia CP and 12 healthy controls walked at a self-selected pace in a gait laboratory while their kinematic and forceplate data were measured and analyzed during loading response, mid-stance, terminal stance and pre-swing. For calculating the leg stiffness, each of the lower limbs was modeled as a non-linear spring, connecting the hip joint center and the corresponding center of pressure, with varying stiffness that was calculated as the slope (gradient) of the axial force vs. the deformation curve. The leg stiffness was further decomposed into skeletal and muscular components considering the alignment of the lower limb. The ankle, knee and hip of the limb were modeled as revolute joints with torsional springs whose stiffness was calculated as the slope of the moment vs. the angle curve of the joint. Independent t-tests were performed for between-group comparisons of all the variables. The CP group significantly decreased the leg stiffness but increased the joint stiffness during stance phase, except during terminal stance where the leg stiffness was increased. They appeared to rely more on muscular contributions to achieve the required leg stiffness, increasing the muscular demands in maintaining the body posture against collapse. Leg stiffness plays a critical role in modulating the kinematics and kinetics of the locomotor system during gait in the diplegic CP. PMID- 26629701 TI - Association between Time on Protease Inhibitors and the Incidence of Squamous Cell Carcinoma of the Anus among U.S. Male Veterans. AB - Protease inhibitors (PIs) have been shown to have anti-tumor activity in addition to their antiretroviral properties. We sought to assess the association between PI use and the incidence of squamous cell carcinoma of the anus (SCCA) in HIV infected individuals. We performed a retrospective cohort study among male US veterans diagnosed with HIV who were diagnosed between 1985 and 2010, using the Veterans Affairs HIV Clinical Case Registry (CCR). We calculated hazards ratios associated with PI use (both as percent time on PI and as 12-month intervals of PI use), utilizing time-dependent Cox models. We adjusted for risk factors, including age, race, year of enrolment into CCR, recent and nadir CD4, and percent time undetectable HIV viral load. A total of 28, 886 HIV-infected men met inclusion criteria. Of these, 373 were newly diagnosed with SCCA during the study period. In multivariate analysis, increasing percent time on PIs was associated with an increased risk of SCCA (aHR 1.07; 95% CI = 1.03-1.10 per 10% increase in time on PI). Poor immunologic recovery and virologic control, a history of condylomata acuminata, and CCR enrolment in the late combined antiretroviral therapy era were also associated with increased SCCA risk. Increasing percent time on a PI-based combined antiretroviral therapy regimen may be associated with an increased risk of developing SCCA in HIV-infected male US veterans. Future studies, better accounting for HIV control and treatment compliance, are necessary to further clarify this association. PMID- 26629702 TI - Size Scaling in Western North Atlantic Loggerhead Turtles Permits Extrapolation between Regions, but Not Life Stages. AB - INTRODUCTION: Sea turtles face threats globally and are protected by national and international laws. Allometry and scaling models greatly aid sea turtle conservation and research, and help to better understand the biology of sea turtles. Scaling, however, may differ between regions and/or life stages. We analyze differences between (i) two different regional subsets and (ii) three different life stage subsets of the western North Atlantic loggerhead turtles by comparing the relative growth of body width and depth in relation to body length, and discuss the implications. RESULTS AND DISCUSSION: Results suggest that the differences between scaling relationships of different regional subsets are negligible, and models fitted on data from one region of the western North Atlantic can safely be used on data for the same life stage from another North Atlantic region. On the other hand, using models fitted on data for one life stage to describe other life stages is not recommended if accuracy is of paramount importance. In particular, young loggerhead turtles that have not recruited to neritic habitats should be studied and modeled separately whenever practical, while neritic juveniles and adults can be modeled together as one group. Even though morphometric scaling varies among life stages, a common model for all life stages can be used as a general description of scaling, and assuming isometric growth as a simplification is justified. In addition to linear models traditionally used for scaling on log-log axes, we test the performance of a saturating (curvilinear) model. The saturating model is statistically preferred in some cases, but the accuracy gained by the saturating model is marginal. PMID- 26629704 TI - Detection of Heart Sounds in Children with and without Pulmonary Arterial Hypertension--Daubechies Wavelets Approach. AB - BACKGROUND: Automatic detection of the 1st (S1) and 2nd (S2) heart sounds is difficult, and existing algorithms are imprecise. We sought to develop a wavelet based algorithm for the detection of S1 and S2 in children with and without pulmonary arterial hypertension (PAH). METHOD: Heart sounds were recorded at the second left intercostal space and the cardiac apex with a digital stethoscope simultaneously with pulmonary arterial pressure (PAP). We developed a Daubechies wavelet algorithm for the automatic detection of S1 and S2 using the wavelet coefficient 'D6' based on power spectral analysis. We compared our algorithm with four other Daubechies wavelet-based algorithms published by Liang, Kumar, Wang, and Zhong. We annotated S1 and S2 from an audiovisual examination of the phonocardiographic tracing by two trained cardiologists and the observation that in all subjects systole was shorter than diastole. RESULTS: We studied 22 subjects (9 males and 13 females, median age 6 years, range 0.25-19). Eleven subjects had a mean PAP < 25 mmHg. Eleven subjects had PAH with a mean PAP >= 25 mmHg. All subjects had a pulmonary artery wedge pressure <= 15 mmHg. The sensitivity (SE) and positive predictivity (+P) of our algorithm were 70% and 68%, respectively. In comparison, the SE and +P of Liang were 59% and 42%, Kumar 19% and 12%, Wang 50% and 45%, and Zhong 43% and 53%, respectively. Our algorithm demonstrated robustness and outperformed the other methods up to a signal-to noise ratio (SNR) of 10 dB. For all algorithms, detection errors arose from low amplitude peaks, fast heart rates, low signal-to-noise ratio, and fixed thresholds. CONCLUSION: Our algorithm for the detection of S1 and S2 improves the performance of existing Daubechies-based algorithms and justifies the use of the wavelet coefficient 'D6' through power spectral analysis. Also, the robustness despite ambient noise may improve real world clinical performance. PMID- 26629703 TI - Human Metapneumovirus Is Capable of Entering Cells by Fusion with Endosomal Membranes. AB - Human metapneumovirus (HMPV), a member of the Paramyxoviridae family, is a leading cause of lower respiratory illness. Although receptor binding is thought to initiate fusion at the plasma membrane for paramyxoviruses, the entry mechanism for HMPV is largely uncharacterized. Here we sought to determine whether HMPV initiates fusion at the plasma membrane or following internalization. To study the HMPV entry process in human bronchial epithelial (BEAS-2B) cells, we used fluorescence microscopy, an R18-dequenching fusion assay, and developed a quantitative, fluorescence microscopy assay to follow virus binding, internalization, membrane fusion, and visualize the cellular site of HMPV fusion. We found that HMPV particles are internalized into human bronchial epithelial cells before fusing with endosomes. Using chemical inhibitors and RNA interference, we determined that HMPV particles are internalized via clathrin-mediated endocytosis in a dynamin-dependent manner. HMPV fusion and productive infection are promoted by RGD-binding integrin engagement, internalization, actin polymerization, and dynamin. Further, HMPV fusion is pH-independent, although infection with rare strains is modestly inhibited by RNA interference or chemical inhibition of endosomal acidification. Thus, HMPV can enter via endocytosis, but the viral fusion machinery is not triggered by low pH. Together, our results indicate that HMPV is capable of entering host cells by multiple pathways, including membrane fusion from endosomal compartments. PMID- 26629705 TI - The Cytochrome bd Oxidase of Porphyromonas gingivalis Contributes to Oxidative Stress Resistance and Dioxygen Tolerance. AB - Porphyromonas gingivalis is an etiologic agent of periodontal disease in humans. The disease is associated with the formation of a mixed oral biofilm which is exposed to oxygen and environmental stress, such as oxidative stress. To investigate possible roles for cytochrome bd oxidase in the growth and persistence of this anaerobic bacterium inside the oral biofilm, mutant strains deficient in cytochrome bd oxidase activity were characterized. This study demonstrated that the cytochrome bd oxidase of Porphyromonas gingivalis, encoded by cydAB, was able to catalyse O2 consumption and was involved in peroxide and superoxide resistance, and dioxygen tolerance. PMID- 26629706 TI - Environmental Predictors of US County Mortality Patterns on a National Basis. AB - A growing body of evidence has found that mortality rates are positively correlated with social inequalities, air pollution, elevated ambient temperature, availability of medical care and other factors. This study develops a model to predict the mortality rates for different diseases by county across the US. The model is applied to predict changes in mortality caused by changing environmental factors. A total of 3,110 counties in the US, excluding Alaska and Hawaii, were studied. A subset of 519 counties from the 3,110 counties was chosen by using systematic random sampling and these samples were used to validate the model. Step-wise and linear regression analyses were used to estimate the ability of environmental pollutants, socio-economic factors and other factors to explain variations in county-specific mortality rates for cardiovascular diseases, cancers, chronic obstructive pulmonary disease (COPD), all causes combined and lifespan across five population density groups. The estimated models fit adequately for all mortality outcomes for all population density groups and, adequately predicted risks for the 519 validation counties. This study suggests that, at local county levels, average ozone (0.07 ppm) is the most important environmental predictor of mortality. The analysis also illustrates the complex inter-relationships of multiple factors that influence mortality and lifespan, and suggests the need for a better understanding of the pathways through which these factors, mortality, and lifespan are related at the community level. PMID- 26629708 TI - Manipulation resolves non-trivial structure of corrole monolayer on Ag(111). AB - Non-trivial arrangement of molecules within a molecular network complicates structure determination due to interdigitation, partial overlap, or stacking. We demonstrate that combined imaging and lateral manipulation with a scanning tunneling microscope resolves the intricate structure of a molecular network in two-dimensions in a straightforward manner. The network, formed by a monolayer of 5,10,15-tris(pentafluorophenyl)-corrole molecules on Ag(111), is manipulated for the first time with single-molecule precision. Our results reveal a shingle-like packing of partially overlapping corrole molecules. Density functional theory calculations support our findings. PMID- 26629707 TI - A Randomized Controlled Trial on The Beneficial Effects of Training Letter-Speech Sound Integration on Reading Fluency in Children with Dyslexia. AB - A recent account of dyslexia assumes that a failure to develop automated letter speech sound integration might be responsible for the observed lack of reading fluency. This study uses a pre-test-training-post-test design to evaluate the effects of a training program based on letter-speech sound associations with a special focus on gains in reading fluency. A sample of 44 children with dyslexia and 23 typical readers, aged 8 to 9, was recruited. Children with dyslexia were randomly allocated to either the training program group (n = 23) or a waiting list control group (n = 21). The training intensively focused on letter-speech sound mapping and consisted of 34 individual sessions of 45 minutes over a five month period. The children with dyslexia showed substantial reading gains for the main word reading and spelling measures after training, improving at a faster rate than typical readers and waiting-list controls. The results are interpreted within the conceptual framework assuming a multisensory integration deficit as the most proximal cause of dysfluent reading in dyslexia. TRIAL REGISTRATION: ISRCTN register ISRCTN12783279. PMID- 26629709 TI - Synthetic Phenolic Antioxidants and Their Metabolites in Indoor Dust from Homes and Microenvironments. AB - Synthetic phenolic antioxidants (SPAs), including 2,6-di-tert-butyl-4 hydroxytoluene (BHT), are extensively used in food, cosmetic and plastic industries. Nevertheless, limited information is available on human exposures, other than the dietary sources, to SPAs. In this study, occurrence of 9 SPAs and their metabolites/degradation products was determined in 339 indoor dust collected from 12 countries. BHT was found in 99.5% of indoor dust samples from homes and microenvironments at concentrations that ranged from < LOQ to 118 MUg/g and 0.10 to 3460 MUg/g, respectively. This is the first study to measure BHT metabolites in house dust (0.01-35.1 MUg/g) and their concentrations accounted for 9.2-58% of the sum concentrations (?SPAs). 3,5-di-tert-butyl-4 hydroxybenzaldehyde (BHT-CHO), 2,6-di-tert-butyl-4-(hydroxymethyl)phenol (BHT OH), 2,6-di-tert-butyl-1,4-benzoquinone (BHT-Q) were the major derivatives of BHT found in dust samples. The concentrations of gallic acid esters (gallates) in dust from homes and microenvironments ranged from < LOQ to 18.2 and < LOQ to 684 MUg/g, respectively. The concentrations and profiles of SPAs varied among countries and microenvironments. Significantly elevated concentrations of SPAs were found in dust from an e-waste workshop (1530 MUg/g). The estimated daily intake (EDI) of BHT via house dust ingestion ranged from 0.40 to 222 ng/kg/d (95th percentile). PMID- 26629710 TI - Reduction Responsive Self-Assembled Nanoparticles Based on Disulfide-Linked Drug Drug Conjugate with High Drug Loading and Antitumor Efficacy. AB - Most anticancer drugs are poorly soluble and nonspecific, which restricts their clinical application. Drug conjugates, as a prodrug strategy, provide the possibility to overcome these shortcomings, especially combined with nanotechnology. Drug conjugate nanoparticles possess the advantages of high drug loading capacity and passive tumor targeting ability. Here, we prepared doxorubicin drug-drug conjugate nanoparticles (DOX-SS-DOX NPs) based on disulfide linked doxorubicin drug-drug conjugate (DOX-SS-DOX). Dynamic light scattering (DLS) and transmission electron microscope (TEM) characterization indicated that DOX-SS-DOX NPs were spherical with a uniform size distribution around 89 nm. DLS and in vitro release experiment revealed that DOX-SS-DOX NPs possessed reduction responsive activity. In vitro cellular uptake studies reflected that DOX-SS-DOX NPs could increase the uptake level substantially compared with DOX liposomes. Endocytosis mechanism assay demonstrated that DOX-SS-DOX NPs internalized into cells through a clathrin-mediated endocytosis pathway in an energy-dependent manner. In this manner, the amidase in lysosomes could break the amide bond to release free DOX, which would be helpful to antitumor activity. The in vitro cytotoxicity of DOX-SS-DOX NPs was a bit weaker than that of DOX liposomes, which might be the result of the slow cleavage of the disulfide bridge; but the antitumor efficacy of DOX-SS-DOX NPs evaluated in MCF-7 bearing mice was demonstrated to be higher than that of DOX liposomes. This might be because of the long lasting effect resulting from the slow cleavage of the disulfide bond. In summary, DOX-SS-DOX NPs, prepared nearly totally with drug, provide a good strategy for cancer therapy. PMID- 26629711 TI - Hidden Hydration Structure of Halide Ions: an Insight into the Importance of Lone Pairs. AB - An elusive tetrahedral hydration structure for bromide in aqueous solution has been unveiled through the use of ab initio molecular dynamics. It has been revealed that a subset of first shell water molecules has a preferential strong interaction with the ion lone pairs, giving rise to a tetrahedral short-lived complex. Through the use of a new geometric descriptor correlated to the ion water pair interaction energy, we managed to divide the conventional first hydration shell into a tight first shell and a loose first shell, highlighting their different structural and dynamic behavior. This picture suggests the mandatory role of lone pairs in the study of highly disordered systems where the hydrogen bond is the most relevant interaction in the solvation process, such as weakly hydrated anions. This interaction-based approach leads to an improvement in the description of halide hydration given up to now by radial models. PMID- 26629712 TI - Dehydration of Ions in Voltage-Gated Carbon Nanopores Observed by in Situ NMR. AB - Ion transport through nanochannels is of fundamental importance in voltage-gated protein ion channels and energy storage devices. Direct microscopic observations are critical for understanding the intricacy of ionic processes in nanoconfinement. Here we report an in situ nuclear magnetic resonance study of ion hydration in voltage-gated carbon nanopores. Nucleus-independent chemical shift was employed to monitor the ionic processes of NaF aqueous electrolyte in nanopores of carbon supercapacitors. The state of ion hydration was revealed by the chemical shift, which is sensitive to the hydration number. A large energy barrier was observed for ions to enter nanopores smaller than the hydrated ion size. Increasing the gating voltage above 0.4 V overcomes this barrier and brings F(-) into the nanopores without dehydration. Partial dehydration of F(-) occurs only at gating voltage above 0.7 V. No dehydration was observed for Na(+) cations, in agreement with their strong ion hydration. PMID- 26629714 TI - Oral Pemphigus Vulgaris in Pregnancy. PMID- 26629713 TI - [(18)F]Fluorobenzoyllysinepentanedioic Acid Carbamates: New Scaffolds for Positron Emission Tomography (PET) Imaging of Prostate-Specific Membrane Antigen (PSMA). AB - Radiolabeled urea-based low-molecular weight inhibitors of the prostate-specific membrane antigen (PSMA) are under intense investigation as imaging and therapeutic agents for prostate and other cancers. In an effort to provide agents with less nontarget organ uptake than the ureas, we synthesized four (18)F labeled inhibitors of PSMA based on carbamate scaffolds. 4-Bromo-2 [(18)F]fluorobenzoyllysineoxypentanedioic acid (OPA) carbamate [(18)F]23 and 4 iodo-2-[(18)F]fluorobenzoyllysine OPA carbamate [(18)F]24 in particular exhibited high target-selective uptake in PSMA+ PC3 PIP tumor xenografts, with tumor-to kidney ratios of >1 by 4 h postinjection, an important benchmark. Because of its high tumor uptake (90% injected dose per gram of tissue at 2 h postinjection) and high tumor-to-organ ratios, [(18)F]23 is promising for clinical translation. Prolonged tumor-specific uptake demonstrated by [(18)F]24, which did not reach equilibrium during the 4 h study period, suggests carbamates as alternative scaffolds for mitigating dose to nontarget tissues. PMID- 26629715 TI - The Road to Contraceptive Consensus: New Recommendations for Contraceptive Use in Canada. PMID- 26629716 TI - An Algorithm for Predicting Neonatal Mortality in Threatened Very Preterm Birth. AB - OBJECTIVE: To develop a prediction model for neonatal mortality using information readily available in the antenatal period. METHODS: A multiple logistic regression model of a complete population-based geographically defined cohort of very preterm infants of 23+0 to 30+6 weeks' gestation was used to identify antenatal factors which were predictive of mortality in this population. Infants lt; 23 weeks and those with major anomalies were excluded. RESULTS: Between 1996 and 2012, 1240 live born infants lt; 31 weeks' gestation were born to women residing in Nova Scotia. Decreasing gestational age strongly predicted an increased mortality rate. Other factors significantly contributing to increased mortality included classification as small for gestational age, oligohydramnios, maternal psychiatric disorders, antenatal antibiotic therapy, and monochorionic twins. Reduced neonatal mortality was associated with antenatal use of antihypertensive agents and use of corticosteroids of any duration of therapy given at least 24 hours before delivery. An algorithm was developed to estimate the risk of mortality without the need for a calculator. CONCLUSION: Prediction of the probability of neonatal mortality is influenced by maternal and fetal factors. An algorithm to estimate the risk of mortality facilitates counselling and informs shared decision making regarding obstetric management. PMID- 26629717 TI - Learning From Experience: Qualitative Analysis to Develop a Cognitive Task List for Vaginal Breech Deliveries. AB - OBJECTIVE: Achieving clinical competence in managing safe vaginal breech delivery (VBD) is challenging in contemporary obstetrics. Novel educational strategies are required, as exposure of obstetric trainees to VBD remains limited. The aim of this study was to identify the verbal and non-verbal skills required to manage VBD through filmed demonstration by experts. METHODS: Labour and delivery nursing staff at three large university-affiliated hospitals identified clinicians whom they considered skilled in VBD. Obstetricians consistently identified were invited to participate in the study. Participants were filmed performing a VBD on a birth simulator while discussing their assessment, technique, and providing clinical pearls based on their experience. Two study members reviewed all videos and documented verbal and non-verbal components of the assessment, grouped them into common themes, and produced an integrated summary. This was circulated to all participants and reviewed by senior obstetricians from outside Canada. RESULTS: Seventeen clinicians were identified; 12 (70%) consented to participation. Themes identified were meticulous assessment and pre-pregnancy counselling; roles of the multidisciplinary team; need for careful and appropriate communication with parents; specific techniques of the delivery; and postpartum care and documentation. A clinical task list was generated based on this analysis. CONCLUSION: Derived from clinicians with extensive experience, we have developed a comprehensive task list outlining the important features involved in safe VBD. Common themes in the experts' teaching for safe VBD included rigorous antepartum selection and counselling, appreciation for when to convert to Caesarean section, and a "hands off" delivery technique. PMID- 26629718 TI - Magnesium Sulphate for Eclampsia and Fetal Neuroprotection: A Comparative Analysis of Protocols Across Canadian Tertiary Perinatal Centres. AB - BACKGROUND: Magnesium sulphate (MgSO4) has been recommended for fetal neuroprotection to prevent cerebral palsy, with national societies adopting new guidelines for its use. A knowledge translation project to implement Canadian guidelines is ongoing. Discussion about MgSO4 for fetal neuroprotection could not occur distinct from MgSO4 for eclampsia prophylaxis and treatment. Thus, in order to explore standardization of MgSO4 use in Canada, we sought to compare local protocols for eclampsia and fetal neuroprotection across tertiary perinatal centres. METHODS: Twenty-five Canadian tertiary perinatal centres were asked to submit their protocols for use of MgSO4 for eclampsia prophylaxis/treatment and fetal neuroprotection. Information abstracted included date of protocol, definitions of indications for treatment, details of MgSO4 administration, maternal and fetal monitoring, antidote for toxicity, and abnormal signs requiring physician attention. Descriptive analyses were used to compare site protocols with known definitions of preeclampsia. Data from the Canadian Perinatal Network (CPN) were used to verify what was done in clinical practice. RESULTS: Twenty-two of the 25 centres submitted protocols for eclampsia prevention/treatment. Eleven of these provided a definition of preeclampsia that warranted treatment; five of the 22 advised treatment of severe preeclampsia only. Criteria for treatment and monitoring procedures varied across centres. Sixteen of the 22 sites with protocols had data from the CPN. Of 635 women with pre-eclampsia, 422 (66.5%) received MgSO4. Twenty of 25 centres provided protocols for fetal neuroprotection. Definitions of indications were consistent across sites, except for gestational age cut-off. CONCLUSION: This study suggests that local protocols are often inconsistent with published evidence. While this may be related to local institutional practices, relevant processes must be put in place to maximize uniformity of practice and improve patient care. PMID- 26629719 TI - Emergency Caesarean Section in Obese Parturients: Is a 30-Minute Decision-to Incision Interval Feasible? AB - OBJECTIVE: To determine the effect of obesity on decision-to-incision and decision-to-delivery time intervals in emergency Caesarean section. METHODS: We performed a retrospective study of emergency Caesarean sections performed between 2005 and 2009. Indications for emergency Caesarean section were defined as those posing an immediate threat to the life of the mother or fetus. The primary outcomes were the time intervals from decision for emergency delivery to skin incision, and decision to delivery of the infant. The secondary outcome was a composite of poor neonatal outcomes comprising umbilical cord artery pH lt; 7.20, Apgar score lt; 7 at five minutes, admission to NICU, or neonatal death. RESULTS: A total of 232 women underwent emergency Caesarean section, and 140 of these met the inclusion criteria. At the time of delivery, 78/140 (55.7%) patients were categorized as obese (BMI >= 30kg/m2). The median decision-to-incision and decision-to-delivery intervals were significantly longer in the obese group, with a median delay of 4.5 minutes in both time intervals. Time-to-event analysis demonstrated prolongation of the decision-to-incision interval in the obese group (hazard ratio 0.71, P lt; 0.05). There was no difference in the neonatal composite outcome, but there was a significant reduction in median five-minute Apgar score in the obese group (P = 0.02). CONCLUSION: Obesity is associated with prolonged decision-to-incision and decision-to-delivery intervals, without associated neonatal morbidity, in a tertiary hospital setting. Further studies are required to assess the specific factors limiting expedient delivery in this population. PMID- 26629720 TI - Provoked Vestibulodynia and the Health Care Implications of Comorbid Pain Conditions. AB - OBJECTIVE: Sexual pain secondary to provoked vestibulodynia (PVD) is a chronic pain condition affecting up to 16% of women. Women with PVD may report other chronic pain conditions. The goals of this study were (1) to identify the prevalence of self-reported chronic pain conditions in a sample of women with a diagnosis of PVD and seeking treatment, and (2) to compare demographic and clinical characteristics and health care needs of women with PVD alone and women with PVD and two or more self-reported chronic pain conditions. METHODS: We assessed the characteristics of 236 women with PVD alone and 55 women with PVD and comorbid chronic pain using a standardized questionnaire, the Beck Depression Inventory, the State-Trait Anxiety Inventory, the Pain Vigilance and Awareness Questionnaire, and the Female Sexual Distress Scale. RESULTS: Compared with women with PVD alone, women with PVD and other concurrent pain reported a significantly longer duration of pain, pain radiating to other parts of the vulva, and pain interfering in a variety of daily activities. This group was also significantly more likely to have seen more gynaecologists, and to have had more office visits with their gynaecologist than women with PVD alone. They were more likely to have tried anticonvulsants, antidepressants, and stress/relaxation therapy for their PVD and were also more likely to have allergies and skin sensitivities. Finally, this group of women had higher symptoms of depression, trait anxiety, and showed a trend towards more pain vigilance. CONCLUSION: Taken together, these findings suggest that physicians caring for women with PVD and concurrent chronic pain must be alert to the potentially greater health needs among this subsample of women. PMID- 26629721 TI - A Systematic Review of the Association Between Psychiatric Disturbances and Endometriosis. AB - OBJECTIVE: An association between endometriosis and psychiatric disturbances has been identified by some researchers. The purpose of this systematic review was to consolidate existing empirical findings to clarify the association between endometriosis and psychiatric conditions. DATA SOURCES: We searched three electronic databases (Medline/PubMed, PsychInfo, and ClinicalTrials.gov) using the following search items: "endometriosis" combined with "mood," "bipolar disorder," "major depressive disorder," "anxiety," "psychiatric," "psychosocial," "antidepressants," "antianxiety," "pharmacotherapy," or "psychotherapy." STUDY SELECTION: We included all relevant articles published in English. We identified 18 original research studies examining the association between endometriosis and psychiatric symptoms, with a combined total of 999 endometriosis patients being examined. DATA EXTRACTION AND SYNTHESIS: Of the 18 studies examined, 14 reported that endometriosis was associated with at least some aspect of reduced psychological functioning or mental health quality of life. Tabulation of raw frequencies of the studies using clinical diagnostic criteria and a comparison group revealed that at least 56.4% of women (44/78) with a diagnosis of endometriosis and 43.6% of women (48/110) without such a diagnosis met the criteria for a psychiatric disorder. CONCLUSION: The limited research suggests that women presenting with endometriosis are at risk for psychosocial disturbances or psychiatric distress. Whether such disruptions are a consequence of endometriosis, the associated chronic gynaecological pain, or another factor such as inflammation remains to be delineated. In the interim, women presenting with symptoms of endometriosis should also be screened for psychosocial and psychiatric disturbances. PMID- 26629722 TI - Conservative Management of Cervical Ectopic Pregnancy. AB - OBJECTIVE: To evaluate the safety and effectiveness of conservative management for cervical ectopic pregnancies. METHODS: We conducted a retrospective review of all cases of cervical ectopic pregnancy diagnosed at our tertiary care academic centre between January 2002 and July 2014. The diagnosis of cervical ectopic pregnancy was made using transvaginal ultrasound according to published criteria. Management decisions were made by individual clinicians. RESULTS: Cervical ectopic pregnancy was diagnosed in 27 women with a median age of 34 years. Two thirds of them were nulliparous, and 44% (12/27) reported infertility. The mean gestational age at diagnosis was seven weeks. The median serum human chorionic gonadotropin level was 11 300 IU/L (range 610 to 163 700). Fetal cardiac activity was present in 19 pregnancies (70%). Vaginal bleeding was the most common presentation, occurring in 23 cases (85%). Three women presented with acute life threatening hemorrhage. All cases were successfully managed conservatively, allowing uterine preservation. Systemic methotrexate (single or multi-dose protocol) was the mainstay of therapy. Other minimally invasive interventions included ultrasound-guided injection of potassium chloride into the pregnancy, uterine artery embolization, vaginal ligation of cervical branches of the uterine arteries, and dilatation and curettage, with or without dilute vasopressin cervical infiltration and Foley catheter tamponade. CONCLUSION: Systemic methotrexate alone or in combination with other minimally invasive techniques can be effective conservative treatment for cervical pregnancies. A fertility-sparing approach is the optimal treatment for this patient population, which has high rates of infertility and nulliparity. We present a management algorithm based on our results to aid in standardizing the management of cervical ectopic pregnancies. PMID- 26629723 TI - Spontaneous Rupture of an Unscarred Uterus Diagnosed Postpartum: A Case Report. AB - BACKGROUND: Uterine rupture is a tear in the uterine wall involving its full thickness, resulting in the formation of a defect in the uterine wall. The major risk factor is the presence of uterine scarring (specifically from Caesarean section), but it can also occur in an unscarred uterus. Although rare, this has been shown to result in more severe complications. CASE: A 31-year-old woman, gravida 6 para 6, without prior uterine incision or manipulation developed significant postpartum bleeding. She was found to have a uterine rupture with retroperitoneal extension, and surgical management was required. CONCLUSION: Early diagnosis of uterine rupture with rapid initiation of supportive and surgical care may significantly improve prognosis. It is imperative to consider uterine rupture in any obstetrical patient with hemodynamic instability or hemorrhage, regardless of whether risk factors (including a previous uterine scar) are present. PMID- 26629724 TI - Simulation Training in Obstetrics and Gynaecology Residency Programs in Canada. AB - OBJECTIVE: The integration of simulation into residency programs has been slower in obstetrics and gynaecology than in other surgical specialties. The goal of this study was to evaluate the current use of simulation in obstetrics and gynaecology residency programs in Canada. METHODS: A 19-question survey was developed and distributed to all 16 active and accredited obstetrics and gynaecology residency programs in Canada. The survey was sent to program directors initially, but on occasion was redirected to other faculty members involved in resident education or to senior residents. Survey responses were collected over an 18-month period. RESULTS: Twelve programs responded to the survey (11 complete responses). Eleven programs (92%) reported introducing an obstetrics and gynaecology simulation curriculum into their residency education. All respondents (100%) had access to a simulation centre. Simulation was used to teach various obstetrical and gynaecological skills using different simulation modalities. Barriers to simulation integration were primarily the costs of equipment and space and the need to ensure dedicated time for residents and educators. The majority of programs indicated that it was a priority for them to enhance their simulation curriculum and transition to competency-based resident assessment. CONCLUSION: Simulation training has increased in obstetrics and gynaecology residency programs. The development of formal simulation curricula for use in obstetrics and gynaecology resident education is in early development. A standardized national simulation curriculum would help facilitate the integration of simulation into obstetrics and gynaecology resident education and aid in the shift to competency-based resident assessment. Obstetrics and gynaecology residency programs need national collaboration (between centres and specialties) to develop a standardized simulation curriculum for use in obstetrics and gynaecology residency programs in Canada. PMID- 26629726 TI - Dried Saliva Spot (DSS) as a Convenient and Reliable Sampling for Bioanalysis: An Application for the Diagnosis of Diabetes Mellitus. AB - This paper proposes the dried saliva spot (DSS) as a convenient sampling technique for bioanalysis. The analytical method with the DSS was used for the determination of D,L-lactic acid (D,L-LA) and the D/L ratio of diabetic patients and prediabetic persons for the simple screening of the disease. The D,L-LA in the DSS was labeled with a chiral reagent (DMT-3(S)-Apy) for carboxylic acids and determined by UPLC-ESI-MS/MS. The limits of detection (signal-to-noise ratio (S/N) = 3) for the DSS analysis were on the amol level (~30 amol). Because good stability, recovery, accuracy, and precision of the D,L-LA for the DSS method was also obtained from the proposed procedure, the DSS method was applied to the determination of the D- and L-isomers of LA of diabetic patients, and prediabetic and healthy persons. The D/L-LA ratio by the present DSS method and the HbA1c value in blood were well-correlated to the serious diabetic patients, whereas the relation in the prediabetic persons was not very good. The reason seems to be due to the rough saliva sampling, and not to the DSS method, because strict regulation was not requested for the prediabetic and healthy persons. In order to have a successful DSS analysis, the stability of the target molecule, the detection sensitivity to the target molecule, and the validated determination method are important. PMID- 26629725 TI - Canadian Contraception Consensus (Part 2 of 4). AB - OBJECTIVE: To provide guidelines for health care providers on the use of contraceptive methods to prevent pregnancy and on the promotion of healthy sexuality. OUTCOMES: Guidance for Canadian practitioners on overall effectiveness, mechanism of action, indications, contraindications, non contraceptive benefits, side effects and risks, and initiation of cited contraceptive methods; family planning in the context of sexual health and general well-being; contraceptive counselling methods; and access to, and availability of, cited contraceptive methods in Canada. EVIDENCE: Published literature was retrieved through searches of Medline and The Cochrane Database from January 1994 to January 2015 using appropriate controlled vocabulary (e.g., contraception, sexuality, sexual health) and key words (e.g., contraception, family planning, hormonal contraception, emergency contraception). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from January 1994 to January 2015. Searches were updated on a regular basis and incorporated in the guideline to June 2015. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The quality of the evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). Chapter 1: Contraception in Canada Summary Statements 1. Canadian women spend a significant portion of their lives at risk of an unintended pregnancy. (II-2) 2. Effective contraceptive methods are underutilized in Canada, particularly among vulnerable populations. (II-2) 3. Long-acting reversible contraceptive methods, including contraceptive implants and intrauterine contraception (copper-releasing and levonorgestrel-releasing devices/systems), are the most effective reversible contraceptive methods and have the highest continuation rates. (II-1) 4. Canada currently does not collect reliable data to determine the use of contraceptive methods, abortion rates, and the prevalence of unintended pregnancy among reproductive-age women. (II-2) 5. A universal subsidy for contraceptive methods as provided by many of Canada's peer nations and a few Canadian provinces may produce health system cost-savings. (II-2) 6. Health Canada approval processes for contraceptives have been less efficient than those of other drug approval agencies and Health Canada processes for other classes of pharmaceuticals. (II-2) 7. It is feasible and safe for contraceptives and family planning services to be provided by appropriately trained allied health professionals such as midwives, registered nurses, nurse practitioners, and pharmacists. (II-2) Recommendations 1. Contraceptive counselling should include a discussion of typical use failure rates and the importance of using the contraceptive method consistently and correctly in order to avoid pregnancy. (II 2A) 2. Women seeking contraception should be counselled on the wide range of effective methods of contraception available, including long-acting reversible contraceptive methods (LARCs). LARCs are the most effective methods of reversible contraception, have high continuation rates, and should be considered when presenting contraceptive options to any woman of reproductive age. (II-2A) 3. Family planning counselling should include counselling on the decline of fertility associated with increasing female age. (III-A) 4. Health policy supporting a universal contraception subsidy and strategies to promote the uptake of highly effective methods as cost-saving measures that improve health and health equity should be considered by Canadian health decision makers. (III-B) 5. Canadian health jurisdictions should consider expanding the scope of practice of other trained professionals such as nurses, nurse practitioners, midwives, and pharmacists and promoting task-sharing in family planning. (II-2B) 6. The Canadian Community Health Survey should include adequate reproductive health indicators in order for health care providers and policy makers to make appropriate decisions regarding reproductive health policies and services in Canada. (III-B) 7. Health Canada processes and policies should be reviewed to ensure a wide range of modern contraceptive methods are available to Canadian women. (III-B) Chapter 2: Contraceptive Care and Access Summary Statements 8. Although there are many contraceptive options in Canada, only a narrow range of contraceptive methods are commonly used by those of reproductive age. (II-3) 9. Condom use decreases with longer relationship tenure and when the sexual partner is considered to be the main partner, likely due to a lower perceived risk of sexually transmitted infection in that relationship. Condom use may also decrease markedly as an unintended consequence when an effective non-barrier method, such as hormonal contraception or intrauterine contraception, is initiated. (II-3) 10. Family planning counselling provides a natural segue into screening for concerns about sexual function or intimate partner violence. (III) 11. Well-informed and well-motivated individuals who have developed skills to practise safer sex behaviours are more likely to use contraceptive and safer sex methods effectively and consistently. (II-2) Recommendations 8. Comprehensive family planning services, including abortion services, should be accessible to all Canadians regardless of geographic location. These services should be confidential, non judgemental, and respectful of individuals' privacy and cultural contexts. (III A) 9. A contraceptive visit should include history taking, screening for contraindications, dispensing or prescribing a method of contraception, and exploring contraceptive choice and adherence in the broader context of the individual's sexual behaviour, reproductive health risk, social circumstances, and relevant belief systems. (III-B) 10. Health care providers should provide practical information on the wide range of contraceptive options and their potential non-contraceptive benefits and assist women and their partners in determining the best user-method fit. (III-B) 11. Health care providers should assist women and men in developing the skills necessary to negotiate the use of contraception and the correct and consistent use of a chosen method. (III-B) 12. Contraceptive care should include discussion and management of the risk of sexually transmitted infection, including appropriate recommendations for condom use and dual protection, STI screening, post-exposure prophylaxis, and Hepatitis B and human papillomavirus vaccination. (III-B) 13. Health care providers should emphasize the use of condoms not only for protection against sexually transmitted infection, but also as a back-up method when adherence to a hormonal contraceptive may be suboptimal. (I-A) 14. Health care providers should be aware of current media controversies in reproductive health and acquire relevant evidence-based information that can be briefly and directly communicated to their patients. (III-B) 15. Referral resources for intimate partner violence, sexually transmitted infections, sexual dysfunction, induced abortion services, and child protection services should be available to help clinicians provide contraceptive care in the broader context of women's health. (III-B) Chapter 3: Emergency Contraception Summary Statements 12. The copper intrauterine device is the most effective method of emergency contraception. (II-2) 13. A copper intrauterine device can be used for emergency contraception up to 7 days after unprotected intercourse provided that pregnancy has been ruled out and there are no other contraindications to its insertion. (II-2) 14. Levonorgestrel emergency contraception is effective up to 5 days (120 hours) after intercourse; its effectiveness decreases as the time between unprotected intercourse and ingestion increases. (II-2) 15. Ulipristal acetate for emergency contraception is more effective than levonorgestrel emergency contraception up to 5 days after unprotected intercourse. This difference in effectiveness is more pronounced as the time from unprotected intercourse increases, especially after 72 hours. (I) 16. Hormonal emergency contraception (levonorgestrel emergency contraception and ulipristal acetate for emergency contraception) is not effective if taken on the day of ovulation or after ovulation. (II-2) 17. Levonorgestrel emergency contraception may be less effective in women with a body mass index > 25 kg/m2 and ulipristal acetate for emergency contraception may be less effective in women with a body mass index > 35 kg/m2. However, hormonal emergency contraception may still retain some effectiveness regardless of a woman's body weight or body mass index. (II-2) 18. Hormonal emergency contraception is associated with higher failure rates when women continue to have subsequent unprotected intercourse. (II 2) 19. Hormonal contraception can be initiated the day of or the day following the use of levonorgestrel emergency contraception, with back-up contraception used for the first 7 days. (III) 20. Hormonal contraception can be initiated 5 days following the use of ulipristal acetate for emergency contraception, with back-up contraception used for the first 14 days. (III) Recommendations 16. All emergency contraception should be initiated as soon as possible after unprotected intercourse. (II-2A) 17. Women should be informed that the copper intrauterine device (IUD) is the most effective method of emergency contraception and can be used by any woman with no contraindications to IUD use. (II-3A) 18. PMID- 26629727 TI - Towards the Synthesis of Dihydrooxepino[4,3-b]pyrrole-Containing Natural Products via Cope Rearrangement of Vinyl Pyrrole Epoxides. AB - An approach to the dihydrooxepino[4,3-b]pyrrole core of diketopiperazine natural products which utilizes a vinyl pyrrole epoxide Cope rearrangement was investigated. It was found that an ester substituent on the epoxide was essential for the [3,3]-rearrangement to occur. Density functional calculations with M06-2X provided explanations for the effects of the pyrrole and ester groups on these rearrangements. PMID- 26629728 TI - Controlling seepage in discrete particle simulations of biological systems. AB - It is now commonplace to represent materials in a simulation using assemblies of discrete particles. Sometimes, one wishes to maintain the integrity of boundaries between particle types, for example, when modelling multiple tissue layers. However, as the particle assembly evolves during a simulation, particles may pass across interfaces. This behaviour is referred to as 'seepage'. The aims of this study were (i) to examine the conditions for seepage through a confining particle membrane and (ii) to define some simple rules that can be employed to control seepage. Based on the force-deformation response of spheres with various sizes and stiffness, we develop analytic expressions for the force required to move a 'probe particle' between confining 'membrane particles'. We analyse the influence that particle's size and stiffness have on the maximum force that can act on the probe particle before the onset of seepage. The theoretical results are applied in the simulation of a biological cell under unconfined compression. PMID- 26629729 TI - Gender-moderated links between urgency, binge drinking, and excessive exercise. AB - OBJECTIVE: Exercise correlates with alcohol use, but the nature of this relation and the extent to which it is maladaptive remains unclear. Urgency and motives for engaging in drinking and exercise might indicate when these behaviors are problematic. The current study examined whether urgency moderated the association between exercise motivated by weight loss and drinking. PARTICIPANTS: College students (N = 589, 45.7% male) completed the study during the spring of 2012. METHODS: Participants completed self-report assessment measures, including frequency/quantity of alcohol consumption, exercise for weight loss, and urgency, during a single session. RESULTS: Negative urgency moderated the relation between exercise and alcohol consumption in men but not women; the link between excessive exercise and alcohol use was stronger for men with higher levels of urgency. CONCLUSIONS: Further clarification of the mechanisms underlying alcohol use and physical activity-particularly maladaptive approaches to exercise-will inform health interventions among college students. PMID- 26629730 TI - Tumor lysis syndrome: review of pathogenesis, risk factors and management of a medical emergency. AB - Tumor lysis syndrome (TLS) is a rare but potentially life-threatening complication of neoplasms, preferentially hematological malignancies. Well known since at least ninety years ago, this condition can be misdiagnosed and incorrectly managed due to rapid onset of symptoms, sometimes overlapping with cancer-derived clinical conditions. Our purpose is to discuss some old and new issues of this syndrome. Predisposing factors as type of malignancy, chemotherapy regimen and age are promptly available and useful tools for inducing TLS suspicion. Management of clinical syndrome requires hydration, fluid balance, electrolytes and hyperuricemia correction, and ultimately dialysis when acute kidney injury is worsening. PMID- 26629731 TI - Advances in the treatment of idiopathic pulmonary fibrosis. AB - INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a lung limited, progressive fibrotic disease with a poor prognosis. The cause is unknown, and currently there is no treatment that reverses the disease or stops progression. This combination of a poor prognosis and the absence of curative therapy has prompted a sustained investigative effort to identify beneficial treatments. Recently released trial results suggest progress. AREAS COVERED: Although the mechanism of disease is poorly understood, a number of compounds that influence pathways thought to play a mechanistic role have been studied for use in IPF. This article discusses a number of these landmark trials. EXPERT OPINION: From these studies we conclude that the future treatment of IPF will include expanding pharmacological options. Recent studies have identified two agents that appear to slow disease progression and may offer a window into pathogenesis and future drug targets. PMID- 26629732 TI - Corrigendum. PMID- 26629733 TI - Response to Letter "End-of-Life Preferences in Advanced Cancer Patients". PMID- 26629734 TI - Telomeres and Female Reproductive Aging. AB - Reproductive aging involves declines both in oocyte number and developmental capacity. Declining oocyte number alone cannot explain the manifestations of reproductive aging in women. We have proposed the Telomere Theory of Reproductive Aging to explain the complex phenotype found in oocytes from older women. Telomeres are TTAGGG repeats and associated proteins, which form loops at the ends of chromosomes to provide structural and genomic stability. Studies in mice and women show that telomere shortening in oocytes provides a parsimonious explanation for the effects of reproductive aging on oocyte quality. Measurement of polar body telomere length may predict oocyte quality in women undergoing ART. PMID- 26629735 TI - Multifunctional nanosheets based on folic acid modified manganese oxide for tumor targeting theranostic application. AB - It is highly desirable to develop smart nanocarriers with stimuli-responsive drug releasing and diagnostic-imaging functions for cancer theranostics. Herein, we develop a reduction and pH dual-responsive tumor theranostic platform based on degradable manganese dioxide (MnO2) nanosheets. The MnO2 nanosheets with a size of 20-60 nm were first synthesized and modified with (3-Aminopropyl) trimethoxysilane (APTMS) to get amine-functionalized MnO2, and then functionalized by NH2-PEG2000-COOH (PEG). The tumor-targeting group, folic acid (FA), was finally conjugated with the PEGylated MnO2 nanosheets. Then, doxorubicin (DOX), a chemotherapeutic agent, was loaded onto the modified nanosheets through a physical adsorption, which was designated as MnO2-PEG FA/DOX. The prepared MnO2-PEG-FA/DOX nanosheets with good biocompatibility can not only efficiently deliver DOX to tumor cells in vitro and in vivo, leading to enhanced anti-tumor efficiency, but can also respond to a slightly acidic environment and high concentration of reduced glutathione (GSH), which caused degradation of MnO2 into manganese ions enabling magnetic resonance imaging (MRI). The longitudinal relaxation rate r1 was 2.26 mM(-1) s(-1) at pH 5.0 containing 2 mM GSH. These reduction and pH dual-responsive biodegradable nanosheets combining efficient MRI and chemotherapy provide a novel and promising platform for tumor-targeting theranostic application. PMID- 26629743 TI - Distinct structural changes in wild-type and amyloidogenic chicken cystatin caused by disruption of C95-C115 disulfide bond. AB - Human cystatin C (HCC) amyloid angiopathy (HCCAA) is characterized by tissue deposition of amyloid fibrils in blood vessels, which can lead to recurrent hemorrhagic stroke. Wild-type HCC forms part of the amyloid deposits in brain arteries of elderly people with amyloid angiopathy. A point mutation causing a glutamine to a leucine substitution at residue 68 in the HCC polypeptide chain greatly increases the amyloidogenic propensity of HCC and causes a more severe cerebral hemorrhage and premature death in young adults. In this study, we used molecular dynamics simulations to assess the importance of disulfide bridge formation upon the stability of chicken cystatin and how this may influence the propensity for amyloid formation. We found that disulfide bridge formation between Cys95 and Cys115 in human cystatin played a critical role in overall protein stability. Importantly, Cys95-Cys115 influenced cystatin structure in regions of the protein that play key roles in the protein-folding transitions that occur, which enable amyloid fibril formation. We hypothesized that correct disulfide bridge formation is a critical step in stabilizing cystatin toward its native conformation. Disrupting Cys95-Cys115 disulfide bridge formation within cystatin appears to significantly enhance the amyloidogenic properties of this protein. In addition, by combining in silico studies with our previous experimental results on Eps1, a molecular chaperone of the PDI family, we proposed that age-related HCCAA, may possess a different pathogenic mechanism compared with its amyloidogenic counterpart, the early onset amyloidogenic cystatin-related CAA. PMID- 26629744 TI - Anthropometric Study of the Piriformis Muscle and Sciatic Nerve: A Morphological Analysis in a Polish Population. AB - BACKGROUND The aim of this study was to determine relationships between piriformis muscle (PM) and sciatic nerve (SN) with reference to sex and anatomical variations. MATERIAL AND METHODS Deep dissection of the gluteal region was performed on 30 randomized, formalin-fixed human lower limbs of adults of both sexes of the Polish population. Anthropometric measurements were taken and then statistically analyzed. RESULTS The conducted research revealed that, apart from the typical structure of the piriformis muscle, the most common variation was division of the piriformis muscle into two heads, with the common peroneal nerve running between them (20%). The group with anatomical variations of the sciatic nerve course displayed greater diversity of morphometric measurement results. There was a statistically significant correlation between the lower limb length and the distance from the sciatic nerve to the greater trochanter in the male specimens. On the other hand, in the female specimens, a statistically significant correlation was observed between the lower limb length and the distance from the sciatic nerve to the ischial tuberosity. The shortest distance from the sciatic nerve to the greater trochanter measured at the level of the inferior edge of the piriformis was 21 mm, while the shortest distance to the ischial tuberosity was 63 mm. Such correlations should be taken into account during invasive medical procedures performed in the gluteal region. CONCLUSIONS It is possible to distinguish several anatomical variations of the sciatic nerve course within the deep gluteal region. The statistically significant correlations between some anthropometric measurements were only present within particular groups of male and female limbs. PMID- 26629745 TI - Budget impact of pasireotide LAR for the treatment of acromegaly, a rare endocrine disorder. AB - BACKGROUND: Acromegaly is a rare disorder characterized by the over-production of growth hormone (GH). Patients often experience a range of chronic comorbidities including hypertension, cardiac dysfunction, diabetes, osteoarthropathy, and obstructive sleep apnea. Untreated or inadequately controlled patients incur substantial healthcare costs, while normalization of GH levels may reduce morbidity and mortality rates to be comparable to the general population. OBJECTIVE: To assess the 3-year budget impact of pasireotide LAR on a US managed care health plan following pasireotide LAR availability. METHODS: Two separate economic models were developed: one from the perspective of an entire health plan and another from the perspective of a pharmacy budget. The total budget impact model includes costs of drug therapies and other costs for treatment, monitoring, management of adverse events, and comorbidities. The pharmacy cost calculator only considers drug costs. RESULTS: The total estimated budget impact associated with the introduction of pasireotide LAR is 0.31 cents ($0.0031) per member per month (PMPM) in the first year, 0.78 cents ($0.0078) in the second year, and 1.42 cents ($0.0142) in the third year following FDA approval. Costs were similar or lower from a pharmacy budget impact perspective. For each patient achieving disease control, cost savings from reduced comorbidities amounted to $10,240 per year. LIMITATIONS: Published data on comorbidities for acromegaly are limited. In the absence of data on acromegaly-related costs for some comorbidities, comorbidity costs for the general population were used (may be under-estimates). CONCLUSIONS: The budget impact of pasireotide LAR is expected to be modest, with an expected increase of 1.42 cents PMPM on the total health plan budget in the third year after FDA approval. The efficacy of pasireotide LAR in acromegaly, as demonstrated in head-to-head trials compared with currently available treatment options, is expected to be associated with a reduction of the prevalence of comorbidities. PMID- 26629747 TI - Theoretical investigations on the interactions of glucokinase regulatory protein with fructose phosphates. AB - Glucokinase (GK) plays a critical role in maintaining glucose homeostasis in the human liver and pancreas. In the liver, the activity of GK is modulated by the glucokinase regulatory protein (GKRP) which functions as a competitive inhibitor of glucose to bind to GK. Moreover, the inhibitory intensity of GKRP-GK is suppressed by fructose 1-phosphate (F1P), and reinforced by fructose 6-phosphate (F6P). Here, we employed a series of computational techniques to explore the interactions of fructose phosphates with GKRP. Calculation results reveal that F1P and F6P can bind to the same active site of GKRP with different binding modes, and electrostatic interaction provides a major driving force for the ligand binding. The presence of fructose phosphate severely influences the motions of protein and the conformational space, and the structural change of sugar phosphate influences its interactions with GKRP, leading to a large conformational rearrangement of loop2 in the SIS2 domain. In particular, the binding of F6P to GKRP facilitates the protruding loop2 contacting with GK to form the stable GK-GKRP complex. The conserved residues 179-184 of GKRP play a major role in the binding of phosphate group and maintaining the stability of GKRP. These results may provide deep insight into the regulatory mechanism of GKRP to the activity of GK. PMID- 26629748 TI - Pluripotent stem cell-based disease modeling: current hurdles and future promise. AB - Human induced pluripotent stem cells (hiPSCs) can yield unlimited numbers of patient-specific cells of any type and may be an important tool in efforts to overcome current shortcomings in biomedical research. In vitro disease models based on the use of hiPSCs have been proposed for various applications. Those include drug discovery and validation, efficacy, safety and toxicity assays, the elucidation of previously unknown disease mechanisms, the enhancement of animal based assays, the promise of conducting clinical trials in the dish and the identification of cell types and stages suitable for cell replacement therapies. Here, we provide an overview of the current state of hiPSC-based disease modeling and discuss recent progress and remaining challenges on the road to realizing the full potential of this novel technology. PMID- 26629746 TI - Bidirectional Regulation of Innate and Learned Behaviors That Rely on Frequency Discrimination by Cortical Inhibitory Neurons. AB - The ability to discriminate tones of different frequencies is fundamentally important for everyday hearing. While neurons in the primary auditory cortex (AC) respond differentially to tones of different frequencies, whether and how AC regulates auditory behaviors that rely on frequency discrimination remains poorly understood. Here, we find that the level of activity of inhibitory neurons in AC controls frequency specificity in innate and learned auditory behaviors that rely on frequency discrimination. Photoactivation of parvalbumin-positive interneurons (PVs) improved the ability of the mouse to detect a shift in tone frequency, whereas photosuppression of PVs impaired the performance. Furthermore, photosuppression of PVs during discriminative auditory fear conditioning increased generalization of conditioned response across tone frequencies, whereas PV photoactivation preserved normal specificity of learning. The observed changes in behavioral performance were correlated with bidirectional changes in the magnitude of tone-evoked responses, consistent with predictions of a model of a coupled excitatory-inhibitory cortical network. Direct photoactivation of excitatory neurons, which did not change tone-evoked response magnitude, did not affect behavioral performance in either task. Our results identify a new function for inhibition in the auditory cortex, demonstrating that it can improve or impair acuity of innate and learned auditory behaviors that rely on frequency discrimination. PMID- 26629749 TI - Hearing impairment and vowel production. A comparison between normally hearing, hearing-aided and cochlear implanted Dutch children. AB - This study investigated the acoustic characteristics of the Belgian Standard Dutch vowels in children with hearing impairment and in children with normal hearing. In a balanced experimental design, the 12 vowels of Belgian Standard Dutch were recorded in three groups of children: a group of children with normal hearing, a group with a conventional hearing aid and a group with a cochlear implant. The formants, the surface area of the vowel space and the acoustic differentiation between the vowels were determined. The analyses revealed that many of the vowels in hearing-impaired children showed a reduction of the formant values. This reduction was particularly significant with respect to F2. The size of the vowel space was significantly smaller in the hearing-impaired children. Finally, a smaller acoustic differentiation between the vowels was observed in children with hearing impairment. The results show that even after 5 years of device use, the acoustic characteristics of the vowels in hearing-assisted children remain significantly different as compared to their NH peers. PMID- 26629751 TI - Electroencephalography and Evoked Potentials in the Intensive Care Unit, When the Steamer Becomes a Jet. PMID- 26629752 TI - Should Postanoxic Status Epilepticus be Treated Aggressively?-No! AB - Electrographic status epilepticus and myoclonus represent frequent findings in patients surviving cardiac arrest; both features have been related to poor clinical outcome. Recent data have outlined that status epilepticus appearing during therapeutic hypothermia and sedation is practically and invariably related to a fatal issue, as opposed to some patients presenting status epilepticus and/or myoclonus after return to normothermic conditions. Although it seems reasonable to give a chance of awakening to the latter patients by administering consequent antiepileptic treatment, especially if other favorable prognostic markers are observed, an aggressive treatment of status epilepticus arising during hypothermia seems futile in view of the existing evidence. PMID- 26629753 TI - Should Postanoxic Status Epilepticus Be Treated Agressively? Yes! AB - Cardiac arrest is common and has a high mortality rate. For resuscitated patients, the development of hypoxic-ischemic brain injury is the major culprit. Withdrawal of life-sustaining therapy is the cause of death for majority of patients with presumed severe brain injury, and assessment of prognosis should be evidence based and multimodal. Postanoxic status epilepticus is not an established criterion of a poor neurologic prognosis, and a good outcome is possible. Patients with postanoxic status epilepticus should therefore be actively treated with prolonged intensive care including antiepileptic and sedative agents to suppress seizure activity, if reliable indicators of a poor prognosis are absent. PMID- 26629754 TI - ACNS Critical Care EEG Terminology: Value, Limitations, and Perspectives. AB - The interpretation of the EEG in the critically ill remains a clinical challenge. Because continuous EEG monitoring plays an increasing role in patients' care, it is important that research efforts investigate the clinical significance of periodic and rhythmic discharges and of background abnormalities. The 2012 American Clinical Neurophysiology Society critical care EEG terminology was designed to provide a comprehensive and objective vocabulary for that purpose. The interrater reliability of most of the proposed terms has been established, confirming that they represent a solid basis for research. Studies using the terminology have already started to define the clinical and prognostic values of several known or newly described EEG patterns. Yet, as the field of critical care EEG evolves, improvements will be required to further enhance the clarity of the terminology and incorporate new findings from ongoing research. PMID- 26629755 TI - EEG for Diagnosis and Prognosis of Acute Nonhypoxic Encephalopathy: History and Current Evidence. AB - The term encephalopathy encompasses a wide variety of complex syndromes caused by a large number of different toxic, metabolic, infectious, and degenerative derangements. Acute encephalopathy typically presents with a fluctuating course involving alteration of mental status or confusion and decreased (or rarely increased) motor activity. There usually are lethargy, cognitive impairment, altered memory and mental processing of information, and disturbed sleep-wake cycles. Encephalopathy mainly occurs in the elderly and is frequently encountered in intensive care units and postoperatively. Despite new diagnostic procedures and advances in intensive medical care, acute encephalopathy constitutes a significant cause of morbidity and mortality in hospitalized patients. EEG enables rapid bedside electrophysiological monitoring providing dynamic real-time information on neocortical brain activity and dysfunction. Hence, EEG complements clinical and neuroimaging assessments of encephalopathic patients. Progressive slowing of EEG background activity with increasing cerebral compromise, the emergence of episodic electrographic transients, seizures, and decreased EEG reactivity to external stimuli provide important diagnostic and prognostic information. The aim of this review was to provide a comprehensive overview of the current evidence for the diagnostic and prognostic value of EEG in adult intensive care unit patients with acute nonhypoxic encephalopathy. PMID- 26629756 TI - EEG as an Indicator of Cerebral Functioning in Postanoxic Coma. AB - Postanoxic coma after cardiac arrest is one of the most serious acute cerebral conditions and a frequent cause of admission to critical care units. Given substantial improvement of outcome over the recent years, a reliable and timely assessment of clinical evolution and prognosis is essential in this context, but may be challenging. In addition to the classic neurologic examination, EEG is increasingly emerging as an important tool to assess cerebral functions noninvasively. Although targeted temperature management and related sedation may delay clinical assessment, EEG provides accurate prognostic information in the early phase of coma. Here, the most frequently encountered EEG patterns in postanoxic coma are summarized and their relations with outcome prediction are discussed. This article also addresses the influence of targeted temperature management on brain signals and the implication of the evolution of EEG patterns over time. Finally, the article ends with a view of the future prospects for EEG in postanoxic management and prognostication. PMID- 26629757 TI - Clinical Applications for EPs in the ICU. AB - In critically ill patients, evoked potential (EP) testing is an important tool for measuring neurologic function, signal transmission, and secondary processing of sensory information in real time. Evoked potential measures conduction along the peripheral and central sensory pathways with longer-latency potentials representing more complex thalamocortical and intracortical processing. In critically ill patients with limited neurologic exams, EP provides a window into brain function and the potential for recovery of consciousness. The most common EP modalities in clinical use in the intensive care unit include somatosensory evoked potentials, brainstem auditory EPs, and cortical event-related potentials. The primary indications for EP in critically ill patients are prognostication in anoxic-ischemic or traumatic coma, monitoring for neurologic improvement or decline, and confirmation of brain death. Somatosensory evoked potentials had become an important prognostic tool for coma recovery, especially in comatose survivors of cardiac arrest. In this population, the bilateral absence of cortical somatosensory evoked potentials has nearly 100% specificity for death or persistent vegetative state. Historically, EP has been regarded as a negative prognostic test, that is, the absence of cortical potentials is associated with poor outcomes while the presence cortical potentials are prognostically indeterminate. In recent studies, the presence of middle-latency and long-latency potentials as well as the amplitude of cortical potentials is more specific for good outcomes. Event-related potentials, particularly mismatch negativity of complex auditory patterns, is emerging as an important positive prognostic test in patients under comatose. Multimodality predictive algorithms that combine somatosensory evoked potentials, event-related potentials, and clinical and radiographic factors are gaining favor for coma prognostication. PMID- 26629758 TI - Clinical Use of EEG in the ICU: Technical Setting. AB - Neurophysiology is an essential tool for clinicians dealing with patients in the intensive care unit. Because of consciousness disorders, clinical examination is frequently limited. In this setting, neurophysiological examination provides valuable information about seizure detection, treatment guidance, and neurological outcome. However, to acquire reliable signals, some technical precautions need to be known. EEG is prone to artifacts, and the intensive care unit environment is rich in artifact sources (electrical devices including mechanical ventilation, dialysis, and sedative medications, and frequent noise, etc.). This review will discuss and summarize the current technical guidelines for EEG acquisition and also some practical pitfalls specific for the intensive care unit. PMID- 26629759 TI - Blink Reflex May Help Discriminate Alzheimer Disease From Vascular Dementia. AB - PURPOSE: Dementia has several different etiologies, and vascular dementia (VaD) is considered the second leading cause of dementia after Alzheimer disease (AD). Various studies used blink reflex in different spectrum of neurological diseases as a complementary diagnostic test. We performed blink test in AD, VaD, and mixed dementia to investigate different usefulness of blink reflex in differentiating these types of dementia. METHODS: Blink reflex was performed for patients with AD (n = 18), VaD (n = 17), mixed dementia (n = 19), and normal subjects (n = 20). The absolute latency of R1, R2, and contralateral R2 (R2c) was determined and then compared with normal values. We used ROC curve to determine the screening cut-off value for R2 and R2c to discriminate dementia with vascular component and AD. RESULTS: The mean age +/- SD of patients was 71.61 +/- 8.23, 66.71 +/- 11.48, 75.26 +/- 8.32, and 66.60 +/- 3.91 years in 4 groups of AD, VaD, mixed dementia, and normal, respectively. R2 and R2c were recorded in fewer number of subjects with VaD or mixed dementia than AD and normal subjects. For mean R2 latency higher than 45 milliseconds, the sensitivity and specificity were 42% and 100%, respectively, and for latency higher than 45 milliseconds, the sensitivity and specificity were 72% and 89%, respectively. CONCLUSIONS: R2 and R2c components of blink reflex could specifically discriminate between Alzheimer and dementia with vascular component. The interruption of descending corticoreticular pathways by small infarcts could explain it. PMID- 26629760 TI - Clinical Usefulness of Somatosensory Evoked Potentials for Detection of Peripheral Nerve and Brachial Plexus Injury Secondary to Malpositioning in Microvascular Decompression. AB - PURPOSE: Neurologic injury secondary to positioning is a significant perioperative problem and a common cause of patient injury in the practice of surgery. Somatosensory evoked potentials' (SSEPs) monitoring has also been noted useful in evaluating upper extremity conduction changes related to positioning. The purpose of this article was to evaluate the effectiveness of intermittent monitoring of SSEPs, which detects peripheral nerve and brachial plexus injury caused by malpositioning during microvascular decompression (MVD). This article will also discuss the etiology and pathogenesis of nerve injury after MVD and the means to prevent them. METHODS: Intraoperative SSEP monitorings for 485 patients who underwent MVD surgery were reviewed. A greater than or equal to 50% decrease in SSEPs amplitude and/or a greater than or equal to 10% increase in latency are considered significant change to produce potential postoperative neurological deficit. Risk factors were reviewed and a Student t-test was performed for significant differences. RESULTS: The overall incidence of position-related upper extremity SSEP changes was 2.89%. No patient with a reversible SSEP change developed a new postoperative deficit in the affected extremity. Patients with low body mass index, diabetes mellitus had a higher rate of brachial plexus injury during MVD. Gender, age, and operation duration did not increase the risk of brachial plexus injury. Of the 14 patients who had a significant change of SSEP, there were 6 ulnar nerve on the contralateral side and 8 median nerve on the ipsilateral side. All the changes occurred within 10 minutes after the patients were positioned. CONCLUSIONS: When positioning the patient for MVD with lateral position, careful attention should be paid to both the dependent (lower) arm extremities and the upper shoulders to prevent peripheral nerve injury. Additional precautions should be taken if the patient has a low body mass index or diabetes. Continuous intraoperative SSEP monitoring of ulnar/median nerve function is a valid and useful technique to minimize intraoperative neurologic injuries during surgery. PMID- 26629762 TI - Vasculopathy, Ischemia, and the Lateral Lumbar Interbody Fusion Surgery: Report of Three Cases. AB - Multi-modal neurophysiologic monitoring consisting of triggered and spontaneous electromyography and transcranial motor-evoked potentials may detect and prevent both acute and slow developing mechanical and vascular nerve injuries in lateral lumbar interbody fusion (LLIF) surgery. In case report 1, a marked reduction in the transcranial motor-evoked potentials on the operative side alerted to a 28% decrease in mean arterial blood pressure in a 54-year-old woman during an L3-4, L4-5 LLIF. After hemodynamic stability was regained, transcranial motor-evoked potentials returned to baseline and the patient suffered no postoperative complications. In case report 2, a peroneal nerve train-of-four stimulation threshold of 95 mA portended the potential for a triggered electromyography false negative in a 70-year-old woman with type 2 diabetes, peripheral neuropathy, and body mass index of 30.7 kg/m undergoing an L3-4, L4-5 LLIF. Higher triggered electromyography threshold values were applied to this patient's relatively quiescent triggered electromyography and the patient suffered no postoperative complications. In case report 3, the loss of right quadriceps motor-evoked potentials detected a retractor related nerve injury in a 59-year-old man undergoing an L4-5 LLIF. The surgery was aborted, but the patient suffered persistent postoperative right leg paresthesia and weakness. These reports highlight the sensitivity of peripheral nerve elements to ischemia (particularly in the presence of vascular risk factors) during the LLIF procedure and the need for dynamic multi-modal intraoperative monitoring. PMID- 26629761 TI - Prognostic Value of Heart Rate Variability in Patients With Cancer. AB - INTRODUCTION: Previous studies have shown that autonomic dysfunction is associated with shorter survival in patients with advanced cancer. We examined the association between heart rate variability, a measure of autonomic function, and survival in a large cohort of patients with cancer. METHODS: We retrospectively examined the records of 651 patients with cancer who had undergone ambulatory electrocardiogram monitoring for 20 to 24 hours. Time domain heart rate variability (SD of normal-to-normal beat interval [SDNN]) was calculated using power spectral analysis. Survival data were compared between patients with SDNN >= 70 milliseconds (Group 1, n = 520) and SDNN < 70 milliseconds (Group 2, n = 131). RESULTS: Two groups were similar in most variables, except that patients in group 2 had a significantly higher percentage of male patients (P = 0.03), hematological malignancies (P = 0.04), and use of non-selective serotonin reuptake inhibitor antidepressants (P = 0.04). Patients in group 2 had a significantly shorter survival rate (25% of patients in group 2 died by 18.7 weeks vs. 78.9 weeks in group 1 patients; P < 0.0001). Multivariate analysis showed that SDNN < 70 milliseconds remained significant for survival (hazard ratio 1.9 [95% confidence interval: 1.4-2.5]) independent of age, cancer stage, and performance status. CONCLUSION: The presence of cancer in combination with decreased heart rate variability (SDNN < 70 milliseconds) is associated with shorter survival time. PMID- 26629763 TI - Telemetry-assisted early detection of STEMI in patients with atypical symptoms by paramedic-performed 12-lead ECG with subsequent cardiological analysis. AB - OBJECTIVES: ECG is an essential diagnostic tool in patients with acute coronary syndrome. We aimed to determine how many patients presenting with atypical symptoms for an acute myocardial infarction show ST-segment elevations on prehospital ECG. We also aimed to study the feasibility of telemetric-assisted prehospital ECG analysis. PATIENTS AND METHODS: Between April 2010 and February 2011, consecutive emergency patients presenting with atypical symptoms such as nausea, vomiting, atypical chest pain, palpitations, hypertension, syncope, or dizziness were included in the study. After basic measures were completed, a 12 lead ECG was written and telemetrically transmitted to the cardiac center, where it was analyzed by attending physicians. Any identification of an ST-elevation myocardial infarction resulted in patient admission at the closest coronary angiography facility. RESULTS: A total of 313 emergency patients presented with the following symptoms: dyspnea, nausea, vomiting, dizziness/collapse, or acute hypertension. Thirty-four (11%) patients of this cohort were found to show ST segment elevations on the 12-lead ECG. These patients were directly admitted to the closest coronary catheterization facility rather than the closest hospital. The time required for transmission and analysis of the ECG was 3.6+/-1.2 min. CONCLUSION: Telemetry-assisted 12-lead ECG analysis in a prehospital setting may lead to earlier detection of ST-elevation myocardial infarction in patients with atypical symptoms. Thus, a 12-lead ECG should be considered in all prehospital patients both with typical and atypical symptoms. PMID- 26629764 TI - Patient and organizational characteristics predict a long length of stay in the emergency department - a Swedish cohort study. AB - BACKGROUND: Emergency departments (EDs) constitute a central part of the healthcare system that receives patients with complaints of varied urgency. A long length of stay (LOS) in the ED is associated with crowding, low patient satisfaction and poor patient outcomes. Therefore, it is important to understand the key drivers and patient characteristics associated with long LOS. AIMS: To identify patient-related and organization-related characteristics associated with the longest ED LOS. METHODS: All adult visits (n=19 503) to the ED at Karolinska University Hospital in Solna, Sweden, between 8 a.m. and 9 p.m. during 2012 were divided into quartiles on the basis of their LOS. The quartile with the longest LOS (n=4876) was compared with the two intermediate quartiles (n=9752) and the shortest quartile (n=4875). Differences in patient and organizational characteristics were assessed using multivariate logistic regression models to achieve odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: The patient-related factors associated with long LOS were female sex (OR 1.22, 95% CI 1.14-1.30), age 65-79 (OR 1.82, 95% CI 1.67-1.97), age 80 or older (OR 2.76, 95% CI 2.52-3.02) and the chief complaint of dyspnoea (OR 1.55, 95% CI 1.39-1.73). CONCLUSION: Long LOS in the ED is associated with both patient and organizational characteristics and the elderly are at particular risk of long LOS. These insights may be used to improve patient outcome metrics and enhance ED efficiency. Further studies are needed to clarify the role of additional factors as well as the causality of the studied factors. PMID- 26629765 TI - Using ambulance data to reduce community violence: critical literature review. AB - BACKGROUND: Previous work has demonstrated that much violence requiring medical help is not recorded by the police. Sharing emergency department data on victims of violence is associated with reductions in community violence and is well established throughout the UK. We undertook a critical literature review to determine whether sharing ambulance data was useful to identify violence hotspots and offered unique information for violence prevention. METHOD: A search of the major medical and criminological databases was undertaken using search terms related to the ambulance service, violence and assault, as well as data collection. The search was conducted within the NICE Evidence, Cochrane Library, Google Scholar, Criminal Justice Abstracts, Scopus and National Criminal Justice Reference Service databases, along with the websites of various relevant institutions. RESULTS: Overall, 36 papers were identified by abstract scanning and bibliography search, of which 10 were considered relevant. A further nine papers were detected in the grey literature, and two were considered to be useful in providing evidence for use of ambulance data in violence surveillance. Two of the identified papers were interventional studies, and the other 10 were observational studies. DISCUSSION: Although the standard of evidence was generally low, most studies demonstrated that ambulance services detected a substantial proportion of assaults that were not recorded by the police or the emergency departments. We identified only two interventional studies, but they were of low quality. Although the interventional evidence base is currently weak, ambulance data provide a unique source of information about the epidemiology of community violence and have the potential to improve current violent crime surveillance methods. PMID- 26629766 TI - Characteristics of people who rapidly and frequently reattend the emergency department for mental health needs. AB - OBJECTIVE: This paper identifies the characteristics of emergency department (ED) attendees with a referral to their Mental Health Liaison Service (MHLS) who are at increased risk for rapidly reattending, attending frequently, or attending intensely at this service (which is defined here as rapid and frequent reattendance). METHODS: A retrospective 5-year longitudinal study was conducted of all visitors (n=24 010) attending four busy EDs with a referral to their MHLS from the beginning of 2009 until the end of 2013. A Cox proportional hazards regression was used to identify factors associated with intense use, and a negative binomial regression was used to identify factors associated with frequent attendance. RESULTS: People with certain characteristics were more likely to make 'intense' use of mental health emergency services, which we define as shorter time to reattendance and a higher number of visits over 5 years. The people more likely to make intense use are more likely to have certain clinical diagnoses such as substance misuse, stress disorder, personality disorder and learning disability, to have certain social characteristics such as not being in a relationship, or living alone, and to have healthcare issues such as having been detained under the Mental Health Act and having a greater number of care coordinators over 5 years. CONCLUSION: Individuals with certain clinical and social characteristics were significantly more likely to reattend EDs and have referral to MHLS rapidly and frequently (i.e. intensely). PMID- 26629767 TI - Cellular and molecular effects of metronomic vinorelbine and 4-O deacetylvinorelbine on human umbilical vein endothelial cells. AB - Metronomic oral vinorelbine (VRL; Navelbine) was shown in clinical trials to yield sustainable antitumor activity possibly through antiangiogenic mechanisms. We investigated the effects of protracted low-dose VRL on human umbilical vein endothelial cells, compared with a conventional chemotherapy model. Human umbilical vein endothelial cell cultures were treated with different concentrations of VRL (0.001 nmol/l to 1 mmol/l) for 4, 24 and 96 h. The effects of different drug concentrations on cell growth, cell cycle, apoptosis and expression of the angiogenesis-modulating genes interleukin-8, cyclooxygenase-2, CD36 and peroxisome proliferator-activated receptor gamma were assessed using the metronomic or conventional chemotherapy model. Apoptosis and cell-cycle effects were assessed by flow cytometry. Gene expression was measured at the transcript level by quantitative reverse transcriptase-PCR, protein expression by immunoblotting and levels of proteins secreted in the cell medium by enzyme linked immunosorbent assay. Activation of the nuclear factor-kappaB pathway was investigated by immunoblot analysis of cytosolic and nuclear protein extracts. The half-maximal inhibitory concentrations (IC50) of VRL at 96 h were four orders lower compared with those after a 24-h exposure (1.23 nmol/l vs. 32 mmol/l for VRL). Drug concentrations at high nanomolar levels and above, which are relevant to conventional pulsatile dosing of VRL, induced a dose-dependent and nuclear factor-kappaB-related increase in proangiogenic interleukin-8 and cyclooxygenase 2 and a decrease in the thrombospondin-1 receptor CD36 and peroxisome proliferator-activated receptor gamma at mRNA and protein levels. In contrast, the opposite was evident with protracted picomolar to low nanomolar concentrations (metronomic dosing). Our data provide experimental support for metronomic VRL by showing that a protracted low dose outperforms pulsed high-dose administration in inducing antiangiogenic effects in proliferating human endothelial cells. PMID- 26629768 TI - Sorafenib induces autophagic cell death and apoptosis in hepatic stellate cell through the JNK and Akt signaling pathways. AB - Increasing hepatic stellate cell (HSC) death is an attractive approach for limiting liver fibrosis. We investigated the molecular mechanisms underlying the effects of sorafenib on HSCs. LX2 cells were incubated with sorafenib and a variety of inhibitors of apoptosis, autophagy, and necrosis. Electron microscopy was used to observe autophagosomes. Inhibitors and siRNA were used to examine the role of the Akt/mTOR/p70S6K and JNK pathways. Ultrastructural analysis revealed that rat HSCs treated with 5 MUmol/l sorafenib accumulated residual digested material and empty or autophagic vacuoles. Incubating LX2 cells with lysosomal protease inhibitors increased the accumulation of LC3-II, indicating that sorafenib enhances autophagic flux in HSCs. Autophagy may precede apoptosis. Lower concentrations of sorafenib and a shorter treatment time resulted in the dominance of autophagic cell death over apoptosis. Further analysis showed that Beclin 1 is inactivated by the caspases induced by sorafenib during apoptosis. Inhibition of autophagy in LX2 cells using 3-methyladenine treatment or siRNA mediated knockdown of Atg5 resulted in a marked increase in apoptosis. Finally, sorafenib induced programmed cell death by attenuation and activation of Akt/mTOR/p70S6K and JNK signaling. Sorafenib-induced cell death is mediated by both autophagy and apoptosis. Elucidation of the signaling pathways activated by sorafenib could potentially lead to novel antifibrosis therapies for chronic liver diseases. PMID- 26629769 TI - Long-term response to first-line trabectedin in an elderly female patient with a metastatic leiomyosarcoma unfit for anthracycline. AB - Systemic chemotherapy comprising anthracycline monotherapy is the standard regimen for metastatic soft tissue sarcomas, particularly leiomyosarcomas, which have limited sensitivity to ifosfamide. However, the optimal chemotherapy regimen for elderly patients, especially those considered unfit for anthracyclines, is undefined. Trabectedin is a potent marine-derived antineoplastic drug with documented activity in liposarcomas and leiomyosarcomas. It is registered in Europe for the treatment of adult patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. We report the long-term response to first-line trabectedin therapy in an elderly patient with metastatic leiomyosarcoma unfit for standard therapy. A 66-year-old woman underwent resection of a pelvic epithelioid leiomyosarcoma with positive margins in December 2002, followed by postoperative radiotherapy. In February 2012, she was diagnosed with multiple lung lesions and local relapse in the pelvis. As she was considered unsuitable for both anthracycline and ifosfamide because of cardiovascular comorbidities and because she was highly anxious at the prospect of developing alopecia, vomiting, and fatigue, we commenced treatment with trabectedin at 75% of the standard dose of 1.5 mg/m every 3 weeks. Treatment was well tolerated, and the patient continued treatment for 25 cycles, with disease stabilization according to the RECIST criteria and a partial response according to the Choi criteria. Disease progression was observed in November 2013 and the patient died 20 months after the diagnosis of metastases. Trabectedin may represent an alternative option for highly selected elderly patients with metastatic sarcoma and unfit for anthracyclines; careful monitoring of toxicities is strongly recommended. PMID- 26629770 TI - Whole-body dynamic imaging with continuous bed motion PET/CT. AB - Most dynamic imaging protocols require long scan times that are beyond the range of what can be supported in a routine clinical environment and suffer from various difficulties related to step and shoot imaging techniques. In this short communication, we describe continuous bed motion (CBM) imaging techniques to create clinically relevant 15 min whole-body dynamic PET imaging protocols. We also present initial data that suggest that these CBM methods may be sufficient for quantitative analysis of uptake rates and rates of glucose metabolism. Multipass CBM PET was used in conjunction with a population-based input function to perform Patlak modeling of normal tissue. Net uptake rates were estimated and metabolic rates of glucose were calculated. Estimations of k3 (Ki/Vd) were calculated along with modeling of liver regions of interest to assess model stability. Calculated values of metabolic rates of glucose were well within normal ranges found in the previous literature. CBM techniques can potentially be used clinically to obtain reliable, quantitative multipass whole-body dynamic PET data. Values calculated for normal brain were shown to be within previously published values for normal brain glucose metabolism. PMID- 26629771 TI - Feasibility study with 99mTc-HYNIC-betaAla-Bombesin(7-14) as an agent to early visualization of lung tumour cells in nude mice. AB - AIM: More sensitive and accurate imaging approaches for early detection and therapy monitoring of lung tumours are needed to ameliorate prognosis and outcome. Lung tumours are known to overexpress receptors for bombesin-like peptides. However, thus far, no study has demonstrated the potential role of bombesin-like peptides in identifying A549 lung tumour cells in xenograft animal models. Thus, we evaluate the feasibility of Tc-HYNIC-betaAla-Bombesin(7-14) as an imaging probe in lung cancer. METHODS AND RESULTS: Xenograft lung tumours were implanted in nude mice and evaluated by histopathological analysis. Tumours were easily visualized by Tc-HYNIC-betaAla-Bombesin(7-14) within 30 days after inoculation of the A549 cell line into mice. Scintigraphic images showed high tumour-to-background ratio. DISCUSSION: The data obtained in this study indicate that Tc-HYNIC-betaAla-Bombesin(7-14) may be useful as an imaging probe to detect A549 lung cancer cells. To our knowledge, this is the first time that this specific radiocompound has been used to visualize non-small-cell lung cancer A549 in mice. Further translational research in humans is required to establish the potential role of this radiocompound in clinical practice. PMID- 26629772 TI - Voluntary Wheel Running in Mice. AB - Voluntary wheel running in the mouse is used to assess physical performance and endurance and to model exercise training as a way to enhance health. Wheel running is a voluntary activity in contrast to other experimental exercise models in mice, which rely on aversive stimuli to force active movement. This protocol consists of allowing mice to run freely on the open surface of a slanted, plastic saucer-shaped wheel placed inside a standard mouse cage. Rotations are electronically transmitted to a USB hub so that frequency and rate of running can be captured via a software program for data storage and analysis for variable time periods. Mice are individually housed so that accurate recordings can be made for each animal. Factors such as mouse strain, gender, age, and individual motivation, which affect running activity, must be considered in the design of experiments using voluntary wheel running. PMID- 26629773 TI - Tests for Anxiety-Related Behavior in Mice. AB - Phenotyping of inbred mouse strains and genetically modified mouse models for characteristics related to neuropsychiatric diseases includes assessing their anxiety-related behavior. A variety of tests have been developed to measure anxiety in laboratory rodents and these tests have been placed under scrutiny over the years concerning their validity. Here we describe the most widely used tests for anxiety in mice. The protocols we present are established methods used in the German Mouse Clinic (GMC), with which alterations in anxiety could successfully be discovered in mouse mutants. Moreover, since baseline anxiety levels in mice are easily influenced by a great variety of disturbances, we carefully outline the critical parameters that need to be considered. PMID- 26629774 TI - A Mouse Primary Hepatocyte Culture Model for Studies of Circadian Oscillation. AB - Circadian rhythms regulate many aspects of behavior and physiological processes, and, through external signals, help an organism entrain to its environment. These rhythms are driven by circadian clocks in many cells and tissues within our bodies, and are synchronized by a central pacemaker in the brain, the suprachiasmatic nucleus. Peripheral oscillators include the liver, whose circadian clock controls persistent daily rhythms in gene expression and in liver specific functions such as metabolic homeostasis and drug metabolism. Chronic circadian clock disruption, as in rotating shiftwork, has been linked to disorders including obesity, diabetes, and cardiovascular disease. The mouse primary hepatocyte culture model allows the examination of circadian rhythms in these cells. This article describes a transgenic mouse model that uses a bioluminescent reporter to examine the circadian properties of a core clock gene Period2. Hepatocytes are isolated using a modified collagenase perfusion technique and cultured in a sandwich configuration, then sealed in a buffered medium containing luciferin for detection of whole-culture or single-cell bioluminescence. After synchronization by a medium change, cultures demonstrate coherent circadian period and phase measures of bioluminescence from the PERIOD2::LUCIFERASE reporter. PMID- 26629775 TI - Assessing Cognition in Mice. AB - Genetically modified mouse models have proven useful to study learning and memory processes and the neurocircuitry and molecular mechanisms involved, as well as to develop therapies for diseases involving cognitive impairment. A variety of tests have been developed to measure cognition in mice, and here we present those established and regularly used in the German Mouse Clinic. The test paradigms have been carefully chosen according to reliability of results and disease relevance of the cognitive functions assessed. Further criteria were time efficiency and ease of application. All tests assess slightly different but also overlapping or interacting aspects of learning and memory so that they can be used to complement each other in a comprehensive assessment of cognitive function. The five protocols described are for spontaneous alternation in the Y maze, social discrimination, object recognition, automated assessment of learning and memory using the IntelliCage, and olfactory discrimination learning. PMID- 26629776 TI - Optimized Heart Sampling and Systematic Evaluation of Cardiac Therapies in Mouse Models of Ischemic Injury: Assessment of Cardiac Remodeling and Semi-Automated Quantification of Myocardial Infarct Size. AB - Cardiac therapies are commonly tested preclinically in small-animal models of myocardial infarction. Following functional evaluation, post-mortem histological analysis is essential to assess morphological and molecular alterations underlying the effectiveness of treatment. However, non-methodical and inadequate sampling of the left ventricle often leads to misinterpretations and variability, making direct study comparisons unreliable. Protocols are provided for representative sampling of the ischemic mouse heart followed by morphometric analysis of the left ventricle. Extending the use of this sampling to other types of in situ analysis is also illustrated through the assessment of neovascularization and cellular engraftment in a cell-based therapy setting. This is of interest to the general cardiovascular research community as it details methods for standardization and simplification of histo-morphometric evaluation of emergent heart therapies. (c) 2015 by John Wiley & Sons, Inc. PMID- 26629777 TI - Age-related synaptic dysfunction in Tg2576 mice starts as a failure in early long term potentiation which develops into a full abolishment of late long-term potentiation. AB - Tg2576 mice are widely used to study amyloid-dependent synaptic dysfunction related to Alzheimer's disease. However, conflicting data have been reported for these mice with regard to basal transmission as well as the in vitro correlate of memory, long-term potentiation (LTP). Some studies show clear impairments, whereas others report no deficiency. The present study uses hippocampal slices from 3-, 10-, and 15-month-old wild-type (WT) and Tg2576 mice to evaluate synaptic function in each group, including experiments to investigate basal synaptic transmission, short- and long-term plasticity by inducing paired-pulse facilitation, and both early and late LTP. We show that synaptic function remains intact in hippocampal slices from Tg2576 mice at 3 months of age. However, both early and late LTP decline progressively during aging in these mice. This deterioration of synaptic plasticity starts affecting early LTP, ultimately leading to the abolishment of both forms of LTP in 15-month-old animals. In comparison, WT littermates display normal synaptic parameters during aging. Additional pharmacological investigation into the involvement of NMDA receptors and L-type voltage-gated calcium channels in LTP suggests a distinct mechanism of induction among age groups, demonstrating that both early and late LTP are differentially affected by these channels in Tg2576 mice during aging. PMID- 26629778 TI - Systemically Injectable Enzyme-Loaded Polyion Complex Vesicles as In Vivo Nanoreactors Functioning in Tumors. AB - The design and construction of nanoreactors are important for biomedical applications of enzymes, but lipid- and polymeric-vesicle-based nanoreactors have some practical limitations. We have succeeded in preparing enzyme-loaded polyion complex vesicles (PICsomes) through a facile protein-loading method. The preservation of enzyme activity was confirmed even after cross-linking of the PICsomes. The cross-linked beta-galactosidase-loaded PICsomes (beta-gal@PICsomes) selectively accumulated in the tumor tissue of mice. Moreover, a model prodrug, HMDER-betaGal, was successfully converted into a highly fluorescent product, HMDER, at the tumor site, even 4 days after administration of the beta gal@PICsomes. Intravital confocal microscopy showed continuous production of HMDER and its distribution throughout the tumor tissues. Thus, enzyme-loaded PICsomes are useful for prodrug activation at the tumor site and could be a versatile platform for enzyme delivery in enzyme prodrug therapy. PMID- 26629779 TI - Interacting Carbon Nitride and Titanium Carbide Nanosheets for High-Performance Oxygen Evolution. AB - Free-standing flexible films, constructed from two-dimensional graphitic carbon nitride and titanium carbide (with MXene phase) nanosheets, display outstanding activity and stability in catalyzing the oxygen-evolution reaction in alkaline aqueous system, which originates from the Ti-N(x) motifs acting as electroactive sites, and the hierarchically porous structure with highly hydrophilic surface. With this excellent electrocatalytic ability, comparable to that of the state-of the-art precious-/transition-metal catalysts and superior to that of most free standing films reported to date, they are directly used as efficient cathodes in rechargeable zinc-air batteries. Our findings reveal that the rational interaction between different two-dimensional materials can remarkably promote the oxygen electrochemistry, thus boosting the entire clean energy system. PMID- 26629781 TI - Molecular epidemiology and genetic diversity of hepatitis B virus in Ethiopia. AB - Although hepatitis B virus (HBV) infection is hyperendemic in Ethiopia and constitutes a major public health problem, little is known about its genetic diversity, genotypes, and circulation. The aim of this study was to determine the molecular epidemiology and genetic diversity of HBV in Ethiopia, using 391 serum samples collected from HBsAg-positive blood donors living in five different geographic regions. The HBV S/pol gene was amplified, sequenced, and HBV genotypes, subgenotypes, serotypes, and major hydrophilic region (MHR) variants were determined. Phylogenetic analysis of 371 samples (95%) revealed the distribution of genotypes A (78%) and D (22%) in Ethiopia. Further phylogenetic analysis identified one subgenotype (A1) within genotype A, and 4 subgenotypes within genotype D (D1; 1.3%, D2; 55%, D4; 2.5%, and D6; 8.8%). Importantly, 24 isolates (30%) of genotype D formed a novel phylogenetic cluster, distinct from any known D subgenotypes, and two A/D recombinants. Analysis of predicted amino acid sequences within the HBsAg revealed four serotypes: adw2 (79%), ayw1 (3.1%), ayw2 (7.8%), and ayw3 (11.6%). Subsequent examination of sequences showed that 51 HBV isolates (14%) had mutations in the MHR and 8 isolates (2.2%) in the reverse transcriptase known to confer antiviral resistance. This study provides the first description of HBV genetic diversity in Ethiopia with a predominance of subgenotypes A1 and D2, and also identified HBV isolates that could represent a novel subgenotype. Furthermore, a significant prevalence of HBsAg variants in Ethiopian population is revealed. PMID- 26629780 TI - Effect of Early Adult Patterns of Physical Activity and Television Viewing on Midlife Cognitive Function. AB - IMPORTANCE: Sedentary behaviors and physical inactivity are not only increasing worldwide but also are critical risk factors for adverse health outcomes. Yet, few studies have examined the effects of sedentary behavior on cognition or the long-term role of either behavior in early to middle adulthood. OBJECTIVE: To investigate the association between 25-year patterns of television viewing and physical activity and midlife cognition. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 3247 adults (black and white races; aged 18-30 years) enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study (March 25, 1985, to August 31, 2011). Data analysis was performed June 1, 2014, through April 15, 2015. MAIN OUTCOMES AND MEASURES: We assessed television viewing and physical activity at repeated visits (>=3 assessments) over 25 years using a validated questionnaire. A 25-year pattern of high television viewing was defined as watching TV above the upper baseline quartile (>3 hours/d) for more than two-thirds of the visits, and a 25-year pattern of low physical activity was defined as activity levels below the lower, sex-specific baseline quartile for more than two-thirds of the of the visits. We evaluated cognitive function at year 25 using the Digit Symbol Substitution Test (DSST), Stroop test, and Rey Auditory Verbal Learning Test. RESULTS: At baseline, the mean (SD) age of the 3247 study participants was 25.1 (3.6) years, 1836 (56.5%) were female, 1771 (54.5%) were white, and 3015 (92.9%) had completed at least high school. Compared with participants with low television viewing, those with high television viewing during 25 years (353 of 3247 [10.9%]) were more likely to have poor cognitive performance (<1 SD below the race-specific mean) on the DSST and Stroop test, with findings reported as adjusted odds ratio (95% CI): DSST, 1.64 (1.21-2.23) and Stroop test, 1.56 (1.13-2.14), but not the Rey Auditory Verbal Learning Test, adjusted for age, race, sex, educational level, smoking, alcohol use, body mass index, and hypertension. Low physical activity during 25 years in 528 of 3247 participants (16.3%) was significantly associated with poor performance on the DSST, 1.47 (1.14-1.90). Compared with participants with low television viewing and high physical activity, the odds of poor performance were almost 2 times higher for adults with both high television viewing and low physical activity in 107 of 3247 (3.3%) (DSST, 1.95 [1.19-3.22], and Stroop test, 2.20 [1.36-3.56]). CONCLUSIONS AND RELEVANCE: High television viewing and low physical activity in early adulthood were associated with worse midlife executive function and processing speed. This is one of the first studies to demonstrate that these risk behaviors may be critical targets for prevention of cognitive aging even before middle age. PMID- 26629782 TI - Unveiling the optical properties of a metamaterial synthesized by electron-beam induced deposition. AB - Direct writing using a focused electron beam allows for fabricating truly three dimensional structures of sub-wavelength dimensions in the visible spectral regime. The resulting sophisticated geometries are perfectly suited for studying light-matter interaction at the nanoscale. Their overall optical response will strongly depend not only on geometry but also on the optical properties of the deposited material. In the case of the typically used metal-organic precursors, the deposits show a substructure of metallic nanocrystals embedded in a carbonaceous matrix. Since gold-containing precursor media are especially interesting for optical applications, we experimentally determine the effective permittivity of such an effective material. Our experiment is based on spectroscopic measurements of planar deposits. The retrieved permittivity shows a systematic dependence on the gold particle density and cannot be sufficiently described using the common Maxwell-Garnett approach for effective medium. PMID- 26629784 TI - Reassessment of (90)Sr, (137)Cs, and (134)Cs in the Coast off Japan Derived from the Fukushima Dai-ichi Nuclear Accident. AB - The years following the Fukushima Dai-ichi nuclear power plant (FDNPP) accident, the distribution of (90)Sr in seawater in the coast off Japan has received limited attention. However, (90)Sr is a major contaminant in waters accumulated within the nuclear facility and in the storage tanks. Seawater samples collected off the FDNPP in September 2013 showed radioactive levels significantly higher than pre-Fukushima levels within 6 km off the FDNPP. These samples, with up to 8.9 +/- 0.4 Bq.m(-3) for (90)Sr, 124 +/- 3 Bq.m(-3) for (137)Cs, and 54 +/- 1 Bq.m(-3) for (134)Cs, appear to be influenced by ongoing releases from the FDNPP, with a characteristic (137)Cs/(90)Sr activity ratio of 3.5 +/- 0.2. Beach surface water and groundwater collected in Sendai Bay had (137)Cs concentrations of up to 43 +/- 1 Bq.m(-3), while (90)Sr was close to pre-Fukushima levels (1-2 Bq.m(-3)). These samples appear to be influenced by freshwater inputs carrying a (137)Cs/(90)Sr activity ratio closer to that of the FDNPP fallout deposited on land in the spring of 2011. Ongoing inputs of (90)Sr from FDNPP releases would be on the order of 2.3-8.5 GBq.d(-1) in September 2013, likely exceeding river inputs by 2-3 orders of magnitude. These results strongly suggest that a continuous surveillance of artificial radionuclides in the Pacific Ocean is still required. PMID- 26629785 TI - Anticancer Potencies of Pt(II) - and Pd(II)-linked M2L4 Coordination Capsules with Improved Selectivity. AB - Pt(II) - and Pd(II)-linked M2 L4 coordination capsules, providing a confined cavity encircled by polyaromatic frameworks, exhibit anticancer activities superior to cisplatin against two types of leukemic cells (HL-60 and SKW-3) and pronounced toxicity against cisplatin-resistant cells (HL-60/CDDP). Notably, the cytotoxic selectivities of the Pt(II) and Pd(II) capsules toward cancerous cells are up to 5.3-fold higher than that of cisplatin, as estimated through the non malignant/malignant-cells toxicity ratio employing normal kidney cells (HEK-293). In addition, the anticancer activity of the coordination capsules can be easily altered upon encapsulation of organic guest molecules. PMID- 26629783 TI - Clinical Observations and Molecular Variables of Primary Vascular Leiomyosarcoma. AB - IMPORTANCE: Vascular leiomyosarcomas are a rare subtype of leiomyosarcomas that most commonly affect the inferior vena cava and account for 5% of all leiomyosarcomas. These tumors are aggressive malignant tumors for which adjuvant modalities have not shown increased efficacy compared with surgery. OBJECTIVES: To evaluate the outcomes of patients with vascular leiomyosarcoma and the association between vascular leiomyosarcomas and immunohistochemical molecular markers, to determine their potential prognostic and therapeutic utility. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review of a cohort of 77 patients who presented to the University of Texas MD Anderson Cancer Center in Houston during the period from January 1993 to April 2012. Data were analyzed during the period from November 2012 to May 2015. All of the patients received a confirmed diagnosis of vascular leiomyosarcoma. Immunohistochemical studies for biomarkers were performed on a tissue microarray that included 26 primary specimens of vascular leiomyosarcoma. MAIN OUTCOMES AND MEASURES: Demographic and clinical factors were evaluated to assess clinical course, patterns of recurrence, and survival outcomes for patients with primary vascular leiomyosarcoma. A univariate Cox proportional hazards model was used to correlate disease-specific survival and time to recurrence with potential prognostic indicators. RESULTS: Sixty-three patients with localized disease who underwent surgical resection formed the study population, and their data were used for subsequent outcomes analysis. The median age at diagnosis was 58 years (range, 22 78 years). The majority of patients were female (41 patients [65%]) and white (51 patients [81%]). The 5-year disease-specific survival rate after tumor resection was 65%. The median time to local recurrence was 43 months, the median time to distant recurrence was 25 months, and the median time to concurrent local and distant recurrences was 15 months (P = .04). Strong expressions of cytoplasmic beta-catenin (hazard ratio, 5.33 [95% CI, 0.97-29.30]; P = .06) and insulinlike growth factor 1 receptor (hazard ratio, 2.74 [95% CI, 1.14-6.56]; P = .02) were associated with inferior disease-specific survival. CONCLUSIONS AND RELEVANCE: Vascular leiomyosarcomas are aggressive malignant tumors, with high recurrence rates. Expressions of beta-catenin and insulinlike growth factor 1 receptor were associated with poor disease-specific survival. Prospective studies should evaluate the clinical and therapeutic utility of these molecular markers. PMID- 26629786 TI - Adolescent pregnancy, nutrition, and health outcomes in low- and middle-income countries: what we know and what we don't know. PMID- 26629787 TI - Whole USH2A Gene Sequencing Identifies Several New Deep Intronic Mutations. AB - Deep intronic mutations leading to pseudoexon (PE) insertions are underestimated and most of these splicing alterations have been identified by transcript analysis, for instance, the first deep intronic mutation in USH2A, the gene most frequently involved in Usher syndrome type II (USH2). Unfortunately, analyzing USH2A transcripts is challenging and for 1.8%-19% of USH2 individuals carrying a single USH2A recessive mutation, a second mutation is yet to be identified. We have developed and validated a DNA next-generation sequencing approach to identify deep intronic variants in USH2A and evaluated their consequences on splicing. Three distinct novel deep intronic mutations have been identified. All were predicted to affect splicing and resulted in the insertion of PEs, as shown by minigene assays. We present a new and attractive strategy to identify deep intronic mutations, when RNA analyses are not possible. Moreover, the bioinformatics pipeline developed is independent of the gene size, implying the possible application of this approach to any disease-linked gene. Finally, an antisense morpholino oligonucleotide tested in vitro for its ability to restore splicing caused by the c.9959-4159A>G mutation provided high inhibition rates, which are indicative of its potential for molecular therapy. PMID- 26629789 TI - Effects of Lipids on in Vitro Release and Cellular Uptake of beta-Carotene in Nanoemulsion-Based Delivery Systems. AB - beta-Carotene (BC) nanoemulsions were successfully prepared by microfluidization. BC micellarization was significantly affected by bile salts and pancreatin concentration. Positive and linear correlation was observed between BC release and bile salts concentration. Pancreatin facilitated BC's release in simulated digestion. Compared to the control (bulk oil) (4.6%), nanoemulsion delivery systems significantly improved the micellarization of BC (70.9%). The amount of BC partitioned into micelles was positively proportional to the length of carrier oils. Unsaturated fatty acid (UFA)-rich oils were better than saturated fatty acid (SFA)-rich oils in transferring BC (p < 0.05). No significant difference was observed between monounsaturated fatty acid (MUFA)-rich oils and polyunsaturated fatty acid (PUFA)-rich oils (p > 0.05). A positive and linear relationship between the degree of lipolysis and the release of BC in vitro digestion was observed. Bile salts showed cytotoxicity to Caco-2 cells below 20 times dilution. BC uptake by Caco-2 cells was not affected by fatty acid (FA) compositions in micelles, but BC uptake was proportional to its concentration in the diluted micelle fraction. The results obtained are beneficial to encapsulate and deliver BC or other bioactive lipophilic carotenoids in a wide range of commercial products. PMID- 26629788 TI - Opposing Effects of Cucurbit[7]uril and 1,2,3,4,6-Penta-O-galloyl-beta-d glucopyranose on Amyloid beta25-35 Assembly. AB - Alzheimer's disease (AD) is a neurodegenerative disease characterized by extracellular deposits of amyloid beta protein (Abeta) in the brain. The conversion of soluble monomers to amyloid Abeta fibrils is a complicated process and involves several transient oligomeric species, which are widely believed to be highly toxic and play a crucial role in the etiology of AD. The development of inhibitors to prevent formation of small and midsized oligomers is a promising strategy for AD treatment. In this work, we employ ion mobility spectrometry (IMS), transmission electron microscopy (TEM), and molecular dynamics (MD) simulations to elucidate the structural modulation promoted by two potential inhibitors of Abeta oligomerization, cucurbit[7]uril (CB[7]) and 1,2,3,4,6-penta O-galloyl-beta-d-glucopyranose (PGG), on early oligomer and fibril formation of the Abeta25-35 fragment. One and two CB[7] molecules bind to Abeta25-35 monomers and dimers, respectively, and suppress aggregation by remodeling early oligomer structures and inhibiting the formation of higher-order oligomers. On the other hand, nonselective binding was observed between PGG and Abeta25-35. The interactions between PGG and Abeta25-35, surprisingly, enhanced the formation of Abeta aggregates by promoting extended Abeta25-35 conformations in both homo- and hetero-oligomers. When both ligands were present, the inhibitory effect of CB[7] overrode the stimulatory effect of PGG on Abeta25-35 aggregation, suppressing the formation of large amyloid oligomers and eliminating the structural conversion from isotropic to beta-rich topologies induced by PGG. Our results provide mechanistic insights into CB[7] and PGG action on Abeta oligomerization. They also demonstrate the power of the IMS technique to investigate mechanisms of multiple small-molecule agents on the amyloid formation process. PMID- 26629792 TI - Halogen Exchange Reaction of Aliphatic Fluorine Compounds with Organic Halides as Halogen Source. AB - The halogen exchange reaction of aliphatic fluorine compounds with organic halides as the halogen source was achieved. Treatment of alkyl fluorides (primary, secondary, or tertiary fluorides) with a catalytic amount of titanocene dihalides, trialkyl aluminum, and polyhalomethanes (chloro or bromo methanes) as the halogen source gave the corresponding alkyl halides in excellent yields under mild conditions. In the case of a fluorine/iodine exchange, no titanocene catalyst is needed. Only C-F bonds are selectively activated under these conditions, whereas alkyl chlorides, bromides, and iodides are tolerant to these reactions. PMID- 26629791 TI - Warm White Light Emitting Diodes with Gelatin-Coated AgInS2/ZnS Core/Shell Quantum Dots. AB - Cadmium-free and water-soluble AgInS2/ZnS core/shell quantum dots (QDs) with a cost of 2.5 $/g are synthesized in an electric pressure cooker. The QD powders with different Ag/In ratios exhibit bright yellow, orange, and orange-red luminescence under UV light. Their absolute photoluminescence quantum yields (PLQYs) can reach as high as 50.5, 57, and 52%, respectively. Because gelatin is used as the capping agent, the concentrated QDs/gelatin solution can be directly utilized as phosphor for the fabrication of white light-emitting diodes (LEDs) by a simple drop-drying process without the need of resin package. Warm-white LEDs are obtained by combining orange-emitting QDs with blue InGaN chip. As-fabricated warm-white LED exhibits a luminous efficacy of 39.85 lm/W, a correlated color temperature (CCT) of 2634 K and a color rendering index (CRI) of 71 at a drive current of 20 mA. Furthermore, the electroluminescence (EL) stability of LED device and thermal stability of as-prepared QDs are evaluated. PMID- 26629790 TI - Crystal Structures of IAPP Amyloidogenic Segments Reveal a Novel Packing Motif of Out-of-Register Beta Sheets. AB - Structural studies of amyloidogenic segments by X-ray crystallography have revealed a novel packing motif, consisting of out-of-register beta sheets, which may constitute one of the toxic species in aggregation related diseases. Here we sought to determine the presence of such a motif in islet amyloid polypeptide (IAPP), whose amyloidogenic properties are associated with type 2 diabetes. We determined four new crystal structures of segments within IAPP, all forming steric zippers. Most interestingly, one of the segments in the fibril core of IAPP forms an out-of-register steric zipper. Analysis of this structure reveals several commonalities with previously solved out-of-register fibrils. Our results provide additional evidence of out-of-register beta sheets as a common structural motif in amyloid aggregates. PMID- 26629793 TI - Evaluation of hydrophobicity and quantitative analysis of biofilm formation by Alicyclobacillus sp. AB - Alicyclobacillus sp. are acidothermophilic bacteria frequently contaminating fruit based products (juices and juice concentrates). These sporulating bacteria are able to survive at elevated temperatures and highly acidic environments which causes difficulties in their removal from industrial environments. Although numerous literature data examine Alicyclobacillus sp. presence in fruit based products and methods of their elimination, there is still a limited knowledge on ability of these bacteria to adhere to abiotic surfaces. Therefore, the objective of this study was to determine Alicyclobacillus sp. cells' hydrophobicity and capability of biofilm formation on a glass surface. The degree of cells hydrophobicity, according to Microbial Adhesion to Hydrocarbon (MATH) and Salt Aggregation Test (SAT), was investigated for eleven environmental isolates from natural Polish habitats, identified as Alicyclobacillus sp., and a Alicyclobacillus acidoterrestris DSM 3922 reference strain. The dynamics of biofilm formation within 3-day incubation on a glass surface was evaluated and quantified by a plate count method both, for cultures with and without agitation. All of the bacterial strains tested expressed ability to colonize a glass surface and four environmental isolates were classified as fast-adherent strains. The mature biofilm structures were predominantly formed after 48 hours of incubation. Dynamic culturing conditions were observed to accelerate the biofilm formation. The majority of strains expressed a moderate hydrophobicity level both, in SAT (41.7%) and MATH-PBS (75.0%), as well as MATH-PUM (91.7%) tests. However, no correlation between hydrophobicity and cell adherence to a glass slide surface was observed. PMID- 26629794 TI - Quaternary ammonium biocides as antimicrobial agents protecting historical wood and brick. AB - Quaternary ammonium compounds (QACs) are widely used in disinfection of water, surfaces and instruments as well as in textile, leather and food industries because of their relatively low toxicity, broad antimicrobial spectrum, non volatility and chemical stability. Due to these advantages, QACs are also used in restoration and can be applied on historical material. The aim of this study was to determine the usefulness of biocides based on quaternary ammonium salts and containing various excipients in the protection of historical materials against microbial growth. The study determined the antimicrobial activity of three biocides against bacteria: Pseudomonas fluorescens, Staphylococcus equorum, Bacillus cereus, Bacillus muralis, Sporosarcina aquimarina and Rhodococcus fascians, and moulds: Chaetomium globosum, Penicillium citreonigrum, Cladosporium cladosporioides I, Acremonium strictum, Aspergillus fumigatus and Cladosporium cladosporioides II, all isolated from historical wood and brick. Staphylococcus equorum, Bacillus cereus, Sporosarcina aquimarina and Rhodococcus fascians bacteria, and Cladosporium cladosporioides I and Acremonium strictum moulds showed high sensitivity to quaternary ammonium biocides. Historical wood can be effectively disinfected by three applications of biocide A (30% v/v) containing dodecyl dimethyl ammonium chloride (DDAC), citric acid, propiconazole and propanol. Disinfection of historical brick can be carried out by three applications of 6% v/v solutions of biocide B (based on DDAC and ethylenediaminetetraacetic acid - EDTA) or biocide C (containing a non-ionic surfactant, DDAC and EDTA). Effective protection of historical building materials against microbial growth for a period of seven days can be achieved by the application of biocide A (30% v/v) on the wood surface and biocide B (6% v/v) on the brick surface. PMID- 26629795 TI - Application of the BIOLOG system for characterization of Serratia marcescens ss marcescens isolated from onsite wastewater technology (OSWT). AB - The scope of this study was to apply the Biolog system to identify and characterize a Serratia strain isolated from the surface of black plastic pieces which constitute the fluidized bed filter (onsite wastewater technology, OSWT). The preliminary isolation of the strain was done in the medium with tetracycline at a 16 mg/l concentration. To characterize the isolated strain, the following Biolog methods were applied: (1) EcoPlates microplates for evaluation of physiological profiling, (2) GEN III OmniLog(r) ID System for identification of the isolate, and (3) phenotypic microarrays (PM) technology for evaluation of sensitivity to antibiotics (PM11 and PM12). Results were recorded using the original OmniLog(r) software. The Serratia strain was identified as Serratia marcescens ss marcescens with similarity index 0.569. The same identification was obtained by the 16S rDNA analysis. PM analysis showed an enhancement of phenotype (resistance or growth) of this strain to 35 antibiotics. The loss of phenotype (sensitivity or non-growth) was observed only for 5 antibiotics: lomefloxacin (0.4 ug/ml), enoxacin (0.9 ug/ml), nalidixic acid (18.0 ug/ml), paromomycin (25.0 ug/ml) and novobiocin (1100 ug/ml). This study acknowledges that the methods proposed by the Biolog system allow correct and complete identification and characterization of the microbes isolated from different environments. Phenotypic microarrays could be successfully used as a new tool for identification of the multi-antibiotic resistance of bacteria and for determination of the minimal inhibition concentrations (MIC). PMID- 26629796 TI - Structural Characterization of a Monoclonal Antibody-Maytansinoid Immunoconjugate. AB - Structural characterization was performed on an antibody-drug conjugate (ADC), composed of an IgG1 monoclonal antibody (mAb), mertansine drug (DM1), and a noncleavable linker. The DM1 molecules were conjugated through nonspecific modification of the mAb at solvent-exposed lysine residues. Due to the nature of the lysine conjugation process, the ADC molecules are heterogeneous, containing a range of species that differ with respect to the number of DM1 per antibody molecule. The DM1 distribution profile of the ADC was characterized by electrospray ionization mass spectrometry (ESI-MS) and capillary isoelectric focusing (cIEF), which showed that 0-8 DM1s were conjugated to an antibody molecule. By taking advantage of the high-quality MS/MS spectra and the accurate mass detection of diagnostic DM1 fragment ions generated from the higher-energy collisional dissociation (HCD) approach, we were able to identify 76 conjugation sites in the ADC, which covered approximately 83% of all the putative conjugation sites. The diagnostic DM1 fragment ions discovered in this study can be readily used for the characterization of other ADCs with maytansinoid derivatives as payload. Differential scanning calorimetric (DSC) analysis of the ADC indicated that the conjugation of DM1 destabilized the C(H)2 domain of the molecule, which is likely due to conjugation of DM1 on lysine residues in the C(H)2 domain. As a result, methionine at position 258 of the heavy chain, which is located in the C(H)2 domain of the antibody, is more susceptible to oxidation in thermally stressed ADC samples when compared to that of the naked antibody. PMID- 26629797 TI - Does This Make Sense? PMID- 26629798 TI - Letter to the Editor. PMID- 26629799 TI - Are You Connected to the Best Apps? AB - While the vast majority of pharmacists use computers to access medical information, many prefer a mobile device to find information quickly. This review discusses pharmacists' use of mobile device applications (apps) and highlights an assortment of apps that are particularly helpful. Epocrates, which provides drug information and clinical content, was the first popular smartphone app developed in this area and was used to introduce the concept. Today, apps that provide a wide range of drug information can be supplemented with apps that fine-tune specific information about drug monitoring, disease states, and cost. PMID- 26629801 TI - Mirtazapine-Associated Hypertriglyceridemia and Hyperglycemia. AB - The patient is a 75-year-old male who was admitted to the long-term care unit because of advancing dementia and was being treated with mirtazapine to improve his mood and stimulate his appetite. This case report outlines an interesting occurrence of hypertriglyceridemia followed by hyperglycemia, which resembled diabetes mellitus and required insulin therapy. The patient continued to have elevated triglyceride levels that persisted despite discontinuation of mirtazapine therapy. PMID- 26629800 TI - Comparing Direct Oral Anticoagulants and Warfarin for Atrial Fibrillation, Venous Thromboembolism, and Mechanical Heart Valves. AB - OBJECTIVES: To summarize available data for use of direct oral anticoagulants in nonvalvular atrial fibrillation, venous thromboembolism, and mechanical heart valves including dose-response consistency to offer considerations for pharmacotherapeutic decision-making for oral anticoagulants. DATA SOURCES: A Medline search of English-language studies published between 2000 and March 2015 was conducted to identify pertinent papers using combinations of the following words: apixaban, atrial fibrillation, dabigatran, direct oral anticoagulant, edoxaban, factor IIa inhibitors, factor Xa inhibitors, mechanical heart valves, novel oral anticoagulant, rivaroxaban, venous thromboembolism, and warfarin. STUDY SELECTION AND EXTRACTION: Original studies, guidelines, and approved prescribing information were evaluated and included if contributing new or complementary data toward the objective. References for all identified studies were reviewed and entries included if contributory. DATA SYNTHESIS: Randomized controlled trials have established the safety and efficacy of direct oral anticoagulants in atrial fibrillation and venous thromboembolism for most patient groups. Direct oral anticoagulants should not be used in patients with mechanical heart valves until proven safe and effective. There are groups for which questions remain regarding inter-patient dose-response consistency for direct oral anticoagulants. There are postmarketing data suggesting poorer real-world performance of dabigatran relative to clinical trial data. CONCLUSION: Direct oral anticoagulants offer several advantages over warfarin, and large clinical trial data establish the appropriateness of their use in broad populations. There remain groups for whom the relative benefit and risk of these agents relative to warfarin are uncertain. A patient-specific approach in pharmacotherapeutic decision-making is appropriate. PMID- 26629802 TI - Patient-Centered Pharmacy Services: A Descriptive Report. AB - This paper describes a proactive, patient-centered, interprofessional approach to medication review in a long-term care facility. Clinical pharmacy services were provided to residents in multiple high-risk areas including transition of care; medication reconciliation; monitoring of infectious disease, pain, anticoagulation, psychotropic drugs, and falls; and requested consults for any change in condition. Process outcomes were evaluated, specifically the number of patients reviewed, number and type of recommendations made, and acceptance rate of recommendations by physicians; 1,333 medication regimen reviews were conducted. A total of 274 recommendations were made, and 56 recommendations were excluded as "lost to follow-up" because the recommendation was not acknowledged by the physician. Of the 218 acknowledged recommendations, 157 (72%) were accepted. Collective workload statistics suggest that the service identified and eliminated potential drugrelated problems such as inappropriate medications, drug interactions, and discrepancies during medication reconciliation. The large number of reviews conducted in a short time period show that there is a need for regular pharmacist review. PMID- 26629803 TI - Understanding of Medication Directions: Assessment of Native Korean Older Adults. AB - OBJECTIVE: Investigate the knowledge and understanding of older adult Korean immigrants concerning prescription and over-the-counter medication directions. DESIGN: A pre- postsurvey study. SETTING: Four Korean churches located in the suburbs of Chicago, Illinois. PARTICIPANTS: Korean-born, community-dwelling older adults older than 50 years of age. INTERVENTION: A presurvey in English was administered to older Korean immigrants residing in the Northwest Chicago suburbs, who completed it independently. Two student pharmacists then conducted a short medication seminar in Korean, and a postsurvey was given to determine if the information improved their overall understanding about the medications. MAIN OUTCOME MEASURES: The primary goal of this study was to determine if Korean older adults' understanding of medication directions improved when explained in their native language. RESULTS: After two student pharmacists delivered the seminar, there was an improvement in both the participants' understanding of medication directions and their perceived trust in pharmacists. CONCLUSIONS: There is a lack of understanding of medication directions by Korean immigrant older adults, even when information is communicated in their native tongue. This research demonstrates that educating the Korean older adult population, while also building a relationship of trust with pharmacists, will improve their understanding of the medication directions and possibly reduce the rate of medication errors. PMID- 26629804 TI - Changes in the Congressional Landscape. PMID- 26629805 TI - Lights, camera, condoms! Assessing college men's attitudes toward condom use in pornography. AB - OBJECTIVE: Investigate male college students' attitudes toward actors' use of condoms in pornography. PARTICIPANTS: Two hundred thirteen undergraduate males attending a large, state-supported midwestern university in the fall semester, 2012. METHODS: Using a Web-based procedure, participants completed questionnaires assessing their pornography use, sexual history characteristics, and their attitudes toward condom use by adult performers. RESULTS: Factor analysis of the 11-item condom use attitudes questionnaire supported 2 distinct subscales: Condom Supportive Attitudes and Condom Critical Attitudes. Although participants typically agreed with statements supportive of condom use and generally disagreed with statements critical of condom use in pornography, gay men had significantly higher condom supportive subscale scores than did heterosexual men. Neither subscale was correlated with weekly viewing of pornography. CONCLUSIONS: Although some producers of adult films argue that actors wearing condoms will displease many viewers, current findings suggest that young men express support for use of condoms by pornographic film actors. PMID- 26629806 TI - HIV immunotherapy comes of age: implications for prevention, treatment and cure. AB - Antiretroviral therapy (ART) has reshaped the lives of millions of individuals infected with human immunodeficiency virus (HIV). Patients initiating ART early in the course of infection benefit from a considerable reduction in the risks of acquired immune deficiency syndrome (AIDS) and HIV-related inflammatory events. However, the absence of cure and lifelong requirements of treatment highlight the need of a vaccine and an immunotherapeutic strategy. Like for cancer, a paradigm shift has occurred with the contribution of immune activation and microbial translocation priming aberrant systemic immunity in restricting the ability of the host to mount an effective immune response. The approaches of implementing an effective vaccine to prevent infection and inhibition of immune activation with breakage of viral latency followed by vaccination should lead to an HIV-free generation. PMID- 26629808 TI - The Chronic Consequences of Neurotrauma. PMID- 26629807 TI - Deciphering the human antigenome. AB - Recent technological advances in genomics, mass spectrometry, and epitope identification algorithms offer significant potential to identify novel antigenic targets for vaccine and immunotherapeutic development. On 30 April 2015, leading immunologists and bioinformatics scientists met to consider how best to utilize these advances towards deciphering the human antigenome and exploiting this information for prevention and control of infectious and neoplastic diseases. PMID- 26629809 TI - Adherence to Current COPD Guidelines in Turkey. AB - INTRODUCTION-OBJECTIVE: Despite the availability of national and international guidelines, chronic obstructive pulmonary diseases (COPD) treatment is not always prescribed according to these recommendations. We aimed to see if COPD patients in Turkey have been treated appropriately according to COPD guidelines. METHODS: This is a cross-sectional study carried out in six different chest diseases clinics. The COPD outpatients were categorized by spirometry classification (SC) and the combined classification (CC) of COPD. The treatment protocols were evaluated to check whether they were suitable for both classifications. RESULTS: Overall, 307 patients were included in the study. Of the treatment protocols, 40.4% were suitable for both classifications: 30.9% for CC and 20.8% for SC. A total of 51.8% of the patients were reported to be using an unsuitable therapy for SC and 38.4% for CC. Ninety-eight per cent of the unsuitable treatment was overtreatment. Fifty-eight per cent of the patients were using LABA + LAMA + ICS. Improper ICS usage was identified in 97.1% in CC, 93.1% in SC. The cost savings of all patients in one year would be 17,099$ with an appropriate treatment protocol following COPD guidelines. CONCLUSION: The most common type of inappropriate COPD treatments is overtreatment, generally with ICS. As treatment protocols following COPD guidelines change over time, there is still a low rate of adherence by clinicians in their clinical practice to guideline recommendations. Awareness of these guidelines by pulmonary specialists should be improved. PMID- 26629811 TI - Gender Difference in Relationship between Health-Related Quality of Life and Work Status. AB - This study investigated the association of employment status with health-related quality of life in adult Koreans, as well as the gender difference in the relationship, using a large, nationally representative sample. Using data from the Korea Health Panel survey, we examined the relationship between quality of life measured by EQ-5D and work status among Korean adults. We also tested whether and how the relationship between quality of life and work status differed by gender. Quality of life among working adults was better than among non-working adults. The gap between the two groups was larger among male than female participants. Further, the gender differential effect was larger in the 41-60 year-old age group than in the 18-40-year-old and 61-or-older groups. Being employed has a positive relation to quality of life among adults. Work status plays a more important role in quality of life for men than for women, especially for the working elderly men than working elderly women. PMID- 26629810 TI - Neutrophil Gelatinase Associated Lipocalin (NGAL) in Leptospirosis Acute Kidney Injury: A Multicenter Study in Thailand. AB - AKI is one of the most serious complications of leptospirosis, an important zoonosis in the tropics. Recently, NGAL, one of the novel AKI biomarkers, is extensively studied in various specific settings such as sepsis, cardiac surgery, and radiocontrast nephropathy. In this multicenter study, we aimed to study the role of NGAL as an early marker and an outcome predictor of leptospirosis associated AKI. Patients who presented with clinical suspiciousness of leptospirosis were prospectively enrolled in 9 centers from August 2012 to November 2014. The first day of enrollment was the first day of clinical suspicious leptospirosis. Blood and urine samples were serially collected on the first three days and day 7 after enrollment. We used three standard techniques (microscopic agglutination test, direct culture, and PCR technique) to confirm the diagnosis of leptospirosis. KDIGO criteria were used for AKI diagnosis. Recovery was defined as alive and not requiring dialysis during hospitalization or maintaining maximum KDIGO stage at hospital discharge. Of the 221 recruited cases, 113 cases were leptospirosis confirmed cases. Thirty seven percent developed AKI. Median uNGAL and pNGAL levels in those developing AKI were significantly higher than in patients not developing AKI [253.8 (631.4) vs 24.1 (49.6) ng/ml, p < 0.001] and [1,030 (802.5) vs 192.0 (209.0) ng/ml, p < 0.001], respectively. uNGAL and pNGAL levels associated with AKI had AUC-ROC of 0.91, and 0.92, respectively. Both of urine NGAL and pNGAL level between AKI-recovery group and AKI-non recovery were comparable. From this multicenter study, uNGAL and pNGAL provided the promising result to be a marker for leptospirosis associated AKI. However, both of them did not show the potential role to be the predictor of renal recovery in this specific setting. PMID- 26629812 TI - Effect of Systematic Follow-Up by General Practitioners after Deliberate Self Poisoning: A Randomised Controlled Trial. AB - OBJECTIVE: To assess whether systematic follow-up by general practitioners (GPs) of cases of deliberate self-poisoning (DSP) by their patients decreases psychiatric symptoms and suicidal behaviour compared with current practice. DESIGN: Randomised clinical trial with two parallel groups. SETTING: General practices in Oslo and the eastern part of Akershus County. PARTICIPANTS: Patients aged 18-75 years admitted to hospital for DSP. We excluded patients diagnosed with psychoses, without a known GP, those not able to complete a questionnaire, and patients admitted to psychiatric in-patient care or other institutions where their GP could not follow them immediately after discharge. INTERVENTION: The GPs received a written guideline, contacted the patients and scheduled a consultation within one week after discharge, and then provided regular consultations for six months. We randomised the patients to either intervention (n = 78) or treatment as usual (n = 98). MAIN OUTCOME MEASURES: Primary outcome measure was the Beck Scale for Suicide Ideation (SSI). Secondary outcomes were Beck Depression Inventory (BDI) and Beck Hopelessness Scale (BHS), self-reported further self harm and treatment for DSP in a general hospital or an emergency medical agency (EMA). We assessed patients on entry to the trial and at three and six months. We collected data from interviews, self-report questionnaires, and hospital and EMA medical records. RESULTS: There were no significant differences between the groups in SSI, BDI, or BHS mean scores or change from baseline to three or six months. During follow-up, self-reported DSP was 39.5% in the intervention group vs. 15.8% in controls (P = 0.009). Readmissions to general hospitals were similar (13% in both groups (P = 0.963), while DSP episodes treated at EMAs were 17% in the intervention group and 7% in the control group (P = 0.103). CONCLUSION: Structured follow-up by GPs after an episode of DSP had no significant effect on suicide ideation, depression or hopelessness. There was no significant difference in repeated episodes of DSP in hospitals or EMAs. However, the total number of incidents of deliberate self-harm reported by the patients was significantly higher in the intervention group. TRIAL REGISTRATION: Trial registration ClinicalTrials.gov Identifier: NCT01342809. PMID- 26629813 TI - Level, Trend and Correlates of Mistimed and Unwanted Pregnancies among Currently Pregnant Ever Married Women in India. AB - Unintended pregnancy accounts for more than 40% of the total pregnancies worldwide. An Unintended pregnancy can have serious implications on women and their families. With more than one-fourth of the children in India born out of unintended pregnancies such pregnancies are considered to be one of the major public health concerns today. The present study is aimed at determining major predictors of unintended pregnancy among currently pregnant ever-married women in India. The present study has used National Family Health Survey (NFHS) data, conducted by the International Institute for Population Sciences (IIPS), Mumbai, to show the trend, pattern and determinants of mistimed and unwanted pregnancies. Bivariate and multinomial logistic regression model have been used with the help of Stata 13 software. The results show that the likelihood of a mistimed pregnancy is more prevalent among young women whereas the prevalence of unwanted pregnancy is observed more among the women aged 35 years or more. The results also show that the risk of experiencing mistimed pregnancy decreases if the woman belongs to 'other' castes and has higher education. The likelihood of unwanted pregnancy decreases among married women aged 18 years and above, those women having higher education, some autonomy and access to any mode of mass communication. Knowledge of these predictors of mistimed and unwanted pregnancy will be helpful in identifying the most vulnerable group and prioritize the intervention strategies of the reproductive health programmes for the population in need. PMID- 26629814 TI - Evaluating Models of Cellulose Degradation by Fibrobacter succinogenes S85. AB - Fibrobacter succinogenes S85 is an anaerobic non-cellulosome utilizing cellulolytic bacterium originally isolated from the cow rumen microbial community. Efforts to elucidate its cellulolytic machinery have resulted in the proposal of numerous models which involve cell-surface attachment via a combination of cellulose-binding fibro-slime proteins and pili, the production of cellulolytic vesicles, and the entry of cellulose fibers into the periplasmic space. Here, we used a combination of RNA-sequencing, proteomics, and transmission electron microscopy (TEM) to further clarify the cellulolytic mechanism of F. succinogenes. Our RNA-sequence analysis shows that genes encoding type II and III secretion systems, fibro-slime proteins, and pili are differentially expressed on cellulose, relative to glucose. A subcellular fractionation of cells grown on cellulose revealed that carbohydrate active enzymes associated with cellulose deconstruction and fibro-slime proteins were greater in the extracellular medium, as compared to the periplasm and outer membrane fractions. TEMs of samples harvested at mid-exponential and stationary phases of growth on cellulose and glucose showed the presence of grooves in the cellulose between the bacterial cells and substrate, suggesting enzymes work extracellularly for cellulose degradation. Membrane vesicles were only observed in stationary phase cultures grown on cellulose. These results provide evidence that F. succinogenes attaches to cellulose fibers using fibro-slime and pili, produces cellulases, such as endoglucanases, that are secreted extracellularly using type II and III secretion systems, and degrades the cellulose into cellodextrins that are then imported back into the periplasm for further digestion by beta-glucanases and other cellulases. PMID- 26629815 TI - ADAR1 Facilitates HIV-1 Replication in Primary CD4+ T Cells. AB - Unlike resting CD4+ T cells, activated CD4+T cells are highly susceptible to infection of human immunodeficiency virus 1 (HIV-1). HIV-1 infects T cells and macrophages without activating the nucleic acid sensors and the anti-viral type I interferon response. Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA editing enzyme that displays antiviral activity against several RNA viruses. Mutations in ADAR1 cause the autoimmune disorder Aicardi-Goutieeres syndrome (AGS). This disease is characterized by an inappropriate activation of the interferon-stimulated gene response. Here we show that HIV-1 replication, in ADAR1-deficient CD4+T lymphocytes from AGS patients, is blocked at the level of protein translation. Furthermore, viral protein synthesis block is accompanied by an activation of interferon-stimulated genes. RNA silencing of ADAR1 in Jurkat cells also inhibited HIV-1 protein synthesis. Our data support that HIV-1 requires ADAR1 for efficient replication in human CD4+T cells. PMID- 26629816 TI - Levan Enhances Associated Growth of Bacteroides, Escherichia, Streptococcus and Faecalibacterium in Fecal Microbiota. AB - The role of dietary fiber in supporting healthy gut microbiota and overall well being of the host has been revealed in several studies. Here, we show the effect of a bacterial polyfructan levan on the growth dynamics and metabolism of fecal microbiota in vitro by using isothermal microcalorimetry. Eleven fecal samples from healthy donors were incubated in phosphate-buffered defined medium with or without levan supplementation and varying presence of amino acids. The generation of heat, changes in pH and microbiota composition, concentrations of produced and consumed metabolites during the growth were determined. The composition of fecal microbiota and profile of metabolites changed in response to substrate (levan and amino acids) availability. The main products of levan metabolism were acetic, lactic, butyric, propionic and succinic acids and carbon dioxide. Associated growth of levan-degrading (e.g. Bacteroides) and butyric acid-producing (e.g. Faecalibacterium) taxa was observed in levan-supplemented media. The study shows that the capacity of levan and possibly also other dietary fibers/prebiotics to modulate the composition and function of colon microbiota can be predicted by using isothermal microcalorimetry of fecal samples linked to metabolite and consortia analyses. PMID- 26629817 TI - An Identity-Based (IDB) Broadcast Encryption Scheme with Personalized Messages (BEPM). AB - A broadcast encryption scheme with personalized messages (BEPM) is a scheme in which a broadcaster transmits not only encrypted broadcast messages to a subset of recipients but also encrypted personalized messages to each user individually. Several broadcast encryption (BE) schemes allow a broadcaster encrypts a message for a subset S of recipients with public keys and any user in S can decrypt the message with his/her private key. However, these BE schemes can not provide an efficient way to transmit encrypted personalized messages to each user individually. In this paper, we propose a broadcast encryption scheme with a transmission of personalized messages. Besides, the scheme is based on multilinear maps ensure constant ciphertext size and private key size of each user and the scheme can achieve statically security. More realistically, the scheme can be applied to the Conditional Access System (CAS) of pay television (pay-TV) efficiently and safely. PMID- 26629818 TI - Spatial Distribution and Temporal Patterns of Cassin's Auklet Foraging and Their Euphausiid Prey in a Variable Ocean Environment. AB - Krill (Euphausiids) play a vital ecosystem role in many of the world's most productive marine regions, providing an important trophic linkage. We introduce a robust modeling approach to link Cassin's auklet (Ptychoramphus aleuticus) abundance and distribution to large-scale and local oceanic and atmospheric conditions and relate these patterns to similarly modeled distributions of an important prey resource, krill. We carried out at-sea strip transect bird surveys and hydroacoustic assessments of euphausiids (2004-2013). Data informed separate, spatially-explicit predictive models of Cassin's auklet abundance (zero-inflated negative binomial regression) and krill biomass (two-part model) based on these surveys. We established the type of prey responsible for acoustic backscatter by conducting net tows of the upper 50 m during surveys. We determined the types of prey fed to Cassin's auklet chicks by collecting diet samples from provisioning adults. Using time-depth-recorders, we found Cassin's auklets utilized consistent areas in the upper water column, less than 30 m, where krill could be found (99.5% of dives were less than 30 m). Birds primarily preyed upon two species of euphausiids, Euphausia pacifica and Thysanoessa spinifera, which were available in the upper water column. Cassin's auklet abundance was best predicted by both large scale and localized oceanic processes (upwelling) while krill biomass was best predicted by local factors (temperature, salinity, and fluorescence) and both large scale and localized oceanic processes (upwelling). Models predicted varying krill and bird distribution by month and year. Our work informs the use of Cassin's auklet as a valuable indicator or krill abundance and distribution and strengthens our understanding of the link between Cassin's auklet and its primary prey. We expect future increases in frequency and magnitude of anomalous ocean conditions will result in decreased availability of krill leading to declines in the Farallon Islands population of Cassin's auklets. PMID- 26629819 TI - Frost Induces Respiration and Accelerates Carbon Depletion in Trees. AB - Cellular respiration depletes stored carbohydrates during extended periods of limited photosynthesis, e.g. winter dormancy or drought. As respiration rate is largely a function of temperature, the thermal conditions during such periods may affect non-structural carbohydrate (NSC) availability and, ultimately, recovery. Here, we surveyed stem responses to temperature changes in 15 woody species. For two species with divergent respirational response to frost, P. integerrima and P. trichocarpa, we also examined corresponding changes in NSC levels. Finally, we simulated respiration-induced NSC depletion using historical temperature data for the western US. We report a novel finding that tree stems significantly increase respiration in response to near freezing temperatures. We observed this excess respiration in 13 of 15 species, deviating 10% to 170% over values predicted by the Arrhenius equation. Excess respiration persisted at temperatures above 0 degrees C during warming and reoccurred over multiple frost-warming cycles. A large adjustment of NSCs accompanied excess respiration in P. integerrima, whereas P. trichocarpa neither excessively respired nor adjusted NSCs. Over the course of the years included in our model, frost-induced respiration accelerated stem NSC consumption by 8.4 mg (glucose eq.) cm(-3) yr(-1) on average in the western US, a level of depletion that may continue to significantly affect spring NSC availability. This novel finding revises the current paradigm of low temperature respiration kinetics. PMID- 26629820 TI - The Gamma Gap and All-Cause Mortality. AB - BACKGROUND: The difference between total serum protein and albumin, i.e. the gamma gap, is a frequently used clinical screening measure for both latent infection and malignancy. However, there are no studies defining a positive gamma gap. Further, whether it is an independent risk factor of mortality is unknown. METHODS AND FINDINGS: This study examined the association between gamma gap, all cause mortality, and specific causes of death (cardiovascular, cancer, pulmonary, or other) in 12,260 participants of the National Health and Nutrition Examination Survey (NHANES) from 1999-2004. Participants had a comprehensive metabolic panel measured, which was linked with vital status data from the National Death Index. Cause of death was based on ICD10 codes from death certificates. Analyses were performed with Cox proportional hazards models adjusted for mortality risk factors. The mean (SE) age was 46 (0.3) years and the mean gamma gap was 3.0 (0.01) g/dl. The population was 52% women and 10% black. During a median follow up period of 4.8 years (IQR: 3.3 to 6.2 years), there were 723 deaths. The unadjusted 5-year cumulative incidences across quartiles of the gamma gap (1.7 2.7, 2.8-3.0, 3.1-3.2, and 3.3-7.9 g/dl) were 5.7%, 4.2%, 5.5%, and 7.8%. After adjustment for risk factors, participants with a gamma gap of >=3.1 g/dl had a 30% higher risk of death compared to participants with a gamma gap <3.1 g/dl (HR: 1.30; 95%CI: 1.08, 1.55; P = 0.006). Gamma gap (per 1.0 g/dl) was most strongly associated with death from pulmonary causes (HR 2.22; 95%CI: 1.19, 4.17; P = 0.01). CONCLUSIONS: The gamma gap is an independent risk factor for all-cause mortality at values as low as 3.1 g/dl (in contrast to the traditional definition of 4.0 g/dl), and is strongly associated with death from pulmonary causes. Future studies should examine the biologic pathways underlying these associations. PMID- 26629821 TI - Regional Heterogeneity of Cerebral Microvessels and Brain Susceptibility to Oxidative Stress. AB - The hippocampus is one of the earliest and most affected regions in Alzheimer's disease (AD), followed by the cortex while the cerebellum is largely spared. Importantly, endothelial dysfunction is a common feature of cerebral blood vessels in AD. In this study, we sought to determine if regional heterogeneity of cerebral microvessels might help explain the susceptibility of the hippocampus and cortex as compared to the cerebellum. We isolated microvessels from wild type mice from the cerebellum, cortex, and hippocampus to characterize their vascular phenotype. Superoxide anion was significantly higher in microvessels isolated from the cortex and hippocampus as compared to the cerebellum. Importantly, protein levels of NADPH oxidase (NOX)-2 and NOX-4 were significantly higher in the cortical and hippocampal microvessels as compared to microvessels from the cerebellum. In addition, expression of manganese superoxide dismutase protein was significantly lower in microvessels from the cortex and hippocampus as compared to cerebellum while other antioxidant enzymes were unchanged. There was no difference in eNOS protein expression between the microvessels of the three brain regions; however, bioavailability of tetrahydrobiopterin (BH4), an essential cofactor for eNOS activity, was significantly reduced in microvessels from the hippocampus and cortex as compared to the cerebellum. Higher levels of superoxide and reduced tetrahydrobiopterin bioavailability may help explain the vulnerability of the hippocampus and cortical microvessels to oxidative stress and development of endothelial dysfunction. PMID- 26629822 TI - Protection against Foot-and-Mouth Disease Virus in Guinea Pigs via Oral Administration of Recombinant Lactobacillus plantarum Expressing VP1. AB - Mucosal vaccination is an effective strategy for generating antigen-specific immune responses against mucosal infections of foot-and-mouth disease virus (FMDV). In this study, Lactobacillus plantarum strains NC8 and WCFS1 were used as oral delivery vehicles containing a pSIP411-VP1 recombinant plasmid to initiate mucosal and systemic immune responses in guinea pigs. Guinea pigs were orally vaccinated (three doses) with NC8-pSIP411, NC8-pSIP411-VP1, WCFS1-pSIP411, WCFS1 pSIP411-VP1 or milk. Animals immunized with NC8-pSIP411-VP1 and WCFS1-pSIP411-VP1 developed high levels of antigen-specific serum IgG, IgA, IgM, mucosal secretory IgA (sIgA) and neutralizing antibodies, and revealed stronger cell-mediated immune responses and enhanced protection against FMDV challenge compared with control groups. The recombinant pSIP411-VP1 effectively improved immunoprotection against FMDV in guinea pigs. PMID- 26629824 TI - Looking at the Camp: Paleolithic Depiction of a Hunter-Gatherer Campsite. AB - Landscapes and features of the everyday world were scarcely represented in Paleolithic art, especially those features associated with the human landscape (huts and campsites). On the contrary, other figurative motifs (especially animals) and signs, traditionally linked to the magic or religious conceptions of these hunter-gatherer societies, are the predominant themes of Upper Paleolithic art. This paper seeks to present an engraved schist slab recently found in the Moli del Salt site (North-eastern Iberia) and dated at the end of the Upper Paleolithic, ca. 13,800 years ago. This slab displays seven semicircular motifs that may be interpreted as the representation of dome-shaped huts. The analysis of individual motifs and the composition, as well as the ethnographic and archeological contextualization, suggests that this engraving is a naturalistic depiction of a hunter-gatherer campsite. Campsites can be considered the first human landscape, the first area of land whose visible features were entirely constructed by humans. Given the social meaning of campsites in hunter-gatherer life-styles, this engraving may be considered one of the first representations of the domestic and social space of a human group. PMID- 26629825 TI - Improved Neural Networks with Random Weights for Short-Term Load Forecasting. AB - An effective forecasting model for short-term load plays a significant role in promoting the management efficiency of an electric power system. This paper proposes a new forecasting model based on the improved neural networks with random weights (INNRW). The key is to introduce a weighting technique to the inputs of the model and use a novel neural network to forecast the daily maximum load. Eight factors are selected as the inputs. A mutual information weighting algorithm is then used to allocate different weights to the inputs. The neural networks with random weights and kernels (KNNRW) is applied to approximate the nonlinear function between the selected inputs and the daily maximum load due to the fast learning speed and good generalization performance. In the application of the daily load in Dalian, the result of the proposed INNRW is compared with several previously developed forecasting models. The simulation experiment shows that the proposed model performs the best overall in short-term load forecasting. PMID- 26629823 TI - Non-Specific Blocking of miR-17-5p Guide Strand in Triple Negative Breast Cancer Cells by Amplifying Passenger Strand Activity. AB - Conventional wisdom holds that only one of the two strands in a micro ribonucleic acid (miRNA) precursor duplex is selected as the active miRNA guide strand. The complementary miRNA passenger strand, however, is thought to be inactive. High levels of the oncogenic miRNA (oncomiR) guide strand called miR-17-5p is overexpressed in triple negative breast cancer (TNBC) and can inhibit ribosomal translation of tumor suppressor gene mRNAs, such as programmed cell death 4 (PDCD4) or phosphatase and tensin homolog (PTEN). We hypothesized that knocking down the oncogenic microRNA (oncomiR) miR-17-5p might restore the expression levels of PDCD4 and PTEN tumor suppressor proteins, illustrating a route to oligonucleotide therapy of TNBC. Contrary to conventional wisdom, antisense knockdown of oncomiR miR-17-5p guide strand reduced PDCD4 and PTEN proteins by 1.8+/-0.3 fold in human TNBC cells instead of raising them. Bioinformatics analysis and folding energy calculations revealed that mRNA targets of miR-17-5p guide strand, such as PDCD4 and PTEN, could also be regulated by miR-17-3p passenger strand. Due to high sequence homology between the antisense molecules and miR-17-3p passenger strand, as well as the excess binding sites for the passenger strand on the 3'UTR of PDCD4 and PTEN mRNAs, introducing a miR-17-3p DNA-LNA mimic to knock down miR-17-5p reduced PDCD4 and PTEN protein expression instead of raising them. Our results imply that therapeutic antisense sequences against miRNAs should be designed to target the miRNA strand with the greatest number of putative binding sites in the target mRNAs, while minimizing affinity for the minor strand. PMID- 26629826 TI - Malaria Parasite-Infected Erythrocytes Secrete PfCK1, the Plasmodium Homologue of the Pleiotropic Protein Kinase Casein Kinase 1. AB - Casein kinase 1 (CK1) is a pleiotropic protein kinase implicated in several fundamental processes of eukaryotic cell biology. Plasmodium falciparum encodes a single CK1 isoform, PfCK1, that is expressed at all stages of the parasite's life cycle. We have previously shown that the pfck1 gene cannot be disrupted, but that the locus can be modified if no loss-of-function is incurred, suggesting an important role for this kinase in intra-erythrocytic asexual proliferation. Here, we report on the use of parasite lines expressing GFP- or His-tagged PfCK1 from the endogenous locus to investigate (i) the dynamics of PfCK1 localisation during the asexual cycle in red blood cells, and (ii) potential interactors of PfCK1, so as to gain insight into the involvement of the enzyme in specific cellular processes. Immunofluorescence analysis reveals a dynamic localisation of PfCK1, with evidence for a pool of the enzyme being directed to the membrane of the host erythrocyte in the early stages of infection, followed by a predominantly intra parasite localisation in trophozoites and schizonts and association with micronemes in merozoites. Furthermore, we present strong evidence that a pool of enzymatically active PfCK1 is secreted into the culture supernatant, demonstrating that PfCK1 is an ectokinase. Our interactome experiments and ensuing kinase assays using recombinant PfCK1 to phosphorylate putative interactors in vitro suggest an involvement of PfCK1 in many cellular processes such as mRNA splicing, protein trafficking, ribosomal, and host cell invasion. PMID- 26629827 TI - Hyperreactivity of Blood Leukocytes in Patients with NAFLD to Ex Vivo Lipopolysaccharide Treatment Is Modulated by Metformin and Phosphatidylcholine but Not by Alpha Ketoglutarate. AB - INTRODUCTION AND AIMS: Toll-like receptor 4 and proinflammatory cytokines play a central role in the progression of nonalcoholic fatty liver disease. We investigated IL-1, IL-6 and TNFalpha production and toll-like receptor 4 in both- obese and lean patients with non-alcoholic fatty liver disease who met different sets of metabolic syndrome criteria and linked the results with the disease burden. MATERIALS AND METHODS: 95 subjects were divided into four groups depending on the following criteria: presence or absence of metabolic syndrome and/or non-alcoholic fatty liver disease, glucose tolerance (prediabetes or normoglycemia) and BMI value (obese or lean). We determined the levels of IL 1beta, IL-6, TNFalpha, and monocyte toll-like receptor 4 expression in fresh blood as well as in blood cultures treated with lipopolysaccharide with or without metformin, alphaketoglutarate or phosphatidylcholine supplementation. RESULTS: The blood leukocytes of patients with non-alcoholic fatty liver disease are hypersensitive to lipopolysaccharide treatment and produce elevated levels of pro-inflammatory cytokines in response to ex vivo treatment with lipopolysaccharide. Moreover, they overexpress toll-like receptor-4. Hyperreactivity was typical mainly for obese patients with non-alcoholic fatty liver disease together with metabolic syndrome and decreased with the severity of disease. Metformin was the most effective in attenuation of hyperreactivity in all groups of patients with non-alcoholic fatty liver disease, but in obese patients the effectiveness of metformin was weaker than in lean. The reduction of cytokine level by metformin was accompanied by the decrease in toll-like receptor 4 expression. phosphatidylcholine also attenuated hyperreactivity to lipopolysaccharide but mainly in obese patients. Alpha ketoglutarate did not modulate cytokines' level and toll-like receptor 4 expression in non-alcoholic fatty liver disease patients. CONCLUSIONS: Metformin and phosphatidylcholine attenuated lipopolysaccharide induced toll-like receptor 4 overexpression and overproduction of pro-inflammatory cytokines; however, their efficacy depended on combined presence of non-alcoholic fatty liver disease, metabolic syndrome and obesity. PMID- 26629829 TI - Glutathione Responsive Hyaluronic Acid Nanocapsules Obtained by Bioorthogonal Interfacial "Click" Reaction. AB - Azide-functionalized hyaluronic acid and disulfide dialkyne have been used for "click" reaction polymerization at the miniemulsion droplets interface leading to glutathione responsive nanocapsules (NCs). Inverse miniemulsion polymerization was chosen, due to its excellent performance properties, for example, tuning of size and size distribution, shell thickness/density, and high pay loading efficiency. The obtained size, size distribution, and encapsulation efficiency were checked via fluorescent spectroscopy, and the tripeptide glutathione was used to release an encapsulated fluorescent dye after cleavage of the nanocapsules shell. To show the glutathione-mediated intracellular cleavage of disulfide-containing NC shells, CellTracker was encapsulated into the nanocapsules. The cellular uptake in dendritic cells and the cleavage of the nanocapsules in the cells were studied using confocal laser scanning microscopy. Because of the mild reaction conditions used during the interfacial polymerization and the excellent cleavage properties, we believe that the synthesis of glutathione responsive hyaluronic acid NCs reported herein are of high interest for the encapsulation and release of sensitive compounds at high yields. PMID- 26629828 TI - Regulatory T Cell Responses to High-Dose Methylprednisolone in Active Systemic Lupus Erythematosus. AB - BACKGROUND/PURPOSE: A slight increase in the proportion of circulating regulatory T (Treg) cells has been reported in systemic lupus erythematosus (SLE) patients taking oral prednisone. The effects of intravenous (IV) high dose methylprednisolone (MP) on Tregs have not yet been described, especially in active SLE. METHODS: We prospectively analyzed the proportion of circulating CD4+ Treg cell subsets defined as follows: (1) naive Treg (nTreg) FoxP3lowCD45RA+ cells; (2) effector Treg (eTreg) FoxP3highCD45RA- cells; and (3) non-suppressive FoxP3lowCD45RA- cells (non-regulatory Foxp3low T cells). Peripheral blood mononuclear cells of patients with active SLE were analyzed before the first infusion of IV high dose MP (day 0) and the following days (day 1, day 2, +/-day 3 and +/-day 8). The activity of SLE was assessed by the SLEDAI score. RESULTS: Seventeen patients were included. Following MP infusions, the median (range) percentage of eTregs significantly increased from 1.62% (0.53-8.43) at day 0 to 2.80% (0.83-14.60) at day 1 (p = 0.003 versus day 0), 4.64% (0.50-12.40) at day 2 (p = 0.06 versus day 1) and 7.50% (1.02-20.70) at day 3 (p = 0.008 versus day 2), and declined to baseline values at day 8. Expanding eTreg cells were actively proliferating, as they expressed Ki-67. The frequency of non-regulatory FoxP3low T cells decreased from 6.39% (3.20-17.70) at day 0 to 4.74% (1.03-9.72) at day 2 (p = 0.005); nTreg frequency did not change. All patients clinically improved immediately after MP pulses. The absence of flare after one year of follow up was associated with a higher frequency of eTregs at day 2. CONCLUSION: IV high dose MP induces a rapid, dramatic and transient increase in circulating regulatory T cells. This increase may participate in the preventive effect of MP on subsequent flares in SLE. PMID- 26629830 TI - Intranasal delivery of paroxetine nanoemulsion via the olfactory region for the management of depression: formulation, behavioural and biochemical estimation. AB - Paroxetine is a selective serotonin reuptake inhibitor (SSRI) and is used for the treatment of depression and anxiety problems, but suffers from the drawback of poor oral bioavailability (less than 50%) due to its extensive first pass metabolism. The objective of the present study was to develop a paroxetine loaded nanoemulsion (o/w type) for direct nose-to-brain delivery. Nanoemulsions were prepared by the spontaneous emulsification technique using Capmul MCM, Solutol HS 15 and propylene glycol as oil phase, surfactant and co-surfactant, respectively, for delivery of drug directly to the brain through the nasal route for better management of depression. Formulations were studied for droplet size, polydispersity index (PDI), percentage transmittance, refractive index, viscosity, zeta potential, surface morphology and in vitro permeation study. TEM images of optimized formulation showed spherical droplets with a mean diameter of 58.47 +/- 3.02 nm, PDI of 0.339 +/- 0.007 and zeta potential values of -33 mV. The formulation showed good results for transmittance (100.60 +/- 0.577%), refractive index (1.412 +/- 0.003) and viscosity (40.85 +/- 6.40 cP). Permeation studies revealed a 2.57-fold enhancement in permeation as compared to the paroxetine suspension. Behavioural studies such as the forced swimming test and locomotor activity test were done on Wistar rats to study the antidepressant effect of the optimized formulation. Treatment of depressed rats with paroxetine nanoemulsion (administered intranasally) significantly improved the behavioural activities in comparison to paroxetine suspension (orally administered). Biochemical estimation results revealed that the prepared nanoemulsion was effective in enhancing the depressed levels of glutathione and decreasing the elevated levels of TBARS. PMID- 26629831 TI - A Common Genetic Variant in the Insulin Receptor Gene Is Associated with Eating Difficulties at 2 Years of Age in a Cohort of Preterm Infants. AB - BACKGROUND/AIMS: Children born preterm are more likely than full-term infants to develop eating difficulties that can affect their growth. Although this behavior is certainly influenced by their fetal and postnatal history, a large individual variability exists that results from a complex interaction between genetic and environmental factors. We performed an original pilot study to identify common genetic variants associated with eating difficulties at 2 years of age in the POLYNUCA cohort of preterm infants. METHODS: Eating behavior was assessed using a parental questionnaire in a cohort of 234 very preterm infants (including 38 pairs of twins). Eighty-two common single nucleotide polymorphisms (SNPs) were selected in a total of 40 candidate genes involved in the regulation of energy homeostasis and food intake. RESULTS: Eating behavior was strongly correlated in monozygotic (r = 0.92, p = 0.001) but not dizygotic twins (r = 0.27, p = 0.14), suggesting a strong heritability of this trait. One SNP (rs11671975) in the insulin receptor (INSR) gene was significantly associated with eating behavior. This effect was maintained after adjustment for birth weight Z score and maternal education level, two factors that are associated with eating difficulties at 2 years of age. CONCLUSION: The INSR gene is potentially associated with eating difficulties in preterm infants. PMID- 26629840 TI - Different Types of Luciferase Reporters Show Distinct Susceptibility to T3-Evoked Downregulation. AB - BACKGROUND: The firefly luciferase reporter protein is a crucial tool for studies targeting a broad range of biological questions. Importantly, luciferase assays are also widely used to explore mechanisms underlying thyroid hormone dependent regulation of gene expression. However, it was demonstrated that the firefly luciferase reporter is subject to triiodothyronine (T3)-evoked, promoter independent downregulation that is mediated by the thyroid hormone receptor. Since this effect can interfere with readout accuracy, the study aimed to find luciferase reporters that are not susceptible to this phenomenon. METHODS: Luciferase reporter constructs were generated under the control of a minimal thymidine kinase (TK) promoter and transiently transfected into JEG-3 cells to test their activity upon T3 treatment. RESULTS: Activity of the TK-(dCpG)Luc encoding a synthetic (dCpG)Luciferase and TK-NanoLuc expressing the NanoLuc reporter was not significantly changed by T3 treatment while the firefly luciferase control was suppressed by ~2.6-fold. T3 also downregulated the activity of Renilla luciferase by ~30%. CONCLUSIONS: Novel types of luciferase reporters, especially the synthetic (dCpG)Luciferase, can be more accurate to study T3-regulated gene expression than the classical firefly luciferase reporter. Renilla luciferase, a popular transfection control of dual luciferase assays, should be used with caution in conditions with T3 treatment. PMID- 26629841 TI - Early rehabilitation treatment combined with equinovarus foot deformity surgical correction in stroke patients: safety and changes in gait parameters. AB - BACKGROUND: Equinovarus foot deformity (EVFD) compromises several prerequisites of walking and increases the risk of falling. Guidelines on rehabilitation following EVFD surgery are missing in current literature. AIM: The aim of this study was to analyze safety and adherence to an early rehabilitation treatment characterized by immediate weight bearing with an ankle-foot orthosis (AFO) in hemiplegic patients after EVFD surgery and to describe gait changes after EVFD surgical correction combined with early rehabilitation treatment. DESIGN: Retrospective observational cohort study. SETTING: Inpatient rehabilitation clinic. POPULATION: Forty-seven adult patients with hemiplegia consequent to ischemic or haemorrhagic stroke (L/R 20/27, age 56+/-15 years, time from lesion 6+/-5 years). METHODS: A specific rehabilitation protocol with a non-articulated AFO, used to allow for immediate gait training, started one day after EVFD surgery. Gait analysis (GA) data before and one month after surgery were analyzed. The presence of differences in GA space-time parameters, in ankle dorsiflexion (DF) values and peaks at initial contact (DF at IC), during stance (DF at St) and swing (DF at Sw) were assessed by the Wilcoxon Test while the presence of correlations between pre- and post-operative values by Spearman's correlation coefficient. RESULTS: All patients completed the rehabilitation protocol and no clinical complications occurred in the sample. Ankle DF increased one month after surgery at all investigated gait phases (Wilcoxon Test, P<0.0001), becoming neutral at IC. Significant (P<0.05) variations were found for stride length, stride width, anterior step length of the affected side and for the duration of the double support phase of the contralateral side. The postsurgery ankle DF at St was found to be correlated (R=0.81, P<0.0001) with its pre-surgery value, thus being predictable. Weaker significant correlations were found for DF at Sw and DF at IC, where contribution from the dorsiflexor muscles is required in addition to calf muscle passive lengthening. CONCLUSIONS: An orthosis-assisted immediate rehabilitation associated with surgical procedure is safe and may be suitable to correct EVFD by restoring both the neutral heel foot ground contact and the ankle DF peaks during stance and swing at one month from surgery. CLINICAL REHABILITATION IMPACT: The proposed protocol is a safe and potentially useful rehabilitative approach after EVFD surgical correction in stroke patients. PMID- 26629842 TI - Recommendations for the rehabilitation of children with cerebral palsy. AB - The SINPIA-SIMFER (Italian Society of Child and Adolescent Neuropsychiatry - Italian Society of Physical Medicine and Rehabilitation) Intersociety Commission was set up in December 2000 and is composed of members from both scientific societies, who are experts in the field of rehabilitation of patients with cerebral palsy (CP). In accordance with the indications of the Italian Health Ministry's Planning Department, in 1999 this Commission was entrusted with the task of drawing up "Guidelines for the Rehabilitation of Children Affected by Cerebral Palsy", and to successively revise and update it every five years. The present document is a summary of the latest update, drawn up through meetings of the Intersociety Commission, held in 2012 and 2013, and discussed and approved at the annual SINPIA-SIMFER meeting held in Brindisi in October 2013. The current version of the Recommendations extends and updates the previous one, also addressing new areas of intervention and adding some in-depth analysis. The document as a whole is not so much a proposal for treatment updated on the basis of advancing knowledge in the field of rehabilitation of CP, as a presentation of the method that should be applied by professionals seeking to define the most appropriate intervention and treatment strategies. The text is the offspring of a process of careful exchanges, which have been conducted in a collegial and collaborative fashion among professionals working in different fields (rehabilitation medicine and child neuropsychiatry) and in healthcare settings at different levels (ranging from first-level local settings to third-level national ones) and of different types (affiliated outpatient clinics and centers, local health authorities, hospitals, "IRCCS" research hospitals, universities). PMID- 26629843 TI - Technology-aided behavioral programs for helping persons in or emerged from a minimally conscious state. PMID- 26629844 TI - What medical doctors and medical students know about physical medicine and rehabilitation: a survey from Central Europe. AB - BACKGROUND: Physical and rehabilitation medicine (PRM) is a relatively new and dynamically developing branch of the contemporary medicine. The unique role of PRM is bridging pure clinical outcomes with overall functional improvement. The concepts of disability and rehabilitation may be difficult to comprehend by medical students (MS) and Non-PRM specialists (NPRMS). AIM: The aim of this study was to assess the level of knowledge of NPRMS and MS regarding the role of PRM in health care systems in Poland, Hungary and Croatia. DESIGN: Cross-sectional observational study. SETTING: Anonymous questionnaire distributed in Hungarian, Polish and Croatian universities. RESULTS: Knowledge of definitions of a person with disability and PRM was poor (MS: 58% and 35%, NPRMS: 39% and 30%, PRMT: 72% and 62%). Prevalence of disability was correctly estimated by 58% of MS and 62% of doctors. 76% of MS, 72% of NPRMS and 99% of PRMT perceived PRM as a basic medical specialty. Leading role of PRM physician in comprehensive management of patients with stroke, multiple injury, spinal cord injury and congenital limb defect was perceived respectively by 42%, 49%, 53% and 64% of respondents. Functional statement as an important criterion in referring a patient for rehabilitation was perceived by 48% of NPRMS. Inadequate perception of the PRM role in health care system results from the lack of unified programme and scope of PRM in under- and postgraduate medical education, inappropriate allocation of funds in public PRM services, and claims of certain paramedical professions to extend their qualifications over interventions assigned to PRM doctors. CONCLUSIONS: Low knowledge of PRM among all studied groups testifies to the inadequacy of education of the medical community in rehabilitation. CLINICAL REHABILITATION IMPACT: The existing system of under- and postgraduate education of PRM should be urgently rearranged according to European harmonized guidelines. PMID- 26629845 TI - Maternal cytokines and disease severity influence pregnancy outcomes in women with rheumatoid arthritis. AB - OBJECTIVES: To assess the influence of maternal cytokine levels, disease activity and severity on preterm delivery, small for gestational age (SGA) and cesarean delivery in pregnant women with rheumatoid arthritis (RA). METHODS: A prospective study in 47 pregnant women with RA and 22 healthy pregnant controls. The main outcome measures were birth weight in relation to maternal serum levels of interleukin-6 (IL-6), interleukin-10 (IL-10), and RA activity and severity at three different time points: preconception and during the first and third trimesters. RESULTS: During the third trimester, IL-10 was detectable in 23.4% of patients with RA, IL-6 in 76.6%. Mean birth weight born to mothers with RA was higher when IL-10 level was high compared with low (p = 0.001), and lower when IL 6 was high compared with low (p = 0.035). Also increase in disease activity score 28 (in 60.1%, p = 0.001), Health Assessment Questionnaire-Disability Index (in 87.5%, p = 0.013), and pain score (56.9 +/- 11.4, p = 0.003) associated with increased risk of SGA. High patient's global scale was associated with unfavorable pregnancy outcome (preterm, SGA, and cesarean). CONCLUSION: High maternal IL-10 levels are associated with higher birth weight and high IL-6 levels are associated with lower birth weight (SGA). Among women with RA, disease activity and severity are predictive of unfavorable pregnancy outcomes suggesting that better disease management early in the pregnancy could improve pregnancy outcomes. PMID- 26629846 TI - Exploiting CRISPR-Cas immune systems for genome editing in bacteria. AB - The CRISPR-Cas immune system is a DNA-encoded, RNA-mediated, DNA-targeting defense mechanism, which provides sequence-specific targeting of DNA. This molecular machinery can be engineered into the sgRNA:Cas9 technology, for programmable cleavage of DNA. Following the genesis of double-stranded DNA breaks, the DNA repair machinery generates mutations at the cleavage site using various pathways. This technology has revolutionized eukaryotic genome editing, and we are at the cusp of full exploitation in bacteria. Here, we discuss the potential of CRISPR-based technologies for use in bacteria, and highlight the application of single stranded DNA recombineering combined with CRISPR-Cas selection to edit the genome of a probiotic organism. We envision that CRISPR-Cas technologies will play a key role in the development of next-generation industrial bacteria. PMID- 26629848 TI - Rare case of a strangulated intercostal flank hernia following open nephrectomy: A case report and review of literature. AB - INTRODUCTION: Flank incisions may be associated with incisional flank hernias, which may progress to incarceration and strangulation. Compromised integrity of the abdominal and intercostal musculature due to previous surgery may be associated with herniation of abdominal contents into the intercostal space. There have been six previously reported cases of herniation into the intercostal space after a flank incision for a surgical procedure. This case highlights the clinical picture associated with an emergent strangulated hernia and highlights the critical steps in its management. PRESENTATION OF CASE: We present a case of a 79-year-old adult man with multiple comorbidities presenting with a strangulated flank hernia secondary to an intercostal incision for a right-sided open nephrectomy. The strangulated hernia required emergent intervention including right-sided hemi-colectomy with ileostomy and mucous fistula. DISCUSSION: Abdominal incisional hernias are rare and therefore easily overlooked, but may result in significant morbidity or even death in the patient.. The diagnosis can be made with a thorough clinical examination and ultrasound or computed topographical investigation. Once a hernia has become incarcerated, emergent surgical management is necessary to avoid strangulation and small bowel obstruction. CONCLUSION: Urgent diagnosis and treatment of this extremely rare hernia is paramount especially in the setting of strangulation. PMID- 26629849 TI - Upper airway obstruction by a fragmented tracheostomy tube: Case report and review of the literature. AB - INTRODUCTION: Many objects were described in the literature as causes of upper airway obstruction including seeds, nuts and household particles but fragmented tracheostomy tube is a rarely reported cause of airway obstruction. We report a case of foreign body aspiration in the tracheobronchial tree due to a fragmented and migrated tracheostomy tube. PRESENTATION OF CASE: We report a 4.5 year old female patient who had upper airway obstruction due to a fragmented and migrated tracheostomy tube. She was diagnosed by chest X-ray and the tube was removed by rigid bronchoscopy. DISCUSSION: Several factors contribute to fragmentation of the tracheostomy tube including repeated removal and reinsertion, cleaning, boiling or chemicals. Early breakage is most often due to manufacturing defects. The occurrence of a fractured tracheostomy tube in children is rare. Nevertheless, tracheobronchial foreign bodies in children can be life threatening and pose a dire emergency. CONCLUSION: Based on our experience, the doctors and other staff should check for any manufacturing defects before the first use of a tracheostomy tube, which should reduce the occurrence of this rare, but life threatening. PMID- 26629850 TI - A case report of an 80 year old man with mesenteric panniculitis, a raised lactate and hyperglycaemia. AB - INTRODUCTION: Mesenteric panniculitis is a rare condition which presents as abdominal pain. It involves benign inflammatory or fibrotic changes affecting the mesentery of the bowel. PRESENTATION OF CASE: An 80 year old man presented with severe abdominal pain of acute onset. He was found to have a high lactate and high blood glucose. He was not a known diabetic. A computed tomography (CT) scan revealed a diagnosis of mesenteric panniculitis, and the patient rapidly responded to steroid treatment. DISCUSSION: Mesenteric panniculitis has been known to present as an acute abdomen. However, an associated high lactate and hyperglycaemia is hitherto unreported in the literature. With no obvious precipitant for an increased lactate, we propose it is potentially caused by the subsequent fat necrosis and regional ischaemia associated with mesenteric panniculitis. CONCLUSION: This case report underlines the importance of further research into the relationship between mesenteric panniculitis, a high lactate, and diabetes. In addition, short term steroid treatment (one month) seemed to confer the same benefit as long term steroid treatment. PMID- 26629847 TI - A Functional Cartography of Cognitive Systems. AB - One of the most remarkable features of the human brain is its ability to adapt rapidly and efficiently to external task demands. Novel and non-routine tasks, for example, are implemented faster than structural connections can be formed. The neural underpinnings of these dynamics are far from understood. Here we develop and apply novel methods in network science to quantify how patterns of functional connectivity between brain regions reconfigure as human subjects perform 64 different tasks. By applying dynamic community detection algorithms, we identify groups of brain regions that form putative functional communities, and we uncover changes in these groups across the 64-task battery. We summarize these reconfiguration patterns by quantifying the probability that two brain regions engage in the same network community (or putative functional module) across tasks. These tools enable us to demonstrate that classically defined cognitive systems-including visual, sensorimotor, auditory, default mode, fronto parietal, cingulo-opercular and salience systems-engage dynamically in cohesive network communities across tasks. We define the network role that a cognitive system plays in these dynamics along the following two dimensions: (i) stability vs. flexibility and (ii) connected vs. isolated. The role of each system is therefore summarized by how stably that system is recruited over the 64 tasks, and how consistently that system interacts with other systems. Using this cartography, classically defined cognitive systems can be categorized as ephemeral integrators, stable loners, and anything in between. Our results provide a new conceptual framework for understanding the dynamic integration and recruitment of cognitive systems in enabling behavioral adaptability across both task and rest conditions. This work has important implications for understanding cognitive network reconfiguration during different task sets and its relationship to cognitive effort, individual variation in cognitive performance, and fatigue. PMID- 26629851 TI - Surgical resection and chemoradiotherapy for metachronous pulmonary metastasis of basaloid squamous cell carcinoma of the oesophagus. AB - INTRODUCTION: Basaloid squamous cell carcinoma of the oesophagus (BSCCE) is a relatively rare variant of oesophageal malignancy. There are no established treatment strategies for pulmonary metastases of BSCCE. PRESENTATION OF CASE: A 72-year-old man underwent oesophagectomy and subsequently received a pathological diagnosis of stage IIIA (T3N1M0) BSCCE according to Union for International Cancer Control. One year and 5 months later, he underwent partial resection of the right lung because of metastasis of the BSCCE. One year and 6 months after the pulmonary resection, recurrence in the right lung was observed. The patient was treated with concurrent chemoradiotherapy using cisplatin and 5-fluorouracil, and the lesion completely disappeared. The patient is doing well without recurrence 5 years after chemoradiotherapy. DISCUSSION: In our case, the recurrent lesion in the right lung was observed after the pulmonary resection. It is difficult to determine whether the recurrent lesion is solitary or multiple and whether it is a local or pleural metastasis. Therefore, surgical indication must be decided carefully. Systemic chemotherapy or radiotherapy is useful to treat BSCCE metastasis, however, appropriate, but which agents and their regimens are appropriate is not clear. Concurrent chemotherapy using cisplatin and 5 fluorouracil and radiotherapy for pulmonary BSCCE metastases may provide curative therapy and should be considered. CONCLUSION: This report describes a case of recurrent pulmonary metastasis after pulmonary resection of BSCCE metastasis, successfully treated by concurrent chemotherapy and radiotherapy. Further studies are required to establish the indications and efficacy of these therapeutic approaches. PMID- 26629852 TI - Rapunzel syndrome due to ingested hair extensions: Surgical and psychiatric considerations. AB - INTRODUCTION: Rapunzel syndrome is a unique clinical manifestation of trichotillomania and trichophagia. The resulting gastric trichobezoar can be massive and necessitate surgical extraction. PRESENTATION OF CASE: We present a case involving a 15 year-old female with a known history of trichotillomania. The patient possessed symptoms of nausea and early satiety, and admitted that she had recently consumed a large number of hair extensions. Computed tomography imaging revealed a massive gastric bezoar not amenable to endoscopic extraction. The patient underwent surgical laparotomy, and a large gastric trichobezoar was removed through an anterior gastrotomy. The trichobezoar extended past the pylorus into the duodenum, thus confirming a diagnosis of Rapunzel syndrome. DISCUSSION: Trichobezoars formed from the consumption of hair extensions is a rare cause of Rapunzel syndrome. Surgical extraction is often necessitated due to the sheer size of the gastric bezoar that results from consuming hair extensions. If not previously established, psychiatric consultation should be pursued in the immediate post-operative course as these patients may require pharmacologic management along with behavioral therapy to avoid further episodes of trichotillomania. CONCLUSION: This case presents a unique and modern manifestation of Rapunzel syndrome. Surgical treatment most often is required when a patient presents with a massive gastric trichobezoar. Regular post operative psychiatric follow-up is necessary to prevent recurrent episodes. PMID- 26629853 TI - Snapping scapular syndrome secondary to rib intramedullary fixation device. AB - BACKGROUND: Scapulo-thoracic joint disorders, including bursitis and crepitus, are commonly misdiagnosed problems and can be a source of persistent pain and dysfunction PRESENTATION OF THE CASE: This article describes an unusual case of a snapping scapula syndrome secondary to a migration through the lateral cortex of a rib splint intramedullary fixation device into the scapulothoracic joint. DISCUSSION: Recently, the operative fixation of multiple ribs fractures with intramedullary fixation devices has become popular. Despite the good outcomes with new rib splint designs, concern remains about the potential complications related to potential loss of fracture reduction with migration of the wire resulting in pain or additional injury to the surrounding tissues. CONCLUSION: Surgeons should pay attention to any protrusion of intramedullary rib implants, especially in the evaluation of routine X-rays following surgical treatment. We should be aware of the possibility of this rare cause of snapping scapula syndrome to avoid delayed diagnosis and consider removing the implant will resolve the pain. PMID- 26629857 TI - Novel leucine ureido derivatives as aminopeptidase N inhibitors. Design, synthesis and activity evaluation. AB - Aminopeptidase N (APN/CD13) over-expressed on tumor cells and tumor microenvironment, plays critical roles in tumor invasion, metastasis and angiogenesis. Here we described the design, synthesis and preliminary activity studies of novel leucine ureido derivatives as aminopeptidase N (APN/CD13) inhibitors. The results showed that compound 7a had the most potent inhibitory activity against APN with the IC50 value of 20 nM, which could be used for further anticancer agent research. PMID- 26629854 TI - Metabolic control of methylation and acetylation. AB - Methylation and acetylation of DNA and histone proteins are the chemical basis for epigenetics. From bacteria to humans, methylation and acetylation are sensitive to cellular metabolic status. Modification rates depend on the availability of one-carbon and two-carbon substrates (S-adenosylmethionine, acetyl-CoA, and in bacteria also acetyl-phosphate). In addition, they are sensitive to demodification enzyme cofactors (alpha-ketoglutarate, NAD(+)) and structural analog metabolites that function as epigenetic enzyme inhibitors (e.g., S-adenosylhomocysteine, 2-hydroxyglutarate). Methylation and acetylation likely initially evolved to tailor protein activities in microbes to their metabolic milieu. While the extracellular environment of mammals is more tightly controlled, the combined impact of nutrient abundance and metabolic enzyme expression impacts epigenetics in mammals sufficiently to drive important biological outcomes such as stem cell fate and cancer. PMID- 26629855 TI - Covalent targeting of acquired cysteines in cancer. AB - The thiolate side chain of cysteine has a unique functionality that drug hunters and chemical biologists have begun to exploit. For example, targeting cysteine residues in the ATP-binding pockets of kinases with thiol-reactive molecules has afforded increased selectivity and potency to drugs like imbrutinib, which inhibits the oncogene BTK, and CO-1686 and AZD9291 that target oncogenic mutant EGFR. Recently, disulfide libraries and targeted GDP-mimetics have been used to selectively label the G12C oncogenic mutation in KRAS. We reasoned that other oncogenes contain mutations to cysteine, and thus screened the Catalog of Somatic Mutations in Cancer for frequently acquired cysteines. Here, we describe the most common mutations and discuss how these mutations could be potential targets for cysteine-directed personalized therapeutics. PMID- 26629858 TI - Synthesis and evaluation of gallocyanine dyes as potential agents for the treatment of Alzheimer's disease and related neurodegenerative tauopathies. AB - In search of safe and effective anti-Alzheimer disease agents a series of gallocyanine dyes have been synthesized and evaluated for their ability to inhibit LRPs/DKK1 interactions. Modulation of the interactions between LRPS and DKK1, regulate Wnt signaling pathway and affect Tau phosphorylation. The current efforts resulted in the identification of potent DKK1 inhibitors which are able to inhibit prostaglandin J2-induced tau phosphorylation at serine 396. PMID- 26629860 TI - Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitors. AB - In the last decades, inhibitors of histone deacetylases (HDAC) have become an important class of anti-cancer agents. In a previous study we described the synthesis of spiro[chromane-2,4'-piperidine]hydroxamic acid derivatives able to inhibit histone deacetylase enzymes. Herein, we present our exploration for new derivatives by replacing the piperidine moiety with various cycloamines. The goal was to obtain highly potent compounds with a good in vitro ADME profile. In addition, molecular modeling studies unravelled the binding mode of these inhibitors. PMID- 26629861 TI - Synthesis of novel trifluoromethyl substituted furo[2,3-b]pyridine and pyrido[3',2':4,5]furo[3,2-d]pyrimidine derivatives as potential anticancer agents. AB - A series of novel trifluoromethyl substituted furo[2,3-b]pyridine and pyrido[3',2':4,5]furo[3,2-d] pyrimidine derivatives 3a-b, 6a-k, 9, 10a-b, 11a-c and 12a-c were prepared from 2-carbethoxy-3-amino-6-trifluoromethyl furo[2,3 b]pyridine 1 under different set of conditions. Compounds functionalized with oxadiazole 11a-c were also prepared from 2-carbohydrazide-3-amino-6 trifluoromethyl furo[2,3-b]pyridine 4. All the final products were screened for anticancer activity against four human cancer cell lines such as Neuro-2a, Hela, A549 and COLO 205 as well as normal human lung cell line, IMR-90. All the compounds showed promising anticancer activity against all the tested cell lines at <25 MUM concentration except 5b, 6d, 6e and 6k. The selectivity index (SI) values have also been calculated for all the tested compounds in comparison to the normal cell line. Compounds 6g, 10a, 10b, and 11a were considered as potential leads which showed cytotoxicity with IC50 values of 10, 10.7, 11.0 and 10.5 MUM, respectively. Compounds 7 and 12a were considered as highly potent exhibiting promising cytotoxicity with IC50 value of 5.8 and 3.6 MUM, respectively. PMID- 26629859 TI - Novel iodoacetamido benzoheterocyclic derivatives with potent antileukemic activity are inhibitors of STAT5 phosphorylation. AB - Signal Transducer and Activator of Transcription 5 (STAT5) protein, a component of the STAT family of signaling proteins, is considered to be an attractive therapeutic target because of its involvement in the progression of acute myeloid leukemia. In an effort to discover potent molecules able to inhibit the phosphorylation-activation of STAT5, twenty-two compounds were synthesized and evaluated on the basis of our knowledge of the activity of 2-(3',4',5' trimethoxybenzoyl)-3-iodoacetamido-6-methoxy benzo[b]furan derivative 1 as a potent STAT5 inhibitor. Most of these molecules, structurally related to compound 1, were characterized by the presence of a common 3',4',5'-trimethoxybenzoyl moiety at the 2-position of different benzoheterocycles such as benzo[b]furan, benzo[b]thiophene, indole and N-methylindole. Effects on biological activity of the iodoacetamido group and of different moieties (methyl and methoxy) at the C-3 to C-7 positions were examined. In the series of benzo[b]furan derivatives, moving the iodoacetylamino group from the C-4 to the C-5 or C-6 positions did not significantly affect antiproliferative activity. Compounds 4, 15, 20 and 23 blocked STAT5 signals and induced apoptosis of K562 BCR-ABL positive cells. For compound 23, the trimethoxybenzoyl moiety at the 2-position of the benzo[b]furan core was not essential for potent inhibition of STAT5 activation. PMID- 26629862 TI - A novel triazole derivative of betulinic acid induces extrinsic and intrinsic apoptosis in human leukemia HL-60 cells. AB - In an attempt to arrive at more potent cytotoxic agent than the bioactive natural product betulinic acid, influence of small structural modifications of its 1, 2, 3 triazole derivatives tethered at C-28 and both C3, C-28 using click chemistry approach has been studied. The chemically characterized triazoles have been screened for in vitro cytotoxicity against four human cancer cell lines HL-60, MiaPaCa-2, PC-3 and A549 which has allowed to identify triazole derivative 28{1N (4-fluoro phenyl)-1H-1, 2, 3-triazol-4-yl} methyloxy betulinic ester having better potency profile than the parent compound with IC50 values in the range of 5-7 MUM. It caused disruption of mitochondrial membrane potential, rendered Bcl-2 cleavage, Bax translocation and decrease Bcl-2/Bax ratio. These events are accompanied by activation of caspases -9, -3, which cleave the PARP-1. It also induces caspase-8, which is involved in extrinsic apoptotic pathway. Therefore, it induces apoptosis through both intrinsic and extrinsic pathways in human leukemia HL-60 cells. PMID- 26629863 TI - The role of imidoselenium(II) chlorides in the formation of cyclic selenium imides via cyclocondensation. AB - The third member of the series of imidoselenium(II) chlorides ClSe[N(tBu)Se]nCl (n = 3) (9) has been isolated from the cyclocondensation reaction of tBuNH2 and SeCl2 in THF in a molar ratio of ca. 3:1 and characterized in the form of two polymorphs 9a and 9b by single crystal X-ray analysis. The unusual structural features of this nine-atom chain are explained satisfactorily in terms of a bonding model that invokes intra-molecular secondary bonding interactions and hyperconjugation. The reaction of the bifunctional reagent ClSe[N(tBu)Se]2Cl (8) with tBuNH2 in THF occurs via concurrent pathways to give 1,3,5-Se3(NtBu)3 (1) and 1,3-Se3(NtBu)2 (3a). The energetics of the reactions of tBuNH2 and SeCl2 in THF have been calculated at the PBE0/def2-TZVPP level of theory in order to assess the feasibility of ClSe[N(tBu)Se]nCl (7-9, n = 1-3) as intermediates in the formation of known cyclic selenium imides. DFT calculations were also employed to explore the energy profile of the pathway of the formation of the first member of the series ClSeN(tBu)SeCl (7) from tBuNH2 and SeCl2 in THF at 298 K. The neutral ligand ClSeN(tBu)SeCl (7) is Se,Se'-coordinated to the metal centre in the unusual adduct [PdCl2{Se,Se'-(SeCl)2N(tBu)}].[PdCl2{Se,Se' Se4(NtBu)3}].MeCN (10.MeCN), which is the first metal complex of an imidoselenium(II) chloride. PMID- 26629864 TI - Cardiac Effects of Obesity: PATHOPHYSIOLOGIC, CLINICAL, AND PROGNOSTIC CONSEQUENCES-A REVIEW. AB - Obesity produces various hemodynamic alterations and changes in cardiac morphology that predispose to ventricular dysfunction and heart failure (HF). Obesity may serve as a risk factor for or the primary cause of HF. Obesity is also associated with impairment of cardiorespiratory fitness. An obesity paradox exists with respect to mortality in those with HF wherein overweight and mildly to moderately obese individuals have a better prognosis than underweight or normal weight persons. Cardiorespiratory fitness is an important determinant of the prognosis in obesity. Many of the alterations in cardiac structure and function as well as the clinical manifestations of HF are reversible with substantial weight loss in moderately to severely obese individuals. PMID- 26629865 TI - Changes in BODE Quartiles After Pulmonary Rehabilitation Do Not Predict 2-Year Survival in Patients With COPD. AB - PURPOSE: Pulmonary rehabilitation (PR) has well documented positive effects in patients with chronic obstructive pulmonary disease (COPD). The BODE (body mass index, airflow obstruction, dyspnea, and exercise) index reflects the multicomponent nature of COPD. We aimed to determine whether changes in BODE quartiles after a PR program might affect 2-year survival and which characteristics drive changes in BODE quartiles after PR intervention. METHODS: Ninety-five patients with COPD participated in a PR program. The BODE index and anxiety, depression, and quality of life questionnaires were completed before and after the PR program. Five-year survival was recorded for all patients, irrespective of changes in BODE quartiles. RESULTS: Up to 62% of patients with COPD had an improvement in the BODE index, whereas 42% of patients had a change in BODE quartile. Survival did not differ between patients who did not and who did show an improvement in BODE quartiles, despite a trend in favor of the latter (log-rank P = .202). Similar results were observed for patients who did and did not demonstrate a change in the BODE index >=2 (log-rank P = .679). Significant changes in BODE quartiles were mainly attributed to the duration of the disease, current smoking status, hospitalization rate in the previous year, and the presence of poorer quality of life, as well as to anxiety and depression at baseline. CONCLUSIONS: Pulmonary rehabilitation significantly influenced the BODE index. The significant changes in BODE quartiles were associated with the duration of the disease, current smoking status, increased hospitalization rate, poorer quality of life, anxiety, and depression at baseline, but failed to predict 2-year survival. PMID- 26629866 TI - When the Topic Turns to Sex: CASE SCENARIOS IN SEXUAL COUNSELING AND CARDIOVASCULAR DISEASE. AB - Patients with cardiovascular disease and their partners frequently have concerns about sexual intimacy, and sexual counseling is needed across health care settings to ensure that patients receive information to safely resume sexual activity. The purpose of this review is to provide practical, evidence-based approaches to enable health care providers to discuss sexual counseling, illustrated by several case scenarios. Evidence shows that patients expect health care providers to initiate sexual activity discussions, although providers may be hesitant and often rely on patients to ask questions. Although some providers cite lack of knowledge or confidence in their ability to provide sexual counseling, others mention time pressures in the clinical setting. Although such barriers exist, sexual counseling can be individualized to the cardiac condition of a patient with a few select questions. The representative examples of patients with angina pectoris, myocardial infarction, coronary artery bypass surgery, heart failure, and implantable cardioverter defibrillator are used to illustrate key points and provide a model for sexual counseling in practice. PMID- 26629867 TI - Hepatocellular carcinoma in cirrhotic versus noncirrhotic livers: results from a large cohort in the Netherlands. AB - OBJECTIVES: Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis, but can also develop in noncirrhotic livers. In the present study we explored associated risk factors for HCC without cirrhosis and compared patient and tumor characteristics and outcomes in HCC patients with and without underlying cirrhosis. METHODS: Patients with HCC diagnosed in the period 2005 2012 in five Dutch academic centers were evaluated. Patients were categorized according to the presence of cirrhosis on the basis of histology or combined radiological and laboratory features. RESULTS: In total, 19% of the 1221 HCC patients had no underlying cirrhosis. Noncirrhotic HCC patients were more likely to be female and to have nonalcoholic fatty liver disease or no risk factors for underlying liver disease, and less likely to have hepatitis C virus or alcohol related liver disease than did cirrhotic HCC patients. HCCs in noncirrhotic livers were more often unifocal (67 vs. 48%), but tumor size was significantly larger (8 vs. 4 cm). Despite the larger tumors, more patients underwent resection (50 vs. 10%) and overall survival was significantly better than in cirrhotics. In multivariate analyses, absence of cirrhosis [hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.38-0.63] and presence of hepatitis B (HR 0.68, 95% CI 0.51-0.91) were independent predictors for lower mortality, whereas hepatitis C virus was associated with higher mortality (HR 1.32, 95% CI 1.01-1.65). CONCLUSION: HCC without cirrhosis was strongly associated with female sex and presence of nonalcoholic fatty liver disease or no risk factors for underlying liver disease. In absence of cirrhosis, resections were more often performed, with better survival despite larger tumor size. PMID- 26629868 TI - Predicting In-hospital Postoperative Mortality for the Practitioner: Beyond the Numbers. PMID- 26629869 TI - Disruptive Education: Training the Future Generation of Perioperative Physicians. PMID- 26629870 TI - Prevention of Late Onset Sepsis and Central-line Associated Blood Stream Infection in Preterm Infants. AB - AIM: Late onset sepsis (LOS) and central-line associated blood stream infection (CLA-BSI) contribute toward the mortality and morbidity in prematurely born infants. The aim of this study is to investigate the effects of hospital-wide and unit-based interventions on LOS and CLA-BSI in infants born at <32 weeks gestation. METHODS: Intensive care, high dependency days and catheter days were obtained from the unit database and blood culture results from a microbiology laboratory database. Poisson regression was used to evaluate the effects of interventions on LOS and CLA-BSI. RESULTS: Quarterly rates of LOS reduced from 26.1 to 2.9 per 1000 intensive care, high dependency days and CLA-BSI from 31.6 to 4.3 per 1000 catheter days between 2007 and 2012. Appointment of a hospital specialist vascular device nurse, a change in the mode of administration of vancomycin, standardization of the hospital skin and hub disinfection policy and the introduction of a venous infusion phlebitis scoring system were associated with a reduction of LOS to 55% (95% confidence interval: 40-74%) and CLA-BSI 45% (95% confidence interval: 33-61%) of pre-intervention levels. The standardization of the neonatal unit policy for skin disinfection and a move to a new building were associated with reductions of LOS to 64% (47-87%) and 54% (34-88%), respectively, and aseptic no touch technique for infusion access with CLA-BSI to 53% (37-75%) of pre-intervention levels. CONCLUSION: A multifaceted approach involving changes in antimicrobial and skin disinfection policy, training for aseptic no touch technique and surveillance resulted in sustained reduction in LOS and CLA-BSI rates. PMID- 26629871 TI - Application of a Prognostic Scale to Estimate the Mortality of Children Hospitalized with Community-acquired Pneumonia. AB - BACKGROUND: Pneumonia is a major cause of mortality in children. The objective of this study was to construct a prognostic scale for estimation of mortality applicable to children with community-acquired pneumonia (CAP). METHODS: This observational study included patients younger than 15 years with a diagnosis of CAP who were hospitalized between 2004 and 2013. A point-based scoring system based on the modification of the PIRO scale used in adults with pneumonia was applied to each child hospitalized with CAP. It included the following variables: predisposition (age <6 months, comorbidity), insult [hypoxia (O2 saturation < 90), hypotension (according to age) and bacteremia], response (multilobar or complicated pneumonia) and organ dysfunction (kidney failure, liver failure and acute respiratory distress syndrome). One point was given for each feature that was present (range, 0-10 points). The association between the modified PIRO score and mortality was assessed by stratifying patients into 4 levels of risk: low (0 2 points), moderate (3-4 points), high (5-6 points) and very high risk (7-10 points). RESULTS: Eight hundred sixty children hospitalized with CAP were eligible for study. The mean age was 2.8 +/- 3.2 years. The observed mortality was 6.5% (56/860). Mortality ranged from 0% for a low PIRO score (0/708 pts), 18% (20/112 pts) for a moderate score, 83% (25/30 pts) for a high score and 100% (10/10 pts) for a very high modified PIRO score (P < 0.001). CONCLUSION: The present score accurately discriminated the probability of death in children hospitalized with CAP, and it could be a useful tool to select candidates for admission to intensive care unit and for adjunctive therapy in clinical trials. PMID- 26629872 TI - Health Outcomes of International HIV-infected Adoptees in the US. AB - BACKGROUND: International adoption of HIV-infected children is becoming increasingly common. Their health has not yet been described. METHODS: HIV infected international adoptees or refugees in foster care aged 0-20 years followed at Seattle Children's Hospital or Children's Hospital Colorado between January 1, 2004 and May 31, 2013 were included. Parameters were collected through retrospective chart review of baseline (first 6 months at study site) and annual follow-up visits. RESULTS: Africa (90%) was the primary region of origin for the 79 children who met inclusion criteria. Median follow-up was 3 years (range: 0 7). At baseline, acute malnutrition was uncommon (8%); however, stunting occurred in 32%. Most stunting resolved during the study period. The most common medical issues at baseline were dermatologic (Tinea and Molluscum contagiosum) and gastrointestinal (parasites and diarrhea). Almost half (48%) had either mental health issues or behavioral problems. Educational delays (50%) were also common. Upon adoption, only 1% was severely (CD4% < 15%) immunosuppressed. Fifty-nine (75%) were on antiretroviral therapy (ART); 45 of these (76%) had suppressed viral load (VL). Of 14 children on ART with detectable VL, 11 (79%) demonstrated non-nucleoside reverse transcriptase inhibitor resistance and 1 (7%) protease inhibitor resistance. CONCLUSIONS: In this cohort of HIV-infected international adoptees, severe immunosuppression was uncommon. Most medical issues were mild. Stunting was common at baseline but largely resolved. Mental health issues, behavioral problems, and educational delays were common. Most children were on ART at adoption and most of these showed suppressed VL. Non-nucleoside reverse transcriptase inhibitor mutations were present in most viremic children. PMID- 26629873 TI - Delays in Initiation of Antiretroviral Therapy Among HIV-infected Children in Rural Zambia. AB - BACKGROUND: Although care and treatment are available to many HIV-infected children, barriers remain that delay initiation of antiretroviral therapy (ART). Minimizing these barriers is critical to starting ART at earlier ages. METHODS: Reasons for delay were evaluated among 200 children younger than 15 years of age initiating treatment in an HIV clinic in rural Zambia from 2011 to 2013. RESULTS: The median age of children at ART eligibility was 2.9 years, and 49% were male. After being determined eligible, 60% of children delayed ART initiation for a median of 28 days (interquartile range: 14, 75). Primary reasons for delay included waiting for test results, adherence issues and concurrent treatment for tuberculosis. When reasons for delay were categorized by type, 36% of children had family-related delays, 32% had delays because of clinic logistics, 27% had health-related delays and 6% had other or no identified reasons for delay. The median time between eligibility and ART initiation was shortest for children with delays because of clinic logistics (median: 18 days; interquartile range: 14, 35). Children with family-related delays tended to be older and orphaned, whereas children with delays because of clinic logistics tended to be younger, and children with health-related delays tended to have more advanced disease. In the first year of ART, no association was found between adherence and type of delay. CD4 T-cell percentages and weight-for-age Z scores were lower for children with health-related delays. CONCLUSIONS: Strategies to reduce delays in ART initiation will need to address a diverse set of issues, so children can benefit from earlier treatment. PMID- 26629874 TI - IL-1alpha Counteract TGF-beta Regulated Genes and Pathways in Human Fibroblasts. AB - Dysregulated wound healing is commonly associated with excessive fibrosis. Connective tissue growth factor (CTGF/CCN2) is characteristically overexpressed in fibrotic diseases and stimulated by transforming growth factor-beta (TGF-beta) in dermal fibroblasts. We previously showed that interleukin-1 (IL-1alpha) counteracts TGF-beta-stimulated CTGF mRNA and protein expression in these cells. The aim of this study was to explore the effects of IL-1alpha on further genes and pathways in TGF-beta regulated fibroblasts. Transcriptional microarray and multiple comparison analysis showed that the antagonizing effects of IL-1alpha was much more prominent than the synergistic effects, both with respect to number of genes and extent of changes in gene expression. Moreover, comparing canonical pathways by gene set enrichment analysis and the Ingenuity Pathway Analysis tool revealed that IL-1alpha counteracted TGF-beta in the top six most confident pathways regulated by both cytokines. Interferon and IL-1 signaling, as well as two pathways involved in apoptosis signaling were suppressed by TGF-beta and activated by IL-1alpha. Pathways involving actin remodeling and focal adhesion dynamics were activated by TGF-beta and suppressed by IL-1alpha. Analyzing upstream regulators in part corroborate the comparison of canonical pathways and added cell cycle regulators as another functional group regulated by IL-1alpha. Finally, gene set enrichment analysis of fibrosis-related genes indicated that IL 1 moderately counteracts the collective effect of TGF-beta on these genes. Microarray results were validated by qPCR. Taken together, the results indicate prominent antagonistic effects of IL-1alpha on TGF-beta regulated interferon signaling, as well as on a wide variety of other genes and pathways in fibroblasts. J. Cell. Biochem. 117: 1622-1632, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26629875 TI - Chinese innovation in cardiovascular drug discovery. PMID- 26629876 TI - Free Superoxide is an Intermediate in the Production of H2O2 by Copper(I)-Abeta Peptide and O2. AB - Oxidative stress is considered as an important factor and an early event in the etiology of Alzheimer's disease (AD). Cu bound to the peptide amyloid-beta (Abeta) is found in AD brains, and Cu-Abeta could contribute to this oxidative stress, as it is able to produce in vitro H2O2 and HO in the presence of oxygen and biological reducing agents such as ascorbate. The mechanism of Cu-Abeta catalyzed H2O2 production is however not known, although it was proposed that H2O2 is directly formed from O2 via a 2-electron process. Here, we implement an electrochemical setup and use the specificity of superoxide dismutase-1 (SOD1) to show, for the first time, that H2O2 production by Cu-Abeta in the presence of ascorbate occurs mainly via a free O2(-) intermediate. This finding radically changes the view on the catalytic mechanism of H2O2 production by Cu-Abeta, and opens the possibility that Cu-Abeta-catalyzed O2(-) contributes to oxidative stress in AD, and hence may be of interest. PMID- 26629877 TI - Aryl Polyenes, a Highly Abundant Class of Bacterial Natural Products, Are Functionally Related to Antioxidative Carotenoids. AB - Bacterial pigments of the aryl polyene type are structurally similar to the well known carotenoids with respect to their polyene systems. Their biosynthetic gene cluster is widespread in taxonomically distant bacteria, and four classes of such pigments have been found. Here we report the structure elucidation of the aryl polyene/dialkylresorcinol hybrid pigments of Variovorax paradoxus B4 by HPLC-UV MS, MALDI-MS and NMR. Furthermore, we show for the first time that this pigment class protects the bacterium from reactive oxygen species, similarly to what is known for carotenoids. An analysis of the distribution of biosynthetic genes for aryl polyenes and carotenoids in bacterial genomes is presented; it shows a complementary distribution of these protective pigments in bacteria. PMID- 26629878 TI - Linear Scars in a 4-Week-Old Girl. PMID- 26629879 TI - Differential effects of three echovirus strains on cell lysis and insulin secretion in beta cell derived lines. AB - In an earlier study, infection of human pancreatic islets with epidemic strains of echovirus (E4, E16, E30), with proven but differently ability to induce islet autoimmunity, resulted either in a severe damage (i.e., E16 and E30) or proceeded without visible changes in infected islets (i.e., E4). In this study, the ability of these strains to replicate in beta cells and the consequence of such an infection for beta cell lysis and beta cell function was studied in the pancreatic beta cell lines INS-1, MIN6, and NIT-1. The strains of E16 and E30 did replicate in INS1, MIN6, and NIT1 cells and resulted in a pronounced cytopathic effect within 3 days following infection. By contrast, E4 replicated in all examined insulinoma cells with no apparent cell destruction. The insulin release in response to high glucose stimulation was hampered in all infected cells (P < 0.05) when no evidence of cytolysis was present; however, the adverse effect of E16 and E30 on insulin secretion appeared to be higher than that of the E4 strain. The differential effects of echovirus infection on cell lysis, and beta cell function in the rodent insulinoma INS1, MIN6, and NIT 1 cells reflect those previously obtained in primary human islets and support the notion that the insulin-producing beta cells can harbor a non-cytopathic viral infection. PMID- 26629880 TI - Transition metal oxide hierarchical nanotubes for energy applications. AB - We report a general synthetic method for transition metal oxide (TMO) hierarchical nanotube (HNT) structures by a solution-phase cation exchange method from Cu2O nanowire templates. This method leads to the formation of hollow, tubular backbones with secondary, thin nanostructures on the tube surface, which substantially increases the surface reactive sites for electrolyte contacts and electrochemical reactions. As proofs-of-concept, several representative first-row TMO HNTs have been synthesized, including CoOx, NiOx, MnOx, ZnOx and FeOx, with specific surface areas much larger than nanotubes or nanoparticles of corresponding materials. An example of the potential energy storage applications of CoOx HNTs as supercapacitors is also demonstrated. PMID- 26629882 TI - Twelve Principles for Green Energy Storage in Grid Applications. AB - The introduction of energy storage technologies to the grid could enable greater integration of renewables, improve system resilience and reliability, and offer cost effective alternatives to transmission and distribution upgrades. The integration of energy storage systems into the electrical grid can lead to different environmental outcomes based on the grid application, the existing generation mix, and the demand. Given this complexity, a framework is needed to systematically inform design and technology selection about the environmental impacts that emerge when considering energy storage options to improve sustainability performance of the grid. To achieve this, 12 fundamental principles specific to the design and grid application of energy storage systems are developed to inform policy makers, designers, and operators. The principles are grouped into three categories: (1) system integration for grid applications, (2) the maintenance and operation of energy storage, and (3) the design of energy storage systems. We illustrate the application of each principle through examples published in the academic literature, illustrative calculations, and a case study with an off-grid application of vanadium redox flow batteries (VRFBs). In addition, trade-offs that can emerge between principles are highlighted. PMID- 26629881 TI - Initial Surgery and Survival in Stage IV Breast Cancer in the United States, 1988 2011. AB - IMPORTANCE: Management of the primary tumor site in patients with metastatic breast cancer remains controversial. OBJECTIVE: To evaluate the patterns of receipt of initial breast surgery for female patients with stage IV breast cancer in the United States, with particular attention to women who survived at least 10 years. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) program. Female patients diagnosed as having stage IV breast cancer between 1988 and 2011 and who did not receive radiation therapy as part of the first course of treatment were included (N = 21 372). Kaplan-Meier estimates of median survival and descriptive statistics were used to compare patient and tumor characteristics by receipt of breast surgery at diagnosis. A Royston-Parmar survival model and logistic regression analysis assessed demographic and clinical factors associated with survival and prolonged survival (of at least 10 years). MAIN OUTCOMES AND MEASURES: Differences in survival, particularly survival of at least 10 years, by receipt of initial surgery to the primary tumor. RESULTS: Among the 21 372 patients, the median survival increased from 20 months (1988-1991) to 26 months (2007-2011). During this time, the rate of surgery declined (odds ratio [OR], 0.16; 95% CI, 0.12-0.21). Even so, receipt of surgery was associated with improved survival in multivariate analysis, which controlled for patient and clinical characteristics, along with time period (hazard ratio, 0.60; 95% CI, 0.57-0.63). For women diagnosed as having cancer before 2002 (n = 7504), survival of at least 10 years was seen in 9.6% (n = 353) and 2.9% (n = 107) of those who did and did not receive surgery, respectively (OR, 3.61; 95% CI, 2.89-4.50). In multivariate analysis, survival of at least 10 years was associated with receipt of surgery (odds ratio, 2.80; 95% CI, 2.08-3.77), hormone receptor-positive disease (OR, 1.76; 95% CI, 1.25-2.48), older age (OR, 0.41; 95% CI, 0.32-0.54), larger tumor size (OR, 0.37; 95% CI, 0.27-0.51), marital status of being separated at the time of diagnosis (OR, 0.67; 95% CI, 0.51-0.88), and more recent year of diagnosis (OR, 1.43; 95% CI, 1.02-1.99). CONCLUSIONS AND RELEVANCE: Survival in stage IV breast cancer has improved and is increasingly of prolonged duration, particularly for some women undergoing initial breast surgery. As systemic therapy advances provide better control of distant disease in stage IV breast cancer, and as women present with lower distant disease burdens, these findings on initial surgery to the primary tumor may be of importance. PMID- 26629883 TI - Tetranuclear Heterometallic {Zn2Eu2} Complexes With 1-Naphthoate Anions: Synthesis, Structure and Photoluminescence Properties. AB - A series of new tetranuclear heterometallic Zn(II) -Eu(III) complexes have been synthesized, that is, (bpy)2 Zn2Eu2 (naph)10 (1), (bpy)2 Zn2Eu2 (naph)8 (NO3)2 (2), and (phen)2 Zn2Eu2 (naph)8 (NO3)2 (3), and other ones, where naph(-) is the 1-naphthoate anion, bpy=2,2'-bipyridyl, and phen=1,10-phenanthroline. The solid phase complexes consist of large supramolecular ensembles due to stacking interactions between the aromatic ligands. Photoluminescence (PL) measurements were carried out to study PL spectra, lifetimes and quantum yields (QY) of the synthesized complexes at different temperatures. The external QY for the solid phases of complexes under UV excitation was found to exceed 20 %. It has been shown that partial replacement of naphthoate ligands in the coordination environment of Eu(3+) by NO3(-) anions influences the PL properties. To investigate the behavior of these complexes in solvent, we dissolved complex 3 in MeCN, put it on a transparent glass as a substrate, and studied the PL properties at room temperature. PMID- 26629884 TI - Interventions to enhance maternal awareness of decreased fetal movement: a systematic review. AB - BACKGROUND: Decreased fetal movement is associated with adverse pregnancy and birth outcomes; timely reporting and appropriate management may prevent stillbirth. OBJECTIVES: Determine effects of interventions to enhance maternal awareness of decreased fetal movement. SEARCH STRATEGY: Cinahl, The Cochrane Library, EMBASE, MEDLINE, PsycINFO and SCOPUS databases; without limitation on language or publication year. SELECTION CRITERIA: Randomised or non-randomised studies evaluating interventions to enhance maternal awareness of decreased fetal movement. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed quality. MAIN RESULTS: We included 23 publications from 16 studies of fair to poor quality. We were unable to pool results due to substantial heterogeneity between studies. Three randomised controlled trials (RCTs) and five non-randomised studies (NRSs), involving 72 888 and 115 435 pregnancies, respectively, assessed effects of interventions on stillbirth and perinatal death. One large cluster RCT (n = 68 654) reported no stillbirth reduction, one RCT (n = 3111) reported significant stillbirth reduction, and one RCT (n = 1123) was small with no deaths. All NRSs favoured intervention over standard care; three studies (n = 31 131) reported significant reduction, whereas two studies (n = 84 304) reported non-significant reductions in stillbirth or perinatal deaths. Promising results from NRSs warrant further research. We found no evidence of increased maternal concern following interventions. No cost-effectiveness data were available. CONCLUSIONS: We found no clear evidence of benefit or harm; indirect evidence suggests improved pregnancy and birth outcomes. The optimal approach to support women in monitoring their pregnancies needs to be established. Meanwhile, women need to be informed about the importance of fetal movement for fetal health. TWEETABLE ABSTRACT: The benefits and risks of interventions to increase pregnant women's awareness of fetal movement are unclear. PMID- 26629885 TI - Hapalindole/Ambiguine Biogenesis Is Mediated by a Cope Rearrangement, C-C Bond Forming Cascade. AB - Hapalindoles are bioactive indole alkaloids with fascinating polycyclic ring systems whose biosynthetic assembly mechanism has remained unknown since their initial discovery in the 1980s. In this study, we describe the fam gene cluster from the cyanobacterium Fischerella ambigua UTEX 1903 encoding hapalindole and ambiguine biosynthesis along with the characterization of two aromatic prenyltransferases, FamD1 and FamD2, and a previously undescribed cyclase, FamC1. These studies demonstrate that FamD2 and FamC1 act in concert to form the tetracyclic core ring system of the hapalindoles from cis-indole isonitrile and geranyl pyrophosphate through a presumed biosynthetic Cope rearrangement and subsequent 6-exo-trig cyclization/electrophilic aromatic substitution reaction. PMID- 26629886 TI - Force-Field Induced Bias in the Structure of Abeta21-30: A Comparison of OPLS, AMBER, CHARMM, and GROMOS Force Fields. AB - In this work we examine the dynamics of an intrinsically disordered protein fragment of the amyloid beta, the Abeta21-30, under seven commonly used molecular dynamics force fields (OPLS-AA, CHARMM27-CMAP, AMBER99, AMBER99SB, AMBER99SB ILDN, AMBER03, and GROMOS53A6), and three water models (TIP3P, TIP4P, and SPC/E). We find that the tested force fields and water models have little effect on the measures of radii of gyration and solvent accessible surface area (SASA); however, secondary structure measures and intrapeptide hydrogen-bonding are significantly modified, with AMBER (99, 99SB, 99SB-ILDN, and 03) and CHARMM22/27 force-fields readily increasing helical content and the variety of intrapeptide hydrogen bonds. On the basis of a comparison between the population of helical and beta structures found in experiments, our data suggest that force fields that suppress the formation of helical structure might be a better choice to model the Abeta21-30 peptide. PMID- 26629887 TI - Comprehensive Study of an Earth-Abundant Bifunctional 3D Electrode for Efficient Water Electrolysis in Alkaline Medium. AB - We report efficient electrolysis of both water-splitting half reactions in the same medium by a bifunctional 3D electrode comprising Co3O4 nanospheres nucleated on the surface of nitrogen-doped carbon nanotubes (NCNTs) that in turn are grown on conductive carbon paper (CP). The resulting electrode exhibits high stability and large electrochemical activity for both oxygen and hydrogen evolution reactions (OER and HER). We obtain a current density of 10 mA/cm(2) in 0.1 M KOH solution at overpotentials of only 0.47 and 0.38 V for OER and HER, respectively. Additionally, the experimental observations are understood and supported by analyzing the Co3O4:NCNT and NCNT:CP interfaces by ab initio calculations. Both the experimental and the theoretical studies indicate that firm and well established interfaces along the electrode play a crucial role on the stability and electrochemical activity for both OER and HER. PMID- 26629889 TI - Intramolecular Gold-Catalyzed and NaH-Supported Cyclization Reactions of N Propargyl Indole Derivatives with Pyrazole and Pyrrole Rings: Synthesis of Pyrazolodiazepinoindole, Pyrazolopyrazinoindole, and Pyrrolopyrazinoindole. AB - Gold-catalyzed and NaH-supported intramolecular cyclization of N-propargyl indole derivatives with pyrazole and pyrrole units attached to indole is described. An efficient route to the synthesis of pyrazolodiazepinoindole, pyrazolopyrazinoindole, and pyrrolopyrazinoindole has been established. First, N propargyl 2-(1H-pyrazol-5-yl)-1H-indole and 2-(1H-pyrrol-2-yl)-1H-indole were synthesized. Introduction of various substituents into the alkyne functionality was accomplished by Sonogashira cross-coupling reaction. Gold-catalyzed cyclization of pyrazoles having a terminal alkyne afforded the 6-exo-dig cyclization product. However, exclusive formation of 7-endo-dig cyclization products was observed with internal alkynes. On the other hand, cyclization with NaH only resulted in the formation of 6-exo-dig cyclization products regardless of the substitution of the alkyne functionality. Allenic intermediates were postulated for this outcome. PMID- 26629888 TI - A Systems Oncology Approach Identifies NT5E as a Key Metabolic Regulator in Tumor Cells and Modulator of Platinum Sensitivity. AB - Altered metabolism in tumor cells is required for rapid proliferation but also can influence other phenotypes that affect clinical outcomes such as metastasis and sensitivity to chemotherapy. Here, a genome-wide association study (GWAS) guided integration of NCI-60 transcriptome and metabolome data identified ecto-5' nucleotidase (NT5E or CD73) as a major determinant of metabolic phenotypes in cancer cells. NT5E expression and associated metabolome variations were also correlated with sensitivity to several chemotherapeutics including platinum-based treatment. NT5E mRNA levels were observed to be elevated in cells upon in vitro and in vivo acquisition of platinum resistance in ovarian cancer cells, and specific targeting of NT5E increased tumor cell sensitivity to platinum. We observed that tumor NT5E levels were prognostic for outcomes in ovarian cancer and were elevated after treatment with platinum, supporting the translational relevance of our findings. In this work, we integrated and analyzed a plethora of public data, demonstating the merit of such a systems oncology approach for the discovery of novel players in cancer biology and therapy. We experimentally validated the main findings of the NT5E gene being involved in both intrinsic and acquired resistance to platinum-based drugs. We propose that the efficacy of conventional chemotherapy could be improved by NT5E inhibition and that NT5E expression may be a useful prognostic and predictive clinical biomarker. PMID- 26629890 TI - Chemoselective Alkylation for Diversity-Oriented Synthesis of 1,3,4 Benzotriazepin-2-ones and Pyrrolo[1,2][1,3,4]benzotriazepin-6-ones, Potential Turn Surrogates. AB - 1,3,4-Benzotriazepin-2-ones garner interest for medicinal applications, in part due to their relationship with benzodiazepinones. Ten 1,3,4-benzotriazepin-2-ones 6 and 19 and six pyrrolo[1,2][1,3,4]benzotriazepin-6-ones 7 and 23 were prepared in four to seven steps and 4-60% overall yields by a divergent strategy from methyl anthranilate employing chemoselective alkylations of common linear and cyclic precursors to diversify three triazepinone ring positions (N1, N3, and C5). X-ray crystallography demonstrated that benzotriazepinone 19g may serve as a gamma-turn mimic. PMID- 26629891 TI - Introduction. PMID- 26629892 TI - Increased Sleep Disturbances in Thai Children With Attention-Deficit Hyperactivity Disorder Compared With Typically Developing Children. AB - This study compares sleep disturbances in Thai children aged 5-12 years with attention-deficit hyperactivity disorder (ADHD) and typically developing children using the Children's Sleep Habits Questionnaire (CSHQ)-Thai version. Fifty-five children with ADHD and 110 typically developing children were enrolled. Their parents completed the CSHQ, the ADHD rating scales, and the Strengths and Difficulties Questionnaire (SDQ). Children with ADHD had significantly higher scores in all subscales of the CSHQ compared to controls. Among children with ADHD, children with higher SDQ scores (> 15) appeared to have more sleep disturbances than those with relatively lower SDQ scores. Moreover, fewer sleep related behavioral problems were observed in the medication treated group, which is particularly new to the field and for some perhaps not unexpected clinically. PMID- 26629893 TI - Nanoparticle siRNA against BMI-1 with a Polyethylenimine-Laminarin Conjugate for Gene Therapy in Human Breast Cancer. AB - The B-cell-specific Moloney leukemia virus inset site 1 gene (BMI-1) has attracted considerable attention in recent years because of its key role in breast cancer development and metastasis. The downregulation of BMI-1 expression via small interfering RNA (siRNA) effectively inhibits tumor growth. However, the successful application of this therapy is limited by the unavailability of an appropriate vector for siRNA transfer. Therefore, this study aimed to construct a novel laminarin-based nonviral gene transfer vector to carry a constructed BMI-1 targeting siRNA and to investigate the in vitro and in vivo antitumor effects of this siRNA on breast cancer cells. To enhance the siRNA-carrying capacity, we introduced polyethylenimine (PEI) to laminarin's surface via N,N' carbonyldiimidazole, which produced the cationic PEI-modified laminarin conjugate nLP. Subsequent in vitro experiments indicated that nLP not only formed a nanoparticle with a diameter of 200 nm through electrostatic interactions with siRNA but also showed high efficiency (95.0%) in the delivery siRNA to MCF-7 cells. The nanoparticle targeting BMI-1 (nLP/siBMI-2) reduced BMI-1 expression in breast MCF-7 cells by 90.9% reduction. An in vivo tumor suppression experiment demonstrated that the nLP/siBMI-2 nanoparticle had relatively low toxicity and good gene-therapeutic efficacy, with a tumor inhibition rate of 46.6%. PMID- 26629894 TI - Baseline assessment of campus-wide general health status and mental health: Opportunity for tailored suicide prevention and mental health awareness programming. AB - OBJECTIVE: A campus-wide assessment examined the physical and mental health status of a midsize midwestern public university. PARTICIPANTS: Two thousand and forty-nine students, faculty, and staff on a single college campus were assessed in March-April 2013. METHODS: Participants completed an online survey with sections devoted to demographics, physical and mental health status, and suicide knowledge and experiences. RESULTS: This study captured broad physical and mental health indicators. Students, faculty, and staff in certain demographic groups were more likely to report significant problems associated with mental and physical health. Specifically, women, faculty and staff of color, and nonheterosexual persons reported worse health outcomes. Across 8 mental health indicators, students reported consistently worse mental health than their faculty/staff counterparts. CONCLUSIONS: This paper presents findings from a significant campus-wide physical and mental health surveillance initiative. Results indicate the need for targeted physical and mental health support and intervention among these demographic groups. PMID- 26629895 TI - An update on the current pharmacotherapy for endometrial cancer. AB - INTRODUCTION: Endometrial cancer (EC) is the most common gynecologic malignancy in the developed world and is increasing in incidence. While the mainstay of treatment for EC is surgery followed by chemotherapy and/or radiation therapy, the available pharmacotherapies are rapidly and constantly evolving. Understanding these new therapies is an important part of the research and clinical care of women with EC. A review of available literature from MEDLINE (1879-2015) was conducted for the historic treatments and current therapies available for endometrial tumors. AREAS COVERED: This article reviews the current conventional therapies and discusses novel therapeutic agents, some of which are available to clinicians while others are currently being investigated in the preclinical setting. EXPERT OPINION: Genomic and immunohistochemical characterization of endometrial cancer may soon be the best approach for the identification of aggressive forms of tumor. Targeted therapies will soon be standard in the management of endometrial cancer. PMID- 26629896 TI - Antibody Binding Selectivity: Alternative Sets of Antigen Residues Entail High Affinity Recognition. AB - Understanding the relationship between protein sequence and molecular recognition selectivity remains a major challenge. The antibody fragment scFv1F4 recognizes with sub nM affinity a decapeptide (sequence 6TAMFQDPQER15) derived from the N terminal end of human papilloma virus E6 oncoprotein. Using this decapeptide as antigen, we had previously shown that only the wild type amino-acid or conservative replacements were allowed at positions 9 to 12 and 15 of the peptide, indicating a strong binding selectivity. Nevertheless phenylalanine (F) was equally well tolerated as the wild type glutamine (Q) at position 13, while all other amino acids led to weaker scFv binding. The interfaces of complexes involving either Q or F are expected to diverge, due to the different physico chemistry of these residues. This would imply that high-affinity binding can be achieved through distinct interfacial geometries. In order to investigate this point, we disrupted the scFv-peptide interface by modifying one or several peptide positions. We then analyzed the effect on binding of amino acid changes at the remaining positions, an altered susceptibility being indicative of an altered role in complex formation. The 23 starting variants analyzed contained replacements whose effects on scFv1F4 binding ranged from minor to drastic. A permutation analysis (effect of replacing each peptide position by all other amino acids except cysteine) was carried out on the 23 variants using the PEPperCHIP(r) Platform technology. A comparison of their permutation patterns with that of the wild type peptide indicated that starting replacements at position 11, 12 or 13 modified the tolerance to amino-acid changes at the other two positions. The interdependence between the three positions was confirmed by SPR (Biacore(r) technology). Our data demonstrate that binding selectivity does not preclude the existence of alternative high-affinity recognition modes. PMID- 26629897 TI - Does Severe Maternal Morbidity Affect Female Sexual Activity and Function? Evidence from a Brazilian Cohort Study. AB - OBJECTIVE: to assess Female Sexual Function Index (FSFI) scores and delay to resume sexual activity associated with a previous severe maternal morbidity. METHOD: This was a multidimensional retrospective cohort study. Women who gave birth at a Brazilian tertiary maternity between 2008 and 2012 were included, with data extraction from the hospital information system. Those with potentially life threatening conditions and maternal near miss episodes (severe maternal morbidity) were considered the exposed group. The control group was a random sample of women who had had uncomplicated pregnancy. Female sexual function was evaluated through FSFI questionnaire, and general and reproductive aspects were addressed through specific questions. Statistical analyses were performed using Mann-Whitney and Pearson's Chi-square for bivariate analyses. Logistic regression was used to identify variables independently associated with lower FSFI scores. RESULTS: 638 women were included (315 at exposed and 323 at not exposed groups). The majority of women were under 30 years-old in the control group and between 30 and 46 years-old in the exposed group (p = 0.003). Women who experienced severe maternal morbidity (SMM) had statistically significant differences regarding cesarean section (82.4% versus 47.1% among deliveries without complications, p<0.001), and some previous pathological conditions. FSFI mean scores were similar among groups ranging from 24.39 to 24.42. It took longer for exposed women to resume sexual activity after index pregnancy (mean 84 days after SMM and 65 days for control group, p = 0.01). Multiple analyses showed no significant association of FSFI below cut-off value with any predictor. CONCLUSION: FSFI scores were not different in both groups. However, they were lower than expected. SMM delayed resumption of sexual activity after delivery, beyond postpartum period. However, the proportion of women in both groups having sex at 3 months after delivery was similar. Altered sexual response may be evaluated as one of possible long-term consequences after SMM episodes. Further studies on the growing population of women surviving severe maternal conditions might be worth for improvement of care for women. PMID- 26629898 TI - On the Order of the Fractional Laplacian in Determining the Spatio-Temporal Evolution of a Space-Fractional Model of Cardiac Electrophysiology. AB - Space-fractional operators have been used with success in a variety of practical applications to describe transport processes in media characterised by spatial connectivity properties and high structural heterogeneity altering the classical laws of diffusion. This study provides a systematic investigation of the spatio temporal effects of a space-fractional model in cardiac electrophysiology. We consider a simplified model of electrical pulse propagation through cardiac tissue, namely the monodomain formulation of the Beeler-Reuter cell model on insulated tissue fibres, and obtain a space-fractional modification of the model by using the spectral definition of the one-dimensional continuous fractional Laplacian. The spectral decomposition of the fractional operator allows us to develop an efficient numerical method for the space-fractional problem. Particular attention is paid to the role played by the fractional operator in determining the solution behaviour and to the identification of crucial differences between the non-fractional and the fractional cases. We find a positive linear dependence of the depolarization peak height and a power law decay of notch and dome peak amplitudes for decreasing orders of the fractional operator. Furthermore, we establish a quadratic relationship in conduction velocity, and quantify the increasingly wider action potential foot and more pronounced dispersion of action potential duration, as the fractional order is decreased. A discussion of the physiological interpretation of the presented findings is made. PMID- 26629899 TI - Correction: Obesity Resistance and Enhanced Insulin Sensitivity in Ahnak-/- Mice Fed a High Fat Diet Are Related to Impaired Adipogenesis and Increased Energy Expenditure. PMID- 26629900 TI - Plasma Levels of Middle Molecules to Estimate Residual Kidney Function in Haemodialysis without Urine Collection. AB - BACKGROUND: Residual Kidney Function (RKF) is associated with survival benefits in haemodialysis (HD) but is difficult to measure without urine collection. Middle molecules such as Cystatin C and beta2-microglobulin accumulate in renal disease and plasma levels have been used to estimate kidney function early in this condition. We investigated their use to estimate RKF in patients on HD. DESIGN: Cystatin C, beta2-microglobulin, urea and creatinine levels were studied in patients on incremental high-flux HD or hemodiafiltration(HDF). Over sequential HD sessions, blood was sampled pre- and post-session 1 and pre-session 2, for estimation of these parameters. Urine was collected during the whole interdialytic interval, for estimation of residual GFR (GFRResidual = mean of urea and creatinine clearance). The relationships of plasma Cystatin C and beta2 microglobulin levels to GFRResidual and urea clearance were determined. RESULTS: Of the 341 patients studied, 64% had urine output>100 ml/day, 32.6% were on high flux HD and 67.4% on HDF. Parameters most closely correlated with GFRResidual were 1/beta2-micoglobulin (r2 0.67) and 1/Cystatin C (r2 0.50). Both these relationships were weaker at low GFRResidual. The best regression model for GFRResidual, explaining 67% of the variation, was: GFRResidual = 160.3 . (1/beta2m) - 4.2. Where beta2m is the pre-dialysis beta2 microglobulin concentration (mg/L). This model was validated in a separate cohort of 50 patients using Bland-Altman analysis. Areas under the curve in Receiver Operating Characteristic analysis aimed at identifying subjects with urea clearance>=2 ml/min/1.73 m2 was 0.91 for beta2-microglobulin and 0.86 for Cystatin C. A plasma beta2-microglobulin cut-off of <=19.2 mg/L allowed identification of patients with urea clearance >=2 ml/min/1.73 m2 with 90% specificity and 65% sensitivity. CONCLUSION: Plasma pre-dialysis beta2-microglobulin levels can provide estimates of RKF which may have clinical utility and appear superior to cystatin C. Use of cut-off levels to identify patients with RKF may provide a simple way to individualise dialysis dose based on RKF. PMID- 26629901 TI - Consistency Analysis of Genome-Scale Models of Bacterial Metabolism: A Metamodel Approach. AB - Genome-scale metabolic models usually contain inconsistencies that manifest as blocked reactions and gap metabolites. With the purpose to detect recurrent inconsistencies in metabolic models, a large-scale analysis was performed using a previously published dataset of 130 genome-scale models. The results showed that a large number of reactions (~22%) are blocked in all the models where they are present. To unravel the nature of such inconsistencies a metamodel was construed by joining the 130 models in a single network. This metamodel was manually curated using the unconnected modules approach, and then, it was used as a reference network to perform a gap-filling on each individual genome-scale model. Finally, a set of 36 models that had not been considered during the construction of the metamodel was used, as a proof of concept, to extend the metamodel with new biochemical information, and to assess its impact on gap-filling results. The analysis performed on the metamodel allowed to conclude: 1) the recurrent inconsistencies found in the models were already present in the metabolic database used during the reconstructions process; 2) the presence of inconsistencies in a metabolic database can be propagated to the reconstructed models; 3) there are reactions not manifested as blocked which are active as a consequence of some classes of artifacts, and; 4) the results of an automatic gap filling are highly dependent on the consistency and completeness of the metamodel or metabolic database used as the reference network. In conclusion the consistency analysis should be applied to metabolic databases in order to detect and fill gaps as well as to detect and remove artifacts and redundant information. PMID- 26629903 TI - Determinants of Mammal and Bird Species Richness in China Based on Habitat Groups. AB - Understanding the spatial patterns in species richness is a central issue in macroecology and biogeography. Analyses that have traditionally focused on overall species richness limit the generality and depth of inference. Spatial patterns of species richness and the mechanisms that underpin them in China remain poorly documented. We created a database of the distribution of 580 mammal species and 849 resident bird species from 2376 counties in China and established spatial linear models to identify the determinants of species richness and test the roles of five hypotheses for overall mammals and resident birds and the 11 habitat groups among the two taxa. Our result showed that elevation variability was the most important determinant of species richness of overall mammal and bird species. It is indicated that the most prominent predictors of species richness varied among different habitat groups: elevation variability for forest and shrub mammals and birds, temperature annual range for grassland and desert mammals and wetland birds, net primary productivity for farmland mammals, maximum temperature of the warmest month for cave mammals, and precipitation of the driest quarter for grassland and desert birds. Noteworthily, main land cover type was also found to obviously influence mammal and bird species richness in forests, shrubs and wetlands under the disturbance of intensified human activities. Our findings revealed a substantial divergence in the species richness patterns among different habitat groups and highlighted the group-specific and disparate environmental associations that underpin them. As we demonstrate, a focus on overall species richness alone might lead to incomplete or misguided understanding of spatial patterns. Conservation priorities that consider a broad spectrum of habitat groups will be more successful in safeguarding the multiple services of biodiversity. PMID- 26629902 TI - Functional Mimetics of the HIV-1 CCR5 Co-Receptor Displayed on the Surface of Magnetic Liposomes. AB - Chemokine G protein coupled receptors, principally CCR5 or CXCR4, function as co receptors for HIV-1 entry into CD4+ T cells. Initial binding of the viral envelope glycoprotein (Env) gp120 subunit to the host CD4 receptor induces a cascade of structural conformational changes that lead to the formation of a high affinity co-receptor-binding site on gp120. Interaction between gp120 and the co receptor leads to the exposure of epitopes on the viral gp41 that mediates fusion between viral and cell membranes. Soluble CD4 (sCD4) mimetics can act as an activation-based inhibitor of HIV-1 entry in vitro, as it induces similar structural changes in gp120, leading to increased virus infectivity in the short term but to virus Env inactivation in the long term. Despite promising clinical implications, sCD4 displays low efficiency in vivo, and in multiple HIV strains, it does not inhibit viral infection. This has been attributed to the slow kinetics of the sCD4-induced HIV Env inactivation and to the failure to obtain sufficient sCD4 mimetic levels in the serum. Here we present uniquely structured CCR5 co-receptor mimetics. We hypothesized that such mimetics will enhance sCD4 induced HIV Env inactivation and inhibition of HIV entry. Co-receptor mimetics were derived from CCR5 gp120-binding epitopes and functionalized with a palmitoyl group, which mediated their display on the surface of lipid-coated magnetic beads. CCR5-peptidoliposome mimetics bound to soluble gp120 and inhibited HIV-1 infectivity in a sCD4-dependent manner. We concluded that CCR5-peptidoliposomes increase the efficiency of sCD4 to inhibit HIV infection by acting as bait for sCD4-primed virus, catalyzing the premature discharge of its fusion potential. PMID- 26629904 TI - Combined Application of Gadoxetic Acid Disodium-Enhanced Magnetic Resonance Imaging (MRI) and Diffusion-Weighted Imaging (DWI) in the Diagnosis of Chronic Liver Disease-Induced Hepatocellular Carcinoma: A Meta-Analysis. AB - OBJECTIVE: Gadoxetic acid disodium (Gd-EOB-DTPA) is a magnetic resonance imaging (MRI) contrast agent to target the liver cells with normal function. In clinical practice, the Gd-EOB-DTPA produces high quality hepatocyte specific image 20 minutes after intravenous injection, so DWI sequence is often performed after the conventional dynamic scanning. However, there are still some disputes about whether DWI sequence will provide more effective diagnostic information in clinical practice. This study aimed to explore the diagnostic value of combining Gd-EOB-DTPA-enhanced MRI and DWI in the detection of hepatocellular carcinoma (HCC) in patients with chronic liver disease. METHODS: A systematic literature search was performed in the PubMed and Cochrane library database up to March 2015. The quality assessment of diagnostic accuracy studies (QUADAS) was used to evaluate the quality of studies. Heterogeneous test on the included literature was performed by using the software Review Manager 5.3. The MetaDiSc 1.4 software was used to calculate the pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio; meanwhile the summary receiver operating characteristics (SROC) curve was drawn to compare the diagnostic performance. RESULTS: A total of 13 literatures were included in this study. In 8 literatures regarding HCC diagnosis based on Gd-EOB-DTPA-enhanced MRI, the pooled sensitivity: 0.90 (95% confidence interval (CI): 0.88-0.93); specificity: 0.89 (95% CI: 0.85-0.92); positive likelihood ratio: 8.60 (95% CI: 6.20-11.92); negative likelihood ratio: 0.10 (95% CI: 0.08-0.14) were obtained. The area under curve (AUC) and Q values were 0.96 and 0.90, respectively. In 5 literatures relating to HCC diagnosis by combination of Gd-EOB-DTPA-enhanced MRI and DWI sequence, the pooled sensitivity: 0.88 (95% CI: 0.85-0.91), specificity: 0.96 (0.94-0.97), positive likelihood ratio: 19.63 (12.77-30.16), negative likelihood ratio: 0.10 (0.07-0.14) were obtained. The AUC value was 0.9833 and Q value was 0.9436. The AUC value of comprehensive evaluation method was significantly higher than that of Gd-EOB-DTPA-enhanced MRI alone(P<0.05). CONCLUSION: Combination of Gd-EOB-DTPA-enhanced MRI and DWI sequence significantly improves in both the diagnostic accuracy and specificity of chronic liver disease-associated HCC. PMID- 26629905 TI - Associated Factors and Consequences of Risk of Bias in Randomized Controlled Trials of Yoga: A Systematic Review. AB - BACKGROUND: Bias in randomized controlled trials (RCTs) of complementary therapy interventions seems to be associated with specific factors and to potentially distort the studies' conclusions. This systematic review assessed associated factors of risk of bias and consequences for the studies' conclusions in RCTs of yoga as one of the most commonly used complementary therapies. METHODS: Medline/PubMed, Scopus, IndMED and the Cochrane Library were searched through February 2014 for yoga RCTs. Risk of selection bias was assessed using the Cochrane tool and regressed to a) publication year; b) country of origin; c) journal type; and d) impact factor using multiple logistic regression analysis. Likewise, the authors' conclusions were regressed to risk of bias. RESULTS: A total of 312 RCTs were included. Impact factor ranged from 0.0 to 39.2 (median = 1.3); 60 RCT (19.2%) had a low risk of selection bias, and 252 (80.8%) had a high or unclear risk of selection bias. Only publication year and impact factor significantly predicted low risk of bias; RCTs published after 2001 (adjusted odds ratio (OR) = 12.6; 95% confidence interval (CI) = 1.7, 94.0; p<0.001) and those published in journals with impact factor (adjusted OR = 2.6; 95%CI = 1.4, 4.9; p = 0.004) were more likely to have low risk of bias. The authors' conclusions were not associated with risk of bias. CONCLUSIONS: Risk of selection bias was generally high in RCTs of yoga; although the situation has improved since the publication of the revised CONSORT statement 2001. Pre-CONSORT RCTs and those published in journals without impact factor should be handled with increased care; although risk of bias is unlikely to distort the RCTs' conclusions. PMID- 26629906 TI - When Love Is in the Air: Understanding Why Dogs Tend to Mate when It Rains. AB - Seasonality of reproduction is observed in many species of organisms, across taxa, and is influenced by both biotic and abiotic factors. While such seasonality is easy to understand in temperate species exposed to extreme climates, it is more difficult to explain in the tropics. In many tropical species offspring are born during the season of high precipitation, which also coincides with high resource availability. Interestingly, in India, free-ranging dogs seem to mate, and not whelp, when it rains--an observation that cannot be explained by the resource abundance hypothesis. We carried out an extensive study to identify the mating seasons of free-ranging dogs, and observed a strong correlation between both the incidence and frequency of mating related behaviours of dogs, and precipitation levels. There are two clear mating seasons, of which the primary mating season coincides with the monsoon (rainy season) and the secondary mating season coincides with the nor'westerlies in this part of India. We speculate that this strong correlation is an effect of chemistry, rather than biology. While male dogs can mate round the year, females come into estrous seasonally. In the urban environment, dogs are exposed to a lot of olfactory noise, which can dilute the signal present in sex pheromones of the females in heat. A shower leads to increased humidity and reduced temperature of the air, leading to intensification of pheromone signals that trigger a sexual response in the dogs. PMID- 26629907 TI - Electroosmotic Pumps with Frits Synthesized from Potassium Silicate. AB - Electroosmotic pumps employing silica frits synthesized from potassium silicate as a stationary phase show strong electroosmotic flow velocity and resistance to pressure-driven flow. We characterize these pumps and measure an electroosmotic mobility of 2.5 * 10(-8) m(2)/V s and hydrodynamic resistance per unit length of 70 * 10(17) Pa s/m(4) with a standard deviation of less than 2% even when varying the amount of water used in the potassium silicate mixture. Furthermore, we demonstrate the simple integration of these pumps into a proof-of-concept PDMS lab-on-a-chip device fabricated from a 3D-printed template. PMID- 26629908 TI - Abnormal Motor Activity and Thermoregulation in a Schizophrenia Rat Model for Translational Science. AB - BACKGROUND: Schizophrenia is accompanied by altered motor activity and abnormal thermoregulation; therefore, the presence of these symptoms can enhance the face validity of a schizophrenia animal model. The goal was to characterize these parameters in freely moving condition of a new substrain of rats showing several schizophrenia-related alterations. METHODS: Male Wistar rats were used: the new substrain housed individually (for four weeks) and treated subchronically with ketamine, and naive animals without any manipulations. Adult animals were implanted with E-Mitter transponders intraabdominally to record body temperature and locomotor activity continuously. The circadian rhythm of these parameters and the acute effects of changes in light conditions were analyzed under undisturbed circumstances, and the effects of different interventions (handling, bed changing or intraperitoneal vehicle injection) were also determined. RESULTS: Decreased motor activity with fragmented pattern was observed in the new substrain. However, these animals had higher body temperature during the active phase, and they showed wider range of its alterations, too. The changes in light conditions and different interventions produced blunted hyperactivity and altered body temperature responses in the new substrain. Poincare plot analysis of body temperature revealed enhanced short- and long-term variabilities during the active phase compared to the inactive phase in both groups. Furthermore, the new substrain showed increased short- and long-term variabilities with lower degree of asymmetry suggesting autonomic dysregulation. CONCLUSIONS: In summary, the new substrain with schizophrenia-related phenomena showed disturbed motor activity and thermoregulation suggesting that these objectively determined parameters can be biomarkers in translational research. PMID- 26629909 TI - Central GLP-1 receptor activation improves cholesterol metabolism partially independent of its effect on food intake. AB - Glucagon-like peptide-1 (GLP-1) receptor agonists modulate lipid metabolism, apart from controlling glucose homeostasis. We investigated the role of central GLP-1 receptor (GLP-1R) agonism in regulation of hepatic lipid metabolism in cholesterol-fed hamsters. Cholesterol-fed hamsters were treated by intracerebroventricular (i.c.v.) route with exendin-4, as acute or repeated dose regimen and compared with hamsters pair-fed to the exendin-treated hamsters and with hamsters co-treated with GLP-1 antagonist exendin-9. Effect of acute treatment was observed on food intake, tyloxapol-induced hypertriglyceridemia, and corn oil induced post prandial lipemia. Plasma and hepatic lipids and changes in the expression of hepatic genes involved in lipid metabolism were assessed after chronic administration. Acute, as well as repeated dose, treatment of exendin-4 showed significant changes in hepatic lipids, circulating fatty acids, triglycerides, LDL, and cholesterol. Expression of SREBP-1c was reduced while that of LDLR and CYP7A1 was increased after the repeated dose treatment, and there was no change in HMG CoA reductase. These changes were blocked by co treatment of exendin-9, and not replicated by pair feeding to the significant extent. Central GLP-1 receptor activation showed profound effects on peripheral lipid metabolism, which were partially independent of its effect on food intake. PMID- 26629910 TI - Straight but Not Narrow; Within-Gender Variation in the Gender-Specificity of Women's Sexual Response. AB - Gender differences in the specificity of sexual response have been a primary focus in sexual psychophysiology research, however, within-gender variability suggests sexual orientation moderates category-specific responding among women; only heterosexual women show gender-nonspecific genital responses to sexual stimuli depicting men and women. But heterosexually-identified or "straight" women are heterogeneous in their sexual attractions and include women who are exclusively androphilic (sexually attracted to men) and women who are predominantly androphilic with concurrent gynephilia (sexually attracted to women). It is therefore unclear if gender-nonspecific responding is found in both exclusively and predominantly androphilic women. The current studies investigated within-gender variability in the gender-specificity of women's sexual response. Two samples of women reporting concurrent andro/gynephilia viewed (Study 1, n = 29) or listened (Study 2, n = 30) to erotic stimuli varying by gender of sexual partner depicted while their genital and subjective sexual responses were assessed. Data were combined with larger datasets of predominantly gyne- and androphilic women (total N = 78 for both studies). In both studies, women reporting any degree of gynephilia, including those who self-identified as heterosexual, showed significantly greater genital response to female stimuli, similar to predominantly gynephilic women; gender-nonspecific genital response was observed for exclusively androphilic women only. Subjective sexual arousal patterns were more variable with respect to sexual attractions, likely reflecting stimulus intensity effects. Heterosexually-identified women are therefore not a homogenous group with respect to sexual responses to gender cues. Implications for within-gender variation in women's sexual orientation and sexual responses are discussed. PMID- 26629911 TI - Post-exercise pulse pressure is a better predictor of executive function than pre exercise pulse pressure in cognitively normal older adults. AB - Exercise "stress tests" are widely used to assess cardiovascular function and to detect abnormalities. In line with the view of exercise as a stressor, the present study examined the relationship between cognitive function and cardiovascular activity before and after light physical exercise in a sample of 84 non-demented community-dwelling older adults. Based on known relationships between hypertension, executive function and cerebral white matter changes, we hypothesized that greater post-exercise reactivity, as indexed by higher pulse pressure, would be more related to worse performance on frontal-executive tasks than pre-exercise physiologic measures. All participants were administered a comprehensive neuropsychological battery and underwent a Six Minute Walk Test (6MWT), with blood pressure (BP) measures obtained immediately before and after the walk. Pulse pressure (PP) was derived from BP as an indicator of vascular auto-regulation and composite scores were computed for each cognitive domain assessed. As predicted, worse executive function scores exhibited a stronger relationship with post-exercise PP than pre-exercise PP. Results suggest that PP following system stress in the form of walking may be more reflective of the state of vascular integrity and associated executive dysfunction in older adults than baseline physiologic measures. PMID- 26629913 TI - Fabrication and Characterization of Poly(epsilon-caprolactone)/alpha-Cyclodextrin Pseudorotaxane Nanofibers. AB - Multifunctional scaffolds comprising neat poly(epsilon-caprolactone) (PCL) and alpha-cyclodextrin pseudorotaxanated in alpha-cyclodextrin form have been fabricated using a conventional electrospinning process. Thorough in-depth characterizations were performed on the pseudorotaxane nanofibers prepared from chloroform (CFM) and CFM/dimethylformamide (DMF) utilizing scanning electron microscopy (SEM), transmission electron microscopy (TEM), rheology, differential scanning calorimetry (DSC), thermogravimetric analyses (TGA), wide-angle X-ray diffraction (WAXD), and Instron tensile testing. The results indicate the nanofibers obtained from chloroform retain the rotaxanated structure; while those obtained from CFM/DMF had significantly dethreaded during electrospinning. As a consequence, the nanowebs obtained from CFM showed higher moduli and lower elongations at break compared to neat PCL nanowebs and PCL/alpha-CD nanowebs electrospun from CFM/DMF. PMID- 26629912 TI - Impact of Altitude on Power Output during Cycling Stage Racing. AB - PURPOSE: The purpose of this study was to quantify the effects of moderate-high altitude on power output, cadence, speed and heart rate during a multi-day cycling tour. METHODS: Power output, heart rate, speed and cadence were collected from elite male road cyclists during maximal efforts of 5, 15, 30, 60, 240 and 600 s. The efforts were completed in a laboratory power-profile assessment, and spontaneously during a cycling race simulation near sea-level and an international cycling race at moderate-high altitude. Matched data from the laboratory power-profile and the highest maximal mean power output (MMP) and corresponding speed and heart rate recorded during the cycling race simulation and cycling race at moderate-high altitude were compared using paired t-tests. Additionally, all MMP and corresponding speeds and heart rates were binned per 1000 m (<1000 m, 1000-2000, 2000-3000 and >3000 m) according to the average altitude of each ride. Mixed linear modelling was used to compare cycling performance data from each altitude bin. RESULTS: Power output was similar between the laboratory power-profile and the race simulation, however MMPs for 5 600 s and 15, 60, 240 and 600 s were lower (p <= 0.005) during the race at altitude compared with the laboratory power-profile and race simulation, respectively. Furthermore, peak power output and all MMPs were lower (>= 11.7%, p <= 0.001) while racing >3000 m compared with rides completed near sea-level. However, speed associated with MMP 60 and 240 s was greater (p < 0.001) during racing at moderate-high altitude compared with the race simulation near sea level. CONCLUSION: A reduction in oxygen availability as altitude increases leads to attenuation of cycling power output during competition. Decrement in cycling power output at altitude does not seem to affect speed which tended to be greater at higher altitudes. PMID- 26629914 TI - Intra-Gene DNA Methylation Variability Is a Clinically Independent Prognostic Marker in Women's Cancers. AB - We introduce a novel per-gene measure of intra-gene DNA methylation variability (IGV) based on the Illumina Infinium HumanMethylation450 platform, which is prognostic independently of well-known predictors of clinical outcome. Using IGV, we derive a robust gene-panel prognostic signature for ovarian cancer (OC, n = 221), which validates in two independent data sets from Mayo Clinic (n = 198) and TCGA (n = 358), with significance of p = 0.004 in both sets. The OC prognostic signature gene-panel is comprised of four gene groups, which represent distinct biological processes. We show the IGV measurements of these gene groups are most likely a reflection of a mixture of intra-tumour heterogeneity and transcription factor (TF) binding/activity. IGV can be used to predict clinical outcome in patients individually, providing a surrogate read-out of hard-to-measure disease processes. PMID- 26629915 TI - Comparative evaluation of antibacterial activity of caffeic acid phenethyl ester and PLGA nanoparticle formulation by different methods. AB - The aim of the present study was to evaluate the antimicrobial activity of nanoparticle and free formulations of the CAPE compound using different methods and comparing the results in the literature for the first time. In parallel with this purpose, encapsulation of CAPE with the PLGA nanoparticle system (CAPE-PLGA NPs) and characterization of nanoparticles were carried out. Afterwards, antimicrobial activity of free CAPE and CAPE-PLGA-NPs was determined using agar well diffusion, disk diffusion, broth microdilution and reduction percentage methods. P. aeroginosa, E. coli, S. aureus and methicillin-resistant S. aureus (MRSA) were chosen as model bacteria since they have different cell wall structures. CAPE-PLGA-NPs within the range of 214.0 +/- 8.80 nm particle size and with an encapsulation efficiency of 91.59 +/- 4.97% were prepared using the oil in-water (o-w) single-emulsion solvent evaporation method. The microbiological results indicated that free CAPE did not have any antimicrobial activity in any of the applied methods whereas CAPE-PLGA-NPs had significant antimicrobial activity in both broth dilution and reduction percentage methods. CAPE-PLGA-NPs showed moderate antimicrobial activity against S. aureus and MRSA strains particularly in hourly measurements at 30.63 and 61.25 MUg ml(-1) concentrations (both p < 0.05), whereas they failed to show antimicrobial activity against Gram negative bacteria (P. aeroginosa and E. coli, p > 0.05). In the reduction percentage method, in which the highest results of antimicrobial activity were obtained, it was observed that the antimicrobial effect on S. aureus was more long-standing (3 days) and higher in reduction percentage (over 90%). The appearance of antibacterial activity of CAPE-PLGA-NPs may be related to higher penetration into cells due to low solubility of free CAPE in the aqueous medium. Additionally, the biocompatible and biodegradable PLGA nanoparticles could be an alternative to solvents such as ethanol, methanol or DMSO. Consequently, obtained results show that the method of selection is extremely important and will influence the results. Thus, broth microdilution and reduction percentage methods can be recommended as reliable and useful screening methods for determination of antimicrobial activity of PLGA nanoparticle formulations used particularly in drug delivery systems compared to both agar well and disk diffusion methods. PMID- 26629916 TI - The Relationship between Vessel Traffic and Noise Levels Received by Killer Whales (Orcinus orca). AB - Whale watching has become increasingly popular as an ecotourism activity around the globe and is beneficial for environmental education and local economies. Southern Resident killer whales (Orcinus orca) comprise an endangered population that is frequently observed by a large whale watching fleet in the inland waters of Washington state and British Columbia. One of the factors identified as a risk to recovery for the population is the effect of vessels and associated noise. An examination of the effects of vessels and associated noise on whale behavior utilized novel equipment to address limitations of previous studies. Digital acoustic recording tags (DTAGs) measured the noise levels the tagged whales received while laser positioning systems allowed collection of geo-referenced data for tagged whales and all vessels within 1000 m of the tagged whale. The objective of the current study was to compare vessel data and DTAG recordings to relate vessel traffic to the ambient noise received by tagged whales. Two analyses were conducted, one including all recording intervals, and one that excluded intervals when only the research vessel was present. For all data, significant predictors of noise levels were length (inverse relationship), number of propellers, and vessel speed, but only 15% of the variation in noise was explained by this model. When research-vessel-only intervals were excluded, vessel speed was the only significant predictor of noise levels, and explained 42% of the variation. Simple linear regressions (ignoring covariates) found that average vessel speed and number of propellers were the only significant correlates with noise levels. We conclude that vessel speed is the most important predictor of noise levels received by whales in this study. Thus, measures that reduce vessel speed in the vicinity of killer whales would reduce noise exposure in this population. PMID- 26629917 TI - Lysosomal Enzyme Glucocerebrosidase Protects against Abeta1-42 Oligomer-Induced Neurotoxicity. AB - Glucocerebrosidase (GCase) functions as a lysosomal enzyme and its mutations are known to be related to many neurodegenerative diseases, including Gaucher's disease (GD), Parkinson's disease (PD), and Dementia with Lewy Bodies (DLB). However, there is little information about the role of GCase in the pathogenesis of Alzheimer's disease (AD). Here we demonstrate that GCase protein levels and enzyme activity are significantly decreased in sporadic AD. Moreover, Abeta1-42 oligomer treatment results in neuronal cell death that is concomitant with decreased GCase protein levels and enzyme activity, as well as impairment in lysosomal biogenesis and acidification. Importantly, overexpression of GCase promotes the lysosomal degradation of Abeta1-42 oligomers, restores the lysosomal impairment, and protects against the toxicity in neurons treated with Abeta1-42 oligomers. Our findings indicate that a deficiency of GCase could be involved in progression of AD pathology and suggest that augmentation of GCase activity may be a potential therapeutic option for the treatment of AD. PMID- 26629927 TI - Dynamics of avian coronavirus circulation in commercial and non-commercial birds in Asia--a review. AB - It is essential to understand the latest situation regarding avian coronaviruses (ACoVs), commonly referred to as the well-known avian infectious bronchitis virus (IBV), given that new and diverse types of IBV are continually being identified worldwide, particularly ones that are isolated from commercial poultry and associated with a wide range of disease conditions. The existing IBVs continue to evolve in various geographic areas in Asia, which results in the recombination and co-circulation between IBV types. This makes it increasingly difficult to prevent and control IBV infections, despite routine vaccination. Some ACoVs have also been identified in other avian species and they may pose a threat of cross transmission to commercial sectors. The present review provides an overview of IBV circulation and the dynamic emergence of new variants found throughout Asia via the recombination of IBV strains. In addition to commercial poultry, backyard poultry and free-ranging birds may serve as a 'hub' for ACoV transmission within a particular area. These birds may be capable of spreading viruses, either to areas of close proximity, or to remote places via migration and trade. PMID- 26629928 TI - Preoperative diagnosis of cerebral hydatid cyst and its therapeutic implications. PMID- 26629926 TI - Assessment of the Effect of Intestinal Permeability Probes (Lactulose And Mannitol) and Other Liquids on Digesta Residence Times in Various Segments of the Gut Determined by Wireless Motility Capsule: A Randomised Controlled Trial. AB - BACKGROUND: Whilst the use of the mannitol/lactulose test for intestinal permeability has been long established it is not known whether the doses of these sugars modify transit time Similarly it is not known whether substances such as aspirin that are known to increase intestinal permeability to lactulose and mannitol and those such as ascorbic acid which are stated to be beneficial to gastrointestinal health also influence intestinal transit time. METHODS: Gastric and intestinal transit times were determined with a SmartPill following consumption of either a lactulose mannitol solution, a solution containing 600 mg aspirin, a solution containing 500 mg of ascorbic acid or an extract of blackcurrant, and compared by doubly repeated measures ANOVA with those following consumption of the same volume of a control in a cross-over study in six healthy female volunteers. The dominant frequencies of cyclic variations in gastric pressure recorded by the Smartpill were determined by fast Fourier transforms. RESULTS: The gastric transit times of lactulose mannitol solutions, of aspirin solutions and of blackcurrant juice did not differ from those of the control. The gastric transit times of the ascorbic acid solutions were significantly shorter than those of the other solutions. There were no significant differences between the various solutions either in the total small intestinal or colonic transit times. The intraluminal pHs during the initial quartiles of the small intestinal transit times were lower than those in the succeeding quartiles. This pattern did not vary with the solution that was consumed. The power of the frequencies of cyclic variation in intragastric pressure recorded by the Smartpill declined exponentially with increase in frequency and did not peak at the reported physiological frequencies of gastric contractile activity. CONCLUSIONS: Whilst the segmental residence times were broadly similar to those using other methods, the high degree of variation between subjects generally precluded the identification of all but gross variation between treatments. The lack of any differences between treatments in either total small or large intestinal transit times indicates that the solutions administered in the lactulose mannitol test of permeability had no consistent influence on the temporal pattern of absorption. The negatively exponential profile and lack of any peaks in the frequency spectra of cyclic variation in gastric intraluminal pressure that were consistent with reported physiological frequencies of contractile activity profile suggests that the principal source of this variation is stochastic likely resulting from the effects of external events occasioned by normal daily activities on intra abdominal pressure. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615000596505. PMID- 26629929 TI - Retroperitoneal PEComa related to the femoral nerve. PMID- 26629931 TI - Clostridium thermocellum Nitrilase Expression and Surface Display on Bacillus subtilis Spores. AB - Nitrilases are an important class of industrial enzymes. They require mild reaction conditions and are highly efficient and environmentally friendly, so they are used to catalyze the synthesis of carboxylic acid from nitrile, a process considered superior to conventional chemical syntheses. Nitrilases should be immobilized to overcome difficulties in recovery after the reaction and to stabilize the free enzyme. The nitrilase from Clostridium thermocellum was expressed, identified and displayed on the surface of Bacillus subtilis spores by using the spore coat protein G of B. subtilis as an anchoring motif. In a free state, the recombinant nitrilase catalyzed the conversion of 3-cyanopyridine to niacin and displayed maximum catalytic activity (8.22 units/mg protein) at 40 degrees C and pH 7.4. SDS-PAGE and Western blot were used to confirm nitrilase display. Compared with the free enzyme, the spore-immobilized nitrilase showed a higher tolerance for adverse environmental conditions. After the reaction, recombinant spores were recovered via centrifugation and reused 3 times to catalyze the conversion of 3-cyanopyridine with 75.3% nitrilase activity. This study demonstrates an effective means of nitrilase immobilization via spore surface display, which can be applied in biological processes or conversion. PMID- 26629933 TI - The effects of cognitive-behavioral therapy on intrinsic functional brain networks in adults with attention-deficit/hyperactivity disorder. AB - Cognitive-behavioral therapy (CBT) is an efficacious psychological treatment for adults with attention-deficit/hyperactivity disorder (ADHD), but the neural processes underlying the benefits of CBT are not well understood. This study aims to unravel psychosocial mechanisms for treatment ADHD by exploring the effects of CBT on functional brain networks. Ten adults with ADHD were enrolled and resting state functional magnetic resonance imaging scans were acquired before and after a 12-session CBT. Twelve age- and gender-matched healthy controls were also scanned. We constructed whole-brain functional connectivity networks using graph theory approaches and further computed the changes of regional functional connectivity strength (rFCS) between pre- and post-CBT in ADHD for measuring the effects of CBT. The results showed that rFCS was increased in the fronto-parietal network and cerebellum, the brain regions that were most often affected by medication, in adults with ADHD following CBT. Furthermore, the enhanced functional coupling between bilateral superior parietal gyrus was positively correlated with the improvement of ADHD symptoms following CBT. Together, these findings provide evidence that CBT can selectively modulate the intrinsic network connectivity in the fronto-parietal network and cerebellum and suggest that the CBT may share common brain mechanism with the pharmacology in adults with ADHD. PMID- 26629932 TI - Arbovirus-mosquito interactions: RNAi pathway. AB - Arthropod-borne (arbo) viruses infect hematophagous arthropods (vectors) to maintain virus transmission between vertebrate hosts. The mosquito vector actively controls arbovirus infection to minimize its fitness costs. The RNA interference (RNAi) pathway is the major antiviral response vectors use to restrict arbovirus infections. We know this because depleting RNAi gene products profoundly impacts arbovirus replication, the antiviral RNAi pathway genes undergo positive, diversifying selection and arboviruses have evolved strategies to evade the vector's RNAi responses. The vector's RNAi defense and arbovirus countermeasures lead to an arms race that prevents potential virus-induced fitness costs yet maintains arbovirus infections needed for transmission. This review will discuss the latest findings in RNAi-arbovirus interactions in the model insect (Drosophila melanogaster) and in specific mosquito vectors. PMID- 26629935 TI - Suppression of Cellular Proliferation and Invasion by HMGB1 Knockdown in Bladder Urothelial Carcinoma Cells. AB - HMGB1, which acts as a DNA chaperone to help maintain nuclear homeostasis, was reported to play a prominent role in cancer progression, angiogenesis, invasion, and metastasis development. Increased expression of HMGB1 has been observed in several tumor entities. However, the molecular mechanisms of HMGB1 in tumorigenesis of bladder cancer have rarely been reported. In the present study, real-time quantitative RT-PCR analysis revealed that the expression of HMGB1 in human bladder urothelial carcinoma (BUC) cells was much higher than that in human normal urethra epithelial cells. In order to investigate the role of HMGB1 in BUC cells, RNA interference and Talen-mediated gene knockout (KO) were used to knockdown and knockout HMGB1, respectively, in BUC cell lines BIU-87 and T24. HMGB1 knockdown/out greatly inhibited proliferation, invasion, and cell cycle G1/S transition of BUC cells. The decrease in cell viability caused by HMGB1 knockdown/out was due to an increase in apoptosis via Bax/Bcl-2, both of which were important molecules involved in the apoptotic pathway. We then investigated the effect of HMGB1 knockdown/out on the sensitivity of BUC cells treated with the anticancer drug cisplatin. Knockdown or knockout of HMGB1 rendered BUC cells more sensitive to cisplatin. The decreased expression of LC3-II and Beclin 1, which resulted in decreased levels of autophagy, could probably explain this phenomenon. Thus, HMGB1 may become a novel promising candidate for the prognosis and therapy for bladder cancer. PMID- 26629934 TI - Protein-protein interactions and the spatiotemporal dynamics of bacterial outer membrane proteins. AB - It has until recently been unclear whether outer membrane proteins (OMPs) of Gram negative bacteria are organized or distributed randomly. Studies now suggest promiscuous protein-protein interactions (PPIs) between beta-barrel OMPs in Escherichia coli govern their local and global dynamics, engender spatiotemporal patterning of the outer membrane into micro-domains and are the basis of beta barrel protein turnover. We contextualize these latest advances, speculate on areas of bacterial cell biology that might be influenced by the organization of OMPs into supramolecular assemblies, and highlight the new questions and controversies this revised view of the bacterial outer membrane raises. PMID- 26629936 TI - CXCL12-CXCR4 Axis Promotes Proliferation, Migration, Invasion, and Metastasis of Ovarian Cancer. AB - The CXCL12-CXCR4 chemokine axis may play a very important role in ovarian cancer cells proliferation, migration, invasion, and peritoneal metastasis in vitro and in vivo. In this study, transfected SKOV3-CXCR4, transfected vector SKOV3 negative, nontransfected SKOV3 ovarian cancer cells, and human peritoneal mesothelial cells (HPMCs) were cultivated in vitro, and the proliferation, migration, and invasion of these ovarian cancer cells were investigated with or without the influence of the CXCL12-CXCR4 axis. Nude mice models of ovarian cancer were created by injection of ovarian cancer cells into the peritoneal cavity for investigation of ovarian cancer cells metastasis. Our results demonstrated that in the SKOV3-CXCR4 group, the cell number of proliferation, migration, or penetration through the Matrigel membrane treated with CXCL12 was significantly (p < 0.05) greater than those treated with CXCR4 antibody or CXCR4 antagonist AMD 3100 in a concentration-dependent manner. In the SKOV3-negative and the nontransfected SKOV3 groups, no significant (p > 0.05) differences existed in the cell number of proliferation, migration, or penetration. Coculture of HPMCs and SKOV3-CXCR4 had significantly (p < 0.05) higher migration and invasion rates than the SKOV3-CXCR4-only group. In nude mice seeded with ovarian cancer cells, the tumor weight in the nude mice injected with SKOV3-CXCR4 cells was significantly (p < 0.05) greater than in the group injected with the SKOV3 negative or nontransfected SKOV3 cells. Taken together, our results show that the CXCL12-CXCR4 chemokine axis can significantly promote the proliferation, migration, invasion, and peritoneal metastasis of ovarian cancer cells, and interference with this axis may serve as a new therapeutic target in treating ovarian cancers. PMID- 26629937 TI - Knockdown of Peripheral Myelin Protein 22 Inhibits the Progression of Chronic Myeloid Leukemia. AB - We aimed to explore the underlying mechanism of peripheral myelin protein 22 (PMP22) in the development of chronic myeloid leukemia (CML). The level of PMP22 expression in CD34(+) cells isolated from CML patients' bone marrow samples (BMMCs) and peripheral blood samples (PBMCs) was determined by RT-PCR. In addition, PMP22-siRNA and scrambled control siRNA were transfected into human CML cell line K562 with Lipofectamine 2000 reagent. Cell viability and apoptosis were, respectively, determined by MTT assay and flow cytometry. Besides, the level of caspase 3 and Bcl-xL was then detected using Western blot. The level of PMP22 expression in CML patients' CD34(+) cells isolated from both PBMCs and BMMCs was significantly higher than the control group. PMP22 expression in K562 cells was successfully knocked down by siRNA. MTT analysis showed that knockdown of PMP22 inhibited the proliferation of CML cells. Flow cytometry showed that knockdown of PMP22 promoted the apoptosis of CML cells. Besides, Bcl-xL expression markedly decreased, while the expression of caspase 3 in CML cells significantly increased after knockdown of PMP22 expression. Our findings indicate that high expression of PMP22 may promote cell proliferation and inhibit cell apoptosis via upregulation of Bcl-xL or inhibition of caspase 3 activation, and thus may contribute to the development of CML. PMP22 may serve as a novel therapeutic target for the treatment of CML. PMID- 26629938 TI - Ursolic Acid Inhibits the Proliferation of Gastric Cancer Cells by Targeting miR 133a. AB - Ursolic acid (UA), a potential chemotherapeutic agent, has the properties of inhibition of the growth of many human cancer cell lines. Whether UA can inhibit the growth and metastasis of human gastric cancer cells remains unknown. In this study, it was found that UA inhibited the growth and metastasis of human gastric cancer cells in vitro. Our results showed the increase of the percent of apoptotic cells and G1 phase, the inhibition of cell migrations well as the decrease of the expression of Bax, caspase 3 and Bcl-2 in BGC-823 cells after the treatment with UA. Real-time quantitative PCR analysis showed that UA treatment upregulated the level of miR-133a in BGC-823 cells. Overexpression of miR-133a increased the G1 phase of cell cycle and decreased Akt1 expression in BGC-823 cells. These outcomes might be secondary to the increased expression of miR-133a after the treatment with UA. PMID- 26629939 TI - Inhibition of Glioblastoma Cell Growth In Vitro and In Vivo by Brucine, a Component of Chinese Medicine. AB - Glioblastoma multiforme (GBM) is one of the most common glial cell tumors and has drawn more and more attention in the clinic in recent years. Brucine has been reported to significantly suppress gastric cancer, lung cancer, and prostate cancer growth in vivo by inducing cell apoptosis. Here, the effects of brucine on U251 human glioma cell growth were investigated in vitro by cell proliferation assay, FACs, and qPCR in a xenograft tumor model. Treatment with brucine reduced the expression of BCL-2 and cyclooxygenase-2 (COX-2), while upregulated BAX expression in U251 human glioma cells resulted in reduced glioma cell survival rate and inhibited the growth of xenograft tumors. We concluded that brucine has a suppressive effect on U251 human glioma cells in vitro and in vivo, which could help in understanding the role of brucine in glioma cells and guiding drug use in the clinic. PMID- 26629940 TI - Mechanistic Study on Triptorelin Action in Protecting From 5-FU-Induced Ovarian Damage in Rats. AB - Triptorelin, a kind of GnRH agonist, is widely used in the treatment of hormone responsive cancers in the clinic. This study aimed to discover the underlying mechanism of triptorelin in protection from 5-fluorouracil (5-FU)-induced ovarian damage in Sprague-Dawley rats. In the present study, after using 5-FU to induce ovarian damage in rats, body weight and wet ovaries were weighed, the levels of estradiol (E2), follicle-stimulating hormone (FSH), and anti-Mullerian hormone (AMH) in blood were detected, and the expression of Bcl-2, Bax, and NF-kappaB was determined. It suggested that, compared to the control, body weight gain, the ratio of ovarian wet weight to body weight, primary follicle numbers, and the levels of AMH were significantly decreased, while the concentration of E2 and FSH was heavily increased following 5-FU administration. In contrast, after coadministration of triptorelin with 5-FU, the ratio of ovarian wet weight to body weight and the levels of AMH were significantly increased, whereas the level of E2 and FSH was decreased significantly when compared with the 5-FU group. Furthermore, at indicated times, 5-FU led to the reduced Bcl-2 and NF-kappaB expression and increased Bax expression while triptorelin plus 5-FU increased Bcl 2 and NF-kappaB expression and decreased Bax expression. It was indicated that triptorelin could protect rats from 5-FU-induced ovarian damage by modulation of hormones, Bcl-2, Bax, and NF-kappaB. These results might highlight the mechanism of triptorelin as a protective agent in clinical chemotherapy for ovarian damage. PMID- 26629941 TI - Overexpression of SMAR1 Enhances Radiosensitivity in Human Breast Cancer Cell Line MCF7 via Activation of p53 Signaling Pathway. AB - This study sought to investigate the effect of overexpression of SMAR1 (scaffold/matrix-associated region-binding protein 1) on cell radiosensitivity in breast cancer, as well as elucidate its regulatory mechanism. We constructed a lentiviral expression system to successfully overexpress SMAR1 in human breast cancer cell line MCF7. In addition, overexpression of SMAR1 in MCF7 cells enhanced the radiosensitivity to (89)SrCl2. Moreover, overexpression of SMAR1 significantly induced cell apoptosis rate and G2/M phase arrest under the irradiation of (89)SrCl2. In addition, Western blot analysis showed that overexpression of SMAR1 in MCF cells significantly increased the expression levels of pP53 (ser15), pP53 (ser20), acP53, and p21 and obviously decreased the expression of MDM2 under the irradiation of (89)SrCl2. Notably, these expression changes could be neutralized by PFTalpha, an inhibitor of p53 signaling pathway that could inhibit p53-dependent transactivation of p53-responsive genes. Therefore, overexpression of SMAR1 may increase radiosensitivity to (89)SrCl2 in breast cancer cell line MCF7 by p53-dependent G2/M checkpoint arrest and apoptosis. Enhanced expression of SMAR1 in tumors will help to improve the clinical efficiency of radiation therapy. PMID- 26629942 TI - Calcitriol Inhibits Cervical Cancer Cell Proliferation Through Downregulation of HCCR1 Expression. AB - Calcitriol (1alpha,25-dihydroxyvitamin D3) has demonstrated anticancer activity against several tumors. However, the underlying mechanism for this activity is not yet fully understood. Our experiment was designed and performed to address one aspect of this issue in cervical cancer. HeLa S3 cells were cultured in media with various concentrations of calcitriol. Cell proliferation and cell cycle were assessed by spectrophotometry and flow cytometry, respectively. The mRNA and protein expression levels of human cervical cancer oncogene (HCCR-1) and p21 were determined by RT-PCR and Western blot, respectively. Results indicated that calcitriol inhibited HeLa S3 cell proliferation and induced cell cycle arrest at the G1 phase. Calcitriol decreased HCCR-1 protein expression in a dose- and time dependent manner. Furthermore, promoter activity analyses revealed that transcriptional regulation was involved in the inhibition of HCCR-1 expression. Overexpression of HCCR-1 in HeLa S3 cells reversed the inhibition of cell proliferation and G1 phase arrest that resulted from calcitriol treatment. In addition, calcitriol increased p21 expression and promoter activity. HCCR-1 overexpression decreased p21 expression and promoter activity. Thus, our results suggested that calcitriol inhibited HeLa S3 cell proliferation by decreasing HCCR 1 expression and increasing p21 expression. PMID- 26629943 TI - Cost-Effectiveness Analysis of Adjuvant Stage III Colon Cancer Treatment at Veterans Affairs Medical Centers. AB - The objective of this study was to evaluate the real-world cost effectiveness of adjuvant stage III colon cancer chemotherapy regimens, given that previous analyses have been based on data from clinical trials. The study was designed using integrated decision tree and Markov model, which was developed to evaluate the cost effectiveness of 5-fluorouracil/leucovorin (5-FU/LV), capecitabine, and the combination of each with oxaliplatin. The analysis was performed from a US Veterans Affairs perspective via retrospectively collected data, over a 5-year model time horizon. Outcome and cost data were used to calculate cost per quality adjusted life year (QALY), and one-way and probabilistic sensitivity analyses were performed. In the base case analysis, capecitabine and capecitabine plus oxaliplatin both cost more and were less effective than other regimens, and 5 FU/LV plus oxaliplatin, compared to 5-FU/LV alone, resulted in a cost of $25,997 per QALY gained. Model results were generally robust to parameter variation. Capecitabine plus oxaliplatin could be economically reasonable if full dosing occurred >=76% of the time (base case 42%). In a real-world setting, the addition of oxaliplatin to 5-FU/LV is more effective but also more costly than 5-FU/LV alone. If full dosing of capecitabine-containing regimens can be assured, they may also be cost-effective strategies. PMID- 26629944 TI - Radiation Recall Pneumonitis During Systemic Treatment With Everolimus. AB - Radiation recall syndrome is an acute inflammatory reaction developing at anatomical sites of previously irradiated tissue, weeks to months after the completion of radiation therapy. The distribution pattern of inflammation typically involves, and remains limited to, the boundaries of prior radiation treatment fields. Several classical chemotherapy drugs have been reported to have the potential for causing radiation recall syndrome. With the increasing availability and expanding use of novel biologic and targeted therapy anticancer drugs, isolated reports of radiation recall syndrome secondary to this class of agents are starting to appear in the literature. We describe a case of everolimus induced radiation recall pneumonitis in a patient with metastatic renal cell cancer. PMID- 26629946 TI - BLID: A Novel Tumor-Suppressor Gene. AB - BLID (BH3-like motif containing, cell death inducer), also known as breast cancer cell 2 (BRCC2), was first reported in the human breast cancer cell line in 2004. BLID is a BH3-like motif containing apoptotic member of the Bcl-2 family. Recently, the BLID tumor-suppressor roles have been fully established. Several studies have found that BLID is frequently downregulated in many human cancers and the downregulation is often associated with tumor progression. Multivariate analysis indicated that BLID is an independent prognostic factor for overall survival and distant metastasis-free survival. Moreover, BLID can inhibit breast cancer cell growth and metastasis and promote apoptosis. BLID can regulate the expression of various tumor-related genes and proteins, such as AKT and MMP. In this review, we provide an overview of current knowledge concerning the role of BLID in tumor development and progression. To our knowledge, this is the first review about the role of this novel tumor-suppressor gene in tumor development and progression. PMID- 26629945 TI - Efficacy and Safety of Capecitabine and Oxaliplatin (CapOX) as an Adjuvant Therapy in Japanese for Stage II/III Colon Cancer in a Group at High Risk of Recurrence in Retrospective Study. AB - A number of large-scale clinical trials have demonstrated that using a combination of oxaliplatin and fluoropyrimidines as an adjuvant chemotherapy for stage II/III colon cancer improved the prognosis. However, there has only been experience in Japanese patients with using CapOX therapy, in which capecitabine and oxaliplatin are used in combination. Therefore, our objective was to evaluate the efficacy and safety of CapOX in Japanese patients as an adjuvant chemotherapy for colon cancer in a single institute retrospective study. The efficacy and safety of CapOX as an adjuvant chemotherapy for patients with stage III colon cancer and stage II patients who had a signature for high risk of recurrence were evaluated in patients who had undergone surgery at our institution between December 1, 2009 and March 31, 2013. Forty-one patients received CapOX therapy during the study period: 23 men and 18 women with median age of 68.0 years (35-79 years). Performance status was 0 for 33 patients, and PS 1 for eight patients. The clinical stages were stage II in 14 patients, stage IIIA in 15 patients, and stage IIIB in 12 patients. The median number of CapOX cycles was eight (two to eight courses). The treatment completion rate was 82.9%. Five-year DFS rates were 63.8%. Five-year OS rates were 71.0%. In terms of adverse events, the serious adverse events of grade 3 or higher seen among all patients were neutropenia in four patients, thrombocytopenia in one patient, and peripheral sensory neuropathy in seven patients. However, hand-foot syndrome, which is characteristic of capecitabine, was not observed. Efficacy and tolerability of CapOX in Japanese patients as an adjuvant chemotherapy after colon cancer surgery was demonstrated. PMID- 26629947 TI - TIP30: A Novel Tumor-Suppressor Gene. AB - TIP30/CC3 was first identified and characterized as a "candidate" tumor suppressor gene in 1997. Recently, the TIP30 tumor-suppressor status has been fully established since several studies have described that TIP30 protein expression is frequently downregulated in diverse types of human tumors, and the downregulation is often associated with tumor progression. TIP30 is involved in the control of cell apoptosis, growth, metastasis, angiogenesis, DNA repair, and tumor cell metabolism. Moreover, TIP30(-/-) mice spontaneously develop hepatocellular carcinoma and other tumors at a higher incidence than that of wild type mice. In this review, we provide an overview of current knowledge concerning the role of TIP30 in tumor development and progression. To our knowledge, this is the first review about the role of novel tumor-suppressor gene TIP30 in tumor development and progression. PMID- 26629948 TI - The antimalarial drug primaquine targets Fe-S cluster proteins and yeast respiratory growth. AB - Malaria is a major health burden in tropical and subtropical countries. The antimalarial drug primaquine is extremely useful for killing the transmissible gametocyte forms of Plasmodium falciparum and the hepatic quiescent forms of P. vivax. Yet its mechanism of action is still poorly understood. In this study, we used the yeast Saccharomyces cerevisiae model to help uncover the mode of action of primaquine. We found that the growth inhibitory effect of primaquine was restricted to cells that relied on respiratory function to proliferate and that deletion of SOD2 encoding the mitochondrial superoxide dismutase severely increased its effect, which can be countered by the overexpression of AIM32 and MCR1 encoding mitochondrial enzymes involved in the response to oxidative stress. This indicated that ROS produced by respiratory activity had a key role in primaquine-induced growth defect. We observed that Deltasod2 cells treated with primaquine displayed a severely decreased activity of aconitase that contains a Fe-S cluster notoriously sensitive to oxidative damage. We also showed that in vitro exposure to primaquine impaired the activity of purified aconitase and accelerated the turnover of the Fe-S cluster of the essential protein Rli1. It is suggested that ROS-labile Fe-S groups are the primary targets of primaquine. Aconitase activity is known to be essential at certain life-cycle stages of the malaria parasite. Thus primaquine-induced damage of its labile Fe-S cluster - and of other ROS-sensitive enzymes - could inhibit parasite development. PMID- 26629950 TI - Formation of 2-nitrophenol from salicylaldehyde as a suitable test for low peroxynitrite fluxes. AB - There has been some dispute regarding reaction products formed at physiological peroxynitrite fluxes in the nanomolar range with phenolic molecules, when used to predict the behavior of protein-bound aromatic amino acids like tyrosine. Previous data showed that at nanomolar fluxes of peroxynitrite, nitration of these phenolic compounds was outcompeted by dimerization (e.g. biphenols or dityrosine). Using 3-morpholino sydnonimine (Sin-1), we created low fluxes of peroxynitrite in our reaction set-up to demonstrate that salicylaldehyde displays unique features in the detection of physiological fluxes of peroxynitrite, yielding detectable nitration but only minor dimerization products. By means of HPLC analysis and detection at 380nm we could identify the expected nitration products 3- and 5-nitrosalicylaldehyde, but also novel nitrated products. Using mass spectrometry, we also identified 2-nitrophenol and a not fully characterized nitrated dimerization product. The formation of 2-nitrophenol could proceed either by primary generation of a phenoxy radical, followed by addition of the NO2-radical to the various resonance structures, or by addition of the peroxynitrite anion to the polarized carbonyl group with subsequent fragmentation of the adduct (as seen with carbon dioxide). Interestingly, we observed almost no 3- and 5-nitrosalicylic acid products and only minor dimerization reaction. Our results disagree with the previous general assumption that nitration of low molecular weight phenolic compounds is always outcompeted by dimerization at nanomolar peroxynitrite fluxes and highlight unique features of salicylaldehyde as a probe for physiological concentrations of peroxynitrite. PMID- 26629949 TI - Breast cancer 1 (BRCA1)-deficient embryos develop normally but are more susceptible to ethanol-initiated DNA damage and embryopathies. AB - The breast cancer 1 (brca1) gene is associated with breast and ovarian cancers, and heterozygous (+/-) brca1 knockout progeny develop normally, suggesting a negligible developmental impact. However, our results show BRCA1 plays a broader biological role in protecting the embryo from oxidative stress. Sox2-promoted Cre expressing hemizygous males were mated with floxed brca1 females, and gestational day 8 +/- brca1 conditional knockout embryos with a 28% reduction in protein expression were exposed in culture to the reactive oxygen species (ROS) initiating drug ethanol (EtOH). Untreated +/- brca1-deficient embryos developed normally, but when exposed to EtOH exhibited increased levels of oxidatively damaged DNA, measured as 8-oxo-2'-deoxyguanosine, gammaH2AX, which is a marker of DNA double strand breaks that can result from 8-oxo-2'-deoxyguanosine, formation, and embryopathies at EtOH concentrations that did not affect their brca1-normal littermates. These results reveal that even modest BRCA1 deficiencies render the embryo more susceptible to drug-enhanced ROS formation, and corroborate a role for DNA oxidation in the mechanism of EtOH teratogenesis. PMID- 26629951 TI - DC-SIGN as an attachment factor mediates Japanese encephalitis virus infection of human dendritic cells via interaction with a single high-mannose residue of viral E glycoprotein. AB - The skin-resident dendritic cells (DCs) are thought to be the first defender to encounter incoming viruses and likely play a role in Japanese encephalitis virus (JEV) early infection. In the current study, following the demonstration of JEV productive infection in DCs, we revealed that the interaction between JEV envelope glycoprotein (E glycoprotein) and DC-SIGN was important for such infection as evidenced by antibody neutralization and siRNA knockdown experiments. Moreover, the high-mannose N-linked glycan at N154 of E glycoprotein was shown to be crucial for JEV binding to DC-SIGN and subsequent internalization, while mutation of DC-SIGN internalization motif did not affect JEV uptake and internalization. These data together suggest that DC-SIGN functions as an attachment factor rather than an entry receptor for JEV. Our findings highlight the potential significance of DC-SIGN in JEV early infection, providing a basis for further understanding how JEV exploits DC-SIGN to gain access to dendritic cells. PMID- 26629953 TI - The p22 RNA silencing suppressor of the crinivirus Tomato chlorosis virus preferentially binds long dsRNAs preventing them from cleavage. AB - Viruses encode silencing suppressor proteins to counteract RNA silencing. Because dsRNA plays a key role in silencing, a general silencing suppressor strategy is dsRNA binding. The p22 suppressor of the plant virus Tomato chlorosis virus (ToCV; genus Crinivirus, family Closteroviridae) has been described as having one of the longest lasting local suppressor activities. However, the mechanism of action of p22 has not been characterized. Here, we show that ToCV p22 binds long dsRNAs in vitro, thus interfering with their processing into small RNAs (sRNAs) by an RNase III-type Dicer homolog enzyme. Additionally, we have studied whether a putative zinc finger motif found in p22 has a role in dsRNA binding and suppressor function. The efficient ability of p22 to suppress RNA silencing, triggered by hairpin transcripts transiently expressed in planta, supports the relationship between its ability to bind dsRNA in vitro and its ability to inhibit RNA silencing in vivo. PMID- 26629952 TI - A novel eight amino acid insertion contributes to the hemagglutinin cleavability and the virulence of a highly pathogenic avian influenza A (H7N3) virus in mice. AB - In 2012, an avian influenza A H7N3 (A/Mexico/InDRE7218/2012; Mx/7218) virus was responsible for two confirmed cases of human infection and led to the death or culling of more than 22 million chickens in Jalisco, Mexico. Interestingly, this virus acquired an 8-amino acid (aa)-insertion (..PENPK-DRKSRHRR-TR/GLF) near the hemagglutinin (HA) cleavage site by nonhomologous recombination with host rRNA. It remains unclear which specific residues at the cleavage site contribute to the virulence of H7N3 viruses in mammals. Using loss-of-function approaches, we generated a series of cleavage site mutant viruses by reverse genetics and characterized the viruses in vitro and in vivo. We found that the 8-aa insertion and the arginine at position P4 of the Mx/7218 HA cleavage site are essential for intracellular HA cleavage in 293T cells, but have no effect on the pH of membrane fusion. However, we identified a role for the histidine residue at P5 position in viral fusion pH. In mice, the 8-aa insertion is required for Mx/7218 virus virulence; however, the basic residues upstream of the P4 position are dispensable for virulence. Overall, our study provides the first line of evidence that the insertion in the Mx/7218 virus HA cleavage site confers its intracellular cleavability, and consequently contributes to enhanced virulence in mice. PMID- 26629954 TI - Two-photon fluorescence and fluorescence imaging of two styryl heterocyclic dyes combined with DNA. AB - Two new styryl heterocyclic two-photon (TP) materials, 4-[4-(N-methyl)styrene] imidazo [4,5-f][1,10] phenanthroline-benzene iodated salt (probe-1) and 4,4-[4-(N methyl)styrene]-benzene iodated salt (probe-2) were successfully synthesized and studied as potential fluorescent probes of DNA detection. The linear and nonlinear photophysical properties of two compounds in different solvents were investigated. The absorption, one- and two-photon fluorescent spectra of the free dye and dye-DNA complex were also examined to evaluate their photophysical properties. The binding constants of dye-DNA were obtained according to Scatchard equation with good values. The results showed that two probes could be used as fluorescent DNA probes by two-photon excitation, and TP fluorescent properties of probe-1 are superior to that of probe-2. The fluorescent method date indicated that the mechanisms of dye-DNA complex interaction may be groove binding for probe-1 and electrostatic interaction for probe-2, respectively. The MTT assay experiments showed two probes are low toxicity. Moreover, the TP fluorescence imaging of DNA detection in living cells at 800 nm indicated that the ability to locate in cell nuclei of probe-1 is better than that of probe-2. PMID- 26629955 TI - AutoDockFR: Advances in Protein-Ligand Docking with Explicitly Specified Binding Site Flexibility. AB - Automated docking of drug-like molecules into receptors is an essential tool in structure-based drug design. While modeling receptor flexibility is important for correctly predicting ligand binding, it still remains challenging. This work focuses on an approach in which receptor flexibility is modeled by explicitly specifying a set of receptor side-chains a-priori. The challenges of this approach include the: 1) exponential growth of the search space, demanding more efficient search methods; and 2) increased number of false positives, calling for scoring functions tailored for flexible receptor docking. We present AutoDockFR AutoDock for Flexible Receptors (ADFR), a new docking engine based on the AutoDock4 scoring function, which addresses the aforementioned challenges with a new Genetic Algorithm (GA) and customized scoring function. We validate ADFR using the Astex Diverse Set, demonstrating an increase in efficiency and reliability of its GA over the one implemented in AutoDock4. We demonstrate greatly increased success rates when cross-docking ligands into apo receptors that require side-chain conformational changes for ligand binding. These cross docking experiments are based on two datasets: 1) SEQ17 -a receptor diversity set containing 17 pairs of apo-holo structures; and 2) CDK2 -a ligand diversity set composed of one CDK2 apo structure and 52 known bound inhibitors. We show that, when cross-docking ligands into the apo conformation of the receptors with up to 14 flexible side-chains, ADFR reports more correctly cross-docked ligands than AutoDock Vina on both datasets with solutions found for 70.6% vs. 35.3% systems on SEQ17, and 76.9% vs. 61.5% on CDK2. ADFR also outperforms AutoDock Vina in number of top ranking solutions on both datasets. Furthermore, we show that correctly docked CDK2 complexes re-create on average 79.8% of all pairwise atomic interactions between the ligand and moving receptor atoms in the holo complexes. Finally, we show that down-weighting the receptor internal energy improves the ranking of correctly docked poses and that runtime for AutoDockFR scales linearly when side-chain flexibility is added. PMID- 26629957 TI - Study on Prevalence, Antibiotic Susceptibility, and tuf Gene Sequence-Based Genotyping of Species-Level of Coagulase-Negative Staphylococcus Isolated From Keratitis Caused by Using Soft Contact Lenses. AB - OBJECTIVE: To study on antibiotic susceptibility and identify coagulase-negative Staphylococcus (CoNS) species based on tuf gene sequencing from keratitis followed by using soft contact lenses in Isfahan, Iran, 2013. METHODS: This study examined 77 keratitis cases. The samples were cultured and the isolation of CoNS was done by phenotypic tests, and in vitro sensitivity testing was done by Kirby Bauer disk diffusion susceptibility method. RESULTS: Thirty-eight of isolates were conveniently identified as CoNS. In this study, 27 (71.1%), 21 (55.3%), and 16 (42.1%) were resistant to penicillin, erythromycin, and tetracycline, respectively. One hundred percent of isolates were sensitive to gentamicin, and 36 (94.7%) and 33 (86.8%) of isolates were sensitive to chloramphenicol and ciprofloxacin, respectively. Also, resistances to cefoxitin were 7 (18.4%). Analysis of tuf gene proved to be discriminative and sensitive in which all the isolates were identified with 99.0% similarity to reference strains, and Staphylococcus epidermidis had the highest prevalence among other species. CONCLUSIONS: Results of this study showed that CoNS are the most common agents causing contact lens-associated microbial keratitis, and the tuf gene sequencing analysis is a reliable method for distinguishing CoNS species. Also gentamycin, chloramphenicol, and ciprofloxacin are more effective than the other antibacterial agents against these types of bacteria. PMID- 26629958 TI - Dry Eye Disease: Concordance Between the Diagnostic Tests in African Eyes. AB - OBJECTIVE: To assess the concordance between the diagnostic tests for dry eye disease (DED) in a Nigerian hospital population. METHODS: The study was a hospital-based cross-sectional survey of adults (>=18 years) presenting at the eye clinic of the University of Nigeria Teaching Hospital (UNTH), Enugu; September-December, 2011. Participants' socio-demographic data were collected. Each subject was assessed for DED using the "Ocular Surface Disease Index" (OSDI) questionnaire, tear-film breakup time (TBUT), and Schirmer test. The intertest concordance was assessed using kappa statistic, correlation, and regression coefficients. RESULTS: The participants (n=402; men: 193) were aged 50.1+/-19.1 standard deviation years (range: 18-94 years). Dry eye disease was diagnosed in 203 by TBUT, 170 by Schirmer test, and 295 by OSDI; the concordance between the tests were OSDI versus TBUT (Kappa, kappa=-0.194); OSDI versus Schirmer (kappa= 0.276); and TBUT versus Schirmer (kappa=0.082). Ocular Surface Disease Index was inversely correlated with Schirmer test (Spearman rho=-0.231, P<0.001) and TBUT (rho=-0.237, P<0.001). In the linear regression model, OSDI was poorly predicted by TBUT (beta=-0.09; 95% confidence interval (CI): -0.26 to -0.03, P=0.14) and Schirmer test (beta=-0.35, 95% CI: -0.53 to -0.18, P=0.18). CONCLUSION: At UNTH, there is poor agreement, and almost equal correlation, between the subjective and objective tests for DED. Therefore, the selection of diagnostic test for DED should be informed by cost-effectiveness and diagnostic resource availability, not diagnostic efficiency or utility. PMID- 26629959 TI - The Influence of Overnight Orthokeratology on Ocular Surface and Meibomian Glands in Children and Adolescents. AB - PURPOSE: The aim of this study was to investigate the influence of overnight orthokeratology (OOK) on ocular surface and meibomian glands in children and adolescents. METHODS: Prospective, noncomparative study included the ocular surface disease index (OSDI), tear osmolarity, corneal and conjunctival fluorescein staining, tear film breakup time (TBUT), the Schirmer I test, and meiboscore using noncontact meibography. Immunofluorescence confocal microscopy of interleukin-1beta (IL1beta), interleukin-6 (IL6), epidermal growth factor (EGF), and matrix metalloproteinase (MMP)-9 using impression cytology filter paper was performed. The tests were performed before and at 6, 12, 24, and 36 months after OOK wear. RESULTS: Fifty-eight subjects using OOK were observed. Significant increases in OSDI score (P=0.0009) and corneal and conjunctival staining score (P<0.0001) were observed compared with baseline values at 36 and 24 months, respectively. Ocular surface and meibomian changes were noted in 2 patients (3.5%). One patient exhibited an increase in OSDI score, concurrent with a decrease in TBUT at 36 months and minor loss of the meibomian gland at the distal portion of the lower lid at 24 months. The other patients exhibited the development of papillary hypertrophy and meibomian gland distortion at 24 months. No significant changes were detected in IL1beta, IL6, EGF, or MMP expression after OOK use. CONCLUSION: Based on the findings, OOK was a relatively safe modality. However, given the potential changes in the meibomian gland and tear film stability, special attention must be paid to children with baseline meibomian gland distortions or a history of allergic conditions. PMID- 26629960 TI - Intraocular Pressure After 2 Hours of Small-Diameter Scleral Lens Wear. AB - OBJECTIVES: Compression of episcleral veins or deformation of tissue in the Schlemm's canal beneath the landing zone of scleral lenses could elevate intraocular pressure (IOP). We examined the effect of 2 hr of small-diameter scleral lens wear on IOP. METHODS: Twenty-nine participants, 29 +/- 6 years old (mean +/- SD) who experienced no history of eye disease or scleral lens wear, were included in the study. Each participant was fitted with a 15-mm Jupiter scleral lens on one eye (study eye). Intraocular pressure was measured in both eyes by pneumatonometry centrally on the cornea and peripherally on the sclera. The lens was then placed on one eye and was worn for 2 hr. Intraocular pressure was remeasured immediately after lens placement, at 1 and 2 hr of lens wear, and immediately after lens removal. Intraocular pressure after removal of the scleral lens was compared with IOP before placing the lens and to IOP in the control eye using paired t tests. RESULTS: Immediately after removing the scleral lens, mean central IOP in the study eye (13.9 +/- 3.1 mm Hg) was not different from mean central IOP in the control eye (13.5 +/- 2.2 mm Hg, P = 0.4) or in the same eye before lens wear (13.6 +/- 1.9 mm Hg, P = 0.6). There were also no differences in IOP measured peripherally at 2 hr of lens wear (P = 0.8). CONCLUSIONS: Neophyte scleral lens wear of a 15-mm scleral lens for 2 hr does not increase IOP in healthy eyes. PMID- 26629961 TI - Blending materials composed of boron, nitrogen and carbon to transform approaches to liquid hydrogen stores. AB - Mixtures of hydrogen storage materials containing the elements of boron, nitrogen, carbon, i.e., isomers of BN cyclopentanes are examined to find a 'fuel blend' that remains a liquid phase throughout hydrogen release, maximizes hydrogen storage density, minimizes impurities and remains thermally stable at ambient temperatures. We find that the mixture of ammonia borane dissolved in 3 methyl-1,2-dihydro-1,2-azaborolidine (compound B) provide a balance of these properties and provides ca. 5.6 wt% hydrogen. The two hydrogen storage materials decompose at a faster rate than either individually and products formed are a mixture of molecular trimers. Digestion of the product mixture formed from the decomposition of the AB + B fuel blend with methanol leads to the two corresponding methanol adducts of the starting material and not a complex mixture of adducts. The work shows the utility of using blends of materials to reduce volatile impurities and preserve liquid phase. PMID- 26629962 TI - What Future Role Might N-Acetyl-Cysteine Have in the Treatment of Obsessive Compulsive and Grooming Disorders?: A Systematic Review. AB - Licensed pharmacological treatments for obsessive-compulsive disorders include selective serotonin reuptake inhibitors and tricyclic antidepressants. However, a large proportion of patients show minimal or no therapeutic response to these treatments. The glutamatergic system has been implicated in the etiology of obsessive-compulsive spectrum disorders, and it has been postulated that n-acetyl cysteine (NAC) could have a therapeutic effect on these conditions through its actions on the glutamatergic system and the reduction of oxidative stress. A systematic review was conducted on the existing methodologically robust literature regarding the efficacy of NAC on obsessive-compulsive spectrum disorders in adults and children. Four randomized, double-blind placebo controlled studies were identified, investigating the effects of NAC on obsessive compulsive disorder, trichotillomania, and onychophagia. Results remain inconclusive, but NAC may still be useful as a treatment for obsessive-compulsive spectrum disorders on an individual level, particularly as the compound has a relatively benign side-effect profile. The dearth of methodologically robust work is clinically important: larger randomized controlled trials are required to inform of any meaningful clinical effectiveness, and to better determine which, if any, clinical populations might most benefit. PMID- 26629964 TI - Knots "Choke Off" Polymers upon Stretching. AB - Long polymer chains inevitably get tangled into knots. Like macroscopic ropes, polymer chains are substantially weakened by knots and the rupture point is always located at the "entry" or "exit" of the knot. However, these phenomena are only poorly understood at a molecular level. Here we show that when a knotted polyethylene chain is tightened, most of the stress energy is stored in torsions around the curved part of the chain. The torsions act as "work funnels" that effectively localize mechanical stress in the immediate vicinity of the knot. As a result, the knot "chokes" the chain at its entry or exit, thus leading to bond rupture at much lower forces than those needed to break a linear, unknotted chain. Our work not only explains the weakening of the polymer chain and the position of the rupture point, but more generally demonstrates that chemical bonds do not have to be extensively stretched to be broken. PMID- 26629963 TI - Extracellular matrix-blood composite injection reduces post-traumatic osteoarthritis after anterior cruciate ligament injury in the rat. AB - The objective of this study was to determine if an injection of a novel extracellular matrix scaffold and blood composite (EMBC) after anterior cruciate ligament (ACL) injury would have a mitigating effect on post-traumatic osteoarthritis (PTOA) development in rat knees. Lewis rats underwent unilateral ACL transection and were divided into three groups as follows: (1) no further treatment (ACLT; n = 10); (2) an intra-articular injection of EMBC on day 0 (INJ0; n = 11); and (3) an intra-articular injection of EMBC on day 14 (INJ14; n = 11). Ten additional animals received capsulotomy only (n = 10, SHAM group). The OARSI histology scoring of the tibial cartilage and micro-CT of the tibial epiphysis were performed after 35 days. The ratio of intact/treated hind limb forces during gait was determined using a variable resistor walkway. The OARSI cartilage degradation sum score and total degeneration width were significantly greater in the ACLT group when compared to the INJ0 (p = 0.031, and p = 0.005) and INJ14 (p = 0.022 and p = 0.04) group. Weight bearing on the operated limb only decreased significantly in the ACLT group (p = 0.048). In the rat ACL transection model, early or delayed injection of EMBC ameliorated the significant decrease in weight bearing and cartilage degradation seen in knees subjected to ACL transection without injection. The results indicate that the injection of EMBC may slow the process of PTOA following ACL injury and may provide a promising treatment for PTOA. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:995-1003, 2016. PMID- 26629965 TI - Structural Implications of Homopyrimidine Base Pairs in the Parallel-Stranded d(YGA) Motif. AB - DNA can adopt many other structures beyond the canonical B-form double helix. These alternative DNA structures have become increasingly significant as new biological roles are found for them. Additionally, there has been a growing interest in using non-canonical base pairs to provide structural diversity for designing DNA architectures for nanotechnology applications. We recently described the crystal structure of d(ACTCGGATGAT), which forms a tetraplex through parallel-stranded homo-base pairs and nucleobase intercalation. The homoduplex region contains a d(YGA?YGA) motif observed in crystal and solution structures. Here, we examine the structural implications of the homopyrimidine base pair within this motif. We determined crystal structures of two variants that differ from the original structure in the homopyrimidine base pairs and number of d(YGA) motifs. Our results show that the intercalation-locked tetraplex motif is predictable in these different sequence contexts and that substituting C?C base pairs for T?T base pairs introduces asymmetry to the homoduplex. These results have important implications for utilizing d(YGA) motifs in DNA crystal design and could provide a basis for understanding how local structures could be associated with repeat expansions. PMID- 26629966 TI - Isotretinoin Laboratory Test Monitoring--A Call to Decrease Testing in an Era of High-Value, Cost-Conscious Care. PMID- 26629968 TI - Enabling novel functionality in heavily doped ZnO:Ga by nanostructuring: an efficient plasmonic refractive index sensor. AB - We demonstrate a proof-of-concept refractive index sensor based on heavily doped ZnO:Ga nanostructured in a grating configuration, which supports free space excitation of propagating surface plasmons. The bulk sensitivity of the sensor of 4.9 * 10(3) nm per refractive index unit, achieved in the mid-infrared spectral range with the first grating prototype, surpasses that of the noble metal counterparts by three to four times. Sensing performance is discussed in the light of numerical simulations of the spatial profile of the near field of surface plasmon polaritons. PMID- 26629967 TI - Safety evaluation of chemically modified beta-lactoglobulin administered intravaginally. AB - Currently, there is no specific antiviral therapy for treatment of HPV infection. Jiang and colleagues previously reported that anhydride-modified proteins have inhibitory activities against multiple viruses including HPV. Here, we evaluated the safety of 3-hydroxyphthalic anhydride-modified bovine beta-lactoglobulin, designated JB01, vaginally applied in women infected by high-risk HPV. After the vaginal application of JB01 in 38 women for 3 months, no serious adverse events were reported, and normalization of the vaginal micro-environment has been observed. It can be concluded that JB01-BD is safe for vaginal use in HPV infected women, suggesting its potential application for the treatment of HPV infection. PMID- 26629969 TI - An Evidence-Based Approach to the Treatment of Gastroesophageal Reflux Disease. AB - IMPORTANCE: Gastroesophageal reflux disease (GERD) is prevalent worldwide, particularly in developed countries. It is estimated that the prevalence of GERD in the United States is approximately 20% and that it is increasing because of the epidemic of obesity. OBJECTIVE: To review the pathophysiology, clinical presentation, diagnostic evaluation, and treatment of GERD. EVIDENCE REVIEW: A search of PubMed was conducted for the years spanning 1985 to 2015 and included the following terms: heartburn, regurgitation, dysphagia, gastroesophageal reflux disease, cough, aspiration, laryngitis, GERD, GORD, endoscopy, manometry, pH monitoring, proton pump inhibitors, open fundoplication, and laparoscopic fundoplication. Only articles in English were included. FINDINGS: Lifestyle modifications, proton pump inhibitors, and laparoscopic fundoplication are proven treatment modalities for GERD. Endoscopic procedures have not been proven as effective. A Roux-en-Y gastric bypass is the procedure of choice when GERD and morbid obesity coexist. CONCLUSIONS AND RELEVANCE: Gastroesophageal reflux disease is a highly prevalent disease. Once the diagnosis has been established, the best results are obtained by a multidisciplinary team with the goal of individualizing treatment for patients. PMID- 26629970 TI - The infrapatellar fat pad from diseased joints inhibits chondrogenesis of mesenchymal stem cells. AB - Cartilage repair by bone marrow derived mesenchymal stem cells (MSCs) can be influenced by inflammation in the knee. Next to synovium, the infrapatellar fat pad (IPFP) has been described as a source for inflammatory factors. Here, we investigated whether factors secreted by the IPFP affect chondrogenesis of MSCs and whether this is influenced by different joint pathologies or obesity. Furthermore, we examined the role of IPFP resident macrophages. First, we made conditioned medium from IPFP obtained from osteoarthritic joints, IPFP from traumatically injured joints during anterior cruciate ligament reconstruction, and subcutaneous adipose tissue. Additionally, we made conditioned medium of macrophages isolated from osteoarthritic IPFP and of polarised monocytes from peripheral blood. We evaluated the effect of different types of conditioned medium on MSC chondrogenesis. Conditioned medium from IPFP decreased collagen 2 and aggrecan gene expression as well as thionin and collagen type 2 staining. This anti-chondrogenic effect was the same for conditioned medium from IPFP of osteoarthritic and traumatically injured joints. Furthermore, IPFP from obese (Body Mass Index >30) donors did not inhibit chondrogenesis more than that of lean (Body Mass Index <25) donors. Finally, conditioned medium from macrophages isolated from IPFP decreased the expression of hyaline cartilage genes, as did peripheral blood monocytes stimulated with pro-inflammatory cytokines. The IPFP and the resident pro-inflammatory macrophages could therefore be targets for therapies to improve MSC-based cartilage repair. PMID- 26629971 TI - Recent developments for Staphylococcus aureus vaccines: clinical and basic science challenges. AB - Bacterial vaccines have made dramatic impacts upon morbidity and mortality caused by a number of common pathogens, but a vaccine to prevent Staphylococcus aureus infections has proven to be illusive. With successful bacterial vaccines, the organisms are all part of the transient flora, whereas, S. aureus is part of the normal human flora. This means that S. aureus has had a prolonged time to adapt to the host milieu and its defences. The failure of several staphylococcal antigens to protect humans from infection in vaccine clinical trials using active or passive immunisation has stimulated a re-examination of the fundamental assumptions about staphylococcal immunity in humans vs. animals, especially rodents. This has spurred an active debate about the appropriate models for vaccine development and an examination of our current understanding of the protective immunity in humans. A major factor in the development of previous bacterial vaccines was a biomarker that predicted human protection, e.g., antibodies to tetanus toxoid or to pneumococcal polysaccharide. While antibodies against a number of staphylococcal antigens have proven to be an excellent biomarker for protection in rodents, these have not been translated to human infections. Thus, while much work remains, there is a growing consensus that T cell immunity plays an important role in protecting humans. Moreover, the presence of anti-staphylococcal toxin antibodies correlates with reduced disease severity in humans. The most important recent advances concerning potential biomarkers, and the role of pre-existing immune status of vaccines in vaccine associated mortality are considered in this review. PMID- 26629972 TI - Three-Dimensional Ordered Mesoporous MnO2-Supported Ag Nanoparticles for Catalytic Removal of Formaldehyde. AB - Three-dimensional (3D) ordered mesoporous Ag/MnO2 catalyst was prepared by impregnation method based on 3D-MnO2 and used for catalytic oxidation of HCHO. Ag nanoparticles are uniformly distributed on the polycrystalline wall of 3D-MnO2. The addition of Ag does not change the 3D ordered mesoporous structure of the Ag/MnO2, but does reduce the pore size and surface area. Ag nanoparticles provide sufficient active site for the oxidation reaction of HCHO, and Ag (111) crystal facets in the Ag/MnO2 are active faces. The 8.9% Ag/MnO2 catalyst shows a higher normalized rate (10.1 nmol.s(-1).m(-2) at 110 degrees C) and TOF (0.007 s(-1) at 110 degrees C) under 1300 ppm of HCHO and 150 000 h(-1) of GHSV, and its apparent activation energy of the reaction is the lowest (39.1 kJ/mol). More Ag active sites, higher low-temperature reducibility, more abundant surface lattice oxygen species, oxygen vacancies, and lattice defects generated from interaction Ag with MnO2 are responsible for the excellent catalytic performance of HCHO oxidation on the 8.9% Ag/MnO2 catalyst. The 8.9% Ag/MnO2 catalyst remained highly active and stable under space velocity increasing from 60 000 to 150 000 h(-1), under initial HCHO concentration increasing from 500 to 1300 ppm, and under the presence of humidity, respectively. PMID- 26629973 TI - Evidence-Based Practice Point-of-Care Resources: A Quantitative Evaluation of Quality, Rigor, and Content. AB - OBJECTIVE: Clinicians and other healthcare professionals need access to summaries of evidence-based information in order to provide effective care to their patients at the point-of-care. Evidence-based practice (EBP) point-of-care resources have been developed and are available online to meet this need. This study aimed to develop a comprehensive list of available EBP point-of-care resources and evaluate their processes and policies for the development of content, in order to provide a critical analysis based upon rigor, transparency and measures of editorial quality to inform healthcare providers and promote quality improvement amongst publishers of EBP resources. DESIGN: A comprehensive and systematic search (Pubmed, CINAHL, and Cochrane Central) was undertaken to identify available EBP point-of-care resources, defined as "web-based medical compendia specifically designed to deliver predigested, rapidly accessible, comprehensive, periodically updated, and evidence-based information (and possibly also guidance) to clinicians." MAIN OUTCOME MEASURES: A pair of investigators independently extracted information on general characteristics, content presentation, editorial quality, evidence-based methodology, and breadth and volume. RESULTS: Twenty-seven summary resources were identified, of which 22 met the predefined inclusion criteria for EBP point-of-care resources, and 20 could be accessed for description and assessment. Overall, the upper quartile of EBP point-of-care providers was assessed to be UpToDate, Nursing Reference Centre, Mosby's Nursing Consult, BMJ Best Practice, and JBI COnNECT+. LINKING EVIDENCE TO ACTION: The choice of which EBP point-of-care resources are suitable for an organization is a decision that depends heavily on the unique requirements of that organization and the resources it has available. However, the results presented in this study should enable healthcare providers to make that assessment in a clear, evidence-based manner, and provide a comprehensive list of the available options. PMID- 26629974 TI - "WHAT'S BUGGING THE GUT IN OCD?" A REVIEW OF THE GUT MICROBIOME IN OBSESSIVE COMPULSIVE DISORDER. AB - The gut microbiome has become a topic of major interest as of late, with a new focus specifically on psychiatric disorders. Recent studies have revealed that variations in the composition of the gut microbiota may influence anxiety and mood and vice versa. Keeping the concept of this bidirectional "microbiota-gut brain" axis in mind, this review aims to shed light on how these findings may also be implicated in obsessive-compulsive disorder (OCD); potentially outlining a novel etiological pathway of interest for future research in the field. PMID- 26629975 TI - Regiodivergent Enantioselective gamma-Additions of Oxazolones to 2,3 Butadienoates Catalyzed by Phosphines: Synthesis of alpha,alpha-Disubstituted alpha-Amino Acids and N,O-Acetal Derivatives. AB - Phosphine-catalyzed regiodivergent enantioselective C-2- and C-4-selective gamma additions of oxazolones to 2,3-butadienoates have been developed. The C-4 selective gamma-addition of oxazolones occurred in a highly enantioselective manner when 2-aryl-4-alkyloxazol-5-(4H)-ones were employed as pronucleophiles. With the employment of 2-alkyl-4-aryloxazol-5-(4H)-ones as the donor, C-2 selective gamma-addition of oxazolones took place in a highly enantioselective manner. The C-4-selective adducts provided rapid access to optically enriched alpha,alpha-disubstituted alpha-amino acid derivatives, and the C-2-selective products led to facile synthesis of chiral N,O-acetals and gamma-lactols. Theoretical studies via DFT calculations suggested that the origin of the observed regioselectivity was due to the distortion energy that resulted from the interaction between the nucleophilic oxazolide and the electrophilic phosphonium intermediate. PMID- 26629976 TI - The Analog Revolution and Its On-Going Role in Modern Analytical Measurements. AB - The electronic revolution in analytical instrumentation began when we first exceeded the two-digit resolution of panel meters and chart recorders and then took the first steps into automated control. It started with the first uses of operational amplifiers (op amps) in the analog domain 20 years before the digital computer entered the analytical lab. Their application greatly increased both accuracy and precision in chemical measurement and they provided an elegant means for the electronic control of experimental quantities. Later, laboratory and personal computers provided an unlimited readout resolution and enabled programmable control of instrument parameters as well as storage and computation of acquired data. However, digital computers did not replace the op amp's critical role of converting the analog sensor's output to a robust and accurate voltage. Rather it added a new role: converting that voltage into a number. These analog operations are generally the limiting portions of our computerized instrumentation systems. Operational amplifier performance in gain, input current and resistance, offset voltage, and rise time have improved by a remarkable 3-4 orders of magnitude since their first implementations. Each 10-fold improvement has opened the doors for the development of new techniques in all areas of chemical analysis. Along with some interesting history, the multiple roles op amps play in modern instrumentation are described along with a number of examples of new areas of analysis that have been enabled by their improvements. PMID- 26629977 TI - Microwave Heating of Poly(N-isopropylacrylamide)-Conjugated Gold Nanoparticles for Temperature-Controlled Display of Concanavalin A. AB - We demonstrate microwave-induced heating of gold nanoparticles and nanorods. An appreciably higher and concentration-dependent microwave-induced heating rate was observed with aqueous dispersions of the nanomaterials as opposed to pure water and other controls. Grafted with the thermoresponsive polymer poly(N isopropylacrylamide), these gold nanomaterials react to microwave-induced heating with a conformational change in the polymer shell, leading to particle aggregation. We subsequently covalently immobilize concanavalin A (Con A) on the thermoresponsive gold nanoparticles. Con A is a bioreceptor commonly used in bacterial sensors because of its affinity for carbohydrates on bacterial cell surfaces. The microwave-induced thermal transitions of the polymer reversibly switch on and off the display of Con A on the particle surface and hence the interactions of the nanomaterials with carbohydrate-functionalized surfaces. This effect was determined using linear sweep voltammetry on a methyl-alpha-d mannopyranoside-functionalized electrode. PMID- 26629978 TI - SpectroGene: A Tool for Proteogenomic Annotations Using Top-Down Spectra. AB - In the past decade, proteogenomics has emerged as a valuable technique that contributes to the state-of-the-art in genome annotation; however, previous proteogenomic studies were limited to bottom-up mass spectrometry and did not take advantage of top-down approaches. We show that top-down proteogenomics allows one to address the problems that remained beyond the reach of traditional bottom-up proteogenomics. In particular, we show that top-down proteogenomics leads to the discovery of previously unannotated genes even in extensively studied bacterial genomes and present SpectroGene, a software tool for genome annotation using top-down tandem mass spectra. We further show that top-down proteogenomics searches (against the six-frame translation of a genome) identify nearly all proteoforms found in traditional top-down proteomics searches (against the annotated proteome). SpectroGene is freely available at http://github.com/fenderglass/SpectroGene . PMID- 26629979 TI - Copper(I)-Catalyzed Sulfonylation of 8-Aminoquinoline Amides with Sulfonyl Chlorides in Air. AB - A simple and mild protocol for copper(I)-mediated sulfonylation of 8 aminoquinoline amides with sulfonyl chlorides was developed, affording desired products in moderate to good yields. This reaction proceeds in air and features excellent substrate tolerance, especially for aliphatic sulfonyl chlorides. PMID- 26629981 TI - Relationships of Sleep Duration With Weight-Related Behaviors of U.S. College Students. AB - This study describes sleep behaviors of U.S. college students (N = 1,252; 18-24 years old; 59% female) and examines associations of sleep duration with weight related behaviors. More than one quarter of participants slept < 7 hr/night and had mean Pittsburgh Sleep Quality Index (PSQI) scores indicating poor sleep quality. There were significant differences for all PSQI scales among sleep duration categories, < 7 hr (n = 344), 7-8 hr (n = 449), >= 8 hr (n = 459) sleep/night. Compared to those who slept >= 8 hr, those who slept < 8 hr had significantly more negative eating attitudes (2% higher), poorer internal regulation of food (4% lower), and greater binge eating (4% higher) scores. Findings advocate for health care professionals to evaluate sleep behaviors of college students during office visits and promote good sleep behaviors. PMID- 26629982 TI - Multifunctional pH-Sensitive Amino Lipids for siRNA Delivery. AB - RNA interference (RNAi) represents a powerful modality for human disease therapy that can regulate gene expression signature using small interfering RNA (siRNA). Successful delivery of siRNA into the cytoplasm of target cells is imperative for efficient RNAi and also constitutes the primary stumbling block in the clinical applicability of RNAi. Significant progress has been made in the development of lipid-based siRNA delivery systems, which have practical advantages like simple chemistry and easy formulation of nanoparticles with siRNA. This review discusses the recent development of pH-sensitive amino lipids, with particular focus on multifunctional pH-sensitive amino lipids for siRNA delivery. The key components of these multifunctional lipids include a protonatable amino head group, distal lipid tails, and two cross-linkable thiol groups, which together facilitate the facile formation of stable siRNA-nanoparticles, easy surface modification for target-specific delivery, endosomal escape in response to the pH decrease during subcellular trafficking, and reductive dissociation of the siRNA-nanoparticles for cytoplasmic release of free siRNA. By virtue of these properties, multifunctional pH-sensitive lipids can mediate efficient cytosolic siRNA delivery and gene silencing. Targeted siRNA nanoparticles can be readily formulated with these lipids, without the need for other helper lipids, to promote systemic delivery of therapeutic siRNAs. Such targeted siRNA nanoparticles have been shown to effectively regulate the expression of cancer related genes, resulting in significant efficacy in the treatment of aggressive tumors, including metastatic triple negative breast cancer. These multifunctional pH-sensitive lipids constitute a promising platform for the systemic and targeted delivery of therapeutic siRNA for the treatment of human diseases. This review summarizes the structure-property relationship of the multifunctional pH sensitive lipids and their efficacy in in vitro and in vivo siRNA delivery and gene silencing. PMID- 26629983 TI - Using a pattern-centered approach to assess sexual risk-taking in study abroad students. AB - OBJECTIVES: The purpose of this study was to examine the impact of several potential factors related to sexually risky behaviors in study abroad students. The authors utilized a pattern-centered analysis to identify specific groups that can be targeted for intervention. PARTICIPANTS: The sample consisted of 173 students who studied abroad in a variety of international locations for an average of 4 months. METHODS: Participants completed questionnaires informed by the Triandis Theory of Interpersonal Behavior that have been predictive of risky sex in traditional traveling environments. RESULTS: The analyses revealed 3 different pathways for risky sexual behavior: Environmental involvement, historical condom use, and intentions to engage in risky sex. CONCLUSION: These findings can be used for identification of specific high-risk groups of students who can be targeted for predeparture prevention programs. PMID- 26629985 TI - The locus of taboo context effects in picture naming. AB - Speakers respond more slowly when naming pictures presented with taboo (i.e., offensive/embarrassing) than with neutral distractor words in the picture-word interference paradigm. Over four experiments, we attempted to localize the processing stage at which this effect occurs during word production and determine whether it reflects the socially offensive/embarrassing nature of the stimuli. Experiment 1 demonstrated taboo interference at early stimulus onset asynchronies of -150 ms and 0 ms although not at 150 ms. In Experiment 2, taboo distractors sharing initial phonemes with target picture names eliminated the interference effect. Using additive factors logic, Experiment 3 demonstrated that taboo interference and phonological facilitation effects do not interact, indicating that the two effects originate at different processing levels within the speech production system. In Experiment 4, interference was observed for masked taboo distractors, including those sharing initial phonemes with the target picture names, indicating that the effect cannot be attributed to a processing level involving responses in an output buffer. In two of the four experiments, the magnitude of the interference effect correlated significantly with arousal ratings of the taboo words. However, no significant correlations were found for either offensiveness or valence ratings. These findings are consistent with a locus for the taboo interference effect prior to the processing stage responsible for word form encoding. We propose a pre-lexical account in which taboo distractors capture attention at the expense of target picture processing due to their high arousal levels. PMID- 26629984 TI - Subcutaneous tocilizumab for the treatment of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is characterized by inflammatory synovitis and is mediated by several cytokines; this includes interleukin-6, whose receptor has been successfully targeted by the humanized monoclonal antibody tocilizumab. Intravenous tocilizumab (TCZ-IV) is registered for use in RA (alone or as combination therapy), systemic juvenile idiopathic arthritis and Castleman disease. Subcutaneous tocilizumab (TCZ-SC) is a desirable alternative to existing subcutaneous biological disease modifying antirheumatic drugs (bDMARDs) targeting tumor necrosis factor. TCZ-SC efficacy has been evaluated in three randomized controlled trials. BREVACTA demonstrated superiority to placebo, and both MUSASHI and SUMMACTA demonstrated non-inferiority to TCZ-IV. TCZ-SC has a similar safety profile to TCZ-IV apart from increased rates of injection site reactions and development of anti-TCZ antibodies (the latter of uncertain clinical significance). TCZ-SC 162 mg fortnightly is equivalent to TCZ-IV 4 mg/kg fourth weekly; TCZ-SC 162 mg weekly is equivalent to TCZ-IV 8 mg/kg fourth weekly. TCZ SC is a suitable bDMARD for RA, particularly when monotherapy is preferred. PMID- 26629986 TI - Pharmacologic treatment of status epilepticus. AB - INTRODUCTION: Status epilepticus (SE) requires rapid identification of its cause and urgent pharmacological treatment. Despite an estimated incidence of up to 61 per 100,000 per year, evidence from high-class clinical trials is only available for the early stages of SE. AREAS COVERED: Following a four-stage approach of SE (early, established, refractory and super-refractory), we present pharmacological treatment options and their clinical utility. EXPERT OPINION: Intravenous lorazepam and intramuscular midazolam appear as most effective treatments for early SE. In children, buccal midazolam has emerged as first-line non-intravenous drug with similar efficacy and safety to other intravenous or rectal benzodiazepines. In established SE intravenous antiepileptic drugs are in use. There are no double-blind, but six randomized open studies with valproate and two with levetiracetam. A meta-analysis found higher rates of seizure cessation with valproate 75.7% (95% CI 63.7-84.8) and phenobarbital 73.6%, (95% CI 58.3-84.8) than with levetiracetam (68.5%, 95% CI 56.2-78.7) or phenytoin (50.2%, 95% CI 34.2-66.1). Based on the favourable tolerability profile of levetiracetam and valproate, the authors prefer these drugs in established SE over phenytoin. Treatment options in refractory SE are intravenous anaesthetics. In super refractory SE ketamine, magnesium, steroids and other drugs have been used with variable outcomes. At this stage therapeutic decisions are based on doctors' preferences, patient factors such as age and comorbidity, and cause of SE, if identified. PMID- 26629987 TI - Epidemiology of Chronic Obstructive Pulmonary Disease (COPD) in Aging Populations. AB - Current epidemiologic practice evaluates COPD based on self-reported symptoms of chronic bronchitis, self-reported physician-diagnosed COPD, spirometry confirmed airflow obstruction, or emphysema diagnosed by volumetric computed chest tomography (CT). Because the highest risk population for having COPD includes a predominance of middle-aged or older persons, aging related changes must also be considered, including: 1) increased multimorbidity, polypharmacy, and severe deconditioning, as these identify mechanisms that underlie respiratory symptoms and can impart a complex differential diagnosis; 2) increased airflow limitation, as this impacts the interpretation of spirometry confirmed airflow obstruction; and 3) "senile" emphysema, as this impacts the specificity of CT-diagnosed emphysema. Accordingly, in an era of rapidly aging populations worldwide, the use of epidemiologic criteria that do not rigorously consider aging related changes will result in increased misidentification of COPD and may, in turn, misinform public health policy and patient care. PMID- 26629988 TI - Bioinformatics Analysis of the Effects of Tobacco Smoke on Gene Expression. AB - This study was designed to explore the effects of tobacco smoke on gene expression through bioinformatics analyses. Gene expression profile GSE17913 was downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) in buccal mucosa tissues between 39 active smokers and 40 never smokers were identified. Gene Ontology Specifically, the DEG distribution in the pathway of Metabolism of xenobiotics by cytochrome P450 was shown in Fig 2[corrected] were performed, followed by protein-protein interaction (PPI) network, transcriptional regulatory network as well as miRNA-target regulatory network construction. In total, 88 up-regulated DEGs and 106 down-regulated DEGs were identified. Among these DEGs, cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) and CYP1B1 were enriched in the Metabolism of xenobiotics by cytochrome P450 pathway. In the PPI network, tyrosine 3 monooxygenase/tryptophan 5-monooxygenase activation protein, zeta (YWHAZ), and CYP1A1 were hub genes. In the transcriptional regulatory network, transcription factors of MYC associated factor X (MAX) and upstream transcription factor 1 (USF1) regulated many overlapped DEGs. In addition, protein tyrosine phosphatase, receptor type, D (PTPRD) was regulated by multiple miRNAs in the miRNA-DEG regulatory network. CYP1A1, CYP1B1, YWHAZ and PTPRD, and TF of MAX and USF1 may have the potential to be used as biomarkers and therapeutic targets in tobacco smoke-related pathological changes. PMID- 26629989 TI - Usage Position and Virtual Keyboard Design Affect Upper-Body Kinematics, Discomfort, and Usability during Prolonged Tablet Typing. AB - PURPOSE: The increase in tablet usage allows people to perform computer work in non-traditional office environments. The aim of this study was to assess the effects of changes in tablet keyboard design on postures of the upper extremities and neck, discomfort, and usability under different usage positions during prolonged touch-typing. METHODS: Eighteen healthy participants familiar with touch-screen devices were randomized into three usage positions (desk, lap, and bed) and completed six, 60-minute typing sessions using three virtual keyboard designs (standard, wide, split). Electrogoniometers continuously measured the postures of the wrists, elbow, and neck. Body discomfort and system usability were evaluated by questionnaires before and immediately after each typing session. RESULTS: Separate linear mixed effects models on various postural measures and subjective ratings are conducted with usage position as the between subject factors, keyboard design and typing duration as the with-in subject factors were conducted. Using the tablet in bed led to more extended wrists but a more natural elbow flexion than the desk position. The angled split virtual keyboard significantly reduced the extent of wrist ulnar deviation than the keyboard with either standard or wide design. However, little difference was observed across the usage position and keyboard design. When the postural data were compared between the middle and end of typing sessions, the wrists, elbow, and neck all exhibited a substantially increased range of joint movements (13% to 38%). The discomfort rating also increased significantly over time in every upper body region investigated. Additionally, the split keyboard design received a higher usability rating in the bed position, whereas participants had more satisfactory experience while using the wide keyboard in the traditional desk setting. CONCLUSIONS: Prolonged use of tablets in non-traditional office environments may result in awkward postures in the upper body that may expose users to greater risks of developing musculoskeletal symptoms. Adequate virtual keyboard designs show the potential to alleviate some postural effects and improve the user experience without changing the tablet form factors. PMID- 26629990 TI - Positron Emission Tomography and Magnetic Resonance Imaging of the Brain in Fabry Disease: A Nationwide, Long-Time, Prospective Follow-Up. AB - BACKGROUND: Fabry disease is a rare metabolic glycosphingolipid storage disease caused by deficiency of the lysosomal enzyme alpha-galactosidase A--leading to cellular accumulation of globotriasylceramide in different organs, vessels, tissues, and nerves. The disease is associated with an increased risk of cerebrovascular disease at a young age in addition to heart and kidney failure. OBJECTIVE: The objective of this study was to assess brain function and structure in the Danish cohort of patients with Fabry disease in a prospective way using 18 fluoro-deoxyglucose (F-18 FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI). PATIENTS: Forty patients with Fabry disease (14 males, 26 females, age at inclusion: 10-66 years, median: 39 years) underwent a brain F 18-FDG-PET-scan at inclusion, and 31 patients were followed with FDG-PET biannually for up to seven years. All patients (except one) had a brain MRI-scan at inclusion, and 34 patients were followed with MRI biannually for up to nine years. IMAGE ANALYSIS: The FDG-PET-images were inspected visually and analysed using a quantitative 3-dimensional stereotactic surface projection analysis (Neurostat). MRI images were also inspected visually and severity of white matter lesions (WMLs) was graded using a visual rating scale. RESULTS: In 28 patients brain-FDG-PET was normal; in 23 of these 28 patients brain MRI was normal--of the remaining five patients in this group, four patients had WMLs and one patient never had an MRI-scan. In 10 patients hypometabolic areas were observed on brain FDG-PET; all of these patients had cerebral infarcts/hemorrhages visualized on MRI corresponding to the main hypometabolic areas. In two patients brain-FDG-PET was ambiguous, while MRI was normal in one and abnormal in the other. CONCLUSION: Our data indicated that, in patients with Fabry disease, MRI is the preferable clinical modality--if applicable--when monitoring cerebral status, as no additional major brain-pathology was detected with FDG-PET. PMID- 26629992 TI - Correction: Enhanced Performance of Brain Tumor Classification via Tumor Region Augmentation and Partition. PMID- 26629991 TI - Metformin and Resveratrol Inhibited High Glucose-Induced Metabolic Memory of Endothelial Senescence through SIRT1/p300/p53/p21 Pathway. AB - Endothelial senescence plays crucial roles in diabetic vascular complication. Recent evidence indicated that transient hyperglycaemia could potentiate persistent diabetic vascular complications, a phenomenon known as "metabolic memory." Although SIRT1 has been demonstrated to mediate high glucose-induced endothelial senescence, whether and how "metabolic memory" would affect endothelial senescence through SIRT1 signaling remains largely unknown. In this study, we investigated the involvement of SIRT1 axis as well as the protective effects of resveratrol (RSV) and metformin (MET), two potent SIRT1 activators, during the occurrence of "metabolic memory" of cellular senescence (senescent "memory"). Human umbilical vascular endothelial cells (HUVECs) were cultured in either normal glucose (NG)/high glucose (HG) media for 6 days, or 3 days of HG followed by 3 days of NG (HN), with or without RSV or MET treatment. It was shown that HN incubation triggered persistent downregulation of deacetylase SIRT1 and upregulation of acetyltransferase p300, leading to sustained hyperacetylation (at K382) and activation of p53, and subsequent p53/p21-mediated senescent "memory." In contrast, senescent "memory" was abrogated by overexpression of SIRT1 or knockdown of p300. Interestingly, we found that SIRT1 and p300 could regulate each other in response to HN stimulation, suggesting that a delicate balance between acetyltransferases and deacetylases may be particularly important for sustained acetylation and activation of non-histone proteins (such as p53), and eventually the occurrence of "metabolic memory." Furthermore, we found that RSV or MET treatment prevented senescent "memory" by modulating SIRT1/p300/p53/p21 pathway. Notably, early and continuous treatment of MET, but not RSV, was particularly important for preventing senescent "memory." In conclusion, short term high glucose stimulation could induce sustained endothelial senescence via SIRT1/p300/p53/p21 pathway. RVS or MET treatment could enhance SIRT1-mediated signaling and thus protect against senescent "memory" independent of their glucose lowering mechanisms. Therefore, they may serve as promising therapeutic drugs against the development of "metabolic memory." PMID- 26629993 TI - Dynamics of Chytridiomycosis during the Breeding Season in an Australian Alpine Amphibian. AB - Understanding disease dynamics during the breeding season of declining amphibian species will improve our understanding of how remnant populations persist with endemic infection, and will assist the development of management techniques to protect disease-threatened species from extinction. We monitored the endangered Litoria verreauxii alpina (alpine treefrog) during the breeding season through capture-mark-recapture (CMR) studies in which we investigated the dynamics of chytridiomycosis in relation to population size in two populations. We found that infection prevalence and intensity increased throughout the breeding season in both populations, but infection prevalence and intensity was higher (3.49 and 2.02 times higher prevalence and intensity, respectively) at the site that had a 90-fold higher population density. This suggests that Bd transmission is density dependent. Weekly survival probability was related to disease state, with heavily infected animals having the lowest survival. There was low recovery from infection, especially when animals were heavily infected with Bd. Sympatric amphibian species are likely to be reservoir hosts for the disease and can play an important role in the disease ecology of Bd. Although we found 0% prevalence in crayfish (Cherax destructor), we found that a sympatric amphibian (Crinia signifera) maintained 100% infection prevalence at a high intensity throughout the season. Our results demonstrate the importance of including infection intensity into CMR disease analysis in order to fully understand the implications of disease on the amphibian community. We recommend a combined management approach to promote lower population densities and ensure consistent progeny survival. The most effective management strategy to safeguard the persistence of this susceptible species might be to increase habitat area while maintaining a similar sized suitable breeding zone and to increase water flow and area to reduce drought. PMID- 26629995 TI - Ocular nerve growth factor administration (oNGF) affects disease severity and inflammatory response in the brain of rats with experimental allergic encephalitis (EAE). AB - The rat acute experimental autoimmune encephalomyelitis (EAE) model was used to investigate the effects of ocularly administered nerve growth factor (oNGF) on disease development and brain inflammation. It was found that oNGF affects clinical scores. However, EAE rats receiving oNGF treatment showed reduced expression of pro-inflammatory cytokines and chemokines in the cerebellum and the hippocampus, but not in the frontal cortex. These data confirm the ability of oNGF to counteract the effects of EAE in the brain and suggest a role for oNGF in the regulation of local inflammatory responses observed in the acute phase of EAE. PMID- 26629994 TI - Relationship between Fungal Colonisation of the Respiratory Tract in Lung Transplant Recipients and Fungal Contamination of the Hospital Environment. AB - BACKGROUND: Aspergillus colonisation is frequently reported after lung transplantation. The question of whether aspergillus colonisation is related to the hospital environment is crucial to prevention. METHOD: To elucidate this question, a prospective study of aspergillus colonisation after lung transplantation, along with a mycological survey of the patient environment, was performed. RESULTS: Forty-four consecutive patients were included from the day of lung transplantation and then examined weekly for aspergillus colonisation until hospital discharge. Environmental fungal contamination of each patient was followed weekly via air and surface sampling. Twelve patients (27%) had transient aspergillus colonisation, occurring 1-13 weeks after lung transplantation, without associated manifestation of aspergillosis. Responsible Aspergillus species were A. fumigatus (6), A. niger (3), A. sydowii (1), A. calidoustus (1) and Aspergillus sp. (1). In the environment, contamination by Penicillium and Aspergillus was predominant. Multivariate analysis showed a significant association between occurrence of aspergillus colonisation and fungal contamination of the patient's room, either by Aspergillus spp. in the air or by A.fumigatus on the floor. Related clinical and environmental isolates were genotyped in 9 cases of aspergillus colonisation. For A. fumigatus (4 cases), two identical microsatellite profiles were found between clinical and environmental isolates collected on distant dates or locations. For other Aspergillus species, isolates were different in 2 cases; in 3 cases of aspergillus colonisation by A. sydowii, A. niger and A. calidoustus, similarity between clinical and environmental internal transcribed spacer and tubulin sequences was >99%. CONCLUSION: Taken together, these results support the hypothesis of environmental risk of hospital acquisition of aspergillus colonisation in lung transplant recipients. PMID- 26629996 TI - Impaired H-Reflex Gain during Postural Loaded Locomotion in Individuals Post Stroke. AB - OBJECTIVE: Successful execution of upright locomotion requires coordinated interaction between controllers for locomotion and posture. Our earlier research supported this model in the non-impaired and found impaired interaction in the post-stroke nervous system during locomotion. In this study, we sought to examine the role of the Ia afferent spinal loop, via the H-reflex response, under postural influence during a locomotor task. We tested the hypothesis that the ability to increase stretch reflex gain in response to postural loads during locomotion would be reduced post-stroke. METHODS: Fifteen individuals with chronic post-stroke hemiparesis and 13 non-impaired controls pedaled on a motorized cycle ergometer with specialized backboard support system under (1) seated supported, and (2) non-seated postural-loaded conditions, generating matched pedal force outputs of two levels. H-reflexes were elicited at 90 degrees crank angle. RESULTS: We observed increased H-reflex gain with postural influence in non-impaired individuals, but a lack of increase in individuals post stroke. Furthermore, we observed decreased H-reflex gain at higher postural loads in the stroke-impaired group. CONCLUSION: These findings suggest an impaired Ia afferent pathway potentially underlies the defects in the interaction between postural and locomotor control post-stroke and may explain reduced ability of paretic limb support during locomotor weight-bearing in individuals post-stroke. SIGNIFICANCE: These results support the judicious use of bodyweight support training when first helping individuals post-stroke to regain locomotor pattern generation and weight-bearing capability. PMID- 26629997 TI - Deficiency of Thrombospondin-4 in Mice Does Not Affect Skeletal Growth or Bone Mass Acquisition, but Causes a Transient Reduction of Articular Cartilage Thickness. AB - Although articular cartilage degeneration represents a major public health problem, the underlying molecular mechanisms are still poorly characterized. We have previously utilized genome-wide expression analysis to identify specific markers of porcine articular cartilage, one of them being Thrombospondin-4 (Thbs4). In the present study we analyzed Thbs4 expression in mice, thereby confirming its predominant expression in articular cartilage, but also identifying expression in other tissues, including bone. To study the role of Thbs4 in skeletal development and integrity we took advantage of a Thbs4 deficient mouse model that was analyzed by undecalcified bone histology. We found that Thbs4-deficient mice do not display phenotypic differences towards wildtype littermates in terms of skeletal growth or bone mass acquisition. Since Thbs4 has previously been found over-expressed in bones of Phex-deficient Hyp mice, we additionally generated Thbs4-deficient Hyp mice, but failed to detect phenotypic differences towards Hyp littermates. With respect to articular cartilage we found that Thbs4-deficient mice display transient thinning of articular cartilage, suggesting a protective role of Thbs4 for joint integrity. Gene expression analysis using porcine primary cells revealed that Thbs4 is not expressed by synovial fibroblasts and that it represents the only member of the Thbs gene family with specific expression in articular, but not in growth plate chondrocytes. In an attempt to identify specific molecular effects of Thbs4 we treated porcine articular chondrocytes with human THBS4 in the absence or presence of conditioned medium from porcine synovial fibroblasts. Here we did not observe a significant influence of THBS4 on proliferation, metabolic activity, apoptosis or gene expression, suggesting that it does not act as a signaling molecule. Taken together, our data demonstrate that Thbs4 is highly expressed in articular chondrocytes, where its presence in the extracellular matrix is required for articular cartilage integrity. PMID- 26629998 TI - The Use and Abuse of Transcranial Magnetic Stimulation to Modulate Corticospinal Excitability in Humans. AB - The magnitude and direction of reported physiological effects induced using transcranial magnetic stimulation (TMS) to modulate human motor cortical excitability have proven difficult to replicate routinely. We conducted an online survey on the prevalence and possible causes of these reproducibility issues. A total of 153 researchers were identified via their publications and invited to complete an anonymous internet-based survey that asked about their experience trying to reproduce published findings for various TMS protocols. The prevalence of questionable research practices known to contribute to low reproducibility was also determined. We received 47 completed surveys from researchers with an average of 16.4 published papers (95% CI 10.8-22.0) that used TMS to modulate motor cortical excitability. Respondents also had a mean of 4.0 (2.5-5.7) relevant completed studies that would never be published. Across a range of TMS protocols, 45-60% of respondents found similar results to those in the original publications; the other respondents were able to reproduce the original effects only sometimes or not at all. Only 20% of respondents used formal power calculations to determine study sample sizes. Others relied on previously published studies (25%), personal experience (24%) or flexible post-hoc criteria (41%). Approximately 44% of respondents knew researchers who engaged in questionable research practices (range 30-81%), yet only 18% admitted to engaging in them (range 6-38%) [corrected]. These practices included screening subjects to find those that respond in a desired way to a TMS protocol, selectively reporting results and rejecting data based on a gut feeling. In a sample of 56 published papers that were inspected, not a single questionable research practice was reported. Our survey revealed that approximately 50% of researchers are unable to reproduce published TMS effects. Researchers need to start increasing study sample size and eliminating--or at least reporting--questionable research practices in order to make the outcomes of TMS research reproducible. PMID- 26629999 TI - Report from Paris. PMID- 26630000 TI - Environmental Implications of Hydroxyl Radicals ((*)OH). AB - The hydroxyl radical ((*)OH) is one of the most powerful oxidizing agents, able to react unselectively and instantaneously with the surrounding chemicals, including organic pollutants and inhibitors. The (*)OH radicals are omnipresent in the environment (natural waters, atmosphere, interstellar space, etc.), including biological systems where (*)OH has an important role in immunity metabolism. We provide an extensive view on the role of hydroxyl radical in different environmental compartments and in laboratory systems, with the aim of drawing more attention to this emerging issue. Further research on processes related to the hydroxyl radical chemistry in the environmental compartments is highly demanded. A comprehensive understanding of the sources and sinks of (*)OH radicals including their implications in the natural waters and in the atmosphere is of crucial importance, including the way irradiated chromophoric dissolved organic matter in surface waters yields (*)OH through the H2O2-independent pathway, and the assessment of the relative importance of gas-phase vs aqueous phase reactions of (*)OH with many atmospheric components. Moreover, considering the fact that people spend so much more time in dwellings than outside, the impact of the reactivity of indoor hydroxyl radicals on health and well-being is another emerging research topic of great concern. PMID- 26630001 TI - Silica Vesicle Nanovaccine Formulations Stimulate Long-Term Immune Responses to the Bovine Viral Diarrhoea Virus E2 Protein. AB - Bovine Viral Diarrhoea Virus (BVDV) is one of the most serious pathogen, which causes tremendous economic loss to the cattle industry worldwide, meriting the development of improved subunit vaccines. Structural glycoprotein E2 is reported to be a major immunogenic determinant of BVDV virion. We have developed a novel hollow silica vesicles (SV) based platform to administer BVDV-1 Escherichia coli expressed optimised E2 (oE2) antigen as a nanovaccine formulation. The SV-140 vesicles (diameter 50 nm, wall thickness 6 nm, perforated by pores of entrance size 16 nm and total pore volume of 0.934 cm3 g(-1)) have proven to be ideal candidates to load oE2 antigen and generate immune response. The current study for the first time demonstrates the ability of freeze-dried (FD) as well as non FD oE2/SV140 nanovaccine formulation to induce long-term balanced antibody and cell mediated memory responses for at least 6 months with a shortened dosing regimen of two doses in small animal model. The in vivo ability of oE2 (100 MUg)/SV-140 (500 MUg) and FD oE2 (100 MUg)/SV-140 (500 MUg) to induce long-term immunity was compared to immunisation with oE2 (100 MUg) together with the conventional adjuvant Quil-A from the Quillaja saponira (10 MUg) in mice. The oE2/SV-140 as well as the FD oE2/SV-140 nanovaccine generated oE2-specific antibody and cell mediated responses for up to six months post the final second immunisation. Significantly, the cell-mediated responses were consistently high in mice immunised with oE2/SV-140 (1,500 SFU/million cells) at the six-month time point. Histopathology studies showed no morphological changes at the site of injection or in the different organs harvested from the mice immunised with 500 MUg SV-140 nanovaccine compared to the unimmunised control. The platform has the potential for developing single dose vaccines without the requirement of cold chain storage for veterinary and human applications. PMID- 26630002 TI - Climate and topography control the size and flux of sediment produced on steep mountain slopes. AB - Weathering on mountain slopes converts rock to sediment that erodes into channels and thus provides streams with tools for incision into bedrock. Both the size and flux of sediment from slopes can influence channel incision, making sediment production and erosion central to the interplay of climate and tectonics in landscape evolution. Although erosion rates are commonly measured using cosmogenic nuclides, there has been no complementary way to quantify how sediment size varies across slopes where the sediment is produced. Here we show how this limitation can be overcome using a combination of apatite helium ages and cosmogenic nuclides measured in multiple sizes of stream sediment. We applied the approach to a catchment underlain by granodiorite bedrock on the eastern flanks of the High Sierra, in California. Our results show that higher-elevation slopes, which are steeper, colder, and less vegetated, are producing coarser sediment that erodes faster into the channel network. This suggests that both the size and flux of sediment from slopes to channels are governed by altitudinal variations in climate, vegetation, and topography across the catchment. By quantifying spatial variations in the sizes of sediment produced by weathering, this analysis enables new understanding of sediment supply in feedbacks between climate, tectonics, and mountain landscape evolution. PMID- 26630003 TI - Ammonite habitat revealed via isotopic composition and comparisons with co occurring benthic and planktonic organisms. AB - Ammonites are among the best-known fossils of the Phanerozoic, yet their habitat is poorly understood. Three common ammonite families (Baculitidae, Scaphitidae, and Sphenodiscidae) co-occur with well-preserved planktonic and benthic organisms at the type locality of the upper Maastrichtian Owl Creek Formation, offering an excellent opportunity to constrain their depth habitats through isotopic comparisons among taxa. Based on sedimentary evidence and the micro- and macrofauna at this site, we infer that the 9-m-thick sequence was deposited at a paleodepth of 70-150 m. Taxa present throughout the sequence include a diverse assemblage of ammonites, bivalves, and gastropods, abundant benthic foraminifera, and rare planktonic foraminifera. No stratigraphic trends are observed in the isotopic data of any taxon, and thus all of the data from each taxon are considered as replicates. Oxygen isotope-based temperature estimates from the baculites and scaphites overlap with those of the benthos and are distinct from those of the plankton. In contrast, sphenodiscid temperature estimates span a range that includes estimates of the planktonic foraminifera and of the warmer half of the benthic values. These results suggest baculites and scaphites lived close to the seafloor, whereas sphenodiscids sometimes inhabited the upper water column and/or lived closer to shore. In fact, the rarity and poorer preservation of the sphenodiscids relative to the baculites and scaphites suggests that the sphenodiscid shells may have only reached the Owl Creek locality by drifting seaward after death. PMID- 26630004 TI - Upper atmospheric gravity wave details revealed in nightglow satellite imagery. AB - Gravity waves (disturbances to the density structure of the atmosphere whose restoring forces are gravity and buoyancy) comprise the principal form of energy exchange between the lower and upper atmosphere. Wave breaking drives the mean upper atmospheric circulation, determining boundary conditions to stratospheric processes, which in turn influence tropospheric weather and climate patterns on various spatial and temporal scales. Despite their recognized importance, very little is known about upper-level gravity wave characteristics. The knowledge gap is mainly due to lack of global, high-resolution observations from currently available satellite observing systems. Consequently, representations of wave related processes in global models are crude, highly parameterized, and poorly constrained, limiting the description of various processes influenced by them. Here we highlight, through a series of examples, the unanticipated ability of the Day/Night Band (DNB) on the NOAA/NASA Suomi National Polar-orbiting Partnership environmental satellite to resolve gravity structures near the mesopause via nightglow emissions at unprecedented subkilometric detail. On moonless nights, the Day/Night Band observations provide all-weather viewing of waves as they modulate the nightglow layer located near the mesopause (~ 90 km above mean sea level). These waves are launched by a variety of physical mechanisms, ranging from orography to convection, intensifying fronts, and even seismic and volcanic events. Cross-referencing the Day/Night Band imagery with conventional thermal infrared imagery also available helps to discern nightglow structures and in some cases to attribute their sources. The capability stands to advance our basic understanding of a critical yet poorly constrained driver of the atmospheric circulation. PMID- 26630005 TI - Neurotrophic-priming of glucocorticoid receptor signaling is essential for neuronal plasticity to stress and antidepressant treatment. AB - Neurotrophins and glucocorticoids are robust synaptic modifiers, and deregulation of their activities is a risk factor for developing stress-related disorders. Low levels of brain-derived neurotrophic factor (BDNF) increase the desensitization of glucocorticoid receptors (GR) and vulnerability to stress, whereas higher levels of BDNF facilitate GR-mediated signaling and the response to antidepressants. However, the molecular mechanism underlying neurotrophic-priming of GR function is poorly understood. Here we provide evidence that activation of a TrkB-MAPK pathway, when paired with the deactivation of a GR-protein phosphatase 5 pathway, resulted in sustained GR phosphorylation at BDNF-sensitive sites that is essential for the transcription of neuronal plasticity genes. Genetic strategies that disrupted GR phosphorylation or TrkB signaling in vivo impaired the neuroplasticity to chronic stress and the effects of the antidepressant fluoxetine. Our findings reveal that the coordinated actions of BDNF and glucocorticoids promote neuronal plasticity and that disruption in either pathway could set the stage for the development of stress-induced psychiatric diseases. PMID- 26630006 TI - An RNA motif advances transcription by preventing Rho-dependent termination. AB - The transcription termination factor Rho associates with most nascent bacterial RNAs as they emerge from RNA polymerase. However, pharmacological inhibition of Rho derepresses only a small fraction of these transcripts. What, then, determines the specificity of Rho-dependent transcription termination? We now report the identification of a Rho-antagonizing RNA element (RARE) that hinders Rho-dependent transcription termination. We establish that RARE traps Rho in an inactive complex but does not prevent Rho binding to its recruitment sites. Although translating ribosomes normally block Rho access to an mRNA, inefficient translation of an open reading frame in the leader region of the Salmonella mgtCBR operon actually enables transcription of its associated coding region by favoring an RNA conformation that sequesters RARE. The discovery of an RNA element that inactivates Rho signifies that the specificity of nucleic-acid binding proteins is defined not only by the sequences that recruit these proteins but also by sequences that antagonize their activity. PMID- 26630008 TI - Mandibular and dental characteristics of Late Triassic mammaliaform Haramiyavia and their ramifications for basal mammal evolution. AB - As one of the earliest-known mammaliaforms, Haramiyavia clemmenseni from the Rhaetic (Late Triassic) of East Greenland has held an important place in understanding the timing of the earliest radiation of the group. Reanalysis of the type specimen using high-resolution computed tomography (CT) has revealed new details, such as the presence of the dentary condyle of the mammalian jaw hinge and the postdentary trough for mandibular attachment of the middle ear-a transitional condition of the predecessors to crown Mammalia. Our tests of competing phylogenetic hypotheses with these new data show that Late Triassic haramiyids are a separate clade from multituberculate mammals and are excluded from the Mammalia. Consequently, hypotheses of a Late Triassic diversification of the Mammalia that depend on multituberculate affinities of haramiyidans are rejected. Scanning electron microscopy study of tooth-wear facets and kinematic functional simulation of occlusion with virtual 3D models from CT scans confirm that Haramiyavia had a major orthal occlusion with the tallest lingual cusp of the lower molars occluding into the lingual embrasure of the upper molars, followed by a short palinal movement along the cusp rows alternating between upper and lower molars. This movement differs from the minimal orthal but extensive palinal occlusal movement of multituberculate mammals, which previously were regarded as relatives of haramiyidans. The disparity of tooth morphology and the diversity of dental functions of haramiyids and their contemporary mammaliaforms suggest that dietary diversification is a major factor in the earliest mammaliaform evolution. PMID- 26630007 TI - Gourds and squashes (Cucurbita spp.) adapted to megafaunal extinction and ecological anachronism through domestication. AB - The genus Cucurbita (squashes, pumpkins, gourds) contains numerous domesticated lineages with ancient New World origins. It was broadly distributed in the past but has declined to the point that several of the crops' progenitor species are scarce or unknown in the wild. We hypothesize that Holocene ecological shifts and megafaunal extinctions severely impacted wild Cucurbita, whereas their domestic counterparts adapted to changing conditions via symbiosis with human cultivators. First, we used high-throughput sequencing to analyze complete plastid genomes of 91 total Cucurbita samples, comprising ancient (n = 19), modern wild (n = 30), and modern domestic (n = 42) taxa. This analysis demonstrates independent domestication in eastern North America, evidence of a previously unknown pathway to domestication in northeastern Mexico, and broad archaeological distributions of taxa currently unknown in the wild. Further, sequence similarity between distant wild populations suggests recent fragmentation. Collectively, these results point to wild-type declines coinciding with widespread domestication. Second, we hypothesize that the disappearance of large herbivores struck a critical ecological blow against wild Cucurbita, and we take initial steps to consider this hypothesis through cross-mammal analyses of bitter taste receptor gene repertoires. Directly, megafauna consumed Cucurbita fruits and dispersed their seeds; wild Cucurbita were likely left without mutualistic dispersal partners in the Holocene because they are unpalatable to smaller surviving mammals with more bitter taste receptor genes. Indirectly, megafauna maintained mosaic-like landscapes ideal for Cucurbita, and vegetative changes following the megafaunal extinctions likely crowded out their disturbed-ground niche. Thus, anthropogenic landscapes provided favorable growth habitats and willing dispersal partners in the wake of ecological upheaval. PMID- 26630009 TI - Nuclear and mitochondrial DNA sequences from two Denisovan individuals. AB - Denisovans, a sister group of Neandertals, have been described on the basis of a nuclear genome sequence from a finger phalanx (Denisova 3) found in Denisova Cave in the Altai Mountains. The only other Denisovan specimen described to date is a molar (Denisova 4) found at the same site. This tooth carries a mtDNA sequence similar to that of Denisova 3. Here we present nuclear DNA sequences from Denisova 4 and a morphological description, as well as mitochondrial and nuclear DNA sequence data, from another molar (Denisova 8) found in Denisova Cave in 2010. This new molar is similar to Denisova 4 in being very large and lacking traits typical of Neandertals and modern humans. Nuclear DNA sequences from the two molars form a clade with Denisova 3. The mtDNA of Denisova 8 is more diverged and has accumulated fewer substitutions than the mtDNAs of the other two specimens, suggesting Denisovans were present in the region over an extended period. The nuclear DNA sequence diversity among the three Denisovans is comparable to that among six Neandertals, but lower than that among present-day humans. PMID- 26630010 TI - Augmentor alpha and beta (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand-receptor interactions. AB - Receptor tyrosine kinases (RTKs) are a class of cell surface receptors that, upon ligand binding, stimulate a variety of critical cellular functions. The orphan receptor anaplastic lymphoma kinase (ALK) is one of very few RTKs that remain without a firmly established protein ligand. Here we present a novel cytokine, FAM150B, which we propose naming augmentor-alpha (AUG-alpha), as a ligand for ALK. AUG-alpha binds ALK with high affinity and activates ALK in cells with subnanomolar potency. Detailed binding experiments using cells expressing ALK or the related receptor leukocyte tyrosine kinase (LTK) demonstrate that AUG-alpha binds and robustly activates both ALK and LTK. We show that the previously established LTK ligand FAM150A (AUG-beta) is specific for LTK and only weakly binds to ALK. Furthermore, expression of AUG-alpha stimulates transformation of NIH/3T3 cells expressing ALK, induces IL-3 independent growth of Ba/F3 cells expressing ALK, and is expressed in neuroblastoma, a cancer partly driven by ALK. These experiments reveal the hierarchy and specificity of two cytokines as ligands for ALK and LTK and set the stage for elucidating their roles in development and disease states. PMID- 26630011 TI - Geometrical Frustration in Interleukin-33 Decouples the Dynamics of the Functional Element from the Folding Transition State Ensemble. AB - Interleukin-33 (IL-33) is currently the focus of multiple investigations into targeting pernicious inflammatory disorders. This mediator of inflammation plays a prevalent role in chronic disorders such as asthma, rheumatoid arthritis, and progressive heart disease. In order to better understand the possible link between the folding free energy landscape and functional regions in IL-33, a combined experimental and theoretical approach was applied. IL-33 is a pseudo- symmetrical protein composed of three distinct structural elements that complicate the folding mechanism due to competition for nucleation on the dominant folding route. Trefoil 1 constitutes the majority of the binding interface with the receptor whereas Trefoils 2 and 3 provide the stable scaffold to anchor Trefoil 1. We identified that IL-33 folds with a three-state mechanism, leading to a rollover in the refolding arm of its chevron plots in strongly native conditions. In addition, there is a second slower refolding phase that exhibits the same rollover suggesting similar limitations in folding along parallel routes. Characterization of the intermediate state and the rate limiting steps required for folding suggests that the rollover is attributable to a moving transition state, shifting from a post- to pre-intermediate transition state as you move from strongly native conditions to the midpoint of the transition. On a structural level, we found that initially, all independent Trefoil units fold equally well until a QCA of 0.35 when Trefoil 1 will backtrack in order to allow Trefoils 2 and 3 to fold in the intermediate state, creating a stable scaffold for Trefoil 1 to fold onto during the final folding transition. The formation of this intermediate state and subsequent moving transition state is a result of balancing the difficulty in folding the functionally important Trefoil 1 onto the remainder of the protein. Taken together our results indicate that the functional element of the protein is geometrically frustrated, requiring the more stable elements to fold first, acting as a scaffold for docking of the functional element to allow productive folding to the native state. PMID- 26630013 TI - Hydrodynamic confinement and capillary alignment of gold nanorods. AB - Controlling the alignment and orientation of nanorods on various surfaces poses major challenges. In this work, we investigate hydrodynamic confinement and capillary alignment of gold nanorod assembly on chemically stripe-patterned substrates. The surface patterns consist of alternating hydrophilic and hydrophobic micrometer wide stripes; a macroscopic wettability gradient enables controlling the dynamics of deposited suspension droplets. We show that drying of residual liquid on the hydrophilic stripes gives rise to spatially localized deposition and alignment of the nanorods. Moreover, a universal relation between the extent of order within the single layers of nanoparticles and the lateral dimension of the deposits is presented and discussed. PMID- 26630012 TI - Midregional Proadrenomedullin Improves Risk Stratification beyond Surgical Risk Scores in Patients Undergoing Transcatheter Aortic Valve Replacement. AB - BACKGROUND: Conventional surgical risk scores lack accuracy in risk stratification of patients undergoing transcatheter aortic valve replacement (TAVR). Elevated levels of midregional proadrenomedullin (MR-proADM) levels are associated with adverse outcome not only in patients with manifest chronic disease states, but also in the general population. OBJECTIVES: We investigated the predictive value of MR-proADM for mortality in an unselected contemporary TAVR population. METHODS: We prospectively included 153 patients suffering from severe aortic stenosis who underwent TAVR from September 2013 to August 2014. This population was compared to an external validation cohort of 205 patients with severe aortic stenosis undergoing TAVR. The primary endpoint was all cause mortality. RESULTS: During a median follow-up of 258 days, 17 out of 153 patients who underwent TAVR died (11%). Patients with MR-proADM levels above the 75th percentile (>= 1.3 nmol/l) had higher mortality (31% vs. 4%, HR 8.9, 95% CI 3.0 26.0, P < 0.01), whereas patients with EuroSCORE II scores above the 75th percentile (> 6.8) only showed a trend towards higher mortality (18% vs. 9%, HR 2.1, 95% CI 0.8-5.6, P = 0.13). The Harrell's C-statistic was 0.58 (95% CI 0.45 0.82) for the EuroSCORE II, and consideration of baseline MR-proADM levels significantly improved discrimination (AUC = 0.84, 95% CI 0.71-0.92, P = 0.01). In bivariate analysis adjusted for EuroSCORE II, MR-proADM levels >=1.3 nmol/l persisted as an independent predictor of mortality (HR 9.9, 95% CI (3.1-31.3), P <0.01) and improved the model's net reclassification index (0.89, 95% CI (0.28 1.59). These results were confirmed in the independent validation cohort. CONCLUSIONS: Our study identified MR-proADM as a novel predictor of mortality in patients undergoing TAVR. In the future, MR-proADM should be added to the commonly used EuroSCORE II for better risk stratification of patients suffering from severe aortic stenosis. PMID- 26630014 TI - Removing Phosphorus from Aqueous Solutions Using Lanthanum Modified Pine Needles. AB - The renewable pine needles was used as an adsorbent to remove phosphorus from aqueous solutions. Using batch experiments, pine needles pretreated with alkali isopropanol (AI) failed to effectively remove phosphorus, while pine needles modified with lanthanum hydroxide (LH) showed relatively high removal efficiency. LH pine needles were effective at a wide pH ranges, with the highest removal efficiency reaching approximately 85% at a pH of 3. The removal efficiency was kept above 65% using 10 mg/L phosphorus solutions at desired pH values. There was no apparent significant competitive behavior between co-existing anions of sulfate, nitrate, and chloride (SO4(2-), NO3(-) and Cl(-)); however, CO3(2-) exhibited increased interfering behavior as concentrations increased. An intraparticle diffusion model showed that the adsorption process occurred in three phases, suggesting that a boundary layer adsorption phenomena slightly affected the adsorption process, and that intraparticle diffusion was dominant. The adsorption process was thermodynamically unfavorable and non-spontaneous; temperature increases improved phosphorus removal. Total organic carbon (TOC) assays indicated that chemical modification reduced the release of soluble organic compounds from 135.6 mg/L to 7.76 mg/L. This new information about adsorption performances provides valuable information, and can inform future technological applications designed to remove phosphorus from aqueous solutions. PMID- 26630025 TI - Sensitivity and Acclimation of Three Canopy-Forming Seaweeds to UVB Radiation and Warming. AB - Canopy-forming seaweeds, as primary producers and foundation species, provide key ecological services. Their responses to multiple stressors associated with climate change could therefore have important knock-on effects on the functioning of coastal ecosystems. We examined interactive effects of UVB radiation and warming on juveniles of three habitat-forming subtidal seaweeds from Western Australia-Ecklonia radiata, Scytothalia dorycarpa and Sargassum sp. Fronds were incubated for 14 days at 16-30 degrees C with or without UVB radiation and growth, health status, photosynthetic performance, and light absorbance measured. Furthermore, we used empirical models from the metabolic theory of ecology to evaluate the sensitivity of these important seaweeds to ocean warming. Results indicated that responses to UVB and warming were species specific, with Sargassum showing highest tolerance to a broad range of temperatures. Scytothalia was most sensitive to elevated temperature based on the reduced maximum quantum yields of PSII; however, Ecklonia was most sensitive, according to the comparison of activation energy calculated from Arrhenius' model. UVB radiation caused reduction in the growth, physiological responses and thallus health in all three species. Our findings indicate that Scytothalia was capable of acclimating in response to UVB and increasing its light absorption efficiency in the UV bands, probably by up-regulating synthesis of photoprotective compounds. The other two species did not acclimate over the two weeks of exposure to UVB. Overall, UVB and warming would severely inhibit the growth and photosynthesis of these canopy forming seaweeds and decrease their coverage. Differences in the sensitivity and acclimation of major seaweed species to temperature and UVB may alter the balance between species in future seaweed communities under climate change. PMID- 26630027 TI - Adjusting ventilator off-cycling in invasively ventilated COPD patients needs comprehensive adjustments. AB - BACKGROUND: Patient-ventilator asynchrony that prolongs weaning and increases morbidity and mortality is common during invasive ventilation of patients with chronic obstructive pulmonary disease (COPD). In this context, the inspiratory cycling criteria (iCC) of the ventilator during assisted pressure support (PS) ventilation is a poorly acknowledged key factor. We investigated the changes of flow and pressure parameters that resulted from varying the iCC in a simulated COPD lung model. METHODS: A lung simulator was connected to an ICU ventilator through an endotracheal tube. We studied iCC settings from 10% to 70% at different respiratory rates (RR) (15 and 30 bpm) and pressure support (PS) (5 and 15 cmH2O) settings and registered asynchrony-index, double-triggering, expiratory trigger latency (TLEXP), intrinsic PEEP (PEEPi), expiratory pressure time product (PTPEXP) and tidal volume. RESULTS: At iCC<=20%, asynchrony occurred in 50% of all recordings in high RR/high PS. At a low RR, double triggering occurred at high iCC settings. It appeared at 50% iCC with low PS and at 60% iCC with high PS. TLEXP was positive at iCC 10% to 30% but decreased with increasing iCC (P<0.001). At low RR/high PS settings, PEEPi decreased at iCC<=40% but increased at iCC>=50%. High RR/low PS constantly reduced PTPEXP up to 60% iCC. Changes in iCC strongly influenced the resulting tidal volume. CONCLUSIONS: Non-adapted ventilator iCC can cause patient-ventilator asynchrony. The success of assisted invasive ventilation and weaning relies on meticulous adjustments. PMID- 26630026 TI - Di-(2-Ethylhexyl)-Phthalate (DEHP) Causes Impaired Adipocyte Function and Alters Serum Metabolites. AB - Di-(2-ethylhexyl)-phthalate (DEHP), an ubiquitous environmental contaminant, has been shown to cause adverse effects on glucose homeostasis and insulin sensitivity in epidemiological studies, but the underlying mechanisms are still unknown. We therefore tested the hypothesis that chronic DEHP exposure causes impaired insulin sensitivity, affects body weight, adipose tissue (AT) function and circulating metabolic parameters of obesity resistant 129S6 mice in vivo. An obesity-resistant mouse model was chosen to reduce a potential obesity bias of DEHP effects on metabolic parameters and AT function. The metabolic effects of 10 weeks exposure to DEHP were tested by insulin tolerance tests and quantitative assessment of 183 metabolites in mice. Furthermore, 3T3-L1 cells were cultured with DEHP for two days, differentiated into mature adipocytes in which the effects on insulin stimulated glucose and palmitate uptake, lipid content as well as on mRNA/protein expression of key adipocyte genes were investigated. We observed in female mice that DEHP treatment causes enhanced weight gain, fat mass, impaired insulin tolerance, changes in circulating adiponectin and adipose tissue Pparg, adiponectin and estrogen expression. Serum metabolomics indicated a general increase in phospholipid and carnitine concentrations. In vitro, DEHP treatment increases the proliferation rate and alters glucose uptake in adipocytes. Taken together, DEHP has significant effects on adipose tissue (AT) function and alters specific serum metabolites. Although, DEHP treatment led to significantly impaired insulin tolerance, it did not affect glucose tolerance, HOMA-IR, fasting glucose, insulin or triglyceride serum concentrations. This may suggest that DEHP treatment does not cause impaired glucose metabolism at the whole body level. PMID- 26630028 TI - NIRS brain-monitoring in septic patients? PMID- 26630029 TI - Patients with severe ARDS already positioned prone: why don't we leave them in the prone position during transport and CT scan? PMID- 26630030 TI - Determining Possible Professionals and Respective Roles and Responsibilities for a Model Comprehensive Elder Abuse Intervention: A Delphi Consensus Survey. AB - OBJECTIVE: We have undertaken a multi-phase, multi-method program of research to develop, implement, and evaluate a comprehensive hospital-based nurse examiner elder abuse intervention that addresses the complex functional, social, forensic, and medical needs of older women and men. In this study, we determined the importance of possible participating professionals and respective roles and responsibilities within the intervention. METHODS: Using a modified Delphi methodology, recommended professionals and their associated roles and responsibilities were generated from a systematic scoping review of relevant scholarly and grey literatures. These items were reviewed, new items added for review, and rated/re-rated for their importance to the intervention on a 5-point Likert scale by an expert panel during a one day in-person meeting. Items that did not achieve consensus were subsequently re-rated in an online survey. ANALYSIS: Those items that achieved a mean Likert rating of 4+ (rated important to very important), and an interquartile range<1 in the first or second round, and/or for which 80% of ratings were 4+ in the second round were retained for the model elder abuse intervention. RESULTS: Twenty-two of 31 recommended professionals and 192 of 229 recommended roles and responsibilities rated were retained for our model elder abuse intervention. Retained professionals were: public guardian and trustee (mean rating = 4.88), geriatrician (4.87), police officer (4.87), GEM (geriatric emergency management) nurse (4.80), GEM social worker (4.78), community health worker (4.76), social worker/counsellor (4.74), family physician in community (4.71), paramedic (4.65), financial worker (4.59), lawyer (4.59), pharmacist (4.59), emergency physician (4.57), geriatric psychiatrist (4.33), occupational therapist (4.29), family physician in hospital (4.28), Crown prosecutor (4.24), neuropsychologist (4.24), bioethicist (4.18), caregiver advocate (4.18), victim support worker (4.18), and respite care worker (4.12). CONCLUSION: A large and diverse group of multidisciplinary, intersectoral collaborators was deemed necessary to address the complex needs of abused older adults, each having important roles and responsibilities to fulfill within a model comprehensive elder abuse intervention. PMID- 26630031 TI - Gradual Rewarming with Gradual Increase in Pressure during Machine Perfusion after Cold Static Preservation Reduces Kidney Ischemia Reperfusion Injury. AB - In this study we evaluated whether gradual rewarming after the period of cold ischemia would improve organ quality in an Isolated Perfused Kidney Model. Left rat kidneys were statically cold stored in University of Wisconsin solution for 24 hours at 4 degrees C. After cold storage kidneys were rewarmed in one of three ways: perfusion at body temperature (38 degrees C), or rewarmed gradually from 10 degrees C to 38 degrees C with stabilization at 10 degrees C for 30 min and rewarmed gradually from 10 degrees C to 38 degrees C with stabilization at 25 degrees C for 30 min. In the gradual rewarming groups the pressure was increased stepwise to 40 mmHg at 10 degrees C and 70 mmHg at 25 degrees C to counteract for vasodilatation leading to low perfusate flows. Renal function parameters and injury biomarkers were measured in perfusate and urine samples. Increases in injury biomarkers such as aspartate transaminase and lactate dehydrogenase in the perfusate were lower in the gradual rewarming groups versus the control group. Sodium re-absorption was improved in the gradual rewarming groups and reached significance in the 25 degrees C group after ninety minutes of perfusion. HSP-70, ICAM-1, VCAM-1 mRNA expressions were decreased in the 10 degrees C and 25 degrees C groups. Based on the data kidneys that underwent gradual rewarming suffered less renal parenchymal, tubular injury and showed better endothelial preservation. Renal function improved in the gradual rewarming groups versus the control group. PMID- 26630032 TI - The Effect of Infection Control Nurses on the Occurrence of Pseudomonas aeruginosa Healthcare-Acquired Infection and Multidrug-Resistant Strains in Critically-Ill Children. AB - BACKGROUND: Healthcare-acquired Pseudomonas aeruginosa (P. aeruginosa) infections in the Pediatric Intensive Care Unit (PICU), which have a high incidence, increase treatment costs and mortality, and seriously threaten the safety of critically ill children. It is essential to seek convenient and effective methods to control and prevent healthcare-acquired infections (HAIs). This research was conducted to study the effect of infection control nurses on the occurrence of P. aeruginosa HAIs and multi-drug resistance (MDR) strains in PICU. METHODS: The clinical data was divided into two groups, with the age ranging from 1 month to 14 years. One group of the critically ill patients(N = 3,722) was admitted to PICU from 2007 to 2010, without the management of infection control nurses. The other group of the critically ill patients (N = 3,943) was admitted to PICU from 2011 to 2013, with the management of infection control nurses. Compare the mortality, morbidity and the incidence of acquired P. aeruginosa infections to evaluate the effect of infection control nurses. RESULTS: After implementation of the post of infection control nurses, the patient's overall mortality fell from 4.81% to 3.73%. Among the patients with endotracheal intubation more than 48 hours, the incidence of endotracheal intubation-related pneumonia decreased from 44.6% to 34.32%. The mortality of patients with endotracheal intubation decreased from 16.96% to 10.17%, and the morbidity of HAIs with P. aeruginosa decreased from 1.89% to 1.07%. The mutual different rate (MDR) dropped from 67.95% to 44.23%. There were remarkable differences in these rates between the two groups (p<0.05). CONCLUSION: Implementing the post of infection control nurses is associated with effectively reducing the HAI rate, especially the incidence and morbidity of P. aeruginosa HAIs, reducing PICU mortality, improving P. aeruginosa drug resistance. PMID- 26630033 TI - Mother-child reminiscing at risk: Maternal attachment, elaboration, and child autobiographical memory specificity. AB - Mother-child reminiscing, the process by which mothers and their children discuss past events and emotional experiences, has been robustly linked with child outcomes, including autobiographical memory. To advance previous work linking elaborative maternal reminiscing with child autobiographical memory specificity, the ability to generate and retrieve specific memories from one's past, it is essential to make distinctions among aspects of elaboration and to consider how maternal risk factors may influence the reminiscing context. The current study evaluated (a) an interaction between emotional and structural elaboration predicting child autobiographical memory specificity and (b) the potential moderating role of maternal adult attachment. Participants consisted of 95 preschool-aged children and their mothers. The sample was predominantly low income and racially diverse. Dyads completed a reminiscing task that was coded for emotional and structural elaboration. Mothers completed the Experiences in Close Relationships questionnaire (ECR-R) to assess attachment-related avoidance and anxiety, and children completed the Autobiographical Memory Test-Preschool Version (AMT-PV) to assess memory specificity. Results indicated that the association between structural reminiscing and child memory specificity was moderated by emotional elements of reminiscing. At high levels of emotional elaboration, mothers with high levels of structural elaboration had children with more specific memory than mothers with low levels of structural elaboration. Moreover, emotional elaboration (a) predicted less specific child memory without high structural support and (b) negatively predicted child specificity at high levels of maternal attachment avoidance and anxiety, a profile associated with fearful avoidance. Future directions and implications are discussed. PMID- 26630034 TI - Fukushima derived radiocesium in subsistence-consumed northern fur seal and wild celery. AB - In July 2014, our investigative team traveled to St. Paul Island, Alaska to measure concentrations of radiocesium in wild-caught food products, primarily northern fur seal (Callorhinus ursinus). The 2011 Fukushima Daiichi Nuclear Power Plant accident released radiocesium into the atmosphere and into the western Pacific Ocean; other investigators have detected Fukushima-derived radionuclides in a variety of marine products harvested off the western coast of North America. We tested two subsistence-consumed food products from St. Paul Island, Alaska for Fukushima-derived radionuclides: 54 northern fur seal, and nine putchki (wild celery, Angelica lucida) plants. Individual northern fur seal samples were below minimum detectable activity concentrations of (137)Cs and (134)Cs, but when composited, northern fur seal tissues tested positive for trace quantities of both isotopes. Radiocesium was detected at an activity concentration of 37.2 mBq (134)Cs kg(-1) f.w. (95% CI: 35.9-38.5) and 141.2 mBq (137)Cs kg(-1) f.w. (95% CI: 135.5-146.8). The measured isotopic ratio, decay-corrected to the date of harvest, was 0.26 (95% CI: 0.25-0.28). The Fukushima nuclear accident released (134)Cs and (137)Cs in roughly equal quantities, but by the date of harvest in July 2014, this ratio was 0.2774, indicating that this population of seals has been exposed to small quantities of Fukushima-derived radiocesium. Activity concentrations of both (134)Cs and (137)Cs in putchki were below detection limits, even for composited samples. Northern fur seal is known to migrate between coastal Alaska and Japan and the trace (134)Cs in northern fur seal tissue suggests that the population under study had been minimally exposed Fukushima-derived radionuclides. Despite this inference, the radionuclide quantities detected are small and no impact is expected as a result of the measured radiation exposure, either in northern fur seal or human populations consuming this species. PMID- 26630035 TI - Distance to faults as a proxy for radon gas concentration in dwellings. AB - This research was done to demonstrate the usefulness of the local structural geology characteristics to predict indoor radon concentrations. The presence of geologic faults near dwellings increases the vulnerability of the dwellings to elevated indoor radon by providing favorable pathways from the source uranium rich bedrock units to the surface. Kruskal-Wallis one-way analyses of variance by ranks were used to determine the distance where faults have statistically significant influence on indoor radon concentrations. The great-circle distance between the 640 spatially referenced basement radon concentration measurements and the nearest fault was calculated using the Haversine formula and the spherical law of cosines. It was shown that dwellings located less than 150 m from a major fault had a higher radon potential. The 150 m threshold was determined using Kruskal-Wallis ANOVA on: (1) all the basement radon measurements dataset and; (2) the basement radon measurements located on uranium-rich bedrock units only. The results indicated that 22.8% of the dwellings located less than 150 m from a fault exceeded the Canadian radon guideline of 200 Bq/m(3) when using all the basement radon measurements dataset. This percentage fell to 15.2% for the dwellings located between 150 m and 700 m from a fault. When using only the basement radon measurements located on uranium-rich bedrock units, these percentages were 30.7% (0-150 m) and 17.5% (150 m-700 m). The assessment and management of risk can be improved where structural geology characteristics base maps are available by using this proxy indicator. PMID- 26630036 TI - Study of water mixing in the coastal waters of the western Taiwan Strait based on radium isotopes. AB - Radium is considered to be a useful tracer for studying the physical processes of seawater. In this work, three naturally occurring radium isotopes, (224)Raex, (226)Ra and (228)Ra, were measured in the coastal zone of the western Taiwan Strait during the summer seasons. Based on the distributions of the three radium isotopes and the salinity, we conclude that the water mixing pattern in the study area in summer consists of diluted water flowing from the Jiulong River to the open sea towards the east and southeast, and open sea seawater flowing inward from south to north. The submarine ground water discharges in the estuarine region, as suggested by the radium and salinity data. The residence times of the Jiulong River estuary, ranging from 7 to 49 d, were estimated using the radium isotope pairs (224)Raex and (226)Ra. PMID- 26630037 TI - Bioindicating potential of strontium contamination with Spanish moss Tillandsia usneoides. AB - Tillandsia species have been recognized as efficient biomonitors of air pollution, but rarely exploited in bioindicating of strontium, an important nuclide. We exposed Tillandsia usneoides, colloquially known as Spanish moss due to its filamentous morphology but is an atypical angiosperm in the family Bromeliaceae, to the solutions with different Sr concentrations (0.1-100 mmol/L). The results showed that plants were able to endure Sr stress for a relatively long period, which suggests that T. usneoides is able to resist this toxic element. T. usneoides had the highest uptake ratio of Sr (82.21 +/- 0.12%) when the plants were exposed to 0.1 mmol/L Sr solutions. Sr contents in T. usneoides increased significantly with the increase in applied metal solution concentrations. Low Sr stimulated the formation of chlorophyll, but high Sr decreased the contents of chlorophyll, and no significant effect on the total biomass was found in T. usneoides. In contrast, the permeability of plasma membrane based on the relative electronic conductivity in T. usneoides increased significantly under Sr stress, indicating that Sr probably caused oxidative stress. Moreover, correlation analysis showed that the leaf relative conductivity was significantly positively correlated with Sr contents in the plants after Sr treatments. Therefore, T. usneoides has considerable potential for monitoring Sr polluted environments through measuring Sr contents in the plant directly or exploiting the leaf relative conductivity as an indirect biomarker. PMID- 26630038 TI - Radiocesium immobilization to leaf litter by fungi during first-year decomposition in a deciduous forest in Fukushima. AB - Vast forest areas in eastern Japan have been contaminated with radio-isotopes by the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident. Radiocesium (radioCs) is known to remain bioavailable in forest ecosystems for a long time, and it is necessary to terminate the cycling process to decontaminate the forest ecosystem. We observed radiocesium concentrations of leaf litter during decomposition on a forest floor where radiocesium ((137)Cs) contamination was ~155 kBq/m(2). Litter bag experiments were conducted with newly fallen mixed deciduous leaf litter in a deciduous forest (alt. 610 m) about 50 km from the FDNPP. Litter bags were retrieved in April, June, August, October, and December 2012. Fresh litter (137)Cs concentration was ~3000 Bq/kg in December 2011. During the decomposition process on the forest floor, litter (137)Cs concentration increased rapidly and exceeded 25,000 Bq/kg after 6 months, whereas potassium (K) concentration in the litter was rather stable, indicating that radiocesium and K showed contrasting dynamics during the early decomposition phase. Nitrogen, phosphorus, and (137)Cs contents were positively correlated to fungal biomass, evaluated by phospholipid fatty acids in the litter during decomposition. The increase of radiocesium concentration mainly occurred during from April to October, when fungal growth peaked. Therefore, this suggests fungal translocation of nutrients from outside the litter substrate (immobilization) is the mechanism to increase radiocesium in the decomposing litter. The amount of (137)Cs contained in the 1-year-old decomposed leaf litter was estimated to be 4% per area of the soil-contaminated (137)Cs. PMID- 26630039 TI - Radiochemical characterization of produced water from two production offshore oilfields in Ghana. AB - Produced water from two Ghanaian offshore production oilfields has been characterized using alpha spectrometry after radiochemical separation, non destructive gamma spectrometry and ICP-MS and other complimentary analytical tools. The measured concentrations of main NORM components were in the range of 6.2-22.3 Bq.L(-1), 6.4-35.5 Bq.L(-1), and 0.7-7.0 Bq.L(-1) for (226)Ra, (228)Ra and (224)Ra respectively. A good correlation between several physico-chemical parameters and radium isotopes was observed in each production oilfield. The radium concentrations obtained in this study for produced water from the two oilfields of Ghana are of radiological importance and hence there may be the need to put in place measures for future contamination concerns due to their bioavailability in the media and bioaccumulation characteristics. The results will assist in critical decision making for future set up of appropriate national guidelines for the management of NORM waste from the emerging oil and gas industry in Ghana. PMID- 26630040 TI - Population modelling to compare chronic external radiotoxicity between individual and population endpoints in four taxonomic groups. AB - In this study, we modelled population responses to chronic external gamma radiation in 12 laboratory species (including aquatic and soil invertebrates, fish and terrestrial mammals). Our aim was to compare radiosensitivity between individual and population endpoints and to examine how internationally proposed benchmarks for environmental radioprotection protected species against various risks at the population level. To do so, we used population matrix models, combining life history and chronic radiotoxicity data (derived from laboratory experiments and described in the literature and the FREDERICA database) to simulate changes in population endpoints (net reproductive rate R0, asymptotic population growth rate lambda, equilibrium population size Neq) for a range of dose rates. Elasticity analyses of models showed that population responses differed depending on the affected individual endpoint (juvenile or adult survival, delay in maturity or reduction in fecundity), the considered population endpoint (R0, lambda or Neq) and the life history of the studied species. Among population endpoints, net reproductive rate R0 showed the lowest EDR10 (effective dose rate inducing 10% effect) in all species, with values ranging from 26 MUGy h(-1) in the mouse Mus musculus to 38,000 MUGy h(-1) in the fish Oryzias latipes. For several species, EDR10 for population endpoints were lower than the lowest EDR10 for individual endpoints. Various population level risks, differing in severity for the population, were investigated. Population extinction (predicted when radiation effects caused population growth rate lambda to decrease below 1, indicating that no population growth in the long term) was predicted for dose rates ranging from 2700 MUGy h(-1) in fish to 12,000 MUGy h(-1) in soil invertebrates. A milder risk, that population growth rate lambda will be reduced by 10% of the reduction causing extinction, was predicted for dose rates ranging from 24 MUGy h(-1) in mammals to 1800 MUGy h(-1) in soil invertebrates. These predictions suggested that proposed reference benchmarks from the literature for different taxonomic groups protected all simulated species against population extinction. A generic reference benchmark of 10 MUGy h(-1) protected all simulated species against 10% of the effect causing population extinction. Finally, a risk of pseudo-extinction was predicted from 2.0 MUGy h(-1) in mammals to 970 MUGy h(-1) in soil invertebrates, representing a slight but statistically significant population decline, the importance of which remains to be evaluated in natural settings. PMID- 26630041 TI - Mesalamine Intolerance in Three Children with Crohn's Disease. AB - OBJECTIVE: To present the mesalamine-induced acute exacerbation of symptoms and inflammatory markers in children with Crohn's disease (CD). CLINICAL PRESENTATION AND INTERVENTION: Three children who presented with CD had acute exacerbation of colitis symptoms or elevated inflammatory markers when mesalamine was added to treatment while tapering/ceasing steroid treatment. While on steroid treatment, the patients maintained clinical and laboratory remission, but with the initiation of mesalamine treatment, they had abdominal pain and bloody mucoid diarrhoea and/or elevation of white blood cell count, C-reactive protein level and erythrocyte sedimentation rate. Bacterial pathogens were excluded from the urine, throat and blood cultures, parasites with stool examination, viral pathogens with serology. Within 3-7 days after the mesalamine treatment had been stopped, the patients showed improvement of colitis symptoms and normalisation of white blood cell count, C-reactive protein level and erythrocyte sedimentation rate. CONCLUSION: In this study mesalamine mimicked CD relapse in children with CD while tapering or after stopping steroid treatment. Awareness of this side effect of mesalamine could prevent a misdiagnosis of steroid dependency. PMID- 26630042 TI - Enhanced performance of PVDF nanocomposite membrane by nanofiber coating: A membrane for sustainable desalination through MD. AB - Membrane distillation (MD) is a promising separation technique capable of being used in the desalination of marine and brackish water. Poly(vinylidene fluoride) (PVDF) flat sheet nano-composite membranes were surface modified by coating with electro-spun PVDF nano-fibres to increase the surface hydrophobicity. For this purpose, the nano-composite membrane containing 7 wt.% superhydrophobic SiO2 nano particles, which showed the highest flux in our previous work, was first subjected to pore size augmentation by increasing the concentration of the pore forming agent (Di-ionized water). Then, the prepared flat sheet membranes were subjected to nanofibres coating by electro-spinning. The uncoated and coated composite fabricated membranes were characterized using contact angle, liquid entry pressure of water, and scanning electron microscopy. The membranes were further tested for 6 h desalination by direct contact membrane distillation (DCMD) and vacuum membrane distillation (VMD), with a 3.5 wt.% synthetic NaClaq as the feed. In DCMD the feed liquid and permeate side temperature were maintained at 27.5 degrees C and 15 degrees C, respectively. For VMD, the feed liquid temperature was 27 degrees C and a vacuum of 94.8 kPa was applied on the permeate side. The maximum permeate flux achieved was 3.2 kg/m(2).h for VMD and 6.5 kg/m(2).h for DCMD. The salt rejection obtained was higher than 99.98%. The coated membranes showed a more stable flux than the uncoated membranes indicating that the double layered membranes have great potential in solving the pore wetting problem in MD. PMID- 26630043 TI - Negatively charged hyperbranched polyglycerol grafted membranes for osmotic power generation from municipal wastewater. AB - Osmotic power holds great promise as a clean, sustainable and largely unexploited energy resource. Recent membrane development for pressure-retarded osmosis (PRO) is making the osmotic power generation more and more realistic. However, severe performance declines have been observed because the porous layer of PRO membranes is fouled by the feed stream. To overcome it, a negatively charged antifouling PRO hollow fiber membrane has been designed and studied in this work. An antifouling polymer, derived from hyperbranched polyglycerol and functionalized by alpha-lipoic acid and succinic anhydride, was synthesized and grafted onto the polydopamine (PDA) modified poly(ether sulfone) (PES) hollow fiber membranes. In comparison to unmodified membranes, the charged hyperbranched polyglycerol (CHPG) grafted membrane is much less affected by organic deposition, such as bovine serum albumin (BSA) adsorption, and highly resistant to microbial growths, demonstrated by Escherichia coli adhesion and Staphylococcus aureus attachment. CHPG-g-TFC was also examined in PRO tests using a concentrated wastewater as the feed. Comparing to the plain PES-TFC and non-charged HPG-g-TFC, the newly developed membrane exhibits not only the smallest decline in water flux but also the highest recovery rate. When using 0.81 M NaCl and wastewater as the feed pair in PRO tests at 15 bar, the average power density remains at 5.6 W/m(2) in comparison to an average value of 3.6 W/m(2) for unmodified membranes after four PRO runs. In summary, osmotic power generation may be sustained by properly designing and anchoring the functional polymers to PRO membranes. PMID- 26630046 TI - ICASM 2015, AsMA 2016, and Pilot Mental Health. PMID- 26630044 TI - Photocatalytic transformation of acesulfame: Transformation products identification and embryotoxicity study. AB - Artificial sweeteners have been recognized as emerging contaminants due to their wide application, environmental persistence and ubiquitous occurrence. Among them, acesulfame has attracted much attention. After being discharged into the environment, acesulfame undergoes photolysis naturally. However, acesulfame photodegradation behavior and identity of its transformation products, critical to understanding acesulfame's environmental impact, have not been thoroughly investigated. The present study aimed to fill this knowledge gap by a laboratory simulation study in examining acesulfame transformation products and pathways under UV-C photolysis in the presence of TiO2. Photodegradation products of acesulfame were isolated and analyzed using the LC-IM-QTOF-MS coupled with LC Ion Trap MS in the MS(n) mode. Our results show six new transformation products that have not been previously identified. The molecular structures and transformation pathways were proposed. Further embryotoxicity tests showed that acesulfame transformation products at the low g L(-1) level produced significant adverse effects in tail detachment, heart rate, hatching rate and survival rate during fish embryo development. The identification of additional transformation products with proposed transformation pathways of acesulfame, the increased toxicity of acesulfame after photolysis, and the fact that the accumulation of acesulfame transformation products is increasingly likely make acesulfame contamination even more important. Water resource control agencies need to consider legislation regarding acesulfame and other artificial sweeteners, while further studies are carried out, in order to protect the safety of this most vital resource. PMID- 26630047 TI - Assessment of an Alternative Army Aircrew Eyewear. AB - BACKGROUND: Currently, Army aircrews needing refractive correction are issued the HGU-4/P aviator spectacles. However, a recently published survey found dissatisfaction with the current spectacle frame. The Aircrew Flight Frame (AFF) has been used by the Air Force for over 14 yr, with the AFF-OP (Operational) style used the longest. The purpose of this study was to evaluate AFF-OP performance and compatibility among U.S. Army aircrew under operational conditions. METHODS: At 1-, 6-, and 12-wk intervals, 73 Army aircrew members wore the AFF-OP eyewear and completed a Likert scale survey. There were 14 outcome measures surveyed, with the main outcome measure being frame preference. RESULTS: The AFF-OP was preferred significantly more than the HGU-4/P spectacle. Overall, 94% of aircrew responses preferred the AFF-OP and the three highest subjective reasons for AFF-OP preference were: 1) comfort around the ears without helmet or headset; 2) comfort around the ears with helmet or headset; and 3) the effect on ear cup seal. There were no statistically significant differences in responses over the three surveyed time intervals. DISCUSSION: Army aviation aircrew preferred the AFF-OP over the current HGU-4/P spectacles. Two of the top three highest subjective reasons for AFF-OP preference coincided with two of the top three operational eyewear problems reported in the recently published survey. If Army aircrew do not wear their issued eyewear, they may purchase their own frame "out of pocket." However, this can lead to use of a frame that has not been tested for compatibility and may compromise performance of aircrew life support equipment. PMID- 26630048 TI - First Aid Oxygen Treatment for Decompression Illness in the Goat After Simulated Submarine Escape. AB - BACKGROUND: Personnel responding to a distressed submarine incident require information on likely casualty levels and the severity and progression of decompression illness (DCI). Recompression may not be immediately available. First aid oxygen (FAo2) can be administered; however, there is no direct evidence of its efficacy in this scenario. METHODS: Trials were conducted between 2004 and 2006. Goats exposed to raised pressure for 24 h ('saturation') were either returned directly to atmospheric pressure (Phase A, N = 40) or exposed to simulated submarine escape at a depth of 656 ft (200 m; assumed seawater density = 1019.72 kg . m(-3); Phase B, N = 39). The pressure during saturation was selected to provoke 50% DCI. Cases of DCI were randomly assigned to receive FAo2or air. RESULTS: DCI cases were: limb pain in 39 subjects, neurological in 6, respiratory in 4, and pulmonary barotrauma in 1 subject. In Phase A, 5/12 subjects in the FAo2group and 0/11 in the air control group achieved permanent resolution of DCI. In Phase B, 6/8 subjects in the FAo2group and 5/8 in the air control group achieved permanent resolution. In both Phases, levels of venous gas bubbles reduced sooner with FAo2. Of three cases of neurological DCI receiving FAo2, two showed permanent resolution. In total, four cases of respiratory DCI occurred; none of these resolved, with three being treated with FAo2and one in the air control. DISCUSSION: Oxygen can be an effective first aid measure for DCI following submarine escape. However, it should not be used as a replacement for recompression therapy. PMID- 26630049 TI - Rebreather Unit to Prolong Underwater Survival Time. AB - INTRODUCTION: This study investigated whether the timing of activation affects the utility of an emergency underwater rebreather unit (RBU) when submerged in cold water. METHOD: On two successive occasions, 16 male UK Royal Marines were submerged in stirred water at 12.2 degrees C for up to 78 s. The subjects were lowered (taking 18 s) into the water in a seated position and were instructed to take a large breath in, activate the unit, breath-hold for as long as possible, exhale into the unit, and breathe normally to and from the unit for the remainder of submersion. On one occasion the subjects were instructed to activate the RBU when the water reached chest height (Condition-1) and, on the other, prior to the feet entering the water (Condition-2). Measurements were made of the duration of breath-hold, rebreathing and submersion, exhaled oxygen and carbon dioxide concentrations, skin temperature, and heart rate. RESULTS: In 16 of the 32 submersions, the breath-hold was released before the subject became fully submerged and in 8 submersions the subject requested early withdrawal from the water. Mean (SD) breath-hold duration was 14.0 (13.8) s and the duration of rebreathing was 45.9 (21.9) s. The duration of breath-hold once completely submerged was longer in Condition-1 (9.1 s) than Condition-2 (4.1 s). CONCLUSIONS: The study indicates the RBU should be activated just before the mouth becomes submerged rather than before entering the water, and that the RBU will prolong underwater stay time, thereby increasing survival prospects. House CM, Shaw AM, Roiz de Sa DG. Rebreather unit to prolong underwater stay time, thereby increasing survival prospects. PMID- 26630050 TI - Concept of Operations Evaluation for Using Remote-Guidance Ultrasound for Exploration Spaceflight. AB - BACKGROUND: Remote-guidance (RG) techniques aboard the International Space Station (ISS) have enabled astronauts to collect diagnostic-level ultrasound (US) images. Exploration-class missions will likely require nonformally trained sonographers to operate with greater autonomy given longer communication delays (> 6 s for missions beyond the Moon) and blackouts. Training requirements for autonomous collection of US images by non-US experts are being determined. METHODS: Novice US operators were randomly assigned to one of three groups to collect standardized US images while drawing expertise from A) RG only, B) a computer training tool only, or C) both RG and a computer training tool. Images were assessed for quality and examination duration. All operators were given a 10 min standardized generic training session in US scanning. The imaging task included: 1) bone fracture assessment in a phantom and 2) Focused Assessment with Sonography in Trauma (FAST) examination in a healthy volunteer. A human factors questionnaire was also completed. RESULTS: Mean time for group B during FAST was shorter (20.4 vs. 22.7 min) than time for the other groups. Image quality scoring was lower than in groups A or C, but all groups produced images of acceptable diagnostic quality. DISCUSSION: RG produces US images of higher quality than those produced with only computer-based instruction. Extended communication delays in exploration missions will eliminate the option of real-time guidance, thus requiring autonomous operation. The computer program used appears effective and could be a model for future digital US expertise banks. Terrestrially, it also provides adequate self-training and mentoring mechanisms. PMID- 26630051 TI - Otosclerosis and Fitness to Fly. AB - BACKGROUND: When an aircrew member is referred for otosclerosis, his flight fitness may be questionable. The objective of this retrospective study was to describe a case series of otosclerosis in an aircrew population and to discuss the decisions about their flight waivers. METHODS: There were 27 aircrew members who were referred to the ENT-Head and Neck Surgery Department of the National Pilot Expertise Center. Their medical files were retrospectively examined. RESULTS: Out of 16 patients who had surgery, 2 did not obtain a flight fitness waiver afterwards. Among the 14 who received waivers, 12 had no restrictions on their flight fitness. Among the nonoperated patients, 1 of 11 did not obtain a waiver. Seven patients were declared medically fit to fly without a waiver and three obtained a waiver. DISCUSSION: Fitness was based on auditory and balance statuses and the follow-up of these findings. A postoperative CT-scan and the operative report were used to determine the quality of stapes surgery. Professional speech audiometry in noise might be as interesting. The results made it possible to determine a patient's fitness to fly with a waiver, which is more or less associated with restrictions. In our series, only 3 aircrew members out of 27 did not obtain a flight fitness waiver. The few published studies on the resumption of flight for patients who underwent surgery and our experience in France with similar waivers in commercial and military aviation suggest that under certain conditions and after relevant vestibulocochlear assessment, stapes surgery may allow for a safe recovery of aviation activity. PMID- 26630052 TI - The Aeromedical Implications of Parkinson's Disease. AB - BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder which is encountered in the pilot population and has clinical features that can impact on the flying role. This retrospective study reviewed the United Kingdom Civil Aviation Authority (UK CAA) experience of Parkinson's disease. The aeromedical implications of the condition are discussed and the UK CAA policy for the certificatory assessment of pilots with Parkinson's disease is described. METHODS: A search of the UK CAA medical records database from 1990 to 2015 identified 34 pilots with a diagnosis of Parkinson's disease. Data was extracted for the class of medical certificate, time from first symptoms to diagnosis, age at diagnosis, the time from diagnosis to loss of certification and the reasons for loss of certification. RESULTS: Of 15 professional (Class 1) and 19 private (Class 2) pilots, the mean time from onset of symptoms to diagnosis was 36 and 19 mo, respectively. The mean ages at diagnosis were 55 and 59 yr, respectively. The mean interval from diagnosis to loss of certification was 21 (0-93) and 37 (0-84) mo, respectively. The reasons for loss of certification are considered. CONCLUSION: In the UK, pilots diagnosed with Parkinson's disease may be granted medical certification depending on their functional ability and the side effect profile of medication. The aeromedical implications of Parkinson's disease and the UK CAA policy for the certification of pilots with Parkinson's disease are discussed. PMID- 26630053 TI - Cognitive Workload and Psychophysiological Parameters During Multitask Activity in Helicopter Pilots. AB - BACKGROUND: Helicopter pilots are involved in a complex multitask activity, implying overuse of cognitive resources, which may result in piloting task impairment or in decision-making failure. Studies usually investigate this phenomenon in well-controlled, poorly ecological situations by focusing on the correlation between physiological values and either cognitive workload or emotional state. This study aimed at jointly exploring workload induced by a realistic simulated helicopter flight mission and emotional state, as well as physiological markers. METHOD: The experiment took place in the helicopter full flight dynamic simulator. Six participants had to fly on two missions. Workload level, skin conductance, RMS-EMG, and emotional state were assessed. RESULTS: Joint analysis of psychological and physiological parameters associated with workload estimation revealed particular dynamics in each of three profiles. 1) Expert pilots showed a slight increase of measured physiological parameters associated with the increase in difficulty level. Workload estimates never reached the highest level and the emotional state for this profile only referred to positive emotions with low emotional intensity. 2) Non-Expert pilots showed increasing physiological values as the perceived workload increased. However, their emotional state referred to either positive or negative emotions, with a greater variability in emotional intensity. 3) Intermediate pilots were similar to Expert pilots regarding emotional states and similar to Non-Expert pilots regarding physiological patterns. DISCUSSION: Overall, high interindividual variability of these results highlight the complex link between physiological and psychological parameters with workload, and question whether physiology alone could predict a pilot's inability to make the right decision at the right time. PMID- 26630054 TI - Identifying the Subtle Presentation of Decompression Sickness. AB - BACKGROUND: Decompression sickness is an inherent occupational hazard that has the possibility to leave its victims with significant long-lasting effects that can potentially impact an aircrew's flight status. The relative infrequency of this hazard within the military flying community along with the potentially subtle presentation of decompression sickness (DCS) has the potential to result in delayed diagnosis and treatment, leading to residual deficits that can impact a patient's daily life or even lead to death. CASE REPORT: The patient presented in this work was diagnosed with a Type II DCS 21 h after a cabin decompression at 35,000 ft (10,668 m). The patient had been asymptomatic with a completely normal physical/neurological exam following his flight. The following day, he presented with excessive fatigue and on re-evaluation was recommended for hyperbaric therapy, during which his symptoms completely resolved. He was re-evaluated 14 d later and cleared to resume flight duties without further incident. DISCUSSION: The manifestation of this patient's decompression sickness was subtle and followed an evaluation that failed to identify any focal findings. A high index of suspicion with strict follow-up contributed to the identification of DCS in this case, resulting in definitive treatment and resolution of the patient's symptoms. Determination of the need for hyperbaric therapy following oxygen supplementation and a thorough history and physical is imperative. If the diagnosis is in question, consider preemptive hyperbaric therapy as the benefits of treatment in DCS outweigh the risks of treatment. Finally, this work introduces the future potential of neuropsychological testing for both the diagnosis of DCS as well as assessing the effectiveness of hyperbaric therapy in Type II DCS. PMID- 26630055 TI - Scrotal Hematoma Precipitated by Centrifuge Training in a Fighter Pilot with an Asymptomatic Varicocele. AB - BACKGROUND: Varicocele is quite common in the general population, affecting up to 15% of men. It is not considered disqualifying for the pilot's training program of the Israeli Air Force as long as there are no related symptoms or associated pathologies. During combat flight, increased venous pressure due to acceleration forces and anti-G straining maneuvers, used to counteract high gravitational G forces, can theoretically aggravate the venous blood pooling in varicocele, leading to rupture. CASE REPORT: We describe a case of a young fighter-jet pilot presenting with a painful inguinal hematoma extending to the scrotum a day after participating in centrifuge training. Sonographic examination demonstrated dilated spermatic veins and intratesticular varicocele along with subcutaneous thickening of the scrotal wall consistent with hematoma. DISCUSSION: The effects of high G loads on blood flow in spermatic veins, and especially in varicocele, still need to be determined. Varicocele rupture has been described in relation to increased intra-abdominal pressure and could theoretically occur during anti-G straining maneuvers. Such an acute adverse event during combat flight can be detrimental to flight safety and the pilot's well-being. PMID- 26630056 TI - Cervical Manipulation Leading to Cerebellar Stroke in a Pilot. AB - BACKGROUND: Stroke is a decidedly devastating event for any patient, but particularly for a military aviator in a single-seat aircraft. Incidence of acute ischemic infarct in men ages 25 to 29 ranges from 3.4 to 5.6/100,000. The neurological sequelae of stroke can have a lasting and profound impact on an aviator's career. Literature review revealed a relatively small number of cases where stroke was attributable to cervical manipulation. CASE REPORT: A 29-yr-old male jet pilot with a 2-wk history of cervicalgia following a mountain bike ride performed self-manipulation of his neck at home following a visit to a chiropractor. He sustained an immediate onset of euphoria, nausea, dysarthria, vertigo, diploplia, and occipital headache, and was transported via ambulance to the nearest emergency department. The patient's MRI/MRA imaging revealed a dissection of his right vertebral artery, as well as bilateral cerebellar infarcts. During the course of the following months, the patient's residual symptoms included neck pain, headaches, disequilibrium, and quadrantanopia. DISCUSSION: The ability to recognize the symptoms of stroke and seek treatment in a timely manner are paramount and can drastically reduce the potential for permanent deficit. The evaluation of residual sequelae in military aviators who fly single-seat aircraft is of particular interest to aerospace medicine physicians when it comes time to return a pilot to flight duties. Additionally, the link between cervical manipulation and vertebral artery dissection leading to stroke remains equivocal, and further research is warranted. PMID- 26630057 TI - Comments on Body Mass Changes During Long-Duration Spaceflight. AB - The paper "Body Mass Changes During Long-Duration Spaceflight" allows a comparison of devices, their application, results obtained and their interpretation from the two programs of such studies to date. There were significant differences in all aspects of the two programs which are briefly commented on here. PMID- 26630058 TI - Human Computing and Super Forecasting. PMID- 26630059 TI - You're the Flight Surgeon: white matter hyperintensities. AB - Park B. You're the flight surgeon: white matter hyperintensities. Aerosp Med Hum Perform. 2015; 86(12):1075-1077. PMID- 26630060 TI - You're the Flight Surgeon: lateral epicondylitis. AB - Wolf SJ. You're the flight surgeon: lateral epicondylitis. Aerosp Med Hum Perform. 2015; 86(12):1077-1080. PMID- 26630061 TI - This Thing We Called the Schneider Index. PMID- 26630062 TI - This Month in Aerospace Medicine History. PMID- 26630067 TI - Mumps outbreaks in a highly vaccinated population: Investigation of a neutralization titre against the current circulating wildtype genotype G5 mumps virus. AB - BACKGROUND: Mumps outbreaks continue to occur globally, despite high levels of uptake of the mumps vaccine. OBJECTIVES: In order to address immunity to the current circulating wildtype virus, we sought to determine a mumps G5 specific IgG quantitative value which correlates with genotype G5 specific neutralization ability in vitro. STUDY DESIGN: Sera from 199 individuals including controls and acute mumps cases were assessed for mumps specific IgG titres using five different enzyme immunoassays coated with antigen from different mumps virus strains. A subset of 66 sera was also assessed for in vitro neutralizing antibody against a contemporary circulating genotype G5 mumps virus. RESULTS: For all the different antigenic targets, mumps specific IgG titres were higher in patients following acute mumps infection compared to controls. In acute mumps infected patients, females showed significantly higher serum titres of anti-G5 IgG compared to males (p<0.05). Furthermore, control males did not show any change in G5 specific IgG with increasing age whereas females show a progressive rise in titre. Linear regression analysis revealed a significant association between the mumps G5 specific IgG levels in the EIA and the in vitro neutralization titres (r(2)=0.59). CONCLUSIONS: Specific IgG to the current circulating genotype G5 mumps strain showed significantly lower titres in males which supports our previous observation that there is a male gender bias in cases of acute mumps infection. Furthermore, in this preliminary study, the data indicate that genotype G5 specific IgG levels of >40 RU/ml are required for neutralization capability to be observed in vitro. PMID- 26630068 TI - Mathematical Modeling of Interacting Glucose-Sensing Mechanisms and Electrical Activity Underlying Glucagon-Like Peptide 1 Secretion. AB - Intestinal L-cells sense glucose and other nutrients, and in response release glucagon-like peptide 1 (GLP-1), peptide YY and other hormones with anti-diabetic and weight-reducing effects. The stimulus-secretion pathway in L-cells is still poorly understood, although it is known that GLP-1 secreting cells use sodium glucose co-transporters (SGLT) and ATP-sensitive K+-channels (K(ATP)-channels) to sense intestinal glucose levels. Electrical activity then transduces glucose sensing to Ca2+-stimulated exocytosis. This particular glucose-sensing arrangement with glucose triggering both a depolarizing SGLT current as well as leading to closure of the hyperpolarizing K(ATP) current is of more general interest for our understanding of glucose-sensing cells. To dissect the interactions of these two glucose-sensing mechanisms, we build a mathematical model of electrical activity underlying GLP-1 secretion. Two sets of model parameters are presented: one set represents primary mouse colonic L-cells; the other set is based on data from the GLP-1 secreting GLUTag cell line. The model is then used to obtain insight into the differences in glucose-sensing between primary L-cells and GLUTag cells. Our results illuminate how the two glucose sensing mechanisms interact, and suggest that the depolarizing effect of SGLT currents is modulated by K(ATP)-channel activity. Based on our simulations, we propose that primary L-cells encode the glucose signal as changes in action potential amplitude, whereas GLUTag cells rely mainly on frequency modulation. The model should be useful for further basic, pharmacological and theoretical investigations of the cellular signals underlying endogenous GLP-1 and peptide YY release. PMID- 26630070 TI - Spherical aberration correction with threefold symmetric line currents. AB - It has been shown that N-fold symmetric line current (henceforth denoted as N SYLC) produces 2N-pole magnetic fields. In this paper, a threefold symmetric line current (N3-SYLC in short) is proposed for correcting 3rd order spherical aberration of round lenses. N3-SYLC can be realized without using magnetic materials, which makes it free of the problems of hysteresis, inhomogeneity and saturation. We investigate theoretically the basic properties of an N3-SYLC configuration which can in principle be realized by simple wires. By optimizing the parameters of a system with beam energy of 5.5keV, the required excitation current for correcting 3rd order spherical aberration coefficient of 400 mm is less than 1AT, and the residual higher order aberrations can be kept sufficiently small to obtain beam size of less than 1 nm for initial slopes up to 5 mrad. PMID- 26630069 TI - Fabrication of tungsten probe for hard tapping operation in atomic force microscopy. AB - We propose a method of producing a tungsten probe with high stiffness for atomic force microscopy (AFM) in order to acquire enhanced phase contrast images and efficiently perform lithography. A tungsten probe with a tip radius between 20nm and 50nm was fabricated using electrochemical etching optimized by applying pulse waves at different voltages. The spring constant of the tungsten probe was determined by finite element analysis (FEA), and its applicability as an AFM probe was evaluated by obtaining topography and phase contrast images of a Si wafer sample partly coated with Au. Enhanced hard tapping performance of the tungsten probe compared with a commercial Si probe was confirmed by conducting hard tapping tests at five different oscillation amplitudes on single layer graphene grown by chemical vapor deposition (CVD). To analyze the damaged graphene sample, the test areas were investigated using tip-enhanced Raman spectroscopy (TERS). The test results demonstrate that the tungsten probe with high stiffness was capable of inducing sufficient elastic and plastic deformation to enable obtaining enhanced phase contrast images and performing lithography, respectively. PMID- 26630071 TI - Segmentation of 3D EBSD data for subgrain boundary identification and feature characterization. AB - Subgrain structures formed during plastic deformation of metals can be observed by electron backscatter diffraction (EBSD) but are challenging to identify automatically. We have adapted a 2D image segmentation technique, fast multiscale clustering (FMC), to 3D EBSD data using a novel variance function to accommodate quaternion data. This adaptation, which has been incorporated into the free open source texture analysis software package MTEX, is capable of segmenting based on subtle and gradual variation as well as on sharp boundaries within the data. FMC has been further modified to group the resulting closed 3D segment boundaries into distinct coherent surfaces based on local normals of a triangulated surface. We demonstrate the excellent capabilities of this technique with application to 3D EBSD data sets generated from cold rolled aluminum containing well-defined microbands, cold rolled and partly recrystallized extra low carbon steel microstructure containing three magnitudes of boundary misorientations, and channel-die plane strain compressed Goss-oriented nickel crystal containing microbands with very subtle changes in orientation. PMID- 26630072 TI - Performance of a direct detection camera for off-axis electron holography. AB - The performance of a direct detection camera (DDC) is evaluated in the context of off-axis electron holographic experiments in a transmission electron microscope. Its performance is also compared directly with that of a conventional charge coupled device (CCD) camera. The DDC evaluated here can be operated either by the detection of individual electron events (counting mode) or by the effective integration of many such events during a given exposure time (linear mode). It is demonstrated that the improved modulation transfer functions and detective quantum efficiencies of both modes of the DDC give rise to significant benefits over the conventional CCD cameras, specifically, a significant improvement in the visibility of the holographic fringes and a reduction of the statistical error in the phase of the reconstructed electron wave function. The DDC's linear mode, which can handle higher dose rates, allows optimisation of the dose rate to achieve the best phase resolution for a wide variety of experimental conditions. For suitable conditions, the counting mode can potentially utilise a significantly lower dose to achieve a phase resolution that is comparable to that achieved using the linear mode. The use of multiple holograms and correlation techniques to increase the total dose in counting mode is also demonstrated. PMID- 26630073 TI - Purpose in Life and Its Relationship to All-Cause Mortality and Cardiovascular Events: A Meta-Analysis. AB - OBJECTIVE: To assess the net impact of purpose in life on all-cause mortality and cardiovascular events. METHODS: The electronic databases PubMed, Embase, and PsycINFO were systematically searched through June 2015 to identify all studies investigating the relationship between purpose in life, mortality, and cardiovascular events. Articles were selected for inclusion if, a) they were prospective, b) evaluated the association between some measure of purpose in life and all-cause mortality and/or cardiovascular events, and c) unadjusted and/or adjusted risk estimates and confidence intervals (CIs) were reported. RESULTS: Ten prospective studies with a total of 136,265 participants were included in the analysis. A significant association was observed between having a higher purpose in life and reduced all-cause mortality (adjusted pooled relative risk = 0.83 [CI = 0.75-0.91], p < .001) and cardiovascular events (adjusted pooled relative risk = 0.83 [CI = 0.75-0.92], p = .001). Subgroup analyses by study country of origin, questionnaire used to measure purpose in life, age, and whether or not participants with baseline cardiovascular disease were included in the study all yielded similar results. CONCLUSIONS: Possessing a high sense of purpose in life is associated with a reduced risk for all-cause mortality and cardiovascular events. Future research should focus on mechanisms linking purpose in life to health outcomes, as well as interventions to assist individuals identified as having a low sense of purpose in life. PMID- 26630074 TI - Current Role of Uterine Artery Embolization in the Management of Uterine Fibroids. AB - Uterine artery embolization (UAE) is a well-established therapy for uterine fibroids, with safety and efficacy demonstrated in several comparative randomized trials. It is a minimally invasive procedure, which allows for rapid recovery and return to normal activities. Most studies demonstrate outcomes similar to those of myomectomy with a reintervention rate of 20% to 30% at 5 years after therapy. While pregnancy is often successful after UAE, limited comparative data suggest that myomectomy may be preferred in those patients who have not had prior fibroid interventions. UAE should be discussed as an option for most women presenting for treatment of fibroids. PMID- 26630075 TI - The Role of Hysteroscopic and Robot-assisted Laparoscopic Myomectomy in the Setting of Infertility. AB - Fibroids, the most common gynecologic condition in women of reproductive age, have traditionally been treated with hysterectomy. As more women delay childbearing, myomectomy becomes an essential component of the gynecologist's armamentarium. Minimally invasive approaches to myomectomy have been shown to decrease morbidity and reduce care-related costs, while improving reproductive outcomes. Hysteroscopic myomectomy is a reproducible and easily learned technique for the treatment of submucosal fibroids. Robot-assisted laparoscopic myomectomy overcomes most of the technical challenges of laparoscopic myomectomy for intramural and subserosal fibroids. The combined adoption of these technologies will allow more patients with fibroids to benefit from a minimally invasive approach. PMID- 26630076 TI - Bipyricorrole: A Corrole Homologue with a Monoanionic Core as a Fluorescence Zn(II) Sensor. AB - In the corrole homologue, 6,11,16-triarylbipyricorrole, the bipyrrole unit is replaced by a 2,2'-bipyridine unit. This modification effectively alters the corrole N4 coordination sphere from the trianionic [(NH)3 N] to the monoanionic [N3NH] state. The newly formed monoanionic core stabilizes Zn(II) ions with enhanced emission properties. The enhanced emission was further utilized for metal ion sensing studies and exploited for the selective detection of Zn(II) ions. PMID- 26630077 TI - Parallel Post-Polyketide Synthase Modification Mechanism Involved in FD-891 Biosynthesis in Streptomyces graminofaciens A-8890. AB - To isolate a key polyketide biosynthetic intermediate for the 16-membered macrolide FD-891 (1), we inactivated two biosynthetic genes coding for post polyketide synthase (PKS) modification enzymes: a methyltransferase (GfsG) and a cytochrome P450 (GfsF). Consequently, FD-892 (2), which lacks the epoxide moiety at C8-C9, the hydroxy group at C10, and the O-methyl group at O-25 of FD-891, was isolated from the gfsF/gfsG double-knockout mutant. In addition, 25-O-methyl-FD 892 (3) and 25-O-demethyl-FD-891 (4) were isolated from the gfsF and gfsG mutants, respectively. We also confirmed that GfsG efficiently catalyzes the methylation of 2 and 4 in vitro. Further, GfsF catalyzed the epoxidation of the double bond at C8-C9 of 2 and 3 and subsequent hydroxylation at C10, to afford 4 and 1, respectively. These results suggest that a parallel post-PKS modification mechanism is involved in FD-891 biosynthesis. PMID- 26630078 TI - Calculating the hip center of rotation using contralateral pelvic anatomy. AB - Failure to place an artificial hip in the optimal center of rotation results in poor hip function and costly complications. The aim of this study was to develop robust methodology to estimate hip center of rotation (hCoR) from preoperative computed tomography (CT) scans, using contralateral anatomy, in patients with unilateral diseased hips. Ten patients (five male, five female) with normal pelvic anatomy, and one patient with a unilateral dysplastic acetabulum were recruited from the London Implant Retrieval center image bank. 3D models of each pelvis were generated using commercial software. Two methods for estimation of hCoR were compared. Method 1 used a mirroring technique alone. Method 2 utilized mirroring and automatic alignment. Predicted versus actual hCoR co-ordinates were compared using intraclass correlation coefficients and paired T-tests. Both methods predicted hCoR with excellent agreement to original co-ordinates (>0.9) in all axes. Both techniques allowed prediction of the hCoR within +/- 5 mm in all axes. Both techniques provided useful clinical information for planning acetabular reconstruction in patients with unilateral defects. Method 1 was less complex and is suitable for patients with developmental and degenerative pathologies. Method 2 may provide greater accuracy in a discrete group of patients with normal development prior to pathology (e.g., acetabular fractures). (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1077-1083, 2016. PMID- 26630079 TI - Tofacitinib Citrate for the Treatment of Nail Dystrophy Associated With Alopecia Universalis. PMID- 26630080 TI - Seroprevalence rates of HPyV6, HPyV7, TSPyV, HPyV9, MWPyV and KIPyV polyomaviruses among the healthy blood donors. AB - Human polyomaviruses HPyV6, HPyV7, TSPyV, HPyV9, MWPyV, and KIPyV have been discovered between 2007 and 2012. TSPyV causes a rare skin disease trichodysplasia spinulosa in immunocompromised patients, the role of remaining polyomaviruses in human pathology is not clear. In this study, we assessed the occurrence of serum antibodies against above polyomaviruses in healthy blood donors. Serum samples were examined by enzyme-linked immunoassay (ELISA), using virus-like particles (VLPs) based on the major VP1 capsid proteins of these viruses. Overall, serum antibodies against HPyV6, HPyV7, TSPyV, HPyV9, MWPyV, and KIPyV were found in 88.2%, 65.7%, 63.2%, 31.6%, 84.4%, and 58%, respectively, of this population. The seroprevalence generally increased with age, the highest rise we observed for HPyV9 and KIPyV specific antibodies. The levels of anti-HPyV antibodies remained stable across the age-groups, except for TSPyV and HPyV9, where we saw change with age. ELISAs based on VLP and GST-VP1 gave comparable seroprevalence for HPyV6 antibodies (88.2% vs.85.3%) but not for HPyV7 antibodies (65.7% vs. 77.2%), suggesting some degree of crossreactivity between HPyV6 and HPyV7 VP1 proteins. In conclusion, these results provide evidence that human polyomaviruses HPyV6, HPyV7, TSPyV, HPyV9, MwPyV, and KIPyV circulate widely in the Czech population and their seroprevalence is comparable to other countries. PMID- 26630081 TI - Positron annihilation spectroscopy: a new frontier for understanding nanoparticle loaded polymer brushes. AB - Nanoparticle-loaded polymer brushes are powerful tools for the development of innovative devices. However, their characterization is challenging and arrays of different techniques are typically required to gain sufficient insight. Here we demonstrate for the first time the suitability of positron annihilation spectroscopy (PAS) to investigate, with unprecedented detail and without making the least damage to samples, the physico-chemical changes experienced by pH responsive polymer brushes after protonation and after loading of silver nanoparticles. One of the most important findings is the depth profiling of silver nanoparticles inside the brushes. These results open up a completely new way to understand the structure and behavior of such complex systems. PMID- 26630084 TI - Errors in Text and Tables 2 and 3. PMID- 26630085 TI - Error in Table Footnote. PMID- 26630087 TI - Thermodynamic and Experimental Study of the Energetic Cost Involved in the Capture of Carbon Dioxide by Aqueous Mixtures of Commonly Used Primary and Tertiary Amines. AB - The capture of carbon dioxide with chemical solvents is one solution to mitigate greenhouse gas emissions from anthropogenic sources and thus tackle climate change. Recent research has been focused on optimizing new kinds of advanced absorbents including aqueous amine blends, but critical downsides such as the large energetic cost involved with the industrial process remain. To address this issue, a better understanding of the energetic interactions existing in solution is necessary. In this paper, we report direct experimental measurements of the energy cost involved in the solvation of CO2 in two aqueous amine blends at different temperatures. The chemical solvents were designed as aqueous mixtures of commonly used primary and tertiary amines to study the influence of the different chemical properties inferred by the amine class. We have also applied a thermodynamic model to represent the energetic effects that take place in solution during CO2 dissolution in these mixtures, where all parameters were taken from previous studies focused on single amine absorbents. The noteworthy agreement observed with the reported experimental heats of absorption and with literature vapor liquid equilibrium properties confirmed the relevance of the underlying molecular mechanisms considered in our model, and suggest that this model would prove useful to investigate CO2 dissolution in other amine blends. PMID- 26630086 TI - The Effect of Potassium Impurities Deliberately Introduced into Activated Carbon Cathodes on the Performance of Lithium-Oxygen Batteries. AB - Rechargeable lithium-air (Li-O2) batteries have drawn much interest owing to their high energy density. We report on the effect of deliberately introducing potassium impurities into the cathode material on the electrochemical performance of a Li-O2 battery. Small amounts of potassium introduced into the activated carbon (AC) cathode material in the synthesis process are found to have a dramatic effect on the performance of the Li-O2 cell. An increased amount of potassium significantly increases capacity, cycle life, and round-trip efficiency. This improved performance is probably due to a larger amount of LiO2 in the discharge product, which is a mixture of LiO2 and Li2O2, resulting from the increase in the amount of potassium present. No substantial correlation with porosity or surface area in an AC cathode is found. Experimental and computational studies indicate that potassium can act as an oxygen reduction catalyst, which can account for the dependence of performance on the amount of potassium. PMID- 26630088 TI - The Influence of Clinical Decision Support on Diagnostic Accuracy in Nurse Practitioners. AB - BACKGROUND: Clinical decision support systems (CDSSs) at the point of care are evidence-based interventions that have demonstrated incremental positive impact on quality of healthcare delivery over the past two decades. Existing best practices inform strategies to promote adoption and achievement of targeted outcomes. The purpose of this improvement project was to conduct a pilot implementation to understand the contextual factors and readiness for dissemination of a newly acquired electronic CDSS by evaluating its influence on diagnostic accuracy in nurse practitioners (NPs) functioning in a community health setting. AIMS: The specific aims of this project were to measure and compare diagnostic accuracy in a pilot group before and after CDSS use, educate clinicians about the system and pilot its use, and then leverage the experience to design the practice-wide CDSS dissemination strategy. METHODS: The project engaged a subset of NPs from a home-based primary care practice and other organizational stakeholders who provided tangible support and necessary resources for successful adoption of this innovation in practice. A structured conceptual model of Evidence-Based Practice Improvement enhanced with elements of the Promoting Action on Research Implementation in Health Sciences framework was used to guide the development, implementation and evaluation of this practice improvement initiative. A group of seven NP representatives of the practice participated in the project. Data collection was composed of small tests of change (plan-do-study-act) cycles at the local practice level, measuring achievement of improvement of the chosen outcome of correctness of medical diagnosis evidenced by appropriate substantiating clinical documentation. LINKING EVIDENCE TO ACTION: In this home visiting primary care practice setting, use of a CDSS by NPs achieved eventual improvement in diagnostic accuracy and clinical documentation, as demonstrated on chart audit, though the improvement was not sustained over time. The pilot findings ultimately informed decision making about CDSS dissemination strategies and future uses of the system. When appropriately deployed, a CDSS offers the potential to improve professional practice, support differential diagnosis and evidence-based treatment, and provide detailed information about the disease state to facilitate robust clinical documentation. PMID- 26630090 TI - Hypolipidemia in a Special Operations Candidate: Case Report and Review of the Literature. AB - BACKGROUND: A 19-year-old male military recruit who presented for a screening physical for US Naval Special Warfare Duty was found to have hypolipidemia. Medical history revealed mildly increased frequency of bowel movements, but was otherwise unremarkable. His presentation was most consistent with heterozygous familial hypobetalipoproteinemia (FHBL), and the patient was cleared for Special Operations duty. METHODS: A literature search was conducted using PubMed/MEDLINE. Keywords included familial hypobetalipoproteinemia, heterozygous familial hypobetalipoproteinemia, abetalipoproteinemia, hypolipidemia, diving, special operations, and military. Results that included cases of familial hypobetalipoproteinemia were included. RESULTS: Review of the literature reveals that FHBL is a genetic disorder frequently, but not always, due to a mutation in the apolipoprotein B (apoB) gene. Those with the condition should be screened for ophthalmologic, neurologic, and gastrointestinal complications. Analysis of the disease, as well as the absence of reported cases of FHBL in diving and Special Operations, suggest there is minimal increased risk in diving and Special Operations for patients who are likely heterozygous, are asymptomatic, and have a negative workup for potential complications from the disease. CONCLUSION: Individuals with presumed or proven heterozygous FHBL seeking clearance for Special Operations duty should be given precautions, undergo careful questioning for history of disease-specific complications, and should have a baseline evaluation. If negative, it seems reasonable to clear the patient for Special Operations and diving. PMID- 26630089 TI - DISTINCT ETIOLOGICAL INFLUENCES ON OBSESSIVE-COMPULSIVE SYMPTOM DIMENSIONS: A MULTIVARIATE TWIN STUDY. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is characterized by five major dimensions, including contamination/washing, harm/checking, symmetry/ordering, hoarding, and forbidden thoughts. How these dimensions may relate etiologically to the symptoms of other obsessive-compulsive related disorders (OCRDs) and anxiety disorders (ADs) is not well known. The aim of this study was to examine the genetic and environmental overlap between each major obsessive-compulsive dimension with the symptoms of other OCRDs and ADs. METHODS: Two thousand four hundred ninety-five twins of both sexes, aged between 18 and 45 years, were recruited from the Australian Twin Registry. Measures used scores on four dimensions (obsessing (forbidden thoughts), washing, checking, and ordering) of the Obsessive-Compulsive Inventory-Revised, Dysmorphic Concerns Questionnaire, Hoarding Rating Scale, Anxiety Sensitivity Index, Social Phobia Inventory, and Stress subscale of the Depression, Anxiety, and Stress Scale. Multivariate twin modeling methods using continuous and categorized variables were performed, also controlling for age and gender. RESULTS: Our findings suggested that forbidden thoughts and washing demonstrated the strongest genetic overlap with other AD symptoms, while ordering was genetically related to OCRD symptoms. Common genetic influences on checking symptoms were best estimated when modeling OCRDs together with AD symptoms. Common environmental factors of ordering and checking were shared with AD symptoms. CONCLUSIONS: Important shared genetic and environmental risk factors exist between OCD, OCRDs, and ADs, but which vary alongside the expression of its major dimensions. PMID- 26630092 TI - Testing Tourniquet Use in a Manikin Model: Two Improvised Techniques. AB - BACKGROUND: Improvised tourniquets may be used to treat limb wound hemorrhage, but there is little evidence for best techniques of use. The purpose of the present study is to compare use of two techniques of improvised tourniquet application and use of a common commercial tourniquet that is nonimprovised. METHODS: A laboratory experiment was conducted to assess three groups of strap and-windlass tourniquet designs on a manikin to test for differences in performance. Groups included two types of improvised tourniquets (bandage and bandana) and a third group that served as a control, the commercial Combat Application Tourniquet. Two users performed 10 tests of each group. RESULTS: The commercial CAT had 100% effectiveness, but both improvised tourniquets had poor effectiveness (40% and 10% for the bandage and bandana groups, respectively). The commercial CAT performed fastest; the two improvised tourniquet groups were slower than the commercial group (p<.0001, both) but were not statistically different from each other. All time-of-application results in the commercial group were less than the minimums of either improvised group. The commercial CAT had the highest mean pressures, and all such pressures were within safe and effective ranges. Low pressures generated by both improvised tourniquet groups were ineffective. All results of simulated blood loss with the commercial CAT group were less than the minimums of either improvised tourniquet group. CONCLUSION: In the present experiment, the commercial CAT performed better than either improvised tourniquet. PMID- 26630091 TI - The Combat Medic Aid Bag: 2025. CoTCCC Top 10 Recommended Battlefield Trauma Care Research, Development, and Evaluation Priorities for 2015. AB - While the list presented here is by no means a comprehensive list of all of the research areas of interest in battlefield trauma care, much less a list of research needs across the entire continuum of combat casualty care, it does provide the collective judgment of the CoTCCC about the highest priorities for RDT&E that relate to battlefield trauma care. Two additional observations should be made regarding that point: (1) As the landmark Eastridge et al. 2012 study convincingly documented, most combat fatalities occur in the prehospital phase of care, so research efforts that enable Combat medics, corpsmen, and PJs to care for their casualties more effectively will convey the highest probability of further reducing the case fatality rate and preventable deaths among US Combat casualties; and (2) inasmuch as the mission of the CoTCCC is to update the TCCC Guidelines as needed, this group has excellent visibility of the most important current research questions in battlefield trauma care. PMID- 26630093 TI - Different Width and Tightening System: Emergency Tourniquets on Distal Limb Segments. AB - BACKGROUND: Tourniquets are used on distal limb segments. We examined calf and forearm use of four thigh-effective, commercial tourniquets with different widths and tightening systems: 3.8 cm windlass Combat Application Tourniquet(r) (CAT, combattourrniquet.com) and Special Operations Forces(r) Tactical Tourniquet-Wide (SOFTTW, www.tacmedsolutions.com), 3.8 cm ratchet Ratcheting Medical Tourniquet - Pediatric (RMT-P, www.ratchetingbuckles. com), and 10.4 cm elastic Stretch-Wrap And-Tuck Tourniquet(r) (SWATT, www.swattourniquet.com). METHODS: From Doppler indicated occlusion, windlass completion was the next securing opportunity; ratchet completion was one additional tooth advance; elastic completion was end tucked under a wrap. RESULTS: All applications on the 16 recipients achieved occlusion. Circumferences were calf 38.1+/-2.5 cm and forearm 25.1+/-3.0 cm (p<.0001, t-test, mean+/-SD). Pressures at Occlusion, Completion, and 120-seconds after Completion differed within each design (p<.05, one-way ANOVA; calf: CAT 382+/-100, 510+/-108, 424+/-92 mmHg; SOFTT-W 381+/-81, 457+/-103, 407+/-88 mmHg; RMT-P 295+/-35, 350+/-38, 301+/-30 mmHg; SWATT 212+/-46, 294+/-59, 287+/-57 mmHg; forearm: CAT 301+/-100, 352+/-112, 310+/-98 mmHg; SOFTT-W 321+/-70, 397+/-102, 346+/-91 mmHg; RMT-P 237+/-48, 284+/-60, 256+/-51 mmHg; SWATT 181+/-34, 308+/-70, 302+/-70 mmHg). Comparing designs, pressures at each event differed (p<.05, one way ANOVA), and the elastic design had the least pressure decrease over time (p<.05, one-way ANOVA). Occlusion losses differed among designs on the calf (p<.05, chi2; calf: CAT 1, SOFTT-W 5, RMT-P 1, SWATT 0; forearm: CAT 0, SOFTT-W 1, RMT-P 2, SWATT 0). CONCLUSIONS: All four designs can be effective on distal limb segments, the SWATT doing so with the lowest pressures and least pressure losses over time. The pressure change from Occlusion to Completion varies by tourniquet tightening system and can involve a pressure decrease with the windlass tightening systems. Pressure losses occur in as little as 120 seconds following Completion and so can loss of Occlusion. This is especially true for nonelastic strap tourniquet designs. PMID- 26630094 TI - Comprehensive Performance Nutrition for Special Operations Forces. AB - Special Operations Forces (SOF) training, combat, and contingency operations are unique and demanding. Performance nutrition within the Department of Defense has emphasized that nutrition is relative to factors related to the desired outcome, which includes successful performance of mentally and physically demanding operations and missions of tactical and strategic importance, as well as nonoperational assignments. Discussed are operational, nonoperational, and patient categories that require different nutrition strategies to facilitate category-specific performance outcomes. Also presented are 10 major guidelines for a SOF comprehensive performance nutrition program, practical nutrition recommendations for Special Operators and medical providers, as well as resources for dietary supplement evaluation. Foundational health concepts, medical treatment, and task-specific performance factors should be considered when developing and systematically implementing a comprehensive SOF performance nutrition program. When tailored to organizational requirements, SOF unit- and culture-specific nutrition education and services can optimize individual Special Operator performance, overall unit readiness, and ultimately, mission success. PMID- 26630096 TI - OK, Doc . . . What Do I Really Have? Posttraumatic Stress Disorder Versus Traumatic Brain Injury. AB - The authors review the diagnostic overlap that exists between posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI). Achieving the correct diagnosis is much more difficult and the potential to inappropriately treat patients is greater than most physicians realize. The need to properly diagnose and select appropriate treatment strategies is essential, especially with TBI cases. A number of new and experimental therapies are being used to treat PTSD effectively and reverse the neurological sequelae of TBI, potentially returning to active duty Servicemembers who are undergoing a medical review board. PMID- 26630095 TI - Evaluating Alternatives to Traditional Cotton Laparotomy Sponges for Blood Absorption in the Austere and Mobile Surgical Environment. AB - BACKGROUND: The operative control of noncompressible hemorrhage is the single largest impact that could be addressed in reducing the mortality on the battlefield. Laprotomy pads, traditionally used for hemorrhage evacuation, are made of woven cotton, and, while effective, their use requires a substantial amount of space and adds weight. This poses no concern in traditional operating rooms but is a hindrance for mobile providers and providers in austere environments. We sought to compare different absorptive compunds to ascertain their utility as alternatives for traditional laparotomy pads. METHODS: Samples of cotton laparotomy pads, pure rayon sheets, rayon-polypropylene composite sheets, and non-polyester composite "microfiber" sheets were weighed and submerged in heparinized whole bovine blood. After saturation, the favrics were weighed, wrung dry, reweighed, and resubmerged. This process was performed for a total of three sequential submersions. The saturated weights and dry weights of each fabric were used to calculate how much blood each fabric could absorb initially and after multiple repeated uses. The initial densities of the four fabrics was calculated and compared. RESULTS: The initial submersions demonstrated that 1g each of cotton, rayon, rayon-polypropylene, and nylon polyester were able to absorb 7.58 g, 12.98 g, 10.16 g, and 9.73 g of blood respectively. The second and third sequential trials, which were statistically similar, demonstrated that 1g of cotton, rayon, rayon-polypropolyene, and nylon polyester were able to absorb 1.73 g, 2.83 g, 2.3g, and 2.3g of blood, respectively. The calculated densities of cotton, rayon, rayon-polypropylene, and nylon-polyester were 0.087 g/cm3, .012 g/cm3, 0.098 g/cm3, and 0.093 g/cm3, respectively. CONCLUSION: Per gram, rayon absorbed approximately 1.7 times more blood thancotton and three-quarters the amount of the storage space. Rayon also retained its superior absorption abilites on repeated uses, demonstrating the potential for re-use in remote and austere environments. Thus, rayon could serve as a viable alternative to traditional cotton laparotomy pads in the austere environments. PMID- 26630097 TI - Garrison Clinical Setting Inadequate for Maintenance of Procedural Skills for Emergency Medicine Physicians: A Cross-Sectional Study. AB - BACKGROUND: Emergency medicine physicians (EPs) are often placed in far-forward, isolated areas in theater. Maintenance of their emergency intervention skills is vital to keep the medical forces deployment ready. The US Army suggests that working at a Military Treatment Facility (MTF) is sufficient to keep emergency procedural skills at a deployment-ready level. We sought to compare the volume of emergency procedures that providers reported necessary to maintain their skills with the number available in the MTF setting. METHODS: EPs were surveyed to quantify the number of procedures they reported they would need to perform yearly to stay deployment-ready. We obtained procedure data for their duty stations and compared the procedure volume with the survey responses to determine if working at an MTF is sufficient to keep providers' skills deployment ready. RESULTS: The reported necessary average numbers per year were as follows: tube thoracostomy (5.9), intubation (11.4), cricothyrotomy (4.2), lumbar puncture (5.2), central line (10.0), focused assessment with sonography for trauma (FAST) (21.3), reductions (10.6), splints (10.5), and sedations (11.7). None of the procedure volumes at MTFs met provider requirements with the exception of FAST examinations at the only trauma center. CONCLUSIONS: This suggests the garrison clinical environment is inadequate for maintaining procedure skills. Further research is needed to determine modalities that will provide adequate training volume. PMID- 26630098 TI - Remote Telementored Ultrasound-Directed Compression to Potentially Accelerate Hemostasis in Exsanguinating Junctional Vascular Injuries. AB - Bleeding to death has been identified as the leading cause of potentially preventable injury-related death worldwide. Temporary hemorrhage control could allow the patient to be transported to a site capable of damage- control surgery. A novel device that may offer a fast and effective means of controlling nontruncal bleeding (junctional and extremity) is the iTClamp (Innovative Trauma Care; http://innovativetraumacare.com). This case study demonstrated that a motivated and intelligent, but untrained, first responder could successfully localize the actual anatomic site of an exsanguinating bleed and then could relatively easily compress this site to control the bleeding site by using ultrasound-guided manual-compression techniques. PMID- 26630099 TI - Fever and Thrombocytopenia in a Returning Soldier. AB - A case of fever and thrombocytopenia in a 33-year-old Special Forces Soldier with recent deployment to the Philippines is discussed, as are differential diagnosis and initial medical management at an overseas, fixed US military medical treatment facility. The authors discuss lessons learned that are applicable for Special Operations Forces (SOF) medical providers and recommend a renewed and continued emphasis on tropical medicine and infectious disease training for SOF medical providers. PMID- 26630100 TI - Taser and Conducted Energy Weapons. AB - It is clear that CEWs are an increasingly prevalent law enforcement tool, adopted to address a complex and challenging problem. The potential for serious injury from a single deployment of a CEW is extremely low. The debate regarding the link between these electrical weapons and sudden in-custody death is likely to continue because their use is often in complex and volatile situations. Any consideration of injuries has to be put into that context. One must also consider what injuries to a subject would result if an alternative force method was used. Furthermore, the potential benefits of CEWs, including reduction in injuries to the public and law-enforcement officers, need to be considered. PMID- 26630101 TI - US Military Dietary Protein Recommendations: A Simple But Often Confused Topic. AB - Military recommendations for dietary protein are based on the recommended dietary allowance (RDA) of 0.8 g of protein per kilogram of body mass (BM) established by the Food and Nutrition Board, Institute of Medicine (IOM) of the National Academies. The RDA is likely adequate for most military personnel, particularly when activity levels are low and energy intake is sufficient to maintain a healthy body weight. However, military recommendations account for periods of increased metabolic demand during training and real-world operations, especially those that produce an energy deficit. Under those conditions, protein requirements are higher (1.5-2.0 g/kg BM) in an attempt to attenuate the unavoidable loss of muscle mass that occurs during prolonged or repeated exposure to energy deficits. Whole foods are recommended as the primary method to consume more protein, although there are likely operational scenarios where whole foods are not available and consuming supplemental protein at effective, not excessive, doses (20-25 g or 0.25-0.3 g/kg BM per meal) is recommended. Despite these evidence-based, condition-specific recommendations, the necessity of protein supplements and the requirements and rationale for consuming higher-protein diets are often misunderstood, resulting in an overconsumption of dietary protein and unsubstantiated health-related concerns. This review will provide the basis of the US military dietary protein requirements and highlight common misconceptions associated with the amount and safety of protein in military diets. PMID- 26630102 TI - Crimean-Congo Hemorrhagic Fever. AB - In mid-September 2009, a 22-year-old critically ill Soldier was medically evacuated from a treatment facility in southern Afghanistan to Landstuhl Regional Medical Center in Germany. Despite the efforts of the team at Landstuhl, this patient died and became the US military's first known victim of Crimean-Congo hemorrhagic fever (CCHF). CCHF is caused by a virus, which bears the same name. Because a vaccine is lacking, as well as an effective antiviral treatment, prevention is key. PMID- 26630103 TI - Middle East Respiratory Syndrome. AB - Middle East respiratory syndrome (MERS) emerged in the Arabian Peninsula in 2012, and subsequently spread to other countries in Europe and Asia, and to the United States. As of August 2015, the disease has infected 1,400 patients, of whom 500 have died, yielding a 36% mortality rate. The exact mode of transmission is unknown and there are no proven treatments. While the overall case rate for MERS has been low, its presence in countries that house US troops, unknown mode of transmission, and high mortality rate make it a significant health concern among US military personnel. PMID- 26630105 TI - Real-World Experience With Three Point-of-Care Blood Analyzers in Deployed Environments. AB - Austere environments such as Africa pose clinical challenges, which are multiplied for Special Operations Forces (SOF) providers who must face these challenges with limited resources against the tyranny of distance. These limited resources apply not only to treatment tools but to diagnostic tools as well. Laboratory diagnostics may provide critical information in diagnosis, initial triage, and/or evacuation decisions, all of which may enhance a patient's survival. However, unlike in climate-controlled, fixed-facility hospitals, the deployed SOF provider must have access to a simple, reliable device for point-of care testing (POCT) to obtain clinically meaningful data in a practical manner given the surroundings. PMID- 26630104 TI - Injuries and Footwear (Part 1): Athletic Shoe History and Injuries in Relation to Foot Arch Height and Training in Boots. AB - This article traces the history of the athletic shoe, examines whether selecting running shoes based on foot arch height influences injuries, and examines historical data on injury rates when physical training (PT) is performed in boots versus running shoes. In the 1980s and into the 2000s, running shoe companies were advertising specialized shoes with "motion control," "stability," and "cushioning," designed for individuals with low, normal, and high arches, respectively. Despite marketing claims that these shoes would reduce injury rates, coordinated studies in Army, Air Force, and Marine Corps basic training showed that assigning or selecting shoes on this basis had no effect on injury rates. Consistent with this finding, biomechanical studies have shown that the relationships between arch height, foot joint mobility, and rear-foot motion are complex, variable, and frequently not as strong as often assumed. In 1982, the US Army switched from PT in boots to PT in running shoes because of the belief that boots were causing injuries and that running shoes would reduce injury rates. However, a historical comparison of injury rates before and after the switch to running shoes showed virtually no difference in injury risk between the two periods. It is not clear at this point if the type of footwear effects injury incidence. PMID- 26630106 TI - Recovery of Bacteria and Fungi From a Leg Wound. AB - Acute and chronic wound infections can both be encountered in the deployed setting. These wounds are often contaminated by bacteria and fungi derived from the external environment. In this article, we present the case of a wound infection simultaneously colonized by Enterobacter cloacae (a bacterial pathogen) and Trichosporon asahii (an unusual fungal pathogen). We describe the examination and treatment of the patient and review the distinguishing characteristics of each organism. PMID- 26630107 TI - Application of Medical Intelligence Prep of the Environment: A Review of Operational Vignettes. AB - Medical intelligence is an underused or sometimes misapplied tool in the protection of our Soldiers and the execution of nonkinetic operations. The somewhat improved infrastructure of the operational environment in Iraq and Afghanistan led to an inevitable sense of complacency in regard to the threat of disease nonbattle injury (DNBI). The picture changed somewhat in 2010 with the advent of the village stability program and the establishment of SOF camps in austere locations with degraded living situations rife with exposure risks. In addition, the increasing deployments to unstable locations around the globe, reminiscent of typical Special Operations Forces (SOF) missions before the Global War on Terrorism, indicate a need for better preparation for deployment from the standpoint of disease risk and force health protection. A knowledge gap has developed because we simply did not need to apply as stringent an evaluation of DNBI risk in environments where improved life support mitigated the risk for us. The tools necessary to decrease or even eliminate the impact of DNBI exist but they must be shared and implemented. This article will present four vignettes from current and former SOF Force Health Protection personnel starting with a simple method of executing Medical Intelligence Prep of the Environment (MIPOE) and highlighting situations in which it either was or could have been implemented to mitigate risk and decrease the impact on mission accomplishment and individual operators. A follow-on article will present vignettes of the successful application of MIPOE to nonkinetic operations. PMID- 26630108 TI - The Continuing Threat of Intentional Mass Casualty Events in the U.S. Observations of federal law enforcement. PMID- 26630109 TI - Deconstructing the Definition of Prolonged Field Care. PMID- 26630110 TI - Military History of Increasing Survival: The U.S. Military Experience with Tourniquets and Hemostatic Dressings in the Afghanistan and Iraq Conflicts. PMID- 26630111 TI - Hemorrhage Control Devices: Tourniquets and Hemostatic Dressings. PMID- 26630112 TI - Intentional Mass Casualty Events: Implications for Prehospital Emergency Medical Services Systems. PMID- 26630113 TI - Integrated Education of All Responders. PMID- 26630114 TI - Broad Spectrum Enolate Equivalent for Catalytic Chemo-, Diastereo-, and Enantioselective Addition to N-Boc Imines. AB - Alkynyl ketones are attractive but challenging nucleophiles in enolate chemistry. Their susceptibility to other reactions such as Michael additions and the difficulty of controlling the enolate geometry make them difficult substrates. Mannich-type reactions, which previously have not been reported using N-carbamoyl imines with simple ketone enolates, became our objective. In this report, we describe the first direct catalytic Mannich-type reaction between various ynones and N-Boc imines, whose stereocontrol presumably derives from catalyst control of enolate geometry. This method produces alpha-substituted beta-amino ynones with excellent chemo-, diastereo-, and enantioselectivity. The products can be readily transformed into a broad range of molecular scaffolds upon further one-step transformations, demonstrating the utility of ynones as masked synthetic equivalents for a variety of unsymmetrically substituted acyclic ketones. In particular, alkynyl alkyl ketones resolve the long-standing problem of the inability to use the enolates of unsymmetrical dialkyl ketones lacking alpha branching for regio- and stereoselective reactions. PMID- 26630115 TI - Exploring the Mechanism of beta-Lactam Ring Protonation in the Class A beta lactamase Acylation Mechanism Using Neutron and X-ray Crystallography. AB - The catalytic mechanism of class A beta-lactamases is often debated due in part to the large number of amino acids that interact with bound beta-lactam substrates. The role and function of the conserved residue Lys 73 in the catalytic mechanism of class A type beta-lactamase enzymes is still not well understood after decades of scientific research. To better elucidate the functions of this vital residue, we used both neutron and high-resolution X-ray diffraction to examine both the structures of the ligand free protein and the acyl-enzyme complex of perdeuterated E166A Toho-1 beta-lactamase with the antibiotic cefotaxime. The E166A mutant lacks a critical glutamate residue that has a key role in the deacylation step of the catalytic mechanism, allowing the acyl-enzyme adduct to be captured for study. In our ligand free structures, Lys 73 is present in a single conformation, however in all of our acyl-enzyme structures, Lys 73 is present in two different conformations, in which one conformer is closer to Ser 70 while the other conformer is positioned closer to Ser 130, which supports the existence of a possible pathway by which proton transfer from Lys 73 to Ser 130 can occur. This and further clarifications of the role of Lys 73 in the acylation mechanism may facilitate the design of inhibitors that capitalize on the enzyme's native machinery. PMID- 26630116 TI - Charge Generation Dynamics in Efficient All-Polymer Solar Cells: Influence of Polymer Packing and Morphology. AB - All-polymer solar cells exhibit rapid progress in power conversion efficiency (PCE) from 2 to 7.7% over the past few years. While this improvement is primarily attributed to efficient charge transport and balanced mobility between the carriers, not much is known about the charge generation dynamics in these systems. Here we measured exciton relaxation and charge separation dynamics using ultrafast spectroscopy in polymer/polymer blends with different molecular packing and morphology. These measurements indicate that preferential face-on configuration with intermixed nanomorphology increases the charge generation efficiency. In fact, there is a direct quantitative correlation between the free charge population in the ultrafast time scales and the external quantum efficiency, suggesting not only the transport but also charge generation is key for the design of high performance all polymer solar cells. PMID- 26630120 TI - Chronic spontaneous urticaria: immune system, blood coagulation, and more. PMID- 26630121 TI - The Use of Traditional Vietnamese Medicine Among Vietnamese Immigrants Attending an Urban Community Health Center in the United States. AB - OBJECTIVES: Little is known about Traditional Vietnamese Medicine (TVM) and its use among Vietnamese immigrants in the United States. This study aimed to characterize TVM and improve understanding of its use among Vietnamese outpatients attending an urban clinic. METHODS: This cross-sectional observation study was performed by mailing bilingual surveys to a stratified random sample of 400 Vietnamese adult patients (>=18 years of age) who had visited a community health center in Boston, Massachusetts, at least once in the prior 12 months. The data were analyzed by using descriptive and multivariable regression statistics. The use of TVM and the factors influencing their use were reported. RESULTS: Among the 216 respondents, 68% reported using TVM. Of those users, the median age was 56 years and 68% were female, 51% had lived in the United States for less than 13 years, and 91% spoke English "not well or not at all." Among the 89% who reported using TVM of indigenous origin, 62% used "wind scraping," 35% used herbal pills/products, and 30% used "wind snatching." Sixty-one percent used therapies of foreign origin; of those, 51% used Asian-originated TVM (herbs, 25%; Eastern massage, 23%) and 38% used Western-influenced TVM (diet supplements, 28%; Western massage, 8%). TVM was mostly used for pain conditions (57%), "staying well" (38%), and cough/colds (27%). Forty-five percent ignored the question on revealing TVM use to providers; of those who answered, 57% said "no." Fifty-one percent of TVM users reported using Western medicine for the same problem, while 46% used TVM and Western medicine within 2 days of each other. Self-rated health (odds ratio [OR], 2.61; 95% confidence interval [CI], 1.34-5.06), household size (OR, 2.09; 95% CI, 1.04-4.22), and education (OR, 2.65; 95% CI, 1.03-6.80) were associated with TVM use. CONCLUSION: TVM is an important component of the healthcare of urban Vietnamese and needs to be further investigated. Healthcare providers need to encourage open discussion to better care for this population. PMID- 26630122 TI - Developmental Differences in Functioning in Youth With Social Phobia. AB - Social phobia (SoP) in youth may manifest differently across development as parent involvement in their social lives changes and social and academic expectations increase. This cross-sectional study investigated whether self reported and parent-reported functioning in youth with SoP changes with age in social, academic, and home/family domains. Baseline anxiety impairment data from 488 treatment-seeking anxiety-disordered youth (ages 7-17, N = 400 with a SoP diagnosis) and their parents were gathered using the Child Anxiety Impact Scale and were analyzed using generalized estimating equations. According to youth with SoP and their parents, overall difficulties, social difficulties, and academic difficulties increased with age, even when controlling for SoP severity. These effects significantly differed for youth with anxiety disorders other than SoP. Adolescents may avoid social situations as parental involvement in their social lives decreases, and their withdrawn behavior may result in increasing difficulty in the social domain. Their avoidance of class participation and oral presentations may increasingly impact their academic performance as school becomes more demanding. Implications are discussed for the early detection and intervention of SoP to prevent increased impairment over the course of development. PMID- 26630123 TI - Mutations to R. sphaeroides Reaction Center Perturb Energy Levels and Vibronic Coupling but Not Observed Energy Transfer Rates. AB - The bacterial reaction center is capable of both efficiently collecting and quickly transferring energy within the complex; therefore, the reaction center serves as a convenient model for both energy transfer and charge separation. To spectroscopically probe the interactions between the electronic excited states on the chromophores and their intricate relationship with vibrational motions in their environment, we examine coherences between the excited states. Here, we investigate this question by introducing a series of point mutations within 12 A of the special pair of bacteriochlorophylls in the Rhodobacter sphaeroides reaction center. Using two-dimensional spectroscopy, we find that the time scales of energy transfer dynamics remain unperturbed by these mutations. However, within these spectra, we detect changes in the mixed vibrational-electronic coherences in these reaction centers. Our results indicate that resonance between bacteriochlorophyll vibrational modes and excitonic energy gaps promote electronic coherences and support current vibronic models of photosynthetic energy transfer. PMID- 26630124 TI - Covalent Chemical Ligation Strategy for Mono- and Polyclonal Immunoglobulins at Their Nucleotide Binding Sites. AB - Nonspecific ligation methods have been traditionally used to chemically modify immunoglobulins. Site-specific ligation of compounds (toxins or ligands) to antibodies has become increasingly important in the fields of therapeutic antibody-drug conjugates and bispecific antibodies. In this present study, we took advantage of the reported nucleotide-binding pocket (NBP) in the Fab arms of immunoglobulins by developing indole-based, 5-fluoro-2,4-dinitrobenzene derivatized OBOC peptide libraries for the identification of affinity elements that can be used as site-specific derivatization agents against both mono- and polyclonal antibodies. Ligation can occur at any one of the few lysine residues located at the NBP. Immunoconjugates resulting from such affinity elements can be used as therapeutics against cancer or infectious agents. PMID- 26630127 TI - Targeted therapy for renal cell carcinoma: focus on 2nd and 3rd line. AB - INTRODUCTION: Second- and third-line treatments are more and more frequently administered to metastatic renal cell carcinoma (mRCC) patients. AREAS COVERED: Here we discuss the various levels of evidence supporting presently available recommendations, trying to address a number of as yet unanswered issues, and also to take a glowing glance at the future. To do this, we interrogated the Medline database, as well as the proceedings of the main Oncological and Urological conferences for relevant studies. EXPERT OPINION: Until recently, with regard to choosing the second line treatment after the failure of therapy with vascular endothelial growth factor receptors-tyrosine kinase inhibitors (VEGFR-TKIs), the continued inhibition of the VEGF/VEGR pathway, or else the switch to an mTOR inhibitor, is recommended. These two options are characterized by partly different targets, completely different toxicity profiles, but a comparable efficacy. This scenario will change soon, after the publication of two randomized, controlled, phase III trials in which cabozantinib and nivolumab proved to be superior as compared to everolimus. As regards third line treatment, where a sequence of two VEGFR-TKIs has been used beforehand, the choice is represented by the mTOR inhibitor everolimus, whilst if a VEGFR-TKI followed by everolimus has been chosen, a return to VEGF pathway inhibition is suggested. PMID- 26630128 TI - Current views on inducing synthetic lethal RNAi responses in the treatment of cancer. AB - INTRODUCTION: Cancer cells arise from normal cells that have incurred mutations in oncogenes and tumor suppressor genes. The mutations are often unique and not readily found in normal cells, giving rise to the opportunity of exploiting these mutations to induce synthetic lethality. Synthetic lethality occurs when inhibition or mutation in two or more separate genes leads to cell death while inhibition or mutations of either gene alone has no lethal effect on the cell. Using RNA interference (RNAi) to identify synthetic lethality has become a growingly popular screening approach. AREAS COVERED: In this review, we cover the use of RNAi therapeutics to induce synthetic lethality in cancer. Additionally, we discuss several select small molecule inhibitors that were identified or verified by RNAi that induce synthetic lethality in specific cancers. We also discuss the identification of novel synthetic lethal combinations and the cancer model that the combination was validated in. Lastly, we discuss RNAi delivery vehicles. EXPERT OPINION: While RNAi therapeutics have great potential to treat cancer, due to the siRNA delivery problem, RNAi remains more commonly used as a tool, rather than a therapeutic. However, with emerging technological advances in the field of RNAi therapeutics, it is only a matter of time before RNAi-induced synthetic lethal clinical studies are initiated in cancer patients. PMID- 26630130 TI - The Expanded Use of Percutaneous Resection for Upper Tract Urothelial Carcinoma: A 30-Year Comprehensive Experience. AB - INTRODUCTION: The gold standard treatment for upper tract urothelial carcinoma (UTUC) is radical nephroureterectomy (RNU). The role of endoscopic resection is limited to low-risk patients. In this study, we present our 30-year experience in the endoscopic management of UTUC. METHODS: In this retrospective study, we identified 141 patients who underwent percutaneous UTUC resection. Demographic and clinical data were collected, including tumor characteristics, bacillus Calmette-Guerin (BCG) and mitomycin use, tumor recurrence, progression to RNU, and overall survival (OS), and compared in univariate and multivariate analyses. RESULTS: Median follow-up was 66 months. Recurrence occurred in 37% of low-grade patients and 63% of high-grade (HG) patients, with a median time to recurrence of 71.4 vs 36.4 months, respectively. Grade was the only predictor of recurrence (HR 2.12, p = 0.018). The latest time to recurrence occurred after 116 months of surveillance. RNU was avoided by 87% of patients. Age, imperative indications for endoscopy, a history of bladder cancer, and tumor stage and grade were predictors of OS; however, in multivariate analysis, grade and stage lost significance. BCG and mitomycin did not protect against recurrence, progression to RNU, or death over resection alone. CONCLUSION: Percutaneous management of UTUC allows for renal preservation in the majority of patients with resectable disease. Patients with HG tumors are more likely to experience recurrence, but are not at an increased risk of death. Intraluminal BCG and mitomycin continue to have a limited adjuvant role to resection. Recurrence may occur many years following initial resection and therefore prolonged surveillance is advised. PMID- 26630129 TI - Transcriptional Profiling Identifies Location-Specific and Breed-Specific Differentially Expressed Genes in Embryonic Myogenesis in Anas Platyrhynchos. AB - Skeletal muscle growth and development are highly orchestrated processes involving significant changes in gene expressions. Differences in the location specific and breed-specific genes and pathways involved have important implications for meat productions and meat quality. Here, RNA-Seq was performed to identify differences in the muscle deposition between two muscle locations and two duck breeds for functional genomics studies. To achieve those goals, skeletal muscle samples were collected from the leg muscle (LM) and the pectoral muscle (PM) of two genetically different duck breeds, Heiwu duck (H) and Peking duck (P), at embryonic 15 days. Functional genomics studies were performed in two experiments: Experiment 1 directly compared the location-specific genes between PM and LM, and Experiment 2 compared the two breeds (H and P) at the same developmental stage (embryonic 15 days). Almost 13 million clean reads were generated using Illumina technology (Novogene, Beijing, China) on each library, and more than 70% of the reads mapped to the Peking duck (Anas platyrhynchos) genome. A total of 168 genes were differentially expressed between the two locations analyzed in Experiment 1, whereas only 8 genes were differentially expressed when comparing the same location between two breeds in Experiment 2. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) were used to functionally annotate DEGs (differentially expression genes). The DEGs identified in Experiment 1 were mainly involved in focal adhesion, the PI3K-Akt signaling pathway and ECM-receptor interaction pathways (corrected P value<0.05). In Experiment 2, the DEGs were associated with only the ribosome signaling pathway (corrected P-value<0.05). In addition, quantitative real-time PCR was used to confirm 15 of the differentially expressed genes originally detected by RNA-Seq. A comparative transcript analysis of the leg and pectoral muscles of two duck breeds not only improves our understanding of the location specific and breed-specific genes and pathways but also provides some candidate molecular targets for increasing muscle products and meat quality by genetic control. PMID- 26630131 TI - The Relative Impacts of Disease on Health Status and Capability Wellbeing: A Multi-Country Study. AB - BACKGROUND: Evaluations of the impact of interventions for resource allocation purposes commonly focus on health status. There is, however, also concern about broader impacts on wellbeing and, increasingly, on a person's capability. This study aims to compare the impact on health status and capability of seven major health conditions, and highlight differences in treatment priorities when outcomes are measured by capability as opposed to health status. METHODS: The study was a cross-sectional four country survey (n = 6650) of eight population groups: seven disease groups with: arthritis, asthma, cancer, depression, diabetes, hearing loss, and heart disease and one health population 'comparator' group. Two simple self-complete questionnaires were used to measure health status (EQ-5D-5L) and capability (ICECAP-A). Individuals were classified by illness severity using condition-specific questionnaires. Effect sizes were used to estimate: (i) the difference in health status and capability for those with conditions, relative to a healthy population; and (ii) the impact of the severity of the condition on health status and capability within each disease group. FINDINGS: 5248 individuals were included in the analysis. Individuals with depression have the greatest mean reduction in both health (effect size, 1.26) and capability (1.22) compared to the healthy population. The effect sizes for capability for depression are much greater than for all other conditions, which is not the case for health. For example, the arthritis group effect size for health (1.24) is also high and similar to that of depression, whereas for the same arthritis group, the effect size for capability is much lower than that for depression (0.55). In terms of severity within disease groups, individuals categorised as 'mild' have similar capability levels to the healthy population (effect sizes <0.2, excluding depression) but lower health status than the healthy population (>=0.4). CONCLUSION: Significant differences exist in the relative effect sizes across diseases when measured by health status and capability. In terms of treating morbidity, a shift in focus from health gain to capability gain would increase funding priorities for patients with depression specifically and severe illnesses more generally. PMID- 26630133 TI - Correction: Petasites japonicus Stimulates the Proliferation of Mouse Spermatogonial Stem Cells. PMID- 26630132 TI - Brain Meta-Transcriptomics from Harbor Seals to Infer the Role of the Microbiome and Virome in a Stranding Event. AB - Marine diseases are becoming more frequent, and tools for identifying pathogens and disease reservoirs are needed to help prevent and mitigate epizootics. Meta transcriptomics provides insights into disease etiology by cataloguing and comparing sequences from suspected pathogens. This method is a powerful approach to simultaneously evaluate both the viral and bacterial communities, but few studies have applied this technique in marine systems. In 2009 seven harbor seals, Phoca vitulina, stranded along the California coast from a similar brain disease of unknown cause of death (UCD). We evaluated the differences between the virome and microbiome of UCDs and harbor seals with known causes of death. Here we determined that UCD stranded animals had no viruses in their brain tissue. However, in the bacterial community, we identified Burkholderia and Coxiella burnetii as important pathogens associated with this stranding event. Burkholderia were 100% prevalent and ~2.8 log2 fold more abundant in the UCD animals. Further, while C. burnetii was found in only 35.7% of all samples, it was highly abundant (~94% of the total microbial community) in a single individual. In this harbor seal, C. burnetii showed high transcription rates of invading and translation genes, implicating it in the pathogenesis of this animal. Based on these data we propose that Burkholderia taxa and C. burnetii are potentially important opportunistic neurotropic pathogens in UCD stranded harbor seals. PMID- 26630134 TI - Streptozocin-Based Chemotherapy in Patients with Advanced Neuroendocrine Neoplasms--Predictive and Prognostic Markers for Treatment Stratification. AB - BACKGROUND AND AIM: Chemotherapy with streptozocin (STZ) in combination with 5-FU or doxorubicin (Dox) represents a standard of care for patients with metastatic pancreatic neuroendocrine neoplasms (pNEN). However, predictive markers for patient selection are still missing. The aim of this study was a retrospective evaluation of the clinicopathological characteristics of pNEN patients receiving STZ-based chemotherapies and to identify predictive and prognostic markers. PATIENTS AND METHODS: We retrospectively analyzed 77 patients treated at our center between 1995 and 2013. The median overall survival (OS) and progression free survival (PFS) were calculated using Kaplan-Meier and Cox regression methods, respectively. Uni- and multivariate analyses were performed. RESULTS: The median PFS (mPFS) in patients receiving STZ/5-FU/Dox was 16 months with a median OS (mOS) of 28 months. Objective response rate (ORR) and disease control rate (DCR) were 34% and 72%, respectively. Biochemical response and positive octreotide scintigraphy predicted objective response. Univariate analysis revealed Ki-67 > 10% and the absence of biochemical or objective response by imaging as independent risk factors for shorter PFS. Additionally, performance status (PS) and resection of the primary tumor were observed to influence mOS. Treatment was well tolerated with less than 10% grade 3 and 4 toxicities. CONCLUSIONS: STZ-based chemotherapy is an effective and well-tolerated treatment option in patients with well differentiated neuroendocrine neoplasms. Positive octreotide scintigraphy and biochemical response predict objective response. PMID- 26630135 TI - Using Exclusion-Based Sample Preparation (ESP) to Reduce Viral Load Assay Cost. AB - Viral load (VL) measurements are critical to the proper management of HIV in developing countries. However, access to VL assays is limited by the high cost and complexity of existing assays. While there is a need for low cost VL assays, performance must not be compromised. Thus, new assays must be validated on metrics of limit of detection (LOD), accuracy, and dynamic range. Patient plasma samples from the Joint Clinical Research Centre in Uganda were de-identified and measured using both an existing VL assay (Abbott RealTime HIV-1) and our assay, which combines low cost reagents with a simplified method of RNA isolation termed Exclusion-Based Sample Preparation (ESP).71 patient samples with VLs ranging from <40 to >3,000,000 copies/mL were used to compare the two methods. We demonstrated equivalent LOD (~50 copies/mL) and high accuracy (average difference between methods of 0.08 log, R2 = 0.97). Using expenditures from this trial, we estimate that the cost of the reagents and consumables for this assay to be approximately $5 USD. As cost is a significant barrier to implementation of VL testing, we anticipate that our assay will enhance access to this critical monitoring test in developing countries. PMID- 26630136 TI - Initial Experience with a Wireless Ultrasound-Guided Vacuum-Assisted Breast Biopsy Device. AB - OBJECTIVE: To determine the imaging characteristic of frequent target lesions of wireless ultrasound (US)-guided, vacuum-assisted breast biopsy (Wi-UVAB) and to evaluate diagnostic yield, accuracy and complication of the device in indeterminate breast lesions. MATERIALS AND METHODS: From March 2013 to October 2014, 114 women (age range, 29-76 years; mean age, 50.0 years) underwent Wi-UVAB using a 13-gauge needle (Mammotome Elite(r); Devicor Medical Products, Cincinnati, OH, USA). In 103 lesions of 96 women with surgical (n = 81) or follow up (n = 22) data, complications, biopsy procedure, imaging findings of biopsy targets and histologic results were reviewed. RESULTS: Mean number of biopsy cores was 10 (range 4-25). Nine patients developed moderate bleeding. All lesions were suspicious on US, and included non-mass lesions (67.0%) and mass lesions (33.0%). Visible calcifications on US were evident in 57.3% of the target lesions. Most of the lesions (93.2%) were nonpalpable. Sixty-six (64.1%) were malignant [ductal carcinoma in situ (DCIS) rate, 61%] and 12 were high-risk lesions (11.7%). Histologic underestimation was identified in 11 of 40 (27.5%). DCIS cases and in 3 of 9 (33.3%) high-risk lesions necessitating surgery. There was no false-negative case. CONCLUSION: Wi-UVAB is very handy and advantageous for US-unapparent non-mass lesions to diagnose DCIS, especially for calcification cases. Histologic underestimation is unavoidable; still, Wi-UVAB is safe and accurate to diagnose a malignancy. PMID- 26630137 TI - Study of Bioreductive Anticancer Agent RH-1-Induced Signals Leading the Wild-Type p53-Bearing Lung Cancer A549 Cells to Apoptosis. AB - Aziridinylquinone RH-1 (2,5-diaziridinyl-3-hydroxymethyl-6-methyl-cyclohexa-2,5 diene-1,4-dione) is a potential anticancer agent. RH-1 action is associated with NAD(P)H: quinone oxidoreductase (NQO1) which reduces this diaziridinylbenzoquinone into DNA-alkylating hydroquinone and is overexpressed in many tumors. Another suggested mechanism of RH-1 toxicity is the formation of reactive oxygen species (ROS) arising from its redox cycling. In order to improve anticancer action of this and similar antitumor quinones, we investigated the involvement of different signaling molecules in cytotoxicity induced by RH-1 by using wild-type tumor suppressor p53 bearing nonsmall cell lung carcinoma A549 cells as a model. Gradual and prolonged increase of mitogen-activated protein kinases (MAPK) ERK, P38, and JNK phosphorylation was observed during 24-h RH-1 treatment. In parallel, activation of DNA damage-sensing ATM kinase, upregulation, and phosphorylation of TP53 (human p53) took place. Inhibition studies revealed that RH-1-induced A549 apoptosis involved the NQO1-ATM-p53 signaling pathway and ROS generation. TP53 participated in ROS- and DNA damage induced cell death differently. Moreover, MAP kinase JNK was another TP53 activator and death inducer in A549 cells. At the same time, rapid and prolonged activation of AKT kinase during RH-1 treatment was found, and it proved to be antiapoptotic kinase in our model system. Therefore, we identified that different and opposite cell death regulating signaling pathways, which may counteract one another, are induced in cancer cells during chemotherapeutic RH-1 treatment. PMID- 26630138 TI - The Brazilian Portuguese Lexicon: An Instrument for Psycholinguistic Research. AB - In this article, we present the Brazilian Portuguese Lexicon, a new word-based corpus for psycholinguistic and computational linguistic research in Brazilian Portuguese. We describe the corpus development, the specific characteristics on the internet site and database for user access. We also perform distributional analyses of the corpus and comparisons to other current databases. Our main objective was to provide a large, reliable, and useful word-based corpus with a dynamic, easy-to-use, and intuitive interface with free internet access for word and word-criteria searches. We used the Nucleo Interinstitucional de Linguistica Computacional's corpus as the basic data source and developed the Brazilian Portuguese Lexicon by deriving and adding metalinguistic and psycholinguistic information about Brazilian Portuguese words. We obtained a final corpus with more than 30 million word tokens, 215 thousand word types and 25 categories of information about each word. This corpus was made available on the internet via a free-access site with two search engines: a simple search and a complex search. The simple engine basically searches for a list of words, while the complex engine accepts all types of criteria in the corpus categories. The output result presents all entries found in the corpus with the criteria specified in the input search and can be downloaded as a.csv file. We created a module in the results that delivers basic statistics about each search. The Brazilian Portuguese Lexicon also provides a pseudoword engine and specific tools for linguistic and statistical analysis. Therefore, the Brazilian Portuguese Lexicon is a convenient instrument for stimulus search, selection, control, and manipulation in psycholinguistic experiments, as also it is a powerful database for computational linguistics research and language modeling related to lexicon distribution, functioning, and behavior. PMID- 26630139 TI - Individual Responsibility and Community Solidarity--The Swiss Health Care System. PMID- 26630141 TI - Tenuous Tether. PMID- 26630142 TI - Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. AB - BACKGROUND: The outcomes of immunosuppressive therapy, when added to supportive care, in patients with IgA nephropathy are uncertain. METHODS: We conducted a multicenter, open-label, randomized, controlled trial with a two-group, parallel, group-sequential design. During a 6-month run-in phase, supportive care (in particular, blockade of the renin-angiotensin system) was adjusted on the basis of proteinuria. Patients who had persistent proteinuria with urinary protein excretion of at least 0.75 g per day were randomly assigned to receive supportive care alone (supportive-care group) or supportive care plus immunosuppressive therapy (immunosuppression group) for 3 years. The primary end points in hierarchical order were full clinical remission at the end of the trial (protein to-creatinine ratio <0.2 [with both protein and creatinine measured in grams] and a decrease in the estimated glomerular filtration rate [eGFR] of <5 ml per minute per 1.73 m(2) of body-surface area from baseline) and a decrease in the eGFR of at least 15 ml per minute per 1.73 m(2) at the end of the trial. The primary end points were analyzed with the use of logistic-regression models. RESULTS: The run in phase was completed by 309 of 337 patients. The proteinuria level decreased to less than 0.75 g of urinary protein excretion per day in 94 patients. Of the remaining 162 patients who consented to undergo randomization, 80 were assigned to the supportive-care group, and 82 to the immunosuppression group. After 3 years, 4 patients (5%) in the supportive-care group, as compared with 14 (17%) in the immunosuppression group, had a full clinical remission (P=0.01). A total of 22 patients (28%) in the supportive-care group and 21 (26%) in the immunosuppression group had a decrease in the eGFR of at least 15 ml per minute per 1.73 m(2) (P=0.75). There was no significant difference in the annual decline in eGFR between the two groups. More patients in the immunosuppression group than in the supportive-care group had severe infections, impaired glucose tolerance, and weight gain of more than 5 kg in the first year of treatment. One patient in the immunosuppression group died of sepsis. CONCLUSIONS: The addition of immunosuppressive therapy to intensive supportive care in patients with high-risk IgA nephropathy did not significantly improve the outcome, and during the 3-year study phase, more adverse effects were observed among the patients who received immunosuppressive therapy, with no change in the rate of decrease in the eGFR. (Funded by the German Federal Ministry of Education and Research; STOP-IgAN ClinicalTrials.gov number, NCT00554502.). PMID- 26630144 TI - Cardiac Complications in Patients Undergoing Major Noncardiac Surgery. PMID- 26630145 TI - IMAGES IN CLINICAL MEDICINE. Pylephlebitis as a Complication of Diverticulitis. PMID- 26630146 TI - CLINICAL PROBLEM-SOLVING. Back to Nature. PMID- 26630147 TI - Retraction: Ahimastos AA, Dart AM, Kingwell BA. Angiotensin II blockade in Marfan's syndrome. N Engl J Med 2008;359:1732. PMID- 26630148 TI - Prenatal Factors in Cerebral Palsy. PMID- 26630149 TI - Prenatal Factors in Cerebral Palsy. PMID- 26630151 TI - Estimating the Long-Term Treatment Benefits of Sacubitril-Valsartan. PMID- 26630152 TI - IMAGES IN CLINICAL MEDICINE. Cystine Crystals in Bone Marrow. PMID- 26630153 TI - Plasma Levels of Neopterin and C-Reactive Protein (CRP) in Tuberculosis (TB) with and without HIV Coinfection in Relation to CD4 Cell Count. AB - BACKGROUND: While the risk of TB is elevated in HIV-positive subjects with low CD4 cell counts, TB may in itself be associated with CD4 lymphocytopenia. We investigated markers of immune activation (neopterin) and inflammation (CRP) in TB patients with and without HIV coinfection and their association with CD4 cell levels, and determined their predictive capacity as alternative markers of advanced immunosuppression. METHODS: Participants selected from a cohort of adults with TB at Ethiopian health centers (195 HIV+/TB+, 170 HIV-/TB+) and 31 controls were tested for plasma levels of neopterin and CRP. Baseline levels of neopterin and CRP were correlated to CD4 cell count before and after anti-TB treatment (ATT). The performance to predict CD4 cell strata for both markers were investigated using receiver operating curves. RESULTS: Levels of both biomarkers were elevated in TB patients (neopterin: HIV+/TB+ 54 nmol/l, HIV-/TB+ 23 nmol/l, controls 3.8 nmol/l; CRP: HIV+/TB+ 36 MUg/ml, HIV-/TB+ 33 MUg/ml, controls 0.5 MUg/ml). Neopterin levels were inversely correlated (-0.53, p<0.001) to CD4 cell count, whereas this correlation was weaker for CRP (-0.25, p<0.001). Neither of the markers had adequate predictive value for identification of subjects with CD4 cell count <100 cells/mm3 (area under the curve [AUC] 0.64 for neopterin, AUC 0.59 for CRP). CONCLUSION: Neopterin levels were high in adults with TB, both with and without HIV coinfection, with inverse correlation to CD4 cell count. This suggests that immune activation may be involved in TB-related CD4 lymphocytopenia. However, neither neopterin nor CRP showed promise as alternative tests for immunosuppression in patients coinfected with HIV and TB. PMID- 26630155 TI - Hierarchical ultrathin alumina membrane for the fabrication of unique nanodot arrays. AB - Ultrathin alumina membranes (UTAMs) as evaporation masks have been a powerful tool for the fabrication of high-density nanodot arrays and have received much attention in magnetic memory devices, photovoltaics, and nanoplasmonics. In this paper, we report the fabrication of a hierarchical ultrathin alumina membrane (HUTAM) with highly ordered submicro/nanoscale channels and its application as an evaporation mask for the realization of unique non-hexagonal nanodot arrays dependent on the geometrical features of the HUTAM. This is the first report of a UTAM with a hierarchical geometry, breaking the stereotype that only limited sets of nanopatterns can be realized using the UTAM method (with typical inter-pore distance of 100 nm). The fabrication of a HUTAM is discussed in detail. An improved, longer wet etching time than previously reported is found to effectively remove the barrier layer and widen the pores of a HUTAM. A growth sustainability issue brought about by pre-patterning is discussed. Spectral comparison was made to distinguish the UTAM nanodots and HUTAM nanodots. Our results can be an inspiration for more sophisticated applications of pre patterned anodized aluminum oxide in photocatalysis, photovoltaics, and nanoplasmonics. PMID- 26630154 TI - Can Inconsistent Association between Hypertension and Cognition in Elders be Explained by Levels of Organochlorine Pesticides? AB - The relation between hypertension and cognition in elders remains unclear, and studies on the effect of antihypertensive drugs on cognition have demonstrated conflicting results. This study was performed to evaluate if the association between hypertension and cognition in elders differed depending on serum concentrations of organochlorine (OC) pesticides, common neurotoxic chemicals. Participants were 644 elders aged 60-85 years who participated in the National Health and Nutrition Examination Survey 1999-2002 and were able to complete a cognitive test. We selected 6 OC pesticides that were commonly detected in the elderly. Cognition was assessed by the Digit Symbol Substitution Test (DSST), a relevant tool for evaluating hypertension-related cognitive function, and low cognition was defined by the DSST score < 25th percentile. When OC pesticides were not considered in the analyses, elders with hypertension had about 1.7 times higher risk of low cognition than those without hypertension. However, in analyses stratified by serum concentrations of OC pesticides, the associations between hypertension and low cognition were stronger the higher the serum concentrations of p,p'-DDT, p,p'-DDE, beta-hexachlorocyclohexane, and trans nonachlor increased. Among elders in the 3rd tertile of these pesticides, adjusted odds ratios were from 2.5 to 3.5. In contrast, hypertension was not clearly associated with the risk of low cognition in elders in the 1st tertile of these pesticides. Similar patterns were observed for the continuous DSST score dependent variable. The difference in the association between hypertension and DSST scores according to the levels of OC pesticides suggest a key role of OC pesticides in the development of hypertension-related cognitive impairment and may help to identify hypertensive elders who are at a high risk of cognitive impairment. PMID- 26630156 TI - Fitting and Calibrating a Multilevel Mixed-Effects Stem Taper Model for Maritime Pine in NW Spain. AB - Stem taper data are usually hierarchical (several measurements per tree, and several trees per plot), making application of a multilevel mixed-effects modelling approach essential. However, correlation between trees in the same plot/stand has often been ignored in previous studies. Fitting and calibration of a variable-exponent stem taper function were conducted using data from 420 trees felled in even-aged maritime pine (Pinus pinaster Ait.) stands in NW Spain. In the fitting step, the tree level explained much more variability than the plot level, and therefore calibration at plot level was omitted. Several stem heights were evaluated for measurement of the additional diameter needed for calibration at tree level. Calibration with an additional diameter measured at between 40 and 60% of total tree height showed the greatest improvement in volume and diameter predictions. If additional diameter measurement is not available, the fixed effects model fitted by the ordinary least squares technique should be used. Finally, we also evaluated how the expansion of parameters with random effects affects the stem taper prediction, as we consider this a key question when applying the mixed-effects modelling approach to taper equations. The results showed that correlation between random effects should be taken into account when assessing the influence of random effects in stem taper prediction. PMID- 26630170 TI - "What-Where-Which" Episodic Retrieval Requires Conscious Recollection and Is Promoted by Semantic Knowledge. AB - Episodic memory is defined as the conscious retrieval of specific past events. Whether accurate episodic retrieval requires a recollective experience or if a feeling of knowing is sufficient remains unresolved. We recently devised an ecological approach to investigate the controlled cued-retrieval of episodes composed of unnamable odors (What) located spatially (Where) within a visual context (Which context). By combining the Remember/Know procedure with our laboratory-ecological approach in an original way, the present study demonstrated that the accurate odor-evoked retrieval of complex and multimodal episodes overwhelmingly required conscious recollection. A feeling of knowing, even when associated with a high level of confidence, was not sufficient to generate accurate episodic retrieval. Interestingly, we demonstrated that the recollection of accurate episodic memories was promoted by odor retrieval-cue familiarity and describability. In conclusion, our study suggested that semantic knowledge about retrieval-cues increased the recollection which is the state of awareness required for the accurate retrieval of complex episodic memories. PMID- 26630171 TI - Dystroglycan Depletion Impairs Actin-Dependent Functions of Differentiated Kasumi 1 Cells. AB - BACKGROUND: Dystroglycan has recently been characterised in blood tissue cells, as part of the dystrophin glycoprotein complex involved in the differentiation process of neutrophils. PURPOSE: In the present study we have investigated the role of dystroglycan in the human promyelocytic leukemic cell line Kasumi-1 differentiated to macrophage-like cells. METHODS: We characterised the pattern expression and subcellular distribution of dystroglycans in non-differentiated and differentiated Kasumi-1 cells. RESULTS: Our results demonstrated by WB and flow cytometer assays that during the differentiation process to macrophages, dystroglycans were down-regulated; these results were confirmed with qRT-PCR assays. Additionally, depletion of dystroglycan by RNAi resulted in altered morphology and reduced properties of differentiated Kasumi-1 cells, including morphology, migration and phagocytic activities although secretion of IL-1beta and expression of markers of differentiation are not altered. CONCLUSION: Our findings strongly implicate dystroglycan as a key membrane adhesion protein involved in actin-based structures during the differentiation process in Kasumi-1 cells. PMID- 26630172 TI - Fast Room Temperature Very Low Field-Magnetic Resonance Imaging System Compatible with MagnetoEncephaloGraphy Environment. AB - In recent years, ultra-low field (ULF)-MRI is being given more and more attention, due to the possibility of integrating ULF-MRI and Magnetoencephalography (MEG) in the same device. Despite the signal-to-noise ratio (SNR) reduction, there are several advantages to operating at ULF, including increased tissue contrast, reduced cost and weight of the scanners, the potential to image patients that are not compatible with clinical scanners, and the opportunity to integrate different imaging modalities. The majority of ULF MRI systems are based, until now, on magnetic field pulsed techniques for increasing SNR, using SQUID based detectors with Larmor frequencies in the kHz range. Although promising results were recently obtained with such systems, it is an open question whether similar SNR and reduced acquisition time can be achieved with simpler devices. In this work a room-temperature, MEG-compatible very-low field (VLF)-MRI device working in the range of several hundred kHz without sample pre-polarization is presented. This preserves many advantages of ULF-MRI, but for equivalent imaging conditions and SNR we achieve reduced imaging time based on preliminary results using phantoms and ex-vivo rabbits heads. PMID- 26630173 TI - Alpha-amylase serum levels in professional soccer players are not related with physical fitness. AB - BACKGORUND: Recent evidence has showed that serum or salivary values of alpha amylase predict endurance running performance. In this study we investigate whether serum alpha-amylase concentration may be associated with training status during a competitive season and after a detraining period in professional soccer players. METHODS: The study population consisted in 15 male professional soccer players from an Italian major league team (age [mean+/-SD] 27+/-5 years, weight 76.9+/-4.1 kg, height 1.82+/-0.05 m). Serum alpha-amylase levels were measured 3 times during the last part of a competitive season (January, March and May) and just before preseason training (July). RESULTS: Metabolic and cardiovascular fitness of soccer players was improved during the last part of the season. The levels of alpha-amylase did not change significantly throughout the study period (chi2=7.331, P=0.062), nor they were found to be associated with variation of physical fitness and training status. CONCLUSIONS: The alpha-amylase fluctuations throughout a competitive season and after vacation time were meaningless in professional soccer players. No significant associations with physical fitness variations could be observed. These results suggest that alpha-amylase concentration may be a useful parameter for identifying individual inclination to endurance exercise, but not for predicting actual training status. PMID- 26630174 TI - Systematics and Evolution of the Miocene Three-Horned Palaeomerycid Ruminants (Mammalia, Cetartiodactyla). AB - Palaeomerycids were strange three-horned Eurasian Miocene ruminants known through fossils from Spain to China. We here study their systematics, offering the first cladistic phylogeny of the best-known species of the group, and also reassess their phylogenetic position among ruminants, which is currently disputed. The beautifully preserved remains of a new palaeomerycid from middle Miocene deposits of Spain, Xenokeryx amidalae gen. et sp. nov., helps us to better understand palaeomerycid anatomy, especially that of the nuchal region in the skull, significantly improving our current knowledge on these enigmatic ruminants. Our results show two main lineages of palaeomerycids, one containing the genus Ampelomeryx diagnosed by a characteristic type of cranium / cranial appendages and some dental derived traits, and another one that clusters those forms more closely related to Triceromeryx than to Ampelomeryx, characterized by a more derived dentition and a set of apomorphic cranial features. Xenokeryx branches as a basal offshoot of this clade. Also, we find that Eurasian palaeomerycids are not closely related to North American dromomerycids, thus rejecting the currently more accepted view of palaeomerycids as the Eurasian part of the dromomerycid lineage. Instead of this, palaeomerycids are nested with the African Miocene pecoran Propalaeoryx and with giraffoids. On the other hand, dromomerycids are closely related to cervids. We define a clade Giraffomorpha that includes palaeomerycids and giraffids, and propose an emended diagnosis of the Palaeomerycidae based on cranial and postcranial characters, including several features of the cranium not described so far. We also define the Palaeomerycidae as the least inclusive clade of pecorans containing Triceromeryx and Ampelomeryx. Finally, we reassess the taxonomy of several palaeomerycid taxa. PMID- 26630175 TI - Activity and expression of acetylcholinesterase in PC12 cells exposed to intermittent 1.8 GHz 217-GSM mobile phone signal. AB - PURPOSE: Due to its role in learning, memory and in many neurodegenerative diseases, acetylcholinesterase (AChE) represents an interesting endpoint to assess possible targets of exposure to radiofrequency electromagnetic fields (RF EMF) generated by mobile phones. We investigated possible alterations of enzymatic activity, gene and protein expression of AChE in neuronal-like cells exposed to a 1.8 GHz Global System for Mobile Communication (GSM) modulated signal (217-GSM). MATERIALS AND METHODS: Rat PC12 cells were exposed for 24 h to 1.8 GHz 217-GSM signal. Specific adsorption rate (SAR) was 2 W/kg. AChE enzyme activity was assessed spectrophotometrically by Ellman's method, mRNA expression level was evaluated by real time polymerase chain reaction, and protein expression was assessed by Western blotting. RESULTS: AChE enzymatic activity increased of 1.4-fold in PC12 cells exposed to 217-GSM signal for 24 h, whilst AChE transcriptional or translational pathways were not affected. CONCLUSION: Our results provide the first evidence of effects on AChE activity after in vitro exposure of mammalian cells to the RF-EMF generated by GSM mobile phones, at the SAR value 2 W/kg. The obtained evidence promotes further investigations on AChE as a possible target of RF-EMF and confirm the ability of 1.8 GHz 217-GSM signal to induce biological effects in different mammalian cells. PMID- 26630177 TI - StIKKing it to a death kinase: IKKs prevent TNF-alpha-induced cell death by phosphorylating RIPK1. AB - Signaling pathways activated by the cytokine TNF-alpha are among the most intensively studied and well-understood in all mammalian biology. In a simplistic model, two primary signals emanate from the TNF-alpha receptor, one that activates cell survival via an NF-kappaB transcriptional response and a second that triggers cell death when cell survival signals are neutralized. The kinase RIPK1 participates in both these axes, and its poly-ubiquitylation was thought to represent the primary mechanism by which it toggles between survival versus death signaling. When RIPK1 is ubiquitylated, it acts non-enzymatically as an adaptor protein in IKK recruitment and subsequent NF-kappaB activation; when ubiquitylation of RIPK1 is prevented, it functions as a cell death kinase capable of triggering apoptosis or necroptosis. Bertrand and colleagues (Dondelinger et al., 2015) now demonstrate that phosphorylation of RIPK1 represents an additional mechanism by which this protein switches between its life and death duties. They show that both IKK-alpha and IKK-beta phosphorylate RIPK1, dampening its capacity to assemble the death effectors FADD and caspase 8 into a functional pro apoptotic signalsome. These IKKs also protect against RIPK1-mediated necroptosis. Importantly, IKK-alpha/beta prevent RIPK1-driven cell death independently of NF kappaB transcriptional responses. These findings identify phosphorylation of RIPK1 by IKKs as a new mechanism by which cell fate decisions downstream of TNFR1 are regulated. PMID- 26630176 TI - NKp46+ Innate Lymphoid Cells Dampen Vaginal CD8 T Cell Responses following Local Immunization with a Cholera Toxin-Based Vaccine. AB - Innate and adaptive immune cells work in concert to generate efficient protection at mucosal surface. Vaginal mucosa is an epithelial tissue that contains innate and adaptive immune effector cells. Our previous studies demonstrated that vaginal administration of Cholera toxin -based vaccines generate antigen-specific CD8 T cells through the stimulation of local dendritic cells (DC). Innate lymphoid cells (ILC) are a group of lymphocytes localized in epithelial tissues that have important immune functions against pathogens and in tissue homeostasis. Their contribution to vaccine-induced mucosal T cell responses is an important issue for the design of protective vaccines. We report here that the vaginal mucosa contains a heterogeneous population of NKp46+ ILC that includes conventional NK cells and ILC1-like cells. We show that vaginal NKp46+ ILC dampen vaccine-induced CD8 T cell responses generated after local immunization. Indeed, in vivo depletion of NKp46+ ILC with anti-NK1.1 antibody or NKG2D blockade increases the magnitude of vaginal OVA-specific CD8 T cells. Furthermore, such treatments also increase the number of DC in the vagina. NKG2D ligands being expressed by vaginal DC but not by CD8 T cells, these results support that NKp46+ ILC limit mucosal CD8 T cell responses indirectly through the NKG2D-dependent elimination of vaginal DC. Our data reveal an unappreciated role of NKp46+ ILC in the regulation of mucosal CD8 T cell responses. PMID- 26630178 TI - A Zebrafish Model for Studies on Esophageal Epithelial Biology. AB - Mammalian esophagus exhibits a remarkable change in epithelial structure during the transition from embryo to adult. However, the molecular mechanisms of esophageal epithelial development are not well understood. Zebrafish (Danio rerio), a common model organism for vertebrate development and gene function, has not previously been characterized as a model system for esophageal epithelial development. In this study, we characterized a piece of non-keratinized stratified squamous epithelium similar to human esophageal epithelium in the upper digestive tract of developing zebrafish. Under the microscope, this piece was detectable at 5dpf and became stratified at 7dpf. Expression of esophageal epithelial marker genes (Krt5, P63, Sox2 and Pax9) was detected by immunohistochemistry and in situ hybridization. Knockdown of P63, a gene known to be critical for esophageal epithelium, disrupted the development of this epithelium. With this model system, we found that Pax9 knockdown resulted in loss or disorganization of the squamous epithelium, as well as down-regulation of the differentiation markers Krt4 and Krt5. In summary, we characterized a region of stratified squamous epithelium in the zebrafish upper digestive tract which can be used for functional studies of candidate genes involved in esophageal epithelial biology. PMID- 26630179 TI - Ranking Mammal Species for Conservation and the Loss of Both Phylogenetic and Trait Diversity. AB - The 'edge of existence' (EDGE) prioritisation scheme is a new approach to rank species for conservation attention that aims to identify species that are both isolated on the tree of life and at imminent risk of extinction as defined by the World Conservation Union (IUCN). The self-stated benefit of the EDGE system is that it effectively captures unusual 'unique' species, and doing so will preserve the total evolutionary history of a group into the future. Given the EDGE metric was not designed to capture total evolutionary history, we tested this claim. Our analyses show that the total evolutionary history of mammals preserved is indeed much higher if EDGE species are protected than if at-risk species are chosen randomly. More of the total tree is also protected by EDGE species than if solely threat status or solely evolutionary distinctiveness were used for prioritisation. When considering how much trait diversity is captured by IUCN and EDGE prioritisation rankings, interestingly, preserving the highest-ranked EDGE species, or indeed just the most threatened species, captures more total trait diversity compared to sets of randomly-selected at-risk species. These results suggest that, as advertised, EDGE mammal species contribute evolutionary history to the evolutionary tree of mammals non-randomly, and EDGE-style rankings among endangered species can also capture important trait diversity. If this pattern holds for other groups, the EDGE prioritisation scheme has greater potential to be an efficient method to allocate scarce conservation effort. PMID- 26630143 TI - Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. AB - BACKGROUND: Cardiovascular morbidity and mortality are higher among patients with type 2 diabetes, particularly those with concomitant cardiovascular diseases, than in most other populations. We assessed the effects of lixisenatide, a glucagon-like peptide 1-receptor agonist, on cardiovascular outcomes in patients with type 2 diabetes who had had a recent acute coronary event. METHODS: We randomly assigned patients with type 2 diabetes who had had a myocardial infarction or who had been hospitalized for unstable angina within the previous 180 days to receive lixisenatide or placebo in addition to locally determined standards of care. The trial was designed with adequate statistical power to assess whether lixisenatide was noninferior as well as superior to placebo, as defined by an upper boundary of the 95% confidence interval for the hazard ratio of less than 1.3 and 1.0, respectively, for the primary composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina. RESULTS: The 6068 patients who underwent randomization were followed for a median of 25 months. A primary end-point event occurred in 406 patients (13.4%) in the lixisenatide group and in 399 (13.2%) in the placebo group (hazard ratio, 1.02; 95% confidence interval [CI], 0.89 to 1.17), which showed the noninferiority of lixisenatide to placebo (P<0.001) but did not show superiority (P=0.81). There were no significant between-group differences in the rate of hospitalization for heart failure (hazard ratio in the lixisenatide group, 0.96; 95% CI, 0.75 to 1.23) or the rate of death (hazard ratio, 0.94; 95% CI, 0.78 to 1.13). Lixisenatide was not associated with a higher rate of serious adverse events or severe hypoglycemia, pancreatitis, pancreatic neoplasms, or allergic reactions than was placebo. CONCLUSIONS: In patients with type 2 diabetes and a recent acute coronary syndrome, the addition of lixisenatide to usual care did not significantly alter the rate of major cardiovascular events or other serious adverse events. (Funded by Sanofi; ELIXA ClinicalTrials.gov number, NCT01147250.). PMID- 26630180 TI - Teacher Competencies in Health Education: Results of a Delphi Study. AB - OBJECTIVE: The aim of this research study was to identify the core competencies for health education teachers in supporting the development of health literacy among their students. METHOD/RESULTS: A three round Delphi method was employed. Experts in health education were asked to identify core competencies for school health educators. Twenty six participants from the academic field were invited to participate in the study. Twenty participants completed the first round of the Delphi, while eighteen took part in round two and fifteen participated in the final round. Data were collected using an electronic questionnaire. The first round contained an open ended question in which participants were asked to name and define all the competencies they perceived were important. Thematic analysis was undertaken on these data. A list of 36 competencies was created from this round. This list was then returned to the same participants and they were asked to rate each competency on a 7 point semantic differential scale in terms of importance. The resulting data were then analysed. For the final round, participants were presented with a list of 33 competencies and were asked to rank them again, in order of importance. CONCLUSION: Twelve core competencies emerged from the analysis and these competencies comprised of a mixture of knowledge, attitude and skills. The authors suggest that how these competencies are achieved and operationalised in the school context can be quite complex and multi-faceted. While the authors do not seek to generalise from the study they suggest that these competencies are an important input for all stakeholders, in order to question national and international teacher guidelines. In addition the competencies identified may provide a useful starting point for others to undertake deeper analysis of what it means to be an effective health educator in schools. PMID- 26630181 TI - Angiotensin 1-7 significantly reduces diabetes-induced leukocyte recruitment both in vivo and in vitro. AB - OBJECTIVE: Recent studies have demonstrated that Ang1-7 has anti-inflammatory effects. Since the formation of Ang1-7 is significantly altered in the setting of diabetes, here we aimed to evaluate whether Ang1-7 infusion could ameliorate diabetes-induced leukocyte recruitment. METHODS: Wild-type male Wistar rats were randomly allocated to the following groups: control + saline, control + Ang1-7, diabetes + saline, diabetes + Ang1-7. Diabetes was induced by streptozotocin. Saline and Ang1-7 (576 MUg/kg/day) were injected intraperitoneally daily. After 4 weeks leukocyte trafficking was studied in vivo by intravital microscopy in the mesenteric bed, where the expression of pro-oxidative, proinflammatory, and profibrotic molecules was also assessed. In parallel in vitro studies, HUVEC were grown in 5 mM, 22 mM, 30 mM, 40 mM, 50 mM, and 75 mM glucose media for 48 h, 72 h and 6 days and were treated either with placebo, or with Ang1-7, or with Ang1-7 and its inhibitor A779 in order to evaluate the expression of ICAM-1 and VCAM-1. We further studied leukocytes recruitment in vitro by evaluating PMN-HUVEC adhesion. RESULTS: Ang1-7 prevented in vivo diabetes-induced leukocyte adhesion and extravasation, and it significantly reduced vascular hypertrophy and the other molecular changes due to diabetes. Ang 1-7 prevented also in vitro the hyperglycemia-induced increase of ICAM-1 and VCAM-1 as well as the hyperglycemia induced PMN adhesion. A779 inhibited Ang 1-7 effects. CONCLUSIONS: Ang1-7 significantly reduced diabetes-induced leukocyte recruitment both in vivo and in vitro. These findings emphasize the potential utility of ACE2/Ang1-7/Mas repletion as a strategy to reduce diabetes-induced atherosclerosis. PMID- 26630183 TI - Foretelling plaque disruption: Is the journey to Ithaca reaching destination? PMID- 26630182 TI - Toxic acrolein production due to Ca(2+) influx by the NMDA receptor during stroke. AB - BACKGROUND AND PURPOSE: N-Methyl-d-aspartate (NMDA) receptors have a high permeability to Ca(2+), contributing to neuronal cell death after stroke. We recently found that acrolein produced from polyamines is a major toxic compound during stroke. Thus, it was determined whether over-accumulation of Ca(2+) increases the production of acrolein from polyamines in a photochemically-induced thrombosis mouse model of stroke and in cell culture systems. METHODS: A unilateral infarction was induced in mouse brain by photoinduction after injection of Rose Bengal. The volume of the infarction was analyzed using the public domain National Institutes of Health image program. Protein-conjugated acrolein levels at the locus of infarction and in cells were measured by Western blotting. Levels of polyamines were measured by high-performance liquid chromatography. RESULTS: When the size of brain infarction was decreased by N(1), N(4), N(8)-tribenzylspermidine, a channel blocker of the NMDA receptors, levels of Ca(2+) and protein-conjugated acrolein (PC-Acro) were reduced, while levels of polyamines were increased at the locus of infarction. When cell growth of mouse mammary carcinoma FM3A cells and neuroblastoma Neuro2a cells was inhibited by Ca(2+), the level of polyamines decreased, while that of PC-Acro increased. It was also shown that Ca(2+) toxicity was decreased in an acrolein toxicity decreasing FM3A mutant cells recently isolated. In addition, 20-40 MUM Ca(2+) caused the release of polyamines from ribosomes. The results indicate that acrolein is produced from polyamines released from ribosomes through Ca(2+) increase. CONCLUSION: The results indicate that toxicity of Ca(2+) during brain infarction is correlated with the increase of acrolein. PMID- 26630184 TI - Association between FKBP5 Functional Polymorphisms and Completed Suicide. AB - OBJECTIVES: Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis leads to impaired stress response. FK506-binding protein 51 (FKBP5), which influences HPA axis activity via glucocorticoid receptors, is supposed to play an important role in the regulation of negative feedback and glucocorticoid resistance. Since ineffective stress response mechanisms are considered as a biological background of suicide behavior, we aimed to analyze a possible association between FKBP5 functional polymorphisms and completed suicide. METHODS: The selected FKBP5 polymorphisms rs1360780 and rs3800373 were genotyped in a sample of 563 suicide victims and 475 controls. RESULTS: A significant association between the high induction rs3800373 C allele and completed suicide was detected (OR = 1.36, p = 0.007). In this polymorphism, genotype distribution supported a codominant model of inheritance. The analyzed SNPs were in strong linkage disequilibrium (D' = 0.916 and r2 = 0.826) with the rs1360780 (T)-rs3800373 (C) haplotype apparently responsible for the observed association (OR = 1.34, p = 0.010). CONCLUSION: The results of the present study indicate that genetic alterations in FKBP5 may influence vulnerability to suicide. PMID- 26630185 TI - The impact of cationic substituents in phenalen-1-one photosensitizers on antimicrobial photodynamic efficacy. AB - Light-mediated killing of pathogens by cationic photosensitizers (PS) is a promising antimicrobial approach avoiding resistance as being present upon the use of antibiotics. In this study we focused on the impact of the substituents in phenalen-1-one PS. Photodynamic efficacy depending on positively charged moieties including a primary aliphatic, quaternary aliphatic, aromatic ammonium and a guanidinium cation was investigated against Gram-positive and Gram-negative pathogens. Considering the altered steric demand and lipophilicity of these functional groups we deduced a structure-activity relationship. SAGUA was the most potent PS in this series reaching a maximum efficacy of >=6log10 steps of bacteria killing at a concentration of 10 MUM upon irradiation with blue light (20 mW cm(-2)) for 60 s (1.2 J cm(-2)) without exhibiting inherent dark toxicity. Its guanidinium moiety may be able to form strong bidentate and directional hydrogen bonds to carboxylate groups of bacterial surfaces in addition to ionic charge attraction. This may supplement fast and effective antimicrobial activity. PMID- 26630186 TI - Disorders of early language development in Dravet syndrome. AB - The aim of this study was to investigate language disorders prospectively in patients with Dravet syndrome (DS) during the first years of life in order to identify their features and possibly the underlying mechanisms of the disease. At the Child Neurology Unit of Catholic University in Rome (Italy), thirteen patients with typical findings of DS were enrolled in the study. Full clinical observations, including neurological examination and long-term EEG monitoring, were prospectively and serially performed until a mean of 6years of age (range: 4years to 7years and 8months). The epileptic history was also collected in each case. In particular, developmental, cognitive, and detailed language assessments were performed with different tests according to the age of the patient. In addition to cognitive decline, characteristic language impairment was also found with a relative preservation of receptive abilities (comprehension) and a strong impairment of productive skills. This defect in sensorimotor verbal processing integration is discussed to highlight the possible mechanisms underlying cognitive decline. PMID- 26630187 TI - The First Decade of ISS Exercise: Lessons Learned on Expeditions 1-25. AB - INTRODUCTION: Long-duration spaceflight results in musculoskeletal, cardiorespiratory, and sensorimotor deconditioning. Historically, exercise has been used as a countermeasure to mitigate these deleterious effects that occur as a consequence of microgravity exposures. The International Space Station (ISS) exercise community describes their approaches, biomedical surveillance, and lessons learned in the development of exercise countermeasure modalities and prescriptions for maintaining health and performance among station crews. This report is focused on the first 10 yr of ISS defined as Expeditions 1-25 and includes only crewmembers with missions > 30 d on ISS for all 5 partner agencies (United States, Russia, Europe, Japan, and Canada). All 72 cosmonauts and astronauts participated in the ISS exercise countermeasures program. This Supplement presents a series of papers that provide an overview of the first decade of ISS exercise from a multidisciplinary, multinational perspective to evaluate the initial countermeasure program and record its operational limitations and challenges. In addition, we provide results from standardized medical evaluations before, during, and after each mission. Information presented in this context is intended to describe baseline conditions of the ISS exercise program. This paper offers an introduction to the subsequent series of manuscripts. PMID- 26630190 TI - Exercise Countermeasure Hardware Evolution on ISS: The First Decade. AB - The hardware systems necessary to support exercise countermeasures to the deconditioning associated with microgravity exposure have evolved and improved significantly during the first decade of the International Space Station (ISS), resulting in both new types of hardware and enhanced performance capabilities for initial hardware items. The original suite of countermeasure hardware supported the first crews to arrive on the ISS and the improved countermeasure system delivered in later missions continues to serve the astronauts today with increased efficacy. Due to aggressive hardware development schedules and constrained budgets, the initial approach was to identify existing spaceflight certified exercise countermeasure equipment, when available, and modify it for use on the ISS. Program management encouraged the use of commercial-off-the-shelf (COTS) hardware, or hardware previously developed (heritage hardware) for the Space Shuttle Program. However, in many cases the resultant hardware did not meet the additional requirements necessary to support crew health maintenance during long-duration missions (3 to 12 mo) and anticipated future utilization activities in support of biomedical research. Hardware development was further complicated by performance requirements that were not fully defined at the outset and tended to evolve over the course of design and fabrication. Modifications, ranging from simple to extensive, were necessary to meet these evolving requirements in each case where heritage hardware was proposed. Heritage hardware was anticipated to be inherently reliable without the need for extensive ground testing, due to its prior positive history during operational spaceflight utilization. As a result, developmental budgets were typically insufficient and schedules were too constrained to permit long-term evaluation of dedicated ground-test units ("fleet leader" type testing) to identify reliability issues when applied to long duration use. In most cases, the exercise unit with the most operational history was the unit installed on the ISS. PMID- 26630191 TI - Physical Training for Long-Duration Spaceflight. AB - INTRODUCTION: Physical training has been conducted on the International Space Station (ISS) for the past 10 yr as a countermeasure to physiological deconditioning during spaceflight. Each member space agency has developed its own approach to creating and implementing physical training protocols for their astronauts. We have divided physical training into three distinct phases (preflight, in-flight, and postflight) and provided a description of each phase with its constraints and limitations. We also discuss how each member agency (NASA, ESA, CSA, and JAXA) prescribed physical training for their crewmembers during the first 10 yr of ISS operations. It is important to understand the operational environment, the agency responsible for the physical training program, and the constraints and limitations associated with spaceflight to accurately design and implement exercise training or interpret the exercise data collected on ISS. As exploration missions move forward, resolving agency differences in physical training programs will become important to maximizing the effectiveness of exercise as a countermeasure and minimizing any mission impacts. PMID- 26630192 TI - Russian Countermeasure Systems for Adverse Effects of Microgravity on Long Duration ISS Flights. AB - INTRODUCTION: The system of countermeasures for the adverse effects of microgravity developed in the USSR supported the successful implementation of long-duration spaceflight (LDS) programs on the Salyut and Mir orbital stations and was subsequently adapted for flights on the International Space Station (ISS). From 2000 through 2010, crews completed 26 ISS flight increments ranging in duration from 140 to 216 d, with the participation of 27 Russian cosmonauts. These flights have made it possible to more precisely determine a crew-member's level of conditioning, better assess the advantages and disadvantages of training processes, and determine prospects for future developments. PMID- 26630193 TI - Evolution of Russian Microgravity Countermeasures. AB - INTRODUCTION: Countermeasures to prevent or partially offset the negative physiologic changes that are caused by the effects of microgravity play an important role in supporting the performance of crewmembers in flight and their safe return to Earth. Research conducted in Russia on the orbital stations Salyut and Mir, as well as simulation experiments on the ground, have demonstrated that changes that occur during extended spaceflight in various physiologic systems can be prevented or significantly decreased by using countermeasures. Hardware and techniques used on the ISS have been substantially improved to reflect the experience of previous extended missions on Russian orbital stations. Countermeasures used during early ISS missions consisted of the U.S. treadmill (TVIS), cycle ergometer (VB-3), a set of resistance bands, a postural muscle loading suit (Penguin-3), electrical stimulator (Tonus-3), compression thigh cuffs (Braslet-M), a lower body negative pressure (LBNP) suit (Chibis), a lower body g-loading suit (Kentavr), and water/salt supplements. These countermeasures are described in this article. PMID- 26630194 TI - Evaluating Bone Loss in ISS Astronauts. AB - INTRODUCTION: The measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) is the Medical Assessment Test used at the NASA Johnson Space Center to evaluate whether prolonged exposure to spaceflight increases the risk for premature osteoporosis in International Space Station (ISS) astronauts. The DXA scans of crewmembers' BMD during the first decade of the ISS existence showed precipitous declines in BMD for the hip and spine after the typical 6-mo missions. However, a concern exists that skeletal integrity cannot be sufficiently assessed solely by DXA measurement of BMD. Consequently, use of relatively new research technologies is being proposed to NASA for risk surveillance and to enhance long-term management of skeletal health in long duration astronauts. Sibonga JD, Spector ER, Johnston SL, Tarver WJ. Evaluating bone loss in ISS astronauts. PMID- 26630195 TI - Assessing Sensorimotor Function Following ISS with Computerized Dynamic Posturography. AB - INTRODUCTION: Postflight postural ataxia reflects both the control strategies adopted for movement in microgravity and the direct effects of deconditioning. Computerized dynamic posturography (CDP) has been used during the first decade of the International Space Station (ISS) expeditions to quantify the initial postflight decrements and recovery of postural stability. METHODS: The CDP data were obtained on 37 crewmembers as part of their pre- and postflight medical examinations. Sensory organization tests evaluated the ability to make effective use of (or suppress inappropriate) visual, vestibular, and somatosensory information for balance control. This report focuses on eyes closed conditions with either a fixed or sway-referenced base of support, with the head erect or during pitch-head tilts (+/- 20 degrees at 0.33 Hz). Equilibrium scores were derived from peak-to-peak anterior-posterior sway. Motor-control tests were also used to evaluate a crewmember's ability to automatically recover from unexpected support-surface perturbations. RESULTS: The standard Romberg condition was the least sensitive. Dynamic head tilts led to increased incidence of falls and revealed significantly longer recovery than head-erect conditions. Improvements in postflight postural performance during the later expeditions may be attributable to higher preflight baselines and/or advanced exercise capabilities aboard the ISS. CONCLUSIONS: The diagnostic assessment of postural instability is more pronounced during unstable-support conditions requiring active head movements. In addition to supporting return-to-duty decisions by flight surgeons, the CDP provides a standardized sensorimotor measure that can be used to evaluate the effectiveness of countermeasures designed to either minimize deconditioning on orbit or promote reconditioning upon return to Earth. PMID- 26630196 TI - Orthostatic Intolerance After ISS and Space Shuttle Missions. AB - INTRODUCTION: Cardiovascular deconditioning apparently progresses with flight duration, resulting in a greater incidence of orthostatic intolerance following long-duration missions. Therefore, we anticipated that the proportion of astronauts who could not complete an orthostatic tilt test (OTT) would be higher on landing day and the number of days to recover greater after International Space Station (ISS) than after Space Shuttle missions. METHODS: There were 20 ISS and 65 Shuttle astronauts who participated in 10-min 80 degrees head-up tilt tests 10 d before launch, on landing day (R+0), and 3 d after landing (R+3). Fisher's Exact Test was used to compare the ability of ISS and Shuttle astronauts to complete the OTT. Cox regression was used to identify cardiovascular parameters associated with OTT completion and mixed model analysis was used to compare the change and recovery rates between groups. RESULTS: The proportion of astronauts who completed the OTT on R+0 (2 of 6) was less in ISS than in Shuttle astronauts (52 of 65). On R+3, 13 of 15 and 19 of 19 of the ISS and Shuttle astronauts, respectively, completed the OTT. An index comprised of stroke volume and diastolic blood pressure provided a good prediction of OTT completion and was altered by spaceflight similarly for both astronaut groups, but recovery was slower in ISS than in Shuttle astronauts. CONCLUSIONS: The proportion of ISS astronauts who could not complete the OTT on R+0 was greater and the recovery rate slower after ISS compared to Shuttle missions. Thus, mission planners and crew surgeons should anticipate the need to tailor scheduled activities and level of medical support to accommodate protracted recovery after long-duration microgravity exposures. PMID- 26630197 TI - Isokinetic Strength Changes Following Long-Duration Spaceflight on the ISS. AB - INTRODUCTION: Long-duration spaceflight results in a loss of muscle strength that poses both operational and medical risks, particularly during emergency egress, upon return to Earth, and during future extraterrestrial exploration. Isokinetic testing of the knee, ankle, and trunk quantifies movement-specific strength changes following spaceflight and offers insight into the effectiveness of in flight exercise countermeasures. METHODS: We retrospectively evaluated changes in isokinetic strength for 37 ISS crewmembers (Expeditions 1-25) following 163 +/- 38 d (mean +/- SD) of spaceflight. Gender, in-flight resistance exercise hardware, and preflight strength were examined as potential modifiers of spaceflight-induced strength changes. RESULTS: Mean isokinetic strength declined 8-17% following spaceflight. One month after return to Earth, strength had improved, but small deficits of 1-9% persisted. Spaceflight-induced strength losses were not different between men and women. Mean strength losses were as much as 7% less in crewmembers who flew after the Advanced Resistive Exercise Device (ARED) replaced the interim Resistive Exercise Device (iRED) as the primary in-flight resistance exercise hardware, although these differences were not statistically significant. Absolute and relative preflight strength were moderately correlated (r = -0.47 and -0.54, respectively) with postflight strength changes. DISCUSSION: In-flight resistance exercise did not prevent decreased isokinetic strength after long-duration spaceflight. However, continued utilization of ARED, a more robust resistance exercise device providing higher loads than iRED, may result in greater benefits as exercise prescriptions are optimized. With reconditioning upon return to Earth, strength is largely recovered within 30 d. PMID- 26630198 TI - The First 10 Years of Aerobic Exercise Responses to Long-Duration ISS Flights. AB - INTRODUCTION: Aerobic deconditioning may occur during International Space Station (ISS) flights. This paper documents findings from exercise testing conducted before, during, and after ISS expeditions. METHODS: There were 30 male and 7 female astronauts on ISS missions (48 to 219 d, mean 163 d) who performed cycle exercise protocols consisting of 5-min stages eliciting 25%, 50%, and 75% peak oxygen uptake (Vo(2peak)). Tests were conducted 30 to 90 d before missions, on flight day 15 and every 30 flight days thereafter, and on recovery (R) days +5 and +30. During pre- and postflight tests, heart rate (HR) and metabolic gas exchange were measured. During flight, extrapolation of the HR and Vo2 relationship to preflight-measured peak HR provided an estimate of Vo(2peak), referred to as the aerobic capacity index (ACI). RESULTS: HR during each exercise stage was elevated (P < 0.05) and oxygen pulse was reduced (P < 0.05) on R+5 compared to preflight; however, no other metabolic gas analysis values significantly changed. Compared to preflight, the ACI declined (P < 0.001) on R+5, but recovered to levels greater than preflight by R+30 (P = 0.008). During flight, ACI decreased below preflight values, but increased with mission duration (P < 0.001). CONCLUSIONS: Aerobic deconditioning likely occurs initially during flight, but ACI recovers toward preflight levels as flight duration increases, presumably due to performance of exercise countermeasures. Elevated HR and lowered oxygen pulse on R+5 likely results from some combination of relative hypovolemia, lowered cardiac stroke volume, reduced cardiac distensibility, and anemia, but recovery occurs by R+30. PMID- 26630199 TI - Functional Fitness Testing Results Following Long-Duration ISS Missions. AB - INTRODUCTION: Long-duration spaceflight missions lead to the loss of muscle strength and endurance. Significant reduction in muscle function can be hazardous when returning from spaceflight. To document these losses, NASA developed medical requirements that include measures of functional strength and endurance. Results from this Functional Fitness Test (FFT) battery are also used to evaluate the effectiveness of in-flight exercise countermeasures. The purpose of this paper is to document results from the FFT and correlate this information with performance of in-flight exercise on board the International Space Station. METHODS: The FFT evaluates muscular strength and endurance, flexibility, and agility and includes the following eight measures: sit and reach, cone agility, push-ups, pull-ups, sliding crunches, bench press, leg press, and hand grip dynamometry. Pre- to postflight functional fitness measurements were analyzed using dependent t-tests and correlation analyses were used to evaluate the relationship between functional fitness measurements and in-flight exercise workouts. RESULTS: Significant differences were noted post space flight with the sit and reach, cone agility, leg press, and hand grip measurements while other test scores were not significantly altered. The relationships between functional fitness and in-flight exercise measurements showed minimal to moderate correlations for most in-flight exercise training variables. DISCUSSION: The change in FFT results can be partially explained by in-flight exercise performance. Although there are losses documented in the FFT results, it is important to realize that the crewmembers are successfully performing activities of daily living and are considered functional for normal activities upon return to Earth. PMID- 26630200 TI - Exercise Countermeasures on ISS: Summary and Future Directions. AB - INTRODUCTION: The first decade of the International Space Station Program (ISS) yielded a wealth of knowledge regarding the health and performance of crewmembers living in microgravity for extended periods of time. The exercise countermeasures hardware suite evolved during the last decade to provide enhanced capabilities that were previously unavailable to support human spaceflight, resulting in attenuation of cardiovascular, muscle, and bone deconditioning. The ability to protect crew and complete mission tasks in the autonomous exploration environment will be a critical component of any decision to proceed with manned exploration initiatives.The next decade of ISS habitation promises to be a period of great scientific utilization that will yield both the tools and technologies required to safely explore the solar system. Leading countermeasure candidates for exploration class missions must be studied methodically on ISS over the next decade to ensure protocols and systems are highly efficient, effective, and validated. Lessons learned from the ISS experience to date are being applied to the future, and international cooperation enables us to maximize this exceptional research laboratory. PMID- 26630201 TI - Cytotoxicity and preliminary mode of action studies of novel 2-aryl-4-thiopyrone based organometallics. AB - Organometallic complexes with thiopyrone-based ligands have shown promising cytotoxic activity in vitro. To investigate the impact of the ligand backbone modification of these biologically active compounds and enhance the solubility in aqueous solution, the (thio)pyrone scaffold was modified via Suzuki-Miyaura coupling reaction and converted into corresponding organometallic Ru(ii) and Rh(iii) complexes. Characterization of the synthesized compounds was carried out by means of 1D and 2D NMR, ESI MS, and also by X-ray diffraction analysis. The stability in aqueous solution was investigated via(1)H NMR spectroscopy. Due to the close structural resemblance to flavonoids, topoisomerase inhibition, the cytotoxicity in human cancer cell lines as well as ROS generation was investigated by means of the topoisomerase II drug screening assay, the MTT assay and DCFH-DA assay, respectively. PMID- 26630202 TI - Cerebellar Nuclear Neurons Use Time and Rate Coding to Transmit Purkinje Neuron Pauses. AB - Neurons of the cerebellar nuclei convey the final output of the cerebellum to their targets in various parts of the brain. Within the cerebellum their direct upstream connections originate from inhibitory Purkinje neurons. Purkinje neurons have a complex firing pattern of regular spikes interrupted by intermittent pauses of variable length. How can the cerebellar nucleus process this complex input pattern? In this modeling study, we investigate different forms of Purkinje neuron simple spike pause synchrony and its influence on candidate coding strategies in the cerebellar nuclei. That is, we investigate how different alignments of synchronous pauses in synthetic Purkinje neuron spike trains affect either time-locking or rate-changes in the downstream nuclei. We find that Purkinje neuron synchrony is mainly represented by changes in the firing rate of cerebellar nuclei neurons. Pause beginning synchronization produced a unique effect on nuclei neuron firing, while the effect of pause ending and pause overlapping synchronization could not be distinguished from each other. Pause beginning synchronization produced better time-locking of nuclear neurons for short length pauses. We also characterize the effect of pause length and spike jitter on the nuclear neuron firing. Additionally, we find that the rate of rebound responses in nuclear neurons after a synchronous pause is controlled by the firing rate of Purkinje neurons preceding it. PMID- 26630203 TI - Nutritional Status and Daytime Pattern of Protein Intake on Match, Post-Match, Rest and Training Days in Senior Professional and Youth Elite Soccer Players. AB - The nutritional status of elite soccer players across match, postmatch, training and rest days has not been defined. Recent evidence suggests the pattern of dietary protein intake impacts the daytime turnover of muscle proteins and, as such, influences muscle recovery. We assessed the nutritional status and daytime pattern of protein intake in senior professional and elite youth soccer players and compared findings against published recommendations. Fourteen senior professional (SP) and 15 youth elite (YP) soccer players from the Dutch premier division completed nutritional assessments using a 24-hr web-based recall method. Recall days consisted of a match, postmatch, rest, and training day. Daily energy intake over the 4-day period was similar between SP (2988 +/- 583 kcal/day) and YP (2938 +/- 465 kcal/day; p = .800). Carbohydrate intake over the combined 4-day period was lower in SP (4.7 +/- 0.7 g.kg-1 BM.day-1) vs. YP (6.0 +/- 1.5 g.kg-1 BM.day-1, p = .006) and SP failed to meet recommended carbohydrate intakes on match and training days. Conversely, recommended protein intakes were met for SP (1.9 +/- 0.3 g.kg-1 BM.day-1) and YP (1.7 +/- 0.4 g.kg-1 BM.day-1), with no differences between groups (p = .286). Accordingly, both groups met or exceeded recommended daily protein intakes on individual match, postmatch, rest and training days. A similar "balanced" daytime pattern of protein intake was observed in SP and YP. To conclude, SP increased protein intake on match and training days to a greater extent than YP, however at the expense of carbohydrate intake. The daytime distribution of protein intake for YP and SP aligned with current recommendations of a balanced protein meal pattern. PMID- 26630204 TI - Mapping of TBARS distribution in frozen-thawed pork using NIR hyperspectral imaging. AB - In this study, NIR hyperspectral imaging technology was applied to determine the distribution of TBARS in frozen-thawed pork. A total of 240 fresh pork samples were assigned to 4 treatment groups (0, 1, 3, 5 frozen-thawed cycles). For each sample, a hyperspectral image (874-1734nm) was collected, followed by chemical TBARS analysis. Successive projection algorithm (SPA) was applied to choose effective wavelengths (EWs). The selected 13 EWs of the calibration set and relevant TBARS value were used as inputs of partial least squares regression (PLSR) model, yielding correlation coefficient of prediction of 0.81 and root mean square error of prediction of 0.33. The developed PLSR model were applied pixel-wise to produce chemical maps of TBARS for 24 selected samples in the prediction set. The results indicated that NIR hyperspectral imaging combined with image processing has the potential to visualize TBARS distribution in frozen thawed pork. This technique could be useful in real-time quality monitoring in meat industry. PMID- 26630205 TI - Construct damage and loosening around glenoid implants: A longitudinal micro-CT study of five cadaver specimens. AB - The evolution of failure of bone and cement leading to loosening of glenoid components following shoulder arthroplasty is not well understood. The purpose of this study was to identify and visualize potential mechanisms of mechanical failure within cadavers, cemented with two types of components, and subject to cyclic loading. Five glenoid cadaver bones were implanted with either a three pegged polyethylene component, or prototype posteriorly augmented component which addresses posterior bone loss. Specimens were loaded by constant glenohumeral compression combined with cyclic anterior-posterior displacement of the humeral head relative to the glenoid. At six time points across 100,000 cycles, implant loosening micromotions were optically measured, and specimens were imaged by micro-computed tomography. Scans were 3D registered and inspected for crack initiation and progression, and micro-CT based time-lapse movies were created. Cement cracking initiated at stress concentrations and progressed with additional cyclic loading. Failure planes within trabecular bone and the bone-cement interface were identified in four of the five specimens. Implant subsidence increased to greater than 1.0 mm in two specimens. Cemented glenoid structural failure can occur within the cement, along planes of trabecular bone, or at the bone cement interface. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1053-1060, 2016. PMID- 26630206 TI - Utility of novel fetal echocardiographic morphometric measures of the aortic arch in the diagnosis of neonatal coarctation of the aorta. AB - OBJECTIVES: Prenatal diagnosis of neonatal coarctation of the aorta (CoA) is challenging; there is a high false-positive rate, yet 60-80% are not identified prenatally. We aimed to identify novel fetal echocardiographic measures to improve prenatal identification of CoA. METHODS: A retrospective review was conducted of subjects seen from 1/2007-1/2014 with prenatal suspicion for CoA and postnatal follow-up. The last fetal echocardiogram prior to delivery was evaluated for right/left ventricular dimensions, ascending (AAo), transverse (TAo), descending aorta (DAo), aortic isthmus (AoI), ductus arteriosus (DA), and main pulmonary artery diameters, and AoI and DA spectral Doppler. Three novel fetal measurements were performed: left common carotid-to-left subclavian artery distance (LCSA), AAo-DAo angle, and TAo-DAo angle. Postnatal data included diagnosis, surgical approach, and timing. RESULTS: Forty subjects were identified (mean gestational age at fetal echo 32.8 +/- 4.2 weeks) with prenatal suspicion for CoA. Comparing subjects with (n = 20) and without CoA (n = 20), significant differences were detected for LCSA, AAo-DAo angle, and TAo-DAo angle (p < 0.0001). An LCSA >4.5 mm (sensitivity 80%,specificity 95%), AAo-DAo angle <=20.31 degrees (sensitivity 95%,specificity 100%) and TAo-DAo angle >=96.15 degrees (sensitivity 90%,specificity 100%) identified CoA. CONCLUSIONS: Fetal LCSA, AAo DAo angle, and TAo-DAo angles are novel measures that can differentiate between subjects with and without CoA. PMID- 26630207 TI - Antihypertensive therapy in patients on chronic lithium treatment for bipolar disorders. AB - Bipolar disorders are chronic conditions treated with lithium, which exerts deleterious effects on the kidney, among which nephrogenic diabetes insipidus, tubular acidosis and ultimately chronic kidney disease. Conversely, drugs that alter renal function can modify its serum levels and lead to the potentially fatal lithium intoxication. A search in the main library databases from 1975 to 2015 to identify interactions between antihypertensive drugs and lithium using the Population Intervention Comparison Outcome strategy provided only 30 reports of lithium intoxication. A regression analysis showed that the severity of lithium intoxication was significantly predicted by female, age, and use of certain classes of antihypertensive agents. A model including certain albeit not all diuretics and/or inhibitors of the renin-angiotensin system, but not age, serum lithium or creatinine levels at baseline and/or on admission to the hospital, predicted lithium toxicity. The true incidence of lithium intoxication is unknown but probably low, albeit underestimated. Nonetheless, in patients treated with lithium, monitoring of the serum lithium levels and clinical conditions is mandatory after the introduction of antihypertensive drugs, as diuretics and renin-aldosterone system inhibitors. PMID- 26630208 TI - Hypertension in China: a large and increasing public health challenge. PMID- 26630209 TI - A multi-omics glimpse into the biology of arterial stiffness. PMID- 26630210 TI - T-regulatory cells and vascular function: the importance of their immunosuppressive action in hypertensive disease. PMID- 26630212 TI - Impact of adolescent pregnancy on hypertension in postmenopausal women. AB - OBJECTIVE: Several studies have reported the detrimental effects on maternal health due to pregnancy during adolescence, but no studies have reported the influence of adolescent pregnancy on blood pressure in women's later life. METHOD: We investigated whether there was an association between adolescent pregnancy and the risk of hypertension in Korean postmenopausal women. This study used the data of 2538 postmenopausal women from the Korean National Health and Nutrition Examination Survey in 2010-2011. Multivariate logistic regression analyses were used to evaluate the independent association between adolescent pregnancy and hypertension by adjusting for potential confounding factors. RESULTS: Postmenopausal women with a history of adolescent pregnancy had a higher prevalence of hypertension than those without a history of adolescent pregnancy. After fully adjusting for potential confounding factors such as age, lifestyle, sociodemographic factors, known hypertension risk factors, and reproductive factors, a history of adolescent pregnancy was significantly associated with hypertension (odds ratio, 1.702; 95% confidence interval, 1.125-2.574). CONCLUSION: This study showed that a history of adolescent pregnancy is significantly and independently associated with a higher risk of hypertension in postmenopausal women. PMID- 26630213 TI - White-coat and masked hypertension as risk factors for progression to sustained hypertension: the Finn-Home study. AB - OBJECTIVES: To assess the risk of progression from white-coat hypertension (WCHT) and masked hypertension (MHT) to sustained hypertension (SHT) in a nationwide unselected population sample. METHODS: Both office and home blood pressure (BP), along with other cardiovascular risk factors, were measured in an unselected population sample of 944 participants in 2000 and 2011. We compared the risk of progression to SHT (office BP >=140/90 mmHg and home BP >=135/85 mmHg or start of treatment with antihypertensive medication) between 528 participants with normotension (office BP <140/90 mmHg and home BP <135/85 mmHg), 142 participants with WCHT (office BP >=140/90 mmHg and home BP < 135/85 mmHg), and 63 participants with MHT (office BP < 140/90 mmHg and home BP >=135/85 mmHg) at baseline. We used the chi test and a multivariable-adjusted log-binomial regression model to evaluate the association between baseline BP categories and incident SHT. RESULTS: During an 11-year follow-up, the rate of progression to SHT increased from normotension (18%) to WCHT (52%) and MHT (73%), P < 0.0001. Progression to SHT became more likely with an increasing baseline home BP category (Ptrend < 0.0001). The multivariable-adjusted relative risks (95% confidence interval) for developing SHT, as compared with normotension, were 2.8 (2.2-3.6, P < 0.0001) for WCHT and 3.8 (2.9-5.0, P < 0.0001) for MHT. CONCLUSIONS: Persons with WCHT and MHT have a three to four-fold risk for developing SHT than those with NT and could benefit from active follow-up and lifestyle counselling. PMID- 26630214 TI - Agreement between ambulatory, home, and office blood pressure variability. AB - OBJECTIVE: Ambulatory, home, and office blood pressure (BP) variability are often treated as a single entity. Our aim was to assess the agreement between these three methods for measuring BP variability. METHODS: Twenty-four-hour ambulatory BP monitoring, 28 home BP measurements, and eight office BP measurements were performed on 461 population-based or hypertensive participants. Five variability indices were calculated for all measurement methods: SD, coefficient of variation, maximum-minimum difference, variability independent of the mean, and average real variability. Pearson's correlation coefficients were calculated for indices measured with different methods. The agreement between different measurement methods on the diagnoses of extreme BP variability (participants in the highest decile of variability) was assessed with kappa (kappa) coefficients. RESULTS: SBP/DBP variability was greater in daytime (coefficient of variation: 9.8 +/- 2.9/11.9 +/- 3.6) and night-time ambulatory measurements (coefficient of variation: 8.6 +/- 3.4/12.1 +/- 4.5) than in home (coefficient of variation: 4.4 +/- 1.8/4.7 +/- 1.9) and office (coefficient of variation: 4.6 +/- 2.4/5.2 +/- 2.6) measurements (P < 0.001/0.001 for all). Pearson's correlation coefficients for systolic/diastolic daytime or night-time ambulatory-home, ambulatory-office, and home-office variability indices ranged between 0.07-0.25/0.12-0.23, 0.13 0.26/0.03-0.22 and 0.13-0.24/0.10-0.19, respectively, indicating, at most, a weak positive (r < 0.3) relationship. The agreement between measurement methods on diagnoses of extreme SBP/DBP variability was only slight (kappa < 0.2), with the kappa coefficients for daytime and night-time ambulatory-home, ambulatory-office, and home-office agreement varying between-0.014-0.20/0.061-0.15, 0.037-0.18/0.082 0.15, and 0.082-0.13/0.045-0.15, respectively. CONCLUSION: Shorter-term and longer-term BP variability assessed by different methods of BP measurement seem to correlate only weakly with each other. Our study suggests that BP variability measured by different methods and timeframes may reflect different phenomena, not a single entity. PMID- 26630211 TI - Hypertension prevalence, awareness, treatment, and control in 115 rural and urban communities involving 47 000 people from China. AB - BACKGROUND: Identification and treatment of hypertension in China remain suboptimal despite high prevalence of hypertension and increasing incidence of stroke and myocardial infarction. OBJECTIVE: This study reported blood pressure levels, prevalence, awareness, treatment, and control rates of hypertension, in addition to drug treatments in China. METHODS: This is a country-specific analysis of 45 108 individuals, average age 51.4 (standard deviation 9.6) (35-70) years, enrolled between 2005 and 2009, from 70 rural and 45 urban communities in 12 provinces. RESULTS: Among 18 915 (41.9% overall population) hypertensive participants, 7866 (41.6%) were aware, 6503 (34.4%) treated but only 1545 (8.2%) controlled. Prevalence of hypertension was higher, but awareness, treatment, and control were lower in rural than urban residents. Prevalence of hypertension was highest in eastern (44.3%), intermediate in central (39.3%), and lowest in western regions (37.0%). Awareness was higher in central (44.3%) and eastern (42.4%) but lower in western regions (37.0%). Similar patterns were observed in treatment rates, 37.7% central, 35.2% eastern, and 26.7% in western regions with control rates of 8.3% in eastern, 7.6% central, and 5.3% west regions. Of 4744 participants receiving documented treatments, 37.5% received traditional combination drugs alone, 55.4% western drugs alone and 7.1% combination of traditional combination drug in addition to western drugs. CONCLUSION: In China, hypertension is common, and while recent studies suggest some improvements, more than half of affected individuals were unaware that they had hypertension. Rates of control remain low. National programs effective in preventing and controlling hypertension in China are urgently needed. PMID- 26630215 TI - Deficiency of T-regulatory cells exaggerates angiotensin II-induced microvascular injury by enhancing immune responses. AB - AIMS: T-regulatory lymphocyte (Treg) adoptive transfer prevented angiotensin (Ang) II-induced hypertension and microvascular injury. Scurfy mice are deficient in Treg because of a mutation in the transcription factor forkhead box P3 (Foxp3) gene. Enhanced Ang II effects in the absence of Treg would unambiguously demonstrate their vascular protective role. We hypothesized that adoptive transfer of Scurfy vs. wild-type T cells will exacerbate Ang II-induced microvascular damage in T and B-cell-deficient recombination-activating gene 1 (Rag1) knockout mice. METHODS AND RESULTS: Rag1 knockout mice were injected with vehicle, 10(7) T cells from wild-type or Scurfy mice or 10 (6)wild-type Treg alone or in combination with Scurfy T cells, and then infused or not with Ang II (490 ng/kg per min, subcutaneous) for 14 days. Ang II increased SBP in all the groups, but DBP only in wild-type and Scurfy T-cell groups. Ang II-induced endothelial dysfunction and oxidative stress in perivascular adipose tissue (PVAT) of mesenteric arteries of the wild-type T-cell group, whereas these were exaggerated in the Scurfy T-cell group. Ang II enhanced microvascular remodeling and stiffness in vehicle and Scurfy T-cell groups. Ang II increased monocyte chemotactic protein-1 expression in the vascular wall and PVAT, monocyte/macrophage infiltration and proinflammatory polarization in PVAT and the renal cortex, and T-cell infiltration in the renal cortex only in the Scurfy T cell group. Treg coinjection in the vehicle and Scurfy T-cell groups prevented or reduced the effects of Ang II. CONCLUSION: FOXP3+ Treg deficiency exaggerates Ang II-induced microvascular injury by modulating innate and adaptive immune responses. PMID- 26630217 TI - Hypertension, antihypertensive treatment and cancer incidence and mortality: a pooled collaborative analysis of 12 Australian and New Zealand cohorts. AB - BACKGROUND: Observational studies examining associations between hypertension and cancer are inconsistent. We explored the association of hypertension, graded hypertension and antihypertensive treatment with cancer incidence and mortality. METHOD: Eighty-six thousand five hundred and ninety-three participants from the Australian and New Zealand Diabetes and Cancer Collaboration were linked to the National Death Index and Australian Cancer Database. Cox proportional hazards models estimated hazard ratios and 95% confidence intervals (95% CI) for the association of treated and untreated hypertension with cancer incidence and mortality. RESULTS: Over a median follow-up of 15.1 years, 12 070 incident and 4350 fatal cancers were identified. Untreated and treated hypertension, compared with normotension, were associated with an increased risk for cancer incidence [hazard ratio 1.06, 95% CI (1.00-1.11) and 1.09 (1.02-1.16) respectively], and cancer mortality (1.07, 0.98-1.18) and (1.15, 1.03-1.28), respectively. When compared with untreated hypertension, treated hypertension did not have a significantly greater risk for cancer incidence (1.03, 0.97-1.10) or mortality (1.07, 0.97-1.19). A significant dose-response relationship was observed between graded hypertension and cancer incidence and mortality; Ptrend = 0.053 and Ptrend = 0.001, respectively. When stratified by treatment status, these relationships remained significant in untreated, but not in treated, hypertension. CONCLUSION: Hypertension, both treated and untreated, is associated with a modest increased risk for cancer incidence and mortality. Similar risks in treated and untreated hypertension suggest that the increased cancer risk is not explained by the use of antihypertensive treatment. PMID- 26630218 TI - Effects of orally administered antibiotics on the bioavailability of amlodipine: gut microbiota-mediated drug interaction. AB - BACKGROUND: Amlodipine is a representative calcium channel blocker that is frequently prescribed for the treatment of hypertension. In this study, the possibility of drug-drug interactions between amlodipine and coadministered antibiotics (ampicillin) was investigated in rats; thus, changes in the metabolic activities of gut microflora and the consequent pharmacokinetic pattern of amlodipine following ampicillin treatment were characterized. METHODS AND RESULTS: In human and rat fecalase incubation samples, amlodipine was metabolized to yield a major pyridine metabolite. The remaining amlodipine decreased and the formation of pyridine metabolite increased with incubation time, indicating the involvement of gut microbiota in the metabolism of amlodipine. Pharmacokinetic analyses showed that systemic exposure of amlodipine was significantly elevated in antibiotic-treated rats compared with controls. CONCLUSION: These results showed that antibiotic intake might increase the bioavailability of amlodipine by suppressing gut microbial metabolic activities, which could be followed by changes in therapeutic potency. Therefore, coadministration of amlodipine with antibiotics requires caution and clinical monitoring. PMID- 26630219 TI - Paradoxical Reaction During a Course of Terbinafine Treatment of Trichophyton interdigitale Infection in a Child. PMID- 26630216 TI - Effects of the lercanidipine-enalapril combination vs. the corresponding monotherapies on home blood pressure in hypertension: evidence from a large database. AB - OBJECTIVE: To compare a combination of a dihydropyridine calcium-channel blocker with an angiotensin converting enzyme inhibitor vs. monotherapy with one or the other drug and placebo for their effects on home blood pressure (HBP). METHODS: After a 2-week placebo wash-out, patients with an elevated office blood pressure (BP) (diastolic 100-109 and systolic <180 mmHg) and HBP (diastolic >=85 mmHg) were randomized double-blind to a 10-week treatment with placebo, lercanidipine, 10 or 20 mg daily, enalapril, 10 or 20 mg daily, or the four possible combinations. In addition to office BP, HBP was self-measured via a validated semiautomatic device twice in the morning and twice in the evening during the 7 days before randomization and at the end of treatment. Baseline and treatment HBP values were separately averaged for each day, morning, evening or the whole monitoring period, excluding the first day. Day-by-day HBP variability was defined as the SD or the variation coefficient of the daily BP averages. RESULTS: Eight hundred and fifty-four patients with valid HBP recordings at baseline and at the end of treatment were analyzed (intention-to-treat population). From the baseline value (147.0+/-11.6 mmHg) systolic/diastolic HBP showed a small reduction (average baseline-adjusted change: -1.8/-1.6 mmHg) with placebo, a more marked significant fall with monotherapies (-8.8/-5.9 mmHg, P < 0.001/<0.001 vs. placebo) and even more with combination treatment (11.6/-7.6 mmHg, P < 0.001/ < 0.001 vs. placebo and P < 0.01/ < 0.05 vs. monotherapy). A similar pattern was observed for each of the days of the BP self-monitoring period as well as for either morning or evening values, although the difference between mono and combination treatment appeared to be consistently significant for the morning values only. Day-by-day systolic BP-SD was unaffected by placebo and slightly reduced by drug treatments, with no, however, significant changes in SBP variation coefficient. Baseline and end of treatment HBP values showed a limited correlation with office BP values, this being particularly the case for treatment induced changes (correlation coefficients: 0.37 for systolic and 0.45 for diastolic BP). CONCLUSION: This large HBP database shows that the lercanidipine enalapril combination lowers HBP more effectively than the corresponding monotherapies and placebo, and that this greater effect is consistent between days. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01093807. PMID- 26630220 TI - Malignant Struma Ovarii With a Predominant Component of Anaplastic Carcinoma. AB - Struma ovarii exhibiting malignant histology are uncommon, and aggressive clinical courses with initial extraovarian spread are even more rare. This report describes a case of malignant struma ovarii with a predominant anaplastic carcinoma component. A 65-yr-old, gravida 2, para 2, female presented with lower abdominal discomfort and pain. She had a 12*10*7.5 cm tumor in the right ovary. Intraoperative diagnosis was high-grade spindle cell tumor. Right salpingo oophorectomy and hysterectomy were performed. Macroscopically, the tumor invading the right tube was a yellow-white solid mass with focal microcysts containing greenish liquid and focal calcification. The tumor was histologically characterized by a spindle cell and pleomorphic sarcomatous component, and a minor component of benign-looking thyroid tissue with ossification. Immunohistochemically, the sarcomatous component was focally positive for CAM 5.2, EMA, thyroid transcription factor-1, and thyroglobulin, indicating anaplastic carcinoma. The patient was treated with chemotherapy and is alive, yet with tumor, 25 mo after surgery. This is the first case of malignant struma ovarii with a predominant component of anaplastic carcinoma. This type of malignant struma ovarii may lead to diagnostic problems, and sampling and differential diagnosis among sarcomatous ovarian tumors are important for making the correct diagnoses. PMID- 26630221 TI - Incidental Serous Tubal Intraepithelial Carcinoma and Non-Neoplastic Conditions of the Fallopian Tubes in Grossly Normal Adnexa: A Clinicopathologic Study of 388 Completely Embedded Cases. AB - Serous tubal intraepithelial carcinoma (STIC), the putative precursor of the majority of extrauterine high-grade serous carcinomas, has been reported in both high-risk women (those with a germline BRCA mutation, a personal history of breast carcinoma, and/or family history of breast or ovarian carcinoma) and average risk women from the general population. We reviewed grossly normal adnexal specimens from 388 consecutive, unselected women undergoing surgery, including those with germline BRCA mutation (37 patients), personal history of breast cancer or family history of breast/ovarian cancer (74 patients), endometrial cancer (175 patients), and a variety of other conditions (102 patients). Among 111 high-risk cases and 277 non-high-risk cases, 3 STICs were identified (0.8%), all in non-high-risk women (high risk vs. non-high risk: P=not significant). STIC was found in 2 women with nonserous endometrial carcinoma and 1 with complex atypical endometrial hyperplasia. Salpingoliths (mucosal calcifications), found in 9% of high-risk cases, and fimbrial adenofibromas in 9.9% of high-risk cases, were significantly more common in high-risk as compared with non-high-risk women (1.8% and 2.5%, respectively; P<0.007). Mucinous metaplasia was found in 3.1%, salpingitis isthmica nodosa in 3.4%, hemosiderin or pseudoxanthoma cells in 4.9%, and fibrous luminal nodules in 4.1%. None of these latter features differed significantly in the high-risk versus non-high-risk groups. These findings suggest a possible association between STIC and endometrial hyperplasia and carcinoma, and clarify the frequency of non neoplastic tubal findings in grossly normal fallopian tubes. PMID- 26630222 TI - An Ovarian Carcinoid Tumor With Peptide YY-Positive Insular Component: A Case Report and Review of the Literature. AB - Ovarian carcinoid tumors are uncommon and account for 1% of all carcinoid tumors. The insular type of ovarian carcinoid tumor is common in western countries; in contrast, the strumal and trabecular types seem to be common in Asian countries. Strumal and trabecular types are associated with peptide YY (PYY) production, which may cause constipation. Here, we report the case of a 70-yr-old Japanese woman with chronic constipation who was referred to Kumamoto University Hospital because of a right adnexal mass. Imaging tests suggested that the solid mass might be malignant; therefore, abdominal total hysterectomy, bilateral salpingo oophorectomy, and omentectomy were performed. A subsequent histopathologic examination confirmed an insular carcinoid tumor with a trabecular component in the right ovary. Both components were positive for PYY but not for serotonin. The patient complained of diarrhea instead of constipation soon after the surgery. Because PYY-positive insular carcinoid tumor in the ovary has not been previously reported, we reviewed 19 reported cases of patients with PYY-positive ovarian carcinoid tumors. The origins, common histologic types and symptoms caused by specific peptides secreted in ovarian carcinoid tumors differ between western and Asian countries. PMID- 26630223 TI - Histopathology of Placenta Creta: Chorionic Villi Intrusion into Myometrial Vascular Spaces and Extravillous Trophoblast Proliferation are Frequent and Specific Findings With Implications for Diagnosis and Pathogenesis. AB - Placenta creta is characterized by invasion of placental villi into the myometrium in the setting of a dysfunctional or absent decidua. Histopathologic diagnosis of placenta creta is important, particularly in cases of hysterectomy because of unanticipated intractable postpartum hemorrhage. Previous studies have documented a higher amount and depth of myometrial infiltration by the implantation site intermediate trophoblast compared with controls. In addition, we have anecdotally observed chorionic villi in myometrial vascular spaces in specimens with placenta creta. The aim of this study was to explore the prevalence and specificity of these features. Sixty-one postpartum hysterectomies, 44 with placenta creta and 17 without were reviewed. Villous intrusion into vascular spaces was recorded. Using immunohistochemistry for GATA3, the amount of intermediate trophoblast (number of positive cells in five 40* fields) and depth of trophoblast myometrial infiltration were assessed. Mean gestational ages of the creta group (34.4 yr; range, 20-43 yr) and control group (35 yr; range, 25-51 yr) were comparable. Presence of chorionic villi in myometrial vascular spaces was frequent in placenta creta: 31/44 versus 1/17 controls (70.4% vs. 5.8%, P<0.0001). This finding was more common in the percreta (87.5%) and increta (84%) than in the accreta (27.2%, P=0.0008). Mean depth of trophoblast myometrial invasion was greater in cretas (47.9%) than in controls (14.5%, P=0.004). Likewise, mean distance of deepest trophoblast to serosa was shorter in the cretas (7.3 mm) than in controls (23.8 mm, P<0.0001). These differences were, however, attributable to placentas increta and percreta. When only accretas and controls were compared, the myometrial depth of trophoblast was similar. The mean intermediate trophoblast cell count in the placental bed was greater in cretas (664) than in controls (288, P<0.0001). Such difference was seen in all creta cases despite the type (accreta 639, increta 676, percreta 661). A trophoblast count of >=100 cells/high-power field was seen in 75.8% of cretas and 11.1% of controls (P=0.0009). For the first time, we document the finding of chorionic villi intrusion into myometrial vascular spaces, which is highly specific of placenta creta. In addition, assessment of the amount of intermediate trophoblast using GATA3 immunohistochemistry can assist in the diagnosis. We hypothesize that placental invasion in placenta creta is due, at least partially, to transformation of low-resistance myometrial vessels leading to subsequent protrusion of villi into their lumens, in the context of absent decidua. PMID- 26630224 TI - An Isolated Metastasis From Clear Cell Renal Cell Carcinoma to the Uterus: A Case Report and Review of Literature. AB - Ovaries are a favored site for metastatic tumors arising in the female genital tract. Other organs of the mullerian system, that is, the uterine corpus as well as the fallopian tubes, cervix, and the vagina are less commonly involved by metastases. If there is no clinical history of a known extramullerian primary tumor, suspicion that a uterine mass represents metastatic disease is low. We report the case of a renal clear cell carcinoma presenting as an isolated uterine mass and morphologically mimicking a primary endometrial clear cell adenocarcinoma. A review of the English literature yielded only a recent abstract describing 3 cases of renal clear cell carcinoma metastasizing to the endometrium. PMID- 26630226 TI - Frequency and Spectrum of MED12 Exon 2 Mutations in Multiple Versus Solitary Uterine Leiomyomas From Russian Patients. AB - Uterine leiomyomas (ULs) are common benign tumors affecting women of different ethnicities. A large proportion of UL has mutations in MED12. Multiple and solitary ULs usually manifest with different severities, suggesting that their origin and growth pattern may be driven by different molecular mechanisms. Here, we compared the frequency and the spectrum of MED12 exon 2 mutations between multiple (n=82) and solitary (n=40) ULs from Russian patients. Overall, we detected MED12 exon 2 mutations in 51.6% (63/122) of ULs. The frequency of MED12 exon 2 mutations was almost two-fold higher in samples from the multiple UL patients than in those from the solitary UL patients - 61% (50/82) versus 32.5% (13/40). The increased MED12 exon 2 mutation frequency in the multiple ULs was not accompanied by significant alterations in the spectrum of mutation categories, which included missense mutations, deletions, splicing defects, and multiple (double/triple) mutations. Each mutation category had a unique mutation set, comprising both frequent and rarely encountered mutations, which did and did not overlap between the studied groups, respectively. We conclude that in contrast to the solitary ULs, the multiple ULs predominantly originate through MED12-associated mechanisms. The nature of these mechanisms seems to be similar in solitary and multiple ULs, as they contain similar mutations. In multiple UL patients, they are likely to be nonsporadic, indicating the existence of specific factors predisposing to multiple UL development. These data suggest that to clearly understand UL pathogenesis, solitary and multiple tumors should probably be analyzed as separate sets. PMID- 26630225 TI - Low-Stage High-Grade Serous Ovarian Carcinomas: Support for an Extraovarian Origin. AB - Many adnexal high-grade serous carcinomas (HGSCs) may derive from microscopic precursors in the fallopian tube. By studying a series of low-stage ovarian carcinomas, we anticipated that HGSCs would be distributed in a pattern suggesting secondary involvement, helping to indirectly validate the fallopian tube origin theory, and that most ovarian carcinomas other than serous carcinomas would demonstrate features consistent with derivation from precursors located in or transplanted to the ovary. Seventy-six patients with low-stage (FIGO I/II) sporadic ovarian carcinoma who underwent primary surgical management at Memorial Sloan Kettering Cancer Center from 1980 to 2000 were included in the study. Histologic type was assigned using Gilks' criteria. Similar to the approach taken when distinguishing primary and metastatic mucinous or endometrioid carcinoma involving ovary, cases interpreted as showing a "primary" pattern of ovarian involvement had >=3 of the following features: unilateral tumor, size >12 cm, no surface involvement, no multinodularity, and no destructive stromal invasion. All other cases were considered to show a "metastatic" pattern of ovarian involvement. Cases were evaluated for p53 and WT-1 expression, using standard techniques on a tissue microarray. TP53 gene sequencing was also performed. Cases comprised HGSC (n=22), endometrioid carcinoma (n=30), clear cell carcinoma (n=13), and mucinous carcinoma (n=11). HGSCs displayed substantially more "metastatic features" than the non-HGSC group and a mean overall size that was smaller (8.85 vs. 14.1 cm). Statistically significant differences were found for bilaterality (63% vs. 7.3%), P=0.0001; multinodularity (55% vs. 7.3%), P=0.0001; tumor size, P=0.003; and surface involvement (50% vs. 13%), P=0.002. Five of 22 (23%) of HGSCs showed a "primary pattern" of ovarian involvement. There were no significant differences between these cases and "metastatic pattern" HGSCs when comparing morphology, immunophenotype, TP53 mutational status, and clinical outcomes. Most low-stage HGSCs demonstrate patterns of ovarian involvement that suggest metastasis from another source, such as the fallopian tube. Both metastatic pattern HGSCs and unilateral, low-stage HGSCs can behave aggressively. PMID- 26630227 TI - Ovarian Tumors in Children and Adolescents: A 10-Yr Histopathologic Review in Korle-Bu Teaching Hospital, Ghana. AB - To determine the histopathologic types, frequency of occurrence, age distribution, presenting signs, and symptoms of ovarian tumors in children and adolescents diagnosed at the Korle-Bu Teaching Hospital all histopathology slides and request cards of ovarian tumors diagnosed in subjects aged, 0 to 19 yr over a 10-yr period (2001-2010) were reviewed. Biographical and clinical data of the patients were collected. The results were entered into Epi-info to determine the frequency of various ovarian tumors in different age groups and their association with presenting signs and symptoms. A total of 67 (9.5%) ovarian tumors were diagnosed in patients aged 0 to 19 yr of a total of 706 diagnosed in all age groups during the period. The majority [44 (65.7%)] were germ cell tumors, the commonest being mature cystic teratoma. Burkitt lymphoma was the single most common malignant tumor, comprising 6(9%) of all the tumors, although as a group malignant germ cell tumors were still the most common malignant ovarian tumors in children and adolescents. Although germ cell tumors were the most common tumors in this age group (both benign and malignant), Burkitt lymphoma, a peculiar malignant tumor in this subregion, was the single most common malignant tumor of the ovary. PMID- 26630229 TI - Epithelioid Glomus Tumor of the Uterine Cervix: A Case Report and Review. AB - Herein, we report a case of epithelioid glomus tumor involving the uterine cervix. A 67-yr-old woman with a long-standing history of cervical dysplasia underwent cervical conization. In addition to the patient's high-grade squamous intraepithelial lesion, histologic examination demonstrated an incidental, 0.2-cm glomus tumor in the cervical submucosa. The tumor was composed of bland epithelioid cells in scattered nests closely associated with small-caliber blood vessels. Immunohistochemically, the tumor cells were diffusely positive for smooth muscle actin and caldesmon and only focally positive for desmin and CD34. To our knowledge, only 2 similar case reports exist in the literature. The present case is the first cervical case seen with epithelioid features and in association with cervical dysplasia. PMID- 26630228 TI - Clinicopathologic Analysis of Postchemotherapy Gestational Trophoblastic Neoplasia: An Entity Overlapping With Epithelioid Trophoblastic Tumor. AB - Surgery is generally not required for the majority of gestational trophoblastic neoplasias (GTNs) because they are potentially curable by chemotherapy alone. The histologic assessment is rarely available although the identification of a specific subtype of GTN is relevant to clinical intervention and prognostic prediction. In this study, we analyzed the clinicopathologic features of 4 postchemotherapy GTNs. They presented as a persistent uterine (Cases 1, 2, and 3) or pelvic mass (Case 4) with a raised serum beta-hCG level after multiple courses of chemotherapy. All patients were alive without evidence of disease at follow-up periods of 58 to 109 mo after surgery and salvage chemotherapy except for Case 4 which had a recurrent pelvic mass. These GTNs had a characteristic histopathologic pattern of extensive necrosis and a rim of scant viable mononucleated tumor cells at the periphery of the lesion. Immunostaining showed that these tumor cells had a lower Ki67 index than choriocarcinoma, and epithelioid trophoblastic cell tumor although they exhibited an epithelioid trophoblastic cell tumor-like immunostaining pattern (CD146, hPL, and p63). A small number of beta-hCG-positive multinucleated trophoblastic cells were also present in 3 of the 4 cases. We suggest that these postchemotherapy GTNs may represent a "snap shot" of the hypothetical choriocarcinoma-epithelioid trophoblastic cell tumor transition. Our findings should provide insights into the pathogenesis of GTNs. PMID- 26630230 TI - Virilizing Hilus Cell Tumor of the Ovary Associated With Efferent Ductules-like Metaplasia Within Paratubal Mesonephric Remnants. PMID- 26630231 TI - p16 Immunostaining Allows for Accurate Subclassification of Vulvar Squamous Cell Carcinoma Into HPV-Associated and HPV-Independent Cases. AB - The aim of this study was to compare morphologic assessment and p16 immunohistochemistry (IHC) in the determination of human papilloma virus (HPV) status in vulvar squamous cell carcinoma (VSCC). A total of 201 invasive VSCC cases were classified as "HPV-associated" when warty/basaloid VSCC or high-grade squamous intraepithelial lesion (vulvar intraepithelial neoplasia 2/3) was observed, or "HPV-independent" in the presence of well-differentiated keratinizing invasive SCC or differentiated vulvar intraepithelial neoplasia. For p16 IHC, strong nuclear and cytoplasmic staining of all cells in at least the lowermost third of the epithelium was scored as positive. All cases with discrepant HPV predictions by hematoxylin and eosin morphology versus p16 IHC were further analyzed by polymerase chain reaction for HPV DNA. On the basis of hematoxylin and eosin morphologic assessment, 50/201 tumors showed features suggestive of HPV-associated, and 47 of those showed p16 immunoreactivity (94% concordance). Of the 146 cases considered HPV-independent based on hematoxylin and eosin, 115 (79%) showed negative p16 immunostaining. Thus 83% (162/196) concordance between morphologic assessment and p16 IHC was observed, overall. In 34 cases, where morphologic assessment and p16 IHC did not agree, HPV polymerase chain reaction agreed with p16 IHC in 32/34 (94%). The sensitivity and specificity of p16 IHC in classification of VSCC as HPV-independent or HPV associated was 100% and 98.4%, respectively. Morphologic assessment and p16 IHC are concordant in classifying VSCC as HPV-independent or HPV-associated in a majority of cases (83%). Most of the discrepant cases are p16-positive well differentiated keratinizing VSCC, and HPV polymerase chain reaction supports classification of a large majority of these (94%) as HPV-associated. p16 IHC is validated as an accurate surrogate marker for determination of HPV status in VSCC. PMID- 26630232 TI - Application of a Pattern-based Classification System for Invasive Endocervical Adenocarcinoma in Cervical Biopsy, Cone and Loop Electrosurgical Excision (LEEP) Material: Pattern on Cone and LEEP is Predictive of Pattern in the Overall Tumor. AB - A pattern-based classification system has been recently proposed for invasive endocervical adenocarcinoma, which is predictive of the risk of nodal metastases. Identifying cases at risk of nodal involvement is most relevant at the time of biopsy and loop electrosurgical excision procedure (LEEP) to allow for optimal surgical planning, and, most importantly, consideration of lymphadenectomy. This study aims to determine the topography of patterns of stromal invasion in invasive endocervical adenocarcinoma with emphasis on patterns in biopsy, cone, and LEEP. Invasive pattern was assessed following the pattern-based classification (Patterns A, B, and C) in 47 invasive endocervical adenocarcinomas treated with hysterectomy or trachelectomy and correlated with pattern of invasion at the tumor surface (2 mm of tumor depth) and on preoperative biopsy and cone/LEEP. Patterns A, B, and C were present in 21.3%, 36.2%, and 42.5% of cases, respectively. Most pattern A cases were Stage IA (90%), whereas most Pattern B and C cases were Stage IB (76.5% and 80%, respectively). Horizontal spread was on average larger in Pattern C (24.1 mm) than in Patterns A and B (7.7 and 12.3 mm, respectively). Pattern at the tumor surface correlated with the overall pattern in 95.7% of cases. Concordance between patterns at cone/LEEP and hysterectomy was 92.8%; the only discrepant case was upgraded from Pattern A on LEEP to C on final excision. Agreement between patterns in biopsy and the overall tumor, however, was only 37.5%. In all discrepant cases, biopsy failed to reveal destructive invasion, which was evident on excision. All discrepant biopsies with pattern A showed glandular complexity resembling exophytic papillary growth but did not meet criteria for destructive invasion. On excision, marked gland confluence with papillary architecture was evident. We conclude that the pattern of invasion on cone/LEEP is a good predictor of pattern of invasion on hysterectomy, particularly if there is destructive invasion (B or C). Thus, pattern-based classification can be successfully applied in these samples to guide definitive surgical treatment. Prediction of the overall pattern based on biopsy material alone appears to be suboptimal. However, glandular confluence and complexity on biopsy, regardless of its size, appears to be associated with destructive invasion in the overall tumor. PMID- 26630233 TI - Cervical Carcinomas With Neuroendocrine Differentiation: A Report of 28 Cases With Immunohistochemical Analysis and Molecular Genetic Evidence of Common Clonal Origin With Coexisting Squamous and Adenocarcinomas. AB - Cervical neuroendocrine carcinomas are rare, aggressive tumors and their immunohistochemical features and clonal relationship to coexisting tumors are incompletely described. Twenty-eight cases were identified (17 small cell, 9 large cell, and 2 mixed), 10 of which had an invasive squamous or adenocarcinoma component. Staining for synaptophysin, chromogranin A, TTF1, c-kit, CD44, and p16 was performed. Analyses for loss of heterozygosity (LOH) at 5 polymorphic microsatellite markers (D3S1300, D9S171, D11S914, D13S319, and TP53) and X chromosome inactivation were performed. Of 17 cases with available blocks, 13 (76%) were synaptophysin+, 8 (47%) were chromogranin A+, 8 (47%) were TTF1+, 7 (41%) were c-kit+, and 6 (35%) were CD44+. Strong patchy or strong diffuse p16 staining was seen in all cases. LOH and X-chromosome inactivation analysis were performed for 17 cases, 8 of which had a coexisting squamous or adenocarcinoma component. Five of the 8 (63%) cases with 2 components showed allelic loss in both components. All 5 of these cases demonstrated identical LOH between the neuroendocrine and squamous or adenocarcinoma components. Nonrandom X-chromosome inactivation was seen in the neuroendocrine and other components in 4 of the 8 cases. In all 4 cases the pattern of inactivation was identical between the 2 components. Cervical neuroendocrine carcinomas have features similar to other extrapulmonary neuroendocrine carcinomas, including expression of TTF1, c-kit, and CD44. Consistent staining for p16 is also seen. Concordant genetic alterations support common clonal origin for neuroendocrine carcinomas with a coexisting squamous or adenocarcinoma component. PMID- 26630234 TI - Free-Standing Conducting Polymer Films for High-Performance Energy Devices. AB - Thick, uniform, easily processed, highly conductive polymer films are desirable as electrodes for solar cells as well as polymer capacitors. Here, a novel scalable strategy is developed to prepare highly conductive thick poly(3,4 ethylenedioxythiophene):polystyrene sulfonate (HCT-PEDOT:PSS) films with layered structure that display a conductivity of 1400 S cm(-1) and a low sheet resistance of 0.59 ohm sq(-1). Organic solar cells with laminated HCT-PEDOT:PSS exhibit a performance comparable to the reference devices with vacuum-deposited Ag top electrodes. More importantly, the HCT-PEDOT:PSS film delivers a specific capacitance of 120 F g(-1) at a current density of 0.4 A g(-1). All-solid-state flexible symmetric supercapacitors with the HCT-PEDOT:PSS films display a high volumetric energy density of 6.80 mWh cm(-3) at a power density of 100 mW cm(-3) and 3.15 mWh cm(-3) at a very high power density of 16160 mW cm(-3) that outperforms previous reported solid-state supercapacitors based on PEDOT materials. PMID- 26630235 TI - Insights into the Biosynthesis of Dehydroalanines in Goadsporin. AB - Dehydroalanines in goadsporin are proposed to be formed by GodF and GodG, which show slight homology to the N-terminal glutamylation and C-terminal elimination domains, respectively, of LanB, a class I lanthipeptide dehydratase. Although similar, separated-type LanBs are conserved among thiopeptides and indispensable for their biosynthesis and biological activities, these enzymes had not yet been characterized. Here, we identified goadsporin B, which has unmodified Ser4 and Ser14, from both godF and godG disruptants. The godG disruptant also produced goadsporin C, a glutamylated-Ser4 variant of goadsporin B. These results suggested that dehydroalanines are formed by glutamylation and glutamate elimination. NMR analysis revealed for the first time that the glutamyl group was attached to a serine via an ester bond, by the catalysis of LanB-type enzymes. Our findings provide insights into the function of separated-type LanBs involved in the biosynthesis of goadsporin and thiopeptides. PMID- 26630236 TI - Bigger Isn't Always Bigger. AB - As Aetna seeks to acquire Humana Inc. in a $37 billion deal, TMA and physicians across Texas worry the merger would weaken their contract negotiating power with health plans while shrinking already narrow provider networks. PMID- 26630237 TI - Reaching Patients Across the Web. AB - The explosion of social media and the expectations of frequently refreshed content have changed the rules for physicians and practices looking to market themselves and bolster their online reputation. Just as static websites have become a relatively archaic part of the online equation, the marketing expectations for physician and practice websites have changed substantially. PMID- 26630238 TI - Navigating Value Based Care. AB - TMA is collaborating with TMF Health Quality Institute to connect Texas physicians to free TMF resources that will better position doctors for the rapid transition to value-based payment. PMID- 26630239 TI - Holding Firm. AB - Medicine has tried to convince state lawmakers of the need to update antiquated Texas law to give physicians the power to hold dangerous patients for a finite length of time. PMID- 26630240 TI - Paying to Get Paid. AB - Some health plans and third-party vendors that process plan payments are moving to virtual credit cards, without warning and without much explanation of fees or opt-out procedures. Physician practices don't have to accept the financial and administrative costs associated with virtual cards. TMA officials say doctors have a choice and the right to demand that their payers issue payments via direct deposit. PMID- 26630241 TI - Structure-Property Relationships in Hydroxide-Exchange Membranes with Cation Strings and High Ion-Exchange Capacity. AB - A series of poly(2,4-dimethyl-1,4-phenylene oxide) hydroxide-exchange membranes (HEMs) with cation strings containing a well-defined number of cations (CS-n) and similar, high ion-exchange capacities are synthesized to investigate the effect of cation distribution on key HEM properties. As the number of cations on each string grows, the size of the ionic clusters increases from 10 to 55 nm. Well connected ion pathways and a hydrophobic framework are observed for n>=4. The enhanced phase segregation increases the hydroxide conductivity from CS-1 to CS-6 (30 to 65 mS cm(-1) ) and suppresses the water uptake (from 143 % to 62 %). Moreover, molar hydroxide conductivities for CS-n membranes show two distinctive stages as n increases: ~23 S cm(2) mol(-1) for n<=3; and ~34 cm(2) mol(-1) for n>=4. PMID- 26630242 TI - SERIAL "EN FACE" OPTICAL COHERENCE TOMOGRAPHY IMAGING OF SLOWLY RESORBING SUBRETINAL FLUID AFTER PNEUMATIC RETINOPEXY. AB - PURPOSE: To describe the use and utility of serial "en face" C-scan optical coherence tomography in following the postoperative subretinal fluid status in a patient after pneumatic retinopexy treatment of a rhegmatogenous retinal detachment. METHOD: Case study. RESULTS: Serial "en face" optical coherence tomography imaging enhanced postoperative follow-up of persistent subretinal fluid, demonstrating its spontaneous disappearance over time. CONCLUSION: Previous studies showed that subretinal fluid persists in a large proportion of patients after rhegmatogenous retinal detachment repair (especially in those with a chronic component). "En face" optical coherence tomography imaging is a valuable tool for demonstrating postoperative fluid status and aids in the ability of the practitioner to evaluate for spontaneous disappearance of fluid with time. PMID- 26630243 TI - INTRAVITREAL MELPHALAN AS SALVAGE THERAPY FOR REFRACTORY RETINAL AND SUBRETINAL RETINOBLASTOMA. AB - PURPOSE: This case series highlights the novel use of intravitreal melphalan for nonvitreous retinoblastoma. It assesses the efficacy and toxicity of intravitreal melphalan for nonvitreous retinoblastoma. METHODS: This observational small case series investigates three patients treated with intravitreal melphalan for nonvitreous retinoblastoma that was refractory to multiple-course ophthalmic artery chemosurgery. Patients' demographics, response to treatment, and toxicity of treatment as clinically evaluated are measured by electroretinogram. PATIENTS: Three eyes of three patients received a median of 7 weekly intravitreal melphalan injections (30 MUg/0.07 cc) for persistent retinal or subretinal tumors refractory to treatment with multiple-course ophthalmic artery chemosurgery. RESULTS: Eyes remain tumor free at a median of 14-month follow-up. One eye was enucleated because of a vitreous hemorrhage that obscured fundus details. One eye had extinguished electroretinogram recordings before injections and two eyes had a decrease in electroretinogram responses over the intravitreal treatment course. The eye with subretinal seeding demonstrated marked retinopathy by ophthalmoscopy and fluorescein angiography and one eye was enucleated because of the development of a vitreous hemorrhage. CONCLUSION: This small case series highlights that nonvitreous disease that is, refractory or persistent despite previous ophthalmic artery chemosurgery can regress with intravitreal melphalan. However, this treatment may result in retinal toxicity. PMID- 26630244 TI - ELEVATED INTRAOCULAR PRESSURE FOLLOWING PARS PLANA VITRECTOMY DUE TO TRAPPED GAS IN THE POSTERIOR CHAMBER. AB - PURPOSE: Elevated intraocular pressure is relatively common following pars plana vitrectomy and intraocular gas tamponade. We discuss a series of patients who experienced elevated intraocular pressure from pupillary block and angle closure secondary to trapped gas in the posterior chamber. METHODS: Case series. RESULTS: Case 1 is a patient who underwent pars plana vitrectomy for retinal detachment repair. The intraocular pressure was elevated on postoperative Day 3 because of trapped gas in the posterior chamber, and it did not lower with prone positioning, maximal medical therapy, and laser peripheral iridotomies. Aspiration of the trapped gas was done with the patient sitting upright using a 27-gauge needle at the limbus, which was curative. Case 2 provides anterior segment optical coherence tomography images that confirmed the location of the trapped gas resulting in angle closure. Case 3 demonstrates the unfortunate sequelae of a central retinal artery occlusion following delayed recognition of this entity. Case 4 highlights the challenges encountered when migratory gas is also seen elsewhere in the eye. CONCLUSION: Clinicians should be aware of elevated intraocular pressure secondary to trapped gas in the posterior chamber, which may be recalcitrant to medical therapy. Aspiration of the trapped gas can alleviate both pupillary block and angle closure without compromising the gas tamponade. PMID- 26630245 TI - ROLLER COASTER RETINOPATHY: CASE REPORT OF SYMPTOMATIC BILATERAL INTRARETINAL HEMORRHAGES AFTER SHAKING INJURY IN AN OTHERWISE HEALTHY ADULT. AB - PURPOSE: Traumatic head injuries not involving the eye have been known to cause retinal injury through multiple mechanisms. Abusive head trauma remains the prototypical example. We propose to demonstrate the first case of bilateral multiple retinal hemorrhages in a young healthy adult related to riding multiple theme park roller coasters. METHODS: The patient was evaluated with a complete ophthalmic examination including dilated extended ophthalmoscopy, fluorescein angiography, optical coherence tomography, and fundus photography. RESULTS: The patient was found to have a bilateral symptomatic macular retinopathy characterized by multiple intraretinal hemorrhages. Given the lack of other systemic findings and negative medical workup, her signs and symptoms were thought to be attributed to the same day attendance of a theme park and riding of multiple roller coasters. CONCLUSION: Theme park roller coasters, as well as other attractions, may affect the eye at the vitreoretinal interface. This type of acceleration-deceleration injury should be considered in the differential of an adolescent or adult patient with retinal hemorrhage in the absence of other pathologic processes to explain clinical findings. PMID- 26630246 TI - A novel algorithm for the calculation of physical and biological irradiation quantities in scanned ion beam therapy: the beamlet superposition approach. AB - The calculation algorithm of a modern treatment planning system for ion-beam radiotherapy should ideally be able to deal with different ion species (e.g. protons and carbon ions), to provide relative biological effectiveness (RBE) evaluations and to describe different beam lines. In this work we propose a new approach for ion irradiation outcomes computations, the beamlet superposition (BS) model, which satisfies these requirements. This model applies and extends the concepts of previous fluence-weighted pencil-beam algorithms to quantities of radiobiological interest other than dose, i.e. RBE- and LET-related quantities. It describes an ion beam through a beam-line specific, weighted superposition of universal beamlets. The universal physical and radiobiological irradiation effect of the beamlets on a representative set of water-like tissues is evaluated once, coupling the per-track information derived from FLUKA Monte Carlo simulations with the radiobiological effectiveness provided by the microdosimetric kinetic model and the local effect model. Thanks to an extension of the superposition concept, the beamlet irradiation action superposition is applicable for the evaluation of dose, RBE and LET distributions. The weight function for the beamlets superposition is derived from the beam phase space density at the patient entrance. A general beam model commissioning procedure is proposed, which has successfully been tested on the CNAO beam line. The BS model provides the evaluation of different irradiation quantities for different ions, the adaptability permitted by weight functions and the evaluation speed of analitical approaches. Benchmarking plans in simple geometries and clinical plans are shown to demonstrate the model capabilities. PMID- 26630247 TI - Carbon Capture in the Cement Industry: Technologies, Progress, and Retrofitting. AB - Several different carbon-capture technologies have been proposed for use in the cement industry. This paper reviews their attributes, the progress that has been made toward their commercialization, and the major challenges facing their retrofitting to existing cement plants. A technology readiness level (TRL) scale for carbon capture in the cement industry is developed. For application at cement plants, partial oxy-fuel combustion, amine scrubbing, and calcium looping are the most developed (TRL 6 being the pilot system demonstrated in relevant environment), followed by direct capture (TRL 4-5 being the component and system validation at lab-scale in a relevant environment) and full oxy-fuel combustion (TRL 4 being the component and system validation at lab-scale in a lab environment). Our review suggests that advancing to TRL 7 (demonstration in plant environment) seems to be a challenge for the industry, representing a major step up from TRL 6. The important attributes that a cement plant must have to be "carbon-capture ready" for each capture technology selection is evaluated. Common requirements are space around the preheater and precalciner section, access to CO2 transport infrastructure, and a retrofittable preheater tower. Evidence from the electricity generation sector suggests that carbon capture readiness is not always cost-effective. The similar durations of cement-plant renovation and capture-plant construction suggests that synchronizing these two actions may save considerable time and money. PMID- 26630248 TI - Disinvesting in Ineffective and Inappropriate Practice: The Neglected Side of Evidence-Based Health Care? PMID- 26630249 TI - Dialysis modality, vascular access and mortality in end-stage kidney disease: A bi-national registry-based cohort study. AB - AIM: There remains debate on which dialysis modality offers better survival outcomes for patients. We compare the survival of patients undergoing home haemodialysis (HD) with a permanent vascular access, facility HD with a permanent vascular access, facility HD with a central venous catheter or peritoneal dialysis. METHODS: We considered adult patients from the Australia and New Zealand Dialysis and Transplant Registry who commenced dialysis between 1 October 2003 and 31 December 2011. Patients were followed until death, transplant, loss to follow-up or 31 December 2011. Marginal structural models for mortality were used to account for time-varying treatment, comorbidities and baseline covariates. Unmeasured differences between treatment groups may remain even after adjustment for measured differences, so the potential effects of unmeasured confounding were explicitly modelled. RESULTS: There were 20,191 patients who underwent >=90 days of dialysis (median 2.25 years, interquartile range 1-3.75 years). There were significant differences in age, gender, comorbidities and other variables between treatment groups at baseline. Thirty per cent of patients had at least one treatment change. Relative to facility HD with permanent access, the risk of death for home HD patients with a permanent access was lower in the first year (at 9 months: hazard ratio 0.41, 95% CI 0.25-0.67, adjusted for all baseline covariates). Findings were robust to unmeasured confounding within plausible ranges. CONCLUSION: Relative to facility HD with permanent vascular access, home HD conferred better survival prospects, while peritoneal dialysis was associated with a higher risk and facility HD with a catheter the highest risk, especially within the first year of dialysis. PMID- 26630250 TI - Nonlinear Ballistic Transport in an Atomically Thin Material. AB - Ultrashort devices that incorporate atomically thin components have the potential to be the smallest electronics. Such extremely scaled atomically thin devices are expected to show ballistic nonlinear behavior that could make them tremendously useful for ultrafast applications. While nonlinear diffusive electron transport has been widely reported, clear evidence for intrinsic nonlinear ballistic transport in the growing array of atomically thin conductors has so far been elusive. Here we report nonlinear electron transport of an ultrashort single layer graphene channel that shows quantitative agreement with intrinsic ballistic transport. This behavior is shown to be distinctly different than that observed in similarly prepared ultrashort devices consisting, instead, of bilayer graphene channels. These results suggest that the addition of only one extra layer of an atomically thin material can make a significant impact on the nonlinear ballistic behavior of ultrashort devices, which is possibly due to the very different chiral tunneling of their charge carriers. The fact that we observe the nonlinear ballistic response at room temperature, with zero applied magnetic field, in non ultrahigh vacuum conditions and directly on a readily accessible oxide substrate makes the nanogap technology we utilize of great potential for achieving extremely scaled high-speed atomically thin devices. PMID- 26630251 TI - A Potent and Site-Selective Agonist of TRPA1. AB - TRPA1 is a member of the transient receptor potential (TRP) cation channel family that is expressed primarily on sensory neurons. This chemosensor is activated through covalent modification of multiple cysteine residues with a wide range of reactive compounds including allyl isothiocyanate (AITC), a spicy component of wasabi. The present study reports on potent and selective agonists of TRPA1, discovered through screening 1657 electrophilic molecules. In an effort to validate the mode of action of hit molecules, we noted a new TRPA1-selective agonist, JT010 (molecule 1), which opens the TRPA1 channel by covalently and site selectively binding to Cys621 (EC50 = 0.65 nM). The results suggest that a single modification of Cys621 is sufficient to open the TRPA1 channel. The TRPA1 selective probe described herein might be useful for further mechanistic studies of TRPA1 activation. PMID- 26630252 TI - Alternative lipid emulsions versus pure soy oil based lipid emulsions for parenterally fed preterm infants. AB - BACKGROUND: The pure soybean oil based lipid emulsions (S-LE) conventionally used for parenteral nutrition (PN) in preterm infants have high polyunsaturated fatty acid (PUFA) content. The newer lipid emulsions (LE) from alternative lipid sources with reduced PUFA content may improve clinical outcomes in preterm infants. OBJECTIVES: To determine the safety and efficacy of the newer alternative LE compared with the conventional S-LE for PN in preterm infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group (CNRG) to search the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 7), MEDLINE (1946 to 31 July 2015), EMBASE (1947 to 31 July 2015), CINAHL (1982 to 31 July 2015), Web of Science (31 July 2015), conference proceedings, trial registries (clinicaltrials.gov, controlled-trials.com, WHO's ICTRP), and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi randomised controlled trials in preterm infants (< 37 weeks), comparing newer alternative LE with S-LE. DATA COLLECTION AND ANALYSIS: Data collection and analysis conformed to the methods of the CNRG. We assessed the quality of evidence for important outcomes using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, in addition to reporting the conventional statistical significance of results. MAIN RESULTS: Fifteen studies (N = 979 infants) are included in this review. Alternative LE including medium chain triglycerides/long chain triglycerides (MCT/LCT) LE (3 studies; n = 108), MCT-olive-fish-soy oil-LE (MOFS-LE; 7 studies; n = 469), MCT-fish-soy oil-LE (MFS LE; 1 study; n = 60), olive-soy oil-LE (OS-LE; 7 studies; n = 406), and borage soy oil-LE (BS-LE; 1 study; n = 34) were compared with S-LE. The different LE were also considered together to compare 'all fish oil containing-LE' versus S-LE (7 studies; n = 499) and 'all alternative LE' versus S-LE (15 studies; n = 979). Some studies had multiple intervention arms and were included in more than one comparison. No study compared pure fish oil-LE or structured-LE to S-LE.The GRADE quality of evidence (GRADE QoE) ranged from 'low' to 'very low.' Evidence came mostly from small single centre studies, many focusing on biochemical aspects as their primary outcomes, with optimal information size not achieved for the important clinical outcomes in any comparison.In the primary outcomes of the review there was a pooled effect towards decreased bronchopulmonary dysplasia (BPD) in OS-LE vs S-LE (4 studies, n = 261) not reaching statistical significance (typical risk ratio (RR) 0.69, 95% confidence interval (CI) 0.46 to 1.04, I2 = 32%; typical risk difference (RD) -0.08, 95% CI -0.17 to 0.00, I2 = 76%; GRADE QoE: 'very low'). No difference in BPD was observed in any other comparison. There were no statistically significant differences in the primary outcomes of death, growth rate (g/kg/day) or days to regain birth weight in any comparison.Retinopathy of prematurity (ROP) stage 1-2 was reported to be statistically significantly lower in one single centre study (n = 80) in the MOFS LE group compared with the S-LE group (1/40 vs 12/40, respectively; RR 0.08, 95% CI 0.01 to 0.61; RD -0.27, 95% CI -0.43 to -0.12; number needed to benefit (NNTB) 4, 95% CI 2 to 8). However there were no statistically significant differences in the secondary outcome of ROP >= stage 3 in any of the individual studies or in any comparison (GRADE QoE: 'low' to 'very low'). No other study reported on ROP stages 1 and 2 separately.There were no statistically significant differences in the secondary outcomes of sepsis, PN associated liver disease (PNALD)/cholestasis, ventilation duration, necrotising enterocolitis (NEC) >= stage 2, jaundice requiring treatment, intraventricular haemorrhage grade III-IV, periventricular leukomalacia (PVL), patent ductus arteriosus (PDA), hypertriglyceridaemia, and hyperglycaemia in any comparison.No study reported on neurodevelopmental outcomes or essential fatty acid deficiency. AUTHORS' CONCLUSIONS: All lipid emulsions in this review appeared to be safe and were well tolerated in preterm infants. Compared with the pure soy oil based LE, use of MOFS-LE was associated with a decrease in the early stages (1-2) of ROP in one study. However there were no statistically significant differences in clinically important outcomes including death, growth, BPD, sepsis, ROP >= stage 3, and PNALD with the use of newer alternative LE versus the conventional pure soy oil based LE (GRADE QoE ranged from 'low' to 'very low'). Currently there is insufficient evidence to recommend any alternative LE over S-LE or vice versa in preterm infants.Larger randomised studies focusing on important clinical outcomes, targeting specific 'at risk' population subgroups (e.g. extreme prematurity, long term PN, etc), and exploring the effect of different proportions of lipid constituents are required to evaluate the effectiveness of newer lipid emulsions compared with the conventional pure soy based LE in preterm infants. PMID- 26630253 TI - A Stationary Reaction Current Effect in Mesoporous Pt/ZrO2 System Under H2/O2 Environment. AB - There have been many works analyzing thermionic currents and chemicurrents generated on various electrolyte-free metal/semiconductor nanostructures. More recently, the chemicurrent phenomenon was reported for mesoporous Pt/semiconductor systems adept at converting surface-released chemical energy into a stationary electrical signal at room-temperature conditions. The present work points out the existence of an entire class of such surface-driven functional nanosystems. Here, the reaction current generation of Pt/ZrO2 systems was studied at room temperature under exposure to oxyhydrogen environments for mesoporous zirconia; this nanostructure was capable of the continuous oxidation of hydrogen, producing a long-standing stationary current. Synthesis parameters during the anodization process were manipulated to control sample pore density and the average pore diameter. Deposited via wide-angle PVD sputtering, the Pt phase forms an electrically continuous topographical nanomesh layer, and thus the Pt/ZrO2/gas interface is regulated through the manipulation of zirconia porosity. We observed reaction current enhancements with increasing porosity due to the lengthening of the Pt/ZrO2 interface. The most porous sample was significantly more sensitive to initial hydrogen additions, pointing toward the spillover of positive ionic charge across the Pt/ZrO2 interface as the origin of the observed electromotive force. PMID- 26630256 TI - Hydrophilic Hollow Molecularly Imprinted Polymer Microparticles with Photo- and Thermoresponsive Template Binding and Release Properties in Aqueous Media. AB - A facile, general, and efficient approach to prepare hydrophilic hollow molecularly imprinted polymer (MIP) microparticles with photo- and thermoresponsive template binding and release behaviors in aqueous media is described, which includes the preparation of uniform "living" silica submicrospheres bearing surface atom transfer radical polymerization (ATRP) initiating groups (i.e., alkyl halide groups) via a one-pot sol-gel method, their subsequent grafting of azobenzene (azo)-containing MIP shell and poly(N isopropylacrylamide)-block-poly(2-hydroxyethyl methacrylate) (PNIPAAm-b-PHEMA) brushes via successive surface-initiated ATRP, and final removal of the silica core. The successful synthesis of such hydrophilic hollow MIP microparticles was confirmed with SEM, FT-IR, water dispersion stability, and static contact angle studies. They proved to show apparently higher template binding capacities than the corresponding solid ones and obvious photo- and thermoresponsive template binding properties in aqueous solutions. Moreover, their pronounced light- and temperature-controlled template release in aqueous media was also demonstrated. In particular, the introduction of PNIPAAm-b-PHEMA brushes onto hollow MIP microparticles imparted them with high surface hydrophilicity both below and above the lower critical solution temperature of PNIPAAm, which paves the way for their applications in such areas as controlled drug/chemical delivery and smart bioanalysis. PMID- 26630257 TI - Teachers' Promotion or Inhibition of Children's Aggression Depends on Peer-Group Characteristics. AB - Researchers have increasingly started to pay attention to how contextual factors, such as the classroom peer context and the quality of student-teacher interactions, influence children's aggressive behavior. This longitudinal study was designed to examine the degree to which benefits and costs of different teaching practices (child-centered and child-dominated) would be dependent on the initial peer-group composition (aggregate levels of aggression and victimization at the beginning of first grade). Teachers provided ratings of aggression and victimization (N = 523 first-grade students; M age at the beginning of first grade = 7.49 years, SD = 0.52). Information about different teaching practices was obtained via observations. Our results show that whereas child-centered practices are beneficial in high-victimization classrooms, child-dominated practices inhibit the development of aggression in low-victimization classroom contexts. Our findings highlight the importance of moving beyond main-effect models to studying how different contextual influences interact to promote, or inhibit, the development of aggression. PMID- 26630258 TI - Comment on "Computational Study on the Vinyl Azide Decomposition". PMID- 26630259 TI - Validity and reliability of 6-a-side small-sided game locomotor performance in assessing physical fitness in football players. AB - In order to determine whether small-sided game (SSG) locomotor performance can serve as a fitness indicator, we (1) compared 6-a-side (6v6) SSG-intensity of players varying in fitness and skill, (2) examined the relationship of the 6v6 SSG and Yo-Yo IR2 and (3) assessed the reliability of the 6v6-SSG. Thirty-three professional senior, 30 professional youth, 62 amateur and 16 professional woman football players performed 4 * 7 min 6v6-SSGs recorded by a Local Position Measurement system. A substantial subgroup (N = 113) also performed the Yo-Yo IR2. Forty-seven amateur players performed two or three 6v6-SSGs. No differences in 6v6-SSG time-motion variables were found between professional senior and professional youth players. Amateurs showed lower values than professional seniors on almost all time-motion variables (ES = 0.59-1.19). Women displayed lower high-intensity time-motion variables than all other subgroups. Total distance run during 6v6-SSG was only moderately related to Yo-Yo IR2 distance (r = 0.45), but estimated metabolic power, high speed (>14.4 km . h(-1)), high acceleration (>2 m . s(-2)), high power (>20 W . kg(-1)) and very high (35 W . kg(-1)) power showed higher correlations (r = 0.59-0.70) with Yo-Yo IR2 distance. Intraclass correlation coefficient values were higher for total distance (0.84) than other time-motion variables (0.74-0.78). Although total distance and metabolic power during 6v6-SSG showed good reproducibility (coefficient of variation (CV) < 5%), CV was higher (8-14%) for all high-intensity time-motion variables. It was therefore concluded that standardised SSG locomotor performance cannot serve used as a valid and reliable fitness indicator for individual players. PMID- 26630260 TI - Advancing treatment options for chronic idiopathic constipation. AB - INTRODUCTION: Chronic constipation is a global problem affecting all ages and associated with considerable morbidity and significant financial burden for society. Though formerly defined on the basis of a single symptom, infrequent defecation; constipation is now viewed as a syndrome encompassing several complaints such as difficulty with defecation, a sense of incomplete evacuation, hard stools, abdominal discomfort and bloating. AREAS COVERED: The expanded concept of constipation has inevitably led to a significant change in outcomes in clinical trials, as well as in patient expectations from new therapeutic interventions. The past decades have also witnessed a proliferation in therapeutic targets for new agents. Foremost among these have been novel prokinetics, a new category, prosecretory agents and innovative approaches such as inhibitors of bile salt transport. In contrast, relatively few effective therapies exist for the management of those anorectal and pelvic floor problems that result in difficult defecation. EXPERT OPINION: Though constipation is a common and often troublesome disorder, many of those affected can resolve their symptoms with relatively simple measures. For those with more resistant symptoms a number of novel, effective and safe options now exist. Those with defecatory difficulty (anismus, pelvic floor dysfunction) continue to represent a significant management challenge. PMID- 26630261 TI - Improving the Network Scale-Up Estimator: Incorporating Means of Sums, Recursive Back Estimation, and Sampling Weights. AB - Researchers interested in studying populations that are difficult to reach through traditional survey methods can now draw on a range of methods to access these populations. Yet many of these methods are more expensive and difficult to implement than studies using conventional sampling frames and trusted sampling methods. The network scale-up method (NSUM) provides a middle ground for researchers who wish to estimate the size of a hidden population, but lack the resources to conduct a more specialized hidden population study. Through this method it is possible to generate population estimates for a wide variety of groups that are perhaps unwilling to self-identify as such (for example, users of illegal drugs or other stigmatized populations) via traditional survey tools such as telephone or mail surveys--by asking a representative sample to estimate the number of people they know who are members of such a "hidden" subpopulation. The original estimator is formulated to minimize the weight a single scaling variable can exert upon the estimates. We argue that this introduces hidden and difficult to predict biases, and instead propose a series of methodological advances on the traditional scale-up estimation procedure, including a new estimator. Additionally, we formalize the incorporation of sample weights into the network scale-up estimation process, and propose a recursive process of back estimation "trimming" to identify and remove poorly performing predictors from the estimation process. To demonstrate these suggestions we use data from a network scale-up mail survey conducted in Nebraska during 2014. We find that using the new estimator and recursive trimming process provides more accurate estimates, especially when used in conjunction with sampling weights. PMID- 26630262 TI - Characterization of Proliferating Neural Progenitors after Spinal Cord Injury in Adult Zebrafish. AB - Zebrafish can repair their injured brain and spinal cord after injury unlike adult mammalian central nervous system. Any injury to zebrafish spinal cord would lead to increased proliferation and neurogenesis. There are presences of proliferating progenitors from which both neuronal and glial loss can be reversed by appropriately generating new neurons and glia. We have demonstrated the presence of multiple progenitors, which are different types of proliferating populations like Sox2+ neural progenitor, A2B5+ astrocyte/ glial progenitor, NG2+ oligodendrocyte progenitor, radial glia and Schwann cell like progenitor. We analyzed the expression levels of two common markers of dedifferentiation like msx-b and vimentin during regeneration along with some of the pluripotency associated factors to explore the possible role of these two processes. Among the several key factors related to pluripotency, pou5f1 and sox2 are upregulated during regeneration and associated with activation of neural progenitor cells. Uncovering the molecular mechanism for endogenous regeneration of adult zebrafish spinal cord would give us more clues on important targets for future therapeutic approach in mammalian spinal cord repair and regeneration. PMID- 26630264 TI - Structure of the Varicella Zoster Virus Thymidylate Synthase Establishes Functional and Structural Similarities as the Human Enzyme and Potentiates Itself as a Target of Brivudine. AB - Varicella zoster virus (VZV) is a highly infectious human herpesvirus that is the causative agent for chicken pox and shingles. VZV encodes a functional thymidylate synthase (TS), which is the sole enzyme that produces dTMP from dUMP de novo. To study substrate binding, the complex structure of TSVZV with dUMP was determined to a resolution of 2.9 A. In the absence of a folate co-substrate, dUMP binds in the conserved TS active site and is coordinated similarly as in the human encoded TS (TSHS) in an open conformation. The interactions between TSVZV with dUMP and a cofactor analog, raltitrexed, were also studied using differential scanning fluorimetry (DSF), suggesting that TSVZV binds dUMP and raltitrexed in a sequential binding mode like other TS. The DSF also revealed interactions between TSVZV and in vitro phosphorylated brivudine (BVDUP), a highly potent anti-herpesvirus drug against VZV infections. The binding of BVDUP to TSVZV was further confirmed by the complex structure of TSVZV and BVDUP solved at a resolution of 2.9 A. BVDUP binds similarly as dUMP in the TSHS but it induces a closed conformation of the active site. The structure supports that the 5-bromovinyl substituent on BVDUP is likely to inhibit TSVZV by preventing the transfer of a methylene group from its cofactor and the subsequent formation of dTMP. The interactions between TSVZV and BVDUP are consistent with that TSVZV is indeed a target of brivudine in vivo. The work also provided the structural basis for rational design of more specific TSVZV inhibitors. PMID- 26630266 TI - Correction: Differential microRNA Expression in Fast- and Slow-Twitch Skeletal Muscle of Piaractus mesopotamicus during Growth. PMID- 26630263 TI - Targeting ubiquitination for cancer therapies. AB - Ubiquitination, the structured degradation and turnover of cellular proteins, is regulated by the ubiquitin-proteasome system (UPS). Most proteins that are critical for cellular regulations and functions are targets of the process. Ubiquitination is comprised of a sequence of three enzymatic steps, and aberrations in the pathway can lead to tumor development and progression as observed in many cancer types. Recent evidence indicates that targeting the UPS is effective for certain cancer treatment, but many more potential targets might have been previously overlooked. In this review, we will discuss the current state of small molecules that target various elements of ubiquitination. Special attention will be given to novel inhibitors of E3 ubiquitin ligases, especially those in the SCF family. PMID- 26630265 TI - Analysis of Microtubule-Associated-Proteins during IBA-Mediated Adventitious Root Induction Reveals KATANIN Dependent and Independent Alterations of Expression Patterns. AB - Adventitious roots (AR) are post embryonic lateral organs that differentiate from non-root tissues. The understanding of the molecular mechanism which underlies their differentiation is important because of their central role in vegetative plant propagation. Here it was studied how the expression of different microtubule (MT)-associated proteins (MAPs) is affected during AR induction, and whether expression differences are dependent on MT organization itself. To examine AR formation when MTs are disturbed we used two mutants in the MT severing protein KATANIN. It was found that rate and number of AR primordium formed following IBA induction for three days was reduced in bot1-1 and bot1-7 plants. The reduced capacity to form ARs in bot1-1 was associated with altered expression of MAP-encoding genes along AR induction. While the expression of MAP65-4, MAP65-3, AURORA1, AURORA2 and TANGLED, increased in wild-type but not in bot1-1 plants, the expression of MAP65-8 and MDP25 decreased in wild type plants but not in the bot1-1 plant after two days of IBA-treatment. The expression of MOR1 was increased two days after AR induction in wild type and bot1-1 plants. To examine its expression specifically in AR primordium, MOR1 upstream regulatory sequence was isolated and cloned to regulate GFP. Expression of GFP was induced in the primary root tips and lateral roots, in the pericycle of the hypocotyls and in all stages of AR primordium formation. It is concluded that the expression of MAPs is regulated along AR induction and that reduction in KATANIN expression inhibits AR formation and indirectly influences the specific expression of some MAPs. PMID- 26630267 TI - Oocyte Scoring Enhances Embryo-Scoring in Predicting Pregnancy Chances with IVF Where It Counts Most. AB - CONTEXT: Our center's quality improvement optimization process on many occasions anecdotally suggested that oocyte assessments might enhance embryo assessment in predicting pregnancy chances with in vitro fertilization (IVF). OBJECTIVE: To prospectively compare a morphologic oocyte grading system to standard day-3 morphologic embryo assessment. DESIGN, SETTING, PATIENTS: We prospectively investigated in a private academically-affiliated infertility center 94 consecutive IVF cycles based on 6 criteria for oocyte quality: morphology, cytoplasm, perivitelline space (PVS), zona pellucida (ZP), polar body (PB) and oocyte size, each assigned a value of -1 (worst), 0 (average) or +1 (best), so establishing an average total oocyte score (TOS). Embryo assessment utilized grade and cell numbers of each embryo on day-3 after oocyte retrieval. Clinical pregnancy was defined by presence of at least one intrauterine gestational sac. INTERVENTIONS: Standard IVF cycles in infertile women. MAIN OUTCOME MEASURES: Predictability of pregnancy based on oocyte and embryo-grading systems. RESULTS: Average age for all patients was 36.5 +/- 7.3 years; mean oocyte yield was 7.97+/ 5.76; Patient specific total oocyte score (PTOS) was -1.05 +/- 2.24. PTOS, adjusted for patient age, was directly related to odds of increased embryo cell numbers (OR 1.12, P = 0.025), embryo grade (OR 1.19, P < 0.001) and clinical pregnancy [OR 1.58 (95%CI 1.23 to 2.02), P < 0.001]. Restricting the analysis to day three embryos of high quality (8-cell/ good grades), TOS was still predictive of clinical pregnancy (OR 2.08 (95%CI 1.26 to 3.44, P = 0.004). Among the 69 patients with embryos of Grade 4 or better available for transfer 23 achieved Clinical Pregnancy. When the analysis was restricted to the 69 transfers with good quality embryos (>= Grade 4) the Oocyte Scoring System (TOS) (AUC+/-SE 0.863+/-0.044, oocyte score) provided significantly greater predictive value for clinical pregnancy compared to the embryo grade alone (AUC 0.646 +/- 0.072, embryo grade) p = 0.015. CONCLUSIONS: Oocyte-scoring, thus, provides useful clinical information especially in good prognosis patients with large numbers of high quality embryos. This finding appears of particular importance at a time when many IVF centers are committing sizable investments to closed incubation systems with time-lapse photography, which are exclusively meant to define embryo morphology. PMID- 26630269 TI - Regularly patterned multi-section GaN nanorod arrays grown with a pulsed growth technique. AB - The growth of regularly patterned multi-section GaN nanorod (NR) arrays based on a pulsed growth technique with metalorganic chemical vapor deposition is demonstrated. Such an NR with multiple sections of different cross-sectional sizes is formed by tapering a uniform cross section to another through stepwise decreasing of the Ga supply duration to reduce the size of the catalytic Ga droplet. Contrast line structures are observed in either a scanning electron microscopy or transmission electron microscopy image of an NR. Such a contrast line-marker corresponds to a thin Ga-rich layer formed at the beginning of GaN precipitation of a pulsed growth cycle and illustrates the boundary between two successive growth cycles in pulsed growth. By analyzing the geometry variation of the contrast line-markers, the morphology evolution in the growth of a multi section NR, including a tapering process, can be traced. Such a morphology variation is controlled by the size of the catalytic Ga droplet and its coverage range on the slant facets at the top of an NR. The comparison of emission spectra between single-, two-, and three-section GaN NRs with sidewall InGaN/GaN quantum wells indicates that a multi-section NR can lead to a significantly broader sidewall emission spectrum. PMID- 26630268 TI - Physical Performance and Physical Activity in Older Adults: Associated but Separate Domains of Physical Function in Old Age. AB - BACKGROUND: Physical function is a crucial factor in the prevention and treatment of health conditions in older adults and is usually measured objectively with physical performance tests and/or physical activity monitoring. OBJECTIVE: To examine whether 1) physical performance (PP) and physical activity (PA) constitute separate domains of physical function; 2) differentiation of PA classes is more informative than overall PA. DESIGN: Cross-sectional study to explore the relationships within and among PP and PA measures. METHODS: In 49 older participants (83 +/- 7 years; M +/- SD), performance-based tests were conducted and PA was measured for one week. Activity monitor data were reduced in terms of duration, periods, and mean duration of periods of lying, sitting, standing and locomotion. The relation between and within PP scores and PA outcomes were analysed using rank order correlation and factor analysis. RESULTS: Factor structure after varimax rotation revealed two orthogonal factors explaining 78% of the variance in the data: one comprising all PA variables and one comprising all PP variables. PP scores correlated moderately with PA in daily life. Differentiation of activity types and quantification of their duration, intensity and frequency of occurrence provided stronger associations with PP, as compared to a single measure of acceleration expressing overall PA. LIMITATIONS: For independent validation, the conclusions about the validity of the presented conceptual framework and its clinical implications need to be confirmed in other studies. CONCLUSIONS: PP and PA represent associated but separate domains of physical function, suggesting that an improvement of PP does not automatically imply an increase of PA, i.e. a change to a more active lifestyle. Differentiation of activity classes in the analysis of PA provides more insights into PA and its association with PP than using a single overall measure of acceleration. PMID- 26630270 TI - Caring for Blind Parents: Cost to the Education and Well-Being of Children in Tamale, Ghana. AB - In this study we explored the experiences of the guide children (children who guide adults with visual impairment to beg for a living on the streets) in Tamale, Ghana, to unearth the impact of the guiding role on their educational participation and well-being. Data were gathered from 104 children and 57 adults using a set of questionnaires and interviews. The results showed that adults chose many of the children to take on the guide role and many of the children did not attend school. The implications for the children's well-being are discussed in relation to needs and rights. PMID- 26630271 TI - The Effects of Individualized Resistance Strength Programs on Knee Muscular Imbalances in Junior Elite Soccer Players. AB - The purpose of this study was to investigate the effects of a resistance training program on the muscular strength of soccer players' knees that initially presented unilateral and bilateral differences. For this study, a team of 24 male well-trained junior soccer players was divided into two strength program training groups: a Resistance Training Control Group (RTCG) composed of 10 players that did not have muscular imbalances and a Resistance Training Experimental Group (RTEG) composed of 14 players that had muscular imbalances. All players followed a resistance training program for six weeks, two times per week, during the transition period. The program of individualized strength training consisted of two parts. The first part, which was identical in terms of the choice of training loads, was intended for both training groups and contained two series of exercises including upper and lower body exercises. The second part of the program was intended only for RTEG and consisted of two additional series for the groups of muscles that had identified unilateral and bilateral differences. The applied program showed various directions in the isokinetic profile of changes. In the case of RTCG, the adaptations related mainly to the quadriceps muscle (the peak torque (PT) change for the dominant leg was statistically significant (p < 0.05)). There were statistically significant changes in RTEG (p < 0.05) related to PT for the hamstrings in both legs, which in turn resulted in an increase in the conventional hamstring/quadriceps ratio (H/Q). It is interesting that the statistically significant (p < 0.05) changes were noted only for the dominant leg. No statistically significant changes in bilateral differences (BD) were noted in either group. These results indicate that individualized resistance training programs could provide additional benefits to traditional strength training protocols to improve muscular imbalances in post-adolescent soccer players. PMID- 26630273 TI - Maternal Smoking during Pregnancy and Daughters' Preeclampsia Risk. AB - BACKGROUND: An obstetrical paradox is that maternal smoking is protective for the development of preeclampsia. However, there are no prior studies investigating the risk of preeclampsia in women who were exposed to tobacco smoking during their own fetal period. We aimed to study the subsequent risk of preeclampsia in women who were exposed to tobacco smoke in utero, using a national population based register. METHODS: Data were obtained from the Medical Birth Register of Sweden for women who were born in 1982 (smoking data first recorded) or after, who had given birth to at least one child; 153 885 pregnancies were included. RESULTS: The associations between intrauterine smoking exposure (three categories: non-smokers, 1-9 cigarettes/day [moderate exposure], and >9 cigarettes/day [heavy exposure]) and subsequent preeclampsia (n = 5721) were assessed using logistic regressions. In models adjusted for maternal age, parity and own smoking, the odds ratios (OR) for preeclampsia were 1.06 [95% CI: 0.99,1.13 for moderate intrauterine exposure, and 1.18, [95% CI: 1.10,1.27] for heavy exposure. Estimates were slightly strengthened in non-smoking women who experienced heavy intrauterine exposure (adjusted OR 1.24 [95% CI: 1.14,1.34]). Results were no longer statistically significant after adjustment for the woman's own BMI, gestational age and birthweight Z-scores. CONCLUSION: These data revealed some evidence of a possible weak positive association between intrauterine smoking exposure and the risk of subsequent preeclampsia, however, results were not significant over all manifestations of preeclampsia and confounder adjustment. The increased risk might be mediated through exposed women's own BMI or birthweight. PMID- 26630272 TI - Combination of alpha-Tomatine and Curcumin Inhibits Growth and Induces Apoptosis in Human Prostate Cancer Cells. AB - alpha-Tomatine is a glycoalkaloid found in tomatoes and curcumin is a major yellow pigment of turmeric. In the present study, the combined effect of these two compounds on prostate cancer cells was studied. Treatment of different prostate cancer cells with curcumin or alpha-tomatine alone resulted in growth inhibition and apoptosis in a concentration-dependent manner. Combinations of alpha-tomatine and curcumin synergistically inhibited the growth and induced apoptosis in prostate cancer PC-3 cells. Effects of the alpha-tomatine and curcumin combination were associated with synergistic inhibition of NF-kappaB activity and a potent decrease in the expression of its downstream gene Bcl-2 in the cells. Moreover, strong decreases in the levels of phospho-Akt and phosphor ERK1/2 were found in PC-3 cells treated with alpha-tomatine and curcumin in combination. In animal experiment, SCID mice with PC-3 xenograft tumors were treated with alpha-tomatine and curcumin. Combination of alpha-tomatine and curcumin more potently inhibited the growth of PC-3 tumors than either agent alone. Results from the present study indicate that alpha-tomatine in combination with curcumin may be an effective strategy for inhibiting the growth of prostate cancer. PMID- 26630276 TI - Lectures/Symposia. PMID- 26630274 TI - C-Terminal Fragment of Agrin (CAF): A Novel Marker for Progression of Kidney Disease in Type 2 Diabetics. AB - BACKGROUND: Diabetes is the leading cause of CKD in the developed world. C terminal fragment of agrin (CAF) is a novel kidney function and injury biomarker. We investigated whether serum CAF predicts progression of kidney disease in type 2 diabetics. METHODS: Serum CAF levels were measured in 71 elderly patients with diabetic nephropathy using a newly developed commercial ELISA kit (Neurotune(r)). Estimated glomerular filtration rate (eGFR) and proteinuria in spot urine were assessed at baseline and after 12 months follow up. The presence of end stage renal disease (ESRD) was evaluated after 24 months follow-up. Correlation and logistic regression analyses were carried out to explore the associations of serum CAF levels with GFR, proteinuria, GFR loss and incident ESRD. Renal handling of CAF was tested in neurotrypsin-deficient mice injected with recombinant CAF. RESULTS: We found a strong association of serum CAF levels with eGFR and a direct association with proteinuria both at baseline (r = 0.698, p<0.001 and r = 0. 287, p = 0.02) as well as after 12 months follow-up (r = 0.677, p<0.001 and r = 0.449, p<0.001), respectively. Furthermore, in multivariate analysis, serum CAF levels predicted eGFR decline at 12 months follow-up after adjusting for known risk factors (eGFR, baseline proteinuria) [OR (95%CI) = 4.2 (1.2-14.5), p = 0.024]. In mice, injected CAF was detected in endocytic vesicles of the proximal tubule. CONCLUSION: Serum CAF levels reflect renal function and are highly associated with eGFR and proteinuria at several time points. Serum CAF was able to predict subsequent loss of renal function irrespective of baseline proteinuria in diabetic nephropathy. CAF is likely removed from circulation by glomerular filtration and subsequent endocytosis in the proximal tubule. These findings may open new possibilities for clinical trial design, since serum CAF levels may be used as a selection tool to monitor kidney function in high-risk patients with diabetic nephropathy. PMID- 26630275 TI - Even a Chronic Mild Hyperglycemia Affects Membrane Fluidity and Lipoperoxidation in Placental Mitochondria in Wistar Rats. AB - It is known the deleterious effects of diabetes on embryos, but the effects of diabetes on placenta and its mitochondria are still not well known. In this work we generated a mild hyperglycemia model in female wistar rats by intraperitoneal injection of streptozotocin in 48 hours-old rats. The sexual maturity onset of the female rats was delayed around 6-7 weeks and at 16 weeks-old they were mated, and sacrificed at day 19th of pregnancy. In placental total tissue and isolated mitochondria, the fatty acids composition was analyzed by gas chromatography, and lipoperoxidation was measured by thiobarbituric acid reactive substances. Membrane fluidity in mitochondria was measured with the excimer forming probe dipyrenylpropane and mitochondrial function was measured with a Clark-type electrode. The results show that even a chronic mild hyperglycemia increases lipoperoxidation and decreases mitochondrial function in placenta. Simultaneously, placental fatty acids metabolism in total tissue is modified but in a different way than in placental mitochondria. Whereas the chronic mild hyperglycemia induced a decrease in unsaturated to saturated fatty acids ratio (U/S) in placental total tissue, the ratio increased in placental mitochondria. The measurements of membrane fluidity showed that fluidity of placenta mitochondrial membranes increased with hyperglycemia, showing consistency with the fatty acids composition through the U/S index. The thermotropic characteristics of mitochondrial membranes were changed, showing lower transition temperature and activation energies. All of these data together demonstrate that even a chronic mild hyperglycemia during pregnancy of early reproductive Wistar rats, generates an increment of lipoperoxidation, an increase of placental mitochondrial membrane fluidity apparently derived from changes in fatty acids composition and consequently, mitochondrial malfunction. PMID- 26630277 TI - Oral Presentation. PMID- 26630278 TI - Poster Session. PMID- 26630279 TI - The Role of Informative and Ambiguous Feedback in Avoidance Behavior: Empirical and Computational Findings. AB - Avoidance behavior is a critical component of many psychiatric disorders, and as such, it is important to understand how avoidance behavior arises, and whether it can be modified. In this study, we used empirical and computational methods to assess the role of informational feedback and ambiguous outcome in avoidance behavior. We adapted a computer-based probabilistic classification learning task, which includes positive, negative and no-feedback outcomes; the latter outcome is ambiguous as it might signal either a successful outcome (missed punishment) or a failure (missed reward). Prior work with this task suggested that most healthy subjects viewed the no-feedback outcome as strongly positive. Interestingly, in a later version of the classification task, when healthy subjects were allowed to opt out of (i.e. avoid) responding, some subjects ("avoiders") reliably avoided trials where there was a risk of punishment, but other subjects ("non-avoiders") never made any avoidance responses at all. One possible interpretation is that the "non-avoiders" valued the no-feedback outcome so positively on punishment based trials that they had little incentive to avoid. Another possible interpretation is that the outcome of an avoided trial is unspecified and that lack of information is aversive, decreasing subjects' tendency to avoid. To examine these ideas, we here tested healthy young adults on versions of the task where avoidance responses either did or did not generate informational feedback about the optimal response. Results showed that provision of informational feedback decreased avoidance responses and also decreased categorization performance, without significantly affecting the percentage of subjects classified as "avoiders." To better understand these results, we used a modified Q-learning model to fit individual subject data. Simulation results suggest that subjects in the feedback condition adjusted their behavior faster following better-than-expected outcomes, compared to subjects in the no-feedback condition. Additionally, in both task conditions, "avoiders" adjusted their behavior faster following worse-than-expected outcomes, and treated the ambiguous no-feedback outcome as less rewarding, compared to non-avoiders. Together, results shed light on the important role of ambiguous and informative feedback in avoidance behavior. PMID- 26630280 TI - The application of the linear quadratic model to compensate the effects of prolonged fraction delivery time on a Balb/C breast adenocarcinoma tumor: An in vivo study. AB - Purpose To investigate the effect of increasing the overall treatment time as well as delivering the compensating doses on the Balb/c breast adenocarcinoma (4T1) tumor. Materials and methods A total of 72 mice were divided into two aliquots (classes A and B) based on the initial size of their induced tumor. Each class was divided into a control and several treatment groups. Among the treatment groups, group 1 was continuously exposed to 2 Gy irradiation, and groups 2 and 3 received two subfractions of 1 Gy over the total treatment times of 30 and 60 min, respectively. To investigate the effect of compensating doses, calculated based on the developed linear quadratic model (LQ) model, the remaining two groups (groups 4 and 5) received two subfractions of 1.16 and 1.24 Gy over the total treatment times of 30 and 60 min, respectively. The growing curves, Tumor Growth Time (TGT), Tumor Growth Delay Time (TGDT) and the survival of the animals were studied. Results For class A (tumor size <= 30 mm(3)), the average tumor size in the irradiated groups 1-5 was considerably different compared to the control group as one unit (day) change in time, by amount of 160.8, -158.9, +39.4 and +44.0, respectively. While these amounts were +22.0, +17.9, -21.7 and -0.1 for class B (tumor size >= 400 mm(3)). For the class A of animals, the TGT and TGDT parameters were significantly lower (0 <= 0.05) for the groups 2 and 3, compared to group 1. There was no significant difference (p > 0.05) between groups 1, 4 and 5 in this class. There was no significant difference (p > 0.05) between all the treated groups in class B. Conclusions Increasing total treatment time affects the radiobiological efficiency of treatment especially in small-sized tumor. The compensating doses derived from the LQ model can be used to compensate the effects of prolonged treatment times at in vivo condition. PMID- 26630281 TI - Three New Species of Phytotelm-Breeding Melanophryniscus from the Atlantic Rainforest of Southern Brazil (Anura: Bufonidae). AB - Three new species of Melanophryniscus are described from the Serra do Mar mountain range of the state of Santa Catarina, southern Brazil. All species are found at intermediate to high altitudes and share phytotelm-breeding as their reproductive strategy. The new species are distinguished from other phytotelm breeding Melanophryniscus based on different combinations of the following traits: snout-vent length, presence of white and/or yellow spots on forearms, mouth, belly and cloaca, pattern and arrangement of warts, and presence and number of corneous spines. The discovery of these species in a rather restricted geographical area suggests that the diversity of phytotelm-breeding species of Melanophryniscus might be severely underestimated. The conservation status of these species is of particular concern, given that one of them is at risk of extinction not only due to its restricted habitat, but also because of anthropogenic disturbances. PMID- 26630283 TI - An integrated microfluidic system for diagnosis of the resistance of Helicobacter pylori to quinolone-based antibiotics. AB - Helicobacter pylori (H. pylori) is a species of bacteria that can colonize the human stomach mucosa. It is closely associated with gastric diseases such as ulcer and inflammation. Recently, some H. pylori strains were found to express resistance to a family of antibiotics known as quinolones due to single-point mutations. Although traditional polymerase chain reaction (PCR) and molecular diagnostic-based approaches can be used to determine the presence and abundance of antibiotic-resistant H. pylori strains, such processes are relatively expensive, labor-intensive, and require bulky and costly equipment. This study therefore reports an advanced diagnostic assay performed on an integrated microfluidic system for rapid detection of antibiotic resistance in H. pylori. The assay features three components: (1) nucleic acid extraction by specific probe-conjugated magnetic beads, (2) amplification of the target deoxyribonucleic acid (DNA) fragments by using single-nucleotide-polymorphism polymerase chain reaction (SNP-PCR), and (3) optical detection of the PCR products. The device integrates several microfluidic components including micro-pumps, normally-closed micro-valves, and reaction chambers such that the entire diagnostic assay can be automatically executed on a single microfluidic system within one hour with detection limits of 10(0), 10(2), and 10(2) bacterial cells for H. pylori detection and two different SNP sites strains. Three PCR-based assays for determining presence of H. pylori infection and two DNA single-point mutation assays aimed at determining whether the infected strains were resistant to quinolone can be performed simultaneously on a single chip, suggesting that this microfluidic system could be a promising tool for rapid diagnosis of the presence of antibiotic-resistant H. pylori strains. PMID- 26630284 TI - Flexible opto-electronics enabled microfluidics systems with cloud connectivity for point-of-care micronutrient analysis. AB - In developing countries, the deployment of medical diagnostic technologies remains a challenge because of infrastructural limitations (e.g. refrigeration, electricity), and paucity of health professionals, distribution centers and transportation systems. Here we demonstrate the technical development and clinical testing of a novel electronics enabled microfluidic paper-based analytical device (EE-MUPAD) for quantitative measurement of micronutrient concentrations in decentralized, resource-limited settings. The system performs immune-detection using paper-based microfluidics, instrumented with flexible electronics and optoelectronic sensors in a mechanically robust, ultrathin format comparable in size to a credit card. Autonomous self-calibration, plasma separation, flow monitoring, timing and data storage enable multiple devices to be run simultaneously. Measurements are wirelessly transferred to a mobile phone application that geo-tags the data and transmits it to a remote server for real time tracking of micronutrient deficiencies. Clinical tests of micronutrient levels from whole blood samples (n=95) show comparable sensitivity and specificity to ELISA-based tests. These results demonstrate instantaneous acquisition and global aggregation of diagnostics data using a fully integrated point of care system that will enable rapid and distributed surveillance of disease prevalence and geographical progression. PMID- 26630282 TI - ITS and trnH-psbA as Efficient DNA Barcodes to Identify Threatened Commercial Woody Angiosperms from Southern Brazilian Atlantic Rainforests. AB - The Araucaria Forests in southern Brazil are part of the Atlantic Rainforest, a key hotspot for global biodiversity. This habitat has experienced extensive losses of vegetation cover due to commercial logging and the intense use of wood resources for construction and furniture manufacturing. The absence of precise taxonomic tools for identifying Araucaria Forest tree species motivated us to test the ability of DNA barcoding to distinguish species exploited for wood resources and its suitability for use as an alternative testing technique for the inspection of illegal timber shipments. We tested three cpDNA regions (matK, trnH psbA, and rbcL) and nrITS according to criteria determined by The Consortium for the Barcode of Life (CBOL). The efficiency of each marker and selected marker combinations were evaluated for 30 commercially valuable woody species in multiple populations, with a special focus on Lauraceae species. Inter- and intraspecific distances, species discrimination rates, and ability to recover species-specific clusters were evaluated. Among the regions and different combinations, ITS was the most efficient for identifying species based on the 'best close match' test; similarly, the trnH-psbA + ITS combination also demonstrated satisfactory results. When combining trnH-psbA + ITS, Maximum Likelihood analysis demonstrated a more resolved topology for internal branches, with 91% of species-specific clusters. DNA barcoding was found to be a practical and rapid method for identifying major threatened woody angiosperms from Araucaria Forests such as Lauraceae species, presenting a high confidence for recognizing members of Ocotea. These molecular tools can assist in screening those botanical families that are most targeted by the timber industry in southern Brazil and detecting certain species protected by Brazilian legislation and could be a useful tool for monitoring wood exploitation. PMID- 26630285 TI - Supportless electrochemical sensor based on molecularly imprinted polymer modified nanoporous microrod for determination of dopamine at trace level. AB - In this work, we developed a novel freestanding metallic microrod as working electrode for highly sensitive and selective electrochemical detection of trace dopamine (DA). The electrode was facilely fabricated via first dealloying smooth Au-Ag alloy microrod (AMR) into nanoporous Au-Ag alloy microrod (NPAMR) and further modifying with electro-polymerized molecularly imprinted polymer (MIP). Influencing factors during electro-polymerization process including pH value and molar ratio of monomer to template molecule were optimized. Under the optimal conditions, a linear range from 2 * 10(-13) to 2 * 10(-8)M for measuring DA was obtained with an ultralow detection limit of 7.63 * 10(-14)M (S/N=3). In addition, the MIP-modified electrode (MIP/NPAMR) was successfully employed to test DA in serum and brain samples. PMID- 26630286 TI - Transmedulla Neurons in the Sky Compass Network of the Honeybee (Apis mellifera) Are a Possible Site of Circadian Input. AB - Honeybees are known for their ability to use the sun's azimuth and the sky's polarization pattern for spatial orientation. Sky compass orientation in bees has been extensively studied at the behavioral level but our knowledge about the underlying neuronal systems and mechanisms is very limited. Electrophysiological studies in other insect species suggest that neurons of the sky compass system integrate information about the polarization pattern of the sky, its chromatic gradient, and the azimuth of the sun. In order to obtain a stable directional signal throughout the day, circadian changes between the sky polarization pattern and the solar azimuth must be compensated. Likewise, the system must be modulated in a context specific way to compensate for changes in intensity, polarization and chromatic properties of light caused by clouds, vegetation and landscape. The goal of this study was to identify neurons of the sky compass pathway in the honeybee brain and to find potential sites of circadian and neuromodulatory input into this pathway. To this end we first traced the sky compass pathway from the polarization-sensitive dorsal rim area of the compound eye via the medulla and the anterior optic tubercle to the lateral complex using dye injections. Neurons forming this pathway strongly resembled neurons of the sky compass pathway in other insect species. Next we combined tracer injections with immunocytochemistry against the circadian neuropeptide pigment dispersing factor and the neuromodulators serotonin, and gamma-aminobutyric acid. We identified neurons, connecting the dorsal rim area of the medulla to the anterior optic tubercle, as a possible site of neuromodulation and interaction with the circadian system. These neurons have conspicuous spines in close proximity to pigment dispersing factor-, serotonin-, and GABA-immunoreactive neurons. Our data therefore show for the first time a potential interaction site between the sky compass pathway and the circadian clock. PMID- 26630287 TI - Size Reduction in Early European Domestic Cattle Relates to Intensification of Neolithic Herding Strategies. AB - Our analysis of over 28,000 osteometric measurements from fossil remains dating between c. 5600 and 1500 BCE reveals a substantial reduction in body mass of 33% in Neolithic central European domestic cattle. We investigate various plausible explanations for this phenotypic adaptation, dismissing climatic change as a causal factor, and further rejecting the hypothesis that it was caused by an increase in the proportion of smaller adult females in the population. Instead we find some support for the hypothesis that the size decrease was driven by a demographic shift towards smaller newborns from sub-adult breeding as a result of intensifying meat production strategies during the Neolithic. PMID- 26630288 TI - Aboveground Whitefly Infestation Modulates Transcriptional Levels of Anthocyanin Biosynthesis and Jasmonic Acid Signaling-Related Genes and Augments the Cope with Drought Stress of Maize. AB - Up to now, the potential underlying molecular mechanisms by which maize (Zea mays L.) plants elicit defense responses by infestation with a phloem feeding insect whitefly [Bemisia tabaci (Genn.)] have been barely elucidated against (a)biotic stresses. To fill this gap of current knowledge maize plants were infested with whitefly and these plants were subsequently assessed the levels of water loss. To understand the mode of action, plant hormone contents and the stress-related mRNA expression were evaluated. Whitefly-infested maize plants did not display any significant phenotypic differences in above-ground tissues (infested site) compared with controls. By contrast, root (systemic tissue) biomass was increased by 2-fold by whitefly infestation. The levels of endogenous indole-3-acetic acid (IAA), jasmonic acid (JA), and hydrogen peroxide (H2O2) were significantly higher in whitefly-infested plants. The biosynthetic or signaling-related genes for JA and anthocyanins were highly up-regulated. Additionally, we found that healthier plants were obtained in whitefly-infested plants under drought conditions. The weight of whitefly-infested plants was approximately 20% higher than that of control plants at 14 d of drought treatment. The drought tolerance-related genes, ZmbZIP72, ZmSNAC1, and ZmABA1, were highly expressed in the whitefly-infected plants. Collectively, our results suggest that IAA/JA-derived maize physiological changes and correlation of H2O2 production and water loss are modulated by above ground whitefly infestation in maize plants. PMID- 26630289 TI - Dissipation of hydrological tracers and the herbicide S-metolachlor in batch and continuous-flow wetlands. AB - Pesticide dissipation in wetland systems with regard to hydrological conditions and operational modes is poorly known. Here, we investigated in artificial wetlands the impact of batch versus continuous-flow modes on the dissipation of the chiral herbicide S-metolachlor (S-MET) and hydrological tracers (bromide, uranine and sulforhodamine B). The wetlands received water contaminated with the commercial formulation Mercantor Gold((r)) (960 g L(-1) of S-MET, 87% of the S enantiomer). The tracer mass budget revealed that plant uptake, sorption, photo- and presumably biodegradation were prominent under batch mode (i.e. characterized by alternating oxic-anoxic conditions), in agreement with large dissipation of S MET (90%) under batch mode. Degradation was the main dissipation pathway of S-MET in the wetlands. The degradate metolachlor oxanilic acid (MOXA) mainly formed under batch mode, whereas metolachlor ethanesulfonic acid (MESA) prevailed under continuous-flow mode, suggesting distinct degradation pathways in each wetland. R enantiomer was preferentially degraded under batch mode, which indicated enantioselective biodegradation. The release of MESA and MOXA by the wetlands as well as the potential persistence of S-MET compared to R-MET under both oxic and anoxic conditions may be relevant for groundwater and ecotoxicological risk assessment. This study shows the effect of batch versus continuous modes on pollutant dissipation in wetlands, and that alternate biogeochemical conditions under batch mode enhance S-MET biodegradation. PMID- 26630292 TI - Photostable ester-substituted bis-cyclometalated cationic iridium(III) complexes for continuous monitoring of oxygen. AB - Three bis-cyclometalated cationic Ir(iii) complexes , and with an ester substituent at the 4-position of the phenyl ring on the 2-phenylpyridine (ppy) have been synthesized and fully characterized. The emission maxima of ester substituted Ir(iii) complexes show a notable blue-shift compared to the parent complex [Ir(ppy)2(phen)](+)PF6(-) (phen = 1,10-phenanthroline). The influence of an ester group on the photoelectric properties of the Ir(iii) complexes has been investigated systematically. The oxygen sensing films prepared from ethyl cellulose immobilized with Ir(iii) complexes exhibit excellent operational stability, high photostability and a quick response to oxygen. show extended luminescence lifetimes relative to , and display better sensitivity to changes in oxygen partial pressure. PMID- 26630290 TI - Euterpe oleracea Mart.-Derived Polyphenols Protect Mice from Diet-Induced Obesity and Fatty Liver by Regulating Hepatic Lipogenesis and Cholesterol Excretion. AB - The aim of this study was to investigate the effect of a polyphenol-rich Acai seed extract (ASE, 300 mg/kg-1d-1) on adiposity and hepatic steatosis in mice that were fed a high-fat (HF) diet and its underlying mechanisms based on hepatic lipid metabolism and oxidative stress. Four groups were studied: C57BL/6 mice that were fed with standard diet (10% fat, Control), 10% fat + ASE (ASE), 60% fat (HF), and 60% fat + ASE (HF + ASE) for 12 weeks. We evaluated the food intake, body weight gain, serum glucose and lipid profile, hepatic cholesterol and triacyglycerol (TG), hepatic expression of pAMPK, lipogenic proteins (SREBP-1c, pACC, ACC, HMG-CoA reductase) and cholesterol excretion transporters, ABCG5 and ABCG8. We also evaluated the steatosis in liver sections and oxidative stress. ASE reduced body weight gain, food intake, glucose levels, accumulation of cholesterol and TG in the liver, which was associated with a reduction of hepatic steatosis. The increased expressions of SREBP-1c and HMG-CoA reductase and reduced expressions of pAMPK and pACC/ACC in HF group were antagonized by ASE. The ABCG5 and ABCG8 transporters expressions were increased by the extract. The antioxidant effect of ASE was demonstrated in liver of HF mice by restoration of SOD, CAT and GPx activities and reduction of the increased levels of malondialdehyde and protein carbonylation. In conclusion, ASE substantially reduced the obesity and hepatic steatosis induced by HF diet by reducing lipogenesis, increasing cholesterol excretion and improving oxidative stress in the liver, providing a nutritional resource for prevention of obesity-related adiposity and hepatic steatosis. PMID- 26630291 TI - Dynamics of Fat Mass in DUhTP Mice Selected for Running Performance - Fat Mobilization in a Walk. AB - OBJECTIVE: Reduction of body fat can be achieved by dietary programs and/or aerobic exercise training. More convenient methods to rid the body of excess fat are needed. However, it is unclear whether it is possible to more easily lose body weight at all. METHODS: DUhTP mice bred through phenotype selection for high treadmill performance and unselected controls were voluntarily physically active in a running wheel over a period of 3 weeks. Phenotypical data were collected, and subcutaneous fat was analyzed for expression of mitochondria-relevant proteins. RESULTS: Voluntary physical activity over 3 weeks exclusively in DUhTP mice severely reduced subcutaneous (-38%; p < 0.05) and epididymal (-32%; p < 0.05) fat. Following mild physical activity, subcutaneous fat derived from DUhTP mice showed increased levels of long chain acyl dehydrogenase (LCAD; +230%; p < 0.05) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-alpha; p < 0.01). Mitochondrial transcription factor A (Tfam) expression was similar in both sedentary genotypes but physical activity increased Tfam levels exclusively in DUhTP (p < 0.05). CONCLUSION: Our findings indicate that the mitochondrial mass is highly active in DUhTP mice and responsive even to mild physical activity. While genetic predisposition could not prevent fat accretion in DUhTP mice, voluntary activity was sufficient to reduce excess body fat almost completely. PMID- 26630294 TI - New HIV prevention methods: recognizing boundaries between individual autonomy and public policies. PMID- 26630293 TI - Paeoniflorin ameliorates symptoms of experimental Sjogren's syndrome associated with down-regulating Cyr61 expression. AB - Paeoniflorin (PF), an active compound extracted from Paeony root, has been used in therapy of autoimmune diseases with effective clinical efficiency and higher safety. Sjogren's syndrome (SS) is a chronic, systemic, immune-mediated inflammatory disease. In this study, we demonstrated that novel pro-inflammatory factor Cyr61/CCN1 was up-regulated in epithelial cells of salivary glands of primary SS patients and submandibular gland autoantigen-induced experimental SS mice. Blocking Cyr61 expression with special monoclonal antibody improved saliva secretion by ameliorating inflammatory infiltration and cytokines production in vivo. Furthermore, we showed that PF could alleviate inflammation by down regulating Cyr61 expression in experimental SS mice. In conclusion, our new findings revealed for the first time that Cyr61 involves the pathogenesis of primary SS and PF alleviates SS-like symptoms associated with inhibiting Cyr61 expression, providing new insights into the potential molecular mechanism of PF in primary SS treatment. PMID- 26630295 TI - Global targets, local epidemics: the ultimate challenge for AIDS in Brazil? PMID- 26630296 TI - The Peer and Non-peer: the potential of risk management for HIV prevention in contexts of prostitution. AB - Sex workers have been the protagonists and focus of HIV prevention campaigns and research since the late 1980s in Brazil. Through a review of national and international literature, combined with a history of sex workers' involvement in the construction of the Brazilian response, this article explores the overlaps and disconnects between research and practice in contexts of prostitution over the past three decades. We review the scientific literature on the epidemiology of HIV among sex workers and prevention methodologies. We conclude that although research focus and designs often reinforce the idea that sex workers' vulnerability is due to their sexual relationships with clients, their greatest vulnerability has been found to be with their nonpaying intimate partners. Few studies explore their work contexts and structural factors that influence safe sex practices with both types of partners. The negative effects of criminalization, stigma, and exclusively biomedical and peer education-based approaches are well documented in the scientific literature and experiences of sex worker activists, as is the importance of prevention programs that combine empowerment and human rights-based approach to reduce HIV infection rates. We conclude that there is a need for actions, policies, and research that encompass the environment and context of sex workers' lives and reincorporate the human rights and citizenship frame that dominated the Brazilian response until the end of the 2000s. As part of HIV prevention efforts, female sex workers need to be considered above all as women, equal to all others. PMID- 26630297 TI - What is the benefit of the biomedical and behavioral interventions in preventing HIV transmission? AB - INTRODUCTION: Scientific evidence supports the synergy between biomedical and behavioral interventions aimed at preventing the transmission of HIV as a strategy to eradicate AIDS. OBJECTIVE: To characterize comparatively the benefits from biomedical and behavioral interventions to prevent HIV transmission. METHODS: Narrative review. We performed a comparative analysis of the benefits of studied interventions by means of estimating the number needed to treat (NNT). Evaluated interventions: counseling activities for behavior change to prevent exposure to HIV; antiretroviral pre-exposure prophylaxis (PrEP) and antiretroviral post-exposure prophylasis (PEP) for HIV and treatment of serodiscordant couples as a strategy for prevention of HIV transmission (TasP). RESULTS: counseling interventions and TasP have smaller NNTs, equal to, respectively, 11 (95%CI 9 - 18) at 12 months and 34 (95%CI 23 - 54) in 42 months comparatively to PrEP interventions, that resulted in 41 (95%CI 28 - 67) individuals receiving antiretrovirals in order to prevent one case of HIV infection at 36 months for men and serodiscordant couples. PEP interventions are associated with protective effects estimated at 81%. Lack of trials evaluating PEP prevents estimate of NNT. CONCLUSION: The estimate of the NNT can be a helpful parameter in the comparison between the effectiveness of different behavioral and biomedical HIV prevention strategies. Studies evaluating the benefit and safety of combined behavioral and biomedical interventions are needed, especially considering the attributable fraction of each component. Integration of behavioral and biomedical interventions is required to achieve complete suppression of the virus, and thus reducing viral replication, infectivity and the number of cases. PMID- 26630298 TI - The effect of prevention methods on reducing sexual risk for HIV and their potential impact on a large-scale: a literature review. AB - A spectrum of diverse prevention methods that offer high protection against HIV has posed the following challenge: how can national AIDS policies with high coverage for prevention and treatment make the best use of new methods so as to reverse the current high, and even rising, incidence rates among specific social groups? We conducted a narrative review of the literature to examine the prevention methods and the structural interventions that can have a higher impact on incidence rates in the context of socially and geographically concentrated epidemics. Evidence on the protective effect of the methods against sexual exposure to HIV, as well as their limits and potential, is discussed. The availability and effectiveness of prevention methods have been hindered by structural and psychosocial barriers such as obstacles to adherence, inconsistent use over time, or only when individuals perceive themselves at higher risk. The most affected individuals and social groups have presented limited or absence of use of methods as this is moderated by values, prevention needs, and life circumstances. As a result, a substantial impact on the epidemic cannot be achieved by one method alone. Programs based on the complementarity of methods, the psychosocial aspects affecting their use and the mitigation of structural barriers may have the highest impact on incidence rates, especially if participation and community mobilization are part of their planning and implementation. PMID- 26630299 TI - Revisiting the use of condoms in Brazil. AB - INTRODUCTION: It is known that a single prevention strategy is not enough to control multiple HIV epidemics around the world and in Brazil. However, it is not only necessary to recognize the importance of condoms as part of the policy of HIV/AIDS prevention but also discuss its limits. In this article, we aim to investigate the use of condoms in Brazil, draw critical reflections, and understand how they can once again be highlighted in Brazil's prevention strategy going forward. METHODS: A narrative review of literature was conducted using keywords in PubMed. Reports from national surveys that guide the epidemiological and behavioral surveillance of the Brazilian Ministry of Health were also included. RESULTS: A total of 40 articles and 3 reports were included in the review and 11 intervention studies to promote the condom use; the main findings were as follows: 1) Despite the increase in national studies on sexual behavior, little attention is given to the role of condom use; 2) There are few studies examining the factors associated with condom use among key populations such as men who have sex with men (MSM), female sex workers (FSW), drug users (DU), and transvestites and transexuals (TT), while substantial studies focus on adolescents and women; 3) Evidence suggests that a combination of interventions is more effective. DISCUSSION: new prevention technologies must not lose sight of the critical importance of condoms, and efforts to reintroduce them should focus on the role of pleasure in addition to their potential to minimize the risk of HIV. PMID- 26630300 TI - Sex, human rights and AIDS: an analysis of new technologies for HIV prevention in the Brazilian context. AB - Worldwide, HIV prevention is challenged to change because clinical trials show the protective effect of technologies such as circumcision, preexposure prophylaxis, and the suppression of viral load through antiretroviral treatment. In the face of demands for their implementation on population levels, the fear of stimulating risk compensation processes and of increasing riskier sexual practices has retarded their integration into prevention programs. In this article, following a narrative review of the literature on risk compensation using the PubMed database, we offer a critical reflection on the theme using a constructionist approach of social psychology integrated to the theoretical framework of vulnerability and human rights. The use of biomedical technologies for prevention does not consistently induce its users to the increase of riskier practices, and variations on the specificity of each method need to be carefully considered. Alternatives to the theories of sociocognitive studies, such as social constructionist approaches developed in the social sciences and humanities fields, indicate more comprehensive interpretations, valuing the notions of agency and rights. The critical analysis suggests priority actions to be taken in the implementation process: development of comprehensive programs, monitoring and fostering dialog on sexuality, and technical information. We highlight the need to implement a human rights-based approach and to prioritize dialog, stressing how complementary these technologies can be to meet different population needs. We conclude by stressing the need to prioritize sociopolitical changes to restore participation, dialog about sexuality, and emphasis on human rights such as core elements of the Brazilian AIDS policy. PMID- 26630301 TI - Technologies for HIV prevention and care: challenges for health services. AB - This article aims to consider some relevant challenges to the provision of "new prevention technologies" in health services in a scenario where the "advances" in the global response to AIDS control are visible. We take as material for analysis the information currently available on the HIV post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP), treatment as prevention (TASP) and over the counter. The methodology consisted of the survey and analysis of the Biblioteca Virtual em Saude (BVS: MEDLINE, LILACS, WHOLIS, PAHO, SciELO) articles that addressed the issue of HIV prevention and care in the context of so-called new prevention technologies. The results of the studies show that there is assistance on the ground of clinics for the treatment of disease responses, but there are several challenges related to the sphere of prevention. The articles list some challenges regarding to management, organization of services and the attention given by health professionals to users. The current context shows evidence of the effectiveness of antiretroviral therapy in reducing the risk of HIV transmission, but the challenges for the provision of preventive technologies in health services permeate health professionals and users in their individual dimensions and health services in organizational and structural dimension. Interventions should be made available in a context of community mobilization; there should be no pressure on people to make HIV testing, antiretroviral treatment or for prevention. In the management is responsible for the training of health professionals to inform, clarify and make available to users, partners and family information about the new antiretroviral use strategies. PMID- 26630302 TI - Critical remarks on strategies aiming to reduce drug related harm: substance misuse and HIV/AIDS in a world in turmoil. AB - In the last decades, the initiatives implemented under the conceptual umbrella of Harm Reduction have gained momentum, with a vigor and scope (both from a geographic and social perspective) never seen before. A more balanced reevaluation could and should rather say such initiatives have resumed, to a large extent, ideas and actions launched much earlier, in the first decades of the 20th century. Notwithstanding, the dissemination of HIV/AIDS in recent years conferred an exceptional visibility and legitimacy to proposals formerly viewed as subsidiary or openly neglected. Nowadays, initiatives inspired by the Harm Reduction philosophy have faced an "identity crisis", not secondary (according to our perspective) to challenges faced by its concepts and operations, but rather as consequence of a world in a turmoil. Such fast-changing dynamics have reconfigured both drug scenes and the patterns and prospects of HIV/AIDS worldwide. This article briefly summarizes some of such recent, ongoing, changes, which have been deeply affecting both concepts and practices to the point of asking for a deep reformulation of most of the initiatives implemented so far. PMID- 26630303 TI - Prevention of the heterosexual HIV infection among women: Is it possible to think about strategies without considering their reproductive demands? AB - This article aims to discuss the prevention of the heterosexual HIV infection among women, considering and relationship between this practice and their reproductive demands, based on a critical analysis of the recent literature on the issue. It is assumed the relative exhaustion in the discourse about male condom use in all sexual relations, and the need to recognize that for many women in childbearing age, HIV prevention cannot be dissociated of the contraception practices, although the symbolic and technologically distinction between them. Furthermore, not always the contexts in which the sex occurs allows preventive practices. Women are different, and also their risks, vulnerabilities and needs, and this differences must be identified. The adequacy of preventive strategies to their particularities and situations experienced by each requires an effort of incorporation of available scientific knowledge to the actions taken by the health services, as well as conducting research on specific points relating to heterosexual practices. PMID- 26630304 TI - The invisibility of heterosexuality in HIV/AIDS prevention for men. AB - Heterosexual men have been a forgotten group for HIV/AIDS interventions and research. Our goal was to identify the different elements that interfere in the prevention of HIV/AIDS among heterosexual men, covering both traditional methods of prevention (especially safe sex practices and testing) and new strategies for prevention (pre- and post-sexual exposure prophylaxis, prevention treatment, and circumcision) in this population. This exploratory article consists of a nonsystematic review of the literature. We discuss the invisibility of heterosexual men in policies, in programs, and in health services. The several interventions analyzed are still poorly monitored and evaluated, so there is a lack of consistent evidence regarding the impact of prevention strategies in this population. Different masculinities, including hegemonic conceptions of masculinity, must be the foundation for interventions targeting men. Men must not be seen merely as a "bridge" in the spread of the HIV/AIDS epidemic, but also as victims of gender patterns that make them vulnerable. PMID- 26630305 TI - Different preventions methods lead to different choices? Questions on HIV/AIDS prevention for men who have sex with men and other vulnerable populations. AB - On the basis of an ethnographic narrative on sexual interactions observed in urban parks in large Brazilian cities, the article discusses the adoption of new strategies and methods for AIDS prevention in vulnerable populations, especially in men who have sex with men (MSM). By following some guiding questions, the text debates when, why, with whom, and in which context the new prevention methods should be adopted. It emphasizes, in agreement to the initial narrative, the importance of taking into account the prevention strategies created by the population itself to manage HIV risk infection. It also addresses how prevention practices and messages are adapted and recreated by individuals and groups in an attempt to suit them to their sexual desires, practices, and choices. In this perspective, the article recommends the inclusion of the experiences and voices of individuals and groups considered vulnerable in the new AIDS prevention methods and programs targeted to them. PMID- 26630306 TI - Strategies to prevent HIV transmission to serodiscordant couples. AB - INTRODUCTION: The use antiretroviral reduces the sexual transmission of HIV, expanding interventions for serodiscordant couples. OBJECTIVE: This article aims to review the use of antiretroviral and other prevention interventions among serodiscordant couples and to analyze its use in Brazil. METHODS: A retrospective review was performed through the MEDLINE database and bases included in the Biblioteca Virtual em Saude. RESULTS: The articles recovered exhibit four main strategies: (1) condom; (2) reduction of risks in sexual practices; (3) use of antiretrovirals, particularly early initiation of antiretroviral therapy (TASP) and pre-exposure prophylaxis (PrEP); (4) risk reduction in reproduction. DISCUSSION: TASP is highly effective in reducing sexual transmission, PrEP was tested in serodiscordant couples and both reduce the sexual transmission risk in different sexual practices, enabling individualized prevention strategies. CONCLUSIONS: When used in combination, antiretrovirals and sexual practices with condoms offer greater efficacy than any single strategy. The combined use of new and old strategies allows us to build a prevention policy for all. PMID- 26630307 TI - Effect of oral administration of Kudoa septempunctata genotype ST3 in adult BALB/c mice. AB - Kudoa septempunctata (Myxozoa: Multivalvulida) infects the muscles of olive flounder (Paralichthys olivaceus, Paralichthyidae) in the form of spores. To investigate the effect of K. septempunctata spores in mammals, adult BALB/c mice were fed with spores of K. septempunctata genotype ST3 (1.35 * 10(5) to 1.35 * 10(8) spores/mouse). After ingestion of spores, the mice remained clinically normal during the 24-h observation period. No spores were found in any tissue examined by histopathological screening. Quantitative PCR screening of the K. septempunctata 18S rDNA gene revealed that the K. septempunctata spores were detected only in the stool samples from the spore-fed groups. Collectively, these findings suggest that K. septempunctata spores are excreted in faeces and do not affect the gastrointestinal tract of adult mice. PMID- 26630309 TI - Effect of Acute Dietary Nitrate Consumption on Oxygen Consumption During Submaximal Exercise in Hypobaric Hypoxia. AB - Reduced partial pressure of oxygen impairs exercise performance at altitude. Acute nitrate supplementation, at sea level, may reduce oxygen cost during submaximal exercise in hypobaric hypoxia. Therefore, we investigated the metabolic response during exercise at altitude following acute nitrate consumption. Ten well-trained (61.0 +/- 7.4 ml/kg/min) males (age 28 +/- 7 yr) completed 3 experimental trials (T1, T2, T3). T1 included baseline demographics, a maximal aerobic capacity test (VO2max) and five submaximal intensity cycling determination bouts at an elevation of 1600 m. A 4-day dietary washout, minimizing consumption of nitrate-rich foods, preceded T2 and T3. In a randomized, double-blind, placebo-controlled, crossover fashion, subjects consumed either a nitrate-depleted beetroot juice (PL) or ~12.8 mmol nitrate rich (NR) beverage 2.5 hr before T2 and T3. Exercise at 3500 m (T2 and T3) via hypobaric hypoxia consisted of a 5-min warm-up (25% of normobaric VO2max) and four 5-min cycling bouts (40, 50, 60, 70% of normobaric VO2max) each separated by a 4-min rest period. Cycling RPM and watts for each submaximal bout during T2 and T3 were determined during T1. Preexercise plasma nitrite was elevated following NR consumption compared with PL (1.4 +/- 1.2 and 0.7 +/- 0.3 uM respectively; p < .05). There was no difference in oxygen consumption (-0.5 +/- 1.8, 0.1 +/- 1.7, 0.7 +/- 2.1, and 1.0 +/- 3.0 ml/kg/min) at any intensity (40, 50, 60, 70% of VO2max, respectively) between NR and PL. Further, respiratory exchange ratio, oxygen saturation, heart rate and rating of perceived exertion were not different at any submaximal intensity between NR and PL either. Blood lactate, however, was reduced following NR consumption compared with PL at 40 and 60% of VO2max (p < .0.05). Our findings suggest that acute nitrate supplementation before exercise at 3500 m does not reduce oxygen cost but may reduce blood lactate accumulation at lower intensity workloads. PMID- 26630308 TI - A Simple Model-Based Approach to Inferring and Visualizing Cancer Mutation Signatures. AB - Recent advances in sequencing technologies have enabled the production of massive amounts of data on somatic mutations from cancer genomes. These data have led to the detection of characteristic patterns of somatic mutations or "mutation signatures" at an unprecedented resolution, with the potential for new insights into the causes and mechanisms of tumorigenesis. Here we present new methods for modelling, identifying and visualizing such mutation signatures. Our methods greatly simplify mutation signature models compared with existing approaches, reducing the number of parameters by orders of magnitude even while increasing the contextual factors (e.g. the number of flanking bases) that are accounted for. This improves both sensitivity and robustness of inferred signatures. We also provide a new intuitive way to visualize the signatures, analogous to the use of sequence logos to visualize transcription factor binding sites. We illustrate our new method on somatic mutation data from urothelial carcinoma of the upper urinary tract, and a larger dataset from 30 diverse cancer types. The results illustrate several important features of our methods, including the ability of our new visualization tool to clearly highlight the key features of each signature, the improved robustness of signature inferences from small sample sizes, and more detailed inference of signature characteristics such as strand biases and sequence context effects at the base two positions 5' to the mutated site. The overall framework of our work is based on probabilistic models that are closely connected with "mixed-membership models" which are widely used in population genetic admixture analysis, and in machine learning for document clustering. We argue that recognizing these relationships should help improve understanding of mutation signature extraction problems, and suggests ways to further improve the statistical methods. Our methods are implemented in an R package pmsignature (https://github.com/friend1ws/pmsignature) and a web application available at https://friend1ws.shinyapps.io/pmsignature_shiny/. PMID- 26630311 TI - Erratum. PMID- 26630310 TI - Incomplete type of intestinal metaplasia has the highest risk to progress to gastric cancer: results of the Spanish follow-up multicenter study. AB - BACKGROUND AND AIM: In high or moderate risk populations, periodic surveillance of patients at risk of progression from gastric precursor lesions (PL) to gastric cancer (GC) is the most effective strategy for reducing the burden of GC. Incomplete type of intestinal metaplasia (IIM) may be considered as the best candidate, but it is still controversial and more research is needed. To further assess the progression of subtypes of IM as predictors of GC occurrence. METHODS: A follow-up study was carried-out including 649 patients, diagnosed with PL between 1995-2004 in 9 participating hospitals from Spain, and who repeated the biopsy during 2011-2013. Medical information and habits were collected through a questionnaire. Based on morphology, IM was sub-classified as complete (small intestinal type, CIM) and incomplete (colonic type, IIM). Analyses were done using Cox (HR) models. RESULTS: At baseline, 24% of patients had atrophic gastritis, 38% CIM, 34% IIM, and 4% dysplasia. Mean follow-up was 12 years. 24 patients (3.7%) developed a gastric adenocarcinoma during follow-up. The incidence rate of GC was 2.76 and 5.76 per 1,000 person-years for those with CIM and IIM, respectively. The HR of progression to CG was 2.75 (95% CI 1.06-6.26) for those with IIM compared with those with CIM at baseline, after adjusting for sex, age, smoking, family history of GC and use of NSAIDs. CONCLUSIONS: IIM is the PL with highest risk to progress to GC. Sub-typing of IM is a valid procedure for the identification of high risk patients that require more intensive surveillance. PMID- 26630313 TI - INTRAVITREAL CONBERCEPT (KH902) FOR SURGICAL TREATMENT OF SEVERE PROLIFERATIVE DIABETIC RETINOPATHY. AB - PURPOSE: To evaluate the role, safety, and effectiveness of intravitreal conbercept (KH902) injections as an adjunct to vitrectomy in the management of severe proliferative diabetic retinopathy. METHODS: A randomized controlled trial was performed on 36 eyes of 36 patients affected by vitreous hemorrhage and tractional retinal detachment, which occurred as a consequence of active proliferative diabetic retinopathy. The patients were randomly assigned to two groups. The patients in one of the groups received an intravitreal injection of conbercept in the inferior temporal sector 4 mm from the sclerocorneal limbus with a sterile technique 1 week before vitrectomy. RESULTS: In the group without conbercept, intraoperative bleeding occurred in 14 patients (77.8%), and in five of these cases, bleeding was significant. The use of endodiathermy was necessary in 8 patients (44.4%). In 3 patients (16.6%), iatrogenic retinal breaks occurred, and in 1 patient (5.5%), a relaxing retinotomy was performed. Endotamponade with silicone oil was performed in 12 patients (66.6%). In the group treated with conbercept, intraoperative bleeding occurred in 2 cases (11.1%). The use of endodiathermy was necessary in 1 patient (5.5%). No patients experienced iatrogenic breaks or relaxing retinotomy during the surgery. Endotamponade with silicone oil was performed in 2 patients (11.1%). CONCLUSION: Preoperative intravitreal injection of conbercept could reduce the chances of intraoperative bleeding, which are beneficial in the management of proliferative diabetic retinopathy. PMID- 26630314 TI - Safety Barricade Suture for Preventing Pupillary Capture of Intraocular Lens With Scleral Fixation: H-Technique. PMID- 26630315 TI - Optical Coherence Tomography Features Of Active And Inactive Retinal Neovascularization In Proliferative Diabetic Retinopathy. AB - PURPOSE: To describe spectral domain-optical coherence tomography features of retinal neovascularization in proliferative diabetic retinopathy and thus to identify novel signs of new vessel activity. METHODS: Retrospective, cross sectional study. Data were collected over a 9-month period. Spectral domain optical coherence tomography scans were performed over areas of new vessel complexes (NVC) in both the disk and elsewhere, and were qualitatively graded by two masked observers. New vessel complexes activity was determined using clinical and angiographic criteria and correlated with spectral domain optical coherence tomography features. RESULTS: Forty-three eyes of 30 patients with proliferative diabetic retinopathy were included. Sixty-one NVC lesions (neovascularization of the disk-37.7%, neovascularization elsewhere-62.3%) were captured by spectral domain-optical coherence tomography and analyzed. Among them, 63.9% were classified as active and 36.1% as quiescent. Five distinctive features were identified as significantly different between active and quiescent NVC: the presence of vitreous hyperreflective dots in active NVC (P = 0.002) and the presence of epiretinal membrane (P = 0.04), inner retinal tissue contracture (P = 0.03), vitreous invasion (P = 0.02), and protrusion towards vitreous (P = 0.002) in quiescent NVC. CONCLUSION: In this exploratory study, the presence of vitreous hyperreflective dots, epiretinal membrane, inner retinal tissue contracture, vitreous invasion, and vitreous protrusion were identified as distinct signs of disease activity. Such parameters may be useful as a noninvasive imaging modality in eyes undergoing treatment for proliferative diabetic retinopathy. PMID- 26630316 TI - TREATMENT OUTCOMES FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION PATIENTS WITH INITIAL VISION BETTER THAN 20/40 USING A TREAT-AND-EXTEND REGIMEN. AB - PURPOSE: To determine treatment outcomes in eyes with neovascular age-related macular degeneration having visual acuity better than 20/40 after 1 years to 2 years of ranibizumab or bevacizumab therapy using a treat-and-extend regimen. METHODS: Retrospective observational case series. Clinical records were reviewed from patients with treatment-naive neovascular age-related macular degeneration and baseline best-corrected Snellen visual acuity >20/40 treated with intravitreal ranibizumab or bevacizumab for a minimum of 1 year using a treat-and extend regimen. The primary outcome measures were change from initial visual acuity, proportion of eyes losing <3 best-corrected visual acuity lines, proportion of eyes maintaining visual acuity >=20/40, change from baseline central retinal thickness, and mean number of injections after 1 years and 2 years of follow-up. RESULTS: A total of 42 eyes from 40 patients were included. The mean follow-up period was 1.44 years. The mean initial logMAR visual acuity was 0.226, and remained stable at 0.257 and 0.267 after 1 years and 2 years of follow-up, respectively. At baseline, mean central retinal thickness was 305.8 MUm, improved to 272.6 MUm after 1 year of treatment (P < 0.001), and remained stable at 266.2 MUm (P = 0.015) after 2 years. At 1-year follow-up period, 94.4% of eyes had lost less than 3 Snellen lines, and 94.1% of eyes lost less than 3 Snellen lines after 2 years. The percentage of eyes maintaining visual acuity >=20/40 was 81% and 75% after each year. Eyes received on average 7.8 injections during the first year of treatment and 6.1 injections over the second year. CONCLUSION: Eyes with neovascular age-related macular degeneration presenting with initial visual acuity better than 20/40 on average maintained vision, lost less than 3 lines of acuity, and achieved anatomical improvements using a treat and-extend regimen over a 2-year period. PMID- 26630317 TI - SYSTEMIC RISK FACTORS IN BILATERAL PROLIFERATIVE DIABETIC RETINOPATHY REQUIRING VITRECTOMY. AB - PURPOSE: The visual outcome after vitrectomy for proliferative diabetic retinopathy (PDR) is often poor. Bilateral vitrectomy has been especially associated with a poor visual prognosis in patients with PDR. The authors investigated the systemic risk factors for PDR requiring bilateral vitrectomy compared with unilateral vitrectomy. METHODS: The authors retrospectively reviewed 86 consecutive patients with Type 2 diabetes mellitus with PDR who underwent vitrectomy. These patients were divided into 2 groups: bilateral vitrectomy within 1 year (n = 25) and unilateral vitrectomy (n = 61). The authors compared the systemic risk factors: age, sex, duration of diabetes, hemoglobin A1c, body mass index, estimated glomerular filtration rate, uric albumin, hypertension, dyslipidemia, history of ischemic heart disease, arteriosclerosis obliterans, and smoking. RESULTS: There were significantly more cases with severe renal dysfunction in the bilateral vitrectomy group compared with the unilateral one (estimated glomerular filtration rate <30 mL/minute/1.73 m; bilateral cases = 5/25; unilateral cases = 2/61; P = 0.02). CONCLUSION: The authors found that severe renal dysfunction may be a risk factor in PDR requiring bilateral vitrectomy, indicating that careful attention needs to be paid to prevent the progression of diabetic retinopathy to severe PDR in the other eye if patients have severe unilateral PDR and severe renal dysfunction. PMID- 26630318 TI - Correspondence. PMID- 26630319 TI - INTRAVITREOUS CHEMOTHERAPY FOR ACTIVE VITREOUS SEEDING FROM RETINOBLASTOMA: Outcomes After 192 Consecutive Injections. The 2015 Howard Naquin Lecture. AB - PURPOSE: To investigate on the safety and efficacy of intravitreous chemotherapy for retinoblastoma seeding in a relatively large cohort and provide information on the necessary number of injections and long-term control. METHODS: Retrospective interventional case series of 40 consecutive eyes with viable vitreous seeding after standard treatment of retinoblastoma. All eyes received intravitreal melphalan injection (20-30 MUg) and additional topotecan (20 MUg) as needed using the trans pars plana route with triple freeze-thaw cryotherapy at needle withdrawal for prevention of extraocular seeding for planned six cycles. RESULTS: The mean patient age at presentation was 36 months, and interval to need for vitreous injection was 14 months. Viable vitreous (n = 40 eyes) and additional subretinal (n = 2 eyes) seeds were documented. There was a total of 192 injections using melphalan (n = 148) and/or topotecan (n = 44) with mean number of injections per eye of melphalan at 4 (median, 4; range, 1-6) and topotecan at 3 (median, 3; range, 1-5). Fewer than six planned melphalan injections (n = 31 cases, 78%) were necessary because of rapid and complete vitreous seed control (n = 30 eyes) or melphalan allergy (n = 1 eye). Fewer than six planned topotecan injections (n = 14 cases, 100%) were necessary because of rapid and complete vitreous seed control in all cases. At median 3-year follow up, therapeutic success with continued seed regression was observed in all 40 eyes (100%). Globe salvage was attained in 35 cases (88%), and enucleation (n = 5) was necessary for extensive recurrent subretinal seeds (n = 2), neovascular glaucoma with vitreous hemorrhage (n = 2), and hemorrhagic retinal necrosis (n = 1). Side effects included focal retinal pigment epithelial mottling at the site of injection (n = 12), minor focal paraxial lens opacity (not requiring cataract surgery) (n = 11), transient focal vitreous hemorrhage (n = 5), transient hypotony (n = 3), transient retinal hemorrhage (n = 2), optic disc edema (n = 1), and hemorrhagic retinal necrosis (n = 1). There was no case of endophthalmitis, extraocular tumor extension, metastasis, or death. CONCLUSION: Intravitreal melphalan and/or topotecan injection for retinoblastoma vitreous seeding provides lasting tumor control at 3 years with approximately 4 injections. PMID- 26630320 TI - Reply. PMID- 26630321 TI - Lorentzian sparsity based spectroscopic reconstruction for fast high-dimensional magnetic resonance spectroscopy. AB - Two-dimensional magnetic resonance spectroscopy (2D MRS) is challenging, even with state-of-art compressive sensing methods, such as L1-sparsity method. In this work, using the prior that the 2D MRS can be regarded as a series of Lorentzian functions, we aim to develop a robust Lorentzian-sparsity based spectroscopy reconstruction method for high-dimensional MRS. The proposed method sparsifies 2D MRS in Lorentzian functions. Instead of thousands of pixel-wise variables, this Lorentzian-sparsity method significantly reduces the number of unknowns to several geometric variables, such as the center, magnitude and shape parameters for each Lorentzian function. The spectroscopy reconstruction is formulated as a nonlinear and nonconvex optimization problem, and the simulated annealing algorithm is developed to solve the problem. The proposed method was compared with inverse FFT method and L1-sparsity method, under various undersampling factors. While FFT and L1 results contained severe artifacts, the Lorentzian-sparsity results provided significantly improved spectroscopy. A new 2D MRS reconstruction method is proposed using the Lorentzian sparsity, with significantly improved MRS reconstruction quality, in comparison with standard inverse FFT method or state-of-art L1-sparsity method. PMID- 26630322 TI - Well-Defined, Mononuclear Bi(I) and Bi(II) Compounds: Towards Transition-Metal Like Behavior. PMID- 26630324 TI - Tablet Apps and Dexterity: Comparison Between 3 Age Groups and Proof of Concept for Stroke Rehabilitation. AB - BACKGROUND AND PURPOSE: Touch screen tablet technology might be suitable for self training of impaired dexterity poststroke. We compared performance of app-based hand activities in individuals without a disability from 3-age groups, and assessed the feasibility of using tablet apps in individuals with stroke. METHODS: Experiment I included 172 Individuals without a disability: 79 young adults (26.2 [3.9] years old), 61 middle-aged adults (55.9 [5.1] years old), and 32 older adults (68.7 [3.0] years old). Experiment II included 20 individuals with stroke, aged 59.3 +/- 13.7 years with impairment of the upper extremity. All participants performed the app-based "Tap-it" (tapping) task twice and the Nine Hole Peg Test. The stroke group practiced with additional apps and underwent clinical assessments. RESULTS: Significant differences in the tapping task performance were found between the 3 age groups (dominant hand time: F(2,169) = 30.57; P = 0.0001; and accuracy F(2,169) = 25.20; P = 0.0001; nondominant hand time: F(2,169) = 35.09; P = 0.0001; and accuracy F(2,169) = 19.62; P = 0.0001). Of the 20 individuals with stroke, 15 were able to complete the 2 trials of the tapping task, but all participants reported enjoying the experience and thought the apps may have potential for stroke rehabilitation to improve performance of the stroke-affected hand. DISCUSSION AND CONCLUSIONS: Performance of tablet app based hand activities was affected by impaired hand dexterity in older participants without a disability and in participants with stroke. Tablet apps may potentially provide a way to facilitate self-training of repetitive, task oriented, isolated finger and hand movements to improve hand dexterity and function after stroke.Video abstract available for additional insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A118). PMID- 26630323 TI - Laboratory Monitoring During Isotretinoin Therapy for Acne: A Systematic Review and Meta-analysis. AB - IMPORTANCE: Oral isotretinoin has been associated with several adverse effects, but evidence-based estimates of laboratory changes during isotretinoin therapy in large patient samples are limited. OBJECTIVE: To develop estimates of the laboratory changes that occur during isotretinoin therapy for acne using extant data and meta-analytic methods. DATA SOURCES: A comprehensive search strategy using Ovid/MEDLINE, EMBASE, and gray literature was conducted (1960-August 1, 2013) to identify all relevant studies of isotretinoin use in acne vulgaris. Terms related to acne treatment, isotretinoin, and diagnostic procedures were searched with all available synonyms. STUDY SELECTION: Inclusion criteria consisted of clinical trials using oral isotretinoin, doses of 40 mg/d or more, duration of at least 4 weeks, patients aged 9 to 35 years with acne vulgaris, and 10 or more participants. Studies from all countries published in any language were included. Exclusion criteria were use of modified isotretinoin products, isotretinoin therapy for conditions other than acne vulgaris, and concomitant acne therapy. The initial search yielded 342 records; 116 of these were screened for full-text examination. DATA EXTRACTION AND SYNTHESIS: Two authors independently reviewed the publications to determine eligibility, and disagreements were resolved by a third author. Generated weighted means and 99% CIs were calculated using the reported means (SDs or SEs). A random effects model was created, and statistical heterogeneity was quantified. Data were analyzed from August 25, 2014, to December 4, 2015. MAIN OUTCOMES AND MEASURES: Laboratory values for lipid levels, hepatic function, and complete blood cell count were evaluated. RESULTS: Data from 61 of the 116 studies were evaluated; 26 studies (1574 patients) were included in the meta-analysis. The mean (99% CI) values during treatment (nonbaseline) for triglycerides was 119.98 mg/dL (98.58-141.39 mg/dL); for total cholesterol, 184.74 mg/dL (178.17-191.31 mg/dL); for low density lipoprotein cholesterol, 109.23 mg/dL (103.68-114.79 mg/dL); for high density lipoprotein cholesterol, 42.80 mg/dL (39.84-45.76 mg/dL); for aspartate aminotransferase, 22.67 U/L (19.94-25.41 U/L); for alanine aminotransferase, 21.77 U/L (18.96-24.59 U/L); for alkaline phosphatase, 88.35 U/L (58.94-117.76 U/L); and for white blood cell count, 6890/uL (5700/uL-8030/uL). This meta analysis showed that (1) isotretinoin is associated with a statistically significant change in the mean value of several laboratory tests (white blood cell count and hepatic and lipid panels), yet (2) the mean changes across a patient group did not meet a priori criteria for high-risk and (3) the proportion of patients with laboratory abnormalities was low. CONCLUSIONS AND RELEVANCE: The evidence from this study does not support monthly laboratory testing for use of standard doses of oral isotretinoin for the standard patient with acne. PMID- 26630326 TI - Proposal to Change the Neurology Section's Name to the Academy of Neurologic Physical Therapy. PMID- 26630325 TI - Variability of Anticipatory Postural Adjustments During Gait Initiation in Individuals With Parkinson Disease. AB - BACKGROUND AND PURPOSE: In people with Parkinson disease (PD), difficulties with initiating stepping may be related to impairments of anticipatory postural adjustments (APAs). Increased variability in step length and step time has been observed in gait initiation in individuals with PD. In this study, we investigated whether the ability to generate consistent APAs during gait initiation is compromised in these individuals. METHODS: Fifteen subjects with PD and 8 healthy control subjects were instructed to take rapid forward steps after a verbal cue. The changes in vertical force and ankle marker position were recorded via force platforms and a 3-dimensional motion capture system, respectively. Means, standard deviations, and coefficients of variation of both timing and magnitude of vertical force, as well as stepping variables, were calculated. RESULTS: During the postural phase of gait initiation the interval was longer and the force modulation was smaller in subjects with PD. Both the variability of timing and force modulation were larger in subjects with PD. Individuals with PD also had a longer time to complete the first step, but no significant differences were found for the variability of step time, length, and speed between groups. DISCUSSION AND CONCLUSIONS: The increased variability of APAs during gait initiation in subjects with PD could affect posture-locomotion coupling, and lead to start hesitation, and even falls. Future studies are needed to investigate the effect of rehabilitation interventions on the variability of APAs during gait initiation in individuals with PD.Video abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A119). PMID- 26630329 TI - Neurology Section Poster Presentations 2016 Combined Sections Meeting: (abstracts are available on the JNPT website at: www.JNPT.org). PMID- 26630328 TI - Neurology Section Platform Presentations 2016 Combined Sections Meeting: (abstracts are available on the JNPT website at: www.JNPT.org). PMID- 26630330 TI - Monofluorination and Trifluoromethylation of BODIPY Dyes for Prolonged Single Molecule Detection. AB - Electrophilic monofluorination with Selectfluor and nucleophilic trifluoromethylation with the Ruppert-Prakesh reagent of dimethyl-, tetramethyl- and pentamethyl-substituted boron dipyrromethenes (BODIPY) are investigated. Monofluorinated dyes are synthesized with low yields (<30%), however trifluoromethyl derivatives are obtained in moderate to high yields (~40-90%). All compounds are characterized by steady-state and time-resolved fluorescence spectroscopy, the photostability is investigated with fluorescence correlation spectroscopy (FCS) and total internal reflection fluorescence microscopy (TIRF). Monofluorination hardly affects the spectroscopic parameters of the unsubstituted parent compounds, but distinctly enhances the photostability, whereas trifluoromethylation leads to a hypsochromic shift by up to 17 nm in both absorption and emission, slightly enhanced intersystem crossing, and higher photostability. Further development of soft fluorination and trifluoromethylation methods is therefore highly desired. PMID- 26630331 TI - Aeromonas rivipollensis sp. nov., a novel species isolated from aquatic samples. AB - Two gram-negative, facultatively anaerobic, motile and rod-shaped bacteria, strains P2G1(T) and P1A11, were isolated from the Ter River in Ripoll, Spain. Phylogenetic analysis based on 16S rRNA gene sequences showed that both strains are closely related to each other and that their closest relatives were Aeromonas media ATCC 33907(T) (99.4%) and Aeromonas hydrophila ATCC 7966(T) (99.3%). Multilocus sequence analysis (MLSA) based on the partial sequences of gyrA, gyrB, rpoD, recA, and dnaJ genes suggested that these two strains represent a novel species that clustered with A. media ATCC 33907(T). This was further supported by DNA-DNA hybridization analysis between P2G1(T) and A. media LMG 9073(T). Phenotypic features also allowed their differentiation from closely related species. These two strains should, therefore, be considered to represent a novel species within the genus Aeromonas, for which the name Aeromonas rivipollensis sp. nov. is proposed. PMID- 26630332 TI - Particle size measurement from infrared laser ablation of tissue. AB - The concentration and size distribution were measured for particles ablated from tissue sections using an infrared optical parametric oscillator laser system. A scanning mobility particle sizer and light scattering particle sizer were used in parallel to realize a particle sizing range from 10 nm to 20 MUm. Tissue sections from rat brain and lung ranging in thickness between 10 and 50 MUm were mounted on microscope slides and irradiated with nanosecond laser pulses at 3 MUm wavelength and fluences between 7 and 21 kJ m(-2) in reflection geometry. The particle size distributions were characterized by a bimodal distribution with a large number of particles 100 nm in diameter and below and a large mass contribution from particles greater than 1 MUm in diameter. The large particle contribution dominated the ablated particle mass at high laser fluence. The tissue type, thickness, and water content did not have a significant effect on the particle size distributions. The implications of these results for laser ablation sampling and mass spectrometry imaging under ambient conditions are discussed. PMID- 26630333 TI - Risk and outcomes of metachronous gastric cancer following endoscopic resection of early gastric cancer: some answers, more questions. PMID- 26630334 TI - Patient satisfaction: current and future effects on daily clinical (colonoscopy) practice. PMID- 26630335 TI - Look to Poland! Conversion from opportunistic screening to a randomized, national screening program for colorectal cancer. PMID- 26630339 TI - [Not Available]. PMID- 26630336 TI - Effect of acetylsalicylic acid, clopidogrel, and indomethacin on bleeding after sphincterotomy: the good, the better, and no-one is ugly. PMID- 26630340 TI - [Not Available]. PMID- 26630341 TI - [Not Available]. PMID- 26630342 TI - Video Comment on Ann Langerth et al. PMID- 26630343 TI - Video Comment on Michal F. Kaminski et al. PMID- 26630344 TI - Video Comment on Peter Klare et al. PMID- 26630345 TI - Changes in the Milk Metabolome of the Giant Panda (Ailuropoda melanoleuca) with Time after Birth--Three Phases in Early Lactation and Progressive Individual Differences. AB - Ursids (bears) in general, and giant pandas in particular, are highly altricial at birth. The components of bear milks and their changes with time may be uniquely adapted to nourish relatively immature neonates, protect them from pathogens, and support the maturation of neonatal digestive physiology. Serial milk samples collected from three giant pandas in early lactation were subjected to untargeted metabolite profiling and multivariate analysis. Changes in milk metabolites with time after birth were analysed by Principal Component Analysis, Hierarchical Cluster Analysis and further supported by Orthogonal Partial Least Square-Discriminant Analysis, revealing three phases of milk maturation: days 1-6 (Phase 1), days 7-20 (Phase 2), and beyond day 20 (Phase 3). While the compositions of Phase 1 milks were essentially indistinguishable among individuals, divergences emerged during the second week of lactation. OPLS regression analysis positioned against the growth rate of one cub tentatively inferred a correlation with changes in the abundance of a trisaccharide, isoglobotriose, previously observed to be a major oligosaccharide in ursid milks. Three artificial milk formulae used to feed giant panda cubs were also analysed, and were found to differ markedly in component content from natural panda milk. These findings have implications for the dependence of the ontogeny of all species of bears, and potentially other members of the Carnivora and beyond, on the complexity and sequential changes in maternal provision of micrometabolites in the immediate period after birth. PMID- 26630346 TI - Validity and Calibration of the Youth Activity Profile. AB - PURPOSE: The purpose of this study was to calibrate and cross-validate the Youth Activity Profile (YAP), a self-report tool designed to capture physical activity (PA) and sedentary behaviors (SB) in youth. METHODS: Eight schools in the Midwest part of the U.S. were involved and a total of 291 participants from grades 4-12 agreed to wear an accelerometer (SWA Armband) and complete the YAP in two separate weeks (5-7 days apart). Individual YAP items capture PA behavior during specific segments of the week and these items were combined with temporally matched estimates of moderate-to-vigorous PA (MVPA) and sedentary time from the SWA to enable calibration. Quantile regression procedures yielded YAP prediction algorithms that estimated MVPA at School, MVPA at Out-of-School, MVPA on Weekend, as well as time spent in SB. The YAP estimates of time spent in MVPA and SB were cross-validated using Pearson product correlations and limits of agreement, as indicative of individual error and, equivalence testing techniques as indicative of group-level error. RESULT: Following calibration, the correlations between YAP and SWA estimates of MVPA were low to moderate (rrange = .19 to .58) and individual-level YAP estimates of MVPA ranged from -134.9% to +110.0% of SWA MVPA values. Differences between aggregated YAP and SWA MVPA ranged from -3.4 to 21.7 minutes of MVPA at the group-level and predicted YAP MVPA estimates were within 15%, 20%, and 30%, of values from the SWA for the School, Out-of-School, and Weekend time periods, respectively. Estimates of time spent in SB were highly correlated with each other (r = .75). The individual estimates of SB ranged from 54.0% to +44.0% of SWA sedentary time, and the aggregated group-level estimates differed by 49.7 minutes (within 10% of the SWA aggregated estimates). CONCLUSIONS: This study provides preliminary evidence that the calibration procedures enabled the YAP to provide estimates of MVPA and SB that approximated values from an objective monitor. The YAP provides a simple, low-cost and educationally sound method to accurately estimate children's MVPA and SB at the group level. PMID- 26630347 TI - Comparative Allometric Growth of the Mimetic Ephippid Reef Fishes Chaetodipterus faber and Platax orbicularis. AB - Mimesis is a relatively widespread phenomenon among reef fish, but the ontogenetic processes relevant for mimetic associations in fish are still poorly understood. In the present study, the allometric growth of two allopatric leaf mimetic species of ephippid fishes, Chaetodipterus faber from the Atlantic and Platax orbicularis from the Indo-Pacific, was analyzed using ten morphological variables. The development of fins was considered owing to the importance of these structures for mimetic behaviors during early life stages. Despite the anatomical and behavioral similarities in both juvenile and adult stages, C. faber and P. orbicularis showed distinct patterns of growth. The overall shape of C. faber transforms from a rounded-shape in mimetic juveniles to a lengthened profile in adults, while in P. orbicularis, juveniles present an oblong profile including dorsal and anal fins, with relative fin size diminishing while the overall profile grows rounder in adults. Although the two species are closely related, the present results suggest that growth patterns in C. faber and P. orbicularis are different, and are probably independent events in ephippids that have resulted from similar selective processes. PMID- 26630348 TI - Reversible Fluorescent Probes for Biological Redox States. AB - The redox chemistry of the cell is key to its function and health, and the development of chemical tools to study redox biology is important. While fluxes in oxidative state are essential for healthy cell function, a chronically elevated oxidative capacity is linked to disease. It is therefore essential that probes of biological redox states distinguish between these two conditions by the reversible sensing of changes over time. In this review, we discuss the current progress towards such probes, and identify key directions for future research in this nascent field of vital biological interest. PMID- 26630349 TI - Lifestyle interventions for the treatment of urinary incontinence in adults. AB - BACKGROUND: Low cost, non-invasive alterations in lifestyle are frequently recommended by healthcare professionals or those presenting with incontinence. However, such recommendations are rarely based on good evidence. OBJECTIVES: The objective of the review was to determine the effectiveness of specific lifestyle interventions (i.e. weight loss; dietary changes; fluid intake; reduction in caffeinated, carbonated and alcoholic drinks; avoidance of constipation; stopping smoking; and physical activity) in the management of adult urinary incontinence. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and MEDLINE in process, and handsearching of journals and conference proceedings (searched 3 July 2013), and the reference lists of relevant articles. We incorporated the results of these searches fully in the review. We undertook an updated search of the Specialised Register, which now includes searches of ClinicalTrials.gov and WHO ICTRP, on 27 October 2014; potentially eligible studies from this search are currently awaiting classification. SELECTION CRITERIA: Randomised and quasi-randomised studies of community-based lifestyle interventions compared with no treatment, other conservative therapies, or pharmacological interventions for the treatment of urinary incontinence in adults. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. We collected information on adverse effects from the trials. Data were combined in a meta-analysis when appropriate. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We included 11 trials in the review, involving a total of 5974 participants.Four trials involving 4701 women compared weight loss programmes with a control intervention. Low quality evidence from one trial suggested that more women following weight loss programmes reported improvement in symptoms of incontinence at six months (163/214 (76%) versus 49/90 (54%), risk ratio (RR) 1.40, 95% confidence interval (CI) 1.14 to 1.71), and this effect was sustained at 18 months (N = 291, 75% versus 62%, RR not estimable, reported P value 0.02). No data were available for self-reported cure and quality of life. One of the weight loss trials involving 1296 women reported very low quality evidence for a reduction in weekly urinary incontinence a mean of 2.8 years after following a lifestyle weight loss intervention that had been compared with a pharmacological weight loss intervention.Three trials involving 181 women and 11 men compared change in fluid intake with no change. Limited, very low quality evidence suggested that symptom-specific quality of life scores improved when fluid intake was reduced, although some people reported headaches, constipation or thirst. A further three trials involving 160 women and nine men compared reduction in caffeinated drinks with no change, and one trial involving 42 women compared a soy-rich diet with soy-free diet. However, it was not possible to reach any conclusions about the effects of these changes, due to methodological limitations, that resulted in very low quality evidence.Adverse effects appeared relatively uncommon for all interventions studied.All included studies had a high or unclear risk of bias across all bias parameters, but most notably for allocation concealment. The main factors for our downgrading of the evidence were risk of bias, indirect evidence (less than 12 months of follow-up; and not all participants having confirmed urinary incontinence at baseline in some studies), and imprecise results with wide confidence intervals.Other interventions such as reduction in consumption of sweetened fizzy or diet drinks; reduction in alcohol consumption; avoiding constipation; smoking cessation; restricting strenuous physical forces; or reducing high levels of, or increasing low levels of, physical activity, could not be assessed in this review, as no evidence from randomized controlled trials or quasi-randomised trials was available. AUTHORS' CONCLUSIONS: Evidence for the effect of weight loss on urinary incontinence is building and should be a research priority. Generally, there was insufficient evidence to inform practice reliably about whether lifestyle interventions are helpful in the treatment of urinary incontinence. PMID- 26630351 TI - Formation of Bromate and Halogenated Disinfection Byproducts during Chlorination of Bromide-Containing Waters in the Presence of Dissolved Organic Matter and CuO. AB - Previous studies showed that significant bromate (BrO3(-)) can be formed via the CuO-catalyzed disproportionation of hypobromous acid (HOBr) pathway. In this study, the influence of CuO on the formation of BrO3(-) and halogenated disinfection byproducts (DBPs) (e.g., trihalomethanes, THMs and haloacetic acids, HAAs) during chlorination of six dissolved organic matter (DOM) isolates was investigated. Only in the presence of slow reacting DOM (from treated Colorado River water, i.e., CRW-BF-HPO), significant BrO3(-) formation is observed, which competes with bromination of DOM (i.e., THM and HAA formation). Reactions between HOBr and 12 model compounds in the presence of CuO indicates that CuO-catalyzed HOBr disproportionation is completely inhibited by fast reacting phenols, while it predominates in the presence of practically unreactive compounds (acetone, butanol, propionic, and butyric acids). In the presence of slow reacting di- and tricarboxylic acids (oxalic, malonic, succinic, and citric acids), BrO3(-) formation varies, depending on its competition with bromoform and dibromoacetic acid formation (i.e., bromination pathway). The latter pathway can be enhanced by CuO due to the activation of HOBr. Therefore, increasing CuO dose (0-0.2 g L(-1)) in a reaction system containing chlorine, bromide, and CRW-BF-HPO enhances the formation of BrO3(-), total THMs and HAAs. Factors including pH and initial reactant concentrations influence the DBP formation. These novel findings have implications for elevated DBP formation during transportation of chlorinated waters in copper-containing distribution systems. PMID- 26630350 TI - Advances in therapeutic strategies for the treatment of pruritus. AB - INTRODUCTION: Chronic pruritus is a common symptom that arises from both dermatologic and non-dermatologic conditions including chronic kidney disease, cholestasis, lymphoma and neuropathy. Over the past decade, research has elucidated many of the receptors, neuropeptides and cytokines involved in itch sensation and transmission. In addition, the first biomarker for cholestatic itch has been discovered. These findings have led to the development of a host of novel antipruritic medications, both on the market and in the pipeline. AREAS COVERED: A summary of new and emerging treatments for pruritus, as well as possible targets for future therapeutic development is provided. EXPERT OPINION: At present, there is no universally effective treatment available for all types of chronic pruritus. A combination of topical and systemic therapies addressing peripheral mediators, and a top-down approach targeting the brain and spinal cord, seems preferable to a single agent approach. Neural hypersensitization plays a significant role in many forms of chronic pruritus and may be downregulated by new treatments. In addition, specific neuropeptides are now targeted by novel antipruritic therapies. Furthermore, targeted biologic agents are anticipated to play a significant role in treating pruritus of inflammatory origin. PMID- 26630352 TI - Validity and reliability of the Japanese version of the Therapeutic Factors Inventory-19: A study of family peer education self-help groups. AB - AIM: Therapeutic factors are crucial mechanisms that promote change in self-help group members. Measuring therapeutic factors may improve practitioners' skills for assessment in whole-group contexts. The present authors, therefore, examined the validity and reliability of a Japanese version of the Therapeutic Factors Inventory-19. METHODS: The Therapeutic Factors Inventory-19 was examined using a self-report questionnaire completed by members of 38 family peer education self help groups. The instrument measured the following four factors: instillation of hope, secure emotional expression, awareness of relational impact, and social learning. RESULTS: Participants were 246 group members. Test-retest reliability was analyzed using data from 46 participants. Confirmatory factor analysis showed a goodness of fit of 0.85 and a root mean square error of approximation of 0.088. Multitrait scaling analyses showed that items for instillation of hope and secure emotional expression factors correlated higher with their own factors than other factors. Each factor and the total average of the 19 items were significantly correlated with the Group Benefit Scale and Client Satisfaction Questionnaire. When level of interaction with other members was higher, subjects perceived a stronger presence of therapeutic factors. The intraclass correlation coefficients of each factor at a week interval were 0.848-0.915. Cronbach's alpha of each factor and all items ranged 0.767-0.960. CONCLUSION: In the case of family peer education self-help groups, there is acceptable validity and reliability for the average score of all items, and for the instillation of hope and secure emotional expression factors. However, more work is needed to increase the generalizability. PMID- 26630354 TI - The use of progestogen-only pill in migraine patients. AB - Migraine is a debilitating neurovascular disorder which is estimated to affect 18% of women and 6% of men. Two main forms of this neurological disorder must be considered: Migraine without Aura and Migraine with Aura. Migraine without aura often has a strict menstrual relationship: the International Headache Society classification gives criteria for Pure Menstrual Migraine and Menstrually Related Migraine. The higher prevalence of migraine among women suggests that this sex difference probably results from the trigger of fluctuating hormones during the menstrual cycle. Safe and effective contraception is essential for all women of childbearing age, but Combined Oral Contraceptives have been associated with worsening of attacks and cardiovascular risk in these patients. We analyzed characteristics, effects and benefits of progestogen-only pill, a possible alternative for contraception in women with migraine. PMID- 26630353 TI - Randomized Comparison of Two Vaginal Self-Sampling Methods for Human Papillomavirus Detection: Dry Swab versus FTA Cartridge. AB - BACKGROUND: Human papillomavirus (HPV) self-sampling (self-HPV) is valuable in cervical cancer screening. HPV testing is usually performed on physician collected cervical smears stored in liquid-based medium. Dry filters and swabs are an alternative. We evaluated the adequacy of self-HPV using two dry storage and transport devices, the FTA cartridge and swab. METHODS: A total of 130 women performed two consecutive self-HPV samples. Randomization determined which of the two tests was performed first: self-HPV using dry swabs (s-DRY) or vaginal specimen collection using a cytobrush applied to an FTA cartridge (s-FTA). After self-HPV, a physician collected a cervical sample using liquid-based medium (Dr WET). HPV types were identified by real-time PCR. Agreement between collection methods was measured using the kappa statistic. RESULTS: HPV prevalence for high risk types was 62.3% (95%CI: 53.7-70.2) detected by s-DRY, 56.2% (95%CI: 47.6 64.4) by Dr-WET, and 54.6% (95%CI: 46.1-62.9) by s-FTA. There was overall agreement of 70.8% between s-FTA and s-DRY samples (kappa = 0.34), and of 82.3% between self-HPV and Dr-WET samples (kappa = 0.56). Detection sensitivities for low-grade squamous intraepithelial lesion or worse (LSIL+) were: 64.0% (95%CI: 44.5-79.8) for s-FTA, 84.6% (95%CI: 66.5-93.9) for s-DRY, and 76.9% (95%CI: 58.0 89.0) for Dr-WET. The preferred self-collection method among patients was s-DRY (40.8% vs. 15.4%). Regarding costs, FTA card was five times more expensive than the swab (~5 US dollars (USD)/per card vs. ~1 USD/per swab). CONCLUSION: Self-HPV using dry swabs is sensitive for detecting LSIL+ and less expensive than s-FTA. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 43310942. PMID- 26630355 TI - Inter-repetition rest training and traditional set configuration produce similar strength gains without cortical adaptations. AB - This study compared the functional and neural effects of two strength training programmes differing in set configuration. Thirteen participants performed 10 sessions, over a period of 5 weeks, of unilateral leg extensions with different set configurations but with identical work-to-rest ratios for each limb: a traditional configuration (4 sets of 8 repetitions, 10RM load, 3-min pause between sets) and an inter-repetition rest configuration (32 repetitions, 10RM load, 17.4 s of rest between each repetition). Mean propulsive velocity of the traditional sessions was lower than for inter-repetition rest sessions (0.48 +/- 0.06 vs. 0.54 +/- 0.06 m . s(-1); P < 0.001), while perceived exertion was higher (8.3 +/- 0.9 and 6.56 +/- 1.6 for traditional training and IRT; P = 0.002). One repetition maximum (RM), work with 10RM load, maximum mean propulsive power, maximum voluntary contraction and time to failure with 50% of maximum isometric force improved similarly in both legs (time effect, P < 0.001; effect size range, 0.451-1.190). Time and set configuration did not show significant main effects or interactions for cortical adaptations (motor-evoked potentials, short-interval intracortical inhibition, intracortical facilitation). There were no significant correlations between changes in cortical and peripheral neural adaptations and strength improvement. In conclusion, inter-repetition rest configuration was as effective as traditional training in improving muscle performance. PMID- 26630357 TI - Understanding Programming of Fungal Iterative Polyketide Synthases: The Biochemical Basis for Regioselectivity by the Methyltransferase Domain in the Lovastatin Megasynthase. AB - Highly reducing polyketide synthases (HR-PKSs) from fungi synthesize complex natural products using a single set of domains in a highly programmed, iterative fashion. The most enigmatic feature of HR-PKSs is how tailoring domains function selectively during different iterations of chain elongation to afford structural diversity. Using the lovastatin nonaketide synthase LovB as a model system and a variety of acyl substrates, we characterized the substrate specificity of the LovB methyltransferase (MT) domain. We showed that, while the MT domain displays methylation activity toward different beta-ketoacyl groups, it is exceptionally selective toward its naturally programmed beta-keto-dienyltetraketide substrate with respect to both chain length and functionalization. Accompanying characterization of the ketoreductase (KR) domain displays broader substrate specificity toward different beta-ketoacyl groups. Our studies indicate that selective modifications by tailoring domains, such as the MTs, are achieved by higher kinetic efficiency on a particular substrate relative to the rate of transformation by other competing domains. PMID- 26630356 TI - Microbiota Promotes Chronic Pulmonary Inflammation by Enhancing IL-17A and Autoantibodies. AB - RATIONALE: Changes in the pulmonary microbiota are associated with progressive respiratory diseases including chronic obstructive pulmonary disease (COPD). Whether there is a causal relationship between these changes and disease progression remains unknown. OBJECTIVES: To investigate the link between an altered microbiota and disease, we used a murine model of chronic lung inflammation that is characterized by key pathological features found in COPD and compared responses in specific pathogen-free (SPF) mice and mice depleted of microbiota by antibiotic treatment or devoid of a microbiota (axenic). METHODS: Mice were challenged with LPS/elastase intranasally over 4 weeks, resulting in a chronically inflamed and damaged lung. The ensuing cellular infiltration, histological damage, and decline in lung function were quantified. MEASUREMENTS AND MAIN RESULTS: Similar to human disease, the composition of the pulmonary microbiota was altered in diseased animals. We found that the microbiota richness and diversity were decreased in LPS/elastase-treated mice, with an increased representation of the genera Pseudomonas and Lactobacillus and a reduction in Prevotella. Moreover, the microbiota was implicated in disease development as mice depleted, or devoid, of microbiota exhibited an improvement in lung function, reduced inflammation, and lymphoid neogenesis. The absence of microbial cues markedly decreased the production of IL-17A, whereas intranasal transfer of fluid enriched with the pulmonary microbiota isolated from diseased mice enhanced IL-17A production in the lungs of antibiotic-treated or axenic recipients. Finally, in mice harboring a microbiota, neutralizing IL-17A dampened inflammation and restored lung function. CONCLUSIONS: Collectively, our data indicate that host-microbial cross-talk promotes inflammation and could underlie the chronicity of inflammatory lung diseases. PMID- 26630358 TI - Optimizing the DNA yield for molecular analysis from cytologic preparations. AB - BACKGROUND: Cytology smears and cytospin preparations are increasingly being used for molecular testing. With these limited samples, optimizing tissue extraction to maximize the DNA yield is, therefore, critical. This study examined 2 common methods of tissue extraction and compared DNA yields from different types of glass slides. METHODS: The H226 lung cancer cell line and 5 clinical samples of cellular effusions were used to prepare Diff-Quik-stained cytospins on 4 types of glass slides: fully frosted (FF), nonfrosted (NF), positively charged (PC), and silane-coated (SC). Tissue extraction was performed by either scalpel-blade scraping or cell lifting with the Pinpoint Slide DNA Isolation System (Zymo Research). DNA was extracted with the QIAamp DNA Mini Kit (Qiagen) and was quantified with the Quant-iT PicoGreen Kit (Life Technologies). RESULTS: The DNA yield in cell-line cytospins was significantly lower from FF slides versus NF, PC, and SC slides with both scraping and cell-lifting methods. In addition, scraping yielded significantly more DNA than cell lifting (P = .005). DNA yields from 5 clinical effusion cases with FF and NF slides showed results similar to the results for cell-line samples, with scraping consistently yielding more DNA than cell lifting and with NF slides outperforming FF slides. CONCLUSIONS: Optimizing the DNA yield extracted from cytology specimens maximizes the chances of successful molecular testing and is critical in cases of low or marginal cellularity. This study demonstrates the following: 1) scraping yields more DNA than cell lifting, and 2) NF slides yield more DNA than FF slides. PMID- 26630360 TI - Evidence-based practice: 'walking the talk'. PMID- 26630362 TI - Relationships between duration of practice, educational level, and perception of barriers to implement evidence-based practice among critical care nurses. AB - AIMS: Globally, a greater emphasis has been placed on the delivery of safe, patient-centered, evidence-based nursing care. As point-of-care providers, critical care nurses play a key role in ensuring that patients receive the safest, most effective treatment available. In order to deliver scientific-based care, critical care nurses must stay abreast of the current trends, as well as engage in the evidence-based practice process. This study aimed to describe research activities, to identify barriers to implement evidence-based practice and to explore professional factors related to the use of evidence-based practice among critical care nurses at three teaching hospitals in south-eastern United States. METHODS: A survey design and convenience sampling method was used. A sample of 30 critical care staff nurses participated in the study. A 61-item online questionnaire composed of a demographic survey - BARRIERS scale - and Evidence-Based Practice Questionnaire was used. Simple descriptive statistics, Pearson's product moment correlations, and independent-sample t test procedures were used to analyze the data. RESULTS: Critical care nurses' reported positive attitudes, but viewed knowledge and use of evidence-based practice less favorably. These results may indicate that having a positive attitude towards evidence-based practice does not necessarily translate to knowledge and use of the evidence-based practice process in clinical practice. An unwillingness to change and time constraints were identified as the top barriers to use evidence based practice in this study. Perceptions of barriers to use evidence-based practice were higher in those critical care nurses who had less practical experience and educational preparation. CONCLUSION: The results suggest that critical care nurses possess the foundation to engage in the evidence-based practice process; however, their knowledge, practice, and attitudes just need to be cultivated and strengthened. Understanding the nurses' professional factors, current use and barriers to implement evidence-based practice is an essential step to ensuring competency and value for engaging in the evidence-based practice process. The results of this study support the need for future research to address barriers that impact critical care nurses' ability to deliver state-of the-science care. PMID- 26630361 TI - Clinical effectiveness of and attitudes and beliefs of health professionals towards the use of health technology in falls prevention among older adults. AB - AIMS: To analyse the evidence on the effectiveness, usability and acceptability of health technology in falls detection and prevention among older adults. METHODS: Five databases were searched from February 2004 to February 2014: PubMed, Medline, Embase, Cochrane and CINAHL, with reference lists reviewed and researchers contacted for additional articles. The interventions were health technology tools used for falls detection and prevention (e.g. computers, mobile phones, motion sensors). The outcomes were effectiveness of, and the attitudes of healthcare staff towards, health technology in preventing falls. Two review authors independently assessed full texts using modified versions of the Joanna Briggs Institute Critical Appraisal Checklists. RESULTS: Full-texts of 51 out of 7927 articles were examined and 17 articles accepted following appraisal using Joanna Briggs Institute modified criteria. These were divided into subheadings of health information technology tool with visual cues (n = 2), sensors (n = 4), Webcam (n = 1) and electronic medical records (n = 3). Three of the seven systematic reviews evaluated sensor technology alone, whereas the remainder examined multicomponent interventions. There is a lack of research into the efficacy of and staff attitudes towards health technology in falls detection and prevention. One study found nurses accepted a health information technology toolkit with visual cues, with a single randomized controlled trial demonstrating a reduction in falls rates. Most studies regarding sensor technology were of low quality and did not find reduced falls rates or number of falls-related injuries. There was also mixed response from healthcare staff and users regarding the use of sensors, with concerns about privacy and false alarms. Video camera surveillance effectively reduced falls rates and was well accepted by nursing staff. However, patients had concerns for their privacy. Electronic medical records have not so far demonstrated a reduction in falls, with ongoing staff concerns about their usability. CONCLUSION: Good-quality literature regarding the effectiveness and acceptability of health technology in falls detection and prevention is lacking. Further research into both these fields is vital prior to wider implementation of such tools in clinical practice. PMID- 26630363 TI - Length of stay in hospital for people with severe mental illness. PMID- 26630364 TI - Improved Selectivity and Sensitivity of Gas Sensing Using a 3D Reduced Graphene Oxide Hydrogel with an Integrated Microheater. AB - Low-cost, one-step, and hydrothermal synthesized 3D reduced graphene oxide hydrogel (RGOH) is exploited to fabricate a high performance NO2 and NH3 sensor with an integrated microheater. The sensor can experimentally detect NO2 and NH3 at low concentrations of 200 ppb and 20 ppm, respectively, at room temperature. In addition to accelerating the signal recovery rate by elevating the local silicon substrate temperature, the microheater is exploited for the first time to improve the selectivity of NO2 sensing. Specifically, the sensor response from NH3 can be effectively suppressed by a locally increased temperature, while the sensitivity of detecting NO2 is not significantly affected. This leads to good discrimination between NO2 and NH3. This strategy paves a new avenue to improve the selectivity of gas sensing by using the microheater to raise substrate temperature. PMID- 26630359 TI - Ion Activation Methods for Peptides and Proteins. PMID- 26630365 TI - Conduct Problems Among Boston-Area Youth Following the 2013 Marathon Bombing: The Moderating Role of Prior Violent Crime Exposure. AB - A large body of work documents the heavy mental health burden of youth exposure to disasters, but the majority of this research has focused on posttraumatic stress and internalizing symptoms. Less is known about associations between disaster exposure and children's conduct problems (CPs), or variables that may moderate such relationships. Given well-documented links between CPs and children's exposure to community violence, youth with greater prior community violence exposure through residence in high-crime areas may be particularly vulnerable to the impacts of disaster exposure on CPs. We surveyed Boston-area caregivers (N = 460) in the first 6 months following the 2013 Marathon bombing on their children's event-related exposures, as well as CPs. To estimate prior violent crime exposure, children's neighborhoods were assigned corresponding violent crime rates obtained from the Federal Bureau of Investigation's uniform crime reporting statistics. Almost 1 in 6 Boston-area children assessed in this convenience sample showed clinically elevated CPs in the aftermath of the Boston Marathon bombing and subsequent manhunt. Prior violent crime exposure significantly moderated the link between children's manhunt exposure (but not bombing exposure) and child CPs. Manhunt exposure was related to increased CPs among children living in areas with high and medium (but not low) levels of prior violent crime. Children living in neighborhoods characterized by violent crime may be at particularly increased risk for developing CPs after violent manmade disasters. As most postdisaster child intervention efforts focus on posttraumatic stress, efforts are needed to develop programs targeting child CPs, particularly for youth dwelling in violent neighborhoods. PMID- 26630366 TI - Vulnerability of wives of Nepalese labor migrants to HIV infection: Integrating quantitative and qualitative evidence. AB - HIV risk is determined by the interaction between social and individual risk factors, but information about such factors among Nepalese women is not yet understood. Therefore, to assess the risk factors and vulnerability of the wives of Nepalese labor migrants to HIV infection, the authors conducted a mixed methods study in which a descriptive qualitative study was embedded within a case control study. Two hundred twenty-four wives of labor migrants were interviewed in the case-control study, and two focus group discussions (n = 8 and 9) were conducted in the qualitative study. The authors found that illiteracy, low socio economic status, and gender inequality contributed to poor knowledge and poor sexual negotiation among the wives of labor migrants and increased their risk of HIV through unprotected sex. Among male labor migrants, illiteracy, low socio economic status, migration to India before marriage, and alcohol consumption contributed to liaisons with female sex workers, increasing the risk of HIV to the men and their wives through unprotected sex. Both labor migrants and their wives feared disclosure of positive HIV status due to HIV stigma and thus were less likely to be tested for HIV. HIV prevention programs should consider the interaction among these risk factors when targeting labor migrants and their wives. PMID- 26630367 TI - Design of an Advanced Membrane Electrode Assembly Employing a Double-Layered Cathode for a PEM Fuel Cell. AB - The membrane electrolyte assembly (MEA) designed in this study utilizes a double layered cathode: an inner catalyst layer prepared by a conventional decal transfer method and an outer catalyst layer directly coated on a gas diffusion layer. The double-layered structure was used to improve the interfacial contact between the catalyst layer and membrane, to increase catalyst utilization and to modify the removal of product water from the cathode. Based on a series of MEAs with double-layered cathodes with an overall Pt loading fixed at 0.4 mg cm(-2) and different ratios of inner-to-outer Pt loading, the MEA with an inner layer of 0.3 mg Pt cm(-2) and an outer layer of 0.1 mg Pt cm(-2) exhibited the best performance. This performance was better than that of the conventional single layered electrode by 13.5% at a current density of 1.4 A cm(-2). PMID- 26630368 TI - A new phenylethanoid glycoside from Incarvillea compacta. AB - A new phenylethanoid glycoside, 3'''-O-methylcampneoside I (1), was isolated from the 90% ethanolic extract of the roots of Incarvillea compacta, together with three known compounds, campneoside I (2), ilicifolioside A (3), and campneoside II (4). Their structures were determined spectroscopically and compared with previously reported spectral data. Compound 1 existed as epimers and displayed better 1,1-diphenyl-2-picrylhydrazyl (DPPH)-free radical scavenging activity using di-tert-butyl-4-methylphenol (BHT) as the positive control. In addition, pretreatment of human HepG2 cells with compound 1 significantly increased the viability on CCl4-induced cell death. PMID- 26630374 TI - Sheltered women's perceptions of their abusive marital relationship: Conflictual themes of dominance and submissiveness. AB - The Core Conflictual Relationship Themes (CCRT) approach was applied in order to examine the conflictual nature of sheltered women's perceptions of their marital relationship following domestic violence in Israel. Thirty-six sheltered women and 89 community-based women were compared. The CCRT method was useful in revealing that battered women, when thinking retrospectively about their relationships with their abusive partners, are concerned with conflictual themes of dominance and submissiveness. The sheltered women reported a desire to be more dominant and less submissive in their relationships with their abusive spouse, despite being less dominant than they wished in practice. These findings help clarify the emotional conflicts that battered women may be dealing with after leaving an abusive relationship and imply that interventions should promote their empowerment. PMID- 26630375 TI - Proteomic Analysis of Silk Viability in Maize Inbred Lines and Their Corresponding Hybrids. AB - A long period of silk viability is critical for a good seed setting rate in maize (Zea mays L.), especially for inbred lines and hybrids with a long interval between anthesis and silking. To explore the molecular mechanism of silk viability and its heterosis, three inbred lines with different silk viability characteristics (Xun928, Lx9801, and Zong3) and their two hybrids (Xun928*Zong3 and Lx9801*Zong3) were analyzed at different developmental stages by a proteomic method. The differentially accumulated proteins were identified by mass spectrometry and classified into metabolism, protein biosynthesis and folding, signal transduction and hormone homeostasis, stress and defense responses, and cellular processes. Proteins involved in nutrient (methionine) and energy (ATP) supply, which support the pollen tube growth in the silk, were important for silk viability and its heterosis. The additive and dominant effects at a single locus, as well as complex epistatic interactions at two or more loci in metabolic pathways, were the primary contributors for mid-parent heterosis of silk viability. Additionally, the proteins involved in the metabolism of anthocyanins, which indirectly negatively regulate local hormone accumulation, were also important for the mid-parent heterosis of silk viability. These results also might imply the developmental dependence of heterosis, because many of the differentially accumulated proteins made distinct contributions to the heterosis of silk viability at specific developmental stages. PMID- 26630376 TI - Plasmonic Biofoam: A Versatile Optically Active Material. AB - Owing to their ability to confine and manipulate light at the nanoscale, plasmonic nanostructures are highly attractive for a broad range of applications. While tremendous progress has been made in the synthesis of size- and shape controlled plasmonic nanostructures, their integration with other materials and application in solid-state is primarily through their assembly on rigid two dimensional (2D) substrates, which limits the plasmonically active space to a few nanometers above the substrate. In this work, we demonstrate a simple method to create plasmonically active three-dimensional biofoams by integrating plasmonic nanostructures with highly porous biomaterial aerogels. We demonstrate that plasmonic biofoam is a versatile optically active platform that can be harnessed for numerous applications including (i) ultrasensitive chemical detection using surface-enhanced Raman scattering; (ii) highly efficient energy harvesting and steam generation through plasmonic photothermal heating; and (iii) optical control of enzymatic activity by triggered release of biomolecules encapsulated within the aerogel. Our results demonstrate that 3D plasmonic biofoam exhibits significantly higher sensing, photothermal, and loading efficiency compared to conventional 2D counterparts. The design principles and processing methodology of plasmonic aerogels demonstrated here can be broadly applied in the fabrication of other functional foams. PMID- 26630377 TI - Correction: Neuroanatomical Correlates of Theory of Mind Deficit in Parkinson's Disease: A Multimodal Imaging Study. PMID- 26630378 TI - Isolation and Genetic Characterization of Mangshi Virus: A Newly Discovered Seadornavirus of the Reoviridae Family Found in Yunnan Province, China. AB - BACKGROUND: Seadornavirus is a genus of viruses in the family Reoviridae, which consists of Banna virus, Kadipiro virus, and Liao ning virus. Banna virus is considered a potential pathogen for zoonotic diseases. Here, we describe a newly discovered Seadornavirus isolated from mosquitos (Culex tritaeniorhynchus) in Yunnan Province, China, which is related to Banna virus, and referred to as Mangshi virus. METHODS AND RESULTS: The Mangshi virus was isolated by cell culture in Aedes albopictus C6/36 cells, in which it replicated and caused cytopathic effects, but not in mammalian BHK-21 or Vero cells. Polyacrylamide gel analysis revealed a genome consisting of 12 segments of double-stranded RNA, with a "6-4-2" pattern in which the migrating bands were different from those of the Banna virus. Complete genome sequencing was performed by full-length amplification of cDNAs. Sequence analysis showed that seven highly conserved nucleotides and three highly conserved nucleotides were present at the ends of the 5'- and 3'-UTRs in each of 12 genome segments. The amino acid identities of Mangshi virus shared with Balaton virus varied from 27.3% (VP11) to 72.3% (VP1) with Banna virus varying from 18.0% (VP11) to 63.9% (VP1). Phylogenetic analysis based on amino acid sequences demonstrated that Mangshi virus is a member of the genus Seadornavirus and is most closely related to, but distinct from, Balaton virus and Banna virus in the genus Seadornavirus of the family Reoviridae. CONCLUSION: Mangshi virus isolated from mosquitoes (C. tritaeniorhynchus) was identified as a newly discovered virus in the genus Seadornavirus and is phylogenetically close to Banna virus, suggesting that there is genetic diversity of seadornaviruses in tropical and subtropical areas of Southeast Asia. PMID- 26630379 TI - Fabrication of high aspect ratio tungsten nanostructures on ultrathin c-Si membranes for extreme UV applications. AB - In this work, we demonstrate a full process for fabricating high aspect ratio diffraction optics for extreme ultraviolet lithography. The transmissive optics consists in nanometer scale tungsten patterns standing on flat, ultrathin (100 nm) and highly transparent (>85% at 13.5 nm) silicon membranes (diameter of 1 mm). These tungsten patterns were achieved using an innovative pseudo-Bosch etching process based on an inductively coupled plasma ignited in a mixture of SF6 and C4F8. Circular ultra-thin Si membranes were fabricated through a state-of the-art method using direct-bonding with thermal difference. The silicon membranes were sputter-coated with a few hundred nanometers (100-300 nm) of stress-controlled tungsten and a very thin layer of chromium. Nanoscale features were written in a thin resist layer by electron beam lithography and transferred onto tungsten by plasma etching of both the chromium hard mask and the tungsten layer. This etching process results in highly anisotropic tungsten features at room temperature. The homogeneity and the aspect ratio of the advanced pattern transfer on the membranes were characterized with scanning electron microscopy after focus ion beam milling. An aspect ratio of about 6 for 35 nm size pattern is successfully obtained on a 1 mm diameter 100 nm thick Si membrane. The whole fabrication process is fully compatible with standard industrial semiconductor technology. PMID- 26630380 TI - Impaired Hyperemic Response to Exercise Post Stroke. AB - Individuals with chronic stroke have reduced perfusion of the paretic lower limb at rest; however, the hyperemic response to graded muscle contractions in this patient population has not been examined. This study quantified blood flow to the paretic and non-paretic lower limbs of subjects with chronic stroke after submaximal contractions of the knee extensor muscles and correlated those measures with limb function and activity. Ten subjects with chronic stroke and ten controls had blood flow through the superficial femoral artery quantified with ultrasonography before and immediately after 10 second contractions of the knee extensor muscles at 20, 40, 60, and 80% of the maximal voluntary contraction (MVC) of the test limb. Blood flow to the paretic and non-paretic limb of stroke subjects was significantly reduced at all load levels compared to control subjects even after normalization to lean muscle mass. Of variables measured, increased blood flow after an 80% MVC was the single best predictor of paretic limb strength, the symmetry of strength between the paretic and non-paretic limbs, coordination of the paretic limb, and physical activity. The impaired hemodynamic response to high intensity contractions was a better predictor of lower limb function than resting perfusion measures. Stroke-dependent weakness and atrophy of the paretic limb do not explain the reduced hyperemic response to muscle contraction alone as the response is similarly reduced in the non-paretic limb when compared to controls. These data may suggest a role for perfusion therapies to optimize rehabilitation post stroke. PMID- 26630381 TI - Adolescent Repeated Alcohol Intoxication as a Predictor of Young Adulthood Alcohol Abuse: The Role of Socioeconomic Context. AB - AIMS: Trajectories of alcohol abuse from adolescence onwards are not well known. We examined the relationship between repeated alcohol intoxication in adolescence and later alcohol abuse, testing whether this association varies depending on individuals' socioeconomic context. METHODS: Study participants (n = 674, age 22 35 years in 2009) belong to the French TEMPO cohort study; their parents also participate in an epidemiological study-the GAZEL cohort. Repeated alcohol intoxication was assessed by questionnaire in adolescence (1999) (defined by >=3 episodes of alcohol intoxication in the preceding 12 months). In young adulthood (2009), alcohol abuse was assessed by the WHO AUDIT questionnaire. Socioeconomic characteristic studied was childhood family income. Data were analyzed using logistic regression models controlling for age, sex, childhood temperament, parental history of alcohol use, and the quality of family relations. RESULTS: Among adolescents who reported repeated alcohol intoxication, 30.8% reported alcohol abuse in young adulthood (adjusted OR=4.27, 95%CI 2.21-8.27). This association appeared stronger in participants who grew up in families with low income (adjusted OR=11.86, 95%CI 3.35-41.94 vs. 2.49, 95%CI 1.09-5.68 for youths from families with intermediate or high income). CONCLUSIONS: In most adolescents (69.2%), alcohol abuse is a time-limited behavior. Nonetheless, in participants from low income families, the likelihood of persistent alcohol abuse beyond adolescence may be increased. Although some limitations are noted, a preliminary conclusion is that alcohol abuse trajectories over time need to be monitored, particularly in certain subgroups. PMID- 26630382 TI - Spatial Patterns in Biofilm Diversity across Hierarchical Levels of River Floodplain Landscapes. AB - River-floodplain systems are among the most diverse and productive ecosystems, but the effects of biophysical complexity at multiple scales on microbial biodiversity have not been studied. Here, we investigated how the hierarchical organization of river systems (i.e., region, floodplain, zone, habitats, and microhabitats) influences epilithic biofilm community assemblage patterns by characterizing microbial communities using 16S rRNA gene sequence data and analyzing bacterial species distribution across local and regional scales. Results indicate that regional and local environmental filters concurrently sort bacterial species, suggesting that spatial configuration of epilithic biofilms resembles patterns of larger organisms in floodplain ecosystems. Along the hierarchical organization of fluvial systems, floodplains constitute a vector of maximum environmental heterogeneity and consequently act as a major landscape filter for biofilm species. Thus, river basins and associated floodplains may simply reflect very large scale 'patches' within which environmental conditions select for community composition of epilithic biofilms. PMID- 26630383 TI - Analysis of Enterovirus 68 Strains from the 2014 North American Outbreak Reveals a New Clade, Indicating Viral Evolution. AB - Enterovirus 68 (EVD68) causes respiratory illness, mostly in children. Despite a reported low-level of transmission, the occurrence of several recent outbreaks worldwide including the 2014 outbreak in North America has raised concerns regarding the pathogenesis and evolution of EVD68. To elucidate the phylogenetic features of EVD68 and possible causes for the 2014 outbreak, 216 EVD68 strain sequences were retrieved from Genbank, including 22 from the 2014 outbreak. Several geographic and genotypic origins were established for these 22 strains, 19 of which were classified as Clade B. Of these 19 strains, 17 exhibited subsequent clustering and variation in protein residues involved in host-receptor interaction and/or viral antigenicity. Approximately 18 inter-clade variations were detected in VP1, which led to the identification of a new Clade D in EVD68 strains. The classification of this new clade was also verified by the re construction of a Neighbor-Joining tree during the phylogenetic analysis. In addition, our results indicate that members of Clade B containing highly specific alterations in VP1 protein residues were the foremost contributors to the 2014 outbreak in the US. Altered host-receptor interaction and/or host immune recognition may explain the evolution of EVD68 as well as the global emergence and ongoing adaptation of this virus. PMID- 26630384 TI - Fidelity and Promiscuity in an Ant-Plant Mutualism: A Case Study of Triplaris and Pseudomyrmex. AB - The association between the myrmecophyte Triplaris and ants of the genus Pseudomyrmex is an often-reported example of mutualism but no molecular studies have examined this association to date. In this study, the interspecific relationships of Triplaris were reconstructed using five molecular markers (two chloroplast and three nuclear), and the relationships of the associated Pseudomyrmex using two molecular regions (one mitochondrial and one nuclear). A data set including all known collections of plant hosts and resident ants was also compiled. The pattern of distribution of both organisms reveals that there are varying degrees of host specificity; most ants show broader host usage (promiscuous) but one species (P. dendroicus) is faithful to a single species of Triplaris. In most ant-plant interactions, host usage is not specific at the species level and preferences may result from geographical or ecological sorting. The specificity of P. dendroicus could be based on chemical recognition of the host they were raised on. PMID- 26630385 TI - Vitamin D Status Is an Independent Risk Factor for Global Cognitive Impairment in Peritoneal Dialysis Patients. AB - OBJECTIVE: Vitamin D (VD) deficiency is an independent risk factor for cognitive impairment (CI) in the general population, but VD status in peritoneal dialysis (PD) patients has not been investigated. In this study, we aimed to investigate the relationship between serum VD levels and global and specific cognitive functions in PD patients. DESIGN AND SETTING: Cross-sectional study, simultaneously conducted at two PD centers. PATIENTS: Clinically stable patients (n = 273) undergoing PD for at least 3 months were enrolled over a period of one year. MAIN OUTCOME MEASURES: Demographic and comorbidity data were recorded, and routine biochemical parameters and serum 25-hydroxyvitamin D (25(OH) D) levels of overnight fasted patients were determined. Global cognitive function was assessed by the Modified Mini-Mental State Examination (3MS) score; executive function, by the trail making tests (Trails A and B); and immediate memory, delayed memory, and language ability by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) sub-tests. RESULTS: In the univariate analysis, serum 25(OH) D levels significantly correlated with 3MS scores (r = -0.139; P = 0.02), and Trail A (r = -0.188; P = 0.002) and B (r = -0.154; P = 0.01) completion times. In the multivariate analysis, 25(OH) D was found to be independently associated with global CI, but not with executive dysfunction. Serum 25(OH) D could not predict scores of immediate/delayed memory and language ability. CONCLUSIONS: VD deficiency is highly prevalent in PD patients and is an independent risk factor for global CI in this patient cohort. PMID- 26630387 TI - Temporal Changes in Forest Contexts at Multiple Extents: Three Decades of Fragmentation in the Gran Chaco (1979-2010), Central Argentina. AB - The context in which a forest exists strongly influences its function and sustainability. Unveiling the multi-scale nature of forest fragmentation context is crucial to understand how human activities affect the spatial patterns of forests across a range of scales. However, this issue remains almost unexplored in subtropical ecosystems. In this study, we analyzed temporal changes (1979 2010) in forest contexts in the Argentinean dry Chaco at multiple extents. We classified forests over the last three decades based on forest context amount (Pf) and structural connectivity (Pff), which were measured using a moving window approach fixed at eight different extents (from local, ~ 6 ha, to regional, ~ 8300 ha). Specific multi-scale forest context profiles (for the years 1979 and 2010) were defined by projecting Pf vs. Pff mean values and were compared across spatial extents. The distributions of Pf across scales were described by scalograms and their shapes over time were compared. The amount of agricultural land and rangelands across the scales were also analyzed. The dry Chaco has undergone an intensive process of fragmentation, resulting in a shift from landscapes dominated by forests with gaps of rangelands to landscapes where small forest patches are embedded in agricultural lands. Multi-scale fragmentation analysis depicted landscapes in which local exploitation, which perforates forest cover, occurs alongside extensive forest clearings, reducing forests to small and isolated patches surrounded by agricultural lands. In addition, the temporal diminution of Pf's variability along with the increment of the mean slope of the Pf 's scalograms, indicate a simplification of the spatial pattern of forest over time. The observed changes have most likely been the result of the interplay between human activities and environmental constraints, which have shaped the spatial patterns of forests across scales. Based on our results, strategies for the conservation and sustainable management of the dry Chaco should take into account both the context of each habitat location and the scales over which a forest pattern might be preserved, altered or restored. PMID- 26630386 TI - Associated Liver Partition and Portal Vein Ligation (ALPPS) vs Selective Portal Vein Ligation (PVL) for Staged Hepatectomy in a Rat Model. Similar Regenerative Response? AB - Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage hepatectomy technique which can be associated with a hypertrophic stimulus on the future liver remnant (FLR) stronger than other techniques--such as portal vein ligation (PVL). However, the reason of such hypertrophy is still unclear, but it is suggested that liver transection combined with portal vein ligation (ALPPS) during the first stage of this technique may play a key role. The aim of this study is to compare the hypertrophic stimulus on the FLR and the clinical changes associated with both ALPPS and PVL in a rat surgical model. For this purpose, three groups of SD rats were used, namely ALPPS (n = 30), PVL (n = 30) and sham-treated (n = 30). The second stage of ALPPS (hepatectomy of the atrophic lobes), was performed at day 8. Blood and FLR samples were collected at 1, 24, 48 hours, 8 days and 12 weeks after the surgeries. ALPPS provoked a greater degree of hypertrophy of the FLR than the PVL at 48 hours and 8 days (p<0.05). The molecular pattern was also different, with the highest expression of IL-1beta at 24h, IL-6 at 8 days, and HGF and TNF-alpha at 48 hours and 8 days (p<0.05). ALPPS also brought about a mild proliferative stimulus at 12 weeks, with a higher expression of HGF and TGF-beta (p<0.05) than PVL. Clinically, ALPPS caused a significant liver damage during the first 48 hours, with a recovery of liver function at day 8. In conclusion, ALPPS seems to induce higher functional hypertrophy on the FLR than PVL at day 8. Such regenerative response seems to be leaded by a complex interaction between pro mitogenic (IL-6, HGF, TNF-alpha) and antiproliferative (IL1-beta and TGF-beta) cytokines. PMID- 26630390 TI - Salivary cortisol and explicit memory in postmenopausal women using hormone replacement therapy. AB - Circulating cortisol levels are known to influence explicit memory in humans and other primates. The present study investigated salivary cortisol and its association with explicit memory performance in 99 postmenopausal women (64 treated with conjugated equine estrogens or estradiol, and 35 matched controls not using any form of hormone therapy). Controls were compared with treated women taking estrogens alone (n=39), or taking estrogens in combination with a progestin (n=25). Mean time on hormone therapy was approximately 5 years, with initiation of treatment in close proximity to the onset of menopause. Explicit memory was assessed with the California Verbal Learning Test (CVLT). Saliva was collected before (basal or resting sample) and after (post-test sample) completing a set of cognitive tasks. Cortisol was measured using a high sensitivity radioimmunoassay. Treated women were found to have higher resting cortisol concentrations than controls matched for time of day. Basal cortisol was a modest predictor of learning and memory on the CVLT. Higher cortisol was associated with better recall and fewer memory errors, which is consistent with experimental studies examining explicit memory under small increases in circulating cortisol load. Potential cumulative effects on the central nervous system of sustained exposure to mildly increased cortisol in conjunction with the long-term use of oral estrogens are discussed in the context of aging and dementia. PMID- 26630388 TI - Involvement of the oxytocin system in the bed nucleus of the stria terminalis in the sex-specific regulation of social recognition. AB - Sex differences in the oxytocin (OT) system in the brain may explain why OT often regulates social behaviors in sex-specific ways. However, a link between sex differences in the OT system and sex-specific regulation of social behavior has not been tested. Here, we determined whether sex differences in the OT receptor (OTR) or in OT release in the posterior bed nucleus of the stria terminalis (pBNST) mediates sex-specific regulation of social recognition in rats. We recently showed that, compared to female rats, male rats have a three-fold higher OTR binding density in the pBNST, a sexually dimorphic area implicated in the regulation of social behaviors. We now demonstrate that OTR antagonist (5 ng/0.5 MUl/side) administration into the pBNST impairs social recognition in both sexes, while OT (100 pg/0.5 MUl/side) administration into the pBNST prolongs the duration of social recognition in males only. These effects seem specific to social recognition, as neither treatment altered total social investigation time in either sex. Moreover, baseline OT release in the pBNST, as measured with in vivo microdialysis, did not differ between the sexes. However, males showed higher OT release in the pBNST during social recognition compared to females. These findings suggest a sex-specific role of the OT system in the pBNST in the regulation of social recognition. PMID- 26630389 TI - CRF-R1 activation in the anterior-dorsal BNST induces maternal neglect in lactating rats via an HPA axis-independent central mechanism. AB - Adequate maternal behavior in rats requires minimal corticotropin-releasing factor receptor (CRF-R) activation in the medial-posterior bed nucleus of the stria terminalis (mpBNST). Based on the architectural heterogeneity of the BNST and its distinct inter-neural connectivity, we tested whether CRF-R manipulation in another functional part, the anterior-dorsal BNST (adBNST), differentially modulates maternal behavior. We demonstrate that in the adBNST, activation of CRF R1 reduced arched back nursing (ABN) and nursing, whereas activation of CRF-R2 resulted in an initial reduction in nursing but significantly increased the incidence of ABN 5h after the treatment. Following stressor exposure, which is detrimental to maternal care, ABN tended to be protected by CRF-R1 blockade. Maternal motivation, maternal aggression, and anxiety were unaffected by any manipulation. Furthermore, under basal and stress conditions, activation of adBNST CRF-R1 increased plasma ACTH and corticosterone concentrations, whereas stimulation of adBNST CRF-R2 increased basal plasma ACTH and corticosterone concentrations, but blocked the stress-induced increase in plasma corticosterone secretion. Moreover, both the CRF-R1 and -R2 antagonists prevented the stress induced increase in plasma corticosterone secretion. Importantly, elevated levels of circulating corticosterone induced by intra-adBNST administration of CRF-R1 or -R2 agonist did not impact maternal care. Finally, Crf mRNA expression in the adBNST was increased during lactation; however, Crfr1 mRNA expression was similar between lactating and virgin rats. In conclusion, maternal care is impaired by adBNST CRF-R1 activation, and this appears to be the result of a central action, rather than an effect of elevated circulating levels of CORT. These data provide new insights into potential causes of disturbed maternal behavior postpartum. PMID- 26630391 TI - Diurnal neurobiological alterations after exposure to clozapine in first-episode schizophrenia patients. AB - BACKGROUND: Irregular circadian rhythm and some of its most characteristic symptoms are frequently observed in patients with schizophrenia. However, changes in the expression of clock genes or neuropeptides that are related to the regulation of circadian rhythm may influence the susceptibility to recurrence after antipsychotic treatment in schizophrenia, but this possibility has not been investigated. METHODS: Blood samples were collected from 15 healthy male controls and 13 male schizophrenia patients at 4h intervals for 24h before and after treatment with clozapine for 8 weeks. The outcome measures included the relative expression of clock gene mRNA PERIOD1 (PER1), PERIOD2 (PER2), PERIOD3 (PER3) and the levels of plasma cortisol, orexin, and insulin. RESULTS: Compared with healthy controls, schizophrenia patients presented disruptions in diurnal rhythms of the expression of PER1, PER3, and NPAS2 and the release of orexin, accompanied by a delayed phase in the expression of PER2, decreases in PER3 and NPAS2 expression, and an increase in cortisol levels at baseline. Several of these disruptions (i.e., in PER1 and PER3 expression) persisted after 8 weeks of clozapine treatment, similar to the decreases in the 24-h expression of PER3 and NPAS2. Clozapine treatment for 8 weeks significantly decreased the 24-h levels of PER2 and increased the 24-h levels of insulin. CONCLUSION: These persistent neurobiological changes that occur after 8 weeks of clozapine treatment may contribute to the vulnerability to recurrence and efficacy of long-term maintenance treatment in schizophrenia. PMID- 26630392 TI - "Rate My Therapist": Automated Detection of Empathy in Drug and Alcohol Counseling via Speech and Language Processing. AB - The technology for evaluating patient-provider interactions in psychotherapy observational coding-has not changed in 70 years. It is labor-intensive, error prone, and expensive, limiting its use in evaluating psychotherapy in the real world. Engineering solutions from speech and language processing provide new methods for the automatic evaluation of provider ratings from session recordings. The primary data are 200 Motivational Interviewing (MI) sessions from a study on MI training methods with observer ratings of counselor empathy. Automatic Speech Recognition (ASR) was used to transcribe sessions, and the resulting words were used in a text-based predictive model of empathy. Two supporting datasets trained the speech processing tasks including ASR (1200 transcripts from heterogeneous psychotherapy sessions and 153 transcripts and session recordings from 5 MI clinical trials). The accuracy of computationally-derived empathy ratings were evaluated against human ratings for each provider. Computationally-derived empathy scores and classifications (high vs. low) were highly accurate against human-based codes and classifications, with a correlation of 0.65 and F-score (a weighted average of sensitivity and specificity) of 0.86, respectively. Empathy prediction using human transcription as input (as opposed to ASR) resulted in a slight increase in prediction accuracies, suggesting that the fully automatic system with ASR is relatively robust. Using speech and language processing methods, it is possible to generate accurate predictions of provider performance in psychotherapy from audio recordings alone. This technology can support large scale evaluation of psychotherapy for dissemination and process studies. PMID- 26630394 TI - Association between the serotonin transporter and cytokines: Implications for the pathophysiology of bipolar disorder. AB - BACKGROUND: Reduced brain serotonin transporter (SERT) has been demonstrated in bipolar disorder (BD). The aim of this study was to explore the potential role of cytokines on reduced SERT in BD. METHODS: Twenty-eight BD type I patients and 28 age- and gender-matched healthy controls (HCs) were recruited. Single photon emission computed tomography with the radiotracer 123I ADAM was used for SERT imaging. Regions of interest included the midbrain, thalamus, putamen and caudate. Seven cytokines, including tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1alpha (IL-1alpha), IL-1beta, IL-4, IL 6 and IL-10, were measured using an enzyme linked immune-sorbent assay. RESULTS: SERT availability in the midbrain and caudate was significantly lower in BD compared to HCs. IL-1beta was significantly lower, whereas IL-10 was significantly higher in BD compared to HCs. Multiple linear regression analyses revealed that there were associations between cytokines, IL-1alpha, IL-1beta, IL 6 and SERT availability in the midbrain but not in the thalamus, putamen and caudate. Furthermore, linear mixed effect analyses demonstrated that these associations were not different between HCs and BD. CONCLUSION: While many cytokines have been proposed to be important in the pathophysiology of BD, our results demonstrated that significant associations between cytokines and SERT availability may explain the role of cytokines in mood regulation. However, these associations were not different between HCs and BD, which imply the role of these cytokines is not specific for BD. PMID- 26630393 TI - Space-Use Patterns of the Asiatic Wild Ass (Equus hemionus): Complementary Insights from Displacement, Recursion Movement and Habitat Selection Analyses. AB - The way in which animals move and use the landscape is influenced by the spatial distribution of resources, and is of importance when considering species conservation. We aimed at exploring how landscape-related factors affect a large herbivore's space-use patterns by using a combined approach, integrating movement (displacement and recursions) and habitat selection analyses. We studied the endangered Asiatic wild ass (Equus hemionus) in the Negev Desert, Israel, using GPS monitoring and direct observation. We found that the main landscape-related factors affecting the species' space-use patterns, on a daily and seasonal basis, were vegetation cover, water sources and topography. Two main habitat types were selected: high-elevation sites during the day (specific microclimate: windy on warm summer days) and streambed surroundings during the night (coupled with high vegetation when the animals were active in summer). Distribution of recursion times (duration between visits) revealed a 24-hour periodicity, a pattern that could be widespread among large herbivores. Characterizing frequently revisited sites suggested that recursion movements were mainly driven by a few landscape features (water sources, vegetation patches, high-elevation points), but also by social factors, such as territoriality, which should be further explored. This study provided complementary insights into the space-use patterns of E. hemionus. Understanding of the species' space-use patterns, at both large and fine spatial scale, is required for developing appropriate conservation protocols. Our approach could be further applied for studying the space-use patterns of other species in heterogeneous landscapes. PMID- 26630395 TI - Decreased medial frontal gyrus in patients with adjustment disorder. AB - BACKGROUNDS: Adjustment disorder is a frequent mental illness that occurs under various stressful situations. Whereas adjustment disorder has distinct clinical manifestations and diagnostic entity, few studies have investigated its underlying neural substrate. This study aimed to identify brain structural abnormalities among patients with adjustment disorder. METHODS: Twenty-five patients with adjustment disorder and 25 healthy controls participated in the study. Structural magnetic resonance imaging was performed, and a voxel-based morphometry was applied. Family-wise error-corrected p values for statistical analysis of comparative gray matters between patients with adjustment disorder and healthy controls were used. RESULTS: Patients with adjustment disorder had decreased gray matter volume in the right medial frontal gyrus as compared to healthy controls. There were no brain regions that were decreased in the healthy controls as compared to patients with adjustment disorder. LIMITATIONS: This study was a cross-sectional design. CONCLUSIONS: Our results suggest that adjustment disorder arises from characteristic neural abnormalities, contrary to previous notions suggesting that adjustment disorder is a non-specific and/or residual diagnostic term. Moreover, future studies should examine the underlying neural substrates responsible for successful adaptation to unfamiliar and stressful situations. PMID- 26630396 TI - Pulmonary Hypertension in Patients with Chronic Fibrosing Idiopathic Interstitial Pneumonias. AB - BACKGROUND: Pulmonary hypertension (PH) is a common finding in patients with chronic fibrosing idiopathic interstitial pneumonias (IIP). Little is known about the response to pulmonary vasodilator therapy in this patient population. COMPERA is an international registry that prospectively captures data from patients with various forms of PH receiving pulmonary vasodilator therapies. METHODS: We retrieved data from COMPERA to compare patient characteristics, treatment patterns, response to therapy and survival in newly diagnosed patients with idiopathic pulmonary arterial hypertension (IPAH) and PH associated with IIP (PH IIP). RESULTS: Compared to patients with IPAH (n = 798), patients with PH-IIP (n = 151) were older and predominantly males. Patients with PH-IIP were treated predominantly with phosphodiesterase-5 inhibitors (88% at entry, 87% after 1 year). From baseline to the first follow-up visit, the median improvement in 6MWD was 30 m in patients with IPAH and 24.5 m in patients with PH-IIP (p = 0.457 for the difference between both groups). Improvements in NYHA functional class were observed in 22.4% and 29.5% of these patients, respectively (p = 0.179 for the difference between both groups). Survival rates were significantly worse in PH IIP than in IPAH (3-year survival 34.0 versus 68.6%; p<0.001). Total lung capacity, NYHA class IV, and mixed-venous oxygen saturation were independent predictors of survival in patients with PH-IIP. CONCLUSIONS: Patients with PH-IIP have a dismal prognosis. Our results suggest that pulmonary vasodilator therapy may be associated with short-term functional improvement in some of these patients but it is unclear whether this treatment affects survival. TRIAL REGISTRATION: clinicaltrials.gov NCT01347216. PMID- 26630398 TI - Two stages of XRCC1 recruitment and two classes of XRCC1 foci formed in response to low level DNA damage induced by visible light, or stress triggered by heat shock. AB - Induction of local photosensitised DNA damage has been used to study recruitment of repair factors, spatial organisation and subsequent stages of the repair processes. However, the damage induced by a focused laser beam interacting with a photosensitiser may not fully reflect the types of damage and repair encountered in cells of an animal under typical conditions in vivo. We report on two characteristic stages of recruitment of XRCC1 (a protein engaged in BER and SSB repair pathways), in response to low level DNA damage induced by visible light. We demonstrate that, when just a few DNA breaks are induced in a small region of the nucleus, the recruited XRCC1 is initially distributed uniformly throughout this region, and rearranges into several small stationary foci within minutes. In contrast, when heavy damage of various types (including oxidative damage) is induced in cells pre-sensitized with a DNA-binding drug ethidium bromide, XRCC1 is also recruited but fails to rearrange from the stage of the uniform distribution to the stage of several small foci, indicating that this heavy damage interferes with the progress and completion of the repair processes. We hypothesize that that first stage may reflect recruitment of XRCC1 to poly(ADP ribose) moieties in the region surrounding the single-strand break, while the second-binding directly to the DNA lesions. We also show that moderate damage or stress induces formation of two types of XRCC1-containing foci differing in their mobility. A large subset of DNA damage-induced XRCC1 foci is associated with a major component of PML nuclear bodies--the Sp100 protein. PMID- 26630397 TI - SNP Regulation of microRNA Expression and Subsequent Colon Cancer Risk. AB - INTRODUCTION: MicroRNAs (miRNAs) regulate messenger RNAs (mRNAs) and as such have been implicated in a variety of diseases, including cancer. MiRNAs regulate mRNAs through binding of the miRNA 5' seed sequence (~7-8 nucleotides) to the mRNA 3' UTRs; polymorphisms in these regions have the potential to alter miRNA-mRNA target associations. SNPs in miRNA genes as well as miRNA-target genes have been proposed to influence cancer risk through altered miRNA expression levels. METHODS: MiRNA-SNPs and miRNA-target gene-SNPs were identified through the literature. We used SNPs from Genome-Wide Association Study (GWAS) data that were matched to individuals with miRNA expression data generated from an Agilent platform for colon tumor and non-tumor paired tissues. These samples were used to evaluate 327 miRNA-SNP pairs for associations between SNPs and miRNA expression levels as well as for SNP associations with colon cancer. RESULTS: Twenty-two miRNAs expressed in non-tumor tissue were significantly different by genotype and 21 SNPs were associated with altered tumor/non-tumor differential miRNA expression across genotypes. Two miRNAs were associated with SNP genotype for both non-tumor and tumor/non-tumor differential expression. Of the 41 miRNAs significantly associated with SNPs all but seven were significantly differentially expressed in colon tumor tissue. Two of the 41 SNPs significantly associated with miRNA expression levels were associated with colon cancer risk: rs8176318 (BRCA1), ORAA 1.31 95% CI 1.01, 1.78, and rs8905 (PRKAR1A), ORGG 2.31 95% CI 1.11, 4.77. CONCLUSION: Of the 327 SNPs identified in the literature as being important because of their potential regulation of miRNA expression levels, 12.5% had statistically significantly associations with miRNA expression. However, only two of these SNPs were significantly associated with colon cancer. PMID- 26630399 TI - Temporal Trends in Fertility Rates: A Nationwide Registry Based Study from 1901 to 2014. AB - OBJECTIVE: Increasing age at first childbirth has been suggested to increase the risk for infertility. Our objective is to determine whether women above thirty years of age historically have been able to sustain fertility rates above replacement level. DESIGN: A descriptive nationwide Danish study using birth registries from 1901-2014. SETTING: Information on women's age at childbirth was obtained by using records from primary, secondary and tertiary institutions. PARTICIPANTS: Mothers to 8,024,969 live births. MAIN OUTCOME MEASURES: Mothers were stratified according to age at childbirth to determine total and age specific fertility rates. RESULTS: Total fertility rate (TFR) decreased from 4.1 to 1.8 children per woman and age specific fertility also decreased from 1901 to 2014. Women aged 30-34, 35-39 or 40-44 years in the first decade of the 20th century had higher fertility rates than the corresponding five year younger age groups (25-29, 30-34 and 35-39, respectively) have had for the last 65 years. On average, women gave birth to two children after the age of 30 and one or more child after 35 years of age in the beginning of the 1900s. Furthermore, women more than 40 years of age accounted for 10% of TFR in 1901 compared with 4% in 2014 despite usage of assisted reproduction. CONCLUSION: This nationwide study shows that women above 30 years of age historically have been able to sustain fertility rates above replacement level. This implies that other factors besides age are strong determinants of fertility in women above 30 years of age. PMID- 26630400 TI - Ranibizumab for High-Risk Proliferative Diabetic Retinopathy: An Exploratory Randomized Controlled Trial. AB - PURPOSE: To compare the efficacy and safety of intravitreal ranibizumab (IVR) in monotherapy or associated with panretinal photocoagulation (PRP) versus conventional PRP, for high-risk proliferative diabetic retinopathy (PDR) without vitreoretinal traction. PROCEDURES: Multicenter randomized trial, with 3 treatment arms: PRP versus IVR alone and PRP + IVR combined treatment. Follow-up was performed at months 3, 6 and 12. RESULTS: Thirty-five subjects were randomized and 32 used for analysis. Complete regression of neovessels elsewhere occurred in 100% (PRP + IVR), 75% (IVR) and 69.2% (PRP) and for neovessels of the disk in 44.4% (PRP + IVR), 37.5% (IVR) and 30.8% (PRP). During the 1-year duration of treatment, there was no need for laser rescue treatment in IVR treated eyes. CONCLUSIONS: This trial suggests that the use of IVR is safe and may have a beneficial effect in the treatment of eyes with high-risk PDR. MESSAGE: Ranibizumab appears to have a place in the treatment of PDR. PMID- 26630401 TI - Exposure to methylphenidate during infancy and adolescence in non-human animals and sensitization to abuse of psychostimulants later in life: a systematic review. AB - INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric pathology that has an important prevalence among young people and is difficult to diagnose. It is usually treated with methylphenidate, a psychostimulant with a mechanism of action similar to that of cocaine. Previous studies show that repeated use of psychostimulants during childhood or adolescence may sensitize subjects, making them more prone to later abuse of psychostimulant drugs such as cocaine and methamphetamine. OBJECTIVE: To review experimental studies in non-human models (rodents and monkeys) treated with methylphenidate during infancy or adolescence and tested for reinforcing effects on psychostimulant drugs in adulthood. METHOD: Systematic collection of data was performed on four databases (Web of Knowledge, PsycARTICLE, PubMed and SciELO). The initial search identified 202 articles published from 2009 to 2014, which were screened for eligibility. Seven articles met the inclusion criteria and were reviewed in this study. RESULTS: The findings indicate that early exposure to methylphenidate has an effect on an ADHD animal model, specifically, on spontaneously hypertensive strain rats, especially those tested using the self administration paradigm. CONCLUSION: Future studies should prioritize the spontaneously hypertensive rat strain - an animal model of ADHD. Experimental designs comparing different behavioral paradigms and modes of administration using this strain could lead to improved understanding of the effects of exposure to methylphenidate during childhood and adolescence. PMID- 26630402 TI - Systematic review of research investigating psychotherapy and information and communication technologies. AB - INTRODUCTION: Information and communication technologies (ICTs) are devices, services and knowledge that reproduce, process and distribute information. Psychotherapy has been influenced by these technologies, and there is a tendency for their role to expand. OBJECTIVE: To describe the current panorama of the scientific literature on psychotherapy and ICTs. METHOD: This is a systematic and descriptive review. Searches were run on the electronic databases Biblioteca Virtual em Saude (BVS), PsycINFO, Scopus, PePSIC, ScienceDirect and Index Psi, using the Boolean operator AND and the descriptors psychotherapy, computers, Internet, cell phones and social networks. RESULTS: A considerable volume of empirical research was found, published recently in many different parts of the world, especially in the United States. There is very little Brazilian research on the subject. The majority of the studies identified assess the efficacy or describe the development of techniques and psychotherapies, via ICTs, for prevention, diagnosis or treatment of mental and behavioral disorders. The psychopathology most investigated in this area is depression and it was not possible to draw conclusions on a possible trend for research into the subject to increase. The technology most investigated was the Internet and cognitive behavioral therapy was the most common theoretical approach in these studies. CONCLUSIONS: Systematic reviews of published studies can detect gaps in the research agenda within a specific field of knowledge. PMID- 26630403 TI - Profile and pattern of crack consumption among inpatients in a Brazilian psychiatric hospital. AB - INTRODUCTION: Crack cocaine use is associated with polydrug abuse, and inpatients dependent on crack exhibit profiles of serious consumption patterns. Use of alcohol and tobacco and other drugs is a risk factor for experimentation of additional drugs, including crack cocaine. OBJECTIVES: The present study describes the characteristics and crack consumption patterns among inpatients in treatment during 2011 and 2012 at the Hospital Psiquiatrico Sao Pedro (Porto Alegre, Brazil). An additional objective was to identify the sequence of alcohol and tobacco consumption prior to crack use. METHODS: The participants were 53 male inpatients addicted to crack with a mean age of 27.5+/-7.3 years. A sociodemographic questionnaire; the Alcohol, Smoking and Substance Involvement Screening Test and the Mini Mental State Examination were all administered to participants. Inclusion criteria were crack cocaine dependency (based on the 10th edition of the International Classification of Diseases [ICD-10]) and being abstinent for 7 days. Patients with cognitive difficulties who were unable to understand and/or respond to the questionnaires were excluded from the sample. RESULTS: The participants were young male adults with low educational level and low incomes and were polydrug users. The majority had made more than one attempt to quit. Use of legal drugs in early adolescence, prior to crack use, was identified. CONCLUSIONS: The profiles of the inpatients addicted to crack treated at this hospital indicate a serious usage pattern among those who seek specialized support. Crack use is frequent and is associated with use of other drugs and with difficulty sustaining abstinence. The pattern of progression from alcohol and tobacco use to crack cocaine dependency demands the attention of those responsible for prevention policies. PMID- 26630404 TI - Countertransference and therapeutic alliance in the early stage of adult psychodynamic psychotherapy. AB - OBJECTIVES: The primary objective of this study was to assess the relationship between countertransference (CT) and therapeutic alliance (TA) during the early stages of psychodynamic psychotherapy. A secondary objective is to assess associations between CT and variables related to therapist and patient and between CT and other patient variables investigated, which were defense mechanisms, symptomology and functionality. METHODOLOGY: This was a cross sectional study that enrolled 30 patients treated by 17 different therapists at the psychotherapy clinics of two psychiatry centers. Assessments of each patient therapist pair were conducted between their fourth and 10th sessions. RESULTS: The CT distance domain exhibited a moderate negative correlation with TA, particularly its sub-dimension representing the patient's capacity for work in therapy. Moderate positive correlations were observed between CT distance and the splitting defense mechanism and between CT closeness and suppression defenses, in addition to moderate negative correlation between CT indifference and the fantasy defense mechanism. Another finding was higher scores for CT indifference in association with socioeconomic classes D and E. CONCLUSIONS: The quality of CT may provide a source of information about TA. A high degree of CT distance represents a low level of TA, particularly with relation to the patient's working capacity, although presence of the splitting defense mechanism can affect CT, to the extent that it constitutes a confounding variable. The concept of CT is useful to psychotherapists, providing a source of information about the patient's internal world and about certain elements of therapy, such as the quality of TA, which is important for good treatment results. PMID- 26630405 TI - Ethanol during adolescence decreased the BDNF levels in the hippocampus in adult male Wistar rats, but did not alter aggressive and anxiety-like behaviors. AB - OBJECTIVE: To investigate the effects of ethanol exposure in adolescent rats during adulthood by assesssing aggression and anxiety-like behaviors and measuring the levels of inflammatory markers. METHODS: Groups of male Wistar rats (mean weight 81.4 g, n = 36) were housed in groups of four until postnatal day (PND) 60. From PNDs 30 to 46, rats received one of three treatments: 3 g/kg of ethanol (15% w/v, orally, n = 16), 1.5 g/kg of ethanol (12.5% w/v, PO, n = 12), or water (n = 12) every 48 hours. Animals were assessed for aggressive behavior (resident x intruder test) and anxiety-like behaviors (elevated plus maze) during adulthood. RESULTS: Animals that received low doses of alcohol showed reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus as compared to the control group. No significant difference was found in prefrontal cortex. CONCLUSIONS: Intermittent exposure to alcohol during adolescence is associated with lower levels of BDNF in the hippocampus, probably due the episodic administration of alcohol, but alcohol use did not alter the level agression toward a male intruder or anxiety-like behaviors during the adult phase. PMID- 26630406 TI - Insight in bipolar disorder: a comparison between mania, depression and euthymia using the Insight Scale for Affective Disorders. AB - OBJECTIVE: To evaluate whether having general insight into bipolar disorder and its symptoms is affected by the mood state of the patient, using the Insight Scale for Affective Disorders, a hetero-application scale for people with mood disorders. METHODS: Ninety-five patients with bipolar disorder were evaluated and divided into different groups according to the mood state presented during assessment (i.e., euthymia, mania and depression). Sociodemographic and clinical data (Hamilton Depression Scale, Young Mania Rating Scale, and Clinical Global Impressions Scale) were recorded. Insight was evaluated using the Insight Scale for Affective Disorders. RESULTS: Patients with bipolar disorder in mania show less insight about their condition than patients in depression or euthymia, and less insight about their symptoms than patients with depression, with the exception of awareness of weight change. CONCLUSIONS: Loss of insight during mania may have important implications for treatment compliance and adherence and needs to be taken into account in the clinical management of people with bipolar disorder. PMID- 26630407 TI - Attention deficit hyperactivity disorder is an independent risk factor for lower resilience in adolescents: a pilot study. AB - OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is associated with impaired daily functioning in a wide range of domains. Resilience, the ability to overcome and recover from challenges, has been scarcely investigated in ADHD and could potentially provide novel strategies for treatment. However, since ADHD is often comorbid with other clinical conditions, it is necessary to better understand if it impairs resilience levels when controlled for other variables. This pilot study is the first to investigate the correlation between quantitative measures of resilience and ADHD using strict diagnostic criteria by controlling this correlation for comorbid conditions. METHODS: Twelve adolescents diagnosed with ADHD via semi-structured interview using Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) were compared to 12 adolescents exhibiting typical development, regarding resilience, in an analysis controlled for anxiety and depression levels, socioeconomic status, and intelligence quotient (IQ). RESULTS: The ADHD group was less resilient than the control group (p < 0.01). Importantly, resilience in the ADHD group was not correlated with depression or anxiety, age, intelligence level, and socioeconomic status. CONCLUSIONS: ADHD seems to be associated with lower resilience, which cannot be explained by depression, anxiety, intelligence level, age, or socioeconomic status. PMID- 26630408 TI - Assessing levels of similarity to a "psychodynamic prototype" in psychodynamic psychotherapy with children: a case study approach (preliminary findings). AB - OBJECTIVE: To analyze the degree of similarity to a "psychodynamic prototype" during the first year of two children's once-weekly psychodynamic psychotherapy. METHODS: This study used a longitudinal, descriptive, repeated-measures design based on the systematic case study method. Two male school children (here referred to as Walter and Peter) and their therapists took part in the study. All sessions were video and audio recorded. Ten sessions from each case were selected for analysis in this preliminary study. Trained examiners (randomly selected in pairs) independently and blindly evaluated each session using the Child Psychotherapy Q-Set (CPQ). Experts in psychodynamic therapy and cognitive behavioral therapy from several countries rated each of the 100 CPQ items with regard to how well it characterized a hypothetical ideal session of either treatment modality. A series of paired t tests comparing analogous adherence scores within each session were conducted. RESULTS: There were no significant correlations between time elapsed and adherence to the prototypes. Walter's treatment adhered to both prototypes and Peter's treatment did not adhere to either prototype. CONCLUSION: Child psychotherapy theory and practice are not absolutely coincident. Real psychotherapy sessions do not necessarily resemble the ideal prototypes. PMID- 26630409 TI - Electroconvulsive therapy for a psychotic adolescent during the first trimester of pregnancy: case study. PMID- 26630410 TI - Structured Organic-Inorganic Perovskite toward a Distributed Feedback Laser. AB - A general strategy for the in-plane structuring of organic-inorganic perovskite films is presented. The method is used to fabricate an industrially relevant distributed feedback (DFB) cavity, which is a critical step toward all electrially pumped injection laser diodes. This approach opens the prospects of perovskite materials for much improved optical control in LEDs, solar cells, and also toward applications as optical devices. PMID- 26630411 TI - Waist-to-Hip Ratio is Related to Body Fat Content and Distribution Regardless of the Waist Circumference Measurement Protocol in Nonalcoholic Fatty Liver Disease Patients. AB - Central accumulation and distribution of body fat (BF) is an important cardiometabolic risk factor. Waist-to-hip ratio (WHR), commonly elevated in nonalcoholic fatty liver disease (NAFLD) patients, has been endorsed as a risk related marker of central BF content and distribution, but no standardized waist circumference measurement protocol (WCmp) has been proposed. We aimed to investigate whether using different WCmp affects the strength of association between WHR and BF content and distribution in NAFLD patients. BF was assessed with dual energy X-ray absorptiometry (DXA) in 28 NAFLD patients (19 males, 51 +/ 13 years, and 9 females, 47 +/- 13 years). Waist circumference (WC) was measured using four different WCmp (WC1: minimal waist; WC2: iliac crest; WC3: mid distance between iliac crest and lowest rib; WC4: at the umbilicus) and WHR was calculated accordingly (WHR1, WHR2, WHR3 and WHR4, respectively). High WHR was found in up to 84.6% of subjects, depending on the WHR considered. With the exception of WHR1, all WHR correlated well with abdominal BF (r = .47 for WHR1; r = .59 for WHR2 and WHR3; r = .58 for WHR4) and BF distribution (r = .45 for WHR1; r = .56 for WHR2 and WHR3; r = .51 for WHR4), controlling for age, sex and body mass index (BMI). WHR2 and WHR3 diagnosed exactly the same prevalence of high WHR (76.9%). The present study confirms the strong relation between WHR and central BF, regardless of WCmp used, in NAFLD patients. WHR2 and WHR3 seemed preferable for use in clinical practice, interchangeably, for the diagnosis of high WHR in NAFLD patients. PMID- 26630412 TI - Motivational Interviewing as an Adjunct to Cognitive Behavioral Therapy for Anxiety. AB - OBJECTIVE: This study examined the effect of a single session motivational interviewing (MI) intervention on engagement in a 12-week transdiagnostic group cognitive behavioral therapy (CBT) treatment for anxiety. METHOD: Participants were randomized to MI (N = 20) or non-MI (N = 19) conditions before enrolling in a 12-week group CBT program. Participants in the MI condition received an individual 50-minute MI session adapted from the longer MI pretreatment protocol, developed by Westra and Dozois () and Westra (). RESULTS: Rates of treatment initiation and treatment expectancies were significantly higher among participants who received the MI pretreatment intervention. Results indicate substantial reduction in clinician-rated anxiety severity after transdiagnostic group CBT, with no significant differences between MI and non-MI conditions. CONCLUSION: These findings suggest that a single MI pretreatment session may have positive effects on proximal measures of treatment engagement, but that these effects may not affect the severity of anxiety symptoms over the course of CBT. PMID- 26630414 TI - Is There any Correlation Between Pathological Profile of Facet Joints and Clinical Feature in Patients With Thoracolumbar Kyphosis Secondary to Ankylosing Spondylitis?: An Immunohistochemical Investigation. AB - STUDY DESIGN: An immunohistochemical analysis. OBJECTIVE: The aim of this study was to systematically and extensively evaluate the immunopathology of the facet joints in patients with thoracolumbar kyphosis secondary to ankylosing spondylitis (AS). SUMMARY OF BACKGROUND DATA: The facet joints may be predominantly involved in the process of spinal inflammation in AS. Thus, a detailed investigation of the immunopathology at sites of facet joints is of crucial importance in understanding the pathogenesis of AS. METHODS: The facet joints were obtained from 30 AS patients and 23 age- and gender-matched controls (patients with fresh thoracolumbar fracture). The facet joints were assessed immunohistochemically by analyzing the number of infiltrating T cells (CD3, CD4, CD8), B cells (CD20), microvessel density (CD34), osteoblasts (CD56), bone marrow macrophages (CD68), and osteoclasts (CD68) per high-power field (hpf). According to the presence or absence of persistent inflammation, AS patients were divided into 2 groups: A (patients with persistent inflammation) and B (patients without persistent inflammation). Lumbar spinal mobility was assessed using the modified Schober index (MSI). RESULTS: Two or more CD3+ T cell aggregates were found in the facet joints from 18 of 30 AS patients, whereas 1 CD3+ T cell aggregate was noted in 5 of 23 patients with thoracolumbar fracture. The levels of T cells (CD4+ and CD8+), CD20+B cells, CD56+ osteoblasts, and CD34+ microvessel density were significantly higher in AS patients than in the controls (all P < 0.01). Notably, the MSI score in group A was significantly higher than that in group B (P < 0.01). CONCLUSION: Active spinal inflammation is frequently observed in AS patients with thoracolumbar kyphosis. In addition, persistent inflammation in facet joints may further contribute to the loss of spinal mobility in the later stages of AS. These findings indicate that careful monitoring of disease activity is mandatory for AS patients in its advanced stage. LEVEL OF EVIDENCE: 4. PMID- 26630413 TI - Top2 and Sgs1-Top3 Act Redundantly to Ensure rDNA Replication Termination. AB - Faithful DNA replication with correct termination is essential for genome stability and transmission of genetic information. Here we have investigated the potential roles of Topoisomerase II (Top2) and the RecQ helicase Sgs1 during late stages of replication. We find that cells lacking Top2 and Sgs1 (or Top3) display two different characteristics during late S/G2 phase, checkpoint activation and accumulation of asymmetric X-structures, which are both independent of homologous recombination. Our data demonstrate that checkpoint activation is caused by a DNA structure formed at the strongest rDNA replication fork barrier (RFB) during replication termination, and consistently, checkpoint activation is dependent on the RFB binding protein, Fob1. In contrast, asymmetric X-structures are formed independent of Fob1 at less strong rDNA replication fork barriers. However, both checkpoint activation and formation of asymmetric X-structures are sensitive to conditions, which facilitate fork merging and progression of replication forks through replication fork barriers. Our data are consistent with a redundant role of Top2 and Sgs1 together with Top3 (Sgs1-Top3) in replication fork merging at rDNA barriers. At RFB either Top2 or Sgs1-Top3 is essential to prevent formation of a checkpoint activating DNA structure during termination, but at less strong rDNA barriers absence of the enzymes merely delays replication fork merging, causing an accumulation of asymmetric termination structures, which are solved over time. PMID- 26630415 TI - An Independent Inter- and Intraobserver Agreement Evaluation of the AOSpine Subaxial Cervical Spine Injury Classification System. AB - STUDY DESIGN: An agreement study. OBJECTIVE: The aim of this study was to perform an independent interobserver and intraobserver agreement assessment of the AOSpine subaxial cervical spine injury classification system. SUMMARY OF BACKGROUND DATA: The AOSpine subaxial cervical spine injury classification system was recently described. It showed substantial inter- and intraobserver agreement in the study describing it; however, an independent evaluation has not been performed. METHODS: Anteroposterior and lateral radiographs, computed tomography scans, and magnetic resonance imaging of 65 patients with acute traumatic subaxial cervical spine injuries were selected and classified using the morphologic grading of the subaxial cervical spine injury classification system by 6 evaluators (3 spine surgeons and 3 orthopedic surgery residents). After a 6 week interval, the 65 cases were presented to the same evaluators in a random sequence for repeat evaluation. The kappa coefficient (kappa) was used to determine the inter- and intraobserver agreement. RESULTS: The interobserver agreement was substantial when considering the fracture main types (A, B, C, or F), with kappa = 0.61 (0.57-0.64), but moderate when considering the subtypes: kappa = 0.57 (0.54-0.60). The intraobserver agreement was substantial considering the fracture types, with kappa = 0.68 (0.62-0.74) and considering subtypes, kappa = 0.62 (0.57-0.66). No significant differences were observed between spine surgeons and orthopedic residents in the overall inter- and intraobserver agreement, or in the inter- and intraobserver agreement of specific A, B, C, or F type of injuries. CONCLUSION: This classification allows adequate agreement among different observers and by the same observer on separate occasions. Future prospective studies should determine whether this classification allows surgeons to decide the best treatment for patients with subaxial cervical spine injuries. LEVEL OF EVIDENCE: 3. PMID- 26630416 TI - Preoperative MRI in Patients With Intermittent Neurogenic Claudication: Relevance for Diagnosis and Prognosis. AB - STUDY DESIGN: We studied baseline magnetic resonance images of 155 patients with intermittent neurogenic claudication and lumbar spinal stenosis (LSS). Magnetic resonance imaging (MRI) and patient data were gathered from participants of a randomized trial. OBJECTIVE: It is believed that the narrowness of the lumbar spinal canal correlates to the severity of complaints and that it may be a good predictor of clinical outcome if treated. However, this hypothesis has never been (prospectively) tested. SUMMARY OF BACKGROUND DATA: MRI is an important tool to confirm the diagnosis of LSS as a cause for intermittent neurogenic claudication. METHODS: Three raters were asked to evaluate the magnetic resonance images (Schizas scale). Symptom severities at baseline and 1-year follow-up were quantified. The radiological scores were correlated with clinical baseline and outcome scores to assess diagnostic and prognostic value of MRI findings at baseline. RESULTS: There was good agreement on the clinically relevant level of LSS (kappa range 0.57-0.64). MRI assessment of grading of compression (kappa 0.33 0.46) did not correlate with baseline MRDQ nor with outcome based on postoperative change in MRDQ (P = 0.61). However, both absence of epidural fat and presence of tortuous caudal nerves on magnetic resonance images (kappa 0.53 0.72 and 0.67-0.70) in patients with LSS were relatively good predictors for satisfactory recovery after surgery (P = 0.03 and P < 0.01). CONCLUSION: The grading of compression on the preoperative MRI is neither ambiguous nor correlating to severity of clinical condition. It does, furthermore, not have the ability to predict the outcome after 1 year if surgically treated. LEVEL OF EVIDENCE: 2. PMID- 26630417 TI - Percutaneous Vertebroplasty Versus Conservative Treatment in Aged Patients With Acute Osteoporotic Vertebral Compression Fractures: A Prospective Randomized Controlled Clinical Study. AB - STUDY DESIGN: A prospective randomized clinical trial. OBJECTIVE: In this study, we determine whether percutaneous vertebroplasty (PVP) offers extra benefits to aged patients with acute osteoporotic vertebral compression fractures (OVCFs) over conservative therapy (CV). SUMMARY OF BACKGROUND DATA: OVCFs are common in the aged population with osteoporosis. While the optimal treatment of aged patients with acute OVCFs remains controversial, PVP, a minimally invasive procedure, is a treatment option to be considered. METHODS: Patients aged at 70 years or above with acute OVCF and severe pain from minor or mild trauma were assigned randomly to PVP and CV groups. The primary outcome was pain relief as measured by VAS score in 1-year follow-up period. The second outcome was quality of life assessed with ODI and Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO). Patient satisfaction surveys were also recorded. RESULTS: A total of 135 patients were enrolled, and 107 (56 in PVP group; 51 in CV group) completed 1-year follow-up. In PVP group, the vertebroplasty procedure was performed at a mean of 8.4 +/- 4.6 days (range, 2-21 days) after onset. Vertebroplasty resulted in much greater pain relief than did conservative treatment at postoperative day 1 (P < 0.0001). At every time point of follow-up, pain relief and quality of life were significantly improved in PVP group than in CV group at 1 week, 1 month, 3 months, 6 months, and 1 year (all P < 0.0001). The final follow-up surveys indicated that patients in PVP group were significantly more satisfied with given treatment (P < 0.0001). In addition, lower rate of complications was observed in PVP group (P < 0.0001). CONCLUSION: In aged patients with acute OVCF and severe pain, early vertebroplasty yielded faster, better pain relief and improved functional outcomes, which were maintained for 1 year. Furthermore, it showed fewer complications than conservative treatment. LEVEL OF EVIDENCE: 2. PMID- 26630418 TI - Influence of the Number of Cervical Fusion Levels on Cervical Spine Motion and Health-Related Quality of Life. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To analyze the influence of the number of cervical fusion levels on total cervical motion and health-related quality of life (HRQoL) in patients with solid anterior cervical fusions (ACFs). SUMMARY OF BACKGROUND DATA: Few studies have analyzed the degree to which cervical range of motion (ROM) and HRQoL are affected by the number of cervical fusion segments. METHODS: We analyzed a cohort of patients who underwent ACF for degenerative disc disease. To assess the clinical outcomes and HRQoL, preoperative, 1- and 2-year postoperative neck and arm pain, visual-analogue scale, neck disability index, and short form-36 were analyzed. Radiographically, C2-7 and C0-2 ROM, C2-7 sagittal vertical axis (SVA), and Kellgren grade of radiographic adjacent segment pathology (RASP) were evaluated. RESULTS: A total of 105 patients (M:F = 46:59, mean age of 51.4 yr) were enrolled. There were 36 patients who underwent single-level ACF (group 1), 41 patients who had a double level ACF (group 2), and 28 patients who underwent ACF involving 3 or more levels (group 3). There was no decrease in C2-7 motion in group 1, a mean 7-degree decrease in group 2, a mean 18-degree decrease in those who underwent a 3-level ACF, and a mean 22-degree decrease after 4-level ACF. The grade of RASP was not influenced by the number of fusion levels. All HRQoL parameters showed no significant correlation between number of fusion levels, cervical ROM, and SVA. CONCLUSION: Single-level ACF showed no decrease in total cervical motion; multilevel ACF decreased cervical motion by a mean of 7.8 degrees per segment of fusion. Progression of RASP showed no correlation with the number of fusion levels. HRQoLs were not influenced by the number of fusion levels, cervical ROM, or SVA after solid ACF. LEVEL OF EVIDENCE: 3. PMID- 26630420 TI - Adding-on Phenomenon After Surgery in Lenke Type 1, 2 Adolescent Idiopathic Scoliosis: Is it Predictable? AB - STUDY DESIGN: A retrospective study. OBJECTIVE: The aim of this study was to detect risk factors for Adding-on after posterior correction surgery in patients with Lenke 1 or 2 AIS, and to explore whether Adding-on Index could be used to predict Adding-on effectively. SUMMARY OF BACKGROUND DATA: Adding-on phenomenon is a common complication in Lenke 1 or 2 AIS patients after correction surgery. However, whether it can be predicted after surgery remains unknown. METHODS: Lenke 1 or 2 AIS patients receiving correction surgery in our center from January 2009 to July 2013 were analyzed. Antero-posterior and lateral films were evaluated before surgery, at 2 weeks' and 2 years' follow-up. Patients were divided into 2 groups according to whether Adding-on occurred at the 2 years' follow-up. Risk factors of Adding-on were analyzed, and Adding-on Index was proposed and verified. RESULTS: Sixteen patients (16.3%) suffered from distal Adding-on at 2-year follow-up. Several parameters were found to be significantly different between 2 groups, including Risser's sign, postoperative Cobb angle of main thoracic, postoperative Cobb angle of main thoracic curve at 2-year follow up, preoperative and postoperative Cobb angle of lumbar curve, postoperative Cobb angle of lumbar curve at 2-year follow-up, LIV-EV, LIV-SV, LIV-CSVL, LAV-CSVL, LAV-LIV, DnfS, and postoperative TJK. No significant differences in SRS-22 scores were observed. Binary logistic regression analysis showed that DnfS and postoperative residual Cobb angle of lumbar curve were primary factors for occurrence of Adding-on. According to the regression equation, Adding-on Index was defined as 4 * DnfS-postoperative lumbar curves Cobb angle. On the basis of ROC curve, if Adding-on Index was more than 12, the occurrence rate of Adding-on was 88%. On the contrary, the rate of no Adding-on phenomenon was 80%. CONCLUSION: DnfS and posterior Cobb angle of lumbar curve were 2 important factors for Adding-on in Lenke 1, 2 AIS patients. Adding-on Index can be used to predict the occurrence of Adding-on effectively. LEVEL OF EVIDENCE: 4. PMID- 26630421 TI - Assessment of Intraoperative Blood Loss at Different Surgical Stages During Posterior Spinal Fusion Surgery in the Treatment of Adolescent Idiopathic Scoliosis. AB - STUDY DESIGN: Prospective clinical study. OBJECTIVE: To analyze the amount of blood loss at different stages of Posterior Instrumented Spinal Fusion (PSF) surgery in adolescent idiopathic scoliosis (AIS) patients. SUMMARY OF BACKGROUND DATA: Knowing the pattern of blood loss at different surgical stages may enable the surgical team to formulate a management strategy to reduce intraoperative blood loss. METHODS: One hundred AIS patients who underwent PSF from January 2013 to December 2014 were recruited. The operation was divided into six stages; stage 1-exposure, stage 2-screw insertion, stage 3-release, stage 4-correction, stage 5 corticotomies and bone grafting, and stage 6-closure. The duration and blood loss at each stage was documented. The following values were calculated: total blood loss, blood loss per estimated blood volume, blood loss per minute, blood loss per vertebral level fused, and blood loss per minute per vertebral level fused. RESULTS: There were 89 females and 11 males. The mean age was 17.0 +/- 5.8 years old. Majority (50.0%) were Lenke 1 curve type. The mean preoperative major Cobb angle was 64.9 +/- 15.0 degrees . The mean number of levels fused was 9.5 +/- 2.3 levels. The mean operating time was 188.5 +/- 53.4 minutes with a mean total blood loss 951.0 +/- 454.0 mLs. The highest mean blood loss occurred at stage 2 (301.0 +/- 196.7 mL), followed by stage 4 (226.8 +/- 171.2 mL) and stage 5 (161.5 +/- 146.6 mL). The highest mean blood loss per minute was at stage 5 (17.1 +/- 18.3 mL/min), followed by stage 3 (12.0 +/- 10.8 mL/min). The highest mean blood loss per vertebral levels fused was at stage 2 (31.0 +/- 17.7 mL/level), followed by stage 4 (23.9 +/- 18.1 mL/level) and stage 5 (16.6 +/- 13.3 mL/level). CONCLUSION: All stages were significant contributors to the total blood loss except exposure (stage 1) and closure (stage 6). Blood loss per minute and blood loss per minute per level was highest during corticotomies (stage 5), followed by release (stage 3). However, the largest amount of total blood loss occurred during screw insertion (stage 2). LEVEL OF EVIDENCE: 2. PMID- 26630422 TI - Effects of Lumbar Stiffness After Lumbar Fusion Surgery on Activities of Daily Living. AB - STUDY DESIGN: A retrospective cohort study. OBJECTIVE: The aim of this study was to assess the effects of lumbar stiffness after lumbar fusion surgery on functional limitations, health-related quality of life, and activities of daily living (ADL). SUMMARY OF BACKGROUND DATA: Postoperative outcomes after fusion surgery are usually assessed using patient-reported instruments to describe disability related to pain and health status. There are few studies on the effects of lumbar stiffness on ADL after lumbar fusion surgery. METHODS: This study included 93 patients who underwent lumbar fusion surgery for degenerative lumbar disease. Their mean age was 69 years (range 51-79), and the mean follow-up was 34 months (24-46). The patients were categorized into 5 groups according to the number of segments involved: 0 level (decompression), 1 level, 2 levels, 3 levels, and 4 levels. They completed a 21-item questionnaire about their ADL and the Short Form Health Survey 36 (SF-36) to evaluate the effects of lumbar stiffness on ADL after surgery. RESULTS: There was a linear trend toward a decreased rating in all items in our questionnaire and in the physical component summary in the SF-36 related to postoperative lumbar stiffness. These trends were significantly related to the number of fused segments (P < 0.05 and P < 0.001, respectively). Patient satisfaction did not differ between the groups (P = 0.381). Patients who received a 1- or 2-level fusion reported no serious limitations in most ADL. Patients who received a 3- or 4-level fusion, especially 4-level fusion, reported more limitations because of postoperative lumbar stiffness. CONCLUSION: This study investigated in detail the effects of lumbar stiffness after fusion surgery on ADL. Spine surgeons should consider the patient's occupation and lifestyle in preoperative planning. These results will help the surgeon explain the possible outcomes to patients planning to undergo fusion surgery. LEVEL OF EVIDENCE: 2. PMID- 26630423 TI - Comparison of a Stratified Group Intervention (STarT Back) With Usual Group Care in Patients With Low Back Pain: A Nonrandomized Controlled Trial. AB - STUDY DESIGN: A nonrandomized controlled trial. OBJECTIVE: This study aims to explore the effectiveness of group-based stratified care in primary care. SUMMARY OF BACKGROUND DATA: Stratified care based on psychosocial screening (STarT Back) has demonstrated greater clinical and cost-effectiveness in patients with low back pain. However, low back pain interventions are often delivered in groups and evaluating this system of care in a group setting is important. METHODS: Patients were recruited from 60 general practices and linked physiotherapy services. A new group stratified intervention was compared with a historical nonstratified control group. Patients stratified as low, medium and high risk were offered risk matched group care. Consenting participants completed self-report measures of functional disability (primary outcome measure), pain, psychological distress, and beliefs. The historical control received a generic group intervention. Analysis was by intention to treat. RESULTS: In total, 251 patients in the new stratified intervention and 332 in the historical control were included in the primary analysis at 12 weeks. The mean age of patients was 43 +/- 10.98 years. Overall adjusted mean changes in the RMDQ scores were higher in the stratified intervention than in the control arm at 12-week follow-up (P = 0.028). Exploring the risk groups, individually the high-risk stratified group, demonstrated better outcome over the controls (P = 0.031). The medium-risk stratified intervention demonstrated equally good outcomes (P = 0.125), and low-risk stratified patients, despite less intervention, did as well as the historical controls (P = 0.993). CONCLUSION: Stratified care delivered in a group setting demonstrated superior outcomes in the high-risk patients, and equally good outcomes for the medium and low-risk groups. This model, embedded in primary care, provides an early and effective model of chronic disease management and adds another dimension to the utility of the STarT Back system of care. LEVEL OF EVIDENCE: 2. PMID- 26630424 TI - Biomechanical Comparison of Modified TARP Technique Versus Modified Goel Technique for the Treatment of Basilar Invagination: A Finite Element Analysis. AB - STUDY DESIGN: A finite element analysis. OBJECTIVE: The aim of this study was to determine the biomechanical differences between atlantoaxial fusion cage combined with transoral atlantoaxial reduction plate fixation (TARP + Cage, modified TARP technique) and that combined with C1 lateral mass screw and C2 pedicle screw fixation (C1LS + C2PS + Cage, modified Goel technique) in the treatment of basilar invagination (BI) by finite element analysis. SUMMARY OF BACKGROUND DATA: Clinical studies have shown that transoral anterior atlantoaxial release followed by TARP fixation can achieve reduction, decompression, fixation, and fusion of C1 C2 through a transoral-only approach. Although cage has been used to reduce the BI through posterior approach, there are no studies referred to the cage combined with TARP for C1-C2 fusion. METHODS: A finite element model was used to investigate and compare the stability between TARP + Cage fixation and C1LS + C2PS + Cage fixation in the treatment of BI. Vertical load of 40 N was applied on the C0, to simulate head weight, and 1.5 Nm torque was applied to the C0 to simulate flexion, extension, lateral bending, and rotation. RESULTS: In comparison with the C1LS + C2PS + Cage model, the TARP + Cage model reduced the ROM by 44.7%, 30.0%, and 10.5% in extension, lateral bending, and axial rotation, while the TARP + Cage model increased the ROM by 30.0% in flexion, and the TARP + Cage model also led to lower screw stress in all motions with one exception (anterior C2PS stress in extension). CONCLUSION: Our results indicate that the TARP + Cage fixation may offer higher stability to C1LS + C2PS + Cage in extension, lateral bending, and axial rotation but lower stability in flexion. Compared with modified Goel technique, the modified TARP technique not only has the capability of transferring the load and distributing the stress but also can provide neural decompression, stabilization and fusion, and restore C1-C2 normal fusion angle. LEVEL OF EVIDENCE: N/A. PMID- 26630426 TI - New Magnetic Resonance Imaging Features Predictive for Post-Treatment Ambulatory Function: Imaging Analysis of Metastatic Spinal Cord Compression. AB - STUDY DESIGN: This is a retrospective, single-institute, radiographical study. OBJECTIVE: The study aimed to determine the correlation of magnetic resonance imaging (MRI) findings observed in metastatic spinal cord compression (MSCC) with post-treatment ambulatory status. SUMMARY OF BACKGROUND DATA: Previous studies have reported various predictors of ambulatory outcome in patients with MSCC, but the relationship between the MRI features and post-treatment ambulatory function remains to be elucidated. METHODS: Fifty-six hospitalized patients with MSCC and risk of MSCC were examined using MRI before therapeutic intervention. Circumferential ratio of cord compression (CRCC), clock position of compression, cross-sectional area (CSA), and change in signal intensity of the spinal cord were recorded. Each imaging feature was analyzed statistically regarding unassisted ambulatory status at the time of hospital discharge as the endpoint. RESULTS: CRCC showed a prognostic value for post-treatment ambulatory function. More than half of CRCC predicted poor functional prognosis with statistical significance. However, the site of cord compression expressed by clock position on axial plane showed no relationship with functional prognosis. CSA of the spinal cord was enlarged in 23% of patients at the level of MSCC, which indicated that cord compression could also be formed by a relative relationship between cord swelling and surrounding mass effect. The said patients showed a better functional outcome. High intensity of the spinal cord on T2-weighted sagittal image was not useful because of lack of inter-rater reliability. CONCLUSION: CRCC on axial T2 image can guide clinicians to identify cancer patients at risk of paraplegia because of MSCC. More than half of CRCC entails urgent treatment despite preserved ambulatory function. Furthermore, some cases of MSCC accompany increased cord CSA. The measurement is also a useful guide to balance the risk and benefit of systemic steroid therapy. MRI is the key imaging modality in the risk assessment of MSCC. LEVEL OF EVIDENCE: 4. PMID- 26630427 TI - Sustained Local Release of Methylprednisolone From a Thiol-Acrylate Poly(Ethylene Glycol) Hydrogel for Treating Chronic Compressive Radicular Pain. AB - STUDY DESIGN: A preclinical animal model of chronic ligation of the sciatic nerve was used to compare the effectiveness of a slow-release hydrogel carrying methylprednisolone to methylprednisolone injection alone, which simulates the current standard of care for chronic compressive radiculopathy (CR). OBJECTIVE: To extend the short-term benefits of steroid injections by using a nonswelling, biodegradable hydrogel as carrier to locally release methylprednisolone in a regulated and sustained way at the site of nerve compression. SUMMARY OF BACKGROUND DATA: CR affects millions worldwide annually, and is a cause of costly disability with significant societal impact. Currently, a leading nonsurgical therapy involves epidural injection of steroids to temporarily alleviate the pain associated with CR. However, an effective way to extend the short-term effect of steroid treatment to address the chronic component of CR does not exist. METHODS: We induced chronic compression injury of the sciatic nerves of rats by permanent ligation. Forty-eight hours later we injected our methylprednisolone infused hydrogel and assessed the effectiveness of our treatment for 4 weeks. We quantified mechanical hyperalgesia using a Dynamic Plantar Aesthesiometer (Ugo Basile, Stoelting Co., IL, USA), whereas gait analysis was conducted using the Catwalk automated gait analysis platform (Noldus, Leesburg, VA, USA). Macrophage staining was performed with immunohistochemistry and quantification of monocyte chemoattractant protein-1 in sciatic nerve lysates was performed with multiplex immunoassay using a SECTOR Imager 2400A (Meso Scale Discovery, Rockville, MA, USA). RESULTS: We demonstrate that using the hydrogel to deliver methylprednisolone results in significant (P < 0.05) reduction of hyperalgesia and improvement in the gait pattern of animals with chronic lesions as compared with animals treated with steroid alone. In addition, animals treated with hydrogel plus steroid showed significant reduction in the number of infiltrating macrophages at the sciatic nerve and reduced expression of the neuroinflammatory chemokine monocyte chemoattractant protein-1 (P < 0.05). CONCLUSION: Use of hydrogels as carriers for sustained local release of steroids provides significantly better control of pain in an animal model of chronic CR. Our steroid-infused hydrogel could be an effective extender of the short-term benefits of epidural steroid injections for patients with chronic compression induced radicular pain. LEVEL OF EVIDENCE: N/A. PMID- 26630428 TI - Herbal Medicine for Low Back Pain: A Cochrane Review. AB - STUDY DESIGN: Systematic review of randomized controlled trials (RCTs). OBJECTIVES: To determine the effectiveness of herbal medicine for nonspecific low back pain (LBP). SUMMARY OF BACKGROUND DATA: Many people with chronic LBP use complementary and alternative medicine (CAM), visit CAM practitioners, or both. Several herbal medicines have been purported for use in treating people with LBP. This is an update of a Cochrane Review first published in 2006. METHODS: We searched numerous electronic databases up to September 2014; checked reference lists in review articles, guidelines and retrieved trials; and personally contacted individuals with expertise in this area. We included RCTs examining adults (over 18 years of age) suffering from acute, sub-acute, or chronic nonspecific LBP. The interventions were herbal medicines that we defined as plants used for medicinal purposes in any form. Primary outcome measures were pain and function. Two review authors assessed risk of bias, GRADE criteria (GRADE 2004), and CONSORT compliance and a random subset were compared with assessments by a third individual. Two review authors assessed clinical relevance and resolved any disagreements by consensus. RESULTS: Fourteen RCTs (2050 participants) were included. Capsicum frutescens (cayenne) reduces pain more than placebo. Although Harpagophytum procumbens (devil's claw), Salix alba (white willow bark), Symphytum officinale L. (comfrey), Solidago chilensis (Brazilian arnica), and lavender essential oil also seem to reduce pain more than placebo, evidence for these substances was of moderate quality at best. No significant adverse events were noted within the included trials. CONCLUSIONS: Additional well-designed large trials are needed to test these herbal medicines against standard treatments. In general, the completeness of reporting in these trials was poor. Trialists should refer to the CONSORT statement extension for reporting trials of herbal medicine interventions. LEVEL OF EVIDENCE: N/A. PMID- 26630429 TI - Fixed-Angle, Posteriorly Connected Anterior Cage Reconstruction Improves Stiffness and Decreases Cancellous Subsidence in a Spondylectomy Model. AB - STUDY DESIGN: An idealized biomechanical model. OBJECTIVE: The aim of this study was to evaluate the biomechanical properties of a construct designed to minimize intervertebral cage subsidence and maximize stiffness. SUMMARY OF BACKGROUND DATA: Reconstruction after vertebral resection typically involves posterior segmental fixation and anterior interbody support. However, poor bone density, adjuvant radiation, or the oncologic need for endplate resection make interbody device subsidence and resultant instrumentation failure a significant concern. METHODS: An idealized thoracolumbar spondylectomy reconstruction model was constructed using titanium segmental instrumentation and Delrin plastic. In vivo mechanical stress was simulated on a custom multi-axis spine simulator. Rigid body position in space was measured using an optical motion-capture system. Cancellous subsidence was modeled using a 1 cm thick wafer of number 3 closed cell Sawbones foam at one endplate. Ten foam specimens were tested in a control state consisting of posterior segmental fixation with a free interbody cage. Ten additional foam specimens were tested in the test state, with the Delrin interbody cage "connected" to the posterior rods using two additional pedicle screws placed into the cage. Foam indentation was quantified using a precision digital surface-mapping device, and subsidence volume calculated using geometric integration. RESULTS: The control group exhibited significantly greater foam indentation after cycling, with a mean subsidence volume of 1906 mm [95% confidence interval (95% CI) 1810-2001] than the connected cage group subsidence volume of 977 mm (95% CI 928-1026 mm; P < 0.001]. Construct stiffness was greater in the connected cage group (3.1 Nm/degree, 95% CI 3.1-3.2) than in the control group (2.3 Nm/degree, 95% CI 2.2-2.4; P < 0.001). CONCLUSION: In an idealized spondylectomy model, connecting the anterior column cage to the posterior instrumentation using additional pedicle screws results in a construct that is nearly 40% stiffer and exhibits 50% less cancellous subsidence compared with a traditional unconnected cage. LEVEL OF EVIDENCE: N/A. PMID- 26630430 TI - Are We Underestimating the Significance of Pedicle Screw Misplacement? AB - STUDY DESIGN: A retrospective review of charts, x-rays (XRs) and computed tomography (CT) scans was performed. OBJECTIVE: To evaluate the accuracy of pedicle screw placement using a novel classification system to determine potentially significant screw misplacement. SUMMARY OF BACKGROUND DATA: The accuracy rate of pedicle screw (PS) placement varies from 85% to 95% in the literature. This demonstrates technical ability but does not represent the impact of screw misplacement on individual patients. This study quantifies the rate of screw misplacement on a per-patient basis to highlight its effect on potential morbidity. METHODS: A retrospective review of charts, XRs and low-dose CT scans of 127 patients who underwent spinal fusion with pedicle screws for spinal deformity was performed. Screws were divided into four categories: screws at risk (SAR), indeterminate misplacements (IMP), benign misplacements (BMP), accurately placed (AP). RESULTS: A total of 2724 screws were placed in 127 patients. A total of 2396 screws were placed accurately (87.96%). A total of 247 screws (9.07%) were BMP, 52 (1.91%) were IMP, and 29 (1.06%) were considered SAR. Per-patient analysis showed 23 (18.11%) of patients had all screws AP. Thirty-five (27.56%) had IMP and 18 (14.17%) had SAR. Risk factor analysis showed smaller Cobb angles increased likelihood of all screws being AP. Sub-analysis of adolescent idiopathic scoliotic patients showed no curve or patient characteristic that correlated with IMP or SAR. Over 40% of patients had screws with either some/major concern. CONCLUSION: Overall reported screw misplacement is low, but it does not reflect the potential impact on patient morbidity. Per-patient analysis reveals more concerning numbers toward screw misplacement. With increasing pedicle screw usage, the number of patients with misplaced screws will likely increase proportionally. Better strategies need to be devised for evaluation of screw placement, including establishment of a national database of deformity surgery, use of intra-operative image guidance, and reevaluation of postoperative low-dose CT imaging. LEVEL OF EVIDENCE: 3. PMID- 26630431 TI - Bone Marrow Stem Cells in Response to Intervertebral Disc-Like Matrix Acidity and Oxygen Concentration: Implications for Cell-based Regenerative Therapy. AB - STUDY DESIGN: In vitro culture of porcine bone marrow stem cells (BMSCs) in varying pH microenvironments in a three-dimensional hydrogel system. OBJECTIVE: To characterize the response of BMSCs to varying pH environments (blood [pH 7.4], healthy intervertebral disc (IVD) (pH 7.1), mildly degenerated IVD (pH 6.8), and severely degenerated IVD (pH 6.5) in three-dimensional culture under normoxic (20%) and hypoxic (5%) conditions. SUMMARY OF BACKGROUND DATA: The IVD is an avascular organ relying on diffusion of essential nutrients through the cartilaginous endplates (CEPs) thereby creating a challenging microenvironment. Within a degenerated IVD, oxygen and glucose concentrations decrease further (<5% oxygen, <5 mmol/L glucose) and matrix acidity (30 years of age, and those with severe disc degeneration (P < 0.01). CONCLUSION: We evaluated a new surgical technique for the treatment of patients with spondylolysis with or without slight spondylolisthesis. Besides the good clinical results, the indications for this new surgery are much wider and can potentially overcome the limitations of earlier techniques. LEVEL OF EVIDENCE: 4. PMID- 26630437 TI - On the Monte Carlo simulation of small-field micro-diamond detectors for megavoltage photon dosimetry. AB - Monte Carlo (MC) calculated detector-specific output correction factors for small photon beam dosimetry are commonly used in clinical practice. The technique, with a geometry description based on manufacturer blueprints, offers certain advantages over experimentally determined values but is not free of weaknesses. Independent MC calculations of output correction factors for a PTW-60019 micro diamond detector were made using the EGSnrc and PENELOPE systems. Compared with published experimental data the MC results showed substantial disagreement for the smallest field size simulated ([Formula: see text] mm). To explain the difference between the two datasets, a detector was imaged with x rays searching for possible anomalies in the detector construction or details not included in the blueprints. A discrepancy between the dimension stated in the blueprints for the active detector area and that estimated from the electrical contact seen in the x-ray image was observed. Calculations were repeated using the estimate of a smaller volume, leading to results in excellent agreement with the experimental data. MC users should become aware of the potential differences between the design blueprints of a detector and its manufacturer production, as they may differ substantially. The constraint is applicable to the simulation of any detector type. Comparison with experimental data should be used to reveal geometrical inconsistencies and details not included in technical drawings, in addition to the well-known QA procedure of detector x-ray imaging. PMID- 26630439 TI - Porta Hepatis Mass. PMID- 26630438 TI - An Amidinohydrolase Provides the Missing Link in the Biosynthesis of Amino Marginolactone Antibiotics. AB - Desertomycin A is an aminopolyol polyketide containing a macrolactone ring. We have proposed that desertomycin A and similar compounds (marginolactones) are formed by polyketide synthases primed not with gamma-aminobutanoyl-CoA but with 4 guanidinylbutanoyl-CoA, to avoid facile cyclization of the starter unit. This hypothesis requires that there be a final-stage de-amidination of the corresponding guanidino-substituted natural product, but no enzyme for such a process has been described. We have now identified candidate amidinohydrolase genes within the desertomycin and primycin clusters. Deletion of the putative desertomycin amidinohydrolase gene dstH in Streptomyces macronensis led to the accumulation of desertomycin B, the guanidino form of the antibiotic. Also, purified DstH efficiently catalyzed the in vitro conversion of desertomycin B into the A form. Hence this amidinohydrolase furnishes the missing link in this proposed naturally evolved example of protective-group chemistry. PMID- 26630440 TI - Quantitative sensory testing using DFNS protocol in Europe: an evaluation of heterogeneity across multiple centers in patients with peripheral neuropathic pain and healthy subjects. AB - Quantitative sensory testing (QST) in accordance with the DFNS (German Research Network on Neuropathic Pain) protocol assesses the function of afferent nerve fibers on the basis of 13 parameters. Within the consortia IMI (Innovative Medicines Initiative) Europain and Neuropain, QST results from pain research units experienced in QST across Europe can be compared for the first time. Aim of this analysis was to identify possible biases in the QST assessment between 10 centers from 8 different European countries. In total, 188 healthy subjects, 217 patients with painful polyneuropathy, and 150 patients with painful peripheral nerve injury were included in the analysis. Mixed effects models were constructed for each of the 11 normally distributed QST parameters with z-value as the dependent variable, and center as the random effect. The I statistic for heterogeneity was calculated, an index ranging from 0% (no heterogeneity) to 100% (perfect heterogeneity). Data from healthy subjects were comparable with the existing reference data base. Patients with polyneuropathy mainly displayed loss of sensory function, whereas patients with peripheral nerve injury often showed sensory loss combined with mechanical hyperalgesia. Heterogeneity was overall low between different centers and parameters. There was no systematic heterogeneity for patients with painful peripheral nerve injury and painful polyneuropathy. For healthy subjects, only blunt pressure pain threshold showed a considerable heterogeneity of 42% (95% confidence interval: 0%-66%). In conclusion, QST of both healthy subjects and patients with peripheral neuropathic pain is largely homogenous within the European centers, an essential prerequisite for performing multicenter QST-based studies. PMID- 26630441 TI - Non-Bonded Interactions Drive the Sub-Picosecond Bilin Photoisomerization in the P(fr) State of Phytochrome Cph1. AB - Phytochromes are protein-based photoreceptors harboring a bilin-based photoswitch in the active site. The timescale of photosignaling via C15 =C16 E-to-Z photoisomerization has been ambiguous in the far-red-absorbing Pfr state. Here we present a unified view of the structural events in phytochrome Cph1 post excitation with femtosecond precision, obtained via stimulated Raman and polarization-resolved transient IR spectroscopy. We demonstrate that photoproduct formation occurs within 700 fs, determined by a two-step partitioning process initiated by a planarization on the electronic excited state with a 300 fs time scale. The ultrafast isomerization timescale for Pfr -to-Pr conversion highlights the active role of the nonbonding methyl-methyl clash initiating the reaction in the excited state. We envision that our results will motivate the synthesis of new artificial photoswitches with precisely tuned non-bonded interactions for ultrafast response. PMID- 26630442 TI - The Architecture of Chemical Alternatives Assessment. AB - Chemical alternatives assessment is a method rapidly developing for use by businesses, governments, and nongovernment organizations seeking to substitute chemicals of concern in production processes and products. Chemical alternatives assessment is defined as a process for identifying, comparing, and selecting safer alternatives to chemicals of concern (including those in materials, processes, or technologies) on the basis of their hazards, performance, and economic viability. The process is intended to provide guidance for assuring that chemicals of concern are replaced with safer alternatives that are not likely to be later regretted. Conceptually, the assessment methods are developed from a set of three foundational pillars and five common principles. Based on a number of emerging alternatives assessment initiatives, in this commentary, we outline a chemical alternatives assessment blueprint structured around three broad steps: Scope, Assessment, and Selection and Implementation. Specific tasks and tools are identified for each of these three steps. While it is recognized that on-going practice will further refine and develop the method and tools, it is important that the structure of the assessment process remain flexible, adaptive, and focused on the substitution of chemicals of concern with safer alternatives. PMID- 26630445 TI - [Communication Test for Foreign Physicians in Germany: The Patient Communication Test]. AB - INTRODUCTION: The number of foreign doctors in Germany has increased steadily in recent years. To obtain the German medical license, sufficient language competence is mandatory. Nevertheless, in practice, foreign doctors have considerable difficulties in their communication with patients, medical colleagues and other health professionals. This can lead to misunderstandings and thus impair patient safety. To overcome this problem, the "patient communication test" was developed and piloted as an additional requirement to be granted license to practice medicine in Germany. The aim of this study is to present our results in the development and piloting of this test. METHODS: 3 OSCE stations (Objective Structured Clinical Examination) were designed, which evaluate communication skills in 3 medical competences: history taking, case presentation and explaining to patients before obtaining informed consent. After extensive instruction of actors as patients and raters on the basis of the evaluation criteria, the communication test was subjected to pilot studies in 6 different cities (Freiburg, Jena, Mainz, Mannheim, Tubingen, and Ulm). RESULTS: In 2013, 639 foreign doctors participated in the test; 461 (72.14%) of these doctors passed the test on their first try, 51 (7.98%) on their second attempt and 6 (0.93%) on their third try. CONCLUSION: The patient communication test evaluates the communication skills of foreign doctors in OSCE-setting using standardized actor-patients. This improves the communication skills and enhances patient safety in the German health care system by smooth inter-professional and patient centered communication. PMID- 26630444 TI - A Methylene Group on C-2 of 24,24-Difluoro-19-nor-1alpha,25-dihydroxyvitamin D3 Markedly Increases Bone Calcium Mobilization in Vivo. AB - Four side chain fluorinated analogues of 1alpha,25-dihydroxy-19-norvitamin D have been prepared in convergent syntheses using the Wittig-Horner reaction as a key step. Structures and absolute configurations of analogues 3 and 5 were confirmed by X-ray crystallography. All analogues showed high potency in HL-60 cell differentiation and vitamin D-24-hydroxylase (24-OHase) transcription as compared to 1alpha,25-dihydroxyvitamin D3 (1). Most important is that all of the 20S configured derivatives (4 and 6) had high bone mobilizing activity in vivo. However, in the 20R series, a 2-methylene group was required for high bone mobilizing activity. A change in positioning of the 20R molecule in the vitamin D receptor when the 2-methylene group is present may provide new insight into the molecular basis of bone calcium mobilization induced by vitamin D. PMID- 26630446 TI - [Influence of Fissure Sealants on Dental Health of Elementary School Children in Weimar - A Longitudinal Observational Study under Real-life Conditions]. AB - The aim of the present observational study was to assess the effect of the number and timing of placing fissure sealants (FS) on caries prevalence in elementary school children under real-life conditions. Methods: Oral health data from 7- to 10-year-old elementary school children (n=505) attending 4 consecutive annual checkups between 2004 and 2009 was extracted from the public health service database. The number of intact FS and the number of teeth affected by caries was scored according to WHO standard (1997). Results: 34.9% pupils had at least one, 10% 4 FS. Children without FS had a higher dental caries rate compared to peers with FS (0.2 DT/0.4 DMFT vs. 0.1 DT/0.2 DMFT). Pupils with 4 FS showed the lowest number of teeth with caries (0 DT/0 DMFT). Children with an early application of FS had a lower D-component than children with a later or missing application (0.1 DT vs. 0.2 DT). Pupils with less than 4 FS had a higher risk of developing caries in their permanent dentition compared to peers with 4 FS (OR 4.36). Conclusion: FS is an effective caries preventive measure under real-life conditions. Early application and sealing of all 4 molars can optimize the prevention of caries in the permanent dentition. PMID- 26630447 TI - [Poverty, public transfers and health: An analysis on self-rated health of social benefit recipients in Germany]. AB - BACKGROUND: Prevention and reduction of poverty are key elements of social welfare policy in Germany. This study is the first analysis of self-rated health of individuals that escape poverty by benefiting form public transfers. METHODS: Analyses are based on the German Socio-economic Panel (GSOEP) of 2010. Self-rated health was based on subjective assessment of general health status. Subjects were directly asked about receipt of public transfers. Income poverty was based on the equalized disposable income and is applied to a threshold of 60% of the median based average income. We analyzed the association between self-rated health and pre- and post-transfer poverty by means of descriptive analyses and binary logistic regression. RESULTS: After adjusting for age, we found a significantly higher risk of poor self-rated health among those who escaped income poverty due to the receipt of social transfers compared to others (ORWomen: 1.85; 95%-CI: 1.27-2.69; ORMen: 2.57; 95%-CI: 1.63-4.05), in particular to those at risk of post-transfer poverty. These poverty-related inequalities in health were predominantly explained by nationality, occupational status, household type and long-term care within the household. CONCLUSION: This study provides first evidence that the receipt of public transfers is associated with increased risk of poor health in the light of impending income-poverty. This study adds to the current debate about the social and health implications of public transfers in the relationship between poverty and health. PMID- 26630448 TI - Composition Dependence of Dynamic Heterogeneity Time- and Length Scales in [Omim][BF4]/Water Binary Mixtures: Molecular Dynamics Simulation Study. AB - Composition dependence of four-point dynamic susceptibilities, overlap functions, and other dynamic heterogeneity (DH) parameters have been investigated by using all-atom molecular dynamics simulations for aqueous solutions of the ionic liquid (IL), 1-octyl-3-methyl imidazolium tetrafluoroborate ([Omim][BF4]) covering the pure-to-pure range. Upon addition of water in the IL, the DH time scales become faster and the four-point dynamic susceptibility time scale softens. Evidences for jump motions for both water and ions have been found from the simulated single particle displacements that show strong deviation from Gaussian distribution. Estimated dynamic correlation length for water reflects effects of IL, whereas those for ions remain largely insensitive to the mixture composition. Simulated structural aspects and DH time scales provide microscopic explanations to the existing experimental observations from time-resolved fluorescence and Kerr spectroscopic measurements. PMID- 26630450 TI - Effects of Secondary Metal Carbonate Addition on the Porous Character of Resorcinol-Formaldehyde Xerogels. AB - A deeper understanding of the chemistry and physics of growth, aggregation, and gelation processes involved in the formation of xerogels is key to providing greater control of the porous characteristics of such materials, increasing the range of applications for which they may be utilized. Time-resolved dynamic light scattering has been used to study the formation of resorcinol-formaldehyde gels in the presence of combinations of Group I (Na and Cs) and Group II (Ca and Ba) metal carbonates. It was found that the combined catalyst composition, including species and times of addition, is crucial in determining the end properties of the xerogels via its effect on growth of clusters involved in formation of the gel network. Combination materials have textural characteristics within the full gamut offered by each catalyst alone; however, in addition, combination materials that retain the small pores associated with sodium carbonate catalyzed xerogels exhibit a narrowing of the pore size distribution, providing an increased pore volume within an application-specific range of pore sizes. We also show evidence of pore size tunability while maintaining ionic strength, which significantly increases the potential of such systems for biological applications. PMID- 26630449 TI - Catalytic, Stereoselective Dihalogenation of Alkenes: Challenges and Opportunities. AB - Although recent years have witnessed significant advances in the development of catalytic, enantioselective halofunctionalizations of alkenes, the related dihalogenation of olefins to afford enantioenriched vicinal dihalide products remains comparatively underdeveloped. However, the growing number of complex natural products bearing halogen atoms at stereogenic centers has underscored this critical gap in the synthetic chemist's arsenal. This Review highlights the selectivity challenges inherent in the design of enantioselective dihalogenation processes, and formulates a mechanism-based classification of alkene dihalogenations, including those that may circumvent the "classical" haliranium (or alkene-dihalogen pi-complex) intermediates. A variety of metal and main group halide reagents that have been used for the dichlorination or dibromination of alkenes are discussed, and the proposed mechanisms of these transformations are critically evaluated. PMID- 26630451 TI - Etrolizumab for induction of remission in ulcerative colitis. AB - BACKGROUND: Etrolizumab (rhuMAb beta7) is an anti-integrin that selectively targets the beta7 subunits of the alpha4beta7 and alphaEbeta7 integrins, which are involved in the pathogenesis of ulcerative colitis. OBJECTIVES: The objectives of this review were to assess the efficacy and safety of etrolizumab for induction of remission in ulcerative colitis. SEARCH METHODS: We searched PubMed, MEDLINE, EMBASE, and the Cochrane Library (CENTRAL) from inception to 12 March 2015. References and conference abstracts were searched to identify additional studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) trials in which etrolizumab was compared to placebo or another active comparator in patients with active ulcerative colitis were included. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies for inclusion, assessed methodological quality and extracted data. We assessed methodological quality using the Cochrane risk of bias tool. The primary outcome was failure to induce clinical remission (as defined by the primary studies). Secondary outcomes included failure to induce clinical improvement (as defined by the primary studies), failure to induce endoscopic remission (as defined by the primary studies), adverse events, serious adverse events, withdrawal due to adverse events, and health-related quality of life (as defined by the primary studies). We assessed the overall quality of the evidence using the GRADE criteria. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome. MAIN RESULTS: Two RCTs including 172 patients with moderate to severe UC who failed conventional therapy met the inclusion criteria. Both studies were rated as low risk of bias. We did not pool efficacy data from the two included studies due to differences in dose and route of administration. The small phase I study found no statistically significant differences between etrolizumab and placebo in the proportion of patients who failed to enter remission (RR 1.04, 95% CI 1.04 to 1.69; participants = 23) or respond at week 10 (RR 1.67, 95% CI 0.26 to 10.82; participants = 23). The phase II study reported on failure to enter clinical remission at weeks 6 and 10. In the etrolizumab group 91% (71/78) of patients failed to enter remission at week 6 compared to 95% (39/41) of placebo patients (RR 0.96, 95% CI 0.87 to 1.06). Subgroup analysis revealed no statistically significant differences by dose. At week 10, there was a statistically significant difference in clinical remission rates favouring etrolizumab over placebo. Of the patients who received etrolizumab, 85% (66/78) failed to enter remission at week 10 compared to 100% (41/41) patients in the placebo group (RR 0.86, 95% CI 0.77 to 0.95). A subgroup analysis by dose found a statistically significant difference in clinical remission rates favoring 100 mg etrolizumab over placebo (RR 0.81 CI 95% 0.68 to 0.96), but not 300 mg etrolizumab over placebo (RR 0.91, 95% CI 0.80 to 1.03). No significant heterogeneity was detected for this comparison (P = 0.28, I(2) = 13.5%). GRADE analyses indicated that the overall quality of evidence for the clinical remission outcomes was moderate due to sparse data. Both of the included studies reported on safety. The outcome adverse events was initially pooled, however this analysis was removed due to high heterogeneity (I(2) = 88%). The phase I study found no statistically significant difference between etrolizumab and placebo in the proportion of patients who had at least one adverse event. Ninety-five per cent (36/38) of etrolizumab patients had at least one adverse event compared to 100% (10/10) of placebo patients (RR 0.98, 95% CI 0.84 to 1.14). Common adverse events reported in the phase I study included exacerbation of UC, headache, fatigue, abdominal pain, dizziness, nasopharyngitis, nausea, arthralgia and urinary tract infection. There was a statistically significant difference between etrolizumab and placebo in the proportion of patients who had at least one adverse event. Fifty-six per cent (44/78) of etrolizumab patients had at least one adverse event compared to 79% of placebo patients (RR 0.71, 95% CI 0.55 to 0.91). A GRADE analysis indicates that the overall quality of the evidence for this outcome was moderate due to sparse data. Common adverse events reported in the phase II study included worsening UC, nasopharyngitis, nervous system disorders, headache and arthralgia . A pooled analysis of two studies indicates that there was no statistically significant difference in the proportion of patients who had a serious adverse event. Twelve per cent (14/116) of etrolizumab patients had a serious adverse event compared to 12% of placebo patients (6/49) (RR 0.92, 95% CI 0.36 to 2.34). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (20 events). Common serious adverse events included worsening of UC, impaired wound healing and bacterial peritonitis. AUTHORS' CONCLUSIONS: Moderate quality evidence suggests that etrolizumab may be an effective induction therapy for some patients with moderate to severe ulcerative colitis who have failed conventional therapy. Due to small numbers of patients in dose subgroups the optimal dosage of etrolizumab is unclear. Due to sparse data we are uncertain regarding the risk of adverse events and serious adverse events. Further studies are needed to determine the efficacy and safety of etrolizumab in this patient population. There are five ongoing phase III etrolizumab trials and two ongoing open-label extension studies that will provide important new information on the efficacy, safety and optimal dose of this drug for the treatment of UC. PMID- 26630452 TI - Pharmacotherapeutic treatment of germ cell tumors: standard of care and recent developments. AB - INTRODUCTION: Testicular germ cell tumors are the most common malignancy among men aged 40 and less. Since the introduction of cisplatin-based combination chemotherapy, germ cell tumors are among the most curable solid tumors with cure rates of 95% in all patients and > 80% in metastatic disease. AREAS COVERED: Current standards and future developments in GCT treatment, including adjuvant chemotherapy, first line treatment for metastatic disease, and salvage regimens in case of relapse and refractory disease. EXPERT OPINION: Maintaining therapeutic success while further reducing treatment-related toxicity is paramount. Cancer-specific survival in localized disease approximates 100%. Therefore, orchidectomy followed by active surveillance is the preferred approach for all seminomas and non-seminomas lacking lymphovascular invasion. Non seminomas with lymphovascular invasion should be offered adjuvant treatment with one cycle of bleomycin, etoposide and cisplatin (BEP). The BEP regimen remains standard of care for metastatic disease, while the role of primary high-dose chemotherapy in case of inadequate tumor-marker decline or presence of high-risk features (i.e. mediastinal origin, non-pulmonary visceral metastases) remains to be elucidated. Several curative salvage chemotherapy combinations are available, i.e. TIP, VeIP, GIP or high-dose carboplatin and etoposide. GOP is the current option of choice in cisplatin-refractory patients. Novel targeted agents failed to improve treatment outcome so far. PMID- 26630453 TI - Deriving Multiple Benefits from Carbon Market-Based Savanna Fire Management: An Australian Example. AB - Carbon markets afford potentially useful opportunities for supporting socially and environmentally sustainable land management programs but, to date, have been little applied in globally significant fire-prone savanna settings. While fire is intrinsic to regulating the composition, structure and dynamics of savanna systems, in north Australian savannas frequent and extensive late dry season wildfires incur significant environmental, production and social impacts. Here we assess the potential of market-based savanna burning greenhouse gas emissions abatement and allied carbon biosequestration projects to deliver compatible environmental and broader socio-economic benefits in a highly biodiverse north Australian setting. Drawing on extensive regional ecological knowledge of fire regime effects on fire-vulnerable taxa and communities, we compare three fire regime metrics (seasonal fire frequency, proportion of long-unburnt vegetation, fire patch-size distribution) over a 15-year period for three national parks with an indigenously (Aboriginal) owned and managed market-based emissions abatement enterprise. Our assessment indicates improved fire management outcomes under the emissions abatement program, and mostly little change or declining outcomes on the parks. We attribute improved outcomes and putative biodiversity benefits under the abatement program to enhanced strategic management made possible by the market-based mitigation arrangement. For these same sites we estimate quanta of carbon credits that could be delivered under realistic enhanced fire management practice, using currently available and developing accredited Australian savanna burning accounting methods. We conclude that, in appropriate situations, market based savanna burning activities can provide transformative climate change mitigation, ecosystem health, and community benefits in northern Australia, and, despite significant challenges, potentially in other fire-prone savanna settings. PMID- 26630454 TI - Spatiotemporal Cadence of Macrophage Polarisation in a Model of Light-Induced Retinal Degeneration. AB - BACKGROUND: The recruitment of macrophages accompanies almost every pathogenic state of the retina, and their excessive activation in the subretinal space is thought to contribute to the progression of diseases including age-related macular degeneration. Previously, we have shown that macrophages aggregate in the outer retina following damage elicited by photo-oxidative stress, and that inhibition of their recruitment reduces photoreceptor death. Here, we look for functional insight into macrophage activity in this model through the spatiotemporal interplay of macrophage polarisation over the course of degeneration. METHODS: Rats were exposed to 1000 lux light damage (LD) for 24 hrs, with some left to recover for 3 and 7 days post-exposure. Expression and localisation of M1- and M2- macrophage markers was investigated in light-damaged retinas using qPCR, ELISA, flow cytometry, and immunohistochemistry. RESULTS: Expression of M1- (Ccl3, Il-6, Il-12, Il-1beta, TNFalpha) and M2- (CD206, Arg1, Igf1, Lyve1, Clec7a) related markers followed discrete profiles following light damage; up-regulation of M1 genes peaked at the early phase of cell death, while M2 genes generally exhibited more prolonged increases during the chronic phase. Moreover, Il-1beta and CD206 labelled accumulations of microglia/macrophages which differed in their morphological, temporal, and spatial characteristics following light damage. CONCLUSIONS: The data illustrate a dynamic shift in macrophage polarisation following light damage through a broad swathe of M1 and M2 markers. Pro-inflammatory M1 activation appears to dominate the early phase of degeneration while M2 responses appear to more heavily mark the chronic post exposure period. While M1/M2 polarisation represents two extremes amongst a spectrum of macrophage activity, knowledge of their predominance offers insight into functional consequences of macrophage activity over the course of damage, which may inform the spatiotemporal employment of therapeutics in retinal disease. PMID- 26630455 TI - The Prognostic Value of Family History for the Estimation of Cardiovascular Mortality Risk in Men: Results from a Long-Term Cohort Study in Lithuania. AB - AIM: To evaluate the additional prognostic value of family history for the estimation of cardiovascular (CVD) mortality risk in middle-aged urban Lithuanian men. METHODS: The association between family history of CVD and the risk of CVD mortality was examined in a population-based cohort of 6,098 men enrolled during 1972-1974 and 1976-1980 in Kaunas, Lithuania. After up to 40 years of follow-up, 2,272 deaths from CVD and 1,482 deaths from coronary heart disease (CHD) were identified. Multivariate Cox proportional hazards models were used to estimate hazard ratios (HR) for CVD and CHD mortality. RESULTS: After adjustment for traditional CVD risk factors, the HR for CVD mortality was 1.24 (95% CI 1.09 1.42) and for CHD mortality 1.20 (1.02-1.42) in men with first-degree relatives having a history of myocardial infarction (MI), compared to men without positive family history. A significant effect on the risk of CVD and CHD mortality was also observed for the family history of sudden cardiac death and any CVD. Addition of family history of MI, sudden death, and any CVD to traditional CVD risk factors demonstrated modest improvement in the performance of Cox models for CVD and CHD mortality. CONCLUSIONS: Family history of CVD is associated with a risk of CVD and CHD mortality significantly and independently of other risk factors in a middle-aged male population. Addition of family history to traditional CVD risk factors improves the prediction of CVD mortality and could be used for identification of high-risk individuals. PMID- 26630456 TI - Primary biliary cholangitis associated with warm autoimmune hemolytic anemia. AB - There are many autoimmune diseases associated with primary biliary cholangitis (PBC), known as primary biliary cirrhosis; however, the association between PBC and warm autoimmune hemolytic anemia (wAIHA) has rarely been reported. It is documented that hemolysis is present in over 50% of the patients with chronic liver disease, regardless of the etiologies. Due to the clear and frequent relationship between PBC and many autoimmune diseases, it is reasonable to suppose that wAIHA may be another autoimmune disorder seen in association with PBC. Here we reported a 53-year-old female patient diagnosed with wAIHA associated with PBC. PMID- 26630457 TI - The efficacy of oral adenosine A(2A) antagonist istradefylline for the treatment of moderate to severe Parkinson's disease. AB - The moderate and severe stages of Parkinson's disease (PD) are marked by motor and non-motor complications that still remain difficult to control with the currently available therapy. Adenosine A(2A) receptor antagonists target non dopaminergic systems, and have emerged as promising add-on therapy in the management of PD, a little more than a decade ago. While the development of this new drug class was slower than initially expected, istradefylline was recently registered in Japan, because it provides reduction of the off-time, when given in association with levodopa. Effects on some non-motor features have also been suggested, and preliminary studies further suggest a potential neuroprotective effect. Associations of A(2A) receptor antagonists with dopaminergic agents, as well as enzyme blockers like catechol-O-methyltransferase (COMT) and monoamine oxidase-B (MAO-B) inhibitors, should provide even greater benefit in advanced PD patients, and, thus, a more individualized treatment approach would be at hand. PMID- 26630458 TI - Running for your life: A review of physical activity and cardiovascular disease risk reduction in individuals with schizophrenia. AB - Individuals with schizophrenia have a greater risk for cardiometabolic risk factors (e.g. central obesity, insulin resistance, hypertension and dyslipidaemia), cardiovascular diseases and mortality. This risky profile may be explained by the adverse effects of antipsychotic medications and an unhealthy lifestyle (e.g. smoking, poor nutrition and low physical activity). In the general population, physical activity has been shown to be the optimal strategy to improve both cardiometabolic parameters and cardiorespiratory fitness levels. Accordingly, an emerging literature of non-pharmacological interventions (e.g. cognitive behavioural therapy, diet and physical activity) has been studied in individuals with schizophrenia. Therefore, the purpose of this review was 1) to conduct a critical literature review of non-pharmacological interventions that included some kind of physical activity (including supervised and unsupervised exercise training) and target cardiometabolic risk factors in individuals with schizophrenia. 2) To describe the contribution of physical activity alone by reviewing trials of supervised exercise training programmes only. A literature review via systematic keyword search for publications in Medline, PubMed, Embase and PsycINFO was performed. Many non-pharmacological interventions are efficient in reducing cardiovascular disease risk factors when combined with physical activity. Supervised physical activity has been successful in decreasing cardiovascular disease risk, and aerobic interval training appears to provide more benefits by specifically targeting cardiorespiratory fitness levels. In conclusion, physical activity is an effective strategy for addressing cardiovascular disease risk in individuals with schizophrenia. Long-term studies are needed to evaluate the feasibility and impact of exercise training programmes in individuals with schizophrenia. PMID- 26630459 TI - Triazatruxene-Based Hole Transporting Materials for Highly Efficient Perovskite Solar Cells. AB - Four center symmetrical star-shaped hole transporting materials (HTMs) comprising planar triazatruxene core and electron-rich methoxy-engineered side arms have been synthesized and successfully employed in (FAPbI3)0.85(MAPbBr3)0.15 perovskite solar cells. These HTMs are obtained from relatively cheap starting materials by adopting facile preparation procedure, without using expensive and complicated purification techniques. Developed compounds have suitable highest occupied molecular orbitals (HOMO) with respect to the valence band level of the perovskite, and time-resolved photoluminescence indicates that hole injection from the valence band of perovskite into the HOMO of triazatruxene-based HTMs is relatively more efficient as compared to that of well-studied spiro-OMeTAD. Remarkable power conversion efficiency over 18% was achieved using 5,10,15 trihexyl-3,8,13-tris(4-methoxyphenyl)-10,15-dihydro-5H-diindolo[3,2-a:3',2' c]carbazole (KR131) with compositive perovskite absorber. This result demonstrates triazatruxene-based compounds as a new class of HTM for the fabrication of highly efficient perovskite solar cells. PMID- 26630460 TI - Optimized Ratiometric Fluorescent Probes by Peptide Self-Assembly. AB - We report in this study on optimized ratiometric fluorescent probes by peptide self-assembly. The resulting self-assembled nanoprobes show extraordinary stability in aqueous solutions and extremely low background fluorescence in buffer solutions. Our optimized probes with much bigger ratiometric fluorescence ratios also show an enhanced cellular uptake, lower background noise, and much brighter fluorescence signal in the cell experiment. Our study provides a versatile and very useful strategy to design and produce fluorescent probes with better performance. PMID- 26630462 TI - Aptamers: current challenges and future prospects. AB - INTRODUCTION: Aptamers are oligonucleotide molecules raised in vitro from large combinatorial libraries of nucleic acids and developed to bind to targets with high affinity and specificity. Whereas novel target molecules are proposed for therapeutic intervention and diagnostic, aptamer technology has a great potential to become a source of lead compounds. AREAS COVERED: In this review, the authors address the current status of the technology and highlight the recent progress in aptamer-based technologies. They also discuss the current major technical limitations of aptamer technology and propose original solutions based on existing technologies that could result in a solid aptamer-discovery platform. EXPERT OPINION: Whereas aptamers have shown to bind to targets with similar affinities and specificities to those of antibodies, aptamers have several advantages that could outweigh antibody technology and open new opportunities for better medical and diagnostic solutions. However, the current status of the aptamer technology suffers from several technical limitations that slowdown the progression of novel aptamers into the clinic and makes the business around aptamers challenging. PMID- 26630461 TI - Sox7, Sox17, and Sox18 Cooperatively Regulate Vascular Development in the Mouse Retina. AB - Vascular development and maintenance are controlled by a complex transcriptional program, which integrates both extracellular and intracellular signals in endothelial cells. Here we study the roles of three closely related SoxF family transcription factors-Sox7, Sox17, and Sox18 -in the developing and mature mouse vasculature using targeted gene deletion on a mixed C57/129/CD1 genetic background. In the retinal vasculature, each SoxF gene exhibits a distinctive pattern of expression in different classes of blood vessels. On a mixed genetic background, vascular endothelial-specific deletion of individual SoxF genes has little or no effect on vascular architecture or differentiation, a result that can be explained by overlapping function and by reciprocal regulation of gene expression between Sox7 and Sox17. By contrast, combined deletion of Sox7, Sox17, and Sox18 at the onset of retinal angiogenesis leads to a dense capillary plexus with a nearly complete loss of radial arteries and veins, whereas the presence of a single Sox17 allele largely restores arterial identity, as determined by vascular smooth muscle cell coverage. In the developing retina, expression of all three SoxF genes is reduced in the absence of Norrin/Frizzled4-mediated canonical Wnt signaling, but SoxF gene expression is unaffected by reduced VEGF signaling in response to deletion of Neuropilin1 (Npn1). In adulthood, Sox7, Sox17, and Sox18 act in a largely redundant manner to maintain blood vessel function, as adult onset vascular endothelial-specific deletion of all three SoxF genes leads to massive edema despite nearly normal vascular architecture. These data reveal critical and partially redundant roles for Sox7, Sox17 and Sox18 in vascular growth, differentiation, and maintenance. PMID- 26630463 TI - Quantitative Kinetics Evaluation of Blocks Versus Granules of Biphasic Calcium Phosphate Scaffolds (HA/beta-TCP 30/70) by Synchrotron Radiation X-ray Microtomography: A Human Study. AB - INTRODUCTION: Successful bone regeneration using both granules and blocks of biphasic calcium phosphate materials has been reported in the recent literature, in some clinical applications for maxillary sinus elevation, but the long-term kinetics of bone regeneration has still not been fully investigated. MATERIALS AND METHODS: Twenty-four bilateral sinus augmentation procedures were performed and grafted with hydroxyapatite/beta-tricalcium phosphate 30/70, 12 with granules and 12 with blocks. The samples were retrieved at different time points and were evaluated for bone regeneration, graft resorption, neovascularization, and morphometric parameters by computed microtomography and histology. RESULTS: A large amount of newly formed bone was detected in the retrieved specimens, together with a good rate of biomaterial resorption and the formation of a homogeneous and rich net of new vessels. The morphometric values were comparable at 5/6 months from grafting but, 9 months after grafting, revealed that the block based specimens mimicked slightly better than granule-based samples the healthy native bone of the maxillary site. CONCLUSION: The scaffold morphology was confirmed to influence the long-term kinetics of bone regeneration. PMID- 26630464 TI - Megaprostheses in the Revision of Infected Total Hip Arthroplasty. Clinical Series and Literature Review. AB - PURPOSE: The management of severe femoral bone loss associated with hip infection is a major problem in joint replacement surgery. Femoral megaprostheses have been rarely reported in reconstructive procedure for this complex condition. The aim of the study was to evaluate clinical results observed after such uncommon reconstruction in our case series and in a similar group of patients extracted by literature review. METHODS: We evaluated clinical outcomes and eradication of sepsis in five patients who underwent femoral revision with modular femoral resection stems at our institution, and we reviewed the literature about this topic. In our case series, the femoral bone loss was grade III-B in three cases and grade IV in two cases according to the Paprosky classification. One patient was operated with one-stage revision, and four patients were operated with two stage revision. The mean age was 72 years (range: 60 to 81 years), and the mean time of follow-up was 62 months (range: 36 to 82 months). RESULTS: We observed sepsis eradication in four out of five patients in our series, and clinical results were satisfactory with a mean Harris Hip Score of 74 points (range: 46 to 95 points). Cumulative results obtained considering our series and data obtained by literature review showed a mean Harris Hip Score of 75 points (range: 42 to 95 points) in patients able to walk and an overall incidence of recurrent infection in 33% of patients. Complications were observed in 8 out of 20 patients (dislocation, 6 cases; greater trochanter displacement 2 cases; and transient sciatic palsy, 1 case). CONCLUSIONS: Revision with megaprostheses in case of infected total hip arthroplasty with severe femoral bone loss have a high risk of complication and should be carefully evaluated and used in selected patients when other surgical procedures are not feasible. PMID- 26630465 TI - Identification of Risk Factors for Acute Surgical Site Infections in Musculoskeletal Tumor Patients Using CDC/NHSN Criteria. AB - BACKGROUND: Acute surgical site infections (SSI) are well-recognized postoperative complications, representing a significant source of patient morbidity and cost to the healthcare system. This study is among the first to use standardized criteria for the diagnosis of acute SSI in orthopaedic oncology. METHODS: The medical records of 165 patients were retrospectively reviewed for the occurrence of superficial or deep SSI as defined by the Center for Disease Control's National Healthcare Safety Network (CDC/NHSN) criteria. Patient, disease, and procedure-specific variables were evaluated as potential risk factors for infection. RESULTS: The overall rate of acute SSI was 10.3%. Univariate analysis demonstrated the significance of malignant pathology (p < 0.001), ASA classification (p = 0.009), operative duration (p < 0.001), intraoperative RBC transfusions (p = 0.03), the performance of an amputation (p = 0.016), and race (p = 0.008) on the incidence of SSI. Prolonged operative duration (p = 0.014) and race (p = 0.005) were found to be independent risk factors with odds ratios of 1.89 (95%, CI: 1.14 to 3.14) and 0.047 (95%, CI: 0.006 to 0.387), respectively. CONCLUSIONS: By using the CDC/NHSN guidelines for the diagnosis of acute SSI, we identified prolonged operative time and non Caucasian race as independent risk factors for infection in musculoskeletal tumor patients. PMID- 26630466 TI - The Clinical and Economic Impact of Preoperative Transthoracic Echocardiography in Elderly Patients with Hip Fractures. AB - PURPOSE: The purpose of this study was to evaluate preoperative transthoracic echocardiography (TTE) on cardiac intervention, length of stay (LOS), inpatient mortality, and costs. METHODS: A retrospective series of 43 preoperative TTE and 161 non-TTE (control) hip fracture patients (> 65 years) was reviewed. The data collected included ASA score, comorbidities, indication for TTE, perioperative cardiac intervention, LOS, inpatient mortality, and cost. RESULTS: One of 43 (2.4%) (TTE) had a cardiac intervention (PTCA/CABG). Zero interventions occurred in the control group. The average time to operation was 1.5 days (TTE) and 0.93 days (control) (p < 0.001). The average LOS was 7.2 days (TTE) and 6.0 days (control), (p = 0.04). Patients (American Society of Anesthesiologists Physical Status Classification 3 and 4 patients), LOS was 7.3 days (TTE) and 6.3 days (control) (p = 0.18). Inpatient mortality was 2.3% (TTE) and 3% (control) (p = 0.493). There was no correlation between TTE and anesthesia. Hospital costs were different between groups (TTE $24,445 and control $18,429, p = 0.02). CONCLUSIONS: Preoperative TTE in elderly patients with hip fractures resulted in a low cardiac intervention rate. Patients undergoing preoperative TTE prior to surgery had longer times to operation, LOS, and higher hospital costs. The utility of TTE as a preoperative screening tool is limited in the geriatric hip fracture population and does not appear to effect perioperative mortality rates. PMID- 26630467 TI - Prevention of Venous Thromboembolism after Arthroscopic Knee Surgery in a Low Risk Population with the Use of Aspirin. A Randomized Trial. AB - INTRODUCTION: Historically, venous thromboembolism (VTE) in the setting of elective knee arthroscopy has been considered rare. However, more recently, the rate of deep vein thrombosis (DVT) has been reported to be approximately 10%. With increasing recognition of the potential for the development of thromboembolic events, several randomized trials have evaluated the efficacy of chemoprophylaxis in reducing the risk of VTE following knee arthroscopy. However, all of these studies have evaluated the efficacy of low molecular weight heparins (LMWH), with reductions in the risk of DVT ranging from 65% to 93%, but with the potential side effect of bleeding. At the present time, there have been no randomized studies reported evaluating the utility of aspirin, an agent with a reportedly lower bleeding risk than LMWH, as pharmacologic prophylaxis against VTE after arthroscopic knee surgery. METHODS: In a single-center, randomized, single-blind prospective trial, the efficacy of aspirin as postoperative pharmacologic VTE prophylaxis was evaluated in a low risk population undergoing knee arthroscopy. One hundred seventy patients were randomized to a treatment group of 325 mg of aspirin daily for 14 days postoperatively (66 patients) or to the control group with no intervention (104 patients). Bilateral, whole leg, compression venous duplex ultrasonography was performed 10 to 14 days postoperatively to document the incidence of DVT. The primary endpoint of the current study was the development of DVT or pulmonary embolism (PE), and the secondary endpoint was the development of a postoperative complication. RESULTS: The study cohort was comprised of 104 males (61%) and 66 females (39%) with a mean age of 44.4 +/- 14.4 years (range: 18 to 75 years). Within both the aspirin treatment and control groups, the surgical procedures included meniscectomy, ACL reconstruction, chondroplasty, and meniscus repair. No cases of postoperative deep vein thrombosis (DVT) or pulmonary embolism (PE) were identified in either arm of the study during the observation period. Twenty-three patients experienced a complication, including pain or swelling (9%), residual joint line tenderness (3%), arthrofibrosis (0.6%), and instability after a fall (0.6%). Three patients developed knee swelling, two of them in the aspirin group and one of whom required a knee aspiration. However, there was no difference in the development of complications between the two patient populations (p = 0.76, odds ratio [OR] 1.14, 95% confidence interval [CI] 0.5-2.56). CONCLUSIONS: With no cases of VTE identified in our patient population, the use of aspirin in a low-risk population undergoing arthroscopic knee surgery is not warranted. PMID- 26630468 TI - Comparative Readability of Shoulder and Elbow Patient Education Materials within Orthopaedic Websites. AB - There is growing concern that the readability of online orthopaedic patient education materials are too difficult for the general public to fully understand. It is recommended that this information be at the sixth grade reading level or lower. This study compared the readability of shoulder and elbow education articles from the American Academy of Orthopaedic Surgeons (AAOS) and American Society for Surgery of the Hand (ASSH) websites. Seventy-six patient education articles from the AAOS and ASSH concerning shoulder and elbow disorders were evaluated. Each article was assessed for the number of years since its last update, word count, percentage of passive sentences, Flesch Reading Ease score, Flesch-Kincaid grade level, Simple Measure of Gobbledygook (SMOG) grade, and New Dale-Chall grade level. Only one article was at or below the sixth grade reading level. The AAOS and ASSH articles had the following respective scores: a mean Flesch Reading Ease score of 54.3 and 51.8, Flesch-Kincaid grade level of 9.4 and 10.3, SMOG grade of 8.5 and 9.4, and New Dale-Chall grade of 10.4 and 11.0. Articles from the AAOS were longer (p < 0.001), had a lower percentage of passive sentences (p < 0.001), and were more recently updated (p = 0.02) than their ASSH counterparts. Higher percentages of passive sentences were found to correlate with more difficult readability. Patient education materials regarding the shoulder and elbow on the AAOS and ASSH websites have readability scores above the recommended reading level. These may be too challenging for the majority of patients to read and consequently serve as a barrier to proper patient education. Reducing the percentage of passive sentences may serve as a novel target for improving readability. PMID- 26630469 TI - Preoperative Planning in Orthopaedic Surgery. Current Practice and Evolving Applications. AB - Preoperative planning is an essential prerequisite for the success of orthopaedic procedures. Traditionally, the exercise has involved the written down, step by step "blueprint" of the surgical procedure. Preoperative planning of the technical aspects of the orthopaedic procedure has been performed on hardcopy radiographs using various methods such as copying the radiographic image on tracing papers to practice the planned interventions. This method has become less practical due to variability in radiographic magnification and increasing implementation of digital imaging systems. Advances in technology along with recognition of the importance of surgical safety protocols resulted in widespread changes in orthopaedic preoperative planning approaches. Nowadays, perioperative "briefings" have gained particular importance and novel planning methods have started to integrate into orthopaedic practice. These methods include using software that enables surgeons to perform preoperative planning on digital radiographs and to construct 3D digital models or prototypes of various orthopaedic pathologies from a patient's CT scans to practice preoperatively. Evidence-to-date suggests that preoperative planning and briefings are effective means of favorably influencing the outcomes of orthopaedic procedures. PMID- 26630470 TI - Etiology of Readmissions Following Orthopaedic Procedures and Medical Admissions. A Comparative Analysis. AB - INTRODUCTION: The Federal Government, the largest payer of health care, considers readmission within 30 days of discharge an indicator of quality of care. Many studies have focused on causes for and strategies to reduce readmissions following medical admissions. However, few studies have focused on the differences between them. We believe that the causes for readmission following orthopaedic surgery are markedly different than those following medical admissions, and therefore, the strategies developed to reduce medical readmissions will not be as effective in reducing readmissions after elective orthopaedic surgery. METHODS: All unplanned 30-day readmissions following an index hospitalization for an elective orthopaedic procedure (primary and revision total joint arthroplasty and spine procedure) or for one of the three publicly reported medical conditions (AMI, HF, and pneumonia, which accounted for 11% of readmissions) were identified at our institution from 2010 through 2012. A total of 268 patients and 390 medical patients were identified as having an unplanned 30-day readmission. We reviewed a prospectively collected data base to determine the reason for readmission in each encounter. RESULTS: A total of 233 (86.9%) orthopaedic patients were readmitted for surgical complications, most commonly for a wound infection (56.0%) or wound complication (11.6%). Following an index admission of HF or AMI, the primary reason for readmission was a disease of the circulatory system (55.9% and 57.4%, respectively). Following an index admission for pneumonia, the primary reason for readmission was a disease of the respiratory system (34.5%). CONCLUSION: The causes of readmissions following orthopaedic surgery and medical admissions are different. Patients undergoing orthopaedic procedures are readmitted for surgical complications, frequently unrelated to aftercare, and medicine patients are readmitted for reasons related to the index diagnosis. Interventions designed to reduce orthopaedic readmissions must focus on reducing surgical complications, differing from interventions designed to reduce readmissions following medical admissions, which focus on medical diagnoses. PMID- 26630471 TI - Risk Factors for Developing Staphylococcus aureus Nasal Colonization in Spine and Arthroplasty Surgery. AB - Staphylococcus aureus nasal colonization is a risk factor for surgical site infection. We conducted a retrospective case-control study of 1,708 consecutively enrolled patients to identify criteria that places orthopaedic surgery patients undergoing spine and total joint arthroplasty surgery at risk for nasal colonization by MRSA and MSSA. Multivariate analysis showed obesity and asthma as significant risk factors for MRSA colonization. The identification of these two risk factors for MRSA colonization may help decolonization programs target patients with these factors for treatment prior to surgery, which could potentially lead to reductions in the rates of surgical site infections. PMID- 26630472 TI - Maffucci Syndrome. An Interesting Case and a Review of the Literature. AB - Maffucci syndrome, a rare sporadic form of enchondromatosis, is characterized by hemangiomas and multiple enchondromas, benign cartilaginous tumors that arise near growth plates. Previous studies demonstrate that individuals diagnosed with Maffucci syndrome have approximately 100% lifetime risk of malignant transformation. Identification of Maffucci syndrome by surgical excision and pathological diagnosis can be life-saving due to its high malignant potential relative to other subtypes of enchondromatosis such as Ollier's disease. We report a case of a 58-year-old man with enchondromatosis who experienced malignant transformation of the enchondroma in his distal femur into a chondrosarcoma. He underwent a right distal femoral replacement without complications. Two years later, new masses were identified in his left hand and excised following progressive growth, pain, and functional limitation. Pathology confirmed these to be hemangiomas, and he was diagnosed with Maffucci syndrome. At last follow-up, patient reported additional nodular tumor growths occurring unilaterally on the left side. For patients with Maffucci syndrome, continual follow-up and careful surveillance of these masses is crucial as these lesions can cause fractures, deformities, pain, and undergo malignant transformation. Our report reviews the literature and outlines the treatment and management plans for patients with this rare and potentially dangerous disorder. PMID- 26630473 TI - Two Cases of Retained Cement after Hip Hemiarthroplasty. Don't Forget the Basics. AB - Hemiarthroplasty as a treatment for femoral neck fractures is controversial with evolving understanding of its complications. One set of complications relates to the use of cement for these procedures. This case study presents two cases that were complicated by retained cement in the acetabulum that was identified in final intraoperative check with x-rays. In both cases, the incision was reopened and retained fragments were removed. We aim to remind the orthopaedic surgery community that this complication can occur even to the careful, experienced surgeon and to recommend the steps necessary to minimize the risk of its occurrence. PMID- 26630474 TI - Cytotoxic scalarane-type sesterterpenes from the Saudi Red Sea sponge Hyrtios erectus. AB - The CHCl3/MeOH extract of the marine sponge Hyrtios erectus showed cytotoxicity against three cancer cell lines HepG2, A549, and PC-3 with IC50 0.055, 0.044, and 0.023 MUg/ml, respectively. The CH2Cl2 soluble fraction afforded three scalarane sesterterpenes (1-3) along with a cholestane derivative (4) and an indole alkaloid (5). Chemical structures were established by spectroscopic techniques and comparison with data reported in the literature. Scalarinol (1) was found as a new metabolite, while heteronemin (2) and 12-O-deacetyl-19-deoxyscalarin (3) are known compounds. 1-3 exhibited cytotoxic activity against the cancer cell lines with IC50 values ranging from 14 to 230 MUM. The molecular affinity to the DNA was employed as marker to examine the proposed mechanism of cytotoxic activities. Compound 2, with IC50 28 MUg/ml, displayed the highest affinity to the DNA. PMID- 26630478 TI - Light-Directed Particle Patterning by Evaporative Optical Marangoni Assembly. AB - Controlled particle deposition on surfaces is crucial for both exploiting collective properties of particles and their integration into devices. Most available methods depend on intrinsic properties of either the substrate or the particles to be deposited making them difficult to apply to complex, naturally occurring or industrial formulations. Here we describe a new strategy to pattern particles from an evaporating drop, regardless of inherent particle characteristics and suspension composition. We use light to generate Marangoni surface stresses resulting in flow patterns that accumulate particles at predefined positions. Using projected images, we generate a broad variety of complex patterns, including multiple spots, lines and letters. Strikingly, this method, which we call evaporative optical Marangoni assembly (eOMA), allows us to pattern particles regardless of their size or surface properties, in model suspensions as well as in complex, real-world formulations such as commercial coffee. PMID- 26630475 TI - Thiostrepton Variants Containing a Contracted Quinaldic Acid Macrocycle Result from Mutagenesis of the Second Residue. AB - The thiopeptides are a family of ribosomally synthesized and post-translationally modified peptide metabolites, and the vast majority of thiopeptides characterized to date possess one highly modified macrocycle. A few members, including thiostrepton A, harbor a second macrocycle that incorporates a quinaldic acid moiety and the four N-terminal residues of the peptide. The antibacterial properties of thiostrepton A are well established, and its recently discovered ability to inhibit the proteasome has additional implications for the development of antimalarial and anticancer therapeutics. We have conducted the saturation mutagenesis of Ala2 in the precursor peptide, TsrA, to examine which variants can be transformed into a mature thiostrepton analogue. Although the thiostrepton biosynthetic system is somewhat restrictive toward substitutions at the second residue, eight thiostrepton Ala2 analogues were isolated. The TsrA Ala2Ile and Ala2Val variants were largely channeled through an alternate processing pathway wherein the first residue of the core peptide, Ile1, is removed, and the resulting thiostrepton analogues bear quinaldic acid macrocycles abridged by one residue. This is the first report revealing that quinaldic acid loop size is amenable to alteration during the course of thiostrepton biosynthesis. Both the antibacterial and proteasome inhibitory properties of the thiostrepton Ala2 analogues were examined. While the identity of the residue at the second position of the core peptide influences thiostrepton biosynthesis, our report suggests it may not be crucial for antibacterial and proteasome inhibitory properties of the full-length variants. In contrast, the contracted quinaldic acid loop can, to differing degrees, affect both types of biological activity. PMID- 26630479 TI - Capitalizing on mobile technology to support healthy eating in ethnic minority college students. AB - OBJECTIVE: To evaluate the capacity of a mobile technology-based intervention to support healthy eating among ethnic minority female students. PARTICIPANTS: Forty three African American and Hispanic female students participated in a 3-week intervention between January and May 2013. METHODS: Participants photographed their meals using their smart phone camera and received motivational text messages 3 times a day. At baseline, postintervention, and 10 weeks after the intervention, participants reported on fruit, vegetable, and sugar-sweetened beverage consumption. Participants were also weighed at baseline. RESULTS: Among participants with body mass index (BMI) >=25, fruit and vegetable consumption increased with time (p < .01). Among participants with BMI <21, consumption of fruit decreased (p < .05), whereas the consumption of vegetables remained stable. No effects were found for sugar-sweetened beverage consumption. CONCLUSION: Mobile technology-based interventions could facilitate healthy eating among female ethnic minority college students, particularly those with higher BMI. PMID- 26630480 TI - Ultrafast growth of carbon nanotubes on graphene for capacitive energy storage. AB - We have demonstrated a novel three-dimensional (3D) architecture of a graphene/carbon nanotube (G-CNT) hybrid synthesized at large scale within just 5 s via a simple microwave-heating method without the usage of any other conducting or expanding agent for the first time. The carbon composites obtained consist of evenly grown CNTs with an average diameter of about 15 nm on the surface of graphene nanosheets. The G-CNT hybrid exhibits enhanced electrochemical performance for both aqueous and organic supercapacitor devices. Particularly, the G-CNT electrodes demonstrate an enhanced specific capacitance of 361 F g(-1) at a current density of 1.1 A g(-1) in an aqueous electrolyte and a volumetric capacitance of 254 F cm(-3) in an organic electrolyte. They also display excellent cycle stability with nearly 91.2% of the initial capacitance retained after 10 000 charging-discharging cycles at a current density of 15 A g(-1). This demonstrates that the developed composites have potential applications in supercapacitors and other energy storage devices. PMID- 26630481 TI - Spatial and Dietary Overlap Creates Potential for Competition between Red Snapper (Lutjanus campechanus) and Vermilion snapper (Rhomboplites aurorubens). AB - Understanding the complex nature of direct and indirect species interactions is a critical precursor to successful resource management. In the northern Gulf of Mexico fisheries ecosystem, red snapper (Lutjanus campechanus) and vermilion snapper (Rhomboplites aurorubens) are two commercially harvested species within a larger reef fish complex. These two species share similar habitats and diets; however, little is known about how these species partition habitat and dietary resources. In this study we examined the extent of spatial and dietary overlap between red snapper and vermilion snapper, and experimentally compared their feeding behavior. Field data from multiple gear types demonstrates that red snapper and vermilion snapper frequently cohabited reefs in the northern Gulf of Mexico, and Pianka's niche overlap indices suggest significantly overlapping diets. Experimental manipulations show that red snapper are the dominant forager of the two species, as red snapper foraging alone ate more shrimp per fish than vermilion snapper in both the single species (p = 0.003) and mixed species (p = 0.02) treatments. In addition, red snapper ate significantly more shrimp per fish in the mixed species treatment than in the single species treatment (p = 0.04). Vermilion snapper shrimp consumption per fish did not differ significantly between mixed and single species treatments. Cumulatively, our results suggest that spatial and dietary overlap could lead to competition between red and vermilion snapper in the study area; however, conclusively determining the existence of such competition would require further research. PMID- 26630482 TI - Correction: Risk Factors for Mercury Exposure of Children in a Rural Mining Town in Northern Chile. PMID- 26630483 TI - Time Clustered Sampling Can Inflate the Inferred Substitution Rate in Foot-And Mouth Disease Virus Analyses. AB - With the emergence of analytical software for the inference of viral evolution, a number of studies have focused on estimating important parameters such as the substitution rate and the time to the most recent common ancestor (tMRCA) for rapidly evolving viruses. Coupled with an increasing abundance of sequence data sampled under widely different schemes, an effort to keep results consistent and comparable is needed. This study emphasizes commonly disregarded problems in the inference of evolutionary rates in viral sequence data when sampling is unevenly distributed on a temporal scale through a study of the foot-and-mouth (FMD) disease virus serotypes SAT 1 and SAT 2. Our study shows that clustered temporal sampling in phylogenetic analyses of FMD viruses will strongly bias the inferences of substitution rates and tMRCA because the inferred rates in such data sets reflect a rate closer to the mutation rate rather than the substitution rate. Estimating evolutionary parameters from viral sequences should be performed with due consideration of the differences in short-term and longer-term evolutionary processes occurring within sets of temporally sampled viruses, and studies should carefully consider how samples are combined. PMID- 26630484 TI - Influence of Habitat and Intrinsic Characteristics on Survival of Neonatal Pronghorn. AB - Increased understanding of the influence of habitat (e.g., composition, patch size) and intrinsic (e.g., age, birth mass) factors on survival of neonatal pronghorn (Antilocapra americana) is a prerequisite to successful management programs, particularly as they relate to population dynamics and the role of population models in adaptive species management. Nevertheless, few studies have presented empirical data quantifying the influence of habitat variables on survival of neonatal pronghorn. During 2002-2005, we captured and radiocollared 116 neonates across two sites in western South Dakota. We documented 31 deaths during our study, of which coyote (Canis latrans) predation (n = 15) was the leading cause of mortality. We used known fate analysis in Program MARK to investigate the influence of intrinsic and habitat variables on neonatal survival. We generated a priori models that we grouped into habitat and intrinsic effects. The highest-ranking model indicated that neonate mortality was best explained by site, percent grassland, and open water habitat; 90-day survival (0.80; 90% CI = 0.71-0.88) declined 23% when grassland and water increased from 80.1 to 92.3% and 0.36 to 0.40%, respectively, across 50% natal home ranges. Further, our results indicated that grassland patch size and shrub density were important predictors of neonate survival; neonate survival declined 17% when shrub density declined from 5.0 to 2.5 patches per 100 ha. Excluding the site covariates, intrinsic factors (i.e., sex, age, birth mass, year, parturition date) were not important predictors of survival of neonatal pronghorns. Further, neonatal survival may depend on available land cover and interspersion of habitats. We have demonstrated that maintaining minimum and maximum thresholds for habitat factors (e.g., percentages of grassland and open water patches, density of shrub patches) throughout natal home ranges will in turn, ensure relatively high (>0.50) neonatal survival rates, especially as they relate to coyote predation. Thus, landscape level variables (particularly percentages of open water, grassland habitats, and shrub density) should be incorporated into the development or implementation of pronghorn management plans across sagebrush steppe communities of the western Dakotas, and potentially elsewhere within the geographic range of pronghorn. PMID- 26630485 TI - The Relationship between Cortisol Activity during Cognitive Task and Posttraumatic Stress Symptom Clusters. AB - BACKGROUND: The latest development in the dimensional structure of posttraumatic stress disorder (PTSD) is a novel 6-factor model, which builds on the newly released DSM-5. One notable gap in the literature is that little is known about how distinct symptom clusters of PTSD are related to hypothalamic-pituitary adrenal (HPA) axis activity when people perform a relatively less stressful cognitive task. The purpose of this study was to investigate the relationship between cortisol activity when individuals perform cognitive tasks in the laboratory and a contemporary phenotypic model of posttraumatic stress symptomatology in earthquake survivors. METHODS: Salivary cortisol while performing cognitive tasks was collected and analyzed in 89 adult earthquake survivors. The PTSD Checklist for the DSM-5 (PCL-5) was used to assess the severity of total PTSD as well as six distinct symptom clusters. Regression analyses were conducted to examine the associations between the six distinct PTSD symptom clusters and cortisol profiles. RESULTS: The results showed that the score of the negative affect symptom cluster, but not anhedonia or other clusters, was positively associated with cortisol levels before and during the cognitive tasks. CONCLUSION: The results showed that higher cortisol levels before and during cognitive tasks might be specifically linked to a distinct symptom cluster of PTSD-negative affect symptomatology. This suggests that a distinction should be made between negative affect and anhedonia symptom clusters, as the 6-factor model proposed. PMID- 26630486 TI - Ethylene Regulates Energy-Dependent Non-Photochemical Quenching in Arabidopsis through Repression of the Xanthophyll Cycle. AB - Energy-dependent (qE) non-photochemical quenching (NPQ) thermally dissipates excess absorbed light energy as a protective mechanism to prevent the over reduction of photosystem II and the generation of reactive oxygen species (ROS). The xanthophyll cycle, induced when the level of absorbed light energy exceeds the capacity of photochemistry, contributes to qE. In this work, we show that ethylene regulates the xanthophyll cycle in Arabidopsis. Analysis of eto1-1, exhibiting increased ethylene production, and ctr1-3, exhibiting constitutive ethylene response, revealed defects in NPQ resulting from impaired de-epoxidation of violaxanthin by violaxanthin de-epoxidase (VDE) encoded by NPQ1. Elevated ethylene signaling reduced the level of active VDE through decreased NPQ1 promoter activity and impaired VDE activation resulting from a lower transthylakoid membrane pH gradient. Increasing the concentration of CO2 partially corrected the ethylene-mediated defects in NPQ and photosynthesis, indicating that changes in ethylene signaling affect stromal CO2 solubility. Increasing VDE expression in eto1-1 and ctr1-3 restored light-activated de epoxidation and qE, reduced superoxide production and reduced photoinhibition. Restoring VDE activity significantly reversed the small growth phenotype of eto1 1 and ctr1-3 without altering ethylene production or ethylene responses. Our results demonstrate that ethylene increases ROS production and photosensitivity in response to high light and the associated reduced plant stature is partially reversed by increasing VDE activity. PMID- 26630487 TI - Contrasting the Chromosomal Organization of Repetitive DNAs in Two Gryllidae Crickets with Highly Divergent Karyotypes. AB - A large percentage of eukaryotic genomes consist of repetitive DNA that plays an important role in the organization, size and evolution. In the case of crickets, chromosomal variability has been found using classical cytogenetics, but almost no information concerning the organization of their repetitive DNAs is available. To better understand the chromosomal organization and diversification of repetitive DNAs in crickets, we studied the chromosomes of two Gryllidae species with highly divergent karyotypes, i.e., 2n(?) = 29,X0 (Gryllus assimilis) and 2n = 9, neo-X1X2Y (Eneoptera surinamensis). The analyses were performed using classical cytogenetic techniques, repetitive DNA mapping and genome-size estimation. Conserved characteristics were observed, such as the occurrence of a small number of clusters of rDNAs and U snDNAs, in contrast to the multiple clusters/dispersal of the H3 histone genes. The positions of U2 snDNA and 18S rDNA are also conserved, being intermingled within the largest autosome. The distribution and base-pair composition of the heterochromatin and repetitive DNA pools of these organisms differed, suggesting reorganization. Although the microsatellite arrays had a similar distribution pattern, being dispersed along entire chromosomes, as has been observed in some grasshopper species, a band-like pattern was also observed in the E. surinamensis chromosomes, putatively due to their amplification and clustering. In addition to these differences, the genome of E. surinamensis is approximately 2.5 times larger than that of G. assimilis, which we hypothesize is due to the amplification of repetitive DNAs. Finally, we discuss the possible involvement of repetitive DNAs in the differentiation of the neo-sex chromosomes of E. surinamensis, as has been reported in other eukaryotic groups. This study provided an opportunity to explore the evolutionary dynamics of repetitive DNAs in two non-model species and will contribute to the understanding of chromosomal evolution in a group about which little chromosomal and genomic information is known. PMID- 26630488 TI - The Complete Chloroplast Genome of Guadua angustifolia and Comparative Analyses of Neotropical-Paleotropical Bamboos. AB - To elucidate chloroplast genome evolution within neotropical-paleotropical bamboos, we fully characterized the chloroplast genome of the woody bamboo Guadua angustifolia. This genome is 135,331 bp long and comprises of an 82,839-bp large single-copy (LSC) region, a 12,898-bp small single-copy (SSC) region, and a pair of 19,797-bp inverted repeats (IRs). Comparative analyses revealed marked conservation of gene content and sequence evolutionary rates between neotropical and paleotropical woody bamboos. The neotropical herbaceous bamboo Cryptochloa strictiflora differs from woody bamboos in IR/SSC boundaries in that it exhibits slightly contracted IRs and a faster substitution rate. The G. angustifolia chloroplast genome is similar in size to that of neotropical herbaceous bamboos but is ~3 kb smaller than that of paleotropical woody bamboos. Dissimilarities in genome size are correlated with differences in the lengths of intergenic spacers, which are caused by large-fragment insertion and deletion. Phylogenomic analyses of 62 taxa yielded a tree topology identical to that found in preceding studies. Divergence time estimation suggested that most bamboo genera diverged after the Miocene and that speciation events of extant species occurred during or after the Pliocene. PMID- 26630489 TI - Mice Lacking Serotonin 2C Receptors Have increased Affective Responses to Aversive Stimuli. AB - Although central serotonergic systems are known to influence responses to noxious stimuli, mechanisms underlying serotonergic modulation of pain responses are unclear. We proposed that serotonin 2C receptors (5-HT2CRs), which are expressed within brain regions implicated in sensory and affective responses to pain, contribute to the serotonergic modulation of pain responses. In mice constitutively lacking 5-HT2CRs (2CKO mice) we found normal baseline sensory responses to noxious thermal, mechanical and chemical stimuli. In contrast, 2CKO mice exhibited a selective enhancement of affect-related ultrasonic afterdischarge vocalizations in response to footshock. Enhanced affect-related responses to noxious stimuli were also exhibited by 2CKO mice in a fear sensitized startle assay. The extent to which a brief series of unconditioned footshocks produced enhancement of acoustic startle responses was markedly increased in 2CKO mice. As mesolimbic dopamine pathways influence affective responses to noxious stimuli, and these pathways are disinhibited in 2CKO mice, we examined the sensitivity of footshock-induced enhancement of startle to dopamine receptor blockade. Systemic administration of the dopamine D2/D3 receptor antagonist raclopride selectively reduced footshock-induced enhancement of startle without influencing baseline acoustic startle responses. We propose that 5-HT2CRs regulate affective behavioral responses to unconditioned aversive stimuli through mechanisms involving the disinhibition of ascending dopaminergic pathways. PMID- 26630490 TI - Connexin 43 Upregulation in Mouse Lungs during Ovalbumin-Induced Asthma. AB - BACKGROUND: Connexin (Cx)-based gap junction channels play important roles in the inflammatory response. Cx43 is involved in the pathogenesis of some lung diseases such as acute lung injury. However, the Cx43 expression in asthma is unclear. In the present study, we used a murine model of ovalbumin (OVA)-induced allergic airway disease to examine the levels of Cx43 and analyze the relationship between Cx43 and airway inflammation in allergic airway disease. METHODS: Asthma was induced in mice via sensitization and challenge with OVA. Cx43 mRNA and protein expression levels were investigated via QT-PCR, western blot, and immunohistochemistry 0 h, 8 h, 1 d, 2 d and 4 d after the first challenge. The relationship between Cx43 protein levels and inflammatory cell infiltration, cytokine levels was analyzed. RESULTS: The OVA-induced mice exhibited typical pathological features of asthma, including airway hyper-responsiveness; strong inflammatory cell infiltration surrounding the bronchia and vessels; many inflammatory cells in the bronchoalveolar lavage fluid (BALF); higher IL-4, IL-5 and IL-13 levels; and high OVA specific IgE levels. Low Cx43 expression was detected in the lungs of control (PBS) mice. A dramatic increase in the Cx43 mRNA and protein levels was found in the asthmatic mice. Cx43 mRNA and protein expression levels increased in a time-dependent manner in asthma mice, and Cx43 was mostly localized in the alveolar and bronchial epithelial layers. Moreover, lung Cx43 protein levels showed a significant positive correlation with inflammatory cell infiltration in the airway and IL-4 and IL-5 levels in the BALF at different time points after challenge. Interestingly, the increase in Cx43 mRNA and protein levels occurred prior to the appearance of the inflammatory cell infiltration. CONCLUSION: Our data suggest that there is a strong upregulation of Cx43 mRNA and protein levels in the lungs in asthma. Cx43 levels also exhibited a positive correlation with allergic airway inflammation. Cx43 may represent a target to treat allergic airway diseases in the future. PMID- 26630492 TI - Young People's Preferences for Family Planning Service Providers in Rural Malawi: A Discrete Choice Experiment. AB - OBJECTIVE: To quantify the impact of service provider characteristics on young people's choice of family planning (FP) service provider in rural Malawi in order to identify strategies for increasing access and uptake of FP among youth. METHODS AND FINDINGS: A discrete choice experiment was developed to assess the relative impact of service characteristics on preferences for FP service providers among young people (aged 15-24). Four alternative providers were included (government facility, private facility, outreach and community based distribution of FP) and described by six attributes (the distance between participants' home and the service delivery point, frequency of service delivery, waiting time at the facility, service providers' attitude, availability of FP commodities and price). A random parameters logit model was used to estimate preferences for service providers and the likely uptake of services following the expansion of outreach and community based distribution (CBDA) services. In the choice experiment young people were twice as likely to choose a friendly provider (government service odds ratio [OR] = 2.45, p<0.01; private service OR = 1.99, p<0.01; CBDA OR = 1.88, p<0.01) and more than two to three times more likely to choose a provider with an adequate supply of FP commodities (government service OR = 2.48, p<0.01; private service OR = 2.33, p<0.01; CBDA = 3.85, p<0.01). Uptake of community based services was greater than facility based services across a variety of simulated service scenarios indicating that such services may be an effective means of expanding access for youth in rural areas and an important tool for increasing service uptake among youth. CONCLUSIONS: Ensuring that services are acceptable to young people may require additional training for service providers in order to ensure that all providers are friendly and non judgemental when dealing with younger clients and to ensure that supplies are consistently available. PMID- 26630491 TI - Aquaporin 5 Interacts with Fluoride and Possibly Protects against Caries. AB - Aquaporins (AQP) are water channel proteins and the genes coding for AQP2, AQP5, and AQP6 are clustered in 12q13. Since AQP5 is expressed in serous acinar cells of salivary glands, we investigated its involvement in caries. DNA samples from 1,383 individuals from six groups were studied. Genotypes of eight single nucleotide polymorphisms covering the aquaporin locus were tested for association with caries experience. Interaction with genes involved in enamel formation was tested. The association between enamel microhardness at baseline, after creation of artificial caries lesion, and after exposure to fluoride and the genetic markers in AQP5 was tested. Finally, AQP5 expression in human whole saliva, after exposure to fluoride in a mammary gland cell line, which is known to express AQP5, and in Wistar rats was also verified. Nominal associations were found between caries experience and markers in the AQP5 locus. Since these associations suggested that AQP5 may be inhibited by levels of fluoride in the drinking water that cause fluorosis, we showed that fluoride levels above optimal levels change AQP5 expression in humans, cell lines, and rats. We have shown that AQP5 is involved in the pathogenesis of caries and likely interacts with fluoride. PMID- 26630495 TI - Mn(II) complexes of different nuclearity: synthesis, characterization and catecholase-like activity. AB - Two "end-off" compartmental ligands, 2-formyl-4-chloro-6-N-ethylmorpholine iminomethyl-phenol (HL1) and 2-formyl-4-methyl-6-N-ethylpyrrolidine-iminomethyl phenol (HL2) have been designed and three complexes of Mn(ii), one mono-, one di- and a polynuclear, namely Mn(L1)(SCN)2(H2O)] (), [Mn2(L1)(OAc)2](BPh4)] (), and [Mn2(L2)(OAc)2(dca)]n () have been synthesized and structurally characterized. Variable temperature magnetic studies of and have been performed and data analyses reveal that Mn centers are antiferromagnetic coupled with J = -9.15 cm( 1) and J = -46.89, respectively. Catecholase activity of all the complexes has been investigated using 3,5-di-tert-butyl catechol (3,5-DTBC). All are highly active and the activity order on the basis of the kcat value is > > . In order to unveil whether the metal centered redox participation or the radical pathway is responsible for the catecholase-like activity of the complexes, detailed EPR and cyclic voltammetric (CV) studies have been performed. In addition to the six-line EPR spectrum characteristic to Mn(ii), an additional peak at g ~ 2 is observed when the EPR study is done with the mixture of 3,5-DTBC and the catalyst, suggesting the formation of an organic radical, most likely ligand centered. The CV experiment with the mixture of 3,5-DTBC and the catalyst reveals ligand centered reduction rather than reduction of Mn(ii) to Mn(i). It is thus inferred that complexes show catecholase-like activity due to radical generation. PMID- 26630494 TI - Chronic Powder Diet After Weaning Induces Sleep, Behavioral, Neuroanatomical, and Neurophysiological Changes in Mice. AB - The purpose of this study is to clarify the effects of chronic powder diet feeding on sleep patterns and other physiological/anatomical changes in mice. C57BL/6 male mice were divided into two groups from weaning: a group fed with solid food (SD) and a group fed with powder food (PD), and sleep and physiological and anatomical changes were compared between the groups. PD exhibited less cranial bone structure development and a significant weight gain. Furthermore, these PD mice showed reduced number of neurogenesis in the hippocampus. Sleep analysis showed that PD induced attenuated diurnal sleep/wake rhythm, characterized by increased sleep during active period and decreased sleep during rest period. With food deprivation (FD), PD showed less enhancement of wake/locomotor activity compared to SD, indicating reduced food-seeking behavior during FD. These results suggest that powder feeding in mice results in a cluster of detrimental symptoms caused by abnormal energy metabolism and anatomical/neurological changes. PMID- 26630493 TI - Sports and Exercise at Different Ages and Leukocyte Telomere Length in Later Life -Data from the Berlin Aging Study II (BASE-II). AB - Physical activity and sports have repeatedly been reported to be associated with telomere length. We studied the association of different types of sports across different stages of life on relative leukocyte telomere length (rLTL) in advanced age.815 participants (397 men) from the Berlin Aging Study II aged over 61 years were included in the analysis. rLTL was measured by real time PCR and physical activity was determined retrospectively by questionnaire, assessing type and duration of sports in the past as well as currently. Five separate multiple linear regression models adjusted for various control variables were performed. 67.3% of participants exercised currently, whereas 19.4% performed sports only between the age of 20 and 30. rLTL was higher in subjects who stated to exercise currently (N = 456), and in subjects who engaged in endurance (N = 138) or intensive activity sports (N = 32). Current physical activity was positively associated with rLTL in the risk factor adjusted regression model (beta = 0.26, p < 0.001) and practicing sports for a minimum of 10 years preceding the assessment had a significant effect on rLTL (beta = 0.39, p = 0.011). The highest impact was seen for intensive activity sports (beta = 0.79, p < 0.001) and physical activity since at least 42 years (beta = 0.47, p = 0.001). However, physical activity only between 20 and 30 years of age did not affect rLTL in old age when compared to no sports at all (beta = -0.16, p = 0.21). Physical activity is clearly associated with longer rLTL. The effect is seen with longer periods of physical activity (at least 10 years), with intensive sports activities having the greatest impact on rLTL. Our data suggest that regular physical activity for at least 10 years is necessary to achieve a sustained effect on rLTL. PMID- 26630496 TI - A Novel Cascade Classifier for Automatic Microcalcification Detection. AB - In this paper, we present a novel cascaded classification framework for automatic detection of individual and clusters of microcalcifications (MUC). Our framework comprises three classification stages: i) a random forest (RF) classifier for simple features capturing the second order local structure of individual MUCs, where non-MUC pixels in the target mammogram are efficiently eliminated; ii) a more complex discriminative restricted Boltzmann machine (DRBM) classifier for MUC candidates determined in the RF stage, which automatically learns the detailed morphology of MUC appearances for improved discriminative power; and iii) a detector to detect clusters of MUCs from the individual MUC detection results, using two different criteria. From the two-stage RF-DRBM classifier, we are able to distinguish MUCs using explicitly computed features, as well as learn implicit features that are able to further discriminate between confusing cases. Experimental evaluation is conducted on the original Mammographic Image Analysis Society (MIAS) and mini-MIAS databases, as well as our own Seoul National University Bundang Hospital digital mammographic database. It is shown that the proposed method outperforms comparable methods in terms of receiver operating characteristic (ROC) and precision-recall curves for detection of individual MUCs and free-response receiver operating characteristic (FROC) curve for detection of clustered MUCs. PMID- 26630497 TI - Combined Bronchial Artery Embolization and Endobronchial Resection for Bronchial Carcinoid: A Safety and Feasibility Pilot Study. AB - BACKGROUND: There is growing evidence to support bronchoscopic resection of well circumscribed typical carcinoids. However, massive bleeding and risk of recurrence can potentially complicate this approach. OBJECTIVES: The aim of this study was to assess the safety and feasibility of endobronchial resection of carcinoids preceded by bronchial artery embolization. METHODS: Five patients with centrally located typical carcinoids were recruited, 4 with a curative intent and 1 for palliation of a carcinoid with mediastinal invasion. All patients underwent selective embolization of the feeding bronchial artery 24-48 h prior to endobronchial resection, which was performed with a rigid bronchoscope and neodymium:yttrium-aluminium-perovskite laser. RESULTS: Minimal bleeding was noted during tumour resection. After a median (range) follow-up of 20 (14-48) months, only the case with segmental extension of the tumour had local recurrence, which was treated successfully using cryotherapy (with negative endobronchial biopsies since), and no cases of metastatic spread occurred. One patient, in whom the histopathological diagnosis was changed from typical to atypical carcinoid following resection, went on to have a surgical bilobectomy 3 months later. Extensive fibrosis was noted at the site of original tumour resection with no evidence of residual disease. CONCLUSIONS: Bronchial artery embolization prior to endobronchial resection of centrally located carcinoids is feasible and safe. The reduction in bleeding may facilitate and simplify the procedure. The possible application of this combined therapy to the management of atypical carcinoids warrants the design of a larger prospective clinical trial. PMID- 26630498 TI - A Conjugate Fluid-Porous Approach for Simulating Airflow in Realistic Geometric Representations of the Human Respiratory System. AB - Simulation of flow in the human lung is of great practical interest as a means to study the detailed flow patterns within the airways for many physiological applications. While computational simulation techniques are quite mature, lung simulations are particularly complicated due to the vast separation of length scales between upper airways and alveoli. Many past studies have presented numerical results for truncated airway trees, however, there are significant difficulties in connecting such results with respiratory airway models. This article presents a new modeling paradigm for flow in the full lung, based on a conjugate fluid-porous formulation where the upper airway is considered as a fluid region with the remainder of the lung being considered as a coupled porous region. Results are presented for a realistic lung geometry obtained from computed tomography (CT) images, which show the method's potential as being more efficient and practical than attempting to directly simulate flow in the full lung. PMID- 26630500 TI - Constitutive Effects of Lead on Aryl Hydrocarbon Receptor Gene Battery and Protection by beta-carotene and Ascorbic Acid in Human HepG2 Cells. AB - Lead (Pb) is an environmental pollutant that can get entry into human body through contaminated foods, drinks, and inhaled air leading to severe biological consequences, and has been responsible for many deaths worldwide. The objectives of this study were 1st to investigate the modulatory effects of environmentally relevant concentrations of Pb on AhR gene battery, which is controlling xenobiotics metabolism. 2nd, trials to reduce Pb-induced adverse effects were done using some phytochemicals like beta-carotene or ascorbic acid. Human hepatoma (HepG2) cell lines were exposed to a wide range of Pb concentrations varying from physiological to toxic levels (0 to 10 mg/L) for 24 h. High Pb concentrations (1 to 10 mg/L) significantly reduced phase I (CYP1A1 and 1A2) and phase II (UGT1A6 and NQO1) xenobiotic metabolizing enzyme mRNA expression in a mechanistic manner through the AhR regulation pathway. Additionally, these Pb concentrations induced oxidative stress in HepG2 cells in terms of production of reactive oxygen species (ROS) and induced heme oxygenase-1 mRNA expression in a concentration-dependent phenomenon. Coexposure of HepG2 cells to physiological concentrations of some micronutrients, like beta-carotene (10 MUM) or ascorbic acid (0.1 mM), along with Pb (1 mg/L) for 24 h significantly reduced the levels of ROS production and recovered AhR mRNA expression into the normal levels. Thus, consumption of foods rich in these micronutrients may help to reduce the adverse effects of lead in areas with high levels of pollution. PMID- 26630501 TI - Supplement Use of Elite Australian Swimmers. AB - This study examined the influence the Australian Institute of Sport (AIS) Sport Supplement Program had on supplement practices of elite Australian swimmers, comparing those guided by the Program with others in the same national team. Thirty-nine elite swimmers (13 AIS, 26 Other; 20 female, 19 male; age 21.8 +/- 3.3 y) completed a questionnaire investigating supplement use. Ninety-seven percent of swimmers reported taking supplements or sports foods over the preceding 12 months. AIS swimmers reported using more total brands (p = .02) and supplements considered Ergogenic (p = .001) than Other swimmers who used more supplements considered to be lacking scientific support (p = .028). Swimmers rated the risk of a negative outcome from the use of supplements available in Australia (Mdn = 3.0) as less than the risk of supplements from international sources (Mdn = 4.0; p < .001). AIS swimmers were more likely to report dietitians (p < .001) and sports physicians (p = .017) as advisors of their supplement use. Other swimmers more frequently reported fellow athletes as a source of supplement advice (p = .03). AIS swimmers sourced a greater percentage of their supplements from an organized program (94 +/- 16%) compared with Other (40 +/- 32%; p < .001) who sourced a greater percentage (30 +/- 30%) of their dietary supplements from supermarkets. These findings suggest that swimmers influenced by this sport supplement program more frequently use supplements that are recommended by allied health trained individuals, classified as evidence based and provided by the program. PMID- 26630499 TI - Differential Impact of LPG-and PG-Deficient Leishmania major Mutants on the Immune Response of Human Dendritic Cells. AB - BACKGROUND: Leishmania major infection induces robust interleukin-12 (IL12) production in human dendritic cells (hDC), ultimately resulting in Th1-mediated immunity and clinical resolution. The surface of Leishmania parasites is covered in a dense glycocalyx consisting of primarily lipophosphoglycan (LPG) and other phosphoglycan-containing molecules (PGs), making these glycoconjugates the likely pathogen-associated molecular patterns (PAMPS) responsible for IL12 induction. METHODOLOGY/PRINCIPAL FINDINGS: Here we explored the role of parasite glycoconjugates on the hDC IL12 response by generating L. major Friedlin V1 mutants defective in LPG alone, (FV1 lpg1-), or generally deficient for all PGs, (FV1 lpg2-). Infection with metacyclic, infective stage, L. major or purified LPG induced high levels of IL12B subunit gene transcripts in hDCs, which was abrogated with FV1 lpg1- infections. In contrast, hDC infections with FV1 lpg2- displayed increased IL12B expression, suggesting other PG-related/LPG2 dependent molecules may act to dampen the immune response. Global transcriptional profiling comparing WT, FV1 lpg1-, FV1 lpg2- infections revealed that FV1 lpg1- mutants entered hDCs in a silent fashion as indicated by repression of gene expression. Transcription factor binding site analysis suggests that LPG recognition by hDCs induces IL-12 in a signaling cascade resulting in Nuclear Factor kappa B (NFkappaB) and Interferon Regulatory Factor (IRF) mediated transcription. CONCLUSIONS/SIGNIFICANCE: These data suggest that L. major LPG is a major PAMP recognized by hDC to induce IL12-mediated protective immunity and that there is a complex interplay between PG-baring Leishmania surface glycoconjugates that result in modulation of host cellular IL12. PMID- 26630502 TI - Stretchable Active Matrix Temperature Sensor Array of Polyaniline Nanofibers for Electronic Skin. AB - A stretchable polyaniline nanofiber temperature sensor array with an active matrix consisting of single-walled carbon nanotube thin-film transistors is demonstrated. The integrated temperature sensor array gives mechanical stability under biaxial stretching of 30%, and the resultant spatial temperature mapping does not show any mechanical or electrical degradation. PMID- 26630503 TI - A Highly Oxidized Cobalt Porphyrin Dimer: Spin Coupling and Stabilization of the Four-Electron Oxidation Product. AB - A highly oxidized cobalt porphyrin dimer is reported. Each cobalt(II) ion and porphyrin ring underwent 1e oxidation with iodine as the oxidant to give a 4e oxidized cobalt(III) porphyrin pi-cation radical dimer. The bridging ethylene group allows for substantial conjugation of the porphyrin macrocycles, thus leading to a strong antiferromagnetic coupling between the pi-cation radicals and to stabilization of the singlet state. X-ray crystallography clearly showed that the complex may be considered as a real supramolecule rather than two cobalt(III) porphyrin pi-cation radicals that interact through space. PMID- 26630505 TI - The Role of M2 Macrophages in the Progression of Chronic Kidney Disease following Acute Kidney Injury. AB - INTRODUCTION: Acute kidney injury (AKI) is a major risk factor in the development of chronic kidney disease (CKD). However, the mechanisms linking AKI to CKD remain unclear. We examined the alteration of macrophage phenotypes during an extended recovery period following ischemia/reperfusion injury (IRI) and determine their roles in the development of fibrosis. METHODS: The left renal pedicle of mice was clamped for 40 min. To deplete monocyte/macrophage, liposome clodronate was injected or CD11b-DTR and CD11c-DTR transgenic mice were used. RESULTS: Throughout the phase of IRI recovery, M2-phenotype macrophages made up the predominant macrophage subset. On day 28, renal fibrosis was clearly shown with increased type IV collagen and TGF-beta. The depletion of macrophages induced by the liposome clodronate injection improved renal fibrosis with a reduction of kidney IL-6, type IV collagen, and TGF-beta levels. Additionally, the adoptive transfer of the M2c macrophages partially reversed the beneficial effect of macrophage depletion, whereas the adoptive transfer of the M1 macrophages did not. M2 macrophages isolated from the kidneys during the recovery phase expressed 2.5 fold higher levels of TGF-beta than the M1 macrophages. The injection of the diphtheria toxin into CD11b or CD11c-DTR transgenic mice resulted in lesser depletion or no change in M2 macrophages and had little impact on renal fibrosis. CONCLUSION: Although M2 macrophages are known to be indispensible for short-term recovery, they are thought to be main culprit in the development of renal fibrosis following IRI. PMID- 26630506 TI - Health of the Elderlies and Healthy Ageing: Challenge for Europe. AB - Population ageing is a major challenge for European Union (EU) society and economy, particularly for Italy, which is the oldest country in Europe. According to the World Health Organization, two-thirds of European citizens who have reached the retirement age suffer from at least two chronic conditions, with a strong pressure on healthcare systems. Moreover, EU countries already spend, on average, more than a quarter of their gross domestic product on social protection, above all pensions, health and long term care. The current financial crisis is putting a strain on this system. In this context, it becomes increasingly necessary to promote a healthy and independent ageing, by improving outcomes for patients and society while ensuring health systems sustainability. To this purpose a proactive approach to chronic diseases prevention (primary, secondary and tertiary) as well as an integrated healthcare approach and also patients' empowerment are required so as to make daily life more age-friendly. It is also necessary to share health and social best practices, adopt policies really effective against elderly social exclusion and strengthen older people participation in society. A joint effort of all key stakeholders is needed to create a society in which older people can play an active role. PMID- 26630504 TI - Peroxisomes in Different Skeletal Cell Types during Intramembranous and Endochondral Ossification and Their Regulation during Osteoblast Differentiation by Distinct Peroxisome Proliferator-Activated Receptors. AB - Ossification defects leading to craniofacial dysmorphism or rhizomelia are typical phenotypes in patients and corresponding knockout mouse models with distinct peroxisomal disorders. Despite these obvious skeletal pathologies, to date no careful analysis exists on the distribution and function of peroxisomes in skeletal tissues and their alterations during ossification. Therefore, we analyzed the peroxisomal compartment in different cell types of mouse cartilage and bone as well as in primary cultures of calvarial osteoblasts. The peroxisome number and metabolism strongly increased in chondrocytes during endochondral ossification from the reserve to the hypertrophic zone, whereas in bone, metabolically active osteoblasts contained a higher numerical abundance of this organelle than osteocytes. The high abundance of peroxisomes in these skeletal cell types is reflected by high levels of Pex11beta gene expression. During culture, calvarial pre-osteoblasts differentiated into secretory osteoblasts accompanied by peroxisome proliferation and increased levels of peroxisomal genes and proteins. Since many peroxisomal genes contain a PPAR-responsive element, we analyzed the gene expression of PPARalpha/beta/gamma in calvarial osteoblasts and MC3T3-E1 cells, revealing higher levels for PPARbeta than for PPARalpha and PPARgamma. Treatment with different PPAR agonists and antagonists not only changed the peroxisomal compartment and associated gene expression, but also induced complex alterations of the gene expression patterns of the other PPAR family members. Studies in M3CT3-E1 cells showed that the PPARbeta agonist GW0742 activated the PPRE-mediated luciferase expression and up-regulated peroxisomal gene transcription (Pex11, Pex13, Pex14, Acox1 and Cat), whereas the PPARbeta antagonist GSK0660 led to repression of the PPRE and a decrease of the corresponding mRNA levels. In the same way, treatment of calvarial osteoblasts with GW0742 increased in peroxisome number and related gene expression and accelerated osteoblast differentiation. Taken together, our results suggest that PPARbeta regulates the numerical abundance and metabolic function of peroxisomes via Pex11beta in parallel to osteoblast differentiation. PMID- 26630507 TI - Active and Healthy Ageing as a Wicked Problem: The Contribution of a Multidisciplinary Research University. AB - The quest for an active and healthy ageing can be considered a "wicked problem." It is a social and cultural problem, which is difficult to solve because of incomplete, changing, and contradictory requirements. These problems are tough to manage because of their social complexity. They are a group of linked problems embedded in the structure of the communities in which they occur. First, they require the knowledge of the social and cultural context in which they occur. They can be solved only by understanding of what people do and why they do it. Second, they require a multidisciplinary approach. Wicked problems can have different solutions, so it is critical to capture the full range of possibilities and interpretations. Thus, we suggest that Universita Cattolica del Sacro Cuore (UCSC) is well suited for accepting and managing this challenge because of its applied research orientation, multidisciplinary approach, and integrated vision. After presenting the research activity of UCSC, we describe a possible "systems thinking" strategy to consider the complexity and interdependence of active ageing and healthy living. PMID- 26630509 TI - Demographic Changes and the Challenge for a Healthy Ageing. AB - Demographic changes bring about a wide range of new research fields including policy topics, health, social welfare, work & productivity, urban & rural development, communication tools, and mobility. This new situation requires a new multi-disciplinary approach bringing together different research programs in order to provide solutions for the upcoming challenges. National Health services are now facing a huge shift in the population structure with a predominance of older generations in the total number of citizens. Good health is the most important factor to live independently in old age. A better understanding of ageing processes and the related "plasticity" of individual performance for environmental adaptation, the prevention for age-related illnesses and healthcare strategies are the basis for keeping very old people healthy and active throughout the course of their lives. We will face mainly the biological, cognitive and psychological dimensions of ageing. Afterwards, we will focus on the relationships linking various biological and lifestyle factors - such as nutrition - that are crucial to obtain a comprehensive picture of ageing and to promote preventing strategies against degenerative neurological diseases. Finally we will investigate which interventions - nutritional and physical - could help in keeping people healthy, in particular which factors could promote people's physical, social and psychological functional abilities and the systemic multilevel consequences induced by a healthy ageing. PMID- 26630510 TI - Food for Healthy Living and Active Ageing. AB - The link between diet and health has been recognized since the Grecian period; as Hippocrates said, "Let food be your medicine and medicine be your food". Although the primary goals of diet are meeting nutritional requirements and providing energy, there is increasing awareness that a correct and balanced diet may prevent the insurgence of diet-related pathologies and/or improve well-being and life expectancy, also reflecting on the ageing process. Research on the interaction among nutrients, gut microbiota and host metabolism is presently unravelling the molecular mechanisms underlying the positive and negative effects of traditional diets on health and ageing, providing useful information for the design of innovative foods targeting specific needs and segments of the population. The food supply chain plays a key role in ensuring quality and safety through both comprehensive quality management and inspection systems and a focused innovation process mainly devoted to the creation of functional foods. However, innovation and scientific development pose a problem of information asymmetry towards final consumers; thus, regulatory aspects and private and public communication strategies must be efficiently developed. PMID- 26630511 TI - Positive Technology for Healthy Living and Active Ageing. AB - Information and communication technologies are widely and rapidly spreading in people's daily lives. But what is the possible role of the mass proliferation of digital devices in supporting healthy living and active ageing? Are they useful in fostering personal growth and individual integration of the elderly, by promoting satisfaction, opportunities for action, and self-expression? Rather, do they enhance automation, impose constraints on personal initiative, and result in compulsive consumption of information? In this chapter, we suggest that possible answers to these questions will be offered by the "Positive Technology" approach, i.e., the scientific and applied approach to using technology so that it improves the quality of our personal experiences through its structuring, augmentation, and/or replacement. First, we suggest that it is possible to use technology to manipulate the quality of experience with the goal of increasing wellness and generating strengths and resilience in individuals, organizations, and society. Then, we classify positive technologies according to their effects on these three features of personal experience - Hedonic: technologies used to induce positive and pleasant experiences; Eudaimonic: technologies used to support individuals in reaching engaging and self-actualizing experiences; Social/Interpersonal: technologies used to support and improve the connectedness between individuals, groups, and organizations. Finally, we discuss the possible role of positive technologies for healthy living and active ageing by presenting different practical applications of this approach. PMID- 26630512 TI - Active Ageing: Intergenerational Relationships and Social Generativity. AB - This contribution is a reflection on the concept of active ageing from the perspective of relational sociology. At the same time, it offers practical implications and outlines possible future courses of action, in the face of demographic and relational scenarios rapidly changing, and the challenges that each day people of all generations are called to cope with. Active ageing is quite a recent concept and indicates an attitude towards ageing that enhances the quality of life as people become older. The goal of active ageing is to enable people to realise their potential for physical, social and mental well-being and to participate in social life also in the last stage of the life cycle. In this phase, the presence of a network of support, security and care adequate to the possible onset of problems and criticalities is crucial. Relational sociology frames the phenomenon of an ageing population in a dense network of social relations, primarily at the level of family and community. For this reason, as supported by the most recent sociological literature and evidence from studies conducted in Italy and abroad (cf. SHARE), it is extremely important to investigate the link between active ageing, intergenerational orientation (solidarity and exchanges) and practices of prosociality (i.e. engagement in third-sector activities and volunteering in later life). PMID- 26630513 TI - Financial Well-being in Active Ageing. AB - In developed countries, economic and financial well-being is playing a crucial positive role in ageing and inclusion processes. Due to the complexity and pervasiveness of financial economy in the real life, more and more social as well as individual well-being are perceived as influenced by financial conditions. On the other hand, the demographic circumstances drive scholars as well as politicians to reflect on ageing dynamics. Bridging the two domains, the following research focuses on the role of the financial well-being as a mediating role of general well-being in elder people. The assumption is that elderly people have specific financial needs that sometimes are not covered by financial providers' offers. The motivation is mainly on the role of information asymmetries between elder consumers and financial institutions. On the dynamics of these asymmetries, the research will specifically investigate the role of financial literacy, as the ability of comprehension of elder people of their needs and of financial information. The applicative implication of this research work consists in finding the determinants of financial well-being for elders and the definition of their specific financial competencies, in order to 1) identify educational and regulatory guidelines for policy makers in charge of creating financial market transparency conditions, and to 2) support design of organizational mechanisms as well as financial product/services for this specific target of client. The following chapter presents preliminary explorative results of a survey delivered on 200 elder individuals (65-80 yrs.) leaving in Milan. Findings show that active elders consider the ability of managing personal wealth as one of the core determinant of well-being, although the economic and financial literacy is limited. Furthermore, the chapter proposes a research agenda for scholars interested in exploring the relationship between financial well-being and ageing. PMID- 26630514 TI - Frailty, Physical Frailty, Sarcopenia: A New Conceptual Model. AB - In the literature, different criteria have been validated to identify frail older subjects, which mainly refer to two conceptual models: the cumulative deficit approach proposed by Rockwood and the Physical Frailty (PF) phenotype proposed by Fried. Both models have received empirical validation. Nevertheless, the frailty phenotype is the most widely used and presents a characterized pathophysiologic background. The PF condition depicted by the frailty phenotype has shown to be predictive of major negative health-related outcomes, including mobility disability, disability for activities of daily living, institutionalization, and mortality. At the same time, it cannot be ignored that the PF phenotype presents substantial overlaps with sarcopenia, "a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability, poor quality of life and death". In fact, many of the adverse outcomes of frailty are probably mediated by sarcopenia. Therefore, sarcopenia may be considered both as the biological substrate for the development of PF and the pathway through which the negative health outcomes of frailty ensue. Although PF encompasses only a part of the frailty spectrum, the identification of a definite biological basis (i.e., skeletal muscle decline) opens new venues for the development of interventions to slow or reverse the progression of this condition. Here, we present a novel conceptualisation of PF which will possibly promote significant advancements over the traditional approaches to this syndrome by enabling the precise operationalisation of the condition, a clear identification of the affected population and the rapid translation of findings to the clinical arena. PMID- 26630515 TI - Patient Engagement: The Key to Redesign the Exchange Between the Demand and Supply for Healthcare in the Era of Active Ageing. AB - The last decades' changes in the epidemiological trends of chronic disease - also due to the ageing population - and the increased length and quality of life among the majority of Western population have introduced important changes in the organization and management of the healthcare systems. Consequently, health systems throughout the world are searching for new and effective ways to make their services more responsive to new patients and the public's health needs and demands. The idea of patient engagement - borrowed from the marketing conceptualization of consumer engagement - moves from the assumption that making patients/clients co-producers of their health can enhance their satisfaction with the healthcare system as well as their responsibility in both care and prevention by improving clinical outcomes and reducing health delivery costs. To make people aware of their health services options by supporting them in the decision-making process and to engage them in enacting preventive and healthy behaviors is vital for achieving successful health outcomes and preventing waste of resources. In this chapter, we outline a model (PHE model) that explains the patients' subjective experience with their health management process and the levers that may enact the passage from one phase of the process to the other. Based on this conceptual model of patient engagement will be proposed a tool kit of priority actions that may sustain the patient in its process of engagement. PMID- 26630517 TI - Lifestyles and Ageing: Targeting Key Mechanisms to Shift the Balance from Unhealthy to Healthy Ageing. AB - The increase in life expectancy has dramatically enhanced the prevalence of age related chronic diseases resulting in growing costs for both society and individuals. Identification of strategies contributing to healthy ageing is thus one of the major challenges of the coming years. Lifestyle has a primary role among non-genetic factors affecting health and lifespan. In particular, nutrition, mental and physical activity impact the molecular and functional mechanisms whose alterations cause the major age-related diseases. A better understanding of mechanisms underlying the beneficial action of correct lifestyles is useful to develop interventions aimed at preventing and/or delaying the onset of chronic degenerative diseases, to identify high-risk populations who could be targeted in intervention trials as well as to identify novel biomarkers of healthy ageing. A multidisciplinary team of basic scientists and clinicians operating at the Catholic University Medical School in Rome is actively working on this topic to determine the ability of healthy lifestyles to promote active ageing and counteract the major age-related diseases affecting brain health, musculoskeletal function and gut microenvironment. This chapter summarizes our strategic approaches, the major results we obtained so far and the main experimental and translational perspectives. PMID- 26630518 TI - Nutrition and Ageing. AB - The world elderly population is rapidly increasing. This demographic change represents a new challenge for the society and demands for a multisectorial intervention to promote a long, healthy, and active life span. Between the factors that contribute in fostering a long healthy life, the nutritional regime plays a central role and is recognized as a major factor in the onset of chronic diseases. A better understanding of the interaction between nutrition and ageing is essential to unravel the mechanisms responsible for these positive/negative effects and to identify diet components promoting the quality of life in the old age and to contribute to the prevention of late-life disabilities. At Universita Cattolica del Sacro Cuore, the research activity in food science is focusing on four main objectives: food quality, food safety, functional foods and diet balancing. These objectives are the target of multidisciplinary ongoing and future research activities for a better understanding of the link between diet and ageing. Briefly, the different activities are addressed to the study of the following subjects: the most relevant factors affecting food choices and habits of old aged persons; the effects of long term low dose supplementation of conjugated linoleic acid in mouse; the use of low glycemic index and high resistant starch foods to prevent diabetes and obesity; the adjuvant effect of food bacteria for vaccination; the role of food ingredients in disease; the immunosuppression effect of mycotoxins, and its relevance in ageing people; the production of sustainable and natural antioxidant ingredients to encourage a healthy diet. Our research projects emphasize an holistic and integrated approach that, by bringing together complementary research groups, can combine the collective expertise and thus provide a comprehensive assessment of the role of nutrition in healthy ageing people. PMID- 26630519 TI - The Role of Psychogeriatrics in Healthy Living and Active Ageing. AB - A healthy and active life is a key issue for elderly citizens, above all when psychological complications such as depression and anxiety disorders, late delusion or loneliness can be observed. Moreover, medical pathologies in elderly patients often have a multi-factorial etiology and many psychopathological dimensions and psychosocial risk factors are underestimated. From the perspective of clinical health psychology, psychogeriatrics could play an important role in promoting active ageing and a healthy lifestyle in elderly persons through tailored clinical approaches based on specific research and advanced professional training in this area. More research is needed in order to study which determinants affect the process of an active and functional ageing. Possible research ageing areas are: 1) evaluation of psychosocial risk-protective factors related to the individual's biography and personality. 2) Evaluation of enrichment programs and clinical protocols focused on the management of different topics such as health system areas, behavioral areas, social and physical environment areas, psychological factors and economic determinants. The goal of Psychogeriatrics endeavors to develop and evaluate interventions designed to stimulate improvement in friendship, self-esteem and subjective well-being, as well as to reduce loneliness among older citizens. 3) Evaluation of self management programs in chronic disease conditions (such as obesity, diabetes, hypertension, poor nutrition, physical inactivity, alcohol abuse and tobacco smoking), that could enhance risk factors for health in elderly citizens. Typical key elements of self-management, such as decision making, problem solving, motivation, self-efficacy, resource utilization, and citizen's empowerment have to be studied. PMID- 26630520 TI - Age Management and Sustainable Careers for the Improvement of the Quality of Ageing at Work. AB - Prolonging working careers by increasing the statutory age for retirement has become compulsory in most Western societies in order to tackle the shrinking of the labour force, preserve economic productivity, foster knowledge transfer and reduce the risks of financial imbalances in social security systems. This imperative currently results in working careers that already exceed 40 years and come to an end after the age of 65 (e.g. in Italy). Over the next few decades, both career length and retirement age are expected to rise. Thus, creating more inclusive workplaces by increasing their quality is the precondition of a win-win situation for both employers and employees, regardless of age. A request for support in the development of sustainable careers from both private and public labour organisations has led to innovating the mainstream methodologies and research tools in the field of age management. Based on the key elements of the mainstream "work ability concept" - i.e. health, competencies, motivation and work organisation - the Quality of Ageing at Work questionnaire (QAW-q), developed by a team from the WWELL Research Centre, broadens its perspective by surveying elements bridging intra-organisational dimensions and which affect employees' conditions and external socio-institutional constraints: i.e. work life balance, economic stability, professional identity and relationships in the workplace. The QAW-q is designed to analyse the influence of the different meanings of age (chronological age, seniority within the company and in the labour market) and correlate them with the different dimensions at individual and organisational levels; all these dimensions are weighted by the effect exerted by the passage of time. The results of the QAW-q survey, taken by employees of both private and public companies, serve as a basis for the implementation of measures addressing all the relevant dimensions of the human resource management cycle. PMID- 26630521 TI - "Stay Tuned": The Role of ICTs in Elderly Life. AB - Ageing in western society has become a key issue in political and academic debate: politicians, sociologists, doctors, demographers, psychologists, economists are trying to understand how ageing will impact our future society. In this frame, media and communication technologies seem to be more and more relevant for the elderly, thanks to those services and devices helping people to grow old actively. Technologies, the Internet and ICTs could help the elderly to improve their quality of life, to be healthy and independent and to get better assistance. Our ongoing research investigates the relationship between the elderly and use of technologies, and explores the role played by media and ICTs in building a friendly and positive environment for the elderly, and in constructing and maintaining social relations and promoting healthy ageing. Specifically, the research will investigate the use of ICTs by the elderly by taking into account two different perspectives: a) Exchanges between generations: lengthening of life corresponds to a longer period of cohabitation between at least three generations (grandparents, children, grandchildren), and also of co use of digital media. The research wants to investigate relations between two age groups (grandparents and grandchildren; young people and older people) to understand the dynamics of intergenerational mutuality in the use of technologies and ICTs. b) Media, ICTs, Health: the Western world is increasingly populated by elderly population. Technologies and ICTs can help elderly people to improve their quality of life, to be healthy and independent and to get better assistance. ICTs should encourage active ageing and, in the case of health technologies, new models of care. The project, lasting 1 year, is based on (1) a survey on young elderly (65-74 yrs) population in Italy, and (2) a field-work which consists of family interviews and ethnographical sections in natural contexts. PMID- 26630522 TI - Empowering Skills for an Active Ageing and Healthy Living. AB - The chapter is aimed at describing four different approaches, each supported by experimental findings, which can be adopted to empower life skills in the elderly. The first approach consists in stimulating aged persons by asking them to carry out some tasks aimed at activating the brain and mental processes which are targeted by the intervention. In the second approach the elderly are hinted at thinking about their mental states to understand one's own and others' behavior to act as a reflective agent. The third approach is based on the assumption that the communication context can support and improve old people's skills, if the messages they receive are devised so to focus their attention on relevant information and to elicit relevant cognitive frameworks. According to the fourth approach, aged people can be engaged in activities which enjoy them so to express themselves in personal ways and to practice a wide set of mental functions. Becoming aware of the pros and cons of each approach enables us to choose the kind of intervention which is most suited to the elderly, taking into account the features of the context and the actual resources which can be employed. We also aim at integrating the different approaches so to devise a holistic intervention in which synergies among the methodologies to be applied occur. PMID- 26630523 TI - Work, Retirement and Health: An Analysis of the Socio-economic Implications of Active Ageing and their Effects on Health. AB - In recent decades many industrialized countries experienced a substantial decrease in the working age population as a proportion of the total population. Demographic factors, such as declining fertility and increasing life expectancy, as well as institutional factors, such as the generosity of state-funded pension, both determined a change in the age distribution and a marked anticipation in retirement age. A lively debate among researchers and policymakers is currently taking place in Europe, as there are concerns that working longer may not be healthy for workers, or that it will be hard for older workers to get a job. Conversely, if working longer leads to higher employment rates and better health conditions, policies aimed at increasing peoples' retirement age may represent a "win-win" strategy both in terms of fiscal policies as well as in terms of healthy life expectancy. Unfolding this controversy is essentially an empirical matter which is also of paramount importance for public policy. In this study we first review the main findings of the socio-economic literature. Second, we highlight the main research avenues that are currently investigated in the area of Social Science and Health Economics at the Universita Cattolica. Finally we discuss the policy implications and the prospects for future research. PMID- 26630524 TI - Predicting Ageing: On the Mathematical Modelization of Ageing Muscle Tissue. AB - The ageing of biological tissues can be accelerated by many factors, mainly of physiological and nutritional nature. In the case of skeletal muscle tissue, one of the main consequences of ageing is a progressive loss of muscle mass and a worsening of the quality of muscle tissue, termed "sarcopenia". The correlation between the deterioration of muscle tissue and what we usually refer to as the "lifestyle", although being the subject of several studies, up to now has been considered only from a clinical and a statistical viewpoint. However, the construction of a sound mathematical model of the muscle tissue, accounting for the changes due to ageing, can provide a more refined quantitative tool. Such a tool could determine in an improved way the variations of some measurable physiological parameters, such as the mass and the electrical impedance of the tissue, caused by the variation of other controllable factors, such as diet, physical activity, pharmacological treatments, air pollution exposure. A specific mathematical model, once implemented on a computer, makes it possible to perform "virtual" experiments, facilitating the search for a suitable treatment of sarcopenia. Moreover, test situations can be studied which would not be reproducible in vivo, such as drug overdoses, extreme nutritional deficiencies, environmental overexposure to harmful substances, and so on. PMID- 26630525 TI - Healthy Reasoning: The Role of Effective Argumentation for Enhancing Elderly Patients' Self-management Abilities in Chronic Care. AB - One of the biggest challenges for doctors working in chronic care is the correct management of the argumentation phases during the encounters with their patients. During these phases doctors should provide patients with acceptable reasons for being adherent to treatment and for changing certain unhealthy behaviors and lifestyles, something which is particularly difficult for elderly patients, for whom changing life long habits can be extremely hard. However, the medical literature on the subject of communication in the chronic care encounter shows lack of theoretical models and methodological approaches that can highlight which specific linguistic structures or elements in different communication styles favor or impede patient commitment, trust in the relationship and adherence to treatment. The contribution describes ongoing research on argumentative strategies in the encounter with diabetes patients. I describe one recently concluded research project on the argumentation phases of medical encounters in diabetes care, which highlighted critical areas in need of improvement. I also describe the design and aims of a new research project, aimed at testing the effectiveness and usability of certain argumentation schemes in the medical encounter. PMID- 26630528 TI - PREFACE. PMID- 26630529 TI - Survival in familial and non-familial breast cancer by age and stage at diagnosis. AB - We aimed to compare the survival in familial and sporadic breast cancer (BC) patients who were diagnosed at an identical age and TNM stage. The Nationwide Swedish Family-Cancer Database including all Swedes born after 1931 and their biological parents, totalling >14.7 million individuals, was used. Hazard ratios (HRs) were calculated for women with BC in a first-degree relative (FDR) versus BC patients without positive family history. There was no difference in survival of familial BC patients who were diagnosed at higher TNM status or older age (>40) compared to sporadic BC cases diagnosed at the same late TNM stage. Young BC patients (age <40) in early stages had the worst survival when their FDR was diagnosed with single (HR: 2.0-3.7) or multiple (HR: 2.4-7.1) BC at any age. We concluded that there is no difference in survival of familial and non-familial BC patients who are diagnosed at higher TNM status or older ages (>40). Young familial BC patients (age <40), diagnosed at early stage, have the poorer survival compared to sporadic cases. Our results urge the need for identifying the underling genetic component for such a difference in survival of familial BC. PMID- 26630530 TI - Use of metformin and risk of kidney cancer in patients with type 2 diabetes. AB - BACKGROUND: The anticancer effect of metformin has been reported in the literature but requires additional confirmation in epidemiologic studies. With respect to kidney cancer scarce data are available. This study investigates whether metformin use in patients with type 2 diabetes mellitus (T2DM) might affect kidney cancer risk. METHODS: The reimbursement database of the National Health Insurance in Taiwan was used. T2DM patients aged >= 40 years and newly treated with either metformin (n=171,753, "ever users of metformin") or other antidiabetic drugs (n=75,499, "never users of metformin") within 1998-2002 were followed for at least 6 months for kidney cancer until 31 December 2009. The treatment effect was estimated by Cox regression using propensity score weighting by inverse probability of treatment weighting approach. Hazard ratios were estimated for ever versus never users, and for tertiles of cumulative duration of metformin therapy. RESULTS: During follow-up, 917 ever users and 824 never users developed kidney cancer, with respective incidence of 80.09 and 190.30 per 100,000 person-years. The hazard ratio (95% confidence intervals) for ever versus never users is 0.279 (0.254-0.307); and is 0.598 (0.535-0.668), 0.279 (0.243 0.321) and 0.104 (0.088-0.124), respectively, for the first, second, and third tertile of cumulative duration of <14.5, 14.5-45.8 and >45.8 months. In subgroup analyses, the lower risk of kidney cancer associated with metformin use is consistently observed in both sexes, and in patients with or without concomitant use of other antidiabetic drugs. CONCLUSION: Metformin use is associated with a decreased risk of kidney cancer in patients with T2DM. PMID- 26630531 TI - Aggregated adverse-events outcomes in oncology phase III reports: A systematic review. AB - BACKGROUND: Randomised controlled trials (RCTs) represent a major source of information on treatment-related adverse events (AEs). In this study, we reviewed the use and the reporting methods of aggregated-AEs (A-AEs) outcomes in RCTs reports published in oncology and compared that to the expectations of European Organisation for Research and Treatment of Cancer (EORTC) membership. METHODS: RCTs reports published between 2007 and 2011 were reviewed regarding the reporting of A-AEs-outcomes. A-AEs were defined as summary outcome combining several related AEs, usually grouped by organ system e.g. cardiac-AEs, dermatologic-AEs. Trial characteristics associated with the use of A-AEs outcomes were investigated. The expectation of EORTC members concerning A-AEs utilisation was queried through a survey. RESULTS: Among 325 RCTs published between 2007 and 2011, 94 (29%) included one or more A-AE outcomes. A clear description of the nature of AEs included in such aggregations was provided in 19 articles (20%). No description of A-AEs was conversely provided in the other 75 articles (80%). The most commonly used A-AEs-outcomes were dermatologic-AEs (45%) and cardiac-AEs (33%). In multivariate analysis, the use of A-AEs outcomes was more frequent when trials were conducted in Europe (p = 0.038) and in trials performed on colon/rectal cancers (p = 0.016). Finally, there is no consensus of EORTC members regarding the utilisation of A-AEs but a majority of them (88%) felt that a clear description of A-AEs should systematically be reported. CONCLUSIONS: The use of A AEs is infrequent in oncology RCT manuscripts although their use is accepted by most clinicians. However, a clear definition of A-AEs is strongly recommended if they are to be used in order to avoid a loss of important details about drug toxicities that is useful to clinicians. PMID- 26630533 TI - Trastuzumab for HER2+ metastatic breast cancer in clinical practice: Cardiotoxicity and overall survival. AB - The evidence on efficacy and safety of trastuzumab in metastatic breast cancers (MBC) mainly derives from randomized clinical trials. We assessed short- and long term overall survival (OS) and cardiotoxicity in a large cohort of women with MBC treated with trastuzumab in clinical settings. Using healthcare administrative data of Lombardy (10 millions inhabitants), we identified a cohort of women receiving trastuzumab for MBC between 2006 and 2009. The cumulative risk of severe cardiac events and the OS from the first trastuzumab administration were estimated using the Kaplan-Meier method. Their predictors were assessed using Cox regression models. We found 681 trastuzumab MBC users. Thirty two (4.7%) women experienced severe cardiac adverse events. The cumulative risk increased sharply, reaching a value of 2.4% and 4.3% during the first and second year; thereafter it increased of about 1% per year. Age was a strong predictor of cardiotoxicity. The OS was 81.8%, 64.0%, 50.2%, 41.1% and 37.2% at 1, 2, 3, 4 and 5 years, respectively. Independent predictors of worse OS were: age, brain liver or lung metastasis compared to other metastasis, use of taxanes and other chemotherapies, a cardiac adverse event after trastuzumab use, and a higher time between metastasis and BC diagnoses. The incidence of cardiotoxicity among women treated with trastuzumab for HER2-positive MBC appeared higher than that reported in RCTs, particularly in elder patients. In spite of this, median survival, was, if anything, better. PMID- 26630532 TI - The prognostic value of biological markers in paediatric Hodgkin lymphoma. AB - BACKGROUND: Many biological and inflammatory markers have been proposed as having a prognostic value at diagnosis of Hodgkin lymphoma (HL), but very few have been validated in paediatric patients. We explored the significance of these markers in a large population of 769 affected children. PATIENTS AND METHODS: By using the database of patients enrolled in A.I.E.O.P. (Associazione Italiana di Emato Oncologia Pediatrica) trial LH2004 for paediatric HL, we identified 769 consecutive patients treated with curative intent from 1st June 2004 to 1st April 2014 with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), or hybrid COPP/ABV (cyclophosphamide, vincristine, prednisone, procarbazine, doxorubicin, bleomycin and vinblastine) regimens. RESULTS: On multivariate analysis with categorical forms, the 5-year freedom from progression survival was significantly lower in patients with stage IV or elevated value of platelets, eosinophils and ferritin at diagnosis. Furthermore, stage IV and eosinophils seem to maintain their predictive value independently of interim (after IV cycles of chemotherapy) positron emission tomography. CONCLUSION: Using the combination of four simple markers such as stage IV and elevated levels of platelets, ferritin and eosinophils, it is possible to classify the patients into subgroups with very different outcomes. PMID- 26630534 TI - Low Osteoporosis Treatment Initiation Rate in Women after Distal Forearm or Proximal Humerus Fracture: A Healthcare Database Nested Cohort Study. AB - Treatment initiation rates following fragility fractures have often been reported to be low and in recent years numerous programs have been implemented worldwide to increase them. This study aimed at describing osteoporosis (OP) treatment initiation in a representative sample of women who were hospitalized for a distal forearm fracture (DFF) or proximal humerus fracture (PHF) in 2009-2011 in France. The data source was a nationwide sample of 600,000 individuals, extracted from the French National Insurance Healthcare System database. All women aged 50 years and older who were hospitalized for a DFF or PHF between 2009 and 2011 and who had not received any OP treatment in the preceding 12 months were included in a retrospective cohort study. OP treatments initiated during the year following the fracture were analyzed. From 2009 to 2011, 729 women were hospitalized for a DFF or a PHF and 284 were on OP treatment at the time of the fracture occurrence. Among the 445 women who had no prevalent OP treatment, 131 (29.4%) received supplementation treatment only (vitamin D and/or calcium) and 42 (9.4%) received a pharmacologic OP treatment in the year following their fracture. Pharmacological OP treatments included bisphosphonates (n = 21), strontium ranelate (n = 14), hormone replacement therapy (n = 4), or raloxifene (n = 3). General practitioners prescribed 75% of initial OP treatments. Despite the guidelines published in 2006 and the numerous initiatives to promote post fracture OP treatment, OP treatment initiation rate in women who were hospitalized for a fragility fracture remained low in 2009-2011 in France. PMID- 26630535 TI - Clinical Features and Treatment Outcomes of Childhood Autoimmune Hemolytic Anemia: A Retrospective Analysis of 68 Cases. AB - Autoimmune hemolytic anemia (AIHA) is a rare disease in children, and its clinical severity varies. To better understand disease manifestation and treatment outcome, we analyzed 68 children diagnosed as AIHA for clinical characteristics, laboratory findings, and treatment outcomes. Data show that primary AIHA accounted for 39.7% of all patients, whereas secondary AIHA accounted for 60.3%. Among them, Evans syndrome (ES) accounted for 20 cases (29.4%). Average hemoglobin was lower in the 1-year or below age group than in the above 1-year age group, combined-antibody group than single-antibody group, and IgM-contained group than non-IgM-contained group (P<0.05 for all). The duration of therapy in the ES group was longer than that in the AIHA-only group (P<0.05). During the follow-up period, 29 cases (29/45, 64.4%) remained in continuous remission. In total, 35.6% of patients relapsed after first complete remission and 56.3% of them still showed good response to glucocorticoid after relapse. There was no difference in the duration of therapy or relapse rate between the intravenous immunoglobulin (IVIG)-treatment group and the non-IVIG treatment group. In conclusion, the severity of anemia correlates with age and serologic types of direct antiglobulin test. Glucocorticoid is efficacious for AIHA regardless of whether it is a first attack or relapse in this cohort of young patients. ES needs longer treatment duration. IVIG does not improve the outcome of AIHA. PMID- 26630536 TI - Pediatric Oncology Providers' Attitudes and Practice Patterns Regarding Fertility Preservation in Adolescent Male Cancer Patients. AB - BACKGROUND: The aim of this study was to evaluate pediatric oncology providers' attitudes toward fertility preservation (FP), their use of educational materials, their approach to FP discussion, and their FP knowledge specifically pertaining to adolescent males. METHODS: A 40-item online survey was distributed to physicians, advanced practice nurses (APN), and nurses within pediatric oncology. RESULTS: About 78.7% of physicians, 81.4% of APN, and 51.9% of nurses reported high levels of comfort in discussing FP options with adolescent males (P<0.05). Fifty-one percent of physicians and 54.2% of APN reported using educational materials, compared with 38.9% of nurses (P<0.05). Regarding knowledge of FP technologies, 48.7% of physicians, 52.5% of APN, and 81.1% of nurses reported being unfamiliar with intracytoplasmic sperm injection (P<0.05). An overwhelming majority (92.9%) of respondents reported having no formal training in discussing FP. Finally, 84.8% of respondents believed formal training on this issue would be useful to them. CONCLUSIONS: This study illustrates an unmet need in the education of pediatric oncology providers, as knowledge gaps and discomfort are common themes reported by health care professionals within the context of adolescent male FP care. In addition, this study reveals a high level of receptiveness to FP training by these same providers. PMID- 26630538 TI - Relapse risk of endometrial hyperplasia after treatment with the levonorgestrel impregnated intrauterine system or oral progestogens. AB - OBJECTIVE: To investigate relapse rates after the successful treatment of patients with non-atypical endometrial hyperplasia who were randomised to either a levonorgestrel-impregnated intrauterine system (LNG-IUS; Mirena((r)) ) or two regimens of oral medroxyprogesterone acetate (MPA) after primary histological response. DESIGN: A multicentre randomised trial. SETTING: Ten different outpatient clinics localised in hospitals and seven gynaecological private practices in Norway. POPULATION: One hundred and fifty-three women aged 30-70 years with low- or medium-risk endometrial hyperplasia met the inclusion criteria, and 153 completed the therapy. METHODS: Patients were randomly assigned to one of the following three treatment arms: LNG-IUS; 10 mg of oral MPA administered for 10 days per cycle for 6 months; or 10 mg of oral MPA administered daily for 6 months. The women were followed for 24 months after ending therapy. MAIN OUTCOME MEASURES: Histological relapse of endometrial hyperplasia. RESULTS: Histological relapse was observed in 55/135 (41%) women who had an initial complete treatment response. The relapse rates were similar in the three therapy groups (P = 0.66). In the multivariable analyses relapse was dependent on menopausal status (P = 0.0005) and estrogen level (P = 0.0007). CONCLUSIONS: The risk of histological relapse of non-atypical endometrial hyperplasia is high within 24 months of ceasing therapy with either the LNG-IUS or oral MPA. Continued endometrial surveillance and prolonging progestogen therapy should be considered. TWEETABLE ABSTRACT: Relapse of endometrial hyperplasia after successful treatment is independent of therapy regime. PMID- 26630539 TI - Pretransplant Tacrolimus Dose Requirements Predict Early Posttransplant Dose Requirements in Blood Group AB0-Incompatible Kidney Transplant Recipients. AB - BACKGROUND: The aim of this study was to investigate whether pretransplant tacrolimus (Tac) dose requirements of patients scheduled to undergo living donor kidney transplantation correlate with posttransplantation dose requirements. METHODS: The predictive value of Tac dose requirements (defined as the ratio of the Tac predose concentration, C0, divided by the total daily Tac dose, D) pretransplantation on this same parameter posttransplantation was assessed retrospectively in a cohort of 57 AB0-incompatible kidney transplant recipients. These patients started immunosuppressive therapy 14 days before transplant surgery. All patients were using a stable dose of glucocorticoids and were at steady-state Tac exposure before transplantation. RESULTS: Tac dose requirements immediately before transplantation (C0/Dbefore) explained 63% of the Tac dose requirements on day 3 after transplantation: r = 0.633 [F (1, 44) = 75.97, P < 0.01]. No other clinical and demographic variables predicted Tac dose requirements early after transplantation. CONCLUSIONS: Steady-state Tac dose requirement before transplantation largely predicted posttransplantation Tac dose requirements in AB0-incompatible kidney transplant recipients. The importance of this finding is that the posttransplantation Tac dose can be individualized based on a patient's pretransplantation Tac concentration/dose ratio. Pretransplant Tac phenotyping therefore has the potential to improve transplantation outcomes. PMID- 26630540 TI - Finding the Common Thread in Rare Diseases. PMID- 26630541 TI - New Scenario of Dynamical Heterogeneity in Supercooled Liquid and Glassy States of 2D Monatomic System. AB - Via analysis of spatiotemporal arrangements of atoms based on their dynamics in supercooled liquid and glassy states of a 2D monatomic system with a double-well Lennard-Jones-Gauss (LJG) interaction potential, we find a new scenario of dynamical heterogeneity. Atoms with the same or very close mobility have a tendency to aggregate into clusters. The number of atoms with high mobility (and size of their clusters) increases with decreasing temperature passing over a maximum before decreasing down to zero. Position of the peak moves toward a lower temperature if mobility of atoms in clusters is lower together with an enhancement of height of the peak. In contrast, the number of atoms with very low mobility or solidlike atoms (and size of their clusters) has a tendency to increase with decreasing temperature and then it suddenly increases in the vicinity of the glass transition temperature leading to the formation of a glassy state. A sudden increase in the number of strongly correlated solidlike atoms in the vicinity of a glass transition temperature (Tg) may be an origin of a drastical increase in viscosity of the glass-forming systems approaching the glass transition. In fact, we find that the diffusion coefficient decays exponentially with a fraction of solidlike atoms exhibiting a sudden decrease in the vicinity of the glass transition region. PMID- 26630543 TI - Effects of midodrine in patients with ascites due to cirrhosis: Systematic review and meta-analysis. AB - OBJECTIVE: Midodrine has been reported to improve systemic and renal hemodynamics in patients with cirrhotic ascites. However, the results of clinical trials are conflicting. The aim of this study is to evaluate the effects of midodrine on cirrhotic ascites through a meta-analysis and systematic review. METHODS: We searched PubMed (January 1966-December 2014), EMBASE (January 1966-December 2014), the Cochrane Library (Issue 11, 2014), ScienceDirect (January 1966 December 2014), and the China National Knowledge Infrastructure (January 1979 December 2014) databases using the terms 'midodrine' AND 'cirrhosis' AND 'ascites' AND 'paracentesis' for all relevant randomized controlled trials using midodrine for treatment of cirrhotic ascites. RESULTS: In all, 10 trials with a total of 462 patients were included. As a novel therapy for cirrhotic ascites, midodrine was not found to improve survival [odds ratio (OR) 0.81, 95% confidence interval (CI) 0.23-2.91]; although it might improve response rates (OR 3.36, 95% CI 1.47-7.69) and reduce plasma renin activity (MD -3.10, 95% CI -5.37 to -0.84). When midodrine was used as an alternative to albumin in large-volume paracentesis, the mortality was higher for midodrine than for albumin (OR 10.76, 95% CI 1.35-85.97). However, there was no statistically significant difference in the development of paracentesis-induced circulatory dysfunction between midodrine group and albumin group (OR 1.69, 95% CI 0.43-6.72). CONCLUSIONS: Midodrine may have treatment effects on cirrhotic ascites. Better powered and well-designed trials are required to assess the extent of the efficacy of midodrine in specifically targeted patients. PMID- 26630544 TI - Adaptive Governance, Uncertainty, and Risk: Policy Framing and Responses to Climate Change, Drought, and Flood. AB - As climate change impacts result in more extreme events (such as droughts and floods), the need to understand which policies facilitate effective climate change adaptation becomes crucial. Hence, this article answers the question: How do governments and policymakers frame policy in relation to climate change, droughts, and floods and what governance structures facilitate adaptation? This research interrogates and analyzes through content analysis, supplemented by semi structured qualitative interviews, the policy response to climate change, drought, and flood in relation to agricultural producers in four case studies in river basins in Chile, Argentina, and Canada. First, an epistemological explanation of risk and uncertainty underscores a brief literature review of adaptive governance, followed by policy framing in relation to risk and uncertainty, and an analytical model is developed. Pertinent findings of the four cases are recounted, followed by a comparative analysis. In conclusion, recommendations are made to improve policies and expand adaptive governance to better account for uncertainty and risk. This article is innovative in that it proposes an expanded model of adaptive governance in relation to "risk" that can help bridge the barrier of uncertainty in science and policy. PMID- 26630542 TI - NDK Interacts with FtsZ and Converts GDP to GTP to Trigger FtsZ Polymerisation--A Novel Role for NDK. AB - INTRODUCTION: Nucleoside diphosphate kinase (NDK), conserved across bacteria to humans, synthesises NTP from NDP and ATP. The eukaryotic homologue, the NDPK, uses ATP to phosphorylate the tubulin-bound GDP to GTP for tubulin polymerisation. The bacterial cytokinetic protein FtsZ, which is the tubulin homologue, also uses GTP for polymerisation. Therefore, we examined whether NDK can interact with FtsZ to convert FtsZ-bound GDP and/or free GDP to GTP to trigger FtsZ polymerisation. METHODS: Recombinant and native NDK and FtsZ proteins of Mycobacterium smegmatis and Mycobacterium tuberculosis were used as the experimental samples. FtsZ polymersation was monitored using 90 degrees light scattering and FtsZ polymer pelleting assays. The gamma32P-GTP synthesised by NDK from GDP and gamma32P-ATP was detected using thin layer chromatography and quantitated using phosphorimager. The FtsZ bound 32P-GTP was quantitated using phosphorimager, after UV-crosslinking, followed by SDS-PAGE. The NDK-FtsZ interaction was determined using Ni2+-NTA-pulldown assay and co immunoprecipitation of the recombinant and native proteins in vitro and ex vivo, respectively. RESULTS: NDK triggered instantaneous polymerisation of GDP precharged recombinant FtsZ in the presence of ATP, similar to the polymerisation of recombinant FtsZ (not GDP-precharged) upon the direct addition of GTP. Similarly, NDK triggered polymerisation of recombinant FtsZ (not GDP-precharged) in the presence of free GDP and ATP as well. Mutant NDK, partially deficient in GTP synthesis from ATP and GDP, triggered low level of polymerisation of MsFtsZ, but not of MtFtsZ. As characteristic of NDK's NTP substrate non-specificity, it used CTP, TTP, and UTP also to convert GDP to GTP, to trigger FtsZ polymerisation. The NDK of one mycobacterial species could trigger the polymerisation of the FtsZ of another mycobacterial species. Both the recombinant and the native NDK and FtsZ showed interaction with each other in vitro and ex vivo, alluding to the possibility of direct phosphorylation of FtsZ-bound GDP by NDK. CONCLUSION: Irrespective of the bacterial species, NDK interacts with FtsZ in vitro and ex vivo and, through the synthesis of GTP from FtsZ-bound GDP and/or free GDP, and ATP (CTP/TTP/UTP), triggers FtsZ polymerisation. The possible biological context of this novel activity of NDK is presented. PMID- 26630545 TI - Non-pharmacological management of infant and young child procedural pain. AB - BACKGROUND: Infant acute pain and distress is commonplace. Infancy is a period of exponential development. Unrelieved pain and distress can have implications across the lifespan. This is an update of a previously published review in the Cochrane Database of Systematic Reviews, Issue 10 2011 entitled 'Non pharmacological management of infant and young child procedural pain'. OBJECTIVES: To assess the efficacy of non-pharmacological interventions for infant and child (up to three years) acute pain, excluding kangaroo care, and music. Analyses were run separately for infant age (preterm, neonate, older) and pain response (pain reactivity, immediate pain regulation). SEARCH METHODS: For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 2 of 12, 2015), MEDLINE-Ovid platform (March 2015), EMBASE-OVID platform (April 2011 to March 2015), PsycINFO-OVID platform (April 2011 to February 2015), and CINAHL-EBSCO platform (April 2011 to March 2015). We also searched reference lists and contacted researchers via electronic list-serves. New studies were incorporated into the review. We refined search strategies with a Cochrane-affiliated librarian. For this update, nine articles from the original 2011 review pertaining to Kangaroo Care were excluded, but 21 additional studies were added. SELECTION CRITERIA: Participants included infants from birth to three years. Only randomised controlled trials (RCTs) or RCT cross-overs that had a no-treatment control comparison were eligible for inclusion in the analyses. However, when the additive effects of a non pharmacological intervention could be assessed, these studies were also included. We examined studies that met all inclusion criteria except for study design (e.g. had an active control) to qualitatively contextualize results. There were 63 included articles in the current update. DATA COLLECTION AND ANALYSIS: Study quality ratings and risk of bias were based on the Cochrane Risk of Bias Tool and GRADE approach. We analysed the standardized mean difference (SMD) using the generic inverse variance method. MAIN RESULTS: Sixty-three studies, with 4905 participants, were analysed. The most commonly studied acute procedures were heel sticks (32 studies) and needles (17 studies). The largest SMD for treatment improvement over control conditions on pain reactivity were: non-nutritive sucking-related interventions (neonate: SMD -1.20, 95% CI -2.01 to -0.38) and swaddling/facilitated tucking (preterm: SMD -0.89; 95% CI -1.37 to -0.40). For immediate pain regulation, the largest SMDs were: non-nutritive sucking-related interventions (preterm: SMD -0.43; 95% CI -0.63 to -0.23; neonate: SMD -0.90; 95% CI -1.54 to -0.25; older infant: SMD -1.34; 95% CI -2.14 to -0.54), swaddling/facilitated tucking (preterm: SMD -0.71; 95% CI -1.00 to -0.43), and rocking/holding (neonate: SMD -0.75; 95% CI -1.20 to -0.30). Fifty two of our 63 trials did not report adverse events. The presence of significant heterogeneity limited our confidence in the findings for certain analyses, as did the preponderance of very low quality evidence. AUTHORS' CONCLUSIONS: There is evidence that different non-pharmacological interventions can be used with preterms, neonates, and older infants to significantly manage pain behaviors associated with acutely painful procedures. The most established evidence was for non-nutritive sucking, swaddling/facilitated tucking, and rocking/holding. All analyses reflected that more research is needed to bolster our confidence in the direction of the findings. There are significant gaps in the existing literature on non-pharmacological management of acute pain in infancy. PMID- 26630546 TI - Nanoscale Electrochemistry Revisited. PMID- 26630547 TI - Pilates vs. Balance Training in Health Community-Dwelling Seniors: a 3-arm, Randomized Controlled Trial. AB - The study examined effects of traditional balance vs. mat-based Pilates training on balance and trunk strength in healthy community dwellers. Forty-eight seniors were either stratified to a balance training group (BAL, n=16, 69.1 (SD 5.8) y), Pilates training group (PIL, n=17, 70.8 (6.5) y) or control group (CON, n=15, 69.2 (6.1) y). BAL performed traditional balance training, while PIL conducted mat-based Pilates-exercises (8 weeks, 2 sessions/week 66 min each). Balance performance (single limb stance and perturbed kneeling, Y-Balance test), dynamic and isometric trunk flexion and extension were assessed during pre- and post testing. According to the magnitude-based inference approach, substantial positive effects in favor of BAL compared to CON were found for the Y-balance score (right leg, effect size (d)=0.68; left leg, d=0.56), trunk extension (d=0.68) and single leg stance (right leg, d=0.61; left leg, d=0.38). Dynamic (d=0.32) and isometric (d=0.15) trunk flexion revealed unclear effects. For the Y balance score (right leg, d=0.48, left leg, d=0.75) and single leg stance (right leg, +d=0.61%; left leg, d=0.67), interestingly, BAL substantially exceeded PIL. PIL vs. CON revealed unclear effects for most parameters (0.05 dcb with significant contributions of the NCS ligands. Transient absorption, time-resolved infrared, and transient resonance Raman spectroscopic techniques were used to probe the photophysics of the complexes and relatively short-lived {Ru(NCS)2} -> dcb/dpb (dpb = 4,4' diphenylethenyl-2,2'-bipyridine) excited states were observed with the exception of [Ru(dcb)(dab)(NCS)2] (dab = 4,4'-dianthracenethenyl-2,2'-bipyridine), which showed a long-lived excited state assigned as ligand centered charge separated. PMID- 26630552 TI - Morphology and Kinetics of Aggregation of Silver Nanoparticles Induced with Regioregular Cationic Polythiophene. AB - The aggregation kinetics of negatively charged borate-stabilized silver nanoparticles (NPs) induced by the cationic regioregular polythiophene polyelectrolyte poly{3-[6-(1-methylimidazolium-3-yl)hexyl]thiophene-2,5-diyl bromide} (PMHT-Br) and the morphology of formed aggregates have been investigated via ultraviolet-visible light (UV-vis) spectroscopy, transmission electron microscopy (TEM), zeta (zeta) potential measurements, dynamic light scattering (DLS), and time-resolved small-angle X-ray scattering (SAXS). Two or three populations of NPs are formed within milliseconds upon mixing the components, which differ in the mean size, extent of polymer coating, and time stability. These characteristics are primarily controlled by the PMHT-Br to Ag-NPs ratio. Population of single NPs of a mean size of ~5 nm is present in every system and is mostly stable for a long time. At low ratios, the single NPs are most probably almost free of polymer chains and the second population includes slow, but in a limited extent, growing NPs in which single NPs might be interconnected by polymer chains. At the ratios corresponding to the charge balance in the system (ca. zero zeta-potential of NPs), the NPs aggregate, forming a second population that continuously grows in size, and finally undergo sedimentation. At the high ratios, three long-time stable populations of NPs are observed, having mean sizes of ca. 5, 13, and 35 nm; all NPs should be fully coated with PMHT-Br, giving them a positively charged stabilizing shell. PMID- 26630551 TI - Resolvin D1 attenuates CCl4-induced acute liver injury involving up-regulation of HO-1 in mice. AB - Acute hepatic failure involves in excessive oxidative stress and inflammatory responses, leading to a high mortality due to lacking effective therapy. Resolvin D1 (RvD1), an endogenous lipid mediator derived from polyunsaturated fatty acids, has been shown anti-inflammatory and anti-oxidative actions, however, whether RvD1 has protective effects on hepatic failure remains elusive. In this study, the roles and molecular mechanisms of RvD1 were explored in carbon tetrachloride (CCl4)-induced acute liver injury. Our results showed that RvD1 protected mice against CCl4-induced hepatic damage, as evaluated by reduced aminotransferase activities and malondialdehyde content, elevated glutathione and superoxide dismutase activities, and alleviated hepatic pathological damage. Moreover, RvD1 significantly attenuated serum tumor necrosis factor-alpha and interleukin-6 levels as well as hepatic myeloperoxidase activity, whereas enhanced serum IL-10 level in CCl4-administered mice. Further, RvD1 markedly up-regulated the expression and activity of heme oxygenase-1 (HO-1). However, inhibition of HO-1 activity reversed the protective effects of RvD1 on CCl4-induced liver injury. These results suggest that RvD1 could effectively prevent CCl4-induced liver injury by inhibition of oxidative stress and inflammation, and the underlying mechanism may be related to up-regulation of HO-1. PMID- 26630554 TI - A Framework for Establishing Standard Reference Scale of Texture by Multivariate Statistical Analysis Based on Instrumental Measurement and Sensory Evaluation. AB - A framework of establishing standard reference scale (texture) is proposed by multivariate statistical analysis according to instrumental measurement and sensory evaluation. Multivariate statistical analysis is conducted to rapidly select typical reference samples with characteristics of universality, representativeness, stability, substitutability, and traceability. The reasonableness of the framework method is verified by establishing standard reference scale of texture attribute (hardness) with Chinese well-known food. More than 100 food products in 16 categories were tested using instrumental measurement (TPA test), and the result was analyzed with clustering analysis, principal component analysis, relative standard deviation, and analysis of variance. As a result, nine kinds of foods were determined to construct the hardness standard reference scale. The results indicate that the regression coefficient between the estimated sensory value and the instrumentally measured value is significant (R(2) = 0.9765), which fits well with Stevens's theory. The research provides reliable a theoretical basis and practical guide for quantitative standard reference scale establishment on food texture characteristics. PMID- 26630553 TI - Discovery of (R)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1 yl)piperidin-1-yl)-2-(dimethylamino)ethanone (CHMFL-FLT3-122) as a Potent and Orally Available FLT3 Kinase Inhibitor for FLT3-ITD Positive Acute Myeloid Leukemia. AB - FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of the structure of PCI-32765 (ibrutinib), a BTK kinase inhibitor that was recently reported to bear FLT3 kinase activity through a structure-guided drug design approach, we have discovered compound 18 (CHMFL-FLT3-122), which displayed an IC50 of 40 nM against FLT3 kinase and achieved selectivity over BTK kinase (over 10-fold). It significantly inhibited the proliferation of FLT3-ITD positive AML cancer cell lines MV4-11 (GI50 = 22 nM), MOLM13/14 (GI50 = 21 nM/42 nM). More importantly, 18 demonstrated 170-fold selectivity between FLT3 kinase and c-KIT kinase (GI50 = 11 nM versus 1900 nM) in the TEL-fusion isogenic BaF3 cells indicating a potential to avoid the FLT3/c-KIT dual inhibition induced myelosuppression toxicity. In the cellular context it strongly affected FLT3-ITD mediated signaling pathways and induced apoptosis by arresting the cell cycle into the G0/G1 phase. In the in vivo studies 18 demonstrated a good bioavailability (30%) and significantly suppressed the tumor growth in MV4-11 cell inoculated xenograft model (50 mg/kg) without exhibiting obvious toxicity. Compound 18 might be a potential drug candidate for FLT3-ITD positive AML. PMID- 26630555 TI - Message From the MIRC President. PMID- 26630557 TI - Message From the ISMICS President. PMID- 26630559 TI - Identification of L84F mutation with a novel nucleotide change c.255G > T in the superoxide dismutase gene in a North Indian family with amyotrophic lateral sclerosis. AB - Mutations in the superoxide dismutase (SOD1) gene account for ~15% and in the transactive response DNA binding protein (TARDBP) gene for ~5% of familial amyotrophic lateral sclerosis (FALS) cases. These two genes were analysed in two siblings from North India with ALS and a positive family history. The coding region of SOD1 and TARDBP genes was sequenced in both siblings. Genetic variation identified in SOD1 was typed in unaffected family members (n = 11), sporadic ALS patients (n = 48) and healthy controls (n = 35). Molecular dynamic (MD) simulations were performed on wild-type (WT) and mutant monomers of SOD1 to determine structural changes due to the identified mutation. A novel heterozygous nucleotide variation (c.255G > T) was identified in exon 4 of SOD1 in the two siblings and two asymptomatic family members but not in SALS patients and healthy controls. This variation results in a known non-synonymous substitution from leucine to phenylalanine at position 84 (L84F), making it a triallelic variation. Large conformational changes were observed in the zinc loop and electrostatic loop in an L84F mutant compared to WT SOD1 in MD simulations. In conclusion, this is the first report of mutation in SOD1 associated with FALS in India. Structural perturbations in L84F SOD1 may cause dimer destabilization, with decreased metal affinity leading to oligomerization. PMID- 26630560 TI - Correction: The Association of Vitamin D Receptor Polymorphisms with Multiple Sclerosis in a Case-Control Study from Kuwait. PMID- 26630561 TI - Impact of specific training and competition on myocardial structure and function in different age ranges of male handball players. AB - Handball activity involves cardiac changes and demands a mixture of both eccentric and concentric remodeling within the heart. This study seeks to explore heart performance and cardiac remodeling likely to define cardiac parameters which influence specific performance in male handball players across different age ranges. Forty three players, with a regular training and competitive background in handball separated into three groups aged on average 11.78 +/- 0.41 for youth players aka "schools", "elite juniors" 15.99 +/- 0.81 and "elite adults" 24.46 +/- 2.63 years, underwent echocardiography and ECG examinations. Incremental ergocycle and specific field (SFT) tests have also been conducted. With age and regular training and competition, myocardial remodeling in different age ranges exhibit significant differences in dilatation's parameters between "schools" and "juniors" players, such as the end-diastolic diameter (LVEDD) and the end-systolic diameter of the left ventricle (LVESD), the root of aorta (Ao) and left atrial (LA), while significant increase is observed between "juniors" and "adults" players in the interventricular septum (IVS), the posterior wall thicknesses (PWT) and LV mass index. ECG changes are also noted but NS differences were observed in studied parameters. For incremental maximal test, players demonstrate a significant increase in duration and total work between "schools" and "juniors" and, in total work only, between "juniors" and "seniors". The SFT shows improvement in performance which ranged between 26.17 +/- 1.83 sec to 31.23 +/- 2.34 sec respectively from "seniors" to "schools". The cross sectional approach used to compare groups with prior hypothesis that there would be differences in exercise performance and cardiac parameters depending on duration of prior handball practice, leads to point out the early cardiac remodeling within the heart as adaptive change. Prevalence of cardiac chamber dilation with less hypertrophy remodeling was found from "schools" to "juniors" while a prevalence of cardiac hypertrophy with less pronounced chamber dilation remodeling was noted later. PMID- 26630563 TI - Expiratory Snoring Predicts Obstructive Pulmonary Disease in Patients with Sleep disordered Breathing. AB - RATIONALE: Sleep-disordered breathing and chronic obstructive pulmonary disease are two common conditions that may present concomitantly. The effects of chronic obstructive pulmonary disease on the polysomnographic manifestation of sleep disordered breathing have not been studied. OBJECTIVES: We hypothesized that the presence of airflow obstruction could be predicted by the presence of expiratory upper airway narrowing during sleep in patients with sleep-disordered breathing. METHODS: Ninety-three patients with sleep-disordered breathing (19 men; age, 51.6 yr; body mass index, 40.1 kg/m(2); apnea-hypopnea index, 37.4 events/h) were observed. Every patient had an in-lab polysomnography study and complete pulmonary function tests. Sleep and respiratory events were scored using American Academy of Sleep Medicine recommended scoring criteria. Expiratory snoring events were identified on polysomnography using microphone sensor and/or pressure flow sensor in each patient. The FEV1/FVC ratio less than 70 was used to define the presence of airflow obstruction. MEASUREMENTS AND MAIN RESULTS: The proportion analysis demonstrated that patients with expiratory snoring have 11 times higher odds of having evidence of lower airway obstruction, defined as FEV1/FVC less than 70 (odds ratio [OR], 11.03; P < 0.001), whereas smokers have increased odds by 13 times (OR, 13.18; P < 0.001). Spearman correlation analysis showed that FEV1 was positively related to mean SaO2 (P < 0.05) and negatively related to expiratory snoring, smoking, 3% oxygen desaturation index, 2% oxygen desaturation index, and age (P < 0.05). Epworth sleepiness scale, sex, and body mass index did not have any association with FEV1. The multiple logistic regression analysis demonstrated that chronic obstructive pulmonary disease (FEV1/FVC < 70) correlated significantly with expiratory snoring and smoking (OR, 11.76; confidence interval, 3.23-42.83; and OR, 9.95; confidence interval, 2.67-37.09), respectively. The multiple linear regression analysis revealed that the linear combination of mean SaO2 and expiratory snoring (P < 0.05) predicted FEV1. However, age and 2% oxygen desaturation index did not predict FEV1. CONCLUSIONS: The presence of expiratory snoring predicts obstructive airway disorders. Patients with expiratory snoring and low mean oxygen saturation during sleep should be carefully assessed for pulmonary disorders such as asthma and chronic obstructive pulmonary disease. PMID- 26630562 TI - A Combination of Culture Conditions and Gene Expression Analysis Can Be Used to Investigate and Predict hES Cell Differentiation Potential towards Male Gonadal Cells. AB - Human embryonic stem cell differentiation towards various cell types belonging to ecto-, endo- and mesodermal cell lineages has been demonstrated, with high efficiency rates using standardized differentiation protocols. However, germ cell differentiation from human embryonic stem cells has been very inefficient so far. Even though the influence of various growth factors has been evaluated, the gene expression of different cell lines in relation to their differentiation potential has not yet been extensively examined. In this study, the potential of three male human embryonic stem cell lines to differentiate towards male gonadal cells was explored by analysing their gene expression profiles. The human embryonic stem cell lines were cultured for 14 days as monolayers on supporting human foreskin fibroblasts or as spheres in suspension, and were differentiated using BMP7, or spontaneous differentiation by omitting exogenous FGF2. TLDA analysis revealed that in the undifferentiated state, these cell lines have diverse mRNA profiles and exhibit significantly different potentials for differentiation towards the cell types present in the male gonads. This potential was associated with important factors directing the fate of the male primordial germ cells in vivo to form gonocytes, such as SOX17 or genes involved in the NODAL/ACTIVIN pathway, for example. Stimulation with BMP7 in suspension culture resulted in up-regulation of cytoplasmic SOX9 protein expression in all three lines. The observation that human embryonic stem cells differentiate towards germ and somatic cells after spontaneous and BMP7-induced stimulation in suspension emphasizes the important role of somatic cells in germ cell differentiation in vitro. PMID- 26630564 TI - Correction: Validation of the FEEL-KJ: An Instrument to Measure Emotion Regulation Strategies in Children and Adolescents. PMID- 26630565 TI - Observation of Localized Vibrational Modes of Graphene Nanodomes by Inelastic Atom Scattering. AB - Inelastic helium atom scattering (HAS) is suitable to determine low-energy (few meV) vibrations spatially localized on structures in the nanometer range. This is illustrated for the nanodomes that appear often on graphene (Gr) epitaxially grown on single crystal metal surfaces. The nature of the inelastic losses observed in Gr/Ru(0001) and Gr/Cu/Ru(0001) has been clarified by intercalation of Cu below the Gr monolayer, which decouples the Gr layer from the Ru substrate and changes substantially the out-of-plane, flexural phonon dispersion of epitaxial Gr, while maintaining the nanodomes and their localized vibrations. He diffraction proves that the Cu-intercalated Gr layer is well ordered structurally, while scanning tunneling microscopy reveals the persistence of the (slightly modified) periodic array of Gr nanodomes. A simple model explains the order of magnitude of the energy losses associated with the Gr nanodomes and their size dependence. The dispersionless, low-energy phonon branches may radically alter the transport of heat in intercalated Gr. PMID- 26630566 TI - Cardiac Exposure in the Dynamic Conformal Arc Therapy, Intensity-Modulated Radiotherapy and Volumetric Modulated Arc Therapy of Lung Cancer. AB - PURPOSE: To retrospectively evaluate the cardiac exposure in three cohorts of lung cancer patients treated with dynamic conformal arc therapy (DCAT), intensity modulated radiotherapy (IMRT), or volumetric modulated arc therapy (VMAT) at our institution in the past seven years. METHODS AND MATERIALS: A total of 140 lung cancer patients were included in this institutional review board approved study: 25 treated with DCAT, 70 with IMRT and 45 with VMAT. All plans were generated in a same commercial treatment planning system and have been clinically accepted and delivered. The dose distribution to the heart and the effects of tumor laterality, the irradiated heart volume and the beam-to-heart distance on the cardiac exposure were investigated. RESULTS: The mean dose to the heart among all 140 plans was 4.5 Gy. Specifically, the heart received on average 2.3, 5.2 and 4.6 Gy in the DCAT, IMRT and VMAT plans, respectively. The mean heart doses for the left and right lung tumors were 4.1 and 4.8 Gy, respectively. No patients died with evidence of cardiac disease. Three patients (2%) with preexisting cardiac condition developed cardiac disease after treatment. Furthermore, the cardiac exposure was found to increase linearly with the irradiated heart volume while decreasing exponentially with the beam-to-heart distance. CONCLUSIONS: Compared to old technologies for lung cancer treatment, modern radiotherapy treatment modalities demonstrated better heart sparing. But the heart dose in lung cancer radiotherapy is still higher than that in the radiotherapy of breast cancer and Hodgkin's disease where cardiac complications have been extensively studied. With strong correlations of mean heart dose with beam-to-heart distance and irradiated heart volume, cautions should be exercised to avoid long-term cardiac toxicity in the lung cancer patients undergoing radiotherapy. PMID- 26630567 TI - Glucose Evokes Rapid Ca2+ and Cyclic AMP Signals by Activating the Cell-Surface Glucose-Sensing Receptor in Pancreatic beta-Cells. AB - Glucose is a primary stimulator of insulin secretion in pancreatic beta-cells. High concentration of glucose has been thought to exert its action solely through its metabolism. In this regard, we have recently reported that glucose also activates a cell-surface glucose-sensing receptor and facilitates its own metabolism. In the present study, we investigated whether glucose activates the glucose-sensing receptor and elicits receptor-mediated rapid actions. In MIN6 cells and isolated mouse beta-cells, glucose induced triphasic changes in cytoplasmic Ca(2+) concentration ([Ca(2+)]c); glucose evoked an immediate elevation of [Ca(2+)]c, which was followed by a decrease in [Ca(2+)]c, and after a certain lag period it induced large oscillatory elevations of [Ca(2+)]c. Initial rapid peak and subsequent reduction of [Ca(2+)]c were independent of glucose metabolism and reproduced by a nonmetabolizable glucose analogue. These signals were also blocked by an inhibitor of T1R3, a subunit of the glucose sensing receptor, and by deletion of the T1R3 gene. Besides Ca(2+), glucose also induced an immediate and sustained elevation of intracellular cAMP ([cAMP]c). The elevation of [cAMP]c was blocked by transduction of the dominant-negative Gs, and deletion of the T1R3 gene. These results indicate that glucose induces rapid changes in [Ca(2+)]c and [cAMP]c by activating the cell-surface glucose-sensing receptor. Hence, glucose generates rapid intracellular signals by activating the cell-surface receptor. PMID- 26630568 TI - Improvement in Human Immune Function with Changes in Intestinal Microbiota by Salacia reticulata Extract Ingestion: A Randomized Placebo-Controlled Trial. AB - Plants belonging to the genus Salacia in the Hippocrateaceae family are known to inhibit sugar absorption. In a previous study, administration of Salacia reticulata extract in rats altered the intestinal microbiota and increased expression of immune-relevant genes in small intestinal epithelial cells. This study aimed to investigate the effect of S. reticulata extract in human subjects by examining the gene expression profiles of blood cells, immunological indices, and intestinal microbiota. The results revealed an improvement in T-cell proliferation activity and some other immunological indices. In addition, the intestinal microbiota changed, with an increase in Bifidobacterium and a decrease in Clostridium bacteria. The expression levels of many immune-relevant genes were altered in blood cells. We concluded that S. reticulata extract ingestion in humans improved immune functions and changed the intestinal microbiota. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000011732. PMID- 26630569 TI - Organohalogen Compounds in Pet Dog and Cat: Do Pets Biotransform Natural Brominated Products in Food to Harmful Hydroxlated Substances? AB - There are growing concerns about the increase in hyperthyroidism in pet cats due to exposure to organohalogen contaminants and their hydroxylated metabolites. This study investigated the blood contaminants polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) and their hydroxylated and methoxylated derivatives (OH-PCBs, OH-PBDEs, and MeO-PBDEs), in pet dogs and cats. We also measured the residue levels of these compounds in commercially available pet foods. Chemical analyses of PCBs and OH-PCBs showed that the OH-PCB levels were 1 to 2 orders of magnitude lower in cat and dog food products than in their blood, suggesting that the origin of OH-PCBs in pet dogs and cats is PCBs ingested with their food. The major congeners of OH-/MeO-PBDEs identified in both pet food products and blood were natural products (6OH-/MeO-BDE47 and 2'OH-/MeO BDE68) from marine organisms. In particular, higher concentrations of 6OH-BDE47 than 2'OH-BDE68 and two MeO-PBDE congeners were observed in the cat blood, although MeO-BDEs were dominant in cat foods, suggesting the efficient biotransformation of 6OH-BDE47 from 6MeO-BDE47 in cats. We performed in vitro demethylation experiments to confirm the biotransformation of MeO-PBDEs to OH PBDEs using liver microsomes. The results showed that 6MeO-BDE47 and 2'MeO-BDE68 were demethylated to 6OH-BDE47 and 2'OH-BDE68 in both animals, whereas no hydroxylated metabolite from BDE47 was detected. The present study suggests that pet cats are exposed to MeO-PBDEs through cat food products containing fish flavors and that the OH-PBDEs in cat blood are derived from the CYP-dependent demethylation of naturally occurring MeO-PBDE congeners, not from the hydroxylation of PBDEs. PMID- 26630570 TI - Evolution Analysis of Simple Sequence Repeats in Plant Genome. AB - Simple sequence repeats (SSRs) are widespread units on genome sequences, and play many important roles in plants. In order to reveal the evolution of plant genomes, we investigated the evolutionary regularities of SSRs during the evolution of plant species and the plant kingdom by analysis of twelve sequenced plant genome sequences. First, in the twelve studied plant genomes, the main SSRs were those which contain repeats of 1-3 nucleotides combination. Second, in mononucleotide SSRs, the A/T percentage gradually increased along with the evolution of plants (except for P. patens). With the increase of SSRs repeat number the percentage of A/T in C. reinhardtii had no significant change, while the percentage of A/T in terrestrial plants species gradually declined. Third, in dinucleotide SSRs, the percentage of AT/TA increased along with the evolution of plant kingdom and the repeat number increased in terrestrial plants species. This trend was more obvious in dicotyledon than monocotyledon. The percentage of CG/GC showed the opposite pattern to the AT/TA. Forth, in trinucleotide SSRs, the percentages of combinations including two or three A/T were in a rising trend along with the evolution of plant kingdom; meanwhile with the increase of SSRs repeat number in plants species, different species chose different combinations as dominant SSRs. SSRs in C. reinhardtii, P. patens, Z. mays and A. thaliana showed their specific patterns related to evolutionary position or specific changes of genome sequences. The results showed that, SSRs not only had the general pattern in the evolution of plant kingdom, but also were associated with the evolution of the specific genome sequence. The study of the evolutionary regularities of SSRs provided new insights for the analysis of the plant genome evolution. PMID- 26630571 TI - Evolution of the Northern Rockweed, Fucus distichus, in a Regime of Glacial Cycling: Implications for Benthic Algal Phylogenetics. AB - Northern hemisphere rockweeds (Fucus) are thought to have evolved in the North Pacific and then spread to the North Atlantic following the opening of the Bering Strait. They have dispersed and widely speciated in the North Atlantic and its tributary seas. Fucus distichus is likely near the ancestral member of this genus, and studies have shown that there are several species/subspecies in this complex (i.e. F. evanescens and F. gardneri). We used phylogenetic and haplotype analyses to test the phylogenetic relationships and biogeography of F. distichus. Our data and subsequent analyses demonstrate that, unlike previous studies that lacked samples from an extensive geographical area of the Arctic and Subarctic, there is a distinct Arctic haplotype that is the source of subspecies in both the North Pacific and North Atlantic. Fucus distichus occupies a low tide zone habitat, and in Arctic/Subarctic regions it is adapted to the severe stress of sea ice coverage and disturbance during many months per year. We hypothesize that the very large geographic area of Arctic and Subarctic rocky shores available to this species during interglacials, supported by large Arctic/Subarctic fringe areas as well as unglaciated refugia during glacial cycles, provided a robust population and gene pool (described by the Thermogeographic Model). This gene pool dilutes that of the more fragmented and area-limited Temperate/Boreal area populations when they are brought together during glacial cycles. We suggest that similar subspecies complexes for a variety of Arctic/Subarctic shore biota should be examined further in this context, rather than arbitrarily being split up into numerous species. PMID- 26630573 TI - Contact-dependent mechanical properties of graphene nanoribbons: an ab initio study. AB - The mechanical properties of graphene nanoribbons on Ni(111) surfaces with different contact sizes are investigated by means of density functional theory. For finite contact sizes, the stress behavior of graphene nanoribbons on metal electrodes is likely to be similar to that of suspended graphene, however the critical strain is not reached due to the sliding friction at the interface. The competition between frictional and external forces is responsible for the nonmonotonic stress behavior. It is indicated that the stick-slip motions of graphene on Ni(111) are as a result of applied external forces on the GNR/metal contact. Moreover, the effect of vacancies and chemical doping on the sliding friction are addressed. Graphene starts to slide on the surface under a much lower external force in the case of defected graphene, due to the weaker binding to the surface. For infinite contact sizes, a linear relationship between stress and strain are found until structural failure occurs by 11% applied strain. The corresponding critical strain for the suspended GNR (without electrodes) has been found to be 13%. PMID- 26630572 TI - Exploring the Gastrointestinal "Nemabiome": Deep Amplicon Sequencing to Quantify the Species Composition of Parasitic Nematode Communities. AB - Parasitic helminth infections have a considerable impact on global human health as well as animal welfare and production. Although co-infection with multiple parasite species within a host is common, there is a dearth of tools with which to study the composition of these complex parasite communities. Helminth species vary in their pathogenicity, epidemiology and drug sensitivity and the interactions that occur between co-infecting species and their hosts are poorly understood. We describe the first application of deep amplicon sequencing to study parasitic nematode communities as well as introduce the concept of the gastro-intestinal "nemabiome". The approach is analogous to 16S rDNA deep sequencing used to explore microbial communities, but utilizes the nematode ITS-2 rDNA locus instead. Gastro-intestinal parasites of cattle were used to develop the concept, as this host has many well-defined gastro-intestinal nematode species that commonly occur as complex co-infections. Further, the availability of pure mono-parasite populations from experimentally infected cattle allowed us to prepare mock parasite communities to determine, and correct for, species representation biases in the sequence data. We demonstrate that, once these biases have been corrected, accurate relative quantitation of gastro-intestinal parasitic nematode communities in cattle fecal samples can be achieved. We have validated the accuracy of the method applied to field-samples by comparing the results of detailed morphological examination of L3 larvae populations with those of the sequencing assay. The results illustrate the insights that can be gained into the species composition of parasite communities, using grazing cattle in the mid-west USA as an example. However, both the technical approach and the concept of the 'nemabiome' have a wide range of potential applications in human and veterinary medicine. These include investigations of host-parasite and parasite parasite interactions during co-infection, parasite epidemiology, parasite ecology and the response of parasite populations to both drug treatments and control programs. PMID- 26630575 TI - Spatial Patterns in Water Quality Changes during Dredging in Tropical Environments. AB - Dredging poses a potential risk to tropical ecosystems, especially in turbidity sensitive environments such as coral reefs, filter feeding communities and seagrasses. There is little detailed observational time-series data on the spatial effects of dredging on turbidity and light and defining likely footprints is a fundamental task for impact prediction, the EIA process, and for designing monitoring projects when dredging is underway. It is also important for public perception of risks associated with dredging. Using an extensive collection of in situ water quality data (73 sites) from three recent large scale capital dredging programs in Australia, and which included extensive pre-dredging baseline data, we describe relationships with distance from dredging for a range of water quality metrics. Using a criterion to define a zone of potential impact of where the water quality value exceeds the 80th percentile of the baseline value for turbidity-based metrics or the 20th percentile for the light based metrics, effects were observed predominantly up to three km from dredging, but in one instance up to nearly 20 km. This upper (~20 km) limit was unusual and caused by a local oceanographic feature of consistent unidirectional flow during the project. Water quality loggers were located along the principal axis of this flow (from 200 m to 30 km) and provided the opportunity to develop a matrix of exposure based on running means calculated across multiple time periods (from hours to one month) and distance from the dredging, and summarized across a broad range of percentile values. This information can be used to more formally develop water quality thresholds for benthic organisms, such as corals, filter-feeders (e.g. sponges) and seagrasses in future laboratory- and field-based studies using environmentally realistic and relevant exposure scenarios, that may be used to further refine distance based analyses of impact, potentially further reducing the size of the dredging footprint. PMID- 26630574 TI - A Low Frequency of Losses in 11q Chromosome Is Associated with Better Outcome and Lower Rate of Genomic Mutations in Patients with Chronic Lymphocytic Leukemia. AB - To analyze the impact of the 11q deleted (11q-) cells in CLL patients on the time to first therapy (TFT) and overall survival (OS), 2,493 patients with CLL were studied. 242 patients (9.7%) had 11q-. Fluorescence in situ hybridization (FISH) studies showed a threshold of 40% of deleted cells to be optimal for showing that clinical differences in terms of TFT and OS within 11q- CLLs. In patients with >=40% of losses in 11q (11q-H) (74%), the median TFT was 19 months compared with 44 months in CLL patients with <40% del(11q) (11q-L) (P<0.0001). In the multivariate analysis, only the presence of 11q-L, mutated IGHV status, early Binet stage and absence of extended lymphadenopathy were associated with longer TFT. Patients with 11q-H had an OS of 90 months, while in the 11q-L group the OS was not reached (P = 0.008). The absence of splenomegaly (P = 0.02), low LDH (P = 0.018) or beta2M (P = 0.006), and the presence of 11q-L (P = 0.003) were associated with a longer OS. In addition, to detect the presence of mutations in the ATM, TP53, NOTCH1, SF3B1, MYD88, FBXW7, XPO1 and BIRC3 genes, a select cohort of CLL patients with losses in 11q was sequenced by next-generation sequencing of amplicons. Eighty % of CLLs with 11q- showed mutations and fewer patients with low frequencies of 11q- had mutations among genes examined (50% vs 94.1%, P = 0.023). In summary, CLL patients with <40% of 11q- had a long TFT and OS that could be associated with the presence of fewer mutated genes. PMID- 26630576 TI - High-Throughput Mutation Profiling Changes before and 3 Weeks after Chemotherapy in Newly Diagnosed Breast Cancer Patients. AB - BACKGROUND: Changes in tumor DNA mutation status during chemotherapy can provide insights into tumor biology and drug resistance. The purpose of this study is to analyse the presence or absence of mutations in cancer-related genes using baseline breast tumor samples and those obtained after exposure to one cycle of chemotherapy to determine if any differences exist, and to correlate these differences with clinical and pathological features. METHODS: Paired breast tumor core biopsies obtained pre- and post-first cycle doxorubicin (n = 18) or docetaxel (n = 22) in treatment-naive breast cancer patients were analysed for 238 mutations in 19 cancer-related genes by the Sequenom Oncocarta assay. RESULTS: Median age of patients was 48 years (range 32-64); 55% had estrogen receptor-positive tumors, and 60% had tumor reduction >=25% after cycle 1. Mutations were detected in 10/40 (25%) pre-treatment and 11/40 (28%) post treatment samples. Four mutation pattern categories were identified based on tumor mutation status pre- -> post-treatment: wildtype (WT)->WT, n = 24; mutant (MT)->MT, n = 5; MT->WT, n = 5; WT->MT, n = 6. Overall, the majority of tumors were WT at baseline (30/40, 75%), of which 6/30 (20%) acquired new mutations after chemotherapy. Pre-treatment mutations were predominantly in PIK3CA (8/10, 80%), while post-treatment mutations were distributed in PIK3CA, EGFR, PDGFRA, ABL1 and MET. All 6 WT->MT cases were treated with docetaxel. Higher mutant allele frequency in baseline MT tumors (n = 10; PIK3CA mutations n = 8) correlated with less tumor reduction after cycle 1 chemotherapy (R = -0.667, p = 0.035). No other associations were observed between mutation pattern category with treatment, clinicopathological features, and tumor response or survival. CONCLUSION: Tumor mutational profiles can change as quickly as after one cycle of chemotherapy in breast cancer. Understanding of these changes can provide insights on potential therapeutic options in residual resistant tumors. TRIAL REGISTRATION: ClinicalTrials.gov NCT00212082. PMID- 26630577 TI - (Un)Healthy in the City: Respiratory, Cardiometabolic and Mental Health Associated with Urbanity. AB - BACKGROUND: Research has shown that health differences exist between urban and rural areas. Most studies conducted, however, have focused on single health outcomes and have not assessed to what extent the association of urbanity with health is explained by population composition or socioeconomic status of the area. Our aim is to investigate associations of urbanity with four different health outcomes (i.e. lung function, metabolic syndrome, depression and anxiety) and to assess whether these associations are independent of residents' characteristics and area socioeconomic status. METHODS: Our study population consisted of 74,733 individuals (42% males, mean age 43.8) who were part of the baseline sample of the LifeLines Cohort Study. Health outcomes were objectively measured with spirometry, a physical examination, laboratory blood analyses, and a psychiatric interview. Using multilevel linear and logistic regression models, associations of urbanity with lung function, and prevalence of metabolic syndrome, major depressive disorder and generalized anxiety disorder were assessed. All models were sequentially adjusted for age, sex, highest education, household equivalent income, smoking, physical activity, and mean neighborhood income. RESULTS: As compared with individuals living in rural areas, those in semi-urban or urban areas had a poorer lung function (beta -1.62, 95% CI -2.07; 1.16), and higher prevalence of major depressive disorder (OR 1.65, 95% CI 1.35;2.00), and generalized anxiety disorder (OR 1.58, 95% CI 1.35;1.84). Prevalence of metabolic syndrome, however, was lower in urban areas (OR 0.51, 95% CI 0.44;0.59). These associations were only partly explained by differences in residents' demographic, socioeconomic and lifestyle characteristics and socioeconomic status of the areas. CONCLUSIONS: Our results suggest a differential health impact of urbanity according to type of disease. Living in an urban environment appears to be beneficial for cardiometabolic health but to have a detrimental impact on respiratory function and mental health. Future research should investigate which underlying mechanisms explain the differential health impact of urbanity. PMID- 26630578 TI - In Vivo Detection of Mitochondrial Dysfunction Induced by Clinical Drugs and Disease-Associated Genes Using a Novel Dye ZMJ214 in Zebrafish. AB - Mitochondrial dysfunction has been implicated in various drug-induced toxicities and genetic disorders. Recently, the zebrafish has emerged as a versatile animal model for both chemical and genetic screenings. Taking advantage of its transparency, various in vivo fluorescent imaging methods have been developed to identify novel functions of chemicals and genes in zebrafish. However, there have not been fluorescent probes that can detect mitochondrial membrane potential in living zebrafish. In this study, we identified a novel cyanine dye called ZMJ214 that detects mitochondrial membrane potential in living zebrafish from 4 to 8 days post fertilization and is administered by simple immersion. The fluorescence intensity of ZMJ214 in zebrafish was increased and decreased by oligomycin and FCCP, respectively, suggesting a positive correlation between ZMJ214 fluorescence and mitochondrial membrane potential. In vivo imaging of zebrafish stained with ZMJ214 allowed for the detection of altered mitochondrial membrane potential induced by the antidiabetic drug troglitazone and the antiepileptic drug tolcapone, both of which have been withdrawn from the market due to mitochondrial toxicity. In contrast, pioglitazone and entacapone, which are similar to troglitazone and tolcapone, respectively, and have been used commercially, did not cause a change in mitochondrial membrane potential in zebrafish stained with ZMJ214. Live imaging of zebrafish stained with ZMJ214 also revealed that knock down of slc25a12, a mitochondrial carrier protein associated with autism, dysregulated the mitochondrial membrane potential. These results suggest that ZMJ214 can be a useful tool to identify chemicals and genes that cause mitochondrial dysfunction in vivo. PMID- 26630580 TI - Predictors of well-being among college students. AB - OBJECTIVES: Identification of health-related risk behaviors associated with well being in college students is essential to guide the development of health promotion strategies for this population. The purposes were to evaluate well being among undergraduate students and to identify health-related risk behaviors that predict well-being in this population. METHODS: A cross-sectional Web-based survey of undergraduate students was conducted at a metropolitan university in the Southeast United States. A total of 568 students responded (response rate 14.2%). Data were collected on health-related risk behaviors using the National College Health Assessment II. RESULTS: Controlling demographic characteristics, the best predictive model included physical activity, current tobacco user, depression, ever received mental health services, and sleep quality, which was the strongest predictor (beta = .45, p < .001). This model explained 35% of the variance in well-being. CONCLUSIONS: Interventions that promote sleep quality among college students may be most beneficial in improving well-being. PMID- 26630579 TI - Comparison of the Fluid Resuscitation Rate with and without External Pressure Using Two Intraosseous Infusion Systems for Adult Emergencies, the CITRIN (Comparison of InTRaosseous infusion systems in emergency medicINe)-Study. AB - INTRODUCTION: Intraosseous infusion is recommended if peripheral venous access fails for cardiopulmonary resuscitation or other medical emergencies. The aim of this study, using body donors, was to compare a semi-automatic (EZ-IO(r)) device at two insertion sites and a sternal intraosseous infusion device (FASTRTM). METHODS: Twenty-seven medical students being inexperienced first-time users were randomized into three groups using EZ-IO and FASTR. The following data were evaluated: attempts required for successful placement, insertion time and flow rates with and without external pressure to the infusion. RESULTS: The first-pass insertion success of the EZ-IO tibia, EZ-IO humerus and FASTR was 91%, 77%, and 95%, respectively. Insertion times (MW +/- SD) did not show significant differences with 17 +/- 7 (EZ-IO tibia) vs. 29 +/- 42 (EZ-IO humerus) vs. 33 +/- 21 (FASTR), respectively. One-minute flow rates using external pressures between 0 mmHg and 300 mmHg ranged between 27 +/- 5 to 69 +/- 54 ml/min (EZ-IO tibia), 16 +/- 3 to 60 +/- 44 ml/min (EZ-IO humerus) and 53 +/- 2 to 112 +/- 47 ml/min (FASTR), respectively. Concerning pressure-related increases in flow rates, negligible correlations were found for the EZ-IO tibia in all time frames (c = 0.107-0.366; p <= 0.013), moderate positive correlations were found for the EZ-IO humerus after 5 minutes (c = 0.489; p = 0.021) and strong positive correlations were found for the FASTR in all time frames (c = 0.63-0.80; p <= 0.007). Post-hoc statistical power was 0.62 with the given sample size. CONCLUSIONS: The experiments with first-time users applying EZ-IO and FASTR in body donors indicate that both devices may be effective intraosseous infusion devices, likely suitable for fluid resuscitation using a pressure bag. Variations in flow rate may limit their reliability. Larger sample sizes will prospectively be required to substantiate our findings. PMID- 26630581 TI - Two new compounds from the leaves of Indocalamus latifolius. AB - Two new compounds, erythro-syringylglycerol-9-O-trans-4-hydroxycinnamate 7-O-beta d-glucopyranoside (1) and indocalatin A (2), together with three known ones, 5,7,3'-trihydroxy-6-C-beta-d-digitoxopyranosyl-4'-O-beta-d-glucopyranosyl flavonoid (3), 5,4'-dihydroxy-3',5'-dimethoxy-7-O-[beta-d-apiose-(1->2)]-beta-d glucopyranosyl flavonoid (4), and tricin-6-C-beta-boivinopyranosyl-8-C-beta glucopyranoside (5), were isolated from the 95% EtOH extract of Indocalamus latifolius leaves. Their molecular structures were determined by UV, IR, HRESIMS, CD, and 1D and 2D NMR data analyses. PMID- 26630582 TI - Fast microwave-assisted preparation of a low-cost and recyclable carboxyl modified lignocellulose-biomass jute fiber for enhanced heavy metal removal from water. AB - A low-cost and recyclable biosorbent derived from jute fiber was developed for high efficient adsorption of Pb(II), Cd(II) and Cu(II) from water. The jute fiber was rapidly pretreated and grafted with metal binding groups (COOH) under microwave heating (MH). The adsorption behavior of carboxyl-modified jute fiber under MH treatment (CMJFMH) toward heavy metal ions followed Langmuir isotherm model (R(2)>0.99) with remarkably high adsorption capacity (157.21, 88.98 and 43.98mg/g for Pb(II), Cd(II) and Cu(II), respectively). Also, CMJFMH showed fast removal ability for heavy metals in a highly significant correlation with pseudo second-order kinetics model. Besides, CMJFMH can be easily regenerated with EDTA 2Na solution and reused up to at least four times with equivalent high adsorption capacity. Overall, cheap and abundant production, rapid and facile preparation, fast and efficient adsorption of heavy metals and high regeneration ability can make the CMJFMH a preferred biosorbent for heavy metal removal from water. PMID- 26630583 TI - Biological conversion of biogas to methanol using methanotrophs isolated from solid-state anaerobic digestate. AB - The aim of this work was to isolate methanotrophs (methane oxidizing bacteria) that can directly convert biogas produced at a commercial anaerobic digestion (AD) facility to methanol. A methanotrophic bacterium was isolated from solid state anaerobic digestate. The isolate had characteristics comparable to obligate methanotrophs from the genus Methylocaldum. This newly isolated methanotroph grew on biogas or purified CH4 and successfully converted biogas from AD to methanol. Methanol production was achieved using several methanol dehydrogenase (MDH) inhibitors and formate as an electron donor. The isolate also produced methanol using phosphate with no electron donor or using formate with no MDH inhibitor. The maximum methanol concentration (0.43+/-0.00gL(-1)) and 48-h CH4 to methanol conversion (25.5+/-1.1%) were achieved using biogas as substrate and a growth medium containing 50mM phosphate and 80mM formate. PMID- 26630590 TI - Genome editing. PMID- 26630591 TI - Medicine: Expanding possibilities. PMID- 26630592 TI - Epigenetics: The genome unwrapped. PMID- 26630593 TI - Q&A: Cocktail maker. PMID- 26630594 TI - Agriculture: A new breed of edits. PMID- 26630595 TI - Genome editing: 4 big questions. PMID- 26630596 TI - Three technologies that changed genetics. PMID- 26630597 TI - Research: Biology's big hit. PMID- 26630598 TI - Perspective: Embryo editing needs scrutiny. PMID- 26630599 TI - Perspective: Encourage the innovators. PMID- 26630600 TI - Disease: Closing the door on HIV. PMID- 26630601 TI - Troubling Muddy Waters: Problematizing Reflective Practice in Global Medical Education. AB - The idea of exporting the concept of reflective practice for a global medical education audience is growing. However, the uncritical export and adoption of Western concepts of reflection may be inappropriate in non-Western societies. The emphasis in Western medical education on the use of reflection for a specific end -that is, the improvement of individual clinical practice--tends to ignore the range of reflective practice, concentrating on reflection alone while overlooking critical reflection and reflexivity. This Perspective places the concept of reflective practice under a critical lens to explore a broader view for its application in medical education outside the West. The authors suggest that ideas about reflection in medicine and medical education may not be as easily transferable from Western to non-Western contexts as concepts from biomedical science are. The authors pose the question, When "exporting" Western medical education strategies and principles, how often do Western-trained educators authentically open up to the possibility that there are alternative ways of seeing and knowing that may be valuable in educating Western physicians? One answer lies in the assertion that educators should aspire to turn exportation of educational theory into a truly bidirectional, collaborative exchange in which culturally conscious views of reflective practice contribute to humanistic, equitable patient care. This discussion engages in troubling the already-muddy waters of reflective practice by exploring the global applicability of reflective practice as it is currently applied in medical education. The globalization of medical education demands critical reflection on reflection itself. PMID- 26630602 TI - Playing in the "Gutter": Cultivating Creativity in Medical Education and Practice. AB - In comics, "gutters" are the empty spaces between panels that readers must navigate to weave disjointed visual sequences into coherent narratives. A gutter, however, is more than a blank space--it represents a creative zone for making connections and for constructing meaning from disparate ideas, values, and experiences. Over the course of medical training, learners encounter various "gutters" created by the disconnected subject blocks and learning experiences within the curriculum, the ambiguity and uncertainty of medical practice, and the conflicts and tensions within clinical encounters. Navigating these gutters requires not only medical knowledge and skills but also creativity, defined as the ability to make connections between disparate fragments to create meaningful, new configurations. To cultivate medical students' creative capacity, the authors developed the Integrated Clinical Arts (ICA) program, a required component of the first-year curriculum at the Warren Alpert Medical School of Brown University. ICA workshops are designed to place students in a metaphorical gutter, wherein they can practice making connections between medicine and arts-based disciplines. By playing in the gutter, students have opportunities to broaden their perspectives, gain new insights into both medical practice and themselves, and explore different ways of making meaning. Student feedback on the ICA program highlights an important role for creativity and the arts in medicine: to transform gutters from potential learning barriers into opportunities for discovery, self-reflection, and personal growth. PMID- 26630603 TI - Contextual Errors in Medical Decision Making: Overlooked and Understudied. AB - Although it is widely recognized that effective clinical practice requires attending to the circumstances and needs of individual patients-their life context-rather than just treating disease, the implications of not doing so are rarely assessed. What are, for instance, the consequences of prescribing a medication that is appropriate for treating a clinical condition but inappropriate for a particular individual either because she or he cannot afford it, lacks the skills to administer it correctly, or is unable to adhere to the regimen because of competing responsibilities such as working the night shift? Conversely, what are the gains to health and health care when such contextual factors are addressed? Finally, can performance measures be employed and developed for the clinician behaviors associated with contextualizing care to guide improvements in care? The authors have explored these questions through observational and experimental studies to define the parameters of patient context, introduce strategies for measuring clinician attention to patient context, and assess the impact of that attention on care planning, patient health care outcomes, and costs. The authors suggest that inattention to patient context is an underrecognized cause of medical error ("contextual error"), that detecting its presence usually requires listening in on the visit, and that it has significant implications for quality of care. Also described is preliminary work to reduce contextual errors. Evidence suggests that this nascent area of research has significant implications for performance assessment and medical education in addressing deficits in quality of care. PMID- 26630604 TI - Integrating Neuroscience Knowledge and Neuropsychiatric Skills Into Psychiatry: The Way Forward. AB - Increasing the integration of neuroscience knowledge and neuropsychiatric skills into general psychiatric practice would facilitate expanded approaches to diagnosis, formulation, and treatment while positioning practitioners to utilize findings from emerging brain research. There is growing consensus that the field of psychiatry would benefit from more familiarity with neuroscience and neuropsychiatry. Yet there remain numerous factors impeding the integration of these domains of knowledge into general psychiatry.The authors make recommendations to move the field forward, focusing on the need for advocacy by psychiatry and medical organizations and changes in psychiatry education at all levels. For individual psychiatrists, the recommendations target obstacles to attaining expanded neuroscience and neuropsychiatry education and barriers stemming from widely held, often unspoken beliefs. For the system of psychiatric care, recommendations address the conceptual and physical separation of psychiatry from medicine, overemphasis on the Diagnostic and Statistical Manual of Mental Disorders and on psychopharmacology, and different systems in medicine and psychiatry for handling reimbursement and patient records. For psychiatry residency training, recommendations focus on expanding neuroscience/neuropsychiatry faculty and integrating neuroscience education throughout the curriculum.Psychiatry traditionally concerns itself with helping individuals construct meaningful life narratives. Brain function is one of the fundamental determinants of individuality. It is now possible for psychiatrists to integrate knowledge of neuroscience into understanding the whole person by asking, What person has this brain? How does this brain make this person unique? How does this brain make this disorder unique? What treatment will help this disorder in this person with this brain? PMID- 26630605 TI - In Pursuit of Meaningful Use of Learning Goals in Residency: A Qualitative Study of Pediatric Residents. AB - PURPOSE: Medical education aims to equip physicians for lifelong learning, an objective supported by the conceptual framework of self-regulated learning (SRL). Learning goals have been used to develop SRL skills in learners across the medical education continuum. This study's purpose was to elicit residents' perspectives on learning goal use and to develop explanations suggesting how aspects of the learning environment may facilitate or hinder the meaningful use of learning goals in residency. METHOD: Resident focus groups and program director interviews were conducted in 2012-2013, audio-recorded, and transcribed. Programs were selected to maximize diversity of size, geographic location, type of program, and current use of learning goals. Data were analyzed using the constant comparative method associated with grounded theory. Further analysis compared themes frequently occurring together to strengthen the understanding of relationships between the themes. Through iterative discussions, investigators built a grounded theory. RESULTS: Ninety-five third-year residents and 12 program directors at 12 pediatric residency programs participated. The analysis identified 21 subthemes grouped into 5 themes: program support, faculty roles, goal characteristics and purposes, resident attributes, and accountability and goal follow-through. Review of relationships between the themes revealed a pyramid of support with program support as the foundation that facilitates the layers above it, leading to goal follow-through. CONCLUSIONS: Program support facilitates each step of the SRL process that leads to meaningful use of learning goals in residency. A strong foundation of program support should include attention to aspects of the implicit curriculum as well as the explicit curriculum. PMID- 26630606 TI - Entrustment Decision Making in Clinical Training. AB - The decision to trust a medical trainee with the critical responsibility to care for a patient is fundamental to clinical training. When carefully and deliberately made, such decisions can serve as significant stimuli for learning and also shape the assessment of trainees. Holding back entrustment decisions too much may hamper the trainee's development toward unsupervised practice. When carelessly made, however, they jeopardize patient safety. Entrustment decision making processes, therefore, deserve careful analysis.Members (including the authors) of the International Competency-Based Medical Education Collaborative conducted a content analysis of the entrustment decision-making process in health care training during a two-day summit in September 2013 and subsequently reviewed the pertinent literature to arrive at a description of the critical features of this process, which informs this article.The authors discuss theoretical backgrounds and terminology of trust and entrustment in the clinical workplace. The competency-based movement and the introduction of entrustable professional activities force educators to rethink the grounds for assessment in the workplace. Anticipating a decision to grant autonomy at a designated level of supervision appears to align better with health care practice than do most current assessment practices. The authors distinguish different modes of trust and entrustment decisions and elaborate five categories, each with related factors, that determine when decisions to trust trainees are made: the trainee, supervisor, situation, task, and the relationship between trainee and supervisor. The authors' aim in this article is to lay a theoretical foundation for a new approach to workplace training and assessment. PMID- 26630607 TI - Transforming Scientific Inquiry: Tapping Into Digital Data by Building a Culture of Transparency and Consent. AB - With over 1.7 billion individuals engaged in social media, patients and consumers share more about their lives than ever before through wearable devices, smartphone applications, and social media outlets. This cornucopia of data offers significant opportunity for health researchers and clinicians to track and explore how digital presence contributes to patients' health outcomes and use of health care resources. While patients readily share their information with online communities, it is imperative that they maintain a sense of autonomy over who has access to such data. Recent data breaches of major insurance companies and retailers illustrate the challenges and vulnerabilities related to information safety and privacy. Many Web sites and mobile apps require users to agree to data policies, but how those data are mined, protected, used, and externally shared is frequently nontransparent, resulting in a climate of fear and distrust around all forums of digital information sharing. Although such skepticism is perhaps justified, it should not deter health researchers from attempting to collect and analyze these novel data for the purpose of designing unique health interventions. By clarifying intent around digital data acquisition, simplifying consent procedures, and affirming a commitment to privacy, the authors contend that health researchers can partner with patients to transform the boundaries of scientific inquiry. PMID- 26630608 TI - Beyond Medical "Missions" to Impact-Driven Short-Term Experiences in Global Health (STEGHs): Ethical Principles to Optimize Community Benefit and Learner Experience. AB - Increasing demand for global health education in medical training has driven the growth of educational programs predicated on a model of short-term medical service abroad. Almost two-thirds of matriculating medical students expect to participate in a global health experience during medical school, continuing into residency and early careers. Despite positive intent, such short-term experiences in global health (STEGHs) may exacerbate global health inequities and even cause harm. Growing out of the "medical missions" tradition, contemporary participation continues to evolve. Ethical concerns and other disciplinary approaches, such as public health and anthropology, can be incorpo rated to increase effectiveness and sustainability, and to shift the culture of STEGHs from focusing on trainees and their home institutions to also considering benefits in host communities and nurtur ing partnerships. The authors propose four core principles to guide ethical development of educational STEGHs: (1) skills building in cross-cultural effective ness and cultural humility, (2) bidirectional participatory relationships, (3) local capacity building, and (4) long-term sustainability. Application of these principles highlights the need for assessment of STEGHs: data collection that allows transparent compar isons, standards of quality, bidirectionality of agreements, defined curricula, and ethics that meet both host and sending countries' standards and needs. To capture the enormous potential of STEGHs, a paradigm shift in the culture of STEGHs is needed to ensure that these experiences balance training level, personal competencies, medical and cross cultural ethics, and educational objectives to minimize harm and maximize benefits for all involved. PMID- 26630609 TI - Entrustability Scales: Outlining Their Usefulness for Competency-Based Clinical Assessment. AB - Meaningful residency education occurs at the bedside, along with opportunities for situated in-training assessment. A necessary component of workplace-based assessment (WBA) is the clinical supervisor, whose subjective judgments of residents' performance can yield rich and nuanced ratings but may also occasionally reflect bias. How to improve the validity of WBA instruments while simultaneously capturing meaningful subjective judgment is currently not clear. This Perspective outlines how "entrustability scales" may help bridge the gap between the assessment judgments of clinical supervisors and WBA instruments. Entrustment-based assessment evaluates trainees against what they will actually do when independent; thus, "entrustability scales"-defined as behaviorally anchored ordinal scales based on progression to competence-reflect a judgment that has clinical meaning for assessors. Rather than asking raters to assess trainees against abstract scales, entrustability scales provide raters with an assessment measure structured around the way evaluators already make day-to-day clinical entrustment decisions, which results in increased reliability. Entrustability scales help raters make assessments based on narrative descriptors that reflect real-world judgments, drawing attention to a trainee's readiness for independent practice rather than his/her deficiencies. These scales fit into milestone measurement both by allowing an individual resident to strive for independence in entrustable professional activities across the entire training period and by allowing residency directors to identify residents experiencing difficulty. Some WBA tools that have begun to use variations of entrustability scales show potential for allowing raters to produce valid judgments. This type of anchor scale should be brought into wider circulation. PMID- 26630610 TI - Health Care Transformation: A Strategy Rooted in Data and Analytics. AB - Today's consumers purchasing any product or service are armed with information and have high expectations. They expect service providers and payers to know about their unique needs. Data-driven decisions can help organizations meet those expectations and fulfill those needs.Health care, however, is not strictly a retail relationship-the sacred trust between patient and doctor, the clinician patient relationship, must be preserved. The opportunities and challenges created by the digitization of health care are at the crux of the most crucial strategic decisions for academic medicine. A transformational vision grounded in data and analytics must guide health care decisions and actions.In this Commentary, the authors describe three examples of the transformational force of data and analytics to improve health care in order to focus attention on academic medicine's vital role in guiding the needed changes. PMID- 26630611 TI - The Business of Trust. AB - New mobile devices, social networks, analytics, and communications technologies are emerging at an unparalleled rate. As a result, academic health centers will face both new opportunities and formidable challenges. Unlike previous transitions from paper-based systems to networked computer systems, these new technologies are the product of new entrepreneurial and commercial interests driven by consumers. As these new commercial products and services are more widely adopted, the likelihood grows that data will be used in unanticipated ways inconsistent with societal norms. Academic health centers will have to understand the implications of these technologies and engage more actively in processes governing the collection, aggregation, and use of health data produced in a new era of consumer-driven health care technology. Maintaining public trust should be a paramount concern. PMID- 26630612 TI - Fast-response and highly selective fluorescent probes for biological signaling molecule NO based on N-nitrosation of electron-rich aromatic secondary amines. AB - Nitric oxide (NO) is a ubiquitous biological messenger molecule, and plays the active roles in the regulation of various physiological processes. Although numerous NO fluorescent probes have also been successfully developed in the past ten years, it still remains challenging to increase the response rate for NO while having the high selectivity and sensitivity. In this work, a simple N nitrosation reaction of the electron-rich aromatic secondary amine with NO under aerobic condition has been utilized for the first time to construct fluorescent probe for NO. The resulting probe 1, containing a N-benzyl-4-hydroxyaniline moiety as reaction group and a BODIPY dye as fluorescence reporter, could detect NO with the fast fluorescence off-on response (within seconds), high sensitivity (nM level), and excellent selectivity over various reactive oxygen species (ROS) as well as dehydroascorbic acid (DHA), ascorbic acid (AA), and methylglyoxal (MGO). Even in the presence of glutathione (GSH, a high reactive biothiol for NO), the probe still works well for NO. Further, a mitochondria-targetable probe 2 was exploited by introducing a targeted triphenylphosphonium cation into probe 1 scaffold. It's excellent NO sensing performance as well as its ability to specifically target mitochondria and image NO there have been nicely demonstrated. With the two probes, the basal and stimulation-induced NO in RAW264.7 murine macrophages as well as the endogenous NO in endothelial cells after oxygen-glucose deprivation (OGD) have been successfully visualized. PMID- 26630614 TI - Predicting neurodevelopmental outcomes at preschool age for children with very low birth weight. AB - The purpose of this study was to examine predictors of neurodevelopmental outcome in very low birth weight children without major impairment at 5 years of age, as well as to identify the contribution of early neurodevelopmental assessment to preterm children's later developmental outcomes. The participants in this study included 126 children who were prematurely born with very low birth weight. Outcomes of the childrens' later development were measured in tests that factored cognitive function, motor performance, and adaptive behavior. The results indicated that more than 50% of full-scale intelligence and 30% of both motor performance and adaptive behavior at the age of 5 can be explained by four predictors. The four predictors include preterm children's medical complications at birth, maternal education, early motor assessments, and cognitive assessments. Adding each test score obtained in early ages provides additional information to predict children's cognitive, motor, and adaptive behavior at 5 years of age. Manifold assessments conducted in multiple time periods strengthen the predictive values of later developmental outcomes. In addition, the findings of this study indicate that very low birth weight children tend to have lower adaptive behavior at 5 years old. With regard to our findings, we believe that having adaptive function is a reflection of a child's overall integrated abilities. Further study is warranted to increase understanding of this topic, as well as to be able to predict adaptive strengths and weakness and pinpoint limiting factors that may be useful for targeting behaviors in intervention. PMID- 26630613 TI - Structural connectivity and response to ketamine therapy in major depression: A preliminary study. AB - BACKGROUND: Ketamine elicits an acute antidepressant effect in patients with major depressive disorder (MDD). Here, we used diffusion imaging to explore whether regional differences in white matter microstructure prior to treatment may predict clinical response 24h following ketamine infusion in 10 MDD patients. METHODS: FSL's Tract-Based Spatial Statistics (TBSS) established voxel-level differences in fractional anisotropy (FA) between responders (patients showing >50% improvement in symptoms 24h post-infusion) and non-responders in major white matter pathways. Follow-up regions-of-interest (ROI) analyses examined differences in FA and radial (RD), axial (AD) and mean diffusivity (MD) between responders and non-responders and 15 age- and sex-matched controls, with groups compared pairwise. RESULTS: Whole brain TBSS (p<0.05, corrected) and confirmatory tract-based regions-of-interest analyses showed larger FA values in the cingulum and forceps minor in responders compared to non-responders; complementary decreases in RD occurred in the cingulum (p<0.05). Only non-responders differed from controls showing decreased FA in the forceps minor, increased RD in the cingulum and forceps minor, and increased MD in the forceps minor (p<0.05). LIMITATIONS: Non-responders showed an earlier age of onset and longer current depressive episode than responders. Though these factors did not interact with diffusion metrics, results may be impacted by the limited sample size. CONCLUSIONS: Though findings are considered preliminary, significant differences in FA, RD and MD shown in non-responders compared to responders and controls in fronto-limbic and ventral striatal pathways suggest that the structural architecture of specific functional networks mediating emotion may predict ketamine response in MDD. PMID- 26630615 TI - Validating Kohler's Taxonomy of Transition Programming for adolescents with intellectual disability in the Chinese context. AB - BACKGROUND: School-to-work transition programmes play a crucial role in the achievement of post-secondary outcomes for young adults with intellectual disability (ID). Although special education in China has progressed in the last two decades, systematically planned transition education and services are not usually available for Chinese school leavers. AIMS: The present study aimed to validate Kohler's Taxonomy of Transition Programming (KTTP) in the Chinese context for adolescents with ID. METHODS AND PROCEDURES: Five Chinese transition experts reviewed KTTP items, 14 Chinese transition teachers and 14 parents of adolescents with ID who would transition from school in the next 12 months were interviewed, and 329 transition teachers were surveyed. OUTCOME AND RESULTS: Most items in KTTP were found to be important and relevant to the Chinese context. Based on KTTP, a modified transition framework appropriate to the Chinese context was generated. CONCLUSIONS AND IMPLICATIONS: The Chinese transition framework may assist parents and professionals to better support adolescents with ID in China. Future validation checks of the framework will add confidence that the framework captures the essential components of effective transition practices appropriate in the Chinese context. PMID- 26630616 TI - Early motor development of children with a congenital cytomegalovirus infection. AB - BACKGROUND: Congenital cytomegalovirus (cCMV) infection is the most important etiology of non-hereditary childhood hearing loss and an important cause of neurodevelopmental delay. The current study aimed to investigate the early motor development of symptomatic and asymptomatic cCMV infected children with and without sensorineural hearing loss (SNHL). METHODS: Sixty-four children with a cCMV infection, without cerebral palsy, were compared to a control group of 107 normal hearing children. They were assessed around the ages of 6, 12, and 24 months with the Peabody Developmental Motor Scales-2 (PDMS-2), Alberta Infant Motor Scales (AIMS), and Ghent Developmental Balance Test (GDBT). The cCMV infected children were subdivided into a symptomatic (n=26) and asymptomatic cCMV group (n=38) but also into a cCMV group with SNHL (n=19) and without SNHL (n=45). RESULTS: Symptomatic cCMV infected children and cCMV infected children with SNHL performed significantly weaker for all gross motor outcome measures. CONCLUSION: A congenital CMV infection is a risk factor for a delay in the early motor development. Follow-up will be necessary to gain insight into the exact cause of this motor delay and to define the predictive value of early motor assessment of cCMV infected children. PMID- 26630617 TI - Immediate Effects of 3% Diquafosol and 0.1% Hyaluronic Acid Ophthalmic Solution on Tear Break-Up Time in Normal Human Eyes. AB - PURPOSE: The purpose of this study was to evaluate the immediate effect of 3% diquafosol ophthalmic solution on tear break-up time (TBUT) in normal human eyes, and to compare it with that of saline and 0.1% hyaluronate ophthalmic solution. METHODS: Cross sectional comparative study in the first study, 10 healthy volunteers underwent topical application of 2 different ophthalmic solutions in each eye. Saline was randomly applied to one eye and 3% diquafosol ophthalmic solution was added to the fellow eye. TBUT was measured and video recorded before application and at 5, 10, 15, and 20 min after. The TBUT in each eye was compared at each time point with regard to the 2 different ophthalmic solutions. In the second study, another 10 healthy volunteers were included. The same methods were used to compare the immediate effects of 0.1% hyaluronate and 3% diquafosol ophthalmic solution application on TBUT. RESULTS: In the first study, topical instillation of saline did not increase TBUT. However, 3% diquafosol significantly increased TBUT for up to 15 min after application. At every time point, the TBUT increased more significantly from baseline in the diquafosol group than it did in the saline group. In the second study, 0.1% hyaluronate increased TBUT for up to 5 min after application, while 3% diquafosol increased TBUT for up to 15 min. Although the TBUT changes after 5 min were not significantly different between the 2 groups, the TBUT changes at 10, 15, and 20 min were significantly greater in the 3% diquafosol group than they were in the 0.1% hyaluronic acid group (+1.58 +/- 0.82 vs. +0.53 +/- 1.36 at 10 min, +0.67 +/ 0.91 vs. -0.04 +/- 1.29 at 15 min, and -0.06 +/- 0.96 vs. -0.59 +/- 0.90, diquafosol group vs. hyaluronic acid group). CONCLUSIONS: One drop of 3% diquafosol increased TBUT for up to 15 min after application. The immediate effect of 3% diquafosol on TBUT was greater than that of saline and even that of 1% hyaluronate ophthalmic solution. PMID- 26630618 TI - Meal patterning in the treatment of bulimia nervosa. AB - OBJECTIVE: This study examined the relationship between changes in meal and snack consumption and eating disorder behaviors in a treatment sample of bulimic adults. METHOD: Eighty adults with bulimia nervosa (BN) were randomized to one of two treatments. Meal and snack consumption, binge eating frequency, and purging behavior frequency were assessed at baseline, end-of-treatment, and at four month follow-up using the Eating Disorder Examination (EDE). RESULTS: Generalized linear models indicated that increased consumption of evening meals over the course of treatment was related to a significant decrease in the rate of binge eating and purging at four month follow-up; these results remained significant when controlling for changes in depression over the course of treatment. CONCLUSIONS: The findings support the importance of focusing efforts on developing a pattern of regular evening meal consumption among individuals in the treatment of BN. PMID- 26630619 TI - Following the Trail From Genotype to Phenotypes. PMID- 26630620 TI - The in vitro respiratory toxicity of cristobalite-bearing volcanic ash. AB - Ash from dome-forming volcanoes poses a unique hazard to millions of people worldwide due to an abundance of respirable cristobalite, a crystalline silica polymorph. Crystalline silica is an established respiratory hazard in other mixed dusts, but its toxicity strongly depends on sample provenance. Previous studies suggest that cristobalite-bearing volcanic ash is not as bio-reactive as may be expected for a dust containing crystalline silica. We systematically address the hazard posed by volcanic cristobalite by analysing a range of dome-related ash samples, and interpret the crystalline silica hazard according to the mineralogical nature of volcanic cristobalite. Samples are sourced from five well characterized dome-forming volcanoes that span a range of magmatic compositions, specifically selecting samples rich in cristobalite (up to 16wt%). Isolated respirable fractions are used to investigate the in vitro response of THP-1 macrophages and A549 type II epithelial cells in cytotoxicity, cellular stress, and pro-inflammatory assays associated with crystalline silica toxicity. Dome related ash is minimally reactive in vitro for a range of source compositions and cristobalite contents. Cristobalite-based toxicity is not evident in the assays employed, supporting the notion that crystalline silica provenance influences reactivity. Macrophages experienced minimal ash-induced cytotoxicity and intracellular reduction of glutathione; however, production of IL-1beta, IL-6 and IL-8 were sample-dependent. Lung epithelial cells experienced moderate apoptosis, sample-dependent reduction of glutathione, and minimal cytokine production. We suggest that protracted interaction between particles and epithelial cells may never arise due to effective clearance by macrophages. However, volcanic ash has the propensity to incite a low, but significant, and sample-dependent response; the effect of this response in vivo is unknown and prolonged exposure may yet pose a hazard. PMID- 26630621 TI - Intracranial hemorrhage with target specific oral anticoagulants in patients with atrial fibrillation: An updated meta-analysis of randomized controlled trials. PMID- 26630622 TI - Optimization of Stentys Xposition S self-apposing sirolimus eluting stent expansion and apposition with coronary lesion debulking strategy utilizing cutting balloon. PMID- 26630623 TI - Prosthesis choice for transcatheter aortic valve replacement: Improved outcomes with the adoption of a patient-specific transcatheter heart valve selection algorithm. PMID- 26630624 TI - Ventricular arrhythmias as an autoimmune disorder? PMID- 26630625 TI - Reply to letter "Prognostic value of computed tomography based SYNTAX score in coronary artery disease". PMID- 26630626 TI - Atrial fibrillation and long-term prognosis of patients with stable coronary heart disease: Relevance of routine electrocardiogram. PMID- 26630627 TI - Under-developed bronchial arteries as a risk factor for complications in balloon pulmonary angioplasty. PMID- 26630628 TI - Fulminant eosinophilic myocarditis following ICD implantation in a patient with undisclosed nickel allergy. PMID- 26630629 TI - Thinking beyond borders. Infective myocarditis on top of MELAS-cardiomyopathy first case description. PMID- 26630630 TI - Apnea-hypopnea and desaturations in heart failure with reduced ejection fraction: Are we aiming at the right target? AB - BACKGROUND: Sleep disordered breathing (SDB) is common in patients with heart failure with reduced ejection fraction (HFrEF). An increased apnea-hypopnea index (AHI) is associated with poor outcomes. We examined whether an analysis of nocturnal desaturations (NDs) can improve the risk stratification. METHODS: Three hundred seventy-six consecutive patients with stable chronic HFrEF and LVEF <= 45% were prospectively screened using polygraphy. Sleep apnea (SA) was defined as an AHI >= 15. The mean age was 59 +/- 13 years, the mean LVEF was 30 +/- 6%, and the median AHI was 18 [IQR: 9.33). The composite end-point of death, heart transplantation or LV assistance occurred in 98 patients (26%) within 3 years. Minimal oxygen saturation (MOS) during sleep, the number of desaturations <90%/h and the time spent with oxygen saturation <90% were significantly associated with adverse events (adjusted HR 1.25 [1.03-1.52], 1.25 [1.03-1.53], and 1.28 [1.04 1.59]), whereas the AHI was not (1.10 [0.86-1.39]). The best MOS cut-off value for poor outcomes was <= 88%. The patients with an MOS <= 88% had a significantly higher event rate (31.9%) than those with an MOS >88% (15.6%; p<0.01). The risk assessment using an MOS of <= 88% in addition to established prognostic markers yielded a net reclassification index (NRI) of nearly 6% and was particularly useful in the subgroup of patients with events (NRI: 8.4%). CONCLUSIONS: In HFrEF patients, ND <= 88% appears to be predictive of adverse events, independent of the presence of SA. This suggests that the risk assessment in HFrEF should also include ND in top of AHI. PMID- 26630631 TI - Sudden deaths during the largest community running event in Australia: A 25-year review. PMID- 26630632 TI - Impact of intracoronary adenosine administration during primary PCI: A meta analysis. AB - BACKGROUND: Aim of the present study was to evaluate all randomized trials, comparing intracoronary adenosine versus placebo in STEMI patients undergoing primary PCI. METHODS AND RESULTS: PubMed, the Cochrane Library and ISI Web of Knowledge electronic databases were scanned for eligible studies up to February 23rd 2015. The summary measure used was risk ratio (RR) with 95% confidence intervals. A total of 13 studies were eligible, including 1487 patients. Incidence of ST resolution was significantly higher in the IC adenosine group than in the placebo group (RR = 1.20 [1.05-1.38]; p = 0.008). At metaregression, a significant correlation was found between the magnitude of the adenosine related effect on ST resolution and the mean ischemic time (p = 0.011) or the percentage of patients with the LAD as the infarct-related artery (p = 0.03). Furthermore, we found a larger increase in LVEF (p = 0.02) with a parallel reduction in the incidence of heart failure (HF) (RR = 0.50 [0.28-0.89]; p = 0.02) in the IC adenosine group. Finally, IC adenosine administration was associated with a significantly lower incidence of major adverse cardiac events (MACE) both at short- (RR = 0.62 [0.39-0.98] p = 0.04) and long-term (RR = 0.61 [0.39-0.95] p = 0.03). CONCLUSIONS: This is the first meta-analysis demonstrating a clinical benefit for IC adenosine in hard endpoints, such as adverse cardiovascular events, in patients undergoing primary PCI. PMID- 26630633 TI - [Not Available]. PMID- 26630634 TI - Preparing the oral health workforce to effectively address public health challenges. PMID- 26630635 TI - Developing a flexible core Dental Public Health curriculum for predoctoral dental and dental hygiene schools. AB - OBJECTIVE: The curriculum for graduating dental and dental hygiene students must prepare them to contribute to the improvement or maintenance of health for individual patient's and the public's health. The objective is to describe the background for and the process used to develop a core Dental Public Health Curriculum for such students. METHODS: The process used was to solicit and review existing dental public health curriculum in dental and dental hygiene schools; review curriculum for other health professionals; identify the themes needed to frame the curriculum; select usable materials and identify gaps in existing curricular materials; and develop appropriate curriculum materials that would embody the competencies developed for undergraduate dental and dental hygiene education. RESULTS: Twenty-three topics were identified as embodying the eight competencies. Based on these topics, six courses, Principles of Dental Public Health, Evidence-Based Dentistry, Ethics and Dental Public Health, Dental Public Health Policy and Advocacy, Oral Health Promotion and Disease Prevention, and Oral Health Literacy and Dental Public Health, were prepared. Each course includes syllabus, PowerPoint presentations, student assignments and activities, instructor guide, and classroom discussion points. Depending on the hours available in the existing curriculum at the dental or hygiene school, lecture presentations and take home assignments/discussions may be used independently or in combination with presentations from other courses. In addition, individual discussions and activities may be used to integrate dental public health materials into other courses. CONCLUSION: A flexible curriculum is available at the AAPHD website to enable the incorporation of DPH topics into the curriculum. PMID- 26630636 TI - Pilot testing a predoctoral dental public health curriculum: reporting process and outcomes. AB - OBJECTIVES: The purpose of this study was to pilot test the predoctoral dental public health (DPH) curriculum developed by the American Association of Public Health Dentistry (AAPHD) in various US dental schools and dental hygiene programs. METHODS: Following the Lewy's theoretical framework, we used all three curriculum tryout methods (laboratory tryout, pilot tryout, and field tryout) for the pilot testing process. Open-ended questions on the structure, presentation, and content of the curriculum were sent to faculty pilot testing the DPH curriculum to obtain critical feedback and comments. RESULTS: Between Summer 2013 and Spring 2015, the curriculum was pilot tested in nine dental schools and seven dental hygiene programs with over 1,300 students. The majority of the comments from the faculty were favorable. Positive comments about the structure of the curriculum focused on the well-organized nature of the curriculum, the value of the instructor guide and speaker notes, rubrics, and the flow of the presentations. In terms of the content, faculty commented on the wide range of public health issues covered and the clarity of course and lecture objectives. Negative comments dealt with the level of detail, some confusing assignments, and outdated data. Problems identified in pilot testing were corrected in the final DPH curriculum. CONCLUSIONS: The curriculum was successfully utilized in varied formats and well received. Through AAPHD, this standardized DPH core curriculum is now available for widespread use at dental schools and dental hygiene programs. PMID- 26630637 TI - Establishing a speaker's bureau to teach dental public health curriculum in predoctoral dental and dental hygiene programs. AB - The opening of new dental schools and dental hygiene programs in the past decade has further exacerbated the shortage of faculty, including those with dental public health (DPH) expertise to teach. Therefore, one of the aims for the American Association of Public Health Dentistry's (AAPHD) Predoctoral Dental Public Health Competencies and Curriculum Project (Project), to develop DPH competencies and curriculum, was to establish a speakers bureau of interested dental professionals to teach the curriculum in dental schools and dental hygiene programs at the predoctoral level. This paper describes the process for establishing a speakers bureau including identifying and training individuals to teach the developed DPH curriculum. The speakers bureau and its availability were promoted through the AAPHD website and through letters to deans of dental schools and directors of dental hygiene programs. PMID- 26630638 TI - Role of AAPHD in the dissemination of the public health dentistry competencies and curriculum for dental and dental hygiene students. PMID- 26630639 TI - Developing core dental public health competencies for predoctoral dental and dental hygiene students. AB - Dental professionals are an "underutilized" workforce, when it comes to advocating for prevention and wellness in populations. The goal of this HRSA funded project is to develop dental public health (DPH) competencies and curriculum for US predoctoral dental and dental hygiene programs. These competencies and accompanying curriculum are designed to better prepare the oral health workforce to meet the needs of the entire population, including the chronically underserved, those challenged by poor health literacy, or communities encountering barriers to accessing oral health care. By increasing the DPH competency of all graduating dental providers, in population-based approaches to preventing oral diseases rather than the existing exclusive focus on treatment, the number of providers who can respond to a population or the public's unmet needs and challenges, both in private practices and publicly supported clinics, will increase. This paper describes the competency development process and the eight competencies that were identified. PMID- 26630640 TI - Engineered Asymmetric Composite Membranes with Rectifying Properties. AB - Asymmetric composite membranes with rectifying properties are developed by grafting pH-stimulus-responsive materials onto the top layer of the composite structure, which is prepared by two novel block copolymers using a phase separation technique. This engineered asymmetric composite membrane shows potential applications in sensors, filtration, and nanofluidic devices. PMID- 26630641 TI - Gender-Related and Age-Related Differences in Implantable Defibrillator Recipients: Results From the Pacemaker and Implantable Defibrillator Leads Survival Study ("PAIDLESS"). AB - OBJECTIVES: The purpose of this study was to investigate the influences of gender and age on defibrillator lead failure and patient mortality. BACKGROUND: The specific influences of gender and age on defibrillator lead failure have not previously been investigated. METHODS: This study analyzed the differences in gender and age in relation to defibrillator lead failure and mortality of patients in the Pacemaker and Implantable Defibrillator Leads Survival Study ("PAIDLESS"). PAIDLESS includes all patients at Winthrop University Hospital who underwent defibrillator lead implantation between February 1, 1996 and December 31, 2011. Male and female patients were compared within each age decile, beginning at 15 years old, to analyze lead failure and patient mortality. Statistical analyses were performed using Wilcoxon rank-sum test, Fisher's exact test, Kaplan-Meier analysis, and multivariable Cox regression models. P<.05 was considered statistically significant. No correction for multiple comparisons was performed for the subgroup analyses. RESULTS: A total of 3802 patients (2812 men and 990 women) were included in the analysis. The mean age was 70 +/- 13 years (range, 15-94 years). Kaplan-Meier analysis found that between 45 and 54 years of age, leads implanted in women failed significantly faster than in men (P=.03). Multivariable Cox regression models were built to validate this finding, and they confirmed that male gender was an independent protective factor of lead failure in the 45 to 54 years group (for male gender: HR, 0.37; 95% confidence interval, 0.14-0.96; P=.04). Lead survival time for women in this age group was 13.4 years (standard error, 0.6), while leads implanted in men of this age group survived 14.7 years (standard error, 0.3). Although there were significant differences in lead failure, no differences in mortality between the genders were found for any ages or within each decile. CONCLUSIONS: This study is the first to compare defibrillator lead failure and patient mortality in relation to gender and age deciles at a single large implanting center. Within the 45 to 54 years group, leads implanted in women failed faster than in men. Male gender was found to be an independent protective factor in lead survival. This study emphasizes the complex interplay between gender and age with respect to implantable defibrillator lead failure and mortality. PMID- 26630642 TI - Outcomes of Patients Undergoing Balloon Aortic Valvuloplasty in the TAVI Era: A Multicenter Registry. AB - BACKGROUND: Few clinical data about indications and prognoses of patients undergoing balloon aortic valvuloplasty (BAV) in the transcatheter aortic valve implantation (TAVI) era have been reported. METHODS: Data from all consecutive patients undergoing BAV in seven European centers from 2006 to 2013 were collected. Acute results and long-term outcomes were assessed. RESULTS: A total of 811 patients aged 82 +/- 9 years were included; 416 patients (51%) underwent BAV as palliative destination therapy, 320 patients (40%) as bridge to TAVI, and 75 patients (9%) as bridge to surgical aortic valve replacement (SAVR). Patients undergoing BAV as destination therapy had a higher risk profile (logistic EuroSCORE, 20 +/- 17 vs 22 +/- 14 vs 11 +/- 8, respectively; P<.001). Post procedure, peak gradient decreased from 87 +/- 22 mm Hg to 66 +/- 22 mm Hg (P<.001) and aortic valve area increased from 0.61 +/- 0.2 cm2 to 0.8 +/- 0.2 cm2 (P<.001). At 30 days, the all-cause death rate (6.5% vs 6.2% vs 7.4%, respectively; P=.56) and the rate of life-threatening and major bleedings (8.0% vs 5.7% vs 6.0%, respectively) did not differ between groups. After a mean follow up of 318 days (range, 116-500 days), rates of all-cause death were similar (30% vs 34% vs 31%, respectively; P>.99), although patients undergoing BAV as bridge to SAVR showed a lower cardiovascular death rate (11% vs 11% vs 3%, respectively; P=.04). CONCLUSION: In the TAVI era, BAV may represent a reasonable option for patients with severe aortic stenosis and temporary contraindications to definite therapy. Given the mortality rates at 30 days, patients should be carefully selected, while events at follow-up are deeply influenced by the decision of whether or not subsequent interventions are performed. PMID- 26630643 TI - Effect of Extended-Release Niacin on Carotid Intima Media Thickness, Reactive Hyperemia, and Endothelial Progenitor Cell Mobilization: Insights From the Atherosclerosis Lesion Progression Intervention Using Niacin Extended Release in Saphenous Vein Grafts (ALPINE-SVG) Pilot Trial. AB - BACKGROUND: Thirty-eight patients with intermediate (30%-60% diameter stenosis) saphenous vein graft lesions were randomized to extended-release niacin (ER niacin) or placebo for 12 months. We sought to evaluate the impact of ER-niacin on carotid intima media thickness (CIMT), endothelial function, and endothelial progenitor cell (EPC) mobilization. METHODS: Carotid B-mode ultrasound was used to image the common and internal carotid arteries, at baseline and at 12 months after enrollment. Reactive hyperemia peripheral arterial tonometry, as assessed with EndoPAT 2000 (Itamar Medical, Inc) and EPC mobilization assessed with flow cytometry, were measured at enrollment, and at 1 and 12 months. RESULTS: The baseline clinical characteristics were similar in the two study groups. High density lipoprotein cholesterol levels tended to increase more in the ER-niacin group (5.9 +/- 8.7 mg/dL vs 1.4 +/- 7.1 mg/dL; P=.14). Between baseline and 12 months, right common carotid artery (0.96 +/- 0.44 mm vs 0.70 +/- 0.24 mm; P=.04), and left common carotid artery (0.80 +/- 0.30 mm vs 0.70 +/- 0.20 mm; P=.08) CIMT tended to decrease in the ER-niacin group, compared with no change in the placebo group. The change in logarithmic reactive hyperemia index between 1 month and 12 months was similar in patients receiving ER-niacin vs placebo (0.003 +/- 0.12 vs -0.058 +/- 0.12; P=.39), whereas EPC mobilization increased in the ER niacin group and decreased in the placebo group (8.65 +/- 28.41 vs -5.87 +/- 30.23 EPC colony forming units/mL of peripheral blood; P=.02). CONCLUSIONS: ER niacin did not have a significant impact on CIMT or endothelial function, but increased EPC mobilization. PMID- 26630644 TI - Percutaneous Closure of Intracardiac Defects in Adults: State of the Art. AB - The number of adults with congenital heart disease is expected to increase over the next decade. Although acquired defects are being increasingly recognized in adults, congenital heart disease remains the most common etiology. With advances in cardiac imaging, device technology, and transcatheter techniques, percutaneous closure is now feasible and safe for most intracardiac defects. Device closure is considered the first-line therapy for a variety of congenital intracardiac defects, including ostium secundum atrial septal defects and muscular ventricular septal defects. Percutaneous closure may prevent recurrent cerebrovascular events after a cryptogenic stroke in high-risk patients with patent foramen ovale. It is also an alternative therapeutic option for patients with acquired defects such as posttraumatic or postinfarction ventricular septal defects and paravalvular regurgitation associated with prosthetic valves. Complications after device closure are uncommon, and may be avoided with appropriate patient and device selection. This is a comprehensive review of the current transcatheter management of the most common intracardiac defects encountered in the adult population. PMID- 26630645 TI - Repeated Aortic Balloon Valvuloplasty in Elderly Patients With Aortic Stenosis Who Are Not Candidates for Definitive Treatment. PMID- 26630646 TI - Impact of Aging on Radial Spasm During Coronary Catheterization. AB - AIMS: To assess the impact of aging on the incidence and severity of radial spasm during coronary catheterization. BACKGROUND: One of the main predictors for transradial approach failure during coronary catheterization is the occurrence of radial spasm. Although it has been suggested that radial spasm might be more common in old patients, the role of confounding factors in older populations and the intuitive thinking that younger patients are more prone to spasm render this debate still active. METHODS: This was a transversal study, which prospectively included consecutive patients referred to our center for elective coronary catheterization during a 6-month period. RESULTS: A total of 190 patients were included. The mean age was 67.9 +/- 3.6 years and 130 (68%) were males. Overall, 32 (16.8%) presented with radial spasm. Patients with radial spasm were younger (64.8 +/- 12.1 years vs 69.6 +/- 12.6 years; P=.04). In the quartile analysis, the largest difference was observed between patients <=61 years and those >80 years, who presented with a rate of spasm of 25.6% and 9.1%, respectively (P=.04). Multivariable analysis showed that the age of patients was inversely related to the occurrence of radial spasm, decreasing 3% with every additional year (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.94-0.99), and the number of catheters, increasing around 50% with every additional used catheter (OR, 1.54; 95% CI, 1.07-2.23). CONCLUSION: The main finding of the present paper is the inverse association between aging and radial spasm. The present study suggests the need to intensify preventive measures in young patients in order to reduce the incidence of radial spasm. PMID- 26630647 TI - Hemodynamic Assessment of Severe Aortic Stenosis via Transradial Approach is Safe. AB - BACKGROUND: Patients with a discrepancy between clinical presentation and echocardiographic severity of aortic stenosis require invasive hemodynamic assessment. The comparative safety and feasibility of transradial cardiac catheterization in comparison with the traditional transfemoral approach in this usually complex subset of patients is not known. We sought to evaluate the safety, feasibility, and time to cross severely stenosed aortic valves via radial approach. METHODS: All patients who were successfully assessed for aortic stenosis with a dual-lumen catheter and found to have severe aortic stenosis (calculated aortic valve area <1.0 cm2) in the last 2 years at our institution were retrospectively evaluated. Demographic, clinical, and procedural data were compared between the TF group (femoral arterial and venous access) and TR group (radial artery and basilic or cephalic vein access). RESULTS: A total of 176 patients underwent left and right heart catheterization using femoral access, while 58 patients had their procedures performed via radial artery and arm vein access. Fluoroscopy time was comparable between TR and TF groups (14.97 +/- 4.6 minutes vs 12.90 +/- 3.9 minutes, respectively; P=.23), as was the time to cross the aortic valve (132 +/- 209 seconds vs 128 +/- 226 seconds, respectively; P=.39). Incidence of cerebrovascular events was not different between the two groups (2.3% vs 1.75%, respectively; P=.14). Access-site complications were significantly higher in the TF group vs the TR group (5.11% vs 0%, respectively; P<.01). CONCLUSION: Transradial retrograde crossing of severely stenosed aortic valve is feasible using ordinary equipment, with reduced access-site related complications. PMID- 26630648 TI - Mycobacterium ulcerans in the Elderly: More Severe Disease and Suboptimal Outcomes. AB - BACKGROUND: The clinical presentation of M. ulcerans disease and the safety and effectiveness of treatment may differ in elderly compared with younger populations related to relative immune defficiencies, co-morbidities and drug interactions. However, elderly populations with M. ulcerans disease have not been comprehensively studied. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective analysis was performed on an observational cohort of all confirmed M. ulcerans cases managed at Barwon Health from 1/1/1998-31/12/2014. The cohort included 327 patients; 131(40.0%) >=65 years and 196(60.0%) <65 years of age. Patients >=65 years had a shorter median duration of symptoms prior to diagnosis (p<0.01), a higher proportion with diabetes (p<0.001) and immune suppression (p<0.001), and were more likely to have lesions that were multiple (OR 4.67, 95% CI 1.78-12.31, p<0.001) and WHO category 3 (OR 4.59, 95% CI 1.98-10.59, p<0.001). Antibiotic complications occurred in 69(24.3%) treatment episodes at an increased incidence in those aged >=65 years (OR 5.29, 95% CI 2.81-9.98, p<0.001). There were 4(1.2%) deaths, with significantly more in the age-group >=65 years (4 compared with 0 deaths, p = 0.01). The overall treatment success rate was 92.2%. For the age group >=65 years there was a reduced rate of treatment success overall (OR 0.34, 95% CI 0.14-0.80, p = <0.01) and when surgery was used alone (OR 0.21, 95% CI 0.06-0.76, p<0.01). Patients >=65 years were more likely to have a paradoxical reaction (OR 2.06, 95% CI 1.17-3.62, p = 0.01). CONCLUSIONS/SIGNIFICANCE: Elderly patients comprise a significant proportion of M. ulcerans disease patients in Australian populations and present with more severe and advanced disease forms. Currently recommended treatments are associated with increased toxicity and reduced effectiveness in elderly populations. Increased efforts are required to diagnose M. ulcerans earlier in elderly populations, and research is urgently required to develop more effective and less toxic treatments for this age-group. PMID- 26630649 TI - Selective Cross-Electrophile Coupling by Dual Catalysis. AB - Palladium and nickel: This Highlight summarizes recent developments in the area of dual-catalytic Ullman-type coupling reactions of aryl bromides and triflates: Weix and co-workers took advantage of the different selectivities and stabilities of palladium and nickel catalysts to favor the desired cross-coupling and suppress homocoupling. PMID- 26630650 TI - Isolation, N-glycosylations and Function of a Hyaluronidase-Like Enzyme from the Venom of the Spider Cupiennius salei. AB - STRUCTURE OF CUPIENNIUS SALEI VENOM HYALURONIDASE: Hyaluronidases are important venom components acting as spreading factor of toxic compounds. In several studies this spreading effect was tested on vertebrate tissue. However, data about the spreading activity on invertebrates, the main prey organisms of spiders, are lacking. Here, a hyaluronidase-like enzyme was isolated from the venom of the spider Cupiennius salei. The amino acid sequence of the enzyme was determined by cDNA analysis of the venom gland transcriptome and confirmed by protein analysis. Two complex N-linked glycans akin to honey bee hyaluronidase glycosylations, were identified by tandem mass spectrometry. A C-terminal EGF like domain was identified in spider hyaluronidase using InterPro. The spider hyaluronidase-like enzyme showed maximal activity at acidic pH, between 40-60 degrees C, and 0.2 M KCl. Divalent ions did not enhance HA degradation activity, indicating that they are not recruited for catalysis. FUNCTION OF VENOM HYALURONIDASES: Besides hyaluronan, the enzyme degrades chondroitin sulfate A, whereas heparan sulfate and dermatan sulfate are not affected. The end products of hyaluronan degradation are tetramers, whereas chondroitin sulfate A is mainly degraded to hexamers. Identification of terminal N-acetylglucosamine or N acetylgalactosamine at the reducing end of the oligomers identified the enzyme as an endo-beta-N-acetyl-D-hexosaminidase hydrolase. The spreading effect of the hyaluronidase-like enzyme on invertebrate tissue was studied by coinjection of the enzyme with the Cupiennius salei main neurotoxin CsTx-1 into Drosophila flies. The enzyme significantly enhances the neurotoxic activity of CsTx-1. Comparative substrate degradation tests with hyaluronan, chondroitin sulfate A, dermatan sulfate, and heparan sulfate with venoms from 39 spider species from 21 families identified some spider families (Atypidae, Eresidae, Araneidae and Nephilidae) without activity of hyaluronidase-like enzymes. This is interpreted as a loss of this enzyme and fits quite well the current phylogenetic idea on a more isolated position of these families and can perhaps be explained by specialized prey catching techniques. PMID- 26630651 TI - Phylogenetic Reconstruction, Morphological Diversification and Generic Delimitation of Disepalum (Annonaceae). AB - Taxonomic delimitation of Disepalum (Annonaceae) is contentious, with some researchers favoring a narrow circumscription following segregation of the genus Enicosanthellum. We reconstruct the phylogeny of Disepalum and related taxa based on four chloroplast and two nuclear DNA regions as a framework for clarifying taxonomic delimitation and assessing evolutionary transitions in key morphological characters. Maximum parsimony, maximum likelihood and Bayesian methods resulted in a consistent, well-resolved and strongly supported topology. Disepalum s.l. is monophyletic and strongly supported, with Disepalum s.str. and Enicosanthellum retrieved as sister groups. Although this topology is consistent with both taxonomic delimitations, the distribution of morphological synapomorphies provides greater support for the inclusion of Enicosanthellum within Disepalum s.l. We propose a novel infrageneric classification with two subgenera. Subgen. Disepalum (= Disepalum s.str.) is supported by numerous synapomorphies, including the reduction of the calyx to two sepals and connation of petals. Subgen. Enicosanthellum lacks obvious morphological synapomorphies, but possesses several diagnostic characters (symplesiomorphies), including a trimerous calyx and free petals in two whorls. We evaluate changes in petal morphology in relation to hypotheses of the genetic control of floral development and suggest that the compression of two petal whorls into one and the associated fusion of contiguous petals may be associated with the loss of the pollination chamber, which in turn may be associated with a shift in primary pollinator. We also suggest that the formation of pollen octads may be selectively advantageous when pollinator visits are infrequent, although this would only be applicable if multiple ovules could be fertilized by each octad; since the flowers are apocarpous, this would require an extragynoecial compitum to enable intercarpellary growth of pollen tubes. We furthermore infer that the monocarp fruit stalks are likely to have evolved independently from those in other Annonaceae genera and may facilitate effective dispersal by providing a color contrast within the fruit. PMID- 26630654 TI - Retrospective Analysis of Therapeutic Drug Monitoring Data for Treatment of Bipolar Disorder with Lamotrigine. PMID- 26630653 TI - Disparities between Ophthalmologists and Patients in Estimating Quality of Life Associated with Diabetic Retinopathy. AB - BACKGROUND: This study aimed to evaluate and compare the utility values associated with diabetic retinopathy (DR) in a sample of Chinese patients and ophthalmologists. METHODS: Utility values were evaluated by both the time trade off (TTO) and rating scale (RS) methods for 109 eligible patients with DR and 2 experienced ophthalmologists. Patients were stratified by Snellen best-corrected visual acuity (BCVA) in the better-seeing eye. The correlations between the utility values and general vision-related health status measures were analyzed. These utility values were compared with data from two other studies. RESULTS: The mean utility values elicited from the patients themselves with the TTO (0.81; SD 0.10) and RS (0.81; SD 0.11) methods were both statistically lower than the mean utility values assessed by ophthalmologists. Significant predictors of patients' TTO and RS utility values were both LogMAR BCVA in the affected eye and average weighted LogMAR BCVA. DR grade and duration of visual dysfunction were also variables that significantly predicted patients' TTO utility values. For ophthalmologists, patients' LogMAR BCVA in the affected eye and in the better eye were the variables that significantly predicted both the TTO and RS utility values. Patients' education level was also a variable that significantly predicted RS utility values. Moreover, both diabetic macular edema and employment status were significant predictors of TTO and RS utility values, whether from patients or ophthalmologists. There was no difference in mean TTO utility values compared to our American and Canadian patients. CONCLUSIONS: DR caused a substantial decrease in Chinese patients' utility values, and ophthalmologists substantially underestimated its effect on patient quality of life. PMID- 26630655 TI - Continuous and caring support right now. PMID- 26630652 TI - Combination of a Selective HSP90alpha/beta Inhibitor and a RAS-RAF-MEK-ERK Signaling Pathway Inhibitor Triggers Synergistic Cytotoxicity in Multiple Myeloma Cells. AB - Heat shock protein (HSP)90 inhibitors have shown significant anti-tumor activities in preclinical settings in both solid and hematological tumors. We previously reported that the novel, orally available HSP90alpha/beta inhibitor TAS-116 shows significant anti-MM activities. In this study, we further examined the combination effect of TAS-116 with a RAS-RAF-MEK-ERK signaling pathway inhibitor in RAS- or BRAF-mutated MM cell lines. TAS-116 monotherapy significantly inhibited growth of RAS-mutated MM cell lines and was associated with decreased expression of downstream target proteins of the RAS-RAF-MEK-ERK signaling pathway. Moreover, TAS-116 showed synergistic growth inhibitory effects with the farnesyltransferase inhibitor tipifarnib, the BRAF inhibitor dabrafenib, and the MEK inhibitor selumetinib. Importantly, treatment with these inhibitors paradoxically enhanced p-C-Raf, p-MEK, and p-ERK activity, which was abrogated by TAS-116. TAS-116 also enhanced dabrafenib-induced MM cytotoxicity associated with mitochondrial damage-induced apoptosis, even in the BRAF-mutated U266 MM cell line. This enhanced apoptosis in RAS-mutated MM triggered by combination treatment was observed even in the presence of bone marrow stromal cells. Taken together, our results provide the rationale for novel combination treatment with HSP90alpha/beta inhibitor and RAS-RAF-MEK-ERK signaling pathway inhibitors to improve outcomes in patients with in RAS- or BRAF-mutated MM. PMID- 26630656 TI - Suture Repair of Simple Transverse Olecranon Fractures and Chevron Olecranon Osteotomy. AB - Tension band wiring of simple transverse olecranon fractures results in a high reoperation rate due to hardware problems. A technique using high-strength braided polyester and polyethylene suture through a bone tunnel has been piloted. This technique is suitable for simple transverse olecranon fractures or olecranon osteotomy with stability of the ulnohumeral articulation. A transverse drill hole was made in the ulna with a 2.5-mm drill. Fracture fixation was achieved using 2 braided synthetic sutures passed through the bone tunnel and grasping the insertion of the triceps tendon. The outcome measures used were Oxford Elbow score and QuickDASH score. Ten consecutive patients with a mean age of 47 years (range, 18 to 88 y) were included. The mean follow-up was 19 months (range, 14 to 30 mo). All fractures were clinically and radiographically united by 6 weeks. One malunion occurred. The mean Oxford score was 41 (20 to 48). The mean QuickDASH Score was 9 (0 to 20). This technique provides a safe and reliable alternative to conventional tension band wiring with no reoperations required in a pilot series. PMID- 26630658 TI - Interaction between Depth Order and Density Affects Vection and Postural Sway. AB - OBJECTIVE: Vection, a feeling of self-motion while being physically stationary, and postural sway can be modulated by various visual factors. Moreover, vection and postural sway are often found to be closely related when modulated by such visual factors, suggesting a common neural mechanism. One well-known visual factor is the depth order of the stimulus. The density, i.e. number of objects per unit area, is proposed to interact with the depth order in the modulation of vection and postural sway, which has only been studied to a limited degree. METHODS: We therefore exposed 17 participants to 18 different stimuli containing a stationary pattern and a pattern rotating around the naso-occipital axis. The density of both patterns was varied between 10 and 90%; the densities combined always added up to 100%. The rotating pattern occluded or was occluded by the stationary pattern, suggesting foreground or background motion, respectively. During pattern rotation participants reported vection by pressing a button, and postural sway was recorded using a force plate. RESULTS: Participants always reported more vection and swayed significantly more when rotation was perceived in the background and when the rotating pattern increased in density. As hypothesized, we found that the perceived depth order interacted with pattern density. A pattern rotating in the background with a density between 60 and 80% caused significantly more vection and postural sway than when it was perceived to rotate in the foreground. CONCLUSIONS: The findings suggest that the ratio between fore- and background pattern densities is an important factor in the interaction with the depth order, and it is not the density of rotating pattern per se. Moreover, the observation that vection and postural sway were modulated in a similar way points towards a common neural origin regulating both variables. PMID- 26630659 TI - Surgery for Stage IV Breast Cancer: Domestic and International Disparities. PMID- 26630657 TI - Utilizing CMP-Sialic Acid Analogs to Unravel Neisseria gonorrhoeae Lipooligosaccharide-Mediated Complement Resistance and Design Novel Therapeutics. AB - Neisseria gonorrhoeae deploys a novel immune evasion strategy wherein the lacto-N neotetraose (LNnT) structure of lipooligosaccharide (LOS) is capped by the bacterial sialyltransferase, using host cytidine-5'-monophosphate (CMP)-activated forms of the nine-carbon nonulosonate (NulO) sugar N-acetyl-neuraminic acid (Neu5Ac), a sialic acid (Sia) abundant in humans. This allows evasion of complement-mediated killing by recruiting factor H (FH), an inhibitor of the alternative complement pathway, and by limiting classical pathway activation ("serum-resistance"). We utilized CMP salts of six additional natural or synthetic NulOs, Neu5Gc, Neu5Gc8Me, Neu5Ac9Ac, Neu5Ac9Az, legionaminic acid (Leg5Ac7Ac) and pseudaminic acid (Pse5Ac7Ac), to define structural requirements of Sia-mediated serum-resistance. While all NulOs except Pse5Ac7Ac were incorporated into the LNnT-LOS, only Neu5Gc incorporation yielded high-level serum-resistance and FH binding that was comparable to Neu5Ac, whereas Neu5Ac9Az and Leg5Ac7Ac incorporation left bacteria fully serum-sensitive and did not enhance FH binding. Neu5Ac9Ac and Neu5Gc8Me rendered bacteria resistant only to low serum concentrations. While serum-resistance mediated by Neu5Ac was associated with classical pathway inhibition (decreased IgG binding and C4 deposition), Leg5Ac7Ac and Neu5Ac9Az incorporation did not inhibit the classical pathway. Remarkably, CMP-Neu5Ac9Az and CMP-Leg5Ac7Ac each prevented serum resistance despite a 100-fold molar excess of CMP-Neu5Ac in growth media. The concomitant presence of Leg5Ac7Ac and Neu5Ac on LOS resulted in uninhibited classical pathway activation. Surprisingly, despite near-maximal FH binding in this instance, the alternative pathway was not regulated and factor Bb remained associated with bacteria. Intravaginal administration of CMP-Leg5Ac7Ac to BALB/c mice infected with gonorrhea (including a multidrug-resistant isolate) reduced clearance times and infection burden. Bacteria recovered from CMP-Leg5Ac7Ac treated mice were sensitive to human complement ex vivo, simulating in vitro findings. These data reveal critical roles for the Sia exocyclic side-chain in gonococcal serum-resistance. Such CMP-NulO analogs may provide a novel therapeutic strategy against the global threat of multidrug-resistant gonorrhea. PMID- 26630660 TI - Increased risk of melanoma in patients with chronic lymphocytic leukaemia: systematic review and meta-analysis of cohort studies. AB - An increased risk of melanoma has been variously reported in patients with chronic lymphocytic leukaemia (CLL), analogous with other immunosuppressed populations. To fully assess this association, we performed a systematic review and meta-analysis of available evidence from observational cohort studies. All such longitudinal studies of patients diagnosed with CLL that enabled quantitative assessment of the risk of melanoma compared with the general population were eligible. We identified seven studies from a search of all published literature to July 2014 in Medline, Embase and ISI science citation index databases. Data were pooled using a random-effects model. There was an almost four-fold increase in the risk of melanoma in patients with CLL compared with the general population (pooled standardized incidence ratio 3.88 [95% confidence interval (CI) 2.08-7.22]), although significant heterogeneity was evident among studies (I2=96.0%, P(het)<0.001). The risk of melanoma was higher for men with CLL (3.41; 95% CI 1.49-7.80) than women (2.61; 95% CI 1.13-6.01). CLL patients are at high risk of developing melanoma and the magnitude of the risk is higher than that found in other immunosuppressed populations. Our findings suggest that patients with CLL, as they are also at a higher risk of developing the more common skin cancers, would benefit from regular skin examinations. PMID- 26630661 TI - Serum adiponectin, insulin resistance, and uveal melanoma: clinicopathological correlations. AB - To investigate the status of insulin resistance, metabolic syndrome, dyslipidemia, and serum adiponectin levels in patients with uveal melanoma and choroidal nevus were investigated. Our study included 86 patients with uveal melanoma, 38 patients with choroidal nevus, and 86 controls. Uveal melanomas were classified as small, medium, and large on the basis of Collaborative Ocular Melanoma Study (COMS) criteria. Patients with uveal melanoma had significantly higher homeostatic model assessment scores compared with patients with choroidal nevus (P<0.001). Patients with uveal melanoma and choroidal nevus had significantly lower levels of serum adiponectin compared with controls (P<0.001). Patients with uveal melanoma who developed systemic metastases had significantly lower levels of serum adiponectin levels compared with patients with nonmetastases during follow-up (P=0.018). When the largest tumors (COMS III) were compared, ciliary body melanomas were associated with significantly lower levels of serum adiponectin than choroidal melanomas. In patients who were treated with enucleation, epitheloid predominant and mixed cell-type tumors were associated with lower levels of serum adiponectin compared with tumors with spindle cell type, but this did not reach statistical significance. By providing an antiapoptotic and proangiogenic environment, low serum adiponectin levels and insulin resistance may play a role in promoting the growth of uveal melanocytic tumors and may contribute toward a more aggressive clinical course, adversely affecting the prognosis. PMID- 26630662 TI - Inhibitors of Ras-SOS Interactions. AB - Activating Ras mutations are found in about 30 % of human cancers. Ras activation is regulated by guanine nucleotide exchange factors, such as the son of sevenless (SOS), which form protein-protein interactions (PPIs) with Ras and catalyze the exchange of GDP by GTP. This is the rate-limiting step in Ras activation. However, Ras surfaces lack any evident suitable pockets where a molecule might bind tightly, rendering Ras proteins still 'undruggable' for over 30 years. Among the alternative approaches is the design of inhibitors that target the Ras-SOS PPI interface, a strategy that is gaining increasing recognition for treating Ras mutant cancers. Herein we focus on data that has accumulated over the past few years pertaining to the design of small-molecule modulators or peptide mimetics aimed at the interface of the Ras-SOS PPI. We emphasize, however, that even if such Ras-SOS therapeutics are potent, drug resistance may emerge. To counteract this development, we propose "pathway drug cocktails", that is, drug combinations aimed at parallel (or compensatory) pathways. A repertoire of classified cancer, cell/tissue, and pathway/protein combinations would be beneficial toward this goal. PMID- 26630663 TI - Primary Tumor-Secreted Lymphangiogenic Factors Induce Pre-Metastatic Lymphvascular Niche Formation at Sentinel Lymph Nodes in Oral Squamous Cell Carcinoma. AB - OBJECTIVES: The objectives of this study were to evaluate the formation of lymphvascular niches in lymph nodes of patients with oral squamous cell carcinoma (OSCC), and investigate the roles of lymphangiogenic and angiogenic factors, such as vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D, expressed in the primary tumors. MATERIALS AND METHODS: Forty-four patients with previously untreated clinically late T2 or T3 OSCC of cN0 were evaluated for primary tumors and 166 sentinel lymph nodes (SLNs). Primary tumors were immunohistochemically analyzed for expressions of VEGFs. Densities of lymphatic vessels (LVDpodoplanin) and high endothelial venules (HEVD) in the SLNs were also calculated using antibodies for each marker, podoplanin and MECA-79, respectively. RESULTS: In 25 patients, all lymph nodes were metastasis-negative, whereas, in 19 patients, metastasis was positive for at least one lymph node (either at SLN, non-SLN, or nodal recurrence). From the analyses of 140 SLNs without metastasis, LVDpodoplanin in 50 SLNs of metastasis-positive cases was significantly higher than that in 90 SLNs of metastasis-negative cases (p = 0.0025). HEVD was not associated with lymph node metastasis. The patients with VEGF-A-High or VEGF-D High tumors had significantly higher LVDpodoplanin than patients with their Low counterparts (p = 0.0233 and p = 0.0209, respectively). In cases with lymph node metastasis, the VEGF-D-expression score was significantly higher than in those without lymph node metastasis (p = 0.0006). CONCLUSIONS: These results suggest that lymph node lymphangiogenesis occurs before metastasis in OSCC. VEGF-A and VEGF-D play critical roles in this process. VEGF-D is a potential predictive marker of positive lymph node metastasis in cN0 patients. PMID- 26630664 TI - Thinking about Death Reduces Delay Discounting. AB - The current study tested competing predictions regarding the effect of mortality salience on delay discounting. One prediction, based on evolutionary considerations, was that reminders of death increase the value of the present. Another prediction, based in part on construal level theory, was that reminders of death increase the value of the future. One-hundred eighteen participants thought about personal mortality or a control topic and then completed an inter temporal choice task pitting the chance to gain $50 now against increasingly attractive rewards three months later. Consistent with the hypothesis inspired by construal theory, participants in the mortality salience condition traded $50 now for $66.67 in three months, whereas participants in the dental pain salience condition required $72.84 in three months in lieu of $50 now. Thus, participants in the mortality salience condition discounted future monetary gains less than other participants, suggesting that thoughts of death may increase the subjective value of the future. PMID- 26630665 TI - Values-Based Measures of Impacts to Indigenous Health. AB - Values-based indicators of risks to Indigenous health have the potential to improve the accuracy and quality of a wide range of decisions affecting Native lands and cultures. Current health impact assessment approaches often omit important health priorities rooted in the history, social structures, and cultural context of Indigenous communities. Insights and methods from the decision sciences can be used to develop more culturally appropriate and context relevant health indicators that can articulate and track changes to important dimensions of Indigenous health. Identifying and addressing priority cultural, social, economic, and environmental contributors to the health of Indigenous communities will help to generate better project alternatives and foster more responsive choices. PMID- 26630666 TI - The Earliest Lead Object in the Levant. AB - In the deepest section of a large complex cave in the northern Negev desert, Israel, a bi-conical lead object was found logged onto a wooden shaft. Associated material remains and radiocarbon dating of the shaft place the object within the Late Chalcolithic period, at the late 5th millennium BCE. Based on chemical and lead isotope analysis, we show that this unique object was made of almost pure metallic lead, likely smelted from lead ores originating in the Taurus range in Anatolia. Either the finished object, or the raw material, was brought to the southern Levant, adding another major component to the already-rich Late Chalcolithic metallurgical corpus known to-date. The paper also discusses possible uses of the object, suggesting that it may have been used as a spindle whorl, at least towards its deposition. PMID- 26630667 TI - WITHDRAWN: Direct versus indirect veneer restorations for intrinsic dental stains. PMID- 26630668 TI - Development and Validation of the 34-Item Disability Screening Questionnaire (DSQ 34) for Use in Low and Middle Income Countries Epidemiological and Development Surveys. AB - BACKGROUND: Although 80% of persons with disabilities live in low and middle income countries, there is still a lack of comprehensive, cross-culturally validated tools to identify persons facing activity limitations and functioning difficulties in these settings. In absence of such a tool, disability estimates vary considerably according to the methodology used, and policies are based on unreliable estimates. METHODS AND FINDINGS: The Disability Screening Questionnaire composed of 27 items (DSQ-27) was initially designed by a group of international experts in survey development and disability in Afghanistan for a national survey. Items were selected based on major domains of activity limitations and functioning difficulties linked to an impairment as defined by the International Classification of Functioning, Disability and Health. Face, content and construct validity, as well as sensitivity and specificity were examined. Based on the results obtained, the tool was subsequently refined and expanded to 34 items, tested and validated in Darfur, Sudan. Internal consistency for the total DSQ-34 using a raw and standardized Cronbach's Alpha and within each domain using a standardized Cronbach's Alpha was examined in the Asian context (India and Nepal). Exploratory factor analysis (EFA) using principal axis factoring (PAF) evaluated the lowest number of factors to account for the common variance among the questions in the screen. Test-retest reliability was determined by calculating intraclass correlation (ICC) and inter-rater reliability by calculating the kappa statistic; results were checked using Bland Altman plots. The DSQ-34 was further tested for standard error of measurement (SEM) and for the minimum detectable change (MDC). Good internal consistency was indicated by Cronbach's Alpha of 0.83/0.82 for India and 0.76/0.78 for Nepal. We confirmed our assumption for EFA using the Kaiser-Meyer-Olkin measure of sampling well above the accepted cutoff of 0.40 for India (0.82) and Nepal (0.82). The criteria for Bartlett's test of sphericity were also met for both India (< .001) and Nepal (< .001). Estimates of reliability from the two countries reached acceptable levels of ICC of 0.75 (p<0.001) for India of 0.77 for Nepal (p<0.001) and good strength of agreement for weighted kappa (respectively 0.77 and 0.79). The SEM/MDC was 0.80/2.22 for India and 0.96/2.66 for Nepal indicating a smaller amount of measurement error in the screen. CONCLUSIONS: In Nepal and India, the DSQ-34 shows strong psychometric properties that indicate that it effectively discriminates between persons with and without disabilities. This instrument can be used in association with other instruments for the purpose of comparing health outcomes of persons with and without disabilities in LMICs. PMID- 26630669 TI - Updated Campylobacter jejuni Capsule PCR Multiplex Typing System and Its Application to Clinical Isolates from South and Southeast Asia. AB - Campylobacter jejuni produces a polysaccharide capsule that is the major determinant of the Penner serotyping scheme. This passive slide agglutination typing system was developed in the early 1980's and was recognized for over two decades as the gold standard for C. jejuni typing. A preliminary multiplex PCR technique covering 17 serotypes was previously developed in order to replace this classic serotyping scheme. Here we report the completion of the multiplex PCR technology that is able to identify all the 47 Penner serotypes types known for C. jejuni. The number of capsule types represented within the 47 serotypes is 35. We have applied this method to a collection of 996 clinical isolates from Thailand, Cambodia and Nepal and were able to successfully determine capsule types of 98% of these. PMID- 26630671 TI - Direct Observation of the Distribution of Gelatin in Calcium Carbonate Crystals by Super-Resolution Fluorescence Microscopy. AB - Biological organic-inorganic hybrid materials often achieve excellent properties and provide inspiration for the design of advanced materials. The organic phase plays a key role in determining the properties of biogenic materials, and the spatial arrangement of organic and inorganic phases provides direct evidence for interaction between the two phases. Super-resolution fluorescence microscopy was used to visualize the gelatin distribution in two different crystalline polymorphs of calcium carbonate (vaterite and calcite) and to investigate the process by which gelatin is excluded from the crystals. The results demonstrated that gelatin is distributed through vaterite microspheres in the form of nanoparticles, whereas it tends to accumulate on the edges of the calcite rhombohedra. PMID- 26630672 TI - Brief Report: Differential Associations of Interleukin 6 and Intestinal Fatty Acid-Binding Protein With Progressive Untreated HIV-1 Infection in Rakai, Uganda. AB - The significance of HIV-associated immune activation and microbial translocation in Sub-Saharan African population remains poorly defined. We assessed biomarkers of inflammation, microbial translocation, and cellular activation and found most factors elevated in Ugandan HIV-1 seroconverters compared with community-matched controls. In contrast to previous findings in Western cohorts, C-reactive protein, neopterin, and intestinal fatty acid binding protein were not elevated. Higher T-cell activation and IL-6 were associated with faster disease progression. Surprisingly, intestinal fatty acid binding protein, indicative of enterocyte turnover, was higher in slow than in fast progressors. These data suggest differential relationships among biomarkers of intestinal barrier integrity and innate immune activation between developed countries and Sub Saharan Africa. PMID- 26630670 TI - Early-Onset Convulsive Seizures Induced by Brain Hypoxia-Ischemia in Aging Mice: Effects of Anticonvulsive Treatments. AB - Aging is associated with an increased risk of seizures/epilepsy. Stroke (ischemic or hemorrhagic) and cardiac arrest related brain injury are two major causative factors for seizure development in this patient population. With either etiology, seizures are a poor prognostic factor. In spite of this, the underlying pathophysiology of seizure development is not well understood. In addition, a standardized treatment regimen with anticonvulsants and outcome assessments following treatment has yet to be established for these post-ischemic seizures. Previous studies have modeled post-ischemic seizures in adult rodents, but similar studies in aging/aged animals, a group that mirrors a higher risk elderly population, remain sparse. Our study therefore aimed to investigate early-onset seizures in aging animals using a hypoxia-ischemia (HI) model. Male C57 black mice 18-20-month-old underwent a unilateral occlusion of the common carotid artery followed by a systemic hypoxic episode (8% O2 for 30 min). Early-onset seizures were detected using combined behavioral and electroencephalographic (EEG) monitoring. Brain injury was assessed histologically at different times post HI. Convulsive seizures were observed in 65% of aging mice post-HI but not in control aging mice following either sham surgery or hypoxia alone. These seizures typically occurred within hours of HI and behaviorally consisted of jumping, fast running, barrel-rolling, and/or falling (loss of the righting reflex) with limb spasms. No evident discharges during any convulsive seizures were seen on cortical-hippocampal EEG recordings. Seizure development was closely associated with acute mortality and severe brain injury on brain histological analysis. Intra-peritoneal injections of lorazepam and fosphenytoin suppressed seizures and improved survival but only when applied prior to seizure onset and not after. These findings together suggest that seizures are a major contributing factor to acute mortality in aging mice following severe brain ischemia and that early anticonvulsive treatment may prevent seizure genesis and improve overall outcomes. PMID- 26630673 TI - Understanding Local Spatial Variation Along the Care Continuum: The Potential Impact of Transportation Vulnerability on HIV Linkage to Care and Viral Suppression in High-Poverty Areas, Atlanta, Georgia. AB - BACKGROUND: Engagement in care is central to reducing mortality for HIV-infected persons and achieving the White House National AIDS Strategy of 80% viral suppression in the US by 2020. Where an HIV-infected person lives impacts his or her ability to achieve viral suppression. Reliable transportation access for healthcare may be a key determinant of this place-suppression relationship. METHODS: ZIP code tabulation areas (ZCTAs) were the units of analysis. We used geospatial and ecologic analyses to examine spatial distributions of neighborhood level variables (eg, transportation accessibility) and associations with: (1) community linkage to care, and (2) community viral suppression. Among Atlanta ZCTAs with data for newly diagnosed HIV cases (2006-2010), we used Moran I to evaluate spatial clustering and linear regression models to evaluate associations between neighborhood variables and outcomes. RESULTS: In 100 ZCTAs with 8413 newly diagnosed HIV-positive residents, a median of 60 HIV cases were diagnosed per ZCTA during the 5-year period. We found significant clustering of ZCTAs with low linkage to care and viral suppression (Moran I = 0.218, P < 0.05). In high poverty ZCTAs, a 10% point increase in ZCTA-level household vehicle ownership was associated with a 4% point increase in linkage to care (P = 0.02, R = 0.16). In low-poverty ZCTAs, a 10% point increase in ZCTA-level household vehicle ownership was associated with a 30% point increase in ZCTA-level viral suppression (P = 0.01, R = 0.08). CONCLUSIONS: Correlations between transportation variables and community-level care linkage and viral suppression vary by area poverty level and provide opportunities for interventions beyond individual-level factors. PMID- 26630674 TI - Segmentation of Image Data from Complex Organotypic 3D Models of Cancer Tissues with Markov Random Fields. AB - Organotypic, three dimensional (3D) cell culture models of epithelial tumour types such as prostate cancer recapitulate key aspects of the architecture and histology of solid cancers. Morphometric analysis of multicellular 3D organoids is particularly important when additional components such as the extracellular matrix and tumour microenvironment are included in the model. The complexity of such models has so far limited their successful implementation. There is a great need for automatic, accurate and robust image segmentation tools to facilitate the analysis of such biologically relevant 3D cell culture models. We present a segmentation method based on Markov random fields (MRFs) and illustrate our method using 3D stack image data from an organotypic 3D model of prostate cancer cells co-cultured with cancer-associated fibroblasts (CAFs). The 3D segmentation output suggests that these cell types are in physical contact with each other within the model, which has important implications for tumour biology. Segmentation performance is quantified using ground truth labels and we show how each step of our method increases segmentation accuracy. We provide the ground truth labels along with the image data and code. Using independent image data we show that our segmentation method is also more generally applicable to other types of cellular microscopy and not only limited to fluorescence microscopy. PMID- 26630675 TI - Effect of Post-Infiltration Soil Aeration at Different Growth Stages on Growth and Fruit Quality of Drip-Irrigated Potted Tomato Plants (Solanum lycopersicum). AB - Soil hydraulic principles suggest that post-infiltration hypoxic conditions would be induced in the plant root-zone for drip-irrigated tomato production in small pots filled with natural soil. No previous study specifically examined the response of tomato plants (Solanum lycopersicum) at different growth stages to low soil aeration under these conditions. A 2 * 6 factorial experiment was conducted to quantify effects of no post-infiltration soil aeration versus aeration during 5 different periods (namely 27-33, 34-57, 58-85, 86-99, and 27-99 days after sowing), on growth and fruit quality of potted single tomato plants that were sub-surface trickle-irrigated every 2 days at 2 levels. Soil was aerated by injecting 2.5 liters of air into each pot through the drip tubing immediately after irrigation. Results showed that post-infiltration aeration, especially during the fruit setting (34-57 DAS) and enlargement (58-85 DAS) growth stages, can positively influence the yield, root dry weight and activity, and the nutritional (soluble solids and vitamin C content), taste (titratable acidity), and market quality (shape and firmness) of the tomato fruits. Interactions between irrigation level and post-infiltration aeration on some of these fruit quality parameters indicated a need for further study on the dynamic interplay of air and water in the root zone of the plants under the conditions of this experiment. PMID- 26630676 TI - T-Tau and P-Tau in Brain and Blood from Natural and Experimental Prion Diseases. AB - Synaptic abnormalities are prominent in prion disease pathogenesis and are responsible for functional deficits. The microtubule associated protein, Tau, binds to and stabilizes microtubules in axons ensuring axonal transport of synaptic components. Tau phosphorylation reduces its affinity for microtubules leading to their instability and resulting in disrupted axonal transport and synaptic dysfunction. We report on the levels of total Tau (T-Tau) and phosphorylated Tau (P-Tau), measured by highly sensitive laser-based immunoassays, in the central nervous system and biofluids from experimentally transmitted prion disease in mice and natural cases of sporadic Creutzfeldt-Jakob Disease (sCJD) in humans. We found that, in contrast to sCJD where only the levels of T-Tau in brain are increased, both T-Tau and P-Tau are increased in the brains of symptomatic mice experimentally infected with the ME7, 139A and 22L mouse-adapted scrapie strains. The increased levels of T-Tau in sCJD brain, compared to control samples, were also observed in patient plasma. In contrast, there was no detectable increase in T-Tau and P-Tau in plasma from symptomatic experimentally infected mice. Furthermore, our data suggests that in mice showing clinical signs of prion disease the levels and/or ratios of T-Tau and P-Tau are only a useful parameter for differentiating the mouse-adapted scrapie strains that differ in the extent of disease. We conclude that the neuropathogenesis associated with P-Tau and synaptic dysfunction is similar for at least two of the mouse-adapted scrapie strains tested but may differ between sporadic and experimentally transmitted prion diseases. PMID- 26630677 TI - A Tool for Multiple Targeted Genome Deletions that Is Precise, Scar-Free, and Suitable for Automation. AB - Many advances in synthetic biology require the removal of a large number of genomic elements from a genome. Most existing deletion methods leave behind markers, and as there are a limited number of markers, such methods can only be applied a fixed number of times. Deletion methods that recycle markers generally are either imprecise (remove untargeted sequences), or leave scar sequences which can cause genome instability and rearrangements. No existing marker recycling method is automation-friendly. We have developed a novel openly available deletion tool that consists of: 1) a method for deleting genomic elements that can be repeatedly used without limit, is precise, scar-free, and suitable for automation; and 2) software to design the method's primers. Our tool is sequence agnostic and could be used to delete large numbers of coding sequences, promoter regions, transcription factor binding sites, terminators, etc in a single genome. We have validated our tool on the deletion of non-essential open reading frames (ORFs) from S. cerevisiae. The tool is applicable to arbitrary genomes, and we provide primer sequences for the deletion of: 90% of the ORFs from the S. cerevisiae genome, 88% of the ORFs from S. pombe genome, and 85% of the ORFs from the L. lactis genome. PMID- 26630678 TI - Identification and Characterization of Novel Variations in Platelet G-Protein Coupled Receptor (GPCR) Genes in Patients Historically Diagnosed with Type 1 von Willebrand Disease. AB - The clinical expression of type 1 von Willebrand disease may be modified by co inheritance of other mild bleeding diatheses. We previously showed that mutations in the platelet P2Y12 ADP receptor gene (P2RY12) could contribute to the bleeding phenotype in patients with type 1 von Willebrand disease. Here we investigated whether variations in platelet G protein-coupled receptor genes other than P2RY12 also contributed to the bleeding phenotype. Platelet G protein-coupled receptor genes P2RY1, F2R, F2RL3, TBXA2R and PTGIR were sequenced in 146 index cases with type 1 von Willebrand disease and the potential effects of identified single nucleotide variations were assessed using in silico methods and heterologous expression analysis. Seven heterozygous single nucleotide variations were identified in 8 index cases. Two single nucleotide variations were detected in F2R; a novel c.-67G>C transversion which reduced F2R transcriptional activity and a rare c.1063C>T transition predicting a p.L355F substitution which did not interfere with PAR1 expression or signalling. Two synonymous single nucleotide variations were identified in F2RL3 (c.402C>G, p.A134 =; c.1029 G>C p.V343 =), both of which introduced less commonly used codons and were predicted to be deleterious, though neither of them affected PAR4 receptor expression. A third single nucleotide variation in F2RL3 (c.65 C>A; p.T22N) was co-inherited with a synonymous single nucleotide variation in TBXA2R (c.6680 C>T, p.S218 =). Expression and signalling of the p.T22N PAR4 variant was similar to wild-type, while the TBXA2R variation introduced a cryptic splice site that was predicted to cause premature termination of protein translation. The enrichment of single nucleotide variations in G protein-coupled receptor genes among type 1 von Willebrand disease patients supports the view of type 1 von Willebrand disease as a polygenic disorder. PMID- 26630679 TI - Time-Dependent and Organ-Specific Changes in Mitochondrial Function, Mitochondrial DNA Integrity, Oxidative Stress and Mononuclear Cell Infiltration in a Mouse Model of Burn Injury. AB - Severe thermal injury induces a pathophysiological response that affects most of the organs within the body; liver, heart, lung, skeletal muscle among others, with inflammation and hyper-metabolism as a hallmark of the post-burn damage. Oxidative stress has been implicated as a key component in development of inflammatory and metabolic responses induced by burn. The goal of the current study was to evaluate several critical mitochondrial functions in a mouse model of severe burn injury. Mitochondrial bioenergetics, measured by Extracellular Flux Analyzer, showed a time dependent, post-burn decrease in basal respiration and ATP-turnover but enhanced maximal respiratory capacity in mitochondria isolated from the liver and lung of animals subjected to burn injury. Moreover, we detected a tissue-specific degree of DNA damage, particularly of the mitochondrial DNA, with the most profound effect detected in lungs and hearts of mice subjected to burn injury. Increased mitochondrial biogenesis in lung tissue in response to burn injury was also observed. Burn injury also induced time dependent increases in oxidative stress (measured by amount of malondialdehyde) and neutrophil infiltration (measured by myeloperoxidase activity), particularly in lung and heart. Tissue mononuclear cell infiltration was also confirmed by immunohistochemistry. The amount of poly(ADP-ribose) polymers decreased in the liver, but increased in the heart in later time points after burn. All of these biochemical changes were also associated with histological alterations in all three organs studied. Finally, we detected a significant increase in mitochondrial DNA fragments circulating in the blood immediately post-burn. There was no evidence of systemic bacteremia, or the presence of bacterial DNA fragments at any time after burn injury. The majority of the measured parameters demonstrated a sustained elevation even at 20-40 days post injury suggesting a long-lasting effect of thermal injury on organ function. The current data show that there are marked time-dependent and tissue-specific alterations in mitochondrial function induced by thermal injury, and suggest that mitochondria specific damage is one of the earliest responses to burn injury. Mitochondria may be potential therapeutic targets in the future experimental therapy of burns. PMID- 26630681 TI - A Comparative Study of Immunohistochemical Myoepithelial Cell Markers in Cutaneous Benign Cystic Apocrine Lesions. AB - The use of immunohistochemical markers for myoepithelial cells (MEC) is a useful tool in the distinction of benign from malignant epithelial neoplasms. Although their use in breast tumors is well recognized, little is known concerning its application in comparable cutaneous lesions. Using benign cutaneous cystic apocrine lesions as a study model, the aim of this study was to compare 5 immunohistochemical markers [calponin, p63, smooth muscle actin (SMA), cytokeratin 14, and CD10] in their effectiveness to highlight MEC. Cases of apocrine hidrocystoma and cystadenoma (n = 44) were reviewed with a particular emphasis on proliferative features and apocrine change. The MEC staining pattern and the intensity and distribution scores in proliferative (n = 29) and nonproliferative (n = 15) lesions were assessed, and the differences between the 2 groups were statistically analyzed using Fisher exact test. Calponin and SMA stained MEC in the most consistent manner. Being a nuclear stain, p63 was easy to interpret but typically showed discontinuous staining. Cytokeratin 14 not only effectively highlighted MEC but also stained some luminal epithelial cells in an unpredictable manner. Because of prominent background dermal fibroblast staining, CD10 was often difficult to interpret. Only SMA and p63 showed a statistically significant difference in MEC staining intensity scores between the proliferative and nonproliferative groups. Our results show that immunohistological staining for MEC in benign cystic apocrine lesions of the skin is variable. The authors recommend that a panel of markers that includes calponin and p63 be used and highlight the need for awareness of specific caveats associated with individual markers. PMID- 26630680 TI - Methyltetrahydrofolate vs Folic Acid Supplementation in Idiopathic Recurrent Miscarriage with Respect to Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphisms: A Randomized Controlled Trial. AB - PURPOSE: To determine whether 5-methylenetetrahydrofolate (MTHF) is more effective than folic acid supplementation in treatment of recurrent abortion in different MTHFR gene C677T and A1298C polymorphisms. METHODS: A randomized, double blind, placebo-controlled trial conducted April 2011-September 2014 in recurrent abortion clinics in Tehran, Iran. The participants were women with three or more idiopathic recurrent abortion, aged 20 to 45 years. Two hundred and twenty eligible women who consented to participate were randomly assigned to receive either folic acid or 5-MTHF according to the stratified blocked randomization by age and the number of previous abortions. Participants took daily 1 mg 5-methylentetrahydrofolate or 1 mg folic acid from at least 8 weeks before conception to the 20th week of the pregnancy. The primary outcome was ongoing pregnancy rate at 20th week of pregnancy, and the secondary outcomes were serum folate and homocysteine at the baseline, after 8 weeks, and at the gestational age of 4, 8, 12, and 20 weeks, MTHFR gene C677T and A1298C polymorphisms. RESULTS: There was no significant difference in abortion rate between two groups. Serum folate increased significantly in both groups over time; these changes were significantly higher in the group receiving 5-MTHF than the group receiving folic acid (value = 2.39, p<00.1) and the result was the same by considering the time (value = 1.24, p<0.01). Plasma tHcys decreased significantly in both groups over time; however these changes were not significantly different between the groups (value = 0.01, p = 0.47). CONCLUSION: The results do not support any beneficial effect of 5-MTHF vs. folate supplementation in women with recurrent abortion with any MTHFR C677T and/or A1298C polymorphism. TRIAL REGISTRATION: ClinicalTrials.gov NCT01976676. PMID- 26630682 TI - Interstitial Mycosis Fungoides With Lichen Sclerosus-Like Clinical and Histopathological Features. AB - Mycosis fungoides (MF) simulates a variety of dermatologic disorders histopathologically and clinically, well deserving the designation of a great mimicker. Interstitial MF is a rare, but well-recognized histopathological variant resembling the interstitial form of granuloma annulare or the inflammatory phase of morphea. From a clinical standpoint, MF can have a wide array of manifestations, including an anecdotal presentation with lesions clinically suggestive of lichen sclerosus (LS). We herein report a 25-year-old man with a history of patch-stage MF who later developed widespread LS-like lesions histopathologically consistent with interstitial MF. In some biopsies, additional features resembling LS were discerned. We think that our case might represent a unique variant of interstitial MF presenting with LS-like lesions. The diagnostic challenge arising from this uncommon presentation is discussed together with review of the literature. PMID- 26630683 TI - BRAF-V600 Mutation Heterogeneity in Primary and Metastatic Melanoma: A Study With Pyrosequencing and Immunohistochemistry. AB - BACKGROUND: The BRAF-V600 mutation is the most common mutation in cutaneous melanomas and is currently considered a target mutation when planning treatment for metastatic melanoma patients. Various techniques are used to determine the mutation status. The aim of this study was to determine the BRAF-V600 mutation status in primary and metastatic foci of melanoma cases and the consistency between the results of immunohistochemical and molecular methods. METHODS: A total of 48 primary or metastatic cases were included in the study. Pyrosequencing was used as the molecular method and the VE1 antibody for immunohistochemical evaluation when determining the BRAF-V600 mutation. RESULTS: The BRAF-V600 mutation was found in 75 of the 96 tumors (78.1%) from the 48 cases. V600E and V600K were present in 60 and 10 tumors, respectively, whereas V600R and V600M were present in 2 tumors and V600G in 1 tumor. There was no mutation in 5 metastases (12.8%) of the 39 cases with a V600 mutation in the primary tumor and no mutation in the primary tumor of 2 of the 36 cases (5.6%) with the V600 mutation in the metastasis. Fifty-six tumors were immunohistochemically positive where a V600E mutation was detected with pyrosequencing. Wild-type tumors (n = 20) and tumors with non-V600E mutations (n = 15) on pyrosequencing were immunonegative with VE1. The sensitivity and specificity of immunohistochemistry were 93.3% and 97.2%, respectively. CONCLUSIONS: In conclusion, BRAF-V600 mutation inconsistencies of up to 14.5% can be seen between the primary and metastatic foci in melanoma cases. These findings should be taken into account when planning targeted therapy and deciding on treatment responsiveness/unresponsiveness. An immunohistochemical method can be used as the first step to detect a BRAF-V600 mutation but additional molecular methods should be used when immunohistochemistry results are negative. PMID- 26630684 TI - Dermatitis Herpetiformis: A Review of Direct Immunofluorescence Findings. AB - Direct immunofluorescence (DIF) findings in dermatitis herpetiformis (DH) are incompletely defined. The presence and localization of immune reactants in this disorder are reviewed. A retrospective study on 72 biopsies from 71 patients with DH was performed. Deposits of IgG, IgA, IgM, C'3, C1q, and fibrinogen in skin using a DIF test were analyzed. Granular IgA was observed at the dermal-epidermal junction in 65 biopsies and in the fibers of the papillary dermis in 72 samples. IgG, IgM, C'3, C1q, and fibrinogen were detected in the same locations in lower percentages. IgA was present in the vessels of the papillary dermis in 33 biopsies and in the reticular dermis in 10, followed by fibrinogen, C'3, IgM, and IgG. IgA and IgM were detected in the elastic fibers in 17 and 5 samples, respectively. IgA was observed in 19 cases in the arrector pili muscles, and in a few cases, C'3, IgM, and IgG. IgA and other immune reagents were present in the fibers around hair follicles and in the basement membrane of sweat glands and ducts. Immunofluorescence findings in routine DIF studies from skin biopsies of patients with DH cover a much wider spectrum than previously known. PMID- 26630685 TI - Histopathology of the Exanthema in DRESS Is Not Specific but May Indicate Severity of Systemic Involvement. AB - OBJECTIVE: Exanthema in drug reaction with eosinophilia and systemic symptoms (DRESS) has no specific clinical diagnostic hallmark and there are few histopathologic studies. The aim of this study was to describe dermal-epidermal histopathologic features in DRESS and correlate them with the culprit drug, viral reactivation, or systemic organ involvement. METHODS: Skin biopsies were independently evaluated by 2 dermatopathologists who characterized the main histological patterns and scored dermal and epidermal changes, which were further correlated with clinical and laboratorial data. RESULTS: In 15 DRESS patients (9 male/6 female patients, mean age 53.3 years), the main observation was lymphocyte exocytosis (1.87 +/- 1.25), spongiosis (0.93 +/- 0.94), scattered keratinocyte necrosis (1.70 +/- 1.44), basal cell vacuolization (2.13 +/- 1.42), lymphocyte infiltration around dermal vessels (2.93 +/- 0.92) or at the dermal-epidermal junction (2.07 +/- 1.12), often with eosinophils and extravasated erythrocytes, swollen endothelial cells, and intravascular neutrophils but no vasculitis. Histopathologic patterns were classified mainly as spongiotic (5), erythema multiforme-like (3), or lichenoid (2). There was a significant positive correlation between the intensity of lymphocyte infiltration and the severity of hepatic cytolysis (r = 0.51; P < 0.05) and eosinophilia (r = 0.51; P < 0.05). No correlation was observed between the intensity and type of dermal inflammation and the degree of epidermal damage or the culprit drug. Human herpes virus type 6 positive patients had a pseudolymphomatous reaction or a perifollicular localization of the infiltrate. CONCLUSIONS: Histopathology in DRESS is variable with no specific diagnostic aspect, but there is a possible correlation between the intensity of the lymphocyte infiltrate and DRESS severity, namely, liver cytolysis. PMID- 26630686 TI - Video-based detection of device interaction in the operating room. AB - The establishment of modern workflow management technologies requires the integration of dated devices. The extraction of the essential device data and usage time spans is a central requirement for an integrated OR environment. Therefore, methods are required that extract such information from the output provided by older generation devices, namely video signals. We developed a four level approach for video-based device information extraction. Usually, video streams contain all relevant patient data and device usage information. We propose an approach consisting of defining regions of interest, grabbing video signals, analyzing the signals and storing the data in a centralized and structured location. The analysis considers textual information and graphical visualization. A prototype of the analysis approach was implemented and applied to a neurosurgical case. An evaluation study was conducted to measure the performance of the approach on video recordings of real interventions. Three medical devices were considered: intraoperative ultrasound, neuro-navigation and microscope. Overall, recognition rates for device usage higher than 95% were obtained. The approach is not limited to a single surgical discipline and does not require modification of medical devices. Furthermore, the analysis of microscopic video streams expands the detectable aspects of the surgical workflow beyond the recognition of device usage. PMID- 26630687 TI - Finite element study of the acetabulum in cemented hip arthroplasty investigating retention or removal of the subchondral bone plate. AB - The importance of the subchondral bone plate of the acetabulum when preparing the pelvis for a cemented acetabular cup during total hip arthroplasty (THA) has been investigated using finite element analysis. The effect of retaining or removing the subchondral bone plate and the use of anchoring holes are compared. Loading was applied via both hip joint contact force and the activity of up to 22 muscles at five stages through the load bearing phase of the gait cycle. Removing the subchondral bone plate leads to decreased stresses in the cancellous bone and slightly increased stresses in the cortical shell superior to the acetabulum. The differences between the two cases are small, nevertheless there are indications that removal of the subchondral bone plate reduces the stresses. Increasing the cement penetration depth leads to a slightly more rigid structure, due to cement penetrating the cancellous bone. Adding anchoring holes moves the position of the highest cancellous bone strains from the bone-cement interface into the cancellous bone. Thus removal of the subchondral bone plate should lead to an increased potential for cement penetration into the cancellous bone which should be beneficial for cup fixation and thus improve long term implant survival. PMID- 26630688 TI - Prospective risk of intrauterine death of monochorionic twins: update. AB - OBJECTIVE: To calculate an updated prospective risk of fetal death in monochorionic-biamniotic (MCBA) twins. STUDY DESIGN: We evaluated 520 MCBA twin pregnancies that had intensive prenatal surveillance and delivered in a single Portuguese referral center. The prospective risk of fetal death was calculated as the total number of deaths at the beginning of the gestational period divided by the number of continuing pregnancies at or beyond that period. Data were compared to the 2006 previous report. RESULTS: Nearly 80% of the neonates weighed <2500 g, including 13.5% who weighed <1500 g. Half were born at <36 weeks, including 13.8% who were born at <32 weeks. The data indicate an increased IUFD rate over time - 16 fetal deaths per pregnancy (3.1%) and 22 IUFDs per fetus (2.1%). The rate of IUFD after 32-33 weeks, however, was halved (1/187 pregnancies and 1/365 fetuses, 0.5 and 0.3%, respectively). CONCLUSION: Intensive prenatal surveillance might decrease the unexpected fetal death rates after 33 week's gestation and our data do not support elective preterm birth for uncomplicated MCBA twins. PMID- 26630689 TI - Differences in parental involvement in the care of children and adolescents with type 1 diabetes mellitus on multiple daily insulin injections versus continuous subcutaneous insulin infusion. AB - BACKGROUND: Assessing the degree of involvement of caregivers for children with type 1 diabetes mellitus (T1DM) in their diabetes care, differences in the degree of involvement based on the method of insulin administration (multiple daily injections: MDI/continuous subcutaneous insulin infusion: CSII), and its effect on glycemic control. METHODS: This was a cross-sectional study with T1DM patients, ages 6-13 years using a six question survey derived from the Diabetes Family Responsibility Questionnaire (DFRQ). All caregivers (n=140) and participants between ages 11 and 13 (n=60) completed the survey. RESULTS: Significant differences between MDI and CSII caregiver responses were found for responsibility for giving insulin boluses, as well as for rotation of infusion/injection sites (p<0.001 and p=0.03, respectively). A sub-analysis of caregiver responses for caregiver versus child responsibility for giving infusion boluses (excluding shared responsibility) showed that 36% of children in the CSII group had primary responsibility for giving insulin boluses, compared to 17% in the MDI group (p<0.001). The median agreement for all questions combined between participants and caregivers for ages 11-13 (n=60 pairs) was "poor" (kappa=0.18). No significant effect of parental involvement on last 2-year average HbA1C was found for CSII or MDI groups (p>0.20). CONCLUSIONS: Caregiver reported diabetes care responsibility (mostly parent, mostly child, shared between parent and child) varies for certain aspects of diabetes related care for children ages 6 13, depending upon the mode of insulin administration. Based on the reported degree of parental collaboration, HbA1C did not differ significantly. However, long-term effects are yet to be determined in longitudinal studies. PMID- 26630690 TI - Role of nutrition in preventing insulin resistance in children. AB - Nutrition during prenatal, early postnatal and pubertal period is crucial for the development of insulin resistance and its consequences. During prenatal period fetal environment and nutrition seems to interfere with metabolism programming later in life. The type of dietary carbohydrates, glycemic index, protein, fat and micronutrient content in maternal nutrition could influence insulin sensitivity in the newborn. The effects of lactation on metabolism and nutritional behavior later in life have been studied. Dietary habits and quality of diet during puberty could prevent the onset of a pathological insulin resistance through an adequate distribution of macro- and micronutrients, a diet rich in fibers and vegetables and poor in saturated fats, proteins and sugars. We want to overview the latest evidences on the risk of insulin resistance later in life due to both nutritional behaviors and components during the aforementioned periods of life, following a chronological outline from fetal development to adolescence. PMID- 26630691 TI - The shortened combined clonidine and arginine test for growth hormone deficiency is practical and specific: a diagnostic accuracy study. AB - BACKGROUND: The growth hormone (GH) stimulation protocols for clonidine and arginine tests are non-standardized and can be lengthy. We examined the specificity of both tests using a shorter duration of timed samples: 90 min for clonidine and 60 min for arginine. METHODS: We retrospectively studied all children who had GH stimulation with clonidine and arginine to test for GH deficiency (GHD). We compared the diagnostic accuracy of both reference and new shortened test (index). RESULTS: We reviewed 243 charts (11.4+/-4.1 years old; 74.5% males). The combined reference test was performed on 159 children, 29 (18.3%) tested positive for GHD on the combined index test, Kappa 0.98, false positive rate 1 (0.8%), specificity 0.99, 95th CI (0.96-1), and p=1.0. The specificity of both the clonidine and arginine single index tests was 0.98%. CONCLUSIONS: The shortened clonidine and arginine stimulation index tests have good specificity. This is a viable option for testing children for GHD. PMID- 26630692 TI - It's high time to revise Indian guidelines on vitamin D supplementation in children. PMID- 26630693 TI - Phenotypic variations in osmotic lysis of Sahel goat erythrocytes in non-ionic glucose media. AB - BACKGROUND: Erythrocyte osmotic lysis in deionised glucose media is regulated by glucose influx, cation efflux, and changes in cell volume after water diffusion. Transmembrane fluxes may be affected by varied expression of glucose transporter protein and susceptibility of membrane proteins to glucose-induced glycosylation and oxidation in various physiologic states. METHODS: Variations in haemolysis of Sahel goat erythrocytes after incubation in hyposmotic non-ionic glucose media, associated with sex, age, late pregnancy, and lactation, were investigated. RESULTS: The osmotic fragility curve in glucose media was sigmoidal with erythrocytes from goats in late pregnancy (PRE) or lactation (LAC) or from kid (KGT) or middle-aged (MGT) goats. Non-sigmoidal phenotype occurred in yearlings (YGT) and old (OGT) goats. The composite fragility phenotype for males and non pregnant dry (NPD) females was non-sigmoidal. Erythrocytes with non-sigmoidal curves were more stable than those with sigmoidal curves because of inflectional shift of the curve to the left. Erythrocytes tended to be more fragile with male than female sex, KGT and MGT than YGT and OGT, and LAC and PRE than NPD. Thus, sex, age, pregnancy, and lactation affected the haemolytic pattern of goat erythrocytes in glucose media. CONCLUSIONS: The physiologic state of the goat affected the in vitro interaction of glucose with erythrocytes, causing variations in osmotic stability with variants of fragility phenotype. Variations in the effect of high extracellular glucose concentrations on the functions of membrane-associated glucose transporter, aquaporins, and the cation cotransporter were presumed to be relevant in regulating the physical properties of goat erythrocytes under osmotic stress. PMID- 26630694 TI - Comparative analysis of prostate cancer specific biomarkers PCA3 and ERG in whole urine, urinary sediments and exosomes. AB - BACKGROUND: PCA3 and ERG are mRNA-based prostate cancer (PCa) specific biomarkers that can be detected in urine. However, urine is a complex substrate that can be separated in several fractions. In this study we compared the levels of PCa specific biomarkers (PCA3 and ERG) and KLK3 as prostate-specific reference gene in three urine substrates-whole urine, urinary sediment (cell pellet) and exosomes-and evaluated the influence of performing a digital rectal examination (DRE) prior to urine sampling. METHODS: First-voided urine samples were prospectively obtained before and after DRE from 29 men undergoing prostate biopsies. The urine was separated in whole urine, cell pellet and exosomes and the biomarker levels were measured with RT-qPCR. RESULTS: PCa was identified in 52% (15/29) of men. In several samples the mRNA levels were below the analytical limit of detection (BDL). The biomarker levels were highest in whole urine and significantly higher after DRE in all substrates. In PCa patients higher levels of PCA3 and ERG were found in all urine substrates after DRE compared to non-PCa patients. CONCLUSIONS: This is the first study in which urinary PCa-specific biomarker levels were compared directly in three separate urine fractions. These results suggest that whole urine could be the urine substrate of choice for PCa diagnostics based on analytical sensitivity, which is reflected directly in the high informative rate. Moreover, the significant positive effect of performing a DRE prior to urine sampling is confirmed. These findings could be of influence in the development of PCa-diagnostic urine tests. PMID- 26630695 TI - Mean corpuscular volume levels and all-cause and liver cancer mortality. AB - BACKGROUND: An elevated mean corpuscular volume (MCV) is associated with aging, nutrition, alcohol abuse and more, and it is known as a survival predictor in chronically ill patients. The aim of this study was to investigate the association between MCV levels and mortality from all-causes, cancer and site specific cancer in a non-anemic healthy population. METHODS: A total of 36,260 participants aged 40 years or older who underwent routine check-ups at Seoul National University Hospital Health Promotion Center between 1995 and 2008 were followed-up for mortality until December 31, 2008, retrospectively. RESULTS: During an average follow-up of 8.0 years, 1107 deaths including 547 cancer deaths were observed. The adjusted hazard ratios (aHRs) of the subjects with the highest quartile of MCV >=95.8 fL in men and MCV >=94.2 fL in women for all-cause and cancer mortality were 1.44 [95% confidence interval (CI), 1.15-1.80] and 1.51 (95% CI, 1.10-2.07) for men and 1.55 (95% CI, 1.08-2.22) and 1.25 (95% CI, 0.74 2.11) for women, respectively, compared with those in the reference group (90.5 fL<=MC <93.0 fL in men and 89.2 fL<=MCV<91.6 fL in women). Elevated MCV level was related to an increased risk of liver cancer mortality in men (aHR, 3.55; 95% CI, 1.75-7.21). CONCLUSIONS: This study suggests that the elevated MCV level in non anemic cancer-free individuals was associated with increased all-cause mortality in both men and women, and with cancer mortality, in particular liver cancer mortality in men. Future prospective studies are required to consolidate our findings. PMID- 26630696 TI - Measurement of plasma vitamin K1 (phylloquinone) and K2 (menaquinones-4 and -7) using HPLC-tandem mass spectrometry. AB - BACKGROUND: Given the growing interest in the health benefits of vitamin K, there is great need for development of new high-throughput methods for quantitative determination of vitamin K in plasma. We describe a simple and rapid method for measurement of plasma vitamin K1 (phylloquinone [PK]) and K2 (menaquinones [MK]-4 and -7). Furthermore, we investigated the association of fasting plasma vitamin K with functional vitamin K insufficiency in renal transplant recipients (RTR). METHODS: We used HPLC-tandem mass spectrometry with atmospheric pressure chemical ionization for measurement of plasma PK, MK-4, and MK-7. Solid-phase extraction was used for sample clean-up. Mass spectrometric detection was performed in multiple reaction monitoring mode. Functional vitamin K insufficiency was defined as plasma desphospho-uncarboxylated matrix Gla protein (dp-ucMGP) >500 pmol/L. RESULTS: Lower limits of quantitation were 0.14 nmol/L for PK and MK-4 and 4.40 nmol/L for MK-7. Linearity up to 15 nmol/L was excellent. Mean recoveries were >92%. Fasting plasma PK concentration was associated with recent PK intake (rho=0.41, p=0.002) and with plasma MK-4 (rho=0.49, p<0.001). Plasma PK (rho=0.38, p=0.003) and MK-4 (rho=0.46, p<0.001) were strongly correlated with plasma triglyceride concentrations. Furthermore, we found that MK-4-triglyceride ratio, but not PK-triglyceride ratio, was significantly associated with functional vitamin K insufficiency (OR 0.22 [0.07-0.70], p=0.01) in RTR. CONCLUSIONS: The developed rapid and easy-to-use LC-MS/MS method for quantitative determination of PK, MK-4, and MK-7 in human plasma may be a good alternative for the labor-intensive and time-consuming LC-MS/MS methods and enables a higher sample throughput. PMID- 26630697 TI - Building a bridge to safe diagnosis in health care. The role of the clinical laboratory. PMID- 26630698 TI - Particulate Exposure at two Arkansas Racinos; Unsafe Environments? AB - The purpose of this pilot project was to initiate data collection on secondhand smoke (SHS) for two racinos (racetrack casinos) exempted from Arkansas' 2006 Clean Indoor Air Act. Air quality was assessed during regular hours in sites open to the public. All measurements of fine particulates (PM2.5) within both facilities exceeded maximal safe EPA standards for an equivalent 24-hour average exposure. The exemptions as they stand, fail to protect all interested citizens. PMID- 26630700 TI - Symposium: Adult strabismus: techniques to alleviate visual discomfort. Introduction. PMID- 26630699 TI - Authors' response. PMID- 26630701 TI - Lyme Carditis in the Fast Lane: From Alternating Bundle Branch Block to Asystole in 12 Hours. AB - Lyme borreliosis is a multisystem infectious disease with well-known cardiac involvement, including potential carditis as well as conduction abnormalities. We report a case of Lyme disease in a previously healthy 24-year-old male presenting with alternating right- and left-bundle branch block, indicating infra-Hisian atrioventricular (infra-His) block with an accelerated fascicular escape rhythm. Inless than 12 hours, the conduction abnormalities progressed to asystole requiring the urgent placement of a temporary transvenous pacemaker. Subsequently, with appropriate antibiotic treatment, the patient's conduction abnormalities resolved in a week without the need for a permanent pacemaker. PMID- 26630702 TI - No Ceiling Dose: Effective Pain Control with Extraordinary Opiate Dosing in Cancer. AB - A 62-year-old woman with advanced cancer was admitted to the hospital experiencing inadequate pain control. Underdosing of opiates resulted from the persistent and inappropriate labeling of her behavior as drug-seeking, and the medical staff expressed discomfort about the administration of high doses of opiates. Palliative care personnel achieved better symptom control by the use of more confident and more liberal opiate dosing. The patient's quality of life improved immensely without adverse effects. We investigated reasons that account for the widespread practice of opiate underdosing. These include biases such as opiophobia--often unspoken and sometimes unrecognized. We share these insights to enhance the practice of others. PMID- 26630703 TI - Seminoma Presenting as a Mediastinal Mass in an Elderly Patient. AB - Primary mediastinal germ cell tumors are relatively rare and represent 10% - 20% of all mediastinal tumors. About one-third of these are primary mediastinal seminomas, occurring in males in their third and fourth decades, with the median age of presentation ranging between 20 and 30 years of age. We report an unusual case of a 69-year old male with mediastinal seminoma, who presented at an age much higher than the usual affected patient and responded well to the conventional mode of therapy for this tumor. A review of literature pertaining to clinical presentation, diagnosis, and management is also presented. PMID- 26630705 TI - Use of a Tourniquet by LIFE STAR Air Medical Crew: A Case Report. AB - For many years tourniquets were perceived as dangerous due to the belief that they led to loss of limb because of ischemia. Their use in civilian and military environments was discouraged. Emergency medical responders were not taught about tourniquets and commercial tourniquets were not available. However, research by the United States military during the wars in Iraq and Afghanistan has demonstrated that tourniquets are safe life-saving devices. As a consequence, they have been widely deployed in combat situations and there are now calls for the use of tourniquets in the civilian prehospital setting. This article presents a report of the successful application of a tourniquet by the LIFE STAR crew to control bleeding that local emergency medical services (EMS) personnel could not control with direct pressure. Tourniquets should be readily available in public places and carried by all EMS. PMID- 26630704 TI - Dual HER2 Blockade in Non-Small Cell Lung Cancer Harboring a HER2 Mutation. AB - Identification of targetable oncogenic mutations in non-small cell lung cancer (NSCLC) has been a major advance in cancer treatment. Laboratory techniques to assess human epidermal growth factor receptor 2 (HER2) positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression, fluorescent in situ hybridization (FISH) for gene amplification, and next generation sequencing (NGS) for HER2 gene mutations. These tests have a controversial prognostic and predictive value, with an emerging association between HER2 gene mutations and treatment response to HER2 targeted therapy. We present a case of a woman with metastatic lung adenocarcinoma with HER2 positivity assessed by IHC and FISH, as well as a high gene copy number noted on NGS. She was observed to have significant disease progression following standard first-line platinum doublet chemotherapy. She was started on dual HER2 blockade in the second-line setting, which yielded a great response in the liver with stable disease elsewhere. To our knowledge, this is the first report describing successful use of dual HER2 blockade in metastatic HER2 positive NSCLC. We also review common laboratory techniques for determining HER2 positivity in NSCLC and their clinical applications. PMID- 26630706 TI - Cranial Nerve Palsies: A Rare, Long-Term Complication of Radiotherapy for Nasopharyngeal Carcinoma. AB - Cranial nerves (CN) are believed to be relatively resistant to radiotherapy (RT); however, there have been case reports of cranial nerve palsy (CNP) following RT. We present a case of a gentleman with cranial nerve palsy of CN V and VII after RT for nasopharyngeal carcinoma (NPC). CASE PRESENTATION: A 54-year-old male presented to our clinic with masticatory difficulty, facial hypoesthesia, and dysphagia. In 1998, he was treated with external beam RT for NPC. He underwent sural nerve grafting, anastomosing his functioning hypoglossal nerve to the buccal branch of the facial nerve in an end-to-side fashion, and direct implantation of a nerve graft from the spinal accessory to the masseter muscle. He unfortunately was unable to regain masticatory function postoperatively. CONCLUSION: Cranial nerve palsies are severely debilitating to patients and difficult to treat. Radiation-induced CNP is important to consider in the differential diagnosis in patients previously treated for NPC. PMID- 26630707 TI - A Case of Spontaneous Intracranial Hypotension: The Role of Dynamic CT Myelography and Epidural Blood Patch in Diagnosis and Treatment. AB - Spontaneous intracranial hypotension (SIH) most commonly results from cerebrospinal fluid (CSF) leaks in the upper spinal canal. Alterations in the equilibrium between the volumes of intracranial blood and CSF lead to compensatory dilatation of the vascular spaces, mostly on the venous side. Dynamic computerized tomogram (CT) myelography can be very helpful in diagnosing the site of a CSF leak in the spinal canal. Subsequently, the site of the leak can be sealed with epidural blood patch (EBP). PMID- 26630708 TI - Caseous Calcification of Mitral Annulus: A Rare Monster Leading to Cerebrovascular Accident. AB - Caseous calcification of the mitral annulus (CCMA) is a rare variant of mitral annular calcification that maybe easily misdiagnosed or confused with an abscess, a tumor, or infective vegetation. The main pathophysiological mechanism leading to CCMA involves degeneration and calcium deposition on the mitral valve. We present a case of CCMA to help understand this clinical entity. PMID- 26630709 TI - New Options in Insulin Therapy. PMID- 26630711 TI - Advances in Anesthesiology. PMID- 26630710 TI - Advocating For Advocacy. PMID- 26630712 TI - Physician Re-Entry: I'll Be Back. PMID- 26630713 TI - "Trust Me, I'm a Doctor". PMID- 26630714 TI - Change Through Education. PMID- 26630715 TI - "Too Soon Old, Too Late Smart". PMID- 26630716 TI - Relationship between CSMS and the County associations. PMID- 26630717 TI - Four-Month Assessment of the Dentrust and Oral-B P35 Toothbrushes in Orthodontic Patients. AB - The efficacy and safety of two manual toothbrushes (Dentrust and the Oral-B P35) were evaluated in orthodontic patients classified by their treating orthodontist as having established gingivitis. Fifty-seven healthy adolescent subjects, who were fully bonded and banded with fixed orthodontic appliances, were randomly assigned to use one of the two toothbrushes for the duration of the four-month study. The subjects were given instructions with their new assigned toothbrush and agreed to use only these products at home, twice a day between orthodontic visits. On evaluation days at one, two and four months the patients reported to the clinic having not brushed for 12-16 hours, and were evaluated for plaque area and gingivitis in this single blind study. Gingivitis scores decreased significantly in the Dentrust group from baseline to the conclusion of the study. There was no significant statistical decline in gingivitis in the Oral-B P35 group until the four-month evaluation. Overnight plaque formation scores were similar for both groups during the study. After brushing for a timed one-minute period, both toothbrushes removed significant plaque area throughout the study. On total plaque levels, the Dentrust group was significantly lower on after toothbrushing plaque area mean scores compared to the Oral-B P35 group at two and four months. No side effects were reported or observed during the study attributed to the use of the assigned toothbrushes. PMID- 26630718 TI - Duration and Intensity of Anesthetic Effect Produced by Canker Sore Medications. AB - Canker sore medications are often recommended to patients for relief of pain associated with aphthous ulcers or other minor irritations of the mouth. The anesthetic effect of these medications is achieved by incorporation of local anesthetics, such as benzocaine, into the products' formulations. To determine the duration and intensity of the anesthetic effect of benzocaine-containing products, three topical oral health care medications, Red Cross Canker Sore Medication, Maximum Strength Anbesol and Orajel Mouth Aid, were compared. In this double blind cross-over study, each product was tested on 21 subjects with normal mucosa and gingiva. All three products produced anesthetic effects. Red Cross Canker Sore Medication was shown to have the longest duration and greatest intensity. PMID- 26630720 TI - Evaluation of Cetylpyridinium Chloride-Containing Mouthwashes Using In Vitro Disk Retention and Ex Vivo Plaque Glycolysis Methods. AB - The Disk Retention Assay (DRA) is an in vitro method developed to measure the available level of cetylpyridinium chloride (CPC) in mouthwash formulations. This method is based on the binding of the cationic CPC molecule to the anionic surface of a cellulose filter disk. Aqueous CPC solutions demonstrate a linear response (A545) for concentrations up to 0.3%. Higher levels of CPC showed no increased response in the assay. Among common oral product ingredients, at relevant concentrations, surfactants are the primary compounds which inhibit CPC detection and hence, chemical availability. Poloxamer-407 decreased CPC availability to 60% at 0.1%, to 10% at 0.5%, and to 24-33% for 0.2-0.4%. Polysorbate-80 decreased CPC availability to 30% at 0.1% and 6% at 0.25%. A range (4-54%) of available levels of CPC were determined for several commercial products containing 0.045-0.05% nominal levels of CPC indicating significant formulation excipient influence. A plaque glycolysis (PG) assay was used to determine the biological activity of all mouthwash products analyzed by DRA. An experimental series of mouthwash formulations having nominal CPC levels of 0 0.10% demonstrated a good correlation (r2 = 0.955) between the calculated available level of CPC (DRA) and inhibition of plaque glycolysis. The calculated available level of CPC from select commercial mouthwash products, also fit the established correlation with biological activity. The combination of DRA and plaque glycolysis methods are valuable tools which can be used during development to maximize the biological activity of CPC mouthwash formulations prior to clinical evaluation. PMID- 26630719 TI - Ketoprofen Dental Pain Study. AB - Ketoprofen is a nonsteroidal antiinflammatory drug, recently approved as an over the-counter (OTC) analgesic at a 12.5 mg dosage strength. This is the first published study which explores the analgesic efficacy and safety of ketoprofen 12.5 mg in patients experiencing pain following the removal of impacted third molars. This study was single-dose, double-blind and randomized utilizing a 6 hour in-patient evaluation period. Patients ingested a single dose of ketoprofen 12.5 mg (n = 30), ketoprofen 37.5 mg (n = 32) or placebo (n = 15) when their post surgical pain reached at least a moderate intensity on a 5-point categorical (CAT) scale and greater than 50 mm on a 100 mm visual analog scale (VAS). Measures of pain intensity and relief were gathered every 20 minutes for the first 2 hours, and then hourly from hours 3 through 6. Adverse drug reactions were also recorded as they occurred. Both dosages of ketoprofen were significantly more efficacious than placebo (two way ANOVAs, p < 0.05). For pain intensity difference (PID) and pain relief, the 12.5 mg dose exhibited statistical superiority from hours 1 through 3, while the 37.5 mg dose exhibited statistical superiority from 40 minutes through 4 hours. Ketoprofen 37.5 mg was significantly more efficacious than the 12.5 mg dose only at 40 minutes for PID(VAS) and relief, and at 60 minutes for PID(VAS). Both ketoprofen dosages displayed significantly greater 3-hr, 4-hr and 6-hr summary analgesic measures (SPID(VAS), SPID(CAT), TOTPAR) than placebo, with the exception of the 6-hr SPID(CAT) measure for ketoprofen 12.5 mg. No serious side effects were observed in this study. We conclude that ketoprofen in a dose range of 12.5 mg to 37.5 mg is a safe and effective analgesic for the relief of post-operative dental pain. PMID- 26630721 TI - A Review of Laboratory Methods to Determine Toothbrush Safety and Efficacy. AB - Laboratory toothbrush evaluations have focused on three primary areas: hardness, efficacy and end-rounding. There is an accepted ISO standard for toothbrush texture, to categorize products from extra soft to extra firm. New toothbrush designs, with changes in bristle tufting, alignments, and lengths, yield reproducible results in the ISO procedure. New research has focused on a mathematical model that predicts stiffness, which overestimates in the 25-30% range. Efficacy testing has focused on the ability of toothbrush bristles to achieve interproximal penetration or access between and around artificial teeth or simulated tooth models. The majority of methods reviewed use "cleaning" or removal of deposited materials adherent to dentoform teeth. One test procedure uses deposition of ink from toothbrush bristles onto dentoform tooth surfaces. Many different approaches have been used over the years to evaluate efficacy. One method used since 1979 in several laboratories, and 3 methods developed in 1993 and 1994 are compared in detail for similarities and differences in testing performance criteria. Two of these procedures have been predictive of clinical plaque removal efficacy testing. Lack of bristle end-rounding was recognized in the 1930s and was related to gingival tissue damage. A revival of interest in end rounding has occurred since the mid-80s using SEM and definitions and drawings of acceptable endings. The primary use of the new procedure has been to determine the % of acceptable and/or highest degree of end-roundness for the various toothbrush brands studied. No clinical gingival safety studies have been located related to these new laboratory end-rounded methods. PMID- 26630722 TI - A Thirty-Day Safety and Efficacy Evaluation of the Rowenta, Braun and Sonicare Powered Toothbrushes and a Manual Toothbrush. AB - A 30-day study was conducted to compare a new powered toothbrush (Rowenta Plaque Dentacontrol Plus) with a standard manual ADA-approved toothbrush (Oral-B P35) and two marketed powered toothbrushes (Braun Oral-B Ultra and Sonicare) for safety, plaque area before and after toothbrushing with dentifrice, gingivitis and bleeding on probing. The three powered toothbrushes had label directions giving somewhat different times for brushing. It was presumed that these stated times were justified on the basis of some observations or measurements of thorough cleaning. One brush, the Rowenta, had labelled time requirements involving both a flat-surface brush and an interproximal brush head. The manual toothbrush came with no recommended time reference for brushing. It was thought to assess the relative efficacy of the four toothbrushes for plaque removal and soft tissue changes, if subjects were to follow label directions. The subjects used only their randomly assigned toothbrush during the study. Assessments at baseline and on days 15 and 30 were performed with the subjects having not brushed for 10-16 hours prior to the examination (overnight plaque formation). There were no side effects reported by the subjects or observed by the examiners attributed to toothbrush use at any time in the study. All groups had similar plaque levels at the beginning of the study and all toothbrushes removed statistically significant amounts of plaque after brushing. On gingivitis measurements at baseline, there were no significant statistical differences among the toothbrushes tested; however, by day 15 the Rowenta was significantly lower than the Braun group. By day 30, the Rowenta was statistically significantly lower than all the groups in gingivitis scores. For bleeding on probing assessments, there were no significant statistical differences among the toothbrush means at baseline or day 15. By day 30, the Rowenta was statistically significantly lower than the Oral-B P35 on this measurement. The Rowenta toothbrush significantly lowered the bleeding on probing scores from baseline to day 15 and from day 15 to day 30. The Braun, Sonicare and Oral-B P35 significantly lowered scores from baseline to day 30, but not from day 15 to day 30. The Rowenta toothbrush was found to be an effective device for the removal of plaque, and for significantly lowering gingivitis compared to the Braun, Sonicare and Oral-B P35 toothbrushes by the conclusion of the study. The Rowenta was significantly better than the Oral-B P35 manual toothbrush for reducing bleeding on probing over the 30 days of this study. PMID- 26630723 TI - [Intentional and Non-Intentional Distortion of Research Findings]. AB - The flood of scientific information increases the risk of research findings distortion. The authors brought attention to the possible pitfalls of statistical inference in biomedical research. Due to intentional or non-intentional errors in study design and size, data collection and inappropriate statistical analysis some of research findings are false or exaggerated. Researchers excessively motivated to publish all possible study results sometimes seek any possible way to achieve p-value less than 0.05. False-positive study results can be obtained in underpowered studies, excessive flexibility in study designs and participants recruitment, probing different control groups, creating special subgroups or changing statistical tests. PMID- 26630724 TI - Crosslinked Porous Starch Particles--a Promising Carrier. AB - Background. Starch is one of the most potential natural polymers used for various bio applications. Literature reports a num- ber of modification strategies such as physical, chemical, enzymatic and genetic to enhance the positive attributes and iron out the undesired features of neat starch. OBJECTIVES: To synthesize a crosslinked porous starch (CPS) as an efficient cargo for the delivery of calcium carbonate in an efficiently controlled manner for the treatment of hyperphosphatemia. MATERIAL AND METHODS: The CPS carrier was synthesized using a natural crosslinker, malic acid. The drug delivery system was formulated, followed by the in situ loading of calcium carbonate during the preparation of the CPS. The developed system was characterized with respect to FTIR, DSC, SEM, moisture content, zeta potential, encapsulation efficiency, phosphate binding efficiency and dissolution studies. RESULTS: The developed formulation was observed to deliver calcium carbonate in an enterically controlled manner. The binding of calcium to phosphate was established to be pH dependent and efficient at pH 7. The moisture content of CPS was in the range of 0.2-0.8%. The zeta potential of the colloidal system was noted to be sufficiently high, indicating the stability. The encapsulation efficiency of CPS particles for calcium was found to be 88-96%. CONCLUSIONS: An efficient, cost-effective, facile and commercially-viable formulation was demonstrated to deliver calcium carbonate for the treatment of hyperphosphatemia. PMID- 26630725 TI - Dissolution Studies of Papaverine Hydrochloride from Tablets in Three Pharmacopoeia Apparatuses. AB - BACKGROUND: In tablet production, the most important aspects are the physical properties of the tablets and their dissolution studies, which can be performed in four pharmacopoeial apparatuses. There are differences between them in construction and action, so differences in the results obtained are possible. OBJECTIVES: The aim of the study was to compare the release of a model drug substance (papaverine hydrochloride) from tablets in three pharmacopoeial dissolution apparatus: a basket, a paddle (closed system) and flow-through cell (open system). MATERIAL AND METHODS: The one series of tablets were produced by direct compression in a tablet press. The physical properties of the tablets (weight and size uniformity test, friability and hardness tests, disintegration time test), drug content and the release study of papaverine hydrochloride from tablets were studied in three dissolution apparatuses. The content of the active substance was studied spectrophotometrically. RESULTS: All tablets met the pharmacopoeic requirements. Over 80% of the model substance released from the tablets after 14 min in flow through the cell apparatus, while in the basket and paddle apparatuses after about 7 min 30 sec. After 20 min, the amount of the substance released in all apparatuses was over 90%. CONCLUSIONS: The release profiles of the drug substance in paddle and basket apparatuses were similar, while in the flow-through cell apparatus it was slightly slower. When the study conditions and composition of the tablets are the same, the release profile of the drug can be affected by the type of dissolution apparatus. PMID- 26630726 TI - Extraction and Characterization of Boswellia Serrata Gum as Pharmaceutical Excipient. AB - BACKGROUND: This manuscript deals with the purification and characterization of Boswellia serrata gum as a suspending agent. The Boswellia serrata gum was purchased as crude material, purified and further characterized in terms of organoleptic properties and further micromeritic studies were carried out to characterize the polymer as a pharmaceutical excipient. The suspending properties of the polymer were also evaluated. The results showed that the extracted gum possesses optimum organoleptic as well as micromeritic and suspending properties. OBJECTIVES: To characterize Boswellia serrata gum as a natural excipient. MATERIAL AND METHODS: Boswellia serrata gum, paracetamol, distilled water. RESULTS: The results showed that the extracted gum possesses optimum organoleptic as well as micromeritic and suspending properties. CONCLUSIONS: It is concluded from the research work that the gum extracted from Boswellia serrata shows the presence of carbohydrates after chemical tests. All the organoleptic properties evaluated were found to be acceptable. The pH was found to be slightly acidic. Swelling Index reveals that the gum swells well in water. Total ash value was within the limits. The values of angle of repose and Carr's Index of powdered gum powder showed that the flow property was good. IR spectra confirmed the presence of alcohol, amines, ketones, anhydrides and aromatic rings. The suspending properties of Boswellia serrata gum were found to be higher as compared to gum acacia while the flow rate of Boswellia serrata gum (1% suspension) was less than gum acacia (1% suspension). The viscosity measurement of both Boswellia serrata gum suspension and gum acacia suspension showed approximately similar results. PMID- 26630727 TI - Comparison of Occurrence of Free Volumes for Rigid Gas Permeable and Soft Contact Lenses. AB - BACKGROUND: The polymeric materials: hydrogel, silicone--hydrogel and methacrylic acid are used in ophthalmology for the manufacture of contact lenses. It is important to research the structure of these materials, mainly the prevalence of free volumes. OBJECTIVES: The study has been conducted in order to comparison the presence of free volume gaps in the structure of the polymer soft contact lenses: Etafilcon A (hydrogel), Narafilcon A (silicone-hydrogel) and the polymer rigid gas permeable (RGP) contact lens (Fluor-Silicon-Methacrylat-Copolymer). In addition, to demonstrate differences in the occurrence of free volumes between types of represented contact lenses. MATERIAL AND METHODS: Three types of polymer contact lenses were used as materials: Etafilcon A, Narafilcon A and Fluor Silicon-Methacrylat-Copolymer. The study was done by means of positron annihilation lifetime spectroscopy (PALS). RESULTS: As a result of the performed measurements, a graphical curve resulted which describes the relationship between the number of the annihilation acts in the time function. Significant changes were observed in the ortho-positronium long life component tau3 and their intensities between the examined polymer contact lenses. CONCLUSIONS: The conducted study using the Tao-Eldrup model indicates the presence of free volume holes in all research materials. There is a clear difference in the free volume sizes and their fractions between measured contact lenses are connected with oxygen permeability in these lenses. The results lead to the following connection: contact lenses of higher oxygen permeability coefficients and a water content of less, have more and larger free volumes than contact lenses of less oxygen permeability coefficient. PMID- 26630728 TI - [Currently Recommended Restorative Materials in Modern Conservative Dentistry]. AB - Conservative treatment which restores the function, aesthetics and protects remaining tooth structure, and what is the most important, the viability of the tooth pulp, is still needed. Dental fillings replace specialized tissues of the tooth that have been lost due to caries or injury. Any decision concerning the use of a particular restorative material should be individualized and based on the competence regarding the composition, properties and characteristics of the specific restorative material. This requires continuous updating of knowledge about available dental materials as well as education of patients who, according to actual models of dental care, should be active partners in the therapeutic process. The selection of restorative materials is often related to financial abilities of the patients, and more generally to the economic model of organized health care in a particular country. Nowadays, amalgam is increasingly dislodged by adhesive materials which permit to save more tooth structure and allow to preserve natural teeth for a longer time. In the nearest future we can expect further development of minimally invasive techniques and improvements of restorative materials, especially their mechanical properties like strength and wear resistance as well as biocompatibility. The article presents restorative materials used in modern dentistry. PMID- 26630729 TI - [SENSORS IN MYCOBACTERIA FOR THE DETECTION OF REDOX STRESS]. AB - Mycobacterium species are exposed to oxidative and nitrosylative stress from environments within and outside the host cells. After the host is infected with the bacilli, macrophages produce superoxide molecules via NADPH oxidase activity and nitric oxide (NO) via inducible NO synthase activity to kill the bacilli. The pathogenic bacilli can successfully survive in host cells via anti-oxidative and anti-nitrosylative mechanisms. In particular, Mycobacterium tuberculosis persisters pose a great problem for chemotherapy because most anti-mycobacterial drugs are ineffective against mycobacteria that are in the persistent state. In accordance with the changes in redox balance, the bacilli change their metabolic pathways from aerobic to anaerobic ones, thereby leading to a change from an actively growing state to a dormant state. Therefore, M. tuberculosis is expected to be equipped with sensors that detect redox stress in the environment such that it can switch to the dormant state and change its metabolic pathways accordingly. In this review, roles of the mycobacterial O2, NO, and CO gas sensors, DosS and DosT, consisting of the DosR regulon, and mycobacterial DNA binding proteins WhiBs, which contain iron-sulfur clusters, in latent infection are discussed. PMID- 26630730 TI - [TUBERCULOSIS ANNUAL REPORT 2013--(4) Tuberculosis Treatment and Treatment Outcomes]. AB - The frequency of re-treatment among patients newly notified with tuberculosis (TB) may indicate inadequate prior treatment. Out of 20,495 new TB patients notified in 2013, 1,262 patients had a previous history of TB treatment. More than half of these patients had received previous TB treatment after 2000. A combination of isoniazid, rifampicin, pyrazinamide, and ethambutol (or streptomycin) has been the standard initial treatment regimen recommended in Japan, and it was used in approximately 90% of all forms of TB patients aged 15 49 years. However, there was a substantial decline in this percentage in the >= 80 years age group. Of the 12,660 patients who were initiated on TB treatment regimen with pyrazinamide in 2012, approximately 13% had not completed the 2 month long regimen with pyrazinamide by the end of 2013. In 2013, 15,972 patients were newly notified with pulmonary TB (PTB). The proportion of hospitalizations at the beginning of TB treatment increased among patients aged >= 40 years. As of end-of-year 2012, the median treatment duration for all forms of TB notified in 2012 was 273 days. The corresponding figure for cases with smear-positive pulmonary TB was 276 days. The treatment success rates for patients with new sputum smear-positive TB (n = 7,694), re-treatment (n = 579), sputum positive for other bacteriological tests (n = 5,656), and bacteriologically negative sputum and other PTB patients (n = 2,482) registered in 2012 were 49.4%, 45.1%, 58.0%, and 62.0%, respectively. The rates of patients lost to follow-up among new sputum smear-positive patients and of patients undergoing re-treatment were 3.7% and 3.5%, respectively--both well below 5%. The death rate among the new sputum smear positive PTB patients was 22.6%, of which more than one-fifth died before the completion of their treatment course. The death rate was relatively high in the 70-79, 80-89 and >= 90 years age groups (23.7%, 36.1%, and 47.8%, respectively). PMID- 26630731 TI - [THE PROS AND CONS OF A NEW MEDICAL ACCIDENT INVESTIGATION SYSTEM]. PMID- 26630732 TI - [CURRENT STATUS AND PERSPECTIVE OF NATIONAL CLINICAL DATABASE IN JAPAN]. PMID- 26630733 TI - [THE CURRENT STATUS AND FUTURE OF MINIMALLY INVASIVE ROBOTIC AND ENDOSCOPIC SURGERY]. PMID- 26630734 TI - [UPPER GASTROINTESTINAL SURGERY ON THE ESOPHAGUS AND STOMACH]. AB - In recent years, the number of facilities performing endoscopic surgeries, i.e., thoracoscopic and laparoscopic surgery, of the upper gastrointestinal tract has increased. Endoscopic surgery has many advantages, such as magnification effects, good lighting, and a wide field of view in deep, narrow spaces. On the other hand, there are some technical difficulties in performing endoscopic procedures as in conventional open surgeries. Compared with endoscopic surgery, robotic surgery may facilitate more accurate, safer operations. The da Vinci Surgical System is a high-quality robotic system used for endoscopic surgeries, which offers a three-dimensional view, more degrees of freedom of the instruments, a tremor-filtering system, etc. However, in the absence of adequate operator skill and knowledge, the system cannot provide substantial improvements in the surgical technique. Endoscopic and robotic surgery must be used to offer treatment to patients which is at least equivalent to conventional surgery. PMID- 26630735 TI - [CURRENT STATUS OF AND OUTLOOK FOR THE LATEST MINIMALLY INVASIVE SURGERY FOR COLORECTAL DISEASES]. AB - Randomized clinical trials (RCTs) comparing laparoscopic surgery (LS) with open surgery (OS) in patients with colon cancer showed no statistical differences in, safety, and long-term outcomes. LS for colon cancer has become a standard procedure. LS for rectal cancer has also shown advantages, although RCTs showed no significant differences between groups in the long-term outcome. The magnification of laparoscopy enables surgeons to operate precisely in the narrow pelvis while sparing the autonomic nerves and nerves to the anal sphincter. Good visualization of the pelvis offers better education and will likely be used more frequently for rectal cancer. Invasion of rectal cancer to other organs and massive tumors are, however, technically demanding. The younger generation is more susceptible to Crohn's disease and inflammatory bowel disease (IBD), and high recurrence rates mean more reoperations. Esthetic outcomes and minimal adhesion maximize the advantages of LS in treating Crohn's disease and IBD. Total proctocolectomy LS for IBD and ulcerative colitis is safe and minimally invasive. However, LS may take longer than OS, and emergencies such as toxic megacolon and massive hemorrhage remain contraindications. Ongoing clinical trials should reveal the feasibility of these new LS procedures in robotic and single-port surgery. PMID- 26630736 TI - [CURRENT STATUS AND FUTURE PROSPECTS OF LAPAROSCOPIC HEPATOBILIARY-PANCREATIC SURGERY]. AB - Laparoscopic hepatobiliary-pancreatic surgery (L-HPB), excluding cholecystectomy, is a highly specialized field. However, important technological developments and improved endoscopic procedures are being established. Thus, the number of L-HPB procedures has been increasing. Recent systematic reviews or metaanalyses based on observational data have reported not only the advantage of less invasiveness in early disease stages but also less bleeding, fewer complications, and no oncologic disadvantage, although prospective, randomized trials have not yet been performed. L-HPB is expected to develop further in the future as a new surgical method to improve patients' quality of life. While it is certain that L-HBP surgery will not totally supplant open HBP surgery, the laparoscopic approach in selected patients should be considered as the treatment of choice. However, it must be remembered that the benefits of L-pancreatic duodenectomy as well as liver resection should be balanced against the high degree of difficulty. Robotic assisted L-HBP is expected to support difficult operative procedures by allowing more precise hand manipulations, although a greater accumulation of clinical cases is needed to evaluate this. The success of L-HBP is affected by individual surgeons' learning curves and the selection of patients with appropriate indications. The basic principle of L-HBP as well as other digestive surgery is to achieve minimal invasion with optimal safety. PMID- 26630737 TI - [MINIMALLY INVASIVE THORACIC SURGERY: PRESENT STATUS AND FUTURE PERSPECTIVES]. AB - Minimally invasive general thoracic surgery entered a new era with the introduction of thoracoscopic surgery into clinical practice in the early 1990s. Thoracoscopic surgery is already widely accepted in most countries. However, single-port thoracic surgery, needlescopic thoracic surgery, and robot-assisted thoracic surgery are not yet accepted widely. More advances in the instruments and equipment appear necessary. PMID- 26630738 TI - [UPDATE ON MINIMALLY INVASIVE CARDIAC SURGERY]. AB - Minimally invasive surgery is an attractive choice for patients undergoing major cardiac procedures. This paper focuses on minimally invasive mitral valve repair and robotic surgery using the da Vinci Surgical System. Minimally invasive mitral valve repair is usually performed through a right minithoracotomy with direct vision. The techniques used in this procedure are similar to those in open surgery. The outcome of minimally invasive mitral valve repair is also equivalent to that of open surgery, with high levels of patient satisfaction. On the other hand, minimally invasive cardiac surgery using the da Vinci Surgical System has not been approved in Japan except for internal mammary artery harvesting. A Japanese clinical trial of da Vinci surgery for mitral valve repair and atrial septal defect closure has been completed and approval is awaited. Although da Vinci surgery is technically demanding, this less-invasive technique may provide another choice for patients in the near future. PMID- 26630739 TI - [PRESENT SITUATION AND FUTURE OF ENDOSCOPIC BREAST SURGERY FOR BREAST DISEASE]. AB - Endoscopic breast surgery (EBS) for breast disease has been developed in Japan since 1995. The purpose of EBS is to accomplish the same local control as with conventional breast surgery through small skin incisions. Over the nearly 20-year history of EBS, equipment size has been reduced and procedures have been simplified. Recently, oncoplastic breast surgery, breast surgery using the open window method, and imageguided nonsurgical ablation have been introduced into clinical practice for local breast treatment. Simplified procedures for EBS should be applied with newly introduced local treatments to achieve local control and expand the indications for those local treatments. PMID- 26630740 TI - [CURRENT STATUS AND FUTURE OF PEDIATRIC ENDOSCOPIC SURGERY]. AB - Developments in laparoscopic surgery have undoubtedly improved postoperative discomfort and morbidity, decreased hospital stays, enhanced recovery, and improved wound cosmesis. There are, however, several limitations to the use of conventional laparoscopic and thoracoscopic surgical techniques such as two dimensional visualization of the surgical field with loss of depth perception, counterintuitive movements with rigid, nonarticulated instruments, loss of hand eye coordination, and poor ergonomics for the operating surgeon. However, thoracoscopic repair of tracheoesophageal fistulas and laparoscopic repair of choledochal cysts and biliary atresia have recently been performed. We anticipate that, as the number of complex pediatric laparoscopic/thoracoscopic procedures performed increases, there will be improvements in the hardware with associated measurable benefits in patient outcomes. PMID- 26630741 TI - [SURGICAL STRATEGY FOR LOCALY ADVANCED LUNG CANCER]. PMID- 26630742 TI - [SURGERY FOR LOCALLY ADVANCED NON-SMALL CELL LUNG CANCER]. PMID- 26630743 TI - [WHAT WE CAN LEARN FROM A CASE OF MEDICAL MALPRACTICE--CAREGIVER ACCUSED OF NEGLIGENCE FOR THE DEATH OF A NURSING HOME RESIDENT FROM FOOD ASPIRATION]. PMID- 26630744 TI - [TIPS AND PITFALLS FOR DETECTION AND PRESERVATION OF PARATHYROID IN TOTAL THYROIDECTOMY]. PMID- 26630745 TI - [CURRENT STATUS OF PERIOPERATIVE MANAGEMENT IN PATIENTS UNDERGOING ANTITHROMBOTIC (ANTIPLATELET OR ANTICOAGULATION) THERAPY: RESULTS OF A QUESTIONNAIRE SURVEY]. AB - In non-cardiac surgery patients receiving antithrombotic therapy (antiplatelet therapy (APT) and anticoagulation therapy (ACT)) for prevention of cardiovascular and/or cerebrovascular complications, perioperative antithrombotic management is challenging due to increased risks of both bleeding and thromboembolic complications. The effect of APT and/or ACT on surgical outcomes in patients undergoing general or gastroenterologic surgery is still unknown because of the limited evidence. We conducted a survey of 38 major surgical facilities at Kyoto University Related Hospital Surgical Group of Cancer Research on perioperative management in patients undergoing antithrombotic therapy. In elective surgery, most facilities used heparin substitution during cessation of ACT or APT, while surgery was performed under continuation of APT in 22% of facilities. In emergent surgery, the effect of ACT was reversed before surgery, but surgery was performed without the reversal of APT effect. Laparoscopic surgery was performed in most facilities in spite of the use of ACT or APT. Severe bleeding complications requiring transfusion of fresh frozen plasma or platelet were experienced in over half of facilities. Conclusion : Variation of antithrombotic management has shown to be large between facilities. For safe surgical treatment, creation of the perioperative antithrombotic management guideline on the basis of the evidence from multicenter study is requisite. PMID- 26630746 TI - [CHANGES IN THE PROPORTION OF WOMEN IN THE FIELD OF GENERAL THORACIC SURGERY--IT IS NECESSARY FOR WOMEN TO SUCCESS]. PMID- 26630748 TI - INTERPLAY BETWEEN FOOD SAFETY CLIMATE, FOOD SAFETY MANAGEMENT SYSTEM AND MICROBIOLOGICAL OUTPUT IN FARM BUTCHERIES AND AFFILIATED BUTCHER SHOPS. PMID- 26630749 TI - FARMERS' REASONS TO ACCEPT BIO-BASED FERTILIZERS: A CHOICE EXPERIMENT IN FLANDERS. PMID- 26630750 TI - THE IMPACT OF INITIAL EVENNESS ON THE PRESERVATION OF BIODIVERSITY FOR IN SILICO BACTERIAL COMMUNITIES: A STOCHASTIC, SPATIAL INDIVIDUAL-BASED MODEL. PMID- 26630751 TI - CONTEXT MATTERS: THE IMPORTANCE OF MARKET CHARACTERISTICS IN THE VOLATILITY OF FEEDSTOCK COSTS FOR BIOGAS PLANTS. AB - Recently, biogas plant managers in Flanders face increased financial uncertainty. Between 2011 and 2012, 20% of the Flemish biogas plants went bankrupt. Difficulties in obtaining feedstock at stable and affordable prices is one reason why the biogas sector struggles. In literature, contracting is often proposed as a way to decrease the volatility of the feedstock costs. However, these studies generally do not consider the context in which the biogas plant manager needs to buy the feedstock. Yet, this context could be of specific importance when biogas plant managers are in competition with other users of the same biomass type. Silage maize is an example of such a feedstock, as it is both used by dairy farmers and biogas plant managers. Using a combination of qualitative research and agent-based modelling, we investigated the effect of specific characteristics of the silage maize market on the acquisition of local silage maize by biogas plant managers. This paper details the institutional arrangements of the silage maize market in Flanders and the results of a scenario analysis, simulating three different scenarios. As shown by the results, the time of entry into the market, as well as the different institutional arrangements used by the biogas plant managers as opposed to dairy farmers could explain the difficulties in obtaining a stable supply of local silage maize by biogas plants. Our findings can help to develop mitigation strategies addressing these difficulties. PMID- 26630752 TI - THE INFLUENCE OF SALT CONTENT AT DIFFERENT CONCENTRATIONS OF TERASI TO THE SENSORY CHARACTERISTICS OF SAMBAL TERASI, THE CHILI SAUCE ADDED WITH TERASI. AB - The type of terasi (the Indonesian seafood fermented paste) and the ingredients used can give sambal terasi (ST), the chili sauce added with terasi, its identity and taste distinction. Inherit from its production, salt content differs the flavor(s) of product added with terasi. This research explored the role of terasi salt content, either from the origin of terasi or by salt adjustment, to the products acceptability and sensory characteristics perceived during subsequent sensorial evaluations. Six types of terasi were characterized based on the proximate and salt content, and prepared as STs with and without salt adjustment at several terasi concentrations. 118 panelists conducted sensory evaluations for overall acceptability at 12.5% terasi; at lower concentration specific tastes (sweet, bitter, salty, sour, umami, fishy and rebon) were characterized by 80 panelists. Results showed that the acceptance of ST is more due to its innate origin salt content and to the suitability saltiness perceived. The specific odor of terasi, combining with other taste(s), when prepared at higher terasi concentration as practiced in restaurant, home and commercial products showed masking effect(s). After saltiness adjusted, different types of terasi showed different taste characteristics. Preferred ST were different between higher and lower concentration. Better tastes characteristics and stronger spices taste were found at lower salt content (and terasi concentration). PMID- 26630753 TI - EVALUATION OF THERMOTOLERANT ACETOBACTER PASTEURIANUS STRAINS ISOLATED FROM MOROCCAN FRUITS CATALYZING OXIDATIVE FERMENTATION AT HIGH TEMPERATURE. AB - Six strains of acetic acid bacteria were isolated from Moroccan local products and their potential as industrial strains was evaluated in lab-bioreactor. Three of them, namely TAV01, AF01 and CV01, isolated from traditional apple vinegar, apple and cactus fruit, respectively were selected and their responses to high temperature were assessed. Morphological and biochemical identification confirmed that these strains belong to Acetobacter species. Their growth and acetic acid production were compared with the thermoresistant reference strain, Acetobacter senegalensis and mesophilic strains of Acetobacter pasteurianus. The two strains AF01 and CV01 showed abundant growth and noticeable acetic acid production ability at high temperatures (38 to 41 degrees C). A thermophilic character was observed for AF01 strain. Indeed, this bacterium grew better at 38 than 30 degrees C. PMID- 26630754 TI - DOES THE WATER TEMPERATURE INFLUENCE THE FATTY ACID METABOLISM OF RAINBOW TROUT (ONCORHYNCHUS MYKISS) FED A VEGETABLE DIET? PMID- 26630755 TI - SYNTHESIS AND BIOLOGICAL EVALUATION OF NATURALLY AND NON-NATURALLY OCCURRING HALOGENATED ANALOGUES OF N-ACYL HOMOSERINE LACTONES AS QUORUM SENSING MODULATORS. PMID- 26630756 TI - TREATMENT OF LANDFILL LEACHATE BY COUPLING COAGULATION-FLOCCULATION OR OZONATION TO GRANULAR ACTIVATED CARBON ADSORPTION. AB - A major concern for landfilling facilities is the treatment of their leachate. To optimize organic matter removal from this leachate, the combination of two or more techniques is preferred in order to meet stringent effluent standards. In our study, coagulation-flocculation and ozonation are compared as pre- treatment steps for stabilized landfill leachate prior to granular activated carbon (GAC) adsorption. The efficiency of the pre treatment techniques is evaluated using COD and UVA254 measurements. For coagulation- flocculation, different chemicals are compared and optimal dosages are determined. After this, iron (III) chloride is selected for subsequent adsorption studies due to its high percentage of COD and UVA254 removal and good sludge settle-ability. Our finding show that ozonation as a single treatment is effective in reducing COD in landfill leachate by 66% compared to coagulation flocculation (33%). Meanwhile, coagulation performs better in UVA254 reduction than ozonation. Subsequent GAC adsorption of ozonated effluent, coagulated effluent and untreated leachate resulted in 77%, 53% and 8% total COD removal respectively (after 6 bed volumes). The effect of the pre treatment techniques on GAC adsorption properties is evaluated experimentally and mathematically using Thomas and Yoon-Nelson models. Mathematical modelling of the experimental GAC adsorption data shows that ozonation increases the adsorption capacity and break through time with a factor of 2.5 compared to coagulation flocculation. PMID- 26630757 TI - FUNCTIONAL IMAGING OF LEAF HYDRAULICS USING 11C-PET. PMID- 26630758 TI - THE UNKNOWN SHADOWS OF TREHALASE. AB - Each year brings new facts concerning multiple roles of sugar pathways in plant metabolism. One of them--the trehalose pathway--has been shown to play a role in stress signalling. The last enzyme of this pathway--trehalase--has been proven to be strongly expressed in guard cells. Modifications of its abundance cause changes in stomatal closure and response to abscisic acid. Our phenotypical studies of different mutants of Arabidopsis thaliana and Musa have enabled us to propose a new function of trehalase. It might play a role in the feedback of sucrose as a closing signal for stomata in reaction to an efficient photosynthesis. To characterize the phenotype we measured: the dynamic cumulative water loss, the dynamic leaf surface temperature, and the stomatal conductance. Based on the obtained results we have determined the time points for a proteomics study. The exact role of trehalase and related proteins in the proposed mechanism will be defined with multiple analysis including mass spectrophotometry and enzymatic activities. The samples will be collected from a wide type of plants including model organism (Arabidopsis--wild type, trehalase mutant plants) and crops (banana). The final results will shed light on the complete role of trehalase and the feedback pathway. PMID- 26630759 TI - NITROGEN USE EFFICIENCY IN NATURAL POPULATIONS OF ARABIDOPSIS THALIANA. PMID- 26630760 TI - ROOT MORPHOLOGY OF ARABIDOPSIS THALIANA IN RESPONSE TO MAGNESIUM SUPPLY. PMID- 26630761 TI - GENETIC VARIATION OF ROOT GROWTH DYNAMICS IN MAIZE. PMID- 26630762 TI - INDIVIDUAL-BASED MODELS: POWERFUL OR POWER STRUGGLE? AB - Individual-based models (IBMs) offer endless possibilities to explore various research questions but come with high model complexity and computational burden. Large-scale IBMs have become feasible but the novel hardware architectures require adapted software. The increased model complexity also requires systematic exploration to gain thorough system understanding. We elaborate on the development of IBMs for vaccine-preventable infectious diseases and model exploration with active learning. Investment in IBM simulator code can lead to significant runtime reductions. We found large performance differences due to data locality. Sorting the population once, reduced simulation time by a factor two. Storing person attributes separately instead of using person objects also seemed more efficient. Next, we improved model performance up to 70% by structuring potential contacts based on health status before processing disease transmission. The active learning approach we present is based on iterative surrogate modelling and model-guided experimentation. Symbolic regression is used for nonlinear response surface modelling with automatic feature selection. We illustrate our approach using an IBM for influenza vaccination. After optimizing the parameter spade, we observed an inverse relationship between vaccination coverage and the clinical attack rate reinforced by herd immunity. These insights can be used to focus and optimise research activities, and to reduce both dimensionality and decision uncertainty. PMID- 26630763 TI - MODELLING THE CELL EXPANSION IN MAIZE LEAF. PMID- 26630764 TI - RECIPE COMPLETION USING MACHINE LEARNING TECHNIQUES. AB - Completing a recipe is a non-trivial task, as the success of ingredient combinations depends on a multitude of factors such as taste, smell, texture, etc. The aim of our work is to build a model that adds one or more ingredients to a given number of ingredients. The idea is based on leftover ingredients in a fridge. A person could list the available ingredients in his or her fridge and the model would suggest some additional ingredients to create a full recipe. PMID- 26630765 TI - INCLUDING EXPLICIT MARKER-BY-ENVIRONMENT INTERACTION FOR LARGE-SCALE GENOMIC PREDICTION. PMID- 26630766 TI - PREDICTING CONSUMER ACCEPTANCE OF PACKAGED MEAT USING L1-REGULARIZED ORDINAL REGRESSION. PMID- 26630767 TI - CAN A SINGLE STAGE HYBRID CONSTRUCTED WETLAND ACHIEVE GOOD TOTAL NITROGEN REMOVAL? PMID- 26630768 TI - ANALYSIS OF THE MODE OF ACTION OF A PSEUDOMONAS AERUGINOSA ANTI-PERSISTER COMPOUND. PMID- 26630769 TI - PRIMARY HUMAN SKELETAL MYOBLAST CELLS FROM PATIENTS WITH CHRONIC HEART FAILURE EXHIBIT A DELAYED PROLIFERATIVE CAPACITY. PMID- 26630770 TI - EFFECT OF ADSORBENTS ON MIXED CULTURE INTERACTION WITH DHA AND ITS BIOHYDROGENATION IN VITRO. PMID- 26630771 TI - BACTERIAL COMMUNITY DYNAMICS AND ECOTOXICOLOGICAL ASSESSMENT DURING BIOREMEDIATION OF SOILS CONTAMINATED BY BIODIESEL AND DIESEL/BIODIESEL BLENDS. AB - The gradual introduction of biodiesel in the Brazilian energy landscape has primarily occurred through its blending with conventional petroleum diesel (e.g., B20 (20% biodiesel) and B5 (5% biodiesel) formulations). Because B20 and lower level blends generally do not require engine modifications, their use as transportation fuel is increasing in the Brazilian distribution networks. However, the environmental fate of low-level biodiesel blends and pure biodiesel (B100) is poorly understood and the ecotoxicological-safety endpoints of biodiesel-contaminated environments are unknown. Using laboratory microcosms consisting of closed reactor columns filled with clay loam soil contaminated with pure biodiesel (EXPB100) and a low-level blend (EXPB5) (10% w/v), this study presents soil ecotoxicity assessement and dynamics of culturable heterotrophic bacteria. Most-probable-number (MPN) procedures for enumeration of bacteria, dehydrogenase assays and soil ecotoxicological tests using Eisenia fetida have been performed at different column depths over the course of incubation. After 60 days of incubation, the ecotoxicity of EXPB100-derived samples showed a decrease from 63% of mortality to 0% while EXPB5-derived samples exhibited a reduction from 100% to 53% and 90% on the top and at the bottom of the reactor column, respectively. The dehydrogenase activity of samples from EXPB100 and EXPB5 increased significantly compared to pristine soil after 60 days of incubation. Growth of aerobic bacterial biomass was only observed on the top of the reactor column while the anaerobic bacteria exhibited significant growth at different column depths in EXPB100 and EXPB5. These preliminary results suggest the involvement of soil indigenous microbiota in the biodegradation of biodiesel and blends. However, GC-FID analyses for quantification of fatty acid methyl esters (FAMEs) and aliphatic hydrocarbons and targeted sequencing of 16S rRNA tags using illumina platforms will provide important insights into the profiles and underlying mechanisms of (bio)diesel biodegradation in soil environments. PMID- 26630772 TI - A REDEFINITION OF THE STRUCTURE-FUNCTION PARADIGM EXAMINED BY CROWDING STUDIES AND RAMAN OPTICAL ACTIVITY. PMID- 26630773 TI - BIOAVAILABILITY AND METABOLISM OF GRAPE TRANS-RESVERATROL ON CACO-2 CELLS. PMID- 26630774 TI - ANALYSIS OF INTERACTION OF PHENOLIC COMPOUNDS WITH CHOLECYSTOKININ SIGNALLING PATHWAY TO EXPLAIN EFFECTS ON REDUCING FOOD INTAKE. PMID- 26630775 TI - OXIDATIVE STATUS IN PIGLETS IS AFFECTED BY THE WEANING PROCESS. PMID- 26630776 TI - USING 3D FLOWERS AS NEW TOOLS TO STUDY BUMBLEBEES BEHAVIOUR. PMID- 26630777 TI - Predatory Publisher Statement. PMID- 26630778 TI - Competencies for the Nurse Practitioner Working with Adult Urology Patients. AB - The role of the nurse practitioner (NP) has expanded into specialty domains. This document proposes 24 competencies specific to the urology NP, which are also consistent with the recommendations of National Organization of Nurse Practitioner Faculties (NONPF) and compliment the American Urologic Association (AUA) 2014 white paper on the incorporation of advanced practice providers in urology practices. It describes three levels of practice and experience progression for the urology NP working with adult patients, independent of specific clinical setting. These urology-specific competencies supplement and complement the core competencies and population-focused competencies of generalist nurse practitioners. PMID- 26630779 TI - Transition from Pediatric to Adult Health Care in Patients with Chronic Illnesses: An Integrative Review. AB - A systematic review of the literature was performed to identify barriers, themes, or additional insight specific to the transitional care processes from a pediatric to an adult health care setting for patients with spina bifida. PMID- 26630780 TI - Health Care Utilization and Complications Rates among Users Of Hydrophilic-Coated Catheters. AB - This article presents results from an electronic survey completed by intermittent catheterization users who were registered members of a global web-based database. The results provide data on complication rates, health care utilization, and benefits from using hydrophilic-coated urinary catheters isotonic to urine. PMID- 26630781 TI - Application to the Evidence Base: Health Care Utilization and Complications Rates among Users of Hydrophilic-Coated Catheters. PMID- 26630783 TI - A Message from the President. PMID- 26630782 TI - A Decision Tree Model for Postoperative Pain Management. AB - Postoperative pain management involves many factors. Current information regarding assessment and treatment of postoperative pain is discussed. A decision tree model flowchart was developed based on patient characteristics, comorbidities, and the type of pain. PMID- 26630784 TI - Professionalism in Nursing, Part II. PMID- 26630785 TI - Labeling Patients. PMID- 26630786 TI - [Clinical Characteristics of Metronidazole-induced Encephalopathy: A Report of Two Cases and a Review of 32 Japanese Cases in the Literature]. AB - Metronidazole is an antibiotic classically used against most anaerobic bacteria and protozoa. Because an intravenous form of metronidazole has recently entered the market, the use of this antibiotic is attracting renewed interest in many clinical settings in Japan. However, neurotoxicity is a major adverse event: in the central nervous system metronidazole-induced encephalopathy is a rare but serious condition. We performed a literature review of 34 cases including 2 of our cases, 25 from domestic conference abstracts, and 7 cases presented in full research papers. The mean patient age was 64.7 years. The conditions most commonly treated with metronidazole were brain abscess (35.3%), liver abscess (17.6%), and Clostridium difficile infection (14.7%). The most common predisposing conditions were liver dysfunction (26.5%), diabetes and other metabolic disorders (20.6%), and hematologic or solid organ malignancy (14.7%). The mean period of administration before the onset of encephalopathy symptoms was 61.3 days, and the mean total dose was 95.9g. The initial chief complaints were dysarthria (in 70.6% of the cases) and ataxia (61.8%); 82.4% of the cases were diagnosed on the basis of MRI (T2-weighted or FLAIR imaging). The key imaging finding was high intensity in the dentate nucleus bilaterally (82.4%). Stopping the metronidazole led to symptom remission within 8.5 days, but the MRI changes remained longer than the clinical symptoms. Two patients (6.0%) developed irreversible disturbance of consciousness. Although the mechanisms of this type of encephalopathy have not yet been elucidated, localized nerve-cell edema is likely caused by decreased metronidazole metabolism associated with liver and metabolic dysfunction. Careful observation for neurologic signs should be conducted during the treatment of brain abscesses associated with metronidazole administration, because patients with brain abscesses are naturally at high risk of metronidazole-induced encephalopathy. PMID- 26630787 TI - [Outpatient Parenteral Antimicrobial Therapy (OPAT) with Elastomeric Pumps in Collaboration with Home-visit Nursing Services in Japan: Experience of the First 10 Patients]. AB - In 2014, we reported the first trial based on outpatient parenteral antimicrobial therapy (OPAT) with continuous infusions in Japan. Following this, we found many patients who were eligible for OPAT but could not undertake it owing to difficulties in accessing the clinic daily. To overcome this problem, we created a model in collaboration with visiting nursing stations and started providing OPAT with the services. We report herein on a summary of the investigation of the first 10 patients treated under this model. We collected data pertaining to diseases, organisms, antimicrobials, treatment duration, bed days saved, outcome, readmission rate, and cost reductions associated with these patients. The most commonly targeted disease was osteomyelitis, followed by infective endocarditis. The condition of nine of the patients was complicated by bacteremia. The most commonly targeted organism was Staphylococcus aureus. Cefazolin was the most frequently prescribed antimicrobial, followed by Penicillin G. The median duration for OPAT was 12 days (range: 5-23 days). The total number of bed days saved was 129. All patients completed the planned OPAT. Eight patients were cured and two showed improvement. Only one patient was readmitted within a month after the completion of therapy. The estimated medical cost reduction was 496,540 yen, which is approximately 4,200 US dollars. Collaboration with visiting nursing stations provided OPAT to the patients who had difficulties in accessing the clinic daily. Our study shows that OPAT administered by continuous infusion in collaboration with home-visit nursing services would be a safe and feasible practice for efficient bed utilization and medical cost saving. PMID- 26630788 TI - [Usefulness of a Newly Developed Immunochromatographic Assay Kit for the Detection of Respiratory Syncytial Virus]. AB - We evaluated the usefulness of IMMUNOCATCH-RSV (Eiken chemical Co., Ltd.) (IC-A), a newly developed immunochromatographic assay kit for detection of respiratory syncytial virus (RSV). For the clinical study, 210 nasal swabs and 134 nasopharyngeal aspirates were collected from pediatric patients with acute respiratory tract infections in 2013. Three immunochromatographic assay kits (IC A, IC-B and IC-C), and the RT-PCR method were used for the detection of RSV. The detection times for IC-A, IC-B and IC-C were 8, 15 and 10 minutes, respectively. The positive rates for IC-A using nasal swabs and nasopharyngeal aspirates were 33.8% and 35.8%, respectively. For the nasal swab specimens, the total concordance rates of RT-PCR with IC-A, IC-B and IC-C were 96.2% (202/210), 89.5% (188/210), and 90.5% (143/158), respectively. As for the nasopharyngeal aspirates, the total concordance rates of RT-PCR with IC-A, IC-B and IC-C were 96.3% (129/134), 94.0% (125/133), and 97.7% (130/133), respectively. The minimum detection concentration of IC-A was 3.0 x 10(2) TCID50/mL for the RSV subgroup A strain, and 7.5 x 10 TCID50/mL for the RSV subgroup B strain. In conclusion, the current data indicate that IC-A is a useful kit for more rapid and accurate detection of RSV infection. PMID- 26630789 TI - [Clinical Study of Acute Uncomplicated Cystitis]. AB - Escherichia coli is the most commonly isolated bacterium in urinary tract infections, especially in acute uncomplicated cystitis. It is reported that fluoroquinolone-resistant E. coli is increasing. However, according to the guidelines for antimicrobial use published by the Japanese Associations for Infectious Diseases (JAID) and the Japanese Society of Chemotherapy (JSC) in 2014, the first line antimicrobial regimen for the treatment of acute uncomplicated cystitis is a 3-day regimen with fluoroquinolone. We analyzed the causative bacteria and clinical efficacy of antimicrobial treatment in acute uncomplicated cystitis cases at our institute. Patients diagnosed as having acute uncomplicated cystitis who had >= 10(4) colony-forming units/mL of bacteria in their midstream urine in our outpatient clinic between 2012 and 2013 were enrolled in this study. We analyzed their clinical data retrospectively. From 173 patients, 212 strains were isolated. Of these, 135 (63.7%) were E. coli, including 15 strains (11.1%) that were levofloxacin resistant. One hundred twenty three patients (63.7%) were treated with cephalosporin, and 46 patients (26.6%) were treated with fluoroquinolone. In all, 140 patients (80.9%) visited the outpatient clinic for an average of 8.4 days after their treatment. For 130 patients (92.6%), the clinical outcomes of antimicrobial treatment were judged as effective. The clinical outcomes were effective in 92.1% of the patients with cephalosporin treatment and in 97.1% of those with fluoroquinolone treatment. Only one patient who had levofloxacin-resistant E. coli in her urine was treated with fluoroquinolone. The clinical outcome was effective. Of the E. coli isolated from acute uncomplicated cystitis patients, 11.1% were levofloxacin-resistant strains. However, the clinical efficacy of antimicrobial treatment was relatively high (92.9%) in this study. The antimicrobial treatment for acute uncomplicated cystitis recommended by the guidelines published by the JAID and JSC was effective in the current situation. PMID- 26630790 TI - [Surveillance of Antimicrobial Resistant Esherichia coli by Rectal Swab Method- Annual Change of Prevalence of Quinolone-resistant and ESBL Producing Strains from 2009 to 2013]. AB - Although most of commonly used antimicrobial agents had been susceptible to Esherichia coli, recently there are a lot of reports concerning about community acquired infection caused by resistant E. coli. The aim of this study is to define the prevalence of resistant E. coli in normal flora colonization by the rectal swab method. From June 2009 to December 2013, 251 male patients (50-85 year-old, median 68) planned to transrectal prostate biopsy participated in this study. Stools stuck on the glove at the digital examination were provided for culture specimen. Identification of E. coli and determination of MIC was performed by MicroScan WalkAway40plus (Siemens). Isolated E. coli were deemed quinolone-resistant strains when their MIC of levofloxacine was 4 MUg/mL or above according to the breakpoint MIC by the CLSI criteria. ESBL producing ability was determined by the double disk method used by CVA contained ESBL definition disc (Eikenkagaku). Of the 251 study patients, 224 patients had positive cultures of E. coli. Twenty-four patients had quinolone-resistant strains and 9 patients had ESBL producing strains. The prevalence of quinolone-resistant strains in 2009, 2010, 2011, 2012 and 2013 were 5.9% (2 out of 34 strains), 13.5% (5 out of 37 strains), 12.5% (4 out of 32 strains), 9.0% (6 out of 67) and 13.0% (7 out of 54 strains), respectively. The prevalence of ESBL producing strains in 2009, 2010, 2011, 2012 and 2013 were 0% (0 out of 34 strains), 5.4% (2 out of 37 strains), 3.1% (1 out of 32 strains), 3.0% (2 out of 67 strains) and 7.4% (4 out of 54 strains), respectively. In 2013, the prevalence of antimicrobial resistant E. coli, both quinolone-resistant and ESBL producing strains, were increasing. We have to pay a close attention to the increase of resistant E. coli. PMID- 26630791 TI - [The Great Imitator; Clavicular Tuberculosis Mimics a Metastatic Neoplasm]. AB - In the same manner as syphilis, tuberculosis (TB) was often called "The Great Imitator". We have to consider not only malignancies but also TB as a differential diagnosis when we find any tumorous regions. We report herein on a rare case, clavicular osteomyelitis due to TB. A 72-year-old female, with diabetic nephropathy, was on maintenance hemodialysis. She had a fall 2 months prior to admission followed by pain around her right clavicle. Ulceration occurred in that region a month prior to admission, and CT scan revealed a fracture of the right clavicle with a tumor surrounding that area. Seven days prior to admission, she went to a neurologist because of dizziness. MRI of the brain revealed a tumor in her pons. The physician suspected the tumor was metastasis. Needle biopsies revealed only necrotic tissue so the medical oncologist consulted us because they suspected it was caused by infection of some kind. From the patient's history and the physical examination, we suspected TB osteomyelitis and grew some more cultures, but only MRSA and E. coli were detected. We administered vancomycin and cefmetazole for the secondary bacterial osteomyelitis. After a month of hospitalization, we found miliary regions on her chest CT and Mycobacterium tuberculosis was grown from the needle biopsy specimen. We started multi-antituberculosis therapy and the patient had a good prognosis. We report herein on a rare case of clavicular osteomyelitis due to TB, together with a review of the literature. PMID- 26630792 TI - [A Fatal Case of Severe Fever with Thrombocytopenia Syndrome Complicated by Hemophagocytic Lymphohistiocytosis]. AB - Severe fever with thrombocytopenia syndrome (SFTS) is a recently identified emerging viral infectious disease in China that is caused by a novel phlebovirus in the family Bunyaviridae, SFTS virus, with an average case fatality rate of 12 30%. A cytokine storm with abnormally expressed cytokine profiles is associated with the disease severity. Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and lifethreatening syndrome associated with excessive immune activation. We report herein on a fatal case of SFTS complicated by HLH. Consecutive plasma exchange and immunomodulatory therapy was ineffective in our case. The pathognomonic histological feature was necrotizing lymphadenitis with massive hemophagocytosis of systemic lymphoid tissues with SFTS viruses and SFTS RNA copies. No specific treatment of SFTS is available, and an effective treatment strategy for patients with rapidly progressing SFTS has not been established. Appropriate immunomodulatory therapy is necessary for SFTS patients complicated by HLH. PMID- 26630793 TI - [Intravenous Minocycline and Levofloxacin for Treatment of Two Cases of Japanese Spotted Fever]. AB - We report herein on two cases of Japanese spotted fever (JSF) treated with intravenous minocycline (MINO) and levofloxacin (LVFX). An 80 year-old woman (Case1) and a 63 year-old man (Case2) with high fever (> 39 degrees C) and wide spread skin erythema were admitted because they were suspected of having developed JSF. After admission, we treated them with intravenous MINO and LVFX. The patients' fevers were resolved within 36 hours after antibiotics. They were diagnosed as having JSF based on the serological test, and Rickettsia japonica was detected from the genetic findings (PCR analysis from eschar) only in case 1. In the treatment of fulminant JSF (body temperature > 39 degrees C) the prompt administration of a combination of tetracycline and new quinolone has been recommended. The number of cases of JSF and its endemic area are gradually increasing in Japan. As for new quinolones, ciprofloxacin and tosufloxacin have been used against to JSF in Japan, but LVFX may become a new option. PMID- 26630794 TI - [Case Report: Clindamycin with Primaquine Therapy for Severe Pneumocystis Pneumonia]. AB - A Japanese female in her 60's on 5 years' treatment with prednisolone 5 mg for ulcetarive colitis developed severe bloody stools and diarrhea and was admitted. A total colectomy was performed because leukocytapheresis with intravenous corticosteroid administration (prednisolone 70 mg/day) relieved her symptoms partially. Pneumocystis pneumonia (PCP) prophylaxis was not introduced then. She developed acute respiratory failure on postoperative day (POD) 8, and was intubated and moved to our intensive care unit. PCP was suspected and sulfamethoxazole/trimethoprim (ST) was started with methylprednisolone 40 mg/day. The pneumonia initially improved but got worse around POD 27 and pulse corticosteroid therapy was administered. Antibiotics were first changed to pentamidine and finally changed to clindamycin/primaquine because of adverse reactions due to both of the medications. She recovered fully and experienced no exacerbation after discontinuation of the secondary prophylaxis. This is the first report of primaquine administration for PCP in Japan. Clindamycin/primaquine are second-line drugs but very important because the first line medications such as ST and pentamidine cause adverse reactions and frequently result in discontinuation, as was the case in our present patient. Nowadays immunosuppresive therapy for malingnancies and autoimmune diseases has been introduced more frequently than before, PCP has attracted more attention. Therefore primaquine should be approved for appropriate use without delay in Japan. PMID- 26630795 TI - [Questionnaire Survey About the One Health Concept Among Medical Doctors and Veterinarians in Japan]. PMID- 26630796 TI - [Characterization of Group A Rotavirus Genotypes Isolated from Gastroenteritis among Children during the 2008/2009 through 2013/2014 Seasons in Nara Prefecture, Japan]. PMID- 26630798 TI - [On the present and future of National Sanatorium Tohokushinseien]. PMID- 26630797 TI - [On the present and future of Japanese Leprosariums--the case of Oshima-seishoen Sanatorium]. AB - In all thirteen national sanatorium in Japan, the number of patients have gradually declined year by year. Although it has been long discussed about maintenance and utilization of facilities in the future, clear and specific plans are still not sufficient. Especially Oshima-seishoen sanatorium, Oshima island is an isolated island located off the coast of Takamatsu port. It is very different from the other Leprosy sanatoriums in that there are no general population other than patients and officials of the sanatorium. So it is very difficult to have outlooks of the future of this sanatorium. In the conversation with the patients, two serious concerns have been raised. Whether patients will be provided support and treatment throughout life. The other one is whether the government would manage the ossuary permanently under the responsibility for the isolation policy of leprosy patients. These two points are also written in promotion measures of Oshima formulated by "Meeting to consider the future of Oshima", that was established in 2013 proposed by Takamatsu city authorities. In the situation of aging of patients accelerating, I considered that to promise these two points are the top priority. PMID- 26630799 TI - [The present conditions and future of National Sanatorium Kikuchi Keifuen]. AB - National Sanatorium Kikuchi Keifuen (NSKK), housing 286 residents as of May 2015, is one of the biggest and oldest Hansen's disease sanatoriums in Japan. Located near the center of Kumamoto city, NSKK has maintained an excellent working relationship with Kumamoto University along with other neighboring medical institutions over the years. However, despite its advantages in standing, it may suffer the same problems as other sanatoriums: continually declining numbers of residents combined with the increasing frailty and dementia of existing residents due to aging and an increasing difficulty in maintaining a competent medical staff into the future. By placing our social exchange hall/historical museum as the focal point for the production and dissemination of information, we are producing an educational DVD that records an oral history through actual testimony on film as a cooperative effort between the residents' association and NSKK. Both perspectives are very important to verify the historical problems that Hansen's disease has encountered. One expected benefit of this project is the catharsis found in reminiscing over the past thus promoting the spiritual care of the residents; a matter which remains as a top priority in our sanatorium's "ending period". PMID- 26630800 TI - 50 Years On: The United States-Japan Cooperative Medical Science Program 1965 2015; Part II, the Leprosy Joint Panel. PMID- 26630801 TI - An Update on Sickle Cell Anemia in Children and Adolescents. PMID- 26630802 TI - Top Ten Facts You Need to Know About Inpatient Glycemic Control. PMID- 26630803 TI - Hypophosphatemia Masquerading as Meningitis. PMID- 26630804 TI - The Inaugural Address of the 148th President. DANIEL P. EDNEY, MD--2015-16 MSMA PRESIDENT. PMID- 26630805 TI - Ballot Initiative Measure No. 42. What's Your Opinion, Doctor? PMID- 26630806 TI - A Piller of the Community ... A Love Story. PMID- 26630807 TI - Bulbar and Limb Myorhythmia with "Smooch Sign": A Distinctive Movement Disorder in an Adult Patient with Reversible Anti-NMDA Receptor Encephalitis Associated with an Ovarian Teratoma. AB - Anti-N-Methyl-D-Aspartate receptor encephalitis is a recently described entity (Dalmau et al. 2007, 2008) that may present with a variety of complex movements in addition to other features (Kleinig et al. 2008). The purpose of our presentation of such a patient is twofold: (1) to characterize these complex oculo-oro-linguo-masticatory and limb movements with "smooch sign" as myorhythmia, based on a combined clinical and electrophysiological analysis (Masucci et al. 1984); and (2) to document possibly characteristic EEG evolution in the course of observation in our institution for three weeks from diffuse slowing to evolving rhythmic delta activity, which may represent a pattern of electrographic seizure activity. PMID- 26630808 TI - Predictive Value of Short-Term EEG Recording in Critically ill Adult Patients. AB - We assessed the EEG patterns and their prognostic significance in critically ill adult patients with encephalopathy, by digital EEGs lasting lip to 1 hour Of the 110 patients (age: 43.8 +/- 19.4 years, male: female:1.6:1) studied, 32% had hypoxic ischemic encephalopathy (HIE), 17% severe infections, and 14.5% stroke. Observed EEG patterns were diffuse slowing (41%), low-voltage cerebral activity (LVCA, 18%), nonconvulsive status epilepticus (NCSE, 13.6%), and periodic abnormalities (9.1%). LVCA, age, Glasgow Coma Score (GCS) < 8, HIE, and modified Hockaday's EEG grades of IV and V were associated with poor outcome (p < 0.005) at hospital discharge; generalized slowing was associated with a relatively good outcome (p = 0.003). On multivariate analysis, factors independently predictive of mortality were LVCA, older age, and poor GCS. In conclusion, LVCA and generalized background slowing were common EEG patterns among critically ill intensive care unit (ICU) patients with encephalopathy of varied etiologies. While LVCA was associated with a poor outcome, generalized background slowing predicted better prognosis. Conventional short-duration, bedside EEG studies could aid in the recognition of electrographic patterns of prognostic importance in facilities where continuous EEG monitoring is lacking. PMID- 26630809 TI - Intraoperative Neurophysiological Monitoring (IONM) for Cordotomy Procedures. AB - This case illustrates the benefits of utilizing intraoperative neurophysiological monitoring (IONM) for preventing injury to sensory/motor pathways of the spinal cord during a cordotomy procedure to relieve pain. Cordotomy has been used effectively in the treatment of visceral pain but comes with a high risk of damaging motor and sensory pathways due to close proximity of lesion. The subject is a 47-year-old female with a pancoast tumor of the left lung, left brachialplexopathy, and severe neuropathic pain syndrome, refractory to medical therapy. A palliative cordotomy procedure was elected for pain control. Baseline bilateral posterior tibial and median nerve somatosensory evoked potentials (SSEP) were present except in the left upper extremity. Transcranial electric motor evoked potential (TCeMEP) baselines were present in all extremities except the left upper. Total intravenous anesthesia was used. The spine was exposed at C2-C3 and a right single anterolateral cordotomy was performed with an immediate drop in TCeMEPs (70-80% amplitude reduction) in the right upper and right lower extremities. The surgeon decided to stop the cordotomy at that point. Postoperatively, the patient had no sensory or motor deficit. In this patient, TCeMEPs were used effectively to guide the surgeon in preventing damage to the spinal cord that could lead to motor deficits. PMID- 26630810 TI - Amyotrophic Lateral Sclerosis (ALS) and Related Motor Neuron Diseases: An Overview. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative motor neuron disease, resulting in the destruction and ultimate death of neurons that control muscles. ALS affects motor neurons in the brain, brainstem, and spinal cord (upper motor neurons, bulbar region of the brain, and lower motor neurons). ALS patients have an average life expectancy of 3-5 years, therefore, proper diagnosis, care, and treatment is essential in order to provide the best quality of life for these patients. A thorough understanding of the symptomatology, potential cause(s), progression, and treatment of ALS is essential to provide timely and high-quality patient care. Electrodiagnostic examination, specifically electromyography (EMG) and nerve conduction studies (NCS), is one of the key diagnostics of ALS. PMID- 26630811 TI - WAVEFORM WINDOW #30. A Case of Nocturnal Episodes. PMID- 26630812 TI - WAVEFORM WINDOW #31: Anti-NMDAR Encephalitis and "Extreme Delta Brush". PMID- 26630813 TI - WAVEFORM WINDOW #32: 14 and 6 Hz Positive Spikes: A Normal Variant that Could be Mistaken as Epileptiform. PMID- 26630814 TI - The politics of care in technoscience. AB - Care is a slippery word. Any attempt to define it will be exceeded by its multivocality in everyday and scholarly use. In its enactment, care is both necessary to the fabric of biological and social existence and notorious for the problems that it raises when it is defined, legislated, measured, and evaluated. What care looks and feels like is both context-specific and perspective dependent. Yet, this elusiveness does not mean that it lacks importance. In our engagements with the worlds that we study, construct, and inhabit, we cannot but care: care is an essential part of being a researcher and a citizen. To properly invite you into this Special Issue, then, we need to say something about what we mean when we write about care. PMID- 26630815 TI - Caring for nanotechnology? Being an integrated social scientist. AB - One of the most significant shifts in science policy of the past three decades is a concern with extending scientific practice to include a role for 'society'. Recently, this has led to legislative calls for the integration of the social sciences and humanities in publicly funded research and development initiatives. In nanotechnology--integration's primary field site--this policy has institutionalized the practice of hiring social scientists in technical facilities. Increasingly mainstream, the workings and results of this integration mechanism remain understudied. In this article, I build upon my three-year experience as the in-house social scientist at the Cornell NanoScale Facility and the United States' National Nanotechnology Infrastructure Network to engage empirically and conceptually with this mode of governance in nanotechnology. From the vantage point of the integrated social scientist, I argue that in its current enactment, integration emerges as a particular kind of care work, with social scientists being fashioned as the main caretakers. Examining integration as a type of care practice and as a 'matter of care' allows me to highlight the often invisible, existential, epistemic, and affective costs of care as governance. Illuminating a framework where social scientists are called upon to observe but not disturb, to reify boundaries rather than blur them, this article serves as a word of caution against integration as a novel mode of governance that seemingly privileges situatedness, care, and entanglement, moving us toward an analytically skeptical (but not dismissive) perspective on integration. PMID- 26630816 TI - Abyssal intimacies and temporalities of care: How (not) to care about deformed leaf bugs in the aftermath of Chernobyl. AB - Prompted by a classroom discussion on knowledge politics in the aftermath of the Chernobyl disaster, this article offers a reading of Hugh Raffles' Insectopedia entry on Chernobyl. In that entry, Raffles describes how Swiss science-artist and environmental activist Cornelia Hesse-Honegger collects, studies, and paints morphologically deformed leaf bugs that she finds in the proximity of nuclear power plants. In exploring how to begin to care about beings, such as leaf bugs, this article proposes a notion of care that combines an intimate knowledge practice with an ethical relationship to more-than-human others. Jacques Derrida's notion of 'abyssal intimacy' is central to such a combination. Hesse Honegger's research practices enact and her paintings depict an 'abyssal intimacy' that deconstructs the oppositions between concerns about human suffering and compassion for seemingly irrelevant insects and between knowledge politics and ethics. At the heart of such a careful knowledge production is a fundamental passivity, based on a shared vulnerability. An abyssal intimacy is not something we ought to recognize; rather, it issues from particular practices of care that do not identify their subjects of care in advance. Caring or becoming affected thus entails the dissociation of affection not only from the humanist subject, but also from movements in time: from direct helping action and from the assumption that advocacy necessarily means speaking for an other, usually assumed to be inferior. PMID- 26630817 TI - Making time for soil: Technoscientific futurity and the pace of care. AB - The dominant drive for understanding soil has been to pace its fertility with human demand. Today, warnings about soil's exhaustion and endangered ecology raise concerns marked by fears of gloomy environmental futures, prompting scientists and soil practitioners urgently to develop better ways of taking care of soils. Yet the pace required by ecological soil care could be at odds with the predominant temporal orientation of technoscientific intervention, which is driven by an inherently progressivist, productionist and restless mode of futurity. Through a conceptual and historical approach to the soil sciences and other domains of soil knowledge, this article looks for soil ontologies and relations to soil care that are obscured by the predominant timescape. Contemporary discussions of the future of the soil sciences expose tensions between 'progress as usual'--by intensifying productivity--and the need to protect the pace of soil renewal. The intimate relation of soil science with productionism is being interrogated, as ecology attempts to engage with soil as a living community rather than a receptacle for crops. In this context, and beyond science, the 'foodweb' model of soil ecology has become a figure of alternative human-soil relations that involve environmental practitioners in the soil community. Reading these ways of making time for soil as a form of 'care time' helps to reveal a diversity of more-than-human interdependent temporalities, disrupting the anthropocentric appeal of predominant timescales of technoscientific futurity and their reductive notion of innovation. PMID- 26630818 TI - Unsettling care: Troubling transnational itineraries of care in feminist health practices. AB - Responding to the call by Maria Puig de la Bellacasa for Science and Technology Studies to take up 'matters of care', this article cautions against equating care with positive feelings and, in contrast, argues for the importance of grappling with the non-innocent histories in which the politics of care already circulates, particularly in transnational couplings of feminism and health. The article highlights these histories by tracing multiple versions of the politics of care in a select set of feminist engagements with the pap smear and cervical cancer. Drawing on postcolonial and indigenous feminist commitments, as well as amplifying Donna Haraway's call to 'stay with the trouble', the article seeks to disturb hegemonic histories and arrangements of race, colonialism, and political economy, while simultaneously valuing divergent multi-local itineraries as relevant to technoscientific matters of care. This call for a politics of 'unsettling' care strives to stir up and put into motion what is sedimented, while embracing the generativity of discomfort, critique, and non-innocence. PMID- 26630819 TI - Care in context: Becoming an STS researcher. AB - This collaborative article, written by graduate students who attended the Politics of Care in Technoscience Workshop, brings the themes in this volume to bear on their own developing science and technology study projects and research practices. Exploring the contours of five specific moments where questions of care have arisen in the course of their everyday research, they do not find a single or untroubled definition of care; instead, care is often a site of ambivalence, tension, and puzzlement. However, despite this uneasiness, they argue that taking the time to reflect on the multiple, sometimes conflicting, forms and definitions of care within a specific research context can inform the way that science and technology studies scholars envision and conduct their work. PMID- 26630820 TI - Counting, accounting, and accountability: Helen Verran's relational empiricism. AB - Helen Verran uses the term 'relational empiricism' to describe situated empirical inquiry that is attentive to the relations that constitute its objects of study, including the investigator's own practices. Relational empiricism draws on and reconfigures Science and Technology Studies' traditional concerns with reflexivity and relationality, casting empirical inquiry as an important and non innocent world-making practice. Through a reading of Verran's postcolonial projects in Nigeria and Australia, this article develops a concept of empirical and political 'accountability' to complement her relational empiricism. In Science and an African Logic, Verran provides accounts of the relations that materialize her empirical objects. These accounts work to decompose her original objects, generating new objects that are more promising for the specific postcolonial contexts of her work. The process of decomposition is part of remaining accountable for her research methods and accountable to the worlds she is working in and writing about. This is a practice of narrating relations and learning to tell better technoscientific stories. What counts as better, however, is not given, but is always contextual and at stake. In this way, Verran acts not as participant-observer, but as participant-storyteller, telling stories to facilitate epistemic flourishing within and as part of a historically located community of practice. The understanding of accountability that emerges from this discussion is designed as a contribution, both practical and evocative, to the theoretical toolkit of Science and Technology Studies scholars who are interested in thinking concretely about how we can be more accountable to the worlds we study. PMID- 26630821 TI - FDA Adverse Event Reporting System: Recruiting Doctors to Make Surveillance a Little Less Passive. AB - Within the last few decades, a shift has taken place in FDA's approach to drug development, with greater emphasis put on postmarketing data collection and less on the traditional premarketing scheme. The FDA Adverse Event Reporting System (FAERS) is the primary system for collecting Adverse Events, but has been criticized for years for the low reporting rate into the system and the poor quality of the information submitted. This paper argues that physicians need to be required to submit adverse event reports to FAERS, because such a requirement (1) would produce a greater number of the high quality reports necessary to better determine causality; (2) is merely an extension of physicians' ethical obligations; and (3) aligns with the approach in the Vaccine Adverse Event Reporting System (VAERS). Furthermore, advances in electronic health records can aid in reporting efficiency. PMID- 26630822 TI - Just a Spoonful of Sugar Will Land You Six Feet Underground: Should the Food and Drug Administration Revoke Added Sugar's GRAS Status? AB - This article assesses whether added sugar meets FDA's standard to be generally recognized as safe ("GRAS"). If added sugar is not GRAS, then manufacturers are subject to premarket approval prior to using added sugar in their products. This article advocates that FDA should issue a Federal Register notice determining that added sugar is not GRAS, allowing FDA to regulate the amount of added sugar used in processed foods, decreasing the health adversities that stem from added sugar consumption. PMID- 26630823 TI - The Most Serious Offenses and Penalties Concerning Unsafe Foods under the Food Safety Laws in Bangladesh, India, and Australia: A Critical Analysis. AB - The right to food is an internationally recognized human rignt, which inherently denotes the right to safe food simply because unsafe foods cause different diseases resulting in consumer's disability, organ failure, or even early demise. Food safety currently may not be an issue of public concern in Australia, but it has been a "silent killer" for decades in both Bangladesh and India contributing to deaths of thousands and injuries of millions of others. Unscrupulous businesses have been making money at the cost of immense human casualties with almost complete impunity in Bangladesh. The situation in Bangladesh is so intractable that the government has been making laws one after another; but food traders remain undeterred, and consequently consumers continue to die from adulterated foods. This paper examines the loopholes in the definitions of the most serious offenses under three major pieces of legislation in Bangladesh, India, and Australia. It finds that all three statutes seem flawed to some extent, though they all may mutually benefit from one another in defining and clarifying the most serious food safety offenses and penalties with a view to strengthening their effectiveness. PMID- 26630824 TI - Do We Need Stronger Sanctions to Ensure Legal Compliance By Pharmaceutical Firms? AB - The increasing number of enforcement lawsuits against pharmaceutical firms and the large size of settlement payments suggest that misconduct is widespread and even risks slipping into the banalities of ordinary business practices. It also raises questions as to whether current sanctions are an effective means to ensure compliance. This article explores the causes of the frequent illegal conduct, why prosecutors rarely use the strongest sanctions in their arsenal--criminal penalties and debarment from participation in public programs--and asks whether the use of the strongest sanctions would be desirable. Prosecutors might not use the strongest penalties available because of divided enforcement authority or because they prefer to seek monetary penalties to support their budgets. Moreover, strong sanctions might be perceived as imposing steep collateral damages on the-general public and being politically costly. If prosecutors are reluctant to impose the strongest possible sanctions, then policymakers need to develop alternative responses. One option is to create stronger economic penalties than the ones that currently exist. Corporations and their managers have incentives to increase their income, and their pursuit of profit sometimes leads these managers to violate the law. To deter illegal conduct, legislation typically allows courts to impose penalties--including fines and incarceration- on convicted individuals and firms. The increasing wide-scale illegal conduct by pharmaceutical firms and their employees over the last two decades prompts three questions. Are current sanctions sufficient? Are stronger sanctions and enforcement policy possible? If so, would they effectively deter harmful illegal conduct? PMID- 26630825 TI - A Legislative Reform for the Food Safety System of China: A Regulatory Paradigm Shift and Collaborative Governance. AB - After describing the historical development of China's food safety system from the perspectives of legislation and administration, this article discusses progress in its food law (The Draft Amendments to Food Safety Law). As a further legislative reform for China's food safety system, the Draft Amendments to the Food Safety Law contain innovative institutional designs and manifest a regulatory paradigm shift from government-centered governance to collaborative governance. However, the Draft Amendments face challenges in their implementation. This article argues that developing collaborative governance for food safety in China can be a solution to these challenges. Based on theoretical and empirical studies of collaborative governance, this article proposes that the institutional design of collaborative governance should focus on providing obligations for administrative agencies in the process of food safety rule-making and standard-setting, increasing the independence of nongovernmental organizations, and building two-way electronic platforms for public participation. PMID- 26630826 TI - DR. YUKINARI KOUHARA (1928-2014): A GIANT OF THE CURIOSITY. PMID- 26630827 TI - ENVIRONMENTAL IMPACT ON PHYSIOLOGICAL RESPONSES OF UNDERGROUND COAL MINERS IN THE EASTERN PART OF INDIA. AB - Coal in India is extracted generally by semi-mechanized and mechanized underground mining methods. The Bord and Pillar (B & P) mining method still continues to be popular where deployment of manual miners is more than that of other mining methods. The study is conducted at haulage based mine of Eastern Coalfields of West Bengal. Underground miners confront with a lot of hazards like extreme hostile environment, awkward working posture, dust, noise as well as low luminosity. It is difficult to delay the onset of fatigue. In order to study the physiological responses of trammers, various parameters like working heart rates, net cardiac cost and relative cardiac cost including recovery heart rate patterns are recorded during their work at site. Workload classification of trammers has been done following various scales of heaviness. The effect of environment on the physiological responses has been observed and suitable recommendations are made. The work tasks are bound to induce musculoskeletal problems and those problems could be better managed through rationalizing the work-rest scheduling. PMID- 26630828 TI - THE INFLUENCE OF LATERALITY ON DIFFERENT PATTERNS OF ASYMMETRICAL FOOT PRESSURE AND MUSCLE ACTIVATION DURING A GAIT CYCLE IN MANUAL PUSHING. AB - This study investigated laterality of manual pushing during a gait cycle by measuring pushing force, muscular activation and foot pressure. Subjects were 17 healthy young adult males; (11 right-handed [RH], and 6 left-handed [LH]). They pushed a force plate while walking on a treadmill at 1.5, 3, and 4 km/h. Electromyogram (EMG) data were collected bilaterally from the tibialis anterior, soleus, lumbar erector spinae and triceps brachii. To measure foot pressure, ten pressure sensors were attached bilaterally on five points of the sole. Symmetry assessment was performed by comparing bilateral data and cross-correlation function (CCF). Gait cycle duration was found to be symmetrical in all conditions. LH subjects demonstrated asymmetry in calcaneus contact duration to control ankle flexion, whereas RH were symmetrical. Velocity affected tibialis anterior muscle time lag and soleus muscle CCF coefficients, mainly in LH. We found that triceps brachii muscle CCF coefficients in LH subjects were affected by increasing velocity. Results indicated that LH and RH did not mirror each other, since both had distinct characteristics. Furthermore these asymmetries were not strictly associated with the preferred side, indicating that generalisation of preferred side to whole-body coordination should be avoided, since we could not separate one side from the other. PMID- 26630829 TI - WHO DOES WHAT IN HUMAN FACTORS/ERGONOMICS IN MALAYSIA? AB - Individuals' expertise in human factors and ergonomics in Malaysia was studied with a view to aiding in gauging the confusion and conjectures of the expertise in this area. The choices and preferences of individuals in dealing with the current issues of human factors and ergonomics were examined. The authors suggest the ways to meet ethical challenges in their work and professions. PMID- 26630831 TI - Infant and Childhood Mortality: What's the Goal? PMID- 26630832 TI - Case Report: Hormone Receptor Positive, HER2/neu Negative Inflammatory Breast Cancer in a Male Patient. AB - Inflammatory breast cancer is a rare and aggressive disease found almost exclusively in women. We present a case of a 51-year-old male with inflammatory breast carcinoma. The patient presented with a mass measuring roughly 7 cm with overlying erythema, peau d'orange appearance, and prominent nipple retraction. Core biopsy analysis demonstrated estrogen and progesterone receptor positive, HER2/neu receptor negative invasive ductal carcinoma. A PET scan revealed contralateral supraclavicular lymph node metastasis. The patient refused chemotherapy and radiation and was not a surgical candidate. Ultimately he opted for therapy with strictly an aromatase inhibitor. Most recent follow-up at 12 months demonstrated improvement of metastatic lesions on PET scan. Local progression of disease was noted on physical exam and the patient decided to add everolimus and radiation therapy while continuing an aromatase inhibitor. Retrospective studies have demonstrated increased survival of inflammatory breast cancer diagnosed in women with the utilization of neoadjuvant chemotherapy, surgical excision, and radiation therapy. Unfortunately, due to the rarity of the disease, no specific optimal treatment guidelines have been established for men diagnosed with this disease. PMID- 26630833 TI - Regional Infant and Child Mortality Review Committee 2014 Final Report. AB - The Regional Infant and Child Mortality Review Committee serves 10 counties in southeastern South Dakota with the aim of using its reviews to prevent future loss of life during childhood. In 2014, the committee reviewed 25 deaths. Consistent with observations made in previous years, in 2014 all infants who died during sleep did so with risks present in the sleep environment. Concern persists about progress in decreasing these infant deaths during sleep in the region. The two teen suicides in 2014 marked a decrease in the number observed in 2013, but represent an ongoing concern. Four deaths involved auto crashes with three of these involving a teen driver. A child homicide did not occur in the region in 2014. The report provides the committee's recommendations for community action that could prevent future deaths of infants and children. PMID- 26630834 TI - Smartphones Enable Teledermatology in South Dakota: An Overview and Primer for Primary Care Providers. AB - Timely access to specialty care by dermatologists is a significant problem in South Dakota. This is especially germane to patients in rural areas, the elderly, and those with socioeconomic barriers. Implementation of a modality utilizing smartphone technology called mobile teledermatology (MTD) should improve access to dermatologic care. MTD provides location- and time-independent dermatologic care and is currently being used successfully across the U.S. MTD has the potential to benefit both patients and providers in South Dakota; however, barriers to its implementation currently exist. Expanding insurance coverage and reimbursement for teledermatology, facilitating multi-state telemedicine licensure, and educating primary care providers and patients about teledermatology would facilitate widespread utilization of teledermatology in South Dakota. Current legislation addressing licensure may soon come to fruition, making it easier for dermatologists to practice teledermatology across state lines. In addition to pay-for-service, Medicaid is currently the only insurer in South Dakota that reimburses for store-and-forward teledermatology. We propose MTD as an apt solution for enabling prompt access to dermatologic care in South Dakota and emphasize the need for greater insurance coverage, improved licensure policy, and user education to fully realize the benefits of this technology for our patients. PMID- 26630835 TI - Pediatric Traumatic Brain Injury. AB - The purpose of this article is to provide a better understanding of pediatric traumatic brain injury and its management. Within the pediatric age group, ages 1 to 19, injuries are the number one cause of death with traumatic brain injury being involved in almost 50 percent of these cases. This, along with the fact that the medical system spends over $1 billion annually on pediatric traumatic brain injury, makes this issue both timely and relevant to health care providers. Over the course of this article the epidemiology, physiology, pathophysiology, and treatment of pediatric traumatic brain injury will be explored. Emphasis will be placed on the role of the early responder and the immediate interventions that should be considered and/or performed. The management discussed in this article follows the most recent recommendations from the 2012 edition of the Guidelines for the Acute Medical Management of Severe Traumatic Brain Injury in Infants, Children, and Adolescents. Despite the focus of this article, it is important not to lose sight of the fact that an ounce of prevention is worth a pound--or, to be more precise and use the average human's brain measurements, just above three pounds--of cure. PMID- 26630836 TI - Antipsychotic Medication Use in Nursing Homes: Approaches to Reduce Use and National Trends. AB - Consensus exists regarding the need to reduce antipsychotic medication use in nursing homes, multiple initiatives have been implemented with the intent to achieve this goal, and progress is being made. While limited high quality research is available documenting the impact of various approaches, resource tool kits and best practice descriptions can help guide efforts. PMID- 26630837 TI - Patient Education: Phantom Visions. PMID- 26630838 TI - Quality Focus: Prediabetes. PMID- 26630839 TI - DAKOTACARE Update: Changes: ICD-10, HHS/CMS, and Quality. PMID- 26630840 TI - Board News. PMID- 26630841 TI - [Analysis of the Neuraminidase Amino Acid Sequences of Influenza A/H1N1pdm09, A/H3N2, and B Viruses Isolated from Influenza Patients in the 2013/14 Japanese Influenza Season]. AB - BACKGROUND: Neuraminidase (NA) is an essential surface protein for influenza virus replication. NA inhibitors are commonly used for the treatment of influenza patients in Japan. Several mutations that reduce the effect of NA inhibitors have been reported. We sequenced the whole NA segment of isolated virus from influenza patients and investigated the relation between the NA amino acid sequence and the 50% inhibitory concentration (IC50) of four NA inhibitors. MATERIALS AND METHODS: A total of 20 viruses that showed high or low IC50 of NA inhibitors were selected from A/H1N1pdm09, A/H3N2, and B isolates from the viruses isolated from patients in the 2013-14 influenza season. Viral RNA was extracted and RT-PCR was done. The amplified genome was sequenced using a next generation sequencer", and the deduced amino acid sequences were analyzed. RESULTS: Two A/H1N1pdm09 viruses that showed very high IC50 for oseltamivir (150 nM and 130 nM) contained the H275Y mutation. Otherwise, no significant relation was found between the NA amino acids and the IC50 of the four NA inhibitors. There was no significant relation between the NA amino acids and the IC50 of the four NA inhibitors for A/H3N2 viruses. The B viruses that showed a high IC50 for oseltamivir and laninamivir shared some amino acids. The B viruses that showed a high IC50 of zanamivir and peramivir also shared some amino acids. They were different from the shared amino acids found for oseltamivir and laninamivir. CONCLUSION: The previously reported H275Y mutation that causes oseltamivir resistance was found in the two A/H1N1pdm09 viruses that showed a very high IC50 for oseltamivir. No additional NA amino acid sequences related to the IC50 of the four NA inhibitors was found. The meaning of the shared amino acids among B viruses that showed a high IC50 would be an interesting target for further investigation. PMID- 26630842 TI - Laparoscopic and Open Resection of Gastrointestinal Stromal Tumors of the Stomach. AB - INTRODUCTION: Laparoscopic resection has been reported as reasonable for patients with gastrointestinal stromal tumors (GISTs). In this study, we report the feasibility of the laparoscopic approach for GIST of the stomach. We also discuss the laparoscopic approach for GIST larger than 5 cm, which is reported to be difficult to treat by laparoscopic surgery. MATERIALS AND METHODS: We retrospectively reviewed 22 patients with GIST of the stomach resected by laparoscopic or open procedures between January 2006 and February 2014. RESULTS: Laparoscopic resections were performed in 9 patients and open resections in 13 patients. Curative resections with negative resection margins were successfully completed for all patients. Although the size of the tumors was greater in open surgery cases than in laparoscopic patients (P = 0.03), the loss of blood was lower and the hospital stay was shorter in laparoscopic cases (P = 0.01 and 0.003, respectively). Laparoscopic resection was performed for 2 patients with GISTs larger than 5 cm. Both were located at greater curvature, and curatively resected without any complications or recurrence. DISCUSSION: Our experience suggests that laparoscopic surgery for GISTs of the stomach, including those larger than 5 cm, may be feasible after careful deliberation of its indications. Laparoscopic resection for GIST was associated with lower loss of blood and shorter hospital stay in comparison with open resection. PMID- 26630843 TI - Assessing and Improving Physician Organization Governance. PMID- 26630844 TI - MIGHTY CROWDED: Welcome to the virtual doctor's lounge. PMID- 26630845 TI - HEALTH CARE HACKERS: Hackers of medical devices pose a potential threat to patient safety. PMID- 26630846 TI - TECH SAVVY: Weighing the benefits of adding a nurse technology expert to the C suite. PMID- 26630847 TI - PATIENT SAFETY: Three questions with: David Bernd. PMID- 26630848 TI - MOST WIRED: How hospitals safeguard patient information on mobile devices. PMID- 26630849 TI - GOING TO BEAD: Family stress relieved by NICU beading program. PMID- 26630850 TI - 1, 2,3, PLEDGE: Hospitals raising targets for equity of care. PMID- 26630851 TI - A physician who loathes prescriptions. PMID- 26630852 TI - Three practical approaches to POPULATION HEALTH. AB - Start now, experts advise, with strategies that marry the technical with the personal. Here's a trio of pop health approaches that may hold useful lessons for everyone. PMID- 26630853 TI - Discovering the 'Heartfelt Why'. AB - Disappointing patient satisfaction scores spurred CEO Loren Hamel, M.D., and his team at Lakeland Health to launch the "Bring Your Heart to Work" initiative. Hamel describes how they did it. PMID- 26630854 TI - Outsmarting Data Thieves. PMID- 26630855 TI - Four Ways to Design a Better ED. AB - As these hospitals have shown, when emergency department wait times go down and throughput speeds up, quality of care, work efficiency and even patient volumes benefit. Here's how they did it. PMID- 26630856 TI - LEADERSHIP DIVERSITY: The Path to Value-Based Care. PMID- 26630857 TI - Getting the measure of quality. PMID- 26630858 TI - Modern Endodontic Planning Part 1: Assessing Complexity and Predicting Success. AB - Following a diagnosis of irreversible pulpal disease, periapical disease or failed endodontic therapy, the options for the tooth are extraction or root canal treatment. There is increasing evidence that certain factors may allow the clinician to predict the likely outcome of root canal therapy (RCT) and thus better inform the patient of the possible success rates. Should the patient choose root canal treatment, the clinician must also be able to gauge the potential difficulties that may be encountered and consequently determine whether it is within their competency. CPD/CLINICAL RELEVANCE: Assessing outcomes and complexity of care is an essential part of informed consent. Knowing when to refer is an essential component of best clinical practice. PMID- 26630859 TI - Rehabilitation of Oncology Patients with Hard Palate Defects Part 3: Construction of an Acrylic Hollow Box Obturator. AB - This article will discuss the clinical stages in the fabrication of a definitive acrylic hollow box obturator to restore a hard palate defect. The first two papers described the restorative/surgical planning phase and the principles of obturator design. CPD/CLINICAL RELEVANCE: Each of the clinical stages required to make a hollow box obturator must be performed to the highest possible standard to ensure than an optimal prosthesis.is fabricated. PMID- 26630860 TI - Pain Part 4: Odontogenic Pain. AB - Pain is one of the major reasons that lead patients to seek dental care. For the majority of patients, the pain is of odontogenic origin, as a consequence of dental disease. The timely diagnosis and management of dental pain is an essential component of dental care, and this article reminds readers of the common presenting symptoms of simple dental pain, diagnoses and pragmatic management. CLINICAL RELEVANCE: Pain of odontogenic origin is common, and distressing. However, the pathology is consistent, as are the symptoms, and an understanding of this underpins the careful history-taking that will lead the clinician to the diagnosis. PMID- 26630861 TI - Class II Division 1: An Evidence- Based Review of Management and Treatment Timing in the Growing Patient. AB - Class II division 1 malocclusion is common and various methods have been suggested for successful treatment in the growing patient. A number of recent high-quality studies have been undertaken to assess the efficacy of these treatments. We aim to outline the existing best evidence that supports current practice, with a review of the effect of treatment timing on outcome. This will provide a sound evidence-base for General Dental Practitioners for assessing, advising and referring young patients for treatment. CPD/CLINICAL RELEVANCE: General Dental Practitioners should understand the management options and optimal time for treating growing patients with a Class II division 1 malocclusion. PMID- 26630862 TI - Mouth Cancer for Clinicians Part 4: Risk Factors (Traditional: Alcohol, Betel and Others). AB - A MEDLINE search early in 2015 revealed more than 250,000 papers on head and neck cancer; over 100,000 on oral cancer; and over 60,000 on mouth cancer. Not all publications contain robust evidence. We endeavour to encapsulate the most important of the latest information and advances now employed in practice, in a form comprehensible to healthcare workers, patients and their carers. This series offers the primary care dental team, in particular, an overview of the aetiopathogenesis, prevention, diagnosis and multidisciplinary care of mouth cancer, the functional and psychosocial implications, and minimization of the impact on the quality of life of patient and family. CLINICAL RELEVANCE: This article offers the dental team an overview of the main cancer risk factors, namely tobacco and alcohol, betel and other chewing habits, and environmental factors. PMID- 26630863 TI - Juvenile Hyaline Fibromatosis: Impact of Periodontal Care on Quality of Life and a Patient Perspective. AB - Juvenile hyaline fibromatosis (JHF) is a rare autosomal recessive inherited condition presenting early in life and characterized by the accumulation of hyaline-like tissue in the skin as well as various organs. Gingival overgrowth is a significant oral manifestation. This paper highlights how early and essential periodontal intervention may be necessary to improve mastication and subsequent weight gain, and to eliminate pain and improve the patient's quality of life. Here we highlight the key features of this condition and demonstrate how appropriate surgical management can have a significant impact on a patient's wellbeing. CPD/CLINICAL RELEVANCE: Juvenile hyaline fibromatosis has a significant impact on patient wellbeing and it is therefore important that clinicians are able to recognize the condition and ensure that patients receive appropriate care and management. PMID- 26630864 TI - Dental Management of a Patient with Multiple Idiopathic Cervical Root Resorption. AB - Multiple Idiopathic Cervical Root Resorption (MICRR) is a rare condition. It initiates at the cemento-enamel junction of multiple teeth. The lesions continue to grow until they unite, thereby undermining the entire coronal structure of affected teeth. Its distribution can vary from a single region to the entire dentition and the number of teeth affected by resorption tends to increase as the condition is followed over time. The teeth themselves appear clinically normal. The aetiology of MICRR is unknown and it is considered to be a diagnosis of exclusion. The condition tends to be progressive. Consequently, root treatments/surgical curettage and restoration of the lesions have been unsuccessful at arresting the condition. Affected teeth are often extracted in anticipation of catastrophic fracture and have been replaced with partial or complete dentures. In this case report, we describe how a young female patient was dentally managed over 10 years and ultimately rehabilitated with dental implants. CPD/CLINICAL RELEVANCE: Patients suspected of having multiple idiopathic cervical root resorption may require specialist, multidisciplinary care and require referral to an appropriate secondary care unit for treatment planning and potential oral rehabilitation. PMID- 26630865 TI - A PREP Panel, Practice-Based, Evaluation of the Handling of the Kerr Demi-Ultra Light Curing Unit. AB - This paper describes the handling evaluation (by a group of practice-based researchers, the PREP Panel) of a recently introduced Light Curing Unit (LCU), the Kerr Demi-Ultra, which possesses a number of novel features such as its ultracapacitor power source, and the Light Emitting Diodes (LEDs) which provide the light output being placed close to the tip of the light guide. CPD/CLINICAL RELEVANCE: Testing of new devices and materials with respect to their handling is of importance, given that an easy to handle device should produce better clinical results than one which is difficult to use. PMID- 26630867 TI - Essentials of medical history--taking in dental patients. PMID- 26630866 TI - Dental Abrasion of Incisor caused by a Babies' Dummy Clip: A Case Report. AB - Tooth surface loss (TSL), the non-carious loss of tooth tissue, is considered pathological if the teeth involved experience sensitivity and pain, are functionally compromised or they detract from the patient's appearance. TSL is a common clinical finding in many patient groups, although differences between the primary and permanent dentition contribute to TSL occurring at a faster rate and with worse outcomes in the primary dentition. This case report presents localized abrasion and associated apical periodontitis affecting a single primary tooth in a 2-year-old infant following the misuse of a babies' dummy clip whilst teething. Abrasion is rare in the primary dentition. CPD/CLINICAL RELEVANCE: This article highlights an unusual presentation of dental abrasion affecting the primary dentition caused by a previously unreported foreign object; abrasion in this case was a side-effect of soothing the discomfort of teething. PMID- 26630868 TI - The other side of facial cosmetic surgery. PMID- 26630869 TI - 'Don't bite off more than you can chew'. PMID- 26630870 TI - Clinical Challenges Q&A 13. Painful Lip and Mouth Ulceration. PMID- 26630871 TI - Technique Tips--The Cost of One Post-Operative Sensitivity following Placement of a Posterior Composite Restoration. AB - Use a low shrinkage stress composite but, if not, use incremental placement and a layer of flowable at the gingival box; Ensure good bonding to dentine and enamel and avoid (over) etching the dentine; Ensure good adaptation at the gingival floor of a Class II box; Make sure that the restoration has received sufficient light; Provide good isolation; Use reliable and tested materials throughout. PMID- 26630872 TI - In vitro antiviral activity against rotavirus and astrovirus infection exerted by substances obtained from Achyrocline bogotensis (Kunth) DC. (Compositae). AB - BACKGROUND: Achyrocline bogotensis has been traditionally used to treat infections of skin, respiratory, tract urinary and other infections, but not to treat viral gastrointestinal disease. In this study, this Colombian native medicinal plant was investigated by its in vitro anti-rotavirus and anti astrovirus activity. METHODS: Several extracts and fractions phytochemically obtained from A. bogotensis were evaluated initially for their cell toxicity on MA104 and Caco2 cells and then for their anti-rotavirus (RRV) and anti-astrovirus (Yuc8) activity following three strategies: pre-treatment of cells (blocking effect), direct viral activity (virucidal effect) and post-treatment of infected cells (reduction of viral yield post-infection). In addition qualitative chemical studies were developed for the active compounds. RESULTS: Non-toxic concentrations of a fraction obtained exhibited antiviral activity against both viruses characterized by a virucidal effect and by the reduction of the infectious particles produced post-infection. Steroids, sterols, terpenes, phenols, flavonoids and sesquiterpenlactones were identified qualitatively in the active fraction. CONCLUSIONS: A. bogotensis contains substances with in vitro antiviral activity against rotavirus and astrovirus. This study confirms their anti-microbial properties and describes by the first time its antiviral activity in vitro. PMID- 26630873 TI - Detection of potentially inappropriate prescribing in the very old: cross sectional analysis of the data from the BELFRAIL observational cohort study. AB - BACKGROUND: Little is known about the prevalence and clinical importance of potentially inappropriate prescribing instances (PIPs) in the very old (>80 years). The main objective was to describe the prevalence of PIPs according to START (Screening Tool to Alert doctors to Right Treatment; omissions) and,STOPP (Screening Tool of Older Person's Prescriptions; over/misuse) and the Beers list (over/misuse). Secondary objectives were to identify determinants if PIPs and to assess the clinical importance to modify the treatment in case of PIPs. METHODS: Cross-sectional analysis of baseline data of the BELFRAIL cohort, which included 567 Belgian patients aged 80 and older in primary care. Two independent researchers applied the screening tools to the study population to detect PIPs. Next, a multidisciplinary panel of experts rated the clinical importance of the PIPs on a subsample of 50 patients. RESULTS: In this very old population (median age 84 years, 63 % female), the screening detected START-PIPs in 59 % of patients, STOPP-PIPs in 41 % and Beers-PIPs in 32 %. Assessment of the clinical importance revealed that the most frequent PIPs were of moderate or major importance. In 28 % of the subsample, the relevance of the PIP was challenged by the global medical, functional and social background of the patient hence the validity of some criteria was questioned. CONCLUSION: Potentially inappropriate prescribing is highly prevalent in the very old. A good understanding of the patients' medical, functional and social context is crucial to assess the actual appropriateness of drug treatment. PMID- 26630874 TI - Prognostic values of interim and post-therapy 18F-FDG PET/CT scanning in adult patients with Burkitt's lymphoma. AB - BACKGROUND: The prognostic values of interim and post-therapy fluorine-18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) and PET/computed tomography (CT) scanning have been confirmed in several subtypes of lymphoma. However, its prognostic value in Burkitt's lymphoma has not been clearly defined. The aim of the present study was to assess the prognostic value of PET/CT scanning during different treatment processes of Burkitt's lymphoma. METHODS: A total of 29 adult patients with newly diagnosed Burkitt's lymphoma were retrospectively involved in this study; of them, 23 patients underwent baseline PET/CT, 15 patients underwent mid-therapy PET/CT after 1-4 cycles of chemotherapy, and 17 patients underwent post-therapy PET/CT after all planned first-line chemotherapy cycles. Mid-therapy and post-therapy PET/CT results (positive vs. negative) were visually interpreted according to the criteria of the International Harmonization Project. The reduction in the maximum standardizes uptake values (?SUVmax) of 25%, 50%, and 75% were regarded as cutoff points. Overall survival (OS) and progression-free survival (PFS) were regarded as the major endpoints. RESULTS: The median OS and PFS were 27.6 months (range 6.5-78.3 months) and 27.2 months (range 3.0-78.3 months), respectively. The median SUVmax of the baseline PET/CT was 18.3 (range 1.6-35.9), whereas the median SUVmax of the mid-therapy and post-therapy PET/CT decreased to 4.0 (range 0-17.6) and 3.0 (range 0-14.5), respectively. The patients' Eastern Cooperative Oncology Group (ECOG) scores (<2 vs. >=2) were significantly associated with the baseline PET/CT SUVmax. The mid-therapy and post-therapy PET/CT results (positive vs. negative) showed no significant association with OS or PFS. The optimal cutoff ?SUVmax from the baseline to the post-therapy PET/CT that could predict a change in OS in patients with Burkitt's lymphoma was 50% (P = 0.019). CONCLUSIONS: (18)F-FDG uptake was intense in Burkitt's lymphoma, and there was a significant reduction in SUVmax during the interim and post-therapy PET/CT procedures. A ?SUVmax of greater than 50% was a favorable cutoff point to predict the OS of Burkitt's lymphoma patients. PMID- 26630875 TI - Prevention of sickle cell disease: observations on females with the sickle cell trait from the Manchester project, Jamaica. AB - Screening for haemoglobin genotype was offered to senior school students in Manchester parish in south central Jamaica to test whether this knowledge would influence choice of partner and reduce births with sickle cell disease. Over six academic years, 15,539 students, aged mostly 15-19 years, were screened with voluntary compliance rising from 56 to 92 % over this period. All subjects were given permanent genotype cards and carriers of abnormal genes were offered counselling which explained the reproductive options but avoided recommendations. Prior to screening, all had been offered illustrated lectures on the genetics and clinical features of sickle cell disease. The current study, confined to females with the sickle cell trait, interviewed 763/845 (90.3 %) subjects seeking to assess retention of this knowledge and their response to subsequent boyfriends. Of those interviewed, 42 subjects were excluded (38 emigrated, one died, three received incorrect genotype cards) leaving 721 with complete information. Knowledge of genotype was retained in 95 %, the outcome of future offspring correctly recalled in 91 %, and haemoglobin genotype cards were still possessed by 89 %. A current 'boyfriend' was acknowledged in 403 (56 %) of whom the partner's genotype was known in 88 (74 determined by the project laboratory; 14 by other laboratories) and unknown in 315 (78 %). Offers of free blood tests to all these partners were accepted by only 14 (4 %). Seventeen (2.4 %) were married but the husbands genotype was known in only five (four AA, one AS) of these. Most subjects retain knowledge of their genotype and of its significance for having affected children but the reluctance of partners to be tested was a major obstacle. PMID- 26630876 TI - Accurate prediction of nuclear receptors with conjoint triad feature. AB - BACKGROUND: Nuclear receptors (NRs) form a large family of ligand-inducible transcription factors that regulate gene expressions involved in numerous physiological phenomena, such as embryogenesis, homeostasis, cell growth and death. These nuclear receptors-related pathways are important targets of marketed drugs. Therefore, the design of a reliable computational model for predicting NRs from amino acid sequence has now been a significant biomedical problem. RESULTS: Conjoint triad feature (CTF) mainly considers neighbor relationships in protein sequences by encoding each protein sequence using the triad (continuous three amino acids) frequency distribution extracted from a 7-letter reduced alphabet. In addition, chaos game representation (CGR) can investigate the patterns hidden in protein sequences and visually reveal previously unknown structure. In this paper, three methods, CTF, CGR, amino acid composition (AAC), are applied to formulate the protein samples. By considering different combinations of three methods, we study seven groups of features, and each group is evaluated by the 10 fold cross-validation test. Meanwhile, a new non-redundant dataset containing 474 NR sequences and 500 non-NR sequences is built based on the latest NucleaRDB database. Comparing the results of numerical experiments, the group of combined features with CTF and AAC gets the best result with the accuracy of 96.30% for identifying NRs from non-NRs. Moreover, if it is classified as a NR, it will be further put into the second level, which will classify a NR into one of the eight main subfamilies. At the second level, the group of combined features with CTF and AAC also gets the best accuracy of 94.73%. Subsequently, the proposed predictor is compared with two existing methods, and the comparisons show that the accuracies of two levels significantly increase to 98.79% (NR-2L: 92.56 %; iNR-PhysChem: 98.18%; the first level) and 93.71% (NR-2L: 88.68%; iNR-PhysChem: 92.45%; the second level) with the introduction of our CTF-based method. Finally, each component of CTF features is analyzed via the statistical significant test, and a simplified model only with the resulting top-50 significant features achieves accuracy of 95.28%. CONCLUSIONS: The experimental results demonstrate that our CTF-based method is an effective way for predicting nuclear receptor proteins. Furthermore, the top-50 significant features obtained from the statistical significant test are considered as the "intrinsic features" in predicting NRs based on the analysis of relative importance. PMID- 26630877 TI - Is this critically ill patient immunocompromised? PMID- 26630878 TI - Is LiFe worth living? It all depends on the liver. PMID- 26630879 TI - Massive open online nutrition and cooking course for improved eating behaviors and meal composition. AB - BACKGROUND: Behavioral shifts in eating, favoring the increased consumption of highly processed foods over healthier, home-cooked alternatives, have led to widespread health problems. This study reports on the effectiveness of a massive open online course (MOOC), offering integrated nutrition and cooking instruction, for improving eating behaviors and meal composition among course participants. METHODS: The course, consisting of 47 short (4-6 min.) videos, was offered through Coursera, an open, online learning platform, available to individuals worldwide who have access to the Internet. Beginning in January 2014, participants viewed course videos, completed quizzes and participated in optional cooking assignments, over a 5-week period. Participants were invited to complete optional pre- and post-course surveys assessing their eating behaviors, typical meal composition and perceived barriers to home cooking. McNemar-Bowker tests of symmetry and within subject t-tests were conducted to evaluate pre-post survey changes in the primary variables measured. RESULTS: 7,422 participants from more than 80 countries completed both pre- and post-course surveys, while 19,374 participants completed the pre-survey only. Class participants were primarily women in the child-rearing ages (20-49 years of age). There were significant positive changes in eating behaviors and meal composition over time, including an increase in the percentage of participants who reported cooking dinner at home using mostly fresh ingredients 5-7 times in the previous week (63.4 % to 71.4 %), and who felt that yesterday's dinner was very/extremely healthy (39.3 % to 56.4 %) and enjoyable (55.2 % to 66.7 %) (all p values < .0001). CONCLUSIONS: Integrated nutrition and cooking courses, delivered via open online learning platforms, offer a free and flexible venue for reaching adults worldwide and have the potential to catalyze powerful behavioral shifts that align well with efforts to improve eating behaviors and meal composition. PMID- 26630880 TI - Cardiovascular risk among hypertensive adolescents and the potential benefit of a screen-and-treat strategy. AB - To evaluate whether screening for hypertension should start early in life, information on the risk of diseases associated with the level of blood pressure in childhood or adolescence is needed. The study by Leiba et al. that is reported in the current issue of Pediatric Nephrology demonstrates convincingly that hypertensive adolescents are at higher risk of cardiovascular death than normotensive adolescents. Nevertheless, it can be shown that this excess risk is not sufficient to justify a screen-and-treat strategy. Since the large majority of cardiovascular deaths occur among normotensive adolescents, measures for primordial prevention of cardiovascular diseases could have a much larger impact at the population level. PMID- 26630881 TI - Geographic variation in the intended choice of adjuvant treatments for women diagnosed with screen-detected breast cancer in Queensland. AB - BACKGROUND: Although early diagnosis and improved treatment can reduce breast cancer mortality, there still appears to be a geographic differential in patient outcomes. This study aims to determine and quantify spatial inequalities in intended adjuvant (radio-, chemo- and hormonal) therapy usage among women with screen-detected breast cancer in Queensland, Australia. METHODS: Linked population-based datasets from BreastScreen Queensland and the Queensland Cancer Registry during 1997-2008 for women aged 40-89 years were used. We adopted a Bayesian shared spatial component model to evaluate the relative intended use of each adjuvant therapy across 478 areas as well as common spatial patterns between treatments. RESULTS: Women living closer to a cancer treatment facility were more likely to intend to use adjuvant therapy. This was particularly marked for radiotherapy when travel time to the closest radiation facility was 4 + h (OR =0.41, 95 % CrI: [0.23, 0.74]) compared to <1 h. The shared spatial effect increased towards the centres with concentrations of radiotherapy facilities, in north-east (Townsville) and south-east (Brisbane) regions of Queensland. Moreover, the presence of residual shared spatial effects indicates that there are other unmeasured geographical barriers influencing women's treatment choices. CONCLUSIONS: This highlights the need to identify the additional barriers that impact on treatment intentions among women diagnosed with screen-detected breast cancer, particularly for those women living further away from cancer treatment centers. PMID- 26630882 TI - Brain functional network abnormality extends beyond the sensorimotor network in brachial plexus injury patients. AB - Brachial plexus injury (BPI) is a type of severe peripheral nerve trauma that leads to central remodeling in the brain, as revealed by functional MRI analysis. However, previously reported remodeling is mostly restricted to sensorimotor areas of the brain. Whether this disturbance in the sensorimotor network leads to larger-scale functional remodeling remains unknown. We sought to explore the higher-level brain functional abnormality pattern of BPI patients from a large scale network function connectivity dimension in 15 right-handed BPI patients. Resting-state functional MRI data were collected and analyzed using independent component analysis methods. Five components of interest were recognized and compared between patients and healthy subjects. Patients showed significantly altered brain local functional activities in the bilateral fronto-parietal network (FPN), sensorimotor network (SMN), and executive-control network (ECN) compared with healthy subjects. Moreover, functional connectivity between SMN and ECN were significantly less in patients compared with healthy subjects, and connectivity strength between ECN and SMN was negatively correlated with patients' residual function of the affected limb. Functional connectivity between SMN and right FPN were also significantly less than in controls, although connectivity between ECN and default mode network (DMN) was greater than in controls. These data suggested that brain functional disturbance in BPI patients extends beyond the sensorimotor network and cascades serial remodeling in the brain, which significantly correlates with residual hand function of the paralyzed limb. Furthermore, functional remodeling in these higher-level functional networks may lead to cognitive alterations in complex tasks. PMID- 26630883 TI - Unexpected tissue and the biobank that closed: an exploration of value and the momentariness of bio-objectification processes. AB - Unanticipated situations can arise in biobanking. This paper empirically documents unexpected situations at the anonymous biobank 'Xbank'. Firstly, Xbank received an unexpected and significant quantity of tissue from the historical archive of a hospital network. Secondly, Xbank had its funding withdrawn before the designated end date for the grant, meaning the bank needed to either re-house or destroy its holdings. This paper articulates and uses the theoretical frameworks of bio-objectification and tissue economies to analyse the experiences of Xbank and draw out further implications of the potential precariousness of biobanking practice. The case study allows an inspection of how the value of tissue is configured and reconfigured as institutional contexts shift. We introduce the notion of momentariness as a way of grappling with the related temporariness and perpetualness of biobanking practice in both a theoretical and practical policy context. PMID- 26630884 TI - Prevalence of asymptomatic malaria infection and use of different malaria control measures among primary school children in Morogoro Municipality, Tanzania. AB - BACKGROUND: Malaria is a public health problem in Tanzania affecting all age groups. It is known that school children are the age group most commonly infected with malaria parasites. Their infections are usually asymptomatic, go unnoticed and thus never get treated, result in anaemia, reduced ability to concentrate and learn in school and if fallen sick may lead to school absenteeism. Effective malaria control requires frequent evaluation of effectiveness of different malaria interventions. METHODS: A cross-sectional study design involving 317 out of 350 school children aged 6-13 years from five primary schools within municipality was conducted. Multistage cluster sampling and simple random sampling methods were used to obtain primary school and study participants, respectively. Finger-prick blood samples were collected for Plasmodium parasite detection by malaria rapid diagnostic test (mRDT) and haemoglobin level assessment by Easy Touch((r)) GHb system machine. A questionnaire was administered to assess use of insecticide-treated nets (ITNs) and anti-malarial drugs. RESULTS: The prevalence of asymptomatic malaria was 5.4 % (95 % CI 3.3-8.6 %) and anaemia was 10.1 % (95 % CI 7.2-13.9 %). School children aged 6-9 years were more affected by malaria than those aged 10-13 years. The proportion of ITNs used was 90.6 % (95 % CI 86.3-93.9 %) while that of artemisinin combination therapy (ACT) was 71.9 % (95 % CI 66.2-77.1 %). CONCLUSION: Findings show existence of asymptomatic malaria and walking anaemia among primary school children in Morogoro municipality. The majority of school children reported use of ITNs and ACT for malaria control. These findings provide a rationale for using schools and school children to assess effectiveness of malaria interventions. PMID- 26630885 TI - Multifocal osteonecrosis related to corticosteroid: ten years later, risk of progression and observation of subsequent new osteonecroses. AB - PURPOSE: No study has reported the risk of other site osteonecroses after the diagnosis of multifocal osteonecrosis related to corticosteroids in patients who continue this corticosteroid treatment. An analysis of the time-course to other sites of osteonecrosis, as well as the effects of underlying corticosteroid risk factor on the evolution of asymptomatic lesions at the time of diagnosis, is presented. METHODS: Two hundred patients were followed prospectively every year during a minimum ten years with a radiograph if a joint became symptomatic. In absence of evidence of osteonecrosis on radiographs of a symptomatic or non symptomatic joint (hips, shoulders, knees, ankles), patients had an MRI performed at the most recent follow up. The average duration of follow-up after inclusion of the patient in the study was 15 years (range 10-20). RESULTS: Of the 200 patients followed for an average of 15 years (minimum 10 years, maximum 20 years), 35 patients developed new osteonecrosis lesions during the period of study. Asymptomatic lesions became symptomatic and a high number of collapse was observed resulting in 258 arthroplasties (187 hips, 51 shoulders, 20 knees) at the most recent follow up. CONCLUSION: The continuation of peak doses (>200 mg) of corticosteroids predicted (p = 0.04) occurrence of new lesions and the continuation of corticosteroids without peak dose was a risk for quicker progression to collapse. PMID- 26630886 TI - Familiarity Breeds Contempt: "Frequent Fliers" in Medicine. PMID- 26630887 TI - SMJ Response. PMID- 26630888 TI - Impact of Neighborhood Environments on Health Consciousness, Information Seeking, and Attitudes among US-Born and Non-US-Born Free Clinic Patients. AB - OBJECTIVES: This study examined the impact of neighborhood environments on health consciousness, information seeking, and attitudes among uninsured free clinic patients to better understand the specific needs of the population for health promotion and prevention efforts. METHODS: US-born English-speaking, non-US-born English-speaking, and Spanish-speaking free clinic patients completed a self administered survey using reliable measures in autumn 2014 (N = 769). RESULTS: The results of this study suggest that social cohesion is positively associated with health consciousness, information seeking, and attitudes. Lower levels of available healthy food in the community were associated with higher levels of health consciousness. Although Spanish speakers reported lower levels of the availability of healthy food, social cohesion, and access to the Internet or text messaging compared with US-born or non-US-born English speakers, they were more likely to be health conscious and have higher levels of health information seeking. Spanish speakers as well as non-US-born English speakers, were more likely to attend health education classes compared with US-born English speakers. CONCLUSIONS: Health education programs for free clinic patients should include strategies to increase social cohesion. Health education programs should consider the diverse needs of these individual populations to maximize the effectiveness of the programs for free clinic patients. PMID- 26630889 TI - Developing and Implementing a Citywide Asthma Action Plan: A Community Collaborative Partnership. AB - OBJECTIVES: Asthma affects 1 in 10 children in the United States, with higher prevalence among children living in poverty. Organizations in San Antonio, Texas, partnered to design and implement a uniform, citywide asthma action plan to improve asthma management capacity in schools. METHODS: The asthma action plan template was modified from that of the Global Initiative for Asthma. School personnel were trained in symptom recognition, actions to take, and use of equipment before the asthma action plan implementation. The annual Asthma Action Plan Summit was organized as a forum for school nurses, healthcare providers, and members of the community to exchange ideas and strategies on implementation, as well as to revise the plan. RESULTS: The asthma action plan was implemented in all 16 local school districts. Feedback received from school nurses suggests that the citywide asthma action plan resulted in improved asthma management and student health at schools. CONCLUSIONS: The evidence in this study suggests that community organizations can successfully collaborate to implement a citywide health initiative similar to the asthma action plan. PMID- 26630890 TI - Pain Scores and Exposure Rates after Polypropylene Mesh for Pelvic Organ Prolapse. AB - OBJECTIVES: To characterize pain and exposure after Prolift placement and identify risk factors. METHODS: A case series of women who underwent Prolift vaginal mesh were surveyed. Pain was assessed using a visual analog scale. Exposure was evaluated clinically. RESULTS: Of 183 eligible patients, 160 completed the survey, and 45 returned for examination. Mean preoperative pain score was 0.97 and postoperative was 1.35 (P = 0.12). Pre- and postoperative pain scores by compartment were: anterior (1.34 vs 1.25, mean change -0.09, P = 0.84), posterior (1.30 vs 1.56, mean change 0.26, P = 0.72), and total (0.63 vs 1.34, mean change 0.71, P = 0.05). Graft exposure was confirmed in 23 of 183 patients (12.6%); however, because asymptomatic patients were not examined, the true exposure rate may be underestimated. Hematoma formation is independently associated with mesh exposure, adjusted odds ratio 18.4 (95% confidence interval 3.4-147.4, P = 0.01). CONCLUSIONS: Although pain scores did not increase overall, there was a trend toward increased pain score in the patients with total (anterior and posterior) Prolift. Hematoma formation was significantly associated with mesh exposure. PMID- 26630891 TI - Commentary on "Pain Scores and Exposure Rates after Polypropylene Mesh for Pelvic Organ Prolapse". PMID- 26630893 TI - Commentary on "Limitations of A1c Interpretation". PMID- 26630892 TI - Limitations of A1c Interpretation. AB - Hemoglobin A1c is the measurement of glycated hemoglobin and can aid in both the diagnosis and continued management of diabetes mellitus. Accurate glycosylated hemoglobin A1c (A1c) measurements are an essential part of decision making in the diagnosis and treatment of type 2 diabetes mellitus. Although national standards exist to eliminate technical error with A1c testing, multiple patient conditions can falsely decrease or elevate the A1c. In this review, we discuss the methods to measure A1c and the corresponding conditions that can affect the clinical utility of the test. Conditions that affect the A1c can be either those that impair erythrocyte production or alter the normal process of glycation. Some variation also has been associated with patient ethnicity and even with normal aging. We describe alternatives to A1c testing for the above clinical scenarios in an effort to make the practicing clinician aware of alternatives for glucose evaluation. PMID- 26630894 TI - Overuse of Acid-Suppression Therapy at an Urban Tertiary Hospital. AB - OBJECTIVES: Acid-suppressive therapy (AST) is widely used for gastrointestinal prophylaxis in hospitalized patients, particularly to prevent stress-related mucosal bleeding in critically ill individuals. Previous reports suggest gross overutilization and continuation of unnecessary therapy, which have been linked to several adverse effects. METHODS: Retrospective chart review at a large tertiary care hospital, evaluating the use of AST for ulcer prophylaxis in accordance with American Society of Health-System Pharmacists' guidelines and the less commonly studied nonsteroidal anti-inflammatory drug-related ulcer prophylaxis guidelines. RESULTS: A total of 119 (39.3%) patients who received AST met either American Society of Health-System Pharmacists guidelines or nonsteroidal anti-inflammatory drug-related prophylaxis guidelines. Subjects whose AST was appropriate were older, had a higher Charlson Comorbidity Index (P < 0.001), and were more often men (P = 0.005). The rate of discontinuation at discharge was 70.7%; subjects whose prescriptions were not discontinued were older, had a higher Charlson Comorbidity Index, and longer hospital and intensive care unit lengths of stay (P < 0.001). Family medicine physicians, hospitalists, and surgeons prescribed AST similarly; internal medicine physicians demonstrated higher adherence with guidelines than all others (P = 0.02). Adherence varied by etiology; cardiology patients were treated with the highest level of appropriateness (53.6%), whereas those admitted for gastrointestinal diagnoses demonstrated the lowest (17.6%, P = 0.03). CONCLUSIONS: Inappropriate prescribing of AST for ulcer prophylaxis remains problematic. There may be differences in prescribing habits of physicians of different specialties. Age and comorbidity scores were associated with inappropriate prescribing and continuation of medication at discharge. Interventions to raise prescribers' awareness of ulcer risk factors in hospitalized patients, both in the intensive care unit and those who are noncritically ill, are needed. PMID- 26630895 TI - Open-Access Single Balloon Enteroscopy: A Tertiary Care Experience. AB - OBJECTIVES: To compare single balloon enteroscopy (SBE) between patients seen in consultation by a member of our gastroenterology team with those performed as open-access cases. METHODS: Retrospective study of all patients who underwent SBE at a single tertiary care center from April 2008 to January 2012. Open- and closed-access procedures were compared in terms of diagnostic and therapeutic yield, adverse events, and procedural success. RESULTS: A total of 125 SBEs were performed on 125 patients. The mean age was 63.1 (53% men) years. In all, 43 procedures were performed open access and 82 after face-to-face consultation. Indications included anemia/gastrointestinal bleeding (110), abdominal pain (8), and other (7). Diagnostic yield for open- and closed-access procedures was 53% and 60%, respectively (P = 0.501) and therapeutic yield was 37% and 52%, respectively (P = 0.11). Overall technical success was 91% with no difference between the groups (P = 0.27). There were no major adverse events in either group. CONCLUSIONS: SBE can be performed as an open-access procedure without compromise to safety or diagnostic yield. PMID- 26630896 TI - Chronic Opioid Users Are More Difficult to Sedate than Alcoholics and Controls. AB - OBJECTIVES: Diagnostic and therapeutic colonoscopy is performed using conscious sedation. Excessive alcohol users, chronic benzodiazepine and opioid users, and polysubstance users are commonly cited as difficult to sedate. Few studies have compared and analyzed medication dosages to achieve sedation in these groups. METHODS: The endoscopic database was searched for patients who underwent colonoscopy. A retrospective chart review was performed to determine whether each patient was an abuser/chronic user of opioids, benzodiazepines, marijuana, alcohol, or a combination of the above. The mean dose of fentanyl and versed administered in each group was compared. RESULTS: A total of 239 patients were enrolled. Compared with the alcohol and control groups, the opioid group used a statistically higher mean medication dosage to achieve sedation. The mean dose of fentanyl in the opioid group was 124 MUg, the mean dose in the alcohol group was 101 MUg, and the mean dose in the control group was 101 MUg. The mean dose of midazolam in the opioid group was 4.1 mg, the mean dose in the alcohol group was 3.3 mg, and the mean dose in the control group was 3.3 mg. CONCLUSIONS: Identifying patients who are difficult to sedate before colonoscopy is important because adequate sedation is associated with better adenoma detection, a better procedural completion rate, and patient satisfaction. In patients using daily opioids, it is important to anticipate the need for higher doses of medication to achieve adequate sedation. PMID- 26630897 TI - Enteral Nutrition Support Reduces the Necessity of Total Parenteral Nutrition to Reach Patient-Specific Caloric Goals Postpancreaticoduodenectomy. AB - OBJECTIVES: Pancreaticoduodenectomy (PD) is associated with significant rates of postoperative complications. Although there is evidence that enteral nutrition support (ENS) may reduce postoperative sepsis, the true value of ENS in the abrogation of septic complications remains controversial. The aim of our study is to investigate the postoperative outcome of patients post-PD with and without ENS. METHODS: Using our prospective institutional database, we identified 202 patients from 2001 through 2009 who underwent PD. Of the 202 patients, 121 matched our inclusion criteria. In total, 67 of 121 (55.4%) patients received ENS, whereas 54 (44.6%) patients had no ENS and served as controls. Postoperative morbidity and mortality were recorded and analyzed. RESULTS: No significant differences were found in the postoperative morbidity of the patients. The anastomotic leak rate was 13% in both the ENS and control groups (P = 0.846). There was no difference in mortality within the two groups (4% vs 5%, P = 0.881). Significantly more patients in the control group received total parenteral nutrition (P = 0.033). CONCLUSIONS: ENS is not associated with lower rates of postoperative morbidity and mortality. It does, however, reduce the necessity of additional total parenteral nutrition to reach patient-specific caloric goals. PMID- 26630898 TI - Is Early Reperfusion a Good Thing? Optimal Timing of CABG Surgery Postacute Myocardial Infarction. AB - OBJECTIVES: The optimal timing of coronary artery bypass grafting (CABG) following an acute myocardial infarction (AMI) is a topic of debate. The present study was designed to evaluate patients undergoing CABG both early (<5 days) and late (>5 days) after AMI in the era of percutaneous coronary intervention. METHODS: The medical records at our institution from 2008 through 2012 were reviewed. A total of 128 patients underwent CABG after AMI during this time period and fulfilled criteria for the study. Death, stroke, renal failure, need for intraaortic balloon pump, postoperative ventilator days, and length of stay were examined. RESULTS: Patients undergoing early CABG had an increased need for an intraaortic balloon pump. There were no other correlations that we could discern between early and late CABG. CONCLUSIONS: Our data demonstrate no statistical difference in mortality or in the factors of morbidity studied between either early or late CABG after AMI. PMID- 26630899 TI - Reducing Readmission Rates by Improving Transitional Care. PMID- 26630900 TI - Characteristic Predictors that Increase the Pretest Probability of Legionnaires Disease: "Don't Order a Test Just Because You Can" Revisited. PMID- 26630901 TI - Performance of feedlot lambs fed palm kernel cake-based diets. AB - Fifty-four castrated male lambs with an average body weight of 23 +/- 0.35 kg were randomly assigned to five treatments that consisted of different levels of palm kernel cake in the diet (0.0, 7.5, 15.0, 22.5, and 30.0 % on a DM basis) in order to evaluate the effects on intake, digestibility, empty body weight, and body gain composition. The intakes of dry matter, organic matter, crude protein, and non-fiber carbohydrates (NFC) presented with a decreasing linear effect. However, the intakes of EE and NDF presented with increased linear results as the palm kernel cake was added to the concentrate. There was a quadratic effect for the digestibility coefficient of all nutrients, except for NFC. The palm kernel cake had a decreasing linear effect on final body weight, empty body weight, and the average daily gain of the animals that were fed increased levels of palm kernel cake. The inclusion of palm kernel cake as a partial substitute for concentrate decreases the intake of the majority of nutrients, except for EE and NDF, and consequently, causes deleterious effects on the nutrient digestibility and performance of lambs that are fed a 50:50 roughage/concentrate ratio. PMID- 26630902 TI - Annual HIV incidence fell by a third from 2000 to 2014. PMID- 26630904 TI - Editorial. Role of Drug Transport and Pharmacokinetics in Drug Efficacy and Safety Part 1. PMID- 26630905 TI - Effects of Drug Transporters on Pharmacological Responses and Safety. AB - Recently, it is realized that transporters, apart from enzymes, play a key role in drug metabolism and pharmacokinetics. More and more pharmaceutical researchers focused on transporter study and found that drug transporters not only involved in pharmacokinetics including absorption, distribution, metabolism and excretion (ADME). but also in Drug-Drug interactions (DDIs). DDIs induced by drug transporters are the important safety evaluation factors which have to be taken into account at stage of drug discovery and development. Therefore, it should pay more attention to the studies on step of preclinical and clinical trial. In this review, the author focused on the effects of drug transporters on pharmacological and safety responses, such as the effects on plasma elimination half-lives, on drug accumulation in body after repeated dosing, on potentiating either pharmacological or adverse effects and molecular mechanisms of transporter mediated DDIs. Present studies showed that DDIs involving the drug transporters including ABC transporters, organic anion and cation transporters, peptide transporters, monocarboxylate transporters, nucleoside transporters and folate transporters, and the possible side effects derived from clinical combination therapy must pay attention. The author also discussed the molecular mechanisms of transporter-mediated DDIs by the data obtained from preclinical and clinical studies, and inferred the available curative effects and the potential risk of the drug combination involving these drug transporters, which provides a reference for the safety of clinical medication and a consideration for a successful drug discovery. This article carefully reviewed transporter-based DDIs and highlighted areas that DDIs were poorly predicted through transporters or areas are still confronted with challenges in future. PMID- 26630906 TI - Interaction of Drug or Food with Drug Transporters in Intestine and Liver. AB - Oral bioavailability (F) is determined as fraction of the drug dose absorbed through the gastrointestinal membranes (Fa), the unmetabolized fraction of the absorbed dose that passes through the gut into the portal blood (Fg), and the hepatic first pass availability (Fh), namely F is expressed as the product of Fa, Fg and Fh (F = Fa.Fg.Fh). Current evidence suggests that transporter proteins play a role in intestinal absorption and hepatobiliary clearance of drugs. Among those transporters, this review will focus on PEPT1 and OATP2B1 as influx transporter and p-glycoprotein (P-gp) and BCRP as efflux transporter in intestinal epithelial cells, and on OATP1B1 and 1B3 as influx transporter and MRP2 as efflux transporter in hepatocytes, respectively, because drug-drug (DDI) and -food (DFI) interactions on these transporter are considered to affect bioavailability of their substrate drugs. DDI and DFI may reduce systemic exposure to drug by blocking influx transporters in intestine, but increase it by modulating influx and efflux transporters in liver and efflux transporters in intestines. Namely, drug disposition and efficacy are likely affected by DDI and DFI, resulting in treatment failures or increase in adverse effect. Therefore, it is of significantly importance to understand precise mechanism of DDI and DFI. This review will present information about transporter-based DDI and DFI in the processes of intestinal absorption and hepatic clearance of drugs, and discuss about their clinical implication. PMID- 26630907 TI - Challenges and Solutions of Pharmacokinetics for Efficacy and Safety of Traditional Chinese Medicine. AB - Traditional Chinese medicine (TCM), including herbal and folk medicine have been widely applied in healthcare field for a very long time. Based on the principle of kinetics, pharmacokinetics of TCM was developed to investigate the absorption, distribution, metabolism and excretion of active ingredients/components, single or mixed formulations, as well as the relationship between concentration and efficacy presented. Due to the complexity of TCM and its preparation, selection of molecules as markers for detection has become very difficult. So far, in which way or what indicators can be chosen for representing the pharmacodynamic action of single TCM or mixed is still controversial. Currently, a widely accepted approach is that the action of mixed preparation can be correlated by detecting pharmacokinetic behavior of one or several known active ingredients. According to the complexity of TCM, we presented a new concept of pharmacokinetic (PK) marker. The PK Marker should possess three conditions: (1) PK marker must be associated with efficacy, (2) PK marker exists in biological sample and can be determined by analytic method, and (3) PK marker should reflect the relationship between concentration and time. In TCM, four elements, "king-minister-assistant-guide", are the basic prescription principles for the individual therapy in TCM. We presented an idea of Point-line-area-cubic for four elements of TCM to study herb herb interactions. PMID- 26630908 TI - Adrenalectomy reduces the risk of vertebral fractures in patients with monolateral adrenal incidentalomas and subclinical hypercortisolism. AB - OBJECTIVE: Subclinical hypercortisolism (SH) is associated with increased risk of vertebral fractures (VFx). The effect on bone following recovery from SH is unknown. DESIGN: Of the 605 subjects consecutively referred for monolateral adrenal incidentalomas (AIs) to our outpatient clinics, 55 SH patients (recruited on the basis of the exclusion criteria) were enrolled. We suggested to all patients to undergo adrenalectomy, which was accepted by 32 patients (surgical group, age 61.3+/-8.1 years) and refused by 23 patients, who were followed with a conservative management (non-surgical group, age 65.4+/-7.1 years). METHODS: We diagnosed SH in patients with serum cortisol after 1 mg dexamethasone suppression test (1 mg-DST) >5.0 MUg/dl or with greater than or equal to two criteria among 1 mg-DST >3.0 MUg/dl, urinary free cortisol >70 MUg/24 h and ACTH <10 pg/ml. We assessed: bone mineral density (BMD) at lumbar spine (LS) and femoral neck (as Z-score) by dual-energy X-ray absorptiometry and the VFx presence by X-ray at baseline and at the end of follow up (surgical group 39.9+/ 20.9 months and non-surgical group 27.7+/-11.1 months). RESULTS: The LS Z-score (DeltaZ-score/year) tended to increase in the surgical group (0.10+/-0.20) compared with the non-surgical group (-0.01+/-0.27, P=0.08) and in the former, the percentage of patients with new VFx was lower (9.4%) than in the latter (52.2%, P<0.0001). Surgery in AI patients with SH was associated with a 30% VFx risk reduction (odds ratio 0.7, 95% CI 0.01-0.05, P=0.008) regardless of age, gender, follow up duration, 1 mg-DST, LS BMD, and presence of VFx at baseline. CONCLUSION: In patients with monolateral AI and SH, adrenalectomy reduces the risk of VFx. PMID- 26630909 TI - Immunological adjuvant effect of the peptide fraction from the larvae of Musca domestica. AB - BACKGROUND: The larvae of Musca domestica (Diptera: Muscidae) have been used traditionally for malnutritional stagnation, decubital necrosis, osteomyelitis, ecthyma and lip scald and also to treat coma and gastric cancer in the traditional Chinese medicine. Its immunomodulatory effects in naive mice in relation to the traditional uses were also reported. However, the immunological adjuvant potentials of this insect have not yet been studied. METHODS: The peptide fraction from the larvae of Musca domestica L. (MDPF) was evaluated for its adjuvant potentials on the immune responses to ovalbumin (OVA) and avian influenza vaccine (rL-H5) by determining antigen-specific antibody titers, splenocyte proliferation, activity of natural killer (NK) cell, the secretion of cytokines from splenocytes in the immunized mice. RESULTS: MDPF significantly enhanced not only the concanavalin A (Con A)-, lipopolysaccharide (LPS)- and antigen-stimulated splenocyte proliferation, but serum antigen-specific IgG, IgG1, IgG2a, and IgG2b antibody titers in the mice immunized with OVA and rL-H5. MDPF also remarkably promoted the killing activities of NK cells in splenocytes from the mice immunized with rL-H5. Furthermore, MDPF significantly promoted the production of Th1 (IL-2 and IFN-gamma) and Th2 (IL-10) cytokines from splenocytes in the immunized mice. CONCLUSIONS: The results indicated that MDPF had a potential to increase both cellular and humoral immune responses and elicit a balanced Th1/Th2 response, and that MDPF may be a safe and efficacious vaccine adjuvant candidate. PMID- 26630910 TI - Long-term effects of a 12 weeks high-intensity functional exercise program on physical function and mental health in nursing home residents with dementia: a single blinded randomized controlled trial. AB - BACKGROUND: Research indicates that exercise can have a positive effect on both physical and mental health in nursing home patients with dementia, however the lasting effect is rarely studied. In a previously published article we investigated the immediate effect of a 12 weeks functional exercise program on physical function and mental health in nursing home residents with dementia. In this paper we studied the long-term effect of this exercise program. We explored the differences between the exercise and control group from baseline to 6 months follow-up and during the detraining period from month 3 to 6. METHODS: A single blind, randomized controlled trial was conducted and a total of 170 nursing home residents with dementia were included. The participants were randomly allocated to an intervention (n = 87) or a control group (n = 83). The intervention consisted of intensive strengthening and balance exercises in small groups twice a week for 12 weeks. The control condition was leisure activities. Thirty participants were lost between baseline and six-month follow-up. Linear mixed model analyses for repeated measurements were used to investigate the effect of exercise after detraining period. RESULTS: The exercise group improved their scores on Berg Balance Scale from baseline to 6 months follow-up by 2.7 points in average. The control group deteriorated in the same period and the difference between groups was statistically significant (p = 0.031). The exercise group also scored better on NPI agitation sub-score after 6 months (p = 0.045). CONCLUSION: The results demonstrate long-time positive effects of a high intensity functional exercise program on balance and indicate a positive effect on agitation, after an intervention period of 12 weeks followed by a detraining period of 12 weeks. Identifier at ClinicalTrials.gov: NCT02262104. PMID- 26630913 TI - Erratum to: Positive selection in octopus haemocyanin indicates functional links to temperature adaptation. PMID- 26630911 TI - Microtargeting cancer metabolism: opening new therapeutic windows based on lipid metabolism. AB - Metabolic reprogramming has emerged as a hallmark of cancer. MicroRNAs are noncoding RNAs that posttranscriptionally repress the expression of target mRNAs implicated in multiple physiological processes, including apoptosis, differentiation, and cancer. MicroRNAs can affect entire biological pathways, making them good candidates for therapeutic intervention compared with classical single target approaches. Moreover, microRNAs may become more relevant in the fine-tuning adaptation to stress situations, such as oncogenic events, hypoxia, nutrient deprivation, and oxidative stress. Furthermore, artificial microRNAs can be designed to modulate the expression of multiple targets of a specific pathway. In this review, we describe the metabolic reprogramming associated to cancer, with a special interest in the altered lipid metabolism. Next, we describe specific features of microRNAs that make them relevant to target cancer cell metabolism. Finally, in an attempt to open new therapeutic windows, we emphasize two exciting scenarios for microRNA-mediated intervention that need to be further explored: 1) the cooperation between FA biosynthesis (lipogenesis) and FA oxidation as complementary partners for the survival of cancer cells; and 2) the regulation of the intracellular lipid content modulating both lipid storage into lipid droplets, and lipid mobilization through lipolysis and/or lipophagy. PMID- 26630912 TI - Cholesterol in mouse retina originates primarily from in situ de novo biosynthesis. AB - The retina, a thin tissue in the back of the eye, has two apparent sources of cholesterol: in situ biosynthesis and cholesterol available from the systemic circulation. The quantitative contributions of these two cholesterol sources to the retinal cholesterol pool are unknown and have been determined in the present work. A new methodology was used. Mice were given separately deuterium-labeled drinking water and chow containing 0.3% deuterium-labeled cholesterol. In the retina, the rate of total cholesterol input was 21 MUg of cholesterol/g retina * day, of which 15 MUg of cholesterol/g retina * day was provided by local biosynthesis and 6 MUg of cholesterol/g retina * day was uptaken from the systemic circulation. Thus, local cholesterol biosynthesis accounts for the majority (72%) of retinal cholesterol input. We also quantified cholesterol input to mouse brain, the organ sharing important similarities with the retina. The rate of total cerebral cholesterol input was 121 MUg of cholesterol/g brain * day with local biosynthesis providing 97% of total cholesterol input. Our work addresses a long-standing question in eye research and adds new knowledge to the potential use of statins (drugs that inhibit cholesterol biosynthesis) as therapeutics for age-related macular degeneration, a common blinding disease. PMID- 26630914 TI - Impact of Chronic Sleep Disturbance for People Living With T1 Diabetes. AB - AIM: The aim was to explore personal experiences and to determine the impact of impaired sleep on well-being and diabetes-related activities/decision making among a cohort of people living with T1D. METHOD: Adults with T1D over the age of 18 and parents/carers of children with T1D were invited to complete an online questionnaire about their quality and quantity of sleep. Questions included impact of sleep on diabetes-related decision making, effective calculation of bolus doses, important aspects of psychosocial functioning, and frequency of waking. Diasend download data were used to objectively determine frequency of nocturnal blood glucose testing in children. RESULTS: A total of 258 parent/carer participants (n = 221 female, 85.6%) and 192 adults with T1D (n = 145, 75.5% female, age range 19 to 89 years) took part. In all, 239 parents/carers and 160 adults believed waking in the night has an impact on their usual daily functioning. Of these, 236 parents/carers and 151 (64%) adults reported the impact as negative. Chronic sleep interruption was associated with detrimental impact on mood, work, family relationships, ability to exercise regularly, ability to eat healthily, and happiness. CONCLUSION: Chronic sleep interruption is highly prevalent in adults with T1D and parents/carers of children with T1D with negative effects on daily functioning and well-being. Appropriate interventions are required to alleviate this burden of T1D, address modifiable risk factors for nocturnal hypoglycemia, and reduce the (perceived) need for nocturnal waking. PMID- 26630915 TI - Integration of Administrative, Clinical, and Environmental Data to Support the Management of Type 2 Diabetes Mellitus: From Satellites to Clinical Care. AB - A very interesting perspective of "big data" in diabetes management stands in the integration of environmental information with data gathered for clinical and administrative purposes, to increase the capability of understanding spatial and temporal patterns of diseases. Within the MOSAIC project, funded by the European Union with the goal to design new diabetes analytics, we have jointly analyzed a clinical-administrative dataset of nearly 1.000 type 2 diabetes patients with environmental information derived from air quality maps acquired from remote sensing (satellite) data. Within this context we have adopted a general analysis framework able to deal with a large variety of temporal, geo-localized data. Thanks to the exploitation of time series analysis and satellite images processing, we studied whether glycemic control showed seasonal variations and if they have a spatiotemporal correlation with air pollution maps. We observed a link between the seasonal trends of glycated hemoglobin and air pollution in some of the considered geographic areas. Such findings will need future investigations for further confirmation. This work shows that it is possible to successfully deal with big data by implementing new analytics and how their exploration may provide new scenarios to better understand clinical phenomena. PMID- 26630916 TI - Association of physical activity with blood pressure and blood glucose among Malaysian adults: a population-based study. AB - BACKGROUND: The health-enhancing benefits of physical activity (PA) on hypertension and diabetes have been well documented for decades. This study aimed to determine the association of PA with systolic and diastolic blood pressure as well as blood glucose in the Malaysian adult population. METHODS: Data were extracted from the 2011 National Health and Morbidity Survey (NHMS), a nationally representative, cross-sectional study. A two-stage stratified sampling method was used to select a representative sample of 18,231 Malaysian adults aged 18 years and above. The PA levels of the respondents were categorised as low, moderate or high according to the International Physical Activity Questionnaire (IPAQ)-short form. Blood pressure and fasting blood glucose levels were measured using a digital blood pressure-measuring device and finger-prick test, respectively. RESULTS: Systolic blood pressure (SBP) level was positively associated with PA level (p = 0.02) whilst no significant association was noted between PA level and diastolic blood pressure (DBP). In contrast, respondents with low (adjusted coefficient = 0.17) or moderate (adjusted coefficient = 0.03) level of PA had significantly higher blood glucose level as compared to those who were highly active (p = 0.04). CONCLUSIONS: A significant negative association was observed between PA level and blood glucose only. Future studies should employ an objective measurement in estimating PA level in order to elucidate the actual relationship between PA, hypertension and diabetes for the development of effective interventions to combat the increasing burden of premature-mortality and cardiovascular disease-related morbidity in Malaysia. PMID- 26630917 TI - Transfection with thymidine kinase permits bromodeoxyuridine labelling of DNA replication in the human malaria parasite Plasmodium falciparum. AB - BACKGROUND: Plasmodium falciparum, the causative agent of severe human malaria, is an early-diverging protozoan whose lifecycle has many unusual features, including its modes of replication. Research on the Plasmodium cell cycle, which occurs primarily via schizogony instead of canonical binary fission, has been hampered by a lack of tools and markers that can be transferred from cell cycle studies in model organisms. A common tool used to study DNA replication and the cell cycle in human cells is the labelling of newly-replicated DNA with the modified nucleotide bromodeoxyuridine (BrdU), followed by immunofluorescent detection. Plasmodium parasites, however, do not incorporate BrdU because they rely only on de novo synthesis of pyrimidines and do not salvage thymidine analogues like BrdU for conversion into nucleotides. METHODS: Analysis of biochemical pathways in Plasmodium indicated that the absence of the enzyme thymidine kinase (TK) may be the only impediment to BrdU incorporation in this organism. A TK gene from Herpes simplex was, therefore, introduced into the Plasmodium falciparum 3D7 strain and the effect on BrdU labelling was assessed by enzyme-linked immunosorbent assay and immunofluorescence microscopy. RESULTS: Introduction of a TK gene produces parasites that can indeed incorporate BrdU. This forms a sensitive indicator of DNA replication, which can be detected by both quantitative and qualitative assays on either a population level or a single cell level. Plasmodium falciparum, when expressing TK, becomes unusually sensitive to BrdU toxicity. CONCLUSIONS: BrdU labelling represents a significant new tool for investigating DNA replication and the cell cycle in Plasmodium. PMID- 26630919 TI - Potential Role of Polyphenols in the Prevention of Cardiovascular Diseases: Molecular Bases. AB - Cardiovascular diseases (CVD) are the leading cause of mortality worldwide. It is widely accepted that oxidative stress plays a key role in their development and progression; hence oxidative damage might be abrogated by antioxidants. Polyphenols are phytochemicals showing extensively studied antioxidant properties in-vivo. Most representative sources of these compounds include fruits, greens, nuts, herbs, cocoa, tea and coffee. Epidemiological evidence suggests an association between the consumption of polyphenol-rich vegetables and the reduction of cardiovascular disease prevalence. This fact could be related to the anti-inflammatory, antithrombotic and vasodilatory effects of polyphenols. Even though these biological effects could be mainly attributed to the antioxidant activity of polyphenols, other pharmacological mechanisms should also be considered. The latter could comprise direct anti-inflammatory effects, modulation of intracellular signaling and gene expression, improvement of nitric oxide homeostasis, as well as platelet antiaggregation. However, it is noticeable that protocols of interventions to evaluate the properties of polyphenols have failed to show the same positive results reported from observational studies. At present, a controversy exists regarding the actual effectiveness of polyphenols in preventing cardiovascular diseases. Therefore, an improvement of the available knowledge about polyphenol pharmacokinetics, together with a better understanding of the mechanisms of action of these compounds, could be of great benefit. Thus, a rational support for the development of interventional designs could provide reliable evidence on the actual role of polyphenols in CVD prevention. PMID- 26630920 TI - Neuroprotective Activities of Marine Natural Products from Marine Sponges. AB - This review covers the compounds isolated from marine sponges with neuroprotective activities during the period between 1999 and 2014 based on their chemical structures, collections sites, sponge taxonomy and neuroprotective effects. These compounds were isolated from marine sponges collected from 18 countries, most of them in Indonesia, followed by Japan. A total of 90 compounds were reported to exhibit a range of neuroprotective efficacy. These compounds were shown to inhibit beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), modulate the synthesis or activity of some neurotransmitters such as acetylcholinesterase and glutamate, enhancement of serotonin, reducing oxidative stress, inhibition of kinases and proteases, and enhancement of neurite growth. None of them have yet progressed into any marine pharmaceutical development pipeline, therefore sustained researches will be required to enhance the potential of utilizing these compounds in the future for prevention and therapeutic treatment of neurodegenerative diseases. PMID- 26630918 TI - Derivatives of Procaspase-Activating Compound 1 (PAC-1) and their Anticancer Activities. AB - PAC-1 induces the activation of procaspase-3 in vitro and in cell culture by chelation of inhibitory labile zinc ions via its ortho-hydroxy-N-acylhydrazone moiety. First reported in 2006, PAC-1 has shown promise in cell culture and animal models of cancer, and a Phase I clinical trial in cancer patients began in March 2015 (NCT02355535). Because of the considerable interest in this compound and a well-defined structure-activity relationship, over 1000 PAC-1 derivatives have been synthesized in an effort to vary pharmacological properties such as potency and pharmacokinetics. This article provides a comprehensive examination of all PAC-1 derivatives reported to date. A survey of PAC-1 derivative libraries is provided, with an indepth discussion of four derivatives on which extensive studies have been performed. PMID- 26630921 TI - Wrap-and-Strip Technology of Protein-Polyelectrolyte Complex for Biomedical Application. AB - A polyelectrolyte is a polymer composed of repeating units of an electrolyte group that enables reversible complex formation with proteins in aqueous solutions. This review introduces "wrap-and-strip" technology of protein polyelectrolyte complex (PPC) by noncovalent interaction. Storage: protein is stabilized against physical and chemical stresses. Enrichment: precipitation through PPC can be used as an enrichment method without irreversible unfolding. Catalytic activity switch: a complementary charged pair of polyelectrolytes functions as a reversible enzyme activity switch. Hyperactivation: a specific combination of a polyelectrolyte and substrate enhances enzyme activity by one order of magnitude compared with an enzyme alone. Stabilization: PPC increases protein stability against chemical and physical stresses, such as covalently modified polyethylene glycosylated protein. Simple PPC-based technology can expand the applicable fields of soluble proteins in aqueous solutions. PMID- 26630922 TI - Natural Endoperoxides as Drug Lead Compounds. AB - Natural products, especially bioactive molecules as drug lead compounds, have attracted extensive attention in health promotion and in drug discovery and development. It is essential to understand the structures and functional mechanisms of these lead molecules prior to drug development. This review provides comprehensive information for more than 130 newly reported peroxides appeared in the literature in the recent years. The compounds are natural peroxides with bioactivities. While some of them appeared in previous reviews, a great number of newly-found natural peroxides with up-dated information are extensively reviewed in this article, which focuses on the biological activities based on various structural classes including monoterpenoids, sesquiterpenoids, diterpenoids, sesterterpenoids, triterpenoids and steroidal peroxy compounds isolated from terrestrial and marine sources. These natural peroxides are valuable sources in drug discovery with antitumor and antimalarial activities. PMID- 26630923 TI - Preliminary validation of the short physical performance battery in older adults with multiple sclerosis: secondary data analysis. AB - BACKGROUND: There are relatively few standard, objective measures for studying physical function among older adults with multiple sclerosis (MS), yet such measures are necessary considering the shift in prevalence and associated consequences of both MS and older age on physical function. We undertook a preliminary examination of the construct validity of Short Physical Performance Battery (SPPB) scores in older adults with MS based on an expected differential pattern of associations with measures of lower and upper extremity function. METHODS: The sample included 48 persons with MS aged 50 years and older who were enrolled in a pilot, randomized controlled trial of exercise training. Participants completed the SPPB and other objective and self-report measures of lower and upper extremity function as part of baseline testing. RESULTS: SPPB scores demonstrated strong associations with measures of lower extremity function (|r s| = .66-.79), and weak associations with measures of upper extremity function (|r s| = .03-.33). CONCLUSIONS: We provide preliminary evidence that supports the validity of scores from the SPPB as a measure of lower extremity function for inclusion in clinical research and practice involving older adults with MS. PMID- 26630924 TI - Volunteer experiences and perceptions of the informed consent process: Lessons from two HIV clinical trials in Uganda. AB - BACKGROUND: Informed consent as stipulated in regulatory human research guidelines requires that a volunteer is well-informed about what will happen to them in a trial. However researchers are faced with a challenge of how to ensure that a volunteer agreeing to take part in a clinical trial is truly informed. We conducted a qualitative study among volunteers taking part in two HIV clinical trials in Uganda to find out how they defined informed consent and their perceptions of the trial procedures, study information and interactions with the research team. METHODS: Between January and December 2012, 23 volunteers who had been in the two trials for over 6 months, consented to be interviewed about their experience in the trial three times over a period of nine months. They also took part in focus group discussions. Themes informed by study research questions and emerging findings were used for content analysis. RESULTS: Volunteers defined the informed consent process in terms of their individual welfare. Only two of the volunteers reported having referred during the trial to the participant information sheets given at the start of the trial. Volunteers remembered the information they had been given at the start of the trial on procedures that involved drawing blood and urine samples but not information about study design and randomisation. Volunteers said that they had understood the purpose of the trial. They said that signing a consent form showed that they had consented to take part in the trial but they also described it as being done to protect the researcher in case a volunteer later experienced side effects. CONCLUSION: Volunteers pay more attention during the consent process to procedures requiring biological tests than to study design issues. Trust built between volunteers and the research team could enhance the successful conduct of clinical trials by allowing for informal discussions to identify and review volunteers' perceptions. These results point to the need for researchers to view informed consent as a process rather than an event. PMID- 26630925 TI - Phylogenetic relationships of ?Luisiella feruglioi (Bordas) and the recognition of a new clade of freshwater teleosts from the Jurassic of Gondwana. AB - BACKGROUND: Teleosts constitute more than 99 % of living actinopterygian fishes and fossil teleosts have been studied for about two centuries. However, a general consensus on the definition of Teleostei and the relationships among the major teleostean clades has not been achieved. Our current ideas on the origin and early diversification of teleosts are mainly based on well-known Mesozoic marine taxa, whereas the taxonomy and phylogenetic relationships of many Jurassic continental teleosts are still poorly understood despite their importance to shed light on the early evolutionary history of this group. Here, we explore the phylogenetic relationships of the Late Jurassic (Oxfordian - Tithonian) freshwater ?Luisiella feruglioi from Patagonia, in a comprehensive parsimony analysis after a thorough revision of characters from previous phylogenetic studies on Mesozoic teleosts. RESULTS: We retrieved ?Luisiella feruglioi as the sister taxon of the Late Jurassic ?Cavenderichthys talbragarensis, both taxa in turn forming a monophyletic group with the Early Cretaceous ?Leptolepis koonwarri. This new so far exclusively Gondwanan freshwater teleost clade, named ?Luisiellidae fam. nov. herein, is placed outside crown Teleostei, as a member of the stem-group immediately above the level of ?Leptolepis coryphaenoides. In addition, we did not retrieve the Late Jurassic ?Varasichthyidae as a member of ?Crossognathiformes. The position of ?Crossognathiformes within Teleocephala is confirmed whereas ?Varasichthyidae is placed on the stem. CONCLUSIONS: The general morphology of luisiellids is that of basal, stem Teleocephala; however, most of their synapomorphies have evolved independently in teleocephalans. Similarly, the resemblance between varasichthyids and crossognathiforms might be due to parallel evolution. In accordance to most teleostean phylogenies, our analysis shows that a major morphological change occurred along the stem line and are currently recorded at the level of ?Leptolepis coryphaenoides. A stem-based total clade Teleostei has been accepted for this work. PMID- 26630926 TI - Inequities in energy-balance related behaviours and family environmental determinants in European children: baseline results of the prospective EPHE evaluation study. AB - BACKGROUND: Tackling inequalities in overweight, obesity and related determinants has become a top priority for the European research and policy agendas. Although it has been established that such inequalities accumulate from early childhood onward, they have not been studied extensively in children. The current article discusses the results of an explorative analysis for the identification of inequalities in behaviours and their determinants between groups with high and low socio-economic status. METHODS: This study is part of the Epode for the Promotion of Health Equity (EPHE) evaluation study, the overall aim of which is to assess the impact and sustainability of EPODE methodology to diminish inequalities in childhood obesity and overweight. Seven community-based programmes from different European countries (Belgium, Bulgaria, France, Greece, Portugal, Romania, The Netherlands) participate in the EPHE study. In each of the communities, children aged 6-8 years participated, resulting in a total sample of 1266 children and their families. A parental self-administrated questionnaire was disseminated in order to assess the socio-economic status of the household, selected energy balance-related behaviours (1. fruit and vegetable consumption; 2. soft drink/ fruit juices and water consumption; 3. screen time and 4. sleep duration) of the children and associated family environmental determinants. The Mann-Whitney U test and Pearson's chi-square test were used to test differences between the low and high education groups. The country-specific median was chosen as the cut-off point to determine the educational level, given the different average educational level in every country. RESULTS: Children with mothers of relatively high educational level consumed fruits and vegetables more frequently than their peers of low socio-economic status. The latter group of children had a higher intake of fruit juices and/or soft drinks and had higher screen time. Parental rules and home availability were consistently different between the two socio-economic groups in our study in all countries. However we did not find a common pattern for all behaviours and the variability across the countries was large. CONCLUSIONS: Our findings are indicative of socio-economic inequalities in our samples, although the variability across the countries was large. The effectiveness of interventions aimed at chancing parental rules and behaviour on health inequalities should be studied. PMID- 26630929 TI - Historical development and current status of organ procurement from death-row prisoners in China. AB - BACKGROUND: In December 2014, China announced that only voluntarily donated organs from citizens would be used for transplantation after January 1, 2015. Many medical professionals worldwide believe that China has stopped using organs from death-row prisoners. DISCUSSION: In the present article, we briefly review the historical development of organ procurement from death-row prisoners in China and comprehensively analyze the social-political background and the legal basis of the announcement. The announcement was not accompanied by any change in organ sourcing legislations or regulations. As a fact, the use of prisoner organs remains legal in China. Even after January 2015, key Chinese transplant officials have repeatedly stated that death-row prisoners have the same right as regular citizens to "voluntarily donate" organs. This perpetuates an unethical organ procurement system in ongoing violation of international standards. CONCLUSIONS: Organ sourcing from death-row prisoners has not stopped in China. The 2014 announcement refers to the intention to stop the use of organs illegally harvested without the consent of the prisoners. Prisoner organs procured with "consent" are now simply labelled as "voluntarily donations from citizens". The semantic switch may whitewash sourcing from both death-row prisoners and prisoners of conscience. China can gain credibility only by enacting new legislation prohibiting use of prisoner organs and by making its organ sourcing system open to international inspections. Until international ethical standards are transparently met, sanctions should remain. PMID- 26630928 TI - The Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation does not improve the underestimation of Glomerular Filtration Rate (GFR) in people with diabetes and preserved renal function. AB - BACKGROUND: Our hypothesis was that both the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations would underestimate directly measured GFR (mGFR) to a similar extent in people with diabetes and preserved renal function. METHODS: In a cross-sectional study, bias (eGFR - mGFR) was compared for the CKD-EPI and MDRD equations, after stratification for mGFR levels. We also examined the ability of the CKD-EPI compared with the MDRD equation to correctly classify subjects to various CKD stages. In a longitudinal study of subjects with an early decline in GFR i.e., initial mGFR > 60 ml/min/1.73 m(2) and rate of decline in GFR (DeltamGFR) > 3.3 ml/min/1.73 m(2) per year, DeltamGFR (based on initial and final values) was compared with DeltaeGFR by the CKD-EPI and MDRD equations over a mean of 9 years. RESULTS: In the cross-sectional study, mGFR for the whole group was 80 +/- 2.2 ml/min/1.73 m(2) (n = 199, 75 % type 2 diabetes). For subjects with mGFR >90 ml/min/1.73 m(2) (mGFR: 112 +/- 2.0, n = 76), both equations significantly underestimated mGFR to a similar extent: bias for CKD-EPI: -12 +/- 1.4 ml/min/1.73 m(2) (p < 0.001) and for MDRD: -11 +/- 2.1 ml/min/1.73 m(2) (p < 0.001). Using the CKD-EPI compared with the MDRD equation did not improve the number of subjects that were correctly classified to a CKD-stage. No biochemical or clinical patient characteristics were identified to account for the under estimation of mGFR values in the normal to high range by the CKD-EPI equation. In the longitudinal study (n = 30, 66 % type 1 diabetes), initial and final mGFR values were 102.8 +/- 6 and 54.6 +/- 6.0 ml/min/1.73 m(2), respectively. Mean DeltaGFR (ml/min/1.73 m(2) per year) was 6.0 by mGFR compared with only 3.0 by MDRD and 3.2 by CKD-EPI (both p < 0.05 vs mGFR) CONCLUSIONS: Both the CKD-EPI and MDRD equations underestimate reference GFR values > 90 ml/min/1.73 m(2) as well as an early decline in GFR to a similar extent in people with diabetes. There is scope to improve methods for estimating an early decline in GFR. PMID- 26630927 TI - Health systems readiness and management of febrile outpatients under low malaria transmission in Vanuatu. AB - BACKGROUND: Vanuatu, an archipelago country in Western Pacific harbouring low Plasmodium falciparum and Plasmodium vivax malaria transmission, has been implementing a malaria case management policy, recommending parasitological testing of patients with fever and anti-malarial treatment for test-positive only patients. A health facility survey to evaluate the health systems readiness to implement the policy and the quality of outpatient management for patients with fever was undertaken. METHODS: A cross-sectional, cluster sample survey, using a range of quality-of-care methods, included all health centres and hospitals in Vanuatu. The main outcome measures were coverage of health facilities and health workers with commodities and support interventions, adherence to test and treatment recommendations, and factors influencing malaria testing. RESULTS: The survey was undertaken in 2014 during the low malaria season and included 41 health facilities, 67 health workers and 226 outpatient consultations for patients with fever. All facilities had capacity for parasitological diagnosis, 95.1 % stocked artemether-lumefantrine and 63.6 % primaquine. The coverage of health workers with support interventions ranged from 50 to 70 %. Health workers' knowledge was high only regarding treatment policy for uncomplicated P. falciparum malaria (83.4 %). History taking and clinical examination practices were sub-optimal. Some 35.0 % (95 % CI 23.4-48.6) of patients with fever were tested for malaria, of which all results were negative and only one patient received anti-malarial treatment. Testing was significantly higher for patients age 5 years and older (OR = 2.33; 95 % CI 1.48-5.02), seen by less qualified health workers (OR = 2.73; 95 % CI 1.48-5.02), health workers who received malaria case management training (OR = 2.39; 95 % CI 1.28-4.47) and patients with increased temperature (OR = 2.56; 95 % CI 1.17-5.57), main complaint of fever (OR = 5.82; 95 % CI 1.26-26.87) and without runny nose (OR = 3.75; 95 % CI 1.36 10.34). Antibiotic use was very high (77.4 %) with sub-optimal dispensing and counselling practices. CONCLUSIONS: Health facility and health worker readiness to implement policy is higher for falciparum than vivax malaria. Clinical and malaria testing practices are sub-optimal, however adherence to test negative results is nearly universal. Use of antibiotics is irrational. Quantitative and qualitative improvements of ongoing interventions are needed to re-inforce clinical practices in this area characterized by difficult access, human resource shortages but aspiring towards malaria elimination. PMID- 26630931 TI - Recent Advances in Developmental Signaling Pathway Inhibitors for the Treatment of Cancer. PMID- 26630932 TI - Genetic diversity, multiplicity of infection and population structure of Schistosoma mansoni isolates from human hosts in Ethiopia. AB - BACKGROUND: Human intestinal schistosomiasis caused by Schistosoma mansoni and urinary schistosomiasis caused by Schistosoma haematobium are endemic in Ethiopia. Although schistosomes look morphologically uniform, there is variation in infectivity, egg productivity and virulence due to variation in their genetic make. Knowing the genetic diversity and population structure of S. mansoni isolates will enable to understand and consider the possible variability in terms of infectivity, egg productivity and virulence. METHODS: Between 2010 and 2011, genetic diversity and population structure of Schistosoma mansoni isolates from four endemic areas of Ethiopia was assessed using previously published 11 polymorphic microsatellite loci. Miracidia were hatched from eggs of S. mansoni collected from stools of human subjects residing in Kemissie, Wondo Genet, Ziway and Sille-Elgo villages. DNA was extracted from single miracidium and PCR was run following standard protocol. Allelic polymorphism and population genetic structure was analyzed using different software. RESULT: At a population level (i.e. different villages), the mean number of alleles per locus, allelic richness, expected heterozygosity in Hardy-Weinberg equilibrium and pairwise F ST values ranged from 8.5 to 11.5, 3.46-20.8, 0.66-0.73 and 3.57-13.63%, respectively. All analyzes on population genetic structure reveals strong genetic structuration corresponding to the four sampled villages. At infrapopulation level (i.e. different hosts) the mean number of alleles per locus, allelic richness, expected heterozygosity in Hardy-Weinberg equilibrium and F IS values ranged from 3.09 to 7.55, 1-1.96, 0.59-0.73 and 0.1763-0.4989, respectively. Mean estimated genetically unique adult worm pairs within hosts ranged from 66 to 92% revealing the occurrence of infection of a single host with genetically unique multiple S. mansoni strains. The data also indicated the occurrence of genetic variation within inter- and intra-hosts. CONCLUSION: High level of genetic diversity and significant population differentiation characterized the S. mansoni isolates of Ethiopia. These results are quite different from previous studies demonstrating that it is difficult to generalize schistosome transmission patterns because epidemiological situation tends to vary. These are important factors to be considered in relation with morbidity, drug resistance or vaccine development. PMID- 26630933 TI - Incidental gastrointestinal 18F-Fluorodeoxyglucose uptake associated with lung cancer. AB - BACKGROUND: F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is increasingly used for the initial staging and restaging of lung cancer. Incidental gastrointestinal findings are often observed on (18)F-FDG PET/CT. The objective of this study was to assess incidental 18F-FDG uptake by the gastrointestinal tract (GIT) in patients with lung cancer. METHODS: Two hundred thirty consecutive 18F-FDG PET/CT examinations performed for lung cancer over a 3-year period were retrospectively reviewed for the presence of incidental FDG uptake in the GIT. The charts of patients with positive FDG uptake were then reviewed and analysed to determine the GIT uptake sites, the standardized uptake value (SUV) max and the final clinical diagnosis. RESULTS: Fifty-two patients (52/230, 23%) demonstrated incidental FDG uptake in the GIT. Thirty-three patients (63.5%) had diffuse uptake (oesophagus, n = 2, colon, n = 31) and 19 patients (36.5%) had focal uptake (oesophagus, n = 1, small bowel, n = 1, ascending colon, n = 5, descending colon, n = 4, sigmoid, n = 4, rectum, n = 3, and anal margin, n = 1). Twelve of the 52 patients with GIT uptake were further investigated, revealing, a diagnosis of malignancy in 4 patients with focal FDG uptake. No significant differences in mean SUVmax were observed between patients with malignant and benign GIT diseases. CONCLUSION: This study demonstrates a high incidence of FDG uptake in the GIT associated with lung cancer. Focal GIT uptake was frequently associated with malignant disease. These results suggest that further GIT investigations should be performed in patients with focal GIT uptake. PMID- 26630934 TI - Consolidating strategic planning and operational frameworks for integrated vector management in Eritrea. AB - BACKGROUND: Contemporary malaria vector control relies on the use of insecticide based, indoor residual spraying (IRS) and long-lasting insecticidal nets (LLINs). However, malaria-endemic countries, including Eritrea, have struggled to effectively deploy these tools due technical and operational challenges, including the selection of insecticide resistance in malaria vectors. This manuscript outlines the processes undertaken in consolidating strategic planning and operational frameworks for vector control to expedite malaria elimination in Eritrea. CASE DESCRIPTION: The effort to strengthen strategic frameworks for vector control in Eritrea was the 'case' for this study. The integrated vector management (IVM) strategy was developed in 2010 but was not well executed, resulting in a rise in malaria transmission, prompting a process to redefine and relaunch the IVM strategy with integration of other vector borne diseases (VBDs) as the focus. The information sources for this study included all available data and accessible archived documentary records on malaria vector control in Eritrea. Structured literature searches of published, peer-reviewed sources using online, scientific, bibliographic databases, Google Scholar, PubMed and WHO, and a combination of search terms were utilized to gather data. The literature was reviewed and adapted to the local context and translated into the consolidated strategic framework. DISCUSSION: In Eritrea, communities are grappling with the challenge of VBDs posing public health concerns, including malaria. The global fund financed the scale-up of IRS and LLIN programmes in 2014. Eritrea is transitioning towards malaria elimination and strategic frameworks for vector control have been consolidated by: developing an integrated vector management (IVM) strategy (2015-2019); updating IRS and larval source management (LSM) guidelines; developing training manuals for IRS and LSM; training of national staff in malaria entomology and vector control, including insecticide resistance monitoring techniques; initiating the global plan for insecticide resistance management; conducting needs' assessments and developing standard operating procedure for insectaries; developing a guidance document on malaria vector control based on eco-epidemiological strata, a vector surveillance plan and harmonized mapping, data collection and reporting tools. CONCLUSION: Eritrea has successfully consolidated strategic frameworks for vector control. Rational decision-making remains critical to ensure that the interventions are effective and their choice is evidence-based, and to optimize the use of resources for vector control. Implementation of effective IVM requires proper collaboration and coordination, consistent technical and financial capacity and support to offer greater benefits. PMID- 26630935 TI - Correlation of Tc-99 m ethyl cysteinate dimer single-photon emission computed tomography and clinical presentations in patients with low cobalamin status. AB - BACKGROUND: Cobalamin (Cbl) deficiency has been associated with various neuropsychiatric symptoms of different severities. While some studies dedicated in structural neuroimaging credibly address negative impact of low Cbl status, functional imaging reports are limited. We herein retrospectively review the correlation of Tc-99 m ethyl cysteinate dimer single-photon emission computed tomography (Tc-99 m-ECD SPECT) and clinical presentations among patients with low serum cobalamin (Cbl) status (<250 pg/ml). METHODS: Twelve symptomatic patients with low serum Cbl status were enrolled. Clinical presentations, Tc-99 m-ECD SPECT, and neuropsychological tests were reviewed. RESULTS: Dysexecutive syndrome (67 %), forgetfulness (50 %), attention deficits (42 %), and sleep disorders (33 %) constituted the major clinical presentations. All patients (100 %) had temporal hypoperfusion on the Tc-99 m-ECD SPECT. Five patients (42 %) had hypoperfusion restricted within temporal regions and deep nuclei; seven patients (58 %) had additional frontal hypoperfusion. In patients with hypoperfusion restricted within temporal regions and deep nuclei, psychiatric symptoms with spared cognition were their main presentations. Among patients with additional frontal hypoperfusion, six of seven patients (86 %) showed impaired cognitive performances (two of them were diagnosed as having dementia). Among ten patients who finished neuropsychological tests, abstract thinking (70 %) was the most commonly affected, followed by verbal fluency (60 %), short-term memory (50 %), and attention (50 %). Anxiety and sleep problems were the major clinically remarkable psychiatric features (33 % both). Four Tc-99 m-ECD SPECT follow-up studies were available; the degree and extent of signal reversal correlated with cognitive changes after Cbl replacement therapy. CONCLUSIONS: Our TC-99 m-ECD SPECT observations provide pivotal information of neurobiological changes within basal ganglia and fronto-temporal regions in conjunction with disease severity among patients with Cbl deficiency. Hypoperfusion within thalamus/basal ganglia and temporal regions may be seen in the earlier state of Cbl deficiency, when psychiatric symptoms predominate. Hypoperfusion beyond thalamus/basal ganglia and involving frontal regions appears when cognitive problems, mostly dysexecutive syndrome, are manifested. Symmetric hypofrontality of SPECT in the context of dysexcutive syndrome serves as a distinguishing feature of non-amnestic mild cognitive impairment attributed to Cbl deficiency. Concordant with TC-99 m-ECD SPECT findings, the psychiatric symptoms and dysexcutive syndrome undergird impaired limbic and dorsolateral prefrontal circuits originating from basal ganglia respectively. PMID- 26630936 TI - Canadian research ethics board members' attitudes toward benefits from clinical trials. AB - BACKGROUND: While ethicists have for many years called for human subject trial participants and, in some cases, local community members to benefit from participation in pharmaceutical and other intervention-based therapies, little is known about how these discussions are impacting the practice of research ethics boards (REBs) that grant ethical approval to many of these studies. METHODS: Telephone interviews were conducted with 23 REB members from across Canada, a major funder country for human subject research internationally. All interviews were digitally recorded and transcribed verbatim. After coding, the data was analyzed to identify central themes and topics. Themes were identified, application of the themes was confirmed, and these themes were then used to populate the findings of this manuscript. RESULTS: Our analysis of the interviews identified two primary themes when considering what benefits are owed to research participants and their communities. 1) Most study participants felt that given that these studies are led by persons in the role of researcher rather than health care provider, they had a limited obligation to provide benefits to study participants. 2) These REB members were all working in Canada, a high income country where most residents enjoy high levels of access to health care. As a result of this context, the study participants tended to focus on ethical concerns including obtaining informed consent and avoiding undue inducement to participate in research rather than ensuring that study participants directly benefit from successful trials. CONCLUSIONS: Research on REB members' attitudes toward what benefits are owed to study participants and community members is needed in other countries in order to determine how context affects these attitudes. PMID- 26630937 TI - The Global Burden of Esophageal Cancer: A Disability-Adjusted Life-Year Approach. AB - INTRODUCTION: Esophageal cancer is the eighth most common cancer worldwide and the sixth leading cause of cancer-related deaths. As a significant cause of morbidity and mortality, its burden on society has yet to be fully characterized. The aim of this study is to examine its global burden through estimation of the disability-adjusted life years (DALYs) attributable to it. METHODS: Global incidence and mortality estimates for esophageal cancer were obtained from the International Agency for Research on Cancer GLOBOCAN 2008 database. DALYs were calculated, using methodology established by the World Health Organization. RESULTS: In 2008, 3,955,919 DALYs were attributed to esophageal cancer, at a global rate of 0.58 DALYs per 1000 people annually. Years of life lost (YLL) accounted for 96.8 % of DALYs, while years lived with disability (YLD) accounted for 3.2 %. 83.8 % of the global DALYs occurred in less-developed countries, with most accrued in Eastern Asia, comprising 50.9 % of the total. The highest rate of DALY accrual was in Southern Africa, at 1.62 DALYs per 1000 people annually. CONCLUSIONS: A substantial number of years of life were lost or affected by esophageal cancer worldwide in 2008, with the burden resting disproportionately on less-developed countries. Geographically, the greatest burden is in Eastern Asia. The vast majority of DALYs were due to YLL, rather than YLD, indicating the need to focus resources on disease prevention and early detection. Our findings provide an additional basis upon which to formulate global priorities for interventions that affect DALY reduction in esophageal cancer. PMID- 26630938 TI - Clinicopathologic Differences in Patients with Gallbladder Cancer According to the Presence of Anomalous Biliopancreatic Junction. AB - BACKGROUND: Anomalous biliopancreatic junction (ABPJ) is a risk factor for gallbladder cancer (GBC). This study investigated the significance of ABPJ in patients with GBC. METHODS: Of the 453 patients with GBC underwent surgery at Seoul National University Hospital between 2000 and 2014, the 401 patients who can be assessed for the presence of ABPJ with radiologic image were analyzed. RESULTS: The 401 patients with GBC included 183 (45.6 %) males and 218 (54.4 %) females. ABPJ was identified in 69 (17.2 %) patients, 22 (31.9 %) males and 47 (68.1 %) females. Choledochal cyst (CC) was identified in 18 (4.5 %) patients, all of whom had ABPJ. Curative surgery was accomplished in 68.1 %. A comparison of patients with and without ABPJ showed that mean age (59.9 vs. 65.1 years, p < 0.001) and association with gallbladder stone (8.7 vs. 24.7 %, p = 0.002) were significantly lower in the ABPJ group, while the proportion of female (68.1 vs. 51.5 %, p = 0.012), bile duct resection rate (47.8 vs. 18.4 %, p < 0.001), and curative resection rate (81.1 vs. 65.7 %, p = 0.003) were significantly higher in the ABPJ group. Overall 5-year survival rates were similar in the ABPJ and non ABPJ groups (74.4 vs. 69.0 %, p = 0.533). In patients with ABPJ, the presence of CC did not have a significant effect on survival (p = 0.099). CONCLUSIONS: ABPJ was found in 17.2 % of patients with GBC. ABPJ is associated with younger age, female gender, absence of gallbladder stones, higher BDR rate, and higher curative resection rate. However, neither ABPJ nor CC was prognostic of survival in curatively treated patients with GBC. PMID- 26630939 TI - Clinical Significance of Splenic Hilar Dissection with Splenectomy in Advanced Proximal Gastric Cancer: An Analysis at a Single Institution in Japan. AB - BACKGROUND: Significance of splenic hilar node dissection with splenectomy is now denied for advanced gastric cancer of upper one-third of the stomach without invasion to the greater curvature by the Japan Clinical Oncology Group 0110, a pivotal randomized study from Japan. However, a question remains for tumors which involve the greater curvature, as this study excluded such tumors. METHODS: We retrospectively analyzed 421 consecutive patients with gastric cancer who underwent curative total gastrectomy with splenectomy from 1992 to 2009. The survival curves, state of lymph node (LN) metastasis, and index of the estimated benefit from LN dissection of each station were evaluated according to the tumor location. RESULTS: The incidence of No. 10 metastasis was 9.3 % (39/421), with 15.9 % in patients with tumors involving the greater curvature (Gre group, n = 132) and 6.2 % in those without (non-Gre group, n = 289) (P = 0.032). The 5-year overall survival (OS) of patients with and without No. 10 metastasis was 35.4 and 43.1 % (P = 0.135) in the Gre group and 32.8 and 66.5 % (P = 0.0006) in the non Gre group, respectively. The index of No. 10 LN dissection was 5.6 and 2.0 in the Gre and non-Gre groups, respectively. In the Gre group, the index was relatively higher in patients aged < 65 years, within pT3, and with Borrmann type 4 tumors. CONCLUSIONS: Splenectomy may have a survival benefit when a tumor shows involvement with the greater curvature, especially in relatively young patients and those without serosal exposure. PMID- 26630940 TI - Mucinous adenocarcinoma of the bladder associated with long term suprapubic tube: a case report. AB - BACKGROUND: Chronic indwelling catheters may induce histologic changes within the bladder, and these changes are sometimes pre-malignant. There are many documented cases of squamous cell carcinoma associated with indwelling catheters, but only three cases of catheter-associated adenocarcinoma have been reported. In this case report, we present radiographic findings of a case of mucinous adenocarcinoma of the bladder and suprapubic (SP) tract in a quadriplegic patient. CASE PRESENTATION: A 71-year-old male with a history of spinal cord injury presented with hematuria and SP discharge after SP catheterization for 51 years. CT urography was performed and revealed an irregular, infiltrative, and heterogeneous mass arising from the anterior bladder at the level of the suprapubic catheter and extending along the SP tube tract. Cystoscopy and biopsy revealed an adenocarcinoma of the anterior bladder and stoma with extensive associated mucin production and a background of acute and chronic inflammation. Surgical therapy included cystoprostatectomy, abdominal wall resection, ileal conduit creation, and abdominal wall reconstruction. The final diagnosis was a high-grade, T2a/N0/M0 (Stage II) mucinous adenocarcinoma of the bladder. There has been no evidence of tumor recurrence over the previous 5 years. CONCLUSION: Few cases of adenocarcinoma associated with long term indwelling catheter have been reported in the literature, and due to the rarity of this disease process, the prognosis with surgical therapy is not well known. The patient described herein has been free of recurrence for the previous five years, suggesting that surgery is a viable management option for these patients. PMID- 26630942 TI - Matched Cohort Analysis of the Effects of Limb Remote Ischemic Conditioning in Patients with Aneurysmal Subarachnoid Hemorrhage. AB - Remote ischemic conditioning (RIC) is a powerful innate response to transient subcritical ischemia that protects against severe ischemic insults at distant sites. We have previously shown the safety and feasibility of limb RIC in aneurysmal subarachnoid hemorrhage (aSAH) patients, along with changes in neurovascular and cerebral metabolism. In this study, we aim to detect the potential effect of an established lower-limb conditioning protocol on clinical outcomes of aSAH patients. Neurologic outcome (modified Rankin Scale (mRS)) of patients enrolled in a prospective trial (RIPC-SAH) was measured. A matching algorithm was applied to identify control patients with aSAH from an institutional departmental database. RIC patients underwent four lower-limb conditioning sessions, consisting of four 5-min cycles per session over nonconsecutive days. Good functional outcome was defined as mRS of 0 to 2. The study population consisted of 21 RIC patients and 61 matched controls. There was no significant intergroup difference in age, gender, aneurysm location, clipping vs coiling, Fisher grades, Hunt and Hess grades, or vasospasm. RIC was independently associated with good outcome (OR 5.17; 95% confidence interval (CI) 1.21-25.02). RIC also showed a trend toward lower incidence of stroke (28.6 vs. 47.5%) and death (4.8 vs. 19.7%). Lower-limb RIC following aSAH appears to have a positive effect in the functional outcomes of patients with aSAH. While this effect is consistent with prior preclinical studies, future trials are necessary to conclusively evaluate the effects of RIC for aSAH. PMID- 26630941 TI - Metabolic characteristics of dominant microbes and key rare species from an acidic hot spring in Taiwan revealed by metagenomics. AB - BACKGROUND: Microbial diversity and community structures in acidic hot springs have been characterized by 16S rRNA gene-based diversity surveys. However, our understanding regarding the interactions among microbes, or between microbes and environmental factors, remains limited. RESULTS: In the present study, a metagenomic approach, followed by bioinformatics analyses, were used to predict interactions within the microbial ecosystem in Shi-Huang-Ping (SHP), an acidic hot spring in northern Taiwan. Characterizing environmental parameters and potential metabolic pathways highlighted the importance of carbon assimilatory pathways. Four distinct carbon assimilatory pathways were identified in five dominant genera of bacteria. Of those dominant carbon fixers, Hydrogenobaculum bacteria outcompeted other carbon assimilators and dominated the SHP, presumably due to their ability to metabolize hydrogen and to withstand an anaerobic environment with fluctuating temperatures. Furthermore, most dominant microbes were capable of metabolizing inorganic sulfur-related compounds (abundant in SHP). However, Acidithiobacillus ferrooxidans was the only species among key rare microbes with the capability to fix nitrogen, suggesting a key role in nitrogen cycling. In addition to potential metabolic interactions, based on the 16S rRNAs gene sequence of Nanoarchaeum-related and its potential host Ignicoccus-related archaea, as well as sequences of viruses and CRISPR arrays, we inferred that there were complex microbe-microbe interactions. CONCLUSIONS: Our study provided evidence that there were numerous microbe-microbe and microbe-environment interactions within the microbial community in an acidic hot spring. We proposed that Hydrogenobaculum bacteria were the dominant microbial genus, as they were able to metabolize hydrogen, assimilate carbon and live in an anaerobic environment with fluctuating temperatures. PMID- 26630943 TI - LncRNA NONRATT021972 involved the pathophysiologic processes mediated by P2X7 receptors in stellate ganglia after myocardial ischemic injury. AB - Adenosine triphosphate (ATP) acts on P2X receptors to initiate signal transmission. P2X7 receptors play a role in the pathophysiological process of myocardial ischemic injury. Long noncoding RNAs (lncRNAs) participate in numerous biological functions independent of protein translation. LncRNAs are implicated in nervous system diseases. This study investigated the effects of NONRATT021972 small interference RNA (siRNA) on the pathophysiologic processes mediated by P2X7 receptors in stellate ganglia (SG) after myocardial ischemic injury. Our results demonstrated that the expression of NONRATT021972 in SG was significantly higher in the myocardial ischemic (MI) group than in the control group. Treatment of MI rats with NONRATT021972 siRNA, the P2X7 antagonist brilliant blue G (BBG), or P2X7 siRNA improved the histology of injured ischemic cardiac tissues and decreased the elevated concentrations of serum myocardial enzymes, creatine kinase (CK), CK isoform MB (CK-MB), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) compared to the MI rats. NONRATT021972 siRNA, BBG, or P2X7 siRNA treatment in MI rats decreased the expression levels of P2X7 immunoreactivity, P2X7 messenger RNA (mRNA), and P2X7 protein, interleukin-6 (IL 6), tumor necrosis factor-alpha (TNF-alpha), and phosphorylated p38 mitogen activated protein kinase (p38 MAPK) in the SG compared to MI rats. NONRATT021972 siRNA treatment prevented the pathophysiologic processes mediated by P2X7 receptors in the SG after myocardial ischemic injury. PMID- 26630944 TI - Perceived stress, unhealthy eating behaviors, and severe obesity in low-income women. AB - BACKGROUND: Stress has been associated with poor eating behaviors and diet quality, as well as high body mass index (BMI). Low-income women may be particularly vulnerable to stress and severe obesity. Yet it is unknown how stress increases the risk of severe obesity through disordered eating behaviors and poor diet quality or through mechanisms independent of diet. METHODS: We examined cross-sectional data from women (n = 101) with a child enrolled in the Special Supplemental Nutrition Program for Women, Infants, and Children in Cumberland County, North Carolina (spring 2012). We collected measured heights and weights to calculate BMI. Using structural equation modeling, we differentiated pathways from stress to weight status: (1) indirectly through eating behaviors (cognitive restraint, emotional eating, and uncontrolled eating) and diet quality, which we examined with the Healthy Eating Index 2010 and 24-h dietary recalls, and (2) directly through possible unmeasured risk factors independent of diet. The analysis controlled for race/ethnicity, income, age, whether the dietary recall day was typical, and whether the respondent completed one or two 24-h dietary recalls. RESULTS: Perceived stress was positively associated with uncontrolled eating (beta = 0.38, p < 0.001) and emotional eating (beta = 0.50, p < 0.001). However, higher stress was not associated with weight status through eating behaviors and diet quality. Independent of eating behaviors and diet quality, stress was positively associated with severe obesity (beta = 0.26, p = 0.007). CONCLUSIONS: Improving stress coping strategies for low-income women may improve eating behaviors and reduce severe obesity. PMID- 26630945 TI - Toward appropriate criteria in medication adherence assessment in older persons: Position Paper. AB - Nonadherence to medication regimens is a worldwide challenge; adherence rates range from 38 to 57 % in older populations with an average rate of less than 45 % and nonadherence contributes to adverse drug events, increased emergency visits and hospitalisations. Accurate measurement of medication adherence is important in terms of both research and clinical practice. However, the identification of an objective approach to measure nonadherence is still an ongoing challenge. The aim of this Position Paper is to describe the advantages and disadvantages of the known medication adherence tools (self-report, pill count, medication event monitoring system (MEMS) and electronic monitoring devices, therapeutic drug monitoring, pharmacy records based on pharmacy refill and pharmacy claims databases) to provide the appropriate criteria to assess medication adherence in older persons. To the best of our knowledge, no gold standard has been identified in adherence measurement and no single method is sufficiently reliable and accurate. A combination of methods appears to be the most suitable. Secondly, adherence assessment should always consider tools enabling polypharmacy adherence assessment. Moreover, it is increasingly evident that adherence, as a process, has to be assessed over time and not just at one evaluation time point (drug discontinuation). When cognitive deficits or functional impairments may impair reliability of adherence assessment, a comprehensive geriatric assessment should be performed and the caregiver involved. Finally, studies considering the possible implementation in clinical practice of adherence assessment tools validated in research are needed. PMID- 26630946 TI - Cone-beam CT-guided radiotherapy in the management of lung cancer: Diagnostic and therapeutic value. AB - BACKGROUND: Recent studies have demonstrated an increase in the necessity of adaptive planning over the course of lung cancer radiation therapy (RT) treatment. In this study, we evaluated intrathoracic changes detected by cone beam CT (CBCT) in lung cancer patients during RT. METHODS AND MATERIALS: A total of 71 lung cancer patients treated with fractionated CBCT-guided RT were evaluated. Intrathoracic changes and plan adaptation priority (AP) scores were compared between small cell lung cancer (SCLC, n = 13) and non-small cell lung cancer (NSCLC, n = 58) patients. RESULTS: The median cumulative radiation dose administered was 54 Gy (range 30-72 Gy) and the median fraction dose was 1.8 Gy (range 1.8-3.0 Gy). All patients were subjected to a CBCT scan at least weekly (range 1-5/week). We observed intrathoracic changes in 83 % of the patients over the course of RT [58 % (41/71) regression, 17 % (12/71) progression, 20 % (14/71) atelectasis, 25 % (18/71) pleural effusion, 13 % (9/71) infiltrative changes, and 10 % (7/71) anatomical shift]. Nearly half, 45 % (32/71), of the patients had one intrathoracic soft tissue change, 22.5 % (16/71) had two, and three or more changes were observed in 15.5 % (11/71) of the patients. Plan modifications were performed in 60 % (43/71) of the patients. Visual volume reduction did correlate with the number of CBCT scans acquired (r = 0.313, p = 0.046) and with the timing of chemotherapy administration (r = 0.385, p = 0.013). CONCLUSION: Weekly CBCT monitoring provides an adaptation advantage in patients with lung cancer. In this study, the monitoring allowed for plan adaptations due to tumor volume changes and to other anatomical changes. PMID- 26630947 TI - Prospective randomized comparison of the transobturator mid-urethral sling with the single-incision sling among women with stress urinary incontinence: 1-year follow-up study. AB - INTRODUCTION AND HYPOTHESIS: The objective was to compare the efficacy and safety of an innovative single-incision sling (SIS) with the inside-out transobturator sling (TOT) in the treatment of female stress urinary incontinence (SUI). METHODS: A prospective randomized trial was performed in a tertiary referral urogynecology center from January 2012 to December 2013. The study included women with pure urodynamic SUI. Patients were randomized to either the SIS or the TOT anti-incontinence procedure. Surgery duration, blood loss, and groin pain scores were recorded for each patient. The 1-year follow-up visit included objective and subjective cure parameters, postoperative de novo urgency, complications, and the impact on the patient's life quality. RESULTS: Of 285 patients assessed for eligibility, a total of 93 patients (32.6 %) were randomized into TOT (n = 48) and SIS groups (n = 45). There were no significant differences in either operating time or blood loss. A statistically significant difference between the two groups was found in pain scores three (5.6 +/- 1.8 vs 3.1 +/- 2.1, p < 0.001) and 12 h postoperatively (3.8 +/- 1.7 vs 2.1 +/- 1.7, p < 0.001). After 1 year, there were no significant differences between the TOT and SIS groups in objective cure rates (87.0 % vs 90.9 %; p = 0.399) or patient-reported success rates (91.3 % vs 93.2 %; p = 0.999). Incidence of postoperative de novo urgency did not differ between TOT and SIS patients. Both groups registered a significant improvement in quality of life. CONCLUSIONS: The Ophira SIS procedure has 1-year success rates comparable to standard TOT with significantly less groin pain in the early postoperative period. Both methods were safe and effective in terms of postoperative urgency and life quality improvement. PMID- 26630948 TI - Concomitant apical suspensory procedures in women with anterior vaginal wall prolapse in the United States in 2011. AB - INTRODUCTION: Although the surgical restoration of apical support has been shown to decrease reoperation rates, it is unclear whether this has been incorporated into current practice. The aims of this study were to determine the rate of concomitant apical suspensory procedures in women with anterior vaginal wall prolapse undergoing surgical repair in 2011 and to identify associated factors. METHODS: This cross-sectional study queried the Nationwide Inpatient Sample for women with a primary diagnosis of cystocele who underwent prolapse repair in 2011. The study cohort was analyzed for demographics, concomitant procedures, and hospital characteristics. The rate of apical suspensory procedures was determined. Factors potentially associated with receiving concomitant apical suspensory procedure were evaluated using univariate analysis and multivariate logistic regression. RESULTS: A total of 2,900 women in the database had a primary diagnosis of cystocele and underwent surgical prolapse repair in 2011. 925 (31.9 %) subjects underwent a concomitant apical suspensory procedure. The mean age in the study cohort was 61.9 +/- 12.8 years. Hysterectomies were performed in 11.1 % of subjects. 61.1 % were performed vaginally, 26.5 % laparoscopically, and 12.5 % abdominally. On multivariate analysis, age greater than 50 years, Caucasian race, concomitant hysterectomy, and an urban teaching hospital setting were independently associated with receiving concomitant apical suspensory procedure in 2011. CONCLUSIONS: Despite evidence that the restoration of apical support is important for optimal anterior support, the overall rate of concomitant apical suspensory procedures is low. Several factors may play a role in whether or not women receive an apical suspensory procedure. This study highlights opportunities to improve the quality of surgical care provided to women with anterior vaginal prolapse. PMID- 26630949 TI - Developing and implementing a complex Complementary and Alternative (CAM) nursing intervention for breast and gynecologic cancer patients undergoing chemotherapy- report from the CONGO (complementary nursing in gynecologic oncology) study. AB - PURPOSE/OBJECTIVES: The purpose of this study was to develop a complex nursing intervention including complementary and alternative medicine (CAM) for breast and gynecologic cancer patients during chemotherapy to improve quality of life. METHODS: Data sources Theoretical framework and concepts, practical nursing knowledge, and evidence-based studies were compiled in interprofessional meetings. Data synthesis The final complex intervention consists of three autonomous, but interacting components: (1) CAM nursing package, (2) resource oriented counseling, and (3) evidence-based information material on CAM. CAM interventions include acupressure, aromatherapy, compress, and massage, targeting 14 clinically relevant symptoms during chemotherapy. Participants receive these interventions during chemotherapy with instructions for self care. During a counseling interview, the patient's needs and preferences are assessed by trained nurses. Furthermore, participants are equipped with evidence-based information material (booklet and DVD). Prior to study start, nurses attended training modules for administering CAM therapies and for communicating and counseling within the salutogenic approach. CONCLUSIONS: It was possible to design a multimodal CAM nursing intervention based on a theoretical concept, evidence based studies, and practical nursing experience targeting the prevention or relief of side-effects women suffer during chemotherapy. The systematic analysis of the CONGO study will contribute to evidence-based CAM nursing care within supportive cancer care. IMPLICATIONS FOR INTEGRATIVE CANCER CARE: Oncology nurses play an important role in supportive CAM care of breast and gynecologic cancer patients in daily clinical practice. Within oncology outpatient services, the implementation of evidence-based CAM nursing interventions and counseling may contribute to understand the impact of nursing on patient quality of life and symptom relief. This can lead to a new understanding of the nurse's professional role. PMID- 26630950 TI - Assessing cancer-related distress in cancer patients and caregivers receiving outpatient psycho-oncological counseling. AB - PURPOSE: The diagnosis of cancer, the symptoms of the illness and its treatment have an influence on how patients and their caregivers experience distress. However, data focusing on caregivers and their cancer-related distress in the outpatient setting is sparse. This study aimed to compare cancer-related distress of caregivers and patients and to derive implications for the system of outpatient psycho-oncological care. METHODS: One hundred thirty-eight patients and 102 caregivers receiving psycho-oncological counseling completed a standardized interview based on a self-assessment questionnaire (Questionnaire on Stress in Cancer Patients, FBK). RESULTS: Group comparisons for cancer-related distress revealed one statistically significant difference for the subscale 'Fear' of the FBK, Z = 2.308, p = .021, and d = .44. Caregivers showed higher cancer-related fear (M = 2.76, SD = 1.14) than patients (M = 2.41, SD = 1.29). There were no differences in 'psychosomatic complaints', 'information deficit', 'restrictions in everyday life', 'social strains', or the total score of the FBK. CONCLUSIONS: Caregivers seem to experience cancer-related distress equal to or even more severely than patients themselves. Results suggest that there is a need for more low-threshold offers of outpatient psycho-oncological counseling for caregivers. PMID- 26630951 TI - Sex, Race, and the Quality of Life Factors Most Important to Patients' Well-Being Among Those Seeking Bariatric Surgery. AB - BACKGROUND: Evidence suggests obesity-related social stigma and impairment in work function may be the two most detrimental quality of life (QOL) factors to overall well-being among patients seeking weight loss surgery (WLS); whether the relative importance of QOL factors varies across patient sex and race/ethnicity is unclear. METHODS: We interviewed 574 patients seeking WLS at two centers. We measured patient's health utility (preference-based well-being measure) as determined via standard gamble scenarios assessing patients' willingness to risk death to achieve weight loss or perfect health. Multivariable models assessed associations between patients' utility and five weight-related QOL domains stratified by gender and race: social stigma, self-esteem, physical function, public distress (weight stigma), and work life. RESULTS: Depending on patients' sex and race/ethnicity, mean utilities ranged from 0.85 to 0.91, reflecting an average willingness to assume a 9-15 % risk of death to achieve their most desired health/weight state. After adjustment, African Americans (AAs) reported higher utility than Caucasians (+0.054, p = 0.03), but utilities did not vary significantly by sex. Among Caucasian and AA men, impairment in physical functioning was the most important factor associated with diminished utility; social stigma was also a leading factor for Caucasian men. Among Caucasian women, self-esteem and work function appeared equally important. Social stigma was the leading contributor to utility among AA women; QOL factors did not appear as important among Hispanic patients. CONCLUSION: AAs reported higher utilities than Caucasian patients. Individual QOL domains that drive diminished well-being varied across race/ethnicity and sex. PMID- 26630953 TI - Editorial. New Targets of Medical Treatment in Psychiatric Disorders. PMID- 26630954 TI - The Role of Muscarinic Receptors in the Pathophysiology of Mood Disorders: A Potential Novel Treatment? AB - The central cholinergic system has been implicated in the pathophysiology of mood disorders. An imbalance in central cholinergic neurotransmitter activity has been proposed to contribute to the manic and depressive episodes typical of these disorders. Neuropharmacological studies into the effects of cholinergic agonists and antagonists on mood state have provided considerable support for this hypothesis. Furthermore, recent clinical studies have shown that the pan-CHRM antagonist, scopolamine, produces rapid-acting antidepressant effects in individuals with either major depressive disorder (MDD) or bipolar disorder (BPD), such as bipolar depression, contrasting the delayed therapeutic response of conventional mood stabilisers and antidepressants. This review presents recent data from neuroimaging, post-mortem and genetic studies supporting the involvement of muscarinic cholinergic receptors (CHRMs), particularly CHRM2, in the pathophysiology of MDD and BPD. Thus, novel drugs that selectively target CHRMs with negligible effects in the peripheral nervous system might produce more rapid and robust clinical improvement in patients with BPD and MDD. PMID- 26630955 TI - Neural Basis of Anhedonia and Amotivation in Patients with Schizophrenia: The Role of Reward System. AB - Anhedonia, the inability to feel pleasure, and amotivation, the lack of motivation, are two prominent negative symptoms of schizophrenia, which contribute to the poor social and occupational behaviors in the patients. Recently growing evidence shows that anhedonia and amotivation are tied together, but have distinct neural correlates. It is important to note that both of these symptoms may derive from deficient functioning of the reward network. A further analysis into the neuroimaging findings of schizophrenia shows that the neural correlates overlap in the reward network including the ventral striatum, anterior cingulate cortex and orbitofrontal cortex. Other neuroimaging studies have demonstrated the involvement of the default mode network in anhedonia. The identification of aspecific deficit in hedonic and motivational capacity may help to elucidate the mechanisms behind social functioning deficits in schizophrenia, and may also lead to more targeted treatment of negative symptoms. PMID- 26630956 TI - Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: New Targets for Future Antidepressants. AB - Cannabis and analogs of Delta9-tetrahydrocannabinol have been used for therapeutic purposes, but their therapeutic use remains limited because of various adverse effects. Endogenous cannabinoids have been discovered, and dysregulation of endocannabinoid signaling is implicated in the pathophysiology of major depressive disorder (MDD). Recently, endocannabinoid hydrolytic enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have become new therapeutic targets in the treatment of MDD. Several FAAH or MAGL inhibitors are reported to have no cannabimimetic side effects and, therefore, are new potential therapeutic options for patients with MDD who are resistant to first-line antidepressants (selective serotonin and serotonin-norepinephrine reuptake inhibitors). In this review, we focus on the possible relationships between MDD and the endocannabinoid system as well as the inhibitors' therapeutic potential. MAGL inhibitors may reduce inflammatory responses through activation of cannabinoid receptor type 2. In the hypothalamic-pituitary-adrenal axis, repeated FAAH inhibitor administration may be beneficial for reducing circulating glucocorticoid levels. Both FAAH and MAGL inhibitors may contribute to dopaminergic system regulation. Recently, several new inhibitors have been developed with strong potency and selectivity. FAAH inhibitor, MAGL inhibitor, or dual blocker use would be promising new treatments for MDD. Further pre-clinical studies and clinical trials using these inhibitors are warranted. PMID- 26630957 TI - New Pharmacotherapy Targeting Cognitive Dysfunction of Schizophrenia via Modulation of GABA Neuronal Function. AB - Schizophrenia is considered a neurodevelopmental and neurodegenerative disorder. Cognitive impairment is a core symptom in patients with the illness, and has been suggested a major predictor of functional outcomes. Reduction of parvalbumin (PV) positive gamma-aminobutyric acid (GABA) interneurons has been associated with the pathophysiology of schizophrenia, in view of the link between the abnormality of GABA neurons and cognitive impairments of the disease. It is assumed that an imbalance of excitatory and inhibitory (E-I) activity induced by low activity of glutamatergic projections and PV-positive GABA interneurons in the prefrontal cortex resulted in sustained neural firing and gamma oscillation, leading to impaired cognitive function. Therefore, it is important to develop novel pharmacotherapy targeting GABA neurons and their activities. Clinical evidence suggests serotonin (5-HT) 1A receptor agonist improves cognitive disturbances of schizophrenia, consistent with results from preclinical studies, through mechanism that corrects E-I imbalance via the suppression of GABA neural function. On the other hand, T-817MA, a novel neurotrophic agent, ameliorated loss of PV-positive GABA neurons in the medial prefrontal cortex and reduction of gamma-band activity, as well as cognitive dysfunction in animal model of schizophrenia. In conclusion, a pharmacotherapy to alleviate abnormalities in GABA neurons through 5-HT1A agonists and T-817MA is expected to prevent the onset and/or progression of schizophrenia. PMID- 26630959 TI - The Role of Topiramate in the Management of Cocaine Addiction: a Possible Therapeutic Option. AB - Topiramate (TPM) is an antiepileptic drug able to play a role in both neurological and psychiatric disorders. TPM facilitates gamma-aminobutyric acid (GABA) transmission and inhibits glutamatergic transmission (i.e. AMPA/kainate receptors). Several studies reported that the modulation of GABAergic and glutamatergic synaptic transmission may reduce cocaine reinforcement. Therefore, TPM could be used in the management of cocaine dependence. PMID- 26630958 TI - The Role of the Catechol-o-Methyltransferase (COMT) GeneVal158Met in Aggressive Behavior, a Review of Genetic Studies. AB - Aggressive behaviors have become a major public health problem, and early-onset aggression can lead to outcomes such as substance abuse, antisocial personality disorder among other issues. In recent years, there has been an increase in research in the molecular and genetic underpinnings of aggressive behavior, and one of the candidate genes codes for the catechol-O-methyltransferase (COMT). COMT is involved in catabolizing catecholamines such as dopamine. These neurotransmitters appear to be involved in regulating mood which can contribute to aggression. The most common gene variant studied in the COMT gene is the Valine (Val) to Methionine (Met) substitution at codon 158. We will be reviewing the current literature on this gene variant in aggressive behavior. PMID- 26630960 TI - Use of Push-Pull Superfusion Technique for Identifying Neurotransmitters Involved in Brain Functions: Achievements and Perspectives. AB - The push-pull superfusion technique (PPST) is a procedure for in vivo examination of transmitter release in distinct brain areas. This technique allows to investigate dynamics of transmitter release both under normal and experimentally evoked conditions. The PPST can be modified so that it is possible to determine release of endogenous transmitters simultaneously with electroencephalogram (EEG) recordings, recordings of evoked potentials or the on-line determination of endogenous nitric oxide (NO) released into the synaptic cleft. Because of the good time resolution, the method provides further the possibility to modify the collection periods of superfusates depending on the neuronal function that is analyzed. For instance, investigation of central cardiovascular control, behavioral tasks or mnemonic processes requires very short collection periods, because changes in transmitter release occur within seconds. Even more important is the time resolution when rates of transmitter release are correlated with evoked extracellular potentials or EEG recordings. This review provides an overview of the different devices which might be combined with the PPST and perspectives for future work. PMID- 26630961 TI - An Endogenous Tachykinergic NK2/NK3 Receptor Cascade System Controlling the Release of Serotonin from Colonic Mucosa. AB - 5-Hydroxytryptamine (5-HT) released from colonic mucosal enterochromaffin (EC) cells is a major signaling molecule, which participates in the pathophysiological regulation of colonic functions in gut disorder including irritable bowel syndrome (IBS), but the endogenous modulator system for the 5-HT release is not yet well elucidated. Our in vitro studies in guinea-pig colon have indicated that the cascade pathway of neuronal tachykinergic NK3 receptors and NK2 receptors on peptide YY (PYY)-containing endocrine L cells represents an endogenous modulator system for 5-HT release from EC cells and that melatonin, endogenous tachykinins and PYY play important roles in modulation of the release of 5-HT from EC cells via the endogenous NK2/NK3 receptor cascade system. This review aims at examining the potential role of the endogenous tachykinergic NK2/NK3 receptor cascade system controlling the release of 5-HT from EC cells, with special attention being paid to the pathophysiology of gut disorders including IBS. PMID- 26630964 TI - ERRATUM. AB - Due to an overlook on the author's side, author's name in the article entitled as: "Neurodegeneration and the Brain Tumor Microenvirnment: Glutamate in the Limelight" by Dr. Nicolai E. Savaskan (Co-author) published in the journal "Current Neuropharmacology" Volume 13, No 2, Page no 258-265, was wrong. The correct title is as follows: Neurodegeneration and the Brain Tumor Microenviornment. Curr. Neuropharmacol., 2015, 13(2), 258 - 265. PMID- 26630962 TI - Tyrosine Kinase Inhibitor as a new Therapy for Ischemic Stroke and other Neurologic Diseases: is there any Hope for a Better Outcome? AB - The relevance of tyrosine kinase inhibitors (TKIs) in the treatment of malignancies has been already defined. Aberrant activation of tyrosine kinase signaling pathways has been causally linked not only to cancers but also to other non-oncological diseases. This review concentrates on the novel plausible usage of this group of drugs in neurological disorders, such as ischemic brain stroke, subarachnoid hemorrhage, Alzheimer's disease, multiple sclerosis. The drugs considered here are representatives of both receptor and non-receptor TKIs. Among them imatinib and masitinib have the broadest spectrum of therapeutic usage. Both drugs are effective in ischemic brain stroke and multiple sclerosis, but only imatinib produces a therapeutic effect in subarachnoid hemorrhage. Masitinib and dasatinib reduce the symptoms of Alzheimer's disease. In the case of multiple sclerosis several TKIs are useful, including apart from imatinib and masitinib, also sunitinib, sorafenib, lestaurtinib. Furthermore, the possible molecular targets for the drugs are described in connection with the underlying pathophysiological mechanisms in the diseases in question. The most frequent target for the TKIs is PDGFR which plays a pivotal role particularly in ischemic brain stroke and subarachnoid hemorrhage. The collected data indicates that TKIs are very promising candidates for new therapeutic interventions in neurological diseases. PMID- 26630965 TI - Establishing a centralised telehealth service increases telehealth activity at a tertiary hospital. AB - BACKGROUND: The Princess Alexandra Hospital Telehealth Centre (PAH-TC) is a project jointly funded by the Australian national government and Queensland Health. It seeks to provide a whole-of-hospital telehealth service using videoconferencing and store-and-forward capabilities for a range of specialities. The aim of this study was to investigate whether the introduction of a new telehealth coordination service provided by a tertiary hospital centre increased telehealth activities of a tertiary hospital. Evaluation included service delivery records and stakeholder satisfaction. METHODS: Telehealth service delivery model before and after the establishment of the centre is described as well as the project implementation. The study retrieved data related to the number and scope of previous, and current, telehealth service episodes, to ascertain any change in activity levels following the introduction of the new telehealth coordination service. In addition, using a cross-sectional research design, the satisfaction of patients, clinicians and administrators was surveyed. The survey focused on technical utility and perceived clinical validity. RESULTS: Introduction of a new centralised telehealth coordination service was associated with an increase in the scope of telehealth from five medical disciplines, in the year before the establishment, to 34 disciplines two years after the establishment. The telehealth consultations also increases from 412 (the year before), to 735 (one year after) and 1642 (two years after) the establishment of the centre. Respondents to the surveys included patients (27), clinicians who provided the consultations (10) and clinical or administrative staff who hosted the telehealth consultations in the remote site (8). There were high levels of agreement in relation to the telehealth option saving time and money, and an important health service delivery model. There was evidence from the remote site that modifying roles to incorporate this new service was challenging. CONCLUSION: The introduction of a centralised coordination for telehealth service of a tertiary hospital was associated with the increase in the scope and level of telehealth activity of the hospital. The project and model of health care delivery described in this paper can be adopted by tertiary hospitals to grow their telehealth activities, and potentially reduce costs associated with the delivery of services at a distance. PMID- 26630966 TI - Comparing Percutaneous Transluminal Angioplasty and Stent Placement for Treatment of Subclavian Arterial Occlusive Disease: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND PURPOSE: Subclavian artery occlusive disease (SAOD) is often associated with cerebrovascular symptoms such as subclavian steal syndrome and stroke. We conducted a systematic review and meta-analysis to compare percutaneous transluminal angioplasty (PTA) and stent placement for the treatment of SAOD. MATERIALS AND METHODS: We searched Medline, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus through October 16, 2014. From each study, we abstracted baseline patient characteristics, study design variables, and outcome data including rates of technical success, primary patency (<=2 and >2 years follow-up), symptom resolution, and complications. Meta-analysis was performed using a random-effects model. RESULTS: A total of 35 non-comparative studies with 1726 patients were included. Technical success rate was significantly higher in the stent group than the PTA group (92.8 vs 86.8%, p = 0.007). Long-term primary patency rates (76.9 vs 79.6%, p = 0.729) and symptom resolution rates (82.2 vs 73.0%, p = 0.327) were not statistically different. There was no statistically significant difference in the rates of stroke or death. CONCLUSION: Stent placement for treatment of SAOD may be associated with higher rates of technical success but similar rates of symptom resolution and long-term outcomes. The confidence in the available estimates is low. Further comparative studies are needed to guide patients and clinicians in shared decision making. PMID- 26630967 TI - Recurrent Nicolau syndrome associated with subcutaneous glatiramer acetate injection--a case report. AB - BACKGROUND: Glatiramer acetate is worldwide used as first line treatment in relapsing remitting multiple sclerosis. Local skin reactions associated with glatiramer acetate are common, however, only isolated cases of severe local injection site reactions known as Nicolau Syndrome have been reported so far. CASE PRESENTATION: We describe the case of a recurrent Nicolau Syndrome occurred during longstanding glatiramer acetate treatment in a woman with multiple sclerosis. The haemorrhagic patch necrotized and was treated locally as a deep second degree burn with excision of dead skin tissue and was healed. Treatment with glatiramer acetate was definitely suspended. CONCLUSIONS: GA injections can be complicated by isolated or recurrent Nicolau Syndrome, a potentially life threatening condition of which neurologists should be aware. PMID- 26630968 TI - Downsizing: policy options to reduce portion sizes to help tackle obesity. PMID- 26630970 TI - Morning blood pressure surge and target organ damage in newly diagnosed type 2 diabetic patients: a cross sectional study. AB - BACKGROUND: Type 2 diabetic patients display significantly higher incidence of cardiovascular (CV) events including stroke compared to non-diabetics. Morning blood pressure surge (MBPS) and blunted systolic night-day (SND) ratio have been associated with CV events in hypertensive patients. No studies have evaluated MBPS in newly diagnosed diabetic patients or studied the association with vascular target organ damage at this early time point of the diabetes disease. METHODS: Ambulatory blood pressure monitoring was performed in 100 patients with newly diagnosed type 2 diabetes and 100 age and sex matched controls. MBPS and SND-ratio were calculated. Markers of early vascular target organ damage included pulse wave velocity (PWV), white matter lesions (WML) on brain MRI, and urine albumin/creatinine ratio (UAE). RESULTS: No significant differences in MBPS were found between diabetic patients and controls. Neither MBPS or SND-ratio were associated with PWV, UAE or WML in the diabetic group independently of age, gender and 24-h systolic blood pressure. 40.2 % of diabetic patients and 25.8 % of controls were classified as non-dippers (p = 0.03). CONCLUSION: MBPS and SND ratio are not associated with subclinical markers of vascular target organ damage in our study sample of newly diagnosed type 2 diabetic patients. PMID- 26630969 TI - SJP-L-5, a novel small-molecule compound, inhibits HIV-1 infection by blocking viral DNA nuclear entry. AB - BACKGROUND: Small-molecule compounds that inhibit human immunodeficiency virus type 1 (HIV-1) infection can be used not only as drug candidates, but also as reagents to dissect the life cycle of the virus. Thus, it is desirable to have an arsenal of such compounds that inhibit HIV-1 infection by various mechanisms. Until now, only a few small-molecule compounds that inhibit nuclear entry of viral DNA have been documented. RESULTS: We identified a novel, small-molecule compound, SJP-L-5, that inhibits HIV-1 infection. SJP-L-5 is a nitrogen containing, biphenyl compound whose synthesis was based on the dibenzocyclooctadiene lignan gomisin M2, an anti-HIV bioactive compound isolated from Schisandra micrantha A. C. Smith. SJP-L-5 displayed relatively low cytotoxicity (50% cytoxicity concentrations were greater than 200 MUg/ml) and high antiviral activity against a variety of HIV strains (50% effective concentrations (EC50)) of HIV-1 laboratory-adapted strains ranged from 0.16-0.97 MUg/ml; EC50s of primary isolates ranged from 1.96-5.33 MUg/ml). Analyses of the viral DNA synthesis indicated that SJP-L-5 specifically blocks the entry of the HIV-1 pre-integration complex (PIC) into the nucleus. Further results implicated that SJP-L-5 inhibits the disassembly of HIV-1 particulate capsid in the cytoplasm of the infected cells. CONCLUSIONS: SJP-L-5 is a novel small-molecule compound that inhibits HIV-1 nuclear entry by blocking the disassembly of the viral core. PMID- 26630971 TI - Different levels of hyphal self-incompatibility modulate interconnectedness of mycorrhizal networks in three arbuscular mycorrhizal fungi within the Glomeraceae. AB - Arbuscular mycorrhizal fungi (AMF) live in symbiosis with most plant species and produce underground extraradical hyphal networks functional in the uptake and translocation of mineral nutrients from the soil to host plants. This work investigated whether fungal genotype can affect patterns of interconnections and structural traits of extraradical mycelium (ERM), by comparing three Glomeraceae species growing in symbiosis with five plant hosts. An isolate of Funneliformis coronatus consistently showed low ability to form interconnected ERM and self incompatibility that represented up to 21% of hyphal contacts. The frequency of post-fusion self-incompatible interactions, never detected before in AMF extraradical networks, was 8.9%. In F. coronatus ERM, the percentage of hyphal contacts leading to perfect hyphal fusions was 1.2-7.7, while it ranged from 25.8 48 to 35.6-53.6 in Rhizophagus intraradices and Funneliformis mosseae, respectively. Low interconnectedness of F. coronatus ERM resulted also from a very high number of non-interacting contacts (83.2%). Such findings show that AMF genotypes in Glomeraceae can differ significantly in anastomosis behaviour and that ERM interconnectedness is modulated by the fungal symbiont, as F. coronatus consistently formed poorly interconnected networks when growing in symbiosis with five different host plants and in the asymbiotic stage. Structural traits, such as extent, density and hyphal self-compatibility/incompatibility, may represent key factors for the differential performance of AMF, by affecting fungal absorbing surface and foraging ability and thus nutrient flow from soil to host roots. PMID- 26630972 TI - Perceived discrimination among Maghrebi users of health services in Tarragona (Spain). AB - BACKGROUND: Discrimination in health services for reasons of nationality or ethnicity is not a rare occurrence. This work aims to qualitatively analyse the perceived discrimination among Maghrebi community in Tarragona (Spain) with regard to the healthcare services they receive. METHODS: A qualitative study was carried by means of 12 semi-structured interviews and 10 focus groups with Maghrebi adults living in Tarragona. The scope of the study was public health services in the area. A content analysis was performed using open coding. RESULTS: Our results show that perceived discrimination is greater than actual discrimination because the deficiencies of the healthcare system are often interpreted as unfairness. However, our subjects also recounted incidents of clear discrimination against Maghrebi users of the healthcare system. The tendency to feel discriminated against is the culmination of an interaction between the group's low self-esteem and locals' often negative sentiments towards the group. CONCLUSIONS: We suggest addressing the shortcomings of the healthcare system in order to reduce this level of perceived discrimination and thus improve patient satisfaction. To improve this group's self-esteem and change how they are perceived, public policies should be put into effect which promote social inclusion and the respect for Maghrebis' rights as people, with actions taken on both fronts: in the host society and within the Maghrebi community itself. Furthermore, an active role for the patient with regard to his or her rights should be encouraged in order to minimize abuse from professionals and to facilitate institutional control of individual actions. PMID- 26630973 TI - Multimodal In Vivo Imaging of Tumorigenesis and Response to Chemotherapy in a Transgenic Mouse Model of Mammary Cancer. AB - PURPOSE: Transgenic mice expressing the polyoma middle T oncoprotein (PyMT) in the mammary epithelium were explored by multimodal imaging to monitor longitudinally spontaneous tumor growth and response to chemotherapy. PROCEDURES: Positron emission tomography (PET) with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) and 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT), single photon emission tomography (SPECT) with [(99m)Tc]TcO4 ([(99m)Tc]TEC), X-ray computed tomography, and fluorescent confocal endomicroscopy (FCE) images were acquired during tumor progression in female PyMT mice. Imaging with [(18)F]FDG and [(99m)Tc]TEC was also performed in untreated, doxorubicin-treated, and docetaxel treated PyMT mice. Total tumor volumes were quantified. Tumors were collected and macroscopic and histological examinations were performed. RESULTS: All PyMT mice developed multifocal tumors of the mammary epithelium that became palpable at 8 weeks of age (W8). Computed tomography (CT) detected tumors at W14, while a clear tumoral uptake of [(99m)Tc]TEC and [(18)F]FDG was present as early as W6 and W8, respectively. No contrast between mammary tumors and surrounding tissue was observed at any stage with [(18)F]FLT. FCE detected an angiogenic switch at W10. Lung metastases were not clearly evidenced by imaging. Doxorubicin and docetaxel treatments delayed tumor growth, as shown by [(18)F]FDG and [(99m)Tc]TEC, but tumor growth resumed upon treatment discontinuation. Tumor growth fitted an exponential model with time constant rates of 0.315, 0.145, and 0.212 week(-1) in untreated, doxorubicin, and docetaxel groups, respectively. CONCLUSIONS: Molecular imaging of mammary tumors in PyMT is precocious, precise, and predictive. [(18)F]FDG-PET and [(99m)Tc]TEC SPECT monitor tumor response to chemotherapy. PMID- 26630974 TI - A combination of low serum concentrations of vitamins K1 and D is associated with increased risk of hip fractures in elderly Norwegians: a NOREPOS study. AB - The present study investigated the risk of incident hip fractures according to serum concentrations of vitamin K1 and 25-hydroxyvitamin D in elderly Norwegians during long-term follow-up. The results showed that the combination of low concentrations of both vitamin D and K1 provides a significant risk factor for hip fractures. INTRODUCTION: This case-cohort study aims to investigate the associations between serum vitamin K1 and hip fracture and the possible effect of 25-hydroxyvitamin D (25(OH)D) on this association. METHODS: The source cohort was 21,774 men and women aged 65 to 79 years who attended Norwegian community-based health studies during 1994-2001. Hip fractures were identified through hospital registers during median follow-up of 8.2 years. Vitamins were determined in serum obtained at baseline in all hip fracture cases (n = 1090) and in a randomly selected subcohort (n = 1318). Cox proportional hazards regression with quartiles of serum vitamin K1 as explanatory variable was performed. Analyses were further performed with the following four groups as explanatory variable: I: vitamin K1 >= 0.76 and 25(OH)D >= 50 nmol/l, II: vitamin K1 >= 0.76 and 25(OH)D < 50 nmol/l, III: vitamin K1 < 0.76 and 25(OH)D >= 50 nmol/l, and IV: vitamin K1 < 0.76 and 25(OH)D < 50 nmol/l. RESULTS: Age- and sex-adjusted analyses revealed an inverse association between quartiles of vitamin K1 and the risk of hip fracture. Further, a 50 % higher risk of hip fracture was observed in subjects with both low vitamin K1 and 25(OH)D compared with subjects with high vitamin K1 and 25(OH)D (HR 1.50, 95 % CI 1.18-1.90). The association remained statistically significant after adjusting for body mass index, smoking, triglycerides, and serum alpha-tocopherol. No increased risk was observed in the groups low in one vitamin only. CONCLUSION: Combination of low concentrations of vitamin K1 and 25(OH)D is associated with increased risk of hip fractures. PMID- 26630975 TI - Bone material strength is associated with areal BMD but not with prevalent fractures in older women. AB - Reference point indentation is a novel method to assess bone material strength index (BMSi) in vivo. We found that BMSi at the mid-tibia was weakly associated with spine and hip areal bone mineral density but not with prevalent fracture in a population-based cohort of 211 older women. INTRODUCTION: Reference point indentation is a novel method to assess BMSi in vivo. Lower BMSi has been observed in patients with prior fracture than in controls, but no association between BMSi and areal bone mineral density (aBMD) has been found. Population based association studies and prospective studies with BMSi and fractures are lacking. We hypothesized that BMSi would be associated with prevalent fractures in older Swedish women. The aim was to investigate the associations between BMSi, aBMD, and prevalent fracture in older women. METHODS: Two hundred eleven women, mean age 78.3 +/- 1.1 years, were included in this cross-sectional, population based study. BMSi was assessed using the OsteoProbe device at the mid-tibia. Areal BMD of the hip, spine, and non-dominant radius was measured using dual energy X-ray absorptiometry (DXA). Fracture history was retrieved using questionnaires, and vertebral fractures were identified using vertebral fracture assessment (VFA) by DXA. RESULTS: One hundred ninety-eight previous fractures in 109 subjects were reported. A total of 106 women had a vertebral fracture, of which 58 women had moderate or severe fractures. An inverse correlation between BMSi and weight (r = -0.14, p = 0.04) was seen, and BMSi differed according to operator (ANOVA p < 0.01). Adjusting for weight and operator in a linear regression model, we found that BMSi was positively associated with aBMD of the total hip (beta = 0.14, p = 0.04), non-dominant radius (beta = 0.17, p = 0.02), and lumbar spine (L1-L4) (beta = 0.14, p < 0.05). Using logistic regression, we could not find any association in crude or adjusted BMSi (for age, weight, height, walking speed, calcium intake, smoking, bisphosphonate and glucocorticoid use, and operator) with prevalent fractures. CONCLUSION: We conclude that BMSi is associated with aBMD but not with prevalent fracture in a population-based cohort of 211 older women. PMID- 26630976 TI - Risk of vertebral and non-vertebral fractures in patients with sarcoidosis: a population-based cohort. AB - In this retrospective cohort study using the Clinical Practice Research Datalink (CPRD), patients with sarcoidosis have an increased risk of clinical vertebral fractures and when on recent treatment with oral glucocorticoids, also an increased risk of any fractures and osteoporotic fractures. INTRODUCTION: Sarcoidosis is a chronic inflammatory disease, in which fragility fractures have been reported despite normal BMD. The aim of this study was to assess whether patients with sarcoidosis have an increased risk of clinical fractures compared to the general population. METHODS: A retrospective cohort study was conducted using the CPRD. All patients with a CPRD code for sarcoidosis between January 1987 and September 2012 were included. Cox proportional hazards models were used to derive adjusted relative risks (RRs) of fractures in all sarcoidosis patients compared to matched controls, and within the sarcoidosis group according to use and dose of systemic glucocorticoids. RESULTS: Five thousand seven hundred twenty two sarcoidosis patients (mean age 48.0 years, 51 % females, mean follow-up 6.7 years) were identified. Compared to 28,704 matched controls, the risk of any fracture was not different in patients with sarcoidosis. However, the risk of clinical vertebral fractures was significantly increased (adj RR 1.77; 95 % CI 1.06-2.96) and the risk of non-vertebral fractures was decreased although marginally significant (adj RR 0.87; 95 % CI 0.77-0.99). Compared to sarcoidosis patients not taking glucocorticoids, recent use of systemic glucocorticoids was associated with an increased risk of any fracture (adj RR 1.50; 95 % CI 1.20 1.89) and of an osteoporotic fracture (adj RR 1.47; 95 % CI 1.07-2.02). CONCLUSIONS: Patients with sarcoidosis have an increased risk of clinical vertebral fractures, and when using glucocorticoid therapy, an increased risk of any fractures and osteoporotic fractures. In contrast, the risk of non-vertebral fractures maybe decreased. Further investigation is needed to understand the underlying mechanisms of these contrasting effects on fracture risk. PMID- 26630977 TI - Regional and seasonal variations in ultraviolet B irradiation and vitamin D synthesis in India. AB - Evaluation of ultraviolet B index (UVBI) and its impact on vitamin D synthesis is important. We observed the maximum UVBI between 11 am and 1 pm. There was no increase in serum 25(OH)D levels following sun exposure during winter as the UVBI was significantly low, emphasizing the need for vitamin D supplementation during these months. INTRODUCTION: The amount of vitamin D3 synthesizing UVB irradiation (290-320 nm) reaching the earth's surface at different altitudes and seasons in different parts of India and it's impact on vitamin D synthesis has not been well studied. METHODS: The hourly UVB index (UVBI) from 10 am to 3 pm everyday for 12 months was measured by a solar meter in 4 different zones (North, Northeast, West and South) of the country. To study the impact of sun light exposure on vitamin D synthesis during winter, healthy school children aged 10-15 years were exposed to sunlight for a period of 30 min per day, between 11 am to 12 noon with 10 % body surface area, for 4 weeks. The main outcome measures were serum 25(OH)D, PTH, calcium, phosphate, and alkaline phosphatase levels before and after sun exposure. RESULTS: The mean UVBI was highest between 11 am and 1 pm throughout the year in all locations. The highest UVBI was recorded from the North zone (4.5 +/- 2.7 MUW/Cm(2)), while the least was recorded in the Northeast zone (2.1 +/- 1.2 MUW/Cm(2)). UVBI readings in the Northeast zone were consistently low throughout the year, while all the other three zones showed significant seasonal fluctuations. Surprisingly, we observed a significant decrease in serum 25(OH)D levels from baseline (6.3 +/- 4.6 to 5.1 +/- 2.7 ng/mL; p < 0.001) despite sun exposure. CONCLUSION: The mean UVBI was highest between 11 am and 1 pm throughout the year in all locations. No increase in the serum 25(OH)D levels was observed following sun exposure in winter, emphasizing the need for vitamin D supplementation during these months. PMID- 26630978 TI - Are bone turnover markers associated with volumetric bone density, size, and strength in older men and women? The AGES-Reykjavik study. AB - Association between serum bone formation and resorption markers and bone mineral, structural, and strength variables derived from quantitative computed tomography (QCT) in a population-based cohort of 1745 older adults was assessed. The association was weak for lumbar spine and femoral neck areal and volumetric bone mineral density. INTRODUCTION: The aim of this study was to examine the relationship between levels of bone turnover markers (BTMs; osteocalcin (OC), C terminal cross-linking telopeptide of type I collagen (CTX), and procollagen type 1N propeptide (P1NP)) and quantitative computed tomography (QCT)-derived bone density, geometry, and strength indices in the lumbar spine and femoral neck (FN). METHODS: A total of 1745 older individuals (773 men and 972 women, aged 66 92 years) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort were studied. QCT was performed in the lumbar spine and hip to estimate volumetric trabecular, cortical, and integral bone mineral density (BMD), areal BMD, bone geometry, and bone strength indices. Association between BTMs and QCT variables were explored using multivariable linear regression. RESULTS: Major findings showed that all BMD measures, FN cortical index, and compressive strength had a low negative correlation with the BTM levels in both men and women. Correlations between BTMs and bone size parameters were minimal or not significant. No associations were found between BTMs and vertebral cross sectional area in women. BTMs alone accounted for only a relatively small percentage of the bone parameter variance (1-10 %). CONCLUSION: Serum CTX, OC, and P1NP were weakly correlated with lumbar spine and FN areal and volumetric BMD and strength measures. Most of the bone size indices were not associated with BTMs; thus, the selected bone remodeling markers do not reflect periosteal bone formation. These results confirmed the limited ability of the most sensitive established BTMs to predict bone structural integrity in older adults. PMID- 26630979 TI - Addressing Risk and Reluctance at the Nexus of HIV and Anal Cancer Screening. AB - Anal cancer disproportionately burdens persons living with human immunodeficiency virus (PLHIV) regardless of natal sex, sexual orientation, gender expression, and ethnic identity. Culturally competent communications are recommended to address health disparities, with sociocultural relevance ensured through constituent dialogic processes. Results are presented from six provider focus groups conducted to inform the promotion/education component of a Hawai'i-based project on anal cancer screening tools. Krueger's focus group methodology guided discussion queries. Verbatim transcripts of digitally recorded discussions were analyzed using grounded theory and PEN-3 procedures. Adherence to an audit trail ensured analytic rigor. Grounded theory analysis detected the overall theme of risk and reluctance to anal cancer screening, characterized by anal cancer not being "on the radar" of PLHIV, conflicting attributions of the anus and anal sex, fear of sex-shaming/-blaming, and other interrelated conceptual categories. PEN-3 analysis revealed strategies for destigmatizing anal cancer, through "real talk" (proactive, candid, nonjudgmental discussion) nested in a framework of sexual health and overall well-being, with additional tailoring for relevance to Native Hawaiians/Pacific Islanders, transgender persons, and other marginalized groups. Application of strategies for health practice are specific to the Hawai'i context, yet may offer considerations for developing strengths-based, culturally relevant screening promotion/education with diverse PLHIV in other locales. PMID- 26630980 TI - Disorder in Milk Proteins: Formation, Structure, Function, Isolation and Applications of Casein Phosphopeptides. AB - This article is a continuation of a series of reviews on the presence and the role of intrinsic disorder in milk proteins in the journal of Current Protein and Peptide Science. The focus of this article is on casein phosphopeptides, which are liberated during digestion of the milk protein casein. Structurally these phosphopeptides have multiphosphorylated regions making them highly charged. The high degree of charge coupled with relatively low instances of hydrophobic amino acids makes them intrinsically disordered. These peptides have anticariogenic, antimicrobial, immunomodulatory, and cytomodulatory properties. Recent work using in vivo and in vitro models suggests that in addition to transporting calcium, these peptides can also enhance its bioaccessibility. The mechanism of this enhancement has yet to be determined. We review the current state of their structure, function, and isolation of these peptides. PMID- 26630981 TI - A national study of Continuous Professional Competence (CPC) amongst pre-hospital practitioners. AB - BACKGROUND: Internationally, continuing professional competence (CPC) is an increasingly important issue for all health professionals. With the introduction of the first CPC framework for Emergency Medical Technicians (EMTs) and the imminent introduction of CPC for Paramedics and Advanced Paramedics (APs) in Ireland, this study aimed to identify attitudes towards CPC and factors that might influence such a framework. METHODS: All EMTs (n = 925), Paramedics and APs (n = 1816) registered in Ireland were invited by email to complete an anonymous on-line survey. The study instrument was designed based on continuous professional development (CPD) questionnaires used by other healthcare professions. Quantitative and qualitative analyses were performed. RESULTS: The overall response rates were: EMTs 43% (n = 399), Paramedics and APs 43% (n = 789), with 82% of APs and 38% of Paramedics participating. The majority of participants in all groups agreed that registration was of personal importance and that evidence of CPC should be maintained; 39% of Paramedics/APs and 78% of EMTs believed that persistent failure to meet CPC requirements should mandate denial of registration. From a pre-determined list of activities, in excess of 88% of all respondents indicated practical training scenarios, cardiac re certification, e-learning supplemented by related practice, and training with simulation manikins were most relevant to these roles. However, least relevant to them were: e-learning alone (Paramedic/AP 36%; EMT 35%); project work (Paramedic/AP 27%; EMT 48%); and appraisal of journal articles (Paramedic/AP 24%; EMT 39%). CONCLUSION: Irish EMTs, Paramedics and Advanced Paramedics were supportive of CPC and favoured a 'mixed' model approach which includes: blended learning, practical skills, simulation, practical/team-based exercises, e learning combined with practical skills, and evidence of patient contact. It is hoped that these insights will inform the CPC guidelines to be introduced. PMID- 26630982 TI - Erratum to: Normal karyotype acute myeloid leukemia patients with CEBPA double mutation have a favorable prognosis but no survival benefit from allogeneic stem cell transplant. PMID- 26630983 TI - Which pamidronate protocol is the best for treating osteoporosis in beta thalassemia major? AB - One of the most common complications in thalassemia major patients is osteopenia and osteoporosis. In this study, we compare the therapeutic effect of two treatment protocols involving infusion of 45 mg of pamidronate injection every 6 weeks (P45) and 90 mg pamidronate infusion every 4 weeks (P90). Bone mineral density was measured using dual energy X-ray absorptiometry (DEXA). Z-score of lumbar vertebra (as L total) and the femoral head (as F total) were compared before and after administration of two protocols. Bone density between the two groups was compared by Student t test and by the paired t test before and after the intervention. Data were analyzed using SPSS (18). Ninety-one patients were treated with pamidronate 45 mg (P45), and 36 patients were treated with pamidronate 90 mg (P90). Ninety-one and 36 patients received P45 and P90 protocol, respectively. Mean age was 29.4 +/- 8.1 and 30.9 +/- 8.0 years old in P45 and P90 groups, respectively. Sixty-two and 58 % of P45 and P90 group were female. The means of F total were -1.73 +/- 1.11 and -1.47 +/- 0.92 before and after treatment in patients P45 (P = 0.01) and were -1.83 +/- 0.75 and -1.57 +/- 0.99 in group P90 (P = 0.005), respectively. Before treatment, the means of L total were -2.95 +/- 0.81 and -2.92 +/- 0.66 (P = 0.8) and after treatment were 2.53 +/- 1.13 and 2.81 +/- 0.98 (P = 0.1) in P45 and P90 groups, respectively. In P45, between the mean of L total was statistically significant difference before and after treatment (P < 0.0001); however, there was no significant difference in the P90 group (P = 0.3). The study showed effectiveness of both protocols. As the medication is expensive and should be administrated parenterally, we recommend P45 protocol which is less expensive with fewer injections. PMID- 26630984 TI - Overview and evaluation of 15 years of Creutzfeldt-Jakob disease surveillance in Belgium, 1998-2012. AB - BACKGROUND: In 1998, following the detection of variant Creutzfeldt-Jakob disease (vCJD) in the UK, Belgium installed a surveillance system for Creutzfeldt-Jakob disease (CJD). The objectives of this system were to identify vCJD cases and detect increases in CJD incidence. Diagnostic confirmation of CJD is based on autopsy after referral by neurologists. Reference centres perform autopsies and report to the surveillance system. The aim of this study was to assess whether the system met its objectives and to assess its acceptability. METHODS: For 1999 2010, we linked surveillance data with hospital discharge data. We calculated the proportion of CJD suspected patients who died in hospitals and were captured by the surveillance system. We surveyed stakeholders on knowledge of the surveillance system, referral practices and acceptability. We compared proportions using the chi-square test and investigated variables associated with capture using a multivariable logistic regression model. RESULTS: On average 60 % of hospitalised patients who died with suspected CJD were captured by the surveillance system. This proportion did not significantly differ over the years (p = 0.1). The odds of capture significantly decreased with every 1 year increase in age (OR = 0.95, 95 % CI 0.92-0.98, p = 0.001). Eleven percent of surveyed neurologists would not refer suspect vCJD cases for autopsy, nor contact a reference centre for diagnostic support. Sixty-one percent of surveyed neurologists were not familiar with the surveillance system. Awareness of the existence of the system did not impact referral behaviour (p = 0.18). CJD and vCJD surveillance were considered important by the majority of stakeholders. CONCLUSIONS: Although 40 % of the suspect CJD cases were not referred for autopsy, our data suggest that the Belgian CJD surveillance system meets one of its main objectives: it can detect changes in CJD incidence. However, we do not have sufficient evidence to conclude that the system meets its second objective of detecting vCJD cases arising in Belgium. Although not well known, the system was considered acceptable by its stakeholders. PMID- 26630985 TI - Study links negative news stories about statins to patients' likelihood of giving them up. PMID- 26630986 TI - ? PMID- 26630987 TI - Recombinant growth hormone therapy in children with short stature in Kuwait: a cross-sectional study of use and treatment outcomes. AB - BACKGROUND: Recombinant Growth hormone (rGH) therapy is approved in many countries for treatment of short stature in a number of childhood diagnoses. Despite the increasing body of international literature on rGH use, there is paucity of data on rGH use in Kuwait and the broader Middle-East which share unique ethnic and socio-cultural backgrounds. This study aimed to describe the pattern of use and treatment outcomes of rGH therapy in Kuwait. METHODS: This is a cross-sectional retrospective review of children treated with rGH in the Department of Pediatrics, in a major hospital in Kuwait between December 2013 and December 2014. Data were extracted using standard data extraction form and the response to rGH therapy was defined as a gain of >= 0.3 standard deviation score (SDS) of height per year. RESULTS: A total of 60 children were treated with rGH in the center. Their Median (Interquartile) age at rGH initiation was 9.0 (6.2, 10.7) years. The most common indications for rGH therapy were Growth Hormone Deficiency (GHD) 23 (38.3 %), Idiopathic Short Stature (ISS) 12 (20.0 %) and Small for Gestational Age (SGA) 9 (15.0 %). After excluding patients with TS, no significant differences were found in gender of those who received rGH therapy in all indications combined or in each group (p >= 0.40). At 1-year follow-up, children in all groups had median height SDS change of >= 0.3 SDS except for children with ISS. Age at rGH initiation was negatively associated with 1-year treatment response, Adjusted odds ratio (AOR) 0.56 (95 % CI: 0.04-1.49); p = 0.011). CONCLUSIONS: GHD is the most common indication of rGH therapy. All indications except for ISS showed significant 1-year treatment response to therapy. Treatment outcomes in patients with ISS should be further investigated in Kuwait. Younger age at initiation of rGH therapy was independently associated with significant response to therapy suggesting the importance of identifying children with short stature and prompt initiation of rGH therapy. PMID- 26630988 TI - Silk flow diverter in the treatment of complex intracranial aneurysms: a single center experience with 60 patients. AB - BACKGROUND: Flow diverters are used to treat complex aneurysms that are not amenable to coiling. The aim of the present work was to retrospectively evaluate our experience with the Silk flow diverter. Technical nuances and complications are specifically discussed. METHODS: Retrospectively data was collected on patients treated with Silk between October 2008 and October 2013. RESULTS: Sixty patients harboring 67 aneurysms were treated using the Silk. Fifteen aneurysms were located in the posterior circulation and 52 in the anterior. A good angiographic result was achieved in 88 % (53/60) of the aneurysms available for imaging follow-up. There were ten treatment-related complications, 80 % were ischemic. Risk of complications increased with aneurysm size and in aneurysms of the posterior circulation. CONCLUSIONS: Silk flow diverters are a good treatment option for aneurysms of the anterior circulation. Additional stents may be required in specific cases due to the Silk's low radial resistance. Treatment of giant fusiform aneurysms of the posterior circulation with Silk flow diverters is associated with a high rate of severe complications. PMID- 26630990 TI - On the Consistency of Q-Matrix Estimation: A Commentary. AB - This commentary concerns the theoretical properties of the estimation procedure in "A General Method of Empirical Q-matrix Validation" by Jimmy de la Torre and Chia-Yi Chiu. It raises the consistency issue of the estimator, proposes some modifications to it, and also makes some conjectures. PMID- 26630989 TI - Effects and mechanism of moderate aerobic exercise on impaired fasting glucose improvement. AB - BACKGROUND: Exercise is beneficial for blood glucose metabolism. However, whether moderate aerobic exercise could improve impaired fasting glucose is unknown. And the mechanism is also needed to investigate. METHODS: A cross-sectional research was performed and 120 participants with impaired fasting glucose (IFG) were randomly assigned into active and controlled groups. Briefly, participants in active group were required to take moderate aerobic exercise at least 30 min for five times per week, whereas in controlled group, participants were also advised to take exercise but not mandatorily required the same degree as that of active group. At baseline and 3 month's follow-up, laboratory and demographic variables were compared. RESULTS: At baseline, no significant between-group differences were observed. Generally, leukocyte ROCK2 activity in the active and controlled groups were 58.7 +/- 6.0 mg/mL and 60.2 +/- 7.3 mg/mL, and daily average exercise time at baseline in both groups was extremely little, with 5.2 +/- 3.8 min and 5.9 +/- 3.5 min, respectively. After 3 months' follow-up, 52 and 56 participants in the active and controlled groups completed the whole program. Compared to baseline, leukocyte ROCK2 activity and daily average exercise time were improved in both groups. Nonetheless, compared to the controlled group, leukocyte ROCK2 activity was reduced more profoundly and the daily average exercise time was longer in the active group (37.5 +/- 6.3 min versus 18.3 +/- 7.2 min, p < 0.05). Moreover, the percentage of IFG in the active group was decreased more prominently than the controlled group (76.9% versus 82.1%, p < 0.05). Multivariate regression analyses revealed that exercise time and leukocyte ROCK2 activity was significantly associated with IFG, with OR of 0.836 (active group versus controlled group, 95% CI 0.825-0.852, p < 0.05) in exercise time, and 1.043 (controlled group versus active group, 95% CI 1.021-1.069, p < 0.05) in leukocyte ROCK2 activity. In addition, exercise time was significantly associated with leukocyte ROCK2 activity, with OR of 0.822 (active group versus controlled group, 95% CI 0.818-0.843, p < 0.05). CONCLUSION: In subjects with IFG, increased daily average exercise time is beneficial for improving fasting blood glucose metabolism, and the mechanism may be associated with its effects on attenuating leukocyte ROCK2 activity. PMID- 26630991 TI - Using Cross-Classified Structural Equation Models to Examine the Accuracy of Personality Judgments. AB - Whether, when, and why perceivers are able to accurately infer the personality traits of other individuals is a key topic in psychological science. Studies examining this question typically ask a number of perceivers to judge a number of targets with regard to a specific trait. The resulting data are then analyzed by averaging the judgments across perceivers or by computing the respective statistic for each single perceiver. Here, we discuss the limitations of the average-perceiver and single-perceiver approaches. Furthermore, we argue that and illustrate how cross-classified structural equation models can be used for the flexible analysis of accuracy data. PMID- 26630992 TI - Acute effects of BZP, TFMPP and the combination of BZP and TFMPP in comparison to dexamphetamine on an auditory oddball task using electroencephalography: a single dose study. AB - RATIONALE: Piperazine-based designer drugs such as benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) have been marketed and sold as legal alternatives to dexamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) until 2008 in New Zealand. When administered in combination, BZP + TFMPP have been reported to produce drug-drug synergism in rodents by stimulating the release of dopamine and serotonin. OBJECTIVES: This study was to evaluate the acute event related potential effects of BZP, TFMPP or the combination of BZP + TFMPP compared with dexamphetamine in young healthy male adults. METHODS: A double blind, randomised, placebo-controlled study investigated the effects of BZP, TFMPP, the combination of BZP + TFMPP, and dexamphetamine on the event-related potentials during an auditory oddball task. Healthy, right-handed males were given a single oral dose of either BZP (200 mg), TFMPP (60 mg), a combination of BZP + TFMPP (100/30 mg), dexamphetamine (20 mg) or placebo (lactose) and tested both before and 120 min after drug administration. RESULTS: A single dose of either TMFPP (t = -2.29, p = 0.03) or dexamphetamine (t = -2.33, p = 0.02) significantly reduced the P300 amplitude. A similar trend was also found in BZP. In contrast, BZP and TFMPP in combination has no effect. Neither P300 latency nor the mean reaction time was affected by any of the drug treatments. In addition, neither the P100 nor the P200 component was significantly affected following any of the drug treatments. CONCLUSIONS: A single oral dose of BZP or TFMPP, but not the combination of BZP/TFMPP, affected auditory sensory-evoked P300 potential in a manner similar to dexamphetamine. PMID- 26630995 TI - Prehospital transportation to therapeutic hypothermia centers and survival from out-of-hospital cardiac arrest. AB - BACKGROUND: Clinical trials supporting the use of therapeutic hypothermia (TH) in the treatment of out-of-hospital cardiac arrest (OHCA) are based on small patient samples and do not reflect the wide variation in patient selection, cooling methods, and other elements of post-arrest care that are used in everyday practice. This study provides a real world evaluation of the effectiveness of post-arrest care in TH centers during a time of growing TH dissemination in the state of New Jersey (NJ). METHODS: Using a linked database of prehospital, hospital, and mortality records for NJ in 2009-2010, we compared rates of neurologically intact survival at discharge and at 30 days for OHCA patients transported to TH centers (N = 2363) versus other hospitals (N = 2479). We used logistic regression to adjust for patient and hospital covariates. To account for potential endogeneity in prehospital transportation decisions, we used an instrumental variable (IV) based on differential distance to the nearest TH and non-TH hospitals. RESULTS: Patients taken to TH centers were older, more likely to have a witnessed arrest, more likely to receive defibrillation, and waited a shorter amount of time for initial EMS response. Also, TH hospitals were larger, more likely to be teaching facilities, and operated in a service area with a relatively lower poverty rate compared to hospitals statewide. A Stock-Yogo test confirmed the strength of our IV (F = 2349.91, p < 0.0001). Nevertheless, the data showed no evidence of endogenous transportation to TH centers related to in hospital survival (Z = -0.08, p = 0.934) or 30-day survival (Z = 0.94, p = 0.349). In logistic regression models, treatment at a TH center was associated with greater odds of 30-day neurologically intact survival (OR = 1.70; 95% CI: 1.19 - 2.42) but not associated with the odds of neurologically intact survival to hospital discharge (OR = 0.90; 95% CI: 0.61 - 1.31). CONCLUSIONS: Post-arrest outcomes are more favorable at TH centers but these improved outcomes are not apparent until after hospital discharge. This finding may reflect superior care by TH centers in later stages of post-arrest treatment such as care provided in the intensive care unit, which has greater potential to affect longer term outcomes than initial treatment in the emergency department. PMID- 26630997 TI - Lowering iodinated contrast concentration in infrainguinal endovascular interventions: a three-armed randomized controlled non-inferiority trial. AB - OBJECTIVES: To determine the influence of lowering iodinated contrast concentration on confidence of interventional radiologists in diagnosing and treating lesions during endovascular interventions in patients with symptomatic peripheral arterial disease (PAD). METHODS: A randomized controlled non inferiority trial was performed in 60 patients. Intervention was performed with contrast concentrations (in mg of iodine per mL, mgI/mL) of 300 (standard), 240, or 140 mgI/mL. Primary outcome was confidence (score 0-100 %) of radiologists in diagnosing and treating arterial lesions. Secondary outcomes were procedural iodine load and image quality (i.e. non-diagnostic, limited, diagnostic, exemplary). RESULTS: Median confidence scores in diagnosing lesions were 100 % (range 81-100 %) for the 300 group (n = 21), 100 % (range 82-100 %) for the 240 group (n = 19), and 100 % (range 91-100 %) for the 140 group (n = 20) (both p = 1.00 compared to the 300 group). Median scores for treating lesions in the 240 and 140 groups, 100 % (range 79-100 %, p = 0.40), and 100 % (range 63-100 %, p = 0.25), respectively, were not lower compared to the 300 group (median 100 %, range 78-100 %). Procedural iodine load was lower in the 240 (24.3 +/- 7.6 g, p = 0.022) and 140 groups (17.8 +/- 5.6 g, p < 0.001) compared to the 300 group (29.7 +/- 6.3 g). Image quality was diagnostic for all groups. CONCLUSION: Using iodine contrast of 140 mgI/mL for diagnosis and interventions in PAD patients significantly reduces administered iodine load without compromising image quality. Future use of lower iodine dose is recommended. KEY POINTS: * Lower iodinated contrast concentration during endovascular intervention does not decrease radiologist's confidence. * Image quality of standardized angiographies remains diagnostic using 140 mgI/mL iodinated contrast concentration. * Iodine load during intervention can be decreased by >40 % when using 140 mgI/mL. * Implementing the use of a lower iodinated contrast concentration will reduce the costs of the procedure. PMID- 26630998 TI - Effect of red cyst cell inoculation and iron(II) supplementation on autotrophic astaxanthin production by Haematococcus pluvialis under outdoor summer conditions. AB - The negative effect of heat stress on the autotrophic astaxanthin production by Haematococcus pluvialis has been observed during outdoor culture in summer. Under the summer conditions, the proliferation of vegetative cells was highly halted in the green stage and the inducibility in the biosynthesis of astaxanthin was partly hindered in the red stage. Herein, under outdoor summer conditions in which variations of the diurnal temperature occur, heat-stress-driven inefficient vegetative growth of H. pluvialis was highly improved by inoculating the red cyst cells; thereby, maintaining relatively moderate intracellular carotenoid levels in the green stage. Subsequently, a remarkably enhanced astaxanthin titer was successfully obtained by supplementing 50 MUM iron(II) to induce the heat stress driven Haber-Weiss reaction in the red stage. As a result, the productivity of astaxanthin in the cells cultured under summer temperature conditions (23.4-33.5 degrees C) using the two methods of red cell (cyst) inoculation and the iron(Fe(2+)) supplementation was increased by 147% up to 5.53 mg/L day compared with that of the cells cultured under spring temperature conditions (17.5-27.3 degrees C). Our technical solutions will definitely improve the annual natural astaxanthin productivity in H. pluvialis in locations confronted by hot summer weather, particularly in large-scale closed photobioreactor systems. PMID- 26630993 TI - Medication and aggressiveness in real-world schizophrenia. Results from the FACE SZ dataset. AB - INTRODUCTION: The primary objective of this study was to determine if second generation antipsychotic (SGA) administration was associated with lower aggressiveness scores compared to first-generation (FGA) in schizophrenia (SZ). The secondary objective was to determine if antidepressants, mood stabilizers, and benzodiazepines administration were respectively associated with lower aggressiveness scores compared to patients who were not administered these medications. METHODS: Three hundred thirty-one patients with schizophrenia (N = 255) or schizoaffective disorder (N = 76) (mean age = 32.5 years, 75.5 % male gender) were systematically included in the network of FondaMental Expert Center for Schizophrenia and assessed with the structured clinical interview for DSM-IV Axis I disorders and validated scales for psychotic symptomatology, insight, and compliance. Aggressiveness was measured by the Buss-Perry Aggression Questionnaire (BPAQ) score. Ongoing psychotropic treatment was recorded. RESULTS: Patients who received SGA had lower BPAQ scores than patients who did not (p = 0.01). More specifically, these patients had lower physical and verbal aggression scores. On the contrary, patients who received benzodiazepines had higher BPAQ scores than patients who did not (p = 0.04). No significant difference was found between BPAQ scores of patients respectively being administered mood stabilizers (including valproate), antidepressant, and the patients who were not. These results were found independently of socio-demographical variables, psychotic symptomatology, insight, compliance into treatment, daily-administered antipsychotic dose, the way of antipsychotic administration (oral vs long acting), current alcohol disorder, and daily cannabis consumption. CONCLUSION: The results of the present study are in favor of the choice of SGA in SZ patients with aggressiveness, but these results need further investigation in longitudinal studies. Given the potent side effects of benzodiazepines (especially dependency and cognitive impairment) and the results of the present study, their long-term prescription is not recommended in patients with schizophrenia and aggressive behavior. PMID- 26630996 TI - Optimal boundary detection method and window settings for coronary atherosclerotic plaque volume analysis in coronary computed tomography angiography: comparison with intravascular ultrasound. AB - OBJECTIVE: To evaluate optimal methodology for quantitative plaque volume analysis by coronary CT angiography (QCT). METHODS: Fifty-one coronary artery segments were evaluated and contour measurements based on two different methods [(1) no gap, or (2) fixed 0.3-mm gap between inner and outer boundary] were compared with intravascular ultrasound (IVUS). In addition, three different window width (WW) and level (WL) settings [fixed (740/220) Hounsfield unit (HU), adjusted (155 % and 65 % of mean luminal intensity of the segment, and aorta adjusted (155 % and 65 % of mean luminal intensity of central aorta)] were used for semiautomated plaque volume analysis. RESULTS: For boundary detection, the no gap method led to underestimation compared with IVUS (105.4 +/- 82.3 vs. 136.1 +/ 72.8 mm(3), p < 0.001), while fixed 0.3-mm gap showed no difference between IVUS and QCT (136.1 +/- 72.8 vs. 139.8 +/- 93.9 mm(3), p = 0.50). Comparison of the three different window settings demonstrated that the aorta adjusted setting underestimated (120.5 +/- 74.3 vs. 136.1 +/- 72.8 mm(3), p = 0.003), while fixed setting showed the least mean difference compared with IVUS (3.8 +/- 39.8 mm(3), p = 0.50). CONCLUSION: For plaque volumetric assessment, optimal results were obtained with fixed 0.3-mm gap with fixed HU setting (740/220). KEY POINTS: * Quantitative plaque volume analysis by coronary CT angiography has recently emerged. * Different boundary detection methods and window width and level settings were evaluated. * Fixed 0.3-mm gap with fixed HU setting (740/220) afforded optimal results. PMID- 26630999 TI - Complete genome sequence of deoxynivalenol-degrading bacterium Devosia sp. strain A16. AB - The strain A16, capable of degrading deoxynivalenol was isolated from a wheat field and identified preliminarily as Devosia sp. Here, we present the genome sequence of the Devosia sp. A16, which has a size of 5,032,994 bp, with 4913 coding sequences (CDSs). The annotated full genome sequence of the Devosia sp. A16 strain might shed light on the function of its degradation. PMID- 26631002 TI - Preface. PMID- 26631000 TI - Implementation of a new prenatal care model to reduce office visits and increase connectivity and continuity of care: protocol for a mixed-methods study. AB - BACKGROUND: Most low-risk pregnant women receive the standard model of prenatal care with frequent office visits. Research suggests that a reduced schedule of visits among low-risk women could be implemented without increasing adverse maternal or fetal outcomes, but patient satisfaction with these models varies. We aim to determine the effectiveness and feasibility of a new prenatal care model (OB Nest) that enhances a reduced visit model by adding virtual connections that improve continuity of care and patient-directed access to care. METHODS AND DESIGN: This mixed-methods study uses a hybrid effectiveness-implementation design in a single center randomized controlled trial (RCT). Embedding process evaluation in an experimental design like an RCT allows researchers to answer both "Did it work?" and "How or why did it work (or not work)?" when studying complex interventions, as well as providing knowledge for translation into practice after the study. The RE-AIM framework was used to ensure attention to evaluating program components in terms of sustainable adoption and implementation. Low-risk patients recruited from the Obstetrics Division at Mayo Clinic (Rochester, MN) will be randomized to OB Nest or usual care. OB Nest patients will be assigned to a dedicated nursing team, scheduled for 8 pre planned office visits with a physician or midwife and 6 telephone or online nurse visits (compared to 12 pre-planned physician or midwife office visits in the usual care group), and provided fetal heart rate and blood pressure home monitoring equipment and information on joining an online care community. Quantitative methods will include patient surveys and medical record abstraction. The primary quantitative outcome is patient-reported satisfaction. Other outcomes include fidelity to items on the American Congress of Obstetricians and Gynecologists standards of care list, health care utilization (e.g. numbers of antenatal office visits), and maternal and fetal outcomes (e.g. gestational age at delivery), as well as validated patient-reported measures of pregnancy-related stress and perceived quality of care. Quantitative analysis will be performed according to the intention to treat principle. Qualitative methods will include interviews and focus groups with providers, staff, and patients, and will explore satisfaction, intervention adoption, and implementation feasibility. We will use methods of qualitative thematic analysis at three stages. Mixed methods analysis will involve the use of qualitative data to lend insight to quantitative findings. DISCUSSION: This study will make important contributions to the literature on reduced visit models by evaluating a novel prenatal care model with components to increase patient connectedness (even with fewer pre-scheduled office visits), as demonstrated on a range of patient-important outcomes. The use of a hybrid effectiveness-implementation approach, as well as attention to patient and provider perspectives on program components and implementation, may uncover important information that can inform long-term feasibility and potentially speed future translation. TRIAL REGISTRATION: Trial registration identifier: NCT02082275 Submitted: March 6, 2014. PMID- 26631003 TI - Editorial (Thematic Issue: Protein as Networks: Will Contact Maps Hold the Promise to Represent the 'Structural-Formula' of Protein Molecules?). PMID- 26631005 TI - Support the volunteer doctors helping the world's refugees. PMID- 26631004 TI - C-Reactive protein reactions to glucose-insulin-potassium infusion and relations to infarct size in patients with acute coronary syndromes. AB - BACKGROUND: Some benefits of glucose-insulin-potassium (GIK) in patients with acute coronary syndromes (ACS) may be from an anti-inflammatory effect. The primary aim of this study was to assess the impact of GIK administration early in the course of ACS on inflammatory marker C-reactive protein (CRP) levels. A secondary aim was to investigate the association between CRP and 30-day infarct size. METHODS AND RESULTS: Retrospective analysis of participants with ACS randomly assigned to GIK or placebo for at least 8 h in the IMMEDIATE Trial biological mechanism cohort (n = 143). High sensitivity CRP (hs-CRP) was measured at emergency department presentation, and 6 and 12 h into infusion. Logarithmically transformed hs-CRP values at 12-hours were lower with GIK vs. placebo (mean =0.65 mg/L in GIK, 0.84 mg/L in placebo), with a marginal trend toward significance (P = 0.053). Furthermore, using mixed models of hs-CRP, time, and study group, there was a significant increase in hs-CRP levels over time, but the rate of change did not differ between treatment arms (P = 0.3). Multivariable analysis showed that an elevation in hs-CRP, measured at 12 h, was an independent predictor of 30-day infarct size (beta coefficient, 6.80; P = 0.04) using sestamibi SPECT imaging. CONCLUSIONS: The results of this study show no significant effect of GIK on hs-CRP. In addition our results show that in patients with ACS, hs-CRP measured as early as 12 h can predict 30-day infarct size. PMID- 26631006 TI - Transcriptional Regulation of Genes Involved in 3-Hydroxypropionic Acid Production in Response to Aeration of Recombinant Klebsiella pneumoniae. AB - We have described a metabolically engineered strain of Klebsiella pneumoniae/pUC18kan-aldHec that could convert glycerol to 3-hydroxypropionic acid (3-HP) effectively. In this study, the transcription of the genes encoding aldehyde dehydrogenase (AldH) and glycerol dehydratase (DhaB) responsible to 3-HP biosynthesis, key enzymes in PP pathway and TCA cycle, as well as hydrogenases was observed under anaerobic, microaerobic, and aerobic conditions using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). During the fast growth and slow growth phases of cell growth, the aldH transcription levels were 7.0- and 2.1-fold enhanced under microaerobic condition, and 12.4- and 0.14-fold under fully aerobic condition, compared to the anaerobic control, while transcription of dhaB showed a downregulated manner due to aeration. Moreover, aeration increased the transcription levels of zwf, sucA, and sdhAB during the fast growth phase of the cell growth. The results also indicated that the hydrogenase 3 (hycBCDFG) and formate dehydrogenase (fdhA) mediated formate hydrogen lyase pathway was the main route to produce hydrogen and consume the excess NADH. These characteristics are useful for understanding and improving 3 HP biosynthesis in K. pneumoniae. PMID- 26631007 TI - [Unemployment and Health: An overview of current research results and data from the 2010 and 2012 German Health Update]. AB - This study analyzes the association of unemployment and health using national and international research data. It is based on data from the 2010 and 2012 German Health Update (GEDA), conducted by the Robert Koch Institute. For our analysis, participants aged from 18 to 64 years were selected if they gave information on their unemployment experiences within the five years prior to the study (n = 31,955). The results show that the self-rated health of the unemployed in Germany is significantly worse compared to the workforce. Additionally, the unemployed suffer from medically diagnosed depression. The association of unemployment and health is more pronounced in men than in women for all major outcomes. When compared to workers of the same age, the unemployed smoke more frequently and do less sports. Regarding alcohol consumption, no systematic relationship was found. While the use of medical screening measures for the early detection of diseases is lower among the unemployed than among the employed, they visit general practitioners and hospitals more often than their counterparts. Overall, our findings suggest that unemployed people should remain an important target group of preventive measures in Germany and that the corresponding measures should be intensified. PMID- 26631008 TI - [Social inequality and health: Status and prospects of socio-epidemiological research in Germany]. AB - Social differences in morbidity and mortality have always been a central topic in public health research. In recent years, there has been a growing research interest that has clearly resonated with the general public and the political arena as well. This article describes the development and establishment of social epidemiology in Germany and presents the current status of research. In addition, it describes different models for explaining health inequalities. On this basis, selected challenges and prospects of socio-epidemiological research are demonstrated. The reason why the analysis of social differences in morbidity and mortality will continue to be a key task of public health research in the national and international context in the future is also explained. PMID- 26631009 TI - [Social disparities in outpatient and inpatient care: An overview of current findings in Germany]. AB - There is controversy about social disparities in healthcare services in Germany, but a differentiated analysis regarding various dimensions of healthcare is lacking. This narrative review intends to summarize conceptually the current state of research and draw subsequent conclusions. Separated into access, utilization and quality, the findings of social inequality in outpatient and inpatient care in Germany are summarized. Besides the common individual indicators of socioeconomic status (SES), regional deprivation and health insurance status are also included. Despite methodical diversity, the results show that healthcare inequalities due to SES exist, but not universally. Furthermore, there is a differentiated pattern respecting separate dimensions of healthcare. Concerning access (e.g. waiting times, co-payments) lower status groups and patients covered by statutory health insurance are deprived. Higher utilization becomes apparent among higher status groups and privately insured patients in terms of specialist consultations and prevention services. The findings regarding quality of process and outcome differ depending on quality indicator and disease. In different dimensions of medical healthcare, social disparities still exist, though the impact on health remains unclear for some types of healthcare inequalities. Moreover, it is often difficult to conclude from unequal outcome quality the inequalities of healthcare. Depending on access, utilization and quality, separate interventions for reducing these disparities are to be introduced. PMID- 26631010 TI - [Violence and health]. PMID- 26631011 TI - [Social inequality in medical rehabilitation]. AB - BACKGROUND: The analysis of inequalities in health care provision in Germany is of high sociopolitical relevance. For medical rehabilitation, which is an essential part of health care provision, only a few studies exist. OBJECTIVE: With the example of psychosomatic and orthopedic medical rehabilitation, the present article investigates how features of social inequality influence different aspects of medical rehabilitation. METHODS: The database consists of a written survey on the quality assurance of medical rehabilitation in northern Germany that includes 687 patients aged between 21 and 87 years. Aspects of the access to rehabilitation (e.g., the motivation for application), the process (participation in therapies) and the outcomes (e.g., subjective health and occupational risk) of rehabilitation were investigated in relation to social inequality. Social inequality was measured by means of a social class index. For the analysis, Chi-squared tests, t tests and a repeated measures analysis of variance, adjusted for sex and age, were conducted. RESULTS AND DISCUSSION: Initially, the analyses indicate that social inequality is of minor importance for access to rehabilitation and processes within rehabilitation. As subjective health is unequally distributed at the beginning of rehabilitation, however, equal treatment has to be discussed critically in terms of demand-driven treatment. In rehabilitation outcome distinct differences between social classes exist. To reduce these differences, rehabilitation aftercare close to the individual's living environment is necessary, which promotes the empowerment of vulnerable social groups in burdensome living conditions. PMID- 26631012 TI - [Social inequalities in adolescent smoking: A cross-national perspective of the role of individual and macro-structural factors]. AB - BACKGROUND: In an EU-funded project, we examined on the basis of international comparative analyses which factors were associated with and contributed to socioeconomic inequalities in adolescent smoking. This paper presents the results obtained and discusses their implications for policy and research. METHODS: Analyses were based on the "Health Behaviour in School-aged Children (HBSC)" study in 2006 and included more than 50,000 adolescents from 37 countries. The focus was on the association between family affluence and weekly smoking (regularly, at least once a week) among adolescents. Explanatory variables at the individual level refer to psychosocial resources and burdens of school, family, and peers. At the country level, national income, various tobacco control policies, and an index of external differentiation of the educational system were used. RESULTS: The psychosocial factors of school and family explained many of the inequalities in the smoking behavior of adolescents. In an international comparison, socioeconomic inequalities in smoking were stronger in richer countries. Absolute smoking rates were lower and inequalities in smoking smaller for boys in countries with higher tobacco prices. On the other hand, educational systems with higher degrees of external differentiation showed lower inequalities in smoking beahviour by girls, and relatively higher rates of smoking (for boys and girls). Stronger inequalities in smoking behaviour were demonstrated in countries with a greater range of preventative measures for tobacco dependence (for boys) and with higher levels of government spending on tobacco control (for girls). CONCLUSION: Experiences in richer countries revealed that tobacco control needs to be strengthened for socially disadvantaged adolescents. The reduction of smoking prevalence and socioeconomic inequalities in smoking behavior should be based not only on a strengthening of psychosocial resources in the family and at school, but also on an increase in tobacco prices. PMID- 26631013 TI - [Social inequality, health and nursing care in old age]. AB - BACKGROUND: Health and care services are an important aspect of public services as a basic obligation of the welfare state. Particularly in old-age, social inclusion, relatedness and integrity become the aims of health and care services beyond independence and autonomy. OBJECTIVES: Provide an overview of inequalities related to socio-economic status, gender, and immigrant background in the context of health and care services. MATERIALS AND METHODS: Analysis of differences in risks and problem situations, access to prevention measures, ambulatory and in patient treatment, availability of social support, and care services in middle and older adulthood. Thereby, the contribution proceeds from our own contributions to prevention and rehabilitation research as well as from representative surveys. RESULTS: People with lower socio-economic status, women, and migrants more often suffer from risks and problem situations and have less access to prevention measures and medical specialist care. Regarding in-patient treatment, people with private health insurance have a higher probability of being admitted to hospital. Migrants more often visit emergency rooms and less often get rehabilitation measures. The availability of social support depends on age, gender, and education; applicants from higher status groups more often receive services from nursing care insurance. CONCLUSION: The results point to the necessity of status-, milieu- and culture-sensitive counselling, particularly focusing on patient rights and usefulness of optional health and nursing care services. Qualified professionals could take responsibility for respective tasks. PMID- 26631014 TI - [Multidrug-resistant organisms (MDRO) in patients in outpatient care in the Rhine Main region, Germany, in 2014: Prevalence and risk factors]. AB - BACKGROUND: Data on the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in outpatient care are scarce and those on the prevalence of multidrug resistant Gram-negative bacteria (MRGN) are lacking completely. Therefore, the network on multidrug-resistant organisms (MDRO) in the Rhine-Main region (MRE Netz Rhein-Main) performed a multicenter study on current prevalence data and risk factors for MDRO. MATERIALS AND METHODS: Characteristics of all patients were obtained according to a modified healthcare-associated infections in long term care facilities (HALT) questionnaire and swabs from the nares/throat and anus were tested for MRSA and extended-spectrum beta-lactamase (ESBL)/MRGN. Risk factors were calculated via odds ratios. RESULTS: Ten nursing services with 486 patients participated in this study, 269 patients agreed to having swabs of the nares/throat taken, and 132 patients had anal swabs. MRSA was detected in 3.7%, and ESBL/MRGN in 14.4% of the patients (6.8% ESBL, 7.6% MRGN, 0% MRGN). Risk factors for MRSA were high dependency on care (stage 3 or above; OR 5.1), antibiotic use during the preceding 3 months (O R 3.7), hospital stay during the last 6 months (OR 4.3), and a positive history for MRSA (OR 18.1). Incontinence and preceding hospital stays proved to be risk factors for ESBL colonization (OR 9.5 or 6.5), whereas risk factors for MRGN colonization were a high level of care dependency (OR 7.5), urinary catheter (OR 8.3), percutaneous endoscopic gastrostomy tube and other stomata (OR 6.2), and artificial respiration (OR 5), in addition to a positive history for MRSA (OR 20) and ESBL (OR 6.7). CONCLUSION: Considering the high prevalence of colonization with MDRO in outpatient care, nursing services must be competent in caring for such patients: good hygiene procedures, including hand hygiene and appropriate handling in wound management, punctures and injections, with catheters, stomata, and if necessary with artificial respiration should be practiced. The guidelines of the German Commission on hospital hygiene and infection prevention should also be observed. PMID- 26631015 TI - Oral health and HIV infection among female sex workers in Abidjan, Cote d'Ivoire. AB - BACKGROUND: Worldwide, female sex workers (FSW) represent a vulnerable population for oral diseases due to many risk factors including HIV infection and drug abuse. In sub-Saharan Africa, little is known about the burden of oral diseases and their determinants in vulnerable populations. The aim of the study was to estimate the prevalence and associated factors of oral diseases among FSW. METHODS: A cross sectional study was conducted among FSW who attended a dedicated non-profit clinic in Abidjan, Cote d'Ivoire from June to August 2013. Data about the presence of dental caries, periodontitis and oral-mucosal lesions were collected by a dentist during an oral examination. Behavioural information related to oral hygiene habits as well as tobacco and alcohol consumption were collected through a standardized questionnaire. Information related to HIV infection including HIV diagnosis, last known CD4 count and antiretroviral therapy were documented through a medical chart review. Logistic regression models were used to identify factors associated with oral diseases. RESULTS: A total of 249 FSW with a median age of 29 years, [Inter Quartile Range (IQR) = 23 36] and a median duration of sex work of 24 months [IQR 9-60]) were included. Current tobacco use and hazardous alcohol use were reported in 21.7 % and 19.7 % of FSW, respectively. The estimated prevalence of HIV infection was 33.7 % [95 % confidence interval (CI); 27.8 - 39.6]) and 82.1 % of HIV-infected FSW were on antiretroviral therapy . The prevalence of dental caries, periodontitis and oral mucosal lesions were 62.3 % [95 % CI 55.5 - 67.5], 14.5 % [95 % CI 10.2 - 18.9] and 8.2 % [95 % CI 4.8 - 11.5], respectively. In multivariate analysis, periodontitis, oral-mucosal lesions and HIV infection were associated with odds ratio of 2.6 [95 % CI, 1.2-5.8]) and 50.0 [95 % CI; 6.4-384.6]. CONCLUSIONS: This study showed a high prevalence of oral diseases among FSW in Abidjan. HIV infection was common and significantly associated with periodontal diseases and oral-mucosal lesions. There is a need to integrate regular screening and treatment of oral lesions into the medical follow-up of FSW along with strategies for HIV prevention. PMID- 26631016 TI - MAPK-mediated regulation of growth and essential oil composition in a salt tolerant peppermint (Mentha piperita L.) under NaCl stress. AB - Peppermint (Mentha * piperita L.) is an important and commonly used flavoring agent worldwide, and salinity is a major stress that limits plant growth and reduces crop productivity. This work demonstrated the metabolic responses of essential oil production including the yield and component composition, gene expression, enzyme activity, and protein activation in a salt-tolerant peppermint Keyuan-1 with respect to NaCl stress. Our results showed that Keyuan-1 maintained normal growth and kept higher yield and content of essential oils under NaCl stress than wild-type (WT) peppermint.Gas chromatography-mass spectrometry (GC MS) and qPCR results showed that compared to WT seedlings, a 150-mM NaCl stress exerted no obvious changes in essential oil composition, transcriptional level of enzymes related to essential oil metabolism, and activity of pulegone reductase (Pr) in Keyuan-1 peppermint which preserved the higher amount of menthol and menthone as well as the lower content of menthofuran upon the 150-mM NaCl stress. Furthermore, it was noticed that a mitogen-activated protein kinase (MAPK) protein exhibited a time-dependent activation in the Keyuan-1 peppermint and primarily involved in the modulation of the essential oil metabolism in the transcript and enzyme levels during the 12-day treatment of 150 mM NaCl. In all, our data elucidated the effect of NaCl on metabolic responses of essential oil production, and demonstrated the MAPK-dependent regulation mechanism of essential oil biosynthesis in the salt-tolerant peppermint, providing scientific basis for the economic and ecological utilization of peppermint in saline land. PMID- 26631017 TI - A comparison of aquaporin function in mediating stomatal aperture gating among drought-tolerant and sensitive varieties of rice (Oryza sativa L.). AB - Climate change drastically affects the cultivation of rice, and its production is affected significantly by water stress. Adaptation of a plant to water deficit conditions is orchestrated by efficient water uptake and a stringently regulated water loss. Transpiration remains the major means of water loss from plants and is mediated by microscopic pores called stomata. Stomatal aperture gating is facilitated by ion channels and aquaporins (AQPs) which regulate the turgidity of the guard cells. In a similar manner, efficient water uptake by the roots is regulated by the presence of AQPs in the plasma membrane of root cells. In this study, we compare the efficiency of transmembrane water permeability in guard cells and root protoplasts from drought-tolerant and sensitive varieties of Oryza sativa L. In this report, we studied the transmembrane osmotic water permeability (Pos) of guard cell and root protoplasts of drought-sensitive and tolerant cultivars. The guard cells isolated from the drought-sensitive lowland rice variety ADT-39 show significant low osmotic permeability than the drought tolerant rice varieties of Anna (lowland) and Dodda Byra Nellu (DBN) (upland local land rice). There is no significant difference in relative gene expression patterns of PIPs (Plasma membrane Intrinsic Proteins "PIP1" and "PIP2" subfamilies) in guard cells isolated from ADT-39 and Anna. While the expression levels of AQP genes remain the same between ADT-39 and Anna, there is a drastic difference in their osmotic permeability in the guard cells in spite of a higher number of stomata in Anna and DBN, hinting at a more efficient gating mechanism of AQP in the stomata of the drought-tolerant varieties studied. PMID- 26631019 TI - Hospital admissions due to diseases of arteries and veins peaked at physiological equivalent temperature -10 to 10 degrees C in Germany in 2009-2011. AB - We aimed to understand relationships of the weather as biometeorological and hospital admissions due to diseases of arteries and veins by subtypes, which have been scarcely studied, in a national setting in recent years. This is an ecological study. Ten percent of daily hospital admissions from the included hospitals (n = 1,618) across Germany that were available between 1 January 2009 and 31 December 2011 (n = 5,235,600) were extracted from Statistisches Bundesamt, Germany. We identified I70-I79 Diseases of arteries, arterioles and capillaries and I80-I89 Diseases of veins, lymphatic vessels and lymph nodes by International Classification of Diseases version 10 as the study outcomes. Daily weather data from 64 weather stations that covered 13 German states including air temperature, humidity, wind speed, cloud cover, radiation flux and vapour pressure were obtained and generated into physiologically equivalent temperature (PET). Two-way fractional-polynomial prediction was plotted with 95 % confidence intervals. For most of the subtypes from diseases of arteries and veins, hospital admissions slightly peaked in spring and dropped when PET was at 10 degrees C. There were no other large differences across 12 months. Admissions of peripheral vascular diseases, arterial embolism and thrombosis, phlebitis and thrombophlebitis, oesophageal varices and nonspecific lymphadenitis peaked when PET was between 0 and -10 degrees C, while others peaked when PET was between 0 and 10 degrees C. More medical resources could have been needed on days when PETs were at -10 to 10 degrees C than on other days. Adaptation to such weather change for health professionals and the general public would seem to be imperative. PMID- 26631020 TI - No tillage combined with crop rotation improves soil microbial community composition and metabolic activity. AB - Soil microbial community can vary with different agricultural managements, which in turn can affect soil quality. The objective of this work was to evaluate the effects of long-term tillage practice (no tillage (NT) and conventional tillage (CT)) and crop rotation (maize-soybean (MS) rotation and monoculture maize (MM)) on soil microbial community composition and metabolic capacity in different soil layers. Long-term NT increased the soil organic carbon (SOC) and total nitrogen (TN) mainly at the 0-5 cm depth which was accompanied with a greater microbial abundance. The greater fungi-to-bacteria (F/B) ratio was found in NTMS at the 0-5 cm depth. Both tillage and crop rotation had a significant effect on the metabolic activity, with the greatest average well color development (AWCD) value in NTMS soil at all three soil depths. Redundancy analysis (RDA) showed that the shift in microbial community composition was accompanied with the changes in capacity of utilizing different carbon substrates. Therefore, no tillage combined with crop rotation could improve soil biological quality and make agricultural systems more sustainable. PMID- 26631018 TI - Research advances in the relationship between nonalcoholic fatty liver disease and atherosclerosis. AB - Nonalcoholic fatty liver disease (NAFLD) is a metabolic stress-induced liver disease that is closely related not only to genetic susceptibility but also to insulin resistance and highly linked with metabolic syndrome. In recent years, the prevalence of NAFLD has increased rapidly, paralleling the epidemic of type 2 diabetes mellitus and obesity leading to cardiovascular disease. It has been demonstrated that NAFLD is highly associated with atherosclerosis. With recently gained knowledge, it appears that NAFLD may induce insulin resistance, dyslipidemia, oxidative stress, inflammation, and fluctuation of adipokines associated with atherosclerosis. In this review, we aimed to summarize recent discoveries related to both NAFLD and atherosclerosis, and to identify possible mechanisms linking them. PMID- 26631021 TI - Effect of dimethyl phthalate (DMP) on germination, antioxidant system, and chloroplast ultrastructure in Cucumis sativus L. AB - Pollution of agricultural soils caused by widely employed plastic products, such as phthalic acid esters (PAEs), are becoming widespread in China, and they have become a threat to human health and the environment. However, little information is available on the influence of PAEs on vegetable crops. In this study, effects of different dimethyl phthalate (DMP) treatments (0, 30, 50, 100, and 200 mg L( 1)) on seed germination and growth of cucumber seedlings were investigated. Although germination rate showed no significant difference compared to control, seed germination time was significantly delayed at DMP greater than 50 mg L(-1). Concentrations of DMP greater than 30 mg L(-1) reduced cucumber lateral root length and number. The measurement of five physiological indexes in cucumber leaves with increasing DMP concentration revealed a decrease in leaf chlorophyll content, while proline and H2O2 contents increased. Peroxidase (POD) and catalase (CAT) activities increased in cucumber plants under 30 and 50 mg L(-1) DMP treatments compared to control; while after a 7-day treatment, these activities were seriously reduced under 100 and 200 mg L(-1) DMP treatments. According to transmission electron microscopy (TEM) micrographic images, the control and 30 mg L(-1) DMP treatments caused no change to leaf chloroplast shape with well structured thylakoid membrane and parallel pattern of lamellae. At concentrations higher than 30 mg L(-1), DMP altered the ultrastructure of chloroplast, damaged membrane structure, disordered the lamellae, and increased the number and volume of starch grains. Moreover, the envelope of starch grains began to degrade under 200 mg L(-1) DMP treatment. PMID- 26631022 TI - Assessment of selected metals in the ambient air PM10 in urban sites of Bangkok (Thailand). AB - Estimating the atmospheric concentrations of PM10-bounded selected metals in urban air is crucial for evaluating adverse health impacts. In the current study, a combination of measurements and multivariate statistical tools was used to investigate the influence of anthropogenic activities on variations in the contents of 18 metals (i.e., Al, Sc, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Cd, Sb, Ba, La, Ce and Pb) in ambient air. The concentrations of PM10-bounded metals were measured simultaneously at eight air quality observatory sites during a half year period at heavily trafficked roads and in urban residential zones in Bangkok, Thailand. Although the daily average concentrations of Al, V, Cr, Mn and Fe were almost equivalent to those of other urban cities around the world, the contents of the majority of the selected metals were much lower than the existing ambient air quality guidelines and standard limit values. The sequence of average values of selected metals followed the order of Al > Fe > Zn > Cu > Pb > Mn > Ba > V > Sb > Ni > As > Cr > Cd > Se > Ce > La > Co > Sc. The probability distribution function (PDF) plots showed sharp symmetrical bell-shaped curves in V and Cr, indicating that crustal emissions are the predominant sources of these two elements in PM10. The comparatively low coefficients of divergence (COD) that were found in the majority of samples highlight that site-specific effects are of minor importance. A principal component analysis (PCA) revealed that 37.74, 13.51 and 11.32 % of the total variances represent crustal emissions, vehicular exhausts and the wear and tear of brakes and tires, respectively. PMID- 26631023 TI - Initial diagnosis of chronic myelogenous leukemia based on quantification of M BCR status using droplet digital PCR. AB - Formed from a reciprocal translocation t(9:22)(q34;q11) of genetic material between the long arms of human chromosomes 9 and 22, the constitutively active breakpoint cluster region (BCR) Abelson 1 (ABL) tyrosine kinase BCR-ABL is known to be causative of chronic myelogenous leukemia (CML). In 98% of CML patients harboring the t(9:22)(q34;q11) translocation, known as the Philadelphia chromosome, the chimeric BCR-ABL oncogene is created through cleavage of the BCR gene within its major breakpoint region (M-BCR) and breakage of the ABL gene within a 100-kbp region downstream of exon 2a. Clinical detection of the fused BCR-ABL oncogene currently relies on direct visualization by fluorescence in situ hybridization (FISH), a relatively tedious assay that typically offers a detection limit of ca. 2%. Here, we describe a novel assay that uses droplet digital PCR (ddPCR) technology to reliably measure M-BCR status and the presence of BCR-ABL. When applied to cell-line models of CML, the assay accurately quantifies BCR-ABL frequency to a detection limit of 0.25%. It therefore offers improved specificity relative to FISH, and may allow identification of variant translocation patterns, including derivative chromosome 9 deletions. PMID- 26631024 TI - Quo vadis, analytical chemistry? AB - This paper presents an open, personal, fresh approach to the future of Analytical Chemistry in the context of the deep changes Science and Technology are anticipated to experience. Its main aim is to challenge young analytical chemists because the future of our scientific discipline is in their hands. A description of not completely accurate overall conceptions of our discipline, both past and present, to be avoided is followed by a flexible, integral definition of Analytical Chemistry and its cornerstones (viz., aims and objectives, quality trade-offs, the third basic analytical reference, the information hierarchy, social responsibility, independent research, transfer of knowledge and technology, interfaces to other scientific-technical disciplines, and well oriented education). Obsolete paradigms, and more accurate general and specific that can be expected to provide the framework for our discipline in the coming years are described. Finally, the three possible responses of analytical chemists to the proposed changes in our discipline are discussed. PMID- 26631026 TI - A biomarker of tissue damage, lactate dehydrogenase, is associated with fibulin-1 and oxidative stress in blacks: the SAfrEIC study. AB - CONTEXT: Extracellular matrix (ECM) remodeling and oxidative stress is present in hypertension and associated arterial stiffness, but little is known on the physiological link among lactate dehydrogenase (LDH), fibulin-1, and reactive oxygen species (ROS). OBJECTIVE: The objective of this study is to explore the link among a marker of tissue damage (LDH), fibulin-1 (as ECM biomarker), and ROS. METHODS: We included 316 black and 305 white South Africans and determined the above-mentioned biomarkers along with additional cardiometabolic risk factors. RESULTS: LDH associated positively with fibulin-1 (beta = 0.23; p < 0.001) and ROS (beta = 0.11; p = 0.30) in blacks only. CONCLUSION: Our finding suggests that increased circulating levels of LDH may be due to early ECM remodeling and oxidative stress in blacks that are subjected to detrimental and uncontrolled lifestyle risk factors. PMID- 26631027 TI - Assessing ageist behaviours in undergraduate nursing students using the Relating to Older People Evaluation (ROPE) survey. AB - AIM: To describe the prevalence of ageist behaviours amongst first-year undergraduate nursing students. METHODS: A cross-sectional survey design. The Relating to Older People Evaluation (ROPE) survey was administered to first-year undergraduate nursing students in one Australian university. RESULTS: One hundred and eighty-five students responded (response rate (RR) 85.3%). Up to 97.8% of students reported engaging in some ageist behaviours, with positive ageist behaviours ranked highest. Up to 87.5% of the cohort reported engaging in negative behaviours, such as talking slow and loud to an older person. Most students (63.2%) indicated that they would work in aged care in the future. CONCLUSION: Nursing students report engaging in ageist behaviours that can have a negative effect on their future relationships with older patients. The ROPE survey can be used to make collective ageist behaviours explicit to students. Combining explicit collective information on ageist behaviours with educational strategies is proposed to address ageism in undergraduate nursing curricula. PMID- 26631028 TI - Synthesis of Allenes by Catalytic Coupling of Propargyl Carbonates with Aryl Iodides in the Presence of Diboron Species. AB - Bimetallic copper-/palladium-catalyzed multicomponent reaction of propargyl carbonates, aryl iodides, and diboron species was studied. This procedure can be used for synthesis of di-, tri-, and tetra-substituted allenes. Using diboronic acid, the reaction is supposed to proceed via allenylboronic acid intermediate. PMID- 26631029 TI - Putative invasive pulmonary aspergillosis in critically ill patients with chronic obstructive pulmonary disease: a matched cohort study. AB - INTRODUCTION: Patients with advanced chronic obstructive pulmonary disease (COPD) are at risk for developing invasive pulmonary aspergillosis. A clinical algorithm has been validated to discriminate colonization from putative invasive pulmonary aspergillosis (PIPA) in Aspergillus-positive respiratory tract cultures of critically ill patients. We focused on critically ill patients with COPD who met the criteria for PIPA. METHODS: This matched cohort study included critically ill patients with COPD from two university hospital intensive care units (ICUs). We studied the risk factors for PIPA as well as the impact of PIPA on short- and long-term outcomes. Whether PIPA was associated with a pattern of bacterial colonization and/or infection 6 months before and/or during ICU stay was assessed. In addition, antifungal strategies were reviewed. RESULTS: Fifty cases of PIPA in critically ill patients with COPD in the ICU were matched with one hundred control patients with COPD. The ICU short- and the long-term (at 1 year) mortality were significantly increased in the PIPA group (p < 0.001 for all variables). PIPA was a strong independent risk factor for mortality in the ICU (odds ratio 7.44, 95 % confidence interval 2.93-18.93, p < 0.001) before vasopressor therapy, renal replacement therapy, and duration of mechanical ventilation. Before ICU admission, the use of corticosteroids and antibiotics significantly increased the risk of PIPA (p = 0.004 and p < 0.001, respectively). No significant difference in bacterial etiologic agents responsible for colonization and/or infection was found between the groups. Antifungal treatment was started in 64 % of PIPA cases, with a poor impact on the overall outcome. CONCLUSIONS: PIPA was a strong death predictor in critically ill patients with COPD. The use of corticosteroids and antibiotics before ICU admission was a risk factor for PIPA. PIPA was not associated with a specific bacterial pattern of colonization or infection. Prompting antifungal treatment in critically ill patients with COPD who have PIPA may not be the only factor involved in prognosis reversal. PMID- 26631030 TI - Genetic variants in IL12 influence both hepatitis B virus clearance and HBV related hepatocellular carcinoma development in a Chinese male population. AB - IL12 plays a major role not only in inducing appropriate immune responses against viral infections (including HBV) but also in the antitumor immune response. This study was conducted to investigate the relationships of genetic variants in IL12 with hepatitis B virus (HBV) clearance and development of HBV-related hepatocellular carcinoma (HCC). We genotyped three single nucleotide polymorphisms (SNPs) of the IL12A (rs568406 and rs2243115) and IL12B (rs3212227) in 395 HBV-positive HCC patients, 293 persistent HBV carriers and 686 subjects with HBV natural clearance from southern China, using the improved multiplex ligase detection reaction (iMLDR) method. Logistic regression analysis adjusted for age, smoking, and alcohol consumption status showed that rs568408 variant genotypes were significantly associated with host HBV-related HCC risk when compared with persistent HBV carriers, and carriers of the GA + AA genotype decreased the HCC risk in comparison with GG carriers (adjusted OR = 0.53, 95 % CI 0.35-0.80, P = 0.002). No relationships between the rs2243115 and rs3212227 SNPs and HCC risk were observed (all P > 0.05). Besides, rs568408 showed an approaching significant effect on susceptibility to HBV persistent infection (adjusted OR = 1.34, 95 % CI 0.99-1.81, P = 0.057 in dominant genetic models). Furthermore, the TG haplotype was observed to be associated with a significantly increased risk of HBV-related HCC (OR = 1.42, 95 % CI 1.10-1.83, P = 0.006), while TA haplotype was associated with a decreased risk of HBV-related HCC (OR = 0.61, 95 % CI 0.45-0.83, P = 0.002). Our results reveal that the IL12A rs568408 variant may be a marker SNP for risk of both HBV clearance and HBV-related HCC development. PMID- 26631031 TI - Diagnostic marker signature for esophageal cancer from transcriptome analysis. AB - Esophageal cancer is often diagnosed at an advanced stage. Diagnostic markers are needed for achieving a cure in esophageal cancer detecting and treating tumor cells earlier. In patients with locally advanced squamous cell carcinoma of the esophagus (ESCC), we profiled the gene expression of ESCC compared to corresponding normal biopsies for diagnostic markers by genome microarrays. Profiling of gene expression identified 4844 genes differentially expressed, 2122 upregulated and 2722 downregulated in ESCC. Twenty-three overexpressed candidates with best scores from significance analysis have been selected for further analysis by TaqMan low-density array-technique using a validation cohort of 40 patients. The verification rate was 100 % for ESCC. Twenty-two markers were additionally overexpressed in adenocarcinoma of the esophagus (EAC). The markers significantly overexpressed already in earlier tumor stages (pT1-2) of both histological subtypes (n = 19) have been clustered in a "diagnostic signature": PLA2G7, PRAME, MMP1, MMP3, MMP12, LIlRB2, TREM2, CHST2, IGFBP2, IGFBP7, KCNJ8, EMILIN2, CTHRC1, EMR2, WDR72, LPCAT1, COL4A2, CCL4, and SNX10. The marker signature will be translated to clinical practice to prove its diagnostic impact. This diagnostic signature may contribute to the earlier detection of tumor cells, with the aim to complement clinical techniques resulting in the development of better detection of concepts of esophageal cancer for earlier therapy and more favorite prognosis. PMID- 26631032 TI - Interference with endogenous EZH2 reverses the chemotherapy drug resistance in cervical cancer cells partly by up-regulating Dicer expression. AB - Cervical cancer is one of the most common female malignancies in the world, and chemotherapeutic drug resistance is a major obstacle to cancer therapy. Enhancer of zeste homolog 2 (EZH2) is an enzymatic subunit of polycomb repressive complex 2 (PRC2) and catalyzes the repressive histone H3 lysine 27 trimethylation (H3K27me3). However, the role of EZH2 on the chemotherapy drug resistance in cervical cancers remains unclear. In the present study, the cervical carcinoma specimens and paired normal tissue specimens were obtained and the expression of EZH2 was detected by western blotting. The results showed that high levels of EZH2 were detected in cervical carcinoma tissues, compared with paired control tissues (**p < 0.01). Next, three pairs of shRNA specific to EZH2 were designed and used to interfere with endogenous EZH2 expression. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays following treatment with various concentrations of cisplatin in HeLa and HeLa/DDP cells. The MTT assay results showed that knockdown of EZH2 in HeLa/DDP cells caused a 2.29- or 1.83-fold decrease in the cisplatin IC50 values (for shRNA1-EZH2, 34.88 vs. 15.21 MUg/mL; p < 0.01; for shRNA3-EZH2, 34.88 vs. 19.09 MUg/mL; p < 0.01). The EZH2 activity was also suppressed by 3-deazaneplanocin A (DZNep), EZH2 inhibitor, and the results demonstrated that, meanwhile, DZNep potently inhibited cell viability of HeLa/DDP cells, partly by suppression the levels of EZH2 and H3K27me3, but not H3K27me2, which was detected by western blotting analysis. Moreover, cell migration assay results showed that knockdown of EZH2 decreased cell metastasis of cervical cancer cells. Furthermore, cell cycle was detected by fluorescence-activated cell sorting (FACS) assay and the results demonstrated that interference with EZH2 expression increased the percentage of cells at G0/G1 phase and the HeLa/DDP cells were blocked at G0/G1 phase. Interestingly, western blotting results revealed that higher expression of EZH2 was related with lower level of Dicer in HeLa/DDP cells. Finally, in vivo tumorigenicity experiments results demonstrated that interference with endogenous EZH2 by shRNA specific to EZH2 or inhibition EZH2 by DZNep could significantly increase antitumor effects in nude mice. Thus, inhibiting the levels of endogenous EZH2 effectively reversed the cisplatin resistance and increased the cisplatin sensitivity in cisplatin-resistant HeLa/DDP cells. EZH2 might be a potential target for treating chemotherapeutic drug-resistant cervical cancers. PMID- 26631033 TI - Regulation of CXCR4/AKT-signaling-induced cell invasion and tumor metastasis by RhoA, Rac-1, and Cdc42 in human esophageal cancer. AB - CXC chemokines and their cognate receptors have been implicated wildly in cancer pathogenesis. In the present study, we report a critical cause relationship between CXCR4 expression and tumorigenesis in the setting of human esophageal squamous cell carcinoma (ESCC). In ESCC cells, CXCR4 expression was significantly higher than in human esophageal epithelial cells (HEEC). Reduction of CXCR4 in ESCC cells reduced cell proliferation and invasion in vitro and tumor growth in vivo. Among the potential downstream targets of CXCR4-CXCL12 are RhoA, Rac-1, and Cdc42, which are likely to contribute to the invasiveness of ESCC cells. Finally, we found that CXCR4-CXCL12/AKT axis regulates RhoA, Rac-1, and Cdc42 to modulate cell invasion and tumor metastasis. Together, these results demonstrate a role for CXCR4 in ESCC metastasis and progression and suggest potential targets for therapeutic intervention. PMID- 26631034 TI - Genetic variation in vitamin D-related genes and risk of breast cancer among women of European and East Asian descent. AB - Studies of vitamin D-related genetic variants and breast cancer have been inconsistent. This study aimed to investigate associations of vitamin D-related polymorphisms and breast cancer risk among European and East Asian women and potential interactions with menopausal status and breast tumour subtypes. Data from a case-control study of breast cancer (1037 cases and 1050 controls) were used to assess relationships between 21 polymorphisms in two vitamin D-related genes (GC and VDR) and breast cancer risk. Odds ratios were calculated in stratified analyses of European and East Asian women, using logistic regression in an additive genetic model. An interaction term was used to explore modification by menopausal status. Polytomous regression was used to assess heterogeneity by breast tumour subtype. False discovery rate adjustments were conducted to account for multiple testing. No association was observed between GC or VDR polymorphisms and breast cancer risk. Modification of these relationships by menopausal status was observed for select polymorphisms in both Europeans (VDR rs4328262 and rs11168292) and East Asians (GC rs7041 and VDR rs11168287). Heterogeneity by tumour subtype was seen for three VDR polymorphisms (rs1544410, rs7967152 and rs2239186) among Europeans, in which associations with ER-/PR /HER2+ tumours, but not with other subtypes, were observed. In conclusion, associations between vitamin D-related genetic variants and breast cancer were not observed overall, although the relationships between vitamin D pathway polymorphisms and breast cancer may be modified by menopausal status and breast tumour subtype. PMID- 26631035 TI - Cooperative effect of BI-69A11 and celecoxib enhances radiosensitization by modulating DNA damage repair in colon carcinoma. AB - Amplification of PI3K-Akt pathway promotes radioresistance in various cancers including colorectal carcinoma. Local recurrence in colon cancer causes poor prognosis affecting overall survival of cancer-affected patient population. To avoid local recurrence, pre-operative or post-operative additional radiotherapy is given. However, main concern regarding radiotherapy is to increase the radiosensitivity of malignant cell without hampering the activities of normal cells. In this context, addition of two or more than two chemotherapeutic drugs as a radiosensitizer is a common practice in radiation biology. BI-69A11 earlier showed potential apoptosis-inducing effect in melanoma and colon carcinoma. Celecoxib showed anti-cancer effects in both COX-2 dependent and independent pathways and used to act as a radiosensitizing enhancer. Here, we suggest that the combination of BI-69A11 and celecoxib inhibits the phosphorylation of ataxia telangiectasia mutated (ATM) kinase and DNA-PK responsible for ionizing radiation (IR)-induced double-strand break (DSB) repair. Moreover, the combinatorial effect of BI-69A11 and celecoxib attenuates the IR-induced G2/M cell cycle arrest. Furthermore, this combination also impairs IR-induced activation of Akt and downstream targets of ATM. This might lead to induced activation of apoptotic pathway after triple therapy treatment modulating pro-apoptotic and anti apoptotic proteins. This activation of apoptotic pathway also showed the interdependence of PUMA and BAD in triple combination-treated colon cancer cells in a p53 independent manner. This study reveals the therapeutic potential of the triple combination therapy in prevention of radioresistance. Besides, it also demonstrates the cytotoxic effects of triple combination therapy in colon cancer. This study shows utility and potential implication on safety of the patients undergoing radiation therapy. PMID- 26631036 TI - The role of lysosome in cell death regulation. AB - Lysosome is a highly membrane-bound organelle which possesses a sequence of biological functions including protein degradation, cell signal transduction, plasma membrane repairment, homoeostasis, and autophagy. The lysosome contains more than 50 soluble acid hydrolases, and the acidification of lysosome is the most important biological characteristic. The integrity of lysosome is of vital importance. During the past few years, it was reported that the destabilization of lysosomal membrane can result in the release of lysosomal contents into cytosol and trigger cell death in a caspase-dependent or caspase-independent pathway. Lysosome functions at the late stage of autophagy and degrades cellular components delivered by autophagosome, which is a complicated process. The present article will summarize the current knowledge on the role of lysosome in cell death regulation and the underlying mechanisms. PMID- 26631037 TI - MicroRNA-17 family as novel biomarkers for cancer diagnosis: a meta-analysis based on 19 articles. AB - Cancer remains as the leading cause of death all over the world due to the lack of efficient diagnostic techniques and therapeutic methods. Many studies have reported the potential diagnostic value of microRNA-17 (miRNA-17, miR-17) family members as biomarkers for cancer detection. However, inconsistent results were revealed from a wide range of studies. As a result of this, a meta-analysis based on 19 studies was conducted to assess the diagnostic performance of miR-17 family for cancer detection. A total of 1772 patients with certain types of cancer and 1320 healthy controls were involved in these studies. The overall diagnostic accuracy was measured by the following: sensitivity, 0.67 (95 % confidence interval (CI) 0.60-0.74); specificity, 0.83 (95 % CI 0.74-0.85); positive likelihood ratio (PLR), 3.9 (95 % CI 2.6-5.9); negative likelihood ratio (NLR), 0.40 (95 % CI 0.34-0.48); and diagnostic odds ratio (DOR), 10 (95 % CI 6-16), respectively. Additionally, the pooled area under the summary receiver operator characteristic (SROC) curve (area under the curve (AUC)) was 0.79 (95 % CI 0.75 0.82), indicating a relatively low accuracy of miR-17 family as biomarkers for cancer detection. Subgroup analysis further showed that miR-17 family had more reliable performance in cancer diagnosis for Asian than that for Caucasian. Moreover, multiple miRNAs containing miR-17, -20a/b, and -93 reflected higher diagnostic accuracy than both miR-106a/b (single miRNA) and the overall miR-17 family assay. Therefore, appropriate combinations of miR-17 family may be used as non-invasive screening biomarkers for cancer, and it is necessary to carry out a large-scale population-based study to further assess the potential diagnostic value of miR-17 family. PMID- 26631038 TI - Prognostic significance of GPC5 expression in patients with prostate cancer. AB - The objective of this study was to evaluate the protein level of glypican-5 (GPC5) and its relationship with clinicopathologic significance in prostate cancer. The protein level of GPC5 in 160 prostate cancer tissues and 60 adjacent normal samples was examined by immunohistochemistry analysis, and the results were correlated with clinicopathologic parameters. The level of GPC5 in prostate cancer tissues was markedly lower than that in normal cases, especially in high risk prostate cancer. Additionally, the low expression of GPC5 was closely associated with increased serum prostate-specific antigen (PSA), higher Gleason scores, advanced tumor stage (T3), positive lymph node metastasis, and biochemical recurrence. Moreover, GPC5 low expression was an independent prognostic factor for overall survival of patients with prostate cancer. GPC5 protein expression showed a close correlation with the tumorigenesis and tumor progression of prostate cancer, and that might be applied as a novel biomarker for the prediction of diagnosis and prognosis of prostate cancer. PMID- 26631039 TI - H2.0-like homeobox 1 acts as a tumor suppressor in hepatocellular carcinoma. AB - H2.0-like homeobox 1 (HLX1) is a homeobox transcription factor gene expressed primarily in cytotrophoblast cell types in the early pregnancy human placenta and involved in the development of enteric nervous system. However, the biological function of HLX1 in hepatocellular carcinoma (HCC) remains unclear. In the present study, semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), quantitative real-time RT-PCR, western blot, and immunohistochemical staining were used to examine the expression level of HLX1 in a total of 125 cases of HCC tissues and their matched adjacent nontumorous tissues (ANLTs), and its correlation with clinical features of HCC patients was analyzed. Our findings showed that the expression level of HLX1 was significantly reduced in HCCs compared to ANLTs. Besides, it was also remarkably downregulated in HCC cell lines compared to normal liver cell line. We further found that the HLX1 level was significantly associated with the tumor size (p = 0.016), tumor number (p = 0.004), vascular invasion (p = 0.031), Edmondson-Steiner grade (p = 0.041), tumor node-metastasis (TNM) stage (p < 0.001), and Barcelona clinic liver cancer (BCLC) stage (p = 0.008). Moreover, HLX1 was an independent risk factor for overall survival (OS, p = 0.020) and disease-free survival (DFS, p = 0.024) of HCC patients. In vitro experiments showed that overexpression of HLX1 markedly suppressed the invasion, migration, proliferation, and colony formation of HCC cells; in contrast, downregulation of HLX1 significantly promoted the invasion, migration, proliferation, and colony formation of HCC cells. In vivo study indicated that overexpression of HLX1 significantly inhibited the tumorigenic capacity of HCC cells in nude mice. Based on these findings, we suggest that HLX1 acts as a tumor suppressor in HCC. PMID- 26631040 TI - The expression levels of the sirtuins in patients with BCC. AB - Basal cell carcinoma (BCC) is the most common tumor in humans. Reduced expression of sirtuins interferes with DNA repair, which may cause mutations and genomic instability, and eventually leads to tumor development. In the present study, we investigate the expression levels of SIRT genes in non-tumoral and tumor tissues of patients with BCC. A total of 27 patients (16 males, 11 females) with BCC were included in the study; the mean age was 65.40 +/- 10.74 years and mean follow-up was 2.5 +/- 0.5 years. There were multiple synchronous lesions in six patients, and the remaining 21 patients had a single lesion. Tumor and non-tumoral tissue samples were collected from all patients, and mRNA expression levels of SIRT1-7 (Sirt1.1, Sirt1.2, Sirt2, Sirt3, Sirt4, Sirt5, Sirt6, and Sirt7) were examined by real-time PCR. The results showed that expressions of SIRT1.1, SIRT1.2, SIRT4, SIRT5, SIRT6, and SIRT7 mRNAs were unchanged in tumor tissues of BCC patients compared with non-tumoral tissue samples. Importantly, the expressions of SIRT2 and SIRT3 mRNAs were significantly reduced in tumor tissue samples from BCC patients compared with non-tumoral tissues (P = 0.02 and P = 0.03, respectively). In light of the previous reports that have demonstrated a link between SIRT proteins and cancer, our findings suggest that SIRT2 and SIRT3 may plan important roles in BCC pathogenesis and could be candidate prognostic biomarkers for BCC. PMID- 26631041 TI - Anticancer function of alpha-solanine in lung adenocarcinoma cells by inducing microRNA-138 expression. AB - Currently, lung cancer is still a main cause of malignancy-associated death worldwide. Even though various methods for prevention and treatment of lung cancer have been improved in recent decades, the 5-year survival rate has remained very low. Insights into the anticancer function of small-molecule anticancer compounds have opened our visual field about cancer therapy. alpha Solanine has been well studied for its antitumor properties, but its effect in lung cancer and associated molecular mechanisms have not yet been evaluated. To explore the anticancer function of alpha-solanine, we performed an MTT assay, Transwell arrays, colony-forming survival assay, quantitative reverse transcription PCR (qRT-PCR), Western blotting, and dual luciferase reporter assays in A549 and H1299 cells. We found that alpha-solanine not only inhibited cell migration and invasion ability but also enhanced the chemosensitivity and radiosensitivity of A549 and H1299 cells. Moreover, we discovered that alpha solanine could affect the expression of miR-138 and focal adhesion kinase (FAK), both of which were also found to affect the chemosensitivity and radiosensitivity of A549 and H1299 cells. In conclusion, alpha-solanine could affect miR-138 and FAK expression to restrict cell migration and invasion and enhance the chemosensitivity and radiosensitivity of A549 and H1299 cells. The alpha solanine/miR-138/FAK cascade can probably be a potential therapy target against lung adenocarcinoma. PMID- 26631042 TI - miR-874 suppresses the proliferation and metastasis of osteosarcoma by targeting E2F3. AB - Increasing evidence indicates that microRNAs (miRNAs) play critical roles in osteosarcoma (OS) occurrence and development. MicroRNA-874 (miR-874) has proven to be dysregulated in several human cancers. However, the biological function and underlying molecular mechanism of miR-874 in OS remain unclear. In this study, we aimed to investigate the biological role and potential mechanism of miR-874 in OS. Here, we found that miR-874 expression was significantly decreased in OS cell lines and tissues by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and its expression was correlated with tumor-node-metastasis (TNM) stage, tumor size, and lymph node metastasis (all P < 0.01). Functional study revealed that overexpression of miR-874 in OS cells could remarkably inhibit proliferation, migration, and invasion and induce cell apoptosis. In addition, E2F transcription factor 3 (E2F3) was confirmed as a target of miR-874 in OS cells. E2F3 mRNA expression was upregulated and was inversely correlated with the level of miR-874 in OS tissues. Importantly, downregulation of E2F3 mimicked the effect of overexpression miR-874 in OS cells, and E2F3 overexpression partially attenuated the tumor-suppressive effects of miR-874 in OS cells. Taken together, these findings suggested that miR-874 might suppress the growth and metastasis of OS cells partially by targeting E2F3. PMID- 26631043 TI - MiR-195 inhibits the proliferation of human cervical cancer cells by directly targeting cyclin D1. AB - MicroRNAs are important regulators of multiple cellular processes, and aberrant miRNA expression has been observed in human cervical cancer (CC). The present study was to evaluate the level of miR-195 and cyclin D1 in CC tissues and cells. We further investigated the molecular mechanisms of miR-195 and cyclin D1 in CC cell lines HeLa and SiHa. Here, we found that miR-195 expression was down regulated in CC tissues, and HeLa and SiHa cells (all p < 0.001). By contrast, cyclin D1 was up-regulated. Furthermore, the expression of miR-195 was inversely proportional to that of cyclin D1 mRNA or protein (p = 0.013, p = 0.015, respectively). In vitro studies demonstrated that the overexpression of miR-195 played a suppressor role in the proliferation of HeLa and SiHa cells and promoted cell apoptosis. Luciferase reporter assays confirmed that miR-195 binding to the 3'-UTR regions of cyclin D1 inhibited the expression of cyclin D1 in HeLa and SiHa cells. However, the inhibitor of miR-195 promoted the expression of cyclin D1 and cell proliferation. In conclusion, our data suggest that miR-195 may have the potential role in treatment of CC patients, as well as miR-195 is a novel regulator of invasiveness and tumorigenicity in CC cells by targeting cyclin D1. MiR-195/cyclin D1 pathway may be a useful therapeutic agent in CC patients. PMID- 26631044 TI - Postmastectomy radiotherapy benefit in Chinese breast cancer patients with T1-T2 tumor and 1-3 positive axillary lymph nodes by molecular subtypes: an analysis of 1369 cases. AB - The aim of this study was to examine the association between molecular subtype (MST) and prognosis and research the postmastectomy radiotherapy (PMRT) effect in T1-T2 tumors with 1-3 positive axillary lymph nodes (ALNs). This retrospective study studied breast cancer patients with T1-T2 tumors and 1-3 positive ALNs according to MST: Luminal A, Luminal B, human epidermal growth factor receptor-2 (Her-2) positive, and Triple negative. The impact of adjuvant PMRT in T1-T2 tumors with 1-3 positive ALNs was also assessed. This study included 1369 patients: 33.0 % Luminal A, 42.9 % Luminal B, 11.9 % Her-2 positive, and 12.2 % Triple negative. On univariate and multivariate analyses, MST was associated with locoregional relapse (LRR). Kaplan-Meier analysis showed that PMRT significantly decreased LRR risk (p = 0.017) and distant metastasis (DM) risk (p < 0.0001). In subgroup analysis, PMRT showed significant benefits of improvement in LRR in patients with younger age, positive lymphovascular invasion (LVI), and ratio of positive lymph nodes (LNs) >25 %. Moreover, the nomogram could more accurately predict LRR (c-index 0.75) in T1-2N1 breast cancer patients. MST associated with patient outcomes in breast cancer patients with T1-T2 tumors and 1-3 positive ALN. It makes sense to offer PMRT for patients aged<40 years old, LVI, 2 and 3 positive lymph nodes, and ratio of positive LNs >25 %. PMID- 26631046 TI - [Pain and deterioration of vision following previous lens implantation]. PMID- 26631045 TI - MicroRNA-613 inhibited ovarian cancer cell proliferation and invasion by regulating KRAS. AB - MicroRNAs (miRNAs) play several important roles in carcinogenesis, and the dysregulation of miRNAs is associated with cancer progression. Little is known about the role of miR-613 in ovarian cancer. In the present study, we demonstrate that miR-613 expression is downregulated in human ovarian cancer cell lines and tissues. Additionally, miR-613 overexpression suppressed ovarian cancer cell proliferation, colony formation, and invasion. Furthermore, KRAS was identified as a target of miR-613. Reintroducing KRAS rescued the inhibitory effects exerted by miR-613 on ovarian cancer cell proliferation and invasion. Taken together, our findings suggest that miR-613 functions as a candidate tumor suppressor miRNA in ovarian cancer by directly targeting KRAS. To the best of our knowledge, this is the first study to show that miR-613 affects the proliferation and invasion of ovarian cancer. PMID- 26631047 TI - [International ophthalmology and travel medicine]. AB - Medical eye care in developing countries is very different from the situation in industrialized nations. In order to prevent rising numbers of blind people worldwide due to increased life expectancy and population growth, the global initiative Vision 2020 "The Right to Sight" was established in 1999. Coordinated initiatives are important as most causes of blindness are either preventable or curable (e.g. cataract surgery); however, due to a lack of resources eye care in developing countries cannot implement all necessary preventive and therapeutic measures at present. The epidemiology of causes of blindness and the situation of ophthalmic care are discussed. Because of increased mobility of people and goods (e.g. air travel and trucking), imported eye diseases are of increasing importance. The difference between travel medicine, which deals with the medical situation of travelers and international ophthalmology (i.e. diseases in tropical countries) is discussed and illustrated on the basis of several important disease patterns. PMID- 26631049 TI - Use of power of attorney in Scotland. AB - BACKGROUND AND AIMS: Power of Attorney as a form of surrogate decision making was introduced within the Adults with Incapacity, Scotland Act (2000) to help individuals who lack mental capacity due to illnesses like dementia. Even after a decade, little was known if it has been useful. We sought to find out how useful the power of attorney document has been so far in supporting people when they lose their capacity and identify any barriers. METHODS AND RESULTS: We did a survey and approached a random sample of 5000 attorneys in Scotland. A total of 1226 attorneys responded; 59% of the respondents had never used their powers but still considered it useful for 'peace of mind'. For the majority, the costs of arranging a power of attorney ranged in between L150 and L300. CONCLUSIONS: The study confirms that power of attorney is useful to safeguard interests of people when they lose capacity. Costs remain a big barrier. Further studies are required to understand the long-term impact of providing financial support to arrange a power of attorney at an early stage on reducing delayed discharges in hospitals. PMID- 26631048 TI - Benchmarking health system performance across regions in Uganda: a systematic analysis of levels and trends in key maternal and child health interventions, 1990-2011. AB - BACKGROUND: Globally, countries are increasingly prioritizing the reduction of health inequalities and provision of universal health coverage. While national benchmarking has become more common, such work at subnational levels is rare. The timely and rigorous measurement of local levels and trends in key health interventions and outcomes is vital to identifying areas of progress and detecting early signs of stalled or declining health system performance. Previous studies have yet to provide a comprehensive assessment of Uganda's maternal and child health (MCH) landscape at the subnational level. METHODS: By triangulating a number of different data sources - population censuses, household surveys, and administrative data - we generated regional estimates of 27 key MCH outcomes, interventions, and socioeconomic indicators from 1990 to 2011. After calculating source-specific estimates of intervention coverage, we used a two-step statistical model involving a mixed-effects linear model as an input to Gaussian process regression to produce regional-level trends. We also generated national level estimates and constructed an indicator of overall intervention coverage based on the average of 11 high-priority interventions. RESULTS: National estimates often veiled large differences in coverage levels and trends across Uganda's regions. Under-5 mortality declined dramatically, from 163 deaths per 1,000 live births in 1990 to 85 deaths per 1,000 live births in 2011, but a large gap between Kampala and the rest of the country persisted. Uganda rapidly scaled up a subset of interventions across regions, including household ownership of insecticide-treated nets, receipt of artemisinin-based combination therapies among children under 5, and pentavalent immunization. Conversely, most regions saw minimal increases, if not actual declines, in the coverage of indicators that required multiple contacts with the health system, such as four or more antenatal care visits, three doses of oral polio vaccine, and two doses of intermittent preventive therapy during pregnancy. Some of the regions with the lowest levels of overall intervention coverage in 1990, such as North and West Nile, saw marked progress by 2011; nonetheless, sizeable disparities remained between Kampala and the rest of the country. Countrywide, overall coverage increased from 40% in 1990 to 64% in 2011, but coverage in 2011 ranged from 57% to 70% across regions. CONCLUSIONS: The MCH landscape in Uganda has, for the most part, improved between 1990 and 2011. Subnational benchmarking quantified the persistence of geographic health inequalities and identified regions in need of additional health systems strengthening. The tracking and analysis of subnational health trends should be conducted regularly to better guide policy decisions and strengthen responsiveness to local health needs. PMID- 26631051 TI - Iodine Status in Pregnant Women, Lactating Mothers, and Newborns in an Area with More Than Two Decades of Successful Iodine Nutrition. AB - Pregnant women, lactating mothers, and their newborns constitute the target population for prevention and control of iodine deficiency. Hence, the aim of this study was to evaluate the iodine nutrition status among these vulnerable groups in an area with more than two decades of successful elimination of iodine deficiency. In this cross-sectional study conducted in health care centers of Tehran, 100 pregnant women and 84 lactating mothers and their newborn were randomly selected. Urinary iodine concentration and iodine content of salts were measured using the Sandell-Kolthoff and titration methods, respectively. Urinary iodine concentration <150 MUg/L for pregnant women and <100 MUg/L for lactating mothers and newborns was considered as iodine nutrition inadequacy, respectively. Median (interquartile range [IQR]) urinary iodine concentration (UIC) was 103 (59 155) MUg/L in pregnant women, 77 (42-194) MUg/L in lactating mothers, and 198 (84 260) MUg/L in newborns. Median (IQR) iodine content of salt was 26 (21-30) ppm and 25 (18-28) ppm in pregnant women and lactating mothers, respectively (P = 0.462). Iodine content of salt was significantly correlated with UIC of pregnant women (r = 0.24, P = 0.019), but no correlation was found among lactating mothers (r = 0.12, P = 0.316). Neonatal UIC was significantly correlated with iodine content of salt consumed by their mothers (r = 0.49, P = 0.001). Despite suboptimal iodine status among subgroups of Tehranian pregnant and lactating women, iodine nutrition status of newborns was within optimal levels, which may be explained by a compensatory mechanism in the mammary glands. PMID- 26631050 TI - Administration of granulocyte-colony stimulating factor accompanied with a balanced diet improves cardiac function alterations induced by high fat diet in mice. AB - BACKGROUND/OBJECTIVES: High fat diet (HFD) is a major contributor to the development of obesity and cardiovascular diseases due to the induction of cardiac structural and hemodynamic abnormalities. We used a model of diabetic cardiomyopathy in C57Bl/6 mice fed with a HFD to investigate the effects of granulocyte-colony stimulating factor (G-CSF), a cytokine known for its beneficial effects in the heart, on cardiac anatomical and functional abnormalities associated with obesity and type 2 diabetes. METHODS: Groups of C57Bl/6 mice were fed with standard diet (n = 8) or HFD (n = 16). After 36 weeks, HFD animals were divided into a group treated with G-CSF + standard diet (n = 8) and a vehicle control group + standard diet (n = 8). Cardiac structure and function were assessed by electrocardiography, echocardiography and treadmill tests, in addition to the evaluation of body weight, fasting glicemia, insulin and glucose tolerance at different time points. Histological analyses were performed in the heart tissue. RESULTS: HFD consumption induced metabolic alterations characteristic of type 2 diabetes and obesity, as well as cardiac fibrosis and reduced exercise capacity. Upon returning to a standard diet, obese mice body weight returned to non-obese levels. G-CSF administration accelerated the reduction in of body weight in obese mice. Additionally, G-CSF treatment reduced insulin levels, diminished heart fibrosis, increased exercise capacity and reversed cardiac alterations, including bradycardia, elevated QRS amplitude, augmented P amplitude, increased septal wall thickness, left ventricular posterior thickening and cardiac output reduction. CONCLUSION: Our results indicate that G-CSF administration caused beneficial effects on obesity associated cardiac impairment. PMID- 26631052 TI - Cadmium Levels in Tissue and Plasma as a Risk Factor for Prostate Carcinoma: a Meta-Analysis. AB - Cadmium is a heavy metal that has been suggested to be a carcinogen by evidence. A number of published studies have investigated the association between cadmium levels and prostate cancer, but the results were inconsistent. Thus, we conducted a meta-analysis to get a precise estimate of this subject. After a careful searching and screening, a total of 11 publications containing 14 separated studies were included. Based on a random-effect model, the pooled data showed that cadmium levels of prostate tissues (standard mean difference (SMD) = 3.17, 95 % confidence interval (CI) = 0.60-5.74, P < 0.05) and plasma (SMD = 4.07, 95 % CI = 2.01-6.13, P < 0.05) were significantly higher in prostate cancer patients than those in the healthy controls. No difference of hair and nail cadmium levels between the prostate cancer cases and the controls was found. The data suggested that cadmium exposure might exert an influence on the tumorigenesis of prostate tissues. Future investigations with large sample sizes are needed to verify the results. PMID- 26631053 TI - Selenium Deficiency Mainly Influences Antioxidant Selenoproteins Expression in Broiler Immune Organs. AB - Selenoprotein has many functions in chicken, and the expression of selenoproteins is closely associated with the selenium (Se) level. However, little is known about the expression patterns of selenoproteins in chicken immune organs. Here, we investigated the effect of dietary Se deficiency on the expressions of 23 selenoproteins in broiler immune organs. In this study, 150 broilers were randomly divided into two groups (75 chickens per group). The chickens were maintained either on a diet supplemented with Se through the addition of 0.2 mg/kg of Se (C group) via sodium selenite or on a Se-deficient granulated diet (L group) until the broilers exhibited an onset of exudative diathesis (ED). Following euthanasia, the samples from the immune tissues (including the spleen, thymus, and bursa of Fabricius) were quickly collected, and the messenger RNA (mRNA) expression levels of 23 selenoproteins were examined by real-time quantitative PCR and analyzed using principal component analysis. The results showed that Se deficiency decreased the mRNA levels of 23 selenoproteins in the thymus, spleen, and bursa of the Fabricius tissues of broiler chickens. Furthermore, we found that among 23 selenoproteins, the mRNA levels of Dio1 in the thymus, Txnrd2 in the spleen, and Txnrd3 in the bursa of Fabricius decreased significantly (90.9 %, 83.3 %, and 96.8 %, respectively). In addition, the principal component analysis (PCA) results suggested that Se deficiency mainly influenced the expression of antioxidative selenoproteins, especially glutathione peroxidases (Gpxs), thioredoxin reductases (Txnrds), and iodothyronine deiodinases (Dios) in chicken immune organs. The results of this study are valuable for understanding the relevance of selenoprotein activity in vivo. PMID- 26631054 TI - Influence of Dietary Copper on Serum Growth-Related Hormone Levels and Growth Performance of Weanling Pigs. AB - To investigate the effect of dietary copper on serum growth-related hormones levels and growth performance, a total of 60 weanling pigs were randomly assigned to six groups each containing 10 pigs, fed on basal diets supplemented with 0 (control), 100, 150, 200, 250, and 300 mg/kg copper sulfate for 80 days, respectively. The average daily gain (ADG), feed to gain ratio (F/G), feed intake and serum growth hormone (GH), insulin (INS), insulin-like growth factor 1 (IGF 1), and insulin-like growth factor-binding protein 3 (IGFBP-3) levels were detected at interval of 20 days. The results revealed that ADG, and serum GH, INS, IGF-1, and IGFBP-3 concentrations were increased significantly in the pigs fed on diets added with 100, 150, 200, 250, and 300 mg/kg copper sulfate. Meanwhile, in the pigs supplemented with 250 mg/kg copper sulfate, ADG was increased significantly from the 40th to the 60th day of the experiment (P < 0.01), and the levels of GH, INS, IGF-1, and IGFBP-3 in serum were elevated significantly from the 20th to the 40th day of the experiment (P < 0.01). It is concluded that effects of copper supplemented in the diet on the growth of pigs were related to the increasing levels of GH, INS, IGF-1, and IGFBP-3 in serum which were induced by copper. High dietary copper increase the concentrations of growth-related hormones in serum, resulting in improving the growth performance of weanling pigs. PMID- 26631055 TI - Risk factors for hospital admission in the 28 days following a community-acquired pneumonia diagnosis in older adults, and their contribution to increasing hospitalisation rates over time: a cohort study. AB - OBJECTIVES: To determine factors associated with hospitalisation after community acquired pneumonia (CAP) among older adults in England, and to investigate how these factors have contributed to increasing hospitalisations over time. DESIGN: Cohort study. SETTING: Primary and secondary care in England. POPULATION: 39,211 individuals from the Clinical Practice Research Datalink, who were eligible for linkage to Hospital Episode Statistics and mortality data, were aged >= 65 and had at least 1 CAP episode between April 1998 and March 2011. MAIN OUTCOME MEASURES: The association between hospitalisation within 28 days of CAP diagnosis (a 'post-CAP' hospitalisation) and a wide range of comorbidities, frailty factors, medications and vaccinations. We examined the role of these factors in post-CAP hospitalisation trends. We also looked at trends in post-CAP mortality and length of hospitalisation over the study period. RESULTS: 14 comorbidities, 5 frailty factors and 4 medications/vaccinations were associated with hospitalisation (of 18, 12 and 7 considered, respectively). Factors such as chronic lung disease, severe renal disease and diabetes were associated with increased likelihood of hospitalisation, whereas factors such as recent influenza vaccination and a recent antibiotic prescription decreased the odds of hospitalisation. Despite adjusting for these and other factors, the average predicted probability of hospitalisation after CAP rose markedly from 57% (1998 2000) to 86% (2009-2010). Duration of hospitalisation and 28-day mortality decreased over the study period. CONCLUSIONS: The risk factors we describe enable identification of patients at increased likelihood of post-CAP hospitalisation and thus in need of proactive case management. Our analyses also provide evidence that while comorbidities and frailty factors contributed to increasing post-CAP hospitalisations in recent years, the trend appears to be largely driven by changes in service provision and patient behaviour. PMID- 26631056 TI - [Congenital erythropoietic porphyria : An update]. AB - BACKGROUND: Congenital erythropoetic porphria is a very rare type of autosomal recessive nonacute porphyria. Homozygous or compound heterozygous mutations in the uroporphyrinogen III consynthase gene cause a marked enzymatic deficiency of uroporphyrinogen III consynthase, the fourth enzyme along the heme biosynthetic pathway. CLINICAL PRESENTATION: Clinically, affected patients are characterized by a moderate to severe photosensitivity. Starting early in infancy, they develop blisters, erosions, and exulcerations in sun-exposed areas of the body, often resulting in scar formation and mutilation. Besides the cutaneous changes, hemolytic anemia, transfusion-dependent pancytopenia, hepatosplenomegaly and liver cirrhosis can occur. Due to increased susceptibility for infections and because of the hematological and hepatic complications, affected individuals have a decreased life expectancy, rarely exceeding 40 years of age. TREATMENT: Currently, no causal treatment is available for the disorder. Therefore, the most important therapeutic modality is strict avoidance of sunlight, preferably by inversion of the day-night rhythm, or at least consequent photoprotection with adequate clothing. In severe cases, bone marrow or stem cell transplantation should be considered. PMID- 26631057 TI - Salivary microflora and mode of delivery: a prospective case control study. AB - BACKGROUND: Previous cross-sectional studies have suggested that the mode of delivery can influence the composition of oral microflora. The aim of this prospective study was to compare the salivary colonization in vaginally delivered children with children delivered by Caesarian section (C-section) during their first 6 months of life. METHODS: The study group consisted of 149 consecutively enrolled infants, delivered either vaginally (n = 96) or by C-section (n = 53) that volunteered after consent of their parents. Saliva samples were collected within 2 days after birth and then after 1, 3, and 6 months. A saliva sample from the mothers was obtained 6 months after delivery. The parents were asked to complete a questionnaire on socioeconomic factors, lifestyle, and hygiene at baseline and throughout the study period. All samples were analyzed with 13 pre determined bacterial probes using checkerboard DNA-DNA hybridization. RESULTS: The groups were balanced at baseline concerning all relevant background factors. Gram-positive streptococci (S. mitis, S. salivarius) displayed the highest counts in both groups but a greater diversity was observed in the vaginally delivered group. A. naeslundi, A. odontolytics, F. nucleatum and L. salivarius were only detected among the vaginally delivered infants. The prevalence of S. sanguinis, S. gordoni, R. denticariosa, and B. dentinum increased by age in both groups but the prevalence was significantly lower in the C-section group (p < 0.05). There was a link between the mothers and their offspring's concerning the salivary microbial profile. CONCLUSION: The microbial composition in saliva differs by the mode of delivery during the first six months of life. PMID- 26631058 TI - Effects of omega-3 fatty acids on arterial stiffness in patients with hypertension: a randomized pilot study. AB - BACKGROUND: Omega-3 fatty acids prevent cardiovascular disease (CVD) events in patients with myocardial infarction or heart failure. Benefits in patients without overt CVD have not been demonstrated, though most studies did not use treatment doses (3.36 g) of omega-3 fatty acids. Arterial stiffness measured by pulse wave velocity (PWV) predicts CVD events independent of standard risk factors. However, no therapy has been shown to reduce PWV in a blood pressure independent manner. We assessed the effects of esterified omega-3 fatty acids on PWV and serum markers of inflammation among patients with hypertension. DESIGN AND METHODS: We performed a prospective, randomized; double-blinded pilot study of omega-3 fatty acids among 62 patients in an urban, safety net hospital. Patients received 3.36 g of omega-3 fatty acids vs. matched placebo daily for 3 months. The principal outcome measure was change in brachial-ankle PWV. Serum inflammatory markers associated with CVD risk were also assessed. RESULTS: The majority (71 %) were of Latino ethnicity. After 3-months, mean change in arterial PWV among omega-3 and placebo groups was -97 cm/s vs. -33 cm/s respectively (p = 0.36 for difference, after multivariate adjustment for baseline age, systolic blood pressure, and serum adiponectin). Non-significant reductions in lipoprotein associated phospholipase A2 (LpPLA2) mass and high sensitivity C-reactive protein (hsCRP) relative to placebo were also observed (p = 0.08, and 0.21, respectively). CONCLUSION: High-dose omega-3 fatty acids did not reduce arterial PWV or markers of inflammation among patients within a Latino-predominant population with hypertension. CLINICAL TRIAL REGISTRATION: NCT00935766 , registered July 8 2009. PMID- 26631059 TI - Effect of intervention using a messaging app on compliance and duration of treatment in orthodontic patients. AB - OBJECTIVES: This study aims to determine the effectiveness of a messaging app (WeChat) in improving patients' compliance and reducing the duration of orthodontic treatment (DOT). MATERIALS AND METHODS: A randomized controlled trial was performed in a dental hospital and a clinic from August 2012 to May 2015. Orthodontic patients were included at the beginning of treatment. Patients with multiphase treatment or braceless technique were excluded. Participants were randomized to WeChat group (received regular reminders and educational messages) or control group (received conventional management) and were followed up until the treatment was completed. Primary outcome measure was DOT. Others were late and failed attendance, bracket bond failure, and oral hygiene condition. RESULTS: One hundred twelve patients in each group participated and completed the trial. DOT in WeChat group were 7.3 weeks shorter (P = 0.007). There were less failed attendance (3.1 vs. 10.9 %, P < 0.001), late attendance (20.1 vs. 29.9 %, P < 0.001), and bracket bond failure (11.8 vs. 16.1 %, P < 0.001) in WeChat group than control. There was no difference in orthodontic plaque index nor modified gingivitis index between the two groups before and after treatment. Number of failed attendances was identified as an independent factor affecting DOT (P = 0.004; HR = 0.89, 95 % CI 0.84 to 0.95). CONCLUSIONS: The intervention with WeChat is effective in reducing the treatment duration and bracket bond failure, and improving the attendance in orthodontic patients. CLINICAL RELEVANCE: DOT can be reduced by improving patient's compliance. The messaging app is useful for outpatient education and management. PMID- 26631060 TI - Effect of mold type, diameter, and uncured composite removal method on depth of cure. AB - OBJECTIVE: This study compared the effects of mold material and diameter on the thickness of cured composite remnants and depth of cure (DOC) of resin-based composites (RBC). MATERIAL AND METHODS: One Polywave(r) curing light was used to photo-cure two shades of the same "bulk-fill" RBC in 4, 6, or 10-mm internal diameter metal or white Delrin(r) molds. For 60 specimens, the uncured RBC was manually scraped away as described in the ISO 4049 depth of cure test. The remaining 60 specimens were immersed in tetrahydrofuran for 48 hours in the dark. Maximum lengths of remaining hard RBC and their DOC values were compared using analysis of variance (ANOVA) and Tukey-Kramer post hoc multiple comparison tests (alpha = 0.05). RESULTS: Specimen thickness and DOC were always greater using the white Delrin(r) molds compared to metal molds (p < 0.001). Increase in mold diameter significantly increased specimen thickness and DOC when made in the metal molds and in the 6-mm diameter Delrin(r) molds (p < 0.01). Increasing the diameter of the Delrin(r) molds to 10-mm did not increase specimen thickness or DOC. Sectioning and staining of specimens revealed an internal, peripheral transition zone of porous RBC in the solvent-dissolved specimens only. CONCLUSION: Mold material and internal diameter significantly influenced cured composite remnant thickness as well as depth of cure. The existence of an outer region of RBC that is hard, yet susceptible to solvent dissolution, requires further investigation. CLINICAL RELEVANCE: The depth of cure results obtained from a 4-mm diameter metal mold may not represent the true potential for evaluating composite depth of cure. A universally acceptable mold material and diameter size need to be established if this type of testing is to be useful for evaluating the relative performance of a given type of LCU and RBC. PMID- 26631061 TI - Contrast-free detection of myocardial fibrosis in hypertrophic cardiomyopathy patients with diffusion-weighted cardiovascular magnetic resonance. AB - BACKGROUNDS: Previous studies have shown that diffusion-weighted cardiovascular magnetic resonance (DW-CMR) is highly sensitive to replacement fibrosis of chronic myocardial infarction. Despite this sensitivity to myocardial infarction, DW-CMR has not been established as a method to detect diffuse myocardial fibrosis. We propose the application of a recently developed DW-CMR technique to detect diffuse myocardial fibrosis in hypertrophic cardiomyopathy (HCM) patients and compare its performance with established CMR techniques. METHODS: HCM patients (N = 23) were recruited and scanned with the following protocol: standard morphological localizers, DW-CMR, extracellular volume (ECV) CMR, and late gadolinium enhanced (LGE) imaging for reference. Apparent diffusion coefficient (ADC) and ECV maps were segmented into 6 American Heart Association (AHA) segments. Positive regions for myocardial fibrosis were defined as: ADC > 2.0 MUm(2)/ms and ECV > 30%. Fibrotic and non-fibrotic mean ADC and ECV values were compared as well as ADC-derived and ECV-derived fibrosis burden. In addition, fibrosis regional detection was compared between ADC and ECV calculating sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) using ECV as the gold-standard reference. RESULTS: ADC (2.4 +/- 0.2 MUm(2)/ms) of fibrotic regions (ADC > 2.0 MUm(2)/ms) was significantly (p < 0.01) higher than ADC (1.5 +/- 0.2 MUm(2)/ms) of non fibrotic regions. Similarly, ECV (35 +/- 4%) of fibrotic regions (ECV > 30%) was significantly (p < 0.01) higher than ECV (26 +/- 2%) of non-fibrotic regions. In fibrotic regions defined by ECV, ADC (2.2 +/- 0.3 MUm(2)/ms) was again significantly (p < 0.05) higher than ADC (1.6 +/- 0.3 MUm(2)/ms) of non-fibrotic regions. In fibrotic regions defined by ADC criterion, ECV (34 +/- 5%) was significantly (p < 0.01) higher than ECV (28 +/- 3%) in non-fibrotic regions. ADC derived and ECV-derived fibrosis burdens were in substantial agreement (intra class correlation = 0.83). Regional detection between ADC and ECV of diffuse fibrosis yielded substantial agreement (kappa = 0.66) with high sensitivity, specificity, PPV, NPV, and accuracy (0.80, 0.85, 0.81, 0.85, and 0.83, respectively). CONCLUSION: DW-CMR is sensitive to diffuse myocardial fibrosis and is capable of characterizing the extent of fibrosis in HCM patients. PMID- 26631062 TI - Concomitant administration of rifampicin and oxcarbazepine results in a significant decrease of the active MHD metabolite of oxcarbazepine. PMID- 26631064 TI - Difference in resistance to Salmonella enteritidis infection among allelic variants of TLR4 (903, 1832) in SPF chickens. PMID- 26631063 TI - Loss of function of myosin chaperones triggers Hsf1-mediated transcriptional response in skeletal muscle cells. AB - BACKGROUND: Mutations in myosin chaperones Unc45b and Hsp90aa1.1 as well as in the Unc45b-binding protein Smyd1b impair formation of myofibrils in skeletal muscle and lead to the accumulation of misfolded myosin. The concomitant transcriptional response involves up-regulation of the three genes encoding these proteins, as well as genes involved in muscle development. The transcriptional up regulation of unc45b, hsp90aa1.1 and smyd1b is specific to zebrafish mutants with myosin folding defects, and is not triggered in other zebrafish myopathy models. RESULTS: By dissecting the promoter of unc45b, we identify a Heat shock factor 1 (Hsf1) binding element as a mediator of unc45b up-regulation in myofibers lacking myosin folding proteins. Loss-of-function of Hsf1 abolishes unc45b up-regulation in mutants with defects in myosin folding. CONCLUSIONS: Taken together, our data show that skeletal muscle cells respond to defective myosin chaperones with a complex gene program and suggest that this response is mediated by Hsf1 activation. PMID- 26631065 TI - Transient Neonatal Diabetes Mellitus followed by recurrent asymptomatic hypoglycaemia: a case report. AB - BACKGROUND: Transient Neonatal Diabetes Mellitus is the commonest cause of diabetes presenting in the first week of life. Majority of infants recover by 3 months of age but are predisposed to developing type 2 diabetes later on in life. This condition is usually due to genetic aberrations at the 6q24 gene locus, and can be sporadic or inherited. This disorder has three phases: neonatal diabetes, apparent remission, relapse of diabetes. CASE PRESENTATION: Our case, a neonate presented with low birth weight and growth retardation along with the metabolic profile consistent with transient diabetes mellitus at birth. We report a novel clinical observation of recurrent asymptomatic hypoglycaemia detected on pre-feed blood glucose level monitoring in our case with transient neonatal diabetes mellitus at 6 weeks of age, 4 weeks after the remission of diabetes mellitus. CONCLUSION: This case demonstrates that neonates in remission following transient diabetes mellitus can present with recurrent asymptomatic hypoglycaemia without any other obvious congenital malformations seen. This asymptomatic hypoglycaemia may persist for weeks and may be missed if pre-feed blood glucose level monitoring is not done in these infants. Also, these infants may require an aggressive enteral feeding regimen with high glucose delivery rate to maintain normoglycemia. PMID- 26631066 TI - Predictive validity of a two-step tool to map frailty in primary care. AB - BACKGROUND: EASY-Care Two step Older people Screening (EASY-Care TOS) is a stepped approach to identify frail older people at risk for negative health outcomes in primary care, and makes use of General Practitioners' (GPs) readily available information. We aimed to determine the predictive value of EASY-Care TOS for negative health outcomes within the year from assessment. METHODS: A total of 587 patients of four GP practices in and around Nijmegen (The Netherlands) consented to participate in a longitudinal primary care registry based cohort study. Participants' frailty was judged by their GP following the EASY-Care TOS procedure and by a Comprehensive Geriatric Assessment (CGA) at baseline. After one year health outcomes of the participants were measured by reassessment with the EASY-Care TOS procedure. RESULTS: Follow up information was available for 520 of 587 participants. In the non-frail group 9% showed any negative health outcomes (death, ADL decline, institutionalisation, too ill to undergo assessment), against 30% in the frail group (95% confidence interval of the difference (CI): 14%-28%). Area under the receiver operating curve (AUC) of the EASY-Care TOS frailty judgement for a composite of negative health outcomes mentioned was 0.67 (95% CI: 0.62-0.73). Compared with discrimination on the basis of age, sex and GP practice (AUC 0.70), adding EASY-Care TOS frailty judgement increased the AUC to 0.75 (+0.05, p = 0.02). The AUC on the basis of a full CGA is almost comparable to the AUC of the model with age, sex, and frailty judgement with EASY-Care TOS: 0.76 (+0.07, p = 0.005). CONCLUSIONS: GPs applying the EASY Care TOS procedure, where they only perform additional assessment when they judge this as necessary, can predict negative health outcomes in their older populations efficiently and almost as accurately as a complete specialist CGA. PMID- 26631067 TI - Estradiol via estrogen receptor beta inhibits chondrogenesis of mouse vertebral growth plate in vitro. AB - PURPOSE: Abnormal growth of vertebral growth plate (VGP) was considered as one of the etiologic factors in adolescent idiopathic scoliosis (AIS). Previous studies described that estrogen played an important role in the pathogenesis of AIS. The present study was aimed to investigate the effect of estrogen/estrogen receptor axis on mouse VGP chondrocytes in vitro. METHODS: Chondrocytes were isolated from mouse VGP and treated with or without 17beta-estradiol (E2). Cell proliferation was measured by the cell growth rate assay. Gene expression of collagen type II and aggrecan were evaluated by real-time PCR. Expression of the proliferating cell nuclear antigen (PCNA), Sox9, and Smad4 were detected by Western blotting. RESULTS: Estradiol inhibited the proliferation of VGP chondrocytes and the gene expression of collagen type II and aggrecan and downregulated the protein expression of PCNA, Sox9, and Smad4. In addition, the inhibitory effect of estradiol was reversed by ERbeta small interfering RNA (siRNA) or PHTPP, an ERbeta antagonist. CONCLUSIONS: Estradiol via estrogen/estrogen receptor beta axis inhibits the proliferation and differentiation of VGP chondrocytes, which might give some new insight into the regulatory mechanism of bone development. PMID- 26631068 TI - Acculturation is associated with left ventricular mass in a multiethnic sample: the Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND: Acculturation involves stress-related processes and health behavioral changes, which may have an effect on left ventricular (LV) mass, a risk factor for cardiovascular disease (CVD). We examined the relationship between acculturation and LV mass in a multiethnic cohort of White, African-American, Hispanic and Chinese subjects. METHODS: Cardiac magnetic resonance assessment was available for 5004 men and women, free of clinical CVD at baseline. Left ventricular mass index was evaluated as LV mass indexed by body surface area. Acculturation was characterized based on language spoken at home, place of birth and length of stay in the United States (U.S.), and a summary acculturation score ranging from 0 = least acculturated to 5 = most acculturated. Mean LV mass index adjusted for traditional CVD risk factors was compared across acculturation levels. RESULTS: Unadjusted mean LV mass index was 78.0 +/- 16.3 g/m(2). In adjusted analyses, speaking exclusively English at home compared to non-English language was associated with higher LV mass index (81.3 +/- 0.4 g/m(2) vs 79.9 +/ 0.5 g/m(2), p = 0.02). Among foreign-born participants, having lived in the U.S. for >= 20 years compared to < 10 years was associated with greater LV mass index (81.6 +/- 0.7 g/m(2) vs 79.5 +/- 1.1 g/m(2), p = 0.02). Compared to those with the lowest acculturation score, those with the highest score had greater LV mass index (78.9 +/- 1.1 g/m(2) vs 81.1 +/- 0.4 g/m(2), p = 0.002). There was heterogeneity in which measure of acculturation was associated with LV mass index across ethnic groups. CONCLUSIONS: Greater acculturation is associated with increased LV mass index in this multiethnic cohort. Acculturation may involve stress-related processes as well as behavioral changes with a negative effect on cardiovascular health. PMID- 26631069 TI - Autoantibodies and their Judicious Use in Pediatric Rheumatology Practice. AB - Autoantibody testing forms an important part of diagnostic workup of patients in Pediatric rheumatology practice. However it is important to understand that the mere presence of autoantibodies does not necessarily mean the presence of an underlying autoimmune disease. Autoantibodies may be present decades before the development of clinical manifestations of an autoimmune disease and may be viewed as harbingers of Autoimmune disease. On the other hand, low-affinity autoantibodies may be present in normal healthy individuals; these natural autoantibodies serve an important function in immune regulation and tolerance. Autoantibody testing in pediatric practice mainly includes testing for anti nuclear antibodies, anti-dsDNA antibodies, anti-neutrophil cytoplasmic autoantibodies and antiphospholipid antibodies. Rheumatoid factor and anti-CCP do not have much significance in the diagnostic schema in pediatric rheumatology, except perhaps for classification of juvenile idiopathic arthritis (JIA) and prognostication in late-onset polyarticular JIA. The positive predictive value (PPV) of any laboratory test depends on the prevalence of the disease in the population being tested. Hence, test ordering practices greatly impact the performance characteristics and positive predictive value of any laboratory test. A restricted test ordering only in patients with clinical signs and symptoms suggestive of autoimmune disease would thus greatly increase the PPV of tests such as antinuclear antibody used for diagnosing autoimmunity. PMID- 26631070 TI - Recurrent Fusions in MYB and MYBL1 Define a Common, Transcription Factor-Driven Oncogenic Pathway in Salivary Gland Adenoid Cystic Carcinoma. AB - Adenoid cystic carcinoma (ACC), the second most common malignancy of salivary glands, is a rare tumor with a bleak prognosis for which therapeutic targets are unavailable. We used RNA sequencing (RNA-seq) to analyze low-quality RNA from archival, formaldehyde-fixed, paraffin-embedded samples. In addition to detecting the most common ACC translocation, t(6;9) fusing the MYB proto-oncogene to NFIB, we also detected previously unknown t(8;9) and t(8;14) translocations fusing the MYBL1 gene to the NFIB and RAD51B genes, respectively. RNA-seq provided information about gene fusions, alternative RNA splicing, and gene expression signatures. Interestingly, tumors with MYB and MYBL1 translocations displayed similar gene expression profiles, and the combined MYB and MYBL1 expression correlated with outcome, suggesting that the related MYB proteins are interchangeable oncogenic drivers in ACC. Our results provide important details about the biology of ACC and illustrate how archival tissue samples can be used for detailed molecular analyses of rare tumors. SIGNIFICANCE: Using RNA-seq to perform whole-transcriptome analysis of archival ACC tumor samples, we identified novel, recurrent gene fusions, detected alternative RNA splicing, and established gene expression signatures that provide detailed information about the biology of ACC tumors. PMID- 26631071 TI - Fine needle aspiration cytology of lymph nodes in breast cancer follow-up is a feasible alternative to watchful waiting and to histology. AB - BACKGROUND: Early detection of loco-regional breast cancer recurrence improves patients' overall survival, as treatment can be initiated or active treatment can be changed. If a suspicious lymph node is diagnosed during a follow-up exam, surgical excision is often performed. The aim of this study was to evaluate the diagnostic performance of the minor invasive ultrasound-guided fine-needle aspiration cytology (FNAC) in sonomorphologically suspicious lymph nodes in breast cancer follow-up. METHODS: Between April 2010 and November 2012, we performed ultrasound-guided FNAC in 38 sonographically suspicious lymph nodes of 37 breast cancer follow-up patients. Cytological specimens were evaluated if the sample material was sufficient for diagnosis and if they contained cancer cells. Patients with negative cytology were followed up clinically and sonographically. To evaluate the diagnostic performance we calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for physical examination, the different sonomorphological malignancy criteria and FNAC. RESULTS: In 36/38 (94.7 %) lymph nodes, the pathologist had enough material to establish a final diagnosis; in 2/38 (5.3 %) lymph nodes, the probe material was non-evaluable during cytology, these 2 were excluded from further statistical evaluation. Cytology revealed malignancy in 21 lymph nodes and showed no evidence for malignancy in 15 lymph nodes. There was no evidence for malignant disease in follow-up exams in the 15 cytologically benign lymph nodes with an average follow up time of 3 years. The diagnostic performances of physical examination and FNAC were: Sensitivity 52/100 %, specificity 88/100 %, PPV 85/100 %, NPV 60/100 %, respectively. CONCLUSIONS: Our preliminary results show that FNAC is a safe and fast diagnostic approach for the evaluation of suspicious lymph nodes in the follow-up of patients with breast cancer and, thus, together with follow-up represents a feasible alternative to surgery. PMID- 26631072 TI - Theoretical study of tautomers and photoisomers of avobenzone by DFT methods. AB - Organic ultraviolet (UV) filters such as cinnamates, benzophenones, p aminobenzoic derivatives, and avobenzone (which have well-established and recognized UV-filtering efficacies) are employed in cosmetic/pharmaceutical products to minimize the harm caused by exposure of the skin to sunlight. In this study, a detailed investigation of the photostability and tautomerism mechanisms of avobenzone was performed utilizing DFT methods. The UV spectral profile of avobenzone was also simulated, and the results showed good agreement with experimental data. Furthermore, the calculations were able to distinguish tautomers and photoisomers of the studied organic filter based on their properties, thus showing the potential to develop new organic UV filters. Graphical Abstract Theoretical studies of avobenzone and its tautomers by TD-DFT. PMID- 26631073 TI - Theoretical investigations of the electronic structures of carbazole-based triphenylphosphine oxide derivatives, potential bipolar host materials in blue phosphorescent devices. AB - Density functional theory calculations were performed to investigate the electronic structures of bipolar host materials comprising a backbone of linked acceptor moieties where each acceptor was also linked to a pendant donor moiety. The acceptor was triphenylphosphine oxide with two of its phenyls substituted with fluorine atoms or nitrile groups (CN). The donor was carbazole (CZ) substituted, or not, with t-butyl groups. The HOMO and LUMO energy levels of these host molecules were mainly influenced by their respective hole- and electron-transport units. The t-butyl substituents on the CZ moieties had an adverse effect on the triplet energies (E T) of the host molecules, especially for molecules where the phenyls of the backbone chain were substituted with CN groups. While introducing CN substituents onto the backbone chain decreased the energy difference between the lowest singlet and triplet excited states (DeltaE ST), it also caused the energy gap between the HOMO and LUMO to narrow. Among the host molecules investigated, that in which one of the phenyls in the acceptor moiety was linked to the donor while the other two phenyls in the acceptor were substituted with CN substituents exhibited the highest E T, balanced charge transport, a low charge-injection barrier, and a small DeltaE ST, and is therefore a promising candidate host material for use in blue-phosphorescent devices. Graphical Abstract Density functional theory calculations were performed to explore the electronic properties of bipolar host materials comprising a backbone of linked acceptor moieties where each acceptor was also linked to a pendant donor moiety. All of the designed molecules with high triplet energies were found to be suitable for use as host materials when matched with a blue light guest material. The results demonstrate that the host molecule in which one of the phenyls in the triphenylphosphine oxide acceptor moiety was linked to the carbazole donor while the other two phenyls in the acceptor moiety were substituted with CN substituents yields the highest blue-phosphorescent device performance, as this host molecule has interesting features such as a high E T, balanced charge transport, a low charge-injection barrier, and a small DeltaE ST. PMID- 26631074 TI - Chinese cross-cultural adaptation and validation of the Oxford shoulder score. AB - BACKGROUND: The Oxford Shoulder Score (OSS) is a reliable and valid construct measuring non-specific shoulder pain, which are widely used to evaluate shoulder related quality of life. This study was to cross-culturally adapt and psychometrically validate a simplified Chinese version of the OSS (SC-OSS). METHODS: Cross-cultural adaptation was performed according to the international recognized guidelines. Consecutive patients with nonspecific shoulder pain were recruited to test the psychometric properties of SC-OSS. Item response trend and item-total correlation were evaluated to measure homogeneity. Principal component analysis (PCA) was used to evaluate the factorial structure. Cronbach's alpha and intra-class correlations were used to determine the reliability. Construct validity was analyzed by evaluating the correlations between SC-OSS and the Constant-Murley shoulder outcome score (CMSOS), the short form (36) health survey (SF-36) containing eight domains, and pain visual analogue scale (VAS). RESULTS: Overall, 121 patients were recruited. Each of the 12 items was properly responded and correlated with the total items. PCA extracted one factor for SC-OSS. SC-OSS had excellent reliability, with a Cronbach's alpha of 0.92 and intra-class correlation coefficient of 0.97 (95 % CI: 0.94-0.98). SC-OSS had a high correlation with CMSOS, physical functioning (PF) and bodily pain (BP) domains of SF-36 and VAS (r = -0.70, -0.65, -0.53, and -0.66, respectively). SC-OSS moderately correlated with role-physical (RP), social functioning (SF), general health perception (GH) and vitality (VT) (r = -0.45, -0.42, -0.39 and -0.36, respectively), but had a low correlation with role-emotional (RE) and mental health (MH) domains of SF-36 (r = -0.28 and -0.23, respectively). CONCLUSIONS: SC OSS demonstrated excellent acceptability, internal consistency, reliability and construct validity, which can be recommended for application in mainland China. PMID- 26631075 TI - Whole-body MRI in paediatric oncology. AB - Imaging plays a crucial role in the diagnosis and follow-up of paediatric malignancies. Until recently, computed tomography (CT) has been the imaging technique of choice in children with cancer, but nowadays there is an increasing interest in the use of functional imaging techniques like positron emission tomography and single-photon emission tomography. These later techniques are often combined with CT allowing for simultaneous acquisition of image data on the biological behaviour of tumour, as well as the anatomical localisation and extent of tumour spread. Because of the small but not negligible risk of radiation induced secondary cancers and the significantly improved overall survival rates of children with cancer, there is an increasing interest in the use of alternative imaging techniques that do not use ionising radiation. Magnetic resonance imaging (MRI) is a radiation-free imaging tool that allows for acquiring images with a high spatial resolution and excellent soft tissue contrast throughout the body. Moreover, recent technological advances have resulted in fast diagnostic sequences for whole-body MR imaging (WB-MRI), including functional techniques such as diffusion weighted imaging. In this review, the current status of the technique and major clinical applications of WB MRI in children with cancer will be discussed. PMID- 26631076 TI - 4D flow MRI assessment of extracranial-intracranial bypass: qualitative and quantitative evaluation of the hemodynamics. AB - INTRODUCTION: Our aim was to assess the feasibility of using time-resolved 3D phase-contrast (4D flow) MRI to characterize extracranial-intracranial (EC-IC) bypass. METHODS: We enrolled 32 patients who underwent EC-IC bypass (15 men, 17 women; mean age 66.4 years). In all, 16 underwent radial artery graft (RAG) bypass and 16 underwent superficial temporal artery (STA) bypass. 4D flow MRI, time-of-flight (TOF) magnetic resonance angiography (MRA), and computed tomography angiography (CTA) were performed. Bypass patency, flow direction, and blood flow volume (BFV) of each artery were determined by 4D flow MRI. Arterial diameters were measured by TOF-MRA and CTA. We compared RAG and STA bypasses by evaluating the flow direction and BFV of each artery. We evaluated the correlation between arterial diameters (measured by CTA or MRA) and the BFV and the detectability of flow direction (measured by 4D flow MRI) of each artery. RESULTS: 4D flow MRI confirmed the patency of each bypass artery. Flow direction of the M1 segment of the middle cerebral artery and BFV in the bypass artery differed between RAG and STA groups (p < 0.01). BFV in the bypass slightly correlated with the diameters on CTA (p < 0.05, R (2) = 0.287). Of the 29 arteries in the circle of Willis, nine were not depicted on 4D flow MRI. Cutoff values for arterial diameters on CTA and TOF-MRA for detecting the artery on 4D flow MRI were 2.4 and 1.8 mm, respectively. CONCLUSION: 4D flow MRI provided unique information for characterizing EC-IC bypasses, although this detectability is limited when addressing small arteries with slow flow. PMID- 26631077 TI - Prediction of cerebral hyperperfusion syndrome after carotid artery stenting by CT perfusion imaging with acetazolamide challenge. AB - INTRODUCTION: Cerebral hyperperfusion syndrome (HPS) is an uncommon but serious complication of carotid artery stenting (CAS). The purpose of this study was to investigate the efficacy of CT perfusion imaging (CTP) with acetazolamide challenge to identify patients at risk for HPS after CAS. METHODS: We retrospectively analyzed 113 patients who underwent CTP with rest and acetazolamide challenge before CAS. CTP maps were assessed for absolute and relative cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and change of each parameter before and after acetazolamide challenge. Patients were divided into two groups according to the HPS after the CAS. Receiver-operating characteristic (ROC) curve analysis was performed to determine the most accurate CTP parameter for the prediction of HPS. RESULTS: Nine of 113 patients had HPS. There were significant differences for absolute and relative values of resting CBF (p = 0.001 and p = 0.026), resting MTT (p < 0.001 and p = 0.004), post-acetazolamide CBF (p < 0.001 and p = 0.001), post acetazolamide MTT (p < 0.001 and p = 0.002), and % changes of CBF (p = 0.009) between the HPS and non-HPS groups. ROC curve analysis showed that the CTP parameters with the maximal area under the receiver-operating characteristic curve (AUC) for HPS was the absolute value of post-acetazolamide MTT (AUC 0.909) and the absolute value of resting MTT (AUC 0.896). CONCLUSION: Pretreatment CTP with acetazolamide challenge could identify patients at risk for HPS after CAS. Although the CTP parameter that most accurately identified patients at risk for HPS was the absolute value of post-acetazolamide MTT, resting MTT was sufficiently accurate. PMID- 26631078 TI - Erratum to: Visualizing translocation dynamics and nascent transcript errors in paused RNA polymerases in vivo. PMID- 26631079 TI - Microglia-derived HIV Nef+ exosome impairment of the blood-brain barrier is treatable by nanomedicine-based delivery of Nef peptides. AB - The negative factor (Nef) of human immunodeficiency virus (HIV) is an accessory protein that is thought to be integral to HIV-associated immune- and neuroimmune pathogenesis. Here, we show that nef-transfected microglia-released Nef+ exosome (exNef) disrupts the apical blood-brain barrier (BBB) and that only nef transfected microglia release Nef in exosomes. nef-gfp-transduced neurons and astrocytes release exosomes but did not release exNef in the extracellular space. Apical administration of exNef derived from nef-transfected 293T cells reduced transendothelial electrical resistance (TEER) and increased permeability of the BBB. Microglia-derived exNef applied to either the apical/basal BBB significantly reduced expression of the tight junction protein, ZO-1, suggesting a mechanism of exNef-mediated neuropathogenesis. Microglia exposed to exNef release elevated levels of Toll-like receptor-induced cytokines and chemokines IL-12, IL-8, IL-6, RANTES, and IL-17A. Magnetic nanoparticle delivery of Nef peptides containing the Nef myrisolation site across an in vitro BBB ultimately reduced nef-transfected microglia release of Nef exosomes and prevented the loss of BBB integrity and permeability as measured by TEER and dextran-FITC transport studies, respectively. Overall, we show that exNef is released from nef-gfp-transfected microglia; exNef disrupts integrity and permeability, and tight junctions of the BBB, and induces microglial cytokine/chemokine secretion. These exNef-mediated effects were significantly restricted by Nef peptides. Taken together, this study provides preliminary evidence of the role of exNef in HIV neuroimmune pathogenesis and the feasibility of a nanomedicine-based therapeutics targeting exNef to treat HIV-associated neuropathogenesis. PMID- 26631081 TI - Visual mental imagery and symptoms of depression - results from a large-scale web based study. AB - BACKGROUND: Mental imagery may influence the onset and maintenance of depression, but specific mechanisms have not yet been determined. METHODS: Nine hundred twelve participants completed questionnaires on positive and negative mental images, as well as images of injury and death that lead to positive emotions ("ID images"), and depressive symptomatology. The assessment was carried out online to reduce effects of social desirability. RESULTS: Positive images were reported by 87 % of the sample, negative images by 77 %. ID-images were present in one-third of the sample. A connection with depression severity was found for the absence of positive mental images and the presence of negative images as well as ID-images. Higher depression scores were associated with more frequent and vivid negative images, greater imagery distress, and a higher proportion of negative relative to positive images. CONCLUSIONS: Mental images are clearly related to depression. Future research should focus on ID-images and their connection to suicide-risk in depressed patients. PMID- 26631080 TI - Depletion of Olig2 in oligodendrocyte progenitor cells infected by Theiler's murine encephalomyelitis virus. AB - Theiler's murine encephalomyelitis virus (TMEV) infects the central nervous system of mice and causes a demyelinating disease that is a model for multiple sclerosis. During the chronic phase of the disease, TMEV persists in oligodendrocytes and macrophages. Lack of remyelination has been attributed to insufficient proliferation and differentiation of oligodendrocyte progenitor cells (OPCs), but the molecular mechanisms remain unknown. Here, we employed pluripotent stem cell technologies to generate pure populations of mouse OPCs to study the temporal and molecular effects of TMEV infection. Global transcriptome analysis of RNA sequencing data revealed that TMEV infection of OPCs caused significant up-regulation of 1926 genes, whereas 1853 genes were significantly down-regulated compared to uninfected cells. Pathway analysis revealed that TMEV disrupted many genes required for OPC growth and maturation. Down-regulation of Olig2, a transcription factor necessary for OPC proliferation, was confirmed by real-time PCR, immunofluorescence microscopy, and western blot analysis. Depletion of Olig2 was not found to be specific to viral strain and did not require expression of the leader (L) protein, which is a multifunctional protein important for persistence, modulation of gene expression, and cell death. These data suggest that direct infection of OPCs by TMEV may inhibit remyelination during the chronic phase of TMEV-induced demyelinating disease. PMID- 26631082 TI - Pharmacokinetics/pharmacodynamics of marbofloxacin in a Pasteurella multocida serious murine lung infection model. AB - BACKGROUND: Marbofloxacin is a third-generation fluoroquinolone developed solely for veterinary medicine with a broad spectrum of antibacterial activity against some Gram-positive and most Gram-negative bacteria, including the bovine respiratory tract pathogen, Pasteurella multocida. The objective of our study was to elucidate the pharmacokinetics and pharmacodynamics of marbofloxacin in a Pasteurella multocida infected murine lung model, and to estimate the magnitudes of pharmacokinetics-pharmacodynamics parameters associated with various effects. RESULTS: The pharmacokinetic studies revealed marbofloxacin kinetics in infected mice were linear over a dose ranging from 1.25 to 10 mg/kg of body weight. The protein binding in the plasma of neutropenic infected mice was 29.77 %. The magnitudes of the ratio of the free-drug area under the concentration-time curve over 24 h to MIC (fAUC 0-24h/MIC) associated with static effect, a 2 log10 reduction and a 3 log10 reduction of bacterial counts were 40.84, 139.34, and 278.08 h, respectively. CONCLUSIONS: Based on the dose range study, marbofloxacin exhibited concentration-dependent killing and the fAUC/MIC was the PK/PD index that correlated best with efficacy (R(2) = 83 %). On the basis of a bactericidal effect goal of fAUC 0-24h/MIC of 278.08 h, if marbofloxacin is used for the treatment of P. multocida serious lung infection with an MIC90 of 0.12 MUg/ml, the current dose (2 mg/kg) would fail to achieve a bactericidal effect. It would benefit from higher doses (4 ~ 6 mg/kg) than those commonly used in clinical practice. PMID- 26631083 TI - [Problems, complications, and emergencies during pacemaker implantation. Importance of access]. AB - Pacemaker implantation represents a standard procedure with a perceived 100% success rate, without mortality and with extremely rare complications. However, some pacemaker implantations may develop into a very difficult procedure or even be associated with significant complications. Good venous access is crucial and may distinguish between comfortable, successful implantation and futile implantation with severe complications (e.g., pneumo- or hematothorax, venous dissection or perforation, accidental arterial implantation, or air embolism). This review summarizes acute problems and complications during lead implantation and provides tips and hints for prevention and acute reaction during implantation. If these simple precautions are considered, the majority of acute complications during implantation of pacemaker leads can be prevented. PMID- 26631084 TI - Detection of occult paroxysmal atrial fibrilation by implantable long-term electrocardiographic monitoring in cryptogenic stroke and transient ischemic attack population: a study protocol for prospective matched cohort study. AB - BACKGROUND: Cardio-embolic etiology is the most frequently predicted cause of cryptogenic stroke/TIA. Detection of occult paroxysmal atrial fibrillation is crucial for selection of appropriate medication. METHODS: Enrolment of eligible cryptogenic stroke and TIA patients began in 2014 and will continue until 2018. The patients undergo long-term (12 months) ECG monitoring (implantable loop recorder) and testing for PITX2 (chromosome 4q25) and ZFHX3 (chromosome 16q22) gene mutations. There will be an appropriate control group of age- and sex matched healthy volunteers. To analyse the results descriptive statistics, statistical tests for group differences, and correlation analyses will be used. DISCUSSION: In our study we are focusing on a possible correlation between detection of atrial fibrillation by an implantable ECG recorder, and PITX2 and/or ZFHX3 gene mutations in cryptogenic stroke/TIA patients. A correlation could lead to implementation of this genomic approach to cryptogenic stroke/TIA diagnostics and management. The results will be published in 2018. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02216370 . PMID- 26631085 TI - Effect of a Behavioral Self-Regulation Intervention on Patient Adherence to Fluid Intake Restrictions in Hemodialysis: a Randomized Controlled Trial. AB - OBJECTIVE: The purpose of this study is to evaluate the efficacy of a behavioral self-regulation intervention vs. active control condition using a parallel-group randomized clinical trial with a sample of center hemodialysis patients with chronic kidney disease. METHOD: Participants were recruited from 8 hemodialysis treatment centers in the Midwest. Eligible patients were (a) fluid nonadherent as defined by an interdialytic weight gain >2.5 kg over a 4-week period, (b) >18 years of age, (c) English-speaking without severe cognitive impairment, (d) treated with center-based hemodialysis for >3 months, and (e) not living in a care facility in which meals were managed. Medical records were used to identify eligible patients. Patients were randomly assigned to either a behavioral self regulation intervention or active control condition in which groups of 3-8 patients met for hour-long, weekly sessions for 7 weeks at their usual hemodialysis clinic. Primary analyses were intention-to-treat. RESULTS: Sixty-one patients were randomized to the intervention while 58 were assigned to the attention-placebo support and discussion control. Covariate-adjusted between subjects analyses demonstrated no unique intervention effect for the primary outcome, interdialytic weight gain (beta = 0.13, p = 0.48). Significant within subjects improvement over time was observed for the intervention group (beta = 0.32, p = 0.014). CONCLUSIONS: The present study found that participation in a behavioral self-regulation intervention resulted in no unique intervention effect on a key indicator of adherence for those with severe chronic kidney disease. There was, however, modest within-subjects improvement in interdialytic weight gain for the intervention group which meshes with other evidence showing the utility of behavioral interventions in this patient population. ClinicalTrials.gov Identifier: NCT01066949. PMID- 26631086 TI - Associations between Depressive Symptoms and Social Support in Adults with Diabetes: Comparing Directionality Hypotheses with a Longitudinal Cohort. AB - BACKGROUND: Individuals with diabetes are at increased risk of elevated depressive symptoms, and social support has been identified as a key factor in the health of this population. Cross-sectional associations between depressive symptoms and social support have been demonstrated. Three classes of hypotheses differentially describe the direction of this association: (1) depressive symptoms influence social support, (2) social support influences depressive symptoms, and (3) reciprocal associations exist between depressive symptoms and social support. PURPOSE: The aim of this study was to compare these hypotheses. METHODS: Depressive symptoms and social support were measured via telephone survey in a large cohort study of individuals with diabetes (n = 1754) in Quebec, Canada. After baseline, data were collected annually for 4 years. Path models depicting each hypothesis, as well as a stability model containing only autoregressive effects, were generated, and model fit was compared with Akaike's Information Criterion (AIC). RESULTS: The reciprocal model was selected as the best fitting model because it had the lowest AIC. This model demonstrated that depressive symptoms predicted subsequent social support at all time points and that social support predicted subsequent depressive symptoms at most time points. CONCLUSIONS: It appears that the association between depressive symptoms and social support in people with diabetes is best characterized as reciprocal. Results underscore the importance of directly comparing competing hypotheses and offer a more accurate depiction of the association between depressive symptoms and social support among people with diabetes. PMID- 26631087 TI - [Treatment of tuberculosis. Current standards]. AB - The treatment of drug-sensitive tuberculosis consists of 2 months of isoniazid, rifampin, pyrazinamide and ethambutol, followed by 4 months of isoniazid and rifampin. These drugs are well tolerated and cure rate are above 95 %. In contrast the treatment of drug-resistent tuberculosis is difficult, mostly due to side effects of the drugs used under these circumstances. Therefore, any treatment of drug-resistant tuberculosis has to be done by experts. PMID- 26631092 TI - GABAergic Agonists Modulate the Glutamate Release from Frontal Cortex Synaptosomes of Rats with Experimental Autoimmune Encephalomyelitis. AB - Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease that mimics many of the clinical and pathological features of multiple sclerosis. We have previously described a significant diminution in the GABAergic regulation of glutamate release from synaptosomes of EAE rats isolated during the acute stage of the disease. In order to explore the possible metabolic pathways responsible for this alteration, in this work we evaluate the direct effect of different GABAergic agonists on the glutamate release and concomitant synapsin I phosphorylation in synaptosomes from the frontal cortex of control and EAE animals. The results show that GABA as well as the GABA receptor agonists Muscimol (GABAA agonist) and Baclofen (GABAB agonist) caused a decrease in glutamate release in control rats paralleled by a similar reduction in synapsin I phosphorylation. Meanwhile synaptosomes from EAE animals are responsive only to Baclofen with respect to nontreated EAE synaptosomes, since glutamate release from the synaptosomes treated with Muscimol was similar to that observed in EAE rat synaptosomes which was already reduced as consequence of the disease. In the case of the benzodiazepines Diazepam and Clonazepam (GABAA allosteric agonists), both of them induced a reduction in glutamate release in synaptosomes from the CFA rats, effect that was only observed in synaptosomes of EAE rats treated with Clonazepam. In all cases both benzodiazepines showed a higher effect on synapsin I phosphorylation than in glutamate release. These results indicate that the extent of GABAergic modulation of presynaptic terminals depends on the type of agonist employed and this regulation is altered in the frontal cortex during the acute phase of EAE with respect to control animals. PMID- 26631093 TI - LPS Up-Regulates Cystathionine gamma -Lyase Gene Expression in Primary Human Macrophages via NF-kappaB/ERK Pathway. AB - Hydrogen sulfide (H2S) is an endogenous inflammatory mediator produced by the activity of cystathionine gamma-lyase (CSE) in mammals. Macrophages are a key element of the immune system and play a crucial role in inflammation. To determine the role of H2S and macrophages in inflammation, we investigated the expression of CSE in human primary macrophages. Our results show that H2S is produced by the activity of CSE in these cells. To investigate the role of common signalling pathway in biosynthesis of CSE in human primary macrophages, specific inhibitors were used to block NF-kappaB, ERK, p38 and JNK. Inhibition of NF kappaB, ERK significantly reduced levels of CSE gene and protein expression in these cells but inhibition of JNK and p38 did not have an inhibitory effect on the expression of CSE gene in macrophages. Inhibition of NF-kappaB and ERK prevented the effect of LPS on H2S synthesizing activity in human primary macrophages. These data showed that H2S acts as an inflammatory mediator via NF kappaB/ERK pathway in macrophages. PMID- 26631094 TI - Design, Synthesis and In Vitro Release Studies of Co-Drugs for Rheumatoid Arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease that results in a chronic, systemic inflammation that may affect many tissues and organs, but principally the synovial joints. The tendency for joint destruction is greatest in the early stages of disease hence current trend is to introduce a disease modifying anti-rheumatic drug (DMARD) immediately after the diagnosis of RA in a step- up approach which is generally followed by its combination with a corticosteroid or NSAID. OBJECTIVE: Hydroxychloroquine (HCQ) is a slow acting DMARD used in the early stage of RA. NSAIDs if given in combination with HCQ would provide immediate symptomatic relief from pain and inflammation even before HCQ starts showing its disease modifying effects. Long half life of HCQ results in its accumulation in the body while frequent intake of NSAIDs results in severe GI side effects. Present project aims at minimizing these shortcomings by designing co-drugs of HCQ and NSAIDs as a potential combination RA therapy. METHOD: Synthesis of two co-drugs was achieved by CDI coupling, followed by their spectral characterization. In vitro release kinetics was studied by HPTLC in aqueous buffers and tissue homogenates of upper GIT. RESULTS: Prodrugs were resistant to hydrolysis in buffers (pH 1.2 and 7.4) and stomach homogenates of Wistar rat but 32- 65% hydrolysis was observed in small intestinal homogenates. CONCLUSION: We propose that the mutual prodrug strategy of a DMARD with NSAID could be useful in initial management of RA wherein NSAIDs would produce their anti-inflammatory effect and simultaneously the process of joint reconstruction by hydroxychloroquine could be initiated. PMID- 26631095 TI - Effectiveness of a low dose testosterone undecanoate to improve sexual function in postmenopausal women. AB - BACKGROUND: Adding testosterone to hormonal therapy could improve sexual function and general well-being among women during climacteric. We evaluated the effectiveness of testosterone undecanoate on sexual function in postmenopausal women utilizing the standardized questionnaire FSFI score. METHODS: Postmenopausal women with sexual complaints and Female Sexual Function Index (FSFI) <= 26.5 were enrolled in to this randomized, double-blinded, placebo controlled trial. Participants were randomly assigned to 8-week treatment with either oral testosterone undecanoate 40 mg or placebo twice weekly with daily oral estrogen. The FSFI scores before and after treatment were compared to assess any improvement of sexual function. RESULTS: Seventy women were recruited of which each group had 35 participants. The baseline characteristics and baseline FSFI scores were comparable between both groups. After 8 weeks of treatment, the FSFI scores significantly improved in both groups when compared to the baseline but the FSFI scores from the testosterone group were significantly higher than in the placebo group post-treatment (28.6 +/- 3.6, 25.3 +/- 6.7, respectively, p = 0.04). There was no difference in adverse effect between the two groups CONCLUSIONS: The twice weekly addition of testosterone undecanoate to daily oral estrogen was associated with a significant improvement in sexual function among postmenopausal women than the use of the estrogen alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01724658 (February 17, 2012). PMID- 26631096 TI - Capsule Commentary on Kuczmarska et al., Detection of Delirium in Hospitalized Older General Medicine Patients: A Comparison of the 3S-CAM and CAM-ICU. PMID- 26631097 TI - Capsule commentary on Rosenthal et al., A Difference-in-Difference Analysis of Changes in Quality, Utilization and Cost Following the Colorado Multi-Payer Patient-Centered Medical Home Pilot. PMID- 26631098 TI - Transforming Care for Complex Patients: Addressing Interconnected Medical, Social, and Behavioral Challenges. PMID- 26631099 TI - Retail Clinics Shine a Harsh Light on the Failure of Primary Care Access. PMID- 26631100 TI - Combination therapy with Bosentan and Sildenafil improves Raynaud's phenomenon and fosters the recovery of microvascular involvement in systemic sclerosis. AB - The aim of this study was to evaluate in systemic sclerosis (SSc) retrospectively the effect of Bosentan and Sildenafil and their combination on Raynaud's phenomenon (RP), function, and capillaroscopic patterns. One hundred and twenty three SSc patients (mean age +/- sd, 57.69 +/- 14.07 years) were retrospectively evaluated and divided into two groups according to American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification score: group 1 score < 10, group 2 score > 10. Each group was divided into three subgroups according to treatment: Bosentan, Sildenafil, and Bosentan + Sildenafil. Nailfold videocapillaroscopy (NVC), Scleroderma Health Assessment Questionnaire (SHAQ) and Raynaud Condition Score (RCS) were performed at baseline and after 3 and 6 months. In Bosentan (29 patients: 12, group 1; 17, group 2), NVC changed significantly in both groups, after 3 and 6 months (p = 0.00439, group 1; p = 0.00035, group 2). In group 1, the "active" and the "late" patterns reduced, and the "aspecific" increased. In group 2, there was a reduction of late patterns, a worsening of SHAQ (p < 0.005) and an improvement of RCS (p = 0.00014). In Sildenafil (63 patients: 35, group 1; 28, group 2), after 3 months, NVC patterns changed significantly in both groups(p = 0.042 group 1, p = 0.00089 group 2). In group 1, the late and early patterns increased, and the aspecific decreased. In group 2, a significant change of NVC pattern was observed also after 6 months (p = 0.00089): the late pattern increased while the active one reduced. After 6 months, SHAQ was significantly reduced in group 1 (p = 0.00027) and in group 2 (p = 0.0043). RCS improved in both groups (p = 0.0042, group 1; p = 0.0016, group 2). Combination therapy (Bosentan + Sildenafil) (31 patients: 14, group 1; 17, group 2) induced significant changes on NVC only in group 1 after 3 (p = 0.00256) and 6 months (p = 0.000349) with a reduction of the late and active patterns and an increase of the early pattern. In both groups, after 6 months, SHAQ (p < 0.05, group 1; p = 0.00049, group 2) and RCS significantly reduced (group 1, p = 0.00024; group 2, p = 0.0021). Patients treated with Bosentan + Sildenafil show a significant improvement of RCS and NVC. This combination therapy may exert a vascular activity achieving an amelioration of the structure of microvasculature in SSc. PMID- 26631101 TI - Lights and shadows in autoinflammatory syndromes from the childhood and adulthood perspective. AB - In a high percentage of cases, the monogenic autoinflammatory syndromes (AIS), caused by subversion in the inflammasome homeostasis leading to cytokine oversecretion and characterized by multiple inflammatory pictures, start in childhood. However, the description of tardive manifestations, veiled phenotypes, and atypical clinical signs beginning in adulthood has been more and more reported in recent times, requiring that many specialists become confident with concepts, details, and management strategies of AIS. Differences between child- and adult-onset syndromes raise the question of whether pathogenic mechanisms might differ when the timetable of AIS onset diverges, but show that carefulness is needed to establish a straightforward diagnosis. PMID- 26631102 TI - Predictive factors for achieving low disease activity at 52 weeks after switching from tumor necrosis factor inhibitors to abatacept: results from a multicenter observational cohort study of Japanese patients. AB - This study aimed to identify predictive factors for achieving low disease activity (LDA) in rheumatoid arthritis (RA) patients switching from tumor necrosis factor inhibitors (TNFis) to abatacept (ABT). Patients who were registered in the multicenter observational Tsurumai Biologics Communication Registry (TBCR) were enrolled in this study. Predictive factors for LDA achievement at each time point were determined by univariate and multivariate logistic regression analyses. The cutoffs of 28-point count Disease Activity Score (DAS28)-C-reactive protein (CRP) and DeltaDAS28-CRP from baseline up to 24 weeks for LDA achievement at 52 weeks were explored using receiver operating characteristic (ROC) curves. Of 2771 RA patients registered until 2013, 76 with moderate or high disease activity were selected. Twenty-six percent of the patients achieved LDA. Multivariate analysis confirmed that DAS28-CRP at 12 weeks and DeltaDAS28-CRP from baseline to 12 weeks were independent factors for LDA achievement at 52 weeks [odds ratio (OR) 0.26, 95% confident interval (CI) (0.12 0.56), OR 0.25, 95% CI (0.11-0.57), respectively]. The best cutoff values of DAS28-CRP at 12 weeks and DeltaDAS28-CRP from baseline to 12 weeks for LDA at 52 weeks were 3.9 (sensitivity 0.85, specificity 0.78) and -0.97 (sensitivity 0.70, specificity 0.70), respectively. Seventy-one percent of patients who achieved both of these cutoff values at 12 weeks achieved LDA at 52 weeks. Our findings suggest that the clinical course up to 12 weeks is important for predicting long term outcomes when switching from TNFis to ABT. PMID- 26631103 TI - A pilot randomized, placebo-controlled clinical trial to investigate the efficacy and safety of an extract of Artemisia annua administered over 12 weeks, for managing pain, stiffness, and functional limitation associated with osteoarthritis of the hip and knee. AB - The objective of this study was to investigate the safety and efficacy of a dietary supplement, Arthrem, containing an extract from the medicinal plant Artemisia annua, on pain, stiffness, and functional limitation in osteoarthritis (OA) of the hip or knee. Forty-two patients were randomized to one of three groups (n = 14 in each group): 150-mg Artemisia annua extract (ART) twice daily (BD) (ART low dose), 300-mg ART BD (ART high dose), or placebo BD administered over 12 weeks. Efficacy was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC(r)) and visual analog scale (VAS) for pain. Participants treated with ART low dose demonstrated significant improvement in WOMAC total scores from baseline to 12 weeks (mean change, -12.2; standard deviation, [SD] 13.84; p = 0.0159); improvement was not shown in the placebo group (mean change, -7.8; SD, 19.80; p = 0.1029). Statistically significant reductions were seen from baseline in the ART low-dose group for individual WOMAC components stiffness and physical function. VAS pain scores were statistically significantly reduced from baseline to 12 weeks in the ART low-dose group (mean change, -21.4 mm; SD, 23.48 mm; p = 0.0082) but not the placebo group (mean change, -11.5 mm; SD, 28.97 mm, p = 0.1757). No statistically significant changes occurred from baseline in the placebo or ART high-dose groups for any parameter. ART low dose was well tolerated. ART has potential as an anti inflammatory/analgesic in OA. Treatment with ART 150 mg BD is associated with clinically relevant reductions in pain over 12 weeks. Further studies are warranted. PMID- 26631104 TI - Thoracic perfusion of matrine as an adjuvant treatment improves the control of the malignant pleural effusions. AB - BACKGROUND: Many studies have investigated the efficacy and safety of matrine in treating malignant pleural effusion by thoracic perfusion. This study is an analytic value of available evidence. METHODS: Twelve studies were analyzed in this study. Pooled odds ratios and hazard ratio with 95 % confidence intervals were calculated using the fixed effects model. RESULTS: Overall response rate of matrine combined with other medications in treating malignant pleural effusion (MPE) was significantly higher than those of other medications alone (p < 0.05). Time to pleural effusion relief and quality of life were improved after the treatment of matrine combined with other medications (p < 0.05). Moreover, matrine combined with other medications had a lower incidence of adverse reactions (p < 0.05). CONCLUSIONS: Matrine combined with other medications improves the control of the malignant pleural effusions and decreases the incidence of adverse reactions. PMID- 26631105 TI - Improving robustness against electrode shift of high density EMG for myoelectric control through common spatial patterns. AB - BACKGROUND: Most prosthetic myoelectric control studies have concentrated on low density (less than 16 electrodes, LD) electromyography (EMG) signals, due to its better clinical applicability and low computation complexity compared with high density (more than 16 electrodes, HD) EMG signals. Since HD EMG electrodes have been developed more conveniently to wear with respect to the previous versions recently, HD EMG signals become an alternative for myoelectric prostheses. The electrode shift, which may occur during repositioning or donning/doffing of the prosthetic socket, is one of the main reasons for degradation in classification accuracy (CA). METHODS: HD EMG signals acquired from the forearm of the subjects were used for pattern recognition-based myoelectric control in this study. Multiclass common spatial patterns (CSP) with two types of schemes, namely one versus one (CSP-OvO) and one versus rest (CSP-OvR), were used for feature extraction to improve the robustness against electrode shift for myoelectric control. Shift transversal (ST1 and ST2) and longitudinal (SL1 and SL2) to the direction of the muscle fibers were taken into consideration. We tested nine intact-limb subjects for eleven hand and wrist motions. The CSP features (CSP-OvO and CSP-OvR) were compared with three commonly used features, namely time-domain (TD) features, time-domain autoregressive (TDAR) features and variogram (Variog) features. RESULTS: Compared with the TD features, the CSP features significantly improved the CA over 10 % in all shift configurations (ST1, ST2, SL1 and SL2). Compared with the TDAR features, a. the CSP-OvO feature significantly improved the average CA over 5 % in all shift configurations; b. the CSP-OvR feature significantly improved the average CA in shift configurations ST1, SL1 and SL2. Compared with the Variog features, the CSP features significantly improved the average CA in longitudinal shift configurations (SL1 and SL2). CONCLUSION: The results demonstrated that the CSP features significantly improved the robustness against electrode shift for myoelectric control with respect to the commonly used features. PMID- 26631106 TI - Auditory Model-Based Sound Direction Estimation With Bilateral Cochlear Implants. AB - Users of bilateral cochlear implants (CIs) show above-chance performance in localizing the source of a sound in the azimuthal (horizontal) plane; although localization errors are far worse than for normal-hearing listeners, they are considerably better than for CI listeners with only one implant. In most previous studies, subjects had access to interaural level differences and to interaural time differences conveyed in the temporal envelope. Here, we present a binaural model that predicts the azimuthal direction of sound arrival from a two-channel input signal as it is received at the left and right CI processor. The model includes a replication of a clinical speech-coding strategy, a model of the electrode-nerve interface and binaural brainstem neurons, and three different prediction stages that are trained to map the neural response rate to an azimuthal angle. The model is trained and tested with various noise and speech stimuli created by means of virtual acoustics. Localization error patterns of the model match experimental data and are explicable largely in terms of the nonmonotonic relationship between interaural level difference and azimuthal angle. PMID- 26631107 TI - Direct Intracochlear Acoustic Stimulation Using a PZT Microactuator. AB - Combined electric and acoustic stimulation has proven to be an effective strategy to improve hearing in some cochlear implant users. We describe an acoustic microactuator to directly deliver stimuli to the perilymph in the scala tympani. The 800 um by 800 um actuator has a silicon diaphragm driven by a piezoelectric thin film (e.g., lead-zirconium-titanium oxide or PZT). This device could also be used as a component of a bimodal acoustic-electric electrode array. In the current study, we established a guinea pig model to test the actuator for its ability to deliver auditory signals to the cochlea in vivo. The actuator was placed through the round window of the cochlea. Auditory brainstem response (ABR) thresholds, peak latencies, and amplitude growth were calculated for an ear canal speaker versus the intracochlear actuator for tone burst stimuli at 4, 8, 16, and 24 kHz. An ABR was obtained after removal of the probe to assess loss of hearing related to the procedure. In some animals, the temporal bone was harvested for histologic analysis of cochlear damage. We show that the device is capable of stimulating ABRs in vivo with latencies and growth functions comparable to stimulation in the ear canal. Further experiments will be necessary to evaluate the efficiency and safety of this modality in long-term auditory stimulation and its ability to be integrated with conventional cochlear implant arrays. PMID- 26631108 TI - Comparison of Interaural Electrode Pairing Methods for Bilateral Cochlear Implants. AB - In patients with bilateral cochlear implants (CIs), pairing matched interaural electrodes and stimulating them with the same frequency band is expected to facilitate binaural functions such as binaural fusion, localization, and spatial release from masking. Because clinical procedures typically do not include patient-specific interaural electrode pairing, it remains the case that each electrode is allocated to a generic frequency range, based simply on the electrode number. Two psychoacoustic techniques for determining interaurally paired electrodes have been demonstrated in several studies: interaural pitch comparison and interaural time difference (ITD) sensitivity. However, these two methods are rarely, if ever, compared directly. A third, more objective method is to assess the amplitude of the binaural interaction component (BIC) derived from electrically evoked auditory brainstem responses for different electrode pairings; a method has been demonstrated to be a potential candidate for bilateral CI users. Here, we tested all three measures in the same eight CI users. We found good correspondence between the electrode pair producing the largest BIC and the electrode pair producing the maximum ITD sensitivity. The correspondence between the pairs producing the largest BIC and the pitch-matched electrode pairs was considerably weaker, supporting the previously proposed hypothesis that whilst place pitch might adapt over time to accommodate mismatched inputs, sensitivity to ITDs does not adapt to the same degree. PMID- 26631109 TI - A principle of organization which facilitates broad Lamarckian-like adaptations by improvisation. AB - BACKGROUND: During the lifetime of an organism, every individual encounters many combinations of diverse changes in the somatic genome, epigenome and microbiome. This gives rise to many novel combinations of internal failures which are unique to each individual. How any individual can tolerate this high load of new, individual-specific scenarios of failure is not clear. While stress-induced plasticity and hidden variation have been proposed as potential mechanisms of tolerance, the main conceptual problem remains unaddressed, namely: how largely non-beneficial random variation can be rapidly and safely organized into net benefits to every individual. PRESENTATION OF THE HYPOTHESIS: We propose an organizational principle which explains how every individual can alleviate a high load of novel stressful scenarios using many random variations in flexible and inherently less harmful traits. Random changes which happen to reduce stress, benefit the organism and decrease the drive for additional changes. This adaptation (termed 'Adaptive Improvisation') can be further enhanced, propagated, stabilized and memorized when beneficial changes reinforce themselves by auto regulatory mechanisms. This principle implicates stress not only in driving diverse variations in cells tissues and organs, but also in organizing these variations into adaptive outcomes. Specific (but not exclusive) examples include stress reduction by rapid exchange of mobile genetic elements (or exosomes) in unicellular, and rapid changes in the symbiotic microorganisms of animals. In all cases, adaptive changes can be transmitted across generations, allowing rapid improvement and assimilation in a few generations. TESTING THE HYPOTHESIS: We provide testable predictions derived from the hypothesis. IMPLICATIONS OF THE HYPOTHESIS: The hypothesis raises a critical, but thus far overlooked adaptation problem and explains how random variation can self-organize to confer a wide range of individual-specific adaptations beyond the existing outcomes of natural selection. It portrays gene regulation as an inseparable synergy between natural selection and adaptation by improvisation. The latter provides a basis for Lamarckian adaptation that is not limited to a specific mechanism and readily accounts for the remarkable resistance of tumors to treatment. PMID- 26631110 TI - Evaluation of the toxic effect of the herbicide 2, 4-D on rat hepatocytes: an FT IR spectroscopic study. AB - Infrared spectroscopy is a powerful technique used to investigate molecular structures to the level of bond lengths and angles. In this study, the hepatotoxic effect of 2, 4-dichlorophenoxyacetic acid (2, 4-D) was investigated using Fourier transform infrared (FT-IR) spectroscopy. The experiment was performed on 15 male albino Wister rats (250-350 g) divided randomly into a control group (5 rats) and 2, 4-D-treated group (10 rats). The 2, 4-D-treated group received a single oral gavage LD50 dose of 639 mg/kg body weight; the rats were then killed and the livers excised 24 h after 2, 4-D administration. Spectroscopic results revealed that there was a significant reduction in protein content as well as a marked decrease in the secondary structure of protein after 2, 4-D intoxication. Moreover, looseness of membrane lipid chain packing, lipid polarity and/or significant increases in the formation of lipids with hydroperoxyl groups and carbonyl compounds were shown in the 2, 4-D LD50-treated group compared to the control group. Glycogen is dramatically decreased in rat liver after the induction of 2, 4-D. In conclusion, FTIR spectroscopy proved to be a rapid and sensitive approach to cytotoxicity diagnosis and monitoring of toxin-induced damage in biological membranes and proteins. In addition, the FTIR parameters employed in this study can be used as biophysical indicators of toxin induced cell or membrane damage during apoptosis. PMID- 26631111 TI - Down-regulated ECRG4 expression in breast cancer and its correlation with tumor progression and poor prognosis--A short Report. AB - BACKGROUND: Recently, we identified the esophageal carcinoma related gene 4 (ECRG4) as a novel candidate tumor suppressor gene and a promising therapeutic target in nasopharyngeal carcinoma (NPC). In addition, we found that reduced ECRG4 expression in NPC was associated with promoter hypermethylation. The aim of the current study was to assess the expression status of the ECRG4 protein in breast cancer and to clarify its clinicopathological significance and potential prognostic implications. METHODS: Western blotting was used to examine ECRG4 protein levels in 20 paired breast cancer tissues and adjacent noncancerous tissues. In addition, we performed ECRG4 immunohistochemistry on 113 clinicopathologically well-characterized breast cancer samples and assessed putative associations between its expression and overall patient survival rates. RESULTS: We found that ECRG4 protein expression was significantly reduced in the breast cancer tissues compared to the noncancerous tissues. Clinicopathological analyses revealed that loss of ECRG4 protein expression, observed in 41.6 % (47/113) of the primary breast cancer tissues tested, was significantly correlated with lymph node metastasis (P = 0.026), advanced tumor stage (P = 0.042) and unfavorable overall survival (P = 0.004). Additional multivariate analyses revealed that ECRG4 protein expression may serve as an independent prognostic factor for the prediction of patient survival (P = 0.033). CONCLUSION: Our data suggest that loss of ECRG4 protein expression may be involved in tumor progression and may serve as a prognostic biomarker for breast cancer. PMID- 26631112 TI - Blood at 70: its roots in the history of hematology and its birth. AB - This year we celebrate Blood's 70th year of publication. Created from the partnership of the book publisher Henry M. Stratton and the prominent hematologist Dr William Dameshek of Tufts School of Medicine, Blood has published many papers describing major advances in the science and clinical practice of hematology. Blood's founding antedated that of the American Society of Hematology (ASH) by more than 11 years and Stratton and Dameshek helped galvanize support for the creation of ASH. In this review, I place the birth of Blood in the context of the history of hematology before 1946, emphasizing the American experience from which it emerged, and focusing on research conducted during World War II. I also provide a few milestones along Blood's 70 years of publication, including: the growth in Blood's publications, the evolution of its appearance, the countries of submission of Blood papers, current subscriptions to Blood, and the evolution of topics reported in Blood's papers. The latter provides a snapshot of the evolution of hematology as a scientific and clinical discipline and the introduction of new technology to study blood and bone marrow. Detailed descriptions of the landmark discoveries reported in Blood will appear in later papers celebrating Blood's birthday authored by past Editors-in-Chief. PMID- 26631113 TI - Targeting acute myeloid leukemia with a small molecule inhibitor of the Myb/p300 interaction. AB - The transcription factor Myb plays a key role in the hematopoietic system and has been implicated in the development of leukemia and other human cancers. Inhibition of Myb is therefore emerging as a potential therapeutic strategy for these diseases. However, because of a lack of suitable inhibitors, the feasibility of therapeutic approaches based on Myb inhibition has not been explored. We have identified the triterpenoid Celastrol as a potent low-molecular weight inhibitor of the interaction of Myb with its cooperation partner p300. We demonstrate that Celastrol suppresses the proliferative potential of acute myeloid leukemia (AML) cells while not affecting normal hematopoietic progenitor cells. Furthermore, Celastrol prolongs the survival of mice in a model of an aggressive AML. Overall, our work demonstrates the therapeutic potential of a small molecule inhibitor of the Myb/p300 interaction for the treatment of AML and provides a starting point for the further development of Myb-inhibitory compounds for the treatment of leukemia and, possibly, other tumors driven by deregulated Myb. PMID- 26631114 TI - Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma. AB - Immunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pretreated MM, and preliminary results from studies with relapsed/refractory patients have shown enhanced therapeutic efficacy when daratumumab and isatuximab are combined with other agents. Furthermore, although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotuzumab is added to lenalidomide-dexamethasone or bortezomib-dexamethasone. Importantly, there has been no significant additive toxicity when these monoclonal antibodies are combined with other anti-MM agents, other than infusion-related reactions specific to the therapeutic antibody. Prevention and management of infusion reactions is important to avoid drug discontinuation, which may in turn lead to reduced efficacy of anti-MM therapy. Therapeutic antibodies interfere with several laboratory tests. First, interference of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting antibodies, interfere with blood compatibility testing and thereby complicate the safe release of blood products. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates daratumumab interference with transfusion laboratory serologic tests. Finally, therapeutic antibodies may complicate flow cytometric evaluation of normal and neoplastic plasma cells, since the therapeutic antibody can affect the availability of the epitope for binding of commercially available diagnostic antibodies. PMID- 26631115 TI - Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML. AB - There is interest in using leukemia-gene panels and next-generation sequencing to assess acute myelogenous leukemia (AML) response to induction chemotherapy. Studies have shown that patients with AML in morphologic remission may continue to have clonal hematopoiesis with populations closely related to the founding AML clone and that this confers an increased risk of relapse. However, it remains unknown how induction chemotherapy influences the clonal evolution of a patient's nonleukemic hematopoietic population. Here, we report that 5 of 15 patients with genetic clearance of their founding AML clone after induction chemotherapy had a concomitant expansion of a hematopoietic population unrelated to the initial AML. These populations frequently harbored somatic mutations in genes recurrently mutated in AML or myelodysplastic syndromes and were detectable at very low frequencies at the time of AML diagnosis. These results suggest that nonleukemic hematopoietic stem and progenitor cells, harboring specific aging-acquired mutations, may have a competitive fitness advantage after induction chemotherapy, expand, and persist long after the completion of chemotherapy. Although the clinical importance of these "rising" clones remains to be determined, it will be important to distinguish them from leukemia-related populations when assessing for molecular responses to induction chemotherapy. PMID- 26631118 TI - Corrigendum: A Method for Exploring Adult Neurogenesis in the Songbird Brain. PMID- 26631116 TI - Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. AB - Panobinostat is a potent pan-deacetylase inhibitor that affects the growth and survival of multiple myeloma (MM) cells through alteration of epigenetic mechanisms and protein metabolism. Panobinostat plus bortezomib and dexamethasone (PAN-BTZ-Dex) led to a significant increase in progression-free survival (PFS) vs placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex) in patients with relapsed or relapsed and refractory MM in the phase 3 PANORAMA 1 trial. This subgroup analysis evaluated outcomes in patients in the PANORAMA 1 trial based on prior treatment: a prior immunomodulatory drug (IMiD; n = 485), prior bortezomib plus an IMiD (n = 193), and >=2 prior regimens including bortezomib and an IMiD (n = 147). Median PFS with PAN-BTZ-Dex vs Pbo-BTZ-Dex across subgroups was as follows: prior IMiD (12.3 vs 7.4 months; hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.43-0.68), prior bortezomib plus IMiD (10.6 vs 5.8 months; HR, 0.52; 95% CI, 0.36-0.76), and >=2 prior regimens including bortezomib and an IMiD (12.5 vs 4.7 months; HR, 0.47; 95% CI, 0.31-0.72). Common grade 3/4 adverse events and laboratory abnormalities in patients who received PAN-BTZ-Dex across the prior treatment groups included thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/fatigue. Incidence of on-treatment deaths among patients who received prior bortezomib and an IMiD (regardless of number of prior regimens) was similar between treatment arms. This analysis demonstrated a clear PFS benefit of 7.8 months with PAN-BTZ-Dex among patients who received >=2 prior regimens including bortezomib and an IMiD, a population with limited treatment options and poorer prognosis. This trial was registered at www.clinicaltrials.gov as #NCT01023308. PMID- 26631117 TI - IL-10Ralpha expression is post-transcriptionally regulated by miR-15a, miR-185, and miR-211 in melanoma. AB - BACKGROUND: IL-10 is an immunoregulatory cytokine that increases during malignant diseases. The purpose of this study was to: i) determine the mRNA amounts of IL 10, IL-10Ralpha, and IL-10Rbeta in cutaneous and uveal melanoma cells and specimens; ii) evaluate their post-transcriptional regulation by miRNAs; iii) ascertain whether miRNA dysregulation may affect IL-10-induced proliferation. METHODS: Genome-wide miRNA expression profiling was performed using a human microarray platform. The reference gene mRNA was measured through qPCR. miRNAs/mRNAs interactions were predicted by TargetScan, microRNA, and PITA. Transfections of specific miRNA mimics/inhibitors were carried out. Cell proliferation was assessed by MTT assay in the presence of IL-10 after transfection with miRNA mimics/inhibitors. RESULTS: There were no differences in IL-10 mRNA levels between any of the 3 melanoma cell lines tested and normal melanocytes. However, lower IL-10Ralpha expression was found in G361 and OCM-1 cells, and higher levels of IL-10Rbeta were observed in G361 cells compared with normal melanocytes. GR-M cells did not exhibit any modifications in IL-10Ralpha and IL-10Rbeta expression. miR-15a, miR-185, miR-211, and miR-30d were upregulated in G361 and OCM-1 cells, remaining at similar levels in GR-M cells. miR-409-3p and miR-605were down-regulated exclusively in G361 cells. Prediction tools revealed that miR-15a, miR-185, and miR-211 targeted IL-10Ralpha whereas none of the miRNAs exclusively downregulated in G361 cells targeted IL-10Rbeta. Luciferase reporter and western blot assays showed that IL-10Ralpha expression is directly regulated by miR-15a, miR-185, and miR-211, either alone or in combination. An inverse expression pattern between IL-10Ralpha, on one side, and miR-15a, miR-185, and miR-211 on the other one was also shown in melanoma samples. Ectopic expression of individual miR-15a, miR-185, and miR-211, and even more their co-expression, caused a marked decrease in the proliferation rate of all the cell lines. Likewise, inhibition of any specific miRNA promoted cell growth, an effect that further increased when inhibition concerned all three miRNA. Moreover, specific knockdown of IL-10Ralpha prevented the proliferative effect of miRNA inhibitors. CONCLUSIONS: Our results support a key role of IL 10Ralpha in the development and progression of melanoma and suggest that the IL 10/IL-10 receptor system may become a new therapeutic target for melanoma treatment. PMID- 26631119 TI - The Cleared Mammary Fat Pad Transplantation Assay for Mammary Epithelial Organogenesis. AB - Cleared mammary fat pad (MFP) transplantation has been a standard technique for studies of mammary development and cancer for several decades. The mammary gland is comprised of several fundamental components: The epithelial compartment contains basal/myoepithelial cells and luminal cells, and the stromal compartment (called the MFP) contains adipocytes, smooth muscle cells, fibroblasts, and immune cells. In 3- to 4-wk-old female mice, the mammary epithelium is concentrated very close to the nipple and has not yet grown beyond the mammary lymph node to penetrate the bulk of the MFP. This developmental feature provides an anatomical fixed point, and enables one to cut away the portion of the MFP from the nipple to the lymph node, leaving behind the majority of the MFP free of epithelium. The "cleared" MFP can serve as a supportive native microenvironment fully sufficient for the organogenesis of injected donor epithelium. Normal mammary epithelial donor cells will produce histologically and functionally normal mammary ductal epithelium several weeks posttransplant, with the exception that the ducts will not be connected to the nipple. The assay described here provides a powerful platform for assessing the developmental and tumorigenic potential of engineered cells of interest. PMID- 26631120 TI - Isolation of Macrophage Early and Late Endosomes by Latex Bead Internalization and Density Gradient Centrifugation. AB - Immortalized macrophage lines and primary macrophages display the ability to internalize small latex beads through the endocytic pathway. This protocol describes a simple and robust method for separating endocytic organelles from macrophages on a sucrose gradient, taking advantage of the significantly lower density of the organelles containing latex beads compared with other intracellular organelles. The latex beads are retained in the endosomes as they mature; therefore, harvesting cells at different time points after internalization permits the purification of different organelle fractions, particularly early and late endosomes. PMID- 26631121 TI - In Vitro Assembly and Analysis of the Apoptosome Complex. AB - This protocol describes an in vitro model for studying the mechanisms of caspase activation and native apoptosome complex assembly in cell-free extracts. Active caspases in dATP-activated lysates are detected by fluorimetry using a tetrapeptide substrate (DEVD) tagged with a fluorophore (AFC), which, when released, produces a real-time readout for caspase-3 and -7 (DEVDase) activity. Gel filtration is used to isolate the apoptosome complex from the activated lysates, and assembly of Apaf-1 and caspase-9 from their monomeric forms into the multiprotein apoptosome can be confirmed via western blot. Apoptosome complex activity can be shown by incubation with exogenous procaspase-3 and -7 followed by fluorimetric bioassay (to confirm functionality of the processed effector caspases) and/or western blotting (for detection of cleaved caspase-3 and -7). A method for preparation of free procaspases for the bioassay is also described. PMID- 26631122 TI - Activation, Isolation, and Analysis of the Death-Inducing Signaling Complex. AB - This protocol describes activation, isolation, and analysis of the CD95 (APO 1/Fas) death-inducing signaling complex (DISC) using affinity purification. Activation is achieved using a biotin-labeled anti-CD95 antibody and the native DISC complex is captured using streptavidin beads. This approach minimizes both the number of steps involved and any potential nonspecific interactions or cross reactivity of antibodies commonly seen in immunoprecipitations using unlabeled antibodies and protein A/G beads. Composition of the isolated complex is analyzed via western blot to identify known DISC components, and dimerization-induced autocatalytic processing of procaspase-8 at the DISC can be confirmed by detection of caspase-8 cleavage products. The potential for DISC-associated caspase-8 to activate the caspase cascade can be determined by measuring caspase 8-dependent cleavage of the fluorigenic substrate Ac-IETD.AFC, or by performing a bioassay using exogenous protein substrates. PMID- 26631123 TI - The Saccharomyces Genome Database: Exploring Biochemical Pathways and Mutant Phenotypes. AB - Many biochemical processes, and the proteins and cofactors involved, have been defined for the eukaryote Saccharomyces cerevisiae. This understanding has been largely derived through the awesome power of yeast genetics. The proteins responsible for the reactions that build complex molecules and generate energy for the cell have been integrated into web-based tools that provide classical views of pathways. The Yeast Pathways in the Saccharomyces Genome Database (SGD) is, however, the only database created from manually curated literature annotations. In this protocol, gene function is explored using phenotype annotations to enable hypotheses to be formulated about a gene's action. A common use of the SGD is to understand more about a gene that was identified via a phenotypic screen or found to interact with a gene/protein of interest. There are still many genes that do not yet have an experimentally defined function and so the information currently available can be used to speculate about their potential function. Typically, computational annotations based on sequence similarity are used to predict gene function. In addition, annotations are sometimes available for phenotypes of mutations in the gene of interest. Integrated results for a few example genes will be explored in this protocol. This will be instructive for the exploration of details that aid the analysis of experimental results and the establishment of connections within the yeast literature. PMID- 26631124 TI - The Saccharomyces Genome Database: Advanced Searching Methods and Data Mining. AB - At the core of the Saccharomyces Genome Database (SGD) are chromosomal features that encode a product. These include protein-coding genes and major noncoding RNA genes, such as tRNA and rRNA genes. The basic entry point into SGD is a gene or open-reading frame name that leads directly to the locus summary information page. A keyword describing function, phenotype, selective condition, or text from abstracts will also provide a door into the SGD. A DNA or protein sequence can be used to identify a gene or a chromosomal region using BLAST. Protein and DNA sequence identifiers, PubMed and NCBI IDs, author names, and function terms are also valid entry points. The information in SGD has been gathered and is maintained by a group of scientific biocurators and software developers who are devoted to providing researchers with up-to-date information from the published literature, connections to all the major research resources, and tools that allow the data to be explored. All the collected information cannot be represented or summarized for every possible question; therefore, it is necessary to be able to search the structured data in the database. This protocol describes the YeastMine tool, which provides an advanced search capability via an interactive tool. The SGD also archives results from microarray expression experiments, and a strategy designed to explore these data using the SPELL (Serial Pattern of Expression Levels Locator) tool is provided. PMID- 26631125 TI - The Saccharomyces Genome Database: Gene Product Annotation of Function, Process, and Component. AB - An ontology is a highly structured form of controlled vocabulary. Each entry in the ontology is commonly called a term. These terms are used when talking about an annotation. However, each term has a definition that, like the definition of a word found within a dictionary, provides the complete usage and detailed explanation of the term. It is critical to consult a term's definition because the distinction between terms can be subtle. The use of ontologies in biology started as a way of unifying communication between scientific communities and to provide a standard dictionary for different topics, including molecular functions, biological processes, mutant phenotypes, chemical properties and structures. The creation of ontology terms and their definitions often requires debate to reach agreement but the result has been a unified descriptive language used to communicate knowledge. In addition to terms and definitions, ontologies require a relationship used to define the type of connection between terms. In an ontology, a term can have more than one parent term, the term above it in an ontology, as well as more than one child, the term below it in the ontology. Many ontologies are used to construct annotations in the Saccharomyces Genome Database (SGD), as in all modern biological databases; however, Gene Ontology (GO), a descriptive system used to categorize gene function, is the most extensively used ontology in SGD annotations. Examples included in this protocol illustrate the structure and features of this ontology. PMID- 26631126 TI - The Saccharomyces Genome Database: Exploring Genome Features and Their Annotations. AB - Genomic-scale assays result in data that provide information over the entire genome. Such base pair resolution data cannot be summarized easily except via a graphical viewer. A genome browser is a tool that displays genomic data and experimental results as horizontal tracks. Genome browsers allow searches for a chromosomal coordinate or a feature, such as a gene name, but they do not allow searches by function or upstream binding site. Entry into a genome browser requires that you identify the gene name or chromosomal coordinates for a region of interest. A track provides a representation for genomic results and is displayed as a row of data shown as line segments to indicate regions of the chromosome with a feature. Another type of track presents a graph or wiggle plot that indicates the processed signal intensity computed for a particular experiment or set of experiments. Wiggle plots are typical for genomic assays such as the various next-generation sequencing methods (e.g., chromatin immunoprecipitation [ChIP]-seq or RNA-seq), where it represents a peak of DNA binding, histone modification, or the mapping of an RNA sequence. Here we explore the browser that has been built into the Saccharomyces Genome Database (SGD). PMID- 26631127 TI - Recovery of Replication-Competent and G-Gene-Deleted Rabies Viruses from cDNA. AB - This protocol describes the recovery of replication-competent rabies viruses (RV) such as SAD L16 or SAD L16-eGFP. It is suggested that at least three parallel transfection experiments are performed to increase the success rate (in three 3.5 cm(2) dishes or in three wells in a six-well plate). The entire protocol takes 10 d, and successful rescue can be obtained after 6 d. An additional procedure for the recovery of G-gene-deleted viruses is also included. Please note that appropriate biosafety measures are needed. PMID- 26631128 TI - Pseudotyping of G-Gene-Deficient Rabies Virus. AB - G-deleted fluorescent rabies virus (RV) pseudotyped with RV G proteins, SAD DeltaG eGFP (RV CVS-G), can be used as single-round vectors for efficient retrograde labeling of neurons. For these experiments, as well as for monosynaptic tracing, which involves pseudotyping in situ, the use of the CVS strain G is recommended because of its high tropism for neurons. Pseudotype virus stocks generated by transfection of pCAGGS-G (or in MG139-on cells) contain the G protein of the vaccine strain SAD L16, which is broader in its tropism, and infects astrocytes, glia, and oligodendrocytes. We also describe a procedure for pseudotyping with ASLV Env A, which uses a cell-line expressing a version of the EnvA protein that is incorporated efficiently into the RV envelope (EnvARG(RGct)). PMID- 26631129 TI - Tissue Recombination Models for the Study of Epithelial Cancer. AB - Animal models of cancer provide fundamental insight into the cellular and molecular mechanisms of human cancer development. As an alternative to genetically engineered mouse models, increasing evidence shows that tissue recombination and transplantation models represent an efficient approach to faithfully recapitulate solid epithelial cancer in mice. Cancer can be rapidly initiated through lentiviral delivery of defined genetic alterations into target cells that are grown in a physiological milieu with an appropriate epithelial stromal interaction. Through genetic manipulation of distinct subpopulations of epithelial cells and mesenchymal cells, this powerful system can readily test both cell-autonomous roles of genetic events in the epithelial compartment and the paracrine effects of the microenvironment. Here we review the recent advances in mouse models of several epithelial cancers achieved using orthotopic transplantation and tissue recombination strategies, with an emphasis on the dissociated cell in vivo prostate regeneration model to investigate prostate cancer. PMID- 26631130 TI - Biochemical Analysis of Initiator Caspase-Activating Complexes: The Apoptosome and the Death-Inducing Signaling Complex. AB - Apoptosis is a highly regulated process that can be initiated by activation of death receptors or perturbation of mitochondria causing the release of apoptogenic proteins. This results in the activation of caspases, which are responsible for many of the biochemical and morphological changes associated with apoptosis. Caspases are normally inactive and require activation in a cascade emanating from an "initiator" or activating caspase, which in turn activates a downstream or "effector" caspase. Activation of initiator caspases is tightly regulated and requires the assembly of caspase-9 (via mitochondrial perturbation) or caspase-8/10 (via death receptor ligation) activating complexes, which are termed the apoptosome and the death-inducing signaling complex (DISC), respectively. These large multiprotein complexes can initially be separated according to size by gel filtration chromatography and subsequently analyzed by affinity purification or immunoprecipitation. The advantage of combining these techniques is one can first assess the assembly of individual components into a multiprotein complex, and then assess the size and composition of the native functional signaling platform within a particular cell type alongside a biochemical analysis of the enriched/purified complex. Here, we describe various methods currently used for characterization of the apoptosome and DISC. PMID- 26631131 TI - Purification of Early and Late Endosomes. AB - Proteomic analysis of early and late endosomes has been constrained by the limited purity of the endosomal fractions that can be achieved by biochemical methods. Here we briefly review endocytic pathways, and then introduce fractionation strategies that have been used to improve the purity of isolated endosomes. In addition, we describe innovative proteomics analysis methods that have been shown to partially circumvent the limitations found in the enrichment steps. PMID- 26631132 TI - The Saccharomyces Genome Database: A Tool for Discovery. AB - The Saccharomyces Genome Database (SGD) is the main community repository of information for the budding yeast, Saccharomyces cerevisiae. The SGD has collected published results on chromosomal features, including genes and their products, and has become an encyclopedia of information on the biology of the yeast cell. This information includes gene and gene product function, phenotype, interactions, regulation, complexes, and pathways. All information has been integrated into a unique web resource, accessible via http://yeastgenome.org. The website also provides custom tools to allow useful searches and visualization of data. The experimentally defined functions of genes, mutant phenotypes, and sequence homologies archived in the SGD provide a platform for understanding many fields of biological research. The mission of SGD is to provide public access to all published experimental results on yeast to aid life science students, educators, and researchers. As such, the SGD has become an essential tool for the design of experiments and for the analysis of experimental results. PMID- 26631133 TI - Recombinant Fluorescent Rabies Virus Vectors for Tracing Neurons and Synaptic Connections. AB - Recombinant rabies virus (RV) vectors expressing fluorescent proteins allow staining of neurons from many mammalian species and enable the study of neuron morphology. Because viral spread occurs only between neurons that have synaptic connections, these vectors also permit transsynaptic tracing. A recently established system for restriction of transsynaptic tracing to a single transsynaptic jump, dubbed monosynaptic tracing, uses glycoprotein gene defective, pseudotyped RV. This allows infection of defined cells and transient complementation with the glycoprotein in situ to support a single step of transsynaptic crossing to presynaptic cells. Here, we introduce protocols describing the production of RV vectors, including the recovery of recombinant RV from complementary DNA (cDNA) and virus pseudotyping in vitro. This allows retrograde staining of neurons projecting to the inoculation site. PMID- 26631134 TI - Enabling people, not completing tasks: patient perspectives on relationships and staff morale in mental health wards in England. AB - BACKGROUND: Mental health inpatient wards are stressful places to work and concerns have been raised regarding quality of patient care and staff wellbeing on these wards. Recent research has suggested that robust support systems and conditions that allow staff to exercise professional autonomy in their clinical work result in better staff morale. Staff value having a voice in their organisations, and say that they would like more interaction with patients and processes to reduce violent incidents on wards. There has been little research into patients' views on staff morale and on how it may impact on their care. This study aimed to explore staff morale and staff-patient relationships from a patient perspective. METHODS: A qualitative investigation was conducted using purposive sampling to select seven inpatient wards in England representing various subspecialties. Semi-structured interviews were carried out with three patients on each ward. A thematic approach to analysis was used, supported by NVivo 10 software. RESULTS: Patients valued staff who worked together as a cohesive team, treated them as individuals, practised in a collaborative way and used enabling approaches to support their recovery. Participating patients described observing staff closely and feeling concerned at times about their well being and the impact on them of stress and adverse incidents. They tended to perceive ward staff and patients as closely and reciprocally linked, with staff morale having a significant impact on patient well-being and vice versa. Some participants also described modifying their own behaviour because of concerns about staff well-being. Administrative duties, staff shortages and detrimental effects of violent incidents on the ward were seen as compromising staff members' ability to be involved with patients' lives and care. CONCLUSION: Patient views about the factors impacting on staff morale on inpatient wards are similar to those of staff in qualitative studies. Their accounts suggest that staff and patient morale should be seen as interlinked, suggesting there is scope for interventions to benefit both. PMID- 26631135 TI - Early macular ganglion cell-inner plexiform layer analysis in non-arteritic anterior ischemic optic neuropathy. AB - PURPOSE: To investigate the potential usefulness of early macular ganglion cell inner plexiform layer (mGCIPL) measurement for detecting retinal ganglion cell damage in eyes with non-arteritic anterior ischemic optic neuropathy (NAION). METHODS: Thirteen patients with NAION were examined within 1 month of visual disturbance onset and underwent spectral domain optical coherence tomography (SD OCT) measurement of the mGCIPL and peripapillary retinal nerve fiber layer (pRNFL). Complete ophthalmologic evaluations, including visual acuity and visual field (VF) test, were performed. The time to minimum and average mGCIPL and pRNFL thinning were investigated. The correlation between the area of mGCIPL thinning and the affected VF area was also analyzed. RESULTS: Thirteen eyes of 13 patients with NAION were included. The length of time from visual disturbance onset to minimum and average mGCIPL thinning was 32.5 +/- 12.1 days and 46.1 +/- 23.2 days, respectively, and the time to pRNFL thinning was 79.2 +/- 19.7 days. There was a significant regional correlation between the area of mGCIPL loss and that of the VF defect in the early phase (r = 0.610; p = 0.027). However, the area of mGCIPL thinning in the late phase did not correlate with that of late VF defects. CONCLUSIONS: In the early phase, mGCIPL thinning was observed, and the area of mGCIPL thinning correlated with that of the VF defect in eyes with NAION. Therefore, early retinal ganglion cell damage and dysfunction may be detected in NAION by measurement of mGCIPL using SD-OCT. PMID- 26631136 TI - Intravitreal bevacizumab injections combined with laser photocoagulation for adult-onset Coats' disease. AB - PURPOSE: To evaluate the efficacy of intravitreal bevacizumab injections combined with laser photocoagulation in the treatment of adult-onset Coats' disease. METHODS: Thirteen eyes of 13 patients suffering from adult-onset Coats' disease were retrospectively included and analyzed. All patients were treated at baseline using intravitreal bevacizumab injections combined with laser photocoagulation. Follow-up treatment was performed as necessary. RESULTS: The mean age of the subjects was 40.3 years, and the mean follow-up period was 24.8 months. The mean number of bevacizumab injections was 2.69, and the mean number of laser treatment sessions was 1.68. The mean baseline best-corrected visual acuity (BCVA) was 0.72 logarithm of the minimum angle of resolution (logMAR; 20/104 Snellen equivalent), while the mean BCVA at the final visit was 0.68 logMAR (20/95; P = 0.548). In three patients (23.0 %), BCVA had improved by more than 3 lines, and seven patients (54.0 %) showed stable BCVA (changes within 2 lines of visual acuity) after treatment. The mean central foveal thickness improved significantly, from 473 MUm at baseline to 288 MUm at the final visit (P = 0.023). Final BCVA was significantly correlated with a baseline BCVA (P < 0.001; rho = 0.882). The final BCVA of patients who had subfoveal hard exudates at baseline was significantly worse than that of patients without such exudates (P = 0.005). CONCLUSIONS: Intravitreal bevacizumab injection combined with laser photocoagulation may be an effective treatment option for adult-onset Coats' disease. Both poor initial BCVA and the occurrence of subfoveal hard exudates at baseline were associated with poor prognosis and poor therapeutic response. PMID- 26631137 TI - Interpretation of fundus autofluorescence changes in choriocapillaritis: a multi modality imaging study. AB - PURPOSE: We aimed to describe imaging findings in primary inflammatory choriocapillaropathies (PICCPs) after a photobleaching process. METHODS: 2Images from six consecutive cases of patients affected by PICCPs (four with multiple evanescent white dot syndrome and two with multifocal choroiditis) were reviewed. Patients underwent fundus autofluorescence (FAF), fluorescein angiography (FA), indocyanine green angiography (ICGA), and spectral-domain optical coherence tomography (SD-OCT) by means of the Spectralis HRA (Heidelberg Engineering, Heidelberg, Germany). FAF images were acquired at the beginning of the examination in partially dark-adapted conditions followed by light adapted conditions. RESULTS: During the active phase of the diseases, all patients showed areas of increased FAF that became isoautofluorescent after photobleaching. Simultaneously with increased FAF, the ICGA showed typical hypofluorescent dark areas that were more evident in the late phase. SD-OCT showed disruptions in the hyper-reflective band at the ellipsoid zone. CONCLUSIONS: FAF and SD-OCT are complementary imaging techniques that show alterations in the outer retina of patients affected by PICCPs. PMID- 26631138 TI - Process quality indicators in family medicine: results of an international comparison. AB - BACKGROUND: The aim of our study was to describe variability in process quality in family medicine among 31 European countries plus Australia, New Zealand, and Canada. The quality of family medicine was measured in terms of continuity, coordination, community orientation, and comprehensiveness of care. METHODS: The QUALICOPC study (Quality and Costs of Primary Care in Europe) was carried out among family physicians in 31 European countries (the EU 27 except for France, plus Macedonia, Iceland, Norway, Switzerland, and Turkey) and three non-European countries (Australia, Canada, and New Zealand). We used random sampling when national registers of practitioners were available. Regional registers or lists of facilities were used for some countries. A standardized questionnaire was distributed to the physicians, resulting in a sample of 6734 participants. Data collection took place between October 2011 and December 2013. Based on completed questionnaires, a three-dimensional framework was established to measure continuity, coordination, community orientation, and comprehensiveness of care. Multilevel linear regression analysis was performed to evaluate the variation of quality attributable to the family physician level and the country level. RESULTS: None of the 34 countries in this study consistently scored the best or worst in all categories. Continuity of care was perceived by family physicians as the most important dimension of quality. Some components of comprehensiveness of care, including medical technical procedures, preventive care and health care promotion, varied substantially between countries. Coordination of care was identified as the weakest part of quality. We found that physician-level characteristics contributed to the majority of variation. CONCLUSIONS: A comparison of process quality indicators in family medicine revealed similarities and differences within and between countries. The researchers found that the major proportion of variation can be explained by physicians' characteristics. PMID- 26631139 TI - Involvement of small heat shock proteins, trehalose, and lipids in the thermal stress management in Schizosaccharomyces pombe. AB - Changes in the levels of three structurally and functionally different important thermoprotectant molecules, namely small heat shock proteins (sHsps), trehalose, and lipids, have been investigated upon heat shock in Schizosaccharomyces pombe. Both alpha-crystallin-type sHsps (Hsp15.8 and Hsp16) were induced after prolonged high-temperature treatment but with different kinetic profiles. The shsp null mutants display a weak, but significant, heat sensitivity indicating their importance in the thermal stress management. The heat induction of sHsps is different in wild type and in highly heat-sensitive trehalose-deficient (tps1Delta) cells; however, trehalose level did not show significant alteration in shsp mutants. The altered timing of trehalose accumulation and induction of sHsps suggest that the disaccharide might provide protection at the early stage of the heat stress while elevated amount of sHsps are required at the later phase. The cellular lipid compositions of two different temperature-adapted wild type S. pombe cells are also altered according to the rule of homeoviscous adaptation, indicating their crucial role in adapting to the environmental temperature changes. Both Hsp15.8 and Hsp16 are able to bind to different lipids isolated from S. pombe, whose interaction might provide a powerful protection against heat-induced damages of the membranes. Our data suggest that all the three investigated thermoprotectant macromolecules play a pivotal role during the thermal stress management in the fission yeast. PMID- 26631140 TI - Galectin-3 suppresses mucosal inflammation and reduces disease severity in experimental colitis. AB - Galectin-3, a member of the beta-galactoside-binding lectin family, expresses in many different immune cells and modulates broad biological functions including cell adhesion, cell activation, cell growth, apoptosis, and inflammation. However, the role of galectin-3 in mucosal immunity or inflammatory bowel diseases is still not clear. We demonstrate here that galectin-3 knockout mice have more severe disease activity in the dextran sulfate sodium (DSS)-induced colitis model, indicating that galectin-3 may protect from inflammation in DSS induced colitis. Furthermore, treating with galectin-3 reduced body weight loss, shortened colonic length, and ameliorated mucosal inflammation in mice having DSS induced colitis. However, the protective effects of galectin-3 were eliminated by the administration of anti-CD25 mAb. In addition, primary T cells treated with galectin-3 ex vivo induced the expression of FOXP3, ICOS, and PD-1 with a Treg cell phenotype having a suppression function. Moreover, adoptive transfer of galectin-3-treated T cells reduced bowel inflammation and colitis in the T cell transfer colitis model. In conclusion, our results indicate that galectin-3 inhibited colonic mucosa inflammation and reduced disease severity by inducing regulatory T cells, suggesting that it is a potential therapeutic approach in inflammatory bowel disease. KEY MESSAGES: Galectin-3 offers protection from inflammation in experimental colitis. Galectin-3 knockout mice have more severe disease activity in DSS-induced colitis. Adoptive transfer of galectin-3-treated T cells reduced bowel inflammation. Galectin-3 inhibited colonic mucosa inflammation by inducing regulatory T cells. Galectin-3 is a potential therapeutic approach in inflammatory bowel disease. PMID- 26631141 TI - NFkappaB-sensitive Orai1 expression in the regulation of FGF23 release. AB - Fibroblast growth factor (FGF23) plasma levels are elevated in cardiac and renal failure and correlate with poor clinical prognosis of those disorders. Both disorders are associated with inflammation and activation of the inflammatory transcription factor NFkappaB. An excessive FGF23 level is further observed in Klotho-deficient mice. The present study explored a putative sensitivity of FGF23 expression to transcription factor NFkappaB, which is known to upregulate Orai1, the Ca(2+) channel accomplishing store-operated Ca(2+) entry (SOCE). In osteoblastic cells (UMR106) and immortalized primary periosteal (IPO) cells, protein abundance was determined by Western blotting, and in UMR106 cells, transcript levels were quantified by RT-PCR, cytosolic Ca(2+) activity utilizing Fura-2-fluorescence, and SOCE from Ca(2+) entry following store depletion by thapsigargin. As a result, UMR106 and IPO cells expressed Ca(2+) channel Orai1. SOCE was lowered by NFkappaB inhibitor wogonin as well as by Orai1 inhibitors 2 APB and YM58483. UMR106 cell Fgf23 transcripts were increased by stimulation of SOCE and Ca(2+) ionophore ionomycin and decreased by Orai inhibitors 2-APB, YM58483 and SK&F96365, by Orai1 silencing, as well as by NFkappaB inhibitors wogonin, withaferin A, and CAS 545380-34-5. In conclusion, Fgf23 expression is upregulated by stimulation of NFkappaB-sensitive, store-operated Ca(2+) entry. KEY MESSAGES: Osteoblast UMR106 and IPO cells express Ca(2+) channel Orai1. Osteoblast store-operated Ca(2+) entry is accomplished by NFkappaB-sensitive Orai1. Osteoblast Fgf23 transcription is upregulated by increase in the cytosolic Ca(2+) activity. Fgf23 transcription is decreased by Orai inhibitors and Orai1 silencing. Fgf23 transcription is lowered by NFkappaB inhibitors. PMID- 26631142 TI - Electrical signal propagated across acupoints along Foot Taiyang Bladder Meridian in rats. AB - OBJECTIVE: To investigate the electrical signals propagated along Foot Taiyang Bladder Meridian (BL) in a rat model. METHODS: The experiments were performed on Dark-Agouti (DA), DA.1U and Sprague Dawley (SD) rats. The antidromic electrical stimulation was applied on the nerve innervating "Pishu" (BL 20) to mimic the acupoint electro-acupuncture (EA). The activities recording from adjacent nerve innervating acupoint "Danshu" (BL 19) or "Weishu" (BL 21) were recorded as indics for acupoint, including the mechanical threshold and discharge rate. RESULTS: After mimic EA on BL 20, C and Adelta units from adjacent BL 19 or BL 21 were sensitized including the decrease in mechanical threshold and increase in discharge rates in DA, DA.1U and SD rats, especially in DA rats. The average discharge rate increased from 2.40+/-0.26 to 6.06+/-0.55 and from 1.92+/-0.42 to 6.17+/-1.10 impulse/min (P<0.01), and the mechanical threshold decreased from 0.52+/-0.12 to 0.24+/-0.05 and from 0.27+/-0.02 to 0.16+/-0.01 mmol/L (P<0.01) in C (n=15) and Adelta (n=18) units in DA rats. The net change in discharge rates from C units were 152.5%, 144.7% and 42.4% in DA, DA.1U and SD rats, respectively, among which DA rat's was the highest (P<0.05). In Adelta units, the net change in DA rats were also the highest (221.5%, 139.2% and 49.2% in DA, DA.1U and SD rats). CONCLUSIONS: These results showed that mimic acupoint EA activated adjacent acupoints along BL in three rat strains, which might be related to propagated sensation along meridians (PSM). In addition, DA rats were more sensitive and might be a good model animal for PSM research. PMID- 26631143 TI - Can explicit visual feedback of postural sway efface the effects of sensory manipulations on mediolateral balance performance? AB - Explicit visual feedback on postural sway is often used in balance assessment and training. However, up-weighting of visual information may mask impairments of other sensory systems. We therefore aimed to determine whether the effects of somatosensory, vestibular, and proprioceptive manipulations on mediolateral balance are reduced by explicit visual feedback on mediolateral sway of the body center of mass and by the presence of visual information. We manipulated sensory inputs of the somatosensory system by transcutaneous electric nerve stimulation on the feet soles (TENS) of the vestibular system by galvanic vestibular stimulation (GVS) and of the proprioceptive system by muscle-tendon vibration (VMS) of hip abductors. The effects of these manipulations on mediolateral sway were compared with a control condition without manipulation under three visual conditions: explicit feedback of sway of the body center of mass (FB), eyes open (EO), and eyes closed (EC). Mediolateral sway was quantified as the sum of energies in the power spectrum and as the energy at the dominant frequencies in each of the manipulation signals. Repeated-measures ANOVAs were used to test effects of each of the sensory manipulations, of visual conditions and their interaction. Overall, sensory manipulations increased body sway compared with the control conditions. Absence of normal visual information had no effect on sway, while explicit feedback reduced sway. Furthermore, interactions of visual information and sensory manipulation were found at specific dominant frequencies for GVS and VMS, with explicit feedback reducing the effects of the manipulations but not effacing these. PMID- 26631144 TI - Flexible adaptation to an artificial recurrent connection from muscle to peripheral nerve in man. AB - Controlling a neuroprosthesis requires learning a novel input-output transformation; however, how subjects incorporate this into limb control remains obscure. To elucidate the underling mechanisms, we investigated the motor adaptation process to a novel artificial recurrent connection (ARC) from a muscle to a peripheral nerve in healthy humans. In this paradigm, the ulnar nerve was electrically stimulated in proportion to the activation of the flexor carpi ulnaris (FCU), which is ulnar-innervated and monosynaptically innervated from Ia afferents of the FCU, defined as the "homonymous muscle," or the palmaris longus (PL), which is not innervated by the ulnar nerve and produces similar movement to the FCU, defined as the "synergist muscle." The ARC boosted the activity of the homonymous muscle and wrist joint movement during a visually guided reaching task. Participants could control muscle activity to utilize the ARC for the volitional control of wrist joint movement and then readapt to the absence of the ARC to either input muscle. Participants reduced homonymous muscle recruitment with practice, regardless of the input muscle. However, the adaptation process in the synergist muscle was dependent on the input muscle. The activity of the synergist muscle decreased when the input was the homonymous muscle, whereas it increased when it was the synergist muscle. This reorganization of the neuromotor map, which was maintained as an aftereffect of the ARC, was observed only when the input was the synergist muscle. These findings demonstrate that the ARC induced reorganization of neuromotor map in a targeted and sustainable manner. PMID- 26631145 TI - Transfer of tactile perceptual learning to untrained neighboring fingers reflects natural use relationships. AB - Tactile learning transfers from trained to untrained fingers in a pattern that reflects overlap between the representations of fingers in the somatosensory system (e.g., neurons with multifinger receptive fields). While physical proximity on the body is known to determine the topography of somatosensory representations, tactile coactivation is also an established organizing principle of somatosensory topography. In this study we investigated whether tactile coactivation, induced by habitual inter-finger cooperative use (use pattern), shapes inter-finger overlap. To this end, we used psychophysics to compare the transfer of tactile learning from the middle finger to its adjacent fingers. This allowed us to compare transfer to two fingers that are both physically and cortically adjacent to the middle finger but have differing use patterns. Specifically, the middle finger is used more frequently with the ring than with the index finger. We predicted this should lead to greater representational overlap between the former than the latter pair. Furthermore, this difference in overlap should be reflected in differential learning transfer from the middle to index vs. ring fingers. Subsequently, we predicted temporary learning-related changes in the middle finger's representation (e.g., cortical magnification) would cause transient interference in perceptual thresholds of the ring, but not the index, finger. Supporting this, longitudinal analysis revealed a divergence where learning transfer was fast to the index finger but relatively delayed to the ring finger. Our results support the theory that tactile coactivation patterns between digits affect their topographic relationships. Our findings emphasize how action shapes perception and somatosensory organization. PMID- 26631147 TI - Vestibulo-spinal and vestibulo-ocular reflexes are modulated when standing with increased postural threat. AB - We investigated how vestibulo-spinal reflexes (VSRs) and vestibulo-ocular reflexes (VORs) measured through vestibular evoked myogenic potentials (VEMPs) and video head impulse test (vHIT) outcomes, respectively, are modulated during standing under conditions of increased postural threat. Twenty-five healthy young adults stood quietly at low (0.8 m from the ground) and high (3.2 m) surface height conditions in two experiments. For the first experiment (n = 25) VEMPs were recorded with surface EMG from inferior oblique (IO), sternocleidomastoid (SCM), trapezius (TRP), and soleus (SOL) muscles in response to 256 air-conducted short tone bursts (125 dB SPL, 500 Hz, 4 ms) delivered via headphones. A subset of subjects (n = 19) also received horizontal and vertical head thrusts (~150 degrees /s) at each height in a separate session, comparing eye and head velocities by using a vHIT system for calculating the functional VOR gains. VEMP amplitudes (IO, TRP, SOL) and horizontal and vertical vHIT gains all increased with high surface height conditions (P < 0.05). Changes in IO and SCM VEMP amplitudes as well as horizontal vHIT gains were correlated with changes in electrodermal activity (rho = 0.44-0.59, P < 0.05). VEMP amplitude for the IO also positively correlated with fear (rho = 0.43, P = 0.03). Threat-induced anxiety, fear, and arousal have significant effects on VSR and VOR gains that can be observed in both physiological and functional outcome measures. These findings provide support for a potential central modulation of the vestibular nucleus complex through excitatory inputs from neural centers involved in processing fear, anxiety, arousal, and vigilance. PMID- 26631146 TI - Neuronal selectivity for spatial positions of offers and choices in five reward regions. AB - When we evaluate an option, how is the neural representation of its value linked to information that identifies it, such as its position in space? We hypothesized that value information and identity cues are not bound together at a particular point but are represented together at the single unit level throughout the entirety of the choice process. We examined neuronal responses in two-option gambling tasks with lateralized and asynchronous presentation of offers in five reward regions: orbitofrontal cortex (OFC, area 13), ventromedial prefrontal cortex (vmPFC, area 14), ventral striatum (VS), dorsal anterior cingulate cortex (dACC), and subgenual anterior cingulate cortex (sgACC, area 25). Neuronal responses in all areas are sensitive to the positions of both offers and of choices. This selectivity is strongest in reward-sensitive neurons, indicating that it is not a property of a specialized subpopulation of cells. We did not find consistent contralateral or any other organization to these responses, indicating that they may be difficult to detect with aggregate measures like neuroimaging or studies of lesion effects. These results suggest that value coding is wed to factors that identify the object throughout the reward system and suggest a possible solution to the binding problem raised by abstract value encoding schemes. PMID- 26631148 TI - A foveal target increases catch-up saccade frequency during smooth pursuit. AB - Images that move rapidly across the retina of the human eye blur because the retina has sluggish temporal dynamics. Voluntary smooth pursuit eye movements are modeled as matching object velocity to minimize retinal motion and prevent retinal blurring. However, "catch-up" saccades that are ubiquitous during pursuit interrupt it and disrupt clear vision. But catch-up saccades may not be a common feature of ocular pursuit, because their existence has been documented with a small moving spot, the classic pursuit stimulus, which is a weak motion stimulus that may poorly emulate larger pursuit objects. We found that spot pursuit does not generalize to that of larger objects. Observers pursued a spot or a larger virtual object with or without a superimposed spot target. Single-spot targets produced lower pursuit acceleration than larger objects. Critically, more saccadic intrusions occurred when stimuli had a central dot, even when position and velocity errors were equated, suggesting that catch-up saccades result from pursuing a single, small object or a feature on a large one. To determine what differentiates a large object from a small one, we progressively shrank the featureless virtual object and found that catch-up saccade frequency was highest when it fit in the fovea. The results suggest that pursuit of a small target or an object feature recruits a saccade mechanism that does not compensate for a weak motion signal; rather, the target compels foveation. Furthermore, catch-up saccades are likely generated by neural circuitry typically used to foveate small objects or features. PMID- 26631149 TI - The tactile speed aftereffect depends on the speed of adapting motion across the skin rather than other spatiotemporal features. AB - After prolonged exposure to a surface moving across the skin, this felt movement appears slower, a phenomenon known as the tactile speed aftereffect (tSAE). We asked which feature of the adapting motion drives the tSAE: speed, the spacing between texture elements, or the frequency with which they cross the skin. After adapting to a ridged moving surface with one hand, participants compared the speed of test stimuli on adapted and unadapted hands. We used surfaces with different spatial periods (SPs; 3, 6, 12 mm) that produced adapting motion with different combinations of adapting speed (20, 40, 80 mm/s) and temporal frequency (TF; 3.4, 6.7, 13.4 ridges/s). The primary determinant of tSAE magnitude was speed of the adapting motion, not SP or TF. This suggests that adaptation occurs centrally, after speed has been computed from SP and TF, and/or that it reflects a speed cue independent of those features in the first place (e.g., indentation force). In a second experiment, we investigated the properties of the neural code for speed. Speed tuning predicts that adaptation should be greatest for speeds at or near the adapting speed. However, the tSAE was always stronger when the adapting stimulus was faster (242 mm/s) than the test (30-143 mm/s) compared with when the adapting and test speeds were matched. These results give no indication of speed tuning and instead suggest that adaptation occurs at a level where an intensive code dominates. In an intensive code, the faster the stimulus, the more the neurons fire. PMID- 26631151 TI - Beyond the point of no return: effects of visual distractors on saccade amplitude and velocity. AB - Visual transients, such as a bright flash, reduce the proportion of saccades executed, ~60-125 ms after flash onset, a phenomenon known as saccadic inhibition (SI). Across three experiments, we apply a similar time-course analysis to the amplitudes and velocities of saccades. Alongside the expected reduction of saccade frequency in the key time period, we report two perturbations of the "main sequence": one before and one after the period of SI. First, saccades launched between 30 and 70 ms, following the flash, were hypometric, with peak speed exceeding that expected for a saccade of similar amplitude. This finding was in contrast to the common idea that saccades have passed a "point of no return," ~60 ms before launching, escaping interference from distractors. The early hypometric saccades observed were not a consequence of spatial averaging between target and distractor locations, as they were found not only following a localized central flash (experiment 1) but also following a spatially generalized flash (experiment 2). Second, across experiments, saccades launched at 110 ms postflash, toward the end of SI, had normal amplitude but a peak speed higher than expected for that amplitude, suggesting increased collicular excitation at the time of launching. Overall, the results show that saccades that escape inhibition following a visual transient are not necessarily unaffected but instead, can reveal interference in spatial and kinematic measures. PMID- 26631150 TI - Early postnatal switch in GABAA receptor alpha-subunits in the reticular thalamic nucleus. AB - The GABAergic neurons of the thalamic reticular nucleus (nRt) provide the primary source of inhibition within the thalamus. Using physiology, pharmacology, and immunohistochemistry in mice, we characterized postsynaptic developmental changes in these inhibitory projection neurons. First, at postnatal days 3-5 (P3-5), inhibitory postsynaptic currents (IPSCs) decayed very slowly, followed by a biphasic developmental progression, becoming faster at P6-8 and then slower again at P9-11 before stabilizing in a mature form around P12. Second, the pharmacological profile of GABA(A) receptor (GABA(A)R)-mediated IPSCs differed between neonatal and mature nRt neurons, and this was accompanied by reciprocal changes in alpha3 (late) and alpha5 (early) subunit expression in nRt. Zolpidem, selective for alpha1- and alpha3-containing GABA(A)Rs, augmented only mature IPSCs, whereas clonazepam enhanced IPSCs at all stages. This effect was blocked by the alpha5-specific inverse agonist L-655,708, but only in immature neurons. In alpha3(H126R) mice, in which alpha3-subunits were mutated to become benzodiazepine insensitive, IPSCs were enhanced compared with those in wild-type animals in early development. Third, tonic GABA(A)R activation in nRt is age dependent and more prominent in immature neurons, which correlates with early expression of alpha5-containing GABA(A)Rs. Thus neonatal nRt neurons show relatively high expression of alpha5-subunits, which contributes to both slow synaptic and tonic extrasynaptic inhibition. The postnatal switch in GABA(A)R subunits from alpha5 to alpha3 could facilitate spontaneous network activity in nRt that occurs at this developmental time point and which is proposed to play a role in early circuit development. PMID- 26631153 TI - Femtosecond to Microsecond Dynamics of Soret-Band Excited Corroles. AB - We present a comprehensive photophysical investigation on a series of three corroles (TTC, P-TTC, Ge-TTC dissolved in toluene), employing femtosecond and nanosecond transient absorption spectroscopy (TAS) measurements. Systematic analyses of the TAS data determined the rates and corresponding time constants of photophysical processes: internal conversion (tauIC) in the 898-525 fs range, vibrational relaxation (tau_VR) in the 7.44-13.6 ps range, intersystem crossing (tauISC ) in the 033-1.09 ns range and triplet lifetime (tau_triplet) in the 0.8 3.5MUs range. The estimated triplet quantum yields (PhiTriplet) were in the 0.42 0.61 range. Comparatively, GeTTC displayed faster tauIC and higher(PhiTriplet). Additionally, the time-dependent density functional theory (DFT) calculations were performed for the three molecules. The HOMO/LUMO energy levels and the oscillator strengths of various transitions were determined and presented. PMID- 26631152 TI - Optogenetic spatial and temporal control of cortical circuits on a columnar scale. AB - Many circuits in the mammalian brain are organized in a topographic or columnar manner. These circuits could be activated-in ways that reveal circuit function or restore function after disease-by an artificial stimulation system that is capable of independently driving local groups of neurons. Here we present a simple custom microscope called ProjectorScope 1 that incorporates off-the-shelf parts and a liquid crystal display (LCD) projector to stimulate surface brain regions that express channelrhodopsin-2 (ChR2). In principle, local optogenetic stimulation of the brain surface with optical projection systems might not produce local activation of a highly interconnected network like the cortex, because of potential stimulation of axons of passage or extended dendritic trees. However, here we demonstrate that the combination of virally mediated ChR2 expression levels and the light intensity of ProjectorScope 1 is capable of producing local spatial activation with a resolution of ~200-300 MUm. We use the system to examine the role of cortical activity in the experience-dependent emergence of motion selectivity in immature ferret visual cortex. We find that optogenetic cortical activation alone-without visual stimulation-is sufficient to produce increases in motion selectivity, suggesting the presence of a sharpening mechanism that does not require precise spatiotemporal activation of the visual system. These results demonstrate that optogenetic stimulation can sculpt the developing brain. PMID- 26631154 TI - Plasma microRNA profiling of children with idiopathic dilated cardiomyopathy. AB - CONTEXT: Dilated cardiomyopathy (DCM) is the most common cardiomyopathy in children. MicroRNAs (miRNA) are small RNAs which have regulatory functions in many biological processes. OBJECTIVE: We aimed to determine miRNA expression levels in plasma of children with DCM. MATERIALS AND METHODS: Plasma expression levels of 379 miRNAs were compared between 23 DCM and 26 healthy children. RESULTS: The expression levels of miR-618, miR-875-3p, miR-205, miR-194, miR 302a, miR-147, and miR-544 were found decreased. The expression levels of miR 518f and miR-454 were found increased in DCM patients. DISCUSSION: miRNA level differences may provide the chance of using these miRNAs as new biomarkers. PMID- 26631155 TI - Using Questions in Cognitive Therapy with People with Intellectual Disabilities. AB - BACKGROUND: There is increasing interest in the provision of cognitive behaviour therapy (CBT) to people with intellectual disabilities. A small number of studies have begun to address therapy process issues. AIMS: The aim of this paper is to contribute to process research through the development of a taxonomy of question types for use in analysing therapy interactions in CBT for people with intellectual disabilities. METHOD: A taxonomy of CBT question types was adapted and applied to the transcriptions of session 4 and 9 of 15 CBT therapy dyads. RESULTS: The taxonomy was reliably applied to the data. Therapists used significantly more questions in session 4 than in session 9, therapists used fewer questions in the final quarter of all sessions, and therapists used more questions with people with higher IQ scores in session 4 but not in session 9. CONCLUSIONS: The taxonomy of questions is reliable and may be used in future studies of CBT therapy process with people with intellectual disabilities. PMID- 26631156 TI - Predictive factors for time to recurrence, treatment and post-recurrence survival in patients with initially resected colorectal liver metastases. AB - BACKGROUND: Despite progress in resection for colorectal liver metastases (CLM), the majority of patients experience recurrence. We aimed to evaluate factors influencing time to recurrence (TTR), treatment and post-recurrence survival (PRS) related to site of recurrence. METHODS: This is a retrospective population based cohort study (1998-2012) of consecutive patients without extrahepatic disease treated with resection for CLM in a referral centre. RESULTS: A total of 311 patients underwent resection for CLM. After a median follow-up of 4.2 years (range 1.2-15.2), 209 (67.4 %) patients developed recurrence, hepatic 90, extrahepatic 59 and both 60. Median TTR was 14.0 months, and 5-year recurrence free status was 25.7 %. Five- and 10-year overall survival (OS) was 38.8 and 22.0 %, respectively. Median OS was 45 months. A multivariate analysis displayed synchronous disease (hazard ratio (HR) 1.50), American Society of Anaesthesiologists (ASA) score (HR 1.40), increasing number (HR 1.24) and size of metastases (HR 1.08) to shorten TTR (all p < 0.05). Perioperative chemotherapy (n = 59) increased overall TTR (HR 0.63) and overall survival (OS; HR 0.55). Hepatic TTR was correlated to synchronous disease (HR 2.07), number of lesions (HR 1.20), R1 resection (HR 2.00) and ASA score (HR 1.69), whereas extrahepatic TTR was correlated to N stage of the primary (HR 1.79), number (HR 1.27) and size of metastases (HR 1.16). Single-site recurrence was most common (135 of 209, 64.5 %), while 58 patients had double- and 16 triple-site relapses. Median PRS was 24.3 months. There was a difference in median PRS (months) according to site of relapse: liver 30.5, lung 32.3, abdominal 22.0, liver and lung 14.3, others 14.8 (p = 0.002). Repeated liver resections were performed in n = 57 patients resulting in 40.6 months median OS and 36.8 % 5-year OS. CONCLUSIONS: An adverse overall TTR was correlated to number and size of metastases, ASA score and synchronous disease. Perioperative chemotherapy increased TTR and OS after surgery for CLM. Patients with solitary post-resection relapse in the liver or lungs had the potential for longevity due to multimodal treatment. PMID- 26631157 TI - Development of a fluorescent probe-based recombinase polymerase amplification assay for rapid detection of Orf virus. AB - BACKGROUND: Orf virus (ORFV) is the causative agent of Orf (also known as contagious ecthyma or contagious papular dermatitis), a severe infectious skin disease in goats, sheep and other ruminants. The rapid detection of ORFV is of great importance in disease control and highly needed. A isothermal molecular diagnostic approach, termed recombinase polymerase amplification (RPA), is considered as an novel and rapid alternative techonology to PCR assay. RESULTS: In the present study, a novel fluorescent probe based on RPA assay (ORFV exo RPA assay) was developed. The developed ORFV exo RPA assay was capable of as low as 100 copies of ORFV DNA /reaction and was highly specific, with no cross-reaction with closely related viruses (capripox virus, foot-and-mouth disease virus or peste des petits ruminants virus). Further assessment with clinical samples showed that the developed ORFV exo RPA assay has good correlation with qPCR assays for detection of ORFV. CONCLUSIONS: These results suggest that the developed ORFV exo RPA assay is suitable for rapid detection of ORFV. PMID- 26631158 TI - Primary hyperparathyroidism during pregnancy: management by minimally invasive surgery based on ultrasound localization. AB - BACKGROUND: Primary hyperparathyroidism in pregnancy has the potential to seriously impact the mother and foetus. Management may be difficult because the condition is usually diagnosed during pregnancy necessitating a rapid decision to proceed with surgery. Minimally invasive surgery is appealing due to shorter operative times and lower risk of complications. METHOD: We present a consecutive series of eight women diagnosed with hyperparathyroidism during pregnancy. RESULTS: All eight women were treated successfully by parathyroidectomy during pregnancy with no maternal or foetal complications. Seven of these 8 women were treated with minimally invasive parathyroidectomy based on ultrasound localization. CONCLUSION: Where ultrasound localization is performed by experienced endocrine surgeons, minimally invasive parathyroidectomy is a feasible and safe approach in the pregnant patient with primary hyperparathyroidism. PMID- 26631159 TI - The impact of global budgeting on health service utilization, health care expenditures, and quality of care among patients with pneumonia in Taiwan. AB - This study evaluated the effect of global budgeting on health service utilization, health care expenditures, and the quality of care among patients with pneumonia in Taiwan. The National Health Insurance Research Database (NHIRD) was used for analysis. Data on patients diagnosed with pneumonia during 2000-2001 (the prebudget group) were used as the baseline data, and data on patients diagnosed with pneumonia during 2004-2005 (the postbudget group) were used as the postintervention data. The length of stay (LOS), diagnostic costs, drug costs, therapy costs, total costs, risk of readmission within 14 days, and risk of revisiting the Emergency Department (ED) within 3 days of discharge before and after implementing the global budget system were analyzed and compared. Data on 32,535 patients with pneumonia were analyzed. The mean LOS increased from 6.36 +/ 0.07 to 10.78 +/- 0.09 days after implementing the global budget system. The mean total costs in the prebudget and postbudget groups were 22,697.82 +/- 542.40 and 62,016.7 +/- 793.19 New Taiwan dollars (NT$), respectively. The mean rate of revisiting the ED within 3 days decreased from 5.5 +/- 0.2 % to 4.6 +/- 0.1 % in the prebudget and postbudget groups, respectively. The mean rates of readmission within 14 days before were 6.1 +/- 0.2 % and 8.2 +/- 0.2 % in the prebudget and postbudget groups, respectively. Global budgeting is associated with a significantly longer LOS, higher health care costs, and poorer quality of care among patients with pneumonia. PMID- 26631160 TI - Eyes wide open: Pupil size as a proxy for inhibition in the masked-priming paradigm. AB - A core assumption underlying competitive-network models of word recognition is that in order for a word to be recognized, the representations of competing orthographically similar words must be inhibited. This inhibitory mechanism is revealed in the masked-priming lexical-decision task (LDT) when responses to orthographically similar word prime-target pairs are slower than orthographically different word prime-target pairs (i.e., inhibitory priming). In English, however, behavioral evidence for inhibitory priming has been mixed. In the present study, we utilized a physiological correlate of cognitive effort never before used in the masked-priming LDT, pupil size, to replicate and extend behavioral demonstrations of inhibitory effects (i.e., Nakayama, Sears, & Lupker, Journal of Experimental Psychology: Human Perception and Performance, 34, 1236 1260, 2008, Exp. 1). Previous research had suggested that pupil size is a reliable indicator of cognitive load, making it a promising index of lexical inhibition. Our pupillometric data replicated and extended previous behavioral findings, in that inhibition was obtained for orthographically similar word prime target pairs. However, our response time data provided only a partial replication of Nakayama et al. Journal of Experimental Psychology: Human Perception and Performance, 34, 1236-1260, 2008. These results provide converging lines of evidence that inhibition operates in word recognition and that pupillometry is a useful addition to word recognition researchers' toolbox. PMID- 26631162 TI - Austin L. Hughes 1949-2015. PMID- 26631161 TI - Effects of acupuncture and computer-assisted cognitive training for post-stroke attention deficits: study protocol for a randomized controlled trial. AB - BACKGROUND: A majority of stroke survivors present with cognitive impairments. Attention disturbance, which leads to impaired concentration and overall reduced cognitive functions, is strongly associated with stroke. The clinical efficacy of acupuncture with Baihui (GV20) and Shenting (GV24) as well as computer-assisted cognitive training in stroke and post-stroke cognitive impairment have both been demonstrated in previous studies. To date, no systematic comparison of these exists and the potential beneficial effects of a combined application are yet to be examined. The main objective of this pilot study is to evaluate the effects of computer-assisted cognitive training compared to acupuncture on the outcomes of attention assessments. The second objective is to test the effects of a combined cognitive intervention that incorporates computer-assisted cognitive training and acupuncture (ACoTrain). METHODS/DESIGN: An international multicentre, single blinded, randomised controlled pilot trial will be conducted. In a 1:1:1 ratio, 60 inpatients with post-stroke cognitive dysfunction will be randomly allocated into either the acupuncture group, the computer-assisted cognitive training group, or the ACoTrain group in addition to their individual rehabilitation programme. The intervention period of this pilot trial will last 4 weeks (30 minutes per day, 5 days per week, Monday to Friday). The primary outcome is the test battery for attentional performance. The secondary outcomes include the Trail Making Test, Test des Deux Barrages, National Institute of Health Stroke Scale, and Modified Barthel Index for assessment of daily life competence, and the EuroQol Questionnaire for health-related quality of life. DISCUSSION: This trial mainly focuses on evaluating the effects of computer-assisted cognitive training compared to acupuncture on the outcomes of attention assessments. The results of this pilot trial are expected to provide new insights on how Eastern and Western medicine can complement one another and improve the treatment of cognitive impairments in early stroke rehabilitation. Including patients with different cultural backgrounds allows a more generalisable interpretation of the results but also poses risks of performance bias. Using standardised and well described assessments, validated for each region, is pivotal to allow pooling of the data. TRIAL REGISTRATION: Clinical Trails.gov ID: NCT02324959 (8 December 2014). PMID- 26631163 TI - Retraction notice. PMID- 26631164 TI - Sperm-associated antigen 9 overexpression correlates with poor prognosis and insensitive to Taxol treatment in breast cancer. AB - Sperm-associated antigen 9 (SPAG9) has been reported to express in several cancers and have clinical significance. Using immunohistochemistry, we found that there was a strong association among SPAG9 expression and tumor size, TNM stage, histological grade, lymph node metastasis, and recurrence. It suggested that SPAG9-elevated expression was an independently prognostic indicator for both OS and DFS. Furthermore, the selected treatment of chemotherapy with Taxol/non-Taxol significantly affects OS and DFS. To sum up, SPAG9-elevated expression contributes to malignant behavior and poor prognosis of breast cancer and may support a potential indicator in treatment selection. PMID- 26631166 TI - Target rates for caesarean section may be too low, say researchers. PMID- 26631165 TI - Conformational dynamics of stem II of the U2 snRNA. AB - The spliceosome undergoes dramatic changes in both small nuclear RNA (snRNA) composition and structure during assembly and pre-mRNA splicing. It has been previously proposed that the U2 snRNA adopts two conformations within the stem II region: stem IIa or stem IIc. Dynamic rearrangement of stem IIa into IIc and vice versa is necessary for proper progression of the spliceosome through assembly and catalysis. How this conformational transition is regulated is unclear; although, proteins such as Cus2p and the helicase Prp5p have been implicated in this process. We have used single-molecule Forster resonance energy transfer (smFRET) to study U2 stem II toggling between stem IIa and IIc. Structural interconversion of the RNA was spontaneous and did not require the presence of a helicase; however, both Mg(2+) and Cus2p promote formation of stem IIa. Destabilization of stem IIa by a G53A mutation in the RNA promotes stem IIc formation and inhibits conformational switching of the RNA by both Mg(2+) and Cus2p. Transitioning to stem IIa can be restored using Cus2p mutations that suppress G53A phenotypes in vivo. We propose that during spliceosome assembly, Cus2p and Mg(2+) may work together to promote stem IIa formation. During catalysis the spliceosome could then toggle stem II with the aid of Mg(2+) or with the use of functionally equivalent protein interactions. As noted in previous studies, the Mg(2+) toggling we observe parallels previous observations of U2/U6 and Prp8p RNase H domain Mg(2+)-dependent conformational changes. Together these data suggest that multiple components of the spliceosome may have evolved to switch between conformations corresponding to open or closed active sites with the aid of metal and protein cofactors. PMID- 26631167 TI - Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C terminal negative amino acids. AB - Transient receptor potential canonical (TRPC) 4 channels are calcium-permeable, nonselective cation channels and are widely expressed in mammalian tissue, especially in the GI tract and brain. TRPC4 channels are known to be involved in neurogenic contraction of ileal smooth muscle cells via generating cationic current after muscarinic stimulation (muscarinic cationic current (mIcat)). Polyamines exist in numerous tissues and are believed to be involved in cell proliferation, differentiation, scar formation, wound healing, and carcinogenesis. Besides, physiological polyamines are essential to maintain inward rectification of cardiac potassium channels (Kir2.1). At membrane potentials more positive than equilibrium potential, intracellular polyamines plug the cytosolic surface of the Kir2.1 so that potassium ions cannot pass through the pore. Recently, it was reported that polyamines inhibit not only cardiac potassium channels but also nonselective cation channels that mediate the generation of mIcat. Here, we report that TRPC4, a definite mIcat mediator, is inhibited by intracellular spermine with great extent. The inhibition was specific to TRPC4 and TRPC5 channels but was not effective to TRPC1/4, TRPC1/5, and TRPC3 channels. For this inhibition to occur, we found that glutamates at 728th and 729th position of TRPC4 channels are essential whereby we conclude that spermine blocks the TRPC4 channel with electrostatic interaction between negative amino acids at the C-terminus of the channel. PMID- 26631168 TI - TRPM4-dependent post-synaptic depolarization is essential for the induction of NMDA receptor-dependent LTP in CA1 hippocampal neurons. AB - TRPM4 is a calcium-activated but calcium-impermeable non-selective cation (CAN) channel. Previous studies have shown that TRPM4 is an important regulator of Ca(2+)-dependent changes in membrane potential in excitable and non-excitable cell types. However, its physiological significance in neurons of the central nervous system remained unclear. Here, we report that TRPM4 proteins form a CAN channel in CA1 neurons of the hippocampus and we show that TRPM4 is an essential co-activator of N-methyl-D-aspartate (NMDA) receptors (NMDAR) during the induction of long-term potentiation (LTP). Disrupting the Trpm4 gene in mice specifically eliminates NMDAR-dependent LTP, while basal synaptic transmission, short-term plasticity, and NMDAR-dependent long-term depression are unchanged. The induction of LTP in Trpm4 (-/-) neurons was rescued by facilitating NMDA receptor activation or post-synaptic membrane depolarization. Accordingly, we obtained normal LTP in Trpm4 (-/-) neurons in a pairing protocol, where post synaptic depolarization was applied in parallel to pre-synaptic stimulation. Taken together, our data are consistent with a novel model of LTP induction in CA1 hippocampal neurons, in which TRPM4 is an essential player in a feed-forward loop that generates the post-synaptic membrane depolarization which is necessary to fully activate NMDA receptors during the induction of LTP but which is dispensable for the induction of long-term depression (LTD). These results have important implications for the understanding of the induction process of LTP and the development of nootropic medication. PMID- 26631169 TI - Nicorandil stimulates a Na+/Ca2+ exchanger by activating guanylate cyclase in guinea pig cardiac myocytes. AB - Nicorandil, a hybrid of an ATP-sensitive K(+) (KATP) channel opener and a nitrate generator, is used clinically for the treatment of angina pectoris. This agent has been reported to exert antiarrhythmic actions by abolishing both triggered activity and spontaneous automaticity in an in vitro study. It is well known that delayed afterdepolarizations (DADs) are caused by the Na(+)/Ca(2+) exchange current (I NCX). In this study, we investigated the effect of nicorandil on the cardiac Na(+)/Ca(2+) exchanger (NCX1). We used the whole-cell patch clamp technique and the Fura-2/AM (Ca(2+) indicator) method to investigate the effect of nicorandil on I NCX in isolated guinea pig ventricular myocytes and CCL39 fibroblast cells transfected with dog heart NCX1. Nicorandil enhanced I NCX in a concentration-dependent manner. The EC50 (half-maximum concentration for enhancement of the drug) values were 15.0 and 8.7 MUM for the outward and inward components of I NCX, respectively. 8-Bromoguanosine 3',5'-cyclic monophosphate (8 Br-cGMP), a membrane-permeable analog of guanosine 3',5'-cyclic monophosphate (cGMP), enhanced I NCX. 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor (10 MUM), completely abolished the nicorandil-induced I NCX increase. Nicorandil increased I NCX in CCL39 cells expressing wild-type NCX1 but did not affect mutant NCX1 without a long intracellular loop between transmembrane segments (TMSs) 5 and 6. Nicorandil at 100 MUM abolished DADs induced by electrical stimulation with ouabain. Nicorandil enhanced the function of NCX1 via guanylate cyclase and thus may accelerate Ca(2+) exit via NCX1. This may partially contribute to the cardioprotection by nicorandil in addition to shortening action potential duration (APD) by activating KATP channels. PMID- 26631170 TI - [Mechanical thrombectomy: Acute complications and delayed sequelae]. AB - BACKGROUND: Due to the positive evidence for mechanical thrombectomy (mTE), it will be increasingly used in future. Profound knowledge of potential complications, prevention and management of complications is necessary to safely implement mTE into clinical practice. AIM: Description of specific complications of mTE and their clinical relevance, measures for prevention and management. Summary of the current knowledge on long-term side effects of mTE. MATERIAL AND METHODS: Analysis of current trial results and selected case series to address specific topics. Summary of own practical clinical experience. RESULTS: Vascular injury (1-5%) and emboli (5-9%) are the most relevant intraprocedural complications but the clinical outcome is variable. Measures for prevention and management are described in detail. Vasospasms frequently occur (20-26%) but rarely need specific treatment and do not affect the clinical course. In the case of restrictive indications the frequency of symptomatic hemorrhage is similar to that for medicinal treatment (up to 8%). Contrast medium enhancement in the area of the infarction on post-treatment imaging should not be mistaken for hemorrhages. Focal subarachnoid contrast medium enhancement or hemorrhage occurs in up to 24% of cases and is predominantly benign. In follow-up imaging stenoses or occlusions can be detected in 4-10% of the treated vessels, most of which are asymptomatic. They are considered to be caused by microtrauma to the vascular wall. CONCLUSION: Clinically relevant complications of mTE are rare. Preventive measures and effective management of complications may even increase safety. Stenoses occasionally occur as a long-term side effect but are asymptomatic in the majority of cases. PMID- 26631171 TI - The acceptability of dietary tools to improve maternal and child nutrition in Western Kenya. AB - OBJECTIVE: Dietary practices in Kenya often fail to provide adequate nutrition during the first 1000 days of life, from conception to 2 years of age. We developed and qualitatively assessed the acceptability of easy-to-use dietary tools consisting of a marked bowl, slotted spoon and illustrated counselling card to support appropriate dietary practices during pregnancy, exclusive breast feeding and complementary feeding of children aged 6-24 months. DESIGN: We conducted qualitative research to assess community acceptability and obtain feedback on the design of the dietary tools. SETTING: This research took place in urban and rural communities in Western Kenya. SUBJECTS: We conducted twelve focus group discussions with community members (mothers, husbands, mothers-in-law, community leaders) and five interviews with government nutritionists to assess acceptability and obtain recommendations on design and delivery of the tools. We conducted 24-28 d of user testing with fourteen pregnant women, fourteen breast feeding women and thirty-two mothers with infants aged 6-18 months. RESULTS: Tools were positively received by communities. Mothers perceived improvements in their own and their children's food intakes including quantity, frequency, consistency and diversity. Many attributed perceived own and child's weight gain and/or increased energy to tool use. A minority reported using the bowl for other activities (n 9) or not using the bowl due to food insecurity (n 5). CONCLUSIONS: Results suggest that such tools have the potential to positively impact maternal and child dietary practices. Future work should quantitatively assess the impact on diet and nutrition outcomes and the underlying behavioural domains associated with changes. PMID- 26631172 TI - Development track of the modern activating blood circulation and removing stasis (ABCRS) school on inheritance and innovation. PMID- 26631173 TI - Auricular acupuncture and biomedical research--A promising Sino-Austrian research cooperation. AB - Treatment by auricular acupuncture has a long history. Ear-acupoint research has been advancing step by step in China and also in Europe. Auricles are rich in nerves, therefore a close relationship with different functions of the human body has been proved by the research teams of the two main authors of this article from China and Austria. In recent years, great progress has been made in the research of regulating human body functions through electroacupuncture at the auricular branch of the vagus nerve, which is part of auricular acupuncture therapy. It is well known that the auricular branch of the vagus nerve is the only peripheral pathway to the cerebral cortex. Studies of the Chinese team on hypertension, diabetes, epilepsy and depression have shown that the mechanism of auricular vagus nerve stimulation (VNS) may be comparable with cervical VNS in terms of pathways. Auricular VNS has a broad clinical application prospect. PMID- 26631174 TI - One-stop-shop cardiac CT: 3D fusion of CT coronary anatomy and myocardial perfusion for guiding revascularization in complex multivessel disease. PMID- 26631175 TI - Proteomic Analysis of Neutrophil Priming by PAF. AB - Polymorphonuclear neutrophils are the main cells of the innate immunity inflammatory response. Several factors can activate or stimulate neutrophils, including platelet-activating factor (PAF), a lipid mediator. Some authors consider the activation induced by PAF priming because it triggers limited production of reactive oxygen species (ROS) and it amplifies the response of the cell to a subsequent activator. The stimulation is reversible, which is critical for modulating the inflammatory response. Exacerbated inflammatory responses lead to serious diseases, such as systemic inflammatory response syndrome (SIRS), among others. Characterizing the stimulation of neutrophils during the possible reversion or prevention of an exaggerated inflammatory response is critical for the development of control strategies. In this study, a proteomic approach was used to identify 36 proteins that differ in abundance between quiescent neutrophils and PAFstimulated neutrophils. The identified proteins were associated with increased DNA repair processes, calcium flux, protein transcription, cytoskeleton alterations that facilitate migration and degranulation, and the release of proinflammatory cytokines and proteins that modulate the inflammatory response. Some of the identified proteins have not been previously reported in neutrophils. PMID- 26631176 TI - Tamoxifen and Antidepressant Drug Interaction in a Cohort of 16,887 Breast Cancer Survivors. AB - BACKGROUND: Controversy persists about whether certain antidepressants reduce tamoxifen's effectiveness on lowering breast cancer recurrence. We investigated whether taking tamoxifen and antidepressants (in particular, paroxetine) concomitantly is associated with an increased risk of recurrence or contralateral breast cancer. METHODS: We examined 16 887 breast cancer survivors (TNM stages 0 II) diagnosed between 1996 and 2007 and treated with tamoxifen in two California health plans. Women were followed-up through December 31, 2009, for subsequent breast cancer. The main exposure was the percent of days of overlap when both tamoxifen and an antidepressant (paroxetine, fluoxetine, other selective serotonin reuptake inhibitors, tricyclics, and other classes) were used. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox regression models with time-varying medication variables. RESULTS: Of the 16 887 women, half (n = 8099) used antidepressants and 2946 women developed subsequent breast cancer during the 14-year study period. We did not find a statistically significant increased risk of subsequent breast cancer in women who concurrently used paroxetine and tamoxifen. For 25%, 50%, and 75% increases in percent overlap days between paroxetine and tamoxifen, hazard ratios were 1.06 (95% CI = 0.98 to 1.14, P = .09), 1.13 (95% CI = 0.98 to 1.30, P = .09), and 1.20 (95% CI = 0.97 to 1.49, P = .09), respectively, in the first year of tamoxifen treatment but were not statistically significant. Hazard ratios decreased to 0.94 (95% CI = 0.81 to 1.10, P = .46), 0.89 (95% CI = 0.66 to 1.20, P = .46), and 0.85 (95% CI = 0.54 to 1.32, P = .46) by the fifth year (all non statistically significantly). Absolute subsequent breast cancer rates were similar among women who used paroxetine concomitantly with tamoxifen vs tamoxifen only users. For the other antidepressants, we again found no such associations. CONCLUSIONS: Using the comprehensive electronic health records of insured patients, we did not observe an increased risk of subsequent breast cancer in women who concurrently used tamoxifen and antidepressants, including paroxetine. PMID- 26631177 TI - Acetylcholinesterase histochemistry (AChE)--A helpful technique in the diagnosis and in aiding the operative procedures of Hirschsprung disease. AB - BACKGROUND: Hirschsprung's disease (HD) is an anomaly characterized by the absence of myenteric and submucosal ganglion cells (GC) in the distal alimentary tract. Diagnosis of HD is made by the absence of GC and missing out on even a single ganglion cell can be very devastating. Acetylcholinesterase (AChE) histochemistry, done on frozen sections is said to be a very useful ancillary technique in the diagnosis and in aiding the operative procedures of HD. METHODS: To assess this, 73 samples from 42 suspected/known cases of HD were subjected to frozen section analysis with rapid haematoxylin and eosin, toluidin blue stain along with AChE histochemistry. The remnant sample was paraffin embedded for routine haematoxylin and eosin staining. RESULTS: On frozen section analysis, 33 samples showed absence of ganglion cells, AChE histochemistry showed a positive staining pattern in 17 samples and paraffin embedded routine, H&E stained sections showed absence of ganglion cells in 19 samples. Sensitivity and specificity of both tests ie frozen section rapid H&E/AChE histochemistry in the diagnosis of HD, were calculated taking paraffin embedded H&E stained sections as the gold standard. Sensitivity of frozen section rapid H&E in the diagnosis of HD is 57.57 % and specificity is 79.10 %. The p-value is <0.0001, which is significant. The sensitivity of AChE histochemistry in the diagnosis of HD is 90.47 % and specificity is 96.36 %. The p-value is <0.0001, which is significant. CONCLUSIONS: Acetylcholineesterase (AChE) histochemistry is a very useful ancillary technique in the diagnosis and in aiding the operative procedures of HD. It acts as a double check in the diagnosis of HD. PMID- 26631178 TI - Aberrant overexpression of EZH2 and H3K27me3 serves as poor prognostic biomarker for esophageal squamous cell carcinoma patients. AB - It has been reported that the trimethylation of histone 3 on lysine 27 (H3K27me3) is required for enhancer of zeste homology 2 (EZH2)-mediated repression of various genes essential for tumorigenesis and tumor development. Here, we reported the expression of EZH2 and H3K27me3 in esophageal squamous cell carcinoma (ESCC) specimens was higher than the pericarcinoma esophageal specimens. Their expression was positively associated with the poor prognosis of ESCC patients. EZH2 expression, histological grade and distant lymph node metastasis were all independent factors for poor prognosis of ESCC. In addition, enforced expression of EZH2 in esophageal cancer-derived cells could increase the overall H3K27me3 level. Our results suggested the expression of EZH2 and H3K27me3 could serve as biomarkers in the prediction of ESCC patients' survival and ESCC metastasis. PMID- 26631179 TI - Natural disaster, older adults, and mental health--a dangerous combination. PMID- 26631180 TI - Head circumference as a useful surrogate for intracranial volume in older adults. AB - BACKGROUND: Intracranial volume (ICV) has been proposed as a measure of maximum lifetime brain size. Accurate ICV measures require neuroimaging which is not always feasible for epidemiologic investigations. We examined head circumference as a useful surrogate for ICV in older adults. METHODS: 99 older adults underwent Magnetic Resonance Imaging (MRI). ICV was measured by Statistical Parametric Mapping 8 (SPM8) software or Functional MRI of the Brain Software Library (FSL) extraction with manual editing, typically considered the gold standard. Head circumferences were determined using standardized tape measurement. We examined estimated correlation coefficients between head circumference and the two MRI based ICV measurements. RESULTS: Head circumference and ICV by SPM8 were moderately correlated (overall r = 0.73, men r = 0.67, women r = 0.63). Head circumference and ICV by FSL were also moderately correlated (overall r = 0.69, men r = 0.63, women r = 0.49). CONCLUSIONS: Head circumference measurement was strongly correlated with MRI-derived ICV. Our study presents a simple method to approximate ICV among older patients, which may prove useful as a surrogate for cognitive reserve in large scale epidemiologic studies of cognitive outcomes. This study also suggests the stability of head circumference correlation with ICV throughout the lifespan. PMID- 26631181 TI - Effectiveness of a self-management intervention with personalised genetic and lifestyle-related risk information on coronary heart disease and diabetes-related risk in type 2 diabetes (CoRDia): study protocol for a randomised controlled trial. AB - BACKGROUND: Many patients with type 2 diabetes fail to achieve good glycaemic control. Poor control is associated with complications including coronary heart disease (CHD). Effective self-management and engagement in health behaviours can reduce risks of complications. However, patients often struggle to adopt and maintain these behaviours. Self-management interventions have been found to be effective in improving glycaemic control. Recent developments in the field of genetics mean that patients can be given personalised information about genetic- and lifestyle-associated risk of developing CHD. Such information may increase patients' motivation to engage in self-management. The Coronary Risk in Diabetes (CoRDia) trial will compare the effectiveness of a self-management intervention, with and without provision of personalised genetic- and lifestyle-associated risk information, with usual care, on clinical and behavioural outcomes, the cognitive predictors of behaviour, and psychological wellbeing. METHODS/DESIGN: Participants will be adults aged 25-74 years registered with general practices in the East of England, diagnosed with type 2 diabetes, with no history of heart disease, and with a glycated haemoglobin level of >=6.45% (47 mmol/mol). Consenting participants will be randomised to one of three arms: usual care control, group self-management only, group self-management plus personalised genetic- and lifestyle-associated risk information. The self-management groups will receive four weekly 2-hour group sessions, focusing on knowledge and information sharing, problem solving, goal setting and action planning to promote medication adherence, healthy eating, and physical activity. Primary outcomes are glycaemic control and CHD risk. Clinical data will be collected from GP records, including HbA1c, weight, body mass index, blood pressure, and HDL and total cholesterol. Self-reported health behaviours, including medication adherence, healthy eating and physical activity, and cognitive outcomes will be assessed by questionnaire. Measures will be taken at baseline, 3 months (questionnaire only), 6 months and 12 months post-baseline. DISCUSSION: This study will determine whether the addition of personalised genetic- and lifestyle-associated CHD risk information to a group self-management intervention improves diabetes control and CHD risk compared with group self-management and usual care. Effectiveness of the combined intervention on health behaviours cognitions theorised to predict them, and psychological outcomes will also be investigated. TRIAL REGISTRATION: This study has been registered at ClinicalTrials.gov; registration identifier NCT01891786 , registered 28 June 2013. PMID- 26631182 TI - Global Transcriptome Analysis of Gracilaria changii (Rhodophyta) in Response to Agarolytic Enzyme and Bacterium. AB - Many bacterial epiphytes of agar-producing seaweeds secrete agarase that degrade algal cell wall matrix into oligoagars which elicit defense-related responses in the hosts. The molecular defense responses of red seaweeds are largely unknown. In this study, we surveyed the defense-related transcripts of an agarophyte, Gracilaria changii, treated with beta-agarase through next generation sequencing (NGS). We also compared the defense responses of seaweed elicited by agarase with those elicited by an agarolytic bacterium isolated from seaweed, by profiling the expression of defense-related genes using quantitative reverse transcription real time PCR (qRT-PCR). NGS detected a total of 391 differentially expressed genes (DEGs) with a higher abundance (>2-fold change with a p value <0.001) in the agarase-treated transcriptome compared to that of the non-treated G. changii. Among these DEGs were genes related to signaling, bromoperoxidation, heme peroxidation, production of aromatic amino acids, chorismate, and jasmonic acid. On the other hand, the genes encoding a superoxide-generating NADPH oxidase and related to photosynthesis were downregulated. The expression of these DEGs was further corroborated by qRT-PCR results which showed more than 90 % accuracy. A comprehensive analysis of their gene expression profiles between 1 and 24 h post treatments (hpt) revealed that most of the genes analyzed were consistently upregulated or downregulated by both agarase and agarolytic bacterial treatments, indicating that the defense responses induced by both treatments are highly similar except for genes encoding vanadium bromoperoxidase and animal heme peroxidase. Our study has provided the first glimpse of the molecular defense responses of G. changii to agarase and agarolytic bacterial treatments. PMID- 26631183 TI - The influence of group membership on cross-contextual imitation. AB - Research on mimicry has demonstrated that individuals imitate in-group members more strongly than out-group members. In the present study, we tested whether such top-down modulation also applies for more extreme forms of direct mapping, such as for cross-contextual imitation settings, in which individuals imitate others' movements without sharing a common goal or context. Models on self-other control suggest that top-down modulations are based merely on a direct link between social sensory processing and imitation. That is, perceived similarities between oneself and another person is sufficient to amplify a shared representation between own and others' actions, which then trigger imitation. However, motivational accounts explain such findings with the assumption that individuals are motivated to affiliate with others. Because imitation is linked to positive social consequences, individuals should imitate in-group members more strongly than out-group members. We tested these two theoretical accounts against each other by applying a cross-contextual imitation paradigm. The results demonstrate that in-group members are more strongly cross-contextually imitated than out-group members the higher individuals' motivation to affiliate with the in-group is. This supports motivational models but not self-other control accounts. Further theoretical implications are discussed. PMID- 26631184 TI - Cell surface engineering of Saccharomyces cerevisiae combined with membrane separation technology for xylitol production from rice straw hydrolysate. AB - Xylitol, a value-added polyol deriving from D-xylose, is widely used in both the food and pharmaceutical industries. Despite extensive studies aiming to streamline the production of xylitol, the manufacturing cost of this product remains high while demand is constantly growing worldwide. Biotechnological production of xylitol from lignocellulosic waste may constitute an advantageous and sustainable option to address this issue. However, to date, there have been few reports of biomass conversion to xylitol. In the present study, xylitol was directly produced from rice straw hydrolysate using a recombinant Saccharomyces cerevisiae YPH499 strain expressing cytosolic xylose reductase (XR), along with beta-glucosidase (BGL), xylosidase (XYL), and xylanase (XYN) enzymes (co )displayed on the cell surface; xylitol production by this strain did not require addition of any commercial enzymes. All of these enzymes contributed to the consolidated bioprocessing (CBP) of the lignocellulosic hydrolysate to xylitol to produce 5.8 g/L xylitol with 79.5 % of theoretical yield from xylose contained in the biomass. Furthermore, nanofiltration of the rice straw hydrolysate provided removal of fermentation inhibitors while simultaneously increasing sugar concentrations, facilitating high concentration xylitol production (37.9 g/L) in the CBP. This study is the first report (to our knowledge) of the combination of cell surface engineering approach and membrane separation technology for xylitol production, which could be extended to further industrial applications. PMID- 26631185 TI - Emerging resistance to aminoglycosides in lactic acid bacteria of food origin-an impending menace. AB - Aminoglycosides are the most preferred choice of therapy against serious infections in humans. Therefore, its use in animal husbandry has been strictly regulated in the EU, UK, and USA to avoid the hazards of aminoglycoside resistance in gut microflora. Nevertheless, aminoglycosides are recommended for prophylaxis and therapeutics in food animals and agriculture owing to its bactericidal nature. In the recent past, the global surge in aminoglycoside resistant lactic acid bacteria (LAB) from food sources has been noticed that might question its continued use in animal husbandry. Upon antibiotic administration, a selective pressure is created in the gut environment; in such instances, LAB could act as reservoirs of antibiotic resistance which may facilitate their transfer to pathogenic organisms contradicting its probiotic and industrial significance. This may be a risk to human health as the presence of one aminoglycoside resistance gene renders the bacteria tolerant to almost all antibiotics of the same class, thereby challenging its therapeutic efficacy. Low doses of aminoglycosides are recommended in farm animals due to its toxic nature and insolubility in blood. However, recent investigations indicate that use of aminoglycosides in sub-lethal concentrations can trigger the selection and conjugal transfer of aminoglycoside resistance in probiotic LAB. Resistance to erythromycin, tetracyclines, and fluoroquinolones in LAB were reported earlier to which immediate regulatory measures were adopted by some countries. Paradoxically, lack of regulations on antibiotic use in farms in most developing countries makes them a potential source of antibiotic resistance and its uncontrolled spread around the globe. The prevalence of aminoglycoside resistance was observed in enterococci from food origin earlier; however, its emergence in lactobacilli and pediococci suggests its spread in probiotic cultures which prompts immediate precautionary methods. This review highlights the emergence and hazards of aminoglycoside-resistant LAB which is in prime commercial demand both for preparing fermented food and also pharma-based therapeutics. It further focuses on the mode of aminoglycoside resistance and its occurrence in food-grade LAB, thus relating to its role in worldwide transfer via the food chain in spite of its limited use as compared to other antibiotics. PMID- 26631186 TI - Photoinactivation of Staphylococcus aureus using protoporphyrin IX: the role of haem-regulated transporter HrtA. AB - Light- and photosensitiser-based antimicrobial photodynamic therapy is a very promising approach to the control of microbial infections. How the phenotypic features of a microorganism affect its response to photosensitiser-based photokilling represents an area of substantial research interest. To understand the mechanisms governing the phenomenon of a strain-dependent response to photodynamic inactivation (PDI), we analysed the possible role of the membrane located haem transporter HrtA in Staphylococcus aureus. We used a S. aureus strains with an inactivated component of the haem-regulated transporter, HrtA, along with its wild-type counterpart to determine differences in PDI outcome and photosensitiser uptake between the studied isogenic strains. We observed that a lack of HrtA protein potentiates the phototoxic effect towards S. aureus but only when extracellular protoporphyrin IX is used. The observed effect may depend on the function of the HrtA transporter but is likely to result from changed membrane properties following the absence of the protein in the membrane. This indicates that disturbing the membrane properties is an attractive method for improving the efficacy of the photodynamic inactivation of microorganisms. PMID- 26631187 TI - First report of fatal systemic Halicephalobus gingivalis infection in two Lipizzaner horses from Romania: clinical, pathological, and molecular characterization. AB - Halicephalobus gingivalis (H. gingivalis) causes a rare and fatal infection in horses and humans. Despite the zoonotic potential and severity of the disease, the epidemiology and pathogenesis of halicephalobiasis are still poorly understood. Several European cases of equine halicephalobiasis have been documented; however, in South-Eastern European countries, including Romania, equine neurohelminthiasis caused by H. gingivalis has not been previously described. Two Lipizzaner horses with a clinical history of progressive neurological signs were referred to the Pathology Department of the Cluj-Napoca (Romania) for necropsy. Both horses died with severe neurological signs. Gross examination and cytological, histological, and molecular analyses were performed. The stallions came from two different breeding farms. No history of traveling outside Romania was recorded. At necropsy, granulomatous and necrotizing lesions were observed in the kidneys, lymph nodes, brain, retroperitoneal adipose tissue, and lungs, indicating a systemic infection. Parasitological and histopathological analyses evidenced larval and adult forms of rhabditiform nematodes consistent with Halicephalobus species. Parasites were observed in both lymph and blood vessels of different organs and were also identified in urine samples. A subunit of the large-subunit ribosomal RNA gene (LSU rDNA) of H. gingivalis (673 bp) was amplified from lesions in both horses.To the authors' knowledge, this is the first report of equine systemic H. gingivalis infection in Romania and in South Eastern Europe. Our findings provide new insights into the geographic distribution of specific genetic lineages of H. gingivalis, while also raising public health awareness, as the parasite is zoonotic. PMID- 26631188 TI - Comparative study of viscerotropic pathogenicity of Leishmania major amastigotes and promastigotes based on identification of mitochondrial and nucleus sequences. AB - Experimental viscerotropic leishmaniasis is regularly caused by Leishmania tropica promastigotes. In the current investigation, the viscerotropic pathogenicities of Leishmania major amastigotes and promastigotes were compared and evaluated based on their heterogeneity traits and number of inoculated parasites in experimental mammalian hosts. Serous exudate from 50 patients was infected, 44 with L. major and 6 with L. tropica; only BALB/c mice inoculated with 1-2 * 10(4-6) L. major amastigotes manifested cutaneous lesions at the base of their tails. Five out of the 44 BALB/c mice inoculated with L. major died of sequela of viscerotropic adverse effect, while 2 * 10(6) L. major promastigotes showed viscerotropic signs in four BALB/c mice. The sequencing of the Cyt b gene showed a strain of L. major (GenBank accession number KM393221: haplotype diversity 0.9) containing two codon mutations, 86 and 126 in dead mice, whereas no significant mutant was observed in internal transcribed spacer (ITS)-ribosomal DNA (rDNA) sequences (haplotype diversity 0). Findings show that a lower dose of L. major amastigotes than promastigotes has more potential viscerotropic intensity in susceptible hosts. It illustrates that testing Cyt b as an evolutionary mitognome marker because of having its semi-conserved structure and low copy number is able to be utilized in the discrimination of new mutants. PMID- 26631189 TI - Reverse Shoulder Arthroplasty Prosthesis Design Classification System. AB - Multiple different reverse total shoulder arthroplasty (rTSA) prosthesis designs are available in the global marketplace for surgeons to perform this growing procedure. Subtle differences in rTSA prosthesis design parameters have been shown to have significant biomechanical impact and clinical consequences. We propose an rTSA prosthesis design classification system to objectively identify and categorize different designs based upon their specific glenoid and humeral prosthetic characteristics for the purpose of standardizing nomenclature that will help the orthopaedic surgeon determine which combination of design configurations best suit a given clinical scenario. The impact of each prosthesis classification type on shoulder muscle length and deltoid wrapping are also described to illustrate how each prosthesis classification type impacts these biomechanical parameters. PMID- 26631190 TI - The Impact of Posterior Wear on Reverse Shoulder Glenoid Fixation. AB - INTRODUCTION: Achieving glenoid fixation with posterior bone loss can be challenging. The purpose of this study was to quantify the impact of two different sizes of posterior glenoid defects (10 degrees and 20 degrees ) on reverse shoulder arthroplasty (rTSA) glenoid baseplate fixation and determine if utilizing different sizes of posterior augmented baseplates (8 degrees and 16 degrees ) with off-axis reaming provides comparable fixation to using a standard baseplate with different amounts of eccentric reaming. METHODS: We quantified the impact of 10 degrees and 20 degrees posterior glenoid defects on rTSA baseplate fixation in composite scapulae using the ASTM F2028-14 rTSA glenoid loosening test method. Forty-two total implants (N = 7 for each size defect and for each type of baseplate) were tested at 750 N for 10,000 cycles. Baseplate displacement was measured before and after cyclic loading in the superior-inferior and anterior-posterior directions. Statistical analysis was performed with a two tailed unpaired Student's t-test (significance defined as p < 0.05) to compare prosthesis displacements relative to each scapula (10 degrees and 20 degrees posterior defects for each type of baseplate versus the non-defect control) before and after cyclic loading. RESULTS: All glenoid baseplates remained well fixed after cyclic loading in composite scapulae without a defect and in scapulae with posterior defects. Increased pre- and post-cyclic displacement was observed with increased posterior defect size and differences in displacement were observed between standard and augmented baseplates. Augmented baseplates were observed to remove significantly less bone than standard baseplates when correcting posterior defects, regardless of size. DISCUSSION: Both standard baseplates with eccentric reaming and two different sizes of augmented baseplates with off-axis reaming successfully maintained fixation following cyclic loading in composite scapula with corrected 10 degrees and 20 degrees posterior glenoid defects. Augmented glenoids may be more advantageous long-term from a fixation perspective as they preserve more subchondral glenoid bone due to the minimal reaming occurring by the off-axis method. Mid and long-term clinical follow-up comparisons of outcomes are necessary between these two techniques. PMID- 26631191 TI - Role of Subscapularis Repair on Muscle Force Requirements with Reverse Shoulder Arthroplasty. AB - Concomitant repair of the subscapularis with reverse shoulder arthroplasty (rTSA) is controversial. To evaluate the biomechanical impact of subscapularis repair with rTSA, a cadaveric shoulder controller quantified the muscle forces required to elevate the arm during scapular abduction with the elbow flexed at 90 degrees . The results of this study demonstrate that concomitant subscapularis repair with rTSA creates a biomechanically unfavorable condition during arm elevation. Specifically, repair of the subscapularis significantly increased the force required by the deltoid and posterior rotator cuff and also significantly increased the joint reaction force relative to when the subscapularis was not repaired. These results also demonstrated that both the 42 mm Grammont and 42 mm Equinoxe(r) rTSA prostheses significantly decreased the mean force required by the posterior rotator cuff and also significantly decreased the mean joint reaction force over the range of motion relative to the native joint with a rotator cuff tear (supraspinatus). As the posterior rotator cuff is often compromised in patients undergoing rTSA, patients may not be able to sustain these elevated forces in the infraspinatus and teres minor required to counteract the adduction and internal rotation moments generated by the subscapularis during activities of daily living. Similarly, the elevated posterior deltoid force and joint reaction loads could be deleterious to the long-term life of the prosthesis and can also increase the risk of loosening and fractures. For all these reasons, rTSA functional outcomes may be compromised if the subscapularis is repaired. PMID- 26631192 TI - Assessment of the Anatomic Neck as an Accurate Landmark for Humeral Head Resurfacing Implant Height Placement. AB - INTRODUCTION: Humeral head resurfacing has been described as a more anatomic replacement alternative for proximal humerus arthroplasties when compared to conventional stemmed implants. However, not all studies show that humeral head resurfacing is better at reproducing the proximal humeral anatomy with overstuffing of the joint being a common complication. The purpose of this study was to assess the use of the anatomic neck as a landmark for proper placement of humeral head replacements. METHODS: Sixty-six cadaveric shoulder CT scans were reconstructed using Mimics to create 3D models of the humerus. After 3D reconstruction, each bone model was analyzed in Rapidform to establish the anatomic neck plane, the humeral head average radius of curvature, and anatomic center of rotation (CoR) using a best fit sphere over the articular surface. Humeral head resurfacing implants (Equinoxe(r), Exactech, Inc.) were assembled onto the 3D humeral models, selected by matching the closest implant size available with the anatomic radius of curvature. Implants were constrained to match the anatomic neck angle and version and were spaced 2 mm away from the anatomic neck. The 3D distances between the anatomic center of rotation and the implant CoR and the implanted head thickness deviations were measured using Unigraphics to observe anatomic reproduction with the resurfacing implants. RESULTS: When placing all resurfacing implants 2 mm from the anatomic neck, the average implant CoR offset from the anatomic CoR was determined to be 1.03 mm +/- 0.75 mm. The average implant Humeral Head Thickness (HHT) deviation from the anatomic HHT was determined to be -0.36 mm +/- 0.84 mm. There were no significant differences in CoR offset or HHT offset between implant sizes used. DISCUSSION: Newer generation resurfacing implant designs allow for more anatomic reproduction of the humeral articular surface. Depth of reaming and resurfacing implant height placement are potential pitfalls in humeral head replacement and have been shown to have negative effects on reproducing the CoR and HHT. Using the anatomic neck as a landmark for the depth of reaming has been observed to closely reproduce anatomic HHT and CoR. Further work aims to validate the use of the anatomic neck as a consistent landmark in cadaveric studies and to investigate if these findings are clinically relevant. PMID- 26631193 TI - Optimization of Cemented Glenoid Peg Geometry. A Comparison of Resistance to Axial Distraction. AB - INTRODUCTION: Glenoid loosening is one of the most common complications of anatomic total shoulder arthroplasty (aTSA). Numerous glenoid pegged designs exist within the market place; however, little effort has been made to optimize peg geometry, and as a result, there is no consensus regarding the superiority of one design over another. The aim of this study was to determine the impact of peg design on the fixation strength by comparing the force and displacement associated with five different geometries of cemented glenoid components when each is axially displaced from two different densities of polyurethane bone substitute substrates. METHODS: An axial pull-out test was conducted on five different cemented peg geometries in both low- and high- density polyurethane bone-substitute blocks. All substrates were prepared utilizing a drill, which created a 7.3 mm diameter hole to a depth of 26.8 mm. Cemex (r) brand bone cement was prepared and used to cement all pegs. After cementation of each peg, an electromechanical load frame applied a linear ramp displacement of 10 mm/minute axially to each peg while the polyurethane block was fully con strained. Load and displacement of each peg was sampled at 100 Hz until failure and axial distraction of each peg where the peak pull-out force and associated displacement were recorded. The average load to failure and associated displacement for each peg geometry were compared utilizing the Student's t-test where a p-value < 0.05 determined significance. RESULTS: Cemented peg design #3 was associated with the greatest axial load to failure (675.3 N +/- 18.8 N in low density and 707.3 N +/- 11.7 N in high density) for both densities of bone-substitute blocks. Peg designs #5 and #2 were associated with the next highest axial loads to failure in both low and high density blocks. Finally, peg designs #1 and #4 were associated with the lowest axial loads to failure in both low and high density blocks. Only design #3 had a statistically significant difference between peak pull-out forces between the low- and high-density bone substitute blocks, as compared to all other designs. CONCLUSIONS: The results of this study demonstrate that glenoid peg geometry can significantly influence the resistance to axial distraction where the continuous threaded geometry exemplified by peg design #3 demonstrated significantly superior cemented fixation relative to the other peg designs. It can be concluded that overall macrostructure and design of the peg itself plays a key role in pull-out force; however, performance in a clinical setting is required to confirm these biomechanical results. PMID- 26631194 TI - Optimizing Deltoid Efficiency with Reverse Shoulder Arthroplasty Using a Novel Inset Center of Rotation Glenosphere Design. AB - INTRODUCTION: Paul Grammont's hemispherical gleno sphere concept medializes the center of rotation (CoR) to the glenoid face to increase deltoid abductor moment arms and improve muscle efficiency. Reducing glenosphere thickness to less than half its spherical radius further medializes the CoR and offers the potential for even greater improvements in efficiency. To that end, this study quantifies deltoid abducttor moment arms for six different rTSA prostheses during scapular abduction from 0 degrees to 140 degrees . METHODS: A 3D computer model was developed in Uni graphics to quantify deltoid moment arms during scapular abduction for the normal anatomic shoulder, the 36 mm Grammont Delta III (Depuy, Inc.), 36 mm BIO-RSA (r) (Tornier, Inc.), the 32 mm RSP(r) (DJO, Inc.), and the Equinoxe(r) rTSA (Exactech, Inc.) with three different glenosphere geometries: 38 mm x 21 mm, 46 mm x 25 mm, and the novel 46 mm x 21 mm. Each muscle was simulated as three lines from origin to insertion as the arm was elevated; positional data was exported to Matlab where the abductor moment arms were calculated for the anterior, middle, and posterior deltoid from 0 degrees to 140 degrees humeral abduction in the scapular plane using a 1.8:1 scapular rhythm. RESULTS: The 46 mm x 21 mm glenosphere had the larg est average abductor moment arms and also the largest efficiency for all three heads of the deltoid, having a 4.8% to 40.7% increase in the average deltoid efficiency relative to all other designs tested. The glenosphere design with the next most efficient deltoid was the 36 mm Delta III, which had the next most medialized CoR. The two least efficient designs were the BIO-RSA (r) and the DJO RSP(r) , which had the most lateral CoR. DISCUSSION: These results provide new biomechanical insights on the impact of glenosphere geometry on deltoid abductor moment arms and demonstrate that subtle changes in rTSA prosthesis design can result in dramatic improvements. Increasing glenosphere diameter while also decreasing thickness to be less than half its spherical radius may minimize the muscle forces required to perform activities of daily living. Clinical follow-up is necessary to demonstrate a reduction in complications related to joint over-loading and also demonstrate greater increases in range of motion for patients with weak musculature. PMID- 26631195 TI - Improving Distal Fixation with Total Shoulder Arthroplasty in Cases of Severe Humeral Bone Loss. AB - The usage of and indications for total shoulder arthroplasty have grown in recent years. Certain aspects of these arthroplasty procedures can be very complex, especially in revision and fracture cases, often leading to proximal humerus bone loss. For cases with significant bone loss, there is a need for improved devices with additional options to treat a wider range of deformities while also mitigating existing complications and rates, such as poor distal fixation, inadequate soft tissue reattachment options, and joint instability. To that end, a fatigue and torsional test was conducted on two different devices to assess the ability of each to survive an extreme fatigue and torsional load when assembled in worst-case configurations. Evaluation of the Equinoxe(r) humeral reconstruction prosthesis demonstrated superior fixation in both the fatigue loading scenario and also the torsional loading scenario as compared to the 8 mm x 215 mm cemented humeral long stem, where each had only 80 mm of cemented fixation. The results of the fatigue test demonstrated that despite the humeral reconstruction prosthesis being subjected to a 960 N force and 45 Nm bending moment (which was significantly more challenging than the 576 N force and 24.2 Nm bending moment subjected to the cemented humeral long stem), the humeral reconstruction prosthesis completed 1 M cycles without fracture or failure. Additionally, the Equinoxe(r) humeral reconstruction prosthesis was associated with a significantly greater torsional resistance in both the torque to initial slip (29.4 Nm versus 8.2 Nm; p = 0.0002) and also the maximum torque to failure (44.3 Nm versus 12.1 Nm; p < 0.0001). These significant improvements in fixation are at least partially attributed to the application of a novel distal fixation ring, which is press fit around the diaphysis of the humerus to supplement the cemented fixation of the distal stem. These fatigue and torsional test results paired with several novel features of fer the potential for the Equinoxe(r) humeral reconstruction prosthesis to be an improved treatment option for patients with proximal humeral bone loss, though clinical follow-up is necessary to confirm these positive biomechanical results. PMID- 26631196 TI - Evaluation of Preoperative Implant Placement in Total Shoulder Arthroplasty. AB - INTRODUCTION: New technology to assist with glenoid placement in shoulder arthroplasty has evolved to include preoperative planning tools and intraoperative guides. These tools provide surgeons with a more complete understanding of glenoid anatomy prior to surgery. However, there have been no studies identifying the information that most influences surgical decision making. Further, there have been few studies that quantify intraoperative identification of scapular landmarks required to execute a preoperative plan. The purpose of this study is to examine the variables that are considered when making a preoperative plan in shoulder arthroplasty. METHODS: The first part of this study was a cadaveric lab in which three surgeons identified the neutral axis in surgical simulation. The second part of the study utilized a preliminary software tool in which surgeons were able to place glenoid implants in a set of CT reconstructions utilizing standard pegged glenoid components. In the third part of the study, surgeons utilized a novel planning software that included the ability to view the 3D reconstructed glenoid in all planes simultaneously and place either standard or augmented glenoid implants. The results of these three studies were compared. RESULTS: The center of the glenoid identified in the cadaver lab was 1.69 mm +/- 1.58 mm anterior and 1.99 mm +/- 2.49 mm superior to center. The identified neutral axis was tilted 14.2 degrees +/- 9.2 degrees superior to the Friedman axis with 11.8 degrees +/- 7.9 degrees of retroversion relative to that axis. Using the novel preoperative planning tool, the surgeons placed implants less than 0.5 mm from the center of the glenoid (AP = -0.07 mm +/ 0.42 mm, SI = 0.44 mm +/- 0.82 mm) with an average retroversion of less than 1 degrees (-0.96 degrees +/- 3.04 degrees ). CONCLUSION: There was a discernible difference between the neutral axis identified in the cadaveric simulation (aver age of 14.2 degrees superior and 11.8 degrees retroverted) and the implant orientation planned using preoperative software (average of 3.26 degrees superior and 0.96 degrees retroverted). Based on the variability of position and orientation seen cadaverically, it is concluded that additional intraoperative guidance is needed alongside a preoperative plan in order to execute ideal placement of the glenoid component. PMID- 26631197 TI - Distribution of Glenoid Implant Options for Correcting Deformities Using a Preoperative Planning Tool. AB - Preoperative planning tools in shoulder arthroplasty are a recently developing technology with the advantage of being able to clearly assess patient anatomy and deformities before entering the OR. Addressing retroverted glenoids remains one of the most difficult aspects of primary shoulder arthroplasty. In this study, five surgeons were provided with a preoperative planning tool with posterior augmented glenoid implant options (0 degrees , 8 degrees , and 16 degrees ) to treat 10 cadaveric cases with a range of versions from 7.8 degrees anteversion to 25.1 degrees retroversion. Surgeons were able to remove less bone using 8 degrees augmented implants over standard non-augmented implants (2.8 degrees reamed vs. 6.4 degrees reamed) and were able to correct each case on average within +/- 1.8 degrees of neutral version. Slight glenoid vault perforation was observed in 18% of the plans. Eight degrees posterior augmented implants were used in scans averaging 9.0 degrees retroversion, and 16 degrees posterior augmented implants were used in scans averaging 20.6 degrees retroversion. Results were then compared to 14 preoperative CT scans provided by one of the surgeons in which both 8 degrees and 16 degrees posterior augmented glenoid implants were used in actual patients, showing 8 degrees posterior augmented implants were used in cases averaging 12.3 degrees retroversion, and 16 degrees posterior augmented implants were used in cases averaging 20.7 degrees retroversion. The study shows that surgeons can effectively and predictably use a preoperative planning tool to correct glenoid abnormalities using augmented implant solutions while minimizing both scapular bone removal and vault perforation and maximizing version correction. PMID- 26631198 TI - Analysis of Glenoid Fixation with Anatomic Total Shoulder Arthroplasty in an Extreme Cyclic Loading Scenario. AB - INTRODUCTION: ASTM F2028-14 was adopted to recom mend a cyclic eccentric glenoid edge loading test that simulates the rocking horse loading mechanism beleived to cause aTSA glenoid loosening. While this method accurately simulates that failure mechanism, the recommended 750 N load may not be sufficient to simulate worst case loading magnitudes, and the recommended 100,000 cycles may not be sufficient to simulate device fatigue-related failure modes. Finally, if greater loading magnitude or a larger number of cycles is performed, the recommended substrate density may not be sufficiently strong to support the elevated loads and cycles. To this end, a new test method is proposed to supplement ASTM F2028-14. METHODS: A series of cyclic tests were performed to evaluate the long-term fixation strength of two different hybrid glenoid designs in both low (15 pcf) and high (30 pcf) density polyurethane blocks at elevated loads relative to ASTM F2028-14. To simulate a worst case clinical condition in which the humeral head is superiorly migrated, a cyclic load was applied to the superior glenoid rim to induce a maximum torque on the fixation pegs for three different cyclic loading tests: 1. 1,250 N load for 0.75 M cycles in a 15 pcf block, 2. 1,250 N load for 1.5 M cycles in a 30 pcf block, and 3. 2,000 N load for 0.65 M cycles in a 30 pcf block. RESULTS: All devices completed cyclic loading without failure, fracture, or loss of fixation regardless of glenoid design, polyurethane density, loading magnitude, or cycle length. No significant difference in post-cyclic displacement was noted between designs in any of the three tests. Post-cyclic radiographs demonstrated that each device maintained fixa - tion with the metal pegs within the bone-substitute blocks with no fatigue related failures. DISCUSSION: These results demonstrate that both cemented hybrid glenoids maintained fixation when tested according to each cyclic loading scenario, with no difference in post cyclic displacement observed between designs. The lack of fatigue-related failures in these elevated load and high cycle test scenarios are promising, as are the relatively low displacements given the extreme nature of each test. This cyclic loading method is intended to supplement the ASTM F2028-14 standard that adequately simulates the rocking horse loading mechanism but may not adequately simulate the fatigue-related failure modes. PMID- 26631199 TI - Impact of Posterior Wear on Muscle Length with Reverse Shoulder Arthroplasty. AB - The use of reverse total shoulder arthroplasty (rTSA) in patients with posterior glenoid wear can be challenging. Implanting a baseplate in the correct version may require significant eccentric reaming, which further medializes the joint line and results in greater rotator cuff muscle shortening. To restore the joint line, bone graft may be required, though it is associated with additional risks. As an alternative solution, augmented glenoid baseplates offer the potential to restore the joint line and improve rotator cuff muscle tensioning without the need for eccentric reaming or supplemental bone graft. To that end, this computer analysis quantifies the rotator cuff muscle length for standard and augmented rTSA when used in a normal and posteriorly worn glenoid. These results demonstrate that shortening of the rotator cuff occurred for both the standard and posterior augmented reverse shoulder designs with additional muscle shortening occurring in scapula with posteriorly worn glenoids. More anatomic rotator cuff muscle tensioning was observed with augmented glenoid baseplates. The use of posterior augmented glenoid baseplates has the potential to improve stability and better restore active internal and external rotation, a current limitation of rTSA. However, clinical follow-up is necessary to confirm these favorable biomechanical results. PMID- 26631200 TI - Glenohumeral Anatomic Study. A Comparison of Male and Female Shoulders with Similar Average Age and BMI. AB - INTRODUCTION: Numerous anatomic studies of the shoulder have quantified the size, shape, and variability of either the humerus or scapula individually. However, few have attempted to quantify the relationship of the humerus to the scapula to better understand the spatial variation of these bones in both male and female shoulders. METHODS: Seventy-four cadaveric shoulder CT scans (37 males and 37 females with statistically equivalent age and BMI) were reconstructed using Mimics (r) to create 3D models of the humerus and scapula. After 3D reconstruction, each CT bone model was analyzed in Rapidform(r) to quantify the morphology of the humerus, scapula, and the spatial relationship between the two to better understand the role of gender on the morphological variability of the glenohumeral joint. RESULTS: Spatial glenohumeral relationships of male shoulders were significantly larger than female shoulders in 13 of 16 measurements; morphology of male humeri were significantly larger than female humeri in 17 of 24 measurements, and scapula and glenoid morphology of male shoulders were significantly larger than female scapula and glenoids in 11 of 22 measurements. DISCUSSION: Numerous significant gender differences in spatial relationships and morphology were identified in this anatomic study of the glenohumeral joint. An improved understanding of these observed binomial distributions has utility for shoulder arthroplasty prosthesis design, computer navigation, and may also be useful to the orthopaedic surgeon during surgical preoperative planning. PMID- 26631201 TI - Preliminary Results of a Posterior Augmented Glenoid Compared to an all Polyethylene Standard Glenoid in Anatomic Total Shoulder Arthroplasty. AB - INTRODUCTION: Osteoarthritis of the shoulder often results in significant posterior glenoid wear. The options for treating this have been eccentric glenoid reaming and occasionally bone grafting. More recently reverse total shoulder arthroplasty (rTSA) with or without bone grafting and posterior augmented glenoids (PAGs) has been introduced. The PAG restores the native joint line while reaming a minimal amount of glenoid bone. The purpose of this study is to compare osteoarthritic shoulders with significant posterior glenoid wear treated with anatomic total shoulder arthroplasty (aTSA) using a PAG to shoulders without glenoid wear treated with aTSA using a standard all poly pegged glenoid. METHODS: The patients' data in this study were retrospectively queried from prospectively acquired data in a multi-institutional IRB approved database. The study population consisted of 24 patients with osteoarthritis and posterior glenoid wear who were treated with aTSA using a PAG with a minimum of two-year follow-up. This population was age, sex, and follow-up matched to patients treated with an all poly non-augmented pegged glenoid (NAG) for osteoarthritis. Seven females and 17 males with an average age of 65.8 +/- 11.5 years received a posterior augmented glenoid. The control group consisted of 7 females and 17 males with an average age of 66.4 +/- 9.1 years who underwent aTSA for osteoarthritis using an all poly standard glenoid. These age, gender, and follow-up matched patients were evaluated and scored preoperatively and at latest follow-up using the SST, UCLA, ASES, Constant, and SPADI scoring metrics; active abduction, elevation, and external rotation were also measured. A Grashey and axillary lateral radiograph was evaluated at two-year follow-up. The Shoulder Arthroplasty Subluxation Index was used to determine the degree of humeral component subluxation on the glenoid component. A Student's two-tailed, unpaired t-test was used to identify differences in preoperative and postoperative results, where p < 0.05 denoted a significant difference. RESULTS: All patients demonstrated significant improvements in pain and function with the primary aTSA. Sixty per-cent of PAG shoulders had a radiolucent line with an average radiographic line score of 1.10, and 33.3% of NAG had a radiolucent line with an average radiographic line score of 0.438. One glenoid in the PAG group is radiographically but not clinically loose. In the PAG group, the Grashey view showed that 18/20 humeral heads were centered with the two remaining joints demonstrating superior subluxation. On the axillary lateral in the PAG group, 17/20 humeral heads were centered, and three were anteriorly subluxated; none were posteriorly subluxated. There were no differences in any of the measured postoperative clinical outcomes or any difference in improvement between the two groups. DISCUSSION: At a minimum of two year follow-up, there were no statistical clinical differences between the PAG and NAG groups despite the PAG group being disadvantaged with posterior worn glenoids. There were no revisions in either group. No humeral heads resubluxated posteriorly. The PAG group had a higher incidence of lucent lines. Based on this short-term follow-up, a posterior augmented glenoid is a viable option for the posterior worn osteoarthritic glenoid. PMID- 26631202 TI - Preliminary Results of a Novel Hybrid Cage Glenoid Compared to an All Polyethylene Glenoid in Total Shoulder Arthroplasty. AB - INTRODUCTION: The aim of this study was to evaluate the preliminary outcomes of a hybrid cage glenoid design in comparison to pegged all-polyethylene glenoid components in anatomic total shoulder arthroplasty (aTSA). MATERIALS AND METHODS: Ninety-two patients undergoing primary anatomic total shoulder arthroplasty with minimum two-year follow-up were reviewed. Forty-six patients had an ultra-high molecular weight polyethylene (UHMWPE) cemented pegged glenoid component, and 46 had a hybrid cage glenoid component. Patient data was retrospectively reviewed from prospectively acquired data in a multi-institutional IRB approved database. These age, gender, and follow-up matched patients were evaluated and scored preoperatively and a latest follow-up using the SST, UCLA, ASES, Constant, and SPADI scoring metrics. Additional measures included active abduction, elevation, and external rotation. Radiolucent line assessment of the glenoid was performed by use of a Grashey and axillary radiograph at latest follow-up. A Student's two tailed, unpaired t-test was used to identify differences in preoperative and postoperative results, where p < 0.05 denoted a significant difference. RESULTS: All patients demonstrated significant improvements in pain and function following treatment with the primary aTSA. The database contained three complications for the aTSA patients with a cage glenoid, and three complications for patients with a UHMWPE pegged glenoid. Radiographic data was available for 37 of 46 cage glenoid patients and 29 of 46 UHMWPE pegged glenoid patients. Five of 37 cage glenoid patients had a radiolucent line (13.5%) with an average radiographic line score of 0.22. Eight of 29 UHMWPE peg glenoid patients had a radiolucent line (27.6%) with an average radiographic line score of 0.57. Cage aTSA patients were associated with significantly less blood loss than aTSA UHMWPE pegged glenoid patients (avg. blood loss = 242 vs. 337; p = 0.022). CONCLUSION: At minimum two year follow-up, hybrid cage aTSA components show equal clinical outcomes to UHMWPE pegged glenoids. However, the hybrid cage components had significantly fewer radiolucent lines and less intra-operative blood loss. Additional and longer-term clinical and radiographic follow-up is necessary to confirm these promising early results. PMID- 26631203 TI - Correlation Between Clinical Outcomes and Anatomic Reconstruction with Anatomic Total Shoulder Arthroplasty. AB - Many glenohumeral studies have demonstrated how anatomy varies across the population. Third and fourth generation shoulder prosthesis designs were developed to provide greater modularity and size ranges to better reproduce this anatomy and thus achieve better results in terms of shoulder function. This study quantifies the quality of anatomic reconstruction and compares that to long-term clinical outcomes using one fourth generation platform shoulder system. METHODOLOGY: One hundred and forty primary total shoulder arthroplasties were performed by one experienced single surgeon between 2001 and 2009, using the same fourth generation modular prosthesis. Pre- and postoperative clinical assessments were quantified with the Constant, ASES, SPADI, SST, and UCLA scores, and active range of motion was measured. Five anatomic parameters were defined, measured, and compared pre- and postoperatively on the anterior-posterior (AP) radiographs: Humeral Head Height (HHH), Humeral Head Centering (HHC), Humeral Head Medial Offset (HHMO), Humeral Head Diameter (HHD), and Humeral Neck Angle (HNA). The differences between each of the parameters were then calculated and rated from 0 to 2 and then summed for each patient to obtain the Anatomic Reconstruction Index (ARI), which objectively quantifies and assesses the quality of the anatomic reconstruction. Patients were sorted based upon their ARI score into two groups (ARI 5 to 7 and ARI 8 to 10), and their latest follow-up outcomes were compared using the Mann-Whitney test to identify differences in preoperative and postoperative results, where p < 0.05 denoted a significant difference. RESULTS: Of the 140 primary prostheses performed, 78 patients were lost to follow-up, and 13 were excluded for complications that were not related to the anatomic reconstruction. Forty-nine patients (75.8 yrs., 31F/18M) were included with an average follow-up of 9.1 years. The average score for HHH was 1.9 +/- 0.4, 1.8 +/ 0.5 for HHC, 1.7 +/- 0.5 for HHMO, 1.7 +/- 0.5 for HHD, and 1.5 +/- 0.7 for HNA. Thus, all reconstructions were rated good to excellent with 86% of very good/excellent reconstruction (ARI 8 to 10) and 14% good reconstruction (ARI 5 to 7). A comparison of radiographic anatomic parameters was performed for these two cohorts: HHC (< 0.0001), HNA (0.000), and ARI (<0.0001) were significantly greater for the ARI 8 to 10 cohort. Four of five postoperative clinical outcome metrics for the ARI 8 to 10 cohort were significantly greater than the mean values for the ARI 5 to 7 cohort. Additionally, mean postoperative pain on a daily basis and shoulder function for the ARI 8 to 10 cohort were significantly greater than that for the ARI 5 to 7 cohort. DISCUSSION: The relatively small number of good reconstructions (14%) compared to very good/excellent reconstructions (86%) and the absence of fair/poor reconstructions limited the ability for any strong linear correlations between anatomical reconstruction and clinical parameters. Despite this, patients with larger mean ARI scores were associated with significantly better outcomes for some measures. This study is limited by the use of 2D assessments from standard AP radiographs; this method can be further refined by the use of 3D quantitative assessment of each parameter. CONCLUSION: This study confirmed that an improved anatomic reconstruction results in better postoperative clinica outcomes. The fourth generation prosthesis used for this study allows continuous in-situ adjustment of the humeral head orientation through use of the spherical taper on the replicator plate and also a double adjustment of offset through the use of the offset humeral head and offset taper on the replicator plate. PMID- 26631204 TI - Effects of Body Mass Index on Outcomes in Total Shoulder Arthroplasty. AB - Body Mass Index (BMI) is one of the metrics used to assess overall health and has been implicated in having predictive value in many aspects of health, including outcomes after shoulder replacement surgery. Outcome data from a multi- institutional database with an average follow-up period of 39.8 months (minimum 24-months) demonstrated that all patients, regardless of BMI, improved significantly after treatment with anatomic total shoulder arthroplasty (aTSA) or reverse total shoulder arthroplasty (rTSA). Improvements in outcomes were stratified and compared based upon BMI in three groups: less than 25, 25 to 35, and greater than 35. Comparing these measures demonstrated that aTSA patients with higher BMI were generally associated with lower functional postoperative outcome metric scores than aTSA patients with lower BMI, though the preoperative to postoperative gains were generally equivalent regardless of BMI. Interestingly, postoperative outcome metric scores with rTSA patients were equivalent regardless of BMI as were the pre-to-postoperative gains. Additionally, differences in the magnitude of pre-to-postoperative improvement of range of motion (ROM) measurements between patients of BMI less than 25 and BMI greater than 35 were noted for forward flexion, internal rotation, and active and passive external rotation. The actual clinical significance of these differences is unknown. Finally, patients with lower BMI appeared to have a higher incidence of low-grade scapular notching. PMID- 26631205 TI - Management of Proximal Humerus Fractures with the Equinoxe(r) Locking Plate System. AB - There is no consensus on surgical fixation and treatment of proximal humerus fractures, even though they are common fractures with several fixation techniques. This retrospective study quantifies the outcomes of patients who sustained a proximal humerus fracture and were treated with open reduction and internal fixation by at a single academic center between December 2010 and December 2014 using the Equinoxe(r) proximal humerus locking plate. Following enrollment, injury and surgical data was recorded. Forty-nine patients (31 female, 18 male) with 50 fractures were identified who met the inclusion criteria. Mean follow-up period was 16.8 months (range: 6 to 44 months). Mean age was 60.7 years with no significant difference in mean age by gender. Mean age adjusted Charlson Comorbidity Index (CCI) was 2.9 (range: 0 to 6). The overall complication rate was 10% (N = 5) with the most common complication being osteonecrosis (N = 3). Four patients required reoperation. At final follow-up, mean active forward flexion for the cohort was 140.8o +/- 30.1o, mean passive forward flexion was 155.7o +/- 25.2o, and mean active external rotation was 50.1o +/- 17.9o. For patients with postoperative complications, mean active forward flexion was 106.0o +/- 23.0o, mean passive forward flexion was 136.7o +/- 23.1o, and mean active external rotation was 34.2o +/- 24.4. Active forward flexion and external rotation were significantly different in the presence of a complication (p = 0.005 and p = 0.038, respectively). Mean DASH score for the cohort was 19.1 +/- 20.9. Mean DASH score for patients who developed complications or underwent reoperations was 34.2 +/- 24.3. This study demonstrates that the Equinoxe(r) proximal humerus locking plate provides stable fracture treatment with excellent clinical results and a low complication rate when performed by experienced orthopaedic traumatologists. PMID- 26631206 TI - Rate of Improvement in Clinical Outcomes with Anatomic and Reverse Total Shoulder Arthroplasty. AB - INTRODUCTION: The rate of clinical improvement has never been studied after anatomic (aTSA) and reverse (rTSA) total shoulder arthroplasty. This study quantifies the rate of improvement after aTSA and rTSA using five different scoring metrics for 1,641 patients. METHODS: We evaluated 1,641 (69 +/- 9.3 years old) patients treated by 14 orthopaedic surgeons using either aTSA or rTSA with a single platform shoulder system. Seven hundred twenty-nine patients received aTSA, and 912 patients received rTSA. Each patient was scored preoperatively and at various follow-up intervals (2 weeks, 6 weeks, 3 months, 6 months, annually, etc.) with a maximum follow-up time of 139 months using the SST, UCLA, ASES, Constant, and SPADI metrics. In addition, range of motion was measured. The rate of improvement was analyzed using a 40-point moving filter treadline over the entire range of follow-up. RESULTS: All metrics improved in a majority of patients with less than 5% worsening after 6 months. While gains in motion were present in the majority of patients after aTSA, a higher incidence of patients failed to experience improvement in range of motion after rTSA. Clinical worsening was seen in up to 10% and 20% of the visits for active flexion and abduction and external rotation, respectively. The majority of clinical improvement after aTSA and rTSA was noted in the first 6 months with full improvement noted by 12 to 24 months. During the first 12 months, the rate of improvement associated with rTSA patients was generally 30% larger than that of aTSA patients. DISCUSSION: The results of this large-scale database analysis demonstrate the reliability of improvements in outcomes and motion achieved with both aTSA and rTSA for various indications. For both aTSA and rTSA, less than 5% of patients reported worsening in each of the five clinical metrics after 6 months postoperative follow-up time. This study is significant because it quantifies how patient outcomes improve with time following treatment with both aTSA and rTSA. These results can be used to establish realistic patient expectations regarding the typical follow-up time required for pain to be reduced and function restored following surgical treatment with a total shoulder prosthesis. PMID- 26631207 TI - A Comparison and Correlation of Clinical Outcome Metrics in Anatomic and Reverse Total Shoulder Arthroplasty. AB - INTRODUCTION: Indications for anatomic (aTSA) and reverse (rTSA) total shoulder arthroplasty are well defined and dependent on the function of the rotator cuff; however, indications for rTSA have gradually extended to complex fractures, revisions, and primary arthritis in very elderly patients. The risk of secondary rupture of a weakened or degenerative rotator cuff is difficult to assess and can lead the orthopaedic surgeon to hesitate between aTSA or rTSA. It, therefore, seems appropriate to compare these two types of prostheses in terms of pain, functional, clinical outcome metric scores, and complications, despite suspected differences between populations and the respective diseases. METHODOLOGY: 1,145 patients (69.2 +/- 8.9 years) were treated by 12 orthopaedic surgeons in France and in the USA, using either aTSA or rTSA with one platform shoulder system. Five hundred twenty-eight patients received aTSA (66.2 +/- 9.0 years; 283 female, 245 male) for treatment of degenerative arthritis, and 617 patients received rTSA (71.8 +/- 8.0 years; 392 female, 225 male) for treatment of cuff tear arthroplasty, rotator cuff tear, and osteoarthritis. Each patient was scored preoperatively and at latest follow-up using the SST, UCLA, ASES, Constant, and SPADI metrics; active range of motion was also measured. The average follow-up for all patients was 39.7 +/- 18.7 months (aTSA: 42.7 +/- 21.9 months; rTSA: 37.1 +/- 15.1 months). Improvements in outcome using each metric score were normalized on a 100 point scale, correlated, and compared. A Student's two-tailed, unpaired t-test was used to identify differences in preoperative, postoperative, and pre to-postoperative improvements, where p < 0.05 denoted a significant difference. RESULTS: Preoperatively, rTSA patients had significantly lower mean outcome scores and significantly lower mean active range of motion as compared to aTSA patients. Post-operatively, rTSA and aTSA patients showed no significant difference in active forward flexion or in mean outcome scores as measured by four of the five metrics. rTSA patients had significantly lower active abduction, internal rotation, and active and passive external rotation than aTSA patients. However, they had significantly better strength (9.7 vs. 7.3 lbs, p < 0.0001). Preoperative to postoperative mean improvements were compared between both cohorts. rTSA patients were associated with significantly larger improvements in outcomes and also had significantly better improvements in active forward flexion and strength. Conversely, aTSA patients had significantly better improvement in active and passive external rotation and active internal rotation. Analysis of complications demonstrated a very similar rate between cohorts, with aTSA patients associated with a slightly lower rate (6.6 vs. 7.3%). CONCLUSION: This retrospective analysis of prospectively acquired data from 1,145 patients who received either a primary aTSA or rTSA prosthesis demonstrates that each device provides significant improvements with very similar mean results. In fact, the mean clinical outcomes associated with the reverse shoulder prostheses approach that of the "gold standard" anatomic device for their respective indications. Furthermore, the complication rates in this series are very similar and also favorable relative to the clinical literature. Findings, such as these, may at some point extend the indications of the reverse prosthesis to patients for whom an anatomical prosthesis could lead to a premature deterioration of the result. PMID- 26631208 TI - Reverse Shoulder Arthroplasty Augments for Glenoid Wear. Comparison of Posterior Augments to Superior Augments. AB - INTRODUCTION: Patients who are candidates for a reverse total shoulder arthroplasty (rTSA) may have varying amounts and patterns of glenoid wear. The usual treatment of these deformities has been eccentric reaming or bone grafting. Eccentric reaming often removes a large amount of subchondral bone. Bone grafting is technically more difficult and introduces another mode of failure if the graft does not heal. The purpose of this study is to evaluate patients undergoing a rTSA with concomitant superior or posterior glenoid wear who were treated with a superior augmented baseplate (SAB) or posterior augmented baseplate (PAB) without eccentric reaming or bone grafting. MATERIALS AND METHODS: Prospectively obtained data were queried from a multi-institutional IRB-approved database. Preoperative and postoperative data were analyzed from 39 patients who received a primary rTSA with either an 8 degrees PAB or a 10 degrees SAB and a minimum of 2 years follow-up. Twenty-four (10 females and 14 males, aged 72.3 +/- 8.2 years) received a primary rTSA shoulder with a PAB. Fifteen patients (4 females and 11 males, aged 71.7 +/- 9.2 years) received a primary rTSA shoulder with a SAB. Each patient was scored preoperatively and at latest follow-up using the SST, UCLA, ASES, Constant, and SPADI metrics. Active abduction, forward flexion, and active and passive external rotation with the arm at the side were also measured. The average follow-up for rTSA patients with a PAB was 25.6 +/- 3.1 months, and the average follow-up for rTSA patients with a SAB was 32.5 +/- 6.5 months. A Student's two-tailed, unpaired t-test was used to identify differences in preoperative and postoperative results, where p < 0.05 denoted a significant difference. RESULTS: All patients in both groups demonstrated significant improvements in pain and function following treatment with the reverse shoulder arthroplasty. The PAB rTSA cohort had a scapular notching rate of 6.3%, whereas the SAB rTSA cohort had a scapular notching rate of 14.3%. The PAB outperformed the SAB with the ASES, Constant, and active forward elevation measures. DISCUSSION: The PAB group outperformed the SAB group with the ASES and Constant outcome scores and forward flexion. The reason for this is unknown; however, it may be due to the posterior augment baseplate itself tensioning the remaining external rotators better than the superior augment, or it may be that the posterior augment group had a better posterior cuff. Both implant groups had no revisions or dislocations and had a low notching rate. It appears that a SAB for superior glenoid wear and a PAB for posterior glenoid wear are viable simple solutions in patients undergoing a rTSA, where each preserves glenoid bone and eliminates the need for glenoid bone grafting. PMID- 26631209 TI - Bone Grafting the Glenoid Versus Use of Augmented Glenoid Baseplates with Reverse Shoulder Arthroplasty. AB - BACKGROUND: Large glenoid defects are a difficult reconstructive problem for surgeons performing reverse shoulder arthroplasty (rTSA). Options to address glenoid defects include eccentric reaming, bone grafting, and augmented glenoid baseplates. Augmented glenoid baseplates may provide a simpler, cost-effective, bone-preserving option compared to other techniques. No studies report the use of augmented baseplates to correct glenoid deformity in rTSA relative to the use of glenoid bone graft. MATERIALS AND METHODS: We retrospectively reviewed 80 patients that received a primary rTSA and received either a structural bone graft or an augmented glenoid baseplate to address a significant glenoid defect. There were 39 patients in the augmented baseplate cohort and 41 patients in the bone graft cohort. The augmented baseplate cohort contained 24 8 degrees posterior augment implants and 15 10 degrees superior augment baseplates. The bone graft cohort consisted of 36 autograft humeral heads and 5 allograft femoral heads. The average follow-up for rTSA patients with an augmented baseplate was 28.3 +/- 5.7 months, and the average follow-up for rTSA patients with glenoid bone graft was 34.1 +/- 15.0 months. Each patient was scored preoperatively and at latest follow up using the SST, UCLA, ASES, Constant, and SPADI metrics. Range of motion data was obtained as well. RESULTS: All patients demonstrated significant improvements in pain, ROM, and functional scores following treatment with rTSA using either augmented baseplates or glenoid bone graft to correct glenoid defects. The database contained no complications for the augmented glenoid baseplate cohort, and six complications (14.6%) for the glenoid bone graft cohort (including two glenoid loosenings and graft failures). Additionally, the augmented baseplate cohort showed a lower scapular notching rate of 10% as compared to the bone graft cohort which had a notching rate of 18.5%. DISCUSSION: The results of this study suggest that either augmented glenoid baseplates or glenoid bone graft can be used to address large glenoid defects during rTSA with significant improvement in outcomes. Augmented glenoid baseplates may achieve a lower complication and scapular notching rate, but additional and longer-term clinical follow-up is required to confirm these results. PMID- 26631210 TI - Revision Total Shoulder Arthroplasty without Humeral Component Removal. A Preliminary Report on the Role of a Platform Humeral Component. AB - BACKGROUND: Revision total shoulder arthroplasty to a reverse system without removing the humeral component-- i.e., a platform system--has been in use since 2006. This preliminary report compares the outcomes of revision total shoulder replacement in patients who underwent revision utilizing a platform system as compared to those patients requiring stem removal. METHODS: The data banks from two academic centers were utilized to review patients who underwent revision total shoulder surgery requiring removal of a well fixed humeral stem and those revised with a well fixed platform humeral stem. All patients underwent revision to reverse total shoulder arthroplasty. Measured variables were pre and postoperative Constant scores, blood loss, operating room time, complications, and cost. RESULTS: The use of a platform system resulted in fewer complications, less operating room time, and a decrease in blood loss (p < 0.05). The Constant scores were not significantly different between the two groups. The cost of implants and operating room time was also less in the platform system group. CONCLUSION: Revision total shoulder arthroplasty utilizing a platform system that does not require humeral component removal resulted in a significant decrease in complications, blood loss, and operating room time compared with revisions that did not utilize a platform system. The Constant score was similar between the two groups. The overall cost of the procedure was less when the platform system was used. PMID- 26631211 TI - Infection Prevention in Shoulder Surgery. AB - The microbiome of the shoulder demonstrates distinctive differences to other orthopaedic surgical sites. Recent studies have demonstrated that the most common organisms found in deep shoulder infections are coagulase-negative staph lococcal species and Propionibacterium acnes . Many studies support diligent hand washing, decreasing operative time, routine glove changing, minimizing operating room traffic, and covering instruments as means for decreasing the risk of deep infection. On the other hand, hair clipping and the use of adhesive drapes may have little effect on decreasing the incidence of deep infection. Although generally considered the most efficacious skin preparation solution, chlorhexidine gluconate has minimal effect on eradication of P. acnes from the surgical site; however, the addition of preoperative topical applications of benzoyl peroxide to standard surgical preparation has shown promise in decreasing the rate of P . acnes culture positivity. Additionally, the use of local antibiotic formulations seems to be an effective means of preventing deep infection. PMID- 26631212 TI - Stemless and Short Stem Humeral Components in Shoulder Arthroplasty. AB - Humeral-sided arthroplasty design evolution continues to be supported by the published literature in the transition away from traditional stemmed devices. Early studies have shown not only absence of failure with these newer shorter and stemless designs but also equivalence in terms of early outcomes compared to traditional stemmed devices with the benefits of shorter operative time, less blood loss, easier revision, and the potential to reduce stress shielding and periprosthetic fractures. We will review the literature available on the different designs of both short stem and stemless humeral devices. PMID- 26631213 TI - The Subscapularis-Sparing Approach in Humeral Head Replacement. AB - INTRODUCTION: Failure of the subscapularis repair can be detrimental to patient outcome and shoulder function in shoulder replacement surgery. This report details an approach to resurfacing the humeral head that preserves the majority of the subscapularis attachment to the humerus, allowing a more rapid rehabilitation and minimizing post-operative subscapularis insufficiency. METHODS: In this approach, only the inferior 30% to 50% of the subscapularis tendon is detached from the humerus, leaving the critical superior aspect of the tendon attached to the lesser tuberosity. In a previous study, we evaluated this approach in 43 patients. Nineteen had postoperative magnetic resonance imaging (MRI), and 24 patients had ultrasound (US) evaluation. Physical examination included belly press and lift-off tests; follow-up included visual analog scale (VAS), American Shoulder and Elbow Surgeons (ASES), Constant, UCLA, Rowe, and SF 12 scores. RESULTS: All patients had a minimum 2-year follow-up (range 2 to 6, average 4). All patients had subscapularis strength equal to the opposite side as measured by lift-off, belly press, and bear hug tests. Average postoperative scores included ASES, 74.4; Constant, 78.3; UCLA, 27; Rowe, 81.7; and VAS, 2.2; SF-12 averages all showed statistically significant improvement except for general health, which showed improvement approaching significance. All had an intact subscapularis tendon attachment as evaluated by either MRI or US imaging. None had atrophy in the muscle belly. CONCLUSIONS: The subscapularis-sparing, minimally-invasive approach to the glenohumeral joint provides adequate exposure for shoulder replacement surgery and provides a decreased risk of postoperative failure (rupture or atrophy) of the subscapularis tendon. PMID- 26631214 TI - Subscapularis Preserving Technique in Anatomic Total Shoulder Arthroplasty. The Superior and Inferior Approach. AB - Subscapularis tenotomy for anatomic total shoulder arthroplasty has been the standard approach for shoulder surgeons that use the deltopectoral approach. The risk of subscapularis insufficiency after this approach has been well documented. In order to avoid subscapularis complications, subscapularis sparing approaches through the rotator interval have been developed. We present two alternative subscapularis preserving techniques that are performed through the deltopectoral interval and allow more complete osteophyte excision and accurate humeral head sizing. These techniques require modified instrumentation and are facilitated by the use of an adaptable prosthesis with dual eccentricity. Future studies will examine the comparative clinical and radiographic outcomes of these techniques. PMID- 26631215 TI - The PARsylation activity of tankyrase in adipose tissue modulates systemic glucose metabolism in mice. AB - AIMS/HYPOTHESIS: Tankyrase (TNKS) is a ubiquitously expressed molecular scaffold that is implicated in diverse processes. The catalytic activity of TNKS modifies substrate proteins through poly-ADP-ribosylation (PARsylation) and is responsive to cellular energetic state. Global deficiency of the TNKS protein in mice accelerates glucose utilisation and raises plasma adiponectin levels. The aim of this study was to investigate whether the PARsylation activity of TNKS in adipocytes plays a role in systemic glucose homeostasis. METHODS: To inhibit TNKS mediated PARsylation, we fed mice with a diet containing the TNKS-specific inhibitor G007-LK. To genetically inactivate TNKS catalysis in adipocytes while preserving its function as a molecular scaffold, we used an adipocyte-selective Cre transgene to delete TNKS exons that encoded the catalytic domain at the C terminus. Tissue-specific insulin sensitivity in mice was investigated using hyperinsulinaemic-euglycaemic clamps. To model adipose-liver crosstalk ex vivo, we applied adipocyte-conditioned media to hepatocytes and assessed the effect on gluconeogenesis. RESULTS: The TNKS inhibitor G007-LK improved glucose tolerance and insulin sensitivity and promptly increased plasma adiponectin levels. In female mice, but not in male mice, adipocyte-selective genetic inactivation of TNKS catalysis improved hepatic insulin sensitivity and post-transcriptionally increased plasma adiponectin levels. Both pharmacological and genetic TNKS inhibition in female mouse-derived adipocytes induced a change in secreted factors to decrease gluconeogenesis in primary hepatocytes. CONCLUSIONS/INTERPRETATION: Systemic glucose homeostasis is regulated by the PARsylation activity of TNKS in adipocytes. This regulation is mediated in part by adipocyte-secreted factors that modulate hepatic glucose production. Pharmacological TNKS inhibition could potentially be used to improve glucose tolerance. PMID- 26631217 TI - Metformin in obese teenagers does not improve glycaemic control, study finds. PMID- 26631216 TI - Night-time blood pressure: a role in the prediction and prevention of diabetes? AB - This commentary discusses and reviews the implications of two studies published in this issue of Diabetologia by Hermida et al (DOIs: 10.1007/s00125-015-3748-8 and 10.1007/s00125-015-3749-7 ) suggesting that high nocturnal blood pressure could have a role in the prediction of diabetes and act as a therapeutic target to prevent diabetes. This overview addresses the clinical implications of this work and new research that is likely to advance this field. It also provides a framework for interpreting claims of causality from observational studies and clinical trials. PMID- 26631218 TI - Routine multidisciplinary cerebrovascular meetings do not reduce aneurysm clipping case load: a cohort study. AB - BACKGROUND: Structured multidisciplinary care is an increasingly popular tool in the management of many complex disease processes; however, there is little published data regarding the effects of such a process on management of intracranial aneurysms and neurosurgical case loads. There is some resistance in the neurosurgical community to routine involvement of interventional neuroradiologists in the care of patients with intracranial aneurysms due to concerns regarding maintenance of neurosurgical case loads and training capabilities. At our tertiary Australian hospital, we have implemented a weekly multidisciplinary cerebrovascular meeting (MDCVM) facilitating routine discussion of these cases between neurosurgeons and interventional neuroradiologists. METHODS: This study identified management modalities for ruptured and unruptured cerebral aneurysms diagnosed at our centre for a 2-year period before and after the implementation of MDCVM culminating in a 4-year retrospective cohort study. The pre- and post-MDCVM cohorts were well matched for demographics with 162 and 224 patients, respectively. RESULTS: There is no significant difference in percentage or absolute numbers of endovascular or surgical cases in the pre-MDCVM (103; 73.0% versus 38; 27.0%, respectively) or post-MDCVM cohorts (105; 79.5% versus 27; 20.5%, respectively), reflecting a maintained surgical case load after the implementation of MDCVM (P = 0.21). There were no significant differences in any confounding variables including age, sex, aneurysm size/location, Fisher or World Federation of Neurosurgical Societies (WFNS) grade. CONCLUSIONS: Implementation of MDCVM did not impact on active management case loads with consistent numbers and percentages for both endovascular and microsurgical management. PMID- 26631219 TI - Is 60 mg a suitable dosage for same-day spinal prilocaine? PMID- 26631220 TI - In reply: Is 60 mg a suitable dosage for same-day spinal prilocaine? PMID- 26631221 TI - Comparative Analysis of Ultrafast Excitation Energy-Transfer Pathways in Three Strains of Divinyl Chlorophyll a/b-Containing Cyanobacterium, Prochlorococcus marinus. AB - Prochlorococcus, a unique marine picocyanobacterium, contains the divinyl- (DV-) type chlorophylls (Chls), DV-Chl a and DV-Chl b, as its photosynthetic pigments. We comprehensively investigated the light-harvesting mechanisms in three strains of Prochlorococcus marinus (P. marinus) at physiological temperature (293 K) by ultrafast time-resolved fluorescence (TRF), steady-state fluorescence, and absorption measurements. These strains differ in their relative amounts of DV-Chl a, DV-Chl b, and carotenoids and in the pigment coupling conditions. All of the strains showed ultrafast excitation energy transfer from DV-Chl b to DV-Chl a, and the low-light-adapted strains, P. marinus CCMP1375 and CCMP2773, exhibited relatively higher DV-Chl b contents than P. marinus CCMP1986. It appears that carotenoid is another important antenna pigment, especially in the low-light adapted strains (CCMP1375 and CCMP2773), that transfers the excitation energy to lower-energy DV-Chl a. PMID- 26631222 TI - Collagen interactions: Drug design and delivery. AB - Collagen is a major component in a wide range of drug delivery systems and biomaterial applications. Its basic physical and structural properties, together with its low immunogenicity and natural turnover, are keys to its biocompatibility and effectiveness. In addition to its material properties, the collagen triple-helix interacts with a large number of molecules that trigger biological events. Collagen interactions with cell surface receptors regulate many cellular processes, while interactions with other ECM components are critical for matrix structure and remodeling. Collagen also interacts with enzymes involved in its biosynthesis and degradation, including matrix metalloproteinases. Over the past decade, much information has been gained about the nature and specificity of collagen interactions with its partners. These studies have defined collagen sequences responsible for binding and the high resolution structures of triple-helical peptides bound to its natural binding partners. Strategies to target collagen interactions are already being developed, including the use of monoclonal antibodies to interfere with collagen fibril formation and the use of triple-helical peptides to direct liposomes to melanoma cells. The molecular information about collagen interactions will further serve as a foundation for computational studies to design small molecules that can interfere with specific interactions or target tumor cells. Intelligent control of collagen biological interactions within a material context will expand the effectiveness of collagen-based drug delivery. PMID- 26631223 TI - Localized Surface Plasmon-Enhanced Electroluminescence in OLEDs by Self-Assembly Ag Nanoparticle Film. AB - We fabricated Ag nanoparticle (NP) film in organic light emission diodes (OLEDs), and a 23 times increase in electroluminescence (EL) at 518 nm was probed by time resolved EL measurement. The luminance and relative external quantum efficiency (REQE) were increased by 5.4 and 3.7 times, respectively. There comes a new energy transport way that localized surface plasmons (LSPs) would absorb energy that corresponds to the electron-hole pair before recombination, promoting the formation of electron-hole pair and exciting local surface plasmon resonance (LSPR). The extended lifetime of Alq3 indicates the existence of strong interaction between LSPR and exciton, which decreases the nonradiative decay rate of OLEDs. PMID- 26631224 TI - Implementing international osteoarthritis treatment guidelines in primary health care: study protocol for the SAMBA stepped wedge cluster randomized controlled trial. AB - BACKGROUND: Previous research indicates that people with osteoarthritis (OA) are not receiving the recommended and optimal treatment. Based on international treatment recommendations for hip and knee OA and previous research, the SAMBA model for integrated OA care in Norwegian primary health care has been developed. The model includes physiotherapist (PT) led patient OA education sessions and an exercise programme lasting 8-12 weeks. This study aims to assess the effectiveness, feasibility, and costs of a tailored strategy to implement the SAMBA model. METHODS/DESIGN: A cluster randomized controlled trial with stepped wedge design including an effect, process, and cost evaluation will be conducted in six municipalities (clusters) in Norway. The municipalities will be randomized for time of crossover from current usual care to the implementation of the SAMBA model by a tailored strategy. The tailored strategy includes interactive workshops for general practitioners (GPs) and PTs in primary care covering the SAMBA model for integrated OA care, educational material, educational outreach visits, feedback, and reminder material. Outcomes will be measured at the patient, GP, and PT levels using self-report, semi-structured interviews, and register based data. The primary outcome measure is patient-reported quality of care (OsteoArthritis Quality Indicator questionnaire) at 6-month follow-up. Secondary outcomes include referrals to PT, imaging, and referrals to the orthopaedic surgeon as well as participants' treatment satisfaction, symptoms, physical activity level, body weight, and self-reported and measured lower limb function. The actual exposure to the tailor made implementation strategy and user experiences will be measured in a process evaluation. In the economic evaluation, the difference in costs of usual OA care and the SAMBA model for integrated OA care will be compared with the difference in health outcomes and reported by the incremental cost-effectiveness ratio (ICER). DISCUSSION: The results from the present study will add to the current knowledge on tailored strategies, which aims to improve the uptake of evidence-based OA care recommendations and improve the quality of OA care in primary health care. The new knowledge can be used in national and international initiatives designed to improve the quality of OA care. TRIAL REGISTRATION: ClinicalTrials.gov NCT02333656. PMID- 26631225 TI - Analysis of superiorly projecting anterior communicating artery aneurysms: anatomy, techniques, and outcome. A proposed classification system. AB - Superiorly projecting (SP) anterior communicating artery (AComA) aneurysms are typically described as a homogenous group. Clinically and microsurgically, these aneurysms vary in multiple important characteristics. We propose a microsurgical classification system for these complex aneurysms and review its implications regarding presentation, microsurgical techniques, and outcome. This retrospective analysis reviews patients undergoing clipping of SP AComA aneurysms (2005-2013). The classification system is based on the virtual plane created by the A2 segments and its relationship to the aneurysm. Aneurysm type was assessed by intraoperative images and videos. Type 1 is defined by bisection of the dome by the virtual plane. Type 2 is defined by dome projection posterior to this plane. Sagittal rotation of the plane defines type 3. We analyzed clinical presentation, morphology, angiographic characteristics, operative technique, and outcome relative to the classification types. There were 44 SP AComA aneurysms. 3D angiographic images predicted classification type in 83%. Type 1 presented more often with SAH (95.5%, p = 0.0046). There was no statistically significant difference between the types regarding patient demographics or aneurysm characteristics. In type 2, fenestrated clips were used frequently (87.5% p= 0.0016), and there was higher rate of intraoperative rupture (37.5%). Although there was no statistically significant difference between the types in respect to HH grade upon presentation, patients with type 2 aneurysms experienced higher rates of poor GOS (50%). The proposed classification system for SP AComA aneurysms has implications regarding surgical planning, micro-dissection, clipping, and outcome. Type 2 aneurysms carry significant surgical risk. PMID- 26631226 TI - Development of an immunochromatographic strip for the serodiagnosis of Theileria infection in sheep. AB - BACKGROUND: Theileria uilenbergi and T. luwenshuni are tick-borne protozoan parasites, transmitted by Haemaphysalis qinghaiensis and H. longicornis, respectively. They are the main causative agents of theileriosis in small ruminants in China. The disease has resulted in severe economic losses and hindered the development of sheep and goat husbandry industry in the endemic regions. METHODS: In this study, a colloidal gold-based immunochromatographic strip (ICS) was developed for the detection of T. uilenbergi and/or T. luwenshuni infections. A recombinant T. uilenbergi immunodominant protein (rTuIP) was used as antigen for the ICS. The nitrocellulose membrane was incubated with rTuIP on the test (T) line and anti-rTuIP antiserum on the control (C) line, respectively. The rTuIP conjugated to colloidal gold particles was used as the detection system for visualization of the lines. Then the sample pad, conjugate pad, nitrocellulose membrane and absorbent pad were assembled onto a backing plate in the appropriate order. RESULTS: The ICS was able to detect antibodies in the sera of animals experimentally infected with T. uilenbergi from 14 to 85 days. It also reacted with the serum from T. luwenshuni infected sheep. However, there was no cross-reactivity with sera from animals infected with Babesia motasi and Anaplasma ovis. Comparison of the ICS with the rTuIP antigen based indirect enzyme-linked immunosorbent assays (ELISA) using test field samples showed good correlations with 93.1 % (81/87) sensitivity and 100 % (40/40) specificity, respectively, with an almost perfect agreement (Kappa = 0.895, P < 0.01). CONCLUSION: An immunochromatographic strip test based on a recombinant T. uilenbergi immunodominant protein (rTuIP) was developed. This is a rapid test (approximately 15 min to completion) for the detection of T. uilenbergi and/or T. luwenshuni infection that is easy to perform and; delivers results that are visible to the naked eye. PMID- 26631227 TI - Shelter-Building Insects and Their Role as Ecosystem Engineers. AB - Amelioration of harsh conditions, manipulation of host plant quality, and protection from natural enemies have all been suggested as potential forces in the evolution and maintenance of concealed feeding in insects. The construction of shelters--either in the form of mines, galls, and leaf rolls--are expected to increase larval survivorship and might influence other organisms of the community through non-trophic direct and indirect effects when shelters are co-occupied or occupied after abandonment, placing leaf and stem shelter-builders within the context of ecosystem engineering. In this review, we evaluate the potential of shelter built by insects to reduce pressure exerted by natural enemies, increase tissue quality, and provide shelter against abiotic conditions experienced during insect development. Through a quantitative analysis, we also examined the effects of insect shelters on patterns of richness and abundance of local communities, reviewing the data published in the last 15 years. We demonstrate strong effects of shelters on several arthropods, with increased richness and abundance when shelters are present in the host plants. These results reinforce the importance of the physical structures created by insects that although subtle, might have important roles in facilitative interactions. PMID- 26631228 TI - Genetic engineering of mammals. AB - Historically, genetic engineering for mammalian reproductive questions has been accomplished primarily in the mouse. However, all the genetic manipulations that can be done in the mouse can now be accomplished in most domesticated mammals. Random integration of transgenes, homologous recombination and gene editing are now routine for several mammalian species. For livestock, queries related to fertility can be asked directly for the species in question, without a need for a mouse model. For human clinical concerns, the most appropriate model should be selected based on physiology, anatomy, or even size. The mouse will continue to be a useful genetically engineered model. However, other species are now amenable to the full range of genetic manipulations and should be considered as possible models for human conditions when appropriate. PMID- 26631229 TI - Eating disorders in a multi-ethnic inner-city UK sample: prevalence, comorbidity and service use. AB - PURPOSE: No studies have investigated the prevalence of eating disorders (ED) according to DSM-5 criteria and few have explored their comorbidity and service use in the general population in the UK. We aimed to estimate the prevalence, comorbidity, and service use in individuals with ED in a multi-ethnic inner city sample. METHODS: A total of 1698 individuals (age 16/90) were screened for ED in the first phase of the South East London Community Health Study and 145 were followed up with a diagnostic interview. Data was weighed for survey design and Chi Square tests were used to investigate socio-demographic distribution, comorbidity and service use in participants with ED. RESULTS: The point prevalence of ED was 4.4 % (Binge Eating Disorder (BED) 3.6 %; Bulimia Nervosa (BN) 0.8 %) and 7.4 % when including sub-threshold diagnoses (Purging Disorder (PD) 0.6 %; Other Specified Feeding and Eating Disorders (OSFED) 2.4 %). No cases of AN were identified. Purging Disorder was the ED with the highest proportion of comorbid disorders. A minority of participants with ED had accessed specialist care services. CONCLUSIONS: ED are common, the comorbidity of ED was in line with previous studies and no ethnic differences were identified. Although PD is not a full diagnosis in DSM-5, we found some evidence of high comorbidity with other disorders, that needs to be replicated using larger samples. Service use was low across ED diagnoses, despite high levels of comorbidity. PMID- 26631230 TI - David Oliver: Grill the politicians live on TV. PMID- 26631231 TI - Audit of submissions: July 2014-June 2015. PMID- 26631232 TI - When Lack of Evidence Is Evidence of Lack. AB - In their recent article "A Gentle Ethical Defence of Homeopathy," Levy, Gadd, Kerridge, and Komesaroff use the claim that "lack of evidence is not equivalent to evidence of lack" as a component of their ethical defence of homeopathy. In response, this article argues that they cannot use this claim to shore up their ethical arguments. This is because it is false. PMID- 26631233 TI - Prevalence, incidence, and age at diagnosis in Marfan Syndrome. AB - BACKGROUND: Marfan syndrome is a genetic disorder with considerable morbidity and mortality. Presently, clinicians use the 2010 revised Ghent nosology, which includes optional genetic sequencing of the FBN1 gene, to diagnose patients. So far, only a few studies based on older diagnostic criteria have reported a wide range of prevalence and incidence. Our aim was to study prevalence, incidence, and age at diagnosis in patients with Marfan syndrome. METHOD: Using unique Danish patient-registries, we identified all possible Marfan syndrome patients recorded by the Danish healthcare system (1977-2014). Following, we confirmed or rejected the diagnosis according to the 2010 revised Ghent nosology. RESULTS: We identified a total of 1628 persons with possible Marfan syndrome. We confirmed the diagnosis in 412, whereof 46 were deceased, yielding a maximum prevalence of 6.5/100,000 at the end of 2014. The annual median incidence was 0.19/100,000 (range: 0.0-0.7) which increased significantly with an incidence rate ratio of 1.03 (95% CI: 1.02-1.04, p < 0.001). We found a median age at diagnose of 19.0 years (range: 0.0-74). The age at diagnosis increased during the study period, uninfluenced by the changes in diagnostic criteria. We found no gender differences. CONCLUSION: The increasing prevalence of Marfan syndrome during the study period is possibly due to build-up of a registry. Since early diagnosis is essential in preventing aortic events, diagnosing Marfan syndrome remains a task for both pediatricians and physicians caring for adults. PMID- 26631234 TI - Cervical non-invasive vagus nerve stimulation (nVNS) for preventive and acute treatment of episodic and chronic migraine and migraine-associated sleep disturbance: a prospective observational cohort study. AB - BACKGROUND: The debilitating nature of migraine and challenges associated with treatment-refractory migraine have a profound impact on patients. With the need for alternatives to pharmacologic agents, vagus nerve stimulation has demonstrated efficacy in treatment-refractory primary headache disorders. We investigated the use of cervical non-invasive vagus nerve stimulation (nVNS) for the acute treatment and prevention of migraine attacks in treatment-refractory episodic and chronic migraine (EM and CM) and evaluated the impact of nVNS on migraine-associated sleep disturbance, disability, and depressive symptoms. METHODS: Twenty patients with treatment-refractory migraine were enrolled in this 3-month, open-label, prospective observational study. Patients administered nVNS prophylactically twice daily at prespecified times and acutely as adjunctive therapy for migraine attacks. Pain intensity (visual analogue scale [VAS]); number of headache days per month and number of migraine attacks per month; number of acutely treated attacks and time to achieve pain relief; sleep quality (Pittsburgh Sleep Quality Index [PSQI]); migraine disability assessment (MIDAS); depressive symptoms (Beck Depression Inventory((r)) [BDI]); and adverse events (AEs) were evaluated. RESULTS: Of the 20 enrolled patients, 10 patients each had been diagnosed with EM and CM. Prophylaxis with nVNS was associated with significant overall reductions in patient-perceived pain intensity (mean VAS scores at baseline vs 3 months: 7.75 +/- 0.64 vs 4.05 +/- 0.76; 95 % CI: 3.3, 4.1; p < 0.0001), mean number of headache days per month (baseline vs 3 months: 14.7 +/- 4.1 vs 8.9 +/- 3.66; 95 % CI: 3.3, 8.3; p < 0.0001), and mean number of migraine attacks per month (baseline vs 3 months: 7.3 +/- 3.85 vs 4.45 +/- 2.48; 95 % CI: 0.8, 4.9; p < 0.01). For acutely treated migraine attacks, a reduction in mean time (minutes) to achieve pain relief (baseline vs 3 months: 84.5 +/- 39.1 vs 52.75 +/- 16.42; 95 % CI: 12.6, 51.0; p < 0.002) was noted. Significant improvements, more evident in patients with EM, were noted in MIDAS and BDI scores along with a trend toward improvement in PSQI daytime dysfunction subscore (p = 0.07). No severe or serious AEs occurred. CONCLUSION: In this study, treatment with nVNS was safe and provided clinically meaningful decreases in the frequency, intensity, and duration of migraine attacks in patients with treatment refractory migraine. Improvements in migraine-associated disability, depression, and sleep quality were also noted. PMID- 26631235 TI - Higher migraine risk in healthcare professionals than in general population: a nationwide population-based cohort study in Taiwan. AB - BACKGROUND: High stress levels and shift work probably trigger migraine in healthcare professionals (HCPs). However, the migraine risk differences between HCPs and the general population is unknown. METHODS: This nationwide population based cohort study used Taiwan's National Health Insurance Research Database. Physicians (50,226), nurses (122,357), and other HCPs (pharmacists, technicians, dietitians, rehabilitation therapists, social workers, etc.) (45,736) were enrolled for the study cohort, and randomly selected non-HCPs (218,319) were enrolled for the comparison cohort. Conditional logistical regression analysis was used to compare the migraine risks. Comparisons between HCPs and between physician specialties were also done. RESULTS: Physicians, nurses, and other HCPs had higher migraine risks than did the general population (adjusted odds ratio [AOR]: 1.672; 95 % confidence interval [CI]: 1.468-1.905, AOR: 1.621; 95 % CI: 1.532-1.714, and AOR: 1.254; 95 % CI: 1.124-1.399, respectively) after stroke, hypertension, epilepsy, anxiety, depression, and insomnia had been adjusted for. Nurses and physicians had higher migraine risks than did other HCPs (AOR: 1.303; 95 % CI: 1.206-1.408, and AOR: 1.193; 95 % CI: 1.069-1.332, respectively). Obstetricians and gynecologists had a lower migraine risk than did other physician specialists (AOR: 0.550; 95 % CI: 0.323-0.937). CONCLUSION: HCPs in Taiwan had a higher migraine risk than did the general population. Heavy workloads, emotional stress, and rotating night shift sleep disturbances appear to be the most important risk factors. These findings should provide an important reference for promoting occupational health in HCPs in Taiwan. PMID- 26631236 TI - Hookworm infestation is not an uncommon cause of obscure occult and overt gastrointestinal bleeding in an endemic area: A study using capsule endoscopy. AB - Obscure gastrointestinal bleeding (OGIB), particularly occult, has been reported to be caused by hookworm infestation rarely from tropical countries, particularly India. Hence, we undertook a retrospective study evaluating frequency, clinical spectrum, and outcome of patients with OGIB associated with worm infestation. Data of consecutive patients with OGIB undergoing capsule endoscopy in a multilevel university hospital in northern India were retrospectively analyzed. Twenty-one out of 163 (13 %) patients with OGIB had hookworm infestation detected on capsule endoscopy. Of 21 patients (median age 65 years [range 19-82], 17 [81 %] male), 16 had overt and 5 had occult OGIB. Another lesion that could explain OGIB was present in 8/21 patients, 3/5 with OGIB occult, and 5/16 overt (p = ns). All the patients received treatment with albendazole and appropriate measures for the associated lesion, if any. Patients with hookworm infestation with another lesion experienced recurrent bleeding more often than those with worm infestation only. Hookworm infestation is an important cause of occult as well as overt OGIB and may be present even in association with another lesion. Those with additional lesion had recurrent bleeding more often than those with worm infestation alone. PMID- 26631237 TI - Combined Angiotensin Receptor Modulation in the Management of Cardio-Metabolic Disorders. AB - Cardiovascular and metabolic disorders, such as hypertension, insulin resistance, dyslipidemia or obesity are linked with chronic low-grade inflammation and dysregulation of the renin-angiotensin system (RAS). Consequently, RAS inhibition by ACE inhibitors or angiotensin AT1 receptor (AT1R) blockers is the evidence based standard for cardiovascular risk reduction in high-risk patients, including diabetics with albuminuria. In addition, RAS inhibition reduces the new onset of diabetes mellitus. Yet, the high and increasing prevalence of metabolic disorders, and the high residual risk even in properly treated patients, calls for additional means of pharmacological intervention. In the past decade, the stimulation of the angiotensin AT2 receptor (AT2R) has been shown to reduce inflammation, improve cardiac and vascular remodeling, enhance insulin sensitivity and increase adiponectin production. Therefore, a concept of dual AT1R/AT2R modulation emerges as a putative means for risk reduction in cardio metabolic diseases. The approach employing simultaneous RAS blockade (AT1R) and RAS stimulation (AT2R) is distinct from previous attempts of double intervention in the RAS by dual blockade. Dual blockade abolishes the AT1R-linked RAS almost completely with subsequent risk of hypotension and hypotension-related events, i.e. syncope or renal dysfunction. Such complications might be especially prominent in patients with renal impairment or patients with isolated systolic hypertension and normal-to-low diastolic blood pressure values. In contrast to dual RAS blockade, the add-on of AT2R stimulation does not exert significant blood pressure effects, but it may complement and enhance the anti-inflammatory and antifibrotic/de-stiffening effects of the AT1R blockade and improve the metabolic profile. Further studies will have to investigate these putative effects in particular for settings in which blood pressure reduction is not primarily desired. PMID- 26631238 TI - Preclinical and first clinical experience with the gastrin-releasing peptide receptor-antagonist [68Ga]SB3 and PET/CT. AB - PURPOSE: Gastrin-releasing peptide receptors (GRPR) represent attractive targets for tumor diagnosis and therapy because of their overexpression in major human cancers. Internalizing GRPR agonists were initially proposed for prolonged lesion retention, but a shift of paradigm to GRPR antagonists has recently been made. Surprisingly, radioantagonists, such as [(99m)Tc]DB1 ((99m)Tc-N4'-DPhe(6),Leu NHEt(13)]BBN(6-13)), displayed better pharmacokinetics than radioagonists, in addition to their higher inherent biosafety. We introduce here [(68)Ga]SB3, a [(99m)Tc]DB1 mimic-carrying, instead of the (99m)Tc-binding tetraamine, the chelator DOTA for labeling with the PET radiometal (68)Ga. METHODS: Competition binding assays of SB3 and [(nat)Ga]SB3 were conducted against [(125)I-Tyr(4)]BBN in PC-3 cell membranes. Blood samples collected 5 min postinjection (pi) of the [(67)Ga]SB3 surrogate in mice were analyzed using high-performance liquid chromatography (HPLC) for degradation products. Likewise, biodistribution was performed after injection of [(67)Ga]SB3 (37 kBq, 100 MUL, 10 pmol peptide) in severe combined immunodeficiency (SCID) mice bearing PC-3 xenografts. Eventually, [(68)Ga]SB3 (283 +/- 91 MBq, 23 +/- 7 nmol) was injected into 17 patients with breast (8) and prostate (9) cancer. All patients had disseminated disease and had received previous therapies. PET/CT fusion images were acquired 60-115 min pi. RESULTS: SB3 and [(nat)Ga]SB3 bound to the human GRPR with high affinity (IC50: 4.6 +/- 0.5 nM and 1.5 +/- 0.3 nM, respectively). [(67)Ga]SB3 displayed good in vivo stability (>85 % intact at 5 min pi). [(67)Ga]SB3 showed high, GRPR-specific and prolonged retention in PC-3 xenografts (33.1 +/- 3.9%ID/g at 1 h pi - 27.0 +/ 0.9%ID/g at 24 h pi), but much faster clearance from the GRPR-rich pancreas (~160%ID/g at 1 h pi to <17%ID/g at 24 h pi) in mice. In patients, [(68)Ga]SB3 elicited no adverse effects and clearly visualized cancer lesions. Thus, 4 out of 8 (50 %) breast cancer and 5 out of 9 (55 %) prostate cancer patients showed pathological uptake on PET/CT with [(68)Ga]SB3. CONCLUSION: [(67)Ga]SB3 showed excellent pharmacokinetics in PC-3 tumor-bearing mice, while [(68)Ga]SB3 PET/CT visualized lesions in about 50 % of patients with advanced and metastasized prostate and breast cancer. We expect imaging with [(68)Ga]SB3 to be superior in patients with primary breast or prostate cancer. PMID- 26631239 TI - Selective internal radiation therapy in patients with progressive neuroendocrine liver metastases. AB - PURPOSE: To evaluate the safety and efficacy of selective internal radiation therapy (SIRT) in patients with unresectable liver metastases from neuroendocrine tumours (NETLMs). METHODS: This retrospective study included 40 patients with progressive NETLMs (22 women, 18 men, mean age 61.6 years) who underwent SIRT with (90)Y-labelled resin microspheres. Tumour response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) on CT or MR images. Medical records were reviewed. RESULTS: In the 40 patients, 54 evaluable SIRT procedures were performed, 33 to the right liver lobe (mean activity 1.31 GBq), 13 to the left lobe (mean activity 0.85 GBq), and 8 to both lobes (mean activity 1.61 GBq). Late follow-up imaging (mean 20 months) was performed after 44 of the treatments. Objective tumour response and disease control rates were 54 % (29 of 54 treatments) and 94 % (51 treatments), respectively, at the early follow-up examination (mean 3 months) and 34 % (15 treatments) and 57 % (25 treatments), respectively at the late follow-up examination. Mean overall survival from the first SIRT was 34,8 months and survival rates at 1, 2, 3 and 5 years were 76 %, 59 %, 52 % and 35 % respectively. Adverse effects were generally mild and easily manageable, except in one patient who died from radiation-induced liver failure. Of the 45 patients, 18 (45 %) had received peptide receptor radionuclide therapy (PRRT) prior to SIRT. CONCLUSION: SIRT with (90)Y-labelled resin microspheres is a safe and effective treatment for patients with progressive NETLM, and also for those who have received prior PRRT. PMID- 26631240 TI - Assessing the role of 18F-FDG PET and 18F-FDG PET/CT in the diagnosis of soft tissue musculoskeletal malignancies: a systematic review and meta-analysis. AB - PURPOSE: Twelve years ago a meta-analysis evaluated the diagnostic performance of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in assessing musculoskeletal soft tissue lesions (MsSTL). Currently, PET/CT has substituted PET imaging; however, there has not been any published meta-analysis on the use of PET/CT or a comparison of PET/CT with PET in the diagnosis of MsSTL. Therefore, we conducted a meta-analysis to identify the current diagnostic performance of (18)F-FDG PET/CT and determine if there is added value when compared to PET. METHODS: A systematic review of English articles was conducted, and MEDLINE PubMed, the Cochrane Library, and Embase were searched from 1996 to March 2015. Studies exploring the diagnostic accuracy of (18)F-FDG PET/CT (or dedicated PET) compared to histopathology in patients with MsSTL undergoing investigation for malignancy were included. RESULTS: Our meta-analysis included 14 articles composed of 755 patients with 757 soft tissue lesions. There were 451 (60 %) malignant tumors and 306 benign lesions. The (18)F-FDG PET/CT (and dedicated PET) mean sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for diagnosing MsSTL were 0.96 (0.90, 1.00), 0.77 (0.67, 0.86), 0.88 (0.85, 0.91), 0.86 (0.78, 0.94), and 0.91 (0.83, 0.99), respectively. The posterior mean (95 % highest posterior density interval) for the AUC was 0.92 (0.88, 0.96). PET/CT had higher specificity, accuracy, and positive predictive value when compared to a dedicated PET (0.85, 0.89, and 0.91 vs 0.71, 0.85, and 0.82, respectively). CONCLUSION: (18)F-FDG PET/CT and dedicated PET are both highly accurate in the diagnosis of MsSTL. PET/CT is more accurate and specific and has a higher positive predictive value than PET. PMID- 26631241 TI - Senior students' experience as tutors of their junior peers in the hospital setting. AB - BACKGROUND: Student-led teaching has long been regarded as a useful ancillary educational method. It is also a valuable tool in the development of aspects of professionalism in student tutors and contributes to a sense of community within the student body. In 2014, a peer-assisted learning (PAL) program, organised by students at Sydney Medical School (Central), explored students' experience of tutoring their junior peers. METHODS: Year 3 and 4 students within Central Clinical School (CCS) were invited to be tutors for Year 1 and 2 students respectively. Tutorials centered on the application of clinical skills. All tutors were asked to complete an end of year questionnaire. RESULTS: A total of 40% of senior students participated as tutors and 65% of junior students as tutees. The end of year questionnaire response rate was 48% (20/42). Most tutors (19/20, 95%) felt confident to teach tutorials although one-third (6/20, 30%) would have preferred more training in teaching. Tutors felt that the program better prepared them for their exams. Almost all tutors (19/20, 95%) enjoyed teaching and felt it fostered a sense of community at CCS (17/20, 85%). Tutors stated they were likely to be involved in teaching in the future (17/20, 85%). CONCLUSION: This student initiated PAL program provided tutors with the opportunity for content and clinical skills revision and assisted in the development of professional competencies required on entering the medical workforce. The resultant sense of community at CCS will aid the expansion of the program in 2015 with an aim to review quality assurance measures. PMID- 26631242 TI - Mobile dating apps could be driving HIV epidemic among adolescents in Asia Pacific, report says. PMID- 26631243 TI - Adult and hatch-year blackpoll warblers exhibit radically different regional scale movements during post-fledging dispersal. AB - Using a broad-scale automated telemetry array, we explored post-fledging movements of blackpoll warblers breeding in Atlantic Canada. We sought to determine the full spatial scale of post-fledging dispersal, to assess support for three hypotheses for regional-scale post-fledging movement, and to determine whether learning influenced movement during this period. We demonstrated that both young and adults moved over distances more than 200 km prior to initiating migration. Adults moved southwest, crossing the Gulf of Maine (GOM), consistent with the commencement of migration hypothesis. Hatch-year birds exhibited less directional movements constrained geographically by the GOM. Their movements were most consistent with exploration hypotheses--that young birds develop a regional scale map to aid in habitat selection, natal dispersal and subsequent migrations. PMID- 26631244 TI - A Turing test for collective motion. AB - A widespread problem in biological research is assessing whether a model adequately describes some real-world data. But even if a model captures the large scale statistical properties of the data, should we be satisfied with it? We developed a method, inspired by Alan Turing, to assess the effectiveness of model fitting. We first built a self-propelled particle model whose properties (order and cohesion) statistically matched those of real fish schools. We then asked members of the public to play an online game (a modified Turing test) in which they attempted to distinguish between the movements of real fish schools or those generated by the model. Even though the statistical properties of the real data and the model were consistent with each other, the public could still distinguish between the two, highlighting the need for model refinement. Our results demonstrate that we can use 'citizen science' to cross-validate and improve model fitting not only in the field of collective behaviour, but also across a broad range of biological systems. PMID- 26631245 TI - Involvement of the avian song system in reproductive behaviour. AB - The song system of songbirds consists of an interconnected set of forebrain nuclei that has traditionally been regarded as dedicated to the learning and production of song. Here, however, we suggest that the song system could also influence muscles used in reproductive behaviour, such as the cloacal sphincter muscle. We show that the same medullary nucleus, retroambigualis (RAm), that projects upon spinal motoneurons innervating expiratory muscles (which provide the pressure head for vocalization) and upon vocal motoneurons for respiratory vocal coordination also projects upon cloacal motoneurons. Furthermore, RAm neurons projecting to sacral spinal levels were shown to receive direct projections from nucleus robustus arcopallialis (RA) of the forebrain song system. Thus, by indicating a possible disynaptic relationship between RA and motoneurons innervating the reproductive organ, in both males and females, these results potentially extend the role of the song system to include consummatory as well as appetitive aspects of reproductive behaviour. PMID- 26631246 TI - Is the scaling of swim speed in sharks driven by metabolism? AB - The movement rates of sharks are intrinsically linked to foraging ecology, predator-prey dynamics and wider ecosystem functioning in marine systems. During ram ventilation, however, shark movement rates are linked not only to ecological parameters, but also to physiology, as minimum speeds are required to provide sufficient water flow across the gills to maintain metabolism. We develop a geometric model predicting a positive scaling relationship between swim speeds in relation to body size and ultimately shark metabolism, taking into account estimates for the scaling of gill dimensions. Empirical data from 64 studies (26 species) were compiled to test our model while controlling for the influence of phylogenetic similarity between related species. Our model predictions were found to closely resemble the observed relationships from tracked sharks, providing a means to infer mobility in particularly intractable species. PMID- 26631247 TI - Warming alters food web-driven changes in the CO2 flux of experimental pond ecosystems. AB - Evidence shows the important role biota play in the carbon cycle, and strategic management of plant and animal populations could enhance CO2 uptake in aquatic ecosystems. However, it is currently unknown how management-driven changes to community structure may interact with climate warming and other anthropogenic perturbations to alter CO2 fluxes. Here we showed that under ambient water temperatures, predators (three-spined stickleback) and nutrient enrichment synergistically increased primary producer biomass, resulting in increased CO2 uptake by mesocosms in early dawn. However, a 3 degrees C increase in water temperatures counteracted positive effects of predators and nutrients, leading to reduced primary producer biomass and a switch from CO2 influx to efflux. This confounding effect of temperature demonstrates that climate scenarios must be accounted for when undertaking ecosystem management actions to increase biosequestration. PMID- 26631248 TI - Autism spectrum disorder in tuberous sclerosis complex: searching for risk markers. AB - BACKGROUND: Neuropsychiatric disorders are present in up to 90% of patients with Tuberous Sclerosis Complex (TSC), and represent an important issue for families. Autism Spectrum Disorder (ASD) is the most common neurobehavioral disease, affecting up to 61% of patients. The aims of this study were: 1) to assess the prevalence of ASD in a TSC population; 2) to describe the severity of ASD; 3) to identify potential risk factors associated with the development of ASD in TSC patients. METHODS: We selected 42 individuals over age 4 years with a definite diagnosis of TSC and followed at a TSC clinic in Northern Italy. We collected and reported clinical and genetic data, as well as cognitive level, for each of them. We administered the Social Communication Questionnaire (SCQ) as a reliable screening tool for ASD, and performed comparisons between the average scores and each clinical and genetic feature. RESULTS: Seventeen out of 42 patients (40.5%) had a score at the SCQ suggestive of ASD (>=15 points). When calculated for each cognitive level category, the average SCQ score tended to be progressively higher in patients with a worse cognitive level, and the number of pathological SCQ scores increased with worsening of intellectual disability. With respect to ASD severity, the scores were equally distributed, indicating that the degree of ASD in TSC patients may have a large variability. By comparing the average SCQ scores with the clinical features, we found statistically significant correlations with epilepsy, seizure onset before age one year, spasms, mutations in TSC2, cognitive level, sleep disorders, and other psychiatric problems, but not with seizure frequency, tubers localization and gender. CONCLUSIONS: Our study showed a prevalence of ASD of 40.5%, confirming the higher risk for this disorder in patients with TSC. However, the severity seems to have a notable variability in TSC patients. Risk factors for ASD are epilepsy, infantile spams, and mutations in TSC2. PMID- 26631250 TI - UN climate chief attacks billions spent on subsidising fossil fuels. PMID- 26631251 TI - Computerized measurement of anticipated anxiety from eating increasing portions of food in adolescents with and without anorexia nervosa: Pilot studies. AB - Dieting and excessive fear of eating coexist in vulnerable individuals, which may progress to anorexia nervosa [AN], but there is no objective measure of this fear. Therefore, we adapted a computer program that was previously developed to measure the satiating effects of foods in order to explore the potential of food to induce anxiety and fear of eating in adolescent girls. Twenty four adolescents (AN) and ten healthy controls without eating disorders rated pictures of different types of foods in varying sized portions as too large or too small and rated the expected anxiety of five different portions (20-320 kcal). Two low energy dense (potatoes and rice) and two high energy dense (pizza and M&Ms) foods were used. The regression coefficient of line lengths (0-100 mm) marked from "No anxiety" to "this would give me a panic attack", regressed from portions shown, was the measure of "expected anxiety" for a given food. The maximum tolerated portion size [kcal] (MTPS), computed by method of constant stimulus from portions shown, was significantly smaller for high energy dense foods, whereas the expected anxiety response was greater, for all foods, for patients compared to controls. For both groups, expected anxiety responses were steeper, and maximum tolerated portion sizes were larger, for low, than high, energy dense foods. Both maximum tolerated portion size and expected anxiety response were significantly predicted by severity of illness for the patients. Those who had larger maximum tolerated portion sizes had smaller anticipated anxiety to increasing portion sizes. Visual size had a greater influence than energy content for these responses. This method could be used to quantify the anxiety inducing potential of foods and for studies with neuro-imaging and phenotypic clarifications. PMID- 26631249 TI - Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC. AB - Neurons in the anterior cingulate cortex (ACC) are assumed to play important roles in the perception of nociceptive signals and the associated emotional responses. However, the neuronal types within the ACC that mediate these functions are poorly understood. In the present study, we used optogenetic techniques to selectively modulate excitatory pyramidal neurons and inhibitory interneurons in the ACC and to assess their ability to modulate peripheral mechanical hypersensitivity in freely moving mice. We found that selective activation of pyramidal neurons rapidly and acutely reduced nociceptive thresholds and that this effect was occluded in animals made hypersensitive using Freund's Complete Adjuvant (CFA). Conversely, inhibition of ACC pyramidal neurons rapidly and acutely reduced hypersensitivity induced by CFA treatment. A similar analgesic effect was induced by activation of parvalbumin (PV) expressing interneurons, whereas activation of somatostatin (SOM) expressing interneurons had no effect on pain thresholds. Our results provide direct evidence of the pivotal role of ACC excitatory neurons, and their regulation by PV expressing interneurons, in nociception. PMID- 26631252 TI - Food neophobia and enjoyment of tactile play: Associations between preschool children and their parents. AB - A cross-sectional study was conducted to examine whether the relationship between enjoyment of tactile play and food neophobia observed in children (Coulthard & Thakker, 2015) would be related to levels seen in their parents. One hundred and twenty six participants were recruited from playgroup centres in the Walsall area of the West Midlands, UK; 63 children (2-5 years; 30 girls and 33 boys) and 63 attendant parents (53 mothers and 10 fathers). Children and their parents' enjoyment of a tactile play task was rated by both the parent and a researcher, and questionnaire measures of food neophobia and tactile sensitivity were completed by the parent for both themselves and their children. Strong associations were found between parent and child scores across all the measures; food neophobia, tactile sensitivity and tactile play enjoyment. The variables most strongly related to child food neophobia were parental neophobia and enjoyment of tactile play (parent and child). These findings indicate that family resemblance exists not only for food neophobia, but for tactile sensory processing as well, and may represent a possible inherited route to neophobia. The findings strengthen the suggestion that tactile processing is associated with food neophobia although the causal nature of this relationship is still not known. PMID- 26631253 TI - A daily diary study of perceived social isolation, dietary restraint, and negative affect in binge eating. AB - Negative affect and dietary restraint are key predictors of binge eating, yet less is known about the impact of social factors on binge eating. The study sought to replicate and extend research on the relationships between negative affect, dietary restraint, perceived social isolation and binge eating using a daily diary methodology. College women (N = 54) completed measures of dietary restraint, negative affect, perceived social isolation, and binge eating daily for 14 days. Participants completed the measures nightly each day. A series of generalized estimating equations showed that dietary restraint was associated with less binge eating while controlling for negative affect and for perceived social isolation separately. Negative affect and perceived social isolation were associated with greater binge eating while controlling for restraint in separate analyses, but only perceived social isolation was significant when modeled simultaneously. All two-way interactions between negative affect, dietary restraint, and perceived social isolation predicting binge eating were nonsignificant. This study furthers our understanding of predictors of binge eating in a nonclinical sample. Specifically, these data suggest perceived social isolation, negative affect, and dietary restraint are important variables associated with binge eating in daily life and warrant further research. PMID- 26631255 TI - Anterior superior alveolar nerve (ASAN). AB - The anterior superior alveolar nerve (ASAN) is a branch of the infraorbital nerve. Only few studies have morphometrically evaluated the course of the ASAN. Midfacial segments of ten hemisectioned fresh adult cadaver heads were dissected to uncover the anterior wall of the maxilla. Specimens were subsequently decalcified and the bone overlying the ASAN was removed under a microscope to expose the ASAN. Its branching pattern from the infraorbital nerve was recorded, and the course of the ASAN within the anterior wall of the maxillary sinus was morphometrically assessed measuring distances to predefined landmarks using a digital caliper. A distinct ASAN was observed in all specimens. It arose lateral (six cases) or inferior (four cases) from the infraorbital nerve. The point of origin was located at a mean distance of 12.2 +/- 5.79 mm posterior to the infraorbital foramen. The ASAN was located on average 2.8 +/- 5.13 mm lateral to the infraorbital foramen. After coursing medially, the ASAN ran inferior to the foramen at a mean distance of 5.5 +/- 3.07 mm. When approaching the nasal aperture, the loop of the ASAN was on average 13.6 +/- 3.07 mm above the nasal floor. The horizontal mean distance from the ASAN to the nasal aperture was 4.3 +/- 2.74 mm halfway down from the loop, and 3.3 +/- 2.60 mm at the floor of the nose, respectively. In conclusion, the present study evaluated the course of the ASAN relative to the infraorbital foramen and nasal aperture. This information is helpful to avoid damage to this anatomical structure during interventions in the infraobrital region of the maxilla. Further, knowledge of the course of the ASAN and of its bony correlate (canalis sinuosus) may be valuable in interpreting anesthetic or radiologic findings in the anterior maxilla. PMID- 26631254 TI - Acellular approaches for regenerative medicine: on the verge of clinical trials with extracellular membrane vesicles? AB - Extracellular vesicles (EVs) are a heterogeneous population of naturally occurring secreted small vesicles, with distinct biophysical properties and different functions both in physiology and under pathological conditions. In recent years, a number of studies have demonstrated that EVs might hold remarkable potential in regenerative medicine by acting as therapeutically promising nanodrugs. Understanding their final impact on the biology of specific target cells as well as clarification of their overall therapeutic impact remains a matter of intense debate. Here we review the key principles of EVs in physiological and pathological conditions with a specific highlight on the most recently described mechanisms regulating some of the EV-mediated effects. First, we describe the current debates and the upcoming research on EVs as potential novel therapeutics in regenerative medicine, either as unmodified agents or as functionalized small carriers for targeted drug delivery. Moreover, we address a number of safety aspects and regulatory limitations related to the novel nature of EV-mediated therapeutic applications. Despite the emerging possibilities of EV treatments, these issues need to be overcome in order to allow their safe and successful application in future explorative clinical studies. PMID- 26631256 TI - Is urine intercellular adhesion molecule-1 a marker of renal disorder in children with ureteropelvic junction obstruction? AB - AIM: We aimed to investigate whether urine intercellular adhesion molecule-1 (ICAM-1) might serve as a marker of renal disorder in children with ureteropelvic junction obstruction. MATERIAL AND METHODS: Twenty-nine children with severe hydronephrosis (HN) were compared with 23 participants with mild HN and with 19 healthy peers. RESULTS: Urine ICAM-1/uCre levels were significantly higher in HN children than healthy controls (P<0.01), and in severe HN when compared with mild HN (p<0.05). CONCLUSIONS: It seemed to us that uICAM-1 is a biomarker of renal disorder, and might have the potential to predict which patients will require surgery. PMID- 26631257 TI - Pneumocephalus following thoracic trauma: a rare entity along the carotid sheath. PMID- 26631258 TI - Can Avoiding Light at Night Reduce the Risk of Breast Cancer? AB - Excessive exposure to artificial light at night (ALAN) suppresses nocturnal melatonin (MLT) production in the pineal gland and is, therefore, associated with an increased risk of breast cancer (BC). We examined indoor and outdoor light habits of 278 women, BC patients (n = 93), and controls (n = 185; 2010-2014). Cases and controls were age and residential area matched. Data regarding behavior in the sleeping habitat in a 5-year period, 10 to 15 years prior to disease diagnosis, were collected using a questionnaire. Sleep quality, bedtime, sleep duration, TV watching habits, presleeping reading habits, subjective illumination intensity, and type of illumination were collected. Binary logistic regression models were used to calculate odds ratios with 95% confidence intervals (ORs with 95% CIs) for BC patients in relation to those habits. OR results revealed that women who had slept longer (controls), 10 to 15 years before the time of the study, in a period of 5 years, had a significant (OR = 0.74; 95% CI = 0.57-0.97; P < .03) reduced BC risk. Likewise, women who had been moderately exposed to ALAN as a result of reading using bed light (reading lamp) illumination and women who had slept with closed shutters reduced their BC risk: OR = 0.81, 95% CI = 0.67 0.97, P < .02, and OR = 0.82, 95% CI = 0.68-0.99, P < .04, respectively. However, women who had been exposed to ALAN as a result of living near strong illumination sources were at a significantly higher BC risk (OR = 1.52; 95% CI = 1.10-2.12; P < .01). These data support the hypothesis that diminishing nighttime light exposure will diminish BC risk and incidence. This hypothesis needs to be tested directly using available testing strategies and technologies that continuously measure an individual's light exposure, its timing, and sleep length longitudinally and feed this information back to the individual, so that BC risk can be distinguished prospectively. PMID- 26631259 TI - Palliative Care: A Holistic Discipline. AB - Although mind and body are inextricably interwoven, psychological factors have received insufficient attention within medicine. The biomedical model though necessary is not sufficient. In medicine and particularly in palliative care, a holistic biopsychosocial approach is required. A number of examples from clinical practice in a hospice setting are presented. PMID- 26631260 TI - Consumption of Whole Grains, Refined Cereals, and Legumes and Its Association With Colorectal Cancer Among Jordanians. AB - Background The role of whole grains, refined cereals, and legumes in preventing or initiating colorectal cancer (CRC) is still uncertain. The aim of this study is to examine the possible association between the consumption of whole grains, refined cereals, and legumes and the risk of developing CRC among Jordanian population. Methods A validated food frequency questionnaire was used to collect dietary data with regard to intake of whole grains, refined cereals, and legumes. A total of 220 diagnosed CRC participants and 281 CRC-free control participants matched by age, gender, occupation, and marital status were recruited. Logistic regression was used to estimate the odds of developing CRC in relation to the consumption of different types of whole grains, refined cereals, and legumes. Results The odds ratio (OR) for developing CRC among cases consumed refined wheat bread at all meals was 3.1 compared with controls (95% CI: 1.2-7.9, P-Trend = 0.001); whereas the OR associated with whole wheat bread was 0.44 (95% CI: 0.22 0.92, P-Trend = 0.001). The statistical evaluation for daily consumption of rice suggested a direct association with the risk of developing CRC, OR = 3.0 (95% CI: 0.27-33.4, P-Trend = 0.020). Weekly consumption of macaroni was associated with CRC with OR of 2.4 (95% CI: 1.1-5.3, P-Trend = 0.001). The consumption of corn, bulgur, lentils, and peas suggested a protective trend, although the trend was not statistically significant. Conclusion This study provides additional indicators of the protective role of whole grains and suggests a direct association between consumption of refined grains and higher possibility for developing CRC. PMID- 26631261 TI - India's "health camps": the drug rep will see you now. PMID- 26631263 TI - Apelin-13 protects against apoptosis by activating AMP-activated protein kinase pathway in ischemia stroke. AB - Apelin has been proved to be protective against apoptosis induced by ischemic reperfusion. However, mechanisms whereby apelin produces neuroprotection remain to be elucidated. AMP-activated protein kinase (AMPK) is a master energy sensor that monitors levels of key energy metabolites. It is activated via AMPKalphaThr172 phosphorylation during cerebral ischemia and appears to be neuroprotective. In this study, we investigated the effect of apelin on AMPKalpha and tested whether apelin protecting against apoptosis was associated with AMPK signals. Focal transient cerebral ischemia/reperfusion (I/R) model in male ICR mice was induced by 60 min of ischemia followed by reperfusion. Apelin-13 was injected intracerebroventricularly 15 min before reperfusion. AMPK inhibitor, compound C, was injected to mice intraperitoneally at the onset of ischemia. In experiment 1, the effect of apelin-13 on AMPKalpha was measured. In experiment 2, the relevance of AMPKalpha and apelin-13' effect on apoptosis was measured. Data showed that apelin-13 significantly increased AMPKalpha phosphorylation level after cerebral I/R. Apelin-13, with the co-administration of saline, reduced apoptosis cells, down-regulated Bax and cleaved-caspase3 and up-regulated Bcl2. However, with the co-administration of compound C, apelin-13 was inefficient in affecting apoptosis and Bax, Bcl2 and cleaved-caspase3. The study provided the evidence that apelin-13 up-regulated AMPKalpha phosphorylation level in cerebral ischemia insults and AMPK signals participated in the mechanism of apelin mediated neuroprotection. PMID- 26631264 TI - Measurement issues associated with quantitative molecular biology analysis of complex food matrices for the detection of food fraud. AB - Following a report on a significant amount of horse DNA being detected in a beef burger product on sale to the public at a UK supermarket in early 2013, the Elliott report was published in 2014 and contained a list of recommendations for helping ensure food integrity. One of the recommendations included improving laboratory testing capacity and capability to ensure a harmonised approach for testing for food authenticity. Molecular biologists have developed exquisitely sensitive methods based on the polymerase chain reaction (PCR) or mass spectrometry for detecting the presence of particular nucleic acid or peptide/protein sequences. These methods have been shown to be specific and sensitive in terms of lower limits of applicability, but they are largely qualitative in nature. Historically, the conversion of these qualitative techniques into reliable quantitative methods has been beset with problems even when used on relatively simple sample matrices. When the methods are applied to complex sample matrices, as found in many foods, the problems are magnified resulting in a high measurement uncertainty associated with the result which may mean that the assay is not fit for purpose. However, recent advances in the technology and the understanding of molecular biology approaches have further given rise to the re-assessment of these methods for their quantitative potential. This review focuses on important issues for consideration when validating a molecular biology assay and the various factors that can impact on the measurement uncertainty of a result associated with molecular biology approaches used in detection of food fraud, with a particular focus on quantitative PCR-based and proteomics assays. PMID- 26631262 TI - Paediatric arterial ischemic stroke: acute management, recent advances and remaining issues. AB - Stroke is a rare disease in childhood with an estimated incidence of 1-6/100.000. It has an increasingly recognised impact on child mortality along with its outcomes and effects on quality of life of patients and their families. Clinical presentation and risk factors of paediatric stroke are different to those of adults therefore it can be considered as an independent nosological entity. The relative rarity, the age-related peculiarities and the variety of manifested symptoms makes the diagnosis of paediatric stroke extremely difficult and often delayed. History and clinical examination should investigate underlying diseases or predisposing factors and should take into account the potential territoriality of neurological deficits and the spectrum of differential diagnosis of acute neurological accidents in childhood. Neuroimaging (in particular diffusion weighted magnetic resonance) is the keystone for diagnosis of paediatric stroke and other investigations might be considered according to the clinical condition. Despite substantial advances in paediatric stroke research and clinical care, many unanswered questions remain concerning both its acute treatment and its secondary prevention and rehabilitation so that treatment recommendations are mainly extrapolated from studies on adult population. We have tried to summarize the pathophysiological and clinical characteristics of arterial ischemic stroke in children and the most recent international guidelines and practical directions on how to recognise and manage it in paediatric emergency. PMID- 26631265 TI - Progenitor-like cells derived from mouse kidney protect against renal fibrosis in a remnant kidney model via decreased endothelial mesenchymal transition. AB - INTRODUCTION: Pathophysiological changes associated with chronic kidney disease impair angiogenic processes and increase renal fibrosis. Progenitor-like cells derived from adult kidney have been previously used to promote regeneration in acute kidney injury, even though it remained unclear whether the cells could be beneficial in chronic kidney disease (CKD). METHODS: In this study, we established a CKD model by five-sixths nephrectomy and mouse kidney progenitor like cells (MKPCs) were intravenously administered weekly for 5 weeks after establishing CKD. We examined the impact of MKPCs on the progression of renal fibrosis and the potential of MKPCs to preserve the angiogenic process and prevent endothelial mesenchymal transition in vivo and in vitro. RESULTS: Our results demonstrate that the MKPCs delayed interstitial fibrosis and the progression of glomerular sclerosis and ameliorated the decline of kidney function. At 17 weeks, the treated mice exhibited lower blood pressures, higher hematocrit levels, and larger kidney sizes than the control mice. In addition, the MKPC treatment prolonged the survival of the mice with chronic kidney injuries. We observed a decreased recruitment of macrophages and myofibroblasts in the interstitium and the increased tubular proliferation. Notably, MKPC both decreased the level of vascular rarefaction and prevented endothelial mesenchymal transition (EndoMT) in the remnant kidneys. Moreover, the conditioned medium from the MKPCs ameliorated endothelial cell death under hypoxic culture conditions and prevented TGF-beta-induced EndoMT through downregulation of phosphorylated Smad 3 in vitro. CONCLUSIONS: MKPCs may be a beneficial treatment for kidney diseases characterized by progressive renal fibrosis. The enhanced preservation of angiogenic processes following MKPC injections may be associated with decreased fibrosis in the remnant kidney. These findings provide further understanding of the mechanisms involved in these processes and will help develop new cell-based therapeutic strategies for regenerative medicine in renal fibrosis. PMID- 26631266 TI - Targeted Deletion of p53 in Lgr5-Expressing Intestinal Stem Cells Promotes Colon Tumorigenesis in a Preclinical Model of Colitis-Associated Cancer. AB - p53 has been shown to mediate cancer stem-like cell function by suppressing pluripotency and cellular dedifferentiation. However, there have been no studies to date that have addressed the specific effects of p53 loss in colonic adult stem cells. In this study, we investigated the consequences of conditionally ablating p53 in the highly relevant Lgr5(+) stem cell population on tumor initiation and progression in the colon. In a mouse model of carcinogen (AOM) induced colon cancer, tamoxifen-inducible Lgr5-driven deletion of p53 reduced apoptosis and increased proliferation of crypt stem cells, but had no effect on tumor incidence or size. Conversely, in a mouse model of colitis-associated cancer, in which mice are exposed to AOM and the potent inflammation inducer DSS, stem cell-specific p53 deletion greatly enhanced tumor size and incidence in the colon. These novel findings suggest that the loss of p53 function in stem cells enables colonic tumor formation only when combined with DNA damage and chronic inflammation. Furthermore, we propose that stem cell targeting approaches are valuable for interrogating prevention and therapeutic strategies that aim to specifically eradicate genetically compromised stem cells. PMID- 26631267 TI - SLC46A3 Is Required to Transport Catabolites of Noncleavable Antibody Maytansine Conjugates from the Lysosome to the Cytoplasm. AB - Antibody-drug conjugates (ADC) target cytotoxic drugs to antigen-positive cells for treating cancer. After internalization, ADCs with noncleavable linkers are catabolized to amino acid-linker-warheads within the lysosome, which then enter the cytoplasm by an unknown mechanism. We hypothesized that a lysosomal transporter was responsible for delivering noncleavable ADC catabolites into the cytoplasm. To identify candidate transporters, we performed a phenotypic shRNA screen with an anti-CD70 maytansine-based ADC. This screen revealed the lysosomal membrane protein SLC46A3, the genetic attenuation of which inhibited the potency of multiple noncleavable antibody-maytansine ADCs, including ado-trastuzumab emtansine. In contrast, the potencies of noncleavable ADCs carrying the structurally distinct monomethyl auristatin F were unaffected by SLC46A3 attenuation. Structure-activity experiments suggested that maytansine is a substrate for SLC46A3. Notably, SLC46A3 silencing led to relative increases in catabolite concentrations in the lysosome. Taken together, our results establish SLC46A3 as a direct transporter of maytansine-based catabolites from the lysosome to the cytoplasm, prompting further investigation of SLC46A3 as a predictive response marker in breast cancer specimens. PMID- 26631268 TI - Stromal Fibroblasts Induce CCL20 through IL6/C/EBPbeta to Support the Recruitment of Th17 Cells during Cervical Cancer Progression. AB - Cervical cancer is a consequence of persistent infection with human papillomaviruses (HPV). Progression to malignancy is linked to an inflammatory microenvironment comprising T-helper-17 (Th17) cells, a T-cell subset with protumorigenic properties. Neoplastic cells express only low endogenous levels of the Th17 chemoattractant CCL20, and therefore, it is unclear how Th17 cells are recruited to the cervical cancer tissue. In this study, we demonstrate that CCL20 was predominantly expressed in the stroma of cervical squamous cell carcinomas in situ. This correlated with stromal infiltration of CD4(+)/IL17(+) cells and with advancing International Federation of Gynecology and Obstetrics (FIGO) stage. Furthermore, we show that cervical cancer cells instructed primary cervical fibroblasts to produce high levels of CCL20 and to attract CD4/IL17/CCR6-positive cells, generated in vitro, in a CCL20/CCR6-dependent manner. Further mechanistic investigations identified cervical cancer cell-derived IL6 as an important mediator of paracrine CCL20 induction at the promoter, mRNA, and protein level in fibroblasts. CCL20 was upregulated through the recently described CCAAT/enhancer binding protein beta (C/EBPbeta) pathway as shown with a dominant-negative version of C/EBPbeta and through siRNA-mediated knockdown. In summary, our study defines a novel molecular mechanism by which cervical neoplastic cells shape their local microenvironment by instructing fibroblasts to support Th17 cell infiltration in a paracrine IL6/C/EBPbeta-dependent manner. Th17 cells may in turn maintain chronic inflammation within high-grade cervical lesions to further promote cancer progression. PMID- 26631270 TI - [In Process Citation]. AB - Ectodermal dysplasias (EDs) form a large clinically and genetically heterogeneous group of manifestations characterized by dystrophy or agenesis of embryologic ectodermal derivatives. Therefore skin, nails, hair, teeth and secretory organs are mainly affected. Hypohidrotic ectodermal dysplasia (HED) is the most common ED syndrom. It is characterized by atrichosis or hypotrichosis, anodontia or hypodontia and hypohidrosis. Missing teeth or retarded eruption of teeth often leads to the diagnosis of ED, which emphasizes the significance of an appropriate dental examination. Tooth agenesis and its effects on craniofacial structures are often the most signicificant clinical and therapeutical problem. It is a challenge to manage the functional, esthetic and psychosocial needs of these patients and therefore requires the involvement of different specialists, such as pediatrists, pedodontists, oral surgeons and prosthodontists. PMID- 26631269 TI - TGFbeta Treatment Enhances Glioblastoma Virotherapy by Inhibiting the Innate Immune Response. AB - Oncolytic viruses, including oncolytic herpes simplex virus (oHSV), have produced provocative therapeutic responses in patients with glioblastoma, the most aggressive brain tumor. Paradoxically, innate immune responses mediated by natural killer (NK) cells and macrophages/microglia appear to limit oHSV efficacy. Therefore, we investigated whether pretreatment with an immunosuppressive cytokine, TGFbeta, might reverse these effects and thereby potentiate oHSV efficacy. TGFbeta treatment of NK cells rendered them less cytolytic against oHSV-infected glioblastoma cells and stem-like cells in vitro. Furthermore, TGFbeta treatment of NK cells, macrophages, or microglia increased viral titers of oHSV in cocultures with glioblastoma cells. In a syngeneic mouse model of glioblastoma, administering TGFbeta prior to oHSV injection inhibited intracranial infiltration and activation of NK cells and macrophages. Notably, a single administration of TGFbeta prior to oHSV therapy was sufficient to phenocopy NK-cell depletion and suppress tumor growth and prolong survival in both xenograft and syngeneic models of glioblastoma. Collectively, our findings show how administering a single dose of TGFbeta prior to oncolytic virus treatment of glioblastoma can transiently inhibit innate immune cells that limit efficacy, thereby improving therapeutic responses and survival outcomes. PMID- 26631271 TI - Families' opinions about caring for patients with psychiatric disorders after involuntary hospitalization in Japan. AB - OBJECTIVE: It is imperative to know families' opinions about where patients should live after discharge from involuntary hospitalization in the era of community mental health. METHODS: Questionnaires were sent (March-May 2011) to 808 guardians of patients who were involuntarily hospitalized in Japan (response rate = 54.2%). The final sample size was 365 family members. Whether families wanted to live with the patient after discharge from the hospital was the primary outcome variable. The associations of the demographic characteristics of the patients and families with the outcome variable were tested using logistic regression analysis. RESULTS: Approximately, 19% of the family guardians wanted to live with the patient after discharge from the hospital. Their wish to cohabit was positively associated with being a female (vs male) patient, having three or more cohabitants in the home and having lived together before hospitalization, after adjusting for the other covariates. Long-term hospitalization (10 years or longer) and siblings were significantly associated with the families not wanting to cohabit, after adjusting for the other covariates. CONCLUSION: It is important to know families' opinions about patients' living situations after discharge from involuntary hospitalization to provide them with an effective support system. PMID- 26631272 TI - Many in US Congress hold health industry investments, news site reports. PMID- 26631273 TI - Assemblages, territories, contexts. AB - Human geographers have been at the forefront of efforts across the social sciences to develop "assemblage thinking", applying and extending this model in a series of highly original empirical studies. This commentary assesses some of the conceptual, methodological and procedural implications of this research for contemporary drug studies. I will argue that the most useful way of approaching assemblage thinking in the analysis of drug problems is to focus on the ways assemblages draw together social, affective and material forces and entities. I will briefly review these three nodes before indicating how their analysis may inspire novel empirical assessments of drug assemblages. I will conclude by exploring how the assemblage may replace the 'subject' and 'social context' as a discrete unit of analysis in drug studies. PMID- 26631275 TI - Why has canine rabies remained endemic in the Kilosa district of Tanzania? Lessons learnt and the way forward. AB - BACKGROUND: Domestic dogs are the main targets for rabies control as they are the principal reservoir for transmission of the rabies virus to humans and other domestic animals. The purpose of this study was to identify the factors that contribute to the rabies virus infecting the human population in a rural community of Eastern Tanzania. METHODS: Using a cross-sectional study design, field visits were conducted to gather information on villagers' knowledge on and practices associated with canine rabies control and dog vaccination campaigns. RESULTS: A total of 248 individuals were interviewed in the Kilosa district, Tanzania. Almost two-thirds (61.3 %) had a primary school education. The majority (91.1 %) of the respondents were aware that rabies is acquired through dog bites and 66.9 % knew about the clinical signs of rabies in an animal. Very few (17.7 %), however, were aware of the clinical signs of rabies in humans. Only 20.4 % of the respondents knew how rabies is controlled in dogs and 71 % were not aware of dog vaccination campaigns. The average number of dogs kept per household was 4 +/ 3.3; 70.0 % of the respondents had one to five dogs, 28.3 % had six to dog dogs, and 1.6 % had 16-20 dogs. The dogs were primarily used to guard livestock and property, and to hunt. About 59.7 % of the respondents indicated that rabies was a public health problem. Low vaccination coverage was observed in the study area, with previous mass vaccination campaigns covering only 24.4 % of the dog population. Dogs appeared to have limited value in the studied community. Furthermore, there were no proper waste disposal facilities and oftentimes wild canids and felids visited the villages to scavenge on kitchen leftovers. CONCLUSION: Although communities in the Kilosa district had knowledge on rabies in dogs, they were not aware of the public health implication of the disease, which thus led a poor response during mass dog vaccination campaigns. Establishment of a well-coordinated rabies control program, strategic public health awareness campaigns, and active and passive surveillance systems for humans and domestic and wild animals should be considered as strategies to control and eradicate rabies. PMID- 26631276 TI - Hemostatic, inflammatory, and oxidative markers in pesticide user farmers. AB - The aim of this work was to investigate inflammatory, oxidative, and thrombotic parameters as biomarkers in farmers exposed to pesticides. Fifty farmers using chemical pesticides and 60 unexposed control men participated in this study. The Mediterranean diet compliance, the duration of pesticide use, and personal protection for pesticides handling were recorded using self-administered questionnaires. Serum biochemical parameters, oxidant/antioxidant, inflammatory, and thrombosis markers were determined. Our findings showed oxidative stress reflected by an increase in malondialdehyde, carbonyl proteins and superoxide anion levels and a decrease in vitamins C and E, glutathione, catalase, and superoxide dismutase activities in farmers. Serum C-reactive protein, prothrombin, and fibrinogen levels were enhanced in these farmers. In conclusion, inflammation, oxidative stress, and metabolic perturbations reflected the possibility of the effects of pesticides to farmers. PMID- 26631274 TI - Innate and adaptive immunity in the development of depression: An update on current knowledge and technological advances. AB - The inflammation theory of depression, proposed over 20years ago, was influenced by early studies on T cell responses and since then has been a stimulus for numerous research projects aimed at understanding the relationship between immune function and depression. Observational studies have shown that indicators of immunity, especially C reactive protein and proinflammatory cytokines, such as interleukin 6, are associated with an increased risk of depressive disorders, although the evidence from randomized trials remains limited and only few studies have assessed the interplay between innate and adaptive immunity in depression. In this paper, we review current knowledge on the interactions between central and peripheral innate and adaptive immune molecules and the potential role of immune-related activation of microglia, inflammasomes and indoleamine-2,3 dioxygenase in the development of depressive symptoms. We highlight how combining basic immune methods with more advanced 'omics' technologies would help us to make progress in unravelling the complex associations between altered immune function and depressive disorders, in the identification of depression-specific biomarkers and in developing immunotherapeutic treatment strategies that take individual variability into account. PMID- 26631277 TI - Integration of trauma and rehabilitation services is the answer to more cost effective care. AB - BACKGROUND: The pathway from acute trauma care to inpatient rehabilitation has not been previously studied in New South Wales (NSW), Australia. This study aimed to examine the outcomes of patients transferred from a trauma service to its 'in house' rehabilitation service (Group A) compared with outcomes of patients transferred from a designated trauma centre to an external rehabilitation service (Group B). This is carried out to identify any inefficiencies, delays and opportunities for improvement. METHODS: This is a retrospective cohort study using linked registry data. This study included all patients admitted after a motor vehicle collision to trauma services in NSW over the period of 2009-2012, who required inpatient rehabilitation. Those requiring specialized brain or spinal injury rehabilitation or those who went to private rehabilitation units were excluded. RESULTS: There were 249 patients in this cohort with majority (59%) in Group A and the remainder in Group B. There was no significant difference between the age of the patients, injury severity or acute length of stay (LOS) between the two groups. Admission and discharge functional independence measure scores were also similar between the two groups. There was a significant difference in the LOS in rehabilitation (30 days for Group A compared with 40 days in Group B, P = 0.02). CONCLUSIONS: Transferring patients to an external rehabilitation service from a designated trauma service is less efficient than providing the same care by the 'in-house' rehabilitation service. There may be opportunities to improve the efficiency of trauma management and reduce costs. PMID- 26631278 TI - Mechanical effects of different Swiss market-leading dentifrices on dentin. AB - In order to estimate the potential of dentifrices to harm exposed dentin, the mechanical properties of 15 dentifrices available in the Swiss market were investigated. A total of 120 bovine dentin samples were irradiated and analyzed for relative dentin abrasion (RDA). To investigate subsequent increases in surface roughness (Ra), dentin specimens (n = 180) were analyzed profilometrically at baseline and after brushing with test slurries. The cleaning efficacy (Ce) was determined using artificially stained tooth specimens (n = 180). The available fluoride content of the dentifrices was measured in respective slurries using an ion-selective electrode. The results of the mechanical analyses were categorized into four or five groups for each parameter. Four potential user groups were defined according to individual problem specifications and user demands. The results were compared to those of an earlier investigation of dentifrices published in 1998. The RDA results exceeded the values declared by the manufacturers and correlated significantly with the results of the Ra measurements. A significant positive correlation of RDA and Ce values was also shown. The measured fluoride content was often below the fluoride, declared by the manufactures. Only a few of the tested dentifrices qualified as suitable for all potential user groups. Major differences were observed between the mechanical properties found in the present study compared to those found in 1998. These changes in the properties of dentifrices during the past decade should be considered with respect to providing adequate recommendations for individual user demands. PMID- 26631280 TI - Select Synch and Co-Synch protocols using a CIDR yield similar pregnancy rates after a fixed-time insemination in suckled Bos indicus * Bos taurus cows. AB - Primiparous and multiparous suckled Bos indicus * Bos taurus cows were used to compare a Select Synch + controlled internal drug release (CIDR) and timed artificial insemination (AI) protocol (SSC) to a modified CO-Synch + CIDR protocol (COS). Five separate groups of cows were utilized (n = 659) and within a group, cows were allotted to two treatments on the basis of body condition score (BCS) taken 10 days before and days postpartum at CIDR insertion (Day 0). Blood samples were collected on Day -10 and 0 for assessment of circulating concentrations of progesterone to determine estrous cycling status. Cows in both treatments received intramuscular (im) GnRH (100 MUg) and a CIDR inserted on Day 0. On Day 7, the SSC treatment had CIDR removed and received im PGF2alpha (25 mg), whereas COS treatment had CIDR removed and received im PGF2alpha (25 mg) on Day 7.5. In the SSC treatment, estrus was detected daily at 0700 and 1700 hours for 72 hours after PGF2alpha administration, and cows were artificially inseminated 8 to 12 hours after a detected estrus. Cows failing to exhibit estrus were subjected to timed-AI and received im GnRH (100 MUg) 76 +/- 4 hours after PGF2alpha administration. In the COS treatment, cows received im GnRH (100 MUg) and were fixed-time artificially inseminated at 64 +/- 4 hours after PGF2alpha administration. Although group differences (P < 0.05) existed for synchronized AI pregnancy rates, there were no significant interactions of group with any variable analyzed; hence, groups were pooled for further evaluation. Within the SSC treatment, the 72-hour estrous response was 50.6% (168 of 332). Conception rate of cows in estrus was 66.1% (111 of 168), and timed-AI pregnancy rate for nonresponders was 32.3% (53 of 164). Overall synchronized AI pregnancy rates were similar (P > 0.05) for SSC (49.4%; n = 164 of 332) and COS (47.1%; n = 154 of 327). Estrous cycling status and days postpartum did not (P > 0.05) influence synchronized AI pregnancy rates but BCS did (P < 0.05). Cows with a BCS greater than or equal to 5 had synchronized AI pregnancy rates of 50% compared to 39% for cows with BCS lesser than 5.0. In summary, the modified COS protocol yielded similar synchronized AI pregnancy rates compared to the SSC protocol, and it appears that the modified COS protocol has the potential to be an effective timed AI protocol in suckled Bos indicus * Bos taurus cows. PMID- 26631281 TI - [In Process Citation]. AB - Local anaesthetics are an integral part of most dental procedures and are therefore widely used and safely applied. Though rare, complications may occur and can be categorized as local or systemic. In the majority they are of minor nature but there is a potential for severe and possibly lethal side effects. Local complications are nerve damage (mainly the lingual and the inferior alveolar nerve), lesions of vascular structures, hematoma formation, temporary palsy of the facial nerve and post injection pain being the most common local complication. Examples for systemic complications are allergic reactions, cardiovascular complications, intoxication and psychogenic reactions. PMID- 26631279 TI - Multiple regulation pathways and pivotal biological functions of STAT3 in cancer. AB - STAT3 is both a transcription activator and an oncogene that is tightly regulated under normal physiological conditions. However, abundant evidence indicates that STAT3 is persistently activated in several cancers, with a crucial position in tumor onset and progression. In addition to its traditional role in cancer cell proliferation, invasion, and migration, STAT3 also promotes cancer through altering gene expression via epigenetic modification, inducing epithelial mesenchymal transition (EMT) phenotypes in cancer cells, regulating the tumor microenvironment, and promoting cancer stem cells (CSCs) self-renewal and differentiation. STAT3 is regulated not only by the canonical cytokines and growth factors, but also by the G-protein-coupled receptors, cadherin engagement, Toll-like receptors (TLRs), and microRNA (miRNA). Despite the presence of diverse regulators and pivotal biological functions in cancer, no effective therapeutic inventions are available for inhibiting STAT3 and acquiring potent antitumor effects in the clinic. An improved understanding of the complex roles of STAT3 in cancer is required to achieve optimal therapeutic effects. PMID- 26631282 TI - Biosensors and nanobiosensors for therapeutic drug and response monitoring. AB - Therapeutic drug monitoring (TDM) is required for pharmaceutical drugs with dosage limitations or toxicity issues where patients undergoing treatment with these drugs require frequent monitoring. This allows for the concentration of such pharmaceutical drugs in a patient's biofluid to be closely monitored in order to assess the pharmacokinetics, which could result in an adjustment of dosage or in medical intervention if the situation becomes urgent. Biosensors are a class of analytical techniques competent in the rapid quantification of therapeutic drugs and recent developments in instrumental platforms and in sensing schemes, as well as the emergence of nanobiosensors, have greatly contributed to the principal examples of these sensors for therapeutic drug monitoring. Based on initial success stories, it is clear that (nano)biosensors could pave the way for therapeutic drug monitoring of many commonly administered drugs and for new drugs that will be introduced to the market allowing for safe and optimal dosing across a wide range of pharmaceuticals. In this review, we report on the recent developments in biosensing and nanobiosensing techniques and, focussing mainly on anti-cancer agents and antibiotics, we discuss the different classes of molecules upon which therapeutic drug monitoring has already been successfully applied. The potential contributions of (nano)biosensors are also reviewed for the emerging areas of therapeutic response monitoring, where markers are monitored to ensure compliance of a patient to a treatment and in the area of cellular response to therapeutic drugs in order to identify cytotoxic effects of drugs on cells or to identify patients responding to a drug. PMID- 26631283 TI - How Much Do Patients Value Total Hip and Knee Arthroplasty? A Prospective, Multicenter Study. AB - BACKGROUND: With increasing health care expenditures, reform has largely focused on cost containment, particularly in elective procedures such as total hip and knee arthroplasty (THA and TKA, respectively). The primary objective of this study is to determine what financial value patients place on these highly successful procedures. METHODS: An anonymous survey was administered to 670 patients at 4 different institutions (2 private practice and 2 academic centers) in the outpatient setting over a 15-month period. Patients were asked what reimbursement a surgeon should receive for a primary total joint arthroplasty (TJA), their perception of how much Medicare actually reimburses for TJA, how much they would pay out of pocket for the procedure, and their opinion of current Medicare reimbursement rates. RESULTS: Of the 557 patients who participated in the survey (83% response rate), patients on average felt that orthopedic surgeons should be reimbursed $27,430 for a THA and $19,830 for a TKA. Patients would be willing to pay a significant amount of out-of-pocket costs for their procedure, mean of $14,397 for THA (50.3% of total costs) and $12,797 for TKA (46.3% of total costs). Although patients in private practice groups had higher education and household income (P < .001), patients in academic centers would be willing to pay more out-of-pocket costs ($15,922 vs $5782, P = .034 for THA, $14,419 vs $4556, P = .052 for TKA). CONCLUSION: Patients in both private practice and academic centers feel that surgeons are underpaid for primary THA and TKA. As controversy continues to surround orthopedic surgeons' participation in Medicare, many patients are still willing to pay a significant amount of out-of-pocket expenses for TJA. PMID- 26631284 TI - Closed Suction Drainage Is Not Necessary for Total Knee Arthroplasty: A Prospective Study on Simultaneous Bilateral Surgeries of a Mean Follow-Up of 5.5 Years. AB - BACKGROUND: Closed suction drainage has been widely used for orthopedic surgeries including total knee arthroplasty (TKA) to prevent fluid collections at the operative site such as blood around the wound. However, it is still controversial whether suction drainage is necessary for TKA. The present study aimed to clarify the need for suction drainage by assessing short-term and long-term clinical outcomes of simultaneous bilateral TKA. METHODS: Our subjects were 63 patients (126 knees) who underwent simultaneous bilateral TKA using a cemented posterior stabilized prosthesis, classified into 3 groups: 20 patients with a closed suction drain on both sides (bilateral group), 22 patients with a closed suction drain on one side and no drain on the other side (unilateral group), and 21 patients with no drain (no-drainage group). Short- and long-term clinical outcomes were evaluated. RESULTS: Mean hemoglobin drop on the day after surgery was significantly greater in the bilateral group (2.2 g/dL, P = .038) and unilateral group (2.2 g/dL, P = .045) compared with the no-drainage group (1.5 g/dL). The incidence of short-term and long-term complications was not significantly different between knees with drainage and those without drainage. In side-to-side comparisons, no significant differences were found in knee extension, flexion, or circumference in the unilateral group. In group comparisons, we found no significant differences in clinical outcomes between the bilateral group and no-drainage group, either. CONCLUSION: These findings suggest closed suction drainage is not necessary after TKA with cemented posterior stabilized prostheses. PMID- 26631285 TI - Factors Associated With 20-Year Cumulative Risk of Infection After Aseptic Index Revision Total Knee Arthroplasty. AB - BACKGROUND: The purpose of this study was to calculate the cumulative risk of periprosthetic joint infection (PJI) after aseptic index knee revisions and to identify the surgical, perioperative, and medical comorbidity risk factors associated with deep infection. METHODS: We retrospectively reviewed 1802 aseptic index revision total knee arthroplasties performed at our institution from 1970 to 2000. From this cohort, there were 60 reoperations performed for deep infection. RESULTS: The cumulative risk of infection at 1, 5, 10, and 20 years after index revision was 1%, 2.4%, 3.3%, and 5.6%, respectively. CONCLUSIONS: Male gender, use of constrained implants, increased operative times, increased Charlson Comorbidity Index, and a history of liver disease were all significantly associated with PJI. The development of cardiovascular disease, endocrine disorders, and renal disease were also associated with PJI. PMID- 26631287 TI - Total Hip Arthroplasty Functional Outcomes Are Independent of Acetabular Component Orientation When a Polyethylene Liner Is Used. AB - BACKGROUND: This study evaluated patient-reported outcomes in patients undergoing primary total hip arthroplasty with a polyethylene liner to determine the influence of cup orientation and other variables on patient-reported outcomes. METHODS: A total of 477 cases were prospectively monitored through average 4.7 years follow-up. Cup position was measured on pelvis radiographs. Patients completed the Western Ontario and McMaster Universities Osteoarthritis Index and Short Form 12 Health Survey questionnaires. RESULTS: Average cup abduction was 43.1 degrees +/- 7.5 degrees and anteversion was 13.3 degrees +/- 7.5 degrees . Three hundred cups were within the target zone. All outcomes' improvement from baseline and cup position was not an independent risk factor for the Western Ontario and McMaster Universities Osteoarthritis Index or Short Form 12 Health Survey improvement. CONCLUSION: Accurate cup orientation may not be critical to maximizing patient-perceived outcomes if the combined anteversion is within a normal range, the hip joint is properly balanced, and a polyethylene liner is coupled with a metal or ceramic femoral head. PMID- 26631286 TI - Gender Differences in Wear Rates for 28- vs 32-mm Ceramic Femoral Heads on Modern Highly Cross-linked Polyethylene at Midterm Follow-Up in Young Patients Undergoing Total Hip Arthroplasty. AB - BACKGROUND: We report on the midterm linear and volumetric wear of highly cross linked polyethylene (HXLPE) and survivorship of 2 prospective young total hip arthroplasty (THA) cohorts that differed by the size of ceramic femoral head used: 28 vs 32 mm. METHODS: We prospectively analyzed 220 consecutive primary THAs in patients aged <=50 years who received a cementless THA with a ceramic femoral head on HXLPE liner (C-HXLPE). There were 101 patients (46%) with 28-mm heads and 119 patients (54%) who received 32-mm heads at a mean follow-up of 5.5 years (range, 60-109 months). Wear was calculated using Martell Software. RESULTS: The 28-mm C-HXLPE cohort demonstrated average linear and volumetric wear of 0.020 mm/y (standard deviation [SD], 0.074; 95% CI, 0.003-0.037) and 18.775 mm(3)/y (SD, 21.743; 95% CI, 13.773-23.778) compared with 0.032 mm/y (SD, 0.087; 95% CI, 0.013-0.050]) and 29.847 mm(3)/y (SD, 35.441; 95% CI, 22.294-37.401) in the 32-mm C-HXLPE group. Subgroup analysis by gender and head size discovered significantly greater wear in females with 32-mm heads compared with 28-mm heads in both linear (0.01, 95% CI = -0.014 to 0.033 vs 0.048, 95% CI = 0.022-0.074 mm/y, P = .004) and volumetric wear (14.11, 95% CI = 8.957-19.271] vs 29.71, 95% CI = 17.584-41.840] mm(3)/y, P = .009). We found a 96% (95% CI = 92.30%-97.94%]) survivorship by Kaplan-Meier analysis at minimum 5 years with no failures because of osteolysis. CONCLUSIONS: Ceramic on HXLPE demonstrates extremely low wear properties in young patients at midterm follow-up. We identified a gender dependent difference in wear based on head size, with 32-mm heads being associated with increased wear in females. PMID- 26631288 TI - Prosthetic reconstruction to restore function in transcarpal amputees. AB - Mutilated hands at the distal level may pose a challenge for reconstruction. Biological treatment options may require multiple surgical interventions and a long rehabilitation course with little hope of good functional outcome. Standard hand prostheses are also not an ideal solution, as they are too long and cumbersome for partial hand injuries. This paper outlines the functional outcomes of prosthetic reconstruction with devices customized for the transcarpal amputation levels. The functional outcome was evaluated with the Action Research Arm Test (ARAT), Southampton Hand Assessment Procedure (SHAP), and the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH). Functional evaluation was performed at least 12 months after final fitting. Psychological assessment was performed with the Short Form-36. The three patients achieved a mean ARAT score of 35.67 +/- 0.58. The average SHAP score was 74 +/- 7.81. The average DASH score was found to be 16.11 +/- 12.03. The reconstructed hand achieved a score of 75.27 +/- 8.16% in SHAP and 62.57 +/- 1.02% in ARAT in relation to the healthy hand. All patients exhibited average physical and mental component summary scales in the Short Form-36. The majority of transcarpal amputations are seen in manual laborers due to work-related trauma. Returning to work is the main goal in such young and otherwise-healthy patients. As shown with this study, prosthetic fitting results in quick and reliable functional reconstruction. Therefore, this treatment should be considered as an option during the initial decision-making process of reconstructing difficult traumatic injuries of the hand. PMID- 26631289 TI - Neuregulin-1 released by biodegradable gelatin hydrogels can accelerate facial nerve regeneration and functional recovery of traumatic facial nerve palsy. AB - BACKGROUND AND AIM: Neuregulin-1 is an essential axoglial signal required for peripheral nerve development, and evidence that neuregulin-1 is also required for effective nerve repair is growing. In this study, the effects of neuregulin-1 impregnated gelatin hydrogels on nerve regeneration and functional recovery after anastomosis of the facial nerve were investigated in a rat model of traumatic facial nerve paralysis. MATERIALS AND METHODS: Twenty-four adult male rats underwent complete resection of the facial nerve trunk, followed by end-to-end anastomosis with epineural sutures. The animals were then randomly allocated to one of three treatment groups (eight rats/group): no additional intervention (Group I), single-shot injection of neuregulin-1 into the epineurium of the facial nerve at the suture sites (Group II), or implantation of a hydrogel impregnated with neuregulin-1 at the injury site (Group III). After surgery, mimetic muscle movements were evaluated weekly. Eight weeks after surgery, the mimetic muscles were injected with a neural tracer (1,10-dioctadecyl-3,3,30,30 tetramethylindocarbocyanin perchlorate, DiI). Retrograde-labeled neurons were counted in the facial nuclei, and facial nerve specimens were stained with toluidine blue for histological examination of axon density. RESULTS: Group III exhibited significantly faster recovery of mimetic muscle function, a higher density of large-diameter axons (>5 MUm) in the facial nerve, and greater numbers of retrogradely labeled neurons in the ipsilateral facial nucleus compared with Groups I and II. CONCLUSIONS: Continuous release of neuregulin-1 from impregnated gelatin hydrogels can accelerate facial nerve regeneration. PMID- 26631290 TI - Prophylactic amifostine prevents a pathologic vascular response in a murine model of expander-based breast reconstruction. AB - BACKGROUND: Although expander-based breast reconstruction is the most commonly used method of reconstruction worldwide, it continues to be plagued with complication rates as high as 60% when radiotherapy is implemented. We hypothesized that quantitative measures of radiotherapy-induced vascular injury can be mitigated by utilizing amifostine in a murine model of expander-based breast reconstruction. METHODS: 30 rats were divided into three groups: expander placement (Control), expander placement followed by radiotherapy (XRT), and expander placement followed by radiotherapy with amifostine (AMF/XRT). All groups underwent placement of a sub-latissimus tissue expander. After a 45 day recovery period, all groups underwent vascular perfusion and micro-CT analysis. RESULTS: Micro-CT analysis was used to calculate vessel volume fraction (VVF), vessel number (VN), and vessel separation (VSp). A significant increase in VN was seen in the XRT group as compared to the Control (p = 0.021) and the AMF/XRT (p = 0.027). There was no difference between Control and AMF/XRT (p = 0.862). VVF was significantly higher in XRT than either Control (p = 0.043) and AMF/XRT (p = 0.040), however no difference was seen between Control and AMF/XRT (p = 0.980). VSp of XRT was smaller when compared to both Control and AMF/XRT specimens (p = 0.05 and p = 0.048, respectively), and no difference was seen between Control and AMF/XRT (p = 0.339). CONCLUSIONS: Amifostine administered prior to radiotherapy preserved vascular metrics similar to those of non-radiated specimens. Elevated vascularity demonstrated within the XRT group was not seen in either the Control or AMF/XRT groups. These results indicate that amifostine protects soft tissue in our model from a radiotherapy-induced pathologic vascular response. PMID- 26631291 TI - Editorial overview: Protein-protein interactions. PMID- 26631292 TI - Increased Risk of Developing Breast Cancer after a False-Positive Screening Mammogram. AB - BACKGROUND: Women with a history of a false-positive mammogram result may be at increased risk of developing subsequent breast cancer. METHODS: Using 1994 to 2009 Breast Cancer Surveillance Consortium data, we included women ages 40 to 74 years with a screening mammogram that resulted in a false-positive with recommendation for additional imaging, false-positive with recommendation for biopsy, or true-negative with no cancer within one year following the examination. We used partly conditional Cox proportional hazards survival models to assess the association between a false-positive mammogram result and subsequent breast cancer, adjusting for potential confounders. Adjusted survival curves stratified by breast density and false-positive result were used to evaluate changes in risk over time. RESULTS: During 12,022,560 person-years of follow-up, 48,735 cancers were diagnosed. Compared with women with a true negative examination, women with a false-positive with additional imaging recommendation had increased risk of developing breast cancer [adjusted HR (aHR) = 1.39; 95% confidence interval (CI), 1.35-1.44] as did women with a false positive with a biopsy recommendation (aHR = 1.76; 95% CI,1.65-1.88). Results stratifying by breast density were similar to overall results except among women with almost entirely fatty breasts in which aHRs were similar for both the false positive groups. Women with a false-positive result had persistently increased risk of developing breast cancer 10 years after the false-positive examination. CONCLUSION/IMPACT: Women with a history of a false-positive screening mammogram or biopsy recommendation were at increased risk of developing breast cancer for at least a decade, suggesting that prior false-positive screening may be useful in risk prediction models. PMID- 26631293 TI - Glycoprotein isolated from Styrax japonica Siebold et al. Zuccarini inhibits oxidative and pro-inflammatory responses in HCT116 colonic epithelial cells and dextran sulfate sodium-treated ICR mice. AB - This study was carried out to investigate the anti-inflammatory potentials of a 38 kDa glycoprotein isolated from Styrax japonica Siebold et al Zuccarini (SJSZ glycoprotein). We found that SJSZ glycoprotein has concentration-dependent scavenging activity against DPPH and hydroxyl radicals in the cell-free systems. In colonic epithelial cells (HCT116 cells), the results showed that SJSZ glycoprotein inhibits the production of reactive oxygen species (ROS) induced by glucose/glucose oxidase (G/GO) in a concentration-dependent manner. Experimental mouse colitis was induced by adding dextran sulfate sodium (DSS) to the drinking water at a concentration of 4% (w/v) for 7 days. We figured out that administration of SJSZ glycoprotein (10 mg/kg) lowers the levels of disease activity index, myeloperoxidase activity, and histological inflammation in DSS treated mice. In addition, SJSZ glycoprotein inhibited plasmic thiobarbituric acid reactive substances (TBARS) formation, nitric oxide (NO) production, and lactate dehydrogenase (LDH) release, accompanying the inhibition of colonic inflammatory signal proteins (NF-kappaB, iNOS, and COX-2) and inflammation related cytokines (IL-1beta, IL-6, and TNF-alpha). These results indicate that SJSZ glycoprotein inhibits oxidative and pro-inflammatory responses in mouse colitis. PMID- 26631294 TI - The mycotoxins deoxynivalenol and nivalenol show in vivo synergism on jejunum enterocytes apoptosis. AB - The mycotoxins deoxynivalenol (DON) and nivalenol (NIV), worldwide cereal contaminants, raise concerns for human and animal gut health, following exposure through contaminated food and feed. The aim of this work was to analyze the effects of DON and NIV, alone or associated, on the intestinal pig mucosa. Jejunal loops were used for testing DON and NIV individually and in combination (1:1) after a single exposure, for 24 h. For repeated exposure, piglets received a natural contaminated feed, with DON or with DON + NIV for 28 days. Histological investigations, proliferation and apoptosis assessments were conducted. Both experiments were concordant for the total-cell proliferation decreased at the villus tips after DON or DON + NIV at 10 MUM acutely, or repeatedly, by 30-35% and 20-25%, respectively. In loops model, apoptotic enterocytes at villus tips increased dose-dependently after DON, NIV alone or DON + NIV in combination. The combination in loops at 10 MUM showed higher effects on proliferation and apoptosis than DON alone, and synergism was shown for villus apoptotic enterocyte. These results are to be considered for NIV consumer risk assessment. Our results demonstrate the in vivo disruption of the intestinal balance proliferation/apoptosis explaining, at least partly, the disruption of intestinal barrier by these mycotoxins. PMID- 26631295 TI - New in vitro insights on a cell death pathway induced by magnolol and honokiol in aristolochic acid tubulotoxicity. AB - Aristolochic acids (AA) are nephrotoxic agents found in Aristolochia species whose consumption leads to the onset of a progressive tubulointerstitial fibrosis. This AA-nephropathy was first reported during the Belgian outbreak of the 1990's in which more than a hundred patients consumed slimming pills containing an Aristolochia species and Magnolia officinalis. The patients developed an end-stage kidney disease requiring dialysis or transplantation. Magnolol and honokiol are bioactive compounds from M. officinalis known for their potent antioxidant activity. As they can alleviate oxidative stress, we investigated their respective effects on AA-mediated tubulotoxicity using HK-2 cells. Magnolol and honokiol were able to reduce the oxidative stress associated with AA-treatment. Cytotoxicity alleviation was further investigated and overall cell viability measurements unexpectedly revealed that both compounds worsened the survival of AA-treated cells. Flow cytometry analyses of annexin V/PI stained cells indicated that the lignans efficiently prevented AA-induced apoptosis; but favored necrosis. Microscopy observations highlighted extensive vacuolization; other types of cell death, including autophagy, paraptosis or accelerated senescence were excluded. Ki-67 index and cell cycle analysis indicated that both magnolol and honokiol inhibited proliferation by blocking the cell cycle at the G1 phase; they also prevented the AA-induced G2/M arrest. PMID- 26631297 TI - A panel of four decreased serum microRNAs as a novel biomarker for early Parkinson's disease. AB - CONTEXT: Sensitive, non-invasive biomarkers that facilitate Parkinson's disease (PD) detection and stage assignment are currently unavailable. OBJECTIVE: The objective of this study is to investigate the potential of circulating microRNAs (miRNAs) as novel biomarkers for PD. MATERIALS AND METHODS: Solexa sequencing technology and quantitative real-time PCR were applied to screen and verify altered serum miRNAs in PD patients. RESULTS: Serum miR-141, miR-214, miR-146b 5p, and miR-193a-3p were decreased significantly in PD patients compared with controls. Furthermore, the 4-miRNA panel enabled the differentiation of HY stage 1 and 2 PD patients from controls. DISCUSSION AND CONCLUSION: The four serum miRNAs may represent novel biomarkers for the early detection of PD. PMID- 26631296 TI - Association of hip pain with radiographic evidence of hip osteoarthritis: diagnostic test study. AB - STUDY QUESTION: Is there concordance between hip pain and radiographic hip osteoarthritis? METHODS: In this diagnostic test study, pelvic radiographs were assessed for hip osteoarthritis in two cohorts: the Framingham Osteoarthritis Study (community of Framingham, Massachusetts) and the Osteoarthritis Initiative (a multicenter longitudinal cohort study of osteoarthritis in the United States). Using visual representation of the hip joint, participants reported whether they had hip pain on most days and the location of the pain: anterior, groin, lateral, buttocks, or low back. In the Framingham study, participants with hip pain were also examined for hip pain with internal rotation. The authors analysed the agreement between radiographic hip osteoarthritis and hip pain, and for those with hip pain suggestive of hip osteoarthritis they calculated the sensitivity, specificity, positive predictive value, and negative predictive value of radiographs as the diagnostic test. STUDY ANSWER AND LIMITATIONS: In the Framingham study (n=946), only 15.6% of hips in patients with frequent hip pain showed radiographic evidence of hip osteoarthritis, and 20.7% of hips with radiographic hip osteoarthritis were frequently painful. The sensitivity of radiographic hip osteoarthritis for hip pain localised to the groin was 36.7%, specificity 90.5%, positive predictive value 6.0%, and negative predictive value 98.9%. Results did not differ much for hip pain at other locations or for painful internal rotation. In the Osteoarthritis Initiative study (n=4366), only 9.1% of hips in patients with frequent pain showed radiographic hip osteoarthritis, and 23.8% of hips with radiographic hip osteoarthritis were frequently painful. The sensitivity of definite radiographic hip osteoarthritis for hip pain localised to the groin was 16.5%, specificity 94.0%, positive predictive value 7.1%, and negative predictive value 97.6%. Results also did not differ much for hip pain at other locations. WHAT THIS STUDY ADDS: Hip pain was not present in many hips with radiographic osteoarthritis, and many hips with pain did not show radiographic hip osteoarthritis. Most older participants with a high suspicion for clinical hip osteoarthritis (groin or anterior pain and/or painful internal rotation) did not have radiographic hip osteoarthritis, suggesting that in many cases, hip osteoarthritis might be missed if diagnosticians relied solely on hip radiographs. FUNDING, COMPETING INTERESTS, DATA SHARING: See the full paper on thebmj.com for funding. The authors have no competing interests. Additional data are available from bevochan@bu.edu. PMID- 26631298 TI - Cryopreserved arterial allograft vascular reconstruction for lower limb salvage during sarcoma surgery. PMID- 26631299 TI - Micro-Computed Tomography Analysis of the Root Canal Morphology of Palatal Roots of Maxillary First Molars. AB - INTRODUCTION: A thorough knowledge of root canal anatomy is critical for successful root canal treatments. This study evaluated the internal anatomy of the palatal roots of maxillary first molars with micro-computed tomography (microCT). METHODS: The palatal roots of extracted maxillary first molars (n = 169) were scanned with microCT to determine several anatomic parameters, including main canal classification, lateral canal occurrence and location, degree of curvature, main foramen position, apical constriction presence, diameters 1 and 2 mm from the apex and 1 mm from the foramen, minor dentin thickness in those regions, canal volume, surface area, and convexity. RESULTS: All canals were classified as Vertucci type I. The cross sections were oval in 61% of the canals. Lateral canals were found in 25% of the samples. The main foramen did not coincide with the root apex in 95% of the cases. Only 8% of the canals were classified as straight. Apical constriction was identified in 38% of the roots. The minor and major canal diameters and minor dentin thickness were decreased near the apex. The minor dentin thickness 1 mm from the foramen was 0.82 mm. The palatal canals exhibited a volume of 6.91 mm(3) and surface area of 55.31 mm(2) and were rod-shaped. CONCLUSIONS: The root canals of the palatal roots were classified as type I. However, some factors need to be considered during the treatment of these roots, including the frequent ocurrence of moderate/severe curvatures, oval-shaped cross-sections, and lateral canals, noncoincidence of the apical foramen with the root apex, and absence of apical constriction in most cases. PMID- 26631300 TI - Cone-beam Computed Tomography for Detecting Vertical Root Fractures in Endodontically Treated Teeth: A Systematic Review. AB - INTRODUCTION: A vertical root fracture (VRF), commonly found in teeth with endodontic treatment, is challenging to diagnose and has poor treatment outcomes. Cone-beam computed tomography (CBCT) has become an increasingly popular imaging modality in endodontics, but image artifacts arising from root-filling materials may hinder VRF detection. The aim of this investigation was to conduct a systematic review to assess the diagnostic ability of CBCT for detecting VRFs in endodontically treated teeth. METHODS: A systematic review of in vivo clinical diagnostic literature (initial search December 2014, updated August 2015) was conducted. Assessment of methodological quality was performed by using the modified Quality Assessment of Diagnostic Accuracy Studies tool. RESULTS: Four studies with a total of 130 patients were included. The reported ranges of values were 40%-90% for VRF prevalence, 84% (0.64-0.95) to 100% (0.83-1.00) for sensitivity, 64% (0.35-0.87) to 100% (0.03-1.00) for specificity, 71% (0.51-0.87) to 100% (0.63-1.00) for positive predictive value, and 50% (0.01-0.99) to 100% (0.84-1.00) for negative predictive value. All 4 studies revealed multiple items at high risk or unclear risk of bias. CONCLUSIONS: Because of the significant imprecision in the range of reported estimates and the biases observed in the included studies, there is currently insufficient evidence to suggest that CBCT is a reliable test in detecting VRFs in endodontically treated teeth. PMID- 26631301 TI - Autologous Platelet Concentrates for Pulp and Dentin Regeneration: A Literature Review of Animal Studies. AB - INTRODUCTION: The purpose of this study was to evaluate the effectiveness of autologous platelet concentrates (APCs) in promoting pulp and dentin regeneration in animal models. METHODS: An electronic search was performed on MEDLINE, Embase, Scopus, SciELO, LILACS, and CENTRAL. Animal studies using APC as a root filling material after pulpectomy in mature or immature teeth were included. Articles underwent risk of bias assessment. Histologic evaluation of intracanal neoformed tissue was the primary outcome; root development, root wall thickening, apical closure, and periapical healing in apical periodontitis were the secondary outcomes. RESULTS: Seven articles were included. Platelet-rich plasma (PRP) was used as root filling material during regenerative procedures in the experimental group in either mature or immature teeth. After revascularization with PRP alone or in conjunction with stem cells of a different source, the histologic analyses revealed that, in addition to an odontoblastic cell layer or dentinlike structure, the neoformed intracanal tissues were mainly cementumlike, bonelike, and connective tissues. CONCLUSIONS: True regeneration of necrotic pulp may not be achieved with current techniques using PRP, all of which stimulated tissue repair. Benefits of PRP adjunct for pulp tissue regeneration in preclinical studies remain unclear. Further studies with standardized protocols are necessary to assess the actual contribution of PRP in endodontic regenerative therapies. PMID- 26631302 TI - Troubled adolescents: substance abuse and mental disorder in young offenders. AB - INTRODUCTION: Many studies indicate the high prevalence of juvenile substance abuse. There is increasingly more dual diagnosis and mental illnesses in adolescents and many juvenile offenses are related to drug abuse. METHOD: This is a descriptive study about the relationship between drug abuse and clinical, demographic and criminal characteristics in a sample of 144 youths seen in the Therapeutic Juvenile Justice Unit (UTJJ) of the Parc Sanitari Sant Joan de Deu. RESULTS: A total of 65.3% of the sample had a disorder on Axis I, 22.2% of which were related with the psychotic spectrum and 18.1% ADHD. Personality disorder occurred in 42.4%, the most frequent ones being antisocial disorder (16%), and borderline personality disorder (6.9%). Of the sample, 78.5% were drug consumers and 51.4% of the total only consumed 1 substance. There is a tendency among psychotic teenagers to consume cannabis and ADHD patients to consume cannabis and cocaine. A significant relationship is found between nationality and inhalants drugs, social and economic level and sedative drugs and alcohol, and parental death and alcohol (p<0.05-0.005). CONCLUSIONS: The level of drug use/abuse in juvenile justice is very high. Although there is no evidence about the relationship between the substance they consume and the profile of the young offender, some tendencies are observed. PMID- 26631303 TI - Medical Professional Liability in Psychiatry. AB - INTRODUCTION: The safety of patients and the risk of malpractice claims are overriding concerns in medicine and psychiatry. MATERIAL AND METHODS: Claims for alleged malpractice in psychiatry managed by the Council of Colleges of Physicians of Catalonia between 1986 and 2009 were analyzed to evaluate their clinical and legal characteristics. RESULTS: Ninety-four malpractice claims were found in a 23-year period, mainly claims related to diagnosis (63.83%, including assessment of suicide risk) and the legal figure of serious professional negligence resulting in death (46.8%). Most claims were for hospital (62.77%), emergency (52.5%), and team (53.75%) care. The possible affected party was male (51.58%) with a mean age of 36.6 years. In one-half of the cases, the harm claimed was death. The cases involved 139 specialists, predominantly male (69.57%), with a mean age of 41 years, and of Spanish nationality (91.4%). The time between the medical act and the respective claim was 1.28 years and the time to resolution was 2.68 years. Most of the cases (77.66%) were processed through the courts. The outcome of the cases was filing or dismissal in 91 (95.77%), conviction in 2 (2.81%), and settlement in 1 (1.41%). CONCLUSIONS: The cumulative incidence of 0.013 claims (1.35%) in 23 years suggests that there is a very low risk of lawsuits in psychiatry, with a similarly low rate of sentences of professional liability and awards for financial compensation. Specific actions could improve clinical safety, particularly in suicide risk assessment. PMID- 26631304 TI - Prevalence of Oppositional Defiant Disorder in a sample of Spanish children between six and sixteen years: teacher’s report. AB - INTRODUCTION: Our main objective is to study the prevalence of Oppositional Defiant Disorder (ODD) in school children aged 6-16 years of an autonomous region of Spain (Castile and Leon), according to reports from the teachers and to analyze the impact of the disorder on academic performance and school behavior. METHODS: Population study with stratified multistage, proportional and cluster design sample. Sample analyzed: 1,049. Cases were defined according to DSM-IV-TR criteria. RESULTS: An overall prevalence rate of 4.2% was found, this being significantly higher in males (5.7%) compared to females (2.6%) and in rural (6.8%) than in urban areas (3%). No significant differences by grade or type of school were found. ODD prevalence without considering functional impairment would increase to 5.1%. ODD cases have significantly worse academic outcomes (overall academic performance, reading, math and writing) and entail worse classroom behavior (relationship with peers, respect for rules, organizational skills, academic tasks and disruption of the class). CONCLUSIONS: Based on the prevalence, early onset, persistence of symptoms and social and academic dysfunction of ODD, early diagnosis and preventive intervention are necessary. PMID- 26631305 TI - Characterizing offspring of bipolar parents: a review of the literature. AB - Offspring of parents with bipolar disorder (O-BP) is a high-risk cohort for mental illness in general and bipolar disorder (BD) specifically. This review aims to delineate the main clinical features of O-BP, including the psychopathology, interpersonal functioning, temperamental and personality features, neurocognitive deficits and neurobiological dysfunctions. Evidence indicates that several internalizing and externalizing symptoms/disorders are more prevalent in O-BP than in offspring of healthy control parents (O-HC). Furthermore, O-BP exhibits poorer interpersonal functioning than O-HC. Moreover, O-BP also endorses higher activity level, emotionality and behavioral disinhibition compared to O-HC. Besides, O-BP displays greater deficits on memory, cognitive flexibility and social cognition compared to O-HC. Finally, O BP exhibits dysfunctional modulation in cortico- subcortical areas, more white matter abnormalities and higher cortisol basal levels compared to O-HC. Overall, these findings are discussed regarding the natural course and potential risk factors or endophenotypes for major mood disorders in general and BD specifically. PMID- 26631306 TI - Brugada type 1 pattern and lithium therapy. PMID- 26631307 TI - The question of metabolic syndrome X. PMID- 26631308 TI - Incidence of cutaneous malignant melanoma by socioeconomic status in Canada: 1992 2006. AB - BACKGROUND: There are no nationwide studies documenting changes in cutaneous malignant melanoma incidence or association of incidence with socioeconomic status (SES) in Canada. We sought to determine whether melanoma incidence increased from 1992 to 2006 and if there was an association between SES and melanoma incidence. Additionally, we studied whether there was a correlation between province of residence and melanoma incidence. METHODS: Cases from the Canadian Cancer Registry were reviewed. Demographic and socioeconomic information were extracted from the Canadian Census of Population data. Cases were linked to income quintiles by postal code. A negative binomial regression was performed to identify relationships among these variables. RESULTS: Overall incidence of melanoma in Canada increased by 67 % from 1992 to 2006 (p < 0.0001). The increase in incidence was greater for melanoma in situ compared with invasive melanoma (136 % versus 52 % [p < 0.0001]). Incidence was positively correlated with higher income quintiles; the incidence rates among patients in the lowest income quintiles were 67 % of that for the highest income quintiles (p < 0.0001). DISCUSSION: A wide variety of explanations have been postulated for an increased incidence in melanoma among persons of higher SES, including access to and awareness of screening, more access to vacations in sunny climates, and increased leisure time. Variations in incidence of melanoma by urban vs. rural location and province may indicate differences in access to dermatologists across Canada. CONCLUSIONS: Melanoma incidence is increasing in Canada and is higher among people in high SES groups. This rise is likely due to a combination of factors including a true rise in incidence due to increases in sun exposure, and also an increased detection rate, particularly in those who are more aware of the disease and have access to resources for detection. PMID- 26631309 TI - Effect of disulfide bonding and multimerization on proteoglycan 4's cartilage boundary lubricating ability and adsorption. AB - PURPOSE: The objectives of this study were to assess the cartilage boundary lubricating ability of (1) nonreduced (NR) disulfide-bonded proteoglycan 4 (PRG4) multimers versus PRG4 monomers and (2) NR versus reduced and alkylated (R/A) PRG4 monomers and to assess (3) the ability of NR PRG4 multimers versus monomers to adsorb to an articular cartilage surface. MATERIALS AND METHODS: PRG4 was separated into two preparations, PRG4 multimer enriched (PRG4Multi+) and PRG4 multimer deficient (PRG4Multi-), using size exclusion chromatography (SEC) and characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE). The cartilage boundary lubricating ability of PRG4Multi+ and PRG4Multi- was compared at a physiological concentration (450 MUg/mL) and assessed over a range of concentrations (45, 150, and 450 MUg/mL). R/A and NR PRG4Multi- were evaluated at 450 MUg/mL. Immunohistochemistry with anti-PRG4 antibody 4D6 was performed to visualize the adsorption of PRG4 preparations to the surface of articular cartilage explants. RESULTS: Separation into enriched populations of PRG4Multi+ and PRG4Multi- was achieved using SEC and was confirmed by SDS-PAGE. PRG4Multi+ and PRG4Multi- both functioned as effective friction-reducing cartilage boundary lubricants at 450 MUg/mL, with PRG4Multi+ being more effective than PRG4Multi-. PRG4Multi+ lubricated in a dose-dependent manner, however, PRG4Multi- did not. R/A PRG4Multi- lubricated similar to NR PRG4Multi-. PRG4 containing solutions showed 4D6 immunoreactivity at the articular surface; the immunoreactive intensity of PRG4Multi+ appeared to be similar to SF, whereas PRG4Multi- appeared to have less intensity. CONCLUSIONS: These results demonstrate that the intermolecular disulfide-bonded multimeric structure of PRG4 is important for its ability to adsorb to a cartilage surface and function as a boundary lubricant. These findings contribute to a greater understanding of the molecular basis of cartilage boundary lubrication of PRG4. Elucidating the PRG4 structure-lubrication function relationship will further contribute to the understanding of PRG4's role in diarthrodial joint homeostasis and disease. PMID- 26631310 TI - The next generation cell-penetrating peptide and carbon dot conjugated nano liposome for transdermal delivery of curcumin. AB - To overcome the problems associated with conventional liposomes in transdermal drug delivery like limited penetration ability and poor stability, in this article we report a new generation of cell penetrating peptide polyarginine containing nano-liposomes conjugated with carbon dots. The newly synthesized, cost-effective liposomic precursors were used for the fabrication of liposomes. The resulting liposomes have a bilayer structure like that of conventional liposomes with much smaller size, higher stability, and high penetration ability. The nano-liposomes show high stability at room temperature for three months without any change in size or encapsulation efficiency. The incorporation of carbon dots also opens up their application in fluorescence cell imaging studies, which is very well supported by the fluorescence microscopic analysis of the liposome skin penetration. The as-prepared nano-liposomes do not show any cytotoxicity for MCF-7 cells, even at high concentrations; however, when drug loaded liposomes are applied, they can kill the cancer cells with a high rate. The synthesized nano-liposomes have the potential to be used as an efficient, stable, biocompatible nanocarrier for transdermal drug delivery. PMID- 26631311 TI - [T2HD Study. Oral anticoagulants and antiplatelet agents: Practices, benefits, and risks in the chronic hemodialysis population. Observational data]. AB - INTRODUCTION: Chronic hemodialysis patients have disorders of hemostasis associated with End Stage Renal Disease, cardiovascular disease, and treatments they receive. They have more thrombotic and bleeding events than the general population. The balance of risks and benefits of drugs is not precisely defined. The aim of this study is to describe the practices patterns concerning oral anticoagulants (AVK) and antiplatelet agents (APA), and to investigate their impact on the survival and the occurrence of thrombotic and bleeding events. METHODS: Based on REIN registry, we performed a multicenter study of 502 incident patients on hemodialysis in Lorraine from 2009 to 2010. Until June 2013, we collected retrospectively the prescription of oral anticoagulants and APA, the occurrence of thrombotic or hemorrhagic events. RESULTS: During follow-up, there were 550 events, including 454 thrombotic events and 96 bleeding events. The most common event was the dialysis vascular access thrombosis; 60.8% of patients were treated with APA, and 29.5% with AVK. Bleeding and thrombosis occurred the most in the APA plus AVK patient group. Events had often recurrences. Patients survived longer in no anticoagulant or antiplatelet group, but with no statistic difference. DISCUSSION: Although literature is centered on bleeding events, we found a more significant occurrence of thrombosis than bleeding. Patients without APA or AVK have less comorbidities, less bleeding and thrombotic events, and better survival. Analytic description of our data is expected to get a risk/benefit ratio of APA and AVK treatment in their different uses. PMID- 26631312 TI - [Conservative treatment, hemodialysis or peritoneal dialysis for elderly patients: The choice of treatment does not influence the survival]. AB - Hemodialysis is the predominant replacement therapy in the 70 year-old French population (18% in peritoneal dialysis, 72% in hemodialysis from the REIN registry). Managing older patients reaching the end stage renal disease poses many ethical questions, since outcomes balanced regarding survival and quality of life. The aim of this study was to compare the survival of patients aged over 70 years according to the ESRD treatment choice: conservative treatment without dialysis (CT), hemodialysis (HD) and peritoneal dialysis (PD). We included all patients over 70 years reaching stade IV CKD integrated in a predialysis information program between 01/01/2005 and 31/12/2010. We compared their survival from the start of their program, in function of their treatment choice: HD, PD or CT. On this period, 148 patients were included, we excluded from analysis 17 patients who had a contraindication to PD, 26 patients who did not make a choice because their kidney function was stabilized, 4 patients lost to follow-up and 12 patients who died before the treatment choice. The average age was 79+/-6 years, 40% of patients were women, and the mean eGFR was 16+/-9 mL/min/1.73 m(2) at the entry in the program. Among the 89 patients, 21 choose CT (24%), 68 accepted dialysis (76%), including 48 HD (71%) and 20 PD (29%). No significant eGFR difference at the inclusion time between the groups. The time initiation of dialysis was significantly shorter in the PD group (146 days vs 442 in the HD group; P=0.004). Survival between the groups of patients who accepted or refused dialysis was not statistically different (749 days or 2 years in the HD + PD group vs 562 days, or 1 year and 6 months in the CT group; P=0.95) and between the HD group (760 days or 2 years and 2 months) and the PD group (343 days or 11 months; P=0.32). As measured from the time they entered in the predialysis program, the survival of older patients over 70 years does not seem to depend on their choice of treatment modality. Whether they accepted or refused dialysis, whatever their choice concerning hemodialysis or peritoneal dialysis, their survival was close to one year. PMID- 26631313 TI - Design and optimization of selective azaindole amide M1 positive allosteric modulators. AB - Selective activation of the M1 receptor via a positive allosteric modulator (PAM) is a new approach for the treatment of the cognitive impairments associated with schizophrenia and Alzheimer's disease. A novel series of azaindole amides and their key pharmacophore elements are described. The nitrogen of the azaindole core is a key design element as it forms an intramolecular hydrogen bond with the amide N-H thus reinforcing the bioactive conformation predicted by published SAR and our homology model. Representative compound 25 is a potent and selective M1 PAM that has well aligned physicochemical properties, adequate brain penetration and pharmacokinetic (PK) properties, and is active in vivo. These favorable properties indicate that this series possesses suitable qualities for further development and studies. PMID- 26631314 TI - Cytotoxicity of electrophilic iron(II)-clathrochelates in human promyelocytic leukemia cell line. AB - We observed that electrophilic iron(II)-clathrochelates exhibit significant cytotoxicity in human promyelocytic leukemia cells (IC50=6.5+/-4.6MUM), which correlates with the enhancement of intracellular oxidative stress (17-fold increase with respect to the cells treated with the solvent only). Based on in vitro studies we suggested that this effect is caused by alkylation of glutathione leading to inhibition of the cellular antioxidative system and by catalytic generation of reactive oxygen species by products of the alkylation reaction. PMID- 26631315 TI - Stabilizing G-quadruplex DNA by methylazacalix[n]pyridine through shape complementary interaction. AB - It is found that G-quadruplexes have important functions in biological systems, such as gene expression. Molecules which can stabilize the G-quadruplex structure may have potential application in regulating the expression of gene. A series of methylazacalix[n]pyridine (n=4, 6, 7, 8, 9) has been tested to stabilize the intermolecular human telomeric G-quadruplex (T12 and H12), intramolecular TBA, c kit and bcl-2 G-quadruplex by CD denaturation experiments. The results showed that only methylazacalix[6]pyridine (MACP6) can stabilize the intermolecular G quadruplex formed from the 12bp human telomere. Further studies evidenced that the shape-complementary binding mode was what contributed to the interaction between MACP6 and T12 G-quadruplex. PMID- 26631316 TI - Self-assembling tryptophan-based designer peptides as intracellular delivery vehicles. AB - A series of tryptophan-based peptides W1a, b-W4a, b, with diverse architectures were designed and synthesized. These tryptophan containing peptides can self assemble to spherical particle. This self-assembled system was demonstrated to encapsulate rhodamine B and penetrate the cell membrane. PMID- 26631317 TI - Cysteine and arginine-rich peptides as molecular carriers. AB - A number of linear and cyclic peptides containing alternative arginine and cysteine residues, namely linear (CR)3, linear (CR)4, linear (CR)5, cyclic [CR]4, and cyclic [CR]5, were synthesized. The peptides were evaluated for their ability to deliver two molecular cargos, fluorescence-labeled cell-impermeable negatively charged phosphopeptide (F'-GpYEEI) and fluorescence-labeled lamivudine (F'-3TC), intracellularly in human leukemia cancer (CCRF-CEM) cells. We investigated the role of cyclization and the number of amino acids in improving the transporting ability of the peptides. The flow cytometry studies suggested that the synthesized peptides were able to work efficiently as transporters for both cargos. Among all compounds, cyclic [CR]4 was found to be the most efficient peptide in transporting the cargo into cells. For instance, the cellular uptake of F'-3TC (5MUM) and F'-GpYEEI (5MUM) was enhanced by 16- and 20-fold, respectively, in the presence of cyclic [CR]4 compared to that of the parent compound alone. The mechanism of F'-GpYEEI uptake by cells was found to be energy independent. The results showed that the number of amino acids and their cyclic nature can impact the efficiency of the peptide in transporting the molecular cargos. PMID- 26631318 TI - Gambogic acid induces apoptotic cell death in T98G glioma cells. AB - Gambogic acid (GA), a natural product with a xanthone structure, has a broad range of anti-proliferative effects on cancer cell lines. We evaluated GA for its cytotoxic effects on T98G glioblastoma cells. GA exhibited potent anti proliferative activity and induced apoptosis in T98G glioblastoma cells in a dose dependent manner. Incubation of cells with GA revealed apoptotic features including increased Bax and AIF expression, cytochrome c release, and cleavage of caspase-3, -8, -9, and PARP, while Bcl-2 expression was downregulated. Furthermore, GA induced reactive oxygen species (ROS) generation in T98G cells. Our results indicate that GA increases Bax- and AIF-associated apoptotic signaling in glioblastoma cells. PMID- 26631319 TI - Synthesis of novel coumarin appended bis(formylpyrazole) derivatives: Studies on their antimicrobial and antioxidant activities. AB - A series of novel coumarin pyrazole hybrids of biological interest were synthesized from the hydrazones, carbazones and thiocarbazones via Vilsmeier Haack formylation reaction. These intermediates and formyl pyrazoles were evaluated for antimicrobial and antioxidant activities. Among the series, compounds 6g and 6h showed excellent antimicrobial activity against different bacterial and fungal strains and compounds 7g, 7h were found to be potent antioxidant agents in both DPPH and hydroxyl radical scavenging assays. Further, detailed quantitative structure-activity relationship (QSAR) analysis indicated the molecular parameters that contribute to increased potency of inhibition. The above findings would further encourage our understanding in employing coumarin pyrazole hybrids as potential antibiotic agents for treating infections caused by pathogenic microbes and fungi. Further, it also paves the way for exploration of these compounds as potential therapeutic agents to treat conditions arising because of excessive oxidative damage. PMID- 26631320 TI - New mannose derivatives: The tetrazole analogue of mannose-6-phosphate as angiogenesis inhibitor. AB - Two novel compounds with mannose-derived structure, bearing a tetrazole (compound 3) and a sulfone group (compound 4) in terminal position, have been prepared from methyl alpha-d-mannopyranoside in reduced number of steps. The angiogenic activity of 3 and 4 has been screened using the chick chorioallantoic membrane (CAM) method. Tetrazole 3 has been identified to possess a promising bioactivity, being identified as angiogenesis inhibitor, with 68% of neovascular vessels when compared to control (PBS). PMID- 26631321 TI - Discovery and synthesis of cyclohexenyl derivatives as modulators of CC chemokine receptor 2 activity. AB - A novel cyclohexenyl series of CCR2 antagonists has been discovered. This series of small, rigid compounds exhibits submicromolar binding affinity for CCR2. Modification of the substituents on the cyclohexene ring led to the identification of potent CCR2 antagonists. Progress from initial lead 5 (IC50=700nM) to (-)-38 (IC50=9.0nM) is discussed. PMID- 26631323 TI - Twitter in urology and other surgical specialties at global conferences. AB - BACKGROUND: Over recent years, Twitter has demonstrated an expanding role in scientific discussion, surgical news and conferences. This study evaluates the role of Twitter in urological conferences, with comparison to other surgical specialties. METHODS: A retrospective analysis of Twitter metrics during the two largest recent English-speaking conferences for each surgical specialty was performed. Using www.symplur.com, all 'tweets' under the official conference hashtag from 0000 hour the first day to 24.00 hour the final day were assessed. The number of impressions, 'tweeters' and rates of 'tweeting' were analysed. RESULTS: Nine of 18 conferences examined had official hashtags registered with Symplur Healthcare Hashtags. Plastic and urological surgery had both major conferences registered. Only one of two conferences for each cardiothoracic, general, orthopaedic, otolaryngology and paediatric was registered. Both major neurosurgical and vascular conferences were unregistered. Urological conferences were associated with significantly more Twitter activity than non-urological surgical conferences in all parameters, with greater than triple the number of impressions, tweets and 'tweeters'. Urological surgical conferences were associated with 337% more tweets and 164% more impressions per conference day, than non-urological surgical conferences. CONCLUSION: Twitter has been used to supplement surgical conferences. In this regard, the urological community leads the way compared to the remainder of surgical specialty communities. PMID- 26631322 TI - Exaggerated arsenic nephrotoxicity in female mice through estrogen-dependent impairments in the autophagic flux. AB - Gender is one of the essential factors in the development of various diseases and poisoning. Therefore, we herein examined gender differences in sodium arsenite (NaAsO2)-induced acute renal dysfunction. When male and female BALB/c mice were subcutaneously injected with NaAsO2 (12.5mg/kg), serum and urinary markers for proximal tubular injury were significantly higher in female mice than in male ones. NaAsO2-induced histopathological alterations were consistently more evident in females than in males. Ovariectomy, but not orchiectomy significantly attenuated NaAsO2-induced renal injury. These results imply that the hypersusceptibility of female mice is attributed to estrogen signals. NaAsO2 suppressed the autophagic flux in tubular cells through the activation of ERK. Enhancements in the activation of ERK were significantly greater in females than in males, with the eventual accumulation of LC3-II and P62 in the kidneys, implying that the autophagic flux is impaired in females. The IL-6/STAT3 signaling pathway had protective roles in NaAsO2-induced nephrotoxicity through the suppression of ERK activation. Despite the absence of differences in intrarenal IL-6 expression between male and female mice, STAT3 was less activated with enhanced SOCS3 expression in females than in males. An in vitro study using mProx24 cells revealed that the estrogen treatment induced SOCS3 expression, and eventually suppressed the autophagic flux, as evidenced by greater increases in the accumulation of LC3-II and p62 with ERK activation, which was canceled by the knockdown of Socs3. Collectively, these results indicate that estrogen has a negative impact on the development of NaAsO2 nephrotoxicity through its suppression of the autophagic flux. PMID- 26631324 TI - [Frequency of rhinitis and orofacial disorders in patients with dental malocclusion]. AB - OBJECTIVE: To describe the frequency and etiology of rhinitis, oral breathing, types of malocclusion and orofacial disorders in patients treated for dental malocclusion. METHODS: Patients with poor dental occlusion (n=89, 8-15 years) undergoing orthodontic treatment at the Postgraduate Orthodontics Center (Sao Paulo, Brazil) participated in the study. Rhinitis and oral breathing were diagnosed by anamnesis, clinical assessment and allergic etiology of rhinitis through immediate hypersensitivity skin prick test (SPT) with airborne allergens. The association between types of breathing (oral or nasal), rhinitis and types of dental malocclusion, bruxism and cephalometric alterations (increased Y axis of facial growth) compared to standard cephalometric tracing (Escola de Odontologia da Universidade de Sao Paulo) were assessed. RESULTS: The frequency of rhinitis in patients with dental malocclusion was 76.4% (68), and, of these, 81.7% were allergic (49/60 positive skin prick test), whereas the frequency of oral breathing was 62.9%. There was a significant association between an increased Y axis of facial growth and oral breathing (p<0.001), as well as between oral breathing and rhinitis (p=0.009). There was no association between rhinitis and bruxism. CONCLUSIONS: The frequency of rhinitis in children with dental malocclusion is higher than that in the general population, which is approximately 30%. Patients with oral breathing have a tendency to a dolichofacial growth pattern (increased Y axis of facial growth). In patients with rhinitis, regardless of the presence of oral breathing, the dolichofacial growth tendency was not observed. PMID- 26631325 TI - The anterior cruciate ligament-lateral meniscus complex: A histological study. AB - The anterior root of the lateral meniscus (LM) dives underneath the tibial attachment of the anterior cruciate ligament (ACL). Although the distinct role of meniscal attachments has been investigated, the relationship between the LM anterior insertion (LMAI) and ACL tibial insertion (ACLTI) remains unclear. This study histologically analyzed the LMAI and ACLTI. Samples were divided into four regions in an anterior-to-posterior direction. Histological measurements of these insertion sites were performed using safranin O-stained coronal sections. Distribution and signal densities of type I and II collagen were quantified. The ACLTI and LMAI formed the ACL-LM complex via fiber connections. The anterior part of the ACLTI had a widespread attachment composed of dense fibers. Attachment fibers of the LMAI became dense and wide gradually at the middle-to-posterior region. The ACL-LM transition zone (ALTZ) was observed between the LMAI and the lateral border of the ACLTI at the middle part of the ACL tibial footprint. Type II collagen density of the LMAI was higher than that of the ACLTI and ALTZ. Our results can help create an accurate tibial bone tunnel within the dense ACL attachment during ACL reconstruction surgery. PMID- 26631326 TI - Five minutes with . . . Sarah Wollaston. PMID- 26631327 TI - Glucose metabolism disorders and vestibular manifestations: evaluation through computerized dynamic posturography. AB - INTRODUCTION: Global sugar consumption has increased in the past 50 years; its abusive intake is responsible for peripheral insulin resistance, which causes the metabolic syndrome - obesity, diabetes mellitus, hypertension, and coronary heart disease. OBJECTIVE: To evaluate the effect of a fractionated diet without glucose as treatment for labyrinthine disorders associated with glucose-insulin index. METHODS: The study design was a prospective randomized controlled trial. Fifty one patients were divided into two groups: the diet group (DG), which comprised subjects treated with a fractionated diet with glucose restriction, and the control group (CG), in which individuals were not counseled regarding diet. Patients underwent computerized dynamic posturography (CDP) and visual analog scale (VAS) on the first and 30th days of the study. RESULTS: There was improvement in the assessed posturographic conditions and VAS self-assessment in the DG group after 30 days when compared to the control group. CONCLUSION: The fractionated diet with glucose restriction was effective for the treatment of vestibular dysfunction associated with glucose metabolism disorders. PMID- 26631328 TI - Impact of delay in the diagnosis and treatment of head and neck cancer. AB - INTRODUCTION: Head and neck tumors can be easily recognized through clinical evaluation. However, they are often diagnosed at advanced stages. OBJECTIVE: To evaluate the delay from the patient's initial symptoms to the definitive treatment. METHODS: Retrospective study of patients enrolled in 2011 and 2012. A questionnaire was filled in about socioeconomic aspects, patient history, tumor data, professionals who evaluated the patients, and the respective time delays. RESULTS: The following time delay medians were observed: ten months between symptom onset and the first consultation; four weeks between the latter and the first consultation with a specialist; four weeks between the specialist consultation and diagnosis attainment; and 12 weeks between diagnosis and the start of treatment. CONCLUSIONS: Most head and neck tumors are diagnosed at advanced stages, due to patient and health care factors. PMID- 26631329 TI - Speech auditory brainstem response (speech ABR) in the differential diagnosis of scholastic difficulties. PMID- 26631330 TI - Treatment of tympanic membrane perforation using bacterial cellulose: a randomized controlled trial. AB - INTRODUCTION: Promising treatments for tympanic membrane perforation closure have been studied. Therapies derived from tissue engineering probably eliminate the need for conventional surgery. Bacterial cellulose is presented as an alternative that is safe, biocompatible, and has low toxicity. OBJECTIVES: To investigate the effect on healing of direct application of a bacterial cellulose graft on the tympanic membrane compared to the conventional approach with autologous fascia. METHODS: Randomized controlled trial. Forty patients with tympanic membrane perforations secondary to chronic otitis media were included, and were randomly assigned to an experimental group (20), treated with a bacterial cellulose graft (BC) and control group (20), treated with autologous temporal fascia (fascia). We evaluated the surgical time, hospital stay, time of epithelialization and the rate of tympanic perforation closure. Hospital costs were compared. The statistical significance level accepted was established at p<0.05. RESULTS: The closure of perforations was similar in both groups. The average operation time in the fascia group was 76.50 min versus 14.06 min bacterial cellulose in the group (p=0.0001). The hospital cost by the Brazilian public health system was R$ 600.00 for the bacterial cellulose group, and R$ 7778.00 for the fascia group (p=0.0001). CONCLUSION: Bacterial cellulose grafts promoted the closure of the tympanic membrane perforations, and were demonstrated to be innovative, effective, safe, minimally invasive, efficacious and to have a very low cost. PMID- 26631331 TI - Landmark-free geometric methods in biological shape analysis. AB - In this paper, we propose a new approach for computing a distance between two shapes embedded in three-dimensional space. We take as input a pair of triangulated genus zero surfaces that are topologically equivalent to spheres with no holes or handles, and construct a discrete conformal map f between the surfaces. The conformal map is chosen to minimize a symmetric deformation energy Esd(f) which we introduce. This measures the distance of f from an isometry, i.e. a non-distorting correspondence. We show that the energy of the minimizing map gives a well-behaved metric on the space of genus zero surfaces. In contrast to most methods in this field, our approach does not rely on any assignment of landmarks on the two surfaces. We illustrate applications of our approach to geometric morphometrics using three datasets representing the bones and teeth of primates. Experiments on these datasets show that our approach performs remarkably well both in shape recognition and in identifying evolutionary patterns, with success rates similar to, and in some cases better than, those obtained by expert observers. PMID- 26631332 TI - Prey should hide more randomly when a predator attacks more persistently. AB - When being searched for and then (if found) pursued by a predator, a prey animal has a choice between choosing very randomly among hiding locations so as to be hard to find or alternatively choosing a location from which it is more likely to successfully flee if found. That is, the prey can choose to be hard to find or hard to catch, if found. In our model, capture of prey requires both finding it and successfully pursuing it. We model this dilemma as a zero-sum repeated game between predator and prey, with the eventual capture probability as the pay-off to the predator. We find that the more random hiding strategy is better when the chances of repeated pursuit, which are known to be related to area topography, are high. Our results extend earlier results of Gal and Casas, where there was at most only a single pursuit. In that model, hiding randomly was preferred by the prey when the predator has only a few looks. Thus, our new multistage model shows that the effect of more potential looks is opposite. Our results can be viewed as a generalization of search games to the repeated game context and are in accordance with observed escape behaviour of different animals. PMID- 26631333 TI - The microscopic network structure of mussel (Mytilus) adhesive plaques. AB - Marine mussels of the genus Mytilus live in the hostile intertidal zone, attached to rocks, bio-fouled surfaces and each other via collagen-rich threads ending in adhesive pads, the plaques. Plaques adhere in salty, alkaline seawater, withstanding waves and tidal currents. Each plaque requires a force of several newtons to detach. Although the molecular composition of the plaques has been well studied, a complete understanding of supra-molecular plaque architecture and its role in maintaining adhesive strength remains elusive. Here, electron microscopy and neutron scattering studies of plaques harvested from Mytilus californianus and Mytilus galloprovincialis reveal a complex network structure reminiscent of structural foams. Two characteristic length scales are observed characterizing a dense meshwork (approx. 100 nm) with large interpenetrating pores (approx. 1 um). The network withstands chemical denaturation, indicating significant cross-linking. Plaques formed at lower temperatures have finer network struts, from which we hypothesize a kinetically controlled formation mechanism. When mussels are induced to create plaques, the resulting structure lacks a well-defined network architecture, showcasing the importance of processing over self-assembly. Together, these new data provide essential insight into plaque structure and formation and set the foundation to understand the role of plaque structure in stress distribution and toughening in natural and biomimetic materials. PMID- 26631335 TI - Correction to 'Estimation of gestational age from fundal height: a solution for resource-poor settings'. PMID- 26631334 TI - Biomechanical rupture risk assessment of abdominal aortic aneurysms based on a novel probabilistic rupture risk index. AB - A rupture risk assessment is critical to the clinical treatment of abdominal aortic aneurysm (AAA) patients. The biomechanical AAA rupture risk assessment quantitatively integrates many known AAA rupture risk factors but the variability of risk predictions due to model input uncertainties remains a challenging limitation. This study derives a probabilistic rupture risk index (PRRI). Specifically, the uncertainties in AAA wall thickness and wall strength were considered, and wall stress was predicted with a state-of-the-art deterministic biomechanical model. The discriminative power of PRRI was tested in a diameter matched cohort of ruptured (n = 7) and intact (n = 7) AAAs and compared to alternative risk assessment methods. Computed PRRI at 1.5 mean arterial pressure was significantly (p = 0.041) higher in ruptured AAAs (20.21(s.d. 14.15%)) than in intact AAAs (3.71(s.d. 5.77)%). PRRI showed a high sensitivity and specificity (discriminative power of 0.837) to discriminate between ruptured and intact AAA cases. The underlying statistical representation of stochastic data of wall thickness, wall strength and peak wall stress had only negligible effects on PRRI computations. Uncertainties in AAA wall stress predictions, the wide range of reported wall strength and the stochastic nature of failure motivate a probabilistic rupture risk assessment. Advanced AAA biomechanical modelling paired with a probabilistic rupture index definition as known from engineering risk assessment seems to be superior to a purely deterministic approach. PMID- 26631336 TI - Irregularities of crystallographic orientation and residual stresses in the crossed-lamellar shell as a natural functionally graded material. AB - The microstructures of different groups of molluscs are characterized by preferential orientations of crystallites (texture), leading to a significant anisotropy of the physical properties of the shells. A complementary characteristic, usually neglected, is the distribution of the residual stresses existing within the shell wall. By means of X-ray diffraction, we study the distribution of stresses with thickness in the shell wall of the gastropod Conus marmoreus, which has a microstructure of the crossed-lamellar type. The results revealed an extraordinary texture inhomogeneity and the existence of tensional residual stresses along the shell thickness, the origins of which are unknown. Some of the observed changes in textural parameters and stresses coincide with the transitions between shell layers, although other features are of unknown origin. Our results provide insight into the microstructural regularities that govern the mesoscale construction of shells, such as that of C. marmoreus. PMID- 26631337 TI - Grand challenges in space synthetic biology. AB - Space synthetic biology is a branch of biotechnology dedicated to engineering biological systems for space exploration, industry and science. There is significant public and private interest in designing robust and reliable organisms that can assist on long-duration astronaut missions. Recent work has also demonstrated that such synthetic biology is a feasible payload minimization and life support approach as well. This article identifies the challenges and opportunities that lie ahead in the field of space synthetic biology, while highlighting relevant progress. It also outlines anticipated broader benefits from this field, because space engineering advances will drive technological innovation on Earth. PMID- 26631338 TI - Functional characterization of the RYR1 mutation p.Arg4737Trp associated with susceptibility to malignant hyperthermia. AB - Aside from the in vitro contracture test, genetic screening for causative RYR1 mutations is the established procedure to diagnose susceptibility to malignant hyperthermia (MH). However, currently only 34 out of more than 300 known RYR1 mutations have been confirmed to be causative for MH by experimental studies addressing their functional impact on intracellular calcium homeostasis. The RYR1 mutation p.Arg4737Trp has been recently detected in a German MH family. To evaluate the effects of that mutation on intracellular calcium handling, the response after stimulation with the RYR1 agonist 4-chloro-m-cresol was investigated in immortalized B lymphocytes containing the p.Arg4737Trp mutation and compared to the response of wild type RYR1 from unaffected family members and unrelated controls. Intracellular resting calcium was slightly but significantly elevated in mutation positive cells. Calcium release following stimulation with 4 chloro-m-cresol was significantly increased in B lymphocytes carrying the p.Arg4737Trp mutation compared to mutation negative controls. Hence, the functional properties of the RYR1 mutation p.Arg4737Trp are consistent with susceptibility to MH. Together with previously published data, the mutation has now been reported in three independent MH positive families. PMID- 26631339 TI - Proteomic analysis for early neurodegenerative biomarker detection in an animal model. AB - The exposure to xenobiotics in the early stages of life represents the most important component in the etiology of many neurodegenerative disorders. Proteomic analysis of plasma and brain samples from early life treated animal model was performed in order to identify early biomarkers of neurodegeneration. Two-dimensional gel electrophoresis followed by liquid chromatography-tandem mass spectrometry identified four proteins in the plasma of adolescent rats that deviated from the control group. Low expression levels of transthyretin and plasma transferrin, and the absence of long-chain fatty acid transport 1 were measured. On the other hand, the same proteomic approach was done on striatum of an adult rat model of neurodegeneration. Mitochondrial aspartate aminotransferase and voltage-dependent anion channel were under expressed, while mitochondrial malate dehydrogenase, myelin basic protein and ubiquitin-60S ribosomal protein L40 were absent in striatum of animal model compared to control group. Data show that early biomarkers for the diagnosis of neurodegeneration can be obtained by proteomic analysis, starting from adolescent age and the results highlight the time frame for the onset of neurodegeneration due to early exposure to xenobiotics. PMID- 26631340 TI - Neoadjuvant chemoradiotherapy for rectal cancer: how important is tumour regression? AB - BACKGROUND: Pathological complete response following neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer is associated with reduced local recurrence and improved long-term outcome. However, the prognostic value of a partial response, or of tumour regression in patients with metastatic disease, is less clear. METHODS: We present a single-centre cohort study of 205 patients with stage II-IV rectal cancer treated with surgery and neoadjuvant CRT between 2006 and 2013. Tumour regression was assessed using the Dworak system. RESULTS: The probability of 3-year recurrence-free survival (RFS) was 95% for Dworak grade 4, 82% for grade 3, 64% for grade 2 and 53% for grade 1 (P = 0.0005). In univariate regression analysis, Dworak grade was associated with RFS (hazard ratio (HR) 0.51, P < 0.0001; trend analysis) and cancer-specific survival (HR 0.52, P = 0.002). In multivariate analysis, Dworak grade remained an independent predictor of RFS (HR 0.62, P = 0.012), along with clinical metastases stage, resection margin status, the presence or absence of extramural venous invasion and type of surgical procedure. CONCLUSIONS: Tumour regression grade after neoadjuvant CRT was an independent prognostic factor for RFS, highlighting the importance of the degree of local response to CRT. PMID- 26631341 TI - Visual and instrumental shade matching using CIELAB and CIEDE2000 color difference formulas. AB - OBJECTIVES: To compare visual and instrumental shade matching performances using two shade guides and three color difference formulas. METHODS: One hundred dental students (DS) volunteers (35 males and 65 females) with normal color vision participated in the study. The spectral reflectance of 4 extracted human upper central incisors (UCI) and shade tabs from Vita Classical (VC) and Vita Toothguide 3D-Master (3D) shade guides were measured using a spectroradiometer (SP) under D65 illuminant (diffuse/0 degrees geometry) inside a viewing booth with a gray background. Color coordinates (CIE L*, a*, b*, C* and h degrees ) were calculated according to CIE D65 illuminant and CIE 2 degrees Standard Observer. Color coordinates of UCI were also evaluated using a dental spectrophotometer (EA - Easyshade Advance). DS used VC and 3D to visually select the best shade match for each UCI, under same experimental conditions used for the SP evaluation. Three color difference metrics (CIELAB, CIEDE2000(1:1:1) and CIEDE2000(2:1:1)) were used to calculate the best instrumental shade matching based on minimum color difference. RESULTS: The agreement between visual and instrumental shade matching was greater using SP (25-75%) than EA (0-25%). The percentage of best match for the visual assessment was more consistent using VC (23-55%) than 3D (19-34%). Considering the best performance (using SP and VC), the CIEDE2000(2:1:1) color difference formula showed the best estimate to the visual perception from DS. SIGNIFICANCE: Within the limitations of this study, combining the use of SP, CIEDE2000(2:1:1) and Vita Classical shade guide most closely represented the visual perception of DS. Instrumental shade determination should be accompanied by experienced human visual assessment. PMID- 26631342 TI - Severe phlegmon of the upper extremity with digital necrosis after a cat scratch. PMID- 26631343 TI - One-year results of needle fasciotomy and collagenase injection in treatment of Dupuytren's contracture: A two-centre prospective randomized clinical trial. AB - The objective of this study was to compare early and 1 year outcome of needle fasciotomy and collagenase injection for Dupuytren's disease. Inclusion criteria were primary Dupuytren's contracture excluding the thumb with a palpable cord and a total extension deficit, i.e. a fixed flexion from 30 degrees to 135 degrees with less than 60 degrees in the proximal interphalangeal joint. The most affected ray was randomized to either treatment at two centres. Passive extension deficits for each joint before and after treatment, and at 3 and 12 months, were recorded together with complications. A total of 96 rays in 93 patients were included. The average total extension deficits before treatment were 60 degrees or more in both groups, and were largely made up of contractures at the metacarpophalangeal joints. The deficits were reduced by 75% in both groups at 3 months and by 70% in both groups at 12 months. Four patients in the needle fasciotomy group and eight patients in the collagenase group had skin ruptures. At 3 months and 1 year, the outcomes of needle fasciotomy and collagenase injection are the same in Dupuytren's disease with predominantly metacarpophalangeal joint involvement. LEVEL OF EVIDENCE: 2. PMID- 26631344 TI - MatOrtho proximal interphalangeal joint arthroplasty: minimum 2-year follow-up. AB - The MatOrtho proximal interphalangeal replacement is a cementless cobalt-chromium metal-on-polyethylene mobile-bearing surface replacement arthroplasty. The aim of this study is to report the outcome and complications of this implant at a minimum of 2 years follow-up from a single institution. A retrospective case review was performed on all MatOrtho proximal interphalangeal joint replacements performed with a minimum of 2 years follow-up. Patient demographics, diagnosis, implant revision and other surgical interventions were recorded. Subjective and objective outcomes were evaluated at latest follow-up, including pain scores, range of motion, function and radiographic assessment. A total of 109 implants were inserted in 56 patients. Nine implants (six patients) were lost to follow up. Of the remaining 100 implants, 75 had been undertaken in females. The mean age at time of surgery was 64 years and the principal diagnosis was osteoarthritis in 74%. The mean follow-up was 47 months (range 24-77). Within the group there was a statistically significant diminution in pain. There was also an improvement in functional scores post-operatively. Improvement in range of motion was seen in those joints with a pre-operative range of motion greater than 20 degrees . Radiologically there was no evidence of loosening or of implant subsidence at final follow-up. The revision rate was 13%. Nine joints were revised to the NeuFlex (silicone rubber) prosthesis, three were converted to an arthrodesis and one had exchange of the MatOrtho prosthesis. The survival of the MatOrtho proximal interphalangeal joint arthroplasty was 85% at a minimum of 2 years follow-up. Patients can be advised that the procedure achieves good pain relief, improvement in functional scores and may improve range of motion. We would, however, caution against this implant's use in joints that are either stiff or have significant deformity and/or instability pre-operatively. PMID- 26631345 TI - Intraosseous suture fixation of a sagittal fracture of the distal phalanx. PMID- 26631346 TI - Dual Color Plasmonic Pixels Create a Polarization Controlled Nano Color Palette. AB - Color filters based upon nanostructured metals have garnered significant interest in recent years, having been positioned as alternatives to the organic dye-based filters which provide color selectivity in image sensors, as nonfading "printing" technologies for producing images with nanometer pixel resolution, and as ultra high-resolution, small foot-print optical storage and encoding solutions. Here, we demonstrate a plasmonic filter set with polarization-switchable color properties, based upon arrays of asymmetric cross-shaped nanoapertures in an aluminum thin-film. Acting as individual color-emitting nanopixels, the plasmonic cavity-apertures have dual-color selectivity, transmitting one of two visible colors, controlled by the polarization of the white light incident on the rear of the pixel and tuned by varying the critical dimensions of the geometry and periodicity of the array. This structural approach to switchable optical filtering enables a single nanoaperture to encode two information states within the same physical nanoaperture, an attribute we use here to create micro image displays containing duality in their optical information states. PMID- 26631347 TI - Effects of electromagnetic fields on the metabolism of lubricin of rat chondrocytes. AB - Electromagnetic fields (EMFs) can improve pain, stiffness and physical function in osteoarthritis (OA) patients and have been proposed for the treatment of OA. However, the precise mechanisms involved in this process are still not fully understood. In the present study, we investigated the effects of exposure for different durations with 75 Hz, 2.3 mT sinusoidal EMFs (SEMFs) on the metabolism of lubricin of rat chondrocytes cultured in vitro. Our results showed that SEMFs exposure promoted lubricin synthesis in a time-dependent manner, and the expression of transforming growth factor (TGF)-beta1 was also enhanced after SEMFs treatment. The up-regulation effect of the expression of lubricin under SEMF was partly reduced by SB431542, an inhibitor of TGF-RI kinase. The Smad pathway was also investigated in our study. Smad2 synthesis was higher in EMF exposed condition than in controls, whereas no effects were observed on inhibitory Smads (Smad6 and Smad7) production. Altogether, these data suggest that SEMF exposure can promote lubricin synthesis of rat chondrocytes in a time dependent manner and that the TGF-beta/Smads signaling pathway plays a partial role. PMID- 26631348 TI - Profiling of conserved non-coding elements upstream of SHOX and functional characterisation of the SHOX cis-regulatory landscape. AB - Genetic defects such as copy number variations (CNVs) in non-coding regions containing conserved non-coding elements (CNEs) outside the transcription unit of their target gene, can underlie genetic disease. An example of this is the short stature homeobox (SHOX) gene, regulated by seven CNEs located downstream and upstream of SHOX, with proven enhancer capacity in chicken limbs. CNVs of the downstream CNEs have been reported in many idiopathic short stature (ISS) cases, however, only recently have a few CNVs of the upstream enhancers been identified. Here, we set out to provide insight into: (i) the cis-regulatory role of these upstream CNEs in human cells, (ii) the prevalence of upstream CNVs in ISS, and (iii) the chromatin architecture of the SHOX cis-regulatory landscape in chicken and human cells. Firstly, luciferase assays in human U2OS cells, and 4C-seq both in chicken limb buds and human U2OS cells, demonstrated cis-regulatory enhancer capacities of the upstream CNEs. Secondly, CNVs of these upstream CNEs were found in three of 501 ISS patients. Finally, our 4C-seq interaction map of the SHOX region reveals a cis-regulatory domain spanning more than 1 Mb and harbouring putative new cis-regulatory elements. PMID- 26631349 TI - Understanding the 'work' of caseload midwives: A mixed-methods exploration of two caseload midwifery models in Victoria, Australia. AB - BACKGROUND: Caseload midwifery models are becoming more common in Australian maternity care. Little is known about how caseload midwifery compares with mainstream models of midwifery care in terms of both the organisation of the work and the meaning of the work for caseload midwives. AIM: To explore caseload and standard care midwives' views and experiences of midwifery work in two new caseload models in Victoria, Australia. METHODS: A mixed-methods approach was used. Quantitative data were collected using two cross-sectional surveys of midwives at the two study sites at the commencement of the caseload model and after two years. Qualitative data were collected using in-depth interviews with caseload midwives six months and two years after commencing in the role. Content analysis was used to analyse open-ended survey questions, and interview data were analysed thematically. Themes arising from these data sources were then considered using Normalization Process Theory. FINDINGS: Two themes emerged from the data. Caseload midwifery was a 'different' way of working, involving activity based work, working on-call, fluid navigation between work and personal time and avoiding burnout. Working in caseload was also perceived by caseload midwives to be 'real' midwifery, facilitating relationships with women, and requiring responsibility, accountability, autonomy and legitimacy in their practice. Perceptions of caseload work were influenced by understanding these differences in caseload work compared to mainstream maternity care. CONCLUSION: Increased understanding of the differences between caseload work and mainstream maternity models, and introducing opportunities to be exposed to caseload work may contribute to sustainability of caseload models. PMID- 26631350 TI - Sixty seconds on . . . pre-exposure prophylaxis. PMID- 26631351 TI - The determination of apoptosis rates on articular cartilages of ovariectomized rats with and without alendronate treatment. AB - Osteoporosis (OP) is a major health problem characterized by compromised bone strength. Osteoarthritis (OA) is a joint disease that progresses slowly and is characterized by breakdown of the cartilage matrix. Alendronate (ALN), a nitrogen containing bisphosphonate (BIS), inhibits bone loss and increases bone mineralization, and has been used clinically for the treatment of OP. It is still controversial whether BIS is effective in inhibiting the progression of OA. Chondrocyte apoptosis has been described in both human and experimentally induced OA models. In our study we aimed to detect whether ALN could protect articular cartilage from degeneration and reduce apoptosis rates in experimentally OA induced rats. For this rats were ovariectomized (ovex), nine weeks after operation rats were injected 30 ug/kg/week ALN subcutaneously for six weeks. After six weeks articular cartilages were obtained. We did Safranin O staining and Mankin and Pritzker scorings to evaluate degeneration and investigated the expressions of p53, cleaved caspase 3, Poly ADP-ribose (PAR), Poly ADP-ribose polymerase 1 (PARP 1), and applied TUNEL technique to determine apoptotis rates. We found a significant decrease in glycosaminoglycan (GAG) amount and increased apoptosis which indicates damage on articular cartilages of ovex rats. GAG amount was higher and apoptosis rate was lower on articular cartilages of ALN treated ovex rats compared to the ovex group. In contrary to studies showing that early ALN treatment has a protective effect, our study shows late ALN treatment has a chondroprotective effect on articular cartilage since we treated rats nine weeks after ovariectomy. PMID- 26631352 TI - EEG alpha frequency correlates of burnout and depression: The role of gender. AB - EEG alpha frequency band biomarkers of depression are widely explored. Due to their trait-like features, they may help distinguish between depressive and burnout symptomatology, which is often referred to as "work-related depression". The present correlational study strived to examine whether individual alpha frequency (IAF), power, and coherence in the alpha band can provide evidence for establishing burnout as a separate diagnostic entity. Resting EEG (eyes closed) was recorded in 117 individuals (42 males). In addition, the participants filled out questionnaires of burnout and depression. Regression analyses highlighted the differential value of IAF and power in predicting burnout and depression. IAF was significantly related to depressive symptomatology, whereas power was linked mostly to burnout. Moreover, seven out of twelve interactions between EEG indicators and gender were significant. Connectivity patterns were significant for depression displaying gender-related differences. The results offer tentative support for establishing burnout as a separate clinical syndrome. PMID- 26631353 TI - Novelty and emotion: Pupillary and cortical responses during viewing of natural scenes. AB - Given the remarkable similarities in the antecedent conditions-stimulus motivational relevance and novelty (i.e., probability of occurrence)-that elicit amplitude modulation of the late positive potential (LPP) and the pupillary dilation response, the present study examines whether these two indexes of orienting response reflect common processes that are responsible for modulatory patterns in motivationally relevant contexts. In the present study, the LPP and the pupillary dilation response were co-registered in a free-picture viewing context in which stimulus novelty was manipulated through repeated presentation of the same picture exemplar. More specifically, pictures depicting both emotional and neutral contents could be novel, that is never seen before in the course of the study, or repeated 4-8 times in a row (i.e., massed repetition). Results showed that, despite massed repetitions, the late positive potential amplitude continued to be highly modulated by picture content, whereas affective modulation of pupil dilation decreased with picture repetition. These findings indicate that, although the LPP and pupil dilation are similarly affected by motivational relevance during the viewing of novel pictures, they differ when pictures are highly familiar, possibly reflecting different functional meanings in the context of the orienting response. PMID- 26631354 TI - The experiences of nurses implementing the Modified Early Warning Score and a 24 hour on-call Mobile Intensive Care Nurse: An exploratory study. AB - AIMS AND OBJECTIVES: To explore experiences of nurses implementing and using the Modified Early Warning Score (MEWS) and a Mobile Intensive Care Nurse (MICN) providing 24-hour on-call nursing support. BACKGROUND: To secure patient safety in hospital wards, nurses may increase the quality of care using a tool to detect the failure of vital functions. Possibilities for support can be provided through on-call supervision from a qualified team or nurse. DESIGN: This exploratory qualitative investigation used focus group interviews with nurses from two wards of a university hospital in Norway. METHODS: A purposive sample of seven registered nurses was interviewed in focus groups. A semi-structured guide and an inductive thematic analysis were used to identify interview themes. RESULTS: Three themes emerged: (1) experiences with the early recognition of deterioration using the MEWS, (2) supportive collaboration and knowledge transfer between nurses and (3) a "new" precise language using the score for communicating with physicians. The use of scores and support were perceived as improving care for deteriorating patients and for supporting the collaboration of nurses with other professionals. CONCLUSION: In our study, nurses described increased confidence in the recognition of deteriorating patients and in the management of such situations. The non-critical attitude, supportive communication and interactive learning according to the MICN were essential elements for success. PMID- 26631355 TI - Improving hand surgery access and care through service redesign. AB - BACKGROUND: The hand surgery service in our major trauma centre comprised predominantly emergency surgery with poor theatre access, resulting in many cases being postponed and performed after hours and with low rates of supervision. METHOD: We report the results of a before-and-after study describing the change in processes and outcomes associated with a change in the model of care to a sequestered, area-wide hand surgery service. The study uses data from 12 months prior to and 12 months after the change in practice. RESULTS: The hand service experienced a 24.7% increase in demand for surgery in the first 12 months after the relocation. However, demand for overnight beds fell by 303%, the rate of specialist supervision increased from 23.5% to 81.3% (P < 0.0001), the time between admission and surgery fell from 5.1 to 2.7 h (P < 0.0001), the rate of cancellations fell from 21.8% to 7.7% (P < 0.0001), the proportion of emergency surgery conducted in normal hours increased from 65.8% to 93.6% (P < 0.0001), the 28-day unplanned reoperation rate fell from 1.2% to 0.5% (P = 0.02) and surgical time decreased to an equivalent of 41 half day operating sessions per year. CONCLUSION: These outcomes are in line with international experiences of service centralization. The project may be used as a template for practice change in other surgical fields. PMID- 26631356 TI - Embolic central retinal artery occlusion after subcutaneous auricular steroid injection. PMID- 26631357 TI - Static and Dynamic Performance of Complementary Inverters Based on Nanosheet alpha-MoTe2 p-Channel and MoS2 n-Channel Transistors. AB - Molybdenum ditelluride (alpha-MoTe2) is an emerging transition-metal dichalcogenide (TMD) semiconductor that has been attracting attention due to its favorable optical and electronic properties. Field-effect transistors (FETs) based on few-layer alpha-MoTe2 nanosheets have previously shown ambipolar behavior with strong p-type and weak n-type conduction. We have employed a direct imprinting technique following mechanical nanosheet exfoliation to fabricate high performance complementary inverters using alpha-MoTe2 as the semiconductor for the p-channel FETs and MoS2 as the semiconductor for the n-channel FETs. To avoid ambipolar behavior and produce alpha-MoTe2 FETs with clean p-channel characteristics, we have employed the high-workfunction metal platinum for the source and drain contacts. As a result, our alpha-MoTe2 nanosheet p-channel FETs show hole mobilities up to 20 cm(2)/(V s), on/off ratios up to 10(5), and a subthreshold slope of 255 mV/decade. For our complementary inverters composed of few-layer alpha-MoTe2 p-channel FETs and MoS2 n-channel FETs we have obtained voltage gains as high as 33, noise margins as high as 0.38 VDD, a switching delay of 25 MUs, and a static power consumption of a few nanowatts. PMID- 26631358 TI - Light-Induced Rearrangement of the beta5 Strand in the BLUF Photoreceptor SyPixD (Slr1694). AB - The structural changes that facilitate signal transduction in blue light sensors using FAD (BLUF) photoreceptors and confer the stability of the rearranged hydrogen bond network between flavin and protein in the signaling state are still poorly understood. Here, we investigate a semiconserved Trp residue in SyPixD (Slr1694) by isotope-edited vibrational spectroscopy and site-directed mutagenesis. In the signaling state, a beta-sheet structure involving the backbone of W91 is formed without apparent change of environment of the W91 indole side chain. Mutation of W91, however, significantly influences the stability of the light-adapted state, suggesting that backbone rigidity rather than discrete side-chain conformations govern the stability of the light-adapted state. On the basis of computational and crystallographic models, we interpret these changes as a +1 register shift of the beta2/beta5 interaction with an unaffected indole side-chain conformation, rather than a +2 register shift accompanied by an indole side-chain flip that was previously proposed on the basis of X-ray structures. PMID- 26631359 TI - Are Mobilities in Hybrid Organic-Inorganic Halide Perovskites Actually "High"? PMID- 26631360 TI - Does Nonadiabatic Transition State Theory Make Sense Without Decoherence? AB - We analyze thermal rate constants as computed with surface hopping dynamics and resolve certain inconsistencies that have permeated the literature. On one hand, according to Landry and Subotnik (J. Chem. Phys. 2012, 137, 22A513), without decoherence, direct dynamics with surface hopping overestimates the rate of relaxation for the spin-boson Hamiltonian. On the other hand, according to Jain and Subotnik (J. Chem. Phys. 2015, 143, 134107), without decoherence, a transition state theory with surface hopping underestimates spin-boson rate constants. In this Letter, we resolve this apparent contradiction. We show that, without decoherence, direct dynamics and transition state theory should not agree; agreement is guaranteed only with decoherence. We also show that, even though the effects of decoherence may be hidden for isoenergetic reactions, these decoherence failures are exposed for exothermic reactions. We believe these lessons are essential when interpreting surface hopping papers published in the literature without any decoherence corrections. PMID- 26631361 TI - Material Innovation in Advancing Organometal Halide Perovskite Functionality. AB - Organometal halide perovskites (OMHPs) have garnered much attention recently for their unprecedented rate of increasing power conversion efficiency (PCE), positioning them as a promising basis for the next-generation photovoltaic devices. However, the gap between the rapid increasing PCE and the incomplete understanding of the structure-property-performance relationship prevents the realization of the true potential of OMHPs. This Perspective aims to provide a concise overview of the current status of OMHP research, highlighting the unique properties of OMHPs that are critical for solar applications but still not adequately explained. Stability and performance challenges of OMHP solar cells are discussed, calling upon combined experimental and theoretical efforts to address these challenges for pioneering commercialization of OMHP solar cells. Various material innovation strategies for improving the performance and stability of OMHPs are surveyed, showing that the OMHP architecture can serve as a promising and robust platform for the design and optimization of materials with desired functionalities. PMID- 26631362 TI - Back to the Photovoltaic Future with Perovskites. PMID- 26631363 TI - Different responses of articular cartilage to strenuous running and joint immobilization. AB - OBJECTIVE: To compare the pathological changes in cartilage derived from rats that developed osteoarthritis either by joint immobilization or by strenuous treadmill running in order to better understand their respective pathomechanism. METHOD: A total of 24 male Wistar rats were randomly assigned to three groups: sedentary control (CON), immobilization (IM), and strenuous running (SR). For rats in the IM group, unilateral knee joint was immobilized in flexion. Rats in the SR group underwent treadmill running with high intensity. Eight weeks later, all animals were sacrificed. Femoral condyles were collected to take histological observation for cartilage characteristic and immunohistochemistry for collagen type II. In addition, cartilage samples were obtained to assess gene expression of aggrecan, collagen type II, biglycan, and fibromodulin by quantitative RT-PCR. RESULTS: Gross and histological observation showed osteoarthritic changes in groups SR and IM; however, more severe cartilage degradation was revealed in the latter. Proteoglycan and collagen II content decreased in groups SR and IM in comparison to group CON, with more loss in group IM. In group SR, mRNA levels in femoral cartilage were found to be unaltered for all the molecules measured. On the contrary, these molecules were significantly downregulated in group IM. CONCLUSION: Differences in gross observation, histological characteristics, and gene expression of proteoglycans and collagen II suggest that both knee immobilization and strenuous running would lead to degenerative change of cartilage, but at different stages of the degenerative process. PMID- 26631364 TI - beta-sitosterol interacts with pneumolysin to prevent Streptococcus pneumoniae infection. AB - Pneumolysin is one of the major virulence factors elaborated by Streptococcus pneumoniae; this toxin is a member of the cholesterol-dependent cytolysins. Engagement of cholesterol induces the formation of a multi-subunit complex by pneumolysin that lyses host cells by forming pores on the membrane. Because pneumolysin released by bacteria which have been killed by conventional antibiotics is still active, agents capable of directly attacking the toxin are considered advantageous against antimicrobials in the treatment of S. pneumoniae infections. Here we found that the phytosterol, beta-sitosterol, effectively protects against cell lysis caused by pneumolysin. This compound interacts with the toxin at Thr459 and Leu460, two sites important for being recognized by its natural ligand, cholesterol. Similar to cholesterol, beta-sitosterol induces pneumolysin oligomerization. This compound also protects cells from damage by other cholesterol-dependent toxins. Finally, this compound protects mice against S. pneumoniae infection. Thus, beta-sitosterol is a candidate for the development of anti-virulence agents against pathogens that rely on cholesterol-dependent toxins for successful infections. PMID- 26631365 TI - Diminishing striatal activation across adolescent development during reward anticipation in offspring of schizophrenia patients. AB - Schizophrenia is a severe psychiatric disorder associated with impaired fronto striatal functioning. Similar deficits are observed in unaffected siblings of patients, indicating that these deficits are linked to a familial risk for the disorder. Fronto-striatal deficits may arise during adolescence and precede clinical manifestation of the disorder. However, the development of the fronto striatal network in adolescents at increased familial risk for schizophrenia is still poorly understood. In this cross-sectional study, we investigate the impact of familial risk on fronto-striatal functioning across age related to reward anticipation and receipt in 25 adolescent offspring of schizophrenia patients (SZ offspring) and 36 age-matched healthy controls (range 10-19years). Subjects performed a reward task while being scanned with functional MRI. Overall response times and the amount of money won did not differ between the groups. Striatal activation during reward anticipation decreased across age in the SZ offspring, while it did not in the healthy controls. Activation in the orbitofrontal cortex during reward receipt did not differ between the groups. These results, taken together with data from adult schizophrenia patients and their siblings, indicate that the diminishing striatal activation across adolescence may signify a familial vulnerability for schizophrenia. PMID- 26631367 TI - Negative photoconductivity of InAs nanowires. AB - Negative photoconductivity is observed in InAs nanowires (NWs) without a surface defective layer. The negative photoconductivity is strongly dependent on the wavelength and intensity of the light, and is also sensitive to the environmental atmosphere. Two kinds of mechanisms are discerned to work together. One is related to gas adsorption, which is photodesorption of water molecules and photo assisted chemisorption of O2 molecules. The other one can be attributed to the photogating effect introduced by the native oxide layer outside the NWs. PMID- 26631366 TI - Inhibitory Control of Spanish-Speaking Language-Minority Preschool Children: Measurement and Association With Language, Literacy, and Math Skills. AB - Children's self-regulation, including components of executive function such as inhibitory control, is related concurrently and longitudinally with elementary school children's reading and math abilities. Although several recent studies have examined links between preschool children's self-regulation or executive function and their academic skill development, few included large numbers of Spanish-speaking language-minority children. Among the fastest growing segments of the U.S. school-age population, many of these children are at significant risk of academic difficulties. We examined the relations between inhibitory control and academic skills in a sample containing a large number of Spanish-speaking preschoolers. Overall, the children demonstrated substantial academic risk based on preschool-entry vocabulary scores in the below-average range. Children completed assessments of language, literacy, and math skills in English and Spanish, when appropriate, at the start and end of their preschool year, along with a measure of inhibitory control, the Head-Toes-Knees-Shoulders task, which was administered at the start of the preschool year in the child's dominant conversational language. Scores on this last measure were lower for children for whom it was administered in Spanish. For both English and Spanish outcomes, those scores were significantly and uniquely associated with higher scores on measures of phonological awareness and math skills but not vocabulary or print knowledge skills. PMID- 26631368 TI - Steroid sulfatase in the human MG-63 preosteoblastic cell line: Antagonistic regulation by glucocorticoids and NFkappaB. AB - Steroid sulfatase (STS) converts sulfated steroids into active forms in cells. Preosteoblastic cells possess STS, but its role and regulation in bone are unclear. We examined STS activity and gene expression during differentiation of human MG-63 preosteoblasts. STS activity and gene expression were decreased during differentiation in cells treated with osteogenic supplement containing dexamethasone (DEX). DEX also inhibited STS activity and expression in undifferentiated cells, and the glucocorticoid antagonist RU486 reversed DEX inhibition of STS. These data may have implications for glucocorticoid-induced osteoporosis. The NFkappaB activators lipopolysaccharide and phorbol myristate acetate increased STS expression in undifferentiated and differentiated MG-63 cells, while the NFkappaB inhibitor BAY-11-7082 partially blocked these responses. The antagonistic actions of glucocorticoids and NFkB on STS expression are similar to the regulation of inflammatory response proteins. We propose a model of STS regulation whereby inflammation leads to increased STS, resulting in increased estrogen, which modulates the inflammatory response. PMID- 26631369 TI - Interventions for treating gas gangrene. AB - BACKGROUND: Gas gangrene is a rapidly progressive and severe disease that results from bacterial infection, usually as the result of an injury; it has a high incidence of amputation and a poor prognosis. It requires early diagnosis and comprehensive treatments, which may involve immediate wound debridement, antibiotic treatment, hyperbaric oxygen therapy, Chinese herbal medicine, systemic support, and other interventions. The efficacy and safety of many of the available therapies have not been confirmed. OBJECTIVES: To evaluate the efficacy and safety of potential interventions in the treatment of gas gangrene compared with alternative interventions or no interventions. SEARCH METHODS: In March 2015 we searched: The Cochrane Wounds Group Specialized Register, The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), Ovid MEDLINE, Ovid EMBASE, EBSCO CINAHL, Science Citation Index, the China Biological Medicine Database (CBM-disc), the China National Knowledge Infrastructure (CNKI), and the Chinese scientific periodical database of VIP INFORMATION (VIP) for relevant trials. We also searched reference lists of all identified trials and relevant reviews and four trials registries for eligible research. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: We selected randomized controlled trials (RCTs) and quasi RCTs that compared one treatment for gas gangrene with another treatment, or with no treatment. DATA COLLECTION AND ANALYSIS: Independently, two review authors selected potentially eligible studies by reviewing their titles, abstracts and full-texts. The two review authors extracted data using a pre-designed extraction form and assessed the risk of bias of each included study. Any disagreement in this process was solved by the third reviewer via consensus. We could not perform a meta-analysis due to the small number of studies included in the review and the substantial clinical heterogeneity between them, so we produced a narrative review instead. MAIN RESULTS: We included two RCTs with a total of 90 participants. Both RCTs assessed the effect of interventions on the 'cure rate' of gas gangrene; 'cure rate' was defined differently in each study, and differently to the way we defined it in this review.One trial compared the addition of Chinese herbs to standard treatment (debridement and antibiotic treatment; 26 participants) against standard treatment alone (20 participants). At the end of the trial the estimated risk ratio (RR) of 3.08 (95% confidence intervals (CI) 1.00 to 9.46) favoured Chinese herbs. The other trial compared standard treatment (debridement and antibiotic treatment) plus topical hyperbaric oxygen therapy (HBOT; 21 participants) with standard treatment plus systemic HBOT (23 participants). There was no evidence of difference between the two groups; RR of 1.10 (95% CI 0.25 to 4.84). For both comparisons the GRADE assessment was very low quality evidence due to risk of bias and imprecision so further trials are needed to confirm these results.Neither trial reported on this review's primary outcomes of quality of life, and amputation and death due to gas gangrene, or on adverse events. Trials that addressed other therapies such as immediate debridement, antibiotic treatment, systemic support, and other possible treatments were not available. AUTHORS' CONCLUSIONS: Re-analysis of the cure rate based on the definition used in our review did not show beneficial effects of additional use of Chinese herbs or topical HBOT on treating gas gangrene. The absence of robust evidence meant we could not determine which interventions are safe and effective for treating gas gangrene. Further rigorous RCTs with appropriate randomisation, allocation concealment and blinding, which focus on cornerstone treatments and the most important clinical outcomes, are required to provide useful evidence in this area. PMID- 26631370 TI - Patient-related factors influence the risk of developing intestinal stoma complications in early post-operative period. AB - BACKGROUND: Few studies have investigated the risk factors associated with developing intestinal stoma complications using appropriate multivariable methods. We aimed to determine the prevalence of, and risk factors for, stomal complications. METHODS: A retrospective, case-control methodology was used to investigate 12 explanatory variables and four outcome variables in 202 consecutive patients receiving stomas in a district general hospital in the United Kingdom between January 2013 and December 2014. Univariable and multivariable logistic regression were used to calculate odds ratios (ORs). RESULTS: There were 69 complications (69/202; 34.2%) in the early post-operative period (median 12 months) in total, the most common being retraction (30.4%). Performance status (World Health Organization score 1 or more; OR 2.67; 95% confidence intervals (CIs) 1.33-5.33; P = 0.006) and body mass index (>30 kg/m2 ; OR 3.30; 95% CIs 1.61-6.78; P = 0.001) were significantly associated with developing complications in multivariable analysis. Surgery-related risk factors, such as time of day or week of operation and grade of surgeon, were not associated with the development of stoma complications. Thirty-eight patients (18.8%) died over the follow-up period, but mortality was not related to the development of stoma complications (1.01; 0.48-2.13, P = 0.98). CONCLUSION: Patient-related risk factors influence the risk of developing a stoma complication more than surgery-related risk factors. Preoperative and post operative interventions, planning, vigilance and management should be focussed to at-risk groups, particularly obese patients. PMID- 26631371 TI - Colorimetric Assay for the Detection of Typical Biomarkers for Periodontitis Using a Magnetic Nanoparticle Biosensor. AB - Periodontitis is a chronic disease which affects at least 10% of the population. If untreated, periodontitis can lead to teeth loss. Unfortunately, current diagnostic tests are limited in their sensitivity and specificity. In this study, a novel multiplex hand-held colorimetric diagnostic biosensor, using two typical inflammatory salivary biomarkers, Human Neutrophil Elastase (HNE) and Cathepsin G, was constructed as proof of concept to potentially detect periodontitis. The biosensing method was based on the measurement of proteolytic activity using specific proteases probes. These probes consist of specific proteases substrates covalently bound to a magnetic bead from one end and to the gold sensor surface by the other end. When intact, this renders the golden sensor black. Upon proteolysis, the cleaved magnetic beads will be attracted by an external magnet revealing the golden color of the sensor surface observable by the naked eye. The biosensor was capable of specific and quantitative detection of HNE and Cathepsin G in solution and in spiked saliva samples with a lower detection limit of 1 pg/mL and 100 fg/mL for HNE and Cathepsin-G, respectively. Examination of periodontitis patients' sample and a healthy control showed the potential of the multiplex biosensor to detect the presence of HNE and Cathepsin-G activity in situ. This approach is anticipated to be a useful biochip array amenable to low cost point-of-care devices. PMID- 26631372 TI - Ruth Hussey: Fire in her belly. PMID- 26631374 TI - Corrigendum. PMID- 26631373 TI - Mirtazapine in pregnancy and lactation - A systematic review. AB - Depression is common in pregnancy and associated with increased risk of adverse effects for the neonate. Treatment and prevention options include antidepressant therapy. The aim of this paper was to review the literature on safety of mirtazapine during pregnancy and lactation. In 31 papers a total of 390 cases of neonates exposed to mirtazapine during pregnancy or lactation have been described. There might be an association between mirtazapine and spontaneous abortion, however, this might be attributable to underlying psychiatric disease. An increased risk of major neonatal malformations associated with mirtazapine in pregnancy has not been reported. Although one study showed a nearly significant increase in occurrence of respiratory problems and hypoglycaemia, no indication of causality could be given. No other significant adverse effects on neonates were reported. Limited available data, four papers on 11 exposed neonates, suggest that use of mirtazapine during breastfeeding is safe due to a low relative infant dose. High plasma levels might be associated with increased body weight and sleep. However, the reported data are too scarce to come to a clear assessment of the risk of mirtazapine in lactation. No information is available on the use of mirtazapine in pregnancy and Poor Neonatal Adaptation Syndrome (PNAS) or neurobehavioral development at an age over one year. In conclusion, mirtazapine seems to be safe in pregnancy, especially regarding incidence of congenital malformations. There are not enough data available to come to a conclusion on the safety of mirtazapine during lactation. PMID- 26631375 TI - Acute macular neuroretinopathy associated with systemic lupus erythematosus. AB - Acute macular neuroretinopathy (AMN) is a rare disorder that presents with abrupt visual change with wedge-shaped or flower-like lesions pointing towards the fovea. Ischemic insults to the retinal capillary plexus may be important for development of this disease. While many case reports have been published on AMN, none have described AMN in association with systemic lupus erythematosus (SLE). Here, we report a case of AMN associated with newly-diagnosed SLE. We speculate that in patients with lupus flares, immune complex-mediated vascular injury and microvascular thrombosis may disrupt the deep retinal capillary network, causing ischemic damages to the outer retina and leading to the development of AMN. AMN can develop in patients with lupus flares, and must be considered as an SLE associated ophthalmologic complication. To the best of our knowledge, this is the first case report of AMN associated with SLE. PMID- 26631376 TI - Supergroup C Wolbachia, mutualist symbionts of filarial nematodes, have a distinct genome structure. AB - Wolbachia pipientis is possibly the most widespread endosymbiont of arthropods and nematodes. While all Wolbachia strains have historically been defined as a single species, 16 monophyletic clusters of diversity (called supergroups) have been described. Different supergroups have distinct host ranges and symbiotic relationships, ranging from mutualism to reproductive manipulation. In filarial nematodes, which include parasites responsible for major diseases of humans (such as Onchocerca volvulus, agent of river blindness) and companion animals (Dirofilaria immitis, the dog heartworm), Wolbachia has an obligate mutualist role and is the target of new treatment regimens. Here, we compare the genomes of eight Wolbachia strains, spanning the diversity of the major supergroups (A-F), analysing synteny, transposable element content, GC skew and gene loss or gain. We detected genomic features that differ between Wolbachia supergroups, most notably in the C and D clades from filarial nematodes. In particular, strains from supergroup C (symbionts of O. volvulus and D. immitis) present a pattern of GC skew, conserved synteny and lack of transposable elements, unique in the Wolbachia genus. These features could be the consequence of a distinct symbiotic relationship between C Wolbachia strains and their hosts, highlighting underappreciated differences between the mutualistic supergroups found within filarial nematodes. PMID- 26631377 TI - The miR-302/367 cluster: a comprehensive update on its evolution and functions. AB - microRNAs are a subclass of small non-coding RNAs that fine-tune the regulation of gene expression at the post-transcriptional level. The miR-302/367 cluster, generally consisting of five members, miR-367, miR-302d, miR-302a, miR-302c and miR-302b, is ubiquitously distributed in vertebrates and occupies an intragenic cluster located in the gene La-related protein 7 (LARP7). The cluster was demonstrated to play an important role in diverse biological processes, such as the pluripotency of human embryonic stem cells (hESCs), self-renewal and reprogramming. This paper provides an overview of the mir-302/367 cluster, discusses our current understanding of the cluster's evolutionary history and transcriptional regulation and reviews the literature surrounding the cluster's roles in cell cycle regulation, epigenetic regulation and different cellular signalling pathways. PMID- 26631378 TI - A systematic investigation of production of synthetic prions from recombinant prion protein. AB - According to the protein-only hypothesis, infectious mammalian prions, which exist as distinct strains with discrete biological properties, consist of multichain assemblies of misfolded cellular prion protein (PrP). A critical test would be to produce prion strains synthetically from defined components. Crucially, high-titre 'synthetic' prions could then be used to determine the structural basis of infectivity and strain diversity at the atomic level. While there have been multiple reports of production of prions from bacterially expressed recombinant PrP using various methods, systematic production of high titre material in a form suitable for structural analysis remains a key goal. Here, we report a novel high-throughput strategy for exploring a matrix of conditions, additives and potential cofactors that might generate high-titre prions from recombinant mouse PrP, with screening for infectivity using a sensitive automated cell-based bioassay. Overall, approximately 20,000 unique conditions were examined. While some resulted in apparently infected cell cultures, this was transient and not reproducible. We also adapted published methods that reported production of synthetic prions from recombinant hamster PrP, but again did not find evidence of significant infectious titre when using recombinant mouse PrP as substrate. Collectively, our findings are consistent with the formation of prion infectivity from recombinant mouse PrP being a rare stochastic event and we conclude that systematic generation of prions from recombinant PrP may only become possible once the detailed structure of authentic ex vivo prions is solved. PMID- 26631379 TI - Lst4, the yeast Fnip1/2 orthologue, is a DENN-family protein. AB - The folliculin/Fnip complex has been demonstrated to play a crucial role in the mechanisms underlying Birt-Hogg-Dube (BHD) syndrome, a rare inherited cancer syndrome. Lst4 has been previously proposed to be the Fnip1/2 orthologue in yeast and therefore a member of the DENN family. In order to confirm this, we solved the crystal structure of the N-terminal region of Lst4 from Kluyveromyces lactis and show it contains a longin domain, the first domain of the full DENN module. Furthermore, we demonstrate that Lst4 through its DENN domain interacts with Lst7, the yeast folliculin orthologue. Like its human counterpart, the Lst7/Lst4 complex relocates to the vacuolar membrane in response to nutrient starvation, most notably in carbon starvation. Finally, we express and purify the recombinant Lst7/Lst4 complex and show that it exists as a 1 : 1 heterodimer in solution. This work confirms the membership of Lst4 and the Fnip proteins in the DENN family, and provides a basis for using the Lst7/Lst4 complex to understand the molecular function of folliculin and its role in the pathogenesis of BHD syndrome. PMID- 26631380 TI - The Vicious Cycle: Pediatric Facial Trauma from Bicycling. AB - OBJECTIVES: Although prevention of head injuries through helmet use is widespread, there has been a paucity of inquiry and publicity regarding the potential for facial injury stemming from cycling. Our objectives included estimating the incidence of emergency department (ED) visits for bicycle-related facial trauma among the pediatric population and detailing injury patterns. STUDY DESIGN AND SETTING: Analysis of a nationwide database. METHODS: The National Electronic Injury Surveillance System, offered by the Consumer Product Safety Commission, was accessed for ED visits related to bicycle-related facial trauma among individuals 21 years old and younger. These data were used to estimate national incidence and examine patient demographics and injury characteristics. RESULTS: From 2010 to 2014, there were 5420 entries extrapolating to an estimated 178,457 ED visits for pediatric bicycle-related facial trauma. Median age was 8 years, and 71.9% of patients were male. Lacerations (63.1%), abrasions/contusions (27%), and fractures (7%) were most common, with fractures dramatically increasing in prevalence with age. Nasal fractures were the most common fracture type. Injury patterns varied by age. CONCLUSION: Bicycle-related facial trauma is prevalent among the pediatric population, with nearly 180,000 visits to EDs between 2010 and 2014. Soft tissue injuries predominated among all age groups, although fractures increased significantly with age. Knowledge of injury patterns described may be a useful adjunct assisting history, examination, and decision making regarding the use of medical imaging. There is a clear void in inquiry regarding the use of facial protection, reinforcing the need for further study into prevention and efforts to raise public awareness among youth. PMID- 26631381 TI - Lower fasting blood glucose in neurofibromatosis type 1. AB - Studies indicate a lower occurrence of diabetes mellitus (DM) in patients with neurofibromatosis type 1 (NF1). Fasting blood glucose (FBG) level is the main criterion used to diagnose DM and glucose intolerance. Therefore, this study compared FBG level between adults with NF1 and non-NF1 controls. We selected clinical records of 57 out of 701 individuals attending the Neurofibromatosis Outpatient Reference Center of the Clinics Hospital of the Federal University of Minas Gerais in Brazil. The selected patients with NF1 were matched to non-NF1 controls selected from the Brazilian Longitudinal Study of Adult Health according to sex, age (range, 35-74 years) and BMI at a ratio of 1:3. In both groups, individuals with DM were excluded. Median FBG level in the NF1 group (86 mg/dl (range, 56-127 mg/dl)) was lower than that in the non-NF1 control group (102 mg/dl (range, 85-146 mg/dl)) (P<0.001). Prevalence of FBG level >=100 mg/dl in the NF1 group (16%) was lower than that in the non-NF1 control group (63%) (P<0.05). The chance of a high FBG level was 89% lower in the NF1 group (odds ratio, 0.112; 95% CI, 0.067-0.188) (P<0.05). In conclusion, adults with NF1 showed a lower FBG level and a lower prevalence of high FBG level compared with non-NF1 controls. PMID- 26631382 TI - Changing Discourses in Climate Health: An Anti-disciplinary Perspective. PMID- 26631383 TI - Future Earth and EcoHealth: A New Paradigm Toward Global Sustainability and Health. PMID- 26631385 TI - To Cull, or Not To Cull, Bat is the Question. PMID- 26631386 TI - Standard method for ultrasound evaluation of renal arterial lesions. PMID- 26631387 TI - Decision Making Around Optimal Management of Liver-Limited Metastatic Colorectal Cancer. PMID- 26631388 TI - Pain in Hidradenitis Suppurativa: A Pilot Study. PMID- 26631389 TI - Chemokine Receptors CXCR3 and CCR6 and Their Ligands in the Liver and Blood of Patients with Chronic Hepatitis C. AB - We performed a comprehensive analysis of CCR6 and CXCR3 chemokine receptors and their ligands CCL20/MIP-3alpha, CXCL9/MIG, CXCL10/IP-10, and CXCL11/ITAC in the liver and blood of patients with chronic hepatitis C at different stages of the disease. TaqMan PCR was used to determine mRNA gene expression of chemokines and their receptors in liver specimens, xMAP multiplex analysis was performed to estimate the concentration of chemokines in blood plasma, and fl ow cytofluorometry was used to evaluate CCR6 and CXCR3 expression on peripheral blood lymphocyte populations. In the liver of patients with hepatitis C, mRNA expression of CXCL10, CCR6, and CXCR3 genes increases with fibrosis progression in the liver tissue. In the plasma, concentrations of all studied chemokines increased depending on the stage of liver fibrosis, CCR6 and CXCR3 expression was changed in various lymphocyte populations. Thus, chemokines are involved in the immunopathogenesis and fibrogenesis in chronic viral hepatitis C. The results suggest using these chemokines in the diagnosis and prognosis of the disease. PMID- 26631390 TI - CD30-positive Cutaneous Pseudolymphoma Caused by Tocilizumab in a Patient with Rheumatoid Arthritis: Case Report and Literature Review. PMID- 26631391 TI - Squamous Cell Carcinoma of the Skin has More Than Doubled Over the Last Decade in the UK. PMID- 26631392 TI - Impact of Intracoronary Adenosine on Myonecrosis in Patients with Unstable Angina Pectoris Undergoing Percutaneous Coronary Intervention. AB - BACKGROUND: In this study, we aimed to investigate the impact of prophylactic intracoronary adenosine administered during percutaneous coronary intervention (PCI) due to unstable angina pectoris on myonecrosis by measuring post-procedural levels of cardiac troponin I (cTnI) and creatine kinase-myocardial band (CK-MB). METHODS: A total of 122 patients with unstable angina undergoing PCI were included in this single-center, double-blind, randomized study. The patients were randomly allocated to adenosine and placebo groups. In the adenosine group, a single-dose of intracoronary adenosine (100 MUg for the right coronary artery and 150 MUg for the left coronary artery) was administered. Primary endpoint was post PCI myonecrosis, which was defined as abnormal levels of periprocedural cTnI. Secondary endpoints were defined as elevated cTnI levels [5 * upper limit of normal (ULN)], abnormal CK-MB levels, angiographic coronary flow measured by Thrombolysis In Myocardial Infarction (TIMI) frame count (TFC), the cumulative incidence of in-hospital death and in-hospital urgent target vessel revascularization (TVR). RESULTS: Clinical and angiographic characteristics of both adenosine (61 patients, 61 +/- 9 years) and placebo (61 patients, 59 +/- 10 years) groups were similar (p > 0.05 for all). Post-procedural abnormal cTnI levels in the adenosine group were significantly lower than the placebo group (32 % vs. 55 %, p: 0.011). cTnI >5 * ULN (21 % vs. 31 %, p: 0.217) and abnormal CK-MB levels (11 % vs. 19 %, p: 0.263) were similar in both groups. Post-procedural TFCs in the adenosine group were significantly lower than the placebo group (24 +/- 4 vs. 27 +/- 5, p: 0.004). In-hospital events including death and urgent TVR were not observed in either group. CONCLUSION: Intracoronary administration of single-dose adenosine in patients with unstable angina undergoing PCI is associated with decreased periprocedural myonecrosis and improved coronary blood flow. PMID- 26631393 TI - Autoantibody Profile of a Cohort of 78 Italian Patients with Mucous Membrane Pemphigoid: Correlation Between Reactivity Profile and Clinical Involvement. AB - Direct diagnosis of mucous membrane pemphigoid (MMP) is not easy. Circulating autoantibodies targeting bullous pemphigoid antigens of 180 kDa and 230 kDa (BP180 and BP230), alpha6beta4 integrin, laminin 332 and type VII collagen (Col VII) are not always present. The aims of this study were to characterize the humoral immune response of a cohort of Italian patients with MMP, its association with clinical involvement and severity, and to design an algorithm for efficient serological diagnosis. Seventy-eight MMP sera were studied retrospectively by indirect immunofluorescence on salt-split skin, enzyme-linked immunosorbent assay (ELISA) and immunoblotting. Indirect immunofluorescence on salt-split skin resulted in the most sensitive approach for diagnosis of MMP. BP180 was the major autoantigen in MMP patients with oral and cutaneous involvement. Significant associations were found between BP180 reactivity and oral and cutaneous localization of the lesions (p = 0.006), and between Col VII positivity and Setterfield severity score (p = 0.020). PMID- 26631394 TI - An Inducible, Large-Intestine-Specific Transgenic Mouse Model for Colitis and Colitis-Induced Colon Cancer Research. AB - BACKGROUND: Animal models are an important tool to understand intestinal biology. Our laboratory previously generated C57BL/6-Tg(Car1-cre)5Flt transgenic mice (CAC) with large-intestine-specific Cre recombinase (Cre) expression as a model to study colon health. AIM: To expand the utility of the CAC mouse model by determining the impact of chemically induced colitis on CAC transgene expression. METHODS: CAC mice were crossed to Rosa reporter mice (Rosa26R (flox/flox) ) with a lox-STOP-lox signal controlling beta-galactosidase (betagal) expression and then further crossed with Apc(CKO/CKO) mice in some experiments to delete Apc alleles (Apc (Delta580) ). Initially, 8-week-old CAC(Tg/WT);Rosa26R (flox/WT) ;Apc (Delta580/WT) mice were treated with dextran sulfate sodium (DSS) in drinking water (5 days, 0, 0.65, 1.35, or 2.0 %). Colon tissue damage and betagal labeling were analyzed 10 day after stopping DSS. Next, 8-week-old CAC(Tg/WT);Rosa26R(flox/flox) mice were treated with 0 or 1.35 % DSS, and colonic betagal labeling was assessed at 30 day post-DSS treatment. Finally, 10-week-old CAC(Tg/WT);Apc (Delta580/WT) mice were treated with DSS (0 or 2 %) for 5 days and colonic tumors were analyzed at 20 weeks. RESULTS: CAC(Tg/WT);Rosa26R (flox/WT) ;Apc (Delta580/WT) mice had a DSS dose-dependent increase in colon epithelial damage that correlated with increased epithelial betagal labeling at 10 days (r (2) = 0.9, beta = 0.75). The betagal labeling in CAC(Tg/WT);Rosa26R(flox/flox) mice colon remained high at 30 days, especially in the crypts of the healed ulcer. DSS also increased colon tumor incidence and multiplicity in CAC(Tg/WT);Apc (Delta580/WT) mice. CONCLUSIONS: DSS-mediated epithelial damage induces a persistent, Cre-mediated recombination of floxed alleles in CAC mice. This enables the examination of gene function in colon epithelium during experimental colitis and colitis-induced colon cancer. PMID- 26631395 TI - [Device therapy of chronic heart failure: Update 2015]. AB - Cardiac pacemakers, implantable cardioverter defibrillators (ICD) and systems for cardiac resynchronization therapy (CRT) represent an important component of heart failure therapy. Pacemakers only play a role in bradycardia-associated heart failure and require optimal programming to prevent ventricular desynchronization. Primary prophylactic ICD implantation is indicated in patients with a left ventricular ejection fraction of <= 35 %, clinical stages NYHA II-III and a life expectancy > 1 year. The CRT is indicated in patients with a left bundle branch block but only in individual cases for other QRS morphologies of < 150 ms duration. The combination of CRT with a pacemaker or defibrillator must be decided on an individual basis. Device therapy in heart failure should always include remote monitoring to detect events early and to implement treatment accordingly. New developments include quadripolar left ventricular leads and pacing from multiple sites simultaneously thus enabling better resynchronization. Stimulation for modulation of cardiac contractility and the autonomous nervous system are currently being clinically tested. The optimal utilization of device therapy improves the course of heart failure and prevents cardiac decompensation and fatalities. PMID- 26631396 TI - Human and animal health risk assessment of metal contamination in soil and plants from Ait Ammar abandoned iron mine, Morocco. AB - The goal of this paper is to investigate metal pollution in food chain and assess the resulting health risks to native citizens in Ait Ammar village. The results showed that cadmium (Cd), lead (Pb), and copper (Cu) concentrations in animal organs were above the metal concentration safety limit. Nevertheless, soils and plants from mining area were contaminated with iron (Fe), chromium (Cr), zinc (Zn), and Cr, Cu, Zn respectively. Cd concentrations in almost animal organs were higher than the acceptable daily upper limit, suggesting human consumption of this livestock meat and offal may pose a health risk. The estimated intake of Pb and Cd for Ait Ammar population could be a cause of concern because it exceeded the Provisional Tolerable Weekly Intake (PTWI) proposed by Joint Expert Committee on Food Additives (JECFA) in this area. Thus, conducting regular periodic studies to assess the dietary intake of mentioned elements are recommended. PMID- 26631397 TI - Development and validation of a novel, simple, and accurate spectrophotometric method for the determination of lead in human serum. AB - The determination of blood lead levels is the most useful indicator of the determination of the amount of lead that is absorbed by the human body. Various methods, like atomic absorption spectroscopy (AAS), have already been used for the detection of lead in biological fluid, but most of these methods are based on complicated, expensive, and highly instructed instruments. In this study, a simple and accurate spectroscopic method for the determination of lead has been developed and applied for the investigation of lead concentration in biological samples. In this study, a silica gel column was used to extract lead and eliminate interfering agents in human serum samples. The column was washed with deionized water. The pH was adjusted to the value of 8.2 using phosphate buffer, and then tartrate and cyanide solutions were added as masking agents. The lead content was extracted into the organic phase containing dithizone as a complexion reagent and the dithizone-Pb(II) complex was formed and approved by visible spectrophotometry at 538 nm. The recovery was found to be 84.6 %. In order to validate the method, a calibration curve involving the use of various concentration levels was calculated and proven to be linear in the range of 0.01 1.5 MUg/ml, with an R (2) regression coefficient of 0.9968 by statistical analysis of linear model validation. The largest error % values were found to be 5.80 and +11.6 % for intra-day and inter-day measurements, respectively. The largest RSD % values were calculated to be 6.54 and 12.32 % for intra-day and inter-day measurements, respectively. Further, the limit of detection (LOD) was calculated to be 0.002 MUg/ml. The developed method was applied to determine the lead content in the human serum of voluntary miners, and it has been proven that there is no statistically significant difference between the data provided from this novel method and the data obtained from previously studied AAS. PMID- 26631398 TI - Rainfall-induced nutrient losses from manure-fertilized farmland in an alluvial plain. AB - Nutrient transport and loss in farmlands are affected by factors such as land cover, fertilization, soil type, rainfall, and management practices. We investigated the temporal and spatial changes in macronutrient transport and loss after fertilization and precipitation in manure-fertilized eggplant farmland in an alluvial plain. Upon adding topical fertilizer, concentrations of most nutrients in runoff and groundwater increased, and nitrogen runoff increased from 22.11 to 35.81 kg/ha, although eggplant yield did not increase correspondingly. Incorporation of fertilizer by plowing reduced nutrient losses (nitrogen runoff/fertilizer decreased from 18.40 to 12.29 %). Measurements taken along the nutrient transport route (runoff, drainage ditch, groundwater, river water, and finally rainfall) revealed that concentrations of most nutrients declined at each stage. Nutrient characteristics varied by transport, and the forms of nitrogen and phosphorus differed greatly between runoff and groundwater (nitrate/nitrogen in runoff was ~43.49 %, while in groundwater ~5.41 %). Most nutrient concentrations in runoff decreased greatly during the planting season (total nitrogen decreased from 62.25 to 4.17 mg/L), correlated positively with temperature and stage of plant growth, but little temporal change was observed in groundwater. This field investigation during one planting season exemplifies the basic principles of nutrient loss and transport from manure-fertilized farmland in an alluvial plain. PMID- 26631399 TI - Fatal Thrombosis of a Flow Diverter due to Ibuprofen-related Antagonization of Acetylsalicylic Acid. PMID- 26631400 TI - Intradural Incarceration of the Conus Medullaris Above a Site of Thoracolumbar Spinal Stenosis. PMID- 26631401 TI - Management of iatrogenic crystalline lens injury occurred during intravitreal injection. AB - To evaluate the approach to management of iatrogenic crystalline lens injury occurred during intravitreal injection (IVI). The patients who were managed operatively or followed-up without intervention after the iatrogenic lens injury due to IVI were included in the study. Capsular breaks remained either quiescent or resulted in cataract formation in the patients with inadvertent crystalline lens capsule damage. Phacoemulsification surgery was performed in patients with cataract formation with lower fluidic settings. A total of 9 cases included in the study. Seven cases underwent phacoemulsification with intraocular lens implantation. Two cases remained as quiescent lens injury during the follow-up. In 2 cases, dislocation of lens fragments occurred during phacoemulsification where pars plana vitrectomy was performed at the same session. After iatrogenic crystalline lens injury, capsular damage could remain quiescent or progress to cataract formation. Although phacoemulsification surgery can be performed with appropriate parameters, lens fragment dislocation can be observed in cases with traumatic lens damage secondary to IVI. PMID- 26631402 TI - Does reducing gamete co-incubation time improve clinical outcomes: a retrospective study. AB - PURPOSE: The objective of this retrospective study was to determine whether patients undergoing in vitro fertilization (IVF) benefit from reducing the gamete co-incubation time. METHODS: Patients (n = 570) were enrolled, including 281 patients in the reduced incubation time group (2-h incubation) and 289 patients in the standard IVF group (18-h incubation). RESULTS: The observed outcomes, including the clinical pregnancy rate (CPR), implantation rate (IR), live birth rate (LBR), and miscarriage rate (MR), were similar between the two groups. When the data were divided into two subgroups based on the maternal age (<=30 and >30 years), the rates of top-quality embryos (30.83 vs. 25.89 %; p = 0.028), CPR (66.67 vs. 42.11 %; p = 0.013), and IR (41.90 vs. 31.25 %, p = 0.019) of the 2-h incubation group were significantly higher in the younger subgroup. However, for older patients, only a lower MR (7.59 vs. 20.83 %; p = 0.019) was achieved. Reducing the time of incubation still improved the CPR (OR = 1.993, 95 % CI 1.141 3.480) and MR (OR = 3.173, 95 % CI 1.013-9.936) in the younger and older subgroups, respectively, after it was adjusted for potential confounders. CONCLUSIONS: Reducing incubation time improves the clinical results of IVF, although the LBR is not statistically different between the 2- and 18-h incubation time groups. And the specific clinical outcomes of reducing incubation time varied between the >30-year-old and the <=30-year-old. PMID- 26631403 TI - The anti-Mullerian hormone (AMH) acts as a gatekeeper of ovarian steroidogenesis inhibiting the granulosa cell response to both FSH and LH. AB - PURPOSE: Anti Mullerian Hormone (AMH) has a negative and inhibitory role in many functions of human granulosa-lutein cells (hGCs) including notoriously the reduction of the aromatase CYP19A1 expression induced by follicle-stimulating hormone (FSH). No data have been provided on the possible role of AMH in modulating the response to luteinizing hormone (LH) (alone or combined with FSH) as well as its effect on other enzymes involved in steroidogenesis including aromatase P450scc. The aim of this study was to investigate the role of AMH as regulator of the basal and stimulated steroids production by hGCs. METHODS: Primary culture of hGCs were incubated with hormones AMH, LH, and FSH, alone or in combination. The CYP19A1 and P450scc messenger RNA (mRNA) expression, normalized by housekeeping ribosomal protein S7 (RpS7) gene, was evaluated by reverse transcriptase quantitative PCR (RT-qPCR). Each reaction was repeated in triplicate. Negative controls using corresponding amount of vehicle control for each hormone treatment were performed. RESULT: AMH did not modulate the basal mRNA expression of both aromatase genes at any of the concentrations tested. Meanwhile, the strong mRNA induction of CYP19A1 and P450scc generated by a 24-h gonadotropin treatment (alone and combined) was suppressed by 20 ng/ml AMH added to culture medium. CONCLUSIONS: These findings contribute in clarifying the relationship between hormones regulating the early phase of steroidogenesis confirming that AMH is playing a suppressive role on CYP19A1 expression stimulated by gonadotropin in hGCs. Furthermore, a similar inhibitory effect for AMH was observed on P450scc gene expression when activated by gonadotropin treatment. PMID- 26631405 TI - [Supplementary arthrolysis of the proximal interphalangeal joint of fingers in surgical treatment of Dupuytren's contracture]. AB - OBJECTIVE: Correction of residual flexion deformity of the proximal interphalangeal (PIP) joint after excision of diseased connective tissue in Dupuytren's contracture by stepwise arthrolysis. INDICATIONS: Flexion deformity of the PIP joint of 20 degrees or more after excision of the diseased connective tissue in Dupuytren's contracture. CONTRAINDICATIONS: Joint deformities, osteoarthrosis, intrinsic muscle contracture, instability of the PIP joint. SURGICAL TECHNIQUE: Arthrolysis of the PIP joint is performed by six consecutive steps: dissection of the remaining skin ligaments, opening the flexor tendon sheath by transverse incision at the distal end of the A2 pulley, dissection of the checkrein ligaments, dissection of the accessory collateral ligaments, releasing the palmar plate proximally, releasing the palmar plate up to its insertion at the middle phalanx base. POSTOPERATIVE MANAGEMENT: Dorsal plaster of Paris with extended fingers and compressive dressing in the palm for 2 days, occupational/physical therapy, static and possible dynamic extension splint several weeks/months. RESULTS: A total of 31 fingers in 28 patients with Dupuytren's contracture were evaluated an average of 22 months after arthrolysis of the PIP joint. In all, 26 joints with an average recurrent flexion contracture of 29 degrees were improved compared to the preoperative flexion contracture of 81 degrees ; 4 PIP joints with a recurrent flexion contracture averaging 60 degrees were worse. In one patient, PIP flexion contracture of 90 degrees was unchanged at follow-up although the joint could be extended intraoperatively to 10 degrees of flexion. PMID- 26631404 TI - Downregulation of adiponectin system in granulosa cells and low levels of HMW adiponectin in PCOS. AB - PURPOSE: The purpose of the study was to investigate changes in adiponectin system expression in granulosa cells (GCs) and high molecular weight adiponectin levels in serum and follicular fluid (FF) of 40 women with polycystic ovary syndrome (PCOS) compared to those in 40 women with normal ovary function. METHODS: Adiponectin (Adipo), adiponectin receptor 1 (AdipoR1), and adiponectin receptor 2 (AdipoR2) messenger RNA (mRNA) expression levels were measured using quantitative real-time polymerase chain reaction (qRT-PCR). High molecular weight (HMW) adiponectin protein concentration was evaluated by ELISA method. Data were analyzed using Student's t test and one-way ANOVA in SPSS 21 software. At oocyte retrieval, FF was aspirated and GCs were obtained from a pooled collection of FF per each patient. RESULTS: PCR results showed expression of adiponectin, AdipoR1, AdipoR2, follicle-stimulating hormone receptor (FSHR), and luteinizing hormone receptor (LHR) in GCs. After controlling body mass index (BMI) values, qRT-PCR demonstrated a decreased expression of adiponectin system in GCs of PCOS patients compared to those in controls (p = 0.001). There was a strong positive correlation among AdipoR1 and AdipoR2 expression and also among FSH and LH receptor expression. (Both r = 0.8, p = 0.001). There were low levels of high molecular weight adiponectin in the serum of PCOS patients with controlled ovarian hyperstimulation (30.19 +/- 4.3 ng/ml) compared to the controls (48.47 +/ 5.9 ng/ml) and in the FF of PCOS patients with controlled ovarian hyperstimulation (7.86 +/- 1.44 ng/ml) compared to the controls (14.22 +/- 2.01 ng/ml; p = 0.02). CONCLUSIONS: Lower expression of adiponectin and its receptors in GCs might be an important manifestation in gonadotropin-stimulated PCOS patients which could influence the physiologic adiponectin roles such as interaction with insulin and LH in induction of GC gene expression. PMID- 26631406 TI - Using the Specialization Framework to Determine Degree of Dietary Specialization in a Herbivorous Woodrat. AB - To be considered a dietary specialist, mammalian herbivores must consume large quantities of a plant species considered "difficult" with respect to nutrient or toxin content, and possess specialized adaptations to deal with plant defensive compounds or low nutritional content. Populations of Neotoma lepida in the Great Basin consume Juniperus osteosperma, a plant heavily defended by terpenes, but a detailed dietary analysis of this population is lacking. Therefore, we investigated the extent of dietary specialization in this species in comparison with the better-studied specialist species, N. stephensi. Microhistological analysis of feces from N. lepida revealed that greater than 90% of their diet in nature was comprised of juniper. In laboratory tolerance trials, N. lepida tolerated a diet of 80% J. osteosperma, similar to that observed for N. stephensi. There was no difference in the abilities of N. lepida and N. stephensi to metabolize hexobarbital, a proxy compound for terpene metabolism. In preference tests of native and non-native juniper species, N. lepida did not exhibit a preference for its native or co-occurring juniper, J. osteosperma, over the non-native species, J. monosperma, whereas N. stephensi preferred its native or co-occurring juniper J. monosperma over non-native J. osteosperma. Behavioral and habitat differences between these woodrat species lead to the categorization of N. stephensi as an obligate juniper specialist with a small range that overlaps that of its preferred food, J. monosperma, and N. lepida as a facultative juniper specialist with a large range, and only a portion of its distribution containing populations that feed extensively on J. osteosperma. PMID- 26631407 TI - Flight Tunnel Response of Male European Corn Borer Moths to Cross-Specific Mixtures of European and Asian Corn Borer Sex Pheromones: Evidence Supporting a Critical Stage in Evolution of a New Communication System. AB - Previous flight tunnel studies showed that 3-5 % of male European corn borer (ECB) moths, Ostrinia nubilalis, could fly upwind and make contact with sources releasing the sex pheromone of the closely related Asian corn borer (ACB), Ostrina furnacalis, [2:1 (Z)-12-tetradecenyl acetate (Z12-14:OAc) : (E)-12 teradecenyl acetate (E12-14:OAc)] and that 2-4 % of ACB males could similarly fly upwind to the sex pheromone blends of the ECB Z- [97:3 (Z)-tetradecenyl acetate (Z11-14:OAc) : (E)-tetradecenyl acetate (E11-14:Ac)] and E-strains (1:99 Z/E11 14:OAc) pheromones. The results supported the hypothesis that the evolution of the ACB pheromone system from an ECB-like ancestor included a stage in which males could be attracted to the unusual females emitting Z12- and E12-14:OAc while retaining their responsiveness to the ancestral pheromone blend of Z11- and E11-14:OAc. Here, we showed further that ECB E-strain males exhibited upwind oriented flight and source contacts to sources containing all combinations of ECB and ACB components. Maximal response levels were observed with the E-strain 99:1 E11/Z11-14:OAc blend, and high response levels also were observed with two other blends containing E11-14:OAc as the major component (E11:E12 and E11:Z12). Upwind flight and source contact also occurred at lower levels with the remaining blend combinations in which Z11-, E12-, or Z12-14:OAc was the major component. Our current results support the hypothesis concerning the evolution of ACB from an ECB-like ancester by showing that males were able to respond to females producing either the 12-14:Ac isomers, 11-14:Ac isomers, or even mixtures of all four components. PMID- 26631408 TI - Uremic parkinsonism with atypical phenotypes and radiologic features. AB - Uremic encephalopathy with bilateral basal ganglia lesions has been reported as an acute neurometabolic disease which shows reversible clinical course and brain imaging features. The exact nature and pathophysiology have not been well established. We encountered two patients who showed a relapsing and aggravating course and an atypical phenotype including parkinsonism with paroxysmal dystonic head tremor and acute onset monoparesis of the lower extremity. They also showed unusual radiological findings which revealed combined lesions in the basal ganglia and cortex, persistent hemorrhagic transformation, and focal ischemic lesion in the internal capsule. Herein, we present the unusual phenomenology with atypical radiologic findings and suggest the possible multifactorial pathogenesis of uremic encephalopathy. PMID- 26631409 TI - Occurrence of Tourmaline in Metasedimentary Rocks of the Isua Supracrustal Belt, Greenland: Implications for Ribose Stabilization in Hadean Marine Sediments. AB - Abiotic formation of RNA was important for the emergence of terrestrial life, but the acknowledged difficulties of generating and stabilizing ribose have often raised questions regarding how the first RNA might have formed. Previous researchers have proposed that borate could have stabilized ribose; however, the availability of borate on the early Earth has been the subject of intense debate. In order to examine whether borate was available on the early Earth, this study examined metasedimentary rocks from the Isua Supracrustal Belt. Garnet, biotite, and quartz comprise the major constituents of the examined rocks. Field relationships and the chemical compositions of the examined rocks suggest sedimentary origin. The present study found that garnet crystals contain a number of inclusions of tourmaline (a type of borosilicate mineral). All tourmaline crystals are Fe-rich and categorized as schorl. Both garnet and tourmaline often contain graphite inclusions and this close association of tourmaline with garnet and graphite has not been recognized previously. Garnet-biotite and graphite geothermometers suggest that the tourmaline in garnet experienced peak metamorphic conditions (~500 degrees C and 5 kbar). The mineralogical characteristics of the tourmaline and the whole rock composition indicate that the tourmaline formed authigenically in the sediment during diagenesis and/or early metamorphism. Clay minerals in modern sediments have the capability to adsorb and concentrate borate, which could lead to boron enrichment during diagenesis, followed by tourmaline formation under metamorphic conditions. Clay minerals, deposited on the early Archean seafloor, were the precursors of the garnet and biotite in the examined samples. The studied tourmaline crystals were most likely formed in the same way as modern tourmaline in marine sediments. Therefore, boron enrichment by clays must have been possible even during the early Archean. Thus, similar enrichment could have been possible during the Hadean, providing a stabilization agent for ribose. PMID- 26631410 TI - Cation dependencies and turnover rates of the human K+-dependent Na+-Ca2+ exchangers NCKX1, NCKX2, NCKX3 and NCKX4. AB - The Solute Carrier Family 24 (SLC24) belongs to the CaCA super family of Ca(2+)/cation antiporters and codes for five different K(+)- dependent Na(+)- Ca(2+) exchangers (NCKX1-5). NCKX proteins play a critical role in Ca(2+) homeostasis in a wide variety of biological processes such as vision, olfaction, enamel formation, Melanocortin-4-receptor-dependent satiety and skin pigmentation. NCKX transcripts are widely found throughout the brain. In this study we examine the differences between NCKX1-4 in terms of cation dependencies. We measured changes to Ca(2+) influx via the reverse exchange mode while manipulating external Ca(2+) or K(+) or internal Na(+) concentrations (External Ca(2+) Dependence, External K(+) Dependence and Internal Na(+) Dependence respectively); we also looked at the effect of external Na(+)/Ca(2+) competition and 3' 4'-Dichlorobenzamil on the transport of ions in HEK 293 cell lines. A fluorescence based assay was used to determine differences in transport kinetics of the four membrane spanning exchangers using the Michaelis-Menten constant (Km). Our results show that there are no significant differences between the NCKX isoforms to explain the variation in the specific expression pattern of these exchangers. PMID- 26631411 TI - A liquid biopsy for head and neck cancers. AB - Head and neck cancer patients often present with advanced metastatic disease resulting in a poor 5-year survival. Therefore, there is a need for non-invasive diagnostic tools that could complement conventional imaging to inform clinicians of patient outcomes and treatment responses. A liquid biopsy addresses this unmet clinical need; a simple peripheral blood draw could provide information about the disseminated disease in terms of circulating tumor cells and circulating tumor DNA. Moreover, detectable tumor DNA in the saliva of head and neck cancer patients could signify the early signs of the disease and present an opportunity for clinical intervention. This review provides an overview of the current literature with regard to the feasibility of such a test in the head and neck cancer field and highlights the need for such a test. PMID- 26631413 TI - Unusual presentation of an inguinoscrotal hernia. PMID- 26631414 TI - Poly(3,4-ethylenedioxythiophene)-Modified Electrodes for Microfluidics Pumping with Redox-Magnetohydrodynamics: Improving Compatibility for Broader Applications by Eliminating Addition of Redox Species to Solution. AB - A new approach using electrodes modified with poly(3,4-ethylenedioxythiophene) (PEDOT) was implemented to perform redox-magnetohydrodynamics (MHD) microfluidics and eliminate the need to add redox species to solution, thus removing interferences with detection, sample, and reagents for lab-on-a-chip applications. This accomplishment not only retains the unique properties of redox MHD pumping (i.e., programmable fluid speeds and flow patterns without the need for side walls, horizontal flat flow profiles, looping flow, no electrode corrosion, and no bubble formation), but also achieves a wider sustainable voltage range and currents that can be as much as 7+ times higher (and therefore correspondingly higher velocities) than in past studies involving unmodified electrodes and redox species in solution. PEDOT, a conducting polymer that has been shown to exhibit low cytotoxicity, was electropolymerized on microband gold electrodes (25 mm long *103 MUm wide). A cell (325 MUL) with distant side walls was formed by placing a 620 MUm thick poly(dimethylsiloxane), PDMS, gasket with an opening of 3.2 cm * 1.5 cm on the chip, and a glass slide lid prevented evaporation. A 0.37 T magnet under the chip generated a magnetic field perpendicular to the chip surface. The cell was filled with 0.095 M NaCl electrolyte containing 10 MUm polystyrene beads to visualize and quantify fluid flow using optical video microscopy. Fluid speeds of 590 MUm s(-1) were observed immediately after applying a potential step. A linear relationship between applied electronic current and fluid velocity was shown. Vertical flow profiles under applied current conditions were curved, with a weak parabolic fit. PMID- 26631412 TI - Transportation in the Interstitial Space of the Brain Can Be Regulated by Neuronal Excitation. AB - The transportation of substances in the interstitial space (ISS) is crucial for the maintenance of brain homeostasis, however its link to neuronal activity remains unclear. Here, we report a marked reduction in substance transportation in the ISS after neuronal excitation. Using a tracer-based method, water molecules in the interstitial fluid (ISF) could be specifically visualized in magnetic resonance (MR) imaging. We first observed the flow of ISF in the thalamus and caudate nucleus of a rat. The ISF flow was then modulated using a painful stimulation model. We demonstrated that the flow of ISF slowed significantly following neuronal activity in the thalamus. This reduction in ISF flow continued for hours and was not accompanied by slow diffusion into the ISS. This observation suggests that the transportation of substances into the ISS can be regulated with a selective external stimulation. PMID- 26631415 TI - Operational performance and analysis of two rabies vaccination campaigns in N'Djamena, Chad. AB - Transmission of rabies from animals to people continues despite availability of good vaccines for both human and animal use. The only effective strategy to achieve elimination of dog rabies and the related human exposure is to immunize dogs at high coverage levels. We present the analysis of two consecutive parenteral dog mass vaccination campaigns conducted in N'Djamena in 2012 and 2013 to advocate the feasibility and effectiveness for rabies control through proof of concept. The overall coverage reached by the intervention was >70% in both years. Monthly reported rabies cases in dogs decreased by more than 90% within one year. Key points were a cooperative collaboration between the three partner institutions involved in the control program, sufficient information and communication strategy to access local leaders and the public, careful planning of the practical implementation phase and the effective motivation of staff. The dynamic and semi to non-restricted nature of dog populations in most rabies endemic areas is often considered to be a major obstacle to achieve sufficient vaccination coverage. However, we show that feasibility of dog mass vaccination is highly dependent on human determinants of dog population accessibility and the disease awareness of dog owners. Consequently, prior evaluation of the human cultural and socio-economic context is an important prerequisite for planning dog rabies vaccination campaigns. PMID- 26631416 TI - Optimizing age of cytomegalovirus screening and vaccination to avert congenital disease in the US. AB - Cytomegalovirus (CMV) infection is the leading cause of congenital cognitive deficit, visual impairment and hearing loss in the US. Clinical trials are underway to evaluate the efficacy of CMV vaccine candidates in seronegative females. The optimal age of such vaccination depends on the interplay among age specific transmission dynamics, vaccine efficacy and vaccine waning. We developed an age-structured model of CMV transmission dynamics in the US and estimated age specific transmission rates of CMV based on age-stratified CMV prevalence, congenital infections per birth, breastfeeding patterns and demographic data. We found that the optimal age of vaccination depended on the duration of vaccine protection. For most scenarios, the optimal age of vaccination was between 19 and 21 years of age. However, for a rapidly waning vaccine, the optimal age of vaccination can shift to infants under 1 year. This shift arises when the duration of vaccine efficacy is too brief to offer appreciable protection during the child-bearing years. In this case, it becomes more effective to achieve indirect protection by reducing transmission from infants, the transmissibility from whom was estimated to be an order of magnitude higher than other age classes. Knowledge of vaccine waning is paramount to optimizing CMV vaccination and is thus a key parameter for longitudinal clinical evaluation. PMID- 26631417 TI - Genome sequence of the marine flavobacterium Croceitalea dokdonensis DOKDO 023 that contains proton- and sodium-pumping rhodopsins. AB - Bacteroidetes are considered as efficient degraders of the high-molecular-weight particulate organic matter that is present in the marine environment. Here, we report the first genome sequence of the genus Croceitalea that belongs to Flavobacteriia. Gratifying the reputation, the genome of Croceitalea dokdonensis DOKDO 023 encodes many hydrolytic enzymes for utilizing biopolymers, mainly polysaccharides and proteins. The genome also harbors two genes for microbial rhodopsins, proteorhodopsin and a recently discovered sodium pump. This research provides a genetic basis for better understanding of Croceitalea, as well as insights into the strategies adapted by a rhodopsin-containing photoheterotroph to thrive in the marine environment. PMID- 26631418 TI - Mechanisms for glyproline protection in hypercholesterolemia. AB - Comparative analysis of the hypocholesterolemic and antithrombotic action of small regulatory glyproline peptides (Pro-Gly-Pro, Arg-Pro-Gly-Pro and Pro-Gly Pro-Leu) was performed on an experimental hypercholesterolemia model of rats. Repeated intranasal introduction of glyproline peptides to fat-diet-fed animals led to more active functioning of the anticoagulation system (the anticoagulant and fibrinolytic properties of the plasma increased and platelet aggregation decreased) and to normalization of the total cholesterol level as a parameter of lipid metabolism. The largest anticoagulant and hypocholesterolemic effect was detected for the Pro-Gly-Pro-Leu peptide. Hypothetical mechanisms of antithrombotic and hypocholesterolemic effects of glyproline peptides are presented. PMID- 26631419 TI - Rosetta Stone of NLR Innate Immunity. AB - The formation of NLR inflammasomes is a central step in the initiation of the innate immune response. Two recent publications describe the structure of the NAIP2-NLRC4 inflammasome and derive an elegant model of NLR inflammasome formation, whereby binding of the pathogen-molecule-bound NLR NAIP2 to NLRC4 leads to the activation of NLRC4 and initiation of self-propagating NLRC4 inflammasome formation. PMID- 26631420 TI - Multimethod prediction of physical parent-child aggression risk in expectant mothers and fathers with Social Information Processing theory. AB - The Social Information Processing (SIP) model postulates that parents undergo a series of stages in implementing physical discipline that can escalate into physical child abuse. The current study utilized a multimethod approach to investigate whether SIP factors can predict risk of parent-child aggression (PCA) in a diverse sample of expectant mothers and fathers. SIP factors of PCA attitudes, negative child attributions, reactivity, and empathy were considered as potential predictors of PCA risk; additionally, analyses considered whether personal history of PCA predicted participants' own PCA risk through its influence on their attitudes and attributions. Findings indicate that, for both mothers and fathers, history influenced attitudes but not attributions in predicting PCA risk, and attitudes and attributions predicted PCA risk; empathy and reactivity predicted negative child attributions for expectant mothers, but only reactivity significantly predicted attributions for expectant fathers. Path models for expectant mothers and fathers were remarkably similar. Overall, the findings provide support for major aspects of the SIP model. Continued work is needed in studying the progression of these factors across time for both mothers and fathers as well as the inclusion of other relevant ecological factors to the SIP model. PMID- 26631421 TI - The relationship between parental presence and child sexual violence: Evidence from thirteen countries in sub-Saharan Africa. AB - There are compelling reasons to believe that orphans - many millions due to the AIDS epidemic - are more likely to be sexually victimized during childhood. Few studies have empirically investigated sexual violence disparities, and those that do suffer from methodological limitations and limited geographic scope. We used nationally representative data on female adolescents (15-17 years) from 13 countries in sub-Saharan Africa. We built multilevel logistic models to test for an association between the dependent variables (orphanhood and parental absence) and sexual violence, both within countries and pooled across all countries. Approximately 10% of adolescent girls reported past experiences of sexual violence; a third of those victimized were 14 years or younger at the time of their first forced encounter. Paternal orphaning (OR 1.36, p<=0.01), double orphaning (OR 1.47, p<=0.05), and paternal absence (OR 1.28; p<=0.05) were significantly associated with experiencing sexual violence in pooled analyses. Fewer findings reached significance within individual countries. Our findings suggest that the lack of a father in the home (due to death or absence) places girls at heightened risk for childhood sexual abuse; further research identifying pathways of vulnerability and resilience specific to this population is needed. Our findings also indicate that abuse often starts at an early age; thus promising programs should be adapted for younger age groups and rigorously tested. PMID- 26631422 TI - Beneficial effects of dexpanthenol on mesenteric ischemia and reperfusion injury in experimental rat model. AB - BACKGROUND AND AIM: It has been reported that intestinal ischemia-reperfusion (I/R) injury results from oxidative stress caused by increased reactive oxygen species. Dexpanthenol (Dxp) is an alcohol analogue with epitelization, anti inflammatory, antioxidant, and increasing peristalsis activities. In the present study, the aim was to investigate protective and therapeutic effects of Dxp against intestinal I/R injury. MATERIALS AND METHODS: Overall, 40 rats were assigned into five groups including one control, one alone Dxp, and three I/R groups (40-min ischemia; followed by 2-h reperfusion). In two I/R groups, Dxp (500 mg/kg, i.m.) was given before or during ischemia. The histopathological findings including apoptotic changes, and also tissue and serum biochemical parameters levels, were determined. Oxidative stress and ileum damage were assessed by biochemical and histological examination. In the control (n = 8) and alone Dxp (n = 8; 500 mg/kg, i.m. of Dxp was given at least 30 min before recording), groups were incised via laparotomy, and electrical activity was recorded from their intestines. In this experiment, the effect of Dxp on the motility of the intestine was examined by analyzing electrical activity. RESULTS: In ileum, oxidant levels were found to be higher, while antioxidant levels were found to be lower in I/R groups when compared with controls. Dxp approximated high levels of oxidants than those in the control group, while it increased antioxidant values compared with I/R groups. Histopathological changes caused by intestinal I/R injury and histological improvements were observed in both groups given Dxp. In the Dxp group, electrical signal activity markedly increased compared with the control group. CONCLUSIONS: Here, it was seen that Dxp had protective and therapeutic effects on intestinal I/R injury and gastrointestinal system peristaltism. PMID- 26631424 TI - Reactivity of aminophosphonic acids. Oxidative dephosphonylation of 1 aminoalkylphosphonic acids by aqueous halogens. AB - The reactions of 1-aminoalkylphosphonic acids with bromine-water, chlorine-water and iodine-water were investigated. The formation of phosphoric(v) acid, as a result of a halogen-promoted cleavage of the Calpha-P bond, accompanied by nitrogen release, was observed. The dephosphonylation of 1-aminoalkylphosphonic acids was found to occur quantitatively. In the reactions of 1 aminoalkylphosphonic acids with other halogen-water reagents investigated by (31)P NMR, scission of the Calpha-P bond was also observed, the reaction rates being comparable for bromine and chlorine, but much slower for iodine. PMID- 26631423 TI - Mating dynamics in a nematode with three sexes and its evolutionary implications. AB - Nematodes have diverse reproductive strategies, which make them ideal subjects for comparative studies to address how mating systems evolve. Here we present the sex ratios and mating dynamics of the free-living nematode Rhabditis sp. SB347, in which males, females and hermaphrodites co-exist. The three sexes are produced by both selfing and outcrossing, and females tend to appear early in a mother's progeny. Males prefer mating with females over hermaphrodites, which our results suggest is related to the female-specific production of the sex pheromones ascr#1 and ascr#9. We discuss the parallels between this system and that of parasitic nematodes that exhibit alternation between uniparental and biparental reproduction. PMID- 26631425 TI - Hydride Generation for Headspace Solid-Phase Extraction with CdTe Quantum Dots Immobilized on Paper for Sensitive Visual Detection of Selenium. AB - A low-cost, simple, and highly selective analytical method was developed for sensitive visual detection of selenium in human urine both outdoors and at home, by coupling hydride generation with headspace solid-phase extraction using quantum dots (QDs) immobilized on paper. The visible fluorescence from the CdTe QDs immobilized on paper was quenched by H2Se from hydride generation reaction and headspace solid-phase extraction. The potential mechanism was investigated by using X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) as well as Density Functional Theory (DFT). Potential interferences from coexisting ions, particularly Ag(+), Cu(2+), and Zn(2+), were eliminated. The selectivity was significantly increased because the selenium hydride was effectively separated from sample matrices by hydride generation. Moreover, due to the high sampling efficiency of hydride generation and headspace solid phase extraction, the sensitivity and the limit of detection (LOD) were significantly improved compared to conventional methods. A LOD of 0.1 MUg L(-1) and a relative standard deviation (RSD, n = 7) of 2.4% at a concentration of 20 MUg L(-1) were obtained when using a commercial spectrofluorometer as the detector. Furthermore, a visual assay based on the proposed method was developed for the detection of Se, 5 MUg L(-1) of selenium in urine can be discriminated from the blank solution with the naked eye. The proposed method was validated by analysis of certified reference materials and human urine samples with satisfactory results. PMID- 26631426 TI - The law of Yin and Yang for controlled drugs ecosystem: Maximal analgesia with minimal abuse. PMID- 26631427 TI - Molecular Taxonomy and Tumourigenesis of Colorectal Cancer. AB - Over the last 5 years there has been a surge in interest in the molecular classification of colorectal cancer. The effect of molecular subtyping on current treatment decisions is limited to avoidance of adjuvant 5-fluorouracil chemotherapy in stage II microsatellite unstable-high disease and avoidance of epidermal growth factor receptor-targeted antibodies in extended RAS mutant tumours. The emergence of specific novel combination therapy for the BRAF-mutant cohort and of the microsatellite unstable-high cohort as a responsive group to immune checkpoint inhibition shows the growing importance of a clinically relevant molecular taxonomy. Clinical trials such as the Medical Research Council FOCUS4 trial using biomarkers to select patients for specific therapies are currently open and testing such approaches. The integration of mutation, gene expression and pathological analyses is refining our understanding of the biological subtypes within colorectal cancer. Sharing of data sets of parallel sequencing and gene expression of thousands of cancers among independent groups has allowed the description of disease subsets and the need for a validated consensus classification has become apparent. This biological understanding of the disease is a key step forward in developing a stratified approach to patient management. The discovery of stratifiers that predict a response to existing and emerging therapies will enable better use of these treatments. Improved scientific understanding of the biological characteristics of poorly responsive subgroups will facilitate the design of novel biologically rational combinations. Novel treatment regimens, including the combination of new drugs with radiation, and the discovery and validation of their associated predictive biomarkers will gradually lead to improved outcomes from therapy. PMID- 26631428 TI - Pharmacokinetics and Tolerability of Lurasidone in Children and Adolescents With Psychiatric Disorders. AB - PURPOSE: The aim of this study was to evaluate the pharmacokinetic (PK) profile and tolerability of lurasidone in children and adolescents with a range of psychiatric disorders. METHODS: This multicenter, open-label, single and multiple ascending-dose study of the PK profile of lurasidone (20, 40, 80, 120, and 160 mg/d) enrolled outpatients aged 6 to 17 years with a diagnosis of attention deficit/hyperactivity disorder, bipolar spectrum disorder, or other psychiatric disorder. Serial blood samples were collected for analysis of PK parameters, including Cmax, Tmax, and AUC0-24. FINDINGS: Exposure (Cmax and AUC0-24) to lurasidone and its active metabolites showed linear increases across the entire dose range. Slope estimates (95% CI) across the dose range studied was 0.90 ng . h/mL (0.74-1.06) for AUC0-24 and 0.70 ng/mL (0.52-0.87) for Cmax on day 10 or 12. Lurasidone exposure, after multiple-dose administration in this child and adolescent population, was similar to exposure observed at steady state in adults. The effects of dose on exposure to the 3 active metabolites of lurasidone were linear and similar after the administration of single and multiple doses. Adverse events were qualitatively similar to those reported in adults. Discontinuations due to adverse events were dose related, with doses <120 mg/d being better tolerated than higher doses, especially in younger children. IMPLICATIONS: In this child and adolescent population, exposure parameters for lurasidone and its active metabolites were dose proportional in the range of 20 to 160 mg/d after the administration of single and multiple doses. These results suggest that lurasidone doses <120 mg/d were better tolerated compared with higher doses, especially in younger children. ClinicalTrials.gov identifier: NCT01620060. PMID- 26631429 TI - Pregnancy and childbirth in women with autoimmune hepatitis is safe, even in compensated cirrhosis. AB - INTRODUCTION: Autoimmune hepatitis (AIH) is a liver disease that primarily affects women. Many become ill during childbearing age, and medication can be lifelong. Few studies exist on pregnancy outcome in women with AIH. Objectives The aim was to assess the outcome of women with AIH and their children during pregnancy and postpartum. MATERIALS AND METHODS: Sixty-four women from a well characterised cohort with AIH filled out a questionnaire with information about their disease, miscarriage/abortion, pregnancies and potential birth defects in 2012. In 2004, 106 women answered the same questionnaire and their results were analysed along with the new questionnaires. RESULTS: One hundred and thirty-eight women have completed the questionnaire and 100 children have been born by 58 women. Fifty-seven women (41%) had cirrhosis. In 84% of the pregnancies, the AIH was stable or milder, 32% had an increase in activity postpartum. The proportion of preterm births (before week 38) was 22%, caesarean sections 17%, malformations 3%, and two children died. Twenty-three women with cirrhosis had children after diagnosis of cirrhosis but without more complications than for non-cirrhotic mothers. However, they did have a higher prevalence of caesarean sections. CONCLUSION: Pregnancy and childbirth in AIH appear to be safe for both child and mother, even in women with compensated liver cirrhosis. PMID- 26631431 TI - Solvent-induced Mn(II)/Zn(II)/Co(II) organopolymolybdate compounds constructed by bis-pyridyl-bis-amide ligands through the Mo-N bond: synthesis, structures and properties. AB - Three transition metal organopolymolybdate hybrid compounds, namely, H2[Mn(H2O)4L3(gamma-Mo8O26)] 8H2O (), H[M2(CH3O)(H2O)6L3(gamma-Mo8O26)] [M = Zn () and Co ()] [L = 1,4-bis(3-pyridinecarboxamido)benzene] have been synthesized under solvothermal conditions and characterized by IR spectroscopy, TG analysis, powder XRD and single-crystal X-ray diffraction. Compounds were obtained by the one-pot method, and the mixture of methanol and water with different ratios was used as the solvent. In compound , the gamma-Mo8 anions were connected with pyridine groups of ligand L by the Mo-N bond, forming an uncommon 1D gamma-Mo8-L chain. The adjacent chains were connected by [MnL2(H2O)4](2+) moieties through hydrogen bonding interaction to construct a 2D supramolecular network. Compounds and are isostructural, which show a 3D 2,4,6-connected {4(4).6(2)}{4(4).6(6).8(4).10}{6} framework. The gamma-Mo8 anions were connected by [M(H2O)2(CH3O)](+) [M = Zn () and Co ()] subunits forming 1D M-Mo8 chains, which were connected by [ML2(H2O)4](2+) moieties to construct a 2D layer. In compounds and , there also exist the same 1D gamma-Mo8-L chains as in , which extended the 2D networks to 3D frameworks. The Mo-N bond with pyridyl groups was formed under the solvothermal conditions, which is scarcely reported to our knowledge. The effect of the solvent on the assembly of the title compounds and the formation of the Mo-N bond, as well as the role of metal-organic moieties on the construction of diverse organopolymolybdate compounds have been discussed in detail. Furthermore, the electrochemical and photocatalytic properties of have been investigated. PMID- 26631430 TI - Sex-specific increase in susceptibility to metabolic syndrome in adult offspring after prenatal ethanol exposure with post-weaning high-fat diet. AB - Prenatal ethanol exposure (PEE) is an established risk factor for intrauterine growth retardation. The present study was designed to determine whether PEE can increase the susceptibility of high-fat diet (HFD)-induced metabolic syndrome (MS) in adult offspring in a sex-specific manner, based on a generalized linear model analysis. Pregnant Wistar rats were administered ethanol (4 g/kg.d) from gestational day 11 until term delivery. All offspring were fed either a normal diet or a HFD after weaning and were sacrificed at postnatal week 20, and blood samples were collected. Results showed that PEE reduced serum adrenocorticotropic hormone (ACTH) and corticosterone levels but enhanced serum glucose, insulin, insulin resistant index (IRI), triglyceride and total cholesterol (TC) concentrations. Moreover, the analysis showed interactions among PEE, HFD and sex. In the PEE offspring, HFD aggravated the decrease in ACTH and corticosterone levels and further increased serum glucose, insulin, triglyceride and TC levels. The changes of serum ACTH, glucose and IRI levels in the female HFD rats were greater than those in the male HFD rats. Our findings suggest that PEE enhances the susceptibility to MS induced by HFD in a sex-specific manner, which might be primarily associated with the neuroendocrine metabolic programming by PEE. PMID- 26631432 TI - Human Disease Insight: An integrated knowledge-based platform for disease-gene drug information. AB - The scope of the Human Disease Insight (HDI) database is not limited to researchers or physicians as it also provides basic information to non professionals and creates disease awareness, thereby reducing the chances of patient suffering due to ignorance. HDI is a knowledge-based resource providing information on human diseases to both scientists and the general public. Here, our mission is to provide a comprehensive human disease database containing most of the available useful information, with extensive cross-referencing. HDI is a knowledge management system that acts as a central hub to access information about human diseases and associated drugs and genes. In addition, HDI contains well-classified bioinformatics tools with helpful descriptions. These integrated bioinformatics tools enable researchers to annotate disease-specific genes and perform protein analysis, search for biomarkers and identify potential vaccine candidates. Eventually, these tools will facilitate the analysis of disease associated data. The HDI provides two types of search capabilities and includes provisions for downloading, uploading and searching disease/gene/drug-related information. The logistical design of the HDI allows for regular updating. The database is designed to work best with Mozilla Firefox and Google Chrome and is freely accessible at http://humandiseaseinsight.com. PMID- 26631433 TI - Successful treatment of multi-focal XDR tuberculous osteomyelitis. AB - We herein describe the nosocomial transmission of a pre-XDR or MDR case of pulmonary tuberculosis in a HIV-negative health care worker in an area endemic for MDR and XDR tuberculosis. Following inadequate therapy and non-compliance, he presented with extra-pulmonary XDR tuberculosis in the form of multi-focal osteomyelitis and encysted pleural effusion. He was cured after two years of treatment with various anti-tuberculous drugs in addition to interferon gamma. PMID- 26631434 TI - High frequency of Panton-Valentine leukocidin in Staphylococcus aureus causing pediatric infections in the city of Cartagena-Colombia. AB - Panton-Valentine leucocidin (PVL) is a pore-forming toxin that has been epidemiologically associated with CA-MRSA infections. However, its role in the pathogenicity of Staphylococcus aureus is still unclear. We evaluated the prevalence of PVL-coding genes in methicillin-resistant (MRSA) and methicillin sensitive (MSSA) isolates that cause infections in pediatric patients in the city of Cartagena, Colombia. We obtained S. aureus isolates from patients at the Napoleon Franco Pareja Children's Hospital in Cartagena. Then, we evaluated the presence of the nuc, mecA, and PVL genes in these isolates by multiplex PCR and determined the antibiotic susceptibility profiles using CLSI standards. We further correlated methicillin susceptibility and the presence of PVL genes with clinical variables. Overall PVL prevalence in S. aureus isolates was 73.91%, with a frequency of 80.92% among MRSA isolates and 67.59% among MSSA. We found a correlation between erythromycin resistance and lack of PVL and found that PVL+ cases were more common in older patients. We found a high PVL prevalence in both MRSA and MSSA isolates, in concordance with previous regional reports. PMID- 26631435 TI - The detection and antimicrobial susceptibility profile of Shigella isolates from meat and swab samples at butchers' shops in Gondar town, Northwest Ethiopia. AB - Food borne pathogens are major causes of deaths, illnesses and billions of dollars of expenses. The burden of food borne illness is worsened by the ever increasing rate of antimicrobial resistance microbes. Shigella, a bacterial pathogen associated with food, is reported to account for higher prevalence rates of food borne illness in different settings. A cross-sectional study was conducted from February 10 to June 30, 2013, at the butcher houses of Gondar town in the Northwest of Ethiopia to assess the prevalence and antimicrobial susceptibility pattern of Shigella. Cattle raw meat and swab samples from selected critical control points, including knives, chopping boards, and the hands and noses of butchers, were collected and analyzed. The identification of Shigella was carried out using colony characteristics, the Gram reaction, and biochemical tests. Antimicrobial susceptibility testing was performed using the Kirby-Bauer disc diffusion method. The overall hygienic status of the butcher shops was also assessed using a checklist. An observational analysis revealed that the sanitary condition of the butcher shops and their premises was poor. Of 306 samples screened, 10.5% were positive for Shigella. Approximately 7.4% of meat samples and 10.2% of swab samples were contaminated with Shigella. Out of the total Shigella isolates, 90.6%, 46.9%, 18.8% and 9.4% were resistant to ampicillin, amoxicillin, ceftriaxone and tetracycline, respectively. A multidrug resistance pattern was recorded in 27.8% of the isolates. In conclusion, the safety of meat sold at Gondar butchers houses was poor. The identified Shigella isolates showed high levels of drug resistance and multidrug resistance patterns for commonly used antimicrobials in veterinary and human medicine. Practicing wise use of antimicrobials and strict sanitary interventions at different critical control points is strongly recommended, in addition to further in-depth studies to prevent unprecedented consequences from shigellosis. PMID- 26631436 TI - Distribution and factors associated with Salmonella enterica genotypes in a diverse population of humans and animals in Qatar using multi-locus sequence typing (MLST). AB - Salmonella enterica is one of the most commonly reported causes of bacterial foodborne illness around the world. Understanding the sources of this pathogen and the associated factors that exacerbate its risk to humans will help in developing risk mitigation strategies. The genetic relatedness among Salmonella isolates recovered from human gastroenteritis cases and food animals in Qatar were investigated in the hope of shedding light on these sources, their possible transmission routes, and any associated factors. A repeat cross-sectional study was conducted in which the samples and associated data were collected from both populations (gastroenteritis cases and animals). Salmonella isolates were initially analyzed using multi-locus sequence typing (MLST) to investigate the genetic diversity and clonality. The relatedness among the isolates was assessed using the minimum spanning tree (MST). Twenty-seven different sequence types (STs) were identified in this study; among them, seven were novel, including ST1695, ST1696, ST1697, ST1698, ST1699, ST1702, and ST1703. The pattern of overall ST distribution was diverse; in particular, it was revealed that ST11 and ST19 were the most common sequence types, presenting 29.5% and 11.5% within the whole population. In addition, 20 eBurst Groups (eBGs) were identified in our data, which indicates that ST11 and ST19 belonged to eBG4 and eBG1, respectively. In addition, the potential association between the putative risk factors and eBGs were evaluated. There was no significant clustering of these eBGs by season; however, a significant association was identified in terms of nationality in that Qataris were six times more likely to present with eBG1 compared to non-Qataris. In the MST analysis, four major clusters were presented, namely, ST11, ST19, ST16, and ST31. The linkages between the clusters alluded to a possible transmission route. The results of the study have provided insight into the ST distributions of S. enterica and their possible zoonotic associations in Qatar. PMID- 26631437 TI - Upper-normal waist circumference is a risk marker for metabolic syndrome in normal-weight subjects. AB - BACKGROUND AND AIMS: To elucidate implication of upper-normal waist circumference (WC), we examined whether the normal range of WC still represents a risk of metabolic syndrome (MetS) or non-adipose MetS components among normal-weight subjects. METHODS AND RESULTS: A total of 173,510 persons (100,386 men and 73,124 women) with normal WC (<90/80 cm in men/women) and body mass index (BMI) of 18.5 24.9 were included. Subjects were categorized as having low, moderate, and upper normal WC for those with WC < 80, 80-84, and 85-89 cm in men and <70, 70-74, and 75-79 cm in women, respectively. The prevalence of all the non-adipose MetS components (e.g. prediabetes and borderline dyslipidemia) was significantly higher in subjects with upper-normal WC on comparison with those with low WC. Overall, the prevalence of MetS (having three or more of four non-adipose MetS components) gradually increased with increasing WC (12%, 21%, and 27% in men and 11%, 14%, and 19% in women for low, moderate, and upper-normal WC, respectively). Moreover, the risk of having a greater number of MetS components increased in subjects with upper-normal WC compared with those with low WC (odds ratios for the number of one, two, three, and four MetS components: 1.29, 1.81, 2.53, and 2.47 in men and 1.16, 1.55, 1.49, and 2.20 in women, respectively). CONCLUSION: Upper-normal WC represents a risk for acquiring a greater number of MetS components and the early stage of MetS components (prediabetes and borderline dyslipidemia), after adjusting for BMI, in a large general population with normal WC and BMI. PMID- 26631438 TI - (E)-2-Cyano-3-(substituted phenyl)acrylamide analogs as potent inhibitors of tyrosinase: A linear beta-phenyl-alpha,beta-unsaturated carbonyl scaffold. AB - In this study, we synthesized (E)-2-cyano-3-(substituted phenyl)acrylamide (CPA) derivatives which possess a linear beta-phenyl-alpha,beta-unsaturated carbonyl scaffold and examined their inhibitory activities against tyrosinase. CPA analogs exerted inhibitory activity against mushroom tyrosinase. Results from the docking simulation indicated that CPA2 could bind directly to the active site of mushroom tyrosinase and the binding affinity of CPA2 for tyrosinase might be higher than that of kojic acid, a well-known potent tyrosinase inhibitor. In B16F10 cells, CPA2 significantly suppressed tyrosinase activity and melanogenesis in a dose dependent manner. At the concentration of 25MUM, CPA2 exhibited tyrosinase inhibitory activity comparable to that of kojic acid with no cytotoxic effect. Results from the present study suggest that CPA2 bearing a linear beta-phenyl alpha,beta-unsaturated carbonyl scaffold may be the potential candidate for treatment of diseases associated with hyperpigmentation and that a linear beta phenyl-alpha,beta-unsaturated carbonyl scaffold might be closely related to potent tyrosinase inhibition. PMID- 26631439 TI - Pyrazole clubbed triazolo[1,5-a]pyrimidine hybrids as an anti-tubercular agents: Synthesis, in vitro screening and molecular docking study. AB - A series of novel pyrazole linked triazolo-pyrimidine hybrids were synthesized and evaluated for their anti-tuberculosis activity against M.tb H37Rv strain. Some of the screened entities rendered promising anti-tb activity (MIC: 0.39MUg/mL) and were found non toxic against Vero cells (IC50: ?20MUg/mL). Further, the docking study against wild type InhA enzyme of Mycobacterium tuberculosis using Glide reproduced the most active inhibitors (J21 and J27) with lowest binding energies and highest Glide XP scores demonstrating efficient binding to the active pocket. Additionally, the enzyme inhibition assay and ADME prediction of the active proved to be an attest to the possibility of developing compound J27 as a potent anti-tubercular lead. PMID- 26631440 TI - Phenolic group on A-ring is key for dracoflavan B as a selective noncompetitive inhibitor of alpha-amylase. AB - A high throughput assay was applied to guide the isolation of a new pancreatic alpha-amylase inhibitor, dracoflavan B, from the dragon's blood resin from Daemonorops draco. Applying C18 column, we successfully isolated both diastereomers and their structures verified by (1)H NMR spectra in comparison with the literature values. Their activity in inhibition of pancreatic alpha amylase with comparable IC50 values of 23MUM (A type) and 27MUM (B type) that are similar to that of acarbose. Dracoflavan B shows much weaker activity in inhibiting bacterial alpha-amylase and no activity towards fungal alpha-amylase. Moreover, both isomers show no inhibitory activity towards mammalian alpha glucosidase. Kinetic analysis revealed that using starch as the substrate, dracoflavan B was a non-competitive alpha-amylase inhibitor with a Ki value of 11.7MUM. Lack of alpha-amylase inhibition for proanthocyanidin A2 dimer demonstrated that dracoflavan B hydrophobic nature of the B, A', C' and B' rings are important for its alpha-amylase inhibition. In addition, selective chemical modification studies revealed that the phenolic group is also vital to dracoflavan B for its pancreatic alpha-amylase inhibition activity. Without the A ring phenolic hydrogen bond donor, the derivatives of dracoflavan B showed detrimental alpha-amylase inhibition. On the contrary, galloylation on the A ring phenolic OH group enhanced the activity as shown by the low IC50 (12MUM) against alpha-amylase which is 56% more potent as compared to dracoflavan B. PMID- 26631441 TI - Discovery of 2-aryloxy-4-amino-quinazoline derivatives as novel protease activated receptor 2 (PAR2) antagonists. AB - Protease-activated receptor 2 (PAR2) is a member of G protein-coupled receptor and its activation initiates diverse inflammatory responses. Recent studies suggest that antagonists of PAR2 may provide a novel therapeutic strategy for inflammatory diseases. In this study, we have developed a series of 2-aryloxy-4 amino-quinazoline derivatives as PAR2 antagonists and examined their effects against LPS-induced inflammatory responses in RAW 264.7 macrophages. Among these derivatives, compound 2f displayed the greatest antagonistic activity with the IC50 value of 2.8MUM. Binding modes of the newly identified PAR2 antagonists were analyzed by molecular docking using IFD/MM-GBSA methods in the putative binding site of PAR2 homology model. Moreover, 2f demonstrated significant inhibitory effects on the LPS-activated pro-inflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) through the regulation of various intracellular signaling pathways involving nuclear factor-kappaB (NF-kappaB), activator protein 1 (AP-1) and the mitogen-activated protein kinases (MAPK). Furthermore, administration of 2f significantly reduced the mortality of LPS induced sepsis in mice. These results provide useful insights into the development of novel PAR2 antagonists with anti-inflammatory activity in vitro and in vivo. PMID- 26631442 TI - Synthesis and activity of novel 16-dehydropregnenolone acetate derivatives as inhibitors of type 1 5alpha-reductase and on cancer cell line SK-LU-1. AB - Testosterone (T) plays a crucial role in prostate growth. In androgen-dependent tissues T is reduced to dihydrotestosterone (DHT) because of the presence of the 5alpha-reductase enzyme. This androgen is more active than T, since it has a higher affinity for the androgen receptor (AR). When this mechanism is altered, androgen-dependent diseases, including prostate cancer, could result. The aim of this study was to synthesize several 16-dehydropregnenolone acetate derivatives containing a triazole ring at C-21 and a linear or alicyclic ester moiety at C-3 of the steroidal skeleton. These steroids were designed as potential inhibitors of the activity of both types (1 and 2) of 5alpha-reductase. The cytotoxic activity of these compounds was also evaluated on a panel of PC-3, MCF7, and SK LU-1 human cancer cell lines. The results from this study showed that with the exception of steroids 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3beta-yl propionate and 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3beta-yl pentanoate, the compounds exhibit a lower inhibitory activity for both isoenzymes of 5alpha-reductase than finasteride. Furthermore the 3beta-hydroxy-21-(1H-1,2,4 triazole-1-yl)pregna-5,16-dien-20-one and 20-oxo-21-(1H-1,2,4-triazole-1 yl)pregna-5,16-dien-3beta-yl-acetate derivatives display 80% cytotoxic activity on the SK-LU-1 cell line. These results also indicated that the triazole derivatives, which have a hydroxyl or acetoxy group at C-3, could have an anticancer effect, whereas the derivatives with a alicyclic ester group at C-3 do not show biological activity. PMID- 26631443 TI - [Subcutaneous calcinosis, a late and severe complication of radiotherapy: Three cases]. AB - BACKGROUND: Radiation-induced subcutaneous calcinosis is a rare and special form of potentially severe subcutaneous calcinosis of late onset. Herein, we report three cases of this disease, occurring in each instance more than 10 years after use of radiotherapy as an adjuvant treatment in breast cancer. PATIENTS AND METHODS: Our report concerns 3 women aged 69-88 years consulting for pre-sternal ulcers (n=2) and/or subcutaneous nodules (n=2). These lesions developed on areas irradiated between 10 and 38 years earlier for breast cancer. In all three cases, radiological explorations showed extensive subcutaneous calcification. In one case, calcification extended into the mediastinum. In each patient, a diagnosis of radiation-induced subcutaneous calcinosis was made and symptomatic treatment was given. DISCUSSION: Radiation-induced subcutaneous calcinosis is an irreversible and rare complication of high-dose radiation that usually occurs several years after radiotherapy. Its severity is related to potential ulcerations, pain and a risk for in-depth extension up to the mediastina. This complication remains unclear and treatment has not been codified. The only option seems to be "heavy" plastic surgery. PMID- 26631444 TI - [Lycanthropy and medicine]. PMID- 26631445 TI - [Antia-Bush chondrocutaneous advancement flap for repair of a helical rim defect of the ear following excision of a squamous-cell carcinoma]. PMID- 26631446 TI - [Dynamic phototherapy of limited value in infective dermatoses]. PMID- 26631447 TI - Glycodelin expression in pregnant patients with cervical intraepithelial neoplasia: a case-control study. AB - We aimed to evaluate glycodelin immunostaining in pregnant women with a first diagnosis of cervical intraephitelial neoplasia (CIN) and to correlate the expression of CIN with Ki-67 and glycodelin immunostaining. A retrospective case control study was performed including 20 patients with natural pregnancy and with first time onset of CIN occurring not later than 16 gestational weeks. The control group included 20 non-pregnant patients matched for age, parity, smoking status and number of previous sexual partners. Exclusion criteria included previous cervical treatment, immunocompromised status and chronic hepatitis B and/or C. Staining for Glycodelin and for Ki-67 was expressed using a classification based on the distribution of positivity on a semi-quantitative three-point scale. An inverse relationship was observed between glycodelin immunostaining and CIN grade in pregnant patients (p = 0.01), with a significantly higher expression in CIN1 than in CIN2 and CIN3, but not in non pregnant patients (p = 0.81). Positivity for Ki-67 was less intense in pregnant than in non-pregnant patients. A significant inverse relationship was observed between glycodelin immunostaining and Ki-67 expression (p = 0.02). We suggest that the higher expression of glycodelin in pregnancy is related to a lower proliferative activity in CIN, which is probably associated to hormonal status of pregnancy. Further clinical studies are needed to support these findings. PMID- 26631448 TI - Fate of HIV-1 cDNA intermediates during reverse transcription is dictated by transcription initiation site of virus genomic RNA. AB - Retroviral reverse transcription is accomplished by sequential strand-transfers of partial cDNA intermediates copied from viral genomic RNA. Here, we revealed an unprecedented role of 5'-end guanosine (G) of HIV-1 genomic RNA for reverse transcription. Based on current consensus for HIV-1 transcription initiation site, HIV-1 transcripts possess a single G at 5'-ends (G1-form). However, we found that HIV-1 transcripts with additional Gs at 5'-ends (G2- and G3-forms) were abundantly expressed in infected cells by using alternative transcription initiation sites. The G2- and G3-forms were also detected in the virus particle, although the G1-form predominated. To address biological impact of the 5'-G number, we generated HIV clone DNA to express the G1-form exclusively by deleting the alternative initiation sites. Virus produced from the clone showed significantly higher strand-transfer of minus strong-stop cDNA (-sscDNA). The in vitro assay using synthetic HIV-1 RNAs revealed that the abortive forms of sscDNA were abundantly generated from the G3-form RNA, but dramatically reduced from the G1-form. Moreover, the strand-transfer of -sscDNA from the G1-form was prominently stimulated by HIV-1 nucleocapsid. Taken together, our results demonstrated that the 5'-G number that corresponds to HIV-1 transcription initiation site was critical for successful strand-transfer of -sscDNA during reverse transcription. PMID- 26631449 TI - Safe disposal of radioactive iodide ions from solutions by Ag2O grafted sodium niobate nanofibers. AB - Radioactive iodine isotopes are released into the environment by the nuclear industry and medical research institutions using radioactive materials, and have negative effects on organisms living within the ecosystem. Thus, safe disposal of radioactive iodine is necessary and crucial. For this reason, the uptake of iodide ions was investigated in Ag2O nanocrystal grafted sodium niobate nanofibers, which were prepared by forming a well-matched phase coherent interface between them. The resulting composite was applied as an efficient adsorbent for I(-) anions by forming an AgI precipitate, which also remained firmly attached to the substrates. Due to their one-dimensional morphology, the new adsorbents can be easily dispersed in liquids and readily separated after purification. This significantly enhances the adsorption efficiency and reduces the separation costs. The change in structure from the pristine sodium niobate to Ag2O anchored sodium niobate and to the used adsorbent was examined by using various characterization techniques. The effects of Ag(+) concentration, pH, equilibration time, ionic strength and competing ions on the iodide ion removal ability of the composite were studied. The Ag2O nanocrystal grafted sodium niobate adsorbent showed a high adsorption capacity and excellent selectivity for I(-) anions in basic solutions. Our results are useful for the further development of improved adsorbents for removing I(-) anions from basic wastewater. PMID- 26631450 TI - Seasonal variation in diagnosis of invasive cutaneous melanoma. PMID- 26631451 TI - QUENCH: A software package for the determination of quenching curves in Liquid Scintillation counting. AB - In Liquid Scintillation Counting (LSC), the scintillating source is part of the measurement system and its detection efficiency varies with the scintillator used, the vial and the volume and the chemistry of the sample. The detection efficiency is generally determined using a quenching curve, describing, for a specific radionuclide, the relationship between a quenching index given by the counter and the detection efficiency. A quenched set of LS standard sources are prepared by adding a quenching agent and the quenching index and detection efficiency are determined for each source. Then a simple formula is fitted to the experimental points to define the quenching curve function. The paper describes a software package specifically devoted to the determination of quenching curves with uncertainties. The experimental measurements are described by their quenching index and detection efficiency with uncertainties on both quantities. Random Gaussian fluctuations of these experimental measurements are sampled and a polynomial or logarithmic function is fitted on each fluctuation by chi(2) minimization. This Monte Carlo procedure is repeated many times and eventually the arithmetic mean and the experimental standard deviation of each parameter are calculated, together with the covariances between these parameters. Using these parameters, the detection efficiency, corresponding to an arbitrary quenching index within the measured range, can be calculated. The associated uncertainty is calculated with the law of propagation of variances, including the covariance terms. PMID- 26631452 TI - Activity determination of (59)Fe by 4pi beta-gamma counting using liquid scintillation in the beta channel. AB - This paper reports on absolute activity measurements of iron-59 made at the National Metrology Institute of South Africa (NMISA) via 4pi(LS)beta-gamma coincidence counting. The exercise formed part of an Asia Pacific Metrology Program (APMP) regional key comparison. Source data were analysed by the extrapolation technique for a number of gamma-ray window settings. In addition, a feasibility study was undertaken on a second technique; a non-extrapolation method based on a detection efficiency analysis. The reported activity concentration of the (59)Fe solution was determined with a relative uncertainty of 0.28% (k=1), the uncertainty being due mainly to the rate vs. efficiency fitting process. The result from the non-extrapolation method was lower than that given by extrapolation by 0.33%, within two standard deviations. Possible reasons for the small discrepancy are discussed. PMID- 26631453 TI - Comparison of different sampling methods for the determination of low-level radionuclides in air. AB - The aim of this work is to check the consistency of results given by different air dust samplers (flow-rates between 2 and 700m(3)/h) and measurement protocols at a single location. The study is focussed on (210)Pb since is the only nuclide that can be easily assessed through all the studied sampler types. Results from high- and mid-volume samplers agreed well to within the associated uncertainties. Gross beta activity from low-volume samplers can be used as a good indicator of the evolution of (210)Pb concentration in air. PMID- 26631454 TI - Systematic comparison of beta spectra calculations using improved analytical screening correction with experimental shape factors. AB - From a review of the available literature, a database of experimental shape factors from measured beta spectra was created in previous work. Classical assumptions applied in beta spectra calculations which avoid the determination of the electron and nuclear wave functions were tested by comparison with each measured spectrum present in the database. From this systematic comparison, it was demonstrated that the typical assumption lambdak=1 is inappropriate for all forbidden unique transitions. Moreover, the equally common xi-approximation was also proved to be incorrect for about half of the listed first forbidden non unique transitions and for all second non-unique ones. In present work, this study has been performed once again using an improved analytical screening correction. General results from previous study still remain the same. Except for allowed transitions, the mean energies in current nuclear databases are expected to be erroneous. Some selected beta spectra are also given to illustrate these results. PMID- 26631455 TI - Certified reference materials for radionuclides in Bikini Atoll sediment (IAEA 410) and Pacific Ocean sediment (IAEA-412). AB - The preparation and characterization of certified reference materials (CRMs) for radionuclide content in sediments collected offshore of Bikini Atoll (IAEA-410) and in the open northwest Pacific Ocean (IAEA-412) are described and the results of the certification process are presented. The certified radionuclides include: (40)K, (210)Pb ((210)Po), (226)Ra, (228)Ra, (228)Th, (232)Th, (234)U, (238)U, (239)Pu, (239+240)Pu and (241)Am for IAEA-410 and (40)K, (137)Cs, (210)Pb ((210)Po), (226)Ra, (228)Ra, (228)Th, (232)Th, (235)U, (238)U, (239)Pu, (240)Pu and (239+240)Pu for IAEA-412. The CRMs can be used for quality assurance and quality control purposes in the analysis of radionuclides in sediments, for development and validation of analytical methods and for staff training. PMID- 26631456 TI - Expression of orexin B and its receptor 2 in rat testis. AB - The peptides orexin A (OxA) and orexin B (OxB) deriving from a common precursor molecule, prepro-orexin, by proteolytic cleavage, bind the two G-coupled OX1 and OX2 receptors. While OX1 selectively binds OxA, OX2 shows similar affinity for both orexins. Firstly discovered in the hypothalamus, orexins and their receptors have been found in other brain regions as well as in peripheral tissues of mammals, thus resulting involved in the regulation of a broad variety of physiological functions. While the functional localization of OxA and OX1 in the mammalian genital tract has been already described, the expression of OxB and OX2 and their potential role in the reproductive functions remain to be explored. Here, we investigated the presence of OxB and OX2 in the rat testis by immunohistochemical and biochemical analyses. The results definitely demonstrated the localization of OxB and OX2 in pachytene and second spermatocytes as well as in spermatids at all stages of the cycle of the seminiferous epithelium. The expression of both OX2 mRNA and protein in the rat testis was also established by RT-PCR and Western blotting, respectively. The analysis of the molecular mechanism of action of OxB in the rat testis showed that OxB, in contrast with OxA, is unable to promote steroidogenesis. These results translate into the regulation of diverse biological actions by OxA and OxB in the male gonad. PMID- 26631457 TI - Unexpected lower testosterone in faster growing farmed saltwater crocodile (Crocodylus porosus) hatchlings. AB - Agricultural production of the saltwater crocodile (Crocodylus porosus) is an emergent industry in northern Australia with many of the factors affecting production remaining unknown. In this study, we sought to expand upon our previous findings of reference corticosterone and immune function by reporting baseline sex hormone levels [testosterone (TEST) and estradiol (ESTR)] and their association with growth. This was achieved by sampling 253 hatchling crocodiles repeatedly at 3, 6, and 9months of age. Sampling age had a significant effect on both TEST (p<0.001) and ESTR (p<0.001) suggesting climatic/abiotic factors have an influence even in prepubescent crocodiles. Stress, as measured by plasma corticosterone, had no detectable effect on plasma ESTR or TEST levels. Unexpectedly however, TEST was higher in slower-growing crocodiles, which is contrary to what has been reported for the American alligator. ESTR was not associated with growth. PMID- 26631458 TI - Patients' poor communication with their doctors in the first visit of the gynecological endocrinology outpatient clinics. AB - OBJECTIVE: To investigate patients' communication with their gynecologists in the first visit of the gynecological endocrinology outpatient clinics. STUDY DESIGN: We developed a questionnaire to evaluate 379 women' expectations of their first visit, information-giving about illness, and understanding of the consultation they encountered from April to August 2010. Descriptive statistics and multiple linear regression analysis were used to analyze the data. RESULTS: Before the first visit, 55% (208/379) of participants hoped to get the doctors' special attention, and 60% (227/379) of patients expected a very satisfying consultation. During the consultation, only 34% (129/379) of patients provided their case history clearly according to physicians' inquiry, 21% (81/379) of patients understood the examination and 28% (105/379) of patients understood the therapeutic regime after doctors' explanation. Correlation analysis showed that sociodemographic characteristics such as young age (under 20 years old), low level of education (primary school or less), and lack of medical knowledge affected patients' information-giving about illness and understanding of their first visit (all ps < 0.05). CONCLUSIONS: Patients expected a patient-centered doctor-patient communication in gynecological endocrinology outpatient clinics. They could not communicate well with their doctors, which was affected by age, education, and medical background. PMID- 26631459 TI - Comprehensive analysis of lncRNA-mRNA co-expression patterns identifies immune associated lncRNA biomarkers in ovarian cancer malignant progression. AB - Ovarian cancer (OV) is the most common and lethal gynecological tumor with a poor prognosis for women; however, the regulatory roles of the long non-coding RNAs (lncRNAs) in ovarian malignant progression are insufficiently understood. Here, we investigated the expression patterns of lncRNAs and mRNAs in the high throughput molecular profiles of 399 OV patients and constructed a functional lncRNA-mRNA co-expression network across OV malignant progression. We found that two protective lncRNAs, RP11-284N8.3.1 and AC104699.1.1, were not only differentially expressed throughout the progression of malignant OV but were also independently predictive of the survival of patients with different OV stages. A functional analysis of the two lncRNAs predicted their roles in immune system activation and other anti-tumor processes in the OV microenvironment. Integrating these two lncRNAs into an OV risk model was able to significantly stratify patients into different risk groups. Overall, our analysis effectively provides insights into the lncRNA association with malignant OV progression. The two lncRNA signature is a candidate biomarker for the prognosis of patients with OV and may enable a more accurate prediction of survival. PMID- 26631460 TI - Encoding Voxels with Deep Learning. PMID- 26631461 TI - KCC2 Gates Activity-Driven AMPA Receptor Traffic through Cofilin Phosphorylation. AB - Expression of the neuronal K/Cl transporter KCC2 is tightly regulated throughout development and by both normal and pathological neuronal activity. Changes in KCC2 expression have often been associated with altered chloride homeostasis and GABA signaling. However, recent evidence supports a role of KCC2 in the development and function of glutamatergic synapses through mechanisms that remain poorly understood. Here we show that suppressing KCC2 expression in rat hippocampal neurons precludes long-term potentiation of glutamatergic synapses specifically by preventing activity-driven membrane delivery of AMPA receptors. This effect is independent of KCC2 transporter function and can be accounted for by increased Rac1/PAK- and LIMK-dependent cofilin phosphorylation and actin polymerization in dendritic spines. Our results demonstrate that KCC2 plays a critical role in the regulation of spine actin cytoskeleton and gates long-term plasticity at excitatory synapses in cortical neurons. PMID- 26631462 TI - Very Early Brain Damage Leads to Remodeling of the Working Memory System in Adulthood: A Combined fMRI/Tractography Study. AB - The human brain can adapt to overcome injury even years after an initial insult. One hypothesis states that early brain injury survivors, by taking advantage of critical periods of high plasticity during childhood, should recover more successfully than those who suffer injury later in life. This hypothesis has been challenged by recent studies showing worse cognitive outcome in individuals with early brain injury, compared with individuals with later brain injury, with working memory particularly affected. We invited individuals who suffered perinatal brain injury (PBI) for an fMRI/diffusion MRI tractography study of working memory and hypothesized that, 30 years after the initial injury, working memory deficits in the PBI group would remain, despite compensatory activation in areas outside the typical working memory network. Furthermore we hypothesized that the amount of functional reorganization would be related to the level of injury to the dorsal cingulum tract, which connects medial frontal and parietal working memory structures. We found that adults who suffered PBI did not significantly differ from controls in working memory performance. They exhibited less activation in classic frontoparietal working memory areas and a relative overactivation of bilateral perisylvian cortex compared with controls. Structurally, the dorsal cingulum volume and hindrance-modulated orientational anisotropy was significantly reduced in the PBI group. Furthermore there was uniquely in the PBI group a significant negative correlation between the volume of this tract and activation in the bilateral perisylvian cortex and a positive correlation between this activation and task performance. This provides the first evidence of compensatory plasticity of the working memory network following PBI. PMID- 26631463 TI - Can Neural Activity Propagate by Endogenous Electrical Field? AB - It is widely accepted that synaptic transmissions and gap junctions are the major governing mechanisms for signal traveling in the neural system. Yet, a group of neural waves, either physiological or pathological, share the same speed of ~0.1 m/s without synaptic transmission or gap junctions, and this speed is not consistent with axonal conduction or ionic diffusion. The only explanation left is an electrical field effect. We tested the hypothesis that endogenous electric fields are sufficient to explain the propagation with in silico and in vitro experiments. Simulation results show that field effects alone can indeed mediate propagation across layers of neurons with speeds of 0.12 +/- 0.09 m/s with pathological kinetics, and 0.11 +/- 0.03 m/s with physiologic kinetics, both generating weak field amplitudes of ~2-6 mV/mm. Further, the model predicted that propagation speed values are inversely proportional to the cell-to-cell distances, but do not significantly change with extracellular resistivity, membrane capacitance, or membrane resistance. In vitro recordings in mice hippocampi produced similar speeds (0.10 +/- 0.03 m/s) and field amplitudes (2.5 5 mV/mm), and by applying a blocking field, the propagation speed was greatly reduced. Finally, osmolarity experiments confirmed the model's prediction that cell-to-cell distance inversely affects propagation speed. Together, these results show that despite their weak amplitude, electric fields can be solely responsible for spike propagation at ~0.1 m/s. This phenomenon could be important to explain the slow propagation of epileptic activity and other normal propagations at similar speeds. PMID- 26631464 TI - Synaptic Targets of Medial Septal Projections in the Hippocampus and Extrahippocampal Cortices of the Mouse. AB - Temporal coordination of neuronal assemblies among cortical areas is essential for behavioral performance. GABAergic projections from the medial septum and diagonal band complex exclusively innervate GABAergic interneurons in the rat hippocampus, contributing to the coordination of neuronal activity, including the generation of theta oscillations. Much less is known about the synaptic target neurons outside the hippocampus. To reveal the contribution of synaptic circuits involving the medial septum of mice, we have identified postsynaptic cortical neurons in wild-type and parvalbumin-Cre knock-in mice. Anterograde axonal tracing from the septum revealed extensive innervation of the hippocampus as well as the subiculum, presubiculum, parasubiculum, the medial and lateral entorhinal cortices, and the retrosplenial cortex. In all examined cortical regions, many septal GABAergic boutons were in close apposition to somata or dendrites immunopositive for interneuron cell-type molecular markers, such as parvalbumin, calbindin, calretinin, N-terminal EF-hand calcium-binding protein 1, cholecystokinin, reelin, or a combination of these molecules. Electron microscopic observations revealed septal boutons forming axosomatic or axodendritic type II synapses. In the CA1 region of hippocampus, septal GABAergic projections exclusively targeted interneurons. In the retrosplenial cortex, 93% of identified postsynaptic targets belonged to interneurons and the rest to pyramidal cells. These results suggest that the GABAergic innervation from the medial septum and diagonal band complex contributes to temporal coordination of neuronal activity via several types of cortical GABAergic interneurons in both hippocampal and extrahippocampal cortices. Oscillatory septal neuronal firing at delta, theta, and gamma frequencies may phase interneuron activity. PMID- 26631465 TI - Frequency-Dependent Representation of Reinforcement-Related Information in the Human Medial and Lateral Prefrontal Cortex. AB - The feedback-related negativity (FRN) is a commonly observed potential in scalp electroencephalography (EEG) studies related to the valence of feedback about a subject's performance. This potential classically manifests as a negative deflection in medial frontocentral EEG contacts following negative feedback. Recent work has shown prominence of theta power in the spectral composition of the FRN, placing it within the larger class of "frontal midline theta" cognitive control signals. Although the dorsal anterior cingulate cortex (dACC) is thought to be the cortical generator of the FRN, conclusive data regarding its origin and propagation are lacking. Here we examine intracranial electrophysiology from the human medial and lateral prefrontal cortex (PFC) to better understand the anatomical localization and communication patterns of the FRN. We show that the FRN is evident in both low- and high-frequency local field potentials (LFPs) recorded on electrocorticography. The FRN is larger in medial compared with lateral PFC, and coupling between theta band phase and high-frequency LFP power is also greater in medial PFC. Using Granger causality and conditional mutual information analyses, we provide evidence that feedback-related information propagates from medial to lateral PFC, and that this information transfer oscillates with theta-range periodicity. These results provide evidence for the dACC as the cortical source of the FRN, provide insight into the local computation of frontal midline theta, and have implications for reinforcement learning models of cognitive control. PMID- 26631466 TI - Visualization of Ca2+ Filling Mechanisms upon Synaptic Inputs in the Endoplasmic Reticulum of Cerebellar Purkinje Cells. AB - The endoplasmic reticulum (ER) plays crucial roles in intracellular Ca(2+) signaling, serving as both a source and sink of Ca(2+), and regulating a variety of physiological and pathophysiological events in neurons in the brain. However, spatiotemporal Ca(2+) dynamics within the ER in central neurons remain to be characterized. In this study, we visualized synaptic activity-dependent ER Ca(2+) dynamics in mouse cerebellar Purkinje cells (PCs) using an ER-targeted genetically encoded Ca(2+) indicator, G-CEPIA1er. We used brief parallel fiber stimulation to induce a local decrease in the ER luminal Ca(2+) concentration ([Ca(2+)]ER) in dendrites and spines. In this experimental system, the recovery of [Ca(2+)]ER takes several seconds, and recovery half-time depends on the extent of ER Ca(2+) depletion. By combining imaging analysis and numerical simulation, we show that the intraluminal diffusion of Ca(2+), rather than Ca(2+) reuptake, is the dominant mechanism for the replenishment of the local [Ca(2+)]ER depletion immediately following the stimulation. In spines, the ER filled almost simultaneously with parent dendrites, suggesting that the ER within the spine neck does not represent a significant barrier to Ca(2+) diffusion. Furthermore, we found that repetitive climbing fiber stimulation, which induces cytosolic Ca(2+) spikes in PCs, cumulatively increased [Ca(2+)]ER. These results indicate that the neuronal ER functions both as an intracellular tunnel to redistribute stored Ca(2+) within the neurons, and as a leaky integrator of Ca(2+) spike inducing synaptic inputs. PMID- 26631467 TI - Disruption of Epithalamic Left-Right Asymmetry Increases Anxiety in Zebrafish. AB - Differences between the left and right sides of the brain are found throughout the animal kingdom, but the consequences of altered neural asymmetry are not well understood. In the zebrafish epithalamus, the parapineal is located on the left side of the brain where it influences development of the adjacent dorsal habenular (dHb) nucleus, causing the left and right dHb to differ in their organization, gene expression, and connectivity. Left-right (L-R) reversal of parapineal position and dHb asymmetry occurs spontaneously in a small percentage of the population, whereas the dHb develop symmetrically following experimental ablation of the parapineal. The habenular region was previously implicated in modulating fear in both mice and zebrafish, but the relevance of its L-R asymmetry is unclear. We now demonstrate that disrupting directionality of the zebrafish epithalamus causes reduced exploratory behavior and increased cortisol levels, indicative of enhanced anxiety. Accordingly, exposure to buspirone, an anxiolytic agent, significantly suppresses atypical behavior. Axonal projections from the parapineal to the dHb are more variable when it is located on the right side of the brain, revealing that L-R reversals do not necessarily represent a neuroanatomical mirror image. The results highlight the importance of directional asymmetry of the epithalamus in the regulation of stress responses in zebrafish. PMID- 26631468 TI - Excitatory Postrhinal Projections to Principal Cells in the Medial Entorhinal Cortex. AB - The postrhinal cortex (POR) provides substantial input to the entorhinal cortex, mainly targeting superficial layers of the medial entorhinal cortex (MEC). Major inputs to POR originate in the visual and parietal cortex, thus providing neurons in MEC with a subset of cortical information relevant to their spatial firing properties. The POR takes a position that is comparable with that of the perirhinal cortex (PER) with regard to the lateral entorhinal cortex (LEC). Neurons in LEC and MEC show different functional properties likely reflecting differences in their respective inputs. Projections from PER to LEC exert a main inhibitory influence, which may relate to the sparse object-selective firing in LEC. In view of the continuous, spatially modulated firing properties of principal neurons in MEC, we tested in rats the hypothesis that projections from POR to MEC are functionally different from the PER-to-LEC counterpart in providing an excitatory drive to MEC. Our combined confocal and quantitative electron-microscopic observations indicated that POR projections target mainly principal cells in MEC, including neurons that project to the hippocampus. The ultrastructure of the majority of the synapses indicated that they are excitatory. Voltage-sensitive dye imaging in sagittal slices confirmed this morphologically derived conclusion, showing that the MEC network always responded with an overall depolarization, indicative for net excitatory transmission. In vitro single-cell recordings from principal cells showed only excitatory responses upon POR stimulation. These results show that POR provides an excitatory projection to MEC, differing fundamentally from the inhibitory projection of PER to LEC. PMID- 26631470 TI - Maternal Stress Combined with Terbutaline Leads to Comorbid Autistic-Like Behavior and Epilepsy in a Rat Model. AB - Human autism is comorbid with epilepsy, yet, little is known about the causes or risk factors leading to this combined neurological syndrome. Although genetic predisposition can play a substantial role, our objective was to investigate whether maternal environmental factors alone could be sufficient. We examined the independent and combined effects of maternal stress and terbutaline (used to arrest preterm labor), autism risk factors in humans, on measures of both autistic-like behavior and epilepsy in Sprague-Dawley rats. Pregnant dams were exposed to mild stress (foot shocks at 1 week intervals) throughout pregnancy. Pups were injected with terbutaline on postnatal days 2-5. Either maternal stress or terbutaline resulted in autistic-like behaviors in offspring (stereotyped/repetitive behaviors and deficits in social interaction or communication), but neither resulted in epilepsy. However, their combination resulted in severe behavioral symptoms, as well as spontaneous recurrent convulsive seizures in 45% and epileptiform spikes in 100%, of the rats. Hippocampal gliosis (GFAP reactivity) was correlated with both abnormal behavior and spontaneous seizures. We conclude that prenatal insults alone can cause comorbid autism and epilepsy but it requires a combination of teratogens to achieve this; testing single teratogens independently and not examining combinatorial effects may fail to reveal key risk factors in humans. Moreover, astrogliosis may be common to both teratogens. This new animal model of combined autism and epilepsy permits the experimental investigation of both the cellular mechanisms and potential intervention strategies for this debilitating comorbid syndrome. PMID- 26631469 TI - Olig1 Acetylation and Nuclear Export Mediate Oligodendrocyte Development. AB - The oligodendrocyte transcription factor Olig1 is critical for both oligodendrocyte development and remyelination in mice. Nuclear to cytoplasmic translocation of Olig1 protein occurs during brain development and in multiple sclerosis, but the detailed molecular mechanism of this translocation remains elusive. Here, we report that Olig1 acetylation and deacetylation drive its active translocation between the nucleus and the cytoplasm in both mouse and rat oligodendrocytes. We identified three functional nuclear export sequences (NES) localized in the basic helix-loop-helix domain and one specific acetylation site at Lys 150 (human Olig1) in NES1. Olig1 acetylation and deacetylation are regulated by the acetyltransferase CREB-binding protein and the histone deacetylases HDAC1, HDAC3, and HDAC10. Acetylation of Olig1 decreased its chromatin association, increased its interaction with inhibitor of DNA binding 2 and facilitated its retention in the cytoplasm of mature oligodendrocytes. These studies establish that acetylation of Olig1 regulates its chromatin dissociation and subsequent translocation to the cytoplasm and is required for its function in oligodendrocyte maturation. PMID- 26631471 TI - From Memory Impairment to Posttraumatic Stress Disorder-Like Phenotypes: The Critical Role of an Unpredictable Second Traumatic Experience. AB - Arousal and stress critically regulate memory formation and retention. Increasing levels of stress produce an inverted U-shaped effect on cognitive performance, including the retention of explicit memories, and experiencing a severe stress during a traumatic event may lead to posttraumatic stress disorder (PTSD). The molecular mechanisms underlying the impairing effect of a severe stress on memory and the key contribution of traumatic experiences toward the development of PTSD are still unknown. Here, using increasing footshock intensities in an inhibitory avoidance paradigm, we reproduced the inverted U-shaped curve of memory performance in rats. We then show that the inverted U profile of memory performance correlates with an inverted U profile of corticosterone level in the circulation and of brain-derived neurotrophic factor, phosphorylated tropomyosin receptor kinase B, and methyl CpG binding protein in the dorsal hippocampus. Furthermore, training with the highest footshock intensity (traumatic experience) led to a significant elevation of hippocampal glucocorticoid receptors. Exposure to an unpredictable, but not to a predictable, highly stressful reminder shock after a first traumatic experience resulted in PTSD-like phenotypes, including increased memory of the trauma, high anxiety, threat generalization, and resistance to extinction. Systemic corticosterone injection immediately after the traumatic experience, but not 3 d later, was sufficient to produce PTSD-like phenotypes. We suggest that, although after a first traumatic experience a suppression of the corticosterone-dependent response protects against the development of an anxiety disorder, experiencing more than one trauma (multiple hits) is a critical contributor to the etiology of PTSD. PMID- 26631472 TI - Brief Dark Exposure Reduces Tonic Inhibition in Visual Cortex. AB - Tonic inhibition mediated by extrasynaptic GABA(A) receptors (GABARs) sensing ambient levels of GABA can profoundly alter the membrane input resistance to affect cellular excitability. Therefore, regulation of tonic inhibition is an attractive mechanism to control the levels of cortical firing. In cortical pyramidal cells, tonic inhibition is regulated by age and several neurotransmitters and is affected by stroke and epilepsy. However, the possible role of sensory experience has not been examined. Here, we report that a brief 2 day exposure to dark reduces by 1/3 the inhibitory tonic conductance recorded in layer II/III pyramidal cells of the mouse juvenile (postnatal day 12-27) visual cortex. In these cells, tonic inhibition is carried primarily by GABARs containing the delta subunit. Consistently, the dark exposure reduction in conductance was associated with a reduction in delta subunit levels, which were not affected in control frontal cortex. We propose that a deprivation-induced reduction in tonic inhibition might serve a homeostatic function by increasing the firing levels of cells in deprived cortical circuits. PMID- 26631473 TI - ER Chaperone BiP/GRP78 Is Required for Myelinating Cell Survival and Provides Protection during Experimental Autoimmune Encephalomyelitis. AB - Myelinating cells synthesize large amounts of membrane protein through the secretory pathway, which makes these cells particularly sensitive to perturbations of the endoplasmic reticulum (ER). Ig binding protein (BiP), also known as glucose-regulated protein 78 (GRP78), is a critical ER chaperone that also plays a pivotal role in controlling the cellular response to ER stress. To examine the potential importance of BiP to myelinating cells, we used a conditional knock-out approach to BiP gene inactivation in oligodendrocytes during development, in adulthood, and in response to experimental autoimmune encephalomyelitis (EAE), an animal model of the inflammatory demyelinating disorder multiple sclerosis (MS). During development, mice lacking functional BiP gene expression in oligodendrocytes developed tremors and ataxia and died before reaching maturity. When BiP gene inactivation in oligodendrocytes was initiated in adulthood, the mice displayed severe neurological symptoms including tremors and hind-limb paralysis. The inactivation of BiP in oligodendrocytes during development or in adulthood resulted in oligodendrocyte loss and corresponding severe myelin abnormalities. Mice heterozygous for the oligodendrocyte-specific inactivation of BiP, which were phenotypically normal without evidence of neuropathology, displayed an exacerbated response to EAE that correlated with an increased loss of oligodendrocytes. Furthermore, mice in which the BiP gene was specifically inactivated in developing Schwann cells displayed tremor that progressed to hindlimb paralysis, which correlated with diminished numbers of myelinating Schwann cells and severe PNS hypomyelination. These studies demonstrate that BiP is critical for myelinating cell survival and contributes to the protective response of oligodendrocyte against inflammatory demyelination. PMID- 26631474 TI - CCL2 Mediates Neuron-Macrophage Interactions to Drive Proregenerative Macrophage Activation Following Preconditioning Injury. AB - CNS neurons in adult mammals do not spontaneously regenerate axons after spinal cord injury. Preconditioning peripheral nerve injury allows the dorsal root ganglia (DRG) sensory axons to regenerate beyond the injury site by promoting expression of regeneration-associated genes. We have previously shown that peripheral nerve injury increases the number of macrophages in the DRGs and that the activated macrophages are critical to the enhancement of intrinsic regeneration capacity. The present study identifies a novel chemokine signal mediated by CCL2 that links regenerating neurons with proregenerative macrophage activation. Neutralization of CCL2 abolished the neurite outgrowth activity of conditioned medium obtained from neuron-macrophage cocultures treated with cAMP. The neuron-macrophage interactions that produced outgrowth-promoting conditioned medium required CCL2 in neurons and CCR2/CCR4 in macrophages. The conditioning effects were abolished in CCL2-deficient mice at 3 and 7 d after sciatic nerve injury, but CCL2 was dispensable for the initial growth response and upregulation of GAP-43 at the 1 d time point. Intraganglionic injection of CCL2 mimicked conditioning injury by mobilizing M2-like macrophages. Finally, overexpression of CCL2 in DRGs promoted sensory axon regeneration in a rat spinal cord injury model without harmful side effects. Our data suggest that CCL2-mediated neuron macrophage interaction plays a critical role for amplification and maintenance of enhanced regenerative capacity by preconditioning peripheral nerve injury. Manipulation of chemokine signaling mediating neuron-macrophage interactions may represent a novel therapeutic approach to promote axon regeneration after CNS injury. PMID- 26631475 TI - Rewarding Effects of Optical Stimulation of Ventral Tegmental Area Glutamatergic Neurons. AB - Ventral tegmental area (VTA) neurons play roles in reward and aversion. The VTA has three major neuronal phenotypes: dopaminergic, GABAergic, and glutamatergic. VTA glutamatergic neurons--expressing vesicular glutamate transporter-2 (VGluT2)- project to limbic and cortical regions, but also excite neighboring dopaminergic neurons. Here, we test whether local photoactivation of VTA VGluT2 neurons expressing Channelrhodopsin-2 (ChR2) under the VGluT2 promoter causes place preference and supports operant responding for the stimulation. By using a Cre dependent viral vector, ChR2 (tethered to mCherry) was expressed in VTA glutamatergic neurons of VGluT2::Cre mice. The mCherry distribution was evaluated by immunolabeling. By confocal microscopy, we detected expression of mCherry in VTA cell bodies and local processes. In contrast, VGluT2 expression was restricted to varicosities, some of them coexpressing mCherry. By electron microscopy, we determined that mCherry-VGluT2 varicosities correspond to axon terminals, forming asymmetric synapses on neighboring dopaminergic neurons. These findings indicate that ChR2 was present in terminals containing glutamatergic synaptic vesicles and involved in local synaptic connections. Photoactivation of VTA slices from ChR2-expressing mice induced AMPA/NMDA receptor-dependent firing of dopaminergic neurons projecting to the nucleus accumbens. VTA photoactivation of ChR2-expressing mice reinforced instrumental behavior and established place preferences. VTA injections of AMPA or NMDA receptor antagonists blocked optical self-stimulation and place preference. These findings suggest a role in reward function for VTA glutamatergic neurons through local excitatory synapses on mesoaccumbens dopaminergic neurons. PMID- 26631476 TI - Parallel Inhibition of Dopamine Amacrine Cells and Intrinsically Photosensitive Retinal Ganglion Cells in a Non-Image-Forming Visual Circuit of the Mouse Retina. AB - An inner retinal microcircuit composed of dopamine (DA)-containing amacrine cells and melanopsin-containing, intrinsically photosensitive retinal ganglion cells (M1 ipRGCs) process information about the duration and intensity of light exposures, mediating light adaptation, circadian entrainment, pupillary reflexes, and other aspects of non-image-forming vision. The neural interaction is reciprocal: M1 ipRGCs excite DA amacrine cells, and these, in turn, feed inhibition back onto M1 ipRGCs. We found that the neuropeptide somatostatin [somatotropin release inhibiting factor (SRIF)] also inhibits the intrinsic light response of M1 ipRGCs and postulated that, to tune the bidirectional interaction of M1 ipRGCs and DA amacrine cells, SRIF amacrine cells would provide inhibitory modulation to both cell types. SRIF amacrine cells, DA amacrine cells, and M1 ipRGCs form numerous contacts. DA amacrine cells and M1 ipRGCs express the SRIF receptor subtypes sst(2A) and sst4 respectively. SRIF modulation of the microcircuit was investigated with targeted patch-clamp recordings of DA amacrine cells in TH-RFP mice and M1 ipRGCs in OPN4-EGFP mice. SRIF increases K(+) currents, decreases Ca(2+) currents, and inhibits spike activity in both cell types, actions reproduced by the selective sst(2A) agonist L-054,264 (N-[(1R)-2 [[[(1S*,3R*)-3-(aminomethyl)cyclohexyl]methyl]amino]-1-(1H-indol-3-ylmethyl)-2 oxoethyl]spiro[1H-indene-1,4'-piperidine]-1'-carboxamide) in DA amacrine cells and the selective sst4 agonist L-803,087 (N(2)-[4-(5,7-difluoro-2-phenyl-1H-indol 3-yl)-1-oxobutyl]-L-arginine methyl ester trifluoroacetate) in M1 ipRGCs. These parallel actions of SRIF may serve to counteract the disinhibition of M1 ipRGCs caused by SRIF inhibition of DA amacrine cells. This allows the actions of SRIF on DA amacrine cells to proceed with adjusting retinal DA levels without destabilizing light responses by M1 ipRGCs, which project to non-image-forming targets in the brain. PMID- 26631477 TI - NMDA Receptors Containing the GluN2D Subunit Control Neuronal Function in the Subthalamic Nucleus. AB - The GluN2D subunit of the NMDA receptor is prominently expressed in the basal ganglia and associated brainstem nuclei, including the subthalamic nucleus (STN), globus pallidus, striatum, and substantia nigra. However, little is known about how GluN2D-containing NMDA receptors contribute to synaptic activity in these regions. Using Western blotting of STN tissue punches, we demonstrated that GluN2D is expressed in the rat STN throughout development [age postnatal day 7 (P7)-P60] and in the adult (age P120). Immunoelectron microscopy of the adult rat brain showed that GluN2D is predominantly expressed in dendrites, unmyelinated axons, and axon terminals within the STN. Using subunit-selective allosteric modulators of NMDA receptors (TCN-201, ifenprodil, CIQ, and DQP-1105), we provide evidence that receptors containing the GluN2B and GluN2D subunits mediate responses to exogenously applied NMDA and glycine, as well as synaptic NMDA receptor activation in the STN of rat brain slices. EPSCs in the STN were mediated primarily by AMPA and NMDA receptors and GluN2D-containing NMDA receptors controlled the slow deactivation time course of EPSCs in the STN. In vivo recordings from the STN of anesthetized adult rats demonstrated that the spike firing rate was increased by the GluN2C/D potentiator CIQ and decreased by the GluN2C/D antagonist DQP-1105, suggesting that NMDA receptor activity can influence STN output. These data indicate that the GluN2B and GluN2D NMDA receptor subunits contribute to synaptic activity in the STN and may represent potential therapeutic targets for modulating subthalamic neuron activity in neurological disorders such as Parkinson's disease. PMID- 26631478 TI - The Role of 5-HT3 Receptors in Signaling from Taste Buds to Nerves. AB - Activation of taste buds triggers the release of several neurotransmitters, including ATP and serotonin (5-hydroxytryptamine; 5-HT). Type III taste cells release 5-HT directly in response to acidic (sour) stimuli and indirectly in response to bitter and sweet tasting stimuli. Although ATP is necessary for activation of nerve fibers for all taste stimuli, the role of 5-HT is unclear. We investigated whether gustatory afferents express functional 5-HT3 receptors and, if so, whether these receptors play a role in transmission of taste information from taste buds to nerves. In mice expressing GFP under the control of the 5 HT(3A) promoter, a subset of cells in the geniculate ganglion and nerve fibers in taste buds are GFP-positive. RT-PCR and in situ hybridization confirmed the presence of 5-HT(3A) mRNA in the geniculate ganglion. Functional studies show that only those geniculate ganglion cells expressing 5-HT3A-driven GFP respond to 10 MUM 5-HT and this response is blocked by 1 MUM ondansetron, a 5-HT3 antagonist, and mimicked by application of 10 MUM m-chlorophenylbiguanide, a 5 HT3 agonist. Pharmacological blockade of 5-HT3 receptors in vivo or genetic deletion of the 5-HT3 receptors reduces taste nerve responses to acids and other taste stimuli compared with controls, but only when urethane was used as the anesthetic. We find that anesthetic levels of pentobarbital reduce taste nerve responses apparently by blocking the 5-HT3 receptors. Our results suggest that 5 HT released from type III cells activates gustatory nerve fibers via 5-HT3 receptors, accounting for a significant proportion of the neural taste response. PMID- 26631480 TI - MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease. AB - In sickle cell disease (SCD), treatment of recurrent vasoocclusive episodes, leading to pain crises and organ damage, is still a therapeutic challenge. Vasoocclusion is caused primarily by adherence of homozygous for hemoglobin S (SS) red blood cells (SSRBCs) and leukocytes to the endothelium. We tested the therapeutic benefits of MEK1/2 inhibitors in reversing vasoocclusion in nude and humanized SCD mouse models of acute vasoocclusive episodes using intravital microscopy. Administration of 0.2, 0.3, 1, or 2 mg/kg MEK1/2 inhibitor to TNF alpha-pretreated nude mice before human SSRBC infusion inhibited SSRBC adhesion in inflamed vessels, prevented the progression of vasoocclusion, and reduced SSRBC organ sequestration. By use of a more clinically relevant protocol, 0.3 or 1 mg/kg MEK1/2 inhibitor given to TNF-alpha-pretreated nude mice after human SSRBC infusion and onset of vasoocclusion reversed SSRBC adhesion and vasoocclusion and restored blood flow. In SCD mice, 0.025, 0.05, or 0.1 mg/kg MEK1/2 inhibitor also reversed leukocyte and erythrocyte adhesion after the inflammatory trigger of vasoocclusion and improved microcirculatory blood flow. Cell adhesion was reversed by shedding of endothelial E-selectin, P-selectin, and alphavbeta3 integrin, and leukocyte CD44 and beta2 integrin. Thus, MEK1/2 inhibitors, by targeting the adhesive function of SSRBCs and leukocytes, could represent a valuable therapeutic intervention for acute sickle cell vasoocclusive crises. PMID- 26631479 TI - Miro1 Regulates Activity-Driven Positioning of Mitochondria within Astrocytic Processes Apposed to Synapses to Regulate Intracellular Calcium Signaling. AB - It is fast emerging that maintaining mitochondrial function is important for regulating astrocyte function, although the specific mechanisms that govern astrocyte mitochondrial trafficking and positioning remain poorly understood. The mitochondrial Rho-GTPase 1 protein (Miro1) regulates mitochondrial trafficking and detachment from the microtubule transport network to control activity dependent mitochondrial positioning in neurons. However, whether Miro proteins are important for regulating signaling-dependent mitochondrial dynamics in astrocytic processes remains unclear. Using live-cell confocal microscopy of rat organotypic hippocampal slices, we find that enhancing neuronal activity induces transient mitochondrial remodeling in astrocytes, with a concomitant, transient reduction in mitochondrial trafficking, mediated by elevations in intracellular Ca(2+). Stimulating neuronal activity also induced mitochondrial confinement within astrocytic processes in close proximity to synapses. Furthermore, we show that the Ca(2+)-sensing EF-hand domains of Miro1 are important for regulating mitochondrial trafficking in astrocytes and required for activity-driven mitochondrial confinement near synapses. Additionally, activity-dependent mitochondrial positioning by Miro1 reciprocally regulates the levels of intracellular Ca(2+) in astrocytic processes. Thus, the regulation of intracellular Ca(2+) signaling, dependent on Miro1-mediated mitochondrial positioning, could have important consequences for astrocyte Ca(2+) wave propagation, gliotransmission, and ultimately neuronal function. PMID- 26631481 TI - mTOR disruption causes intestinal epithelial cell defects and intestinal atrophy postinjury in mice. AB - Intestinal stem cells (ISCs) drive small intestinal epithelial homeostasis and regeneration. Mechanistic target of rapamycin (mTOR) regulates stem and progenitor cell metabolism and is frequently dysregulated in human disease, but its physiologic functions in the mammalian small intestinal epithelium remain poorly defined. We disrupted the genes mTOR, Rptor, Rictor, or both Rptor and Rictor in mouse ISCs, progenitors, and differentiated intestinal epithelial cells (IECs) using Villin-Cre. Mutant tissues and wild-type or heterozygous littermate controls were analyzed by histologic immunostaining, immunoblots, and proliferation assays. A total of 10 Gy irradiation was used to injure the intestinal epithelium and induce subsequent crypt regeneration. We report that mTOR supports absorptive enterocytes and secretory Paneth and goblet cell function while negatively regulating chromogranin A-positive enteroendocrine cell number. Through additional Rptor, Rictor, and Rptor/Rictor mutant mouse models, we identify mechanistic target of rapamycin complex 1 as the major IEC regulatory pathway, but mechanistic target of rapamycin complex 2 also contributes to ileal villus maintenance and goblet cell size. Homeostatic adult small intestinal crypt cell proliferation, survival, and canonical wingless-int (WNT) activity are not mTOR dependent, but Olfm4(+) ISC/progenitor population maintenance and crypt regeneration postinjury require mTOR. Overall, we conclude that mTOR regulates multiple IEC lineages and promotes stem and progenitor cell activity during intestinal epithelium repair postinjury. PMID- 26631482 TI - The alternative complement pathway aids in vascular regression during the early stages of a murine model of proliferative retinopathy. AB - Proliferative retinopathic diseases often progress in 2 phases: initial regression of retinal vasculature (phase 1) followed by subsequent neovascularization (NV) (phase 2). The immune system has been shown to aid in vascular pruning in such retinopathies; however, little is known about the role of the alternative complement pathway in the initial vascular regression phase. Using a mouse model of oxygen-induced retinopathy (OIR), we observed that alternative complement pathway-deficient mice (Fb(-/-)) exhibited a mild decrease in vascular loss at postnatal day (P)8 compared with age- and strain-matched controls (P = 0.035). Laser capture microdissection was used to isolate the retinal blood vessels. Expression of the complement inhibitors Cd55 and Cd59 was significantly decreased in blood vessels isolated from hyperoxic retinas compared with those from normoxic control mice. Vegf expression was measured at P8 and found to be significantly lower in OIR mice than in normoxic control mice (P = 0.0048). Further examination of specific Vegf isoform expression revealed a significant decrease in Vegf120 (P = 0.00032) and Vegf188 (P = 0.0092). In conjunction with the major modulating effects of Vegf during early retinal vascular development, our data suggest a modest involvement of the alternative complement pathway in targeting vessels for regression in the initial vaso obliteration stage of OIR. PMID- 26631483 TI - L-plastin Ser5 phosphorylation in breast cancer cells and in vitro is mediated by RSK downstream of the ERK/MAPK pathway. AB - Deregulated cell migration and invasion are hallmarks of metastatic cancer cells. Phosphorylation on residue Ser5 of the actin-bundling protein L-plastin activates L-plastin and has been reported to be crucial for invasion and metastasis. Here, we investigate signal transduction leading to L-plastin Ser5 phosphorylation using 4 human breast cancer cell lines. Whole-genome microarray analysis comparing cell lines with different invasive capacities and corresponding variations in L-plastin Ser5 phosphorylation level revealed that genes of the ERK/MAPK pathway are differentially expressed. It is noteworthy that in vitro kinase assays showed that ERK/MAPK pathway downstream ribosomal protein S6 kinases alpha-1 (RSK1) and alpha-3 (RSK2) are able to directly phosphorylate L plastin on Ser5. Small interfering RNA- or short hairpin RNA-mediated knockdown and activation/inhibition studies followed by immunoblot analysis and computational modeling confirmed that ribosomal S6 kinase (RSK) is an essential activator of L-plastin. Migration and invasion assays showed that RSK knockdown led to a decrease of up to 30% of migration and invasion of MDA-MB-435S cells. Although the presence of L-plastin was not necessary for migration/invasion of these cells, immunofluorescence assays illustrated RSK-dependent recruitment of Ser5-phosphorylated L-plastin to migratory structures. Altogether, we provide evidence that the ERK/MAPK pathway is involved in L-plastin Ser5 phosphorylation in breast cancer cells with RSK1 and RSK2 kinases able to directly phosphorylate L-plastin residue Ser5. PMID- 26631484 TI - Loner or socializer? Ravens' adrenocortical response to individual separation depends on social integration. AB - Non-breeding common ravens (Corvus corax) live in complex social groups with a high degree of fission-fusion dynamics. They form valuable relationships and alliances with some conspecifics, while taking coordinated action against others. In ravens, affiliates reconcile their conflicts, console each other after conflicts with a third party, and provide each other with social support - all behaviors that presumably reduce corticosterone levels and alleviate stress. However, how well an individual is socially integrated in a (sub)group might vary substantially. This raises the question whether the social integration of a raven affects its stress responses to fission-fusion dynamics. The present study aims to investigate this effect experimentally by separating single ravens (n=16) individually from their group for four days and subsequently reintroducing them. To determine stress response patterns in the separated individuals we measured the amounts of immunoreactive corticosterone metabolites (CM) in droppings. We compared two enzyme immunoassays, which we validated by conducting an ACTH challenge, and finally decided to apply an 11-oxoetiocholanolone enzyme immunoassay. Additionally, we determined levels of social integration using focal observations. Our findings suggest that a strong social integration is related to low CM levels when the individuals are within the group and high levels during separations, implying that separation leads to stress in these birds. In contrast, poorly socially integrated ravens seem to exhibit the opposite pattern, indicating that to them group living is more stressful than being temporarily separated. We, therefore, conclude that the birds' adrenocortical activity is modulated by their social integration. PMID- 26631485 TI - Depression mediates impaired glucose tolerance and cognitive dysfunction: A neuromodulatory role of rosiglitazone. AB - Comorbidity of depression and diabetes is a serious risk factor worsening the complications such as cognitive function and locomotion. Treatment under this condition becomes extremely complicated. Insulin signaling and autophagy pathways are involved in modulation of learning and memory. Rosiglitazone (ROSI) ameliorate cognitive deficit associated with depression and insulin resistance. In the present study, we investigated the effect of ROSI against chronic unpredictable stress (CUS) induced depression as a risk factor for diabetes and behavioral dysfunctions. Adult male Swiss albino mice were exposed to CUS alongside ROSI (5mg/kg/day) treatment for 21days. Thereafter, animals were subjected to different behavioral studies to assess depressive like behavior, cognition and locomotion. The effect of ROSI on insulin signaling, autophagy and apoptosis were evaluated in the hippocampus. CUS resulted in depressive like behavior, cognitive impairment and hypolocomotion associated with oxidative stress, impaired glucose tolerance and hypercorticosteronemia. CUS significantly impaired hippocampal insulin signaling, membrane translocation of glucose transporter type 4 (GLUT4) as well as decreased the expression of autophagy5, autophagy7, B-cell lymphoma 2 and apoptosis inhibitory protein 2. ROSI significantly reduced depressive like behavior, postprandial blood glucose, hypercorticosteronemia, oxidative and inflammatory stress, and apoptosis in stressed mice. Moreover, ROSI treatment effectively improved hippocampal insulin signaling, GLUT4 membrane translocation and cognitive performance in depressed mice. ROSI administration might prove to be effective for neurological disorders associated with depressive like behavior and impaired glucose tolerance. PMID- 26631486 TI - Inflammatory markers predict episodes of wheezing during the first year of life in Bangladesh. AB - BACKGROUND: Environmental factors that influence wheezing in early childhood in the developing world are not well understood and may be useful in predicting respiratory outcomes. Therefore, our objective was to determine the factors that can predict wheezing. METHODS: Children from Dhaka, Bangladesh were recruited at birth and episodes of wheezing were measured alongside nutritional, immunological and socioeconomic factors over a one-year period. Poisson Regression with variable selection was utilized to determine what factors were associated with wheezing. RESULTS: Elevated serum IL-10 (rate ratio (RR) = 1.51, 95% confidence interval (CI): 1.22-1.87), IL-1beta (RR = 1.55, 95% CI: 1.26-1.93) C-reactive protein (CRP) (RR = 1.41, 95% CI: 1.03-1.93) in early life, and male gender (RR = 1.52, 95% CI: 1.27-1.82) predicted increased wheezing episodes. Conversely, increased fecal alpha-1-antitrypsin (RR = 0.87, 95% CI: 0.76-1.00) and family income (RR = 0.98, 95% CI: 0.97-0.99) were associated with a decreased number of episodes of wheezing. CONCLUSIONS: Systemic inflammation early in life, poverty, and male sex placed infants at risk of more episodes of wheezing during their first year of life. These results support the hypothesis that there is a link between inflammation in infancy and the development of respiratory illness later in life and provide specific biomarkers that can predict wheezing in a low-income country. PMID- 26631488 TI - Occurrence of Borrelia burgdorferi s.l. in different genera of mosquitoes (Culicidae) in Central Europe. AB - Lyme disease or Lyme borreliosis is a vector-borne infectious disease caused by spirochetes of the Borrelia burgdorferi sensu lato complex. Some stages of the borrelial transmission cycle in ticks (transstadial, feeding and co-feeding) can potentially occur also in insects, particularly in mosquitoes. In the present study, adult as well as larval mosquitoes were collected at 42 different geographical locations throughout Germany. This is the first study, in which German mosquitoes were analyzed for the presence of Borrelia spp. Targeting two specific borrelial genes, flaB and ospA encoding for the subunit B of flagellin and the outer surface protein A, the results show that DNA of Borrelia afzelii, Borrelia bavariensis and Borrelia garinii could be detected in ten Culicidae species comprising four distinct genera (Aedes, Culiseta, Culex, and Ochlerotatus). Positive samples also include adult specimens raised in the laboratory from wild-caught larvae indicating that transstadial and/or transovarial transmission might occur within a given mosquito population. PMID- 26631487 TI - Rop, the Sec1/Munc18 homolog in Drosophila, is required for furrow ingression and stable cell shape during cytokinesis. AB - Physically separating daughter cells during cytokinesis requires contraction of an actin-myosin ring and vesicle-mediated membrane addition at the cleavage furrow. To identify vesicle trafficking proteins that function in cytokinesis, we screened deficiencies and mutations of candidate genes by live imaging the mitotic domains of the Drosophila embryo. In embryos homozygous for some of these deficiencies, we observed several cytokinesis phenotypes, including slow furrow ingression and increased membrane blebbing. We also found that cytokinesis required the Sec1/Munc18 homolog Rop, which interacts with syntaxin and mediates exocytosis at the plasma membrane. In a temperature-sensitive Rop mutant (Rop(TS)), the contractile ring disassembled during furrow ingression, indicating that maintenance of the ring required vesicle addition. Furthermore, in some dividing Rop(TS) cells, the shape of the daughter cells became unstable, causing cytokinesis failure. These results further highlight the importance of vesicle trafficking in animal cytokinesis and show that vesicle fusion influences cell shape during cytokinesis. PMID- 26631489 TI - metilene: fast and sensitive calling of differentially methylated regions from bisulfite sequencing data. AB - The detection of differentially methylated regions (DMRs) is a necessary prerequisite for characterizing different epigenetic states. We present a novel program, metilene, to identify DMRs within whole-genome and targeted data with unrivaled specificity and sensitivity. A binary segmentation algorithm combined with a two-dimensional statistical test allows the detection of DMRs in large methylation experiments with multiple groups of samples in minutes rather than days using off-the-shelf hardware. metilene outperforms other state-of-the-art tools for low coverage data and can estimate missing data. Hence, metilene is a versatile tool to study the effect of epigenetic modifications in differentiation/development, tumorigenesis, and systems biology on a global, genome-wide level. Whether in the framework of international consortia with dozens of samples per group, or even without biological replicates, it produces highly significant and reliable results. PMID- 26631490 TI - A role for palindromic structures in the cis-region of maize Sirevirus LTRs in transposable element evolution and host epigenetic response. AB - Transposable elements (TEs) proliferate within the genome of their host, which responds by silencing them epigenetically. Much is known about the mechanisms of silencing in plants, particularly the role of siRNAs in guiding DNA methylation. In contrast, little is known about siRNA targeting patterns along the length of TEs, yet this information may provide crucial insights into the dynamics between hosts and TEs. By focusing on 6456 carefully annotated, full-length Sirevirus LTR retrotransposons in maize, we show that their silencing associates with underlying characteristics of the TE sequence and also uncover three features of the host-TE interaction. First, siRNA mapping varies among families and among elements, but particularly along the length of elements. Within the cis regulatory portion of the LTRs, a complex palindrome-rich region acts as a hotspot of both siRNA matching and sequence evolution. These patterns are consistent across leaf, tassel, and immature ear libraries, but particularly emphasized for floral tissues and 21- to 22-nt siRNAs. Second, this region has the ability to form hairpins, making it a potential template for the production of miRNA-like, hairpin-derived small RNAs. Third, Sireviruses are targeted by siRNAs as a decreasing function of their age, but the oldest elements remain highly targeted, partially by siRNAs that cross-map to the youngest elements. We show that the targeting of older Sireviruses reflects their conserved palindromes. Altogether, we hypothesize that the palindromes aid the silencing of active elements and influence transposition potential, siRNA targeting levels, and ultimately the fate of an element within the genome. PMID- 26631491 TI - Antiatherosclerotic Effects of 1-Methylnicotinamide in Apolipoprotein E/Low Density Lipoprotein Receptor-Deficient Mice: A Comparison with Nicotinic Acid. AB - 1-Methylnicotinamide (MNA), the major endogenous metabolite of nicotinic acid (NicA), may partially contribute to the vasoprotective properties of NicA. Here we compared the antiatherosclerotic effects of MNA and NicA in apolipoprotein E (ApoE)/low-density lipoprotein receptor (LDLR)-deficient mice. ApoE/LDLR(-/-) mice were treated with MNA or NicA (100 mg/kg). Plaque size, macrophages, and cholesterol content in the brachiocephalic artery, endothelial function in the aorta, systemic inflammation, platelet activation, as well as the concentration of MNA and its metabolites in plasma and urine were measured. MNA and NicA reduced atherosclerotic plaque area, plaque inflammation, and cholesterol content in the brachiocephalic artery. The antiatherosclerotic actions of MNA and NicA were associated with improved endothelial function, as evidenced by a higher concentration of 6-keto-prostaglandin F1 alpha and nitrite/nitrate in the aortic ring effluent, inhibition of platelets (blunted thromboxane B2 generation), and inhibition of systemic inflammation (lower plasma concentration of serum amyloid P, haptoglobin). NicA treatment resulted in an approximately 2-fold higher concentration of MNA and its metabolites in urine and a 4-fold higher nicotinamide/MNA ratio in plasma, compared with MNA treatment. In summary; MNA displays pronounced antiatherosclerotic action in ApoE/LDLR(-/-) mice, an effect associated with an improvement in prostacyclin- and nitric oxide-dependent endothelial function, inhibition of platelet activation, inhibition of inflammatory burden in plaques, and diminished systemic inflammation. Despite substantially higher MNA availability after NicA treatment, compared with an equivalent dose of MNA, the antiatherosclerotic effect of NicA was not stronger. We suggest that detrimental effects of NicA or its metabolites other than MNA may limit beneficial effects of NicA-derived MNA. PMID- 26631492 TI - Analyses of movement and contact of two nucleated cells using a gas-driven micropipette aspiration technique. AB - Adhesion between two nucleated cells undergoes specific significances in immune responses and tumor metastasis since cellular adhesive molecules usually express on two apposed cell membranes. However, quantification of the interactions between two nucleated cells is still challenging in microvasculature. Here distinct cell systems were used, including three types of human cells (Jurkat cell or PMN vs. MDA-MB-231 cell) and two kinds of murine native cells (PMN vs. liver sinusoidal endothelial cell). Cell movement, compression to, and relaxation from the counterpart cell were quantified using an in-house developed gas-driven micropipette aspiration technique (GDMAT). This assay is robust to quantify this process since cell movement and contact inside a pipette are independent of the repeated test cycles. Measured approaching or retraction velocity follows well a normal distribution, which is independent on the cycle period. Contact area or duration also fits a Gaussian distribution and moreover contact duration is linearly correlated with the cycle period. Cell movement is positively related to gas flux but negatively associated to medium viscosity. Cell adhesion tends to reach an equilibrium state with increase of cycle period or contact duration. These results further the understanding in the dynamics of cell movement and contact in microvasculature. PMID- 26631493 TI - Radio Frequency Magnetron Sputtering Deposition of TiO2 Thin Films and Their Perovskite Solar Cell Applications. AB - In this work, we report a physical deposition based, compact (cp) layer synthesis for planar heterojunction perovskite solar cells. Typical solution-based synthesis of cp layer for perovskite solar cells involves low-quality of thin films, high-temperature annealing, non-flexible devices, limitation of large scale production and that the effects of the cp layer on carrier transport have not been fully understood. In this research, using radio frequency magnetron sputtering (RFMS), TiO2 cp layers were fabricated and the thickness could be controlled by deposition time; CH3NH3PbI3 films were prepared by evaporation &immersion (E &I) method, in which PbI2 films made by thermal evaporation technique were immersed in CH3NH3I solution. The devices exhibit power conversion efficiency (PCE) of 12.1% and the photovoltaic performance can maintain 77% of its initial PCE after 1440 h. The method developed in this study has the capability of fabricating large active area devices (40 * 40 mm(2)) showing a promising PCE of 4.8%. Low temperature and flexible devices were realized and a PCE of 8.9% was obtained on the PET/ITO substrates. These approaches could be used in thin film based solar cells which require high-quality films leading to reduced fabrication cost and improved device performance. PMID- 26631494 TI - National Health Spending In 2014: Faster Growth Driven By Coverage Expansion And Prescription Drug Spending. AB - US health care spending increased 5.3 percent to $3.0 trillion in 2014. On a per capita basis, health spending was $9,523 in 2014, an increase of 4.5 percent from 2013. The share of gross domestic product devoted to health care spending was 17.5 percent, up from 17.3 percent in 2013. The faster growth in 2014 that followed five consecutive years of historically low growth was primarily due to the major coverage expansions under the Affordable Care Act, particularly for Medicaid and private health insurance, which contributed to an increase in the insured share of the population. Additionally, the introduction of new hepatitis C drugs contributed to rapid growth in retail prescription drug expenditures, which increased by 12.2 percent in 2014. Spending by the federal government grew at a faster rate in 2014 than spending by other sponsors of health care, leading to a 2-percentage-point increase in its share of total health care spending between 2013 and 2014. PMID- 26631495 TI - Persistent phenotypic shift in cardiac fibroblasts: impact of transient renin angiotensin system inhibition. AB - Fibrotic cardiac remodeling ultimately leads to heart failure - a debilitating and costly condition. Select antihypertensive agents have been effective in reducing or slowing the development of cardiac fibrosis. Moreover, some experimental studies have shown that the reduction in fibrosis induced by these agents persists long after stopping treatment. What has not been as well investigated is whether this transient treatment results in a protection against future fibrotic cardiac remodeling. In the present review, previously published studies are re-examined to assess whether the relative percent increase in collagen deposition over an off-treatment period is attenuated, relative to control, following transient antihypertensive treatment in young or adult rats. Present findings suggest that transient inhibition of the renin angiotensin system (RAS) not only produces a sustained reduction in cardiac fibrosis, but also results in a degree of protection against future collagen deposition. In addition, prior transient RAS inhibition appears to alter the cardiac fibroblast phenotype such that these cells show a muted response to myocardial injury - namely reduced proliferation, chemokine release, and collagen deposition. This review puts forth several potential mechanisms underlying this long-term cardiac protection that is afforded by transient RAS inhibition. Specifically, fibroblast phenotypic change, cardiac fibroblast apoptosis, sustained suppression of the RAS, persistent reduction in left ventricular hypertrophy, and persistent reduction in arterial pressure are each discussed. Identifying the mechanisms ultimately responsible for this change in cardiac fibroblast response to injury, hypertension, and aging may reveal novel targets for therapy. PMID- 26631497 TI - New anthyarrhythmic drugs for atrial fibrillation. AB - Atrial fibrillation (AF) is a common arrhythmia associated with increased mortality and morbidity. Different studies have shown no significant difference between rhythm and rate control strategies in terms of mortality. Moreover, the use of antiarrhythmic drugs is afflicted by cardiac and extracardiac toxicity and related costs of hospitalization. Nevertheless, some patients require a rhythm control strategy and new anti-AF agents are being sought. Only few novel agents showed promising results in term of efficacy and safety. Dronedarone and vernakalant are two of these compounds, respectively introduced for the chronic and acute rhythm control of AF. This article will review pharmacology and clinical evidence on the use of dronedarone and vernakalant and will mention currently investigated new antiarrhythmic drugs. PMID- 26631496 TI - Modifying the mechanics of healing infarcts: Is better the enemy of good? AB - Myocardial infarction (MI) is a major source of morbidity and mortality worldwide, with over 7 million people suffering infarctions each year. Heart muscle damaged during MI is replaced by a collagenous scar over a period of several weeks, and the mechanical properties of that scar tissue are a key determinant of serious post-MI complications such as infarct rupture, depression of heart function, and progression to heart failure. Thus, there is increasing interest in developing therapies that modify the structure and mechanics of healing infarct scar. Yet most prior attempts at therapeutic scar modification have failed, some catastrophically. This article reviews available information about the mechanics of healing infarct scar and the functional impact of scar mechanical properties, and attempts to infer principles that can better guide future attempts to modify scar. One important conclusion is that collagen structure, mechanics, and remodeling of healing infarct scar vary so widely among experimental models that any novel therapy should be tested across a range of species, infarct locations, and reperfusion protocols. Another lesson from past work is that the biology and mechanics of healing infarcts are sufficiently complex that the effects of interventions are often counterintuitive; for example, increasing infarct stiffness has little effect on heart function, and inhibition of matrix metalloproteases (MMPs) has little effect on scar collagen content. Computational models can help explain such counterintuitive results, and are becoming an increasingly important tool for integrating known information to better identify promising therapies and design experiments to test them. Moving forward, potentially exciting new opportunities for therapeutic modification of infarct mechanics include modulating anisotropy and promoting scar compaction. PMID- 26631498 TI - Plasmon-gating photoluminescence in graphene/GeSi quantum dots hybrid structures. AB - The ability to control light-matter interaction is central to several potential applications in lasing, sensing, and communication. Graphene plasmons provide a way of strongly enhancing the interaction and realizing ultrathin optoelectronic devices. Here, we find that photoluminescence (PL) intensities of the graphene/GeSi quantum dots hybrid structures are saturated and quenched under positive and negative voltages at the excitation of 325 nm, respectively. A mechanism called plasmon-gating effect is proposed to reveal the PL dependence of the hybrid structures on the external electric field. On the contrary, the PL intensities at the excitation of 405 and 795 nm of the hybrid structures are quenched due to the charge transfer by tuning the Fermi level of graphene or the blocking of the excitons recombination by excitons separation effect. The results also provide an evidence for the charge transfer mechanism. The plasmon gating effect on the PL provides a new way to control the optical properties of graphene/QD hybrid structures. PMID- 26631499 TI - Expression of Genes Involved in Cellular Adhesion and Extracellular Matrix Remodeling Correlates with Poor Survival of Patients with Renal Cancer. AB - PURPOSE: Renal cell carcinoma is the most common highly metastatic kidney malignancy. Adhesion has a crucial role in the metastatic process. TGF (transforming growth factor)-beta1 is a pleiotropic cytokine that influences cancerous transformation. We hypothesized that 1) changes in the expression of adhesion related genes may influence survival rate of patients with renal cell carcinoma and 2) TGF-beta1 may contribute to changed expression of adhesion related genes. MATERIALS AND METHODS: Two-step quantitative real-time polymerase chain reaction arrays were used to analyze the expression of adhesion related genes in 77 tumors and matched pair controls. The prognostic significance of genes was evaluated in TCGA (The Cancer Genome Atlas) data on 468 patients with renal cell carcinoma. Quantitative real-time polymerase chain reaction and Western blot were applied for TGF-beta1 analysis. TGF-beta1 mediated regulation of gene expression was analyzed by TGF-beta1 supplementation of Caki-2 cells and quantitative real-time polymerase chain reaction. RESULTS: The expression of 19 genes related to adhesion and extracellular matrix remodeling was statistically significantly disturbed in renal cell carcinoma compared with controls. The 10 gene expression signature (COL1A1, COL5A1, COL11A1, FN1, ICAM1, ITGAL, ITGAM, ITGB2, THBS2 and TIMP1) correlated with poor survival (HR 2.85, p = 5.7e-10). TGF beta1 expression was 22 times higher in renal cell carcinoma than in controls (p <0.0001). TGF-beta1 induced expression of TGFBI, COL1A1, COL5A1, COL8A1, FN1, ITGA5, ITGAM and TIMP1 in a renal cell carcinoma derived cell line. CONCLUSIONS: Disturbed expression of genes involved in adhesion and extracellular matrix remodeling develops early during renal cell carcinoma carcinogenesis and correlates with poor survival. TGF-beta1 contributes to changed expression of extracellular matrix and adhesion related genes. Bioinformatic analysis performed on a broad panel of cancers of nonkidney origin suggests that disturbed expression of genes related to extracellular matrix and adhesion may be a universal feature of cancerous progression. PMID- 26631501 TI - Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. AB - New insights into the interaction between the immune system and the tumor microenvironment have led to the development of checkpoint inhibitors that target the PD-1/PD-L1 pathway. Pembrolizumab (MK-3475, lambrolizumab, Keytruda((r))) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non small-cell lung cancer and for unresectable/metastatic melanoma. This article will discuss the results of early-phase trials of pembrolizumab in thoracic malignancies as well as ongoing studies aimed to confirm clinical benefit. PMID- 26631502 TI - Toward High-Value Care: A Quality Improvement Initiative to Reduce Unnecessary Repeat Complete Blood Counts and Basic Metabolic Panels on a Pediatric Hospitalist Service. AB - OBJECTIVE: Achieving high-value health care is a goal of health care providers who strive to increase quality and decrease cost. Decreasing laboratory tests is a potential method to increase value. We used quality improvement methodology to decrease the percentage of unnecessary complete blood counts (CBCs) and basic metabolic panels (BMPs) obtained on a pediatric hospital medicine service from 13.5% to <5%. METHODS: A pre- and postintervention design was conducted including all patients admitted to 2 hospital medicine teams between May 2013 and December 2014. Multiple interventions linked to key drivers were tested through rapid plan do-study-act cycles. Primary and secondary outcome measures, percent reduction of unnecessary CBCs and BMPs, and consecutive day tests were analyzed using statistical process control. Total billed charges, laboratory charges, 7-day readmission rates, and length of stay were compared pre- and postintervention. RESULTS: Primary outcome of unnecessary CBCs and BMPs was reduced from a baseline of 13.5% to 4.5%. Secondary outcome measure of consecutive day testing was reduced from 20.9% to 8.5%. Median laboratory charges decreased significantly ($842 [$256-$1863] vs $800 [$222-$1616], P = .002), with no significant differences in total billed charges, 7-day readmission rates, or length of stay. CONCLUSIONS: Rapid cycle plan-do-study-act methodology, initially focusing on the inclusion of a daily laboratory plan in progress notes, was an effective means to improve laboratory utilization and decrease laboratory charges without adversely affecting other quality measures. Spreading these efforts to different patient populations and laboratory tests could have a demonstrable effect on the value of health care. PMID- 26631503 TI - Mouse Crumbs3 sustains epithelial tissue morphogenesis in vivo. AB - The human apical protein CRB3 (Crb3 in mouse) organizes epithelial cell polarity. Loss of CRB3 expression increases the tumorogenic potential of cultured epithelial cells and favors metastasis formation in nude mice. These data emphasize the need of in vivo models to study CRB3 functions. Here, we report the phenotypic analysis of a novel Crb3 knockout mouse model. Crb3-deficient newborn mice show improper clearance of airways, suffer from respiratory distress and display perinatal lethality. Crb3 is also essential to maintain apical membrane identity in kidney epithelial cells. Numerous kidney cysts accompany these polarity defects. Impaired differentiation of the apical membrane is also observed in a subset of cells of the intestinal epithelium. This results in improper remodeling of adhesive contacts in the developing intestinal epithelium, thereby leading to villus fusion. We also noted a strong increase in cytoplasmic beta-catenin levels in intestinal epithelial cells. beta-catenin is a mediator of the Wnt signaling pathway, which is overactivated in the majority of colon cancers. In addition to clarifying the physiologic roles of Crb3, our study highlights that further functional analysis of this protein is likely to provide insights into the etiology of diverse pathologies, including respiratory distress syndrome, polycystic kidney disease and cancer. PMID- 26631504 TI - Inhibitory effect of imperatorin on insulin-like growth factor-1-induced sebum production in human sebocytes cultured in vitro. AB - AIMS: Acne is a common skin disease that originates in the sebaceous gland. The pathogenesis of acne is very complex, involving the increase of sebum production and perifollicular inflammation. In this study, we screened the anti-lipogenic material and demonstrated its effect using cultured human sebocytes. MAIN METHODS: Normal human sebocytes were cultured by explanting the sebaceous glands. To evaluate the anti-lipogenic effect, sebocytes were treated with test materials and (14)C-acetate incorporation assay was performed. KEY FINDINGS: To screen the anti-lipogenic materials, we tested the effect of many herbal plant extracts. We found that Angelica dahurica extract inhibited the insulin-like growth factor-1 (IGF-1)-induced sebum production in terms of squalene synthesis in sebocytes. Furthermore, imperatorin isolated from A. dahurica showed remarkable inhibitory effect on squalene production as well as squalene synthase promoter activity. To investigate the putative action mechanism, we tested the effect of imperatorin on intracellular signaling. The results showed that imperatorin inhibited IGF-1 induced phosphorylation of Akt. In addition, imperatorin significantly down regulated PPAR-gamma and SREBP-1, the important transcription factors for lipid synthesis. SIGNIFICANCE: These results suggest that imperatorin has a potential for reducing sebum production in sebocytes, and can be applicable for acne treatment. PMID- 26631505 TI - 7,8-Dihydroxyflavone inhibits adipocyte differentiation via antioxidant activity and induces apoptosis in 3T3-L1 preadipocyte cells. AB - AIMS: Anti-obesity effects of a natural plant flavonoid 7,8-dihydroxyflavone (7,8 DHF) were evaluated using 3T3-L1 preadipocyte cells. MAIN METHODS: The cell viability was determined using MTT assay. Effects of 7,8-DHF on intracellular lipid droplets and intracellular reactive oxygen species (ROS) were measured using a 2,7-dichlorofluorescein diacetate (DCF-DA) assay and Oil Red O staining method, respectively. Apoptotic cell death was monitored by annexin V-FITC/PI double staining and by a TUNEL assay. Antioxidant enzyme mRNA levels and protein expression of adipogenic transcription factors were determined by real-time PCR and Western blotting, respectively. KEY FINDINGS: Whereas the cell viability of 3T3-L1 preadipocytes was not affected by lower concentrations of 7,8-DHF (<20 MUM), higher concentrations of 7,8-DHF (>20 MUM) induced apoptotic cell death. 7,8-DHF (<20 MUM) significantly reduced the intracellular lipid droplets and the expression of major adipogenic transcription factors, such as CCAAT/enhancer binding protein-alpha (C/EBP-alpha), C/EBP-beta, and peroxisome proliferator activated receptor-gamma (PPAR-gamma). 7,8-DHF treatment also dose-dependently reduced the intracellular ROS level, attenuated MAPK pathway activation, and increased the expression of antioxidant enzymes, such as Mn-superoxide dismutase (Mn-SOD), catalase (CAT), and heme oxygenase-1 (HO-1). SIGNIFICANCE: The results of this study indicated that 7,8-DHF inhibits the adipogenesis of 3T3-L1 preadipocyte cells by down-regulating the expression of adipogenic transcription factors, reduces lipid accumulation, and attenuates ROS accumulation by inducing antioxidant enzymes in differentiated 3T3-L1 cells, suggesting for the first time that 7,8-DHF has an anti-obesity effect in vitro via its anti-oxidant activity. PMID- 26631506 TI - Linagliptin attenuates diabetes-induced cerebral pathological neovascularization in a blood glucose-independent manner: Potential role of ET-1. AB - AIMS: We have shown that glycemic control with metformin or endothelin-1 (ET-1) inhibition with bosentan prevents and restores diabetes-mediated cerebral pathological remodeling and neovascularization. Our recent data suggest that linagliptin, a member of the dipeptidyl peptidase-4 inhibitor class of glucose lowering agents, prevents cerebrovascular remodeling and dysfunction independent of its blood glucose lowering effects. We hypothesized that linagliptin prevents pathological neovascularization via the modulation of the ET-1 system. MATERIALS AND METHODS: 24-week old diabetic Goto-Kakizaki and nondiabetic Wistar rats were treated for 4weeks with either vehicle chow or chow containing 166mg/kg linagliptin. At termination, FITC-dextran was injected to visualize the vasculature. Brain sections were imaged by confocal microscopy for vascular density, tortuosity, vascular volume, and surface in both the cortex and striatum. Retinal acellular capillary formation was measured. Brain microvascular endothelial cells (BMVEC) isolated from control or diabetic rats were treated with linagliptin with or without ET-1 dual receptor antagonist and tested for angiogenic properties with cell migration and tube formation assays. KEY FINDING: Linagliptin reduced all indices of cerebral neovascularization compared with control rats. In vitro, linagliptin normalized the augmented angiogenic properties of BMVECs isolated from diabetic animals and bosentan reversed this response. Cells from diabetic animals had higher ET-1 and less ETB receptors than in control cells. Linagliptin significantly decreased ET-1 levels and increased ETB receptors. SIGNIFICANCE: ET system contributes to pathological neovascularization in diabetes as evidenced by restoration of functional angiogenesis by bosentan treatment and prevention of linagliptin-mediated improvement of angiogenesis in the in vitro model. PMID- 26631507 TI - Dietary effects on inositol phosphate breakdown in the crop of broilers. AB - The effect of diets differing in enzyme supplements, mineral phosphorus (P) and microwave wheat treatment on phytate hydrolysis and lower inositol phosphate isomers (InsPs) appearance in broiler crops was studied. The broilers (16- and 15 day-old) were assigned to 48 pens of 15 or 20 birds each (n = 8 pens per treatment) in Experiments 1 and 2, respectively. In Experiment 1, birds received a low-P wheat-soybean meal diet where the wheat was either microwave treated or not. These diets were offered without further supplementation or with added phytase (500 FTU/kg diet), alone or in combination with a xylanase (16,000 BXU/kg diet). In Experiment 2, two maize-soybean meal-based diets were fed, without or with monocalcium phosphate supplementation. Furthermore, these diets were offered without further supplementation or with phytase at 500 or 12,500 FTU/kg diet. On day 23 or 24 (Experiments 1 and 2, respectively), crop digesta were pooled per pen, freeze-dried and analysed for InsPs and the marker TiO2. Microwaving reduced the intrinsic phytase activity and InsP6 hydrolysis, but increased the concentration of Ins(1,2,3,4,5)P5 and Ins(1,2,4,5,6)P5 in the digesta of crop (Experiment 1). Microwave treatment significantly interacted with enzyme supplementation for Ins(1,2,5,6)P4 concentration, indicating a synergistic effect of intrinsic and supplied phytase in the crop. Xylanase tended to support phytase hydrolysis in diets with microwave-treated wheat. Phytase addition increased InsP6 hydrolysis up to 79% (Experiment 2). Thus, wheat phytase activity can cause high InsP6 hydrolysis in the crop. Treatment differences in lower InsPs indicated that hydrolysis of the first InsP6 phosphate group is not the only step in the degradation cascade in the crop of broilers that is influenced by dietary factors. PMID- 26631508 TI - Reduced Mucin-7 (Muc7) Sialylation and Altered Saliva Rheology in Sjogren's Syndrome Associated Oral Dryness. AB - Sjogren's syndrome is a chronic autoimmune disorder characterized by lymphocytic infiltration and hypofunction of salivary and lacrimal glands. This loss of salivary function leads to oral dryness, impaired swallowing and speech, and increased infection and is associated with other autoimmune diseases and an increased risk of certain cancers. Despite the implications of this prevalent disease, diagnosis currently takes years, partly due to the diversity in patient presentation. Saliva is a complicated biological fluid with major constituents, including heavily glycosylated mucins MUC5B and MUC7, important for its viscoelastic and hydrating and lubricating properties. This study investigated Sjogren's patient's perception of dryness (bother index questionnaires) along with the rheological, protein composition, and glycan analysis of whole mouth saliva and the saliva on the mucosal surface (residual mucosal saliva) to understand the properties that most affect patient wellbeing. Sjogren's patients exhibited a statistically significant reduction in residual mucosal saliva, salivary flow rate, and extensional rheology, spinnbarkeit (stringiness). Although the concentration of mucins MUC5B and MUC7 were similar between patients and controls, a comparison of protein Western blotting and glycan staining identified a reduction in mucin glycosylation in Sjogren's, particularly on MUC7. LC-MS/MS analysis of O-glycans released from MUC7 by beta-elimination revealed that although patients had an increase in core 1 sulfation, the even larger reduction in sialylation resulted in a global decline of charged glycans. This was primarily due to the loss of the extended core 2 disialylated structure, with and without fucosylation. A decrease in the extended, fucosylated core 2 disialylated structure on MUC7, residual mucosal wetness, and whole mouth saliva flow rate appeared to have a negative and cumulative effect on the perception of oral dryness. The observed changes in MUC7 glycosylation could be a potential diagnostic tool for saliva quality and taken into consideration for future therapies for this multifactorial syndrome. PMID- 26631510 TI - Quantitative Profiling of Protein Tyrosine Kinases in Human Cancer Cell Lines by Multiplexed Parallel Reaction Monitoring Assays. AB - Protein tyrosine kinases (PTKs) play key roles in cellular signal transduction, cell cycle regulation, cell division, and cell differentiation. Dysregulation of PTK-activated pathways, often by receptor overexpression, gene amplification, or genetic mutation, is a causal factor underlying numerous cancers. In this study, we have developed a parallel reaction monitoring-based assay for quantitative profiling of 83 PTKs. The assay detects 308 proteotypic peptides from 54 receptor tyrosine kinases and 29 nonreceptor tyrosine kinases in a single run. Quantitative comparisons were based on the labeled reference peptide method. We implemented the assay in four cell models: 1) a comparison of proliferating versus epidermal growth factor-stimulated A431 cells, 2) a comparison of SW480Null (mutant APC) and SW480APC (APC restored) colon tumor cell lines, and 3) a comparison of 10 colorectal cancer cell lines with different genomic abnormalities, and 4) lung cancer cell lines with either susceptibility (11-18) or acquired resistance (11-18R) to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib. We observed distinct PTK expression changes that were induced by stimuli, genomic features or drug resistance, which were consistent with previous reports. However, most of the measured expression differences were novel observations. For example, acquired resistance to erlotinib in the 11-18 cell model was associated not only with previously reported up-regulation of MET, but also with up-regulation of FLK2 and down-regulation of LYN and PTK7. Immunoblot analyses and shotgun proteomics data were highly consistent with parallel reaction monitoring data. Multiplexed parallel reaction monitoring assays provide a targeted, systems-level profiling approach to evaluate cancer related proteotypes and adaptations. Data are available through Proteome eXchange Accession PXD002706. PMID- 26631509 TI - An Analysis of the Sensitivity of Proteogenomic Mapping of Somatic Mutations and Novel Splicing Events in Cancer. AB - Improvements in mass spectrometry (MS)-based peptide sequencing provide a new opportunity to determine whether polymorphisms, mutations, and splice variants identified in cancer cells are translated. Herein, we apply a proteogenomic data integration tool (QUILTS) to illustrate protein variant discovery using whole genome, whole transcriptome, and global proteome datasets generated from a pair of luminal and basal-like breast-cancer-patient-derived xenografts (PDX). The sensitivity of proteogenomic analysis for singe nucleotide variant (SNV) expression and novel splice junction (NSJ) detection was probed using multiple MS/MS sample process replicates defined here as an independent tandem MS experiment using identical sample material. Despite analysis of over 30 sample process replicates, only about 10% of SNVs (somatic and germline) detected by both DNA and RNA sequencing were observed as peptides. An even smaller proportion of peptides corresponding to NSJ observed by RNA sequencing were detected (<0.1%). Peptides mapping to DNA-detected SNVs without a detectable mRNA transcript were also observed, suggesting that transcriptome coverage was incomplete (~80%). In contrast to germline variants, somatic variants were less likely to be detected at the peptide level in the basal-like tumor than in the luminal tumor, raising the possibility of differential translation or protein degradation effects. In conclusion, this large-scale proteogenomic integration allowed us to determine the degree to which mutations are translated and identify gaps in sequence coverage, thereby benchmarking current technology and progress toward whole cancer proteome and transcriptome analysis. PMID- 26631511 TI - A two-phase model for drug release from microparticles with combined effects of solubilisation and recrystallisation. AB - The present study aims to provide a comprehensive mathematical model for drug release from microparticles to the adjacent tissues. In the elucidation of drug release mechanisms, the role of mathematical modelling has been depicted thereby facilitating the development of new therapeutic drug by a systematic approach, rather than expensive experimental trial-and-error methods. In order to study the whole process, a two-phase mathematical model describing the dynamics of drug transport in two coupled media is presented. Drug release is described taking into consideration both solubilisation dynamics of drug crystallites and diffusion of the solubilised drug through the microparticle. In the coupled media, reversible dissociation/recystallisation processes are taking place. The model has led to a system of partial differential equations that are solved analytically. The model points out the important roles played by the diffusion, mass-transfer and reaction parameters, which are the main architects behind drug kinetics across two layers. The dependence of drug masses on the main parameters is also analysed. PMID- 26631513 TI - Meiotic Silencing in Mammals. AB - Meiosis is essential for reproduction in sexually reproducing organisms. A key stage in meiosis is the synapsis of maternal and paternal homologous chromosomes, accompanied by exchange of genetic material to generate crossovers. A decade ago, studies found that when chromosomes fail to synapse, the many hundreds of genes housed within them are transcriptionally inactivated. This process, meiotic silencing, is conserved in all mammals studied to date, but its purpose is not yet defined. Here, I review the molecular genetics of meiotic silencing and consider the many potential functions that it could serve in the mammalian germ line. In addition, I discuss how meiotic silencing influences sex differences in meiotic infertility and the profound impact that meiotic silencing has had on the evolution of mammalian sex chromosomes. PMID- 26631514 TI - Accessing the Inaccessible: The Organization, Transcription, Replication, and Repair of Heterochromatin in Plants. AB - Eukaryotic genomes often contain large quantities of potentially deleterious sequences, such as transposons. One strategy for mitigating this risk is to package such sequences into so-called constitutive heterochromatin, where the dense chromatin environment is thought to inhibit transcription by excluding transcription factors and RNA polymerase. This type of model makes it tempting to think of heterochromatin as an inert region that is isolated from the rest of the nucleus. Recent work on heterochromatin, however, reveals that it is a dynamic environment. Despite its dense packaging, heterochromatin must remain accessible for a host of processes, including DNA replication and repair, and, paradoxically, transcription. In plants, transcripts produced by specialized RNA polymerases are used to target regions of the genome for silencing via DNA methylation. Thus, the maintenance of heterochromatin requires a careful balancing act of access and exclusion, which is achieved through the action of a host of interrelated pathways. PMID- 26631512 TI - Clusters of Multiple Mutations: Incidence and Molecular Mechanisms. AB - It has been long understood that mutation distribution is not completely random across genomic space and in time. Indeed, recent surprising discoveries identified multiple simultaneous mutations occurring in tiny regions within chromosomes while the rest of the genome remains relatively mutation-free. Mechanistic elucidation of these phenomena, called mutation showers, mutation clusters, or kataegis, in parallel with findings of abundant clustered mutagenesis in cancer genomes, is ongoing. So far, the combination of factors most important for clustered mutagenesis is the induction of DNA lesions within unusually long and persistent single-strand DNA intermediates. In addition to being a fascinating phenomenon, clustered mutagenesis also became an indispensable tool for identifying a previously unrecognized major source of mutation in cancer, APOBEC cytidine deaminases. Future research on clustered mutagenesis may shed light onto important mechanistic details of genome maintenance, with potentially profound implications for human health. PMID- 26631516 TI - Understanding Metabolic Regulation at a Systems Level: Metabolite Sensing, Mathematical Predictions, and Model Organisms. AB - Metabolic networks are extensively regulated to facilitate tissue-specific metabolic programs and robustly maintain homeostasis in response to dietary changes. Homeostatic metabolic regulation is achieved through metabolite sensing coupled to feedback regulation of metabolic enzyme activity or expression. With a wealth of transcriptomic, proteomic, and metabolomic data available for different cell types across various conditions, we are challenged with understanding global metabolic network regulation and the resulting metabolic outputs. Stoichiometric metabolic network modeling integrated with "omics" data has addressed this challenge by generating nonintuitive, testable hypotheses about metabolic flux rewiring. Model organism studies have also yielded novel insight into metabolic networks. This review covers three topics: the feedback loops inherent in metabolic regulatory networks, metabolic network modeling, and interspecies studies utilizing Caenorhabditis elegans and various bacterial diets that have revealed novel metabolic paradigms. PMID- 26631517 TI - Modulation of Chromatin by Noncoding RNA. AB - Noncoding RNAs (ncRNAs) are remarkably powerful, flexible, and pervasive cellular regulators. The involvement of these molecules in virtually all aspects of eukaryotic chromatin function is notable. Long and short ncRNAs play broadly complementary roles in these processes. Short ncRNAs underlie a programmable system of chromatin modification that silences mobile elements, identifies boundaries, and initiates the formation of constitutive heterochromatin in yeast. In contrast, long noncoding RNAs (lncRNAs) enforce developmentally appropriate expression and switch gene expression programs. lncRNAs accomplish this through diverse mechanisms, but often by modulating the activity or localization of chromatin regulatory complexes. Both long and short ncRNAs play key roles in organization of complex genomes of higher eukaryotes, and their coordinated actions appear to underlie some of the more dramatic examples of epigenetic regulation. This review contrasts well-studied examples of chromatin regulation by RNA and introduces examples of coordination between these systems. PMID- 26631515 TI - Genetic and Epigenetic Regulation of Human Cardiac Reprogramming and Differentiation in Regenerative Medicine. AB - Regeneration or replacement of lost cardiomyocytes within the heart has the potential to revolutionize cardiovascular medicine. Numerous methodologies have been used to achieve this aim, including the engraftment of bone marrow- and heart-derived cells as well as the identification of modulators of adult cardiomyocyte proliferation. Recently, the conversion of human somatic cells into induced pluripotent stem cells and induced cardiomyocyte-like cells has transformed potential approaches toward this goal, and the engraftment of cardiac progenitors derived from human embryonic stem cells into patients is now feasible. Here we review recent advances in our understanding of the genetic and epigenetic control of human cardiogenesis, cardiac differentiation, and the induced reprogramming of somatic cells to cardiomyocytes. We also cover genetic programs for inducing the proliferation of endogenous cardiomyocytes and discuss the genetic state of cells used in cardiac regenerative medicine. PMID- 26631519 TI - Transitions. PMID- 26631518 TI - Cell Competition During Growth and Regeneration. AB - Tissue growth and regeneration are autonomous, stem-cell-mediated processes in which stem cells within the organ self-renew and differentiate to create new cells, leading to new tissue. The processes of growth and regeneration require communication and interplay between neighboring cells. In particular, cell competition, which is a process in which viable cells are actively eliminated by more competitive cells, has been increasingly implicated to play an important role. Here, we discuss the existing literature regarding the current landscape of cell competition, including classical pathways and models, fitness fingerprint mechanisms, and immune system mechanisms of cell competition. We further discuss the clinical relevance of cell competition in the physiological processes of tissue growth and regeneration, highlighting studies in clinically important disease models, including oncological, neurological, and cardiovascular diseases. PMID- 26631520 TI - An Integrative Professional Theory and Practice Paper: Personal Reflections from the Journey through Clinical Pastoral Education. AB - CPE is an experience-based approach to learning spiritual care which combines clinical care with qualified supervision, in-class education and group reflection (CASC--http://www.spiritualcare.ca/). Through didactic seminars, group presentations and personal reading there is opportunity for the student to acquire, apply and integrate relevant theoretical information into their practice. Written for my CPE Specialist application, this paper describes how, through the course of advanced CPE education, I learn to utilize and integrate theory into my clinical work. Beginning with three strands--authenticity, listening and storytelling--I then discuss how the behavioural sciences and theology inform my practice. Focusing on empathy, I speak of the application of disclosure, the use of counter-transference as a diagnostic tool, and the place of therapeutic termination. Group theory, family systems theory, theological reflection, liturgical ministry, and multi-faith practices are considered. PMID- 26631521 TI - Physician-Assisted Suicide and Other Forms of Euthanasia in Islamic Spiritual Care. AB - The muteness in the Qur'an about suicide due to intolerable pain and a firm opposition to suicide in the hadith literature formed a strong opinion among Muslims that neither repentance nor the suffering of the person can remove the sin of suicide or mercy 'killing' (al-qatl al-rahim), even if these acts are committed with the purpose of relieving suffering and pain. Some interpretations of the Islamic sources even give advantage to murderers as opposed to people who commit suicide because the murderers, at least, may have opportunity to repent for their sin. However, people who commit suicide are 'labeled' for losing faith in the afterlife without a chance to repent for their act. This paper claims that Islamic spiritual care can help people make decisions that may impact patients, family members, health care givers and the whole community by responding to questions such as 'What is the Islamic view on death?', 'What is the Islamic response to physician-assisted suicide and other forms of euthanasia?', 'What are the religious and moral underpinnings of these responses in Islam?' PMID- 26631522 TI - Taking Inventory and Moving Forward: A Review of the Research Literature and Assessment of Qualitative Research in JPCC, 2010-2014. AB - As the foremost journal in spiritual care and counseling (SCC), Journal of Pastoral Care & Counseling (JPCC) functions as a barometer for the discipline's research and interests. This article presents the findings of a review of the research literature in JPCC between 2010 and 2014. It examines research articles by asking the following questions: What are the quantity and types of research published? What are the dominant themes in this research? What are the quantity and methodologies of qualitative research? Findings are presented, discussed and recommendations are made in an effort to assess and further build the research base of the discipline. PMID- 26631523 TI - The Evolution of Research Paradigms in Pastoral/Spiritual Care, Counseling, and Education. AB - This partially autobiographical article is presented as a chapter in the narrative of the evolution of research methodology in the social sciences and the impact that evolution has had on pastoral/spiritual care research as the author has experienced and observed it during the latter part of the 20th century and the early years of the 21st century. PMID- 26631524 TI - Walking the Labyrinth: Considering Mental Health Consumer Experience, Meaning Making, and the Illumination of the Sacred in a Forensic Mental Health Setting. AB - The purpose of this study is to explore the unique meaning and experience associated with walking a unicursal seven circuit outdoor Chartress Labyrinth and 11 circuit indoor Chartress Labyrinth for persons residing at a forensic mental health care facility. Over the past several decades labyrinths have enjoyed something of a renaissance and are often utilized by spiritual care practitioners and health care clinicians in order to support reflection, stress reduction, and the exploration of personal wellness in a sacred setting. Labyrinths are used in many settings including places of worship, hospitals, long-term care facilities, and parks. While labyrinths are becoming more prevalent, an understanding of their impact, particularly in the mental health context, is limited. This qualitative study supports a novel investigation of the meaning associated with participation in walking a labyrinth for persons residing at a forensic mental health care facility. The study design is a qualitative methodology involving transcribed interviews with 12 individuals resident at the Southwest Centre for Forensic Mental Health Care who participated in the 'Walking the Labyrinth' program as facilitated by spiritual care staff. A standardized interview protocol was utilized and the collected data was coded for themes. Several methods were employed to establish trustworthiness including triangulation by analyst and by theory/perspective. Member checking was also utilized in order to further validate the themes. Recommendations related to potential health care applications for labyrinths are identified. These include a focus upon the linkage between mental health care planning and labyrinth participation. PMID- 26631525 TI - Distressing Visions at the End of Life: Case Report and Review of the Literature. AB - There is a growing body of literature documenting dreams, visions, and other trans-personal communications that occur as part of the dying process, often called end-of-life dreams and visions (ELDVs) or deathbed communications (DBCs). This paper describes a unique case involving distressing visions at the end of life, provides a review of existing literature around ELDVs, and will provide a framework within which to approach the patient experiencing distressing ELDVs. PMID- 26631526 TI - Scar Tissue. AB - Scar tissue is associated with physical wounds and their mending, but it is also descriptive in portraying the emotional scarring that occurs following adversity, resulting in potential psychological morbidity. Provided the adversity is not severe, such challenges to adaptability may provoke Andrew Solomon's process of forging meaning and building identity. Perceiving an emotional constitution as analogous to the immune system provides a metaphor for appreciating the benefits of emotional challenges, which may provoke greater emotional resilience or posttraumatic growth. PMID- 26631530 TI - Impaired endothelium independent vasodilation in the cutaneous microvasculature of young obese adults. AB - Microvascular dysfunction contributes to the development of cardiovascular and metabolic disease. This study tested the hypothesis that young obese (BMI>30 kg m(-2)), otherwise healthy, adults (N=15) have impaired microvascular function relative to age and sex matched, lean (BMI<25 kg m(-2)) individuals (N=14). Participants were instrumented with two microdialysis probes in the cutaneous vasculature of one forearm; one for a wide dose range of infusions of the endothelium-dependent vasodilator methacholine (MCh) and the other for the endothelium-independent vasodilator sodium nitroprusside (SNP). Local temperature at each site was clamped at 33 degrees C and cutaneous blood flow was indexed by laser Doppler flowmetry (LDF). LDF was recorded while 7 doses of each drug (MCh: 10(-6)-1M; SNP: 5 * 10(-8)-5 * 10(-2)M) were infused at a rate of 2 MUl/min for 8 min per dose. Both sites finished with heating to 43 degrees C and 5 * 10(-2)M SNP to achieve site specific maximal vasodilation. Mean arterial blood pressure (MAP) was assessed in the last minute of each dose and was used for subsequent calculation of cutaneous vascular conductance (CVC; LDF/MAP) and responses were normalized to each individual site's maximal response (%CVCmax). Group four parameter dose response curves were compared with an extra sum of squares F-test. SNP EC50 was greater in obese relative to lean (-2.931 +/- 0.10 vs -3.746 +/- 0.18 Log[SNP]M, P<0.001); however, there was no difference in MCh EC50 between groups (-3.796 +/- 0.23 vs -3.852 +/- 0.25 Log[MCh]M, P=0.81). Additionally, baseline and maximal CVC in both sites were similar between groups (all P>0.05). These results suggest attenuated endothelium-independent response to nitric oxide while endothelium-dependent vasodilation function is maintained. PMID- 26631531 TI - Development of PEGylated solid lipid nanoparticles of pentoxifylline for their beneficial pharmacological potential in pathological cardiac hypertrophy. AB - OBJECTIVE: The present study was designed to develop PEGylated solid lipid nanoparticles (SLNs) of pentoxifylline (with increased t1/2) for the management of cardiac hypertrophy. MATERIALS AND METHODS: PEGylated SLNs were prepared by melt emulsification method and characterised by zeta potential, polydispersity index, entrapment efficiency, in vitro release and pharmacokinetic profile. Hypertrophy was assessed as increase in tumour necrosis factor-alpha, mean arterial blood pressure, LV protein content and left ventricular end diastolic pressure. RESULT: PEGylated SLNs (F19) with increased t1/2 were developed and characterised. F19 attenuates hypertrophy assessed in terms of parameters employed. CONCLUSION: Thus, PEGylated SLNs (F19) of pentoxifylline have enhanced t1/2 and consequently more significantly preclude cardiac hypertrophy as compared to pentoxifylline. PMID- 26631532 TI - Regulation of mGluR7 trafficking by SUMOylation in neurons. AB - SUMOylation is a post-translational modification by which Small Ubiquitin-like MOdifier (SUMO) proteins are covalently linked to the lysine residues of target proteins via an enzymatic cascade. SUMOylation at the synapse plays an important regulatory role in a wide variety of neuronal function such as synapse formation and receptor endocytosis. The metabotropic glutamate receptor type 7 (mGluR7), a presynaptic G protein-coupled receptor, modulates excitatory neurotransmission and synaptic plasticity by inhibiting neurotransmitter release. The SUMO conjugation of mGluR7 has been demonstrated from several in vitro studies, however, it has not been successful in identifying SUMOylation of full-length mGluR7 in vivo. In the present study, we find that mGluR7 at Lys889 is a target of SUMO conjugation, which is impeded by SUMO-specific isopeptidase SENP1 in HEK 293T cells. In addition, we identify SUMOylated mGluR7 both in brain and primary cortical neurons, that is reduced by the treatment of L-AP4, mGluR7 agonist. We find that deSUMOylated mutation in mGluR7 or overexpression of SENP-1 markedly increases mGluR7 internalization in hippocampal neurons, indicating that endocytosis of mGluR7 is enhanced by the reduced SUMO conjugation of mGluR7. Furthermore, Ser862 phosphorylation facilitates SUMO conjugation of mGluR7. Together, these results reveal that SUMOylation of mGluR7 at Lys889 is required for stable surface expression of mGluR7 in neurons. PMID- 26631533 TI - Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist is neuroprotective and stimulates PGC-1alpha expression and CREB phosphorylation in human dopaminergic neurons. AB - Mitochondrial dysfunction has been linked to several neurodegenerative diseases such as Parkinson's disease (PD). Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a master gene for mitochondrial biogenesis and has been shown to be neuroprotective in models of PD. In this work we have studied the mechanisms by which peroxisome proliferator-activated receptor-gamma (PPARgamma) selective agonist N-(2-benzoylphenyl)-O-[2-(methyl-2 pyridinylamino)ethyl]-l-tyrosine hydrate (GW1929) acts on human dopaminergic neurons in culture. Data showed that GW1929 increased the viability of human dopaminergic neurons and protected them against oxidative stress induced by H2O2 and the mitochondrial toxin Rotenone. The enhanced resilience of the neurons was attributed to increased levels of mitochondrial antioxidants and of PGC-1alpha. GW1929 treatment further increased cell respiration, mitochondrial biogenesis and sirtuin-1 (SIRT1) expression in the human dopaminergic neurons. Phosphorylation of cAMP responsive element-binding protein (CREB) was also robustly increased in GW1929-treated cells. Together these results show that the PPARgamma agonist GW1929 influences CREB signaling and PGC-1alpha activities in the human dopaminergic neurons contributing to an increased cell viability. This supports the view that drugs acting on the PPARgamma-PGC-1alpha signaling in neurons may have beneficial effects in PD and possible also in other brain disorders. PMID- 26631534 TI - Thapsigargin-induced activation of Ca(2+)-CaMKII-ERK in brainstem contributes to substance P release and induction of emesis in the least shrew. AB - Cytoplasmic calcium (Ca(2+)) mobilization has been proposed to be an important factor in the induction of emesis. The selective sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor thapsigargin, is known to deplete intracellular Ca(2+) stores, which consequently evokes extracellular Ca(2+) entry through cell membrane-associated channels, accompanied by a prominent rise in cytosolic Ca(2+). A pro-drug form of thapsigargin is currently under clinical trial as a targeted cancer chemotherapeutic. We envisioned that the intracellular effects of thapsigargin could cause emesis and planned to investigate its mechanisms of emetic action. Indeed, thapsigargin did induce vomiting in the least shrew in a dose-dependent and bell-shaped manner, with maximal efficacy (100%) at 0.5 mg/kg (i.p.). Thapsigargin (0.5 mg/kg) also caused increases in c Fos immunoreactivity in the brainstem emetic nuclei including the area postrema (AP), nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMNX), as well as enhancement of substance P (SP) immunoreactivity in DMNX. In addition, thapsigargin (0.5 mg/kg, i.p.) led to vomit-associated and time dependent increases in phosphorylation of Ca(2+)/calmodulin kinase IIalpha (CaMKIIalpha) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) in the brainstem. We then explored the suppressive potential of diverse chemicals against thapsigargin-evoked emesis including antagonists of: i) neurokinin-1 receptors (netupitant), ii) the type 3 serotonin receptors (palonosetron), iii) store-operated Ca(2+) entry (YM-58483), iv) L-type Ca(2+) channels (nifedipine), and v) SER Ca(2+)-release channels inositol trisphosphate (IP3Rs) (2-APB)-, and ryanodine (RyRs) (dantrolene)-receptors. In addition, the antiemetic potential of inhibitors of CaMKII (KN93) and ERK1/2 (PD98059) were investigated. All tested antagonists/blockers attenuated emetic parameters to varying degrees except palonosetron, however a combination of non-effective doses of netupitant and palonosetron exhibited additive antiemetic efficacy. A low-dose combination of nifedipine and 2-APB plus dantrolene mixture completely abolished thapsigargin evoked vomiting, CaMKII-ERK1/2 activation and SP elevation. In addition, pretreatment with KN93 or PD98059 suppressed thapsigargin-induced increases in SP and ERK1/2 activation. Intracerebroventricular injection of netupitant suppressed vomiting caused by thapsigargin which suggests that the principal site of evoked emesis is the brainstem. In sum, this is the first study to demonstrate that thapsigargin causes vomiting via the activation of the Ca(2+)-CaMKII-ERK1/2 cascade, which is associated with an increase in the brainstem tissue content of SP, and the evoked emesis occurs through SP-induced activation of neurokinin-1 receptors. PMID- 26631535 TI - Stimulation of adenosine A2A receptors reduces intracellular cholesterol accumulation and rescues mitochondrial abnormalities in human neural cell models of Niemann-Pick C1. AB - Niemann Pick C 1 (NPC1) disease is an incurable, devastating lysosomal-lipid storage disorder characterized by hepatosplenomegaly, progressive neurological impairment and early death. Current treatments are very limited and the research of new therapeutic targets is thus mandatory. We recently showed that the stimulation of adenosine A2A receptors (A2ARs) rescues the abnormal phenotype of fibroblasts from NPC1 patients suggesting that A2AR agonists could represent a therapeutic option for this disease. However, since all NPC1 patients develop severe neurological symptoms which can be ascribed to the complex pathology occurring in both neurons and oligodendrocytes, in the present paper we tested the effects of the A2AR agonist CGS21680 in human neuronal and oligodendroglial NPC1 cell lines (i.e. neuroblastoma SH-SY5Y and oligodendroglial MO3.13 transiently transfected with NPC1 small interfering RNA). The down-regulation of the NPC1 protein effectively resulted in intracellular cholesterol accumulation and altered mitochondrial membrane potential. Both effects were significantly attenuated by CGS21680 (500 nM). The protective effects of CGS were prevented by the selective A2AR antagonist ZM241385 (500 nM). The involvement of calcium modulation was demonstrated by the ability of Bapta-AM (5-7 MUM) in reverting the effect of CGS. The A2A-dependent activity was prevented by the PKA-inhibitor KT5720, thus showing the involvement of the cAMP/PKA signaling. These findings provide a clear in vitro proof of concept that A2AR agonists are promising potential drugs for NPC disease. PMID- 26631536 TI - Ultrafine ferroferric oxide nanoparticles embedded into mesoporous carbon nanotubes for lithium ion batteries. AB - An effective one-pot hydrothermal method for in situ filling of multi-wall carbon nanotubes (CNT, diameter of 20-40 nm, length of 30-100 MUm) with ultrafine ferroferric oxide (Fe3O4) nanoparticles (8-10 nm) has been demonstrated. The synthesized Fe3O4@CNT exhibited a mesoporous texture with a specific surface area of 109.4 m(2) g(-1). The loading of CNT, in terms of the weight ratio of Fe3O4 nanoparticles, can reach as high as 66.5 wt%. Compared to the conventional method of using a Al2O3 membrane as template to fill CNT with iron oxides nanoparticles, our strategy is facile, effective, low cost and easy to scale up to large scale production (~1.42 g per one-pot). When evaluated for lithium storage at 1.0 C (1 C = 928 mA g(-1)), the mesoporous Fe3O4@CNT can retain at 358.9 mAh g(-1) after 60 cycles. Even when cycled at high rate of 20 C, high capacity of 275.2 mAh g( 1) could still be achieved. At high rate (10 C) and long life cycling (500 cycles), the cells still exhibit a good capacity of 137.5 mAhg(-1). PMID- 26631537 TI - Expressions of stem cell transcription factors Nanog and Oct4 in renal cell carcinoma tissues and clinical significance. AB - We aimed to detect the expressions of stem cell transcription factors Nanog and Oct4 in renal cell carcinoma (RCC) tissues. Nanog and Oct4 mRNA expressions in RCC tissues significantly exceeded those in paracancerous tissues (p < 0.01 and p < 0.05), being positively correlated with histological grade (p < 0.01 and p < 0.05) and TNM stage (p < 0.05). With increasing TNM stage (p < 0.01) and lymphatic metastasis (p < 0.05), the positive expression rate of Nanog protein increased. RCC patients with low Nanog and Oct4 expressions in tumor tissues had significantly higher survival rates (p < 0.05). High Nanog and Oct4 expressions may be potential therapeutic targets. PMID- 26631538 TI - Gadofosveset-enhanced magnetic resonance venography in patients with venous pathology of the lower limbs - Comparison of diagnostic image quality and inter rater variability with gadobutrol venography and computed tomography venography. AB - Purpose This study was performed to compare the diagnostic quality of Gadofosveset-enhanced magnetic resonance venography with Gadobutrol-enhanced magnetic resonance venography and computed tomography venography for the deep veins of the lower extremities in patients with iliocaval venous pathology. Materials and methods Diagnostic capability and image quality were assessed by two independent readers. Inter-reader variability was analyzed by unweighted and quadratic weighted Cohen's kappa values. Results The diagnostic capability was equal to or higher in the Gadofosveset group for all examined vessel segments compared with both control groups. The image quality score was significantly higher for the Gadofosveset group compared to both control groups. Inter-reader variability expressed by quadratic weighted Cohen's kappa value (k) showed less variability in the Gadofosveset group compared to the control groups. Conclusion Our results show that Gadofosveset-enhanced magnetic resonance venography is a reliable technique in clinical routine practice, with image quality superior to both Gadobutrol-enhanced magnetic resonance venography and computed tomography venography. PMID- 26631539 TI - Inhibiting uncertainty: Priming inhibition promotes reduction of uncertainty. AB - Uncertainty affects performance in many cognitive tasks, including the visual search task, and individual differences in the experience of uncertainty may contribute to several psychological disorders. Despite the importance of uncertainty, to date, no study has explained the basic mechanisms underlying individual differences in the experience of uncertainty. However, it has been suggested that inhibition, a cognitive mechanism aimed at suppressing unwanted thoughts or actions, may affect the development of uncertainty. In the current study, we investigated the relationship between inhibition and behavioral responses to uncertainty in the visual-search task. To accomplish this goal, forty six university students completed a novel combined visual-search and stop signal task, in which we manipulated the degree to which the inhibitory control system was activated by varying the proportions of stop signals in separate blocks. We utilized target-absent trials in the visual-search task as a behavioral probe of responses to uncertainty. We found that activating higher levels of inhibitory control resulted in faster responses to target-absent visual search trials, while not affecting target-present trials. These findings suggest that activation of inhibitory control may causally affect behavioral responses to uncertainty. Thus, individual differences in inhibitory control may influence the ability to rely on internal-ambiguous cues which are common in visual-search and other cognitive tasks. Clinical implications for obsessive-compulsive disorder (OCD) and other disorders involving deficient inhibitory control and difficulty with uncertainty are discussed. PMID- 26631540 TI - Disruption of pupil size modulation correlates with voluntary motor preparation deficits in Parkinson's disease. AB - Pupil size is an easy-to-measure, non-invasive method to index various cognitive processes. Although a growing number of studies have incorporated measures of pupil size into clinical investigation, there have only been limited studies in Parkinson's disease (PD). Convergent evidence has suggested PD patients exhibit cognitive impairment at or soon after diagnosis. Here, we used an interleaved pro and anti-saccade paradigm while monitoring pupil size with saccadic eye movements to examine the relationship between executive function deficits and pupil size in PD patients. Subjects initially fixated a central cue, the color of which instructed them to either look at a peripheral stimulus automatically (pro saccade) or suppress the automatic response and voluntarily look in the opposite direction of the stimulus (anti-saccade). We hypothesized that deficits of voluntary control should be revealed not only on saccadic but also on pupil responses because of the recently suggested link between the saccade and pupil control circuits. In elderly controls, pupil size was modulated by task preparation, showing larger dilation prior to stimulus appearance in preparation for correct anti-saccades, compared to correct pro-saccades, or erroneous pro saccades made in the anti-saccade condition. Moreover, the size of pupil dilation correlated negatively with anti-saccade reaction times. However, this profile of pupil size modulation was significantly blunted in PD patients, reflecting dysfunctional circuits for anti-saccade preparation. Our results demonstrate disruptions of modulated pupil responses by voluntary movement preparation in PD patients, highlighting the potential of using low-cost pupil size measurement to examine executive function deficits in early PD. PMID- 26631541 TI - Neural correlates of mystical experience. AB - Mystical experiences, or subjectively believed encounters with a supernatural world, are widely reported across cultures and throughout human history. Previous theories speculate that executive brain functions underpin mystical experiences. To evaluate causal hypotheses, structural studies of brain lesion are required. Previous studies suffer from small samples or do not have valid measures of cognitive functioning prior to injury. We investigated mystical experience among participants from the Vietnam Head Injury Study and compared those who suffered penetrating traumatic brain injury (pTBI; n=116) with matched healthy controls (HC; n=32). Voxel-based lesion-symptom mapping analysis showed that lesions to frontal and temporal brain regions were linked with greater mystical experiences. Such regions included the dorsolateral prefrontal cortex (dlPFC) and middle/superior temporal cortex (TC). In a confirmatory analysis, we grouped pTBI patients by lesion location and compared mysticism experiences with the HC group. The dlPFC group presented markedly increased mysticism. Notably, longitudinal analysis of pre-injury data (correlating with general intelligence and executive performance) excludes explanations from individual differences. Our findings support previous speculation linking executive brain functions to mystical experiences, and reveal that executive functioning (dlPFC) causally contributes to the down-regulation of mystical experiences. PMID- 26631543 TI - 19F Oximetry with semifluorinated alkanes. AB - This work examines the variation of longitudinal relaxation rate R1(= 1/T1) of the 19F-CF3-resonance of semifluorinated alkanes (SFAs) with oxygen tension (pO2), temperature (T) and pH in vitro. Contrary to their related perfluorocarbons (PFCs), SFA are amphiphilic and facilitate stable emulsions, a prerequisite for clinical use. A linear relationship between R1 and pO2 was confirmed for the observed SFAs at different temperatures. Using a standard saturation recovery sequence, T1 has been successfully measured using fluorine 19F-MRI with a self-constructed birdcage resonator at 9.4 T. A calibration curve to calculate pO2 depending on T and R1 was found for each SFA used. In contrast to the commonly used PFC, SFAs are less sensitive to changes in pO2, but more sensitive to changes in temperature. The influence of pH to R1 was found to be negligible. PMID- 26631542 TI - Middle East respiratory syndrome coronavirus ORF4b protein inhibits type I interferon production through both cytoplasmic and nuclear targets. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel and highly pathogenic human coronavirus and has quickly spread to other countries in the Middle East, Europe, North Africa and Asia since 2012. Previous studies have shown that MERS-CoV ORF4b antagonizes the early antiviral alpha/beta interferon (IFN-alpha/beta) response, which may significantly contribute to MERS-CoV pathogenesis; however, the underlying mechanism is poorly understood. Here, we found that ORF4b in the cytoplasm could specifically bind to TANK binding kinase 1 (TBK1) and IkappaB kinase epsilon (IKKepsilon), suppress the molecular interaction between mitochondrial antiviral signaling protein (MAVS) and IKKepsilon, and inhibit IFN regulatory factor 3 (IRF3) phosphorylation and subsequent IFN-beta production. Further analysis showed that ORF4b could also inhibit IRF3 and IRF7-induced production of IFN-beta, whereas deletion of the nuclear localization signal of ORF4b abrogated its ability to inhibit IRF3 and IRF7-induced production of IFN-beta, but not IFN-beta production induced by RIG I, MDA5, MAVS, IKKepsilon, and TBK-1, suggesting that ORF4b could inhibit the induction of IFN-beta in both the cytoplasm and nucleus. Collectively, these results indicate that MERS-CoV ORF4b inhibits the induction of type I IFN through a direct interaction with IKKepsilon/TBK1 in the cytoplasm, and also in the nucleus with unknown mechanism. Viruses have evolved multiple strategies to evade or thwart a host's antiviral responses. A novel human coronavirus (HCoV), Middle East respiratory syndrome coronavirus (MERS-CoV), is distinguished from other coronaviruses by its high pathogenicity and mortality. However, virulence determinants that distinguish MERS-CoV from other HCoVs have yet to be identified. MERS-CoV ORF4b antagonizes the early antiviral response, which may contribute to MERS-CoV pathogenesis. Here, we report the identification of the interferon (IFN) antagonism mechanism of MERS-CoV ORF4b. MERS-CoV ORF4b inhibits the production of type I IFN through a direct interaction with IKKepsilon/TBK1 in the cytoplasm, and also in the nucleus with unknown mechanism. These findings provide a rationale for the novel pathogenesis of MERS-CoV as well as a basis for developing a candidate therapeutic against this virus. PMID- 26631544 TI - The effect of large milk meals on digestive physiology and behaviour in dairy calves. AB - It is commonly believed that young calves should not be fed more than about 2l of milk per meal. If calves are fed beyond this volume, it is said that the capacity of the abomasum may be exceeded and that milk could enter the rumen. This can disturb the microbial flora/fauna of the rumen and increase the risk of indigestion, diarrhoea and reduced growth. The aim of this study was to examine the effect of large milk meals on digestive physiology and behaviour in dairy calves. Six calves (19-23days of age at the beginning of the experiment) were fed 2l of warm whole milk by teat bottle three times per day, which was the recommended Norwegian feeding regime at the time. The calves were given free access to hay, concentrates and water. During three morning feeding sessions, each separated by 48h, all calves were offered larger meals. The offered amounts were calculated according to the within patient 3-level Response Surface Pathway (RSP) design. The milk given on the three test days contained a contrast medium (barium sulphate), and the animals were radiographed before, during and immediately after intake to reveal whether milk entered the rumen. Four out of the six calves drank more than 5l in one meal and the highest voluntary intake was 6.8l in one meal (13.2% of BW). Abdominal radiographs showed that the abomasum has a large ability for distension. Milk in the rumen was not observed in any of the calves, regardless of intake. The behaviour of the calves was observed for 2h after each test session. No behaviour indicating abdominal pain or discomfort was observed regardless of intake. The results indicate that when warm whole milk is administered from a teat bottle, farmers can increase the amount of milk they offer their calves beyond the traditionally recommended portion size without risk of milk entering the rumen. Hence, farmers who want to feed their calves more milk can do so by increasing meal sizes, and not necessarily by introducing an additional meal. PMID- 26631545 TI - The effect of metformin on neuronal activity in the appetite-regulating brain regions of mice fed a high-fat diet during an anorectic period. AB - Metformin reduces body weight by decreasing food intake in humans and animals. However, the brain regions involved in metformin-induced anorexia remain unclear. Therefore, we investigated c-Fos expression (FOS), a marker of neuronal activity, in the appetite-regulating brain regions after oral administration of metformin (PO, 300mg/kg daily for 1 or 3days) or vehicle. The body weight and food intake decreased in mice treated with metformin for 3days (RM group) and mice that had the same amount of food as the RM group (Pair-fed group; PF) compared to the control group. FOS expression levels increased in the paraventricular nucleus, area postrema, and central amygdala of mice administered an acute single dose of metformin (SM group) compared to the control mice. In the nucleus tractus solitarius, the FOS expression levels increased in both the SM and RM groups compared to the control group. The FOS expression levels also increased in the nucleus accumbens of the RM group compared to other groups. The FOS expression levels decreased in the ventromedial hypothalamic nucleus in the PF group, but not the RM group, compared to the control group, suggesting a potential hypothalamic area involvement for metformin-induced anorexia. These results suggest that both the hypothalamic and extra-hypothalamic regions are associated with metformin-induced anorexia, which is dependent on metformin treatment duration. PMID- 26631546 TI - Assessing positive emotional states in dogs using heart rate and heart rate variability. AB - Since most animal species have been recognized as sentient beings, emotional state may be a good indicator of welfare in animals. The goal of this study was to manipulate the environment of nine beagle research dogs to highlight physiological responses indicative of different emotional experiences. Stimuli were selected to be a more or a less positive food (meatball or food pellet) or social reward (familiar person or less familiar person). That all the stimuli were positive and of different reward value was confirmed in a runway motivation test. Dogs were tested individually while standing facing a display theatre where the different stimuli could be shown by lifting a shutter. The dogs approached and remained voluntarily in the test system. They were tested in four sessions (of 20s each) for each of the four stimuli. A test session consisted of four presentation phases (1st exposure to stimulus, post exposure, 2nd exposure, and access to reward). Heart rate (HR) and heart rate variability (HRV) responses were recorded during testing in the experimental room and also when lying resting in a quiet familiar room. A new method of 'stitching' short periods of HRV data together was used in the analysis. When testing different stimuli, no significant differences were observed in HR and LF:HF ratio (relative power in low frequency (LF) and the high-frequency (HF) range), implying that the sympathetic tone was activated similarly for all the stimuli and may suggest that dogs were in a state of positive arousal. A decrease of HF was associated with the meatball stimulus compared to the food pellet and the reward phase (interacting with the person or eating the food) was associated with a decrease in HF and RMSSD (root mean square of successive differences of inter-beat intervals) compared to the preceding phase (looking at the person or food). This suggests that parasympathetic deactivation is associated with a more positive emotional state in the dog. A similar reduction in HF and RMSSD was found in the test situation compared to the resting situation. This is congruent with the expected autonomic effects related to postural shift i.e. sympathetic activation and parasympathetic withdrawal, during standing versus lying, but it cannot explain the parasympathetic deactivation in response to the more positive stimuli since the dogs were always standing in the test situation. We discuss the systematic pattern of responses, which support that increased HR and LF:HF ratio are associated with emotional arousal, but add the new proposal that a combined decrease in RMSSD and HF may reflect a more positively valenced emotional state even when an individual is already in a positive psychological state. PMID- 26631547 TI - Leveraging a Multi-Omics Strategy for Prioritizing Personalized Candidate Mutation-Driver Genes: A Proof-of-Concept Study. AB - The expression of mutant forms of proteins (e.g., oncogenes and tumor suppressors) has implications in cancer biology and clinical practice. Initial efforts have been made to characterize the transcription of tumor-mutated alleles; however, few studies have been reported to link tumor-mutated alleles to proteomics. We aimed to characterize the transcriptional and translational patterns of tumor-mutated alleles. We performed whole-exome sequencing, RNA-seq, and proteome profiling in a hyper-mutated patient of hepatocellular carcinoma. Using the patient as a model, we show that only a small proportion of tumor mutated alleles were expressed. In this case, 42% and 3.5% of the tumor-mutated alleles were identified to be transcribed and translated, respectively. Compared with genes with germline variations or without mutations, somatic mutations significantly reduced protein expression abundance. Using the transcriptional and translational patterns of tumor-mutated alleles, we classified the mutations into four types, and only one type may be associated with the liver cancer and lead to hepatocarcinogenesis in the patient. Our results demonstrate how tumor-mutated alleles are transcribed and translated, and how the expression enables the classification of somatic mutations that cause cancer. Leveraging multiple 'omics' datasets provides a new avenue for understanding patient-specific mutations that underlie carcinogenesis. PMID- 26631548 TI - Curcumin nanoparticles attenuate cardiac remodeling due to pulmonary arterial hypertension. AB - Herein, we investigate whether curcumin nanoparticles (Cur NPs) are effective for the treatment of monocrotaline (MCT)-induced pulmonary arterial hypertension in Sprague Dawley rat. Echocardiography was performed at the start of the study and 28 days after MCT injection. Compared to MCT only animals, Cur NP administration was associated with reduced right ventricular (RV) wall thickness and a decreased right ventricle weight/body weight ratio. Cur NPs also attenuated MCT induced increase in RV mRNA expression of TNF-alpha and IL-1beta. These changes were also associated with decreased RV expression of nitrotyrosine, fibronectin and myosin heavy chain-beta. PMID- 26631549 TI - Licorice root components in dietary supplements are selective estrogen receptor modulators with a spectrum of estrogenic and anti-estrogenic activities. AB - Licorice root extracts are often consumed as botanical dietary supplements by menopausal women as a natural alternative to pharmaceutical hormone replacement therapy. In addition to their components liquiritigenin (Liq) and isoliquiritigenin (Iso-Liq), known to have estrogenic activity, licorice root extracts also contain a number of other flavonoids, isoflavonoids, and chalcones. We have investigated the estrogenic activity of 7 of these components, obtained from an extract of Glycyrrhiza glabra powder, namely Glabridin (L1), Calycosin (L2), Methoxychalcone (L3), Vestitol (L4), Glyasperin C (L5), Glycycoumarin (L6), and Glicoricone (L7), and compared them with Liq, Iso-Liq, and estradiol (E2). All components, including Liq and Iso-Liq, have low binding affinity for estrogen receptors (ERs). Their potency and efficacy in stimulating the expression of estrogen-regulated genes reveal that Liq and Iso-Liq and L2, L3, L4, and L6 are estrogen agonists. Interestingly, L3 and L4 have an efficacy nearly equivalent to E2 but with a potency ca. 10,000-fold less. The other components, L1, L5 and L7, acted as partial estrogen antagonists. All agonist activities were reversed by the antiestrogen, ICI 182,780, or by knockdown of ERalpha with siRNA, indicating that they are ER dependent. In HepG2 hepatoma cells stably expressing ERalpha, only Liq, Iso-Liq, and L3 stimulated estrogen-regulated gene expression, and in all cases gene stimulation did not occur in HepG2 cells lacking ERalpha. Collectively, these findings classify the components of licorice root extracts as low potency, mixed ER agonists and antagonists, having a character akin to that of selective estrogen receptor modulators or SERMs. PMID- 26631550 TI - Naturally occurring marine steroid 24-methylenecholestane-3beta,5alpha,6beta,19 tetraol functions as a novel neuroprotectant. AB - Steroids have been shown to have multiple effects on the nervous system including neuroprotective activities, and they have the potential to be used for the treatment of neurodegenerative diseases. In this current study, we tested the hypothesis that the marine steroid 24-methylenecholestane-3beta,5alpha,6beta,19 tetraol (Tetrol) has a neuroprotective effect. (1) We synthesized Tetrol through a multiple step reaction starting from hyodeoxycholic acid (HDCA). (2) We then evaluated the neuroprotective effect of Tetrol with a glutamate-induced neuronal injury model in vitro. Tetrol concentration dependently increased the survival rate of cerebellar granule neurons challenged with toxic concentration of glutamate. Consistently, Tetrol significantly decreased glutamate-induced lactate dehydrogenase (LDH) release with a threshold concentration of 2.5 MUM. (3) We further evaluated the neuroprotective effect of Tetrol in a middle cerebral artery occlusion (MCAO)-induced cerebral ischemia model in rat. Tetrol, at a dose of 12 mg/kg, significantly decreased MCAO-induced infarction volume by ~50%. (4) Finally, we probed the mechanism and found that Tetrol concentration dependently attenuated N-methyl-d-aspartate (NMDA)-induced intracellular calcium ([Ca(2+)]i) increase with an IC50 of 7.8+/-0.62 MUM, and inhibited NMDA currents in cortical neurons with an IC50 of 10.28+/-0.71 MUM. Taken together, we have synthesized and characterized Tetrol as a novel neuroprotectant through negative modulation of NMDA receptors. PMID- 26631551 TI - Neurosteroids: Can a 2alpha,3alpha-epoxy ring make up for the 3alpha-hydroxyl group? AB - Seven steroid epoxides were prepared from 5alpha-pregn-2-en-20-one and 5alpha pregn-3-en-20-one and their side-chain derivatives. All compounds were tested in vitro for binding to gamma-aminobutyric acid (GABAA) receptor, some of them also in vivo for anticonvulsant action. 2alpha,3alpha-Epoxy-5alpha-pregnan-20-one inhibited the TBPS binding to the GABAA receptor and showed a moderate anticonvulsant action in immature rats. In contrast, its 3alpha,4alpha-isomer was inactive. More polar epoxide derivatives, modified at the side chain were less active or inactive. Noteworthy, diol 20, the product of trans-diaxial opening of the 2alpha,3alpha-epoxide 4, was not able to inhibit the TBPS binding, showing that the activity of the epoxide is due to the compound itself and not to its hydrolytic product. The 3alpha-hydroxyl group is known to be essential for the GABAA receptor binding. Despite the shortness of in vivo effects which are probably due to metabolic inactivation of the products prepared, our results show that the 2alpha,3alpha-epoxy ring is another structural pattern with ability to bind the GABAAR. PMID- 26631552 TI - A preliminary study of ALPPS procedure in a rat model. AB - Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) has been reported to be a novel surgical technique that provides fast and effective growth of liver remnant. Despite occasional reports on animal studies, the mechanisms of rapid liver regeneration in ALPPS remains unclear. In the present study, we intend to develop a reproducible rat model to mimick ALPPS and to explore the underlying mechanisms. Rats assigned to the portal vein ligation (PVL), left lateral lobe (LLL) resection, transection and sham groups served as controls. Results indicated that the regeneration rate in the remnant liver after ALPPS was two times relative to PVL, whereas rats with transection alone showed minimal volume increase. The expression levels of Ki-67 and PCNA were about ten fold higher after ALPPS compared with the transection and LLL resection groups, and four-fold higher compared with the PVL group. The levels of TNF-alpha, IL-6 and HGF in the regenerating liver remnant were about three-fold higher after ALPPS than the controls. There was a more significant activation of NF-kappaB p65, STAT3 and Yap after ALPPS, suggesting synergistic activation of the pathways by PVL and transection, which might play an important role in liver regeneration after ALPPS. PMID- 26631553 TI - Nerve growth factor stimulates axon outgrowth through negative regulation of growth cone actomyosin restraint of microtubule advance. AB - Nerve growth factor (NGF) promotes growth, differentiation, and survival of sensory neurons in the mammalian nervous system. Little is known about how NGF elicits faster axon outgrowth or how growth cones integrate and transform signal input to motor output. Using cultured mouse dorsal root ganglion neurons, we found that myosin II (MII) is required for NGF to stimulate faster axon outgrowth. From experiments inducing loss or gain of function of MII, specific MII isoforms, and vinculin-dependent adhesion-cytoskeletal coupling, we determined that NGF causes decreased vinculin-dependent actomyosin restraint of microtubule advance. Inhibition of MII blocked NGF stimulation, indicating the central role of restraint in directed outgrowth. The restraint consists of myosin IIB- and IIA-dependent processes: retrograde actin network flow and transverse actin bundling, respectively. The processes differentially contribute on laminin 1 and fibronectin due to selective actin tethering to adhesions. On laminin-1, NGF induced greater vinculin-dependent adhesion-cytoskeletal coupling, which slowed retrograde actin network flow (i.e., it regulated the molecular clutch). On fibronectin, NGF caused inactivation of myosin IIA, which negatively regulated actin bundling. On both substrates, the result was the same: NGF-induced weakening of MII-dependent restraint led to dynamic microtubules entering the actin-rich periphery more frequently, giving rise to faster elongation. PMID- 26631554 TI - Epithelial Sel1L is required for the maintenance of intestinal homeostasis. AB - Inflammatory bowel disease (IBD) is an incurable chronic idiopathic disease that drastically decreases quality of life. Endoplasmic reticulum (ER)-associated degradation (ERAD) is responsible for the clearance of misfolded proteins; however, its role in disease pathogenesis remains largely unexplored. Here we show that the expression of SEL1L and HRD1, the most conserved branch of mammalian ERAD, is significantly reduced in ileal Crohn's disease (CD). Consistent with this observation, laboratory mice with enterocyte-specific Sel1L deficiency (Sel1L(DeltaIEC)) develop spontaneous enteritis and have increased susceptibility to Toxoplasma gondii-induced ileitis. This is associated with profound defects in Paneth cells and a disproportionate increase of Ruminococcus gnavus, a mucolytic bacterium with known association with CD. Surprisingly, whereas both ER stress sensor IRE1alpha and effector CHOP are activated in the small intestine of Sel1L(DeltaIEC) mice, they are not solely responsible for ERAD deficiency-associated lesions seen in the small intestine. Thus our study points to a constitutive role of Sel1L-Hrd1 ERAD in epithelial cell biology and the pathogenesis of intestinal inflammation in CD. PMID- 26631555 TI - Single-particle imaging reveals intraflagellar transport-independent transport and accumulation of EB1 in Chlamydomonas flagella. AB - The microtubule (MT) plus-end tracking protein EB1 is present at the tips of cilia and flagella; end-binding protein 1 (EB1) remains at the tip during flagellar shortening and in the absence of intraflagellar transport (IFT), the predominant protein transport system in flagella. To investigate how EB1 accumulates at the flagellar tip, we used in vivo imaging of fluorescent protein tagged EB1 (EB1-FP) in Chlamydomonas reinhardtii. After photobleaching, the EB1 signal at the flagellar tip recovered within minutes, indicating an exchange with unbleached EB1 entering the flagella from the cell body. EB1 moved independent of IFT trains, and EB1-FP recovery did not require the IFT pathway. Single-particle imaging showed that EB1-FP is highly mobile along the flagellar shaft and displays a markedly reduced mobility near the flagellar tip. Individual EB1-FP particles dwelled for several seconds near the flagellar tip, suggesting the presence of stable EB1 binding sites. In simulations, the two distinct phases of EB1 mobility are sufficient to explain its accumulation at the tip. We propose that proteins uniformly distributed throughout the cytoplasm like EB1 accumulate locally by diffusion and capture; IFT, in contrast, might be required to transport proteins against cellular concentration gradients into or out of cilia. PMID- 26631556 TI - A role of the sphingosine-1-phosphate (S1P)-S1P receptor 2 pathway in epithelial defense against cancer (EDAC). AB - At the initial step of carcinogenesis, transformation occurs in single cells within epithelia, where the newly emerging transformed cells are surrounded by normal epithelial cells. A recent study revealed that normal epithelial cells have an ability to sense and actively eliminate the neighboring transformed cells, a process named epithelial defense against cancer (EDAC). However, the molecular mechanism of this tumor-suppressive activity is largely unknown. In this study, we investigated a role for the sphingosine-1-phosphate (S1P)-S1P receptor 2 (S1PR2) pathway in EDAC. First, we show that addition of the S1PR2 inhibitor significantly suppresses apical extrusion of RasV12-transformed cells that are surrounded by normal cells. In addition, knockdown of S1PR2 in normal cells induces the same effect, indicating that S1PR2 in the surrounding normal cells plays a positive role in the apical elimination of the transformed cells. Of importance, not endogenous S1P but exogenous S1P is involved in this process. By using FRET analyses, we demonstrate that S1PR2 mediates Rho activation in normal cells neighboring RasV12-transformed cells, thereby promoting accumulation of filamin, a crucial regulator of EDAC. Collectively these data indicate that S1P is a key extrinsic factor that affects the outcome of cell competition between normal and transformed epithelial cells. PMID- 26631557 TI - Y-linked variation for autosomal immune gene regulation has the potential to shape sexually dimorphic immunity. AB - Sexually dimorphic phenotypes arise from the differential expression of male and female shared genes throughout the genome. Unfortunately, the underlying molecular mechanisms by which dimorphic regulation manifests and evolves are unclear. Recent work suggests that Y-chromosomes may play an important role, given that Drosophila melanogaster Ys were shown to influence the regulation of hundreds of X and autosomal genes. For Y-linked regulatory variation (YRV) to facilitate sexually dimorphic evolution, however, it must exist within populations (where selection operates) and influence male fitness. These criteria have seldom been investigated, leaving the potential for dimorphic evolution via YRV unclear. Interestingly, male and female D. melanogaster differ in immune gene regulation. Furthermore, immune gene regulation appears to be influenced by the Y chromosome, suggesting it may contribute to dimorphic immune evolution. We address this possibility by introgressing Y-chromosomes from a single wild population into an isogenic background (to create Y-lines) and assessing immune gene regulation and bacterial defence. We found that Y-line males differed in their immune gene regulation and their ability to defend against Serratia marcescens. Moreover, gene expression and bacterial defence were positively genetically correlated. These data indicate that the Y-chromosome has the potential to shape the evolution of sexually dimorphic immunity in this system. PMID- 26631558 TI - Temperature and population density determine reservoir regions of seasonal persistence in highland malaria. AB - A better understanding of malaria persistence in highly seasonal environments such as highlands and desert fringes requires identifying the factors behind the spatial reservoir of the pathogen in the low season. In these 'unstable' malaria regions, such reservoirs play a critical role by allowing persistence during the low transmission season and therefore, between seasonal outbreaks. In the highlands of East Africa, the most populated epidemic regions in Africa, temperature is expected to be intimately connected to where in space the disease is able to persist because of pronounced altitudinal gradients. Here, we explore other environmental and demographic factors that may contribute to malaria's highland reservoir. We use an extensive spatio-temporal dataset of confirmed monthly Plasmodium falciparum cases from 1995 to 2005 that finely resolves space in an Ethiopian highland. With a Bayesian approach for parameter estimation and a generalized linear mixed model that includes a spatially structured random effect, we demonstrate that population density is important to disease persistence during the low transmission season. This population effect is not accounted for in typical models for the transmission dynamics of the disease, but is consistent in part with a more complex functional form of the force of infection proposed by theory for vector-borne infections, only during the low season as we discuss. As malaria risk usually decreases in more urban environments with increased human densities, the opposite counterintuitive finding identifies novel control targets during the low transmission season in African highlands. PMID- 26631560 TI - Dispersal as a source of variation in age-specific reproductive strategies in a wild population of lizards. AB - Dispersal syndromes describe the patterns of covariation of morphological, behavioural, and life-history traits associated with dispersal. Studying dispersal syndromes is critical to understanding the demographic and genetic consequences of movements. Among studies describing the association of life history traits with dispersal, there is anecdotal evidence suggesting that dispersal syndromes can vary with age. Recent theory also suggests that dispersive and philopatric individuals might have different age-specific reproductive efforts. In a wild population of the common lizard (Zootoca vivipara), we investigated whether dispersive and philopatric individuals have different age-specific reproductive effort, survival, offspring body condition, and offspring sex ratio. Consistent with theoretical predictions, we found that young dispersive females have a higher reproductive effort than young philopatric females. Our results also suggest that the early high investment in reproduction of dispersive females trades-off with an earlier onset of senescence than in philopatric females. We further found that young dispersive females produce smaller offspring in lower body condition than do young philopatric females. Overall, our results provide empirical evidence that dispersive and philopatric individuals have different age-specific life-history traits. PMID- 26631559 TI - Interaction between Varroa destructor and imidacloprid reduces flight capacity of honeybees. AB - Current high losses of honeybees seriously threaten crop pollination. Whereas parasite exposure is acknowledged as an important cause of these losses, the role of insecticides is controversial. Parasites and neonicotinoid insecticides reduce homing success of foragers (e.g. by reduced orientation), but it is unknown whether they negatively affect flight capacity. We investigated how exposing colonies to the parasitic mite Varroa destructor and the neonicotinoid insecticide imidacloprid affect flight capacity of foragers. Flight distance, time and speed of foragers were measured in flight mills to assess the relative and interactive effects of high V. destructor load and a field-realistic, chronic sub-lethal dose of imidacloprid. Foragers from colonies exposed to high levels of V. destructor flew shorter distances, with a larger effect when also exposed to imidacloprid. Bee body mass partly explained our results as bees were heavier when exposed to these stressors, possibly due to an earlier onset of foraging. Our findings contribute to understanding of interacting stressors that can explain colony losses. Reduced flight capacity decreases the food-collecting ability of honeybees and may hamper the use of precocious foraging as a coping mechanism during colony (nutritional) stress. Ineffective coping mechanisms may lead to destructive cascading effects and subsequent colony collapse. PMID- 26631561 TI - Preys' exploitation of predators' fear: when the caterpillar plays the Gruffalo. AB - Alike the little mouse of the Gruffalo's tale, many harmless preys use intimidating deceptive signals as anti-predator strategies. For example, several caterpillars display eyespots and face-like colour patterns that are thought to mimic the face of snakes as deterrents to insectivorous birds. We develop a theoretical model to investigate the hypothesis that these defensive strategies exploit adaptive cognitive biases of birds, which make them much more likely to confound caterpillars with snakes than vice versa. By focusing on the information processing mechanisms of decision-making, the model assumes that, during prey assessment, the bird accumulates noisy evidence supporting either the snake escape or the caterpillar-attack motor responses, which compete against each other for execution. Competition terminates when the evidence for either one of the responses reaches a critical threshold. This model predicts a strong asymmetry and a strong negative correlation between the prey- and the predator decision thresholds, which increase with the increasing risk of snake predation and assessment uncertainty. The threshold asymmetry causes an asymmetric distribution of false-negative and false-positive errors in the snake-caterpillar decision plane, which makes birds much more likely to be deceived by the intimidating signals of snake-mimicking caterpillars than by the alluring signals of caterpillar-mimicking snakes. PMID- 26631562 TI - Freezing behaviour facilitates bioelectric crypsis in cuttlefish faced with predation risk. AB - Cephalopods, and in particular the cuttlefish Sepia officinalis, are common models for studies of camouflage and predator avoidance behaviour. Preventing detection by predators is especially important to this group of animals, most of which are soft-bodied, lack physical defences, and are subject to both visually and non-visually mediated detection. Here, we report a novel cryptic mechanism in S. officinalis in which bioelectric cues are reduced via a behavioural freeze response to a predator stimulus. The reduction of bioelectric fields created by the freeze-simulating stimulus resulted in a possible decrease in shark predation risk by reducing detectability. The freeze response may also facilitate other non visual cryptic mechanisms to lower predation risk from a wide range of predator types. PMID- 26631563 TI - Maternal effects on offspring consumption can stabilize fluctuating predator-prey systems. AB - Maternal effects, where the conditions experienced by mothers affect the phenotype of their offspring, are widespread in nature and have the potential to influence population dynamics. However, they are very rarely included in models of population dynamics. Here, we investigate a recently discovered maternal effect, where maternal food availability affects the feeding rate of offspring so that well-fed mothers produce fast-feeding offspring. To understand how this maternal effect influences population dynamics, we explore novel predator-prey models where the consumption rate of predators is modified by changes in maternal prey availability. We address the 'paradox of enrichment', a theoretical prediction that nutrient enrichment destabilizes populations, leading to cycling behaviour and an increased risk of extinction, which has proved difficult to confirm in the wild. Our models show that enriched populations can be stabilized by maternal effects on feeding rate, thus presenting an intriguing potential explanation for the general absence of 'paradox of enrichment' behaviour in natural populations. This stabilizing influence should also reduce a population's risk of extinction and vulnerability to harvesting. PMID- 26631564 TI - On the origin of mongrels: evolutionary history of free-breeding dogs in Eurasia. AB - Although a large part of the global domestic dog population is free-ranging and free-breeding, knowledge of genetic diversity in these free-breeding dogs (FBDs) and their ancestry relations to pure-breed dogs is limited, and the indigenous status of FBDs in Asia is still uncertain. We analyse genome-wide SNP variability of FBDs across Eurasia, and show that they display weak genetic structure and are genetically distinct from pure-breed dogs rather than constituting an admixture of breeds. Our results suggest that modern European breeds originated locally from European FBDs. East Asian and Arctic breeds show closest affinity to East Asian FBDs, and they both represent the earliest branching lineages in the phylogeny of extant Eurasian dogs. Our biogeographic reconstruction of ancestral distributions indicates a gradual westward expansion of East Asian indigenous dogs to the Middle East and Europe through Central and West Asia, providing evidence for a major expansion that shaped the patterns of genetic differentiation in modern dogs. This expansion was probably secondary and could have led to the replacement of earlier resident populations in Western Eurasia. This could explain why earlier studies based on modern DNA suggest East Asia as the region of dog origin, while ancient DNA and archaeological data point to Western Eurasia. PMID- 26631565 TI - Dynamic sensitivity and nonlinear interactions influence the system-level evolutionary patterns of phototransduction proteins. AB - Determining the influence of complex, molecular-system dynamics on the evolution of proteins is hindered by the significant challenge of quantifying the control exerted by the proteins on system output. We have employed a combination of systems biology and molecular evolution analyses in a first attempt to unravel this relationship. We employed a comprehensive mathematical model of mammalian phototransduction to predict the degree of influence that each protein in the system exerts on the high-level dynamic behaviour. We found that the genes encoding the most dynamically sensitive proteins exhibit relatively relaxed evolutionary constraint. We also investigated the evolutionary and epistatic influences of the many nonlinear interactions between proteins in the system and found several pairs to have coevolved, including those whose interactions are purely dynamical with respect to system output. This evidence points to a key role played by nonlinear system dynamics in influencing patterns of molecular evolution. PMID- 26631566 TI - Female preference for multi-modal courtship: multiple signals are important for male mating success in peacock spiders. AB - A long-standing goal for biologists has been to understand how female preferences operate in systems where males have evolved numerous sexually selected traits. Jumping spiders of the Maratus genus are exceptionally sexually dimorphic in appearance and signalling behaviour. Presumably, strong sexual selection by females has played an important role in the evolution of complex signals displayed by males of this group; however, this has not yet been demonstrated. In fact, despite apparent widespread examples of sexual selection in nature, empirical evidence is relatively sparse, especially for species employing multiple modalities for intersexual communication. In order to elucidate whether female preference can explain the evolution of multi-modal signalling traits, we ran a series of mating trials using Maratus volans. We used video recordings and laser vibrometry to characterize, quantify and examine which male courtship traits predict various metrics of mating success. We found evidence for strong sexual selection on males in this system, with success contingent upon a combination of visual and vibratory displays. Additionally, independently produced, yet correlated suites of multi-modal male signals are linked to other aspects of female peacock spider behaviour. Lastly, our data provide some support for both the redundant signal and multiple messages hypotheses for the evolution of multi-modal signalling. PMID- 26631567 TI - Local effects drive heterozygosity-fitness correlations in an outcrossing long lived tree. AB - Heterozygosity-fitness correlations (HFCs) have been used to understand the complex interactions between inbreeding, genetic diversity and evolution. Although frequently reported for decades, evidence for HFCs was often based on underpowered studies or inappropriate methods, and hence their underlying mechanisms are still under debate. Here, we used 6100 genome-wide single nucleotide polymorphisms (SNPs) to test for general and local effect HFCs in maritime pine (Pinus pinaster Ait.), an iconic Mediterranean forest tree. Survival was used as a fitness proxy, and HFCs were assessed at a four-site common garden under contrasting environmental conditions (total of 16 288 trees). We found no significant correlations between genome-wide heterozygosity and fitness at any location, despite variation in inbreeding explaining a substantial proportion of the total variance for survival. However, four SNPs (including two non-synonymous mutations) were involved in significant associations with survival, in particular in the common gardens with higher environmental stress, as shown by a novel heterozygosity-fitness association test at the species-wide level. Fitness effects of SNPs involved in significant HFCs were stable across maritime pine gene pools naturally growing in distinct environments. These results led us to dismiss the general effect hypothesis and suggested a significant role of heterozygosity in specific candidate genes for increasing fitness in maritime pine. Our study highlights the importance of considering the species evolutionary and demographic history and different spatial scales and testing environments when assessing and interpreting HFCs. PMID- 26631568 TI - Size is not everything: rates of genome size evolution, not C-value, correlate with speciation in angiosperms. AB - Angiosperms represent one of the key examples of evolutionary success, and their diversity dwarfs other land plants; this success has been linked, in part, to genome size and phenomena such as whole genome duplication events. However, while angiosperms exhibit a remarkable breadth of genome size, evidence linking overall genome size to diversity is equivocal, at best. Here, we show that the rates of speciation and genome size evolution are tightly correlated across land plants, and angiosperms show the highest rates for both, whereas very slow rates are seen in their comparatively species-poor sister group, the gymnosperms. No evidence is found linking overall genome size and rates of speciation. Within angiosperms, both the monocots and eudicots show the highest rates of speciation and genome size evolution, and these data suggest a potential explanation for the megadiversity of angiosperms. It is difficult to associate high rates of diversification with different types of polyploidy, but it is likely that high rates of evolution correlate with a smaller genome size after genome duplications. The diversity of angiosperms may, in part, be due to an ability to increase evolvability by benefiting from whole genome duplications, transposable elements and general genome plasticity. PMID- 26631569 TI - On being the right size: increased body size is associated with reduced telomere length under natural conditions. AB - Evolution of body size is likely to involve trade-offs between body size, growth rate and longevity. Within species, larger body size is associated with faster growth and ageing, and reduced longevity, but the cellular processes driving these relationships are poorly understood. One mechanism that might play a key role in determining optimal body size is the relationship between body size and telomere dynamics. However, we know little about how telomere length is affected when selection for larger size is imposed in natural populations. We report here on the relationship between structural body size and telomere length in wild house sparrows at the beginning and end of a selection regime for larger parent size that was imposed for 4 years in an isolated population of house sparrows. A negative relationship between fledgling size and telomere length was present at the start of the selection; this was extended when fledgling size increased under the selection regime, demonstrating a persistent covariance between structural size and telomere length. Changes in telomere dynamics, either as a correlated trait or a consequence of larger size, could reduce potential longevity and the consequent trade-offs could thereby play an important role in the evolution of optimal body size. PMID- 26631570 TI - Pharmacodynamics study of zedoary turmeric oil chitosan microspheres administered via arterial embolization. AB - Zedoary turmeric oil, a plant extract currently in clinical use, may provide potent pharmacological actions such as liver injury. In the previous study, to improve the in vivo absorption of ZTO and produce a high oral bioavailability, chitosan was employed to prepare sustained-release microspheres containing ZTO. In this study, a portability liver cancer model of rats was established successfully to compare the pharmacodynamic of ZTO microspheres and injection. In vitro results showed that microspheres had almost uniformly spherical shapes and were well dispersed by a relatively dynamic stable system. In vivo, compared with the control group, all ZTO microspheres groups resulted in growing inhibition of walker-256 cells transplanted solid tumor and the obvious controlled tumor size. At the same dose, ZTO microspheres suggested a better effect. The data showed that three doses of ZTO microspheres could prolong the average survival time considerably. None of the severe signs such as the pimelosis, fibrotic changes and fibrous septum were detected in the histopathology study. PMID- 26631571 TI - TET-catalyzed 5-hydroxymethylcytosine regulates gene expression in differentiating colonocytes and colon cancer. AB - The formation of differentiated cell types from pluripotent progenitors involves epigenetic regulation of gene expression. DNA hydroxymethylation results from the enzymatic oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation (TET) 5-mC dioxygenase enzymes. Previous work has mapped changes in 5-mC during differentiation of intestinal stem cells. However, whether or not 5-hmC regulates colonocyte differentiation is unknown. Here we show that 5-hmC regulates gene expression during colonocyte differentiation and controls gene expression in human colon cancers. Genome-wide profiling of 5-hmC during in vitro colonic differentiation demonstrated that 5-hmC is gained at highly expressed and induced genes and is associated with intestinal transcription factor binding sites, including those for HNF4A and CDX2. TET1 induction occurred during differentiation, and TET1 knockdown altered gene expression and inhibited barrier formation of colonocytes. We find that the 5-hmC distribution in primary human colonocytes parallels the distribution found in differentiated cells in vitro, and that gene-specific 5-hmC changes in human colon cancers are directly correlated with changes in gene expression. Our results support a model in which 5-hmC regulates differentiation of adult human intestine and 5-hmC alterations contribute to the disrupted gene expression in colon cancer. PMID- 26631572 TI - Cancer-Associated Fibroblasts Induce a Collagen Cross-link Switch in Tumor Stroma. AB - Intratumoral collagen cross-links heighten stromal stiffness and stimulate tumor cell invasion, but it is unclear how collagen cross-linking is regulated in epithelial tumors. To address this question, we used Kras(LA1) mice, which develop lung adenocarcinomas from somatic activation of a Kras(G12D) allele. The lung tumors in Kras(LA1) mice were highly fibrotic and contained cancer associated fibroblasts (CAF) that produced collagen and generated stiffness in collagen gels. In xenograft tumors generated by injection of wild-type mice with lung adenocarcinoma cells alone or in combination with CAFs, the total concentration of collagen cross-links was the same in tumors generated with or without CAFs, but coinjected tumors had higher hydroxylysine aldehyde-derived collagen cross-links (HLCC) and lower lysine-aldehyde-derived collagen cross links (LCCs). Therefore, we postulated that an LCC-to-HLCC switch induced by CAFs promotes the migratory and invasive properties of lung adenocarcinoma cells. To test this hypothesis, we created coculture models in which CAFs are positioned interstitially or peripherally in tumor cell aggregates, mimicking distinct spatial orientations of CAFs in human lung cancer. In both contexts, CAFs enhanced the invasive properties of tumor cells in three-dimensional (3D) collagen gels. Tumor cell aggregates that attached to CAF networks on a Matrigel surface dissociated and migrated on the networks. Lysyl hydroxylase 2 (PLOD2/LH2), which drives HLCC formation, was expressed in CAFs, and LH2 depletion abrogated the ability of CAFs to promote tumor cell invasion and migration. IMPLICATIONS: CAFs induce a collagen cross-link switch in tumor stroma to influence the invasive properties of tumor cells. PMID- 26631574 TI - Cell confluence induces switching from proliferation to migratory signaling by site-selective phosphorylation of PDGF receptors on lipid raft platforms. AB - Platelet derived growth factor receptors (PDGFR) play an important role in tumor pathogenesis and are frequently overexpressed in glioblastoma. Earlier we have shown that only confluent glioblastoma cell cultures exhibit a biphasic calcium transient upon PDGF stimulation. Here, we examined how the change in cell density leads to differential cellular responses to the same PDGF stimulus. PDGF beta receptors and their specific phosphotyrosine residues were fluorescently co labeled on A172 and T98G glioblastoma cells. The distribution in cell membrane microdomains (lipid rafts) and the phosphorylation state of PDGFR was measured by confocal microscopy and quantitated by digital image processing. Corresponding bulk data were obtained by Western blotting. Activation of relevant downstream signaling pathways was assessed by immunofluorescence in confocal microscopy and by Western blot analysis. Functional outcomes were confirmed with bulk and single cell proliferation assays and motility measurements. In non-confluent (sparse) cultures PDGF-BB stimulation significantly increased phosphorylation of Tyr716 specific for the Ras/MAPK pathway and Tyr751 specific for the phosphoinositide 3 kinase/Akt pathway. As cell monolayers reached confluence, Tyr771 and Tyr1021 were the prominently phosphorylated residues. Tyr771 serves as adaptor for Ras GAP, which inactivates the MAPK pathway, and Tyr1021 feeds into the phospholipase C-gamma/PKC pathway. Coherent with this, MAPK phosphorylation, Ki-67 positivity and proliferation dominated in dispersed cells, and could be abolished with inhibitors of the MAPK pathway. At the same time, RhoA activation, redistribution of cortactin to leading edges, and increased motility were the prominent output features in confluent cultures. Importantly, the stimulus-evoked confluence specific changes in the phosphorylation of tyrosine residues occurred mainly in GM1-rich lipid microdomains (rafts). These observations suggest that the same stimulus is able to promote distinctly relevant signaling outputs through a confluence dependent, lipid raft-based regulatory mechanism. In particular, cell division and survival in sparse cultures and inhibition of proliferation and promotion of migration in confluent monolayers. In our model, the ability to switch the final output of the same stimulus as a function of cell density could be a key to the balance of proliferation and invasion in malignant glioblastoma. PMID- 26631573 TI - Regulation of cellular oxidative stress and apoptosis by G protein-coupled receptor kinase-2; The role of NADPH oxidase 4. AB - Cardiac myocyte oxidative stress and apoptosis are considered important mechanisms for the development of heart failure (HF). Chronic HF is characterized by increased circulating catecholamines to augment cardiac output. Long-term stimulation of myocardial beta-adrenergic receptors (beta-ARs) is deleterious in cardiac myocytes, however, the potential mechanisms underlying increased cell death are unclear. We hypothesize that GRK2, a critical regulator of myocardial beta-AR signaling, plays an important role in mediating cellular oxidative stress and apoptotic cell death in response to beta-agonist stimulation. Stimulation of H9c2 cells with a non-selective beta-agonist, isoproterenol (Iso) caused increased oxidative stress and apoptosis. There was also increased Nox4 expression, but no change in Nox2, the primary NADPH isoforms and major sources of ROS generation in cardiac myocytes. Adenoviral-mediated overexpression of GRK2 led to similar increases in ROS production and apoptosis as seen with Iso stimulation. These increases in oxidative stress were abolished by pre-treatment with the non-specific Nox inhibitor, apocynin, or siRNA knockdown of Nox4. Adenoviral-mediated expression of a GRK2 inhibitor prevented ROS production and apoptosis in response to Iso stimulation. beta-Arrestins are signaling proteins that function downstream of GRK2 in beta-AR uncoupling. Adenoviral-mediated overexpression of beta-arrestins increased ROS production and Nox4 expression. Chronic beta-agonist stimulation in mice increased Nox4 expression and apoptosis compared to PBS or AngII treatment. These data demonstrate that GRK2 may play an important role in regulating oxidative stress and apoptosis in cardiac myocytes and provides an additional novel mechanism for the beneficial effects of cardiac targeted GRK2 inhibition to prevent the development of HF. PMID- 26631575 TI - [Multimodal imaging of hydroxychloroquine and chloroquine retinopathy]. PMID- 26631576 TI - Preparation and characterization of isoniazid and lamivudine co-loaded polymeric microspheres. AB - Context The rate of co-infection of HIV/Tuberculosis is increasing alarmingly. This calls for a drug delivery approach targeting both diseases. Objective The study aims to investigate co-loading of isoniazid, an antitubercular drug and lamivudine an antiretroviral drug, into polymeric microspheres for simultaneous treatment of both diseases. Materials and methods Microspheres were prepared by o/o emulsion solvent evaporation method by employing ethylcellulose and eudragit RS 100 as polymers. The prepared formulation was suitably characterized for FTIR, DSC, percent yield, loose surface crystals, entrapment efficiency, and in vitro studies. The surface morphology of microspheres was observed using digital microscope and scanning electron microscope. Cell viability study was done on Caco-2 cells. Results and discussion FTIR and DSC studies demonstrated compatibility and stability of excipients. Microscopy studies revealed that particles were spherical in shape and distributed over a range of 120-270 MUm. Percent yield, LSC and %EE have shown promising results. In vitro release showed biphasic release pattern with sustained release up to 12 h. Mechanism of drug release followed Higuchi Kinetics and non-fickian release behaviour. The formulation containing drug/polymer ratio 1:2 and EU/EC of 1:1 showed optimum response in context to achievement of controlled release. The cell viability studies showed that the prepared system had no toxic effect on intestinal epithelial Caco-2 cells. Conclusion Polymeric microspheres were prepared and suitably characterized for simultaneous delivery of two drugs. This matrix system could be used for better therapeutic outcome in this deadly co-infection. PMID- 26631577 TI - How silicene on Ag(111) oxidizes: microscopic mechanism of the reaction of O2 with silicene. AB - We demonstrate, using first-principles molecular-dynamics simulations, that oxidation of silicene can easily take place either at low or high oxygen doses, which importantly helps clarify previous inconsistent reports on the oxidation of silicene on the Ag(111) substrate. We show that, while the energy barrier for an O2 molecule reacting with a Si atom strongly depends on the position and orientation of the molecule, the O2 molecule immediately dissociates and forms an Si-O-Si configuration once it finds a barrier-less chemisorption pathway around an outer Si atom of the silicene overlayer. A synergistic effect between the molecular dissociation and subsequent structural rearrangements is found to accelerate the oxidation process at a high oxygen dose. This effect also enhances self-organized formation of sp(3)-like tetrahedral configurations (consisting of Si and O atoms), which results in collapse of the two-dimensional silicene structure and its exfoliation from the substrate. We also find that the electronic properties of the silicene can be significantly altered by oxidation. The present findings suggest that low flux and low temperature of the oxygen gas are key to controlling oxidation of silicene. PMID- 26631578 TI - Hierarchical One-Dimensional Ammonium Nickel Phosphate Microrods for High Performance Pseudocapacitors. AB - High-performance electrochemical capacitors will drive the next-generation portable, flexible and wearable electronics. Unlike the conventional all-carbon supercapacitors (electric double layer capacitors, EDLC) with high power but poor energy density, pseudocapacitors capitalize the high energy density inherent to reversible redox reactions and provide a facile means to enhancing the energy ratings of supercapacitors. The high length-to-diameter ratio and anisotropic character of 1-D architecture makes them suitable for use in energy storage. For the first time, we report 1-D microrod structures (~ 36 nm width) of ammonium nickel phosphate hydrate (ANPmr) as a pseudocapacitor with high energy rating and power handling. To confirm the data, the ANPmr-based pseudocapacitor was subjected to various configurations (i.e., half-cell, symmetric, asymmetric, and flexible all-solid-state) and in each case it gave excellent values compared to any accessible literature to date. We clearly demonstrate that a flexible all solid-state ANPmr-based pseudocapacitor achieved high areal capacitance of 66 mF cm(-2) with extra-ordinary energy (21.2 mWh cm(-2)) and power (12.7 mW cm(-2)) densities. This work opens doors for a facile, robust and scalable preparation strategy for low-cost, earth-abundant electrode materials for high-performance pseudocapacitors. PMID- 26631579 TI - Plasmonic CROWs for Tunable Dispersion and High Quality Cavity Modes. AB - Coupled resonator optical waveguides (CROWs) have the potential to revolutionise integrated optics, to slow-light and enhance linear and non-linear optical phenomena. Here we exploit the broad resonances and subwavelength nature of localized surface plasmons in a compact CROW design where plasmonic nanoparticles are side coupled to a dielectric waveguide. The plasmonic CROW features a low loss central mode with a highly tunable dispersion, that avoids coupling to the plasmonic nanoparticles close to the band-edge. We show that this low loss character is preserved in finite plasmonic CROWs giving rise to Fabry-Perot type resonances that have high quality factors of many thousands, limited only by the CROW length. Furthermore we demonstrate that the proposed CROW design is surprisingly robust to disorder. By varying the geometric parameters one can not only reduce the losses into dissipative or radiative channels but also control the outcoupling of energy to the waveguide. The ability to minimise loss in plasmonic CROWs while maintaining dispersion provides an effective cavity design for chip-integrated laser devices and applications in linear and non-linear nano photonics. PMID- 26631580 TI - Mitochondrial events responsible for morphine's cardioprotection against ischemia/reperfusion injury. AB - Morphine may induce cardioprotection by targeting mitochondria, but little is known about the exact mitochondrial events that mediate morphine's protection. We aimed to address the role of the mitochondrial Src tyrosine kinase in morphine's protection. Isolated rat hearts were subjected to 30 min ischemia and 2h of reperfusion. Morphine was given before the onset of ischemia. Infarct size and troponin I release were measured to evaluate cardiac injury. Oxidative stress was evaluated by measuring mitochondrial protein carbonylation and mitochondrial ROS generation. HL-1 cells were subjected to simulated ischemia/reperfusion and LDH release and mitochondrial membrane potential (DeltaPsim) were measured. Morphine reduced infarct size as well as cardiac troponin I release which were aborted by the selective Src tyrosine kinase inhibitors PP2 and Src-I1. Morphine also attenuated LDH release and prevented a loss of DeltaPsim at reperfusion in a Src tyrosine kinase dependent manner in HL-1 cells. However, morphine failed to reduce LDH release in HL-1 cells transfected with Src siRNA. Morphine increased mitochondrial Src phosphorylation at reperfusion and this was abrogated by PP2. Morphine attenuated mitochondrial protein carbonylation and mitochondrial superoxide generation at reperfusion through Src tyrosine kinase. The inhibitory effect of morphine on the mitochondrial complex I activity was reversed by PP2. These data suggest that morphine induces cardioprotection by preventing mitochondrial oxidative stress through mitochondrial Src tyrosine kinase. Inhibition of mitochondrial complex I at reperfusion by Src tyrosine kinase may account for the prevention of mitochondrial oxidative stress by morphine. PMID- 26631582 TI - Prolactin monitoring in the acute psychiatry setting. AB - Hyperprolactinaemia is a common side effect associated with psychotropic medication. Limited guidance on its monitoring and management results in inconsistency in practice due to individual clinical variability. A retrospective service evaluation study was conducted on all patients admitted to an acute psychiatric assessment unit in South Wales, United Kingdom, over one calendar year (n=524), to assess the prevalence and possible causes of hyperprolactinaemia, correlation with symptomatology and monitoring and management by clinicians. The prevalence of hyperprolactinaemia in this population (n=67, 13%) was higher than in the general population. The most common association was medication (n=39, 58%), particularly Risperidone (n=19). Illicit substance use (n=10, 15%), and physical conditions (n=12, 18%) may also have contributed. However, only 44 (66%) received follow-up for their hyperprolactinaemia. There was a statistically significant difference in the sample means of those that did receive follow-up and those who did not, suggesting a degree of bias in patients selected to receive follow-up. These findings suggest that hyperprolactinaemia is relatively common in patients with mental illness, and that comprehensive guidelines need to be established for the monitoring and management thereof. PMID- 26631583 TI - Interaction of GABA-mimetics with the taurine transporter (TauT, Slc6a6) in hyperosmotic treated Caco-2, LLC-PK1 and rat renal SKPT cells. AB - The aim of the present study was to investigate if basic GABA-mimetics interact with the taurine transporter (TauT, Slc6a6), and to find a suitable cell based model that is robust towards extracellular changes in osmolality during uptake studies. Taurine uptake was measured in human Caco-2 cells, porcine LLC-PK1 cells, and rat SKPT cells using radiolabelled taurine. Hyperosmotic conditions were obtained by incubation with raffinose (final osmolality of 500mOsm) for 24h prior to the uptake experiments. Expression of the taurine transporter, TauT, was investigated at the mRNA level by real-time PCR. Uptake of the GABA-mimetics gaboxadol and vigabatrin was investigated in SKPT cells, and quantified by liquid scintillation or HPLC-MS/MS analysis, respectively. The uptake rate of [(3)H] taurine was Na(+) and Cl(-) and concentration dependent with taurine with an apparent Vmax of 6.3+/-1.6pmolcm(-2)min(-1) and a Km of 24.9+/-15.0MUM. beta alanine, nipecotic acid, gaboxadol, GABA, vigabatrin, delta-ALA and guvacine inhibited the taurine uptake rate in a concentration dependent manner. The order of affinity for TauT was beta-alanine>GABA>nipecotic acid>guvacine>delta ALA>vigabatrin>gaboxadol with IC50-values of 0.04, 1.07, 2.02, 4.19, 4.94, 31.4 and 39.9mM, respectively. In conclusion, GABA mimetics inhibited taurine uptake in hyperosmotic rat renal SKPT cells. SKPT cells, which seem to be a useful model for investigating taurine transport in the short-term presence of high concentrations of osmolytes. Furthermore, analogues of beta-alanine appear to have higher affinities for TauT than GABA-analogues. PMID- 26631584 TI - Quercetin derivatives as novel antihypertensive agents: Synthesis and physiological characterization. AB - The antihypertensive flavonol quercetin (Q1) is endowed with a cardioprotective effect against myocardial ischemic damage. Q1 inhibits angiotensin converting enzyme activity, improves vascular relaxation, and decreases oxidative stress and gene expression. However, the clinical application of this flavonol is limited by its poor bioavailability and low stability in aqueous medium. In the aim to overcome these drawbacks and preserve the cardioprotective effects of quercetin, the present study reports on the preparation of five different Q1 analogs, in which all OH groups were replaced by hydrophobic functional moieties. Q1 derivatives have been synthesized by optimizing previously reported procedures and analyzed by spectroscopic analysis. The cardiovascular properties of the obtained compounds were also investigated in order to evaluate whether chemical modification affects their biological efficacy. The interaction with beta adrenergic receptors was evaluated by molecular docking and the cardiovascular efficacy was investigated on the ex vivo Langendorff perfused rat heart. Furthermore, the bioavailability and the antihypertensive properties of the most active derivative were evaluated by in vitro studies and in vivo administration (1month) on spontaneously hypertensive rats (SHRs), respectively. Among all studied Q1 derivatives, only the ethyl derivative reduced left ventricular pressure (at 10(-8)M/10(-6)M doses) and improved relaxation and coronary dilation. NOSs inhibition by L-NAME abolished inotropism, lusitropism and coronary effects. Chronic administration of high doses of this compound on SHR reduced systolic and diastolic pressure. Differently, the acetyl derivative induced negative inotropism and lusitropism (at 10(-10)M and 10(-8)/10(-6)M doses), without affecting coronary pressure. Accordingly, docking studies suggested that these compounds bind both beta1/beta2-adrenergic receptors. Taking into consideration all the obtained results, the replacement of OH with ethyl groups seems to improve Q1 bioavailability and stability; therefore, the ethyl derivative could represent a good candidate for clinical use in hypertension. PMID- 26631581 TI - Experimental models of hepatotoxicity related to acute liver failure. AB - Acute liver failure can be the consequence of various etiologies, with most cases arising from drug-induced hepatotoxicity in Western countries. Despite advances in this field, the management of acute liver failure continues to be one of the most challenging problems in clinical medicine. The availability of adequate experimental models is of crucial importance to provide a better understanding of this condition and to allow identification of novel drug targets, testing the efficacy of new therapeutic interventions and acting as models for assessing mechanisms of toxicity. Experimental models of hepatotoxicity related to acute liver failure rely on surgical procedures, chemical exposure or viral infection. Each of these models has a number of strengths and weaknesses. This paper specifically reviews commonly used chemical in vivo and in vitro models of hepatotoxicity associated with acute liver failure. PMID- 26631586 TI - Effects of Heating on Proportions of Azaspiracids 1-10 in Mussels (Mytilus edulis) and Identification of Carboxylated Precursors for Azaspiracids 5, 10, 13, and 15. AB - Azaspiracids (AZAs) are marine biotoxins that induce human illness following the consumption of contaminated shellfish. European Union regulation stipulates that only raw shellfish are tested, yet shellfish are often cooked prior to consumption. Analysis of raw and heat-treated mussels (Mytilus edulis) naturally contaminated with AZAs revealed significant differences (up to 4.6-fold) in AZA1 3 (1-3) and 6 (6) values due to heat-induced chemical conversions. Consistent with previous studies, high levels of 3 and 6 were detected in some samples that were otherwise below the limit of quantitation before heating. Relative to 1, in heat-treated mussels the average (n = 40) levels of 3 (range, 11-502%) and 6 (range, 3-170%) were 62 and 31%, respectively. AZA4 (4) (range, <1-27%), AZA5 (5) (range, 1-21%), and AZA8 (8) (range, 1-27%) were each ~5%, whereas AZA7 (7), AZA9 (9), and AZA10 (10) (range, <1-8%) were each under 1.5%. Levels of 5, 10, AZA13 (13), and AZA15 (15) increased after heating, leading to the identification of novel carboxylated AZA precursors in raw shellfish extracts, which were shown by deuterium labeling to be precursors for 5, 10, 13, and 15. PMID- 26631585 TI - Corticosterone enhances N-methyl-D-aspartate receptor signaling to promote isolated ventral tegmental area activity in a reconstituted mesolimbic dopamine pathway. AB - Elevations in circulating corticosteroids during periods of stress may influence activity of the mesolimbic dopamine reward pathway by increasing glutamatergic N methyl-D-aspartate (NMDA) receptor expression and/or function in a glucocorticoid receptor-dependent manner. The current study employed organotypic co-cultures of the ventral tegmental area (VTA) and nucleus accumbens (NAcc) to examine the effects of corticosterone exposure on NMDA receptor-mediated neuronal viability. Co-cultures were pre-exposed to vehicle or corticosterone (CORT; 1 MUM) for 5 days prior to a 24 h co-exposure to NMDA (200 MUM). Co-cultures pre-exposed to a non-toxic concentration of corticosterone and subsequently NMDA showed significant neurotoxicity in the VTA only. This was evidenced by increases in propidium iodide uptake as well as decreases in immunoreactivity of the neuronal nuclear protein (NeuN). Co-exposure to the NMDA receptor antagonist 2-amino-7 phosphonovaleric acid (APV; 50 MUM) or the glucocorticoid receptor (GR) antagonist mifepristone (10 MUM) attenuated neurotoxicity. In contrast, the combination of corticosterone and NMDA did not produce any significant effects on either measure within the NAcc. Cultures of the VTA and NAcc maintained without synaptic contact showed no response to CORT or NMDA. These results demonstrate the ability to functionally reconstitute key regions of the mesolimbic reward pathway ex vivo and to reveal a GR-dependent enhancement of NMDA receptor dependent signaling in the VTA. PMID- 26631587 TI - Plasma bilirubin values on admission and ventricular remodeling after a first anterior ST-segment elevation acute myocardial infarction. AB - INTRODUCTION: Bilirubin may elicit cardiovascular protection and heme oxygenase-1 overexpression attenuated post-infarction ventricular remodeling in experimental animals, but the association between bilirubin levels and post-infarction remodeling is unknown. MATERIALS AND METHODS: In 145 patients with a first anterior ST-segment elevation acute myocardial infarction (STEMI), we assessed whether plasma bilirubin on admission predicted adverse remodeling (left ventricular end-diastolic volume [LVEDV] increase >=20% between discharge and 6 months, estimated by magnetic resonance imaging). RESULTS: Patients' baseline characteristics and management were comparable among bilirubin tertiles. LVEDV increased at 6 months (P < 0.001) with respect to the initial exam, but the magnitude of this increase was similar across increasing bilirubin tertiles (10.8 [30.2], 10.1 [22.9], and 12.7 [24.3]%, P = 0.500). Median (25-75 percentile) bilirubin values in patients with and without adverse remodeling were 0.75 (0.60 0.93) and 0.73 (0.60-0.92) mg/dL (P = 0.693). Absence of final TIMI flow grade 3 (odds ratio 3.92, 95% CI 1.12-13.66) and a history of hypertension (2.04, 0.93 4.50), but not admission bilirubin, were independently associated with adverse remodeling. Bilirubin also did not predict the increase in ejection fraction at 6 months. CONCLUSIONS: Admission bilirubin values are not related to LVEDV or ejection fraction progression after a first anterior STEMI and do not predict adverse ventricular remodeling. Key messages Bilirubin levels are inversely related to cardiovascular disease, and overexpression of heme oxygenase-1 (the enzyme that determines bilirubin production) has prevented post-infarction ventricular remodeling in experimental animals, but the association between bilirubin levels and the progression of ventricular volumes and function in patients with acute myocardial infarction remained unexplored. In this cohort of patients with a first acute anterior ST-segment elevation myocardial infarction receiving contemporary management, bilirubin levels on admission were not predictive of the changes in left ventricular volumes or ejection fraction at 6 months measured by serial cardiac magnetic resonance imaging. The data are contrary to a significant protective effect of bilirubin against post-infarction ventricular remodeling. PMID- 26631588 TI - Atlantooccipital Overlap and Other Craniocervical Junction Abnormalities in Dogs. AB - The term craniocervical junction abnormality (CJA) is an umbrella term for a variety of malformations that occur in the craniocervical region. These abnormalities include Chiari-like malformation, atlantooccipital overlapping, atlantoaxial instability, occipitoatlantoaxial malformations, atlantoaxial dural bands, and dens abnormalities. Syringomyelia can occur secondary to any of these malformations or a combination. Clinical signs in dogs with a CJA typically include neck pain and varying signs associated with a cervical myelopathy. MRI of CJAs with computed tomography imaging is necessary for a full evaluation. Some dogs with CJAs respond to medical management, but for most surgery is the treatment of choice. PMID- 26631589 TI - Chiari-like Malformation. AB - Chiari-like malformation is a condition of the craniocervical junction in which there is a mismatch of the structures of the caudal cranial fossa causing the cerebellum to herniate into the foramen magnum. This herniation can lead to fluid buildup in the spinal cord, also known as syringomyelia. Pain is the most common clinical sign followed by scratching. Other neurologic signs noted are facial nerve deficits, seizures, vestibular syndrome, ataxia, menace deficit, proprioceptive deficits, head tremor, temporal muscle atrophy, and multifocal central nervous system signs. MRI is the diagnostic of choice, but computed tomography can also be used. PMID- 26631590 TI - Atlantoaxial Instability. AB - Atlantoaxial instability is a congenital neurologic condition predominantly affecting toy breed dogs. Neurologic signs of a cranial cervical myelopathy typically present at a young age and can range from cervical pain (hyperesthesia) to paralysis. Diagnosis is often based on survey radiographs, although advanced diagnostic imaging can facilitate surgical planning, allow evaluation of spinal cord parenchyma, and rule out concurrent neurologic conditions. Treatment options consist of medical or surgical management, with surgical management being preferable in patients with neurologic deficits or those with unresolved cervical pain despite medical management. The prognosis for surgery is generally favorable. PMID- 26631591 TI - The Y137H mutation of VvCYP51 gene confers the reduced sensitivity to tebuconazole in Villosiclava virens. AB - Management of rice false smut disease caused by Villosiclava virens is dependent on demethylation inhibitor (DMI) fungicides. Investigation of molecular mechanisms of resistance is therefore of upmost importance. In this study the gene encoding the target protein for DMI fungicides (VvCYP51) was cloned and investigated. The VvCYP51 gene in the resistant mutant revealed both a change from tyrosine to histidine at position 137 (Y137H) and elevated gene expression compared to the parental isolate. In order to determine which of these mechanisms was responsible for the reduced sensitivity to DMI fungicide tebuconazole, transformants expressing the mutated or the wild type VvCYP51 gene were generated. Transformants carrying the mutated gene were more resistant to tebuconazole compared to control transformants lacking the mutation, but the expression of the VvCYP51 gene was not significantly correlated with EC50 values. The wild type VvCYP51 protein exhibited stronger affinity for tebuconazole compared to the VvCYP51/Y137H in both molecular docking analysis and experimental binding assays. The UV-generated mutant as well as transformants expressing the VvCYP51/Y137H did not exhibit significant fitness penalties based on mycelial growth and spore germination, suggesting that isolates resistant to DMI fungicides based on the Y137H mutation may develop and be competitive in the field. PMID- 26631593 TI - Accelerated 2D magnetic resonance spectroscopy of single spins using matrix completion. AB - Two dimensional nuclear magnetic resonance (NMR) spectroscopy is one of the major tools for analysing the chemical structure of organic molecules and proteins. Despite its power, this technique requires long measurement times, which, particularly in the recently emerging diamond based single molecule NMR, limits its application to stable samples. Here we demonstrate a method which allows to obtain the spectrum by collecting only a small fraction of the experimental data. Our method is based on matrix completion which can recover the full spectral information from randomly sampled data points. We confirm experimentally the applicability of this technique by performing two dimensional electron spin echo envelope modulation (ESEEM) experiments on a two spin system consisting of a single nitrogen vacancy (NV) centre in diamond coupled to a single (13)C nuclear spin. The signal to noise ratio of the recovered 2D spectrum is compared to the Fourier transform of randomly subsampled data, where we observe a strong suppression of the noise when the matrix completion algorithm is applied. We show that the peaks in the spectrum can be obtained with only 10% of the total number of the data points. We believe that our results reported here can find an application in all types of two dimensional spectroscopy, as long as the measured matrices have a low rank. PMID- 26631592 TI - Ex vivo multiscale quantitation of skin biomechanics in wild-type and genetically modified mice using multiphoton microscopy. AB - Soft connective tissues such as skin, tendon or cornea are made of about 90% of extracellular matrix proteins, fibrillar collagens being the major components. Decreased or aberrant collagen synthesis generally results in defective tissue mechanical properties as the classic form of Elhers-Danlos syndrome (cEDS). This connective tissue disorder is caused by mutations in collagen V genes and is mainly characterized by skin hyperextensibility. To investigate the relationship between the microstructure of normal and diseased skins and their macroscopic mechanical properties, we imaged and quantified the microstructure of dermis of ex vivo murine skin biopsies during uniaxial mechanical assay using multiphoton microscopy. We used two genetically-modified mouse lines for collagen V: a mouse model for cEDS harboring a Col5a2 deletion (a.k.a. pN allele) and the transgenic K14-COL5A1 mice which overexpress the human COL5A1 gene in skin. We showed that in normal skin, the collagen fibers continuously align with stretch, generating the observed increase in mechanical stress. Moreover, dermis from both transgenic lines exhibited altered collagen reorganization upon traction, which could be linked to microstructural modifications. These findings show that our multiscale approach provides new crucial information on the biomechanics of dermis that can be extended to all collagen-rich soft tissues. PMID- 26631595 TI - Egg Activation at Fertilization by a Soluble Sperm Protein. AB - The most fundamental unresolved issue of fertilization is to define how the sperm activates the egg to begin embryo development. Egg activation at fertilization in all species thus far examined is caused by some form of transient increase in the cytoplasmic free Ca(2+) concentration. What has not been clear, however, is precisely how the sperm triggers the large changes in Ca(2+) observed within the egg cytoplasm. Here, we review the studies indicating that the fertilizing sperm stimulates a cytosolic Ca(2+) increase in the egg specifically by delivering a soluble factor that diffuses into the cytosolic space of the egg upon gamete membrane fusion. Evidence is primarily considered in species of eggs where the sperm has been shown to elicit a cytosolic Ca(2+) increase by initiating Ca(2+) release from intracellular Ca(2+) stores. We suggest that our best understanding of these signaling events is in mammals, where the sperm triggers a prolonged series of intracellular Ca(2+) oscillations. The strongest empirical studies to date suggest that mammalian sperm-triggered Ca(2+) oscillations are caused by the introduction of a sperm-specific protein, called phospholipase C-zeta (PLCzeta) that generates inositol trisphosphate within the egg. We will discuss the role and mechanism of action of PLCzeta in detail at a molecular and cellular level. We will also consider some of the evidence that a soluble sperm protein might be involved in egg activation in nonmammalian species. PMID- 26631594 TI - The link between abnormal calcium handling and electrical instability in acquired long QT syndrome--Does calcium precipitate arrhythmic storms? AB - Release of Ca(2+) ions from sarcoplasmic reticulum (SR) into myocyte cytoplasm and their binding to troponin C is the final signal form myocardial contraction. Synchronous contraction of ventricular myocytes is necessary for efficient cardiac pumping function. This requires both shuttling of Ca(2+) between SR and cytoplasm in individual myocytes, and organ-level synchronization of this process by means of electrical coupling among ventricular myocytes. Abnormal Ca(2+) release from SR causes arrhythmias in the setting of CPVT (catecholaminergic polymorphic ventricular tachycardia) and digoxin toxicity. Recent optical mapping data indicate that abnormal Ca(2+) handling causes arrhythmias in models of both repolarization impairment and profound bradycardia. The mechanisms involve dynamic spatial heterogeneity of myocardial Ca(2+) handling preceding arrhythmia onset, cell-synchronous systolic secondary Ca(2+) elevation (SSCE), as well as more complex abnormalities of intracellular Ca(2+) handling detected by subcellular optical mapping in Langendorff-perfused hearts. The regional heterogeneities in Ca(2+) handling cause action potential (AP) heterogeneities through sodium-calcium exchange (NCX) activation and eventually overwhelm electrical coupling of the tissue. Divergent Ca(2+) dynamics among different myocardial regions leads to temporal instability of AP duration and - on the patient level - in T wave lability. Although T-wave alternans has been linked to cardiac arrhythmias, non-alternans lability is observed in pre-clinical models of the long QT syndrome (LQTS) and CPVT, and in LQTS patients. Analysis of T wave lability may provide a real-time window on the abnormal Ca(2+) dynamics causing specific arrhythmias such as Torsade de Pointes (TdP). PMID- 26631596 TI - Taste of Fat: A Sixth Taste Modality? AB - An attraction for palatable foods rich in lipids is shared by rodents and humans. Over the last decade, the mechanisms responsible for this specific eating behavior have been actively studied, and compelling evidence implicates a taste component in the orosensory detection of dietary lipids [i.e., long-chain fatty acids (LCFA)], in addition to textural, olfactory, and postingestive cues. The interactions between LCFA and specific receptors in taste bud cells (TBC) elicit physiological changes that affect both food intake and digestive functions. After a short overview of the gustatory pathway, this review brings together the key findings consistent with the existence of a sixth taste modality devoted to the perception of lipids. The main steps leading to this new paradigm (i.e., chemoreception of LCFA in TBC, cell signaling cascade, transfer of lipid signals throughout the gustatory nervous pathway, and their physiological consequences) will be critically analyzed. The limitations to this concept will also be discussed in the light of our current knowledge of the sense of taste. Finally, we will analyze the recent literature on obesity-related dysfunctions in the orosensory detection of lipids ("fatty" taste?), in relation to the overconsumption of fat-rich foods and the associated health risks. PMID- 26631597 TI - Identifying musical difficulties as they relate to congenital amusia in the pediatric population. AB - INTRODUCTIONS/OBJECTIVES: Approximately 4% of the population fails to develop basic music skills and can be identified as "amusic". Congenital amusia (CA), or "tone deafness", is thought to be a hereditary disordera predominantly affecting the perception and production of music. The gold standard for diagnosis is the Montreal Battery for Evaluation of Amusia (MBEA). This study aims to pinpoint factors in the history that may help identify amusic children and to determine if amusic pediatric patients can be identified using a widely available, shorter test validated in adults. METHODS: Subjects ages 7-17 years were recruited to take an online test, validated against the MBEA, for CA. The sections tested recognition of "off-beat" (OB), "mistuned" (MT), and "out-of-key" (OOK) conditions. Parents filled out a questionnaire regarding the subject's past medical, educational, musical exposure, and family history. RESULTS: Of 114 subjects recruited, complete data was available on 105 with a mean age of 12.5 years. According to adult criteria, 63/105 (60%) of subjects scored in the "amusic" range. Children >10 years of age scored significantly higher on the off beat section (p=0.001) and total scores (p=0.025). Subjects who were born prematurely scored significantly lower (p=0.045). Children whose father had difficulties with music scored significantly lower on the off-beat section (p=0.003) and total scores (p=0.008). CONCLUSIONS: CA is a disorder that has implications for quality of life. Earlier identification may help elucidate the pathogenesis of the condition and, in the future, the institution of prompt treatment. Further studies are needed to identify the most appropriate and convenient tests, as well as the optimal timing of testing, for reliably diagnosing CA in children. PMID- 26631598 TI - Nutrient-dependent control of short neuropeptide F transcript levels via components of the insulin/IGF signaling pathway in the desert locust, Schistocerca gregaria. AB - Peptides of the short neuropeptide F (sNPF) family modulate feeding behavior in a wide variety of insect species, including the desert locust, Schistocerca gregaria. Likewise, the nutritional state of the animal can strongly affect sNPF expression. Although several studies have been published describing these nutrient-dependent effects, it remains largely unclear how they are achieved. In this study, we describe a series of in vivo experiments which indicate that it is not the act of feeding in se, but rather the consequent availability of nutrients in the insect's hemolymph that gives rise to the postprandial modulation of sNPF expression. Furthermore, by performing a series of RNAi-mediated knockdown experiments, we were able to show that components of the evolutionarily conserved insulin/insulin-related growth factor (IGF) signaling pathway form a functional link between nutrient levels and sNPF transcript levels. PMID- 26631599 TI - Glutathione S-transferase SlGSTE1 in Spodoptera litura may be associated with feeding adaptation of host plants. AB - Spodoptera litura is polyphagous pest insect and feeds on plants of more than 90 families. In this study the role of glutathione S-transferase epilson 1 (slgste1) in S. litura in detoxification was examined. This gene was up-regulated in the midgut of S. litura at the transcriptional and protein levels when the insect fed on Brassica juncea or diet containing phytochemicals such as indole-3-carbinol and allyl-isothiocyanate that are metabolic products of sinigrin and glucobrassicin in B. juncea. The SlGSTE1 could catalyze the conjugation of reduced glutathione and indole-3-carbinol and allyl-isothiocyanate, as well as xanthotoxin, which is a furanocoumarin, under in vitro condition. When the expression of Slgste1 in the larvae was suppressed with RNAi, the larval growth and feeding rate were decreased. Furthermore, the up-regulated expression of the SlGSTE1 protein in the midgut of larvae that fed on different host plants was detected by 2-DE and ESI/MS analysis. The feeding adaptation from the most to the least of the larvae for the various host plants was Brassica alboglabra, Brassica linn. Pekinensis, Cucumis sativus, Ipomoea batatas, Arachis hypogaea and Capsicum frutescens. All the results together suggest that Slgste1 is a critical detoxifying enzyme that is induced by phytochmicals in the host plants and, inter alia, may be related to host plant adaptation of S. litura. PMID- 26631600 TI - Stink bug predator kills prey with salivary non-proteinaceous compounds. AB - Podisus nigrispinus Dallas (Hemiptera: Pentatomidae) is a predator insect with potential applications in biological control because both nymphs and adults have been shown to prey on other insect pests by injection of toxic salivary gland contents. This study identified non-proteinaceous compounds with insecticidal activity from the saliva of P. nigrispinus in Anticarsia gemmatalis. In particular, the ether extract from P. nigrispinus saliva led to mortality in A. gemmatalis larvae, with a LC50 = 2.04 MUL and LC90 = 3.27 MUL. N,N dimethylaniline and 1,2,5-trithiepane fractions were identified as non proteinaceous extract components. N,N-dimethylaniline had a LC50 = 136.1 nL and LC90 = 413.8 nL, suggesting that it could be responsible for toxicity in P. nigrispinus saliva. PMID- 26631601 TI - Wheel-running reinforcement in free-feeding and food-deprived rats. AB - Rats experiencing sessions of 30min free access to wheel running were assigned to ad-lib and food-deprived groups, and given additional sessions of free wheel activity. Subsequently, both ad-lib and deprived rats lever pressed for 60s of wheel running on fixed ratio (FR) 1, variable ratio (VR) 3, VR 5, and VR 10 schedules, and on a response-initiated variable interval (VI) 30s schedule. Finally, the ad-lib rats were switched to food deprivation and the food-deprived rats were switched to free food, as rats continued responding on the response initiated VI 30-s schedule. Wheel running functioned as reinforcement for both ad lib and food-deprived rats. Food-deprived rats, however, ran faster and had higher overall lever-pressing rates than free-feeding rats. On the VR schedules, wheel-running rates positively correlated with local and overall lever pressing rates for deprived, but not ad-lib rats. On the response-initiated VI 30s schedule, wheel-running rates and lever-pressing rates changed for ad-lib rats switched to food deprivation, but not for food-deprived rats switched to free feeding. The overall pattern of results suggested different sources of control for wheel running: intrinsic motivation, contingencies of automatic reinforcement, and food-restricted wheel running. An implication is that generalizations about operant responding for wheel running in food-deprived rats may not extend to wheel running and operant responding of free-feeding animals. PMID- 26631603 TI - Dose-dependent effects of prostaglandin E2 in macrophage adhesion and migration. AB - Macrophage migration to the focus of infection is a hallmark of the innate immune response. Macrophage spreading, adhesion, and migration through the extracellular matrix require dynamic remodeling of the actin cytoskeleton associated to integrin clustering in podosomes and focal adhesions. Here, we show that prostaglandin E2 (PGE2 ), the main prostaglandin produced by macrophages during inflammation, promote the distinctive dose-dependent formation of podosomes or focal adhesions in macrophages. Low concentrations of PGE2 increased p110gamma PI3K expression, phosphorylation of actin-related protein 2, and formation of podosomes, which enhanced macrophage migration in response to chemokines. However, high doses of PGE2 increased phosphorylation of paxillin and focal adhesion kinase, the expression of serine/threonine protein kinase 1, and promoted focal adhesion formation and macrophage adhesion, reducing macrophage chemotaxis. In summary, we describe the dual role of PGE2 as a promoter of macrophage chemotaxis and adhesion, proposing a new model of macrophage migration to the inflammatory focus in the presence of a gradient of PGE2 . PMID- 26631602 TI - CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field. AB - Proper treatment of nonbonded interactions is essential for the accuracy of molecular dynamics (MD) simulations, especially in studies of lipid bilayers. The use of the CHARMM36 force field (C36 FF) in different MD simulation programs can result in disagreements with published simulations performed with CHARMM due to differences in the protocols used to treat the long-range and 1-4 nonbonded interactions. In this study, we systematically test the use of the C36 lipid FF in NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM. A wide range of Lennard-Jones (LJ) cutoff schemes and integrator algorithms were tested to find the optimal simulation protocol to best match bilayer properties of six lipids with varying acyl chain saturation and head groups. MD simulations of a 1,2-dipalmitoyl-sn phosphatidylcholine (DPPC) bilayer were used to obtain the optimal protocol for each program. MD simulations with all programs were found to reasonably match the DPPC bilayer properties (surface area per lipid, chain order parameters, and area compressibility modulus) obtained using the standard protocol used in CHARMM as well as from experiments. The optimal simulation protocol was then applied to the other five lipid simulations and resulted in excellent agreement between results from most simulation programs as well as with experimental data. AMBER compared least favorably with the expected membrane properties, which appears to be due to its use of the hard-truncation in the LJ potential versus a force-based switching function used to smooth the LJ potential as it approaches the cutoff distance. The optimal simulation protocol for each program has been implemented in CHARMM GUI. This protocol is expected to be applicable to the remainder of the additive C36 FF including the proteins, nucleic acids, carbohydrates, and small molecules. PMID- 26631604 TI - Incorporating Contact Network Structure in Cluster Randomized Trials. AB - Whenever possible, the efficacy of a new treatment is investigated by randomly assigning some individuals to a treatment and others to control, and comparing the outcomes between the two groups. Often, when the treatment aims to slow an infectious disease, clusters of individuals are assigned to each treatment arm. The structure of interactions within and between clusters can reduce the power of the trial, i.e. the probability of correctly detecting a real treatment effect. We investigate the relationships among power, within-cluster structure, cross contamination via between-cluster mixing, and infectivity by simulating an infectious process on a collection of clusters. We demonstrate that compared to simulation-based methods, current formula-based power calculations may be conservative for low levels of between-cluster mixing, but failing to account for moderate or high amounts can result in severely underpowered studies. Power also depends on within-cluster network structure for certain kinds of infectious spreading. Infections that spread opportunistically through highly connected individuals have unpredictable infectious breakouts, making it harder to distinguish between random variation and real treatment effects. Our approach can be used before conducting a trial to assess power using network information, and we demonstrate how empirical data can inform the extent of between-cluster mixing. PMID- 26631605 TI - A small molecule inhibitor for ATPase activity of Hsp70 and Hsc70 enhances the immune response to protein antigens. AB - The ATPase activities of Hsp70 and Hsc70 are known to be responsible for regulation of various biological processes. However, little is known about the roles of Hsp70 and Hsc70 in modulation of immune responses to antigens. In the present study, we investigated the effect of apoptozole (Az), a small molecule inhibitor of Hsp70 and Hsc70, on immune responses to protein antigens. The results show that mice administered with both protein antigen and Az produce more antibodies than those treated with antigen alone, showing that Az enhances immune responses to administered antigens. Treatment of mice with Az elicits production of antibodies with a high IgG2c/IgG1 ratio and stimulates the release of Th1 and Th2-type cytokines, suggesting that Az activates the Th1 and Th2 immune responses. The observations made in the present study suggest that inhibition of Hsp70 and Hsc70 activities could be a novel strategy designing small molecule based adjuvants in protein vaccines. PMID- 26631606 TI - Inverse birth cohort effects in ovarian cancer: Increasing risk in BRCA1/2 mutation carriers and decreasing risk in the general population. AB - OBJECTIVE: BRCA1/2 carriers are at increased risk of ovarian cancer, and some reports suggest an increasing risk in more recent birth cohorts. In contrast, decreasing incidences have been observed in the general population. The aim was to assess the birth cohort effect on ovarian cancer risk in BRCA1/2 carriers relative to their background general population. METHODS: Data on ovarian cancer incidence was collected for a cohort of 1050 BRCA1/2 mutation carriers ascertained by our regional clinic and retrieved from the general Dutch population cancer registry. Birth cohorts were categorized as pre-1935, 1935 1953, post-1953. Birth cohort effects on the ovarian cancer risk were estimated using hazard ratios (HRs) in BRCA1/2 carriers and Poisson rate ratios in the general population. Standardized incidence ratios (SIRs) were calculated to compare populations. HRs were adjusted for mutation position and family history. RESULTS: Compared to the pre-1935 cohort, BRCA1 carriers in the 1935-1953 and post-1953 cohorts had an increased ovarian cancer risk of HRadjusted 1.54 (95% CI 1.11-2.14) and 2.40 (95% CI 1.56-3.69), respectively. BRCA2 carriers in the 1935 1953 cohort had an HRadjusted of 3.01 (95% CI 1.47-6.13). The SIRs for the 1935 1953 and post-1953 cohorts were 1.7 and 2.7, respectively, for the BRCA1 carriers and 1.6 times and 2.4 times, respectively, for BRCA2 carriers. CONCLUSIONS: Mutation carriers, particularly BRCA1 carriers, born in the most recent cohorts, have the highest additional ovarian cancer risk as compared to the general population. PMID- 26631607 TI - Endpoints in clinical trials: What do patients consider important? A survey of the Ovarian Cancer National Alliance. AB - OBJECTIVE: In order to understand the patient's perspective in regards to meaningful surrogate clinical trial endpoints and the impact of treatment-related toxicity, and quality of life, we surveyed women with gynecological cancers to ascertain their preferences. METHODS: A 28-question anonymous online survey was posted on the OCNA website (www.ovariancancer.org). Survey questions included demographic factors, tumor data, and patients' preference regarding side effects and therapy endpoints. Data was analyzed for frequency and percentage of each response. Student t-test, Fisher's exact test and Wilcoxon rank sums were preformed. RESULTS: There were 1413 survey responses. Participants reported that for a new agent to be meaningful, the minimum extension of progression-free survival (PFS) and overall survival (OS) should be five or more months, 77% and 85% of the time, respectively. Most subjects (55%, n=612) were interested in an agent that would keep tumor growth relatively static without change in OS. Addressing the impact of adverse aspects from a hypothetical new agent as a function of response, there was significant migration (p<0.0001) to acceptance of greater toxicity and cost under the scenario of a 5-6months OS gain, despite three-fold higher neurotoxicity, as compared to a PFS gain of 3-4months/no OS gain without toxicity. Response patterns weren't altered by recurrence status. CONCLUSIONS: Herein, we show that magnitude of outcome is a desired effect, even given the prospect of significant toxicity and cost. However, these preferences appear to differ between those with primary and recurrent disease. PMID- 26631608 TI - Investigation of reactions between trace gases and functional CuO nanospheres and octahedrons using NEXAFS-TXM imaging. AB - In order to take full advantage of novel functional materials in the next generation of sensorial devices scalable processes for their fabrication and utilization are of great importance. Also understanding the processes lending the properties to those materials is essential. Among the most sought-after sensor applications are low-cost, highly sensitive and selective metal oxide based gas sensors. Yet, the surface reactions responsible for provoking a change in the electrical behavior of gas sensitive layers are insufficiently comprehended. Here, we have used near-edge x-ray absorption fine structure spectroscopy in combination with x-ray microscopy (NEXAFS-TXM) for ex-situ measurements, in order to reveal the hydrogen sulfide induced processes at the surface of copper oxide nanoparticles, which are ultimately responsible for triggering a percolation phase transition. For the first time these measurements allow the imaging of trace gas induced reactions and the effect they have on the chemical composition of the metal oxide surface and bulk. This makes the new technique suitable for elucidating adsorption processes in-situ and under real operating conditions. PMID- 26631609 TI - Novel MYBL1 Gene Rearrangements with Recurrent MYBL1-NFIB Fusions in Salivary Adenoid Cystic Carcinomas Lacking t(6;9) Translocations. AB - PURPOSE: Adenoid cystic carcinoma (ACC) is an indolent salivary gland malignancy, characterized by t(6;9) translocations and MYB-NFIB gene fusions in approximately 50% of the tumors. The genetic alterations underlying t(6;9)-negative and t(6;9) positive/MYB-NFIB fusion-negative ACC remain unknown. To uncover the genetic alterations in ACC lacking the canonical translocation and fusion transcript and identify new abnormalities in translocation positive tumors. EXPERIMENTAL DESIGN: We performed whole-genome sequencing in 21 salivary ACCs and conducted targeted molecular analyses in a validation set (81 patients). Microarray gene-expression data were also analyzed to explore the biologic differences between fusion positive and negative tumors. RESULTS: We identified a novel MYBL1-NFIB gene fusion as a result of t(8;9) translocation and multiple rearrangements in the MYBL1 gene in 35% of the t(6;9)-negative ACCs. All MYBL1 alterations involved deletion of the C-terminal negative regulatory domain and were associated with high MYBL1 expression. Reciprocal MYB and MYBL1 expression was consistently found in ACCs. In addition, 5'-NFIB fusions that did not involve MYB/MYBL1 genes were identified in a subset of t(6;9)-positive/fusion-negative tumors. We also delineated distinct gene-expression profiles in ACCs associated with the length of the MYB or MYBL1 fusions, suggesting a biologic importance of the C-terminal part of these fusions. CONCLUSIONS: Our study defines new molecular subclasses of ACC characterized by MYBL1 rearrangements and 5'-NFIB gene fusions. PMID- 26631611 TI - Toward Personalized Lymphoma Immunotherapy: Identification of Common Driver Mutations Recognized by Patient CD8+ T Cells. AB - PURPOSE: A fundamental challenge in the era of next-generation sequencing (NGS) is to design effective treatments tailored to the mutational profiles of tumors. Many newly discovered cancer mutations are difficult to target pharmacologically; however, T-cell-based therapies may provide a valuable alternative owing to the exquisite sensitivity and specificity of antigen recognition. To explore this concept, we assessed the immunogenicity of a panel of genes that are common sites of driver mutations in follicular lymphoma, an immunologically sensitive yet currently incurable disease. EXPERIMENTAL DESIGN: Exon capture and NGS were used to interrogate tumor samples from 53 patients with follicular lymphoma for mutations in 10 frequently mutated genes. For 13 patients, predicted mutant peptides and proteins were evaluated for recognition by autologous peripheral blood T cells after in vitro priming. RESULTS: Mutations were identified in 1-5 genes in 81% (43/53) of tumor samples. Autologous, mutation-specific CD8(+) T cells were identified in 23% (3/13) of evaluated cases. T-cell responses were directed toward putative driver mutations in CREBBP and MEF2B. Responding T cells showed exquisite specificity for mutant versus wild-type proteins and recognized lymphoma cells expressing the appropriate mutations. Responding T cells appeared to be from the naive repertoire, as they were found at low frequencies and only at single time points in each patient. CONCLUSIONS: Patients with follicular lymphoma harbor rare yet functionally competent CD8(+) T cells specific for recurrent mutations. Our results support the concept of using NGS to design individualized immunotherapies targeting common driver mutations in follicular lymphoma and other malignancies. Clin Cancer Res; 22(9); 2226-36. (c)2015 AACR. PMID- 26631610 TI - Genetic Effect of Chemotherapy Exposure in Children of Testicular Cancer Survivors. AB - PURPOSE: Cancer survivors express anxiety that chemotherapy exposure may lead to transmissible genetic damage in posttreatment children. Preclinical models suggest that chemotherapy exposure may result in considerable genomic alterations in postexposure progeny. Epidemiologic studies have not demonstrated a significant increase in congenital abnormalities in posttreatment children of cancer survivors, but the inherited genome-wide effect of chemotherapy exposure in humans is unknown. EXPERIMENTAL DESIGN: Two testicular cancer survivors cured with chemotherapy who had children pre- and postexposure without sperm banking were identified. Familial germline whole genome sequencing (WGS) was performed for these families, and analytic methods were utilized to identify de novo alterations, including mutations, recombinations, and structural rearrangements in the pre- and postexposure offspring. RESULTS: No increase in de novo germline mutations in postexposure children compared with their preexposure siblings was found. Furthermore, there were no increased short insertion/deletions, recombination frequency, or structural rearrangements in these postexposure children. CONCLUSIONS: In two families of male cancer survivors, there was no transmissible genomic impact of significant mutagenic exposure in postexposure children. This study may provide possible reassuring evidence for patients undergoing chemotherapy who are unable to have pretreatment sperm cryopreservation. Expanded cohorts that utilize WGS to identify environmental exposure effects on the inherited genome may inform the generalizability of these results. Clin Cancer Res; 22(9); 2183-9. (c)2015 AACR. PMID- 26631612 TI - A Supplemented High-Fat Low-Carbohydrate Diet for the Treatment of Glioblastoma. AB - PURPOSE: Dysregulated energetics coupled with uncontrolled proliferation has become a hallmark of cancer, leading to increased interest in metabolic therapies. Glioblastoma (GB) is highly malignant, very metabolically active, and typically resistant to current therapies. Dietary treatment options based on glucose deprivation have been explored using a restrictive ketogenic diet (KD), with positive anticancer reports. However, negative side effects and a lack of palatability make the KD difficult to implement in an adult population. Hence, we developed a less stringent, supplemented high-fat low-carbohydrate (sHFLC) diet that mimics the metabolic and antitumor effects of the KD, maintains a stable nutritional profile, and presents an alternative clinical option for diverse patient populations. EXPERIMENTAL DESIGN: The dietary paradigm was tested in vitro and in vivo, utilizing multiple patient-derived gliomasphere lines. Cellular proliferation, clonogenic frequency, and tumor stem cell population effects were determined in vitro using the neurosphere assay (NSA). Antitumor efficacy was tested in vivo in preclinical xenograft models and mechanistic regulation via the mTOR pathway was explored. RESULTS: Reducing glucose in vitro to physiologic levels, coupled with ketone supplementation, inhibits proliferation of GB cells and reduces tumor stem cell expansion. In vivo, while maintaining animal health, the sHFLC diet significantly reduces the growth of tumor cells in a subcutaneous model of tumor progression and increases survival in an orthotopic xenograft model. Dietary-mediated anticancer effects correlate with the reduction of mTOR effector expression. CONCLUSIONS: We demonstrate that the sHFLC diet is a viable treatment alternative to the KD, and should be considered for clinical testing. Clin Cancer Res; 22(10); 2482-95. (c)2015 AACR. PMID- 26631613 TI - Identification of a Novel Pathogenic Germline KDR Variant in Melanoma. AB - PURPOSE: The application of pan-cancer next-generation sequencing panels in the clinical setting has facilitated the identification of low frequency somatic mutations and the testing of new therapies in solid tumors using the "basket trial" scheme. However, little consideration has been given to the relevance of nonsynonymous germline variants, which are likely to be uncovered in tumors and germline and which may be relevant to prognostication and prediction of treatment response. EXPERIMENTAL DESIGN: We analyzed matched tumor and normal DNA from 34 melanoma patients using an Ion Torrent cancer-associated gene panel. We elected to study the germline variant Q472H in the kinase insert domain receptor (KDR), which was identified in 35% of melanoma patients in both a pilot and an independent 1,223 patient cohort. Using patient-derived melanoma cell lines and human samples, we assessed proliferation, invasion, VEGF levels, and angiogenesis by analyzing tumor microvessel density (MVD) using anti-CD34 antibody. RESULTS: Serum VEGF levels and tumor MVD were significantly higher in Q472H versus KDR wild-type (WD) patients. Primary cultures derived from melanomas harboring the KDR variant were more proliferative and invasive than KDR wild type. Finally, using a VEGFR2 antibody, we showed that KDR Q472H cells were sensitive to targeted inhibition of VEGFR2, an effect that was not observed in KDR WT cells. CONCLUSIONS: Our data support the integration of germline analysis into personalized treatment decision-making and suggest that patients with germline KDR variant might benefit from antiangiogenesis treatment. Clin Cancer Res; 22(10); 2377-85. (c)2015 AACR. PMID- 26631614 TI - Mechanistic Investigation of Bone Marrow Suppression Associated with Palbociclib and its Differentiation from Cytotoxic Chemotherapies. AB - PURPOSE: Palbociclib (PD-0332991) is the first selective cyclin-dependent kinase (CDK) 4/6 inhibitor approved for metastatic breast cancer. Hematologic effects, especially neutropenia, are dose-limiting adverse events for palbociclib in humans. EXPERIMENTAL DESIGN: Reversible hematologic effects and bone marrow hypocellularity have been identified in toxicology studies in rats and dogs after palbociclib treatment. To understand the mechanism by which the hematologic toxicity occurs, and to further differentiate it from the myelotoxicity caused by cytotoxic chemotherapeutic agents, anin vitroassay using human bone marrow mononuclear cells (hBMNC) was utilized. RESULTS: This work demonstrated that palbociclib-induced bone marrow suppression occurred through cell-cycle arrest, with no apoptosis at clinically relevant concentrations, was not lineage specific, and was reversible upon palbociclib withdrawal. In contrast, treatment with chemotherapeutic agents (paclitaxel and doxorubicin) resulted in DNA damage and apoptotic cell death in hBMNCs. In the presence or absence of the antiestrogen, palbociclib-treated hBMNCs did not become senescent and resumed proliferation following palbociclib withdrawal, consistent with pharmacologic quiescence. The breast cancer cells, MCF-7, conversely, became senescent following palbociclib or antiestrogen treatment with additive effects in combination and remained arrested in the presence of antiestrogen. CONCLUSIONS: Palbociclib causes reversible bone marrow suppression, clearly differentiating it from apoptotic cell death caused by cytotoxic chemotherapeutic agents. This study also distinguished the cell-cycle arresting action of palbociclib on normal bone marrow cells from the senescent effects observed in breast cancer cells. These results shed light on the mechanism and support risk management of palbociclib induced bone marrow toxicity in the clinic. PMID- 26631615 TI - Targeting MYCN-Driven Transcription By BET-Bromodomain Inhibition. AB - PURPOSE: Targeting BET proteins was previously shown to have specific antitumoral efficacy against MYCN-amplified neuroblastoma. We here assess the therapeutic efficacy of the BET inhibitor, OTX015, in preclinical neuroblastoma models and extend the knowledge on the role of BRD4 in MYCN-driven neuroblastoma. EXPERIMENTAL DESIGN: The efficacy of OTX015 was assessed in in vitro and in vivo models of human and murine MYCN-driven neuroblastoma. To study the effects of BET inhibition in the context of high MYCN levels, MYCN was ectopically expressed in human and murine cells. The effect of OTX015 on BRD4-regulated transcriptional pause release was analyzed using BRD4 and H3K27Ac chromatin immunoprecipitation coupled with DNA sequencing (ChIP-Seq) and gene expression analysis in neuroblastoma cells treated with OTX015 compared with vehicle control. RESULTS: OTX015 showed therapeutic efficacy against preclinical MYCN-driven neuroblastoma models. Similar to previously described BET inhibitors, concurrent MYCN repression was observed in OTX015-treated samples. Ectopic MYCN expression, however, did not abrogate effects of OTX015, indicating that MYCN repression is not the only target of BET proteins in neuroblastoma. When MYCN was ectopically expressed, BET inhibition still disrupted MYCN target gene transcription without affecting MYCN expression. We found that BRD4 binds to super-enhancers and MYCN target genes, and that OTX015 specifically disrupts BRD4 binding and transcription of these genes. CONCLUSIONS: We show that OTX015 is effective against mouse and human MYCN-driven tumor models and that BRD4 not only targets MYCN, but specifically occupies MYCN target gene enhancers as well as other genes associated with super-enhancers. Clin Cancer Res; 22(10); 2470-81. (c)2015 AACR. PMID- 26631616 TI - The Landscape of Prognostic Outlier Genes in High-Risk Prostate Cancer. AB - PURPOSE: There is a clear need to improve risk stratification and to identify novel therapeutic targets in aggressive prostate cancer. The goal of this study was to investigate genes with outlier expression with prognostic association in high-risk prostate cancer patients as potential biomarkers and drug targets. EXPERIMENTAL DESIGN: We interrogated microarray gene expression data from prostatectomy samples from 545 high-risk prostate cancer patients with long-term follow-up (mean 13.4 years). Three independent clinical datasets totaling an additional 545 patients were used for validation. Novel prognostic outlier genes were interrogated for impact on oncogenic phenotypes in vitro using siRNA-based knockdown. Association with clinical outcomes and comparison with existing prognostic instruments was assessed with multivariable models using a prognostic outlier score. RESULTS: Analysis of the discovery cohort identified 20 prognostic outlier genes. Three top prognostic outlier genes were novel prostate cancer genes; NVL, SMC4, or SQLE knockdown reduced migration and/or invasion and outlier expression was significantly associated with poor prognosis. Increased prognostic outlier score was significantly associated with poor prognosis independent of standard clinicopathologic variables. Finally, the prognostic outlier score prognostic association is independent of, and adds to existing genomic and clinical tools for prognostication in prostate cancer (Decipher, the cell-cycle progression signature, and CAPRA-S). CONCLUSIONS: To our knowledge, this study represents the first unbiased high-throughput investigation of prognostic outlier genes in prostate cancer and demonstrates the potential biomarker and therapeutic importance of this previously unstudied class of cancer genes. PMID- 26631617 TI - Gene expression variance in hippocampal tissue of temporal lobe epilepsy patients corresponds to differential memory performance. AB - Temporal lobe epilepsy (TLE) is a severe brain disorder affecting particularly young adults. TLE is frequently associated with memory deterioration and neuronal damage of the hippocampal formation. It thereby reveals striking parallels to neurodegenerative disorders including Alzheimer's disease (AD). TLE patients differ with respect to their cognitive performance, but currently little is known about relevant molecular-genetic factors. Here, we correlated differential memory performance of pharmacoresistant TLE patients undergoing neurosurgery for seizure control with in-vitro findings of their hippocampal tissues. We analyzed mRNA transcripts and subsequently promoter variants specifically altered in brain tissue of individuals with 'very severe' memory impairment. TLE patients (n=79) were stratified according to preoperative memory impairment using an established four-tiered grading system ranging from 'average' to 'very severely'. Multimodal cluster analyses revealed molecules specifically associated with synaptic function and abundantly expressed in TLE patients with very impaired memory performance. In a subsequent promoter analysis, we found the single nucleotide polymorphism rs744373 C-allele to be associated with high mRNA levels of bridging integrator 1 (BIN1)/Amphiphysin 2, i.e. a major component of the endocytotic machinery and located in a crucial genetic AD risk locus. Using in vitro luciferase transfection assays, we found that BIN1 promoter activation is genotype dependent and strongly increased by reduced binding of the transcriptional repressor TGIF. Our data indicate that poor memory performance in patients with TLE strongly corresponds to distinctly altered neuronal transcript signatures, which - as demonstrated for BIN1 - can correlate with a particular allelic promoter variant. Our data suggest aberrant transcriptional signaling to significantly impact synaptic dynamics in TLE resulting in impaired memory performance and may serve as basis for future therapy development of this severe comorbidity. PMID- 26631618 TI - Electronically Excited States of Higher Acenes up to Nonacene: A Density Functional Theory/Multireference Configuration Interaction Study. AB - While the optical spectra of the acene series up to pentacene provide textbook examples for the annulation principle, the spectra of the larger members are much less understood. The present work provides an investigation of the optically allowed excited states of the acene series from pentacene to nonacene, the largest acene observed experimentally, using the density functional based multireference configuration method (DFT/MRCI). For this purpose, the ten lowest energy states of the B2u and B3u irreducible representations were computed. In agreement with previous computational investigations, the electronic wave functions of the acenes acquire significant multireference character with increasing acene size. The HOMO -> LUMO excitation is the major contributor to the (1)La state (p band, B2u) also for the larger acenes. The oscillator strength decreases with increasing length. The (1)Lb state (alpha band, B3u), so far difficult to assign for the larger acenes due to overlap with photoprecursor bands, becomes almost insensitive to acene length. The (1)Bb state (beta band, B3u) also moves only moderately to lower energy with increasing acene size. Excited states of B3u symmetry that formally result from double excitations involving HOMO, HOMO-1, LUMO, and LUMO+1 decrease in energy much faster with system size. One of them (D1) has very small oscillator strength but becomes almost isoenergetic with the (1)La state for nonacene. The other (D2) also has low oscillator strength as long as it is higher in energy than (1)Bb. Once it is lower in energy than the (1)Bb state, both states interact strongly resulting in two states with large oscillator strengths. The emergence of two strongly absorbing states is in agreement with experimental observations. The DFT/MRCI computations reproduce experimental excitation energies very well for pentacene and hexacene (within 0.1 eV). For the larger acenes deviations are larger (up to 0.2 eV), but qualitative agreement is observed. PMID- 26631619 TI - Modulatory action of taurine on ethanol-induced aggressive behavior in zebrafish. AB - Alcohol is a potent agent for eliciting aggression in vertebrates. Taurine (TAU) is an amino sulfonic acid with pleiotropic actions on brain function. It is one of the most abundant molecules present in energy drinks frequently used as mixers for alcoholic beverages. However, the combined effects of TAU and ethanol (EtOH) on behavioral parameters such as aggression are poorly understood. Considering that zebrafish is a suitable vertebrate to assess agonistic behaviors using noninvasive protocols, we investigate whether TAU modulates EtOH-induced aggression in zebrafish using the mirror-induced aggression (MIA) test. Since body color can be altered by pharmacological agents and may be indicative of emotional state, we also evaluated the actions of EtOH and TAU on pigment response. Fish were acutely exposed to TAU (42, 150, and 400mg/L), EtOH (0.25%), or cotreated with both molecules for 1h and then placed in the test apparatus for 6min. EtOH, TAU 42, TAU 400, TAU 42/EtOH and TAU 400/EtOH showed increased aggression, while 150mg/L TAU only increased the latency to attack the mirror. This same concentration also prevented EtOH-induced aggression, suggesting that it antagonizes the effects of acute alcohol exposure. Representative ethograms revealed the existence of different aggressive patterns and our results were confirmed by an index used to estimate aggression in the MIA test. TAU did not alter pigment intensity, while EtOH and all cotreated groups presented a substantial increase in body color. Overall, these data show a biphasic effect of TAU on EtOH-induced aggression of zebrafish, which is not necessarily associated with changes in body color. PMID- 26631620 TI - Three-Dimensional Assignment of the Structures of Atomic Clusters: an Example of Au8M (M=Si, Ge, Sn) Anion Clusters. AB - Identification of different isomer structures of atomic and molecular clusters has long been a challenging task in the field of cluster science. Here we present a three-dimensional (3D) assignment method, combining the energy (1D) and simulated (2D) spectra to assure the assignment of the global minimum structure. This method is more accurate and convenient than traditional methods, which only consider the total energy and first vertical detachment energies (VDEs) of anion clusters. There are two prerequisites when the 3D assignment method is ultilized. First, a reliable global minimum search algorithm is necessary to explore enough valleys on the potential energy surface. Second, trustworthy simulated spectra are necessary, that is to say, spectra that are in quantitative agreement. In this paper, we demonstrate the validity of the 3D assignment method using Au8M(-) (M=Si, Ge, Sn) systems. Results from this study indicate that the global minimum structures of Au8Ge(-) and Au8Sn(-) clusters are different from those described in previous studies. PMID- 26631621 TI - Clinical, genetics and bioinformatics characterization of a campomelic dysplasia case report. AB - Campomelic dysplasia is a rare disorder characterized by skeletal and extraskeletal defects. Up to two-thirds of affected XY individuals have a gradation of genital defects or may develop as phenotypic females. This syndrome is caused by alterations in SRY-related HMG-Box Gene 9 (SOX9), a transcription factor essential in both chondrocyte differentiation and sex determination. We report a 27-week fetus with ambiguous genitalia and upper and lower extremities bone malformations. Gross photographs, radiologic and pathological studies led the clinical diagnosis to campomelic dysplasia. A new frameshift mutation (p.Pro415Serfs*163) was identified in the SOX9 gene by genetic analysis. This mutation not only alters almost the entire sequence of the C-terminal transactivation (TA) domain of SOX9, but also enlarges it. This altered sequence does not resemble any other existing sequence. Since TA domain is entirely affected, SOX9 could not establish its normal function. The comparison between p.Pro415Serfs*163 and other frameshift mutations that enlarges SOX9 showed the same nucleotides added. This new sequence is not conserved either. We speculate that the fact of adding a sequence downstream of the C-terminal domain alters SOX9 and leads to campomelic dysplasia. The clinical information is essential not only to achieve a correct diagnosis in fetuses with pathologic ultrasound findings, but also to offer a proper genetic counseling. PMID- 26631622 TI - Molecular evolution of antioxidant and hypoxia response in long-lived, cancer resistant blind mole rats: The Nrf2-Keap1 pathway. AB - The Nrf2-Keap1 pathway is crucial for the cellular antioxidant and hypoxia response in vertebrates. Deciphering its modifications in hypoxia-adapted animals will help understand its functionality under environmental stress and possibly allow for knowledge transfer into biomedical research. The blind mole rat Spalax, a long-lived cancer-resistant rodent, lives in burrows underground and is adapted to severely hypoxic conditions. Here we have conducted a bioinformatical survey of Spalax core genes from the Nrf2-Keap1 pathway on the coding sequence level in comparison to other hypoxia-tolerant and -sensitive rodents. We find strong sequence conservation across all genes, illustrating the pathway's importance. One of the central players however, Spalax Keap1, shows a non-conservative amino acid substitution from tyrosine to cysteine in its intervening region (IVR) domain. Cysteines in this location have been shown to be of high functional relevance to the binding and degradation of Nrf2. Therefore, this peculiar substitution could influence the cellular Nrf2 levels in Spalax and, thereby, downstream gene expression in the antioxidant pathway, contributing to the special adaptive phenotype of the blind mole rat. PMID- 26631623 TI - Upregulation of KSRP by miR-27b provides IFN-gamma-induced post-transcriptional regulation of CX3CL1 in liver epithelial cells. AB - Aberrant cellular responses to pro-inflammatory cytokines, such as IFN-gamma, are pathogenic features in many chronic inflammatory diseases. A variety of feedback regulatory pathways have evolved to prevent an inappropriate cellular reaction to these pro-inflammatory cytokines. CX3CL1 is a unique chemokine and plays an important role in chronic liver diseases. We report here that IFN-gamma stimulation induces a transient CX3CL1 production in liver epithelial cells (i.e., hepatocytes and biliary epithelial cells). This transient CX3CL1 production is accompanied with a destabilization of CX3CL1 mRNA associated with the induction of the KH-type splicing regulatory protein (KSRP). IFN-gamma treatment of liver epithelial cells decreases expression level of miR-27b, a miRNA that targets the 3' untranslated region of KSRP mRNA resulting in translational suppression. Induction of KSRP following IFN-gamma stimulation depends on the downregulation of miR-27b. Functional manipulation of KSRP or miR 27b caused reciprocal alterations in CX3CL1 mRNA stability in liver epithelial cells. Moreover, transfection of miR-27b precursor influences CX3CL1-associated chemotaxis effects of biliary epithelial cells to Jurkat T cells. These findings suggest that miR-27b-mediated post-transcriptional suppression controls the expression of KSRP in liver epithelial cells, and upregulation of KSRP destabilizes CX3CL1 mRNA, providing fine-tuning of cellular inflammatory reactions in response to IFN-gamma stimulation. PMID- 26631624 TI - Antimicrobial resistance--a 'rising tide' of national (and international) risk. PMID- 26631626 TI - NFATc1 releases BCL6-dependent repression of CCR2 agonist expression in peritoneal macrophages from Saccharomyces cerevisiae infected mice. AB - The link between the extensive usage of calcineurin (CN) inhibitors cyclosporin A and tacrolimus (FK506) in transplantation medicine and the increasing rate of opportunistic infections within this segment of patients is alarming. Currently, how peritoneal infections are favored by these drugs, which impair the activity of several signaling pathways including the Ca(++) /CN/NFAT, Ca(++) /CN/cofilin, Ca(++) /CN/BAD, and NF-kappaB networks, is unknown. Here, we show that Saccharomyces cerevisiae infection of peritoneal resident macrophages triggers the transient nuclear translocation of NFATc1beta isoforms, resulting in a coordinated, CN-dependent induction of the Ccl2, Ccl7, and Ccl12 genes, all encoding CCR2 agonists. CN inhibitors block the CCR2-dependent recruitment of inflammatory monocytes (IM) to the peritoneal cavities of S. cerevisiae infected mice. In myeloid cells, NFATc1/beta proteins represent the most prominent NFATc1 isoforms. NFATc1/beta ablation leads to a decrease of CCR2 chemokines, impaired mobilization of IMs, and delayed clearance of infection. We show that, upon binding to a composite NFAT/BCL6 regulatory element within the Ccl2 promoter, NFATc1/beta proteins release the BCL6-dependent repression of Ccl2 gene in macrophages. These findings suggest a novel CN-dependent cross-talk between NFAT and BCL6 transcription factors, which may affect the outcome of opportunistic fungal infections in immunocompromised patients. PMID- 26631625 TI - Genome-wide Annotation and Comparative Analysis of Long Terminal Repeat Retrotransposons between Pear Species of P. bretschneideri and P. Communis. AB - Recent sequencing of the Oriental pear (P. bretschneideri Rehd.) genome and the availability of the draft genome sequence of Occidental pear (P. communis L.), has provided a good opportunity to characterize the abundance, distribution, timing, and evolution of long terminal repeat retrotransposons (LTR-RTs) in these two important fruit plants. Here, a total of 7247 LTR-RTs, which can be classified into 148 families, have been identified in the assembled Oriental pear genome. Unlike in other plant genomes, approximately 90% of these elements were found to be randomly distributed along the pear chromosomes. Further analysis revealed that the amplification timeframe of elements varies dramatically in different families, super-families and lineages, and the Copia-like elements have highest activity in the recent 0.5 million years (Mys). The data also showed that two genomes evolved with similar evolutionary rates after their split from the common ancestor ~0.77-1.66 million years ago (Mya). Overall, the data provided here will be a valuable resource for further investigating the impact of transposable elements on gene structure, expression, and epigenetic modification in the pear genomes. PMID- 26631627 TI - Clinical effect of cerebrovascular atherosclerosis on cognition in Alzheimer's disease. AB - BACKGROUND: The association between cerebrovascular atherosclerosis and Alzheimer's disease (AD) has been examined in many cross-sectional studies; however, there are few data regarding the role of cerebrovascular atherosclerosis on the longitudinal course of cognitive decline in AD. The aim of this study was to examine the progression of cognitive function in AD patients with cerebrovascular atherosclerosis compared to those without atherosclerosis over a two-year period. METHODS: Forty-seven AD patients with cerebrovascular atherosclerosis and 81 AD patients without atherosclerosis were assessed for cognitive function at the time of diagnosis and again at follow-up after two years. The cognitive functions were evaluated by neuropsychological tests including mini-mental state examination (MMSE) and clinical dementia scale (CDR). RESULTS: Repeated-measures multivariate analyses showed that there was a significant group-by-time interactions for the temporal changes of the MMSE and CDR between the two groups. The group-by-time interactions remained significant when the atherosclerotic patients were sub-classified into either an extracranial stenosis (EC) group or an intracranial stenosis(IC) group. Comparing either the EC or IC group with the non-atherosclerosis group, there were no main effects by time or group alone, but there were significant group-by-time interactions for the MMSE and CDR. CONCLUSIONS: Cognitive function worsened more in terms of progressive impairment in AD patients with cerebrovascular atherosclerosis compared to AD patients without cerebrovascular atherosclerosis, regardless of whether the atherosclerosis was extracranial or intracranial. PMID- 26631628 TI - Chronic nicotine and withdrawal affect glutamatergic but not nicotinic receptor expression in the mesocorticolimbic pathway in a region-specific manner. AB - Tobacco addiction is a complex form of dependence process that leads high relapse rates in people seeking to stop smoking. Nicotine elicits its primary effects on neuronal nicotinic cholinergic receptors (nAChRs), alters brain reward systems, and induces long-term changes during chronic nicotine use and withdrawal. We analysed the effects of chronic nicotine treatment and withdrawal on the mesocorticolimbic pathway (a brain reward circuit in which addictive drugs induce widespread adaptations) by analysing the expression of nAChRs in the midbrain, striatum and prefrontal cortex (PFC) of mice receiving intravenous infusions of nicotine (4mg/kg/h) or saline (control) for 14 days and mice sacrified two hours, and one, four and 14 days after treatment withdrawal. We biochemically fractionated whole tissue homogenates in order to obtain crude synaptosomal membranes. Western blotting analyses of these membrane fractions, ligand binding and immunoprecipitation studies, showed that chronic nicotine up-regulates heteromeric beta2* nAChRs in all three mesocorticolimbic areas, and that these receptors are rapidly removed from synapses upon the cessation of nicotine treatment. The extent of nicotine-induced nAChR up-regulation, and the time course of its reversal were comparable in all three areas. We also analysed the expression of glutamate receptor subunits (GluRs) and scaffold proteins, and found that it was altered in an area-specific manner during nicotine exposure and withdrawal. As the functional properties of GluRs are determined by their subunit composition, the observed changes in subunit expression may indicate alterations in the excitability of mesocorticolimbic circuitry, and this may underlie the long-term biochemical and behavioural effects of nicotine dependence. PMID- 26631629 TI - The Nobel Prize in Medicine 2015: Two drugs that changed global health. PMID- 26631630 TI - Replacing and safeguarding pancreatic beta cells for diabetes. AB - Pluripotent stem cells are a scalable source of pancreatic cells for transplantation into patients with diabetes. Here, we describe how the field is gaining momentum toward a beta cell replacement therapy. PMID- 26631633 TI - Riluzole blocks perioperative ischemia-reperfusion injury and enhances postdecompression outcomes in cervical spondylotic myelopathy. AB - Although surgical decompression is considered the gold standard treatment for cervical spondylotic myelopathy (CSM), a proportion of cases show postoperative decline or continue to exhibit substantial neurological dysfunction. To investigate this further, we first examined data from the prospective multicenter AOSpine North America CSM study, finding that 9.3% of patients exhibited postoperative functional decline (DeltamJOA, <=-1) and that 44% of patients were left with substantial neurological impairment 6 months postoperatively. Notably, 4% of patients experienced perioperative neurological complications within 20 days after surgery in otherwise uneventful surgeries. To shed light on the mechanisms underlying this phenomenon and to test a combination therapeutic strategy for CSM, we performed surgical decompression in a rat model of CSM, randomizing some animals to also receive the U.S. Food and Drug Administration approved drug riluzole. Spinal cord blood flow measurements increased after decompression surgery in rats. CSM rats showed a transient postoperative neurological decline akin to that seen in some CSM patients, suggesting that ischemia-reperfusion injury may occur after decompression surgery. Riluzole treatment attenuated oxidative DNA damage in the spinal cord and postoperative decline after decompression surgery. Mechanistic in vitro studies also demonstrated that riluzole preserved mitochondrial function and reduced oxidative damage in neurons. Rats receiving combined decompression surgery and riluzole treatment displayed long-term improvements in forelimb function associated with preservation of cervical motor neurons and corticospinal tracts compared to rats treated with decompression surgery alone. PMID- 26631631 TI - Immune history profoundly affects broadly protective B cell responses to influenza. AB - Generating a broadly protective influenza vaccine is critical to global health. Understanding how immune memory influences influenza immunity is central to this goal. We undertook an in-depth study of the B cell response to the pandemic 2009 H1N1 vaccine over consecutive years. Analysis of monoclonal antibodies generated from vaccine-induced plasmablasts demonstrated that individuals with low preexisting serological titers to the vaccinating strain generated a broadly reactive, hemagglutinin (HA) stalk-biased response. Higher preexisting serum antibody levels correlated with a strain-specific HA head-dominated response. We demonstrate that this HA head immunodominance encompasses poor accessibility of the HA stalk epitopes. Further, we show polyreactivity of HA stalk-reactive antibodies that could cause counterselection of these cells. Thus, preexisting memory B cells against HA head epitopes predominate, inhibiting a broadly protective response against the HA stalk upon revaccination with similar strains. Consideration of influenza exposure history is critical for new vaccine strategies designed to elicit broadly neutralizing antibodies. PMID- 26631634 TI - A cocktail of humanized anti-pertussis toxin antibodies limits disease in murine and baboon models of whooping cough. AB - Despite widespread vaccination, pertussis rates are rising in industrialized countries and remain high worldwide. With no specific therapeutics to treat disease, pertussis continues to cause considerable infant morbidity and mortality. The pertussis toxin is a major contributor to disease, responsible for local and systemic effects including leukocytosis and immunosuppression. We humanized two murine monoclonal antibodies that neutralize pertussis toxin and expressed them as human immunoglobulin G1 molecules with no loss of affinity or in vitro neutralization activity. When administered prophylactically to mice as a binary cocktail, antibody treatment completely mitigated the Bordetella pertussis induced rise in white blood cell counts and decreased bacterial colonization. When administered therapeutically to baboons, antibody-treated, but not untreated control animals, experienced a blunted rise in white blood cell counts and accelerated bacterial clearance rates. These preliminary findings support further investigation into the use of these antibodies to treat human neonatal pertussis in conjunction with antibiotics and supportive care. PMID- 26631632 TI - Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker. AB - Chronic kidney disease (CKD) affects 8 to 16% people worldwide, with an increasing incidence and prevalence of end-stage kidney disease (ESKD). The effective management of CKD is confounded by the inability to identify patients at high risk of progression while in early stages of CKD. To address this challenge, a renal biopsy transcriptome-driven approach was applied to develop noninvasive prognostic biomarkers for CKD progression. Expression of intrarenal transcripts was correlated with the baseline estimated glomerular filtration rate (eGFR) in 261 patients. Proteins encoded by eGFR-associated transcripts were tested in urine for association with renal tissue injury and baseline eGFR. The ability to predict CKD progression, defined as the composite of ESKD or 40% reduction of baseline eGFR, was then determined in three independent CKD cohorts. A panel of intrarenal transcripts, including epidermal growth factor (EGF), a tubule-specific protein critical for cell differentiation and regeneration, predicted eGFR. The amount of EGF protein in urine (uEGF) showed significant correlation (P < 0.001) with intrarenal EGF mRNA, interstitial fibrosis/tubular atrophy, eGFR, and rate of eGFR loss. Prediction of the composite renal end point by age, gender, eGFR, and albuminuria was significantly (P < 0.001) improved by addition of uEGF, with an increase of the C-statistic from 0.75 to 0.87. Outcome predictions were replicated in two independent CKD cohorts. Our approach identified uEGF as an independent risk predictor of CKD progression. Addition of uEGF to standard clinical parameters improved the prediction of disease events in diverse CKD populations with a wide spectrum of causes and stages. PMID- 26631635 TI - High level production of active streptokinase in Pichia pastoris fed-batch culture. AB - Streptokinase is a biological macromolecule involved in dissolution of fibrin blood clot and favourably used in various clinical applications. This protein is poorly expressed in soluble form due to its toxic effects on host physiology. The extracellular expression of recombinant streptokinase (SK) with and without 6xHis tag was obtained by cloning its gene under the alpha-mating factor signal sequence and alcohol inducible AOX1 promoter. Host-vector combinations were optimized to select a hyper producer. From shake flask optimization studies, a maximum expression of 582 mg/L of rSK (non-tagged) and 538 mg/L of rSK-His (His tagged) protein was obtained when cells were induced at OD600 of 20. The high cell density fermentation increased the volumetric product concentration of rSK His to a level of 4.25 g/L with a 7.9 folds increase from shake flask results. The specific product yield (YP/X) was 49.75 mg/g DCW along with a high volumetric productivity of 57.43 mg/L/h. The protein was predicted to have 15.43% alpha helix and 26.43% beta-sheet with tryptophan emission maxima of around 347 nm. The highest specific activity of rSK-His was 64,903 IU/mg with 1.48 folds purification whereas specific activity of rSK was 55,240 IU/mg with 1.22 folds purification. PMID- 26631636 TI - Lignosulfonate as reinforcement in polyvinyl alcohol film: Mechanical properties and interaction analysis. AB - Recently, there has been a growing research interest on renewable composite due to sustainability concerns. This work demonstrated the possibility of using eucalyptus lignosulfonate calcium (HLS) particles as reinforcement in polyvinyl alcohol (PVA) matrix. 41% and 384.7% improvement of pure PVA tensile strength and Young's modulus were achieved with incorporation of 5 wt% HLS. The above results were ascribed to specific intermolecular interactions between HLS and PVA, suggested by the increasing PVA glass transition and crystalline relaxations temperature, depression of melting point with HLS incorporation. Moreover, this interaction was quantitatively determined by q value of -62.4+/-10.0 in Kwei equation. Additionally, the remarkable red shift of wavenumber corresponding to hydroxyl group also indicated the formation of strong hydrogen bond in HLS/PVA blend. SEM characterization confirmed that HLS/PVA blends are at least miscible. PMID- 26631637 TI - Unraveling Binding Effects of Cobalt(II) Sepulchrate with the Monooxygenase P450 BM-3 Heme Domain Using Molecular Dynamics Simulations. AB - One of the major limitations to exploit enzymes in industrial processes is their dependence on expensive reduction equivalents like NADPH to drive their catalytic cycle. Soluble electron-transfer (ET) mediators like cobalt(II) sepulchrate have been proposed as a cost-effective alternative to shuttle electrons between an inexpensive electron source and an enzyme's redox center. The interactions of these molecules with enzymes have not yet been elucidated at the molecular level. Herein, molecular dynamics simulations are performed to understand the binding and ET mechanism of the cobalt(II) sepulchrate with the heme domain of cytochrome P450 BM-3. The study provides a detailed map of ET mediator binding sites on the protein surface that are prevalently composed of Asp and Glu amino acids. The cobalt(II) sepulchrate does not show a preferential binding to these sites. However, among the observed binding sites, only few of them provide efficient ET pathways to heme iron. The results of this study can be used to improve the ET mediator efficiency of the enzyme for possible biotechnological applications. PMID- 26631638 TI - Preclinical detection of infectivity and disease-specific PrP in blood throughout the incubation period of prion disease. AB - Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disorder characterised by accumulation of pathological isoforms of the prion protein, PrP. Although cases of clinical vCJD are rare, there is evidence there may be tens of thousands of infectious carriers in the United Kingdom alone. This raises concern about the potential for perpetuation of infection via medical procedures, in particular transfusion of contaminated blood products. Accurate biochemical detection of prion infection is crucial to mitigate risk and we have previously reported a blood assay for vCJD. This assay is sensitive for abnormal PrP conformers at the earliest stages of preclinical prion disease in mice and precedes the maximum infectious titre in blood. Not only does this support the possibility of screening asymptomatic individuals, it will also facilitate the elucidation of the complex relationship that exists between the ensemble of abnormal PrP conformers present in blood and the relationship to infectivity. PMID- 26631639 TI - Preactivated thiolated nanoparticles: A novel mucoadhesive dosage form. AB - Within this study a novel form of mucoadhesive nanoparticles (NPs) exhibiting a prolonged residence time on mucosal tissues was developed. In order to achieve this goal a new thiomer was synthesized by the covalent attachment of the amino acid l-cysteine ethyl ester to poly(acrylic acid) (100 kDa). The free thiol groups were in the following preactivated with the aromatic thiol bearing ligand 2-mercaptonicotinic acid (2-MNA) and the amount of coupled l-cysteine ethyl ester as well as the amount of attached 2-MNA was determined. Based on this, preactivated thiomer NPs were prepared by ionic gelation with polyethylenimine (PEI). The resulting NPs were characterized regarding size and zeta potential. Furthermore their mucoadhesive properties were investigated via rheological measurements with porcine intestinal mucus and via determination of the particles' mucosal residence time. Results showed that 1666.74 MUmol l-cysteine ethyl ester and 603.07 MUmol 2-MNA could be attached per gram polymer. NPs were in a size range of 112.67-252.84 nm exhibiting a zeta potential of -29 mV. Thiolated NPs only led to a 2-fold increase in mucus viscosity whereas preactivated NPs showed a 6-fold higher mucus viscosity than unmodified NPs. The mucosal residence time of thiolated NPs was 1.6-fold prolonged and that of preactivated NPs even 4.4-fold higher compared to unmodified particles. Accordingly, preactivated thiolated NPs providing a prolonged residence time on mucosal membranes could be a promising dosage form for various applications. PMID- 26631640 TI - Synergistic interactions between doxycycline and terpenic components of essential oils encapsulated within lipid nanocapsules against gram negative bacteria. AB - The combination of essential oils (EOs) with antibiotics provides a promising strategy towards combating resistant bacteria. We have selected a mixture of 3 major components extracted from EOs: carvacrol (oregano oil), eugenol (clove oil) and cinnamaldehyde (cinnamon oil). These compounds were successfully encapsulated within lipid nanocapsules (LNCs). The EOs-loaded LNCs were characterised by a noticeably high drug loading of 20% and a very small particle diameter of 114nm. The in vitro interactions between EOs-loaded LNCs and doxycycline were examined via checkerboard titration and time-kill assay against 5 Gram-negative strains: Acinetobacter baumannii SAN, A. baumannii RCH, Klebsiella pneumoniae, Escherichia coli and Pseudomonas aeruginosa. No growth inhibition interactions were found between EOs-loaded LNCs and doxycycline (FIC index between 0.7 and 1.30). However, when bactericidal effects were considered, a synergistic interaction was observed (FBC index equal to 0.5) against all tested strains. A synergistic effect was also observed in time-kill assay (a difference of at least 3 log between the combination and the most active agent alone). Scanning electron microscopy (SEM) was used to visualise the changes in the bacterial membrane. The holes in bacterial envelope and leakage of cellular contents were observed in SE micrographs after exposure to the EOs-LNCs and the doxycycline combination. PMID- 26631641 TI - Decoding the view expectation during learned maze navigation from human fronto parietal network. AB - Humans use external cues and prior knowledge about the environment to monitor their positions during spatial navigation. View expectation is essential for correlating scene views with a cognitive map. To determine how the brain performs view expectation during spatial navigation, we applied a multiple parallel decoding technique to functional magnetic resonance imaging (fMRI) when human participants performed scene choice tasks in learned maze navigation environments. We decoded participants' view expectation from fMRI signals in parietal and medial prefrontal cortices, whereas activity patterns in occipital cortex represented various types of external cues. The decoder's output reflected participants' expectations even when they were wrong, corresponding to subjective beliefs opposed to objective reality. Thus, view expectation is subjectively represented in human brain, and the fronto-parietal network is involved in integrating external cues and prior knowledge during spatial navigation. PMID- 26631642 TI - Differential evolution of a CXCR4-using HIV-1 strain in CCR5wt/wt and CCR5?32/?32 hosts revealed by longitudinal deep sequencing and phylogenetic reconstruction. AB - Rare individuals homozygous for a naturally-occurring 32 base pair deletion in the CCR5 gene (CCR5?32/?32) are resistant to infection by CCR5-using ("R5") HIV-1 strains but remain susceptible to less common CXCR4-using ("X4") strains. The evolutionary dynamics of X4 infections however, remain incompletely understood. We identified two individuals, one CCR5wt/wt and one CCR5?32/?32, within the Vancouver Injection Drug Users Study who were infected with a genetically similar X4 HIV-1 strain. While early-stage plasma viral loads were comparable in the two individuals (~4.5-5 log10 HIV-1 RNA copies/ml), CD4 counts in the CCR5wt/wt individual reached a nadir of <20 CD4 cells/mm(3) within 17 months but remained >250 cells/mm(3) in the CCR5?32/?32 individual. Ancestral phylogenetic reconstructions using longitudinal envelope-V3 deep sequences suggested that both individuals were infected by a single transmitted/founder (T/F) X4 virus that differed at only one V3 site (codon 24). While substantial within-host HIV-1 V3 diversification was observed in plasma and PBMC in both individuals, the CCR5wt/wt individual's HIV-1 population gradually reverted from 100% X4 to ~60% R5 over ~4 years whereas the CCR5?32/?32 individual's remained consistently X4. Our observations illuminate early dynamics of X4 HIV-1 infections and underscore the influence of CCR5 genotype on HIV-1 V3 evolution. PMID- 26631644 TI - Linking log files with dosimetric accuracy--A multi-institutional study on quality assurance of volumetric modulated arc therapy. AB - PURPOSE: To systematically evaluate machine specific quality assurance (QA) for volumetric modulated arc therapy (VMAT) based on log files by applying a dynamic benchmark plan. METHODS AND MATERIALS: A VMAT benchmark plan was created and tested on 18 Elekta linacs (13 MLCi or MLCi2, 5 Agility) at 4 different institutions. Linac log files were analyzed and a delivery robustness index was introduced. For dosimetric measurements an ionization chamber array was used. Relative dose deviations were assessed by mean gamma for each control point and compared to the log file evaluation. RESULTS: Fourteen linacs delivered the VMAT benchmark plan, while 4 linacs failed by consistently terminating the delivery. The mean leaf error (+/-1SD) was 0.3+/-0.2 mm for all linacs. Large MLC maximum errors up to 6.5 mm were observed at reversal positions. Delivery robustness index accounting for MLC position correction (0.8-1.0) correlated with delivery time (80-128 s) and depended on dose rate performance. Dosimetric evaluation indicated in general accurate plan reproducibility with gamma(mean)(+/-1 SD)=0.4+/-0.2 for 1 mm/1%. However single control point analysis revealed larger deviations and attributed well to log file analysis. CONCLUSION: The designed benchmark plan helped identify linac related malfunctions in dynamic mode for VMAT. Log files serve as an important additional QA measure to understand and visualize dynamic linac parameters. PMID- 26631645 TI - Improving radiotherapy through medical physics developments. PMID- 26631643 TI - Screening of nursing home residents for colonization with carbapenem-resistant Enterobacteriaceae admitted to acute care hospitals: Incidence and risk factors. AB - BACKGROUND: There are increasing reports of multidrug-resistant gram-negative bacilli in nursing homes and acute care hospitals. METHODS: We performed a point prevalence survey to detect fecal carriage of gram-negative bacteria carrying carbapenem resistance genes or which were otherwise resistant to carbapenem antibiotics among 500 consecutive admissions from local nursing homes to 2 hospitals in Providence, Rhode Island. We performed a case-control study to identify risk factors associated with carriage of carbapenem-resistant Enterobacteriaceae (CRE). RESULTS: There were 404 patients with 500 hospital admissions during which they had rectal swab samples cultured. Fecal carriage of any carbapenem-resistant or carbapenemase- producing gram-negative bacteria was found in 23 (4.6%) of the 500 hospital admissions, including 7 CRE (1.4%), 2 (0.4%) of which were Klebsiella pneumoniae carbapenemase (ie, blaKPC) producing (CPE) Citrobacter freundii, 1 of which was carbapenem susceptible by standard testing methods. Use of a gastrostomy tube was associated with CRE carriage (P = .04). We demonstrated fecal carriage of carbapenem-resistant or carbapenemase producing gram-negative bacteria in 4.6% of nursing home patients admitted to 2 acute care hospitals, but only 0.4% of such admissions were patients with fecal carriage of CPE. Use of gastrostomy tubes was associated with fecal carriage of gram-negative bacteria with detectable carbapenem resistance. CONCLUSION: CRE fecal carriage is uncommon in our hospital admissions from nursing homes. PMID- 26631646 TI - The potential of MRI-guided online adaptive re-optimisation in radiotherapy of urinary bladder cancer. AB - BACKGROUND AND PURPOSE: Adaptive radiotherapy (ART) using plan selection is being introduced clinically for bladder cancer, but the challenge of how to compensate for intra-fractional motion remains. The purpose of this study was to assess target coverage with respect to intra-fractional motion and the potential for normal tissue sparing in MRI-guided ART (MRIGART) using isotropic (MRIGARTiso), an-isotropic (MRIGARTanIso) and population-based margins (MRIGARTpop). MATERIALS AND METHODS: Nine bladder cancer patients treated in a phase II trial of plan selection underwent 6-7 weekly repeat MRI series, each with volumetric scans acquired over a 10 min period. Adaptive re-planning on the 0 min MRI scans was performed using density override, simulating a hypo-fractionated schedule. Target coverage was evaluated on the 10 min scan to quantify the impact of intra fractional motion. RESULTS: MRIGARTanIso reduced the course-averaged PTV by median 304 cc compared to plan selection. Bladder shifts affected target coverage in individual fractions for all strategies. Two patients had a v95% of the bladder below 98% for MRIGARTiso. MRIGARTiso decreased the bowel V25 with 15-46 cc compared to MRIGARTpop. CONCLUSION: Online re-optimised ART has a considerable normal tissue sparing potential. MRIGART with online corrections for target shift during a treatment fraction should be considered in ART for bladder cancer. PMID- 26631647 TI - Geometric uncertainties in voluntary deep inspiration breath hold radiotherapy for locally advanced lung cancer. AB - BACKGROUND AND PURPOSE: Deep inspiration breath hold (DIBH) increases lung volume and can potentially reduce treatment-related toxicity in locally advanced lung cancer. We estimated geometric uncertainties in visually guided voluntary DIBH and derived the appropriate treatment margins for different image-guidance strategies. MATERIAL AND METHODS: Seventeen patients were included prospectively. An optical marker-based respiratory monitoring with visual guidance enabled comfortable DIBHs, adjusted to each patient's performance. All patients had three consecutive DIBH CTs at each of the treatment fractions 2, 16 and 31. DIBH reproducibility was evaluated as inter- and intra-fractional variations in lung volume, tumour position and differential motion between primary tumour and mediastinal lymph nodes. RESULTS: Lung volume increased by median 60% in DIBH. Inter- and intra-fractional lung volume variations were median 2.1% and 1.1%, respectively. Inter- and intra-fractional uncertainties in 3D tumour position were 4.8 +/- 2.8 mm and 1.7 +/- 1.4 mm (mean +/- SD). Inter- and intra-fractional differential motion was 4.8 +/- 3.3 mm and 0.0 +/- 1.1 mm. CONCLUSIONS: For single targets, visually guided voluntary DIBH radiotherapy is highly reproducible provided an image-guidance strategy with tumour registration is performed. If the primary tumour is separated from the mediastinal lymph nodes, inter-fractional differential motion remains a challenge and margins must be adapted to reflect the image registration strategy. PMID- 26631649 TI - Identification and functional characterization of an endoplasmic reticulum oxidoreductin 1-alpha gene in Litopenaeus vannamei. AB - In the current study, full-length sequence of endoplasmic reticulum oxidoreductin 1-alpha (LvERO1-alpha) was cloned from Litopenaeus vannamei. Real-time RT-PCR results showed that LvERO1-alpha was highly expressed in hemocytes, gills, and intestines. White spot syndrome virus (WSSV) challenge was performed, and the expression of LvERO1-alpha and two other downstream genes of the double-stranded RNA-activated protein kinase-like ER kinase-eIF2alpha (PERK-alpha) pathway, namely, homocysteine-induced endoplasmic reticulum protein (LvHERP) and acylamino acid-releasing enzyme (LvAARE), strongly increased in the hemocytes. Flow cytometry assay results indicated that the apoptosis rate of L. vannamei hemocytes in the LvERO1-alpha knockdown group was significantly lower than that of the controls. Moreover, shrimps with knockdown expression of LvERO1-alpha exhibited decreased cumulative mortality upon WSSV infection. Downregulation of L. vannamei immunoglobulin-binding protein (LvBip), which had been proven to induce unfolded protein response (UPR) in L. vannamei, did not only upregulate LvERO1-alpha, LvHERP, and LvAARE in hemocytes, but also increased their apoptosis rate, as well as the shrimp cumulative mortality. Furthermore, reporter gene assay results showed that the promoter of LvERO1-alpha was activated by L. vannamei activating transcription factor 4, thereby confirming that LvERO1-alpha was regulated by the PERK-eIF2alpha pathway. These results suggested that LvERO1 alpha plays a critical role in WSSV-induced apoptosis, which likely occurs through the WSSV-activated PERK-eIF2alpha pathway. PMID- 26631650 TI - A New Algorithm for Efficient Direct Dynamics Calculations of Large-Curvature Tunneling and Its Application to Radical Reactions with 9-15 Atoms. AB - We present a new algorithm for carrying out large-curvature tunneling calculations that account for extreme corner-cutting tunneling in hydrogen atom, proton, and hydride transfer reactions. The algorithm is based on two-dimensional interpolation in a physically motived set of variables that span the space of tunneling paths and tunneling energies. With this new algorithm, we are able to carry out density functional theory direct dynamics calculations of the rate constants, including multidimensional tunneling, for a set of hydrogen atom transfer reactions involving 9-15 atoms and up to 7 nonhydrogenic atoms. The reactions considered involve the abstraction of a hydrogen atom from hydrocarbons by a trifluoromethyl radical, and in particular, we consider the reactions of CF3 with CH4, C2H6, and C3H8. We also calculate several kinetic isotope effects. The electronic structure is treated by the MPWB1K/6-31+G(d,p) method, which is validated by comparison to experimental results and to CBS-Q, MCG3, and G3SX(MP3) calculations for CF3 + CH4. Harmonic vibrational frequencies along the reaction path are calculated in curvilinear coordinates with scaled frequencies, and anharmonicity is included in the lowest-frequency torsion. PMID- 26631651 TI - Does a Sodium Atom Bind to C60? AB - A Multi-Reference Configuration-Interaction study of the NaC60 system is presented. It is shown that the experimentally measured dipole moment of this system can be explained by the existence of a charge-transfer state of Na(+)C60( ) nature. Moreover, the present work shows that Configuration-Interaction techniques based on local orbitals permit a Multi-Reference treatment of systems containing several tens of atoms. PMID- 26631652 TI - Chemical Notions from the Electron Density. AB - The study of density and the role played by its atomic representation is proposed as a way for the rationalization of chemical behavior. As this behavior has been long rationalized in terms of the basic concepts of empirical structural chemistry, a direct link between both approaches is searched for by using the exact representation of the density provided by the deformed atoms in molecules method (Rico, J. F.; Lopez, R.; Ema, I.; Ramirez, G.; Ludena, E. J. Comput. Chem. 2004, 25, 1355-1363). Noting that the spherical terms of the pseudoatoms cannot be mainly responsible for the chemical behavior, we study the small nonspherical deformations and find that they reflect and support all basic concepts of empirical structural chemistry. Lone pairs; single, double, and triple bonds; different classes of atoms; functional groups; and so forth are paralleled by the density deformations in a neat manner. These facts are illustrated with several examples. PMID- 26631648 TI - Transcriptomics analysis of iPSC-derived neurons and modeling of neuropsychiatric disorders. AB - Induced pluripotent stem cell (iPSC)-derived neurons and neural progenitors are great resources for studying neural development and differentiation and their disruptions in disease conditions, and hold the promise of future cell therapy. In general, iPSC lines can be established either specifically from patients with neuropsychiatric disorders or from healthy subjects. The iPSCs can then be induced to differentiate into neural lineages and the iPSC-derived neurons are valuable for various types of cell-based assays that seek to understand disease mechanisms and identify and test novel therapies. In addition, it is an ideal system for gene expression profiling (i.e., transcriptomic analysis), an efficient and cost-effective way to explore the genetic programs regulating neurodevelopment. Moreover, transcriptomic comparison, which can be performed between patient-derived samples and controls, or in control lines in which the expression of specific genes has been disrupted, can uncover convergent gene targets and pathways that are downstream of the hundreds of candidate genes that have been associated with neuropsychiatric disorders. The results, especially after integration with spatiotemporal transcriptomic profiles of normal human brain development, have indeed helped to uncover gene networks, molecular pathways, and cellular signaling that likely play critical roles in disease development and progression. On the other hand, despite the great promise, many challenges remain in the usage of iPSC-derived neurons for modeling neuropsychiatric disorders, for example, how to generate relatively homogenous populations of specific neuronal subtypes that are affected in a particular disorder and how to better address the genetic heterogeneity that exists in the patient population. PMID- 26631653 TI - Interacting Quantum Atoms: A Correlated Energy Decomposition Scheme Based on the Quantum Theory of Atoms in Molecules. AB - We make use of the Quantum Theory of Atoms in Molecules (QTAM) to partition the total energy of a many-electron system into intra- and interatomic terms, by explicitly computing both the one- and two-electron contributions. While the general scheme is formally equivalent to that by Bader et al., we focus on the separation and computation of the atomic self-energies and all the interaction terms. The partition is ultimately performed within the density matrices, in analogy with McWeeny's Theory of Electronic Separability, and then carried onto the energy. It is intimately linked with the atomistic picture of the chemical bond, not only allowing the separation of different two-body contributions (point charge-like, multipolar, total Coulomb, exchange, correlation, ...) to the interaction between a pair of atoms but also including an effective many-body contribution to the binding (self-energy, formally one-body) due to the deformation of the atoms within the many-electron system as compared to the free atoms. Many qualitative ideas about the chemical bond can be quantified using this scheme. PMID- 26631654 TI - A Theoretical Investigation of the Geometries and Binding Energies of Molecular Tweezer and Clip Host-Guest Systems. AB - A quantum chemical study of host-guest systems with dimethylene-bridged clips and tetramethylene-bridged tweezers as host molecules and six different aliphatic and aromatic substrates as guests is presented. The geometries and binding energies of the complexes are investigated using the recently developed density functional theory with empirical corrections for dispersion interactions (DFT-D) in combination with the BLYP functional and basis sets of TZVP quality. It is found that the DFT-D method provides accurate geometries for the host-guest complexes that compare very favorably to experimental X-ray data. Without the dispersion correction, all host-guest complexes are unbound at the pure DFT level. Calculations of the clip complexes show that the DFT-D binding energies of the guests agree well with those from a more sophisticated SCS-MP2/aug-cc-pVTZ treatment. By a partitioning of the host into molecular fragments it is shown that the binding energy is clearly dominated by the aromatic units of the clip. An energy decomposition analysis of the interaction energies of some tweezer complexes revealed the decisive role of the electrostatic and dispersion contributions for relative stabilities. The calculations on the tweezer complexes show that the benzene spaced tweezer is a better receptor for aliphatic substrates than its naphthalene analogue that has a better topology for the binding of aromatic substrates. The tweezer with a OAc substituent in the central spacer unit is found to favor complex formation with both aliphatic and aromatic substrates. The theoretical results are qualitatively in very good agreement with previous experimental findings although direct comparison with experimental binding energies which include solvent effects is not possible. The good results obtained with the DFT-D-BLYP method suggest this approach as a standard tool in supramolecular chemistry and as the method of choice for theoretical structure determinations of large complexes where both electrostatic and dispersive interactions are crucial. PMID- 26631655 TI - Considerations for Reliable Calculation of (77)Se Chemical Shifts. AB - The theoretical chemical shifts of a large series of selenium compounds have been calculated using GIAO-MP2 and -DFT methods in several basis sets. Reliable chemical shifts are calculated for many compounds, especially with the mPW1PW91 exchange-correlation functional and either a triple-zeta basis set (tzvp: 13% mean absolute error) or a limited RECP set chosen for practical applications on complex molecules (BSL: 11.8% mean absolute error). Molecules with three-center four-electron bonding or low-lying n->pi* states require additional diffuse functions and nonperturbative methods, respectively, but terminal selenium anions cannot be calculated reliably in the gas phase due to the neglect of solvation. When these cases are excluded, the mean absolute error decreases from 16.5% to 8.9% in GIAO-MP2/BSL but only slightly for DFT methods. PMID- 26631656 TI - Distributed Multipole Analysis: Stability for Large Basis Sets. AB - The distributed multipole analysis procedure, for describing a molecular charge distribution in terms of multipole moments on the individual atoms (or other sites) of the molecule, is not stable with respect to a change of basis set, and indeed, the calculated moments change substantially and unpredictably when the basis set is improved, even though the resulting electrostatic potential changes very little. A revised procedure is proposed, which uses grid-based quadrature for partitioning the contributions to the charge density from diffuse basis functions. The resulting procedure is very stable, and the calculated multipole moments converge rapidly to stable values as the size of the basis is increased. PMID- 26631657 TI - SM6: A Density Functional Theory Continuum Solvation Model for Calculating Aqueous Solvation Free Energies of Neutrals, Ions, and Solute-Water Clusters. AB - A new charge model, called Charge Model 4 (CM4), and a new continuum solvent model, called Solvation Model 6 (SM6), are presented. Using a database of aqueous solvation free energies for 273 neutrals, 112 ions, and 31 ion-water clusters, parameter sets for the mPW0 hybrid density functional of Adamo and Barone (Adamo, C.; Barone, V. J. Chem. Phys. 1998, 108, 664-675) were optimized for use with the following four basis sets: MIDI!6D, 6-31G(d), 6-31+G(d), and 6-31+G(d,p). SM6 separates the observable aqueous solvation free energy into two different components: one arising from long-range bulk electrostatic effects and a second from short-range interactions between the solute and solvent molecules in the first solvation shell. This partition of the observable solvation free energy allows SM6 to effectively model a wide range of solutes. For the 273 neutral solutes in the test set, SM6 achieves an average error of ~0.50 kcal/mol in the aqueous solvation free energies. For solutes, especially ions, that have highly concentrated regions of charge density, adding an explicit water molecule to the calculation significantly improves the performance of SM6 for predicting solvation free energies. The performance of SM6 was tested against several other continuum models, including SM5.43R and several different implementations of the Polarizable Continuum Model (PCM). For both neutral and ionic solutes, SM6 outperforms all of the models against which it was tested. Also, SM6 is the only model (except for one with an average error 3.4 times larger) that improves when an explicit solvent molecule is added to solutes with concentrated charge densities. Thus, in SM6, unlike the other continuum models tested here, adding one or more explicit solvent molecules to the calculation is an effective strategy for improving the prediction of the aqueous solvation free energies of solutes with strong local solute-solvent interactions. This is important, because local solute-solvent interactions are not specifically accounted for by bulk electrostatics, but modeling these interactions correctly is important for predicting the aqueous solvation free energies of certain solutes. Finally, SM6 retains its accuracy when used in conjunction with the B3LYP and B3PW91 functionals, and in fact the solvation parameters obtained with a given basis set may be used with any good density functional or fraction of Hartree-Fock exchange. PMID- 26631658 TI - Electron-Impact Ionization Cross Sections of Molecules Containing Heavy Elements (Z > 10). AB - The binary-encounter-Bethe (BEB) theory has been successful for computing electron-impact ionization cross sections of many molecules. For molecules that contain heavy atoms (defined here as atoms with valence principal quantum number n > 2), there are two alternative BEB procedures in the literature. The first involves a kinetic-energy correction for molecular orbitals that are dominated by atomic orbitals with n > 2. The second alternative is to use effective core potentials (ECPs), which were developed for other purposes but yield valence pseudo-orbitals with reduced kinetic energies. In the present study, the results of these two approaches are compared with experimental cross sections for several molecules containing heavy elements. Although both procedures perform well, the ECP results agree somewhat better with experimental measurements. Cross sections are presented for C2Cl6, C2HCl5, C2Cl4, both isomers of C2H2Cl4, CCl4, TiCl4, CBr4, CHBr3, CH2Br2, P2, P4, As2, As4, GaCl, CS2, H2S, CH3I, Al(CH3)3, Ga(CH3)3, hexamethyldisiloxane, and Zn(C2H5)2. Incorrect BEB calculations have been reported in the literature for several of these molecules. As an ancillary result, the dipole polarizability of Zn(C2H5)2 is predicted to be 12.1 A(3). PMID- 26631659 TI - Ab Initio Study of Spin-Vibronic Dynamics in the Ground X(2)E and Excited A(2)A1 Electronic States of CH3S(*). AB - A spin-vibronic Hamiltonian including the linear, quadratic, cubic, and quartic Jahn-Teller terms with account for all important anharmonic effects was applied to study electronic and nuclear dynamics in the ground X(2)E and first excited A(2)A1 electronic states of the CH3S methylthio radical (C3v). The E?(3a1+3e) problem of spin-vibronic eigenvalues and eigenfunctions was solved in a basis set of products of electronic, electron spin, and vibrational functions. The Jahn Teller distortions in X(2)E CH3S are totally quenched by the strong spin-orbit coupling. However, Jahn-Teller interaction terms in the spin-vibronic Hamiltonian cannot be neglected for the high precision evaluation of energy levels of CH3S. The results of calculations show the importance of inclusion of at least quadratic vibronic terms into variational treatment. The nonadiabatic (pseudo Jahn-Teller) coupling of the X(2)E and A(2)A1 electronic states was found small and safely removable from the spin-vibronic Hamiltonian of CH3S. PMID- 26631660 TI - Metal-Polyhydride Molecules Are Compact Inside a Fullerene Cage. AB - Quantum chemical calculations show that metal-hydride molecules are more compact when they are placed inside a fullerene cage than when they are isolated molecules. The metal-hydrogen bond distance in ZrH4 becomes 0.15 A shorter when it is placed inside a C60 cage. Metal-polyhydride molecules with a large number of H atoms such as ScH15 and ZrH16, which are not bound as isolated molecules, are predicted to be bound inside a fullerene cage. It is also shown that two TiH16 clusters are bound inside a bicapped (9,0) carbon nanotube. Possible ways to make metal-hydrides inside C60 and nanotubes are suggested. PMID- 26631661 TI - An Efficient Real Space Multigrid QM/MM Electrostatic Coupling. AB - A popular strategy for simulating large systems where quantum chemical effects are important is the use of mixed quantum mechanical/molecular mechanics methods (QM/MM). While the cost of solving the Schrodinger equation in the QM part is the bottleneck of these calculations, evaluating the Coulomb interaction between the QM and the MM part is surprisingly expensive. In fact it can be just as time consuming as solving the QM part. We present here a novel real space multigrid approach that handles Coulomb interactions very effectively and implement it in the CP2K code. This novel scheme cuts the cost of this part of the calculation by 2 orders of magnitude. The method does not need very fine-tuning or adjustable parameters, and it is quite accurate, leading to a dynamics with very good energy conservation. We exemplify the validity of our algorithms with simulations of water and of a zwitterionic dipeptide solvated in water. PMID- 26631662 TI - 1-Fluoropropane. Torsional Potential Surface. AB - The systematic deletion of orbital interactions, using natural bond orbital (NBO) theory at the B3LYP/ 6-311++G(3df,2p) level, provides validation for the anti-C H/C-F* hyperconjugative interaction providing the backbone for the gauche preference of 1-fluoropropane (FP). The FCCC torsional coordinate taking trans FP to gauche FP is predicted to be strongly contaminated by CCC bending with the result that a large part of the trans -> gauche stabilization energy stems from mode coupling. The anti-C-H/C-F* hyperconjugative interaction is also found to play a major, if not determining, role in the coupling. The results of Rydberg deletion calculations suggest that Rydberg interactions play a role in NBO analysis, contrary to the usual assumption that interactions involving Rydberg orbitals can be ignored. PMID- 26631663 TI - Slater's Exchange Parameters alpha for Analytic and Variational Xalpha Calculations. AB - Recently, we formulated a fully analytical and variational implementation of a subset of density functional theory using Gaussian basis sets to express orbital and the one-body effective potential. The implementation, called the Slater Roothaan (SR) method, is an extension of Slater's Xalpha method, which allows arbitrary scaling of the exchange potential around each type of atom in a heteroatomic system. The scaling parameter is Slater's exchange parameter, alpha, which can be determined for each type of atom by choosing various criteria depending on the nature of problem undertaken. Here, we determine these scaling parameters for atoms H through Cl by constraining some physical quantity obtained from the self-consistent solution of the SR method to be equal to its exact value. Thus, the sets of alpha values that reproduce the exact atomic energies have been determined for four different combinations of basis sets. A similar set of alpha values that is independent of a basis set is obtained from numerical calculations. These sets of alpha parameters are subsequently used in the SR method to compute atomization energies of the G2 set of molecules. The mean absolute error in atomization energies is about 17 kcal/mol and is smaller than that of the Hartree-Fock theory (78 kcal/mol) and the local density approximation (40 kcal/mol) but larger than that of a typical generalized gradient approximation (~8 kcal/mol). A second set of alpha values is determined by matching the highest occupied eigenvalue of the SR method to the negative of the first ionization potential. Finally, the possibility of obtaining alpha values from the exact atomization energy of homonuclear diatomic molecules is explored. We find that the molecular alpha values show much larger deviation than what is observed for the atomic alpha values. The alpha values obtained for atoms in combination with an analytic SR method allow elemental properties to be extrapolated to heterogeneous molecules. In general, the sets of different alpha values might be useful for calculations of different properties using the analytic and variational SR method. PMID- 26631664 TI - Effects of Peripheral Substituents on the Electronic Structure and Properties of Unligated and Ligated Metal Phthalocyanines, Metal = Fe, Co, Zn. AB - The effects of peripheral, multiple -F as well as -C2F5 substituents, on the electronic structure and properties of unligated and ligated metal phthalocyanines, PcM, PcM(acetone)2 (M = Fe, Co, Zn), PcZn(Cl), and PcZn(Cl(-)), have been investigated using a DFT method. The calculations provide a clear explanation for the changes in the ground state, molecular orbital (MO) energy levels, ionization potentials (IP), electron affinities (EA), charge distribution on the metal (QM), axial binding energies, and in electronic spectra. While the strongly electron-withdrawing -C2F5 groups on the Pc ring change the ground state of PcFe, they do not influence the ground state of PcCo. The IP is increased by ~1.3 eV from H16PcM to F16PcM and by another ~1.1 eV from F16PcM to F48PcM. A similar increase in the EA is also found on going from H16PcM to F48PcM. Substitution by the -C2F5 groups also considerably increases the binding strength between PcM and the electron-donating axial ligand(s). Numerous changes in chemical and physical properties observed for the F64PcM compounds can be accounted for by the calculated results. PMID- 26631665 TI - Stability of K-Montmorillonite Hydrates: Hybrid MC Simulations. AB - NPzzT and MUPzzT simulations of K-montmorillonite hydrates were performed employing hybrid Monte Carlo simulations. Two condition sets were studied: P = 1 atm and T = 300 K (ground level conditions) and P = 600 atm and T = 394 K; this last condition mimics a burial depth close to 4 km. For these conditions, swelling curves as a function of the reservoir water vapor pressure were built. We found the single layer K-montmorillonite hydrate stable for high vapor pressures for both burial and ground level conditions. A simple explanation for this high stability is given. PMID- 26631666 TI - Hydrogen Bond Properties and Dynamics of Liquid-Vapor Interfaces of Aqueous Methanol Solutions. AB - The hydrogen bonded structure and dynamics of liquid-vapor interfaces of aqueous methanol solutions of varying compositions are investigated by means of molecular dynamics simulations. The dynamical aspects of the interfaces are investigated in terms of the single-particle dynamical properties such as the relaxation of velocity autocorrelation and the translational diffusion coefficients along the perpendicular and parallel directions and the dipole orientational relaxation of the interfacial water and methanol molecules and also in terms of the relaxation of water-water, water-methanol, and methanol-methanol hydrogen bonds at interfaces at 298 K. The results of the interfacial dynamics are compared with those of the corresponding bulk phases. The inhomogeneous density, anisotropic orientational profiles, surface tension, and the pattern of hydrogen bonding are calculated in order to characterize the location, width, microscopic structure, and the thermodynamic aspects of the interfaces and to explore their effects on the interfacial dynamical properties of water and methanol molecules. PMID- 26631667 TI - Modeling Proton Transfer in Zeolites: Convergence Behavior of Embedded and Constrained Cluster Calculations. AB - We have studied the convergence properties of embedded and constrained cluster models of proton transfer in zeolites. We applied density functional theory to describe clusters and ONIOM to perform the embedding. We focused on converging the reaction energy and barrier of the O(1) to O(4) jump in H-Y zeolite as well as vibrational and structural aspects of this jump. We found that using successively larger clusters in vacuo gives convergence of this reaction energy to 14 +/- 2 kJ mol(-)(1) and the barrier to 135 +/- 5 kJ mol(-)(1) at a cluster size of 5 A, which contains 11 tetrahedral (Si or Al) atoms. We embedded quantum clusters of various sizes in larger clusters with total radii in the range 7-20 A, using the universal force field as the lower level of theory in ONIOM. We found convergence to the same values as the constrained clusters, without the use of reactive force fields or periodic boundary conditions in the embedding procedure. For the reaction energy, embedded cluster calculations required smaller clusters than in vacuo calculations, reaching converged reaction energies for quantum systems containing at least 8 tetrahedral atoms. In addition, optimizations on embedded clusters required many fewer cycles, and hence much less CPU time, than did optimizations on comparable constrained clusters. PMID- 26631668 TI - Accurate QM/MM Free Energy Calculations of Enzyme Reactions: Methylation by Catechol O-Methyltransferase. AB - We recently described a method to compute accurate quantum mechanical free energies [Rod, T. H.; Ryde, U. Phys. Rev. Lett. 2005, 94, 138302]. The method, which we term quantum mechanical thermodynamic cycle perturbation (QTCP), employs a molecular mechanics force field to sample phase space and, subsequently, a thermodynamic cycle to estimate QM/MM free energy changes. Here, we discuss the methodology in detail and test an approach based on a different thermodynamic cycle. We also show that a new way of treating hydrogen link atoms makes the free energy changes converge faster and that extrapolation to higher accuracy can be performed. We finally discuss the quantum mechanical free energy (QM/MM-FE) method in the framework of the QTCP method. All methods considered are applied to the methylation of catecholate catalyzed by catechol O-methyltransferase. We compute the free energy barrier for the reaction by computing free energy changes in steps between fixed QM regions along a predetermined reaction pathway. Using the QTCP approach, an extrapolated activation free energy of 69 kJ/mol for the forward reaction and 90 kJ/mol for the reverse reaction are obtained at the level of the B3LYP functional and the 6-311++G(2d,2p) basis set. The value for the forward reaction is in excellent agreement with the experimental value of 75 kJ/mol. Results based on the QM/MM-FE method differ by less than 10 kJ/mol from those values, indicating that QM/MM-FE may be a fairly accurate and cheap alternative to calculate QM/MM free energy changes. Moreover, the results are compared to barriers obtained with a fixed molecular mechanics environment as well as with structures optimized in a vacuum. All the computed free energy barriers are well converged. A major approximation in the current implementation of the QTCP method is that the QM region is fixed. The approximation leads to well-converged free energy barriers, which has been a problem in similar studies. PMID- 26631669 TI - Helix Interactions in Membranes: Lessons from Unrestrained Monte Carlo Simulations. AB - We describe one of the first attempts at unrestrained modeling of self association of alpha-helices in implicit heterogeneous membrane-mimic media. The computational approach is based on the Monte Carlo conformational search for peptides in dihedral angles space. The membrane is approximated by an effective potential. The method is tested in calculations of two hydrophobic segments of human glycophorin A (GpA), known to form membrane-spanning dimers in real lipid bilayers. Our main findings may be summarized as follows. Modeling in vacuo does not adequately describe the behavior of GpA helices, failing to reproduce experimental structural data. The membrane environment stabilizes alpha-helical conformation of GpA monomers, inducing their transmembrane insertion and facilitating interhelical contacts. The voltage difference across the membrane promotes "head-to-head" orientation of the helices. "Fine-tuning" of the monomers in a complex is shown to be regulated by van der Waals interactions. Detailed exploration of conformational space of the system starting from arbitrary locations of two noninteracting helices reveals only several groups of energetically favorable structures. All of them represent tightly packed transmembrane helical dimers. In overall, they agree reasonably well with mutagenesis data, some of them are close to NMR-derived structures. A possibility of left-handed dimers is discussed. We assume that the observed moderate structural heterogeneity (the existence of several groups of states with close energies) reflects a real equilibrium dynamics of the monomers [Formula: see text] at least in membrane mimics used in experimental studies of GpA. The elaborated computational approach is universal and may be employed in studies of a wide class of membrane peptides and proteins. PMID- 26631670 TI - Quantum Mechanics/Molecular Mechanics Calculations of the Vanadium Dependent Chloroperoxidase. AB - Large quantum mechanics/molecular mechanics (QM/MM) calculations are used to probe the resting and initial protonated states of the vanadium dependent chloroperoxidase from the pathogenic fungus Curvularia inaequalis. QSite was used to model 433 residues and 24 structural waters with molecular mechanics, while 8 active-site residues and the vanadate cofactor (161 atoms) were represented at the B3LYP/lacvp* level of theory. Our previous study of small model systems implied that the resting state of the enzyme contains a trigonal bipyramidal vanadate with one hydroxyl group in the equatorial plane and another in the axial position. This study uses a much larger model of the biological system at a higher level of theory to identify the location of the equatorial hydroxo group with respect to the enzyme active site. We also identify a second resting-state configuration with an axial water and three equatorial oxo moieties that is nearly isoenergetic with the previously identified state. We propose that the resting state is a hybrid of these two configurations, stabilized by the long range electrostatic field of the protein environment. The first step in catalysis is believed to be protonation of the vanadate. Our previous small models indicated that there were two protonated configurations, but this study shows that the configuration containing an axial water and one hydroxo group in the equatorial plane is significantly lower in energy than any other configuration. Additionally, we can now assign an important role for lysine 353 in the catalytic cycle. Based on our calculations and other model studies, we provide an updated catalytic cycle for vanadium dependent haloperoxidase activity. Further, we demonstrate the importance of system set up. In particular, maintaining the proper electrostatic field at the active site is crucial for identifying the correct minima in a truncated protein model. PMID- 26631671 TI - A Semiempirical Quantum Model for Hydrogen-Bonded Nucleic Acid Base Pairs. AB - An exploratory semiempirical Hamiltonian (PM3BP) is developed to model hydrogen bonding in nucleic acid base pairs. The PM3BP Hamiltonian is a novel reparametrization of the PM3 Hamiltonian designed to reproduce experimental base pair dimer enthalpies and high-level density-functional results. The parametrization utilized a suite of integrated nonlinear optimization algorithms interfaced with a d-orbital semiempirical program. Results are compared with experimental values and with benchmark density-functional (mPWPW91/MIDI!) calculations for hydrogen-bonded nucleic acid dimers and trimers. The PM3BP Hamiltonian is demonstrated to outperform the AM1, PM3, MNDO, and MNDO/H Hamiltonians for dimer and trimer structures and interaction enthalpies and is shown to reproduce experimental dimer interaction enthalpies that rival density functional results for an over 3 orders of magnitude reduction in computational cost. The tradeoff between a high accuracy gain for hydrogen bonding at the expense of sacrificing some generality is discussed. These results provide insight into the limits of conventional semiempirical forms for accurate modeling of biological interactions. PMID- 26631672 TI - Effects of Calcium Binding on Structure and Autolysis Regulation in Trypsins. A Molecular Dynamics Investigation. AB - The calcium ion was proposed to be involved in protein structure stabilization against thermal and proteolytic degradation, such as autolysis phenomena, in trypsin-like serine proteases. However, molecular details related to the role played by the metal ion are still largely unknown. Several molecular dynamics simulations of 6 ns have been used to investigate the dynamic behavior of bovine and salmon trypsins in calcium-bound and calcium-free forms, with the aim of evaluating the role of the calcium ion in trypsin three-dimensional structure and autoproteolysis propensity. It turned out that the calcium-free trypsins are characterized by a more flexible structure, revealing structure-function relationships connecting Ca(2+) binding and autoproteolysis propensity. In particular, the removal of Ca(2+) not only increases the flexibility of regions around its binding site, in the N-terminal domain, but also leads to channeling of the fluctuations to remote sites in the C-terminal domain, possibly involving the interdomain loop. Two primary autolysis sites are strongly influenced by calcium binding (R117 and K188) in bovine trypsin, whereas Ca(2+) plays a less crucial role in salmon trypsin. PMID- 26631673 TI - Theoretical Group 14 Chemistry. 4. Cyclotriplumbanes: Relativistic and Substituents Effects. AB - We report a study on the first newly synthesized homonuclear lead ring system, the cyclotriplumbane Pb3R6. Its geometrical features can be best reproduced using perturbation theory (MP2) together with the Stuttgart-Dresden basis set and ECP for lead. The experimentally observed tilting of the groups R in the cyclotriplumbanes is attributed to the bonding situation: the lead-lead contacts, formed from weak interactions of plumbylene lone pairs with empty p orbitals of neighboring lead atoms, try to maximize overlap. Surprisingly and in contrast to the inert pair effect, hybridization of the former plumbylene lone pair orbitals in the cyclotriplumbane Pb3R6 is observed, depending on the substituent. Hybrid orbitals with a 6s orbital contribution of only about 40% are found. Hydrogen atoms and methyl groups promote this effect, while for phenyl substitution the expected 6s lone pair orbital is identified as the bond-forming orbital. PMID- 26631674 TI - PELE: Protein Energy Landscape Exploration. A Novel Monte Carlo Based Technique. AB - Combining protein structure prediction algorithms and Metropolis Monte Carlo techniques, we provide a novel method to explore all-atom energy landscapes. The core of the technique is based on a steered localized perturbation followed by side-chain sampling as well as minimization cycles. The algorithm and its application to ligand diffusion are presented here. Ligand exit pathways are successfully modeled for different systems containing ligands of various sizes: carbon monoxide in myoglobin, camphor in cytochrome P450cam, and palmitic acid in the intestinal fatty-acid-binding protein. These initial applications reveal the potential of this new technique in mapping millisecond-time-scale processes. The computational cost associated with the exploration is significantly less than that of conventional MD simulations. PMID- 26631675 TI - Sociocultural Influences on Arab Women's Participation in Breast Cancer Screening in Qatar. AB - Breast cancer, the most common cancer among Arab women in Qatar, significantly affects the morbidity and mortality of Arab women largely because of low participation rates in breast cancer screening. We used a critical ethnographic approach to uncover and describe factors that influence Arab women's breast cancer screening practices. We conducted semistructured interviews with 15 health care practitioners in Qatar. Through thematic analysis of the data, we found three major factors influencing breast cancer screening practices: (a) beliefs, attitudes, and practices regarding women's bodies, health, and illness; (b) religious beliefs and a culturally sensitive health care structure; and (c) culturally specific gender relations and roles. Arab women's health practices cannot be understood in isolation from the sociocultural environment. The problem of low rates of breast cancer screening practices and supportive interventions must be addressed within the context and not be limited to the individual. PMID- 26631676 TI - Obstacles to Shared Expectations in a Burn Intensive Care Unit. AB - Critical care patients are dependent on the health care team and their family members to effect care goals that are consistent with their core values and wishes. This study aimed to identify and understand how obstacles to communication affect these two disparate groups. Ten burn intensive care unit (BICU) care team and 20 family members participated in in-depth semistructured interviews. A two-cycle coding, inductive analytical approach was used to derive three obstacle metathemes: family engagement, information exchange, and process transparency and standardization. However, care team and family members' themes within each metatheme were different. Although the thematic structure was derived inductively, our findings in retrospect appeared to be consistent with Law's four resistances associated with actor-networks. From this perspective, actor-network theory provides a plausible explanation for perceived obstacles and may, in the future, guide the development of interventions to improve shared agency across networks. PMID- 26631678 TI - Concept Mapping: A Dynamic, Individualized and Qualitative Method for Eliciting Meaning. AB - The purpose of this theoretical article is to explore the use of concept mapping as a qualitative research method that is represented as a form of multimodal communication. This framework strives to move mapping beyond quantitative analysis by inserting art and humanness into the process. This proposed framework provides a means to highlight the ways in which people learn, understand, and interpret the world around them. Three categories for understanding have been identified by the authors to help individuals create, interpret, and understand qualitative concept maps. These categories include the following: Voice: Tri directional Voice and Mutual Absorption; Detail in the Parts & Recognition of the Whole: Uniqueness, Aesthetic Distance and Emplacement; and Sensory Experience: Intellectual + Emotional Investment and Humanness. Each of these categories is interconnected, and informs each other in a dialectical way, therefore creating a piece of visual data with which the participant, researcher and audience can interact. PMID- 26631677 TI - Essential Qualitative Inquiry in the Development of a Cancer Literacy Measure for Immigrant Women. AB - In this article, we describe the development of a comprehensive measure of breast and cervical cancer literacy for immigrant populations. To our knowledge, this is the first attempt to use a health literacy framework in this endeavor. Using qualitative strategies, we (a) developed an understanding of the experiences of Mexican and Filipina immigrant women with low health literacy through individual interviews, (b) conducted focus groups to obtain feedback from experts and participants to determine the adequacy of items included in the measure, and (c) refined the set of items to create an empirically based measure. The final measure included 129 items that assess beliefs, attitudes, knowledge, emotions, and contextual factors related to breast and cervical cancer. Processes for adapting the measure for use with other immigrant groups are discussed. PMID- 26631679 TI - Facilitators and Barriers to HIV Screening: A Qualitative Meta-Synthesis. AB - Accomplishments in biomedical research and technology, combined with innovative community and clinically based interventions, have expanded HIV testing globally. However, HIV screening and receipt of results remains a challenge in some areas. To optimize the benefits of HIV screening, it is imperative that there is a better understanding of the barriers to and motivators of testing for HIV infection. This study is a meta-synthesis of the qualitative literature on HIV screening and receipt of results; 128 unique publications had implications for HIV screening and receipt of results. A socioecological perspective provided an appropriate approach for synthesizing the literature. Three levels of influence emerged: individual attributes, interpersonal attributes, and broader patterns of influence. Findings were reviewed and found to have implications for continued engagement in the HIV treatment cascade. Recommendations to enhance HIV screening and to ensure receipt of results are proposed and discussed. PMID- 26631680 TI - Health Conditions Prior to Imprisonment and the Impact of Prison on Health: Views of Detained Women. AB - Detained women have certain health conditions prior to incarceration and these conditions can improve, worsen, or remain the same in prison, depending on the prisoner's background, the characteristics of the prison, and the arrest experience. This study investigated the health of detained women and the influence of incarceration from their perspective. Three focus groups were conducted among 15 inmates, and data were analyzed according to thematic analysis procedures. Detainer's health backgrounds varied with regard to their level of health concerns, contact with health services, and health behaviors. A positive influence of incarceration was described by patients with chronic illness, patients with drug addiction, and victims of interpersonal violence. Among women with mental illnesses or those without previous health problems, reports do not reveal benefits of imprisonment for mental health. These data emphasize the importance of specialized health care and the need to invest in mental health care in corrective institutions. PMID- 26631681 TI - Living in Limbo: Contested Narratives of Patients With Chronic Symptoms Following Lyme Disease. AB - Persistent, subjective symptoms of unknown etiology following treatment for Lyme disease have been termed post- treatment Lyme disease syndrome or chronic Lyme disease (PTLDS/CLD). The objective of this study was to give primacy to the patient experience of this medically contested condition by eliciting patient illness narratives and identifying emergent issues through semistructured interviews conducted among 29 participants. We used thematic narrative analysis to identify three predominant themes: (a) Physical and social limitations lead to a "new normal" characterized by fundamental shifts of ways of being in the world, (b) disease-specific factors contribute to symptom and illness invisibility that affects social support in nuanced ways, and (c) pervasive medical uncertainty regarding PTLDS/CLD promotes an increased sense of personal responsibility for care. Similar to other contested or medically unexplained syndromes, our findings suggest that the social sequelae of PTLDS/CLD can be equally protracted as the physical effects of this illness. PMID- 26631683 TI - Researching Lived Experience of Drugs and Crime: A Phenomenological Study of Drug Dependent Inmates. AB - This study identified the main components of the drugs and crime experience of a sample of 25 drug-dependent inmates interviewed in prison. Text analyses were conducted using a phenomenological method. The sample was characterized by a disruptive childhood in multi-problematic families and deviant social contexts where drug use and crime were considered normal since early adolescence. Drug initiation involved recreational use of dance drugs and/or cocaine, and the pleasure experienced was identified as the cause of subsequent persistent use. Three pathways that led to dependence were identified: The narcissistic pathway was defined as involving uncontrolled cocaine and amphetamines to feel powerful and limitless. The posttraumatic pathway was defined as involving post-trauma self-destructive drug use, while the pain relief pathway was defined as involving multiple substances to relieve pain. The second and third pathways were more directly associated with crime aimed at sustaining drug use. PMID- 26631682 TI - Identity, Representations, and Beliefs: HIV Controllers Living on the Frontier of Good Health and Illness. AB - Some people living with HIV spontaneously control the virus without antiretroviral treatment. They are called HIV controllers, and their status places them at the limits of bio-clinical normality. The objective of this study was to investigate HIV controllers' beliefs and representations of their individual trajectories using a qualitative approach. Fourteen HIV controllers were interviewed. Vertical analysis focused on examining how interviewees' specific beliefs and representational processes help these patients adapt to their particular situation. Horizontal analysis focused on how patients' biographic trajectories and identity positioning help them make sense of their situation. Results highlighted that perceiving oneself to be healthy or ill was linked to change or a lack of change in terms of disease perception, beliefs, and representations, when seropositivity was announced. This study of social representations and the processes involved provide crucial elements for health professionals caring for HIV controllers. PMID- 26631684 TI - Mothers' Continuing Bond With the Baby: The Case of Feticide. AB - The nature of the ongoing bond maintained by the bereaved with the deceased has attracted considerable attention, but studies have generally ignored postdeath relationships when loss occurs in utero. The goal of this research was to reach an interpretive understanding of the continuing bond experience among Israeli mothers who underwent feticide, examining the strategies they use in maintaining a postdeath relationship with a child they did not know, whose death they chose and witnessed, within a social context that ignores their loss and forces them to silence their grief. The results highlight two themes: (a) strategies for relinquishing connection with the baby and (b) strategies for maintaining a postdeath relationship. These processes partially correspond with two theoretical views that shed light on interpretation of the results: the dual process of coping with bereavement and relational dialectic theory. Implications of the results to the practice of health providers are outlined. PMID- 26631685 TI - In-situ microfluidic controlled, low temperature hydrothermal growth of nanoflakes for dye-sensitized solar cells. AB - In this paper, an in-situ microfluidic control unit (MCU) was designed and applied in a hydrothermal synthesis process, which provides an easy way to localize liquid-phase reaction and realize selective synthesis and direct growth of nanostructures as well as their morphology, all in a low-temperature and atmospheric environment. The morphology was controlled through controlling the amount of additivities using the MCU. This achieved a facile fabrication of Al doped ZnO (AZO) nanoflakes vertically grown on flexible polymer substrates with enhanced light scattering and dye loading capabilities. Flexible DSSCs with a significant enhancement (410% compare to ZnO NRs based devices) in power conversion efficiency were obtained using AZO nanoflake photoanodes of 6 MUm thick, due to the enhancement in electron mobility and reduction in recombination. This hydrothermal synthesis using the in-situ MCU provides an efficient and scalable technique to synthesize controllable nanostructures with characteristics of easy set-up, low energy consumption and low cost. PMID- 26631686 TI - Cerebral Glucose Metabolism Assessment in Rat Models of Alzheimer's Disease: An 18F-FDG-PET Study. AB - OBJECTIVE: This study was designed to detect the brain glucose metabolism in rat models of Alzheimer's disease (AD) by the application of (18)F-2-fluoro-deoxy-d glucose positron emission tomography ((18)F-FDG-PET) and to provide new insights for the early detection of AD. METHODS: Forty Wistar rats were randomly divided into 2 groups. Fifteen sham-operated rats were used as a control group. The remaining rats as a premodel group were intracerebroventricularly injected with ibotenic acid and were intraperitoneally injected with d-galactose, of which 15 rats were included as the experimental group. The above-mentioned 2 groups were assigned to Y-maze test and underwent (18)F-FDG-PET scanning. Positron emission tomography images were processed with SPM 2.0. RESULTS: The learning and memory skills were weakened in AD rats. Besides, the glucose metabolic activity of AD rats decreased in hippolampus, hypothalamus, insular cortex, piriform cortex, striatum, cingulate gyrus, stria terminalis, and parietal lobe and increased in olfactory bulb, cerebellum, midbrain, pontine, and retrosplenial cortex compared with the control group. Dorsal thalamus had shown both enhanced and reduced glucose metabolic activity. CONCLUSION: Our data indicate that the changed glucose metabolism in cerebral regions in (18)F-FDG-PET imaging could be an important predictor for early AD. PMID- 26631687 TI - Multisensory Stimulation as an Intervention Strategy for Elderly Patients With Severe Dementia: A Pilot Randomized Controlled Trial. AB - The objective of this study was to compare the effect of multisensory stimulation environment (MSSE) and one-to-one activity sessions in the symptomatology of elderly individuals with severe dementia. Thirty-two participants were randomly assigned to the following 3 groups: MSSE, activity, and control group. The MSSE and activity groups participated in two 30-minute weekly sessions over 16 weeks. Pre-, mid-, and posttrial; 8-week follow-up behavior; mood; cognitive status; and dementia severity were registered. Patients in the MSSE group demonstrated a significant improvement in the Neuropsychiatric Inventory and Bedford Alzheimer Nursing Severity Scale scores compared with the activity group. Both MSSE and activity groups showed an improvement during the intervention in the Cohen Mansfield Agitation Inventory aggressive behavior factor and total score, with no significant differences between groups. The MSSE may have better effects on neuropsychiatric symptoms and dementia severity in comparison with one-to-one activity sessions in patients with severe dementia. PMID- 26631688 TI - A DPOAE assessment of outer hair cell integrity in ears with age-related hearing loss. AB - Distortion product otoacoustic emissions (DPOAEs) were used to assess outer hair cell (OHC) integrity in human ears with age-related hearing loss. Sound pressure measurements were made in the ear canal over the stimulus range 40-90 dB SPL (L2), with L1 = 0.45*L2 + 44 with F2 = 2 and 3 or 4 kHz. Model-generated DPOAE I/O functions were fit to DPOAE data to quantify the contribution of loss of nonlinearity (OHC loss) to the hearing loss. Results suggest OHC loss as a contributing cause of age-related hearing, regardless of audiogram configuration. It seems likely that OHC and strial pathology co-exist in ears with AHL. PMID- 26631689 TI - Cooling of the auditory cortex modifies neuronal activity in the inferior colliculus in rats. AB - There are powerful pathways descending from the auditory cortex (AC) to the inferior colliculus (IC), yet their function is not fully understood. The aim of this study is to examine the effects of a reversible cortical inactivation, achieved by cooling of the AC, on the responses of neurons in the rat IC. Extracellular single-unit or multi-unit activity was recorded in the IC of anaesthetized rats with a 16-channel multielectrode probe introduced along the IC dorso-ventral axis through the dorsal cortex (DCIC) to the central nucleus of the IC (CIC). Cooling of the AC produced an increase in spontaneous activity and magnitude of the sound-evoked response in 47% of the IC neurons. Maximal changes in the neuronal activity were observed in the DCIC and the central part of the CIC. The final segments of the sustained responses to 60 ms stimuli and the off responses were more affected than the onset segments. Inactivation of the AC resulted in a suppression of the post-excitatory inhibition and neuronal adaptation, which was reflected in a pronounced enhancement of synchronized responses to a series of fast repeated clicks. The response parameters recovered, at least partly, to the pre-cooling levels 1 h after the cooling cessation. The frequency tuning properties of the IC neurons did not show any significant changes during the cooling period. The results demonstrate that AC cooling inactivates excitatory corticofugal pathways and results in a less activated intrinsic inhibitory network in the IC. PMID- 26631691 TI - Influence of oral moisturizing jelly as a saliva substitute for the relief of xerostomia in elderly patients with hypertension and diabetes mellitus. AB - Dry mouth is common in elderly patients. However, the use of saliva substitute has been limited due to its inedibility. This study investigated the efficacy of oral moisturizing jelly (OMJ), a novel edible saliva substitute. A pre-post design was conducted in 118 elderly patients diagnosed with hypertension and/or diabetes mellitus. After using OMJ, signs and symptoms of dry mouth were compared with baseline data. The properties of saliva were compared between the OMJ use and non-use periods. The use of OMJ for 2 weeks significantly reduced symptoms of dry mouth, while the use for 1 month reduced the signs of xerostomia, prevented the decline of salivary pH(s) and improved buffering capacities. OMJ was equally effective in patients taking 1 to 2 and 3 to 7 medications. Furthermore, 65% of patients preferred OMJ over a commercial product. OMJ could be new edible saliva substitute for elderly patients suffering from dry mouth. Clinicaltrials.gov ID: NCT02317172. PMID- 26631693 TI - Huge Disulfide-Linkage'S Electron Capture Variation Induced by alpha-Helix Orientation. AB - An active site containing a Cys-X-X-Cys motif (CXXC), where X denotes any amino acid, is always found in the thiol-disulfide oxidoreductase superfamily. Because of its very high propensity for N-termini of alpha-helices, we examine the effect of this secondary structure on the disulfide-linked CXXC electron affinity. A Cys Gly-Pro-Cys motif (CGPC) is chosen as an example, as it is the canonical motif found in thioredoxins. QM/MM calculations (MP2/6-31+G**:CHARMM) establish that the electron capture is strongly favored by an N-terminal alpha-helix, due to the positive electrostatic potential in the vicinity of the active site. The enhancement of adiabatic electron affinity accounts for ca. 0.9 eV for a 12 residues helix and rapidly converges as the number of alanine residues increases. A close agreement between a reference thioredoxin (Trx h) and the corresponding model peptide is found (respectively +2.20 and +2.12 eV), in parallel with experimental redox potentials [Iqbalsyah et al. Protein Sci. 2006, 15, 2026 2030]. This suggests a simple additive rule for geometrical and electrostatic effects. The electron affinity of the CXXC active site is first considered in an isolated way. Then, the strong modulation of the electrostatic field created by the alpha-helix can be added up. This simple partition scheme allows a proper quantification of the ease of attachment of a low-energy electron. PMID- 26631692 TI - Investigation of Tumor Cell Behaviors on a Vascular Microenvironment-Mimicking Microfluidic Chip. AB - The extravasation of tumor cells is a key event in tumor metastasis. However, the mechanism underlying tumor cell extravasation remains unknown, mainly hindered by obstacles from the lack of complexity of biological tissues in conventional cell culture, and the costliness and ethical issues of in vivo experiments. Thus, a cheap, time and labor saving, and most of all, vascular microenvironment mimicking research model is desirable. Herein, we report a microfluidic chip based tumor extravasation research model which is capable of simultaneously simulating both mechanical and biochemical microenvironments of human vascular systems and analyzing their synergistic effects on the tumor extravasation. Under different mechanical conditions of the vascular system, the tumor cells (HeLa cells) had the highest viability and adhesion activity in the microenvironment of the capillary. The integrity of endothelial cells (ECs) monolayer was destroyed by tumor necrosis factor-alpha (TNF-alpha) in a hemodynamic background, which facilitated the tumor cell adhesion, this situation was recovered by the administration of platinum nanoparticles (Pt-NPs). This model bridges the gap between cell culture and animal experiments and is a promising platform for studying tumor behaviors in the vascular system. PMID- 26631690 TI - TLR-3 stimulation improves anti-tumor immunity elicited by dendritic cell exosome based vaccines in a murine model of melanoma. AB - Dendritic cell (DC)-derived exosomes (Dexo) contain the machinery necessary to activate potent antigen-specific immune responses. As promising cell-free immunogens, Dexo have been tested in previous clinical trials for cancer vaccine immunotherapy, yet resulted in limited therapeutic benefit. Here, we explore a novel Dexo vaccine formulation composed of Dexo purified from DCs loaded with antigens and matured with either the TLR-3 ligand poly(I:C), the TLR-4 ligand LPS or the TLR-9 ligand CpG-B. When poly(I:C) was used to produce exosomes together with ovalbumin (OVA), the resulting Dexo vaccine strongly stimulated OVA-specific CD8(+) and CD4(+) T cells to proliferate and acquire effector functions. When a B16F10 melanoma cell lysate was used to load DCs with tumor antigens during exosome production together with poly(I:C), we obtained a Dexo vaccine capable of inducing robust activation of melanoma-specific CD8(+) T cells and the recruitment of cytotoxic CD8(+) T cells, NK and NK-T cells to the tumor site, resulting in significantly reduced tumor growth and enhanced survival as compared to a Dexo vaccine formulation similar to the one previously tested on human patients. Our results indicate that poly(I:C) is a particularly favorable TLR agonist for DC maturation during antigen loading and exosome production for cancer immunotherapy. PMID- 26631695 TI - Mechanism of Ultrafast Photodecay in Restricted Motions in Protonated Schiff Bases: The Pentadieniminium Cation. AB - Ab initio surface-hopping dynamics simulations for the trans-penta-3,5 dieniminium cation (PSB3) are presented imposing different sets of mechanical restrictions in order to investigate the response of the molecular system to certain environmental degrees of hindrance. A general scheme for classification of photoisomerization mechanisms in conjugated chains based on the analysis of torsional angles is proposed allowing direct characterization of the different isomerization mechanisms proposed previously. On the basis of a statistical analysis of 300 trajectories a new photoisomerization mechanism-the Folding Table was found. This mechanism and the One-Bond-Flip are almost entirely responsible for the photoisomerization process in PSB3. PMID- 26631694 TI - Magnetostructural Dynamics with the Extended Broken Symmetry Formalism: Antiferromagnetic [2Fe-2S] Complexes. AB - A general spin-projection framework is laid out which allows one to perform ab initio molecular dynamics simulations of antiferromagnetically coupled spin dimers. The method extends the well-established broken-symmetry formalism and is systematically and consistently improvable. It allows for accessing structure within the same spin-projection approximation as employed to compute the exchange coupling constant J of such complexes in their low-spin state as a function of time. The resulting time evolution of the exchange coupling, J(t), can be analyzed most conveniently in terms of the corresponding power spectrum, J(omega), thus giving access to dynamical magnetostructural properties. The method has been implemented using a well-tested approximation to spin-projection and was applied to a minimal [2Fe-2S] model, i.e. to the [Fe2S2(SH)4](2-) complex at 300 K in vacuo. Thermal fluctuations at room temperature are found to change the antiferromagnetic coupling J by about 50% with respect to the average value, and the features of its power spectrum, J(omega), can be traced back to a coupling of J to particular vibrational modes. PMID- 26631696 TI - A Combined QM/MM Poisson-Boltzmann Approach. AB - A method of solving the mixed quantum mechanical/molecular mechanical (QM/MM) Hamiltonian in solution, using the Poisson-Boltzmann (PB) equation to calculate partial charges and solvation free energies, is presented. This method combines a linear scaling divide and conquer semiempirical algorithm with the PB equation in a QM/MM framework, allowing only a specified region's charges to be polarized by the solvent while using fixed charges from a MM force field for the remaining system. This can save time over a full QM implementation, only requiring self consistency to be achieved in a small QM region, while giving comparable results. The solvation free energy of pentapeptides capped with an acetyl group (ACE) at the N-terminus and an N-methylamine group at the C-terminus (NME) was used to study the accuracy of this method as well as several small protein systems. The solvation free energies for the QM/MM implementation compare well with a full QM treatment of the same system, giving reasonable representations for the solvation free energy of the entire system independent of the QM region's size. In the case of the pentapeptides, the average error was only 4.9 kcal/mol with the smallest QM region. This mixed method will allow an accurate description of solvation effects in an area of interest, such as an active site, using mixed QM/MM Hamiltonians. Possible applications for this method include protein-ligand binding and reaction mechanism studies. PMID- 26631697 TI - Multireference Model Chemistries for Thermochemical Kinetics. AB - By combining the generalized valence bond ansatz of correlated participating orbitals (CPO) with the complete-active-space prescription for selecting configurations and with the use of multireference second order perturbation theory (MRMP2) for including dynamical correlation, we define three levels of multireference (MR) theoretical model chemistries for electronic structure calculations of chemical reaction energies and barrier heights. The three levels differ in their choice of which orbitals are considered to be participating; the choices are called nominal (nom-CPO), moderate (mod-CPO), and extended (ext-CPO). Combining any of these three choices with a method for treatment of dynamical correlation energy and a one-electron basis set yields a theoretical model chemistry. Unlike the full-valence choice of active orbitals, the CPO choices lead to active spaces that contain the orbitals needed to include important static correlation effects on chemical reactions but do not increase with the size of the nonparticipating portion of the system, and hence they remain viable computational options even for many large and complex reacting systems. The accuracies of the new levels, combined with the MG3S basis set (a partially augmented, multiply polarized valence triple-zeta basis with appropriately tight d functions for 3p-block elements) and with the fully augmented correlation consistent aug-cc-pVTZ basis set, are assessed against a previously presented database of barrier heights for diverse reaction types. We find that nom-CPO level captures the bulk of the static correlation energy, and MRMP2/nom-CPO calculations have an average error of only 1.4 kcal/mol in barrier heights, which may be compared to 5.0 kcal/mol for single-reference MP2 theory, 2.5 kcal/mol for CCSD, and 4.1 and 1.0 kcal/mol for the B3LYP and M06-2X density functionals, respectively. The accuracy of MRMP2/CPO for transition structure bond lengths and donor-acceptor distances is excellent, with a mean unsigned error of only 0.007 A as compared to 0.018 A for CCSD, 0.019 A for M06-2X, and 0.039 A for MP2 and B3LYP. We also introduce a new multireference diagnostic, called the M diagnostic, that allows one to measure the importance of static correlation in a given reagent or transition state. PMID- 26631698 TI - Anchoring the Absolute Proton Affinity Scale. AB - Converged first-principles proton affinities (PA) of ammonia and carbon monoxide have been determined by the focal-point analysis (FPA) approach, thus fixing the high and low ends of the molecular proton affinity scale. The electronic structure computations employed the all-electron (AE) coupled-cluster (CC) method up to single, double, triple, quadruple, and pentuple excitations. Aug-cc-pCVXZ [X = 2(D), 3(T), 4(Q), 5, and 6] correlation-consistent (cc) Gaussian basis sets for C, N, and O were used in conjunction with the corresponding aug-cc-pVXZ (X = 2-6) sets for H. Our FPA study supersedes previous computational work by accounting for (a) electron correlation beyond the "gold standard" CCSD(T) level; (b) the nonadditivity of core electron correlation effects; (c) scalar relativity; (d) diagonal Born-Oppenheimer corrections (DBOC); (e) anharmonicity of zero-point vibrational energies, based on accurate AE-CCSD(T)/cc-pCVQZ internal coordinate quartic force fields and fully variational vibrational computations; and (f) thermal corrections to enthalpies by direct summation over rovibrational energy levels. Our final proton affinities at 298.15(0.0) K are DeltapaH degrees (NH3) = 852.6(846.4) +/- 0.3 kJ mol(-1) and DeltapaH degrees (CO) = 592.4(586.5) +/- 0.2 kJ mol(-1). These values have better accuracy and considerably lower uncertainty than the best previous recommendations and thus anchor the proton affinity scale of molecules for future use. PMID- 26631699 TI - Accelerating Density Functional Calculations with Graphics Processing Unit. AB - An algorithm is presented for graphics processing units (GPUs), which execute single-precision arithmetic much faster than commodity microprocessors (CPUs), to calculate the exchange-correlation term in ab initio density functional calculations. The algorithm was implemented and applied to two molecules, taxol and valinomycin. The errors in the total energies were about 10(-5) a.u., which is accurate enough for practical usage. If the exchange-correlation term is split into a simple analytic model potential and the correction to it, and only the latter is calculated with the GPU, the energy error is decreased by an order of magnitude. The resulting time to compute the exchange-correlation term is smaller than it is on the latest CPU by a factor of 10, indicating that a GPU running the proposed algorithm accelerates the density functional calculation considerably. PMID- 26631700 TI - Hybrid Meta-Generalized Gradient Functional Modeling of Boron-Nitrogen Coordinate Covalent Bonds. AB - Truhlar's new generation of hybrid meta-generalized gradient functionals has been evaluated in modeling the binding enthalpies of substituted B-N coordinate covalent bonds. The short-range exchange correlation (XC) energy of coordinate covalent bonding coupled with the medium-range XC energy of noncovalent interactions results in a particularly difficult case for density functional theory (DFT). In this study, M06, M06-2X, M05, M05-2X, MPWB1K, and MPW1B95 with the 6-311++G(3df,2p) basis set have been used to evaluate four methylated ammonia trimethylboranes, (CH3)3B-N(CH3)nH3-n (n = 0 to 3), along with H3B-NH3. The predicted binding enthalpies from the new functionals have been compared to experiment as well as previous DFT (B3LYP, MPW1K) and ab initio (HF, MP2, QCISD, and QCISD(T)) results. Previously, only MP2, QCISD, and QCISD(T) were found to model the experimental energetic trend accurately. The mean absolute deviation (MAD) from experimental binding enthalpies for M06-2X and M05-2X is 0.3 and 1.6 kcal/mol, respectively. M06-2X yields a lower MAD than more expensive ab initio methods (MP2 = 1.9 kcal/mol and QCISD = 2.3 kcal/mol) and a comparable MAD to QCISD(T) (MAD = 0.4 kcal/mol). M06-2X is shown to provide a balanced account of the short- and medium-range XC energies necessary to describe the binding enthalpy of coordinate covalent bonds accurately in sterically congested molecular systems. PMID- 26631701 TI - Assessment of a Middle-Range Hybrid Functional. AB - While hybrid functionals are largely responsible for the utility of modern Kohn Sham density functional theory, they are not without their weaknesses. In the solid state, the slow decay of their nonlocal Hartree-Fock-type exchange makes hybrids computationally demanding and can introduce unphysical effects. Both problems can be remedied by a screened hybrid which uses exact exchange only at short-range. Many molecular properties, in contrast, benefit from the inclusion of long-range exact exchange. Recently, the authors reconciled these two seemingly contradictory requirements by introducing the HISS functional [ J. Chem. Phys. 2007 , 127 , 221103 ], which uses exact exchange only in the middle range. In this paper, we expand upon our previous work, benchmarking the performance of the HISS functional for several simple properties and applying it to the dissociation of homonuclear diatomic cations and to the polarizability of linear H2 chains to determine the importance of middle-range exact exchange for these systems, which are expected to be sensitive to the asymptotic exchange potential. PMID- 26631702 TI - Photoisomerization Reactions of Cyclopropene and 1,3,3-Trimethylcyclopropene: A Theoretical Study. AB - The mechanisms of the photochemical isomerization reactions were investigated theoretically using two model systems, cyclopropene and 1,3,3 trimethylcyclopropene with the CASSCF/6-311G(d) (six-electron/six-orbital active space) and MP2-CAS/6-311G(d,p)/CASSCF/6-311G(d) methods. The structures of the conical intersections, which play a decisive role in such photorearrangements, were obtained. The intermediates and transition structures of the ground states were also calculated to assist in providing a qualitative explanation of the reaction pathways. Our model investigations suggest that the preferred reaction route for both cyclopropene and 1,3,3-trimethylcyclopropene is as follows: reactant -> Franck-Condon region -> local minimum -> transition state -> conical intersection -> local intermediate -> transition state -> photoproduct. The theoretical findings suggest that the conical intersection mechanism found in this work gives a good explanation and supports the experimental observations. We also investigated the thermal (dark) reaction mechanisms for the hydrogen migration reactions. Again, all the relative yields of final products predicted based on the present work are in good agreement with the available experimental findings. PMID- 26631703 TI - Computational Study of Tungsten(II)-Catalyzed Rearrangements of Norbornadiene. AB - Rearrangements of norbornadiene (NBD, C7H8) to various alkylidenes, via a hypothetical 7-coordinate tungsten(II) complex W(CO)3I2(NBD), were studied using density-functional theory computations. An extensive search for intermediates and transition states of rearrangement was made. The theoretical method (basis sets and level of DFT) used was justified by new benchmark studies which compare optimized structural parameters to those from crystal structures of several different tungsten complexes. Transition-metal-catalyzed rearrangements of NBD are not as well-known as those of norbornene and are considerably more complicated than had been thought. This work predicts a large variety of intermediates which may be feasible targets for experimental synthesis. All the rearrangement paths to alkylidenes found here feature high activation energies of over 45 kcal mol(-1), implying that self-initiation for the ring-opening metathesis polymerization of NBD via tungsten(II) complexes must occur via an alternative mechanism. PMID- 26631704 TI - Theoretical Investigation of the Mechanism of Acid-Catalyzed Oxygenation of a Pd(II)-Hydride To Produce a Pd(II)-Hydroperoxide. AB - Density Functional Theory (DFT) has been applied to a comprehensive mechanistic study of the conversion reaction of the Pd(II)-hydride complex, (IMe)2(RCO2)PdH (R=CH3, Ph, and p-O2NC6H4), to the corresponding Pd(II)-hydroperoxide in the presence of molecular oxygen. The calculations have evaluated the two mechanistic proposed alternatives, that are both considered viable on the basis of current data, of slow RCO2H reductive elimination followed by oxygenation (Path A) and direct O2 insertion (Path B). Results suggest that the mechanism of direct insertion of molecular oxygen into the Pd-H bond of the initial complex is energetically preferred. The activation energy relative to the rate-determining step of Path A, indeed, is calculated to be lower than the activation energy of the rate determining step of the alternative Path B, whatever ligand (CH3CO2, Ph, CO2, p-O2NC6H4CO2) is coordinated to the Pd center. The calculated free activation energy of the rate-determining hydrogen abstraction step (DeltaG* = 24.8 kcal/mol) in the case of the oxygenation reaction of the benzoate-ligated Pd(II)-hydride complex is in very good agreement with the experimentally determined value of 24.4 kcal/mol. In addition, according to the experimentally detected enhancement of the reaction rate due to the presence of a nitro group on the benzoate ligand, our calculations show that the transition state for the hydrogen atom abstraction by molecular oxygen along the pathway for the oxygenation reaction of (IMe)2(p-O2NC6H4CO2)PdH lies lower in energy with respect to the analogous transition state calculated for R=Ph. PMID- 26631705 TI - The "Hot-Solvent/Cold-Solute" Problem Revisited. AB - The temperature steers the equilibrium and nonequilibrium conformational dynamics of macromolecules in solution. Therefore, corresponding molecular dynamics simulations require a strategy for temperature control which should guarantee that the experimental statistical ensemble is also sampled in silico. Several algorithms for temperature control have been proposed. All these thermostats interfere with the macromolecule's "natural" dynamics as given by the Newtonian mechanics. Furthermore, using a single thermostat for an inhomogeneous solute solvent system can lead to stationary temperature gradients. To avoid this "hot solvent/cold solute" problem, two separate thermostats are frequently applied, one to the solute and one to the solvent. However, such a separate temperature control will perturb the dynamics of the macromolecule much more strongly than a global one and, therefore, can introduce large artifacts into its conformational dynamics. Based on the concept that an explicit solvent environment represents an ideal thermostat concerning the magnitude and time correlation of temperature fluctuations of the solute, we propose a temperature control strategy that, on the one hand, provides a homogeneous temperature distribution throughout the system together with the correct statistical ensemble for the solute molecule while, on the other hand, minimally perturbing its dynamics. PMID- 26631706 TI - Development of a Q2MM Force Field for the Asymmetric Rhodium Catalyzed Hydrogenation of Enamides. AB - The rhodium catalyzed asymmetric hydrogenation of enamides to generate amino acid products and derivatives is a widely used method to generate unnatural amino acids. The choice of a chiral ligand is of utmost importance in this reaction and is often based on high throughput screening or simply trial and error. A virtual screening method can greatly increase the speed of the ligand screening process by calculating expected enantiomeric excesses from relative energies of diastereomeric transition states. Utilizing the Q2MM method, new molecular mechanics parameters are derived to model the hydride transfer transition state in the reaction. The new parameters were based off of structures calculated at the B3LYP/LACVP** level of theory and added to the MM3* force field. The new parameters were validated against a test set of experimental data utilizing a wide range of bis-phosphine ligands. The computational model agreed with experimental data well overall, with an unsigned mean error of 0.6 kcal/mol against a set of 18 data points from experiment. The major errors in the computational model were due either to large energetic errors at high e.e., still resulting in qualitative agreement, or cases where large steric interactions prevent the reaction from proceeding as expected. PMID- 26631707 TI - G3//BMK and Its Application to Calculation of Bond Dissociation Enthalpies. AB - On the basis of systematic examinations it was found that the BMK functional significantly outperformed the other popular density functional theory methods including B3LYP, B3P86, KMLYP, MPW1P86, O3LYP, and X3LYP for the calculation of bond dissociation enthalpies (BDEs). However, it was also found that even the BMK functional might dramatically fail in predicting the BDEs of some chemical bonds. To solve this problem, a new composite ab initio method named G3//BMK was developed by combining the strengths of both the G3 theory and BMK. G3//BMK was found to outperform the G3 and G3//B3LYP methods. It could accurately predict the BDEs of diverse types of chemical bonds in various organic molecules within a precision of ca. 1.2 kcal/mol. PMID- 26631708 TI - An Accurate and Transferable Intermolecular Diatomic Hydrogen Potential for Condensed Phase Simulation. AB - An anisotropic many-body H2 potential energy function has been developed for use in heterogeneous systems. The intermolecular potential has been derived from first principles and expressed in a form that is readily transferred to exogenous systems, e.g. in modeling H2 sorption in solid-state materials. Explicit many body polarization effects, known to be important in simulating hydrogen at high density, are incorporated. The analytic form of the potential energy function is suitable for methods of statistical physics, such as Monte Carlo or Molecular Dynamics simulation. The model has been validated on dense supercritical hydrogen and demonstrated to reproduce the experimental data with high accuracy. PMID- 26631709 TI - What Electronic Structures and Geometries of Carborane Mono- and ortho-, meta-, and para-Diradicals are Preferred? AB - Structures, relative stabilities, singlet-triplet gaps, and the ground-state character of mono- and diradicals derived from the three icosahedral carborane cage isomers have been computed by unrestricted broken-symmetry DFT and by CASPT2 methods. Whereas the bond dissociation energies (BDE) leading to the carborane monoradicals are close to the benzene BDE, the most stable carborane radicals are derived from dissociations of hydrogens farthest away from the carbon atoms. All the monomeric carborane diradicals are determined to have singlet ground states. However, the energetic accessibility of triplet states in some of the species offers the potential of building diradical multidimensional carborane network architectures with interesting magnetic properties. PMID- 26631710 TI - A Hamiltonian Replica Exchange Approach and Its Application to the Study of Side Chain Type and Neighbor Effects on Peptide Backbone Conformations. AB - We presented a Hamiltonian replica exchange approach and applied it to investigate the effects of various factors on the conformational equilibrium of peptide backbone. In different replicas, biasing potentials of varying strengths are applied to all backbone (phi,psi) torsional angle pairs to overcome sampling barriers. A general form of constructing biasing potentials based on a reference free energy surface is employed to minimize sampling in physically irrelevant parts of the conformational space. An extension of the weighted histogram analysis formulation allows for conformational free energy surfaces to be computed using all replicas, including those with biased Hamiltonians. This approach can significantly reduce the statistical uncertainties in computed free energies. For the peptide systems considered, it allows for effects of the order of 0.5-1 kJ/mol to be quantified using explicit solvent simulations. We applied this approach to capped peptides of 2-5 peptide units containing Ala, Phe, or Val in explicit water solvent and focused on how the conformational equilibrium of a single pair of backbone angles are influenced by changing the residue types of the same and neighboring residues as well as conformations of neighboring residues. For the effects of changing side-chain types of the same residue, our results consistently showed increased preference of beta for Phe and Val relative to Ala. As for neighbor effects, our results not only indicated that they can be as large as the effects of changing the side-chain type of the same residue but also led to several new insights. We found that for the N-terminal neighbors, their conformations seem to have large effects. Relative to the beta conformer of an N-terminal neighbor, its alpha conformer stabilizes the beta conformer of its next Ala disregarding the residue type of the neighbor. For C-terminal neighbors, their chemical identities seem to play more important roles. Val as the C terminal neighbor significantly increases the PII propensity of its previous Ala disregarding its own conformational state. These results are in good accordance with reported statistics of protein coil structure libraries, proving the persistent presence of such effects in short peptides as well as in proteins. We also observed other side-chain identity and neighbor effects which have been consistently reproduced in our simulations of different small peptide systems but not displayed by coil library statistics. PMID- 26631711 TI - Mechanism of Coupled Folding and Binding in the siRNA-PAZ Complex. AB - The PAZ domain plays a key role in gene silencing pathway. The PAZ domain binds with siRNAs to form the multimeric RNA-induced silencing complex (RISC). RISC identifies mRNAs homologous to the siRNAs and promotes their degradation. It was found that binding with siRNA significantly enhances apo-PAZ folding. However, the mechanism by which folding is coupled to binding is poorly understood. Thus, the coupling relationship between binding and folding is very important for understanding the function of gene silencing. We have performed molecular dynamics (MD) of both bound and apo-PAZ to study the coupling mechanism between binding and folding in the siRNA-PAZ complex. Room-temperature MD simulations suggest that both PAZ and siRNA become more rigid and stable upon siRNA binding. Kinetic analysis of high-temperature MD simulations shows that both bound and apo PAZ unfold via a two-state process. The unfolding pathways are different between bound and apo-PAZ: the order of helix III and helices I & II unfolding is switched. Furthermore, transition probability was used to determine the transition state ensemble for both bound and apo-PAZ. It was found that the transition state of bound PAZ is more compact than that of apo-PAZ. The predicted Phi-values suggest that the Phi-values of helix III and sheets of beta3-beta7 for bound PAZ are more native-like than those of apo-PAZ upon the binding of siRNA. The results can help us to understand the mechanism of gene silencing. PMID- 26631712 TI - Sulfoxide, Sulfur, and Nitrogen Oxidation and Dealkylation by Cytochrome P450. AB - The oxidation and dealkylation of dimethylsulfoxide (DMSO), dimethylsulfide (DMS), and trimethylamine (TMA) by cytochrome P450 has been studied with density functional theory calculations. The results show that the oxidation reactions always occur on the doublet spin surface, whereas dealkylations can take place for both the doublet and quartet spin states. Moreover, DMS is more reactive than DMSO, and S-oxidation is more favorable than S-dealkylation, whereas N dealkylation is more favorable than N-oxidation. This is in perfect agreement with experimental results, showing that density functional activation energies are reliable and comparable for widely different reactions with cytochrome P450. PMID- 26631713 TI - Topologically Based Multipolar Reconstruction of Electrostatic Interactions in Multiscale Simulations of Proteins. AB - We present a new method to incorporate electrostatic interactions in coarse grained representations of proteins. The model is based on a topologically reconstructed multipolar expansion of the all-atom centers of charge, specifically of the backbone dipoles and the polar or charged side chains. The reliability of the model is checked by studying different test cases, namely protein-cofactor/substrate interactions, protein large conformational changes, and protein-protein complexes. In all cases, the model quantitatively reproduces the all-atom electrostatic field in both a static and a dynamic framework. The model is of general applicability and can be used to improve both full coarse grained simulations and hybrid all-atom/coarse-grained multiscale approaches. PMID- 26631714 TI - Cyameluric Acid as Anion-pi Type Receptor for ClO4(-) and NO3(-): pi-Stacked and Edge-to-Face Structures. AB - Based on the binding energies at high levels of ab initio theory including coupled cluster theory at the complete basis limit, we show that cyameluric acid (C6N7O3H3) is a potent receptor for ClO4(-) and NO3(-) anions through the anion pi interactions. In contrast, cyanuric acid (C3N3O3H3) binds Cl(-), NO3(-), and ClO4(-) with the hydrogen bonding type structures, while their anion-pi type structures show slightly weaker binding. Consequently, the cyameluric acid having the C3h symmetric C6N7 nucleus with electron withdrawing oxygen atoms is a novel anion-pi type receptor for trigonal-planar and tetrahedral anions. The structures of the cyameluric acid interacting with Cl(-) and ClO4(-) are considered as the pi stacking type. For the cyameluric acid interacting with NO3(-), the pi(edge) type complex is only slightly more favored over the pi(stack) type in the gas phase, but the pi(stack) type is likely to be as stable as the pi(edge) type in the solvent phase. PMID- 26631716 TI - Tools for automating the imaging of zebrafish larvae. AB - The VAST BioImager system is a set of tools developed for zebrafish researchers who require the collection of images from a large number of 2-7 dpf zebrafish larvae. The VAST BioImager automates larval handling, positioning and orientation tasks. Color images at about 10 MUm resolution are collected from the on-board camera of the system. If images of greater resolution and detail are required, this system is mounted on an upright microscope, such as a confocal or fluorescence microscope, to utilize their capabilities. The system loads a larvae, positions it in view of the camera, determines orientation using pattern recognition analysis, and then more precisely positions to user-defined orientation for optimal imaging of any desired tissue or organ system. Multiple images of the same larva can be collected. The specific part of each larva and the desired orientation and position is identified by the researcher and an experiment defining the settings and a series of steps can be saved and repeated for imaging of subsequent larvae. The system captures images, then ejects and loads another larva from either a bulk reservoir, a well of a 96 well plate using the LP Sampler, or individually targeted larvae from a Petri dish or other container using the VAST Pipettor. Alternative manual protocols for handling larvae for image collection are tedious and time consuming. The VAST BioImager automates these steps to allow for greater throughput of assays and screens requiring high-content image collection of zebrafish larvae such as might be used in drug discovery and toxicology studies. PMID- 26631717 TI - Handedness prevalence in the deaf: Meta-analyses. AB - An under-investigated aspect of handedness, a biological proxy for cerebral laterality for language, is its prevalence amongst deaf individuals. We present four sets of meta-analyses on studies measuring handedness prevalence in deaf individuals, comprising 31 data sets and totaling 5,392 participants (4,606 deaf, 786 hearing). Deaf individuals were found to be 2.61 times more likely to be non right-handed and 2.25 times more likely to be left-handed compared to their hearing counterparts. When handedness was measured by means of manipulative actions, the weighted estimates of handedness prevalence for deaf populations were 17.70% and 14.70% for non-right- and left-handedness respectively; when handedness was measured by means of sign actions, the prevalence was 10.60% and 9.70%, respectively. Yet, when comparing studies that measured handedness in the same deaf individuals using both manipulative and sign actions, no difference was found in their handedness prevalence. This pattern is taken to suggest that the higher prevalence of atypical handedness in the deaf population may be linked to delayed language acquisition. PMID- 26631715 TI - Oligonucleotide aptamers: A next-generation technology for the capture and detection of circulating tumor cells. AB - A critical challenge for treating cancer is the early identification of those patients who are at greatest risk of developing metastatic disease. The number of circulating tumor cells (CTCs) in cancer patients has recently been shown to be a valuable (and non-invasively accessible) diagnostic indicator of the state of metastatic disease. CTCs are rare cancer cells found in the blood circulation of cancer patients believed to provide a means of diagnosing the likelihood for metastatic spread and assessing response to therapy in advanced, as well as early stage disease settings. Numerous technical efforts have been made to reliably detect and quantify CTCs, but the development of a universal assay has proven quite difficult. Notable challenges for developing a broadly useful CTC-based diagnostic assay are the development of easy-to-operate methods that (1) are sufficiently sensitive to reliably detect the small number of CTCs that are present in the circulation and (2) can capture the molecular heterogeneity of tumor cells. In this review, we describe recent progress towards the application of synthetic oligonucleotide aptamers as promising, novel, robust tools for the isolation and detection of CTCs. Advantages and challenges of the aptamer approach are also discussed. PMID- 26631718 TI - Suicidal ideation, suicide attempts and non-suicidal self-injury among lesbian, gay, bisexual and heterosexual adults: Findings from an Australian national study. AB - OBJECTIVES: This study investigated associations between sexual orientation and measures of suicidality and non-suicidal self-injury in Australian adults. Previous studies of sexual orientation and suicidality have been limited by unclear conceptualisations of suicidal intent, failure to differentiate between homosexuality and bisexuality, inattention to gender differences and use of convenience-based samples. METHODS: A large (N = 10,531) representative national sample of Australian adults was used to investigate associations between sexual orientation (heterosexual, homosexual, bisexual) and (1) suicidal ideation, (2) attempted suicide and (3) non-suicidal self-injury, for males and females separately, in a series of sequentially adjusted logistic regression models. RESULTS: Sexual minority participants were at greater risk of suicidality and self-injury than heterosexuals, after adjusting for age and other covariates, with patterns of risk differing by sexual orientation and gender. Compared with their heterosexual counterparts, gay men, but not bisexual men, were more likely to report suicidal ideation (odds ratio = 3.05, 95% confidence interval = [1.65, 5.60]) and suicide attempts (odds ratio = 4.16, confidence interval = [2.18, 7.93]). Bisexual women, but not lesbian women, were more likely to report suicidal ideation (odds ratio = 4.40, confidence interval = [3.00, 6.37]) and suicide attempts (odds ratio = 4.46, confidence interval = [2.41, 8.24]). Neither bisexual nor gay men were more likely than heterosexual men to report self injury. However, bisexual women, but not lesbian women, were more likely than heterosexual women to report self-injury (odds ratio = 19.59, confidence interval = [9.05, 42.40]). Overall, bisexual females were at greatest risk of suicidality and self-injury. CONCLUSION: Clinicians working with sexual minority populations are encouraged to openly discuss suicidal and self-injurious thoughts and behaviours with their clients and may consider using therapeutic strategies to reduce internalised stigma and enhance personal and social resources. PMID- 26631719 TI - Laser propulsion of nanobullets by adiabatic compression of surface plasmon polaritons. AB - Laser propulsion and guide of nanosized objects is fundamental for a wide number of applications. These applications are often limited by the fact that the optical forces acting on nanoparticles are almost negligible even in the favorable case of metallic particles and hence large laser powers are needed to accelerate and guide nanosize devices in practical applications. Furthermore, metallic nanoparticles exhibit strong absorption bands and scattering and this makes more difficult controlling nanopropulsion. Thus, finding some mechanism enhancing the optomechanical interaction at the nanoscale controlled by laser is specifically challenging and pivotal. Here, we demonstrate a novel physical effect where the well-known adiabatic localization of the enhanced plasmonic surface field on the apex of metallic nanocones produces a significant optical pressure employable as a propulsive mechanism. The proposed method gives the possibility to develop new photonics devices to accelerate metallic nanobullets over long distances for a variety of applications. PMID- 26631720 TI - Secreted Frizzled-related Protein 5 Diminishes Cardiac Inflammation and Protects the Heart from Ischemia/Reperfusion Injury. AB - Wnt signaling has diverse actions in cardiovascular development and disease processes. Secreted frizzled-related protein 5 (Sfrp5) has been shown to function as an extracellular inhibitor of non-canonical Wnt signaling that is expressed at relatively high levels in white adipose tissue. The aim of this study was to investigate the role of Sfrp5 in the heart under ischemic stress. Sfrp5 KO and WT mice were subjected to ischemia/reperfusion (I/R). Although Sfrp5-KO mice exhibited no detectable phenotype when compared with WT control at baseline, they displayed larger infarct sizes, enhanced cardiac myocyte apoptosis, and diminished cardiac function following I/R. The ischemic lesions of Sfrp5-KO mice had greater infiltration of Wnt5a-positive macrophages and greater inflammatory cytokine and chemokine gene expression when compared with WT mice. In bone marrow derived macrophages, Wnt5a promoted JNK activation and increased inflammatory gene expression, whereas treatment with Sfrp5 blocked these effects. These results indicate that Sfrp5 functions to antagonize inflammatory responses after I/R in the heart, possibly through a mechanism involving non-canonical Wnt5a/JNK signaling. PMID- 26631721 TI - Two Degradation Pathways of the p35 Cdk5 (Cyclin-dependent Kinase) Activation Subunit, Dependent and Independent of Ubiquitination. AB - Cdk5 is a versatile protein kinase that is involved in various neuronal activities, such as the migration of newborn neurons, neurite outgrowth, synaptic regulation, and neurodegenerative diseases. Cdk5 requires the p35 regulatory subunit for activation. Because Cdk5 is more abundantly expressed in neurons compared with p35, the p35 protein levels determine the kinase activity of Cdk5. p35 is a protein with a short half-life that is degraded by proteasomes. Although ubiquitination of p35 has been previously reported, the degradation mechanism of p35 is not yet known. Here, we intended to identify the ubiquitination site(s) in p35. Because p35 is myristoylated at the N-terminal glycine, the possible ubiquitination sites are the lysine residues in p35. We mutated all 23 Lys residues to Arg (p35 23R), but p35 23R was still rapidly degraded by proteasomes at a rate similar to wild-type p35. The degradation of p35 23R in primary neurons and the Cdk5 activation ability of p35 23R suggested the occurrence of ubiquitin independent degradation of p35 in physiological conditions. We found that p35 has the amino acid sequence similar to the ubiquitin-independent degron in the NKX3.1 homeodomain transcription factor. An Ala mutation at Pro-247 in the degron-like sequence made p35 stable. These results suggest that p35 can be degraded by two degradation pathways: ubiquitin-dependent and ubiquitin-independent. The rapid degradation of p35 by two different methods would be a mechanism to suppress the production of p25, which overactivates Cdk5 to induce neuronal cell death. PMID- 26631722 TI - Replacing the Promoter of the Murine Gene Encoding P-selectin with the Human Promoter Confers Human-like Basal and Inducible Expression in Mice. AB - In humans and mice, megakaryocytes/platelets and endothelial cells constitutively synthesize P-selectin and mobilize it to the plasma membrane to mediate leukocyte rolling during inflammation. TNF-alpha, interleukin 1beta, and LPS markedly increase P-selectin mRNA in mice but decrease P-selectin mRNA in humans. Transgenic mice bearing the entire human SELP gene recapitulate basal and inducible expression of human P-selectin and reveal human-specific differences in P-selectin function. Differences in the human SELP and murine Selp promoters account for divergent expression in vitro, but their significance in vivo is not known. Here we generated knockin mice that replace the 1.4-kb proximal Selp promoter with the corresponding SELP sequence (Selp(KI)). Selp(KI) (/) (KI) mice constitutively expressed more P-selectin on platelets and more P-selectin mRNA in tissues but only slightly increased P-selectin mRNA after injection of TNF-alpha or LPS. Consistent with higher basal expression, leukocytes rolled more slowly on P-selectin in trauma-stimulated venules of Selp(KI) (/) (KI) mice. However, TNF alpha did not further reduce P-selectin-dependent rolling velocities. Blunted up regulation of P-selectin mRNA during contact hypersensitivity reduced P-selectin dependent inflammation in Selp(KI) (/-) mice. Higher basal P-selectin in Selp(KI) (/) (KI) mice compensated for this defect. Therefore, divergent sequences in a short promoter mediate most of the functionally significant differences in expression of human and murine P-selectin in vivo. PMID- 26631723 TI - Loss of SIRT3 Provides Growth Advantage for B Cell Malignancies. AB - B cell malignancies comprise a diverse group of cancers that proliferate in lymph nodes, bone marrow, and peripheral blood. SIRT3 (sirtuin 3) is the major deacetylase within the mitochondrial matrix that promotes aerobic metabolism and controls reactive oxygen species (ROS) by deacetylating and activating isocitrate dehydrogenase 2 (IDH2) and superoxide dismutase 2 (SOD2). There is controversy as to whether SIRT3 acts as an oncogene or a tumor suppressor, and here we investigated its role in B cell malignancies. In mantle cell lymphoma patient samples, we found that lower SIRT3 protein expression was associated with worse overall survival. Further, SIRT3 protein expression was reduced in chronic lymphocytic leukemia primary samples and malignant B cell lines compared to primary B cells from healthy donors. This lower level of expression correlated with hyperacetylation of IDH2 and SOD2 mitochondrial proteins, lowered enzymatic activities, and higher ROS levels. Overexpression of SIRT3 decreased proliferation and diminished the Warburg-like phenotype in SIRT3-deficient cell lines, and this effect is largely dependent on deacetylation of IDH2 and SOD2. Lastly, depletion of SIRT3 from malignant B cell lines resulted in greater susceptibility to treatment with an ROS scavenger but did not result in greater sensitivity to inhibition of the hypoxia-inducible factor-1alpha pathway, suggesting that loss of SIRT3 increases proliferation via ROS-dependent but hypoxia-inducible factor-1alpha-independent mechanisms. Our study suggests that SIRT3 acts as a tumor suppressor in B cell malignancies, and activating the SIRT3 pathway might represent a novel therapeutic approach for treating B cell malignancies. PMID- 26631724 TI - The Prodomain-bound Form of Bone Morphogenetic Protein 10 Is Biologically Active on Endothelial Cells. AB - BMP10 is highly expressed in the developing heart and plays essential roles in cardiogenesis. BMP10 deletion in mice results in embryonic lethality because of impaired cardiac development. In adults, BMP10 expression is restricted to the right atrium, though ventricular hypertrophy is accompanied by increased BMP10 expression in a rat hypertension model. However, reports of BMP10 activity in the circulation are inconclusive. In particular, it is not known whether in vivo secreted BMP10 is active or whether additional factors are required to achieve its bioactivity. It has been shown that high-affinity binding of the BMP10 prodomain to the mature ligand inhibits BMP10 signaling activity in C2C12 cells, and it was proposed that prodomain-bound BMP10 (pBMP10) complex is latent. In this study, we demonstrated that the BMP10 prodomain did not inhibit BMP10 signaling activity in multiple endothelial cells, and that recombinant human pBMP10 complex, expressed in mammalian cells and purified under native conditions, was fully active. In addition, both BMP10 in human plasma and BMP10 secreted from the mouse right atrium were fully active. Finally, we confirmed that active BMP10 secreted from mouse right atrium was in the prodomain-bound form. Our data suggest that circulating BMP10 in adults is fully active and that the reported vascular quiescence function of BMP10 in vivo is due to the direct activity of pBMP10 and does not require an additional activation step. Moreover, being an active ligand, recombinant pBMP10 may have therapeutic potential as an endothelial-selective BMP ligand, in conditions characterized by loss of BMP9/10 signaling. PMID- 26631726 TI - Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity. AB - Disruption of insulin-like growth factor I (IGF-I) signaling is a key step in the development of cancer or neurodegeneration. For example, interference of the prosurvival IGF-I/AKT/FOXO3 pathway by redox activation of the stress kinases p38 and JNK is instrumental in neuronal death by oxidative stress. However, in astrocytes, IGF-I retains its protective action against oxidative stress. The molecular mechanisms underlying this cell-specific protection remain obscure but may be relevant to unveil new ways to combat IGF-I/insulin resistance. Here, we describe that, in astrocytes exposed to oxidative stress by hydrogen peroxide (H2O2), p38 activation did not inhibit AKT (protein kinase B) activation by IGF I, which is in contrast to our previous observations in neurons. Rather, stimulation of AKT by IGF-I was significantly higher and more sustained in astrocytes than in neurons either under normal or oxidative conditions. This may be explained by phosphorylation of the phosphatase PTEN at the plasma membrane in response to IGF-I, inducing its cytosolic translocation and preserving in this way AKT activity. Stimulation of AKT by IGF-I, mimicked also by a constitutively active AKT mutant, reduced oxidative stress levels and cell death in H2O2-exposed astrocytes, boosting their neuroprotective action in co-cultured neurons. These results indicate that armoring of AKT activation by IGF-I is crucial to preserve its cytoprotective effect in astrocytes and may form part of the brain defense mechanism against oxidative stress injury. PMID- 26631725 TI - Purinergic P2Y2 Receptor Control of Tissue Factor Transcription in Human Coronary Artery Endothelial Cells: NEW AP-1 TRANSCRIPTION FACTOR SITE AND NEGATIVE REGULATOR. AB - We recently reported that the P2Y2 receptor (P2Y2R) is the predominant nucleotide receptor expressed in human coronary artery endothelial cells (HCAEC) and that P2Y2R activation by ATP or UTP induces dramatic up-regulation of tissue factor (TF), a key initiator of the coagulation cascade. However, the molecular mechanism of this P2Y2R-TF axis remains unclear. Here, we report the role of a newly identified AP-1 consensus sequence in the TF gene promoter and its original binding components in P2Y2R regulation of TF transcription. Using bioinformatics tools, we found that a novel AP-1 site at -1363 bp of the human TF promoter region is highly conserved across multiple species. Activation of P2Y2R increased TF promoter activity and mRNA expression in HCAEC. Truncation, deletion, and mutation of this distal AP-1 site all significantly suppressed TF promoter activity in response to P2Y2R activation. EMSA and ChIP assays further confirmed that upon P2Y2R activation, c-Jun, ATF-2, and Fra-1, but not the typical c-Fos, bound to the new AP-1 site. In addition, loss-of-function studies using siRNAs confirmed a positive transactivation role of c-Jun and ATF-2 but unexpectedly revealed a strong negative role of Fra-1 in P2Y2R-induced TF up-regulation. Furthermore, we found that P2Y2R activation promoted ERK1/2 phosphorylation through Src, leading to Fra-1 activation, whereas Rho/JNK mediated P2Y2R-induced activation of c-Jun and ATF-2. These findings reveal the molecular basis for P2Y G protein-coupled receptor control of endothelial TF expression and indicate that targeting the P2Y2R-Fra-1-TF pathway may be an attractive new strategy for controlling vascular inflammation and thrombogenicity associated with endothelial dysfunction. PMID- 26631727 TI - Visualization of NO3-/NO2- Dynamics in Living Cells by Fluorescence Resonance Energy Transfer (FRET) Imaging Employing a Rhizobial Two-component Regulatory System. AB - Nitrate (NO3(-)) and nitrite (NO2(-)) are the physiological sources of nitric oxide (NO), a key biological messenger molecule. NO3(-)/NO2(-) exerts a beneficial impact on NO homeostasis and its related cardiovascular functions. To visualize the physiological dynamics of NO3(-)/NO2(-) for assessing the precise roles of these anions, we developed a genetically encoded intermolecular fluorescence resonance energy transfer (FRET)-based indicator, named sNOOOpy (sensor for NO3(-)/NO2(-) in physiology), by employing NO3(-)/NO2(-)-induced dissociation of NasST involved in the denitrification system of rhizobia. The in vitro use of sNOOOpy shows high specificity for NO3(-) and NO2(-), and its FRET signal is changed in response to NO3(-)/NO2(-) in the micromolar range. Furthermore, both an increase and decrease in cellular NO3(-) concentration can be detected. sNOOOpy is very simple and potentially applicable to a wide variety of living cells and is expected to provide insights into NO3(-)/NO2(-) dynamics in various organisms, including plants and animals. PMID- 26631729 TI - WITHDRAWN: Multidrug Transporter LmrP allows Relocation of Catalytic Carboxylates. AB - This article has been withdrawn by the authors. Some lanes in the immunoblots were used to represent different experimental conditions in Figs 3A and 5A. The transport measurements shown in Figs 3D and 5D were the same. Less relevant features were obscured in the immunoblot in Fig 7A. PMID- 26631728 TI - Characterization of Tiki, a New Family of Wnt-specific Metalloproteases. AB - The Wnt family of secreted glycolipoproteins plays pivotal roles in development and human diseases. Tiki family proteins were identified as novel Wnt inhibitors that act by cleaving the Wnt amino-terminal region to inactivate specific Wnt ligands. Tiki represents a new metalloprotease family that is dependent on Mn(2+)/Co(2+) but lacks known metalloprotease motifs. The Tiki extracellular domain shares homology with bacterial TraB/PrgY proteins, known for their roles in the inhibition of mating pheromones. The TIKI/TraB fold is predicted to be distantly related to structures of additional bacterial proteins and may use a core beta-sheet within an alpha+beta-fold to coordinate conserved residues for catalysis. In this study, using assays for Wnt3a cleavage and signaling inhibition, we performed mutagenesis analyses of human TIKI2 to examine the structural prediction and identify the active site residues. We also established an in vitro assay for TIKI2 protease activity using FRET peptide substrates derived from the cleavage motifs of Wnt3a and Xenopus wnt8 (Xwnt8). We further identified two pairs of potential disulfide bonds that reside outside the beta sheet catalytic core but likely assist the folding of the TIKI domain. Finally, we systematically analyzed TIKI2 cleavage of the 19 human WNT proteins, of which we identified 10 as potential TIKI2 substrates, revealing the hydrophobic nature of Tiki cleavage sites. Our study provides insights into the Tiki family of proteases and its Wnt substrates. PMID- 26631730 TI - Reciprocal Changes in Phosphoenolpyruvate Carboxykinase and Pyruvate Kinase with Age Are a Determinant of Aging in Caenorhabditis elegans. AB - Aging involves progressive loss of cellular function and integrity, presumably caused by accumulated stochastic damage to cells. Alterations in energy metabolism contribute to aging, but how energy metabolism changes with age, how these changes affect aging, and whether they can be modified to modulate aging remain unclear. In locomotory muscle of post-fertile Caenorhabditis elegans, we identified a progressive decrease in cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), a longevity-associated metabolic enzyme, and a reciprocal increase in glycolytic pyruvate kinase (PK) that were necessary and sufficient to limit lifespan. Decline in PEPCK-C with age also led to loss of cellular function and integrity including muscle activity, and cellular senescence. Genetic and pharmacologic interventions of PEPCK-C, muscle activity, and AMPK signaling demonstrate that declines in PEPCK-C and muscle function with age interacted to limit reproductive life and lifespan via disrupted energy homeostasis. Quantifications of metabolic flux show that reciprocal changes in PEPCK-C and PK with age shunted energy metabolism toward glycolysis, reducing mitochondrial bioenergetics. Last, calorie restriction countered changes in PEPCK-C and PK with age to elicit anti-aging effects via TOR inhibition. Thus, a programmed metabolic event involving PEPCK-C and PK is a determinant of aging that can be modified to modulate aging. PMID- 26631731 TI - Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1) Mutation and TRAP1 Inhibitor Gamitrinib-triphenylphosphonium (G-TPP) Induce a Forkhead Box O (FOXO) dependent Cell Protective Signal from Mitochondria. AB - TRAP1 (tumor necrosis factor receptor-associated protein 1), a mitochondrial Hsp90 family chaperone, has been identified as a critical regulator of cell survival and bioenergetics in tumor cells. To discover novel signaling networks regulated by TRAP1, we generated Drosophila TRAP1 mutants. The mutants successfully developed into adults and produced fertile progeny, showing that TRAP1 is dispensable in development and reproduction. Surprisingly, mutation or knockdown of TRAP1 markedly enhanced Drosophila survival under oxidative stress. Moreover, TRAP1 mutation ameliorated mitochondrial dysfunction and dopaminergic (DA) neuron loss induced by deletion of a familial Parkinson disease gene PINK1 (Pten-induced kinase 1) in Drosophila. Gamitrinib-triphenylphosphonium, a mitochondria-targeted Hsp90 inhibitor that increases cell death in HeLa and MCF7 cells, consistently inhibited cell death induced by oxidative stress and mitochondrial dysfunction induced by PINK1 mutation in mouse embryonic fibroblast cells and DA cell models such as SH-SY5Y and SN4741 cells. Additionally, gamitrinib-triphenylphosphonium also suppressed the defective locomotive activity and DA neuron loss in Drosophila PINK1 null mutants. In further genetic analyses, we showed enhanced expression of Thor, a downstream target gene of transcription factor FOXO, in TRAP1 mutants. Furthermore, deletion of FOXO almost nullified the protective roles of TRAP1 mutation against oxidative stress and PINK1 mutation. These results strongly suggest that inhibition of the mitochondrial chaperone TRAP1 generates a retrograde cell protective signal from mitochondria to the nucleus in a FOXO-dependent manner. PMID- 26631732 TI - Interaction between RING1 (R1) and the Ubiquitin-like (UBL) Domains Is Critical for the Regulation of Parkin Activity. AB - Parkin is an E3 ligase that contains a ubiquitin-like (UBL) domain in the N terminus and an R1-in-between-ring-RING2 motif in the C terminus. We showed that the UBL domain specifically interacts with the R1 domain and negatively regulates Parkin E3 ligase activity, Parkin-dependent mitophagy, and Parkin translocation to the mitochondria. The binding between the UBL domain and the R1 domain was suppressed by carbonyl cyanide m-chlorophenyl hydrazone treatment or by expression of PTEN-induced putative kinase 1 (PINK1), an upstream kinase that phosphorylates Parkin at the Ser-65 residue of the UBL domain. Moreover, we demonstrated that phosphorylation of the UBL domain at Ser-65 prevents its binding to the R1 domain and promotes Parkin activities. We further showed that mitochondrial translocation of Parkin, which depends on phosphorylation at Ser 65, and interaction between the R1 domain and a mitochondrial outer membrane protein, VDAC1, are suppressed by binding of the UBL domain to the R1 domain. Interestingly, Parkin with missense mutations associated with Parkinson disease (PD) in the UBL domain, such as K27N, R33Q, and A46P, did not translocate to the mitochondria and induce E3 ligase activity by m-chlorophenyl hydrazone treatment, which correlated with the interaction between the R1 domain and the UBL domain with those PD mutations. These findings provide a molecular mechanism of how Parkin recruitment to the mitochondria and Parkin activation as an E3 ubiquitin ligase are regulated by PINK1 and explain the previously unknown mechanism of how Parkin mutations in the UBL domain cause PD pathogenesis. PMID- 26631733 TI - DndEi Exhibits Helicase Activity Essential for DNA Phosphorothioate Modification and ATPase Activity Strongly Stimulated by DNA Substrate with a GAAC/GTTC Motif. AB - Phosphorothioate (PT) modification of DNA, in which the non-bridging oxygen of the backbone phosphate group is replaced by sulfur, is governed by the DndA-E proteins in prokaryotes. To better understand the biochemical mechanism of PT modification, functional analysis of the recently found PT-modifying enzyme DndEi, which has an additional domain compared with canonical DndE, from Riemerella anatipestifer is performed in this study. The additional domain is identified as a DNA helicase, and functional deletion of this domain in vivo leads to PT modification deficiency, indicating an essential role of helicase activity in PT modification. Subsequent analysis reveals that the additional domain has an ATPase activity. Intriguingly, the ATPase activity is strongly stimulated by DNA substrate containing a GAAC/GTTC motif (i.e. the motif at which PT modifications occur in R. anatipestifer) when the additional domain and the other domain (homologous to canonical DndE) are co-expressed as a full-length DndEi. These results reveal that PT modification is a biochemical process with DNA strand separation and intense ATP hydrolysis. PMID- 26631734 TI - Novel Structural Components Contribute to the High Thermal Stability of Acyl Carrier Protein from Enterococcus faecalis. AB - Enterococcus faecalis is a Gram-positive, commensal bacterium that lives in the gastrointestinal tracts of humans and other mammals. It causes severe infections because of high antibiotic resistance. E. faecalis can endure extremes of temperature and pH. Acyl carrier protein (ACP) is a key element in the biosynthesis of fatty acids responsible for acyl group shuttling and delivery. In this study, to understand the origin of high thermal stabilities of E. faecalis ACP (Ef-ACP), its solution structure was investigated for the first time. CD experiments showed that the melting temperature of Ef-ACP is 78.8 degrees C, which is much higher than that of Escherichia coli ACP (67.2 degrees C). The overall structure of Ef-ACP shows the common ACP folding pattern consisting of four alpha-helices (helix I (residues 3-17), helix II (residues 39-53), helix III (residues 60-64), and helix IV (residues 68-78)) connected by three loops. Unique Ef-ACP structural features include a hydrophobic interaction between Phe(45) in helix II and Phe(18) in the alpha1alpha2 loop and a hydrogen bonding between Ser(15) in helix I and Ile(20) in the alpha1alpha2 loop, resulting in its high thermal stability. Phe(45)-mediated hydrophobic packing may block acyl chain binding subpocket II entry. Furthermore, Ser(58) in the alpha2alpha3 loop in Ef ACP, which usually constitutes a proline in other ACPs, exhibited slow conformational exchanges, resulting in the movement of the helix III outside the structure to accommodate a longer acyl chain in the acyl binding cavity. These results might provide insights into the development of antibiotics against pathogenic drug-resistant E. faecalis strains. PMID- 26631735 TI - beta-Subunit Binding Is Sufficient for Ligands to Open the Integrin alphaIIbbeta3 Headpiece. AB - The platelet integrin alphaIIbbeta3 binds to a KQAGDV motif at the fibrinogen gamma-chain C terminus and to RGD motifs present in loops in many extracellular matrix proteins. These ligands bind in a groove between the integrin alpha and beta-subunits; the basic Lys or Arg side chain hydrogen bonds to the alphaIIb subunit, and the acidic Asp side chain coordinates to a metal ion held by the beta3-subunit. Ligand binding induces headpiece opening, with conformational change in the beta-subunit. During this opening, RGD slides in the ligand-binding pocket toward alphaIIb, with movement of the betaI-domain beta1-alpha1 loop toward alphaIIb, enabling formation of direct, charged hydrogen bonds between the Arg side chain and alphaIIb. Here we test whether ligand interactions with beta3 suffice for stable ligand binding and headpiece opening. We find that the AGDV tetrapeptide from KQAGDV binds to the alphaIIbbeta3 headpiece with affinity comparable with the RGDSP peptide from fibronectin. AGDV induced complete headpiece opening in solution as shown by increase in hydrodynamic radius. Soaking of AGDV into closed alphaIIbbeta3 headpiece crystals induced intermediate states similarly to RGDSP. AGDV has very little contact with the alpha-subunit. Furthermore, as measured by epitope exposure, AGDV, like the fibrinogen gamma C terminal peptide and RGD, caused integrin extension on the cell surface. Thus, pushing by the beta3-subunit on Asp is sufficient for headpiece opening and ligand sliding, and no pulling by the alphaIIb subunit on Arg is required. PMID- 26631736 TI - Mesenchymal Stem Cells From Infants Born to Obese Mothers Exhibit Greater Potential for Adipogenesis: The Healthy Start BabyBUMP Project. AB - Maternal obesity increases the risk for pediatric obesity; however, the molecular mechanisms in human infants remain poorly understood. We hypothesized that mesenchymal stem cells (MSCs) from infants born to obese mothers would demonstrate greater potential for adipogenesis and less potential for myogenesis, driven by differences in beta-catenin, a regulator of MSC commitment. MSCs were cultured from the umbilical cords of infants born to normal-weight (prepregnancy [pp] BMI 21.1 +/- 0.3 kg/m(2); n = 15; NW-MSCs) and obese mothers (ppBMI 34.6 +/- 1.0 kg/m(2); n = 14; Ob-MSCs). Upon differentiation, Ob-MSCs exhibit evidence of greater adipogenesis (+30% Oil Red O stain [ORO], +50% peroxisome proliferator activated receptor (PPAR)-gamma protein; P < 0.05) compared with NW-MSCs. In undifferentiated cells, total beta-catenin protein content was 10% lower and phosphorylated Thr41Ser45/total beta-catenin was 25% higher (P < 0.05) in Ob-MSCs versus NW-MSCs (P < 0.05). Coupled with 25% lower inhibitory phosphorylation of GSK-3beta in Ob-MSCs (P < 0.05), these data suggest greater beta-catenin degradation in Ob-MSCs. Lithium chloride inhibition of GSK-3beta increased nuclear beta-catenin content and normalized nuclear PPAR-gamma in Ob-MSCs. Last, ORO in adipogenic differentiating cells was positively correlated with the percent fat mass in infants (r = 0.475; P < 0.05). These results suggest that altered GSK-3beta/beta-catenin signaling in MSCs of infants exposed to maternal obesity may have important consequences for MSC lineage commitment, fetal fat accrual, and offspring obesity risk. PMID- 26631738 TI - High-Fat Diet During Mouse Pregnancy and Lactation Targets GIP-Regulated Metabolic Pathways in Adult Male Offspring. AB - Maternal obesity is a worldwide problem associated with increased risk of metabolic diseases in the offspring. Genetic deletion of the gastric inhibitory polypeptide (GIP) receptor (GIPR) prevents high-fat diet (HFD)-induced obesity in mice due to specific changes in energy and fat cell metabolism. We investigated whether GIP-associated pathways may be targeted by fetal programming and mimicked the situation by exposing pregnant mice to control or HFD during pregnancy (intrauterine [IU]) and lactation (L). Male wild-type (WT) and Gipr(-/-) offspring received control chow until 25 weeks of age followed by 20 weeks of HFD. Gipr(-/-) offspring of mice exposed to HFD during IU/L became insulin resistant and obese and exhibited increased adipose tissue inflammation and decreased peripheral tissue substrate utilization after being reintroduced to HFD, similar to WT mice on regular chow during IU/L. They showed decreased hypothalamic insulin sensitivity compared with Gipr(-/-) mice on control diet during IU/L. DNA methylation analysis revealed increased methylation of CpG dinucleotides and differential transcription factor binding of promoter regions of genes involved in lipid oxidation in the muscle of Gipr(-/-) offspring on HFD during IU/L, which were inversely correlated with gene expression levels. Our data identify GIP-regulated metabolic pathways that are targeted by fetal programming. PMID- 26631739 TI - Apelin Controls Fetal and Neonatal Glucose Homeostasis and Is Altered by Maternal Undernutrition. AB - The adequate control of glucose homeostasis during both gestation and early postnatal life is crucial for the development of the fetoplacental unit and adaptive physiological responses at birth. Growing evidences indicate that apelin and its receptor, APJ, which are expressed across a wide range of tissues, exert important roles in glucose homeostasis in adults. However, little is known about the function of the apelinergic system during gestation. In this study, we evaluated the activity of this system in rats, the role of apelin in fetal and neonatal glucose homeostasis, and its modulation by maternal food restriction. We found that 1) the apelinergic system was expressed at the fetoplacental interface and in numerous fetal tissues, 2) ex vivo, the placenta released high amounts of apelin in late gestation, 3) intravenous apelin injection in mothers increased the transplacental transport of glucose, and 4) intraperitoneal apelin administration in neonates increased glucose uptake in lung and muscle. Maternal food restriction drastically reduced apelinemia in both mothers and growth restricted fetuses and altered the expression of the apelinergic system at the fetoplacental interface. Together, our data demonstrate that apelin controls fetal and neonatal glucose homeostasis and is altered by fetal growth restriction induced by maternal undernutrition. PMID- 26631740 TI - Lack of Prox1 Downregulation Disrupts the Expansion and Maturation of Postnatal Murine beta-Cells. AB - Transcription factor expression fluctuates during beta-cell ontogeny, and disruptions in this pattern can affect the development or function of those cells. Here we uncovered that murine endocrine pancreatic progenitors express high levels of the homeodomain transcription factor Prox1, whereas both immature and mature beta-cells scarcely express this protein. We also investigated if sustained Prox1 expression is incompatible with beta-cell development or maintenance using transgenic mouse approaches. We discovered that Prox1 upregulation in mature beta-cells has no functional consequences; in contrast, Prox1 overexpression in immature beta-cells promotes acute fasting hyperglycemia. Using a combination of immunostaining and quantitative and comparative gene expression analyses, we determined that Prox1 upregulation reduces proliferation, impairs maturation, and enables apoptosis in postnatal beta-cells. Also, we uncovered substantial deficiency in beta-cells that overexpress Prox1 of the key regulator of beta-cell maturation MafA, several MafA downstream targets required for glucose-stimulated insulin secretion, and genes encoding important components of FGF signaling. Moreover, knocking down PROX1 in human EndoC-betaH1 beta-cells caused increased expression of many of these same gene products. These and other results in our study indicate that reducing the expression of Prox1 is beneficial for the expansion and maturation of postnatal beta-cells. PMID- 26631741 TI - Targeted Deep Sequencing in Multiple-Affected Sibships of European Ancestry Identifies Rare Deleterious Variants in PTPN22 That Confer Risk for Type 1 Diabetes. AB - Despite finding more than 40 risk loci for type 1 diabetes (T1D), the causative variants and genes remain largely unknown. Here, we sought to identify rare deleterious variants of moderate-to-large effects contributing to T1D. We deeply sequenced 301 protein-coding genes located in 49 previously reported T1D risk loci in 70 T1D cases of European ancestry. These cases were selected from putatively high-risk families that had three or more siblings diagnosed with T1D at early ages. A cluster of rare deleterious variants in PTPN22 was identified, including two novel frameshift mutations (ss538819444 and rs371865329) and two missense variants (rs74163663 and rs56048322). Genotyping in 3,609 T1D families showed that rs56048322 was significantly associated with T1D and that this association was independent of the T1D-associated common variant rs2476601. The risk allele at rs56048322 affects splicing of PTPN22, resulting in the production of two alternative PTPN22 transcripts and a novel isoform of LYP (the protein encoded by PTPN22). This isoform competes with the wild-type LYP for binding to CSK and results in hyporesponsiveness of CD4(+) T cells to antigen stimulation in T1D subjects. These findings demonstrate that in addition to common variants, rare deleterious variants in PTPN22 exist and can affect T1D risk. PMID- 26631742 TI - In Vitro-In Vivo Extrapolation Scaling Factors for Intestinal P-Glycoprotein and Breast Cancer Resistance Protein: Part I: A Cross-Laboratory Comparison of Transporter-Protein Abundances and Relative Expression Factors in Human Intestine and Caco-2 Cells. AB - Over the last 5 years the quantification of transporter-protein absolute abundances has dramatically increased in parallel to the expanded use of in vitro in vivo extrapolation (IVIVE) and physiologically based pharmacokinetics (PBPK) linked models, for decision-making in pharmaceutical company drug development pipelines and regulatory submissions. Although several research groups have developed laboratory-specific proteomic workflows, it is unclear if the large range of reported variability is founded on true interindividual variability or experimental variability resulting from sample preparation or the proteomic methodology used. To assess the potential for methodological bias on end-point abundance quantification, two independent laboratories, the University of Manchester (UoM) and Bertin Pharma (BPh), employing different proteomic workflows, quantified the absolute abundances of Na/K-ATPase, P-gp, and breast cancer resistance protein (BCRP) in the same set of biologic samples from human intestinal and Caco-2 cell membranes. Across all samples, P-gp abundances were significantly correlated (P = 0.04, Rs = 0.72) with a 2.4-fold higher abundance (P = 0.001) generated at UoM compared with BPh. There was a systematically higher BCRP abundance in Caco-2 cell samples quantified by BPh compared with UoM, but not in human intestinal samples. Consequently, a similar intestinal relative expression factor (REF), derived from distal jejunum and Caco-2 monolayer samples, between laboratories was found for P-gp. However, a 2-fold higher intestinal REF was generated by UoM (2.22) versus BPh (1.11). We demonstrate that differences in absolute protein abundance are evident between laboratories and they probably result from laboratory-specific methodologies relating to peptide choice. PMID- 26631743 TI - How MutS finds a needle in a haystack. PMID- 26631737 TI - Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes. AB - Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 * 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 * 10(-7)) and 13% for RAB38/CTSC (P = 5.8 * 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria. PMID- 26631745 TI - Markets for replication. PMID- 26631744 TI - Conserved factor Dhp1/Rat1/Xrn2 triggers premature transcription termination and nucleates heterochromatin to promote gene silencing. AB - Cotranscriptional RNA processing and surveillance factors mediate heterochromatin formation in diverse eukaryotes. In fission yeast, RNAi machinery and RNA elimination factors including the Mtl1-Red1 core and the exosome are involved in facultative heterochromatin assembly; however, the exact mechanisms remain unclear. Here we show that RNA elimination factors cooperate with the conserved exoribonuclease Dhp1/Rat1/Xrn2, which couples pre-mRNA 3'-end processing to transcription termination, to promote premature termination and facultative heterochromatin formation at meiotic genes. We also find that Dhp1 is critical for RNAi-mediated heterochromatin assembly at retroelements and regulated gene loci and facilitates the formation of constitutive heterochromatin at centromeric and mating-type loci. Remarkably, our results reveal that Dhp1 interacts with the Clr4/Suv39h methyltransferase complex and acts directly to nucleate heterochromatin. Our work uncovers a previously unidentified role for 3'-end processing and transcription termination machinery in gene silencing through premature termination and suggests that noncanonical transcription termination by Dhp1 and RNA elimination factors is linked to heterochromatin assembly. These findings have important implications for understanding silencing mechanisms targeting genes and repeat elements in higher eukaryotes. PMID- 26631746 TI - Peptidic degron in EID1 is recognized by an SCF E3 ligase complex containing the orphan F-box protein FBXO21. AB - EP300-interacting inhibitor of differentiation 1 (EID1) belongs to a protein family implicated in the control of transcription, differentiation, DNA repair, and chromosomal maintenance. EID1 has a very short half-life, especially in G0 cells. We discovered that EID1 contains a peptidic, modular degron that is necessary and sufficient for its polyubiquitylation and proteasomal degradation. We found that this degron is recognized by an Skp1, Cullin, and F-box (SCF) containing ubiquitin ligase complex that uses the F-box Only Protein 21 (FBXO21) as its substrate recognition subunit. SCF(FBXO21) polyubiquitylates EID1 both in vitro and in vivo and is required for the efficient degradation of EID1 in both cycling and quiescent cells. The EID1 degron partially overlaps with its retinoblastoma tumor suppressor protein-binding domain and is congruent with a previously defined melanoma-associated antigen-binding motif shared by EID family members, suggesting that binding to retinoblastoma tumor suppressor and melanoma associated antigen family proteins could affect the polyubiquitylation and turnover of EID family members in cells. PMID- 26631747 TI - Intensity matters: Ryanodine receptor regulation during exercise. PMID- 26631748 TI - Design of a single protein that spans the entire 2-V range of physiological redox potentials. AB - The reduction potential (E degrees ') is a critical parameter in determining the efficiency of most biological and chemical reactions. Biology employs three classes of metalloproteins to cover the majority of the 2-V range of physiological E degrees 's. An ultimate test of our understanding of E degrees ' is to find out the minimal number of proteins and their variants that can cover this entire range and the structural features responsible for the extreme E degrees '. We report herein the design of the protein azurin to cover a range from +970 mV to -954 mV vs. standard hydrogen electrode (SHE) by mutating only five residues and using two metal ions. Spectroscopic methods have revealed geometric parameters important for the high E degrees '. The knowledge gained and the resulting water-soluble redox agents with predictable E degrees 's, in the same scaffold with the same surface properties, will find wide applications in chemical, biochemical, biophysical, and biotechnological fields. PMID- 26631749 TI - Coordinated regulation of vegetative and reproductive branching in rice. AB - Grasses produce tiller and panicle branching at vegetative and reproductive stages; the branching patterns largely define the diversity of grasses and constitute a major determinant for grain yield of many cereals. Here we show that a spatiotemporally coordinated gene network consisting of the MicroRNA 156 (miR156/)miR529/SQUAMOSA PROMOTER BINDING PROTEIN LIKE (SPL) and miR172/APETALA2 (AP2) pathways regulates tiller and panicle branching in rice. SPL genes negatively control tillering, but positively regulate inflorescence meristem and spikelet transition. Underproduction or overproduction of SPLs reduces panicle branching, but by distinct mechanisms: miR156 and miR529 fine-tune the SPL levels for optimal panicle size. miR172 regulates spikelet transition by targeting AP2 like genes, which does not affect tillering, and the AP2-like proteins play the roles by interacting with TOPLESS-related proteins (TPRs). SPLs modulate panicle branching by directly regulating the miR172/AP2 and PANICLE PHYTOMER2 (PAP2)/Rice TFL1/CEN homolog 1 (RCN1) pathways and also by integrating other regulators, most of which are not involved in tillering regulation. These findings may also have significant implications for understanding branching regulation of other grasses and for application in rice genetic improvement. PMID- 26631750 TI - Structural and functional analysis of two di-domain aromatase/cyclases from type II polyketide synthases. AB - Aromatic polyketides make up a large class of natural products with diverse bioactivity. During biosynthesis, linear poly-beta-ketone intermediates are regiospecifically cyclized, yielding molecules with defined cyclization patterns that are crucial for polyketide bioactivity. The aromatase/cyclases (ARO/CYCs) are responsible for regiospecific cyclization of bacterial polyketides. The two most common cyclization patterns are C7-C12 and C9-C14 cyclizations. We have previously characterized three monodomain ARO/CYCs: ZhuI, TcmN, and WhiE. The last remaining uncharacterized class of ARO/CYCs is the di-domain ARO/CYCs, which catalyze C7-C12 cyclization and/or aromatization. Di-domain ARO/CYCs can further be separated into two subclasses: "nonreducing" ARO/CYCs, which act on nonreduced poly-beta-ketones, and "reducing" ARO/CYCs, which act on cyclized C9 reduced poly beta-ketones. For years, the functional role of each domain in cyclization and aromatization for di-domain ARO/CYCs has remained a mystery. Here we present what is to our knowledge the first structural and functional analysis, along with an in-depth comparison, of the nonreducing (StfQ) and reducing (BexL) di-domain ARO/CYCs. This work completes the structural and functional characterization of mono- and di-domain ARO/CYCs in bacterial type II polyketide synthases and lays the groundwork for engineered biosynthesis of new bioactive polyketides. PMID- 26631751 TI - Outcome of Second Allogeneic Hematopoietic Cell Transplantation after Relapse of Myeloid Malignancies following Allogeneic Hematopoietic Cell Transplantation: A Retrospective Cohort on Behalf of the Grupo Espanol de Trasplante Hematopoyetico. AB - Allogeneic stem cell transplantation (allo-HCT) represents the most effective immunotherapy for acute myeloid leukemia (AML) and myeloid malignancies. However, disease relapse remains the most common cause of treatment failure. By performing a second allo-HCT, durable remission can be achieved in some patients. However, a second allo-HCT is of no benefit for the majority of patients, so this approach requires further understanding. We present a retrospective cohort of 116 patients diagnosed with AML, myelodysplastic syndromes, and myeloproliferative disorders who consecutively underwent a second allo-HCT for disease relapse. The median age was 38 years (range, 4 to 69 years). Sixty-three patients were alive at last follow-up. The median follow-up of the whole cohort was 193 days (range, 2 to 6724 days) and the median follow-up of survivors was 1628 days (range, 52 to 5518 days). Overall survival (OS) at 5 years was 32% (SE +/- 4.7%). Multivariate analysis identified active disease status (P < .001) and second allo-HCT < 430 days (the median of the time to second transplantation) after the first transplantation (P < .001) as factors for poor prognosis, whereas the use of an HLA-identical sibling donor for the second allo-HCT was identified as a good prognostic factor (P < .05) for OS. The use of myeloablative conditioning (P = .01), active disease (P = .02), and a donor other than an HLA-identical sibling (others versus HLA-identical siblings) (P = .009) were factors statistically significant for nonrelapse mortality in multivariate analysis. Time to second transplantation was statistically significant (P = .001) in the relapse multivariate analysis, whereas multivariate analysis identified active disease status (P < .001) and time to second transplantation (P < .001) as poor prognosis factors for disease-free survival. This study confirms active disease and early relapse as dismal prognostic factors for a second allo-HCT. Using a different donor at second allo-HCT did not appear to change outcome, but using an HLA identical sibling donor for a second transplantation appears to be associated with better survival. Further studies are warranted. PMID- 26631753 TI - Phylogenetic analysis of nasal avian schistosomes (Trichobilharzia) from aquatic birds in Mazandaran Province, northern Iran. AB - Nasal schistosomes are trematodes in the family Schistosomatidae, many members of which are causative agents of human cercarial dermatitis (HCD). Little is known about the species diversity and distribution of nasal dwelling schistosomes of water birds, particularly in countries outside of Europe; even less is known in countries like Iran. Nasal schistosomes are of particular interest since these species migrate via the central nervous system to the nasal cavity once they penetrate their host. Thus, there must be efforts to determine the incidence of HCD due to nasal schistosomes. HCD outbreaks are reported seasonally in Mazandaran Province, northern Iran, an area well known for rice cultivation leading to increased person contact with water and infected snails. Such places include favorable habitat for both domestic ducks year round, and wild migratory ducks in the winter through spring. Recent reports have detected the presence of both nasal and visceral schistosomes in ducks in this area but with little species characterization. In this study, we examine a diversity of aquatic birds to determine the distribution, prevalence and bird host use of nasal schistosomes. We apply for the first time a molecular identification and phylogenetic analysis of these schistosomes. From 2012 to 2014, the nasal cavity of 508 aquatic birds from Mazandaran Province were examined that included species in Anseriformes, Gruiformes, Charadriiformes and Phoenicopteriformes. Nasal schistosomes were found in 45 (8.9%) birds belonging to Anseriformes (Anas platyrhynchos and Anas clypeata). Phylogenetic analysis of the nuclear internal transcribed spacer 1 rDNA and the mitochondrial cytochrome oxidase1 gene of isolated eggs revealed that all samples grouped in a sister clade to the European Trichobilharzia regenti. However, Trichobilharzia from this study were more similar to a unique haplotype of Trichobilharzia, isolated from the nasals of an A. clypeata in France. The genetic and phenotypic differences between the species found herein and T. regenti from Europe, may prove with additional data to be a distinct species of Trichobilharzia. PMID- 26631752 TI - BH4 domain of Bcl-2 as a novel target for cancer therapy. AB - Overexpression of B cell lymphoma 2 (Bcl-2) proteins is associated with therapy resistance in various human cancers. Traditional approaches target the Bcl-2 homology (BH)3 domain of Bcl-2; however, the BH4 domain represents a superior therapeutic target in light of its unique structure and crucial involvement in many cellular functions. In this critical review, we focus on the structural and functional basis of targeting the BH4 domain of Bcl-2, and highlight the recent advances in drug discovery efforts toward small-molecule BH4 domain inhibitors (e.g. BDA-366). The proof-of-concept studies support the hypothesis that targeting the BH4 domain of Bcl-2 holds promise to offer a novel anticancer therapy through the induction of apoptosis and an increased potential to overcome therapeutic resistance. PMID- 26631754 TI - Infection rate and genetic diversity of Giardia duodenalis in pet and stray dogs in Henan Province, China. AB - Giardia duodenalis is an important protozoan parasite that is known to be zoonotic. To assess the potential zoonotic transmission of giardiasis from dogs and to identify genetic diversity of G. duodenalis in dog populations, we examined the infection rate and genotypes of G. duodenalis in both pet dogs (from pet dog farms, pet shops, pet hospitals, pet markets) and stray dogs of different ages in Henan Province, China. A total of 940 fresh fecal specimens were collected from 2007 to 2013 in Henan Province. The overall infection rate of G. duodenalis was 14.3% (134/940) as determined by microscopy, with the highest infection rate (17.3%) observed in dogs from shelters. Young dogs were more likely to be infected with G. duodenalis than adult dogs, and G. duodenalis cysts were found more frequently in diarrheic dogs. All G. duodenalis-positive isolates were characterized at the triose phosphate isomerase (tpi), glutamate dehydrogenase (gdh), and beta-giardin (bg) loci, and 37, 51, and 48 sequences were obtained, respectively. The dog-specific assemblages C and D were identified using multi-locus sequence analysis. Six novel sequences of the tpi locus, one novel sequence of the gdh locus and two novel sequences of the bg locus were detected among the G. duodenalis assemblage C isolates, while two novel sequences of the gdh locus were found among the G. duodenalis assemblage D isolates. Our data indicate that G. duodenalis is a common parasite and cause of diarrheal disease in dogs in Henan Province. However, there was no evidence for zoonotic G. duodenalis assemblages in the study population. PMID- 26631755 TI - The interaction of MMP-2/B7-H3 in human osteoporosis. AB - The immune costimulatory molecule B7-H3 has been shown to be involved in the regulation of murine bone formation. However, the role of B7-H3 in bone metabolic diseases remains unknown. In our study, matrix metalloproteinase 2 (MMP-2) and soluble B7-H3 (sB7-H3) were found to be correlatively up-regulated in the sera of osteoporosis patients. Furthermore, our results showed that MG63 cells treated with MMP-2 inhibitors produced lower amounts of sB7-H3 while cells with recombinant MMP-2 had an increased membrane B7-H3 (mB7-H3) shedding. Therefore, elevated MMP-2 levels resulted in an elevation of serum sB7-H3 and reduction of osteoblastic mB7-H3. B7-H3 knockdown in MG63 cells significantly decreased osteoblastic markers and substantially decreased the number of mineralized nodules after 21days. Thus, B7-H3-deficient MG63 cells exhibited impaired bone formation. These results suggest that mB7-H3 is required for the later phases of osteoblast differentiation and that MMP-2/B7-H3 plays a negative regulatory role in osteoporosis. PMID- 26631756 TI - MicroRNA-21 deficiency protects from lupus-like autoimmunity in the chronic graft versus-host disease model of systemic lupus erythematosus. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression primarily at the post-transcriptional level. Emerging evidence supports a regulatory role for miRNAs in the immune response and autoimmunity. In this work, we investigated the implication of miR-21 in the experimentally inducible bm12 >B6 cGVHD model of systemic lupus erythematosus (SLE). cGVHD host mice deficient in miR-21 show a 2-fold reduction in splenomegaly, significantly reduced autoantibody titers and down-regulated components of the CD40:CD40L and CD28:CD80/86 co-stimulation pathways. Furthermore, we demonstrate that miR-21 deficient hosts have reduced CD4(+) IL-17(+) cell populations and an expanded CD4(+) CD25(+) FoxP3(+) cell compartment. We propose that miR-21 has a pluripotent role, serving to link distinct lymphocyte signaling pathways and acting as a "rheostat" for signals that promote B and T cell activation in lupus. Collectively, our experiments demonstrate that miR-21 deficiency in cGVHD host mice is sufficient to protect from lupus-like autoimmunity. PMID- 26631757 TI - Isolation, characterization and HPLC quantification of compounds from Aquilegia fragrans Benth: Their in vitro antibacterial activities against bovine mastitis pathogens. AB - ETHNO-PHARMACOLOGICAL RELEVANCE: The underground parts of Aquilegia fragrans are traditionally used for the treatment of wounds and various inflammatory diseases like bovine mastitis. However, there are no reports on the phytochemical characterization and antibacterial studies of A. fragrans. AIM OF THE STUDY: To isolate compounds from the methanol extract of the underground parts of A. fragrans and determine their antibacterial activity against the pathogens of bovine mastitis. The study was undertaken in order to scientifically validate the traditional use of A. fragrans. MATERIALS AND METHODS: Five compounds were isolated from the methanol extract of the underground parts of A. fragrans using silica gel column chromatography. Structural elucidation of the isolated compounds was done using spectral data analysis and comparison with literature. High performance liquid chromatography (HPLC) was used for the qualitative and quantitative determination of isolated compounds in the crude methanol extract. The methanol extract and isolated compounds were evaluated for antibacterial activities against mastitis pathogens using broth micro-dilution technique. RESULTS: The five isolated compounds were identified as (1) 2, 4 dihydroxyphenylacetic acid methyl ester (2) beta-sitosterol (3) Aquilegiolide (4) Glochidionolactone-A and (5) Magnoflorine. A quick and sensitive HPLC method was developed for the first time for qualitative and quantitative determination of four isolated marker compounds from A. fragrans. The crude methanol extract and compound 5 exhibited weak antibacterial activities that varied between the bacterial species (MIC=500-3000 ug/ml). CONCLUSIONS: The above results show that the crude methanol extract and isolated compounds from A. fragrans exhibit weak antibacterial activities. Further phytochemical and pharmacological studies are required for proper scientific validation of the folk use of this plant species in the treatment of various inflammatory diseases like bovine mastitis. PMID- 26631758 TI - Power, policy and the Prunus africana bark trade, 1972-2015. AB - ETHNOPHARMACOLOGICAL RELEVANCE: After almost 50 years of international trade in wild harvested medicinal bark from Africa and Madagascar, the example of Prunus africana holds several lessons for both policy and practice in the fields of forestry, conservation and rural development. Due to recent CITES restrictions on P. africana exports from Burundi, Kenya and Madagascar, coupled with the lifting of the 2007 European Union (EU) ban in 2011, Cameroon's share of the global P. africana bark trade has risen from an average of 38% between 1995 and 2004, to 72.6% (658.6 metric tons) in 2012. Cameroon is therefore at the center of this international policy arena. METHODS AND MATERIALS: This paper draws upon several approaches, combining knowledge in working with P. africana over a 30-year period with a thorough literature review and updated trade data with "ground-truthing" in the field in 2013 and 2014. This enabled the construction of a good perspective on trade volumes (1991-2012), bark prices (and value-chain data) and the gaps between research reports and practice. Two approaches provided excellent lenses for a deeper understanding of policy failure and the "knowing-doing gap" in the P. africana case. A similar approach to Medard's (1992) analyses of power, politics and African development was taken and secondly, studies of commodity chains that assess the power relations that coalesce around different commodities (Ribot, 1998; Ribot and Peluso, 2003). RESULTS: Despite the need to conserve genetically and chemically diverse P. africana, wild populations are vulnerable, even in several "protected areas" in Burundi, Cameroon, the Democratic Republic of Congo and in the forest reserves of Madagascar. Secondly, hopes of decentralized governance of this forest product are misplaced due to elite capture, market monopolies and subsidized management regimes. At the current European price, for P. africana bark (US$6 per kg) for example, the 2012 bark quota (658.675t) from Cameroon alone was worth over US$3.9 million, with the majority of this accruing to a single company. In contrast to lucrative bark exports, the livelihood benefits and financial returns to local harvesters from wild harvest are extremely low. For example, in 2012, the 48 active harvesters working within Mount Cameroon National Park (MCNP) received less than 1US$ per day from bark harvests, due to a net bark price of 0.33 US$ per kg (or 43% of the farm gate price for wild harvested bark). In addition, the costs of inventory, monitoring and managing sustainable wild harvests are far greater than the benefits to harvesters. CONCLUSION: Without the current substantial international donor subsidies, sustainable harvest cannot be sustained. What is required to supply the current and future market is to develop separate, traceable P. africana bark supply chains based on cultivated stocks. On-farm production would benefit thousands of small-scale farmers cultivating P. africana, including local women, for whom wild harvesting is too onerous. This change requires CITES and EU support and would catalyze P. africana cultivation in across several montane African countries and Madagascar, increasing farm-gate prices to harvesters compared to economic returns from wild harvest. PMID- 26631760 TI - Idiopathic ligamentum flavum hematoma. PMID- 26631759 TI - Which interventions are cost-effective for the management of whiplash-associated and neck pain-associated disorders? A systematic review of the health economic literature by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. AB - BACKGROUND CONTEXT: Whiplash-associated disorders (WAD) and neck pain and associated disorders (NAD) are prevalent conditions that impact society and impose a significant economic burden on health-care systems. Health economic evidence on WAD and NAD interventions has been sparse: only three economic evaluations of interventions for NAD were identified by the Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders (NPTF). An updated overview is needed to inform health-care policy and guidelines. PURPOSE: This study aimed to determine the cost-effectiveness of interventions for grades I-III WAD and NAD in children and adults. STUDY DESIGN: Systematic review of health economic literature, best-evidence synthesis. METHODS: We systematically searched CINAHL, the Cochrane economic databases (Health Technology Assessment, NHS Economic Evaluation Database), EconLit, EMBASE, MEDLINE, PsycINFO, and Tufts CEA Registry from 2000 to 2015 for economic evaluations of WAD and NAD interventions. We appraised relevant evaluations using the Scottish Intercollegiate Guidelines Network Methodology Criteria for Economic Evaluations. We extracted data, including mean costs (standardized to 2013 Canadian dollars [CAD]) and quality adjusted life years (QALYs), from studies with adequate methodological quality. We recalculated cost-effectiveness statistics based on the standardized currency using a willingness-to-pay of CAD $50,000 per additional QALY. Funding was provided by the Ministry of Finance. RESULTS: Our search identified 1,616 citations. Six studies fulfilled our selection criteria, including three studies previously reviewed by the NPTF. Structured education appears cost-effective for adults with WAD. For adults with NAD, acupuncture added to routine medical care; manual therapy; multimodal care that includes manual therapy; advice and exercise; and psychological care using cognitive-behavioral therapy appear cost effective. In contrast, adding manual therapy or diathermy to advice and exercise; multimodal care by a physiotherapist or physician; and behavioral graded activity do not appear cost-effective for adults with NAD. CONCLUSIONS: Our review adds to the findings of the NPTF. Recent evidence suggests that structured education is cost-effective for WAD, whereas advice and exercise and multimodal care that include manual therapy are cost-effective for NAD. Obtaining more robust health economic evidence for non-invasive interventions for WAD and NAD in children and adults remains an essential research priority. PMID- 26631761 TI - Temporal lobe in human aging: A quantitative protein profiling study of samples from Chinese Human Brain Bank. AB - The temporal lobe is a portion of the cerebral cortex with critical functionality. The age-related protein profile changes in the human temporal lobe have not been previously studied. This 4-plex tandem mass tag labeled proteomic study was performed on samples of temporal lobe from Chinese donors. Tissue samples were assigned to four age groups: Group A (the young, age: 34+/-13 years); Group B (the elderly, 62+/-5 years); Group C (the aged, 84+/-4 years) and Group D (the old, 95+/-1 years). Pooled samples from the different groups were subjected to proteomics and bioinformatics analysis to identify age-related changes in protein expression and associated pathways. We isolated 5072 proteins, and found that 67 proteins were downregulated and 109 proteins were upregulated in one or more groups during the aging process. Western blotting assays were performed to verify the proteomic results. Bioinformatic analysis identified proteins involved in neuronal degeneration, including proteins involved in neuronal firing, myelin sheath damage, and cell structure stability. We also observed the accumulation of extracellular matrix and lysosomal proteins which imply the occurrence of fibrosis and autophagy. Our results suggest a series of changes across a wide range of proteins in the human temporal lobe that may relate to aging and age-related neurodegenerative disorders. PMID- 26631762 TI - Query-oriented evidence extraction to support evidence-based medicine practice. AB - BACKGROUND: Evidence-based medicine practice requires medical practitioners to rely on the best available evidence, in addition to their expertise, when making clinical decisions. The medical domain boasts a large amount of published medical research data, indexed in various medical databases such as MEDLINE. As the size of this data grows, practitioners increasingly face the problem of information overload, and past research has established the time-associated obstacles faced by evidence-based medicine practitioners. In this paper, we focus on the problem of automatic text summarisation to help practitioners quickly find query-focused information from relevant documents. METHODS: We utilise an annotated corpus that is specialised for the task of evidence-based summarisation of text. In contrast to past summarisation approaches, which mostly rely on surface level features to identify salient pieces of texts that form the summaries, our approach focuses on the use of corpus-based statistics, and domain-specific lexical knowledge for the identification of summary contents. We also apply a target-sentence-specific summarisation technique that reduces the problem of underfitting that persists in generic summarisation models. RESULTS: In automatic evaluations run over a large number of annotated summaries, our extractive summarisation technique statistically outperforms various baseline and benchmark summarisation models with a percentile rank of 96.8%. A manual evaluation shows that our extractive summarisation approach is capable of selecting content with high recall and precision, and may thus be used to generate bottom-line answers to practitioners' queries. CONCLUSIONS: Our research shows that the incorporation of specialised data and domain-specific knowledge can significantly improve text summarisation performance in the medical domain. Due to the vast amounts of medical text available, and the high growth of this form of data, we suspect that such summarisation techniques will address the time-related obstacles associated with evidence-based medicine. PMID- 26631763 TI - Malleus to Stapes Bone Cement Rebridging Ossiculoplasty: Why Don't We Perform Frequently? AB - OBJECTIVE: To evaluate the effectiveness of malleus to stapes bone cement rebridging (MS-BCR) for Austin Kartush group A ossicular defects and compare the audiological results with incus interposition (IP) and incus to stapes bone cement rebridging (IS-BCR). METHODS: Patients for whom type 2 tympanoplasty had been performed in a tertiary referral center were examined. Revision cases and those with graft failure were excluded. Three treatment groups were IS-BCR, IP, and MS-BCR. Preoperative and postoperative audiological results were compared. RESULTS: A total of 92 patients were enrolled. The IS-BCR was performed in 42 (45.65%), IP in 18 (19.56%), and MS-BCR in 32 (34.78%) patients. Postoperative mean air bone gap was 20.1 +/- 9.8 dB HL and did not differ significantly between the groups (P = .271). Postoperative mean air bone gap less than 20 dB HL was achieved in 23 (54.7%) patients in IS-BCR, 10 (55.5%) patients in IP group, and 24 (75%) patients in MS-BCR group (P = .06). Mean closure in air bone gap was 14.0 +/- 11.6 dB HL. The changes in mean and frequency-specific air bone gap were not significantly different between treatment groups (P > .05). CONCLUSION: Malleus to stapes bone cement rebridging may provide hearing results comparable to IS-BCR and IP. PMID- 26631764 TI - Revisiting Place-Pitch Match in CI Recipients Using 3D Imaging Analysis. AB - OBJECTIVE: To improve the estimation of the perceived pitch in a single-sided deaf cochlear implant (CI) listener by using accurate 3-dimensional (3D) image analysis of the cochlear electrode positions together with the predicted tonotopical function for humans. METHODS: An SSD CI user underwent a Cone-Beam computed tomography (CBCT) scan. Electrode contacts were marked in 3D space in relation to the nearest point on the cochlear lateral wall. Distance to the base of the lateral wall was calculated and plotted against the place-pitch function for humans. An adaptive procedure was used to elicit the perceived pitch of electrically evoked stimulation by matching it with a contralateral acoustic pitch. RESULTS: The electrically evoked pitch percept matched well with the calculated frequency. The median mismatch in octaves was 0.12 for our method in comparison to 0.69 using the conventional Stenvers view. CONCLUSION: A method of improved image analysis is described that can be used to predict the pitch percept on corresponding cochlear electrode positions. This method shows the potential of 3D imaging in CI fitting optimization. PMID- 26631765 TI - Response to Letter to the Editor by Bakshi et al. PMID- 26631766 TI - Powering point-of-care diagnostic devices. AB - Effective and rapid point-of-care (POC) diagnostics have the capability to revolutionize public healthcare both in developed and developing countries. One of the key challenges that is critical to address in developing POC devices is to effectively and sufficiently power them. In developing countries, where the electricity grid is not well established and the use of batteries is not cost effective, power supplies are the most problematic issue for stand-alone and self sustained POC devices. In this review, we provide an overview of techniques for powering POC diagnostic devices for use in both developed and developing countries, as well as detailed discussions of recent advancements in POC devices. Then, we discuss next-generation POC diagnostics and their power source strategies. PMID- 26631767 TI - Human Reconstituted Nasal Epithelium, a promising in vitro model to assess impacts of environmental complex mixtures. AB - Considering the impact of respiratory diseases around the world, appropriate experimental tools to help understand the mechanisms involved in such diseases are becoming essential. Our aim was to investigate the cellular and morphological reactivity of a human Reconstituted Nasal Epithelium (hRNE) to evaluate the impact of environmental complex mixture (ECM), with tobacco smoke as a model, after three weeks of repeated exposures. Staining of hRNE showed a multilayered ciliated epithelium, with a regular cilia beats, and a mucus production. When hRNE was exposed to ECM for 5 min once or twice a week, during 3 weeks, significant changes occurred: IL-8 production significantly increased 24h after the first exposure compared with Air-exposure and only during the first week, without any loss of tissue integrity. Immunostaining of F-actin cytoskeleton showed a modification in cellular morphology (number and diameter). Taken together our results indicate that hRNE is well suited to study the cellular and morphological effects of repeated exposures to an environmental complex mixture. Human reconstituted epithelium models are currently the best in vitro representation of human respiratory tract physiology, and also the most robust for performing repeated exposures to atmospheric pollutants. PMID- 26631768 TI - Robotic Versus Laparoscopic Radical Trachelectomy for Early-Stage Cervical Cancer: Case Report and Review of Literature. AB - We conducted a literature review to evaluate the minimally invasive fertility sparing procedures, namely robotic radical trachelectomy (RRT) and laparoscopic radical trachelectomy (LRT), in patients with early-stage cervical cancer. We searched PubMed, MEDLINE, Ovid, Google Scholar, and Scopus up to July 2015 using the following key words and their combinations: cervical cancer, early stage, fertility-sparing surgery, radical trachelectomy, robotic trachelectomy, and laparoscopic trachelectomy. Papers providing details of RRT and LRT separately were included. Extracted papers and their bibliographies were reviewed according to the purpose of the study, and demographic, surgical, and clinical parameters were analyzed. Our review comprised 45 cases of RRT and 216 cases (including our case) of LRT. The median (range) patient age was 29 (9) years in the RRT group and 32 (10) years in the LRT group (p < .001). Histological types and stages were significantly different in the 2 groups (p < .001 for both). The median length of excised parametrial tissue was significantly higher in the RRT group (p < .001). The hysterectomy conversion rate on the results of frozen section examination was significantly higher in the RRT group (37% vs 6.5%; p < .001). There was a significant difference in median lymph node count based on the surgical approach (RRT: 22 [range, 21] vs LRT: 32 [range, 14]; p = .02). Estimated blood loss and length of hospital stay were significantly higher in the LRT group (both p < .001). The mean (range) operative time was 308 (188) minutes in the RRT group and 296 (143) minutes in the LRT group (p < .001). Pregnancy, preterm, and term birth rates were similar in the 2 groups (RRT: 18.5%, 7.4%, and 0, respectively; LRT: 29%, 8%, and 8%, respectively). Thirteen women experienced recurrent cervical cancer in the LRT group, and no recurrence was seen in the RRT group. The median (range) duration of follow-up was 8 (7.5) months in the RRT group and 34 (20) months in the LRT group (p < .001). Based on the reported data, LRT seems comparable to RRT for treating patients with early-stage cervical cancer who wish to preserve fertility. PMID- 26631769 TI - A 13-Year Retrospective Study of Basal Cell Carcinoma in a Canadian Dermatology Practice: A Comparison Between Anatomical Location and Histopathologic Subtypes. AB - BACKGROUND: It is unknown whether the histologic subtypes of basal cell carcinoma (BCC) arise from a common progenitor cell or whether other factors play a role in their development. OBJECTIVE: To investigate the relationship between the different BCC histopathologic subtypes and anatomical distribution of BCCs in a Canadian dermatology practice. METHODS: The charts of all patients diagnosed with BCC between 1993 and 2005 from a single private dermatology practice in Vancouver, Canada, were reviewed. Descriptive data analysis was undertaken to look at the distribution of histologic subtypes based on age, gender, and anatomical location. RESULTS: Nodular BCCs accounted for 58% of all tumors. Sixty six percent of these were situated on the head/neck (odds ratio [OR] = 3.0, 95% confidence interval [CI] = 2.1-4.3, P < .0001). Infiltrative (OR = 2.4, 95% CI = 1.5-4.1, P = .0003) and superficial BCCs were more common in women (OR = 3.7, 95% CI = 2.5-5.7, P < .0001), affected the trunk (OR = 3.2, 95% CI = 2.1-4.9, P < .0001), and appeared in younger individuals (OR = 1.8, 95% CI = 1.2-2.7, P = .004). CONCLUSION: Our results show a preference of distinct BCC subtypes for certain anatomical locations. PMID- 26631770 TI - Chronic False Aneurysm after a Healed Rupture of the Aortic Isthmus: TEVAR, Hybrid Surgery, or Open Arch Repair? AB - We report a case of post-traumatic chronic false aneurysm of the aortic isthmus in a 34-year-old man who had been involved in a car accident 10 years earlier. An initial chest X-ray demonstrated a calcified mass in the upper mediastinum and computed tomography scan revealed a false aneurysm of the aortic isthmus arising above the left subclavian artery. Partial covered rupture of the aorta is not always easy to diagnose and can remain clinically silent in a polytrauma patient. The duration from rupture to false aneurysm formation may extend over many years. This chronic lesion can be managed by surgery, by an endovascular procedure, or by a combined procedure. This case report highlights the current therapeutic approach. A debranching procedure was done in view of a secondary exclusion of the huge false aneurysm by a stent graft. Unfortunately, the false aneurysm ruptured during the procedure and a replacement of the aortic arch and the isthmus under total circulatory arrest was successfully done. The patient was doing well at 9-month follow-up. PMID- 26631771 TI - Endovascular Reconstruction of Aortoiliac Occlusive Disease with an Aberrant Pelvic Kidney. AB - Aortoiliac occlusive disease coincident with a congenital ectopic pelvic kidney is a rare occurrence. Traditionally, the treatment has been open aortobifemoral repair with reimplantation of the renal artery. We present a patient with Trans Atlantic Inter-Society Consensus (TASC) D bilateral aortoiliac occlusive disease, an ectopic pelvic kidney, and prohibitive medical comorbidities. We describe a totally endovascular repair using a chronic total occlusion crossing device, a luminal re-entry device, and balloon-mounted covered stents to revascularize the lower extremities and the ectopic pelvic kidney. We discuss various aspects of this endovascular approach as the incidence of patients with TASC D lesions and prohibitive comorbidities continue to rise. PMID- 26631772 TI - Morphology of Small Abdominal Aortic Aneurysms Should be Considered before Continued Ultrasound Surveillance. AB - BACKGROUND: To evaluate abdominal aortic aneurysm (AAA) morphology in a cohort of patients presenting with ruptured AAA (rAAA) and to explore if aneurysms with diameters below the recommended threshold for elective repair (<55 mm) have some distinctive morphological characteristics. METHODS: All patients diagnosed with rAAA using computed tomography (CT) scans between January 2006 and June 2013 were eligible for this study. Where CT scans of acceptable quality were available, images were reconstructed in a dedicated three-dimensional vascular workstation for evaluation of aneurysm diameters and morphology. All morphological characteristics were defined according to the reporting standards for endovascular aortic aneurysm repair. Additionally, fusiform AAAs were defined as aneurysms involving the whole circumference of the aortic wall and saccular AAAs as spherical aneurysms involving only a portion of the aortic circumference. RESULTS: A total of 248 patients were identified. Of those, 83% (n = 206) had high-quality CT scans available and were included in the study. Patients were on average 75 years old and 85% were men. Mean aneurysm diameter was 76 +/- 14 mm and 95% (n = 197) had fusiform morphology. Six percent (n = 12) were <55 mm and those included all saccular aneurysms in women (n = 3) and 22% of saccular aneurysms in men (n = 2). The remaining saccular aneurysms (n = 4) were small with a maximal diameter of 56 mm. Aneurysms <55 mm had less angulated proximal necks than their larger counterparts (P < 0.01). No other morphological differences were found between the groups. CONCLUSIONS: Ruptured aneurysms are often large and the >=55 mm threshold for elective repair is probably appropriate. However, approximately 6% of rAAAs are <55 mm, with a significant portion being saccular, especially in women. Morphological assessment of AAAs with CT scans should be considered in small aneurysms (40-55 mm), particularly in women, to exclude saccular morphology before continued ultrasound surveillance. PMID- 26631773 TI - Randomized Study of Noninferiority Comparing Prosthetic and Autologous Vein Above Knee Femoropopliteal Bypasses. AB - BACKGROUND: The main aim of this study was to compare the 5 years rates of secondary patency of above-knee femoropopliteal revascularizations with autologous veins or prosthetic grafts. The secondary objectives were to compare the rates of primary patency, limb salvage, morbidity, and mortality between the 2 groups. METHODS: This was a single-blind randomized study of noninferiority (ratio 1:1), carried out in 11 centers of vascular surgery with 2 parallel groups between July 2002 and November 2005. Follow-up finished in May 2011. The monitoring protocol included a clinical examination and an ultrasound control at 1 month, 3 and 6 months, then annually. RESULTS: One hundred patients were included and randomized in the study, 52 in the prosthetic group and 48 in the autologous vein group. Four patients randomized in the vein group received a prosthetic graft. No patient was excluded from the analysis. In the in intent-to treat analysis, the 5 years secondary patency was 84.6% in the prosthetic group (IC 95%, 71.9-93.1) and 70.8% in the autologous vein group (IC 95%: 55.9-83.1), and the difference in secondary patency between the prosthetic and the autologous vein groups was 13.8% (IC 95%, -4.4 to 32.0). In the under treatment analysis, the 5 years secondary patency was 96.2% among patients receiving a prosthesis (IC 95%, 80.4-99.9) and 90.5% among patients receiving an autologous vein (IC 95%, 66.9-98.9), and the difference in the rate of patency between prostheses and veins was 5.7% (IC 95%, -13.2 to 24.6). Although there was no significant difference at 5 years, the death rate and the rate of amputation were higher in the prosthetic group. CONCLUSIONS: Although it is impossible to conclude definitely to the noninferiority of prosthetic bypass compared with venous bypass because of the insufficient number of inclusions, this randomized study nevertheless showed at 5 years the satisfactory results obtained with prostheses compared with autologous vein for above-knee femoropopliteal bypasses. PMID- 26631774 TI - Mediastinoscopy-assisted Treatment of an Aberrant Right Subclavian Artery. AB - Aberrant right subclavian artery (ARSA) is a rare congenital anomaly characterized by the origin of the right subclavian artery from the aortic arch distally to the left subclavian artery. We describe the case of a young patient with symptomatic ARSA treated by mediastinoscopy-assisted ligation at its origin and subclavian-carotid transposition. PMID- 26631775 TI - Automated Event Detection and Activity Monitoring in Long Molecular Dynamics Simulations. AB - Events of scientific interest in molecular dynamics (MD) simulations, including conformational changes, folding transitions, and translocations of ligands and reaction products, often correspond to high-level structural rearrangements that alter contacts between molecules or among different parts of a molecule. Due to advances in computer architecture and software, MD trajectories representing such structure-changing events have become easier to generate, but the length of these trajectories poses a challenge to scientific interpretation and analysis. In this paper, we present automated methods for the detection of potentially important structure-changing events in long MD trajectories. In contrast with traditional tools for the analysis of such trajectories, our methods provide a detailed report of broken and formed contacts that aids in the identification of specific time-dependent side-chain interactions. Our approach employs a coarse-grained representation of amino acid side chains, a contact metric based on higher order generalizations of Delaunay tetrahedralization, techniques for detecting significant shifts in the resulting contact time series, and a new kernel-based measure of contact alteration activity. The analysis methods we describe are incorporated in a newly developed package, called TimeScapes, which is freely available and compatible with trajectories generated by a variety of popular MD programs. Tests based on actual microsecond time scale simulations demonstrate that the package can be used to efficiently detect and characterize important conformational changes in realistic protein systems. PMID- 26631776 TI - SIMUFLEX: Algorithms and Tools for Simulation of the Conformation and Dynamics of Flexible Molecules and Nanoparticles in Dilute Solution. AB - A computer programs suite, SIMUFLEX, has been constructed for the calculation of solution properties of flexible macromolecules modeled as bead-and-connector models of arbitrary topology. The suite consists mainly of two independent programs, BROWFLEX that generates the macromolecular trajectory by using the Brownian dynamics technique and ANAFLEX that analyzes that trajectory to get solution properties of the macromolecule. In this paper, we describe theoretical aspects about the macromolecular model and the Brownian dynamics algorithm used and describe some of the numerous properties that can be evaluated. In order to provide examples of the application of the methodology, we present simulations of dynamic properties of DNA with length ranging from 10 to 10(5) base pairs. SIMUFLEX is able to run simulations with more or less coarse-grained models, thus enabling such multiple-scale studies. PMID- 26631777 TI - Quantum Chemistry on Graphical Processing Units. 3. Analytical Energy Gradients, Geometry Optimization, and First Principles Molecular Dynamics. AB - We demonstrate that a video gaming machine containing two consumer graphical cards can outpace a state-of-the-art quad-core processor workstation by a factor of more than 180* in Hartree-Fock energy + gradient calculations. Such performance makes it possible to run large scale Hartree-Fock and Density Functional Theory calculations, which typically require hundreds of traditional processor cores, on a single workstation. Benchmark Born-Oppenheimer molecular dynamics simulations are performed on two molecular systems using the 3-21G basis set - a hydronium ion solvated by 30 waters (94 atoms, 405 basis functions) and an aspartic acid molecule solvated by 147 waters (457 atoms, 2014 basis functions). Our GPU implementation can perform 27 ps/day and 0.7 ps/day of ab initio molecular dynamics simulation on a single desktop computer for these systems. PMID- 26631778 TI - A Hierarchical Approach to Study the Thermal Behavior of Protonated Water Clusters H(+)(H2O)n. AB - The energy landscape of protonated water clusters H(+)(H2O)n is thoroughly explored at the first-principle level using a hierarchical search methodology. In particular, the distinct configurational isomers of OSS2 empirical potential for n = 5-9 are uncovered and archived systematically using an asynchronous genetic algorithm and are subsequently refined with first-principle calculations. Using the OSS2 model, quantitative agreements in the thermal properties between Monte Carlo and harmonic superposition approximation (HSA) highlighted the reliability of the latter approach for the study of small- to medium-sized protonated water clusters. From the large sets of collected isomers, finite temperature behavior of the clusters can be efficiently examined at first-principle accuracy with the use of HSA. From the results obtained, evidence of structural changes from single ring to treelike (n = 5-7) and multi-ring to single-ring structures (n = 7-9) is observed, as expected for the empirical model. Finally, the relevance of these findings to recent experimental data is discussed. PMID- 26631779 TI - Simulated Tempering Distributed Replica Sampling, Virtual Replica Exchange, and Other Generalized-Ensemble Methods for Conformational Sampling. AB - Generalized-ensemble algorithms in temperature space have become popular tools to enhance conformational sampling in biomolecular simulations. A random walk in temperature leads to a corresponding random walk in potential energy, which can be used to cross over energetic barriers and overcome the problem of quasi nonergodicity. In this paper, we introduce two novel methods: simulated tempering distributed replica sampling (STDR) and virtual replica exchange (VREX). These methods are designed to address the practical issues inherent in the replica exchange (RE), simulated tempering (ST), and serial replica exchange (SREM) algorithms. RE requires a large, dedicated, and homogeneous cluster of CPUs to function efficiently when applied to complex systems. ST and SREM both have the drawback of requiring extensive initial simulations, possibly adaptive, for the calculation of weight factors or potential energy distribution functions. STDR and VREX alleviate the need for lengthy initial simulations, and for synchronization and extensive communication between replicas. Both methods are therefore suitable for distributed or heterogeneous computing platforms. We perform an objective comparison of all five algorithms in terms of both implementation issues and sampling efficiency. We use disordered peptides in explicit water as test systems, for a total simulation time of over 42 MUs. Efficiency is defined in terms of both structural convergence and temperature diffusion, and we show that these definitions of efficiency are in fact correlated. Importantly, we find that ST-based methods exhibit faster temperature diffusion and correspondingly faster convergence of structural properties compared to RE-based methods. Within the RE-based methods, VREX is superior to both SREM and RE. On the basis of our observations, we conclude that ST is ideal for simple systems, while STDR is well-suited for complex systems. PMID- 26631780 TI - Exchange-Dispersion Energy: A Formulation in Terms of Monomer Properties and Coupled Cluster Treatment of Intramonomer Correlation. AB - A new formulation of the second-order exchange-dispersion energy of symmetry adapted perturbation theory is presented. The proposed approach allows to study - for the first time for many-electron monomers - the effect of intramonomer electron correlation on this energy correction. In the new formalism the exchange dispersion energy is expressed in terms of properties of interacting molecules, such as dynamic density-matrix susceptibilities and one-electron reduced density matrices. The resulting formula has been used to obtain the main (noncumulant) part of the exchange-dispersion energy for monomers described by coupled cluster theory limited to single and double excitations. A density fitting approach has been applied in order to reduce the computational effort for obtaining coupled cluster density-matrix susceptibilities. The new coupled cluster exchange dispersion energy has been compared with other available values of this interaction energy component, obtained with monomers treated on the level of Hartree-Fock or density-functional theories. PMID- 26631781 TI - Combined Jahn-Teller and Pseudo-Jahn-Teller Effect in the CO3 Molecule: A Seven State Six-Mode Problem. AB - A complicated problem of seven electronic states in four terms, (1)A1', (1)E'', 1(1)E', and 2(1)E', interacting with six vibrational modes, a1', a2'', e', and e', was solved to take into account the combined two-mode Jahn-Teller (JT) plus two-mode pseudo JT effects and rationalize the electronic structure of the CO3 molecule. The JT and first-order pseudo JT effects in the E'' state are separated from the rest of the problem by symmetry; they do not influence the ground state properties. In the remaining five-state five-mode problem including the ground state, (A1' + 1E' + 2E') ? (a1' + e' + e'), the JT two-mode problem is reduced to the one-mode one by means of coordinate transformations. Several high-level ab initio calculations including all of the five states confirm the previously found coexistence of a central minimum of D3h symmetry and three equivalent minima with a distorted geometry of C2v symmetry in the ground state; the barrier between them is rather small, 0.2-0.3 eV, but large enough to distinguish them spectroscopically. Harmonic vibrational frequencies of the two configurations near the minima of the adiabatic potential energy surface are also evaluated. The calculations show how the distorted configurations are produced by the JT effect in one of the excited E states, similar to a previous finding in O3. Numerical data of ab initio calculations yield also the effective vibronic and primary force constants for all of the terms. An electronic structure problem of this complexity including a reduction of the two-mode problem to one mode with full interpretation of the origin of coexisting different geometries as due to the JTE in the excited state is presented here for the first time. PMID- 26631782 TI - Unrestricted Coupled Cluster and Brueckner Doubles Variations of W1 Theory. AB - Unrestricted coupled cluster spin contamination corrected [UCCSD(T)] and unrestricted Brueckner doubles [UBD(T)] variations of the Weizmann-1 theory (W1), denoted as W1U, W1Usc, and W1BD, respectively, are compared with the restricted open-shell W1 theory [W1(RO)]. The performances of the four W1 variants are assessed with 220 total atomization energies, electron affinities, ionization potentials, and proton affinities in the G2/97 test set, for consistency with the error analysis of the original W1(RO) study. The root-mean-square deviations from the experiment of W1U (0.65 +/- 0.48 kcal/mol), W1Usc (0.57 +/- 0.48 kcal/mol), W1BD (0.62 +/- 0.48 kcal/mol), and W1(RO) (0.57 +/- 0.48 kcal/mol) show that the four methods are virtually indistinguishable. This error analysis excludes the "singlet biradicals," C2 and O3, since single determinantal methods are not really adequate for these strongly multireference systems. The unrestricted W1 variants perform poorly for such highly spin-contaminated and multireference species (the largest deviation from experiment for W1Usc is -4.2 +/- 0.1 kcal/mol for the O3 EA). W1(RO) performs much better than its unrestricted counterparts for these pathological cases (the deviation from experiment is reduced to -1.5 +/ 0.1 kcal/mol for the O3 EA), though the errors are significantly larger than those for the overall test set. The examples of C2, O3, and the F2 potential energy curve indicate that an advantage to using W1BD is that the error in ?S(2)? correlates with the magnitude of the error in energy, whereas W1(RO) loses accuracy without such a warning. PMID- 26631783 TI - Determination of London Susceptibilities and Ring Current Intensities using Conjugated Circuits. AB - Conjugated circuits have been employed to accurately reproduce the aromatic stabilization, London susceptibility, and ring current maps in polycyclic aromatic hydrocarbons, PAHs, focusing on polybenzenoids. Starting from a wave function ansatz, constructed as a superposition of Kekule valence bond structures, the conjugated circuit resonance energy is derived using the second quantization formulation. Approximated expressions for the resonance energy, London susceptibility, and ring electron current intensity have been obtained. In these expressions, the benzene molecule is employed as a reference for the calculation in a graph theoretical fashion of properties in larger polybenzenoids. Comparison of the results obtained with conjugated circuits with those obtained using more accurate quantum chemical methods reflects the power of the conjugated circuit concept as a quantitative tool for the study of magnetic properties in PAHs. Besides the usefulness of this methodology for understanding and interpreting both the aromatic stabilization and the magnetic behavior of small and medium size PAHs, it provides a straightforward alternative way for the computation of these properties in giant PAHs for which ab initio calculations are not applicable. PMID- 26631784 TI - Fully Relativistic, Comparative Investigation of Gold and Platinum Alkyne Complexes of Relevance for the Catalysis of Nucleophilic Additions to Alkynes. AB - For a range of additions to alkynes gold is known to exhibit a much higher catalytic activity than a corresponding platinum compound. In order to approach the origin of this behavior we first investigate the propyne activation by the gold and platinum catalysts AuCl3 and PtCl2(H2O) where both metals possess a d(8) electron configuration and where the catalysts exhibit similar steric effects. Propyne serves as a representative for alkynes. Fully relativistic ab initio calculations of these alkyne-catalyst complexes are presented at the Dirac Hartree-Fock self-consistent field (DHF-SCF), density functional theory (DFT/B3LYP), and Green's function (GF) level in order to properly account for the large relativistic effects of gold and platinum. For the alkyne/catalyst complexes both the perpendicular and in-plane conformations were studied as these possess very similar ground state energies and may easily transform into each other. Strongly varying orbital populations together with sizable energetic and structural differences of the frontier orbitals are found and can be considered as a major source of the differing catalytic activity. These mainly comprise vanishing LUMO densities at the carbon centers in the platinum complex together with increased LUMO energies making a nucleophilic attack harder than in the gold compound. As Green's function calculations show, DFT/B3LYP seems to overestimate correlation contributions leading to an unphysical energetic lowering of many unoccupied orbitals. PMID- 26631785 TI - Benchmark Data for Noncovalent Interactions in HCOOH...Benzene Complexes and Their Use for Validation of Density Functionals. AB - We present benchmark energetic data for the HCOOH...benzene complexes. The benchmark data were determined by a composite approach based on CCSD(T) calculations. Final binding energies (kcal/mol) are in the range of 1.6-4.8 kcal/mol, and they were used as reference data to test density functionals in the literature. Among the tested local density functionals without empirical dispersion corrections, M06-L is the best performing functional, and M06-L/6 31+G(d,p) gives a mean unsigned error (MUE) of only 0.15 kcal/mol. PBEsol and SOGGA also show promising performance. The best local DFT-D methods are BLYP-D and PBEsol-D, and they give an MUE of 0.15 kcal/mol after removing basis set superposition errors by the counterpoise approach. Empirical dispersion corrections greatly improve the descriptions of noncovalent interactions in HCOOH...benzene dimers. The calculated benchmark data and intermolecular potential are useful for the parametrizations of new force fields and coarse grained models for chemical species such as the acrylic polymers. PMID- 26631786 TI - An Automated and Systematic Transition Structure Explorer in Large Flexible Molecular Systems Based on Combined Global Reaction Route Mapping and Microiteration Methods. AB - The global reaction route mapping (GRRM) method enabled an automated and a systematic search for routes of chemical reactions on a potential energy surface based on the anharmonic downward distortion following (ADDF) approach [Chem. Phys. Lett. 2004, 384, 277]. On the other hand, the microiteration technique [Mol. Phys. 2006, 104, 701] has been developed for full optimizations of transition state (TS) structures for reactions/transformations in large flexible molecular systems and successfully used in ONIOM(QM:MM) calculations. In the present paper, combining the GRRM method with the microiteration technique, we developed a microiteration-ADDF (MU-ADDF) method for automated and systematic TS exploration of large flexible molecular systems. We showed that the method works well with two test systems, (H2CO)(H2O)100 and Si6(C12H17)6, in the ONIOM(QM:MM) framework. It is noted that the present MU-ADDF method can be used for pure quantum mechanics (QM) or molecular mechanics (MM) systems (without ONIOM) and has been tested successfully in C6H10O pure QM calculations. PMID- 26631787 TI - Comparison of Global Reactivity Descriptors Calculated Using Various Density Functionals: A QSAR Perspective. AB - Conceptual density functional theory (DFT) based global reactivity descriptors are used to understand the relationship between structure, stability, and global chemical reactivity. Furthermore, these descriptors are employed in the development of quantitative structure-activity (QSAR), structure-property (QSPR), and structure-toxicity (QSTR) relationships. However, the predictive power of various relationships depends on the reliable estimates of these descriptors. The basic working equations used to calculate these descriptors contain both the ionization potential and the electron affinity of chosen molecules. Therefore, efficiency of different density functionals (DFs) in predicting the ionization potential and the electron affinity has to be systematically evaluated. With a view to benchmark the method of calculation of global reactivity descriptors, comprehensive calculations have been carried out on a series of chlorinated benzenes using a variety of density functionals employing different basis sets. In addition, to assess the utility of global reactivity descriptors, the relationships between the reactivity-electrophilicity and the structure-toxicity have been developed. The ionization potential and the electron affinity values obtained from M05-2X method using the DeltaSCF approach are closer to the corresponding experimental values. This method reliably predicts these electronic properties when compared to the other DFT methods. The analysis of a series of QSTR equations reveals that computationally economic DFT functionals can be effectively and routinely applied in the development of QSAR/QSPR/QSTR. PMID- 26631788 TI - Investigation of Exchange Energy Density Functional Accuracy for Interacting Molecules. AB - We present a comparison of exchange-only interaction energies obtained using several standard exchange functionals in the generalized gradient approximation to Hartree-Fock results for interacting molecules. We observe that functionals with an enhancement factor using a 2/5 power dependence on the gradient of the density for large density gradients offer consistently better agreement with Hartree-Fock calculations than that of alternative functionals. We revisit the functional offering the closest agreement and recalculate it to include its exact large gradient dependence. PMID- 26631789 TI - Beryllium Bonds, Do They Exist? AB - The complexes between BeX2 (X = H, F, Cl, OH) with different Lewis bases have been investigated through the use of B3LYP, MP2, and CCSD(T) approaches. This theoretical survey showed that these complexes are stabilized through the interaction between the Be atom and the basic center of the base, which are characterized by electron densities at the corresponding bond critical points larger than those found in conventional hydrogen bonds (HBs). Actually, all bonding indices indicate that, although these interactions that we named "beryllium bonds" are in general significantly stronger than HBs, they share many common features. Both interactions have a dominant electrostatic character but also some covalent contributions associated with a non-negligible electron transfer between the interacting subunits. This electron transfer, which in HBs takes place from the HB acceptor lone-pairs toward the sigmaYH* antibonding orbital of the HB donor, in beryllium bonds goes from the lone pairs of the Lewis base toward the empty p orbital of Be and the sigmaBeX* antibonding orbital. Accordingly, a significant distortion of the BeX2 subunit, which in the complex becomes nonlinear, takes place. Concomitantly, a significant red-shifting of the X-Be-X antisymmetric stretching frequencies and a significant lengthening of the X-Be bonds occur. The presence of the beryllium bond results in a significant blue-shifting of the X-Be-X symmetric stretch. PMID- 26631790 TI - Implementation and Optimization of DFT-D/COSab with Respect to Basis Set and Functional: Application to Polar Processes of Furfural Derivatives in Solution. AB - The implementation, optimization, and performance of DFT-D, including the effects of solvation, has been tested on applications of polar processes in solution, where dispersion and hydrogen bonding is known to be involved. Solvent effects are included using our ab initio continuum solvation strategy, COSab, a conductor like continuum solvation model, modified for ab initio in the quantum chemistry program GAMESS. Structure and properties are investigated across various functionals to evaluate their ability to properly model dispersion and solvation effects. The commonly used S22 set with accurate interaction energies of organic complexes has been used for parametrization studies of dispersion parameters and relevant solvation parameters. Dunning's correlation consistent basis sets, cc pVnZ (n = D, T), are used in the optimization, together with the Grimme B97-D exchange-correlation functional. Both water (epsilon = 78.4) and ether (epsilon = 4.33) environments are considered. Optimized semiempirical dispersion correction parameters and solvent extent radii are proposed for several functionals. We find that special parametrization of the semiempirical dispersion correction when used together in the DFT-D/COSab approach is not necessary. The global performance is quite acceptable in terms of chemical accuracy and suggests that this approach is a reliable as well as economical method for evaluation of solvent effects in systems with dispersive interactions. The resulting theory is applied to a group of push-pull pyrrole systems to illustrate the effects of donor/acceptor and solvation on their conformational and energetic properties. PMID- 26631791 TI - Structures and Energetics of SrFeO2.875 Calculated within the GGA + U Framework. AB - The energetics and electronic properties of SrFeO2.875 have been systematically calculated with the fully relaxed atomic positions at both GGA and GGA + U levels, and different spin-polarized configurations have been considered. Many atoms besides the nearest neighbors of the oxygen vacancy have been found to be influenced by the vacancy in terms of positions and electronic structures. The obtained magnetic moments suggest the high-spin character of the Fe 3d electrons, in combination with the larger exchange splitting compared with the crystal field splitting. The local states at the Fermi level are found to be situated within the pi* band in the nonmagnetic case and the sigma* bands in the ferromagnetic and antiferromagnetic cases. The energy values concerning the oxygen-vacancy formation from SrFeO3 to SrFeO2.875 have been deduced with the correction of the O2 overbinding error and the consideration of the oxygen partial pressure and the temperature. PMID- 26631792 TI - Scaling of Multimillion-Atom Biological Molecular Dynamics Simulation on a Petascale Supercomputer. AB - A strategy is described for a fast all-atom molecular dynamics simulation of multimillion-atom biological systems on massively parallel supercomputers. The strategy is developed using benchmark systems of particular interest to bioenergy research, comprising models of cellulose and lignocellulosic biomass in an aqueous solution. The approach involves using the reaction field (RF) method for the computation of long-range electrostatic interactions, which permits efficient scaling on many thousands of cores. Although the range of applicability of the RF method for biomolecular systems remains to be demonstrated, for the benchmark systems the use of the RF produces molecular dipole moments, Kirkwood G factors, other structural properties, and mean-square fluctuations in excellent agreement with those obtained with the commonly used Particle Mesh Ewald method. With RF, three million- and five million-atom biological systems scale well up to ~30k cores, producing ~30 ns/day. Atomistic simulations of very large systems for time scales approaching the microsecond would, therefore, appear now to be within reach. PMID- 26631793 TI - Polarizable Force Field for Protein with Charge Response Kernel. AB - We present a molecular mechanical force field for polypeptides and proteins involving the electronic polarization effect described with the charge response kernel. All of the electrostatic parameters for 20 amino acids are obtained by ab initio electronic structure calculations and combined with the AMBER99 force field. The refittings of dihedral angle parameters in the torsional potentials are performed so as to reproduce the ab initio optimized geometries and relative energies for the conformers of dipeptides. The present force field is applied to molecular dynamics simulation calculations of the extended alanine tetra and cyclic pentapeptides in aqueous solution. The infrared spectra are calculated in order to analyze the charge polarization effect on the spectral profiles. PMID- 26631794 TI - A Consistent Force Field for the Carboxylate Group. AB - In the light of the important role played by the carboxylate group in bio- and coordination chemistry, its consistent and reliable parametrization for molecular simulations is crucial. The experimental vibrational spectra of three carboxylate anions (formate, acetate, and benzoate) both in the gas phase and in the condensed phase (as sodium salts) are interpreted on the basis of high-quality ab initio calculations. The interaction with the counterion (metal cation) is shown to be of major importance in the interpretation of the spectral features of the carboxylate group both in the solid state and in aqueous solution. Previous attempts to parametrize the carboxylate group within the molecular mechanics approach is critically reviewed, and a new set of the consistent valence force field parameters based on first principles calculations is proposed, which is able to reproduce accurately both the structure and the dynamics of the carboxylate moiety both free and coordinated with metal cations. PMID- 26631795 TI - Performance of DFT Methods in the Calculation of Optical Spectra of TCF Chromophores. AB - We present electronic structure calculations of the ultraviolet/visible (UV-vis) spectra of highly active push-pull chromophores containing the tricyanofuran (TCF) acceptor group. In particular, we have applied the recently developed long range corrected Baer-Neuhauser-Livshits (BNL) exchange-correlation functional. The performance of this functional compares favorably with other density functional theory (DFT) approaches, including the CAM-B3LYP functional. The accuracy of UV-vis results for these molecules is best at low values of attenuation parameters (gamma) for both BNL and CAM-B3LYP functionals. The optimal value of gamma is different for the charge-transfer (CT) and pi-pi* excitations. The BNL and PBE0 exchange correlation functionals capture the CT states particularly well, while the pi-pi* excitations are less accurate and system dependent. Chromophore conformations, which considerably affect the molecular hyperpolarizability, do not significantly influence the UV-vis spectra on average. As expected, the color of chromophores is a sensitive function of modifications to its conjugated framework and is not significantly affected by increasing aliphatic chain length linking a chromophore to a polymer. For selected push-pull aryl-chromophores, we find a significant dependence of absorption spectra on the strength of diphenylaminophenyl donors. PMID- 26631796 TI - Simulated Solute Tempering. AB - For the enhanced conformational sampling in molecular dynamics (MD) simulations, we present "simulated solute tempering" (SST) which is an easy to implement variant of simulated tempering. SST extends conventional simulated tempering (CST) by key concepts of "replica exchange with solute tempering" (REST, Liu et al. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 13749). We have applied SST, CST, and REST to molecular dynamics (MD) simulations of an alanine octapeptide in explicit water. The weight parameters required for CST and SST are determined by two different formulas whose performance is compared. For SST only one of them yields a uniform sampling of the temperature space. Compared to CST and REST, SST provides the highest exchange probabilities between neighboring rungs in the temperature ladder. Concomitantly, SST leads to the fastest diffusion of the simulation system through the temperature space, in particular, if the "even-odd" exchange scheme is employed in SST. As a result, SST exhibits the highest sampling speed of the investigated tempering methods. PMID- 26631797 TI - Adsorption and Diffusion of Alkanes in Na-MOR: Modeling the Effect of the Aluminum Distribution. AB - We investigated the adsorption and the diffusion of alkanes in the sodium exchanged zeolite Mordenite (Na-MOR) using molecular simulations. MOR-type zeolite consists of main channels (6.5 * 7 A) oriented along the z crystallographic axis that are connected to small side pockets (3.4 * 4.8 A). It is well-known that the adsorption of alkanes in Na-MOR strongly depends on the precise location of the framework Al atoms either in the main channel or the side pockets (Calero and co-workers, Angew. Chem. Int. Ed. 2007, 46, 276). We found that this effect can be characterized by a single-order parameter: the number of framework Al in the main channel divided by the number of framework Al in the side pocket (M/S ratio). For any M/S ratio, the adsorption isotherm follows from a linear interpolation between the reference isotherms. This enabled us to predict adsorption isotherms for any distribution of the Al framework atoms or estimate the M/S ratio for a given isotherm. We found that the same model can predict the effect of the M/S ratio on the self-diffusion coefficient, the Maxwell-Stefan diffusion coefficient, and the accessible micropore volume. PMID- 26631798 TI - Electrostatic Potential Derived Atomic Charges for Periodic Systems Using a Modified Error Functional. AB - A method to generate electrostatic potential (ESP) derived atomic charges in crystalline solids from periodic quantum mechanical calculations, termed the REPEAT method, is presented. Conventional ESP fitting procedures developed for molecular systems, in general, will not work for crystalline systems because the electrostatic potential in periodic systems is ill-defined up to a constant offset at each spatial position. In this work the problem is circumvented by introducing a new error functional which acts on the relative differences of the potential and not on its absolute values, as it is currently done with molecular ESP charge derivation methods. We formally demonstrate that the new functional reduces to the conventional error functional used in molecular ESP approaches when the simulation box of the periodic calculation becomes infinitely large. Several tests are presented to validate the new technique. For the periodic calculation of isolated molecules, the REPEAT charges are found to be in good agreement with those determined with established molecular ESP charge derivation methods. For siliceous sodalite, it is demonstrated that conventional molecular ESP approaches generate 'unphysical' charges, whereas the REPEAT method produces charges that are both chemically intuitive and consistent between different periodic electronic structure packages. The new approach is employed to generate partial atomic charges of various microporous materials and compared to both experimentally derived and molecular fragment ESP charges. This method can be used to generate partial atomic charges to be used in simulations of microporous and nanoporous materials, such as zeolites and metal organic framework materials. PMID- 26631799 TI - Quantum Mechanical Quantification of Weakly Interacting Complexes of Peptides with Single-Walled Carbon Nanotubes. AB - We investigated the binding nature of three peptides (inactive NB1 and active B1 and B3) to single-walled carbon nanotubes (SWCNTs) using a density functional tight-binding (DFTB) method with an empirical van der Waals force correction. We show that the three peptides could be spontaneously adsorbed to the carbon nanotube (CNT) surface through pi-pi and/or H-pi stacking at physisorption distances and the geometric and pi-electronic structures of SWCNTs remain basically undamaged upon the adsorption. We also investigated the diameter and chirality dependence of binding energies. The calculated results are consistent with experimental observation, and we found that aromatic residues, such as His and Trp, are the keys in determining peptide/CNT binding. In addition, our calculations predict that noncovalent modification of SWCNTs by the active peptides might increase the electron transfer capabilities of SWCNTs. PMID- 26631800 TI - Binding of an RNA pol II Ligand to the WW Domain of Pin1 Using Molecular Dynamics Docking Simulations. AB - A novel docking protocol using a long, all atom molecular dynamics (MD) simulation, in an explicit solvent medium, without using any distance constraints is presented. This MD docking protocol is able to dock ligands, based on the C terminal domain (CTD) of RNA polymerase II, into the tryptophan-tryptophan (WW) domain of Pin1. In this docking process, a significant loop-bending event occurs in order to encircle the ligand into its solvent exposed binding site, which cannot be simulated using current protocols. The simulations were validated structurally and energetically against an X-ray structure to confirm correct sampling of conformational space. Based on these simulations, and justification of the starting structure as a valid intermediate structure, a potential molecular basis for binding was predicted as well as confirming the key residues involved in the formation of the final strong and stable Pin1 WW domain-ligand complex. PMID- 26631801 TI - Understanding Rubredoxin Redox Potentials: Role of H-Bonds on Model Complexes. AB - The energetics of redox states in different models of rubredoxin-like iron-sulfur complexes (ISC) was computed using a combination of density functional and electrostatic continuum theories. In agreement with experiment, the calculated redox potential for the small ISC model [Fe(SCH2CH3)4](1-,2-) in acetonitrile was -813 mV [Galstyan, A. S.; Knapp, E. W. J. Comput. Chem. 2009, 30, 203-211] as compared to the measured value of -838 mV. Surprisingly the experimental values for rubredoxin (Rd) are much higher ranging between -87 and +39 mV. These large variations in redox potentials of ISC models and ISC in Rd are due to specific conformational symmetries adopted by the ligands due to both the protein environment and type and the number of H-bonds, and the dielectric environment. In a dielectric environment corresponding to proteins (epsilon = 20), the computed ISC redox potentials shift positive by about 64 mV for Fe-S...H-N and 95 mV for Fe-S...H-O H-bonds, correlating well with data estimated from experiments on ISC proteins. In aqueous solutions (epsilon = 80), a positive shift of 58 mV was computed for Fe-S...H-O H-bonds (using a model with the same ISC conformation as in Rd) in agreement with a measured value for Rd with partially solvent exposed ISC. The latter demonstrates the dependence of the ISC redox potentials on the environment (solvent or protein). For a model whose chemical composition is analog to the relevant part of ISC in a specific Rd, the computed redox potential of the model agrees with the measured value in Rd. This study allows to understand redox potential shifts for small ISC models and ISC in proteins. PMID- 26631802 TI - Expression pattern of bcar3, a downstream target of Gata2, and its binding partner, bcar1, during Xenopus development. AB - Primitive hematopoiesis generates red blood cells that deliver oxygen to the developing embryo. Mesodermal cells commit to a primitive blood cell fate during gastrulation and, in order to do so the mesoderm must receive non-cell autonomous signals transmitted from other germ layers. In Xenopus, the transcription factor Gata2 functions in ectodermal cells to generate or transmit the non-cell autonomous signals. Here we have identified Breast Cancer Antiestrogen Resistance 3 (bcar3) as a gene that is induced in ectodermal cells downstream of Gata2. Bcar3 and its binding partner Bcar1 function to transduce integrin signaling, leading to changes in cellular morphology, motility and adhesion. We show that gata2, bcar3 and bcar1 are co-expressed in ventral ectoderm from early gastrula to early tailbud stages. At later stages of development, bcar3 and bcar1 are co expressed in the spinal cord, notochord, fin mesenchyme and pronephros but each shows additional unique sites of expression. These co-expression and unique expression patterns suggest that Bcar3 and Bcar1 may function together but also independently during Xenopus development. PMID- 26631803 TI - A novel SOX18 mutation uncovered in Jordanian patient with hypotrichosis lymphedema-telangiectasia syndrome by Whole Exome Sequencing. AB - The SOX18 gene encodes a transcription factor that plays a notable role in certain developmental contexts such as lymphangiogenesis, hair follicle development and vasculogenesis. SOX18 mutations are linked to recessive and dominant hypotrichosis-lymphedema-telangiectasia syndrome (HLTS). In this study we report on a novel heterozygous mutation in SOX18 in a Jordanian patient suffering from HLTS that was revealed by Whole Exome Sequencing. In this case, a frameshift caused by 14-nucleotide duplication in SOX18 appeared de novo resulting in a premature translational stop at the N-terminal region of the central trans-activation domain. Here we present the clinical manifestations of the above mentioned molecular lesion in the light of what is known from published SOX18 mutations. PMID- 26631804 TI - Molecular importance of prawn large heat shock proteins 60, 70 and 90. AB - Considering the importance of heat shock proteins (HSPs) in the innate immune system of prawn, a comparative molecular approach was proposed to study the crustacean large HSPs 60, 70 and 90. Three different large HSPs were identified from freshwater prawn Macrobrachium rosenbergii (Mr) cDNA library during screening. The structural and functional characteristic features of HSPs were studied using various bioinformatics tools. Also, their gene expression and mRNA regulation upon various pathogenic infections was studied by relative quantification using 2(-DeltaDeltaCT) method. MrHSP60 contains a long chaperonin 60 domain at 46-547 which carries a chaperonin 60 signature motif between 427 and 438, whereas MrHSP70 contains a long HSP70 domain at 21-624 and MrHSP90 carries a HSP90 domain at 188-719. The two dimensional analysis showed that MrHSP60 contains more amino acids (52%) in helices, whereas MrHSP70 (40.6%) and MrHSP90 (51.8%) carried more residues in coils. Gene expression results showed significant (P < 0.05) expression of MrHSP60, 70 and 90 in haemocyte, gill and hepatopancreas, respectively. Further, the expression level was up-regulated upon bacterial (Aeromonas hydrophilla and Vibrio harveyi) and viral [white spot syndrome virus (WSSV) and M. rosenbergii nodo virus (MrNV)] infections during various time periods. The gene expression results exhibited the potential involvement of these three HSPs in the immune system of prawn. The study indicated the potentiality of these molecules, thereby protecting cells against pathogens as well as severe cellular and environmental stresses in crustaceans. PMID- 26631805 TI - Down-regulation of CD53 expression in Epinephelus coioides under LPS, poly (I:C), and cytokine stimulation. AB - Tetraspanins are a group of cell surface molecules involved in cell adhesion, motility, metastasis, signal transduction, and immune cell activation. Members of the tetraspanin family include CD9, CD37, CD63, CD53, and others. However, few tetraspanins have been investigated in teleosts. In this study, we obtained the open reading frame of CD53 cDNA from orange spotted grouper (Epinephelus coioices), an economically important fish. The predicted amino acid structure contains four membrane-spanning domains and a conserved CCG motif. The amino acid identity between human and grouper CD53 was only 38%; however, both CD53 proteins share the same structure. Quantitative real-time PCR revealed that mRNA is abundant in immune organs, including the head and trunk kidneys, spleen, thymus, gill, and blood. Immunochemistry and immunofluorescence analyses further revealed that CD53 was majorly expressed in the leukocytes of various organs. Finally, mRNA and protein expression for CD53 was down-regulated in fish treated with immune stimulators, including LPS, Poly (I:C), Vibrio, recombinant grouper IL-6, and CCL4. Our results indicate that the expression of CD53 may play important roles in pathogen invasion and inflammation reaction. PMID- 26631806 TI - Threonine modulates immune response, antioxidant status and gene expressions of antioxidant enzymes and antioxidant-immune-cytokine-related signaling molecules in juvenile blunt snout bream (Megalobrama amblycephala). AB - A 9-week feeding trial was conducted to investigate the effects of graded dietary threonine (Thr) levels (0.58-2.58%) on the hematological parameters, immune response, antioxidant status and hepatopancreatic gene expression of antioxidant enzymes and antioxidant-immune-cytokine-related signaling molecules in juvenile blunt snout bream. For this purpose, 3 tanks were randomly arranged and assigned to each experimental diet. Fish were fed with their respective diet to apparent satiation 4 times daily. The results indicated that white blood cell, red blood cell and haemoglobin significantly responded to graded dietary Thr levels, while hematocrit didn't. Complement components (C3 and C4), total iron-binding capacity (TIBC), immunoglobulin M (IgM), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) increased with increasing dietary Thr levels up to 1.58-2.08% and thereafter tended to decrease. Dietary Thr regulated the gene expressions of Cu/Zn-SOD, Mn-SOD and CAT, GPx1, glutathione S-transferase mu (GST), nuclear factor erythroid 2-related factor 2 (Nrf2), heat shock protein-70 (Hsp70), tumor necrosis factor-alpha (TNF-alpha), apolipoprotein A-I (ApoA1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and fructose-bisphosphate aldolase B (ALDOB); while the gene expression of peroxiredoxin II (PrxII) was not significantly modified by graded Thr levels. These genes are involved in different functions including antioxidant, immune, and defense responses, energy metabolism and protein synthesis. Therefore, this study could provide a new molecular tool for studies in fish immunonutrition and shed light on the regulatory mechanisms that dietary Thr improved the antioxidant and immune capacities of fish. PMID- 26631807 TI - Comparison of the efficacy of Poly(I:C) immunization with live vaccine and formalin-killed vaccine against viral hemorrhagic septicemia virus (VHSV) in olive flounder (Paralichthys olivaceus). AB - Viral hemorrhagic septicemia (VHS) in olive flounder, Paralichthys olivaceus, causes significant economic loss for the flounder aquaculture industry in Korea. In this study, the immunogenicity of Poly(I:C) immunization with a live vaccine against the VHS virus (VHSV) was compared with that of a formalin-treated vaccine in the olive flounder. In vaccine trial I, fish pre-injected with Poly(I:C) were highly protected from VHSV infection 2 d later (survival rate: 96%) and the surviving fish (Poly(I:C)-VHSV group) showed a 100% survival rate against VHSV re challenge. Mortality in fish pre-injected with diethylpyrocarbonate-treated water followed by injection with formalin-treated VHSV was only 2% (1 of 50 fish), whereas survivors (DEPC-FT VHSV group) showed an 80% survival rate. In vaccine trial II, 100% survival was observed in all Poly(I:C) vaccination groups Poly(I:C)-VHSV 6, Poly(I:C)-VHSV 5, and Poly(I:C)-VHSV 4. In contrast, the survival rates of the groups administered the formalin-treated VHSV at a dose of 10(6), 10(5), and 10(4) TCID50 100 MUL(-1) fish(-1) (DEPC-FT VHSV 6, DEPC-FT VHSV 5, and DEPC-FT VHSV 4) were only 8%, 12%, and 12%, respectively. The differences in the survival rates of the formalin-treated vaccine groups in trial I and trial II were attributed to the difference in the formalin-treatment period: the formalin-treated VHSV administered in trial I was not completely inactivated and worked as a live vaccine, which explains the 80% survival rate against VHSV challenge. Specific antibodies against VHSV were detected in sera from all vaccinated survivors, except the DEPC-VHSV 4 group. Furthermore, the specific antibody titers of fish vaccinated with the live and dead VHSV vaccines were similar, but the protective effects of the live and dead vaccines varied considerably. Our findings show that Poly(I:C) immunization with the live vaccine offers better protection than the formalin-treated vaccine against VHS in olive flounder and revealed that antibody levels are not a reliable indicator of the protective effect of the vaccine against the pathogen. In the future, elements of T cell immunity may be used as a means of evaluating the protective efficacy of a vaccine against VHSV instead of ELISA. PMID- 26631808 TI - Microarray analysis of gene expression in olive flounder liver infected with viral haemorrhagic septicaemia virus (VHSV). AB - The most fatal viral pathogen in olive flounder Paralichthys olivaceus, is viral hemorrhagic septicemia virus, which afflicts over 48 species of freshwater and marine fish. Here, we performed gene expression profiling on transcripts isolated from VHSV-infected olive flounder livers using a 13 K cDNA microarray chip. A total of 1832 and 1647 genes were upregulated and down-regulated over two-fold, respectively, after infection. A variety of immune-related genes showing significant changes in gene expression were identified in upregulated genes through gene ontology annotation. These genes were grouped into categories such as antibacterial peptide, antigen-recognition and adhesion molecules, apoptosis, cytokine-related pathway, immune system, stress response, and transcription factor and regulatory factors. To verify the cDNA microarray data, we performed quantitative real-time PCR, and the results were similar to the microarray data. In conclusion, these results may be useful for the identification of specific genes or for the diagnosis of VHSV infection in flounder. PMID- 26631809 TI - Identification of lymphocytic choriomeningitis mammarenavirus in house mouse (Mus musculus, Rodentia) in French Guiana. AB - Thirty-seven house mice (Mus musculus, Rodentia) caught in different localities in French Guiana were screened to investigate the presence of lymphocytic choriomeningitis mammarenavirus (LCMV). Two animals trapped in an urban area were found positive, hosting a new strain of LCMV, that we tentatively named LCMV "Comou". The complete sequence was determined using a metagenomic approach. Phylogenetic analyses revealed that this strain is related to genetic lineage I composed of strains inducing severe disease in humans. These results emphasize the need for active surveillance in humans as well as in house mouse populations, which is a rather common rodent in French Guianese cities and settlements. PMID- 26631810 TI - HIV infection and hepatitis C virus genotype 1a are associated with phylogenetic clustering among people with recently acquired hepatitis C virus infection. AB - The aim of this study was to identify factors associated with phylogenetic clustering among people with recently acquired hepatitis C virus (HCV) infection. Participants with available sample at time of HCV detection were selected from three studies; the Australian Trial in Acute Hepatitis C, the Hepatitis C Incidence and Transmission Study - Prison and Community. HCV RNA was extracted and Core to E2 region of HCV sequenced. Clusters were identified from maximum likelihood trees with 1000 bootstrap replicates using 90% bootstrap and 5% genetic distance threshold. Among 225 participants with available Core-E2 sequence (ATAHC, n=113; HITS-p, n=90; and HITS-c, n=22), HCV genotype prevalence was: G1a: 38% (n=86), G1b: 5% (n=12), G2a: 1% (n=2), G2b: 5% (n=11), G3a: 48% (n=109), G6a: 1% (n=2) and G6l 1% (n=3). Of participants included in phylogenetic trees, 22% of participants were in a pair/cluster (G1a-35%, 30/85, mean maximum genetic distance=0.031; G3a-11%, 12/106, mean maximum genetic distance=0.021; other genotypes-21%, 6/28, mean maximum genetic distance=0.023). Among HCV/HIV co infected participants, 50% (18/36) were in a pair/cluster, compared to 16% (30/183) with HCV mono-infection (P=<0.001). Factors independently associated with phylogenetic clustering were HIV co-infection [vs. HCV mono-infection; adjusted odds ratio (AOR) 4.24; 95%CI 1.91, 9.39], and HCV G1a infection (vs. other HCV genotypes; AOR 3.33, 95%CI 0.14, 0.61).HCV treatment and prevention strategies, including enhanced antiviral therapy, should be optimised. The impact of targeting of HCV treatment as prevention to populations with higher phylogenetic clustering, such as those with HIV co-infection, could be explored through mathematical modelling. PMID- 26631811 TI - Analysis on the complete genome of a novel caprine parainfluenza virus 3. AB - Parainfluenza virus type 3 (PIV3) is one of the most important viral respiratory pathogens for humans and for many animals. One unique caprine PIV3 (CPIV3) strain named JS2013 was isolated in Chinese goat flocks with respiratory diseases in 2013. Now, the complete genome sequence of the strain JS2013 had been determined. A total of 15 overlapping DNA clones, covering the entire genome of the virus, were obtained by primer walking RT-PCR. The sequences of the 3' and 5' termini of the viral genome were amplified by 3' and 5' RACE. The viral genome was 15,618 nucleotides (nt) in length, which was consisted of six genes in the order 5' leader-N-P/C/V-M-F-HN-L-tailer-3'. The junction sequences between two genes were highly conserved gene start and stop signal sequences, and trinucleotide intergenic regions (IGR) similar to those of other reported PIV3 strains. Phylogenetic analysis based on the complete genomes of JS2013 with other strains of genus Respirovirus demonstrated that the JS2013 obviously differed from HPIV1, Sendai virus, HPIV3 and other reported BPIV3 genotypes. Further analysis of HN genes of JS2013 along with two more CPIV3 strains isolated later indicated that CPIV3 strains formed a separate cluster. The results presented here suggested that CPIV3 is a new member of the genus Respirovirus. PMID- 26631812 TI - Multilocus analysis indicates that Trypanosoma cruzi I genetic substructure associated with sylvatic and domestic cycles is not an attribute conserved throughout Colombia. AB - Trypanosoma cruzi, the causative agent of Chagas disease, has been classified into six discrete typing units (DTUs) named TcI to TcVI. Furthermore, subcontinental scale studies based on analysis of the splice leader intergenic region (SL-IR) of the mini-exon gene have subdivided TcI in five genetic groups (Ia-Ie) related to the domestic and non-domestic cycles. However, a current review of this marker among all the sequences deposited in the GenBank demonstrates no correlation between the genetic structure and the eco epidemiological features of parasite transmission. In this study, we performed a multilocus analysis of TcI isolates from a diverse array of hosts and vectors in a wide eco-geographical area of Colombia. Sequences from SL-IR and mitochondrial cyt b genes as well as PCR-RFLP profiles for four nuclear genes were analyzed. Multilocus analysis indicates that genetic structuration associated with sylvatic and domestic cycles in Colombia is not an attribute conserved across the entire eco-geography where TcI can be found. PMID- 26631813 TI - Can sliding-window correlations reveal dynamic functional connectivity in resting state fMRI? AB - During the last several years, the focus of research on resting-state functional magnetic resonance imaging (fMRI) has shifted from the analysis of functional connectivity averaged over the duration of scanning sessions to the analysis of changes of functional connectivity within sessions. Although several studies have reported the presence of dynamic functional connectivity (dFC), statistical assessment of the results is not always carried out in a sound way and, in some studies, is even omitted. In this study, we explain why appropriate statistical tests are needed to detect dFC, we describe how they can be carried out and how to assess the performance of dFC measures, and we illustrate the methodology using spontaneous blood-oxygen level-dependent (BOLD) fMRI recordings of macaque monkeys under general anesthesia and in human subjects under resting-state conditions. We mainly focus on sliding-window correlations since these are most widely used in assessing dFC, but also consider a recently proposed non-linear measure. The simulations and methodology, however, are general and can be applied to any measure. The results are twofold. First, through simulations, we show that in typical resting-state sessions of 10 min, it is almost impossible to detect dFC using sliding-window correlations. This prediction is validated by both the macaque and the human data: in none of the individual recording sessions was evidence for dFC found. Second, detection power can be considerably increased by session- or subject-averaging of the measures. In doing so, we found that most of the functional connections are in fact dynamic. With this study, we hope to raise awareness of the statistical pitfalls in the assessment of dFC and how they can be avoided by using appropriate statistical methods. PMID- 26631814 TI - Entorhinal volume, aerobic fitness, and recognition memory in healthy young adults: A voxel-based morphometry study. AB - Converging evidence supports the hypothesis effects of aerobic exercise and environmental enrichment are beneficial for cognition, in particular for hippocampus-supported learning and memory. Recent work in humans suggests that exercise training induces changes in hippocampal volume, but it is not known if aerobic exercise and fitness also impact the entorhinal cortex. In animal models, aerobic exercise increases expression of growth factors, including brain derived neurotrophic factor (BDNF). This exercise-enhanced expression of growth hormones may boost synaptic plasticity, and neuronal survival and differentiation, potentially supporting function and structure in brain areas including but not limited to the hippocampus. Here, using voxel based morphometry and a standard graded treadmill test to determine cardio-respiratory fitness (Bruce protocol; .VO2 max), we examined if entorhinal and hippocampal volumes were associated with cardio-respiratory fitness in healthy young adults (N=33). In addition, we examined if volumes were modulated by recognition memory performance and by serum BDNF, a putative marker of synaptic plasticity. Our results show a positive association between volume in right entorhinal cortex and cardio-respiratory fitness. In addition, average gray matter volume in the entorhinal cortex, bilaterally, was positively associated with memory performance. These data extend prior work on the cerebral effects of aerobic exercise and fitness to the entorhinal cortex in healthy young adults thus providing compelling evidence for a relationship between aerobic fitness and structure of the medial temporal lobe memory system. PMID- 26631815 TI - Spectrally resolved fast transient brain states in electrophysiological data. AB - The brain is capable of producing coordinated fast changing neural dynamics across multiple brain regions in order to adapt to rapidly changing environments. However, it is non-trivial to identify multiregion dynamics at fast sub-second time-scales in electrophysiological data. We propose a method that, with no knowledge of any task timings, can simultaneously identify and describe fast transient multiregion dynamics in terms of their temporal, spectral and spatial properties. The approach models brain activity using a discrete set of sequential states, with each state distinguished by its own multiregion spectral properties. This can identify potentially very short-lived visits to a brain state, at the same time as inferring the state's properties, by pooling over many repeated visits to that state. We show how this can be used to compute state-specific measures such as power spectra and coherence. We demonstrate that this can be used to identify short-lived transient brain states with distinct power and functional connectivity (e.g., coherence) properties in an MEG data set collected during a volitional motor task. PMID- 26631816 TI - Neural dynamics of change detection in crowded acoustic scenes. AB - Two key questions concerning change detection in crowded acoustic environments are the extent to which cortical processing is specialized for different forms of acoustic change and when in the time-course of cortical processing neural activity becomes predictive of behavioral outcomes. Here, we address these issues by using magnetoencephalography (MEG) to probe the cortical dynamics of change detection in ongoing acoustic scenes containing as many as ten concurrent sources. Each source was formed of a sequence of tone pips with a unique carrier frequency and temporal modulation pattern, designed to mimic the spectrotemporal structure of natural sounds. Our results show that listeners are more accurate and quicker to detect the appearance (than disappearance) of an auditory source in the ongoing scene. Underpinning this behavioral asymmetry are change-evoked responses differing not only in magnitude and latency, but also in their spatial patterns. We find that even the earliest (~50 ms) cortical response to change is predictive of behavioral outcomes (detection times), consistent with the hypothesized role of local neural transients in supporting change detection. PMID- 26631817 TI - Differential effects of continuous theta burst stimulation over left premotor cortex and right prefrontal cortex on modulating upper limb somatosensory input. AB - Somatosensory evoked potentials (SEPs) represent somatosensory processing in non primary motor areas (i.e. frontal N30 and N60) and somatosensory cortices (i.e. parietal P50). It is well-known that the premotor cortex (PMC) and prefrontal cortex (PFC) are involved in the preparation and planning of upper limb movements but it is currently unclear how they modulate somatosensory processing for upper limb motor control. In the current study, two experiments examined SEP modulations after continuous theta burst stimulation (cTBS) was used to transiently disrupt the left PMC (Experiment 1) and right PFC (Experiment 2). Both Experiment 1 (n=15) and Experiment 2 (n=16) used pre-post experimental designs. In both experiments participants performed a task requiring detection of varying amplitudes of attended vibrotactile (VibT) stimuli to the left index finger (D2) and execution of a pre-matched finger sequence with the right (contralateral) hand to specific VibT targets. During the task, SEPs were measured to median nerve (MN) stimulations time-locked during pre-stimulus (250 ms before VibT), early response selection (250 ms after VibT), late preparatory (750 ms after VibT) and execution (1250 ms VibT) phases. The key findings of Experiment 1 revealed significant decreases in N30 and N60 peak amplitudes after cTBS to PMC. In contrast, the results of Experiment 2, also found significant decreased N60 peak amplitudes as well as trends for increased N30 and P50 peak amplitudes. A direct comparison of Experiment 1 and Experiment 2 confirmed differential modulation of N30 peak amplitudes after PMC (gated) compared to PFC (enhanced) cTBS. Collectively, these results support that both the left PMC and right PFC have modulatory roles on early somatosensory input into non-primary motor areas, such as PMC and supplementary motor area (SMA), represented by frontal N30 and N60 SEPs. These results confirm that PMC and PFC are both part of a network that regulates somatosensory input for upper limb motor control. PMID- 26631818 TI - Characterization of incisional and inflammatory pain in rats using functional tools of MRI. AB - Underlying mechanisms of hyperalgesia differ with regard to the pain entities, which are well-modeled in animals for systematic studies. However, neuroimaging in different animal pain models often lacks clinical relevance and consistency with behavioral studies, which hinders the translation of results. Whereas mechanical stimulation is commonly used to explore hyperalgesia in animals and humans, functional magnetic resonance imaging (fMRI) studies frequently use electrical or heat stimuli to evaluate brain responses relevant to pain and hyperalgesia. To characterize the magnetic resonance (MR) representations of mechanical hyperalgesia after incision and inflammation, we aimed to investigate whole brain functional activities during innocuous and noxious mechanical or electrical stimulation (IMS/NMS; IES/NES), as well as metabolite levels in the thalamus of rats at rest and during electrical stimulation. In behavioral experiments, animal models of pain showed significant mechanical hyperalgesia, with a peak 24h after both injuries, but lasting longer after inflammation. In imaging experiments, mechanical and electrical stimulation revealed a biphasic BOLD response upon noxious stimulation in pain models. Analyses of the BOLD signal changes revealed significantly higher activation in pain models compared to sham animals. Furthermore, significant differences were present upon NMS (but not NES) between incision and inflammation models in all the studied regions except for contralateral somatosensory cortex (S1) and cerebellum (Cb) (F's>4.14, p's<0.05). Additionally, MS (but not ES) induced unexpected bilateral activation of S1 in all three animal groups. Finally, MR spectroscopy (MRS) in the thalamus showed higher concentrations of gamma-aminobutyric acid in both pain models at rest and during stimulation. We conclude that employment of MS in fMRI studies could provide an informative correlate of mechanical hyperalgesia in inflammatory and incisional pain models and might be used to further assess mechanisms and treatments relevant for these clinical pain states. PMID- 26631820 TI - Adaptive immune regulation in autoimmune diabetes. AB - Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the loss of insulin-producing pancreatic beta-cells. The pathogenesis of T1D is complex and multifactorial and involves a genetic susceptibility that predisposes to abnormal immune responses in the presence of ill-defined environmental insults to the pancreatic islets. This review discusses how adaptive immunoregulatory T cells contribute to the modulation of the development and evolution of T1D, together with potential approaches that target these cells for new therapies in the disease. PMID- 26631819 TI - Comparison of glomerular activity patterns by fMRI and wide-field calcium imaging: Implications for principles underlying odor mapping. AB - Functional imaging signals arise from distinct metabolic and hemodynamic events at the neuropil, but how these processes are influenced by pre- and post-synaptic activities need to be understood for quantitative interpretation of stimulus evoked mapping data. The olfactory bulb (OB) glomeruli, spherical neuropil regions with well-defined neuronal circuitry, can provide insights into this issue. Optical calcium-sensitive fluorescent dye imaging (OICa(2+)) reflects dynamics of pre-synaptic input to glomeruli, whereas high-resolution functional magnetic resonance imaging (fMRI) using deoxyhemoglobin contrast reveals neuropil function within the glomerular layer where both pre- and post-synaptic activities contribute. We imaged odor-specific activity patterns of the dorsal OB in the same anesthetized rats with fMRI and OICa(2+) and then co-registered the respective maps to compare patterns in the same space. Maps by each modality were very reproducible as trial-to-trial patterns for a given odor, overlapping by ~80%. Maps evoked by ethyl butyrate and methyl valerate for a given modality overlapped by ~80%, suggesting activation of similar dorsal glomerular networks by these odors. Comparison of maps generated by both methods for a given odor showed ~70% overlap, indicating similar odor-specific maps by each method. These results suggest that odor-specific glomerular patterns by high-resolution fMRI primarily tracks pre-synaptic input to the OB. Thus combining OICa(2+) and fMRI lays the framework for studies of OB processing over a range of spatiotemporal scales, where OICa(2+) can feature the fast dynamics of dorsal glomerular clusters and fMRI can map the entire glomerular sheet in the OB. PMID- 26631821 TI - Kawasaki disease in adults: Observations in France and literature review. AB - OBJECTIVE: Kawasaki disease (KD) is a vasculitis that mostly occurs in young children and rarely in adults. We analyzed the characteristics of adult-onset KD (AKD) in France. METHODS: We collected retrospective and prospective data for patients with a diagnosis of KD occurring after the age of 18 years. Cases were obtained via various French medical networks and identified from the international literature. RESULTS: We included 43 patients of AKD at 26 institution from 1992 to 2015, with mean (SD) age 30 (11) years (range 18-68) and sex ratio (M/F) 1.2; 34 patients met the American Heart Association criteria and 9 were incomplete AKD. The median time to diagnosis was 13 days (interquartile range 8-21). The main symptoms were fever (100%), exanthema (98%), changes in the extremities (91%), conjunctivitis (77%), oral cavity changes (89%), cervical adenitis (55%) and cardiac abnormalities (45%). Overall, 35% of patients showed large-vessel vasculitis: coronary vasculitis (26%) and coronary aneurysm (19%). Treatment was mostly intravenous immunoglobulins (79%) and aspirin (81%). Four patients showed myocardial infarction due to coronary vasculitis, but none were treated with IVIg because of late diagnosis. After a median follow-up of 5 months (range 1-117), persistent aneurysm was noted in 9% of cases. Damage was significantly lower with early treatment than late or no treatment (p=0.01). CONCLUSION: Given the high frequency of cardiac involvement and complications in this series of AKD, diagnosis and treatment should not be delayed, and early IVIg treatment seems to improve the outcome. PMID- 26631822 TI - Sources of moral distress for nursing staff providing care to residents with dementia. AB - The World Health Organization estimates the number of people living with dementia at approximately 35.6 million; they project a doubling of this number by 2030 and tripling by 2050. Although the majority of people living with a dementia live in the community, residential facility care by nursing care providers is a significant component of the dementia journey in most countries. Research has also shown that caring for persons with dementia can be emotionally, physically, and ethically challenging, and that turnover in nursing staff in residential care settings tends to be high. Moral distress has been explored in a variety of settings where nurses provide acute or intensive care. The concept, however, has not previously been explored in residential facility care settings, particularly as related to the care of persons with dementia. In this paper, we explore moral distress in these settings, using Nathaniel's definition of moral distress: the pain or anguish affecting the mind, body, or relationships in response to a situation in which the person is aware of a moral problem, acknowledges moral responsibility, makes a moral judgment about the correct action and yet, as a result of real or perceived constraints, cannot do what is thought to be right. We report findings from a qualitative study of moral distress in a single health region in a Canadian province. Our aim in this paper is to share findings that elucidate the sources of moral distress experienced by nursing care providers in the residential care of people living with dementia. PMID- 26631823 TI - Staff views on how to improve mealtimes for elderly people with dementia living at home. AB - Dementia commonly leads to difficulties in performing daily activities, which can also often affect the ability to prepare and eat meals. As a result, formal support to maintain good nutritional intake might be needed, but there is a lack of knowledge concerning how to support older persons with dementia living at home. The aim of this study was to explore and describe staff views on how to improve mealtimes for persons with dementia who are still living at home. A qualitative descriptive study was performed and data were collected during 2011 2012 through four focus group interviews with staff working in the homes of persons with dementia. Data were analyzed using inductive content analysis. The participants described several ways to improve mealtimes for persons with dementia and advocated adjustments facilitating the preservation of the persons' independence. Finding suitable actions calls for knowledge about the person and his/her individual situation. Proposed actions were enabling meals at home, taking over, and moving meals outside of the home. In addition, it was found that, the types of meals served to these persons should be as familiar to the individual as possible. The results of this study indicate the importance of using a person-centered approach and meeting the individual needs when supporting people with dementia in regards to their meals when living at home. Individualized care in the home may be expensive, however, it is fair to say that people who become malnourished and admitted to hospitals is even more costly. Furthermore, sharing and reflecting experiences and knowledge can assist staff to identify ways to manage complex situations. Therefore, the use of refection should be a part of staff members' everyday work. PMID- 26631825 TI - A Synthetic Route to 2-Alkyl Indoles via Thiophenol-Mediated Ring-Opening of N Tosylaziridines Followed by Copper Powder-Mediated C-N Cyclization/Aromatization. AB - A simple strategy for the syntheses of 2-alkyl indoles via regioselective ring opening of 2-(2-haloaryl)-3-alkyl-N-tosylaziridines with thiophenol, followed by copper powder-mediated intramolecular C-N cyclization and subsequent aromatization by the elimination of thiophenol, with good yields is described. Utilizing this protocol, 2-carboxyindole has been synthesized easily. PMID- 26631824 TI - Immortalization of human corneal epithelial cells using simian virus 40 large T antigen and cell characterization. AB - INTRODUCTION: Primary cultures of human corneal epithelial (HCE) cells usually cease to grow after four or five passages. This result in a small cell yield for experiments such as the eye irritancy test represents a serious problem for human and animal corneal epithelial research. In the present study, we established an HCE cell line immortalized by simian virus 40 (SV40), a polyomavirus, and characterized the inherent morphologic and cytologic cell properties. METHODS: Primary cultured HCE cells were infected with a SV40 large T antigen (SV40 T) expressing retrovirus, and were selected using G418 solution, an aminoglycoside antibiotic. To ensure that the immortalized cell lines express SV40 T and cytokeratin-3, a corneal epithelial-specific marker, we conducted reverse transcription (RT)-PCR and Western blot analysis. RESULTS: These cell lines continued to grow for more than 50 generations, exhibiting a cobble stone-like appearance similar to normal HCE cells and an increased proliferation rate compared to primary cultured HCE cells. RT-PCR results showed that the immortalized cell lines expressed SV40 T while the primary cultured cells did not. In the Western blot assay, protein levels of phosphorylated (Ser15) p53 protein were significantly decreased in the immortalized cell lines while the expression of total p53 protein was constant. In addition, expression of p21(cip1), a cell cycle protein, was down-regulated in the immortalized cells. Moreover, a cornea epithelium-specific marker, cytokeratin-3 (CK-3), was expressed at equal levels in the immortalized cells and primary HCE cells. DISCUSSION: Taken together, these results indicate that immortalized HCE cell lines were successfully established using the SV40-retroviral vector. These cells may be an excellent model for detecting the adverse effects of standard toxic materials and could replace the traditional eye irritation test as an animal-free alternative method. PMID- 26631826 TI - Acquired Gerbode Defects Associated with Infective Endocarditis. AB - Infective endocarditis is associated with a high risk of mortality and complications. A very rare complication is the development of an acquired left ventricle to right atrium (Gerbode) defect secondary to bacterial invasion of the membranous septum. We report two complex cases of infective endocarditis complicated by acquired Gerbode defects, outlining the role of two-dimensional (2D) and three-dimensional (3D) transoesophageal imaging. PMID- 26631827 TI - Correlations between MTP and ROS Levels of Peripheral Blood Lymphocytes and Readmission in Patients with Chronic Heart Failure. AB - BACKGROUND: Peripheral blood lymphocytes exhibit changes that parallel those in failing cardiomyocytes. We hypothesised that mitochondrial transmembrane potential (MTP) and reactive oxygen species (ROS) levels of lymphocytes are associated with serum NT-proBNP and short-term prognosis in patients with chronic heart failure (CHF). METHODS: Fifty-four CHF patients and 30 controls were enrolled in this prospective study. Mitochondrial transmembrane potential and ROS levels of lymphocytes were evaluated by flow cytometry and reported as the JC-1 fluorescence ratio and DCF fluorescence intensity, respectively. Serum NT-proBNP levels and biochemical parameters were also examined. All the participants received follow-up to evaluate clinical end-points after eight months. RESULTS: Chronic heart failure patients had higher levels of DCF fluorescence intensity of lymphocytes and serum NT-proBNP, as well as lower levels of JC-1 fluorescence ratios compared with those of controls (all P<0.05). A closer relationship was found between Lg(DCF fluorescence intensity of lymphocytes) or JC-1 fluorescence ratio of lymphocytes and Lg(NT-proBNP) (both P<0.05) in CHF patients. During the eight-month follow-up period, 14 CHF patients (25.9%) were readmitted for severe HF, but none died. A logistic regression analysis showed that both ROS level and MTP of the lymphocytes were independent predictors (B=7.03, P=0.006; B= - 0.32, P=0.029, respectively) of readmission of CHF patients. CONCLUSIONS: In CHF patients at low risk, MTP and ROS levels of the lymphocytes showed a significant change that is associated with serum NT-proBNP and patient readmission. PMID- 26631829 TI - Cancer survivors' risk of future admission to hospital. PMID- 26631828 TI - The current landscape of the mesenchymal stromal cell secretome: A new paradigm for cell-free regeneration. AB - The unique properties of mesenchymal stromal/stem cells (MSCs) to self-renew and their multipotentiality have rendered them attractive to researchers and clinicians. In addition to the differentiation potential, the broad repertoire of secreted trophic factors (cytokines) exhibiting diverse functions such as immunomodulation, anti-inflammatory activity, angiogenesis and anti-apoptotic, commonly referred to as the MSC secretome, has gained immense attention in the past few years. There is enough evidence to show that the one important pathway by which MSCs participate in tissue repair and regeneration is through its secretome. Concurrently, a large body of MSC research has focused on characterization of the MSC secretome; this includes both soluble factors and factors released in extracellular vesicles, for example, exosomes and microvesicles. This review provides an overview of our current understanding of the MSC secretome with respect to their potential clinical applications. PMID- 26631830 TI - Genetic mutations in paediatric cancer. PMID- 26631831 TI - NICE restructures the Cancer Drugs Fund. PMID- 26631832 TI - The effect of HIV coinfection, HAART and TB treatment on cytokine/chemokine responses to Mycobacterium tuberculosis (Mtb) antigens in active TB patients and latently Mtb infected individuals. AB - Identification of Mtb specific induced cytokine/chemokine host biomarkers could assist in developing novel diagnostic, prognostic and therapeutic tools for TB. Levels of IFN-gamma, IL-2, IL-17, IL-10, IP-10 and MIP-1alpha were measured in supernatants of whole blood stimulated with Mtb specific fusion protein ESAT 6/CFP-10 using xMAP technology. The study groups were HIV positive TB patients (HIV(+)TB(+)), HIV negative TB patients (HIV(-)TB(+)), HIV positive tuberculin skin test positive (TST+) (HIV(+)TST(+)), HIV negative TST+ (HIV(-)TST(+)), and HIV(-)TST(-) individuals. Compared to HIV(-)TST(-), latent TB infection led to increased levels of IP-10, IFN-gamma and IL-17, while levels of IL-2 and IP-10 were increased with active TB. Levels of IFN-gamma, IL-17, MIP-1alpha, and IL-10 were increased in HIV(-)TST(+) individuals compared to HIV(-)TB(+) patients. HIV coinfection decreased the level of IFN-gamma, IL-17, IP-10 and IL-2. After six months (M6) of anti-TB treatment (ATT) in HIV(-)TB(+) patients, IFN-gamma, IL-10, and MIP-1alpha levels normalized. After M6 and M18 of ATT plus HAART in HIV(+)TB(+) patients, levels of MIP-1alpha and IL-10 normalized, while this was not the case for IFN-gamma, IL-2, IL-17, and IP-10 levels. In HIV(+)TST(+) patients on HAART, levels of IFN-gamma, IL-17, IL-10 and MIP-1alpha normalized, while no change in the levels of IL-2 and IP-10 were observed. In conclusion, the simultaneous measurement of IFN-gamma, IL-17 and IP-10 may assist in diagnosing LTBI; IL-2 and IP-10 may assist in diagnosing active TB; while IFN-gamma, IL-17, MIP-1alpha, and IL-10 levels could help to discriminate LTBI and active TB. In addition, IL-10 and MIP-1alpha levels could help to monitor responses to TB treatment and HAART. PMID- 26631834 TI - Do chlorhexidine patient baths prevent catheter-associated urinary tract infections? PMID- 26631833 TI - Effect of body surface decolonisation on bacteriuria and candiduria in intensive care units: an analysis of a cluster-randomised trial. AB - BACKGROUND: Urinary tract infections (UTIs) are common health-care-associated infections. Bacteriuria commonly precedes UTI and is often treated with antibiotics, particularly in hospital intensive care units (ICUs). In 2013, a cluster-randomised trial (REDUCE MRSA Trial [Randomized Evaluation of Decolonization vs Universal Clearance to Eradicate MRSA]) showed that body surface decolonisation reduced all-pathogen bloodstream infections. We aim to further assess the effect of decolonisation on bacteriuria and candiduria in patients admitted to ICUs. METHODS: We did a secondary analysis of a three-group, cluster-randomised trial of 43 hospitals (clusters) with patients in 74 adult ICUs. The three groups included were either meticillin-resistant Staphylococcus aureus (MRSA) screening and isolation, targeted decolonisation (screening, isolation, and decolonisation of MRSA carriers) with chlorhexidine and mupirocin, and universal decolonisation (no screening, all patients decolonised) with chlorhexidine and mupirocin. Protocol included chlorhexidine cleansing of the perineum and proximal 6 inches (15.24 cm) of urinary catheters. ICUs within the same hospital were assigned the same strategy. Outcomes included high-level bacteriuria (>=50 000 colony forming units [CFU]/mL) with any uropathogen, high level candiduria (>=50 000 CFU/mL), and any bacteriuria with uropathogens. Sex specific analyses were specified a priori. Proportional hazards models assessed differences in outcome reductions across groups, comparing an 18-month intervention period to a 12-month baseline period. FINDINGS: 122 646 patients (48 390 baseline, 74 256 intervention) were enrolled. Intervention versus baseline hazard ratios (HRs) for high-level bacteriuria were 1.02 (95% CI 0.88-1.18) for screening or isolation, 0.88 (0.76-1.02) for targeted decolonisation, and 0.87 (0.77-1.00) for universal decolonisation (no difference between groups, p=0.26), with no sex-specific reductions (HRs for men: 1.09 [95% CI 0.85-1.40] for screening or isolation, 1.01 [0.79-1.29] for targeted decolonisation, and 0.78 [0.63-0.98] for universal decolonisation, p=0.12; HRs for women: 0.97 [0.80-1.17] for screening and isolation, 0.83 [0.70-1.00] for targeted decolonisation, and 0.93 [0.79-1.09] for universal decolonisation, p=0.49). HRs for high-level candiduria were 1.14 (0.95-1.37) for screening and isolation, 0.99 (0.83-1.18) for targeted decolonisation, and 0.83 (0.70-0.99) for universal decolonisation (p=0.05). Differences between sexes were due to reductions in men in the universal decolonisation group (HRs: 1.21 [95% CI 0.88-1.68] for screening or isolation, 1.01 [0.73-1.39] for targeted decolonisation, and 0.63 [0.45-0.89] for universal decolonisation, p=0.02). Bacteriuria with any CFU/mL was also reduced in men in the universal decolonisation group (HRs 1.01 [0.81-1.25] for screening or isolation, 1.04 [0.83-1.30] for targeted decolonisation, and 0.74 [0.61-0.90] for universal decolonisation, p=0.04). INTERPRETATION: Universal decolonisation of patients in the ICU with once a day chlorhexidine baths and short-course nasal mupirocin could be a potential preventive strategy in male patients because it significantly decreases candiduria and any bacteriuria, but not for women. FUNDING: HAI Program from AHRQ, US Department of Health and Human Services as part of the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) program, CDC Prevention Epicenters Program. PMID- 26631835 TI - Commentary on: "'Targeted top-down' approach for the investigation of urinary tract infection: A 10-year follow up study in a cohort of 1000 children". PMID- 26631836 TI - Response to letter to the editor Re: "Clinical indications for augmentation in children with neurogenic urinary incontinence following bladder outlet procedures: Results of a 14-year observational study". PMID- 26631837 TI - Asthma in Olympians. AB - High prevalence of asthma has been reported repeatedly among elite athletes, especially among endurance athletes. So many athletes used asthma drugs that the objective demonstration of bronchial hyperresponsiveness was required to obtain approval for their use in international sports until 2012 when the most used inhaled asthma drugs was allowed for free use, but with a maximum dose for inhaled beta2-agonists. Several factors contribute to the development of asthma among the Olympians causing airways inflammation and bronchial hyper responsiveness. PMID- 26631838 TI - Relative Prognostic and Predictive Value of Gene Signature and Histologic Grade in Estrogen Receptor-Positive, HER2-Negative Breast Cancer. AB - BACKGROUND: In estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, first-generation genomic signatures serve predominately as prognostic biomarkers and secondarily as predictors of response to chemotherapy. We compared both the prognostic and predictive value of histologic grades and genomic markers. METHODS: We retrieved publicly available cDNA microarray data from 1373 primary ER(+)/HER2(-) breast cancers and developed a genomic signature simulated from Recurrence Online (http://www.recurrenceonline.com/) to calculate the recurrence score and risk using predefined sets of genes in the cDNA microarray. We then compared the prognostic and predictive information provided by histologic grade and genomic signature. RESULTS: Based on genomic signatures, 55%, 28%, and 17% of breast cancers were classified as low, intermediate, and high risk, respectively, whereas the histologic grades were I, II, and III in 22%, 59%, and 19% of breast cancers, respectively. Univariate analysis in the untreated cohort revealed that both histologic grade (overall P = .007) and genomic signature (P < .001) could predict prognosis. Results were similar using the genomic signature, with pathologic complete response rates of 4.6%, 5.7%, and 16.5% for low-, intermediate-, and high-risk cancers, respectively. Neither biomarker was statistically significant in multivariate analysis for predictive response to neoadjuvant chemotherapy (NAC). CONCLUSION: Genomic signature was better at identifying low-risk cases compared to histologic grade alone, but both markers had similar predictive values for NAC response. Better predictive biomarkers for NAC response are still needed. PMID- 26631839 TI - Consequences of Obstructive Sleep Apnea in Children. AB - Obstructive sleep apnea syndrome (OSAS) has various negative health and behavioral consequences in the pediatric population. As shown in adults, there are metabolic derangements such as obesity, insulin sensitivity, dyslipidemia, and metabolic syndrome, as well as cardiovascular derangements like hypertension, chronic inflammation, endothelial dysfunction, ventricular size/function abnormalities, and even elevated pulmonary arterial pressures, that can be seen in children with OSAS. The first two sections will discuss the metabolic and cardiovascular consequences on OSAS in children. The last section summarizes selected studies and reviews on the behavioral, neurocognitive and academic consequences of OSAS in children. PMID- 26631841 TI - Review of ultrasound appearance in inflammatory breast cancer: A pictorial essay. AB - Inflammatory breast cancer (IBC) is a rare malignancy accounting for 1-2% of breast cancers. It has an aggressive clinical presentation and poor prognosis. The sonographic findings in 41 patients with a clinical diagnosis of IBC and biopsy-proven breast malignancy are presented in this study. The most common finding was the presence of skin thickening (92%). Multiple small anechoic spaces within the dermis, correlating with the presence of dermal lymphatic invasion by tumour emboli on histopathology were noted in approximately one-third of cases. Other sonographic findings included single or multiple masses, parenchymal oedema, axillary lymphadenopathy, echogenic foci consistent with microcalcifications and increased vascularity. PMID- 26631840 TI - Biosafety considerations for attenuated measles virus vectors used in virotherapy and vaccination. AB - Attenuated measles virus (MV) is one of the most effective and safe vaccines available, making it attractive candidate vector to prevent infectious diseases. Attenuated MV have acquired the ability to use the complement regulator CD46 as a major receptor to mediate virus entry and intercellular fusion. Therefore, attenuated MV strains preferentially infect and destroy a wide variety of cancer cells making them also attractive oncolytic vectors. The use of recombinant MV vector has to comply with various regulatory requirements, particularly relating to the assessment of potential risks for human health and the environment. The present article highlights the main characteristics of MV and recombinant MV vectors used for vaccination and virotherapy and discusses these features from a biosafety point of view. PMID- 26631842 TI - Ascorbic acid promotes extracellular matrix deposition while preserving valve interstitial cell quiescence within 3D hydrogel scaffolds. AB - Current options for aortic valve replacements are non-viable and thus lack the ability to grow and remodel, which can be problematic for paediatric applications. Toward the development of living valve substitutes that can grow and remodel, porcine aortic valve interstitial cells (VICs) were isolated and encapsulated within proteolytically degradable and cell-adhesive poly(ethylene glycol) (PEG) hydrogels, in an effort to study their phenotypes and functions. The results showed that encapsulated VICs maintained high viability and proliferated within the hydrogels. The VICs actively remodelled the hydrogels via secretion of matrix metalloproteinase-2 (MMP-2) and deposition of new extracellular matrix (ECM) components, including collagens I and III. The soft hydrogels with compressive moduli of ~4.3 kPa quickly reverted VICs from an activated myofibroblastic phenotype to a quiescent, unactivated phenotype, evidenced by the loss of alpha-smooth muscle actin expression upon encapsulation. In an effort to promote VIC-mediated ECM production, ascorbic acid (AA) was supplemented in the medium to investigate its effects on VIC function and phenotype. AA treatment enhanced VIC spreading and proliferation, and inhibited apoptosis. AA treatment also promoted VIC-mediated ECM remodelling by increasing MMP-2 activity and depositing collagens I and III. AA treatment did not significantly influence the expression of alpha-smooth muscle actin (myofibroblast activation marker) and alkaline phosphatase (osteogenic differentiation marker). No calcification or nodule formation was observed within the cell-laden hydrogels, with or without AA treatment. These results suggest the potential of this system and the beneficial effect of AA in heart valve tissue engineering. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26631843 TI - The role of rhynchophylline in alleviating early brain injury following subarachnoid hemorrhage in rats. AB - Rhynchophylline (Rhy) has been demonstrated protective effects on some neurological diseases. However, the roles of Rhy in the subarachnoid hemorrhage (SAH) are still to be cleared. In the present study, the effects of Rhy on attenuation of early brain injury (EBI) after SAH have been evaluated. The adult male Sprague-Dawley rats (280-300g) were used to establish the SAH models using endovascular perforation method. Rhy was administered by intraperitoneal injection immediately following SAH. Brain edema was assessed by magnetic resonance imaging (MRI) at 24h after SAH. Neurological deficits, brain water content, malondialdehyde (MDA) concentration, myeloperoxidase (MPO) activity and reactive oxygen species (ROS) content in hippocampus were also evaluated. Immunofluorescence and western blot were used to explore the underlying protective mechanism of Rhy. The results showed that, following 10mg/kg Rhy treatment, the brain edema and neurological deficits, and blood-brain barrier (BBB) disruption were significantly attenuated at 24h after SAH. Additionally, in hippocampus, MDA concentration, MPO activity and ROS content were markedly decreased. Meanwhile, the levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase (NQO-1) were increased, while the expressions of p-p53, cleaved-caspase-3 and tumor necrosis factor-alpha (TNF-alpha) were significantly decreased. Our results indicated that Rhy could attenuate early brain injury by reducing inflammation and apoptosis in hippocampus after SAH. PMID- 26631844 TI - Myelin and macrophages in the PNS: An intimate relationship in trauma and disease. AB - Macrophages of the peripheral nervous system belong to the so-called tissue macrophages, with multiple functions during injury and disease. Their origin during ontogeny has not yet been completely resolved, but it is clear that upon injury and disease conditions, they are supplemented by hematopoietic derivatives. In the peripheral nervous system, the most abundantly investigated scenario in which resident and infiltrating macrophages are involved is the so called "Wallerian degeneration", a complex degenerative process where macrophages exhibit mostly beneficial functions by phagocytosing myelin and axonal remnants. Of special interest is the implication of macrophages in inflammatory nerve diseases, like acute Guillain-Barre syndromes and its permanent variant, chronic inflammatory demyelinating polyneuropathy, where macrophages are supposed to be substantial (co-)mediators of the diseases. In inherited peripheral neuropathies nerve macrophages possess a clear disease-amplifying function. In the corresponding animal models, a coordinated interplay between mutant Schwann cells, macrophages, endoneurial fibroblasts and the target structure, myelin, emerged. Along this process, a newly discovered disease mechanism mediated by macrophages is the dedifferentiation of myelinating Schwann cells. As macrophages are amplifiers of the genetically-mediated, non-curable diseases, targeting the mechanisms of their activation might be a promising strategy to treat these disorders. This article is part of a Special Issue entitled SI: Myelin Evolution. PMID- 26631845 TI - Estimation of stature by cephalometric facial dimensions in skeletonized bodies: study from a sample modern Colombians skeletal remains. AB - Estimation of stature is an important factor in the identification of the deceased from unknown fragmentary and dismembered remains. The skull sometimes is the only remain available for identification. The aim of the present study was to estimate the stature of an individual from cephalo-facial dimensions. The study was carried out on 54 males and 16 females from the bone collection of the contemporary Colombian population that belongs to the National Institute of Legal Medicine. Ten cephalo-facial measurements were also made on each subject. The stature of each individual in centimeters was taken from the registration and/or from the autopsy document. The results indicate that the measurements N-M (p<0.001) and G-Op, Ba-N, Ma-SN (p<0.05) are correlated with stature for males. The correlation between these measures with stature for females was not significant. However, the formulae obtained from univariate linear regression analysis using cephalo-facial measurements showed a greater degree of reliability for estimation of stature in males and females. PMID- 26631846 TI - MicroRNA-mediated mechanisms of the cellular stress response in atherosclerosis. PMID- 26631847 TI - Risk factors: Moderate coffee drinking is associated with lower risk of death from CVD. PMID- 26631848 TI - Biomarkers: Novel troponin immunoassay for early ACS rule-out. PMID- 26631849 TI - Ambulatory arterial stiffness in chronic kidney disease: a methodological review. AB - Cardiovascular mortality is the leading cause of death in chronic kidney disease (CKD) and end-stage renal disease (ESRD). This can be explained in part by an increased and progressive calcification of the medial layer of the large arteries leading to arterial stiffening. The prognostic value of measurements of arterial stiffness, especially pulse wave velocity (PWV), in the general population and in CKD and ESRD patients is high, and is above that of traditional risk factors with respect to cardiovascular outcome. In recent years, as an alternative to office measurements, methods for monitoring ambulatory arterial stiffness have been developed. The ambulatory arterial stiffness index (AASI) allows derivation of a parameter from ambulatory blood pressure measurements; however, doubts have emerged about the usefulness of this parameter. Recently, new oscillometric methodologies using simple brachial cuffs, such as Mobil-O-Graph, Vasotens or Arteriograph 24, have been introduced. They measure parameters of 24-h arterial stiffness including PWV, augmentation index and central blood pressure. This enables study of the 24-h variability of these parameters, which will hopefully lead to better cardiovascular risk stratification and improved cardiovascular outcomes of patients. Our review summarizes the present data and future directions of AASI and the methods for monitoring oscillometric 24-h stiffness in different patient populations and especially in CKD. PMID- 26631850 TI - Soluble receptor for advanced glycation end products and increased aortic stiffness in the general population. AB - It has been suggested that accumulation of advanced glycation end products (AGEs) is involved in several pathophysiological processes in the vessel wall. We hypothesized that low levels of the soluble receptor for AGEs (sRAGE) might be associated with increased arterial stiffness, a manifestation of vascular ageing in the general population. Using a cross-sectional design, we analyzed 1077 subjects from the Czech post-MONICA study. The aortic pulse wave velocity (aPWV) was measured using a Sphygmocor device. sRAGE concentrations were assessed in frozen samples using enzyme-linked immunosorbent assay methods (R&D Systems). aPWV significantly (P<0.0001) increased across the sRAGE quartiles. An aPWV of 1 m s(-1) was associated with a 37% increase in the risk of low sRAGE (<918 pg ml( 1), bottom quartile; P-value=0.018). In a categorized manner, subjects in the bottom sRAGE quartile had an odds ratio of an increased aPWV (?9.3 m s(-1)), adjusted for all potential confounders of 2.05 (95% confidence interval: 1.26 3.32; P=0.004), but this was only the case for non-diabetic hypertensive patients. In contrast, a low sRAGE was rejected as an independent predictor of an increased aPWV in normotensive or diabetic subjects using similar regression models. In conclusion, low circulating sRAGE was independently associated with increased arterial stiffness in a general population-based sample, but this was only observed in hypertensive non-diabetic patients. PMID- 26631851 TI - Excessive variability in systolic blood pressure that is self-measured at home exacerbates the progression of brain white matter lesions and cognitive impairment in the oldest old. AB - To investigate the effects of variability in self-measured systolic blood pressure at home on the progression of cognitive impairment and white matter lesions in the oldest old. Between April 2009 and October 2009, 248 oldest old aged 80 years or older were eligibly enrolled from geriatric practices and community-dwelling areas of Shandong, China. Self-measured blood pressure at home (HBP) was measured for 7 consecutive days at the baseline, and the Mini-Mental State Examination (MMSE) score and brain white matter hyperintensities (WMH) were assessed at the baseline and during the final follow-up visit. Variability in systolic HBP was evaluated using coefficient of variation (CV) in serial daily systolic HBP measurements of the last 6 consecutive days. After an average of 2.3 years of follow-up visits, 232 oldest old were included in and 16 were excluded from the analysis. The MMSE score declined -4.76 (interquartile ranges: -10.71, 0.83) %, the periventricular WMH, deep WMH, total WMH and WMH fraction increased 16.46 (s.d.: 6.72)%, 10.05 (s.d.: 6.40)%, 14.69 (s.d.: 6.07)% and 15.95 (s.d.: 6.32)%, respectively, in the total oldest old. A declined percentage of the MMSE score and increased percentages of the periventricular WMH, deep WMH, total WMH and WMH fraction in the high group divided by tertile of the CV of the systolic HBP at baseline were greater than those in the low group (P<0.05). The significant differences were retained after adjusting for covariates, including the MMSE score, periventricular WMH, deep WMH and WMH fraction at the baseline (P<0.05). Excessive variability in self-measured systolic HBP exacerbates the progression of cognitive impairment and brain white matter lesions in the oldest old. PMID- 26631853 TI - Automated plethysmographic measurement of the ankle-brachial index: a comparison with the doppler ultrasound method. AB - The ankle-brachial index is widely regarded as a pivotal tool for the diagnosis and quantification of peripheral arterial disease. It is, however, plagued by issues relating to its time consuming nature and the skills required to undertake its measurement using the gold standard Doppler ultrasound method. Automated ankle-brachial index measurement devices aim to address such issues; this study aimed to compare the performance of such a device with the Doppler method. Three hundred and eighty participants, with risk factors for cardiovascular disease (mean age: 64, 57% male), underwent ankle-brachial index measurement firstly with a plethysmographic device followed by the Doppler method. The mean difference between the two methods was 0.016+/-0.1, 95% limits of agreement:+/-0.2. Sensitivity for detection of peripheral arterial disease, as defined by Doppler ankle-brachial index?0.9, was 70%, specificity 96%, accuracy 94%. A receiver operating curve revealed an area under the curve of.96, with a 1.04 plethysmographic ankle-brachial index cutoff for optimal sensitivity (98%) and specificity (75%). Automated measurements were significantly faster than Doppler measurements (7 min 55 s vs. 17 min 45 s, respectively, P <0.01). Although is it unclear if the plethysmographic device has sufficient diagnostic accuracy to be used as a stand alone test for the diagnosis of peripheral arterial disease, it is concluded that it can be used as a fast and amenable method of identifying people who require further arterial assessment; the higher cutoff point of 1.04 should be used for this purpose. PMID- 26631855 TI - Suicide: Old Problem, New Solutions Needed. PMID- 26631852 TI - Current therapies and investigational drugs for peripheral arterial disease. AB - Peripheral artery disease (PAD) is associated with elevated morbidity and mortality with cardiovascular (CV) disease. The guideline recommends smoking cessation and antiplatelet/antithrombotic drugs for asymptomatic and symptomatic PAD patients. It also recommends that PAD patients with critical limb ischemia (CLI) should be considered to receive endovascular and open surgical treatment for limb salvage. Although PAD patients with CLI receive these treatments, they are sometimes unable to deliver sufficient blood flow to eliminate their symptoms. Thus specific strategies are needed to promote enough blood flow. To establish the effective method, many investigations have been performed using cell-based therapy. Endothelial progenitor cells, mononuclear cells and mesenchymal stem cells have been well investigated in clinical settings. To induce angiogenesis, vascular endothelial growth factor, fibroblast growth factor and hepatocyte growth factor (HGF) have also been transfected in PAD patients. Among them, HGF is the most promising factor because it can induce angiogenesis without the induction of vascular inflammation and increased permeability. In this review article, we summarize current treatments and investigational drugs of PAD. PMID- 26631856 TI - Exploring Helpful Nursing Care in Pediatric Mental Health Settings: The Perceptions of Children with Suicide Risk Factors and Their Parents. AB - This qualitative descriptive study explored helpful nursing care from the perspective of children with suicide-associated risk factors, and their parents. Data were collected through participant observation followed by a debriefing session with children, and semi-structured interviews with parents. The inductive analysis revealed four themes of helpful interventions: (1) caring for the child as a special person; (2) caring for the parents; (3) managing the child's illness; and (4) creating a therapeutic environment. The study findings highlight the importance of the relational aspect of nursing care and provide important insights related to family-centered and strengths-based practice with children at increased risk for suicide later in life. PMID- 26631857 TI - Prevalence and Predictors of Depressive Symptoms in Pregnant African American Women. AB - African American women may be especially vulnerable to antepartum depression, a major health concern during pregnancy. This study investigated the prevalence and predictors of depressive symptoms in a sample of African American women who were between 14-17 weeks pregnant, a timeframe that is typically thought to be a time of general well-being. Two-thirds reported a CES-D score >= 16 indicative of depressive symptomatology. Age, perceived stress (as measured by the Perceived Stress Scale [PSS]), and anxiety (as measured by the State Trait Anxiety Inventory [STAI]) predicted depressive symptoms; the interaction between PSS and STAI scores was also a significant predictor. Our study findings suggest that early identification of stress and anxiety, in addition to depressive symptoms, is vital for intervention with this group. PMID- 26631854 TI - Renal denervation mitigates cardiac remodeling and renal damage in Dahl rats: a comparison with beta-receptor blockade. AB - Chronic activation of the sympathetic nervous system (SNS) contributes to cardiac remodeling and the transition to heart failure (HF). Renal sympathetic denervation (RDN) may ameliorate this damage by improving renal function and sympathetic cardioregulation in hypertensive HF patients with renal injury. The efficacy may be comparable to that of chronic beta-blocker treatment. Dahl salt sensitive hypertensive rats were subjected to RDN in the hypertrophic stage. Another group of Dahl rats were subjected to sham operations and treated chronically with vehicle (CONT) or beta-blocker bisoprolol (BISO). Neither RDN nor BISO altered the blood pressure; however, BISO significantly reduced the heart rate (HR). Both RDN and BISO significantly prolonged survival (22.2 and 22.4 weeks, respectively) compared with CONT (18.3 weeks). Echocardiography revealed reduced left ventricular (LV) hypertrophy and improved LV function, and histological analysis demonstrated the amelioration of LV myocyte hypertrophy and fibrosis in the RDN and BISO rats at the HF stage. Tyrosine hydroxylase and beta1 adrenergic receptor (ADR) expression levels in the LV myocardium significantly increased only in the RDN rats, whereas the alpha1b-, alpha1d- and alpha2c-ADR expression levels increased only in the BISO rats. In both groups, renal damage and dysfunction were also reduced, and this reduction was accompanied by the suppression of endothelin-1, renin and angiotensin-converting enzyme mRNAs. RDN ameliorated the progression of both myocardial and renal damage in the hypertensive rats independent of blood pressure changes. The overall effects were similar to those of beta-receptor blockade with favorable effects on HR and alpha ADR expression. These findings may be associated with the restoration of the myocardial SNS and renal protection. PMID- 26631858 TI - The Stress Gym: An Online Intervention to Improve Stress and Depressive Symptoms in Adults. AB - Finding methods to facilitate efficient assimilation of relevant health care information is important for quality outcomes, including promoting maximal wellness and optimal patient outcomes in vulnerable populations. The Internet is a promising information resource that can be used to reach those suffering from depression, but evidence of its efficacy in this population is lacking. This study was designed to examine The Stress Gym intervention, a web-enhanced behavioral self-management program (WEB-SM) consisting of nine modules focused on the management of stress and depression. The effect of the Stress Gym intervention on depressive symptoms, stress, and attention was examined, from pre to post-intervention, in participants with stress and in participants who were experiencing both stress and depressive symptoms. A statistically significant decrease in depressive symptoms and stress was observed and there was a statistically significant increase in attention after the Stress Gym intervention, on average, for all participants. This study supports the efficacy of Stress Gym as a tool to reduce depressive symptoms, stress, and attentional difficulties. There were significant improvements in participants overall and for participants when they were segregated into two groups, those with stress only and those with depressive symptoms and stress. With many patients choosing to explore health concerns online, it is important to have evidence-based programs available online that can help them manage their symptoms. PMID- 26631859 TI - The Scope of Mental Illness and Status of Psychiatric Care in Uganda. AB - Mental illness in Uganda affects over one-third of the population. Less than half of these individuals seek intervention because of the lack of mental health services, including providers of care, such as nurses; psychotropic medicines; psychosocial interventions; and psychotherapies. Stigma associated with mental illness also is a significant barrier to care. The purpose of this article is to describe the scope of mental illness and the status of psychiatric care in Uganda as well as to provide implications for mental health nursing. PMID- 26631860 TI - Policy and Payment Factors Affecting the PMH-NP in the United States. AB - There are unique policy and reimbursement issues pertinent to the Psychiatric Mental Health-Nurse Practitioner (PMH-NP) that are complex and ever-evolving. In the past decade specifically, mental health legislation at the federal level has made, and will continue to make, a serious impact on PMH-NP practice. Pending legislation and policy trends, namely telehealth, affect how and where PMH-NPs will practice and the rates of reimbursement. This article summarizes some recent developments and trends regarding delivery of care and payment that are germane to the PMH-NP. The Center for Medicaid and Medicare Services' (CMS) guidelines for mental health billing and telehealth also are discussed. PMID- 26631861 TI - Post-Traumatic Stress, Trauma-Informed Care, and Compassion Fatigue in Psychiatric Hospital Staff: A Correlational Study. AB - Assault of staff in psychiatric hospitals is a frequent occurrence, and studies indicate that hospital staff are at risk of developing post-traumatic stress disorder (PTSD). We performed a correlational study with a convenience sample of 172 staff in a psychiatric hospital and compared the rate of traumatic events (TEs), resilience, confidence, and compassion fatigue to PTSD symptoms (PTSS). Regression analyses identified two variables that were unique predictors of PTSS: (1) trauma-informed care (TIC) meeting attendance and (2) burnout symptoms. Severe TEs, age, and compassion satisfaction also contributed to the model. Attention to these factors may help reduce PTSS in psychiatric staff. PMID- 26631862 TI - Impact of Motivational Interviewing on Medication Adherence in Schizophrenia. AB - This literature review addresses the question of whether motivational interviewing (MI) is effective at improving medication adherence in patients with schizophrenia. The databases PsycINFO, OVID Medline, and PubMed were searched using the keywords "schizophrenia," "medication adherence," and one of the following: "motivational interviewing," "adherence therapy," or "compliance therapy." Relevant studies from the last ten years were included, resulting in six studies being included in this literature review. One study presented evidence for a direct relationship between motivational interviewing and medication adherence. Most studies did not support this relationship. Some studies found evidence for a relationship between motivational interviewing and other outcomes such as improved psychotic symptoms and decreased re hospitalization rates. Motivational interviewing may be beneficial for some patients with schizophrenia but should not be considered a first line therapy. Clinicians not already using motivational interviewing in providing care to their patients with schizophrenia should not implement it for this population. PMID- 26631863 TI - The Lived Experience of Getting and Having a Home of One's Own: A Meta-Synthesis. AB - This study aimed to synthesize findings from qualitative studies that explored the lived experiences of persons with serious mental illness with regard to getting and having a home. A systematic search strategy was used. Data from 24 articles were extracted and analyzed using a phenomenological-hermeneutic approach. The total number of informants was N = 769. Four main themes emerged: (1) The Turning Point: The Transition to a Home, (2) The Key to Stability and Thriving: Having and Estating a Home, (3) Home: The Mental Health Hub, and (4) Home: The Base Camp for Reconnecting and Relating. PMID- 26631864 TI - A New Pair of Glasses: Creating a World where Recovery is Possible. PMID- 26631865 TI - The Value of Mental Health First Aid Training. PMID- 26631866 TI - An Ageing Methadone Population: A Challenge to Aged Persons' Mental Health Services? AB - Oral administration of methadone has been used as a treatment strategy for opiate addiction for many years. The state of Victoria, Australia, has a long-running methadone program with a large number of participants. Accordingly, a growing number of adults have utilised methadone maintenance treatment for a number of years and are now moving into older age due to advances in medical treatment and harm reduction initiatives. The objective of this review is to examine the literature pertaining to co-occurring mental illness in older methadone treatment participants and to explore the future challenges this growing cohort of ageing adults pose to aged persons' psychiatry services. As part of a broader study into dual diagnosis in older adults, a search of the Scopus, ProQuest, and CINAHL journal databases was performed. Twenty abstracts from literature published within the previous 15 years (1999-2014) were identified that explored methadone maintenance programs and the older adults maintained on them. A number of researchers have identified the ageing methadone population to have a high degree of comorbid mental illness and psychological distress. Studies also indicate that individuals enrolled in methadone maintenance programs may engage in a degree of continual substance use, potentially leading to deleterious effects on their psychosocial function. An ageing methadone population experiencing a high degree of comorbid mental illness is likely to challenge aged persons' psychiatry services. These services are likely to be increasingly called on to manage these individuals, particularly within Victoria where few substance use services exist for those over the age of 65. It is essential that aged persons' psychiatry services prepare to provide care for these individuals in a responsive manner that is inclusive of both their mental health and substitution pharmacotherapy. PMID- 26631868 TI - Synthesis of characteristic Mycobacterium peptidoglycan (PGN) fragments utilizing with chemoenzymatic preparation of meso-diaminopimelic acid (DAP), and their modulation of innate immune responses. AB - Peptidoglycan (PGN) is a major component of bacterial cell wall and is recognized as a potent immunostimulant. The PGN in the cell envelope of Mycobacterium Tuberculosis has been shown to possess several unique characteristics including the presence of N-glycolyl groups (in addition to N-acetyl groups) in the muramic acid residues, and amidation of the free carboxylic acid of d-Glu or of meso-DAP in the peptide chains. Using a newly developed, highly stereoselective, chemoenzymatic approach for the synthesis of meso-DAP in peptide stems, we successfully synthesized for the first time, a series of Mycobacterium PGN fragments that include both mono- and disaccharides of MurNGlyc or 1,6-anhydro MurNGlyc, as well as peptide-amidated variants. The ability of these PGN fragments to stimulate the immune system through activation of human Nod1 and Nod2 was examined. The PGN fragments were found to modulate immune stimulation, specifically, amidation at the d-Glu and meso-DAP in the peptide stem strongly reduced hNod1 activation. This effect was dependent on modification position. Additionally, N-glycolyl (instead of acetyl) of muramic acid was associated with slightly reduced human Nod1 and Nod2 stimulatory capabilities. PMID- 26631869 TI - Stress tolerances of nullmutants of function-unknown genes encoding menadione stress-responsive proteins in Aspergillus nidulans. AB - A group of menadione stress-responsive function-unkown genes of Aspergillus nidulans (Locus IDs ANID_03987.1, ANID_06058.1, ANID_10219.1, and ANID_10260.1) was deleted and phenotypically characterized. Importantly, comparative and phylogenetic analyses of the tested A. nidulans genes and their orthologs shed light only on the presence of a TANGO2 domain with NRDE protein motif in the translated ANID_06058.1 gene but did not reveal any recognizable protein-encoding domains in other protein sequences. The gene deletion strains were subjected to oxidative, osmotic, and metal ion stress and, surprisingly, only the DeltaANID_10219.1 mutant showed an increased sensitivity to 0.12 mmol l(-1) menadione sodium bisulfite. The gene deletions affected the stress sensitivities (tolerances) irregularly, for example, some strains grew more slowly when exposed to various oxidants and/or osmotic stress generating agents, meanwhile the DeltaANID_10260.1 mutant possessed a wild-type tolerance to all stressors tested. Our results are in line with earlier studies demonstrating that the deletions of stress-responsive genes do not confer necessarily any stress-sensitivity phenotypes, which can be attributed to compensatory mechanisms based on other elements of the stress response system with overlapping functions. PMID- 26631870 TI - Reproducibility and responsiveness of a Danish Pedi-IKDC subjective knee form for children with knee disorders. AB - The modified International Knee Documentation Committee Subjective Knee Form (Pedi-IKDC) is a widely used patient-reported tool ranging on a scale from 0 to 100. We aimed to translate Pedi-IKDC into Danish and assess its reproducibility and responsiveness in children with knee disorders. The translation complied with the international guidelines. Reproducibility was assessed in 53 children (15 years) responding Pedi-IKDC at baseline and after 3-14 days. For analysis of responsiveness, 94 children (15 years) responded Pedi-IKDC again after 3 months. Test-retest reliability was excellent. Intraclass correlation coefficient was 0.9, standard error of measurement was 4.1 points, and smallest detectable change (SDC) was 11.3 points. Evaluating responsiveness as a large effect was found in children reporting improvement compared with children reporting deterioration. The change score was correlated to the external anchor Global Rating Scale consisting of 15 answers from -7 "A very great deal worse" to +7 "A very great deal better," with a Spearmen's rho of 0.45 (P > 0.001). The minimal clinically important changes was 12.0. In conclusion, excellent test-retest reproducibility was found at group level, but at individual level the SDC was high. The Pedi-IKDC showed adequate responsiveness and is suitable for assessing improvement or deterioration in children with knee disorders. PMID- 26631871 TI - A new sensitizer DVDMS combined with multiple focused ultrasound treatments: an effective antitumor strategy. AB - Sonodynamic therapy (SDT) was developed as a promising noninvasive approach. The present study investigated the antitumor effect of a new sensitizer (sinoporphyrin sodium, referred to as DVDMS) combined with multiple ultrasound treatments on sarcoma 180 both in vitro and in vivo. The combined treatment significantly suppressed cell viability, potentiated apoptosis, and markedly inhibited angiogenesis in vivo. In vivo, the tumor weight inhibition ratio reached 89.82% fifteen days after three sonication treatments plus DVDMS. This effect was stronger than one ultrasound alone (32.56%) and than one round of sonication plus DVDMS (59.33%). DVDMS combined with multiple focused ultrasound treatments initiated tumor tissue destruction, induced cancer cell apoptosis, inhibited tumor angiogenesis, suppressed cancer cell proliferation, and decreased VEGF and PCNA expression levels. Moreover, the treatment did not show obvious signs of side effects or induce a drop in body weight. These results indicated that DVDMS combined with multiple focused ultrasounds may be a promising strategy against solid tumor. PMID- 26631874 TI - Cystic Fibrosis: A Review of Associated Phenotypes, Use of Molecular Diagnostic Approaches, Genetic Characteristics, Progress, and Dilemmas. AB - Cystic fibrosis (CF) is an autosomal recessive disease with significant associated morbidity and mortality. It is now appreciated that the broad phenotypic CF spectrum is not explained by obvious genotype-phenotype correlations, suggesting that CF transmembrane conductance regulator (CFTR) related disease may occur because of multiple additive effects. These contributing effects include complex CFTR alleles, modifier genes, mutations in alternative genes that produce CF-like phenotypes, epigenetic factors, and environmental influences. Most patients in the United States are now diagnosed through newborn screening and use of molecular testing methods. We review the molecular testing approaches and laboratory guidelines for carrier screening, prenatal testing, newborn screening, and clinical diagnostic testing, as well as recent developments in CF treatment, and reasons for the lack of a molecular diagnosis in some patients. PMID- 26631872 TI - Target engagement and drug residence time can be observed in living cells with BRET. AB - The therapeutic action of drugs is predicated on their physical engagement with cellular targets. Here we describe a broadly applicable method using bioluminescence resonance energy transfer (BRET) to reveal the binding characteristics of a drug with selected targets within intact cells. Cell permeable fluorescent tracers are used in a competitive binding format to quantify drug engagement with the target proteins fused to Nanoluc luciferase. The approach enabled us to profile isozyme-specific engagement and binding kinetics for a panel of histone deacetylase (HDAC) inhibitors. Our analysis was directed particularly to the clinically approved prodrug FK228 (Istodax/Romidepsin) because of its unique and largely unexplained mechanism of sustained intracellular action. Analysis of the binding kinetics by BRET revealed remarkably long intracellular residence times for FK228 at HDAC1, explaining the protracted intracellular behaviour of this prodrug. Our results demonstrate a novel application of BRET for assessing target engagement within the complex milieu of the intracellular environment. PMID- 26631876 TI - Luminescent bioactive NHC-metal complexes to bring light into cells. AB - Organometallic complexes are mostly used in catalytic applications and nowadays they are attracting more and more attention for biomedical applications. Until the last decade, research in the latter area was focused on screening of complexes against cancer cell lines, bacteria or parasites. For a couple of years mechanistic studies have helped in elucidating the mode of action of such complexes, one of the applied methods consists of studying cell uptake and intracellular distribution of luminescent bioactive complexes, in order to identify the main targets. This perspective summarizes the results obtained with luminescent bioactive NHC-metal complexes in this field of research. PMID- 26631875 TI - A simple and effective approach to prepare injectable macroporous calcium phosphate cement for bone repair: Syringe-foaming using a viscous hydrophilic polymeric solution. AB - In this study, we propose a simple and effective strategy to prepare injectable macroporous calcium phosphate cements (CPCs) by syringe-foaming via hydrophilic viscous polymeric solution, such as using silanized-hydroxypropyl methylcellulose (Si-HPMC) as a foaming agent. The Si-HPMC foamed CPCs demonstrate excellent handling properties such as injectability and cohesion. After hardening the foamed CPCs possess hierarchical macropores and their mechanical properties (Young's modulus and compressive strength) are comparable to those of cancellous bone. Moreover, a preliminary in vivo study in the distal femoral sites of rabbits was conducted to evaluate the biofunctionality of this injectable macroporous CPC. The evidence of newly formed bone in the central zone of implantation site indicates the feasibility and effectiveness of this foaming strategy that will have to be optimized by further extensive animal experiments. STATEMENT OF SIGNIFICANCE: A major challenge in the design of biomaterial-based injectable bone substitutes is the development of cohesive, macroporous and self setting calcium phosphate cement (CPC) that enables rapid cell invasion with adequate initial mechanical properties without the use of complex processing and additives. Thus, we propose a simple and effective strategy to prepare injectable macroporous CPCs through syringe-foaming using a hydrophilic viscous polymeric solution (silanized-hydroxypropyl methylcellulose, Si-HPMC) as a foaming agent, that simultaneously meets all the aforementioned aims. Evidence from our in vivo studies shows the existence of newly formed bone within the implantation site, indicating the feasibility and effectiveness of this foaming strategy, which could be used in various CPC systems using other hydrophilic viscous polymeric solutions. PMID- 26631877 TI - Efficacy of Contrast-enhanced Computed Tomography for the Treatment Strategy of Colonic Diverticular Bleeding. AB - OBJECTIVE: Diverticular bleeding is the most common cause of acute lower gastrointestinal bleeding, and its incidence has recently increased. However, the treatment strategy of diverticular bleeding has not yet been established. The aim of the study was to investigate the efficacy of contrast-enhanced computed tomography (CECT) to determine the indication for urgent colonoscopy to achieve hemostasis. METHODS: A total of 124 patients diagnosed with diverticular bleeding between 2012 and 2013 in our hospital were analyzed. The clinical behavior, factors related to detecting bleeding diverticula, and risk factors for early rebleeding of diverticular bleeding were evaluated. RESULTS: Clinical behavior: Bleeding diverticula were identified in 23 of 124 (19%) patients and most of them (16/23; 70%) were located in the ascending colon. Hemostasis was achieved in all 23 cases, however, six (26%) developed early rebleeding. Factors for detecting bleeding diverticula: In patients in whom extravasation was detected using CECT, the endoscopic detection rate of bleeding diverticula was 60% (12/20), while bleeding diverticula were detected in only 31% (11/35) of patients in whom extravasation was not detected using CECT (p<0.05). The interval between the first hematochezia and colonoscopy in which the bleeding point was detected by colonoscopy (median 23.5 hours) was shorter than that in which bleeding diverticula were not detected (median 43.6 hours) (p<0.01). Risk factors for short term rebleeding: Using a univariate analysis, atherosclerotic comorbidity, anti-inflammatory drugs including low-dose aspirin, antithrombotic agents, vital signs on admission, hemoglobin level on hospitalization, and extravasation on CECT were not found to be significant risk factors. CONCLUSION: The finding of extravasation on CECT is the most important factor for identifying and treating bleeding diverticula by colonoscopy. In such cases, urgent colonoscopy is recommended. PMID- 26631873 TI - Detection of Circulating BRAF(V600E) in Patients with Papillary Thyroid Carcinoma. AB - BRAF(V600E) is a common mutation in papillary thyroid carcinoma (PTC) correlated with aggressive features. Our objective was to assess the feasibility and accuracy of a novel RNA-based blood assay to identify individuals with a high risk tumor mutation in patients with PTC. Patients with benign or malignant thyroid disorders were included between September 2013 and July 2014 before either thyroidectomy (n = 62) or treatment of recurrent or metastatic PTC (n = 8). RNA was isolated from peripheral blood lymphocytes and reverse transcribed and followed by two rounds of nested PCR amplification with a restriction digest specific for wild-type BRAF. BRAF(V600E) levels were quantified with standardization curves. Circulating BRAF(V600E) levels were compared with BRAF mutation status from surgical pathologic DNA-based tissue assays. Testing characteristics and receiving-operator curve using tissue results as the gold standard were assessed. Matched blood and tissue assays for BRAF(V600E) were performed on 70 patients with PTC (stages I to IV, n = 48) or other (n = 22) thyroid tumors. Sixty-three percent of PTC patients tested positive for BRAF(V600E) with conventional tissue assays on surgical specimens. The correlation between the RNA-based blood assay and tissue BRAF status was 0.71. PTC patients harbor detectable BRAF(V600E) circulating tumor cells. This blood assay is feasible and has potential as a biomarker for prognosis, surveillance, clinical decision making, and assessment of treatment response to BRAF-targeted therapies. PMID- 26631879 TI - The Optimal Cut-off Value of Plasma BNP to Differentiate Heart Failure in the Emergency Department in Japanese Patients with Dyspnea. AB - OBJECTIVE: In the emergency department, it is sometimes difficult to differentiate heart failure (HF) from other diseases (e.g., respiratory diseases) in patients who develop dyspnea. The plasma B-type natriuretic peptide (BNP) levels increase in patients with HF, and various levels are associated with specific New York Heart Association classes. Although the diagnosis of HF should not be made based only on the plasma BNP levels, the identification of a cut-off value for BNP to diagnose HF would be helpful. METHODS: Patients admitted to the emergency department of our hospital with dyspnea between January 2010 and December 2011 were retrospectively reviewed. The patients whose estimated glomerular filtration rate was less than 30 mL/min/1.73 m(2) were excluded. Patients were divided into two groups: those with HF (n=131) and those without HF (n=138). The cut-off value for BNP was determined by the receiver-operating characteristic curve. RESULTS: The area under the curve of this curve was 0.934. The optimal cut-off point for detection of HF was 234 pg/mL. The sensitivity and specificity were 87.0% and 85.5%, respectively. The fifth and 95th percentiles of the HF group were 132.2 and 2,420.8 pg/mL, respectively. Those of the non-HF group were 9.7 and 430.2 pg/mL, respectively. CONCLUSION: Our study suggests that a plasma BNP level cut-off value of 234 pg/mL can be used to detect HF in the emergency department. PMID- 26631878 TI - Efficacy of Prophylactic G-CSF in Patients Receiving FOLFIRINOX: A Preliminary Retrospective Study. AB - OBJECTIVE: Recent guidelines have adopted an incidence of febrile neutropenia (FN) threshold of 20% for the use of prophylactic granulocyte colony-stimulating factor (G-CSF). In a Japanese phase II study of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) for Japanese patients with advanced pancreatic cancer, the incidence of FN and severe neutropenia were 24.7% and 77.8%, respectively, without G-CSF prophylaxis. The aim of this retrospective study was to investigate the incidence of FN or severe neutropenia induced by full-dose FOLFIRINOX administration with G CSF prophylaxis during the first cycle of treatment. METHODS: Patients with advanced pancreatic cancer who received FOLFIRINOX with G-CSF prophylaxis during the first cycle of treatment from January 2014 to August 2014 were investigated and the frequency of adverse events during the first cycle was measured. RESULTS: Among seven patients who received FOLFIRINOX, six patients met the eligibility criteria. The patient characteristics were as follows: median age (range), 57 (50 66); men/women, 3/3; performance status 0/1, 2/4. Grade 3/4 hematological adverse events were as follows: leukopenia in 33% of the patients, neutropenia in 33% of the patients, thrombocytopenia in 33% of the patients and FN in 17% of the patients. One patient was heterozygous for the UGT1A1*6 and UGT1A1*28 polymorphisms and experienced FN. Grade3/4 non-hematological adverse events were as follows: anorexia in 33% of the cases and nausea in 50% of the cases. CONCLUSION: Although the present study was retrospective and small, the simultaneous administration of G-CSF might be effective for the prevention of severe neutropenia and FN in patients treated with FOLFIRINOX. PMID- 26631880 TI - A Reduction of HbA1c after 3 Months Predicts 2-year Responsiveness to Sitagliptin Treatment. AB - OBJECTIVE: This retrospective study evaluated the long-term efficacy of sitagliptin and the factors contributing to its glucose-lowering effect. METHODS: Six hundred and sixteen dipeptidyl peptidase-4 inhibitor-naive outpatients with type 2 diabetes who began sitagliptin treatment between December 1, 2009 and December 31, 2011 were included in this study. The inclusion criteria were that the patient had regularly visited our hospital for a period of >=700 days from the initiation of sitagliptin treatment and the measurement of hemoglobin A1c (HbA1c) had been performed at 0, 3, 6, 12, 18, and 24 months after the initiation of treatment. From the population of 616 patients, 447 and 169 had received sitagliptin for >=700 and <700 days, respectively. The primary endpoint was DeltaHbA1c at 24 months. The factors associated with the hypoglycemic effect of sitagliptin were also investigated. RESULTS: Sitagliptin treatment significantly decreased the level of HbA1c, and the hypoglycemic effect was sustained for at least 2 years. The baseline HbA1c level, duration of diabetes, Deltabody weight value, and DeltaHbA1c value at 3 months were independently associated with the hypoglycemic effect of sitagliptin. CONCLUSION: Sitagliptin has a long-term hypoglycemic effect in type 2 diabetes patients. A patient's DeltaHbA1c at 3 months may be a predictor of their DeltaHbA1c at 24 months. PMID- 26631881 TI - Improved Lung Cancer Detection in Cardiovascular Outpatients by the Pulmonologist based Interpretation of Chest Radiographs. AB - OBJECTIVE: Pulmonologists and cardiologists view chest radiographs differently. Lung cancer may therefore go undetected in patients referred to cardiovascular departments. We aimed to determine the clinical benefit of the additional interpretation of chest radiographs by pulmonologists in study involving cardiovascular outpatients. METHODS: A retrospective review of chest radiographs of outpatients attending a Japanese cardiovascular hospital between April 2000 and March 2010 was conducted. Lung cancer patients were categorized into 3 groups: group C, patients in whom tumors were detected by a cardiologist at the first visit; group P, patients in whom tumors were detected by the additional interpretation of a chest radiographs by a pulmonologist after a lesion was missed by a cardiologist; and group H, patients from an earlier period in which chest radiographs were only examined by a cardiologist. RESULTS: Cardiologists detected 9 cases of lung cancer in groups C and H from 2,430 and 2,288 radiographs, respectively. Pulmonologists detected 10 cases of lung cancer (group P) and 3 other malignancies that were previously undetected, giving a miss rate of 52.6% for the cardiologists. Tumor diameters were significantly smaller in group P than in group C or H. Furthermore, a significantly higher number of the tumors in group P were of an early stage and resectable, with more superposing structures than in groups C or H. CONCLUSION: The additional pulmonologist-based interpretations significantly increased the detection rate of operable tumors that mostly corresponded to the early T1 stage; this serves offers a potential clinical benefit in reducing the period of time from patient presentation to the diagnosis of lung cancer. PMID- 26631882 TI - The Infarct Shape Predicts Progressive Motor Deficits in Patients with Acute Lacunae-sized Infarctions in the Perforating Arterial Territory. AB - OBJECTIVE: This study was performed to analyze the lesion patterns of lacunae sized infarctions on diffusion-weighted imaging (DWI) findings in the perforating arterial territory, and to determine whether this pattern of satellite lesions affected progressive motor defect (PMD). METHODS: Seventy-five patients with acute lacunae-sized infarctions in the perforating arterial territory (pons or territory of the lenticulostriate arteries), which was confirmed by cranial magnetic resonance image (MRI), were enrolled in this study. These patients were divided into PMD (n=30) and non-progressive motor defect (NPMD) (n=45) groups according to the dynamic scores of the National Institutes of Health Stroke Scale (NIHSS) within 7 days after stroke. The lesion patterns of lacunae-sized infarctions were divided into single oval or satellite lesions signs based on DWI. The risk factors of stroke and the clinical characteristics of all the subjects, including neurological deficits, infarction lesion patterns in image, and the condition of the basilar artery, were comparatively analyzed. RESULTS: The constituent ratio of satellite lesions signs [20/30 (66.7%)] in the PMD group was higher than that [10/45 (22.2%)] of the NPMD group (chi(2)= 6.1, p=0.013). Mean NIHSS scores in the PMD group on admission were higher than that of the NPMD group (4.60+/-1.40 vs. 3.75+/-1.2, t=2.81, p=0.003). A logistic regression analysis showed that the pattern of satellite lesions was associated with PMD. ?odds ratio (OR): 3.0, 95% confidence interval (CI) 1.25-7.17, p=0.014?. CONCLUSION: Satellite lesions are one of the features of lacunae-sized infarctions patterns, which might be an independent predictor in DWI findings for PMD in patients with lacunae-sized infarctions in the perforating arterial territory. PMID- 26631883 TI - Four Cases of Autochthonous Dengue Infection in Japan and 46 Imported Cases: Characteristics of Japanese Dengue. AB - OBJECTIVE: A dengue outbreak occurred in Japan 2014. We investigated the characteristics of dengue infection among Japanese. METHODS: We investigated the medical charts retrospectively. Patients The study participants are patients who came to our clinic between 2008 and 2014. RESULTS: We investigated 4 domestic cases and 46 imported cases of Japanese with laboratory confirmation of dengue. Major symptoms were fever (100%), rash (86%), fatigue (84%), headache (81%), joint pain (66%), muscle pain (49%), and bleeding (6%). A late rash that appeared near the time of fever resolution was observed in 37 cases (74%). A total of 38/43 (88%) cases had low WBC count (<3,500 /MUL) during the febrile period, 42/48 (88%) cases had a low platelet (PLT) count (<130*10(3)/MUL), and 44/50 (88%) cases had a C-reactive protein (CRP) <2.0 mg/dL. CONCLUSION: Patients with a high fever, late rash, fever-associated leukopenia, low PLT count, low CRP, and elevated aminotransferases are generally suspected of having a dengue infection. PMID- 26631884 TI - The Differences in the Epidemiology and Predictors of Death between Candidemia Acquired in Intensive Care Units and Other Hospital Settings. AB - OBJECTIVE: The burden of candidemia is shifting from intensive care units (ICU) to non-ICU settings. This study aimed to define the differences in epidemiology and predictors of death between ICU-acquired candidemia (ICUAC) and non-ICUAC. METHODS: We conducted a retrospective study of 80 patients with ICUAC and 147 patients with non-IUCAC at five hospitals. RESULTS: The distribution of Candida species and resistance to antifungal agents did not differ between the ICUAC and non-ICUAC groups. ICUAC patients received more echinocandins and less triazoles, as well as more adequate antifungal therapy than non-ICUAC patients (all p<0.05). ICUAC patients had a significantly higher average acute physiology and chronic health evaluation (APACHE) II score (21.0+/-7.9 vs. 17.8+/-8.6; p<0.01), Sequential Organ Failure Assessment score (9.2+/-5.5 vs. 7.4+/-3.9; p<0.05) and day-90 mortality rate (52.5% vs. 36.7%; p<0.05) when compared to non-ICUAC patients. Using a multivariate logistic analysis, adequate antifungal therapy was found to be the only protective factor for death in both groups. Respiratory failure supported with invasive mechanical ventilation, renal failure supported with replacement therapy and an APACHE II score >=20 were independent predictors of death in ICUAC patients, while age >=60 years, concurrent bacteremia and APACHE II score >=20 were independent predictors of death in non-ICUAC patients. CONCLUSION: The Candida species and antifungal resistance profiles in patients with ICUAC were similar to non-ICUAC patients, but led to worse outcomes. The protective and risk factors for death may therefore be relevant for the clinical management of patients with candidemia in ICU and non-ICU settings. PMID- 26631885 TI - Anaplastic Carcinoma Possibly Arising from a Heterotopic Pancreas. AB - Anaplastic carcinoma is a rare pancreatic cancer, and the malignant transformation of a heterotopic pancreas is also rare. We herein report a case of an elderly woman with a mass of unknown origin in the abdominal cavity. Computed tomography identified the extent of the tumor but not the organ of origin. The abdominal tumor eventually metastasized to the liver and lung. An autopsy and immunohistochemical examination revealed an anaplastic carcinoma possibly originating in an ectopic pancreas. PMID- 26631886 TI - Rapid Deterioration of the Renal Function Caused by the Coexistence of Intratubular Amyloidosis and Myeloma Cast Nephropathy. AB - Multiple myeloma presents with various kidney injuries, including cast nephropathy, light chain deposition disease, and amyloidosis. Cast nephropathy is the most common form and mostly consists of monoclonal immunoglobulin light chains with Tamm-Horsfall protein. Immunoglobulin light chain (AL) amyloidosis may affect all compartments of the kidney, but it is rare in the tubuli. We herein present a rare case with rapid progression of renal failure caused by the co-occurrence of intratubular amyloidosis and cast nephropathy due to multiple myeloma. Our case suggests unique amyloidogenic light chain cast, which can form amyloid fibrils under specific tubular fluid conditions, and illustrates the complicated light chain pathophysiology. PMID- 26631887 TI - Parathyroid Hormone-related Peptide-producing Multiple Myeloma and Renal Impairment. AB - A 68-year-old man was hospitalized and examined for renal impairment. A laboratory analysis showed hypercalcemia. Although the serum parathyroid hormone and serum 1-25(OH)2 vitamin D3 levels were not elevated, the serum parathyroid hormone-related peptide (PTHrP) level was increased. Immunoelectrophoresis of the urine and bone marrow aspiration indicated multiple myeloma (MM). He was diagnosed with the coexistence of cast nephropathy and light chain deposition disease by a renal biopsy. Notably, PTHrP expression was detected in the myeloma cells based on immunohistochemistry and in situ hybridization. It is therefore important to examine the PTHrP concentration in MM patients with hypercalcemia. PMID- 26631888 TI - Small Cell Lung Cancer Expressing Glutamate Decarboxylase with Latent Autoimmune Diabetes in Adults. AB - Small cell lung cancer (SCLC) causes paraneoplastic syndromes, such as diabetes mellitus, by eliciting the expression of various antibodies including anti glutamate decarboxylase (GAD) antibody. A 62-year-old woman presented to our hospital with a 1-week history of progressive dyspnea and difficulty in walking. Computed tomography showed a tumor obstructing the left bronchus and obstructive lung abscesses with pleural effusions. A biopsy during bronchoscopy revealed SCLC, and the clinical stage was ultimately determined to be IIIB. SCLC was complicated by diabetes mellitus with high titers of serum anti-GAD antibody. An immunohistochemical analysis showed GAD expression in the cancer cells, which is a novel finding. PMID- 26631889 TI - Human T-cell Lymphotropic Virus Type-1 (HTLV-1)-associated Bronchioloalveolar Disorder Presenting with Mosaic Perfusion. AB - Human T-cell lymphotropic virus type-1 (HTLV-1)-associated bronchioloalveolar disorder (HABA) is a specific state with chronic and progressive respiratory symptoms caused by bronchiolar or alveolar disorder characterized by smoldering adult T-cell leukemia or the HTLV-I carrier state. We herein report a rare case of HABA with an initial presentation of mosaic perfusion in the lung. The diagnosis was made according to the results of a flow cytometry analysis of the bronchoalveolar lavage fluid and pathological findings. Clinicians must be careful to recognize that mosaic perfusion may be a radiological finding of HABA. PMID- 26631891 TI - Cerebral Venous Thromboembolism in Antiphospholipid Syndrome Successfully Treated with the Combined Use of an Anti-Xa Inhibitor and Corticosteroid. AB - We herein report a case presenting with cerebral venous sinus thrombosis (CVST) associated with primary antiphospholipid syndrome (APS). The patient developed recurrent CVST followed by a hemorrhagic ischemic stroke despite the use of warfarin during the appropriate therapeutic window. Thus, we substituted warfarin to rivaroxaban with prednisolone and obtained a good clinical course. In addition to the effect of prednisolone of inhibiting elevated lupus anticoagulants and the recurrence of arterial thrombosis, rivaroxaban may prevent CVST and inhibit hypercoagulability induced by corticosteroids. The combination of an anti-Xa inhibitor and corticosteroid may be an alternative treatment for CVST and arterial thrombus with warfarin-resistant APS. PMID- 26631890 TI - Fever, Dry Cough and Exertional Dyspnea: Pulmonary Lymphomatoid Granulomatosis Masquerading as Pneumonia, Granulomatosis with Polyangiitis and Infectious Mononucleosis. AB - Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus-associated lymphoproliferative disorder. The disease lacks specific clinical and radiological manifestations, which may delay a definitive diagnosis. We report the case of a 39-year-old man with pulmonary LYG who presented to a hospital after experiencing three months of fever, weight loss, dry cough and exertional dyspnea. He was initially misdiagnosed with pneumonia, granulomatosis with polyangiitis and infectious mononucleosis due to the non-specific manifestations of the disease. We herein present the clinical and radiological characteristics of this case and discuss the procedure for pathological diagnosis, which will likely help clinicians in making a timely definitive diagnosis of this disease. PMID- 26631892 TI - Anti-Hu Antibody-associated Paraneoplastic Neurological Syndrome Showing Peripheral Neuropathy and Atypical Multifocal Brain Lesions. AB - A 64-year-old Japanese woman presented with a three-month history of progressive numbness and weakness of the lower extremities. A neurological examination and nerve conduction study indicated sensorimotor polyneuropathy. Since the serum anti-Hu antibody titer was remarkably elevated, paraneoplastic neurological syndrome was highly suspected. A thoracoscopic biopsy of the hilar lymph nodes, in which (18)F-fluorodeoxyglucose uptake was obviously increased, revealed pathological findings for small-cell lung cancer (SCLC). Subsequently, the patient presented with generalized tonic-clonic seizures, and cerebral MRI showed reversible multifocal brain lesions, considered to reflect paraneoplastic encephalopathy. After two courses of chemotherapy for SCLC, the brain lesions totally disappeared. PMID- 26631893 TI - Aripiprazole Can Improve Apraxia of Eyelid Opening in Parkinson's Disease. AB - We herein report three cases of Parkinson's disease associated with difficulty in eyelid opening, referred to as apraxia of eyelid opening (AEO), which improved after aripiprazole treatment. In case 1, aripiprazole was administered as a psychiatric treatment. It proved to be effective in AEO with blepharospasm. In case 2 and case 3, the patients experienced AEO without blepharospasm, and a significant improvement was observed after aripiprazole treatment. In this study, the aripiprazole dosage ranged between 3 and 9 mg/day. This is the first report of aripiprazole as a potentially effective treatment for AEO in Parkinson's disease. PMID- 26631894 TI - Agraphia in Mobile Text Messages in a Case of Amyotrophic Lateral Sclerosis with Frontotemporal Dementia. AB - We herein describe the case of a woman with amyotrophic lateral sclerosis (ALS) showing errors in her choice of Japanese kana characters in her mobile text messages and agraphia of the kana in her handwriting in spite of the absence of weakness, ataxia, or apraxia of her hands. Magnetic resonance imaging showed the atrophy of the frontal lobes. Single-photon emission computed tomography revealed hypoperfusion of the frontal lobes including Exner's area. Although patients with bulbar-onset ALS have been reported to show agraphia of handwriting, in this case the basis of her agraphia might have been the disturbance of the pathway converting phones to graphemes in series, by which errors of spelling or writing would appear in any modality of output. PMID- 26631895 TI - A Sporadic Case of Fabry Disease Involving Repeated Fever, Psychiatric Symptoms, Headache, and Ischemic Stroke in an Adult Japanese Woman. AB - Fabry disease can cause various neurological manifestations. We describe the case of a Japanese woman with Fabry disease who presented with ischemic stroke, aseptic meningitis, and psychiatric symptoms. The patient had a mutation in intron 4 of her alpha-galactosidase A gene, which was not detected in her family. This case suggests that Fabry disease should be considered in young patients who exhibit central nervous system symptoms such as ischemic stroke, even if there is no family history of the condition. The episodes of aseptic meningitis and stroke experienced by our patient suggest that persistent inflammation might be the mechanism underlying Fabry disease. PMID- 26631896 TI - Life-threatening Arrhythmias in a Becker Muscular Dystrophy Family due to the Duplication of Exons 3-4 of the Dystrophin Gene. AB - We herein present a report of three patients with Becker muscular dystrophy in the same family who developed complete atrioventricular block or ventricular tachycardia with severe cardiomyopathy. Our cases became unable to walk in their teens, and were introduced to mechanical ventilation due to respiratory muscle weakness in their twenties and thirties. In all three cases, a medical device such as a permanent cardiac pacemaker or an implantable cardiac defibrillator was considered to be necessary. The duplication of exons 3-4 in the dystrophin gene was detected in two of the patients. In patients with Becker muscular dystrophy, complete atrioventricular block or ventricular tachycardia within a family has rarely been reported. Thus attention should be paid to the possibility of severe arrhythmias in the severe phenotype of Becker muscular dystrophy. PMID- 26631897 TI - Diagnostic Utility of Splenial Lesions in a Case of Legionnaires' Disease due to Legionella pneumophila Serogroup 2. AB - We herein report the case of a 49-year-old man with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) associated with Legionnaires' disease due to Legionella pneumophila serogroup 2. Past reports suggest that Legionella infection is frequent in cases of MERS-associated pneumonia. Obtaining an early diagnosis of legionella infection is a challenge, especially if a Legionella pneumophila serogroup other than serogroup 1 contains the causative agent. In this case, the splenial lesion played an important role in recognizing the legionella infection. We suggest that legionella infection should be considered as a differential diagnosis in cases of splenial lesions associated with pneumonia. PMID- 26631898 TI - Indolent Non-Typhoidal Salmonella Vertebral Osteomyelitis in a Diabetic Patient. AB - We herein describe the case of a 59-year-old Japanese man with diabetes mellitus who presented with vertebral osteomyelitis caused by Salmonella enterica subspecies enterica serovar Enteritidis. The patient presented with a persistent fever without back pain. Extraintestinal infections of Salmonella species are well known and are often reported in immunocompromised patients; however, they are rare in non-immunosuppressed patients. The protracted course and atypical presentation of osteomyelitis in diabetic adults can lead to major diagnostic delays. Moreover, in recent years, decreased fluoroquinolone susceptibility against salmonellosis has become a problem worldwide, a problem that needs to be urgently addressed. PMID- 26631899 TI - Esophageal Candidiasis as the Initial Manifestation of Acute Myeloid Leukemia. AB - A 47-year-old woman presented with persistent dysphagia. A gastroendoscopy revealed massive esophageal candidiasis, and oral miconazole was prescribed. Three weeks later, she returned to our hospital without symptomatic improvement. She was febrile, and blood tests showed leukocytosis (137,150 /MUL, blast 85%), anemia and thrombocytopenia. She was diagnosed with acute myeloid leukemia (AML). She received chemotherapy and antimicrobial agents. During the recovery from the nadir, bilateral ocular candidiasis was detected, suggesting the presence of preceding candidemia. Thus, esophageal candidiasis can be an initial manifestation of AML. Thorough examination to detect systemic candidiasis is strongly recommended when neutropenic patients exhibit local candidiasis prior to chemotherapy. PMID- 26631900 TI - Loffler Endocarditis and Lacking Heart. PMID- 26631901 TI - Giant SVG Aneurysm in an AMI Patient. PMID- 26631902 TI - Congenital Cystic Adenomatoid Malformation in Adults. PMID- 26631903 TI - Development of a regionally sensitive water-productivity indicator to identify sustainable practices for sugarcane growers. AB - Standards that credibly and effectively certify sustainable commodity production are important to both producers and consumers. Agriculture is the dominant user of water worldwide, so water sustainability in agriculture is an area of particular interest. In conjunction with Bonsucro, a sustainability standard setting body for the sugarcane sector, an indicator was developed to ensure that water consumed in sugarcane cultivation is used productively (i.e., that producers achieve high "crop per drop"). To be easily measurable, sugarcane water productivity was adapted so that yield could be compared within a climate zone in which water demand is assumed to be uniform. The indicator identifies efficient performers, defined as those exceeding median historical yield in each climate zone, with rainfed and irrigated systems evaluated separately. Both the expert driven and stakeholder-driven aspects of standard development are discussed. We address the advantages and the limitations of this new indicator, its potential application to other crops, and the possibility of improvement to include further criteria. Integr Environ Assess Manag 2016;12:811-820. (c) 2015 SETAC. PMID- 26631904 TI - Cardioprotective Efficacy of Red Wine Extract of Onion in Healthy Hypercholesterolemic Subjects. AB - The objective of this study was to evaluate the efficacy of the red wine extract of onion (RO) and red wine (RW) on alleviating the risk factors of cardiovascular disease. During in vitro studies, various antioxidant activities [trolox equivalent antioxidant capacity (TEAC), DPPH, and H2 O2 scavenging ability] of RO and RW group were evaluated. Both RO and RW showed the maximum antioxidant capacity. During in vivo studies, 23 healthy hypercholesterolemic volunteers were randomly selected and assigned into two groups, who drunk 250 mL of RO (n = 11) or RW (n = 10) for 10 weeks. No significant changes were observed in anthropometric parameters (body weight, height, body mass, and BMI) in each group. Both RW and RO extracts elevated (p < 0.05) antioxidant activity and thereby prolonging the lag time of low-density lipoprotein oxidation. However, RO extract intake substantially suppressed (p < 0.05) the total cholesterol and low density lipoprotein cholesterol levels when equivalence with RW thus, indicating its additional hypocholesterolemic effect. The inflammatory markers such as factor VII were also positively modulated by RO extract. Results indicated that RO extract consumption rendered better cardio protective effect than RW by altering cholesterol, improving antioxidation and suppressing inflammatory marker levels and thereby, attenuating the cardiovascular disease incidence. PMID- 26631905 TI - Development of ultrasound-assisted emulsification microextraction based on solidification of a floating organic droplet for determination of organochlorine pesticides in water samples. AB - An ultrasound-assisted emulsification microextraction based on the solidification of a floating organic droplet followed by gas chromatography with electron capture detection was developed for the simultaneous determination of 13 organochlorine pesticides in water samples. In the proposed method, ultrasound was applied to achieve the emulsification without addition of any dispersive solvent. In consequence, the volume of extraction phase remained unaffected by the ion strength of aqueous phase and high extraction recoveries were obtained. It was also found that dilution of the floating phase with acetone was necessary for preventing peak splitting in chromatogram. Under optimal conditions, the proposed method provided good sensitivity (the detection limits of organochlorine pesticides ranged from 1.3 to 3.9 ng/L) and good repeatability of extraction (below 6.5%, n = 5). The recoveries in reservoir and river water samples were between 75.8% and 96.9%. PMID- 26631906 TI - Erratum: A novel cancer immunotherapy based on the combination of a synthetic carbohydrate-pulsed dendritic cell vaccine and glycoengineered cancer cells. PMID- 26631907 TI - In vitro comparison of antimicrobial effectiveness of QMix and other final irrigants in human root canals. AB - Final root canal irrigation stands as an effective strategy for eliminating the dentin infection. This study aimed to investigate and compare the antibacterial efficacy of QMix and other four final irrigation regimens in reducing Enterococcus faecalis within human root canals. Single-canal human teeth contaminated with E. faecalis for 4 weeks were prepared chemomechanically with sodium hypochlorite (NaOCl). Then, the teeth were randomly assigned into six groups according to the final irrigation protocols: (1) EDTA/NaOCl, 17% EDTA followed by 5.25% NaOCl; (2) EDTA/chlorhexidine (CHX), 17% EDTA followed by 2% CHX; (3) EDTA/cetrimide (CTR), 17% EDTA followed by 2% CTR; (4) MTAD; (5) QMix; and (6) control, 0.9% saline. Bacterial samples collected before instrumentation and after final irrigation were cultured and the colony-forming units (CFUs) were counted. The CFUs in the QMix, EDTA/CHX, and EDTA/CTR groups were significantly lower than those in the EDTA/NaOCl group. No significant differences were observed between the QMix, EDTA/CHX, and EDTA/CTR groups. MTAD showed weaker ability than QMix and EDTA/CHX to eliminate E. faecalis, but it caused a greater reduction in CFU than EDTA/NaOCl. Hence, the antimicrobial activity of QMix was comparable to that of EDTA/CHX and EDTA/CTR and more effective than that of EDTA/NaOCl against intracanal E. faecalis. PMID- 26631908 TI - Apigenin Attenuates Inflammation in Experimentally Induced Acute Pancreatitis Associated Lung Injury. AB - BACKGROUND: Acute pancreatitis is associated with acute lung injury. The aim of the present study is to evaluate alterations of lungs in an experimental model of acute pancreatitis (AP) following both bilio-pancreatic duct obstruction close to the duodenum. Acute pancreatitis is a common disease with significant mortality. This situation makes the need of finding protective factors for the lung parenchyma, imperative. In the present study there is an effort to clarify the role of apigenin, a substance which is well known for its antioxidant and anti inflammatory effects, on lung injury, following acute pancreatitis in rats. MATERIALS AND METHODS: In the present study, 126 male Wistar-type rats 3-4 months old and 220-350 g weight were used. At time 0 we randomly assigned the following groups: Group Sham: Rats were subjected to virtual surgery. Group Control: Rats were subjected to surgery for induction of acute pancreatitis. Group Apigenin: Rats were subjected to surgery for induction of acute pancreatitis and enteral feeding with apigenin. Immunochemistry for TNF-alpha and IL-6 as well as MPO activity were measured at predetermined time intervals 6, 12, 24, 48, and 72 h, in order to evaluate architectural disturbances of the lung tissue. RESULTS: From the pathological reports we realized that comparing the control group with the apigenin group, there is an improvement of lung tissue damage following apigenin administration, with statistical significance. Apigenin reduces most histopathological alterations of the pulmonary tissue, reduces MPO and TNF-alpha activity at 48 hours and, furthermore, reduces IL-6 activity at 72 hours post administration. CONCLUSIONS: Oral Apigenin administration in rats, following experimental induced acute pancreatitis, seems to be protective on the lung tissue. Apigenin administration to humans could potentially ameliorate acute lung injuries. However, special caution is required for humans' use, as more detailed studies are needed. PMID- 26631909 TI - Phylogenetic conservation of freshwater lake habitat preference varies between abundant bacterioplankton phyla. AB - Despite their homogeneous appearance, aquatic systems harbour heterogeneous habitats resulting from nutrient gradients, suspended particulate matter and stratification. Recent reports suggest phylogenetically conserved habitat preferences among bacterioplankton, particularly for particle-associated (PA) and free-living (FL) habitats. Here, we show that independent of lake nutrient level and layer, PA and FL abundance-weighted bacterial community composition (BCC) differed and that inter-lake BCC varied more for PA than for FL fractions. In low nutrient lakes, BCC differences between PA and FL fractions were larger than those between lake layers. The reverse was true for high-nutrient lakes. Nutrient level affected BCC more in hypolimnia than in epilimnia, likely due to hypolimnetic hypoxia in high-nutrient lakes. In line with previous reports, we observed within-phylum operational taxonomic unit (OTU) habitat preference conservation, although not for all phyla, including the phylum with the highest average relative abundance across all habitats (Bacteroidetes). Consistent phylum level habitat preferences may indicate that the functional traits that underpin ecological adaptation of freshwater bacteria to lake habitats can be phylogenetically conserved, although the levels of conservation are phylum dependent. Resolving taxa preferences for freshwater habitats sets the stage for identification of traits that underpin habitat specialization and associated functional traits that influence differences in biogeochemical cycling across freshwater lake habitats. PMID- 26631910 TI - CK2 induced RIG-I drives metabolic adaptations in IFNgamma-treated glioma cells. AB - Given the known anti-tumorigenic properties of IFNgamma, its effect on glioma cell survival was investigated. Though IFNgamma had no effect on glioma cell viability, it induced cell cycle arrest. This was accompanied by increased expression of p53 and retinoic acid inducible gene (RIG-I). While RIG-I had no effect on glioma cell survival, it increased expression of p53 and its downstream target TP53 induced glycolysis and apoptosis regulator (TIGAR). IFNgamma induced mitochondrial co-localization of RIG-I was concomitant with its ability to regulate ROS generation, oxidative phosphorylation (OXPHOS) and key enzymes involved in glycolysis and pentose phosphate pathway. Importantly, metabolic gene profiling indicated a suppressed glycolytic pathway in glioma cells upon IFNgamma treatment. In addition, IFNgamma mediated increase in casein kinase 2 (CK2) expression positively regulated RIG-I expression. These findings demonstrate how IFNgamma induced CK2 regulates RIG-I to drive a complex program of metabolic adaptation and redox homeostasis, crucial for determining glioma cell fate. PMID- 26631912 TI - The good and the bad faces of STAT1 in solid tumours. AB - Signal transducer and activator of transcription (STAT) 1 is part of the Janus kinase (JAK)/STAT signalling cascade and is best known for its essential role in mediating responses to all types of interferons (IFN). STAT1 regulates a variety of cellular processes, such as antimicrobial activities, cell proliferation and cell death. It exerts important immune modulatory activities both in the innate and the adaptive arm of the immune system. Based on studies in mice and data from human patients, STAT1 is generally considered a tumour suppressor but there is growing evidence that it can also act as a tumour promoter. This review aims at contrasting the two faces of STAT1 in tumourigenesis and providing an overview on the current knowledge of the underlying mechanisms or pathways. PMID- 26631911 TI - Tyrosine kinase 2 - Surveillant of tumours and bona fide oncogene. AB - Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family, which transduces cytokine and growth factor signalling. Analysis of TYK2 loss-of function revealed its important role in immunity to infection, (auto-) immunity and (auto-) inflammation. TYK2-deficient patients unravelled high similarity between mice and men with respect to cellular signalling functions and basic immunology. Genome-wide association studies link TYK2 to several autoimmune and inflammatory diseases as well as carcinogenesis. Due to its cytokine signalling functions TYK2 was found to be essential in tumour surveillance. Lately TYK2 activating mutants and fusion proteins were detected in patients diagnosed with leukaemic diseases suggesting that TYK2 is a potent oncogene. Here we review the cell intrinsic and extrinsic functions of TYK2 in the characteristics preventing and enabling carcinogenesis. In addition we describe an unexpected function of kinase-inactive TYK2 in tumour rejection. PMID- 26631913 TI - Social networks and health-related quality of life among Chinese old adults in urban areas: results from 4th National Household Health Survey. AB - OBJECTIVE: To examine the associations between components of social networks and health-related quality of life (HRQoL) in community-dwelling old adults in urban areas in China. STUDY DESIGN: Data from the 4th National Household Health Survey (NHHS) in China, conducted in 2008, were used. HRQoL of respondents aged >=15 years was assessed using EQ-5D in the NHHS. METHODS: The sample for the current analysis included 9833 old adults aged >=60 years. Multiple linear and logistic regression models were used to assess the associations between indicators of social network and HRQoL. RESULTS: Approximately 6% of the respondents saw their children once a year or less, and approximately 1% reported that they had no children. Thirteen percent of the sample seldom contacted their neighbours and seldom met with relatives or friends; approximately 62% seldom attended social gatherings. The five dimensions of HRQoL (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) were reported to be moderate or severe in 14.5%, 9.4%, 12.6%, 18.3% and 9.3% of the sample, respectively. The mean visual analogue scale (VAS) score and EQ-5D index using the time trade-off method was 70.96 [standard deviation (SD) 14.79] and 0.869 (SD 0.163), respectively. After adjusting for potential confounding variables, old adults with weaker social networks were more likely to report problems on EQ-5D dimensions, lower VAS scores and lower EQ-5D indexes. CONCLUSIONS: For old adults living in urban communities in China, increased social participation has a positive effect on various dimensions of HRQoL. There is a need for policy considerations that will improve integration of community-level public resources in order to encourage frequent social interaction among old adults, and promote health and social care as a whole. PMID- 26631915 TI - Case of pituitary stalk transection syndrome ascertained after breech delivery. AB - Pituitary stalk transection syndrome (PSTS) is a rare complication that can accompany breech delivery. Early diagnosis of this syndrome is difficult, and it may cause a serious delay in the diagnosis. We present a case of PSTS ascertained after breech delivery. A 20-year-old woman presented with primary amenorrhea. The patient was born by breech delivery and had a history of treatment for pituitary dwarfism. Her laboratory findings showed pituitary hypothyroidism, and hormone replacement therapy was initiated. At 28 years old, she became pregnant and had a normal delivery at 38 weeks' gestation. One year after delivery, her thyroid hormone level changed. Laboratory test showed adrenocortical insufficiency, and magnetic resonance imaging of the pituitary gland showed transection of the pituitary stalk and development of an ectopic posterior lobe. These findings were compatible with PSTS. When a patient who has been born by breech delivery presents with symptoms of pituitary deficiency, PSTS should be considered in the differential diagnosis. PMID- 26631914 TI - Eczema and Asthma Symptoms among Schoolchildren in Coastal and Inland Areas after the 2011 Great East Japan Earthquake: The ToMMo Child Health Study. AB - After the Great East Japan Earthquake of 2011, there has been a concern about health problems among children. Therefore, we investigated the prevalence of wheeze and eczema symptoms and associated factors among children in areas primarily affected by the disaster. From 2012 to 2014, we distributed the parent administered questionnaire to 25,198 children in all 233 public schools in the 13 municipalities of Miyagi Prefecture in northeast Japan. A total of 7,155 responses (mean age 10.5 +/- 2.2 years) were received (response rate: 28.4%). The prevalence of allergic symptoms according to the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire in 2nd, 4th, 6th, and 8th graders was 12.4%, 9.9%, 9.3%, and 5.6% for wheeze, and 20.1%, 18.0%, 14.0%, and 12.4% for eczema. In multivariate logistic analysis, younger age, history of hospitalization, and difficulties in children's daily lives as assessed by the Strengths and Difficulties Questionnaire (SDQ), were significantly and consistently associated with both allergic symptoms (both P < 0.05). Living in a coastal municipality was also associated with eczema symptoms (P = 0.0278). The prevalence of eczema symptoms in the 2nd (20.1%) and 8th (12.4%) grades was significantly higher than previously reported in Japan. Living in a coastal municipality was independently associated with eczema symptoms, and psychometric properties were also closely linked to allergic symptoms. These findings are clinically important for understanding the risks of allergic disorders after natural disasters. PMID- 26631916 TI - Empowered to gain a new foothold in life--A study of the meaning of participating in cardiac rehabilitation to patients afflicted by a minor heart attack. AB - This study aimed to investigate what it means to patients afflicted by a minor heart attack to participate in cardiac rehabilitation (CR). CR is well established internationally to support patients towards moving forward in satisfying, healthy, and well-functioning lives. Studies indicate that patients achieve improvement in quality of life when participating in CR. However, knowledge of how patients are supported during CR is sparse. Moreover, knowledge of what participating in CR means to patients afflicted by a minor heart attack is lacking. In-depth knowledge in this area is crucial in order to understand these patients' particular gains and needs. In a phenomenological-hermeneutic frame field observations, focus group interviews, and individual interviews were conducted among 11 patients during and after their participation in CR. Field notes and transcribed interviews underwent three-phased interpretation. It was found that patients were supported to gain renewed balance in their lives during CR. Three themes were identified: (1) receiving a helpful but limited caring hand, (2) being supported to find new values in life, and (3) developing responsibility for the remaining time. The patients were carefully guided through a difficult time and supported to continue in healthy everyday lives. They were given hope which enabled them to find themselves a new foothold in life with respect to their own sense of well-being. This guidance and a sense of hopefulness were provided by heart specialists and more seasoned heart patients. In conclusion, patients were empowered to achieve a healthier lifestyle and improve their personal well-being during CR. However, structural barriers in the programme prevented adequate support regarding the patients' total needs. Knowledge of the benefits of CR emphasizes the significance of the programme and highlights the importance of high inclusion. Efforts should be made to develop more flexible and longer lasting programmes and further involvement of relatives must be considered. PMID- 26631917 TI - Trends in Risk Factors and Treatments in Patients With Stable Ischemic Heart Disease Seen at Cardiology Clinics Between 2006 and 2014. AB - INTRODUCTION AND OBJECTIVES: Chronic ischemic heart disease is the most prevalent of all cardiovascular diseases. Patients are at high risk of complications. In recent decades, changes may have occurred in the clinical characteristics of the disease, its treatment and control of risk factors. METHODS: A direct comparison of 2 national registries of patients with chronic ischemic heart disease carried out in 2006 (n=1583) and 2014 (n=1110). RESULTS: We observed statistically significant differences between the 2 registries, with a higher percentage of men and smokers in the 2014 registry, but a lower prevalence of diabetes mellitus and hypertension. Heart failure and stroke were more prevalent in the 2006 registry. Patients in the 2014 registry had better results for lipid profile, blood glucose, creatinine, and glomerular filtration rate. We observed higher use of recommended drugs for secondary prevention and an increased percentage of patients receiving optimal medical therapy, from 32.5% to 49.5% (P<.01). Use of high-intensity statin doses also increased from 10.5% to 42.8% (P<.01). We found better control of some risk factors (improved dyslipidemia, heart rate, and blood glucose in patients with diabetes) but worse blood pressure control. CONCLUSIONS: The clinical profile of patients with chronic ischemic heart disease is similar in the 2 registries. There has been an improvement in patients' medical therapy and dyslipidemia control, blood glucose, and heart rate, but there is still much room for improvement in the control of other cardiovascular risk factors. PMID- 26631918 TI - The association of F11 genetic variants with the risk of incident venous thrombosis among women, by statin use. PMID- 26631919 TI - The effect of compartmentalization on the kinetics of transition metal ions induced lipoprotein peroxidation. AB - In a previous study, we proposed characterizing the typically observed kinetic profiles of transition metal ion-induced lipid peroxidation in terms of a limited number of characteristic time-points. These time-points can be derived from experimental time-dependencies and be presented in terms of rate constants and concentrations as calculated based on mechanistic considerations. The critical part of that analysis was that we had to assume that the experimental system behaves as if it is homogeneous, i.e., as if the reaction occurs in a solution. In spite of the uncertainties due to the latter assumption, we obtained a reasonable agreement between the experimental data and the theoretically predicted dependencies, which supports our theoretical treatment. Yet, several previous findings could not have been explained in terms of our ('quasi homogeneous') model, indicating that the model is valid not under all conditions. One example is that under certain conditions, rapid peroxidation occurs prior to complete consumption of LDL-associated tocopherol. This can be attributed to compartmentalization of residual tocopherol, namely, after the onset of propagation, part of the LDL particles contain tocopherol, whereas in the other, tocopherol-depleted particles, the PUFA may undergo rapid LOOH-accelerated peroxidation only if they contain at least two hydroperoxides molecules per particle. In the present investigation, we show that the results of all our kinetic studies can be understood if we consider compartmentalization. Specifically, for any given composition of the particles (LDL and/or HDL), the kinetic results may be governed by the distribution and rate of exchange of antioxidants and hydroperoxides between particles. Our analysis is of special importance for systems containing more than one population of lipoprotein particles. PMID- 26631920 TI - Gout on CT of the feet: A symmetric arthropathy. AB - INTRODUCTION: The aim of this study was to assess the distribution of bone erosions in the feet of patients with gout using CT and thereby to test the hypothesis that gout is an asymmetric arthropathy. METHODS: CT scans of both feet were obtained from 25 patients with chronic gout. CT scans were scored for bone erosion using a semi-quantitative method based on the rheumatoid arthritis MRI scoring system (RAMRIS). CT bone erosion was assessed at 22 bones in each foot (total 1,100 bones) by two independent radiologists. Symmetry was assessed by two methods: (i) comparing right and left foot scores for each patient; and (ii) calculating the proportion of paired joints with or without erosions. RESULTS: Observer agreement was excellent (intra-class correlation coefficient 0.92). In the group overall, the difference in scores between the feet was not significant (Student's t-test P = 0.8). In 17 of 25 patients, the difference in erosion scores between the two feet was less than the inter-observer difference. In 24 of 25 patients, the proportion of paired joints was greater than 0.5, indicating symmetric disease. CONCLUSIONS: Erosive disease from gout is, in fact, a symmetric process in our patient group. This finding is contrary to the established view of gout as an asymmetric arthritis and lends new insight into the behaviour of this common disease. PMID- 26631921 TI - The potential role of tissue-engineered urethral substitution: clinical and preclinical studies. AB - Urethral strictures and anomalies remain among the difficult problems in urology, with urethroplasty procedures being the most effective treatment options. The two major types of urethroplasty are anastomotic urethroplasty and widening the urethral lumen using flaps or grafts (i.e. substitution urethroplasty). However, no ideal material for the latter has been found so far. Designing and selecting such a material is a necessary and challenging endeavour, driving the need for further bioengineered urethral tissue research. This article reviews currently available studies on the potentialities of tissue engineering in urethral reconstruction, in particular those describing the use of both acellular and recellularized tissue-engineered constructs in animal and human models. Possible future developments in this field are also discussed. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26631922 TI - [General medicine management of superficial venous thrombosis of the lower limbs: A survey in Saone-et-Loire]. AB - CONTEXT: For a long time, superficial venous thrombosis (SVT) of the lower limbs was considered as benign. Due to lack of clear scientific evidence, its treatment was heterogeneous and even potentially deleterious. Since 2010, several major studies have highlighted the seriousness of SVT, and prophylactic doses of fondaparinux have proven their efficacy for this indication. While the French recommendations have not yet taken on board all this data, has practice already changed? AIM: To describe in general practice the usual management of suspected SVT. METHODS: A descriptive cross-sectional study of general practitioners in Saone-et-Loire. Each doctor taking part was asked to note on a paper questionnaire the details of the last patient in whom they suspected SVT. Data collected included: clinical presentation, diagnostic and therapeutic management and follow-up of the patients. RESULTS: Between 01/01/2014 and 31/03/2014, 88 doctors out of 443 contacted (20%) completed the questionnaire. According to the information they provided, 36 physicians (40.9% [95% CI: 30.6-50.2]) searched for an associated pulmonary embolism. Eighty-two physicians (93.2% [95% CI: 87.9 98.4]) prescribed a venous compression ultrasound (CUS) exploration. Twelve etiological assessments were carried out (13.6% [95% CI: 6.5-20.8]) of which 6 (6.8%) appeared to be justified. 64 (72.7%) of the patients were given an anticoagulant therapy (heparin or fondaparinux), including 15 (17%) at a prophylactic dose and 49 (55.7%) at a curative dose. Forty-nine doctors (55.7% [95% CI: 45.3-66.1]) prescribed a CUS follow-up. CONCLUSION: General practitioners seem to have adapted their diagnostic practices to the data highlighting the potential seriousness of SVT. The treatment they give, however, remains very variable and potentially deleterious, in particular due to a high rate of treatments given at curative doses. PMID- 26631924 TI - Modifiable risk factors for erectile dysfunction: an assessment of the awareness of such factors in patients suffering from ischaemic heart disease. AB - Up to 40% of cases of erectile dysfunction (ED) originate from vascular disturbances associated with atherosclerotic disease, leading to the previously proven concomitance between ischaemic heart disease (IHD) and ED. The aim of this study was to evaluate patients' knowledge about modifiable risk factors for ED. The evaluated group of patients was composed of 502 male patients undergoing cardiac rehabilitation and receiving treatment for IHD. The patients' knowledge of risk factors for ED linked to IHD was assessed with an original survey. The presence of ED was assessed using an abridged version of the International Index of Erectile Function-5 questionnaire. Increase in leisure-time physical activity was estimated using a leaflet based on the Framingham questionnaire. In all, 189 participants were unable to name any modifiable ED risk factors, and only 31 patients knew all 6 of them. The most frequently mentioned ED risk factor was smoking, whereas the least frequently mentioned was sedentary lifestyle. Awareness of smoking as an ED risk factor was closely related to the patients' level of education, place of residence, smoking and underlying ED in the individual patient. The ability to classify diabetes as a risk factor for ED was significantly related to the patients' level of education, place of residence, and the prevalence of diabetes in the evaluated group of respondents. The same relations were observed regarding hyperlipidaemia. Awareness of the negative impact a sedentary lifestyle has on the erectile process was found to be closely related to the patients' age, as well as their level of education. The performed study demonstrates the poor knowledge of IHD patients about the modifiable risk factors for ED. The factor that patients are the least aware of is sedentary lifestyle, which, simultaneously, is the risk factor that most frequently affects the respondents. PMID- 26631923 TI - The effects of four different suture materials on penile tissue of rats. AB - Several types of suture materials are being used for the correction of penile curvature and this study was designed to compare histopathological changes on penile tissue among different suture materials. A total of 30 male Sprague-Dawley rats were divided into five groups and right cavernosal body was sutured with 5/0 sutures (ETB: polyethylene terephthalate; PRL: polypropylene; VCR: polyglactine; and PDS: polydioxanone). An identical needle (3/8-13 mm cutting) was passed through the cavernosal bodies in the sham group (SHAM). After 3 weeks, all rats were killed and penile tissues were examined to assess the level (0-3) of inflammation, granuloma formation and fibrosis. There was a statistically significant difference among five groups regarding inflammation, granuloma formation and fibrosis levels (P<0.01 for all). The histological changes in the PRL group were not different from the SHAM group. Although the levels of granulation and fibrosis in the PDS group were also similar to the SHAM group, inflammation level was significantly higher. The inflammation, granulation and fibrosis levels were the highest in the ETB group. VCR caused similar levels of granulation and fibrosis to ETB. In conclusion, PRL suture is associated with the least histopathological change in the penile tissue. PDS can theoretically be a reasonable alternative to PRL as it causes similar levels of granulation and fibrosis. PMID- 26631925 TI - Priapism caused by 'Tribulus terrestris'. AB - A 36-year-old Caucasian man was diagnosed with a 72-h-lasting priapism that occurred after the assumption of a Herbal supplement based on Tribulus terrestris, which is becoming increasingly popular for the treatment of sexual dysfunction. The patient underwent a cavernoglandular shunt (Ebbehoj shunt) in order to obtain complete detumescence, from which derived negative post-episode outcomes on sexual function. All patients consuming non-FDA-approved alternative supplements such as Tribulus terrestris should be warned about the possible serious side effects. PMID- 26631926 TI - What is being studied as mindfulness meditation? PMID- 26631928 TI - Traits and states in mindfulness meditation. PMID- 26631932 TI - Learning and memory: Face-to-face with fear generalization. PMID- 26631934 TI - Robust estimation of the proportion of treatment effect explained by surrogate marker information. AB - In randomized treatment studies where the primary outcome requires long follow-up of patients and/or expensive or invasive obtainment procedures, the availability of a surrogate marker that could be used to estimate the treatment effect and could potentially be observed earlier than the primary outcome would allow researchers to make conclusions regarding the treatment effect with less required follow-up time and resources. The Prentice criterion for a valid surrogate marker requires that a test for treatment effect on the surrogate marker also be a valid test for treatment effect on the primary outcome of interest. Based on this criterion, methods have been developed to define and estimate the proportion of treatment effect on the primary outcome that is explained by the treatment effect on the surrogate marker. These methods aim to identify useful statistical surrogates that capture a large proportion of the treatment effect. However, current methods to estimate this proportion usually require restrictive model assumptions that may not hold in practice and thus may lead to biased estimates of this quantity. In this paper, we propose a nonparametric procedure to estimate the proportion of treatment effect on the primary outcome that is explained by the treatment effect on a potential surrogate marker and extend this procedure to a setting with multiple surrogate markers. We compare our approach with previously proposed model-based approaches and propose a variance estimation procedure based on a perturbation-resampling method. Simulation studies demonstrate that the procedure performs well in finite samples and outperforms model-based procedures when the specified models are not correct. We illustrate our proposed procedure using a data set from a randomized study investigating a group-mediated cognitive behavioral intervention for peripheral artery disease participants. PMID- 26631935 TI - Dual-responsive vesicles formed by an amphiphile containing two tetrathiafulvalene units in aqueous solution. AB - The first example of tetrathiafulvalene (TTF)-based vesicle fabricated in water solution with 1 vol.% tetrahydrofuran that could be prevented by chemical oxidant Fe(ClO4)3 or electron-deficient cyclobis(paraquat-p-phenylene) tetracation cyclophane (CBPQT(4+)) is described. PMID- 26631936 TI - Opioid abuse-deterrent strategies: role of clinicians in acute pain management. AB - Opioid abuse is a healthcare and societal problem that burdens individuals, their families and the healthcare professionals who care for them. Restricting access to opioid analgesics is one option to deter abuse, but this may prevent pain patients in need from obtaining effective analgesics. Therefore, strategies that mitigate the risk of opioid abuse while maintaining access are being pursued by several stakeholders including federal agencies, state governments, payors, researchers, the pharmaceutical industry and clinicians. Federal agency efforts have included required licensure and documentation for prescribing opioids, implementation of risk evaluation and mitigation strategies, and guidance on assessment and labeling of opioid abuse-deterrent formulations. In addition, state governments and payors have enacted monitoring programs, and pharmaceutical companies continue to develop abuse-deterrent opioid formulations. Strategies for clinicians to mitigate opioid abuse include comprehensive patient assessment and universal precautions (e.g. use of multimodal analgesia and abuse-deterrent opioid formulations, urine toxicology screening, participation in prescription drug monitoring and risk evaluation and mitigation strategy programs). PMID- 26631930 TI - Tau in physiology and pathology. AB - Tau is a microtubule-associated protein that has a role in stabilizing neuronal microtubules and thus in promoting axonal outgrowth. Structurally, tau is a natively unfolded protein, is highly soluble and shows little tendency for aggregation. However, tau aggregation is characteristic of several neurodegenerative diseases known as tauopathies. The mechanisms underlying tau pathology and tau-mediated neurodegeneration are debated, but considerable progress has been made in the field of tau research in recent years, including the identification of new physiological roles for tau in the brain. Here, we review the expression, post-translational modifications and functions of tau in physiology and in pathophysiology. PMID- 26631937 TI - Danish translation and validation of the Oslo Sports Trauma Research Centre questionnaires on overuse injuries and health problems. AB - The Oslo Sports Trauma Research Centre Overuse Injury Questionnaire (OSTRC-O) and the Oslo Sports Trauma Research Centre questionnaire on Health Problems (The OSTRC-H) make it possible to monitor illness and injury at regular intervals capturing prevalence and incidence of acute injury, overuse injury, and illnesses. The aim of this study was to translate, culturally adapt, and establish the face validity of the OSTRC-O and the OSTRC-H into a Danish context (DK) through cognitive interviews and the assessment of test-retest reliability. The OSTRC-O.DK was distributed to 57 heterogenous respondents; response rate was 89%. The OSTRC-H was distributed to 58 heterogenous respondents; response rate was 86%. No major disagreements were observed between the original and translated versions of the questionnaires. The OSTRC-O had high internal consistency (Cronbach's alpha 0.80-0.93). The primary reliability analyses including all participants, showed reliability ICC: 0.62 (95% CI: 0.42-0.77. The secondary reliability analyses that only included subjects who did not change injury region from the test to the retest showed an ICC of 0.86 (95% CI: 0.77-0.92).The questionnaires were found to be valid, reliable, and acceptable for use in a Danish population. PMID- 26631938 TI - Modelling in vivo creatine/phosphocreatine in vitro reveals divergent adaptations in human muscle mitochondrial respiratory control by ADP after acute and chronic exercise. AB - KEY POINTS: Mitochondrial respiratory sensitivity to ADP is thought to influence muscle fitness and is partly regulated by cytosolic-mitochondrial diffusion of ADP or phosphate shuttling via creatine/phosphocreatine (Cr/PCr) through mitochondrial creatine kinase (mtCK). Previous measurements of respiration in vitro with Cr (saturate mtCK) or without (ADP/ATP diffusion) show mixed responses of ADP sensitivity following acute exercise vs. less sensitivity after chronic exercise. In human muscle, modelling in vivo 'exercising' [Cr:PCr] during in vitro assessments revealed novel responses to exercise that differ from detections with or without Cr (+/-Cr). Acute exercise increased ADP sensitivity when measured without Cr but had no effect +/-Cr or with +Cr:PCr, whereas chronic exercise increased sensitivity +/-Cr but lowered sensitivity with +Cr:PCr despite increased markers of mitochondrial oxidative capacity. Controlling in vivo conditions during in vitro respiratory assessments reveals responses to exercise that differ from typical +/-Cr comparisons and challenges our understanding of how exercise improves metabolic control in human muscle. ABSTRACT: Mitochondrial respiratory control by ADP (Kmapp ) is viewed as a critical regulator of muscle energy homeostasis. However, acute exercise increases, decreases or has no effect on Kmapp in human muscle, whereas chronic exercise surprisingly decreases sensitivity despite greater mitochondrial content. We hypothesized that modelling in vivo mitochondrial creatine kinase (mtCK)-dependent phosphate-shuttling conditions in vitro would reveal increased sensitivity (lower Kmapp ) after acute and chronic exercise. The Kmapp was determined in vitro with 20 mm Cr (+Cr), 0 mm Cr (-Cr) or 'in vivo exercising' 20 mm Cr/2.4 mm PCr (Cr:PCr) on vastus lateralis biopsies sampled from 11 men before, immediately after and 3 h after exercise on the first, fifth and ninth sessions over 3 weeks. Dynamic responses to acute exercise occurred throughout training, whereby the first session did not change Kmapp with in vivo Cr:PCr despite increases in -Cr. The fifth session decreased sensitivity with Cr:PCr or +Cr despite no change in -Cr. Chronic exercise increased sensitivity +/-Cr in association with increased electron transport chain content (+33-62% complexes I-V), supporting classic proposals that link increased sensitivity to oxidative capacity. However, in vivo Cr:PCr reveals a perplexing decreased sensitivity, contrasting the increases seen +/-Cr. Functional responses occurred without changes in fibre type or proteins regulating mitochondrial-cytosolic energy exchange (mtCK, VDAC and ANT). Despite the dynamic responses seen with +/-Cr, modelling in vivo phosphate-shuttling conditions in vitro reveals that ADP sensitivity is unchanged after high intensity exercise and is decreased after training. These findings challenge our understanding of how exercise regulates skeletal muscle energy homeostasis. PMID- 26631941 TI - [Postoperative persistent chronic pain: what do we know about prevention, risk factors, and treatment]. AB - BACKGROUND AND OBJECTIVES: Postoperative persistent chronic pain (POCP) is a serious health problem, disabling, undermining the quality of life of affected patients. Although more studies and research have addressed the possible mechanisms of the evolution from acute pain to chronic postoperatively, there are still no consistent data about the risk factors and prevention. This article aims to bring what is in the panorama of the current literature available. CONTENT: This review describes the definition, risk factors, and mechanisms of POCD, its prevention and treatment. The main drugs and techniques are exposed comprehensively. CONCLUSION: Postoperative persistent chronic pain is a complex and still unclear etiology entity, which interferes heavily in the life of the subject. Neuropathic pain resulting from surgical trauma is still the most common expression of this entity. Techniques to prevent nerve injury are recommended and should be used whenever possible. Despite efforts to understand and select risk patients, the management and prevention of this syndrome remain challenging and inappropriate. PMID- 26631940 TI - Nanoscale assembly processes revealed in the nacroprismatic transition zone of Pinna nobilis mollusc shells. AB - Intricate biomineralization processes in molluscs engineer hierarchical structures with meso-, nano- and atomic architectures that give the final composite material exceptional mechanical strength and optical iridescence on the macroscale. This multiscale biological assembly inspires new synthetic routes to complex materials. Our investigation of the prism-nacre interface reveals nanoscale details governing the onset of nacre formation using high-resolution scanning transmission electron microscopy. A wedge-polishing technique provides unprecedented, large-area specimens required to span the entire interface. Within this region, we find a transition from nanofibrillar aggregation to irregular early-nacre layers, to well-ordered mature nacre suggesting the assembly process is driven by aggregation of nanoparticles (~50-80 nm) within an organic matrix that arrange in fibre-like polycrystalline configurations. The particle number increases successively and, when critical packing is reached, they merge into early-nacre platelets. These results give new insights into nacre formation and particle-accretion mechanisms that may be common to many calcareous biominerals. PMID- 26631939 TI - microRNA targeting of the P2X7 purinoceptor opposes a contralateral epileptogenic focus in the hippocampus. AB - The ATP-gated ionotropic P2X7 receptor (P2X7R) modulates glial activation, cytokine production and neurotransmitter release following brain injury. Levels of the P2X7R are increased in experimental and human epilepsy but the mechanisms controlling P2X7R expression remain poorly understood. Here we investigated P2X7R responses after focal-onset status epilepticus in mice, comparing changes in the damaged, ipsilateral hippocampus to the spared, contralateral hippocampus. P2X7R gated inward currents were suppressed in the contralateral hippocampus and P2rx7 mRNA was selectively uploaded into the RNA-induced silencing complex (RISC), suggesting microRNA targeting. Analysis of RISC-loaded microRNAs using a high throughput platform, as well as functional assays, suggested the P2X7R is a target of microRNA-22. Inhibition of microRNA-22 increased P2X7R expression and cytokine levels in the contralateral hippocampus after status epilepticus and resulted in more frequent spontaneous seizures in mice. The major pro inflammatory and hyperexcitability effects of microRNA-22 silencing were prevented in P2rx7(-/-) mice or by treatment with a specific P2X7R antagonist. Finally, in vivo injection of microRNA-22 mimics transiently suppressed spontaneous seizures in mice. The present study supports a role for post transcriptional regulation of the P2X7R and suggests therapeutic targeting of microRNA-22 may prevent inflammation and development of a secondary epileptogenic focus in the brain. PMID- 26631942 TI - Clinical Application of Esophageal High-resolution Manometry in the Diagnosis of Esophageal Motility Disorders. AB - Esophageal high-resolution manometry (HRM) is replacing conventional manometry in the clinical evaluation of patients with esophageal symptoms, especially dysphagia. The introduction of HRM gave rise to new objective metrics and recognizable patterns of esophageal motor function, requiring a new classification scheme: the Chicago classification. HRM measurements are more detailed and more easily performed compared to conventional manometry. The visual presentation of acquired data improved the analysis and interpretation of esophageal motor function. This led to a more sensitive, accurate, and objective analysis of esophageal motility. In this review we discuss how HRM changed the way we define and categorize esophageal motility disorders. Moreover, we discuss the clinical applications of HRM for each esophageal motility disorder separately. PMID- 26631943 TI - [New molecules in the treatment of inflammatory bowel disease]. AB - Inflammatory bowel disease (IBD) is a disorder of unknown aetiology that provokes chronic inflammation of the gastrointestinal tract. Anti-tumor necrosis factor drugs have represented a major advance in the treatment of IBD patients in the last few years and also have a good safety profile. Nevertheless, these treatments are not effective in all patients and, in initial responders, there can be a loss of response in the long-term. Consequently, new treatments are needed for IBD, aimed at distinct therapeutic targets. In the last few years, new molecules have been incorporated into the therapeutic armamentarium of IBD patients. Golimumab is an anti-tumor necrosis factor monoclonal antibody with demonstrated effectiveness in the treatment of ulcerative colitis. The use of CT P13 (biosimilar infliximab) has been approved in Europe for the same indications as the original infliximab. More recently, vedolizumab, an anti-alpha4beta7 integrin monoclonal antibody, has been approved for the treatment of Crohn's disease and ulcerative colitis. A large number of molecules are currently under development, some of which will, in the future, broaden the therapeutic options available in the treatment of IBD patients. Finally, in the next few years, studies should aim to identify factors predictive of response to the distinct biological agents for IBD in order to allow personalized selection of the best therapeutic alternative for each patient. PMID- 26631944 TI - Bovine noroviruses: A missing component of calf diarrhoea diagnosis. AB - Noroviruses are RNA viruses that belong to the Genus Norovirus, Family Caliciviridae, and infect human beings and several animal species, including cattle. Bovine norovirus infections have been detected in cattle of a range of different ages throughout the world. Currently there is no suitable cell culture system for these viruses and information on their pathogenesis is limited. Molecular and serological tests have been developed, but are complicated by the high genetic and antigenic diversity of bovine noroviruses. Bovine noroviruses can be detected frequently in faecal samples of diarrhoeic calves, either alone or in association with other common enteric pathogens, suggesting a role for these viruses in the aetiology of calf enteritis. PMID- 26631946 TI - Serum and fecal canine alpha1-proteinase inhibitor concentrations reflect the severity of intestinal crypt abscesses and/or lacteal dilation in dogs. AB - Gastrointestinal (GI) protein loss, due to lymphangiectasia or chronic inflammation, can be challenging to diagnose. This study evaluated the diagnostic accuracy of serum and fecal canine alpha1-proteinase inhibitor (calpha1PI) concentrations to detect crypt abscesses and/or lacteal dilation in dogs. Serum and fecal calpha1PI concentrations were measured in 120 dogs undergoing GI tissue biopsies, and were compared between dogs with and without crypt abscesses/lacteal dilation. Sensitivity and specificity were calculated for dichotomous outcomes. Serial serum calpha1PI concentrations were also evaluated in 12 healthy corticosteroid-treated dogs. Serum calpha1PI and albumin concentrations were significantly lower in dogs with crypt abscesses and/or lacteal dilation than in those without (both P <0.001), and more severe lesions were associated with lower serum calpha1PI concentrations, higher 3 days-mean fecal calpha1PI concentrations, and lower serum/fecal calpha1PI ratios. Serum and fecal calpha1PI, and their ratios, distinguished dogs with moderate or severe GI crypt abscesses/lacteal dilation from dogs with only mild or none such lesions with moderate sensitivity (56-92%) and specificity (67-81%). Serum calpha1PI concentrations increased during corticosteroid administration. We conclude that serum and fecal alpha1PI concentrations reflect the severity of intestinal crypt abscesses/lacteal dilation in dogs. Due to its specificity for the GI tract, measurement of fecal calpha1PI appears to be superior to serum calpha1PI for diagnosing GI protein loss in dogs. In addition, the serum/fecal calpha1PI ratio has an improved accuracy in hypoalbuminemic dogs, but serum calpha1PI concentrations should be carefully interpreted in corticosteroid-treated dogs. PMID- 26631945 TI - Variance associated with the use of relative velocity for force platform gait analysis in a heterogeneous population of clinically normal dogs. AB - Factors that contribute to variance in ground reaction forces (GRFs) include dog morphology, velocity, and trial repetition. Narrow velocity ranges are recommended to minimize variance. In a heterogeneous population, it may be preferable to minimize data variance and efficiently perform force platform gait analysis by evaluation of each individual dog at its preferred velocity, such that dogs are studied at a similar relative velocity (V*). Data from 27 normal dogs were obtained including withers and shoulder height. Each dog was trotted across a force platform at its preferred velocity, with controlled acceleration (+/-0.5 m/s(2)). V* ranges were created for withers and shoulder height. Variance effects from 12 trotting velocity ranges and associated V* ranges were examined using repeated-measures analysis-of-covariance. Mean bodyweight was 24.4 +/- 7.4 kg. Individual dog, velocity, and V* significantly influenced GRF (P <0.001). Trial number significantly influenced thoracic limb peak vertical force (PVF) (P <0.001). Limb effects were not significant. The magnitude of variance effects was greatest for the dog effect. Withers height V* was associated with small GRF variance. Narrow velocity ranges typically captured a smaller percentage of trials and were not consistently associated with lower variance. The withers height V* range of 0.6-1.05 captured the largest proportion of trials (95.9 +/- 5.9%) with no significant effects on PVF and vertical impulse. The use of individual velocity ranges derived from a withers height V* range of 0.6-1.05 will account for population heterogeneity while minimizing exacerbation of lameness in clinical trials studying lame dogs by efficient capture of valid trials. PMID- 26631947 TI - Metabolic analysis of canine peripheral blood mononuclear cells treated ex vivo with dexamethasone. AB - In dogs, hyperadrenocorticism (HAC) is associated with insulin resistance and diabetes does progress with HAC. There are significant differences in the transcriptomic and proteomic patterns of activated T cells, which parallel the findings in muscle tissues. The aim of this study was to assess how glucocorticoids affect intracellular metabolites in canine peripheral blood mononuclear cells (CnPBMCs) using dexamethasone. A total of 96 metabolites were identified by capillary electrophoresis time-of-flight mass spectrometry (CE TOFMS). After incubation with dexamethasone, the metabolites glucose 1-phosphate, glucose 6-phosphate, fructose 6-phosphate, sedoheptulose 7-phosphate and acetyl CoA were significantly increased. However, ATP, CTP, dATP, pyruvic acid and NADP(+) were significantly decreased. These results show that a glucocorticoid reduces the catabolic reaction of glucose and accordingly decreases the glucose requirements of CnPBMCs. PMID- 26631948 TI - Analysis of c-KIT exon 11 mutations in canine gastrointestinal stromal tumours. AB - The aim of this study was to determine the type and frequency of c-KIT exon 11 mutations in canine gastrointestinal stromal tumours (GISTs) and investigate the association between the c-KIT mutation status and KIT immunohistochemical staining pattern. Mutations in exon 11 of c-KIT were examined in 46 formalin fixed paraffin-embedded canine GISTs using PCR of genomic DNA and reverse transcription-PCR (RT-PCR) of cDNA. Exon 11 c-KIT mutations were detected in 15/46 (32.6%) cases by conventional PCR and 34/46 (73.9%) cases by RT-PCR; the mutation detection rate was significantly higher for RT-PCR (P = 0.004, Fisher's exact test). Ten different mutations, including deletion, internal tandem duplication and point mutations, were identified by RT-PCR. Immunohistochemistry was performed using an anti-KIT antibody; diffuse KIT staining was detected in the tumour cell cytoplasm in 32/46 (69.6%) cases and partial or stippled cytoplasmic staining of KIT was observed in 14/46 (30.4%) cases. Neither pattern was significantly associated with c-KIT exon 11 mutation status (P = 1.000, chi square test). These data indicate that c-KIT exon 11 mutations occur frequently in canine GISTs, similar to human GISTs; however, there is no association between c-KIT mutations and the KIT expression pattern in canine GISTs. This study suggests that RT-PCR is more sensitive than conventional PCR for the detection of c-KIT mutations in canine GISTs. PMID- 26631949 TI - Executive function deficits in pediatric cerebellar tumor survivors. AB - BACKGROUND AND AIMS: Besides motor function the cerebellum subserves frontal lobe functions. Thus, we investigated executive functions in pediatric posterior fossa tumor survivors. METHODS: We tested information processing, aspects of attention, planning and intelligence in 42 pediatric posterior fossa tumor survivors (mean age 14.63 yrs, SD 5.03). Seventeen low-grade tumor patients (LGCT) were treated with surgery only and 25 high-grade tumors patients (HGCT) received postsurgical adjuvant treatment. We evaluated simple reaction time, executive functioning, i.e. visuospatial memory, inhibition, and mental flexibility using the Amsterdam Neuropsychological Tasks program, whereas forward thinking was assessed with the Tower of London-test. Intelligence was determined using the Wechsler Intelligence Scale. Ataxia was assessed with the International Cooperative Ataxia Rating Scale. RESULTS: About one third of each patient group showed forward thinking scores below one standard deviation of the norm. Impaired forward thinking correlated significantly with degree of ataxia (r = -0.39, p = 0.03) but not with fluid intelligence. Both patient groups exhibited executive function deficits in accuracy and reaction speed in more difficult tasks involving information speed and attention flexibility. Still, HGCT patients were significantly slower and committed more errors. Working memory was inferior in HGCT patients. CONCLUSION: Pediatric cerebellar tumor survivors with different disease and treatment related brain damage exhibit similar patterns of impairment in executive functioning, concerning forward thinking, inhibition and mental flexibility. The deficits are larger in high-grade tumor patients. The pattern of function loss seen in both groups is most probably due to comparable lesions to cerebro-cerebellar circuits that are known to modulate critical executive functions. PMID- 26631950 TI - Assessment of compatibility between the nematophagous fungi Arthrobotrys robusta and Duddingtonia flagrans under laboratory conditions. PMID- 26631951 TI - [Azole resistance with environmental origin: What alternatives for the future?]. AB - Azole resistant Aspergillus fumigatus strains are increasingly reported in many countries. One resistance mechanism is attributed to the use of azole fungicides in environment. Two mutations, TR34/L98H and TR46/Y121F/T289A, on the cyp51A gene, have been described. Results of 40 publications about azole resistant strain detections, with TR34/L98H and TR46/Y121F/T289A mutations, in clinical and/or environmental samples, are presented in this review. These cases, observed in many countries, suggest spreading phenomenon. Measures to moderate fungicides treatments and/or alternative treatments in environment should be established to preserve the effectiveness of azole antifungal therapy for at-risk patients. PMID- 26631952 TI - Identification of a panel of five serum miRNAs as a biomarker for Parkinson's disease. AB - BACKGROUND AND OBJECTIVE: Parkinson's disease (PD) is the second most common age related neurodegenerative disorder after Alzheimer's disease. The aim of this work was to determine whether the differences of serum miRNAs profiling could distinguish PD patients from healthy individuals. METHODS: We collected serum samples from 106 sporadic PD patients and 91 age/gender-matched healthy controls. Serum miRNAs were analysed by Solexa sequencing followed by a qRT-PCR examination. The qRT-PCR assay, which was divided into two phases, was used to validate the expression of miRNAs screened by Solexa sequencing. Receiver operating characteristic (ROC) curve analysis and clustering analysis were performed to determine the diagnostic usefulness of the selected miRNAs for PD. RESULTS: In this study, we generated a profile of 5 serum miRNAs: miR-195 was up regulated, and miR-185, miR-15b, miR-221 and miR-181a were down-regulated. CONCLUSION: This group of five miRNAs can precisely distinguish PD patients from health individuals and may be used as a potential serum-based biomarker for the diagnosis of PD. PMID- 26631953 TI - Cost-utility of sentinel lymph node biopsy in cT1-T2N0 oral cancer. AB - OBJECTIVES: To calculate the cost-utility of different strategies for the detection of occult lymph node metastases in cT1-T2N0 oral cancer. METHODS: A decision tree followed by a Markov model was designed to compare the cost-utility of the following strategies: (a) USgFNAC (ultrasound guided fine needle aspiration cytology), (b) SLNB (sentinel lymph node biopsy), (c) USgFNAC and, if negative, SLNB (d) END (elective neck dissection). Data was collected from 62 patients in four Dutch head and neck centres. Utilities were measured with the EQ5D questionnaire and resource use was recorded from patient charts. Costs were calculated from a hospital perspective. Uncertainty was explored with scenario analyses and probabilistic sensitivity analyses. RESULTS: With a 5- or 10-year time horizon, SLNB results in the highest number of additional quality-adjusted life years (QALYs, 0.12 and 0.26, respectively) for the smallest additional costs (?56 and ?74, respectively) compared to USgFNAC. With a lifetime horizon END results in the highest number of additional QALYs (0.55) for an additional ?1.626 per QALY gained compared to USgFNAC. When we make different assumptions regarding the duration of disutilities (?5 years) or the improvement (?3%) of sensitivity of SLNB, SLNB is the most favourable strategy from all time horizons. CONCLUSION: SLNB is a good diagnostic strategy to evaluate cT1-T2N0 oral cancer. SLNB is the preferred strategy in a 5- or 10-year time horizon. From a lifetime horizon, END may be preferred. SLNB may become the optimal strategy from all time horizons if its sensitivity can be slightly improved. PMID- 26631954 TI - Superficial oral mucoceles in cancer patient after radiation therapy: An overlooked yet imperative phenomenon. PMID- 26631955 TI - CD19(+)IL-10(+) regulatory B cells affect survival of tongue squamous cell carcinoma patients and induce resting CD4(+) T cells to CD4(+)Foxp3(+) regulatory T cells. AB - OBJECTIVES: Increase of regulatory T cells (Tregs) in the tumor microenvironment predicts worse survival of patients with various types of cancer including tongue squamous cell carcinoma (TSCC). Recently, the cross-talk between Tregs and regulatory B cells (Bregs) has been shown in several tumor models. However the relevance of Bregs to tumor immunity in humans remains elusive. Our objective was to investigate the distribution and function of Bregs in TSCC microenvironment. MATERIALS AND METHODS: Double staining (Bregs: IL10/CD19 and Tregs: Foxp3/CD4) was performed on tissue sections of 46 TSCC, 20 metastasis lymph nodes, and tumor adjacent normal tissue. Flow cytometry analysis was used to detect the Bregs from magnetic bead-sorted B cells after co-culture with TSCC cell lines, and Tregs from sorted CD4(+)CD25(-) T cells after co-culture with stimulated B cells. RESULTS: The immunohistochemical (IHC) results showed that the frequency of Bregs/CD19(+) B in TSCC (0.80+/-0.08%) was significantly higher than adjacent normal tissue (0.52+/-0.04% p<0.01). And the increase of Bregs in TSCC microenvironment was related to Tregs and predicts worse survival in patients. Cytological experiments indicated that frequency of Bregs increased after co culture with TSCC cell line and that the induced B cells converted CD4(+)CD25(-) T cells into Tregs. CONCLUSION: The increased expression of Bregs in the TSCC microenvironment plays a significant role in the differentiation of resting CD4(+) T cells and influenced the prognosis of TSCC patients. PMID- 26631956 TI - International perspectives on sharing clinical data with patients. AB - OBJECTIVE: Engaging patients in their care has become a topic of increasing importance, and enabling patients to have access to their clinical data is a key aspect of such engagement. We investigated, on an international scale, the current state of approaches for providing patients with access to their own clinical information. METHODS: Individuals from 28 countries were invited to participate in a cross-sectional semi-structured interview. Interview questions focused on social and cultural influences that affected patient engagement activities, government support for current and planned initiatives, data ownership models, and technical issues. RESULTS: Interviews were conducted with individuals from 16 countries representing six continents. Respondents reported substantive initiatives for providing information to patients in the majority of countries interviewed. These initiatives were diverse in nature and stage of implementation. DISCUSSION: Enabling patient access to data is occurring on an international scale. There is considerable variability in the level of maturity, the degree of government involvement, the technical infrastructure, and the plans for future development across the world. As informaticians, we are still in the early stages of deploying patient engagement technologies and have yet to identify optimal strategies in this arena. CONCLUSION: Efforts to improve patient access to data are active on a global-scale. There are many open questions about best practices and much can be learned by adopting an international perspective to guide future implementation efforts. PMID- 26631957 TI - Motor Planning for Loading During Gait in Subacute Stroke. AB - OBJECTIVES: To determine the characteristics of motor planning surrounding initial contact during gait through examination of thigh muscle timing, amplitude, and co-contraction of the paretic and nonparetic limbs in people poststroke, and to investigate whether muscle timing, amplitude, and clinical performance measures of balance and mobility differ based on the level of co contraction. DESIGN: Observational study. SETTING: University-based research laboratory. PARTICIPANTS: Individuals (n=27) in the subacute phase after stroke and healthy controls (n=8) (N=35). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Timing (onset and offset) and normalized amplitude (percent electromyography maximum) of the biceps femoris (BF) and rectus femoris (RF) muscles were measured during terminal swing and early stance. A co-contraction index (CCI) was calculated for the BF and RF muscle activity. Individuals with CCI values equal to or below the mean of the healthy group were in the low CCI group, whereas those with values above the mean were in the high CCI group. Functional balance and mobility evaluation used the Community Balance and Mobility Scale (CB&M). RESULTS: For the paretic and nonparetic limbs, measures of timing, amplitude, and co-contraction were similar for both limbs. Compared with the healthy group, the high CCI group had lower CB&M scores, longer durations, and higher levels of RF and BF muscle activity, whereas the low CCI group had electromyographic measures statistically similar to healthy controls. CONCLUSIONS: The motor control of gait after subacute stroke is characterized by symmetry of timing and amplitude of muscle recruitment at the knee. High co contraction levels surrounding the knee were associated with lower functional balance and mobility. These findings suggest a compensatory strategy of increased co-contraction in those with more impairment while maintaining symmetry of lower limb biomechanics between limbs. PMID- 26631959 TI - Large-pore mesoporous silica nanospheres as vehicles for delivering TRAF3-shRNA plasmids to Kupffer cells. AB - The currently available techniques for transferring exogenous genes into macrophages, especially the targeted import of exogenous genes into Kupffer cells (KCs) in vivo, are inefficient and achieve only low targeting. Novel Large-Pore Mesoporous Silica Nanospheres (LPMSNs) may be a promising gene transfection agent for KCs because of their superior biodegradation and hypotoxic characteristics, as well as their ability to retain the biological function of KCs and the high loading-rate of exogenous plasmid. LPMSNs were able to completely adsorb shRNA TRAF3 (tumor necrosis factor receptor-associated factor-3) plasmid at a mass ratio as low as 30:1, and exhibited a low cytotoxicity for KCs. LPMSNs were detected in KC cytoplasm in vitro, and transmission electron microscopy (TEM) revealed that they were present only in KCs in liver tissue in vivo. The max KC transfection efficiency with LPMSNs was 34.8+/- 0.07%, as evaluated using flow cytometry, and the protein and mRNA levels of TRAF3 were significantly inhibited (P < 0.05) by shRNA-TRAF3 plasmid transfection after 24 h in vitro and 48 h in vivo. In conclusion, KC targeted transfection was achieved successfully by LPMSNs carrying shRNA-TRAF3 plasmids in vitro and vivo. The protein and mRNA levels of TRAF3 were suppressed significantly. These results suggest that LPMSNs are a promising vehicle for delivering exogenous genes into KCs in vitro and vivo. PMID- 26631958 TI - Cervical cancer screening of HPV vaccinated populations: Cytology, molecular testing, both or none. AB - Cervical cancer control includes primary prevention through vaccination to prevent human papillomavirus (HPV) infection and secondary prevention through screening to detect and treat cervical precancerous lesions. This review summarizes the evidence for the population impact of vaccines against oncogenic HPV types in reducing the prevalence of cervical precancerous lesions. We examine the gradual shift in screening technology from cervical cytology alone to cytology and HPV cotesting, and finally to the recognition that HPV testing can serve alone as the new screening paradigm, particularly in the initial post vaccination era. We should expect an impact on screening performance and practices, as cohorts of HPV-vaccinated girls and adolescents reach cervical cancer screening age. In preparation for changes in the screening paradigm for the vaccination era, we propose that policymaking on cervical cancer screening should mirror current practices with other cancers as benchmarks. Cervical precancerous lesions will become a very rare condition following the widespread implementation of HPV vaccines with broader coverage in the number of preventable oncogenic types. Irrespective of screening technology, the false positive results will far outnumber the true positive ones, a tipping point that will herald a new period when the harms from cervical cancer screening will outweigh its benefits. We present a conceptual framework to guide decision making when we reach this point within 25-30 years. PMID- 26631960 TI - alpha-Melanocyte stimulating hormone attenuates dexamethasone-induced osteoblast damages through activating melanocortin receptor 4-SphK1 signaling. AB - Long-term glucocorticoid (GC) usage may cause non-traumatic femoral head osteonecrosis. Dexamethasone (Dex) is shown to exert potent cytotoxic effect to osteoblasts. Here, we investigated the potential activity of alpha-melanocyte stimulating hormone (alpha-MSH) against the process. Our data revealed that pretreatment of alpha-MSH significantly inhibited Dex-induced apoptosis and necrosis in both osteoblastic-like MC3T3-E1 cells and primary murine osteoblasts. Melanocortin receptor 4 (MC4R) acts as the receptor of alpha-MSH in mediating its actions in osteoblasts. The MC4R antagonist SHU9119, or shRNA-mediated knockdown of MC4R, almost abolished alpha-MSH-induced activation of downstream signalings (Akt and Erk1/2) and its pro-survival effect in osteoblasts. Further studies showed that alpha-MSH activated MC4R downstream sphingosine kinase 1 (SphK1) and increased cellular sphingosine-1-phosphate (S1P) content in MC3T3-E1 cells and primary murine osteoblasts, which were blocked by SHU9119 or MC4R shRNAs. SphK1 inhibition by the its inhibitor N,N-dimethylsphingosine (DMS), or SphK1 knockdown by targeted-shRNAs, largely attenuated alpha-MSH-mediated osteoblast protection against Dex. Together, these results suggest that alpha-MSH alleviates Dex induced damages to cultured osteoblasts through activating MC4R-SphK1 signaling. PMID- 26631961 TI - NDRG2 promoted secreted miR-375 in microvesicles shed from M1 microglia, which induced neuron damage. AB - BACKGROUND: Microglia microvesicles (MVs) has shown to have significant biological functions under normal conditions. A diversity of miRNAs is involved in neuronal development, survival, function, and plasticity, but the exact functional role of NDRG2 and secreted miR-375 in MVs in neuron damage is poorly understood. We investigated the effect of NDRG2 and secreted miR-375 in MVs shed from M1 microglia on neuron damage. METHODS: Expression of Nos2, Arg-1, miR-375, syntaxin-1A, NDRG2 and Pdk 1 were evaluated using RT-PCR or western blotting. Cell viability of N2A neuron was quantified by a MTT assay. RESULTS: Microglia can be polarized into different functional phenotypes. Expression of NDRG2 and Nos2 were significantly increased by LPS treatment on N9 cells, whereas treatment with IL-4 dramatically suppressed the expression of NDRG2 and remarkably elevated expression of Arg-1. Besides, MVs shed from LPS-treated N9 microglia significantly inhibited cell viability of N2A neurons and expression of syntaxin 1A, and NDRG2 interference reversed the up-regulated miR-375 in LPS-treated N9 microglia and MVs shed from LPS-treated N9 cells. Furthermore, NDRG2 could modulate miR-375 expression in N9 microglia and MVs. And miR-375 inhibitor remarkably elevated Pdk1 expression in N2A neurons. Finally, miR-375 inhibitor could reverse suppression effect of NDRG2 overexpression on cell viability of N2A neurons and expression of syntaxin-1A. CONCLUSION: Our results demonstrated that NDRG2 promoted secreted miR-375 in microvesicles shed from M1 microglia, which induced neuron damage. The suppression of NDRG2 and secreted miR-375 in MVs shed from M1 microglia may be potential targets for alleviation of neuron damage. PMID- 26631962 TI - Membrane-bound globin X protects the cell from reactive oxygen species. AB - Globin X (GbX) is a member of the globin family that emerged early in the evolution of Metazoa. In vertebrates, GbX is restricted to lampreys, fish, amphibians and some reptiles, and is expressed in neurons. Unlike any other metazoan globin, GbX is N-terminally acylated and anchored in the cell membrane via myristoyl and palmitoyl groups, suggesting a unique function. Here, we compared the capacity of GbX to protect a mouse neuronal cell line from hypoxia and reactive oxygen species (ROS) with that of myoglobin. To evaluate the contribution of membrane-binding, we generated a mutated version of GbX without acyl groups. All three globins enhanced cell viability under hypoxia, with myoglobin having the most pronounced effect. GbX but not myoglobin protected the cells from hydrogen peroxide (H2O2)-induced stress. Membrane-bound GbX was significantly more efficient than its mutated, soluble form. Furthermore, myoglobin and mutated GbX increased production of ROS upon H2O2-treatment, while membrane-bound GbX did not. The results indicate that myoglobin enhances O2 supply while GbX protects the cell membrane from ROS-stress. The ancient origin of GbX suggests that ROS-protection reflects the function of the early globins before they acquired a respiratory role. PMID- 26631963 TI - Triptolide inhibits transcription of hTERT through down-regulation of transcription factor specificity protein 1 in primary effusion lymphoma cells. AB - Primary effusion lymphoma (PEL) is a rare and aggressive non-Hodgkin's lymphoma. Human telomerase reverse transcriptase (hTERT), a key component responsible for the regulation of telomerase activity, plays important roles in cellular immortalization and cancer development. Triptolide purified from Tripterygium extracts displays a broad-spectrum bioactivity profile, including immunosuppressive, anti-inflammatory, and anti-tumor. In this study, it is investigated whether triptolide reduces hTERT expression and suppresses its activity in PEL cells. The mRNA and protein levels of hTERT were examined by real time-PCR and Western blotting, respectively. The activity of hTERT promoter was determined by Dual luciferase reporter assay. Our results demonstrated that triptolide decreased expression of hTERT at both mRNA and protein levels. Further gene sequence analysis indicated that the activity of hTERT promoter was suppressed by triptolide. Triptolide also reduced the half-time of hTERT. Additionally, triptolide inhibited the expression of transcription factor specificity protein 1(Sp1) in PEL cells. Furthermore, knock-down of Sp1 by using specific shRNAs resulted in down-regulation of hTERT transcription and protein expression levels. Inhibition of Sp1 by specific shRNAs enhanced triptolide induced cell growth inhibition and apoptosis. Collectively, our results demonstrate that the inhibitory effect of triptolide on hTERT transcription is possibly mediated by inhibition of transcription factor Sp1 in PEL cells. PMID- 26631964 TI - MicroRNA-24 inhibits serotonin reuptake transporter expression and aggravates irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is a common chronic functional gastrointestinal disorder. MicroRNAs (miRNAs) have been widely demonstrated to take part in various physiological and pathological processes. In the present study, the role of miR-24 in the pathogenesis of IBS and the potential mechanism in this process were evaluated. Human intestinal mucosa epithelial cells of colon from IBS patients and healthy subjects were collected. An IBS mouse model was established with the induction of trinitro-benzene-sulfonic acid (TNBS). The expression levels of miR-24 and serotonin reuptake transporter (SERT) were analyzed using Real-time PCR and western blot in both human specimen and mice. miR-24 was upregulated in IBS patients and mice intestinal mucosa epithelial cells. Luciferase reporter assay showed that SERT was a potential target gene of miR-24. The treatment of miR-24 inhibitor increased pain threshold and nociceptive threshold levels and reduced MPO activity in proximal colon of IBS mice, and up regulated the mRNA and protein expression levels of SERT in intestinal mucosa epithelial cells. miR-24 played a role in the pathogenesis of IBS probably through regulating SERT expression. PMID- 26631965 TI - Molecular modeling and simulation studies of recombinant laccase from Yersinia enterocolitica suggests significant role in the biotransformation of non steroidal anti-inflammatory drugs. AB - The YacK gene from Yersinia enterocolitica strain 7, cloned in pET28a vector and expressed in Escherichia coli BL21 (DE3), showed laccase activity when oxidized with 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) and guaiacol. The recombinant laccase protein was purified and characterized biochemically with a molecular mass of ~58 KDa on SDS-PAGE and showed positive zymogram with ABTS. The protein was highly robust with optimum pH 9.0 and stable at 70 degrees C upto 12 h with residual activity of 70%. Kinetic constants, Km values, for ABTS and guaiacol were 675 MUM and 2070 MUM, respectively, with corresponding Vmax values of 0.125 MUmol/ml/min and 6500 MUmol/ml/min. It also possess antioxidative property against BSA and Cu(2+)/H2O2 model system. Constant pH MD simulation studies at different protonation states of the system showed ABTS to be most stable at acidic pH, whereas, diclofenac at neutral pH. Interestingly, aspirin drifted out of the binding pocket at acidic and neutral pH, but showed stable binding at alkaline pH. The biotransformation of diclofenac and aspirin by laccase also corroborated the in silico results. This is the first report on biotransformation of non-steroidal anti-inflammatory drugs (NSAIDs) using recombinant laccase from gut bacteria, supported by in silico simulation studies. PMID- 26631966 TI - Aptamers to the sigma factor mimic promoter recognition and inhibit transcription initiation by bacterial RNA polymerase. AB - Promoter recognition by bacterial RNA polymerase (RNAP) is a multi-step process involving multiple protein-DNA interactions and several structural and kinetic intermediates which remain only partially characterized. We used single-stranded DNA aptamers containing specific promoter motifs to probe the interactions of the Thermus aquaticus RNAP sigma(A) subunit with the -10 promoter element in the absence of other parts of the promoter complex. The aptamer binding decreased intrinsic fluorescence of the sigma subunit, likely as a result of interactions between the -10 element and conserved tryptophan residues of the sigma DNA binding region 2. By monitoring these changes, we demonstrated that DNA binding proceeds through a single rate-limiting step resulting in formation of very stable complexes. Deletion of the N-terminal domain of the sigma(A) subunit increased the rate of aptamer binding while replacement of this domain with an unrelated N-terminal region 1.1 from the Escherichia coli sigma(70) subunit restored the original kinetics of sigma-aptamer interactions. The results demonstrate that the key step in promoter recognition can be modelled in a simple sigma-aptamer system and reveal that highly divergent N-terminal domains similarly modulate the DNA-binding properties of the sigma subunit. The aptamers efficiently suppressed promoter-dependent transcription initiation by the holoenzyme of RNA polymerase, suggesting that they may be used for development of novel transcription inhibitors. PMID- 26631967 TI - Molecular cloning and expression analysis of an 1-aminocyclopropane-1-carboxylate synthase gene from Oncidium Gower Ramsey. AB - 1-aminocyclopropane-1-carboxylic acid (ACC) synthase (ACS) is a rate-limiting enzyme in the biosynthesis of ethylene which regulates many aspects of the plant development and responses to biotic and abiotic stresses. In this study, a full length cDNA of ACC synthase, OnACS2, was cloned from the senescing flower of Oncidium Gower Ramsey by RACE. The full-length cDNA of OnACS2 (GenBank accession no. JQ822087) was 1557 bp in length with an open reading frame (ORF) of 1308 bp encoding for a protein of 435 amino acid residues. The predicted OnACS2 protein had a molecular mass of 49.1 kDa with pI value of 7.51. Phylogenetic analysis indicated its evolutionary relationships with corresponding orthologous sequences in orchids, Hosta ventricosa and monocots. Real-time PCR assay demonstrated that OnACS2 was constitutively expressed in all tested organs with the highest transcript level in the gynandria. Differential expression pattern of OnACS2 gene correlated to the ethylene production and the subsequent occurrence of senescent symptoms in flower suggested that OnACS2 probably played an important role in the initiation of flower senescence. PMID- 26631968 TI - A novel frameshift variant of COCH supports the hypothesis that haploinsufficiency is not a cause of autosomal dominant nonsyndromic deafness 9. AB - COCH (coagulation factor C homology) encodes cochlin, and certain mutations of COCH cause autosomal dominant nonsyndromic deafness 9 (DFNA9). Hearing loss due to COCH mutation begins in adulthood, and 17 missense mutations and two in-frame mutations have been reported. Studies with animal and cellular models have suggested that the underlying biological mechanism of DFNA9 is the dominant negative effect of mutated COCH and not haploinsufficiency. However, no human cases of DFNA9 that support this hypothesis have been reported. The proband of the present case was an 18-year-old male with congenital or infantile hearing loss. Targeted next-generation sequencing analysis detected a heterozygous novel frameshift mutation of COCH (c.146dupT, p.C50LfsX8) in the proband, whose hearing loss began earlier than what is typical for DFNA9. His mother also carried the mutation but had normal hearing. Consequently, the mutation was not considered to be the cause of the proband's hearing loss. This family is the first case of a truncating COCH variant and supports the hypothesis that COCH haploinsufficiency is not the cause of hearing loss in humans. PMID- 26631969 TI - miR-409-3p suppresses breast cancer cell growth and invasion by targeting Akt1. AB - Altered levels and functions of microRNAs (miRNAs) are correlated with carcinogenesis. While miR-409-3p has been shown to play important roles in several cancer types, its function in the context of breast cancer (BC) remains unknown. In this study, miR-409-3p was significantly downregulated in BC tissues and cell lines, compared with the corresponding control counterparts. Overexpression of miR-409-3p inhibited BC cell proliferation, migration and invasion in vitro and suppressed tumor growth in vivo. Notably, miR-409-3p induced downregulation of Akt1 protein through binding to its 3' untranslated region (UTR). Conversely, restoring Akt1 expression rescued the suppressive effects of miR-409-3p. Our data collectively indicate that miR-409-3p functions as a tumor suppressor in BC through downregulating Akt1, supporting the targeting of the novel miR-409-3p/Akt1 axis as a potentially effective therapeutic approach for BC. PMID- 26631970 TI - Mentoring junior URM scientists to engage in sleep health disparities research: experience of the NYU PRIDE Institute. AB - AIM: The aim of this study was to evaluate the National Institute of Health (NIH) funded PRIDE Institute in Behavioral Medicine and Sleep Disorders Research at New York University (NYU) Langone Medical Center. The NYU PRIDE Institute provides intensive didactic and mentored research training to junior underrepresented minority (URM) faculty. METHOD: The Kirkpatrick model, a mixed-methods program evaluation tool, was used to gather data on participant's satisfaction and program outcomes. Quantitative evaluation data were obtained from all 29 mentees using the PRIDE REDcap-based evaluation tool. In addition, in-depth interviews and focus groups were conducted with 17 mentees to learn about their experiences at the institute and their professional development activities. Quantitative data were examined, and emerging themes from in-depth interviews and focus groups were studied for patterns of connection and grouped into broader categories based on grounded theory. RESULTS: Overall, mentees rated all programmatic and mentoring aspects of the NYU PRIDE Institute very highly (80-100%). They identified the following areas as critical to their development: research and professional skills, mentorship, structured support and accountability, peer support, and continuous career development beyond the summer institute. Indicators of academic self-efficacy showed substantial improvement over time. Areas for improvement included tailoring programmatic activities to individual needs, greater assistance with publications, and identifying local mentors when K awards are sought. CONCLUSIONS: In order to promote career development, numerous factors that uniquely influence URM investigators' ability to succeed should be addressed. The NYU PRIDE Institute, which provides exposure to a well-resourced academic environment, leadership, didactic skills building, and intensive individualized mentorship proved successful in enabling URM mentees to excel in the academic environment. Overall, the institute accomplished its goals: to build an infrastructure enabling junior URM faculty to network with one another as well as with senior investigators, serving as a role model, in a supportive academic environment. PMID- 26631971 TI - Re-engineering cellular physiology by rewiring high-level global regulatory genes. AB - Knowledge of global regulatory networks has been exploited to rewire the gene control programmes of the model bacterium Salmonella enterica serovar Typhimurium. The product is an organism with competitive fitness that is superior to that of the wild type but tuneable under specific growth conditions. The paralogous hns and stpA global regulatory genes are located in distinct regions of the chromosome and control hundreds of target genes, many of which contribute to stress resistance. The locations of the hns and stpA open reading frames were exchanged reciprocally, each acquiring the transcription control signals of the other. The new strain had none of the compensatory mutations normally associated with alterations to hns expression in Salmonella; instead it displayed rescheduled expression of the stress and stationary phase sigma factor RpoS and its regulon. Thus the expression patterns of global regulators can be adjusted artificially to manipulate microbial physiology, creating a new and resilient organism. PMID- 26631973 TI - Self-Growth of Centimeter-Scale Single Crystals by Normal Sintering Process in Modified Potassium Sodium Niobate Ceramics. AB - In this manuscript, an interesting phenomenon is reported. That is the self growth of single crystals in Pb-free piezoelectric ceramics. These crystals are several centimeters in size. They are grown without any seed addition through a normal sintering process in modified potassium sodium niobate ceramics. It has been achieved by the composition designed to compensate the Na(+) loss which occurs during the liquid phase sintering. The composition of the crystals is (K0.4925Na(0.4925-x)Ba(0.015+x/2))Nb(0.995+x)O3 [x is determined by the Na(+) loss, due to Na2O volatilization]. These crystals have high piezoelectric voltage coefficients (g33, 131 10(-3)Vm/N), indicating that they are good candidates for piezoelectric sensors and energy harvesting devices. We hope that this report can offer the opportunity for many researchers to have an interest in these crystals. PMID- 26631972 TI - Sec13 Regulates Expression of Specific Immune Factors Involved in Inflammation In Vivo. AB - The Sec13 protein functions in various intracellular compartments including the nuclear pore complex, COPII-coated vesicles, and inside the nucleus as a transcription regulator. Here we developed a mouse model that expresses low levels of Sec13 (Sec13(H/-)) to assess its functions in vivo, as Sec13 knockout is lethal. These Sec13 mutant mice did not present gross defects in anatomy and physiology. However, the reduced levels of Sec13 in vivo yielded specific immunological defects. In particular, these Sec13 mutant mice showed low levels of MHC I and II expressed by macrophages, low levels of INF-gamma and IL-6 expressed by stimulated T cells, and low frequencies of splenic IFN-gamma+CD8+ T cells. In contrast, the levels of soluble and membrane-bound TGF-beta as well as serum immunoglobulin production are high in these mice. Furthermore, frequencies of CD19+CD5-CD95+ and CD19+CD5-IL-4+ B cells were diminished in Sec13(H/-) mice. Upon stimulation or immunization, some of the defects observed in the naive mutant mice were compensated. However, TGF-beta expression remained high suggesting that Sec13 is a negative modulator of TGF-beta expression and of its immunosuppressive functions on certain immune cells. In sum, Sec13 regulates specific expression of immune factors with key functions in inflammation. PMID- 26631974 TI - Endoscopically Assisted Transumbilical Single-Incision Laparoscopic Gastric Resection for GIST Treatment. AB - PURPOSE: Complete surgical resection with negative margins without lymphadenectomy is the treatment of choice for nonmetastatic Gastrointestinal Stromal Tumors (GISTs). Laparoscopic resection of gastric GISTs <5 cm is an acceptable and oncologically feasible, safe, and effective treatment. We present our experience of an endoscopically assisted minimally invasive transumbilical single-incision laparoscopic (SILS) technique for gastric GISTs resection. METHODS: Four patients with small gastric GISTs <=5 cm located on the greater curvature or the anterior wall were resected with SILS by using a lesion-lifting technique under the guidance of flexible gastroscopy. RESULTS: The technique was feasible and safe and offered significant advantages in locating the tumor and controlling the resection margins. There were no major intraoperative or postoperative complications, conversions, or tumor ruptures. Pathology showed low risk GISTs resected with disease-free margins without tumor rupture. No recurrences have been observed. CONCLUSION: The endoscopically assisted SILS wedge gastrectomy is a feasible, safe, and advantageous technique for the treatment of the greater curvature or anterior wall gastric GISTs. PMID- 26631975 TI - Cross-modal and modality-specific expectancy effects between pain and disgust. AB - Pain sensitivity increases when a noxious stimulus is preceded by cues predicting higher intensity. However, it is unclear whether the modulation of nociception by expectancy is sensory-specific ("modality based") or reflects the aversive affective consequence of the upcoming event ("unpleasantness"), potentially common with other negative events. Here we compared expectancy effects for pain and disgust by using different, but equally unpleasant, nociceptive (thermal) and olfactory stimulations. Indeed both pain and disgust are aversive, associated with threat to the organism, and processed in partly overlapping brain networks. Participants saw cues predicting the unpleasantness (high/low) and the modality (pain/disgust) of upcoming thermal or olfactory stimulations, and rated the associated unpleasantness after stimuli delivery. Results showed that identical thermal stimuli were perceived as more unpleasant when preceded by cues threatening about high (as opposed to low) pain. A similar expectancy effect was found for olfactory disgust. Critically, cross-modal expectancy effects were observed on inconsistent trials when thermal stimuli were preceded by high disgust cues or olfactory stimuli preceded by high-pain cues. However, these effects were stronger in consistent than inconsistent conditions. Taken together, our results suggest that expectation of an unpleasant event elicits representations of both its modality-specific properties and its aversive consequences. PMID- 26631976 TI - A network medicine approach to quantify distance between hereditary disease modules on the interactome. AB - We introduce a MeSH-based method that accurately quantifies similarity between heritable diseases at molecular level. This method effectively brings together the existing information about diseases that is scattered across the vast corpus of biomedical literature. We prove that sets of MeSH terms provide a highly descriptive representation of heritable disease and that the structure of MeSH provides a natural way of combining individual MeSH vocabularies. We show that our measure can be used effectively in the prediction of candidate disease genes. We developed a web application to query more than 28.5 million relationships between 7,574 hereditary diseases (96% of OMIM) based on our similarity measure. PMID- 26631977 TI - Evaluation of Anti-diarrheal Potential of Hydro-alcoholic Extracts of Leaves of Murraya koenigii in Experimental Animals. AB - BACKGROUND: The indigenous medical system of India mentions the use of Murraya koenigii leaves for the treatment of different types of diarrheas over ages. OBJECTIVE: To evaluate the anti-diarrheal activity of hydro-alcoholic extracts of leaves of Murraya koenigii and to check its effects on intestinal transits in experimental rat model. MATERIALS AND METHODS: The hydro-alcoholic extract of Murraya koenigii leaves was obtained with Soxhlet extraction method. Animals were divided into four groups (n = 6) receiving daily for three consecutive days: vehicle, standard drug atropine (3mg/kg, i.p.), leaf extracts 200 & 400 mg/kg respectively in oral route. Effects of the drugs on normal defecation were noted and then castor oil induced diarrhea was used to measure the effects of leaf extract on stool frequency and consistency. Finally, charcoal meal test was used to evaluate the effect of the extract on intestinal transit. Statistical evaluation was done using SPSS version 17, one way ANOVA followed by Dunnett's t test was done and P< 0.001 was considered as significant. RESULTS: Murraya koenigii leaf extracts in 200 and 400 mg/kg dose reduced stool frequency, increased stool consistency and increased small intestinal transit time. CONCLUSION: Hydro-alcoholic extract of Murraya koenigii leaves possesses significant anti-diarrheal activity due to its inhibitory effect on gastrointestinal motility, making it useful for a wide number of gastrointestinal diseases. PMID- 26631978 TI - Optimizing antibody expression by using the naturally occurring framework diversity in a live bacterial antibody display system. AB - Rapid identification of residues that influence antibody expression and thermostability is often needed to move promising therapeutics into the clinic. To establish a method that can assess small expression differences, we developed a Bacterial Antibody Display (BAD) system that overcomes previous limitations, enabling the use of full-length formats for antibody and antigen in a live cell setting. We designed a unique library of individual framework variants using natural diversity introduced by somatic hypermutation, and screened half antibodies for increased expression using BAD. We successfully identify variants that dramatically improve expression yields and in vitro thermostability of two therapeutically relevant antibodies in E. coli and mammalian cells. While we study antibody expression, bacterial display can now be expanded to examine the processes of protein folding and translocation. Additionally, our natural library design strategy could be applied during antibody humanization and library design for in vitro display methods to maintain expression and formulation stability. PMID- 26631979 TI - Classification of octet AB-type binary compounds using dynamical charges: A materials informatics perspective. AB - The role of dynamical (or Born effective) charges in classification of octet AB type binary compounds between four-fold (zincblende/wurtzite crystal structures) and six-fold (rocksalt crystal structure) coordinated systems is discussed. We show that the difference in the dynamical charges of the fourfold and sixfold coordinated structures, in combination with Harrison's polarity, serves as an excellent feature to classify the coordination of 82 sp-bonded binary octet compounds. We use a support vector machine classifier to estimate the average classification accuracy and the associated variance in our model where a decision boundary is learned in a supervised manner. Finally, we compare the out-of-sample classification accuracy achieved by our feature pair with those reported previously. PMID- 26631981 TI - High-density linkage map construction and mapping of seed trait QTLs in chickpea (Cicer arietinum L.) using Genotyping-by-Sequencing (GBS). AB - This study reports the use of Genotyping-by-Sequencing (GBS) for large-scale SNP discovery and simultaneous genotyping of recombinant inbred lines (RILs) of an intra-specific mapping population of chickpea contrasting for seed traits. A total of 119,672 raw SNPs were discovered, which after stringent filtering revealed 3,977 high quality SNPs of which 39.5% were present in genic regions. Comparative analysis using physically mapped marker loci revealed a higher degree of synteny with Medicago in comparison to soybean. The SNP genotyping data was utilized to construct one of the most saturated intra-specific genetic linkage maps of chickpea having 3,363 mapped positions including 3,228 SNPs on 8 linkage groups spanning 1006.98 cM at an average inter marker distance of 0.33 cM. The map was utilized to identify 20 quantitative trait loci (QTLs) associated with seed traits accounting for phenotypic variations ranging from 9.97% to 29.71%. Analysis of the genomic sequence corresponding to five robust QTLs led to the identification of 684 putative candidate genes whose expression profiling revealed that 101 genes exhibited seed specific expression. The integrated approach utilizing the identified QTLs along with the available genome and transcriptome could serve as a platform for candidate gene identification for molecular breeding of chickpea. PMID- 26631982 TI - Mica Nanoparticle, STB-HO Eliminates the Human Breast Carcinoma Cells by Regulating the Interaction of Tumor with its Immune Microenvironment. AB - Mica, an aluminosilicate mineral, has been proven to possess anti-tumor and immunostimulatory effects. However, its efficacy and mechanisms in treating various types of tumor are less verified and the mechanistic link between anti tumor and immunostimulatory effects has not been elucidated. We sought to investigate the therapeutic effect of STB-HO (mica nanoparticles) against one of the most prevalent cancers, the breast cancer. STB-HO was orally administered into MCF-7 xenograft model or directly added to culture media and tumor growth was monitored. STB-HO administration exhibited significant suppressive effects on the growth of MCF-7 cells in vivo, whereas STB-HO did not affect the proliferation and apoptosis of MCF-7 cells in vitro. To address this discrepancy between in vivo and in vitro results, we investigated the effects of STB-HO treatment on the interaction of MCF-7 cells with macrophages, dendritic cells (DCs) and natural killer (NK) cells, which constitute the cellular composition of tumor microenvironment. Importantly, STB-HO not only increased the susceptibility of MCF-7 cells to immune cells, but also stimulated the immunocytes to eliminate cancer cells. In conclusion, our study highlights the possible role of STB-HO in the suppression of MCF-7 cell growth via the regulation of interactions between tumor cells and anti-tumor immune cells. PMID- 26631983 TI - The isolation and characterization of CTC subsets related to breast cancer dormancy. AB - Uncovering CTCs phenotypes offer the promise to dissect their heterogeneity related to metastatic competence. CTC survival rates are highly variable and this can lead to many questions as yet unexplored properties of CTCs responsible for invasion and metastasis vs dormancy. We isolated CTC subsets from peripheral blood of patients diagnosed with or without breast cancer brain metastasis. CTC subsets were selected for EpCAM negativity but positivity for CD44(+)/CD24(-) stem cell signature; along with combinatorial expression of uPAR and int beta1, two markers directly implicated in breast cancer dormancy mechanisms. CTC subsets were cultured in vitro generating 3D CTC tumorspheres which were interrogated for biomarker profiling and biological characteristics. We identified proliferative and invasive properties of 3D CTC tumorspheres distinctive upon uPAR/int beta1 combinatorial expression. The molecular characterization of uPAR/int beta1 CTC subsets may enhance abilities to prospectively identify patients who may be at high risk of developing BCBM. PMID- 26631980 TI - Gastric fluid versus amniotic fluid analysis for the identification of intra amniotic infection due to Ureaplasma species. AB - OBJECTIVE: Early neonatal sepsis is often due to intra-amniotic infection. The stomach of the neonate contains fluid swallowed before and during delivery. The presence of bacteria as well as neutrophils detected by culture or Gram stain of the gastric fluid during the first day of life is suggestive of exposure to bacteria or inflammation. We undertook this study to determine the relationship between gastric fluid analysis and amniotic fluid obtained by transabdominal amniocentesis in the detection of Ureaplasma species, the most frequent microorganisms responsible for intra-amniotic infection. MATERIALS AND METHODS: The study population consisted of 100 singleton pregnant women who delivered preterm neonates (<35 weeks) within 7 days of amniocentesis. Gastric fluid of newborns was obtained by nasogastric intubation on the day of birth. Amniotic fluid and gastric fluid were cultured for genital Mycoplasmas, and polymerase chain reaction (PCR) for Ureaplasma species was performed. Intra-amniotic inflammation was defined as an elevated amniotic fluid matrix metalloproteinase-8 concentration (>23 ng/mL). RESULTS: (1) Ureaplasma species were detected by culture or PCR in 18% (18/100) of amniotic fluid samples and in 5% (5/100) of gastric fluid samples; (2) among the amniotic fluid cases positive for Ureaplasma species, these microorganisms were identified in 27.8% (5/18) of gastric fluid samples; (3) none of the cases negative for Ureaplasma species in the amniotic fluid were found to be positive for these microorganisms in the gastric fluid; (4) patients with amniotic fluid positive for Ureaplasma species but with gastric fluid negative for these microorganisms had a significantly higher rate of intra amniotic inflammation, acute histologic chorioamnionitis, and neonatal death than those with both amniotic fluid and gastric fluid negative for Ureaplasma species; and (5) no significant differences were observed in the rate of intra-amniotic inflammation, acute histologic chorioamnionitis, and neonatal death between patients with amniotic fluid positive for Ureaplasma species but with gastric fluid negative for these microorganisms and those with both amniotic fluid and gastric fluid positive for Ureaplasma species. CONCLUSIONS: Gastric fluid analysis has 100% specificity in the identification of intra-amniotic infection with Ureaplasma species. However, the detection of Ureaplasma species by culture or PCR in the gastric fluid of neonates at birth did not identify these microorganisms in two-thirds of cases with microbial invasion of the amniotic cavity. Thus, amniotic fluid analysis is superior to that of gastric fluid in the identification of intra-amniotic infection. PMID- 26631984 TI - Shortfalls in the global protected area network at representing marine biodiversity. AB - The first international goal for establishing marine protected areas (MPAs) to conserve the ocean's biodiversity was set in 2002. Since 2006, the Convention on Biological Diversity (CBD) has driven MPA establishment, with 193 parties committed to protecting >10% of marine environments globally by 2020, especially 'areas of particular importance for biodiversity' (Aichi target 11). This has resulted in nearly 10 million km(2) of new MPAs, a growth of ~360% in a decade. Unlike on land, it is not known how well protected areas capture marine biodiversity, leaving a significant gap in our understanding of existing MPAs and future protection requirements. We assess the overlap of global MPAs with the ranges of 17,348 marine species (fishes, mammals, invertebrates), and find that 97.4% of species have <10% of their ranges represented in stricter conservation classes. Almost all (99.8%) of the very poorly represented species (<2% coverage) are found within exclusive economic zones, suggesting an important role for particular nations to better protect biodiversity. Our results offer strategic guidance on where MPAs should be placed to support the CBD's overall goal to avert biodiversity loss. Achieving this goal is imperative for nature and humanity, as people depend on biodiversity for important and valuable services. PMID- 26631985 TI - Properties of skyrmions and multi-quanta vortices in chiral p-wave superconductors. AB - Chiral p-wave superconducting state supports a rich spectrum of topological excitations different from those in conventional superconducting states. Besides domain walls separating different chiral states, chiral p-wave state supports both singular and coreless vortices also interpreted as skyrmions. Here, we present a numerical study of the energetic properties of isolated singular and coreless vortex states as functions of anisotropy and magnetic field penetration length. In a given chiral state, single quantum vortices with opposite winding have different energies and thus only one kind is energetically favoured. We find that with the appropriate sign of the phase winding, two-quanta (coreless) vortices are always energetically preferred over two isolated single quanta (singular) vortices. We also report solutions carrying more flux quanta. However those are typically more energetically expensive/metastable as compared to those carrying two flux quanta. PMID- 26631987 TI - The acute lymphoblastic leukemia of Down Syndrome - Genetics and pathogenesis. AB - Children with Down Syndrome (DS) are at markedly increased risk for acute lymphoblastic leukemia (ALL). The ALL is of B cell precursor (BCP) phenotype. T ALL is only rarely diagnosed as well as infant leukemia. Gene expression profiling and cytogenetics suggest that DS-ALL is an heterogeneous disease. More than half of the leukemias are characterized by aberrant expression of the thymic stromal lymphopoietin (TSLP) receptor CRLF2 caused by genomic rearrangements. These rearrangements are often associated with somatic activating mutations in the receptors or in the downstream components of the JAK-STAT pathway. The activation of JAK-STAT pathway suggests that targeted therapy with JAK or downstream inhibitors may be effective for children with DS-ALL. The basis of the increased risk of BCP-ALL and in particular of the CRLF2 aberrations is presently unknown. Neither is it known which genes on the trisomic chromosome 21 are involved. PMID- 26631986 TI - Substance use prevention program for adolescents with intellectual disabilities on special education schools: a cluster randomised control trial. AB - BACKGROUND: Students without intellectual disability (ID) start experimenting with tobacco and alcohol between 12 and 15 years of age. However, data for 12- to 15-year old students with ID are unavailable. Prevention programs, like 'PREPARED ON TIME' (based on the attitude-social influence-efficacy model), are successful, but their efficacy has not been studied in students with ID. The objectives of this study were (1) to undertake a cluster randomised control trial to test the efficacy of the e-learning program among 12- to 15-year old students with mild and borderline ID in secondary special-needs schools and (2) to examine the tobacco and alcohol use for this population. METHODS: Five schools, randomly selected to be part of either the experimental group or the control group, participated in this study. Passive informed consent was used in which parents and their children can refuse to participate in the study, resulting in 111 students in the experimental group and 143 students in the control group. A total of 210 students completed both baseline and follow-up questionnaires. Primary outcome variables are the knowledge and attitude towards alcohol and tobacco use. This study is registered in the ISRCTN registry with number ISRCTN95279686. RESULTS: Baseline findings showed that a large proportion of all respondents had initiated smoking (49%) and drinking (75%), well above the expected numbers based on national figures. 'PREPARED ON TIME' did not affect the behavioural determinants (i.e. attitude, subjective norm and self-efficacy), except modelling on smoking. Additionally, alcohol-related knowledge of students in the experimental group increased after the completion of the program. CONCLUSIONS: To obtain effective results on behavioural outcomes from 'PREPARED ON TIME', a greater degree of flexibility (i.e. repetition, extension of the program, role playing, etc.) is required. Furthermore, prevention needs to be implemented at a younger age, as 6% of the students tried their first cigarette and 15% of the students drank alcohol at the age of 10 years or younger. PMID- 26631988 TI - Secretome analysis of the mycoparasitic fungus Trichoderma harzianum ALL 42 cultivated in different media supplemented with Fusarium solani cell wall or glucose. AB - Trichoderma harzianum is a fungus well known for its potential as a biocontrol agent against many fungal phytopathogens. The aim of this study was to characterize the proteins secreted by T. harzianum ALL42 when its spores were inoculated and incubated for 48 h in culture media supplemented with glucose (GLU) or with cell walls from Fusarium solani (FSCW), a phytopathogen that causes severe losses in common bean and soy crops in Brazil, as well as other crop diseases around the world. Trichoderma harzianum was able to grow in Trichoderma Liquid Enzyme Production medium (TLE) and Minimal medium (MM) supplemented with FSCW and in TLE+GLU, but was unable to grow in MM+GLU medium. Protein quantification showed that TLE+FSCW and MM+FSCW had 45- and 30- fold, respectively, higher protein concentration on supernatant when compared to TLE+GLU, and this difference was observable on 2D gel electrophoresis (2DE). A total of 94 out of 105 proteins excised from 2DE maps were identified. The only protein observed in all three conditions was epl1. In the media supplemented with FSCW, different hydrolases such as chitinases, beta-1,3-glucanases, glucoamylases, alpha-1,3-glucanases and proteases were identified, along with other proteins with no known functions in mycoparasitism, such as npp1 and cys. Trichoderma harzianum showed a complex and diverse arsenal of proteins that are secreted in response to the presence of FSCW, with novel proteins not previously described in mycoparasitic-related studies. PMID- 26631990 TI - Intramedullary Versus Extramedullary Fixation for Unstable Intertrochanteric Fractures: A Prospective Randomized Controlled Trial. AB - BACKGROUND: The use of intramedullary devices for the management of intertrochanteric fractures has steadily increased without good evidence of their clinical efficacy. This prospective randomized multicenter study was designed to compare the clinical and radiographic outcomes of patients who had been treated with a traditional extramedullary hip screw for an unstable (AO/OTA 31-A2) intertrochanteric hip fracture with those of patients who had been treated with the newer intramedullary device for the same injury. METHODS: The Lower Extremity Measure (LEM) was used as the primary hip-specific outcome tool. The Functional Independence Measure (FIM), the timed "Up & Go" (TUG) test, as well as a timed two-minute walk test were used as secondary clinical outcome tools. Specific radiographic parameters were collected to assess for fracture movement, heterotopic ossification, and implant failure. RESULTS: No significant differences were noted between the intramedullary and extramedullary treatment arms with regard to either the primary or the secondary clinical outcome tools. The radiographic parameters favored the intramedullary treatment arm, which had less femoral neck shortening. CONCLUSIONS: While the use of the intramedullary devices led to better radiographic outcomes in this study, this did not translate to improved functional outcomes. PMID- 26631989 TI - Histone modification profiling reveals differential signatures associated with human embryonic stem cell self-renewal and differentiation. AB - In this study, we trace developmental stages using epigenome changes in human embryonic stem cells (hESCs) treated with drugs modulating either self-renewal or differentiation. Based on microscopy, qPCR and flow cytometry, we classified the treatment outcome as inducing pluripotency (hESC, flurbiprofen and gatifloxacin), mesendoderm (sinomenine), differentiation (cyamarin, digoxin, digitoxin, selegeline and theanine) and lineage-commitment (RA). When we analyzed histone PTMs that imprinted these gene and protein expressions, the above classification was reassorted. Hyperacetylation at H3K4, 9, 14, 18, 56 and 122 as well as H4K5, 8, 12 and 16 emerged as the pluripotency signature of hESCs. Methylations especially of H3 at K9, K20, K27 and K36 characterized differentiation initiation as seen in no-drug control and fluribiprofen. Sinomenine-treated cells clustered close to "differentiation initiators", consistent with flow cytometry where it induced mesendoderm, along with cyamarin and possibly selegnine. Neurectoderm, induced by RA and theanine manifested methylations on H3 shifts to H3.3. By both flow cytometry and histone PTM clustering, it appears that cells treated with gatifloxacin, flurbiprofen, digitoxin and digoxin were not yet lineage-committed or mixed cell types. Taken together, our moderate-throughput histone PTM profiling approach highlighted subtle epigenetic signatures that permitted us to predict divergent lineage progression even in differentiating cells with similar phenotype and gene expression. PMID- 26631991 TI - Acetabular Anteversion Changes Due to Spinal Deformity Correction: Bridging the Gap Between Hip and Spine Surgeons. AB - BACKGROUND: Hip osteoarthritis often coexists with adult spinal deformity, an abnormality in which sagittal spinopelvic malalignment is present. Debate exists whether to perform spinal realignment correction or total hip arthroplasty first. Hip extension and pelvic tilt are important compensatory mechanisms in the setting of sagittal spinopelvic malalignment and change after spinal realignment. We performed this study to evaluate the effect that the spinal realignment surgical procedure has on acetabular anteversion. METHODS: This study is a retrospective review of a multicenter, prospective, consecutive database of patients with adult spinal deformity who underwent surgical spinal realignment. Only patients who already had undergone a total hip arthroplasty prior to the spinal realignment procedure were retained for analysis. Patients were excluded if they had insufficient imaging or large-head, metal-on-metal bearings or they had undergone revision total hip arthroplasty in the study period. Acetabular anteversion was calculated via the ellipse method on a standing, posterior anterior, 90-cm radiograph with a well-centered pelvis. Anteversion was measured preoperatively and at six weeks or three months after the spinal realignment procedure. Spinopelvic parameters measured included pelvic incidence, pelvic tilt, sacral slope, lumbar lordosis, T1 pelvic angle, sagittal vertical axis, T1 spinopelvic inclination, and thoracic kyphosis. RESULTS: Forty-one hips (thirty three patients) were identified. Acetabular anteversion significantly reduced (p < 0.001) after spinal correction by mean change of -4.96 degrees (range, -22.32 degrees to +2.36 degrees ). The change in anteversion correlated with the changes in sagittal pelvic orientation (0.828 for the pelvic tilt, -0.757 for the sacral slope, and -0.691 for the lumbar lordosis) and global spinopelvic alignment (0.579 for the sagittal vertical axis and 0.585 for the T1 pelvic angle). Regression analysis revealed that anteversion decreased by 1 degrees for each of the following spinopelvic parameter changes (p < 0.001): 1.105 degrees for spinopelvic tilt, 1.032 degrees for sacral slope, and 3.163 degrees for lumbar lordosis. CONCLUSIONS: Patients with spinopelvic malalignment had a high prevalence of excessively anteverted acetabular components. Sagittal spinal correction following total hip arthroplasty resulted in reduced acetabular anteversion, which may have implications for stability. Changes in anteversion are most closely related to changes in pelvic tilt in an almost one-to-one ratio. PMID- 26631992 TI - Management of Modifiable Risk Factors Prior to Primary Hip and Knee Arthroplasty: A Readmission Risk Assessment Tool. AB - BACKGROUND: Preoperative risk stratification and optimization of preoperative care may be helpful in reducing readmission rates after primary total joint arthroplasty. Assessment of the predictive value of individual modifiable risk factors without a tool to assess cumulative risk may not provide proper risk stratification of patients with regard to potential readmissions. As part of a Perioperative Orthopaedic Surgical Home model, we developed a scoring system, the Readmission Risk Assessment Tool (RRAT), which allows for risk stratification in patients undergoing elective primary total joint arthroplasty at our institution. The purpose of this study was to analyze the relationship between the RRAT score and readmission after primary hip or knee arthroplasty. METHODS: The RRAT, which is scored incrementally on the basis of the number and severity of modifiable comorbidities, was used to generate readmission scores for a cohort of 207 readmitted patients and two cohorts (one random and one age-matched) of 234 non readmitted patients each. Regression analysis was performed to assess the strength of association of individual risk factors and the RRAT score with readmissions. We also calculated the odds and odds ratio (OR) at each RRAT score level to identify patients with relatively higher risk of readmission. RESULTS: There were 207 (2.08%) readmissions among 9930 patients over a six-year period (2008 through 2013). Surgical site infection was the most common cause of readmission (ninety-three cases, 45%). The median RRAT scores were 3 (IQR [interquartile range], 1 to 4) and 1 (IQR, 0 to 2) for readmitted and non readmitted groups, respectively. An RRAT score of >=3 was significantly associated with higher odds of readmission. CONCLUSIONS: Population health management, cost-effective care, and optimization of outcomes to maximize value are the new maxims for health-care delivery in the United States. We found that the RRAT score had a significant association with readmission after joint arthroplasty and could potentially be a clinically useful tool for risk mitigation. PMID- 26631993 TI - Patient-Reported Health Outcomes After in Situ Percutaneous Fixation for Slipped Capital Femoral Epiphysis: An Average Twenty-Year Follow-up Study. AB - BACKGROUND: Percutaneous in situ fixation is the gold-standard treatment for stable slipped capital femoral epiphysis (SCFE). While numerous studies have documented good to excellent long-term clinical and radiographic outcomes, few have documented long-term patient-reported outcomes of patients with this condition. METHODS: This retrospective study was performed to document long-term patient-reported outcomes of a cohort of sixty-four patients with SCFE (ninety one affected hips) and determine whether the slip angle was associated with poorer health outcomes as measured with the Short Form-12 (SF-12) Physical Component Summary (PCS) and Mental Component Summary (MCS) scores, modified Harris hip score (mHHS), and University of California at Los Angeles (UCLA) Activity Scale. RESULTS: The mean age at presentation was 12.6 years, and the mean duration of follow-up was 19.6 years. At the time of follow-up, the cohort reported higher rates of diabetes, obesity, and hypertension than the general U.S. POPULATION: The mean body mass index (BMI) had increased by 10.2 kg/m(2), with 72% of the subjects meeting the criteria for obesity (BMI > 30 kg/m(2)) at the time of follow-up. The mean age and sex-adjusted PCS and MCS scores were 49.6 and 50.0, respectively, and the mean mHHS was 84.9. Multivariable general linear modeling revealed no association between the initial slip angle and the PCS, MCS, mHHS, or UCLA Activity Scale score. Male sex and a lower BMI were the only predictors of better long-term PCS, mHHS, and UCLA Activity Scale scores. Subjects with a bilateral slip had outcomes similar to those with unilateral disease. CONCLUSIONS: The general self-reported health of this cohort was poor compared with that of the general population. The slip angle on presentation did not correlate with any patient-reported outcome measure collected for this study. Higher BMI was one of the only clinical predictors of patient-reported outcomes. PMID- 26631994 TI - The Measurement and Clinical Importance of Syndesmotic Reduction After Operative Fixation of Rotational Ankle Fractures. AB - BACKGROUND: Rotational ankle fractures often have unstable syndesmotic injuries that require reduction and stabilization. Multiple studies have focused on methods to assess syndesmotic reduction; however, the clinical importance of anatomic syndesmotic reduction remains unclear. The purpose of this study was to determine whether the quality of syndesmotic reduction influenced clinical outcomes following operative treatment of ankle fractures with unstable syndesmotic injuries. METHODS: Patients were included from an institutional trauma registry if they had sustained rotational ankle fractures with intraoperative evidence of syndesmotic instability requiring syndesmotic reduction and stabilization. Patients with at least twelve months of disease specific, patient-reported clinical outcomes were included. Computed tomography (CT) imaging of both ankles was performed within two days postoperatively for all patients. Four previously utilized methods of assessing syndesmotic reduction using axial CT images of the operatively treated and the contralateral ankle were used. RESULTS: A total of 155 patients met the study inclusion criteria and underwent analysis. The four methods used to assess syndesmotic reduction had reliabilities ranging from moderate to almost perfect (intraclass correlation coefficient [2,1] range = 0.544 to 0.821). Measurements of the uninjured syndesmosis were consistent with those in several previous studies of normal syndesmotic morphology, and the four methods of syndesmotic assessment had strong internal consistency. The mean measurement differences between the injured and normal ankles ranged from 1.32 to 1.88 mm of displacement and averaged 5.75 degrees of rotation. There were no correlations noted between any of the four syndesmotic reduction assessment methods and any Foot and Ankle Outcome Score domains. CONCLUSIONS: Within the range of syndesmotic malreductions studied, the quality of syndesmotic reduction did not significantly influence clinical outcomes. These results challenge previous definitions of syndesmotic malreduction and the clinical importance of minor syndesmotic changes. It remains unclear, however, whether greater magnitudes of syndesmotic malreduction than those seen in this cohort would lead to inferior patient-reported outcomes. PMID- 26631995 TI - Comparison of Proximal and Distal Oblique Second Metatarsal Osteotomies with Varying Achilles Tendon Tension: Biomechanical Study in a Cadaver Model. AB - BACKGROUND: The optimal surgery for reducing pressure under the second metatarsal head to treat metatarsalgia is unknown. We tested our hypothesis that a proximal oblique dorsiflexion osteotomy of the second metatarsal would decrease second metatarsal plantar pressures in a cadaver model with varying Achilles tendon tension. We also tested the plantar pressure effects of two popular techniques of distal oblique osteotomy. METHODS: Twelve fresh-frozen feet from six cadavers were randomly assigned to either the distal osteotomy group (a classic distal oblique osteotomy followed by a modified distal oblique osteotomy) or proximal metatarsal osteotomy group. Each specimen was tested intact and then after the osteotomy or osteotomies. The feet were loaded with 0, 300, and 600 N of Achilles tendon tension and a 400-N ground reaction force. Plantar pressures were measured by a pressure sensitive mat and analyzed in sections located under each metatarsal. RESULTS: The proximal metatarsal osteotomy significantly reduced average pressures beneath the second metatarsal head during both 300 and 600 N of Achilles tendon loading by an average of 19.4 and 29.7 kPa, respectively (p < 0.05). The modified distal oblique osteotomy significantly decreased these pressures during 600 N of Achilles tendon loading, by a mean of 20.2 kPa, which was to a lesser extent than the proximal metatarsal osteotomy. Interestingly, the classic distal oblique osteotomy was not found to have significant effects on pressures beneath the second metatarsal head. CONCLUSIONS: The proximal oblique dorsiflexion metatarsal osteotomy may be the most effective procedure for decreasing plantar pressures under the second metatarsal. The modified distal oblique osteotomy may be the second most effective. CLINICAL RELEVANCE: The findings of this biomechanical study help shed light on which of the common second metatarsal osteotomies are best for decreasing plantar pressures. PMID- 26631996 TI - The Impact of Hepatitis C on Short-Term Outcomes of Total Joint Arthroplasty. AB - BACKGROUND: With recent advances in the treatment of infection with hepatitis C increasing lifespan and quality of life, the need for total joint arthroplasty in this patient population is expected to grow. Presently, there are limited and conflicting data on the perioperative outcomes of lower-extremity total joint arthroplasty among patients with hepatitis C. The purpose of our study was to assess the association between hepatitis C and perioperative outcomes of lower extremity total joint arthroplasty. METHODS: The Nationwide Inpatient Sample database was used to identify patients who underwent a total hip or knee arthroplasty in the United States from 1998 to 2010. Controls were matched in a three-to-one ratio to patients with hepatitis-C infection according to surgical procedure, age, race, sex, Deyo comorbidity score, and year of surgical procedure. Outcomes included perioperative complications (any, medical, surgical) and mean length of stay. RESULTS: There were 1,700,400 total joint arthroplasties performed and recorded in the database during the study period, among which 8044 patients (0.47%) had a documented hepatitis-C infection. The frequency of hepatitis-C infection increased from 1.9 per 1000 total joint arthroplasties in 1998 to 5.9 per 1000 total joint arthroplasties in 2010 (slope = 0.47; r(2) = 0.93). Compared with matched controls, patients with hepatitis C had a 30% increased risk of any complication (95% confidence interval, 17% to 44%; p < 0.001), a 15% increased risk of a medical complication (95% confidence interval, 2% to 30%; p = 0.025), a 78% increased risk of a surgical complication (95% confidence interval, 49% to 112%; p < 0.001), and a mean length of stay that was 14% longer (95% confidence interval, 12% to 15%; p < 0.001). CONCLUSIONS: Infection with hepatitis C is an infrequent but increasingly common comorbidity among patients undergoing total joint arthroplasty. Given these findings, orthopaedic surgeons should be aware of the increased risks of total joint arthroplasty in patients with hepatitis C and should discuss these risks with potential surgical candidates during a shared decision-making process. PMID- 26631997 TI - A Comparison of Three Diagnostic Tests for Carpal Tunnel Syndrome Using Latent Class Analysis. AB - BACKGROUND: The current reference standard for carpal tunnel syndrome is under debate. Recent studies have demonstrated similar diagnostic accuracy between ultrasound and nerve conduction studies. The purpose of the present study was to determine the sensitivity and specificity of ultrasound, nerve conduction studies, and Carpal Tunnel Syndrome 6 (CTS-6) for the diagnosis of carpal tunnel syndrome using latent class analysis. METHODS: Latent class analysis is a statistical technique that can be used to estimate the accuracy of diagnosis when there is no universally accepted reference standard. This type of analysis is useful in the setting of carpal tunnel syndrome as there remains substantial controversy with respect to the necessity of nerve conduction studies and other confirmatory testing. CTS-6 is a validated clinical diagnostic tool for the diagnosis of carpal tunnel syndrome that has been shown to have a high sensitivity and specificity. Data from a database on the cases of eighty-five consecutive patients who had had nerve conduction studies, CTS-6, and ultrasound were analyzed using classical latent class analysis, assuming that the three tests were imperfect and conditionally independent. RESULTS: The sensitivities of ultrasound, CTS-6, and nerve conduction studies were 91% (95% confidence interval [CI], 81% to 98%), 95% (95% CI, 86% to 99%), and 91% (95% CI, 81% to 97%), respectively. The specificities of ultrasound, CTS-6, and nerve conduction studies were 94% (95% CI, 80% to 100%), 91% (95% CI, 74% to 99%), and 83% (95% CI, 66% to 95%), respectively. CONCLUSIONS: Ultrasound, nerve conduction studies, and CTS-6 have similar sensitivity and specificity for the diagnosis of carpal tunnel syndrome. The currently accepted reference standard (nerve conduction studies) had the lowest sensitivity and specificity of the three tests. These findings support previous studies that have suggested that CTS-6 and ultrasound are highly accurate in the diagnosis of carpal tunnel syndrome and that nerve conduction studies are not necessary in most cases. PMID- 26631998 TI - Diagnosis and Management of Periprosthetic Elbow Infection. AB - ? Periprosthetic elbow infections rarely involve systemic symptoms such as fever or malaise.? Unlike tests for periprosthetic hip and knee infections, the diagnostic utility of blood testing and joint aspiration for periprosthetic elbow infection has not been demonstrated to date.? Intraoperative histological analysis has good specificity (93.1%) but very low sensitivity (51.3%) for periprosthetic elbow infection.? Emerging diagnostic options such as implant sonication, molecular analysis, and advanced synovial fluid cytokine and protein analysis may reduce diagnostic uncertainty in the future.? Recommended surgical treatment options for an infection at the site of an elbow arthroplasty include implant retention and debridement, two-stage revision with or without techniques for restoration of bone stock and triceps continuity, and resection arthroplasty. PMID- 26631999 TI - What's New in Orthopaedic Research. PMID- 26632000 TI - The Growing Gap in Electronic Medical Record Satisfaction Between Clinicians and Information Technology Professionals: Issues of Most Concern and Suggested Remediations. AB - BACKGROUND: With the alarming statistics concerning the quality of national health care, it is hoped that electronic health records (EHRs) will reduce inefficiencies associated with medical delivery and improve patient safety. This study reports the results of a survey that demonstrates a pattern in EHR system implementation that indicates that health-care information technology decisions are based more on the preferences of information technology professionals (ITPs) and hospital administrators than clinicians. METHODS: We present survey data highlighting the growing discrepancy in EHR-related satisfaction between clinicians and ITPs. We conducted a literature search to identify major barriers that must be overcome to achieve optimal EHR benefits. We summarize our recommendations in order to maximize the favorable impact of EHRs on the health care system. RESULTS: The existing gap in postimplementation EHR satisfaction ratings between ITPs and clinicians reveals an underlying systematic problem. Electronic medical record vendors perceive administrators and ITPs as the "buyers" for many EHR systems, and their needs are given higher priority than those of clinicians. This possibly may lead to the lack of clinically optimized EHRs, with systems often presenting as rigid and standardized with a limited exchange of health information. CONCLUSIONS: EHRs have the potential to become a powerful tool that may improve many processes related to health care, including quality, safety, and economical aspects. The involvement of physicians in every step of the process, from electronic medical record selection to acquisition, implementation, and ongoing optimization, is crucial for enabling the achievement of the medical organization's mission. PMID- 26632001 TI - Competency-Based Medical Education: Can Both Junior Residents and Senior Residents Achieve Competence After a Sports Medicine Training Module? AB - BACKGROUND: Competency-based medical education as a resident-training format will move postgraduate training away from time-based training, to a model based on observable outcomes. The purpose of this study was to determine whether junior residents and senior residents could demonstrate clinical skills to a similar level, after a sports medicine rotation. METHODS: All residents undertaking a three-month sports medicine rotation had to pass an Objective Structured Clinical Examination. The stations tested the fundamentals of history-taking, examination, image interpretation, differential diagnosis, informed consent, and clinical decision-making. Performance at each station was assessed with a binary station specific checklist and an overall global rating scale, in which 1 indicated novice, 2 indicated advanced beginner, 3 indicated competent, 4 indicated proficient, and 5 indicated expert. A global rating scale was also given for each domain of knowledge. RESULTS: Over eighteen months, thirty-nine residents (twenty one junior residents and eighteen senior residents) and six fellows (for a total of forty-five participants) completed the examination. With regard to junior residents and senior residents, analysis using a two-tailed t test demonstrated a significant difference (p < 0.01) in both total checklist score and overall global rating scale; the mean total checklist score (and standard deviation) was 56.15% +/- 10.99% for junior residents and 71.87% +/- 8.94% for senior residents, and the mean global rating scale was 2.44 +/- 0.55 for junior residents and 3.79 +/- 0.49 for senior residents. There was a significant difference between junior residents and senior residents for each knowledge domain, with a significance of p < 0.05 for history-taking and p < 0.01 for the remainder of the domains. CONCLUSIONS: Despite intensive teaching within a competency-based medical education model, junior residents were not able to demonstrate knowledge as well as senior residents, suggesting that overall clinical experience is critically important for achieving competency as measured by the Objective Structured Clinical Examination. PMID- 26632002 TI - Erratum. PMID- 26632003 TI - Take Care with Type C: Serious Considerations in the Selection of Patients with Hepatitis C for Total Joint Arthroplasty: Commentary on an article by Kimona Issa, MD, et al.: "The Impact of Hepatitis C on Short-Term Outcomes of Total Joint Arthroplasty". PMID- 26632004 TI - An Alternative Solution for the Diagnosis of Carpal Tunnel Syndrome: Commentary on an article by John R. Fowler, MD, et al.: "A Comparison of Three Diagnostic Tests for Carpal Tunnel Syndrome Using Latent Class Analysis". PMID- 26632006 TI - Asymmetric oxidation of vinyl- and ethynyl terthiophene ligands in triruthenium complexes. AB - A series of ruthenium(ii) complexes [{RuCl(CO)(PMe3)3(-CH[double bond, length as m-dash]CH-)}nX], (: n = 3, X = 3,3''-dimethyl-2,2':3',2''-terthiophene; : n = 2, X = 2,2'-bithiophene; : n = 2, X = 2,3-bis(3-methylthiophen-2-yl)benzothiophene) and [{Cp*(dppe)2Ru(-C[triple bond, length as m-dash]C-)}3X], (X = 3,3''-dimethyl 2,2':3',2''-terthiophene), were prepared and characterized by (1)H, (13)C and (31)P NMR. Their redox, spectroscopic and bonding properties were studied with a range of spectro-electrochemical methods in combination with density functional theory calculations. The first two anodic steps observed for and are largely localized on the lateral frameworks of the molecular triangle, the direct conjugation between them being precluded due to the photostable open form of the dithienyl ethene moiety. The third anodic step is then mainly localized on the centerpiece of the triangular structure, affecting both bithiophene laterals. The experimental IR and UV-vis-NIR spectroelectrochemical data and, largely, also DFT calculations account for this explanation, being further supported by direct comparison with the anodic behavior of reference diruthenium complexes and . PMID- 26632005 TI - Sexual Assault, Sexual Harassment, and Physical Victimization during Military Service across Age Cohorts of Women Veterans. AB - OBJECTIVES: Exposure to sexual and physical trauma during military service is associated with adverse mental and physical health outcomes. Little is known about their prevalence and impact in women veterans across age cohorts. METHODS: Data from a 2013 national online survey of women veterans was used to examine associations between age and trauma during military service, including sexual assault, sexual harassment, and physical victimization. Analyses were conducted using logistic regression, adjusting for service duration and demographic factors. In secondary analyses, the moderating role of age in the relationship between trauma and self-reported health was examined. RESULTS: The sample included 781 women veterans. Compared with the oldest age group (>= 65), all except the youngest age group had consistently higher odds of reporting trauma during military service. These differences were most pronounced in women aged 45 to 54 years (sexual assault odds ratio [OR], 3.81 [95% CI, 2.77-6.71]; sexual harassment, OR, 3.99 [95% CI, 2.25-7.08]; and physical victimization, OR, 5.72 [95% CI, 3.32-9.85]). The association between trauma during military service and self-reported health status also varied by age group, with the strongest negative impact observed among women aged 45 to 54 and 55 to 64. CONCLUSIONS: Compared with other age groups, women in midlife were the most likely to report trauma during military service, and these experiences were associated with greater negative impact on their self-reported health. Providers should be aware that trauma during military service may be particularly problematic for the cohort of women currently in midlife, who represent the largest proportion of women who use Department of Veterans Affairs health care. PMID- 26632008 TI - Storage and Effective Migration of Li-Ion for Defected beta-LiFePO4 Phase Nanocrystals. AB - Lithium iron phosphate, a widely used cathode material, crystallizes typically in olivine-type phase, alpha-LiFePO4 (alphaLFP). However, the new phase beta-LiFePO4 (betaLFP), which can be transformed from alphaLFP under high temperature and pressure, is originally almost electrochemically inactive with no capacity for Li ion battery, because the Li-ions are stored in the tetrahedral [LiO4] with very high activation barrier for migration and the one-dimensional (1D) migration channels for Li-ion diffusion in alphaLFP disappear, while the Fe ions in the beta-phase are oriented similar to the 1D arrangement instead. In this work, using experimental studies combined with density functional theory calculations, we demonstrate that betaLFP can be activated with creation of effective paths of Li-ion migration by optimized disordering. Thus, the new phase of betaLFP cathode achieved a capacity of 128 mAh g(-1) at a rate of 0.1 C (1C = 170 mA g(-1)) with extraordinary cycling performance that 94.5% of the initial capacity retains after 1000 cycles at 1 C. The activation mechanism can be attributed to that the induced disorder (such as FeLiLiFe antisite defects, crystal distortion, and amorphous domains) creates new lithium migration passages, which free the captive stored lithium atoms and facilitate their intercalation/deintercalation from the cathode. Such materials activated by disorder are promising candidate cathodes for lithium batteries, and the related mechanism of storage and effective migration of Li-ions also provides new clues for future design of disordered electrode materials with high capacity and high energy density. PMID- 26632007 TI - Main applications of hybrid PET-MRI contrast agents: a review. AB - In medical imaging, the continuous quest to improve diagnostic performance and optimize treatment strategies has led to the use of combined imaging modalities. Positron emission tomography (PET) and computed tomography (CT) is a hybrid imaging existing already for many years. The high spatial and contrast resolution of magnetic resonance imaging (MRI) and the high sensitivity and molecular information from PET imaging are leading to the development of this new hybrid imaging along with hybrid contrast agents. To create a hybrid contrast agent for PET-MRI device, a PET radiotracer needs to be combined with an MRI contrast agent. The most common approach is to add a radioactive isotope to the surface of a small superparamagnetic iron oxide (SPIO) particle. The resulting agents offer a wide range of applications, such as pH variation monitoring, non-invasive angiography and early imaging diagnosis of atherosclerosis. Oncology is the most promising field with the detection of sentinel lymph nodes and the targeting of tumor neoangiogenesis. Oncology and cardiovascular imaging are thus major areas of development for hybrid PET-MRI imaging systems and hybrid contrast agents. The aim is to combine high spatial resolution, high sensitivity, morphological and functional information. Future prospects include the use of specific antibodies and hybrid multimodal PET-MRI-ultrasound-fluorescence imaging with the potential to provide overall pre-, intra- and postoperative patient care. PMID- 26632010 TI - My approach to the use of aspirin. PMID- 26632011 TI - My approach to risk assessment of asymptomatic patients. PMID- 26632009 TI - Mitochondrially Targeted Nanoparticles Based on alpha-TOS for the Selective Cancer Treatment. AB - The aim of this work is the preparation of an active nanovehicle for the effective administration of alpha-tocopheryl succinate (alpha-TOS). alpha-TOS is loaded in the core of nanoparticles (NPs) based on amphiphilic pseudo-block copolymers of N-vinyl pyrrolidone and a methacrylic derivative of alpha-TOS. These well-defined spherical NPs have sizes below 165 nm and high encapsulation efficiencies. In vitro activity of NPs is tested in hypopharynx squamous carcinoma (FaDu) cells and nonmalignant epithelial cells, demonstrating that the presence of additional alpha-TOS significantly enhances its antiproliferative activity; however, a range of selective concentrations is observed. These NPs induce apoptosis of FaDu cells by activating the mitochondria death pathway (via caspase-9). Both loaded and unloaded NPs act via complex II and produce high levels of reactive oxygen species that trigger apoptosis. Additionally, these NPs effectively suppress the vascular endothelial growth factor (VEGF) expression of human umbilical vein endothelial cells (HUVECs). These results open the possibility to use this promising nanoformulation as an alpha-TOS delivery system for the effective cancer treatment, effectively resolving the current limitations of free alpha-TOS administration. PMID- 26632012 TI - Noninvasive imaging markers associated with sudden cardiac death. AB - Sudden cardiac death (SCD) accounts for approximately 15-20% of all deaths worldwide. While the majority of SCDs occur in adults, children, and adults <35 years (<1%) may also be affected. Currently the most effective strategy for both primary and secondary prevention of SCD is the implantable cardioverter defibrillator (ICD). However, identification of patients who will benefit from ICD implantation remains challenging. Left ventricular ejection fraction (LVEF) is the most frequent imaging parameter used to select patients for ICD implantation for primary prevention. However, LVEF has shown to be suboptimal for prediction of benefit. Non-invasive cardiac imaging permits characterization of the arrhythmogenic substrate, including dispersion of electromechanical activation, presence of myocardial scar, and cardiac innervation status. The arrhythmogenic substrate may change across the different underlying diseases. While in ischemic cardiomyopathy, differentiation and characterization of infarct core and peri-infarct zone have been shown to refine the risk stratification of patients, in non-ischemic cardiomyopathies, the substrate may be more heterogeneous and tissue characterization assessing focal and diffuse fibrosis and inflammation processes may be more relevant. Furthermore, in channelopathies, assessment of mechanical dispersion between myocardial layers may identify the patients with increased risk of ventricular arrhythmias. Finally, potential triggers of ventricular arrhythmias such as myocardial ischemia can be evaluated. The role of noninvasive imaging in the risk stratification of SCD and the selection of candidates for ICD will be discussed in this article. PMID- 26632013 TI - MY APPROACH to the adult patient with newly identified atrial septal defect. PMID- 26632014 TI - Editorial Commentary: The cold facts: Role of therapeutic hypothermia in cardiac arrest survivors. PMID- 26632015 TI - MY APPROACH to cardiovascular risk assessment to reduce atherosclerotic risk. PMID- 26632016 TI - In vitro and in vivo reprogramming for the conduction system. PMID- 26632017 TI - Structural properties and digestion of green banana flour as a functional ingredient in pasta. AB - Gluten free pasta was made from raw banana flour in combination with vegetable gums and protein for comparison to pasta similarly made from wheat flour. After cooking, it was found that the banana flour pasta was less susceptible to alpha amylase digestion compared to conventional wheat flour pasta. Release of glucose by alpha-amylase digestion followed first order kinetics with an initial rapid rate of digestion and a subsequent second slower phase. The structure of green banana pasta starch at the inner and outer pasta surfaces was observed under confocal laser scanning microscopy (CLSM) and the viscosities of the flour mixtures were measured by a Rapid Visco Analyser (RVA). The digestibility of banana flour pasta was found to be related, not only to the properties of the starch granules, but also to the protein network of the surrounding food matrix. The effects of gums and proteins on pasta formation and digestibility are discussed in the context of its potential use as a gluten free lower glycaemic alternative to conventional wheat based pastas. PMID- 26632018 TI - Myth busting in carbon monoxide poisoning. AB - The evidence supporting many beliefs in medicine is based upon opinion, personal experience, hearsay, or "common knowledge." When one searches for the data supporting oft-quoted facts in medicine, they are sometimes found to be old, incorrect, or nonexistent. Such unsupported facts or beliefs can be termed myths. This minireview will summarize 4 examples of "myth busting" by the author when he has discovered widely held beliefs regarding carbon monoxide (CO) poisoning to be untrue during a 25-year career of research in the field. These include the mistaken beliefs that (1) symptoms correlate with presenting blood carboxyhemoglobin levels, (2) residents are safe from CO poisoning if their home does not contain fuel-burning appliances, (3) carboxyhemoglobin levels must be measured rapidly and on arterial blood, and (4) CO poisoning predisposes to premature long-term death from cardiac disease. In addition to providing the evidence disproving these myths, the importance of going back to the original reference when citing prior work is emphasized. PMID- 26632019 TI - High-frequency linear transducer improves detection of an intrauterine pregnancy in first-trimester ultrasonography. AB - OBJECTIVE: The objective was to determine if the need for transvaginal ultrasonographic examination can be decreased by the addition of the transabdominal high-frequency, 12-4-MHz linear transducer after a failed examination with the 6-2-mHz curvilinear transducer when evaluating for an intrauterine pregnancy (IUP). METHODS: This is a prospective pilot study of women in their first trimester of pregnancy presenting to the emergency department with abdominal pain and/or vaginal bleeding. If no IUP was identified using the curvilinear transducer via the transabdominal approach, they were subsequently scanned using the linear transducer. Patients without evidence of an IUP transabdominally were scanned via the transvaginal approach. RESULTS: Eighty-one patients were evaluated; no IUP was visualized in 27 using the standard curvilinear transducer approach, and these then had an ultrasonography performed with the linear transducer. Of these, 9 patients (33.3%; 0.95 confidence interval [CO], 15.5%-51.1%) were found to have an IUP with the linear transducer. For the 18 patients who received a transvaginal scan, 15 patients (83.3%; 0.95 CI, 66.1% 100%) had no IUP identified with the transvaginal transducer, and 3 (16.7%; 0.95 CI, 0%-33.9%) had an IUP identified. CONCLUSIONS: The transabdominal use of a high-frequency linear transducer in the evaluation of patients in the first trimester after failed curvilinear transducer results in a clinically significant reduction in the need for transvaginal ultrasonography to confirm the presence of an IUP. PMID- 26632020 TI - Improving the No-Show Rate of New Patients in Outpatient Psychiatric Practice: An Advance Practice Nurse-Initiated Telephone Engagement Protocol Quality Improvement Project. AB - PURPOSE: The aim is to improve the uptake of psychiatric services for new patients being referred from primary care, counseling, and hospital discharge follow-up care. DESIGN AND METHODS: A convenience sample of 18 new patients participated in a provider-initiated telephone protocol to increase knowledge related to psychiatric treatment and remind patients of appointments the day before the initial visit. FINDINGS: Fifteen patients attended the initial visit, resulting in a 26% reduction rate of no-show rates from 27% the previous year to 20% in a 3-month period. PRACTICE IMPLICATIONS: Introduction and reminder calls by psychiatric providers improve no-show rates. PMID- 26632021 TI - Simultaneous Single-Molecule Force and Fluorescence Sampling of DNA Nanostructure Conformations Using Magnetic Tweezers. AB - We present a hybrid single-molecule technique combining magnetic tweezers and Forster resonance energy transfer (FRET) measurements. Through applying external forces to a paramagnetic sphere, we induce conformational changes in DNA nanostructures, which are detected in two output channels simultaneously. First, by tracking a magnetic bead with high spatial and temporal resolution, we observe overall DNA length changes along the force axis. Second, the measured FRET efficiency between two fluorescent probes monitors local conformational changes. The synchronized orthogonal readout in different observation channels will facilitate deciphering the complex mechanisms of biomolecular machines. PMID- 26632022 TI - Zwitterionic Cellulose Carbamate with Regioselective Substitution Pattern: A Coating Material Possessing Antimicrobial Activity. AB - A polyzwitterion is synthesized by regioselective functionalization of cellulose possessing a uniform charge distribution. The positively charged ammonium group is present at position 6, while the negative charge of carboxylate is located at positions 2 and 3 of the repeating unit. The molecular structure of the biopolymer derivative is proved by NMR spectroscopy. This cellulose-based zwitterion is applied to several support materials by spin-coating and characterized by means of atomic force microscope, contact angle measurements, ellipsometry, and X-ray photoelectron spectroscopy. The coatings possess antimicrobial activity depending on the support materials (glass, titanium, tissue culture poly(styrene)) as revealed by confocal laser scanning microscopy and live/dead staining. PMID- 26632023 TI - Coffee consumption rapidly reduces background DNA strand breaks in healthy humans: Results of a short-term repeated uptake intervention study. AB - SCOPE: Intervention studies provide evidence that long-term coffee consumption correlates with reduced DNA background damage in healthy volunteers. Here, we report on short-term kinetics of this effect, showing a rapid onset after normal coffee intake. METHODS AND RESULTS: In a short-term human intervention study, we determined the effects of coffee intake on DNA integrity during 8 h. Healthy male subjects ingested coffee in 200 mL aliquots every second hour up to a total volume of 800 mL. Blood samples were taken at baseline, immediately before the first coffee intake and subsequently every 2 h, prior to the respective coffee intake. DNA integrity was assayed by the comet assay. The results show a significant (p < 0.05) reduction of background DNA strand breaks already 2 h after the first coffee intake. Continued coffee intake was associated with further decrements in background DNA damage within the 8 h intervention (p < 0.01 and p < 0.001, respectively). Mean tail intensities (TIs%) decreased from 0.33 TI% (baseline, 0 h) to 0.22 TI% (within 8 h coffee consumption). CONCLUSION: Repeated coffee consumption was associated with reduced background DNA strand breakage, clearly measurable as early as 2 h after first intake resulting in a cumulative overall reduction by about one-third of the baseline value. PMID- 26632025 TI - Pay attention to me! Late ERPs reveal gender differences in attention allocated to romantic partners. AB - The present study employed late ERPs to examine differences in the association between neural responses to romantic partners and relationship quality factors across men and women. Participants passively viewed photos of their romantic partners, celebrities, and strangers during a computerized facial processing task. All participants demonstrated enhanced positivity to partner faces at late ERP components (P3 and LPP), furthering the notion that significant others elicit more motivated and sustained attention than do other familiar or unfamiliar individuals. Neural responses to romantic partner faces were influenced by factors including overall relationship quality, investment, and communication quality, with associations varying by gender. Results highlight the key role that relationship quality factors play in the immediate processing of romantic partners-a finding with implications for couples counseling and research. PMID- 26632024 TI - Self-management and quality of life in chronic obstructive pulmonary disease (COPD): The mediating effects of positive affect. AB - OBJECTIVE: This study aimed to increase our understanding of general self management (SM) abilities in COPD by determining if SM can predict disease specific quality of life (QoL), by investigating whether specific SM domains are significant in COPD and by exploring the mediating effect of the positive/negative affect in the association between SM and QoL. METHODS: Cross sectional study based on 292 patients with COPD. Measures included demographics, lung function, gait speed, health care utilization, positive/negative affect, SM abilities, breathlessness and disease specific QoL. We performed, correlation, multiple regression models and mediation analysis (positive/negative affect being mediator between SM and QoL association). RESULTS: After controlling for breathlessness, living alone, marital status, hospitalization history, age and lung function, SM related to QoL (p<0.0001). Investment in behaviors (hobbies and social relationships) and self-efficacy are SM domains independently related to QoL in COPD. Positivity measured by the positive/negative affect ratio completely mediates the relationship of SM with QoL. CONCLUSION: SM is independently associated with disease specific QoL in COPD after adjustment significant covariates but positive/negative affect ratio completely mediates the relationship of SM with QoL. PRACTICE IMPLICATIONS: Measuring positive/negative affect and addressing investment behavior and self-efficacy are important in implementing COPD-SM programs. PMID- 26632026 TI - Health services appraisal and the transition to Medicaid Managed Care from fee for service. AB - BACKGROUND: Many states are transitioning fee-for-service (FFS) Medicaid into Medicaid Managed Care (MMC) for people with disabilities. OBJECTIVE: This study examined managed care's impact on health services appraisal (HSA) and unmet medical needs of individuals with disabilities receiving Medicaid. Key questions included 1) Do participant demographics and enrollment in MMC impact unmet medical needs and HSA? 2) Within MMC, do demographics and continuity of care relate to unmet medical needs? 3) Within MMC, do demographics, unmet medical needs and continuity of care relate to HSA? METHODS: We collected cross-sectional survey data (n = 1615) from people with disabilities in MMC operated by for profit insurance companies (n = 849) and a similar group remaining in FFS (n = 766) in one state. Regression analyses were conducted across these groups and within MMC only. RESULTS: Across Medicaid groups, MMC enrollment was not related to either HSA or unmet needs; health status, having a mental health disability and unmet transportation needs related to HSA and health status, unmet transportation needs and having a mental health or physical disability related to higher unmet medical needs. Within MMC, in addition to better health and fewer unmet medical needs, less continuity of care significantly decreased HSA. Higher unmet transportation needs, poorer health status, having a physical or mental health disability, and less continuity of care significantly decreased unmet medical needs. CONCLUSIONS: This research points to the importance of meeting unmet needs of individuals in MMC and the need for increased continuity of care as people transition from FFS. PMID- 26632027 TI - Food security among young adults with disabilities in the United States: Findings from the National Health Interview Survey. AB - BACKGROUND: Prior research has suggested that young adults with disabilities face economic, health and social disadvantage. Food security, an area of disadvantage that can influence overall health, has not been fully explored for this population. OBJECTIVE/HYPOTHESIS: To examine levels of food security between young adults with and without disabilities, controlling for individual characteristics. METHODS: Logistic regression analysis of a nationally representative sample of young adults (age 18-25) (n = 32,795) with and without disabilities, using pooled data form the 2011-2013 National Health Interview Survey. RESULTS: Young adults with disabilities have significantly higher odds (OR: 2.58, p < 0.001) of living in a household that is food insecure than young adults without disabilities, even when controlling for individual characteristics. Odds of living in a household that is food insecure are particularly high (OR: 5.35, p < 0.001) among young adults with high levels of psychological distress, controlling for other factors. CONCLUSIONS: Young adults with disabilities have increased odds of living in a household that is food insecure. This study has important policy and community program implications. PMID- 26632028 TI - Cardiac transplantation for older patients: Characteristics and outcomes in the septuagenarian population. AB - BACKGROUND: With increasing age of patients with heart failure, it is important to understand the potential role for orthotopic heart transplant (OHT) in elderly patients. We examined recipient and donor characteristics and long-term outcomes of older recipients of OHT in the United States. METHODS: Using the United Network for Organ Sharing database, we identified OHT recipients from the years 1987-2014 and stratified them by age 18-59 years old, 60-69 years old, and >=70 years old. We compared baseline characteristics of recipients and donors and assessed outcomes across groups. RESULTS: During this period, 50,432 patients underwent OHT; 71.8% (n = 36,190) were 18-59 years old, 26.8% (n = 13,527) were 60-69 years old, and 1.4% (n = 715) were >=70 years old. Comparing the >=70 years old group and 60-69 years old group, older patients had higher rates of ischemic etiology (53.6% vs 44.9%) and baseline renal dysfunction (61.4% vs 56.4%) and at the time of OHT were less likely to be currently hospitalized (45.0% vs 50.9%) or supported with left ventricular assist device therapy (21.0% vs 28.3%). Older recipients received organs from older donors (median age 36 years old vs 30 years old) who were more likely to have diabetes and substance use. After OHT, the median length of stay was similar between groups. At 1 year, of patients alive, patients >=70 years old had fewer rejection episodes (17.8%) compared with patients 60-69 years old (29.5%). The 5-year mortality was 26.9% for recipients 18-59 years old, 29.3% for recipients 60-69 years old, and 30.8% for recipients >=70 years old. CONCLUSIONS: Despite advanced age and less ideal donors, OHT recipients in their 70s had similar outcomes to recipients in their 60s. Selected older patients should not routinely be excluded from consideration for OHT. PMID- 26632029 TI - Proximal thoracic aorta dimensions after continuous-flow left ventricular assist device implantation: Longitudinal changes and relation to aortic valve insufficiency. AB - BACKGROUND: In this study we examined the impact of continuous-flow left ventricular assist device (CF-LVAD) support on proximal thoracic aorta dimensions. METHODS: Aortic root and ascending aorta diameter were measured from serial echocardiograms before and after CF-LVAD implantation in patients with >=6 months of support, and correlated with the development of >mild aortic valve insufficiency (AI). RESULTS: Of 162 patients included, mean age was 58 +/- 11 years and 128 (79%) were male. Seventy-nine (63%) were destination therapy patients. Mean aortic root and ascending aorta diameters at baseline, 1 month, 6 months, 12 months and long-term follow-up (mean 2.0 +/- 1.4 years) were 3.5 +/- 0.4, 3.5 +/- 0.3, 3.9 +/- 0.3, 3.9 +/- 0.2 and 4.0 +/- 0.3, and 3.3 +/- 0.2, 3.3 +/- 0.3, 3.6 +/- 0.2, 3.6 +/- 0.3 and 3.6 +/- 0.3 cm, respectively. Only change in aortic root diameter from 1-month to 6-month follow-up reached statistical significance (p = 0.03). Nine (6%) patients had accelerated proximal thoracic aorta expansion (>0.5 cm/year), occurring predominantly in the first 6 months after implantation. These patients were older and more likely to have hypertension and baseline proximal thoracic aorta dilation. Forty-five (28%) patients developed >mild AI at long-term follow-up, including 7 of 9 (78%) of those with accelerated proximal thoracic aorta expansion. All 7 had aortic valves that remained closed throughout the cardiac cycle, and this, along with duration of CF-LVAD support and increase in aortic root diameter, were significantly associated with developing >mild AI. CONCLUSION: CF-LVAD patients have small increases in proximal thoracic aorta dimensions that predominantly occur within the first 6 months after implantation and then stabilize. Increasing aortic root diameter was associated with AI development. PMID- 26632030 TI - Outcomes and risk factors for listing for heart transplantation after the Norwood procedure: An analysis of the Single Ventricle Reconstruction Trial. AB - BACKGROUND: Infants with hypoplastic left heart syndrome after palliation have the worst survival among heart transplant recipients. Heart transplantation is often reserved for use in patients with sub-optimal results after palliative surgery. This study characterized outcomes after listing in infants with a single ventricle who had undergone the Norwood procedure and identified predictors of the decision to list for heart transplantation. METHODS: The public-use database from the multicenter, prospective randomized Single Ventricle Reconstruction trial was used to identify patients who were listed for heart transplantation. Outcomes on the waiting list and after transplantation were determined. Risk factors were compared between those who were listed and those who survived without listing. RESULTS: Among 555 patients, 33 patients (5.9%) were listed and 18 underwent heart transplantation. Mortality was 39% while waiting for a heart and was 33% after heart transplantation. Overall, 1-year survival after listing (including death after transplantation) was 48%. Factors associated with listing were a lower right ventricular fractional area change at birth, non-hypoplastic left heart syndrome diagnosis, and a more complicated post-Norwood course, defined as a higher need for extracorporeal membrane oxygenation, longer intensive care unit stay, more complications, and a higher number of discharge medications. CONCLUSIONS: Worse right ventricular function, non-hypoplastic left heart syndrome diagnosis, and complex intensive care unit stay were significant risk factors for listing for heart transplantation after the Norwood procedure. Heart transplantation as a rescue procedure after the Norwood procedure in the first year of life carries a significant risk of mortality. PMID- 26632031 TI - Characterization of the multiple components of Acanthopanax Senticosus stem by ultra high performance liquid chromatography with quadrupole time-of-flight tandem mass spectrometry. AB - Acanthopanax Senticosus Harms. has been used widely in traditional Chinese medicine for the treatment of chronic bronchitis, neurasthenia, hypertension and ischemic heart disease. However, the in vivo constituents of the stem of Acanthopanax Senticosus remain unknown. In this paper, ultra high performance liquid chromatography with electrospray ionization quadrupole time-of-flight mass spectrometry and the MarkerLynx(TM) software combined with multiple data processing approach were used to study the constituents in vitro and in vivo. The aqueous extract from the Acanthopanax Senticosus stem and the compositions in rat serum after intragastric administration were completely analyzed. Consequently, 115 compounds in the aqueous extract from Acanthopanax Senticosus stem and 41 compounds absorbed into blood were characterized. Of the 115 compounds in vitro, 54 were reported for first time, including sinapyl alcohol, sinapyl alcohol diglucoside, and 1-O-sinapoyl-beta-D-glucose. In the 41 compounds in vivo, 7 were prototype components and 34 were metabolites which were from 21 components of aqueous extract from Acanthopanax Senticosus stem, and the metabolic pathways of the metabolites were elucidated for first time. The results narrowed the range of screening the active components and provided a basis for the study of action mechanism and pharmacology. PMID- 26632032 TI - Alcohol drinking and HIV-related risk among men who have sex with men in Chongqing, China. AB - To estimate the prevalence of any alcohol use and heavy alcohol drinking using the Alcohol Use Disorders Identification Test (AUDIT) and its correlates among men who have sex with men (MSM), a cross-sectional study was conducted among 391 MSM in Chongqing, China to collect data about sociodemographic characteristics, alcohol use, sexual behaviors, and other related factors through a computer assisted self-administered questionnaire. Heavy alcohol drinking in the past 12 months was defined as an AUDIT-C score >= 4. Blood was collected from each potential participant to test for HIV and syphilis status. Twenty three percent of MSM had consumed a drink containing alcohol in the previous year. 7.2% had an AUDIT-C score >= 4, defined as heavy alcohol drinkers. 23.5% were unmarried, but planning to marry, who were more likely to report any alcohol drinking (adjusted odds ratio [AOR], 2.38; 95% confidence interval [CI], 1.40-4.06) and to have AUDIT-C scores >= 4 (AOR, 3.58; 95% CI, 1.60-8.00). MSM who had used any alcohol in the previous year, and MSM who were heavy alcohol drinkers, were more likely to have had anal sex with male casual partners in the previous 6 months, to have been tested for HIV, and to have decreased scores on the scales of general self efficacy, increased scores on the scales of stigma and discrimination. Our findings provided further evidence of the associations of any alcohol use and heavy alcohol consumption with HIV-risky behaviors, lowered sense of general self efficacy, and higher sense of HIV/AIDS-related stigma and discrimination among MSM in the city with the highest HIV epidemic among MSM in China. PMID- 26632034 TI - Point/Counterpoint. Medical use of all high activity sources should be eliminated for security concerns. PMID- 26632033 TI - Phase 1 Study of ABT-751 in Combination With CAPIRI (Capecitabine and Irinotecan) and Bevacizumab in Patients With Advanced Colorectal Cancer. AB - ABT-751 is an orally bioavailable sulfonamide with antimitotic properties. A nonrandomized phase 1 dose-escalation study of ABT-751 in combination with CAPIRI (capecitabine and irinotecan) and bevacizumab was conducted to define the maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics in patients with advanced colorectal cancer. Patients were treated with ABT-751 daily for 7 days (alone) and then began 21-day cycles of treatment with ABT-751 daily and capecitabine twice daily for 14 days plus irinotecan on day 1 intravenously. Bevacizumab was added as standard of care at 7.5 mg/kg on day 1 after the first 2 dose levels. Because of intolerance to the regimen, a reduced dose of ABT-751 was also explored with reduced-dose and full-dose CAPIRI with bevacizumab. ABT-751 and irinotecan pharmacokinetics, ABT-751 glucuronidation, and protein binding were explored. Twenty-four patients were treated over 5 dose levels. The maximum tolerated dose was ABT-751 125 mg combined with full-dose CAPIRI and bevacizumab 7.5 mg/kg on day 1. DLTs were hypokalemia, elevated liver tests, and febrile neutropenia. ABT-751 is metabolized by UGT1A8 and to a lesser extent UGT1A4 and UGT1A1. Irinotecan and APC exposure were increased, SN-38 exposure was similar, and SN-38 glucuronide exposure was decreased. Clinically relevant alterations in ABT-751 and irinotecan pharmacokinetics were not observed. Despite modest efficacy, the combination of ABT-751, CAPIRI, and bevacizumab will not be studied further in colorectal cancer. PMID- 26632035 TI - Beam's-eye-view imaging during non-coplanar lung SBRT. AB - PURPOSE: Beam's-eye-view (BEV) imaging with an electronic portal imaging device (EPID) can be performed during lung stereotactic body radiation therapy (SBRT) to monitor the tumor location in real-time. Image quality for each patient and treatment field depends on several factors including the patient anatomy and the gantry and couch angles. The authors investigated the angular dependence of automatic tumor localization during non-coplanar lung SBRT delivery. METHODS: All images were acquired at a frame rate of 12 Hz with an amorphous silicon EPID. A previously validated markerless lung tumor localization algorithm was employed with manual localization as the reference. From ten SBRT patients, 12 987 image frames of 123 image sequences acquired at 48 different gantry-couch rotations were analyzed. delta was defined by the position difference of the automatic and manual localization. RESULTS: Regardless of the couch angle, the best tracking performance was found in image sequences with a gantry angle within 20 degrees of 250 degrees (delta = 1.40 mm). Image sequences acquired with gantry angles of 150 degrees , 210 degrees , and 350 degrees also led to good tracking performances with delta = 1.77-2.00 mm. Overall, the couch angle was not correlated with the tracking results. Among all the gantry-couch combinations, image sequences acquired at (theta = 30 degrees , phi = 330 degrees ), (theta = 210 degrees , phi = 10 degrees ), and (theta = 250 degrees , phi = 30 degrees ) led to the best tracking results with delta = 1.19-1.82 mm. The worst performing combinations were (theta = 90 degrees and 230 degrees , phi = 10 degrees ) and (theta = 270 degrees , phi = 30 degrees ) with delta > 3.5 mm. However, 35% (17/48) of the gantry-couch rotations demonstrated substantial variability in tracking performances between patients. For example, the field angle (theta = 70 degrees , phi = 10 degrees ) was acquired for five patients. While the tracking errors were <=1.98 mm for three patients, poor performance was found for the other two patients with delta >= 2.18 mm, leading to average tracking error of 2.70 mm. Only one image sequence was acquired for all other gantry-couch rotations (delta = 1.18-10.29 mm). CONCLUSIONS: Non-coplanar beams with gantry couch rotation of (theta = 30 degrees , phi = 330 degrees ), (theta = 210 degrees , phi = 10 degrees ), and (theta = 250 degrees , phi = 30 degrees ) have the highest accuracy for BEV lung tumor localization. Additionally, gantry angles of 150 degrees , 210 degrees , 250 degrees , and 350 degrees also offer good tracking performance. The beam geometries (theta = 90 degrees and 230 degrees , phi = 10 degrees ) and (theta = 270 degrees , phi = 30 degrees ) are associated with substantial automatic localization errors. Overall, lung tumor visibility and tracking performance were patient dependent for a substantial number of the gantry-couch angle combinations studied. PMID- 26632036 TI - Can radiomics features be reproducibly measured from CBCT images for patients with non-small cell lung cancer? AB - PURPOSE: Increasing evidence suggests radiomics features extracted from computed tomography (CT) images may be useful in prognostic models for patients with nonsmall cell lung cancer (NSCLC). This study was designed to determine whether such features can be reproducibly obtained from cone-beam CT (CBCT) images taken using medical Linac onboard-imaging systems in order to track them through treatment. METHODS: Test-retest CBCT images of ten patients previously enrolled in a clinical trial were retrospectively obtained and used to determine the concordance correlation coefficient (CCC) for 68 different texture features. The volume dependence of each feature was also measured using the Spearman rank correlation coefficient. Features with a high reproducibility (CCC > 0.9) that were not due to volume dependence in the patient test-retest set were further examined for their sensitivity to differences in imaging protocol, level of scatter, and amount of motion by using two phantoms. The first phantom was a texture phantom composed of rectangular cartridges to represent different textures. Features were measured from two cartridges, shredded rubber and dense cork, in this study. The texture phantom was scanned with 19 different CBCT imagers to establish the features' interscanner variability. The effect of scatter on these features was studied by surrounding the same texture phantom with scattering material (rice and solid water). The effect of respiratory motion on these features was studied using a dynamic-motion thoracic phantom and a specially designed tumor texture insert of the shredded rubber material. The differences between scans acquired with different Linacs and protocols, varying amounts of scatter, and with different levels of motion were compared to the mean intrapatient difference from the test-retest image set. RESULTS: Of the original 68 features, 37 had a CCC >0.9 that was not due to volume dependence. When the Linac manufacturer and imaging protocol were kept consistent, 4-13 of these 37 features passed our criteria for reproducibility more than 50% of the time, depending on the manufacturer-protocol combination. Almost all of the features changed substantially when scatter material was added around the phantom. For the dense cork, 23 features passed in the thoracic scans and 11 features passed in the head scans when the differences between one and two layers of scatter were compared. Using the same test for the shredded rubber, five features passed the thoracic scans and eight features passed the head scans. Motion substantially impacted the reproducibility of the features. With 4 mm of motion, 12 features from the entire volume and 14 features from the center slice measurements were reproducible. With 6-8 mm of motion, three features (Laplacian of Gaussian filtered kurtosis, gray-level nonuniformity, and entropy), from the entire volume and seven features (coarseness, high gray-level run emphasis, gray-level nonuniformity, sum-average, information measure correlation, scaled mean, and entropy) from the center-slice measurements were considered reproducible. CONCLUSIONS: Some radiomics features are robust to the noise and poor image quality of CBCT images when the imaging protocol is consistent, relative changes in the features are used, and patients are limited to those with less than 1 cm of motion. PMID- 26632037 TI - Technical Note: Preliminary investigations into the use of a functionalised polymer to reduce diffusion in Fricke gel dosimeters. AB - PURPOSE: A modification of the existing PVA-FX hydrogel has been made to investigate the use of a functionalised polymer in a Fricke gel dosimetry system to decrease Fe(3+) diffusion. METHODS: The chelating agent, xylenol orange, was chemically bonded to the gelling agent, polyvinyl alcohol (PVA) to create xylenol orange functionalised PVA (XO-PVA). A gel was created from the XO-PVA (20% w/v) with ferrous sulfate (0.4 mM) and sulfuric acid (50 mM). RESULTS: This resulted in an optical density dose sensitivity of 0.014 Gy(-1), an auto-oxidation rate of 0.0005 h(-1), and a diffusion rate of 0.129 mm(2) h(-1); an 8% reduction compared to the original PVA-FX gel, which in practical terms adds approximately 1 h to the time span between irradiation and accurate read-out. CONCLUSIONS: Because this initial method of chemically bonding xylenol orange to polyvinyl alcohol has inherently low conversion, the improvement on existing gel systems is minimal when compared to the drawbacks. More efficient methods of functionalising polyvinyl alcohol with xylenol orange must be developed for this system to gain clinical relevance. PMID- 26632038 TI - Prior image based temporally constrained reconstruction algorithm for magnetic resonance guided high intensity focused ultrasound. AB - PURPOSE: A prior image based temporally constrained reconstruction (PITCR) algorithm was developed for obtaining accurate temperature maps having better volume coverage, and spatial, and temporal resolution than other algorithms for highly undersampled data in magnetic resonance (MR) thermometry. METHODS: The proposed PITCR approach is an algorithm that gives weight to the prior image and performs accurate reconstruction in a dynamic imaging environment. The PITCR method is compared with the temporally constrained reconstruction (TCR) algorithm using pork muscle data. RESULTS: The PITCR method provides superior performance compared to the TCR approach with highly undersampled data. The proposed approach is computationally expensive compared to the TCR approach, but this could be overcome by the advantage of reconstructing with fewer measurements. In the case of reconstruction of temperature maps from 16% of fully sampled data, the PITCR approach was 1.57* slower compared to the TCR approach, while the root mean square error using PITCR is 0.784 compared to 2.815 with the TCR scheme. CONCLUSIONS: The PITCR approach is able to perform more accurate reconstructions of temperature maps compared to the TCR approach with highly undersampled data in MR guided high intensity focused ultrasound. PMID- 26632039 TI - Accuracy and calibration of integrated radiation output indicators in diagnostic radiology: A report of the AAPM Imaging Physics Committee Task Group 190. AB - Due to the proliferation of disciplines employing fluoroscopy as their primary imaging tool and the prolonged extensive use of fluoroscopy in interventional and cardiovascular angiography procedures, "dose-area-product" (DAP) meters were installed to monitor and record the radiation dose delivered to patients. In some cases, the radiation dose or the output value is calculated, rather than measured, using the pertinent radiological parameters and geometrical information. The AAPM Task Group 190 (TG-190) was established to evaluate the accuracy of the DAP meter in 2008. Since then, the term "DAP-meter" has been revised to air kerma-area product (KAP) meter. The charge of TG 190 (Accuracy and Calibration of Integrated Radiation Output Indicators in Diagnostic Radiology) has also been realigned to investigate the "Accuracy and Calibration of Integrated Radiation Output Indicators" which is reflected in the title of the task group, to include situations where the KAP may be acquired with or without the presence of a physical "meter." To accomplish this goal, validation test protocols were developed to compare the displayed radiation output value to an external measurement. These test protocols were applied to a number of clinical systems to collect information on the accuracy of dose display values in the field. PMID- 26632040 TI - Validation of a novel robot-assisted 3DUS system for real-time planning and guidance of breast interstitial HDR brachytherapy. AB - PURPOSE: In current clinical practice, there is no integrated 3D ultrasound (3DUS) guidance system clinically available for breast brachytherapy. In this study, the authors present a novel robot-assisted 3DUS system for real-time planning and guidance of breast interstitial high dose rate (HDR) brachytherapy treatment. METHODS: For this work, a new computer controlled robotic 3DUS system was built to perform a hybrid motion scan, which is a combination of a 6 cm linear translation with a 30 degrees rotation at both ends. The new 3DUS scanner was designed to fit on a modified Kuske assembly, keeping the current template grid configuration but modifying the frame to allow the mounting of the 3DUS system at several positions. A finer grid was also tested. A user interface was developed to perform image reconstruction, semiautomatic segmentation of the surgical bed as well as catheter reconstruction and tracking. A 3D string phantom was used to validate the geometric accuracy of the reconstruction. The volumetric accuracy of the system was validated with phantoms using magnetic resonance imaging (MRI) and computed tomography (CT) images. In order to accurately determine whether 3DUS can effectively replace CT for treatment planning, the authors have compared the 3DUS catheter reconstruction to the one obtained from CT images. In addition, in agarose-based phantoms, an end-to-end procedure was performed by executing six independent complete procedures with both 14 and 16 catheters, and for both standard and finer Kuske grids. Finally, in phantoms, five end-to-end procedures were performed with the final CT planning for the validation of 3DUS preplanning. RESULTS: The 3DUS acquisition time is approximately 10 s. A paired Student t-test showed that there was no statistical significant difference between known and measured values of string separations in each direction. Both MRI and CT volume measurements were not statistically different from 3DUS volume (Student t-test: p > 0.05) and they were significantly correlated to 3DUS measurement (Pearson test: MRI p < 0.05 and CT p < 0.001). The mean angular separation distance between catheter trajectories segmented from 3DUS and CT images was 0.42 degrees +/- 0.24 degrees , while the maximum and mean trajectory separations were 0.51 +/- 0.19 and 0.37 +/- 0.17 mm, respectively. Overall, the new finer grid has performed significantly better in terms of dosimetric indices. The planning target volume dosimetric indices were not found statistically different between 3DUS and CT planning (Student t-test, p > 0.05). Both the skin and the pectoral muscle dosimetric indices were within ABS guidelines. CONCLUSIONS: A novel robot-assisted 3DUS system was designed and validated. To their knowledge, this is the first system capable of performing real-time guidance and planning of breast multicatheter HDR brachytherapy treatments. Future investigation will test the feasibility of using the system in the clinic and for permanent breast brachytherapy. PMID- 26632041 TI - 3D liver segmentation using multiple region appearances and graph cuts. AB - PURPOSE: Efficient and accurate 3D liver segmentations from contrast-enhanced computed tomography (CT) images play an important role in therapeutic strategies for hepatic diseases. However, inhomogeneous appearances, ambiguous boundaries, and large variance in shape often make it a challenging task. The existence of liver abnormalities poses further difficulty. Despite the significant intensity difference, liver tumors should be segmented as part of the liver. This study aims to address these challenges, especially when the target livers contain subregions with distinct appearances. METHODS: The authors propose a novel multiregion-appearance based approach with graph cuts to delineate the liver surface. For livers with multiple subregions, a geodesic distance based appearance selection scheme is introduced to utilize proper appearance constraint for each subregion. A special case of the proposed method, which uses only one appearance constraint to segment the liver, is also presented. The segmentation process is modeled with energy functions incorporating both boundary and region information. Rather than a simple fixed combination, an adaptive balancing weight is introduced and learned from training sets. The proposed method only calls initialization inside the liver surface. No additional constraints from user interaction are utilized. RESULTS: The proposed method was validated on 50 3D CT images from three datasets, i.e., Medical Image Computing and Computer Assisted Intervention (MICCAI) training and testing set, and local dataset. On MICCAI testing set, the proposed method achieved a total score of 83.4 +/- 3.1, outperforming nonexpert manual segmentation (average score of 75.0). When applying their method to MICCAI training set and local dataset, it yielded a mean Dice similarity coefficient (DSC) of 97.7% +/- 0.5% and 97.5% +/- 0.4%, respectively. These results demonstrated the accuracy of the method when applied to different computed tomography (CT) datasets. In addition, user operator variability experiments showed its good reproducibility. CONCLUSIONS: A multiregion-appearance based method is proposed and evaluated to segment liver. This approach does not require prior model construction and so eliminates the burdens associated with model construction and matching. The proposed method provides comparable results with state-of-the-art methods. Validation results suggest that it may be suitable for the clinical use. PMID- 26632042 TI - Quantitative model selection for enhanced magnetic nanoparticle imaging in magnetorelaxometry. AB - PURPOSE: The performance of an increasing number of biomedical applications is dependent on the accurate knowledge of the spatial magnetic nanoparticle (MNP) distribution in the body. Magnetorelaxometry (MRX) imaging is a promising and noninvasive technique for the reconstruction of this distribution. To date, no accurate and quantitative measure is available to compare and optimize different MRX imaging models and setups independent of the MNP distribution. In this paper, the authors employ statistical parameters to develop quantitative MRX imaging models. Using these models, a straightforward optimization of setups and models is possible resulting in improved MNP reconstructions. METHODS: A MRX imaging setup is considered with different coil configurations, each corresponding to a MRX imaging model. The models can be represented by a sensitivity matrix. These are compared by employing the matrices as inputs to statistical parameters such as conditional entropy and mutual information (MI). These parameters determine the best model to reconstruct the MNP amount for each volume-element (voxel) in the sample. The matrix is transformed by multiplying the columns with different weightings depending on the performance of the MRX imaging model with respect to the other models. This transformed matrix is compared to the original sensitivity matrix without weightings. RESULTS: Compared to the original sensitivity matrix, an increased numerical stability and improved noise robustness for the transformed sensitivity matrix are observed. The reconstruction of the MNP shows improvements: a correlation to the actual MNP distribution of 99.2%, whereas the original matrix only had 82.5%. By selecting the MRX models with the smallest MI, the authors are able to reduce the measurement time by 65% and still obtain an improved imaging accuracy and noise robustness. The statistical parameters allow a direct measure of the relative information content within the setup such that the optimal voxel size for the MRX setup is determined to be between 5 and 15 mm, while other sizes show a significant change in the statistical parameters. CONCLUSIONS: The use of statistical parameters in MRX imaging models results in quantitative models which can optimize MRX setups in a very fast and elegant way such that improved MNP imaging can be realized. Finally, the presented measure allows to quantitatively and accurately compare different MRX models and setups independent of the MNP distribution. PMID- 26632043 TI - Monte Carlo validation of the TrueBeam 10XFFF phase-space files for applications in lung SABR. AB - PURPOSE: To establish the clinical acceptability of universal Monte Carlo phase space data for the 10XFFF (flattening filter free) photon beam on the Varian TrueBeam Linac, including previously unreported data for small fields, output factors, and inhomogeneous media. The study was particularly aimed at confirming the suitability for use in simulations of lung stereotactic ablative radiotherapy treatment plans. METHODS: Monte Carlo calculated percent depth doses (PDDs), transverse profiles, and output factors for the TrueBeam 10 MV FFF beam using generic phase-space data that have been released by the Varian MC research team were compared with in-house measurements and published data from multiple institutions (ten Linacs from eight different institutions). BEAMnrc was used to create field size specific phase-spaces located underneath the jaws. Doses were calculated with DOSXYZnrc in a water phantom for fields ranging from 1 * 1 to 40 * 40 cm(2). Particular attention was paid to small fields (down to 1 * 1 cm(2)) and dose per pulse effects on dosimeter response for high dose rate 10XFFF beams. Ion chamber measurements were corrected for changes in ion collection efficiency (P(ion)) with increasing dose per pulse. MC and ECLIPSE ANISOTROPIC ANALYTICAL ALGORITHM (AAA) calculated PDDs were compared to Gafchromic film measurement in inhomogeneous media (water, bone, lung). RESULTS: Measured data from all machines agreed with Monte Carlo simulations within 1.0% and 1.5% for PDDs and in-field transverse profiles, respectively, for field sizes >1 * 1 cm(2) in a homogeneous water phantom. Agreements in the 80%-20% penumbra widths were better than 2 mm for all the fields that were compared. For all the field sizes considered, the agreement between their measured and calculated output factors was within 1.1%. Monte Carlo results for dose to water at water/bone, bone/lung, and lung/water interfaces as well as within lung agree with film measurements to within 2.8% for 10 * 10 and 3 * 3 cm(2) field sizes. This represents a significant improvement over the performance of the ECLIPSE AAA. CONCLUSIONS: The 10XFFF phase-space data offered by the Varian Monte Carlo research team have been validated for clinical use using measured, interinstitutional beam data in water and with film dosimetry in inhomogeneous media. PMID- 26632044 TI - Evaluation of MRI and cannabinoid type 1 receptor PET templates constructed using DARTEL for spatial normalization of rat brains. AB - PURPOSE: Image registration is one prerequisite for the analysis of brain regions in magnetic-resonance-imaging (MRI) or positron-emission-tomography (PET) studies. Diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) is a nonlinear, diffeomorphic algorithm for image registration and construction of image templates. The goal of this small animal study was (1) the evaluation of a MRI and calculation of several cannabinoid type 1 (CB1) receptor PET templates constructed using DARTEL and (2) the analysis of the image registration accuracy of MR and PET images to their DARTEL templates with reference to analytical and iterative PET reconstruction algorithms. METHODS: Five male Sprague Dawley rats were investigated for template construction using MRI and [(18)F]MK-9470 PET for CB1 receptor representation. PET images were reconstructed using the algorithms filtered back-projection, ordered subset expectation maximization in 2D, and maximum a posteriori in 3D. Landmarks were defined on each MR image, and templates were constructed under different settings, i.e., based on different tissue class images [gray matter (GM), white matter (WM), and GM + WM] and regularization forms ("linear elastic energy," "membrane energy," and "bending energy"). Registration accuracy for MRI and PET templates was evaluated by means of the distance between landmark coordinates. RESULTS: The best MRI template was constructed based on gray and white matter images and the regularization form linear elastic energy. In this case, most distances between landmark coordinates were <1 mm. Accordingly, MRI-based spatial normalization was most accurate, but results of the PET-based spatial normalization were quite comparable. CONCLUSIONS: Image registration using DARTEL provides a standardized and automatic framework for small animal brain data analysis. The authors were able to show that this method works with high reliability and validity. Using DARTEL templates together with nonlinear registration algorithms allows for accurate spatial normalization of combined MRI/PET or PET-only studies. PMID- 26632045 TI - TestDose: A nuclear medicine software based on Monte Carlo modeling for generating gamma camera acquisitions and dosimetry. AB - PURPOSE: The TestDose platform was developed to generate scintigraphic imaging protocols and associated dosimetry by Monte Carlo modeling. TestDose is part of a broader project (www.dositest.com) whose aim is to identify the biases induced by different clinical dosimetry protocols. METHODS: The TestDose software allows handling the whole pipeline from virtual patient generation to resulting planar and SPECT images and dosimetry calculations. The originality of their approach relies on the implementation of functional segmentation for the anthropomorphic model representing a virtual patient. Two anthropomorphic models are currently available: 4D XCAT and ICRP 110. A pharmacokinetic model describes the biodistribution of a given radiopharmaceutical in each defined compartment at various time-points. The Monte Carlo simulation toolkit gate offers the possibility to accurately simulate scintigraphic images and absorbed doses in volumes of interest. The TestDose platform relies on gate to reproduce precisely any imaging protocol and to provide reference dosimetry. For image generation, TestDose stores user's imaging requirements and generates automatically command files used as input for gate. Each compartment is simulated only once and the resulting output is weighted using pharmacokinetic data. Resulting compartment projections are aggregated to obtain the final image. For dosimetry computation, emission data are stored in the platform database and relevant gate input files are generated for the virtual patient model and associated pharmacokinetics. RESULTS: Two samples of software runs are given to demonstrate the potential of TestDose. A clinical imaging protocol for the OctreoscanTM therapeutical treatment was implemented using the 4D XCAT model. Whole-body "step and shoot" acquisitions at different times postinjection and one SPECT acquisition were generated within reasonable computation times. Based on the same OctreoscanTM kinetics, a dosimetry computation performed on the ICRP 110 model is also presented. CONCLUSIONS: The proposed platform offers a generic framework to implement any scintigraphic imaging protocols and voxel/organ-based dosimetry computation. Thanks to the modular nature of TestDose, other imaging modalities could be supported in the future such as positron emission tomography. PMID- 26632046 TI - Scatter and crosstalk corrections for (99m)Tc/(123)I dual-radionuclide imaging using a CZT SPECT system with pinhole collimators. AB - PURPOSE: The energy spectrum for a cadmium zinc telluride (CZT) detector has a low energy tail due to incomplete charge collection and intercrystal scattering. Due to these solid-state detector effects, scatter would be overestimated if the conventional triple-energy window (TEW) method is used for scatter and crosstalk corrections in CZT-based imaging systems. The objective of this work is to develop a scatter and crosstalk correction method for (99m)Tc/(123)I dual radionuclide imaging for a CZT-based dedicated cardiac SPECT system with pinhole collimators (GE Discovery NM 530c/570c). METHODS: A tailing model was developed to account for the low energy tail effects of the CZT detector. The parameters of the model were obtained using (99m)Tc and (123)I point source measurements. A scatter model was defined to characterize the relationship between down-scatter and self-scatter projections. The parameters for this model were obtained from Monte Carlo simulation using SIMIND. The tailing and scatter models were further incorporated into a projection count model, and the primary and self-scatter projections of each radionuclide were determined with a maximum likelihood expectation maximization (MLEM) iterative estimation approach. The extracted scatter and crosstalk projections were then incorporated into MLEM image reconstruction as an additive term in forward projection to obtain scatter- and crosstalk-corrected images. The proposed method was validated using Monte Carlo simulation, line source experiment, anthropomorphic torso phantom studies, and patient studies. The performance of the proposed method was also compared to that obtained with the conventional TEW method. RESULTS: Monte Carlo simulations and line source experiment demonstrated that the TEW method overestimated scatter while their proposed method provided more accurate scatter estimation by considering the low energy tail effect. In the phantom study, improved defect contrasts were observed with both correction methods compared to no correction, especially for the images of (99m)Tc in dual-radionuclide imaging where there is heavy contamination from (123)I. In this case, the nontransmural defect contrast was improved from 0.39 to 0.47 with the TEW method and to 0.51 with their proposed method and the transmural defect contrast was improved from 0.62 to 0.74 with the TEW method and to 0.73 with their proposed method. In the patient study, the proposed method provided higher myocardium-to-blood pool contrast than that of the TEW method. Similar to the phantom experiment, the improvement was the most substantial for the images of (99m)Tc in dual-radionuclide imaging. In this case, the myocardium-to-blood pool ratio was improved from 7.0 to 38.3 with the TEW method and to 63.6 with their proposed method. Compared to the TEW method, the proposed method also provided higher count levels in the reconstructed images in both phantom and patient studies, indicating reduced overestimation of scatter. Using the proposed method, consistent reconstruction results were obtained for both single-radionuclide data with scatter correction and dual radionuclide data with scatter and crosstalk corrections, in both phantom and human studies. CONCLUSIONS: The authors demonstrate that the TEW method leads to overestimation in scatter and crosstalk for the CZT-based imaging system while the proposed scatter and crosstalk correction method can provide more accurate self-scatter and down-scatter estimations for quantitative single-radionuclide and dual-radionuclide imaging. PMID- 26632047 TI - Quantifying the performance of in vivo portal dosimetry in detecting four types of treatment parameter variations. AB - PURPOSE: To quantify the ability of electronic portal imaging device (EPID) dosimetry used during treatment (in vivo) in detecting variations that can occur in the course of patient treatment. METHODS: Images of transmitted radiation from in vivo EPID measurements were converted to a 2D planar dose at isocenter and compared to the treatment planning dose using a prototype software system. Using the treatment planning system (TPS), four different types of variability were modeled: overall dose scaling, shifting the positions of the multileaf collimator (MLC) leaves, shifting of the patient position, and changes in the patient body contour. The gamma pass rate was calculated for the modified and unmodified plans and used to construct a receiver operator characteristic (ROC) curve to assess the detectability of the different parameter variations. The detectability is given by the area under the ROC curve (AUC). The TPS was also used to calculate the impact of the variations on the target dose-volume histogram. RESULTS: Nine intensity modulation radiation therapy plans were measured for four different anatomical sites consisting of 70 separate fields. Results show that in vivo EPID dosimetry was most sensitive to variations in the machine output, AUC = 0.70 - 0.94, changes in patient body habitus, AUC = 0.67 - 0.88, and systematic shifts in the MLC bank positions, AUC = 0.59 - 0.82. These deviations are expected to have a relatively small clinical impact [planning target volume (PTV) D99 change <7%]. Larger variations have even higher detectability. Displacements in the patient's position and random variations in MLC leaf positions were not readily detectable, AUC < 0.64. The D99 of the PTV changed by up to 57% for the patient position shifts considered here. CONCLUSIONS: In vivo EPID dosimetry is able to detect relatively small variations in overall dose, systematic shifts of the MLC's, and changes in the patient habitus. Shifts in the patient's position which can introduce large changes in the target dose coverage were not readily detected. PMID- 26632048 TI - Super-resolution reconstruction in frequency, image, and wavelet domains to reduce through-plane partial voluming in MRI. AB - PURPOSE: To compare and evaluate the use of super-resolution reconstruction (SRR), in frequency, image, and wavelet domains, to reduce through-plane partial voluming effects in magnetic resonance imaging. METHODS: The reconstruction of an isotropic high-resolution image from multiple thick-slice scans has been investigated through techniques in frequency, image, and wavelet domains. Experiments were carried out with thick-slice T2-weighted fast spin echo sequence on the Academic College of Radiology MRI phantom, where the reconstructed images were compared to a reference high-resolution scan using peak signal-to-noise ratio (PSNR), structural similarity image metric (SSIM), mutual information (MI), and the mean absolute error (MAE) of image intensity profiles. The application of super-resolution reconstruction was then examined in retrospective processing of clinical neuroimages of ten pediatric patients with tuberous sclerosis complex (TSC) to reduce through-plane partial voluming for improved 3D delineation and visualization of thin radial bands of white matter abnormalities. RESULTS: Quantitative evaluation results show improvements in all evaluation metrics through super-resolution reconstruction in the frequency, image, and wavelet domains, with the highest values obtained from SRR in the image domain. The metric values for image-domain SRR versus the original axial, coronal, and sagittal images were PSNR = 32.26 vs 32.22, 32.16, 30.65; SSIM = 0.931 vs 0.922, 0.924, 0.918; MI = 0.871 vs 0.842, 0.844, 0.831; and MAE = 5.38 vs 7.34, 7.06, 6.19. All similarity metrics showed high correlations with expert ranking of image resolution with MI showing the highest correlation at 0.943. Qualitative assessment of the neuroimages of ten TSC patients through in-plane and out-of plane visualization of structures showed the extent of partial voluming effect in a real clinical scenario and its reduction using SRR. Blinded expert evaluation of image resolution in resampled out-of-plane views consistently showed the superiority of SRR compared to original axial and coronal image acquisitions. CONCLUSIONS: Thick-slice 2D T2-weighted MRI scans are part of many routine clinical protocols due to their high signal-to-noise ratio, but are often severely affected by through-plane partial voluming effects. This study shows that while radiologic assessment is performed in 2D on thick-slice scans, super resolution MRI reconstruction techniques can be used to fuse those scans to generate a high-resolution image with reduced partial voluming for improved postacquisition processing. Qualitative and quantitative evaluation showed the efficacy of all SRR techniques with the best results obtained from SRR in the image domain. The limitations of SRR techniques are uncertainties in modeling the slice profile, density compensation, quantization in resampling, and uncompensated motion between scans. PMID- 26632049 TI - Investigation of imaging properties for submillimeter rectangular pinholes. AB - PURPOSE: Recently, a multipinhole collimator with inserts that have both rectangular apertures and rectangular fields of view (FOVs) has been proposed for SPECT imaging since it can tile the projection onto the detector efficiently and the FOVs in transverse and axial directions become separable. The purpose of this study is to investigate the image properties of rectangular-aperture pinholes with submillimeter apertures sizes. METHODS: In this work, the authors have conducted sensitivity and FOV experiments for 18 replicates of a prototype insert fabricated in platinum/iridium (Pt/Ir) alloy with submillimeter square-apertures. A sin(q)theta fit to the experimental sensitivity has been performed for these inserts. For the FOV measurement, the authors have proposed a new formula to calculate the projection intensity of a flood image on the detector, taking into account the penumbra effect. By fitting this formula to the measured projection data, the authors obtained the acceptance angles. RESULTS: The mean (standard deviation) of fitted sensitivity exponents q and effective edge lengths we were, respectively, 10.8 (1.8) and 0.38 mm (0.02 mm), which were close to the values, 7.84 and 0.396 mm, obtained from Monte Carlo calculations using the parameters of the designed inserts. For the FOV measurement, the mean (standard deviation) of the transverse and axial acceptances were 35.0 degrees (1.2 degrees ) and 30.5 degrees (1.6 degrees ), which are in good agreement with the designed values (34.3 degrees and 29.9 degrees ). CONCLUSIONS: These results showed that the physical properties of the fabricated inserts with submillimeter aperture size matched our design well. PMID- 26632050 TI - Validation of a method for in vivo 3D dose reconstruction for IMRT and VMAT treatments using on-treatment EPID images and a model-based forward-calculation algorithm. AB - PURPOSE: Radiation treatments are trending toward delivering higher doses per fraction under stereotactic radiosurgery and hypofractionated treatment regimens. There is a need for accurate 3D in vivo patient dose verification using electronic portal imaging device (EPID) measurements. This work presents a model based technique to compute full three-dimensional patient dose reconstructed from on-treatment EPID portal images (i.e., transmission images). METHODS: EPID dose is converted to incident fluence entering the patient using a series of steps which include converting measured EPID dose to fluence at the detector plane and then back-projecting the primary source component of the EPID fluence upstream of the patient. Incident fluence is then recombined with predicted extra-focal fluence and used to calculate 3D patient dose via a collapsed-cone convolution method. This method is implemented in an iterative manner, although in practice it provides accurate results in a single iteration. The robustness of the dose reconstruction technique is demonstrated with several simple slab phantom and nine anthropomorphic phantom cases. Prostate, head and neck, and lung treatments are all included as well as a range of delivery techniques including VMAT and dynamic intensity modulated radiation therapy (IMRT). RESULTS: Results indicate that the patient dose reconstruction algorithm compares well with treatment planning system computed doses for controlled test situations. For simple phantom and square field tests, agreement was excellent with a 2%/2 mm 3D chi pass rate >=98.9%. On anthropomorphic phantoms, the 2%/2 mm 3D chi pass rates ranged from 79.9% to 99.9% in the planning target volume (PTV) region and 96.5% to 100% in the low dose region (>20% of prescription, excluding PTV and skin build-up region). CONCLUSIONS: An algorithm to reconstruct delivered patient 3D doses from EPID exit dosimetry measurements was presented. The method was applied to phantom and patient data sets, as well as for dynamic IMRT and VMAT delivery techniques. Results indicate that the EPID dose reconstruction algorithm presented in this work is suitable for clinical implementation. PMID- 26632051 TI - An in vivo dose verification method for SBRT-VMAT delivery using the EPID. AB - PURPOSE: Radiation treatments have become increasingly more complex with the development of volumetric modulated arc therapy (VMAT) and the use of stereotactic body radiation therapy (SBRT). SBRT involves the delivery of substantially larger doses over fewer fractions than conventional therapy. SBRT VMAT treatments will strongly benefit from in vivo patient dose verification, as any errors in delivery can be more detrimental to the radiobiology of the patient as compared to conventional therapy. Electronic portal imaging devices (EPIDs) are available on most commercial linear accelerators (Linacs) and their documented use for dosimetry makes them valuable tools for patient dose verification. In this work, the authors customize and validate a physics-based model which utilizes on-treatment EPID images to reconstruct the 3D dose delivered to the patient during SBRT-VMAT delivery. METHODS: The SBRT Linac head, including jaws, multileaf collimators, and flattening filter, were modeled using Monte Carlo methods and verified with measured data. The simulation provides energy spectrum data that are used by their "forward" model to then accurately predict fluence generated by a SBRT beam at a plane above the patient. This fluence is then transported through the patient and then the dose to the phosphor layer in the EPID is calculated. Their "inverse" model back-projects the EPID measured focal fluence to a plane upstream of the patient and recombines it with the extra-focal fluence predicted by the forward model. This estimate of total delivered fluence is then forward projected onto the patient's density matrix and a collapsed cone convolution algorithm calculates the dose delivered to the patient. The model was tested by reconstructing the dose for two prostate, three lung, and two spine SBRT-VMAT treatment fractions delivered to an anthropomorphic phantom. It was further validated against actual patient data for a lung and spine SBRT-VMAT plan. The results were verified with the treatment planning system (TPS) (ECLIPSE AAA) dose calculation. RESULTS: The SBRT-VMAT reconstruction model performed very well when compared to the TPS. A stringent 2%/2 mm chi-comparison calculation gave pass rates better than 91% for the prostate plans, 88% for the lung plans, and 86% for the spine plans for voxels containing 80% or more of the prescribed dose. Patient data were 86% for the lung and 95% for the spine. A 3%/3 mm chi-comparison was also performed and gave pass rates better than 93% for all plan types. CONCLUSIONS: The authors have customized and validated a robust, physics-based model that calculates the delivered dose to a patient for SBRT-VMAT delivery using on-treatment EPID images. The accuracy of the results indicates that this approach is suitable for clinical implementation. Future work will incorporate this model into both offline and real-time clinical adaptive radiotherapy. PMID- 26632052 TI - Technical Note: Development and validation of an open data format for CT projection data. AB - PURPOSE: Lack of access to projection data from patient CT scans is a major limitation for development and validation of new reconstruction algorithms. To meet this critical need, this work developed and validated a vendor-neutral format for CT projection data, which will further be employed to build a library of patient projection data for public access. METHODS: A digital imaging and communication in medicine (DICOM)-like format was created for CT projection data (CT-PD), named the DICOM-CT-PD format. The format stores attenuation information in the DICOM image data block and stores parameters necessary for reconstruction in the DICOM header under various tags (51 tags to store the geometry and scan parameters and 9 tags to store patient information). To validate the accuracy and completeness of the new format, CT projection data from helical scans of the ACR CT accreditation phantom were acquired from two clinical CT scanners (Somatom Definition Flash, Siemens Healthcare, Forchheim, Germany and Discovery CT750 HD, GE Healthcare, Waukesha, WI). After decoding (by the authors for Siemens, by the manufacturer for GE), the projection data were converted to the DICOM-CT-PD format. Off-line CT reconstructions were performed by internal and external reconstruction researchers using only the information stored in the DICOM-CT-PD files and the DICOM-CT-PD field definitions. RESULTS: Compared with the commercially reconstructed CT images, the off-line reconstructed images created using the DICOM-CT-PD format are similar in terms of CT numbers (differences of 5 HU for the bone insert and -9 HU for the air insert), image noise (+/-1 HU), and low contrast detectability (6 mm rods visible in both). Because of different reconstruction approaches, slightly different in-plane and cross-plane high contrast spatial resolution were obtained compared to those reconstructed on the scanners (axial plane: GE off-line, 7 lp/cm; GE commercial, 7 lp/cm; Siemens off line, 8 lp/cm; Siemens commercial, 7 lp/cm. Coronal plane: Siemens off-line, 6 lp/cm; Siemens commercial, 8 lp/cm). CONCLUSIONS: A vendor-neutral extended DICOM format has been developed that enables open sharing of CT projection data from third-generation CT scanners. Validation of the format showed that the geometric parameters and attenuation information in the DICOM-CT-PD file were correctly stored, could be retrieved with use of the provided instructions, and contained sufficient data for reconstruction of CT images that approximated those from the commercial scanner. PMID- 26632053 TI - High resolution 3D imaging of synchrotron generated microbeams. AB - PURPOSE: Microbeam radiation therapy (MRT) techniques are under investigation at synchrotrons worldwide. Favourable outcomes from animal and cell culture studies have proven the efficacy of MRT. The aim of MRT researchers currently is to progress to human clinical trials in the near future. The purpose of this study was to demonstrate the high resolution and 3D imaging of synchrotron generated microbeams in PRESAGE(r) dosimeters using laser fluorescence confocal microscopy. METHODS: Water equivalent PRESAGE(r) dosimeters were fabricated and irradiated with microbeams on the Imaging and Medical Beamline at the Australian Synchrotron. Microbeam arrays comprised of microbeams 25-50 MUm wide with 200 or 400 MUm peak-to-peak spacing were delivered as single, cross-fire, multidirectional, and interspersed arrays. Imaging of the dosimeters was performed using a nikon a1 laser fluorescence confocal microscope. RESULTS: The spatial fractionation of the MRT beams was clearly visible in 2D and up to 9 mm in depth. Individual microbeams were easily resolved with the full width at half maximum of microbeams measured on images with resolutions of as low as 0.09 MUm/pixel. Profiles obtained demonstrated the change of the peak-to-valley dose ratio for interspersed MRT microbeam arrays and subtle variations in the sample positioning by the sample stage goniometer were measured. CONCLUSIONS: Laser fluorescence confocal microscopy of MRT irradiated PRESAGE(r) dosimeters has been validated in this study as a high resolution imaging tool for the independent spatial and geometrical verification of MRT beam delivery. PMID- 26632054 TI - Using dual-energy x-ray imaging to enhance automated lung tumor tracking during real-time adaptive radiotherapy. AB - PURPOSE: Real-time, markerless localization of lung tumors with kV imaging is often inhibited by ribs obscuring the tumor and poor soft-tissue contrast. This study investigates the use of dual-energy imaging, which can generate radiographs with reduced bone visibility, to enhance automated lung tumor tracking for real time adaptive radiotherapy. METHODS: kV images of an anthropomorphic breathing chest phantom were experimentally acquired and radiographs of actual lung cancer patients were Monte-Carlo-simulated at three imaging settings: low-energy (70 kVp, 1.5 mAs), high-energy (140 kVp, 2.5 mAs, 1 mm additional tin filtration), and clinical (120 kVp, 0.25 mAs). Regular dual-energy images were calculated by weighted logarithmic subtraction of high- and low-energy images and filter-free dual-energy images were generated from clinical and low-energy radiographs. The weighting factor to calculate the dual-energy images was determined by means of a novel objective score. The usefulness of dual-energy imaging for real-time tracking with an automated template matching algorithm was investigated. RESULTS: Regular dual-energy imaging was able to increase tracking accuracy in left-right images of the anthropomorphic phantom as well as in 7 out of 24 investigated patient cases. Tracking accuracy remained comparable in three cases and decreased in five cases. Filter-free dual-energy imaging was only able to increase accuracy in 2 out of 24 cases. In four cases no change in accuracy was observed and tracking accuracy worsened in nine cases. In 9 out of 24 cases, it was not possible to define a tracking template due to poor soft-tissue contrast regardless of input images. The mean localization errors using clinical, regular dual-energy, and filter-free dual-energy radiographs were 3.85, 3.32, and 5.24 mm, respectively. Tracking success was dependent on tumor position, tumor size, imaging beam angle, and patient size. CONCLUSIONS: This study has highlighted the influence of patient anatomy on the success rate of real-time markerless tumor tracking using dual-energy imaging. Additionally, the importance of the spectral separation of the imaging beams used to generate the dual-energy images has been shown. PMID- 26632055 TI - A patient-specific aperture system with an energy absorber for spot scanning proton beams: Verification for clinical application. AB - PURPOSE: In the authors' proton therapy system, the patient-specific aperture can be attached to the nozzle of spot scanning beams to shape an irradiation field and reduce lateral fall-off. The authors herein verified this system for clinical application. METHODS: The authors prepared four types of patient-specific aperture systems equipped with an energy absorber to irradiate shallow regions less than 4 g/cm(2). The aperture was made of 3-cm-thick brass and the maximum water equivalent penetration to be used with this system was estimated to be 15 g/cm(2). The authors measured in-air lateral profiles at the isocenter plane and integral depth doses with the energy absorber. All input data were obtained by the Monte Carlo calculation, and its parameters were tuned to reproduce measurements. The fluence of single spots in water was modeled as a triple Gaussian function and the dose distribution was calculated using a fluence dose model. The authors compared in-air and in-water lateral profiles and depth doses between calculations and measurements for various apertures of square, half, and U-shaped fields. The absolute doses and dose distributions with the aperture were then validated by patient-specific quality assurance. Measured data were obtained by various chambers and a 2D ion chamber detector array. RESULTS: The patient specific aperture reduced the penumbra from 30% to 70%, for example, from 34.0 to 23.6 mm and 18.8 to 5.6 mm. The calculated field width for square-shaped apertures agreed with measurements within 1 mm. Regarding patient-specific aperture plans, calculated and measured doses agreed within -0.06% +/- 0.63% (mean +/- SD) and 97.1% points passed the 2%-dose/2 mm-distance criteria of the gamma-index on average. CONCLUSIONS: The patient-specific aperture system improved dose distributions, particularly in shallow-region plans. PMID- 26632056 TI - Dosimetric evaluation of three adaptive strategies for prostate cancer treatment including pelvic lymph nodes irradiation. AB - PURPOSE: The movements of the prostate relative to the pelvic lymph nodes during intensity-modulated radiation therapy treatment can limit margin reduction and affect the protection of the organs at risk (OAR). In this study, the authors performed an analysis of three adaptive treatment strategies that combine information from both bony and gold marker registrations. The robustness of those treatments against the interfraction prostate movements was evaluated. METHODS: A retrospective study was conducted on five prostate cancer patients with 7-13 daily cone-beam CTs (CBCTs). The clinical target volumes (CTVs) consisting of pelvic lymph nodes, prostate, and seminal vesicles as well as the OARs were delineated on each CBCT and the initial CT. Three adaptive strategies were analyzed. Two of these methods relied on a two-step patient positioning at each fraction. First step: a bony registration was used to deliver the nodal CTV prescription. Second step: a gold marker registration was then used either to (1) complete the dose delivered to the prostate (complement); (2) or give almost the entire prescription to the prostate with a weak dose gradient between the targets to compensate for possible motions (gradient). The third method (COR) used a pool of precalculated plans based on images acquired at previous treatment fractions. At each new fraction, a plan is selected from that pool based on the daily position of prostate center-of-mass. The dosimetric comparison was conducted and results are presented with and without the systematic shift in the prostate position on the CT planning. The adaptive strategies were compared to the current clinical standard where all fractions are treated with the initial nonadaptive plan. RESULTS: The minimum daily prostate D95% is improved by 2%, 9%, and 6% for the complement, the gradient, and the COR approaches, respectively, compared to the nonadaptive method. The average nodal CTV D95% remains constant across the strategies, except for the gradient approach where a reduction of 7% is observed. However, a correction of the systematic shift reduced the problem, and the adaptive strategies remain robust against the prostate movement across the fraction. The bladder V55Gy is reduced by 35% on average for the adaptive strategies. CONCLUSIONS: Because they offer increased CTV coverage and OAR sparing, adaptive methods may be suitable candidates for simple and efficient adaptive treatment strategies for prostate cancer. Margin reduction and systematic error correction in the prostate position improve the protection of the OAR and the dose coverage. A cumulative dose to simulate a complete treatment would show real effects and allow a better comparison between each method. PMID- 26632057 TI - Depth-resolved registration of transesophageal echo to x-ray fluoroscopy using an inverse geometry fluoroscopy system. AB - PURPOSE: Image registration between standard x-ray fluoroscopy and transesophageal echocardiography (TEE) has recently been proposed. Scanning-beam digital x-ray (SBDX) is an inverse geometry fluoroscopy system designed for cardiac procedures. This study presents a method for 3D registration of SBDX and TEE images based on the tomosynthesis and 3D tracking capabilities of SBDX. METHODS: The registration algorithm utilizes the stack of tomosynthetic planes produced by the SBDX system to estimate the physical 3D coordinates of salient key-points on the TEE probe. The key-points are used to arrive at an initial estimate of the probe pose, which is then refined using a 2D/3D registration method adapted for inverse geometry fluoroscopy. A phantom study was conducted to evaluate probe pose estimation accuracy relative to the ground truth, as defined by a set of coregistered fiducial markers. This experiment was conducted with varying probe poses and levels of signal difference-to-noise ratio (SDNR). Additional phantom and in vivo studies were performed to evaluate the correspondence of catheter tip positions in TEE and x-ray images following registration of the two modalities. RESULTS: Target registration error (TRE) was used to characterize both pose estimation and registration accuracy. In the study of pose estimation accuracy, successful pose estimates (3D TRE < 5.0 mm) were obtained in 97% of cases when the SDNR was 5.9 or higher in seven out of eight poses. Under these conditions, 3D TRE was 2.32 +/- 1.88 mm, and 2D (projection) TRE was 1.61 +/- 1.36 mm. Probe localization error along the source-detector axis was 0.87 +/- 1.31 mm. For the in vivo experiments, mean 3D TRE ranged from 2.6 to 4.6 mm and mean 2D TRE ranged from 1.1 to 1.6 mm. Anatomy extracted from the echo images appeared well aligned when projected onto the SBDX images. CONCLUSIONS: Full 6 DOF image registration between SBDX and TEE is feasible and accurate to within 5 mm. Future studies will focus on real-time implementation and application-specific analysis. PMID- 26632058 TI - Lesion insertion in the projection domain: Methods and initial results. AB - PURPOSE: To perform task-based image quality assessment in CT, it is desirable to have a large number of realistic patient images with known diagnostic truth. One effective way of achieving this objective is to create hybrid images that combine patient images with inserted lesions. Because conventional hybrid images generated in the image domain fails to reflect the impact of scan and reconstruction parameters on lesion appearance, this study explored a projection domain approach. METHODS: Lesions were segmented from patient images and forward projected to acquire lesion projections. The forward-projection geometry was designed according to a commercial CT scanner and accommodated both axial and helical modes with various focal spot movement patterns. The energy employed by the commercial CT scanner for beam hardening correction was measured and used for the forward projection. The lesion projections were inserted into patient projections decoded from commercial CT projection data. The combined projections were formatted to match those of commercial CT raw data, loaded onto a commercial CT scanner, and reconstructed to create the hybrid images. Two validations were performed. First, to validate the accuracy of the forward-projection geometry, images were reconstructed from the forward projections of a virtual ACR phantom and compared to physically acquired ACR phantom images in terms of CT number accuracy and high-contrast resolution. Second, to validate the realism of the lesion in hybrid images, liver lesions were segmented from patient images and inserted back into the same patients, each at a new location specified by a radiologist. The inserted lesions were compared to the original lesions and visually assessed for realism by two experienced radiologists in a blinded fashion. RESULTS: For the validation of the forward-projection geometry, the images reconstructed from the forward projections of the virtual ACR phantom were consistent with the images physically acquired for the ACR phantom in terms of Hounsfield unit and high-contrast resolution. For the validation of the lesion realism, lesions of various types were successfully inserted, including well circumscribed and invasive lesions, homogeneous and heterogeneous lesions, high contrast and low-contrast lesions, isolated and vessel-attached lesions, and small and large lesions. The two experienced radiologists who reviewed the original and inserted lesions could not identify the lesions that were inserted. The same lesion, when inserted into the projection domain and reconstructed with different parameters, demonstrated a parameter-dependent appearance. CONCLUSIONS: A framework has been developed for projection-domain insertion of lesions into commercial CT images, which can be potentially expanded to all geometries of CT scanners. Compared to conventional image-domain methods, the authors' method reflected the impact of scan and reconstruction parameters on lesion appearance. Compared to prior projection-domain methods, the authors' method has the potential to achieve higher anatomical complexity by employing clinical patient projections and real patient lesions. PMID- 26632059 TI - Detection of masses in digital breast tomosynthesis using complementary information of simulated projection. AB - PURPOSE: The purpose of this study is to develop a computer-aided detection system that combines the detection results in 3D digital breast tomosynthesis (DBT) volume and 2D simulated projection (synthesized image which is not provided by the vendor but generated from DBT volume in this study) to improve the accuracy of mass detection in DBT. METHODS: The 3D DBT volume has a problem of blurring in the out-of-focus plane because it is reconstructed from a limited number of projection view images acquired over a limited angular range. To solve the problem, the simulated projection is generated by measuring the blurriness of voxels in the DBT volume and adopting conspicuity voxels. A contour-based detection algorithm is applied to detecting masses in the simulated projection. The DBT volume is analyzed by using an unsupervised mass detection algorithm, which results in mass candidates in the DBT volume. The mass likelihood scores estimated for mass candidates on the DBT volume and the simulated projection are merged in a probabilistic manner through a Bayesian network model to differentiate masses and false positives (FPs). Experiments were conducted on a clinical data set of 320 DBT volumes. In 90 volumes, at least one biopsy-proven malignant mass was presented. The longest diameter of masses ranged from 7.0 to 56.4 mm (mean = 25.4 mm). The sizes of masses in the data set were relatively large compared to the sizes of the masses reported in other detection studies. Three image quality measurements (overall sharpness, sharpness of mass boundary, and contrast) were used to evaluate the image quality of the simulated projection compared to the DBT central slice where the mass was most conspicuous and other projection methods (maximum intensity projection and average projection). A free response receiver operating characteristic (FROC) analysis was adopted for evaluating the accuracy of mass detection in the DBT volume, the simulated projection, and the combined approach. A jackknife FROC analysis (JAFROC) was used to estimate the statistical significance of the difference between two FROC curves. RESULTS: The overall sharpness and the sharpness of mass boundary in the simulated projection are higher than those in the DBT central slice and other projection methods. The contrast of the simulated projection is lower than the DBT central slice. The mass detection in the DBT volume achieved region-based sensitivities of 80% and 85% with 1.75 and 2.11 FPs per DBT volume. The proposed combined mass detection approach achieved same sensitivities with reduced FPs of 1.33 and 1.93 per DBT volume. The difference of the FROC curves between the combined approach and the mass detection in the DBT volume was statistically significant (p < 0.01) by JAFROC analysis. CONCLUSIONS: This study indicates that the combined approach that merges the detection results in the DBT volume and the simulated projection is a promising approach to improve the accuracy of mass detection in DBT. PMID- 26632060 TI - Vision 20/20: Mammographic breast density and its clinical applications. AB - Breast density is a strong predictor of the failure of mammography screening to detect breast cancer and is a strong predictor of the risk of developing breast cancer. The many imaging options that are now available for imaging dense breasts show great promise, but there is still the question of determining which women are "dense" and what imaging modality is suitable for individual women. To date, mammographic breast density has been classified according to the Breast Imaging Reporting and Data System (BI-RADS) categories from visual assessment, but this is known to be very subjective. Despite many research reports, the authors believe there has been a lack of physics-led and evidence-based arguments about what breast density actually is, how it should be measured, and how it should be used. In this paper, the authors attempt to start correcting this situation by reviewing the history of breast density research and the debates generated by the advocacy movement. The authors review the development of breast density estimation from pattern analysis to area-based analysis, and the current automated volumetric breast density (VBD) analysis. This is followed by a discussion on seeking the ground truth of VBD and mapping volumetric methods to BI-RADS density categories. The authors expect great improvement in VBD measurements that will satisfy the needs of radiologists, epidemiologists, surgeons, and physicists. The authors believe that they are now witnessing a paradigm shift toward personalized breast screening, which is going to see many more cancers being detected early, with the use of automated density measurement tools as an important component. PMID- 26632061 TI - Development of a registration framework to validate MRI with histology for prostate focal therapy. AB - PURPOSE: Focal therapy has been proposed as an alternative method to whole-gland treatment for prostate cancer when aiming to reduce treatment side effects. The authors recently validated a radiobiological model which takes into account tumor location and tumor characteristics including tumor cell density, Gleason score, and hypoxia in order to plan optimal dose distributions for focal therapy. The authors propose that this model can be informed using multiparametric MRI (mpMRI) and in this study present a registration framework developed to map prostate mpMRI and histology data, where histology will provide the "ground truth" data regarding tumor location and biology. The authors aim to apply this framework to a growing database to develop a prostate biological atlas which will enable MRI based planning for prostate focal therapy treatment. METHODS: Six patients scheduled for routine radical prostatectomy were used in this proof-of-concept study. Each patient underwent mpMRI scanning prior to surgery, after which the excised prostate specimen was formalin fixed and mounted in agarose gel in a custom designed sectioning box. T2-weighted MRI of the specimen in the sectioning box was acquired, after which 5 mm sections of the prostate were cut and histology sections were microtomed. A number of image processing and registration steps were used to register histology images with ex vivo MRI and deformable image registration (DIR) was applied to 3D T2w images to align the in vivo and ex vivo MRI data. Dice coefficient metrics and corresponding feature points from two independent annotators were selected in order to assess the DIR accuracy. RESULTS: Images from all six patients were registered, providing histology and in vivo MRI in the ex vivo MRI frame of reference for each patient. Results demonstrated that their DIR methodology to register in vivo and ex vivo 3D T2w MRI improved accuracy in comparison with an initial manual alignment for prostates containing features which were readily visible on MRI. The average estimated uncertainty between in vivo MRI and histology was 3.3 mm, which included an average error of 3.1 mm between in vivo and ex vivo MRI after applying DIR. The mean dice coefficient for the prostate contour between in vivo and ex vivo MRI increased from 0.83 before DIR to 0.93 after DIR. CONCLUSIONS: The authors have developed a registration framework for mapping in vivo MRI data of the prostate with histology by implementing a number of processing steps and ex vivo MRI of the prostate specimen. Validation of DIR was challenging, particularly in prostates with few or mostly linear rather than spherical shaped features. Refinement of their MR imaging protocols to improve the data quality is currently underway which may improve registration accuracy. Additional mpMRI sequences will be registered within this framework to quantify prostate tumor location and biology. PMID- 26632062 TI - Experimental observation of acoustic emissions generated by a pulsed proton beam from a hospital-based clinical cyclotron. AB - PURPOSE: To measure the acoustic signal generated by a pulsed proton spill from a hospital-based clinical cyclotron. METHODS: An electronic function generator modulated the IBA C230 isochronous cyclotron to create a pulsed proton beam. The acoustic emissions generated by the proton beam were measured in water using a hydrophone. The acoustic measurements were repeated with increasing proton current and increasing distance between detector and beam. RESULTS: The cyclotron generated proton spills with rise times of 18 MUs and a maximum measured instantaneous proton current of 790 nA. Acoustic emissions generated by the proton energy deposition were measured to be on the order of mPa. The origin of the acoustic wave was identified as the proton beam based on the correlation between acoustic emission arrival time and distance between the hydrophone and proton beam. The acoustic frequency spectrum peaked at 10 kHz, and the acoustic pressure amplitude increased monotonically with increasing proton current. CONCLUSIONS: The authors report the first observation of acoustic emissions generated by a proton beam from a hospital-based clinical cyclotron. When modulated by an electronic function generator, the cyclotron is capable of creating proton spills with fast rise times (18 MUs) and high instantaneous currents (790 nA). Measurements of the proton-generated acoustic emissions in a clinical setting may provide a method for in vivo proton range verification and patient monitoring. PMID- 26632063 TI - BrachyView, a novel in-body imaging system for HDR prostate brachytherapy: Experimental evaluation. AB - PURPOSE: This paper presents initial experimental results from a prototype of high dose rate (HDR) BrachyView, a novel in-body source tracking system for HDR brachytherapy based on a multipinhole tungsten collimator and a high resolution pixellated silicon detector array. The probe and its associated position estimation algorithms are validated and a comprehensive evaluation of the accuracy of its position estimation capabilities is presented. METHODS: The HDR brachytherapy source is moved through a sequence of positions in a prostate phantom, for various displacements in x, y, and z. For each position, multiple image acquisitions are performed, and source positions are reconstructed. Error estimates in each dimension are calculated at each source position and combined to calculate overall positioning errors. Gafchromic film is used to validate the accuracy of source placement within the phantom. RESULTS: More than 90% of evaluated source positions were estimated with an error of less than one millimeter, with the worst-case error being 1.3 mm. Experimental results were in close agreement with previously published Monte Carlo simulation results. CONCLUSIONS: The prototype of HDR BrachyView demonstrates a satisfactory level of accuracy in its source position estimation, and additional improvements are achievable with further refinement of HDR BrachyView's image processing algorithms. PMID- 26632064 TI - Proton minibeam radiation therapy: Experimental dosimetry evaluation. AB - PURPOSE: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy (RT) approach that allies the inherent physical advantages of protons with the normal tissue preservation observed when irradiated with submillimetric spatially fractionated beams. This dosimetry work aims at demonstrating the feasibility of the technical implementation of pMBRT. This has been performed at the Institut Curie - Proton Therapy Center in Orsay. METHODS: Proton minibeams (400 and 700 MUm-width) were generated by means of a brass multislit collimator. Center-to center distances between consecutive beams of 3200 and 3500 MUm, respectively, were employed. The (passive scattered) beam energy was 100 MeV corresponding to a range of 7.7 cm water equivalent. Absolute dosimetry was performed with a thimble ionization chamber (IBA CC13) in a water tank. Relative dosimetry was carried out irradiating radiochromic films interspersed in a IBA RW3 slab phantom. Depth dose curves and lateral profiles at different depths were evaluated. Peak-to-valley dose ratios (PVDR), beam widths, and output factors were also assessed as a function of depth. RESULTS: A pattern of peaks and valleys was maintained in the transverse direction with PVDR values decreasing as a function of depth until 6.7 cm. From that depth, the transverse dose profiles became homogeneous due to multiple Coulomb scattering. Peak-to-valley dose ratio values extended from 8.2 +/- 0.5 at the phantom surface to 1.08 +/- 0.06 at the Bragg peak. This was the first time that dosimetry in such small proton field sizes was performed. Despite the challenge, a complete set of dosimetric data needed to guide the first biological experiments was achieved. CONCLUSIONS: pMBRT is a novel strategy in order to reduce the side effects of RT. This works provides the experimental proof of concept of this new RT method: clinical proton beams might allow depositing a (high) uniform dose in a brain tumor located in the center of the brain (7.5 cm depth, the worst scenario), while a spatial fractionation of the dose is retained in the normal tissues in the beam path, potentially leading to a gain in tissue sparing. This is the first complete experimental implementation of this promising technique. Biological experiments are needed in order to confirm the clinical potential of pMBRT. PMID- 26632066 TI - Simulation study of noise reduction methods for a split MRI system using a finite element method. AB - PURPOSE: To evaluate the acoustic noise levels induced by the split-gradient coils of a MRI-LINAC system, and also propose a scheme for acoustic noise reduction. METHODS: A finite element (FE) modeling method was used to simulate the acoustic environment of a MRI-LINAC system. By optimizing mounting supports between the split gradient assembly and the main magnet, the authors first altered the vibration modes of the acoustic system, smoothed the acoustic frequency responses, and relocated the acoustic field distribution in the central gap, cylindrical tunnels, and outside of the central gap. The acoustic noise was further reduced by means of applying damping treatment on the surfaces of the split-gradient assembly. RESULTS: Compared with conventional bolts that were placed at the ends, when the near supports were fixed and the far adjustable supports were 40 cm away from the further (here near and far are relative to the central gap) ends of the split-gradient assembly, the overall average sound pressure level (SPL) reductions were about 6.3-9.9 dB both inside and outside the central gap for the transverse and longitudinal coils. After applying damping treatment, the average SPLs inside the central gap and outside it were further reduced by 8.5-12.5 and 6.3-8.8 dB for the transverse coils and longitudinal coils, respectively. CONCLUSIONS: The authors' FE results showed that, for the cases of transverse coil and longitudinal coil switching, the overall average-SPL reduction quantities amounted to around 20 dB by applying the proposed noise reduction scheme, resulting in lower SPLs than the human hearing threshold. PMID- 26632065 TI - Evaluation of an active magnetic resonance tracking system for interstitial brachytherapy. AB - PURPOSE: In gynecologic cancers, magnetic resonance (MR) imaging is the modality of choice for visualizing tumors and their surroundings because of superior soft tissue contrast. Real-time MR guidance of catheter placement in interstitial brachytherapy facilitates target coverage, and would be further improved by providing intraprocedural estimates of dosimetric coverage. A major obstacle to intraprocedural dosimetry is the time needed for catheter trajectory reconstruction. Herein the authors evaluate an active MR tracking (MRTR) system which provides rapid catheter tip localization and trajectory reconstruction. The authors assess the reliability and spatial accuracy of the MRTR system in comparison to standard catheter digitization using magnetic resonance imaging (MRI) and CT. METHODS: The MRTR system includes a stylet with microcoils mounted on its shaft, which can be inserted into brachytherapy catheters and tracked by a dedicated MRTR sequence. Catheter tip localization errors of the MRTR system and their dependence on catheter locations and orientation inside the MR scanner were quantified with a water phantom. The distances between the tracked tip positions of the MRTR stylet and the predefined ground-truth tip positions were calculated for measurements performed at seven locations and with nine orientations. To evaluate catheter trajectory reconstruction, fifteen brachytherapy catheters were placed into a gel phantom with an embedded catheter fixation framework, with parallel or crossed paths. The MRTR stylet was then inserted sequentially into each catheter. During the removal of the MRTR stylet from within each catheter, a MRTR measurement was performed at 40 Hz to acquire the instantaneous stylet tip position, resulting in a series of three-dimensional (3D) positions along the catheter's trajectory. A 3D polynomial curve was fit to the tracked positions for each catheter, and equally spaced dwell points were then generated along the curve. High-resolution 3D MRI of the phantom was performed followed by catheter digitization based on the catheter's imaging artifacts. The catheter trajectory error was characterized in terms of the mean distance between corresponding dwell points in MRTR-generated catheter trajectory and MRI-based catheter digitization. The MRTR-based catheter trajectory reconstruction process was also performed on three gynecologic cancer patients, and then compared with catheter digitization based on MRI and CT. RESULTS: The catheter tip localization error increased as the MRTR stylet moved further off-center and as the stylet's orientation deviated from the main magnetic field direction. Fifteen catheters' trajectories were reconstructed by MRTR. Compared with MRI-based digitization, the mean 3D error of MRTR-generated trajectories was 1.5 +/- 0.5 mm with an in-plane error of 0.7 +/- 0.2 mm and a tip error of 1.7 +/- 0.5 mm. MRTR resolved ambiguity in catheter assignment due to crossed catheter paths, which is a common problem in image based catheter digitization. In the patient studies, the MRTR-generated catheter trajectory was consistent with digitization based on both MRI and CT. CONCLUSIONS: The MRTR system provides accurate catheter tip localization and trajectory reconstruction in the MR environment. Relative to the image-based methods, it improves the speed, safety, and reliability of the catheter trajectory reconstruction in interstitial brachytherapy. MRTR may enable in procedural dosimetric evaluation of implant target coverage. PMID- 26632067 TI - Influence of nuclear interactions in body tissues on tumor dose in carbon-ion radiotherapy. AB - PURPOSE: In carbon-ion radiotherapy treatment planning, the planar integrated dose (PID) measured in water is applied to the patient dose calculation with density scaling using the stopping power ratio. Since body tissues are chemically different from water, this dose calculation can be subject to errors, particularly due to differences in inelastic nuclear interactions. In recent studies, the authors proposed and validated a PID correction method for these errors. In the present study, the authors used this correction method to assess the influence of these nuclear interactions in body tissues on tumor dose in various clinical cases. METHODS: Using 10-20 cases each of prostate, head and neck (HN), bone and soft tissue (BS), lung, liver, pancreas, and uterine neoplasms, the authors first used treatment plans for carbon-ion radiotherapy without nuclear interaction correction to derive uncorrected dose distributions. The authors then compared these distributions with recalculated distributions using the nuclear interaction correction (corrected dose distributions). RESULTS: Median (25%/75% quartiles) differences between the target mean uncorrected doses and corrected doses were 0.2% (0.1%/0.2%), 0.0% (0.0%/0.0%), -0.3% (-0.4%/-0.2%), -0.1% (-0.2%/-0.1%), -0.1% (-0.2%/0.0%), -0.4% (-0.5%/-0.1%), and -0.3% ( 0.4%/0.0%) for the prostate, HN, BS, lung, liver, pancreas, and uterine cases, respectively. The largest difference of -1.6% in target mean and -2.5% at maximum were observed in a uterine case. CONCLUSIONS: For most clinical cases, dose calculation errors due to the water nonequivalence of the tissues in nuclear interactions would be marginal compared to intrinsic uncertainties in treatment planning, patient setup, beam delivery, and clinical response. In some extreme cases, however, these errors can be substantial. Accordingly, this correction method should be routinely applied to treatment planning in clinical practice. PMID- 26632068 TI - Sensitivity and variability of Presage dosimeter formulations in sheet form with application to SBRT and SRS QA. AB - PURPOSE: To measure sensitivity and stability of the Presage dosimeter in sheet form for various chemical concentrations over a range of clinical photon energies and examine its use for stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS) QA. METHODS: Presage polymer dosimeters were formulated to investigate and optimize their sensitivity and stability. The dosimeter is composed of clear polyurethane base, leucomalachite green (LMG) reporting dye, and bromoform radical initiator in 0.9-1.0 mm thick sheets. The chemicals are mixed together for 2 min, cast in an aluminum mold, and left to cure at 60 psi for a minimum of two days. Dosimeter response was characterized at energies Co-60, 6 MV, 10 MV flattening-filter free, 15 MV, 50 kVp (mean 19.2 keV), and Ir-192. The dosimeters were scanned by a Microtek Scanmaker i800 at 300 dpi, 2(16) bit depth per color channel. Red component images were analyzed with ImageJ and rit. SBRT QA was done with gamma analysis tolerances of 2% and 2 mm DTA. RESULTS: The sensitivity of the Presage dosimeter increased with increasing concentration of bromoform. Addition of tin catalyst decreased curing time and had negligible effect on sensitivity. LMG concentration should be at least as high as the bromoform, with ideal concentration being 2% wt. Gamma Knife SRS QA measurements of relative output and profile widths were within 2% of manufacturer's values validated at commissioning, except the 4 mm collimator relative output which was within 3%. The gamma pass rate of Presage with SBRT was 73.7%, compared to 93.1% for EBT2 Gafchromic film. CONCLUSIONS: The Presage dosimeter in sheet form was capable of detecting radiation over all tested photon energies and chemical concentrations. The best sensitivity and photostability of the dosimeter were achieved with 2.5% wt. LMG and 8.2% wt. bromoform. Scanner used should not emit any UV radiation as it will expose the dosimeter, as with the Epson 10000 XL scanner. Presage dosimeter in this form was sensitive enough for use in SRS and SBRT QA. The lower gamma pass rate for Presage compared to Gafchromic film can be attributed to the simple equipment used in the fabrication process, which limited the dosimeter's sensitivity uniformity by agglomeration of air bubbles in the material, nonuniform concentration of chemicals throughout the material, and thickness variations. This demands improvements in mixing tools and molds. PMID- 26632069 TI - Air-kerma strength determination of a new directional (103)Pd source. AB - PURPOSE: A new directional (103)Pd planar source array called a CivaSheetTM has been developed by CivaTech Oncology, Inc., for potential use in low-dose-rate (LDR) brachytherapy treatments. The array consists of multiple individual polymer capsules called CivaDots, containing (103)Pd and a gold shield that attenuates the radiation on one side, thus defining a hot and cold side. This novel source requires new methods to establish a source strength metric. The presence of gold material in such close proximity to the active (103)Pd region causes the source spectrum to be significantly different than the energy spectra of seeds normally used in LDR brachytherapy treatments. In this investigation, the authors perform air-kerma strength (S(K)) measurements, develop new correction factors for these measurements based on an experimentally verified energy spectrum, and test the robustness of transferring S(K) to a well-type ionization chamber. METHODS: S(K) measurements were performed with the variable-aperture free-air chamber (VAFAC) at the University of Wisconsin Medical Radiation Research Center. Subsequent measurements were then performed in a well-type ionization chamber. To realize the quantity S(K) from a directional source with gold material present, new methods and correction factors were considered. Updated correction factors were calculated using the MCNP 6 Monte Carlo code in order to determine S(K) with the presence of gold fluorescent energy lines. In addition to S(K) measurements, a low-energy high-purity germanium (HPGe) detector was used to experimentally verify the calculated spectrum, a sodium iodide (NaI) scintillating counter was used to verify the azimuthal and polar anisotropy, and a well-type ionization chamber was used to test the feasibility of disseminating S(K) values for a directional source within a cylindrically symmetric measurement volume. RESULTS: The UW VAFAC was successfully used to measure the S(K) of four CivaDots with reproducibilities within 0.3%. Monte Carlo methods were used to calculate the UW VAFAC correction factors and the calculated spectrum emitted from a CivaDot was experimentally verified with HPGe detector measurements. The well-type ionization chamber showed minimal variation in response (<1.5%) as a function of source positioning angle, indicating that an American Association of Physicists in Medicine (AAPM) Accredited Dosimetry Calibration Laboratory calibrated well chamber would be a suitable device to transfer an S(K)-based calibration to a clinical user. S(K) per well-chamber ionization current ratios were consistent among the four dots measured. Additionally, the measurements and predictions of anisotropy show uniform emission within the solid angle of the VAFAC, which demonstrates the robustness of the S(K) measurement approach. CONCLUSIONS: This characterization of a new (103)Pd directional brachytherapy source helps to establish calibration methods that could ultimately be used in the well established AAPM Task Group 43 formalism. Monte Carlo methods accurately predict the changes in the energy spectrum caused by the fluorescent x-rays produced in the gold shield. PMID- 26632070 TI - Vision 20/20: Positron emission tomography in radiation therapy planning, delivery, and monitoring. AB - Positron emission tomography (PET) is increasingly considered as an effective imaging method to support several stages of radiation therapy. The combined usage of functional and morphological imaging in state-of-the-art PET/CT scanners is rapidly emerging to support the treatment planning process in terms of improved tumor delineation, and to assess the tumor response in follow-up investigations after or even during the course of fractionated therapy. Moreover, active research is being pursued on new tracers capable of providing different insights into tumor function, in order to identify areas of the planning volume which may require additional dosage for improved probability of tumor control. In this respect, major progresses in the next years will likely concern the development and clinical investigation of novel tracers and image processing techniques for reliable thresholding and segmentation, of treatment planning and beam delivery approaches integrating the PET imaging information, as well as improved multimodal clinical instrumentation such as PET/MR. But especially in the rapidly emerging case of ion beam therapy, the usage of PET is not only limited to the imaging of external tracers injected to the patient. In fact, a minor amount of positron emitters is formed in nuclear fragmentation reactions between the impinging ions and the tissue, bearing useful information for confirmation of the delivered treatment during or after therapeutic irradiation. Different implementations of unconventional PET imaging for therapy monitoring are currently being investigated clinically, and major ongoing research aims at new dedicated detector technologies and at challenging applications such as real-time imaging and time-resolved in vivo verification of motion compensated beam delivery. This paper provides an overview of the different areas of application of PET in radiation oncology and discusses the most promising perspectives in the years to come for radiation therapy planning, delivery, and monitoring. PMID- 26632071 TI - Enhancing atlas based segmentation with multiclass linear classifiers. AB - PURPOSE: To present a method to enrich atlases for atlas based segmentation. Such enriched atlases can then be used as a single atlas or within a multiatlas framework. METHODS: In this paper, machine learning techniques have been used to enhance the atlas based segmentation approach. The enhanced atlas defined in this work is a pair composed of a gray level image alongside an image of multiclass classifiers with one classifier per voxel. Each classifier embeds local information from the whole training dataset that allows for the correction of some systematic errors in the segmentation and accounts for the possible local registration errors. The authors also propose to use these images of classifiers within a multiatlas framework: results produced by a set of such local classifier atlases can be combined using a label fusion method. RESULTS: Experiments have been made on the in vivo images of the IBSR dataset and a comparison has been made with several state-of-the-art methods such as FreeSurfer and the multiatlas nonlocal patch based method of Coupe or Rousseau. These experiments show that their method is competitive with state-of-the-art methods while having a low computational cost. Further enhancement has also been obtained with a multiatlas version of their method. It is also shown that, in this case, nonlocal fusion is unnecessary. The multiatlas fusion can therefore be done efficiently. CONCLUSIONS: The single atlas version has similar quality as state-of-the-arts multiatlas methods but with the computational cost of a naive single atlas segmentation. The multiatlas version offers a improvement in quality and can be done efficiently without a nonlocal strategy. PMID- 26632072 TI - A 1.5 T transverse magnetic field in radiotherapy of rectal cancer: Impact on the dose distribution. AB - PURPOSE: MRI guidance during radiotherapy has the potential to enable more accurate dose delivery, optimizing the balance between local control and treatment related toxicity. However, the presence of a permanent magnetic field influences the dose delivery, especially around air cavities. Here, electrons are able to return to the surface through which they entered the air cavity (electron return effect, ERE) locally resulting in dose hot- and cold-spots. Where RT of rectal cancer patients might benefit from MRI guidance for margin reduction, air cavities in and around the target volume are frequently present. The purpose of this research is to evaluate the impact of the presence of a 1.5 T transverse magnetic field on dose delivery in patients with rectal cancer. METHODS: Ten patients treated with 5 * 5 Gy RT having large changes in pelvic air content were selected out of a cohort of 33 patients. On the planning CT, a 1.5 T, 6 MV, 7 field intensity modulated radiotherapy (IMRT) plan was created. This plan was subsequently recalculated on daily CT scans. For each daily CT, the CTV V95% and V107% and bowel area V(5Gy), V(10Gy), V(15Gy), V(20Gy), and V(25Gy) were calculated to evaluate the changes in dose distribution from fraction to fraction. For comparison, the authors repeated this procedure for the 0 T situation. To study the effect of changing air cavities separate from other anatomical changes, the authors also generated artificial air cavities in the CTV of one patient (2 and 5 cm diameter), in the high dose gradient region (2 cm), and in the low dose area (2 cm). Treatment plans were optimized without and with each simulated air cavity. For appearing and disappearing air cavities, the CTV V95% and V107% were evaluated. The authors also evaluated the ERE separate from attenuation changes locally around appearing gas pockets. RESULTS: For the ten patients, at 1.5 T, the V95% was influenced by both appearing and disappearing air, and dropped to <98% in 2 out of 50 fractions due a disappearing air cavity of 150 cm(3). V95% differences between 0 and 1.5 T were all within 2%. The V107% was below 1% in 46 out of 50 fractions, and increased to 3% in the remaining fractions due to appearing air of around 120 cm(3). For comparison, V107% was <1% at 0 T for all fractions. In the bowel area, the V15Gy varied strongest from fraction to fraction, but differences between 1.5 and 0 T were minimal with an average difference of 2.3 cm(3) (SD = 18.7 cm(3), p = 0.38). For the simulated air cavities, the ERE resulted in cold-spots maximally 5% lower than prescribed and hot-spots maximally 6% higher than prescribed. CONCLUSIONS: The presence of a 1.5 T magnetic field has an impact on the dose distribution when the air content changes of within a few percent in these selected rectal cancer patients. The authors consider this influence of the transverse magnetic field on the dose distribution in IMRT for rectal cancer patients clinically acceptable. PMID- 26632074 TI - Erratum: "An automatic registration method for pre- and post-interventional CT images for assessing treatment success in liver RFA treatment" [Med. Phys. 42, 5559-5567 (2015)]. PMID- 26632073 TI - NonCartesian MR image reconstruction with integrated gradient nonlinearity correction. AB - PURPOSE: To derive a noniterative gridding-type reconstruction framework for nonCartesian magnetic resonance imaging (MRI) that prospectively accounts for gradient nonlinearity (GNL)-induced image geometrical distortion during MR image reconstruction, as opposed to the standard, image-domain based GNL correction that is applied after reconstruction; to demonstrate that such framework is able to reduce the image blurring introduced by the conventional GNL correction, while still offering effective correction of GNL-induced geometrical distortion and compatibility with off-resonance correction. METHODS: After introducing the nonCartesian MRI signal model that explicitly accounts for the effects of GNL and off-resonance, a noniterative gridding-type reconstruction framework with integrated GNL correction based on the type-III nonuniform fast Fourier transform (NUFFT) is derived. A novel type-III NUFFT implementation is then proposed as a numerically efficient solution to the proposed framework. The incorporation of simultaneous B0 off-resonance correction to the proposed framework is then discussed. Several phantom and in vivo data acquired via various 2D and 3D nonCartesian acquisitions, including 2D Archimedean spiral, 3D shells with integrated radial and spiral, and 3D radial sampling, are used to compare the results of the proposed and the standard GNL correction methods. RESULTS: Various phantom and in vivo data demonstrate that both the proposed and the standard GNL correction methods are able to correct the coarse-scale geometric distortion and blurring induced by GNL and off-resonance. However, the standard GNL correction method also introduces blurring effects to corrected images, causing blurring of resolution inserts in the phantom images and loss of small vessel clarity in the angiography examples. On the other hand, the results after the proposed GNL correction show better depiction of resolution inserts and higher clarity of small vessel. CONCLUSIONS: The proposed GNL-integrated nonCartesian reconstruction method can mitigate the resolution loss that occurs during standard image-domain GNL correction, while still providing effective correction of coarse-scale geometric distortion and blurring induced by GNL and off resonance. PMID- 26632075 TI - Vascular and Chronological Age in Subjects with Erectile Dysfunction: A Cross Sectional Study. AB - INTRODUCTION: Vascular age, as derived from the SCORE project algorithm for cardiovascular (CV) risk estimation, is an effective way for communicating CV risk. However, studies on its clinical correlates are scanty. AIM: To evaluate if the difference between vascular and chronological age (Deltaage), in a population of subjects with erectile dysfunction (ED), can identify men with a worse risk profile. METHODS: A consecutive series of 2,853 male patients attending the outpatient clinic for erectile dysfunction (ED) for the first time was retrospectively studied. Among them, 85.4% (n = 2,437) were free of previous MACE and were analyzed. MAIN OUTCOME MEASURES: Several clinical, biochemical, and penile color Doppler parameters were studied. Vascular age was derived from the SCORE project algorithm, and the Deltaage was considered. RESULTS: Higher Deltaage is associated with several conventional (family history of CV diseases, hyperglycemia, elevated triglycerides, and increased prevalence of metabolic syndrome) and unconventional (severity of ED, frequency of sexual activity, alcohol abuse, lower education level, fatherhood, extramarital affairs, compensated hypogonadism, and low prolactin levels) risk factors. Deltaage is inversely related to penile color Doppler parameters, including flaccid and dynamic peak systolic velocity and flaccid acceleration (beta = -0.125, -0.113, and -0.134, respectively, all P < 0.0001). CONCLUSIONS: In subjects referring for ED without a personal history of CV events, Deltaage is associated with an adverse cardio-metabolic profile and worse penile color Doppler ultrasound parameters. Deltaage provides a simple method for identifying high-risk men that must undergo significant modification in their lifestyle and risk factors. In addition, it can be considered a simple, inexpensive, and safe surrogate marker of penile arterial damage. PMID- 26632076 TI - Donor Lymphocyte Infusion in Hematologic Malignancies--Good to be Fresh? AB - BACKGROUND: Donor lymphocyte infusion (DLI) has been used with variable success in a variety of hematologic malignancies. PATIENTS AND METHODS: We conducted a retrospective analysis of all patients who were treated with DLI for persistent or relapsed disease at the Temple University Bone Marrow Transplant Unit from July 1, 1993 to December 31, 2013 to evaluate the effect of the type of DLI (fresh vs. cryopreserved) on event-free survival (EFS) and overall survival (OS). Median follow-up was 64.8 months (range, 0.3-142.6 months). RESULTS: We found that EFS and OS were similar between patients receiving cryopreserved cells and those receiving fresh DLI (median OS for cryopreserved cells, 0.39 years; median OS for fresh cells, 0.32 years; P = .793; median EFS for cryopreserved cells, 0.410 years; median EFS for fresh cells, 0.420 years; P = .4264). In the setting of relapsed disease, treatment with any chemotherapy regimen before receiving DLI did not significantly impact OS (n = 63; P = .2203) or EFS (n = 40; P = .542). A subgroup analysis limited to patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) (32 patients) showed that differences in OS and EFS between cryopreserved and fresh DLI approached significance (median OS for cryopreserved cells, 0.34 years; median OS for fresh cells, 0.17 years; P = .16; median EFS for cryopreserved cells, 0.37 years; median EFS for fresh cells, 0.094 years; P = 0.11). CONCLUSION: We conclude that the use of fresh cells versus cryopreserved cells does not have an impact on outcomes, and selected patients can achieve long-term survival with DLI for treatment of relapse after transplantation, although the overall outcomes remain dismal. PMID- 26632077 TI - Neutrophil Gelatinase--Associated Lipocalin and Cystatin C Are Sensitive Markers of Renal Injury in Patients With Multiple Myeloma. AB - BACKGROUND: Renal impairment is a common complication of patients with multiple myeloma (MM). We aimed to evaluate the clinical significance of 2 newly discovered biomarkers of renal injury, cystatin C (CysC), a protein reflecting glomerular filtration rate, and neutrophil gelatinase-associated lipocalin (NGAL), a protein reflecting tubular injuries. PATIENTS AND METHODS: We studied 64 patients with newly diagnosed myeloma: 16 with asymptomatic (smoldering) MM and 48 with symptomatic myeloma; 8 patients with monoclonal gammopathy of undetermined significance (MGUS); and 20 healthy control subjects. Along with common blood and urine chemistry determinations, measurements of CysC, NGAL, beta2-microglobulin, high-sensitivity C-reactive protein, and interleukin 6 were performed. RESULTS: We found that only patients with symptomatic MM had increased levels of CysC compared to controls (P < .01); that serum NGAL levels were elevated in all patients compared to controls P < .001; that NGAL strongly correlated with both estimation of glomerular filtration rate (eGFR) (CysC) and eGFR (Modification of Diet in Renal Disease [MDRD] formula) (r = 0.616, P < .0001; and r = -0.371, P < .01, respectively); that CysC showed strong correlation with eGFR (r = -0.782, P < .001) and with the International Scoring System (ISS) (more pronounced in patients with ISS-3); and that receiver operating characteristic curve analysis showed that NGAL values of > 50.5 MUg/L have a 80.8% sensitivity and 86.4% specificity for eGFR < 60 mL/min (area under the curve = 0.764). CONCLUSION: These findings suggest that both NGAL and CysC are very sensitive markers that reflect renal impairment in newly diagnosed patients with MM. The high levels of NGAL in asymptomatic patients and in MGUS patients support the hypothesis of the presence of renal damage in these patients early in the course of their disease and may reveal NGAL to be an early marker that predicts the presence of renal impairment in MM. PMID- 26632078 TI - Molecularly imprinted porous beads for the selective removal of copper ions. AB - In the present work, novel molecularly imprinted polymer porous beads for the selective separation of copper ions have been synthesized by combining two material-structuring techniques, namely, molecular imprinting and oil-in-water-in oil emulsion polymerization. This method produces monodisperse spherical beads with an average diameter of ~2-3 mm, in contrast to adsorbents produced in the traditional way of grinding and sieving. Field-emission scanning electron microscopy indicates that the beads are porous in nature with interconnected pores of about 25-50 MUm. Brunner-Emmett-Teller analysis shows that the ion imprinted beads possess a high surface area (8.05 m(2) /g), and the total pore volume is determined to be 0.00823 cm(3) /g. As a result of the highly porous nature and ion-imprinting, the beads exhibit a superior adsorption capacity (84 mg/g) towards copper than the non-imprinted material (22 mg/g). Furthermore, selectivity studies indicate that imprinted beads show splendid recognizing ability, that is, nearly fourfold greater selective binding for Cu(2+) in comparison to the other bivalent ions such as Mn(2+) , Ni(2+) , Co(2+) , and Ca(2+) . The imprinted composite beads prepared in this study possess uniform porous morphology and may open up new possibilities for the selective removal of copper ions from waste water/contaminated matrices. PMID- 26632079 TI - Reply to: Response to "Breach of the thyroid capsule and lymph node capsule in node-positive papillary and medullary thyroid cancer: Different biology". PMID- 26632080 TI - Surgical management of advanced gastric cancer: An evolving issue. AB - Worldwide, gastric cancer represents the fifth most common cancer and the third leading cause of cancer deaths. Although the overall 5-year survival for resectable disease was more than 70% in Japan due to the implementation of screening programs resulting in detection of disease at earlier stages, in Western countries more than two thirds of gastric cancers are usually diagnosed in advanced stages reporting a 5-year survival rate of only 25.7%. Anyway surgical resection with extended lymph node dissection remains the only curative therapy for non-metastatic advanced gastric cancer, while neoadjuvant and adjuvant chemotherapies can improve the outcomes aimed at the reduction of recurrence and extension of survival. High-quality research and advances in technologies have contributed to well define the oncological outcomes and have stimulated many clinical studies testing multimodality managements in the advanced disease setting. This review article aims to outline and discuss open issues in current surgical management of advanced gastric cancer. PMID- 26632081 TI - Response to "Breach of the thyroid capsule and lymph node capsule in node positive papillary and medullary thyroid cancer: Different biology". PMID- 26632082 TI - Guaifenesin Pharmacokinetics Following Single-Dose Oral Administration in Children Aged 2 to 17 Years. AB - This study characterized guaifenesin pharmacokinetics in children aged 2 to 17 years (n = 40) who received a single oral dose of guaifenesin (age-based doses of 100-400 mg) 2 hours after breakfast. Plasma samples were obtained before and for 8 hours after dosing and analyzed for guaifenesin using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods, relationships with age were assessed using linear regression, and dose proportionality was assessed on 95% confidence intervals. Based on the upper dose recommended in the monograph (for both children and adolescents), area under the curve from time zero to infinity and maximum plasma concentration both increased with age. However, when comparing the upper dose for children aged 2 to 11 years with the lower dose for adolescents aged 12 to 17 years, similar systemic exposure was observed. As expected due to increasing body size, oral clearance (CLo ) and terminal volume of distribution (Vz /F) increased with age. Due to a larger increase in Vz /F than CLo , an increase in terminal exponential half-life was also observed. Allometric scaling indicated no maturation-related changes in CLo and Vz /F. PMID- 26632083 TI - The feasibility and acceptability of administering a telemedicine objective structured clinical exam as a solution for providing equivalent education to remote and rural learners. AB - INTRODUCTION: Although many medical schools incorporate distance learning into their curricula, assessing students at a distance can be challenging. While some assessments are relatively simple to administer to remote students, other assessments, such as objective structured clinical exams (OSCEs) are not. This article describes a means to more effectively and efficiently assess distance learners and evaluate the feasibility and acceptability of the assessment. METHODS: We developed a teleOSCE, administered online in real time, to two cohorts of students on a rural clerkship rotation and assessed the feasibility and acceptability of using such an approach to assess medical students' clinical skills at rural locations. Project feasibility was defined as having development and implementation costs of less than $5000. Project acceptability was determined by analyzing student interview transcripts. A qualitative case study design framework was chosen due to the novel nature of the activity. RESULTS: The implementation cost of the teleOSCE was approximately US$1577.20, making it a feasible educational endeavor. Interview data indicated the teleOSCE was also acceptable to students. CONCLUSIONS: The teleOSCE format may be useful to other institutions as a method to centrally administer clinical skills exams for assessment of distance medical students. PMID- 26632084 TI - The Clitoral Photoplethysmograph: A Pilot Study Examining Discriminant and Convergent Validity. AB - INTRODUCTION: The clitoral photoplethysmograph (CPP) is a relatively new device used to measure changes in clitoral blood volume (CBV); however, its construct validity has not yet been evaluated. AIM: To evaluate the discriminant and convergent validity of the CPP. For discriminant validity, CBV responses should differ between sexual and nonsexual emotional films if the CPP accurately assesses clitoral vasocongestion associated with sexual arousal; for convergent validity, CBV responses should significantly correlate with subjective reports of sexual arousal. METHODS: Twenty women (M age = 21.2 years, SD = 3.4) watched neutral, anxiety-inducing, exhilarating, and sexual (female-male sex) audiovisual stimuli while their genital responses were measured simultaneously using vaginal and clitoral photoplethysmographs and CPPs. Most of these participants continuously reported sexual arousal throughout each stimulus (n = 16), and all reported their sexual and nonsexual affect before and after each stimulus; subjective responses were recorded via button presses using a keypad. MAIN OUTCOME MEASURES: Vaginal pulse amplitude (VPA), CBV, and self-reported sexual arousal and nonsexual affect were used as main outcome measures. RESULTS: CBV demonstrated both discriminant and convergent validity. CBV responses were similar to VPA responses and self-reported sexual arousal; all responses differed significantly as a function of stimulus content, with the sexual stimulus eliciting greater relative changes than nonsexual stimuli. CBV, but not VPA, was significantly (negatively) correlated with continuous self-reported sexual arousal during the shorter sexual stimulus. CBV was significantly negatively correlated with VPA for the shorter sexual stimulus. CONCLUSION: CBV may be a valid measure of women's genital sexual arousal that provides complementary information to VPA and correlates with self-reported sexual arousal. Given our relatively small sample size, and that this is among the first research to use the CPP, the current findings must be replicated. More research using the CPP and other devices is required for a more comprehensive description of women's physiological sexual arousal. PMID- 26632085 TI - Keratomycosis in a pet rabbit (Oryctolagus cuniculus) treated with topical 1% terbinafine ointment. AB - This report describes the clinical presentation, diagnosis, and medical management of a 2-year-old spayed female dwarf rabbit (Oryctolagus cuniculus) suffering from an ulcerative keratitis and a stromal abscess with a rapid evolution. The diagnosis of fungal keratitis was based on fungal culture identifying the pathogen as Aspergillus fumigatus. Treatment by topical terbinafine was efficacious in resolving the keratomycosis within 8 weeks. To our knowledge, this is the first reported case of spontaneous keratomycosis in a rabbit and the first description of successful therapy by terbinafine. PMID- 26632087 TI - Unraveling the association of heart failure from drug and disease: Insights from recent cardiovascular trials in type 2 diabetes mellitus. PMID- 26632086 TI - Analysis of respiratory events in obstructive sleep apnea syndrome: Inter relations and association to simple nocturnal features. AB - OBJECTIVE: This study carefully evaluates the association of different respiration-related events to each other and to simple nocturnal features in obstructive sleep apnea-hypopnea syndrome (OSAS). The events include apneas, hypopneas, respiratory event-related arousals and snores. METHODS: We conducted a statistical study on 158 adults who underwent polysomnography between July 2012 and May 2014. To monitor relevance, along with linear statistical strategies like analysis of variance and bootstrapping a correlation coefficient standard error, the non-linear method of mutual information is also applied to illuminate vague results of linear techniques. RESULTS: Based on normalized mutual information weights (NMIW), indices of apnea are 1.3 times more relevant to AHI values than those of hypopnea. NMIW for the number of blood oxygen desaturation below 95% is considerable (0.531). The next relevant feature is "respiratory arousals index" with NMIW of 0.501. Snore indices (0.314), and BMI (0.203) take the next place. Based on NMIW values, snoring events are nearly one-third (29.9%) more dependent to hypopneas than RERAs. CONCLUSION: 1. The more sever the OSAS is, the more frequently the apneic events happen. 2. The association of snore with hypopnea/RERA revealed which is routinely ignored in regression-based OSAS modeling. 3. The statistical dependencies of oximetry features potentially can lead to home-based screening of OSAS. 4. Poor ESS-AHI relevance in the database under study indicates its disability for the OSA diagnosis compared to oximetry. 5. Based on poor RERA-snore/ESS relevance, detailed history of the symptoms plus polysomnography is suggested for accurate diagnosis of RERAs. PMID- 26632088 TI - Design of the extraction process for terpenes and other volatiles from allspice by solid-phase microextraction and hydrodistillation. AB - Methods for the separation and determination of terpenes (mono- and sesqui-) and phenylpropanoids such as eugenol and methyleugenol from samples of allspice berries have been developed. Chromatographic analyses of isolated groups of compounds were carried out by means of gas chromatography coupled with mass spectrometry. A comparison of various types of solid-phase microextraction fibers was performed. The highest yields of terpenes were extracted by polydimethylsiloxane and divinylbenzene/Carboxen/polydimethylsiloxane fibers (almost the same for these two fibers), approximately twice as much as by Carbowax/divinylbenzene fiber. The highest amounts of monoterpenes were extracted by divinylbenzene/Carboxen/polydimethylsiloxane fiber, and the highest amounts of sesquiterpenes were extracted by polydimethylsiloxane fiber. Moreover, the effect of water addition on extraction yields as well as time and temperature of extraction were tested. Aroma profiles of extracts obtained by solid-phase microextraction and essential oil obtained by hydrodistillation of allspice berries were compared. The aroma profile of the divinylbenzene/Carboxen/polydimethylsiloxane fiber extract was similar to the aroma profile of essential oil. Particular characteristics of volatile allspice matters were presented. The linear retention indices for each compound were calculated. PMID- 26632089 TI - [Ultrasound-guided peripheral venous access]. AB - International guidelines advocate the use of first-line ultrasound for central venous catheter, particularly for the internal jugular vein. The role of ultrasound in peripheral venous access remains questionable. In some specific situations, such as pediatrics, obesity and patients with poor venous network, problems to cannulate peripheral vein may occur. Success rate of peripheral intravenous access increases with the diameter of the vein and for a depth of the vein between 0.3 and 1.5 cm. The type of puncture (long-axis or short-axis) and the type of catheters have little influence on the success rate. Specific considerations have to be taken concerning infection control. PMID- 26632090 TI - [Rhinocerebral mucormycosis complicating ketoacidosis diabetes]. PMID- 26632093 TI - Editorial Comment on "Psychology Treatment Trials for Hypoactive Sexual Desire Disorder: A Sexual Medicine Critique and Perspective". PMID- 26632091 TI - Dose-Response Analysis of the Effect of Carbidopa-Levodopa Extended-Release Capsules (IPX066) in Levodopa-Naive Patients With Parkinson Disease. AB - Parkinson disease is an age-related disorder of the central nervous system principally due to loss of dopamine-producing cells in the midbrain. Levodopa, in combination with carbidopa, is widely regarded as an effective treatment for the symptoms of Parkinson disease. A dose-response relationship is established for carbidopa-levodopa extended-release capsules (IPX066) in levodopa-naive Parkinson disease patients using a disease progression model. Unified Parkinson Disease Rating Scale (UPDRS) part II plus part III scores from 171 North American patients treated with placebo or IPX066 for approximately 30 weeks from a double blind, parallel-group, dose-ranging study were used to develop the pharmacodynamic model. The model comprised 3 components: a linear function describing disease progression, a component describing placebo (or nonlevodopa) effects, and a component to describe the effect of levodopa. Natural disease progression in early Parkinson disease as measured by UPDRS was 11.6 units/year and faster in patients with more severe disease (Hoehn-Yahr stage 3). Maximum placebo/nonlevodopa response was 23.0% of baseline UPDRS. Maximum levodopa effect from IPX066 was 76.7% of baseline UPDRS, and the ED50 was 450 mg levodopa. Equilibration half-life for the effect compartment was 62.8 days. Increasing age increased and being female decreased equilibration half-life. The quantitative model allowed description of the entire time course of response to clinical trial intervention. PMID- 26632092 TI - An Exploratory Study of the Experience of Ageing with Ankylosing Spondylitis: 'Same Backdrop but a Changing Scene'. AB - OBJECTIVES: People are living longer with a long-term health condition. Our aim was to develop a greater understanding of the experience and needs of people as they age with ankylosing spondylitis (AS). METHODS: Ethical approval was obtained for six focus groups, with participants over 60 years of age, to explore experiences through peer group discussion. The groups were recorded and transcribed. Transcripts were coded and a thematic analysis was conducted using NVIVO 10. RESULTS: Four women and 28 men, with an average age of 68 (range 60-83) years, consented to participate. Analysis identified a central organizing concept, 'same backdrop but a changing scene', which conceptualizes the continued impact of AS set against a backdrop of people transitioning into a new phase of their lives and facing differing challenges. Five themes underpin this concept: 'it doesn't go away' (AS remains active with continuing functional and symptomatic challenges); 'wheels fall off after 60' (perceptions of disease progression within the context of 'normal ageing'); 'keep on pushing, keep on doing' (challenges of remaining active and motivated); 'living a fulfilling life' (actively engaging with life) and a 'price to pay' (significant psychological, physical and financial consequences on participants and their families). CONCLUSIONS: As people living with AS make the transition into retirement, many aspire to live active lives while facing new challenges in relation to their lifestyles and priorities. There is a need to offer tailored interventions to enable older people to remain active and continue to lead the lives they choose within the context of an active and often debilitating condition. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26632094 TI - Invasive phaeochromocytoma presenting as a right atrial mass. PMID- 26632095 TI - Taking action on sugar. PMID- 26632096 TI - Post-transplantation diabetes-state of the art. AB - With increasing success in overcoming the immunological and infectious challenges accompanying solid organ transplantation, susceptibility to post-transplant diabetes and cardiovascular disease has assumed increasing importance. Although some guidance is available from diabetes-related literature pertaining to the general population, some aspects are unique to solid organ allograft recipients. Both insulin resistance and beta-cell dysfunction are generally agreed to contribute to development and manifestation of post-transplant diabetes, but controversy continues about which is most important and to what extent post transplant diabetes is a distinct entity or simply a variant of type 2 diabetes with transplant-specific components. The optimum method and timing for detection and diagnosis of post-transplant diabetes remains an area of uncertainty. However, the greatest needs are to: address the absence of contemporary data for incidence and clinical outcomes associated with post-transplant diabetes; establish the role of glycaemic control; and assess the role of new diabetic therapies in prevention and management of post-transplant diabetes. We place the present knowledge base in the context of other advances in transplantation, challenge some existing ideas, and examine the potential role of emerging diabetes therapies. In highlighting existing deficiencies, we hope to provide direction for future research that will ultimately reduce incidence and improve management of post-transplant diabetes. PMID- 26632097 TI - Clinical outcomes after autograft reconstruction for sternoclavicular joint instability. AB - BACKGROUND: Instability of the sternoclavicular (SC) joint is a rare condition. However, in some cases, SC joint instability may lead to persistent pain and impairment of shoulder function that requires surgical management. This study evaluated clinical outcomes after SC joint reconstruction with hamstring tendon autograft in patients with SC joint instability. METHODS: From December 2010 to January 2014, 21 reconstructions of the SC joint with hamstring tendon autograft were performed. Outcomes data were prospectively collected and retrospectively reviewed. Data analyzed included American Shoulder and Elbow Surgeons score, Quick Disability of the Arm, Shoulder and Hand, physical component of the Short Form 12, and Single Assessment Numeric Evaluation scores. Pain with activities of daily living, work, and sleep were separately analyzed along with painless use of arm for activities. Patients were also questioned regarding postoperative satisfaction. RESULTS: Nine women and 10 men (2 bilaterals), with a mean age of 30 years (range, 15-56 years), were monitored for a mean of 2 years (range, 12-36 months) postoperatively. Mean American Shoulder and Elbow Surgeons, Quick Disability of the Arm, Shoulder and Hand, and Single Assessment Numeric Evaluation scores significantly improved (P < .001). Pain scores also improved over preoperative baselines, including pain with activities of daily living, work, and sleep (P < .001). Median satisfaction at final follow-up was 8.5 (range, 7-10). There were no intraoperative or postoperative complications and no cases of recurrent instability. CONCLUSION: Free hamstring tendon autograft reconstruction for SC joint instability resulted in significantly improved clinical outcomes with high patient satisfaction and no intraoperative or postoperative complications. PMID- 26632098 TI - Evaluation and optimization of the metal-binding properties of a complex ligand for immobilized metal affinity chromatography. AB - The simultaneous determination of two binding parameters for metal ions on an immobilized metal affinity chromatography column was performed by frontal chromatography. In this study, the binding parameters of Cu(2+) to l-glutamic acid were measured, the metal ion-binding characteristics of the complex ligand were evaluated. The linear correlation coefficients were all greater than 99%, and the relative standard deviations of two binding parameters were 0.58 and 0.059%, respectively. The experiments proved that the frontal chromatography method was accurate, reproducible, and could be used to determine the metal binding parameters of the affinity column. The effects of buffer pH, type, and concentration on binding parameters were explored by uniform design experiment. Regression, matching and residual analyses of the models were performed. Meanwhile, the optimum-binding conditions of Cu(2+) on the l-glutamic acid-silica column were obtained. Under these binding conditions, observations and regression values of two parameters were similar, and the observation values were the best. The results demonstrated that high intensity metal affinity column could be effectively prepared by measuring and evaluating binding parameters using frontal chromatography combined with a uniform design experiment. The present work provided a new mode for evaluating and preparing immobilized metal affinity column with good metal-binding behaviors. PMID- 26632099 TI - Improving Patient Care by Incorporation of Multidisciplinary Breast Radiology Pathology Correlation Conference. AB - PURPOSE: It is well known that radiologic-pathologic correlation is critical in managing patients with breast disease. Although regular multidisciplinary conferences addressing radiologic-pathologic correlation are common at most major academic institutions, this approach is not universal in community-based settings or even some of the smaller academic practices. This study was performed to assess the impact of a weekly multidisciplinary conference on patient care to determine whether all breast practices should adopt this approach as a means to streamline and improve the quality of patient care. METHODS: We reviewed cases of percutaneous breast core biopsies presented at our weekly breast radiology pathology correlation conference from July 1, 2008, to June 30, 2012. Each reviewed case was assigned to 1 of 4 categories (concordant -> concordant, concordant -> discordant, discordant -> discordant, and discordant -> concordant) based on the "initial" and "final" impressions of concordance between radiology and pathology. Changes in concordance, histopathological diagnosis, or management that occurred during the conference were recorded prospectively and analysed. Changes in management that were considered significant included changes in recommendations for surgery, repeat core biopsy, or follow-up imaging. RESULTS: Of 1387 presented at the conference, 1313 (94.7%) had no change during the meeting, confirming 1279 (92.2%) concordant and 34 (2.4%) discordant cases. A total of 74 (5.3%) cases had a change during the conference: 22 of 74 (29.7%) were changed from discordant to concordant, avoiding surgical excision in 15 and short interval imaging in 7; 23 of 74 (31.1%) were changed from concordant to discordant; on excision 3 were cancer, 3 atypia, 10 benign, 2 stable on follow-up imaging, and 5 lost to follow-up; the remaining 29 of 74 (39.2%) stayed concordant after review, but had a change in management, avoiding surgery in 14 and short interval imaging in 15. Overall, as a result of this conference, repeat biopsy or excision was recommended in 23, surgery was avoided in 29, short interval imaging avoided in 22, and cancer detected in 3 cases. CONCLUSIONS: Our weekly breast radiology-pathology correlation conference impacted patient management in up to 5.3% of cases. These results support the need to incorporate a weekly multidisciplinary case review of breast core biopsies into all breast care practices. Such a conference maximizes cancer detection, identifies discordant cases in a timely manner, decreases follow-up imaging, and avoids unnecessary surgical intervention. PMID- 26632100 TI - Imaging the Patient With Sacroiliac Pain. AB - Sacroiliac (SI) region pain is a common clinical presentation and is often due to pathology involving the SI joints, usually of inflammatory, infective, neoplastic, or post-traumatic etiology. The SI joints have a unique anatomic layout and composition and can be imaged with a variety of techniques including conventional radiographs, computed tomography, isotope bone scintigraphy, and magnetic resonance imaging. This article reviews a range of common SI joint conditions, illustrated by multimodality imaging findings. We also discuss strategies for choosing the optimal imaging modality, pearls, and pitfalls of imaging and discuss an algorithm for approaching the patient with suspected inflammatory back pain. PMID- 26632102 TI - Corrigendum. PMID- 26632103 TI - Workshop on Industrial Safety and Health (WISH 2014). PMID- 26632101 TI - Population Pharmacokinetics and Exposure-Response of a Fixed-Dose Combination of Azilsartan Medoxomil and Chlorthalidone in Patients With Stage 2 Hypertension. AB - Population pharmacokinetic and exposure-response models for azilsartan medoxomil (AZL-M) and chlorthalidone (CLD) were developed using data from an 8-week placebo controlled phase 3, factorial study of 20, 40, and 80 mg AZL-M every day (QD) and 12.5 and 25 mg CLD QD in fixed-dose combination (FDC) in subjects with moderate to severe essential hypertension. A 2-compartment model with first-order absorption and elimination was developed to describe pharmacokinetics. An Emax model for exposure-response analysis evaluated AZL-M/CLD effects on ambulatory systolic blood pressure (SBP). Estimated oral clearance and apparent volume of distribution (central compartment) were 1.47 L/h and 3.98 L for AZL, and 4.13 L/h and 62.1 L for CLD. Age as a covariate had the largest effect on AZL and CLD exposure (+/-20% change). Predicted maximal SBP responses (Emax ) were -15.6 and 23.9 mm Hg for AZL and CLD. Subgroup analysis identified statistically significant Emax differences for black vs nonblack subjects, whereby the reduced AZL response in black subjects was offset by greater response to CLD. The estimated Emax for AZL and CLD was generally greater in subjects with higher baseline BP. In conclusion, no dose adjustments to AZL-M or CLD are warranted based on identified covariates, and antihypertensive efficacy of AZL-M/CLD combination therapy is comparable in black and nonblack subjects. PMID- 26632104 TI - A visualization method measuring the performance of biomarkers for guiding treatment decisions. AB - Biomarkers that predict efficacy and safety for a given drug therapy become increasingly important for treatment strategy and drug evaluation in personalized medicine. Methodology for appropriately identifying and validating such biomarkers is critically needed, although it is very challenging to develop, especially in trials of terminal diseases with survival endpoints. The marker-by treatment predictiveness curve serves this need by visualizing the treatment effect on survival as a function of biomarker for each treatment. In this article, we propose the weighted predictiveness curve (WPC). Based on the nature of the data, it generates predictiveness curves by utilizing either parametric or nonparametric approaches. Especially for nonparametric predictiveness curves, by incorporating local assessment techniques, it requires minimum model assumptions and provides great flexibility to visualize the marker-by-treatment relationship. WPC can be used to compare biomarkers and identify the one with the highest potential impact. Equally important, by simultaneously viewing several treatment specific predictiveness curves across the biomarker range, WPC can also guide the biomarker-based treatment regimens. Simulations representing various scenarios are employed to evaluate the performance of WPC. Application on a well-known liver cirrhosis trial sheds new light on the data and leads to discovery of novel patterns of treatment biomarker interactions. PMID- 26632105 TI - The utility of 18F-FDG PET/CT in solitary fibrous tumors of the pleura. AB - OBJECTIVE: To demonstrate the utility of (18)F-FDG PET/CT in the differentiation of benign and malignant solitary fibrous tumors of the pleura (SFTP). MATERIALS AND METHODS: A retrospective review was performed on the (18)F-FDG PET/CT data from 17 patients with histopathologically diagnosed benign or malignant SFTP. The size, side of SFTP, presence of necrosis, calcification, pleural effusion, hilar lymphadenopathy (LAP), density on CT images (Hounsfield unit-HU), and (18)F-FDG uptake (SUVmax) were recorded and compared in order to detect malignant SFTP. Statistical significance was set as p<0.05. RESULTS: The difference in size, presence of necrosis, and hilar LAP on CT images were statistically significant (p=0.004, p<0.001, p=0.015, respectively) in a comparison of benign and malignant SFTPs. The mean HU of benign SFTP was 46.16+/-5.52HU, and for malignant SFTP it was 35.03+/-4.61HU (p=0.003). The mean SUVmax was 3.02+/-1.02 for benign SFTP and 4.89+/-2.12 for malignant SFTP (p=0.021). A cut-off value of >=7cm for size, <=39.81HU for density, and >=3.47 for SUVmax was obtained by ROC analysis for detecting malignant SFTP. CONCLUSIONS: (18)F-FDG PET/CT may have a limited role in diagnosing malignant SFTP in suspected patients. PMID- 26632106 TI - Sexual Function and Pessary Management among Women Using a Pessary for Pelvic Floor Disorders. AB - INTRODUCTION: Pessaries are commonly used to treat pelvic floor disorders, but little is known about the sexual function of pessary users. AIM: We aimed to describe sexual function among pessary users and pessary management with regard to sexual activity. METHODS: This is a secondary analysis of a randomized trial of new pessary users, where study patients completed validated questionnaires on sexual function and body image at pessary fitting and 3 months later. MAIN OUTCOME MEASURES: Women completed the Pelvic Organ Prolapse-Urinary Incontinence Sexual Function Questionnaire, International Urogynecological Association Revised (PISQ-IR), a validated measure that evaluates the impact of pelvic floor disorders on sexual function, a modified female body image scale (mBIS), and questions regarding pessary management surrounding sexual activity. RESULTS: Of 127 women, 54% (68/127) were sexually active at baseline and 42% (64/114) were sexually active at 3 months. Sexual function scores were not different between baseline and 3 months on all domains except for a drop of 0.15 points (P = 0.04) for sexually active women, and a drop of 0.34 points for non-sexually active women (P = 0.02) in the score related to the sexual partner. Total mBIS score did not change (P = 0.07), but scores improved by 0.2 points (P = 0.03) in the question related to self-consciousness. Pessary satisfaction was associated with improved sexual function scores in multiple domains and improved mBIS scores. The majority (45/64, 70%) of sexually active women removed their pessary for sex, with over half stating their partner preferred removal for sex (24/45, 53%). CONCLUSION: Many women remove their pessary during sex for partner considerations, and increased partner concerns are the only change seen in sexual function in the first 3 months of pessary use. Pessary use may improve self consciousness and pessary satisfaction is associated with improvements in sexual function and body image. PMID- 26632107 TI - Magnetic solid-phase extraction based on a triethylenetetramine-functionalized magnetic graphene oxide composite for the detection of ten trace phenolic environmental estrogens in environmental water. AB - A novel triethylenetetramine-functionalized magnetic graphene oxide composite was prepared and used as a magnetic solid-phase extraction adsorbent for the fast detection of ten trace-level phenolic environmental estrogens in environmental water. The synthesized material was carefully characterized by scanning electron microscopy, transmission electron microscopy, vibrating sample magnetometry, and X-ray photoelectron spectroscopy to confirm the structure and components. The adsorption and desorption conditions of the adsorbent toward phenolic environmental estrogens were optimized in detailed to obtain the best extraction recovery and elution efficiency. Under the optimum conditions, the limits of detection of the method for ten phenolic environmental estrogens were in range of 0.15-1.5 ng/L, which was lower than the reported methods for phenolic environmental estrogens detection in literatures. This could be contributed to the unique structure and property of the as-prepared material. The developed method was successfully applied for the determination of environmental water samples with recoveries ranging from 88.5 to 105.6%. PMID- 26632108 TI - Bioresorbable vascular scaffold for very late stent thrombosis resulting from ruptured neoatherosclerosis. AB - Very late stent thrombosis is a rare but devastating complication after percutaneous coronary revascularization. Pathological studies have demonstrated that neoatherosclerosis plays a major role in certain patients with very late stent thrombosis. Optical coherence tomography is able to unravel the underlying pathophysiology and may be used to select the best treatment option. This case report describes the use of a bioresorbable vascular scaffold (BVS) in a patient suffering from very late stent thrombosis due to a complicated plaque in the setting of intrastent neoatherosclerosis. To our knowledge, this therapeutic strategy has not been previously reported in patients suffering from very late stent thrombosis. In this scenario, BVS implantation might represent an attractive strategy in selected patients. PMID- 26632109 TI - Appropriate use criteria for transthoracic echocardiography at a tertiary care center. AB - INTRODUCTION AND OBJECTIVES: The American College of Cardiology and American Society of Echocardiography have developed appropriate use criteria for echocardiography. The objective of this study was to assess the rate of appropriate requests for transthoracic echocardiography at a Portuguese tertiary care center and to identify the factors associated with lower adherence to the appropriate use criteria. METHODS: All transthoracic echocardiograms (in- and outpatient) performed over a period of one month were analyzed by two independent imaging cardiologists, who matched each request to a specific indication in the appropriate use criteria document. RESULTS: Overall, 799 echocardiograms were included in the analysis. In 97.5% of cases it was possible to determine an indication listed in the criteria, according to which 78.7% of classifiable echocardiograms were appropriate, 15.3% inappropriate and 6.0% of uncertain appropriateness. The most common appropriate indication (111 echocardiograms) was initial evaluation of patients with symptoms or conditions potentially related to cardiac etiology, while the main inappropriate indication (59 echocardiograms) was routine surveillance of ventricular function in patients with known coronary artery disease and no change in clinical status or cardiac exam. The proportion of inappropriate echocardiograms was significantly higher among outpatients than among inpatients (18.8 vs. 4.3%, p<0.05) and among cardiologists compared to other specialties (19.3% vs. 10.9%, p<0.05). CONCLUSIONS: The majority of requests for transthoracic echocardiograms at a Portuguese tertiary care center were appropriate. Requests by cardiologists and outpatient referrals presented the highest rates of inappropriateness. PMID- 26632110 TI - An unusual case of fulminant myocarditis closely mimicking ST-segment elevation myocardial infarction and presenting as refractory cardiogenic shock complicated by multiple life-threatening arrhythmias. AB - We report a case of severe fulminant myocarditis that closely mimicked acute inferior ST-segment elevation myocardial infarction (STEMI) and presented with refractory cardiogenic shock, multiple life-threatening arrhythmias and rapidly progressive liver failure. This case was successfully differentiated from STEMI by emergency coronary angiography. Recurrent cardiogenic shock was reversed by intra-aortic balloon pumping (IABP). Life-threatening arrhythmias including ventricular tachycardia, ventricular fibrillation, and high-degree atrioventricular block (AVB) were terminated by immediate cardioversion and temporary pacemaker. High-dose hydrocortisone effectively attenuated the inflammatory injury to the myocardium. The patient recovered and was well at the follow-up visit four months after discharge. PMID- 26632111 TI - Inoperable chronic thromboembolic pulmonary hypertension treated with riociguat: A case study. AB - A 51-year-old woman presented with a one-year history of progressive dyspnea, WHO functional class III-IV and exercise-related syncope. Transthoracic echocardiography and computed tomography pulmonary angiography were performed, leading to a diagnosis of pulmonary arterial hypertension. She was referred to our pulmonary hypertension unit, where a complete study was performed, including ventilation/perfusion scan, which was consistent with chronic thromboembolic pulmonary hypertension. Risk factors for this condition were excluded and therapeutic options were evaluated. Imaging studies showed distal pulmonary disease so pulmonary endarterectomy was rejected. Further therapeutic options were evaluated and the patient was subsequently enrolled in an open-label uncontrolled trial with riociguat. After one year of treatment, significant improvement in functional class, 6-minute walk test and NT-proBNP were seen, without significant secondary effects. PMID- 26632112 TI - Combined rotational atherectomy and aortic balloon valvuloplasty as a bridge to transcatheter aortic valve replacement. AB - Patients with obstructive coronary artery disease and severe aortic stenosis have traditionally been managed with open heart surgery. In the era of transcatheter aortic valve replacement (TAVR) and high-risk coronary interventions many of those patients who were previously considered "terminal" can now be successfully managed with percutaneous coronary intervention (PCI) and TAVR. Although simple PCI can be safely combined with TAVR in the same procedure, high-risk coronary interventions often need to be performed separately. We report the first case of combined rotational atherectomy with balloon aortic valvuloplasty as a bridge to TAVR in a frail patient with complex coronary artery disease and critical aortic stenosis. PMID- 26632113 TI - Pacemaker electrocardiogram in a patient with Takotsubo syndrome. PMID- 26632114 TI - Comment on "Appropriate use criteria for transthoracic echocardiography at a tertiary care center". PMID- 26632115 TI - Limb leads in a patient with Takotsubo syndrome and a pacemaker.